The search: NTP in the database(s) CHRIS 2000, ERG2000, HSDB (through 2003/06), IRIS (through 2003/06), NIOSH Pocket Guide (NPG) (2003), OHMTADS (Final version), RTECS (through 2003/06), TSCA (through 2003/02), SERFILE 2003 returned 1119 records Record 1 of 1119 in CHRIS 2000 AN: NTP ID: --------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)-------------- PN: 2-NITROPHENOL- SY: o-Nitrophenol-; 2-Hydroxynitrobenzene-; ONP- RN: 88-75-5 ST: 1,2-HOC6H4NO2 CC: NOT-LISTED SHPN: IMO 6.1, UN 1663 DOT: 1663 GP: 153 SITC: 51243 SITT: Phenols And Phenol-Alcohols, N.E.S. CPP: ---------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)---------- COFO: Solid, Yellow BP: 417 deg F = 214 deg C = 487 deg K FP: 111 deg F = 44 deg C = 313 deg K MW: 139.1 DEN: 1.49 at 20 deg C (solid) HTC: -8,910 Btu/lb = -4,950 cal/g = -207 X 10E5 J/kg SOL: DEG F VALUE ----- ----- 0034 0.097 0036 0.103 0038 0.110 0040 0.117 0042 0.123 0044 0.130 0046 0.137 0048 0.143 0050 0.150 0052 0.157 0054 0.163 0056 0.170 0058 0.177 0060 0.183 0062 0.190 0064 0.197 0066 0.203 0068 0.210 0070 0.217 0072 0.223 0074 0.230 0076 0.237 0078 0.243 0080 0.250 0082 0.257 0084 0.263 OCPP: Physical State at 15 deg C and 1 atm: Solid Reaction with Water: Sinks and mixes slowly with water. Heat of Combustion: -8,910 Btu/lb = -4,950 cal/g = -207 X 10E5 J/kg Heat of Fusion: 26.76 cal/g CA: ----CORRECTIVE RESPONSE ACTIONS AND PRECAUTIONS CATEGORY (USE CODE ZRES)---- RE: Keep people away. Avoid inhalation. Shut off ignition sources and call fire department. Avoid contact with solid and dust. Protect water intakes. CR: Stop discharge Collection Systems: Dredge FF: ---FIRE (FIGHTING) AND FIRE HAZARDS INFORMATION CATEGORY (USE CODE ZFIR)---- FIRP: Combustible. POISONOUS GASES MAY BE PRODUCED IN FIRE. Wear goggles and self-contained breathing apparatus. Extinguish with water, dry chemicals, foam, or carbon dioxide. FLPT: Not pertinent (combustible solid) OFHZ: Fire Extinguishing Agents: Water, foam, dry chemical, carbon dioxide Special Hazards of Combustion Products: Toxic and irritating fumes of unburned material and oxides of nitrogen can form in fire. Stoichiometric Air to Fuel Ratio: 32.1 (calc.) Molar Ratio (Reactant to Product): 9.5 (calc.) HU: ---------HUMAN EXPOSURE AND HEALTH HAZARDS CATEGORY (USE CODE ZHUE)--------- HUEX: CALL FOR MEDICAL AID. DUST: Irritating to eyes, nose and throat. If inhaled will cause headache or loss of consciousness. If in eyes, hold eyelids open and flush with plenty of water. If breathing has stopped, give artificial respiration. If breathing is difficult, give oxygen. SOLID: Irritating to skin and eyes. If swallowed will cause headache, nausea, or loss of consciousness. Remove contaminated clothing and shoes. Flush affected areas with plenty of water. IF IN EYES, hold eyelids open and flush with plenty of water. IF SWALLOWED and victim is CONSCIOUS, have victim drink water or milk. IF SWALLOWED and victim is UNCONSCIOUS OR HAVING CONVULSIONS, do nothing except keep victim warm. EQUP: Self-contained breathing apparatus for fumes; rubber gloves; goggles HTOX: Inhalation or ingestion causes headache, drowsiness, nausea, and blue color in lips, ears, and fingernails (cyanosis). Contact with eyes causes irritation. Can be absorbed through the intact skin to give same symptoms as for inhalation. ANTR: INHALATION or INGESTION: remove victim to fresh air; give artificial respiration; call a doctor if symptoms persist. EYES: flush with water for at least 15 min.; get medical attention. SKIN: cleanse thoroughly with soap and water. OTHH: Toxicity by Ingestion: Grade 2; oral LD50 = 1,297 mg/kg (rat) WPOL: ------------WATER POLLUTION AND TOXICITY CATEGORY (USE CODE ZWAT)----------- WP: HARMFUL TO AQUATIC LIFE IN VERY LOW CONCENTRATIONS. May be dangerous if it enters water intakes. Notify local health and wildlife officials. Notify operators of nearby water intakes. ETXV: Aquatic Toxicity: 46.3-51.6 ppm/48 hr/bluegill/TLm/fresh water BIOD: 4.2% in 0.94 days, acclimated culture BIOC: None HAZP: Bioaccumulation: 0 -> No evidence to support one of the other ratings (+, Z, T) Damage to living resources: 3 -> Moderately toxic (96 hour LC50 1-10 mg/l) Human oral hazard: 1 -> Practically non-hazardous (LD50 500-5000 mg/kg) Human contact hazard: I -> Slightly hazardous (mild irritation, weak sensitizer) Reduction of amenities: XX -> Moderately objectionable because of persistency, smell or poisonous or irritant characteristics GCR: ------------GENERAL CHEMICAL REACTIVITY CATEGORY (USE CODE ZREA)------------ REAC: Reactivity with Water: No reaction SSL: Stable SHPI: ----------------SHIPPING INFORMATION CATEGORY (USE CODE ZSHP)--------------- STRG: Grades of Purity: Commercial; Pure Storage Temperature: Ambient Inert Atmosphere: No requirement Venting: Open IMOP: B SHPT: 2 HAZC: --------------HAZARD CLASSIFICATIONS CATEGORY (USE CODE ZHAZ)--------------- CFRH: Keep Away From Food : 6.1 : III MPOL: N RQ: 100 WPCA: Y RCRA: U170 Record 2 of 1119 in CHRIS 2000 AN: TRP ID: --------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)-------------- PN: TRIXYLENYL-PHOSPHATE- SY: Xylenol,-phosphate- (3:1); Coalite-NTP-; Reofos-95-; Dimethylphenol-phosphate- (3:1); Trixylyl-Phosphate-; Xylyl-phosphate-; Tridimethylphenyl-phosphate- RN: 25155-23-1 ST: C24H27O4P CC: 34 ESTERS SITC: 51639 SITT: Esters Of Inorganic Acids (Not Of Hydrogen Halides) And Their Salts, N.E.S., Their Halogenated, Sulfonated, Nitrated Or Nitrosated Derivatives CPP: ---------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)---------- COFO: Liquid, Slightly colored ODOR: Slight odor BP: 480-510 deg F = 248-265 deg C = 521.2-538.2 deg K FP: -4 deg F = -20 deg C = 253.2 deg K (pour point) MW: 410.4 DEN: 1.130-1.155 LV: DEG F VALUE ----- ----- 0068 190. SOL: INSOLUBLE SP: DEG F VALUE ----- ----- 0302 0.000 0392 0.006 OCPP: Physical State at 15 deg C and 1 atm: Liquid Reaction with Water: Insoluble in water; sinks. Vapor (Gas) Specific Gravity: 14.2 CA: ----CORRECTIVE RESPONSE ACTIONS AND PRECAUTIONS CATEGORY (USE CODE ZRES)---- RE: Call fire department. Avoid contact with liquid and vapor. Notify local Health and Pollution Control Agencies. CR: Stop discharge Collection Systems: Pump; Dredge FF: ---FIRE (FIGHTING) AND FIRE HAZARDS INFORMATION CATEGORY (USE CODE ZFIR)---- FIRP: Combustible. Toxic acidic vapors may form. Extinguish with water fog, alcohol foam, CO2 or dry chemicals. Wear full protective clothing and self-contained breathing apparatus. Cool exposed containers with water. FLPT: 390 deg F C.C. AUTO: 650 deg F OFHZ: Fire Extinguishing Agents: Water fog, carbon dioxide, dry chemicals, alcohol foam. Special Hazards of Combustion Products: Toxic acidic vapors may form. Stoichiometric Air to Fuel Ratio: 142.8 (calc.) Molar Ratio (Reactant to Product): 38.0 (calc.) HU: ---------HUMAN EXPOSURE AND HEALTH HAZARDS CATEGORY (USE CODE ZHUE)--------- HUEX: CALL FOR MEDICAL AID. LIQUID: Harmful if swallowed. IF SWALLOWED and victim is CONSCIOUS, have victim drink water or milk and induce vomiting. Remove clothing and wash skin with soap and water. EQUP: Self contained breathing apparatus. HTOX: Breathing or swallowing large quantities may cause ataxia. May irritate skin, respiratory tract, mucous membrane, and eyes. ANTR: INHALATION: Remove to fresh air. If victim has breathing difficulty, administer oxygen. INGESTION: If victim is conscious, administer a pint of tepid water, then induce vomiting. EYES: Flush with water for at least 15 minutes SKIN: Remove contaminated clothing and wash with soap and water. Call physician if complication develops. OTHH: Toxicity by Ingestion: Grade 1: LD50 = 11.8 g/kg (mouse) Vapor (Gas) Irritant Characteristics: Vapors/mists cause a slight smarting of the eyes or respiratory system if present in high concentrations. The effect is temporary. Liquid or Solid Irritant Characteristics: Minimum hazard. If spilled on clothing and allowed to remain, may cause smarting and reddening of skin. WPOL: ------------WATER POLLUTION AND TOXICITY CATEGORY (USE CODE ZWAT)----------- WP: Harmful to aquatic life. May be dangerous if it enters water intakes. Notify local health and wildlife officials Notify operators of nearby water intakes. HAZP: Bioaccumulation: + -> Bioaccumulated to significant extent and known to produce a hazard to aquatic life or human health Damage to living resources: 3 -> Moderately toxic (96 hour LC50 1-10 mg/l) Human oral hazard: (1) -> (Practically non-hazardous (LD50 500-5000 mg/kg)) Human contact hazard: II -> Hazardous (severe irritation, strong sensitizer, lung injury, percutaneous toxicity, carcinogenic, or other specific long-term adverse health effect. Reduction of amenities: XXX -> Highly objectionable because of persistency, smell or poisonous or irritant characteristics GCR: ------------GENERAL CHEMICAL REACTIVITY CATEGORY (USE CODE ZREA)------------ REAC: Reactivity with Water: No reaction. Reactivity with Common Materials: No reaction. SSL: Stable. POLY: Polymerization: Will not occur. SHPI: ----------------SHIPPING INFORMATION CATEGORY (USE CODE ZSHP)--------------- STRG: Storage Temperature: Ambient. Inert Atmosphere: Nitrogen Atmosphere. Venting: Pressure venting. IMOP: A SHPT: 1 HAZC: --------------HAZARD CLASSIFICATIONS CATEGORY (USE CODE ZHAZ)--------------- MPOL: Y NFPA: - Health Hazard (Blue) -> 2 - Flammability (Red) -> 1 - Reactivity (Yellow) -> 0 Record 3 of 1119 in HSDB (through 2003/06) AN: 35 UD: 200302 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZENE- SY: *AI3-00808-; *(6)ANNULENE; *BENZEEN- (DUTCH); *BENZEN- (POLISH); *BENZOL-; *Benzol-90-; *BENZOLE-; *BENZOLO- (ITALIAN); *BICARBURET-OF-HYDROGEN-; *Caswell-no-077-; *COAL-NAPHTHA-; *CYCLOHEXATRIENE-; *EPA-pesticide-chemical-code-008801-; *FENZEN- (CZECH); *NCI-C55276-; *PHENE-; *PHENYL-HYDRIDE-; *Polystream-; *PYROBENZOL-; *PYROBENZOLE- RN: 71-43-2 RELT: 113 [PHENOL] (metabolite) MF: *C6-H6 SHPN: UN 1114; Benzene IMO 3.2; Benzene STCC: 49 081 10; Benzene HAZN: U019; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. F005; A hazardous waste from nonspecific sources when a spent solvent. D018; A waste containing benzene may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Worldwide, approximately 30% of commercial benzene is produced by catalytic reforming, a process in which aromatic molecules are produced from the dehydrogenation of cycloparaffins, dehydroisomerization of alkyl cyclopentanes, and cyclization and subsequent dehydrogenation of paraffins. The benzene product is most often recovered from the reformate by solvent extraction techniques. [R1, 80] *The production of benzene by reforming-separation processes is assoc with the production of toluene and xylene (BTX plants). The relative production of the various aromatic hydrocarbons is a function of the feedstock, reactor conditions, catalyst, and, primarily, of the boiling range of the prod fraction subjected to solvent extraction. ... In reforming processes, cycloparaffins, such as cyclohexane, methylcyclohexane, and dimethylcyclohexanes are converted to benzene by dehydrogenation or by dehydrogenation and dealkylation, and methylcyclopentane and dimethylcyclpentanes are converted to benzene by isomerization, dehydrogenation, and dealkylation. Straight-chain paraffins such as hexane are converted to benzene by cyclodehydrogenation. The process conditions and the catalyst determine which reaction predominate and their kinetics (Hydrocarbon Process 55 (9): 171-8 (1976); and P Bonnifay and co-workers, Oil Gas J 74 (3): 48 (1976)). [R2] *Two molecules of toluene are converted into one molecule of benzene and one molecule of mixed xylene isomers in a sequence called transalkylation or disproportionation. Economic feasibility of the process strongly depends on the relative prices of benzene, toluene, and xylene. Operation of a transalkylation unit is practical only when there is an excess of toluene and a strong demand for benzene. In recent years, xylene and benzene prices have generally been higher than toluene prices so transalkylation is presently an attractive alternative to hydrodealkylation. [R1, 83] *Benzene has been recovered from coal tar. The lowest boiling fraction is extracted with caustic soda to remove tar acids. The base washed oil is then distilled and further purified by hydrodealkylation. [R1, 85] *Benzene is produced from the hydrodemethylation of toluene under catalytic or thermal conditions. The main catalytic hydrodealkylation processes are Hydeal and DETOL. Two widely used thermal processes are HDA and THD. These processes contribute 25-30% of the world's total benzene supply. [R1, 83] *The steam cracking of heavy naphthas or light hydrocarbons such as propane or butane to produce ethylene yields a liquid by-product rich in aromatic content called pyrolysis gasoline, dripolene, or drip oil. A typical pyrolysis gasoline contains up to about 65% aromatics, about 50% of which is benzene. Approximately 30-35% of benzene produced worldwide is derived from pyrolysis gasoline. [R1, 84] *Purification by washing with water: British patent 863,711 (1961 to Schloven-Chemie and Koppers gmbh), Chem Abstr 55: 16971f (1961). Lab prepn from aniline: Gattermann-Wieland, Praxis des Organischen Chemikers (de Gruyter, Berlin, 40th ed: 247 (1961)). [R3, 1090] IMP: *Major impurities are toluene and xylene, others: phenol, thiophene, carbon disulfide, acetylnitrile, and pyridine. [R4] FORM: *Nitration grade > 99% purity. [R5] *"Benzol 90" contains 80-85% benzene, 13-15% toluene, 2-3% xylene. [R4] *Commercial grades of benzene: Refined benzene-535 (free of H2S and SO2, 1 ppm max thiophene, 0.15% max nonaromatics); Refined benzene-485, Nitration-grade (free of H2S and SO2); Industrial-grade benzene (free of H2S and SO2) [R6, p. 3(78) 762] *Grade: crude, straw color; motor; industrial pure (2C); nitration (1C); thiophene-free; 99 mole%; 99.94 mole%; nanograde. [R7, 124] MFS: *Chevron Chemical Company, 6001 Bollinger Canyon Rd, San Ramon, CA 94583, (925)842-5500; U.S. Chemicals Division, 1301 McKinney St. PO Box 3766, Houston, TX 77253 (713)754-2000; Production sites: Pascagoula, MI 39567; Port Arthur, TX 77640; Richmond, CA 94802 [R8] *Hess Oil Virgin Islands Corp., Kings Hill Rd., P.O. Box 127, Kingshill, VI 00851-0127, (340)778-4000; Production site: St Croix, Virgin Islands 00851 [R8] *Fina Oil and Chemical Co., P.O. Box 2159, Dallas, TX 75221, (214)750-2400; Production site: Port Arthur, TX 77640 [R8] *Amoco Corp, Hq, 200 E Randolph Dr, Chicago, IL 60601, (312) 856-6111; Production site: Texas City, TX 77590 [R8] *Coastal Eagle Point Oil Co., P.O. Box 1000, U.S. Route 130 AND I-295, Westville, NJ 08093, (609)853-3100; Production site: Westville, NJ 08093 [R8] *Coastal Refining and Marketing, Inc.,, 9 Greenway Plaza, Houston, TX 77046, (713)877-7174; Production site: Corpus Christi, TX 78403 [R8] *BP America, Inc, Hq.,, 200 Public Sq, Cleveland, OH 44114-2375, (440)586-4141; Production sites: Lima, OH 45804; Alliance, LA 70037 [R8] *Citgo Petroleum Corp.,, Hq, 6130 S Yale St., Tulsa, OK 74136, (918) 495-4000; Production sites: Lake Charles, LA 70601; Corpus Cristi, TX 78469; Lemont, IL 60439-3659 [R8] *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production sites: Freeport, TX 77541; Plaquemine, LA 70765 [R8] *Equistar Chemicals, LP, One Houston Center, 1221 McKinney St., Suite 1600, Houston, TX 77010, (713)652-7300; Production sites: Alvin, TX 77511; Channelview, TX 77530; Corpus Christi, TX 78410 [R8] *Exxon Chemical Company, 13501 Katy Freeway, Houston, TX 77079, (281)870-6000; Exxon Chemical Americas, P.O. Box 3272, Houston, TX 77253-3272, (281)870-6000; Production sites: Baton Rouge, LA 70821; Baytown, TX 77520 [R8] *Huntsman Corp., 3040 Post Oak Blvd., Houston, TX 77056, (713)235-6000; Production sites: Bayport, TX 77062; Port Arthur, TX 77640 [R8] *Koch Refining Co., P.O. Box 2256, Wichita, KS 67201, (316) 828-5500; Production site: Corpus Christi, TX 78403 [R8] *Lyondell-Citgo Refining Company Ltd., 12000 Lawndale, Houston, TX 77017, (713)321-4111; Production site: Houston, TX 77252 [R8] *Marathon Ashland Petroleum LLC, 539 Sourth Main Street, Findlay, OH 45840-3295, (419)422-2121; Production sites: Catlettsburg, Kentucky 41129; Texas City, Texas 77592-1191 [R8] *Mobil Chemical Company, 3225 Gallows Road, Rairfax, VA 22037-0001, (703)846-3000; Petrochemicals Division, Intercontinental Center, Suite 906, 15600 JF Kennedy Boulevard, Houston, TX 77032-2343, (281)590-7700; Production sites: Beaumont, TX 77704-2295; Chalmette, LA 70043 [R8] *Phillips Petroleum Co., Phillips Bldg, Bartlesville, OK 74004, (918)661-6600, Chemicals Division Olefins and Cyclics Branch; Production site: Sweeny, TX 77480 [R8] *Phillips Puerto Rico Core Inc., Road No. 3, Route 710, Barrio Las Mareas, P.O. Box 10003, Guayama, PR 00785, (787)864-1515; Production site: Guayama, Puerto Rico 00784 [R8] *Shell Chemical Company, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production sites: Deer Park, TX 77536 (Houston Plant); Wood River, IL 62095 [R8] *Sun Company, Inc., 1801 Market Street, Philadelphia, PA 19103, (800)825-3535; Production sites: Marcus Hook, PA 19061; Toledo, OH 43693; Tulsa, OK 74102; Philadelphia, PA 19145 [R8] *Star Enterprise, 12700 Northborough Dr., Houston, TX 77067, (281) 874-7000; Production site: Delaware City, DE 19706 [R8] *Texaco Refining and Marketing Inc., 10 Universal City Plaza, Universal City, CA 91608-1097, (818)505-2000; Production site: El Dorado, KA 67042 [R8] *Ultramar Diamond Shamrock Corp., 6000 N. Loop 1604, W, San Antonio, TX 78249-1112, (210)592-2000; Production site: Three Rivers, TX 78071 [R8] *Valero Energy Corp., San Antonio Valero Towers, 7990 West IH 10, San Antonio, TX 78229-4718, (210)370-2000; Production site: Houston, TX 77012-2408 [R8] OMIN: *Benzene is a component of gasoline; European concn 5-16%, USA concn 0.3-2.0% averaging 0.8%. [R9] *Benzene was first isolated by Michael Faraday in 1825 from the liquid condensed by compressing oil gas. He proposed the name bicarburet of hydrogen for the new compound. In 1833, Eilhard Mischerlich synthesized bicarburet of hydrogen by distilling benzoic acid, obtained from gum benzoin, with lime and suggested the name benzin for the compound. In 1845, A.W. Hoffman and C. Mansfield found benzene in light oil derived from coal tar. The first practical industrial process for recovery of benzene from coal tar was reported by Mansfield in 1849. Coal tar soon became the largest source of benzene. Soon afterward, benzene was discovered in coal gas and this initiated the recovery of coal gas light oil as a source of benzene. Until the 1940's, light oil obtained from the destructive distillation of coal was the principal source of benzene. [R1, 73] *Benzene is the simplest and most important member of the aromatic hydrocarbons and should not be confused with benzine, a low boiling petroleum fraction composed chiefly of aliphatic hydrocarbons. The term benzole, which denotes commercial products that are largely benzene, is not common in the United States, but is still used in Europe. [R1, 73] *The Comission of European Communities ... prohibit the use of benzene in products intended for use as toys (eg, children's balloons). [R10] *... Benzene has been banned as ingredient in products intended for use in the home. [R11] *The 16th highest-volume chemical produced in USA (1995). [R7, 123] *Benzene is a major constituent of the gas phase of the mainstream smoke of unfiltered cigarettes. It makes up 12-50 ug of a cigarette. /From table/ [R12] */Benzene/ is one of the largest volume organic chemicals, with the United States being the largest producer. Benzene is the source of a variety of organic chemicals, many of which are intermediates for the production of a host of commercial products...The commercial sources of benzene...are coal and petroleum. [R13, 477] USE: *Manuf of industrial chemicals such as polymers, detergents, pesticides pharmaceuticals, dyes, plastics, resins. Solvent for waxes, resins, oils, natural rubber, etc. Gasoline additive /Use as solvent is now discouraged/ [R3, 179] *Used for printing and lithography, paint, rubber, dry cleaning, adhesives and coatings, detergents [R14] *Extraction and rectification; preparation and use of inks in the graphic arts industries; as a thinner for paints; as a degreasing agent [R15] *CHEM INT FOR ETHYLBENZENE, CUMENE, CYCLOHEXANE, NITROBENZENE, MALEIC ANHYDRIDE, CHLOROBENZENES, DETERGENT ALKYLATE, ANTHRAQUINONE, BENZENE HEXACHLORIDE, BENZENE SULFONIC ACID, BIPHENYL, HYDROQUINONE, AND RESORCINOL [R16] *Benzol (Benzene) Discontinued by Crowly Tar Products Co. [R17] *... In the tire industry and in shoe factories, ... benzene was used extensively. [R18] *Used primarily as a raw material in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. [R19] *Therap Cat (VET): Has been used as a disinfectant [R3, 179] *Manufacture of explosives, PCB gasoline, tanning; nylon intermediates; food processing; photographic chemicals. [R20, 249] *Uses: Ethylbenzene/styrene 53%; cumene/phenol 22%; cyclohexane 12%; nitrobenzene/aniline 5%; detergent alkylate 3%; chlorobenzenes and other uses 5% [R21] *In the past benzene has been used in the shoe and garment industry as a solvent for natural rubber. Benzene has also found limited application in medicine for the treatment of certain blood disorders, such as polythemia and malignant lymphoma. Benzene, along with other light high octane aromatic hydrocarbons such as toluene and xylene, is used as a component of motor gasoline. Although this use has been largely reduced in the U.S., benzene is still used extensively in many countries for the production of commercial gasoline. [R1, 73] CPAT: *Consumption by chemical industry in USA, 1977: 1.4 billion gallons annually. [R22] *CHEM INT FOR ETHYLBENZENE, 49.1%; CHEM INT FOR CUMENE, 18.4%; CHEM INT FOR CYCLOHEXANE, 15.1%; CHEM INT FOR NITROBENZENE, 4.5%; CHEM INT FOR MALEIC ANHYDRIDE, 2.8%; CHEM INT FOR CHLOROBENZENES, 2.5%; CHEM INT FOR DETERGENT ALKYLATE, 2.4%; EXPORTS, 2.7%; OTHER USES, 2.5% (1981 NON-GASOLINE USES) [R16] *Demand: (1980) 1,586 Million Gal; /Projected demand for/ (1984): 1,708 Million Gal [R23] *BENZENE RANKED 17TH IN 1981 and 1982 IN THE TOP 50 CHEMICAL PRODUCTION: BILLIONS OF LB: 7.87 (1982), 9.61 (1981). [R24] *Ethylbenzene/styrene, 52%; cumene/phenol, 22%; clyclohexane, 15%; nitrobenzene/aniline, 4.5%; detergent alkylate, 2.5%; chlorobenzenes, maleic anhydride and other, 3%; exports, 1% (1984) [R25] *USA benzene demand /is projected to/ climb /from/ 3.8% in 1987, to 5.7 million tons, and reach 6 million tons in 1990 (1987 and 1990) [R26] *In future, coal will increasingly replace petroleum and natural gas as a source of hydrocarbons both for fuel and petrochemicals. Processes such as USA Steel Corporation's Clean Coke process, which yields 38% coke and 20% chemical by-products compared to 73% coke and 2% chemical by-products in conventional coking technology, should soon be used commercially. New coking, liquefaction, and gasification processes for coal are all potential sources of benzene. [R6, p. V3(78) 756] *CHEMICAL PROFILE: Benzene. Ethylbenzene/styrene, 55%; cumene/phenol, 21%; cyclohexane, 14%; nitrobenzene/aniline, 5%; detergent alkylate, 3%; chlorobenzenes, exports and others, 2%. [R27] *CHEMICAL PROFILE: Benzene. Demand: 1986: 1,603 million gal; 1987: 1,667 million gal; 1991 /projected/: 1,790 million gal. (Includes imports; 155 million gal were imported in 1986.) [R27] *World benzene production rose to 6X10+6 tons (1.8X10+9 gallons) in 1988. The United States is the largest producer of benzene and accounts for about 30% of world production. [R1, 85] *U.S. demand: 2,000 million gallons in 1995; 1,900 million gallons 1996; predicted 2,100 million gallons 2000. [R21] PRIE: U.S. PRODUCTION: *(1967) 9.6X10+8 gal (data reported by tar distillers are not included) [R28, 1981.10] *(1977) 4.80X10+12 G [R16] *(1980) 1.5X10+9 gal (data reported by tar distillers are not included) [R28, 1981.10] *(1981) 4.3X10+11 GRAMS [R28, 1981.] *(1981) 1.3X10+9 gal (all grades produced from light-oil distillates of tar and tar crudes) [R28, 1981.9] *(1982) 3.55X10+12 G [R16] *(1983) 1.227X10+8 gallons [R1, 85] *(1984) 1.312X10+8 gallons [R1, 85] *(1988) 1.776X10+8 gallons (from petroleum), 5.25X10+7 gallons (from coal) [R1, 85] *(1985) 3.74X10+9 g (98-100% pure from petroleum and natural gas) [R29] *(1985) 5.16X10+8 g (90-97.9% pure from petroleum and natural gas) [R29] *(1986) 4.39X10+11 g [R26] *(1986) 1.39X10+9 gal [R30] *(1987) 1.59X10+9 gal (est) [R30] *(1989) 5,414,072,000 kg (all grades) [R31] *Benzene ranks 16th in production volume for chemicals produced in the USA, with approx 9.9 billion lb being produced in 1984, 9.1 billion lb in 1983, and 7.8 billion lb in 1982. [R32] *(1990) 12.45 billion lb [R33] *(1991) 11.49 billion lb [R34] *(1992) 11.27 billion lb [R35] *(1993) 12.32 billion lb [R35] U.S. IMPORTS: *(1978) 2.26X10+11 G [R16] *(1979) 1.6 billion kg [R36] *(1983) 4.93X10+11 G [R16] *(1985) 4.96X10+11 g [R37] *(1986) 4.72X10+11 g [R26] *(1986) 1.56X10+8 lb [R38] *Imports in 1987 were estimated to total 175 million gallons. [R39] U.S. EXPORTS: *(1978) 1.52X10+11 G [R16] *(1983) 3.66X10+10 G [R16] *(1979) 1.3 million lb [R36] *(1985) 3.77X10+10 g [R40] *Exports were thought to be less than 10 million gallons. [R41] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear, colorless liq [R3, 179]; *RHOMBIC PRISMS [R42, p. C-105]; *Colorless to light-yellow liquid [Note: A solid below 42 degrees F]. [R43, 26] ODOR: *Aromatic odor. [R43, 26]; *Gasoline-like odor; rather pleasant aromatic odor. Odor threshold = 4.68 ppm. [R44] TAST: *Taste threshold in water is 0.5-4.5 mg/l. [R45] BP: *80.1 deg C [R3, 179] MP: *5.5 deg C [R3, 179] MW: *78.11 [R3, 179] CTP: *Critical temperature: 288.9 deg C; critical pressure: 48.6 atm [R46, p. 6-53] DEN: *0.8787 @ 15 deg C/4 deg C [R3, 179] HTC: *-3275.3 KJ/mol [R13, 476] HTV: *33.83 KJ/mol @ 25 deg C [R46, p. 6-109] OWPC: *log Kow= 2.13 [R47] SOL: *Miscible with alcohol, chloroform, ether, carbon disulfide, acetone, oils, carbon tetrachloride, and glacial acetic acid [R3, 179]; *Miscible in most organic solvents. [R48, 333]; *In water, 1.79X10+3 mg/l @ 25 deg C. [R49] SPEC: *MAX ABSORPTION (ALCOHOL): 243 NM (LOG E= 2.2), 249 NM (LOG E= 2.3), 256 NM (LOG E= 2.4), 261 NM (LOG E= 2.2); SADTLER REF NUMBER: 6402 (IR, PRISM), 1765 (UV) [R42, p. C-146]; *Index of Refraction: 1.50108 @ 20 deg C/D [R3, 179]; *UV: 198 (Sadtler Research Laboratories Spectral Collection) [R50]; *MASS: 102 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R50]; *IR: 136 (Sadtler Research Laboratories IR Grating Collection) [R50]; *NMR: 3429 (Sadtler Research Laboratories Spectral Collection) [R50]; *Intense mass spectral peaks: 78 m/z [R51] SURF: *28.22 mN/m @ 25 deg C [R46, p. 6-137] VAPD: +2.8 (air= 1) [R52, p. 325-16] VAP: *94.8 mm Hg @ 25 deg C [R53] EVAP: *2.8 (ether= 1) [R54] VISC: *0.604 mPa.s @ 25 deg C [R46, p. 6-172] OCPP: *Conversion factors: 1 ppm= 3.26 mg/cu m [R20, 250] *SPECIFIC DISPERSION 189.6; DENSITY OF SATURATED VAPOR-AIR MIXT AT 760 MM HG (AIR= 1) IS 1.22 AT 26 DEG C; PERCENT IN SATURATED IN AIR AT 760 MM HG IS 13.15 AT 26 DEG C [R55, 1222] *Blood/air partition coefficient is 7.8 [R56] *Sublimes -30 to 5 deg C [R42, p. C-664] *Heat of fusion= 9.95 KJ/mol [R46, p. 6-124] *Heat capacity: 135.6 (liquid), 81.6 (gas) J/mol deg K at 1 atm (to convert to calories/mol-K multiply by 0.2390057) [R42, p. D-174] *Vapors burn with smoky flame [R57, 116] *Very useful compilations of the thermodynamic properties of benzene are given by Rossini and co-workers, Selected Values of Physical and Thermodynamic Properties of Hydrocarbons and Related Compounds, Amer Petrol Res Proj 44, Carnegie Press, Pittsburgh, PA (1953); and in American Petroleum Institute Project 44, data sheets, API Data Distribution Office, A and M Press, College Station, Texas [R6, p. V3(78) 745] *A comprehensive collection of general properties of benzene, thermodynamic and transport properties, and benzene in binary multicomponent systems is contained in Hancock and co-workers, Benzene and Its Industrial Derivatives, John Wiley and Sons, Inc, New York, 1975 pp.97-117 [R6, p. V3(78) 745] *Henry's Law constant= 5.56X10-3 atm-cu m/mol @ 25 deg C [R58] *Hydroxyl radical rate constant= 1.23X10-12 cu cm/molecule-sec @ 25 deg C [R59] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R60] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R60] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R60] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R60] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R60] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R60] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R60] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R60] FPOT: *A dangerous fire hazard when exosed to heat or flame. ... Ignites on contact with sodium peroxide + water, dioxygenyl tetrafluoroborate, iodine heptafluoride, and dioxygen difluoride. [R48, 334] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R52, p. 325-16] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R52, p. 325-16] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R52, p. 325-16] FLMT: *Lower flammable limit: 1.2% by volume; Upper flammable limit: 7.8% by volume [R52, p. 49-16] FLPT: *12 DEG F (-11 DEG C) CLOSED CUP [R3, 179] AUTO: *928 deg F [R52, p. 49-16] FIRP: *Approach fire from upwind to avoid hazardous vapors. Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R52, p. 49-25] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. [R61] OFHZ: *VAPORS ARE HEAVIER THAN AIR AND MAY TRAVEL TO A SOURCE OF IGNITION AND FLASH BACK. LIQUID FLOATS ON WATER AND MAY TRAVEL TO A SOURCE OF IGNITION AND SPREAD FIRE. [R52, p. 49-25] EXPL: *LOWER 1.4%, UPPER 8.0% [R48, 333] REAC: *Reacts violently with iodine pentafluoride. [R62] *Hydrogenation of benzene to cyclohexane was effected in a fixed bed reactor at 210-230 deg C, but a fall in conversion was apparent. Increasing the bed temp by 10 deg C and the hydrogen flow led to a large increase in reaction rate which the interbed cooling coils could not handle, and an exotherm to 280 deg C developed, with a hot spot around 600 deg C which bulged the reactor wall. [R63, 612] *Benzene ... ignites in contact with /iodine heptafluoride/ gas ... [R63, 1127] *Dioxygenyl tetrafluoroborate is a very powerful oxidant, addition of a small particle to small samples of benzene ... at ambient temp ... /caused/ ignition. [R63, 60] *... A 2% solution /dioxygen difluoride/ in hydrogen fluoride ignites solid benzene at -78 deg C. [R63, 1110] *Simultaneous contact of sodium peroxide with ... benzene ... causes ignition, (equivalent to contact with concn hydrogen peroxide). [R63, 1383] *Interaction /of uranium hexafluoride/ with benzene ... is very vigorous, with separation of carbon ... [R63, 1126] *Benzene ignites in contact with powdered chromic anhydride. [R52, p. 491-61] *AN EXPLOSION OF BENZENE VAPORS AND CHLORINE (INADVERTENTLY MIXED) WAS INITIATED BY LIGHT. [R52, p. 491-51] *Reacts explosively with bromine pentafluoride, chlorine, chlorine trifluoride, diborane, nitric acid, nitryl perchlorate, oxygen (liquid), ozone, silver perchlorate. [R62] *Interaction of the pentafluoride and methoxide /from arsenic pentafluoride and potassium methoxide/ proceeded smoothly in trichlorotrifluoroethane at 30-40 deg C, whereas in benzene as solvent repeated explosions occurred. [R63, 51] *The effects of the presence of moisture or benzene vapor in air on the spontaneously explosive reaction /of diborane/ have been studied. [R63, 70] *Silver perchlorate forms solid complexes with aniline, pyridine, toluene, benzene and many other aromatic hydrocarbons. A sample of the benzene complex exploded violently on crushing in a mortar. [R63, 7] *Interaction /of nitryl perchlorate/ with benzene gave a slight explosion and flash. ... [R63, 982] *The solution of permanganic acid (or its explosive anhydride, dimanganese heptoxide) produced by interaction of permanganates and sulfuric acid, will explode on contact with benzene ... . [R63, 1146] *Large-scale addition of too-cold nitrating acid to benzene without agitation later caused an uncontrollably violent reaction to occur when stirring was started. The vapor-air mixture produced was ignited by interaction of benzene and nitric acid at 100-170 deg C and caused an extremely violent explosion. [R63, 1166] *Peroxodisulfuric acid ... /is/ a very powerful oxidant; uncontrolled contact with ... benzene ... may cause explosion. [R63, 1223] *Mixtures of /liquid oxygen and/ benzene are specifically described as explosive. [R63, 1408] *During ozonization of rubber dissolved in benzene, an explosion occurred. This seems unlikely to have been ... /due/ to formation of benzene triozonide (which separates as a gelatinous precipitate after prolonged ozonization), since the solution remained clear. A rubber ozonide may have been involved, but the benzene-oxygen system itself has high potential for hazard. [R63, 1419] *Mixtures /of peroxomonosulfuric acid/ with ... benzene ... explodes. [R63, 1222] *Certain metal perchlorates recrystallized from benzene or ethyl alcohol can explode spontaneously. [R52, p. 491-140] *Strong oxidizers, many fluorides and perchlorates, nitric acid. [R43, 26] *Vigorous or incandescent reaction with hydrogen + Raney nickel (above 210 deg C) ... and bromine trifluoride. Can react vigorously with oxidizing materials, such as ... CrO3, oxygen, NClO4, ozone, perchlorates, (AlCl3 + FClO4), (sulfuric acid + permanganates), K2O2, (AgClO4 + acetic acid) ... [R48, 334] *Explodes on contact with diborane, bromine pentafluoride, permanganic acid, peroxomonosulfuric acid, and peroxodisulfuric acid. Forms sensitive, explosive mixtures with iodine pentafluoride, silver perchlorate, nitryl perchlorate, nitric acid, liquid oxygen, ozone, arsenic pentafluoride + potassium methoxide (explodes above 30 deg C). ... Moderate explosion hazard when exposed to heat or flame. [R48, 334] ODRT: *BENZENE HAS DISTINCTIVE /SRP: AROMATIC/ ODOR ... HOWEVER /WARNING PROPERTIES/ ARE INADEQUATE SINCE 100 PPM HAS IRRITATION RATING OF 0 AND ODOR INTENSITY BETWEEN 1 and 2. [R55, 1225] *4.68 PPM [R64] *In air: 4.9 mg/cu m (characteristic odor), in water: 2.0 mg/l. [R65] SERI: *Benzene is irritant to skin. [R66, 1308] *A severe eye and moderate skin irritant. [R48, 334] *Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks. [R67] EQUP: *Protective clothing consisting of coveralls or other full body clothing should be worn and changed at least twice weekly. [R68] *Where there is a possibility of benzene contact to eyes or skin, safety showers, eye-wash fountains, and cleansing facilities shall be installed and maintained. [R69] *WHERE HIGH VAPOR CONCN ARE UNAVOIDABLE, FORCED AIR MASKS SHOULD BE USED. LIFELINE ATTENDED BY ... PERSON OUTSIDE CONTAMINATED ENCLOSURE IS MANDATORY. IF SKIN CONTACT IS UNAVOIDABLE, NEOPRENE GLOVES MUST BE WORN. [R70] *HYDROCARBON VAPOR CANISTER, SUPPLIED AIR OR A HOSE MASK; HYDROCARBON INSOLUBLE RUBBER OR PLASTIC GLOVES; CHEMICAL GOGGLES OR FACE SPLASH SHIELD; HYDROCARBON-INSOLUBLE APRON SUCH AS NEOPRENE. [R64] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R71, 1979.8] *Performance data: For butyl rubber, natural rubber, neoprene, neoprene, neoprene/natural rubber, nitrile rubber, polyethylene, chlorinated polyethylene, polyurethane, and polyvinyl chloride give breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers. Vendor Recommendations: C or D ratings from three or more (apparently independent) vendors. [R72] *Wear appropriate personal protective clothing to prevent skin contact. [R43, 26] *Wear appropriate eye protection to prevent eye contact. [R43, 26] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R43, 26] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities should provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R43, 26] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full face piece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R43, 26] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R43, 26] OPRM: *Contact lenses should not be worn when working with this chemical. [R43, 26] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emmissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *VENTILATION CONTROL: WHEREVER POSSIBLE, PLANT SHOULD BE TOTALLY ENCLOSED ... ENCLOSURES SHOULD BE SUPPLEMENTED BY EXHAUST VENTILATION ... ATMOSPHERE ... SHOULD BE TESTED PERIODICALLY ... [R55, 1221] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R71, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R71, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R71, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R71, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs. ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R71, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R71, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres for chem such as nitrosamines. Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R71, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used. ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R71, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R71, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *The worker should immediately wash the skin when it becomes contaminated. [R43, 26] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R43, 26] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R61] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R61] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R61] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R73] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R74] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R75] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R71, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday. ... /Chemical Carcinogens/ [R71, 1979.13] STRG: *KEEP IN WELL CLOSED CONTAINERS IN A COOL PLACE AND AWAY FROM FIRE. [R3, 179] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R71, 1979.13] CLUP: *For spills on water, contain with booms or barriers, use surface acting agents to thicken spilled materials. Remove trapped materials with suction hoses. [R76] *Small spills of benzene can be taken up by sorption on carbon or synthetic sorbent resins. Flush area with water. For large quantities, if response is rapid, benzene can be skimmed off the surface. Straw may be used to mop slicks. [R77] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms. ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal. ... The plastic bag should be sealed immediately. ... The sealed bag should be labelled properly. ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated. ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R71, 1979.15] *Eliminate all ignition sources. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors, protect personnel, and dilute spills to form nonflammable mixtures. Absorb in noncombustible material for proper disposal. Control runoff and isolate discharged material for proper disposal. [R52, p. 49-25] *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. [R61] *Environmental considerations - Water spill: Use natural barriers or oil spill control booms to limit spill travel. Use surface active agent (e.g., detergent, soaps, alcohols), if approved by EPA. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, in region of 10 ppm or grater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R61] *Environmental considerations - Land spill: Dig a pit, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Apply appropriate foam to diminish vapor and fire hazard. [R61] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F005, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R78] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U019, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R78] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D018, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R78] *Biodegradation, incineration: Benzene is biodegradable. Diluted aqueous soln, therefore, are drained into sewage treatment plants and decomposed there by anaerobic bacteria. Solvent mixtures and sludges of higher concn are burnt in special waste incinerators if a recovery process is uneconomical. [R79] *This flammable liquid burns with a very smoky flame. Dilution with alcohol or acetone is suggested to minimize smoke. Recommendable methods: Use as boiler fuel, incineration. Not recommendable: Landfill, discharge to sewer. [R79] *Incinerate or dispose of via a licensed solvent recycling or disposal company. [R80] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R71, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": Total destruction ... by incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R71, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R71, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R71, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R71, 1979.17] *Chemical Treatability of Benzene; Concentration Process: Biological Treatment; Chemical Classification: Aromatic; Scale of Study: Full Scale; Type of Wastewater Used: Industrial Wastewater; Results of Study: 90-100% reduction; (treated by aerated lagoon). [R81] *Chemical Treatability of Benzene; Concentration Process: Biological Treatment; Chemical Classification: Aromatic; Scale of Study: Full Scale; Type of Wastewater Used: Industrial Wastewater; Results of Study: 95-100% reduction; (completely mixed activated sludge process). [R81] *Chemical Treatability of Benzene; Concentration Process: Biological Treatment; Chemical Classification: Aromatic; Scale of Study: Respirometer Study; Type of Wastewater Used: Domestic Wastewater; Results of Study: 1.44-1.45 g of oxygen utilized/g of substrate added after 72 hr of oxidation. [R81] *Chemical Treatability of Benzene; Concentration Process: Biological Treatment; Chemical Classification: Aromatic; Scale of Study: Respirometer Study; Type of Wastewater Used: Domestic Wastewater; Results of Study: Oxygen uptake of 34 ppm oxygen/hr for 50 ppm chemical and 37 ppm oxygen/hr for 500 ppm chemical. [R81] *Chemical Treatability of Benzene; Concentration Process: Biological Treatment; Chemical Classification: Aromatic; Scale of Study: Full Scale; Type of Wastewater Used: Industrial Wastewater; Results of Study: 95-100% reduction; (Activated sludge process). [R81] *Chemical Treatability of Benzene; Concentration Process: Stripping; Chemical Classification: Aromatic; Scale of Study: Literature Review; Type of Wastewater Used: Unknown; Results of Study: Air and steam strippable. [R82] *Chemical Treatability of Benzene; Concentration Process: Stripping; Chemical Classification: Aromatic; Scale of Study: Continuous Flow, Pilot Scale; Type of Wastewater Used: Synthetic Wastewater; Results of Study: 95-99% reduction by steam stripping; (estimated cost of $3.35/1000 gal based on 0.03 MGD). [R82] *Chemical Treatability of Benzene; Concentration Process: Solvent Extraction; Chemical Classification: Aromatic; Scale of Study: Literature Review; Type of Wastewater Used: Unknown; Results of Study: Extractable with suitable solvent. [R83] *Chemical Treatability of Benzene; Concentration Process: Solvent Extraction; Chemical Classification: Aromatic; Scale of Study: Laboratory Scale, Continuous Flow; Type of Wastewater Used: Industrial Wastewater; Results of Study: 290 ppm @ 3 gal/hr, 97% reduction; (Extraction of wastewater from styrene manufacture using isobutylane (S/W= 0.107), RDC extractor used). [R83] *Chemical Treatability of Benzene; Concentration Process: Solvent Extraction; Chemical Classification: Aromatic; Scale of Study: Laboratory Scale, Continuous Flow; Type of Wastewater Used: Industrial Wastewater; Results of Study: 71 ppm @ 4.6 gal/hr, 96% reduction; (extraction of ethylene quench wastewater using isobutylene (S/W= 0.101) RDC extractor used). [R83] *Chemical Treatability of Benzene; Concentration Process: Solvent Extraction; Chemical Classification: Aromatic; Scale of Study: Laboratory Scale, Continuous Flow; Type of Wastewater Used: Industrial Waste; Results of Study: 81 ppm @ 4.6 gal/hr, 97% reduction; (extraction of ethylene quench wastewater using isobutane (S/W= 0.097) RDC extractor used). [R83] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Pilot Scale, Continuous Flow; Type of Wastewater Used: Hazardous Material Spill Results of Study: 90% removal (to 0.1 ppb effluent conc) achieved in 8.5 min contact time; (Spilled material treated using EPA's mobile treatment trailer). [R84] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Isotherm Test; Type of Wastewater Used: Pure Compound; Results of Study: 0.7 mg/g carbon capacity. [R84] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Isotherm Test; Type of Wastewater Used: Pure Compound; Results of Study: Isotherm kinetics were as follows: Carbon: K= 26.8, l/n= 1.305; Filtrasorb: K= 18.5 l/n= 1.158; carbon dose (mg/l) required to reduce 1 mg/l to 0.1 mg/l; Daro-678 Filtrasorb-705. [R84] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Isotherm Test; Type of Wastewater Used: Pure Compound; Results of Study: 95% reduction, 21 ppm final concn, 0.080 g/g carbon capacity; (Carbon dose with 5 g/l Westvaco Nuchar). [R85] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Literature Review; Type of Wastewater Used: Industrial Wastewater; Results of Study: Effluent concn of 30 ppm TOC achieved; 98% removal; (at contact time of 55 min 0.15 MGD flow; pretreatment including pH adjustment). [R85] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Isotherm Test; Type of Wastewater Used: Pure Compound; Results of Study: Effluent Character (ppm): 500, 95% removal; 250, 91% removal; 50, 60% removal; (24 hr contact time, carbon dose was 10 times chemical concn). [R85] *Chemical Treatability of Benzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Literature Review; Type of Wastewater Used: Unknown; Results of Study: 95% removal at 0.5% carbon dose. [R85] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R86] *Full-scale activated carbon column treatment: Influent concn: 28,000 ug/l; Effluent concn: 1) < 10 ug/l with +99% removal, 2) 73 ug/l with 48-80% removal. [R87] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient; Overall summary evaluation of carcinogenic risk to humans is group 1: The chemical is carcinogenic to humans. /From table/ [R88] +A1; Confirmed human carcinogen. [R89, 2002.16] *WEIGHT-OF-EVIDENCE CHARACTERIZATION: Benzene is classified as a "known" human carcinogen (Category A) under the Risk Assessment Guidelines of 1986. Under the proposed revised Carcinogen Risk Asessment Guidelines (USEPA, 1996), benzene is characterized as a known human carcinogen for all routes of exposure based upon convincing human evidence as well as supporting evidence from animal studies. Epidemiologic studies and case studies provide clear evidence of a causal association between exposure to benzene and acute nonlymphocytic leukemia and also suggest evidence for chronic nonlymphocytic leukemia and chronic lymphocytic leukemia. Other neoplastic conditions that are associated with an increased risk in humans are hematologic neoplasms, blood disorders such as preleukemia and aplastic anemia, Hodgkin's lymphoma, and myelodysplastic syndrome. These human data are supported by animal studies. The experimental animal data add to the argument that exposure to benzene increases the risk of cancer in multiple species at multiple organ sites (hematopoietic, oral and nasal, liver, forestomach, preputial gland, lung, ovary, and mammary gland). It is likely that these responses are due to interactions of the metabolites of benzene with DNA ... Recent evidence supports the viewpoint that there are likely multiple mechanistic pathways leading ... to leukemogenesis from exposure to benzene. HUMAN CARCINOGENICITY DATA: Benzene is a known human carcinogen based upon evidence presented in numerous occupational epidemiological studies. Significantly increased risks of leukemia, chiefly acute myelogenous leukemia, have been reported in benzene-exposed workers in the chemical industry, shoemaking and oil refineries. ANIMAL CARCINOGENICITY DATA:... many experimental animal studies, both inhalation and oral, also support the evidence that exposure to benzene increases the risk of cancer in multiple organ systems, including the hematopoietic system, oral and nasal cavities, liver, forestomach, preputial gland, lung, ovary, and mammary gland .... [R90] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and teat if necessary ... . Monitor for shock and treat if necessary... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Benzene and related compounds. [R91, p. 184-5] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Benzene and related compounds/ [R91, 185] *Animal expt show that benzene sensitizes the myocardium to epinephrine, so that the endogenous hormone may precipitate sudden and fatal ventricular fibrillation. [R11] MEDS: *IF INDIVIDUALS ARE KNOWN TO BE EXPOSED TO BENZENE VAPORS IN THEIR WORKING ENVIRONMENT PROPHYLACTIC MEASURES SHOULD BE TAKEN. ALL POSSIBLE METHODS SHOULD BE USED TO PROTECT SUCH PERSONS AGAINST BREATHING THE FUMES. THEY SHOULD HAVE PERIODIC PHYSICAL EXAM, INCL BLOOD STUDIES. IN ADDN THE URINE SHOULD BE EXAM AT INTERVALS TO DETERMINE EXTENT OF EXCRETION OF BENZENE CONJUGATION PRODUCTS. ONCE POISONING HAS DEVELOPED, IT IS ESSENTIAL TO PREVENT FURTHER EXPOSURE. [R92] *Assessment of fitness should incl consideration of previous medical ... and occupational history. Occupational history should take into account any previous exposure to benzene, radiomimetic substances or ionizing radiations. Medical exam should incl thorough physical ... and hematological examination. The latter ... should cover hemoglobin determination, red cell, white cell and platelet counts, white cell differential count and red cell and leukocyte morphology. Protect young persons of either sex under 18 yr of age from exposure to benzene since ... adolescents have lower resistance to bone-marrow poisons. Pregnant women and nursing mothers should not be exposed ... and special precautions are necessary where women of childbearing age are exposed to benzene hazard. ... Subjects with liver diseases and ... microcytemia should /be protected from exposure/. ... Periodic exam should be carried out in same way as pre-employment examination. ... Particular attention should be paid to any hematological abnormalities found during 1st periodic examination. ... Whenever there is slightest suspicion of leukemia, a bone-marrow biopsy is warranted. [R57, 260] *Biological monitoring: Medical surveillance should incl blood pressure check, lung functions, blood chemistry, hematology, urinalysis and skin exam. [R66, 1326] *PRECAUTIONS FOR "CARCINOGENS": ... In relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may preclude them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical Carcinogens/ [R71, 1979.23] HTOX: *Benzene is irritant to skin, and by defatting the keratin layer may cause erythema, vesiculation, and dry and scaly dermatitis. [R66, 1308] *AFTER A SHORT EXPOSURE TO A LARGE AMT OF BENZENE, BY INGESTION OR BY BREATHING CONCENTRATED VAPORS, THE MAJOR TOXIC EFFECT IS ON THE CNS. SYMPTOMS FROM MILD EXPOSURE INCL DIZZINESS, WEAKNESS, EUPHORIA, HEADACHE, NAUSEA, VOMITING, TIGHTNESS IN CHEST, AND STAGGERING. IF EXPOSURE IS MORE SEVERE, SYMPTOMS PROGRESS TO BLURRED VISION, TREMORS, SHALLOW AND RAPID RESP, VENTRICULAR IRREGULARITIES, PARALYSIS, AND UNCONSCIOUSNESS. [R18] *Long-term exposure to benzene usually is due to the inhalation of vapor or to contact with the skin. Signs and symptoms of long-term exposure to benzene incl effects on the CNS and the GI tract (headache, loss of appetite, drowsiness, nervousness, and pallor), but the major manifestation of toxicity is aplastic anemia. Bone marrow cells in early stages of development are most the sensitive ... and arrest of maturation leads to gradual depletion of circulating cells. [R18] *BENZENE (BENZOL) ... HAS SPECIFIC TOXIC EFFECT ON BLOOD FORMATION, CAUSING APLASTIC ANEMIA AND TENDENCY TO HEMORRHAGE. OCCASIONALLY HEMORRHAGES IN RETINA AND IN CONJUNCTIVA ARE FOUND IN SYSTEMIC POISONING BY BENZENE. IN RARE INSTANCES NEURORETINAL EDEMA AND PAPILLEDEMA HAVE BEEN DESCRIBED ACCOMPANYING RETINAL HEMORRHAGES. IT HAS NOT BEEN ESTABLISHED THAT BENZENE CAN INDUCE RETROBULBAR NEURITIS OR OPTIC NEURITIS ... [R93] *PATHOLOGICAL FINDINGS FROM ... INHALATION INCL ACUTE GRANULAR TRACHEITIS, LARYNGITIS AND BRONCHITIS, MASSIVE HEMORRHAGE OF LUNG, CONGESTIVE GASTRITIS, INFARCT OF SPLEEN, ACUTE CONGESTION OF KIDNEYS, AND MARKED CEREBRAL EDEMA. [R92] *Many acute deaths /from benzene exposure at high concn have been/ ... due to ventricular fibrillation ... /caused by exertion/ and release of epinephrine. This was probably the mechanism involved in the death of workers in tank cars which had contained benzene. Frequently, the man who went into the tank car to carry out an unconscious worker died during the effort of lifting the unconscious man up the ladder. [R94] *... A large number of workers exposed to but not seriously intoxicated by benzene /were studied and results showed/ that serum complement levels, IgG, AND IgA, were depressed but that IgM levels did not drop and were in fact slightly higher (Lange et al 1973; Smolik et al 1973). ... These /and other/ observations, taken together with well-known ability of benzene to depress leukocytes ... may explain why benzene-intoxicated individuals readily succumb to infection and why terminal event in severe ... toxicity is often an acute, overwhelming infection. [R95] *IN EXPT IN VITRO, BENZENE DID NOT CHANGE THE NUMBER OF SISTER-CHROMATID EXCHANGES OR THE NUMBER OF CHROMOSOMAL ABERRATIONS IN HUMAN LYMPHOCYTES. [R96] *THE MUTAGENIC ACTIVITY UPON HUMAN LYMPHOCYTES WAS STUDIED AFTER ITS ADDN TO CULTURE ON THE 28TH HR OF CULTIVATION (G1-S PERIODS). CONCN OF 1, 10, 25, 50, 100, and 250 UG/ML WERE STUDIED. BENZENE IS A WEAK MUTAGEN. IT CAUSED ELONGATION OF CENTROMERE PORTIONS OF CHROMOSOMES AND CHROMOSOMAL ABERRATIONS WERE MAINLY OF SINGLE AND PAIRED FRAGMENT TYPE. MUTAGENIC ACTIVITY WAS ABOUT THE SAME IN THE G0 AND G1-S PERIODS. [R97] *A major concern is the relationship between long-term exposure to benzene and leukemia. Epidemiological studies have been conducted on workers in the tire industry and in shoe factories, where benzene was used extensively. Among workers who died from exposure to benzene, death was caused by either leukemia or aplastic anemia, in approx equal proportions. [R18] *CHRONIC BENZENE TOXICITY IS EXPRESSED AS BONE MARROW DEPRESSION RESULTING IN LEUCOPENIA, ANEMIA, OR THROMBOCYTOPENIA (LEUKEMOGENIC ACTION). WITH CONTINUED EXPOSURE THE DISEASE PROGRESSES TO PANCYTOPENIA RESULTING FROM BONE MARROW APLASIA. EVIDENCE HAS ACCUM IMPLICATING BENZENE IN THE ETIOLOGY OF LEUKEMIAS IN WORKERS IN INDUSTRIES WHERE BENZENE WAS HEAVILY USED. IT HAS BEEN SUGGESTED THAT LEUKEMIA IS AS FREQUENT A CAUSE OF DEATH FROM CHRONIC BENZENE EXPOSURE AS IS APLASTIC ANEMIA. [R98] *MANY CASES OF ACUTE LEUKEMIA DEVELOPING AS TERMINAL STAGE OF APLASTIC ANEMIA RESULTING FROM EXPOSURE TO BENZENE MAY HAVE BEEN MISSED BECAUSE BONE MARROW PUNCTURE WAS NOT PERFORMED. BENZENE LEUKEMIA IS ACUTE STEM CELL OR MYELOBLASTIC LEUKEMIA, SOMETIMES ALEUKEMIA. THERE MAY BE A LATENT PERIOD EXTENDING OVER SEVERAL YEARS BETWEEN CESSATION OF EXPOSURE WITH MORE OR LESS PRONOUNCED ANEMIA, AND THE ONSET OF LEUKEMIA. [R99] *A dose-related increase in the number of cells with chromosomal aberrations occurred in human lymphocyte cultures treated with 4X10-5 M and 3.0X10-3 M benzene for 53 hr prior to metaphase analysis. Cells in late G2 stage were the most susceptible to the effect of benzene. [R100] *Epidemiological studies (exposure to high concn is associated with hematotoxicity and acute myelocytic leukemia in humans ...) [R101] *Italian shoemakers exposed to 200-500 ppm benzene in inks and glues showed an incidence of leukemia of 1 per 1,000. [R102] *Follow up study at Massachusetts rubber coating plants of 38 workers exposed over 1-24 yr at 5-50 ppm (140 ppm peak) showed no evidence of blood dyscrasias or leukemia. [R103] *A significantly incr frequency of chromatid and isochromatid breaks in the cultured lymphocytes of workers in chemical laboratories and in the printing industry has been reported. [R104] *A significant incr of peripheral blood lymphocyte chromosomal aberrations in workers exposed to benzene was reported, but not in those exposed to toluene and xylene. [R105] *A report on 52 workers exposed to benzene found chromosomal aberrations (chromosome breaks, dicentric chromosomes, translocations, and exchange figures) in peripheral lymphocytes at 2-3 times the rates found in controls. The 8 hr TWA exposure was 2-3 ppm, the average concn determined by 15 min sampling was 25 ppm, and the peak concn was 50 ppm. [R106] *An epidemiological study implicating benzene as a leukemogen (acute myelocytic leukemia) followed 748 white males exposed to benzene in the manufacture of a rubber product from 1940-1949. A statistically significant (p < or = 0.002) excess of leukemia was found when compared against two control populations. There was a 5 fold excessive risk of all leukemias and a 10 fold excessive risk of myelocytic and monocytic leukemias combined. [R107] *A hematological investigation was carried out on 147 workers (employed for +10 years) exposed to high benzene levels (320-470 ppm). Abnormalities were noted in at least one parameter in 73%, the most common one being thrombocytopenia, which occurred in 62% followed by anemia (35%) and leucopenia (32%). Pancytopenia occurred in 21% of the workers. During the 3 months following removal from exposure, hematological parameters returned to normal in 120 workers, and one subject died. After one year, 20 of the remaining workers had only minor abnormalities, six were still off work, and one was still hospitalized. [R108] *A retrospective mortality study of a cohort of 594 men exposed to benzene at levels ranging between 2 and 25 ppm (TWA) was carried out at the Dow Chemical Co between 1940-1973. No incr in total mortality was noted with 102 observed/128 expected (Standard Mortality Ratio (SMR) 80). A slight increase was noted in total deaths due to malignancies (30 observed/22.8 expected, SMR 132) and suicide (5 observed/3.2 expected, SMR 147) as well as deaths from leukemia (3 observed/0.8 expected) and cancers of the digestive organs and peritoneum (9 observed/6.9 expected, SMR 125). If 53 workers exposed to other chemicals are excluded from malignancies, the results would then be 24 observed/20.3 expected, SMR 108. [R109] */A subset of 292 men of the 594 in the benzene exposure of Dow cohort who were still employed in 1967/ had an examination of the health status /evaluation/ carried out between 1967-1974 and compared to a control population selected from employees not exposed to benzene, using a matched pair design (matched for age, cigarette smoking habits and length of employment). No clinically significant differences were reported although slight decr in total bilirubin levels and red blood cell counts were noted. [R110] *Thirty two patients who had recovered from a blood disease (bone marrow impairment) caused by benzene poisoning had significantly increased rates of "unstable" and "stable" chromosomes. Aberrations of chromosomes were present for several years after cessation of the exposure and after recovery from poisoning. Persistence of an increase of the "stable" changes was particularly remarkable. [R111] *NUMEROUS STUDIES HAVE BEEN CARRIED OUT ON THE CHROMOSOMES OF BONE-MARROW CELLS AND PERIPHERAL LYMPHOCYTES FROM PEOPLE KNOWN TO HAVE BEEN EXPOSED TO BENZENE. ... IN MANY OF THESE STUDIES, SIGNIFICANT INCR IN CHROMOSOMAL ABERRATIONS HAVE BEEN SEEN, WHICH IN SOME CASES HAVE PERSISTED FOR YEARS AFTER CESSATION OF EXPOSURE. ... BONE-MARROW CELLS AND PERIPHERAL LYMPHOCYTES /HAVE BEEN EXAM/ FROM WORKERS WITH CURRENT SEVERE BLOOD DYSCRASIAS, and ... /FOLLOW-UP STUDIES HAVE BEEN DONE ON/ SEVERAL WORKERS BY REPEATED CYTOGENETIC STUDIES UP TO 12 YR AFTER RECOVERY FROM BENZENE-INDUCED PANCYTOPENIA. GROSS CHROMOSOMAL ABNORMALITIES WERE CHARACTERISTIC OF THESE CELLS; 70% OF THE BONE-MARROW CELLS AND LYMPHOCYTES IN PT WITH ACUTE POISONING SHOWED KARYOTYPIC ABNORMALITIES. THE AUTHORS COULD NOT RELATE THE FREQUENCY OR TYPE OF CHROMOSOMAL ALTERATIONS TO THE SEVERITY OF BLOOD DYSCRASIA. FIVE YR AFTER POISONING, ALL ... 5 PATIENTS STUDIED STILL SHOWED STABLE (Cs) AND UNSTABLE (Cu) CHROMOSOMAL ABERRATIONS IN ... LYMPHOCYTES, ALTHOUGH ONLY 40% OF CELLS WERE NOW ABNORMAL. BY 12 YR ... NO CYTOGENETIC ABNORMALITIES REMAINED IN THE 4 PATIENTS STUDIED. [R112] *METABOLIC ACTIVATION OF BENZENE BY RAT LIVER MICROSOMES AND A REDUCED NADP-GENERATING SYSTEM (S-9 MIX) INDUCED SISTER CHROMATID EXCHANGES (SCE) AND CELL DIVISION DELAYS IN CULTURED HUMAN LYMPHOCYTES. THERE WERE OPTIMAL CONCN OF S-9 MIX FOR THE CONVERSION OF BENZENE INTO THE ACTIVE METABOLITES THAT EXERTED THESE CYTOTOXIC EFFECTS. [R113] *... INCIDENCE OF ACUTE LEUKEMIA OR 'PRELEUKEMIA' AMONG 28,500 SHOE-WORKERS IN TURKEY /WAS ESTIMATED/ ON BASIS OF CASE ASCERTAINMENT BY CONTACT WITH MEDICAL CARE. THIRTY FOUR CASES WERE IDENTIFIED. ... INCIDENCE OF ACUTE LEUKEMIA WAS SIGNIFICANTLY GREATER AMONG WORKERS CHRONICALLY EXPOSED TO BENZENE, WHICH WAS USED AS A SOLVENT BY THESE WORKERS, THAN IN THE GENERAL POPULATION. OCCUPATIONAL EXPOSURES WERE DETERMINED BY WORK HISTORIES AND BY ENVIRONMENTAL MEASUREMENTS. THERE WAS SAID TO BE EXPOSURE ONLY TO BENZENE IN SMALL, POORLY VENTILATED WORK AREAS; PEAK EXPOSURES ... WERE REPORTED TO BE 210-650 PPM (670-2075 MG/CU M). DURATION ... WAS EST TO HAVE BEEN 1 TO 15 YR (MEAN 9.7 YR). ANNUAL INCIDENCE WAS EST TO BE 13/100000, GIVING APPROX RELATIVE RISK OF 2 WHEN COMPARED WITH ANNUAL EST FOR GENERAL POPULATION, 6/100000. (THESE EST ARE LIMITED BY STUDY DESIGN CHARACTERISTICS AND BY UNCERTAINTY ABOUT THE WAY IN WHICH CASES WERE ASCERTAINED, AND HOW MANY OF THE STUDY POPULATION WERE EXPOSED AND HOW MANY UNEXPOSED). [R114] *OCCUPATIONAL EXPOSURES WERE IDENTIFIED IN ROTOGRAVURE PLANTS AND SHOE FACTORIES. BENZENE CONCN NEAR ROTOGRAVURE MACHINES WERE 200-400 PPM (640-1280 MG/CU M), WITH PEAKS UP TO 1500 PPM (4800 MG/CU M); BENZENE CONCN IN AIR NEAR WORKERS HANDLING GLUE IN SHOE FACTORIES WERE 25-600 PPM (80-1920 MG/CU M), BUT WERE MOSTLY AROUND 200-500 PPM (640-1600 MG/CU M). EST LATENCY (YEARS FROM START OF EXPOSURE TO CLINICAL DIAGNOSIS OF LEUKEMIA) RANGED FROM 3-24 YR (MEDIAN, 9 YR). ... THE RELATIVE RISK OF ACUTE LEUKEMIA WAS /EST TO BE/ AT LEAST 20:1 FOR WORKERS HEAVILY EXPOSED TO BENZENE IN ROTOGRAVURE AND SHOE INDUSTRIES IN THE PROVINCES STUDIED, WHEN COMPARED WITH GENERAL POPULATION. (THE RELATIVE RISK IS BASED ON A NON-VALIDATED ESTIMATE). [R115] *A HISTORICAL COHORT MORTALITY STUDY WAS CONDUCTED OF 259 MALE EMPLOYEES OF A CHEM PLANT WHERE BENZENE HAS BEEN USED IN LARGE QUANTITIES. THE STUDY GROUP INCL ALL PERSONS WHO WERE EMPLOYED BY THE COMPANY ANY TIME BETWEEN JAN 1, 1947 AND DEC 31, 1960. THE COHORT WAS FOLLOWED THROUGH DEC 31, 1977 AT WHICH TIME 58 KNOWN DEATHS WERE IDENTIFIED. THE ONLY UNUSUAL FINDING WAS FOUR DEATHS FROM LYMPHORETICULAR CANCERS WHEN 1.1 WOULD HAVE BEEN EXPECTED ON THE BASIS OF NATIONAL MORTALITY RATES. THREE OF THE DEATHS WERE DUE TO LEUKEMIA AND 1 WAS CAUSED BY MULTIPLE MYELOMA. IN ADDN, 1 OF THE LEUKEMIA DEATHS HAD MULTIPLE MYELOMA LISTED ON THE DEATH CERTIFICATE. THE FINDINGS ARE CONSISTENT WITH PREVIOUS REPORTS OF LEUKEMIA FOLLOWING OCCUPATIONAL EXPOSURE TO BENZENE AND RAISE THE POSSIBILITY THAT MULTIPLE MYELOMA COULD BE LINKED TO BENZENE, ALSO. [R116] *HEMATOLOGIC AND IMMUNOCHEMICAL INVESTIGATIONS CARRIED OUT IN 270 WORKERS WITH CHRONIC EXPOSURE TO BENZENE DEMONSTRATED CHANGES OF THE NUCLEOLOGRAM AND OF THE AREA OF LYMPHOCYTE NUCLEOLI AND DISORDERS OF THE HUMORAL IMMUNE RESPONSE REVEALED BY RADIAL IMMUNODIFFUSION. THE NUMERICAL RISE OF BI- AND POLYNUCLEOLATED CELLS, OF CELLS WITH IRREGULAR MACRONUCLEOLI AND AN ENLARGEMENT OF THE NUCLEOLAR AREA REFLECTED INCR ENDOLYMPHOCYTIC AMT OF RNA. AN INCR CAPACITY OF IG FORMATION, PARTICULARLY OF IGM, WAS ALSO OBSERVED. [R117] *SOME ASPECTS OF QUANTITATIVE CANCER RISK ESTIMATION: ... RISK IS GREATEST AMONG THOSE WITH LONGEST EXPOSURE, RELATIVE RISKS OF APPROX 2, 14 and 32 BEING OBSERVED FOR EXPOSURES OF LESS THAN 5 YR (2 CASES), 5-9 YR (2 CASES) and 10+ YR (3 CASES), RESPECTIVELY. THE RELATIVE RISK ASSOC WITH AT LEAST 5 YR OF EXPOSURE IS THUS LIKELY TO BE LOWER BOUND FOR RISK ASSOC WITH LIFETIME EXPOSURE AT SIMILAR LEVELS. FOR THOSE WITH AT LEAST 5 YR EXPOSURE, 5 CASES WERE OBSERVED COMPARED WITH AN EXPECTED NUMBER OF 0.237, GIVING A RELATIVE RISK OF 21.1. SINCE THE EXPECTED CUMULATIVE MALE ADULT LIFETIME (FROM 20 YR TO END OF LIFE, TAKEN AS AGE 75) PROBABILITY OF DYING FROM LEUKEMIA IS APPROX 7 PER 1000 IN THE GENERAL POPULATION OF THE USA, AN EXPECTED RELATIVE RISK OF 21.1 WOULD GIVE AN EXTRA (21.1-1.0)X7= 141 CASES OF LEUKEMIA PER 1000 EXPOSED POPULATION. [R118] *The hematotoxicity of benzene is expressed primarily as a bone marrow effect leading eventually to complete destruction of myeloid and erythroid marrow components. This is manifested as a marked decrease in circulating formed elements, ie red blood cells, and platelets. The resultant aplastic anemia is a potentially fatal disorder which in its severe form has better than a fifty percent mortality rate. In both man and laboratory animals the extent of bone marrow damage appears proportional to the dose of benzene. Lesser degrees of bone marrow toxicity than aplastic anemia are more common in occupational exposure situations. Classically, the discovery of one individual with significant bone marrow toxicity has led to evaluation of the exposed work force and the finding of a wide variation in the extent of hematotoxicity. This has ranged from clinically significant pancytopenia, in which are decreases in white blood cells (leukopenia), red blood cells (anemia), and platelets (thrombocytopenia) to a situation in which only one of these is slightly below normal range. In the latter case it is of course difficult to distinguish a benzene effect from that due to the extremes of normal variation or to mild intercurrent disease. [R119] *The type of leukemia most commonly associated with benzene is acute myelogenous leukemia and its variants, including erythroleukemia and acute myelomonocytic leukemia. Acute myelogenous leukemia is the adult form of acute leukemia and, until recent advances in chemotherapy, it was a rapidly fatal disease. The other major acute form of leukemia, acute lymphocytic leukemia, has been reported to be associated with benzene exposure but evidence of a causal association is weak. There is a somewhat stronger, although still inconclusive, association in the literature between benzene exposure and the two common forms of chronic leukemia: chronic myelogenous leukemia and chronic lymphocytic leukemia. Other hematological disorders possibly associated with benzene exposure include Hodgkin's disease, lymphocytic lymphoma, myelofibrosis and myeloid metaplasia, paroxysmal nocturnal hemoglobinuria, and multiple myeloma. [R119] *An acute hemorrhagic pneumonitis is highly likely if ... aspirated into lung. [R11] *Three cases of chronic leukemia were presented which had a history of chronic benzene exposure. These three patients were part of a larger group of 58 leukemia patients with benzene exposure histories. Case 1 presented at age 43 due to cardiac complaints. The patient owned a printing shop at which he mixed pigmented dyes with solutions of toluene or methyl alcohol ketone. The individual had a practice of sniffing the solutions as control measure. The toluene solution on analysis was shown to contain 2.8% benzene 95.3% toluene. Blood and bone marrow examination revealed chronic lymphatic leukemia. Case 2 was a 51 year old man with pain in the right quadrant. This individual had owned a small plastics facility between 1955 and 1965 where he was intermittently exposed to thinners containing 27.3% benzene. Subsequent exposure included cleaning solutions without benzene. He was also diagnosed with chronic lymphatic leukemia. The third case was a 50 year old manager of a plastic facility who was diabetic for 15 years and was hospitalized due to recurrent gluteal and inguinal furunculosis during the last 3 years. He had been heavily exposed to benzene between 1957 and 1965. He admitted having removed the dirt from his hands using thinners containing benzene. Hairy cell leukemia was diagnosed. The data suggests that differences in distribution of acute or chronic leukemias in chronic benzene exposure may be related to exposure levels, mode of exposure, or exposure to benzene homologs or other chemicals. [R120] *A study conducted to measure the concentration of benzene in the air and solvents at 40 small and large workplaces in Turkey where workers had contracted leukemia and lymphoma. In addition, hematological examinations were performed on the 231 workers employed at the facilities. The facilities manufactured and repaired shoes, tires, leather works, automobiles, and farm equipment. The age of the workers ranged from 14 to 57 years and the mean duration of exposure was 8.8 years (range 1 month to 40 years). Case reports were presented for five workers with 2 to 15 years of exposure who had developed acute myeloblastic leukemia, acute lymphoblastic leukemia, acute myelomonocytic leukemia, Hodgkin's disease and poorly differentiated lymphoma. Benzene concentrations in the solutions and thinners used ranged from 3 to 7.5%. The concn of benzene in air samples from the plants ranged from 0 to 110 ppm while 76.4% of solvents contained more than 1% of benzene. Hematological examinations of the workers showed that 32% of them had abnormal values. There has been a decline in the use of benzene in Turkey since an earlier study in 1972, but that the percentages of benzene in most of the materials are still above permissible limits. [R121] *Benzene is widely recognized as a leukemogen, and the Occupational Safety and Health Administration is currently attempting to limit exposure to it more strictly. The proposed new regulation is a limit of an eight hr time-weighted average of 1 ppm in place of the current limit of 10 ppm. The fundamental rationale for the change is a perception that the current standard is associated with an inordinate excess of leukemia. The epidemiologic literature on benzene and leukemia supports the inference that benzene causes acute myelocytic leukemia. However, the available data are too sparse, or /have/ other limitations, to substantiate the idea that this causal association applies at low levels (ie, 1-10 ppm) of benzene. Nonetheless, under the assumption that causation does apply at such low levels, a number of researchers have performed risk assessments using similar data but different methodologies. The assessments that is considered acceptable suggest that, among 1,000 men exposed to benzene at 10 ppm for a working lifetime of 30 years, there would occur about 50 excess deaths due to leukemia in addition to the baseline expectation of seven deaths. However, this estimate is speculative and whether or not enough confidence can be placed in it to justify a lower occupational benzene standard remain a decision for policy makers. [R122] *Results of epidemiologic studies indicating an association between solvent exposure and the development of malignancies affecting hematopoietic and lymphatic tissues are reviewed. Clinical and cytogenetic data supporting this association are discussed. A variety of malignant disorders have been associated with solvent exposure, ie acute leukemia, Hodgkin's disease (odds ratio 2.8-6.6), non-Hodgkin's lymphoma (odds ratio 3.3) and myeloma, and there are some indications that solvent exposure may be a risk factor for myelofibrosis. The carcinogenic effect of benzene is epidemiologically and experimentally well documented and there are some indications that other solvents may also be hazardous. Possible mechanisms bringing about malignant transformation are discussed. The need for further epidemiologic, cytogenetic and clinical studies on the association between solvent exposure and malignant diseases is emphasized. [R123] *Currently the most applied technique for monitoring biological effects of exposure to genotoxic chemicals in industrial workers is the measurement of chromosome aberrations in peripheral blood lymphocytes. In the Shell petrochemical complex in the Netherlands cytogenetic monitoring studies have been carried out from 1976 till 1981 inclusive, in workers potentially exposed to a variety of genotoxic chemicals, ie vinyl chloride, ethylene oxide, benzene, epichlorohydrin, epoxy resins. Average exposure levels to these chemicals were well below the occupational exposure limits. Results of thesse studies indicate that no biologically significant increase in the frequencies of chromosome aberrations in the exposed populations occurred compared with control populations. ... Experience with this methodology has shown that the results of chromosome analyses are difficult to interpret, due to the variable and high background levels of chromosome aberrations in control populations and in individuals. It is concluded that the method is not sufficiently sensitive for routine monitoring of cytogenetic effect in workers exposed to the low levels of genotoxic compounds. [R124] *The possibility of there being a link between the apparent predominance of men with specific on the job exposures to toxic materials among patients with hairy cell leukemia was explored. Of a total of 105 hairy cell leukemia patients, eight were in the medical profession (two X-ray technicians, one radiologist, two pneumologists, two orthopedists, and one internist), 21 were garage mechanics or divers of trucks or other heavy vehicles, eight worked in construction as painters, decorators or masons, three were in the printing industry as photogravure and equipment maintenance workers, ten were farmers, six were engineers and 49 held various technical or office positions. Interviews were conducted with 69 of the patients. All those in medicine had used radioscopy for periods exceeding 10 years. Exposure to petroleum derived substances was high not only among the garage mechanics and drivers, but among those 49 individuals whose occupations did not have particular exposure, but whose hobbies and paraprofessional activities involved use of benzene or other solvents. Of the 69 interviewed, 52 were able to document exposure to benzene or other solvents. [R125] *The case of a 55 year old male with hairy cell leukemia associated with chronic exposure to benzene in an occupational setting was described. The subject had been employed as a coach paint sprayer for over 25 years at the time of diagnosis. When that patient was questioned, it was admitted that at the job site he did not usually take the normal protective measures to prevent exposure to the chemicals in the paints. The /investigators noted/ that spray painting is the one of the occupations which can involve exposure to benzene, due to the use of benzene containing solvents. The /researchers/ concluded that since three other cases of chronic leukemia have been previously associated with exposure to benzene, more retrospective demographic studies which take occupational exposures into account confirm the possible link between chronic benzene toxicity and leukemia, particularly the very rare hairy cell leukemia. [R126] HTOX: *The mutual metabolic suppression between benzene and toluene was studied. The subjects, 190 male Chinese workers employed in shoe manufacturing, printing, audio equipment manufacture, and automobile industries, were divided into four groups based on occupational exposure: 65 were exposed to benzene, 35 to toluene, 55 to both compounds, and 35 served as comparisons. The arithmetic mean exposure level of benzene was 31.9 and of toluene 44.7 ppm. The mixture contained benzene at 17.9 + - 29.3 and toluene at 20.5 + - 25.8 ppm. The exposure levels were measured using individual diffusive samplers. The geometric mean levels of the metabolites, phenol, catechol, hydroquinone, hippuric acid, and o-cresol, in unexposed workers were 6.9, 9.4, 4.8, 72.5, and 0.066 mg/l, respectively. Values corrected for creatinine and specific gravity were different from the values cited above. Multiple correlation coefficients for benzene exposure versus its three metabolites were for phenol, 0.740; for catechol, 0.629; and for hydroquinone, 0.762. Multiple correlation coefficients for toluene and its two metabolites were 0.649 for hippuric acid and 0.583 for o-cresol. The slopes of regression lines for the exposure to benzene in the presence of toluene were less than half of those obtained when the workers were exposed to benzene alone; however, the regression lines for benzene in mixture versus catechol were out 80% of higher than the lines observed with benzene as the sole pollutant. The regression lines for toluene in the mixture and excretion level of hippuric acid and hydroquinone showed reduced metabolic conversion compared to when exposure was limited to toluene alone. [R127] *A retrospective cohort study was conducted in 233 benzene factories and 83 control factories in 12 cities in China. The benzene cohort and the control cohort consisted of 28,460 benzene exposed workers (178,556 person-years in 1972-81) and 28,257 control workers (199,201 person-years). Thirty cases of leukemia (25 dead and 5 alive) were detected in the former and four cases (all dead) in the latter. The leukemia mortality rate was 14/100,000 person-years in the benzene cohort and 2/100,000 person-years in the control cohort; the standardized mortality ratio was 5.74 (p less than 0.01 by U test). The average latency of benzene leukemia was 11.4 years. Most (76.6%) cases of benzene leukemia were of the acute type. The mortality due to benzene leukemia was high in organic synthesis plants followed by painting and rubber synthesis industries. The concentration of benzene to which patients with a leukemia were exposed ranged from 10 to 1000 mg/cu m (mostly from 50 to 500 mg/cu m). Of the 25 cases of leukemia, seven had a history of chronic benzene poisoning before the leukemia developed. [R128] *Cytogenetic and environmental factors in the etiology of acute leukemias in adults were discussed. Epidemiological aspects of leukemia were considered. The leukemias currently account for approximately 3% of the total cancer incidence and 4% of the cancer deaths in the USA. The average annual incidence is eight cases per 100,000 for females and 11 cases per 100,000 for males. Leukemia is more common in whites than nonwhites and more common in males. Acute nonlymphocytic accounts for about 30% of the total leukemia incidence and for over 85% of the acute leukemia seen in persons over 40 years of age. Recent mortality data show very little change in leukemia death rates except for acute nonlymphocytic leukemia which increased by 20% from 1969 to 1977. Genetic and environmental factors were considered. Chromosome disorders and a family history may be etiological factors in both acute nonlymphocytic leukemia and lymphocytic leukemia. Exposures to benzene, ionizing radiation, and antineoplastic agents are known to cause chromosomal aberrations and leukemia; however, no evidence of a causal sequence of events has been obtained. Environmental risk factors such as ionizing radiation, cigarette smoke, and chemicals were described. Benzene is considered the best known and most widely occurring human leukemogen. A number of case reports and cohort studies have linked benzene exposure and acute leukemias. Benzene associated relative risk for overall leukemia generally range from 1.5 to 2.0. Cytogenetic aspects of leukemia were considered. Some studies have shown that prior chemical exposures are associated with chromosome aberrations in acute nonlymphocytic leukemic patients. Suggestions for improving epidemiological studies of leukemia were discussed. [R129] *A study of mortality in automobile mechanics and gasoline service station workers in New Hampshire was conducted. A proportionate mortality ratio analysis of all deaths occurring among male residents 20 years or older who lived in New Hampshire between 1975 and 1985 was performed. Occupation, industry, age, and date and cause of death were obtained from death certificates. A total of 37,426 deaths were recorded. Of these, 453 were automobile mechanics and 134 were persons who had been employed in the gasoline service station industry. Automobile mechanics had statistically significant proportionate mortality ratio elevations for suicide. Nonsignificant increases in proportionate mortality ratio for leukemia, cancers of the oral cavity, lung, bladder, rectum and lymphatic tissue, and nonmalignant blood dyscrasias and cirrhosis of the liver were observed. Workers in the gasoline service station industry had statistically significant increases in mortality from leukemia and mental and psychoneurotic and personality disorders, proportionate mortality ratio 328 and 394, respectively; however, the number of deaths was small. Proportionate mortality ratio increases were also observed for emphysema and suicide. One or more of the exposures experienced by automobile mechanics and service station workers presents a carcinogenic risk. The finding of excess mortality from leukemia in both groups is consistent with exposure to benzene, a component of gasoline. ... Workers who pump gasoline should be informed of the potential cancer hazard. Gasoline should not be used as a solvent for removing grease and cleaning hands, and gasoline should not be siphoned by mouth. [R130] *This paper presents a critical review more than 100 references on the possible leukemogenic (blastomogenic) effects of benzene, based upon clinical, epidemiological and experimental /studies/. /Evidence supports the conclusion that/ there exists reliable clinical and epidemiological /studies/, concerning increased leukemogenic risk on working place with high benzene concentrations in past years (tens and even hundreds of ppm). Most epidemiological studies, indicate now that this risk is also elevated in more favorable working conditions, although practical valuable dose-effect relationship between benzene concentrations and rate of leukemogenic risks is still unknown. Results of experimental investigations on problem of leukemogenic effects of benzene are contradictory. It was stated recently that there is a lack of adequate experimental models of benzene blastomogenesis. Taking into consideration increasing economic significance of benzene and existence of large contingents of workers dealing with benzene, it is necessary to continue appropriate experimental and epidemiological investigations. [R131] *The possible association of thinner, a mixture of seven organic solvents used in the Mexican auto and paint industry, with the frequency of sister chromatid exchanges in the peripheral lymphocytes of 24 industrial workers was investigated. The subjects worked in a factory and three workshops in which no protective measures against inhalation of vapors were taken. A matched comparison group consisted of 24 administrative and outdoor workers. Use of cigarettes, alcohol, and medicines, and presence of viral infections within the 3 previous months were determined by questionnaire. Blood was cultured for 72 hr with phytohemagglutinin, with 5-bromodeoxyuridine added at 24 hr and colchicine at 70 hr. Sister chromatid exchanges were scored from 50 metaphases from each individual. Air samples to determine concentrations of thinner components in the working atmosphere were taken on the day of blood sampling and analyzed by gas chromatography. Solvent concentrations in the samples from the factory air were methyl isobutyl ketone 2.4 ppm, methanol 0.6 ppm, isopropanol 3.3 ppm, toluene 3.3 ppm, benzene 6.0 ppm, and hexane 3.3 ppm. The concentrations were below the limits recommended by NIOSH ... except for benzene which was six times the NIOSH limit. One way analysis of variance of the sister chromatid exchanges frequency for the exposed and comparison groups showed no differences for exposures of either 5 years or less of 6 to 35 years. However, a significant increase of sister chromatid exchanges was found for tobacco use in the exposed group but not for the comparison group. The implications of this result were discussed principally in relation to benzene. ... Working conditions should be improved by a ventilation system and that a benzene free thinner be substituted for the one being used. [R132] *Dose response analyses for a cohort study of chemical workers exposed to benzene were reported. Exposure information included 8 hour time-weighted averages and peak exposures and was used to calculate the latency, duration of exposure, and peak exposure for several types of lymphatic and hematopoietic cancers. The cohort included 4,602 male chemical workers from seven companies who were occupationally exposed to benzene for at least 6 months between 1946 and 1975. A comparison group included 3,074 workers at the same plants who were employed for at least 6 months without exposure to benzene. Workers exposed to benzene 5 and 14 years showed an increased risk of lung cancer with a statistically significant enhancement of the standardized mortality ratio. Increased in reticulosarcoma and lymphosarcoma were related to the duration of continuous benzene exposure. Increased latency was related to a slight enhancement for all cancers among the exposed workers. Analysis by cumulative exposure demonstrated an increasing trend for death due to lymphatic and hematopoietic cancer, lymphosarcoma, reticulosarcoma, and leukemia. Workers with a cumulative exposure of 180 to 719 ppm month showed a significant increase in lung cancer. No dose response relation was detected for any other causes of death. [R133] *A mortality study of 7,676 male chemical workers occupationally exposed to benzene was described. The subjects were employed at nine plants belonging to seven member companies of the Chemical Manufacturers Association. Workers were classified according to their benzene exposure into occupationally exposed or comparison groups. Occupationally exposed workers received at least 6 months of continuous or intermittent job exposure to benzene between 1946 and 1975. The comparison group comprised workers with at least 6 months of employment at the same plant with no benzene exposure. Approximately 40% of the cohort were not occupationally exposed to benzene, and about 46% of the cohort had received continuous exposure to benzene. The remaining 14% fell into the intermittent exposure group. The observed mortality of the cohort was compared with the expected based on the United States mortality rates appropriately standardized. Standardized mortality ratios were determined for lymphatic and hematopoietic cancer, leukemia, non Hodgkin's lymphoma, and non-Hodgkin's lymphopoietic cancer. The number of observed deaths in the continuous exposure group was slightly but not significantly greater than expected. Deaths from lymphatic and hematopoietic cancers and from leukemia were greater than expected in the continuous exposure group. The mortality of the intermittent exposure group was comparable to the expected mortality. The standardized mortality ratios of the total group were greater than the comparison group. Statistically significant associations were demonstrated between benzene exposure and both lymphopoietic cancer and leukemia. [R134] *Comprehensive comparative studies were conducted on the three groups of 148 male and 167 female workers exposed to benzene, toluene, or a combination of the two to evaluate subjective symptoms and hematologic effects of the compounds. Exposed workers were compared to 127 unexposed referents. The exposure intensity of the workers was estimated by diffusion dosimetry, and their subjective symptoms were obtained from questionnaires. The workers in the benzene group were engaged in shoe making and printing; the toluene group was engaged in shoe making and audio equipment production, and the mixed exposure group was employed in spray painting in automobile body shops. The mean age of the workers ranged from 26.7 to 39.0 years. The average 7 hr time weighted exposure to benzene was 33 and 59 ppm for men and women, respectively; the exposure concentrations of toluene were 46 and 41 ppm for men and women, respectively. In the mixed exposure group, men were exposed to 14 ppm of benzene and 18 ppm of toluene; the female mixed exposure was 18 ppm of benzene and 21 ppm of toluene. Hematological examinations showed no significant differences between exposed and nonexposed workers, although leukocytes were marginally decreased. The prevalence of subjective symptoms was dose related and statistically significant for both men and women. The number of symptoms per person during work was at least ten fold higher in the exposed than in the nonexposed groups. The most frequent symptoms were dizziness, sore throat, and headache which occurred during work as well as during non work time. This study provides no indication of pancytopenia, and that both liver and kidney functions are unchanged under exposure conditions. [R135] *Of a total of 528,729 workers exposed to benzene or benzene mixtures in China, 508,818 (96.23%) were examined. Altogether 2,676 cases of benzene poisoning were found, a prevalence of 0.15%. A higher prevalence of benzene poisoning was found in the cities of Hangjou, Hefei, Nanjing, Shenyang, and Xian. The geometric mean concentration of benzene in 50,255 workplaces was 18.1 mg/cu m but 64.6% of the workplaces had less than 40 mg/cu m. There was a positive correlation between the prevalence of benzene poisoning and the concentration in shoemaking factories. The prevalence of benzene induced aplastic anemia in shoemakers was about 5.8 times that occurring in the general population. The results of this investigation show the need for a practicable hygiene standard to prevent benzene poisoning. [R136] *... CYTOGENETIC APPROACHES APPEAR TO BE NEAREST TO ROUTINE SURVEILLANCE IN DETECTING EARLY BIOLOGIC EFFECTS IN EXPOSED HUMANS. BENZENE SHOWED CONTRADICTORY RESULTS IN CHROMOSOME ABERRATION TESTS AND WAS NEGATIVE FOR SISTER CHROMATID EXCHANGE. [R137] *Investigations on the association between environmental hazards and the development of various /forms/ of leukemia are reviewed. Regarding acute non-lymphocytic leukemia exposure to ionizing radiation is a well documented risk factor. According to several recent studies exposure to strong electronmagnetic fields may be suspected to be of etiologic importance for acute non-lymphocytic leukemia. There is evidence that occupational handling of benzene is a risk factor and other organic solvents may be leukemogenic. Occupational exposure to petroleum products has been proposed to be a risk factor although the hazardous substances have not yet been defined. Results of cytogenic studies in acute non-lymphocytic leukemia suggest that exposure to certain environmental agents may be associated with relatively specific clonal chromosome aberrations. These results are of interest because it has been proposed that chromosomal rearrangements may play a role in the activation of cellular oncogens. Exposure in utero to ionizing radiation has been proposed to be a risk factor for acute lymphocytic leukemia in children. Unlike acute non-lymphocytic leukemia there seems at present to be little evidence that acute lymphocytic leukemia is related to exposure to some chemicals. Chronic myleoid leukemia may follow exposure to high doses of ionizing radiation whereas such exposure seems to be of insignificant importance in the development of chronic lymphocytic leukemia. According to some studies an abnormally high incidence of chronic lymphocytic leukemia may be found among farmers in the USA. These results have not been confirmed in Scandinaavian studies. There seems to be little evidence that chronic myleoid leukemia or chronic lymphocytic leukemia are related to occupational handling of some chemicals. [R138] *Personal air monitors and breath samples were used to measure benzene and other volatile compounds in the breath of 200 smokers and 322 nonsmokers in New Jersey and California during 12 hr sampling periods. The monitor measured only sidestream and exhaled mainstream smoke. Concentrations were also measured in a subsample of homes and outdoor air. Compared to nonsmokers, benzene was significantly higher in the breath of persons who had smoked tobacco the day they were monitored (p < 0.001); values for smokers were 12 to 16 ug/cu m, nearly 10 times the breath level of nonsmokers. Values for personal air samplers were not always significantly higher. Benzene in breath was related to number of cigarettes smoked. Based on direct measurements of mainstream smoke, it was calculated that the typical smoker inhales 2 mg/day compared to the nonsmokers' intake of < 0.2 mg/day. Both smokers and nonsmokers exposed to passive smoking at home or work had increased levels of benzene compared to nonsmoking situations (p < 0.05). Indoor air levels in homes with smokers were significantly greater than in nonsmoking homes in fall and winter but not during spring and summer. [R139] *In both human and animal studies, it appears that benzene-induced bone marrow depression is a dose-dependent phenomenon. [R140, 742] *Toxicities from inhalation /of benzene include/: irritation of conjunctiva and visual blurring, mucous membranes, dizziness, headache, unconsciousness, convulsions, tremors, ataxia, delirium, tightness in chest, irreversible brain damage with cerebral atrophy, fatigue, vertigo, dyspnea, respiratory arrest, cardiac failure and ventricular arrhythmias, leukopenia, anemia, thrombocytopenia, petechiae, blood dyscrasia, leukemia, bone marrow aplasia, fatty degeneration and necrosis of heart, liver, adrenal glands, fatal overdose. /From table/ [R141] *Single exposures to concentrations of 66,000 mg/cu m (20,000 ppm) commercial benzene have been reported to be fatal in man within 5-10 minutes. At lower levels, loss of consciousness, irregular heart-beat, dizziness, headache and nausea are observed. [R95] *In general, acute symptoms are dependent on both the concentration and duration of exposure. Exposure to 7500 ppm for 30 min is life-threatening; 1500 ppm for 60 min produces significant symptoms; 50-150 ppm for 5 hr results in headache and weakness; whereas exposure to 25 ppm or less for 8 hr results in no demonstrable acute effect. [R142, 724] *... Benzene metabolism is a requirement for bone marrow toxicity. [R142, 726] */Researchers/ examined the blood counts of 161 workers for whom pre-employment counts were done prior to exposure in the rubber factory. The results indicated that during the first year of employment in the rubber factory, employees exposed to benzene levels higher than the median exposure (estimated at 40-54 ppm) had significantly lower white and red blood cell counts than employees exposed to benzene levels below the median exposure. [R143] *Leukopenia was observed ... in Chinese workers exposed to 0.69-140 ppm (mean = 6 ppm) benzene for more than 1 year. [R144] *After a fatal occupational exposure to benzene vapors on a chemical cargo ship for only minutes, autopsy reports on three victims revealed hemorrhagic respiratory tissues, and second degree burns on the face, trunk, and limbs. [R145] *Skin irritation has been noted at occupational exposures of greater than 60 ppm for up to three weeks. [R67] *A retrospective cohort study of incident cases of hematopoietic neoplasms and related disorders among 74,828 benzene-exposed workers employed between January 1, 1972 to December 31, 1987 in 672 factories in 12 Chinese cities was conducted. Workers (35,805) not occupationally exposed to benzene employed in 109 factories during the same period were used for comparison. Follow-up of both exposed and nonexposed workers was carried out using occupational and medical records, and histopathologic material were reviewed for all patients with hematopoietic malignancies to ensure correct classification. Among benzene-exposed workers, 82 patients with hematopoietic neoplasms and related disorders were diagnosed: 32 (39%) cases of acute leukemia, 9 (11%) aplastic anemia, 7 (9%) myelodysplastic syndrome, 9 (11%) chronic granulocytic leukemia, 20 (24%) malignant lymphoma and related disorders, and 5 (6%) others. Among the nonexposed group, 13 hematologic malignancies were diagnosed: 6 (46%) patients with acute leukemia, 2 (15%) chronic granulocytic leukemia, 3 (23%) malignant lymphoma, and 2 (15%) others. The hematopathologic features of acute nonlymphocytic leukemia associated with benzene exposure resembled the hematological features following chemotherapy or radiotherapy. In addition, this study documented myelodysplastic syndrome in association with benzene exposure. [R146] *... Benzene metabolites can adversely affect human topoisomerases, enzymes involved in DNA replication and repair. /Benzene metabolites/ [R147] NTOX: *Inhalation of air saturated with benzene vapor resulted in ventricular extrasystole in the cat and primate, with periods of ventricular tachycardia that occasionally terminated in ventricular fibrillation. ... In rabbit, sudden death from ventricular fibrillation has also been observed. ... In acute inhalation by male rats, benzene-induced resp paralysis occurred, followed by ventricular fibrillation. [R66, 1318] *... DOGS INHALING BENZENE ... DEVELOPED HYPERTENSION. THIS WAS SOON FOLLOWED BY PARALYSIS OF VASOMOTOR SYSTEM DUE TO EFFECT OF BENZENE ON SMOOTH MUSCLE OF BLOOD VESSELS. [R55, 1221] *Benzene in rabbit eye is a moderate irritant, causes conjunctival irritation, and ... transient slight corneal injury. [R66, 1318] *IN SERIES OF CHRONIC STUDIES, BILATERAL CATARACTS WERE FOUND IN 50% OF RATS EXPOSED /TO/ ... 50 PPM FOR 600 HR ... [R148, 689] *Rats, guinea-pigs, and rabbits exposed to 80-88 ppm (256-281 mg/cu m) for 7 hr/day for 30-40 wk had incr testicular wt and degeneration of seminiferous tubules. ... Alteration of estrous cycles has been reported in rats exposed to 1.6 or 9.4 ppm (5 or 30 mg/cu m) for 4 mo ... but there was no effect on their subsequent fertility or litter size. ... In C3H(JAX) mice whose ovaries were painted directly ... and which were later mated, a high incidence of sc hemorrhages and tail defects was observed in offspring, which persisted through 4 generations. [R149] *... STUDIES HAVE DEMONSTRATED THE INDUCTION OF CHROMOSOMAL ABERRATIONS IN BONE-MARROW CELLS FROM MICE, RATS, AND RABBITS TREATED WITH SINGLE OR MULTIPLE DAILY DOSES OF BENZENE RANGING FROM ABOUT 0.2 TO 2.0 ML/KG PER DAY AND GIVEN EITHER SC OR IP. MOST OF THE INDUCED ABERRATIONS WERE BREAKS OR DELETIONS; BUT CHROMOSOME-TYPE ABERRATIONS ALSO OCCURRED, PARTICULARLY AFTER PROLONGED EXPOSURE, WHEN TOXICITY, MANIFESTED BY A DROP IN PERIPHERAL BLOOD LEUCOCYTE COUNT, APPEARED. ... A SIGNIFICANT ELEVATED LEVEL OF ABERRATIONS ARE SEEN UP TO 8 DAYS AFTER A SINGLE IP INJECTION OF 0.5 ML/KG BODY WT IN RATS, WHEREAS ABERRATIONS WERE SIGNIFICANTLY INCR IN MICE 24 HR BUT NOT 7 DAYS AFTER RECEIVING A SIMILAR DOSE, 0.5 ML/KG BODY WT. [R150] *... 30 MALE AKR, DBA2, C3H OR C57BL6 MICE WERE GIVEN WEEKLY SC INJECTIONS OF 0.001 ML BENZENE IN 0.1 ML OLIVE OIL FOR LIFE. NO TUMORS WERE FOUND IN MICE OF DBA2, C3H OR C57BL6 STRAINS, THE MAX LIFESPAN BEING 730 DAYS. BETWEEN 7TH AND 16TH MO OF TREATMENT 16/30 TREATED AKR MICE DIED WITH LEUKEMIA, IN ADDITION, 8 DIED BEFORE AGE OF 9 MO WITHOUT LEUKEMIA. HOWEVER, LEUKEMIA WAS ALSO OBSERVED IN 30/35 AKR UNTREATED MICE WHICH LIVED, ON AVG, LONGER THAN TEST ANIMALS. [R151] *... AFTER 5 TO 8 WK OF 5 HR/DAY, 5 DAYS/WK EXPOSURE AT 44 and 47 PPM, RATS DEVELOPED A MODERATE DEGREE OF LEUKOPENIA, BUT ... NONE RESULTED FROM 15 TO 31 PPM. ... DECR IN THE WHITE CELL COUNTS OF RATS /WAS OBSERVED/ FOLLOWING 756 HR OF EXPOSURE AT 50 PPM OF BENZENE ON A SCHEDULE OF 8 HR/DAY, 5 DAY/WK. REDUCED AMT OF DNA IN THE WHITE CELLS, A DEPRESSION IN MYELOCYTIC ACTIVITY, AND AN INCR IN THE RELATIVE NUMBER OF RED CELL PRECURSORS IN THE BONE MARROW WERE ALSO OBSERVED. [R152] *SPRAGUE-DAWLEY RATS WERE EXPOSED TO 100, 300, and 2200 PPM OF BENZENE VAPOR IN AIR FOR 6 HR DAILY ON DAYS 6-15 OF GESTATION. THE MEAN BODY WT AND CROWN-RUMP LENGTH WERE LOWER THAN CONTROL GROUPS ONLY AT THE HIGHEST EXPOSURE LEVEL. SKELETAL EXAM SHOWED AN INCR IN THE NUMBER OF FETUSES WITH DELAYED OSSIFICATION OF STERNEBRAE IN THE 300- and 2200-PPM GROUPS. THE FEMALE OFFSPRING APPEARED TO BE AFFECTED TO A GREATER EXTENT THAN MALE FETUSES WITH RESPECT TO THE INCIDENCE OF DELAYED OSSIFICATION OF STERNEBRAE. LIFETIME EXPOSURE OF C57BL/6J MICE TO 100 OR 300 PPM (320 OR 958 MG/CU M) BENZENE PRODUCES ANEMIA, LYMPHOCYTOPENIA AND NEUTROPHILIA ASSOC WITH A RELATIVE INCR IN THE NUMBER OF IMMATURE LEUCOCYTES AND DECR IN MATURE LEUCOCYTES IN CIRCULATION. SC ADMIN BENZENE LED TO A SELECTIVE DEPRESSION IN B-LYMPHOCYTES IN RABBITS, WHEREAS T LYMPHOCYTES WERE MORE RESISTANT. [R153] *Male Charles River CD-1 mice (number unspecified) were exposed for 6 hr/day, 5 days/wk, for life to atmospheres containing ... levels of 0 (control), 100 ppm (320 mg/cu m) or 300 ppm (958 mg/cu m). Two mice in high-exposure group develop myelogenous (myeloid) leukemia. ... There was no evidence of leukemic response in 45 male 6 wk old Sprague-Dawley rats exposed to ... 900 mg/cu m (300 ppm) ... for 6 hr/day, 5 days/wk, for life. Exposure was terminated at wk 99 when the last test animal died. Controls were 27 males of same strain and age. ... Sprague-Dawley rats and AKR mice exposed to benzene (300 ppm, 958 mg/cu m) for 6 hr/day, 5 days/wk for life had lymphocytopenia, with little evidence of anemia. AKR mice were more sensitive to benzene-induced leucopenia than ... rats. /Mice also displayed agranulocytosis and reticulocytosis. No evidence of leukemia was reported/. [R154] *Single sc injection of 3 ml/kg body wt ... on 1 of days 11-15 of gestation to CFI mice caused cleft palate, agnathia and micrognathia in offspring ... . (No controls were used, and it is very likely that these effects were produced by stress of the injection). Several other studies in pregnant mice exposed to benzene, (2 and 4 ml/kg body wt sc, 0.3 to 1.0 ml/kg body wt orally or 500 ppm (1597 mg/cu m) by inhalation for 7 hr/day all failed to show any teratogenic effect, although reduced fetal wt and occasional embryolethality were observed. Similarly, several inhalation studies in rats have shown embryolethality and reduced fetal wt but only occasional teratogenic effects: Sprague-Dawley rats exposed to 10, 50, or 500 ppm (32, 160 and 1600 mg/cu m) for 7 hr/day had low incidence of brain and skeletal defects but no embryolethality at 50 or 500 ppm, and no abnormality or embryolethality at lower levels ... . No teratogenic effect was seen in pregnant rats exposed to 10 or 40 ppm (32 or 128 mg/cu m) for 6 hr/day ..., to 313 ppm (1000 mg/cu m) for 24 hr/day or for 6 hr/day ... or to 400 mg/cu m (125 ppm) for 24 hr/day (Tatrai et al 1980). No teratogenic effect has been reported in rabbits injected sc with 0.25 ml/kg of a 40% benzene soln daily during pregnancy ... or in rabbits exposed by inhalation to 500 ppm (1600 mg/cu m) for 7 hr/day on days 6-18 of pregnancy. [R149] *Rabbits and rats injected subcutaneously with 0.2 mg/kg/day showed an incr frequency of bone marrow mitoses. [R155] *Bone marrow cells from mice orally dosed with 56-2050 mg/kg on two successive days showed dose-related incr in incidences of chromosomal gaps and single breaks, multiple breaks at or above 139 mg/kg, pulverization at or above 348 mg/kg, and cytotoxicity at 2050 mg/kg. [R156] *Mice orally dosed with 0.22-1.65 g/kg showed a positive dose-related increase in polychromatic erythrocytes in the micronucleus test. [R157] *Rats exposed continuously to 209.7 ppm for 10 days prior to breeding showed a complete absence of pregnancy. 1/10 rats exposed to 19.8 ppm had resorbed embryos. Females showed an inverse relationship between dose (0.3-209.7 ppm) and number of offspring. [R158] *Chromosomal abnormalities in bone marrow cells have been reported as a consequence of experimental benzene exposure in a number of species including rats, rabbits, mice, and amphibians. [R159] *Chromatid deletions in metaphase chromosomes of bone marrow cells have been found in rats given single doses of subcutaneous benzene at 2 ml/kg and in rats given 1 g/kg/day for 12 days. [R159] *After rats were dosed with 0.5 ml/kg intraperitoneally, no dominant lethality was found; however, incr chromatid and chromosomal aberrations were reported. [R159] *Benzene is a mitotic poison, producing a decr in DNA synthesis in animal bone marrow cells in vitro. [R160] *Weanling male C57BL/6N mice were subcutaneously injected twice weekly for 44 weeks and once weekly for the last 10 weeks, gradually incr the dose from 450 mg/kg to 1.8 g/kg. The mice were killed 104 weeks after the first injection, and no evidence of carcinogenic activity was found in either the benzene-treated mice or the negative controls. Butylnitrosourea induced leukemia, lymphomas, and/or intestinal neoplasms/were observed/ in almost all the positive controls. [R161] *TWO GROUPS OF 40 MALE C57BL/6J MICE, 6 WK OLD, WERE EXPOSED TO ATMOSPHERES CONTAINING 0 OR 900 MG/CU M (300 PPM) BENZENE FOR 6 HR/DAY, 5 DAYS/WK, FOR LIFE. THE EXPOSURE ENDED AFTER 488 DAYS WITH THE DEATH OF THE LAST TEST MOUSE. IN ADDN TO ANEMIA, LYMPHOCYTOPENIA, NEUTROPHILIA AND BONE-MARROW HYPERPLASIA, 6 OF 40 MICE EXPOSED ... DEVELOPED LYMPHOCYTIC LYMPHOMA WITH THYMIC INVOLVEMENT (P < 0.01 FOR LYMPHOMAS, ACCORDING TO PETO'S LOG-RANK METHOD), 1 PLASMACYTOMA AND 1 HEMATOCYTOBLASTIC LEUKEMIA. AVG SURVIVAL TIME OF THE 8 TUMOR-BEARING MICE WAS 262 DAYS. TWO OF THE 40 CONTROL ANIMALS DIED FROM LYMPHOCYTIC LYMPHOMA WITH NO THYMIC INVOLVEMENT AFTER 282 and 608 DAYS, RESPECTIVELY. DIFFERENCES IN INCIDENCE AND INDUCTION TIME OF TUMORS BETWEEN THE GROUPS WERE STATISTICALLY SIGNIFICANT (SNYDER ET AL 1980). (THE WORKING GROUP NOTED THAT THYMUS WAS NOT EXAM ROUTINELY). [R154] *THREE GROUPS OF 30 OR 35 MALE AND ... FEMALE SPRAGUE-DAWLEY RATS, 13 WK OLD, RECEIVED 50 OR 250 MG/KG BODY WT BENZENE (PURITY UNSPECIFIED) DISSOLVED IN PURE OLIVE OIL BY STOMACH TUBE ONCE DAILY ON 4 OR 5 DAYS EACH WK DURING 52 WEEKS. GROUPS OF 30 MALE AND 30 FEMALE CONTROLS RECEIVED OLIVE OIL ONLY. THE RATS WERE ALLOWED TO LIVE UNTIL SPONTANEOUS DEATH OR WERE KILLED AT 144 WEEKS, THE END OF EXPT; AVG SURVIVAL TIMES WERE UNSPECIFIED. OF FEMALES OF THE CONTROL, LOW- AND HIGH-DOSE GROUPS, 0/30, 2/30 and 8/32, RESPECTIVELY, DEVELOPED ZYMBAL GLAND CARCINOMAS (COCHRAN-ARMITAGE TEST FOR POS TREND; P= 0.001; FISHER EXACT TEST FOR CONTROL VERSUS HIGH-DOSE GROUP: P= 0.003); 3/30, 4/30 and 7/32 DEVELOPED MAMMARY GLAND CARCINOMAS; and 1/30, 2/30 and 1/32 DEVELOPED LEUKEMIAS. NO SUCH TUMORS WERE FOUND IN MALES, EXCEPT THAT LEUKEMIAS OCCURRED IN 4/32 HIGH-DOSE MALES (COCHRAN-ARMITAGE TEST FOR POS TREND; P= 0.008; FISHER EXACT TEST: P < 0.069). BACKGROUND INCIDENCE OF ZYMBAL GLAND CARCINOMAS IN SEVERAL THOUSAND MALE AND FEMALE RATS OF SAME STRAIN ... /WAS/ ABOUT 0.7%. AVG LATENT PERIOD OF MAMMARY GLAND CARCINOMAS WAS 88 WK IN EACH TEST GROUPS VERSUS 110 WK IN CONTROL ... . [R162] *BLUE CRAB JUVENILES WHEN EXPOSED TO SUBLETHAL CONCN OF BENZENE (0.1 OR 5.0 PPM) IN A STATIC SYSTEM SHOWED AN INCR IN THE TIME NEEDED TO COMPLETE A MOLT CYCLE (50 DAYS IN CASE OF BENZENE-EXPOSED CRAB, AS COMPARED TO 33 DAYS FOR CONTROLS), A SLOWER RATE OF GROWTH OF REGENERATING LIMB BUDS, AND A DEPRESSED ACTIVITY OF ATPASE IN MITOCHRONDRIA. OXYGEN CONSUMPTION BY THE CRAB DECR FROM EXPOSURE TO 1.0 PPM BENZENE. [R163] *Toxicity threshold (cell multiplication inhibition test): bacteria (Pseudomonas putida) 92 mg/l; algae (Microcystis aeruginosa) > 1400 mg/l; green algae (Scenedesmus quadricauda) > 1400 mg/l; protozoa (Entosiphon sulcatum) > 700 mg/l, and (Uronema parduczi Chatton-Lwoff) 486 mg/l. Algae (Chlorella vulgaris) /showed/ 50% reduction of cell numbers versus controls after 1 day incubation at 20 deg C at 525 ppm. Inhibition of photosynthesis (of a freshwater, nonaxenic unialgal culture of Selenastrum capricornutum) at 10 mg/l, 95% carbon-14 fixation (versus controls); at 100 mg/l, 84% carbon-14 fixation (versus controls); at 1000 mg/l, 5% carbon-14 fixation (versus controls). ... Young Coho salmon /showed/ no significant mortalities up to 10 ppm after 96 hr in artificial seawater at 8 deg C ... Mortality /was/ 12/20 at 50 ppm after 24 hr up to 96 hr and 30/30 at 100 ppm after 24 hr in artificial seawater at 8 deg C. Herring and anchovy larvae (Clupea pallasi and Engraulis mordex) /studies showed that/ 35-45 ppm caused delay in development of eggs and /produced/ abnormal larvae; 10-35 ppm caused delay in development of larvae, decrease in feeding and growth, and increase in respiration. [R20, 257] *Groups of 5 to 10 pregnant Swiss-Webster mice were exposed to concentrations of 0, 5, 10, or 20 ppm benzene from days 6 through 15 of gestation and offspring of exposed dams were examined for untoward effects. Litter sizes, fetal weights, numbers of dead, resorbed, or malformed fetuses were within control limits. In the fetuses (day 16 of gestation), the number of mature erythroid precursor cells (CFU-E) was decreased at 20 ppm benzene. In the neonates, the number of CFU-E cells was increased at 20 ppm benzene. Granulocytic colony forming cells (GM-CFU-C) were affected by the 2 higher exposure concentrations. Adult mice treated in utero when re-exposed to benzene showed a more severe decrease in splenic GM-CFU-C than controls. [R164] *The best evidence that benzene must be metabolized to produce bone marrow depression is based on: 1) the observation that benzene toxicity is prevented by coadministration of toluene, which inhibits benzene metabolism; and 2) that partial hepatectomy (which decreases benzene metabolism) also decreases benzene toxicity. [R165] *Reports indicate that protection against benzene toxicity in phenobarbital treated animals reflects the fact that phenobarbital increased the detoxification rate of benzene in the liver. Inhibition of metabolism by toluene and by aminotriazole has been found to protect animals by decreasing the rate of formation of toxic metabolites. [R165] *The principal hydroxy metabolites of benzene, hydroquinone, catechol and phenol were assayed in tests for mitotic segregation induction in Aspergillus nidulans diploid strain 19. Hydroquinone was the most effective chemical, increasing the frequency of mitotic segregants up to 10 fold at 1-3 mM. Catechol was similarly active at 10-20 mM and phenol was weakly positive at 15 mM. Genetic characterization of induced abnormal segregating colonies by replating and complementary assays with haploid strain 35 suggest that gross chromosomal aberrations, instead of numerical abnormalities, are the primary genetic damages induced by hydroxybenzenes in Aspergillus. The protecting activity exerted by L-cysteine against equimolar concentrations of hydroquinone supports a free radical mechanism for hydroxy metabolite genotoxicity in Aspergillus nidulans. [R166] *Benzene hematotoxicity and leukemogenesis were investigated to verify epidemiological estimates to the effect that leukemia had developed in human beings exposed to benzene for about 15% of their lifetime, and that the levels of exposure reached at times as high as 250 to 300 ppm for at least a portion of working day. Based on a review of the literature and ongoing studies, mice were exposed to benzene vapor for 6 hr/day, 5 days/week for 16 weeks. Exposure of male CBA/Ca mice to 300 ppm benzene proved to be highly carcinogenic and leukemogenic compared to unexposed controls. Male and female CBA/Ca mice exposed to 100 ppm benzene, according to the same schedule, showed 30% mortality as compared to 12% in controls, while for neoplasms the respective figures were 10% and 1%. In this case, exposure to benzene reduced the cellularity of the bone marrow and the number of stem cells, while DNA synthesis increased. /Data indicates/ that benzene is carcinogenic in both animals and man and although it is unlikely that the slope for animals and man would be the same, the investigation of the linearity of the response would be helpful. [R167] *A review of recent advances in the metabolism and toxicity of benzene was presented. Metabolism of benzene was discussed including the microsomal metabolism of benzene, mitochondrial metabolism of benzene, effect and its metabolites on replication and transcription, and covalent binding of reactive metabolites of benzene with macromolecules. The toxicity of benzene, including genotoxicity, carcinogenicity, hematopoietic toxicity, and immunotoxicity, was reviewed. Mutagenicity and cytogenic toxicity were also covered. Effects on stem cells, progenitor cells, and on the stromal microenvironment were discussed. Cytogenetic effects observed in animals and humans following exposure to benzene were reviewed. Myeloclastogenic effects and clastogenic effects were covered. Leukemias and related diseases in humans, associated with repeated exposure to benzene at relatively high concentrations, were discussed. Aplastic anemia from benzene poisoning was also discussed. Progress made in understanding the bioactivation of benzene and in the elucidation of metabolites produced in the liver and bone marrow was discussed. [R168] *Environmental exposure to benzene results in both myelotoxicity and immunotoxicity. Although benzene induced immunotoxicity has been well documented, no studies to date have addressed the possibility that benzene toxicity is due in part to altered differentiation of marrow lymphoid cells. The effect of acute exposure to the benzene metabolite, hydroquinone, on murine bone marrow B-lymphopoiesis was investigated. Bone marrow cell suspensions from B6C3F1 (C57BL/6J x C3H/HeJ) mice were depleted of mature surface IgM+ B cells and cultured for 0, 24, 48, or 72 hr and production of newly formed B cells was assayed both by mature surface expression and colony formation in soft agar cultures. One hr exposure of bone marrow cells to hydroquinone before culture reduced the number of mature surface cells generated in liquid cultures. Small pre-B cells (cytoplasmic mu heavy chain+, sIgM-) were numerically elevated as compared with control cultures. Hydroquinone exposure also decreased the number of adherent cells found in cultures of bone marrow cells. These results suggest that short-term exposure to hydroquinone, an oxidative metabolite of benzene, may in some way block the final maturation stages of B cell differentiation. This apparent differentiation block resulted in reduced numbers of B cells generated in culture and a corresponding accumulation of pre-B cells. Reduction of adherent cells in treated cultures may also suggest that toxicity to regulatory cells for the B lineage may be in part responsible for this aspect of hydroquinone myelotoxicity. [R169] *Benzene is a potent bone marrow toxin in animals and man. Animal studies have shown that exposure to benzene can alter lymphocyte functions and decrease the resistance of animals to Listeria monocytogenes and transplanted tumor cells. Mononuclear phagocytes participate in host resistance to Listeria and tumor cells. The purpose of the studies presented here was to determine the effects of benzene and benzene metabolites on macrophage functions and the ability of macrophages to be activated for functions which are important in host defense. Benzene had no effects on macrophage function or activation for any of the functions tested. Conversely, metabolites of benzene, catechol, hydroquinone, benzquinone, and 1,2,4-benzenetriol had potent and varied effects on macrophage function and activation. Benzoquinone inhibited the broadest range of functions including release of hydrogen peroxide, Fc receptor-mediated phagocytosis, interferon gamma priming for tumor cell cytolysis, and bacterial lipopolysaccharide triggering of cytolysis. Benzoquinone was also the most potent metabolite causing inhibition at lower concentrations than the other metabolites. Hydroquinone inhibited hydrogen peroxide release and priming for cytolysis and 1,2,4-benzenetriol inhibited phagocytosis and priming for cytolysis. Catechol only inhibited the release of hydrogen peroxide. None of the compounds tested inhibited the induction of class II histocompatibililty antigens on the cell surface. All of the effects measured occurred using concentrations of compounds which did not disrupt the cell integrity or inhibit general functions such as protein synthesis. Taken together these data suggest that benzene metabolites alter macrophage function through several mechanisms including inhibition of output enzymes and disruption of signal transduction systems. [R170] *Female Wistar rats were exposed to various solvent vapors 8 hr/day for 7 days. The leukocyte suspension and serum were prepared from peripheral blood and utilized for the determination of alkaline phosphatase activity with disodium phenyl phosphate as a substrate (leukocyte alkaline phosphatase and serum assay). While the exposure to benzene at 20 or 50 ppm did not cause significant changes in leukocyte alkaline phosphatase assay activity, the exposure at 100 to 300 ppm resulted in a dose-dependent increase of leukocyte alkaline phosphatase assay activity up to more than 100% over the control. No further increase was observed at 1000 or 3000 ppm. Similar exposure at 300 ppm to either toluene, m-xylene, n-hexane, trichloroethylene, methyl ethyl ketone, ethyl acetate, or methyl alcohol did not induce any changes in leukocyte alkaline phosphatase assay activity. Thus, the increase in leukocyte alkaline phosphatase assay activity was considered to be specific to benzene exposure. When the animals were exposed to toluene (300 ppm) in combination with benzene (300 ppm), not only was the benzene induced leukopenia alleviated as previously reported, but the benzene induced increase in leukocyte alkaline phosphatase assay activity was no longer observed. The parallel inhibitory effects of toluene on benzene induced increase in leukocyte alkaline phosphatase assay and leukopenia suggest that a relation may exist between increase in leukocyte alkaline phosphatase assay activity and leukopenia. No changes in serum alkaline phosphatase assay activities were observed in the rats under the exposure conditions examined. [R171] *A review was presented of data for ... chemicals for which either ovarian toxicity or carcinogenicity, or both, have been documented in recent studies /conducted by/ the National Toxicology Program. In most cases, ovarian atrophy was commonly found after 90 days of exposure, and ovarian hyperplasia and neoplasia after longer periods. Benzene administered by gavage produced ovarian atrophy, cysts, hyperplasia and neoplasia in mice. [R172] *Based on literature, the mechanism of multitoxic effects of benzene and lesions in the peripheral blood of affected animals were postulated. The effects of chronic benzene poisoning upon erythrocytes and erythropoiesis, granulocytes and granulopoiesis, lymphocytes and lymphopoiesis, thrombocytes and thrombopoiesis were presented. Differences were pointed out in toxic effects of benzene varying with the kind, concentration and administration route of benzene and quantitative and qualitative differences in the fodder given to animals during the experiment. [R173] *The effect of a single dose of benzene (0.5 ml/kg body wt ip) on the heme saturation of tryptophan pyrrolase activity in liver was examined /in female albino rats/. There was a significant decrease in the heme saturation of hepatic tryptophan pyrrolase, suggesting depletion of regulatory heme. After benzene administration there was significant increase in delta-aminolevulinate synthetase activity while delta-aminolevulinate dehydratase activity was significantly decreased, however, ferrochelatase and heme oxygenase activities were unaltered. Administration of tryptophan to benzene pretreated rats showed a reversal of benzene effects on heme synthesizing enzymes: there is an increase in the heme saturation of tryptophan pyrrolase and decrease in delta-aminolevulinate synthetase. However, there was no significant alteration in the activity of delta-aminolevulinate dehydratase. [R174] *The effects of five straight alkane petroleum hydrocarbons (nC6 to nC10), as well as benzene and toluene upon lysosomal enzymes of the lung were investigated. Pulmonary alveolar macrophages were obtained from adult male Sprague Dawley rats and from 3 month old New-Zealand white rabbits by bronchial lavage. These cells were cultured and subsequently exposed to hydrocarbons in Leighton tubes. All hydrocarbons examined were cytotoxic to cultured pulmonary alveolar macrophages in a dose dependent manner, with benzene and toluene being least toxic. The concentration of hydrocarbon producing death in 50% of treated rat cells was 1.0 millimolar (mM) for nC8, 2.0 mM for nC7, 5 mM for nC9, and about 10 mM for nC6, nC10, benzene and toluene. Concentrations of hydrocarbons that killed 50% of rabbit macrophages were about half those observed in the rat. Cathepsin-D and, to a lesser extent, cathepsin-B release were stimulated upon addition of hydrocarbons to the cell media. A similar but more pronounced release of cathepsins was observed in isolated lysosomes as well. A significant decrease in cell respiration rate and a time and dose dependent increase in lipid peroxidation were also observed following exposure of macrophages to the tested hydrocarbons, particularly nC7 and nC8 alkanes. These results support the concept of an association between chain length and cytotoxicity of hydrocarbons in pulmonary alveolar macrophages. [R175] NTOX: *... Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice and for female B6C3F1 mice. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas, and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benigh mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. ... [R176] *In animal models, benzene induces anemia, lymphocytopenia, and hypoplastic bone marrow. In addition, it has been suggested recently that this myelotoxicity may be a result of altered differentiative capacity in bone marrow-derived lymphoid cells. [R140, 380] *... Solid tumors have been reported in animals exposed to benzene by inhalation or orally, suggesting that in mice and rats benzene may produce tumors in nonhematopoietic organs. [R140, 742] *When Sprague-Dawley rats and CD-1 mice of either sex were exposed to benzene by inhalation 6 hr/day, 5 d/wk for 13 wk at 1, 10, 30, or 300 ppm, treatment-related pathology was observed in the high-dose (300 ppm) groups of both species. In mice, hematologic changes included decreased hematocrit, total hemoglobin, erythrocyte/leukocyte count, platelet count, and myeloid: erythroid ratio. In rats, decreased lymphocyte count and a relative increase in neutrophil count were the only exposure-related clinical changes. Histopathological changes were observed in the testes and ovaries at concentrations below 300 ppm, and lesions were observed in the thymus, bone marrow, lymph nodes, spleen, ovaries, and testes in mice inhaling 300 ppm. The alterations were more severe in the males than in the females. In rats, the only exposure-related pathology was a slight reduction in femoral marrow cellularity at 300 ppm. [R177, p. BENZENE-2] *Hematopoietic depression in rodents was observed at benzene concentrations as low as 103 ppm after a 5 day exposure. [R177, p. BENZENE-2] *In a lifetime carcinogenicity bioassay in which oral doses of benzene were administered at 50 and 250 mg/kg body weight/day, 4-5 days per week for 52 weeks, there was a dose-dependent increase in total cancers. The most prominent rat tumors observed were Zymbal gland carcinomas, mammary carcinomas, and leukemia. When Wistar rats and Swiss mice were given benzene at 500 mg/kg/day, 4 days/wk for 104 wk or 5 days/wk for 78 wk, the numbers of Zymbal gland carcinomas, hemolymphoreticular neoplasias, and total malignant tumors were increased in the rats; increases in mouse Zymbal gland dysplasia and carcinomas, mammary carcinomas, pulmonary tumors, and total malignant tumors were observed. [R177, p. BENZENE-2] */Researchers/ conducted an inhalation study in which pregnant Sprague-Dawley rats were exposed 7 hr/d to benzene at 10, 50, or 500 ppm on days 6 to 15 of gestation. Significant reductions in mean maternal body weight gain occurred. Mean fetal body weight was reduced. Fetal crown-to-rump distance was decreased significantly at 500 ppm, and developmental delay was evidence upon examination of the fetal skeletons. Benzene was judged ... to be fetotoxic in rats at 50 and 500 ppm and to manifest teratogenicity at 500 ppm. [R177, p. BENZENE-3] */Researchers/ exposed CFLP mice and NZ rabbits 24 hr/day to benzene at 154 or 308 ppm throughout days 6 to 15 of gestation. Benzene was detected in fetal blood and in amniotic fluid. At 308 ppm, retarded skeletal development and reduced fetal body weight were observed in mouse fetuses, and spontaneous abortions were reported in rabbits. [R177, p. BENZENE-3] */Researchers/ found a concentration-dependent increase in DBA/2 mouse bone marrow lymphocytes after a single 4-hr inhalation study of benzene at 28-3000 ppm; an increase in SCE was detected at 28 ppm. This response was strain-dependent because DBA/2 mice were more sensitive than C57BL/6 mice, young DBA/2 mice (3 mos old) were more sensitive than older mice (10 mos old), and male mice were more sensitive than female mice. Following intraperitoneal injection, a linear dose-dependent increase in SCE was observed in DBA/2 mice. [R177, p. BENZENE-4] *When male DBA/2 mice inhaled benzene at 0, 10, 100, or 1000 ppm or male Sprague-Dawley rats inhaled benzene at 0, 0.1, 0.3, 1, 3, 10, or 30 ppm for 6 hr, significant (concentration-dependent) increases in SCE and micronuclei were observed in mice at greater than or equal to 10 ppm, and increased SCE and micronuclei were observed in rats inhaling greater than or equal to 3 ppm and at 1 ppm, respectively. These data are the lowest concentrations of inhaled benzene that have been reported to induce genotoxicity. [R177, p. BENZENE-4] */Benzene/ has been shown to be fetotoxic following inhalation exposure in mice (1600 ug/cu m, 7 hr/day, gestation days 6-15) and in rabbits. [R178] *Toluene and benzene administered concurrently were reported to have an additive effect on induction of chromosomal aberrations. Toluene reduced the number of sister chromatid exchanges induced by benzene when both compounds were administered intraperitoneally to DBA/2 mice and reduced the clastogenic activity of benzene when the two compounds were simultaneously administered orally to CD-1 mice, intraperitoneally to Sprague-Dawley rats, or subcutaneously to NMRI mice. [R179] *Rats exposed to 3,526-8,224 ppm of benzene in a closed chamber for 15 min exhibited an increased number of ectopic ventricular beats. [R180] *Sprague-Dawley SD/Tex rats were exposed to benzene vapor at 0 or 500 ppm for 5 days per week, 6 hr/day for 3 wk. Blood from the animals was evaluated for hematologic changes and the bone marrow for the presence of multinucleated erythroblasts. Animals exposed to 500 ppm showed decreased lymphocyte and leukocyte counts. Erythrocytes and hemoglobin values increased. In the bone marrow differential counts, rats showed a relative decrease in lymphoid and myeloid cells at the 500 ppm dose level and an increase in erythroid cells. In a companion study, purebred Duroc-Jersey pigs were exposed to 0, 20, 100, and 500 ppm benzene vapors 6 hr/day, 5 days/wk for 3 wk. [R181] *Granulocytic hyperplasia has been detected in the bone marrow of mice exposed to 300 ppm benzene in air for 6 hr/day, 5 days/wk for 16 wk, and held 18 mos after the last exposure. [R182] */Researchers/ observed a 26% decrease in spleen weight in male Kunming mice exposed to 12.52 ppm benzene 2 hr/day, 6 days/wk for 30 days. Examination of the bone marrow showed decreases in myelocytes, premyelocytes, myeloblasts, and metamyeloblasts at the same dose level. [R183] *Experimental DBA/2 mice were exposed to 300 ppm benzene for 6 hr/day for 5 days/wk (Regimen 1) or 3 day/wk (Regimen 2) for a duration of 1-13 wk. Polychromatic erythrocytes were affected by benzene inhalation independent of exposure duration and regimen, while normochromatic erythrocytes were affected only following Regimen 1 exposure. Males were more sensitive to benzene inhalation than females. [R184] *Sprague-Dawley rats received a single dose of 950 mg/kg benzene by gavage and were sacrificed 2 hr after treatment. The control group received nothing. Brains were dissected ... Results showed that benzene decreased acetylcholine content of rat hippocampus. 3,4-Dihydroxyphenylalanine and norepinephrine content decreased in the rat midbrain. Dopamine, serotonin and 5-hydroxyindoleacetic acid content increased in the rat midbrain. Dopamine, 3,4-dihydroxyphenylacetic acid, norepinephrine, and 5-hydroxyindoleacetic acid content increased and serotonin content decreased in the rat hypothalamus after oral administration of benzene. Increased dopamine, homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and serotonin content of rat medulla oblongata was observed. Decreased norepinephrine and 5-hydroxyindoleacetic acid content of rat medulla oblongata by benzene treatment was observed. [R185] *In /a/ study of cultured rat embryos, /researchers/ evaluated the embryotoxic effects of benzene and several of its metabolites. Benzene at 1.6 mM produced little embryotoxicity, with or without hepatic activating enzymes, but phenol showed significant embryotoxicity in the presence of hepatic activation at concentrations as low as 0.01 mM. Trans,trans-muconaldehyde was embryotoxic at 0.01 mM and embryolethal at 0.05 mM; hydroquinone, catechol, and benzoquinone were all 100% embryolethal at 0.1 mM. [R186] *MICE WERE GIVEN SINGLE DOSES OF BENZENE SC AND ITS EFFECT ON (59)FE UPTAKE WAS EVALUATED. NO SUPPRESSION WAS FOUND AFTER 1 and 12 HR AND ALSO 72 HR, WHEREAS DOSE-DEPENDENT INHIBITION OF (59)FE UPTAKE WAS OBSERVED 24 HR AND 48 HR AFTER TREATMENT WITH 440 OR 2200 MG/KG DOSE. THUS, THE DATA CAN BE INTERPRETED TO SUGGEST THAT (1) BENZENE DID NOT INTERFERE WITH AN INCORPORATION OF IRON INTO HEME, (2) BENZENE INTERFERED WITH PROLIFERATION OF NORMOBLASTS AND PRONORMOBLASTS, and (3) BENZENE DID NOT DAMAGE HEMOPOIETIC STEM CELLS WHICH WERE IN THE G0 STATE AT THE TIME OF BENZENE INJECTION. [R187] *When mitochondria are incubated in vitro with 2200 mg/kg of benzene there is an inhibition of RNA synthesis. Benzene also caused a dose-dependent inhibition of RNA synthesis in vitro in mitoplasts derived from cat and rabbit bone marrow mitochondria. Exogenous NADPH is required for inhibition of mitochondrial RNA synthesis in all these systems which suggests that benzene must be bioactivated within the organelle. Toluene does not inhibit RNA synthesis and the simultaneous addition of equimolar toluene and benzene results in protection against benzene inhibition. Both liver and bone marrow mitochondria incubated (3H) with benzene appear to activate benzene to a metabolite which can covalently bind to guanine residues of DNA. Benzene also inhibits mitochondrial translation. [R188] *... Benzene hydroxylation was stimulated when rats were pretreated with phenobarbital and then exposed to 1,000 ppm of benzene vapor for 8 hr/day for 2 wk. [R189] NTXV: *LD50 MOUSE INTRAPERITONEAL 0.34 ML/KG 95% CONFIDENCE LIMITS 0.28 TO 0.42; [R190] *LD50 Rat oral 3306 mg/kg; [R48, 334] *LC50 Rat ihl 10,000 ppm/7 hr; [R48, 334] *LD50 Rat ip 2890 ug/kg; [R48, 334] *LD50 Mouse oral 4700 mg/kg; [R48, 334] *LC50 Mouse ihl 9980 ppm; [R48, 334] *LD50 Mouse ip 340 mg/kg; [R48, 334] *LD50 Mouse ip 340 mg/kg; [R48, 334] ETXV: *LC100 Tetrahymena pyriformis (ciliate) 12.8 mmole/l/24 hr /Conditions of bioassay not specified/; [R191] *LC50 Palaemonetes pugio (grass shrimp) 27 ppm/96 hr /Conditions of bioassay not specified/; [R20, 261] *LC50 Cancer magister (crab larvae) stage 1, 108 ppm/96 hr /Conditions of bioassay not specified/; [R20, 258] *LC50 Crangon franciscorum (shrimp) 20 mg/l/96 hr /Conditions of bioassay not specified/; [R20, 258] *LC50 Morone saxatilis (bass) 5.8 to 11 mg/l/96 hr /Conditions of bioassay not specified/; [R43, 259] *LC50 Poecilia reticulata (guppy) 63 mg/l/14 days /Conditions of bioassay not specified/; [R20, 259] *LC50 Salmo trutta (brown trout yearlings) 12 mg/l/1 hr (static bioassay); [R20, 259] *LC50 Ambystoma mexicanum (Mexican axolotl) (3-4 wk after hatching) 370 mg/l/48 hr /Conditions of bioassay not specified/; [R20, 259] *LC50 Clawed toad (3-4 wk after hatching) 190 mg/l/48 hr /Conditions of bioassay not specified/; [R20, 259] *LC50 Carassius auratus (goldfish) 46 mg/l/24 hr /Conditions of bioassay not specified/; [R20, 258] *LC50 Lepomis macrochirus (bluegill sunfish) 20 mg/l/24 to 48 hr /Conditions of bioassay not specified/; [R20, 258] *LD100 Lepomis macrochirus (bluegill sunfish) 34 mg/l/24 hr /Conditions of bioassay not specified/; [R20, 258] *LD100 Lepomis macrochirus (bluegill sunfish) 60 mg/l/2 hr /Conditions of bioassay not specified/; [R20, 258] *LC50 Brine shrimp 66-21 mg/l/24-48 hr /Conditions of bioassay not specified/; [R20, 258] *LC50 Pimephales promelas (fathead minnow) 35 to 33 mg/l/24 hr-96 hr (soft water) /Conditions of bioassay not specified/; [R20, 258] *LC50 Pimephales promelas (fathead minnow) 24 to 32 mg/l/24-96 hr (hard water) /Conditions of bioassay not specified/; [R20, 258] *LC50 Bluegill 22 mg/l/24-96 hr (soft water) /Conditions of bioassay not specified/; [R20, 258] *LC50 Carassius auratus (goldfish) 34.4 mg/l/24-96 hr (soft water) /Conditions of bioassay not specified/; [R20, 258] *TLm Lebistes reticulata (guppy) 36 mg/l/24-96 hr (soft water) /Conditions of bioassay not specified/; [R20, 258] *LC50 Gambusia affinis (mosquito fish) 395 mg/l/24-96 hr /Conditions of bioassay not specified/; [R20, 258] NTP: *Two yr toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days/wk for 103 wk. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 wk. ... Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice and for female B6C3F1 mice. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas, and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), Harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benigh mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. ... [R192] TCAT: ?An evaluation of fertility was made in female Charles River CD rats (26/group) exposed by inhalation to benzene at 0, 1, 10, 30 and 300 ppm for 6 hrs/day, 5 days/week during a 10 week pre-mating treatment period and ensuing mating period, and continued exposure for mated females daily for 6 hrs/day during gestation to day 20. Daily exposure was resumed on day 5 of lactation until weaning (day 21 of lactation). There were significant differences between treated and control animals in the following: decrease in pup survival index (for lactation day 4-21 at 10 ppm, no dose-response), decreased mean pup weights (days 14 and 21 of lactation for high-dose level), and decreased mean absolute liver weights (high-dose female pups). There were no significant differences between treated and control animals in the following: maternal mortality, body weights, in-life observations, pregnancy rates, mean number dead pups, mean liver weights (male pups at all levels), mean relative liver weights (female pups at all levels), mean relative and absolute kidney weights (all female pups), or gross postmortem examinations of adult females or pups. [R193] ?Teratogenic effects were evaluated in pregnant female Sprague Dawley rats (40/group) exposed via inhalation to benzene at 0 (two groups), 1, 10, 40 and 100 ppm for 6 hrs/day from days 6-15 of gestation. On day 20 of gestation, the dams were sacrificed and the fetuses removed by cesarean section. There were significant differences between treated and control groups only in the decreased mean fetal body weights of fetuses from dams exposed at the high-dose level. There were no significant differences between treated and control dams in the following: mortality, clinical observations, body weight data, maternal gross pathology, pregnancy rates, mean number of corpora and implantations, or implantation efficiencies. There were no significant differences between fetuses from treated and control dams in the following: mean incidence of fetal resorptions, mortality, mean percentage of male fetuses/litter, mean fetal body lengths, or fetal development. [R194] ?The mutagenicity of benzene was evaluated in dominant lethal assay using four groups of 20 male Sprague-Dawley rats receiving whole body exposures to nominal concentrations of test material at 1, 10, 30 and 300ppm in a dynamic air flow chamber for 6hours/day, 5days/week for ten consecutive weeks. Following exposure, each male was mated with two untreated females per week for two consecutive weeks. There was no effect of treatment for all dosed male rats as indicated by: mortality, body weight data and in-life physical observations. Pregnancy rates and implantation efficiency ratios of females mated to treated males was not significant different from control group females. Slight increases in the mean number of dead implantations and mean mutagenic ratios (i.e. no. dead implants/total implants) were noted for each week of the post treatment mating period for females mated to high dose males, but these differences were not statistically significant compared to controls. Males were sacrificed after a 10-week post mating period and microscopic examination of testis/epididymides revealed two-high dose males with testicular lesions. [R195] ?As part of subchronic inhalation study, the ability of benzene to cause chromosome aberrations was evaluated in bone marrow cells of (50/sex) CD-1 mice receiving whole body exposures to nominal concentrations of 0, 1, 10, 30 and 300ppm in dynamic air flow chamber for 6hours/day, 5days/week for 13 weeks. Following the last day of exposure, animals received a single intraperitoneal injection of colchicine and were sacrificed. Bone marrow slides of mice at the highest concentration (300ppm) exhibited statistically significant increases chromosome aberrations relative to the control. [R196] ?As part of subchronic inhalation study, the ability of benzene to cause chromosome aberrations was evaluated in bone marrow cells of (50/sex) Sprague Dawley rats receiving whole body exposures to nominal concentrations of 0, 1, 10, 30 and 300ppm in dynamic air flow chamber for 6hours/day, 5days/week for 13 weeks. Following the last day of exposure, animals received a single intraperitoneal injection of colchicine and were sacrificed. Bone marrow slides of female rats at all exposure levels exhibited statistically significant increases in chromosome aberrations relative to the control. No-exposure related cytogenic effects were apparent in any of the male rats. [R196] ?The ability of benzene to increase the incidence of micronucleated polychromatic erythrocytes was evaluated in male and female CD-1 mice receiving nominal concentrations of 1, 10, 30 and 300ppm for 6hours/day, 5days/week for 13 weeks (Micronucleus Test). Groups of 20 mice (10/sex/sample time) were sacrificed after 0, 15, 30, 60 and 90 days of exposure. Exposure to 300ppm benzene caused a significant increases in micronucleated polychromatic erythrocytes (PCEs) and monochromatic erythrocytes (NCEs) in male and female mice at all sample times. Male mice exhibited a greater response than female mice. The frequency of micronucleated PCEs and the frequency micronucleated NCEs achieved steady state by the 30 day sample time. The rate of erythropoiesis, as measured by per cent of polychromatic erythrocytes in the peripheral blood, was not significantly altered by treatment. [R197] ?The levels of benzene and it's metabolites in the blood were evaluated in twenty male Sprague-Dawley rats and eighty male Swiss albino mice receiving nominal concentration of benzene at 300ppm in a dynamic air flow chamber. Sixteen mice and four rats were removed from the chamber after 1, 2, 4, 8 and 12 hours for eye bleeding. The mean levels of benzene in the rat blood were < 1.0, 4.7, 4.8, 5.7, 5.3, and 7.1ppm at intervals of 0, 1, 2, 4, 8 and 12 hours respectively. No free metabolites (phenol, catechol and hydroquinone) were detected at any of the time intervals in rats. The mean levels of benzene in mouse blood were < 1.0, 3.7, 3.0, 2.4, 3.0 and 1.3ppm at intervals of 0, 1, 2, 4, 8 and 12 hours, respectively. The mean levels of free phenol in mouse blood were 2.0, 2.4, 2.2, 2.3, 2.5 and 2.3ppm at respective intervals. No free catechol or hydroquinone were detected at any of the time intervals in mice. Also determined were levels of conjugates in rat and mouse blood. The mean levels of conjugated phenol in rat blood were < 1.0, 3.0, 5.3, 4.2, 7.1 and 4.7ppm and the mean levels in the mouse blood were 2.7, 7.2, 8.7, 8.4, 9.1, and 3.7 at intervals 0, 1, 2, 4, 8 and 12 hours, respectively. No conjugated catechol or hydroquinone were detected at any of the time intervals in rats or mice. It was concluded, that its takes approximately one hour to achieve a steady state level of benzene in rat and mouse blood. [R198] ?The levels of benzene and its's metabolites in blood were evaluated in male Sprague Dawley rats (4/group) and male Swiss albino mice (16/group) receiving nominal concentrations of benzene at 0, 3, 30, 300 or 1000ppm in dynamic air flow chamber for 6 hours. The mean levels of benzene in rat blood were < 1.0, < 1.0, < 1.0, 8.3 and 33.6ppm at exposure levels 0, 3, 30, 300 and 1000ppm, respectively. No free metabolites (phenol, catechol and hydroquinone) were detected at any exposure level in rat blood. The mean levels of benzene in the mouse blood were < 1.0, < 1.0, < 1.0, 1.44 and 29.5ppm at exposure levels 0, 3, 30, 300 and 1000ppm, respectively. A mean level of 1.2ppm of free phenol was only detected at the high dose level in mice. No free catechol or hydroquinone were detected in mouse blood. Also determined were the levels of conjugates in rat and mouse blood. The mean level of conjugated phenol in rat blood were < 1.0, < 1.0, 1.7, 6.0 and 6.3ppm and the mean levels of conjugated phenol in mouse blood were < 1.0, 1.1, 2.9, 7.9 and 15.5ppm at exposure levels of 0, 30, 300 and 1000ppm, respectively. No conjugated catechol or hydroquinone were detected at any exposure level in rats or mice. It was concluded that there was a direct correlation between increased exposure to benzene and increased blood concentration levels of benzene and conjugated phenol. Mice exposed to 1000ppm benzene had double the concentration of conjugated phenol in the blood relative to the 300ppm mice. In contrast, this effect was not observed in rats. [R199] ?The concentration of benzene and it's metabolites were determined after 12, 24, 48 and 72 hours in the urine of five exposed male Sprague Dawley rats and 25 male Swiss albino mice which received a nominal concentration of benzene at 300ppm in dynamic air flow chamber for 6 hours. No level of benzene at or above the detection limit (1.0ppm) were detected in rat and mice urine at any of the sampling intervals. The level of free phenol in the rat urine were 2.0, 2.2, 1.7 and 3.2ppm and in mouse urine were 15.6, 4.7, 5.8 and 4.3ppm at 12, 24, 48 and 72 hours, respectively. The mean levels of free catechol in rat urine were < 2.0, 0.46, 0.32 and < 2.0ppm and in mouse urine were 1.09, 1.29, 1.56 and 7.76ppm at 12, 24, 48 and 72 hours, respectively. No free hydroquinone at or above the detection limit were determined in rat urine at any sampling time. The mean levels of free hydroquinone in mouse urine were 12.87, 1.49, 1.46 and 0.31ppm at 12, 24, 48 and 72 hours, respectively. The expired air of rats was bubbled through dichloromethane and the mean total levels of benzene detected were 440.6, 101.4, not detected and 22.2ug/sampling interval ending at 6, 12, 24 and 48 hours, respectively. Benzene in expired air of mice was only detected at the 48 hour sampling interval. [R200] ?The in vitro percutaneous absorption of 14C-benzene was evaluated in mammalian skin samples maintain in a dynamic culture system. C3H Mice (primary test subject), HRS mice, rabbit and guinea pig (strain not specified) dorsal skin, and human skin from elective surgery were all placed in culture medium chamber for penetration analysis. 14C-Benzene (20ul) was topically applied to cultured C3H mouse skin samples and radioactivity was detected in the effluent medium 15 minutes following treatment with no apparent lag phase. Penetration was linear and the rates were 2.97 +/- 0.03 and 3.70 +/- 0.03%/hr for metabolically viable (fresh skin) and nonviable skin (frozen skin), respectively. Analysis of the effluent medium indicated negligible conversion of benzene to phenol. Different rates of in vitro skin permeation were observed between male and female C3H mice, however this difference was not observed between sexes in similar studies with hairless HRS mice. In vitro penetration of benzene in hairless mice skin (2.44 +/- 0.07%) was lower than C3H mice. Additional in vitro penetration studies with 14C-benzene (20ul) were preformed with metabolically viable guinea pig, rabbit and human skin with rates of penetration of 0.04 +/- 0.01, 0.55 +/- 0.02 and 0.23 +/- 0.04%/hr, respectively. The lag phase of these additional studies were between 45-60 minutes and two hours from application followed by linear radioactivity. Toluene and unleaded gasoline containing 14C-benzene (20ul) produced rates of permeation of 2.32 +/- 0.04 and 2.81 +/- 0.4%/hr, respectively in C3H mice which appeared linear. [R201] ?The benzene uptake rate was evaluated in five male Sprague Dawley rats and twenty five male Swiss albino mice receiving benzene at a nominal concentration of 300ppm in a dynamic air flow chamber for 6 hours. Five individual rats were determined to have an internal mean benzene uptake rate of 152ml/min prior to conducting the six hour test and an mean pretest respiratory minute volume of 145ml/min. The mean benzene uptake rates as compared to pretest values for rats decreased to 33, 22 and 9% of the mean test value 1, 3 and 6 hours after administration, respectively. The mean minute volume for rats decreased to 85, 78 and 66% of the pretest at 1, 3 and 6 hours after administration, respectively. Rats had an estimated retained dose of 56mg/kg. Mice (5/group) had a mean total pretest benzene uptake rate of 188ml/min and a mean pretest total respiratory minute volume of 189ml/min. The mean total benzene uptake for the mice decreased 65, 76 and 81% of the pretest value, after 1, 3 and 6 hours of exposure, respectively. The mean total minute volume for groups of mice decreased 96, 84 and 69% of the pretest after 1, 3 and 6 hours, respectively. The mean total retained dose per mice was estimated to be 377mg/kg. [R202] ?The dermal absorption of benzene vapor was examined in 2 Rhesus monkeys exposed to the test article at saturated concentrations for 30 minutes using a hydration controlled chamber which was held tightly against the skin of the back. The radioactivity measured in the urine was used to determined absorption rate. A correction factor was included to account for radioactivity excreted by other routes. Under the 2 skin conditions, of 40% hydration and 100% hydration, the absorption rates were determined to be 0.02 microliter/sq cm and .15 microliter/sq cm, respectively. Total absorption was found to be 7.5-fold higher from a 100% relative humidity environment than from a 40% relative humidity environment. In a benzene liquid exposure experiment, the concentration of benzene was given by its density of 0.8787 gm/cu cm and the dermal absorption was 5.4 microliter/sq cm. The authors suggested that benzene absorption from the liquid state was less than expected due to a dehydrating effect on the stratum corneum. [R203] POPL: *INDIVIDUALS WITH G6PD /GLUCOSE 6-PHOSPHATE DEHYDROGENASE/ DEFICIENCY HAVE ... BEEN FOUND TO BE MORE SUSCEPTIBLE TO HEMOLYTIC EFFECTS OF ... BENZENE ... [R204] *... /It has been observed/ that levels of leukocyte agglutins were elevated in selected individuals exposed to benzene. ... /This/ suggested that in some people benzene toxicity may be accounted for in part by an allergic blood dyscrasia. [R205] *... Workers with higher activities of /cytochrome P-450(2E1)/ are at more risk /of benzene hematoxicity/. [R206] *... It has been suggested that Thalassemia minor, and presumably other disorders in which there is increased bone marrow turnover, may predispose a person to benzene-induced aplastic anemia. [R206] *People living near hazardous waste sites who are chronically exposed to contaminated air, water, or soil may be at a higher risk for respiratory effects from exposure to /benzene/ ... [R207] ADE: *BENZENE IS READILY ABSORBED VIA LUNG, AND ABOUT 40-50% IS RETAINED. ... IT IS TAKEN UP PREFERENTIALLY BY FATTY AND NERVOUS TISSUES, AND ABOUT 30-50% ... IS EXCRETED UNCHANGED VIA LUNG; A 3-PHASE EXCRETION PATTERN IS SEEN AT ... /APPROX/ 0.7-1.7 HR, 3-4 HR, and 20-30 HR. [R208] *When benzene was placed on skin under closed cup it was absorbed at rate of 0.4 mg/sq cm/hr (Hanke et al 1961) ... [R205] *MICE TREATED SC WITH 2 ML (3)H-LABELED BENZENE/KG CONTAINED IRREVERSIBLY BOUND RADIOACTIVITY WITH DECREASING BINDING MAGNITUDE IN THE FOLLOWING ORGANS: LIVER, BRAIN, KIDNEY, SPLEEN, FAT. MICE TREATED WITH 2 DAILY SC DOSES OF 0.5 ML (3)H-BENZENE/KG FOR 1-10 DAYS SHOWED A RADIOACTIVITY BINDING WITH LIVER AND BONE MARROW RESIDUES WHICH INCREASED WITH TREATMENT DURATION, EXCEPT IN THE CASE OF BINDING TO BONE MARROW WHICH DECREASED AFTER DAY 6. [R209] *When administered to mice subcutaneously, 72% of dose is recovered in expired air. [R210] *Rats were exposed to 500 ppm benzene for 30 min to eight hr. Benzene concentrations reached steady state within four hr in blood (steady-state concn= 11.5 ug/g), six hr in fat (concn= 164.4 ug/g), and two hr in bone marrow (concn= 37.0 ug/g). Lesser concn were detected in the kidney, lung, liver, brain, and spleen. [R211] *Benzene is absorbed from the gastrointestinal tract when ingested. [R212] *BENZENE CROSSES THE HUMAN PLACENTA, AND LEVELS IN CORD BLOOD ARE SIMILAR TO THOSE IN MATERNAL BLOOD. ... THE MOST FREQUENT ROUTE BY WHICH HUMANS ARE EXPOSED TO BENZENE IS VIA INHALATION. TOXIC EFFECTS IN HUMANS HAVE BEEN ATTRIBUTED TO COMBINED EXPOSURE BY BOTH RESPIRATION AND THROUGH THE SKIN ... IT IS ELIMINATED UNCHANGED IN EXPIRED AIR ... IN MEN AND WOMEN EXPOSED TO 52-62 PPM (166-198 MG/CU M) BENZENE FOR 4 HR, A MEAN OF 46.9% WAS TAKEN UP, 30.2% WAS RETAINED AND THE REMAINING 16.8% EXCRETED AS UNCHANGED BENZENE IN EXPIRED AIR. ... WHEN HUMANS WERE EXPOSED TO 100 PPM (300 MG/CU M) BENZENE, IT WAS DETECTED IN EXPIRED AIR 24 HR LATER, SUGGESTING THAT IT IS POSSIBLE TO BACK-EXTRAPOLATE TO THE BENZENE CONCENTRATION IN THE INSPIRED AIR. [R205] *... In female and male rats with large body fat content, benzene was eliminated more slowly and stored longer than in lean animals. ... Distribution in rabbit was highest in adipose tissue, high for bone marrow, and lower for brain, heart, kidney, lung, and muscle, although direct binding was higher in liver than in bone marrow. [R66, 1323] *The solubility characteristics of benzene are such that it is easily taken up by the stratum corneum. Once in the stratum corneum, it does not meet many restraining forces to impede its movement and diffuses easily. The permeability constant for benzene, as determined in vitro, is higher than that of many other small molecules, particularly those having one or more polar groups. ... Even though these uncertainties exist, and more data are needed to support the ... conclusion that there is good overall agreement between in vitro and in vivo data. ... An adult working in ambient air containing 10 ppm of benzene, with 100 cm of glaborous skin in contact with gasoline containing 5% benzene, and his entire skin (2 sq m) in contact with ambient air, will absorb in an hr, 7.5 ul of benzene from inhalation, 7.0 ul from contact with gasoline, and 1.5 ul from body exposure to ambient air. Since ... in vitro techniques measure the penetration of benzene through strongly hydrated stratum corneum, the calculated flux may be higher than under some in vivo conditions. Nevertheless, it seems that unless good hygiene is maintained and care is taken to prevent lengthy exposure to solvents containing benzene, significant amounts of benzene may enter the body through the skin. [R213] *Subjects who inhaled concentrations of 340 mg/cu m (106 ppm) benzene in air for 5 hr excreted 29% as phenol, 3% as catechol and 1% as hydroquinone in the urine, mostly as ethereal sulfates. Most of the phenol and catechol was excreted within 24 hr, and the hydroquinone within 48 hr. [R205] *In men and women exposed to 52-62 ppm (166-198 mg/cu m) benzene for 4 hr, a mean of 46.9% was taken up, 30.2% was retained and the remaining 16.8% excreted as unchanged benzene in expired air. [R205] *In animals, expired air is the main route of elimination of unmetabolized benzene, while urine is the major route of excretion of benzene metabolites (with very little fecal excretion). [R214] *In a series of experiments conducted in a single-family residence from June 11 to 13, 1991, exposure to benzene through contaminated residential water was monitored. The residential water was contaminated with benzene and other hydrocarbons in 1986. Exposure was monitored for a person taking a 20-min shower and for people in other parts of the house during and after the shower. An average dermal dose of 168 ug was calculated for a 20-min shower using this water. The total benzene dose resulting from the shower was estimated to be approximately 281 ug (40% via inhalation, 60% via dermal), suggesting a higher potential exposure to benzene via dermal contact from the water than through vaporization and inhalation. This exposure was 2-3.5 times higher than the mean 6-hr inhalation dose received by the sampling team members in other parts of the house. [R215] *In Sprague-Dawley rats administered a single dose of 0.15, 1.5, 15, 150, or 500 mg/kg of 14C-benzene by gavage, benzene was rapidly absorbed and distributed to various organs and tissues within 1 hr of administration. One hour after rats were dosed with 0.15 or 1.5 mg/kg of benzene, tissue distribution of benzene was highest in liver and kidney, intermediate in blood, and lowest in the Zymbal gland, nasal cavity tissue, and mammary gland. At higher doses, beginning with 15 mg/kg, benzene disproportionately increased in the mammary glands and bone marrow. Bone marrow and adipose tissue proved to be depots of benzene at the higher dose levels. The highest tissue concentrations of benzene's metabolite hydroquinone 1 hr after administration of 15 mg/kg of benzene were in the liver, kidney, and blood, while the highest concentrations of the metabolite phenol were in the oral cavity, nasal cavity, and kidney. The major tissue sites of benzene's conjugated metabolites were blood, bone marrow, oral cavity, kidney, and liver for phenyl sulfate and hydroquinone glucuronide; muconic acid was also found in these sites. Additionally, the Zymbal gland and nasal cavity were depots for phenyl glucuronide, another conjugated metabolite of benzene. The Zymbal gland is a specialized sebaceous gland and a site for benzene-induced tumors. Therefore, it is reasonable to expect that lipophilic chemicals like benzene would partition readily into this gland. However, benzene did not accumulate in the Zymbal gland; within 24 hr after administration, radiolabel derived from 14C-benzene in the Zymbal gland constituted less than 0.0001% of the administered dose. [R216] *Monkeys were dosed intraperitoneally with 5-500 mg/kg radiolabeled benzene, and urinary metabolites were examined. The proportion of radioactivity excreted in the urine decreased with increasing dose, whereas the dose increased, more benzene was exhaled unchanged. This indicated saturation of benzene metabolism at higher doses. Phenyl sulfate was the major urinary metabolite. Hydroquinone conjugates and muconic acid in the urine decreased as the dose increased. [R217] METB: *... In human system /benzene/ is metabolized through a variety of major and minor pathways. The primary site of action is liver, where benzene is oxidized to phenol (hydroxybenzene), catechol (1,2-dihydroxybenzene), or quinol (1,4-dihydroxybenzene). Phenol is subsequently conjugated with inorganic sulfate to phenylsulfate, the other hydroxybenzenes are conjugated to a lesser extent, and all excreted in urine. Minor pathways incl further oxidation of catechol to hydroxyhydroquinol (1,2,4-trihydroxybenzene) or catabolism to cis, cis- or trans, trans-muconic acids, and phenol conjugation with glucuronic acid to form glucuronides, or with cysteine to produce 2-phenylmercapturic acid. [R66, 1320] *METABOLIC PRODUCTS IN RAT ... ARE PHENOL, HYDROQUINONE, CATECHOL, HYDROXYHYDROQUINONE, AND PHENYLMERCAPTURIC ACID. CONJUGATED PHENOLS HAVE BEEN REPORTED ... EXCEPT FOR A SMALL AMT OF FREE PHENOL, ALL THE PHENOLIC METABOLITES WERE EXCRETED IN CONJUGATED FORM. WHEN (3)H-BENZENE WAS ADMIN TO MICE, (3)H2O WAS ALSO RECOVERED FROM URINE. [R148, 688] *YIELDS N-ACETYL-S-PHENYL-CYSTEINE IN RAT. YIELDS BENZYL ALCOHOL IN GUINEA PIGS. ... YIELDS CIS-1,2-DIHYDRO-1,2-DIHYDROXYBENZENE IN PSEUDOMONAS. PHENOL IN PSEUDOMONAS AND ACHROMOBACTER. YIELDS CIS,CIS-MUCONIC ACID IN RABBIT. /FROM TABLE/ [R218] *In the rabbit, the major hydroxylation product of benzene was phenol, which along with some catechol and hydroquinone, was found in the urine conjugated with ethereal sulfate or glucuronic acid. [R219] *Unconjugated phenol has been found in mouse and rat urine after benzene administration. [R219] *The formation of benzene oxide, an epoxide of benzene is involved in the metabolism of benzene. This highly unstable intermediate rearranges non-enzymatically to form phenol. This step accounts for the occurrence of phenol as the major metabolite of benzene in urine. Catechol formation is thought to result from the hydration of benzene oxide by the enzyme epoxide hydratase followed by oxidation to catechol. It appears that catechol and phenol are formed by two distinctly different metabolic pathways. Hydroquinone is thought to result from a second passage of phenol through the mixed function oxidases. [R220] *The metabolism of benzene in vitro can be altered by the use of enzyme inducers administered to animals prior to sacrifice or by the addition of inhibitors to the mixtures. Benzene, phenobarbital, 3-methylcholanthrene and dimethyl sulfoxide are all microsomal stimulants for the metabolism of benzene. Benzene metabolism in vitro can be inhibited by carbon monoxide, aniline, metyrapone, SKF-525A /proadifen/, aminopyrine, cytochrome c, aminotriazole, or toluene. [R221] *Benzene, when administered sc at 880 mg/kg twice daily for 3 days, decreased erythropoiesis much more markedly in DBA/2 mice than in C57BL/6 mice. Total urinary benzene metabolites and the % of the dose excreted in the urine were the same in both strains. Although the metabolic profile differed between the two strains, it was very similar when equitoxic doses of benzene were administered. The levels of both free and covalently bound benzene were higher in all organs of the DBA/2 mice. Phenol, hydroquinone, resorcinol, and catechol had no effect on erythopoiesis. [R222] *The urinary metabolites isolated by DEAE Sephadex A-24 anion-exchange chromatography from mice treated with radiolabeled benzene included phenol as the major component, as well as catechol, hydroquinone, and phenylmercapturic acid. The phenolic metabolites were excreted primarily as glucronides with the exception of a small amount of free phenol. [R223] *Benzene reduced the incorporation of (59)Fe into red cells by 75% at the higher dose when administered at 440 or 880 mg/kg to mice pretreated with (59)Fe 48 hr earlier. However, when toluene was administered simultaneously with benzene in a ratio of 2:1, the depression of (59)Fe uptake was prevented. Toluene reduced the appearance of benzene metabolites to 45% of controls at the higher dose and 30% at the lower dose. Thus toluene appears to inhibit benzene metabolism and by so doing, alleviates its toxicity. [R224] *A sensitive high performance liquid chromatography method is described which separates urinary metabolites from benzene-treated male CD-1 mice. Phenol, trans, trans-muconic acid and quino in the 48 hr urine, accounted, respectively for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the orally administered single dose of benzene (880, 440, and 220 mg/kg body wt). Catechol occurred in trace amounts. Trans, trans-muconic acid was identified and was unique to benzene as none was detected in urine of mice dosed orally with phenol, catechol, or quinol. The potential existence of a toxic metabolite in the form of an aldehyde precursor of muconic acid in vivo is discussed. [R225] *In humans, phenol sulfate is the major metabolite of benzene until 400 mg/l levels are reached in the urine. Beyond than level, glucuronide conjugates are also present in the urine. [R65] *Male Wistar rats were tested to determine the effect of enzymes with different kinetic characteristics on the metabolism of benzene, in vitro. Kinetic analysis of the enzymes in the liver of rats fed a normal diet revealed the presence of two benzene hydroxylases with low Michaelis constant values of 0.01 millimolar and 0.07 millimolar, respectively. After 1 day of food deprivation, the isozyme with a constant equal to 0.01 millimolar disappeared while the activity of the second isozyme increased. Following the administration of phenobarbital there was evidence of a third benzene metabolizing enzyme in the liver of the animals exposed to benzene in concentrations ranging from 0.0055 to 6.25 millimolar, in vitro; the value of the Michaelis constant for this enzyme was equal to 4.5 millimolar and was not evident in control animals. Treatment with phenobarbital failed to affect the activity of the other low Michaelis constants of benzene hydroxylases identified in the liver of normal rats. Treatment with ethanol resulted in significant increase in the activity of both normally occurring benzene hydroxylases in the normal liver. [R226] *Mitoplasts (mitochondria with the outer membrane removed) from the bone marrow of rabbits were incubated sequentially with (3)H-labeled deoxyguanosine triphosphate and (14)C-labeled benzene to study the DNA adducts formed from benzene metabolites in mitochondria. Following isolation and isopycnic density gradient centrifugation in CsCl, the doubly labeled DNA was hydrolyzed to deoxynucleosides and separated on a Sephadex LH 20 column. At least seven deoxyguanosine adducts and one deoxyadenine adduct were present. [R227] *Primary metabolism of benzene occurs predominantly in the liver via cytochrome P-450, the principal product being phenol. Phenol, in turn, undergoes further oxidation via cytochrome P-450 to produce the polyphenolic metabolites of benzene (principally hydroquinone), or alternatively, oxidation via peroxidases in extrahepatic tissues to form biphenols, hydroquinone, and its terminal oxidation product, p-benzoquinone. Muconic acid /is/ ... a minor urinary metabolite of benzene ... [R142, 726] *... Literature identifies the following metabolites after incubation of benzene with mouse liver microsomes: phenol, hydroquinone, trans,trans-muconaldehyde, 6-oxo-trans,trans-2,4-hexadienoic acid, 6-hydroxy-trans,trans,2-4,-hexadienal, and 6-hydroxy-trans,trans-2,4-hexadienoic acid. Beta-hydroxymuconaldehyde, a new metabolite, was also identified. [R228] *Data produced in vitro by mouse and rat liver microsomes ... indicate species differences in benzene metabolism. Quantitation of metabolites from the microsomal metabolism of benzene indicated that after 45 min, mouse liver microsomes from male B6C3F1 mice had converted 20% of the benzene to phenol, 31% to hydroquinone, and 2% to catechol. In contrast, rat liver microsomes from male Fischer 344 rats converted 23% to phenol, 8% to hydroquinone, and 0.5% to catechol. Mouse liver microsomes continued to produce hydroquinone and catechol for 90 min, whereas rat liver microsomes had ceased production of these metabolites by 90 min. Muconic acid production by mouse liver microsomes was < 0.04 and < 0.2% from phenol and benzene, respectively, after 90 min. [R229] *Subjects who inhaled concentrations of 340 mg/cu m (106 ppm) benzene in air for 5 hr excreted 29% as phenol, 3% as catechol and 1% as hydroquinone in the urine, mostly as ethereal sulfates. [R205] BHL: *The excretion of unchanged benzene from the lung of rats was reported to be biphasic, suggesting a two-compartment model for distribution and a half-life of 0.7 hr. This agreed with experimental half-life values for various tissues that ranged from 0.4 to 1.6 hr. [R230] *... The half-time of benzene in /high lipid content/ tissues is approximately 24 hours. [R231, 146] ACTN: *COVALENT INTERACTION OF A BENZENE METABOLITE WITH DNA WAS SHOWN IN VIVO, BUT NO INFORMATION WAS GIVEN ABOUT THE CHEM NATURE OF THIS METABOLITE. A LIKELY INTERMEDIATE IN BENZENE METABOLISM IS BENZENE OXIDE. IN NEUTRAL AQ MEDIA IT REARRANGES ONLY SLOWLY TO THE PHENOL SO THAT ITS LIFETIME COULD BE LONG ENOUGH FOR DIFFUSION FROM THE SITE OF ACTIVATION TO THE DNA. ALTERNATIVELY, THE METABOLIC APPEARANCE OF POLYHYDROXY DERIVATIVES SUGGESTS THE FORMATION OF A PHENOL EPOXIDE, SO THAT THE REACTIVE MOLECULE COULD BE A SECONDARY METABOLITE. [R232] *THE AVAILABLE EVIDENCE SUPPORTS THE CONCEPT THAT BENZENE TOXICITY IS CAUSED BY ONE OR MORE METABOLITES OF BENZENE. ... BENZENE METABOLITES CONTAINING 2 OR 3 HYDROXYL GROUPS INHIBITED MITOSIS. TOLUENE, WHICH INHIBITS BENZENE METABOLISM, PROTECTED ANIMALS AGAINST BENZENE-INDUCED MYELOTOXICITY. BENZENE TOXICITY COULD BE CORRELATED WITH THE APPEARANCE OF BENZENE METABOLITES IN BONE MARROW. ALTHOUGH IT IS CLEAR THAT BENZENE CAN BE METABOLIZED IN BONE MARROW, THE OBSERVATION THAT PARTIAL HEPATECTOMY PROTECTS AGAINST BENZENE TOXICITY SUGGESTS THAT A METABOLITE FORMED IN LIVER IS ESSENTIAL FOR BENZENE TOXICITY. [R233] *... IMPORTANCE OF POLYHYDROXYLATED DERIVATIVES OF BENZENE AND THEIR SEMIQUINONES. ... /IT HAS BEEN/ SHOWN THAT HYDROQUINONE INHIBITS RAT BRAIN MICROTUBULE POLYMERIZATION; THAT HYDROQUINONE AND PARA-BENZOQUINONE ARE THE MOST POTENT INHIBITORS OF T- AND B-LYMPHOCYTE FUNCTION, AS MEASURED IN MOUSE SPLEEN CELLS IN CULTURE; THAT HYDROQUINONE INHIBITS LECTIN-STIMULATED LYMPHOCYTE AGGLUTINATION IN RAT SPLEEN PREPN IN VITRO; AND THAT PARA-BENZOQUINONE IS THE METABOLITE MOST LIKELY TO BE RESPONSIBLE FOR SUPPRESSION OF LYMPHOCYTE TRANSFORMATION AND MICROTUBULE ASSEMBLY IN RAT SPLEEN CELLS IN CULTURE. HOWEVER, ADMIN OF THESE CMPD TO ANIMALS DOES NOT PRODUCE THE TYPICAL PICTURE OF BENZENE TOXICITY ... ADMIN /OF/ MAJOR METABOLITES OF BENZENE TO MICE ... FAILED TO ... DECR ... RED BLOOD CELL PRODUCTION, USING THE (59)FE UPTAKE TECHNIQUE ... /IT'S BEEN/ SUGGESTED THAT RING-OPENING PRODUCTS MAY PLAY A ROLE IN BENZENE TOXICITY. ... IN MICE BENZENE TREATMENT SUPPRESSED SUBSEQUENT COLONY FORMING UNIT-C FORMATION FROM BONE-MARROW CELLS IN VITRO. TREATING THE ANIMALS WITH PHENOL, HYDROQUINONE OR BENZENE DIHYDRODIOL FAILED TO SUPPRESS COLONY FORMING UNIT-C. THUS, THE TOXIC METABOLITES OF BENZENE HAVE YET TO BE IDENTIFIED. [R233] *... RADIOACTIVITY /HAS BEEN DEMONSTRATED/ IN A NUCLEIC ACID FRACTION FROM RAT LIVER FOLLOWING ADMIN OF EITHER (3)H- OR (14)C-LABELLED BENZENE. IT HAS BEEN SHOWN THAT BENZENE BINDS COVALENTLY TO PROTEIN IN LIVER, BONE MARROW, KIDNEY, LUNG, SPLEEN, BLOOD, AND MUSCLE. LESS COVALENT BINDING WAS OBSERVED TO THE PROTEIN OF BONE MARROW, BLOOD, AND SPLEEN OF C57BL/6 MICE, WHICH ARE MORE RESISTANT TO THE BENZENE-INDUCED EFFECTS ON RED CELL PRODUCTION, THAN TO THAT OF SENSITIVE DBA/2 MICE. ... COVALENT BINDING OF BENZENE TO PROTEIN IN PERFUSED BONE-MARROW PREPN /HAS BEEN DEMONSTRATED/. ... A METABOLITE OF PHENOL BINDS TO LIVER PROTEIN MORE EFFICIENTLY THAN DOES BENZENE OXIDE, AND THEY HAVE ELECTROPHORETICALLY SEPARATED HEPATIC PROTEINS TO WHICH BENZENE PREFERENTIALLY BINDS. ... COVALENT BINDING TO MITOCHONDRIA IS A PROMINENT FEATURE OF BENZENE METABOLISM. ... THERE IS RELATIVELY MORE RADIOACTIVITY IN A NUCLEIC ACID-RICH FRACTION OF A BENZENE METABOLITE ISOLATED FROM MOUSE BONE-MARROW CELLS THAN IN A SIMILAR FRACTION FROM LIVER. [R233] *EVIDENCE INDICATES THAT BENZENE MUST BE METABOLICALLY ACTIVATED IN ORDER TO EXERT ITS CHARACTERISTIC TOXICITY ON BONE MARROW. SOME OF THE HYDROXYLATED BENZENE METABOLITES, PHENOL, CATECHOL, HYDROQUINONE, RESORCINOL AND SOME TRIHYDROXYLATED DERIVATIVES IN URINE OF RABBITS ARE SUGGESTED TO BE THE TOXIC METABOLITES. [R234] *THE MECHANISM OF BENZENE OXYGENATION IN LIVER MICROSOMES AND IN RECONSTITUTED ENZYME SYSTEMS FROM RABBIT LIVER WAS INVESTIGATED. THE RESULTS INDICATE THAT THE MICROSOMAL CYTOCHROME P450 DEPENDENT OXIDATION OF BENZENE IS MEDIATED BY HYDROXYL RADICALS FORMED IN A MODIFIED HABER-WEISS REACTION BETWEEN HYDROGEN PEROXIDE AND SUPEROXIDE ANIONS AND SUGGEST THAT ANY CELLULAR SUPEROXIDE-GENERATING SYSTEM MAY BE SUFFICIENT FOR THE METABOLIC ACTIVATION OF BENZENE AND STRUCTURALLY RELATED COMPOUNDS. [R235] *Animal expt show that benzene sensitizes the myocardium to epinephrine, so that the endogenous hormone may precipitate sudden and fatal ventricular fibrillation. [R11] *The protective effects of pyridine and xylene against benzene, benzo(a)pyrene, or cyclophosphamide clastogenicity were studied in mice. Swiss-ICR mice were treated orally with 220 to 880 mg/kg benzene, 150 mg/kg benzo(a)pyrene, or intraperitoneally with 50 mg/kg cyclophosphamide with or without 0 to 500 mg/kg pyridine or xylene. The mice were killed 24 to 72 hours later and the femurs were removed. The bone marrow was isolated and assayed for micronuclei. Xylene inhibited the induction of micronuclei of benzene only when given at an equimolar dose or greater. No delay in the peak micronuclei response was seen. Pyridine at 60 mg/kg completely blocked the induction of micronuclei by 880 mg/kg benzene of 24 hours. Pyridine at 25 mg/kg completely blocked the clastogenic effect of 440 mg/kg benzene at 36 to 76 hours and partially blocked micronuclei induction at 24 hours. The clastogenicity of benzo(a)pyrene was inhibited by pyridine only at doses of 100 mg/kg or more. Pyridine showed no protective effect against micronuclei induction by cyclophosphamide at any concn; micronuclei formation was enhanced by 60 to 260 mg/kg pyridine. Since the results suggested that the biological activation of benzene was due to different cytochrome p450 isozymes than the ones activating benzo(a)pyrene or cyclophosphamide, DBA/2 mice (aryl hydrocarbon hydrolase noninducible) and C57B1/6 mice with or without pretreatment with methylcholanthrene were dosed once or three times with benzene and the effects on bone marrow micronuclei were examined as before. Micronuclei formation was greater in DBA/2 mice. The effect was potentiated by methylcholanthrene. The cytochrome p450 isozyme involved in activating benzene is one of the enzymes induced by methylcholanthrene, independent of the high affinity aryl hydrocarbon hydrolase receptor. [R236] INTC: *DMSO pretreatment enhances benzene metabolism and toxicity in male Wistar rats. [R190] *BENZENE AND ETHANOL INDUCED A COMMON CYTOCHROME P450 SPECIES IN RABBIT LIVER SPECIFICALLY EFFECTIVE IN HYDROXYL RADICAL-MEDIATED OXYGENATION OF ETHANOL. BENZENE OXIDATION BY THE BENZENE-INDUCIBLE FORM OF CYTOCHROME P450 WAS ALMOST COMPLETELY INHIBITED BY CATALASE, SUPEROXIDE DISMUTASE, DMSO, AND MANNITOL. [R237] *Simultaneous treatments with both benzene and toluene, or benzene and piperonyl butoxide, increased the excretion of unchanged benzene in the expired air. These compounds apparently act by inhibiting benzene metabolism. [R238] *Toluene, Aroclor 1254, phenobarbital, acetone, and ethanol are known to alter the metabolism and toxicity of benzene. [R239] *SKF-525A inhibited benzene metabolism in the rat. Injection of 80 mg/kg of SKF-525A in rats resulted in a depression of phenol excretion. It also prolonged phenol excretion and interfered in the conversion of benzene to glucuronides and free phenols. [R240] *Carbon monoxide, aniline, aminopyrine, cytochrome C, and metyrapone inhibited benzene metabolism in vitro by mouse liver microsomes. [R241] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *Benzene exposure is rapidly fatal at concentrations approaching 20,000 ppm. [R142, 724] *... Probable human oral lethal dose would be between 50-500 mg/kg. Human inhalation of approximately 20,000 ppm (2% in air) was fatal in 5-10 min. [R177, p. BENZENE-8] *Estimated oral doses from 9-30 g have proved fatal. [R242] THER: *MEDICATION (VET): HAS BEEN USED AS A DISINFECTANT. /FORMER USE/ [R3, 179] WARN: *Protected intercourse may be prudent following high exposure to benzene. As well, nursing mothers may be advised to discontinue nursing for 5 days following high exposure. [R231, 712] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Benzene's production, existence in gasoline, and use in the production of ethylbenzene and styrene as well as many other chemicals may result in its release to the environment through various waste streams. Benzene is found in volcanoes, as a constituent of crude oil, from forest fires, and as a plant volatile. If released to air, a vapor pressure of 94.8 mm Hg at 25 deg C indicates benzene will exist solely as a vapor in the ambient atmosphere. Vapor-phase benzene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 13 days. Vapor-phase benzene is also degraded by ozone radicals and nitrate found in the atmosphere but at such low rates as to not be important. Since benzene is very water soluble, it may be removed from the atmosphere by rain. If released to soil, benzene is expected to have high mobility based upon a Koc of 85. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 5.56X10-3 atm-cu m/mole. Benzene may volatilize from dry soil surfaces based upon its vapor pressure. Benzene is expected to biodegrade in soils based on a biodegradation study in a base-rich para-brownish soil where 20 ppm benzene was 24% degraded in 1 week, 44% in 5 weeks, and 47% in 10 weeks. If released into water, benzene is not expected to adsorb to sediment and suspended solids in water based upon the Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hr and 3.5 days, respectively. Biodegradation of benzene in water is expected based on an experiment using an enriched aerobic bacterial culture in which benzene began to degrade 12 hrs after incubation in an aqueous (soil-free) solution with 50% of benzene degrading after 60 hrs and almost complete degradation within 90 hrs. In aqueous solution, benzene will react with hydroxyl radical (OH radical ave concn = 1.0X10-17 molec/cu cm) at a reaction rate of 7.8X10+9 L/mol sec which results in an estimated half-life of 103 days. A BCF ranging from 1.1-20 suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to benzene may occur through inhalation and dermal contact with this compound at workplaces where benzene is produced or used. The general population may be exposed to benzene via inhalation of ambient air, ingestion of drinking water, and dermal contact with gasoline products containing benzene. Benzene is widely detected in atmospheric samples due to its presence in gasoline. (SRC) NATS: *... Benzene has been reported to be a natural constituent of fruits, vegetables, meats, and dairy products with concentrations ranging from 2 ug/kg in canned beef to 2100 ug/kg for eggs. [R142, 724] *Benzene is found naturally in the environment from volcanoes, as a natural constituent of crude oil, from forest fires and as a plant volatile(1,2). Benzene concns range from 100-200 parts per trillion over the Pacific and Atlantic Oceans due to seepage and spillage of oil into the oceans(3). [R243] ARTS: *Benzene enters the environment from production, storage, transport, venting, and combustion of gasoline; and from production, storage, and transport of benzene itself. Other sources result from its use as an intermediate in the production of other chemicals, and as a solvent, from spills, including oil spills; from its indirect production in coke ovens; from nonferrous metal manufacture, ore mining, wood processing, coal mining and textile manufacture, and from cigarette smoke(1,2). [R244] *Benzene's production and use in the production of ethylbenzene/styrene (53%), cumene/phenol (22%), cyclohexane (12%), nitrobenzene/aniline (5%), detergent alkylate (3%), chlorobenzenes and other products (5%) may result in its release to the environment through various waste streams(SRC). Benzene has been detected in cigarette smoke ranging from 47-64 ppm(2). The world wide release of benzene into the environment is estimated to be 4-5 Tg/yr with 0.6 Tg/yr coming from the United States alone(3). Leachate from landfills is also a source of benzene in the environment(4). [R245] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 85(2), indicates that benzene is expected to have high mobility in soil(SRC). Volatilization of benzene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 5.56X10-3 atm-cu m/mole(3). The potential for volatilization of benzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 94.8 mm Hg(4). Benzene is expected to biodegrade in soils based on a biodegradation study in a base-rich para-brownish soil where 20 ppm benzene was 24% degraded in 1 week, 44% in 5 weeks, and 47% in 10 weeks(5). Anaerobic degradation of benzene in soil is not expected to be an important loss process based on various studies(6,7). In one study of chemical biotransformation under nitrate- and sulfate-reducing conditions, benzene was found to be stable for 60 days(6). In a related study, benzene did not undergo biodegradation in situ nor in laboratory controlled soil samples under denitrifying conditions(7). [R246] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 85(2), indicates that benzene is not expected to adsorb to sediment and suspended solids in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 5.56X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1 hr and 3.5 days, respectively(SRC). Anaerobic degradation of benzene in water is not expected to be an important loss process based on various studies(5). In one study of chemical biotransformation under nitrate- and sulfate-reducing conditions, benzene was found to be stable for 60 days(5). In aqueous solution, benzene will react with hydroxyl radical at a reaction rate of 7.8X10+9 L/mol sec; using the average OH radical concentration (1.0X10-17 molec/cu cm), benzene would have a half-life of 103 days(6). According to a classification scheme(7), a BCF ranging from 1.1-20(8) suggests the potential for bioconcentration in aquatic organisms is low. [R247] *AQUATIC FATE: Evaporation was the primary loss mechanism in winter in a mesocosm experiment which simulated a northern bay where the half-life was 13 days(1). In spring and summer the half-lives were 23 and 3.1 days, respectively(1). In these cases biodegradation plays a major role and takes about 2 days(1). However, acclimation is critical and this takes much longer in the colder water in spring(1). According to one experiment, benzene has a half-life of 17 days due to photodegradation(2) which could contribute to benzene's removal. In situations of cold water, poor nutrients, or other conditions less conducive to microbial growth, photolysis will play a important role in degradation(SRC). The half-life of benzene in sea water is about 5 hrs(3) based on its high Henry's Law constant of 5.56X10-3 atm-cu m/mole(4). [R248] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), benzene, which has a vapor pressure of 94.8 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase benzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 13 days(SRC), calculated from its rate constant of 1.23X10-12 cu cm/molecule-sec at 25 deg C(3). The half-life in polluted atmospheres which contain nitrogen oxides or sulfur dioxide has been observed to shorten to 4-6 hrs(4). Vapor-phase benzene is also degraded in the atmosphere by atmospheric ozone radicals at an extremely slow rate; the half-life for this reaction in air is estimated to be 170,000 days(5). The reaction rate of benzene with nitrate radical in the atmosphere is estimated to be less than 0.3X10-16 cu cm/molecule sec at 25 deg C(3); the half-life for this reaction in air is estimated to be greater than or equal to 111 days based on an average concentration of nitrate radicals of 2.4X10+8 molec/cu cm(6). Benzene has a maximum absorbance frequency of 253 nm suggesting that direct photolysis will not be an important degradation process(7). Due to benzene's high water solubility, it may be removed from the atmosphere by rainfall(8). [R249] BIOD: *No degradation of benzene as measured by BOD was reported in coarse-filtered (through 1 cm cotton layer) Superior harbor water incubated at 21 deg C for 12 days(1). Biodegradation half-lives of 28 and 16 days were reported in die-away tests for degradation of up to 3.2 ul/l benzene using groundwater and water from Lester River, Minnesota, respectively, under aerobic conditions(2). The half-life in estuarine water was 6 days as measured by radiolabeled C02 produced(3). In a base-rich para-brownish soil, 20 ppm benzene was 24% degraded in 1 week, 44% in 5 weeks, and 47% in 10 weeks(4). In a marine ecosystem biodegradation occurred in 2 days after an acclimation period of 2 days and 2 weeks in the summer and spring, respectively, whereas no degradation occurred in winter(5). [R250] *Benzene, in a mixture with toluene and xylenes, is readily biodegraded (total degradation of 7.5 ppm total mixture) in shallow ground water in the presence of oxygen in the unconfined sand aquifer at Canada Forces' Base Borden, Ontario; laboratory batch experiments demonstrated that the degradation could be attributed to biodegradation(1). Complete biodegradation in 16 days was reported under simulated aerobic groundwater conditions at 20 deg C(2). Reported metabolites of benzene using pure cultures of microorganisms include phenol and unidentified phenols(3), catechol and cis-1,2-dihydroxy-1,2-dihydrobenzene(4). [R251] *Benzene at 50 ppm was 90% degraded by industrial wastewater seed incubated at 23 deg C for 6 hrs(1). Benzene inhibited industrial seed at concn of 100 ppm and above and municipal seed at 50 ppm and above(1). In a bench scale activated-sludge reactor with an 8 hour retention time, complete degradation occurred with 0.5% of the benzene being lost by air stripping(2). In laboratory systems, low concentrations of benzene are degraded in 6-14 days(3,4). 44-100% removal occurred at a sewage treatment plant; percentage by evaporation and biodegradation were not determined(5). [R252] *AEROBIC: Benzene present at 100 mg/l, reached 39-41% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). Benzene reached 24% of its theoretical oxygen demand in a non-acclimated microbial population after 15 days(2). Benzene is metabolized by the avocado fruit and grapes to carbon dioxide(3). Aerobic biodegradation of benzene was studied in pre-equilibrated soil-water slurry microcosms(4). Using an enriched aerobic bacterial culture, benzene began to degrade 12 hrs after incubation in an aqueous(soil-free) solution with 50% of benzene degrading after 60 hrs and almost complete degradation within 90 hrs(4). Using a pre-equilibrated soil-water slurry microcosm, benzene did not begin to degrade until 3 days after application and reached complete degradation after about 12 days(4). The decrease in biodegradation is based on benzene's sorption to soil and organic particles(4). [R253] *ANAEROBIC: Benzene was degraded under methanogenic conditions in an enrichment culture fed ferulic acid for five years. It was also degraded under sulfate-reducing conditions in microcosms containing benzene-contaminated aquifer sediment(1). The biotransformation of benzene in aquifer sediment down gradient of the Wilder's Grove sanitary landfill near Raleigh, NC U.S.A. was studied under anaerobic conditions(1). According to the study, benzene was not found to biodegrade(1). In a study of chemical biotransformation under nitrate- and sulfate-reducing conditions, benzene was found to be stable under these anaerobic conditions for 60 days(2). In a related study, benzene did not undergo biodegradation in situ nor in laboratory controlled soil samples under denitrifying conditions(3). Although benzene appears to be recalcitrant under anaerobic conditions, there was one experiment in which benzene underwent degradation under methanogenic conditions. The microbial inoculum employed in the study originally had been enriched from anaerobic municipal sludge(4). Benzene was transformed into phenol by the microbial inoculum by using water as a source of oxygen(4). [R254] ABIO: *While benzene is considered to be relatively unreactive in photochemical smog situations (in the presence of nitrogen oxides), its rate of degradation is accelerated with about 16% decrease in concentration in 5 hr(1). A typical experiment in the presence of active species such as NOx and SO2 showed that benzene photodegradation was considerably accelerated above that in air alone(2). Its half-life in the presence of active species was 4-6 hr with 50% mineralization to CO2 in approximately 2 days(3). Products of degradation include phenol, 2-nitrophenol, 4-nitrophenol, 2,4-dinitrophenol, 2,6-dinitrophenol, nitrobenzene, formic acid, and peroxyacetyl nitrate(4-6). Hydrolysis is not a significant process for benzene due to the lack of hydrolyzable functional groups(7). [R255] *The rate constant for the vapor-phase reaction of benzene with photochemically-produced hydroxyl radicals is 1.23X10-12 cu cm/molecule-sec(1). This corresponds to an atmospheric half-life of about 13 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The half-life in polluted atmospheres which contain nitrogen oxides or sulfur dioxide has been observed to shorten to 4-6 hrs(2). Vapor phase benzene is also degraded in the atmosphere by atmospheric ozone radicals at an extremely slow rate; the half-life for this reaction in air is estimated to be 170,000 days(3). Reaction of benzene with nitrate radical is estimated to be < 0.3X10-16 cu cm/molecule sec at 25 deg C(1); the half-life for this reaction in air is estimated to be greater than or equal to 111 days based on an average concentration of nitrate radicals of 2.4X10+8 molec/cu cm in the ambient atmosphere(4). Benzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(5) nor to directly photolyze since benzene has a maximum absorbance frequency of 253 nm(6). However, slight shifts in wavelength of absorption might be expected in more representative environmental media, such as water(7); eg, a half-life of 16.9 days was reported for photolysis of benzene dissolved in deionized water saturated with air exposed to sunlight(8). Benzene has an estimated lifetime under photochemical smog conditions in southeastern England of 28 hrs(3). Benzene has an estimated global life-time of 16 days and 4.8 days in the tropics(9). Global conditions were considered as having an average temperature of 2 deg C, OH radical concentration of 6.0X10+5 molecule/cu cm and an ozone radical concentration of 7.4X10+11 molecule/cu cm; while tropical conditions were considered as having an average temperature of 25 deg C, OH radical concentration of 2.0X10+6 molecule/cu cm and an ozone radical concentration of 7.4X10+11 molecule/cu cm(9). In aqueous solution, benzene will react with hydroxyl radical at a reaction rate of 7.8X10+9 L/mol sec; using the average OH radical concentration(1.0X10-17 molec/cu cm), benzene would have a half-life of 103 days(10). [R256] BIOC: *Benzene has a BCF ranging from 1.1-20(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low. The uptake and elimination rate constants for benzene in fathead minnows were studied(3). Fathead minnows were found to have an avg uptake rate of 7 L/kg/hr with an avg elimination rate of 0.384/hr which corresponds to a BCF of 19(3). In a study of BCF values for various aquatic species, benzene was found to have a BCF value of 3.5 in eels(4), 4.4 in pacific herring(5), and 4.3 in goldfish(6). [R257] KOC: *An experimentally derived log Koc of 1.93 (Koc = 85) was obtained via reverse phase HPLC (High Performance Liquid Chromatography) with a cyanopropyl column and a mobile phase of water(1). According to a classification scheme(2), this estimated Koc value suggests that benzene is expected to have high mobility in soil. The sorption equilibrium for benzene in a soil/water mixture (ratio soil/water 0.12 kg/l) took 72 hrs(3). The Koc for benzene has also been experimentally determined to be 79(4). [R258] VWS: *The Henry's Law constant for benzene is 5.56X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that benzene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1 hr(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 3.5 days(SRC). Benzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of benzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 94.8 mm Hg(3). [R259] WATC: *GROUNDWATER: Benzene was the dominant dissolved organic compound in groundwater contaminated by gasoline in the Swan Coastal Plain near Perth, Western Australia at a concn around 15,000 ug/l at depths greater than 4.5 m below ground surface(1). At a distance of 210 m from a petrol storage area, a chalk aquifer, located in the United Kingdom, contained benzene ranging from 1-10 ppb; at 120 m from the petrol storage area it contained benzene concns greater than 250 ppb; and at 10 m from the petrol storage area, benzene concns rose to 1250 ppb(2). Benzene occurs in both groundwater and surface public water supplies with higher levels occurring in groundwater supplies. Based upon U.S. Federal drinking water surveys, approximately 1.3% of all groundwater systems are estimated to contain benzene at levels greater than 0.5 ug/l. The highest level reported in the surveys for groundwater was 80 ug/l(3). [R260] *DRINKING WATER: Out of 113 public drinking water supplies in 1976, 7 sites tested positive for benzene with an avg concn of < 0.2 ppb(1). Of five US cities from 1974-5, benzene concns ranged from 0-0.3 ppb in drinking water supplies(2). Contaminated drinking water wells in NY, NJ, and CT ranged from 30-300 ppb; the highest benzene concns in drinking water were derived from surface water sources at 4.4 ppb(3). In three separate surveys of community water supplies: 0 of 111 samples tested positive for benzene; 7 of 113 samples tested positive with a mean concn of 4 ppb; and 4 of 16 samples tested positive with a benzene max concn of 0.95 ppb(4). In a USA Groundwater Supply Survey (GWS, 1982, finished drinking water), out of 466 samples selected at random from a 1000 sample survey, 0.6% tested positive for benzene at a median value of 3 ppb and max of 15 ppb(5). In a study of Wisconsin drinking water wells (data through Jun 1984), of 1174 community wells sampled, 0.34% tested positive for benzene while of 617 private wells, 2.9% tested positive(6). [R261] *DRINKING WATER: There may be a large number of cases where well water is contaminated by benzene at low concns(1). A number of studies have reported finding benzene at levels on the order of 5 ng/l in surface and well waters(1). [R262] *SURFACE WATER: Surface water samples taken from 14 heavily industrialized areas with water basins between 1975-1976, contained benzene in 20% of the samples at concns ranging from 1-7 ppb(1). Benzene concns in Lake Erie from 1975-6, ranged from 0-1 ppb(2). Benzene concns in Lake Michigan from 1975-6, ranged from 0-7 ppb(2). Out of 700 random surface water sites throughout the US in 1975, benzene had an avg concn of 5.4 ppb(3). In the US EPA STORET database, out of 1,271 surface water samples, 15.0% tested positive for benzene with a median concn of 5.0 ppb(4). Benzene concns in seawater taken from the Gulf of Mexico in 1977, ranged from 5-15 parts per trillion in unpolluted areas and 5-175 parts per trillion in areas affected by anthropogenic activities(5). Approximately 3% of all surface water drinking systems are estimated to be contaminated at levels higher than 0.5 ug/l(6). [R263] *RAIN/SNOW/FOG: Benzene was detected in rainwater in Japan and in the UK at a concn of 87.2 ppb(1,2). [R264] EFFL: *Industries in which mean or max levels of benzene in raw wastewater exceeded 1 ppm are (number of samples, percent pos, mean, max, in ppm): raw wastewater: auto and other laundries (20 samples, 70% pos, < 1.4 ppm mean, 23 ppm max), iron and steel manufacturing (mfg) (9 samples, 77.8% pos, < 8.0 mean, 46 max), aluminum forming (32 samples, 56.2% pos, 0.70 mean, 2.1 max), photographic equipment/supplies (48 samples, 54.2% pos, 0.16 mean, 2.1 max), pharmaceutical mfg (9 samples, 100% pos, 12 mean, 87 max), organic chemical/plastics mfg (number of samples not reported (NR), 63 detections, 22, NR), paint and ink formulation (36 samples, 63.9% pos, 1.2 mean, 9.9 max), petroleum refining (11 samples, number of pos NR, < 0.10, 2.4), rubber processing (4 samples, 100% pos, 0.60 mean, 3.4 max), timber products processing (14 samples, 92.9% pos, 0.2 mean, 2.8 max); treated wastewater: auto and other laundries (4 samples, 50% pos, 0.1 ppm mean, 0.2 ppm max), iron and steel manufacturing (mfg) (13 samples, 76.9% pos, < 14 mean, 120 max), aluminum forming (21 samples, 81.0% pos, < 0.0058 mean, 0.040 max), photographic equipment/supplies (4 samples, 100% pos, 0.016 mean, 0.021 max), pharmaceutical mfg (6 samples, 100% pos, 1.8 mean, 10 max), organic chemical/plastics mfg (number of samples not reported (NR), 42 detections, 26, max NR), paint and ink formulation (24 samples, 62.5% pos, 0.39 mean, 3.8 max), petroleum refining (13 samples, NR, NR, 0.012), rubber processing (5 samples, 100% pos, < 0.0077 mean, 0.010 max), timber products processing (5 samples, 60% pos, 0.010 mean, 0.033 max)(1). [R265] *Wastewater from coal preparation plants ranged from 0.3-48 ppb while wastewater from plants which manufacture or use benzene ranged from < 1-179 parts per trillion(1). Stack emissions from coking plants located in Czechoslovakia contained benzene ranging from 15-50 ppm(2). In 11.2% of groundwater samples taken from 178 CERCLA hazardous waste sites, benzene was detected(3). In the US EPA STORET database, out of 1,474 effluent samples, 16.4% tested positive for benzene at a median concn of 2.50 ppb(4). [R266] *Benzene was emitted by pre-catalyst cars at 114-153 mg/mile while with catalyst cars emissions dropped to 5-32 mg/mile(1). In 4 municipal landfill gases in Southern Finland (1989-1990 data), benzene's avg concn ranged from 0.17-9 mg/cu m with a max concn of 11 mg/cu m(1). Benzene emissions were studied from seven Swedish incineration plants before and after air pollution control systems (APCS) were introduced(2). Benzene concns emitted from plant A (3 incinerators) without APCS were 1.93, 1.95, and 21.16 ug/cu nm and with APCS were 2.46, 0.83 and 1.81 ug/cu nm, respectively. Plant B (3 incinerators) benzene levels were 21.23, 10.81, and 1.63 ug/cu nm before APCS and 14.37, 444.20, and 0.14 ug/cu nm after APCS, respectively(2). Oddly, benzene levels rose on an incinerator after APCS. At the third plant, benzene concns were 2.57 ug/cu nm before APCS and 0.79 ug/cu nm after APCS(2). At the fourth plant, benzene concns were 3.44 ug/cu nm before APCS and 1.32 ug/cu nm after APCS(2). At the fifth plant, benzene concns were 0.82 ug/cu nm before APCS and 0.37 ug/cu nm after APCS(2). At the sixth plant, benzene concns were 2.92 ug/cu nm before APCS and 1.64 ug/cu nm after APCS(2). At the seventh plant (3 incinerators) benzene concns were 4.31, 8.30 and 5.13 ug/cu nm before APCS and 1.49, 1.02, and 11.36 ug/cu nm after APCS, respectively(2). [R267] SEDS: *SOIL: Soil near factories where benzene was used or produced contained benzene ranging from 2-191 ug/kg(1). SEDIMENT: Surface sediments taken from Walvis Bay (off Capetown, South Africa) contained benzene ranging from 0-20 ppb(2). In the US EPA STORET database, out of 355 samples, 9% tested positive for benzene at a median concn of < 5.0 ppb(3). [R268] ATMC: *SUBURBAN/URBAN: Air samples taken in the US from 1977-1980, had an avg benzene concn of 2.8 ppb in 2292 samples(1). Avg benzene concns were 13 ppb (98 ppb max) in Toronto, Canada 1971(2). Avg benzene concns in Los Angeles, California 1966 avgd 15 ppb (57 ppb max)(2). In 24 hr sampling periods conducted in US cities in 1979, benzene concns in Los Angeles, CA in April ranged from 0.72-27.87 ppb(mean 6.04 ppb), in Phoenix, AZ from April-May benzene ranged from 0.39-59.89 ppb (mean 4.74 ppb), in Oakland, CA from June-July benzene ranged from 0.06-4.63 ppb (mean 1.55 ppb)(3). Atmospheric benzene concns were studied in New Jersey in 1978 with the following cities reporting detections: Rutherford, out of 149 samples, 3.8 ppb mean concn with 107 ppb max, Newark, out of 110 samples, 2.6 ppb mean concn with 24 ppb max, Piscataway/Middlesex, out of 18 samples, 1.0 ppb mean concn with 1.9 ppb max, Somerset county, out of 30 samples, 5.6 mean concn with 33 ppb max, Bridgewater Township, out of 22 samples, 1.4 ppb mean concn with 7.9 ppb max(4). In general, the avg concn of benzene in the urban atmosphere is estimated at 0.02 ppm(5). [R269] *URBAN/SUBURBAN: Benzene has been detected in urban air samples in London, U.K., Southampton, U.K., Budapest, Hungary, Oslo, Norweigh, St. Petersburg, Russia, Boston, Chicago, Los Angeles, Houston, Sydney, Australia, and Tokyo, Japan at 9,16, 27, 18, 30, 1, 1.3, 2.7, 18, 2.6, and 1.8 ppbv, respectively(1). The median concn of benzene in 39 U.S. cities from 1984-1985 was 12.6 ppb(2). Benzene's ambient concn was highest at night-time and lowest by mid-day due to deep convective mixing and chemical loss by OH radicals(2). Since the 1960's, the ambient atmospheric concn of benzene has declined(2). Benzene concns were reported for 586 ambient air samples collected from 10 Canadian cities(3). The overall mean was 4.4 ug/cu m, with Ottawa and Montreal ranging between 5.1 and 7.6 ug/cu m(3). Benzene concns in a traffic tunnel in London, that was poorly ventilated, ranged from 0.010-0.21 ppb(4). [R270] *INDOOR: In a recent benzene exposure study, day and night 12-hr avg concns of benzene were measured for 58 residents of Valdez, Alaska(1). The mean benzene concns in the personal, indoor, and outdoor samples were 20, 16, and 5 ug/cu m during the summer, and 28, 25, and 11 ug/cu m during the winter, respectively(1). In a nationwide Canadian study which measured the 24-hr indoor air concns of benzene in 754 randomly selected homes, benzene had a mean indoor air concn of 6.39, 5.60, 2.72, and 6.98 ug/cu m in the winter, spring, summer, and fall seasons, respectively(1). Indoor and outdoor 48-hr avg concns of benzene were measured at 161 homes throughout much of California in which indoor samples had a mean concn of 8.3 ug/cu m compared to 6.1 ug/cu m outdoor samples(1). Concns of benzene emitted from tobacco smoke in 5 workplaces located in Finland, 1995 ranged from 1.5-8 ug/cu m(2). Gasoline leaking from an underground storage tank near an elementary school in the Midwest United States (location not specified) created elevated levels of benzene concns within the school property(3). Benzene was detected in air samples collected from the classrooms, offices/libraries/corridors, boiler room, crawl space beneath floor, soil/duct/floor interface, and outdoor/background at 0-5 ppb, 3-4 ppb, 4 ppb, approx 2600 ppb, 70-80 ppb, and 0-3 ppb, respectively(3). A series of experiments were conducted in a 290 sq m single-family residence from June 11-13, 1991 to ascertain the human exposure to benzene from a contaminated groundwater source(4). It involved an individual taking a 20 min shower with the bathroom door closed, followed by five minutes for drying and dressing, and then opening the bathroom door and allowing the individual to leave and have his blood, breath and urine sampled(4). Whole air samples were collected from the bathroom, shower and living room. Mean concn of benzene coming from the shower head for the three days was 292 ug/l(4). Peak benzene levels were measured in the shower stall at 18-20 mins (758-1670 ug/cu m), in the bathroom at 10-25 mins (366-498 ug/cu m), in the bedroom at 25.5-30 mins (81-146 ug/cu m), and in the living room at 36-70 mins (40-62 ug/cu m)(4). [R271] *RURAL/REMOTE: In 100 rural air samples taken within the US from 1977-1980, the avg concn of benzene was 1.4 ppb avg(1). Ambient air samples taken from Barrows, Alaska in 1967 contained benzene at 0.16 ppb over a 24 hr avg in 5 of 25 samples(2). Avg benzene concn in rural areas range from 0.1-17 ppb(3). Multilatitude background concns of benzene (ppb/deg North): Atlantic Ocean 0.07/35 deg N, Pacific Ocean 0.23/45 deg N, Niwot Ridge (Colorado Rockies) 0.16-0.24 ppb(4). Benzene concns in the Pacific Ocean ranged from 0.05 ppb in the Northern hemisphere to 0.01 ppb in the Southern hemisphere(5). Pacific Ocean, 0.581, Pullman, WA, 0.226, Cape Meares, OR, 0.230, Norwegian Arctic, 0.066(5). In 5 remote tropical sites, benzene concns ranged from not detected to 1.8 ppb; avg concns from the 5 sites ranged from 0.07-0.65 ppb(6). [R272] *RURAL/REMOTE: Benzene was measured at 35 ug/cu m in the plume of a forest fire at a distance of 6 km of the seat of the fire(1). The median concn of benzene in the Southern Appalachian Mountains was 1.1 ppb(2). Benzene concns range from 100-200 parts per trillion over the Pacific and Atlantic Oceans due to seepage and spillage of oil into the oceans(2). Rural sampling for benzene in Canada found concns ranging from 0.6-1.2 ug/cu m(3). Benzene was detected (concn not specified) in ambient air samples taken from Witaker's Forest/Sierra Nevada Mountains, California from June 20-June 22, 1990(4). Measurements were performed in midsummer at high ambient temperatures and under stable meteorological conditions with high solar radiation(4). Although the area was very remote, the air samples could have been influenced by emissions from California's Central Valley and even from the San Francisco Bay area(4). [R273] *SOURCE DOMINATED: Atmospheric benzene concns were studied throughout the USA between 1977-1980 in which out of 487 samples taken, benzene was found at an avg concn of 3.0 ppb(1). The concn of benzene near USA chemical factories where benzene is used ranged from 0.6-34 ppb, near service stations 0.0003-3.2 ppm, and in cigarette smoke 57-64 ppm(2). [R274] FOOD: *Benzene was found in both heat treated and canned beef at 2 ug/kg; in Jamaican rum at 120 ug/kg; in eggs ranging from 500-1900 ug/kg; and it was detected (concns not specified) in fruits, nuts, vegetables, dairy products, meat, fish, poultry, eggs, and beverages(1). [R275] *In 1990, benzene was detected in fruit flavored mineral waters at concns greater than 5.0 ug/kg in Canada(1). When an investigation of benzene concns in beverages was performed, benzene was found at an avg concn of 0.042, 0.67, 0.056, 0.14, 0.29, 0.12, 0.95, 0.062, 0.79, and 0.55 ug/kg in freshly squeezed fruit, retail juice (wth benzoate additive), retail juice (without benzoate), fruit drinks (with benzoate), fruit drinks (with cranberry, without benzoate), fruit drinks (excluding cranberry, without benzoate), cranberry drinks (without benzoate), carbonated soft drinks (without benzoate), carbonated soft drinks (with benzoate), and ice tea (with benzoate), respectively(1). These data suggest the natural occurrence of benzene in fruits and fruit juices, especially from cranberies(1). Benzene is a volatile organic compound emitted by both common and pineapple guava at a concn of 0.10 ug/g(2). [R276] PFAC: PLANT CONCENTRATIONS: *Benzene has been detected as a plant volatile(1). Benzene has been detected from 2 species of macroalgae at 20 ppb(2). [R277] FISH/SEAFOOD CONCENTRATIONS: *Benzene was detected in 5 oyster samples from the Inner Harbor Navigational Canal in Lake Pontchartrain, LA at 220 ppb wet weight(1). Composite clam samples from Chef Menteur Pass in Lake Pontchartain, LA contained benzene at 260 ppb wet weight; however clam samples from The Rigolets did not contain benzene(1). [R278] MILK: *Benzene was detected in all 8 samples of mothers milk from women in 4 US urban areas(1). [R279] OEVC: *In private homes, benzene levels in the air have been shown to be higher in homes with attached garages, or where inhabitants smoke inside the house. [R280] RTEX: *Human populations are primarily exposed to benzene through inhalation of contaminated ambient air particularly in areas with heavy traffic and around filling stations. In addition, air close to manufacturing plants which produce or use benzene may contain high concentrations of benzene(1,2). Another source of exposure is from inhalation of tobacco smoke(1). Although most public drinking water supplies are free of benzene or contain < 0.3 ppb, exposure can be very high from consumption of contaminated sources drawn from wells contaminated by leaking gasoline storage tanks, landfills, etc(SRC). [R281] *Rough estimates of average ambient ground-level benzene concentrations over an 8 hour period were calculated based on an emission rate of 100 g/sec from a manufacturing plant. Benzene concentrations (in pg/cu m) are estimated to be 11,000 at 0.15 km, 6,100 at 0.3 km, 3,800 at 0.45 km, 2,800 at 0.6 km, 2,100 at 0.75 km, 740 at 1.6 km, 370 at 2.5 km, 220 at 4.0 km, 120 at 6.0 km, 62 at 9.0 km, 34 at 14.0 km, and 20 at 20.0 km distance from the manufacturing plant(1). [R282] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 272,275 workers (143,066 of these are female) are potentially exposed to benzene in the US(1). Occupational exposure to benzene may occur through inhalation and dermal contact with this compound at workplaces where benzene is produced or used(SRC). The general population may be exposed to benzene via inhalation of ambient air(2-4), ingestion of drinking water(5), and dermal contact with gasoline products(6) containing benzene(SRC). [R283] *Benzene was detected in 3 out of 70 samples taken from 46 spray painting workshops in Sydney, Australia at a concn of 1 mg/cu m in 1989(1). In a study of in-auto and in-bus exposures to volatile organic compounds for commutes on an urban-suburban route in Korea from November 21 to December 22, 1994, revealed that mean in-auto concns of benzene were 30.6 ug/cu m along urban routes and 18.3 ug/cu m along suburban routes while mean in-bus concns were 20.2 ug/cu m along urban routes and 11.7 ug/cu m along suburban routes(2). In a 200-trip study of in-vehicle air of Los Angeles commuters, an avg concn of benzene at 40 ug/cu m during rush hour was detected(3). [R284] AVDI: *Two recent studies of benzene levels in foods have confirmed the conclusion that ingesting food and beverages are an unimportant pathway for benzene exposure(1). In a study of more than 50 foods, most contained benzene below 2 ng/g ppbw(1). A Canadian review of benzene exposures concluded that food and drinking water each contributed only about 0.02 ug/kg benzene per day compared to a total intake of 2.4 ug/kg per day from airborne exposures (3.3 ug/kg/day if exposed to cigarette smoke). In a 1980's study of non-occupational benzene exposure, it was found that more than 99% of the total personal exposure was through air and that a global avg personal exposure for benzene was about 15 ug/cu m(1). Roughly half the total benzene exposure in the United States was borne by smokers(1). For non-smokers, most benzene exposure ultimately was derived from auto exhaust or gasoline vapor emissions(1). A series of experiments were conducted in a 290 sq m single-family residence from June 11-13, 1991 to ascertain the human exposure to benzene from a contaminated groundwater source(1). It involved an individual taking a 20 min shower with the bathroom door closed, followed by five minutes for drying and dressing, and then opening the bathroom door and allowing the individual to leave and have his blood, breath and urine sampled(1). Whole air samples were collected from the bathroom, shower and living room. The inhalation exposure to benzene of an individual in the living room avgd 72 ug for the three days(1). The individual taking the shower had an avg inhalation dose of 113 ug and an avg dermal dose of 168 ug (exposure = 40% inhalation, 60% dermal)(1). There may be a large number of cases where well water is contaminated by benzene at low concns(1). A number of studies have reported finding benzene at levels on the order of 5 ng/l in surface and well waters(1). However, these levels correspond to a daily intake of < 10 ng benzene, assuming 2 liters of water drunk daily(1). This amount is only 0.5% of the avg daily intake for nonsmokers of 200 ng from air(1). Thus, it is concluded that the effect of contaminated water on total benzene intake is negligible(1). [R262] BODY: *Benzene was detected in all 8 samples of mothers' milk from women living in 4 USA urban areas(1). Breath samples from persons without specific exposure to benzene ranged from 8 to 20 ppb(2). Whole blood samples from 250 subjects (121 males, 129 females) ranged from not detected to 5.9 ppb, (mean 0.8 ppb)(3). In FY82, the National Human Adipose Tissue Survey specimens found that of 46 composite samples, 96% tested positive to benzene (concns were > 4 ppb for wet tissue) with a max concn of 97 ppb max(4). [R285] *In a 1980's study of non-occupational benzene exposure, it was found that smokers had an avg benzene body burden about 6 to 10 times that of nonsmokers, and received about 90% of their benzene exposure from smoking(1). The mean benzene concn found in the breath and blood of 1,683 individuals was 13.1 and 131 ng/l, respectively(1). [R262] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH has recommended that benzene be treated as a potential human carcinogen. [R43, 26] ADI: *Insufficient data are available to calculate a one-day Health Advisory for benzene. The Ten-day Health Advisory (0.235 mg/l) is considered to be adequately protective for a one-day exposure as well. ... Longer-term Health Advisories have not been calculated because of the carcinogenic potency of benzene. [R286] ATOL: *Benzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R287, (7/1/98)] OSHA: *The employer shall assure that no employee is exposed to an airborne concentration of benzene in excess of one part of benzene per million parts of air (1 ppm) as an 8 hr TWA. The employer shall assure that no employee is exposed to an airborne concentration of benzene in excess of 5 ppm as averaged over any 15 min period. [R288] *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 10 ppm. (Note: This standard applies to the industry segments exempt from the 1 ppm 8 hr TWA and 5 ppm STEL of the benzene standard at 1910.1028) [R289] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 25 ppm. (Note: This standard applies to the industry segments exempt from the 1 ppm 8 hr TWA and 5 ppm STEL of the benzene standard at 1910.1028). [R289] *Permissible Exposure Limit: Table Z-2 Acceptable maximum peak above the acceptable ceiling concentration for an 8-hour shift. Concentration: 50 ppm. Maximum Duration: 10 minutes. (Note: This standard applies to the industry segments exempt from the 1 ppm 8 hr TWA and 5 ppm STEL of the benzene standard at 1910.1028.) [R289] NREC: *NIOSH recommends that benzene be regulated as a potential human carcinogen. [R43, 26] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R43, 26] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.1 ppm. [R43, 26] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 1 ppm. [R43, 26] TLV: +A1; Confirmed human carcinogen. [R89, 2002.16] +8 hr Time Weighted Avg (TWA): 0.5 ppm; 15 min Short Term Exposure Limit (STEL): 2.5 ppm, skin. [R89, 2002.16] +Biological Exposure Index (BEI): Determinant: S-phenylmercapturic acid in urine; Sampling Time: end of shift; BEI: 25 ug/g creatinine. Determinant: t,t-muconic acid in urine; Sampling Time: end of shift; BEI: 500 ug/g creatinine. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. [R89, 2002.88] OOPL: *Belgium: TWA (skin) 30 mg/cu m, 10 ppm (1978); Czechoslovakia: TWA 50 mg/cu m, Ceiling 80 mg/cu m/10 min (1976); Finland: TWA (skin) 32 mg/cu m, 10 ppm (1975); Hungary: TWA 20 mg/cu m, may be exceeded 5 times/shift as long as avg does not exceed value (1974); Poland: Ceiling (skin) 30 mg/cu m (1976); Romania: Maximum (skin) 50 mg/cu m (1975); Switzerland: TWA (skin) 6.5 mg/cu m, 2 ppm (1978); USSR: Ceiling (skin) 5 mg/cu m (1980); Yugoslavia: Ceiling (skin) 50 mg/cu m, 15 ppm (1971). [R290] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 50 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 150 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 1000 ppm (not life threatening) up to 1 hr exposure. [R291] *Australia: 5 ppm, Category 1, established human carcinogen (1990); Commission of the European Communities: 0.5 ppm (corresponding to estimated lifetime risk of 0.25-3.3 excess leukemia cases per 1000 workers); Federal Republic of Germany: no MAK, Group A1 carcinogen, capable of inducing malignant tumors in humans, skin, Technical Guiding Concentration (TRK), 1 ppm (1996); Sweden: 0.5 ppm, short-term value, 3 ppm, 15 min, skin, carcinogenic (1991); United Kingdom: 5 ppm (1997). [R177, p. BENZENE-1] ASTD: *National emission standard for equipment leaks (fugitive emission sources) of benzene prohibit detectable benzene emissions from processing equipment (eg, pumps, valves) that contains materials which have a benzene concn of 10% or more by wt. [R292] *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Benzene is produced, as an intermediate or a final product, by process units covered under this subpart. [R293] *Benzene has been designated as a hazardous air pollutant under section 112 of the Clean Air Act. [R294] *The actual standards, if applicable, are contained in 40 CFR Part 61 Subpart V (61.240-61.247), National Emission Standards for Equipment Leaks (Fugitive Emission Sources) and refer to standards of operation of process equipment. EPA regulations establish a national emission standard for equipment leaks of benzene. They apply to pumps, compressors, pressure relief devices, sampling connecting systems, open-ended valves or lines, valves, flanges and other connectors, product accumulator vessels, and control devices, or systems required by this subpart. [R295] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Benzene is included on this list. [R296] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l [R297] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 1 ug/l [R297] +(FL) FLORIDA 1 ug/l [R297] +(NJ) NEW JERSEY 1 ug/l [R297] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 1.3 ug/l [R297] +(CT) CONNECTICUT 1 ug/l [R297] +(ME) MAINE 5 ug/l [R297] +(MN) MINNESOTA 10 ug/l [R297] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R298] +Benzene is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R299] +The maximum contaminant level (MCL) set forth by the National Revised Primary Drinking Water Regulations for the organic contaminant benzene in community and non-transient, non-community water systems is 0.005 mg/l. [R300] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R301] RCRA: *D018; A solid waste containing benzene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R302] *F005; When benzene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F005), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R303] *U019; As stipulated in 40 CFR 261.33, when benzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R304] FIFR: *Benzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R287, (7/1/99)] FDA: *Benzene is an indirect food additive for use only as a component of adhesives. [R305] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *ANALYTE: BENZENE; MATRIX: AIR; RANGE: 13 TO 51.8 PPM; PROCEDURE: ADSORPTION ON CHARCOAL, DESORPTION WITH CARBON DISULFIDE, GC. PRECISION: COEFFICIENT OF VARIATION 0.059 FOR TOTAL ANALYTICAL AND SAMPLING METHOD IN RANGE OF 13 TO 51.8 PPM. [R306] *Analyte: Benzene by portable GC; Matrix: air; Sampler: air bag (Tedlar); Flow rate: 0.02 to 0.05 l/min or higher; Stability: approx 4 hr [R307, p. V1 3700-1] *Analyte: Benzene; Matrix: air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: approx 0.20 l/min; Vol: max: 30 l; Stability: at least 2 wk; Bulk sample: 1 to 10 ml, ship in separate containers from samples. [R307, p. V2 1500-1] *Analyte; Benzene; Matrix: air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: approx 0.20 l/min; Vol: max: 30 l; Stability: not determined; Bulk sample: 1 to 10 ml, ship in separate containers from samples. [R307, p. V2 1501-1] ALAB: *VAPOR-PHASE ORGANICS IN AMBIENT AIR NEAR INDUSTRIAL COMPLEXES AND CHEMICAL WASTE DISPOSAL SITES WERE CHARACTERIZED BY CAPILLARY GAS CHROMATOGRAPHY/MASS SPECTROMETRY/COMPUTER. /VAPOR-PHASE ORGANICS/ [R308] *A SIMPLE METHOD BASED ON A SINGLE DILUTION STEP AND QUANTIFICATION BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) HAS BEEN DEVELOPED FOR DETERMINATION OF BENZENE IN GASOLINE. THIS STUDY INDICATES THAT APART FROM BEING FASTER AND DEMANDING LESS PRETREATMENT, THE HPLC METHOD IS LESS EXPOSED TO INTERFERENCES THAN THE HIGH-RESOLUTION CAPILLARY GAS CHROMATOGRAPHY (HRGC) METHOD. [R309] *GC/FID method to determine benzene in landfill vapors and soil. Adsorb landfill vapors on carbon in glass tubes; desorb with carbon disulfide: (Colenutt BA, Davies DN; Int J Environ Anal Chem 7: 223-9 (1980)). Sparge soil sample with nitrogen; trap in Tenax GC tube; limit of detection 0.1 ug/kg. (Fentiman AF et al; Environmental Monitoring Benzene (PB-295 641) - prepared for USEPA by Battelle Columbus Lab, Springfield, Va, Natl Tech Info Ser, pp 9-15, 26-110 (1979)). [R310] *Analyte: Benzene; Matrix: air; Procedure: Gas chromatography (portable), photoionization detector; Range: 0.1 to 500 ppm; Est LOD: 0.15 ng/injection (0.05 ppm for a 1 ml injection); Precision: 0.127; Interferences: any compound having the same or nearly the same retention time as benzene on the column in use. [R307, p. V1 3700-1] *EPA Method 8020: Aromatic Volatile Organics. For the detection of aromatic volatile organics, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as comtamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. Samples may be analyzed by direct injection or purge-and-trap using gas chromatography, with detection achieved by a photo-ionization detector (PID). A temperature program is used in the gas chromatograph to separate the organic compounds. Column 1 is a 6-ft by 0.082-in ID #304 stainless steel or glass column packed with 5% SP-1200 and 1.75% Bentone-34 on 100/120 mesh Supelcort or equivalent. Column 2 is an 8-ft by 0.1-in stainless steel or glass column packed with 5% 1,2,3-Tris(2-cyanoethoxy)propane on 60/80 mesh Chromosorb W-AW or equivalent. Under the prescribed conditions, benzene has a detection limit of 0.2 ug/l, an average recovery range of four measurements of 10.0-27.9 ug/l, and a limit for the standard deviation of 4.1 ug/l. [R311] *EPA Method 8240: Gas Chromatography/Mass Spectrometry for Volatile Organics Method 8240 can be used to quantify most volatile organic commpounds that have boiling points below 200 C (vapor pressure is approximately equal to mm Hg @ 25 C) and that are insoluble or slightly soluble in water, including the title compound. Volatile water-soluble compounds can be included in this analytical technique, however, for the more soluble compounds, quantitation limits are approximately ten times higher because of poor purging efficiency. The method is also limited to compounds that elute as sharp peaks from a GC column packed with graphitized carbon lightly coated with a carbowax (6-ft by 0.1-in ID glass, packed with 1% SP-1000 on Carbopack-B (60/80 mesh) or equivalant). This gas chromatography/mass spectrometry method is based on a purge-and-trap procedure. The practical quantitation limit (PQL) for Method 8240 for an individual compound is approximately 5 ug/kg (wet weight) for wastes and 5 ug/l for ground water. PQLs will be proportionately higher for sample extracts and samples that require dilution or reduced sample size to avoid saturation of the detector. A representative sample (solid or liquid) is collected in a standard 40 ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. Under the prescribed conditions, benzene has an average recovery range for four samples of 15.2-26.0 ug/l with a limit for the standard deviation of 6.9 ug/l and a retention time of 17.0 min. [R312] *EPA Method 602 A purge and trap gas chromatography method for the determination of benzene in municipal and industrial discharges consists of a stainless steel column, 6 ft x 0.85 in ID, packed with Supelcoport (100/120) coated with 5% SP-1200/1.75% Bentone-34, with photoionization detection and helium as the carrier gas at a flow rate of 36 ml/min. A sample volume of 5.0 ml is used, the column temperature is held at 50 deg C for two minutes, then programmed at 6 deg C/min to a final temperature of 90 deg C. This method has a detection limit of 0.2 ug/l, an overall precision of 0.21 times the average recovery + 0.56 over a working range of 2.1 to 550 ug/l. [R313] *EPA Method 624 - Purgeables: Grab samples of water in industrial and municipal discharges must be collected in glass containers and extracted with methylene chloride. Analysis is performed by a purge and trap gas chromatography/mass spectrometry method. Using this procedure, benzene has a method detection limit of 4.4 ug/l and an overall precision of 0.25 times the average recovery - 1.33, over a working range of 5 to 600 ug/l. [R314] *EPA Method 1624 - Volatile Organic Compounds By GC/MS: Grab samples in municipal and industrial discharges are collected. If residual chlorine is present, add sodium thiosulfate. Extraction is performed by a purge and trap apparatus. An isotope dilution gas chromatography/ mass spectrometry method for the determination of volatile organic compounds in municipal and industrial discharges is described. Unlabeled benzene has a minimum level of 10 ug/l and a mean retention time of 1212 sec. This method has an initial precision of 9.0 ug/l, an accuracy of 13.0-28.2 ug/l, and a labeled compound recovery of > 0-196%. [R314] *NIOSH Method 1500. Determination of Hydrocarbons with the Boiling Point Range of 36 to 126 C, by Gas Chromatography with Flame Ionization Detection. [R315] *NIOSH Method 1501. Determination of Aromatic Hydrocarbons by Gas Chromatography with Flame Ionization Detection. [R315] *NIOSH Method 3700. Determination of Benzene by Portable Gas Chromatography with a Photoionization Detector. [R315] *EPA Method 5021. Volatile Organic Compounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. [R316] *EPA Method 8021. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. [R317] *EPA Method 5041. Analysis of Sorbent Cartridges From Volatile Organic Sampling Train by using the Wide-Bore Capillary Column Technique. [R317] CLAB: *Volatile cmpd such as benzene are separated from blood or tissue homogenate directly on gas-chromatographic column and detected using a flame ionization detector. High volatility permits gas chromatograph to be operated at relatively low temp. The nonvolatile and high boiling components of the biological matrix are left behind in the injection port. This insures long column life and requires only occasional cleaning of the injection chamber: Baker RN et al; Toxic volatiles in alcoholic coma; Bull Los Angles County Neurol Soc 33: 140 (1968); Wallace JE, Dahl EV; Rapid vapor phase method for determining ethanol in blood and urine by gas chromatography; Am J Clin Pathol 46: 152 (1966). [R318] *GLC and colorimetric (phenol metabolite) methods are used to determine benzene in serum, urine, and breath. Conventional reference range: > 1.0 mg/l (toxic concn) for serum; < 10.0 mg/l as phenol, > 75.0 mg/l (toxic concn) as phenol for urine. Internationally recommended conc reference range is: > 13 umol/l (toxic concn) for serum; < 106 umol/l as phenol, > 795 umol/l (toxic concn) as phenol for urine. Substances producing phenol as a metabolite can interfere with color assay. [R319] *GC/MS method to determine benzene in adipose tissue, brain, kidney, liver, lung, muscle, pancreas, and spleen; treat sample with chlorobenzene, ethanol and water at 60 deg C; inject vapor phase into gas chromatograph: Nagata T et al; Koenshu-lyo Masu Kenkyukai 3: 77-82 (1978), (Chem Abstr 92: 192082X). [R310] *The urinary metabolites isolated by DEAE Sephadex A-24 anion-exchange chromatography from mice treated with radiolabeled benzene included phenol as the major component, as well as catechol, hydroquinone, and phenylmercapturic acid. [R223] *A sensitive HPLC method is described which separates urinary metabolites from benzene-treated male CD-1 mice phenol, trans, trans-muconic acid and quinol in the 48 hr urine, accounted, respectively for 12.8-22.8, 1.8-4.7 and 1.5-3.7% of the orally administered single dose of benzene (880, 440, and 220 mg/kg body wt). [R320] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzene in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 289 (1986) NIH Publication No. 86-2545 DHHS/ATSDR; Toxicological Profile for Benzene (Update) TP-92/03 (1993) WHO; Environmental Health Criteria 150: Benzene (1993) U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) for Benzene (71-43-2) Toxicological Review in Adobe PDF. Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of October 16, 1998. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for benzene is completed, and the chemical is in review for further evaluation. Route: gavage; Species: transgenic model evaluation II, mice. [R321] HIST: */On June 30, 1992/ a derailed tank car fell 135 feet from a trestle cracking open and spilling most of its 26,200 gallons of benzene solution into the Nemadji River in Wisconsin. /This accident/ resulted in a 10 hr evacuation of more than 50,000 people. About 25 persons went to hospitals in Superior, WI and Duluth, MN complaining of dizziness, headaches, and burning eyes and skin, after a noxious gas cloud enveloped low-lying areas. The vapor was dispersed later that day by wind and rain. [R322] SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (92) R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 (78) 751 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R4: NIOSH; Criteria Document: Benzene p.20 (1974) DHEW Pub No 74-137 R5: Environment Canada; Tech Info for Problem Spills: Benzene (Draft) p.20 (1981) R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R7: Lewis, R.J., Sr (Ed.). 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Saunders Co., 1983. 76 R320: Gad-el Karim et al; Xerobiotic 15: 211-20 (1985) R321: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 R322: C and E News 70 (27): 5 (1992) RS: 296 Record 4 of 1119 in HSDB (through 2003/06) AN: 36 UD: 200303 RD: Reviewed by SRP on 2/28/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CAFFEINE- SY: *ALERT-PEP-; *CAFEINA-; *Caffedrine-; *CAFFEIN-; *CAFIPEL-; *COFFEINE-; *Dexitac-; *GUARANINE-; *KOFFEIN-; *MATEINA-; *METHYLTHEOBROMINE-; *NO-DOZ-; *1H-PURINE-2,6-DIONE,-3,7-DIHYDRO-1,3,7-TRIMETHYL-; *Quick-Pep-; *REFRESH'N-; *STIM-; *THEIN-; *THEINE-; *THEOBROMINE,-1-METHYL-; *THEOPHYLLINE,-7-METHYL-; *Tirend-; *1,3,7-TRIMETHYL-2,6-DIOXOPURINE-; *1,3,7-TRIMETHYLXANTHINE-; *Vivarin-; *XANTHINE,-1,3,7-TRIMETHYL- RN: 58-08-2 MF: *C8-H10-N4-O2 ASCH: Caffeine, monohydrate; 5743-12-4; Caffeine sodium benzoate; 8000-95-1; Ascophen; 8003-03-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Derivation: By extraction of coffee beans, tea leaves, or kola nuts. Much of the caffiene of commerce is a byproduct of decaffeinated coffee manufacture. [R1] *SYNTHETICALLY PREPARED STARTING WITH DIMETHYLUREA AND MALONIC ACID. [R2, 81] FORM: *Grades: Technical; USP; FCC [R1] *Nodoz Keep Alert Tablets contain 100% caffeine in each tablet [R3, p. V-436] *Vivarin contains 200 mg caffeine alkaloid and 150 mg dextrose in each tablet [R3, p. V-707] MFS: *Pfizer Inc, Hq, 235 E 42nd St, New York, NY 10017, (212) 573-2323; Chemical Division; Production site: Groton, CT 06340 [R4] *Certified Processing Corp, Hq, US Hwy 22, Hillside NJ 07205, (201) 923-5200; Production site: Hillside, NJ 07205 [R5] OMIN: +ALL COLA BEVERAGES CONTAIN CAFFEINE. THE FDA PERMITS THE USE OF CAFFEINE IN THESE BEVERAGES UP TO 1.2 GR (72 MG) PER 12-OUNCE BOTTLE (6 MG/OZ). LOW CALORIE DRINKS ARE ALLOWED ONLY HALF (3 MG/OZ) AS MUCH CAFFEINE. [R6, 394] *FEMA NUMBER 2224 [R2, 808] USE: +MEDICATION *FOOD ADDITIVE; IN BEVERAGES [R7] +MEDICATION (VET) PRIE: U.S. IMPORTS: *(1972) 9.37X10+5 GRAMS [R8] *(1975) 7.1X10+9 GRAMS [R8] *(1984) 1.74x10+9 g [R9] U.S. EXPORTS: *(1984) 4.30x10+8 g /Caffeine and deriv/ [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White, prismatic crystals [R11]; *Prism-like crystals [R2, 81] ODOR: *ODORLESS [R12, 1234] TAST: *Slightly bitter taste [R12, 1234] BP: *178 DEG C (SUBLIMES) [R13] MP: *238 DEG C (ANHYD) [R14] MW: *194.19 [R13] DEN: *1.23 @ 18 DEG C/4 DEG C [R13] DSC: *KB: 0.7X10-14 @ 19 DEG C; KA: LESS THAN 1.0X10-14 @ 25 DEG C [R15] OWPC: +Log Kow= -0.07 [R16] PH: *6.9 (1% SOLN) [R13] SOL: *SOL IN PYRIDINE. [R14]; *FREELY SOL IN PYRROLE; SLIGHTLY SOL IN PETROLEUM ETHER; FREELY SOL IN TETRAHYDROFURAN CONTAINING ABOUT 4% WATER [R13]; *SOL IN ETHYL ACETATE [R17, 188]; *1 gm dissolves in 46 ml water, 5.5 ml water at 80 deg C, 1.5 ml boiling water, 66 ml alcohol, 22 ml alcohol at 60 deg C, 50 ml acetone, 5.5 ml chloroform, 530 ml ether, 100 ml benzene, 22 ml boiling benzene. [R13]; +Water solubility= 21,000 mg/l at 25 deg C [R18] SPEC: *INDEX OF REFRACTION: 1.4936 @ 25 DEG C/D [R17, 297]; *MAX ABSORPTION (ALCOHOL): 227 NM (LOG E= 4.3); 235 NM (LOG E= 4.3); 274 NM (LOG E= 4.3) [R19]; *SADTLER REFERENCE NUMBER: 209 (IR, GRATING) [R19]; *Intense mass spectral peaks: 194 m/z (100%), 109 m/z (88%), 67 m/z (88%), 55 m/z (71%) [R20]; *IR: 1036 (Sadtler Research Laboratories Prism Collection) [R21]; *UV: 315 (Sadtler Research Laboratories Spectral Collection) [R21]; *NMR: 204 (Varian Associates NMR Spectra Catalogue) [R21]; *MASS: 1084 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R21]; *Intense mass spectral peaks: 82 m/z [R22] VAP: +15 mm Hg at 89 deg C /from experimentally derived coefficients/ [R23] OCPP: *ODORLESS; BITTER TASTE; SOLN NEUTRAL TO LITMUS /CAFFEINE MONOHYDRATE/ [R1] *EFFLORESCENT IN AIR /CAFFEINE MONOHYDRATE/ [R7] *SOLUBILITY IN WATER IS INCR BY ALKALI BENZOATES, CINNAMATES, CITRATES OR SALICYLATES [R13] *WHITE, FLEECY MASSES OR LONG, FLEXIBLE, SILKY CRYSTALS /CAFFEINE MONOHYDRATE/ [R1] *AQ SOLN OF CAFFEINE SALTS DISSOCIATE QUICKLY [R13] *FAST SUBLIMATION IS OBTAINED @ 160-165 DEG C UNDER 1 MM PRESSURE @ 5 MM DISTANCE [R13] *pKa= 14 [R24, 508] *Henry's Law constant= 1.9X10-19 atm-cu m/mole at 25 deg C(est) [R25] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: +SLIGHT ... [R26] DCMP: +... WHEN HEATED TO DECOMPOSITION, IT EMITS TOXIC FUMES OF /NITROGEN OXIDES/. [R27] STRG: *Store in airtight containers [R28] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence for the carcinogenicity in humans of caffeine. There is inadequate evidence for the carcinogenicity in experimental animals of caffeine. Overall evaluation: Caffeine is not classifiable as to its carcinogenicity to humans (Group 3). [R29] ANTR: *If caffeine was ingested within 4 hours in amounts over 15 mg/kg, removal from the stomach by syrup of ipecac-induced emesis or gastric lavage is recommended. Watch for spontaneous vomiting and convulsions. Activated charcoal is probably useful within the first 4 hours. Magnesium sulfate cathartic may be useful. [R24, 513] *In most adult and pediatric cases of acute caffeine toxicity in which the patient survived, only symptomatic and supportive therapy was used. It appears that if advanced life support techniques are needed in resuscitation, the prognosis is extremely grave. However, if only seizure control is needed, diazepam (Valium) and phenobarbital appear to work well. Beta-bockers may be useful for managing tachyarrhythmias but may unmask alpha-mediated hypertension. Removal of any caffeine still in the gastrointestinal tract is beneficial, as is the administration of activated charcoal and a cathartic. In one severe case, resin hemoperfusion was effective. Exchange transfusions eliminated the CNS symptoms and markedly lowered the serum caffeine level in a premature infant who had a severe iatrogenic overdose. [R30, 871] *Supportive Care: Hemorrhagic gastritis: iced saline lavage, antacids, monitor. Arrhythmias: treat symptomatically; cardiac monitoring; watch for electrolyte imbalances (low serum potassium). CNS stimulation and seizures: diazepam, phenytoin, or phenobarbital. Diazepam to 10 mg IV slowly in adults; may repeat if required. Children's dose: 0.1 to 0.3 mg/kg. Fluid and electrolyte imbalances: monitor, consider replacement therapy. Watch for hypokalemia. Hyperglycemia is usually not serious. [R24, 513] HTOX: *Although the short-term lethal dose of caffeine in adults appears to be about 5 to 10 g, untoward reactions may be observed following the ingestion of 1 g (15 mg/kg; plasma concentrations above 30 mg/ml). These are mainly referable to the central nervous and circulatory system. Insomnia, restlessness, and excitement are the early symptoms, which may progress to mild delirium; emesis and convulsions are also prominent. The muscles become tense and tremulous. Tachycardia and extrasystoles are frequent, and respiration is quickened. [R31, 625] *The administration of 250 to 350 mg of caffeine to methylxanthine-naive individuals may produce small decreases in heart rate and modest increases in both systolic and diastolic blood pressure, but such doses are usually without effect on those parameters in those who consume caffeine regularly. [R31, 621] *PHYSICAL DEPENDENCE AND WITHDRAWAL ... DEMONSTRATION ... THE HABITUAL COFFEE DRINKER MAY EXPERIENCE HEADACHES ... 18 HR AFTER ... DEPRIVED OF CAFFEINE. THE USER (5 CUPS OR MORE DAILY) RESPONDS TO MORNING CAFFEINE ... WITH POSITIVE SUBJECTIVE FEELINGS ... ABSTAINER BECOMES DYSPHORIC. [R32] *CHRONIC CAFFEINISM IS WELL KNOWN AND PRESENTS NERVOUSNESS, TREMORS, INSOMNIA. [R11] *Most effects of methylxanthines on regional blood flow or vascular resistance in human subjects /vary/. It has been repeatedly demonstrated that methylxanthines cause a marked increase in cerebrovascular resistance with an accompanying decrease in cerebral blood flow and oxygen tension. /Methylxanthines/ [R31, 662] *... AN INTRAVENOUS PREPARATION OF CAFFEINE WAS MISTAKEN FOR GLUCOSE AND ADMINISTERED TO TWO PATIENTS IN INSULIN SHOCK. ONE PATIENT RECEIVED A TOTAL OF 3.2 G (EXPRESSED AS ... FREE BASE) AND PROMPTLY DEVELOPED CONVULSIONS ... DEATH OCCURRED WITHIN A FEW MINUTES. [R3, p. II-243] *ACUTE POISONING IS CHARACTERIZED BY NAUSEA, VOMITING, HEADACHES, VERTIGO, TREMORS, MANIC EXCITEMENT, AND, OCCASSIONALLY, EVEN CONVULSIVE COMA. ADDITIONAL SYMPTOMS ARE TACHYCARDIA, POLYURIA, SOMETIMES FOLLOWED BY OLIGURIA. [R11] *DEATH IS RARE, BUT IS DUE TO EXHAUSTION AND RESPIRATORY AND CIRCULATORY FAILURE. [R33, 16] *DOSE: RECOVERY FROM 30 G OF CAFFEINE HAS BEEN KNOWN. [R33, 15] *A retrospective survey (uncontrolled) on a population group predominantly Mormon revealed that 15 of 16 women who ingested at least 600 mg of caffeine per day had pregnancies that ended in spontaneous abortion, stillbirth, or premature birth. A cause and effect relationship cannot be established by this type of study. These observations were not confirmed in later studies. [R24, 510] *After ingestion of 27 g of caffeine in a suicide attempt, a 37-year-old woman developed recurrent cardiac arrest, hypotension (despite dopamine 20 ug/kg/min and norepinephrine 10 ug/min intravenous drips), seizure activity, opisthotonus, and myoclonic jerks. Resin hemoperfusion for 8 hours was associated with a fall in serum caffeine levels from 199 to 55 ug/ml, a rise in systolic blood pressure and cessation of ventricular ectopy and seizures. [R24, 513] *Acute toxicity is initially manifested by abdominal cramps, nausea, diarrhea, and vomiting. This will often cause the elimination of part of the ingested substance. In severe cases, arrhythmias are frequently seen. [R30, 871] *The spectrum of clinical toxicity of caffeine poisoning is rather wide. Many of the symptoms are based on the stimulatory effect on the central nervous and circulatory systems. Initial effects may include insomnia, dyspnea, and excitement progressing to a mild delirium. There may be alternating states of consciousness and muscle twitching. Subsequent symptoms may include diuresis; arrhythmias, including tachycardias and extrasystoles; paplitations; and photophobia. Severe pulmonary edema is common. The terminal event, which in some cases has been the initial presentation, is normally seizures. Hyperglycemia, hypokalemia, and ketonuria also have been reported. [R30, 870] *The acute lethal dose of caffeine in adults appears to be approximately 5 to 10 g either orally or intravenously. This quantity of caffeine would be approximately that contained in 75 cups of coffee, 125 cups of tea, or 200 cola beverages. [R24, 509] *The administration of caffeine (4 to 8 mg/kg) to normal or obese human subjects elevates the concentration of free fatty acids in plasma and increases the basal metabolic rate. [R31, 623] *Xanthines can increase coronary blood flow in man. They also increase the work of the heart. /Xanthines/ [R31, 622] *This study investigated the effects of terminating low dose levels of caffeine (100 mg/day) in 7 normal humans. Substitution of placebo capsules for caffeine capsules occurred under double-blind conditionas while subjects rated various dimensions of their mood and behavior. In the first phase of the study, substitution of placebo for 12 consecutive days resulted in an orderly withdrawal syndrome in 4 subjects which peaked on days 1 and 2 and progressively decreased toward prewithdrawal levels over 1 wk. Data from the remaining 3 subjects provided no evidence of withdrawal. In the second phase of the study, the generality of the withdrawal effect was examined by repeatedly substituting placebo for 100 mg/day caffeine for 1 day periods separated by an avg of 9 days. Despite differences within and across subjects with respect to the presence, nature and magnitude of symptoms, each of the 7 subjects demonstrated a statistically significant withdrawl effect. ... This report documents that the incidence of caffeine withdrawal is higher (100% of subjects), the daily dose level at which withdrawal occurs is lower (roughly equivalent to the amt of caffeine in a single cup of strong brewed coffee or 3 cans of caffeinated soft drink) and the range of symptoms experienced is broader (including headache, fatigue and other dysphoric mood changes, muscle pain/stiffness, flu like feelings, nausea/vomiting and craving for caffeine) than heretofore recognized. [R34] *A significant percentage of chronic headache suffers use excessive quantities of substances for relief. Drug dependency is frequent in these patients. ... Particular attention is directed to ergotamine, butalbital, analgesics, and caffeine. The mechanism of substance abuse may be related to repeated use of substances that reinforce behavior and stimulate brain reward systems. [R35] *... Studies show that abstinence from caffeine induces a withdrawal syndrome of headache, fatigue, and drowsiness which begins within 12-24 hr and lasts for about 1 wk. ... [R36] NTOX: *... ADMIN OF CAFFEINE TO ANIMALS IN LARGE SINGLE, IN SMALLER REPEATED ... DOSES, OR BY IM INJECTION ... RESULTS IN PATHOLOGICAL CHANGES IN GI TRACT AND ULCER FORMATION. [R37, 371] *CAFFEINE INDUCES CHROMOSOMAL BREAKAGE IN FRUIT FLY, HIGHER PLANTS, AND VARIETY OF MICROORGANISMS. [R37, 373] *CAFFEINE HAS AN INDUCING ACTION IN RATS, BUT AS WITH 3MC, IT DOES NOT APPRECIABLY INCREASE THE CONTENT OF MICROSOMAL CYTOCHROME P450. [R38] *VERY LARGE DOSES OF CAFFEINE ARE NEEDED TO EXCEED THE MARGIN OF SAFETY AND HENCE TO PRODUCE CONVULSIONS. ... REPORTED FATAL POISONING IN A 7 KG DOG FOLLOWING ACCIDENTAL INGESTION OF 50 GRAINS (ABOUT 3 G). [R39] *Caffeine is weakly mutagenic in non-mammalian systems and weakly teratogenic in some laboratory animal species. [R3, p. II-243] *... IT DEPRESSES FORMATION OF UREA FROM AMMONIUM SALTS BOTH IN LIVER SLICES IN VITRO AND IN EXPERIMENTAL ANIMALS. [R31, 371] *FATAL DOSE OF CAFFEINE GIVEN TO ANIMAL PRODUCES CONVULSIONS BECAUSE OF CENTRAL STIMULATING EFFECT. ... DEATH RESULTS FROM RESPIRATORY FAILURE. [R37, 373] *LATENT BEHAVIORAL MODIFICATION APPEARED IN POSTWEANLING ADOLESCENTS IN FORM OF HEIGHTENED EXPLORATORY ACTIVITY AND ALTERED PERFORMANCE IN PROGRESSIVE FIXED RATIO SCHEDULE. [R40] *DE NOVO SYNTHESIS OF PURINES AND UTILIZATION OF EXOGENOUS PURINES IN CULTURED CHO-K1, A CHINESE HAMSTER OVARY CELL LINE, WERE INHIBITED BY CAFFEINE AT DOSES WHICH ENHANCE KILLING ACTION OF UV LIGHT. [R41] *Caffeine was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Caffeine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9, at doses of 0.1, 0.333, 1.0, 3.333, and 10.0 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.0 mg/plate. [R42] *Pregnant Sprague-Dawley rats were divided on day 13 of gestation into two groups. Group 1 received the control diet that contained 20% protein, while group 2 was pair-fed a 20% protein diet supplemented with caffeine (1 mg/100 g of body weight). At parturition, the dams of each group were continued on their respective diets until postnatal day 22, when the pups were weaned. At this time, only male offspring from both groups were continued in the study and they were fed the control diet. On days 57 and 58 after birth, pups were killed and their brains were divided into six different areas: cerebellum, medula oblongata, hypothalamus, striatum, cortex-midbrain, and hippocampus. Significant differences in weight, and cholesterol, DNA, RNA, and protein contents were noted when compared with control values. [R43] *Twelve pregnant Sprague-Dawley rats were treated with a single iv injection of 25 mg/kg caffeine in the tail vein on gestational day 10. Controls (12 rats) received saline in the same manner. A third group of 22 rats were used as untreated controls. Embryos were removed on day 12 of gestation and studied. No anomalies were detected in any of the caffeine-treated and control embryos with respect to yolk sac circulation system or cardiac defects. [R44] *The teratogenic potential of caffeine was evaluated in Wistar rats. Pregnant rats were divided into seven treatment groups of 20 rats each: 1) untreated controls; 2) controls (5 ml/kg distilled water once daily); 3) 10 mg/kg caffeine once daily; 4) 100 mg/kg caffeine once daily; 5) controls (1.25 ml/kg distilled water four times/day; 6) 2.5 mg/kg caffeine four times/day; 7) 25 mg/kg caffeine four times/day. All groups were treated by gavage on days 6-20 of gestation. The dams were killed on day 21 and offspring were prepared for analysis. Caffeine caused a considerable decrease in fetal weight in groups 4 and 7. Malformations (club foot, ectrodactyly, cleft palate, and retarded ossification) were seen in the offspring of groups given the high dose of caffeine once daily (group 4). [R45] NTXV: *LD50 Mouse female oral 137 mg/kg; [R13] *LD50 Hamester female oral 249 mg/kg; [R13] *LD50 Rat female oral 247 mg/kg; [R13] *LD50 Rabbit female oral 224 mg/kg; [R13] *LD50 Mouse male oral 127 mg/kg; [R13] *LD50 Hamster male oral 230 mg/kg; [R13] *LD50 Rat male oral 355 mg/kg; [R13] *LD50 Rabbit male oral 246 mg/kg; [R13] NTP: +The potential reproductive toxicity of caffeine in Sprague-Dawley rats was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Based on decreased body weights and feed consumption, increased water consumption, and mortality noted during Task 1, dose levels for the continuous breeding phase for this study were set at 12.5, 25, and 50 mg/kg. Male and female Sprague-Dawley rats were exposed to caffeine in deionized water by oral gavage at a dose volume of 5 ml/kg. Individual dose volumes were adjusted weekly. During 16 wks of cohabitation, live pup weight adjusted for litter size was decreased by 7, 7, and 8% in the 12.5, 25, and 50 mg/kg dose groups, respectively. No differences were observed in other reproductive endpoints. A crossover mating trial (Task 3) revealed no changes on male or female fertility or in pup weight. Reproductive parameters were comparable between dose groups when naive males were mated with control or 50 mg/kg females and when naive females were mated with control or 50 mg/kg males. The decreased pup weight was observed concomitant with reduced dam weight gain. Throughout the study, the body weights were less than controls in the F0 12.5 (4-7%), 25 (9-15%), and 50 (9-18%) mg/kg males and 12.5 (5-18%), 25 (5-19%), and 50 (8-19%) mg/kg females. Mean feed consumption (g/animal/day) was decreased by approx 17 and 20% in the 25 and 50 mg/kg animals of both sexes, respectively, during the first wk of the study. At necropsy, no differences were noted in F0 male or female absolute organ weight data; however, many relative organ weights (mg/g bw) were increased in all dosed groups when compared to controls. These differences were attributed to the decr in terminal body weights. No treatment-related gross or microscopic lesions were observed in the F0 animals. Evaluation of F0 computer-assisted sperm analysis (CASA) data revealed a treatment-related decr (3%) in percent motile sperm in the 50 mg/kg F0 males compared to controls. The sperm velocity (mm/sec) was decreased (7-12%) in all treated males. The average radius (m) was also decreased (22-36%) in all treated males. The percent normal sperm was decreased slightly in the 50 mg/kg males when compared to controls. The remaining sperm endpoints were comparable among all groups. In Task 4 (second generation evaluation), no treatment-related differences were observed in pup weights during lactation (/postnatal day/ 1-21). From the initiation of dosing (/postnatal day/ 22) through the maturation phase up to the termination of Task 4, mean body weights of the F1 low-to-high dose males and females were decreased by approx 12%, 18%, and 23% when compared to controls. Mean feed consumption values (g/animal/day) were decreased (5-19%) in all treated groups during Task 4. No mortality was observed in any of the F1 animals. Measures of reproductive performance of second generation breeding pairs revealed a decr in the number of live F2 pups/litter (21%) and proportion of pups born alive (4%) in the 50 mg/kg dose group. No differences were observed between dose groups in other endpoints. At necropsy, many decreases were noted in F1 absolute organ weight data and many increases in F1 relative organ weights were observed in all treated groups when compared to controls. These differences may be attributed to the decreased terminal body weights. No treatment-related gross or microscopic lesions were observed in the F1 animals. As observed in the F0 males, a decrease in percent motile sperm (4%) and sperm velocity (9%) was observed in the 50 mg/kg F1 males compared to controls. The average radius (m) was also decreased (23-26%) in the 25 and 50 mg/kg groups. The remaining sperm parameters were unchanged. Results of this study show that caffeine is not a selective reproductive toxicant, because the minor effects on sperm motion parameters and pup weight/viability occurred concomitant with, or at doses greater than, those doses that reduced body weight gain. It was demonstrated that exposure to caffeine reduced pup weights in the F0 females at > or =12.5 mg/kg and litter size and viability in the F1 generation at 50 mg/kg. [R46] +Caffeine, a natural alkaloid drug found in tea, coffee, cocoa, and cola, and a common soft drink additive, was tested for its effects on reproduction and fertility in Swiss CD-1 mice. Caffeine was tested simultaneously at two laboratories, each using a variation on the standard RACB study design. This study used Tasks 1, 2, and 4, while the other study in mice utilized Tasks 1, 2, and 3. Caffeine was among the very first compounds run at these labs using this protocol. Data on body weights, clinical signs, and food and water consumptions were collected during the dose-range-finding phase (Task 1), and used to set exposure concns for Task 2 at 0.0, 0.012, 0.025, and 0.05% in drinking water. Water was chosen to mimic the route of human exposure. Water consumption was not affected by addition of caffeine. These levels of caffeine, and measured water consumption and body weights, produced calculated consumption estimates nearly equal to 22, 44, and 88 mg/kg/d. For the F0 animals, there were no effects on body weight. Alopecia occurred in 55% of the medium dose and 50% of the high dose animals. While there were no exposure-related changes in the number of litters/pair, viability, or adjusted pup weight, the number of live pups/litter, averaged over the 4-5 litters, dropped 15% at the medium dose and 20% for the high dose animals. No crossover mating trial was conducted, and the offspring from the last litter of control and high dose mice were reared by their dams until weaning, when they were given the same treatment as their parents until mating at 74 ± 10 days of age. At the second generation mating trial, there were no changes in any reproductive endpoint. At necropsy, at 0.05% caffeine, male body weight was reduced by 8% while male adjusted liver weight increased by 8%. No change was found in female body or organ weights, or in any sperm endpoint. In summary, a reduction in the number of live pups/litter for the F0 generation was the only reproductive effect observed in this study. This occurred in the absence of a change in body weights in the F0 parental mice. [R47] +Caffeine ... was tested for its effects on reproduction and fertility in Swiss CD-1 mice. Caffeine was tested simultaneously at two laboratories, each using a variation on the standard RACB study design. This study performed Tasks 1, 2, and 3, while the other study in mice performed Tasks 1, 2, and 4. Caffeine was among the very first compounds run at these labs using this protocol. Data on body weights, clinical signs, and food and water consumptions were collected during the dose-range-finding phase (Task 1), and used to set exposure concns for Task 2 at 0.0, 0.012, 0.025, and 0.05% in drinking water. Water was chosen to mimic the route of human exposure. Water consumption was not affected by addition of caffeine. These levels of caffeine, and measured water consumption and body weights, produced calculated consumption estimates nearly equal to 22, 49, and 93 mg/kg/d. Three control, 1 low dose, and 1 middle dose mouse died during the study. Treated mice were also reported to have lost facial hair, but the percentages and groups involved were not specified. There was no effect on the mean number of litters/pair produced, or on the aggregate mean number of pups/litter (the total number of pups/total number of litters for all pairs at a treatment level). There was a 20% reduction in live male pups/litter, however. Evaluating each litter individually, after the first litter, the high dose group always delivered 1-2 pups < the controls; at the fifth litter, the controls delivered a mean of 10.3 ± 7 pups (mean ± SEM), while the high dose group delivered a mean of 8.6 ± 1 pups. The proportion of pups born alive was reduced by 3%, 5%, and 5% in the low, middle and high dose groups, respectively. Additionally, pup body weight adjusted for litter size was reduced by 4% at the high dose. A crossover mating trial (Task 3) was performed. There were no differences between the groups in the mating and fertility indices, and no differences with respect to pup number or viability or weight. Task 4 was not performed on this study. After 7 days of vaginal smears to evaluate cyclicity, the control and high dose Task 2 mice were killed and necropsied. Female body weight at necropsy was reduced by 5%, while body-weight-adjusted organ weights were unchanged. Ante-mortem vaginal cyclicity was unaffected by caffeine exposure. Male body weight was unchanged by consumption of 0.05% caffeine, but adjusted liver weight was increased by 10%. Absolute testis weight dropped by 7% and adjusted seminal vesicles weight decreased by 12%. Sperm motility values for controls was low (47% motile), so the 21% reduction in the treated group should be viewed with caution. Similarly, the control epididymal sperm density was nearly equal to half of the subsequent control values for this lab, so the significant incr in sperm density in the caffeine-treated group is likely erroneous. The slight but significant reductions in (male) pup number, pup viability, and adjusted pup weight suggest that caffeine produced some slight reproductive toxicity. This occured in the presence of very slight indications of other toxicities (body or organ weight changes). [R48] ADE: *THE METHYLXANTHINES ARE READILY ABSORBED AFTER ORAL, RECTAL, OR PARENTERAL ADMINISTRATION. /METHYLXANTHINES/ [R31, 626] *(DOSE 0.5 G IM) CONCN IN BLOOD 0.01 MG% AFTER 1 HR (HUMAN). /FROM TABLE/ [R17, 338] *(DOSE 0.5 G ORAL) CONCN IN BLOOD 0.14 MG% AFTER 0.5 HOUR (HUMAN). /FROM TABLE/ [R17, 338] *CAFFEINE MAY PASS INTO MILK, BUT DOES NOT SEEM TO AFFECT THE BABY; ABOUT 1% OF THAT INGESTED IS FOUND IN THE INFANT. [R6, 122] *ABSORPTION OF CAFFEINE FROM HUMAN STOMACH ... PH-RELATED, WITH ABSORPTION RATE INCR AS PH IS RAISED FROM 1.0-7.0. ... CAFFEINE IS EQUALLY BIOAVAILABLE FROM TEA AND COFFEE, BUT IT IS MORE SLOWLY ABSORBED FROM COCA-COLA. [R49, 135] *PREGNANT ANIMALS GREATLY CONCENTRATE CERTAIN AGENTS, SUCH AS CAFFEINE, IN UTERINE SECRETIONS; RABBIT BLASTOCYSTS CONTAIN SIGNIFICANT AMT OF CAFFEINE ... SHORTLY FOLLOWING ADMIN TO MOTHER. [R50] *AFTER ADMIN ... TO MALE CD-1 MICE ((3)H-(14)C)-CAFFEINE, 64-90% OF ... RADIOACTIVITY ... RECOVERED IN URINE. MAJOR IDENTIFIABLE METAB INCL 3-METHYLXANTHINE, 7-METHYLXANTHINE ... ONLY 3-6% ... RECOVERED UNCHANGED FROM URINE. EXCRETION OF METABOLITES OCCURRED RAPIDLY, 80% COMPLETE IN FIRST 8 HR AFTER 25 MG/KG DOSE. [R49, 350] *AFTER ORAL ADMIN OF 150 MG CAFFEINE SODIUM BENZOATE TO 5 BREAST-FEEDING MOTHERS, PEAK SERUM AND MILK CONCN OF CAFFEINE WERE OBSERVED AFTER 60 MIN. BINDING OF CAFFEINE BY SERUM AND BREAST MILK WAS LOW (25% AND 3.2%, RESPECTIVELY). /CAFFEINE SODIUM BENZOATE/ [R51] *Caffeine and citrated caffeine are well absorbed following oral administration. Absorption of caffeine following oral administration may be more rapid than that foillowing IM injection of caffeine and sodium benzoate. Absorption following rectal administration of caffeine in suppositories may be slow and erratic. Following oral administration of 100 mg of caffeine (as coffee), peak plasma concentrations of about 1.5-1.8 ug/ml are reached after 50-75 minutes. [R12, 1234] *Caffeine is rapidly distrubuted into body tissues, readily crossing the placenta and blood-brain barrier. Approximately 17% of the drug is bound to plasma proteins. Caffeine has been shown to distribute into milk in a milk-to-serum concentration ratio of 0.52. [R12, 1234] *Caffeine and its metabolites are excreted mainly by the kidneys. [R12, 1234] *The pharmacokinetic profile of caffeine was studied in 32 premature newborn infants with apnea: 12 following a single iv dose; 3 after a single dose; 7 during treatment with an initial empirical (high) maintenance dose schedule; and 10 during treatment with a revised (lower) dose schedule. Mean (plus or minus Standard Error) apparent volume of distribution, plasma half-life, elimination rate constant, and clearance following a single iv dose were 0.916 plus or minus 0.070 l/kg, 102.9 plus or minus 17.9 hr, 0.009 plus or minus 0.001/hr and 8.9 plus or minus 1.5 ml/kg/hr, respectively. Rapid absorption was noted with plasma concn of 6 to 10 mg/kg achieved within 30 min to two hr following an oral dose of 10 mg/kg. Plasma concn at steady-state of caffeine in infants given a high empirical dose (11.2 plus or minus 1.5 mg/kg/day) range from 22.5 to 84.2 mg/l (mean= 45.3) whereas a dose schedule based on kinetic data (2.5 mg/kg/day) yielded plasma concn ranging from 7.4 to 19.4 mg/l (mean= 13.7). [R52] METB: *CAFFEINE ... IS METABOLIZED IN MAN TO 1- and 7-METHYLXANTHINE, 1,7-DIMETHYLXANTHINE ... and 1,3-DIMETHYLURIC ACID. [R53] *... METABOLISM ... IN RAT YIELDS MINOR AMT OF ... 1,3-DIMETHYLXANTHINE ... AND LARGER AMT OF ... 3,7-DIMETHYLXANTHINE ... and 1,7-DIMETHYLXANTHINE ... . [R54, 92] *IN METABOLISM OF CAFFEINE, A RECENTLY DISCOVERED PATHWAY INVOLVES OXIDATIVE RING OPENING OF METABOLITE 1,3,7-TRIMETHYLURIC ACID...TO GENERATE 3,6,8-TRIMETHYLALLANTOIN ... . [R54, 115] *Although scarely detectable in adults, the conversion of theophylline to caffeine is an important metabolic pathway in preterm infants. [R31, 627] *The major pathway in man proceeds through the formation of paraxanthine (1,7- dimethylxanthine), leading to the principal urinary metabolite, 1-methylxanthine, 1-methyluric acid, and an acetylated uracil derivative. [R31, 627] BHL: *CHRONIC TOXICITY OF CAFFEINE FOUND WITH SQUIRREL MONKEY, SAIMIRI SCIUREUS, SEEMS TO BE RELATED TO LONG PLASMA T/2 OF CAFFEINE IN THIS SPECIES OF MONKEY. AFTER ADMIN OF 5 MG/KG, T/2 VALUE WAS 11 HR, COMPARED WITH. 2.4 HR FOR RHESUS MONKEY (5 HR OR LESS ... REPORTED PREVIOUSLY FOR DOGS, MICE, AND MAN). [R55] *Caffeine has a plasma half-life of 3 to 4 hours in adults. In one study, when administered to pregnant women prior to delivery, caffeine had a prolonged mean plasma half-life of 80 hours in the neonates prior to delivery. [R12, 1234] *The half-life of caffeine is about 3.5 hours. ... The half-life in an overdosed adult can be as long as 9 hours. The half-life of caffeine is reduced by smoking and prolonged by pregnancy. [R30, 868] INTC: *... ADMINISTERED IM IN DOSES UP TO 250 MG TO HUMANS DID NOT APPEAR TO PRODUCE SIGNIFICANT RESPIRATORY STIMULATION, SIMULTANEOS ADMINISTRATION OF 1/4 TO 1/2 THIS AMT WITH MORPHINE OR CODEINE ... PRODUCED SIGNIFICANT ANTAGONISM OF RESPIRATORY DEPRESSION ... . [R56] *OTHER ARRHYTHMIAS--EG, PAROXYSMAL ATRIAL TACHYCARDIA--USUALLY APPEAR ONLY WHEN THE CAFFEINE EFFECT IS REINFORCED BY TOBACCO AND FATIGUE. [R32] *THE COMBINED ACTION OF CAFFEINE AND HISTAMINE IS GREATER THAN THE SUM OF THEIR INDIVIDUAL ACTIONS WITH RESPECT TO THE SECRETION OF BOTH ACID AND PEPSIN ... . [R31, 371] *... SHARED BIOCHEMICAL MECHANISM OF ACTION OF XANTHINES AND CATECHOLAMINES MAY ACCOUNT FOR THE FACT THAT THE XANTHINES MARKEDLY POTENTIATE THE CARDIAC INOTROPIC RESPONSES TO THE CATECHOLAMINES ... . /XANTHINES/ [R31, 364] *CAFFEINE ... MAY ENHANCE CARDIAC INOTROPIC EFFECTS OF BETA-ADRENERGIC STIMULATING AGENTS. CAFFEINE HAS ALSO BEEN REPORTED TO INCR ITS OWN METABOLISM AND THAT OF OTHER DRUGS, INCL PHENOBARBITAL AND ASPIRIN. [R57] *... MALIGNANT HYPERTHERMIA ... INDUCED ... BY VARIOUS GENERAL ANESTHETICS, CAN BE MIMICKED IN VITRO BY EXPOSURE OF CAFFEINE-TREATED FROG MUSCLE TO HALOTHANE. BOTH CONDITIONS ... CHARACTERIZED BY CONTRACTURE ... PROBABLY DUE TO IMPAIRMENT OF UPTAKE OF CA+2 BY SARCOPLASMIC RETICULUM. CONTRACTURE ... REVERSED ... BY PROCAINAMIDE ... . [R37, 372] *The influence of the antiarrhythmic drug, mexiletine, on caffeine clearance in healthy subjects and in patients with severe liver disease was investigated. After an overnight fast all subjects were given 366 mg caffeine orally. Plasma concentrations of caffeine were determined by gas chromatography. ... 12 healthy volunteers including some patients with cardiac arrhythmias. Volunteers were treated with mexiletine (200-600 mg/kg for 1-7 days). ... Simultaneous administration of mexiletine inhibited caffeine elimination to about 50% of the value obtained during a control period. [R58] *The influence of smoking and the antiarrhythmic drug, mexiletine, on caffeine clearance in healthy subjects and in patients with severe liver disease was investigated. After an overnight fast all subjects were given 366 mg caffeine orally. Plasma concentrations of caffeine were determined by gas chromatography. Subjects were divided into four groups: (1) five smokers tested during a smoking period and during smoking-free periods; (2) 30 patients with viral hepatitis of which nine nonsmokers had a low level of liver disease, seven smokers had a low level of disease, seven nonsmokers had a high level of disease, and seven smokers had a high level of disease; (3) 35 patients with alcoholic liver cirrhosis, 16 of whom were smokers; and (4) 12 healthy volunteers including some patients with cardiac arrhythmias. Group 4 volunteers were treated with mexiletine (200-600 mg/kg for 1-7 days). In group 1, smoking had no effect on caffeine clearance. In group 2, both smoking and liver disease had independent significant influences on caffeine elimination. Smoking increased caffeine clearance in patients with a low level of liver disease; clearance was lowered in nonsmokers with a high level of disease. In group 3, smoking enhanced clearance in patients with liver cirrhosis compared to nonsmokers. In group 4, simultaneous administration of mexiletine inhibited caffeine elimination to about 50% of the value obtained during a control period. [R58] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *In adults, IV doses of 57 mg/kg and oral doses of 18-50 g have been fatal. In one 5 yr old patient, death occurred following oral ingestion of approximately 3 g of caffeine. [R12, 1235] THER: +Central Nervous System Stimulants; Phosphodiesterase Inhibitors [R59] *Caffeine /has/ ... found application in the treatment of the prolonged apnea that is sometimes observed in preterm infants. [R31, 628] *CAFFEINE IN COMBINATION WITH AN ANALGESIC, SUCH AS ASPIRIN, IS WIDELY EMPLOYED IN THE TREATMENT OF ORDINARY TYPES OF HEADACHE. CAFFEINE IS ALSO USED IN COMBINATION WITH AN ERGOT ALKALOID IN THE TREATMENT OF MIGRAINE. [R31, 629] *Caffeine can also be used in the treatment of asthma. [R31, 628] *A loading dose of 10 mg/kg iv or orally followed by a daily maintenance dose of 2.5 mg/kg/day admin as a single dose is suggested for the treatment and prevention of neonatal apnea. [R52] +CNS stimulant [R13] +CAFFEINE AND DERIV USED IN DRUGS AS CARDIOVASCULAR AGENT [R8] *MEDICATION (VET): HAS BEEN USED AS CARDIAC AND RESP STIMULANT AND AS DIURETIC [R13] WARN: *Patients with active peptic ulcer should restrict their intake of both caffeine-containing and roast-grain beverages. [R31, 630] *FATAL OVERDOSE OF CAFFEINE HAS BEEN ESTIMATED TO BE APPROX 10 G. UNTOWARD REACTIONS, HOWEVER, CAN OCCUR AFTER THE INGESTION OF ONE OR MORE G. THESE ARE MAINLY REFERABLE TO THE CENTRAL NERVOUS SYSTEM AND CIRCULATORY SYSTEM. [R6, 394] *... WITHDRAWAL OF CAFFEINE FROM INDIVIDUALS HABITUATED TO IT MAY ALSO RESULT IN HEADACHES. THIS "CAFFEINE-WITHDRAWAL" HEADACHE CAN BE RELIEVED BY THE ADMINISTRATION OF CAFFEINE. [R31, 368] *Overindulgence in xanthine beverages may lead to a condition that might be considered one of long-term poisoning. There are also rare persons who are so sensitive to caffeine that even a single cup of coffee will cause a response bordering on the toxic. [R31, 630] *THEOPHYLLINE IS TRANSFORMED TO CAFFEINE IN HUMAN FETAL LIVER. CAFFEINE MAY ENHANCE THE PHARMACOLOGIC EFFECTS OF THEOPHYLLINE IN NEWBORN INFANTS WITH APNEA. [R60] *THEOPHYLLINE WAS METABOLIZED TO CAFFEINE IN 25 INFANTS GIVEN THEOPHYLLINE ORALLY AS 10% ALCOHOLIC SOLN FOR TREATMENT OF IDIOPATHIC APNEA OF PREMATURITY. [R61] *At very high doses, caffeine appears to have some teratogenic activity in mammals, and in 1980 the US FDA issued a warning advising pregnant women to limit their exposure to caffeine. However, subsequent studies have found no association between maternal consumption of caffeine and the incidence of malformations or of low weight in offspring. [R31, 626] +Maternal Medication usually Compatible with Breast-Feeding: Caffeine: Reported Sign or Symptom in Infant or Effect on Lactation: Irritability, poor sleeping pattern, excreted slowly; no effect with usual amount of caffeine beverages. /from Table 6/ [R62] TOLR: *THERE IS NO DOUBT THAT A CERTAIN DEGREE OF TOLERANCE ... AND OF PSYCHIC DEPENDENCE (... HABITUATION) DEVELOPS TO THE XANTHINE BEVERAGES. /XANTHINES/ [R31, 630] *Prolonged, high intake of caffeine may produce tolerance, habituation, and psychological dependence. Physical signs of withdrawal such as headaches, irritation, nervousness, anxiety, and dizziness may occur upon abrupt discontinuation of the stimulant. [R12, 1235] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Caffeine is both a naturally occurring and a commercially produced organic compound which is used in soft drinks, medicines and other consumer products. It may be released to the environment as a fugitive emission during its production or use and in wastewater effluent, landfill leachate, or incinerator fly ash. If released to soil, caffeine will display very high mobility. It will not volatilize from either moist or dry soil to the atmosphere. Limited data indicate that caffeine has the potential to biodegrade in soil. If release to water, caffeine will not volatilize from water to the atmosphere. It will not bioconcentrate in fish nor will it adsorb to sediment. Limited data indicate that caffeine has the potential to biodegrade in water. If released to the atmosphere, caffeine may undergo a gas-phase reaction with photochemically produced hydroxyl radicals at an estimated half-life of 2.5 hrs; however, caffeine will exist predominately adsorbed to particulates in the atmosphere, which may attenuate the rate of this process. Occupational exposure to caffeine may occur by inhalation of dust or dermal contact during its production, formulation or use. The general population will be exposed to caffeine by the ingestion of foods, medicines or consumer products in which it is contained. (SRC) NATS: *Caffeine is a naturally occurring compound which has been identified in tea, kola nuts, mate leaves, guarana plants and cocoa nuts(1-4). [R63] ARTS: *Caffeine is produced commercially for use in soft drinks, medicines and other consumer products(1-5). It may be released to the environment as a fugitive emission during its production, formulation or use(SRC). It may also be released to the environment in industrial wastewater(6), in the effluent of publicly owned treatment plants(7), in the leachate from landfills(8), and in incinerator fly ash(9). [R64] FATE: *TERRESTRIAL FATE: If released to soil, estimated soil adsorption coefficients ranging from 18 to 22(1-3,SRC) indicate that caffeine will display very high mobility(4). An estimated Henry's Law constant of 1.9X10-19 atm-cu m/mole at 25 deg C(4,SRC) indicates that it will not volatilize from moist soil to the atmosphere(SRC). An estimated vapor pressure of < 1X10-8 mm Hg at 25 deg C(2-4,SRC) indicates that it will also not volatilize from dry soil to the atmosphere(SRC). Limited data indicate that caffeine has the potential to biodegrade in soil(6,7). [R65] *AQUATIC FATE: If released to water, an estimated Henry's Law constant of 1.9X10-19 atm-cu m/mole at 25 deg C(1,SRC) indicates that caffeine will not volatilize from water to the atmosphere. Estimated bioconcentration factors ranging from 0.52 to 2.25(2-4,SRC) indicate that caffeine will not bioconcentrate in fish and aquatic organisms. Estimated soil adsorption coefficients ranging from 18-22(2-4,SRC) indicate that it will not adsorb to sediment and suspended organic matter. Limited data indicate that caffeine will biodegrade in water under aerobic conditions(5-7). The pKa of caffeine, 14(7), and its pKb, 14.2(8), indicates that it is both a weak acid and a weak base; however, it may exist as a dissociated (zwitterionic) species under aqueous conditions(SRC). [R66] *ATMOSPHERIC FATE: If released to the atmosphere, an estimated rate constant for the gas-phase reaction of caffeine with photochemically produced hydroxyl radicals of 1.52X10-10 cu cm/molec-sec(1) translates to an atmospheric half-life of 2.5 hrs(1). The estimated vapor pressure of caffeine, < 1X10-8 mm Hg at 25 deg C(2-4,SRC) indicates that it will exist predominately absorbed to particulates in the atmosphere(5), which may attenuate the rate of hydroxyl radical oxidation(SRC). [R67] BIOD: *The estimated half-life for caffeine in the Rhine River, Netherlands, was 0.8 days, which was thought to occur as a result of biological removal processes(1). Caffeine was found to biodegrade when incubated with a sewage sludge inoculum(2). [R68] ABIO: *An estimated rate constant for the gas-phase reaction of caffeine with photochemically produced hydroxyl radicals of 1.52X10-10 cu cm/molec-sec(1) translates to an atmospheric half-life of 2.5 hrs using an average atmospheric hydroxyl radicals concn of 5X10+5 molec/cu cm(1). The estimated vapor pressure of caffeine, (1X10-8 mm Hg at 25 deg C)(2-4,SRC) indicates that it will exist predominately absorbed to particulates in the atmosphere(5) which may attenuate the rate of hydroxyl radical oxidation(SRC). [R69] BIOC: *Estimated bioconcentration factors for caffeine ranging from 0.52-2.25 obtained from its experimental log octanol/water partition coefficient, -0.07(1), and its experimental water solubility, 21,000 mg/at 25 deg C(2), can be obtained using appropriate regression equations(3). These values indicate that caffeine will not bioconcentrate in fish and aquatic organisms(SRC). [R70] KOC: *Estimated soil adsorption coefficients for caffeine ranging from 18-22(SRC) obtained from its experimental log octanol/water partition coefficient, -0.07(1), and its experimental water solubility, 21,000 mg/at 25 deg C(2), can be obtained using appropriate regression equations(3). These values indicate that caffeine will display very high mobility in soil(4). [R71] VWS: *An estimated Henry's Law constant of 1.9X10-19 atm-cu m/mole at 25 deg C(1,SRC) indicates that it will not volatilize from water or moist soil to the atmosphere. An estimated vapor pressure of < 1X10-8 mm Hg at 25 deg C(2,SRC), obtained from its estimated Henry's Law constant and experimental water solubility, 21,000 mg/L at 25 deg C(3), indicates that caffeine will not volatilize from dry soil to the atmosphere(SRC). [R72] WATC: *SURFACE WATER: Caffeine was detected in 8 of 204 water samples obtained from waterway sites collected throughout the United States, 1975-6, at concns ranging from 1 ppb to 6 ppb(1). It was detected in 4 of 13 samples taken from the Lake Michigan basin at concns ranging from 1-4 ug/L(2). Caffeine was also detected in trace quantities in samples from the River Lee, UK(3), date not provided, and the Delaware River, 1976(4). It was detected, but not quantified, in water samples from the lower Fox River, WI, 1976-77(5). The concn of caffeine in the Rhine River, the Netherlands, was 0.1 ug/L, 1979(6). Caffeine was qualitatively detected in river water samples taken in the Kitakyushu area, Japan, date not given(7). [R73] *DRINKING WATER: Caffeine was qualitatively detected in Philadelphia's drinking water supply, 1975-7(1). It was qualitatively detected in treated drinking water supplies in the U.K.(2). [R74] EFFL: *Caffeine was qualitatively detected in 1 of 10 secondary effluents taken at Illinois wastewater treatment plants, 1980(1). Caffeine was detected in 6 of 6 effluent samples obtained from 3 different publicly owned treatment works in NJ, date not provided, at concns ranging from 3-20 ppb(2). It has been detected in 7 of 46 US industrial effluent samples(3). Caffeine has also been detected in Los Angeles County wastewater treatment plant effluent samples, 1980-81, at 40 ug/L(4). It was detected in the effluent from a municipal wastewater treatment plant in Vancouver, BC, Canada, at concn ranging from 16-292 ug/L(5). Caffeine was qualitatively identified in the leachate of a Barcelona, Spain, sanitary landfill(6). It was qualitatively detected in the fly ash samples collected from a municipal incinerator in Toronto, Canada(7). [R75] *Found in primary domestic sewage plant effluent at 0.010-0.046 mg/l [R76] ATMC: *Concentration in particulate organic matter in New York City, Jan-March 1975: 0.70 ug per 1000 cu m [R76] FOOD: *Caffeine is a constituent of tea, coffee, and chocolate(1-3). It is also used as an additive in beverages, medicines and soft drinks(1-5). [R77] PFAC: PLANT CONCENTRATIONS: *Caffeine has been identified as a naturally occurring compound in tea, kola nuts, mate leaves, guarana plants and cocoa nuts(1-3). [R78] MILK: *Caffeine was detected in 6 of 28 human breast milk samples from France and Canada at concns ranging from < 0.5 ng/L to 4.5 ng/L(1). [R79] RTEX: *Occupational exposure to caffeine may occur by inhalation of dust or dermal contact during its production, formulation or use. The general population may be exposed to caffeine by the ingestion of foods, medicines or consumer products in which it is contained(1-5,SRC). The general population may also be exposed to caffeine by the ingestion of contaminated drinking water(6,7). [R80] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 19,140 workers may be exposed to caffeine in the USA(1). NIOSH (NOHS Survey 1972-1974) has statistically estimated that 5718 workers may be exposed to caffeine in the USA(2). [R81] BODY: *Caffeine was detected in 6 of 28 human breast milk samples from France and Canada at concns ranging from < 0.5 ng/L to 4.5 ng/L(1). Caffeine was detected in the blood from an umbilical cord (0-11 ug/ml), human blood samples (0.36-270 ug/mL), and brain, kidney, lung, heart, saliva (2.6-42.6 ug/mL), semen (0.42-8.54 ug/mL), and urine (mean concn ranging from 0.8-24 ug/mL) samples(2). [R82] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *0.02% [R83, (4/1/91)] FDA: *Caffeine used as a multiple purpose GRAS food substance in food for human consumption is generally recognized as safe when used in accordance with good manufacturing practice. [R83, (4/1/91] *FDA shall waive the requirement for the submission of evidence demonstrating the in vivo bioavailability of a solid oral dosage form (other than an enteric coated or controlled release dosage form) of a drug product determined to be effective for at least one indication in a Drug Efficacy Study Implementation notice or which is identical, related, or similar to such a drug product ... if the drug product is neither the sedative caffeine nor an identical, related, or similar drug product. [R84] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *IN NON-ALCOHOLIC BEVERAGES AND CONCENTRATES USING SPECTROPHOTOMETRY METHOD [R85, p. 15/752 960.22] *IN GREEN COFFEE; CHROMATOGRAPHIC-SPECTROPHOTOMETRIC METHOD. IN TEA BY POWER-CHESTNUT METHOD [R85, p. 15/757 957.04] *SIMULTANEOUS QUANTITATION OF ACETAMINOPHEN, ASPIRIN, CAFFEINE, CODEINE PHOSPHATE, PHENACETIN, AND SALICYLAMIDE BY REVERSED-PHASE HIGH-PRESSURE LIQ CHROMATOGRAPHY. [R86] CLAB: *CAFFEINE IS EXTRACTED FROM SERUM OR URINE ... ITS ABSORBANCE ... MEASURED @ 273 NM ... ANALYZED BY GC ... USING FLAME IONIZATION DETECTOR [R87] *CAFFEINE WAS DETERMINED IN SMALL PLASMA SAMPLES BY GAS-LIQUID CHROMATOGRAPHY WITH THIN-LAYER CHROMATOGRAPHIC SAMPLE CLEAN-UP. [R88] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. 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U.S. EXPORTS, SCHEDULE E, 1984 p.2-108 R11: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 118 R12: McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990). R13: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 248 R14: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-158 R15: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 207 R16: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 44 R17: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R18: Stephen H, Stephen T; in Binary Systems. Stephen H et al. eds., NY,NY: 1: 1-79, 1604-43 (1963) R19: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-234 R20: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 392 R21: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 379 R22: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.285 R23: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R24: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R25: Swann RL et al; Res Rev 85:17-28 (1983) R26: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 459 R27: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 616 R28: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 340 R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 51 357 (1991) R30: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. R31: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R32: Meyers, F.H., E. Jaetz, and A. Golfien. Review of Medical Pharmacology. Los Altos, California: Lange Medical Publications, 1972. 114 R33: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. R34: Griffiths RR et al; J Pharmacol Exp Ther 255 (3): 1123-32 (1990) R35: Elkind AH; Clin J Pain 5 (1): 111-20 (1989) R36: Hughes JR et al; Am J Psychiatry 149 (1): 33-40 (1992) R37: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R38: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 360 R39: Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975. 168 R40: SOBOTKA ET AL; NEUROTOXICOLOGY (PARK FOREST SOUTH, ILL), VOL 1 (2): 403-406, 1979 R41: WALDREN CA, PATTERSON D; CANCER RES VOL 39 (12): 4975-4982 (1979) R42: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R43: Nakamoto T et al; Biol Neonate 49: 277-83 (1986) R44: Ross CP, Persaud TVN; Can J Cardiol 2: 160-63 (1986) R45: Smith SE et al; Food Chem Toxicol 25: 125-33 (1987) R46: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Caffeine (CAS No: 58-08-2) Administered by Gavage to Sprague-Dawley Rats, NTP Study No. RACB94006 (June 28, 1996) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R47: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Caffeine (CAS #58-08-2): Reproduction and Fertility Assessment in CD-1 Mice When Administered in the Drinking Water, NTP Study No. RACB81078 (August 29, 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R48: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Caffeine (CAS #58-08-2): Reproduction and Fertility Assessment in CD-1 Mice When Administered in Drinking Water, NTP Study No. RACB84044 (December 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R49: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. R50: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 353 R51: TYRALA EE, DODSON WE; ARCH DIS CHILD VOL 54(10) 787-789 (1979) R52: Aranda JV; Journal of Pediatrics 94 (4): 663-668 (1979) R53: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 154 R54: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. R55: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. 176 R56: Osol, A., and R. Pratt. (eds.). The United States Dispensatory. 27th ed. Philadelphia: J.B. Lippincott, 1973. 208 R57: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 28:20 R58: Joeres R et al; Arch Toxicol 60 (1-3): 93-4 (1987) R59: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R60: ARANDA ET AL; SCIENCE (WASH, DC), VOL 206 (4424): 1319-1321 (1979) R61: BOUTROY ET AL; LANCET VOL 1 (APR 14 1979): 830 R62: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 140 (1994) R63: (1) Zoumas BL, Finnegan EJ; Kirk-Othmer Encycl Chem Tech. 3rd NY,NY:Wiley 6: 1-19 (1982) (2) Graham H; Kirk-Othmer Encycl Chem Tech. 3rd NY,NY:Wiley 22: 631 (1983) (3) Windholz M et al; The Merck Index 10th ed Rahway, NJ: Merck and Co Inc (1983) (4) Duke SO; Rev Weed Sci 2: 15-44 (1986) R64: (1) Zoumas BL, Finnegan EJ; Kirk-Othmer Encycl Chem Tech. 3rd NY,NY: Wiley 6: 1-19 (1982) (2) Graham H; Kirk-Othmer Encycl Chem Tech. 3rd NY,NY:Wiley 22: 631 (1983) (3) Windholz M et al; The Merck Index 10th ed Rahway, NJ: Merck and Co Inc (1983) (4) Sax, NI; p 616 in Dangerous Properties of Industrial Materials. 6th Ed. Van Nostrand Reinhold Co, NY, NY: (1984) (5) Sax NI, Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 11th ed NY, NY: Van Nostrand Reinhold Co (1987) (6) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Decree Survey USEPA 68-03-2867 (1982) (7) Clark LB et al; Res J WPCF 63: 104-113 (1991) (8) Albaiges J et al; Water Res 20: 1153-9 (1986) (9) Tong HY et al; J Chromatogr 285: 423-41 (1984) R65: (1) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) (2) Stephen H, Stephen T; pp 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems Vol 1 Stephen H et al, eds (1963) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5 (1982) (4) Swann RL et al; Res Rev 85:17-28 (1983) (5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (6) Zoeteman BCJ et al, Chemosphere 9: 231-49 (1980) (7) Richardson ML, Bowron JM; J Pharmcol 37: 1-12 (1985) R66: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (3) Stephen H, Stephen T; pp. 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems Vol 1 Stephen H et al, eds (1963) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 4 and 5 (1982) (5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (6) Zoeteman BCJ et al, Chemosphere 9: 231-49 (1980) (7) Richardson ML, Bowron JM; J Pharm Pharmacol 37: 1-12 (1985) (8) Windholz M et al; The Merck Index 10th ed. Rahway, NJ: Merck and Co Inc (1983) R67: (1) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Stephen H, Stephen T; pp. 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems Vol 1 Stephen H et al, eds (1963) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 15 (1982) (5) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) R68: (1) Zoeteman BCJ et al, Chemosphere 9: 231-49 (1980) (2) Richardson ML, Bowron JM; J Pharm Pharmacol 37: 1-12 (1985) R69: (1) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Stephen H, Stephan T; 1: 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems; Stephan H et al, eds (1963) (4) Lyman WJ et al; HandBook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 15 (1982) (5) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) R70: (1) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (2) Stephen H, Stephen T; pp. 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems Vol 1 Stephen H et al, eds (1963) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 5 (1982) R71: (1) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (2) Stephen H, Stephen T; pp. 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems Vol 1 Stephen H et al, eds (1963) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 5 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R72: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 15 (1982) (3) Stephen H, Stephen T; 1-79, 1604-43 in Solubilities of Inorganic and Organic Compounds in Binary Systems Vol 1 Stephen H et al, eds (1963) R73: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Water USEPA-560/6-77-015 (1977) (2) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in the Lakes Erie, Michigan, Huron and Superior Great Lakes Water Qual Board (1978) (3) Waggott A; Chem Water Reuse 2: 55-9 (1981) (4) Sheldon LS, Hites RA; Environ Sci Technol 12: 1188-94 (1978) (5) Peterman PH et al; Environ Sci Res 16: 145-60 (1980) (6) Zoeteman BCJ et al, Chemosphere 9: 231-49 (1980) (7) Akiyama T et al; J Uoeh 2: 285-300 (1980) R74: (1) Suffet IH et al; Water Res 14: 853-67 (1980) (2) Fielding M et al; Organic Micropollutants in Drinking Water TR-159 Medmenham, England Water Res Ctr (1981) R75: (1) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (2) Clark LB et al; Res J WPCF 63: 104-113 (1991) (3) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Decree Survey USEPA-68-03-2867 (1982) (4) Gossett RW et al; Mar Pollut Bull 14: 387-92 (1983) (5) Rogers IH et al; Water Poll Res J Canada 21: 187-204 (1986) (6) Albaiges J et al; Water Res 20: 1153-9 (1986) (7) Tong HY et al; J Chromatogr 285: 423-41 (1984) R76: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 329 R77: (1) Windholz M et al; The Merck Index 10th ed Rahway, NJ: Merck and Co Inc (1983) (2) Zoumas BL, Finnegan EJ; Kirk-Othmer Encycl Chem Tech. 3rd NY: Wiley 6: 1-19 (1982) (3) Graham H; Kirk-Othmer Encycl Chem Tech. 3rd NY: Wiley 22: 631 (1983) (4) Sax, NI; p.16 in Dangerous Properties of Industrial Materials. 6th ed. Van Nostrand Reinhold Co. NY: (1984) (5) Sax NI, Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 11th ed. NY: Van Nostrand Reinhold Co (1987) R78: (1) Zoumas BL, Finnegan EJ; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 6: 1-19 (1982) (2) Graham H; Kirk-Othmer Encycl Chem Tech. 3rd NY: Wiley 22: 631 (1983) (3) Windholz M et al; The Merck Index 10th ed. Rahway, NJ: Merck and Co Inc (1983) R79: (1) Cone MV et al; Chemicals Identified in Human Brest Milk: A Literature Search. USEPA Oak Ridge Natl Lab, Oak Ridge, TN USEPA-560/5-83-009. NITS PB84-18538 (1983) R80: (1) Windholz M et al; The Merck Index 10th ed. Rahway, NJ: Merck and Co Inc (1983) (2) Zoumas BL, Finnegan EJ; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 6: 1-19 (1982) (3) Graham H; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 22: 631 (1983) (4) Sax, NI; p. 616 in Dangerous Properties of Industrial Materials. 6th ed. Van Nostrand Reinhold Co. NY: (1984) (5) Sax NI, Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 11th ed. NY: Van Nostrand Reinhold Co (1987) (6) Suffet IH et al; Water Res 14: 853-67 (1980) (7) Fielding M et al; Organic Micropollutants in Drinking Water TR-159 Medmenham, England Water Res Ctr (1981) R81: (1) NIOSH; National Occupational Exposure Survey (NOES) (1984) R82: (1) Cone MV et al; Chemicals Identified in Human Brest Milk: A Literature Search. USEPA Oak Ridge Natl Lab, Oak Ridge, TN USEPA-560/5-83-009. NTIS PB84-118538 (1983) (2) Cone MV et al; National Body-Burden Database Chemicals Identified in Human Biological Media 1984. Vol 7. USEPA Oak Ridge Natl Lab, Oak Ridge, TN USEPA-560/5-84-003 (1986) R83: 21 CFR 182.1180 R84: 21 CFR 320.22 (4/1/91) R85: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R86: DAS GUPTA N; J PHARM SCI 69 (1): 110-113 (1980) R87: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 57 R88: HULSHOFF A; ANAL LETT 12 (B14): 1423-1433 (1979) RS: 65 Record 5 of 1119 in HSDB (through 2003/06) AN: 37 UD: 200211 RD: Reviewed by SRP on 5/28/1986 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CAMPHOR- SY: *BICYCLO(2.2.1)HEPTAN-2-ONE, 1,7,7-TRIMETHYL-; *2-BORNANONE-; *2-CAMPHANONE-; *CAMPHOR--NATURAL-; *HUILE-DE-CAMPHRE-; *KAMPFER-; *2-KETO-1,7,7-TRIMETHYLNORCAMPHANE-; *Norcamphor,-1,7,7-trimethyl-; *1,7,7-TRIMETHYLBICYCLO(2.2.1)-2-HEPTANONE; *1,7,7-TRIMETHYLNORCAMPHOR- RN: 76-22-2 RELT: 900 [CAMPHENE] MF: *C10-H16-O SHPN: UN 2717; Camphor, natural or synthetic ASCH: Camphor (dl); 21368-68-3; Camphor (l); 464-48-2; Camphor (d); 464-49-3; Beta-Camphor; 10292-98-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CAN BE OBTAINED FROM STEAM DISTILLATION OF PARTS OF THE CAMPHOR TREE; HOWEVER IT IS USUALLY MADE FROM ALPHA-PINENE VIA CAMPHENE, TO BORNYL ACETATE, FOLLOWED BY SAPONIFICATION AND OXIDATION [R1] */NATURAL/ TRUE CAMPHOR OIL IS /STEAM/ DISTILLED FROM FORMOSAN AND JAPANESE VARIETIES. ... THE WOOD ... CONTAINS CRUDE CRYSTALLINE CAMPHOR THAT IS REMOVED BY FILTER PRESSING. ... OIL IS ... VACUUM RECTIFIED, YIELDING /MORE/ CAMPHOR AND ... FRACTIONS SOLD COMMERCIALLY ... /WHITE, BROWN, YELLOW, AND BLUE CAMPHOR OIL/ [R2, 301] FORM: *Grades: technical (synthetic); USP. [R3] *ALCANFOR [R4] *Bornane, 2-oxo- [R5] *FORMOSA CAMPHOR *GUM CAMPHOR *JAPAN CAMPHOR *LAUREL CAMPHOR *NATRICARIA CAMPHOR *ROOT BARK OIL *SPIRIT OF CAMPHOR +CAMPHO-PHENIQUE LIQUID CONTAINS 10.85% CAMPHOR, CAMPHO-PHENIQUE POWDER CONTAINS 4.38% CAMPHOR [R6, p.V-112] +PREPARATONS OF CAMPHOR FOR LOCAL APPLICATION INCUDE CAMPHOR SPIRIT (10% IN ALCOHOL) AND CAMPHORATED PARACHLOROPHENOL (35% PARACHLOROPHENOL AND 65% CAMPHOR)/AND/... AS A 0.1 TO 3% LOTION [R7] MFS: +Lonza Inc, Hq, 17-17 Route 208, Fair Lawn, NJ 07410, (201) 794-2400; Specialty Chemicals Division; Production site: Williamsport, PA 17701 [R8] OMIN: *MORE THAN 3/4 OF CAMPHOR SOLD IN US IS PRODUCED SYNTHETICALLY, AND MOST IS SOLD IN THE RACEMIC FORM, ALTHOUGH USP SPECIFIES THE D-FORM. INCOMPATIBLE WITH POTASSIUM PERMANGAGANTE; SALTS OF ANY KIND SHOULD NOT BE ADDED TO CAMPHOR WATER. [R9, 238] +CAMPHOR (2-CAMPHANONE) AND CAMPHORATED OILS ARE NO LONGER USED AS STIMULANTS IN CLINICAL MEDICINE. NEITHER IS PERMITTED AS AN INTERNAL MEDICATION (EXCEPT IN PARAGORIC), AND CAMPHORATED OIL HAS BEEN BANNED ON THE AMERICAN MARKET [R6, p.III-84] USE: +USED IN MFR OF PLASTICS; AS PLASTICIZER FOR CELLULOSE ESTERS AND ETHERS; IN LACQUERS AND VARNISHES; IN EXPLOSIVES; IN PYROTECHNICS; IN EMBALMING FLUID; IN MFR OF CYMENE; IN CAMPHORATED PARACHLOROPHENOL, PAREGORIC, AND FLEXIBLE COLLODION [R9, 238] +MEDICATION +MEDICATION (VET) *ISOLATION OF CINEOL, SAFROLE, LINALOOL, AND IN PERFUMERY /CAMPHOR OIL/ [R2, 303] +INSECT REPELLANT (PARTICULARLY TO CONTROL CLOTHES MOTHS); COSMETIC INGREDIENT (DEPILATORIES, DEODORANT); COUNTER-IRRITANT [R1] *IN FLAVORS JAPANESE WHITE CAMPHOR OIL (FEMA NO 2231) HAS BEEN REPORTED USED IN ... NON-ALCOHOLIC BEVERAGES 5.4 PPM, BAKED GOODS 1.6-48 PPM, AND CONDIMENTS 15 PPM. /CAMPHOR OIL/ [R2, 303] PRIE: U.S. PRODUCTION: *(1972) ND [R1] *(1975) ND [R1] +(1986) ND U.S. IMPORTS: *(1972) 3.71X10+7 GRAMS (NATURAL AND SYNTHETIC) [R1] *(1975) 5.8X10+8 GRAMS (NATURAL, SYNTHETIC, ADVANCED) [R1] +(1984) 7.6X10+8 g [R10] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS OR WHITE CRYSTALS, GRANULES, OR CRYSTALLINE MASSES; OR AS COLORLESS TO WHITE, TRANSLUCENT, TOUGH MASSES [R11]; *RHOMBOHEDRAL CRYSTALS FROM ALCOHOL; CUBIC CRYSTALS BY MELTING AND CHILLING [R9, 238]; +Colorless or white crystals. [R12] ODOR: *FRAGRANT AND PENETRATING ODOR [R9, 238]; +Penetrating aromatic odor. [R12] TAST: *SLIGHTLY BITTER AND COOLING TASTE [R9, 238] BP: *204 DEG C [R9, 238] MP: *179.75 DEG C [R9, 238] MW: *152.26 [R5] DEN: *0.992 @ 25 DEG C/4 DEG C [R9, 238] SOL: *1 G DISSOLVES (@ 25 DEG C) IN: 800 ML WATER, 1 ML ALCOHOL, 1 ML ETHER, 0.5 ML CHLOROFORM, 0.4 ML BENZENE, 1.5 ML OIL OF TURPENTINE, 0.5 ML GLACIAL ACETIC ACID; SOL IN ANILINE, NITROBENZENE, CARBON DISULFIDE, TETRALIN, DECALIN, METHYLHEXALIN, PETROLEUM ETHER, HIGHER ALCOHOLS, FIXED AND VOLATILE OILS, CONCN MINERAL ACIDS IN PHENOL, LIQ AMMONIA, AND LIQ SULFUR DIOXIDE [R9, 238]; +water solubility = 1.60X10+3 mg/l @ 25 deg C [R13] SPEC: *INDEX OF REFRACTION: 1.5462 @ 20 DEG C/D; MAX ABSORPTION (ALCOHOL): 290 NM (LOG E= 1.48) [R14, p. C-211]; *MAX ABSORPTION (CHLOROFORM): 292 NM [R9, 238]; *MAX ABSORPTION (ACID AND BASE SALT SOLVENTS): 304 NM [R15, 257] VAPD: *5.24 (AIR= 1) [R16, p. 325M-48] VAP: +0.65 mm Hg @ 25 deg C [R17] OCPP: *Liquefies when triturated with chloral hydrate, menthol, resorcinol, beta-naphthol, salol, thymol, phenol, urethan; peculiar tenacity and cannot be powdered in a mortar unless moistened with an organic solvent; at 80 deg C and 12 mm pressure sublimes within 60 min [R9, 238] *NATURAL FORM-DEXTROROTARY; SYNTHETIC FORM-RACEMIC [R18, 16] *EFFECTIVELY ADSORBED BY ACTIVATED CHARCOAL [R19] *EUTECTIC TEMP WITH BENZIL 50 DEG C [R15, 454] *SUBLIMES @ BOILING POINT [R14, p. C-211] *SPECIFIC OPTICAL ROTATION: 44.26 DEG @ 20 DEG C/D (D FORM); -44.2 DEG @ 16 DEG C/D (ALCOHOL, 16.5%) (L FORM) [R14, p. C-212] *It is precipitated from its alcoholic soln by the addition of water; it is precipitated from camphor water by the addition of sol salts [R11] +IR: 6049 (Coblentz Society Spectral Collection) /Camphor (dl)/ [R20] +UV: 90 (Sadtler Research Laboratories Spectral Collection) /Camphor (dl)/ [R20] +NMR: 30 (Sadtler Research Laboratories Spectral Collection) /Camphor (dl)/ [R20] +MASS: 912 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Camphor (dl)/ [R20] +IR: 6049 (Coblentz Society Spectral Collection) /Camphor (l)/ [R20] +UV: 96 (Sadtler Research Laboratories Spectral Collection) /Camphor (l)/ [R20] +NMR: 2707 (Sadtler Research Laboratories Spectral Collection) /Camphor (l)/ [R20] +MASS: 912 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Camphor (l)/ [R20] +IR: 6049 (Coblentz Society Spectral Collection) /Camphor (d)/ [R20] +UV: 96 (Sadtler Research Laboratories Spectral Collection) /Camphor (d)/ [R20] +NMR: 30 (Sadtler Research Laboratories Spectral Collection) /Camphor (d)/ [R20] +MASS: 912 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Camphor (d)/ [R20] +MASS: 489 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /Beta-Camphor/ [R20] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible material. May be ignited by friction, heat, sparks or flames. Some may burn rapidly with flare burning effect. Powders, dusts, shavings, borings, turnings or cuttings may explode or burn with explosive violence. Substance may be transported in a molten form. May re-ignite after fire is extinguished. [R21] +Health: Fire may produce irritating and/or toxic gases. Contact may cause burns to skin and eyes. Contact with molten substance may cause severe burns to skin and eyes. Runoff from fire control may cause pollution. [R21] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R21] +Protection clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R21] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R21] +Fire: Small fires: Dry chemical, CO2, sand, earth, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Cool containers with flooding quantities of water until well after fire is out. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R21] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch or walk through spilled material. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Large spills: Wet down with water and dike for later disposal. Prevent entry into waterways, sewers, basements or confined areas. [R21] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Removal of solidified molten material from skin requires medical assistance. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R21] FPOT: *Evolves flammable vapors when heated ... [R3] NFPA: *Health: 0. 0= Materials which on exposure under fire conditions would offer no hazard beyond that of ordinary combustible material. [R16, p. 325M-48] *Flammability: 2. 2= Materials which must be moderately heated before ignition will occur. Water spray may be used to extinguish the fire because the material can be cooled below its flash point. [R16, p. 325M-48] *Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R16, p. 325M-48] FLMT: *Lower 0.6%; upper: 3.5% [R16, p. 325M-48] FLPT: *150 deg F; 66 deg C (CC) [R16, p. 325M-48] AUTO: *871 deg F (466 deg C) [R16, p. 325M-48] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEMICAL [R22] EXPL: *... CAMPHOR ... WILL REACT VIOLENTLY WITH CHROMIC ANHYDRIDE. /CHROMIC ANHYDRIDE PLUS NAPHTHALENE/ [R16, p. 491M-126] *Evolves explosive vapors when heated ... [R3] REAC: +Strong oxidizers (especially chromic anhydride and potassium permanganate). /Synthetic/ [R23, 48] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. /Synthetic/ [R23, 49] +Wear appropriate eye protection to prevent eye contact. /Synthetic/ [R23, 49] +Recommendations for respirator selection. Max concn for use: 50 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Eye protection needed. /Synthetic/ [R23, 49] +Recommendations for respirator selection. Max concn for use: 100 mg/cu m. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Eye protection needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. /Synthetic/ [R23, 49] +Recommendations for respirator selection. Max concn for use: 200 mg/cu m. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. /Synthetic/ [R23, 49] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Synthetic/ [R23, 49] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Synthetic/ [R23, 49] OPRM: +Contact lenses should not be worn when working with this chemical. /Synthetic/ [R23, 49] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. /Synthetic/ [R23, 49] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Synthetic/ [R23, 49] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Synthetic/ [R23, 49] SSL: *SUBLIMES APPRECIABLY AT ROOM TEMP AND PRESSURE. [R9, 238] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R24] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R25] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. /Camphor, synthetic/ [R27] ANTR: +A 2-yr old boy drank approx 9.15 ml of Camphophenique (10.8% camphor). Approx 10 min later, while en route to the emergency department, the child experienced a tonic-clonic seizure lasting 4 to 5 min. On arrival, his vital signs showed blood pressure of 100/72 mm Hg, pulse 124/min, unlabored respirations 24/min and temp of 37 deg C. The child was lethargic and initially did not respond to pain. Management included placement of iv lines and infusion of 17 mg/kg phenobarbital. Orogastric lavage was followed by instillation of 15 g activated charcoal. A room air arterial blood gas revealed pH, 7.36, PO2, 110; and PCO2, 36. Complete blood count, electrolytes, liver function test, serum ammonia, and chest radiography were normal. Phenobarbital, 30 mg iv every 12 hr was continued. Mental status cleared over the next 24 hr. [R28] HTOX: *SYMPTOMATOLOGY (WITHIN 5 TO 90 MIN AFTER INGESTION): 1. NAUSEA AND VOMITING ... 2. FEELING OF WARMTH. HEADACHE. 3. CONFUSION, VERTIGO, EXCITEMENT, RESTLESSNESS, DELIRIUM, AND HALLUCINATIONS. 4. INCR MUSCULAR EXCITABILITY, TREMORS, AND JERKY MOVEMENTS. 5. EPILEPTIFORM CONVULSIONS, FOLLOWED BY DEPRESSION. CONVULSIONS SOMETIMES OCCUR EARLY IN SYNDROME AND MAY BE SEVERE ... 6. COMA. CNS DEPRESSION MAY ... BE PRIMARY CLINICAL RESPONSE. 7. DEATH RESULTS FROM RESPIRATORY FAILURE OR FROM STATUS EPILEPTICUS. 8. SLOW CONVALESCENCE (DAYS OR WEEKS), OFTEN WITH PERSISTENT GASTRIC DISTRESS. [R29] *IN CASES WHERE EXCESSIVE DOSE OF 0.06-4 G WERE ADMIN, VISUAL DISTURBANCES HAVE ... BEEN ASSOCIATED WITH GENERAL EXCITATION. AN APPEARANCE OF FLICKERING, DARKENING, OR VEILING OF VISION ... ACCOMPANIED NOISES IN EAR, WEAKNESS, AND ... CONVULSIONS. [R30] *SKIN BECOMES CLAMMY AND THE FACE IS ALTERNATELY FLUSHED AND PALE ... PULSE IS WEAK AND RAPID /WHEN TOXIC CONCN INGESTED/. [R31] *One and one half g have been ingested ... in an adult ... with recovery ... in children 0.7 to 1.0 g has proved fatal. ... Urinary retention, albuminuria, and anuria are ... described in non-fatal cases, but kidney lesions in fatal poisonings are not always prominent. Mild and transient hepatic derangements may occur and widespread hemorrhages are described in one fatal case. ... fetal death ... resulted /after camphor ingestion by mother/ ... postmortem exam revealed severe atelectasis and central neuronal necrosis ... [R29] *Camphor remains in over 950 products listed in Poisindex. ... a review of all camphor ingestions est to be 2 mg/kg or greater was made ... seventy-three patients (90%) remained asymptomatic, three (4%) developed minor symptoms, and five (6%), all ingesting over 59 mg/kg, developed major symptoms. There were no deaths. [R32] NTOX: *When taken by mouth, camphor can cause fatal poisoning. The lethal dose in the dog is 9-14 g. The general effects ... preliminary stimulation, with subsequent paralysis, of the central nervous system. Death is due to asphyxia. [R33] *Neuronal necrosis ... produced exptl in mice by ... admin of multiple doses. [R29] *THE INFLUENCE OF SYSTEMIC CAMPHOR POISONING ON PUPILS HAS BEEN INVESTIGATED IN RABBITS; MYDRIASIS IS CHARACTERISTIC. [R30] *In the liver microsomes of female mice, two induction phases during inhalation of DL-camphor were found. During the first 24 hr the apparent molar activity of the ethylumbelliferone dealkylase decr very much. In the second phase, the molar ethylumbelliferone dealkylase activity was constant. [R34] *In urethane-anesthetized rabbits, ... camphor had a vasodilating action in the isolated rabbit-ear vessels when directly applied to the vessel at 50%. [R35] ADE: *ABSORPTION THROUGH MUCOUS MEMBRANES OCCURS RAPIDLY ... TOXIC LEVEL MAY BE ACHIEVED WITHIN FEW MIN AFTER INGESTION. CAMPHOR ... REMOVED FROM BLOODSTREAM ... EITHER BY THE LIVER ... OR LIPID DEPOSITS ... [R31] *... after camphor ingestion by mothers ... camphor was detectable in maternal blood 15 min after ingestion, but not after 8 hr. At delivery 36 hr later ... it was present in amnionic fluid, cord and fetal blood and fetal brain, liver and kidneys. [R29] *ALIMENTARY ABSORPTION OF PURE CAMPHOR, OR OF ALCOHOL SOLN ... IS QUITE RAPID, BUT FROM THE OIL PREPN ABSORPTION IS CONSTANT. CAMPHOR IS ... SLOWLY ABSORBED FROM SC OR IM DEPOTS. [R18, 16] *ABSORBED CAMPHOR IS MAINLY ELIMINATED AS THE OXIDIZED CAMPHOROL IN THE URINE, ALTHOUGH SOME APPEARS IN THE BREATH, SWEAT, AND FECES. [R4] METB: *CAMPHOR IS PARTIALLY OXIDIZED ... AND PARTIALLY CONJUGATED WITH GLYCURONIC ACID. [R18, 17] *D-CAMPHOR IS HYDROXYLATED BY RAT AND RABBIT-LIVER MICROSOMES TO YIELD THREE PRODUCTS: 5-EXO-HYDROXYCAMPHOR, 5-ENDO-HYDROXYCAMPHOR, AND A 3-HYDROXYCAMPHOR OF UNKNOWN STEREOCHEMISTRY. L-CAMPHOR IS OXIDIZED SIMILARLY. /D-CAMPHOR/ [R36, 462] *THE 2-KETO-GROUP OF D-CAMPHOR WAS NOT REDUCED BY RAT LIVER PREPN, BUT WAS RAPIDLY REDUCED IN RABBIT LIVER CYTOSOL TO YIELD ... BORNEOL, AND A SMALL AMT OF ... ISOBORNEOL. /D-CAMPHOR/ [R36, 519] *BORNANE-2,5-DIONE WAS ALSO DETECTED AS A MINOR METABOLITE OF CAMPHOR ... IN RAT AND RABBIT-LIVER PREPN ... [R36, 438] *THE METABOLISM OF (+)-CAMPHOR AND (-)-CAMPHOR WAS INVESTIGATED IN RABBITS AFTER ADMIN OF STOMACH TUBE; METABOLITES OF (+)-CAMPHOR WERE (+)-BORNEOL, (+)-5-ENDO-HYDROXYCAMPHOR, and (+)-3-ENDOHYDROXYCAMPHOR. [R37] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Local; Antipruritics; Pharmaceutic Aids [R38] *IT /SRP: WAS FORMERLY/ USED ... IN HUMANS FOR INFLAMED JOINTS, SPRAINS, AND RHEUMATIC AND OTHER INFLAMMATORY CONDITIONS SUCH AS COLDS IN THROAT AND CHEST. ... PT MAY FEEL IMPROVED /HOWEVER/ INFLAMMATION IS NOT AFFECTED. [R11] *MEDICATION (VET): LOCALLY, CAMPHOR IS WEAKLY ANTISEPTIC AND HAS A RUBEFACIENT ACTION WHEN APPLIED TO SKIN. IT IS A COMMON INGREDIENT OF MANY LINIMENTS. [R39] *MEDICATION (VET): /CAMPHOR/ ... AS A STEAM INHALANT HAS BEEN POPULAR IN RESPIRATORY DISEASES OF HORSES AND POULTRY. ORALLY, IT HAS BEEN POPULAR IN ANTIFERMENT AND CARMINATIVE MIXTURES FOR CALF SCOURS, AND IN EXPECTORANT MIXTURES. [R4] +MEDICALLY AS TOPICAL ANTI-INFECTIVE AND ANESTHETIC [R9, 238] +MEDICATION (VET): EXTERNALLY AS ANTIPRURITIC, COUNTERIRRITANT AND ANTISEPTIC; /SRP: FORMERLY USED/ INTERNALLY AS STIMULANT AND CARMINATIVE [R9, 239] +MEDICATION: CAMPHORATED PARACHLOROPHENOL ... IS USED IN DENTISTRY FOR THE TREATMENT OF INFECTED ROOT CANALS [R7] WARN: *MEDICATION (VET): /SRP: FORMERLY/ ... DEEP IM INJECTIONS WERE REQUIRED TO AVOID ABSCESSATION. INJECT NECESSARY DOSAGE IN TWO OR MORE SITES. [R4] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *OBTAINED FROM CAMPHOR TREE, CINNAMOMUM CAMPHORA (L), LAURACEAE, WHICH IS NATIVE TO CHINA, FORMOSA, AND JAPAN ALONG WITH RELATED VARIETIES. /FROM TABLE/ [R2, 300] *CAMPHOR SAFROLE, HON-SHO VARIETY /JAPAN AND FORMOSA/: ... OIL FROM LEAVES, WOOD, AND STUMPWOOD CONTAINS FREE CRYSTALLINE CAMPHOR. ... CAMPHOR LINALOOL, HO-SHO VARIETY ... CONTAINS 42% CAMPHOR. [R2, 301] *GC/MS anal of Indian patchouli oil revealed the presence of 39 volatile compds /including camphor/. [R40] *Fifty-three of the 56 gas-chromatog peaks found in the steam-distd oils obtained from foliage collected in Mexico were identified /including camphor/ and amts are tabulated; of these compds, 48 were found in both. ... In general, Juniperus flaccida flaccida had more sesquiterpenoids and diterpenes than Juniperus flaccida poblana, and several compds found were unusual for juniper leaf oils. Morphol and chem anal indicated that these species are considerably different from other juniper species in the Western Hemisphere. [R41] *Terpenes and other constituents /including camphor/ were identified in the volatile leaf oils of the junipers of Guatemala and Chiapas, Mexico: Juniperus comitana, Juniperus gamboana, and Juniperus standleyi by gas chromatography/mass spectrometry. [R42] *The 19 components of the terpenoid and sesquiterpenoid fractions, which were identified, constituted 90.3% of these fractions. Camphor, isobornyl valerate, and isobornyl butyrate (25.7%, 17.8%, and 10% of the essential oil wt, were the main components of ... Salvia garedzhii essential oil. [R43] *Essential oils from all needle and bark samples, collected ... from 46 species of 11 genera of Pinaceae, Taxodiaceae, and Cupressaceae, contained varying amts of ...camphor. [R44] *The avg oil content of the aerial parts of R. officinalis was 1-52 mL/100 g dry material. The oil contained ... camphor. [R45] *S triloba leaves from wild plants in 8 regions of Greece / were found to contain camphor/. [R46] *The major componenents of O. kilimandscharicum oil from Brazil was camphor. [R47] *Samples off oils from A. arborescens L. Leaf and flower was /found to contain camphor/. [R48] RTEX: *CAMPHOR EXPOSURE IN A PACKAGING PLANT IS DISCUSSED. [R49] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +200 mg/cu m /Synthetic/ [R23, 48] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2 mg/cu m. /Synthetic/ [R23, 48] TLV: +8 hr Time Weighted Avg (TWA): 2 ppm; 15 min Short Term Exposure Limit (STEL): 3 ppm. /Camphor, synthetic/ [R27] +A4; Not classifiable as a human carcinogen. [R27] WSTD: STATE DRINKING WATER GUIDELINES: +(NH) NEW HAMPSHIRE 200 ug/l [R50] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *CAMPHOR IN SPIRITS. COLORIMETRIC DETERMINATION. 39.064-39.067. CAMPHOR. GAS CHROMATOGRAPHY AND GAS-LIQUID CHROMATOGRAPHY. [R51] *IODOMETRIC DETERMINATION OF CAMPHOR. [R52] *HIGH-PRESSURE LIQ CHROMATOGRAPHIC DETERMINATION OF CAMPHOR IN CAMPHORATED PARACHLOROPHENOL. [R53] *DETERMINATION OF CAMPHOR IN WATER BY GAS CHROMATOGRAPHY USING FLAME IONIZATION DETECTOR. [R54] *GAS-LIQ CHROMATOGRAPHIC DETERMINATION OF SOLVENTS IN NAIL LACQUER PREPN. [R55] *Analyte: camphor; matrix: air; procedure: adsorption on charcoal, desorption with eluent, gas chromatography; range: 6-27 mg/cu m. [R56] *Chromatographic mass spectrometric study of toxic substances /including camphor/ adsorbed on dust [R57] *The identification and quantitative determination of drugs in vaseline (petrolatum) and plastibase (mineral oil, combination ...) ointment bases ... were carried out with the use of AIR-IR spectrometry. ... This technique was also successfully used for the in situ determination of the solubility of drugs (camphor and thymol) in ointment bases. [R58] *The Chinese medicine Bingpian containing ... camphor was analyzed by gas-liquid chromatography with a column containing 2.81% PEG-20M on Chromosorb G-HP as stationary phase. ... Camphor was calculated by peak height method. [R59] *Camphorated oil (20% camphor) was analyzed by ... reverse-phase HDLC /High-Pressure Liquid Chromatography/ with UV detection. The UV detector was set at 368.5 nm and the samples were eluted from C18 column by 82% acetonitrile in water. [R60] *Samples of oil from A. argorescens L. leaf and flower was analyzed by capillary gas chromatography-mass spectrometry. [R48] CLAB: *A screening and confirmation procedure for drugs and metabolites /including camphor/ in the blood serum and urine of racing animals was developed /using tandem mass spectrometry/. Equine blood serum was spiked with low concn of several drugs of interest. Canine blood serum and urine were collected following oral doses of diethylcarbamazine, procaine, and phenylbutazone. Serum, urine, and exts of each were analyzed, using a triple quadrupole mass spectrometer. Simultaneous screening of up to 50 drugs was possible in a single sample, in < 2 min. Detection limits for most compds were in the ng/ml to mug/ml range, using 1 mul samples. This procedure provided fast, sensitive screening for selected drugs and metabolites in blood serum and urine. [R61] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Briggs GG et al; Drugs In Pregnancy and Lactation: A Reference Guide To Fetal and Neonatal Risk (Drugs C); Drugs Preg Lactation 42-100 (1984) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on dl-camphor is scheduled for peer review. Route: topical; Species: rats and mice. [R62] SO: R1: SRI R2: Fenaroli's Handbook of Flavor Ingredients. Volume 1. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. R3: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 189 R4: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 74 R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 85/8404 R6: GOSSELIN. CTCP 5TH ED 1984 R7: GOODMAN. PHARM BASIS THERAP 7TH ED 1985 R8: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 511 R9: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. R10: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-390 R11: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 724 R12: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 48 R13: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R14: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 64th ed. Boca Raton, Florida: CRC Press Inc., 1983-84. R15: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R16: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978. R17: Jones AH; J Chem Eng Data 5: 196-200 (1960) R18: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. R19: Arena, J.M. Poisoning: Toxicology-Symptoms Treatments. Third Edition. Springfield, Illinois: Charles C. Thomas, 1974. 28 R20: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 381 R21: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-133 R22: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 515 R23: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R24: 49 CFR 171.2 (7/1/96) R25: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 116 R26: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.4017 (1988) R27: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.20 R28: Gibson DE et al; Am J Emerg Med 7 (1): 41-3 (1989) R29: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-85 R30: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 226 R31: Arena, J. M. Poisoning: Toxicology, Symptoms, Treatments. Fourth Edition. Springfield, Illinois: Charles C. Thomas, Publisher, 1979. 404 R32: Geller RJ et al; Vet Hum Toxicol 26(2): 8-10 (1984) R33: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 125 R34: Mohn G; Different phases of hydroxylase induction in liver microsomes of female mice during inhalation of cyclohexane and D,L-camphor; Microsomes Drug Oxid, Proc Int Symp, 3rd: 59-66 (1977) R35: Futami T; Nippon Yakurigaku Zasshi: 83(3): 219-26 (1984) R36: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. R37: ROBERTSON JS, HUSSAIN M; METABOLISM OF CAMPHORS AND RELATED COMPOUNDS; BIOCHEM J 113 (1): 57-65 (1969) R38: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R39: Jones, L.M., et al. Veterinary Pharmacology and Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. 414 R40: Akhila A, Nigam MC; Fitoterapia 55 (6): 363-5 (1984) R41: Adams RP et al; J Nat Prod 47 (6): 1064-5 (1984) R42: Adams RP et al; J Nat Prod 48 (4): 678-81 (1985) R43: Zamureenko VA et al; Khim Prir Soedin (6): 720-2 (1984) R44: Kilesnikova RD; Rastit. Resur 21(2): 130-40 (1985) R45: Hodisan V et al; Clujul Med 57(4): 374-7 (1984) R46: Catsiotis S, Iconomon NG; Pharm Acta Helv 59(1): 29-32 (1984) R47: Codignota A; Essenze Deriv Argum 54(1): 91-101 (1984) R48: Codignola A; Allionia 26: 89-95 (1984) R49: GRONKA PA ET AL; CAMPHOR EXPOSURES IN A PACKAGING PLANT; AM IND HYG ASSOC J 30 (3): 276-9 (1969) R50: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R51: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/752 39.062 R52: EMELYANENKO KV; IODOMETRIC DETERMINATION OF CAMPHOR; FARM ZH (KIEV) 29 (4): 54-7 (1974) R53: MUSTO JD ET AL; HIGH-PRESSURE LIQ CHROMATOGRAPHIC DETERMINATION OF CAMPHOR AND PARACHLOROPHENOL IN CAMPHORATED PARACHLOROPHENOL; J PHARM SCI 67 (2): 266 (1978) R54: WOOD NF, SNOEYINK VL; 2-METHYLISOBORNEOL, IMPROVED SYNTHESIS AND A QUANTITATIVE GAS CHROMATOGRAPHIC METHOD FOR TRACE CONCENTRATIONS PRODUCING ODOR IN WATER; J CHROMATOGR 132 (3): 405-20 (1977) R55: STUTSMAN MJ; GAS-LIQ CHROMATOGRAPHIC DETERMINATION OF SOLVENTS IN COMMERCIAL NAIL LACQUER PREPARATION; J ASSOC OFF ANAL CHEM 60 (MAY): 658-62 (1977) R56: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V2 S10-1 R57: DMITRIEV MT et al; Gig Sanit; 0 (1): 44-47 (1984) R58: Rupprecht H, Lill N; Pharm Ztg 129(Mar 22): 690-694 (1984) R59: DongY; Sepu 2(1): 40-2 (1985) R60: Gallicano KD et al; J Anal Toxicol 9(1): 24-30 (1985) R61: Brotherton HO, Yost RA; Am J Vet Res; 45 (11): 2436-40 (1984) R62: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 35 Record 6 of 1119 in HSDB (through 2003/06) AN: 41 UD: 200302 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACETONE- SY: *ACETON- (GERMAN,DUTCH,POLISH); *AI3-01238-; *Caswell-No.-004-; *DIMETHYL-KETONE-; *EPA-Pesticide-Chemical-Code-004101-; *KETONE,-DIMETHYL-; *KETONE-PROPANE-; *BETA-KETOPROPANE-; *METHYL-KETONE-; *PROPANONE-; *2-propanone- RN: 67-64-1 MF: *C3-H6-O SHPN: UN 1090; Acetone IMO 3.1; Acetone STCC: 49 081 05; Acetone HAZN: U002; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. F003; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *(1) BY DESTRUCTIVE DISTILLATION OF WOOD. (2) BY DISTILLATION OF CALCIUM ACETATE. (3) BY FERMENTATION OF CORN PRODUCTS BY SELECTED BACTERIA. (4) BY CATALYTIC OXIDATION OF ISOPROPYL ALCOHOL, CUMENE, OR NATURAL GAS. [R1, 413] *MOST USA/ACETONE/PRODUCTION BASED ON CUMENE PROCESS /IN WHICH/ BENZENE AND PROPYLENE ARE REACTED TO FORM CUMENE. CUMENE IS THEN OXIDIZED WITH AIR /TO PRODUCE/ CUMENE HYDROPEROXIDE /WHICH/ IS THEN DECOMPOSED OR CLEAVED WITH ACID TO YIELD PHENOL AND ACETONE. [R2] IMP: *PURITY: TECHNICAL AND REAGENT : 99.5% PLUS 0.5% WATER. [R3] *The chief impurity in acetone ... water. Acetone contains no oxidizable impurities, and the color of a few drops of permanganate is retained for several hours. [R4] MFS: *Allied-Signal, Inc, Hq, Columbia Road and Park Avenue, Morristown, NJ 07960, (201) 455-2000; Engineered Materials Sector; Production site: Philadelphia, PA 19137 [R5] *Eastman Chemical Company, Hq, 343 State Street, Rochester, NY 14650, (716) 724-4000; Eastman Chemical Products, Inc; Tennessee Eastman Company; Production site: Kingsport, TN 37662 [R5] *General Electric Company, Hq, 3135 Easton Turnpike, Fairfield, CT 06431, (203) 373-2211; GE Plastics, One Plastics Avenue, Pittsfield, MA 01201; Production site: Mount Vernon, IN 47620 [R5] *Georgia Gulf Corporation, Hq, 400 Perimeter Center Terrace, Suite 595, Atlanta, GA 30348, (404) 395-4500; Production site: Bound Brook, NJ 08805 [R5] *The Goodyear Tire and Rubber Company, Hq, 1144 East Market Street, Akron, OH 44316, (216) 796-2121; General Products Division; Production site: Bayport, TX 77058 [R5] *JLM Chemicals Company, 3350 West 131st Street, P.O. Box 598, Blue Island, IL 60406. (708)388-9373 [R5] *Shell Oil Company, Hq, One Shell Plaza, Houston, TX 77252-2463; Shell Chemical Company, division (address same as Hq); Production sites: Deer Park, TX 77536 (Houston Plant); Wood River, IL 62095 [R5] *Texaco, Inc, Hq, 2000 Westchester Avenue, White Plains, NY 10650, (914) 253-4000; Subsidiary: Texaco Chemical Company, 4800 Fournace Place, Bellaire, TX 77401, (713) 666-8000; Production site: El Dorado, KS 67042 [R5] *Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817, (203) 794-2000; Chemicals and Plastics Business Group; Solvents and Coatings Materials Division; Production site: Institute, WV 25103 [R5] *Aristech Chemical Corp, Hq, 600 Grant St, Pittsburgh, PA 15219, (412) 433-2747; Production site: Haverhill, OH 45638 [R5] *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Oyster Creek, TX 77541 [R5] OMIN: *DISINFECTANT WHEN USED IN HIGH CONCENTRATIONS, BEING RAPIDLY BACTERICIDAL FOR MICROCOCCUS AUREUS, BUT NOT SPORICIDAL, THOUGH IT INDUCES DELAY IN THE GROWTH OF SPORES. [R1, 413] *EXXON AT BAYWAY, NJ AND UNION CARBIDE AT PENUELAS, PR ARE ON STANDBY. MONSANTO, CHEVRON, SHELL AND CYANAMID HAVE CLOSED APPROXIMATELY 445 MILLION LB OF ACETONE CAPACITY SINCE 1982 [R6, (1985)] *DURING 1984, APPROXIMATELY 15% OF US ACETONE OUTPUT WAS DERIVED FROM ISOPROPANOL [R2] *0.40-0.45 kg of acetone per kg of cumene are produced as a coproduct with phenol via cumene peroxidation route. Stated in terms of phenol, one kg of phenol production will result in 0.6 kg of acetone. [R7, p. V1 181] *Acetone is a co-product of liquid-phase-oxidation of butane. It may be produced from isobutane, an impurity present in all commercial butane. [R8, p. 12(80) 842] USE: *SOLVENT FOR FATS, OILS, WAXES, RESINS, RUBBER, PLASTICS, LACQUERS, VARNISHES, RUBBER CEMENTS [R9] *MFR MESITYL OXIDE, ACETIC ACID, DIACETONE ALCOHOL, CHLOROFORM, IODOFORM, BROMOFORM [R9] *MFR EXPLOSIVES, AIRPLANE DOPES, RAYON, ISOPRENE, PHOTOGRAPHIC FILMS, STORING ACETYLENE GAS [R9] *EXTRACTION OF VARIOUS PRINCIPLES FROM ANIMAL AND PLANT SUBSTANCES; IN PAINT AND VARNISH REMOVERS; PURIFYING PARAFFIN [R9] *HARDENING AND DEHYDRATING TISSUES [R9] *NAIL POLISH REMOVER [R10] *CHEM INT FOR METHYL METHACRYLATE, METHACRYLIC ACID AND HIGHER METHACRYLATES, METHYL ISOBUTYL KETONE, METHYL ISOBUTYL CARBINOL, BISPHENOL A, ISOPHORONE; SPINNING SOLVENT IN MFR OF CELLULOSE ACETATE; SOLVENT FOR ADHESIVES AND PRINTING INKS, ACETYLENE [R11] *Manufacture of smokeless powder. [R12, 112] *Acetone is used for the production of modacrylic fibers, for either wet spinning or dry spinning. [R8, p. 1(78) 380] *Acetone is used as a raw material in the manufacturing of acetic anhyride. [R7, p. V1 145] *Preparation of vitamin intermediates. [R7, p. V1 192] *Acetone is used as a brine for low temperature heat transfer in indirect refrigeration. [R8, p. 20(82) 91] *The evaporation rate of acetone makes it quite useful for cleaning and drying precision parts. [R13] CPAT: *25% FOR METHYL METHACRYLATE; 14% FOR METHYL ISOBUTYL KETONE; 10% AS COATING SOLVENT; 10% FOR OTHER ORGANIC CHEMS; 6% IN PHARMACEUTICAL MANUFACTURE; 5% FOR METHACRYLIC ACID AND HIGHER METHACRYLATES; 5% FOR BISPHENOL-A; 4% FOR CELLULOSE ACETATE SPINNING; 21% FOR MISC (1973) [R11] *33% METHYL METHACRYLATE, METHACRYLIC ACID AND HIGHER METHACRYLATES; 17% SOLVENTS; 10% MIBK; 9% BISPHENOL-A; 7% ALDOL CHEMICAL; 6% PHARMACEUTICALS AND COSMETICS; 2% METHYL ISOBUTYL CARBENOL; 4.5% EXPORTS; 11.5% MISC (1985) [R6, 1985] *CHEMICAL PROFILE: Acetone. Methylmethacrylate, methacrylic acid and higher methacrylates, 34%; coatings solvent, 15%; bisphenol-A, 12%; MIBK (methyl isobutyl ketone), 10%; solvent for cellulose acetate, 5%; drug and pharmaceutical applications, 5%; miscellaneous chemical and solvent uses, 6%; exports, 5%. [R14] *CHEMICAL PROFILE: Acetone. Demand: 1986: 1,936 million lb; 1987: 2,050 million lb; 1991 /projected/: 2,140 million lb. [R14] *Demand 1995: 2.76 billion pounds; 1996: 2.72 billion pounds; 2000 (projected) 3.2 billion pounds. [R15] PRIE: U.S. PRODUCTION: *(1972) 7.74X10+11 G [R11] *(1975) 7.45X10+11 G [R11] *(1984) 7.90X10+11 g [R16] *(1984) 5.58X10+10 g [R16] *(1987) 9.5X10+5 tons [R7, p. V1 186] *United States acetone production 1,102,426X10+3 kg [R17] *(1990) 2.33 billion lb [R18] *(1992) 2.43 billion lb [R19] *(1991) 2.35 billion lb [R20] *(1993) 2.46 billion lb [R19] U.S. IMPORTS: *(1972) 1.18X10+10 G [R11] *(1975) 1.36X10+9 G [R11] *(1983) 2.48X10+6 g [R21] *(1987) 7.5X10+4 tons [R7, p. V1 186] U.S. EXPORTS: *(1972) 4.11X10+10 G [R11] *(1975) 2.93X10+10 G [R11] *(1984) 3.76X10+10 g [R22] *(1987) 1.18X10+5 tons [R7, p. V1 186] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R23] ODOR: *Fruity odor [R12, 112] TAST: *PUNGENT, SWEETISH [R9] BP: *56.0 DEG C @ 760 MM HG [R24] MP: *-94.8 DEG C [R24] MW: *58.08 [R24] CTP: *Critical temperature: 455 deg F= 235 deg C= 508 deg K; critical pressure: 46.4 atm [R3] DEN: *0.7899 AT 20 DEG C/4 DEG C [R24] DSC: *pKa = 20 [R25] HTC: *Liquid: -1787 kJ/mol (-427 kcal/mol) [R7, p. V1 178] HTV: *220 Btu/lb= 122 cal/g [R3] OWPC: *Log Kow= -0.24 [R26] SOL: *SOLUBLE IN BENZENE [R24]; *MISCIBLE WITH WATER, ALCOHOL, DIMETHYLFORMAMIDE, ETHER [R9]; *MISCIBLE WITH CHLOROFORM, MOST OILS [R9] SPEC: *INDEX OF REFRACTION: 1.3588 AT 20 DEG C/D [R24]; *IR: 77 (Sadtler Research Laboratories IR Grating Collection) [R27]; *UV: 89 (Sadtler Research Laboratories Spectral Collection) [R27]; *NMR: 9288 (Sadtler Research Laboratories Spectral Collection) [R27]; *MASS: 30 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R27]; *Intense mass spectral peaks: 43 m/z, 58 m/z [R28] SURF: *0 deg C: 26.2 mN/m; 20 deg C: 23.7 mN/m; 40 deg C: 21.2 mN/m [R7, p. V1 177] VAP: *231 mm Hg at 25 deg C [R29] VISC: *0.32 cP at 20 deg C [R7, p. V1 177] OCPP: *Saturation concentration: 553 g/cu m [R12, 112] *Specific heat of liquid: 2.6 J/g (0.62 cal/g) at 20 deg C; specific heat of vapor: 92.1 J/(mol x k) (22.0 cal/mol x k) at 102 deg C; electric conductivity: 5.5x10-8 sec/cm at 25 deg C; heat of formation at 25 deg C: gas -216.5 kJ/mol, liquid: -248 kJ/mol. [R7, p. V1 177-178] *Heat of fusion: 23.42 cal/g [R3] *Partition coefficients at 37 deg C for acetone into blood = 245; into oil = 86. [R30] *Henry's Law constant = 1.87X10-5 atm-cu m/mole at 25 deg C [R31] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R32] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R32] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R32] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R32] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R32] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R32] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R32] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R32] FPOT: *Highly flammable liquid. Dangerous disaster hazard due to fire and explosion hazard ... [R33, 19] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R34, p. 325-10] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R34, p. 325-10] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R34, p. 325-10] FLMT: *LOWER LIMIT 2.15%; UPPER LIMIT 13.0% [R35, 4723] FLPT: +-20 DEG C (-4 DEG F) (CLOSED CUP) [R34, p. 325-10] *0 deg F (closed cup) [R33, 18] AUTO: *869 DEG F [R3] FIRP: *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame - consider evacuation of one-third mile radius. [R36] *If material is on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water and apply water from as far a distance as possible. Use alcohol foam, carbon dioxide, or dry chemical. [R36] *Flammable. Flashback along vapor trail may occur. Vapor may explode if ignited in an enclosed area. Extinguish with dry chemical, alcohol foam, or carbon dioxide. Water may be ineffective on fire. Cool exposed containers with water. [R37, 80] OFHZ: *FLASHBACK ALONG VAPOR TRAIL MAY OCCUR. [R3] EXPL: *Highly flammable liquid. Dangerous disaster hazard due to fire and explosion hazard ... [R33, 19] *UPPER 12.8%, LOWER 2.6%. [R33, 18] *VAPOR MAY EXPLODE IF IGNITED IN AN ENCLOSED AREA. [R3] REAC: +MIXTURE OF ACETONE AND CHLOROFORM IN A RESIDUE BOTTLE EXPLODED. SINCE ADDITION OF CHLOROFORM TO ACETONE IN PRESENCE OF A BASE WILL RESULT IN A HIGHLY EXOTHERMIC REACTION, IT IS THOUGHT THAT A BASE MAY HAVE BEEN IN THE BOTTLE. [R34, p. 491-8] +ACETONE MAY FORM EXPLOSIVE MIXTURES WITH CHROMIC ANHYDRIDE, CHROMYL CHLORIDE, HEXACHLOROMELAMINE, HYDROGEN PEROXIDE, NITRIC ACID, ACETIC ACID, NITRIC ACID AND SULFURIC ACID, NITROSYL CHLORIDE, NITROSYL PERCHLORATE, NITRYL PERCHLORATE, PERMONOSULFURIC ACID, POTASSIUM TERT-BUTOXIDE, THIODIGLYCOL AND HYDROGEN PEROXIDE. [R34, p. 491-8] +AN EXPLOSION OCCURRED DURING AN ATTEMPT TO PREPARE BROMOFORM FROM ACETONE BY THE HALOFORM REACTION. ACETONE IGNITED WHEN IT WAS ACCIDENTALLY SPLASHED INTO A SULFURIC ACID-DICHROMATE SOLUTION. [R34, p. 491-8] +Oxidizers, acids. [R38, 2] *Potentially explosive reaction with nitric acid + sulfuric acid, bromine trifluoride, nitrosyl chloride + platinum, nitrosyl perchlorate, chromyl chloride, thiotrithiazyl perchlorate, and (2,4,6-trichloro-1,3,5-triazine + water). Reacts to form explosive peroxide products with 2-methyl-1,3-butadiene, hydrogen peroxide, and peroxomonosulfuric acid. Ignites on contact with activated carbon, chromium trioxide, dioxygen difluoride + carbon dioxide, and potassium-t-butoxide. Reacts violently with bromoform, chloroform + alkalies, bromine, and sulfur dichloride. Incompatible with CrO, (nitric + acetic acid), NOCl, nitryl perchlorate, permonosulfuric acid, NaOBr, (sulfuric acid + potassium dichromate), (thio-diglycol + hydrogen peroxide), trichloromelamine, air, HNO3, chloroform, and H2SO4. [R33, 19] ODRT: *WATER: 20 MG/L (OR 20 PPM, W/V); AIR: 13 UL/L (OR 13 PPM, V/V). [R39] *Odor low: 47.5 mg/cu m; Odor high: 1613.9 mg/cu m [R40] SERI: *EXPOSURE FOR 15 MINUTES TO 1660 PPM CAUSES IRRITATION OF EYES AND NOSE ... [R41] EQUP: *Protective equipment made from natural rubber, viton, neoprene, polyvinyl alcohol, neoprene/natural rubber, or nitrile have breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers. [R42] *Protective clothing made from polyethylene or chlorinated polyethylene; the data suggests breakthrough times of approximately an hour or more. [R42] *No data is available regarding break-through times for clothing made from styrene-butadiene rubber, nitrile/polyvinyl chloride, or polyurethane. [R42] +Wear appropriate eye protection to prevent eye contact. [R38, 3] +Wear appropriate personal protective clothing to prevent skin contact. [R38, 3] +Recommendations for respirator selection. Max concn for use: 2500 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R38, 3] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R38, 3] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R38, 3] OPRM: *Personnel protection: Avoid breathing vapors. Keep upwind. Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R36] *Direct contact with the skin should be avoided. Acetone should never be used as a cleaning agent for the skin. [R8, p. 1(78) 186] *A major concern in the painting studio is solvents, /including acetone/. ... Precautions include ... use of dilution and local exhaust ventilation, control of storage areas, disposal of solvent soaked rags in covered containers, minimizing skin exposure and the use of respirators and other personal protective equipment. The control of fire hazards is also important, since many of the solvents are highly flammable. [R43] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R36] +Contact lenses should not be worn when working with this chemical. [R38, 3] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. [R38, 3] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R38, 3] *Keep away from plastic eyeglass frames, jewelry, pens and pencils, rayon stockings and other rayon garments. [R9] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R44] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R45] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R46] STRG: *Store acetone in closed containers, and keep away from heat, sparks, and flames. [R8, p. 1(78) 187] *Acetone is stored in steel tanks [R8, p. 1(78) 186] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R47] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U002, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R47] *Incineration: Spray into a furnace. Incineration will become easier by mixing with a more flammable solvent. [R48] *Acetone is a good candidate for fluidized bed incineration with a temperature of 450-980 deg C and with residence times for liquids and gases: seconds. [R49] *Acetone is a good candidate for rotary kiln incineration with a temperature of 820-1,600 deg C and with residence time for liquids and gases: seconds. [R49] *Acetone is a good candidate for liquid injection incineration with a temperature of 650-1,600 deg C with a residence time of 0.1-2 seconds. [R49] *This compound should be susceptible to removal from waste water by air stripping. [R50] *Small amounts can be burned after pouring on dry sand. Larger quantities can be atomized into an approved type combustion chamber. [R37, 78] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +Exposure to acetone results from both natural and anthropogenic sources. Acetone also occurs as a metabolic component in blood, urine and human breath. ... Acetone is one of three ketone bodies that occur naturally throughout the body. It can be formed endogenously in the mammalian body from fatty acid oxidation. Fasting, diabetes mellitus and strenuous exercise increase endogenous generation of acetone. Under normal conditions, the production of ketone bodies occurs almost entirely within the liver and to a smaller extent in the lung and kidney. ... Products are excreted in the blood and transported to all tissues and organs of the body where they can be used as a source of energy. Two of these ketone bodies, acetoacetate and beta-hydroxybutyrate, are organic acids that can cause metabolic acidosis when produced in large amounts, as in diabetes mellitus. ... Endogenous acetone is eliminated from the body either by excretion in urine and exhaled air or by enzymatic metabolism. ... Acetone is rapidly absorbed via the respiratory and gastrointestinal tracts of human and laboratory animals, as indicated by the detection of acetone in blood within 30 min of inhalation exposure and 20 min of oral administration. ... The nasal cavities of human and laboratory animals appear to have a limited ability to absorb and excrete acetone vapor, compared with the remainder of the respiratory tract. Acetone is uniformly distributed among non-adipose tissues and does not accumulate in adipose tissue. ... Acetone is rapidly cleared from the body by metabolism and excretion. ... Exhalation is the major route of elimination for acetone and its terminal metabolite (carbon dioxide), and the fraction of administered acetone that is exhaled as unchanged acetone is dose-related. Urinary excretion of acetone and its metabolites occurs but this route of elimination is minor ... Exogenously supplied acetone enters into many metabolic reactions in tissues throughout the body, but the liver appears to be the site of most extensive metabolism. Carbon from orally administered acetone has been detected in cholesterol, amino acids, fatty acids and glycogen in rat tissues, urea in urine and unchanged acetone and CO2 in exhaled breath. Metabolically, acetone is degraded to acetate and formate ... Oral LD50 values in adult rats are in the range of 5800-7138 mg/kg. ... Experimental animal data characterizing the effects of long term oral or inhalation exposure to acetone are not available, due probably to its low toxicity and its endogenous characteristics. ... Pretreatment of rodents with acetone enhances the hepatotoxic effects of a number of compounds, notably halogenated alkanes. ... Acetone is not considered to be genotoxic or mutagenic. ... In a study of pregnant rats and mice exposed to acetone vapor during days 6-19 of gestation, slight developmental toxicity was observed ... Reports of other reproductive effects of acetone include observations of testicular effects and changes of sperm quality in rats ... Acetone has been used extensively as a solvent vehicle in skin carcinogenicity studies and is not considered carcinogenic when applied to the skin. Acetone is relatively less toxic than many other industrial solvents; however, at high concentrations, acetone vapor can cause CNS depression, cardiorespiratory failure and death. Acute exposures of humans to atmospheric concentrations ... have been reported to produce either no gross toxic effects or minor transient effects, such as eye irritation. More severe transient effects (including vomiting and fainting) were reported for workers exposed to acetone vapor concentrations ... for about 4 hr. Acute exposures to acetone have also been reported to alter performances in neurobehavioral tests in humans. ... Females ... were reported to suffer menstrual irregularities. [R51] CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Based on lack of data concerning carcinogenicity in humans or animals. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: None. [R52] +A4; Not classifiable as a human carcinogen. [R53, 2002.13] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Ketones and related compounds/ [R54] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary. ... For contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport. ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Ketones and related compounds/ [R54] MEDS: *Urinary glucaric acid and the ratio between 6-beta-OH-cortisol and 17-OH-corticosteroids were determined in chemical workers exposed to styrene greater than or equal to 164 mg/cu m, and acetone greater than or equal to 571 mg/cu m, and in a control group. Exposed workers had significantly higher excretion of glucaric acid and a higher ratio. ... Urinary mercapturic acids were also increased. Simultaneous styrene and acetone exposure induces mono-oxygenases in humans. ... [R55] HTOX: *EFFECTS SIMILAR TO ETHYL ALCOHOL ... BUT ANESTHETIC POTENCY IS GREATER. 10-20 ML TAKEN BY MOUTH WITHOUT ILL EFFECT. IN ACUTE CASES A LATENT PERIOD MAY BE FOLLOWED BY RESTLESSNESS AND VOMITING LEADING TO HEMATEMESIS AND PROGRESSIVE COLLAPSE WITH STUPOR. [R56, p. III-168] *WORKERS HAVING BEEN EXPOSED TO 1000 PPM, 3 HR/DAY FOR 7-15 YEARS, ALSO COMPLAINED OF CHRONIC INFLAMMATION OF AIRWAYS, STOMACH AND DUODENUM; SOME OF THEM COMPLAINED OF DIZZINESS AND ASTHENIA. SIMILAR COMPLAINTS WERE REPORTED AFTER EXPOSURE ... TO 700 PPM. [R57] *PROLONGED OR REPEATED SKIN CONTACT MAY DEFAT THE SKIN AND PRODUCE DERMATITIS. [R35, 4720] *... Onset of hepatorenal lesions in two men and two women acutely exposed to acetone /is described/. One person had inhaled acetone vapors whereas the others had ingested acetone. Clinical manifestation of liver injury was observed in all four workers and renal lesions were detected in two. [R35, 4725] *Repeated exposure to 25-920 ppm: chronic conjunctivitis, pharyngitis, bronchitis, gastritis, and gastroduodenitis. /Route not specified/ [R58] *SYMPTOMATOLOGY (acute intoxication): 1. Early emotional lability: exhilariation, boastfulness, talkativeness, remorse, and belligerency. 2. Impaired motor coordination: slowed reaction time, slurred speech, ataxia. 3. Sensory disturbances: diplopia, vertigo. 4. Flushing of face, rapid pulse, sweating. 5. Nausea and vomiting. Eventual incontinence of urine and feces. 6. Drowsiness, stupor and finally coma, with impaired or absent tendon reflexes. Convulsive episodes may indicate hypoglycemia. /Ethyl alcohol/ [R56, p. III-169] *SYMPTOMATOLOGY (acute intoxication): 7. Pupils dilated or normal. 8. Peripheral vascular collapse (shock): hypotension, tachycardia, cold pale skin, hypothermia. 9. Slow stertorous respirations. 10. Death from respiratory or circulatory failure or from aspiration pneumonitis. 11. During convalescence: postalcoholic headache and gastritis; infections (for example, pneumonia, septicemia); alcoholic psychoses (for example, delirium tremens). /Ethyl alcohol/ [R56, p. III-169] *Acute acetone intoxication was reported in a 10-year old boy who wore a hip cast set with a mixture of 90% acetone, 9% pentane and 1% methyl salicylate. The following symptoms were described: restlessness, headache, vomiting (positive benzidine for blood), stupor, blood pressure 80/60, rapid and irregular respiration rate. [R59] *A total of 659 males occupationally exposed to acetone and other solvents were divided into nine unrelated groups working in plastic boat, chemical, plastic button, paint, and shoe factories. Urine samples were collected at the beginning of the workshift and at the end of the first half of the shift. A close relationship (correlation coefficient always above 0.85) between the average environmental solvent concentration (mg/cu m) measured in the breathing zone and the urinary concentration of unchanged solvent (ug/l) was observed. A Biological Equivalent Exposure Limit (56 mg/l) corresponding to the environmental Threshold Limit Value (58 mg/l) was recommended for acetone. The biological exposure data for urine collected over 4 hr during random sampling for at least 1 yr could be used to evaluate long-term exposure and probability of non-compliance for individual or groups of workers. [R60] *Direct contact of acetone with the eyes may produce irritation and corneal injury. [R8, p. 1(78) 186] *High vapor concentrations will produce anesthesia. [R8, p. 1(78) 186] *Acetone can be placed among solvents of comparatively low acute and chronic toxicities. Acetone does not have sufficient warning properties to prevent repeated exposures to vapors which may have adverse effects. There has been no reports that prolonged inhalation of low vapor concentrations result in any serious chronic effects in humans. [R8, p. 1(78) 186] *Severe toxic effects: 4,000 ppm= 9,650 mg/cu m, 60 minutes; symptoms of illness: 800 ppm= 1,930 mg/cu m, 60 minutes. [R58] *Toxic concn in human blood: 200.0-300.0 ug/ml (20.0-30.0 mg %); lethal concn in human blood: 550.0 ug/ml (55.0 mg %) [R61] *Symptoms following acute acetone ingestion include nausea, vomiting, gastric hemorrhage, sedation, respiratory depression, ataxia, and paresthesia. Depression resembles alcoholic stupor, but its onset is quicker than that with ethanol. Coughing and bronchial irritation may be the only clues to ingestion of quantities that are too small to produce sedation. Hyperglycemia and ketonemia with acidosis that resembles acute diabetic coma may be present. [R62] *EXPOSURE FOR 15 MINUTES TO 1660 PPM CAUSES IRRITATION OF EYES AND NOSE ... [R41] NTOX: *SUMMARY OF RESULTS OF SINGLE EXPOSURES OF ANIMALS TO THE VAPORS: MICE 20,256 PPM, 1.5 HR: CNS DEPRESSION. MICE 46,000 PPM, 1 HR: FATAL. RATS 126,600 PPM, 1.75-2.25 HR: FATAL. RATS 42,200 PPM, 1.75-2.0 HR: LOSS OF CORNEAL REFLEX. GUINEA PIGS 20,000 PPM, 8-9 HR: LOSS OF REFLEXES. [R35, 4721] */INVESTIGATORS/ ... STUDIED THE EFFECTS ON CATS OF REPEATED EXPOSURES TO ACETONE VAPORS. THEY USED DOSES OF 3 TO 5 MG/L (1265 TO 2110 PPM) AND OBSERVED NO ILL EFFECTS OTHER THAN SLIGHT IRRITATION OF THE EYES AND NOSE. [R35, 4721] */Investigators/ ... reported that acetone produced moderate corneal injury to rabbit eyes. /Others/ ... reported mild ocular edema. Small multiple doses of acetone admin percutaneously (0.5 ml) or sc (0.05 ml) over a period of 3 to 8 wk produced cataracts in guinea pigs. ... No cataracts were seen in control animals. ... In a subsequent study conducted similarly, acetone produced cataracts in guinea pigs, but not in rabbits. [R35, 4721] *... GRANULAR DEGENERATION IN LESS SEVERE /INTOXICATIONS/, AND NECROSIS OF TUBULAR EPITHELIUM /IN MORE SEVERE INTOXICATIONS/ /OF KIDNEYS/ WERE /OBSERVED/ IN DOGS/. ... /OTHER WORK INDICATED/ LESIONS OF THE CONVOLUTED TUBULES, SOME FATTY INFILTRATION /OF THE KIDNEYS/ IN 1 CAT FOLLOWING INHALATION OF 75,900 PPM ... ALBUMINURIA /WAS SEEN/ IN SOME ... ANIMALS SUBJECTED TO INHALATION. [R1, 418] *WITH ACUTE INTOXICATION PRELIMINARY /SPECIES NOT SPECIFIED/ SYMPTOMS OF ... /CNS DEPRESSION/ ARE IRRITATIVE--SALIVATION, LACRIMATION, GIDDINESS, ATAXIA, TWITCHINGS AND CONVULSIONS. ... AFTER IV AND IM INJECTION FALL IN BLOOD PRESSURE ... /WAS/ REGARDED AS PRIMARILY DUE TO DECREASE IN CARDIAC OUTPUT. [R1, 417] *MALE MICE AND RATS WERE EXPOSED FOR VARYING TIME PERIODS TO VAPOR LEVELS OF 12,600-50,600 PPM ACETONE. UNCONDITIONED PERFORMANCE AND REFLEX TESTS WERE USED TO MEASURE CNS DEPRESSION. ANIMALS BREATHING ACETONE TOOK 9 HR TO RECOVER FROM 5 MIN EXPOSURE. BLOOD LEVELS WERE RELIABLE DEPRESSION INDEX. [R63] *A SHORT INHALATION EXPT WAS PERFORMED ON MICE USING VARIOUS INDUSTRIAL AIRBORNE CHEMICALS, INCL ACETONE. FOR EACH CMPD SYSTEMATIC DETERMINATION OF CONCN ASSOC WITH A 50% DECR IN RESP RATE WAS USED FOR COMPARISONS. DATA MAY HELP ESTABLISH WORKPLACE TLV'S. [R64] *Sensitivity of developing chicken embryos to various solvents was investigated. Acetone (0.10 ml/egg injected) significantly reduced the percentage hatchability and caused a high embryonic mortality during the first wk of incubation. [R65] *10.5 day-old rat embryos were cultured for 2 days in whole rat serum containing 0.1, 0.5, and 2.5 vol% of acetone. No adverse effects occurred at 0.1% concn. The order of increasing embryotoxicity and dysmorphogenesis of the studied liquids was corn oil < acetone/corn oil < dimethyl sulfoxide < ethanol, acetone < Tween 80. Any of the water miscible solvents (at 0.1%) met the criteria of a nontoxic and nonteratogenic water insol cmpd delivery system for in vitro embryo culture. [R66] *Hepatocytes from young male rats were incubated in acetone in closed vessels fitted with side arms for serial sampling for approx 5 hr at 37 deg C with gentle shaking under an oxygen:carbon dioxide atmosphere. Parameters evaluated were glutamate-oxaloacetate transaminase and lactate dehydrogenase release from cells, trypan blue exclusion, cell count, urea synthesis capability, and steady-state ATP levels. Acetone /10 mM/ was without effect /in LDH or GOT release/. Isolated hepatocyte suspensions are useful for identification of cytotoxins in general and hepatotoxins in particular, but their capability for yielding a quantitative index of cytotoxic potential for diverse chemical species remains to be demonstrated. [R67] *Acetone (reagent grade) was evaluated by the standard plate incorporation method in the Ames Salmonella reverse mutation assay with strains TA98, TA100, TA1535, TA1537, AND TA1538. Experiments were done in triplicate with and without metabolic activation (S9 fractions from Aroclor-treated Sprague-Dawley rats). Results were negative in these strains. [R68] *At a concn of 8,100 mg/l of acetone, there was an approximate 50% inhibition of ammonia oxidation of Nitrosomonas. [R12, 114] *Acetone was used as a solvent control in this experiment and 0.2 ml was applied to the shaved dorsa of 50 male and 50 female SHEL:CF1,SPF mice once per week from six weeks of age to two years. All dead and dying animals were autopsied as well as all animals still alive at 2 years. Local irritation was noted at the application site of a few animals. One subcutaneous fibrosarcoma observed in one male was considered ... to be incidental. There were 17/50 tumors in the males and 13/50 tumors in the females, considered to be a normal rate for this strain (primarily tumors of the lymphoreticular or hematopoietic system). A second study using 100 mice for each sex, and identical treatment and autopsy regimens resulted in negative results for the skin and similar background rates for tumors of the lymphoreticular or hematopoietic systems, ie: 30/100 for males and 29/100 for the females. [R69] *The frequency of recessive chlorophyll and embryonic lethals included by N-methyl-N'-nitro-N-nitrosoguanidine in Arabidopsis thaliana was markedly increased when exposure of the seeds to N-methyl-N'-nitro-N-nitrosoguanidene (3 hr) was carried out in the presence of 4-12% acetone, 4-16% ethanol, or 8-32% dimethylformamide. The enhancement of N-methyl-N'-nitro-N-nitrosoguanidene mutagenicity was proportional to the concentrations of these organic solvents. In contrast, none of the solvents, when applied at the same conditions and doses, influenced the mutagenic activity of N-methyl-N-nitrosourea. The solvents without mutagens did not influence the spontaneous rate of mutations and revealed no or very weak toxic effect as measured by the seed germination. [R70] *Female Sprague-Dawley-rats were given 0.5, 1, or 2.5 ml/kg of acetone once by gavage. Sodium phenobarbital (SPB), 100 mg/kg, was administered once a day for 3 days. The animals were killed 24 hours after the last dose. Livers were homogenized and microsomes were prepared by differential centrifugation. Microsomal lipids were extracted with a 2 to 1 chloroform methanol mixture. The extracted samples were assayed for total phosphate or resuspended in saline and assayed for cholesterol. Treatment with acetone did not cause alterations in the concentrations of total phospholipid (TPL) and total cholesterol (TC) in microsomal membranes. Acetone had no effect on microsomal N-demethylation of aminopyrine, however, at the high dose, it significantly increased the metabolism of acetonitrile to cyanide. Acetone did not significantly change the concentration of cytochrome p450. [R71] *The purpose of this study was to determine if acetone could alter the acute nephrotoxicity produced by the experimental fungicide N-(3,5-dichlorophenyl)succinimide. Male Fischer 344 rats were administered acetone (1, 5 or 10 mmol/kg) or acetone vehicle (corn oil, 10 mg/kg) orally followed 16 hr later by a single intraperitoneal injection of N-(3,5-dichlorophenyl)succinimide (0.2 or 0.4 mmol/kg) or N-(3,5-dichlorophenyl)succinimide vehicle (sesame oil, 2.5 ml/kg) and renal function was monitored at 24 and 48 hr. Acetone (1 or 5 mmol/kg) did not alter N-(3,5,-dichlorophenyl)succinimide (0.2 mmol/kg) induced renal effects while acetone (10 mmol/kg) pretreatment attenuated N-(3,5-dichlorophenyl)succinimide (0.4 mmol/kg) induced increases in blood urea nitrogen (BUN) concentration and kidney weight but had no effect on N-(3,5,-dichlorophenyl)succinimide (0.4 mol/kg) induced changes in urine volume or content, organic ion accumulation by renal cortical slices or renal morphology. [R72] *The effects of combinations of chemicals known to individually induce aneuploidy were tested on the diploid Saccharomyces-cerevisiae strain D61.M. Exponential phase cultures of the yeast were treated with nocodazole, ethyl acetate, acetone, and methyl ethyl ketone alone or in combination, incubated at 28 degrees C for 4 hours, held in an ice bath for 16 hours, incubated at 28 degrees C for an additional 4 hours, and then diluted and plated onto selective media. Treatment of yeast strain D61.M with mixtures containing nocodazole levels too low to induce aneuploidy and ineffective low levels of the solvents ethyl acetate, acetone, and methyl ethyl ketone was highly effective in inducing aneuploidy. The synergistic effect did not depend on the cold holding period during treatment. [R73] *In studies of acetone-potentiated liver injury induced by haloalkanes, acetone is usually given by gavage, whereas industrial exposure to acetone normally occurs by inhalation. It was of interest to verify if the route of administration influences the potentiation. Male Sprague-Dawley rats were exposed for 4 hr to acetone vapors or treated orally with acetone; the minimal effective dose levels for potentiating CCl4-induced liver injury were estimated to be 2500 ppm and 0.25 mg/kg, respectively. Groups were treated with acetone using 0.4, 1, 2, 4, or 6 times the minimal effective dose. Half of each group was killed at various time intervals after treatment for blood acetone measurements by gas chromatography; the other half was challenged with CCl4 (0.1 ,l/kg, ip) 18 hr after acetone, and killed 24 hr later. Plasma alanine aminotransferase (ALT) activity and bilirubin concentrations were measured. Inhalation and oral administration of acetone both potentiated CCl4 toxicity. Rats exposed repetitively to acetone vapors (10 daily exposures) and subsequently challenged with CCl4 exhibited liver toxicity that was not significantly different from that of rats subjected to a single exposure. Correlations between ALT activities and maximal bloodacetone concentrations were found to be linear (positive) and significant for both routes. For a given blood acetone concentration, however, toxicity was least severe following acetone exposure by inhalation. [R74] *The susceptibility of New Zealand White rabbits and albino guinea pigs to the cataractogenic effects of dermal acetone treatments. Male and female rabbits treated with 1 ml of acetone 3 days/wk for 3 weeks showed no lens abnormalities during the 6 month observation period. Male and female guinea pigs were treated with 0.5 ml of acetone 5 days/wk for 6 weeks and examined with an ophthalmoscope and slip lamp at regular intervals for 1 yr post-treatment. By 3 months post-treatment, cataracts were observed in 30% of the test animals and none of the control animals. The ascorbate levels in aqueous humor specimens from the test throughout the 1 yr observed period. It was concluded that the development of cataracts in guinea pigs was species specific and related to ascorbate synthesis. [R75, 239] *The reproductive effects of acetone in male Wistar rats administered 0.5% acetone in their drinking water for 6 wk. On fifth week of treatment, the rats were allowed to mate with untreated females and the number of matings were recorded together with the number of pregnancies and the number of fetuses per pregnancy. The absolute weight of the testes was measured along with the diameter of the seminiferous tubules in the treated and control rats. Semiquantitative histopathological scoring was used to detect any effects on vacuole formation, chromatic margination, epithelial disruption, multinucleated giant-cell formation, intracellular debris, or atrophy of the testes. None of these measures of reproductive and testicular toxicity were affected by the acetone treatment relative to the control animals. [R75, 242] *The avoidance and escape behavior of female Carworth rats exposed to acetone vapors for 10 days at 4 hr/day (180). Groups of animals were trained to avoid (conditioned response) or escape (unconditioned response) a shock stimulus by climbing a pole situated in a test chamber with an electric grid on the floor. Each animal was evaluated before and after daily acetone exposures of 3000, 6000, 12,000, and 16,000 ppm. The 3000 ppm exposure were without effect on all exposure days, the 6000 ppm exposure inhibited the avoidance but not the escape response, and the two highest exposures inhibited both responses. Normal responses were obtained after three days of exposure to 6000 and 12,000 ppm, which indicated adaptation and tolerance developed on repeated exposure to acetone vapors. [R75, 176] *Groups of male Sprague-Dawley rats were exposed for 3 hr to acetone concentrations of 12,600, 19,000, 25,300, and 50,600 ppm. The degree of /CNS depression/ was measured at regular intervals during and after the exposure by performing five tests (wire maneuverability, visual pacing, grip strength, tail pinch, and righting reflex) that measured unconditioned performance and involuntary reflex. Each animal was scored between 0 and 8 on each of these tests, and the individual results were averaged to obtain a mean performance score. Performance scores showed a dose-related decline at all but the highest acetone exposure level. Animals exposed to 50,600 ppm of acetone died within 2 hr of initiating the exposure. The performance score for the group of rats exposed to 19,000 ppm of acetone returned to the preexposure level after 9 hr, whereas the group exposed to 25,300 ppm of acetone required 21 hr before its performance score returned to base-line levels. [R75, 176] *Single-dose oral lethality studies have been performed in mice, rats, and rabbits. A 14-day oral LD50 of 10.7 ml/kg (8.5 g/kg) and 95% confidence limits of 7.7 to 15.0 ml/kg (6.2 to 11.9 g/kg) for female Carworth-Wistar rats was reported. Using the same test conditions and test species, ... the LD50 value was found to be 12.6 ml/kg (9.8 g/kg) and the 95% confidence limits to be 10.6 to 14.9 ml/kg (8.5 to 11.9 g/kg). ... An oral LD50 value of 5.3 g/kg for an unstated sex and strain of rabbit and an LD50 value between 4 and 8 g/kg for an unstated sex and strain of mouse was reported. Using male ddY mice, ... the oral LD50, of acetone was found to be 90.39 mmol/kg (5.25 g/kg) with 95% confidence limits of 61.68 to 132.5 mmol/kg (3.58 to 7.70 g/kg). [R75, 180] *A group of male baboons was exposed continuously (24 hr/day) to 500 ppm acetone for 7 days. The percentage of correct and incorrect responses was recorded along with the time necessary to respond precisely to a stimulus-induced discrimination task that resulted in a food reward when performed correctly. The acetone exposure caused no change in the number of correct responses, a highly variable change in the number of extra incorrect responses, and a consistent increase in the response time relative to control values. The authors did not measure blood or urine acetone levels; however, the uninterrupted exposure undoubtedly resulted in an extremely high acetone body burden. Acetone exposures were performed at 150 ppm for times ranging from 30 min to 4 hr. [R75, 178] *Male Swiss mice were placed in a container of water and the lag time between water contact and the initiation of swimming behavior was measured relative to a control group. A nominal concentration of 2000 ppm caused no change in swimming behavior, whereas concentrations ranging from about 2600 to 3000 ppm caused the swimming lag time to decrease up to 59%. [R75, 178] HTXV: *In children 2 to 3 ml/kg is considered to be toxic. [R62] NTXV: *LD50 Rat oral 10.7 ml/kg; [R9] ETXV: *LC50 JAPANESE QUAIL ORAL GREATER THAN 40,000 PPM, IN DIET, AGE 14 DAYS, (NO MORTALITY TO 40,000 PPM); [R76] *LC50 RING-NECKED PHEASANT ORAL GREATER THAN 40,000 PPM, IN DIET, AGE 10 DAYS, (NO MORTALITY TO 40,000 PPM); [R77] *LC50 SALMO GAIRDNERI (RAINBOW TROUT) 5,540 MG/L/96 HR @ 12 DEG C (95% CONFIDENCE LIMIT 4,740-6,330 MG/L), WT 1.0 G /STATIC BIOASSAY/; [R78] *LD100 Asellus aquaticus 3 ml/l (within 3 days of exposure) /Conditions of bioassay not specified/; [R79] *LD100 Gammarus fossarum 10 ml/l (within 48 hr) /Conditions of bioassay not specified/; [R79] *LC50 Pimephales promelas 8,120 mg/l/96 hr /Conditions of bioassay not specified/; [R80] *LC50 Daphnia magna 10 mg/L 24 to 48-Hr /Conditions of bioassay not specified/; [R12, 116] *LC50 Brine shrimp 2,100 mg/L 24 to 48-Hr /Conditions of bioassay not specified/; [R12, 116] *LC50 Mosquito fish 13,000 mg/L 24 to 96-Hr /Conditions of bioassay not specified/; [R12, 116] *LC50 Lepomis macrochirus (bluegill sunfish) 8,300 mg/L 96 hr /Conditions of bioassay not specified/; [R12, 116] *LD50 Goldfish 5,000 mg/L 24-hr /Conditions of bioassay not specified/; [R12, 116] *LC50 Poecilia reticulata (guppy) 7,032 mg/l 14 day /Conditions of bioassay not specified/; [R12, 116] *LC50 Mexican axolotl 20,000 mg/l (3-4 weeks after hatching) 48 hr /Conditions of bioassay not specified/; [R12, 116] *LC50 Clawed toad 24,000 mg/l (3-4 weeks after hatching) 48-hr /Conditions of bioassay not specified/; [R12, 116] *LC50 fingerling trout 6,100 mg/l 24-hr /Flow-through bioassay/; [R12, 116] NTP: +... The potential for acetone to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 440, 2200, or 11000 ppm, and in Swiss (CD-1) mice exposed to 0, 440, 2200, and 6600 ppm acetone vapors, 6 hr/day, 7 days/week. Each of the four treatment groups consisted of 10 virgin females (for comparison), and approximately 32 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 days of gestation. The day of plug or sperm detection was designated as 0 days of gestation. ... Pregnant rats did not exhibit overt symptoms of toxicity other than statistically significant reductions for the 11,000 ppm group in body weight. (14, 17, 20 days of gestation), cumulative weight gain from 14 days of gestation onward, uterine weight and in extragestational weight gain. (EGWG - maternal body weight (20 days of gestation) uterine weight - maternal body weight (0 days of gestation.) Mean body weights of treated virgin females were also reduced, but not significantly. There were no maternal deaths and the mean pregnancy rate was greater than or equal to 93% in all groups. No affect was observed in the mean liver or kidney weights of pregnant dams, the organ to body weight ratios, the number of implantations, the mean percent of live pups/litter, the mean percent of resorptions/litter, or the fetal sex ratio. However, fetal weights were significantly reduced for the 11,000 ppm exposure group relative to the 0 ppm group. The incidence of fetal malformations was not significantly increased by gestational exposure to acetone vapors, although the percent of litters with at least one pup exhibiting malformations was greater for the 11,000 ppm group than for the 0 ppm group, 11.5 and 3.8%, respectively. The diversity of malformations observed in the 11,000 ppm group was greater than that found in the lower dose groups or in the 0 ppm group. There was no increase in the incidence of fetal variations, reduced ossification sites, or in the mean incidence of fetal variations per litter. Analysis of rat plasma samples 30 min post-exposure showed an increase in plasma acetone levels which correlated with increasing exposure concentration. Acetone levels dropped to control levels by 17 hr post-exposure for all exposure groups except the 11,000 ppm group. Plasma acetone-levels for this group were still slightly elevated with respect to the controls at 17 hr post-exposure. The concentration of plasma acetone levels at either 30 min or 17 hr post exposure did not increase over gestation regardless of the exposure concentration. Neither exposure to acetone vapor, nor advancing gestation resulted in alterations of the plasma levels for the other two ketone bodies, acetoacetic acid and b-hydroxybutyric acid, with respect to control animals. Swiss (CD-1) mice exhibited severe ... /CNS depression/ at the 11,000 ppm acetone concentration; consequently, the high exposure concentration was reduced to 6600 ppm acetone after one day of exposure. No further overt signs of toxicity were observed and there were no maternal deaths. No treatment- related effects on maternal or virgin body weight, maternal uterine weight, or on extragestational weight gain were noted in mice. There was a treatment-correlated increase in liver to body weight ratios in pregnant dams which may have been indicative of an induction of the p450 monooxygenase enzyme system. The mean pregnancy rate for all mated mice was greater than or equal to 85% in all groups. There was no effect on the number of implantations per dam, on any other reproductive indices, or on the fetal sex ratio. Developmental toxicity was observed in mice in the 6,600 ppm exposure group as; 1) a statistically significant reduction in fetal weight, and 2) a slight, but statistically significant increase in the percent incidence of late resorptions. However, the increase in the incidence of late resorptions was not sufficient to cause a decrease in the mean number of live fetuses per litter. The incidence of fetal malformations or variations in mice was not altered by exposure to acetone vapors at any of the levels employed. It may be concluded from the results of this study that the 2,200 ppm acetone level was the no observable effect level (NOEL) in both the Sprague-Dawley (CD) rat and the Swiss (CD-1) mouse for developmental toxicity. Furthermore, since only minimal maternal toxicity was observed at 11,000 ppm acetone for rats and 6,600 ppm acetone for mice, it is possible that the actual maternal NOEL is somewhat greater than 2,200 ppm. [R81] ADE: *ACETONE IS ONE OF THE LEAST HAZARDOUS INDUSTRIAL SOLVENTS, BUT IS HIGHLY VOLATILE AND MAY BE INHALED IN LARGE QUANTITIES. IT MAY BE ABSORBED INTO THE BLOOD THROUGH THE LUNGS AND DIFFUSED THROUGHOUT THE BODY. SMALL QUANTITIES MAY BE ABSORBED THROUGH THE SKIN. [R57] *LARGE QUANTITIES OF ACETONE ARE RAPIDLY EXCRETED FOLLOWING EXPOSURE. ONLY A SMALL AMT IS REDUCED. EXCRETION MAINLY VIA LUNGS AND URINE ... ACETONE ABSORBED DURING 8 HOURS AT 200 PPM WILL BE COMPLETELY METABOLIZED OR EXCRETED WITHIN 16 HOURS ... [R57] *... THE AMT OF ACETONE ABSORBED WHEN FOOT OF ANIMAL WAS IMMERSED /WAS ESTIMATED/ BY MEASURING AMT EXHALED AND THAT PRESENT IN BLOOD. [R82, 1727] *ACETONE, BECAUSE OF ITS SOLUBILITY IN WATER, IS READILY ABSORBED INTO BLOOD STREAM AND THUS IS TRANSPORTED RAPIDLY THROUGHOUT BODY. ... A MAN BREATHING AN ESTIMATED CONCN OF 22 MG/L (9300 PPM) FOR 5 MIN ABSORBED 71% OF INHALED ACETONE; 2 MEN BREATHING 11 MG/L ... FOR 15 MIN ABSORBED 76-77% ... [R82, 1729] *... EXCRETION ... IN HUMANS IS RAPID FOR 8 HR AFTER A SINGLE ORAL DOSE BUT WAS NOT COMPLETE IN 24 HR. ... THE RATIO OF EXCRETION ... WAS APPROX 40-70% IN BREATH, 15-30% IN THE URINE, AND 10% OF TOTAL EXCRETED THROUGH SKIN. [R82, 1730] *In order to verify the relationship between urinary acetone concentrations and corresponding mean environmental concentrations in the breathing zone, the urinary concentration of acetone was measured in subjects experimentally or occupationally exposed to acetone. Fifteen healthy volunteers were exposed to acetone vapor concentrations of 56 to 500 ppm/cu m in an exposure chamber for 2 hours at rest or during alternating rest and light physical exercise. The urinary elimination of acetone was also studied in 104 workers occupationally exposed to acetone. The ratio of alveolar concentration to environmental concentration averaged approximately 0.28, and the relative uptake averaged 53%. The urinary acetone concentration showed a linear relationship to the corresponding environmentally time weighted average concentration in both the experimentally exposed subjects and the occupationally exposed subjects. There was also a linear relationship between the amount of acetone absorbed and the urinary concentrations of acetone. [R83] *The upper respiratory tract (URT) deposition of acetone was studied in vivo in male Syrian golden hamsters and in vitro using nasal tissue homogenates. A steady state for acetone deposition was obtained within 3 minutes in hamsters exposed to 1030 mg/cu m. Nasal perfusion of 0.046 ml/min (95% confidence limit, 0.035-0.58 ml/min) was calculated. The effect of flow rate on URT was described by a ventilation perfusion model. Acetone was not metabolized by in vitro homogenates. [R84] METB: *Two pathways for the conversion of acetone to glucose are proposed, the methylglyoxal and the propanediol pathways. The methylglyoxal pathway is responsible for the conversion to acetol, acetol to methylglyoxal, and subsequent conversion of methylglyoxal to glucose. The propanediol pathway involves the conversion of acetol to L-1,2-propanediol by an as yet unknown process. L-1,2-propanediol is converted to L-lactaldehyde by alcohol dehydrogenase, AND L-lactaldehyde is converted to L-lactic acid by aldehyde dehydrogenase. Expression of these metabolic pathways in rat appears to be dependent on the induction of /acetone/ oxygenase and acetol monooxygenase by acetone. [R85] *HEPATIC NAD-DEPENDENT ALCOHOL DEHYDROGENASE ... ENZYME IS CAPABLE OF CATALYZING REVERSE REACTION IN WHICH ... ACETONE ... /IS REDUCED TO ALCOHOL/. [R86] *Acetone may be converted to 1,2-propanediol which enters the glycolytic pathway and possibly the one carbon pool. Acetone has been shown to be converted to lactate in mice. The rate-limiting step appears to be the conversion of acetone to a hydroxylated intermediate. Rats and mice exposed to 30 mg/l of acetone, and rabbits and guinea pigs exposed to 72 mg/l for 2 hr, had increased levels of acetone, acetoacetic acid, and beta-hydroxybutyric acid in the blood and urine immediately after exposure and 24 hr later. [R35, 4726] *Acute admin of acetone to rats resulted in measureable levels of isopropanol in blood. Metabolism of acetone to isopropanol was different in normal and diabetic animals. Blood levels of isopropanol reached a max at 2 g/kg dose in normal rats, but there was a 2-phase response in diabetic rats. In a second series of experiments, acetone was admin on alternate days for a wk. In spite of this chronic admin, there was no enhancement of acetone metabolism to isopropanol. [R87] *The metabolic mechanism responsible for the incorporation of acetone into the glucose and amino acids of lactating cows. Normal and spontaneously ketotic cows (unspecified type) were given a single bolus iv dose of [2-14(C)] acetone. The casein and lactose isolated from milk specimens were digested to obtain their constituent amino acids and hexoses. The glucose and galactose from lactose were labeled to the same degree, indicating that the galactose was derived from labeled glucose. The labeling intensity in the amino acids from casein increased in the following order:glycine < serine < aspartic acid < glutamic and that 40 to 70% of the end genous acetone was metabolized in the citric acid cycle through a common precursor, oxaloacetate. It was concluded that the utilization of acetone for glucose synthesis was not enhanced in ketotic cows and that the glucose from acetone constituted a small and insignificant portion of the total production. [R75, 210] ACTN: *Levels of endogenous acetone in fasted rats correlated with 3-4-fold increase in nitrosodimethylamine demethylase (NDMAd) activity. A dose-response experiment showed endogenous levels of acetone to be capable of causing at most 40% of the induction in fasted rats. This suggests that other ketone bodies or factors may have contributed to the induction. [R88] *... /IT WAS/ SUGGESTED THAT INJURIOUS EFFECT OF ACETONE ON EYE /OF RABBITS/ WAS CAUSED BY DEHYDRATION OF SCLERA WHICH RESULTED IN GELATINOUS FLOCCULATION AND OPACITY OF SCLERA. [R82, 1728] INTC: *Pretreatment with acetone for 6 days (one-tenth the LD50) potentiated acute ethanol toxicity in rats. ... /Investigators/ ... demonstrated that acetone pretreatment potentiates chlorinated hydrocarbon toxicity. ... Acetone protected animals against electroshock or isonicotinic acid hydrazide-induced convulsions. Acetone ... enhanced the hepatotoxicity of 1,1-dichloroethylene (200 ppm) in rats. [R35, 4727] *PRETREATMENT OF MICE WITH ACETONE GREATLY REDUCED THE MINIMUM MUTAGENICALLY EFFECTIVE CONCN OF DIMETHYLNITROSAMINE (DMN) IN SALMONELLA TYPHIMURIUM TA92. THE RESULTS OF THE HOST-MEDIATED ASSAYS SUBSTANTIALLY DIFFERED FROM THOSE OF THE IN VITRO ACTIVATION ASSAYS (A) IN THE RELATIVELY LOW DOSE OF DMN REQUIRED FOR MUTAGENICITY TO OCCUR AND (B) IN THE LACK OF POTENTIATION BY ACETONE PRETREATMENT. ACETONE EVEN LED TO A MARGINAL DECREASE IN MUTAGENICITY OF DIMETHYLNITROSAMINE. [R89] *Pretreatment of rats with acetone potentiated the hepatotoxicity of n-nitrosodimethylamine as indicated by plasma glutamic-pyruvatic transaminase levels and histological data. Pretreatment with acetone (2.5 ml/kg) and 2 days of fasting caused a 2-fold potentiation of n-nitrosodimethylamine-induced plasma glutamic-pyruvatic transaminase elevation. Centrilobular necrosis produced by n-nitrosodimethylamine was more severe after pretreatment with inducers. N-nitrosodimethylamine treatment also decreased hepatic microsomal demethylase activity. Thus, n-nitrosodimethylamine demethylase is responsible for the activation of n-nitrosodimethylamine in vivo to a toxic intermediate, and induction of this enzyme activity potentiates n-nitrosodimethylamine hepatotoxicity. [R90] *Treatment of rats with acetone (2.5-5 ml/kg, intragastric) caused a 3-4.5-fold enhancement in reduced nicotinamide adenine dinucleotide-dependent nitrosodimethylamine demethylase (NDMAd) activity. This was accompanied by only moderate incr in gross cytochrome p450 content and reduced nicotinamide adenine dinucleotide-cytochrome c reductase and 261% incr in ethoxycoumarin O-dealkylase activity. The treatment enhanced the metabolism of nitrosomethylethylamine, nitrosomethylbenzylamine, and nitrosomethylaniline, although to lesser extents than with nitrosodimethylamine. Observations suggest that the enhanced nitrosodimethylamine demethylase was due to induction of 1 or more specific p450 isozyme(s) by pretreatment with acetone or isopropanol. Treatment induced proteins with molecular weights of 50,000 and 52,000 which were in the range of known p450 isozymes. The induction of these proteins and nitrosodimethylamine demethylase activity was inhibited by cobaltous chloride and cycloheximide. The induced microsomes had a peak at 450.6 nm, different from 450.0 nm peak of control microsomes. When added to the incubation mixture, acetone and isopropanol inhibited nitrosodimethylamine demethylase activity. Isopropanol was more potent than acetone. [R91] *... Pretreatment of rats with acetone (15 mmol/kg, po) markedly potentiated the hepatotoxic response to bromodichloromethane and dibromochloromethane ... /in male Sprague-Dawley rats/. [R92] *Chloroform-induced hepato- and nephrotoxicity was evaluated in male, Fischer 344 rats pretreated with various dosages (1.0 to 15.0 mmol/kg, po) of acetone, 2-butanone, 2-pentanone, 2-hexanone, or 2-heptanone. Chloroform ... produced extensive tubular and centrilobular necrosis when administered to ketone-pretreated rats. The relationship between ketone dosage and the magnitude of the potentiated response was non-linear. Maximum potentiation of chloroform toxicity occurred in the dose range of 5.0-10.0 mmol ketone/kg. Ketone dosages > 10.0 mmol/kg were associated with a reduction in the degree of chloroform injury. At the lowest ketone dosage (1.0 mmol/kg), potentiating capacity appeared to be related to ketone C skeleton length. No differences were discernable between ketones at dosages of 5.0-10.0 mmol/kg. ... [R93] *The influence of organo-antimony and organo-bismuth compounds was determined. Significant antagonistic and synergistic solvent-compound interactions occurred when the acetone concentrations exceeded 0.4% (vol/vol). At < 0.4%, only additive responses were observed. The fungitoxicity of the test compounds was determined by using acetone as the carrier solvent at a final concn of 0.1% (vol/vol). Trivalent organo-bismuth compounds were the most fungitoxic. ... [R94] *The toxicity of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane, and aldrin to sugarcane leafhopper (Pyrilla perpusilla) depended on the solvent used; ie, the insecticides were more effective when dissolved in ethanol, than in methanol, followed by acetone. [R95] *Acetone has the ability to induce the enzymatic activity of a specific constitutive cytochrome p450 isozyme that plays an important role in the metabolism of endogenous and exogenous substrates. A considerable amount of information is available on the physiological function and toxicologic consequence of p450 induction by acetone. Because acetone is metabolized by the same p450 isozyme that is induced following high-dose administration the auto-inductive increase in cytochrome p450 levels provides a mechanism for increasing the elimination of acetone when high body burdens develop. The pretreatment of laboratory animals with acetone can also potentiate or antagonize the acute effects of known systemic toxicants that are metabolized by the induced p450 isozyme. The potentiation observed following acetone administration has involved treatments with known nephrotoxins and hepatotoxins; the potentiating effects were generally quantitative in nature and involved an increase in the extent of damage without altering the types of tissues or organs affected. Minimally effective dose thresholds have been shown to exist for the induction of cytochrome p450 by acetone. [R75, 187] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Local; Pharmaceutic Aids; Solvents [R96] *PHARMACEUTICAL AID (SOLVENT) [R9] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Acetone's production and use as a solvent for fats, oils, waxes, resins, rubbers, plastics, pharmaceuticals and rubber cements may result in its release to the environment through various waste streams. Its use as an extracting reagent and starting material or intermediate in the manufacture of chemical products will also lead to its release to the environment. Acetone occurs naturally as a metabolic byproduct of plants and animals and is released into the atmosphere by volcanoes and forest fires. Based on an experimental vapor pressure of 231 mm Hg at 25 deg C, acetone is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase acetone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of 71 days. Acetone also undergoes photodecomposition by sunlight with an estimated half-life of about 80 days. Acetone is expected to have very high mobility in soils based upon an estimated Koc value of 1. Volatilization from dry soil surfaces is expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is also expected based upon the measured Henry's Law constant of 1.87X10-5 atm-cu m/mol. This compound is expected to biodegrade under aerobic and anaerobic conditions. In water, acetone is not expected to adsorb to suspended solids or sediment based upon its estimated Koc value. Volatilization from water surfaces is expected to be an important environmental fate process given its estimated Henry's Law constant. Estimated half-lives for a model river and model lake are 38 and 333 hours, respectively. Experimentally determined volatilization half-lives in a shallow stream were measured in the range of 8-18 hours. Bioconcentration in aquatic organisms is considered low based upon an estimated BCF value of 1. Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where acetone is produced or used. The general population may be exposed to acetone through the use of commercially available products containing this compound such as paints, adhesives, cosmetics, and rubber cements. Exposure will also arise from inhalation of ambient air, ingestion of drinking water, and food that contains acetone. (SRC) NATS: */Component/ of oxidation of humic substances. [R12, 112] *Acetone has been produced by the fermentation of west coast kelp. [R8, p. 15(81) 294] *Acetone occurs naturally as a metabolic byproduct of plants and animals and is released into the atmosphere by volcanoes and forest fires(1). [R97] ARTS: *Emissions from wood-burning fireplaces were measured. Acetone was one of the compounds identified. [R98] *Acetone's production and use as a solvent for fats, oils, waxes, resins, rubbers, plastics, pharmaceuticals and rubber cements(1,2) will result in its release to the environment through various waste streams(SRC). Its use as an extracting reagent and starting material or intermediate in the manufacture of chemical products(1) will also lead to its release to the environment(SRC). [R99] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 1(SRC), determined from an experimental log Kow of -0.24(2), and a recommended regression-derived equation(3), indicates that acetone is expected to have very high mobility in soil(SRC). Volatilization of acetone from moist soil surfaces(SRC) is expected given the measured Henry's Law constant of 1.87X10-5 atm-cu m/mole(4). Volatilization from dry soil surfaces is expected based upon the experimental vapor pressure of 232 mm Hg at 25 deg C(5,SRC). Acetone is expected to biodegrade under both aerobic and anaerobic conditions as indicated by numerous screening tests(6-9). [R100] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 1(SRC), determined from an experimental log Kow of -0.24(2), and a recommended regression-derived equation(3), indicates that acetone will not adsorb to suspended solids and sediment in water(SRC). Acetone is expected to volatilize from water surfaces(3,SRC) based on the measured Henry's Law constant of 1.87X10-5 atm-cu m/mole(4). Estimated half-lives for a model river and model lake are 38 and 333 hours, respectively(3,SRC). Experimentally determined volatilization half-lives in a shallow stream were measured in the range of 8-18 hours(5-7). Biodegradation of this compound is expected, but volatilization has been shown to be the primary removal process of acetone in water(5-7). According to a classification scheme(8), an estimated BCF value of 1(3,SRC), from an experimental log Kow(2,SRC), suggests that bioconcentration in aquatic organisms is low(SRC). [R101] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acetone, which has an experimental vapor pressure of 231 mm Hg at 25 deg C(2), will exist solely as a vapor in the ambient atmosphere. Vapor-phase acetone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 71(3,SRC) days. The average rate constant for the photodissociation of acetone by natural sunlight in the lower troposphere was measured as 1X10-7 sec-1(4). This corresponds to a half-life of about 80 days(4). [R102] BIOD: *Biological oxygen demand: (Theoretical) 122%, 5 days [R3] *The percent theoretical BOD of acetone in water seeded with settled domestic sewage was 56%, 76%, 83% and 84%, over 5, 10, 15 and 20 day incubation periods(1). Percent theoretical BOD's of acetone in a raw sewage inocula were reported as 37% and 81% over 5 and 20 day incubation periods respectively(2), 54% over a 5 day incubation period(3), 71% over a 7 day incubation period(4), 55% and 72% over 5 day and 10 day incubation periods respectively(5) and 38% over a 5 day incubation period(6). Acetone was shown to be readily biodegradable under anaerobic conditions(7-9). The percent theoretical methane recovery of acetone in an anaerobic aquifer was 89% over a 3 week incubation period following a 25 day acclimation period(9). [R103] ABIO: *The rate constant for the vapor-phase reaction of acetone with photochemically-produced hydroxyl radicals has been measured as 2.26X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 71 days at an atmospheric concn of 5.0X10+5 hydroxyl radicals per cu cm(1,SRC). The average rate constant for the photodissociation of acetone by natural sunlight in the lower troposphere was measured as 1X10-7 sec-1(2). This corresponds to a half-life of about 80 days(2). When water containing acetone is treated with chlorine for disinfection purposes, the acetone can react with the hypochlorite ion formed by the hydrolysis of chlorine leading to the production of trichloromethane(3). This reaction is strongly pH dependent and is expected to have a significant effect only at pH values of 6-7(3). [R104] BIOC: *An estimated BCF value of 1 was calculated for acetone(SRC), using an experimental log Kow of -0.24(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R105] KOC: *The Koc of acetone is estimated as approximately 1(SRC), using an experimental log Kow of -0.24(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that acetone is expected to have very high mobility in soil(SRC). Acetone showed no adsorption to montorillonite, kaolinite clay, or stream sediment(4,5). [R106] VWS: *The Henry's Law constant for acetone was measured as 1.87X10-5 atm-cu m/mole(SRC) at 25 deg C(1). This value indicates that acetone will volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 38 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 333 hours(2,SRC). Volatilization rate constants of a model stream (234 m long, water velocity 0.67 m/min) were measured in the range of 8.23X10-4 min-1 to 11.1X10-4 min-1(3). These rate constants correspond to volatilization half-lives of about 10-14 hours(3). Similar experiments in the same stream measured acetone volatilization rate constants in the range of 6.22X10-4 min-1 to 14.5X10-4 min-1(4,5). These rate constants correspond to volatilization half-lives of about 8-18 hours(4,5). Acetone is expected to volatilize from dry soil surfaces given its experimental vapor pressure(1,SRC). [R107] WATC: *A concentration of 0.6 g/l of acetone was found in a sample of a one-year old leachate from a ... sanitary landfill. [R12, 114] *DRINKING WATER: Acetone was identified, not quantified, in 10 out of 10 drinking water samples collected in the US(1). Acetone was identified, not quantified, in the drinking water of New Orleans, LA(2), Seattle, WA(3) and Tuscaloosa, AL(4). Acetone was detected in a drinking water well in New Jersey at a concn of 3,000 ppb(5). Six drinking water wells in the vicinity of a landfill contained 0.2 to 0.7 ppb of acetone(6). An unspecified concn of acetone leached from a section of high density polyethylene tubing supplying drinking water in Paris(7). Acetone was detected in the municipal wells in Waite Park, MN at concns between 74-3,300 ug/l(8). [R108] *GROUNDWATER: Acetone was detected in groundwater near a chemical manufacturing facility in Michigan at a maximum concn of 1,600 ug/l(1). Acetone was detected in groundwater in NJ at a concn of 3,000 ug/l(2). Acetone was detected at a concn of 620 ppb in the groundwater at the Lipari landfill, NJ(3). Acetone was detected at a concn of 11 ug/l in the on-site wells and 0.19 ug/l in the off-site groundwater near a manufacturing facility in MI(4). Acetone was identified, not quantified, in 12.4% of the groundwater samples at 178 sites in the US(5) and in the groundwater of a waste disposal facility in SC(6). The average concn of acetone in groundwater sampled at 5 wood treatment facilities was 20 ug/l(7). Acetone was detected in the groundwater of a coal strip-mine in Ohio at concns of 1,300 mg/l and 2,700 ug/l(8). [R109] *SURFACE WATER: Five of nine sites in Lake Michigan contained 1-4 ppb acetone(1). In a survey of 14 heavily industrialized river basins in the USA (204 samples), 33 contained detectable amounts of acetone including 18 of 31 sites in the Chicago area and the Illinois River basin, 8 of 30 sites in the Delaware River basin, 1 of 45 sites in the Mississippi River basin, 3 of 27 sites in the Ohio River basin, and 3 of 15 west coast sites(2). Acetone was identified, not quantified, in the Black River in Tuscaloosa, AL(3), and the Cuyahoga River in the Lake Erie basin(4). Acetone was detected in the Potomac River at a concn of less than 40 ug/l(5). [R110] *SEAWATER: Samples of seawater and surface slicks taken from Biscayne Bay and the Florida Current contained 39.6 and 89.7 ppb of acetone, respectively(1). Grab samples of surface water from the Straits of Florida and the Eastern Mediterranean contained 20 and 28 ppb of acetone, respectively(2). Samples of ocean water taken at 1,200 m depths contained unspecified concns of acetone(2). [R111] *RAIN/SNOW: 50 ppb of acetone was detected in one of 6 samples tested at 5 cities in California(1). An unspecified concn of acetone was detected in rain in Japan(2). Acetone/acrolein was detected in rainfall in Los Angeles, CA at a concn of 0.05 ug/ml and in ice at Urban Fairbanks, AK at a concn of 0.21 umols/ml(3). Acetone was identified, not quantified, in rainfall in Germany(4). Acetone was detected in the clouds (460 ng/l) and rainfall (0.5 ng/l) at a state park in North Carolina(5). [R112] EFFL: *Acetone was detected in the effluent of a chemical plant located in Sweden at a concn of 5.5 kg/cu m(1). Acetone was detected in the effluent of municipal landfill sites in North America at concns of 6,838 ppb and 32,500 ppb(2). Acetone was identified, not quantified in the emissions of new carpets(3), automobiles(4,5) and common household waste(6-9). Acetone was detected in the effluent from a solid waste composting plant at concns of 6,100 ug/cu m(tipping area), 7,800 ug/cu m(indoor air), 9,200 ug/cu m(fresh compost), 9,500 ug/cu m(middle age compost), 6,100 ug/cu m(old compost) and 2,300 ug/cu m(curing region)(10). Acetone was identified, not quantified, in the emissions of 314 out of 1,005 common household products(11). Acetone was detected in the effluent of a waste incinerator in Germany at a concn of 17.6 ug/cu m(12). Acetone was detected in the emissions of a photocopying machine at rates of less than 100 ug/hr to 2,200 ug/hr(13). Acetone was detected at a concn of 25 ug/cu m in the emissions of a composting facility in Virginia(14). [R113] *Acetone was detected in the leachate of several municipal landfills at concns between 6-4,400 ug/l(1). Acetone was detected in the wastewater of a truck parts producing plant in Michigan at a concn of 44.5 ug/l(2). Acetone was detected in the effluent of an unauthorized hazardous waste disposal facility in New Jersey at a concn of 480 ug/l(3). Acetone was detected at a concn of 46.6 ppb in the leachate of a landfill in Delaware containing industrial and municipal waste(4). Acetone was detected at concns between 0.05-62 mg/l and 0.14-44 mg/l in the leachate of industrial landfills and municipal landfills in the US(5). Acetone was detected in the leachate of a landfill in Connecticut at a concn of 3,500 ug/l(6). [R114] *In gasoline exhaust: 2.3-14.0 ppm (partly propionaldehyde) [R12, 113] SEDS: *Acetone was detected in the soil of a coal strip mine in Ohio at mean concns of 9,484 ug/kg (surface soil), 2,263 ug/kg (2-4 feet), 9644 ug/kg (4-6 feet), 5,272 ug/kg (6-8 feet)(1). Acetone was identified, not quantified, in the sediment and subsurface soil of a gravel mine in Tennessee(2). Acetone was detected at an average concn of 736 ug/kg in the soil of an unauthorized hazardous waste disposal facility in New Jersey(3). [R115] ATMC: *SOURCE DOMINATED: Acetone was detected at 22 source dominated sites in the USA at a median concn of 0.350 ppb and a maximum concn of 53 ppb(1). Acetone was detected at concns between 2.3-3.3 ppb near the Texaco Refinery in Tulsa, OK(2). [R116] *URBAN/SUBURBAN: Acetone was detected at a concn of 1-8 ppb in Denver, CO(1). Acetone was detected at mean concns of 13.9 ppb in Boston, MA, 34.5 ppb(2) and 6.1 ppb(3) in Houston, TX and 12 ppb in Tucson, AZ(4). The average concn of acetone/formaldehyde at 4 southern California locations was 0.30 ppb(5). Acetone was detected at a concn of 2.07 ppb in Columbus, OH(6). The average concn of acetone at 5 sites in Stockholm was between 4.04-19.40 ppb(7). [R117] *INDOOR AIR: Acetone was detected at an average concn of 39 ug/cu m at 14 homes and buildings in Italy(1). Acetone was detected in 2 buildings in Portland, OR at concns between 14.9-66.0 ug/cu m and 7.4-33.9 ug/cu m(2). Acetone was detected in a building in Switzerland at a concn of 7,763 ug/cu m(3). Acetone was detected at a concn of 10 and less than 1 ng/l in 2 elementary school classrooms in France(4). [R118] *RURAL/REMOTE: Acetone was detected at an average concn of 14.72 ng/l in the air of a state park in North Carolina(1). Acetone was identified, not quantified, in the air of a German forest(2). Acetone was detected at concns between 0.39-3.26 ppb and 0.72-3.81 ppb in Egbert Ontario and Dorset Ontario respectively(3). Acetone was detected at a mean concn of 1,140 parts per trillion in Eastern Canada(4). Acetone was detected at a mean concn of 2.6 ppb at 2 rural sites in AZ(5) and 5.1 ppb in Rio Blanco county, CO(6). The acetone concn in air at Pt Barrow, AK (22 measurements) ranged from 0.3 to 2.9 ppb, with a mean concn of 1.21 ppb(7). Acetone was detected at a concn of 1.9 ppb in the Jones State Forest near Houston, TX(8). [R119] FOOD: *Acetone was identified, not quantified, in the volatiles of kiwi fruit(1,2), blue cheese(3), raw chicken(4), cured pork(5), chickpea seeds(6), nectarines(7), mutton, chicken and beef(8). Acetone has been identified, not quantified, as a volatile component of baked potatoes(9), roasted filberts(10), dried beans and legumes(11), and French cognac(12). [R120] PFAC: PLANT CONCENTRATIONS: *Acetone is emitted from Bay Leaf Willows, European Firs and Evergreen Cyprus(1). [R121] MILK: *Acetone was identified, not quantified, in human milk from Bayonne, NJ, Jersey City, NJ, Pittsburgh, PA and Baton Rouge, LA(1). Acetone was identified, not quantified, in all 8 samples of mother's milk analyzed from 4 industrial urban areas in the USA(2). Acetone was identified, not quantified from milk samples in Australia(3). [R122] OEVC: *Cigarette smoke - 1,100 ppm [R12, 113] *Acetone was detected in cigarette smoke at a concn of 1,620 ug per cigarette(1). [R123] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,510,107 workers (466,677 of these are female) are potentially exposed to Acetone in the US(1). Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where acetone is produced or used(SRC). The 8 hour TWA exposure to acetone was in the range of 0-70,000 umols/cu m in a survey of 659 occupationally exposed male subjects working in shoe, plastics and chemical plants in Italy (2). Workers in a Japanese acetate fiber producing plant had detectable levels of acetone in urine samples between 1 and 160 mg/l(3). The average TWA exposure to acetone in 7 spray painting and glue spraying plants was 0.9, 3.2, 2.3 0.9 and 5.6 ppm for higher-aromatic paint spraying, lower-aromatic paint spraying, glue spraying, solvent wiping, and paint mixing respectively(4). [R124] *The general population may be exposed to acetone through the use of commercially available products containing this compound such as paints, adhesives, cosmetics, and rubber cements(SRC). Exposure will also arise from inhalation of ambient air, ingestion of drinking water, and food that contains acetone(SRC). The average blood concn of acetone in 600 non-occupationally exposed persons in the US was 3,100 ppb(1). [R125] AVDI: *AIR INTAKE (assume air concn of 0.05-20 ppb): 24-960 mg; WATER INTAKE - insufficient data; FOOD INTAKE - insufficient data. (SRC) BODY: *Acetone was detected in the expired breath of 23 of 26 smokers and 42 of 43 nonsmokers in the US(1). Acetone was ubiquitous in the expired air from a carefully selected urban population of 54 normal healthy non-smoking people (387 samples) with a geometric mean concn of 101.3 ng/l(2). Acetone loss in the urine is generally 1 mg/24 hr for a normal adult but is about 50 mg in children(3,4). Acetone was detected in the expired breath of children in 2 classrooms in France at an average concn of 800 ng/l(5). [R126] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +2500 ppm (IDLH based on a 10% of the lower explosive limit for safety considerations even though the relevant toxicological data indicated that irreversible health effects or impairment of escape existed only at higher concentrations.) [R38, 2] ATOL: *Residues of acetone are exempted from the requirement of a tolerance when used as a solvent, cosolvent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R127] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1000 ppm (2400 mg/cu m). [R128] +Vacated 1989 OSHA PEL TWA 750 ppm (1800 mg/cu m); STEL 1000 ppm (2400 mg/cu m) is still enforced in some states. [R38, 359] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 250 ppm (590 mg/cu m). [R38, 2] TLV: +8 hr Time Weighted Avg (TWA): 500 ppm; 15 min Short Term Exposure Limit (STEL): 750 ppm. [R53, 2002.13] +A4; Not classifiable as a human carcinogen. [R53, 2002.13] +Biological Exposure Index (BEI): Determinant: acetone in urine; Sampling Time: end of shift; BEI: 50 mg/l. The determinant is nonspecific, since it is also observed after exposure to other chemicals. [R53, 2002.88] OOPL: *Exposure limits: France, TWA limits - 1,800 mg/cu m (1983). [R129] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). These standards implement Section 111 of the Clean Air Act and are based on the Administrator's determination that emissions from the SOCMI cause, or contribute significantly to, air pollution which may reasonably be anticipated to endanger public health or welfare. The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Acetone is produced, as an intermediate or final product, by process units covered under this subpart. These standards of performance become effective upon promulgation but apply to affected facilities for which construction or modification commenced after January 5, 1981. [R130] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 700 ug/l [R131] +(MA) MASSACHUSETTS 3000 ug/l [R131] +(MN) MINNESOTA 700 ug/l [R131] +(NH) NEW HAMPSHIRE 700 ug/l [R131] +(WI) WISCONSIN 1000 ug/l [R131] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R132] RCRA: *F003; When acetone is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F003), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R133] *U002; As stipulated in 40 CFR 261.33, when acetone, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R134] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Activated charcoal, Ambersorb XE-348, and Amberlites XAD-2, XAD-4, and XAD-7 were evaluated as solid adsorbents for work-room air sampling of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl n-butyl ketone, cyclohexanone and isophorone. Activated charcoal had good capacity for the compounds investigated, but most ketones decomposed on this adsorbent during storage. Ambersorb XE-348 also showed good capacity for most of the ketones and decomposition was insignficant. [R135] ALAB: *ANALYTE: ACETONE. MATRIX: AIR. PROCEDURE: ADSORPTION ON CHARCOAL, DESORPTION WITH CARBON DISULFIDE, GC. RANGE: 1200-4500 MG/CU M. SENSITIVITY: 0.082 [R136] *A procedure for the determination of volatile compounds in fish tissue is described. Characterization is by gas chromatography/mass spectrometry using a fused-silica capillary column. [R137] *Emissions of organic compounds from shale oil waste waters were investigated by using headspace and purge and trap sampling followed by analysis by gas chromatography with mass spectral and flame ionization. Acetone was identified. [R138] *EPA Method 1624 - Volatile Organic Compounds By GC/MS: Grab samples in municipal and industrial discharges are collected. If residual chlorine is present, add sodium thiosulfate. Extraction is performed by a purge and trap apparatus. An isotope dilution gas chromatography/ mass spectrometry method for the determination of volatile organic compounds in municipal and industrial discharges is described. Unlabeled acetone has a minimum level of 50 ug/l and a mean retention time of 565 sec. [R139] *Method 8240A - Volatile Organics by gas chromatography/mass spectrometry (GC/MS). Packed column technique. [R140] CLAB: *A gas chromatographic method for determining acetone in biological tissues is described. Solvent was extracted with nitrogen gas from specimen and adsorbed on porous polymer (Porapak Q). Concentrations ranging between 17 nmol/g tissue in nonexposed animals and 1.8 mumol/g tissue in exposed mice were determined. [R141] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Report on the Toxicity Studies of Acetone in F344/N Rats and B6C3F1 Mice (Drinking Water Studies) NTP TOX 3 NIH Pub No. 91-3122 DHHS/ATSDR; Toxicological Profile for Acetone (1994) ATSDR/TP-93/01 HIST: *The wreck of the MV Ariadne, a Panamanian flag container ship, is examined as a case study of a hazardous substance emergency response in a third world country. /The ship/, carrying a cargo of heavy fuel oil, tetraethyl lead, xylene, toluene, methyl isobutyl ketone, butyl acetate, ethyl acetate, and acetone was grounded while departing the harbor of Mogadishu, Somalia. The Somalian government requested a team of technical advisors to help respond appropriately to the emergency. The major issues addressed by the advisory team were the need for additional salvage equipment and expertise, the danger of toxic fumes from the fire and explosions aboard the ship, the presence and possible release of tetraethyl lead, possible port blockage by the wreck, recovery of the chemical drums, and the extent of environmental damage caused by the release of oil, pesticides, and tetraethyl lead into the harbor. ... [R142] SO: R1: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R2: CHEMICAL PRODUCTS SYNOPSIS: ACETONE, 1984 R3: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. 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Windsor Ontario, Canada p. 195 (1983) (5) Hall LWJR et al; Aquat Toxicol 10: 73-99 (1987) R111: (1) Seba DB, Corcoran EF; Pestic Monit J 3: 109-3 (1969) (2) Corwin JF; Bull Mar Sci 19: 504-9 (1969) R112: (1) Grosjean D, Wright B; Atmos Environ 17: 2093-6 (1983) (2) Kato T et al; Yokohama Kokuritsu Daigaku Kankyo Kagaku Kenkyu Senta Kiyo 6: 11-20 (1980) (3) Mazurek MA, Simoneit BRT; CRC Crit Rev Environ Control 16: 140 (1986) (4) Levson K et al; Chemosphere 21: 1037-61 (1990) (5) Aneja VP et al; J Air Waste Manag Assoc 43: 1239-44 (1993) R113: (1) Brorson T et al; Environ Toxicol Chem 13: 543-52 (1994) (2) Brosseau, Heitz M; Atmos Environ 25A: 1473-77 (1994) (3) Hodgeson AT et al; J Air Waste Manage Assoc 43: 316-24 (1993) (4) Sawyer RF; Environ Health Perspect 101: 5-12 (1994) (5) Harley RA et al; Environ Sci Technol 26: 2395-2408 (1992) (6) Wilkins CK, Larsen K; J High Resol Chromatogr 18: 373-77 (1995) (7) Wilkins K, Larsen K; Chemosphere 31: 3225-36 (1995) (8) Wilkins K, Larsen K; Chemosphere 32: 2049-55 (1996) (9) Wilkins K; Chemosphere 29: 47-53 (1994) (10) Eitzer BD; Environ Sci Technol 29: 896-902 (1995) (11) Sack TM et al; Atmos Environ 26A: 1063-70 (1992) (12) Jay K, Stieglitz L; Chemosphere 30: 1249-60 (1995) (13) Leovic KW et al; J Air Waste Manage Assoc 46: 821-29 (1996) (14) Vandurme GP et al; Water Environ Res 64: 19-27 (1992) R114: (1) Christensen TH et al; Crit Rev Environ Sci Technol 24: 119-202 (1994) (2) USEPA; Superfund Record of Decision: Kysor Industrial, Cadillac, MI. USEPA/ROD/R05/-89/113 (1989) (3) USEPA; Superfund Record of Decision: Lang Property, Pemberton Township, NJ. USEPA/ROD/R05/-89/113 (1987) (4) Dewalle FB, Chian Esk; J Am Water Works Assoc 73: 206-11 (1981) (5) Brown KW, Donnelly KC; Haz Waste Haz Mater 5: 1-30 (1988) (6) Sawhney BL; pp 447-74 in Reactions and Movements of Organic Chemicals in Soils SSSA Special Pub No 22 (1989) R115: (1) USEPA; Superfund Record of Decision: Summit National Site, Deerfield OH. USEPA/ROD/R85-88/068 (1988) (2) USEPA; Superfund Record of Decision: Galloway Ponds Site, Galloway, TN. USEPA/ROD/R04-86/013 (1987) (3) USEPA; Superfund Record of Decision: Lang Property Pemberton Township, NJ USEPA/ROD/R02-86/031 (1987) R116: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmos SRI International Contract 68-02-3452 (1982) (2) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) R117: (1) Anderson LG et al; Isr J Chem 34: 341-53 (1994) (2) Kelly TJ et al; Environ Sci Technol 27: 1146-53 (1993) (3) Lagrone FS; Environ Sci Technol 25: 366-68 (1991) (4) Snider JR, Dawson GA; J Geophys Res, D: Atmos 90: 3797-805 (1985) (5) Grosjean E et al; Environ Sci Technol 30: 2687-2703 (1996) (6) Spicer CW et al; Atmos Environ 30: 3443-56 (1996) (7) Jonsson A et al; Environ Int 11: 383-92 (1985) R118: (1) Debortoli M et al; Environ Int 12: 343-50 (1986) (2) Hodgeson AT et al; J Air Waste Manage Assoc 41: 1461-68 (1991) (3) Rothweiler H et al; Atmos Environ 26A: 2219-25 (1992) (4) Cailleux A et al; Chromatographia 37: 57-59 (1993) R119: (1) Aneja VP et al; J Air Waste Manag Assoc 43: 1239-44 (1993) (2) Helmig D et al; Chemosphere 19: 1399-1412 (1989) (3) Shepson PB et al; Atmos Environ 25A: 2001-15 (1991) (4) Singh HB et al; J Geophys Res 99: 1805-19 (1994) (5) Snider JR, Dawson GA; J Geophys Res, D: Atmos 90: 3797-805 (1985) (6) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) (7) Cavanagh LA et al; Environ Sci Technol 3: 251-7 (1969) (8) Seila RL; Non-urban Hydrocarbon concns in Ambient Air North of Houston, TX USEPA USEPA-500/3-79-010 p.38 (1979) R120: (1) Bartley JP, Schwede AM; J Agric Food Chem 37: 1023-25 (1989) (2) Tatsuka K et al; J Food Sci 38: 2176-80 (1990) (3) Day EA, Anderson DF; J Agric Food Chem 13: 2-4 (1965) (4) Grey TC, Shrimpton DH; Brit Poultry Sci 8: 23-33 (1967) (5) Hinrichsen LL, Anderson HJ; J Agric Food Chem 42: 1537-42 (1994) (6) Rembold H et al; J Agric Food Chem 37: 659-62 (1989) (7) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) (8) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) (9) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (10) Kinlin TE et al; J Agric Food Chem 20: 1021 (1972) (11) Lovegren NV et al; J Agric Food Chem 27: 851-3 (1979) (12) TerHeide R et al; pp. 249-81 in Anal Foods Beverages, Chavalambous G, ed. NY,NY: Academic (1978) R121: (1) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-235 (1992) R122: (1) Erickson MD et al; Acquisition and chemical analysis of mother's milk for selected toxic substances. USEPA-560/13-80-029. Washington DC: US EPA Off Pestic Toxic Subst (1980) (2) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (3) Urbach G; J Chromatogr 404: 163-74 (1987) R123: (1) Otson R, Fellin P; pp. 335-421 in Gas Pollut: Charact Cycl, Nriagu JO ed. NY,NY: John Wiley and Sons (1992) R124: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Ghittori S et al; Am Ind Hyg Assoc J 48: 786 (1987) (3) Fujino A et al; Br J Ind Med 49: 654-57 (1992) (4) Whitehead LW et al; Am Ind Hyg Assoc J 45: 767-72 (1984) R125: (1) Ashley DL et al; Clin Chem 40: 1401-04 (1994) R126: (1) Gordon SM; J Chromatogr 511: 291-302 (1990) (2) Krotoszynski BK et al; J Anal Toxicol 3: 225-34 (1979) (3) Harper HA; Review of Physiological Chemistry 12th ed p. 303 (1969) (4) White WL et al; Chemistry for Medical Technologists 3rd ed Mosby Co St Louis, MO (1970) (5) Cailleux A et al; Chromatographia 37: 57-59 (1993) R127: 40 CFR 180.1001(c) (7/1/96) R128: 29 CFR 1910.1000 (7/1/98) R129: Institut National de Research et de S'ecruit'e; Acetone 1-4 (1987) R130: 40 CFR 60.489 (7/1/86) R131: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R132: 40 CFR 302.4 (7/1/96) R133: 40 CFR 261.31 (7/1/96) R134: 40 CFR 261.33 (7/1/96) R135: Levin JO, Carleborg L; Ann Occup Hyg 31 (1): 31-8 (1987) R136: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1300-1 R137: Hiatt MH; Anal Chem 55 (3): 506-16 (1983) R138: Hawthrone SB, Sievers RE; Environ Sci Technol 18 (6): 483-90 (1984) R139: 40 CFR 136 (7/1/86) R140: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R141: Holm S, Lundgren E; Anal Biochem 136 (1): 157-60 (1984) R142: Heare SF et al; 1986 Hazard Matl Spill Conf p.12-18 (1986) RS: 117 Record 7 of 1119 in HSDB (through 2003/06) AN: 42 UD: 200211 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACETONITRILE- SY: *ACETONITRIL- (GERMAN,DUTCH); *CYANOMETHANE-; *CYANURE-DE-METHYL- (FRENCH); *ETHANENITRILE-; *ETHYL-NITRILE-; *METHANECARBONITRILE-; *METHANE,-CYANO-; *METHYL-CYANIDE-; *NCI-C60822- RN: 75-05-8 MF: *C2-H3-N SHPN: UN 1648; Methyl cyanide (Acetonitrile) IMO 3.2; Methyl cyanide STCC: 49 074 05; Acetonitrile HAZN: U003; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *By-product of propylene-ammonia process for acrylonitrile [R1] *Prepd indust by dehydration of acetamide. [R2] *By reacting acetic acid with ammonia at 400-500 deg C in the presence of a dehydration catalyst. [R3, 301] IMP: *The principal organic impurity in commercial acetonitrile is propionitrile; small amounts of allyl alcohol may be present. [R4, 443] *Acidity (max), 0.05 wt%; copper (max), 0.5 ppm; iron (max), 0.5 ppm; water (max), 0.3 wt% [R4, 443] *Maximum limits of impurities: residue after evaporation 0.0005%, acidity (as acetic acid) 0.03%, alkalinity (as ammonia) 0.001%, water 0.05%. /'Photrex' Reagent, for spectrophotometry/ [R5] FORM: *Grades: technical; nanograde; spectrophotometric. [R1] MFS: *BP Amoco Corp., 200 E. Randolph Dr., Chicago, IL 60601, (312) 856-6111; Production site: Green Lake, TX 77031; Lima, OH 45804 [R6] *DuPont, Dupont Specialty Chemicals, 1007 Market St., Wilmington, DE 19898, (800) 441-7515; Production site: Beaumont, TX 77704 [R6] *Sterling Chemicals, Inc., 1200 Smith St., Suite 1900, Houston, TX 77002-4312, (713) 650-3700; Production site: Texas City, TX 77590 [R6] OMIN: *All of the acetonitrile produced commercially in the United States in 1980 was produced as an isolated by-product from the manufacture of acrylonitrile via propylene ammoxidation. [R4, 442] USE: *In organic synthesis as starting material for acetophenone, alpha-naphthaleneacetic acid, thiamine, acetamidine. To remove tars, phenols, and coloring matter from petroleum hydrocarbons which are not soluble in acetonitrile. To extract fatty acids from fish liver oils and other animals and vegetable oils. Can be used to recrystallize steroids. As an indifferent medium in physicochemical investigations. Wherever a polar solvent having a rather high dielectric constant is required. As medium for promoting reactions involving ionization. As a solvent in non-aqueous titrations. As a nonaqueous solvent for inorganic salts. [R2] *Acrylic fibers; pharmaceuticals; perfumes; nitrile rubber; ABS resins [R7] *Acetonitrile is used as a chemical intermediate in pesticide manufacture. [R8, 29] *Starting material for many types of nitrogen-containing compounds, eg, amides, amines, higher molecular weight mono- and dinitriles; halogenated nitriles; ketones; isocyanates; and heterocycles, eg, pyridines and imidazolines [R4, 442] *Acetonitrile is used as a solvent remover of acrylic sculpted nails that are bonded to the natural nail with durable glues. [R9, 1484] *Solvent in hydrocarbon extraction processes, especially for butadiene; specialty solvent; intermediate; catalyst; separation of fatty acids from vegetable oils. [R1] *Widely used as a recoverable reaction medium, particularly for the preparation of pharmaceuticals; used in the separation of other olefins (eg propylene, isoprene, allene, and methylactylene) from hydrocarbon streams; used as a solvent for polymers, spinning fibers, and casting and molding plastics; used with spectrophotometry, electrochemistry, and high pressure liquid chromatography; used as a catalyst and ingredient in transition metal complex catalysts, in the photographic industry, and for the extraction and refining of copper and by-product ammonium sulfate; used for dyeing textiles and in coating compositions; used as a stabilizer for chlorinated solvents in the presence of aluminum; used in the manufacture of perfumes and as reagent in a wide variety of compounds. [R4, 443] *Used as solvent in lithium-sulfur dioxide electrochemical cells. [R10] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R11] *(1989) 3.5X10+7 lb [R12] *(1991) Exceeded 5000 lb or US $5000 in value [R13] U.S. IMPORTS: *(1984) 9.27X10+10 g /NITRILES, NSPF/ [R14] U.S. EXPORTS: *(1984) 9.73X10+9 g /Nitriles and their derivatives, NSPF/ [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, limpid liquid [R1] ODOR: *Aromatic odor [R16]; *Ether-like odor [R2] TAST: *BURNING SWEETISH TASTE [R17] BP: *81.6 deg C @ 760 mm Hg [R2] MP: *-45 deg C [R2] MW: *41.05 [R2] CORR: *Liquid acetonitrile will attack some forms of plastics, rubber, and coatings. [R18, 1981.2] CTP: *Critical temperature = 272.3 deg C; critical pressure = 47.7 atm [R19, 582] DEN: *SP GR: 0.78745 @ 15 deg C/4 deg C [R2] DSC: *pKa = -4.30 [R20] HTC: *31.03X10+6 J/kg @ 25 deg C [R4, 442] HTV: *72.7X10+4 J/kg @ 80 deg C [R4, 442] OWPC: *log Kow= -0.34 [R21] SOL: *Miscible with methanol, methyl acetate, acetone, ethyl acetate, ether, acetamide solutions, chloroform, carbon tetrachloride, ethylene chloride, and with many unsaturated hydrocarbons; immiscible with many saturated hydrocarbons; dissolves somewhat in inorg salts such as silver nitrate, lithium nitrate, magnesium bromide. [R2]; *Soluble in alcohol [R1]; *MISCIBLE WITH BENZENE [R22]; *Equal wt of acetonitrile and the following materials are miscible at room temp: formic acid, acetic acid, levulinic acid, methanol, cellosolve solvent, formaldehyde, acetaldehyde, di-n-butyl amine, acetic anhydride, pyridine, nitrobenzene, aniline, xylene, phenol, acetyl chloride, dibutyl phthalate, diglycol stearate, n-butyl ether, dichloroethyl ether, methyl isobutyl ketone, nitromethane, nitroethane, nitropropane [R23, 578]; *In water, infinite solubility @ 25 deg C [R19, 583] SPEC: *Index of refraction: 1.33934 @ 30 deg C/D [R2]; *MAX ABSORPTION: 274 NM (LOG E= 2.7) UNDILUTED [R24]; *Acetonitrile, 99%, exhibits its two strongest infra red absorption bands at wavelengths of 7.0 and 7.3 micrometers. [R25]; *IR: u SADP 269 (Sadtler Research Laboratories Prism Collection) [R26]; *UV: OES 4-2 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R26]; *1H NMR: SAD 9154 (Sadtler Research Laboratories Spectral Collection) [R26]; *MS: NIST 18850 (NIST/EPA/MSDC Mass SPectral Database 1990 version) [R26] SURF: *29.04 dynes/cm @ 20 deg C [R2] VAPD: *1.42 (air=1) [R27, 3141] VAP: *88.8 mm Hg @ 25 deg C [R28] EVAP: *5.79 (butyl acetate= 1) [R4, 442] VISC: *0.35 cP @ 20 deg C [R4, 442] OCPP: *PERCENT IN SATURATED AIR 9.6; DENSITY OF SATURATED AIR 1.04 (AIR= 1). [R27, 3141] *High polarity; strongly reactive [R1] *Burns with luminous flame; dielectric constant: 38.8 @ 20 deg C; constant boiling mixture with water contains 16% H2O and bp: 76 deg C [R2] *Sat concn 163 g/cu m at 20 deg C, 249 g/cu m at 30 deg C [R27, 117] *Saturated liquid density: 48.730 lb/cu ft; liquid heat capacity: 0.540 Btu/lb-F; saturated vapor pressure: 1.383 lb/sq in; saturated vapor density: 0.00998 lb/cu ft (all at 70 deg F) [R29] *Specific heat= 0.541 Btu/lb/deg F (21 deg to 76 deg C) [R23, 577] *Dielectric constant= 42.0 @ 0 deg C, 38.8 @ 20 deg C, 26.2 @ 81.6 deg C [R23, 577] *Heat of fusion = 21.8X10+4 J/kg @ -45.7 deg C; heat capacity (liquid) = 22.59X10+2 J/kg K @ 20 deg C; coefficient of expansion (@ 20 deg C) = 1.37X10-3/deg C; specific conductance = 5X10-8 S to 9X10-8 S @ 25 deg C; dipole moment = 10.675X10-30 C-m; dielectric constant = 42.0 @ 0 deg C, 38.8 @ 20 deg C, 26.2 @ 81.6 deg C. [R30] *Henry's Law constant = 3.45X10-5 atm-cu m/mole @ 25 deg C [R31] *Hydroxyl radical reaction rate constant = 2.63X10-14 cu cm/molecule-sec @ 25 deg C [R32] *Ideal gas heat capacity = 52.22 J/K mol [R19, 582] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: *Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R33] *Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Some may polymerize (P) explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R33] *Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R33] *Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. [R33] *Evacuation: Spill: Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R33] *Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from the ends of tanks. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R33] *Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R33] *First aid: Move victim to fresh air. Call emergency medical care. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R33] FPOT: *DANGEROUS FIRE HAZARD WHEN EXPOSED TO HEAT, FLAME OR OXIDIZERS. [R34] *Contact with strong oxidizers may cause fires ... . [R18, 1981.2] *Will react with water, steam, acids to produce toxic and flammable vapors. [R34] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R35, p. 325-11] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R35, p. 325-11] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R35, p. 325-11] FLMT: *Lower flammable limit: 3.0%, Upper flammable limit 16.0% [R35, p. 325-11] FLPT: *12.8 DEG C (55 DEG F) (CLOSED CUP) [R36] *42 deg F (6 deg C) (Open Cup) [R35, p. 325-11] AUTO: *524 DEG C (975 DEG F) [R35, p. 325-11] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEMICAL [R34] *Stay upwind and use water spray to knock down vapor. ... Water may be ineffective. [R29] *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire exposed containers cool. [R35, p. 49-10] *If material is on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog, solid streams may be ineffective. Cool all affected containers with flooding quantities of water and apply water from as far a distance as possible. [R37] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame- evacuate for a radius of 1500 feet. If material leaking (not on fire), downwind evacuation must be considered. [R37] TOXC: *Combustion by-products include hydrogen cyanide and oxides of nitrogen. [R35, p. 49-10] OFHZ: *VAPOR HEAVIER THAN AIR AND MAY TRAVEL CONSIDERABLE DISTANCE TO SOURCE OF IGNITION AND FLASH BACK. [R29] *Vapors are heavier than air and may travel to a source of ignition and flash back. [R35, p. 49-10] EXPL: *Upper 16% and lower 3% by vol (at room temp). [R16] *Contact with strong oxidizers may cause ... explosions. [R18, 1981.] *EXOTHERMIC REACTION WITH SULFURIC ACID AT 53 DEG C. ... INCOMPATIBLE WITH OLEUM, CHLOROSULFONIC ACID, PERCHLORATES, NITRATING AGENTS, INDIUM, DINITROGEN TETRAOXIDE, N-FLUORO COMPOUNDS (E.G., PERFLUOROUREA + ACETONITRILE), HNO3, SO3. [R34] *Forms explosive mixtures with air. [R38] *Potentially explosive reaction with lanthanide perchlorates and nitrogen-fluorine compounds. [R34] REAC: *Strong oxidizers. [R16] *WILL REACT WITH WATER, STEAM OR ACIDS TO PRODUCE TOXIC AND FLAMMABLE VAPORS. [R34] *Nitrogen-fluorine compounds are potentially explosive in contact with acetonitrile. ... A solution of an unspecified lanthanide perchlorate in acetonitrile detonated while being heated under reflux. [R39, 251] *A mixture of acetonitrile and sulfuric acid on heating (or self-heating) to 53 deg C underwent an uncontrollable exothermic reaction to 160 deg C in a few seconds. The presence of 28 mol% of sulfur trioxide reduces the initiation temperature to about 15 deg C. Polymerization of the nitrile is suspected. [R39, 251] *When fluorine was condensed onto acetonitrile and chlorine fluoride frozen at -196 deg C, a small explosion occurred in the reactor. [R39, 1096] *... Potentially explosive character of ... 2-cyanopropyl nitrate in acetonitrile. [R39, 1691] *Shaking a slow-reacting mixture /of dinitrogen tetraoxide, acetonitrile and indium/ caused detonation, attributed to indium-catalysed oxidation of acetonitrile. [R39, 1351] *The violent reaction which occurred on dissolution of the anhydrous salt in acetonitrile did not occur with the hydrated salt /of iron(III) perchlorate/. [R39, 1037] *Mixtures of fuming nitric acid and acetonitrile are explosive. [R39, 1149] *Latent hazards in storing and handling the explosive mixtures of perchloric acid with acetonitrile. [R39, 953] DCMP: *WHEN HEATED TO DECOMP, EMITS HIGHLY TOXIC FUMES OF CN- AND NOx /CYANIDES AND NITROGEN OXIDES/. [R34] POLY: *A mixture of acetonitrile and sulfuric acid on heating (or self-heating) to 53 deg C underwent an uncontrollable exothermic reaction to 160 deg C in a few seconds. The presence of 28 mol% of sulfur trioxide reduces the initiation temperature to about 15 deg C. Polymerization of the nitrile is suspected. [R39, 251] ODRT: *Low: 70.0 mg/cu m; High: 70.0 mg/cu m; Irritating: 875 mg/cu m [R40] SERI: *May cause skin irritation. [R36] *Vapor: irritating to eyes, nose and throat. Liquid: irritating to skin and eyes. [R29] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R16] *Wear appropriate eye protection to prevent eye contact. [R16] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R16] *Recommendations for respirator selection. Max concn for use: 200 ppm: Respirator Classes: Any chemical cartridge respirator with organic vapor cartridge(s). Any supplied-air respirator. [R16] *Recommendations for respirator selection. Max concn for use: 500 ppm: Respirator Classes: Any supplied-air respirator operated in a continuous flow mode. Any powered, air-purifying respirator with organic vapor cartridge(s). Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R16] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Classes: Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R16] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Classes: Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R16] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with liquid acetonitrile. ... Employees should be provided with and required to use splash-proof safety goggles where liquid acetonitrile may contact the eyes. [R18, 1981.2] *Personnel protection: Wear self-contained breathing apparatus. If contact with the material anticipated, wear full protective clothing. [R37] OPRM: *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... Clothing wet with liquid acetonitrile should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of acetonitrile from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the acetonitrile, the person performing the operation should be informed of acetonitrile's hazardous properties. Any clothing which becomes wet with or non-impervious clothing which becomes contaminated with acetonitrile should be removed immediately and not reworn until the acetonitrile is removed from the clothing. ... Skin that becomes contaminated with acetonitrile should be immediately washed or showered to remove any acetonitrile. [R18, 1981.2] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R37] *Personnel protection: Keep upwind. Avoid bodily contact with the material. Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material is anticipated, wear full protective clothing. Avoid breathing vapors. [R37] *In view of ... report of severe intoxication ... it seems important that ... protective measures should be applied ... especially education of personnel and proper ventilation. [R27, 3143] *Contact lenses should not be worn when working with this chemical. [R16] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *All nitriles should be handled under carefully controlled conditions and only by personnel having a thorough understanding and knowledge of safe handling techniques. Because of the nature of nitrile cmpd and the lack of complete toxicity data on many nitriles, care should be exercised in handling these cmpd to avoid inhalation of the vapors, ingestion, and contact with the skin. /Nitriles/ [R41, 1447] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *The worker should immediately wash the skin when it becomes contaminated. [R16] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R16] *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R35, p. 49-10] SSL: *Heat /contributes to instability/. [R18, 1981.2] *Vapor forms explosive mixtures with air. [R17] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R42] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R43] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R44] STRG: *Protect containers against physical damage. Outdoor or detached storage is preferable. Separate from any sources of ignition and combustible materials. Storage room should be well-ventilated. [R45, 6] *Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Separate from oxidizing materials. Outside or detached storage is preferred. [R35, p. 49-10] CLUP: *1) REMOVE ALL IGNITION SOURCES. 2) VENTILATE AREA OF SPILL OR LEAK. 3) FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW ... VAPORS TO COMPLETELY CLEAR DUCTWORK. BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. ... /IT/ SHOULD NOT BE ALLOWED TO ENTER CONFINED SPACE, SUCH AS SEWER ... [R18, 1981.4] *Treatment methods: (1) Bench scale activated sludge, fill and draw operations, with a special respirometer: BOD at 20 deg C observed for 1-5 days, feed at 490 mg/l; acclimation at < 1 day, 17% removed. (2) Activated sludge, continuous feed and effluent discharge: measurement of carbon and nitrogen at 22-25 deg C observed for 28 days, feed at 139 mg/l, acclimation at 28 days with 98+% removed. [R46, 151] *Eliminate all ignition sources. Approach release from upwind. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors, protect personnel, and dilute spills to form nonflammable mixtures. Control runoff and isolate discharged material for proper disposal. [R35, p. 49-10] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U003 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R47] *Acetonitrile is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Oxides of nitrogen are removed from the effluent gas by scrubbers and/or thermal devices. [R48] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R49] *Incineration with nitrogen oxide removal from effluent gases by scrubbers or incinerators. Recommendable method: Incineration. Not recommendable methods: Landfill, evaporation. [R50] *... MAY BE DISPOSED OF BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R18, 1981.4] *INCINERATION OF WASTE ACETONITRILE IS DISCUSSED. [R51] *The following wastewater treatment technology has been investigated for acetonitrile: Concentration process: Biological treatment. [R52] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *WEIGHT OF EVIDENCE CHARACTERIZATION: Under the current Risk Assessment Guidelines, acetonitrile is assigned carcinogen class D, not classifiable as to human carcinogenicity. There is an absence of human evidence and the animal evidence is equivocal. Under the Proposed Guidelines for Carcinogen Risk Assessment, the carcinogenic potential of acetonitrile following inhalation, oral or dermal exposure is best characterized as "cannot be determined because the existing evidence is composed of conflicting data (e.g., some evidence is suggestive of carcinogenic effects but other equally pertinent evidence does not confirm any concern)." The National Toxicology Program (NTP) concluded that the evidence for carcinogenicity via inhalation of acetonitrile in the F344/N rat was equivocal based on a positive trend of hepatocellular tumors in male rats. Although there was a statistically significant positive trend in the incidence of hepatocellular adenomas, hepatocellular carcinomas, and hepatocellular adenomas or carcinomas (combined ) in male rats only, the incidences were not statistically significant by pairwise comparison or by life table analysis. In addition, the incidence of adenomas and carcinomas combined in the 400-ppm group was only slightly higher than the historical range for inhalation study controls. Male rats exhibited an increased incidence of basophilic foci in liver that was statistically significant in the 200- and 400- ppm groups. Although these foci were not atypical in appearance, as those more closely related to the carcinogenic process, altered hepatocellular foci are generally considered to be preneoplastic. NTP concluded that "a causal relationship between acetonitrile exposure and liver neoplasia in male rats is uncertain." There was no evidence of carcinogenicity in female rats or in either male or female B6C3F1 mice. The evidence from mutagenicity assays indicates that acetonitrile does not cause point mutations. Acetonitrile was negative in assays with five strains of S. typhimurium in the absence of S9 as well as in the presence of rat or hamster S9 induced with Aroclor 1254. However, acetonitrile does have potential to interfere with chromosome segregation, possible leading to aneuploidy, as evidenced in experiments with D. melanogaster. HUMAN CARCINOGENICITY DATA: Inadequate; none are available. [R53] ANTR: *Rapid support of respiration and circulation is essential to successful treatment of cyanide intoxication. Massive cyanide overdoses have survived with only good supportive care. Immediate attention should be directed toward assisted ventilation, administration of 100% oxygen, insertion of intravenous lines, and institution of cardiac monitoring. Obtain an arterial blood gas immediately and correct any severe metabolic acidosis (pH below 7.15). Oxygen (100%) should be used routinely in moderate or severely symptomatic patients even in the presence of a normal Po2, since 100% O2 increases O2 delivery, may reactivate cyanide-inhibited mitochondrial enzymes, and potentiates the effect of thiosulfate. /Cyanides/ [R9, 1480] *Amyl nitrite perles are designed to produce 3% to 5% methemoglobinemia while an intravenous line is established for intravenous sodium nitrite. As a temporizing measure, the patient inhales the vapors until the sodium nitrite is ready. Because of the variability in methemoglobin production and the potential for cardiovascular collapse, this step may be omitted if sodium nitrite is readily available and the patient is not in extremis. Adequate ventilation and oxygenation are more important than administration of amyl nitrite. One perle is crushed and inhaled ... until intravenous nitrite is given. Sodium nitrite ... is administered IV slowly over 4 minutes to produce a 20% methemoglobin level in adults. ... Administer sodium nitrite doses to children on the basis of body weight, since fatal methemoglobinemia has occurred in children. /Cyanides/ [R9, 1481] *Treatment: Stabilization: Patients should be treated in an intensive care facility immediately after ingestion of acetonitrile where they may be admin antidotes before serious toxic effects occur. Fluid, electrolyte, and acid-base disturbance should be corrected. Supportive care and supplemental oxygen may be sufficient even without concomitant antidotes. Decontamination: Gastric lavage is advised, rather than syrup of ipecac, due to the anticipated onset of severe cardiovascular compromise and seizures. Activated charcoal may have limited efficacy in cases of inorganic cyanide poisoning due to the rapidity of cyanide's systemic absorption and the onset of severe manifestations of cyanide toxicity. Specific data on acetonitrile binding by activated charcoal is not avail. Elimination Enhancement: Acetonitrile has a low volume of distribution and a low molecular weight. Hemodialysis and hemoperfusion may return thiocyanate concn to subtoxic levels. Hemodialysis may be considered for severely poisoned patients since severe symptoms can persist for several days and admin of antidotal therapy may be limited by the sodium content. [R9, 1485] *Antidotes: IV sodium thiosulfate is the drug of choice for treatment of acetonitrile poisoning. Its high sodium content ... and short half-life suggest that a continuous infusion, following an initial bolus, might maintain continuously high thiosulfate levels while minimizing total daily sodium dose. Low-sodium-content IV solutions should be used. Sodium nitrite may exacerbate the hypotension. P-Methyl-aminophenol (250mg) has also been used. Its role in acetonitrile poisoning remains to be determined. Specific antidotes are recommended in seriously poisoned patients who fail to respond immediately to standard supportive measures. Nitrites seem to be of dubious value. ... Animal data suggest that the specific cytochrome p450 enzymes responsible for conversion of acetonitrile to cyanohydron are inducible by ethanol and 4-methylpyrazole. Supportive measures: Ethanol may be useful in acetonitrile toxicity. It may act by competing with acetonitrile for oxidation by p450 IIE1, as well as by acting as a competitive substitute for the peroxidatic activity of catalase-H2O2. [R9, 1485] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Administer amyl nitrite ampules as per protocol and physician order ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Cyanide and related compounds/ [R54] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer cyanide antidote kit as per protocol and physician order ... . Monitor and treat cardiac arrhythmias if necessary ... . Consider vasopressors to treat hypotension without signs of hypovolemia ... . Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Cyanide and related compounds/ [R54] MEDS: *... DETERMINATION OF BLOOD CYANIDE OR URINARY THIOCYANATE SHOULD NOT BE RELIED ON AS EVIDENCE FOR BRIEF INHALATION OF LOWER CONCN OF ... VAPOR. [R27, 3142] *In biological monitoring, pre-exposure levels should be estabished, since smokers show elevated concn of metabolites. [R55] *Consider the skin, resp tract, heart, CNS, renal and liver function in placement and periodic exam. [R8, 30] *The following medical procedures should be made available to each employee who is exposed to acetonitrile at potentially hazardous levels: A complete history and physical examination: The purpose is to detect pre-existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the kidneys, liver, cardiovascular system, and central nervous system should be stressed. The skin should be examined for evidence of chronic disorders. The aforementioned medical examinations should be repeated on an annual basis. [R18, 1981.1] *Accurate identification of acetonitrile is critical to identification of the source of exposure. Reports have indicated mistaken identification of acetonitrile in blood as acetone or ethanol. Multiple methods may be necessary to definitively identify acetonitrile levels in blood. The assessment of acetonitrile exposure can be accomplished through measurement of acetonitrile or cyanide in the blood. This test may be useful for identification of recent exposure. However, no information was located which demonstrated a correlation between cyanide or acetonitrile levels with acetonitrile exposure levels or the onset of adverse health effects. Due to the potential severe toxicity associated with formation of the metabolites cyanide, therapy should be initially based on clinical examination. Whole Blood Reference Ranges: Normal - Acetonitrile: none detected; Cyanide: non-smokers - less than 0.02 ug/ml, smokers - average 0.041 ug/ml. Exposed - not established. Toxic - Peak blood cyanide levels in fatal cases have been found to range from 4.4 to 10.38 ug/ml, depending on the time of analysis post-exposure. [R56, 24] *Serum or Plasma Reference Ranges: Normal - Acetonitrile: none detected; Cyanide: non-smokers - 0.004 ug/ml, smokers - 0.006 ug/ml. Exposed - not established. Toxic - not established. [R56, 25] *The assessment of acetonitrile exposure can be accomplished through measurement of acetonitrile. This test may be useful for identification of recent exposure. However, no information was located which showed a correlation between urinary acetonitrile levels and exposure levels, or the onset of adverse health effects. Urine Reference Ranges: Normal - Acetonitrile, none detected; Exposed - not established; and Toxic - not established. [R56, 25] HTOX: *... Three subjects breathed 40 ppm for 4 hr, while 2 subjects were similarly exposed to 80 ppm and 160 ppm. None of the subjects reported adverse response during the 40 ppm exposure, but one subject experienced a slight tightness of the chest a few hr later, and a cooling sensation in the lung the next morning and the rest of the day similar to that experienced when inhaling menthol. All subjects detected the odor at 40 ppm for the first 2 or 3 hr, then experienced some olfactory fatigue. No detectable cyanide was found in blood specimens, but one subject showed a slightly elevated urinary thiocyanate level. [R57, 1991.13] *... Fatal exposure of a photographic laboratory worker to acetonitrile was reported. After a massive exposure to acetonitrile he left work, ate his evening meal, and began experiencing gastric distress and nausea about 4 hr after the exposure. He vomited during the night. ... The next morning he was sweating profusely and was alternately crying out sharply and lapsing into a comatose state. Other symptoms were hypersalivation, conjunctivitus, very low urine output, low blood pressure, and albumin in the urine and cerebrospinal fluid. He experienced a cardiac and respiratory arrest from which he was resuscitated and ... died 6 days later. [R27, 3143] *Two additional cases were hospitalized with severe symptoms consisting of nausea and vomiting, respiratory depression, extreme weakness, and a semi-comatose state. ... One ... developed a transient weakness of the flexor muscles of the arms and wrists, and both developed urinary frequency, associated in one instance with albuminuria and in the other with passage of a small oxalate-type urinary calculus. /They also showed/ elevated blood cyanide levels and somewhat increased serum thiocyanate levels. All other exposed workers were evaluated; increased blood cyanide and thiocyanate values were found occasionally, and the symptoms described previously were found in lesser degree. ... None of these individuals developed any enlargement of the thyroid or alteration in thyroid function. [R27, 3143] *SYMPTOMATOLOGY: 1. Massive doses may produce, without warning, sudden loss of consciousness and prompt death from respiratory arrest. With smaller but still lethal doses, the illness may be prolonged for 1 or more hr. 2. Upon ingestion, a bitter, acrid, burning taste is sometimes noted, followed by a feeling of constriction or numbness in the throat. Salivation, nausea and vomiting are not unusual ... 3. Anxiety, confusion, vertigo, giddiness, and often a sensation of stiffness in the lower jaw. 4. Hyperpnea and dyspnea. Respirations become very rapid and then slow and irregular. Inspiration is characteristically short while expiration is greatly prolonged. 5. The odor of bitter almonds may be noted on the breath or vomitus ... 6. In the early phases of poisoning, an incr in vasoconstrictor tone causes a rise in blood pressure and reflex slowing of the heart rate. Thereafter the pulse becomes rapid, weak, and sometimes irregular ... A bright pink coloration of the skin due to high concn of oxyhemoglobin in the venous return may be confused with that of carbon monoxide poisoning. 7. Unconsciousness, followed promptly by violent convulsions, epileptiform or tonic, sometimes localized but usually generalized. Opisthotonos and trismus may develop. Involuntary micturition and defecation occur. 8. Paralysis follows the convulsive stage. The skin is covered with sweat. The eyeballs protrude, and the pupils are dilated and unreactive. The mouth is covered with foam, which is sometimes bloodstained ... The skin color may be brick red. Cyanosis is not prominent in spite of weak and irregular gasping. In the unconscious patient, bradycardia and the absence of cyanosis may be key diagnostic signs. 9. Death from respiratory arrest. As long as the heart beat continues, prompt and vigorous treatment offers some promise of survival. /Cyanide/ [R58, p. III-126] *Acute: Headache, dizziness, hyperpnea (respiration incr), rapid pulse, nausea, vomiting, unconsciousness, convulsions (fits), fatal. Chronic: Headache, anorexia (lack of appetite), dizziness, weakness, macular, papular or vesicular dermatitis. [R59] *Fatality occurred in 23-yr old man who had been engaged for a 2 days in hand painting interior of tank with resin containing 30-40% acetonitrile as well as other substances, such as diethylenetriamine and a mercaptan. Acetonitrile was major volatile component. About 4 hr after leaving job ... he complained of chest pain, vomited and had massive hematemesis, followed by convulsions. About 9 hr later he was in a comatose state, with an ashen-gray color and irregular and infrequent respirations; he expired about an hour after admission with convulsive seizures and marked rigidity of the neck. A postmortem examination disclosed only generalized vascular congestion. Examination of the blood and various organs showed high levels of cyanide ion (ug percent: blood, 796; urine, 215; kidney, 204; spleen, 318; lungs, 128; liver, 0) . [R27, p. 3142-3] *... CONSIDERED TOXIC BY INGESTION, INHALATION, AND SKIN CONTAMINATION. [R41, 1445] *Acetonitrile concn up to 500 ppm cause irritation of mucous membranes. Higher concn produce weakness, nausea, convulsions, and death. Urine thiocyanate concn not significantly elevated after exposure to 160 ppm/4 hr. [R55] *Two cases of pediatric accidental ingestion of an acetonitrile-containing cosmetic are reported. One of the children, a 16 month old boy, was found dead in bed the morning after ingesting the product. No therapy had been undertaken, as the product was mistakenly assumed to be an acetone-containing nail polish remover. The second child, a 2 year old boy, experienced signs of severe cyanide poisoning, but survived with vigorous supportive care. Both children had blood cyanide levels in the potentially lethal range. The observed delayed onset of severe toxic reactions supports the proposed mechanism of acetonitrile conversion to inorganic cyanide via hepatic microsomal enzymes. [R60] *Several cases of accidental poisoning were caused by inhalation of acetonitrile in different work places. Signs of toxicity include: bronchial tightness, gastric distress, respiratory distress, hypotension, hypersecretion of saliva, conjunctivitis, skin discoloration, tachypnea, general weakness, absence of deep reflexes, coma and death in some cases. Postmortem analysis for cyanide and thiocyanate revealed that of all tissues, the spleen contained the largest amount of cyanide. While high levels of thiocyanate were found in the lungs, the largest amounts of acetonitrile were found in the liver and kidneys. [R3, 303] *It is toxic by any route of exposure, and massive exposures have been reported to cause death by cyanide asphyxiation after inhalation in workplaces. Intoxication and death following inhalation or accidental ingestion are delayed, sometimes for hours. The course is distinctly different than for inorganic cyanides. Unmetabolized acetonitrile is not lethally toxic. Cyanide is only one of the toxicants liberated by acetonitrile. Cyanate production may also contribute to reported fatal outcomes. Survivors of acute exposures have suffered from a variety of reversible symptoms and findings affecting the CNS, blood, and possibly the kidneys. ... There have been a number of less dramatic overexposures to laboratory personnel, characterized by malaise, nausea, and headache, followed in at least two cases by subjective dyspnea. [R61] *Onset of symptoms are delayed 3 or more hr. Nausea and vomiting are the earliest symptoms. This latent period occurs because the parent molecule has no apparent intrinsic toxicity, but undergoes a two-step activation reaction mediated by cytochrome p450 enzymes (p-450IIE1). This reaction results in the formation of cyanohydrin, which undergoes peroxidation releasing hydrogen cyanide. Cyanide is then eliminated by the rhodanese-mediated oxidation of endogenous thiosulfate to yield the thiocyanate, that is ... renally excreted. Symptoms do not appear until enough cyanide has been produced to exhaust endogenous stores of thiosulfate or to overwhelm the rhodanese pathway. Patients may exhibit signs and symptoms of cyanide intoxication, including lethargy, seizures, respiratory depression, and death. [R9, 1485] NTOX: *In ... dogs, no fatalities occurred up to and including 8000 ppm for a 4-hr exposure; deaths occurred at levels of 16,000 and 32,000 ppm. Symptoms in animals appear to be those of prostration, followed by convulsion seizures. Autopsy findings indicate pulmonary hemorrhage and vascular congestion. At the lower dosage levels, the deaths appeared to be delayed. [R27, 3142] *Rats exposed to 7 hr/day to acetonitrile vapor for a period of 90 days, showed no specific effects at 166 or 330 ppm. At 665 ppm, a pulmonary inflammatory change and minor changes in the kidney and liver were noted in some animals. [R27, 3142] *Dogs and monkeys were exposed to acetonitrile vapor for 7 hr/day, 3 days/week, for 91 days. The mean concentration was approximately 350 ppm. ... Some minor variations in weight, hematocrit, and hemoglobin were reported. At autopsy some cerebral hemorrhage was noted in the septa in the lung. Rather marked pigment-bearing macrophages were consistently noted in monkeys. A similar picture in the lungs was noted in dogs. [R27, 3142] *ANIMAL STUDIES ... SHOW THAT DIFFERENT SPECIES ... VARY WIDELY IN SUSCEPTIBILITY TO ACETONITRILE IN SINGLE DOSE STUDIES BY VARIOUS ROUTES. [R57, 1991.12] *Daily doses /by gavage/ of 125, 190 and 275 mg/kg bw were admin in a water solution to rats on gestational days 6-19, inclusive. The highest dose produced some maternal deaths, and reduced body wt in the dams. Embryotoxic effects occurred at the highest dosage with early resorptions and postimplantation losses. No tetratogenic effects were observed. ... In the hamster teratogenic effects were observed after a 1 hr inhalation exposure on the 8th day of gestation to 5000 and 8000 ppm, but not 1800 and 3800 ppm. Oral and ip doses of 100-400 mg/kg also produced teratogenic effects. The higher dosages and concn caused overt maternal toxicity. It was concluded that the toxicity was due to cyanide liberated from the acetonitrile. [R57, 1991.13] *MALE RATS WERE EXPOSED FOR 4 HR TO DIFFERENT CONCN OF ACETONITRILE. SERUM ENZYMES, GLUTAMIC OXALACETIC TRANSAMINASE, GLUTAMIC PYRUVIC TRANSAMINASE, AND ORNITHINE CARBAMYL TRANSFERASE WERE INCR. [R62] *WHEN INHALED BY RATS AT /SRP: LC50 AND LC84/ DOSE LEVELS, ACETONITRILE CAUSES PULMONARY EDEMA, DECR DRY RESIDUES IN LUNG, AND INCR AMMONIA CONTENT OF TISSUES. [R63] *GROUPS OF PREGNANT GOLDEN HAMSTERS WERE EXPOSED DURING EARLY PRIMITIVE STREAK STAGE OF GESTATION TO EITHER 0, 1800, 3800, 5000 OR 8000 PPM FOR 60 MIN. CONCN OF ACETONITRILE IN CHAMBER AIR (45 L SINGLE PASS CHAMBER) TO WHICH ANIMALS WERE EXPOSED WERE DETERMINED BY GC. CONCN-DEPENDENT INCR IN MATERNAL MORTALITY, RESORPTION SITES AND MALFORMED OFFSPRING WAS NOTED. MOST COMMON ANOMALIES INCL EXENCEPHALY, ENCEPHALOCELE AND RIB FUSIONS AND BIFURCATIONS. ONE FETUS EXHIBITING ECTOPIA CORDIS WAS TAKEN FROM MOTHER EXPOSED TO 8000 PPM. RESULTS OF TISSUE STUDIES SUGGESTED THAT TOXICITY AND TERATA WERE DUE TO METABOLIC LIBERATION OF CYANIDE IN SITU FROM PARENT CMPD. [R64] *Acetonitrile ... tested on rabbit eyes by application of a drop, has caused superficial reversible injury like that caused by acetone; graded 5 on a scale of 1 to 10 after twenty-four hr. [R65] *Acetonitrile was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Acetonitrile was tested at doses of 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Acetonitrile was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 10 mg/plate. [R66] *Acetonitrile, adiponitrile, and propionitrile were evaluated for embryotoxic and teratogenic potential in rats. Mated Sprague Dawley rats were administered 1 of the 3 nitriles by gavage on gestation days 6-19, inclusive. Daily dosage levels (mg/kg) were: acetonitrile at 0, 125, 190, and 275; adiponitrile at 0, 20, 40, and 80; propionitrile at 0, 20, 40, 80. There was evidence of maternal toxicity in each of the high-dose groups treated with acetonitrile, adiponitrile, or propionitrile. Some maternal effects also were seen with adiponitrile at the middle dosage. Embryotoxic effects were observed at the highest dosage tested for acetonitrile and middle and high dose levels for propionitrile. Slight fetotoxicity was observed at the highest dosage for adiponitrile. No teratogenic effects were observed at any dosage level with acetonitrile, adiponitrile, or propionitrile. [R67] *Acetonitrile has been associated with hepatotoxicity. /From table/ [R68] *In rats inhalation of acetonitrile caused dyspnea, cyanosis, anuria, hemorrhage in brain and lungs, bronchial inflammation, desquamation and hypersecretion of mucus, hepatic and renal lesions, and pneumonia and atelectasis. In monkeys, inhalation of acetonitrile caused bronchitis and excitability. Post mortem studies showed moderate inflammation of superior and inferior sagittal sinuses of the brain, subdural hemorrhage, chronic pneumonitis, and pleural adhesions. Inhalation of acetonitrile caused a decrease in hematocrit and hemoglobin in dogs. [R3, 303] *Propionitrile is about 3-4 times more toxic than acetonitrile by the respiratory route of administration. The greater toxicity of propionitrile is due to its higher lipid-water partition coefficient and lower volatility than acetonitrile. These factors increase its ability to penetrate biological membranes and decrease its elimination in the expired air. [R3, 355] *STRUCTURE-ACTIVITY RELATIONSHIPS WERE QUALITATIVELY AND QUANTITIVELY EXAMINED FOR 56 COMPOUNDS (EG DERIVATIVES OF PROPIONITRILE, ACRYLONITRILE, AND CYSTEAMINE) WHICH CAUSED DUODENAL ULCER AND/OR ADRENOCORTICAL NECROSIS IN RATS. ULCEROGENIC ACTIVITY WAS MOST INTENSE IN THE CARBONITRILES ATTACHED TO 2 OR 3-C BACKBONES. [R69] *... Under the conditions of these two yr inhalation studies, there was equivocal evidence of carcinogenic activity of acetonitrile in male F344/N rats based on marginally increased incidences of hepatocellular adenoma and carcinoma. There was no evidence of carcinogenic activity of acetonitrile in female F344/N rats exposed to 100, 200, or 400 ppm. There was no evidence of carcinogenic activity of acetonitrile in male or female B6C3F1 mice exposed to 50, 100, or 200 ppm. [R70] *Acetonitrile has been shown to affect the thyroid. ... Progressive bilateral exoplithalmos ... produced in rabbits with a daily intramuscular injection of 0.05 ml acetonitrile ... /which/ could be inhibited by feeding of fresh vegetables. The degree of exophthalmos was related to the thyroid hyperplasia, and could be prevented by prior administration of iodine. [R27, 3142] *... EFFECTS ... GENERALLY ... OBSERVED ... 3 TO 12 HR AFTER /ACETONITRILE/ EXPOSURE. THIS DELAYED ONSET ... HAS BEEN EXPLAINED AS A SLOW RELEASE OF CYANIDE ... . [R71, 204] *... The final clinical picture is result of effects of the intact molecule /acetonitrile/ combined with the effects of gradually released cyanide ions. [R27, 3143] *ALIPHATIC NITRILES (INCL ACETONITRILE) POSSESS LITTLE IF ANY ACUTE TOXICITY IN ABSENCE OF NORMAL HEPATIC FUNCTION AND ARE ACTIVATED BY HEPATIC MECHANISMS TO RELEASE CYANIDE WHICH ACCOUNTS FOR MAJOR ACUTE TOXIC EFFECTS. [R72] NTXV: *LD50 Rat young oral 200 mg/kg; [R58, p. II-214] *LC50 Rat inhalation 7500 ppm/8 hr; [R46, 152] *LC50 Rat inhalation 330 ppm/90 days; [R46, 152] *LD50 Rat oral 175 mg/kg; [R73] *LD50 Guinea pig oral 140 mg/kg; [R3, 303] *LD50 Mouse ip 175 mg/kg; [R57, 1991.12] *LD50 Rabbit dermal 980 mg/kg; [R3, 303] *LD50 Rabbit dermal 390 mg/kg /with 75% solution/; [R3, 303] */LC50/ Guinea pig inhalation 5655 ppm/4 hr; [R3, 303] */LC50/ Rabbit inhalation 2825 ppm/4 hr; [R3, 303] *LD50 Rat intraperitoneal 920 mg/kg; [R57, 1991.12] *LD50 Rat subcutaneous 3500 mg/kg; [R34] *LD50 Rat iv 1680 mg/kg; [R34] *LD50 Rat parenteral 1100 mg/kg; [R34] *LD50 Mouse oral 269 mg/kg; [R34] *LC50 Mouse inhalation 2693 ppm/ 1 hr; [R34] *LD50 Mouse subcutaneous 4480 mg/kg; [R34] *LC50 Mice 2693 ppm/60 min; [R74] ETXV: *Toxicity Threshold (Cell Multiplication Inhibition Test) Entosiphon sulcatum (protozoa) 1810 mg/l /Conditions of bioassay not specified/; [R46, 152] *Toxicity Threshold (Cell Multiplication Inhibition Test) Uronema parduczi Chatton-Lwoff (protozoa) 5825 mg/l /Conditions of bioassay not specified/; [R46, 152] *Toxicity Threshold (Cell Multiplication Inhibition Test) Scenedesmus quadricauda (green algae) 7300 mg/l /Conditions of bioassay not specified/; [R46, 152] *Toxicity Threshold (Cell Multiplication Inhibition Test) Microcystis aeruginosa (algae) 520 mg/l /Conditions of bioassay not specified/; [R46, 152] *TLm Pimephales promelas (fathead minnow) 1020 mg/l/96 hr (hard water) /Conditions of bioassay not specified/; [R46, 152] *TLm Pimephales promelas (fathead minnow) 1000 mg/l/96 hr (soft water) /Conditions of bioassay not specified/; [R46, 152] *TLm Lepomis macrochirus (bluegill) 1850 mg/l/96 hr (soft water) /Conditions of bioassay not specified/; [R46, 152] *TLm Lebistes reticulatus (guppy) 1650 mg/l/96 hr (soft water) /Conditions of bioassay not specified/; [R46, 152] *LC50 Pimephales promelas (fathead minnow) 1640 mg/l/96 hr (confidence limit 1600 - 1690 mg/l), flow-through bioassay with measured concentrations, 26.1 deg C, dissolved oxygen 6.1 mg/l, hardness 43.0 mg/l calcium carbonate, alkalinity 46.0 mg/l calcium carbonate, and pH 7.4; [R75] *EC50 Pimephales promelas (fathead minnow) 1640 mg/l/96 hr (confidence limit 1600 - 1690 mg/l), flow-through bioassay with measured concentrations, 26.1 deg C, dissolved oxygen 6.1 mg/l, hardness 43.0 mg/l calcium carbonate, alkalinity 46.0 mg/l calcium carbonate, and pH 7.4. Effect: loss of equilibrium; [R75] *Toxicity Threshold (Cell Multiplication Inhibition Test) Pseudomonas putida (bacteria) 680 mg/l; [R46, 152] NTP: *... Groups of 56 male and 56 female F344/N rats were exposed to 0, 100, 200, or 400 ppm (equivalent to 0, 168, 335, or 670 mg/cu m) acetonitrile by inhalation for 6 hr/day, 5 days/wk for 2 yr. ... Groups of 60 male and 60 female B6C3F1 mice were exposed to 0, 50, 100, or 200 ppm (equivalent to 0, 84, 168, or 335 mg/cu m) acetonitrile by inhalation for 6 hr/day, 5 days/wk for 2 yr. ... Under the conditions of these two yr inhalation studies, there was equivocal evidence of carcinogenic activity of acetonitrile in male F344/N rats based on marginally increased incidences of hepatocellular adenoma and carcinoma. There was no evidence of carcinogenic activity of acetonitrile in female F344/N rats exposed to 100, 200, or 400 ppm. There was no evidence of carcinogenic activity of acetonitrile in male or female B6C3F1 mice exposed to 50, 100, or 200 ppm. [R70] +... The potential for acetonitrile to cause developmental toxicity was assessed in Sprague-Dawley rats exposed to 0, 100, 400, or 1,200 ppm acetonitrile, 6 hours/day, 7 days a week. Each of the four treatment groups consisted of 10 non-pregnant females (for comparison), 10 positively mated females for a distribution study evaluating maternal blood for acetonitrile and cyanide, and -33 positively mated females for evaluating developmental toxicity. Rats were exposed for 14 consecutive days (6-19 days of gestation (dg) for pregnant animals). The day of sperm detection was designated as 0 days of gestation. ... Acetonitrile and cyanide concentrations were determined in the maternal blood of the rats (approximately 6/group) on 8 and 18 days of gestation. Exposure of rats to these concentrations of acetonitrile resulted in mortality in the 1200 ppm group (2,133 pregnant females; 1/10 non-pregnant females), and the 400 ppm group (1/33 pregnant females). However, there were no treatment-related effects upon body weights or reproduction indices at any exposure level, nor was there a significant increase in the incidence of fetal malformations or variations. The only effect observed in the fetuses was a slight, but not statistically significant, exposure correlated increase in the incidence of supernumerary ribs. Determination of acetonitrile and cyanide concentrations in maternal rat blood showed that acetonitrile concentration in the blood increased with exposure concentration for all exposed maternal rats. Detectable amounts of cyanide in the blood were found only in the rats exposed to 1,200 ppm acetonitrile (approximately 2 ug of cyanide per gram of blood). In summary, the two highest exposure concentrations were maternally lethal to some rats; however, there was no reduction in body weights, body weight gains, or clinical signs of toxicity in surviving pregnant or non-pregnant rats. The no-observable-adverse-effect-level (NOAEL) for acetonitrile with respect to developmental toxicity in this study was the highest exposure concentration, 1200 ppm. The maternal NOAEL was 100 ppm. [R76] TCAT: ?In a pilot teratology study to establish dosage levels, pregnant Charles River CD rats (5/group) were orally exposed to acetonitrile by gavage at dosage levels of 0, 200, 375, 750, 1500 and 3000 mg/kg/day on gestation days (GD) 6-19 at a constant volume in distilled water vehicle. Toxicity was evidenced by severe loss in maternal body weight and dry red matter on the face and yellow-brown stained anogenital haircoats prior to death in all but the lowest-dose and control groups. An increase in the mean number of early resorptions was observed in the 375 mg/kg group. Marked mortality included 3 rats dying by GD 20 in the 375 mg/kg group. All rats died in the higher dose levels, by GD 18 in the 750 mg/kg/day group, by GD 18 in the 1500 mg/kg/day groups, and by GD 10 in the 3000 mg/kg/day group. [R77] ?An oral teratology study was conducted with groups of 25 pregnant New Zealand white rabbits receiving 0, 2.0, 15.0 or 30.0 mg/kg acetonitrile by oral gavage, once daily on days 6 - 18 of gestation. Observations of dams at the high dose level included mortality (in 5 animals), thinning of the stomach wall in the cardiac region, ataxia, colored exudate in the cage pan, decreased motor activity, bradypnea, dyspnea and impaired or lost righting reflex. Statistically significant maternal effects at the high dose included increased anorexia, decreased average body weight gain during agent administration, and a decreased average number of live fetuses in litters (p=0.011); additionally, a slight but not statistically significant (p > 0.05) increase in resorptions was observed. The incidence of pregnancy, average number of corpora lutea and implantations, average fetal body weights, and fetal sex ratio were not affected at any dose. A statistically significant (p=0.015) increase in the incidence of an extra ossification site in the parietal bones was observed for four fetuses in two high dosage group litters, however, the investigators implied that this was a frequently observed spontaneous effect in this strain of rabbits. No statistically significant change in litter incidence was observed (p > 0.05) at any dose. [R78] ?The ability of acetonitrile to induce mutations at the HGPRT gene locus in Chinese Hamster Ovary (CHO) cells in vitro was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. In nonactivated experiments acetonitrile was tested at 11 concentrations (exposure time = 16 hrs) over the range of 0.1-30 mg/ml, with mean cell survival ranging from > 100% to < 10% relative to the media control. Assays with activation involved 10 concentrations (exposure time = 4 hrs) over the range of 4 - 20 mg/ml, with mean cell survival ranging from > 100% to 39%. Although mutation frequencies at two of the sample concentrations in both the activated and the nonactivated assays were higher than the negative controls, analysis of variance on the combined data from replicate experiments indicated no significant differences. [R79] ?The mutagenicity of acetonitrile was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Acetonitrile was tested for mutagenicity at concentrations of 5, 10, 25, 50, 100, 500, and 1000 ug/plate with activation and 2500, 5000, 7500, and 10,000 ug/plate without activation. Acetonitrile did not cause a reproducible positive response in any of the bacterial tester strains, either with or without metabolic activation. [R80] ?The mutagenicity of acetonitrile was evaluated in Salmonella tester strains TA98, TA100, TA1535, and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, acetonitrile was tested for mutagenicity at concentrations up to 10,000 ug/plate using the plate incorporation method. Acetonitrile did not cause a reproducible positive response in any of the bacterial tester strains, either with or without metabolic activation. [R81] POPL: */Protect/ from exposure those individuals with diseases of CNS, heart and lung. [R45, 7] ADE: *... CAN BE ABSORBED THROUGH SKIN AND RESP TRACT. [R17] *The nature and mechanism of a toxicological interaction between acetonitrile and acetone was investigated. Results of oral dose-response studies utilizing a 1:1 mixture of acetonitrile and acetone, or varying doses of acetonitrile administered together with a constant dose of acetone, indicated that acetone potentiated acute acetonitrile toxicity 3 to 4 fold in rats. The onset of severe toxicity (manifested by tremors and convulsions) was delayed in the groups dosed with both solvents compared to the groups that recieved acetonitrile or acetone alone. Blood cyanide (a metabolite of acetonitrile) and serum acetonitrile and acetone concentrations were measured after oral administration of 25% aqueous solns of acetonitrile, acetone, or acetonitrile and acetone. Concentrations of cyanide in the blood of rats given acetonitrile and acetone remained near baseline, in contrast to the high blood cyanide concentrations found in rats dosed with acetonitrile alone. At 34 to 36 hr, high blood cyanide concentrations were found in rats dosed with both solvents. This delayed onset of elevation of blood cyanide coincided with the occurrence of clinical signs and with the disappearance of serum acetone. In further pharmacokinetic studies, blood cyanide concentrations were measured after similar dosage regimens of acetonitrile and acetone. Peak cyanide concentrations were significantly greater in rats dosed with both than in rats given only acetonitrile. Administration of sodium thiosulfate or a second dose of acetone prevented the toxicity associated with exposure to both solvents. Evidently, the effects of acetone on acetonitrile toxicity are due to a biphasic effect on the metabolism of acetonitrile to cyanide ie, an initial inhibition followed by a stimulation of this metabolism upon acetone elimination. [R82] METB: *... RATS RECEIVED IP INJECTIONS ... IN DOSES RANGING FROM 600 TO 2340 MG/KG. ... IN GENERAL ACETONITRILE WAS ... RATHER EVENLY DISTRIBUTED AMONG VARIOUS ORGANS, AND HYDROGEN CYANIDE WAS FOUND IN NEARLY ALL ORGANS IN VARYING CONCN. ... SUBSEQUENT STUDIES ... /SHOWED/ SIMILAR RESULTS FOLLOWING ADMIN ... TO RATS BY INHALATION ... . [R71, 203] *THIOCYANATE WAS MEASURED AS INDEX OF CYANIDE ION RELEASE IN URINE OF RATS GIVEN EQUIMOLAR DOSES OF NITRILES. MORE THIOCYANATE WAS EXCRETED AFTER ORAL ADMIN THAN AFTER IP ADMIN. ORAL ADMIN OF ACETONITRILE YIELDED 37% OF DOSE AS THIOCYANATE (SCN-), WHEREAS AFTER IP INJECTION, 4.5% OF DOSE WAS EXCRETED AS THIOCYANATE. [R83] *Acetonitrile is metabolized to hydrogen cyanide which can be found in high levels in the brain, heart, kidney and spleen. [R8, 29] *When rat liver microsomes were incubated with glycolonitrile or acetonitrile, cyanide was liberated without the formation of formaldehyde. Based on the amount of cytochrome p450 in the microsomal preparation and the rates of cyanide formed, the action of an enzyme system was postulated in the metabolism of both compounds. [R84] *Rats were pretreated with buthionine sulfoximine (4 mmol/kg, ip at 4 and 2 hr), cobalt heme (90 mumol/kg, sc at 48 hr), dimethylcobalt (1960 mg/kg, orally at 24 hr), or vehicle, and hepatocytes were isolated after collagenase perfusion of the liver. Buthionine sulfoximine reduced the cellular reduced glutathione content by greater than 80%, but did not affect the metabolism of methylcyanide : the liberation of cyanide correlated with cytochrome p450, and not reduced glutathione, concentrations. Cobalt heme depleted hepatocellular cytochrome p450 (-45%) content, decreased cell yield and viability, and resulted in a reduction in the metabolism of methylcyanide to cyanide. Cobalt heme did not affect the recovery of sodium cyanide from hepatocyte suspensions. Pretreatment of rats with dimethylcyanide resulted in a 2-fold increase in the metabolism of methyl cyanide to cyanide. Addition of dimethylcobalt in vitro inhibited methylcyanide metabolism. Apparently, the metabolism of methylcyanide to cyanide occurs by a cytochrome p450 dependent pathway, and not by a nucleophilic substitution reaction with reduced glutathione. [R85] *... Latent period occurs because the parent molecule has no apparent intrinsic toxicity, but undergoes a two-step activation reaction mediated by cytochrome P450 enzymes (P-450IIE1). This reaction results in the formation of cyanohydrin, which undergoes peroxidation releasing hydrogen cyanide. Cyanide is then eliminated by the rhodanese-mediated oxidation of endogenous thiosulfate to thiocyanate, that is, in turn, renally excreted. [R9, 1485] BHL: *Elimination half-lives following an ingestion of 5 ml of 98% acetonitrile were 32 hr for acetonitrile and 15 hr for cyanide. [R9, 1485] ACTN: *... Latent period occurs because the parent molecule has no apparent intrinsic toxicity, but undergoes a two-step activation reaction mediated by cytochrome p450 enzymes (P-450IIE1). This reaction results in the formation of cyanohydrin, which undergoes peroxidation releasing hydrogen cyanide. Cyanide is then eliminated by the rhodanese-mediated oxidation of endogenous thiosulfate the thiocyanate, that is ... renally excreted. Symptoms do not appear until enough cyanide has been produced to exhaust endogenous stores of thiosulfate or to overwhelm the rhodanese pathway. [R9, 1485] INTC: *MALE CD-1 MICE WERE EXPOSED 60 MIN TO TOXIC CONCN AND MAINTAINED FOR 14 DAYS. PRETREATMENT WITH SODIUM SULFITE OR SODIUM NITRITE OR HEPATOTOXIC DOSE OF CARBON TETRACHLORIDE PROVIDED SIGNIFICANT PROTECTION AGAINST MORTALITY FROM INHALATION EXPOSURE. [R86] *The nature and mechanism of a toxicological interaction between acetonitrile and acetone was investigated. Results of oral dose-response studies utilizing a 1:1 mixture of acetonitrile and acetone, or varying doses of acetonitrile administered together with a constant dose of acetone, indicated that acetone potentiated acute acetonitrile toxicity 3 to 4 fold in rats. The onset of severe toxicity (manifested by tremors and convulsions) was delayed in the groups dosed with both solvents compared to the groups that recieved acetonitrile or acetone alone. Blood cyanide (a metabolite of acetonitrile) and serum acetonitrile and acetone concentrations were measured after oral administration of 25% aqueous solns of acetonitrile, acetone, or acetonitrile and acetone. Concentrations of cyanide in the blood of rats given acetonitrile and acetone remained near baseline, in contrast to the high blood cyanide concentrations found in rats dosed with acetonitrile alone. At 34 to 36 hr, high blood cyanide concentrations were found in rats dosed with both solvents. This delayed onset of elevation of blood cyanide coincided with the occurrence of clinical signs and with the disappearance of serum acetone. In further pharmacokinetic studies, blood cyanide concentrations were measured after similar dosage regimens of acetonitrile and acetone. Peak cyanide concentrations were significantly greater in rats dosed with both than in rats given only acetonitrile. Administration of sodium thiosulfate or a second dose of acetone prevented the toxicity associated with exposure to both solvents. Evidently, the effects of acetone on acetonitrile toxicity are due to a biphasic effect on the metabolism of acetonitrile to cyanide ie, an initial inhibition followed by a stimulation of this metabolism upon acetone elimination. [R82] *Acute toxicity, in vitro metabolism, and structure-toxicity relations of aliphatic mononitriles were examined in mice pretreated with carbon tetrachloride. The LD50 in mice pretreated with carbon tetrachloride was increased in most nitriles compared to that in untreated animals with different degrees among compounds. Microsomal metabolism of nitriles to cyanide was completely inhibited when microsomes were prepared from livers of mice pretreated with carbon tetrachloride. [R87] *The effect of ethanol on the metabolism of 20 nitriles was studied in vivo and in vitro in mice. At 13 hr after ethanol dosing (4.0 g/kg), the metabolism of acetonitrile by isolated hepatic microsomes was 1.83 times controls (ie, glucose). [R88] *Mice were exposed for 60 min to acetonitrile, propionitrile, or n-butyronitrile, and were maintained for the following 14 days. The LC50 values for acetonitrile, proprionitrile, and n-butyronitrile were 2693, 163, and 249 ppm, respectively. Pre-treatment with sodium thiosulfate or sodium nitrite, two common inorganic cyanide antagonists, provided significant protection against the mortality associated with these exposures. Administration of the thiosulfate consistently provided greater protection than the nitrile. Pre-treatment with a hepatotoxic dose of carbon tetrachloride also provided protection. [R74] *WHEN SODIUM THIOSULFATE WAS GIVEN IN MULTIPLE INJECTIONS, IT PROTECTED MICE AGAINST DEATH BY PROPIONITRILE. /PROPIONITRILE/ [R72] *The toxic mechanism of nitriles (including acetonitrile) and the effect of metabolic modifiers in mice were studied in relation to their physicochemical properties. All the test nitriles liberated cyanide both in vivo and in vitro, with the exception of benzonitrile, although the extent of liberation and the effect of carbon tetrachloride pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into 3 groups. In group 1, acute toxicity was greatly reduced by carbon tetrachloride pretreatment, in group 2, toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher at death in the brains of mice given group 1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. The relation between log (1/LD50) and log p for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear. For most nitriles, the in vitro metabolism was inhibited when the incubation mixture contained either SKF-525A, carbon monoxide, or microsomes from mice treated with carbon tetrachloride. When mice were closed with ethyl alcohol, metabolic enhancement of nitriles was seen compared with the control. However, ethyl alcohol, when added to the incubation mixture, inhibited the in vitro metabolism of nitriles. [R89] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Acetonitrile's production and wide use as a solvent, chemical intermediate, and catalyst may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 88.8 mm Hg at 25 deg C indicates acetonitrile will exist solely as a vapor in the ambient atmosphere. Vapor-phase acetonitrile will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 621 days. If released to soil, acetonitrile is expected to have very high mobility based upon an estimated Koc of 16. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 3.45X10-5 atm-cu m/mole. Acetonitrile may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, acetonitrile is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Studies using mixed microbial cultures from activated sludge and sewage have shown that biodegradation of acetonitrile proceeds sluggishly without acclimatization. Mixed microbial cultures isolated by an enrichment culture technique degraded 58% acetonitrile in 5 days; river water also biodegraded acetonitrile with 40% theoretical oxygen demand after 12 days. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 12 hours and 7 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. The chemical hydrolysis of acetonitrile in water is base catalyzed but the rate is too slow to be an important fate process. The chemical hydrolysis half-life at pH 7 is > 150,000 years. Occupational exposure to acetonitrile may occur through inhalation and dermal contact with this compound at workplaces where acetonitrile is produced or used. Monitoring data indicate that the general population may be exposed to acetonitrile via ingestion of food and drinking water, and dermal contact with products containing acetonitrile. (SRC) NATS: *Small amounts of acetonitrile occur in coal tar(1). [R90] ARTS: *Acetonitrile ... /has/ been detected in the thermal decomp products of flexible polyurethane foam. [R91] *Acetonitrile's production and wide use as a solvent, chemical intermediate, and catalyst(1,2) may result in its release to the environment through various waste streams(SRC). Acetonitrile is released in the atmosphere as a result of fugitive emission during its manufacture(3,4). Emission of acetonitrile from industrial facilities during its use also occurs(4). It is also released to the atmosphere from incineration of polyacrylonitrile polymers(3,4), automobile exhaust(4,5), tobacco smoke(6), synthetic rubber manufacture(4), off-gas of shale oil retorting(7), manufacture of acrylonitrile(8) and turbine engines(4). Acetonitrile has been detected in shale oil wastewater(9,10) and in wastewater from coal gasification processes(10,11). [R92] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 16(SRC), determined from a log Kow of -0.34(2) and a regression-derived equation(3), indicates that acetonitrile is expected to have very high mobility in soil(SRC). Volatilization of acetonitrile from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 3.45X10-5 atm-cu m/mole(4). The potential for volatilization of acetonitrile from dry soil surfaces may exist(SRC) based upon a vapor pressure of 88.8 mm Hg(5). In water, biodegradation studies of acetonitrile with mixed cultures of microorganisms from activated sludge and sewage show that degradation proceeds sluggishly without acclimatization of microorganisms, particularly at high concns(6,7). Acclimated mixed microbial cultures isolated by an enrichment culture technique degraded 58% acetonitrile in 5 days(8). [R93] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 16(SRC), determined from a log Kow of -0.34(2) and a regression-derived equation(3), indicates that acetonitrile is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 3.45X10-5 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 12 hours and 7 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). The biodegradation studies of acetonitrile with mixed cultures of microorganisms from activated sludge and sewage show that degradation proceeds sluggishly without acclimatization of microorganisms, particularly at high concn(7,8). Acclimated mixed microbial cultures isolated by an enrichment culture technique degraded 58% acetonitrile in 5 days(9). The biodegradability of acetonitrile was also observed with river water; the 12 day ThOD (theoretical oxygen demand) with river water was 40%(10,11). [R94] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acetonitrile, which has a vapor pressure of 88.8 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase acetonitrile is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 621 days(SRC), calculated from its rate constant of 2.63X10-14 cu cm/molecule-sec at 25 deg C(3). Acetonitrile does not undergo direct photolysis in the vapor phase(4,5). [R95] BIOD: *AEROBIC: Enzyme-catalyzed hydrolysis of nitriles, such as acetonitrile, has been shown to proceed by two distinct routes(1,2); a nitrilase transforms the nitriles directly into acids plus ammonium ion, or a nitrile hydratase forms the amide which is hydrolyzed to acid plus ammonium ion by amidase(1,2). A mixed microbial culture isolated from an environment contaminated with organic cyanides and PCBs utilized acetonitrile as the sole source of carbon and nitrogen(3). The mixed microbial culture was grown for 48 hrs at pH 7 with 1 g/l of acetonitrile; the final pH and ammonia concn were determined to be 8.81 and 80.1 umol/ml, respectively(3). The biodegradation studies of acetonitrile with mixed cultures of microorganisms from activated sludge and sewage show that degradation proceeds sluggishly without acclimatization of microorganisms, particularly at high concn(4,5). Degradation is faster with acclimatization(6-11). With activated sludge as microbial inoculum, the lag period of acetonitrile degradation was about 1 day after which the compound degraded with a half-life of 1.2 days(8). Acclimated mixed microbial cultures isolated by an enrichment culture technique degraded 58% acetonitrile in 5 days(9). The biodegradability of acetonitrile was also observed with river water; the 12 day ThOD (theoretical oxygen demand) with river water was 40%(10,11). Acclimation of the microorganisms was examined by redosing; the degradation was 5 times faster after acclimation; it was also 4 times faster at 20 deg C than at 5 deg C(10,11). The biodegradation is expected to be much slower in seawater than in freshwater(12). [R96] *ANAEROBIC: Results of anaerobic tests with acetonitrile suggest that anaerobic biodegradation is not effective for removing the compound from wastewater(1). [R97] ABIO: *The photochemical smog studies show that this compound is unreactive towards photochemically-generated free radicals(2). Due to nonreactivity of acetonitrile in the atmosphere, transport of the compound from troposphere to stratosphere is expected to occur(SRC) and acetonitrile has been detected in the stratosphere(1). [R98] *The rate constant for the vapor-phase reaction of acetonitrile with photochemically-produced hydroxyl radicals is 2.63X10-14 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 621 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The reported rate constant for the reaction of acetonitrile with hydroxyl radicals in aqueous solution at pH 9 is in the range 2.1-3.5X10+6/M-sec(2,3). Assuming the concentration of hydroxyl radicals in natural surface waters as 1X10-17 M, the half-life is > 600 yrs(SRC). The chemical hydrolysis of acetonitrile in water is base catalyzed(4); the rate constant for base catalyzed hydrolysis is 5.8X10-3/M-hr and half-life at pH 7 is more than 150,000 yrs(4). Acetonitrile absorbs light only in the far UV region(5). Therefore, photolysis of the compound in the atmosphere should not be an important process(SRC). [R99] BIOC: *An estimated BCF of 3 was calculated for acetonitrile(SRC), using a log Kow of -0.34(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R100] KOC: *The Koc of acetonitrile is estimated as 16(SRC), using a measured log Kow of -0.34(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that acetonitrile is expected to have very high mobility in soil(SRC). [R101] VWS: *The Henry's Law constant for acetonitrile is estimated as 3.45X10-5 atm-cu m/mole(1). This Henry's Law constant indicates that acetonitrile is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 12 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 7 days(SRC). Acetonitrile's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of acetonitrile from dry soil surfaces may exist(SRC) based upon a vapor pressure of 88.8 mm Hg(3). [R102] EFFL: *Acetonitrile was qualitatively detected in shale oil wastewater(1) and wastewater from coal gasification process(2,3). During the early 1980s, EPA conducted performance testing of eight full-scale hazardous waste incinerators; in this study, the reasonable worst case hazardous stack emissions of acetonitrile was 0.3 ng/l(4). The concn of acetonitrile in the emissions from a municipal waste incineration plant in Germany were 13.7 ug/cu m(5). The concn of acetonitrile in condensate and process retort water from an oil-shale processing facility in Colorado was 38.9 and 5.8 mg/l, respectively(6). [R103] ATMC: *URBAN/SUBURBAN: Acetonitrile was not detected in the 1 sample taken from an urban area(1). It was detected in air near ground levels in both urban and rural areas at concn 2-7 ppb(2). The avg concn of acetonitrile in stratosphere air above Deuselbach, Germany ranged from 117 to 212 parts per trillion between the years 1986-1987(3). Acetonitrile was detected with a frequency of 20% in exhaled air of normal human (non-smoking) at a mean concn 7.4 ng/l(4,5). [R104] *RURAL/REMOTE: Acetonitrile was detected at a mean concn of 0.024 ppb in two samples from a rural area(1). It was detected in air near ground levels in both urban and rural areas at concn 2-7 ppb(2). It was reported to be present in the upper stratosphere(3). [R105] FOOD: *Acetonitrile was detected in some milk products, such as kefir culture(1). [R106] OEVC: *... A standardized second puff of cigarette smoke contains 0.31 mg acetonitrile. [R107] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 31,341 workers (7,975 of these are female) are potentially exposed to acetonitrile in the US(1). Occupational exposure to acetonitrile may occur through inhalation and dermal contact with this compound at workplaces where acetonitrile is produced or used(SRC). Monitoring data indicate that the general population may be exposed to acetonitrile via ingestion of food and drinking water, and dermal contact with products containing acetonitrile(SRC). [R108] BODY: *... A standardized second puff of cigarette smoke contains 0.31 mg acetonitrile. A smoker may absorb between 73 and 82% of this, depending on post smoking habits. [R107] *An individual who died about 2 hours after a 12 hr exposure to acetonitrile had the following cyanide concn detected in his tissues at autopsy: blood= 8 mg/l; lung= 1.3 mg/kg; liver= 0 mg/kg; kidney= 2.0 mg/kg; urine= 2.2 mg/l. [R109] *Blood cyanide concentrations exceeding 0.1 mg/l or plasma or urine thiocyanate exceeding 20 mg/l in workers exposed to acetonitrile are indicative of excessive exposure. [R109] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *500 ppm [R16] ATOL: *Acetonitrile (not more than 0.5% of pesticide formulation) is exempted from the requirement of a tolerance when used as a solvent for blended emulsifiers in all pesticides used before crop emerges from soil and in herbicides before or after crop emerges in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R110] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 40 ppm (70 mg/cu m). [R111] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 20 ppm (34 mg/cu m) [R16] TLV: *8 hr Time Weighted Avg (TWA) 40 ppm; Short Term Exposure Limit (STEL) 60 ppm. [R112] *A4: Not classifiable as a human carcinogen. [R112] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Acetonitrile is produced, as an intermediate or a final product, by process units covered under this subpart. [R113] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Acetonitrile is included on this list. [R114] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 500 ug/l [R115] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Cyanides/ [R116] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R117] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Acetonitrile is included on this list. [R118] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R119] RCRA: *U003; As stipulated in 40 CFR 261.33, when acetonitrile, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R120] FIFR: *Acetonitrile (not more than 0.5% of pesticide formulation) is exempted from the requirement of a tolerance when used as a solvent for blended emulsifiers in all pesticides used before crop emerges from soil and in herbicides before or after crop emerges in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R110] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Measurements to determine employee exposure are best taken so that the avg 8 hr exposure is based on a single 8 hr sample or on two 4 hr samples. Several short-time interval samples (up to 30 min) may also be used to determine the avg exposure level. Air samples should be taken in the employee's breathing zone. ... Sampling ... may be performed by collection of acetonitrile vapors using an adsorption tube ... . [R18, 1981.2] *NIOSH Method 1606. Analyte: Acetonitrile. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 400 mg/200 mg). Flow Rate: 0.01 to 0.2 l/min. Sample Size: 25 liters. Shipment: Routine. Sample Stability: Not determined. [R121] *EPA Method 8015. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R122] ALAB: *KINETIC METHOD FOR DETERMINATION OF MICRO QUANTITIES OF ACETONITRILE (AS AIR POLLUTANT AND CONTAMINANT IN INDUST) BASED ON ITS CATALYTIC ACTIVITY ON OXIDATION OF PYROCATECHOL VIOLET BY HYDROGEN PEROXIDE IS PRESENTED. [R123] *VOLATILE SUBSTANCES CAN BE SEPARATED FROM BIOLOGICAL LIQ AFTER INJECTION ONTO PACKED GC COLUMNS ... /RELATIVE RETENTION TIME OF ACETONITRILE TO ETHANOL 0.65/. [R124] *NIOSH Method 1606. Analyte: Acetonitrile. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. For acetonitrile this method has an estimated detection limit of 0.01 mg/sample. The overall precision/RSD is 0.047 and the recovery is 105%. Applicability: Large (400 mg/200 mg) charcoal tubes are necessary for collection of the analyte since breakthrough volume is low with smaller charcoal tubes. Interferences: None identified. [R125] *EPA Method 8030. GC analysis of acetonitrile. Detection is achieved by a flame ionization detector. For acetonitrile the method detection limit is not determined . The accuracy and precision are dependent on sample matrix. For acetonitrile in reagent water at a spike concentration of 5 ug/l, the average recovery and the standard deviation are not determined. [R126] *EPA Method 8015. Direct Injection or Purge and Trap Gas Chromatography for the determination of nonhalogenated volatile organics in solid waste. Under the prescribed conditions acetonitrile has a practical quantitation limit of 100 ug/l as defined by EPA. No statistical analysis was determined; specific method performance information will be provided as it becomes available. [R122] *OSW Method 8033. Acetonitrile by Gas Chromatography with Nitrogen- Phosphorus Detection. Detection limit unspecified. [R127] *OSW Method 8040B. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit unspecified. [R127] *OSW Method 8015B. Nonhalogenated Organics Using GC/FID. Detection limit unspecified. [R127] *OSW Method 8240B. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit = 100 ug/l. [R127] *OSW Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit unspecified. [R127] CLAB: *SIMPLE AND RAPID HEAD SPACE MS SCREENING TECHNIQUE FOR VOLATILES IN BLOOD AND POSTMORTEM TISSUE IS DESCRIBED. ACETONITRILE IN BLOOD-ENRICHED SPECIMENS EXHIBITED CHARACTERISTIC MASS SPECTRA. [R128] *VOLATILE SUBSTANCE CAN BE SEPARATED FROM BIOLOGICAL LIQUIDS AFTER INJECTION ONTO PACKED GAS-CHROMATOGRAPHIC COLUMNS OR IN A CLOSED VESSEL OR BY CONTROLLED TEMP DIFFUSION FROM LIQ PHASE INTO AIR ABOVE SAMPLE (HEAD SPACE). SEPARATED VOLATILE COMPONENT /INCLUDING ACETONITRILE/ MAY BE IDENTIFIED BY GC. [R124] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: AHMED AE, FAROOQUI M YH; TOXICOL LETT (AMST) 12 (2-3): 157-64 (1982). TOXICITY OF ALIPHATIC NITRILES WHICH IS BELIEVED TO BE CAUSED BY CYANIDE (CN) ION LIBERATION IS DISCUSSED. TSCA CHIPs present a preliminary assessment of acetonitrile's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404 Johannsen FR, Levinskas GJ; Fundam Appl Toxicol 7(4): 690-697 (1986). Relationships between toxicity and structure of aliphatic nitriles. WHO; Environmental Health Criteria 154: Acetonitrile (1993) Kaplita PV, Smith RP; Toxicol Appl Pharmacol 84 (3): 533-540 (1986). Pathways for the bioactivation of aliphatic nitriles to free cyanide in mice. Toxicology and Carcinogenesis Studies of Acetonitrile in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.6-7 Technical Report Series No. 447 (1996) NIH Publication No. 96-3363 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 HIST: *AN ACCIDENTAL EXPOSURE OF A GROUP OF WORKERS TO A HIGH BUT UNKNOWN CONCN OF ACETONITRILE RESULTED IN 1 DEATH AND SEVERAL CASES OF SEVERE ILLNESS ... . [R57, 1991.13] SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 9 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 13 R3: Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990. 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Research Triangle Park, NC: USEPA-450/4-84-007A (1984) (9) Hawthorne SB, Sievers RE; Environ Sci Technol 18: 483-90 (1984) (10) Pellizzari ED et al; pp. 256-74 in ASTM Spec Tech Publ STP 686 (1979) (11) Mohr DH, King CJ; Environ Sci Technol 19: 929-35 (1985) R93: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Gaffney JS et al; Environ Sci Technol 21: 519-23 (1987) (5) Boublik T et al; The vapor pressures of pure substances. Vol 17 Amsterdam, Netherlands: Elsevier Sci Publ (1984) (6) Kalmykova GY, Rogovskaya TI; Biol Vnutr Vod 38: 79-83 (1978) (7) Placak OR, Ruchhoft CC; Sewage Works J 19: 423-40 (1946) (8) Babeu L, Vaishnav DD; J Ind Microbiol 2: 107-15 (1987) R94: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Gaffney JS et al; Environ Sci Technol 21: 519-23 (1987) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) Kalmykova GY, Rogovskaya TI; Biol Vnutr Vod 38: 79-83 (1978) (8) Placak OR, Ruchhoft CC; Sewage Works J 19: 423-40 (1946) (9) Babeu L, Vaishnav DD; J Ind Microbiol 2: 107-15 (1987) (10) Ludzack FJ et al; Proc 13th Ind Waste Conf Purdue Univ Eng Ext Service, p. 297-312 (1958) (11) Ludzack FJ, Ettinger MB; Water Pollut Control Assoc J 32: 1173-2000 (1960) R95: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Boublik T et al; The vapor pressures of pure substances. Vol 17 Amsterdam, Netherlands: Elsevier Sci Publ (1984) (3) Atkinson R; J Phys Chem Ref Data. Monograph 2 (1994) (4) Kagiya T et al; Japan Chem Soc Spring Term Ann Mtg, Japan: Tokyo, April 1-4, Paper No. 1036 (1975) (5) Fujiki M et al; Simulation studies of degradation of chemicals in the environment Chem Res Report No. 1/1978, Japan: Tokyo, Environ Agency Japan, Off Health Studies (1978) R96: (1) Meth-Cohn O, Wang MX; J Chem Soc Perkin Trans 1: 1099-1104 (1997) (2) Kobayashi M et al; Biochem Biophys Res Commun 253: 662-666 (1998) (3) Chapatwala KD et al; Environ Toxicol Chem 11: 1145-51 (1992) (4) Kalmykova GY, Rogovskaya TI; Biol Vnutr Vod 38: 79-83 (1978) (5) Placak OR, Ruchhoft CC; Sewage Works J 19: 423-40 (1946) (6) Ludzack FJ et al; Sewage Ind Wastes 31: 33-44 (1959) (7) Thom NS, Agg AR; Proc R Soc Lond B189: 347-57 (1975) (8) Urano K, Kato Z; J Hazardous Materials 13: 147-59 (1986) (9) Babeu L, Vaishnav DD; J Ind Microbiol 2: 107-15 (1987) (10) Ludzack FJ et al; Proc 13th Ind Waste Conf Purdue Univ Eng Ext Service, p. 297-312 (1958) (11) Ludzack FJ, Ettinger MB; Water Pollut Control Assoc J 32: 1173-2000 (1960) (12) Takemoto S et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) R97: (1) Ludzack FJ et al; J Water Pollut Control Fed 33: 492-505 (1961) R98: (1) Arijs E et al; Nature 303: 314-6 (1983) (2) Dimitriades B, Joshi SB; pp. 705-11 in Inter Conf Photochem Oxidant Poll Control, USEPA-600/3-77-001B Research Triangle Park,NC: USEPA (1977) R99: (1) Atkinson R; J Phys Chem Ref Data. Monograph 2 (1994) (2) Anbar M, Neta P; Inter J Appl Radiation Isotopes 18: 493-523 (1967) (3) Dorfman LM, Adams GE; Reactivity of the hydroxyl radical in aqueous solution NDRD-NBS-46 Washington, DC: Natl Bur Stand (NTIS COM-73-50623) (1973) (4) Ellington JJ et al; Measurement of hydrolysis rate constants for evaluation of hazardous waste land disposal. USEPA-600/S3-88/028 (PB88-234 042/AS) (1988) (5) Arijs E et al; Nature 303: 314-6 (1983) R100: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R101: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R102: (1) Gaffney JS et al; Environ Sci Technol 21: 519-23 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Boublik T et al; The vapor pressures of pure substances. Vol 17. Amsterdam, Netherlands: Elsevier Sci Publ (1984) R103: (1) Hawthorne SB, Sievers RE; Environ Sci Technol 18: 483-90 (1984) (2) Pellizzari ED et al; Identification of organic components in aqueous effluents from energy-related processes. ASTM Spec Tech Publ STP 686: 256-74 (1979) (3) Mohr DH, King CJ; Environ Sci Technol 19: 929-35 (1985) (4) Dempsey CR; J Air Waste Manage Assoc 43: 1374-79 (1993) (5) Jay K et al; Chemosphere 30: 1249-60 (1995) (6) Leenheer JA et al; Environ Sci Technol 16: 714-23 (1982) R104: (1) Shah JJ, Heyerdahl EK; National ambient volatile organic compounds (VOCs) data base update. Res Tri Park, NC: Atmos Sci Res Lab USEPA-600/3-88/010a (1988) (2) Becker KM, Ionescu A; Geophys Res Lett 9: 1349-51 (1982) (3) Hamm S et al; Geophysical Res Lett. 16: 483-86 (1989) (4) Krotoszyniski BK et al; J Anal Toxicol 3: 225-34 (1979) (5) Krotoszyniski BK et al; J Chromatog Sci 15: 239-44 (1977) R105: (1) Shah JJ, Heyerdahl EK; National ambient volatile organic compounds (VOCs) data base update USEPA-600/3-88/010(a) Res Tri Park, NC: Atmos Sci Res Lab USEPA (1988) (2) Becker KM, Ionescu A; Geophys Res Lett 9: 1349-51 (1982) (3) Arijs E et al; Nature 303: 314-6 (1983) R106: (1) Palo V, Ilkova H; J Chromatog 53: 363-7 (1970) R107: USEPA; Chemical Hazard Information Profiles p.9 EPA-560/11-80-011 (1980) R108: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R109: Baselt RC; Biological Monitoring Methods for Industrial Chemicals p.11 (1980) R110: 40 CFR 180.1001(d) (7/1/2000) R111: 29 CFR 1910.1000 (7/1/2000) R112: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 15 R113: 40 CFR 60.489 (7/1/2000) R114: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R115: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R116: 40 CFR 401.15 (7/1/2000) R117: 40 CFR 302.4 (7/1/2000) R118: 40 CFR 716.120 (7/1/2000) R119: 40 CFR 712.30 (7/1/2000) R120: 40 CFR 261.33 (7/1/2000) R121: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994.p. 1606-1 R122: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.10 (1991) OST Pub 21W-4005 R123: MILOVANOVIC GA, BOZILOVIC N; MICROCHEM J 27 (3): 345-50 (1982) R124: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 407 R125: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1606-1 R126: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R127: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R128: URICH RW ET AL; J ANAL TOXICOL 1 (5): 195-9 (1977) RS: 119 Record 8 of 1119 in HSDB (through 2003/06) AN: 46 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZYL-ALCOHOL- SY: *Alcool-benzylique-; *BENZAL-ALCOHOL-; *BENZENECARBINOL-; *BENZENEMETHANOL-; *Benzylicum-; *Euxyl-K-100-; *(HYDROXYMETHYL)BENZENE; *HYDROXYTOLUENE-; *ALPHA-HYDROXYTOLUENE-; *METHANOL,-PHENYL-; *NCI-C06111-; *PHENOLCARBINOL-; *PHENYLCARBINOL-; *PHENYLMETHANOL-; *PHENYLMETHYL-ALCOHOL-; *ALPHA-TOLUENOL- RN: 100-51-6 MF: *C7-H8-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Benzyl alcohol is manufactured on a commercial scale from benzyl chloride and sodium carbonate. [R1, p. V4 116] *Originally prepd by Cannizzaro reaction from benzaldehyde and potassium hydroxide ... Produced on large scale by action of ... potassium carbonate on benzyl chloride: German patent 484,662; Chem Zentr 1930, I, 1052; FRDL 16, 426 ... [R2, 189] FORM: *Grades: free from chlorine (FFC); technical; NF (National Formulary); textile; photographic reagent; FCC [R3] *Euxyl K 100 [R4] *Pure, photo, pharmaceutical, and perfume grades, 99% min purity, liquid form [R5] MFS: *Penta Manufacturing Corp., 50 Okner Pkwy., Livingston, NJ 07039-1604, (973)740-2300; Production site: Fairfield, NJ 07007 [R6] *Quest International, 400 International Dr., Mount Olive, NJ 07828, (973)691-7100; Production site: Mount Olive, NJ 07828 [R6] *Schweizerhall, Inc., 10 Corporate Place South, Piscataway, NJ 08854, (732)981-8200; Production site: Piscataway, NJ 08854 [R6] OMIN: *BENZYL ALCOHOL WAS GRANTED GRAS STATUS BY FEMA (1965). [R7, 127] *REPORTED USES NON-ALCOHOLIC BEVERAGES 15 PPM; ICE CREAM, ICES, ETC 160 PPM; CANDY 47 PPM; BAKED GOODS 220 PPM; GELATINS AND PUDDINGS 21-45 PPM; CHEWING GUM 1,200 PPM. [R8] *Method of purification: Distillation and chemical treatment. [R3] *VIRUCIDAL AGENT IN LOTIONS [R9] USE: *Manufacture of other benzyl cmpd; solvent for cellulose acetate; in perfumery and in flavoring; solvent for gelatin, casein (when hot), and shellac; in microscopy as embedding material [R2, 129] *MEDICATION (VET) *AS A LACQUER SOLVENT AND PLASTICIZER [R10, 393] *Photographic developer for color movie films; dyeing nylon filament, textiles and sheet plastics; heat-sealing polyethylene films; intermediate for benzyl esters and ethers; ball point pen inks; stencil inks [R3] *PRESERVATIVE IN OPHTHALMIC PREPN [R11] *MEDICATION *Degreasing agent in rug cleaners. It is used as a solvent for dyestuffs. Benzyl alcohol is used frequently employed in bar soap fragrances. [R1, p. V4 118] CPAT: *60% IS USED IN THE TEXTILE INDUSTRY AS A DYE ASSISTANT (MOSTLY FOR DYEING NYLON CARPETING); AND 40% IS USED IN OTHER APPLICATIONS (1972) [R12] PRIE: U.S. PRODUCTION: *(1971) 4.22X10+9 G [R12] *(1975) 5.84X10+9 G [R12] U.S. IMPORTS: *(1971) NEGLIGIBLE [R12] *(1975) 3.53X10+6 (PRINCPL CUSTMS DISTS) [R12] *(1983) 8.25X10+8 g [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Water-white liq [R3] ODOR: *Faint aromatic odor [R2, 189] TAST: *Sharp burning taste [R3] BP: *205.3 deg C [R14, p. 3-52] MP: *-15.2 deg C [R14, p. 3-52] MW: *108.14 [R14, p. 3-52] CORR: *Will attack some plastics [R15] CTP: *Critical temperature: 715 K; Critical pressure: 4.3X10+6 Pa [R14, p. 6-54] DEN: *1.0419 @ 20 deg C/4 deg C [R14, p. 3-52] DSC: *pKa= 15.40 [R16] HTC: *894.3 kg cal/g mol wt at 20 deg C [R17, p. D-274] HTV: *50.48 kJ/mol @ 205.31 deg C [R14, p. 6-111] OWPC: *log Kow= 1.10 [R18] PH: *A soln in water is neutral to litmus [R19] SOL: *Soluble in ethanol, ether, and acetone [R14, p. 3-52]; *> 10% in benzene [R20]; *In water, 42,900 mg/l @ 25 deg C [R21]; *35,000 mg/l water at 20 deg C [R22] SPEC: *SADTLER REF NUMBER: 157 (IR, PRISM); 985 (IR, GRATING); MAX ABSORPTION (ALCOHOL): 243 NM (LOG E= 1.91); 258.5 NM (LOG E= 2.26); 268 NM (LOG E= 1.95) [R23]; *Index of refraction: 1.5396 @ 20 deg C/D [R14, p. 3-52]; *MAX ABSORPTION (ETHANOL): 258 NM, 252 NM, 263 NM (A= 183, 1%, 1 CM) [R24]; *IR: 5219 (Coblentz Society Spectral Collection) [R20]; *UV: 62 (Sadtler Research Laboratories Spectral Collection) [R20]; *NMR: 161 (Varian Associates NMR Spectra Catalogue) [R20]; *MASS: 335 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R20] SURF: *39.0 dynes/cm= 0.0390 N/M @ 20 deg C [R1, p. V4 117] VAPD: *3.72 (Air= 1.00) [R2, 819] VAP: *0.094 mm Hg @ 25 deg C [R25] VISC: *5.474 cP @ 25 deg C; 2.760 cP @ 50 deg C; 1.618 cP @ 75 deg C; 1.055 cP @ 100 deg C [R14, p. 6-173] OCPP: *PERCENT IN SATURATED AIR AT 20 DEG C: 0.02; DENSITY OF SATURATED AIR: 1.0005 (AIR= 1) [R26, 2590] *CONVERSION FACTORS: 1 MG/L= 226.1 PPM AND 1 PPM= 4.42 MG/CU M @ 25 DEG C, 760 MM HG [R26, 2591] *Dielectric constant: 1.66; specific heat: 0.5402 cal/g at 15-20 deg C; wt/gal: 9.78 lb at 20 deg C [R27] *Heat of fusion: 19.83 cal/g= 82.97 J/g= 8,972 J/mol [R17, p. C-668] *Heat capacity: 218.0 J/mol-K at 1 atm and 25 deg C (liquid) [R17, p. D-174] *Liquid heat capacity= 0.520 BTU/lb-F @ 68 deg F; Liquid thermal conductivity= 1.088 BTU-in/hr-sq ft-F at 70 deg F; Saturated vapor density= 0.00161 lb/cu ft @ 180 deg F; Ideal gas heat capacity= 0.276 BTU/lb-F @ 60 deg F; Ratio of specific heats of vapor: 1.070 [R15] *Wt/ml 1.043 to 1.046 g [R19] *Forms a large number of azeotropes; coefficient of expansion: 0.00075 [R28] *Enthalpies of formation: -38.49 kcal/mole (liquid); Gibbs (free) energies of formation: -6.57 kcal/mole (liquid); Entropies: 51.8 cal/deg-mole (liquid) [R29, p. 5-6] *Dielectric constant: 13.0 at 20 deg C AND 9.5 at 70 deg C; dipole moment: 1.67 in benzene at 25 deg C [R29, p. 4-47] *Hydroxyl radical rate constant= 2.29X10-11 cu cm/molec-sec [R30] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME ... [R31, 399] *THE LIQ IS FLAMMABLE AND A MODERATE FIRE HAZARD. [R32] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R33, p. 325-17] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R33, p. 325-17] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R33, p. 325-17] FLPT: *213 DEG F (CLOSED CUP); 220 DEG F (OPEN CUP) [R34] *213 deg F (open cup) [R27] *93 deg C (closed cup) [R33, p. 325-17] AUTO: *436 deg C (817 deg F) [R33, p. 325-17] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEM ... [R31, 400] *Water or foam may cause frothing ... [R33, p. 325-17] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Use "alcohol" foam, dry chemical or carbon dioxide. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Keep run-off water out of sewers and water sources. [R33, 137] REAC: *A mixture of /benzyl/ alcohol with 58% sulfuric acid decomp expliosively at about 180 deg C. [R35, 1216] *Benzyl alcohol contaminated with 1.4% of hydrogen bromide and 1.2% of dissolved iron(II) polymerizes exothermally above 100 deg C. [R35, 718] *... Incompatible with oxidizing agents. [R19] *POSSIBLE PROBLEMS ... MAY OCCUR WHEN POLYSTYRENE SYRINGES ARE USED WITH CERTAIN TYPES OF DRUG PRODUCTS THAT CONTAIN PARAALDEHYDE, BENZALDEHYDE, AND BENZYL ALCOHOL SINCE THESE AGENTS CAN EXTRACT AND DISSOLVE THE PLASTIC. AT TIMES THE RUBBER TIP OF THE PLUNGER MAY RELEASE A CONSTITUENT TO THE DRUG PRODUCT. [R36] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R37] ODRT: *5.5 ppm [R15] SERI: *It is slightly irritating to the skin ... . [R32] *Vapor: Irritating to eyes, nose and throat. Liquid: Irritating to skin and eyes. [R15] EQUP: *RUBBER GLOVES; CHEMICAL SAFETY GOGGLES [R15] OPRM: *VENTILATION CONTROL: THE BASIC VENTILATION METHODS ARE LOCAL EXHAUST VENTILATION AND DILUTION OR GENERAL VENTILATION. [R31, 17] *... SUBSTITUTION OF LESS IRRITATING SUBSTANCES ... REDESIGN OF OPERATIONS ... PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, WORK CLOTHING AND STORAGE FACILITIES, PROTECTIVE CLOTHING, AND BARRIER CREAMS. MEDICAL CONTROL ... . [R38] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. [R39, 137] *Personnel protection: Keep upwind. Avoid breathing vapors. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Avoid bodily contact with the material. [R39, p. 137-8] SSL: *OXIDIZES SLOWLY, THEREFORE REMAINS STABLE FOR LONG TIME [R10, 393] *It is slowly oxidized to benzaldehyde and benzoic acid on exposure to air ... . [R19] STRG: *... STORE IN PLACES THAT ARE COOL ... PROVIDE ADEQUATE VENTILATION ... LOCATE THE STORAGE AREA ... AWAY FROM AREAS OF FIRE HAZARD. HIGHLY FLAMMABLE MATERIALS MUST BE KEPT APART FROM POWERFUL OXIDIZING AGENTS, MATERIALS SUSCEPTIBLE TO SPONTANEOUS HEATING, EXPLOSIVES ... [R38] *Store at a temp not exceeding 40 deg C in airtight containers. Protect from light. [R19] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *PURE ALCOHOL IS IRRITATING AND CORROSIVE BUT MUCH LESS TOXIC THAN PHENOL. ... INGESTION OF LARGE VOLUMES IS FOLLOWED BY VOMITING, DIARRHEA, AND CENTRAL NERVOUS DEPRESSION. A HUMAN FATALITY HAS BEEN ASCRIBED TO THE RECTAL ADMIN OF 45 ML. [R40] *HIGH DOSES CAUSE CONVULSIONS FOLLOWED BY PARALYSIS OF THE RESPIRATORY CENTER, BUT IT HAS BEEN USED WITH NO DELETERIOUS EFFECTS AS A LOCAL ANESTHETIC FOR MINOR SURGICAL OPERATIONS. [R10, 394] *... INTRAOCULAR USE OF SODIUM CHLORIDE SOLN PRESERVED WITH 2% BENZYL ALCOHOL DURING CATARACT SURGERY AND PERIPHERAL IRIDECTOMY CAUSED SEVERE STRIATED KERATOPATHY, PROGRESSING TO CHRONIC EDEMA OF CORNEA, WITH VESICLES, BULLAE, AND DIRTY PIGMENTED APPEARANCE OF ENDOTHELIUM. ... IRIS WAS ALSO AFFECTED. [R41, 143] *ETHANOL AND CERTAIN SHORT CHAIN ARYL (BENZYL) AND ALIPHATIC (PROPYL, BUTYL) ALCOHOLS PRODUCED UP TO 10 FOLD INCR IN CYCLIC AMP CONCN IN PURIFIED HUMAN PERIPHERAL BLOOD LYMPHOCYTES. [R42] *LOCAL NECROSIS OF TISSUE FOLLOWING THE ACCIDENTAL INJECTION OF PURE BENZYL ALCOHOL IN PREPARATION FOR CIRCUMCISION HAS BEEN DESCRIBED ... [R43, 4641] *No direct ocular injury from external contact has been reported in human beings, but one death and one case of serious illness with delirium and visual disturbances were supposed to have been caused by absorption of benzyl alcohol from an impure preparation of benzyl benzoate which was employed in massaging the skin. [R41, 144] *Five infants, preterm, received multiple injections of heparinized bacteriostatic sodium chloride for flushing the catheters, and medications reconstituted with bacteriostatic water, both containing 0.9% benzyl alcohol. Daily quantities of benzyl alcohol equaled 99 to 234 mg/kg of body wt. They then developed gradual neurologic deterioration, severe metabolic acidosis, a striking onset of gasping respirations, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, and cardiovascular collapse. [R44] *Benzyl alcohol, which is used as a preservative in intravascular flush solutions has been reported to cause neurological deterioration and deaths in very low birth weight infants. Preterm infants receiving via catheter large volumes of fluids containing 0.9% benzyl alcohol developed "gasping baby syndrome." Estimated intakes of 99 to 405 mg benzyl alcohol/kg body weight for 2 to 28 days caused effects including severe metabolic acidosis, gasping, neurological deterioration, blood abnormalities, skin breakdown, liver and kidney failure, lowered blood pressure, heart failure, and death. No deaths were seen for intakes of 27 to 99 mg/kg body weight over similar periods, although there is one report of 32 to 105 mg/kg body weight for 7 days causing breathing difficulty. [R26, 2706] *Benzyl alcohol is an aromatic organic alcohol that is a preservative, a solvent, and a local anesthetic. It rarely causes allergic contact dermatitis and is patch-tested as a 5% concentration in petrolatum. [R45] *Poison by ingestion, intraperitoneal, intravenous, parenteral routes. Moderately toxic by inhalation, skin contact, and subcutaneous routes. A moderate skin and eye irritant. [R37] *Five infants, preterm, received multiple injections of heparinized bacteriostatic sodium chloride for flushing the catheters and medications reconsitituted with bacteriostatic water, both containing 0.9% benzyl alcohol. Daily quantities of benzyl alcohol equaled 99 to 234 mg/kg of body weight. They then developed gradual neurologic deterioration, severe metabolic acidosis, a striking onset gasping respirations, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, and cardiovascular collapse. [R46, 1207] *With dosages of benzyl alcohol ranging from 99 to 234 mg/kg/day, hypotension, severe metabolic acidosis with an increased anion gap secondary to increased blood concentrations of benzoic acid, changes in consciousness, leukopenia, thrombopenia, hyperammonemia, and respiratory gasping are observed with high mortality rates. [R46, 1163] NTOX: *Undiluted benzyl alcohol was moderately irritating when applied to the depilated skin of guinea pigs for 24 hr. It was moderately irritating when applied to rabbit skin. Benzyl alcohol was severely irritating to the eyes of rabbits. [R26, 2705] *Fischer 344 rats were given oral doses of 50, 100, 200, 400, and 800 mg/kg for 13 weeks. The high dose produced clinical signs indicative of neurotoxicity including staggering, respiratory difficulty, and lethargy. Reduction in weight gain was noted in males at 800 mg/kg and females at equal to or greater than 200 mg/kg. The high dose animals also showed hemorrhages around the mouth and nose, and histological lesions in the brain, thymus, skeletal muscle, and kidney. [R26, 2705] *B6C3FI mice were given oral doses of 50, 100, 200, 400, and 800 mg/kg for 13 weeks. The high dose appeared to produce clinical signs of neurotoxicity. Reduction in weight gain was noted in males at equal to or greater than 400 mg/kg and females at equal to or greater than 200 mg/kg. No treatment related histopathological effects were noted. [R26, 2705] *SIX MALE ALBINO RATS RECEIVED 450 MG/KG BENZYL ALC AS 20% SOLN IN PEANUT OIL FOR 10 TREATMENTS. ALL ... SHOWED INITIAL WT DEPRESSION WITH NO OTHER CLINICAL OR PATHOLOGIC SIGNS OF TOXICITY. ... WHEN ... INSTILLED INTO THE RABBIT EYE IT CAUSED A SEVERE RESPONSE CHARACTERIZED BY MARKED IRRITATION OF CONJUNCTIVE MEMBRANES AND CLOUDINESS OF CORNEA. ... THE UNDILUTED MATERIAL APPLIED TO DEPILATED SKIN OF GUINEA PIGS FOR A PERIOD OF 24 HR CAUSED MODERATELY STRONG PRIMARY IRRITATION, AND THERE WAS EVIDENCE OF SYSTEMIC SYMPTOMS WITH DEATH FROM APPLICATIONS OF LESS THAN 5 ML/KG. SYSTEMIC SYMPTOMS ... STILL NOTED ... UNDER SAME CONDITIONS AS A 20% SOLN IN ACETONE. [R43, 4638] *NO FATALITIES OR SYMPTOMS WERE FOUND IN RATS EXPOSED FOR 6 HR TO A CALCULATED CONCN OF 61 PPM NOR WERE SYMPTOMS PRODUCED BY EXPOSURES OBTAINED BY BUBBLING AIR THROUGH THE LIQ HEATED TO 100 and 150 DEG C. ... DOSES OF 0.2 ML/KG OR MORE, ADMIN TO DOGS BY STOMACH TUBE INDUCED EMESIS AND DEFECATION. THIS WAS APPARENTLY DUE TO IRRITATION OF THE GASTRIC MUCOSA ... DIURESIS WAS MORE PRONOUNCED IN THE RABBIT THAN IN THE DOG, AFTER ADMIN OF BENZYL ALCOHOL BY VARIOUS ROUTES. THE INJECTION OF 5 TO 10% BENZYL ALCOHOL IN OIL OF SWEET ALMOND IN THE REGION OF THE AUDITORY MEATUS OF CATS CAUSED TEMPORARY DEGENERATION OF THE SMALL FACIAL NERVES. [R43, 4639] *MICE SUFFERED RESPIRATORY STIMULATION, RESPIRATORY AND MUSCULAR PARALYSIS, CONVULSIONS, and ... /CNS DEPRESSION/ FOLLOWING SC INJECTION. ... OBSERVED A DECR IN ARTERIAL BLOOD PRESSURE OF RABBITS, CATS, AND DOGS FOLLOWING IV INJECTION OF BENZYL ALCOHOL, BUT FAILED TO FIND SUCH DECR IN THE CASE OF DOGS FOLLOWING ORAL ADMIN OF 0.1-1.0 ML/KG OF BODY WT. ... IV INJECTION OF 94% ... INTO DOGS CAUSED DYSPNEA, DIARRHEA, ATAXIA, MYDRIASIS, NYSTAGMUS, URINATION, RESP ARREST, COLLAPSE, AND CARDIAC ARREST. IN SOME INSTANCES DEATHS WERE DELAYED; IN THESE CASES, DEATH WAS DUE TO PULMONARY HEMORRHAGE AND EDEMA. [R43, 4639] *THE BLOOD SUGAR OF FASTING ANIMALS WAS INCREASED SOMEWHAT BY PROLONGED ADMIN OF BENZYL ALCOHOL. [R43, 4640] *SC INJECTION ... /OF BENZYL ALCOHOL IN MICE FOUND TO BE/ 2.5 TO 3 TIMES MORE TOXIC THAN N-BUTYL OR ISOPROPYL ALCOHOL. [R10, 395] *WHEN AQUEOUS HUMOR WAS REPLACED IN ONE /RABBIT/ EYE WITH PURE STERILE 0.9% SODIUM CHLORIDE SOLN AND IN THE OTHER EYE WAS REPLACED WITH THE SAME SOLN PLUS 2% BENZYL ALCOHOL, NO TOXIC EFFECT WAS PRODUCED BY THE PLAIN SALINE SOLN, BUT THE EYES WITH BENZYL ALCOHOL SOLN RAPIDLY DEVELOPED EVIDENCE OF INJURY OF ENDOTHELIUM, WITH MUCH BLUISH SWELLING OF THE CORNEA. ALSO, THE IRISES IN THE EYE WITH BENZYL ALCOHOL SOLN BECAME HYPEREMIC AND HAD POORLY REACTIVE PUPILS. THE CORNEAL EDEMA IN RABBITS DISAPPEARED MORE RAPIDLY THAN IN THE HUMAN PATIENTS, CLEARING PARTIALLY IN ONE WEEK AND COMPLETELY IN TWO WEEKS. [R41, 143] *BENZYL ALCOHOL (1 ML/KG IV) HAD NO EFFECT ON RESP, ECG, OR BLOOD PRESSURE ON ANESTHETIZED MONKEYS AND DOGS. LETHAL IV DOSE OF 0.9% BENZYL ALCOHOL IN ANESTHETIZED DOGS WAS 0.83-1.06 G/KG. [R47] *BENZYL ALCOHOL APPLIED DAILY TO GUINEA PIGS WITH EXPTL TRICHOPHYTOSIS ON SURFACE OF SCARRED INFECTED SKIN PRODUCED PARALYSIS IN HIND LIMBS AFTER SEVERAL DAYS. [R48] *... 0.01 OR 0.02 ML OF BENZYL ALCOHOL /INJECTED/ INTO YOLK SAC OF THE CHICK FROM BEFORE INCUBATION UP TO THE 7TH DAY. MENINGOCELES AND SKELETAL DEFECTS WERE PRODUCED. [R49] *ADMIN OF 9% BENZYL ALCOHOL PRODUCED TRANSIENT RESP ARREST IN ADULT DOGS AND DEATH IN IMMATURE DOGS, and 7% and 4.5% BENZYL ALCOHOL PRODUCED CLONIC SEIZURES IN PUPPIES. [R50] *BENZYL ALCOHOL DISPLAYED ANTIARRHYTHMIC-ANTIFIBRILLATORY EFFECTS WHEN INJECTED IV (0.2-0.4 ML/KG OF A 4% SOLN) INTO DOGS AND RATS WITH SPONTANEOUS AND DRUG INDUCED ARRHYTHMIAS. IV INJECTIONS OF HIGH DOSES CAUSED INTRAVASCULAR HEMOLYSIS. [R51] *HEMOLYSIS OF RED BLOOD CELLS WASHED WITH NORMAL SALINE CONTAINING BENZYL ALCOHOL WAS STUDIED. IT WAS CONFIRMED THAT BENZYL ALCOHOL WAS RESPONSIBLE FOR HEMOLYSIS, WHEN THE VOL OF SALINE EXCEEDS THE VOL OF BLOOD. [R52] *LOCAL ANESTHETICS AND ALCOHOLS INHIBITED MITOCHONDRIAL ELECTRON TRANSPORT AT SEVERAL POINTS ALONG THE CHAIN. N-BUTANOL AND BENZYL ALC INHIBITED EACH OF SEGMENTS OF RAT LIVER AND BEEF HEART MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ASSAYED; THESE INCL CYTOCHROME C OXIDASE, DUROHYDROQUINONE OXIDASE, SUCCINATE OXIDASE AND DEHYDROGENASE, NADH OXIDASE, SUCCINATE-CYTOCHROME C OXIDOREDUCTASE, AND OTHERS. [R53] *Benzyl alcohol was evaluated for developmental toxicity in a proposed new short term in vivo animal bioassay. In this assay, pregnant mice were dosed with the test agent in mid-pregnancy and allowed to go to term. Observations were then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Fifty pregnant CD-1 mice were given 750 mg/kg/day benzyl alcohol in water by gavage on days 6-13 of gestation and were allowed to deliver. A decrease in the birth weight and weight gain in the pups was observed, but was not toxic to the mothers and had no effect on pup viability. [R54] *Benzyl alcohol was found to be negative when tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program (NTP). Benzyl alcohol was tested at doses of 0.1, 0.333, 1.0, 3.333, 5.0, and 6.666 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. The highest ineffective dose tested without toxicity in any S. typhimurium strains was 5.0 mg/plate. Slight inhibition of the background bacterial lawn occurred in cultures at 6.666 mg/plate but no significant change was seen in the results. [R55] *Full strength benzyl alcohol, not aq soln, tested by application of a drop to rabbits' eyes appears to have moderate potential injurious effect, rated 8 on a scale of 1 to 10. /The most severely injurious substances have been rated 10./ [R41, 143] *Impact on biodegradation process: inhibition of degradation of glucose by Pseudomonas fluorescens at: 350 mg/l; inhibition of degradation of glucose by E coli at: > 1000 mg/l [R56, 283] *After heating at 100 deg C for 30 min at pH 5 to 6, benzyl alcohol 1% was about as effective as phenylmercuric nitrate 0.002% in killing the spores of Bacillus stearothermophilus. At higher pH values it had less effect and at pH 8.6 it had a negligible effect. [R19] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of benzyl alcohol for male or female F344/N rats dosed with 200 or 400 mg/kg. Survival in both dose groups of female rats was 50% that of vehicle controls, primarily due to an incr number of gavage related deaths. There was no evidence of carcinogenic activity of benzyl alcohol for male or female B6C3F1 mice dosed with 100 or 200 mg/kg for 2 years. [R57] NTXV: *LD50 Rat oral 3.1 g/kg; [R34] *LD50 Mouse intravenous < 0.5 ml/kg /94% benzyl alcohol/; [R58] *LC100 Rat inhalation 200-300 ppm/8 hr; [R56, 284] *LD50 Rat oral 1.23 g/kg, 3.1 g/kg, and 2.08 g/kg; [R26, 2705] *LD50 Mouse oral 1.58 g/kg; [R26, 2705] *LD50 Rabbit oral 1.94 g/kg; [R26, 2705] *LD50 Guinea pig dermal was less than 5 ml/kg; [R26, 2705] *LC50 Rat inhalation 1000 ppm/8 hr; [R26, 2705] ETXV: *LC50 Pimephales promelas (fathead minnows) 770 mg/l/48 hr, static bioassay in Lake Superior water at 18-22 deg C; [R56, 283] *LC50 Pimephales promelas (fathead minnows) 480 mg/l/72 hr, static bioassay in Lake Superior water at 18-22 deg C; [R56, 283] *LC50 Pimephales promelas (fathead minnows) 460 mg/l/96 hr, static bioassay in Lake Superior water at 18-22 deg C; [R56, 283] *LC50 Lepomis macrochirus (bluegill sunfish) 10 ppm/96 hr, static bioassay in fresh water at 23 deg C, mild aeration after 24 hr; [R56, 283] *LC50 Menidia beryllina (tidewater silverside fish) 15 ppm/96 hr, static bioassay in synthetic seawater at 23 deg C, mild aeration after 24 hr; [R56, 283] *Lepomis macrochirus (bluegill sunfish) static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr: 100% survival after 5 ppm/96 hr, 20% survival after 18 ppm/96 hr, 20% survival after 32 ppm/48 hr; [R56, 283] *Menidia beryllina (tidewater silverside fish): static bioassay in synthetic seawater at 23 deg C: mild aeration applied after 24 hr: 80% survival after 10 ppm/96 hr, 20% survival after 32 ppm/96 hr ..; [R56, 283] NTP: *... Toxicology and carcinogenesis studies of technical grade benzyl alcohol (99% pure) ... were conducted by admin chemical by gavage in corn oil vehicle to groups of F344/N rats and B6C3F1 mice for ... 2 yr. ... Fifty animals of each species and sex were admin benzyl alcohol in corn oil by gavage 5/days/wk for 103 wk. ... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of benzyl alcohol for male or female F344/N rats dosed with 200 or 400 mg/kg. Survival in both dose groups of female rats was 50% that of vehicle controls, primarily due to an incr number of gavage related deaths. There was no evidence of carcinogenic activity of benzyl alcohol for male or female B6C3F1 mice dosed with 100 or 200 mg/kg for 2 years. [R57] ADE: *RABBITS GIVEN 1 G OF BENZYL ALCOHOL SC ELIMINATED 300-400 MG OF HIPPURIC ACID WITHIN THE FOLLOWING 24 HR. WITHIN 6 HR AFTER ORAL ADMIN OF 0.40 G BENZYL ALC/KG OF BODY WT, RABBITS ELIMINATED 65.7% OF DOSE AS HIPPURIC ACID IN THE URINE. [R26, 2704] *BODY TISSUE POSSIBLY TAKES UP BENZYL ALCOHOL RAPIDLY AND RELEASES IT SLOWLY INTO BLOOD STREAM. [R59] *... VAPORS CAN PENETRATE THE INTACT SKIN ... [R7, 128] *The dermal flux for benzyl alcohol across human skin in vitro was reported at 0.073 mg/sq cm/hr, indicating a low rate of dermal uptake. The percentage of the applied dose that penetrated through human skin in vitro in 6 hr was 1.42 percent for adult skin and 0.73 percent for full term infant skin. [R26, 2704] METB: *... IF DOSE IS SUFFICIENTLY HIGH TO ALLOW THE RATE OF FORMATION OF BENZOIC ACID TO EXCEED THAT OF HIPPURIC ACID SOME OF THE BENZOIC ACID IS EXCRETED AS BENZOYLGLUCURONIDE. [R10, 394] *Benzyl alcohol is readily absorbed from the gastrointestinal tract and rapidly oxidized to benzoic acid, which is conjugated with glycine and excreted as hippuric acid in the urine. Human subjects eliminated 75 to 85 percent of the dose in the urine as hippuric acid within 6 hr after taking 1.5 g of benzyl alcohol orally. [R26, 2704] */BENZYL ALCOHOL IS/ ... OXIDIZED BY LIVER ALCOHOL DEHYDROGENASE. [R60] *YIELDS BENZALDEHYDE IN RABBITS: BRAY ET AL, BIOCHEM J, 70, 570 (1958). YIELDS PHENOL IN GUINEA PIGS: SLOANE, NH, BIOCHEM BIOPHYS ACTA, 107, 573 (1971). /FROM TABLE/ [R61] BHL: *THE PLASMA HALF-LIFE OF BENZYL ALCOHOL ADMIN AS 2.5% SOLN IN SALINE WAS FOUND TO BE APPROX 1.5 HR IN DOGS INJECTED IV AT DOSES OF 52 and 105 MG/KG. [R43, 4640] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Anesthetics, Local; Pharmaceutic Aids [R62] *It has been used for toothache, a few drops being applied to the cavity or exposed nerve. [R19] *MEDICATION (VET): HAS BEEN USED FOR RELIEF OF PRURITUS [R34] *In leukemic patients indwelling cardiac catheters with a non-return slit valve inserted into a tributary of the subclavian vein had been kept free of infection for up to 3 months by filling with benzyl alcohol 0.9% in water for injections when not in use. [R19] WARN: *It is used as a preservative in newborn medication such as bacteriostatic saline, heparin, phenobarbital injection, pancuronium, aquamephyton, and neonatal trace metal soln. [R44] *... Used for the preservation of aqueous and oily parenteral drugs, in cough syrups, ointments, ophthalmic, burn, and dental solutions, insect ointments and repellents, and dermatological aerosol sprays. [R63] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Benzyl alcohol's production and use as a photographic developer, chemical intermediate, solvent and color developer in cosmetic products may result in its release to the environment through various waste streams. Benzyl alcohol occurs naturally in flower oils and tree exudates. If released to air, a vapor pressure of 0.094 mm Hg at 25 deg C indicates benzyl alcohol will exist solely as a vapor in the ambient atmosphere. Vapor-phase benzyl alcohol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 17 hours. If released to soil, benzyl alcohol is expected to have very high mobility based upon Koc values of less than 5 to 15 measured in various soils. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.1X10-7 atm-cu m/mole. Benzyl alcohol is not expected to volatilize rapidly from dry soil surfaces based on its vapor pressure. Benzyl alcohol is expected to undergo biodegradation under both aerobic and anaerobic conditions based upon results in a number of aqueous biodegradation tests. If released into water, benzyl alcohol is not expected to adsorb to suspended solids and sediment based upon the Koc data. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 75 days and 2.2 years, respectively. An estimated BCF of 1 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since benzyl alcohol lacks hydrolyzable functional groups. Occupational exposure to benzyl alcohol may occur through inhalation and dermal contact with this compound at workplaces where benzyl alcohol is produced or used. The general population may be exposed to benzyl alcohol via ingestion of food, inhalation of auto exhaust, and dermal contact with consumer products containing benzyl alcohol. (SRC) NATS: *Benzyl alcohol occurs primarily in flower oils and tree exudates(1). [R64] ARTS: *Benzyl alcohol's production and use as a photographic developer, chemical intermediate, solvent and color developer in cosmetic products and ball point pen and stencil inks(1,2), and its presence in auto exhaust(3) may result in its release to the environment through various waste streams(SRC). [R65] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of less than 5 to 15(2-4), indicate that benzyl alcohol is expected to have very high mobility in soil(SRC). Volatilization of benzyl alcohol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.1X10-7 atm-cu m/mole(SRC), derived from its vapor pressure of 0.094 mm Hg(5) and water solubility of 42,000 mg/l(6). Benzyl alcohol is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(5). Benzyl alcohol, present at 100 mg/l, reached 92-96% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(7), suggesting that biodegradation will occur in soil(SRC). [R66] *AQUATIC FATE: Based on a classification scheme(1), measured Koc values of less than 5 to 15(2-4) indicates that benzyl alcohol is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected to occur slowly(5) based upon an estimated Henry's Law constant of 3.1X10-7 atm-cu m/mole(SRC), derived from its vapor pressure of 0.094 mm Hg(6) and water solubility of 42,000 mg/l(7). Using this Henry's Law constant and an estimation method(5), volatilization half-lives for a model river and model lake are 75 days and 2.2 years, respectively(SRC). According to a classification scheme(8), an estimated BCF of 1(SRC), from its log Kow of 1.1(9) and a regression-derived equation(10), suggests the potential for bioconcentration in aquatic organisms is low. Benzyl alcohol is expected to undergo biodegradation under both aerobic and anaerobic conditions based on results from aqueous biodegradation tests(11,12). [R67] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), benzyl alcohol, which has a vapor pressure of 0.094 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase benzyl alcohol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 17 hours(SRC), calculated from its rate constant of 2.3X10-11 cu cm/molecule-sec at 25 deg C(3). [R68] BIOD: *BOD5/COD ratio for benzyl alcohol: 0.091 /From table/ [R69] *AEROBIC: Benzyl alcohol underwent 70% biological oxygen demand in 5 days under aerobic conditions using an acclimated mixed microbial culture(1). At an initial concn of 250 ppm, benzyl alcohol achieved 29% of the theoretical BOD after 12 hours in a sewage sludge acclimated to this compound, and 31% oxidation in a sludge acclimated to mandelic acid(2). At an initial concn of 500 ppm, it achieved 52%, 42%, and 43% of the theoretical BOD in 12 hours using a settled sewage sludge acclimated to phenol, benzoic acid, and catechol, respectively(2). It is listed as a synthetic organic chemical easily biodegradable by biological sewage treatment(3). Benzyl alcohol at an initial concentration of 500 mg/L was shown to undergo rapid oxygen uptake under aerobic conditions when inoculated with municipal sewage sludge(4,5). Benzyl alcohol achieved 48% of the theoretical BOD in 5 days using a sewage sludge seed(6). Benzyl alcohol underwent 60.8% degradation using an industrial sludge inoculum under aerobic conditions in 5 days(7). Benzyl alcohol, present at 100 mg/l, reached 92-96% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(8). An experimentally derived first-order aerobic biodegradation rate constant of 0.05 days was reported(9), corresponding to a half-life of about 13 days. [R70] *ANAEROBIC: Under anaerobic conditions, benzyl alcohol underwent 100% mineralization within 2 weeks when inoculated with a municipal digester sludge(1). Benzyl alcohol at an initial concentration of 50 ppm underwent greater than 75% mineralization to carbon dioxide and methane within 8 weeks using a municipal sewage sludge inocula under anaerobic conditions(2). Using sediment from anoxic salt marsh, 10 mM benzyl alcohol underwent degradation to carbon dioxide and methane after a 2 month incubation period(3). [R71] ABIO: *Based on an experimentally determined rate constant for the reaction of benzyl alcohol with alkylperoxy radicals, 2.4 l/mole-s(1) and an estimated alkylperoxy concentration in water of 1X10-9 mole/l(2), the half-life for this reaction is 9 years(SRC). The half-life for the reaction of benzyl alcohol with photochemically produced hydroxyl radicals in water can be estimated at approximately 100 days using an experimentally determined rate constant of 8.4X10+9 l/mole-s(3) and an optimal hydroxyl radical concentration of 1X10-17 mole/l in natural waters(2). Exposure of benzyl alcohol to sunlight for 4 hours in natural water did not produce any detectable oxidizing species (detection limit 1.5 uM), demonstrating that photochemical induced oxidation did not occur within that time frame(4). [R72] *The rate constant for the vapor-phase reaction of benzyl alcohol with photochemically-produced hydroxyl radicals has been measured as 2.3X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 17 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Benzyl alcohol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). [R73] BIOC: *An estimated BCF of 1 was calculated for benzyl alcohol(SRC), using a log Kow of 1.1(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R74] KOC: *Experimental Koc values for benzyl alcohol are < 5 for three different soils; Apison (0.11% organic carbon), Fullerton (0.06% organic carbon), and Dormont (1.2% organic carbon)(1). An experimental Koc of 15 was determined for benzyl alcohol on a red-brown Australian soil (1.09% organic carbon)(2,3). According to a classification scheme(4), these Koc values suggest that benzyl alcohol is expected to have very high mobility in soil. [R75] VWS: *The Henry's Law constant for benzyl alcohol is estimated as 3.1X10-7 atm-cu m/mole(SRC) from its vapor pressure, 0.094 mm Hg(1), and water solubility, 42,000 mg/l(2). This Henry's Law constant indicates that benzyl alcohol is expected to volatilize slowly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 75 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 2.2 years(SRC). Benzyl alcohol's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces is not expected to be an important fate process(SRC). Benzyl alcohol is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R76] WATC: *Benzyl alcohol was found in a groundwater sample taken at an unauthorized waste site in Lang, NJ at a concn of 170 ug/l(1). Benzyl alcohol was identified, not quantified, from Putah Creek, CA(2). [R77] EFFL: *Benzyl alcohol has been identified in the waste water effluent from the photographic processing industry(1) and in 6 out of 8 effluent samples from Kraft paper mills located in Georgia at a concentration up to 0.025 mg/l(2). Benzyl alcohol has been qualitatively determined in the secondary effluent from wastewater treatment plants in Illinois(3). The effluent from a Los Angeles county waste water treatment plant contained 500 ug/l of benzyl alcohol(4). Benzyl alcohol was identified, not quantified, in the leachate from a Barcelona, Spain, sanitary landfill(5) and from a municipal refuse disposal site in the Netherlands(6). Benzyl alcohol was identified, not quantified, in the wastewater of a petrochemical company producing olefins and oxygenated hydrocarbons in Louisiana(7). Benzyl alcohol was found in the effluent of 1 out of 4 test waste incinerators in the US(8). The emission rate of benzyl alcohol from motor vehicle traffic in a tunnel in Los Angeles, CA was reported as 1618.1 ug/l (gasoline)(9). Benzyl alcohol was identified, not quantified, in the emissions of various types of furniture coatings(10), some common household wastes(11) and in perfumes(12). [R78] ATMC: *Benzyl alcohol was identified, not quantified, in indoor air from homes in Finland(1). [R79] FOOD: *Benzyl alcohol has been identified as a volatile flavor component of baked potatoes(1), Beaufort (Gruyere) cheese(2), bacon(3), and roasted filberts (nuts)(4). It has been identified as a volatile component of blended nectarines, but not in a headspace analysis of the intact fruit(5). Benzyl alcohol was detected in salt-fermented fish and shrimp pastes at concns of 352-1,230 ng/g(6). Benzyl alcohol was detected in different forms of cooked sweet corn at concns of less than 1 ppb to 8 ppb(7). Benzyl alcohol was identified, not quantified, in the volatile emissions of cooked clams(8) and the edible portion of Korean chamchwi plants(9). [R80] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 273,896 workers (156,657 of these are female) are potentially exposed to benzyl alcohol in the US(1). Occupational exposure to benzyl alcohol may occur through inhalation and dermal contact with this compound at workplaces where benzyl alcohol is produced or used(SRC). The general population may be exposed to benzyl alcohol via ingestion of food, inhalation of auto exhaust, and dermal contact and with consumer products containing benzyl alcohol(SRC). [R81] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 10 ppm. [R82] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non-air quality health and environmental impact and energy requirements. Benzyl alcohol is produced, as an intermediate or final product, by process units covered under this subpart. [R83] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 2,100 ug/l [R84] FDA: *Benzyl alcohol is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. [R85] *Benzyl alcohol is an indirect food additive for use only as a component of adhesives. [R86] *Benzyl alcohol is an indirect food additive for use as a component of resinous and polymeric coatings. [R87] *Diluents in color additive mixtures for externally applied drug use exempt from certification. [R88] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AROMA COMPONENTS, INCL BENZYL ALCOHOL, OF CHINA ROSE CONCENTRATE WERE SEPARATED BY COLUMN CHROMATOGRAPHY OF STEAM DISTILLATE, AND INDIVIDUAL COMPONENTS WERE IDENTIFIED BY MASS SPECTROMETRY COMBINED WITH GAS CHROMATOGRAPHY. [R89] *... A METHOD /IS DESCRIBED/ IN WHICH BENZYL ALCOHOL IN BITTER ALMOND WATER WAS DETERMINED BY MEANS OF ITS ABSORPTION SPECTRUM IN THE ULTRAVIOLET REGION. ... THE MAXIMA AT 267, 264, 258, and 252 NM ARE RECOMMENDED FOR QUANTITATIVE ESTIMATION. THIS METHOD SHOULD BE ADAPTABLE TO AIR ANALYSIS. [R90] *BENZYL ALCOHOL IN BRANDIES OF STONE FRUIT WAS DETERMINED BY GAS CHROMATOGRAPHY. [R91] *ADSORPTION OF POLLUTANTS, INCL BENZYL ALCOHOL, FROM AQ SOLN WAS MONITORED BY GAS-LIQUID CHROMATOGRAPHY WITH A FLAME IONIZATION DETECTOR SYSTEM USING THE DIRECT INJECTION OF AQ SOLN. [R92] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzyl Alcohol in F344/N Rats and B6C3F1 Mice Technical Report Series No. 343 (1989) NIH Publication No. 89-2599 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 129 R4: Estrin, N.F., Crosley, P.A. and Haynes, C.R. (eds.) CTFA Cosmetic Ingredient Dictionary. 3rd ed. Washington, D.C.: The Cosmetic, Toiletry and Fragrance Association, Inc. 1982. 6 R5: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 272 R6: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 617 R7: Opdyke, D.L.J. (ed.). Monographs on Fragrance Raw Materials. New York: Pergamon Press, 1979. R8: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 45 R9: FARAH AE, GORMAN WG; US PATENT NUMBER 4200655 4/29/80 (STERLING DRUG, INC) R10: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R11: CLAUSEN OG ET AL; PHARM IND 39 (7): 726 (1977) R12: SRI R13: USITC. IMPORTS OF BENZENOID CHEM AND PROD 1983 p.11 R14: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999. R15: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R16: Serjeant, E.P., Dempsey B.; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23, 1979. New York, New York: Pergamon Press, Inc. R17: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R18: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 31 R19: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 39 R20: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 268 R21: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ AZ, College of Pharmacy (1992) R22: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 310 R23: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-525 R24: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 256 R25: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R26: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R27: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 264 R28: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 3(78) 793 R29: Dean, J.A. Handbook of Organic Chemistry. New York, NY: McGraw-Hill Book Co., 1987. R30: Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) R31: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R32: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 111 R33: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R34: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 161 R35: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R36: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 545 R37: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 371 R38: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 446 R39: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. R40: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-173 R41: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R42: ATKINSON JP ET AL; J CLIN INVEST 60 (2): 284-94 (1977) R43: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R44: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 528 R45: Marks, J.G. Jr., DeLeo V.A., Contact and Occupational Dermatology. St. Louis, MO: Mosby Year Book 1992. 128 R46: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R47: KIMURA ET ET AL; TOXICOL APP PHARMACOL 18 (1): 60-8 (1971) R48: WOLLMANN H ET AL; PHARMAZIE 22 (8): 455 (1967) R49: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 71 R50: DELAND FH; TOXICOL APPL PHARMACOL 25 (2): 153-6 (1973) R51: EICHBAUM FW, YASAKA WJ; BASIC RES CARDIOL 71 (4): 355-70 (1976) R52: MCORMOND P ET AL; DRUG INTELL CLIN PHARM 14 (JUL-AUG): 549 (1980) R53: CHAZOTTE B, VANDERKOOI G; BIOCHIM BIOPHYS ACTA 636 (2): 153-61 (1981) R54: Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987) R55: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R56: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R57: Toxicology and Carcinogenesis Studies of Benzyl Alcohol in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 343 (1989) NIH Publication No. 89-2599 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R58: Kimura ET et al; Toxicol Appl Pharmacol 18 (1): 60-8 (1971) R59: BOWEN ET AL; CLIN CHIM ACTA, 61 (3): 399 (1975) R60: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 4 R61: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. B-13 R62: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R63: Ringk W, Theimer ET; Kirk-Othmer Encycl Chem Tech 3rd Ed. John-Wiley NY 3: 793-802 (1978); Sax NI, Lewis RJSR; Hawley's Condensed Chemical Dictionary 11th ed NY: Van Nostrand Reinhold Co p 134-5 (1987) R64: (1) Mookherjee BD, Wilson RA; Kirk-Othmer Encycl Chem Technol 4th ed. Kroschwitz JI ed. NY, NY: John-Wiley and Sons 4: 116-120 (1992) R65: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: Van Nostrand Reinhold Co., p. 129 (1997) (2) Mookherjee BD, Wilson RA; Kirk-Othmer Encycl Chem Technol 4th ed. Kroschwitz JI ed. NY, NY: John-Wiley and Sons 4: 116-120 (1992) (3) Fraser MP et al; Environ Sci Technol 32: 2051-60 (1998) R66: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (3) Briggs GG; Aust J Soil Res 19: 61-8 (1981) (4) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (6) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (7) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R67: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (3) Briggs GG; Aust J Soil Res 19: 61-8 (1981) (4) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (6) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (7) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (8) Franke C et al; Chemosphere 29: 1501-14 (1994) (9) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 31 (1995) (10) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (11) Balba MTM et al; Biochem Soc Trans 9: 230-1 (1981) (12) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R68: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (3) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) R69: Lyman, W.J., W.F. Reehl, D.H. Rosenblatt. Handbook of Chemical Property Estimation Methods-Environmental Behavior of Organic Compounds. New York, NY: McGraw-Hill Book Company, 1982.,p. 9-64 R70: (1) Babeu L, Vaishnav DD; J Ind Microbiol 2: 107-15 (1987) (2) McKinney RE et al; Sew Indust Wastes 28: 547-57 (1956) (3) Thom NS and Agg AR; Proc Royal Soc Lond B 189: 347-57 (1975) (4) Marion CV, Malaney, GW; Proc Ind Waste Cong 18: 297-308 (1964) (5) Lutin PA et al; Purdue Univ Eng Bull Ext Series 118: 131-45 (1965) (6) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) (7) Belly RT, Goodhue CT; Proc Int Biodegrad Symp 3: 1103-7 (1976) (8) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (9) Tabak HH, Govind R; in Proc Annu Meet Air Waste Manage Assoc, 85th 8B 92-29.05 (1992) R71: (1) Horowitz A et al; Dev Ind Microbiol 23: 435-44 (1982) (2) Shelton DR, Tiedje JM; App Env Microbiol 47: 850-7 (1984) (3) Balba MTM et al; Biochem Soc Trans 9: 230-1 (1981) R72: (1) Hendry DG et al; J Phys Chem Ref Data 3: 937-78 (1974) (2) Mill T et al; Science 207; 886-7 (1980) (3) Dorfman LM, Adams GE; Reactivity of the Hydroxyl Radical in Aqueous Solution NSRD-NBS-46 Washington DC: National Bureau of Standards pp 51 (1973) (4) Draper WM, Crosby DG; Arch Environ Contam Toxicol 12: 121-126 (1983) R73: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R74: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 31 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R75: (1) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (2) Briggs GG; Aust J Soil Res 19: 61-8 (1981) (3) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R76: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R77: (1) USEPA; Superfund Record of Decision USEPA/ROD/RO2-86/031 (1987) (2) Umano K et al; Bull Environ Contam Toxicol 56: 558-565 (1996) R78: (1) Dagon TJ; J Water Pollut Contrl Fed 45: 2123-35 (1973) (2) Keith LH; Environ Sci Technol 10: 555-64 (1976) (3) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (4) Gossett RW et al; Mar Pollut Bull 14: 387-92 (1983) (5) Albaiges J et al; Wat Res 20: 1153-9 (1986) (6) Harmsen J; Water Res 17: 699-705 (1983) (7) Keith LH; Sci Total Environ 3: 87-102 (1974) (8) James RH et al; J Proc APCA 77th Ann Meeting: Paper 84-18.5 pp. 1-25 (1984) (9) Fraser MP et al; Environ Sci Technol 32:2051-60 (1998) (10) Salthammer T; Indoor Air 7: 187-97 (1997) (11) Wilkins CK, Larsen K; J High Res Chromatogr 18: 373-77 (1995) (12) Cooper SD et al; J Exposure Anal Environ Epidem 5: 57-75 (1995) R79: (1) Kostiainen K; Atmos Environ 29: 693-702 (1995) R80: (1) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (2) Dumont JP, Adda J; J Agric Food Chem 26: 364-7 (1978) (3) Ho CT et al; J Agric Food Chem 31: 336-42 (1983) (4) Kinlin TE et al; J Agr Food Chem 20: 1021-8 (1972) (5) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) (6) Cha YJ, Cadwaller KR; J Food Sci 60: 19-24 (1995) (7) Buttery RG et al; J Agric Food Chem 42: 791-95 (1994) (8) Kubota K et al; J Agric food Chem 39: 1127-30 (1991) (9) Chung TY et al; J Agric Food Chem 41: 1693-97 (1993) R81: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R82: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R83: 40 CFR 60.489 (7/1/99) R84: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R85: 21 CFR 172.515 (7/1/99) R86: 21 CFR 175.105 (7/1/99) R87: 21 CFR 175.300 (4/1/99) R88: 21 CFR 73.1001(b) (4/1/99) R89: OHNO Y ET AL; KANZEI CHUD BUNSEKISHOHO 15: 47-55 (1975) R90: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1473 R91: TUTTAS R, BEYE F; Z LEBENSM-UNTERS-FORSCH 155 (2): 88-91 (1974) R92: AL-BAHRANI KS, MARTIN RJ; WATER RES 10 (8): 731-6 (1976) RS: 58 Record 9 of 1119 in HSDB (through 2003/06) AN: 54 UD: 200303 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLENE-GLYCOL-MONOETHYL-ETHER- SY: *Athylenglykol-monoathylather- (German); *CELLOSOLVE-; *CELLOSOLVE-SOLVENT-; *Celosolv- (Czech); *DOWANOL-EE-; *EKTASOLVE-EE-; *EMKANOL-; *Eter-monoetilico-del-etilenglicol- (Spanish); *ETHANOL,-2-ETHOXY-; *Ether-monoethylique-de-l'ethylene-glycol- (French); *BETA-ETHOXYETHANOL-; *2-ETHOXYETHANOL-; *ETHYL-CELLOSOLVE-; *ETHYLENE-GLYCOL-ETHYL-ETHER-; *Ethylene-glycol-monoethyl-ether-; *ETHYL-ETHYLENE-GLYCOL-; *ETHYL-GLYCOL-; *Etoksyetylowy-alkohol-; *GLYCOL-MONOETHYL-ETHER-; *HYDROXY-ETHER-; *NCI-C54853-; *OXITOL-; *POLY-SOLV-EE-; *SOLVULOSE- RN: 110-80-5 MF: *C4-H10-O2 SHPN: UN 1171; Ethylene glycol monoethyl ether IMO 3.3; Ethylene glycol monoethyl ether STCC: 49 131 16; Ethylene glycol monoethyl ether HAZN: U359; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. F005; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ETHYLENE OXIDE WITH EXCESS ANHYDROUS ETHYL ALCOHOL [R1] FORM: *GRADES OF PURITY: COMMERCIAL [R2] *Grade: Technical [R3] MFS: *Occidental Petroleum Corporation, Hq, 10889 Wilshire Boulevard, Suite 1500, Los Angeles, CA 90024 (213) 879-1700. Petrochemicals, Occidental Tower, 5005 LBJ Freeway, PO Box 809050 (75380), Dallas, TX 75244 (214) 404-3800. Ethylene Oxide and Derviatives Division, 5761 Underwood Road, Pasadena, TX 77587. Production site: Bayport, TX 77000 [R4] *Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817 (203) 794-2000. Solvents and Intermediates. Production site: Seadrift, TX 77983 [R4] OMIN: *Acidity (as acetic acid) 0.01% by wt (max); ... combines a low evaporation rate with a strong solvent action. Has a powerful solvent action on nitrocellulose and alkyd resins and an extremely high dilution ratio with coal-tar hydrocarbons. This solvent will tolerate 4.9 times its own volume of toluene before the mixture will cease to dissolve nitrocellulose ... . [R5] *... Imparts excellent flow properties and high gloss to thermoplastic and thermosetting coating systems. [R6] *Interferences: High humidity reduces sampling capacity. Less volatile compounds may replace more volatile compounds on the charcoal. [R7] USE: *SOLVENT FOR NITROCELLULOSE, LACQUERS AND DOPES; INCR STABILITY OF EMULSIONS; USED IN VARNISH REMOVERS, CLEANSING SOLN, DYE BATHS; FINISHING LEATHER WITH WATER PIGMENTS AND DYE SOLN [R8] *CHEM INT FOR 2-ETHOXYETHYL ACETATE, A SOLVENT [R1] *SOLVENT FOR EPOXY AND OTHER COATINGS [R1] *SOLVENT FOR PRINTING INKS AND DUPLICATING FLUIDS [R1] *OTHER SOLVENT USES, EG, ADHESIVES [R1] *... Natural and synthetic resins; mutual solvent for formulation of soluble oils; lacquers and lacquer thinners, dyeing and printing textiles, varnish removers, ... anti-icing additive for aviation fuels. [R3] CPAT: *CHEM INT FOR 2-ETHOXYETHYL ACETATE, 48%; SOLVENT FOR EPOXY AND OTHER COATINGS, 9%; GENERAL SOLVENT USES (EG, PRINTING INKS AND DUPLICATING FLUIDS), 4%; EXPORTS, 38% (1983) [R1] PRIE: U.S. PRODUCTION: *(1978) 1.16X10+11 G [R1] *(1982) 8.09X10+10 G [R1] U.S. IMPORTS: *(1978) 1.57X10+10 G [R1] *(1982) 1.44X10+8 G [R1] U.S. EXPORTS: *(1978) 1.14X10+10 G [R1] *(1982) 1.65X10+10 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid. [R9]; *Water-white [R10, 555] ODOR: *Sweet, pleasant, ether-like odor. [R9]; *Mild, agreeable odor [R10, 555] TAST: *SLIGHTLY BITTER [R11, 601] BP: *135 DEG C @ 760 MM HG [R12] MP: *-70 deg C (pour point) [R13] MW: *90.12 [R8] DEN: *SP GR: 0.931 @ 20 DEG C/20 DEG C [R8] DSC: *pKa = 14.8 [R14] HTV: *40.53 kJ/mol @ 101.3 kPa [R15] OWPC: *log Kow= -0.32 [R16] SOL: *Miscible in all proportions of acetone, benzene, carbon tetrachloride, ethyl ether, methanol, and water. [R10, 555] SPEC: *SADTLER REFERENCE NUMBER: 5291 (IR, PRISM); 10992 (IR, GRATING) [R17]; *Index of refraction: 1.4080 @ 20 deg C/D [R12]; *INDEX OF REFRACTION: 1.406 @ 25 DEG C/D [R8] SURF: *28.2 dynes/cm @ 25 deg C [R10, 555] VAP: *5.31 mm Hg @ 25 deg C /from experimentally derived coefficients/ [R18] VISC: *1.84 centipoise @ 25 deg C [R10, 555] OCPP: *SOLIDIFIES: -70 DEG C; DISSOLVES MANY OILS, RESINS, WAXES [R8] *WT/GAL 7.74 LB @ 20 DEG C; POUR POINT LESS THAN 37.7 DEG C [R3] *PERCENT IN SATURATED AIR @ 25 DEG C: 0.76; 1 PPM= 3.68 MG/CU M @ 25 DEG C, 760 MM HG; 1 MG/L= 272 PPM @ 25 DEG C, 760 MM HG [R19, 3912] *RATIO OF SPECIFIC HEATS OF VAPOR (GAS): 1.064; HEAT OF SOLUTION: (EST) -5 CAL/G [R2] *Surface tension: 28.2 mN/m (=dyn/cm) @ 25 DEG C; Blush resistance (@ 27 Deg C) 59% rh; Coefficient of expansion: 0.00097 cu cm [R20] *Flash point = 108 deg F [R10, 541] *Specific heat = 0.53 cal/deg C (average), freezing range = -59 deg C, and acidity (as acetic acid) = 0.01 wt% (max) [R10, 555] *Freezing point = -90 deg C [R10, 552] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R21] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R21] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R21] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R21] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R21] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R21] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R21] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R21] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R22] +Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R22] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R22] FLMT: +Upper 15.6% @ 93 deg C; lower 1.7% @ 93 deg C [R22] FLPT: +110 deg F (43 deg C) (closed cup) [R22] AUTO: +455 deg F (235 deg C) [R22] FIRP: *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R23] EXPL: *MODERATE; IN THE FORM OF VAPOR WHEN EXPOSED TO HEAT OR FLAME ... . [R24] REAC: +Strong oxidizers. [R25, 62] ODRT: *GREATER THAN 255 PPM. [R19, 3926] *HUMAN VOLUNTEERS WITH SOME WORK EXPERIENCE IN INDUSTRIAL ENVIRONMENTS REPORTED THAT /ODOR/ LEVELS OF 125 PPM WERE NOTICEABLE. [R19, 3926] SERI: *NOT SIGNIFICANTLY IRRITATING TO SKIN, SLIGHTLY IRRITATING TO EYES AND MUCOUS MEMBRANES ... [R19, 3920] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R25, 131] +Wear appropriate eye protection to prevent eye contact. [R25, 131] +Recommendations for respirator selection. Max concn for use: 5 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R25, 131] +Recommendations for respirator selection. Max concn for use: 12.5 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R25, 131] +Recommendations for respirator selection. Max concn for use: 25 ppm. Respirator Class(es): Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R25, 131] +Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any supplied-air respirator operated in a pressure-demand or other positive-pressure mode. May require eye protection. [R25, 131] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R25, 131] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R25, 131] *Anon Posthearing Brief of the National Institute for Occupational Safety and Health on the Occupational Safety and Health Administration Proposed Rule on Occupational Exposure to 2-Methoxyethanol, 2-Ethoxyethanol and Their Acetates IGlycol Ethers J ~February 1, 1994). 29 CFR Part 1910; Docket No. H-044. NTIS/PB94-175072 Govt Reports Am~ouncements and Index ~GRA and II, Issue 17, 1994 TD3: The testimony presents a review of the findings of a study which predicted that organic vapor chemical cartridges can adsorb glycol ethers at the proposed maximun~ use concentrations. The report reconunended that a cartridge change out schedule of one week be adopted for full face air purifying respirators and two weeks for half face air purifying respirators. However, the migration of glycol ethers through the cartridge sorbent bed over a weekend or overnight was not evaluated. Such a n~igration would result in the wearer being exposed to glycol ehters when the respirator was used again. The National Institute for Occupational Safety and Health ~NIOSH~ recommends that if OSHA were to allow the use of air purifying respirators with organic vapor chemical cartridges to protect workers fron~ glycol ether exposure, the cartridges should be changed after each shift, up to 12 hours. NIOSH recomn~ends the use of air supplied respirators when respiratory protection is necessary. See also PB94-175D80. OPRM: *... SUBSTITUTION OF LESS IRRITATING SUBSTANCES ... REDESIGN OF OPERATIONS ... PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, WORK CLOTHING AND STORAGE FACILITIES ... AND BARRIER CREAMS. MEDICAL CONTROL ... [R26] +Contact lenses should not be worn when working with this chemical. [R25, 131] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. [R25, 131] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R25, 131] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to disperse vapors and dilute standing pools of liquid. [R23] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R23] SSL: *TENDS TO DECOMP ON EXPOSURE TO SUNLIGHT [R11, 601] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers U359, and F005 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R30] *Ethylene glycol monoethyl ether is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Concentrated waste containing no peroxides, discharge liquid at a controlled rate near a pilot flame. Concentrated containing peroxides; perforation of a container of the waste from a safe distance followed by open burning. [R31] *Spray into furnace. Incineration will become easier by mixing with a more flammable solvent. Recommendable method: Incineration. [R32] *The following wastewater treatment technologies have been investigated for ethylene glycol monoethyl ether. Concentration process: Activated carbon. [R33] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *THE EFFECTS /OF ALKYL DERIV OF ETHYLENE GLYCOL/ ... UPON THE CNS INCLUDE HEADACHE, DROWSINESS, WEAKNESS, SLURRED SPEECH, RECRUDESCENT STUTTERING, STAGGERING GAIT, TREMOR, AND BLURRED VISION. CHANGES OF PERSONALITY ARE OFTEN NOTED ... THESE CHANGES ARE SUCH THAT THE PATIENT, IN THE ABSENCE OF AN ACCURATE OCCUPATIONAL HISTORY, MAY BE TREATED FOR SCHIZOPHRENIA OR NARCOLEPSY. IN ACUTE POISONING WITH THE ETHYLENE GLYCOL MONOALKYL ETHERS, THERE IS ... RENAL INJURY: ALBUMINURIA AND HEMATURIA. /ETHYLENE GLYCOL MONOALKYL ETHERS/ [R34] *IN ... TWO CASES, /IN/ WORKMEN WHO HAD BEEN EMPLOYED FOR 13 YR IN LACQUER AND PIGMENT FACTORIES ... INJURIOUS EFFECT /HAS/ BEEN REPORTED. THIS CONSISTED IN ONE OF A SLIGHT YELLOWISH DISCOLORATION OF ... /SCLERA/ AND IN THE OTHER A TRACE OF ALBUMIN IN THE URINE AND A SLIGHTLY INCREASED LEVEL OF UROBILIN IN BLOOD ... [R11, 604] *SYMPTOMATOLOGY: 1. Central nervous depression, although probably less prominent than with ethylene glycol. 2. No hypocalcemic tetany or metabolic acidosis with the possible exception of poisonings due to ethylene glycol monomethyl ether. 3. Nausea, vomiting, and sometimes diarrhea. 4. Prominent headache. Later abdominal and lumbar pain and costovertebral angle tenderness. 5. Transient polyuria and then oliguria, progressing to anuria. 6. Acute renal failure ... 7. Less critical pathological lesions may appear in brain, lungs, liver, meninges and heart. 8. Observations in animals suggest the remote possibility of pulmonary edema, intravascular hemolysis and bone marrow depression, at least with some ether derivatives of ethylene and diethylene glycols. ... /Ethylene glycol (Group B compounds)/ [R35, p. III-176] *CENTRAL NERVOUS DEPRESSION AS WITH ETHYLENE GLYCOL, BUT THE ETHER DERIVATIVES PRODUCE MORE MARKED KIDNEY INJURY AND HEMATURIA (APPARENTLY WITHOUT OXALIC ACID FORMATION OR CRYSTALLURIA). [R35, p. II-182] *Ethylene glycol monomethyl ether and ethylene glycol monoethyl ether have recently been shown to have the potential to induce reproductive toxicity. [R36, 705] *To determine whether 2-ethoxyethanol and 2-methoxyethanol affected the reproductive potential of exposed men, we examined the semen of 73 painters and 40 controls who work in a large shipyard. The industrial hygiene survey revealed that the painters were exposed to 2-ethoxyethanol at a time-weighted average of 0-80.5 mg/cu m with a mean of 9.9 mg/cu m, and to 2-methoxyethanol at a time-weighted average of 0-17.7 mg/cu m with a mean of 2.6 mg/cu m. Painters had an increased prevalence of oligospermia and azoospermia and an increased odds ratio for a lower sperm count per ejaculate, while smoking was controlled. [R37] *To evaluate whether long term exposure to 2-ethoxyethanol may affect semen quality, a cross sectional study was conducted among men exposed to 2-ethoxyethanol in a metal castings process. Full shift breathing zone exposures to 2-ethoxyethanol ranged from non-detectable to 24 ppm (geometric mean 6.6 ppm). Because of the potential for substantial absorption of 2-ethoxyethanol through skin exposure, urine measurements of the metabolite of 2-ethoxyethanol, 2-ethoxyacetic acid were conducted, showing levels of 2-ethoxyacetic acid ranging from non-detectable to 163 mg 2-ethoxyacetic acid/g creatinine. The average sperm count per ejaculate among the workers exposed to 2-ethoxyethanol was significantly lower than that of the unexposed group (113 vs 154 million sperm per ejaculate respectively; p= 0.05) after consideration of abstinence, sample age, subjects' age, tobacco, alcohol and caffeine use, urogenital disorders, fever, and other illnesses. The mean sperm concentrations of the exposed and unexposed groups did not significantly differ from each other (44 and 53 million/ml respectively). No effect of exposure to 2-ethoxyethanol on semen volume, sperm viability, motility, velocity, and normal morphology or testicular volume was detected, although some differences in the proportion of abnormal sperm shapes were observed. [R38] *Hemoglobin, hematocrit, red cell indices, total and differential white blood cell counts, and platelet count were measured in shipyard painters and control subjects as part of a cross-sectional, observational study of the effects of ethylene glycol ethers. Although the means of all variables were comparable between the groups, a significant proportion of painters were anemic (10%) and granulocytopenic (5%); none of the controls were affected. Review of company records documented that most of these abnormalities were acquired during employment. [R39] *Workers exposed at up to 88 mg/cu m 2-ethoxyethanol had significantly lower average sperm counts than controls, although both exposed and control groups had lower sperm counts than those found in other occupational groups. The two groups studied did not differ significantly with respect to other semen characteristics or testicular size. [R40, 1991.565] *Two groups of workers occupationally exposed to glycol ethers in a varnish production plant or the ceramic industry were examined. For 19 persons the external and internal exposure was assessed on the Monday and Tuesday after an exposure-free weekend. In the varnish production area the concentrations of 2-ethoxyethanol, 2-ethoxyethyl acetate, and 2-butoxyethanol in air averaged 2.9, 0.5, and 0.5 ppm, respectively, on the Monday, and 2.1, 0.1, and 0.6 ppm, respectively, on the Tuesday. At the same workplaces the mean urinary 2-ethoxyacetic acid and 2-butoxyacetic acid concentrations were 53.2 and 0.2 mg/l on Monday preshift and 53.8 and 16.4 mg/l on Tuesday postshift. The results show that glycol ethers are very well absorbed through the skin. Therefore biological monitoring is indispensable. To study the kinetics of the toxic metabolite, 17 persons were examined for their excretion of 2-ethoxyacetic acid in urine during an exposure-free weekend. The median values of the calculated half-times were 57.4 and 63.4 hr, respectively, which are longer than the values presented in literature until now. According to our calculations the limit value should not exceed 50 mg 2-ethoxyacetic acid per liter of urine, which is the current German biological tolerance value (BAT value) for 2-ethoxyacetic acid in urine. The maximum concentration value at the workplace (MAK value) for 2-ethoxyethanol and 2-ethoxyethyl acetate in air should be revised. Finally, the subjects from the varnish production plant as well as a group of reference persons were studied for cytogenetic effects of glycol ethers (sister chromatid exchange, micronucleus test). Such effects could not be detected. [R41] NTOX: *ACUTE: NO IMMEDIATE SIGNS OF DISTRESS BUT LATER DYSPNEA AND WEAKNESS, SLIGHT PARALYSIS; AFTER 7 HR PROSTRATION. IN A FEW ANIMALS THE LENS AND CORNEA SHOWED OPACITIES. ... INSTILLATION OF 1 DROP OF PURE MATERIAL /IN EYES/ CAUSED HYPEREMIA AND SLIGHT EDEMA. ... THE KIDNEYS, FOLLOWING ... SC INJECTION /SHOWED/ ACUTE NEPHROSIS, WITH DEGENERATIVE PROCESSES AND HEMORRHAGE INTO INTRACAPSULAR SPACES AND TUBULES, ALSO HEMATURIA ... LUNG /SHOWED/ CONGESTION AND EDEMA; SPLEEN /SHOWED/ FOLLICULAR PHAGOCYTOSIS AND SOME SIDEROSIS; THE STOMACH /SHOWED/ HEMORRHAGE INTO THE MUCOSA. [R11, 603] *... TWO DOGS /WERE EXPOSED/ TO VAPOR CONCN OF 840 PPM ... 7 HR/DAY, 5 DAYS A WK FOR 12 WK AND SLIGHT DECREASE IN HEMOGLOBIN AND RED CELLS /WAS OBSERVED/. THE BLOOD PICTURE WAS CHARACTERIZED BY A GREATER THAN NORMAL NUMBER OF IMMATURE WHITE CELLS. THERE WAS NO EVIDENCE OF KIDNEY INJURY OR OF BONE MARROW INJURY. THERE WAS ... AN INCREASE IN THE NUMBER OF CALCIUM OXALATE CRYSTALS IN THE URINE. [R19, 3924] *... GUINEA PIGS COULD SURVIVE EXPOSURE INTENSITIES OF 6000 PPM FOR 1 HR, 3000 PPM FOR 4 HR, AND 500 PPM FOR 24 HR WITHOUT APPARENT HARM. MORE INTENSE EXPOSURES CAUSED INJURY OF THE LUNGS, HEMORRHAGE IN THE STOMACH AND INTESTINES, AND CONGESTION OF THE KIDNEYS. [R19, 3923] *... THE MAJORITY OF ANIMALS REPEATEDLY EXPOSED TO 1400 PPM, OF ETHYLENE GLYCOL MONOETHYL ETHER 8 HR/DAY DIED AFTER 4 TO 12 EXPOSURES. CATS WERE FOUND TO BE MOST SUSCEPTIBLE, DYING 2 DAYS AFTER 4 OR 5 DAYS OF EXPOSURE. ONE OF TWO MICE DIED AFTER NINE EXPOSURES BUT THE OTHER SURVIVED 12 EXPOSURES WITHOUT EVIDENT EFFECTS. TWO RABBITS SURVIVED 12 EXPOSURES, ONE DYING 7 DAYS LATER, WHILE TWO GUINEA PIGS SURVIVED 12 EXPOSURES WITHOUT EVIDENCE OF INJURY. [R19, 3923] *... RABBITS /WERE FED/ REPEATED DAILY DOSES OF ETHYLENE GLYCOL MONOETHYL ETHER AND /IT WAS/ FOUND THAT SEVEN DOSES OF 0.1 ML/KG (0.093 G/KG) CAUSED TEMPORARY ALBUMINURIA, WHEREAS SEVEN DOSES OF 0.25 ML/KG (0.23 G/KG) CAUSED BOTH ALBUMINURIA AND HEMATURIA AFTER THE SEVENTH FEEDING. WHEN THE DOSAGE WAS INCREASED TO 1 ML/KG (0.93 G/KG), ALBUMINURIA AND HEMATURIA WERE OBSERVED AFTER THE SEVENTH DAY, FOLLOWED BY DEATH ON THE EIGHT DAY DUE TO KIDNEY INJURY. TWO DOSES OF 2 ML/KG (1.86 G/KG) CAUSED EXHAUSTION, REFUSAL TO EAT, ALBUMINURIA, CYLINDERS IN THE URINE, AND DEATH BELIEVED DUE TO KIDNEY INJURY. [R19, 3921] *... Rats /were maintained/ for 90 days on drinking water containing ethylene glycol monoethyl ether. ... Max dose having no effect was 0.21 g/kg/day ... 0.74 g/kg reduced growth and appetite, altered liver and kidney weights and produced microscopic lesions in these organs and that mortality was incr when the dosage was 1.89 g/kg/day. [R19, 3921] *... Dogs /were fed ethylene glycol monoethyl ether/ for 13 wk at levels of 0.046 to 0.185 g/kg/day and found reduced hemoglobin levels and hematocrit values after 5 weeks. These dogs also developed pathologic changes in the kidneys and testes similar to those seen in the rats. [R19, 3921] *... Ethylene glycol monoethyl ether /administered/ sc for 4 wk ... /at/ doses of up to 0.38 g/kg/day caused no deaths in rats. ... Doses of 0.185 and 0.38 g/kg caused dyspnea, somnolence, mild ataxia, some growth depression in the females, and some reduction of hemoglobin levels and hematocrit values. At the 0.38 g/kg level interstitial testicular edema, dissociation of liver parenchyma and tubular lesions of the kidney were observed. [R19, 3922] *2-Ethoxyethanol ... when dropped on rabbit eyes causes discomfort, but only slight reversible injury, graded 3 on a scale of 10 after twenty-four hours. Exposure of rabbits to high vapor concentrations causes symptoms of ocular and respiratory irritation, but even at concn which are probably lethal, causes no significant ocular injury. [R42] *THE ACUTE TOXICITY TO GOLDFISH (CARASSIUS AURATUS) OF ETHYLENE GLYCOL MONOETHYL ETHER WAS DETERMINED. RESULTS WERE GIVEN WITH THE PETROCHEMS GROUPED AS TO TYPE OF CMPD. [R43] *STUDIES UTILIZING INHALATION EXPOSURE OF RATS AND RABBITS ON DAYS 1-19 AND 1-24, RESPECTIVELY, OF GESTATION WERE CONDUCTED WITH 2-ETHOXYETHANOL. IT WAS STRONGLY EMBRYOTOXIC AT THE HIGHER EXPOSURE LEVELS EMPLOYED AND WAS TERATOGENIC AT THE LOWER CONCN. [R44] *ETHYLENE GLYCOL MONOMETHYL (EGM) AND MONOETHYL (EGE) ETHERS WERE ADMIN PER ORAL TO RATS AT DOSAGES VARYING FROM 50 TO 500 MG/KG BODY WT/DAY FOR EGM AND 250 TO 1000 MG/KG BODY WT/DAY EGE FOR 11 DAYS. FIRST EVIDENCE OF TESTICULAR DAMAGE FOLLOWING EGM TREATMENT WAS OBSERVED 24 HR AFTER A SINGLE DOSE OF 100 MG/KG BODY WT WHEN THE LESION APPEARED LOCALIZED IN THE PRIMARY SPERMATOCYTE. AT 16 HR AFTER A SINGLE DOSE OF 500 MG/KG, MITOCHONDRIAL DAMAGE WAS ONE OF THE FIRST SUBCELLULAR CHANGES TO BE DEMONSTRATED. TREATMENT OF ANIMALS WITH EGE RESULTED IN A SIMILAR LESION; HOWEVER, TO OBTAIN DAMAGE OF EQUIVALENT SEVERITY, A LARGER DOSAGE FOR A LONGER PERIOD WAS REQUIRED. NO-EFFECT LEVELS OVER THE 11-DAY TREATMENT PERIODS WERE 250 MG/KG BODY WT/DAY FOR EGE. [R45] *UNDILUTED 2-ETHOXYETHANOL WAS APPLIED TO THE SKIN OF PREGNANT SPRAGUE-DAWLEY RATS ON DAYS 7-16 OF GESTATION (SPERM= DAY 1). APPLICATIONS WERE MADE 4 TIMES DAILY IN VOL OF 0.25 OR 0.50 ML 2-ETHOXYETHANOL. FEMALES EXHIBITED ATAXIA FOLLOWING TREATMENT OF THE HIGH-DOSE GROUP, AND WT GAIN WAS SIGNIFICANTLY REDUCED IN THE LAST HALF OF GESTATION. INTRAUTERINE DEATH WAS 100% IN THE HIGH-DOSE GROUP. IN THE LOWER DOSAGE GROUP, THERE WAS A SIGNIFICANT INCR IN THE NUMBER OF PREGNANT FEMALES WITH 100% DEAD IMPLANTS, A SIGNIFICANT REDN IN THE NUMBER OF LIVE FETUSES PER LITTER, A SIGNIFICANT REDN IN FETAL BODY WT, AND A SIGNIFICANT INCR IN THE INCIDENCE OF SKELETAL VARIATIONS AND CARDIOVASCULAR MALFORMATIONS. [R46] *PREGNANT RATS WERE EXPOSED TO 100 PPM 2-ETHOXYETHANOL FOR 7 HR/DAY ON GESTATION DAYS 7-13 OR 14-20. SLIGHTLY PROLONGED GESTATION WAS OBSERVED IN THE MOTHERS EXPOSED ON DAYS 14-20. BEHAVIORAL TESTING OF OFFSPRING FROM DAMS EXPOSED ON DAYS 7-13 REVEALED IMPAIRED PERFORMANCE ON A ROTOROD TEST OF NEUROMUSCULAR ABILITY, PROLONGED LATENCY OF LEAVING THE START AREA OF AN OPEN FIELD, AND MARGINAL SUPERIORITY IN AVOIDANCE CONDITIONING BEGUN ON DAY 34 OF AGE. OFFSPRING FROM DAMS EXPOSED ON 14-20 WERE LESS ACTIVE THAN CONTROLS IN A RUNNING WHEEL, AND RECEIVED AN INCR NUMBER AND DURATION OF SHOCKS IN AVOIDANCE CONDITIONING BEGUN ON DAY 60 OF AGE. WHOLE-BRAIN SAMPLES FROM NEWBORN PUPS REVEALED SIGNIFICANTLY DECR LEVELS OF NOREPINEPHRINE IN OFFSPRING FROM BOTH EXPOSURE PERIODS. IN REGIONAL ANALYSES OF BRAINS FROM 21-DAY-OLD OFFSPRING FROM DAMS EXPOSED ON DAYS 7-13, THE CEREBRUM HAD SIGNIFICANT ELEVATIONS IN ACETYLCHOLINE, NOREPINEPHRINE, AND DOPAMINE. IN ADDN, THE CEREBELLUM HAD NEARLY A 3-FOLD INCR IN ACETYLCHOLINE; THE BRAINSTEM HAD AN INCR IN NOREPINEPHRINE; AND THE MIDBRAIN HAD EXCESSES OF ACETYLCHOLINE, NOREPINEPHRINE, AND PROTEIN. IN BRAINS FROM 21-DAY-OLD OFFSPRING OF DAMS EXPOSED ON DAYS 14-20, THE CEREBRUM HAD SIGNIFICANT ELEVATIONS IN ACETYLCHOLINE, DOPAMINE, AND 5-HYDROXYTRYPTAMINE. [R47] *The teratogenic potential of ethylene glycol monoethyl ether has also been reported. ... Rabbits were exposed to ethylene glycol monoethyl ether vapors (160 or 617 ppm) seven hr/day during days 1 to 19 of gestation. At 617 ppm there were marked maternal toxicity and 100% embryo mortality. At the 160 ppm level, there was slight maternal toxicity, and no embryo mortality, but the incidence of major cardiovascular malformations was increased. In the same study, pregnant rats were exposed to either 200 ppm or 750 ppm ethylene glycol monoethyl ether vapors. The high exposure level caused maternal toxicity and embryo mortality. The 200 ppm exposure level caused an increased incidence of minor malformations. The teratogenicity of ethylene glycol monoethyl ether has also been demonstrated in rats by the dermal exposure route. ... Applied four times daily either 0.25 or 0.50 ml of ethylene glycol monoethyl ether to skin of rats during days 7 to 15 of gestation. Maternal toxicity and embryo toxicity were seen. The fetuses that survived had an increase incidence of cardiovascular malformations. [R36, 706] *Gestational exposures to 2-ethoxyethanol at 617 ppm (rabbits) or 767 ppm (rats) induced significantly increased incidences of embryomortality at maternally toxic concentrations. Exposure of pregnant rabbits or rats to 2-ethoxyethanol at 160 or 202 ppm, respectively, induced significantly increased incidence of terata, growth retardation, and embryomortality. These lower levels also induced a significant degree of maternal toxicity in rabbits but not in rats. [R40, 1991.565] */IN ANIMALS/ BY INHALATION SERIOUS INJURY CAN ONLY BE PRODUCED AT ROOM TEMPERATURES BY LONG EXPOSURE TO SATURATED AIR. [R11, 602] *An evaluation of the hydra assay (Hydra) for testing potential teratogenic glycols and glycol ethers was reported. Ethylene glycol monoethyl ether is a potential embryotoxin. [R48] *The toxicity of ethylene glycol ethers is reviewed. Testicular changes have been studied in mice. Ethylene glycol monomethyl ether appears to be most toxic, followed by ethylene glycol dimethyl ether, ethylene glycol monomethyl ether acetate, ethylene glycol monoethyl ether, and ethylene glycol monoethyl ether acetate. Preliminary studies have been made of the effect of ethylene glycol monomethyl ether on hamsters and guinea pig testes. Decreased testicular weight had been found in hamsters receiving doses from 62.5 to 500 mg/kg and in guinea pigs receiving 500 or 250 mg/kg. The methyl ethers of propylene and diethylene glycol do not have the same effect. Both ethylene glycol monomethyl ether and ethylene glycol dimethyl ether have been seen demonstrated to have embryotoxic effects. Both methyl and ethyl ethers of ethylene glycol cause testicular atrophy. Esterification of these chemicals does not affect potency of the toxicity. Dimethyl and monomethyl ethers have about the same testicular toxicity. Alkyl ethers of other glycols are without these effects in the testes. Ethylene glycol alkyl ethers appear to affect dividing cells and inhibit cell proliferation. Changes induced by these agents can be distinguished from those induced by hormonal subtances by their lack of effect on Leydig and Sertoli cells. Some ethylene glycol alkyl ethers have toxic effects on both testes and fetus. Substances known to inhibit cell proliferation are expected to damage the fetus if given to pregnant animals. [R49] *The reproductive effects of ethylene monomethyl ether and propylene glycol monomethyl ether inhalation were investigated in rats. To determine the effects on testis and hematology, male Wistar-rats were exposed to 100 or 300 ppm ethylene monomethyl ether or 200 or 600 ppm propylene glycol monomethyl ether for 6 hours per day for 10 consecutive days in an inhalation chamber. The teratogenic potential on the developing embryo was assessed by exposing pregnant female rats to 100 or 300 ppm ethylene monomethyl ether and 200 or 600 ppm propylene glycol monomethyl ether for 6 hours per day on days 6 to 17 of gestation. Other studies investigated the teratogenic potential of diethylene ethylene monomethyl ether in the postnatal development test, effect on route of administration on teratogenic potential of ethylene monomethyl ether, effect of ethylene glycol monoisopropyl ether on the testis and blood, effect of a single inhalation exposure to ethylene monomethyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monomethyl ether, and ethylene glycol monobutyl ether, and exposure of a single exposure to ethylene monomethyl ether on the testis of male rats. Ethylene monomethyl ether caused testicular atrophy at 300 ppm and showed teratogenic potential at 100 ppm; propylene glycol monomethyl ether did not cause testicular atrophy or affect embryonic development at 600 ppm by inhalation. Diethylene ethylene monomethyl ether showed no teratogenic potential when administered subcutaneously in rats up to 1,000 ul/kg, whereas ethylene monomethyl ether had effects at 40 microl/kg. Ethylene monomethyl ether caused testicular changes in rats after a single exposure to 600 ppm or more for 4 hours. Ethylene glycol monoethyl ether caused a reduction in testicular weight following a single exposure to saturated vapor of 17 mg/l for 3 hours; ethylene glycol monoisopropyl ether at 15 mg/l and ethylene glycol monobutyl ether at 4 mg/l showed no effect on the testis. [R50] *Previous NIOSH studies demonstrated the embryo- and fetotoxicity and teratogenicity of ethylene glycol monoethyl ether applied to the shaved skin of pregnant rats. In the present study ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, and diethylene glycol monoethyl ether were tested in the same experimental model, using distilled water as the negative control and ethylene glycol monoethyl ether as a positive control. Water or undiluted glycols were applied four times daily on days 7 to 16 gestation to the shaved interscapular skin with automatic pipetter. Volumes of ethylene glycol monoethyl ether (0.25 ml), ethylene glycol monoethyl ether acetate (0.35 ml), and diethylene glycol monoethyl ether (0.35 ml) were approximately equimolar (2.6 mmole per treatment). Ethylene glycol monobutyl ether at 0.35 mL four times daily (approximately 2.7 mmole per treatment) killed 10 of 11 treated rats, and was subsequently tested at 0.12 ml (0.9 mmole) per treatment. Ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate treated rats showed a reduction in body weight relative to water controls that was associated with completely resorbed litters and significantly fewer live fetuses per litter. Fetal body weights were also significantly reduced in those groups. Visceral malformations and skeletal variations were significantly increased in ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate groups over the negative control group. No embryotoxic, fetotoxic, or teratogenic effects were detected in the ethylene glycol monobutyl ether or diethylene glycol monoethyl ether treated litters. [R51] *Diethylene glycol monomethyl ether has been selected as a replacement anti-icing additive for ethylene glycol monomethyl ether in Navy jet aircraft fuel. This experiment was performed to determine whether diethylene glycol monomethyl ether produced similar toxicity to ethylene glycol monomethyl ether following dermal exposure. Male guinea pigs were dermally exposed to 1.00, 0.20, 0.40, or 0 (control) g/kg/day diethylene glycol monomethyl ether for 13 weeks, 5 days/week, 6 hr/day. Another group of animals was similarly exposed to 1.00 g/kg/day ethylene glycol monomethyl ether. Body weight and testicular and splenic weight were reduced as a result of exposure to ethylene glycol monomethyl ether, diethylene glycol monomethyl ether exposed animals exhibited decreased splenic weight in the high- and medium-dose (1.00 and 0.20 g/kg/day) exposure groups only. Hematologic changes in ethylene glycol monomethyl ether exposed animals included mild anemia with increased erythroytic mean corpuscular volumes and a lymphopenia with increased neutrophils. Similar hematological changes were not observed in any animals exposed to diethylene glycol monomethyl ether. Serum creatine kinase activity was increased in animals exposed to ethylene glycol monomethyl ether, and serum lactate dehydrogenase activity was increaseed in ethylene glycol monomethyl ether and 1.00 g/kg/day diethylene glycol monomethyl ether exposed animals. In general, diethylene glycol monomethyl ether produced minimal toxicological changes following dermal exposure, whereas the toxicological changes observed following similar exposure to ethylene glycol monomethyl were much more profound. [R52] *Pregnant Fischer 344 rats and New Zealand white rabbits were exposed to 2-ethoxyethanol acetate vapor by inhalation on gestational days 6 through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 50, 100, 200, or 300 ppm, 6 hr/day. The animals were terminated on gestational day 21 (rats) or 29 (rabbits). In rabbits, exposure to 100-300 ppm resulted in maternal toxicity: decreased weight gain at 100-300 ppm, clinical signs at 200-300 ppm, alterations in hematology at 100-300 ppm, reduced gravid uterine weight at termination at 200-300 ppm, and elevated absolute liver weight at 300 ppm. Development toxicity was observed at 100-300 ppm: an increased incidence of totally resorbed litters at 200-300 ppm, an increase in nonviable fetuses at 300 ppm, and a decrease in viable implants (live fetuses) per litter at 200-300 ppm. The incidence of fetal malformations (external, visceral, and skeletal) was increased at 200-300 ppm. The incidence of total malformations was 100% at 300 ppm and significantly increased at 200 ppm. Reduced fetal osssification was observed at 100-300 ppm. In rats, exposure to 100-300 ppm also resulted in maternal toxicity: reduced weight gain and reduced food consumption at 200-300 ppm and elevated relative liver weight and alterations in hematology at 100-300 ppm. Absolute meternal liver weight was increased at all 2-ethoxyethanol acetate exposure concentrations; relative liver weight was increased at 100-300 ppm. Development toxicity was observed at 100-300 ppm: increased nonviable implantations/litter (300 ppm), reduced fetal body weight/litter (200-300 ppm), and increased incidence of external (300 ppm), visceral, and skeletal (100-300 ppm) variations indicative of toxicity. The incidence of visceral, skeletal, and total malformations was increased at 200-300 ppm. In conclusion, in both species, inhalation exposure to 2-ethoxyethanol acetate during organogenesis produced maternal toxicity at 100-300 ppm, and developmental toxicity at 100-300 ppm including teratogenicity at 200-300 ppm. At 50 ppm in both species, there was no evidence of maternal or developmental toxicity, including teratogenicity. [R53] *Mice were intubated during gestation and were evaluated for signs of toxicity. In the teratology probe, uterine contents were examined at term. In the postnatal study, offspring were examined and weighed through day 22 postpartum. Ethylene glycol monoethyl ether produced embryo lethality and malformations, and decreased fetal weight at a dose level which was not maternally toxic in the teratology probe. In the postnatal study, ethylene glycol monoethyl ether decreased litter size and neonatal body weight; while litter size continued to decrease beyond neonatal period, body weights of surviving pups were not significantly different from control. Pups exposed prenatally to ethylene glycol monoethyl ether developed kinked tail which was not apparent in fetuses or neonates. Maternally toxic dose levels of ethylene glycol monobutyl ether ethanol were associated with increased embryo lethality in teratology probe studies. In postnatal studies, there were no significant effects on pup growth or survival at maternally toxic dose levels. The teratology probe measures resorption incidence which may be a more sensitive index of prenatal death than number of live born. Neither fetal weight nor neonatal weight reliably predict permanent alteration of growth. [R54] *Ethylene glycol monomethyl ether and ethylene glycol monoethyl ether are potent reproductive toxicants in laboratory animals. The toxicity of these compounds is believed to be due to their metabolites, methoxyacetic acid and ethoxyacetic acid. The primary targets of ethylene glycol monomethyl ether and ethylene glycol monoethyl ether appear to be tissues with rapidly dividing cell systems and high rates of respiration and energy metabolism. At concentrations beginning at 3.85 mM, methoxyacetic acid and ethoxyacetic acid inhibited state 3 respiration and the respiratory control ratio in hepatic mitochondria with either succinate or citrate/malate as substrates. Cytochrome c oxidase activity was also inhibited by both metabolites at similar concentrations. The effects of methoxyacetic acid, the metabolite from the more potent compound, on testicular mitochondria were found to be comparable. Neither ethylene glycol monomethyl ether or ethylene glycol monoethyl ether appeared to affect mitochondrial function at concentrations as high as 238 or 113 mM, respectively. The toxicity of ethylene glycol monomethyl ether and ethylene glycol monoethyl ether are due to their metabolites, methoxyacetic acid and ethoxyacetic acid, and that these metabolites may exert their effects, in part, on mitochondrial function. [R55] *Histologic studies on the effects of ethylene glycol monoethyl ether identified dividing spermatocyte as a primary target cell type in the testis. Studies were undertaken to assess possible effects of ethylene glycol monoethyl ether on late-stage and epididymal spermatids, and spermatogonia. Adult male F344 rats were dosed po with 0, 50, 100, or 200 mg ethylene glycol monoethyl ether/kg/day for 5 days. Each male was then mated with two females/week for 8 weeks. The fertility of males treated with 200 mg ethylene glycol monoethyl ether/kg declined at week 4, and remained low. There was a modest but significant increase in the number of resorption sites at week 5 and 6 in the high dosing group. There was a decrease in the number of litters sired at week 5 after dosing in the 100 mg ethylene glycol monoethyl ether/kg group. There were time- and dose-related decreases in sperm concentration and motility, primarily in the 100 and 200 mg/kg groups, as well as concurrent elevations in the number of abnormal sperm forms in the epididymis. Ethylene glycol monoethyl ether is a very weak inducer of dominant-lethal mutations, and produces effects on late-stage spermatids and spermatogonia. [R56] *Structure activity studies with nine glycol alkyl ethers were conducted with a cellular leukemia transplant model in male Fischer rats to measure the effects on neoplastic progression in transplant recipients. Chemicals were given ad libitum in the drinking water simultaneously with the transplants and continued throughout the study. In all, 20 million leukemic cells were injected sc into syngeneic rats, which after 60 days resulted in a 10-fold increase in relative spleen weights, a 100-fold increase in white blood cell counts, and a 50% reduction in red blood cell indices and platelet counts. Ethylene glycol monomethyl ether given at a dose of 2.5 mg/ml in the drinking water completely eliminated all clinical, morphological, and histopathological evidence of leukemia, whereas the same dose of ethylene glycol monoethyl ether reduced these responses by about 50%. Seven of the glycol ethers were ineffective as anti-leukemic agents, including ethylene glycol, the monopropyl, monobutyl, and monophenyl ethylene glycol ethers, diethylene glycol, and the monomethyl and monoethyl diethylene glycol ethers. 2-Monomethyl ether more than doubled the latency period of leukemia expression and extended survival for at least 210 days. A minimal effective dose for a 50% reduction in the leukemic responses was 0.25 mg/ml 2-monomethyl ether in the drinking water (15 mg/kg body weight), whereas a 10-fold higher dose of 2-ethylene glycol monoethyl ether was required for equivalent antileukemic activity. In addition, the in vitro exposure of a leukemic spleen mononuclear cell culture to 2-monomethyl ether caused a dose- and time-dependent reduction in the number of leukemia cells after a single exposure to 1-100 microM concentrations, whereas the 2-monomethyl ether metabolite, 2-methoxyacetic acid, was only half as effective. [R57] *Structurally related alkyl glycol ethers were examined for their ability to block junction-mediated intercellular communication. Interruption if intercellular communication was measured in vitro by an assay that depends on the transfer of metabolites via gap junctions, ie, metablic cooperation. All compounds tested ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene monopropyl ether, and ethylene glycol monobutyl ether were able to block metabolic cooperation in vitro. The potencies of the compounds were inversely related to the length of the aliphatic chain, the dose required for maximum blockage increasing as the aliphatic chain shortened. Cytotoxicity, as measured by cell survival, was also related to the structure of the compound, generally increasing with increased length of the aliphatic chain. [R58] NTOX: *... Rats /were fed/ ethylene glycol monoethyl ether for 13 wk @ doses of 0.093 to 0.73 g/kg/day. The no-effect level established was 0.093 g/kg/day, whereas the level of 0.185 g/kg/day caused beginning adverse effects, consisting of growth depression, reduced food intake, reduced hemoglobin content and hematocrit values, and histologic changes in the liver, kidney and testes at the 0.73 g/kg/day level. [R19, 3921] HTXV: *The lethal oral dose /of ethylene glycol/ in humans is approximately 1.4 ml/kg, which would be equivalent to approximately 100 ml for a 70 kg person. /Ethylene glycol/ [R36, 703] NTXV: *LD50 Rat oral 3 g/kg; [R8] *LD50 Rabbit oral 3100 mg/kg; [R40, 1991.564] *LD50 Rabbit dermal 3.6 ml/kg occluded; [R40, 1991.564] *LD50 Rabbit dermal 16.3 ml/kg; [R40, 1991.564] *LD50 Guinea pig oral 1400 mg/kg; [R59] *Depression of testicular weight and leukopenia occurred /in mice given oral doses of 2-ethoxyethanol 5 days/week for 5 weeks/ at dosages of 2000 and 1000 mg/kg/day; [R40, 1991.564] ETXV: *LD50 Goldfish > 5000 mg/l/24 hr (modified ASTM D 1345); [R60] *LC50 Lepomis macrochirus > 10,000 ppm/96 hr (static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr); [R60] *LC50 Menidia beryllina > 10,000 ppm/96 hr (static bioassay in synthetic seawater at 23 deg C, mild aeration applied after 24 hr); [R60] NTP: +Ethylene Glycol Monoethyl Ether (EGEE) ... was tested for reproductive toxicity in Swiss CD-1 mice using the RACB protocol. It was part of a series of glycol ethers and congeners evaluated for structure-activity correlations using this design. Data collected on body weights, clinical signs, and food/water consumption during the dose-range-finding segment (Task 1) were used to set concns for the main study (Task 2) at 0.5%, 1.0%, and 2.0% w/v EGEE in drinking water. These concns produced calculated consumption estimates of nearly equal to 0.76, 1.50, and 2.6 g/kg/day. There were no effects on body weights during the continuous cohabitation portion of the study. Two females died in both the control and high dose groups. Water consumption was unchanged by the addition of EGEE. No pairs in the 2% EGEE group had any litters of pups, live or dead. In the middle dose group (1% EGEE), the number of litters/fertile pair was reduced by 35%, there were nearly equal to 2.6 live pups/litter vs. a control mean of 9.8, the proportion of pups born alive was reduced by 50%, and the weight of the live pups, adjusted for litter size, was reduced by 12%. The fertility indices in the low dose (0.5% EGEE) were not affected. Task 3 crossover mating trials were conducted with the controls and both the 2% EGEE AND 1% EGEE groups. With the 2% EGEE mice, no litters were delivered of treated females mated with control males, while 5/18 control females delivered a litter after mating with a treated male (significantly < the 17/20 control x control matings). The proportion born alive, the sex ratio, and the adjusted live pup weight were not affected when one parent had been exposed to 2% EGEE. For the 1% EGEE mice, 78% of control pairs were fertile (bore any young), while only 44% of matings were fertile if the male had consumed 1% EGEE. The fertility of treated females x control male matings was not different from that of controls. Litters from control dams mated with treated males were not different from controls, while litters from treated females x control males had pups that were 12% lighter than controls, when adjusted for litter size. After the last Task 3 mating, and 7 days of lavage for vaginal cytology, the F0 mice from the control, 1% and 2% EGEE groups were killed and necropsied. The 15% reduction in female body weight at 2% EGEE may be related to the fact that these animals never were pregnant. Adjusted liver weight was increased in the 1% EGEE-treated females females, while adjusted brain weight was decreased in 2% EGEE-treated females by 10%. In males, liver weight was unchanged, while adjusted brain weight was decreased by 5% and 8% in the 1%EGEE AND 2% EGEE groups, respectively. Absolute testis weights in the middle and high-dose groups were reduced by 11% and 35%, respectively. Relative epididymis and seminal vesicle weights were reduced in the 2% EGEE group by 18% and 12%, respectively. Abnormal sperm forms were increased by nearly equal to 2.5-fold at 1% EGEE, and by nearly equal to 13-fold at 2% EGEE from a control value of 3.3%. Also at 2% EGEE, sperm motility was reduced by 40% and epididymal sperm density was down by 19%. In the 2% EGEE group, vaginal cycle length was increased to 5.5 days, from a control value of 4.6 days. An analysis of the second generation was not conducted in this study. In conclusion, EGEE was clearly toxic to reproduction in both F0 male and female mice at 1% and 2% in drinking water, based on reduced pup numbers and weight in Task 2, fertility and pup weight effects in Task 3, and alterations in estrous cyclicity and epididymal sperm parameters at necropsy. [R61] TCAT: ?Teratogenicity was evaluated in pregnant Dutch rabbits (23-24/group) exposed by inhalation to 2-ethoxyethanol at nominal concentrations of 0, 10, 50 or 175 ppm for 6hrs/day on gestation days 6-18. The rabbits were sacrificed on gestation day 29. There were significant differences observed between treated and control animals in the following: increased incidence of minor skeletal defects including retarded ossification of the skeleton and incidence of 27-pre-sacral vertebrae (high-dose group), and increased number of fetuses with extra ribs (high-dose group). There were no significant differences observed between treated and control animals in the following: maternal body weight gain, food consumption, clinical condition, and at autopsy: maternal macroscopic observations, alterations in spleen weights, effects on bone marrows, mean fetal weights, litter parameters, visceral defects, and mean manus and PES scores. [R62] ?Teratogenicity was evaluated in pregnant female Alderley Park (Wistar) rats (24/group) exposed to 2-ethoxyethanol by inhalation at nominal concentrations of 0, 10, 50 or 250 ppm for 6 hrs/day on gestation days (GD) 6-15. The rats were sacrificed on GD 21. There were significant differences observed between treated and control animals in the following: decreased maternal body weight gain (low-dose group), decreased maternal hemoglobin, hematocrit and mean cell volume (high-dose group), decreased mean numbers of implantations and increased pre-implantation losses (low- and mid-dose groups), increased proportion and mean percentage of dams with late intra-uterine deaths (high-dose group), decreased mean number of live fetuses (low- and mid-dose groups), decreased total litter weights (low- and high-dose groups), decreased mean fetal weight (high-dose group), increased mean number of fetuses exhibiting external, visceral and skeletal defects including renal pelvic dilatation, partially ossified frontals, parietals, interparietal and occipital bones, and non-ossified hyoid (high-dose group), non-ossified cervical centra (all treated groups), non-ossified thoracic centra and sternebrae (high-dose group), partially ossified sternebrae (mid- and low dose groups), extra ribs (all treated groups), and sternebral abnormalities (high-dose group). There were no significant differences observed between treated and control animals in the following: food consumption, clinical abnormalities, maternal macroscopic abnormalities, spleen or thymus weights, mean numbers of corpora lutea, post-implantation losses, and fetal sex ratios. [R63, ] ?An acute inhalation toxicity study was conducted with groups of male and female albino Wistar rats (3/sex/group) receiving whole body exposure to the vapors of ethylene glycol monoethyl ether in a dynamic air flow chamber. The vapor was generated in a glass flask containing the test substance maintained at 20 +/- 1 degrees celsius. Maximum exposure was for 7 hours, but if deaths occurred during either the exposure period or observation period, exposures were repeated at shorter intervals. During the 7 hour exposure, no animals died during the exposure, but all the animals died on the first day of the 14 day observation period. Therefore the test was repeated, and two additional test were preformed at exposure times of 1 and 3 hours. No deaths were reported for the 3 and 1 hour group rats during or after exposure. During the 7 hour exposure animals were semi-comatose. Post exposure observations were lethargy (7 and 3 hour group rats), blood in urine (7 and 3 hours), ataxia (7 hour), piloerection (7 hour) and hind leg paresis in females (7 hour). Three hour group rats appeared to recover by day 2 of the observation period and no toxic signs were observed in the 1 hour group rats. The theoretical saturated concentration of ethylene glycol monoethyl ether at 20 degrees celsius was calculated to be 5507ppm and the concentrations by weight loss estimation was calculated to be 5200, 5100 and 5300ppm for the 7, 3 and 1 hour exposure, respectively. [R64] ?Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS, CD, BR) given doses of ethylene glycol monoethyl ether equivalent to 0, 1/2, 1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific information regarding doses was not reported) by oral gavage, 5 days/week for six weeks. The incidence of mortality was unchanged for all groups of rats. Food consumption and body weights were reduced in all treatment groups. There was a reduction in mean hemoglobin concentration, packed cell volume, total erythrocyte count and mean corpuscular hemoglobin concentration in rats from the mid- and high-dose groups. An increase in mean corpuscular volume and a decrease in total number of leukocytes was observed only in rats from the high-dose group. Treatment with the test compound did not affect any of the measured parameters of serum chemistry. Relative testes and liver weights were reduced in all treated rats, and smaller than normal thymuses were observed in two rats from the high-dose group. Bloody urine was observed only in rats from the high-dose group. Testicular atrophy, evidenced by atrophy of seminiferous tubules, degenerated spermatozoa, and hypospermia in the epididymis, was observed at all dose levels. The mid- and high-dose levels produced thymic atrophy, and bone vacuolation was found rats at all dose levels. Treatment (response to specific dose levels was not reported) produced congestion, red pulp hypocellularity and hemosiderin-like pigmentation in spleens of rats. [R65] ?In an absorption study, the permeability of human abdominal skin to 2-ethoxyethanol was measured in vitro using Franz-type glass diffusion cells. Epidermal layers from human skin were exposed for 8 hours to a solution containing radiolabeled test compound in the donor chamber and the appearance of radioactivity was measured in the receptor chamber. Damage to skin was calculated by comparing the water absorption rates of skin before and after exposure to the test compound. The rate of absorption of the test compound across human skin was 0.80 mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin to water. [R66] ?In an absorption study, the permeability of human abdominal skin to 2-ethoxyethanol was measured in vitro using Franz-type glass diffusion cells. Epidermal layers from human skin were exposed for 8 hours to a solution containing radiolabeled test compound in the donor chamber and the appearance of radioactivity was measured in the receptor chamber. Damage to skin was calculated by comparing the water absorption rates of skin before and after exposure to the test compound. The rate of absorption of the test compound across human skin was 0.08 mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin to water. [R67] ?Metabolism of Dowanol EE (ethylene glycol ethyl ether) was evaluated in vitro with an equine liver alcohol dehydrogenase assay obtained from the Sigma Chemical Company. The Vmax, Km, and Vmax/Km were 7.97, 7.12X10E-3, and 1.1, respectively. The authors concluded that alcohol dehydrogenase has a high affinity for the test compound, indicating that the test compound is probably metabolized to a significant extent by this enzyme in vivo. [R68] ?Ethylene glycol monoethyl ether (2-ethoxyethanol, CAS# 110-80-5) was studied for reproductive effects in 50 CD-1 mice when administered by oral gavage for 8 days at 3605 mg/kg/day on gestation days 7 through 14. Observations continued through day 3 postpartum. The dose was selected based on the results of a preliminary maximum tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using dosages of 225, 450, 900, 1800 and 3605 mg/kg administered by oral gavage for 8 days. The reproductive test included a water (vehicle) control group. During or after the dosing period 5 mice died, 3 of which were pregnant. The other 32 pregnant mice all resorbed their fetuses in utero. Therefore, the reproductive index (number of females bearing viable litters per number of pregnant females) was 0.00. No other statistical comparisons with the control group were necessary due to the severe reproductive effect of the chemical which apparently is toxic to all stages of pregnancy after fertilization and implantation. [R69] ?Ethylene glycol monoethyl ether (2-ethoxyethanol, CAS# 110-80-5) was studied for reproductive effects in 50 CD-1 mice when administered by oral gavage for 8 days at 3605 mg/kg/day on gestation days 7 through 14. Observations continued through day 3 postpartum. The dose was selected based on the results of a preliminary maximum tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of 225, 450, 900, 1800 and 3605 mg/kg/day administered by oral gavage for 8 days. The reproductive test included a water (vehicle) control group. During or after the dosing period 5 mice died, 3 of which were pregnant. The other 32 pregnant mice all resorbed their fetuses in utero. Therefore, the reproductive index (number of females bearing viable litters number of pregnant females) was 0.00. No other statistical comparisons with the control group were necessary due to the severe reproductive effect of the chemical which apparently is toxic to all stages of pregnancy after fertilization and implantation. [R70] ?Teratogenicity was evaluated in groups of 6 pregnant CD-1 mice administered ethylene glycol monoethyl ether by oral gavage at doses of 0, 1000, 1800, 2600, 3400, and 4200 mg/kg on days 8-14 of gestation. Surviving animals were sacrificed on gestation day 18. Maternal mortality was observed in 3 mice at 3400 mg/kg and in 3 at 4200 mg/kg. Significant reductions in maternal body weights were observed at 3400 and 4200 mg/kg. Clinical signs of maternal toxicity included vaginal discharge at 1000, 2600, and 4200 mg/kg and lethargy, abnormal breathing, an inability of several animals to right themselves, and an uneven gait at 3400 and 4200 mg/kg. Gross necropsy revealed enlargement of the spleen (1800, 2600, and 4200 mg/kg) and distention of the stomach and intestinal tract (3400 and 4200 mg/kg). Significantly reduced uterine weights and increased total resorptions and resorptions/implantations were observed at 1800 mg/kg and above. Significant reductions in the number of live fetuses/implantations were observed at 3400 and 4200 mg/kg and in the mean number of live fetuses at 4200 mg/kg. Fetal malformations, including cleft palates and encephaly were increased at 1800 and 2600 mg/kg). A dose-related reduction in live fetal body weights was observed at 1000, 1800, 2600, and 3400 mg/kg. [R71] ?2-Ethoxyethanol (CAS# 110-80-5) was evaluated for developmental toxicity. It was administered in 10 pregnant Wistar rats per group at dose levels of 0, 50, and 250 mg/kg/day of the test material on days 7-16 of gestation. A dose related increased incidence of piloerection and slight vaginal bleeding were observed between days 17-19 in some rats in the 250 mg/kg/day group. Decreased body weight gain was statistically significant (p < 0.01) at 50 mg/kg/day or above. During dosing only the 250 mg/kg/day dose group had statistically significantly (p < 0.01) reduced body weights. No litters were produced in any of the treatment groups. Uteri examination showed less developed implantation sites in all rats at the 500 mg/kg/day dose level. It was concluded that 2-ethoxyethanol is a developmental toxicant at 50 mg/kg/day and above. [R72] ?Teratogenicity was evaluated in pregnant Dutch rabbits (23-24/group) exposed by inhalation to 2-ethoxyethanol at nominal concentrations of 0, 10, 50 or 175 ppm for 6hrs/day on gestation days 6-18. The rabbits were sacrificed on gestation day 29. There were significant differences observed between treated and control animals in the following: increased incidence of minor skeletal defects including retarded ossification of the skeleton and incidence of 27-pre-sacral vertebrae (high-dose group), and increased number of fetuses with extra ribs (high-dose group). There were no significant differences observed between treated and control animals in the following: maternal body weight gain, food consumption, clinical condition, and at autopsy: maternal macroscopic observations, alterations in spleen weights, effects on bone marrows, mean fetal weights, litter parameters, visceral defects, and mean manus and PES scores. [R73] ?Teratogenicity was evaluated in pregnant female Alderley Park (Wistar) rats (24/group) exposed to 2-ethoxyethanol by inhalation at nominal concentrations of 0, 10, 50 or 250 ppm for 6 hrs/day on gestation days (GD) 6-15. The rats were sacrificed on GD 21. There were significant differences observed between treated and control animals in the following: decreased maternal body weight gain (low-dose group), decreased maternal hemoglobin, hematocrit and mean cell volume (high-dose group), decreased mean numbers of implantations and increased pre-implantation losses (low- and mid-dose groups), increased proportion and mean percentage of dams with late intra-uterine deaths (high-dose group), decreased mean number of live fetuses (low- and mid-dose groups), decreased total litter weights (low- and high-dose groups), decreased mean fetal weight (high-dose group), increased mean number of fetuses exhibiting external, visceral and skeletal defects including renal pelvic dilatation, partially ossified frontals, parietals, interparietal and occipital bones, and non-ossified hyoid (high-dose group), non-ossified cervical centra (all treated groups), non-ossified thoracic centra and sternebrae (high-dose group), partially ossified sternebrae (mid- and low dose groups), extra ribs (all treated groups), and sternebral abnormalities (high-dose group). There were no significant differences observed between treated and control animals in the following: food consumption, clinical abnormalities, maternal macroscopic abnormalities, spleen or thymus weights, mean numbers of corpora lutea, post-implantation losses, and fetal sex ratios. [R63] ?In a single generation reproduction study, 350 female and 60 male Wistar rats were exposed during a pregestation period (PG) to air (163 rats) or to 2-ethoxyethanol at average daily concentrations of 150 ppm (108 rats) or 649 ppm (107 rats). Animals were exposed for 7 hours per day, 5 days per week for 3 weeks. They were then mated and exposed daily on gestation days GD) 1-19 to air or to 2-ethoxyethanol at concentrations of 202 (low) or 767 (high) ppm. The rats exposed to air were broken down into groups of 32, 26 and 31 and exposed during gestation to air, and low and high levels of test article, respectively. The rats exposed to 150 ppm 2-ethoxyethanol during pregestion were broken down into groups of 37 and 34 rats and exposed during gestation to air or 202 ppm 2-ethoxyethanol, respectively. The rats exposed to the high concentration of test article during pregestation were broken down into groups of 34 and 33 rats and exposed during gestation to air or 767 ppm 2-ethoxyethanol, respectively. Animals were sacrificed and examined on GD 21. Maternal toxicity was indicated by significant differences (ANOVA, Duncan's) between treatments group and controls in the following: food consumption during PG (in group exposed to 649 ppm during PG), body weight during PG (in both groups exposed during PG), and weight gain during GD (in animals exposed to the high dose during both periods). In animals exposed to air or the high dose during PG and the high dose during GD, significant differences (ANOVA, Duncan's) from controls were observed in body weight; and liver, lung, kidney, and spleen weight; placental retention; uterine involution; and changes indicative of corpora lutea regression. Significant differences (Fisher's exact test) were observed in the histopathology of the uterus and ovaries of the two previous groups. The 2 high dose groups also displayed significant changes by Chi-Square in number of live fetuses, number of litters with resorptions, and percent litters with resorptions; and by ANOVA, in number of live fetuses per litter, number of resorptions per litter, and resorptions per litters with resorptions. No significant changes were observed in percent pregnant, number of corpora lutea per dam, number of implants per dam, placenta weight, or sex ratio. There were no surviving fetuses in the dose group exposed to the high concentration during both periods. In the dose group exposed to the low concentration during both periods, significant changes were observed in fetal body weight and crown-rump length (ANOVA, Duncan's). The incidence of minor anomalies and variations was significantly elevated in the low dose groups while no significanct increase was seen in the number of malformations. [R74] ?In a single generation reproduction study, 86 female New Zealand White rabbits, were artificially inseminated and exposed to 2-ethoxyethanol at average daily concentrations of 160 or 617 ppm for 7 hours per day on gestation days (GD) 1-18. Animals were sacrificed and examined on GD 30. Mortality was observed in 5 does in the high-exposure group (p < =0.05, Chi-Square). Significant differences between treatment groups and control groups were observed in the following: food consumption, weight gain, mean maternal kidney or liver weights, number of live fetuses per litter, number of resorptions per litter and number of resorptions per litter with resorptions by the ANOVA (analysis of variance) test; involution/retention of placental tissue, and corpora lutea regression (p < 0.05) by the Fisher's Exact test; and total live fetuses, number of litters with resorptions, and percent litters with resorptions (p < =0.05) by the Chi Square test. Significant differences between treatment groups and controls were not observed in fertility rate, number of corpora lutea per doe, number of implants per doe, and number of implants per corpora lutea. No living fetuses were observed in the high dose group. Significant increases in the incidence of major malformations, minor anomalies, and common skeletal variants were seen in the low dose group (p < =0.05, Chi-Square). [R74] ?Developmental toxicity was evaluated in groups of pregnant rats exposed to ethylene glycol monoethyl ether at vapor concentrations of 0, 10, 50, or 250 ppm. Although fetotoxicity was observed in the mid- and high-dose groups, the compound was non-teratogenic. The document summarized this study, and no further information was available regarding experimental methods or results. [R75] ?Developmental toxicity was evaluated in groups of pregnant rabbits exposed to ethylene glycol monoethyl ether at vapor concentrations of 0, 10, 50, or 175 ppm. The high dose was "considered a marginal effect level for teratogenicity". The document summarized this study, and no further information was available regarding experimental methods or results. [R75] ?2-Ethoxyethanol (CAS No. 110-80-5) was tested for reproductive toxicity. The test substance was administered by inhalation at a concentration of 300 ppm for 3-4 hours to 5 male Wistar-derived rats. The animals were observed for 14 days and then sacrificed and subjected to gross macroscopic examination. Hematuria and testicular atrophy was observed; there was a 20% reduction in testis weight when compared to controls. [R76] ?2-Ethoxyethanol (CAS# 110-80-5) was evaluated for developmental toxicity. It was administered in groups of 24 Alderley Park rats exposed to 0, 10, 50, 250 ppm of the test material for 6 hours per day on days 6-15 of gestation. There were no effects on maternal body weight, and food consumption at 10 ppm or above. At autopsy on day 21 of gestation no treatment-related gross maternal abnormalities were observed. Maternal toxicity occurred at 250 ppm in the form of slight hematological changes (statistically significant (p < 0.05) reductions in hemoglobin, hematocrit, and mean cell volume). There were no differences in the mean number of corpora lutea, but the mean numbers of implantations were statistically significantly (p < 0.05) lower at 10 ppm or above. Statistically significant (p < 0.05) increased incidence of intra-uterine deaths, reduced fetal weights, and reduced fetal ossification observed at 250 ppm were indicative of fetotoxicity, but no evidence of teratogenicity was observed. Some evidence of reduced ossification was observed at 50 ppm. It was concluded that 2-ethoxyethanol was not teratogenic at 250 ppm or lower, but it was fetotoxic at 250 ppm and possibly at 50 ppm. No toxicologically significant effects were observed at 10 ppm. [R77] ?Ethoxyethanol (CAS# 100-80-5) was evaluated for reproductive toxicity in 82, 95, and 96 female Wistar rats exposed by inhalation to 0, 150-202 (low dose range), and 649-767 (high dose range) ppm of the test material respectively for 7 hours per day, 5 days per week for 3 weeks. They were then mated and exposed daily through the 19th day of gestation. The rats were killed and examined at the 21st day of gestation. No significant differences were observed in food consumption. The weight gain was significantly depressed at 649-767 ppm. No treatment-related histological changes were observed. Induction of 100% resorptions was associated with the high treatment dose group. The mean number of resorptions per litter at 649-767, and 150-202 ppm were about 24 times, and 2 times the control value respectively. At 150-202 ppm, an approximate 25% reduction in body weight and 10% reduction of the crown-rump length was observed. There was no difference in placental weight or sex ratios of treated groups in comparison with controls. At 150-220 ppm a significant increase in minor skeletal anomalies (rib dysmorphology) and common skeletal variants (extra supernumerary ribs and vertebrae, reduced skeletal ossification). It was concluded that exposure to 649-767 ppm significantly increased the incidence of maternal toxicity as evidenced by reduced body weight and embryomortality and exposure to 150-202 ppm induced intrauterine growth retardation, minor anomalies and common skeletal variants. [R78] ?Ethoxyethanol (CAS# 100-80-5) was evaluated for developmental toxicity in 24, 23, and 22 New Zealand white rabbits artificially inseminated and exposed for 7 hours daily to 0, 160, and 617 ppm of the test material respectively until the 18th day of gestation. Anorexia was noted in both treatment groups during the exposure period. The mean net weight gain was decreased at 617 ppm (not indicated if statistically significant). Mean maternal liver weights (absolute and relative) at 160 ppm or above were significantly higher than controls. The most striking evidence of embryotoxicity was that the uteri of all 617 ppm dose group contained only early resorptions. This incidence of embryomortality was significantly different from the other groups. No fetuses survived at 617 ppm. At 160 ppm the mean number of resorptions per litter was about 6 times that of the controls. There was no evidence of severe intrauterine growth retardation at 160 ppm. Significant increases in the incidence of major malformations (ventral wall defects and fusion of aorta with pulmonary artery), minor anomalies (renal changes), and common skeletal variants (supernumerary ribs associated vertebral variations and sternebral defects) were seen in the 160 ppm dose group compared to controls. Ethoxyethanol caused maternal toxicity, embryotoxicity, and teratogenicity in rabbits at 160 ppm. [R78] ?2-Ethoxyethanol (CAS# 110-80-5) was evaluated for developmental toxicity. Five pregnant Dutch rabbits per group were exposed to 0, 50, 150 or 400 ppm of ethylene glycol monoethyl ether for 6 hours/day on gestational days 6-18. Maternal toxicity was observed at 400 ppm as indicated by markedly reduced body weight gain and food consumption even, though these observations when compared to controls were not statistically different. At 400 ppm the mean number of implantations, live fetuses, gravid uterus weight and litter weight were statistically lower (p < 0.05) than controls. The mean percentage of post-implantation loss and percentage of early and late deaths were statistically higher (p < 0.05) at 400 ppm than controls. Statistically significant (p < 0.05) reductions in the group mean number of implantations and number of live fetuses were observed at 50 ppm or above. Evidence of fetotoxicity included increased intra-uterine deaths and reduced fetal weights at 400 ppm and increased implantation losses at 50 ppm or above. No evidence of teratogenicity was observed at any treatment level. [R79] TCAT: ?2-Ethoxyethanol (CAS# 110-80-5) was evaluated for developmental toxicity. It was administered in 5 pregnant Dutch rabbits per group exposed to 0, 50, 150 or 400 ppm of the test material for 6 hours/day on gestational days 6-18. Maternal toxicity was observed at 400 ppm as indicated by markedly reduced body weight gain and food consumption. At 400 ppm the mean number of implantations, live fetuses, gravid uterus weight and litter weight were statistically lower (p < 0.05) than controls. The mean percentage of post-implantation loss and percentage of early and late deaths were statistically higher (p < 0.05) at 400 ppm. Statistically significant (p < 0.05) reductions in the group mean number of implantations and number of live fetuses were observed at 50 ppm or above. Evidence of fetotoxicity included increased intra-uterine deaths and reduced fetal weights at 400 ppm and increased implantation losses at 50 ppm or above. No evidence of teratogenicity was observed at any treatment level. [R80] ADE: *FEW DETAILS OF FATE IN BODY OF CELLOSOLVE ARE AVAILABLE, BUT ... GLYCOL ETHERS OF LOW MOL WT UNDERGO A LIMITED AMT OF DESTRUCTION AND DO NOT APPEAR TO BE DISTRIBUTED IN THE EXTRACELLULAR FLUIDS OF THE BODY ... /GLYCOL ETHERS/ [R11, 602] *... THEY ARE CLEARED FROM THE PLASMA AT A RATE IDENTICAL WITH THAT OF CREATININE IN THE NORMAL LIGHTLY ANESTHETIZED ANIMALS. /GLYCOL ETHERS/ [R11, 602] *STUDIES TO EVALUATE THE RATE OF ITS ELIMINATION WERE CONDUCTED IN RATS USING A PRIMING DOSE OF 140 MG/KG IV FOLLOWED BY THE INFUSION INITIALLY OF 8, THEN OF 16 MG/KG/MIN. UNDER THESE CONDITIONS IT WAS FOUND THAT THIS PRODUCT WAS EXCRETED VIA THE LUNG AT A RATE OF SLIGHTLY MORE THAN 8 MG/KG/MIN UNCHANGED. [R19, 3925] *... ONCE ABSORBED INTO BODY, ESTERS ARE SAPONIFIED AND SYSTEMIC EFFECT IS QUITE TYPICAL OF PARENT GLYCOL OR GLYCOL ETHER. /ETHER-ESTERS OF GLYCOLS/ [R19, 4010] *The levels measured in this survey ranged from nondetectable to 23.8 ppm (for an 8 hr time-weighted average), and a biomonitoring effort was undertaken to determine if metabolites of the chemical could be detected in the urine of exposed workers or if the parent compound be detected in their blood. No evidence of 2-ethoxyethanol was detected in any of the blood samples; however, exposed workers had measurable levels of 2-ethoxyacetic acid in urine (up to 163 mg/g creatinine), while unexposed control subjects showed nondetectable urine levels of this compound. Urinary monitoring is a method for assessing exposure to 2-ethoxyethanol, particularly when skin absorption is suspected. [R81] METB: *The urinary excretion of ethoxyacetic acid was studied in a group of five women daily exposed to the ethyl ether of ethylene glycol and the ethyl ether of ethylene glycol acetate during 5 days of normal production and 7 days after a 12 day production stop. The mean combined exposure concentration of ethylene ether of ethylene and ethylene glycol ethyl ether acetate (expressed in equivalent weight of ethyl ether of ethylene glycol was 14.0 mg/cu m with occasional slight excursions above the current Belgian occupational exposure limit. The daily combined exposure profiles for ethylene glycol ethyl ether and ethylene glycol ethyl ether acetate were rather constant during the first observation period, but they tended to decrease during the last week. The urinary ethoxyacetic acid excretion clearly increased during the work week. Over the weekends the elimination was far from complete, and even after a prolonged nonexposure period of 12 day of traces of the metabolite were still detectable. Based on the observations from the first period, a good linear correlation was found between the average exposure over 5 days (14.4 mg/cu m) and the ethoxyacetic acid excretion at the end of the week (105.7 mg/g creatinine). An ethoxyacetic acid estimate of 150 + or - 35 mg/g was found to correspond with repeated 5 days full-shift exposures to the respective occupational exposure limit of ethylene glycol ethyl ether (19 mg/cu m) or ethylene glycol ethyl ether acetate (27 mg/cu m). [R82] *Male rats were given a single oral dose of ethylene glycol monoethyl ether, the dose ranging from plausible human exposures (0.5-1 mg/kg) to doses reported in the literature (100 mg/kg). Urinary excretion of ethoxyacetic acid and its glycine conjugate was followed up to 60 hr after dosing and compared to data of experimentally exposed human volunteers. In rats, the mean elimination half-life of free as well as conjugated ethoxyacetic acid was 7.2 hr for all doses. Ethoxyacetic acid was excreted partly as a glycine conjugate (on average 27%), the extent of conjugation being independent of the dose. The relative amount of ethylene glycol monoethyl ether recovered in urine as ethoxyacetic acid was only 13.4% for the lowest dose, but increased as the administered dose of ethylene-glycol-monoethyl-ether was higher, indicating that ethylene glycol monoethyl ether was metabolised at least in two parallel pathways of which one pathway becomes saturated at relatively low doses. In man, urinary excretion of ethoxyacetic acid for equivalent low doses of ethylene glycol monoethyl ether differed from that in the rat by a longer elimination half-life (mean 42 hr), by the absence of ethoxyacetic acid conjugates and by a higher recovery. [R83] *Ten healthy male subjects were exposed to ethylene glycol monoethyl ether and their urinary excretion of ethoxyacetic acid was followed up for 42 hours. Maximal excretion of ethoxyacetic acid was reached three to four hours after the end of the four exposure period. Afterwards, ethoxyacetic acid excretion declined slowly with a biological half-life of 21-24 hours. Ethoxyacetic acid excretion increased as the uptake of ethylene glycol monoethyl ether increased as a consequence of higher exposure concentration or pulmonary ventilation rate during physical exercise. On average, 23.1% of ethylene glycol monoethyl ether was recovered as ethoxyacetic acid within 42 hours. Quantitative relations between ethoxyacetic acid excretion and ethylene glycol monoethyl ether uptake were obtained. [R84] */A group of/ 17 persons who were exposed to glycolethers in a varnish production plant, were examined according to their external and internal solvent exposure. The workers in the production plant (n= 12) were exposed to average concentrations of ethoxyethanol, ethoxyethyl acetate, butoxyethanol, 1-methoxypropanol-2, 2-methoxypropyl-1-acetate and xylene of 2.8; 2.7; 1.1; 7.0; 2.8 and 1.7 ppm. Internal exposure was estimated by measuring butoxyethanol in blood as well as ethoxyacetic acid and butoxyacetic acid in urine samples. As expected, the highest values were found in the varnish production. The average post shift concentrations of butoxyethanol, ethoxyacetic acid and butoxyacetic acid were 121.3 ug/l; 167.8 and 10.5 mg/l. The relatively high concentrations of ethoxyacetic acid and butoxyacetic acid in pre-shift samples can be explained by the long half-lives of these metabolites. Most of the glycolethers were taken up through the skin. The authors think that a future tolerable limit value for the concentration of ethoxyacetic acid in urine should be in the order of 100 to 200 mg/l. [R85] *A study was conducted using 19 employees of four silk screen printing installations, to investigate the usefulness of alkoxyacetic acids in urine as biological indicators of occupational exposure to ethylene glycol ethers. Individual exposures to ethylene glycol ethers were measured by personal air sampling during 1 workday and biological monitoring of urine from these employees. All ethylene glycol ethers air levels were well below the Swedish and American Conference of Governmental Industrial Hygienists threshold limit values. Ethylene glycol monoethyl ether acetate at an average concentration of 5.0 mg/cu m and ethylene glycol monobutyl ether acetate at an average concentration of 2.9 mg/cu m were found in air samples from eight and five subjects, respectively; no ethylene glycol monomethyl ether acetate was found in any air samples. Average urinary levels of methoxyacetic acid, ethoxyacetic acid, and butoxyacetic acid were 6, 80, and 8 micromolar, respectively. [R86] BHL: *Monitoring of the urinary excretion of the alkoxyacetic acid metabolites may be a useful indicator of human exposure to ethylene glycol ethers. In 10 male workers exposed to ethylene glycol monoethyl ether, the maximal urinary excretion of ethoxyacetic acid occurred in 3-4 hours and the urine biological half-life was 21-24 hours. [R87] ACTN: *The toxicity of ethylene glycol monomethyl ether and ethylene glycol monoethyl ether are due to their metabolites, methoxyacetic acid and ethoxyacetic acid, and that these metabolites may exert their effects, in part, on mitochondrial function. [R88] *Ethylene glycol ethers and their acetate derivatives were analyzed for their toxicity in vitro on several hemopoietic cell lines, either growth-factor-dependent or leukemia, in mouse, rat, and human species. Considering the concentrations that reduced the cell viability in culture by 50%, most of the ethylene glycol ethers and in particular ethylene glycol monoethyl ether) or ethylene glycol monobutyl ether should be considered as hemopoietic toxins. Ethylene glycol monomethyl ether was found to be the most potent toxic on the human promyelocytic cell line, NB4 (median inhibitory concentration (IC50) 5 mM at 6 hr; IC50 0.1 mM at 96 hr) but also on the factor-dependent cell line DAl (IC50 80 uM at 48 hr. Factor-dependent cell lines were not significantly more sensitive than leukemic cell lines. The toxicity of these compounds falls in the same range of concentration as benzene or phenol, but hydroquinone was significantly more toxic in the same assay (IC50 3-15 uM at 48 hr). Toxic effects increased linearly with time. The toxicity of ethylene glycol ethers was confirmed by both assays for colony-forming units in culture medium (CFU-C) (human blood cord cells) and murine bone marrow long-term culture (IC50 5-10 mM). Stromal cells in the adherent layer were more resistant than hemopoietic cells. An all or none toxicity was found within a narrow range of concentration l2-5 mM for ethylene glycol monoethylene ether), and chronic exposure over two months did not show cumulative effects on the culture cellularity. The possibility that fibroblastic or macrophage cells worked at the detoxification of the culture is suggested. Results are discussed with regard to epidemiological and in vivo experimental data presently available. [R89] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethylene glycol monoethyl ether's production and use as a solvent may result in its release to the environment through various waste streams. It has been detected in river water, compost exhaust, indoor air, and as a volatile component of fried bacon, beef, pork, and several household products. If released to soil, ethylene glycol monoethyl ether will have very high mobility based on an estimated Koc value of 16. Volatilization of ethylene glycol monoethyl ether should not be important from moist soil surfaces given an estimated Henry's Law constant of 1X10-8 atm-cu m/mole. Volatilization from dry soil surfaces is expected based on an experimental vapor pressure of 5.31 mm Hg. According to several biodegradation studies, biodegradation of ethylene glycol monoethyl ether should occur rapidly in soil and water. If released to water, ethylene glycol monoethyl ether is not expected to adsorb to suspended solids and sediment based on an estimated Koc value of 16. Ethylene glycol monoethyl ether will be essentially non-volatile from water surfaces based on an estimated Henry's Law constant of 1X10-8 atm-cu m/mole. An estimated BCF value of 0.34 suggests that bioconcentration in aquatic organisms is low. If released to the atmosphere, ethylene glycol monoethyl ether, which has an experimental vapor pressure of 5.31 mm Hg, will exist solely as a vapor in the ambient atmosphere. Vapor-phase ethylene glycol monoethyl ether is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 32 hours. The half-lives observed for the reaction of ethylene glycol monoethyl ether with nitrogen dioxides were 9.8 and > 7.5 hr. The general population will be exposed to ethylene glycol monoethyl ether via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with vapors, food and other products containing ethylene glycol monoethyl ether. Occupational exposure may be through inhalation and dermal contact with this compound. (SRC) ARTS: *Ethylene glycol monoethyl ether's production and use as a solvent for nitrocellulose, lacquers and dopes, increment stability of emulsions, in varnish removers, cleansing solutions, dye baths, finishing leather with water pigments and dye solution(1) may result in its release to the environment through various waste streams(SRC). [R90] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 16(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that ethylene glycol monoethyl ether will have very high mobility in soil(SRC). Volatilization of ethylene glycol monoethyl ether is not expected to be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 1X10-8 atm-cu m/mole(SRC), using a recommended regression equation(4). Volatilization from dry soil surfaces(SRC) is expected based on an experimental vapor pressure of 5.31 mm Hg(5). According to several biodegradation studies(6-11), biodegradation of ethylene glycol monoethyl ether may occur rapidly in soil(SRC). [R91] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 16(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(1), indicates that ethylene glycol monoethyl ether is not expected to adsorb to suspended solids and sediment in the water(SRC). Ethylene glycol monoethyl ether will be essentially non-volatile from water surfaces(1,SRC) based on an estimated Henry's Law constant of 1X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). According to a classification scheme(4), an estimated BCF value of 0.34(1,SRC), from an experimental log Kow(2), suggests that bioconcentration in aquatic organisms is low(SRC). According to several biodegradation studies(5-10), biodegradation of ethylene glycol monoethyl ether may occur rapidly in water(SRC). [R92] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethylene glycol monoethyl ether, which has an experimental vapor pressure of 5.31 mm Hg at 25 deg C(2), will exist solely as a vapor in the ambient atmosphere. Vapor-phase ethylene glycol monoethyl ether is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 32 hours(3,SRC). The half-lives observed for the reaction of ethylene glycol monoethyl ether with nitrogen dioxides were 9.8 and > 7.5 hr(4). [R93] BIOD: *Incubation of ethylene glycol monoethyl ether in with effluent from a biological sanitary waste treatment plant at 20 deg C for 5 days resulted in a biological oxygen demand (BOD) 65% of the theoretical oxygen demand (ThOD) when the seeding was adapted and 53% of ThOD when unadapted(1). Five day, 20 deg C ThOD values of 7.6% and 54.3% were observed for ethylene glycol monoethyl ether upon incubation with sewage seed and acclimated activated sludge seed, respectively(2). Upon incubation of 5-10 ppm ethylene glycol monoethyl ether with activated sludge for 5 days at 20 deg C, 81% of the theoretical BOD was achieved(3). After 5 days incubation of 50 mg/l ethylene glycol monoethyl ether in a Warburg respirometer at 20 deg C with acclimated activated sludge 54% of the theoretical BOD was achieved(4). Ethanol and acetate ions were the products of the incubation of ethylene glycol monobutyl ether with Pelobactor venetianus sp nov, a strict anaerobe of marine and limnic orgin(5). Ethoxyacetic acid was obtained from a culture of the soil bacterium, Alcaligenes MC11, supplemented with ethylene glycol monoethyl ether(6). [R94] *A two week biodegradation study using 30 mg/l sludge and a ethylene glycol monoethyl ether concentration of 100 mg/l gave 63-83% theoretical BOD(1). In pilot-scale activated sludge systems, ethylene glycol monoethyl ether reduced from 2284 mg/l in the feed to 18 mg/l in the effluent(ethylene glycol monoethyl ether 2). No ethylene glycol monoethyl ether was detected in the off-gas or waste mixed liquor samples(2). [R95] ABIO: *When ethylene glycol monoethyl ether was mixed with nitrogen dioxides at 20:1 and 2:1 (ethylene glycol monoethyl ether:nitrogen dioxides) in a 440L glass-Teflon smog chamber at relative humidities of 30-60% and 25 deg C, the half-lives observed were 9.8 and > 7.5 hr, respectively(1). A half-life for the reaction of hydroxyl radicals with ethylene glycol monoethyl ether in water at pH 9 of about 2.2 yr was obtained from a rate constant of 1.0X10+9 L/mol sec and a hydroxyl radical concentration in water of 1X10-17 M(2). The rate constant for the vapor-phase reaction of ethylene glycol monoethyl ether with photochemically produced hydroxyl radicals has been experimentally determined to be 1.2X10-11 cu cm/molecule-sec at 25 deg C(3). This corresponds to an atmospheric half-life of about 32 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(3,SRC). [R96] BIOC: *An estimated BCF value of 0.34 was calculated for ethylene glycol monoethyl ether(SRC), using an experimental log Kow of -0.32(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R97] KOC: *The Koc of ethylene glycol monoethyl ether is estimated as approximately 16(SRC), using an experimental log Kow of - 0.32(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that ethylene glycol monoethyl ether has very high mobility in soil(SRC). [R98] VWS: *The Henry's Law constant for ethylene glycol monoethyl ether is estimated as 1X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that ethylene glycol monoethyl ether will be essentially nonvolatile from water surfaces(2,SRC). Ethylene glycol monoethyl ether's experimental values for vapor pressure, 5.31 mm Hg(3), indicates that volatilization from dry soil surfaces may occur(SRC). However, ethylene glycol monoethyl ether's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces should not occur(SRC). [R99] WATC: *Ethylene glycol monoethyl ether was detected in the Hayashida River water (Japan) - 250-1200 ppb(1). [R100] EFFL: *Ethylene glycol monoethyl ether was detected in active compost blower exhaust at 9 ug/cu m(1). [R101] ATMC: *INDOOR AIR: Ethylene glycol monoethyl ether was detected in residential indoor air at three different sites at 6, 60, and 10 ug/cu m(1). [R102] FOOD: *Ethylene glycol monoethyl ether has been qualitatively detected as a volatile flavor component in fried bacon(1), beef(2), and pork(2). [R103] OEVC: *Ethylene glycol monoethyl ether has been identified in the headspace of liquid wax for marble, ceramic, linoleum, plastic, and varnished wood floors(1). [R104] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 233,418 workers (64,967 of these are female) are potentially exposed to ethylene glycol monoethyl ether in the USA(1). Ethylene glycol monoethyl ether was identified in the air of an industrial plant at geometric mean concentrations of 2.4-16.9 ppm (full-time weighted average area samples) for April and June 1984(2). Personal air samples also contained ethylene glycol monoethyl ether at geometric mean concentrations of 3.0-14.5 ppm (full-time weighted average personal samples) for April and June 1984(2). The mean concentration of ethylene glycol monoethyl ether in the air of a Finnish furniture factory during 1975-84 was 7 ppm(3). In a manufacturing plant, personal and area monitoring were ND-0.6 ppm and 0.5-1.5 ppm ethylene glycol monoethyl ether (EGM), respectively(4). Ethylene glycol monoethyl ether was 0.6, 1.1, and 1.5 ppm in the areas MICC (undefined), switchbank and lab sink(4). No ethylene glycol monoethyl ether was detected in personal monitoring samples collected in the drumming areas(4). [R105] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +500 ppm [R25, 130] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 200 ppm (740 mg/cu m). Skin Designation. [R106] NREC: *NIOSH recommends reducing exposure to lowest feasible concn and preventing contact with the skin. /Glycol ethers/ [R107] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.5 ppm (1.8 mg/cu m), skin. [R25, 130] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm, skin. [R108, 2002.31] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R108, 2002.6] +Biological Exposure Index (BEI): Determinant: 2-ethoxyacetic acid in urine; Sampling Time: end of shift at end of workweek; BEI: 100 mg/g creatinine. [R108, 2002.90] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethylene glycol monoethyl ether is produced, as an intermediate or final product, by process units covered under this subpart. [R109] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 25,000 ug/l [R110] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R111] TSCA: *Multi-Substances Rule for the Testing of Neurotoxicity: EPA issued a final rule, under Section 4 of the Toxic Substances Control Act (TSCA), requiring manufacturers and processors of 2-ethoxyethanol to conduct testing for neurotoxicity. ... /This cmpd/ is a volatile solvent with a high production volume, occupational exposure, present in and/or released to the environment. ... This rule requires cognitive function and screening level tests for neurotoxicity. [R112] RCRA: *U359; As stipulated in 40 CFR 261.33, when ethylene glycol monoethyl ether, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R113] *F005; When 2-ethoxyethanol is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F005), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R114] FDA: *Certification of this color additive when used as a ink for making food supplements in tablet form; gum, and confectionary (without leaving a residue) is not necessary for the protection of the public health and therefore batches thereof are exempt from the requirements of section 706(c) of the Federal Food, Drug, and Cosmetic Act. [R115] *Ethylene glycol monoethyl ether is an indirect food additive for use only as a component of adhesives. [R116] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1403. Analyte: Alcohols. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 0.05 l/min. Sample Size: 1 to 10 liters. Shipment: Routine. Sample Stability: Store in freezer, analyze as soon as possible. /Alcohols/ [R7] ALAB: *NIOSH Method 1403. Analyte: Alcohols. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. For 2-ethoxyethanol, this method has an estimated detection limit of 0.01 to 0.02 mg/6 liters. The precision/RSD is 0.059 and the recovery is 107%. Applicability: This method is used to determine two or more analytes simultaneously by varying GC conditions. [R117] CLAB: *A procedure for measurement of 2-ethoxyacetic acid, a metabolite of 2-ethoxyethanol, has been validated. The analytical range for 2-ethoxyacetic acid is 5 to 100 ug/ml of urine; the limit of detection is 4 ug/ml, while the limit of quantitation is 7 ug/ml. The day-to-day relative standard deviation was better than 4.7%; the corresponding within-day standard deviation was less than 2.0%. The procedure was applied to urine-specimens collected from shipyard workers exposed to paints containing 2-ethoxyethanol. [R118] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Johanson G; Aspects of biological monitoring of exposure to glycol ethers; Toxicol Lett 43 (1-3): 5-21 (1988) Paustenback DJ, Assessment of the development risks resulting from occupational exposure to select glycol ethers within the semi-conductor industry; J Toxicol Environ Health 23 (1): 29-75 (1988) Kay GF et al; Solvent Toxicology, Annual Review of Pharmacology and Toxicology 27: 399-427 (1987). Miller RR; Metabolism and Disposition of Glycol Ethers; Drug Metab Rev 18 (1): (1987). Hardin BD, Lyon JP; Environmental Health Perspectives 57: 273-5 (1984) DHHS/NTP; NTP Technical Report on Toxicity Studies of Ethylene Glycol Ethers 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 26 NIH Publication No. 93-3349 (1993) Hotz P; Occupational hydrocarbon exposure and chronic nephropathy; Toxicology 90 (3): 168-283 (1994). This review aims at discussing the questions raised by the hydrocarbon-related chronic nephropathy and its possible consequence, the hydrocarbon-related chronic renal failure. SO: R1: SRI R2: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 489 R4: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 583 R5: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 420 R6: Ash, M. and I. Ash. Encyclopedia of Industrial Chemical Additives. Vols 1, II, III. New York, NY: Chemical Publishing Co., Inc., 1984-1985.,p. V3 210 R7: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1403-1 R8: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 592 R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 130 R10: Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991. R11: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R12: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-159 R13: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 944 (1980) R14: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 1325 R15: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 944 (1980) R16: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 10 R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-297 R18: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R19: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R20: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 21 (1983) 389 R21: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-127 R22: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-51 R23: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 473 R24: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 657 R25: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R26: Sax, N.I. Dangerous Properties of Industrial Materials 3rd. ed. New York: Van Nostrand Reinhold Co., 1968. 450 R27: 49 CFR 171.2 (7/1/96) R28: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 148 R29: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3134 (1988) R30: 40 CFR 240-280, 300-306, 702-799 (7/1/90) R31: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-7 (1981) EPA 68-03-3025 R32: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 175 R33: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-152 (1982) R34: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 301 R35: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R36: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. R37: Welch LS et al; Am J Ind Med 14 (5): 509-26 (1988) R38: Ratcliffe JM et al; Br J Ind Med 46 (6): 399-406 (1989) R39: Welch LS, Cullen MR; Am J Ind Med 14 (5): 527-36 (1988) R40: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R41: S''ohnlein B et al; Int Arch Occup Environ Health 64 (7): 479-84 (1993) R42: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 412 R43: BRIDIE AL ET AL; WATER RES 13 (7): 623-6 (1979) R44: HARDIN BD ET AL; SCAND J WORK ENVIRON HEALTH 7 (SUPPL 4): 66-75 (1981) R45: FOSTER PM ET AL; TOXICOL APPL PHARMACOL 69 (3): 385-99 (1983) R46: HARDIN BD ET AL; DRUG CHEM TOXICOL 5 (3): 277-94 (1982) R47: NELSON BK ET AL; NEUROTOXICOLOGY (PARK FOREST SOUTH, ILL) 2 (2): 231-49 (1981) R48: Johnson EM et al; Environ Health Perspect 57: 135-9 (1984) R49: Nagano K et al; Environ Health Perspect 57: 75-84 (1984) R50: Doe JE; Environ Health Perspect 57: 199-206 (1984) R51: Hardin BD et al; Environ Health Perspect 57: 69-74 (1984) R52: Hobson DW et al; Fundam Appl Toxicol 6 (2): 339-48 (1986) R53: Tyl RW et al; Fundam Appl Toxicol 10 (1): 20-39 (1988) R54: Wier PJ et al; Teratogenesis Carcinog Mutagen 7 (1): 55-64 (1987) R55: Beattie PJ, Brabec MJ; J Biochem Toxicol 1 (3): 61-70 (1986) R56: Chapin RE et al; Fundam Appl Toxicol 5 (1): 182-9 (1985) R57: Dieter MP et al; Cancer Chemother Pharmacol 26 (3): 173-80 (1990) R58: Loch-Caruso R et al; Environ Health Perspect 57: 119-23 (1984) R59: Arena, J.M. and Drew, R.H. (eds.) Poisoning-Toxicology, Symptoms, Treatments. 5th ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 237 R60: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 649 R61: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Ethylene Glycol Monoethyl Ether (CAS No. 110-80-5): Reproduction and Fertility Assessment in CD-1 Mice When Administered in Water, NTP Study No. RACB84050 (September 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R62: Imperial Chemical Industries PLC; Ethylene Gylcol Monoethyl Ether (EE): Inhalation Teratogenicity Study in Rabbits. (1983), EPA Document No. FYI-AX-0683-0178, Fiche No. 0000178-1 R63: Imperial Chemical Industries; Ethylene Glycol Monoethyl Ether (EE): Teratogenicity Study in Rats. (1983), EPA Document No. FYI-AX-0683-0178, Fiche No. 0000178-1 R64: Shell Toxicology Laboratory (Tunstall); Test Standardization: Inhalation Toxicity testing of 8 Chemical According to the OECD Inhalation Hazard Test, (1982), EPA Document No. 878212113, Fiche No. OTS0205969 R65: Eastman Kodak Company; Comparative Toxicology of Nine Glycol Ethers: III. Six Weeks Repeated Dose Study, (1966), EPA Document No. 86-890000206, Fiche No. OTS0516743 R66: Central Toxicology Lab; 2-butylethanol, 2-ethoxyethanol, 2-ethoxyethyl acetate, 2-methoxyethanol, and 1-methoxypropan-2-ol: Absorption Through Human Skin In Vitro, (1982), EPA Document No. 86-890000943; Fiche No. OTS0520381 R67: Central Toxicology Lab; Glycol ethers (2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol, 2-ethoxyethyl acetate, and 1-methoxypropan-2-ol: Relationships Between Human Skin Absorption and Inhaled Doses, (1982), EPA Document No. 86-890000944; Fiche No. OTS0520382 R68: Dow Chemical Company; In Vitro Studies to Evaluate Glycol Ethers as Substrates for Alcohol Dehydrogenase, (1982), EPA Document No. 86-890001231S, Fiche No. OTS0520741 R69: Bioassay Systems Corporation; Determination of the Reproductive Effects in Mice of Nine Selected Chemicals (1983), EPA Document No. FYI-OTS-0483-0240, Fiche No. OTS0000240-0 R70: Bioassay Systems Corporation; Determination of the Reproductive Effects in Mice of Nine Selected Chemicals (1983), EPA Document No. 40-8336210, Fiche No. OTS0506158 R71: Exxon Chem Co; Teratology Probe Study I and II in Mice and Reproduction Study in Mice, (1985), EPA Doc. No. 89-890000248, Fiche No. OTS0516782 R72: ICI AMERS INC; Triethylene glycol ethers: An evaluation of teratogenic potential and developmental toxicity using an in vivo screen in rats; 4/25/86, EPA 88-920006724, Fiche No. OTS0545262 R73: Imperial Chemical Industries PLC; Ethylene Glycol Monoethyl Ether (EE): Inhalation Teratogenicity Study in Rabbits. (1983), EPA Document No. FYI-AX-0683-0178, Fiche No. 0000178-1 R74: Battelle Pacific Northwest Laboratories; Teratologic Assessment of Ethylbenzene and 2-Ethoxyethanol with Cover Letter Dated 061887, (1981), EPA Document No. 86870000402, Fiche No. OTS0513150 R75: Chemical Manufacturers Association; Glycol Ethers Program Panel Research Status Report, (1983), EPA Document No. 86-890001473S, Fiche No. OTS0521087 R76: CENTRAL TOXICOL LAB; Further Studies on the Toxicology of the Glycol Ethers with Emphasis on Rapid Screening and Hazard Assessment with Attachment and Cover Sheet Dated 061289; 06/15/89; Document No. 86-890000732; Fiche No. OTS0521237 R77: SHELL OIL CO; Teratogenicity study of ethylene glycol monoethyl ether in rats; 4/01/83, EPA 88-920003441, Fiche No. OTS0537400 R78: SHELL OIL CO; Teratogenic assessment of ethylbenzene and 2-ethoxyethanol; EPA 88-920002072, 1/01/81, Fiche No. OTS0539167 R79: SHELL OIL CO; Ethylene glycol monoethyl ether: Probe teratogenicity study in rabbits; 2/08/83, EPA 88-920003410, Fiche No. OTS0540061 R80: ICI AMERS INC; Probe teratogenicity study with ethylene glycol monoethyl ether acetate in rabbits; 1/26/83, EPA 88-920006504, Fiche No. OTS0545103 R81: Chester A et al; Teratol 33 (3): 57C (1986) R82: Veulemans H et al; Scand J Work Environ Health 13 (3): 239-42 (1987) R83: Groeseneken D et al; Toxicol Lett 41 (1): 57-68 (1988) R84: Groeseneken D et al; Br J Ind Med 43 (9): 615-9 (1986) R85: Angerer J et al; Int Arch Occup Environ Health 62 (2): 123-6 (1990) R86: Johanson G et al; Archives of Toxicol Suppl 13: 108-111 (1989) R87: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 811 R88: Beattie PJ, Brabec MJ; J Biohem Toxicol 1 (3): 61-70 (1986) R89: Ruchaud S et al; Leukemia (Basingstoke) 6 (4): 328-34 (1992) R90: (1) Budavari S; The Merck Index - Encyclopedia of Chemicals, Drugs, and Biologicals. Rahway, NJ: Merck and Co Inc pg 592 (1989) R91: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR consult. ed., Washington, DC: Amer Chem Soc pg 10 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) (6) Bridie AL et al; Water Res 13: 627-30 (1979) (7) Bogan RH, Sawyer CN; Sewage Ind Waste 27: 917-28 (1955) (8) Heukelekian H, Rand MC; J Water Pollut Control Fed 30: 1040-53 (1955) (9) Ludzack FJ, Ettinger MB; J Water Pollut Control 30: 1173-100 (1960) (10) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (11) Kupferle MJ et al; Proc 16th Ann Haz Waste Res Symp Cincinnati, OH pp 340-9 USEPA-600/9-90-037 (1990) R92: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR consult. ed., Washington, DC: Amer Chem Soc pg 10 (1995) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) (5) Birdie AL et al; Water Res 13: 627-30 (1979) (6) Bogan RH, Sawyer CN; Sewage Ind Waste 27: 917-28 (1955) (7) Heukelekian H, Rand MC; J Water Pollut Control Fed 30: 1040-53 (1955) (8) Ludzack FJ, Ettinger MB; J Water Pollut Control 30: 1173-100 (1960) (9) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (10) Kupferle MJ et al; Proc 16th Ann Haz Waste Res Symp Cincinnati, OH pp 340-9 USEPA-600/9-90-037 (1990) R93: (1) Biddleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) (3) Atkinson R; Journal of Physical and Chemical Reference Data. Monograph No 1 (1989) (4) Joshi SB et al; Atmos Environ 16: 130-10 (1982) R94: (1) Bridie AL et al; Water Res 13: 627-30 (1979) (2) Bogan RH, Sawyer CN; Sewage Ind Waste 27: 917-28 (1955) (3) Heukelekian H, Rand MC; J Water Pollut Control Fed 30: 1040-53 (1955) (4) Ludzack FJ, Ettinger MB; J Water Pollut Control 30: 1173-100 (1960) (5) Schink B, Stieb M; Appl Environ Microbiol 45: 1905-13 (1983) (6) Harada R, Nagashima Y; J Ferment Technol 53: 218-22 (1975) R95: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Kupferle MJ et al; Proc 16th Ann Haz Waste Res Symp Cincinnati, OH pp 340-9 USEPA-600/9-90-037 (1990) R96: (1) Joshi SB et al; Atmos Environ 16: 130-10 (1982) (2) Anbar M, Neta P; Int J Appl Rad Isot 18: 493-523 (1967) (3) Atkinson R; Journal of Physical and Chemical Reference Data. Monograph No 1 (1989) R97: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR consult. ed., Washington, DC: Amer Chem Soc pg 10 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R98: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR consult. ed., Washington, DC: Amer Chem Soc pg 10 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R99: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner,RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) R100: (1) Yasuhara A et al; Environ Sci Technol 15: 570-3 (1981) R101: (1) Van Durme GP et al; Wat Environ Res 64: 19-27 (1992) R102: (1) De Bortoli M et al; Environ Intl 12: 343-50 (1986) R103: (1) Ho CT et al; J Agric Food Chem 31: 336-42 (1983) (2) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R104: (1) Knoeppel H, Schauenburg H; Environ Intl 15: 413-18 (1989) R105: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Clapp DE et al; Appl Ind Hyg 2: 183-87 (1987) (3) Priha E et al; Ann Occup Hyg 30: 289-94 (1986) (4) Clapp DE et al; Environ Health Perspec 57: 91-5 (1984) R106: 29 CFR 1910.1000 (7/1/98) R107: NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988.16 R108: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R109: 40 CFR 60.489 (7/1/94) R110: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R111: 54 FR 33419 (7/1/94) R112: 58 FR 40262 (07/27/1993) R113: 40 CFR 261.33 (7/1/94) R114: 40 CFR 261.31 (7/1/94) R115: 21 CFR 73.1 (4/1/93) R116: 21 CFR 175.105 (4/1/93) R117: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994.p. 1403-1 R118: Smallwood AW et al; Appl Ind Hygiene 3 (2): 47-9 (1988) RS: 123 Record 10 of 1119 in HSDB (through 2003/06) AN: 55 UD: 200302 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLOROBENZENE- SY: *BENZENE-CHLORIDE-; *BENZENE,-CHLORO-; *I-P-Carrier-T-40-; *Caswell-No-183A-; *CHLOORBENZEEN- (DUTCH); *CHLORBENZENE-; *CHLORBENZOL-; *CHLOROBENZEN- (POLISH); *CHLOROBENZOL-; *CLOROBENZENE- (ITALIAN); *CP-27-; *EPA-Pesticide-Chemical-Code-056504-; *MCB-; *MONOCHLOORBENZEEN- (DUTCH); *MONOCHLORBENZENE-; *MONOCHLORBENZOL- (GERMAN); *MONOCHLOROBENZENE-; *MONOCLOROBENZENE- (ITALIAN); *NCI-C54886-; *PHENYL-CHLORIDE-; *Tetrosin-SP- RN: 108-90-7 MF: *C6-H5-Cl SHPN: IMO 3.3; Chlorobenzene UN 1134; Chlorobenzene HAZN: U037; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. F002; A hazardous waste from nonspecific sources when a spent solvent. D021; A waste containing chlorobenzene (such as chlorobenzene) may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN: PRODUCED BY THE CHLORINATION OF BENZENE IN THE PRESENCE OF A CATALYST. [R1] *Benzene + hydrogen chloride, anhydrous (Gulf oxychlorination process; coproduced with o-dichlorobenzene/p-dichlorobenzene). [R2] IMP: *Typical analysis of commercial monochlorobenzene: > 99.9%, < 0.02% benzene, < 0.05% dichlorobenzenes. [R3, p. VA6 338] FORM: *Grades: Technical [R4] MFS: *Monsanto Company, Hq, 800 North Lindbergh Boulevard, St. Louis, MO 63167, (314) 694-1000; Chemical Group; Production site: Route 3, W.G. Krummrich Plant, Sauget, IL 62201. [R5] *PPG Industries, Inc., Hq, One PPG Place, 36 East, Pittsburgh, PA 15272, (412) 434-3131; Chemicals Group; Production site: P.O. Box 191, Natrium, WV 26155. [R5] *Standard Chlorine of Delaware, Inc., Hq, Governor Lea Road, Delaware City, DE 19706-0319, (302) 834-4536; Production site: Delaware City, DE 19706-0319. [R5] OMIN: *MONOCHLOROBENZENE PRODUCTION HAS DECLINED AT AN AVERAGE RATE OF 6.7%/YR SINCE ITS PEAK IN 1969. THE DOMESTIC BAN ON DDT AND SHIFTING MARKETS FOR OTHER PESTICIDES HAVE CONTRIBUTED TO THE DOWNWARD TREND. OVERCAPACITY PERSISTS AND NO NEW USES FOR MCB ARE INVISIONED. PROJECTED GROWTH FOR (1980-1985) IS 0.6%/YR. [R6] *Only if special chlorinating agents are used can benzene be chlorinated to chlorobenzene without dichlorobenzene being formed simultaneously. [R3, p. VA6 336] *Outlook: Production is likely to continue to decline during the balance of the decade due to substitution for monochlorobenzene of more environmentally acceptable or efficient intermediates. [R7] *Chlorobenzene is an end-product produced by the reductive chlorination of di- and trichlorobenzenes under anaerobic conditions. [R8] *The production of phenol, aniline, and DDT from chlorobenzene, formerly carried out on a large scale, has been almost entirely discontinued due to the introduction of new processes and legislation forbidding the use of DDT. [R3, p. VA6 339] USE: *In the manufacture of phenol, aniline, DDT; as a solvent for paints; heat transfer medium. [R1] *SOMETIMES USED IN DRY-CLEANING [R9] *USED IN MFR OF INSECTICIDES AND AS INT IN MFR OF DYESTUFFS [R10] *Used as a fiber swelling agent and dye carrier in textile processing, a ... tar and grease remover in cleaning and degreasing operations, ... a solvent in surface coating and surface coating removers. [R11, 1981.] *Chlorobenzene is a solvent in the production of bitumen and asphalt coatings for building protection. [R3, p. VA24 483] *Chlorobenzene is nitrated in large quantities, the product subsequently converted via such intermediates as nitrophenol, nitroanisole, nitrophenetole, chloroaniline, and phenylenediamine into dyes, crop protection products, pharmaceuticals, rubber chemicals, etc. [R3, p. VA6 339] CPAT: *Solvent (pesticide formulation, TDI processing, degreasing agent), 42%; Nitrochlorobenzenes, 32%; Diphenyl oxide and phenylphenols, 15%; Miscellaneous, 11% (1985) [R12] *CHEMICAL PROFILE: Monochlorobenzene. Nitrochlorobenzenes, 40%; solvent (for pesticide formulations, TDI processing and degreasing), 27%; diphenyl oxide and phenylphenols, 20%; polysulfone polymers, 5%; miscellaneous, 8%. [R13] *CHEMICAL PROFILE: Monochlorobenzene. Demand: 1986: 222 million lb; 1987: 220 million lb; 1991 /projected/: 195 million lb. [R13] *Uses: Nitrochlorobenzenes, 65%; polysulfone polymers, 14%; solvent in pesticide formulations and for processing isocyanates, 14%; miscellaneous, 7%. [R7] *Demand: 250 million pounds (1995); 185 million pounds (1996); estimated 125 million pounds (2000). [R7] *The largest use of monochlorobenzene in the United States is in the production of nitrochlorobenzenes, both ortho and para, which are separated and used as intermediates for rubber chemicals, antioxidants, dye and pigment intermediates, agricultural products, and pharmaceuticals. [R14] PRIE: U.S. PRODUCTION: *(1972) 1.83X10+11 GRAMS [R15] *(1975) 1.48X10+11 GRAMS [R15] *(1984) 1.16X10+11 g [R16] *(1988) 2.7X10+8 lbs [R17] *(1993) 88,555,000 kg [R18] U.S. IMPORTS: *(1972) NEGLIGIBLE [R15] *(1984) 1.45X10+9 g /Mono- and tri-chlorobenzene/ [R19] U.S. EXPORTS: *(1972) NEGLIGIBLE [R15] *(1984) 1.90X10+10 g /Hydrocarbons, Cyclic, NSPF/ [R20] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R1] ODOR: *FAINT, NOT UNPLEASANT ODOR [R1]; *ALMOND-LIKE ODOR [R4]; *Mild amine odor [R21]; *Mild aromatic [R22, 225]; *Characteristic, penetrating odor. [R2]; *Weak, benzene-like odor. [R3, p. VA24 483] BP: *131.7 deg C [R23] MP: *-45.2 deg C [R23] MW: *112.56 [R1] CORR: *Liquid chlorobenzene will attack some forms of plastics, rubber, and coatings [R21] CTP: *Critical temperature: 678 deg F= 359 deg C= 632 K; critical pressure: 44.6 atm [R21]; *Critical temperature = 359.2 deg C; critical pressure = 4.52 mPa. [R3, p. VA6 329] DEN: *1.1058 g/cu cm at 20 deg C [R23] HTC: *-3100 kJ/mol at 25 deg C [R3, p. VA6 329] HTV: *355.5 J/g at 50 deg C [R3, p. VA6 328] OWPC: *log Kow= 2.89 [R24] SOL: *Soluble in ethanol, ethyl ether, and benzene. [R23]; *In water, 502 mg/l at 25 deg C. [R25]; *Miscible with nearly all organic solvents [R26, 120]; *Freely soluble in chloroform. [R1] SPEC: *INDEX OF REFRACTION: 1.5241 @ 20 DEG C/D [R23]; *MAX ABSORPTION (ALCOHOL): 245 NM (LOG E= 1.95); 251 NM (LOG E= 2.34); 258 NM (LOG E= 2.13); 264 NM (LOG E= 2.45) [R27]; *MAX ABSORPTION (ALC): 272 NM (LOG E= 2.32); SADTLER REFERENCE NUMBER: 34 (IR, PRISM); 19 (IR, GRATING); 16 (UV) [R27]; *IR: 5726 (Coblentz Society Spectral Collection) [R28]; *UV: 6-63 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R28]; *NMR: 714 (Sadtler Research Laboratories Spectral Collection) [R28]; *MASS: 370 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R28] SURF: *33 dynes/cm at 25 deg C [R21] VAPD: *3.88 (air=1) [R29] VAP: *12.0 mm Hg at 25 deg C /from experimentally-derived coefficients/ [R30] EVAP: *1 (Butyl acetate= 1) [R11, 1981.2] VISC: *0.806 mPa s at 20 deg C [R3, p. VA6 329] OCPP: *VERY REFRACTIVE LIQ [R1] *PERCENT IN SATURATED AIR: 1.55 (25 DEG C); DENSITY OF SATURATED AIR: 1.05 (AIR= 1) [R31] *EQUIVALENCIES IN AIR: 1 MG/L= 217 PPM AND 1 PPM= 4.60 MG/CU M @ 25 DEG C, 760 MM HG [R31] *Heat of fusion: 20.40 cal/g [R21] *Saturated liquid density= 69.080 lb/cu ft @ 70 deg C [R21] *Liquid heat capacity= 0.321 Btu/lb-F @ 70 deg C [R21] *Liquid thermal conductivity= 0.869 Btu-in/hr-sq ft-F at 70 deg C [R21] *Saturated vapor pressure= 0.195 lb/sq in @ 70 deg C [R21] *Ideal gas heat capacity= 0.207 Btu/lb ft @ 75 deg C [R21] *Partition coefficients at 37 deg C for chlorobenzene into blood= 30.8; into oil= 3,760. [R32] *Henry's Law constant = 3.77X10-3 atm-cu m/mole at 25 deg C [R33] *Chlorobenzene has a good solvency for fats, oils, resins, polymers, binders, rubber, and chlorinated rubber. [R3, p. VA24 483] *Critical density = 0.365 g/cu cm; Heat of fusion = 84.9 J/g; Heat capacity = 1.338 J/g K at 20 deg C; Dielectric constant = 5.641 at 20 deg C. [R3, p. VA6 329] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R34] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R34] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R34] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R34] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R34] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R34] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R34] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R34] FPOT: *Dangerous fire hazard when exposed to heat or flame. [R35] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R36, p. 325-38] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R36, p. 325-38] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R36, p. 325-38] FLMT: *Lower flammable limit: 1.8%; Upper flammable limit: 9.6% [R26, 120] FLPT: *85 DEG F (CLOSED CUP) [R35] *29.2 deg C (closed cup) [R26, 120] *97 deg F (open cup) [R21] AUTO: *638 deg C [R26, 120] FIRP: +Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire exposed containers cool. [R36, p. 49-38] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical or carbon dioxide. [R37] TOXC: *Burning in an open flame can form toxic phosgene and hydrogen chloride gases. [R21] OFHZ: +VAPOR IS HEAVIER THAN AIR (VAPOR-AIR DENSITY AT 100 DEG F, 1.1) AND MAY TRAVEL CONSIDERABLE DISTANCE TO SOURCE OF IGNITION AND FLASH BACK. [R36, p. 49-38] EXPL: *UPPER 7.1%; LOWER 1.3% @ 150 DEG C. [R35] REAC: *Contact with strong oxidizers may cause fires and explosions. [R21] +Reacts with strong oxidizing materials. [R36, p. 49-38] *... Violent reaction with AgClO4 and dimethyl sulfoxide. [R35] +Strong oxidizers. [R38, 62] *Potentially explosive reaction with powdered sodium or phosphorus trichloride + sodium. [R35] ODRT: *Odor recognition in air: 2.10x10-1 ppm. [R39] *Odor Low, 0.98 mg/cu m; Odor High, 280.0 mg/cu m [R40] SERI: *Irritation of the eyes and nose. ... [R22, 226] EQUP: */Wear/ organic vapor-acid gas respirator where appropriate; neoprene or vinyl gloves; chemical safety spectacles, ... rubber footwear; apron or impervious clothing for splash protection; hard hat. [R21] *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Admin ... or by the National Institute for Occupational Safety and Health. [R11, 1981.3] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch min), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with liquid chlorobenzene. ... Employees should be provided with and required to use splash-proof safety goggles where liquid chlorobenzene may contact the eyes. [R11, 1981.2] +Wear appropriate personal protective clothing to prevent skin contact. [R38, 62] +Wear appropriate eye protection to prevent eye contact. [R38, 62] +Recommendations for respirator selection. Max concn for use: 1000 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection needed. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R38, 62] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R38, 62] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R38, 63] OPRM: +Contact lenses should not be worn when working with this chemical. [R38, 62] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Any clothing which becomes /contaminated/ ... with liquid chlorobenzene should be removed immediately and placed in closed containers for storage until it can be discarded, or until provision is made for the removal of the chlorobenzene. [R11, 1981.2] *Skin that becomes wet with liquid chlorobenzene should be promptly washed or showered with soap or mild detergent and water to remove any chlorobenzene. [R11, 1981.3] *If material /is/ not on fire and not involved in /a/ fire keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R37] *Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R37] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R38, 62] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R38, 62] SSL: *Heat /contributes to instability/. [R26, 120] *Stable to air, moisture and light at room temperature and atmospheric pressure. [R41] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R42] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R43] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R44] STRG: *Storage temp: ambient [R21] *Containers should be kept tightly closed and protected against physical damage. Outdoor or detached storage is preferable. Avoid fire. Spark-resistant electric equipment is preferred. [R26, 121] CLUP: *Water Spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R37] *Air Spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. [R37] *Land Spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Apply "universal" gelling to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. [R37] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers U037, F002, and D021 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R45] *Chlorobenzene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Preferably after mixing with another combustible fuel; care must be exercised to assure complete combustion to prevent the formation of phosgene; an acid scrubber is necessary to remove the halo acids produced. [R46] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. [R47] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R48] *Chlorobenzene may be disposed of by atomizing in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. (Afterburner and alkali scrubber). Recommendable method: Incineration. [R49] *The thermolysis of Aroclor-1248 was undertaken in a spiralized quartz tubular flow reactor with hydrogen gas inflow at 221 mmol/hr. Temperatures were increased from 715 to 875 deg C over a series of four runs. The duration of each run was 40 to 65 minutes. The product was collected in a trap cooled with liquid nitrogen and analyzed by gas/liquid chromatography. Model runs were also undertaken with chlorobenzene, 1,2,4-trichlorobenzene, and biphenyl at temperatures decreasing over a series of four runs from 875 degrees to 750. Conversions of PCBs were approximately 10, 28, 70, and greater than 99.9% after runs one through four, respectively. Dichlorobenzene and trichlorobenzene accounted for approximately 6% of the Aroclor feed. Chlorobenzene and biphenyl were also products, although the determination of chlorobenzene was obscured by its use as diluent. Methane and small amounts of ethylene, ethane, ethane, and traces of ethyne were also formed. In model runs with chlorobenzene, trichlorobenzene, and biphenyl the amount of biphenyl left was only 0.75%. Dechlorination was again approximately 95%, leaving only traces of 1,2,4-trichlorophenyl. Increasing temperature to 925 degrees increased dechlorination to 99.95%. [R50] *The following wastewater treatment technologies have been investigated for chlorobenzene: activated carbon. [R51] *The following wastewater treatment technologies have been investigated for chlorobenzene: biological treatment. [R52] *The following wastewater treatment technologies have been investigated for chlorobenzene: stripping. [R53] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: No human data, inadequate animal data and predominantly negative genetic toxicity data in bacterial, yeast, and mouse lymphoma cells. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate. [R54] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R55, 2002.22] ANTR: *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: To keep open, "minimal flow rate"/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Benzene and related compounds/ [R56, 185] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Benzene and related compounds/ [R56, p. 184-5] MEDS: *Consider the points of attack /respiratory system, eyes, skin, CNS, liver/ in preplacement and periodic physical examination. [R22, 226] *Urine: The assessment of chlorobenzene exposure can be accomplished by measurement of the urinary metabolites, 4-chlorocatechol and p-chlorophenylmercapturic acid (p-chlorophenol). Urinary concentrations of the metabolites of chlorobenzene were found to correlate with air chlorobenzene exposure levels. Reference Ranges: Normal - None detected; Exposed - BEI (sampling time is end of shift, measured as the metabolite 4-chlorocatecol): 150 mg/g creatinine; BEI (sampling time is end of shift, measured as the metabolite p-chlorophenol): 25 mg/g creatine; BAT (sampling time is end of exposure or end of shift, measured as total 4-chlorocatechol): 300 mg/g creatinine; BAT (sampling time is at the beginning of the next shift, measured as total 4-chlorocatechol): 70 mg/g creatinine; Toxic - Not established. [R57, 686] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography (EMG); Quantitative sensory testing; Thermography. [R57, 687] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. [R57, 687] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell assessment - standardized odor threshold and identification testing; Vision assessment - standard acuity tests, visual field tests, contrast sensitivity, and color vision measurements (vision assessment); Facial and Trigeminal Nerve assessment: blink reflex (pontogram); Vestibular assessment - pure tone audiometry for bone- and air-conducted sounds, threshold decay at 4 kHz, speech discrimination and speech reception thresholds, tympanograms and acoustic thresholds, electronystamograms; Hearing assessment - audiometry testing. [R57, 687] HTOX: *CHLOROBENZENE IS HEMOLYTIC. /FROM TABLE/ [R58] *SLIGHT SKIN IRRITATION MAY OCCUR FROM APPLICATION OF MONOCHLOROBENZENE ON SKIN. REPEATED CONTACT ... MAY RESULT IN MODERATE ERYTHEMA AND SLIGHT SUPERFICIAL NECROSIS. [R59] *... Three adults developed numbness, loss of consciousness, hyperemia of the conjunctiva and pharynx following exposure to high levels of chlorobenzene. [R60] *Severe anemia and medullary aplasia in a 70 year old woman was related to her employment in hat making, which required the use of glue containing 70% monochlorobenzene. Early complaints included headache and irritation of the upper respiratory tract and mucosa of the eyes. [R61, 1453] *A 2 year old boy who swallowed 5 to 10 mL of Puran, a cleaning agent containing monochlorobenzene. He showed no ill effects for 2.5 hr, but after eating lunch he quickly lost consciousness and suffered vascular paralysis and heart failure, but recovered and survived. The odor of monochlorobenzene in breath and urine persisted for 5 to 6 days. [R61, 1453] *IT IS A CNS DEPRESSANT. LESIONS OF THE LIVER AND KIDNEYS HAS BEEN OBSERVED FOLLOWING ABSORPTION OF TOXIC DOSES. THE HISTOLOGICAL CHANGES MAY PROGRESS AS EXPOSURE BECOMES MORE SEVERE OR AS THE PERIOD OF EXPOSURE IS LENGTHENED. LIVER INJURY MAY PROGRESS TO NECROSIS AND PARENCHYMOUS DEGENERATION. [R61, 1448] *Clinical examination of workers exposed to chlorobenzene in the manufacture of polyvinyl chloride showed that some workers suffered from poisoning, although the concentrations of chlorobenzene in the atmosphere were close to the MAC (50 mg/cu m). Nerve lesions, hepatitis, chronic gastritis with gastric juice hypoacidity, bronchitis, etc were found. [R62] *THE TOXIC EFFECTS OF CHLOROBENZENE SEEM TO BE PRIMARILY LIVER AND KIDNEY INJURY. THE HEMATOPOIETIC EFFECT OF THE PARENT HYDROCARBON (BENZENE) APPEARS TO BE ABSENT. [R63] *ACUTE VAPOR EXPOSURE HAS BEEN RATHER RARE IN INDUSTRY. SLIGHT SKIN IRRITATION MAY OCCUR FROM APPLICATION OF MONOCHLOROBENZENE ON THE SKIN. REPEATED CONTACT FOR A WEEK MAY RESULT IN MODERATE ERYTHEMA AND SLIGHT SUPERFICIAL NECROSIS. [R59] *If spilled on clothing and allowed to remain, may cause smarting and reddening of the skin. [R21] NTOX: *CATS' PHYSIOLOGICAL RESPONSE TO ACUTE EXPOSURE: AT CONCN OF 37 MG/L (8000 PPM) SEVERE /SRP: CNS DEPRESSION/ AFTER 1/2 HR; DEATH 2 HR AFTER REMOVAL FROM EXPOSURE; AT 17 MG/L (3700 PPM) DEATH AFTER 7 HR; AT 5.5 MG/L (1200 PPM) DEFINITE /SRP: CNS DEPRESSIVE/ SYMPTOMS; AT 1-3 MG/L (220-660 PPM) TOLERATED FOR 1 HR. [R61, 1448] *CATS' PHYSIOLOGICAL RESPONSE TO ACUTE EXPOSURE AT 11-13 MG/L (2400-2900 PPM) RESULTED IN UNSTEADINESS AFTER 1 HR; TREMOR, TWITCHING; IF REMOVED WITHIN 7 HR NO SERIOUS INJURY. [R61, 1448] *RATS, RABBITS, AND GUINEA PIGS ... EXPOSED 7 HR/DAY, 5 DAYS/WK FOR TOTAL OF 32 EXPOSURES OVER PERIOD OF 44 DAYS. AT CONCN OF 1000 PPM IN AIR, THERE WERE HISTOPATHOLOGICAL CHANGES IN LUNG, LIVER AND KIDNEYS / and / SLIGHT DEPRESSION OF GROWTH. ... NO MORTALITY IN RATS OR RABBITS. GUINEA PIGS ... /SHOWED/ HIGHER THAN NORMAL MORTALITY. [R61, 1449] *RATS, RABBITS, AND GUINEA PIGS ... EXPOSED 7 HR/DAY, 5 DAYS/WK FOR TOTAL OF 32 EXPOSURES ... AT 475 PPM ... ANIMALS SURVIVED. THERE WAS SLIGHT INCREASE IN LIVER WT AND SLIGHT LIVER HISTOPATHOLOGY. BLOOD WAS ... NORMAL ... AT ... 200 PPM ALL OF ANIMALS APPEARED TO BE NORMAL. [R61, 1449] */ORAL/ DOSES ... GIVEN REPEATEDLY TO RATS 5 DAYS/WEEK FOR TOTAL OF 137 DOSES OVER PERIOD OF 192 DAYS. ... 0.0144 G/KG BODY WT/DAY WAS SURVIVED WITHOUT ANY OBSERVABLE EFFECT. AT 0.144 G/KG THERE WAS ... /TRANSIENT GROWTH RETARDATION/. AT ... 0.144 and 0.288 G/KG THERE WAS SIGNIFICANT INCR IN LIVER AND KIDNEY WT. ... [R61, 1449] *SLIGHT REDDENING OF THE SKIN WAS OBSERVED FROM APPLICATION OF MONOCHLOROBENZENE EITHER ON THE UNCOVERED OR COVERED SKIN. CONTINUOUS CONTACT FOR A WEEK MAY RESULT IN MODERATE ERYTHEMA AND SLIGHT SUPERFICIAL NECROSIS. IN THESE STUDIES, THERE WERE NO INDICATIONS OF TOXIC ABSORPTION. [R61, 1449] */IN RABBITS/, EYE CONTACT WITH CHLOROBENZENE MAY RESULT IN PAIN AND TRANSIENT CONJUNCTIVAL IRRITATION, BUT USUALLY CLEARS UP WITHIN 48 HR. NO CORNEAL INJURY HAS BEEN OBSERVED. [R61, 1449] *STATISTICAL ANALYSIS ON MALE RATS INHALING 0, 75 OR 250 PPM CHLOROBENZENE 7 HR/DAY, 5 DAY/WK FOR 24 WK SUGGESTS TREATMENT RELATED EFFECTS ON RED CELL PARAMETERS. PATHOLOGICAL CHANGES WERE FOCAL LESIONS IN ADRENAL CORTEX, KIDNEY TUBULAR LESIONS AND CONGESTION IN LIVER AND KIDNEYS. [R64] *ELEVATED PLASMA GLUTAMATE-PYRUVATE TRANSAMINASE AND ATTENUATED CLEARANCE OF BROMOSULFOPHTHALEIN FROM ADMIN TO RAINBOW TROUT. LIVER DYSFUNCTION EVIDENT ONLY AT HIGH DOSE AND SPECIFIC TIMES EARLY OR LATE IN COURSE OF INTOXICATION. [R65] *A CONTINUOUS FLOW PROCEDURE WAS DEVELOPED FOR EVALUATING EFFECTS OF INSOL AND VOLATILE ORGANICS ON EMBRYO-LARVAL STAGES OF FISH. OF 11 TEST CMPD SELECTED CHLOROBENZENE WAS 1 OF 4 MOST TOXIC CMPD. CHLOROBENZENE AT 90 UG/L PRODUCED COMPLETE LETHALITY OF TROUT EGGS. [R66] *Chlorobenzene was less hepatotoxic to trout than rats. This difference could not be totally accounted for by reduced absorption in trout. ... Glutathione concentrations in trout livers were 1/3 of those of the rat and prior depletion of the tripeptide /glutathione/ led to irreversible binding of chlorobenzene to trout liver protein; equivalent to that of rats suffering extensive liver necrosis. No consistent correlation between glutathione content or protein binding and liver damage was seen in either species. [R67] *The effective concentration of benzene and 12 chlorobenzenes that reduced 50% of the primary productivity ... of a freshwater green alga, Ankistrodesmus falcatus, were determined. Benzene was the least toxic chemical and the toxicity increased as the degree of chlorine substitution in the aromatic ring increased. /Chlorobenzenes and benzene/ [R68] *Pregnant rats and rabbits were exposed to 0, 75, 210 or 590 ppm monochlorobenzene via inhalation for 6 hr/day during the period of major organogenesis. Exposure to 590 ppm caused elevated liver weights in /dams of/ both species and decreased body weight gain and feed consumption in rats. Inhalation of monochlorobenzene vapors during gestation was not embryotoxic or teratogenic in rats. In rabbits, a few monochlorobenzene exposed fetuses exhibited visceral malformations, which were not observed among concurrent controls, though no dose-related increase in malformations was noticed. Fetal effects were limited to a slight delay in skeletal development, which occurred only in rats exposed to 590 ppm, a maternally toxic concn. [R69] *Time and dose dependent correlations of monochlorobenzenes' hepatotoxic effects were studied in view of: (1) assumed mechanistic similarities to bromobenzene (2) the paucity of /this type of/ data for chlorobenzenes, and (3) the relatively greater environmental importance of chlorobenzenes compared to bromobenzene. An ip dose of 9.8 mmol/kg chlorobenzene in rats produced evidence of liver toxicity over a 72 hr time course. Plasma alanine aminotransferase activity and morphological evidence of damage were maximized about 48 hr after dosing. Maximal covalent binding to liver protein (3.07 nmol/mg) had occurred by 24 hr and approximately 36% of the administered dose had appeared in the urine by 48 hr. Liver and plasma chlorobenzene concn were proportionally increased over the dosage range 2-14.7 mmol/kg but marked centrolobular necrosis and alanine aminotransferase activity elevations were seen only at the two highest doses (9.8 and 14.7 mmol/kg). Overall, doses depressed hepatic glutathione /levels/ (GSH) to between 30 and 40% of control by 4 hr. Evidence of rapid recovery was evident at 2.0 and 4.9 mmol/kg but glutathione levels remained low through 8 hr after /administration of the/ 9.8 or 14.7 mmol/kg /doses/. Liver body weight ratios were increased to a similar extent at all dosages when measured 24 hr post-treatment. Urinary excretion ranged from 59% at the low dosage to only 19% at the highest dosage, by 24 hr. Dose related covalent binding to liver protein at 24 hr occurred up to 9.8 mmol/kg /however/ the binding associated with 14.7 mmol/kg was equivalent /only/ to that seen with the 4.9 mmol/kg dosage (1.6 nmol/mg protein). [R70] *PRETREATMENT OF RATS WITH PHENOBARBITAL INCR LIVER TOXICITY OF CHLOROBENZENE. [R10] *Fischer 344/N rats and hybrid B6C3F1 mice of both sexes received MCB by gavage in single doses ranging from 250 to 4,000 mg/kg of body weight, with mice of both sexes also receiving MCB doses that ranged from 0 to 500 mg/kg on the same schedule. During a 14 day repeated exposure study, rats of both sexes received MCB in doses ranging from 125 to 2,000 mg/kg a day, this substance being administered to both sexes of mice in doses ranging from 0 to 500 mg/kg a day. Over 13 weeks, rats and mice of both sexes received MCB in doses ranging from 60 to 750 mg/kg 5 days a week. Single exposure to 4,000 mg/kg of MCB was lethal to rats of both sexes, while a single MCB dose as low as 1,000 mg/kg was lethal to both male and female mice. Daily exposure to MCB in a dose of 1,000 mg/kg for 14 days caused death in rats of both sexes. During the subchronic 91 day MCB exposure, survival was reduced by doses of 500 mg/kg or higher in rats and by doses of 250 mg/kg or higher in mice. Dose dependent hepatocyte necrosis, the degeneration or focal necrosis of the renal proximal tubules, and lymphoid or myeloid depletion of the spleen, bone marrow, and thymus were produced in both sexes by exposure in MCB in doses of 250 mg/kg or higher. Mild porphyrinuria was detected in all animals of both sexes at the higher MCB doses. [R71] *Chlorobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, with or without ... S9 ... and did not produce DNA damage in E coli strains WP2 uvr A+ rec A+ or WP100 uvr A-recA-, or Salmonella typhimurium strains TA1978 uvr B+ or TA1538 uvr B-. [R72] *This study investigates the effects of chlorobenzenes on the diatom Cyclotella meneghiniana using DNA measurement as a toxicity parameter and related toxicity to different physicochemical properties of chlorobenzenes. The organisms were exposed to chlorobenzene solutions for 48 hr to obtain effective concentration (EC50) values (in terms of percent DNA reduction). The toxicity (EC50) increased with increasing degree of chlorination, as follows: monochlorobenzene (235.74 mg/l), dichlorobenzenes (23.33-51.88 mg/l), trichlorobenzenes 0.59-6.42 mg/l), tetrachlorobenzenes (0.27-1.39 mg/l), pentachlorobenzene (0.008 mg/l) and hexachlorobenzene (0.002 mg/l). Quantitative structure-activity relationships were developed showing high correlations, as follows: water solubility (r2 = 0.96); molecular volume (r2 = 0.92); zero-order connectivity index (r2 = 0.92); second-order connectivity index (r2 = 0.02); molecular surface area (r2 = 0.92); octanol/water partition coefficients (r2 - 0.86); bioconcentration factor (r2 = 0.86); and inorganic/organic character (r2 = 0.83). A poor correlation, however, was obtained with the molecular negentropy index (r2 = 0.25). The toxic effect (EC50) was explained in terms of a partitioning process as a function of the aqueous solubility of the chlorobenzenes and was found to occur at similar degrees of exposure saturation. [R73] *The cytotoxicity of monochlorobenzene (MCB), 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene was examined using precision cut rat liver slices obtained from male Sprague-Dawley and Fischer 344 rats. The liver slices were maintained in dynamic organ culture for up to 6 hr and cytotoxicity was evaluated by intracellular K+ content and protein synthesis. A concentration related injury was observed when liver slices from Sprague-Dawley rats were incubated with the chlorobenzene isomers at concentrations greater than 1 mM. At 2 mM the degree of toxicity produced was dependent on the particular isomer studied with 1,3-dichlorobenzene showing the earliest onset of toxicity (3 hr) followed by 1,2-dichlorobenzene then 1,4-dichlorobenzene (6 hr). At 5 mM the degree of toxicity produced by any of the three dichlorobenzene isomers was not different. MCB, which was not toxic to the slices at 1 or 2 mM, was toxic at 5 mM (6 hr). A significant potentiation of dichlorobenzene toxicity was observed with liver slices prepared from phenobarbital induced Sprague-Dawley rats. This potentiation resulted in the expression of toxicity at either lower concentrations (1 mM for 1,2-dichlorobenzene at 2 mM). In addition, the toxicity of MCB (5 mM) was slightly increased in slices from phenobarbital-induced rats. When Fischer 344 rats slices were incubated with the chlorobenzenes, there was an increase in cytotoxicity and a change in the rank order of toxicity (1,2-dichlorobenzene > 1,3-dichlorobenzene > 1,4-dichlorobenzene > MCB). 1,2-dichlorobenzene and 1,3-dichlorobenzene (1 mM) were toxic in non-induced Fischer 344 rat slices but not toxic in non-induced Sprague-Dawley rat liver, slices. The 1,3-dichlorobenzene isomer was most toxic in Sprague-Dawley rats while 1,2-dichlorobenzene was the most toxic in Fischer 344 rats. Therefore, precision cut rat liver slicing can be used to not only distinguish the rank order of toxicant potency between chemical isomers, but also the effects of strain differences and the role of biotransformation enzyme induction. [R74] *The long term effects of monochlorobenzene (MCB) on parental activities and offspring development through two generations of rats was investigated. Groups of 30 male and female Sprague-Dawley rats (FO generation) were exposed to MCB vapor for 6 hours per day, 7 days per week at 0, 50, 150, and 450 ppm MCB for approximately 10 weeks prior to mating. Exposure to the females continued throughout gestation and lactation, except from day 20 of gestation to day four of lactation. Some of the progeny (F1 generation) were continued on the same concentration of MCB as the parents and were mated to nonsiblings. Progeny (F2 generation) were produced under the same regimen as for the previous generation. Mating and fertility indices for males and females appeared unaffected by treatment. In F1 litters, pup and litter survival for treated groups were comparable to controls. In F2 litters, a slight decrease in pup survival index was observed at the high concentration level only, but this was attributable to excessive mortality in the litters of two dams. Significant increase in mean absolute or relative liver weight occurred in the FO and F1 generations in the 150 ppm and 450 ppm groups. Increased incidence of small flaccid testes and dilated renal pelvis occurred in the 450 ppm group for both FO and F1 adults. Minimal to mild hepatocellular hypertrophy and renal degeneration and inflammatory lesions were found in males. Unilateral or bilateral degeneration of germinal epithelium of the testes was successful in siring litters. It was concluded that exposure to MCB at levels of up to 450 ppm does not have any adverse effects on reproductive performance or fertility of male and female rats through two consecutive generations. [R75] *The developmental, genetic, and reproductive toxicities of benzene, chorobenzene, o-dichlorobenzene, m-dichlorobenzene, and p-dichlorobenzene were determined in a sea-urchin (Paracentrotus lividus) bioassay. Embryos were reared in the presence of the agents for 48 hr, from the zygote to the pluteus larval stage. In addition, sperm inactivation was tested by adding agents to sperm suspensions, which were then used to inseminate untreated eggs. Benzene treatment at 10(-6) molar (M) showed a significant increase in embryo developmental defects and an elevated metaphase to anaphase ratio indicating partial metaphase block, but no increase in total mitotic aberrations. With chlorobenzene, developmental defects were only increased above controls at 10(-4)M. Chlorobenzene increased the metaphase to anaphase ratio, and the percentage of anaphase aberrations increased significantly with 10(-5) and 10(-4)M. A dose related response was found for o-dichlorobenzene in developmental defects and for metaphase to anaphase ratio increases. For m-dichlorobenzene, developmental defects and mitotic abnormalities were strongly increased. Sperm inactivation tests produced entirely differently results. Only o-dichlorobenzene and p-dichlorobenzene caused spermiotoxicity. Developmental defects in the offspring of pretreated sperm were significant for all compounds, but primarily for benzene and chlorobenzene. However, chlorobenzene and o-dichlorobenzene caused clear inhibition of mitosis. Total mitotic aberrations increased with benzene, m-dichlorobenzene, and p-dichlorobenzene, for anaphase aberrations the greatest effect was observed for chlorobenzene, with lesser effects for m-dichlorobenzene, o-dichlorobenzene, and benzene. Both chlorobenzene and o-dichlorobenzene caused a sharp decrease in active mitotic figures and in anaphase figures (increased metaphase to anaphase), so that the lack of increase in total mitotic aberration did not necessarily reflect the absence of any effect. It was concluded that the results show some distinct toxicity patterns for the different agents, thus pointing out the need to reconsider criteria for ranking toxicities, in order to utilize multiple toxic endpoints. [R76] *The DNA damaging effect of chlorobenzene was investigated in peripheral lymphocytes and bone marrow cells from C57BL/6 female mice using a gel electrophoresis assay for DNA from single cells (the single cell gel electrophoresis assay) under alkaline conditions. The effect of chlorobenzene was studied both after single and repeated intraperitoneal injections of 750 mg/kg body weight. The cytostatic agent cyclophosphamide (150 mg/kg, i.p.) was used as a reference substance, and vehicle-treated mice as controls. DNA damage was recorded 16 h after the (last) injection, using an automated computerized image analysis system specifically designed for the single cell gel electrophoresis assay. There was evidence of chlorobenzene-induced DNA damage after 3 days of repeated exposure in peripheral lymphocytes, but no indications of such an effect in bone marrow cells. Cyclophosphamide induced significant damage to DNA both in bone marrow cells and lymphocytes, the effect being most pronounced in the latter cells. It is concluded that high-dose exposure to chlorobenzene is associated with genotoxicity to peripheral lymphocytes. However, this solvent is apparently not a major hazard to bone marrow cells, even after repeated high-dose exposure. [R77] NTXV: *LD50 Rat oral 2.29 g/kg; [R78] *LD50 Mouse oral 1.44 g/kg; [R78] *LD50 Rabbit oral 2.25 g/kg; [R79] *LD50 Guinea pig oral 5.06 g/kg; [R78] *LD50 Rat ip 0.515 ml/kg; [R80] ETXV: *TLm Pimephales promelas (fathead minnow) 29-39 mg/l/24-96 hr /Conditions of bioassay not specified/; [R81] *TLm Lepomis macrochirus (bluegill sunfish) 24 mg/l/24-96 hr /Conditions of bioassay not specified/; [R81] *TLm Poecilia reticulata (guppy) 45 mg/l/24-96 hr /Conditions of bioassay not specified/; [R81] *LC50 Poecilia reticulata (guppy) 19 ppm/14 days /Conditions of bioassay not specified/; [R81] *LD50 Salmo gairdnerii (rainbow trout) 1.8 mg/kg/24 hr /Conditions of bioassay not specified/; [R81] *LC50 Pimephales promelas (fathead minnow) 16.9 mg/l/96 hr (confidence limit 13.8 - 20.6 mg/l), flow-through bioassay with measured concentrations, 25.7 deg C, dissolved oxygen 6.2 mg/l, hardness 43.8 mg/l calcium carbonate, alkalinity 43.4 mg/l calcium carbonate, and pH 7.5; [R82] NTP: *Toxicology and carcinogenesis studies of chlorobenzene (monochlorobenzene, > 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and 50 female B6C3F1 mice at doses of 60 or 120 mg/kg. Groups of 50 male B6C3F1 mice received 30 or 60 mg/kg. Chlorobenzene was administered five times per week for 103 weeks. ... Male rats dosed with chlorobenzene exhibited a significant (p < 0.05) increase in the incidence of animals with neoplastic nodules of the liver (overall incidences: untreated control, 4/50 (8%); vehicle control, 2/50 (4%); low dose, 4/49 (8%); high dose, 8/49 (16%)). Increased incidences of hepatocellular carcinomas in male rats or of neoplastic nodules or hepatocellular carcinomas in female rats were not observed. No increased tumor incidences were observed in female rats or in male or female mice. Under the conditions of these studies, chlorobenzene administration increased the occurrence of neoplastic nodules of the liver in high dose (120 mg/kg/day) male F344/N rats, providing some but not clear evidence of carcinogenicity of chlorobenzene in male rats. Carcinogenic effects of chlorobenzene were not observed in female F344/N rats or in male or female B6C3F1 mice. [R83] TCAT: ?The ability of multiple exposures of chlorobenzene to induce morphological transformation in the Fischer 344 adult rat liver (ARL) cell lines (Cell Transformation Assay) was evaluated without added metabolic activation. Based on preliminary toxicity determinations (exposure time=16 hrs), chlorobenzene was tested at 0.01, 0.05, 0.005 and 0.001% (v/v) in 12 exposures lasting 16 hrs each, with sufficient time between exposures for colonies to recover from toxicity due to exposure. Transformation frequencies were determined after exposures number 5, 9 and 12. Chlorobenzene repeatedly produced a low, but definite anchorage independency in ARL cells. Chlorobenzene induced transformation in ARL cells but was not genotoxic to hepatocytes. [R84] ?Teratogenicity was evaluated in mated Fischer 344 rats (32-33/group) exposed to chlorobenzene by inhalation at nominal concentrations of 0, 75, 210 or 590 ppm on gestation days (GD) 6-15 for 6 hrs/day. There were significant differences observed between treated and control animals in the following: decreased maternal weight gain (high-dose group), increased absolute and relative maternal liver weights (high-dose group), decreased fetal focal necrosia in the liver (mid- and high-dose groups), increased delayed ossification of centra of the cervical vertebrae (low- and high-dose groups), increase in bilobal centra of the thoracic vertebrae (high-dose group), and a decrease in spurs on the fifth cervical vertebra (high-dose group). There were no significant differences observed between treated and control animals in the following: maternal mortality pregnancy rate, mean litter size, resorptions/implantation, fetal sex ratio and body measurements, and incidence of major malformations. [R85] ?Teratogenicity was evaluated in inseminated female New Zealand white rabbits (30/group) exposed to chlorobenzene by inhalation at nominal concentrations of 0, 75, 210 or 590 ppm on gestation days (GD) 6-18 for 6 hrs/day. In a repeat study, rabbits were tested at nominal concentrations of 0, 10, 30, 75 or 590 ppm under the same conditions. In the first tests, there were significant differences observed between treated and control animals in the following: increased absolute and relative liver weights (mid- and high-dose groups), increased percent pre-implantation losses (low- and mid-dose groups), increased male/female ratio (low-dose group), increased fetal crown-rump length (mid-dose group), and increased incidence of extra ribs (high-dose group). In the first tests, there were no significant differences observed between treated and control animals in the following: maternal mortality, body weights, weight gain, pregnancy rate, mean litter size, resorptions/implantation, mean fetal body weight, and single or collective major malformations in external, soft tissue or skeletal examinations. In the repeat study, there were significant differences observed between treated and control animals in the following: increased absolute maternal liver weight (high-dose group, and increased pre-implantation losses (two highest doses), resorptions/litters (high-dose group). All other differences between treated and control animals in the second tests were not significant (see first test results). [R85] ?The ability of chlorobenzene to induce sex-linked recessive lethal mutations in the post-meiotic germ cells was evaluated in Drosophila males (wild-type stock, Canton-S). Based on preliminary toxicity determinations, flies (45, 59, and 84/group in low- and 2 high-dose groups) were treated with chlorobenzene by inhalation at 36,000 or 128,400 (2 groups) ppm.hr (ppm x hrs of exposure) and the surviving flies (35, 59, and 72, respectively, in low- and 2 high-dose groups) were mated with 3 sets of 3 virgin "Basc" females for 72 hrs each. Percent mortalities during exposure and prior to mating on increasing dose level were 0, 0, and 14%, respectively. Percent sterility for the 3 broods ranged from 0% at the low-dose level, to 44, 37, and 42% and 21, 22, and 24% at the high-dose level. There was no indication of any mutagenic effect in any germ cell stage. Percent lethals ranged from a high of 0.27% at low-dose level to a high of 0.174% at high-dose level versus a maximum of 0.349% for the controls. [R86] ?The effect of monochlorobenzene was examined in the rat hepatocyte primary culture/DNA repair assay. The test article did not induce an increase in average net nuclear grain counts when administered to Fischer F344 rat liver cells at concentrations ranging from 1x10E-5 to 1% (v/v) in two separate experiments. Toxicity to cells was observed at mono- chlorobenzene concentrations of 1x10E-1 % and higher. [R87] POPL: */Individuals who suffer from/ skin, liver, kidney, or chronic respiratory disease, will be at an increased risk, if they are exposed to chlorobenzenes. /Chlorobenzenes/ [R11, 1981.] ADE: *... 27% OF /0.5 G/KG OF BODY ADMIN TO RABBITS/ WAS EXCRETED UNCHANGED IN EXPIRED AIR. 25% OF ... /DOSE/ APPEARED IN URINE AS GLUCURONIDE, 27% AS ETHEREAL SULFATE AND 20% AS MERCAPTURIC ACID. TOTAL IS 99%, WHICH IS EXCEPTIONALLY GOOD RECOVERY FOR SUCH STUDY. [R61, 1451] *... Chlorobenzene is absorbed through the lung and from the gastrointestinal tract. Because chlorobenzene is highly lipophilic and hydrophobic, it is thought to be distributed throughout total body water, with body lipids being a major deposition site. [R88] *Chlorobenzene shows dose-dependent changes in pharmacokinetics following inhalation by the rat with storage in fat compartments; the highest tissue concentrations were seen in epididymal and perirenal fat. [R89, 1991.272] METB: *OUTPUT OF MERCAPTURIC ACID IN MAN ... /FROM (14)C-LABELLED CHLOROBENZENE/ WAS SMALL ... MAIN METAB OF CHLOROBENZENE ... ACCOUNTING FOR ABOUT 70% OF EXCRETED RADIOACTIVITY, WAS 4-CHLOROCATECHOL CONJUGATED MAINLY WITH GLUCURONIC ACID AND TO LESSER EXTENT WITH SULFATE. [R90] *CHLOROBENZENE IS CONVERTED INTO MIXT OF 2-, 3-, and 4-CHLOROPHENOL IN PERFUSED RAT LIVER ... BY MICROSOMES, AND BY RECONSTITUTED MICROSOMAL MONO-OXYGENASE. [R91] *... U-(14)-C-LABELLED MATERIAL HAS LED TO IDENTIFICATION IN RABBIT URINE OF NEW MINOR METAB, INCL QUINOL, 3-CHLOROCATECHOL, ORTHO- AND META-CHLOROPHENYLMERCAPTURIC ACIDS. ... ORTHO-, META- AND PARA-CHLOROPHENOLS WERE PRESENT IN SMALL AMT IN URINE WITH PARA-ISOMER PREDOMINATING. ... [R92] *... CHLOROBENZENE APPEARS TO BE CONVERTED TO A METAB THAT CAN PRODUCE TISSUE DAMAGE. THIS DAMAGE MAY BE BLOCKED BY PRIOR ADMIN OF PIPERONYL BUTOXIDE. METAB IS APPARENTLY PRODUCED IN LIVER AND TRANSPORTED TO KIDNEYS BY CIRCULATION. ... THE HEPATOTOXIC METAB MAY BE AN EPOXIDE. [R10] */IN RABBITS/ TRACE AMT OF 3,4-DIHYDRO-3,4-DIHYDROXY-CHOLOROBENZENE (0.03%), THE PRECURSOR OF 4-CHLOROCATECHOL AND POSSIBLY ALSO OF P-CHLOROPHENOL, HAVE BEEN ... ISOLATED FROM URINE. [R93] *The metabolism and binding of ... (14)C-chlorobenzene ... in the respiratory tract of mice was studied. As shown by whole-body autoradiograms, with heated tissue section, a selective localization of non-volatile metabolites occurred in the mucosa of the entire respiratory system. Microautoradiograms showed that tissue bound metabolites were present in the epithelium of the nasal and tracheobronchial mucosa and in subepithelial glands in the olfactory nasal mucosa. In vitro experiments with slices from the nasal mucosa, lung, and liver indicated transformation of chlorobenzene to metabolites which could not be extracted from the tissues; the binding was most pronounced in the nasal mucosa. The formation of nonextractable metabolites by the nasal mucosa and lung in vitro was decreased by metyrapone, piperonylbutoxide, and SKF 525, indicating a cytochrome p450 dependent metabolism of (14)C-chlorobenzene in the respiratory tissues. Autoradiography of lung slices incubated with (14)C-chlorobenzene revealed that a preferential localization of metabolites in the bronchial mucosa also occurred in vitro. ... The binding of metabolites in the nasal mucosa suggest that this tissue may also be a site of toxic action of chlorobenzene. [R94] *Hydroxylation occurs para to the chlorine via an NAPDH-cytochrome p448 dependent microsomal enzyme system. Further hydroxylation then occurs to form the corresponding catechol compound. The diphenolic derivative is a predominant form quantitatively, in comparison to the monophenolic compounds. Various conjugates of these phenolic derivatives are the primary excretory products, /and/ these conjugates are thus formed by the microsomal enzymes, in this case the NADPH-cytochrome p450 dependent system. /The/ ... rate limiting step in /the/ metabolism of monochlorobenzene is the initial hydroxlylation of the ring. [R95] *Wistar rats were injected ip with 2.0 mmol/kg chlorobenzene. Urine was collected every 24 hours for 3 days prior to and 4 days following injection. Metabolites were analyzed by liquid and gas chromatography and mass spectrometry. The chlorobenzene metabolites identified were 4-chlorocatechol, 2-chlorophenol, 4-chlorophenol, and 3-chlorophenol. Also identified was chlorophenylthiol, and alkaline hydrolysis product of 4-chlorophenylmercapturic acid. [R96] *The relationship between environmental exposure to monochlorobenzene (MCB) and the urinary concentration of its two main metabolites, 4-chlorocatechol and 4-chlorophenol, was assessed in workers performing maintenance work in a diphenylmethane-4'-diisocyanate facility. The study group included 44 clinically healthy men from the facility ranging in age from 21 to 49 years. They were monitored during several shifts of the 24 day period required to perform the maintenance activities; 251 whole shift personal air sampling measurements were performed. All time weighted average exposure values of MCB were below the maximum concentration value in the work place that is currently recommended, 50 ppm. A urine sample was also collected which revealed that 4-chlorophenol and 4-chlorocatechol could be detected at exposure levels of MCB below the allowable limits. The production of 4-chlorocatechol was generally three times higher than that of 4-chlorophenol. A statistically significant correlation existed between the MCB time weighted average concentration and the concentration of each metabolite in the urine collected at the end of the workshift. /Results suggest/ caution that biological limit values should be considered as tentative since the metabolite concentration in urine were only characterized for MCB levels below 50 ppm. [R97] *Chlorobenzene was administered to male Wistar rats. Twenty-four hour urine samples were collected over a period of 7 days. p-Chlorophenylmercapturic acid, chlorophenols and a guanine adduct was determined by chromatographic methods. The excretion pattern of p-chlorophenyl-mercapturic acid did not seem to be significantly affected by phenobarbital. To analyze for the chlorophenols and guanine adducts, diluted urine was subjected to cation exchange chromotography using UV-detection. Fractions were found containing chlorophenols and a compound showing chromatographic properties similar to those of the synthetic N7-phenylguanine. The results of the HPLC analyses suggested the presence of a guanine adduct excreted on days 1 and 2 and between days 4 and 6 post-administration. There were no compounds detected which were identical with p-, m- or o-isomers of N7-chlorophenylguanine. The excretion of p- and m-chlorophenols by phenobarbital-pretreated animals was twice as high as that in untreated rats. A 4-fold increase was detected for o-chlorophenol. It is assumed that it is mainly direct hydroxylation that can be induced by phenobarbital. Dehalogenated phenolic metabolites may be capable of covalent binding to DNA. [R98] *RADIOACTIVE CHLOROBENZENE INCUBATED WITH LIVER MICROSOMES FROM CONTROL, PHENOBARBITAL- AND METHYLCHOLANTHRENE-TREATED RATS IN PRESENCE OF NADPH-GENERATING SYSTEM. ITS METABOLITES SHOWED 1 TYPE OF BINDING PATTERN AT 72,000 MR (RELATIVE MOL WT) AND IN 50,000-60,000 MR REGION. [R99] ACTN: *The effects of halogenated hydrocarbons on the mitochondrial membrane were examined in rats. Monohalogenated benzenes decreased state 3 respiration and increased state 4 respiration, resulting in a decrease in respiratory control (RIC) and the ADP/O ratio. The above activity was observed in the decreasing order of iodobenzene, bromobenzene, chlorobenzene and fluorobenzenes. This order was parallel to K releasing activity. [R100] *All 11 chlorobenzenes studied stimulated Bacillus hydrogenase activity as measured by the resazurin method, implying the perturbation of bacterial cellular components or functions by chlorobenzenes. /Chlorobenzenes/ [R101] *The binding of epichlorohydrin, 1,2-dichlorethane, 1,2-dibromoethane, chlorobenzene, bromobenzene, and benzene to nucleic acid and proteins of different murine organs was studied in in vivo and in vitro systems. The extent of in vivo enzymatic activation of brominated compounds was higher than that of chlorinated chemicals. Aryl halides were bound mainly to liver DNA whereas interaction of alkyl halides with DNA of liver, kidney, and lung gave rise to similar binding extent. In vitro activation of all chemicals was mediated by microsomal p450-dependent mixed function oxidase system present in rat and mouse liver and, in smaller amount, in mouse lung. Activation of alkyl halides by liver cytosolic GSH-trasferases even occurred. The relative reactivity of chemicals in vivo, expressed as covalent binding index to rat liver DNA, was: 1,2-dibromoethane > bromobenzene > 1,2-dichloroethane > chlorobenzene > epichlorohydrin > benzene. On the whole, it agreed with in vitro activation of chemicals, with genotoxicity data from other short-term assays ... . Covalent cinding index values of chlorobenzene and bromobenzene gave the first clear evidence of genotoxicity and of possible carcinogenicity of these two chemicals. [R102] *At 22 hr after ip injection into male Wistar rats and BALB/c mice, chlorobenzene was covalently bound to DNA, RNA and proteins of the liver, kidney and lung, as has been found with various weak carcinogens. A microsome-mediated interaction with DNA occurred in vitro. The interaction was enhanced by pretreatment in vivo with phenobarbitone but was suppressed by addition of 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloric acid in vitro. These results indicate the involvement of cytochrome p450. Liver microsomes were efficient bioactivators, whereas cytosol was ineffective. The extent of in vitro interaction of chlorobenzene with synthetic polyribonucleotides was of the same order as that with DNA. Finally, ultraviolet irradiation (lambda= 254 nm or lambda max= 365 nm) activated this environmental contaminant to forms capable of interacting with DNA. [R103] INTC: *In two complete replicates of a 2 times 2 factorial-designed experiment involving chlorobenzene ... and lindane, ... the hepatotoxicity induced by a challenge dose of chlorobenzene was altered by the pretreatments due to selective changes in various metabolic pathways. Pretreatment with either toxicant alone, or in combination, elevated the metabolism of 1.12 g/kg chlorobenzene to conjugated and polar metabolites. The relative importance of these pathways was increased most by pretreatment with chlorobenzene plus lindane and least with chlorobenzene /alone/. The incidence and severity of chlorobenzene induced hepatocellular necrosis depended on how much the pretreatments increased excretion of these metabolites relative to that of p-chlorophenol, since the conjugates and polar metabolites represent an inactivation of the toxic chlorobenzene-3,4-epoxide, whereas, p-chlorophenol reflects its formation. Thus these changes in the metabolic pathways resulted in either (1) a marginally significant decrease in hepatoxicity (chlorobenzene pretreatment); (2) significance in both the incidence and severity of the lesions (lindane pretreatment) or (3) absence of centrilobular necrosis was present (chlorobenzene and lindane pretreatment). Apparently the effect of pretreatment with xenobiotics on chlorobenzene induced hepatotoxicity was dependent on how much the pretreatments altered the inactivation of chlorobenzene-3,4-epoxide relative to its formation. [R104] *The mechanism of bromobenzene hepatotoxicity and its modification by toluene and chlorobenzene were studied in rats. Male Wistar rats were injected ip with 2 mmol/kg bromobenzene, 4 mmol/kg toluene, or 4 mmol/kg chlorobenzene either alone or in combination. Rats were killed 12, 24, or 48 hr after injection and liver injury was assessed biochemically and histopathologically. Serum glutamate pyruvate transaminase and liver glutathione were measured. In vitro experiments were performed on liver microsomes from male Wistar rats pretreated with phenobarbital. Toluene and chlorobenzene each inhibited bromobenzene hepatotoxicity as measured by suppression of glutamate pyruvate transaminase concentrations and by histopathology at 24 hr after treatment; chlorobenzene significantly decreased at 12 hr and recovered at 24 hours when bromobenzene was given alone. This recovery at 24 hr disappeared when chlorobenzene was coadministered. Kinetic analysis of rat liver microsomes of bromobenzene metabolism showed that both toluene and chlorobenzene at 6 mmol/l inhibited p-bromophenol formation but had no effects on o-bromophenol formation. [R105] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Chlorobenzene's production and use in the production of chloronitrobenzenes and as a solvent carrier for methylene diisocyanate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 12 mm Hg at 25 deg C indicates chlorobenzene will exist solely as a vapor in the ambient atmosphere. Vapor-phase chlorobenzene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 21 days. Chlorobenzene absorbs light in the environmental spectrum (> 290 nm), suggesting a potential for direct photolysis. Monochlorobiphenyl has been identified as a photoproduct. Photolysis half-lives of 17.5 hours and 3.80 hours were measured for chlorobenzene in distilled water and Isar River water, Germany, respectively; chlorophenol and phenol were identified as photoproducts in river water. If released to soil, chlorobenzene is expected to have moderate to very high mobility based upon Koc values ranging from 4.8 to 313.1. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 3.77X10-3 atm-cu m/mole. The potential for volatilization of chlorobenzene from dry soil surfaces may exist based upon a vapor pressure of 12 mm Hg. Biodegradation results for chlorobenzene in terrestrial environments vary. Chlorobenzene was not mineralized after 8 months incubation in soil. However, bacterial isolates obtained from groundwater and soils contaminated with chlorobenzene could mineralize approx 54% of the chlorobenzene within 7 days when supplemented with ammonium and phosphate. Biodegradation half-lives of > 540 days, 240 to 281 days, 88 years, and > 490 days were reported in Oklahoma sandy clay, OK gravel, OK sand, and OK sand, respectively. If released into water, some adsorption of chlorobenzene to suspended solids and sediment in the water column is expected based on the Koc range. The biodegradation half-life of chlorobenzene was reported to be 150 days in river water and 75 days in sediment. A half-life of 46.2 days was measured for chlorobenzene in an anaerobic estuarine sediment that was preexposed to various anthropogenic chemicals with benzene identified as the product; in autoclaved sediment, the half-life was approx 400 days. Volatilization from water surfaces is expected to be an important fate process based on its Henry's Law constant. The estimated volatilization half-life from a model river is estimated as approximately 3.3 hours; the estimated volatilization half-life from a model lake is estimated as approximately 4.3 days. A BCF range of 0.25 to 450 suggests bioconcentration in aquatic organisms is low to high. Chlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups. Occupational exposure to chlorobenzene may occur through inhalation and dermal contact with this compound at workplaces where chlorobenzene is produced or used(SRC). The general population may be exposed to chlorobenzene via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with vapors, food and other products containing chlorobenzene. (SRC) ARTS: *... It has been estimated that during the manufacture of monochlorobenzene 800 mg escape into ... streams for every kg manufactured. [R106] *Release of chlorobenzene to the environment is estimated to be due mostly to volatilization losses associated with its use as a solvent in pesticide formulations and in degreasing and other industrial applications. Chlorobenzene is estimated by Dow Chemical to be 30-50% of its production. Disposal of industrial wastes may be another source of chlorobenzene release. The US EPA estimates that < 0.1% of chlorobenzene production would be disposed of in water and < 1% on land(1). [R107] *Chlorobenzene's production and use in the production of chloronitrobenzenes and as a solvent carrier for methylene diisocyanate(1) may result in its release to the environment through various waste streams(SRC). In Japan, approx 32,000 tons of chlorobenzene are manufactured annually for synthetic intermediates and solvents(2). [R108] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values ranging from 4.8 to 313.1(2,3) indicate that chlorobenzene is expected to have moderate to very high mobility in soil(SRC). Volatilization of chlorobenzene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 3.77X10-3 atm-cu m/mole(5). The potential for volatilization of chlorobenzene from dry soil surfaces exists(SRC) based upon a vapor pressure of 12 mm Hg at 25 deg C(6). Biodegradation results for chlorobenzene in terrestrial environments vary. Chlorobenzene was not significantly mineralized after 8 months incubation in soil(7). However, bacterial isolates obtained from groundwater and soils contaminated with chlorobenzene could mineralize approx 54% of the chlorobenzene within 7 days when supplemented with ammonium and phosphate(8). Biodegradation half-lives of > 540 days, 240 to 281 days, 88 years, and > 490 days were reported in Oklahoma sandy clay, OK gravel, OK sand, and OK sand, respectively; aquifer material was not heavily polluted(9). [R109] *AQUATIC FATE: Based on a classification scheme(1), Koc values ranging from 4.8 to 313.1(2,3) indicate that some adsorption of chlorobenzene to suspended solids and sediment in the water column is expected(SRC). Chlorobenzene is expected to volatilize from water surfaces(4,SRC) based upon a Henry's Law constant of 3.77X10-3 atm-cu m/mole(5). Estimated volatilization half-lives for a model river and model lake are 3.3 hours and 4.3 days, respectively(4,SRC). According to a classification scheme(6), BCFs ranging from 0.25 to 450(7,8) suggest bioconcentration in aquatic organisms is low to high(SRC). Photolysis half-lives of 17.5 hours and 3.80 hours were measured in distilled water and Isar River water, Germany, respectively; chlorophenol and phenol were identified as photoproducts in river water(9). Chlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(4). The biodegradation half-life of chlorobenzene was reported to be 150 days in river water and 75 days in sediment(10). A half-life of 46.2 days was measured for chlorobenzene in an anaerobic estuarine sediment that was preexposed to various anthropogenic chemicals from the surrounding industries with benzene identified as the product; in autoclaved sediment, the half-life was approx 400 days(11). [R110] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), chlorobenzene, which has a vapor pressure of 12 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase chlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 21 days(3,SRC). Chlorobenzene absorbs light in the environmental spectrum (> 290 nm)(4), suggesting a potential for direct photolysis(SRC). Monochlorobiphenyl has been identified as a photoproduct(5). [R111] BIOD: *Information ... concerning the biodegradation potential of chlorobenzene indicates that this compound will ... eventually degrade, but not at a substantial rate unless the microorganisms present are already growing on another hydrocarbon source. [R112] *A large number of bacteria and fungi found in the environment are capable of degrading chlorobenzene and mineralizing it. 2- and 4-chlorophenol are products of this biodegradation(1-4). Degradation is generally slow in water and soil, but may be significant in some situations(1-4). Acclimation of the degrading microorganisms is an important factor(1-4). 76.7% was removed after 8 weeks incubation at 22 deg C in a groundwater microcosm(5). The biodegradation half-life of chlorobenzene was reported to be 150 days in river water and 75 days in sediment(6). Chlorobenzene was not significantly mineralized after 8 months incubation in soil(7). A half-life of 7 days was measured in soil-groundwater slurries using a natural microbial consortia isolated from contaminated soils and groundwater(8). No degradation of chlorobenzene occurred over a period of 8 months in a laboratory study using subsurface soil samples from an uncontaminated environment(8). 0% Theoretical biological oxygen demand over 4 weeks was reported for chlorobenzene using an activated sludge inoculum(9). 99.0% removal of chlorobenzene was observed in a pilot-scale activated sludge system, an estimated 82.8% was attributed to biodegradation, 1.5% was adsorbed, and 14.7% was stripped(10). [R113] *In a series of batch transformation studies, after a 25-day lag period, 49% of chlorobenzene was removed in pond water from a strip-pit pond over 43 days(1). In pond water amended with nutrients and in pond water amended with nutrients and sewage inoculum, chlorobenzene was reduced to concns below the detection limit after 12 days incubation; in pond water amended with nutrients and a sewage inoculum, the major product of chlorobenzene biotransformation was carbon dioxide(1). No loss of chlorobenzene was observed in sterile controls(1). The addition of sediment (0.61 g/l) did not significantly affect the biotransformation of chlorobenzene(1). Bacterial isolates obtained from groundwater and soils contaminated with chlorobenzene could mineralize approx 54% of the chlorobenzene within 7 days when supplemented with ammonium and phosphate; 85 and 99% of chlorobenzene added to groundwater microcosms was utilized by 28 days(2). In soil/groundwater microcosms at a former solvent storage site, a 49% reduction in the chlorobenzene concn was observed over a 1-month period; 42% and 59% reduction in the chlorobenzene concn was observed in microcosms amended with nutrients(3). In a second microcosm study at the same site, a 94% reduction in the chlorobenzene concn was observed over 24 days when amended with hydrogen peroxide and nutrients(3). A turnover time of 60,731 hours was measured in Lula, OK aquifer solid slurries under aerobic conditions(4). Biodegradation half-lives in not heavily polluted aquifer material were > 540 days, 240 to 281 days, 88 years, and > 490 days in Oklahoma sandy clay, OK gravel, OK sand, and OK sand, respectively(5). [R114] *ANAEROBIC: A half-life of 46.2 days was measured for chlorobenzene in an anaerobic estuarine sediment that was preexposed to various anthropogenic chemicals from the surrounding industries; benzene was identified as the product; in autoclaved sediment, the half-life was approx 400 days(1). 81.3% loss (half-life of 138 days) of chlorobenzene was observed in sediment samples obtained from the Tsurumi River, Japan over 1 year under anaerobic conditions; in autoclaved sediment, approx 50% loss of chlorobenzene was observed over the 1-year incubation period(2). 82% of the original chlorobenzene concn was removed during a 47-day study using denitrifying bacteria, capable of degrading a mixture of aromatic compounds, isolated from sequential batch cultures; 60% was converted to carbon dioxide(3). [R115] ABIO: *The rate constant for the vapor-phase reaction of chlorobenzene with photochemically-produced hydroxyl radicals is 7.7X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 21 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Chlorobenzene absorbs light in the environmental spectrum (> 290 nm)(3), suggesting a potential for direct photolysis(SRC). Monochlorobiphenyl has been identified as a photoproduct(3). A photolysis half-life of 21 sunlight days was measured in water(4). Photolysis half-lives of 17.5 hours and 3.80 hours were measured in distilled water and Isar River water, Germany, respectively; chlorophenol and phenol were identified as photoproducts in river water(5). Chlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(6). [R116] BIOC: *BCFs of 4.3 to 40 and 3.9 to 23 were measured for chlorobenzene in carp at chemical concns of 0.15 and 0.015 mg/l, respectively(1). In one set of experiments, midge larvae were found to accumulate higher tissue-to-sediment ratios of chlorobenzene from a low-organic content sediment than from a high-organic content sediment(2). BCFs of 0.25 (from sediment), 11 (from interstitial water), and 10 (overlying water) were measured for midge larvae exposed to chlorobenzene under equilibrium exposure conditions(2). BCFs of 0.15 (from sediment), 310 (from interstitial water), and 5 (from overlying water) were measured for midge larvae exposed to chlorobenzene sorbed to high-organic content sediment under nonequilibrium exposure conditions(2). BCFs of 0.72 (from sediment), 18 (from interstitial water), and 2,187 (from overlying water) were measured for midge larvae exposed to chlorobenzene sorbed to low-organic content sediment under nonequilibrium exposure conditions(2). A log BCF of 2.65 has been reported for chlorobenzene in fathead minnows; this corresponds to a BCF of 450(3). According to a classification scheme(4), these BCFs suggest bioconcentration in aquatic organisms is low to high. Dissolved organic matter that is present in interstitial water may greatly reduce the amount of a chemical that is available for accumulation(2). [R117] KOC: *Koc values of 313.1 and 146.5 were measured on Captina silt loam (1.49% organic carbon) and McLaurin sandy loam, (0.66% organic carbon), respectively(1). Equilibrium sorption constatn (Ks) values of 0.295 and 0.09 were determined in Eustis fine sand (13 g/kg clay, 32 g/kg silt, 955 g/kg sand, 3.9 g/kg organic carbon) and Tampa (6 g/kg clay, 23 g/kg silt, 971 g/kg sand, and 1.3 g/kg organic carbon) soils, respectively(2); corresponding Koc values are 76 and 69(SRC). Equilibrium sorption coefficients of 0.014 and 10.20 were measured on Borden (98% sand, 1% silt, 1% clay, 0.29% organic carbon) and Mt. Lemmon (60.3% sand, 24.0% silt, 15.7% clay, 12.6% organic carbon) soils, respectively(3); corresponding Koc values are 4.8 and 81(SRC). According to a classification scheme(4), these Koc values suggest that chlorobenzene is expected to have moderate to very high mobility in soil(SRC). The sorption isotherm for chlorobenzene onto muck soil (49.0% organic carbon) was linear(5). A Kd value of 166.34 was measured for chlorobenzene using dewatered activated sludge (18% solids) that had been dried and sieved; 3.28% of the chlorobenzene was desorbed during the desorption phase of the experiment(6). Partition coefficients of 0.35, 0.33, and 0.38 were measured for chlorobenzene on primary sludge, mixed liquor solids, and digested sludge, respectively(7). Sorption coefficients of 0.48 and 0.29 were measured on primary sludge and anaerobically digested sludge, respectively(8). Partition coefficients of 48 and 29 were measured in high organic carbon (14.5%) and low organic carbon (3.6%) Sherman Island sediments, respectively(9). [R118] VWS: *The evaporation rate of chlorobenzene from water gave a half life of 10-11 hours (est), a figure which is based upon the Henry constant (calc) /3.56x10-3 atmos cu m/mole/ for chlorobenzene. [R119] *The Henry's Law constant for chlorobenzene is 3.77X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that chlorobenzene is expected to volatilize rapidly from water surfaces(2,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is approximately 3.3 hours(2,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is approximately 4.3 days(2,SRC). Chlorobenzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of chlorobenzene from dry soil surfaces may exist(SRC) based on a vapor pressure of 12 mm Hg(3). Chlorobenzene applied to soil at a uniform concn of 1 kg/ha at depths of 1 cm and 10 cm underwent 86.5 and 23.4% loss, respectively, in a day; volatilization half-lives of 0.3 and 12.6 days, respectively, were estimated from this data(4). Volatilization half-lives of 13, 21, and 4.6 days were estimated for chlorobenzene using data obtained from an experimental marine mesocosm under simulated winter, spring, and summer conditions, respectively(5). Chlorobenzene was removed within 8 days in sterile pond water incubated in bottles open to the atmosphere(6). [R120] WATC: *Monochlorobenzene was detected in groundwater in Miami, FL at a concn of 1.0 mg/l. [R121] *Monochlorobenzene was detected in raw water contaminated with municipal waste in Philadelphia, PA ... at concn of 0.1 mg/l. ... [R121] *Monochlorobenzene was detected in raw water contaminated with industrial discharge in Cincinnati, OH and Lawrence, MA at concns of 0.1-0.5 mg/l and 0.12 mg/l, respectively. [R121] *SURFACE WATER: Chlorobenzene was detected in water collected near an industrial outfall in Bayou d'Inde at a concn of 18 ng/l(1). Water samples collected from various locations in and around the Ho-Chin River of Taiwan were found to contain chlorobenzene ranging in concn from 1.6 to 1.65 ug/l(2). Chlorobenzene was identified in an analysis of subsurface riverine and marine waters conducted at the mouths of the Besos and Llobregat Rivers near Barcelona, Spain(3). The concn of chlorobenzene in the Besos and Llobregat Rivers near Barcelona, Spain was determined to be 260 and 210 ng/l, respectively; chlorobenzene was not identified in adjacent marine coastal waters(4). Chlorobenzene was identified in an aqueous sample collected near Quantico, VA as having a concn < 2 ug/l(5). Chlorobenzene was identified in surface water/groundwater samples impacted by municipal landfill leachate in Orange County, Alachua County (southwest), and Alachua County (southeast), FL as having concns ranging from < 0.20 to 302 ug/l(6). The analysis of 315 water samples collected between February and June 1987 from the municipal water supply of Santiago De Compostela, Spain showed no chlorobenzene present(7). The level of chlorobenzene detected in urban rivers and their estuaries in Osaka, Japan was approximately 0.21 ug/l(8). [R122] *GROUNDWATER: Chlorobenzene was detected in groundwater samples from a former solvent storage site at an average concn of 27 mg/l(1). In a survey of 19 small-medium sized municipal landfills in Wisconsin, chlorobenzene was detected in 5 of 113 groundwater samples (max concentration, 16 ug/l) and in 2 of 79 monitoring well samples(2). Well water samples collected over a four-year period from a well on a pesticide plant near Ashdod, Israel were found to contain chlorobenzene concns of 2, 9, 0, and 21 ug/l on 7/88, 6/89, 1/90, and 4/91, respectively(3). In a study conducted between 1986 and 1989 of the alluvial aquifer of the Sava River, Northern Croatia, chlorobenzene was detected, but not quantified, at three field sites near Zagreb, Yugoslavia(4). Chlorobenzene was identified as one of the 20 most abundant organic constituents in groundwater at 479 U.S. waste disposal sites; chlorobenzene was detected at 86 sites (18%)(5). A study of groundwater contamination at 6 Superfund sites across the U.S. detected chlorobenzene in the Biscayne, FL Aquifer study area, concn of 30 ug/l, and in the Eau Claire Municipal well field, WI, concn not specified(6). Chlorobenzene was identified in groundwater samples at a former incinerator site near Amsterdam, The Netherlands, in concns ranging from 2 to 300 ug/l(7). [R123] *DRINKING WATER: Chlorobenzene was detected in samples of California drinking water, concn not specified(1). [R124] *OTHER: Chlorobenzene was detected in strip-pit pond water, formed as a result of past coal mining activities in northeastern Ohio, at a concn of 0.41 ug/l(1). Chlorobenzene was identified but not quantified in gaseous volatiles of wastewater(2). [R125] EFFL: *Monochlorobenzene was detected in industrial discharge in Lawsons Fork Creek, SC at concns of 8.0-17.0 mg/l. [R121] *Monochlorobenzene was detected in the municipal water in Coosa River, GA at a concn of 27.0 mg/l. [R121] *The concentrations of volatile organic chemicals in the air of three wastewater treatment plants were compared on the basis of samplings carried out with charcoal tubes during a period of 7 consecutive days. Combustible organic vapor content was determined with an organic vapor analyzer provided with a flame ionization detector. The highest organic vapor concentrations (300 ppm) in the air were recorded at the plant that was processing the highest proportion of industrial wastewater; at this plant, the air levels of methyl-isobutyl-ketone, chlorobenzene, toluene, and benzene were correlated significantly with the concentration of total organic vapors in the air. Significant correlations between waste water and air space were established only for the concentrations of trichloroethylene, 1,1,1-trichloroethane and perchloroethylene; no such correlations were encountered for the concentrations of total aliphatic and nonaliphatic hydrocarbons or for total specific compounds. Comparison between the time weighted averages of 24 organics in the air obtained with the charcoal tubes and analyzed by gas chromatography and those obtained with the flame ionization detector and organic vapor analyzer system revealed that the total organics calculated according to the former method amounted to less than 10 percent of the time weighted average results from the flame ionization detector and organic vapor analyzer system. [R126] *Chlorobenzene has been detected in municipal landfill leachate at concns ranging from 1 to 685 g/l(1). Chlorobenzene was identified as one of the most frequently observed anthropogenic-specific compounds in landfill leachates; concns range from 0.1 to 110 ug/l(2). The concn of chlorobenzene detected in gas samples from wells in 3 old and 1 active municipal landfills in southern Finland ranged from < 0.01 to 0.19 mg/cu-m(3). Chlorobenzene was detected at 6 sites in Ontario, Canada in shallow aquifers that had been impacted by landfill leachate, concns ranging from < 0.2 to 10 ug/l(4). Chlorobenzene was detected but not quantified in emissions from municipal wastewater treatment plants located throughout California(5). Chlorobenzene was identified in raw wastewater of Love Canal, NY landfill leachate as having an approximate concn of 12.2 mg/l(6). The emission of chlorobenzene from the combustion of pulverized coal has been calculated to range from 3.36-1.30X10-7 lb/10+6 Btu(7). Chlorobenzene was detected in concns ranging from 0.0051 to 0.536 g/hr in emissions from 4 municipal wastewater sludge incinerators located throughout California(8). [R127] SEDS: *SEDIMENT: Chlorobenzene was not detected in sediment in an industrial river location, Lake Ontario (April to Nov 1980)(1) or in sediment from Raritan Bay (Lower Hudson)(2). Chlorobenzene was detected in bottom sediments and suspended sediments collected near an industrial outfall in Bayou d'Inde at concns of 1.5 and 0.22 ug/g organic carbon(3). Chlorobenzene was detected in sediment from a strip-pit pond, formed as a result of past coal mining activities in northeastern Ohio, below the detection limit of 1 ug/l(4). Chlorobenzene was detected as a sewer overflow contaminant in sediment of the lower Passaic River, New Jersey in concns ranging from 7 to 1400 ug/kg(5). SOIL: Chlorobenzene was detected in soil samples from a former solvent storage site at an average concn of 19 mg/kg(6). [R128] ATMC: *SOURCE DOMINATED: Chlorobenzene was detected in air samples collected from emissions of coal-fired power stations(1). [R129] *URBAN/SUBURBAN: Ambient air samples collected between December 1994 and January 1995 from 19 Kuwaiti residences were found to contain chlorobenzene ranging in concn from 0 to 332 ug/cu m(1). The average concn of chlorobenzene in air samples collected between July 6 to August 16, 1981 in Newark, Elizabeth, and Camden, NJ was determined to be 0.11, 0.08, and 0.07 ppb, respectively; the average concn of chlorobenzene in air samples collected between January 18 to February 26, 1982 in Newark, Elizabeth, and Camden, NJ was determined to be 0.22, 0.21, and 0.18 ppb, respectively(2). Chlorobenzene was identified in air samples collected between February 1987 and April 1990 from southeast Chicago and East St. Louis, IL as having mean concns of 0.3 and 3.0 ug/cu m, respectively(3). Chlorobenzene has been identified, but not quantified, in ambient air at 324 of 1400 sites across the U.S. that were sampled over a 5 year period(4). Typical chlorobenzene concns in cities in the USA ranged from 0.0 to 0.8 ppb; the maximum value measured was 12 ppb(5-8). [R130] *URBAN/SUBURBAN: Mean ambient air levels of chlorobenzene in CA were 0.2 to 3.4 ppb in Los Angeles, 0.1 to 0.64 ppb in Oakland, 2.2 in Riverside, and 0.004 in Upland; mean ambient air concns in fifty urban and near-source sites in the U.S. were 0.8 and 0.2 ppb, respectively; ambient air concns in Phoenix, AZ and Portland, OR were 0.2 and 2X10-3 ppb, respectively(1). Three sites in the Netherlands, sampled over a 1-year period in 1980, contained mean ambient air concns of chlorobenzene ranging from 0.06 to 0.1 ppb(1). The ambient air concn of chlorobenzene in 13 study areas across the U.S. (728 samples) ranged from < 0.09 to 9.1 ug/cu m between the years 1989-1991(2). [R131] *INDOOR: The average concn of chlorobenzene in workplace air collected near the shredder and digester of a composting facility ranged from 1 to 2 ug/cu m(1). Indoor air samples collected between December 1994 and January 1995 from 19 Kuwaiti residences contained chlorobenzene ranging in concn from 0 to 682 ug/cu m(2). Air samples collected from 12 Canadian homes in November/December 1986 and February/March 1987 contained a chlorobenzene concn of 0.5 ug/cu m(4). [R132] *RURAL/REMOTE: Air from remote areas of the U.S. contained < 0.02 ppb chlorobenzene(1). Chlorobenzene was identified, but not quantified, in forest air collected in the Eggegebirge in North Rhine-Westphalia between January and October 1988(2). [R133] FOOD: *Chlorobenzene concns ranged from 4.87-40.1 ppb in 2 of 234 foods analyzed, with the highest levels found in clam chowder(1). The concn of chlorobenzene in volatiles of peanut butter, garlic dressing, and flour was determined to be 1.4-2.1, 0.8, and 0.2 ug/kg, respectively(2). The average concn of chlorobenzene in 9 United Kingdom vegetable parts was determined to be 20.2 mg/kg (5.6%) fresh weight and 334 mg/kg dry weight(3). [R134] PFAC: PLANT CONCENTRATIONS: *Saxifrage (Saxifraga oppositofolia) samples collected along the coast of Ellesmere Island in the high Arctic contained chlorobenzene, concn not specified(1). Lichen samples collected from 35 locations across Ontario, Canada between 1985 and 1987 were found to contain chlorobenzene(2). [R135] FISH/SEAFOOD CONCENTRATIONS: *Two studies of chlorobenzenes in fish from the Great Lakes and Japanese coast failed to detect any chlorobenzene (1-2). Chlorobenzene was detected in catfish collected from the junction of the Calcasieu River and the Bayou d'Inde, LA, in the vicinity of an industrial outfall, at a concn of 0.05 ug/g lipid(3). It was also detected in Atlantic croakers, blue crabs, spotted sea trout, and blue catfish collected from the junction of the Calcasieu River and the Bayou d'Inde, LA, at concns of 0.10, 0.41, 0.18, and 0.05 ug/g lipid(3). Chlorobenzene was identified in samples of burbot (Lota lota) liver obtained from 68 fish collected during 1985 and 1986 at 8 sites in remote lakes and rivers of Canada(4). [R136] ANIMAL CONCENTRATIONS: *Breast-muscle of the thick-billed murres bird (Uria lomvia), originating from breeding colonies in the Canadian Arctic and collected off the coast of Newfoundland during the winters of 1986-1987 and 1989-1990, were found to contain chlorobenzene, concn not specified(1). [R137] MILK: *Mothers milk (42 samples from subjects living near manufacturing plants or industrial facilities) contained trace to 10 ppb (0.37 ppb avg) chlorobenzene(1). [R138] OEVC: *SLUDGE: Chlorobenzene was detected in 25% of UK sewage sludges at concns ranging from below the detection limit to 1.92X10+5 ug/kg dry weight, mean 3.36X10+4 ug/kg dry weight(1). The mean chlorobenzene concn in urban UK sewage sludge was 57,300 ug/kg dry weight; the chlorobenzene content in an urban/industrial sludge was 7,010 ug/kg dry weight(1). The concn of chlorobenzene in a series of samples of sewage sludges from 13 municipal wastewater treatment plants in the Federal Republic of Germany ranged from 5.5 to 153.2 ng/g(2). [R139] *OTHER: In a survey of 1,159 household products purchased from stores in 6 cities across the US, chlorobenzene was not found in any of the products at or greater than 0.1% by weight(1). The calculated emission rate for chlorobenzene from polystyrene foam insulation has been determined to be 0.46 ug/sq-m hr(2). Chlorobenzene was identified in garden waste from Denmark, concn unknown(3). Chlorobenzene was identified at a concn of 0.2 ug/l in the leachate of fabric material for collapsible potable water storage tanks(4). Chlorobenzene has been detected in the emissions from new carpet(5). [R140] RTEX: *Inhalation, ingestion, eye and skin contact. [R22, 226] *The only data concerning exposure to monochlorobenzene via air are from the industrial working environment. Reported industrial exposures to monochlorobenzene are 0.02 mg/l (avg value) and 0.3 mg/l (highest value). [R141] *Populations at special risk or exposure include: urban residents - ambient air; people near manufacturing plants; people near locations where products containing chlorobenzene as a solvent is used; and occupational workers in manufacturing plants or where chlorobenzene is used as a solvent. 0.0-1.9 mg/cu m (Dupont- Deepwater, NJ. 10/79)(1). [R142] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 17,056 workers (3,204 of these are female) are potentially exposed to chlorobenzene in the US(1). Occupational exposure to chlorobenzene may occur through inhalation and dermal contact with this compound at workplaces where chlorobenzene is produced or used(SRC). The general population may be exposed to chlorobenzene via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with vapors, food and other products containing chlorobenzene. [R143] BODY: *42 samples of mothers milk from subjects living near manufacturing plants or industrial facilities contained trace to 10 ppb (0.37 ppb avg) chlorobenzene(1). Chlorobenzene was identified in 21% of 1024 blood samples collected from non-occupationally exposed persons in concns above the detection limit of 0.007 ppb(2). Chlorobenzene was detected in composite human adipose tissue samples of 763 individual specimens, concn unknown, collected in fiscal year 1982 for the NHATS Broad Scan Analysis Program(3). The median concn in serum of: current transformer repair workers, 0.32 ppb (thirty-five subjects), former transformer repair workers, 0.30 ppb (seventeen subjects), and a control group, 0.26 ppb (fifty-six subjects)(4). In a study conducted by the USEPA in 1984, the personal air of 188 California residents was sampled; chlorobenzene was detected in 0-13% of the population(5). [R144] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +1000 ppm [R38, 62] ADI: *1.008 mg/day [R145] ATOL: *Chlorobenzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. Limits: Contains not more than 1% impurities. Not for use after edible parts of plant begin to form. Do not graze livestock in treated areas within 48 hr after application. [R146] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 75 ppm (350 mg/cu m). [R147] NREC: +NIOSH questioned whether the PEL [TWA 1 ppm] proposed for chlorobenzene was adequate to protect workers from recognized health hazards. [R38, 62] TLV: +8 hr Time Weighted Avg (TWA): 10 ppm. [R55, 2002.22] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R55, 2002.6] +Biological Exposure Index (BEI): Determinant: total 4-chlorocatechol in urine; Sampling Time: end of shift; BEI: 150 mg/g creatinine. Determinant: total p-chlorophenol in urine; Sampling Time: end of shift; BEI: 25 mg/g creatinine. The determinant is nonspecific, since it is also observed after exposure to other chemicals. [R55, 2002.89] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R55, 2002.22] OOPL: *Australia (1990); 75 ppm; (under review); Federal Republic of Germany (1990): 50 ppm; United Kingdom (1991) 50 ppm. [R89, 1991.273] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Chlorobenzene is produced, as an intermediate or a final product, by process units covered under this subpart. [R148] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Chlorobenzene is included on this list. [R149] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 100 ug/l [R150] FEDERAL DRINKING WATER GUIDELINES: +EPA 100 ug/l [R150] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 70 ug/l [R150] +(NJ) NEW JERSEY 50 ug/l [R150] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 60 ug/l [R150] +(ME) MAINE 47 ug/l [R150] +(MN) MINNESOTA 100 ug/l [R150] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Chlorinated benzenes/ [R151] +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R152] +Two approaches were used to derive criterion levels for monochlorobenzene. Based on available toxicity data, for the protection of public health, the derived level is 488 ug/l. Using available organoleptic data, for controlling undesirable taste and odor quality of ambient water, the estimated level is 20 ug/l. ... Organoleptic data as a basis for establishing a water quality criteria have limitations and have no demonstrated relationship to potential adverse human health effects. [R153] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R154] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Benzene, chloro is included on this list. [R155] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R156] RCRA: *U037; As stipulated in 40 CFR 261.33, when chlorobenzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R157] *F002; When chlorobenzene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F002), as stated in 40 CFR 261.31, and must be managed according to state and/or federal hazardous waste regulations. [R158] *D021; A solid waste containing chlorobenzene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R159] FIFR: *Chlorobenzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. Limits: Contains not more than 1% impurities. Not for use after edible parts of plant begin to form. Do not graze livestock in treated areas within 48 hr after application. [R146] FDA: *Chlorobenzene is an indirect food additive for use only as a component of adhesives. [R160] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Air Sample: ... Ambient air is drawn through a 1.5x6.0 bed of Tenax-Gas Chromatography ... so that vapors were collected completely on the resin. The sample was then thermally desorbed and the vapors passed through a cryogenically cooled trap and subsequently introduced into a gas chromatograph-mass spectrometer. [R161] *A toxic gas collection and treatment system was installed near the Gloucester Environmental Management Services landfill, Gloucester Township, New Jersey, after monitoring at the site indicated that a mixture of combustible and toxic gases were migrating toward two nearby residential areas. The mixture consisted primarily of methane, and smaller amounts of volatile organics such as toluene, benzene, chlorobenzene, xylenes, and styrene. [R162] *NIOSH Method 1003. Analyte: Chlorobenzene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min: Sample Size: 40 liter. Shipment: Routine. Sample Stability: Not determined. [R163] *Carbon hollow tubes (CHT) were prepared and tested as preconcentrators for atmospheric organic compounds. Vicor glass tubes were coated with soot from burning benzene or toluene to about 100 nm thickness. Good adsorption efficiency of analytes was obtained at flow rates of 0.5 to 1.0 l/min. Collectors were also made of carbon coated 60/80 mesh sand packed in Vicor glass tubes. The adsorption capacity for chlorobenzene, was between 16.38 and 436 ug. [R164] *... An air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug is used, to collect chlorobenzenes for gas chromatography analysis. Chlorobenzenes analyzed in air by gas chromatography using a photoionization detector. When using this method the minimum detection limit for monochlorobenezene is 15 ppb (v/v). [R165] *EPA Method 8010. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40-ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R166] *EPA Method 8020. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40-ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R166] ALAB: *A headspace technique was developed for the determination of volatile compounds including chlorobenzene from selected 49 priority pollutants in soil. A 0.5 ml headspace sample in 3 gram soil was used. The relative standard deviation for the 3 gram soil sample was less than 3%. [R167] *NIOSH Method 1003. Analyte: Chlorobenzene. Matrix: Air. Procedure: Gas chromatography, flame ionization detector. For chlorobenzene this method has an estimated detection limit of 0.01 mg/sample. The overall precision/RSD is 0.025. Applicability: The working range is 10 to 430 ppm for 40-liter air sample. Interferences: None identified. [R163] *EPA Method 8020. Direct Injection or Purge-and-Trap Gas Chromatography with photoionization detection for the determination of aromatic volatile organics including chlorobenzene in solid waste. Under the prescribed conditions, for chlorobenzene the method has a detection limit of 0.2 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R168] *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile Organics. This method can be used to quantify most volatile organic compounds including chlorobenzene that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R168] *EPA Method 502.1. Purge-and-Trap Gas Chromatography with halogen-specific detector for the determination of halogenated volatile compounds including chlorobenzene in finished drinking water, raw source water, or drinking water in any treatment stage. Under the prescribed conditions, for chlorobenzene the method detection limit is 0.001 ug/l. [R169, (1986)] *EPA Method 502.2: Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For chlorobenzene the method has a detection limit of 0.003 ug/l, a percent recovery of 100%, and a standard deviation of 1.0 using the photoionization detector; and a method detection limit of 0.01 ug/l, a percent recovery of 103, and a standard deviation of recovery of 3.7 using the electrolytic conductivity detector. [R169, (1986)] *EPA Method 503.1. Purge-and-Trap Gas Chromatography with a Photoionization Detector. The method is applicable for the determination of volatile aromatic and unsaturated organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For chlorobenzene the method has a detection limit of 0.004 ug/l and a relative standard deviation of 5.8%. Overall precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of sample matrix. [R169, (1986)] *EPA Method 524.1. Purge-and-Trap Gas Chromatography/Mass Spectrometry. The method is applicable for the determination of volatile organic compounds in water, finished drinking water, raw source water, or drinking water in any treatment stage. For chlorobenzene the method has a detection limit of 0.047 ug/l and a standard deviation of 4.6%. [R169, (1986)] *EPA Method 524.2. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the determination of volatile aromatic compounds in water including finished drinking water, raw source water, and drinking water in any treatment stage. For chlorobenzene the method has a detection limit of 0.04 ug/l and a relative standard deviation of 5.9% with a wide bore capillary column, and a method detection limit of 0.03 ug/l and a relative standard deviation of 6.4% with a narrow bore capillary column. [R169, (19860] *EPA Method 601. Purge-and-Trap Gas Chromatography with electrolytic conductivity detection for the analysis of purgeable halocarbons including chlorobenzene in municipal and industrial discharges. Under the prescribed conditions, the method detection limit for chlorobenzene is 0.25 ug/l. The method is recommended for use in the concentration range from the method detection limit to 1000 times that limit. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R170] *EPA Method 602. Purge-and-Trap Gas Chromatography with photoionization detection for the determination of purgeable aromatics including chlorobenzene in municipal and industrial discharges. Under the prescribed conditions for chlorobenzene the detection limit is 0.2 ug/l. The method is applicable for use in the concentration range from the method detection limit to 100 times that limit. Precision and method accuracy were found to be directly related to the concentration of the analyte essentially independent of the sample matrix. [R170] *EPA Method 624. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the analysis of purgeable organics including chlorobenzene in the municipal and industrial discharges. Under the prescribed conditions, for chlorobenzene the method has a detection limit of 6.0 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R170] *EPA Method 1624. Isotope Dilution Purge-and-Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of volatile organic compounds in municipal and industrial discharges. By adding a known amount of a labeled compound to every sample prior to purging, a correction of recovery for the pollutant can be made. If labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, for both labeled and unlabeled chlorobenzene the method has a minimum detection level of 10 ug/l. The established acceptance performance criteria at 20 ug/l is 8.2 ug/l for the standard deviation of the recovery, the average recovery of 14.2 to 29.6 ug/l and the /radio/ labeled compound recovery ranging from below detection limit to 205%. [R170] *EPA Method 8260. Gas Chromatography/Mass Spectrometry for the determination of volatile organic compounds. This method can be used to quantitate most volatile organic compounds including chlorobenzene that have boiling points below 200 deg C and are insoluble or slightly soluble in water. Under the prescribed conditions for chlorobenzene, the method has a detection limit of 0.04 ug/l, a percent recovery of 98%, and a percent relative standard deviation of 5.9% using a wide bore capillary column; and a detection limit of 0.03 ug/l, a percent recovery of 91%, and a percent relative standard deviation of 6.4% using a narrow bore capillary column. [R168] *EPA Method 8010. Direct Injection or Purge and Trap Gas Chromatography with halogen-specific detector for the analysis of halogenated volatile organics including chlorobenzene in solid waste. Under the prescribed conditions for chlorobenzene, the method has a detection limit of 0.25 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R168] CLAB: *METHODS ARE DESCRIBED FOR DETERMINATION OF CHLOROBENZENES (INDUSTRIAL PRODUCTS) (MONOCHLOROBENZENES THROUGH HEXACHLOROBENZENE) AT PPB LEVELS AND HUMAN URINE AND BLOOD SAMPLES BY GAS CHROMATOGRAPHY WITH PHOTOIONIZATION DETECTION. [R171] *Breath samples are collected on Tenax gas chromatography cartridges, dried over calcium-sulfate and analyzed using thermal desorption of volatiles into a gas chromatography/ mass spectrometer. ... The method is suitable /for/ ... chlorobenzene ... Approximate measured limits of detection and quantification limits for selected organic compounds in breath are tabulated. [R172] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes (1980) EPA 440/5-80-028 USEPA; Health Assessment Document: Chlorinated Benzenes (1985) EPA 600/8-84-015 DHHS/ATSDR; Toxicological Profile for Chlorobenzene (1990) ATSDR/TP-90/06 USEPA; Health Criteria Document for Chlorobenzene (Final Draft) NTIS/PB89-192116 (June 1988). The Office of Drinking Water, Environmental Protection Agency has prepared a Drinking Water Criteria Document on Monochlorobenzene. The Criteria Document is an extensive review of the following topics: Physical chemical properties of Monochlorobenzene; Toxicokinetics and human exposure to Monochlorobenzene; Health effects of Monochlorobenzene in humans and animals; Mechanisms of toxicological effects of Monochlorobenzene; Quantitification of toxicological effects of Monochlorobenzene. DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorobenzene in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 261 (1985) NIH Publication No. 86-2517 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 354 R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 197 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 263 R5: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 513 R6: CHEM MARKET REPORTER APRIL 1, 1981 R7: Chemical Profile: Chemical Marketing Reporter. Monochlorobenzene, Sept 23, 1996 R8: Trizinsky MA, Bouwer EJ; Hazard Ind Wastes 24: 197-206 (1992) R9: Sax, N.I. Dangerous Properties of Industrial Materials 3rd. ed. New York: Van Nostrand Reinhold Co., 1968. 556 R10: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 709 R11: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R12: CHEMICAL PROFILE: Monochlorobenzene, 1985 R13: Kavaler AR; Chemical Marketing Reporter 231 (27): 50 (1987) R14: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 97 R15: SRI R16: USITC. SYN ORG CHEM-US PROD/SALES 1984 p.25 R17: United States International Trade Commission. Synthetic Organic Chemicals- United States Production and Sales, 1988. USITC Publication 1989. Washington, DC: United States International Trade Commission, 1989.p. 3-2 R18: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-22 R19: BUREAU OF THE CENSUS US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS (1984) p.1-328 R20: BUREAU OF THE CENSUS US EXPORTS, SCHEDULE E, (1984) p.2-71 R21: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R22: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R23: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-33 R24: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. 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Chichester,UK: Horwood (1987) (5) Wallace LA et al; Atmos Environ 22: 2141-63 (1988) R145: USEPA; Ambient Water Quality Criteria Doc: Chlorobenzene p.C-20 (1980) EPA 440/5-80-028 R146: 40 CFR 180.1001(d) (7/1/97) R147: 29 CFR 1910.1000 (7/1/98) R148: 40 CFR 60.489 (7/1/97) R149: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R150: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R151: 40 CFR 401.15 (7/1/91) R152: 40 CFR 116.4 (7/1/91) R153: USEPA; Quality Criteria for Water 1986: Chlorinated Benzenes (May 1,1986) EPA 440/5-86-001 R154: 40 CFR 302.4 (7/1/97) R155: 40 CFR 716.120 (7/1/97) R156: 40 CFR 712.30 (7/1/97) R157: 40 CFR 261.33 (7/1/97) R158: 40 CFR 261.31 (7/1/97) R159: 40 CFR 261.24 (7/1/97 R160: 21 CFR 175.105 (4/1/97) R161: Krost KJ et al; Anal Chem 54 (4): 810-17 (1982) as cited in USEPA; Health Assessment Document: Chlorinated Benzenes p.3-16 (1985) EPA 600/8-84-015 R162: McCracken WE, Henderson DR; Management of Uncontrolled Hazardous Waste Sites: 380-5 (1986) R163: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1003-1 R164: Cobb GP et al; Analytical Chemistry 58 (11): 2213-17 (1986) R165: Langhorst ML, Nestrick TJ; Anal Chem 51 (12): 2018-25 (1985) as cited in USEPA Health Assessment Document: Chlorinated Benzenes p.3-17 (1985) EPA 600/8-84-015 R166: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R167: Kiang PH, Grob RL; J Environ Sci Health Part A Environ Sci Eng 21 (1): 71-100 (1986) R168: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R169: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water R170: 40 CFR 136 (7/1/91) R171: LANGHORST ML AND NESTRICK TJ; ANAL CHEM 51 (12): 2018 (1979) R172: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 413-31 (1985) RS: 145 Record 11 of 1119 in HSDB (through 2003/06) AN: 65 UD: 200211 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-DICHLOROETHANE- SY: *AETHYLENCHLORID- (GERMAN); *1,2-BICHLOROETHANE-; *BICHLORURE-D'ETHYLENE- (FRENCH); *BORER-SOL-; *BROCIDE-; *CHLORURE-D'ETHYLENE- (FRENCH); *CLORURO-DI-ETHENE- (ITALIAN); *1,2-DCE-; *DESTRUXOL-BORER-SOL-; *1,2-DICHLOORETHAAN- (DUTCH); *1,2-DICHLOR-AETHAN- (GERMAN); *DICHLOREMULSION-; *1,2-DICHLORETHANE-; *DICHLOR-MULSION-; *ALPHA,BETA-DICHLOROETHANE-; *beta-Dichloroethane-; *SYM-DICHLOROETHANE-; *1,2-DICLOROETANO- (ITALIAN); *DUTCH-LIQUID-; *DUTCH-OIL-; *EDC-; *ENT-1,656-; *Pesticide-Code-042003.-; *ETHANE-DICHLORIDE-; *ETHANE,-1,2-DICHLORO-; *ETHYLEENDICHLORIDE- (DUTCH); *ETHYLENE-CHLORIDE-; *ETHYLENE-DICHLORIDE-; *1,2-ETHYLENE-DICHLORIDE-; *FREON-150-; *GLYCOL-DICHLORIDE-; *NCI-C00511-; *RY-DICHLORO-1,2-ETHANE- RN: 107-06-2 RELT: 2521 [CHLOROACETALDEHYDE] (Metabolite); 426 [2-CHLOROETHANOL] (Metabolite); 1100 [OXALIC ACID] (Metabolite); 6877 [DICHLOROETHANE] (Mixture) MF: *C2-H4-Cl2 SHPN: UN 1184; Ethylene dichloride IMO 3.2; Ethylene dichloride STCC: 49 091 66; Ethylene dichloride HAZN: U077; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. D028; A waste containing 1,2-dichloroethane may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *1,2-Dichloroethane is produced by the vapor- or liquid-phase chlorination of ethylene. Most liquid-phase processes use ferric chloride as the catalyst. ... [R1, 15] *Action of chlorine on ethylene, with subsequent distillation with metallic catalyst; also by reaction of acetylene and hydrochloric acid. [R2] *Made from ethylene and chlorine; also from acetylene and HCl [R3, 648] *... Industrially produced by chlorination of ethylene ... using chlorine (direct chlorination) or hydrogen chloride (oxychlorination) as a chlorinating agent [R4] *Commercial production is by the chlorination of ethylene, either directly with chlorine or by oxychlorination using hydrogen chloride and oxygen. [R5] *HAS ... BEEN PRODUCED AS BY-PRODUCT IN CHLOROHYDRIN PROCESS FOR MANUFACTURE OF ETHYLENE OXIDE ... . [R6] FORM: *USEPA/OPP Pesticide Code 042003; Trade Names: ENT-1656; Borer Sol; Brocide; Destruxol Borer-Sol; Dichloremulsion; Dowfume; Dutch Liquid; Dutch Oil; Freon 150. [R7] *Granosan: disinfectant composed of 30% carbon tetrachloride and 70% ethylene dichloride. [R8] *Grades: Technical, spectrophotometric. [R2] *Ethylene dichloride - carbon tetrachloride (Dowfume 75). Principal ingredient: 1,2-Dichloroethane, commercial formulation, 70% active ingredient; and tetrachloromethane, commercial formulation, 30% active ingredient ... . [R9] MFS: *Borden Chemicals and Plastics, 180 East Broad St., Columbus, OH 43215-3799, (614) 225-4000, Operating Limited Partnership; Production site: Geismar, LA 70734 [R10] *Dow Chemical USA, 2030 Dow Center, Midland, MI 48674, (517) 832- 1150; Production sites: Freeport, TX 77541; Oyster Creek, TX 77541; Plaquemine, LA 70765 [R10] *Formosa Plastics Corp., U.S.A., 9 Peach Tree Rd., Livingston, NJ 07039, (973) 992-2090; Production sites: Baton Rouge, LA 70821; Point Comfort, TX 77978 [R10] *Georgia Gulf Corp., 400 Perimeter Center Terr., Suite 595, Atlanta, GA 30346, (770) 395-4500; Production sites: Lake Charles, LA 70669; Plaquemine, LA 70765-0629 [R10] *Occidental Chemical Corp., 5005 LBJ Freeway, Dallas, TX 75244, (972) 404-3800, Chloro-Vinyls Group, Basic Chemicals Div.; Production sites: Convent, LA 70723; Corpus Christi, TX 78400 [R10] *Oxymar, P.O. Box CC, Ingelside, TX 78362-0710, (316) 776-6321; Production site: Ingleside, TX 78359 [R10] *OxyVinyls LP, 5005 LBJ Freeway, Suite 500, Dallas, TX 75244, (972) 720-7000; Production sites: Deer Park, TX 77536; La Porte, TX (Independence Plant) 77571 [R10] *PPG Industries, Inc., One PPG Place, 36 East, Pittsburgh, PA 15727, (412) 434-3131. Chemicals Group; Production site: Lake Charles, LA 70602 [R10] *Vulcan Materials Co., P.O. Box 385014, Birmingham, AL 35283-5014, (202) 298-3000. Vulcan Chemicals group, Chloralkali Business Unit; Production site: Geismar, LA 70734 [R10] *Westlake Monomers Corp., Westlake Center, 2801 Post Oak Blvd., Houston, TX 77056; Production site: Calvert City, KY 42029 [R10] OMIN: *It has been replaced as a solvent and degreaser by less toxic compounds [R11, 976] USE: *For 1,2-Dichloroethane (USEPA/OPP Pesticide Code: 042003) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R7] *Solvent for fats, oils, waxes, gums, resins, and particularly for rubber; manuf acetyl cellulose, tobacco extract, etc. [R3, 646] *Fumigant /Former use/ [R2] *Production of vinyl chloride, trichloroethylene, vinylidene chloride, and trichloroethane; lead scavenger in antiknock gasoline; soaps and scouring compounds; wetting and penetrating agents; organic synthesis; ore flotation; solvent. [R2] *FUMIGANT FOR UPHOLSTERY AND CARPETS; /FORMERLY/ REGISTERED FOR AGRIC USE IN THE USA FOR POSTHARVEST FUMIGATION OF GRAIN AND FOR USE IN ORCHARDS, AGRIC PREMISES AND MUSHROOM HOUSES. [R12] *In leather cleaning, rubber goods fabrication, drum filling, and metal cleaning industries. [R13] *In degreaser compounds, rubber cement, and acrylic adhesives. [R14] *Catalyst in production of hexachlorophene. [R15] *Solvent for processing pharmaceutical products. [R16] *MANUFACTURE OF ETHYLENEDIAMINE, SUCCINONITRILE, GLYCOL ETHERS AND ESTERS. [R17] *Manufacture of ethylene glycol, diaminoethylene, polyvinyl chloride, nylon, viscose rayon, styrene-butadiene rubber, and various plastics; solvent for resins, asphalt, bitumen, rubber; used as pickling agent and a dry clean agent; in photography, xerography, water softening and in production of cosmetics. [R18, 425] *Ingredient in cosmetics (nail lacquers) and as a food additive as a result of its use in extracting spices such as annatto, paprika, and turmeric. [R19] *Most commonly used in the production of vinyl chloride monomer [R1, 15] *Starting material for chlorinated solvents such as 1,1,1-trichloroethane, vinylidene chloride, trichloroethylene, and perchloroethylene. [R1, 16] *MEDICATION *Other synthetic resin and rubber adhesives; pharmaceutical preparations; rug and upholstery cleaners [R20] *Polystyrene manufacture solvents; /Styrene Butadiene Rubber/ SBR latex production solvents [R20] CPAT: *Demand: 13.9x10+9 lb (1991); 14.3X10+9 lb (1992); 16.5X10+9 lb (1996) (forecast); includes exports of 1.45x10+9 lb (1991) but not imports estimated at 11X10+6 lb [R21] *Vinyl chloride monomer, 88%; exports, 10%, other including chlorinated solvents and ethyleneamines, 2%. [R21] *... 85% of total ...production used for production of vinyl chloride, 10% used in the production of chlorinated solvents... The rest goes into various processes mainly for the synthesis of ethylenediamines. [R4] *Demand: (1999) 15.089 billion lbs; (2000) 15.632 billion lbs; (2004) 17.938 billion lbs [R5] *Vinyl chloride monomer (VCM), 94 percent; ethyleneamines, 3 percent; 1,1,1-trichloroethane, 1 percent; vinylidene chloride, 1 percent; miscellaneous, including trichloroethylene and perchloroethylene, 1 percent. [R5] PRIE: U.S. PRODUCTION: *(1980) 5.03X10+12 G [R22] *(1981) 9,973,553,000 lb [R23] *(1983) 11,506,143,000 lb [R24] *(1990) 13.85 billion lb [R25] *(1991) 13.72 billion lb [R26] *(1992) 15.15 billion lb [R27] *(1993) 17.95 billion lb [R27] *6,220,003 kg (1991) [R28] *13th-highest-volume chemical produced in the US (1995). [R2] U.S. IMPORTS: *(1985) 6.36X10+9 g [R29] *(1999) 340 million lbs; (2000) 329 million lbs [R30] U.S. EXPORTS: *(1985) 4.42X10+11 g [R31] *(1999) 2.597 billion lbs; (2000) 2.493 billion lbs [R32] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CLEAR, COLORLESS, OILY LIQUID [R33]; *Clear liquid at ambient temperatures [R4]; *Colorless liquid [Note: Decomposes slowly, becomes acidic and darkens in color]. [R34]; *Colorless, oily liquid [R2] ODOR: *Pleasant odor [R3, 646]; *Chloroform-like odor [R2]; *Sweet [R35] TAST: *Sweet taste [R2] BP: *83.5 deg C [R2] MP: *-35.3 deg C [R36] MW: *98.96 [R36] CORR: *Corrodes iron and other metals at elevated temperatures when in contact with water. [R37] *Iron and zinc do not corrode when dry 1,2-dichloroethane is used, whereas aluminum shows strong dissolution. Increased water content leads to increased corrosion of iron and zinc; aluminum, however, corrodes less. [R4] CTP: *CRITICAL TEMP: 290 DEG C; CRITICAL PRESSURE: 52.90 ATM. [R38] DEN: *1.2351 @ 20 deg C [R36] HTC: *12.57 kJ/g [R1, 14] HTV: *76.4 CAL/G [R39] OWPC: *log Kow = 1.48 [R40] SOL: *0.869 G/100 ML WATER @ 20 DEG C [R6]; *Miscible with alcohol, chloroform, ether [R3, 646]; *Soluble in acetone; very soluble in ethanol; miscible in ethyl ether. [R36]; *Soluble in benzene, carbon tetrachloride, and organic solvents. [R41]; *Miscible with alcohol [R42, 685]; *Solubility in water @ 20 deg C - 0.86% wt [R43]; *In water, 8,600 mg/l @ 25 deg C. [R44] SPEC: *UV absorbance (1 cm cell vs water) @ wavelength 400-300 nm= absorbance of 0.01 ... @ wavelength 230 nm= absorbance of 1.0 /from table/. [R45]; *Index of refraction: 1.4448 @ 20 deg C/D [R36]; *Intense mass spectral peaks: 62 m/z (100%), 49 m/z (40%), 64 m/z (32%), 63 m/z (19%) [R46]; *IR: 20 (Sadtler Research Laboratories IR Grating Collection) [R41]; *NMR: 7304 (Sadtler Research Laboratories Spectral Collection) [R41]; *MASS: 216 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R41] SURF: *32.2 dynes/cm = 0.0322 N/m at 20 deg C [R39] VAP: *78.9 mm Hg @ 25 deg C [R47] VISC: *0.84 cP @ 20 deg C [R1, 14] OCPP: *1 PPM IN AIR= 4 MG/CU M [R6] *Resistant to oxidation [R2] *LIQUID-WATER INTERFACIAL TENSION: (EST) 30 DYNES/CM @ 25 DEG C; RATIO OF SPECIFIC HEAT OF VAPOR: 1.118 [R39] *Thermal conductivity: 0.143 W/(MK) @ 20 deg C (liq) [R48] *Dielectric constant: 10.45 @ 20 deg C (liq), 1.0048 @ 120 deg C (vapor) [R1, 14] *Dipole moment: 1.57 debye [R1, 14] *Coefficient of cubical expansion: 0.00116 ml/g @ 0-30 deg C [R1, 14] *Heat of formation: 157.3 kJ/gmole (liq) 122.6 kJ/gmole (vapor) [R1, 14] *Specific heat: 1.288 @ 20 deg C, liq; 1.066 @ 20 deg C, gas [R1, 14] *Latent heat of fusion: 88.36 J/g [R1, 14] *Saturation concn 350 g/cu m (20 deg C), 537 g/cu m (30 deg C). [R49] *Latent heat of sublimation= 35.4 kJ/mole @ 25 deg C. [R50] *Ionization potential= 11.04 eV. [R50] *Heat capacity at constant pressure= 135 J/mole 0 deg C @ 25 deg C, at constant volume= 121 J/mole 0 deg C (25 deg C). [R50] *Liquid interfacial tension with air 24.15 m N/m @ 20 deg C. [R50] *IN PRESENCE OF AIR, MOISTURE AND LIGHT, @ ORDINARY TEMP, DARKENS IN COLOR. [R6] *Gibbs (free) energy of formation @ 25 deg C: -19.03 kcal/mole (liq), -17.65 kcal/mole (gas); entropy @ 25 deg C: 49.84 cal/deg/mole (liq), 73.66 cal/deg/mole (gas) [R51] *Ethylene dichloride forms azeotropes with: 18% allyl alcohol, bp 79.9 deg C; 6% tert-amyl alcohol, bp 83 deg C; 79% carbon tetrachloride, bp 75.6 deg C; 19.5% 1,1-dichloroethane, bp 72 deg C; 17% ethanol, bp 70.3 deg C; 38% formic acid, bp 77.4 deg C; 6.5% isobutanol, bp 83.5 deg C; 43.5% isopropyl alcohol, bp 74.7 deg C; 19% propanol, bp 80.7 deg C; 10% n-propyl formate 84.1, bp deg C; 18% trichloroethylene, bp 82.9 deg C; 12% methanol, bp 61 deg C; 8.2% water, bp 70.5 deg C [R52] *Specific resistivity: 9.0x10+6 ohms/cm. [R52] *Henry's Law constant = 1.18X10-3 atm-cu m/mole @ 25 deg C [R53] *Hydroxyl radical reaction rate constant = 2.48X10-13 cu cm/molecule-sec @ 25 deg C [R54] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R55] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R55] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R55] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R55] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R55] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R55] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R55] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R55] FPOT: *Flammable liquid ... [R56, p. 49-67] *Flammable liquid. A dangerous fire hazard when exposed to heat, flame, or oxidizers. [R57, 1547] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R56, p. 325-50] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R56, p. 325-50] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R56, p. 325-50] FLMT: *Lower flammable limit: 6.2% by volume; Upper flammable limit: 16% by volume [R56, p. 325-50] FLPT: *13 deg C, 56 deg F (closed cup) [R56, p. 325-50] AUTO: *413 deg C (775 deg F) [R56, p. 325-50] FIRP: *Do not extinguish until release can be stopped. Cool fire-exposed containers with water staying clear of tank ends. [R58] *Wear self-contained breathing apparatus with full face-piece operated in positive pressure mode. [R59] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. [R60] *Use dry chemical, foam, carbon dioxide, or water spray. Water may be ineffective. Use water spray to keep fire-exposed containers cool. Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. [R56, p. 49-67] TOXC: *Products of combustion include noxious gases: phosgene, hydrogen chloride, acetylene, and vinyl chloride. [R61] OFHZ: *Vapor is heavier than air and may travel to a source of ignition and flash back. [R56, p. 49-68] EXPL: *lel: 6.2%, uel: 15.9% [R57, 1546] *Moderately explosive in the form of vapor when exposed to flame. [R57, 1547] REAC: *Explosion can result when ethylene dichloride, is mixed with liquid ammonia, dimethylaminopropylamine, nitrogen tetroxide, metal powders, organic peroxides reducing agents, and alkali and alkali earth metals. Mixtures with nitric acid are easily detonated by heat, impact, or friction. Mixtures with mercaptans form thioethers and generate heat while mixtures with nitrides generate heat and ammonia forming toxic fumes. [R62] *In the presence of UV light, air, moisture, or heat liberates toxic quantities of phosgene, hydrogen chloride, carbon monoxide, carbon dioxide, acetylene, or vinyl chloride. [R63] *Incompatibilites: Strong oxidizers and caustics, chemically active metals, such as ... magnesium powder, sodium ... . [R64] *Mixtures of /dinitrogen/ tetraoxide with ... 1,2-dichloroethane are explosive when subjected to shock of 25 g TNT equivalent or less. [R65, 1352] *A virtually unvented aluminum tank containing a 4:1:2 mixture of o-dichlorobenzene, 1,2-dichloroethane, and 1,2-dichloropropane exploded violently seven days after filling. This was attributed to formation of aluminum chloride which catalyzed ... /corrosive action/ on the aluminum tank. [R65, 25] *Although apparently stable on contact, mixtures of potassium (or its alloys) with range of halocarbons are shock-sensitive and may explode with great violence on light impact. Chloroethane, dichloroethane ... are among those investigated. [R65, 1289] *Although some mixtures of the two components /chlorine and 1,2-dichloroethane/ will burn, even that with 34% of haloalkane leads only to 2-fold pressure increase. [R65, 998] *Mixtures /of 1,2-dichloroethane and nitric acid/ are easily detonated by heat, impact or friction. [R65, 1158] *Strong oxidizers and caustics; chemically-active metals such as aluminum or magnesium powder, sodium and potassium; liquid ammonia (Note: decomposes to vinyl chloride and HCl above 1112 deg F). [R64] DCMP: *Ethylene dichloride decomposes slowly becoming acidic and darkening in color. [R63] *AT /TEMP/ GREATER THAN 600 DEG C, DECOMPOSES TO VINYL CHLORIDE, HYDROGEN CHLORIDE, AND ACETYLENE. /SRP: PHOSGENE IS ALSO FORMED/. [R6] ODRT: *Although olfactory warning properties are limited by development of tolerance, this ... liquid has an odor detectable between 6 and 40 ppm. [R11, 976] *Of 20 subjects, 13 could detect ethylene dichloride at 6 ppm (23.2-24.9 mg/cu m), 6 persons could detect it at 4.5 ppm (17.5 mg/cu m), and 1 person at 3 ppm (12.2 mg/cu m). [R66] *Odor is not a dependable guide for avoiding dangerous chronic exposures to EDC. The odor may be considered pleasant until well above 180 ppm, and may be missed below 100 ppm. [R67, p. 2-1] *Detection in air= 2.5X10-2 mg/l (gas), chemically pure [R68] *Odor threshold low: 24 mg/cu m; high: 440 mg/cu m. [R35] SERI: *Vapors are irritating. [R42, 685] EQUP: *Impervious, resistant clothing, gloves, boots, overshoes, and bib-type aprons covering boot tops. Supplied air hoods, or suits in pits or tanks, or where heat stress is likely. [R69] *Half mask or quarter mask facepieces operated with negative pressure below ten times the time-weighted average or full facepieces up to 50 times the time-weighted average. [R70] *Respirator selection: Upper limit devices recommended by NIOSH: At any detectable concentration: any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode or any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other pressure mode; Escape: Any air-purifying full facepiece respirator (gas mask) with a chin-style or front- or back-mounted organic vapor canister or any appropriate escape-type self-contained breathing apparatus. [R64] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R71, 1979.8] *For ethylene dichloride breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for natural rubber, neoprene, neoprene/natural rubber, nitrile, polyethylene (PE), chlorinated polyethylene (CPE), and polyvinyl chloride, (PVC). [R72] *For ethylene dichloride some data (usually from immersion tests) suggesting breakthrough times greater than one hour are not likely for nitrile rubber/polyvinyl chloride (nitrile/PVC). [R72] *For ethylene dichloride breakthrough times greater than one hour reported by (normally) two or more testers for polyvinyl alcohol (PVA), and viton. [R72] *Wear appropriate personal protective clothing to prevent skin contact. [R64] *Wear appropriate eye protection to prevent eye contact. [R64] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL at any detectable cocentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full face piece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R64] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R64] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R64] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R64] OPRM: *If material not on fire and not involved In fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R60] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R60] *Contact lenses should not be worn when working with this chemical. [R64] *Warning signs should be placed on equipment, storage tanks, containers, and entrances to areas of use. [R69] *Employees should wash promptly when skin becomes contaminated. Immediately remove any clothing that becomes wet to avoid flammability hazard. [R64] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *If material /is/ not on fire and not involved in fire keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R73] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R71, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R71, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R71, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used. ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R71, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs. ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R71, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R71, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R71, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R71, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R71, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R64] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R64] SSL: *STABLE IN PRESENCE OF ALKALI, ACIDS. [R74] *STABLE AT ORDINARY TEMP WHEN DRY; IN PRESENCE OF AIR, MOISTURE AND LIGHT, @ ORDINARY TEMP, DARKENS IN COLOR. [R6] *It is stable, resistant to oxidation, and noncorrosive. [R42, 685] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R75] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R76] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R77] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R71, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... . /Chemical Carcinogens/ [R71, 1979.13] STRG: *Store in a clean, cool, well ventilated area away from heat, sparks, or flames. Outside or detached storage is preferred. Small quantities can be stored in brown bottles or opaque containers due to solvent's light sensitivity. Ground and bond metal containers for liquid transfers to prevent static sparks. [R78] *Do not ship or store with food, feeds, drugs, clothing. [R79] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R71, 1979.13] *Store in a cool, dry well ventilated location. Separate from oxidizing materials, aluminum, ammonia. [R56, p. 49-68] CLUP: *Environmental considerations: land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. [R60] *Environmental considerations: water spill: Use natural deep water pockets, excavated lagoons, or sand bag. Barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R60] *In/on soil: Construct barriers to contain spill. Remove with pump on vacuum equip. Absorb residue on sorbent material and shovel into covered metal containers. In/on water: Contain by damming or water diversion. Dredge or vacuum pump to remove contaminant, liquids, and bottom sediment. In/on air: Knock down and disperse vapor with water spray. [R80] *Steaming followed by washing with water for purging tanks. [R81] *Hycar, an absorbent material, may be used for vapor suppression and containment. [R82] *After containment, a universal gelling agent may be used to solidify trapped mass. If solubilized, activated carbon (10%) may be applied. Immobilized masses can be removed using dredges or lift. [R83] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R71, 1979.15] *Biological degradation of 1,2-dichloroethane under groundwater conditions. [R84] *Eliminate all ignition sources. Use appropriate foam to blanket release and suppress vapors. Absorb in noncombustible material for proper disposal. [R56, p. 49-67] *Environmental considerations: air spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. [R60] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U077, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R85] *Waste must never be discharged into sewers or surface waters. Contaminated porous surfaces (sand, vemiculite, etc) should be disposed of at a waste management facility. Recovered liquids may be reprocessed, incinerated, or treated at a waste management facility. [R86] *Potential candidate for liquid injection incineration, with a temp range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. Also a potential candidate for rotary kiln incineration, with a temp range of 820 to 1,600 deg C and a residence time of seconds. Also a potential candidate for fluidized bed incineration, with a temp range of 450 to 980 deg C and a residence time of seconds. [R87] *This compound should be susceptible to removal from waste water by air stripping. [R88] *Concentrated wastes, such as distillation residues, spent catalysts and complex sludges, are disposed of in special waste incinerators since phosgene is liberated during burning of 1,2-dichloroethane. Solvent wastes from small-scale users are collected and regenerated by commercial reprocessing businesses. Aqueous wastes which contain dichloroethane (process effluents) are aerated until the volatile chlorohydrocarbon is evaporated. Special attention has to be given to the emission limits. Recommendable method: Incineration. Peer-review: Dilute with kerosene or fuel oil due to high chlorine content. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R89] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R71, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R71, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... Can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R71, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R71, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R71, 1979.17] *The following wastewater treatment technologies have been investigated for 1,2-dichlorothane: Concentration process: Biological treatment. [R90] *The following wastewater treatment technologies have been investigated for 1,2-dichloroethane: Concentration process: Activated carbon. [R91] *The following wastewater treatment technologies have been investigated for 1,2-dichloroethane: Concentration process: Resin adsorption. [R92] *The following wastewater treatment technologies have been investigated for 1,2-dichloroethane: Concentration process: Stripping. [R93] *The following wastewater treatment technologies have been investigated for 1,2-dichloroethane: Concentration process: Solvent extraction. [R94] *Environment Canada's Wastewater Technology Center operated a pilot plant at a landfill site to treat groundwater contaminated with volatile organic chemicals during the summer of 1986. The treatment system consisted of a packed air stripping column to treat the wastewater and two sequential granular activated carbon adsorbers to treat the off-gases. Among volatile organic chemicals in the wastewater were 1,1-dichloroethane, 1,2-dichloroethane, chloroform, 1,1-dichloroethylene, 1,1,1-trichloroethane, benzene, toluene, and trichloroethylene. Removal efficiencies varied from 27 to 99.9%. Optimal conditions, resulting in 94% removal of all volatile organic chemicals, were met with a 70:1 air-to-water ratio, a liquid flow rate of 4 l/min, and 1.3 cm Intalox saddles. Concentration of all compounds were below the lower detection limit of 2 ug/l in the effluent of the second granular activated carbon adsorber. [R95] *The adsorption capacities and rates of seven principal chlorinated organic compounds for six commercial GACs were investigated. All the adsorption isotherms were expressed by the Freundlich equation and the isotherms for the chloroethylenes such as trans-1,2-dichloroethylene, trichloroethylene and tetrachloroethylene could be shown by the modified Freundlich equation Q = k' (C/Cs)ln for each GAC. The magnitude of adsorption of the chlorinated organic compounds was in the order of: tetrachloroethylene > trichloroethylene > trans-1 2-dichloroethylene > l,l-dichloroethane > carbon tetrachloride > l,l,l-trichloroethane > chloroform. The value of k for a certain GAC could be predicted from the quantity of pores smaller than 2 mm in diameter. The adsorbed amounts were decreased by 10-20% when humic substances coexisted. The working periods of a fixed bed adsorber before regeneration were predicted by calculating breakthrough curves of various influent concentrations of trichloroethylene and tetrachloroethylene at the space velocities of 5 or 10 hr -l and it was certified that the adsorption method by GAC was feasible for removing these compounds from water. [R96] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *... The predominant source of exposure to 1,2-dichloroethane by the general population is indoor and outdoor air, only minor amounts being contributed by drinking water. Intake of 1,2-dichloroethane from food is probably negligible. ... 1,2-dichloroethane is readily absorbed following inhalation, ingestion or dermal exposure and is rapidly and widely distributed throughout the body. It is rapidly and extensively metabolized in rats and mice, with principally sulfur-containing metabolites being eliminated in the urine in a dose-dependent manner. ... 1,2-Dichloroethane appears to be metabolized via two principal pathways: the first involves a saturable microsomal oxidation mediated by cytochrome P-450 to 2-chloroacetaldehyde and 2-chloroethanol followed by conjugation with glutathione. The second pathway entails direct conjugation with glutathione to form S-(2-chloroethyl)-glutathione, which may be nonenzymatically converted to a glutathione episulfonium ion: this ion can form adducts with DNA. Although DNA damage has been induced by the P-450 pathway in vitro, several lines of evidence indicate that the glutathione conjugation pathway is probably of greater significance than the P-450 pathway as the major route for DNA damage. ... The acute toxicity of 1,2-dichloroethane is low in experimental animals. ... The results of short-term and subchronic studies in several species of experimental animals indicate that the liver and kidneys are the target organs ... Morphological changes in the liver were observed in several species following subchronic exposure to airborne concentrations ... Increases in the relative liver weight have been observed in rats following subchronic oral administration ... The carcinogenicity of 1,2-dichloroethane has been investigated in a few limited bioassays on experimental animals ... Significant increases were not reported in the incidence of any type of tumor in Sprague-Dawley rats or Swiss mice /by inhalation/ ... There was a non-significant increase in the incidence of mammary gland adenomas and fibroadenomas in female Sprague-Dawley rats exposed /by inhalation/ ... In contrast, there was convincing evidence of increases in tumor incidence in two species following ingestion. Significant increases in the incidence of tumors at several sites (including squamous cell carcinomas of the stomach (males), hemangiosarcomas (males and females), fibromas of the subcutaneous tissue (males), adenocarcinomas and fibroadenomas of the mammary gland (females)) were observed in Osborne-Mendel rats administered daily doses ... by gavage ... Similar increases in the incidences of tumors at multiple sites (including alveolar/bronchiolar adenomas (males and females), mammary gland adenocarcinomas (females) and endometrial stromal polyp or endometrial stromal sarcoma combined (females) and hepatocellular carcinomas (males)) occurred in B6C3F1 mice administered daily doses ... by gavage ... The incidence of lung tumors (benign papillomas) was significantly increased in female mice following repeated dermal application of 1,2-dichloroethane ... Concomitant exposure to inhaled 1,2-dichloroethane and disulfiram in the diet resulted in an increased incidence of intrahepatic bile duct cholangiomas and cysts, subcutaneous fibromas, hepatic neoplastic nodules, interstitital cell tumors in the testes and mammary adenocarcinomas in rats, compared to rats administered either compound alone or untreated controls. No potential to initiate or promote tumor development was evident ... In in vitro assays, 1,2-dichloroethane has been consistently positive in mutagenicity bioassays in Salmonella typhimurium. In cultured mammalian cells, 1,2-dichloroethane forms adducts with DNA. It also induces unscheduled DNA synthesis in primary cultures of rodent and human cells and gene mutation in several cell lines. Mutation frequency in human cell lines has been correlated with differences in glutathione-S-transferase activity. ... There is no evidence that 1,2-dichloroethane is teratogenic in experimental animals. ... Acute incidental exposure to 1,2-dichloroethane by inhalation or ingestion has resulted in a variety of effects in humans, including effects on the central nervous system, liver, kidney, lung and cardiovascular system. The potential carcinogenicity of 1,2-dichloroethane in exposed human populations has not been extensively investigated. ... [R97] CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1,2-dichloroethane. There is sufficient evidence in experimental animals for the carcinogenicity of 1,2-dichloroethane. Overall evaluation: 1,2-Dichloroethane is possibly carcinogenic to humans (Group 2B). [R98] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on the induction of several tumor types in rats and mice treatd by gavage and lung papillomas in mice after topical application. HUMAN CARCINOGENICITY DATA: None. [R99] *A4. Not classifiable as a human carcinogen. [R100] ANTR: *Treatment: Stabilization: As with most chlorinated hydrocarbons, the immediate life-threatening complications are respiratory arrest and cardiac dysrhythmia. Hence, initially attention should be directed toward establishing an airway, providing ventilation, and improving circulation as dictated by the clinical situation. Decontamination: since ethylene dichloride is a potent hepatorenal toxin, all except minor exposures seen within 4 hours of ingestion should be given the usual methods of decontamination (ipecac or lavage/activated charcoal and cathartics). Contaminated clothes should be removed and the exposed skin washed with green soap and water. Supportive care: No methods to enhance removal and no antidotes have been proven effective. Severe cases require close monitoring of clotting times and serum glucose and calcium levels, as well as hepatic and renal function. Hemodialysis is reserved for renal failure. [R11, 977] */An analysis was conducted/ on the use of acetylcysteine as specific antidote treatment in 37 patients with acute 1,2-dichloroethane poisoning. Admin of dichloroethane did not produce any determining effect on the outcome of the treatment in critical and irreversible concn of 1,2-dichloroethane in the blood. The main component in complex therapy is early hemosorption. Acetylcysteine may be used in the complex treatment of acute 1,2-dichloroethylene intoxications after early extracorporal detoxification with the purpose of reducing the severity of toxic hepatopathies. [R101] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations as needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Minimize physical activity and provide a quiet atmosphere. Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. Rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Treat frostbite with rapid rewarming techniques ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R102] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R102] *Stabilization: Treatment is largely supportive. Watch for respiratory depression and arrhythmias. Obtain arterial blood gases. Administer oxygen if there is evidence of altered mental status or dyspnea. Treat hypotension with volume expansion and vasopression. Use lidocaine or beta-blockers for ventricular arrhythmias. Skin: Remove contaminated clothing. Wash affected area with soap and copious amounts or water. Eye: Irrigate the eye for 15-20 min. Obtain a consultation if symptoms persist. Oral: Most of the halogenated solvents ingested in quantities of 1-2 swallows may be partially removed by ipecac-induces emesis if admin within a few hr to a patient who has not lost the gag reflex, is not seizing, is not markedly lethargic, or is not in coma. Observe the patient in the upright position to lessen the possibility of aspiration. Activated charcoal is probably ineffective. Inhalation: Move from the contaminated area. Provide a source of oxygen and prepare for mechanical ventilation. If the patient is unconscious and the pulse is absent, initiate CPR measures. Enhancement of Elimination: Maintain good ventilation. Hemodialysis or hemoperfusion are not likely to be useful because of the high lipophilic properties of these solvents. Antidote: N-acetylcysteine may restore depleted glutathione stores, but no adequate clinical studies are available to validate this possible treatment. Supportive Care: Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encephalopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, EKG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. /Halogenated hydrocarbons/ [R103] MEDS: *Annual medical exams shall be made available to all workers exposed to ethylene dichloride including medical and work history and comprehensive medical exam with particular attention to cardiovascular, pulmonary, neurological, liver and kidney functions. Records will be maintained for 20 yrs /SRP: OSHA requires 30 years/ after termination of employment. [R104] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R71, 1979.23] *Preplacement physical examinations should focus on establishing a baseline for kidney and cardiac function as well as detecting preexisting conditions (arteriosclerotic heart disease, liver dysfunction, chronic skin conditions, alcoholism) that may predispose the worker to toxic effects of halogenated solvents. Periodic medical exams should be designed to detect alterations in CNS function (e.g., impairment of perceptual speed, reaction time, and manual dexterity), hepatic dysfunction, GI symptoms, and dermatitis. The extent of routine laboratory analyses (serum hepatic transaminases, urinalysis, serum creatinine) depends on the physician's judgment of the severity of exposure based on workplace practice, environmental monitoring, and biologic exposure limits. /Halogenated solvents/ [R105, 744] *The assessment of ethylene dichloride exposure can be accomplished through measurement of ethylene dichloride. However, this measurement should be performed shortly after exposure, since ethylene dichloride is rapidly eliminated form the body. In addition it is not possible from /Whole blood or Urine/ measurement to assess the level of ethylene chloride to which the person was exposed, due to the lack of reference ranges which correlate with exposure levels. [R106, 650] *Chest Radiography: Chest radiographs are widely used to assess pulmonary disease. They are useful for detecting early lung cancer in asymptomatic people, and especially for detecting peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such asbestos, experts' views on the risk-to-benefit ratio in detection of pulmonary disease conflict, so routine annual chest x-rays are not recommended for all people. [R106, 653] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. [R106, 653] *Urine Albumin: Albuminuria has been shown to be a specific marker of glomerular dysfunction. Tubular damage, however, can also result in increased levels of albumin in the urine. [R106, 651] *Urinary Beta-2-Microglobulin and/or Retinal Binding Protein: Measurements for the presence of either of these low molecular weight proteins are useful in detection of early impairment of proximal tubular function. However, beta-2-microglobulin is unstable at urinary pH less than 6, and may degrade in the bladder prior to collection and subsequent neutralization of the urine sample. Measurement of retinal binding protein appears to be a better marker for early tubular dysfunction due to its stability in the urine subsequent to collection and analysis. However, retinal binding protein is produced in the liver and not a constitutive protein of the kidney, so that its presence in the kidney provides only indirect evidence of tubular damage. [R106, 651] *Urinary Enzyme N-Acetylglucosaminidase: This lysosomal enzyme has shown promise in assessment of subclinical nephrotoxic injury. This enzyme is not normally filtered at the glomerulus due to its high molecular weight. In the absence of glomerular injury, this enzyme will be detected in the urine as a result of leakage or exocytosis from damaged, stimulated, or exfoliated renal cells. The sensitivity of measurement for this enzyme has not been thoroughly studied, but it's usefulness has shown some promise. However, this enzyme is unstable at urinary pH > 8, which could diminish the sensitivity of the measurement due to enzyme degradation. [R106, 652] *Routine Urinalysis: Performing a routine urinalysis including parameters such as specific gravity, glucose, and microscopic exam may be useful for assessing renal toxicity. Cylinduria, or formation of various types of casts from material in the renal tubules, is detected only by microscopic analysis, but is often preceded by albuminuria or increases in white cells, red cells, or epithelial cells in the urine. Workers with potential exposure to nephrotoxins should have baseline, pre-exposure measurements of the parameters that will be selected for assessing early renal damage. Periodic measurement should be compared to the baseline results. The normal progression of chronic renal insufficiency usually takes several years to evolve, however glomerulonephritis can occur as early as several months. [R106, 652] *Liver Function Tests: Biochemical tests - Enzymes that reflect cholestasis: alkaline phosphatase (AP), 5'-nucleotidase (5'-NT) and leucine aminopeptidase (LAP); Enzymes that detect direct hepatic damage: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gammma glutamyl Transpeptidase (GGTP); Clearance tests - indocyanine green, antipyrine test and serum bile acids. [R106, 652] HTOX: */Ethylene dichloride/ ... is a central nervous system depressant that produces symptoms ranging from nausea, vomiting, headache, lightheadedness, and weakness to stupor, dysequilibrium, coma, and respiratory arrest. Typically, in severe cases, CNS signs appear first within several hr of exposure and are followed by a quiescent period. On the second day, oliguria and hepatic transaminasemia may develop. Subsequently, over the next several days, hepatorenal failure can occur. Severe ingestions produce widespread organ damage (especially kidney, liver, and adrenal gland) as well as gastrointestinal bleeding. Hepatic and renal dysfunction has been complicated by fatal massive midzonal hepatic necrosis, acute tubular necrosis, hypoglycemia, hypercalcemia, hypoprothombinemia, reduced clotting factors, adrenal necrosis, and gastrointestinal hemorrhage. Heavy exposure produces a bluish purple discoloration of the skin, dermatitis, and corneal abrasions. [R11, 976] *ACCIDENTAL ORAL INGESTION OF A SINGLE DOSE OF 0.5-1.0 G/KG HAS BEEN REPORTED TO RESULT IN DEATH; AUTOPSY REVEALED LIVER NECROSIS AND FOCAL ADRENAL DEGENERATION AND NECROSIS. [R107] *Chronic poisoning: (From inhalation or skin absorption.) Wt loss, low blood pressure, jaundice, oliguria, or anemia may occur after repeated minimal exposure. [R108] *Repeated contact with liquid can produce a dry, scaly, fissured dermatitis. Liquid and vapor may also cause eye damage, including corneal opacity. ... Acute exposures can lead to death from respiratory and circulatory failure. Autopsies ... have revealed widespread bleeding and damage in most internal organs. [R18, 426] *IN CASES OF HUMAN POISONING BY 1,2-DICHLOROETHANE, THE MAX ACTIVITY OF SERUM GLUTAMATE OXALACETATE TRANSAMINASE, GLUTAMATE PYRUVATE TRANSAMINASE, AND GLUTAMATE DEHYDROGENASE WAS OBSERVED AFTER 5-8 DAYS, AND IN 1 CASE AFTER 12 DAYS. [R109] *Agricultural workers received exposure dermally and via inhalation (4-60 ppm) resulting from fumigation practices. 90 of 118 workers reported symptoms including conjunctival congestion and burning sensation, weakness, bronchial and pharyngeal symptoms, metalic taste in mouth, headache, dermatographism, nausea, liver pain, tachycardia, and dyspnea after effort. Liver function measurements showed abnormality in 40/56. [R110] *Aircraft industry workers using glue emitting 5-40 ppm ethylene dichloride while drying were investigated over 5 years. Diseases of the liver and bile ducts (19/83), neurotic conditions (13/89), autonomic dystonia (11/83), asthenic conditions (5/89), and goiter and hyperthyroidism (10/89) were revealed. [R111] *Intensification of light sensitivity due to exposure was measured at concentrations of 1-12.5 ppm (4-50 mg/cu m). 1 ppm produced no change in light sensitivity of the eye while at higher concentrations the threshold of light perception decreased. [R112] *Circulatory changes after ingestion included a reduction in clotting factors, platelet count, blood glucose levels, and albumin to globulin ratio and an increase in fibrinolysis, prothrombin time, serum calcium, aldolase, and bilirubin. Associated pathological changes included thrombi (pulmonary arterioles and capillaries), hemorrhages (mucosa of esophagus, stomach, rectum and cardiac tissue), overt bleeding into visceral organs and lungs, focal hemorrhaging of the liver and kidney damage. [R113] *Ingestion of 1 or 2 oz, 400-800 mg/kg body weight, by an adult male is fatal, deaths caused by circulatory or respiratory failure. The primary target appears to be the central nervous system (CNS). [R114] *Neurotoxic effects: ... Mental confusion; vertigo; ... functional nervous system changes; nervousness; insomnia; memory disorders; tremor; nystagmus. /From table/ [R115] *The cause-specific mortality of 2,510 males employed at an east Texas chemical plant was examined in a historical prospective study to evaluate a suspected incr in deaths from multiple myeloma and brain cancer. Potential exposures from chemicals, either used in manufacturing processes or produced during the study period 1952-1977, included the fuel additive tetraethyl lead, ethylene dibromide, ethylene dichloride, inorganic lead, and vinyl chloride monomer. Overall mortality for all workers (156 observed vs 211.14 expected) and for workers first employed between 1952 and 1959 (131 observed vs 167.33 expected) when tetraethyl lead was the single major product was lower than expected when compared to the (USA) general population. There were no significant increases in mortality from malignancies or other causes of death. The deficits may be due to the small number of total deaths, and the lower power for detecting excess risk of mortality from multiple myeloma (zl-beta= 27, alpha= 0.05), brain cancer (zl-beta= 31, alpha= 0.05), or other rare causes of death; lack of complete workplace exposure data for production workers; and the absence of historical measurements on the extent of environmental exposure. ... [R116] *1,2-Dichloroethane (EDC) and 1,2-dibromoethane (DBE) were tested for the ability to induce gene mutations in 2 human lymphoblastoid cell lines, designated AHH-1 and TK6. Both chemicals were direct-acting mutagens in both cell lines. ... EDC was 25-fold more mutagenic in the AHH-1 cell line than in the TK6 cell line. This differential sensitivity between AHH-1 cells and TK6 cells was related to the levels of glutathione S-transferase activity in these 2 cell lines. [R117] *Repeated skin contact should be avoided since the solvent can cause defatting of the skin, severe irritation, and moderate edema. Eye contact may have slight to severe effects. [R118] *WORKERS EXPOSED FULL-TIME TO CHEMICALS INCL ETHYLENE DICHLORIDE IN PRODN OF ETHYLENE OXIDE SHOWED EXCESS MORTALITY FROM TUMORS AND DISEASES OF THE CIRCULATORY SYSTEM. ETHYLENE DICHLORIDE WAS A PRIME SUSPECT. [R119] *Alpha-proteinase inhibitor can be inactivated by aldehydes found in the cigarette smoke as well as by industrial chemicals. Studies demonstrate the synergistic inactivation of alpha-proteinase inhibitor by 1,2-dichloroethane when mixed with acrolein or pyruvic aldehyde. Smokers exposed to the chemical may be more prone to lung emphysema due to synergistic inactivation of alpha-proteinase inhibitor by chemicals and cigarette smoke components. [R120] *Three workers who spent about 4 hr washing yarn in an open vat became dizzy and nauseated and vomited profusely. They complained of weakness, trembling, and cramplike epigastic pain. When examined about an hr after onset, all were still vomiting frequently, all had red macerated hands, and least one had rales in lungs and a palpable liver. Partial recovery was prompt, but occasional nausea persisted for several days. The men were discharged in a wk but their hands healed only after several more weeks. [R42, 686] *In man, death has resulted from the ingestion of 20 to 50 ml. Ethylene dichloride is hepato- and nephro-toxic. Acute exposure also leads to central nervous depression, reduced blood pressure, and cardiac impairment. In humans, signs of intoxication are headache, nausea, vomiting, dizziness, watery stool, internal bleeding, cyanosis, weak and rapid pulse and loss of consciousness. In one human poisoning by ingestion, hypoglycemia, increased clotting time and hypercalcemia were prominent laboratory findings. Symptoms developed slowly; death occurred after six days. Extensive necrosis of liver, kidney and adrenal glands was found at autopsy. [R121, p. II-163] *Fatal dichloromethane poisoning in 2 workers following inhalation exposure was described. The 2 men (50 and 55 yr old) were employed at an Italian chemical factory and were found dead in a 2 m deep well where they had been burying barrels of chemical waste. The barrels contained mixed solvent and solid wastes. On site air sampling found dichloromethane vapor concns ranging up to 582 mg/l. Concns below 6 mg/l of 1 2-dichloroethane, l,l,l-trichloroethane and styrene were also detected. Blood samples collected 24 hr after death contained 571.6 and 600.9 mg/l dichloromethane. Smaller concns of 1,2-dichloroethane, 1,1,1-trichloroethane and styrene were also found. Blood carboxyhemoglobin concns of 30% saturation were also found. Autopsies revealed extensive brain and lung edema and congestion gastric congestion and erosive multifocal gastritis in both victims. Kidney congestion was manifested as tubular swelling and degeneration, glomerular swelling and congestion of the vessels. Congestion was also seen in the liver, spleen and adrenals. ... Both deaths were caused by acute inhalation of extremely high dichloromethane vapor concns. ... [R122] *The United States National Toxicology Program lists ... 1,2-dichloroethane /as a suspected carcinogen/. This category implies that these chemicals may be reasonably anticipated to be carcinogens based on (1) evidence of carcinogenicity from studies in humans that cannot exclude chance bias or confounding but appear credible; or (2) sufficient evidence of carcinogenicity from studies of animals which indicate an increased incidence of malignant tumors (a) in multiple species or strains, (b) in multiple experiments, or (c) to an unusual degree with regard to the incidence, site, or type of tumor. [R105, 742] *Halogenated solvents tested during the 1800s for use as an anesthetic and discarded included ... 1,2-dichloroethane (/caused/ excessive salivation, convulsive movements, postoperative blue-gray corneal opacities)... . [R105, 732] *Centrilobular hepatic necrosis has been observed in autopsy of one case of a 51-yr old man who died following an inhalation exposure in a confined space. This case was remarkable for the elevation of serum ammonia, serum transaminase (SGOT, SGPT), lactate dehydrogenase (LDH), and creatine kinase isoenzymes (MM-CPK). In addition, elevation of mitochondrial ornithine carbonyl transferase (OCT) and mitochondrial glutonic oxaloacetic transaminase was observed, which indicates that dichloroethane can cause mitochondrial damage. [R105, 813] *In a study of 278 men working in the chlorohydrin unit of a chemical production plant between 1940-1967 and followed up to 1988, there was a significant (p < 0.01) excess of deaths due to pancreatic cancer compared to the USA national rates [Standardized Mortality Ratio (SMR)= 492 (95% CI=158-1140); Observed:Expected (O:E)= 8:16]. The excess was greater when confined to men who worked in the unit for more than 2 yr (SMR= 800). Based on comparison with 2 groups of workers in nearby plants, there were pronounced increases in mortality due to pancreatic cancer as exposure duration increased. Though an excess of deaths due to "lymphatic and hemopoietic cancers" was also observed, it appeared to be attributable principally to leukemia, for which numbers of observed cases were small (O=4) and associations with duration of exposure were less consistent. ... The authors concluded on the basis of considerable qualitative information that workers in this unit had been exposed primarily to 1,2-dichloroethane in combination with bis-chloroethyl ether, ethylene oxide and ethylene chlorohydrin. [R123] *A 51-yr old man who inhaled a concentrated vapor of 1,2-dichloroethane for only 30 min died 4 days later from cardiac arrhythmia ... . No attempt was made to estimate the actual exposure concn. An autopsy revealed congestion of the lungs, degenerative changes in the myocardium, liver necrosis, renal tubular necrosis, and shrunken nerve cells in the brain. [R124] *... ingestion of large amt of 1,2-dichloroethane may be lethal to humans. ... reported a case in which a 63-yr old man accidentally swallowed approx 2 ounces (60 ml) of 1,2-dichloroethane and died 22 hr later of circulatory failure. A 50-yr old man mistakenly ingested approx 30 ml of 1,2-dichloroethane and died after 10 hr ... . A 14-yr old boy died 6 days after ingesting 15 ml of 1,2-dichlorethane ... . A 30-yr old patient in a neuropsychiatric hospital ingested approx 40 ml of 1,2-dichloroethane and died 28 hr later ... . ... reported a case of an 18-yr old man who because drowsy, cyanotic, and exhibited bradycardia after drinking approx 50 ml of Marament which is equivalent to 50 g of 1,2-dichloroethane (714 mg/kg/day); he died 17 hr later in a state of circulatory shock. [R125] *The respiratory effects exhibited by individuals who died following acute oral exposure to 1,2-dichloroethane incl congestion, pulmonary edema (at 570 mg/kg/day) and bronchitis ... . [R126] *Clinical investigation of patients who died following acute ingestion of 1,2-dichloroethane determined that cardiovascular insufficiency and hemorrhage were major factors contributing to death ... . [R126] *GI symptoms have been observed in humans prior to death following oral exposure to 570 or 714 mg/kg/day of 1,2-dichloroethane. These symptoms incl nausea, vomiting, and diarrhea ... . Hemorrhagic colitis, hemorrhagic gastritis, and focal hemorrhages of the GI tract have also been reported upon autopsy ... . [R126] *1,2-Dichloroethane has been implicated as a hepatotoxin humans after acute oral poisoning ... . Ingestion of > or = 570 mg/kg/day of 1,2-dichloroethane resulted in severe hepatocellular damage and liver atrophy ... and necrosis ... . [R127] *Acute renal damage resulting from ingestion of 1,2-dichloroethane has been observed in humans. Ingestion of 714 mg/kg/day resulted in bleeding and hyperemia of kidney in a 50-yr old man ... . In one case study, renal damage that resulted from acute oral poisoning of a 25-yr old man was not considered severe or permanent, and the patient fully recovered ... . The amt of 1,2-dichloroethane ingested was not reported. However, individuals who died following ingestion of 15-30 ml of 1,2-dichloroethane had severe kidney damage, primarily in the form of diffuse renal necrosis ... . These are only crude estimates of ingested dose. [R128] *Neurological effects, such as CNS depression, have been reported in humans following acute oral intoxication with 1,2-dichloroethane ... . Morphological alterations in the nervous system were observed in patients who died of acute oral poisoning by 1,2-dichloroethane. These alterations incl vascular disorders, diffuse changes in cerebellar cells, parenchymatous changes in brain and spinal cord, myelin degeneration, and hyperemia and hemorrhage of the brain ... . The morphological changes observed in the cerebellum may affect the coordination of muscular movements. [R129] NTOX: *... Chronic toxicity of 1,2-dichloroethane /was studied/ by exposing /rats, rabbits, guinea pigs, monkeys, dogs, and cats/ 7 hr/day, 5 days/wk to concn of 100-1000 ppm of the vapor in air. At a concn of 1000 ppm rats, rabbits, and guinea pigs died after a few 7 hr exposures. Dogs and cats ... /were/ more resistant, but deaths eventually occurred. Pathological exams of the various animals showed ... pulmonary congestion, renal tubular degeneration, fatty degeneration of the liver, and less commonly, necrosis and hemorrhage of the adrenal cortex and fatty infiltration of the myocardium. ... Deaths occurred among guinea pigs, rabbits, and rats, although some of the animals survived many exposures. Pathological exam revealed lesions similar to those seen with 1000 ppm. A concn of 200 ppm was ... tolerated by 2 monkeys and 5 rabbits. ... When concn ... was lowered to 100 ppm, even rats, guinea pigs and mice survived exposures for 4 mo and developed no demonstrable lesions. A comparable chronic study was carried out /by others/ ... /in/ animals /exposed/ 7 hr/day, 5 days/wk. They likewise showed high mortality at 400 ppm in rats and guinea pigs in periods of 14 to 56 days of exposure. The animals showed loss of weight and slight incr in weights of liver and kidneys, but relatively slight histopathological changes. Guinea pigs showed more definite histopathological changes in both the liver and kidneys. [R130, 3493] *GROUPS OF 50 MALE AND 50 FEMALE 5 WK-OLD B6C3F1 MICE WERE ADMIN TECHNICAL-GRADE 1,2-DICHLOROETHANE IN CORN OIL BY GAVAGE ON 5 CONSECUTIVE DAYS/WK FOR 78 WK. ... THE TIME-WEIGHTED AVG DOSES WERE 195 AND 299 MG/KG BODY WT/DAY FOR HIGH-DOSE MALES AND FEMALES AND 97 AND 149 MG/KG BODY WT/DAY FOR LOW-DOSE MALES AND FEMALES. A GROUP OF 20 MALE AND 20 FEMALE MICE THAT RECEIVED CORN OIL ALONE SERVED AS MATCHED VEHICLE CONTROLS. ANOTHER GROUP OF 60 MALE AND 60 FEMALE MICE THAT RECEIVED THE SAME VEHICLE SERVED AS POOLED VEHICLE CONTROLS. OF THE HIGH-DOSE MALES, 50% SURVIVED AT LEAST 84 WK, and 42% SURVIVED UNTIL END OF STUDY; 72% (36/50) OF HIGH-DOSE FEMALE MICE DIED BETWEEN WK 60 and 80. IN LOW-DOSE GROUPS, 52% (26/50) OF MALES SURVIVED < 74 WK, and 68% (34/50) OF FEMALES SURVIVED UNTIL END OF STUDY. IN VEHICLE CONTROL GROUPS, 55% (11/20) OF MALES AND 80% (16/20) OF FEMALES SURVIVED UNTIL END OF STUDY. ALMOST ALL ORGANS AND ANY TISSUE CONTAINING VISIBLE LESIONS WERE EXAM HISTOLOGICALLY. THE NUMBERS OF ANIMALS WITH TUMORS AND TOTAL NUMBER OF TUMORS WERE SIGNIFICANTLY GREATER IN MALE AND FEMALE MICE TREATED WITH THE HIGHER DOSE LEVEL, AND IN FEMALE MICE TREATED WITH THE LOW DOSE, THAN IN CONTROLS. INCR INCIDENCE OF THE FOLLOWING NEOPLASMS WERE OBSERVED: MAMMARY ADENOCARCINOMAS, UTERINE ADENOCARCINOMAS ENDOMETRIAL STROMAL NEOPLASMS OF UTERUS AND SQUAMOUS-CELL CARCINOMAS OF FORESTOMACH IN FEMALES; LUNG ADENOMAS AND MALIGNANT HISTIOCYTIC LYMPHOMAS IN MALES AND FEMALES; AND HEPATOCELLULAR CARCINOMAS IN MALE MICE. [R131] *1,2-Dichloroethane is mutagenic in Salmonella typhimurium TA1530, TA1535, AND TA100, presumably causing base-pair substitution mutations; the mutagenic effect was enhanced by addition of cytosol and glutathione. It was ineffective in inducing somatic crossing-over and nondisjunction in Aspergillus nidulans. [R132] *GROUPS OF 50 MALE AND 50 FEMALE OSBORNE MENDEL RATS, 9 WK OLD, WERE ADMIN TECHNICAL-GRADE 1,2-DICHLOROETHANE IN CORN OIL BY GAVAGE ON 5 CONSECUTIVE DAYS/WK FOR 78 WK. ... THE TIME-WEIGHTED AVG DOSES WERE 95 and 47 MG/KG BW/DAY FOR HIGH- AND LOW-DOSE MALES AND FEMALES. A GROUP OF 20 MALE AND 20 FEMALE RATS RECEIVED CORN OIL ALONE AND WERE USED AS MATCHED VEHICLE CONTROLS; ANOTHER GROUP OF 60 MALE AND 60 FEMALE RATS RECEIVED THE SAME VEHICLE AND WERE USED AS THE POOLED VEHICLE CONTROL GROUP. THE LAST HIGH-DOSE MALE RAT DIED DURING WK 23 ... AND THE LAST HIGH-DOSE FEMALE RAT DIES DURING WK 15 OF THE OBSERVATION PERIOD. LOW-DOSE RATS WERE OBSERVED FOR 32 WK AFTER ADMIN. MORTALITY WAS INCR IN HIGH-DOSE GROUPS: 50% OF MALES WERE DEAD BY WK 55 and 50% OF FEMALES BY WK 57; BY WK 75, 84% OF MALES AND 80% OF FEMALES WERE DEAD. IN LOW-DOSE GROUP, 52% OF MALES SURVIVED OVER 82 WK, and 50% OF FEMALES SURVIVED OVER 85 WK. ALL TREATED AND CONTROL ANIMALS WERE EXAM HISTOLOGICALLY. THE TOTAL NUMBER OF TUMORS WAS SIGNIFICANTLY GREATER THAN THAT IN CONTROLS ONLY IN FEMALE RATS TREATED WITH HIGH DOSE; HOWEVER, A SIGNIFICANT INCR IN NUMBER OF SQUAMOUS-CELL CARCINOMAS OF FORESTOMACH IN MALE RATS AND MAMMARY GLAND ADENOCARCINOMAS AND FIBROADENOMAS IN FEMALE RATS TREATED WITH THE HIGH DOSE WAS OBSERVED. ... A GROUP OF 20 MALE AND 20 FEMALE UNTREATED MATCHED CONTROLS WAS INCL, BUT IT WAS NOT CONSIDERED IN STATISTICAL ANALYSES OF TUMORS INCIDENCE. [R133] *... INCR IN MUTATION FREQUENCY /REPORTED/ IN BARLEY (HORDEUM VULGARE) WHEN KERNELS WERE TREATED FOR 24 HR AT 20 DEG C WITH 30.3 MMOL 1,2-DICHLOROETHANE. [R132] *EXPOSURE OF VIRGIN DROSOPHILA MELANOGASTER FEMALES TO 1,2-DICHLOROETHANE VAPORS IN AIR (7 MG IN A 1.5-L DESICCATOR FOR 4 OR 8 HR) LED TO AN INCR IN FREQUENCY OF SEX-LINKED RECESSIVE LETHALS; INCR IN THE FREQUENCY OF SEX-CHROMOSOME NON-DISJUNCTION WAS SEEN AFTER THE 8-HR TREATMENT. [R132] *MALE AND FEMALE ICR SWISS MICE RECEIVED 1,2-DICHLOROETHANE @ 0, 0.03, 0.09, OR 0.29 MG/ML IN WATER. NO DOSE-DEPENDENT EFFECTS ON FERTILITY, GESTATION, VIABILITY, OR LACTATION INDICES WERE OBSERVED AND THE SURVIVAL OF PUPS AND WT GAIN WERE NOT ADVERSELY AFFECTED. [R134] *WHEN HALOETHANES WERE BEING TESTED AS DIRECT-ACTING AGENTS IN THE CHINESE HAMSTER OVARY CELL/HYPOXANTHINE-GUANINE PHOSPHORIBOSYL TRANSFERASE (CHO/HGPRT) SYSTEM ETHYLENE BROMIDE EXHIBITED MORE CYTOTOXIC AND MUTAGENIC ACTIVITY THAN ETHYLENE DICHLORIDE AND ETHYLENE BROMOCHLORIDE. ON A MOLAR BASIS, THE RELATIVE ACTIVITY OF ETHYLENE BROMIDE : ETHYLENE BROMOCHLORIDE : ETHYLENE DICHLORIDE WAS APPROX 100 : 6 : 1. CELL SURVIVAL WAS DECREASED TO 50% BY APPROX 3, 6 and 50 MMOLES OF THESE COMPOUNDS RESPECTIVELY. WHEN THESE 3 HALOETHANES WERE ASSAYED IN PRESENCE OF S9 MIXTURE, THERE WAS 5-25-FOLD INCR IN MUTAGENICITY; HOWEVER, ONLY ETHYLENE BROMOCHLORIDE AND ETHYLENE DICHLORIDE ALSO SHOWED CONCOMITANT INCR IN MUTAGENICITY OF 4-FOLD. [R135] *... 250 or 500 ppm /of 1,2-dichloroethane was admin/ in feed mash to rats for 2 yr period. Approx 60-70% of the dose was consumed. No significant decrease in fertility, litter size or fetal weight was observed. [R136] *... Rats /were exposed/ to vapor at 100 and 300 ppm for 7 hr daily during days 6-15 of gestation. Ten of the 16 rats at 300 ppm died and only one rat had an implanted pregnancy with total resorption. [R136] *Harmful to plants, retarding growth and development along with seedling development. Induces morphological and chlorophyll mutations, resulting in necrosis and atrophy, in some cases. [R137] *1,2-Dichloroethane ... inhibited ... growth of DNA polymerase-deficient /(pol I, pol A1-)/ Escherichia coli. [R138] *1,2-Dichloroethane produced single-stranded breaks in DNA of hamster cells and chromosomal aberrations in barley kernels. [R139] *The effects of 1,2-dibromoethane (DBE) and 1,2-dichloroethane (EDC) on the incorporation of (3)H-thymidine into DNA were evaluated in various tissues of mice. The cmpds were given ip 24 hr before sacrifice in an equimolar dose (293 umol/kg). Two hr before the animals were killed, 0.5 nCi (3)H-thymidine/g was injected ip. Both agents inhibited the (3)H-thymidine incorporation in the forestomach, a site for their carcinogenic action. ... EDC was inhibitory in the kidney. ... [R140] *... The present study examines the effect on liver tumor incidence of continuous treatment of chloroform (CHCl3) (600 mg/l and 1800 mg/l), 1,1-dichloroethane (835 mg/l and 2500 mg/l), and 1,2-dichloroethane (835 mg/l and 2500 mg/l) administered in drinking water to male B6C3F1 mice using a two-stage (initiation/promotion) treatment protocol. Seventy 4-week-old male B6C3F1 mice constituted each treatment group. Of these mice, 35 were initiated by treatment with diethylnitrosamine (10 mg/l) in the drinking water for 4 weeks. The remaining 35 received deionized drinking water. Each group was subsequently treated with one of two concentrations of chloroform, 1,1-dichloroethane or 1,2-dichloroethane in drinking water for 52 weeks. An additional group received phenobarbital (500 mg/l) and served as the positive control for liver tumor promotion. Mice sacrificed after 24 weeks (10 mice) and 52 weeks (25 mice). Liver and lung tumors were detected; /however/, 1,1-dichloroethane, and 1,2-dichloroethane did not affect the incidence or number of liver or lung tumors in the diethylnitrosamine-initiated animals. ... [R141] *Liver tissue from rats administered 13 different alkyl halides /including 1,2-dichloroethane/ and 4 other hepatotoxins were assayed for indexes of hepatic heme synthesis. These included aminolevulinic acid dehydratase activity, porphyrin content, and microsomal cytochrome p450 and glutathione content. Consistent decreases in the dehydratase activity and cytochrome p450 content were found. Significant changes in glutathione and porphyrin content also occurred after exposure to some compounds, but they were not consistent. ... [R142] *Eight chlorinated ethanes and 3 chlorinated ethylenes were tested in the BALB/c-3T3 cell transformation assay. ... Chloroethane, 1,1-dichloroethane, and 1,2-dichloroethane, 1,1,1,2-tetrachloroethane and 1,1,2,2-tetrachloroethane, hexachloroethane, and tetrachloroethylene were all negative in the assay conducted in the absence of an exogenous metabolic activation system. ... [R143] *The effects of food deprivation, carbohydrate restriction, and ethanol consumption on the metabolism of 8 volatile hydrocarbons (benzene, toluene, 1,2-dichloroethane, 1,1-dichloroethylene, and trichloroethylene) in rats were compared with the effects of enzyme induction by phenobarbital, polychlorinated biphenyls and 3-methylcholanthrene on the metabolism of these compounds. Although causing a marked increase in microsomal protein and cytochrome p450 contents, phenobarbital (80 mg/kg/day for 3 days) and polychlorinated biphenyls (a single dose of 500 mg/kg) induced only a limited range of enzyme activity. ... In contrast, food deprivation, carbohydrate restriction, and 3 wk ingestion of ethanol (2.0 g/day) each enhanced the metabolism of all the hydrocarbons with little or no increase in microsomal protein and p450 contents. ... [R144] *Chloroacetaldehyde, a postulated metabolite of 1,2-dichloroethane, is mutagenic in Salmonella typhimurium TA100. /Chloracetaldehyde/ [R132] *1,2-DICHLOROETHANE GIVES A WEAK DIRECT MUTAGENIC EFFECT IN SALMONELLA TYPHIMURIUM TA1535, WHICH IS ENHANCED BY ADDITION OF RAT POSTMITOCHONDRIAL LIVER FRACTION (S-9). THIS ACTIVATION IS NADPH-INDEPENDENT AND NONMICROSOMAL. THIS ACTIVATION IS FURTHER ENHANCED BY ADDITION OF GLUTATHIONE BUT NOT BY ADDN OF L-CYSTEINE, N-ACETYL-L-CYSTEINE OR 2-MERCAPTOETHANOL. ACTIVATION OF 1,2-DICHLOROETHANE WAS ALSO FOUND IN THE PRESENCE OF GLUTATHIONE AND GLUTATHIONE S-TRANSFERASE A AND C BUT NOT WITH GLUTATHIONE S-TRANSFERASE B. APPARENTLY 1,2-DICHLOROETHANE IS ACTIVATED BY CONJUGATION WITH GLUTATHIONE. [R145] *Carbon tetrachloride and 1,2-dichloroethane were added in vitro to freshly prepared slices of rat liver and the time and concentration dependence of their toxic effects on several metabolic parameters determined. With each agent, the most sensitive effect was an increase of malondialdehyde production by a microsomal preparation isolated from the treated slices. The next most sensitive parameter was the inhibition of amino acid incorporation into slice proteins, followed by inhibition of net K+ accumulation and the induction of early necrotic changes, as indicated by loss of histological staining with azure II. Substantially greater exposures were required to reduce cellular ATP and to initiate entry of Ca2+. This sequence was similar with both agents, CCl4 was the more potent in each case. When added in combinations of submaximally effective concentrations, the two agents produced at least additive inhibition of protein synthesis and K+ accumulation. Amino acid incorporation and K+ transport are the most convenient indicator systems. [R146] *In vivo sister chromatid exchange induced by 1,2-dichloroethane was studied in bone marrow cells of mice after acute treatment for 24 hr. With the exception of the lowest concentration (0.5 mg/kg), each series exhibited a statistically significant increase in sister chromatid exchange. [R147] *The studies were designed to determine the early histopathological effects of two known water contaminants, 1,2-dichloroethane and 1,1-dichloroethylene, administered alone or in mixtures to laboratory rats. Both agents cause cytotoxic responses in kidney and liver. Significant changes were seen in cell, cytoplasmic and nuclear volumes, except in the high dose 1,2-dichloroethane group (600 mg/kg). Comparison of measured parameters of the single dosed animals with the mixed dosed exhibited the most significant differences in the lipid droplet compartment. [R148] *The metab and binding of (14)C-labelled 1,2-dichloroethane in female C57BL mice were studied. As shown by whole-body autoradiography of iv injected mice, a selective localization of non-volatile and bound 1,2-dichloroethane metabolites occurred in the nasal olfactory mucosa and the tracheo-bronchial epithelium. Low levels of metabolites were also present in the epithelia of the upper alimentary tract, vagina and eyelid, and in the liver and kidney. A decreased mucosal and epithelial binding was observed after pretreatment with metyrapone, indicating that the binding might be due to an oxidative metab of 1,2-dichloroethane. The levels of in vivo binding were considerably lower in mice injected ip with 1,2-dichloroethane as compared to mice given equimolar doses of (14)C-labelled 1,2-dibromoethane. In vitro experiments with 1000g supernatants from various tissues showed that nasal mucosa has a marked ability to activate 1,2-dichloroethane into products that become irreversibly bound to the tissue. The nasal olfactory mucosa is a target tissue for toxicity of 1,2-dichloroethane. [R149] *The transcriptional and replicative activities of hepatic nuclei during DNA damage induced by 1,2-dichloroethane, a hepatocarcinogen, were examined. DNA damage was measured by DNA alkylation in rodents exposed to 1,2-dichloroethane. A time-dependent DNA damage in vivo and in vitro was observed. A significant inhibition of RNA synthesis was observed when transcription was carried out in vitro using nuclei of 1,2-dichloroethane treated animal. The inhibition in RNA synthesis persisted even when 50% of DNA damage was removed. Similarly, nuclear DNA synthesis in vitro was also significantly inhibited during DNA damage. However, DNA synthesis was recovered rapidly even though 50% of DNA damage persisted. Results on the effect of alpha-amanition RNA synthesis that 50-70% of synthesis was carried out by RNA polymerase II. [R150] *Three chloromethanes and 8 chlorinated ethanes (/including/ 1,1- and 1,2-dichloroethane, were assayed in tests for the induction of mitotic segregation in Aspergillus nidulans diploid strain P1. Eight of the 11 compounds assayed /including/ 1,1- and 1,2-dichloroethane, significantly increased the frequency of morphologically abnormal colonies which produced euploid whole-chromosome segregants (haploids and non-disjunctional diploids). The induction of aneuploidy as the primary genetic event was provided in haploid strain 35f with 1,2-dichloroethane. Lipophilicity, known to be related to c-mitotic activity, did not show any significant relationhip with aneuploidizing activity. [R151] *Chlorinated hydrocarbons found in a bioassay to be carcinogenic to both B6C3F1 mice and Osborne-Mendel rats (1,2-dichloroethane), carcinogenic only to mice (1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, hexachloroethane, trichloroethylene, and tetrachloroethylene, and noncarcinogenic to either species (1,1-dichloroethane and 1,1,1-trichloroethane) were used to investigate the biochemical bases for tumorigenesis. Studies were conducted after chronic oral dosing of adult mice and rats with the MTD and 1/4 MTD of each compound. ... Metabolism of the compounds (nmoles per kg body weight) was 1.7 to 10 times greater in mice than in rats. Hepatic protein binding (nanomole equivalents bound to 1 mg of liver protein) was 1.2 to 8.3 times higher in mice than in rats except for 1,2-dichloroethane and 1,1,1- trichloroethane. The noncarcinogens 1,1-dichloroethane and 1,1,1-trichloroethane exhibited 2 to 18 times more binding in mice than did the carcinogens 1,2-dichloroethane and 1,1,2-trichloroethane. Urinary metabolite patterns of the compounds were similar in both species. The biochemical parameters measured provided no clue to differentiate the carcinogens from the noncarcinogens. [R152] *Five chlorinated aliphatics /including/ 1,1-dichloroethane and 1,2-dichloroethane were examined in a rat liver foci assay for evidence of initiating and promoting potential. Young adult male Osborne-Mendel rats (ten/group) were given partial hepatectomies, followed 24 hr later by a single ip dose of either diethylnitrosamine (30 mg/kg body weight) or chlorinated aliphatics, 1 wk later either a diet containing 0.05% (w/w) phenobarbital or daily oral gavage five times weekly of chlorinated aliphatics in corn oil for 7 weeks, and sacrificed 1 wk later. Putative preneoplastic markers monitored were foci with increased gamma-glutamyltranspeptidase activity. Chlorinated aliphatics were without significant effect in the initiation protocol at the maximum tolerated dose. In the promotion protocol, 1,1-dichloroethane /but not 1,2-dichloroethane/ induced significant increases in gamma-glutamyltranspeptidase activity (+) foci above control levels. Two variants of gamma-glutamyltranspeptidase activity (+) foci were distinguishable, one associated predominantly with phenobarbital promotion, resembling preneoplastic foci in other models, and the other associated with chlorinated aliphatics promotion, which was less intensely strained and exhibited branching, resembling foci undergoing redifferentiation. [R153] *3 of 19 pregnant rabbits exposed to 300 ppm and 4 of the 21 rabbits exposed to 100 ppm died during the study. No pathological changes were observed on gross necropsy. Reproduction was not affected in rats exposed to up to 150 ppm 1,2-dichloroethane by inhalation 6 hr/day for 176 days. [R42, 686] *Corneal clouding is described in poisoned dogs, and several species developed hemorrhagic /CNS depression/ of the adrenal cortex. In rats, radiolabeled ethylene dichloride was excreted primarily in the urine, and the major urinary metabolites were chloroacetic acid, 5-carboxymethyl cysteine, and thiodiacetic acid. Large doses of chloroacetic acid are said to deplete liver glutathione stores, and 1,2-dichloroethane may have a similar effect. Feeding studies have produced a variety of malignant tumors in experimental animals. [R121, p. II-164] *1,2-Dichloroethane was not teratogenic in rats inhaling 100 ppm or in rabbits inhaling 100 or 300 ppm for 7 hr/day throughout the period of major organogenesis. Of the 16 rats exposed to 300 ppm, 10 died, which demonstrates that the 300 ppm exposure concentration was maternally toxic. Symptoms which preceded death included lethargy, ataxia, decreases in body weight and food consumption and vaginal bleeding. [R42, 686] *1,2-Dichloroethane was reported to be carcinogenic in rats in a long term bioassay using gavage in corn oil (24 and 48 mg/kg/day, but not by inhalation (up to 150-250 ppm, 7 hr day, 5 days/wk). The daily dose metabolized was similar in the 2 experiments. In order to address this discrepancy, the genotoxicity of 1,2-dichloroethane was investigated in vivo under different exposure conditions. Female F344 rats (183-188 g) were exposed to 1,2-(14)-C-dichloroethane in a closed inhalation chamber to either a low, constant concn (0.3 mg/l= 80 ppm for 4 hr) or to a peak concn (0.3 mg/l= 80 ppm for 4 hr) or to a peak concn (up to 18 mg/l= 4400 ppm) for a few minutes. After 12 hr in the chamber, the dose metabolized under the two conditions was 34 mg/kg and 140 mg/kg. DNA was isolated from liver and lung and was purified to constant specific radioactivity. DNA was enzymatically hydrolyzed to the 3'-nucleotides which were separated by reverse phase HPLC. Most radioactivity eluted without detectable or with little optical density, indicating that the major part of the DNA radioactivity was due to covalent binding of the test compound. ... [R154] *Thirteen week studies were conducted to investigate potential differences in rat strain susceptibility to 1,2-dichloroethane toxicity. F344/N rats, Sprague-Dawley rats, Osborne-Mendel rats and B6C3F1 mice (10 animals of each sex) were exposed to 1,2-dichloroethane in drinking water at 0, 500, 1,000, 2,000, 4,000 or 8,000 ppm for 13 weeks. No compound related deaths occurred in any of the rat strains exposed to 1,2-dichloroethane in drinking water. Weight gain depression was common in each sex of all three rat strains in the 4,000 and 8,000 ppm groups throughout the studies. Water consumption was decreased by 50%-60% with increasing dose for all exposed male and female rats regardless of strain. Kidney and liver weights were increased in dosed rats of all three strains. No chemical-related lesions were observed except for a dose related incidence of renal tubular regeneration in female F344/N rats. Nine of 10 female mice exposed to 8,000 ppm 1,2-dichloroethane in drinking water died before the end of the study. Mean body weights of males at 500 ppm or more and females at 1,000 ppm or more were lower than those of controls throughout most of the studies. Kidney weights were significantly increased for dosed males and females. 1,2-Dichloroethane admin in drinking water resulted in less toxicity to F344/N rats than admin of similar doses by gavage. [R155] *In dogs, investigators have found fairly consistently that in ten to fifteen hours after systemic administration of 1,2 dichloroethane, either by inhalation or subcutaneous injection, both corneas begin to become blue gray and swollen. Clouding increases to a maximum about two to three days after the intoxication, then subsides in the course of several days to several months, depending on the severity. [R156] *... Rats, guinea pigs, rabbits, and cats tolerated 6 hr daily exposures to 500 ppm 5 days/week for 13 weeks with no adverse effect. Rats, guinea pigs, and rabbits also tolerated injury and increased blood urea. Rats, guinea pigs, and rabbits also tolerated an additional 13 weeks at 1000 ppm but cats showed histological evidence of kidney injury and increased blood urea. [R157, 4095] *Adult male Sprague Dawley rats were given single doses of 0, 0.5, 1.0, 2.0, 4.0, and 8.0 g/kg in corn oil. There was significant mortality only at 8 g/kg and no evidence of treatment-related effects on serum or urinary enzyme levels, organ weights, or tissue morphology. Rats received repeated oral doses of 0, 0.5, 1.0, 2.0, or 4.0 g/kg 5 days/wk for 12 wks. There was marked CNS depression and high mortality only in the 4 g/kg group but little evidence of toxicity other than transient CNS depression at lower levels. [R157, 4094] *Marked fatty degeneration in monkeys was demonstrated at 400 ppm for 8-12 days. [R105, 813] *... The relative susceptibility of 3 strains of rats (F344/N, Sprague-Dawley and Osborne-Mendel) and 1 strain of mice (B6C3F1), exposed to 1,2-dichloroethane in drinking-water at concns of up to 8000 mg/l for 13 wks, and one of the same strains or rats (F344/N) exposed to doses of up to 480 mg/kg bw/day by gavage in corn oil for 13 wks, was investigated. Based on increased relative organ weights, the liver and kidneys were the target organs in both rats and mice, although treatment-related microscopic lesions were noted only in female F344/N rats and B6C3F1 mice. Admin of 1,2-dichloroethane to F344/N rats by gavage resulted in more severe toxic effects (including death) than admin of similar doses in drinking-water, probably due to greater peak levels of the cmpd in the blood, and saturation of elimination mechanisms. The authors considered the NOEL for 1,2-dichloroethane admin to F344/N rats by gavage to be 120 and 150 mg/kg bw/day in males and females, respectively, based on mortality and chemically related lesions in the forestomach. The NOEL of B6C3F1 mice exposed via drinking-water was considered to be 780 mg/kg bw/day (2000 ppm) in males, based on kidney lesions, and 2500 mg/kg bw/day (4000 ppm) in females, based on mortality. The authors did not consider the doses to which the 3 strains of rats were exposed in the drinking-water to be high enough to result in biologically significant toxic effect, although alterations were observed at doses as low as 49-82 mg/kg bw/day in some strains (i.e. Sprague-Dawley and Osborne-Mendel). [R158] NTOX: *In a 10 day toxicity study, Sprague Dawley rats of each sex were given 1,2-dichloroethane at dose levels of 10, 30, 100 or 300 mg/kg body weight per day by gavage. Although 8/10 males and all females in the high-dose group died, no hematological or clinical chemical changes were observed. The only histopathological effect was a slight inflammation of the forestomach in the 100 mg/kg body weight group. In a 90 day study at dose levels of 37.5, 75 and 150 mg/kg body weight per day, no treatment related effect on mortality or gross histopathology was observed. [R159] *In a teratology study, rats and rabbits were exposed to 100 or 300 ppm (400 or 1200 mg/cu m) 1,2-dichloroethane for 7 hours per day on days 6 through 15 (rats) or 6 through 18 Rabbits) of gestation. In rats, 10/16 dams died at the high dose, one exhibited implantation sites but all the implantantations were resorbed. At 100 ppm, 1,2-dichloroethane was not overtly toxic to the dam and did not induce fetotoxicity, teratogenicity or skeletal variations with the exception of a decrease in the number of bilobed thoracic centra. In rabbits, 3/19 dams died at the high dose; there were no adverse effects on fetal or embryonal development. [R160] *Acute exposure (< or = 14 days) /via inhalation/ resulted in death in rats and guinea pigs at 400 ppm and in mice, rabbits, and dogs at 1500 ppm. These were the lowest exposure conc that produced death in animals. Gross observations at necropsy revealed liver and kidney effects ranging from incr organ weight to necrosis, pulmonary congestion, and fatty infiltration and degeneration of the myocardium ... . [R161] *Intermediate-duration exposure (6-25 wk) /via inhalation/ resulted in death in rats and guinea pigs exposed to 200 ppm, rabbits exposed to 400 ppm, and dogs, cats, and monkeys exposed to 1000 ppm ... . Necropsy of these animals revealed effects on the liver, kidnye, heart, and lungs similar to those observed following acute exposure. In a chronic inhalation study, survival of rats intermittently exposed to 50 ppm of 1,2-dichloroethane for 2 yr was similar to controls ... . [R162] *In animals, acute exposure to high concn of 1,2-dichloroethane /via inhalation/ was also assoc with pulmonary congestion. A single 7-hr exposure to 3,000 ppm ... produced death assoc with pulmonary congestion in mice, rats, rabbits, and guinea pigs ... . Lower concn ... did not produce lung lesions. [R162] *Acute lethal concentrations /via inhalation/ produced myocarditis in rats, dogs, and monkeys ... . Guinea pigs that died following intermittent exposure to > or = 200 ppm for 25 wk had fatty infiltration and degeneration of the heart ... . Among animals that survived intermediate-duration exposure ... cardiac changes were observed only in monkeys. [R163] *In animals studies, GI effects, incl emesis and passing of red watery stools, preceded death in dogs intermittently exposed to 1,500 ppm of 1,2-dichloroethane for 6 days ... . Congestion of the GI tract was noted in these animals at necropsy. [R163] *There are also reports of hepatic effects in animals following acute-duration inhalation exposure to 1,2-dichloroethane. Serum levels of enzymes used as indicators of hepatic damage ... were significantly elevated in rats exposed to > or = 850 ppm for 4 hr ... . No effect was seen at 618 ppm. ... Monkeys intermittently exposed to 400 ppm for 8-12 days had marked fatty degeneration of the liver ... . Monkeys exposed to 100 ppm did not show this effect. Slight parenchymatous degradation of the liver was found in guinea pigs exposed to 400 ppm for < or = 14 days ... . ... Longer-term exposure to 1,2-dichloroethane vapor produced hepatic effects in guinea pigs, dogs, and monkeys. Guinea pigs intermittently exposed to 100 ppm ... for 246 days exhibited incr liver weight and hepatic fatty infiltration ... . Monkeys exposed to 200 ppm for 25 wk and dogs exposed to 400 ppm for 8 mo also exhibited fatty degeneration of the liver ... . However, no hepatic effects were observed upon gross and microscopic exam in mice, rats, or rabbits intermittently exposed to concn of 100-400 ppm for 4-30 wk ... . [R164] *Acute-duration inhalation exposure to 1,2- dichloroethane also produced renal effects in animals. Cloudy swelling of the renal tubular epithelium and incr kidney weight were reported in guinea pigs, and degeneration of the tubular epithelium was reported in monkeys following intermittent exposure to 400 ppm for 8-12 days ... . ... Kidney lesions have also been reported following longer-term exposure of animals ... . Dogs intermittently exposed to 400 ppm for 8 mo exhibited fatty changes in the kidney ... . In guinea pigs, degeneration of the kidney was observed but only at lethal concn ... . Renal effects were not detected in rats, mice, guinea pigs, or rabbits intermittently exposed to 100-400 ppm ... for 4-30 wk ... . [R165] *In animals there is evidence that exposure to 1,2-dichlorethane affects the ability to fight infection arising from inhaled microbial pathogens. Female mice exposed to 5-11 ppm ... for 3 hr exhibited incr susceptibility to Streptococcus zooepidemicus (i.e., incr mortality following infection), suggesting reduced pulmonary defenses in the exposed mice ... . No effect was observed at 2.3 ppm. Also in this study, high-dose mice had reduced bactericidal activity in the lungs 3 hr after exposure to Klebsiella pneumoniae ... . Male rats exposed to 200 ppm for 5 hr or 100 ppm 5 hr/day for 12 days did not exhibit any incr susceptibility to infection from these microbes ... . [R166] *Acute-duration exposure to concentrated 1,2-dichloroethane also produced neurological effects in animals. Rats exposed to > or = 12,000 ppm for 30 min experienced CNS depression ... . Exposure to 20,000 ppm for 15 min resulted in CNS depression sufficient to cause death; no histopathology was conducted ... . Tremors, uncertain gait, and narcosis were seen in rats, guinea pigs, and rabbits exposed to 3,000 ppm for 7 hr ... . Longer-term exposure to lower concn ... did not appear to produce neurological effects, although sensitive indicators of subtle neurological effects were not examined. [R167] *Intermittent exposure of female rats /via inhalation/ to 4.7 + or - 7 ppm for 4 mo prior to the mating period, followed by inhalation exposure during pregnancy, produced a statistically significant (p < 0.01) incr in embryo mortality ... . In an earlier study ... reported decr fertility in rats exposed to 14 ppm ... for 6 mo. No adverse effects on the fertility, gestation, or survival of pups were observed in male or female rats exposed to 1,2-dichloroethane concn of < or = 150 ppm in a one-generation reproduction study ... . [R168] *1,2-Dichloroethane has produced genotoxic effects in animals following inhalation exposure. Inhalation of 1,000 ppm ... vapors for 4 hr produced irreversible deoxyribonucleic acid (DNA) damage as evidenced by single-stranded breaks in mouse hepatocytes. This genetic damage was seen at a concn that produced mortality in 80-100% of treated mice within 24 hr ... . In a study investigating the relationship between inhalation exposure ... and covalent binding to liver and lung DNA, female Fischer-344 rats were exposed either to 80 ppm ... for 4 hrs ("constant-low" exposure) or 4,400 ppm for a few minutes ("peak" exposure) ... . The DNA covalent binding index was elevated, compared to controls, after both exposure scenarios. However, in both the liver and the lung the effect was much greater (approx 35 times greater) after peak exposure ... . [R169] *Evidence from animal studies suggests that the immune system is a target of 1,2-dichloroethane after oral exposure. In mice exposed for 14 days by gavage to 4.9 and 49 mg/kg/day, there was a significant dose-related reduction in humoral immunity (measured by immunoglobulin M(IgM) response to sheep erythrocytes), and a significant but not dose-related, reduction in cell-mediated immunity (measured by delayed-type hypersensitivity response to sheep erythrocytes) ... . In mice give 49 mg/kg/day, these effects wee accompanied by a 30% decr in total leukocyte number. [R170] *Neurological effects have also been observed in animals exposed to 1,2-dichloroethane by ingestion. Clinical signs in rats exposed to > or = 240 mg/kg/day by gavage for < or = 13 wk incl tremors, salivation, emaciation, abnormal posture, ruffled fur, and dyspnea ... . Upon microscopic exam, mild necrotic lesions were observed in the cerebellum of rats dosed with 240 or 300 mg/kg/day. [R129] *Oral exposure to 1,2-dichloroethane has produced genotoxic effects in animals. A single oral dose of 100 mg/kg of 1,2-dichloroethane produced irreversible DNA damage, as revealed by single-stranged breaks in the hepatocytes of mice ... . A single oral dose of 150 mg/kg produced high levels of DNA binding in the liver of rats ... . The level of binding produced was similar in rats that had previously been exposed via inhalation to 50 ppm ... vapor for 2 yr, and in rats that had served as controls in the 2-yr study. [R171] *Results of these studies indicate that 1,2-dichloroethane is carcinogenic in rats by the oral route, with a gavage dose > or = 47 mg/kg/day, producing tumors at locations remote from the site of admin ... . Statistically significant incr in multiple tumor types (malignant and benign) were noted in treated animals of both species. An incr incidence of fibromas of the sc tissue and hemangiosarcomas of the spleen, liver, pancreas, and adrenal gland (as well as other organs and tissues) occurred in male rats of both exposure groups (47 and 95 mg/kg/day). In the high-dose group (95 mg/kg/day), male rats had incr squamous cell carcinomas of the forestomach, and female rats had incr frequencies of adenocarcinomas and fibroadenomas of the mammary gland. In mice, the incidence of hepatocellular carcinomas and pulmonary adenomas incr in males given 195 mg/kg/day. In female mice from both the 149- and 299-mg/kg/day exposure groups, there were incr incidences of pulmonary adenomas, adenocarcinomas of the mammary gland, and endometrial polyps and sarcomas. [R171] *The carcinogenicity of 1,2-dichloroethane following dermal exposure has been evaluated in mice ... . In this study, a statistically significant incr in pulmonary papillomas was observed in mice treated with 126 mg ... three times/wk for 428-576 days. These results, which indicate a significant incr in benign tumors remote from the site of application, provide suggestive or supportive evidence that 1,2-dichloroethane is carcinogenic and that it can penetrate through the skin into the circulatory system. [R172] *... Prior to exposure to ethylene dichloride (EDC) groups of male mice were pretreated with phenobarbital or 3-methylcholanthrene to induce metabolism. Other mice were administered SKF525A before ethylene dichloride exposure to inhibit cytochrome p450 metabolism. Following the different pretreatments, mice were exposed to ethylene dichloride at selected concentrations (1000, 1250, or 1500 ppm). Exposure to ethylene dichloride, without pretreatment, produced a dose-dependent increase in mortality at 24 and 48 hr postexposure. This response was enhanced at all concentrations of EDC by phenobarbital pretreatment and attenuated by the administration of SKF 525A. Pretreatment with 3-methylcholanthrene prior to ethylene dichloride exposure at 1000 ppm also produced an increase in mortality as compared to ethylene dichloride exposure without pretreatment. Exposure to ethylene dichloride was associated with an increased kidney wt/body wt ratio. SKF 525A pretreatment prevented the increase in the kidney wt/body wt ratio at an ethylene dichloride exposure concn of 1000 ppm. Pathological changes produced in the kidneys of mice exposed to ethylene dichloride were decreased by SKF 525A pretreatment. [R173] HTXV: *The lethal oral dose of 1,2-dichloroethane in humans has been estimated to be between 20-50 ml. [R174] NTXV: *LD50 Mouse oral 870-950 mg/kg; [R175] *LD50 Rabbit oral 860-970 mg/kg; [R175] *LD50 Rabbit percutaneous 3400-4460 mg/kg; [R175] *LD50 Rat oral 670-890 mg/kg; [R176] *LC50 Rat inhalation 12000 ppm/31.8 min, 3000 ppm/165 min, 1000 ppm/432 min; [R177, 645] *LD50 Mouse ip 370 mg/kg; [R42, 685] *LD50 Rat sc 700 mg/kg; [R42, 685] *LD50 Rat inhalation 1000 ppm/ 7 hr; [R57, 1547] *LD50 Rat ip 807 mg/kg; [R57, 1547] *LD50 Dog oral 5700 mg/kg; [R57, 1547] *LC50 Rat inhalation 6600 mg/cu m/6 hr /From table/; [R178] *LD50 Female mouse oral 413 mg/kg; [R179] *LD50 Male mouse oral 489 mg/kg; [R179] ETXV: *LC50 Daphnia magna (water flea) 218,000 ug/l 48 hr. /Conditions of bioassay not specified/; [R67, p. 2-2] *LC50 Mysid shrimp 113,000 ug/l/96 hr in salt water. /Conditions of bioassay not specified/; [R67, p. 2-2] *LC50 GAMMARUS FASCIATUS (SCUD) GREATER THAN 100 MG/L/96 HR @ 21 DEG C, AGE MATURE, STATIC BIOASSAY; [R180] *LC50 PTERONARCYS (STONEFLY) GREATER THAN 100 MG/L/96 HR @ 15 DEG C, SECOND YEAR CLASS, STATIC BIOASSAY; [R180] *LC50 SALMO GAIRDNERI (RAINBOW TROUT) 225 MG/L/96 HR @ 13 DEG C, WT 1.8 G, STATIC BIOASSAY; [R180] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) 430 MG/L/96 HR (95% CONFIDENCE LIMIT 230-710 MG/L), STATIC BIOASSAY, TEMP 21-23 DEG C, PH 7.9-6.5; [R181] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) > 600 MG/L/24 HR, STATIC BIOASSAY, TEMP 21-23 DEG C, PH 7.9-6.5; [R181] *LC50 CYPRINODON VARIEGATUS (SHEEPSHEAD MINNOWS) > 130 PPM BUT < 230 PPM @ 24 HR, 48 HR, 72 HR AND 96 HR, STATIC TESTS, TEMP 25-31 DEG C; [R182] *LC50 Pimephales promelas (fathead minnow) 136 mg/l/96 hr (95% confidence limit: 129-144 mg/l), temp 25 deg C, dissolved oxygen 7.8 mg/l, water hardness 44.8 mg/l calcium carbonate (CaCO3), alkalinity 41.4 mg/l CaCO3, pH 7.41, static bioassay. (Test 1); [R183] *LC50 Crangon crangon (brown shrimp) 75 mg/l/24 hr, 65 mg/l/48 hr, 65 mg/l/96 hr, + or - 2000 mg/l @ 3 min, + or - 630 mg/l/9 min, 345 mg/l/1 hr in sea water @ 15 deg C. /Conditions of bioassay not specified/; [R177, 644] *LC50 Gobius minutus (gobi) 185 mg/l/60 min, 3 hr and up to 96 hr in sea water @ 15 deg C. /Conditions of bioassay not specified/; [R177, 645] *LC50 Poecilia reticulata (guppy) 106 ppm/7 days. /Conditions of bioassay not specified/; [R177, 645] *Toxicity threshold (cell multiplication inhibition test): bacteria (Pseudomonas putida): 135 mg/l. Algae (Microcystis aeruginosa): 105 mg/l. Green algae (Scenedesmus quadricuda): 719 mg/l. Protozoa (Entosiphon sulcatum): 1127 mg/l; [R177, 644] NTP: *A bioassay of technical grade 1,2-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,2-Dichloroethane in corn oil was admin by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The 78 wk period of chem admin was followed by an observation period of 32 wk for the low dose rats of both sexes. The last high dose male rat died after 23 wk of observation and the last high dose female rat died after 15 wk of observation. All treated groups of mice were observed for an additional 12 or 13 wk following chem admin. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The time weighted avg high and low doses of 1,2-dichloroethane in the chronic study were 95 and 47 mg/kg/day, respectively, for rats of both sexes. The high and low time weighted avg doses for the male mice were 195 and 97 mg/kg/day, respectively, and 299 and 149 mg/kg/day, respectively, for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same times that dosed animals were gavaged with 1,2-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. A statistically significant positive association between dosage and the incidence of squamous cell carcinomas of the forestomach and hemangiosarcomas of the circulatory system occurred in the male rats, but not in the females. There was also a significantly incr incidence of adenocarcinomas of the mammary gland in female rats. The incidences of mammary adenocarcinomas in female mice were statistically significant. There was a statistically significant positive association between chemical admin and the combined incidences of endometrial stromal polyps and endometrial stromal sarcomas in female mice. The incidence of alveolar/bronchiolar adenomas in both male and female mice was also statistically significant. Under the conditions of this study, 1,2-dichloroethane was carcinogenic to Osborne-Mendel rats, causing squamous cell carcinomas of the forestomach, hemangiosarcomas, and subcutaneous fibromas in male rats and causing mammary adenocarcinomas in female rats. This cmpd was also found to be carcinogenic to B6C3F1 mice, causing mammary adenocarcinomas and endometrial tumors in female mice, and causing alveolar/bronchiolar adenomas in mice of both sexes. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R184] TCAT: ?The ability of 1,2-dichloroethane to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary clonal toxicity determinations exposure time=1 day), 1,2-dichloroethane was tested at 0, 4, 20, 100 and 250 ug/ml in one experiment and 5, 10, 25 and 50 ug/ml in a second experiment, with cell survival ranging from 159% to 70% and from 98% to 90% relative to controls, respectively. None of the tested concentrations produced significantly greater transformation frequencies compared to untreated controls. [R185] ?The effects of 1,2-dichloroethane were examined in the mouse hepatocyte primary culture/DNA repair test. Based on preliminary toxicity tests, 1,2-dichloroethane was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4), 1x10(-5), 1x10(-6) and 1x10(-7)% in DMSO solvent. The highest two concentrations were too cytotoxic to be evaluated in the assay. The lower concentrations were not cytotoxic but all these concentrations caused a significant increase in the unscheduled DNA synthesis over the solvent control (DMSO). [R186] ?The effects of 1,2-dichloroethane were examined in the rat hepatocyte primary culture DNA repair assay. Based on preliminary toxicity tests, 1,2-dichloroethane was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4), 1x10(-5) and 1x10(-6)% in DMSO solvent vehicle. The highest two concentrations were too cytotoxic to be evaluated in the assay. The lower concentrations were not cytotoxic but the 0.01, 0.001 and 1x10(-4)% levels caused a significant increase in the unscheduled DNA synthesis over the solvent control (DMSO). [R186] ?The mutagenicity of 1,2-dichloroethane was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. 1,2-Dichloroethane caused a positive response in strains TA100 and TA1535, both in the presence and absence of added metabolic activation. 1,2-Dichloroethane did not cause a positive response in strains TA98 or TA1537 in any of the tests. 1,2-Dichloroethane was evaluated using a protocol in which the test article was usually tested over a minimum of 6 dose levels, the highest nontoxic dose level being 10 mg/plate unless solubility, mutagenicity or toxicity dictated a lower limit. [R187] ?In a one-generation reproduction study, male and female Sprague Dawley rats (F0, 20/treated group, 30 in control group) were exposed to 1,2-dichloroethane by inhalation at nominal doses of 25, 75 or 150 ppm for 6 hrs/day, 5 days/week for 12 weeks. The animals within each group were then bred successively to produce F1a and F1b litters. Exposure of F0 animals increased to 7 days/week during mating, gestation and lactation. Litters were sacrificed at 21 days of age and F0 animals were then sacrificed. There were no significant differences observed between treated and control animals in the following: parental and fetal body weights, reproduction, fertility, external or internal fetal anomalies, fetal or parental organ weights, gross necropsy findings, or histological observations. [R188] ?The effect of 1,2-dichloroethane was examined in a mouse hepatocyte primary culture/DNA repair assay. The test article was administered to B6C3F1 mouse liver hepatocytes at concentrations ranging from 1x10E-7 to 1%, for 18 to 20 hours. A dose related increase in net nuclear grain counts was observed, ranging from 9.4 at 1x10E-7% to 232.4 at 1x10E-2%. At exposure levels greater than 1x10E-2% 1,2-dichloroethane was toxic to cells. [R189] ?The effect of 1,2-dichloroethane was examined in the rat hepatocyte primary culture/DNA repair assay. The test article was administered under liquid exposure conditions to Osborne Mendell rat liver hepatocytes at concentrations ranging from 1x10E-6 to 1%, for 18 to 20 hours. A dose related increase in net nuclear grain counts was observed, ranging from 5.5 at 1x10E-4% to 120.1 at 1x10E-2%. At exposure levels greater than 1x10E-2% 1,2-dichloroethane was toxic to cells. [R189] POPL: *Nursing mothers should not be exposed to 1,2-dichloroethane. [R190] *Phenobarbital, which has been used widely for a number of seizure disorders and as a soporific, is known to induce cytochrome P-450 activity and thus incr the rate of the first metabolic steps involved in 1,2-dichloroethane metabolism ... . Thus, individuals taking phenobarbital are at greater risk for experiencing 1,2-dichloroethane-induced toxicity. [R191] *The synergistic effect of disulfiram ... on 1,2-dichloroethane hepatotoxicity and carcinogenicity in animal studies suggests that individuals exposed concurrently to 1,2-dichloroethane and disulfiram, either in the rubber industry or medically ... have incr risk for liver toxicity ... . Disulfiram and its reduced form diethyldithiocarbamate are known inhibitors of microsomal MFO enzyme, particularly cytochrome P-450 2E1 ... . It is possible that people exposed to other MFO inhibitors of like specificity would be at similar risk. [R191] *Alpha-proteinase inhibitor can be inactivated by aldehydes found in the cigarette smoke as well as by industrial chemicals. Studies demonstrate the synergistic inactivation of alpha-proteinase inhibitor by 1,2-dichloroethane when mixed with acrolein or pyruvic aldehyde. Smokers exposed to the chemical may be more prone to lung emphysema due to synergistic inactivation of alpha-proteinase inhibitor by chemicals and cigarette smoke components. [R120] ADE: *... ETHYLENE DICHLORIDE IS READILY ABSORBED VIA THE LUNG WHEN BREATHED OR VIA THE GI TRACT WHEN TAKEN BY MOUTH. TO A LESSER EXTENT, IT IS ABSORBED THROUGH THE SKIN. [R130, 3495] *The effect of the pretreatment of male Sprague-Dawley rats with phenobarbital, butylated hydroxyanisole and disulfiram on the inhalation kinetics of 1,2-dichloroethane was studied by the gas uptake method. ... The rate curves in all the pretreatment regimens showed saturable dependence on 1,2-dichloroethane concn. These saturable dependencies (Michaelis-Menten) appeared to be associated with enzymatic metab. In general, a two-compartment, steady-state pharmacokinetic model described the uptake data. Data were transformed by Hanes plots to calculate the inhalational Km, the ambient 1,2-dichloroethane concn at which uptake proceeded at half maximum rate, AND Vmax, the maximum rate of uptake (ie, maximum rate of metab). Although phenobarbital and butylated hydroxyanisole pretreatments did not affect the Km of 1,2-dichloroethane, phenobarbital pretreatment increased the Vmax while disulfiram pretreatment decreased both the Km and Vmax. [R192] *The levels of 1,2-dichloroethane (1,2-EDC), and its metabolites 2-chloroethanol, monochloroacetic acid, and 2-chloroacetaldehyde were determined by gas chromatography in the organs of human cadavers in cases of acute poisoning. The highest 1,2-dichloroethane levels were observed in the stomach and omentum; lower levels in the kidney, spleen, brain, heart, large and small intestines, and blood, and no detectable amounts in the liver. 2-Chloroethanol and monochloroacetic acid, minor metabolites of 1,2-dichloroethane, were detected in small amounts in the myocardium, brain, stomach, and small intestine. 2-Chloroacetaldehyde, because it is a reactive intermediate in the biotransformation of 1,2-dichloroethane was not detectable in the organs. The administration of acetylcysteine to acutely intoxicated humans showed no positive clinical effect. ... [R193] *... (14)C-ETHYLENE DICHLORIDE /WAS ADMIN/ TO MALE OSBORNE-MENDEL RATS BY GAVAGE (150 MG/KG IN CORN OIL) OR INHALATION (150 PPM, 6 HR) ... APPROX 85% OF THE TOTAL METABOLITES APPEAR IN THE URINE, WITH 7-8%, 4%, and 2% FOUND IN THE CARBON DIOXIDE, CARCASS, AND FECES, RESPECTIVELY, FOLLOWING EACH ROUTE OF ADMIN. [R130, 3496] *Urinary excretion of thiodiglycolic acid and thioethers after 1 2-dichloroethane dosing was studied in rats. Male Sprague-Dawley rats were admin 0, 0.12, 0.25, 0.50, 1.01, 2.02, 4.04 or 8.08 uM/kg (14)C labeled 1,2-dichloroethane orally. Urine samples were collected for 24 hours and analyzed for thiodiglycolic acid and thioethers before and after alkaline hydrolysis by gas chromatography and the Ellman reagent/absorption spectrophotometry (thioether assay), respectively. The amounts of 1,2-dichloroethane derived radioactivity excreted decreased as a logarithmic function of increasing 1,2-dichloroethane dose ranging from 62.1% of the dose for 0.12 and 0.25 umol/kg 1,2-dichloroethane to 7.4% of the 8.08 umol/kg dose. The concentratlons of urinary thiodiglycolic acid were well correlated with 1,2-dichloroethane dose up to 2.02 umol/kg. When expressed as a percentage of the dose urinary excretion of thiodiglycolic acid was not dependent on the dose over the range 0.12 to l.0l umol/kg 1,2-dichloroethane and amounted to 21.8% of the dose. Before alkaline hydrolysis no thioethers could be detected. After alkaline hydrolysis, urinary excretion of thioethers by rats dosed with 0.12 and 0.25 umol/kg did not differ significantly from the control value. Between 0.25 and 4.04 umol/kg 1,2-dichloroethane, thioether excretion increased linearly with dose. The highest thioether/thiodiglycolic ratio 0.17 occurred ln rats given 8.08 umol/kg 1,2-dichloroethane. Urinary thiodiglycolic acid concentrations were not altered by alkaline hydrolysis. The /results suggest/ that urinary thiodiglycolic acid excretion correlates well with the oral dose of 1,2-dichloroethane in rats. Urinary thiodiglycolic acid excretion may be a useful marker of 1,2-dichloroethane exposure. Thiodiglycolic acid is hydrolyzed under alkaline conditions. The thioether assay is not appropriate for estimating urinary thiodiglycolic acid excretion. [R194] *Dichloroethane is readily absorbed from the GI and respiratory tracts. Blood 1,2-dichloroethane levels plateau in the rat at 8.3 ug/ml after a 2-3 hr exposure at 150 ppm. Steady-state blood concns in the rat increased exponentially as the exposure concn increased; after 6 hr of exposure at 50, 150, and 250 ppm, blood 1,2-dichloroethane levels were 14, 8.3, and 31.3 ug/ml, respectively. During a 6 hr, 150 ppm exposure, the rats were calculated to have absorbed 113 mg 1,2-dichloroethane/kg, or about 70% of the 1,2-dichloroethane they would have inhaled if the minute ventilation was 0.76 liter/min/kg bw. 1,2-Dichloroethane was rapidly cleared form the blood ... even following oral doses (< 50 mg/kg) and inhalation exposure (< 150 ppm)that result in nonlinear kinetics. Urine was the principal route of elimination; approx 85% of the radioactivity recovered following an oral exposure to 150 mg/kg or a 6-hr inhalation exposure to 150 ppm of 1,2-[C14]dichloroethane, was excreted in the urine as thiodiacetic acid and thiodiacetic acid sulfoxide. Anther 29% of the oral dose, but only 1.8% of the inhaled 1,2-[C14]dichloroethane, was excreted unchanged via the lungs. [R42, 685] *The rate of dermal absorption of 1,2-dichloroethane by mice was 479.3 +or- 38.3 nmol/min/sq cm following covered application of 0.5 ml of the undiluted solvent, while the rate of absorption of 1,2-dichloroethane in 0.9% NaCl in vitro in excised skin of rats was 169 +or- 0.44 nmoles/min/sq cm. Dermal absorption of 1,2-dichloroethane in aqueous soln (1000 mg/l) was found to be similar in human and rat epidermis in vitro within 1 hr of occluded application (20.3 ug/sq cm/hr versus 33.1 ug/sq cm/hr), whereas when the substance was applied neat (uncovered), absorption within the first 15 min was approx 4-10 fold greater in the rat epidermis than in the human epidermis. In addition, absorption increased with applied dose in the rat epidermis, whereas absorption was not dependent upon dose in the human epidermis. [R195] *1,2-Dichloroethane has been detected in the breast milk of women occupationally exposed via inhalation and dermal contact. [R196] *The rate of elimination following oral (gavage) admin or inhalation was such that 1,2-dichloroethane was not detected in the blood a few hr after exposure and only small amounts were detected in tissues (liver, kidney, lung, spleen, forestomach, stomach and carcass) 48 hr after exposure ... . The rate of elimination from blood and tissues appeared to depend on the exposure level; the higher the exposure level, the lower the elimination rate of 1,2-dichloroethane, after both oral and inhalation exposure. Elimination from the liver was reported to be biphasic, a higher elimination rate occurring just after the peak levels of 1,2-dichloroethane were reached. Elimination from other organs was monophasic. Following inhalation up to an exposure level of 1012 mg/cu m, elimination was slowest in adipose tissue and most rapid in the lung. [R197] *The % of admin radioactivity excreted in the urine over a 24 hr period in rats decreased with increasing single doses (0.25-8.08 mmol 1,2-dichloroethane/kg bw) admin by gavage in mineral oil. The authors attributed these results to saturation of metabolism rather than kidney damage, as there were no variations in biochemical parameters of nephrotoxicity between the controls and groups exposed to doses up to 4.04 mmol/kg bw. Urinary thiodiglycolic acid increased as a linear function of the dose of 1,2-dichloroethane until at least 1.01 mmol/kg bw; it accounted for 63% of the total metabolites in urine at this dose. [R197] *Although 1,2-dichloroethane is eliminated more slowly from adipose tissue than from blood or other tissues (lung and liver) following exposure, it is unlikely to bioaccumulate, as no significant difference was observed between levels in blood or tissues following single or repeated (10 days) oral doses of 50 mg/kg body weight in rats. [R198] *1,2-Dichloroethane is well absorbed through the lungs following inhalation exposure, the GI tract following oral exposure, and the skin following dermal exposure in humans. In animal studies, equilibrium blood concn of 1,2-dichloroethane were obtained 2-3 hr after inhalation exposure, 15-60 min after oral exposure, and 1-2 hr after aqueous dermal exposure. Absorption probably occurs by passive diffusion for all three routes of exposure. Upon absorption, 1,2-dichloroethane is widely distributed within the body. Experiments in animals exposed orally or by inhalation showed that the highest concn of 1,2-dichloroethane (7-17 times that of the blood) were found in adipose tissue. The liver and lung contained lower equilibrium levels of 1,2-dichloroethane than the blood. [R172] *Excretion of 1,2-dichloroethane and metabolites is rapid; in animal studies, excretion was essentially complete 48 hr after acute exposure. Following inhalation exposure to labeled 1,2-dichloroethane, excretion of 1,2-dichloroethane was primarily in the form of metabolites (thiodiglycolic acid and thiodiglycolic acid sulfoxide) in the urine (84%), and as carbon dioxide (CO2) in the exhaled air (7%). Following oral exposure to labeled 1,2-dichloroethane, the amt of radioactivity excreted by these routes was reduced, and a large percentage of the dose (29%) was excreted as unchanged 1,2-dichloroethane in the exhaled air. The incr exhalation of unchanged 1,2-dichloroethane may reflect the saturation of biotransformation enzymes. [R172] METB: *THE METABOLITE, CHLOROETHANOL, WAS DETECTED IN BLOOD AND LIVER OF RATS DURING THE 1ST 2 DAYS AFTER INGESTION OF 750 MG/KG OF 1,2-DICHLOROETHANE. [R199] *FOLLOWING IP INJECTION OF 50-170 MG/KG BODY WT (14)C-1,2-DICHLOROETHANE TO MICE, 10-42% WAS EXPIRED UNCHANGED AND 12-15% AS CARBON DIOXIDE, DEPENDING ON DOSE; MOST OF REMAINDER WAS EXCRETED IN URINE, PRIMARILY AS CHLOROACETIC ACID, S-CARBOXYMETHYLCYSTEINE AND THIODIACETIC ACID. THE METABOLISM OF 1,2-DICHLOROETHANE TO CHLOROACETIC ACID PROCEEDS POSSIBLY VIA CHLOROACETALDEHYDE TO 2-CHLOROETHANOL. [R200] *... (14)C-ETHYLENE DICHLORIDE /WAS ADMIN/ TO MALE OSBORNE-MENDEL RATS BY GAVAGE (150 MG/KG IN CORN OIL) OR INHALATION (150 PPM, 6 HR). ... THE MAJOR URINARY METABOLITES, THIODIACETIC ACID AND THIODIACETIC ACID SULFOXIDE WERE IDENTIFIED, SUGGESTING A ROLE FOR GLUTATHIONE IN BIOTRANSFORMATION OF ETHYLENE DICHLORIDE. [R130, 3496] *Metabolites (mammalian) of 1,2-dichloroethane include: glycolic acid, oxalic acid, carbon dioxide, and S,S-ethylene-bis-cysteine. [R201] *1,2-(14)C-Dichloroethane was metabolized by rat hepatic microsomes to products that irreversibly bound polynucleotides. The polynucleotides were enzymatically hydrolyzed and the products separated by a high-performance liquid chromatography (HPLC) equipped with an ODS or a SCX column. The products of microsome-mediated binding were identified in the high performance liquid chromatography eluate as 1-N6-ethanoadenosine to polyadenylic acid, 3,N4-ethanocytidine to polycytidylic acid, and 2 cyclic derivatives to polyguanylic acid, 1,2-(14)C-dichloroethane was also metabolized in the presence of a glutathione (GSH)-cytosolic fraction and a polynucleotide. After enzymatic hydrolysis of the polynucleotide, the major peak of radioactivity was eluted from a Sephadex G-25 column in the salt volume which excluded the presence of a product containing glutathione and a nucleoside. Chromatography by ODS-High performance liquid chromatography of the major peak from Sephadex G-25 indicated the presence of a glutathione metabolite of 1,2-dichloroethane that did not contain a nucleoside. A similar hydrophilic peak was obtained for the hydrolysis products of polynucleotides from a glutathione plus cytosol incubation in which the polynucleotide instead of being added prior to the incubation was added after the incubation. The products of the glutathione-cytosol metabolism of 1,2-(14)C-dichloroethane appeared to be glutathione metabolites that coisolated with the polynucleotides rather than covalently bound adducts. Covalently bound adducts were identified for microsome-mediated binding of 1,2-dichloroethane to polynucleotides. ... [R202] *Male mice were pretreated with piperonyl butoxide (PIB), an inhibitor of microsomal oxidative metabolism, and the effect of this pretreatment on the extent of hepatic DNA damage produced by 1,2-dichloroethane (EDC) was determined 4 hr after EDC administration. The in vivo genotoxicity of 2-chloroethanol a product of the microsomal oxidative metabolism of EDC, was also investigated. Hepatic DNA damage was measured with a sensitive, alkaline DNA unwinding assay for the presence of single-strand breaks and alkali-labile lesions in DNA. Pretreatment of mice with piperonyl butoxide to inhibit microsomal oxidative metabolism significantly potentiated the hepatic DNA damage observed 4 hr after a single, 200 mg/kg, ip dose of EDC. Treatment of mice with single, ip doses of 2-chloroethanol as high as 1.2 mmol/kg failed to produce any evidence of single-strand breaks and(or) alkali-labile lesions in hepatic DNA. When 6-di-ethyl maleate (DEM) was used to deplete hepatic glutathione levels prior to administration of 2-chloroethanol, the acute hepatotoxicity of 2-chloroethanol was potentiated. ... [R203] *... Aryl halides were bound mainly to liver DNA whereas interaction of alkyl halides with DNA of liver, kidney, and lung gave rise to similar binding extent. In vitro activation of all chemicals was mediated by microsomal p450-dependent mixed function oxidase system which is present in rat and mouse liver and, in smaller amount, in mouse lung. Activation of alkyl halides by liver cytosolic glutathione transferases also occurred. The relative reactivity of chemicals in vivo, expressed as Covalent Binding Index (CBI) to rat liver DNA, was: 1,2-dibromoethane > bromobenzene > 1,2-dichloroethane > chlorobenzene > epichlorohydrin > benzene. ... [R204] *1,2-Dichloroethane is carcinogenic to both B6C3F1 mice and Osborne-Mendel rats. ... Studies were conducted after chronic oral dosing of adult mice and rats with the maximum tolerated dose (MTD) and 1/4 maximum tolerated dose of each cmpd. The extent to which the cmpd were metabolized in 48 hr, hepatic protein binding, and urinary metabolite patterns were exam. Metabolism of the compounds (mmoles/kg) was 1.7-10 times greater in mice than in rats. Hepatic protein binding (nm equiv bound to 1 mg of liver protein) was 1.2-8.3 times higher in rats than in mice for 1,2-dichloroethane. ... Urinary metabolite patterns were similar in both species. ... [R152] *STIMULATION OF HEPATIC MICROSOMAL CARBON MONOXIDE-INHIBITABLE NADPH OXIDN BY 1,2-DICHLOROETHANE WAS ENHANCED BY INDUCTION WITH PHENOBARBITAL BUT NOT WITH BETA-NAPHTHOFLAVONE. INCUBATION OF DICHLOROETHANES WITH HEPATIC MICROSOMES FROM PHENOBARBITAL-TREATED RATS, NADPH-GENERATING SYSTEM, AND EDTA RESULTED IN THE CONVERSION OF 1,2-DICHLOROETHANE TO CHLOROACETALDEHYDE AND TO A LESSER EXTENT TO CHLOROACETIC ACID AND PROBABLY 2-CHLOROETHANOL. THE OMISSION OF DICHLOROETHANE OR THE NADPH-GENERATING SYSTEM FROM INCUBATION MIXTURES ELIMINATED THESE EFFECTS. SKF-525A AND CARBON MONOXIDE DIMINISHED OR ELIMINATED EFFECTS. [R205] *Ethylene dichloride is metabolized by two competing pathways both of which consume glutathione. Ethylene dichloride undergoes oxidation to form chloroacetaldehyde which is detoxified by glutathione and also reacts directly with glutathione to form 2-(s-chloroethyl)-glutathione. A mathematical model for describing tissue glutathione depletion and resynthesis after ethylene dichloride exposure was developed. The reaction of glutathione with ethylene dichloride and chloroacetaldehyde was simulated. Predicted values for the glutathione content of the liver, lung, forestomach, or glandular stomach were compared with experimental data obtained in male Fischer 344 rats and B6C3F1 mice dosed with 25 or 150 mg/kg ethylene dichloride. The predicted values agreed with the experimental data. Of the tissues modeled, the liver showed the greatest capacity for rapidly resynthesizing glutathione after it was depleted by ethylene dichloride. In rats, liver glutathione synthesis increased rapidly and rebounded past the preexposure concentration 12 hr after exposure. The other tissue showed a much slower rate of glutathione resynthesis. Similar results were seen for mouse liver ad lung glutathione concentrations. [R206] *The metabolism of 1,2-dichloroethane is mediated by enzymes located in the microsomal and cytosolic fraction of the liver. The microsomal pathway is mediated by cytochrome p450 and quantitatively more important in terms of both total metabolism and irreversible binding of 1,2-(14)C-dichloroethane to proteins. The cytosolic pathway is mediated by glutathione transferase and is responsible for the mutagenicity of 1,2-(14)C-dichloroethane and for its binding DNA. The absorption and metabolism of inhaled 1,2-dichloroethane was enhanced in rats pretreated with phenobarbital, a classical inducer of cytochrome p450 and of drug metabolism. [R42, 685] *A study was conducted of the use of freshly isolated hepatocytes to investigate the utilization of glutathione (GSH) in 1,2-dihaloethane metabolism. 1,2-Dichloroethane, 1,2-dibromoethane, and 1-bromo-2-chloroethane were metabolized to S-(2-hydroxyethyl)glutathione), S-(carboxymethyl)glutathione, and S,S -(1,2-ethanediyl)bis(glutathione). 1,2-Dihaloethane induced glutathione depletion was characterized and found to be concomitant with the formation of at least three glutathione containing 1,2-dihaloethane derived metabolites and extensive protein covalent binding. The formation of these glutathione containing metabolites accounted for 58%, 84%, and 71% of the 1,2-dichloroethane, 1-bromo-2-chloroethane, and 1,2-dibromoethane induced loss of intracellular glutathione, respectively. Within 2.0 hours of incubation, the covalent binding of 1,2-dibromoethane to hepatocyte protein reached 18.7 umol/ml of cell suspension. Half of this covalent binding occurred within 0.5 hours of incubation in the presence of high levels of intracellular glutathione. ... [R207] *1,2-Dichloroethane is readily metabolized in the body. The primary metabolic pathways for this chemical are mixed function oxidation (MFO) and glutathione conjugation. Oxidation products incl chloroacetaldehyde, 2-chloroethanol, and 2-chloroacetic acid. MFO metabolism of 1,2-dichloroethane appears to be saturable at oral gavage doses of > or = 25 mg/kg and inhalation concn of > or = 150 ppm (approx 500 mg/kg), both of which correspond to blood levels of 5-10 ug/ml. Glutathione conjugation becomes relatively more important at larger doses, and incr metabolism by this pathway may be responsible for the toxic effects noted at these high doses. [R172] ACTN: *The mechanism of the hepatocellular toxicity of l,2-dichloroethane ... was examined in vitro. Hepatocytes from male Wistar rats were preloaded with tritium (3)H labeled sodium palmitate and (14)C labeled glucosamine. They were incubated with 0 to 6.5 uM 1,2-dichloroethane for 5 to 60 min. Cytotoxicity was assessed by measuring changes in cellular exclusion of trypan blue dye leakage of intracellular lactate dehydrogenase (LDH) into the medium and depletion of intracellular reduced glutathione (GSH). The cells were separated into the cytosolic microsome total Golgi apparatus and secreted lipoglycoprotein fractions which were assayed for changes in the distribution of (3)H and (14)C activity. 1,2-Dichloroethane did not significantly affect cellular trypan blue exclusion and LDH leakage until after 30 and 15 min incubation respectively. Hepatocellular GSH concentrations were significantly decreased after 5 min. Incubation with 4.4 uM 1,2-dichloroethane. 1,2-Dichloroethane large decrease in lipoglycoprotein secretion which was accompanied by significant accumulations of (3)H and (14)C activity in the cells. The levels of (3)H and (14)C activity were significantly increased in the microsomes and Golgi apparatus after 5 and 15 min of 1,2-dichloroethane treatment. Within the lipoglycoprotein fraction 1,2-dichloroethane significantly decreased the amounts of radiolabel in the lipid and sugar moieties. ... [R208] *DNA sequence changes produced by 1,2-dibromoethane, 1,2-dichloroethane and 1-bromo-2-chloroethane were analyzed using the vermilion locus of Drosophila melanogaster. Under excision repair proficient (exr+) conditions (mutagenized exr+ males mated with exr+ females) all mutants isolated from the first generation (Fl) after 1,2-dibromoethane and 1,2-dichloroethane exposure represented rearrangements (multi-locus deletions, small deletions with tandem repeats, duplicate insertions). By contrast mutants expressing a vermilion phenotype only in the F2 (Fl mosaics) all carried single bp changes. When exr+ males after exposure to 1,2-dibromoethane were mated to excision repair deficient (exr-) mus 201 females 11 of 14 mutational events isolated from either Fl or F2 progeny were single bp changes. In general the mutation spectra for the three dihaloalkanes were similar to the spectrum obtained at the same locus for the direct acting monofunctional agent methylmethanesulfonate. The data lend support to the conclusions that these 1,2-dihaloalkanes are genotoxic through modification at ring nitrogens in DNA primarily at the N7 of guanine and, lesser extent, at the N1 of adenine. These N-adducts could be directly miscoding. However, more important for the mutagenic action of chemicals seems to be the formation of non-coding lesions and/or misrepair. [R209] *The mechanism of action for 1,2-dichloroethane-induced toxicity is not known. However, studies in rats and mice indicate that 1,2-dichloroethane may be metabolized to 2-chloroacetaldehyde, S-(2-chloroethyl)glutathione, and other putative reactive intermediates capable of binding covalently to cellular macromolecules ... . The ability of a chemical to bind covalently to cellular macromolecules is often correlated with the induction of toxic effects ... . In addition, 1,2-dichloroethane has been shown to promote lipid peroxidation in vitro ... . Lipid peroxidation is also assoc with production of tissue damage. The lag time between inhalation exposure and onset of effects ... in an occupationally exposed 51-yr old male may have been a reflection, in part, of the time required to metabolize 1,2-dichloroethane to active intermediates. [R210] INTC: *The synergistic hepatotoxicity of dietary disulfiram (DSF) with 1,2-dichloroethane (EDC) subchronically administered by inhalation at three concentration levels (150, 300, and 450 ppm) was studied. The criteria for hepatotoxicity were treatment related increases in serum activities of sorbitol dehydrogenase, 5'-nucleotidase, and alkaline phosphatase, and in liver-to-body weight ratios. Dietary disulfiram alone did not elicit these responses while 1,2-dichloroethane at the highest concentration level increased liver-to-body weight ratios and the activity of 5'-nucleotidase. Exposure to dietary disulfiram alone decreased cytochrome p450 levels, but in combination with 1,2-dichloroethane, the decrement of cytochrome p450 was additive in a 1,2-dichloroethane concn dependent manner. However, depression of cytochrome p450 by 1,2-dichloroethane alone was not concentration dependent. Although dietary disulfiram and dietary disulfiram/1,2-dichloroethane combination increased the activity of glutathione S-transferases (GSTs), both dietary disulfiram and 1,2-dichloroethane singly and in combination increased the tissue levels of reduced glutathione (GSH). [R211] *The interaction of 1,2-dichloroethane with disulfiram or ethanol was investigated in rats. Sprague-Dawley rats were exposed for 24 months to 50 ppm concns of 1,2-dichloroethane in an inhalation study while at the same time being exposed to 0.05% disulfiram in the diet and/or 5% ethanol in the drinking water. A high incidence of intrahepatic bile duct cholangioma were reported in both sexes receiving 1,2-dichloroethane and disulfiram, 18% incidence among males and 34% among females. Male rats also registered 12% incidence of hepatocellular adenomas, 22% incidence for interstitial cell tumors in the testes, 20% subcutis fibroma, and 25% mammary adenocarcinomas in females. The expected rates for these disorders would have been 0, 4, 4, and 8%, respectively. A slight increase in neoplastic nodules occurred in males receiving 1,2-dichloroethane and ethanol, 8% versus 0% expected. The DNA binding by 1,2-dichloroethane was not altered by disulfiram treatment, and the metab of 1,2-dichloroethane was qualitatively the same as in corresponding controls. However, the combined treatment of 1,2-dichloroethane and disulfiram did reduce the rate of elimination of 1,2-dichloroethane, and sustained the blood concn levels of unchanged 1,2-dichloroethane, which may be related to the increased carcinogenic effect of the combination. [R212] *The in vitro metabolism of 1,2-dichloroethane by liver homogenates of rats admin ethanol increased with the dose of ethanol up to 4 g/kg bw, but declined sharply at 5 g/kg bw. [R213] *High doses (1000-2000 mg/kg bw) of several chemicals, including methionine, p-aminobenzoic acid, sulfanilamide and aniline, admin orally to mice were protective against the lethal effects caused by inhalation of 1600 mg/cu m (400 ppm) 1,2-dichloroethane. [R213] *The acute and subacute toxicity of dichloroethane increased when it was administered under conditions of high temperature ... . [R213] *Induction of hepatic cytochrome P-450 enzymes by phenobarbital and/or Aroclor 1254 incr the rate of MFO /mixed function oxidation/ metabolism of 1,2-dichloroethane in vitro ... . Alterations in metabolism could potentially produce profound effects on toxicity. Enhanced enzymatic metabolism of 1,2-dichloroethane also occurs after treatment with ethanol in vitro ... . Ethanol is an inducer of cytochrome P-450 2E1, the primary MFO enzyme involved in 1,2-dichloroethane metabolism ... . [R214] *Concurrent admin of 0.15% disulfiram in the diet and inhaled 1,2-dichloroethane (10, 153-304, 455 ppm) in animals markedly incr hepatotoxicity much more than would occur with exposure to 1,2-dichloroethane alone ... . Similarly, after chronic cotreatment with 50 ppm of 1,2-dichloroethane by inhalation and 0.05% disulfiram in the diet for 2 yr, a series of neoplastic lesions were produced in rats that were not produced by 1,2-dichloroethane (or disulfiram) alone ... . The lesions included intrahepatic bile duct cholangiomas, sc fibromas, hepatic neoplastic nodules, interstitial cell tumors in the testes, and mammary adenocarcinomas. [R214] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *As a general anesthetic instead of chloroform, especially in ophthalmic surgery. /Former use/ [R42, 686] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Dichloroethane's production and use as a chemical intermediate, in soaps, lead scavenger, solvent, and former use as a fumigant may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 78.9 mm Hg at 25 deg C indicates 1,2-dichloroethane will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichloroethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 63 days. Indirect evidence for photooxidation of 1,2-dichloroethane comes from the observation that monitoring levels are highest during the night and early morning. If released to soil, 1,2-dichloroethane is expected to have very high mobility based upon a Koc of 33. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 1.18X10-3 atm-cu m/mole. 1,2-Dichloroethane may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation in soil or water is not expected to be an important environmental fate process based upon a variety of biodegradation test data. If released into water, 1,2-dichloroethane is not expected to adsorb to suspended solids and sediment based upon the Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4 hrs and 4 days, respectively. A BCF of 2 suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to 1,2-dichloroethane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloroethane is produced or used. Monitoring data indicate that the general population may be exposed to 1,2-dichloroethane via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and consumer products containing 1,2-dichloroethane. (SRC) NATS: *1,2-Dichloroethane is not known to occur as a natural product(1). [R215] ARTS: *1,2-Dichloroethane's production and use as a chemical intermediate, in soaps, lead scavenger, solvent(1), and former use as a fumigant(1,2) may result in its release to the environment through various waste streams(SRC). Chlorination of water does not appear to contribute to 1,2-dichloroethane in drinking water(3). [R216] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 33(2) indicates that 1,2-dichloroethane is expected to have very high mobility in soil(SRC). Volatilization of 1,2-dichloroethane from moist soil surfaces is expected to be an important fate process(SRC) given a estimated Henry's Law constant of 1.18X10-3 atm-cu m/mole(3). The potential for volatilization of 1,2-dichloroethane from dry soil surfaces may exist(SRC) based upon a vapor pressure of 78.9 mm Hg(4). Biodegradation is not expected to be an important environmental fate process in soil as indicated by a variety of biodegradation tests(SRC); the percent BOD produced in aerobic systems using sewage seed or activated sludge in 5-10 days was 0-7%(5-7). [R217] *AQUATIC FATE: Based on a classification scheme(1), Koc value of 33(2) indicates that 1,2-dichloroethane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1.18X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 4 hrs and 4 days, respectively(SRC). Hydrolysis is not expected to be an important environmental fate process since 1,2-dichloroethane lacks functional groups that hydrolyze under environmental conditions(5). According to a classification scheme(6), a BCF of 2(7), suggests bioconcentration in aquatic organisms is low(SRC). Biodegradation is not expected to be an important environmental fate process in water(SRC). The percent BOD produced in aerobic systems using sewage seed or activated sludge in 5-10 days was 0-7%(8-10). [R218] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-dichloroethane, which has a vapor pressure of 78.9 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichloroethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 63 days(SRC), calculated from its rate constant of 2.48X10-13 cu cm/molecule-sec at 25 deg C(3). Indirect evidence for photooxidation of 1,2-dichloroethane comes from the observation that monitoring levels are highest during the night and early morning(4). [R219] BIOD: *AEROBIC: Biodegradability tests with 1,2-dichloroethane resulted in little or no biodegradation in aerobic systems using sewage seed or activated sludge(1-5). The one river die-away test reported no degradation(1). The percent BOD produced in 5-10 days was 0-7%(2-4). Another investigator reported slow to moderate biodegradation activity(5). In a bioreactor study using microbial consortia enriched from subsurface sediments contaminated with chlororinated hydrocarbons, a mixed-organic waste containing 21 ug/l of 1,2-dichloroethane was degraded to < 5 ug/l after a 21 day run(6). [R220] *ANAEROBIC: No degradation of 1,2-dichloroethane occurred in an acclimated anaerobic system after 4 months incubation(1). The attenuation rate constant in a groundwater plume for 1,2-dichloroethane was 0.27/yr based on a study at the West KL Avenue Landfill, Kalamazoo, MI via the use of vertical profile sampling of monitoring wells on the site(2). [R221] ABIO: *The rate constant for the vapor-phase reaction of 1,2-dichloroethane with photochemically-produced hydroxyl radicals has been estimated as 2.48X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 63 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The direct photolysis of 1,2-dichlorethane is not an important environmental fate process(2). Indirect evidence for photooxidation of 1,2-dichloroethane comes from the observation that monitoring levels are highest during the night and early morning(5). The products of photooxidation are CO2 and HCl(4). The tropospheric lifetime in the Northern Hemisphere has been estimated at 0.32 yrs(3). A hydrolysis half-life of 50,000 yrs was approximated for 1,2-dichloroethane(3). However, in a test designed to simulate oxygen-deficient natural waters, reaction of 1,2-dichloroethane with water and hydrogen sulfide ion has demonstrated that primary chloroalkanes are susceptible to abiotic dehalogenation by both agents under conditions that are environmentally relevant, i.e. 15 deg C , pH 7, 10-6 to 10-3 total sulfide(6). Although firm experimental data are lacking, the photooxidation of 1,2-dichloroethane in water is expected to be slow(4). [R222] BIOC: *A BCF of 2 was measured for 1,2-dichloroethane in bluegill sunfish, Lepomis macrochirus(1). According to a classification scheme(2), this BCF suggests bioconcentration in aquatic organisms is low(SRC). [R223] KOC: *The Koc for 1,2-dichloroethane is 33(1). According to a classification scheme(2), this estimated Koc value suggests that 1,2-dichloroethane is expected to have very high mobility in soil(SRC). 1,2-Dichloroethane rapidly percolates through sandy soil(3). [R224] VWS: *The Henry's Law constant for 1,2-dichloroethane is 1.18X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that 1,2-dichloroethane is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 4 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). 1,2-Dichloroethane's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,2-dichloroethane from dry soil surfaces may exist(SRC) based upon a vapor pressure of 78.9 mm Hg(3). [R225] WATC: *GROUNDWATER: 1,2-Dichlorethane was detected in raw groundwater samples from 13 US cities at a concn of 0.2 ppb, 7.7% pos(1). In a US State groundwater survey, 2 states reported concns of 400 ppb max, and 7% were positive(2). Well water samples from the Aerojet General Rocket Plant, Sacramento contained up to 52 ppm 1,2-dichloroethane(3). 1,2-Dichloroethane was detected at 0.14 uM, 0.57 uM, and 43 uM and 7.0 uM in slightly, moderately, and heavily contaminated monitoring wells, respectively, from the DuPont Necco Park Landfill in Niagara Falls, NY(4). [R226] *DRINKING WATER: In a survey of 133 US cities, 1,2-dichloroethane was detected in finished surface water at a concn of 0.8-4.8 ppb, 1.8 ppb median, 4.5% pos(1) and in samples of finished groundwater from 25 US cities at a concn of 0.2 ppb avg, 4.0% pos(1). According to the National Organic Monitoring Survey (1976-77), 3 of 218 samples were positive, limits of detection < 0.2 ppb(2). The compound was detected in 7 wells in the Central Sands area of Wisconsin, 2 of which exceeded the recommended health advisory of 7 ppb (detection limit= 0.1-3.0 ppb)(3). Average annual concns of 1,2-dichloroethane in California public drinking water sources are as follows: (1984) 1.55 ug/l; (1985) 4.40 ug/l; (1986) 1.51 ug/l; (1987) 1.68 ug/l; (1988) 2.73 ug/l; (1989) 3.43 ug/l; (1990) 3.32 ug/l; (1991) 3.65 ug/l; (1992) 3.86 ug/l(4). [R227] *SURFACE WATER: 1,2-Dichloroethane was reported in US samples as follows: 6 river basins, 1-90 ppb, 53 of 204 sites pos, only 1 site above 15 ppb(1); Ohio R basin (1977-1978) 0.1-29 ppb, 39 of 243 samples pos(2); Ohio R basin (1980-1981, 4972 samples) 7% pos, 44 samples 1-10 ppb(3); 105 USA cities - raw drinking water 1-4 ppb, 0.55 ppb median, 9.5% pos(4); 80 USA municipal water systems - raw water 0-0.3 ppb, 14% pos(5); Lake Erie - 2 sites, 4 ppb, 1 site pos(6). [R228] *SEAWATER: In samples from the Gulf of Mexico, 1,2-dichloroethane was reported at 0-210 parts/trillion in areas with anthropogenic influence and not detected in unpolluted areas(1). Marine sample concns from various estuaries were as follows (detection limit of 25 ug/l): Humber, UK, 1992: < 25 ug/l; Tees, UK, 1992 720-4,020 ug/l; Tyne, UK 1992: < 25 ug/l; Wear, UK, 1992: < 25 ug/l; Tweed, UK, 1992: < 25 ug/l; Scheldt, Netherlands/Belgium, 1993: 48.0 ug/l; Brazos River, US, 1981-82: 9-51 ug/l(2). [R229] EFFL: *Industries whose wastewater may exceed a mean 1,2-dichloroethane concn of 1000 ppb include: photographic equipment/supplies, pharmaceutical mfg and organic chemicals/plastics mfg; max concn in wastewater was 14 ppm (pharmaceutical mfg)(1). 1,2-Dichloroethane was detected in one of 4 monitoring well headspace gases at a municipal solid waste disposal facility at a concn of 0.09 ng/cu m; not detected in the other three monitoring wells, and absent from groundwater samples(2). The compound was detected, not quantified, in the flue gas of a municipal waste incinerator in Karlsruhe, Germany(3). 1,2-Dichloroethane is one of the priority pollutants released to Newark Bay, NJ(4). The global emission rate to the Northern Hemisphere has been estimated to be 400 - 500 ktons per yr and the mean concn from 1982 to 1985 was 12 parts/trillion volume; the mean concn in the Southern Hemisphere in 1985 was < 1 parts/trillion volume(5). [R230] SEDS: *SOIL: According to the STORET database, 1,2-dichloroethane was not detected in sediment from lower Mississippi (1 sample) and Western Gulf (14 samples). In 20 sediment samples from the Pacific Northwest, 5 ug/g avg and max concns were reported(1). [R231] *SEDIMENT: According to the STORET database, 20 sediment samples from the Pacific Northwest contained 5 ug/g avg and max concns of 1,2-dichloroethane(1). [R231] ATMC: *Atmospheric industrial concn determined: rubber cementing 85-110 ppm (max 200), leather finishing 125 ppm (max 210), drum filling 35 ppm (max 45), metal cleaning 180 ppm (max 250). [R232] *URBAN/SUBURBAN: 1,2-Dichloroethane was detected in 1230 US samples at a concn of 120 parts/trillion avg(1); samples from 7 US cities contained 110-1380 parts/trillion avg, 7300 parts/trillion max(2,3). The compounds was detected in samples from 3 western USA cities at a concn of 83-519 parts/trillion avg, 1450 parts/trillion max(4). Samples from 5 areas in NJ contained 940-1500 parts/trillion avg, with 22-44% pos, 16000 parts/trillion max(5). The estimated air concn for 360,000 Los Angeles residents (Feb 1984) - 0.2 ug/cu m; 330,000 Los Angeles residents (May 1984) - 0.06 g/cu m; 91,000 Contra Costa residents (June 1984) - 0.5 ug/cu m; avg of arithmetic means of day and night 12 hr samples(7). [R233] *RURAL/REMOTE: 1,2-Dichloroethane was not detected in 9 US samples, detection limit not specified(1). [R234] *SOURCE DOMINATED: 1,2-Dichloroethane was detected in 436 US samples at a concn of 1,200 parts/trillion avg(1); concns as high as 16, 38 and 45-113 ppb have been recorded at 3 production and use sites(2). [R235] FOOD: *Market basket samplings of meat, oil and fats, tea, fruits and vegetables contained 1,2-dichloroethane at a concn range of 1-10 ppb, the largest amount being found in olive oil(1). It was not detected in wheat, flour, bran, middlings, and bread(1). Concns in spice oleoresins were 2-23 ppm, 11 of 17 spices positive(1,2). The avg concn from 549 food items surveyed was 30 ng/g in 1 of 849 findings(3). [R236] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Results reported in the STORET database are as follows: fish tissue: Lower Mississippi (2 samples) and Western Gulf (3 samples) - not detected; Pacific Northwest (37 samples) 0.05-20 ppm, 0.7 ppm avg; Alaska (6 samples) 0.05 ppm avg and max Data in this report are listed under dichloroethanes, however 1,2-dichloroethane is the most commonly used isomer(1). 1,2-Dichloroethane was not detected in marine invertebrates and fish from Liverpool Bay, England(2). [R237] MILK: *1,2-Dichloroethane was detected in mothers' milk of women had occupational exposure of up to 14 ppm at a concn of 5.4-6.4 ppm immediately after exposure(1). [R238] RTEX: *... WORKERS PRIMARILY EXPOSED TO 1,2-DICHLOROETHANE WERE THOSE IN HOSPITALS, BLAST FURNACES, STEEL MILLS AND AIR TRANSPORTATION INDUSTRIES. [R239] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 83,246 workers (33,361 of these are female) are potentially exposed to 1,2-dichloroethane in the US(1). Occupational exposure to 1,2-dichloroethane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloroethane is produced or used(SRC). Monitoring data indicate that the general population may be exposed to 1,2-dichloroethane via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and consumer products containing 1,2-dichloroethane(SRC). 5 of 1043 household products were found to contain 1,2-dichlroethane, a 0.5% occurrence(2). These include automotive products (0.6% frequency, 0.1% w/w avg concn), oils, greases and lubricants (2.6% frequency, 0.1% w/w avg concn), and miscellaneous products (3.2% frequency, 0% w/w avg concn)(2). 12.5 million people are estimated to be exposed to avg annual concn of 0.009-9 ppb near production facilities(2). The exposure estimate from filling tank with gasoline is 0.1 ug/day (time-weighted avg)(2). [R240] BODY: *1,2-Dichloroethane was detected in human breath of residents from Old Love Canal, Niagara Falls, NY at a concn of 0-54 parts/trillion, 4 of 9 samples pos and in urine at a concn of 0-140 parts/trillion, 3 of 9 samples pos(1). It was detected in mothers' milk of women had occupational exposure of up to 14 ppm at a concn of 5.4-6.4 ppm immediately after exposure(2). [R241] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH has recommended that 1,2-dichloroethane be treated as a potential human carcinogen. [R64] OSHA: *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 50 ppm. [R242] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 100 ppm. [R242] *Permissible Exposure Limit: Table Z-2 Acceptable maximum peak above the acceptable ceiling concentration for an 8-hour shift. Concentration: 200 ppm. Maximum Duration: 5 minutes in any 3 hours. [R242] NREC: *NIOSH recommends that ethylene dichloride be regulated as a potential human carcinogen. [R64] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R64] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 ppm (4 mg/cu m). [R64] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 2 ppm (8 mg/cu m). [R64] TLV: *8 hr Time Weighted Avg (TWA) 10 ppm [R243, 2001.31] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R243, 2001.6] *A4: Not classifiable as a human carcinogen. [R243, 2001.31] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. 1,2-Dichloroethane is produced, as an intermediate or final product, by process units covered under this subpart. [R244] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,2-Dichloroethane is included on this list. [R245] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l [R246] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 0.5 ug/l [R246] +(FL) FLORIDA 3 ug/l [R246] +(NJ) NEW JERSEY 2 ug/l [R246] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.38 ug/l [R246] +(CT) CONNECTICUT 1 ug/l [R246] +(ME) MAINE 5 ug/l [R246] +(MN) MINNESOTA 4 ug/l [R246] CWA: +Ethylene dichloride is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R247] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R248] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R249] RCRA: *U077; As stipulated in 40 CFR 261.33, when ethylene dichloride, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R250] *D028; A solid waste containing 1,2-dichloroethane may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R251] FDA: *Ethylene dichloride is an indirect food additive for use as a component of adhesives. [R252] *The food additive ethylene dichloride may be safely used in the manufacture of animal feeds in accordance with the following prescribed conditions: (a) It is used as a solvent in the extraction processing of animal byproducts for use in animal feeds. (b) The maximum quantity of the additive permitted to remain in or on the extracted byproducts shall not exceed 300 ppm. (c) The extracted animal byproduct is added as a source of protein to a total ration at levels consistent with good feeding practices, but in no event exceeding 13 percent of the total ration. [R253] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Ethylene dichloride was collected /from air/ on silica gel, and extracted with isopropyl alcohol ... . [R254] *NIOSH Method 1003. Matrix: air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Minimun vol: 0.5 l @ 100 ppm, Max vol: 15 l; Sample stability: Not determined; Shipment: Routine. [R255] ALAB: *NIOSH Method 1003. Analyte: 1,2-Dichloroethane; Technique: Gas chromatography, flame ionization detection; Desorption: 1 ml carbon disulfide; stand 30 min; Injection vol: 5 ul; Temp injection: 225 deg C, detector: 250 deg C, column: 70 deg C; Carrier gas: Helium or nitrogen, 30 ml/min; Column: 3 m x 3 mm outer diameter stainless steel, 10% OV-101 on 100/120 mesh Chromosorb WHP; alternates are SP-2100, SP-2100 with 0.1% Carbowax 1500 or DB-1 fused silica capillary column. Calibration: Std soln of analyte in carbon disulfide; Range: 0.02 to 0.3 mg/sample; Estimated limit of detection: 0.01 mg/sample; Precision (std relative deviation): 0.079 overall, measurement 0.012; Interferences: None identified. The chromatographic column or separation conditions may be changed to circumvent interferences. [R255] *AOAC Method No. 969.29. Ethylene Dichloride and Trichloroethylene in Spice Oleoresins. Gas Chromatographic Method. Detection limit not stated. [R256, 1175] *AOAC Method No. 966.05. Fumigant Mixtures. Gas Chromatographic Method. Detection limit not stated. [R256, 164] *Method is described for the time-weight-average concentration determination of 23 volatile components including 1,2-dichloroethane permeation through a silicone polycarbonate membrane and absorption onto charcoal contained within the sampling device. Analysis consists of desorption of the volatile components with carbon disulfide and then separation and quantification by capillary column gas chromatography. Linear relationship exists between the amount of a volatile organic component collected and the product of the time of exposure of the sampling device to the sampling environment and the concentration of the component in the sampling environment, for the ranges investigated. Temperature is the only other external factor which has been shown to affect the rate of permeation, though the change in the permeation constant has been shown to be approximately linear with a slope of about 0.4. [R257] *EPA Method 502.1: Volatile Halogenated Organic Compounds in Water by Purge-and-Trap Gas Chromatography. This method is applicable for the determination of various halogenated volatile compounds in finished drinking water, raw source water, or drinking water in any treatment stage. ... Organohalides and other highly volatile organic compounds with low water solubility are extracted (purged) from the sample matrix by bubbling an inert gas through the aqueous sample. Purged sample components are trapped in a tube containing suitable sorbent materials. When purging is complete, the sorbent tube is heated and backflushed with an inert gas to desorb trapped sample components into a gas chromatography column. The gas chromatograph is temperature programmed to separate the method analytes which are then detected with a halogen specific detector. Using this method, 1,2-dichloroethane has a method detection limit of 0.002 ug/l. [R258] *AOB Method VG-001-01. Volatile Organics in Soil Gas - Adsorbent Tube Method. Quantitation limit = 20 ng/l. [R259] *EPA Method 1624-S. Volatile Organic Compounds by Isotope Dilution GCMS. Method detection limit = 3 mg/kg. [R259] *EPA Method 1624-W. Volatile Organic Compounds by Isotope Dilution GCMS. Method detection limit = 10 ug/l. [R259] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. Method detection limit = 2.8 ug/l. [R259] *EPA Method 624-S. Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. Method detection limit = 2.8 ug/l. [R259] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. Method detection limit = 0.030 ug/l. [R259] *EPA Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. Method detection limit = 0.20 ug/l. [R259] *EPA Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. Revision 4.0. Method detection limit = 0.060 ug/l. [R259] *EPA Method 502.2-ELCD. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. Method detection limit = 0.030 ug/l. [R259] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Estimated quantitation limit = 5.0 ug/l. [R259] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. Method detection limit = 0.002 ug/l. [R259] *AREAL Method IP-1A. Determination of Volatile Organic Compounds (VOCs) in Indoor Air Using Stainless Steel Canisters. Detection limit not specified. [R259] *AREAL Method IP-1B. Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbent Tubes. Detection limit = 3.80 ng. [R259] *AREAL Method TO-14. Determination of Volatile Organic Compounds (VOCs) in Ambient Air using SUMMA Passivated Canister Sampling and Gas Chromatographic Analysis. Detection limit not specified. [R259] *AREAL Method TO-1. Determination of Volatile Organic Compounds in Ambient Air using Tenax Adsorption and Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit not specified. [R259] *AREAL Method TO-2. Determination of Volatile Organic Compounds In Ambient Air by Carbon Molecular Sieve Adsorption and Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit not specified. [R259] *AREAL Method TO-3. Determination of Volatile Organic Compounds in Ambient Air Using Cryogenic Preconcentration Techniques and Gas Chromatography with Flame Ionization and Electron Capture Detectors. Detection limit not specified. [R259] *CLP Method OHC. Organics Analysis, Multi-Media, High-Concentration. Contract required quantitation limit = 2.500 mg/kg. [R259] *CLP Method MC_VOA-LS. Analysis of Volatile Organics in Low Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. Contract required quantitation limit = 10 mg/kg. [R259] *CLP Method MC_VOA-MS. Analysis of Volatile Organics in Medium Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. Contract required quantitation limit = 1200.0 mg/kg. [R259] *OSW Method 1311. Toxicity Characteristic Leaching Procedure. [R259] *OSW Method 8240B-S. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Estimated quantitation limit = 5.0 ug/kg. [R259] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Method detection limit = 0.060 ug/l. [R259] CLAB: *DETERMINATION OF 1,2-DICHLOROETHANE IN RAT BLOOD, LIVER, LUNG, SPLEEN, BRAIN, KIDNEY AND EPIDIDYMAL ADIPOSE TISSUE BY HEAD-SPACE GAS CHROMATOGRAPHY. METHOD IS SENSITIVE TO 25 NG/ML OF BLOOD OR 50 NG/G OF TISSUE. [R260] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Environment Canada; Tech Info for Problem Spills: Ethylene Dichloride (Draft) (1982) USEPA; Drinking Water Criteria Document (Draft): 1,2-Dichloroethane (1982) USEPA; Office of Drinking Water; Health Advisory 1,2-Dichloroethane (Draft) (1985). USEPA; Health and Environmental Effects Profile for Dichloroethane (1985) ECAO-CIN-P139 DHHS/ATSDR; Toxicological Profille for 1,2-Dichloroethane (Update) (1994) ATSDR/TP-93/06 DHHS/NTP; NTP Report on the Toxicity Studies of 1,2-Dichloroethane (Ethylene Dichloride) in F344/N Rats, Sprague Dawley Rats, Osborne-Mendel Rats, and B6C3F1 Mice (Drinking Water Gavage Studies) NTP TOX 4 (1991) NIH Pub No. 91-3123 DHEW/NCI; Bioassay of 1,2-Dichloroethane for Possible Carcinogenicity (1978) Technical Rpt Series No. 55 DHEW Pub No. (NIH) 78-1361 Health and Safety Executive; 1,2-Dichloroethane Criteria Document for an Occupational Exposure Limit 47pp. (1993). Data on the effects of exposure to 1,2-dichloroethane is examined. Commission of the European Communities; Organo-chlorine Solvents. Health Risks Workers. Pub No. EUR 10531 (1986). A review of the thealth hazards and toxicology of 1,2-dichloroethane. WHO; Environmental Health Criteria 62 1,2-Dichloroethylene (1987) U.S Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Services, Research Triangle Park, NC. (2000) HIST: *1.3 million liters were spilled in a lake due to overfilling of a river barge. One month later a large pool of concn 1,2-dichloroethane 110 m x 36 m x 0.7 m deep was lying in 10 m of water at the river bottom, as detected by a ... sonar laser device. Dispersal was negligible with adjacent water samples showing 1,2-dichloroethane in the ppb range. 1.1 million liters were recovered using a suction pump for purification and resale. Fish concn were in the range of 2-4 ppb at the time of cleanup. [R261] *A train containing hazardous chemicals derailed, and 166,090 gallons of ethylene dichloride and 58,970 gallons of ethylene glycol spilled into ... /a Canadian/ river. Within 1 hr the site was determined as stable, and all persons at the accident site were safe. Local public health officials, the police, and a chemical company worked together to establish confidence and disseminate information. The solubility of ethylene dichloride suggested that it might present problems to the water supply. Ethylene glycol did not pose the same intensity of concern because it was less toxic and soluble in water. Some water systems using water directly from the river were closed. Three days after the spill, laboratory analysis showed that the taste and odor threshold for ethylene dichloride were exceeded. Consequently, the river was closed. A sampling from the river after 8 weeks indicated that the criterion of a concentration of 7 micrograms per liter was reached. No fish were killed, and spawning was not disturbed. A review of the accident, the chemicals, and laboratory data resulted in the closing of other water systems that were at risk from the river. Movements of the chemicals throughout the river were calculated. [R262] SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 (1993) R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 468 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 (1986) 263 R5: ChemExpo; Chemical Profile Database on Ethylene dichloride 107- 06-2). March 19, 2001. Available from the Database Query page at http://www.chemexpo.com/news/newsframe.cfm?framebody=/news/profil e.cfm as of March 23 2001. R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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Final Draft Report p 5-24 (1980) R242: 29 CFR 1910.1000 (7/1/2000) R243: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R244: 40 CFR 60.489 (7/1/2000) R245: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R246: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). 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Washington, DC: Association of Analytical Chemists, 1990 R257: Blanchard RD, Hardy JK; Anal Chem 57 (12): 2349-51 (1985) R258: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water 500 Series Methods (1988) EPA/600/4-88/039 R259: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R260: ZUCCATO E ET AL; ANALYTICAL LETTERS 13 (B5): 363 (1980) R261: Environment Canada; Tech Info for Problem Spills: Ethylene Dichloride (Draft) p.110 (1982) R262: Christian KL, Moorehaead WP; J Environ Health 47 (4): 192-6 (1985) RS: 222 Record 12 of 1119 in HSDB (through 2003/06) AN: 66 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DICHLOROMETHANE- SY: *CHLORURE-DE-METHYLENE- (FRENCH); *DCM-; *METHANE,-DICHLORO-; *Methylene-chloride-; *Methylenum-chloratum-; *METYLENU-CHLOREK- (POLISH); *NCI-C50102- RN: 75-09-2 MF: *C-H2-Cl2 SHPN: UN 1593; Dichloromethane UN 1593; Methylene chloride IMO 6.1; Dichloromethane UN 1912; Methyl chloride-methylene chloride mixture STCC: 49 411 32; Dichloromethane 49 411 32; Methylene chloride 49 057 64; Methyl chloride-methylene chloride mixture HAZN: U080; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off specification commercial chemical product or manufacturing chemical intermediate. F002; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Produced industrially in the U.S. by two methods. The older and currently lesser used method involves a direct reaction of excess methane with chlorine at high temperatures. The predominant method involves the reaction of methyl chloride with chlorine. This reaction is usually carried out thermally in the gas phase, but may be carried out at low temperatures and high pressure in the liquid phase. [R1, p. V5 1044] IMP: *Impurities include tetrachloromethane, trichloromethane, 1,2-dichloroethane, cis- and trans-1,2-dichloroethylene, pentachloroethane, 1,1,12-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1,1-trichloroethane, `,`,1-trichloroethane, 1,1-dichloroethylene, bromodichloroethylene, tetrachloroethylene, bromodichloromethane, and benzene. /Halogenated solvents/ [R2, 733] FORM: *Dichloromethane is available as commercial/technical grade and grades intended specifically for vapor degreasing, aerosol use, food extraction, reagent use and spectrophotometry. Purity, when reported, ranges from 99-99.9% (reagent/high performance liq chromatography grade). Acidity (as hydrochloric acid) may be up to 5-10 mg/kg. The max concn of water in commercial grade dichloromethane is generally 100-200 mg/kg, but anhydrous dichloromethane (less than 50 mg/kg water) is also available ... [R3] *Small amt of stabilizers are often added to dichloromethane at the time of manufacture. Cyclohexane (50 mg/kg) and propylene oxide have been added to commercial aerosols and reagent grades of dichloromethane for this purpose. Other reported stabilizers include 2-methyl-2-butene @ 50 mg/kg, ethanol or methanol at approx 0.2%, and small quantities (1 mg/kg) of phenol ... . [R4] *Additives may include 0.0001-1% of stabilizers such as: amines, 4-cresol, hydroquinone, methanol, 2-methylbut-2-ene, 1-naphthol, nitromethane + 1,4-dioxane, phenol, resorcinol, and thymol. [R5] *In the USA, a standard grade dichloromethane has the following typical specifications: a clear, water white liquid, free of suspended matter ... acidity, 5 mg/kg max; non volatile residue 10 mg/kg max; free halogen none; and a 100% distillation range of 39.5-40.5 deg C. [R6] *Grades available from Mallinkrodt Speciaty Chemicals include AR, ChomAR, NANOGRADE, SpectrAR, UltimAR, ACS Reagent, USP, HPLC, and GC grades. [R7] MFS: *Dow Chemical U.S.A., Hq, 2030 Dow Center, Midland, MI 48674, (517) 636-1000. Production sites: Freeport, TX 77541; Plaquemine, LA 70765 [R8, 744] *Vulcan Materials Company, Vulcan Chemicals Group, Chloralkali Business Unit, Hq, P.O. Box 530390, Birmingham, AL 35253-0390, (205) 877-3484; Production sites: Geismar, LA 70734; Wichita, KS 67277 [R8, 744] OMIN: *Production capacities are flexible since more than one chlorinated hydrocarbon can be produced in the same equipment. [R9] *Chloroform and carbon tetrachloride are coproduced in the production of methylene chloride by the chlorination of methyl chloride. [R1, p. V5 1044] *Although methylene chloride is considered a very stable compound, small amounts of stabilizer are usually added at the time of manufacture. [R1, p. V5 1044] USE: *The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R10] *CHEM INT FOR BROMOCHLOROMETHANE AND OTHER CHEMICALS [R11, p. 5(79) 688] *In pour molding of dental material, the 50:50 mixture of dichloromethane and methylmethacrylate cold curing monomer is used to treat the acrylic teeth to improve the bonding [R11, p. 7(79) 503] *Paint stripping, extraction solvent for decaffeination of coffee, spices, and beer hops, dip-type metal cleaner, vapor degreasing of metals, carrier solvent in textile industry, aerosol, refrigerant, low temperature heat-transfer agent. It is used in chemical processing (e.g., manufacture of polycarbonate plastics, insecticides and herbicides, pharmaceuticals. Other uses include grain fumigation and oil dewaxing. [R1, p. V5 1048] *Solvent in paint removers, for cellulose acetate; degreasing and cleaning fluids; as solvent in food processing. Pharmaceutical aid (solvent). Aerosol propellant; insecticide. [R12] CPAT: *Paint removers, 30%; metal cleaning/degreasing, 22%; miscellaneous solvent uses and other applications, 21%; aerosols, 17%; foam blowing agent, 5%; pharmaceutical solvent, 5% (1978). /From table/ [R13, p. 3-2] *PAINT REMOVER, 30%; AEROSOLS, 20%; VAPOR DEGREASING, 11%; CHEM PROCESS INDUST, 11%; BLOWING AGENT, 6%; FILM PROCESSING, 6%; PLASTICS PROCESSING, 6%; PHARMACEUTICALS, 6%; OTHER, 4% (1981) [R14] *Aerosols, 30%; paint remover, 30%; foam blowing, 15%; fiber and plastic solvent, 5%; metal cleaning, 5%; miscellaneous, 15% (1985) [R15] *CHEMICAL PROFILE: Methylene chloride. Paint stripper, 28%; aerosols, 18%; exports, 15%; chemical processing, 11%; urethane foam blowing agent, 9%; metal degreasing, 8%; electronics, 7%; other, 4%. [R16] *Dichloromethane use in the United States in 1995: Paint removers/strippers 40%; chemical processing 10%; pharmaceuticals 6%; metal degreasing/cleaning 13%; electronics 3%; urethane blowing agent 6%; miscellaneous (includes pesticides, food processing, synthetic fibers, paints and coatings, aerosols, and film processing) 22%. /From table/ [R17] *Paint stripping and removal, 40%; metal cleaning, 13%; plastics (polycarbonate triacetate fiber), 10%; pharmaceuticals, 6%; flexible polyurethane foam, 6%; electronics, 3%; film processing, 2%; miscellaneous, including pesticides, food processing, synthetic fibers, paints and coatings, and aerosols, 20%. [R9] PRIE: U.S. PRODUCTION: *(1978) 2.59X10+11 G [R14] *(1979) 2.97X10+11 g [R11, p. 7(79) 698] *(1981) 2.53X10+11 G [R18] *(1983) 2.46X10+11 G [R14] *(1985) 2.12X10+11 g [R19] *(1986) 5.61X10+8 lb [R20] *(1987) 5.16X10+8 lb [R21] *1986 Production by USA chemcial industry 559 million lbs. [R22] *1987 production by USA chemical industry 516 million lbs. [R23] *CHEMICAL PROFILE: Methylene chloride. Demand: 1988: 500 million lb; 1989: 475 million lb; 1993 /projected/: 410 million lb. (Includes exports, but not imports, which totaled 27 million lb last year). [R16] *Demand: 1982: 530 million lb; 1983: 530 million lb; 1987: 621 million lb. [R24] *1996 Demand: 335 million pounds. Projected demand for 1997: 325 million pounds. Projected demand for 2001: 250 million pounds. (Includes exports which amounted to 133 million pounds in 1996 and averaged 148 million pounds between 1992 and 1996). [R25] *1992: 164,227,000 kilograms [R26] *Production capacity: 770 million pounds (estimate as of 4/1/99) [R8, 742] U.S. IMPORTS: *Imports are in the range of 10 to 20 million pounds per year. [R9] U.S. EXPORTS: *1996: 133 million pounds. 1992-1996: 148 million pounds, average. [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [Note: A gas above 104 degrees F]. [R12] ODOR: *Sweet, pleasant odor, like chloroform [R27]; *Chloroform like odor. [R28] BP: *39.75 deg C @ 760 mm Hg [R12] MP: *-95 deg C [R12] MW: *84.93 [R12] CORR: *Liquid methylene chloride will attack some forms of plastics, rubber and coatings. [R29, 1981.2] CTP: *Critical temperature: 510 K; critical pressure: 6.10 MPa [R30, p. 6-49] DEN: *1.3255 20 deg C/4 deg C [R12] HTV: *28.82 kJ/mol at 25 deg C ; 28.06 kJ/mol at boiling point [R30, p. 6-104] OWPC: *log Kow= 1.25 [R31] SOL: *Miscible with alcohol, ether, dimethylformamide [R12]; *Miscible in ethanol and ethyl ether; soluble in carbon tetrachloride [R30, p. 3-206]; *13,000 mg/l at 25 deg C in water [R32] SPEC: *Index of refraction: 1.4244 @ 20 deg C/D [R12]; *IR: 4354 (Coblentz Society Spectral Collection) [R33]; *NMR: 6401 (Sadtler Research Laboratories Spectral Collection) [R33]; *MASS: 117 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R33]; *IR PRISM: 6620 (gas), 1011, IR GRATING: 28523 [R3]; *Intense mass spectral peaks: 49 m/z, 84 m/z [R34] SURF: *28.12 dyne/cm at 20 deg C. [R35] VAPD: *2.93 (Air=1.02) [R36] VAP: *435 mm Hg at 25 deg C [R37] EVAP: *71 (Ether= 100) [R38] VISC: *0.43 mPa.s @ 20 deg C [R39] OCPP: *1 PPM IN AIR= 3.48 MG/CU M @ 25 DEG C, 760 TORR [R40, 4035] *Conversion factor: 720 mg/cu m= 200 ppm [R41] *RATIO OF SPECIFIC HEATS OF VAPOR (GAS): 1.199 /SRP: SPECIFICS NOT GIVEN/ [R27] *Heat of fusion: 6.00 kJ/mol [R30, p. 6-122] *Heat of melting: 1.1 kcal/mole (@ bp); Heat of sublimation: 6.94 kcal/mole @ 298 K; Specific heat: 14.24 cal/K/mole @ 400 K, 17.30 cal/K/mole @ 600 K, 19.32 cal/K/mole @ 800 K, 20.76 cal/K/mole @ 1000 K [R42, p. 5-52] *Enthalpy of formation: -29.80 kcal/mole (liq), -22.80 kcal/mole (gas); Gibbs free energy of formation: -16.83 kcal/mole (liq), -16.46 kcal/mole (gas); heat capacity: 12.16 cal/deg/mole (gas) [R42, p. 5-14] *READILY CHLORINATED TO CHLOROFORM AND CARBON TETRACHLORIDE IN PRESENCE OF CHLORINATION CATALYSTS [R6] *Ionization potential: 11.35 eV [R43] *Thermal capacity: 1.171 kJ/kg.K @ 15-45 deg C; heat capacity: 54.09 J/mole @ 25 deg C; critical density: 472 kg/cu m; water solubility in methylene chloride @ 20 deg C 1.4 g/kg; kauri-butanol value 136 [R1, p. V5 1042] *Dielectric strength: 94.488 (24.000) V/cm @ 24 deg C; specific resistivity 1.81X10+8 ohm/cm [R1, p. V5 1042] *Henry's Law constant= 3.25X10-3 atm-cu m/mol @ 25 deg C [R44] *Hydroxyl radical rate constant= 1.42X10-13 cu cm/molecule-sec @ 25 deg C [R45] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Vapors may cause dizziness or suffocation. Exposure in an enclosed area may be very harmful. Contact may irritate or burn skin and eyes. Fire may produce irritating and/or toxic gases. Runoff from fire control or dilution water may cause pollution. [R46] +Fire or explosion: Some of these materials may burn, but none ignite readily. Most vapors are heavier than air. Air/vapor mixtures may explode when ignited. Container may explode in heat of fire. [R46] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. Ventilate closed spaces before entering. [R46] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R46] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R46] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R46] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Stop leak if you can do it without risk. Small liquid spills: Take up with sand, earth or other noncombustible absorbent material. Large spills: Dike far ahead of liquid spill for later disposal. Prevent entry into waterways, sewers, basements or confined areas. [R46] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R46] FPOT: *It is flammable in the range of 12-19% in air but ignition is difficult. [R47, 2231] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R48, p. 325-68] *Flammability: 0. 0= This degree includes any material that will not burn. [R48, p. 325-68] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R48, p. 325-68] FLMT: *Lower flammable limit: 13% by volume; Upper flammable limit: 23% by volume [R48, p. 325-68] AUTO: *1033 deg F (556 deg C) [R48, p. 325-68] FIRP: *Use dry chemical, carbon dioxide, foam, or water spray. Use water spray to keep fire-exposed containers cool. [R48, p. 49-52] *Extinguishant: Dry chemical, carbon dioxide, foam. [R29, 1981.2] *If material involved in fire: Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Keep run-off water out of sewers and water sources. [R49] TOXC: *Toxic gases and vapors (such as hydrogen chloride, phosgene and carbon monoxide) may be released in a fire involving methylene chloride. [R29, 1981.2] EXPL: *UPPER 66.4% IN OXYGEN; LOWER 15.5% IN OXYGEN [R47, 2230] *It will not form explosive mixtures with air at ordinary temperatures. [R47, 2231] REAC: *Mixtures of /dinitrogen/ tetraoxide with ... dichloromethane ... are explosive when subjected to shock of 25 g TNT equiv or less. [R50, 1352] *Mixtures of lithium shavings with several halocarbon derivatives are impact sensitive and will explode, sometimes violently. Such materials include: ... dichloromethane .... [R50, 1315] *Dichloromethane dissolves endothermically in concentrated nitric acid to give a detonable soln. [R50, 1158] *Contact of 1.5 g portions of the solid /potassium tert-butoxide/ ... with drops of ... dichloromethane caused ignition after ... 2 min. [R50, 475] *PROLONGED HEATING WITH WATER @ 180 DEG C RESULTS IN FORMATION OF FORMIC ACID, METHYL CHLORIDE, METHANOL, HYDROCHLORIC ACID AND SOME CARBON MONOXIDE. [R6] *... WILL FORM EXPLOSIVE MIXTURES WITH AN ATMOSPHERE HAVING A HIGH OXYGEN CONTENT, IN LIQ OXYGEN, NITROGEN TETROXIDE, POTASSIUM, SODIUM, SODIUM-POTASSIUM ALLOY. [R47, 2231] *Contact with strong oxidizers, strong caustics and chemically active metals such as aluminum or magnesium powder, sodium and potassium may cause fires and explosions. [R29, 1981.2] *Dichloromethane, previously considered to be nonflammable except in oxygen, becomes flammable in air at 102 deg C/1 bar, @ 27 deg C/1.7 bar or @ 27 deg C/1 bar in presence of less than 0.5 vol% of methanol ... [R50, 141] *Strong oxidizers; caustics; chemically-active metals such as aluminum, magnesium powders, potassium and sodium; concentrated nitric acid. [R51] *Mixtures in air with methanol vapor are flammable. ... Reacts violently with ... (potassium hydroxide + N-methyl-N-nitrosourea). [R47, 2231] DCMP: *It can be decomposed by contact with hot surfaces and open flame, and then yield toxic fumes that are irritating and give warning of their presence. When heated to decomposition it emits highly toxic fumes of phosgene and /hydrogen chloride/. [R47, 2231] ODRT: *205-307 ppm [R27] *2.14x10+2 ppm (odor recognition in air; chemically pure sample) [R52] *Odor thresholds: low= 540 mg/cu m; high= 2160 mg/cu m. [R53] SERI: *Irritation of eyes and respiratory tract. [R54] EQUP: *Wear appropriate chemical protective ... boots ... [R55] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-in minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with liq methylene chloride. ... Employees should be provided with and required to use splash-proof safety goggles where liq methylene chloride may contact the eye. [R29, 1981.363] *... Polyvinyl chloride (PVC) and natural rubber should not be used /for protective clothing/. Use neoprene for protective clothing. Do not use closed circuit rebreathing system employing soda lime or other carbon dioxide absorber because of formation of toxic compounds capable of producing cranial nerve paralysis. Equipment should not be iron or metal, susceptible to hydrogen chloride. [R13, p. 8-1] *The permeation of methylene chloride ... through seven protective clothing materials was studied to determine the permeation parameters, and to investigate the effect of solubility (polymer weight gain) and material thickness on the permeation parameters. The materials tested were two different nitrile rubbers, neoprene, combination (a blend of natural rubber, neoprene and nitrile), two different polyvinyl chlorides, and polyvinyl alcohol. Methylene chloride permeated through all materials, except polyvinyl alcohol, with breakthrough times in the range of 2 to 8 min, and permeation rates in the range of 1250-5800 ug/sq cm min. ... It was shown that for /methylene chloride/, there is a correlation between the solubility (weight gain) and the ratio of permeation rate to breakthrough time (PR/BT). For all material/chemical pairs, an increase in solubility, increased (PR/BT). The change in material thickness had an effect on breakthrough time and permeation rate, but no effect on normalized breakthrough time. An increase in thickness reduced permeation rate and increased breakthrough time. [R56] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one piece and close fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R57, 1979.8] *For methylene chloride breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for natural rubber, neoprene/sytrene-butadiene rubber, neoprene/natural rubber, nitrile, polyethylene, and polyvinyl chloride. [R58] *For methylene chloride some data suggesting breakthrough times of approximately an hour or more for polyvinyl alcohol and viton. [R58] *Wear appropriate personal protective clothing to prevent skin contact. [R51] *Wear appropriate eye protection to prevent eye contact. [R51] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R51] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R51] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL at any detectable cocentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R51] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R51] *Compatible protective equipment construction material include: Polyurethane, polyvinyl alcohol, viton. [R49] OPRM: *Contact lenses should not be worn when working with this chemical. [R51] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock down vapors. [R49] *Good industrial hygiene practices recommend that engineering controls be used to reduce environmental concentrations to the permissible level. However, there are some exceptions where respirators may be used to control exposure. Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R29, 1981.3] *Persons not wearing protective equipment and clothing should be restricted from areas of spills or leaks until cleanup has been completed. [R29, 1981.4] *Promptly remove nonimpervious clothing that becomes wet. [R51] *A major concern in the painting studio is solvents, /including dichloromethane/. ... Precautions include ... use of dilution and local exhaust ventilation, control of storage areas, disposal of solvent soaked rags in covered containers, minimizing skin exposure and the use of respirators and other personal protective equipment. The control of fire hazards is also important, since many of the solvents are highly flammable. [R59] *Personnel protection: Avoid breathing vapors. ... Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R49] *Areas in which it is produced or used should be provided with adequate exhaust ventilation, sufficient to keep the atmospheric concn below the exposure limits. Special caution should be exercised when entering tanks which may have contained dichloromethane ... the workers involved should be equipped with oxygen masks or respirators, eye protection, safety belts and life lines, and be under the constant control of a supervisor. [R60] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R57, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one piece and close fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R57, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R57, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak tight. Horizontal laminar flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R57, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R57, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R57, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R57, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be reused ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R57, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R57, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R51] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R51] SSL: *In the absence of moisture @ ordinary temp, dichloromethane is relatively stable when compared with its congeners, chloroform and carbon tetrachloride. [R61] *At elevated temperatures (300-450 deg C) tends to carbonize when vapor contacts steel and metal chlorides. [R61] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R62] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R63] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R64] STRG: *To minimize the decomp of dichloromethane, storage containers should be galvanized or lined with a phenolic coating. [R65] CLUP: *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. [R49] *Environmental considerations: Water spill: Use natural deep water pockets, excavated lagoon, or sand bag barriers to trap material at bottom. remove trapped material with suction hoses. [R49] *Environmental considerations - Land spill: Dig a pit, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. [R49] *Stop or control the leak, if this can be done without undue risk. Control runoff and isolate discharged material for proper disposal. [R48, p. 49-52] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U080, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R66] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F002, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R66] *Potential candidate for liquid injection incineration, with a temperature range of 650 to 1600 deg C and a residence time of 0.1 to 2 seconds; for rotary kiln incineration with a temperature range of 820 to 1600 deg C and residence times of seconds for liquids and gases, hours for solids; and for fluidized bed incineration, with a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, longer for solids. [R67] *Dichloromethane is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration, preferably after mixing with another combustible fuel; care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R68] *Incineration, preferably after mixing with another combustible fuel; care must be exercised to assure complete combustion to prevent the formation of phosgene; an acid scrubber is necessary to remove the halo acids produced. Recommendable method: Incineration. [R69] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R57, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas fired type, in which a first stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R57, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R57, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R57, 1979.16] *The following wastewater treatment technology has been investigated for dichloromethane. Concentration Process: Stripping. [R70] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +Exposure of members of the general public to methylene chloride /i.e., dichloromethane/ will occur from its use in consumer products such as paint removers, which can result in relatively high levels being found in indoor air. Occupational exposure during production arises primarily during filling and packaging (manufacturing is in closed systems). Because of its use in paint strippers, occupational exposure to methylene chloride occurs during formulation of paint remover, original equipment manufacturer, and in commercial furniture refinishing. Methylene chloride is widely used as a process solvent in the manufacture of a variety of products ... Biological monitoring of methylene chloride exposure can be based on measurement of the solvent itself in exhaled air or blood. However, as production of carbon monoxide with exposure for more than 3-4 hr/day appears to be the limiting factor in regard to health risk, biological monitoring based upon either analysis of carbon monoxide in exhaled air or of carboxyhemoglobin in blood is to be preferred. ... Methylene chloride is rapidly absorbed through the alveoli of the lungs into the systemic circulation. It is also absorbed from the gastrointestinal tract, and dermal exposure results in absorption but at a slower rate than via the other routes of exposure. Methylene chloride is quite rapidly excreted, mostly via the lungs in the exhaled air. It can cross the blood-brain barrier and be transferred across the placenta, and small amounts can be excreted in urine or in milk. At high concentrations, most of the absorbed methylene chloride is exhaled unchanged. The remainder is metabolized to carbon monoxide, carbon dioxide, and inorganic chloride. ... One pathway involves oxidative metabolism mediated by cytochrome P-450 and leads to both carbon monoxide and carbon dioxide. This pathway appears to operate similarly in all rodents studied and in man. ... The other pathway involves a glutathione transferase and leads via formaldehyde and formate to carbon dioxide. This route seems only to become important at doses above the saturation level of the "preferred" oxidative pathway ... /in/ man it seems to be used very little at any dose. Species difference in glutathione transferase metabolism correlates well with the observed species diffence in carcinogenicity. ... In the aquatic environment, fish and amphibian embryos have been shown to be the most sensitive ... The acute toxicity of methylene chloride /on laboratory mammals/ by inhalation and oral administration is low. ... Acute effects after methylene chloride administration by various routes of exposure are primarily associated with the central nervous system (CNS), and the liver, and these occurred at high doses. ... Occasionally other organs were affected such as the kidney or respiratory system. ... Cardiac sensitization to adrenaline-induced arrhythmia have been reported. ... Prolonged exposure to high concentrations of methylene chloride caused reversible CNS effects, slight eye irritation and mortality in several laboratory species. Body weight reduction was observed in rats ... and in mice .... Slight effects on the liver were noted in dogs ... Other target organs are the lungs and the kidneys. ... Methylene chloride is moderately irritant to the skin and eyes of experimental animals. Methylene chloride is not teratogenic in rats or mice ... Within the limitations of the short-term tests currently available there is no conclusive evidence that methylene chloride is genotoxic in vivo. ... Methylene chloride is carcinogenic in the mouse, causing both lungs and liver tumors, following exposure to high concentrations ... Syrian hamsters exposed to methylene chloride by inhalation ... showed no evidence of a carcinogenic effect ... Rats exposed to methylene chloride via various routes have shown increased incidences of tumors at certain sites. ... The mechanism by which methylene chloride induces mammary adenomas in the rat is important for human hazard assessment. ... It seems most likely ... that the increased incidence of mammary adenomas is the result of an indirect mechanism operating via hyperprolactinemia. In humans, there is conflicting evidence on whether mammary tumors are responsive to prolactin as is the case in the rat. ... Prolactin is not luteotrophic in primates. It is unlikely, therefore, that this mechanism of tumor development is of relevance to man. ... / In humans/ Methylene chloride irritates the skin and eyes, especially when evaporation is prevented. In these circumstances, prolonged contact may cause chemical burns. ... Fatalities due to accidental inhalation and skin contamination have been reported. The main toxic effects of methylene chloride are reversible CNS depression and /carboxyhemoglobin/ formation. Liver and renal dysfunctions and effects of hematological parameters have also been reported ... Neurophysiological and neurobehavorial disturbances have been observed in human volunteers ... An increased rate of spontaneous abortion ... has been attributed to exposure to methylene chloride. A causal relationship was not established because of insufficiencies in the design of the study. Several mortality studies in relevant cohorts show an inconsistent pattern in the causes of death. ... [R71] CARC: *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on inadequate human data and sufficient evidence of carcinogenicity in animals; increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in male and female mice, and increased incidence of benign mammary tumors in both sexes of rats, salivary gland sarcomas in male rats and leukemia in female rats. This classification is supported by some positive genotoxicity data, although results in mammalian systems are generally negative. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R72] +A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R73, 31] +Evaluation: There is inadequate evidence in humans for the carcinogenicity of dichloromethane. There is sufficient evidence in experimental animals for the carcinogenicity of dichloromethane. Overall evaluation: Dichloromethane is possibly carcinogenic to humans (Group 2B). [R74] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations as needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Minimize physical activity and provide a quiet atmosphere. Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. Rinse mouth and administer 5 mI/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Treat frostbite with rapid rewarming techniques ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R75] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R75] MEDS: *The following medical procedures should be made available to each employee who is exposed to methylene chloride at potentially hazardous levels: Initial Medical Exam: The purpose is to detect existing conditions that might place employee at increased risk, and to establish baseline for future health monitoring. Exam of skin, liver, kidneys, CNS, and blood should be stressed. Clinical impressions of autonomic nervous system and pulmonary function ... made, with additional tests conducted where indicated. Skin disease: Methylene chloride can cause dermatitis on prolonged exposure. Persons with existing skin disorders may be more susceptible to effects of this agent. Liver disease: ... A profile of liver function should be obtained by utilizing medically acceptable array of biochemical tests. Kidney disease: ... justifies special consideration before exposing persons with impaired renal function. Cardiovascular disease: Because of reports of excessive carbon monoxide levels following exposure ... persons with cardiac disease may be at incr risk. ... A complete blood count should be performed ... Carboxyhemoglobin values should be determined periodically, and level above 5% should prompt investigation of worker and his workplace. 2. Periodic medical exam: /SRP/: The aforementioned medical exam should be repeated on an annual basis. Persons should be cautioned against smoking due to smoke induced increase in carboxyhemoglobin levels in blood. [R29, 1981.1] *Dichloromethane exposure in workers may be monitored by analysis of dichloromethane in blood or breath, or carbon monoxide in blood. Blood dichloromethane concn measured during exposure probably should not exceed 1 mg/l in subjects exposed at 100 ppm level for 8 hr. Breath dichloromethane concn avg about 33 ppm during exposure to air containing 100 ppm of chemical ... Blood and breath concn plateau after 2 hr of exposure, and decline rapidly after cessation of exposure. It should be noted that physical exertion during exposure can dramatically incr blood and breath content of dichloromethane. ... Pre-exposure specimens should be analyzed to establish background carboxyhemoglobin levels for each individual. [R76, 116] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R57, 1979.23] HTOX: *... TWO CASES OF /SRP: DICHLOROMETHANE/ POISONING IN PAINTERS WHO SUFFERED FROM HEADACHE, GIDDINESS, STUPOR, IRRITABILITY, NUMBNESS AND TINGLING IN THE LIMBS /ARE REPORTED/. [R77, 1991.984] *METHYLENE CHLORIDE IS MILDLY IRRITATING TO SKIN ON REPEATED CONTACT. PROBLEM MAY BE ACCENTUATED BY CHEMICAL BEING SEALED TO SKIN BY SHOES OR TIGHT CLOTHING. SITUATION IS MOST SEVERE WITH PAINT REMOVER FORMULATIONS THAT FORM A "SKIN" OR FILM. [R40, 4035] *... A CHEMIST DEVELOPED TOXIC ENCEPHALOSIS WITH ACOUSTICAL AND OPTICAL DELUSIONS AND HALLUCINATIONS AFTER BEING EXPOSED TO METHYLENE CHLORIDE FOR 1 YR. [R77, 1991.984] *FOUR NIGHT-SHIFT WORKERS WERE FOUND UNCONSCIOUS ... /AFTER EXPOSURE TO METHYLENE CHLORIDE/ 3 RECOVERED ... 4TH WAS DEAD WHEN AMBULANCE ARRIVED. OF 3 WHO RECOVERED, 1 SHOWED SIGNS OF ACUTE BRONCHITIS, 1 OF IRRITATION OF UPPER RESP TRACT AND 1 CONJUNCTIVITIS AND LACRIMATION. ALL SHOWED SOME ANEMIA AND POLYMORPHONUCLEAR LEUCOCYTOSIS. [R78, 246] *SEVERAL DEATHS HAVE BEEN REPORTED FROM ... /SRP: DICHLOROMETHANE/ USE AS ANESTHETIC ... [R78, 245] *3-YR OCCUPATIONAL EXPOSURE TO 300-1000 PPM DICHLOROMETHANE CAUSED MEMORY LOSS WITH INTELLECTUAL IMPAIRMENT AND BALANCE DISTURBANCES IN 58-YR-OLD MAN. BILATERAL TEMPORAL LOBE DEGENERATION OCCURRED. PERSISTENT HIGH LEVEL OF ENDOGENOUS BLOOD CARBON MONOXIDE FORMED FROM DICHLOROMETHANE WAS THE REASON FOR TOXICITY. [R79] *... Primary cultures of human fibroblasts were treated in closed vessels with 0.5-5.5% dichloromethane in the absence of S9. No increase in grain counts was seen, indicating that unscheduled DNA synthesis was not induced. ... Concn of 2.5, 5 and 10 ul/ml dichloromethane did not induce unscheduled DNA synthesis in human lymphocytes in the presence or absence of phenobarbital-induced rat liver S9. [R80] *CONTROLLED HUMAN-EXPOSURE STUDIES REVEALED DISTURBANCES OF PSYCHOMOTOR PERFORMANCE @ 800 PPM DICHLOROMETHANE, DEPRESSION OF FLICKER FUSION THRESHOLD AND VIGILANCE PERFORMANCE DOWN TO 300 PPM, A PERFORMANCE DECREMENT IN COMBINED TRACKING-MONITORING TASK @ 200 PPM. [R81] *A proportionate mortality study showed no incr in death from malignant neoplasms among workers exposed for up to 30 years to mean concentrations of methylene chloride ranging from 33 ppm to 118.8 ppm, when compared to control populations. [R82] *Twenty liters of methylene chloride (dichloromethane, DCM) were spilled accidentally in a laboratory. Two workers cleaned it up by hand using floor cloths, and inhaled DCM vapors for 20 min. The peak inhaled concn was later estimated, using experimental data, at 3300-5300 ppm. Both workers suffered headache, nausea, drowsiness, giddiness, heaviness of limbs, dryness of the mouth, but all these symptoms except for the headache disappeared after a few hours. No long-term effects were noted. [R83] *Forty-six workers were exposed to methylene chloride at concn < 100 ppm with a group of twelve controls. There was an excess of self reported neurological symptoms in the exposed workers, twenty nine of whom were /examined/ ... to detect any evidence of neurophysiological damage when compared with age matched controls with no solvent exposure. The study included clinical examination, measurement of ulnar and median nerve motor conduction velocity, ECG, and a psychological test battery designed to detect minimal brain damage. No evidence was found of long-term damage that could be attributed to methylene chloride exposure. [R84] *... A 13 year-old boy who was ... using a paint remover that contained dichloromethane (DCM) ... was discovered dead no more than 9 hr after exposure. ... DCM was the primary agent responsible for death. [R85] *Lethal blood level: 280.0 mg/l. [R86] *A case control study was carried out in 44 women who had a spontaneous abortion during employment in the pharmaceutical industry. Three age matched female pharmaceutical factory workers who had given birth to a child were chosen as controls for every case. Information about occupational exposures was obtained from questionnaires completed by the occupational physician or nurse at the factory. Exposure to chemicals was more common among the cases than the controls. For chloride (dichloromethane) the increase in odds ratio (OR) was of significance (OR= 2.3, p= 0.06). [R87] *All solvent-exposed female workers in a factory producing loudspeakers were examined in order to assess neurotoxic signs and symptoms possibly related to organic solvent exposure. ... Symptoms of neurasthenia and paraesthesia were significantly more frequent in the exposed group. Five of the exposed workers, whose neurasthenic symptoms could not be related to alternative causes, underwent neuropsychological testing. One of these workers had test results compatible with toxic encephalopathy caused by solvents. In another worker cerebral dysfunction was suspected. [R88] *To assess the potential chronic health effects of methylene chloride, the mortality experience of a maturing 1964 to 1970 cohort of 1,013 hourly men was /studied/ through 1984. On average, employees were exposed at a rate of 26 ppm (eight hour time weighted average) for 22 years; median latency was 30 years. Compared with the general population, no statistically significant excesses were observed for such hypothesized causes of lung cancer (14 observed vs 21.0 expected), liver cancer (0 vs 0.8), and ischemic heart disease (69 vs 98.1); dose response relationships based on career methylene chloride exposure and latency were not demonstrated. Among nonhypothesized causes a significant deficit was reported for total deaths (176 vs 253.2). None of the industrial referent comparisons achieved statistical significance. Sufficient power was available to detect relative risks of 1.6 for lung /cancer/ and 1.3 for ischemic heart disease. In contrast, there was inadequate power to identify meaningful risk levels for hepatic cancer. With 14 combined lung and liver cancer deaths observed vs 36.3 predicted (p < 0.0001), the mortality estimate projected from a mathematical model derived from an animal bioassay substantially overestimated cancer mortality for these sites. This inconsistency emphasizes the need to incorporate epidemiologic evidence in assessing the human health risks associated with long-term exposure to this widely used solvent. [R89] *THE HOME USE OF PAINT REMOVERS CONTAINING METHYLENE CHLORIDE CAN RESULT IN ELEVATION OF CARBOXYHEMOGLOBIN THAT CONTINUES FOLLOWING EXPOSURE TO LEVELS THAT STRESS CARDIOVASCULAR SYSTEM. PATIENTS WITH DISEASED CNS MAY NOT BE ABLE TO TOLERATE THIS UNEXPECTED STRESS. [R90] *INHALATION OF METHYLENE CHLORIDE IN CONCN SUFFICIENT TO PRODUCE 5% CARBOXYHEMOGLOBIN IMPAIRED HUMAN PERFORMANCE UNDER DIFFICULT OR DEMANDING TASK CONDITIONS. APPARENTLY, CARBON MONOXIDE THE MAIN METABOLITE OF METHYLENE CHLORIDE WAS RESPONSIBLE FOR OBSERVED PERFORMANCE DECREMENTS. [R91] *Phosgene poisoning has been reported to occur in several cases where methylene chloride was used in the presence of an open fire. [R29, 1981.2] *EXPERIMENTAL EXPOSURE OF HUMAN SUBJECTS TO METHYLENE CHLORIDE AT 1000 PPM FOR 2 HR RESULTED IN CARBOXYHEMOGLOBIN SATURATION LEVELS IN EXCESS OF THOSE PERMITTED IN WORKPLACE FROM EXPOSURE TO CARBON MONOXIDE ALONE ... /SRP: CARBOXYHEMOGLOBIN SATURATION LEVELS WERE NOT GIVEN/ [R92] */Produces/ skin inflammation and skin burns. [R54] *... A cohort mortality study /was conducted/ of 1271 white and nonwhite men and women employed in a fiber prodn plant in which dichloromethane was used as a general purpose solvent. The range of exposure was time weighted avg of approx 140-475 ppm. ... Employees who had worked for at least 3 mo subsequent to Jan 1954 and prior to 1 Jan 1977 were included and followed up to 30 June 1977. The observed numbers were compared with the expected numbers from internal referent cohort of 948 acetone exposed employees and with mortality data for US white males, nonwhite males and white females. Vital status was not confirmed for 18% of the exposed cohort or 12% of internal referent cohort. Among exposed white men and women, 7 deaths due to malignant neoplasms were observed compared to 10.1 expected in USA population. No specific cancer site was over represented. Seven malignant neoplasms were observed in referent cohort, whereas 12.3 were expected for white men and women. (The Working Group noted that only 115 men and 154 women with more than 5 years' exposure had been first exposed before 1960, ie, allowing for adequate follow-up time with respect to latency for malignant neoplasms /for only 21% of the cohort/.) [R93] *After a 3-hr exposure to 800 ppm dichloromethane significant deficits in psychomotor tasks (e.g., simple and choice reaction times, reduced tapping speed, and impaired coordination and steadiness) developed in human volunteers. ... Levels of 10,000-25,000 ppm ... dichloromethane produce coma in humans within a short period of time. [R2, 736] NTOX: *... LEVELS OF ... /CNS DEPRESSION/ IN CATS /HAVE BEEN REPORTED/; 32 MG/L OR 9000 PPM CAUSED 'DISPLACEMENT OF EQUILLIBRIUM' IN 20 MINUTES BUT NO ... /CNS DEPRESSION/. AT 37.5 MG/L OR 10,000 PPM, LIGHT ... /CNS DEPRESSION/ OCCURRED IN 220 MINUTES AND DEEP ... /CNS DEPRESSION/ AT 293 MINUTES. [R40, 4036] *GROUPS OF RATS AND MICE WERE EXPOSED BY INHALATION FOR 7 HR DAILY ON DAYS 6-15 OF GESTATION TO 4.4 G/CU M (1250 PPM) DICHLOROMETHANE; NO EFFECTS WERE OBSERVED ON AVG NUMBER OF IMPLANTATION SITES/LITTER, LITTER SIZE, INCIDENCE OF FETAL RESORPTIONS, FETAL SEX RATIOS OR FETAL BODY MEASUREMENTS. [R94] *DICHLOROMETHANE WAS ... MUTAGENIC TO SALMONELLA TYPHIMURIUM WHEN ASSAYED IN A DESICCATOR OR OTHER CLOSED CHAMBER, BOTH IN PRESENCE AND ABSENCE OF AN AROCLOR- OR PHENOBARBITAL INDUCED RAT LIVER METABOLIC SYSTEM. POSITIVE RESPONSES WERE OBTAINED WITH STRAINS TA1535, TA1950, TA100 AND TA98, ALTHOUGH SOME LABORATORIES FOUND NEGATIVE RESULTS WITH TA1535. A FEW STUDIES FOUND THAT DICHLOROMETHANE WAS NOT MUTAGENIC TO S TYPHIMURIUM WHEN ASSAYED IN ABSENCE OF S9 STD PLATE INCORPORATION TESTS. [R95] *GROUPS OF 20 MALE A/ST MICE, 6-8 WK OLD, RECEIVED REAGENT GRADE DICHLOROMETHANE IN TRICAPRYLIN @ DOSES OF 160, 400 and 800 MG/KG BODY WT ... EACH DOSE WAS INJECTED IP THRICE WEEKLY FOR TOTAL OF 16-17 INJECTIONS (TOTAL DOSES, 2720, 6800 and 12800 MG/KG BODY WT IN RESPECTIVE GROUPS). AFTER 24 WK, 18, 5 and 12 ANIMALS IN THE 3 GROUPS WERE STILL ALIVE; THESE WERE KILLED AND THEIR LUNGS EXAM FOR TUMORS AND COMPARED WITH 15 SURVIVORS OUT OF 20 VEHICLE-TREATED CONTROLS. IN TREATED MICE, 0.9, 0.8 and 0.5 LUNG TUMORS PER MOUSE WERE OBSERVED WHICH WERE NOT SIGNIFICANTLY DIFFERENT FROM 0.27 OBSERVED IN CONTROLS INJECTED WITH TRICAPRYLIN (THE WORKING GROUP NOTED THE POOR SURVIVAL OF TREATED ANIMALS AND THE LIMITATIONS OF NEGATIVE RESULTS OBTAINED WITH THIS TEST SYSTEM ...) [R96] *IN MICE, CONTINUOUS INHALATION OF 17.5 G/CU M (5000 PPM) CAUSED SWELLING OF ROUGH ENDOPLASMIC RETICULUM, TRANSIENT SEVERE FATTY CHANGES IN LIVER AND NECROSIS IN ISOLATED HEPATOCYTES. [R94] *FOLLOWING REPEATED EXPOSURE TO 10000 PPM, 3 OUT OF 4 RABBITS AND 2 OUT OF 9 RATS DIED. /PATHOLOGICAL CHANGES INCLUDED/ ... CONGESTION AND EDEMA WITH FOCAL NECROSIS OR EXTRAVASATION OF BLOOD /IN THE LUNGS/. IN 2 DOGS, LIVER SHOWED MODERATE CENTRILOBULAR CONGESTION AND SLIGHT TO MODERATE FATTY DEGENERATION ... . [R78, 244] *Dichloromethane (104, 157 and 209 mM) induced gene conversion, mitotic recombination and gene mutation in Saccharomyces cerevisiae D7 when the cells were grown under conditions that led to the synthesis of endogenous cytochrome p450. Strain D4 (which detects gene conversion only), grown under similar conditions, had one-fifth the p450 activity of strain D7 and responded only marginally to dichloromethane. [R80] *Female Long-Evans rats were exposed to 0 or 4500 ppm (0 or 15600 mg/cu m) dichloromethane (> 97% pure) during either a 3-wk pregestational period or during the first 17 days of gestation or both. Ten females per group were allowed to give birth, and the offspring were exam for abnormal growth and behavior. Dams exposed to dichloromethane during gestation had incr absolute and relative liver weights. There were no effects on litter size or viability, but fetal weight was reduced in both groups exposed during gestation. No treatment related visceral or skeletal abnormality was detected in fetuses of any exposure group, but a greater proportion of litters exposed during both pregestational and gestational periods had fetuses with rudimentary lumbar ribs. No difference in pup birth weight, viability, or growth rate was observed, but alterations in spontaneous locomotor activities were seen in all exposure groups. [R97] *Injection of dichloromethane into the air space of 2, 3, and 6 day old White Leghorn chick embryos induced abnormalities and death. The LD50 was estimated to greater than 100 umol/egg. Dichloromethane was not teratogenic following injection into the yolk sac of 0 hr old White Leghorn chick embryos. The LD50 was estimated to be 14 mg/egg. [R97] *THE FATTY LIVER INDUCED BY METHYLENE CHLORIDE INHALATION IN GUINEA PIG WAS INVESTIGATED. INHALATION OF 5200 PPM METHYLENE CHLORIDE FOR 6 HR RESULTED IN A 2.5-FOLD INCREASE IN HEPATIC TRIGLYCERIDE. ELECTRON MICROSCOPHY REVEALED THE HEPATOCYTES TO BE NORMAL EXCEPT FOR THE PRESENCE OF LIPID DROPLETS IN THE CELL PERIPHERY. EXPOSURE TO METHYLENE CHLORIDE ALSO RESULTED IN A 63% DECREASE IN SERUM TRIGLYCERIDE, SUGGESTING A DEFECT IN TRIGLYCERIDE SECRETION AS A CAUSE OF FATTY LIVER. [R98] *A long term study was conducted to determine the possible chronic toxicity and oncogenicity of methylene chloride. Rats and hamsters were exposed by inhalation to 0, 500, 1500, or 3500 ppm of methylene chloride for 6 hr/day, 5 days/wk, for 2 yr. No exposure related cytogenetic effects were present in male or female rats exposed to 500, 1500, or 3500 ppm. Female rats exposed to 3500 ppm had an increased mortality rate while female hamsters exposed to 1500 or 3500 ppm had decreased mortality rates. Carboxyhemoglobin values were evaluated in rats and hamsters exposed to 500, 1500, or 3500 ppm with the percentage increase in hamsters greater than in rats. Minimal histopathologic effects were present in the livers of rats exposed to 500, 1500, or 3500 ppm. Decreased amyloidosis was observed in the liver and other organs in hamsters exposed to 500, 1500, or 3500 ppm. While the number of female rats with a benign tumor was not increased, the total number of benign mammary tumors was increased in female rats in an exposure-related manner. This effect was also evident in male rats in the 1500- and 3500-ppm exposure groups. Finally, male rats exposed to 1500 or 3500 ppm had an increased number of sarcomas ... located in or around the salivary glands. Therefore, in this 2 yr study, some effects were observed in male and female rats exposed to 500, 1500, or 3500 ppm of methylene chloride. In contrast, hamsters exposed to the same concentrations had less extensive spontaneous geriatric changes, decreased mortality (females), and lacked evidence of definite target organ toxicity. [R99] *SINGLE IP INJECTION OF /SRP: DICHLOROMETHANE (1330 MG/KG) INTO/ ADULT MALE FISCHER 344 RATS CAUSED RENAL PROXIMAL TUBULAR DEGENERATION. MORPHOLOGICAL EFFECTS WERE OBSERVED IN THE CORTEX AND THE OUTER MEDULLA. [R100] *IN ANIMAL STUDIES, DEPRESSION OF MOTOR ACTIVITY WAS OBSERVED @ CONCN OF 5000 PPM DICHLOROMETHANE, WHEREAS DEPRESSION OF REM-SLEEP /SRP: WAS OBSERVED AT LEVELS AS LOW AS/ 1000 PPM. [R81] *Instilling 0.1 and 0.01 ml liquid dichloromethane (DCM) into rabbits' eyes /caused persistent/ lacrimation, ... inflammation of lids and conjunctivae, ... conjunctival edema, ... sloughing and increased intraocular pressure, iritis, and keratitis. Increased corneal thickness developed in rabbits exposed to dichloromethane vapor at concn of 1,750 and 17,500 mg/cu m (504 and 5,040 ppm). [R101] *... Fischer rat embryo cell cultures (F1706, subculture 108) /were exposed/ to dichloromethane (DCM) liquid at concn of 1.6X10+2 and 1.6X10+3 uM for 48 hr. ... After treatment, cells were cultured in growth medium alone at 37 deg C. Transformation of cells treated with either dose level of DCM was observed by 23 and 30 days of incubation, and was characterized by progressively growing foci, composed of cells lacking contact inhibition and orientation. ... Subcutaneous injection of cells treated with 1.6X10+2 uM dichloromethane five subcultures earlier produced local fibrosarcomas in 5/5 newborn Fischer 344 rats within 60 days following treatment. [R102] *Mice (male, Swiss-Webster) exposed via inhalation to dichloromethane (169 mg/l for 0-4 days) were tested for learning ability using a passive avoidance conditioning task. Exposed animals had a significantly decr ability to learn. The exposed animals did not differ from controls in motor activity, weight gain, and absence of analgesia. [R103] *Subacute exposure of male rats to various concn (70-1000 ppm) of DCM produced a selective redn of dopamine levels ... /and/ also produced a discrete dose dependent increase of the noradrenaline turnover. ... Apparently, DCM can produce discrete changes in amine storage and turnover in catecholamine nerve terminal systems of the tel- and diencephalon, some of which may contribute to the DCM induced disturbances of the secretion of anterior pituitary hormones, but actions on other transmitter identified neurons involved in neuroendocrine regulation must also be considered. [R104] *Dichloromethane (1-30 mM) did not induce DNA damage in a DNA repair test with isolated rat hepatocytes ... At higher concn (approx 30 mM), dichloromethane slightly affected replicative DNA synthesis. [R105] *Several short-term mammalian test systems ... were used for mutagenicity testing of the organic solvent dichloromethane. The cmpd was negative in the forward mutation test on the hypoxanthine-guanine phosphoribosyltransferase locus in Chinese hamster cells. In the test on DNA synthesis inhibition, dichloromethane caused an aspecific inhibition in both human and hamster cells, but in this test, the effect did not indicate a DNA-damaging action. A weak positive effect was found in the test on sister-chromatid exchanges in hamster cells. [R106] *The effect of mammalian metabolizing enzymes on the mutagenicity of dichloromethane was investigated in Salmonella typhimurium strain TA 100. The cmpd was directly mutagenic toward this strain, with the mutagenic activity being enhanced upon addition of either rat liver microsomes or cytosol fraction. Further experiments showed that cytochrome /SRP: p450/ oxygenase and glutathione-S-transferase are involved in the bioactivation of dichloromethane. [R107] *Rats were exposed to dichloromethane vapor at 500 ppm, 1000 ppm, or 1000 ppm as a time-weighted average. ... For 6 hr, 5 days/wk for 2 wk. Kidney microsomes displayed a dose-dependent enhancement of the ethoxy-coumarin O-deethylase activity. After the second wk the enhancement was accompanied by an increase in renal glutathione content. In the liver, UDP-glucuronosyltransferase activity showed a dose dependent increase and NADPH-cytochrome c reductase activity decreased. Hepatic glutathione content remained unchanged. Dichloromethane exposure did not effect hemoglobin concn of the blood. An 8-9% carboxyhemoglobin concn was found after exposure in all groups. The similarity of carboxyhemoglobin concn suggests that in the rat, the metabolic pathway converting dichloromethane to carbon dioxide was saturated ... at the lowest exposure level under study. [R108] *Male Wistar rats were exposed to 500, 1000, or 100 ppm as time-weighted average (TWA) concn of dichloromethane vapor. The 1000 (TWA) ppm exposure consisted of two 1 hr peak concn (2800 ppm) on a basal exposure of 100 ppm. All exposures lasted for 6 hr, 5 days/wk for 2 wk. Solvent concns were analyzed in the perirenal fat samples which showed a relation to the dose with the highest values in the 1000 (TWA) ppm exposures. Solvent concn increased in the perirenal fat between the 2 wk of exposure. Blood carbon monoxide concn did not accurately reflect body solvent /concentrations/. Neurochemical effects displayed a dose relationship and included decreased succinate dehydrogenase and acid proteinase activity at 1000 ppm in the cerebrum. Withdrawal of animals for 7 days /after/ ... the 2 wk exposure showed that the biochemical changes were abolished with the exception of decreased succinate dehydrogenase activity at 1000 (TWA)) ppm. [R109] *The influence of different kinds of industrial solvents on the vestibular function of rats was studied by recording nystagmus, induced by accelerated rotation. The effect was related to the blood levels of the solvents. One group of solvents, including halogenated saturated hydrocarbons like dichloromethane, caused depression of the vestibulo-oculomotor reflex. Another group, including ... halogenated unsaturated hydrocarbons like 1,2-trichloroethylene caused an excitation of the vestibulo-oculomotor reflex. ... If the animals were exposed simultaneously to solvents from both groups, the excitatory effect prevailed and was even potentiated. [R110] *Methylene chloride (MC) was evaluated for the induction of micronucleated polychromatic erythrocytes (MPEs) in bone marrow of treated C57BL/6J/Alpk mice. Groups of five male and five female mice were exposed by gavage to doses of 1250, 2500 or 4000 mg/kg MC in corn oil. Bone marrow samples were taken 24, 36, 48 and 72 hr after dosing for analysis. Negative results were obtained in all treatment groups. [R111] *Chemical test results for mutagenicity of dichloromethane in L5178Y mouse lymphoma cells were equivocal (FY1985). [R112] *Animal experiments have shown that continuous exposure to 1,000 ppm can be lethal in 5 to 7 wk for dogs and that fatty livers, icterus, pneumonia and splenic atrophy developed in dogs. [R29, 1981.2] *Cardiac arrhythmias attributed to sensitization of the myocardium have been observed following exposure to high concn of some chlorinated hydrocarbons, but dogs exposed to 10,000 and 20,000 ppm of methylene chloride did not show this phenomenon. [R29, 1981.2] *Mongolian gerbils were exposed to dichloromethane for three months by continuous inhalation at 210 ppm. Total free tissue amino acids, glutathione, and phosphoethanol-amine were determined in the vermis posterior of the cerebellum and the frontal cerebral cortex. These two brain areas were chosen because humans occupationally exposed to dichloromethane have shown abnormalities in the electroencephalogram of the frontal part of the cerebral cortex. This study showed that /subchronic/ of gerbils to dichloromethane (210 ppm) for three months leads to decreased levels of glutamate, gamma-aminobutyric acid, and phosphoethanolamine in the frontal cerebral cortex, while glutamine and gamma-aminobutyric acid are elevated in the posterior cerebellar vermis. [R113] *Rats (200-250 g males) were exposed to 500 or 1000 ppm CH2C12 (DCM) for 8 hr, and a group was exercised within the inhalation chamber in a treadmill cylinder for the last 15 min of every hour of exposure. DCM of orbital sinus blood declined to negligible levels with 2 hr postexposure in both sedentary and exercised rats, with higher levels occurring at the 1000-ppm exposure. The carboxylHb (COHb) levels in rats exposed to 500 ppm DCM were similar in exercised and sedentary rats; at 1000 ppm DCM all levels were higher, but there were small decreases in the COHb of the exercised group compared to the sedentary group. Thus, exercise fails to elevate CLHb levels. [R114] *Dichloromethane (DCM) was administered at levels of 0, 60, 125, 185 and 250 mg/kg body weight/day to a total of 1000 B6C3F1 mice in deionized drinking water for 104 wk. The high dose male and female mice showed a transitory increase in mean leucocyte counts. Treatment related toxic changes were noted in both male and female livers at the highest dose. There was a slight elevation of proliferative hepatocellular lesions in the treated males but no dose related trend was apparent and the effect was absent in the females. Neoplastic lesions observed in the study were homogeneous among all groups and were within the range of incidence in historical controls. The results of this study demonstrated a toxicological no observable effect level for DCM of 185 mg/kg body weight/day in both sexes. [R115] *Dichloromethane (DMC), bromodichloromethane, bromochloromethane (BCM), bromotrichloromethane, and dibromomethane (DBM) were tested for their mutagenic activity. The Ames test and in vitro cell cultures were used. All substances were positive in the Ames test. In the in vitro test with FAF-cells of Chinese hamsters only BCM produced an increase of the sister chromatid exchange frequency. All tested substances induced an increase in the aberration ratio/cell. The highest ratios were induced by DCM, DBM, and BCM. [R116] *... Rats /were exposed/ to 4500 ppm for 6 hr/day before and during the first 17 days of gestation. Some fetal weight reduction occurred but no malformation increase was found. In the same treatment group ... behavioral studies were done. Post natal growth activity and avoidance learning were not impaired but behavioral habituation was more rapid in the exposed group. [R117] *Threshold concn of cell multiplication inhibition of the protozoan Uronema parduczi Chatton-Lwoff: > 16,000 mg/l [R118] *Affected fish swam near the tank bottom. Half of the fish were overreactive to external stimuli while half were underreactive. They also had increased respiration, were darkly covered, and lost equilibrium prior to death. /Sample purity 99+%/ [R119] *In gerbils exposed continuously by inhalation to 350 ppm (1200 mg/cu m) but not in those exposed to 210 ppm (730 mg/cu m), dichloromethane for up to 3 mo, increased brain concn of two astroglial proteins (S-100 AND GFA) and decreased cerebellar DNA concn were observed. Decreased hippocampal DNA concn were observed at both exposure levels. [R120] *Groups of 50 male and 50 female B6C3F1 mice, 8 to 9 wk of age, were exposed to 0, 2000 or 4000 ppm (0, 6940 or 13880 mg/cu m) dichloromethane (> 99% pure) by inhalation for 6 hr/day on 5 days/wk for 102 wk and were killed after 104 wk of study. Survival to the end of the study period in males was: control, 39/50; low-dose, 24/50; and high-dose, 11/50; and that in females was 25/50, 25/49 and 8/49. Significant dose-related incr in incidences of lung and liver tumors were observed in treated mice. The incidences of alveolar/bronchiolar adenomas were: males - 3/50, 19/50 and 24/50 (p < 0.001); and females - 2/50, 23/48 and 28/48 (p < 0.001). Those of alveolar/bronchiolar carcinomas were: male - 2/50, 10/50 and 28/50 (p < 0.001); and females - 1/50, 13/48 and 29/48 (p < 0.001). The incidences of hepatocellular adenomas were: males - 10/50, 14/49 and 14/49 (p= 0.075); females - 2/50, 6/48 and 22/48 (p < 0.001). The incidences of hepatocellular carcinomas were: males - 13/50, 15/49 and 26/49 (p= 0.016); and females - 1/50, 11/48 and 32/48 (p < 0.001) (NTP, 1986). [R121] *Dichloromethane (10 ul) was mutagenic to Escherichia coli WU361089 (mutation to tyrosine prototrophy), using a spot test in a desiccator; the same protocol did not lead to mutation of E coli SD-4 to streptomycin independence. [R80] *Dichloromethane was tested for induction of sex linked recessive lethal mutations in Drosophila melanogaster. Following exposure by feeding (125 and 620 mM) (in which the flies would presumably also be exposed by inhalation), a weak positive response was observed in one of the 3 broods. [R80] *Dichloromethane (2-15 ul/ml) induced dose related chromosomal damage, measured as chromatid gaps, chromatid breaks, isochromatid breaks and exchanges, in cultured Chinese hamster ovary cells. Damage was induced both with and without Aroclor induced rat liver S9, the S9-treated sample giving higher responses. Small but nonsignificant incr in incidence of sister chromatid exchanges were produced, both with and without S9. [R122] *Dichloromethane induced sex linked lethal mutations in nematode Panagrellus redivivus maintained for 120 hr in media containing 1x10-8, 1x10-6 or 1x10-4 mole/l. [R122] *In preparation for the design and performance of chronic toxicity and carcinogenicity studies in rats and mice on dichloromethane (methylene chloride; DCM), biochemical, mutagenicity, short term, metabolic and subchronic feeding studies were carried out. These studies established that it was feasible to present DCM to rodents at adequate levels in drinking water. Saturation of metabolic pathways was demonstrated in both rats and mice at oral doses of approximately 100 mg/kg. The lowest toxic effect levels after 90 days of treatment were found to be approximately 190 and 580 mg/kg for rats and mice, respectively. Dose, vehicles and the exposure regimen were found to affect DCM challenge to target tissues and its metabolism to CO and CO2. [R123] *Liquid dichloromethane applied at concn of 1.17x10-3 M and above for 24 hr was mutagenic in Tradescantia stamen-hair somatic mutation assay. When tested in Tradescantia under conditions that allowed for volatilization of dichloromethane, concn of 0.24-18% resulted in toxicity and a borderline induction of micronuclei (details not given). [R80] *The principal acute toxic action of dichloromethane is exerted on the central nervous system ... or, in high concn, an anesthetic effect ... [R124] *Groups of 68 female B6C3F1 mice, eight to nine weeks of age, were administered dichloromethane (> 99% pure) by whole-body inhalation at concentrations of 0 ppm (control) or 2000 ppm (6940 mg/cu m) for various lengths of time over a 104-wk period. Lung and liver were evaluated histopathologically. Survival was reduced compared with controls in groups exposed to dichloromethane for the first 52, 78, or the complete 104 weeks of the study. The incidences of mice with lung adenomas, carcinomas or adenomas and carcinomas combined and the incidences of mice with hepatocellular adenomas, carcinomas or adenomas and carcinomas combined were increased in all groups in which exposure was begun during the first 26 weeks of the study. [R125] *On rabbit's eyes a single application of 0.1 ml of methylene chloride has caused lacrimation persisting for a week, hyperemia of the conjuctivae and lid margins, small hemorrhages and marked edema of the conjunctiva, subsiding in a week. The corneas lost epithelium and became swollen for a week or two in some rabbits, usually associated with signs of iritis. [R126] *The effects on the mouse liver were studied microscopically ... during continuous exposures. At 347 mg/cu m, fatty infiltration, vacuolization, and enlarged nuclei persisted up to the end of the 10-wk exposure, while an increase in triglycerides concentration was reversible. At 17,350 mg/cu m, body weights fell, and relative liver weights increased up to the end of the 168-hr exposure. Fatty infiltration, an increase in the triglycerides concentration, and hydropic degeneration of the endoplasmic reticulum gradually disappeared. Protein synthesis was depressed. Necrosis was observed in a few hepatocytes. [R127] *CNS depression was noted in dogs, monkeys, rats, rabbits, and guinea pigs during each daily session of repeated exposure to a methylene chloride concentration of 34,700 mg/cu m for 7 hr/day, 5 days/wk, for 6 mos. All animals became inactive, some time after initial excitement. [R128] *Fetuses of 19 rats exposed to a methylene chloride concentration of 4340 mg/cu m air on days 6-15 of pregnancy, for 7 hr/day, showed an increased incidence of dilated renal pelvis. Fetuses of 12 mice, exposed similarly, showed an increased incidence of extra sternebrae. [R129] HTXV: *Blood carboxyhemoglobin levels ... should not exceed 5% in workers exposed to dichloromethane. This carboxyhemoglobin level approximates the concentration obtained following a workday exposure to 100 ppm dichloromethane in resting nonsmokers. [R2, 744] NTXV: *LD50 Mouse inhalation 16000 ppm/7 hr plus 1 hr observation; [R120] *LD50 Rat oral 1600 mg/kg; [R130] *LC50 Rat inhalation 2,000,000 mg/cu m/15 min; [R120] *LC50 Guinea pig inhalation 11600 ppm/6 hr plus 18 hr observation; [R120] *LC50 Rat ihl 88,000 mg/cu m/30 mos; [R47, 2231] *LD50 Mouse ip 437 mg/kg; [R47, 2231] *LC50 Mouse ihl 14,400 ppm/7 hr; [R47, 2231] *LD50 Mouse sc 6460 mg/kg; [R47, 2231] *LD50 Rat oral 3000 mg/kg body weight; [R131] *LC50 Rat ihl 79,000 mg/cu m/2 hr; [R131] *LC50 Rat ihl 52,000 mg/cu m/6 hr; [R131] *LC50 Mouse ihl 56,230 mg/cu m/7 hr; [R131] *LC50 Mouse ihl 49,100 mg/cu m/6 hr; [R131] *LC50 Mouse ihl 51,500 mg/cu m/2 hr; [R131] *LC50 Guinea pig ihl 40,200 mg/cu m/6 hr; [R131] ETXV: *LC50 Pimephales promelas Rafinesque (fathead minnows) 193 mg/l/96 hr, flow-through bioassay; [R118] *LC50 Pimephales promelas Rafinesque (fathead minnows) 310 mg/l/96 hr, static bioassay; [R118] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) 230 MG/L/24 HR, STATIC BIOASSAY; [R132] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) 220 MG/L/96 HR @ 21-23 DEG C (95% CONFIDENCE LIMIT 200-250 MG/L), STATIC BIOASSAY; [R132] *LC50 Poecilia reticulata (guppy) 294 ppm/14 days /Conditions of bioassay not specified/; [R118] *LC50 Daphnia magna 224,000 ug/l/48 hr /Conditions of bioassay not specified/; [R13, p. 2-7] *LC50 Mysid shrimp 256,000 ug/l/96 hr /Conditions of bioassay not specified/; [R13, p. 2-7] *EC10 Pimephales promelas Rafinesque (fathead minnows) 68.5 mg/l/24 hr (95% confidence limit 44.2-86.7 mg/l), flow-through bioassay; [R130] *EC10 Pimephales promelas Rafinesque (fathead minnows) 66.3 mg/l/48 hr (95% confidence limit 42.6-79.7 mg/l), flow-through bioassay; [R130] *EC10 Pimephales promelas Rafinesque (fathead minnows) 66.3 mg/l/72 hr, (95% confidence limit 42.6-79.7 mg/l), flow-through bioassay; [R130] *EC10 Pimephales promelas Rafinesque (fathead minnows) 66.3 mg/l/98 hr, (95% confidence limit 42.6-79.7 mg/l), flow-through bioassay; [R130] *EC50 Pimephales promelas Rafinesque (fathead minnows) 99.0 mg/l/48 hr (95% confidence limit 83.2-121.5 mg/l), flow-through bioassay; [R130] *EC50 Pimephales promelas Rafinesque (fathead minnows) 99.0 mg/l/72 hr, (95% confidence limit 83.2-121.5 mg/l), flow-through bioassay; [R130] *EC50 Pimephales promelas Rafinesque (fathead minnows) 99.0 mg/l/96 hr, (95% confidence limit 83.2-121.5 mg/l), flow-through bioassay; [R130] *EC90 Pimephales promelas Rafinesque (fathead minnows) 220.1 mg/l/24 hr, (95% confidence limit 175.1-335.4 mg/l), flow-through bioassay; [R130] *EC90 Pimephales promelas Rafinesque (fathead minnows) 147.6 mg/l/48 hr, (95% confidence limit 120.5-249.7 mg/l), flow-through bioassay; [R130] *EC90 Pimephales promelas Rafinesque (fathead minnows) 147.6 mg/l/72 hr, (95% confidence limit 120.5-249.7 mg/l), flow-through bioassay; [R130] *EC90 Pimephales promelas Rafinesque (fathead minnows) 147.6 mg/l/96 hr, (95% confidence limit 120.5-249.7 mg/l), flow-through bioassay; [R130] *LC10 Pimephales promelas Rafinesque (fathead minnows) 122.0 mg/l/24 hr, (95% confidence limit 72.7-160.8 mg/l), flow-through test bioassay; [R130] *LC10 Pimephales promelas Rafinesque (fathead minnows) 94.0 mg/l/48 hr, (95% confidence limit 50.7-130.4 mg/l), flow-through test bioassay; [R130] *LC10 Pimephales promelas Rafinesque (fathead minnows) 51.2 mg/l/96 hr (95% confidence limit 22.5-78.2 mg/l), flow-through bioassay; [R130] *LC10 Pimephales promelas Rafinesque (fathead minnows) 67.3 mg/l/72 hr (95% confidence limit 32.3-98.9 mg/l), flow-through bioassay; [R130] *LC50 Pimephales promelas Rafinesque (fathead minnows) 268.0 mg/l/24 hr (95% confidence limit 213.0-346.6 mg/l), flow-through bioassay; [R130] *LC50 Pimephales promelas Rafinesque (fathead minnows) 265.0 mg/l/48 hr (95% confidence limit 202.5-369.7 mg/l), flow-through bioassay; [R130] *LC50 Pimephales promelas Rafinesque (fathead minnows) 232.4 mg/l/72 hr (95% confidence limit 172.4-337.6 mg/l), flow-through bioassay; [R130] *LC90 Pimephales promelas Rafinesque (fathead minnows) 589.0 mg/l/72 hr (95% confidence limit 432.6-1077.4 mg/l), flow-through bioassay; [R130] *LC90 Pimephales promelas Rafinesque (fathead minnows) 746.3 mg/l/48 hr (95% confidence limit 494.7-1712.1 mg/l), flow-through bioassay; [R130] *LC90 Pimephales promelas Rafinesque (fathead minnows) 722.1 mg/l/96 hr (95% confidence limit 447.4-1947.1 mg/l), flow-through bioassay; [R130] NTP: *Male and female F344/N rats inhaled methylene chloride at 0, 1000, 2000, and 4000 ppm 6 hr/day, 5 days/wk for 102 wk. Male and female B6C3F1 mice inhaled methylene chloride for the same time duration and at the same concn, excluding the 1000 ppm concn. All animals tested positive for tumors as follows: 1) male rats: a) mammary glands: fibroadenoma or adenoma; b) tunica vaginalis: mesothelioma; c) multiple sites: mesothelioma; 2) female rats: a) mammary glands: fibroadenoma or adenoma; b) hematopoietic system: mononuclear cell leukemia; 3) male and female mice: a) lung: alveolar/bronchiolar carcinoma; b) liver: hepatocellular adenoma and carcinoma; c) circulatory system (males only): hemangiosarcoma or hemangioma. [R133] TCAT: ?A percutaneous absorption study was conducted with adult male albino rabbits receiving dichloromethane at 15, 50, 100, 200 or 500mg/kg. At each dose level, 4 rabbits (2 animals intact skin, 2 animals abraded skin) were treated for 8hrs/day, 5days/week, for 90 days. The treatment produced no signs of toxicity as indicated by hematology parameters, weight gain, general appearance, food consumption and pathology when compared to both treated (isopropyl alcohol) and nontreated controls. [R134] ?A two-generation inhalation reproduction study was conducted with male and female Fischer 344 rats receiving whole body exposure to methylene chloride at a nominal concentration of 0, 100, 500 or 1500ppm in a dynamic air flow chamber. At each concentration, 30 male and 30 female rats (F0 generation) beginning at approximately 7 weeks of age were exposed 6hrs/day, 5days/week, for 14 weeks and then allowed to mate. From each of the parental treatment groups, 30 male and 30 female weaned F1 generation offspring (4 weeks of age) were exposed 6hrs/day, 5days/week, for 17 weeks then allowed to mate to produce the F2 generation. During the mating, gestation and lactation periods, exposure of the F0 and F1 rats was continued 6hrs/day, 7 days/week, with the exception that dams were not exposed from gestation day 21 through the fourth day post-partum. The treatment produced no signs of maternal, reproductive or neonatal toxicity. There were no treatment-related gross pathologic changes in F0 and F1 adults and F1 and F2 weanlings at necropsy. [R135] ?Chronic toxicity and oncogenicity of dichloromethane were evaluated in groups of B6C3F1 mice exposed to dichloromethane orally in deionized drinking water at nominal target dose levels of (number of males/females): 0 (60/50), 0 (65/50), 60 (200/100), 125 (100/50), 185 (100/50) or 250 mg/kg/day (125/50) for 24 months. There were no significant differences between treated animals and controls in the following: tissue masses, body weights, water consumption, leukocyte counts, necropsy findings, or histopathology with respect to focal or multifocal hepatocellular hyperplasia, proliferative hepatocellular lesions, adenoma or carcinoma. The only significant sign of toxicity was a marginal increase in the amount of positively staining material in the livers of high-dose groups of both sexes. [R136] ?Chronic toxicity and oncogenicity were evaluated in groups of male and female Sprague-Dawley rats (129/sex/concentration) exposed to dichloromethane via inhalation to 0, 500, 1500, or 3500 ppm for 6 hrs/day, 5 days/week, excluding holidays, for 2 years. There were significant differences between treated animals and controls in the following: mortality (increased in females at 3500 ppm at 18th-24th months), palpable masses (increase in number of masses, number of animals not significantly different, in females at 500, 1500 and 3500 ppm and males at 3500 ppm), mean liver weights (relative weights for both sexes and absolute weights for males at 3500 ppm), hepatocellular vacuolization (increased in all groups), multinucleated hepatocytes (increased in females at all dose levels), number of foci and areas of altered hepatocytes (increased females at 3500 ppm), number of pancreatic lesions (decreased in males at 3500 ppm), benign mammary tumors (increased in dose-related manner in females at all dose levels, slight increase in males at 1500 or 3500 ppm), and sarcomas near the salivary gland (increased in males at 3500 ppm). There were no significant differences between treated animals and controls in the following: body weights, hematology, clinical chemistry, urinalysis, carboxyhemoglobin, plasma estradiol, cytogenetics, malignant mammary tumors, total number of animals with tumors or number of carcinomas. [R137] ?Chronic toxicity and oncogenicity were evaluated in groups of male and female Golden Syrian hamsters (107-109/sex/concentration) exposed to dichloromethane via inhalation to 0, 500, 1500, or 3500 ppm for 6 hrs/day, 5 days/week, excluding holidays, for 2 years. There were significant differences between treated animals and controls in the following: mortality (decreased in females at 3500 ppm at 13th-24th months and at 1500 ppm at 20th-24th months), hemoglobin, carboxyhemoglobin and hematocrit levels (increased in all treated groups). There were no significant differences between treated animals and controls in the following: body weights, clinical chemistry, urinalysis, cytogenetics, histopathological lesions, total number of tumors or of specific types of tumors, or number of animals with tumors. [R137] ?The ability of dichloromethane to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Dichloromethane was tested at 1.56x10(-3), 1.56x10(-4), 1.56x10(-5) and 1.56x10(-6)M concentration, with cell survival ranging from 71% to 58%. None of the tested concentrations produced significantly greater transformation relative to the solvent control. [R138] ?In a two-generation reproduction study, male and female Charles River CD rats (10/sex/group) were orally exposed by gavage to dichloromethane at dosage levels of 0, 25, 75 and 225 mg/kg/day for 18 weeks and at approximately 100 days of age were mated 1 to 1. Following weaning of the pups, the parent rats were sacrificed and discarded. The male and female offspring (F1) (15/sex from each dosage group) were orally exposed to dichloromethane in the diet at the same dosage levels as their respective parent rats for 90 days. No significant differences were observed between treated and control F1 animals in the following: general behavior and appearance, food consumption, ophthalmoscopy or hematological, biochemical and urinalysis studies, fertility indices, number of pups/litter or pup survival. No compound related gross pathologic lesions or organ weight variations were observed in any rats which were sacrificed at the end of the 90 days and no compound related microscopic lesions were observed in any tissues from high-dose level F1 rats. [R139] ?In a two-generation reproduction study, male and female Fischer 344 rats, (F0) (30/sex/group) were exposed to dichloromethane by inhalation at nominal dosage levels of 0, 100, 500 or 1500 ppm for 6 hrs/day, 5 days/week for 14 weeks. Male and female rats from the same exposure groups were mated and selected F1 offspring rats (30/sex/group) were exposed to the same concentrations of dichloromethane for 17 weeks, at which point they were mated and gave birth to F2 offspring. No adverse effects on reproduction parameters, neonatal survival or neonatal growth were observed in any of the animals in either the F0 or F1 generations. There were no treatment related gross pathological observations in F0 and F1 adults and F1 and F2 weanlings at necropsy. No treatment related lesions were observed upon histopathological examination of tissues from F1 and F2 weanlings. [R140] ?The mutagenicity of dichloromethane was evaluated in Salmonella bacterial tester strains TA98, TA100, TA1535, TA1537, and TA1538 and Saccharomyces cerevisiae yeast strain D4, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Dichloromethane was tested at concentrations of 0.1, 1, 5, and 10 ul/plate using the plate incorporation method. Dichloromethane did not cause a reproducible positive response in any of the bacterial or yeast tester strains, either with or without metabolic activation. Due to the volatility of the test material, separate tests under an inverted and sealed petri dish, both in the presence and absence of metabolic activation, were conducted using Salmonella tester strains TA98 and TA100. Dichloromethane at a concentration of 0.05 ml/inverted petri dish did not cause a reproducible positive response either with or without metabolic activation. [R141] ?The mutagenicity of dichloromethane was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537, TA1538, and G46, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Dichloromethane was tested using the plate incorporation method in 30 ml closed culture flasks in which 2, 4, 6, and 8 ml/system were allowed to volatilize. Dichloromethane caused a reproducible positive response in bacterial tester strains TA98, TA100, TA1535, and G46 at all doses used with these strains, both with and without metabolic activation. [R142] ?The ability of dichloromethane to cause chromosome aberrations was evaluated in bone marrow cells of Sprague-Dawley albino rats (5/sex/group) receiving nominal concentrations of test material at 0, 500, 1500 and 3500ppm in a dynamic air flow chamber for 6hours/day, 5days/week for 6 months. At the end of the six month exposure, all animals were sacrificed and 200 bone marrow cells per animal were scored. None of the aberration rates in any of the treatment groups were significantly (ANOVA, p < 0.05) greater than the control group. [R143] ?The disposition of 14C-methylene chloride was evaluated in male Sprague-Dawley rats (3/group) receiving a single administration of 1 or 50mg/kg of test material orally by gavage. Immediately following treatment, animals were placed in metabolism cages for collection at 12 hour intervals for 48 hours of urine, feces and expired air. The major metabolites of methylene chloride were carbon monoxide and carbon dioxide found in expired air. Rats receiving the low dose metabolized 88% of the dose compared to the high dose animals which only metabolized 26% of the administered dose. The highest 14C-activity was observed in the liver and no significant accumulation of radioactivity was found in the fat. It was concluded that the dose-dependency was due to saturation of methylene chloride metabolites above the 50mk/kg dose. [R144] ?The fate of methylene chloride (MeCl2) and macromolecular binding in salivary tissue (submaxillary, sublingual and parotid glands) relative to other target (liver) and nontarget tissue (kidney, abdominal muscle and/or fat) were evaluated in ten male Sprague-Dawley rats receiving a single exposure to 14C-MeCl2 at a nominal concentration of 3500ppm for six hours in a dynamic air flow chamber. Five rats were sacrificed for determination of MeCl2 concentrations in selected tissue and the remaining five rats were sacrificed to evaluate macromolecular binding in selected tissue. The highest concentration of 14C-activity per gram of tissue was found in the fat, with approximately 10 fold less 14C-activity per gram found in the liver, kidney, muscle, submaxillary and sublingual glands. The concentration of 14C-activity in parotid gland was approximately 3-5 fold greater than that of the submaxillary and sublingual glands, these values were dependent on the dissection techniques. Radioactivity was observed irreversibly bound to liver macromolecules to the greatest extent, followed in decreasing order by the sublingual gland, kidney, submaxillary gland, parotid gland and muscle. [R145] ?From previously preformed studies, experimental animals were observed to biotransform methyl chloride (MeCl2) in the body to carbon monoxide (CO) resulting in increased carboxyhemoglobin (COHb) levels and also reported were increased COHb in the blood of human subject inhaling MeCl2. The formation of COHb causes a shift in the oxyhemoglobin dissociation curve (OD-Curve), theoretically resulting in a diminished ability to release oxygen at the tissue level. The ability of MeCl2 to alter the OD-Curve was evaluated with and without CO as measured by the P50 (pressure of oxygen which causes 50% saturation of Hb). In vitro studies were preformed with blood (from male Sprague-Dawley rats and from male and female human) which was equilibrated with room air (control), MeCl2 alone (800ppm), CO alone (2500ppm) or MeCl2 (800ppm) plus CO (2500ppm). The in vivo studies consisted of five male Sprague Dawley receiving a nominal concentration of MeCl2 at 500ppm for 3 hours in a dynamic air flow chamber. At the end of the three hour exposure, blood was drawn by cardiac puncture and was incubated with MeCl2 (800ppm). Exposure to MeCl2 in vitro or in vivo did not cause a significant change in the P50 value relative to the controls. [R146] ?The pharmacokinetics of methylene chloride (MeCl2) was evaluated in male Syrian Golden hamsters (4/exposure) receiving nominal concentrations of 14C-MeCl2 at 50 or 1500ppm for six hours in a dynamic air flow chamber. At the end of exposure, hamsters and were placed in metabolic cages and urine, feces and expired air was collected for 48 hours. 14C-MeCl2 was extensively metabolized in the hamster in a dose-dependent manor with approximately 97 and 73% of the total body burden recovered as metabolites at 50 and 1500ppm, respectively. The major metabolites were 14C-labeled carbon monoxide (CO) and 14C-labeled carbon dioxide (CO2), which together accounted for approximately 65 and 48% of the total recovered radioactivity at 50 and 1500ppm, respectively. The remaining radioactivity in the hamster was recovered as either nonvolatile radioactivity in the urine, feces, skin, carcass and cage wash or as unchange 14C-MeCl in expired air. The hamsters were observed to metabolize 1.1 (50ppm) and 1.9-fold (1500ppm) more 14C-MeCl2 on a body weight basis compared to data reported on the rat. [R147] ?The macromolecular binding of methylene chloride (MeCl2) was evaluated in male Syrian Golden hamsters (4/exposure) and male Sprague Dawley rats (4/exposure) receiving nominal concentrations of 14C-MeCl2 at 50 or 1500ppm for 6 hours in a dynamic air flow chamber. At the end of exposure, all animals were sacrificed and the irreversible binding of radioactivity to the liver and submaxillary glands macromolecules were examined. Hamster and rats at the 1500ppm exposure level experienced an 7-8 fold and 3-5 fold increase in the apparent macromolecular binding, respectively, as compared to that at 50ppm. Hamsters exhibited a greater binding of radioactivity per gram of liver and submaxillary gland protein, more than two fold, compared to rats at 1500ppm. [R148] ?The ability of dichloromethane to induce unscheduled DNA synthesis in the salivary tissue, liver and kidneys was evaluated in male Sprague-Dawley rats (5/group) exposed by inhalation to concentrations of 0 or 3500 ppm dichloromethane for 6 hrs/day for 3 consecutive days. There were no statistically significant differences between treated and control animals with respect to DNA content (mg DNA/g tissue) or DNA synthesis (dpm radioactive thymidine incorporated/ug DNA). [R149] ?The ability of dichloromethane to bind to DNA in the liver and submaxillary gland was evaluated in male Sprague-Dawley rats (6 rats) and male Syrian Golden Hamsters (6 animals) exposed by inhalation to a nominal concentration of 3500 ppm for 3.5 hr. The animals were sacrificed 1 hr after the termination of treatment. The incorporation of radiolabelled dichloromethane in DNA (as dpm 14C/mg DNA) was determined for the livers of 6 rats and 6 hamsters and the submaxillary glands of 3 rats and 2 hamsters. The ratios of radioactivity incorporation in hamsters/rats were 1.5 and 3.0 for liver and submaxillary gland tissues, respectively. The 14C activity (dpm 14C/mg DNA) associated with purified liver and submaxillary gland DNA was 169 and 635 for the hamsters, respectively, and 110 and 211 for the rats, respectively. The ratios of incorporation in submaxillary gland/liver were 3.8 and 1.9 for hamsters and rats, respectively. The incorporation of radiolabel appeared, by HPLC results, to be due to incorporation in the carbon skeleton of the parent DNA bases via normal anabolic pathways (not due to alkylation of DNA by dichloromethane). [R150] ?Methylene chloride (CAS # 75-09-2) was evaluated for acute inhalation toxicity in male B6C3F1 mice (10/treatment group) administered single dynamic, whole-body exposures to target atmospheric concentrations of 0, 2000, and 4000 ppm (0, 2010, and 3710 ppm mean analytical). Exposure levels were repeated from a previous chronic inhalation study to illustrate differing acute effects in mice and rats conducive to an observed interspecies inconsistency in methylene chloride tumorigenicity. Lungs and liver were excised and analyzed for histopathologic changes on Study Day 2. In both mice and rats, signs of mild anesthesia characterized the overt toxicity to 4000 ppm exposures only. In mice, exposures to 2000 and 4000 ppm also induced highly specialized vacuolation and pyknosis of the non-ciliated Clara cells of the bronchiolar epithelium. Upon electron microscopic examination, vacuolation and swelling of the endoplasmic reticulum of these cells was visualized, near total in association with 4000 ppm exposures and 25-50% in association with 2000 ppm exposures. Enlarged and pale mitochondria and phagocytozed necrotic cellular debris with myelin whorls of damaged endoplasmic reticulum in the Clara cell cytoplasm were also noted. Loss of cilia from ciliated bronchiolar cells and pale and enlarged mitochondria in alveolar type II cells were observed in association with 4000 ppm exposures. The mild effects on the liver consisted of increased myelin whorls in bile canaliculi of centrilobular hepatocytes, but no ultrastructural changes. The study authors offered that the Clara cell specificity in the mouse suggests a methylene chloride metabolism via the cytochrome P-450 monoxygenase system and related metabolic pathways. [R151] ?Methylene chloride (CAS # 75-09-2) was evaluated for acute inhalation toxicity in the lungs and liver of male Fischer 344 rats (10/treatment group) administered single dynamic, whole-body exposures to target atmospheric concentrations of 0, 2000, and 4000 ppm (0, 1910, and 3910 ppm mean analytical). Exposure levels were repeated from a previous chronic inhalation study to illustrate differing acute effects in mice and rats conducive to an observed interspecies inconsistency in methylene chloride tumorigenicity. In mice and rats, signs of mild anesthesia characterized the overt toxicity to 4000 ppm exposures only. On Study Day 2, lungs and liver were excised and analyzed for histopathologic changes. No compound-related changes were noted in either lung or liver of the rat after acute inhalation exposure. Specifically, the Clara cell of the lung bronchiolus, a target cell of parallel acute inhalation toxicity study in the mouse, showed no effects of treatment. [R151] ?Methylene chloride (CAS # 75-09-2) and its metabolites were evaluated for DNA-binding in the lung and liver of 6 F344 rats and 30 B6C3F1 mice exposed once by inhalation to 14C-methylene chloride at a nominal concentration of 4000 ppm for 3 hours. Enzymatically hydrolyzed DNA samples, isolated from lung and liver tissues at 6, 24, and 48 hours after start of the exposures, were analyzed for amount and distribution of radiolabel. Control groups of mice and rats, likewise exposed to 4000 ppm non-labelled methylene chloride, were subsequently dosed with intravenous 14C-formate (formate, both a metabolite of methylene chloride and used in the biosynthesis of DNA bases) to establish the pattern of formate incorporation into DNA via the C-1 pool. Both rat and mouse liver and lungs showed low level radioactivity (less than 1 dpm/mg DNA), although DNA and protein binding in the mouse was 2-4 fold that in the rat. Mouse pulmonary DNA contained twice as much radiolabel as hepatic DNA with peak binding at 6 hours after initiation of the exposures. As compared to the pattern of DNA incorporation in 14C-formate-treated mice, chromatography revealed binding of methylene chloride radiolabel to the normal constituents of DNA, rather than by formation of altered (alkylated) nucleosides. The authors concluded that the conditions of this study were not conducive to DNA alkylation by reactive metabolites of methylene chloride and provided no evidence of somatic mutation and genotoxicity. [R152] ?Methylene chloride (CAS # 75-09-2) and its metabolites were evaluated for DNA-binding in the lung and liver of 6 male F344 rats and 30 male B6C3F1 mice exposed once by inhalation to 14C-methylene chloride at a nominal concentration of 4000 ppm for 3 hours. Enzymatically hydrolyzed DNA samples, isolated from lung and liver tissues at 6, 24, and 48 hours after start of the exposures, were analyzed for amount and distribution of radiolabel. Control groups of mice and rats, likewise exposed to 4000 ppm non-labelled methylene chloride, were subsequently dosed with intravenous 14C-formate (formate, both a metabolite of methylene chloride and used in the biosynthesis of DNA bases) to establish the pattern of formate incorporation into DNA via the C-1 pool. Both rat and mouse liver and lungs showed low level radioactivity (less than 1 dpm/mg DNA). Rat pulmonary and hepatic DNA contained similar amounts of radiolabel with peak binding at 12 hours after initiation of the exposures. As compared to the pattern of DNA incorporation in 14C-formate-treated mice, chromatography revealed binding of methylene chloride radiolabel to the normal constituents of DNA, rather than by formation of altered (alkylated) nucleosides. The authors concluded that the conditions of this study were not conducive to DNA alkylation by reactive metabolites of methylene chloride and provided no evidence of somatic mutation and genotoxicity. [R152] ?The metabolism of dichloromethane (CAS # 75-09-2) to carbon monoxide was investigated following observation of elevated carboxyhemoglobin levels in humans exposed to dichloromethane vapors. Carboxyhemoglobin levels in the blood of male rats (strain and numbers unspecified) rose and persisted in a dose-dependent manner following intraperitoneal injections of dichloromethane in corn oil at doses of 1.5, 3.0, and 6.0 mmoles/kg. The administration of phenobarbital or methylcholanthrene (enzyme inducers) or SKF 525-A (drug metabolism inhibitor) prior to treatment produced no change in dichloromethane metabolism; however, repeated doses of dichloromethane substantially increased carboxyhemoglobin levels. As compared to a control rat administered 13C-labelled carbon monoxide alone, the blood of a solitary rat administered 13C-labelled dichloromethane showed characteristic peaks by infrared spectrometry representing elevated 13C-carbon monoxide, confirming the dichloromethane source of elevated carbon monoxide levels. [R153] ?The effects of methylene chloride on the oxyhemoglobin dissociation curve (ODC) and, consequently, hemoglobin delivery of oxygen to tissues was investigated in rat (Sprague-Dawley) and human blood incubated in a blood gas tonometer with methylene chloride alone, carbon monoxide alone, and methylene chloride in combination with carbon monoxide (CO). Increased carboxyhemoglobin levels is associated with methylene chloride exposure in rodents and humans. Hemoglobin binding with CO (a metabolite of methylene chloride), in turn, is associated with a shift to the right of the oxyhemoglobin dissociation curve, representing a diminished oxygen release in tissues. In vivo exposure of Sprague-Dawley rats to 500 ppm methylene chloride for 3 hours resulted in a 6% carboxyhemoglobin level; however, the P50 value remained comparable to that of controls. Methylene chloride alone was found to have no effect on the P50 value of the ODC in either rat or human blood in vitro. Consequently, no direct effect on hemoglobin affinity for CO was noted and an observed shift to the left of the ODC in association with exposure in vivo (historical data) is dependent on methylene chloride biotransformation to CO. In human blood, a P50 value was increased by 4 mmHg (a shift of the ODC to the right) after incubation with methylene chloride and CO as compared to CO alone, although carboxyhemoglobin levels were comparable, suggesting an ameliorative effect of methylene chloride on CO-induced effects on the ODC. [R154] TCAT: ?The metabolism of methylene chloride (75-09-2) was compared in vitro in liver and lung fractions of male B6C3F1 mice, Fischer 344 rats, Charles River Lake View hamsters, and 4 human accident victims (liver tissue only) to attempt to explain marked species specificity of tumorigenic response in these tissues. The cytochrome P450 and glutathione-S-transferase dependent pathways, respectively, of isolated microsomal and cytosolic fractions were assessed by carbon monoxide formation (cytochrome P450 pathway) and by formaldehyde production (glutathione-S-transferase pathway) after incubation of the tissues with methylene chloride. Cytochrome P450 biotransformation of methylene chloride to carbon monoxide in mouse and hamster lung and liver was significantly more efficient than that of rat or human (liver only). The rate of methylene chloride conversion to carbon monoxide via glutathione-S-transferase in the mouse liver (Vmax 36.4 nmoles/min/mg protein) markedly exceeded that of any other tissue, being 12 times more active than that of the rat (Vmax 2.9 nmoles/min/mg). Neither human nor hamster liver cytosolic fractions showed any detectable methylene chloride metabolism by this pathway, although positive controls confirmed viability of the system. Slight evidence of such metabolism was detected in mouse lung tissue (Vmax 0.15 nmoles/min/mg), but was barely perceived in that of rat or hamster (human lung was not available). In that known carcinogenicity correlates with methylene chloride metabolism by the glutathione pathway in experimental animals, but not the cytochrome P450 pathway, the relative inactivity of that pathway in humans suggests a low risk of methylene chloride-induced carcinogenicity. [R155] ?The glutathione S-transferase (GST) components of methylene chloride (CAS # 75-09-2) metabolism in male B6C3F1 mouse and rat liver were compared based on the structure and specific activity of the respective theta class GST enzymes to explain characteristic toxic tumorigenicity in exposed mice that is not seen in either rats or hamsters. N-terminal and internal amino acid sequences of the MT1 of 2 identified mouse theta class GST liver enzymes are identical to those of GST 5-5 of 3 known rat GST enzymes. Their specific activities to methylene chloride, as determined by glutathione-mediated conjugation of MC to formaldehyde, are 5.5 and 11 umol/min/mg protein, respectively. Essentially, these enzymes have comparable activity in the metabolism of methylene chloride in mouse and rat liver and fail to demonstrate a cause for species specificity of tumorigenic response. The activity of mouse MT2 enzyme also has its structural equivalent in the rat, GST 12-12, but has been shown to be labile throughout the purification process, with the specific activity to methylene chloride lost upon attempts at isolation. The conjugating activity on methylene chloride of mouse in vivo or in cytosol fractions is 10 fold that in the rat, which does not appear to be attributable to differences in relative specific activities of MT1 and GST 5-5. Consequently, the authors suggested that further study may reveal disparate expression of these enzymes or a distinct contribution by MT2 that will elucidate the significance of glutathione-dependent metabolism rates to methylene chloride-induced carcinogenicity in the mouse and its importance in assessment of human risk. [R156] ?Methylene chloride (CAS # 75-09-2) was evaluated for genotoxicity conducive to mammalian somatic cell mutation in the CHO/HPRT cell mutation assay. The study was intended to elucidate a proposed glutathione-S-transaminase (GST) metabolic pathway-derived genotoxic mechanism of methylene chloride species specific carcinogenicity in the mouse. Previous study using DNA alkaline elution established that methylene chloride causes DNA single strand (ss) breaks in mouse liver and lungs in vivo and in liver hepatocytes and lung Clara cells in vitro which correspond to carcinogenic in vivo exposures. Although CHO cells lack endogenous GST-mediated metabolism of methylene chloride and no DNA ss breaks in association with methylene chloride exposure, GSH metabolites from exogenous activation of methylene chloride with mouse liver S9 or S100 cytosol fractions do produce DNA ss breaks in CHO cells. CHO-K1 cells were therefore incubated with methylene chloride and GSH for 4 hours with mouse S100 fraction to determine if DNA ss breaks in CHO cells are also associated with an increase in HPRT mutation in these cells as compared to that after incubation with formaldehyde (a known mutagen generated by methylene chloride GSH metabolism via a postulated intermediate, S-chloromethylglutathione) or 1,2-dibromomethane (the positive control). Harvested colonies (50 cells minimum/plate) were counted after 10 days and the mutant frequency per 10,000,000 surviving cells determined. Formaldehyde proved only weakly mutagenic (2-fold increase at 0.2 mM), with marked cytotoxicity at concentrations of 0.5 mM and above. Methylene chloride, although still only weakly mutagenic (3-5 fold increase), produced greater mutagenicity in the absence of cytotoxicity (0.2 mM). These results suggest that DNA ss breaks due to GST-mediated metabolism of methylene chloride are associated with mutagenicity and that, in the mouse liver, methylene chloride acts as a genotoxic carcinogen. Exposing the cells at high density in suspension enhanced mutagenicity of both methylene chloride and formaldehyde at non-toxic concentrations which also coincided with DNA ss breaks. Formaldehyde mutagenicity was still considerably lower than that associated with methylene chloride exposure, prompting the authors to suggest that the S-chloromethyl GSH metabolic subconjugate of formaldehyde might contribute significantly to methylene chloride-induced DNA ss breaks and associated mutagenicity. [R157] ?The induction of increased DNA-scheduled hepatocyte synthesis by methylene chloride (CAS # 75-09-2) was evaluated in male B6C3F1 mice (10/group), with variably radiolabelled liver DNA (3 regimes, 120uCi intraperitoneally injected tritiated thymidine), administered whole body exposures once or twice via inhalation to target concentrations of 0 or 4000 ppm for 2 hours. Isolated livers were analyzed for S-phase hepatocytes (% of 3000 hepatocytes/mouse) at 24 and 48 hours post-exposure. Small increases in S-phase hepatocytes reached statistical significance in 2 of 3 experimental protocols, but the biological significance of these marginal findings and given wide variability between test animals of a group was unclear. [R158] POPL: *The quantity of dichloromethane (DCM) absorbed is dependent on body weight and fat content of the body. /The risk of accumulation of DCM in adipose tissue is expected to be greater for obese persons/. [R159] *Artists with cardiovascular impairment should not use materials containing methylene chloride. [R59] *... Acute exposure ... may cause myocardial infarction in individuals with atherosclerotic heart disease. /From table/ [R2, 693] ADE: *HIGHEST LEVELS OF RADIOACTIVITY IN RATS AFTER 1 HR EXPOSURE BY INHALATION TO 1935 MG/CU M (14)C-DICHLOROMETHANE WERE FOUND IN FAT, WITH LOWER LEVELS IN LIVER, KIDNEY AND ADRENALS. 2 HR AFTER EXPOSURE, CONCN IN FAT HAD DECR BY MORE THAN 90% AND THAT IN LIVER BY 25%. FORTY-EIGHT HR AFTER EXPOSURE OF RATS TO DICHLOROMETHANE EITHER ORALLY (1 OR 50 MG/KG BODY WT) OR BY INHALATION (50, 500 OR 1500 PPM; 174, 1735 OR 5200 MG/CU M) < 10% OR 7-23%, RESPECTIVELY, OF THE BODY BURDEN WAS RETAINED. [R97] *AFTER 2-HR EXPOSURE, ABOUT 50% OF INHALED DICHLOROMETHANE IS TAKEN UP INTO BLOODSTREAM /OF HUMANS/; IT IS ALSO ABSORBED THROUGH THE SKIN. IT IS ELIMINATED MAINLY IN EXPIRED AIR. [R94] *When rats (male, Sprague-Dawley) were exposed to 50, 500, and 1500 ppm methylene chloride (dichloromethane, DCM) for 6 hr, plasma dichloromethane levels at apparent steady state were disproportionately higher with increasing exposure concn. Blood carboxyhemoglobin (HbCO) was 3% at 50 ppm and 10-13% at 500 ppm and at 1500 ppm. At the end of the 6 hr exposure, HbCO levels declined with half-life of 23 min. [R160] *In rats exposed to 500 ppm (1735 mg/cu m) dichloromethane for 1 hr on day 21 of gestation, concn in maternal blood were higher than those in fetal blood (176 nmole versus 115 nmole/ml), while carbon monoxide concn were similar in the two compartments (approx 169 nmole/l). [R95] *Dichloromethane is absorbed through the placenta and can be found in the embryonic tissues following exposure of the mother; it is also excreted via milk. [R124] *The tissue distribution and metabolism of dichloromethane (DCM) was investigated in B6C3F1 mice following iv or oral administration. The route of exposure and the compn of the dosing solution had a significant effect on the pharmacokinetics. Following single iv doses of 10 or 50 mg (14)C DCM/kg, dose dependent metabolism to (14)CO2 and (14)CO and rapid pulmonary clearance of unchanged methylene chloride (CH2C12) characterized the elimination of DCM from the body. The highest concns of methylene chloride (CH2C12) were found in the liver, lung and kidney, with > 50% of the total radioactivity in these tissues represented by the parent compound. When DCM was administered orally in single gavage doses for 14 consecutive days at treatment levels of 50 mg/kg in water or 500 and 1000 mg/kg in corn oil, rapid absorption and elimination of DCM characterized the treatment in water while distinctly slower trends were found for the doses in corn oil. No observable pharmacokinetic or metabolic effect resulted from repeated oral dosing over the 2 wk treatment period. [R161] *Radioactivity from (14)C-dichloromethane given orally (8.3 or 26 mmole/kg) to rats was associated preferentially with hepatic proteins and lipids. Trace amt associated with nucleic acids were also reported. After incubation of (14)C-dichloromethane with rat hepatic microsomal fractions fortified with NADPH, metabolites were bound to both lipids and proteins. [R95] *Rats metabolize only 7% of an admin dose of dichloromethane, as much as 5% being converted to carbon monoxide, and excrete 92% unchanged in the breath. [R76, 115] *It is inhaled by persons using products containing the ingredient, with up to 75% of the vapor absorbed through normal respiration. ... Concentrates in the liver and kidneys. [R2, 1160] *Following exposure to 200 ppm dichloromethane for 7.5 hr, human subjects eliminated approximately 30% of the absorbed dose of dichloromethane as carbon monoxide. The elimination of dichloromethane from the lungs is rapid ... [R2, 739] *... Dichloromethane is extensively distributed in the rat, with highest concentrations observed in fat, brain, liver, kidneys, and adrenal tissue. [R162] *Methylene chloride is well absorbed by the lung (55% retention in rats, 35% in humans). [R163] *From the moment of application, dermal absorption of liquid methylene chloride in mice increased linearly with time at a rate of 0.1 mg/sq cm/min. [R164] *In women occupationally exposed to an average methylene chloride concentration of 86 mg/cu m, the compound was found in the placenta, fetus, and breast milk (0.07 mg/l milk average). [R165] METB: *Biotransformation of dihalomethanes leads to dehalogenation and end product is carbon monoxide. In the case of dichloromethane the carbon monoxide appears to arise from formyl halide. This intermediate, as an alternative to losing carbon monoxide, can covalently bind to cellular protein or lipid. The involvement of nonmicrosomal enzymes in dihalomethane biotransformation leads to prodn of formaldehyde and halide. A necessary step is the reaction of dihalomethane with glutathione, which results in loss of one halide. The resulting halomethylglutathione is postulated to undergo nonenzymatic hydrolytic dehalogenation leaving hydroxymethylglutathione. The next step would result in the release of the hydroxymethyl group as formaldehyde. Alternatively it has been shown that in the presence of formaldehyde dehydrogenase and NAD /nicotinamide-adenine dinucleotide/ formic acid can be formed. [R166] *... BIOTRANSFORMATION INTO CARBON MONOXIDE OF DICHLOROMETHANE ... BY RAT HAS BEEN REPORTED ... MORE RECENT STUDIES OF HUMAN EXPOSURE TO DICHLOROMETHANE IN FACTORY WORKERS HAVE CONFIRMED THESE FINDINGS AND HAVE ALSO DEMONSTRATED THAT INCR EXPIRATION OF CARBON MONOXIDE ALSO OCCURS. [R167] *Rats (male, Sprague-Dawley) converted 26, 23, and 14% of body burden of dichloromethane (DCM) to carbon dioxide during a single 6 hr inhalation exposure at 50, 500, and 1500 ppm, respectively; 27, 18, and 10% of body burden of DCM was converted to carbon monoxide at 50, 500, and 1500 ppm, respectively. [R160] *... Carbon dioxide, formaldehyde, and formic acid are additional metabolites of dichloromethane. [R168] *Dichloromethane is metabolized to carbon monoxide in vivo and in vitro by hepatic microsomal cytochrome p450-dependent monoxygenases and by bacteria (Salmonella typhimurium TA100). Dichloromethane is metabolized in vitro by rat hepatic cytosolic fractions to formaldehyde and inorganic chloride, apparently by glutathione-S-transferases. [R95] *... The specific isoenzymes involved in the metabolism of dichloromethane have been identified as the cytochrome CYP2E1 and the theta-class GST, GSTT1-1. [R169] ACTN: *The correlation between biol activity (toxicity and mutagenic effectiveness in Salmonella TA 100) and reactivity towards strong nucleophiles indicates that reactions with nucleophilic groups of high reactivity in biological materials, possibly SH or amino groups in proteins, are involved in dichloromethane's mechanism of action. [R170] *Increases in the concn of dichloromethane (DCM) lower the oxygen affinity of human hemoglobin as demonstrated by the shift of the oxygenation curves to higher partial pressures of oxygen and increase in the p50 (oxygen pressure necessary for fractional saturation of 0.50). Dichloromethane binds weakly to hemoglobin at four different sites, but binding to only one site is responsible for decreasing the oxygen affinity of hemoglobin. [R171] INTC: *ETHANOL, METHANOL, ISOPROPANOL, AND TOLUENE REDUCED THE LEVELS OF CARBOXYHEMOGLOBIN CAUSED BY INHALATION OF METHYLENE CHLORIDE IN SPRAGUE-DAWLEY RATS AND CYNOMOLGUS MONKEYS. [R172] *The influence of different kinds of industrial solvents on the vestibular function of rats was studied by recording nystagmus, induced by accelerated rotation. The effect was related to the blood levels of the solvents. One group of solvents, including halogenated saturated hydrocarbons like dichloromethane, caused depression of the vestibulo-oculomotor reflex. Another group, including ... halogenated unsaturated hydrocarbons like 1,2-trichloroethylene caused an excitation of the vestibulo-oculomotor reflex. ... If the animals were exposed simultaneously to solvents from both groups, the excitatory effect prevailed and was even potentiated. [R110] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dichloromethane's production and use as solvent, chemical intermediate, grain fumigant, paint stripper and remover, metal degreaser, and refrigerant may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 435 mm Hg at 25 deg C indicates dichloromethane will exist solely as a vapor in the ambient atmosphere. Vapor-phase dichloromethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 119 days. It will not be subject to direct photolysis. If released to soil, dichloromethane is expected to have very high mobility based upon an estimated Koc of 24. Volatilization from moist soil surfaces is expected to be an important fate process based upon a estimated Henry's Law constant of 3.25X10-3 atm-cu m/mole. Dichloromethane may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation in soil may occur based on activated sludge studies. If released into water, dichloromethane is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Biodegradation is possible in natural waters but will probably be very slow compared with evaporation. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hr and 4 days, respectively. An estimated BCF of 2 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not an important degradation process under normal environmental conditions. Occupational exposure to dichloromethane may occur through inhalation and dermal contact with this compound at workplaces where dichloromethane is produced or used. The general population may be exposed to dichloromethane via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with consumer products, such as paint strippers, which contain dichloromethane. (SRC) ARTS: *Dichloromethane is formed during the chlorination of water. [R173] *Dichloromethane's production and use as a solvent, chemical intermediate, grain fumigant, and refrigerant(1) may result in its release to the environment through various waste streams(SRC). Air emissions are probable from dichloromethane's use as a paint stripper and remover, metal degreaser, and to a lesser extent, as an aerosol(2). Wastewater emissions are primarily from the following industries: Paint and ink, aluminum forming, coal mining, photographic equipment and supplies, pharmaceutical, organic chemical/plastics, rubber processing, foundries and laundries(3). [R174] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 24(SRC), determined from a structure estimation method(2), indicates that dichloromethane is expected to have very high mobility in soil(SRC). Volatilization of dichloromethane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 3.25X10-3 atm-cu m/mole(3). The potential for volatilization of dichloromethane from dry soil surfaces may exist(SRC) based upon a vapor pressure of 435 mm Hg(4). Biodegradation in soil may occur based on activated sludge studies(5). Biodegradation of dichloromethane in contaminated aquifers may occur under nitrate-reducing conditions via oxidation pathways(6). [R175] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 24(SRC), determined from an estimation method(2), indicates that dichloromethane is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon a estimated Henry's Law constant of 3.25X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1 hr and 4 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 2(SRC), from its log Kow of 1.25(8) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation is possible in natural waters based on sewage studies(9-14) but will probably be very slow compared with evaporation(15). Biodegradation of dichloromethane in contaminated aquifers may occur under nitrate-reducing conditions via oxidation pathways(16). [R176] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dichloromethane, which has a vapor pressure of 435 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase dichloromethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 119 days(SRC), calculated from its rate constant of 1.42X10-13 cu cm/molecule-sec at 25 deg C(3). A small fraction of the chemical will diffuse to the stratosphere where it will rapidly degrade by photolysis and reaction with chlorine radicals(4,5). [R177] BIOD: *AEROBIC: Dichloromethane is reported to completely biodegrade under aerobic conditions with sewage seed or activated sludge between 6 hours to 7 days(1-5). [R178] *ANAEROBIC: Dichloromethane exhibited 86-92% conversion to carbon dioxide (CO2) after acclimation using anaerobic digestion in wastewater(1). Under simulated conditions of a landfills, dichloromethane was degraded at a rate of 0.6 mg/cu m.hr(2). A half-life of 11 days has been reported in a 30-60 day laboratory study using anaerobic groundwater bacteria(3). A rate constant of 0.0064/day, half-life of 108 days, was observed from an initial dichloromethane concentration of 3500 ug/l over a 906 day period at a contaminated methanogenic site in Hawkesbury, Ontario, Canada(4). Biodegradation of dichloromethane in contaminated aquifers may occur under nitrate-reducing conditions via oxidation pathways(5). [R179] ABIO: *The rate constant for the vapor-phase reaction of dichloromethane with photochemically-produced hydroxyl radicals has been estimated as 1.42X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 119 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Hydrolysis is not an important degradation process under normal environmental conditions. The minimum reported half-life for hydrolysis is approximately 18 months(2). Since dichloromethane does not absorb light > 290 nm(3), it will not degrade by direct photolysis in the troposphere. It does not photodegrade when exposed to sunlight for 1 year in aerated water(1). In the stratosphere, it would undergo photolysis and also degrade by reaction with Cl radicals(4,5). Dichloromethane will degrade by reaction with hydroxyl radicals in the troposphere with a half-life of several months(4,6,7). There is some disparity concerning the photooxidation of dichloromethane in the presence of nitrogen oxides. One investigator reported 11.5% degradation in 6 hours(8) and another reported < 5% degradation in the presence of much higher concentrations of nitrogen oxides(9). The importance of photooxidation is supported by the fact that the highest concentrations of dichloromethane are observed at night or in the early morning(10). [R180] BIOC: *An estimated BCF of 2 was calculated for dichloromethane(SRC), using a log Kow of 1.25(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R181] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for dichloromethane can be estimated to be 24(SRC). According to a classification scheme(2), this estimated Koc value suggests that dichloromethane is expected to have very high mobility in soil. It is adsorbed strongly to peat moss, less strongly to clay, only slightly to dolomite limestone, and not at all to sand(3). [R182] VWS: *The Henry's Law constant for dichloromethane is 3.25X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that dichloromethane is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1 hour(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). Half-lives for the evaporation from water of 3-5.6 hours have been determined at moderate mixing conditions(2-4). When released into an estuarine bay, all the chemical dissipated within 4 km of the release point in the spring and within 8 km in the winter under ice(5). Dichloromethane's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of dichloromethane from dry soil surfaces may exist(SRC) based upon a vapor pressure of 435 mm Hg(3). [R183] WATC: *GROUNDWATER: Ground water near 43 Finish landfills was analyzed for dichloromethane and a median concn of 39 ug/l and a maximum concn of 1,600 ug/l were reported(1). Dichloromethane was detected in groundwater samples collected from Japan in 1991 at a concn of < 0.10 ppb(2). Dichloromethane was detected in groundwater samples collected from the Biscayne Aquifer Superfund site, Florida at a maximum concn of 20 ug/l for the entire study area, 6.4 ug/l in the well fields(3). [R184] *DRINKING WATER: Dichloromethane was detected in the following supply systems: 30 Canadian Water Treatment Facilities - 50% positive - 10 ppb, avg, 50 ppb max (summer), 30% pos, 3 ppb avg, 50 ppb max (winter)(1); 10 State survey drinking water from groundwater sources - 2% pos, 3600 ppb max, max surface water conc 13 ppb(2); EPA Region V Survey (83 sites in 5 states: MN, WI, IL, IN, OH) - 8% pos, 1-7 ppb(3), National Organics Monitoring Survey (1976) - 15 of 109 samples positive, 6.1 ppb, mean of positive samples(3). Dichloromethane was detected in 4 of 182 bottled water samples collected from Canada at concns ranging from 22 to 97 ug/kg, with an average concn of 59 ug/kg(4). [R185] *SURFACE WATER: Dichloromethane was detected in water samples collected from 30 sites along selected rivers in Osaka, Japan between August 1993 and February 1995 at a concn of 134 ug/l(1). Dichloromethane was detected in river water samples collected from Japan in 1991 at a concn of 0.38 ppb(2). [R186] *RAIN/SNOW/FOG: Dichloromethane was detected in rain water samples collected from Japan in 1991 at a concn of < 0.10 ppb in urban and rural areas(1). [R187] EFFL: *Weser R, Germany - 72-179 ppb(1). Industries in which wastewater exceeded an avg of 1000 ppb: Coal mining, aluminum forming, photographic equipment and supplies, pharmaceutical mfg, organic chemical/ plastics mfg, paint and ink formulation, rubber processing, foundries, and laundries(2). Max concn measured was 210,000 ppb in paint and ink industry and aluminum forming(2). Outfalls from 4 municipal treatment plants in southern California with primary or secondary treatment - random samples - < 10 to 400 ppb(3). USEPA STORET database, 1,480 data points, 38.8% pos, 10.0 ppb median(4). USA, 178 CERCLA hazardous waste disposal sites, 19.2% pos(5). Minnesota municipal solid waste landfills, leachates, 6 sites, 66.7% pos, 64-1300 ppb, contaminated groundwater (by inorganic indices), 13 sites, 53.8% pos, 1-250 ppb, other groundwater (apparently not contaminated as indicated by inorganic indices), 7 sites, 14.3% pos, 2.1-3.9 ppb(6). 1987 SARA data report an avg emission for dichloromethane of 465 tons/yr(7). Dichloromethane was detected not quantified in 1 of 4 biodegradable waste samples and 1 of 7 mixed household waste samples collected in Copenhagen, Denmark(8). [R188] *In 7 U.K. waste disposal facilities, concns of dichloromethane were found to range between 1 and 85 ug/cu m(1). Air samples were taken from 4 municipal landfill sites (3 old, 1 active) in southern Finland between 1989 and 1990, 100-250 meters from housing, concns ranged between 0.8-112 ug/cu m(2). Leachate samples taken from 3 hazardous wastes sites in Germany showed concns of dichloromethane ranging between 70 and 200,000 ug/l(3). In 1989, Dichloromethane was detected in air samples collected at 6 different sites, in 3 separate campaigns from sources such as vehicle exhaust, gasoline vapor, natural gas, industrial solvents, and drycleaning/ degreasing/wastewater at concns ranging from 0 to 48 ug/cu m, with an average of 1.5 ug/cu m(4). The City of Los Angelels was required to to prepare air toxics emissions inventories on its 4 waste water treatment plants; following are the concns of dichloromethane found at each plant: Hyperion, 4,337 kg/yr; Terminal Island, 249 kg/yr; Tillman, 600 kg/yr; LA-Glendale, 444 kg/yr(5). Air samples from 8 solid waste composting facilities indicated maximum concns of dichloromethane to be: 260 ug/cu m (all samples), 12 ug/cu m (non-carboy), 174,000 ug/cu m (TLV-TWA)(6). Dichloromethane was detected in 507 of 1159 products sampled for volatile organic compounds, average concns ranged from 0.1 wt% to 74.3 wt%(7). Dichloromethane was detected in 26 of 168 wastewater samples collected from 14 of NYC's water pollution control plants between 1989 and 1993 at concns ranging from 2 to 29 mg/l(8). Dichloromethane was detected, not quantified in air samples from the following sources: paint remover; an auto part shop; 8 of 31 samples from frangrance products; 14 of 15 samples taken from microenvironments(9). Dichloromethane was detected in emissions from heated roofing asphalt samples collected in 1990 at average gaseous concns ranging from 0 to 0.5126 ug/cu m, average emissions per area ranged from 0 to 7873 ug/sq m-hr (10). Dichloromethane was detected in off-gas air samples collected from 2 Ontario waste water treatment plants at concns ranging from 333 to 1,158 ug/cu m; concns from water samples ranged from 7.2 to 18.0 ug/l; estimated emission rates were 343 and 1,252 g/d(11). Dichloromethane was detected not quantified in 157 groundwater samples collected from 479 US waste disposal sites in 10 EPA regions(12). [R189] SEDS: *SEDIMENT: Bottom sediment near sewage outfall - Southern California - < 4 ppb. In Lake Pontchartrain, New Orleans: 1.5 ppb wet weight in sediment from Inner Harbor Navigation Canal; 3.2 ppb in sediment from Chef Monteur Pass; and not detected in sediment from Rigolets(1-2). USEPA STORET database, 338 data points, 20.0% pos, 13.0 ppb median(3). Dichloromethane was not detected in sediments which were collected from mouths of several rivers and a port in Niigata Prefecture, Japan in September, 1995, detection limit= 120 ng/g(4). [R190] ATMC: *SOURCE DOMINATED: Avg of 127 samples - 270 parts per trillion(1), 11 - highly industrialized locations - 10-74,000 parts per trillion(2); Industrial sites in Newark, Elizabeth and Camden, NJ (Summer 1981) - 230-720 parts per trillion geometric mean, 10.2 ppb max(3). Estimated U.K. emmissions in 1990 showed a concn of 0.40% dichloromethane (by mass distribution)(4). In southern California and the Los Angeles area, 1.7% of total organic gas emissions was dichloromethane, due to industrial adhesive activities(5). 7-24% of dichloromethane was detected in approximately 50 air samples collected from the Lamato Reserve in Ivory Coast between Feb 9 and 18, 1991 and also from the Kruger national Park in South Africa between Sept 18 and 24, 1992(6). Dichloromethane was detected in air samples collected from 6 municipal solid waste sites in Hamburg, Germany at concns ranging from 0.01 to 2.68 mg/kg(7). Max concn in gas from a lab anaerobic digester was 30 mg/N-cu m, leachate concentration was 0.4 mg/l(7). [R191] *URBAN/SUBURBAN: 11 sites - 414-3751 parts per trillion avg; 12,000 parts per trillion max(2-4); avg of 718 samples - 630 parts per trillion(1). 1987 SARA data report an avg ambient atmospheric concn for dichlormethane from 1987 to 1988 of 2.0 ppb-v(5). A mean concn of 0.5 ug/cu m of dichloromethane was detected in 2966 air samples collected from 78 sites in populated areas of the US(6). Dichloromethane was detected in 24 of 38 ambient air samples collected from Porto Alegre between March 20, 1996 and April 16, 1997 at concns ranging from 0.1 to 2.4 ppb, 0.513 +/- 0.586(7). Dichloromethane was detected in 10 ambient air samples collected from Boston, Chicago, Houston and the Seattle/Tacoma area in 1988 at concns ranging between 0.29 to 0.42 ppbv(8). Dichloromethane was detected in air samples collected from 4 representative areas in Arizona between 1994 and 1996 with average concns ranging from 0.61 to 1.62 ppbv(9). Dichloromethane was detected in air samples collected from California, Houston, TX and Denver, CO between Feb 1984 and December 1985 at concns ranging from 71 to 10,310 parts per trillion, with a mean value of 1688 parts per trillion(10). [R192] *RURAL/REMOTE: Global 32 parts per trillion; Northern Hemisphere - 44 parts per trillion. Southern Hemisphere - 20 parts per trillion(1). (5 samples) - 45 parts per trillion(2); Weighted avg for dichloromethane (parts/trillion): Eastern Pacific Ocean: Northern hemisphere, 38, Southern hemisphere, 21; global avg, 29(3). Estimates of global atmospheric emissions of dichloromethane calculated from air samples taken yearly between 1988 and 1992 decreased from 592,000 to 513,000 metric tonnes; concns for geographical regions included: North America - 167,000-179,000 metric tonnes/yr, Europe - 135,000-187,000 metric tonnes/yr, Far East - 94,000-103,000 metric tonnes/yr, Northern Hemisphere mid-latitudes - 41,000-79,000 metric tonnes/yr, Northern Hemisphere tropical - 43,000-52,000 metric tonnes/yr, Total Northern Hemisphere - 494,000-573,000 metric tonnes/yr, Southern Hemisphere - 16,000-22,000 metric tonnes/yr(4). Reported and accepted odor threshold values of dichloromethane from various air samples and sources showed concns ranging from 500 to 790 ug/cu m, unreviewed sources reported concns of 0.2 to 1.4 ug/l(5). Dichloromethane was detected in air samples collected from Japan between December 1990 and January 1991 at a concn of < 0.1 ppb(6). [R193] *INDOOR: Dichloromethane was detected in ambient air samples collected from a new federal office building in Portland, Oregon between August 1987 and October 1988 at concns ranging from 2.6 to 119.7 ug/cu m(1). Dichloromethane was detected in indoor air samples collected from the Netherlands, the USA and Germany at concns less than 10 ug/cu m(2). Dichloromethane was detected in 41 of 101 indoor air samples collected from several dwellings in several countries between 1978 and 1990 at an average maximum concn of 170 ug/cu m(3). [R194] FOOD: *Dichloromethane was detected in intermediate grain based food (1984); 9 varieties, 77.8% pos, 1.9-30 ppb (max concn in bleached flour, followed by a fudge brownie mix; wheat, corn, oats (1984), 10, 2, and 1 samples, respectivley: not detected(1). Table ready foods: 19 varieties, 42% pos, 1.4-71 ppb; max concn in cheddar cheese; butter, 7 samples, 100% pos; 1.1-280 ppb; margarine, 7 samples, 100% pos, 1.2-81 ppb; cheese, 4 types 8 samples, 100% pos, 3.9-98 ppb, max concn in Parmesan cheese(2). [R195] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Bottomfish, Commencement Bay and adjacent waterways, Tacoma, WA 1982, highest avg level, 0.53 ppm, highest level 0.7 ppm dichloromethane(1). Lake Pontachartrain, New Orleans: oysters from Inner Harbor Navigation Canal, 7.8 ng/g (ppb) wet weight; clams from Chef Manteur Pass, 27 ppb; clams from Rigolets, 4.5 ppb(2). [R196] MILK: *Dichloromethane was detected in all 8 samples of mother's milk from 4 urban areas(1). Mother's milk in Soviet women manufacturing rubber articles - 74 ppb mean in 17 of 28 samples approx 5 hours after start of work, level declined after termination of work(2). [R197] RTEX: *Casting room (1968-1972) - 55-495 ppm; Plastic film factory - 3 year study, 318 samples - 30-5,000 ppm, 627 ppm avg; 1973-1974 study of 7 jobs using dichloromethane: 6 of 7 jobs - 0-74 ppm, chemical plant 0-5,520 ppm(1). Monitoring data suggest that the mean TWA personal exposure to dichloromethane in the workplace may be in the range of 100-200 ppm or higher from its use in the production of acetyl sulfonyl chloride and cellulose acetate/triacetate fibers and during paint stripping operations(2). Dichlormethane occurred in 40% of the 7705 samples of solvent vapor from a variety of different industries in Norway(3). The furniture stripping industry employs an estimated 21,000 workers in approximately 4000 small businesses. Dichloromethane exposure ranged from 300 to > 2,100 ppm(4). A ventilation system reduced this to a geometric mean of 13 ppm(4). Mean level of exposure to dichloromethane in workspace air at a pharmaceutical factory where this substance is used as a solvent was 50.3 mg/cu m during a 4 hr shift(5). 26 samples of model and hobby glues from 12 different manufacturers in Europe and the US have been found to contain dichlormethane at concns ranging from 0.004-9.2% w/w(6). [R198] *Exposure levels between 1-69 mg/cu m (occupational exposure standard of 350 mg/cu m) were detected in 7 U.K. waste disposal facilities(1). Average worker exposure concns ranging between 0 and 25 ug/cu m were detected at various locations within municipal solid waste composting facilities(2). In Denmark, aerosol products were analyzed for dichloromethane, in 21 samples of cosmetics a conc of 0.001-0.05%, in 3 samples of household and hobby products a conc of 0.2-4.0%, 3 samples of paint and paint remover, a conc of 0.02-0.07%, 1 sample of lubricant and anti-rust products, a conc of 55.8%(3). Exposure of dichloromethane was detected in 15 non-production departments of 3 mills at concns ranging from 6.1 to 100 ppm, median concn of 0 ppm(4). [R199] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,147,425 workers (287,914 of these are female) are potentially exposed to dichloromethane in the US(1). Occupational exposure to dichloromethane may occur through inhalation and dermal contact with this compound at workplaces where dichloromethane is produced or used(SRC). The general population may be exposed to dichloromethane via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with consumer products, such as paint strippers(2), soaps, paint, varnish(3) and model and hobby glues(4), which contain dichloromethane(SRC). [R200] BODY: *Detected in all 8 samples of mother's milk from 4 urban areas(1). Mother's milk in Soviet women manufacturing rubber articles - 74 ppb mean in 17 of 28 samples approx 5 hours after start of work, level declined after termination of work(2). Whole block specimens, 250 subjects, not detected to 25 ppb, 0.7 ppb avg(3). ppb, 0.7 ppb avg(3). Mean level of dichloromethane present in urine of workers at a pharmaceutical factory where this substance is used as a solvent was 190.8 ug/l during a 4 hr shift but appears to be nearly eliminated during the night break(5). [R201] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *Niosh recommends that methylene chloride be regulated as an occupational carcinogen. [R51] ATOL: *Dichloromethane is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R202] OSHA: *The employer shall ensure that no employee is exposed to an airborne concentration of methylene chloride in excess of 25 ppm as an 8 hr TWA. The employer shall ensure that no employee is exposed to an airborne concentration of methylene chloride in excess of 125 ppm as determined over a sampling period of 15 minutes. [R203] NREC: *NIOSH recommends that methylene chloride be regulated as an occupational carcinogen. [R51] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R51] TLV: +8 hr Time Weighted Avg (TWA) 50 ppm [R73, 31] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R73, 6] +A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R73, 31] OOPL: *Emergency Response Planning Guidelines (ERPG): ERPG(1) 200 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 750 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 4000 ppm (not life threatening) up to 1 hr exposure. [R204] *AUSTRALIA: 100 PPM, CATEGORY 3, SUSPECTED OF HAVING CARCINOGENIC POTENTIAL, PROPOSED CHANGE 50 PPM (1990); FEDERAL REPUBLIC OF GERMANY: 100 PPM, SHORT-TERM LEVEL 500 PPM, 30 MIN, TWICE PER SHIFT; JUSTIFIABLY SUSPECTED OF HAVING CARCINOGENIC POTENTIAL (1992); SWEDEN: 70 PPM, SHORT-TERM LEVEL 150 PPM, 15 MIN, SKIN (1991); UNITED KINGDOM: 100 PPM, 10 MIN STEL 250 PPM (1991). [R77, 1991.986] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Methylene chloride is produced, as an intermediate or a final product, by process units covered under this subpart. [R205] *Methylene chloride has been designated as a hazardous air pollutant under section 112 of the Clean Air Act. [R206] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l [R207] STATE DRINKING WATER STANDARDS: +(NJ) NEW JERSEY 2 ug/l [R207] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 4.7 ug/l [R207] +(CT) CONNECTICUT 5 ug/l [R207] +(ME) MAINE 48 ug/l [R207] +(MN) MINNESOTA 50 ug/l [R207] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Halomethanes/ [R208] +The maximum contaminant level (MCL) set forth by the National Revised Primary Drinking Water Regulations for the organic contaminant dichloromethane in community and non-transient, non-community water systems is 0.005 mg/l. [R209] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R210] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Dichloromethane is included on this list. [R211] RCRA: *F002; When dichloromethane is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F002), as stated in 40 CFR 261.31, and must be managed according to state and/or federal hazardous waste regulations. [R212] *U080; As stipulated in 40 CFR 261.33, when dichloromethane, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R213] FIFR: *Dichloromethane is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R202] *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Methylene chloride is found on List C. Case No: 3090; Pesticide type: insecticide; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Methylene chloride; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R10] FDA: *Certification of this color additive when used as an ink for marking fruit and vegetables is not necessary for the protection of the public health, and therefore batches thereof are exempt from the certification pursuant to section 721(c) of the act. Restriction: No residues. [R214] *Dichloromethane is an indirect food additive for use only as a component of adhesives. [R215] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EPA Method 601: A purge and trap gas chromatographic method for the analysis of dichloromethane in municipal and industrial discharges, consists of a stainless steel column, 8 ft x 0.1 in ID, packed with Carbopack B (60/80 mesh) coated with SP-1000, with electrolytic conductivity detection, and helium as the carrier gas at a flow rate of 40 ml/min is an EPA approved method. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 45 deg C for 3 minutes then programmed at 8 deg/min to final temperature of 220 deg C. This method has a detection limit of 0.25 ug/l and an overall precision of 0.21 times the average recovery + 1.43, over a working range of 8.0 to 500 ug/l. [R216] *EPA Method 624: A purge and trap gas chromatographic/mass spectrometry method for the analysis of dichloromethane in municipal and industrial discharges, consists of a glass column, 6 ft x 0.1 in, packed with Carbopack B (60/80 mesh) coated with 1% SP-1000, with the detection performed by the mass spectrometer, and helium as the carrier gas at a flow rate of 30 ml/min, is an EPA approved method. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 45 deg C for 3 minutes and then programmed at 8 deg/min to a final temperature of 220 deg C. This method has a detection limit of 2.8 ug/l and an overall precision of 0.26 times the average recovery - 1.72, over a working range of 5 to 600 ug/l. [R216] *EPA OSW Method 8021A. Determination of Halogenated and Aromatic Volatile Organics using Capillary Column Gas Chromatography. Method detection limit 0.030 ug/l. [R217, (1994)] *EPA OSW Method 8260A. Determination of Volatile Organics by Purge and Trap, Capillary Column Gas Chromatography/ Mass Spectroscopy. Method detection limit 0.130 ug/l. [R217, (1997)] *EPA OSW Method 8240B. Determination of Volatile Organics by Purge and Trap Gas Chromatography/ Mass Spectroscopy. Estimated quatitation limit 5 ug/l. [R217, (1997)] *EPA Method 502.1. Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromotography, GC with electroconductivity detection, detection limit not reported. [R218] *EPA EMSL Method 502.2. Volatile Halogenated Organic Compounds in Water by Purge and Trap Capillary Gas Chromotography with Photoionization and Electrolytic Conductivity Detectors in Series, GC with electroconductivity detection, method detection limit 0.020 ug/l. [R218] *EPA EMSL Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography/ Mass Spectroscopy. Method detection limit 1.0 ug/l. [R218] *EPA OSW Method 8021A. Determination of Halogenated and Aromatic Volatile Organics using Capillary Column Gas Chromatography. Electroconductivity detector. Method detection limit 0.020 ug/l. [R217, (1994)] *EPA OSW Method 8240B. Determination of Volatile Organics by Purge and Trap Gas Chromatography/ Mass Spectroscopy. Estimated quantitation limit 5 ug/l. [R217, (1997)] *EPA EAD Method 1624. Determination of Volatile Toxic Organic Pollutants and Additional Compounds Amenable to Purge and Trap GC/MS. Gas chromatography/mass spectroscopy. Minimum detection level 10 ug/l. [R218] *NIOSH Method 1005. Methylene chloride by GC/FID. Gas chromatography with flame ionization detection. Substrate: air. Detection limit 4.0 mg/cu m. [R219] *NIOSH Method 2549. Volatile organic compounds (screening). Thermal desorption tube. Limit of detection 100 ng/tube or less. [R219] CLAB: *Whole blood is diluted with water and specimen is allowed to equilibrate in a sealed container at a constant temp. A sample of the headspace vapor is analyzed by flame-ionization gas chromatography. Breath samples may be analyzed by direct injection of 1-2 ml, using as standards suitably prepared dilutions of appropriate chemical in air. ... Instrumental conditions: ... 2 m x 2 mm id glass column containing 2% OV-17 on 100/120 mesh Chromosorb G-HP; Injector, 150 deg C; column, 60 deg C; detector, 150 deg C. Nitrogen flow rate, 20 ml/min. ... Retention time for dichloromethane 1.3 min. Calculation is based on a std curve prepared each time an assay is performed. Evaluation: Sensitivity: 0.1 mg/l. Linearity: 0.2-5.0 mg/l. Relative recovery: not established. Interferences: ... Many other volatile organic cmpd are detected with this technique and may interfere. [R76, 37] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Health Assessment Document: Dichloromethane (Methylene Chloride) (Draft) (1982) EPA-600/8-82-004B WHO; Environ Health Criteria: Methylene chloride (1984) USEPA; Ambient Water Quality Criteria for Halomethanes (1980) EPA-440/5-80-051 DHHS/ATSDR; Toxicological Profile for Methylene Chloride (Update) TP-92/13 (1993) NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.25. NTP TR No 306; Route: inhalation; Species: rats and mice. NTIS No PB86187903/AS. USEPA; Update Health Assessment and Addendum for Dichloromethane (Methylene Dichloride): Pharmacokinetics, Mechanism of Action, and Epidemiology. (Draft) (1987) EPA/600/8-87/030A U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) HIST: *The Diamond Shamrock Corp has reported that due to an industrial accident in its methylene chloride and chloroform production facility in Belle, WV, two employees were exposed to an airborne mixture of chems which may have included bis(chloromethyl)ether. [R220] SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R2: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 44 (1986) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 45 (1986) R5: WHO; Environ Health Criteria: Methylene chloride p.15 (1984) R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 450 (1979) R7: Rodnan N; Chemcyclopedia 98. Washington, DC: American Chemical Society p. 90 (1997) R8: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. R9: Chemical Marketing Reporter; Chemical Profile. Methylene Chloride. November 24, 1997. NY, NY: Schnell Pub Co p. 33 (1997) R10: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.263 (Spring, 1998) EPA 738-R-98-002 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R12: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1035 R13: Kayser, R., D. Sterling, D. Viviani (eds.). Intermedia Priority Pollutant Guidance Documents. Washington, DC: U.S.Environmental Protection Agency, July 1982. R14: SRI R15: CHEMICAL PRODUCTS SYNOPSIS: Methylene Chloride, 1985 R16: Kavaler AR; Chemical Marketing Reporter 235 (8): 54 (1989) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 255 (1999) R18: US INTERNATIONAL TRADE COMMISSION WASH DC 20436; SOC SERIES C/P-82-1 R19: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.268 R20: USITC. SYN ORG CHEM-U.S. PROD. PRELIMINARY Feb 26, 1988 (SERIES C/P-87-5) R21: USITC. SYN ORG CHEM-U.S. PROD/SALES 1987 p.15-7 R22: CHEM ENG NEWS 65 (23): 31 (1987) R23: CHEM ENG NEWS 66 (25): 40 (1988) R24: Kavaler, A.R. (ed.). Chemical Marketing Reporter. 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Lyon, France: International Agency for Research on Cancer R58: ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.50 (1983) R59: Hart C; Journal of Environmental Health 49 (5): 282-86 (1987) R60: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 624 R61: USEPA; Health Assessment Document: Dichloromethane (Methylene Dichloride) p.3-1 (1982) EPA-600/8-82-004 R62: 49 CFR 171.2 (7/1/99) R63: IATA. Dangerous Goods Regulations. 40th Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 1999. 140 R64: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6127 (1998) R65: USEPA; Health Assessment Document: Dichloromethane (Methylene Dichloride) p.3-3 (1982) EPA-600/8-82-004 R66: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R67: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-12 (1981) EPA 68-03-3025 R68: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-5 (1981) EPA 68-03-3025 R69: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. 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Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 849 R131: WHO; Environmental Health Criteria 32: Methylene Chloride p.28 (1984) R132: BUCCAFUSCO RJ ET AL; BULL ENVIRONM CONTAM TOXICOL 26: 446-52 (1981) R133: NTP; Toxicology and Carcinogenesis Studies of Dichloromethane Report# 306 (1986) NIH Pub# 86-2562 R134: Industrial Biological and Testing Laboratories, Inc.; Ninety Day Percutaneous Absorption study in Rabbits with Chlorothene and Methylene Chloride, (1961), EPA Document No. 40+8224318, Fiche No. OTS0509178 R135: Dow Chemical U.S.A; Methylene Chloride: Two-generation Inhalation Reproduction Study in Fischer 344 Rats, (1985), EPA Document No. 40+8524084, Fiche No. OTS0509187 R136: Hazelton Laboratories America, Inc.; 24-Month Oncogenicity Study of Methylene Chloride in Mice, Final Report, Volume 1. 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(1976), EPA Document No. 878212285, Fiche No. OTS0205979 R142: Litton Bionetics, Inc.; Mutagenicity Evaluation of High Purity Methylene Chloride, Final Report. (1977), EPA Document No. 878210856, Fiche No. OTS0206082 R143: Dow Toxicology Research Laboratory; Cytogenetic Evaluation of Bone Marrow Cells from Rats Exposed to Methylene Chloride for Six Months, Final Report, (1980), EPA Document No. FYI-OTS-0281-0097, Fiche No. OTS0000097-0 R144: Dow Toxicology Research Laboratory; The Dose-Dependent Metabolism of 14C-Methylene Chloride Following Oral Administration to Rats, (no date reported), EPA Document No. 878212096, Fiche No. OTS0206132 R145: Dow Toxicology Research Laboratory; Distribution and Macromolecular Interactions of Inhaled Methylene Chloride in Various Tissues of the Male Sprague Dawley Rat, (1981), EPA Document No. 878211306, Fiche No. OTS0206132 R146: Dow Toxicology Research Laboratory; Effect of Methylene Chloride on the Oxyhemoglobin Dissociation Curve (OD-Curve) of Rat and Human Blood, (1977), EPA Document No. 878211309, Fiche No. OTS0206132 R147: Dow Toxicology Research Laboratory; 14C-Methylene Chloride: Pharmokinetics in the Hamster, (1983), EPA Document No. 878214493, Fiche No. OTS206588 R148: Dow Toxicology Research Laboratory; 14C-Methylene Chloride: Macromolecules Interactions in Hamster and Rat Selected Tissue, (1983), EPA Document No. 878214493, Fiche No. OTS0206588 R149: Dow Chemical Toxicology Research Lab.; Methylene Chloride: Distribution and Macromolecular Interactions of Inhaled Methylene Chloride in Various Tissues of the Male Sprague-Dawley Rat. (1981), EPA Document No. 878211306, Fiche No. OTS0206132 R150: Dow Chemical Toxicology Research Lab.; (14C) Methylene Chloride: Pharmacokinetics and Interaction with Hamster and Rat Liver Tissue Macromolecules. (1983), EPA Document No. 878214493, Fiche No. OTS0206588 R151: Shell Oil Co; Ten Day Inhalation Toxicity Study to Investigate the Effects on Rat and Mouse Liver and Lung with Methylene Chloride; 01/10/86; EPA Document No. 86-880000287; Fiche No. OTS0514365 R152: Shell Oil Co; Methylene Chloride - Interaction with Rat and Mouse Liver and Lung DNA In Vivo; 01/22/86; EPA Document No. 86-880000286; Fiche No. OTS0514364 R153: Dow Chem Co; Metabolism of Dihalomethane to Carbon Monoxide Prepared by Univ of Minnesota; 07/03/73; EPA Document No. 878211823; Fiche No. OTS0206132 R154: Dow Chem Co; Effect of Methylene Chloride on the Oxyhemoglobin Dissociation Curve of Rat and Human Blood; 07/15/77; EPA Document No. 878211309; Fiche No. OTS0206132 R155: Shell Oil Co; In Vitro Metabolism in Rat, Mouse and Hamster Liver and Lung Fractions and In Human Liver Fractions with Methylene Chloride; 09/22/86; EPA Document No. 86-880000289; Fiche No. OTS0514367 R156: Isolation of Two Mouse Theta Glutathione S-Transferases Active with Methylene Chloride; 00/00/00; EPA Document No. 86950000282; Fiche No. OTS0572588 R157: Mouse Liver Glutathione S-Transferase Mediated Metabolism of Methylene Chloride to a Mutagen in the CHO/HPRT Assay; 00/00/00; EPA Document No. 86950000284; Fiche No. OTS0572590 R158: Dow Chem Co; Methylene Chloride - Induction of S-Phase Hepatocytes in Mice After In Vivo Exposure (Final Report); 09/22/86; EPA Document No. 88-920004070; Fiche No. OTS0540418 R159: USEPA; Health Assessment Document: Dichloromethane (Methylene Chloride) (Review Draft) p.4-6 (1983) EPA-600/8-82-004B R160: McKenna MJ et al; Toxicol Appl Pharmacol 65 (1): 1-10 (1982) R161: Angelo MJ et al; Food Chem Toxicol 24 (9): 965-74 (1986) R162: Hayes, W.J., Jr., E.R. 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Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 278 (1999) R170: Osterman-Golkar S; Chem Biol Interact 46 (1): 121-30 (1983) R171: Saxena AM et al; Biochem Biophys Acta 704: 1-6 (1982) R172: CIUCHTA HP ET AL; TOXICOL APPL PHARMACOL 49 (2): 347-54 (1979) R173: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 453 (1979) R174: (1) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station,NJ: Merck and Co., Inc. p. 1035 (1996) (2) Chemical Marketing Reporter; Chemical Profile Methylene Chloride. Nov. 24, 1997. p. 33. NY,NY: Schnell Pub Co (1997) (3) USEPA; Treatability Manual EPA-600/2-82-001A pp. I.12.2-1 to I.12.2-4 (1981) R175: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Leighton DT Jr, Calo JM; J Chem Eng 26: 382-5 (1981) (4) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci. Publ p. 42 (1984) (5) Tabak HH et al; J Water Pollut Control Assoc 53: 1503-18 (1981) (6) Aronson D, Howard PH; Anaerobic biodegradation of organic chemicals in groundwater: a summary of field and laboratory studies. Syracuse, NY; Syr Res Corp. S-97-023f. pp. 121-2 (1997) R176: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. 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Boca Raton, FL: Lewis (1994) (5) Aronson D, Howard PH; Anaerobic biodegradation of organic chemicals in groundwater: a summary of field and laboratory studies. Syracuse, NY; Syr Res Corp. S-97-023f. pp. 121-2 (1997) R180: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Dilling WL et al; Environ Sci Technol 9: 833-8 (1975) (3) Hubrich C, Stuhl F; J Photochem 12: 93-107 (1980) (4) Cox RA et al; Atmos Environ 10: 305-8 (1976) (5) Spence JW et al; J Air Pollut Control Assoc 76: 994-6 (1976) (6) Hampson RF; Chemical Kinetic and Photochemical Data Sheets for Atmospheric Reactions 1 Report FAA-EE-80-17 US Dept of Transportation (1980) (7) Singh HB et al; Atmos Environ 15: 601-12 (1981) (8) Yanagihara S et al; Photochemical Reactivities of Hydrocarbons Proceedings of the 4th Clean Air Congress p 472-7 (1977) (9) Dilling WL et al; Environ Sci Technol 10: 351-6 (1976) (10) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) R181: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R182: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Dilling WL et al; Environ Sci Technol 9: 838-8 (1975) R183: (1) Leighton DT Jr, Calo JM; J Chem Eng 26: 382-5 (1981) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci. Publ p. 42 (1984) (4) Rathbun RE, Tai DY; Water Res 15: 243-50 (1981) (45) Helz GR, Hsu RY; Limnol Oceanogr 23: 858-69 (1978) R184: (1) Assmuth TW, Strandberg T; Water Air Soil Poll 69: 179-99 (1993) (2) Yamasaki T et al; Wat Sci Tech 25: 33-39 (1992) (3) Canter LW, Sabatini DA; Intern J Environ Stud 46: 35-57 (1994) R185: (1) Otson R et al; J Assoc Offic Analyt Chem 65: 1370-4 (1982) (2) Dyksen JE, Hess AF III; J Amer Water Works Assoc 74: 394-403 (1982) (3) USEPA; Ambient Water Quality Criteria for Halomethanes USEPA-440/5-80-051 p. C-6 to C-17 (1980) (4) Page RD et al; J AOAC Inter 76: 26-31 (1993) R186: (1) Yamamoto K et al; Environ Poll 95: 135-43 (1997) (2) Yamasaki T et al; Wat Sci Tech 25: 33-39 (1992) R187: (1) Yamasaki T, et al; Wat Sci Tech 25: 33-39 (1992) R188: (1) Von Dueszeln et al; Z Wasser Abwasser Forsch 15: 272-6 (1982) (2) USEPA; Treatability Manual USEPA-600/2-82-001A pp. I.12.2-1 to I.12.2-4 (1981) (3) Young DR et al; Water Chlorination: Environ Impact Health Effect 4 (Book 2): 871-4 (1983) (4) Staples CA et al Environ Technol Chem 4: 131-42 (1985) (5) Plumb RH Jr; Ground Water Monit Rev 7: 94-100 (1987) (6) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) (7) LaGrone SF; Environ Sci Technol 25: 366-8 (1991) (8) Wilkins K et al; Chemosphere 29: 47-53 (1994) R189: (1) Allen MR et al; Environ Sci Technol 31: 1054-61 (1997) (2) Assmuth T,Kalevi K; Chemosphere 24: 1207-16 (1992) (3) Brack W, et al; Environ Toxicol Chem 17: 982-91 (1998) (4) Mukund R et al; Atmos Environ 30: 3457-70 (5) Mayer GJ; Waste Water Res 66: 140- 44 (1994) (6) Eitzer BD; Environ Sci Technol 29: 896-902 (1995) (7) Sack TM et al; Atmos Environ 26A: 1063-70 (1992) (8) Stubin AI et al; Water Environ Res 68: 1037-44 (1996) (9) USEPA; Identification of polar volatile organic compounds in consumer products and common microenvironments p.1-14 USEPA-600/D-91/074 (1991) (10) USEPA; Evaluation of VOC emissions from heated roofing asphalt p.1-56 USEPA-600/2-91-061 (1991) (11) Bell J et al; Water Environ Res 65: 708-16 (1993) (12) Barbee GC; Ground Water Monit Rem 14: 129-450 (1994) R190: (1) Young DR et al; Water Chlorination: Environ Impact Health Effect 4 (Book 2): 871-4 (1983) (2) Ferrario JB et al; Bull Environ Contam Toxicol 34: 246-55 (1985) (3) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (4) Kawata K et al; Bull Environ Contam Toxicol 58: 893-900 (1997) R191: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data SRI Contract 68-02-3452 (1982) (2) Pellizzari ED; Quantification of Chlorinated Hydrocarbons in Previously Collected Air Samples USEPA-450/3-78-112 (1978) (3) Harkov R et al; J Air Pollut Control Assoc 33: 1177-83 (1983) (4) Derwent RG; p. 1-15 in Issues in Environmental Science and Technology; Hester RE, Harrison RM, eds (1995) (5) Harley RA et al; Environ Sci Technol 26:2395-2408 (1992) (6) Rudolph J et al; Comm Eur Communities 1: 424-30 (1994) (7) Deipser A, Stegmann R; Waste Manag Res 12: 129-39 (1994) R192: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data SRI Contract 68-02-3452 (1982) (2) Singh HB et al; Atmospheric Measurements of Selected Hazardous Organic Chemicals USEPA-600/5-3-81-032 (1981) (3) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) (4) Singh HB et al; Atmos Environ 15: 601-12 (1981) (5) LaGrone SF; Environ Sci Technol 25: 366-8 (1991) (6) Kelly TJ et al; Environ Sci Technol 28: 378A-387A (1994) (7) Grosjean E et al; Environ Sci Technol 33: 1970-78 (1999) (8) Evans GF et al; J Air Waste Manage Assoc 42: 1319-23 (1992) (9) Zielinska B et al; J Air Waste Manage Assoc 48: 1038-50 (1998) (10) Singh HB et al; Atmos Environ 26A: 2929-46 (1992) R193: (1) Singh HB et al; Atmospheric Distributions, Sources and Sinks of Selected Halocarbons, Hydrocarbons, SF6 and H2O USEPA-600/3-79-107 p. 4 (1979) (2) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data SRI Contract 68-02-3452 (1982) (3) Singh HB et al; J Geophys Res 88: 3675-83 (1983) (4) McCulloch A, Midgley PM; Atmos Environ 30: 601-8 (1996) (5) USEPA; Reference Guide to Odor Thresholds for Hazardous Air Pollutants Listed in the Clean Air Act Amendments of 1990 p. 2-25 USEPA-600/R-92/047 (1992) (6) Yamasaki T et al; Wat Sci Tech 25: 33-39 (1992) R194: (1) Hodgson AT et al; Air Waste Manag Assoc 41: 1461-68 (1991) (2) Crump DR; Issues Environ Sci Technol 4: 109-24 (1995) (3) Brown SK et al; Indoor Air 4:123-34 (1994) R195: (1) Heikes DL, Hopper ML; J Assoc Off Anal Chem 69: 990-8 (1986) (2) Heikes DL; J Assoc Off Anal Chem 70: 215-26 (1987) R196: (1) Nicola RM; J Environ Health 49: 342-7 (1987) (2) Ferrario JB et al; Bull Environ Contam Toxicol 34: 246-55 (1985) R197: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Jense AA; Res Rev 89: 1-128 (1983) R198: (1) NIOSH; Criteria for a Recommended Standard Occupational Exposure to Methylene Chloride NIOSH 76-138 pp. 80-81, 152, 164 (1976) (2) Santodonato J et al; Monograph on Human Exposure to Chemicals in the Workplace: Methylene Chloride NCI Contract NO. N01-CP-26002-03 (1985) (3) Fjeldstad PE, Woldbaek T; A National Exposure Database. Spec Publ. Roy Soc Chem. Natl Inst Occup Helath, Oslo, Norway. 108(Clean Air Work): 303-10 (1992) (4) Hall RM et al; Appl Occup Environ Hyg 10: 188-95 (1995) (5) Ghittori S et al; Am Ind Hyg Assoc J 54: 27-31 (1993) (6) Rastogi CS; Bull Environ Contam Toxicol 51: 501-7 (1993) R199: (1) Allen MR, et al; Environ Sci Technol 31: 1054-61 (1997) (2) Eitzer BD; Environ Sci Technol 29: 896-902 (1995) (3) Rastogi SC; Chromatographia 33: 117-21 (1992) (4) Teschke K et al; Amer Indust Hyg Assoc J 60: 73-83 (1999) R200: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Chemical Marketing Reporter; Chemical Profile Methylene Chloride. Nov. 24, 1997. p. 33 NY,NY: Schnell Pub Co (1997) (3) Allen MR, et al; Environ Sci Technol 31: 1054-61 (1997) (4) Rastogi SC; Bull Environ Contam Toxicol 51: 501-7 (1993) R201: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Jensen AA; Res Rev 89: 1-128 (1983) (3) Antoine SR et al; Bull Environ Contam Toxicol 36: 364-71 (1986) (4) Ghittori S et al; Am Ind Hyg Assoc J 54: 27-31 (1993) R202: 40 CFR 180.1001(d) (7/1/99) R203: 29 CFR 1910.1052(c) (7/1/99) R204: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.26 R205: 40 CFR 60.489 (7/1/99) R206: 40 CFR 61.01 (7/1/99) R207: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R208: 40 CFR 401.15 (7/1/99) R209: 40 CFR 141.61 (7/1/99) R210: 40 CFR 302.4 (7/1/99) R211: 40 CFR 716.120 (7/1/99) R212: 40 CFR 261.31 (7/1/99) R213: 40 CFR 261.33 (7/1/99) R214: 21 CFR 73.1 (4/1/99) R215: 21 CFR 175.105 (4/1/99) R216: 40 CFR 136 (7/1/86) R217: USEPA; Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September 1994 R218: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1 PC# 4082. Rockville, MD: Goverment Institutes (1997) R219: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R220: USEPA; Preliminary Evaluations of the Initial TSCA Section 8(e) Substantial Risk Notices July 1, 1979- January 31, 1980 RS: 198 Record 13 of 1119 in HSDB (through 2003/06) AN: 78 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N,N-DIMETHYLFORMAMIDE- SY: *U-4224-; *DIMETHYLAMID-KYSELINY-MRAVENCI- (CZECH); *DIMETHYLFORMAMIDE-; *N,N-DIMETHYL-FORMAMIDE-; *DIMETHYLFORMAMID- (GERMAN); *N,N-DIMETHYLMETHANAMIDE-; *N,N-Dimetilformamida- (Spanish); *DIMETILFORMAMIDE- (ITALIAN); *DIMETYLFORMAMIDU- (CZECH); *DMF-; *DMFA-; *DMF- (AMIDE); *DWUMETYLOFORMAMID- (POLISH); *Pesticide-Code:-366200-; *EPA-Pesticide-Chemical-Code-366200-; *FORMAMIDE,-N,N-DIMETHYL-; *FORMIC-ACID,-AMIDE,-N,N-DIMETHYL-; *N-FORMYLDIMETHYLAMINE-; *NCI-C60913-; *NSC-5356- RN: 68-12-2 RELT: 100 [N-METHYLFORMAMIDE] (Metabolite) MF: *C3-H7-N-O SHPN: UN 2265; N,N-Dimethyl formamide IMO 3.3; N,N-Dimethylformamide STCC: 49 131 57; Dimethylformamide (combustible liquid, nos) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Reaction of methyl formate and dimethylamine [R1] *From dimethyl amine and formic acid: Mitchell, Reid, J Am Chem Soc 53, 1879, 1931; Brown, J Appl Chem (London) 1, suppl issue no 2, S159 (1951) ... from dimethylamine and hydrogen cyanide: Benneville et al, J Org Chem 21, 772 (1956) ... from HCN and methanol: Fukuoka, Kominami, Chem Tech 1972 (Nov), 640. [R2] *Manufactured by the reaction of CO and dimethylamine. The reaction is carried out in the liquid phase using a sodium methoxide catalyst at 110-120 deg C and 350 kPa (3.5 atm). [R3, 969] IMP: *Water (0.05%), dimethylamine (15 ppm), formic acid (20 ppm), iron (0.05 ppm) [R3, 972] MFS: *Air Products and Chemicals, Inc., 7201 Hamilton Blvd., Allentown, PA 18195-1501, (610) 481-4911, Chemicals Group, Industrial Chemicals Division; Production site: Pace, FL 32571 [R4] *DuPont, 1007 Market Street, Wilmington, DE 19898, (800) 441-7515, DuPont Specialty Chemicals; Production site: Belle, WV 25015 [R4] OMIN: *TESTED AS A PARENTERAL DRUG VEHICLE [R5] USE: *For N,N-Dimethylformamide (USEPA/OPP Pesticide Code: 366200) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R6] *Solvent for liquids, gases, for orlon and similar polyacrylic fibers; in synth of org cmpd; /used/ wherever a solvent with a slow rate of evaporation is needed. [R2] *Pharmaceutical processing and acrylic fiber production; reaction and crystallizing solvent; solvent for depositing polyurethane coatings on leather and artificial leather fabrics; separation of aliphatic hydrocarbons; recovery of CO2 in flue gases; quencher and cleaner of hot-dip tinned parts; used in high voltage capacitors; industrial paint stripping applications; solvent, reagent, and catalyst in organic chemistry. [R3, 973] *Carrier for gases; solvent [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R7] *(1975) GREATER THAN 4.54X10+5 G (EST) [R7] *(1991) 25,000 tons [R3, 971] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to very slightly yellow liquid [R2]; *Water-white liquid [R1] ODOR: *Fishy odor [R8]; *Faint, amine-like odor. [R9] BP: *153 deg C @ 760 mm Hg [R2] MP: *-61 deg C [R2] MW: *73.09 [R2] CORR: *Pure dimethylformamide is essentially noncorrosive to metals. However, copper, tin and their alloys should be avoided. [R3, 972] CTP: *Critical temperature: 374 deg C; critical pressure: 4.48 MPa [R3, 968] DEN: *0.9445 @ 25 deg C/4 deg C [R2] DSC: *pKa = -0.01 @ 20 deg C [R10] HTC: *1921 kJ/mole @ 25 deg C [R3, 968] HTV: *47.6 kJ/mole @ 25 deg C [R3, 968] OWPC: *log Kow = -1.01 [R11] PH: *pH = 6.7 (0.5 molar soln in water) [R2] SOL: *Miscible with water and most common organic solvents [R2]; *Soluble in alcohol, ether, acetone [R12]; *Soluble in benzene and chloroform [R13] SPEC: *MAX ABSORPTION (GAS): 162 NM (LOG E= 3.84); 197.4 NM (LOG E= 3.94) [R14]; *Index of refraction: 1.42083 @ 25 deg C/D [R2]; *IR: 156 (Sadtler Research Laboratories Prism Collection) [R15]; *NMR: 39 (Varian Associates NMR Spectra Catalogue) [R15]; *MASS: NIST 62666 (NIST/EPA/MCDC Mass Spectral Database 1990 version) [R15]; *NMR: JJ 34 (Johnson and Janlowski, Carbon-13 NMR Spectra, John Wiley and Sons, NY, NY) [R15] SURF: *36.42 dyne/cm @ 25 deg C [R3, 968] VAPD: *2.51 (Air= 1) [R8] VAP: *3.87 mm Hg @ 25 deg C [R16] VISC: *0.802 cP @ 25 deg C [R3, 968] OCPP: *N,N-Dimethylformamide is a dipolar aprotic solvent. [R3, 968] *Saturated concentration in air: 12 g/cu m @ 20 deg C [R8] *Hygroscopic liquid that forms azeotropes with ortho, meta and para-xylenes, formic acid and tetrachloroethylene. [R17, p. 11(80) 263] *Gases such as acetylene, butadiene, isoprene, sulfur dioxide and hydrochloric acid are soluble in DMF; ammonia, carbon monoxide and dioxide, oxygen and hydrogen are only sparingly soluble. [R17, p. 11(80) 263] *Dipole moment: 12.7X10-30 [R3, 968] *Henry's Law constant = 7.39X10-8 atm-cu m/mole @ 25 deg C [R18] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R19] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R19] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R19] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R19] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R19] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R19] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R19] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R19] FPOT: *Combustible [R20, 414] *Flammable liquid when exposed to heat or flame. [R21, 1327] NFPA: *Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R22] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R22] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R22] FLMT: *Lower flammable limit: 2.2% by volume at 212 deg F (100 deg C); Upper flammable limit: 15.2% by volume [R22] FLPT: *58 deg C (Closed cup) [R23, 3464] *136 DEG F (58 DEG C) (OPEN CUP) [R22] AUTO: *445 DEG C (833 DEG F) [R22] TOXC: *When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [R21, 1327] *In a fire involving DMF, or at temperatures > 350 deg C, the toxic gases and vapors consist primarily of dimethylamine and carbon monoxide. [R24] EXPL: *2.2% BY VOL LOWER; 15.2% UPPER BY VOL AT 100 DEG C [R21, 1326] *HAZARD WHEN EXPOSED TO HEAT OR FLAME. [R21, 1327] REAC: *CAN REACT VIGOROUSLY WITH OXIDIZING AGENTS, HALOGENATED HYDROCARBONS, AND INORG NITRATES. [R25] *Incompatible with carbon tetrachloride; alkyl aluminums. [R26] *Hot solutions of sodium tetrahydroborate (15.7% wt) in DMF will undergo a violent runaway thermal decomposition, the solid residue attaining a temperature of 310 deg C. The induction period depends on temperature and is 45 hr at 62 deg C and 45 min at 90 deg C. [R27, 64] *... DMF /reacts violently when/ ... exposed to nitrates, chromic acid ... [R17, p. 11(80) 264] *WHEN MIXED WITH AIR IN CERTAIN PROPORTIONS, VAPOR ... IS FLAMMABLE. [R28, 116] *Dimethylformamide contact with diisocyanatomethane causes violent polymerization of the isocyanate. [R27, 341] *Cyanuric chloride reacts vigorously and exothermically with DMF after a deceptively long induction period. The 1:1 adduct initially formed decomposes above 60 deg C with evolution of carbon dioxide and formation of a dimeric unsaturated quaternary ammonium salt. [R27, 332] *To effect reduction to the parent heterocycle, a solution of 2,5-bis-endo-dichloro-7-thiabicyclo(2.2.1)heptane in DMF was being added to a hot solution of sodium tetrahydroborate in the same solvent, when a violent explosion occurred. This may have arisen either from interaction of the dichloro cmpd with the solvent or from the known instability of hot solutions of the tetrahydroborate in DMF. [R29] *A mixture of triethylaluminium and DMF explodes when heated. [R27, 663] *A mixture of sodium hydride and dimethylformamide was heated to, and held at 50 deg C. An exothermic reaction, which increased the temperature to 75 deg C, could not be controlled by external cooling and the pilot-scale reactor contents erupted. It was later found that an exotherm began to develop at 26 deg C ... and the subsequent reaction accelerated rapidly. Avoidance of holding mixtures hot is recommended, particularly when scaling up reactions. [R27, 1181] *Lithium azide and DMF are stable at 25 deg C during preparation of tert-alkyl azides, above 200 deg C the mixtures are shock-sensitive and highly explosive. [R27, 1319] *A vigorous reaction occurs on heating DMF with sodium metal. [R27, 1372] *There is a potentially dangerous reaction of carbon tetrachloride with dimethylformamide in presence of iron. The same occurs with 1,2,3,4,5,6-hexachlorocyclohexane. [R27, 122] *Bromine and dimethylformamide interaction is extremely exothermic and under confinement in an autoclave the internal temperature and pressure exceeded 100 deg C and 135 bar, causing failure of the bursting disc. [R27, 99] *After a thermal runaway reaction during chlorination in DMF solution, investigation revealed that saturated solutions of chlorine in DMF are hazardous, and will self-heat and erupt under either adiabatic or non-adiabatic conditions. [R27, 99] *During oxidation of a sec-alcohol to ketone in cold DMF solution, addition of solid chromium trioxide caused ignition. Addition of lumps of trioxide was later found to cause local ignition on addition to ice-cooled DMF under nitrogen. Addition of 2 g chromium trioxide to 18 ml of solvent to form a 10% wt solution caused immediate ignition and ejection of the flask contents. [R27, 1070] *Addition of potassium permanganate to DMF to give a 20% (approx saturated) solution led to an explosion after 5 min. Subsequent tests on 1 g of oxidant with 5 g of solvent showed a rapid exotherm after 3-4 min, accompanied by popping noises from undissolved oxidant. [R27, 1296] *Magnesium nitrate has been reported to undergo spontaneous decomposition in DMF (possibly as a result of hydrolysis of the hexahydrate above its melting point of 90 deg C to liberate nitric acid). [R27, 1326] *Carbon tetrachloride; other halogenated compounds when in contact with iron; strong oxidizers; alkyl aluminums; inorganic nitrates. [R9] *Explosive reaction with bromine, potassium permanganate; triethylaluminum + heat. Forms explosive mixtures with lithium azide (shock sensitive above 200 deg C); uranium perchlorate. [R21, 1327] *Explosive reaction with bromine, potassium permanganate; triethylaluminum + heat. Forms explosive mixtures with lithium azide (shock sensitive above 200 deg C); uranium perchlorate. [R21, 1327] *Contact with carbon tetrachloride and other halogenated hydrocarbons, particularly when in contact with iron, as well as contact with strong oxidizing agents (e.g., methylene diisocyanate, halogens, and permanganates) may cause fires and explosions. [R24] *Ignition on contact with chromium trioxide. [R21, 1327] DCMP: *When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [R21, 1327] *Temperatures > 350 deg C may cause decomposition to form dimethylamine and carbon dioxide, with pressure developing in closed containers. [R24] ODRT: *300 mg/cu m (odor low) 300 mg/cu m (odor high) [R30] SERI: *Strong irritant to skin ... . [R20, 4144] *Some complaints of eye irritation have resulted from vapor exposure in industry. [R31] *DMF was reported to be irritating to the eyes, mucous membranes, and the skin. [R32] EQUP: *CONTACT OF LIQ WITH SKIN IS AVOIDED BY WEARING POLYETHYLENE GLOVES (POLYETHYLENE AND CERTAIN SYNTHETIC RUBBERS, EG, BUTADIENE-STYRENE ... ARE AMONG FEW POLYMERS WHICH ARE INSOL IN DIMETHYLFORMAMIDE). [R28, 116] *USE OF IMPERMEABLE GLOVES WITH LONG SLEEVES APPEARS TO BE BEST METHOD OF PREVENTING SKIN ABSORPTION OF DMF. SILICONE OR GLYCEROL BARRIER CREAMS ARE LESS EFFECTIVE. [R33] *Breakthrough times greater than one hour reported by (normally) two or more testers for Butyl Rubber (Butyl). Breakthrough times less (usually significantly) two or more testers for Natural rubber (Nat.Rub) Neoprene (neop.), Nitrile rubber (nitrile) and polyvinyl alcohol (PVA). No data for chloride (nitrile/PVC), polyethylene (PE); polyurethane (PU), polyvinyl chloride (PVC) and Viton. [R34] *Wear appropriate personal protective clothing to prevent skin contact. [R9] *Wear appropriate eye protection to prevent eye contact. [R9] *Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R9] *Recommendations for respirator selection. Max concn for use: 250 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R9] *Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R9] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R9] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R9] OPRM: *AVOID CONTACT WITH SKIN AND EYES. USE EFFECTIVE FUME REMOVAL DEVICE. [R25] *Contact lenses should not be worn when working with this chemical. [R9] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R9] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R9] *Workers exposed to DMF should be informed about its adverse health effects and trained to avoid skin contact and to use appropriate protective equipment and work practices. Employees should institute engineering controls to ensure that DMF exposure does not exceed the NIOSH recommended exposure limit/OSHA permissible exposure limit of 10 ppm as an 8 hr time-weighted average. NIOSH/OSHA recommend maximum concns for various respirator uses at 100 ppm and above. Eye exposure should be followed by immediate saline irrigations and an ophthalmology review. Skin exposure is followed by prompt water flushing. Oral ingestion of DMF should be treated supportively in a hospital. Liver function tests should be obtained within 24 hr and followed weekly. [R35, 1677] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SSL: *DMF is stable. It is hygroscopic and easily absorbs water form a humid atmosphere and should therefore be kept under dry nitrogen. High purity DMF, required for acrylic fibers, is best stored in aluminum tanks. DMF dose not change under light or oxygen and does not polymerize spontaneously. Temperatures > 350 deg C may cause decomposition to form dimethylamine and carbon dioxide, with pressure developing in closed containers. [R36] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R37] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R38] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R39] STRG: *Ideal materials for ... storage are nonalloy (carbon) steels, austenitic chromium nickel steels ... and aluminum. Seals ... should be made of polytetrafluoroethylene, polyethylene or polypropylene of high molecular weight. Ethylene-propylene rubber may also be used. Graphite can be used for lubricating moving parts in contact with DMF ... Since dimethylformamide (DMF) is hygroscopic, it should be kept under a blanket of dry nitrogen. High purity DMF, as required for acrylic fibers, is best stored in aluminum tanks. [R17, p. 11(80) 265] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Recovering: Burn in soln in flammable solvent in furnace equipped with alkali scrubber. Recovery and recycle is an alternative to disposal for dimethyl formamide (DMF) from fiber spin baths and from PVC /polyvinyl chloride/ reactor cleaning solvents. Recommendable method: Incineration. [R40] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *Dimethylformamide ... is an organic solvent produced in large quantities through-out the world. It is used in the chemical industry as a solvent, an intermediate and an additive. Dimethylformamide is a colorless liquid with an unpleasant slight odor that ... has poor warning properties and individuals may be exposed through the inhalation of vapor. Occupational exposure occurs via skin contact with dimethylformamide liquid and vapors. ... Toxic amounts of dimethylformamide may be absorbed by inhalation and through the skin. Absorbed dimethylformamide is distributed uniformily. The /metabolism/ of dimethylformamide takes place mainly in the liver, with the aid of microsomal enzyme systems. In animals and humans, the main product of dimethylformamide biotransformation is N-hydroxymethyl-N-methylformamide. This metabolite is converted during gas chromatographic analysis to N-methylformamide, which itself (together with N-hydroxymethylformamide and formamide) a minor metabolite. ... In metabolic studies and biological monitoring, urinary concentration are expressed as N-hydroxymethylformamide. ... The determination of the /metabolites/ ... in the urine may be a suitable biological indicator of total dimethylformamide exposure. In experimental animals, it has been demonstrated that dimethylformamide metabolism is saturated at high levels and, at very high levels, dimethylformamide inhibits its own metabolism. Metabolic interaction occurs between dimethylformamide and ethanol. ... The effects of dimethylformamide on the environment have not been well studied. The toxicity for aquatic organisms appears to be low ... The acute toxicity of dimethylformamide in a variety of species is low ... . It is a slight to moderate skin and eye irritant. One study on guinea pigs indicated no sensitization potential. Dimethylformamide can facilitate the absorption of other chemical substances through the skin. Exposure of experimental animals to dimethylformamide via all routes of exposure may cause dose related liver injury. ... In some studies, signs of toxicity in the myocardium and kidneys have been /noted/. Dimethylformamide was ... found to be inactive, both in vitro and in vivo, in an extensive set of short term tests for genetic and related effects. No adequate long term carcinogenicity studies on experimental animals have been reported. ... Skin irritation and conjunctivitis have been reported after direct contact with dimethylformamide in /humans/. After accidental exposure to high levels of /this cmpd/, abdominal pain, nausea, vomiting, dizziness and fatigue occur within 48 hr. Liver function may be disturbed, and blood pressure changes, tachycardia and ECG abnormalities have been reported. ... Following long-term repeated exposure, symptoms include headache, loss of appetite and fatigue. Biochemical signs of liver dysfunction may be observed. Exposure to dimethylformamide, even at concn below 30 mg/cu m may cause alcohol intolerance. Symptoms may include a sudden facial flush, tightness of the chest, and dizziness sometimes accompanied by nausea and dypsnea. ... There is limited evidence that dimethylformamide is carcinogenic for human beings. An incr in testicular tumors was reported in one study, whereas another study showed incr incidence of tumors of the buccal cavity and pharynx, but not the testes. In two studies with limited details, an incr frequency of miscarriages was reported in women exposed to dimethylformamide among other chemicals. [R41] CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of dimethylformamide. There is evidence suggesting the lack of carcinogenicity of dimethylformamide in experimental animals. Overall evaluation: Dimethylformamide is not classifiable as to its carcinogenicity in humans (Group 3). [R42] *A4. A4= Not classifiable as a human carcinogen. [R43] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10-15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R44] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R44] *There are no antidotes to DMF overexposure. [R35, 1677] MEDS: *Preplacement and periodic exams should be concerned particularly with liver and kidney function and with possible effects on the skin. [R26] *The determination of a dimethylformamide metabolite, methylformamide, in the urine of exposed workers has been recommended as a guide to monitoring worker exposure. The fluctuation in the rate of excretion of this metabolite requires that methylformamide determinations be carried out on 24 hr urine specimens. The 24 hr urinary excretion of 50 mg or less of methylformamide is consistent with occupational exposure to 20 ppm of dimethylformamide vapor. [R45, 129] *Concn of N-methylformamide in the urine collected at the end of a work shift that do not exceed 40-50 mg/g of creatinine suggests an exposure that is possibly safe with regard to the acute and possibly also with regard to the long-term (5 yr) effects of DMF on liver function. The long-term data must be corroborated by prospective studies with consecutive measurements of DMF air and urine concns and of its metabolites, together with periodic liver function studies. However, if skin absorption can be ruled out, this concn on N-methylformamide in the postshift sample corresponds to an average concn of DMF vapor of 14 mg/cu m (45 ppm) during a 6-hr period, higher than the NIOSH/OSHA permissible limits of 10 ppm. [R35, 1675] *The assessment of dimethylformamide exposure can be accomplished through measurement of the metabolites, N-methylformamide or N-acetyl-S-(N-methylcarbamoyl) cysteine. Studies have found that there is a linear relationship between dimethylformamide in air and N-methylformamide levels in urine, with the highest correlation from samples collected the end of the shift, for assessing exposure from that day. The determination of N-methylformamide in the urine actually represents the sum of N-(hydroxymethyl)-N-methylformamide and N-methylformamide. Measurement of N-acetyl-S-(N-methylcarbamoyl) cysteine is found to be an index for assessing exposure during several preceding days since its peak in the urine occurs between 16-40 hr post-exposure, but is not as useful for assessing exposure for a particular day only. Urine Reference Ranges: Normal-None detected; Exposed- BEI (sampling time is end of shift, measured as the metabolite, N-methylformamide): 40 mg/g creatinine (Notice of Intent to Establish or Change: BEI (sampling time is end of shift, measured as the metabolite, N-methylformamide) 15 mg/g creatinine, (Notice of Intent to Establish: BEI (sampling time is prior to last shift of workweek, measured as the metabolite, N-acetyl-S-(N-methylcarbamoyl cysteine) 40 mg/l), BAT (sampling time is end of exposure or end of shift, measured as the metabolite, N-methylformamide): 15 mg/l; Toxic- Not established. [R46, 552] *Urine Albumin: Albuminuria has been shown to be a specific marker of glomerular dysfunction. Tubular damage, however, can also result in increased levels of albumin in the urine. [R46, 553] *Urinary Beta-2-Microglobulin and/or Retinal Binding Protein: Measurements for the presence of either of these low molecular weight proteins are useful in detection of early impairment of proximal tubular function. However, beta-2-microglobulin is unstable at urinary pH < 6, and may degrade in the bladder prior to collection and subsequent neutralization of the urine sample. Measurement of retinal binding protein appears to be a better marker for early tubular dysfunction due to its stability in the urine subsequent to collection and analysis. However, retinal binding protein is produced in the liver and not a constitutive protein of the kidney, so that its presence in the kidney provides only indirect evidence of tubular damage. [R46, 553] *Urinary Alpha and Pi Isoenzymes of Glutathione S-Transferase: Radio-immunological and Elisa techniques have been developed for quantitation of /alpha/ and /pi/ isoenzymes of glutathione S-transferase, which are constitutive proteins in the kidney. The /alpha/ isoenzyme is located only in the proximal tubule, while the /pi/ isoenzyme is located in the distal convoluted tubule, the loop of Henle, and the collecting ducts of the kidney. Damage to epithelial cell membranes can result in the increased excretion of these isoenzymes in the urine. This test for assessing renal tubular damage appears to have many advantages over other available tests, such as: (1) the /alpha/ and /pi/ isoenzymes are constitutive proteins in the kidney; (2) these isoenzymes are stable in the urine; (3) the test is simple and reproducible; and (4) due to selective localization of the isoenzymes, differential diagnosis of specific tubular damage is possible. In addition, increased levels of these isoenzymes were seen in patients previously exposed to nephrotoxicants where conventional tests for kidney function were normal, indicating a high degree of sensitivity. [R46, 553] *Urinary Enzyme N-Acetylglucosaminidase: This lysosomal enzyme has shown promise in assessment of subclinical nephrotoxic injury. This enzyme is not normally filtered at the glomerulus due to its high molecular weight. In the absence of glomerular injury, this enzyme will be detected in the urine as a result of leakage or exocytosis from damaged, stimulated, or exfoliated renal cells. The sensitivity of measurement for this enzyme has not been thoroughly studied, but it's usefulness has shown some promise. However, this enzyme is unstable at urinary pH > 8, which could diminish the sensitivity of the measurement due to enzyme degradation. [R46, 554] *Routine Urinalysis: Performing a routine urinalysis including parameters such as specific gravity, glucose, and microscopic examination may be useful for assessing renal toxicity. Cylinduria, or formation of various types of casts from material in the renal tubules, is detected only by microscopic analysis, but is often preceded by albuminuria or increases in white cells, red cells, or epithelial cells in the urine. Workers with potential exposure to nephrotoxins should have baseline, pre-exposure measurements of the parameters that will be selected for assessing early renal damage. Periodic measurement should be compared to the baseline results. The normal progression of chronic renal insufficiency usually takes several years to evolve, however glomerulonephritis can occur as early as several months. [R46, 554] *Liver Function Tests: Biochemical tests - Enzymes that reflect cholestasis: alkaline phosphatase (AP), 5'-nucleotidase (5'-NT) and leucine aminopeptidase (LAP); Enzymes that detect direct hepatic damage: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gammma glutamyl Transpeptidase (GGTP); Clearance tests - indocyanine green, antipyrine test and serum bile acids. [R46, 554] HTOX: *... /FROM 9 INVESTIGATIONS IN POLYACRYLONITRILE FACTORY/ SOME PATIENTS COMPLAINED OF NERVOUSNESS AND DIFFICULTY IN SLEEPING. OTHERS COMPLAINED OF FACIAL CONGESTION. [R28, 115] *... FOLLOWING EXPOSURES ... SYMPTOMS SUCH AS STOMACH PAIN, NAUSEA, VOMITING AND EPIGASTRIC CRAMPS HAVE BEEN REPORTED. BECAUSE OF ABILITY OF DMF TO READILY PENETRATE INTACT SKIN, IT HAS BEEN DIFFICULT TO RELATE EXPOSURES WITHOUT SKIN CONTACT TO CONCN OF DMF IN AIR IN THESE CASES OF ILLNESS. [R47] *Testicular cancer is the most common malignancy among white men aged 15-44. Age-adjusted mortality in the United States has not varied in the past 40 years but the incidence in white males has almost doubled. Three men working as swabbers on the spray lines in the leather finishing process, after latency periods of 8, 13, and 14 years, developed testicular cancers with common histological features. Dimethylformamide (DMF) may have been responsible. [R48] *N,N-DIMETHYLFORMAMIDE IS CONSIDERED TO BE MODERATELY HAZARDOUS BY INHALATION ... AND IS A DEFINITE HAZARD BY SKIN ABSORPTION. [R49] *Points of attack: Liver, kidneys, skin, cardiovascular system. [R26] *Dimethylformamide hepatotoxicity is believed to be dose-dependent. Hepatic necrosis and steatosis have been observed on liver biopsy specimens from exposed workers. ... Elevation of serum aminotransferase concns (aspartate-AST and alanine-ALT) have been observed following occupational exposure to DMF. A finding of the ratio of AST to ALT levels < 1 may be useful in differentiating toxic from alcoholic hepatitis. Resolution of the abnormal liver enzymes may take up to 1 to 7 months. Elevation of liver enzyme levels has been found in 76% of production workers exposed routinely to DMF without accidental overexposure or unusual circumstances. [R35, 1675] *Several studies of workers exposed to DMF indicate a possible role for this chemical in the development of testicular concerns. Animal studies have not demonstrated the DMF is mutagenic or carcinogenic. A DMF manufacturers' study of potentially exposed employees found no excess of testicular cancer, but did find significant excesses of buccal and pharyngeal cancer and malignant melanoma. [R35, 1675] *A number of non-specific symptoms caused by DMF have been reported over the last 30 yr in workers more or less frequently exposed to DMF, among them stomach pain, headache, loss of appetite, nausea, vomiting and general weakness. Other symptoms observed occasionally in humans exposed to DMF are psychotic excitation, hypertension, leukocytosis, dyspepsia and diarrhea. [R50, 156] *In a study of 102 workers, 19 had experienced manifestation of alcohol intolerance, among them facial flushing, sweating, dizziness, and palpitation, mainly within 24 hr of exposure /to DMF/. Of the 34 episodes recorded, 26 occurred after the workers had consumed alcoholic drinks. [R50, 156] *In a questionnaire study... 14% miscarriages in a group of women exposed to about 100 mg DMF/cu m /were reported/, compared with 10% in the control group. ... Perturbations in menstruation in 26 out of 70 women who had been exposed to 30-150 mg DMF/cu m for about a year /were reported/. ... On the basis of company statistics, general morbidity associated with gynecological changes appeared to be increased among DMF-exposed women. [R51] *Several cases of acute accidental occupational poisoning with DMF have been reported. ... They were caused by the malfunctioning of the equipment, splashing of the organic solvent over the body, or working in plants without taking protective measures. Over-exposure has occurred via the skin and/or inhalation. Usually, the symptoms appeared from several hours up to several days after the accident. The major symptoms were epigastric or abdominal pain, which was irradiating and progressive, accompanied by dizziness, nausea, anorexia, vomiting, fatigue, alcohol intolerance, and skin irritation. Clinical laboratory tests showed liver function disturbance. Radioisotope diagnostic tests liver biopsy revealed morphological changes in the liver. No clinical manifestations of renal dysfunction were reported. The patients recovered with symptomatic therapy in hospital for 2-3 wk. Liver function tests returned to normal. Some of the patients, who were followed for several months or several years after the acute poisoning, had normal function tests. [R52] *An outbreak of liver disease in a fabric coating factory was investigated. Dimethylformamide was used as a solvent for fabric coating in poorly ventilated areas without appropriate skin protection. Overall, 36 of 58 workers had elevations of either aspartate aminotransferase or alanine aminotransferase serum activity. Among 46 workers, the following symptoms were reported: anorexia, abdominal pain or nausea by 31 workers; headaches and dizziness by 18 workers; alcohol intolerance (facial flushing and palpitations) by 11 workers. Liver biopsies of workers exposed to several organic solvents, predominantly to dimethylfomamide, showed focal hepatocellular necrosis and micro reticulum, complex lysosomes vesicular steatosis with prominence of smooth endoplasmi and pleomorphic mitochondria with crystalline inclusions. Among workers with longer exposure, no signs of liver fibrosis were found. [R53] *In 183 out of 204 employees in a synthetic leather factory, found a significant correlation between high exposure concns of dimethylformamide (25-60 ppm) and elevated serum alanine aminotransferase and creatine phosphokinase levels. Furthermore, high dimethy1formamide exposure concns were correlated with symptoms such as dizziness, anorexia, nausea and epigastric pain. [R53] *Strong irritant to skin ... . [R20, 4144] *Some complaints of eye irritation have resulted from vapor exposure in industry. [R31] *DMF was reported to be irritating to the eyes, mucous membranes, and the skin. [R32] NTOX: *... DOGS /EXPOSED TO CONCENTRATIONS > 20 PPM/ EXHIBITED POLYCYTHEMIA AND CARDIOVASCULAR EFFECTS: DECREASED PULSE RATE, DECLINE IN SYSTOLIC PRESSURE, AND DEGENERATIVE CHANGES IN HEART MUSCLE. [R5] *... RATS EXPOSED TO 91 PPM DIMETHYLFORMAMIDE (DMF) 6 HR/DAY FOR 10 DAYS SHOWED SLIGHTLY ENLARGED LIVERS. ... A NUMBER OF ANIMALS /WERE EXPOSED/ 5.5 HR/DAY TO 23 PPM, FOLLOWED BY 1/2 HOUR TO 426 PPM. AFTER 58 SUCH EXPOSURES TOXIC EFFECTS, PARTICULARLY ON LIVER, WERE NOTED. [R47] *... REPEATED EXPOSURES TO 100 PPM WERE INJURIOUS TO CATS ... LIVER DAMAGE WAS THE MOST PROMINENT FEATURE OF INTOXICATION. [R47] *THERE IS EXPERIMENTAL EVIDENCE OF LIVER AND KIDNEY DAMAGE IN RABBITS AND CATS AND TO A LESSER EXTENT IN RATS WHEN THE CMPD IS GIVEN BY INJECTION OR INHALATION (RATS TOLERATED 420 PPM DAILY FOR LONG PERIODS, WHILE CATS WERE AFFECTED BY 100 PPM). [R49] *IN MICE EXPOSED TO 1120 MG/KG (1.2 ML/KG) IP, HIND LEG PARALYSIS AND DEPRESSION WERE PRECEDED BY NERVOUSNESS. [R5] *TESTED BY DROP APPLICATION TO RABBIT EYES, A 25% SOLN IN WATER HAD NO EFFECT; 50% SOLN WAS SLIGHTLY IRRITATING; 75-100% PRODUCED A MORE SEVERE REACTION, BUT NO DETAILS OF REACTION WERE REPORTED. A DROP OF PURE DIMETHYLFORMAMIDE APPLIED TO RABBIT EYES ... CAUSED ONLY EDEMA OF CORNEAL EPITHELIUM AND EYES RETURNED TO NORMAL ... . [R54] *ELEVATION OF BLOOD SUGAR OCCURRED IN RATS AFTER ORAL AND IP ADMIN OF DIMETHYLFORMAMIDE. MINIMUM EFFECTIVE DOSES WERE 0.5 ML/KG IP AND 2 ML/KG ORALLY. [R55] *DMF AND DIMETHYL SULFOXIDE INHIBITED MOUSE LIVER ALCOHOL DEHYDROGENASE IN VITRO. INHIBITION IS UNCOMPETITIVE WITH DMF AND DIMETHYL SULFOXIDE. EACH CHEM PROLONGED SIGNIFICANTLY THE ETHANOL-INDUCED LOSS OF RIGHTING REFLEX. [R56] *HUMAN COLON CARCINOMA CELLS TREATED IN VITRO WITH DMF COMPLETELY LOST CLONOGENICITY, WHEREAS UNTREATED CELLS HAD CLONING EFFICIENCIES OF APPROX 77%. AFTER REMOVAL OF DMF FROM CULTURE MEDIUM, ORIGINAL CELL CULTURE CHARACTERISTICS REAPPEARED. [R57] *HISTOCHEMICAL REACTIONS IN WHITE RAT LIVER, KIDNEY AND LUNG IN THE COURSE OF ACUTE DIMETHYLFORMAMIDE TOXICITY ARE DESCRIBED. [R58] *LESIONS WERE INDUCED IN RATS EXPOSED TO INHALATION OF DIMETHYL FORMAMIDE (DMF). THE MOST SERIOUS CHANGES APPEARED TO OCCUR IN THE LIVER. HEPATOCYTES SHOWED MITOTIC TYPE PATTERNS AND ACCUMULATIONS OF LIVER CELLS IN THE REGENERATIVE PHASE. DIFFUSE SINUSOIDAL CONGESTION AND LYMPHOCYTE ACCUMULATIONS WERE OBSERVED. THE KIDNEYS SHOWED SOME CONGESTION, EDEMA AND SPORADIC HEMORRHAGIC FOCI. THERE WERE BLOOD EFFUSIONS IN THE LUNGS AND FOCI OF EDEMA WITH CONGESTION AND SEPTAL THICKENING. CHANGES IN THE MYOCARDIUM ARE ALSO DESCRIBED. DMF HAS PRONOUNCED VASCULOTROPIC PROPERTIES, CAUSING SEVERE VASCULAR CHANGES, WITH MORPHOLOGIC DISRUPTION OF VESSEL WALLS. [R59] *ALBINO RATS WERE GIVEN SINGLE IP INJECTIONS OF 0.6, 0.9 and 1.2 ML/KG DIMETHYL FORMAMIDE (DMF). AT 0.6 ML/KG SOME HISTOLOGICAL LESIONS OF LIVER OCCURRED (MAX AT 48 HR). AT 0.9 and 1.2 ML/KG SEVERE CENTRAL PHLEBITIS WITH CENTRILOBULAR NECROSIS OF CELLS ASSOC WITH HEAVY INFLAMMATORY INFILTRATE OCCURRED. [R60] *DMF IN AQUEOUS SOLN ADMIN BY STOMACH TUBE TO RABBITS FROM 6TH-18TH DAY PAST INSEMINATION SHOWED EMBRYOTOXIC AND WEAKLY TERATOGENIC EFFECTS AT CONCN NOT TOXIC TO MOTHER. RABBIT WAS MORE SENSITIVE TO DMF THAN OTHER SPECIES, WITH FETAL ANOMALIES INDUCED AT DOSES MATERNALLY ACCEPTABLE. [R61] *RATS WERE EXPOSED TO A FOG OF DIMETHYLFORMAMIDE (DMF) FOR 0.5 HR/DAY FOR DAYS AND SACRIFICED. EDEMA IN MYOCARDIAL SECTIONS WAS SEEN. THE MOST SALIENT FINDING SHOWED VACUOLAR FORMATIONS, FREQUENTLY DISPLACED AT INTIMAL LEVEL IN WALLS OF INTRAPARENCHYMAL ARTERIAL VESSELS. [R62] *N,N-Dimethylformamide was tested for mutagenicity in the Salmonella/ microsome preincubation assay using the standard protocol approved by the National Toxicology Program. N,N-Dimethylformamide was tested using a wide range of doses in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, AND TA100) in the presence and absence of rat or hamster liver S-9. N,N-dimethylformamide was negative in these tests and the highest ineffective dose in any Samonella tuphimurium strain was 10 mg/plate. [R63] *ACUTE TOXICITY OF FORMAMIDES TO RATS AND MICE WAS IN INCR ORDER; FORMAMIDE, N-METHYLFORMAMIDE, N,N-DIMETHYLFORMAMIDE, N-ETHYLFORMAMIDE, AND N,N-DIETHYLFORMAMIDE. MICE WERE MORE SUSCEPTIBLE THAN RATS. THE COMPOUNDS INDUCED TESTICULAR LESIONS. REPEATED SMALL DOSES OF DMF STIMULATED GROWTH, WHEREAS THE OTHER DERIVATIVES WERE GROWTH INHIBITORY. [R64] *DMF was applied as a liquid to the skin of pregnant rabbits during the period of fetal organogenesis. Slight teratogenic effects were demonstrated with DMF. The skin approx lethal dose for DMF was lower for pregnant rabbits than for pregnant rats. [R65] *DMF fed to rats for 100 days at 215, 750, or 2500 ppm and to mice at 160, 540, and 1850 ppm resulted in liver weight increases without any histopathological change. Body weight gains reduced only at the highest feeding level in both species. Rats fed 200, 1000, or 5000 ppm for 90 days also showed enlarged livers and weight gain reductions only in the 5000 ppm group. Hepatic steatosis, readily reversible, was reported in rats fed 300 ppm, but not 30 ppm for 90 days. Liver damage was seen in rats given 5000 ppm, but not 1000 ppm, in drinking water for 6 months. [R23, 3466] *Liver changes (necrosis in rats, fatty degeneration in cats) were produced by inhalation of 430 ppm DMF 8 hr/day, 6 days/week for 120 days. This effect was not seen at either 10 or 230 ppm. Liver weights were increased in mice, rats, guinea pigs, rabbits, and dogs exposed for 58 doses, 5 1/2 hr/day to 23 ppm 1/2 hr to 426 ppm ... . Liver changes were seen in mice at all exposures and mortality exposure occurred at 600 ppm and higher. [R23, 3466] *Groups of 5 male and 3 female monkeys were exposed to 30, 100, or 500 ppm DMF 6 hr/day, 5 days/wk for 13 wk. Particular attention was paid to the liver and reproductive tract tissues. No changes were produced by exposure up to 500 ppm. [R23, 3466] *When DMF was given to rats with the drinking water for 2 or 7 wk, hepatic glutathione levels and the activities of the enzymes ethoxycoumarin O-deethylase and UDP-glucuronosyltransferase were significantly increased. [R50, 153] *Swiss mice which received ip doses of DMF at 769 mg/kg or more daily for 21 days displayed irritable and hyperactive behavior for 50 days after the end of treatment. Histological exam at the end of treatment showed hepatic centrilobular necrosis with areas of regeration. Similarly, ip injection of DMF in rats led to liver necrosis, generally centrilobular in nature. [R50, 154] *The acute toxicity in a number of species, following oral, dermal, inhalation, or parenteral admin of DMF is relatively low, with lethal doses generally in the g/kg range for the oral, dermal, and parenteral routes and in the g/cu m for inhalation exposures. Animals given large single doses of DMF or exposed to high air levels showed general depression, anesthesia, loss of appetite, loss of body weight, tremors, labored breathing, convulsions, hemorrhage of the nose and mouth, liver injury, and coma immediately preceding death. [R32] *Rat tails dipped in DMF at 40 deg C for 8 hr became mummified in a few days. [R32] *The effects of DMF on the liver were studied after single or repeated inhalation, dermal, or oral treatment of rats, mice, and rabbits ... . Single oral admin of 2250-5000 mg DMF/kg in rats caused clay-colored liver, congestion and centrilobular necrosis of hepatocytes. Lower doses resulted in deviations in liver function, such as decreased excretion of cholic acid in the bile, bromosulfthalein retention, increased serum activities of GOT, GPT, LAP, OCT, AlcP, ChE, LDH, and gamma-GT, and significant enhancement of cholesterol, triglyceride, and bilirubin contents in the serum and liver homogenates. In rats, following both ip and inhalation exposure, there were no increases in SDH /succinate dehydrogenase/ levels at 420 and 840 mg/cu m but a lower level (210 mg/cu m) raised the serum activity of SDH. Pathomorphological investigation demonstrated lipid degeneration and cloudy swelling of hepatocytes in the central zones of the lobules followed by signs of regeneration. [R66] *Swelling of the kidney tubules occurred after a single oral admin of 2250-5000 mg DMF/kg in rats. [R67] *A number of pathomorphological studies revealed vacuolar degeneration, mainly in the renal tubules ... . Histological, histochemical, and electronmicroscopic renal lesions in groups of rats, exposed to DMF aerosols for 1 hr/day for 15 days or for 0.5 hr/day for 30 days, /were observed/. Degeneration took place in the proximal part of tubules and in the visceral epithelium of the glomerulus with marked mitochondrial changes. [R68] *Repeated inhalation exposure to 130 or 300 mg DMF/cu m increased the kidney/body weight ratio, and decreased diuresis, and the total protein, sodium chloride, and potassium contents in the urine of rats. [R68] *Pathomorphological changes were observed in the spleen after exposure to high doses of DMF. They were accompanied by an incr in the spleen/body weight ratio. ... Inhibited phagocytosis activity of leukocytes and decreased glycogen content in the neutrophiles of rats as a result of combined dermal and inhalation exposure to DMF /was found/. [R69] *After an ip injection of 600 or 1100 mg DMF/kg/day, form day 1-14 after conception, embryotoxic and teratogenic effects were registered. The malformation rates were 18 and 75% respectively, and the effects consisted of absence or retardation of posterior skull ossification, open eye-lids, cerebral edema, sternal hematomas, and spina bifida-like defects in the thoracic region. Embryotoxic effects recorded were late resorptions. Doses of 170 mg/kg/day form day 1-14 after conception, and 250 mg/kg/day from day 6-14, and single doses of 2100 mg/kg each on days 3, 7, 9, or 11 after conception, did not produce any effects. [R70] *DMF caused maternal toxicity and embryotoxicity, including teratogenicity, in rabbits after admin by gavage at 200 ul/kg/day from day 6-18 after conception. All 11 animals in the dose group became pregnant and showed reduced food intake and weight gain. Placental weights were significantly lower and 3 abortions occurred. The fetuses showed weight reduction. The main findings recorded on fetal exam were hernia umbilicalis (7 cases), hydrocephalus internus (6 cases), eventratio simplex (3 cases), exophthalmus (2 cases), cleft palate (1 case), and malposition of limbs (1 case). The number of implantations was not adversely influences. At 68.1 ul/kg/day, no maternal effects were observed among 16 pregnant animals (18 inseminated); decreased numbers of total implantations and of live fetuses occurred, also an incr in skeletal variations and retardations/ litter; 3 cases of hydrocephalus internus were present. At 46.4 ul/kg/day (10/12 does were pregnant) 1 case of hydrocephalus internus occurred; all other parameters were in the range of biological variability. No malformations occurred in the untreated control group (22/24 animals). [R71] *Groups of 78 male and 78 female Crl: CD-1 (ICR) BR mice, 55 days old, were administered dimethylfomamide (purity, 99.9%) at 0, 25, 100 or 400 ppm (0, 75, 300 or 1200 mg/cu m) in air by whole body vapor exposure for 6 hr/day on 5 days/wk for 18 months. Five males and five females/group were killed at 2 wk, 3 months, and 12 months. No compound related effect on survival was evident. At termination, the 100- and 400 ppm males and 400 ppm females had higher liver weights. In both sexes, at the two highest exposures, centrilobular hepatocellular hypertrophy and hepatic single cell necrosis were increased. No increased tumor incidence was observed. [R72] *Groups of 87 male and 87 female Crl:CD BR rats, 47 days old were administered dimethylformamide (purity, 99.9%) at 0, 25, 100 or 400 ppm (0, 75, 300 or 1200 mg/cu m) in air by whole body vapor exposure for 6 hr/day on 5 days/wk for 2 yrs. Exposure to the highest concn reduced body weight gain in both sexes but did not affect survival. The highest concn also increased liver weights in both sexes. Ten males and ten females/group were killed at 12 months. In both sexes of the two highest concn groups, incidences of minimal to mild centrilobular hepatocellular hypertrophy and centrilobular accumulation of lipofuscin/hemosiderin were increased. No incr in tumors occurred, but a 14.8% incidence of uterine endometrial stromal polyps in high dose females was observed compared to 1.7% in controls (numerical data not given). However, the range of historical control incidence for the laboratory was 2.0-15.0%. [R72] *In acetone pretreated male CD 1 mice, dimethy1formamide, given as a single ip dose of 1000 mg/kg bw, resulted in liver necrosis and a strong incr in serum alanine aminotransferase activity. In contrast, no signs of hepatotoxicity were found in non pretreated mice given the same dose or in pretreated or nonpretreated male Sprague Dawley rats given up to 2000 mg/kg bw as a single ip dose. These differences are probably related to the highly different substrate affinities of CYP2EI in rats and mice. [R73] HTXV: *Dimethylformamide exposure to air concn of 3500 ppm is considered immediately dangerous to life or health (IDLH). [R35, 1675] NTXV: *LD50 MOUSE IP 1120 MG/KG (1.2 ML/KG); [R5] *LD50 Mouse oral 6.8 ml/kg; [R74] *LD50 Swiss mouse ip 3.07 g/kg daily for 21 days; [R50, 153] *LD50 Tumor bearing BDF1 mouse ip 1.23 g/kg daily for 9 days; [R50, 153] *LD50 Rat oral 3 g/kg; [R50, 153] *LD50 Rat iv 2.5 g/kg; [R50, 153] *LD50 Albino rat sc 7.4 g/kg; [R50, 153] *LD50 Rat oral 2800 mg/kg; [R21, 1327] *LD50 Rat ip 1400 mg/kg; [R21, 1327] *LD50 Rat sc 3800 mg/kg; [R21, 1327] *LD50 Rat iv 2000 mg/kg; [R21, 1327] *LD50 Mouse oral 3750 mg/kg; [R21, 1327] *LC50 Mouse inhalation 9400 mg/cu m/2 hr; [R21, 1327] *LD50 Mouse ip 650 mg/kg; [R21, 1327] *LD50 Mouse sc 4500 mg/kg; [R21, 1327] *LD50 Mouse iv 2500 mg/kg; [R21, 1327] *LD50 Mouse im 3800 mg/kg; [R21, 1327] *LD50 Dog iv 470 mg/kg; [R21, 1327] *LD50 Cat ip 500 mg/kg; [R21, 1327] *LD50 Rabbit skin 4720 mg/kg; [R21, 1327] *LD50 Mouse dermal > 5000 mg/kg /From table/; [R75] *LD50 Rabbit oral > 5000 mg/kg /From table/; [R75] *LD50 Mongolian gerbil oral 3929 mg/kg /From table/; [R75] *LD50 Rabbit ip 945 mg/kg /From table/; [R76] *LD50 Rabbit iv 1000 mg/kg /From table/; [R76] *LD50 Guinea pig ip 1300 mg/kg /From table/; [R76] *LD50 Guinea pig iv 1030 mg/kg /From table/; [R76] ETXV: *LC50 Salmo gairdneri (rainbow trout) 12,000 mg/l/96 hr; weight 0.8 g, 95% confidence limits 10,000-13,000, mg/l), static bioassay; [R77] *LC50 Pimephales promelas (fathead minnow) 1430 mg/l 96 hr flow-through bioassay, wt 0.12 g, water hardness 45.5 mg/l CaCO3, temp: 25 +/- 1 deg C, pH 7.5, dissolved oxygen greater than 60% of saturation; [R78] NTP: +N,N-Dimethyl Formamide (DMF) ... was evaluated for reproductive toxicity in CD-l (Swiss) mice using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. Male and female mice were exposed to DMF in drinking water at doses of 0, 1,000, 4,000, and 7,000 ppm (mean exposure 193 to 1216 mg/kg/day for non-lactating F0 animals and 259 to 1,934 mg/kg/day for F1 animals). At 1000 ppm in F0 mice, there was increased relative liver weight for males and females and increased relative kidney plus adrenal weight for females. Although liver histopathology was only examined in DMF-treated animals exhibiting gross hepatic lesions (2/10 high-dose males and 2/10 mid-dose females), all those examined exhibited centrilobular hepatic hypertrophy that was considered treatment related. Reproductive toxicity was observed in the F0 generation, primarily at the mid- and high-dose levels. At 4,000 and 7,000 ppm, fertility and fecundity were reduced; pups were observed to have various craniofacial malformations. The crossover mating trial was not able to determine the gender responsible for the decr in fertility observed in the continuous breeding phase of the study. However, females treated with 7,000 ppm DMF produced somewhat smaller litters compared to the control pairs or the treated males. In addition, 7,000 ppm DMF females, mated to control males, produced pups with malformations similar to those observed in Task 2, confirming the developmental toxicity of this compound. Further exam of pups from 7,000 ppm Task 3 females revealed abnormal ossification of the cranial plates and sternebrae. At F0 necropsy, all male and female organ weights, sperm parameters, and estrous cycle length were not adversely affected, with the exception of a slight decr in sperm concn at the high dose and spermatid concn at the low and high doses. F1 postnatal survival at 4,000 and 7,000 ppm was reduced during the pre- and post-weaning periods, AND F1 body weight was reduced at the mid and high doses. Surviving F1 pups in the mid- and high-dose groups exhibited cranial malformations, including small and foreshortened skulls. In the F1 mating trial, the mating index was reduced at 7,000 ppm, while the pregnancy index, litter size, and proportion of pups born alive were reduced at 4,000 and 7,000 ppm. Litter weight was reduced at all doses of DMF. Malformation incidence appeared to be increased at > or = 4,000 ppm in the F2 pups. The F1 animals in the 1,000 ppm group had an incr in relative liver weight in both males and females, associated with treatment- related hepatic hypertrophy. Reproductive toxicity, including decreased indices of fertility or pregnancy, litter size, and malformation incidence in F2 offspring, was observed at doses of 4,000 ppm and above, whereas 7,000 ppm DMF lengthened the estrous cycle of exposed females. At necropsy, F1 animals exposed to > or =4,000 ppm DMF and selected for skeletal evaluation exhibited malformations persistent from birth. In summary, the MTD for generalized toxicity was 1000 ppm for both the F0 AND F1 generations. The No-Observed-Adverse-Effect-Level (NOAEL) for generalized toxicity could not be determined For either the F0 or F1 generation. Reproductive and developmental toxicity, observed at > or =4,000 ppm DMF for the F0 and at > or =1,000 ppm DMF for the F1 generations, occurred in the presence of mild general toxicity. [R79] POPL: *... INVESTIGATIONS SHOW THAT DIMETHYLFORMAMIDE, DESPITE ITS RELATIVELY LOW VAPOR PRESSURE, AFFECTS MOST WORKMEN HANDLING IT, ESP THOSE SUFFERING FROM GASTRIC OR LIVER TROUBLES (ULCERS, GASTRITIS, ALCOHOLISM). [R28, 115] ADE: *THE SOLVENT CAN PASS THROUGH THE INTACT SKIN OR CAN BE ABSORBED THROUGH THE LUNGS. [R80] *Dimethylformamide reached an average level of 2.8 ug/l in the blood of subjects exposed to 21 ppm of the vapor for 4 hr, and was undetectable at 4 hr after the exposure; the metabolite, methylformamide, averaged between 1 and 2 mg/l in the blood and this level was maintained for at least 4 hr after exposure. Maximal blood levels of about 14 and 8 ug/l were observed for dimethylformamide and methylformamide, respectively, at 0 and 3 hr, after a 4 hr exposure to 87 ppm of the vapor. Repeated daily exposures to 21 ppm of dimethylformamide did not result in accumulation of the chemical or its metabolite in blood. /Dimethylformamide and methylformamide/ [R45, 128] *Eight healthy male subjects were exposed to dimethylformamide (DMF) vapor at a concn of 8.79 + or - 0.33 ppm for 6 hr daily for 5 consecutive days. All urine voided by the subjects was collected from the beginning of the first exposure to 24 hr past the end of the last exposure and each sample was analyzed for monomethylformamide. Monomethylformamide was rapidly eliminated from the body with urine values peaking within a few hours following the end of each exposure period. The mean for the 7 hr (end of exposure) sample was 4.74 mg/ml. [R81] *The amount of N-methylformamide recovered in the urine represents only 2-6% of the dose of dimethylformamide inhaled. A substantial portion of an absorbed dose of DMF is excreted unchanged in the expired breath. The urinary concn of N-methylformamide is probably the best index of worker exponent dimethylformamide. [R35, 1675] *... DMF concns in the blood of rats, 24 hr after the oral admin of 200-4000 mg DMF/kg bw /were determined/ and ... mean blood levels ranging from 40 to 1870 mg/liter /were found/. DMF is readily absorbed via inhalation and dermally. Maximal blood and tissue concns were observed in rats up to 3 hr after exposure to 438 and 6015 mg DMF/cu m ... or to 1690 and 6700 mg DMF/cu m. ... At least 0.8 ml of 100% DMF was absorbed through 14 sq cm of exposed skin of the tails of rats in the course of 8 hr, which is equivalent to an absorption rate of about 57 mg/sq cm/8 hr. [R82] *24 hr after an ip dose of 14C-DMF in male rats, about 4% of the radioactivity was recovered in the blood, < 1% in the brain, heart, lungs, stomach, intestines, spleen, and kidneys, and 1-3% in the liver, adipose tissue, and muscles. [R82] *... DMF AND NMF (/N-methylformamide/) (DMF-OH) concns in the blood of rats and dogs after single and repeated respiratory exposure /were studied/. At the highest airborne concn (6015 mg/cu m), DMF was still detectable in the blood of male rats up to 2 days after the end of a 3 hr exposure. At lower concns, DMF levels in the blood decreased rapidly. After 3 hr exposure to 63 mg/cu m or 6 hr exposure to 87 mg/cu m, similar levels of NMF were found in the blood at the end of the periods of exposure, but no NMF was detectable 3 hr after the end of exposure. Only after a 3 hr exposure to a very high concn (6015 mg/cu m) did NMF levels in blood continue to incr for the 2 days following exposure. Blood concns of DMF in male dogs also decreased rapidly following a 6 hr single exposure. However, NMF could be detected in the blood at higher concn and for a longer period of time after exposure. [R82] *The transformation and excretion of DMF in rodents is rapid. When 14C-labeled DMF in 0.1 ml saline was injected ip at 6.8 mmol/kg bw in mice, about 83% of the radioactivity was recovered in the urine within 24 hr following injection. Of this amount, only 5% was unchanged DMF AND 56% was C-hydroxylated or N-demethylated derivatives. About 18% of the dose was excreted in the form of unknown chemicals. [R83] *Percutaneous absorption in vivo was examined ... in two ways, from liquid dimethylformamide and from dimethylformamide vapor. The first was evaluated by dipping one hand into undiluted dimethylformamide for up to 20 min and by the application of 2 mmol dimethy1formamide over an area of 100 sq cm on the forearm (approximately 1.5 mg/sq cm). In both studies, the absorption rate was 9 mg/sq cm/hr. [R84] *Percutaneous uptake of dimethy1formamide vapor was evaluated in volunteers exposed to an atmosphere of 50 mg/cu m dimethylformamide for 4 hr, while wearing light clothing and breathing fresh air through masks. The percutaneous uptake of dimethylformamide increased with increasing ambient temperature and humidity and contributed some 13-36% of the urinary N-hydroxymethyl-N-methylformamide excreted during combined inhalation and percutaneous exposure to the same concentration of dimethylformamide vapor. [R85] *Serial blood and urine samples were collected from two cynomolgus monkeys of each sex in groups subjected to whole body exposure to atmospheres of 30, 100 or 500 ppm (90, 300 or 1500 mg/cu m) dimethylformamide for 6 hr per day on five days per week for 13 weeks. As was found in rats and mice, there were disproportionate increases in plasma AUC values of 19 to 37 fold in male monkeys and 35 to 54 fold in females as the atmospheric concentrations increased five fold from 100 to 500 ppm. Plasma half lives ranged from 1 2 hr for dimethylformamide and 4 15 hr for 'N-methylformamide'. There was rapid metabolism, the plasma 'N-methylfomamide' concentration being higher than that of dimethylformamide at 0.5 hr. N-(Hydroxymethyl)-N-methy1formamide formed 56 95% of the urinary metabolites, depending upon the exposure level and duration of the study. [R84] METB: *... TWO GROUPS OF WORKERS INVESTIGATED METAB OF DMF ON VOLUNTEERS. ... BOTH FOUND THAT MAJORITY OF ABSORBED SUBSTANCE IS ELIMINATED WITHIN 24 HR AND THAT MAIN URINARY METABOLITE IS N-METHYL FORMAMIDE. ITS CONCN WAS RELATED TO INTENSITY OF EXPOSURE. [R86] *It is known that dimethylformamide is metabolized in man by sequential N-demethylation to methylformamide and formamide, which are largely eliminated in the urine. [R45, 128] *Blood and urine samples of rats and dogs which had been exposed to DMF were examined by GLC analysis and N-methylformamide and formamide were detected in addition to DMF. These metabolites were eliminated faster in rats than in dogs. It has been suggested recently that the major metabolite of DMF which has been characterized an NMF by GLD is no NMF but N-hydroxymethyl-N-methylformamide (HMMF). HMMF is the immediate product of methyl C-hydroxylation of DMF and is a relatively stable carbinolamide in aqueous soln. It is, however thermally labile so that it decomposes quantitatively to NMF and presumably formaldehyde on the GLC column. The evidence that the metabolite which has been characterized as NMF is really HMMF is based on three studies. /One study/ found a formaldehyde precursor in the urine of mice which had received DMF. This metabolite liberated formaldehyde only after alkaline hydrolysis. In aqueous soln, authentic HMMF also decomposed to formaldehyde only on alkaline hydrolysis. /Another study/ isolated a urinary metabolite of DMF in rats by HPLC and subjected it to mass spectrometric analysis. The observed fragmentation pattern suggested the presence of HMMF, even though the mass fragments, including the one corresponding to the molecular ion, were also detected in control urine samples. Unequivocal evidence for the contention that HMMF and not NMF is the major metabolite of DMF was recently obtained by high-field proton NMF spectroscopy of urine samples of mice which had received DMF. HMMF exists in 2 rotameric forms and the methyl and formyl protons in the two rotamers are not equivalent. The resonance frequencies corresponding to the methyl and formyl protons of both rotamers were prominent signals in the NMR spectrum of the urine. However, at the resonance frequency of the methyl protons of NMF only a minute signal was observed. In this study dimethylamine and methylamine were found to be minor urinary metabolites of DMF in mice. [R50, 151] *In rats, partial hepatectomy reduced the metabolism of DMF to HMMF. [R50, 152] *There appeared to be a sex difference in metabolic rate: female rats excreted more unchanged DMF than did males. [R50, 152] *In mice, 56% of the dose of 400 mg/kg DMF given ip was metabolized to HMMF. However, C-hydroxylation occurred at a very slow rate when DMF was incubated with liver fractions. The metabolic oxidation of DMF in vitro has been suggested to be mediated, at least in part, by hydroxy radicals and hydrogen peroxide, as this metabolic route measured in rat liver microsomes was reduced in the presence of catalase, superoxide dismutase, and the radical scavengers DMSO, t-butanol, aminopyrine and hydroquinone. DMF itself inhibited the oxidation of DMSO, t-butanol and aminopyrine. [R50, 152] *When a male volunteer inhaled the DMF vapors that were produced over liquid DMF in a beaker for 6 hr, ... the metabolite N-acetyl-S-(N-methylcarbamoyl) cysteine /was identified/ in the urine. [R87] *The major pathway of dimethylformamide metabolism is hydroxylation of one of the methyl groups, giving N-hydroxymethyl-N-methylformamide, which is unstable in many analytical manipulations and readily decomposes to N-methylformamide. N-Hydroxymethyl-N- methylformamide was underestimated, or not detected at all, in a number of early studies for this reason. The formation of N-hydroxymethyl-N-methylformamide is a cytochrome p450 dependent reaction mediated by CYP2EI in rat liver microsomes. The reaction mediated by human liver microsomes was inhibited by a monospecific antibody against rat liver. [R84] INTC: *FACIAL FLUSHING AND OTHER SYMPTOMS WERE REPORTED BY 19/102 MEN WHO WORKED WITH DIMETHYLFORMAMIDE (DMF). OF 34 EPISODES, 26 OCCURRED AFTER WORKERS CONSUMED ALCOHOLIC DRINKS. REACTION IS POSSIBLY ATTRIBUTABLE TO INHIBITION OF ACETALDEHYDE METABOLISM, PROBABLY BY N-METHYLFORMAMIDE. [R88] *N,N-DIMETHYLFORMAMIDE WHEN ADMIN IP TO MICE IN SUBLETHAL DOSES (3.2, 0.77, 2, 1.2, AND 0.75 G/KG), LENGTHENED /SRP: CNS DEPRESSION/ INDUCED BY 100 MG HEXOBARBITAL, 350 MG CHLORAL, OR 1.4 G URETHANE/KG. [R89] *Ingestion of alcohol during or after an exposure to dimethylformamide can produce a disulfiram-like reaction, with facial flushing, dizziness, sweating, nausea, palpitation, breathlessness, and loss of consciousness. This is probably due to the inhibition of acetaldehyde dehydrogenase by methylformamide. [R35, 1675] *DMF given ip (1.15 g/kg) caused a prolongation of the pentobarbital-induced sleeping time in mice. This effect was probably not caused by the inhibition of mixed-function oxidase enzymes as pretreatment of mice with the enzyme inhibitor SKF525A did not exacerbate the DMF effect. DMF also caused an incr in sleeping time induced by thiobarbital, a barbiturate, the duration of action of which is not determined by oxidative metab. DMF, therefore appears to cause this effect by interference with the CNS. [R50, 154] *... 4 subjects /were exposed/ via inhalation to DMF (159 mg/cu m) for 2 hr with, and without, ingestion of 19 g ethanol (50 ml 38% gin), 10 min before they inhaled the DMF. No changes in DMF concns in blood were found. The comparatively lower NMF concns in the blood of subjects with combined exposure to ethanol and DMF indicated that the ethanol decreased the biotransformation of DMF. No significant differences in the blood levels of ethanol and acetaldehyde were detected in subjects with, or without, ethanol exposure, which differed from the effects observed in animal studies. The authors suggested that this was because of the relatively low concns of DMF used in the human studies. [R87] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dimethylformamide's production and use as a solvent may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 3.9 mm Hg at 25 deg C indicates dimethylformamide will exist solely as a vapor in the ambient atmosphere. Vapor-phase dimethylformamide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 22 hours. If released to soil, dimethylformamide is expected to have very high mobility based upon an estimated Koc of 7. Volatilization from moist soil surfaces is not expected to be an important fate process based upon a Henry's Law constant of 7.4X10-8 atm-cu m/mole. Dimethylformamide may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, dimethylformamide is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. An aerobic unacclimated and acclimated river die-away test showed that dimethylformamide at an initial concn of 30 mg/l completely disappeared within 6 and 3 days, respectively. Thus, dimethylformamide is expected to rapidly degrade in the environment. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the slow rate of reaction for amide functional groups. Occupational exposure to dimethylformamide may occur through inhalation and dermal contact with this compound at workplaces where dimethylformamide is produced or used. Monitoring data indicate that the general population may be exposed to dimethylformamide via dermal contact with consumer products containing dimethylformamide. (SRC) ARTS: *Dimethylformamide's production and use as a solvent(1) may result in its release to the environment through various waste streams(SRC). [R90] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 7(SRC), determined from a log Kow of -1.01(2) and a regression-derived equation(3), indicates that dimethylformamide is expected to have very high mobility in soil(SRC). Volatilization of dimethylformamide from moist soil surfaces is not expected to be an important fate process(SRC) given a Henry's Law constant of 7.4X10-8 atm-cu m/mole(4). The potential for volatilization of dimethylformamide from dry soil surfaces may exist(SRC) based upon a vapor pressure of 3.9 mm Hg(5). Dimethylformamide rapidly degrades in water and is expected to degrade in soil(SRC). For example, an aerobic unacclimated and acclimated river die-away test showed that dimethylformamide at an initial concn of 30 mg/l completely disappeared within 6 and 3 days, respectively(6). [R91] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 7(SRC), determined from a log Kow of -1.01(2), indicates that dimethylformamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon a Henry's Law constant of 7.4X10-8 atm-cu m/mole(4). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). An aerobic unacclimated and acclimated river die-away test showed that dimethylformamide at an initial concn of 30 mg/l completely disappeared within 6 and 3 days, respectively(7). However, 24 to 48 hours was required before any degradation was observed among unacclimated samples(7). Thus, dimethylformamide is expected to rapidly degrade in aqueous systems(SRC). [R92] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dimethylformamide, which has a vapor pressure of 3.87 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase dimethylformamide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 22 hours(SRC), calculated from its rate constant of 18X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). [R93] BIOD: *An aerobic unacclimated and acclimated river die-away test showed that dimethylformamide at an initial concn of 30 mg/l completely disappeared within 6 and 3 days, respectively(1). However, 24 to 48 hours was required before any degradation was observed among unacclimated samples(1). Aerobic grab sample data for dimethylformamide in sea water showed a mineralization rate of less than 3% in 24 hours for initial concn of 10 ug/l and 100 ug/l(2). However, 20% of dimethylformamide at a concn of 0.1 ug/l was mineralized in 24 hrs(2). All samples were adjusted to sterilized controls(2). Aqueous screening test data demonstrated that dimethylformamide was easily removed by sewage treatment facilities upon acclimation(3). Wastewater from a polyimide synthesis operation at Kansas City, MO contained dimethylformamide at a concn of 65,500 mg/l before entering a benchscale biological treatment system(4). At feed rates of 90 lb/day/1000 cu ft, effluent from the biological reactor contained dimethylformamide at a concn of less than 10 mg/l(4). The concn of dimethylformamide in the reactor sludge was not documented(4). [R94] ABIO: *The rate constant for the vapor-phase reaction of dimethylformamide with photochemically-produced hydroxyl radicals has been estimated as 18X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 22 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Dimethylformamide is not expected to undergo hydrolysis in the environment due to the slow rate of reaction for amide functional groups(2) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R95] BIOC: *An estimated BCF of 3 was calculated for dimethylformamide(SRC), using a log Kow of -1.01(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R96] KOC: *The Koc of dimethylformamide is estimated as 7(SRC), using a measured log Kow of -1.01(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that dimethylformamide is expected to have very high mobility in soil(SRC). [R97] VWS: *The Henry's Law constant for dimethylformamide is 7.39X10-8 atm-cu m/mole(1). This Henry's Law constant indicates that dimethylformamide is expected to be essentially nonvolatile from water surfaces(2). The potential for volatilization of dimethylformamide from dry soil surfaces may exist(SRC) based upon a vapor pressure of 3.87 mm Hg(3). [R98] WATC: *DRINKING WATER: Dimethylformamide was listed as a contaminant found in drinking water for a survey of US cities including Pomona, Escondido, Lake Tahoe and Orange Co, CA and Dallas, Washington, DC, Cincinnati, Philadelphia, Miami, New Orleans, Ottumwa, IA, and Seattle(1). [R99] *SURFACE WATER: One of 204 samples contained dimethylformamide in a national survey of surface waters(1). [R100] EFFL: *Dimethylformamide was detected in the air over a hazardous waste site in Lowell, MA and a neighboring industry at concn of 2.18 and greater than 50 ppb, respectively(1). Dimethylformamide was detected in 1 of 63 industrial wastewater effluents at a concn less than 10 ug/l(2). Dimethylformamide was detected in the waste effluent of a plastics manufacturer at a concn of 28,378 ng/ul of extract(3). Effluent from a New Jersey publically owned treatment works in a rural area with no industrial contribution contained 32 ppb dimethylformamide(4). [R101] ATMC: *Dimethylformamide was detected in the air of Lowell, MA at concn of 8 ppb(1). Dimethylformamide was detected at a concn of 9.8 ug/cu m (range, < 0.02-13.8 ug/cu m) in a residential area around a waste site at an unspecified location in the Northeast U.S.(2); the concn upwind from this waste site was 0.06 ug/cu m(2). [R102] OEVC: *The specific mass emission of dimethylformamide from a sponge rubber carpet cushion was < 1 ug/cu m hr after a 96 hour period in a 52 liter environmental chamber(1). [R103] RTEX: *WORKERS EXPOSED TO DIMETHYLFORMAMIDE IN AN ACRYLIC FIBER FACTORY ... . [R33] *EXPOSURE CAN OCCUR IN WORKERS HANDLING SURFACE-TREATED AGENTS CONTAINING DMF. [R104] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 124,683 workers (16,011 of these are female) are potentially exposed to dimethylformamide in the US(1). Occupational exposure to dimethylformamide may occur through inhalation and dermal contact with this compound at workplaces where dimethylformamide is produced or used(SRC). Monitoring data indicate that the general population may be exposed to dimethylformamide via dermal contact with consumer products containing dimethylformamide(SRC). [R105] *Dimethylformamide was detected in the urine of synthetic leather factory workers(1); the ave and range of concns at the end of shift were 449 ug/l and 100-990 ug/l for workers exposed to dimethylformamide in the workplace(1). The mean environmental concn of dimethylformamide in this workplace is 16.5 mg/cu m (range, 3-27 mg/cu m)(1). Workers at leather, polyurethane, and shoe-sole production facilities were exposed to dimethylformamide concns (mean value) in air of 9.1 ppm, 3.9 ppm, and 0.7 ppm, respectively(2). Urinary levels of dimethylformamide (detected as N-monomethylformamide) for these workers, were 19.7 ppm, 7.8 ppm, and 2.6 ppm, respectively(3). [R106] BODY: *N,N-Dimethylformamide was detected in the urine of synthetic leather factory workers(1); the ave and range of concns at the end of shift were 449 ug/l and 100-990 ug/l for workers exposed to N,N-dimethylformamide in the workplace(1). Urinary levels of dimethylformamide (detected as N-monomethylformamide) for workers at leather, polyurethane, and shoe-sole production facilities were 19.7 ppm, 7.8 ppm, and 2.6 ppm, respectively(2). [R107] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *500 ppm [R9] ATOL: *Dimethylformamide is exempted from the requirement of a tolerance when used as a solvent or cosolvent in preemergence application, application prior to the formation of edible parts of food plants, and seed and transplant treatment. Also, as part of the USDA witchweed quarantine program, postemergence application to field corn, after silking and tasseling of the corn. [R108] *Residues of dimethylformamide are exempted from the requirement of a tolerance when used in accordance with good agricultural practices in formulations with the fungicide triforine (N,N-(1,4-piperazinediylbis(2,2,2-trichloroethylidene)) bis (formamide)) if such formulations contain not more than 30 percent diemthylformamide in or on the following raw agricultural commodities: almonds; apples; apricots; bell peppers; blueberries; cantaloupes; cherries; cranberries; cucumbers; eggplant; hops; nectarines; peaches; plums; prunes, fresh; strawberries; watermelons. Dimethylformamide (DFM) is exempted from the requirement of a tolerance, when used by the U.S. Department of Interior, Fish and Wildlife Service, as a solvent for the lamprecide, sodium salt of alpha, alpha, alpha-trifluoro-4-nitro-meta- cresol, or 4-nitro-3-(trifluoromethyl)phenol in the Great Lakes. [R109] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 10 ppm (30 mg/cu m). Skin Designation. [R110] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (30 mg/cu m), skin. [R9] TLV: *8 hr Time Weighted Avg (TWA) 10 ppm, skin [R111, 2001.28] *A4; Not classifiable as a human carcinogen. [R111, 2001.28] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R111, 2001.6] *Biological Exposure Index (BEI): Determinant: N-Acetyl-S-(N-methylcarbamoyl) cysteine in urine; Sampling Time: prior to last shift of workweek; BEI: 40 mg/l. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. [R111, 2001.88] *Biological Exposure Index (BEI): Determinant: N-Methylformamide in urine; Sampling Time: end of shift; BEI: 15 mg/l. [R111, 2001.88] OOPL: *MAC USSR 10 mg/cu m [R31] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 2 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 100 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 200 ppm (not life threatening) up to 1 hr exposure. [R112] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. N,N,-Dimethylformamide is produced, as an intermediate or a final product, by process units covered under this subpart. [R113] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. N,N-Dimethyl formamide is included on this list. [R114] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 700 ug/l [R115] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R116] FIFR: *Dimethylformamide is exempted from the requirement of a tolerance when used as a solvent or cosolvent in preemergence application, application prior to the formation of edible parts of food plants, and seed and transplant treatment. Also, as part of the USDA witchweed quarantine program, postemergence application to field corn, after silking and tasseling of the corn. [R108] *Residues of dimethylformamide are exempted from the requirement of a tolerance when used in accordance with good agricultural practices in formulations with the fungicide triforine (N,N-(1,4-piperazinediylbis(2,2,2-trichloroethylidene)) bis (formamide)) if such formulations contain not more than 30 percent diemthylformamide in or on the following raw agricultural commodities: almonds; apples; apricots; bell peppers; blueberries; cantaloupes; cherries; cranberries; cucumbers; eggplant; hops; nectarines; peaches; plums; prunes, fresh; strawberries; watermelons. Dimethylformamide (DFM) is exempted from the requirement of a tolerance, when used by the U.S. Department of Interior, Fish and Wildlife Service, as a solvent for the lamprecide, sodium salt of alpha, alpha, alpha-trifluoro-4-nitro-meta- cresol, or 4-nitro-3-(trifluoromethyl)phenol in the Great Lakes. [R109] FDA: *Dimethylformamide is an indirect food additive for use only as a component of adhesives. [R117] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1004. Analyte: dimethylformamide; Matrix: air; Sampler: solid sorbent tube (silica gel, 150 mg/75 kg); Flow rate: 0.01-1 l/min; Vol: min: 15 l @ 30 mg/cu m, max: 80 l; Sample stability: greater than or equal to 5 days @ 25 deg C. [R118] ALAB: *NIOSH Method 1004. Analyte: dimethylformamide; Matrix: air; Technique: gas chromatography, flame ionization detector; Desorption: 1 ml methanol, 1 hr in ultrasonic bath; Range: 0.5-4 mg/sample; Precision: 0.032, 0.037; Interferences: None identified. [R118] *A HPLC method with UV detection was used for the determination of low mol wt amides in pharmaceutical matrixes. The method was based on Zorbax C8 or Alltech C18 column, mobile phase consisting of 3-5% MeCN in 0.1M phosphate buffer, and flow rate of 1-1.5 ml/min at the room temperature. By strongly retaining the sample matrix and allowing the amide analyte to elute, the method can be generally applied to many types of org matrix for pharmaceutical and agricultural products. /Amides/ [R119] *EPA Method 1625-BNW: Semivolatile Organic Compounds by Isotope Dilution GC-MS. This method is applicable to the determination of base/neutral toxic organic pollutants in water and sludges containing < 1% solids. Detection limit = 10 ug/l. [R120] *EPA Method 1665: Semi-Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by Isotope Dilution GC/MS. This method is applicable for determining semivolatile organic pollutants specific to the pharmaceutical manufacturing industry. This method is applicable to water, soil, and municipal sludge samples. Detection limit = 5 ug/l. [R120] CLAB: *Methylformamide concentrations in urine may be determined by flame-ionization gas chromatography, involving direct sample introduction ... Urine is injected directly into the gas chromatograph. Methylformamide is quantitated by flame-ionization detection; Sensitivity: 8 mg/l; Interferences: occasionally, interfering peaks appear on the chromatogram at heights representing traces of methylformamide (< 2 mg/l). [R45, 129] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: $null$ [R121] DHHS/NTP; NTP Technical Report on Toxicity Studies of N,N-Dimethylformamide Administered by Inhalation to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 22 NIH Publication No. 93-3345 (1992) SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 399 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 549 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V11 (1994) R4: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 563 R5: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-201 R6: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on N,N-Dimethylformamide (68-12-2). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R7: SRI R8: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley and Sons. New York, NY. 2001,p. V1 914 R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 114 R10: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 657 R11: Hansch, C., Leo, A., D. 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Washington, DC: U.S. Government Printing Office, 1980.82 R78: Veith GD et al; Canadian J Fisheries Aquat Sci 40 (6): 743-8 (1983) R79: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of N,N-Dimethyl Formamide (CAS No. 68-12-2) in CD-1 Swiss Mice, NTP Study No. RACB90023 (September 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 16, 2002 R80: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 349 R81: Krivanek ND et al; J Occup Med 20 (3): 179-182 (1978) R82: WHO; Environ Health Criteria 114: Dimethylformamide p.32 (1991) R83: WHO; Environ Health Criteria 114: Dimethylformamide p.39 (1991) R84: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 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Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 6 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Taft RW et al; Nature 313: 384-6 (1985) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (6) Dojlido JR; Investigations of the Biodegradability and Toxicity of Organic Compounds. Cincinnati, OH: Municipal Env Res Lab USEPA 600/2-79-163 p. 118 (1979) R92: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 6 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Taft RW et al; Nature 313: 384-6 (1985) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) Dojlido JR; Investigations of the Biodegradability and Toxicity of Organic Compounds. Cincinnati, OH: Municipal Env Res Lab USEPA 600/2-79-163 p. 118 (1979) R93: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R94: (1) Dojlido JR; Investigations of the Biodegradability and Toxicity of Organic Compounds. Cincinnati OH, Municipal Env Res Lab USEPA 600/2-79-163 p. 118 (1979) (2) Ursin C; Chemosphere 14: 1539-50 (1985) (3) Thom NS, Agg AR; Proc R Soc Lond B 189: 347-57 (1975) (4) Carter JL, Young DA; Proc Ind Waste Conf 38: 481-6 (1984) R95: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R96: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 6 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R97: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 6 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R98: (1) Taft RW et al; Nature 313: 384-6 (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) R99: (1) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p. 397 (1984) R100: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters USEPA-560/6-77-015 p. 75 (1977) R101: (1) Amster MB et al; pp. 98-9 in Natl Conf Manage Uncontrolled Hazard Waste Sites, Silver Springs MD (1986) (2) Perry DL et al; Identity of Org Compounds in Ind Effluent discharges. 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Research Triangle Park, NC: USEPA/600/R-94/090 (1993) R103: (1) Schaeffer VH et al; Air Waste Manage Assoc 46: 813-20 (1996) R104: YONENOTO J ET AL; INT ARCH OCCUP ENVIRON HEALTH 46 (2): 159-66 (1980) R105: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R106: (1) Casal Lareo A, Perbellini L; Int Arch Occup Enviroin Health 67:47-52 (1995) (2) Cai SX et al; Int Arch Occup Environ Health 63: 461-468 (1992) (3) Kawai T et al; Int Arch Occup Environ Health 63: 455-460 (1992) R107: (1) Casal Lareo A, Perbellini L; Int Arch Occup Enviroin Health 67: 47-52 (1995) (2) Kawai T et al; Int Arch Occup Environ Health 63: 455-460 (1992) R108: 40 CFR 180.1001(d) (7/1/2000) R109: 40 CFR 180.1046 (7/1/2000) R110: 29 CFR 1910.1000 (7/1/2000) R111: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R112: American Industrial Hygiene Association. The AIHA 2001 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. AIHA Press, Fairfax, VA. 2001. 24 R113: 40 CFR 60.489 (7/1/2000) R114: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R115: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R116: 40 CFR 302.4 (7/1/2000) R117: 21 CFR 175.105 (4/1/2000) R118: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R119: Snorek SV et al; J Chromatog; 458 : 287-93 (1988) R120: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R121: WHO; Environmental Health Criteria 114: Dimethylformamide (1991) RS: 107 Record 14 of 1119 in HSDB (through 2003/06) AN: 82 UD: 200303 RD: Reviewed by SRP on 03/16/1990 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHANOL- SY: *ABSOLUTE-ETHANOL-; *AETHANOL- (GERMAN); *AETHYLALKOHOL- (GERMAN); *ALCOHOL-; *ALCOHOL-ANHYDROUS-; *ALCOHOL-DEHYDRATED-; *ALCOHOL,-ETHYL-; *ALCOOL-ETHYLIQUE- (FRENCH); *ALCOOL-ETILICO- (ITALIAN); *ALGRAIN-; *ALKOHOL- (GERMAN); *ANHYDROL-; *COLOGNE-SPIRIT-; *ETANOLO- (ITALIAN); *ETHANOL-200-PROOF-; *Ethanol-solution-; *ETHYL-ALCOHOL-; *ETHYL-ALCOHOL-ANHYDROUS-; *ETHYLALCOHOL- (DUTCH); *ETHYL-HYDRATE-; *ETHYL-HYDROXIDE-; *ETYLOWY-ALKOHOL- (POLISH); *FEMA-NUMBER-2419-; *FERMENTATION-ALCOHOL-; *GRAIN-ALCOHOL-; *JAYSOL-S-; *METHYLCARBINOL-; *MOLASSES-ALCOHOL-; *NCI-C03134-; *POTATO-ALCOHOL-; *SPIRITS-OF-WINE-; *TECSOL-; *TECSOL-C- RN: 64-17-5 MF: *C2-H6-O SHPN: UN 1170; Ethyl alcohol IMO 3.2; Ethyl alcohol (Ethanol or ethanol solutions including alcoholic beverages) IMO 3.3; Ethyl alcohol (Ethanol or ethanol solutions including alcoholic beverages) STCC: 49 091 10; Ethyl Alcohol, anhydrous, denatured in part with gasoline content not to exceed 5% (alcohol, nos) 49 091 59; Cologne Spirits (Ethanol or Ethyl Alcohol) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... Chemical uses of n-butane include manufacturing of acetic acid and by-product ... ethyl alcohol ... . [R1, p. 12(80) 917] *MANUFACTURED FROM ACETYLENE, SULFITE WASTE LIQUORS, AND SYNTHESIS GAS (CO + H); BY HYDROLYSIS OF ETHYL SULFATE, AND OXIDN OF METHANE. [R2, 34] *a) From ethylene by direct catalytic hydration ... b) fermentation of biomass, especially agricultural wastes; c) enzymatic hydrolysis of cellulose [R3, 477] *Ethanol can ... be obtained by the reaction of methanol with synthesis gas at 185 deg C and under pressure (6.9-20.7 MPa or 68-204 atm) in the presence of a cobalt octacarbonyl catalyst. [R1, p. 9(80) 351] *Using ... acid catalyst as in the hydration of ethylene to ethanol, ethyl ether can be hydrated to the alcohol. Catalysts that have been used for the hydration of ether include phosphoric acid, sulfuric acid, hydrochloric acid, metallic oxides and silicates. Sulfuric acid concn ranging from 5-25% at 200 deg C to 63-70% at 110-135 deg C and 1.01-1.42 MPa (10-14 atm) have been claimed. [R1, p. 9(80) 350] FORM: *Grades: USP (95% by vol); Absolute; Pure; Completely denatured; Specially denatured; Industrial; Various proofs ... . [R3, 477] *Materials containing alcohol: Apple Distillate K 2/032410; Arnica Distillate 2/378370; Birch Distillate 2/384280; Chamomille Distillate 2/380930; Linden Blossom Distillate 2/382920 [R4] *To every 100 gal of ethyl alcohol add: Four gal of methyl alcohol and one gal of methyl isobutyl ketone; or four gal methyl alcohol and 1/8 avoirdupois oz denatonium benzoate, NF [R5, 203] *To every 100 gal of ethyl alcohol add: One-half gal benzene or one-half gal rubber hydrocarbon solvent. [R5, 204] *To every 100 gal of ethyl alcohol add: Thirty-three pounds, or more metallic sodium and either one-half gal benzene or one-half gal rubber hydrocarbon solvent [R5, 204] *To every 100 gal of ethyl alcohol add: Five gal methyl alcohol [R5, 204] *To every 100 gal of ethyl alcohol add: One gal of pine tar NF [R5, 205] *To every 100 gal of ethyl alcohol add: One gal of the following solution: Five gal of an aq soln containing 40% nicotine; and 3.6 avoirdupois oz of methylene blue, NF; water sufficient to make 100 gal [R5, 206] *To every 100 gal of ethyl alcohol add: Five gal of benzene [R5, 206] *To every 100 gal of ethyl alcohol add: Ten gal of ethyl ether [R5, 206] *To every 100 gal of ethyl alcohol add: Five-hundredths gal of bone oil (Dipple's oil) [R5, 207] *To every 100 gal of ethyl alcohol add: One hundred gal of ethyl ether [R5, 207] *To every 100 gal of ethyl alcohol add: Ten gal of formaldehyde soln (USP) [R5, 207] *To every 100 gal of ethyl alcohol add: Ten gal of acetone, NF [R5, 207] *To every 100 gal of ethyl alcohol add: Three pounds of salicyclic acid, USP, one pound resorcin, USP, and 1 gal bergamont oil, NF, or bay oil, NF [R5, 208] *To every 100 gal of ethyl alcohol add: Eight gal of acetone, NF and 1.5 gal of methyl isobutyl ketone [R5, 208] *To every 100 gal of ethyl alcohol add: Twenty pounds of iodine, USP and 15 pounds of either potassium or sodium iodide USP [R5, 209] *To every 100 gal of ethyl alcohol add: A soln composed of 20 pounds of iodine USP, 15 pounds of potassium or sodium iodide USP and 15 pounds of water. [R5, 209] *To every 100 gal of ethyl alcohol add: One gal of rosemary oil, NF and 30 lb of camphor, USP [R5, 210] *To every 100 gal of ethyl alcohol add: Thirty-five lb of camphor, USP and 1 gal of clove oil, USP [R5, 210] *To every 100 gal of ethyl alcohol add: One gal of lavender oil, USP and 100 lb of medicinal soft soap, USP [R5, 210] *To every 100 gal of ethyl alcohol add: Ten gal of methyl alcohol [R5, 210] *To every 100 gal of ethyl alcohol add: One hundred lb of glycerol, USP and 20 lb of hard soap, NF [R5, 211] *To every 100 gal of ethyl alcohol add: Thirty lb of methyl violet, USP [R5, 212] *To every 100 gal of ethyl alcohol add: 29.75 gal of ethyl acetate having an ester content of 100% by wt or the equivalent thereof not to exceed 35 gal of ethyl acetate with an ester content of not less than 85% by wt [R5, 212] *To every 100 gal of ethyl alcohol add: 4.25 gal of ethyl acetate having an ester content of 100% by wt or the equivalent thereof not to exceed 5 gal of ethyl acetate with an ester content of not less than 85% by wt [R5, 212] *To every 100 gal of ethyl alcohol add: 3 gal of ammonia, aq, 27 to 30% by wt: three gal of strong ammonia soln, USP: 17.5 lb of caustic soda, liq grade, containing 50% sodium hydroxide by wt: or 12.0 lb of caustic soda, liq grade, containing 73% sodium hydroxide by wt. [R5, 212] *To every 100 gal of ethyl alcohol add: 45 fluid oz of eucalyptol, USP, 30 avoirdupois oz of thymol, NF and 20 avoirdupois oz of mentol, USP [R5, 212] *To every 100 gal of ethyl alcohol add: Ten lb of any one or a total of 10 lb of two or more of the oils and substances listed below: anethole, USP; anise oil, USP; bay oil (myrcia oil), NF; benzaldehyde, NF; bergamot oil, NF; bitter almond oil, NF; camphor, USP; cedar leaf oil, USP, XIII; chlorothymol, NF; cinnamic aldehyde, NF, IX; cinnamon oil (cassia oil), USP; citronella oil, natural; clove oil, USP; coal tar, USP; eucalyptol, USP; eucalyptus oil, NF; eugenol, USP; guaiacol, NF; lavender oil, USP; menthol, USP; mustard oil, volatile (allyl isothiocyanate), USP, XII; peppermint oil, USP; phenol, USP; phenyl salicylate (salol), NF; pine oil, NF; pine needle oil, dwarf, NF; rosemary oil, NF; safrol; sassafras oil, NF; spearmint oil, NF; spearmint oil, terpeneless; spike lavender oil, natural; storax, USP; thyme oil, NF; thymol, NF; tolu balsam, USP; turpentine oil, NF; wintergreen oil (methyl salicylate), USP [R5, 213] *To every 100 gal of ethyl alcohol add: 10 lb of menthol, USP and 1.25 gal of formaldehyde soln, USP [R5, 214] *To every 100 gal of ethyl alcohol add: Two and one-half lb of menthol, USP and 2.5 gal of formaldehyde soln, USP [R5, 214] *To every 100 gal of ethyl alcohol add: (1) Six lb of boric acid, USP, 1 and 1/3 lb thymol, NF, 1 and 1/3 lb chlorothymol, NF and 1 and 1/3 lb menthol, USP; or (2) Seven lb of boric acid, USP, and a total of 3 lb of any two or more denaturing materials listed under SDA No 38-B [R5, 214] *To every 100 gal of ethyl alcohol add: Nine lb of sodium salicylate or salicylic acid, USP, 1.25 gal fluid extract of quassia, NF, VII and 1/8 gal of tertiary butyl alcohol [R5, 214] *To every 100 gal of ethyl alcohol add: Sixty avoirdupois oz of any one of the following alkaloids or salts together with 1/8 gal of tertiary butyl alcohol: quinine, NF; quinine bisulfate, NF; quinine hydrochloride, USP; cinchonidine; cinchonidine sulfate, NF, IX [R5, 214] *To every 100 gal of ethyl alcohol add: Two and 1/2 gal of diethylphthalate and 1/8 gal of tertiary butyl alcohol [R5, 215] *To every 100 gal of ethyl alcohol add: One gal of diethylphthalate [R5, 215] *To every 100 gal of ethyl alcohol add: One gal of bay oil, NF and either 50 avoirdupois oz of quinine sulfate, USP, 50 avoirdupois oz of quinine bisulfate, NF, or 200 avoirdupois oz of sodium salicylate, USP [R5, 215] *To every 100 gal of ethyl alcohol add: One and one-half avoirdupois oz of brucine (alkaloid), or brucine sulfate (NF, IX), or quassin, or one and one-half av oz of any combination of two or of three of those denaturants, and 1/8 gal of tertiary butyl alcohol [R5, 216] *To every 100 gal of ethyl alcohol add: One lb of sucrose octa-acetate and 1/8 gal of tertiary butyl alcohol [R5, 216] *To every 100 gal of ethyl alcohol add: One-sixteenth avoirdupois oz of denatonium benzoate, NF, (Bitrex) and 1/8 gal of tertiary butyl alcohol [R5, 216] *To every 100 gal of ethyl alcohol add: Three gal of tertiary butyl alcohol [R5, 217] *To every 100 gal of ethyl alcohol add: Eighty g of potassium iodide, USP and 109 g of red mercuric iodide, NF or 95 g of thimerosal, NF or 76 g of any of the following: phenyl mercuric nitrate, NF; phenyl mercuric chloride, NF; or phenyl mercuric benzoate [R5, 217] *To every 100 gal of ethyl alcohol add: Ten gal of n-butyl alcohol [R5, 217] *To every 100 gal of ethyl alcohol add: Three hundred lb of refined white or orange shellac [R5, 217] *To every 100 gal of ethyl alcohol add: 25 fluid oz of phenol, USP and 4 fluid oz of wintergreen oil (methyl salicylate), USP [R5, 217] *Grades of purity: Anhydrous (200 proof); 190 proof [R6] *Preparations: Alcohol and Dextrose Injectio, USP; Ethanol for Disinfection; Evaporating Lotion; High alcoholic Elixir; Iso-alcoholic Elixir; Low alcoholic Elixir; Spirit Ear-drops [R7, 39] MFS: +American Development Corp, Hq, 3200 Park Center Dr, Costa Mesa, CA 92626, (714) 641-6660; Production site: Hastings, NE 68901 [R8, 607] +Archer Daniels Midland Co, Hq, PO Box 1470, Decatur, IL 62525, (217) 424-5200; ADM Processing Division; Production sites: Cedar Rapids, IA 52413; Clinton, IN 47800; Decatur, IL 62500; Peoria, IL 61600 [R8, 607] +CENEX, Hq, PO Box 43089, St Paul, MN 55164, (612) 451-5151; CENEX Agrifuels Co, Road 9, Walhalla, ND 58282 [R8, 607] +Eastman Kodak Co, Hq, 343 State St, Rochester, NY 14650, (716) 724-4000, Eastman Chemical Products, Inc, PO Box 431, Kingsport, TN 37662; Texas Eastman Co; Production site: Longview, TX 75607 [R8, 607] +Edington Oil Co, Hq, 2400 E Artesia Boulevard, Long Beach, CA 90805, Subsidiary: Agrifuels Refining Corp, New Iberia, LA 70560, (318) 367-3511 [R8, 607] +Energy Fuels Development Corp, Hq, PO Box 892, Portales, NM 88130, (505) 356-8535 [R8, 607] +Georgia-Pacific Corp, Hq, 133 Peachtree St NE, Atlanta, GA 30303, (404) 521-4000; Chemical Division; Production site: 300 Laurel St, Bellingham, WA 98225 [R8, 607] +Grain Processing Corp, Hq, 1600 Oregon St, Muscatine, IA 52761, (319) 264-4265 [R8, 607] +High Plains Corporation, Hq, 412 N First St, Colwich, KS 67030, (316) 796-1234 [R8, 607] +Kentucky Agricultural Energy Corp, 3150 Nashville Rd, Franklin, KY 42134, (502) 586-9586 [R8, 607] +Midwest Grain Products, Inc, Hq, 1300 Main St, (PO Box 130) Atchison, KS 66002, (913) 367-1480; Production sites: Atchison, KS 66002; South Front St, Pekin, IL 61554 [R8, 607] +New Energy Co of Indiana, Hq, 3201 W Calvert St, South Bend, IN 46680, (219) 233-3116 [R8, 607] +Pekin Energy Co, Hq, PO Box 10, Pekin, IL 61555, (309) 347-9200 [R8, 608] +Quantum Chemical Corp, Hq, 99 Park Ave, New York, NY 10016, (212) 949-5000; USI Division, 11500 Northlake Dr, Cincinnati, OH 45249; Production site: Tuscola, IL 61953 [R8, 608] +South Point Ethanol, County Rd 1, Old US 52, PO Box 1004, South Point, OH 45680, (614) 377-2765 [R8, 608] +Staley Continental, Inc, AE Staley Manufacturing Co, Hq, 2200 East Eldorado St, Decatur, IL 62525, (217) 423-4411; Sweetener Business Group, Ethanol Division, Production site: Loudon, TN 37774 [R8, 608] +Tennol Energy Co, Hq, 1901 Research Blvd, Suite 430, Rockville, MD 20850, (301) 738-1933; Production site: Jasper, TN 37347 [R8, 608] +Union Carbide Corp, Hq, Old Ridgebury Rd, Danbury, CT 06817, (203) 794-2000; Chemicals and Plastics Business Group, Solvents and Coatings Materials Division; Production site: Texas City, TX 77591 [R8, 608] +Universal Foods Corp, Hq, 433 E Michigan St, Milwaukee, WI 53202, (414) 271-1820; Fermentation Division; Production site: Juneau, WI 53201 [R8, 608] +Dow Chemical Co, 2020 Willard Highway, Dow Center, Midland, MI 48686-0994, (517) 636-6125 /Ethyl alcohol, synthetic/ [R9, p.15-23] +Eastman Kodak Co, Hq, 34 State St, Rochester, NY 14650, (716) 724-4000; Production site: Texas Eastman Co, Division, Kingsport, TN 37662 /Ethyl alcohol, synthetic/ [R9, p.15-23] +Hoechst Celanese Corp, Hq, Rt 202-206 N, Somerville, NJ 08876, (201) 231-2000/; Production sites: Chemical Grp Division, 1250 W Mockingbird Lane, Dallas, TX 75247, Fibers Division, Charlotte, NC 28232; Sou-Tex, Mount Holly, NC 28120 /Ethyl alcohol, synthetic/ [R9, p.15-23] +Shell Oil Co, Hq, PO Box 3105, Houston, TX 77002; Production site: Shell Chemical Co, Houston TX 77002 /Ethyl alcohol, synthetic/ [R9, p.15-23] +USI Chemical Co, Inc, USI Division, 11500 Northlake Dr, Cincinnati, OH 45249, (513) 530-6580 /Ethyl alcohol, synthetic/ [R9, p.15-23] OMIN: *Industrial ethyl alcohol ... always contains a denaturant, ie, a substance added to render it unfit or undesirable as a beverage or vehicle for any medication intended for ingestion. Denatured alcohols are designed to have objectionable odors or tastes and to provoke vomiting or to induce significant systemic toxicity. The IRS and federal regulations recognize two classes of denatured alcohol, completely denatured (CD) and specifically denatured (SD). [R10, p. II-174] *... Wood consists of 2/3 carbohydrates, considerable attention has been given to the potential of wood residues as a raw material for conversion to ethanol. [R1, p. 24(84) 600] USE: *IN ALCOHOLIC BEVERAGES; MANUFACTURING OF DENATURED ALCOHOLS; PHARMACEUTICALS; IN PERFUMERY; IN ORGANIC SYNTHESIS; OCTANE BOOSTER IN GASOLINE; SOLVENT AND DEHYDRATING AGENT. [R2, 35] *IN SYNTHETIC RUBBER, PAINT AND LACQUER, AND EXPLOSIVES INDUSTRIES; ANTI-FREEZE AGENT. [R11] *Manufacturing of surface coatings; gasohol, yeast growth medium [R3, 478] *Solvent for resins, fats, fatty acids, oils, hydrocarbons [R3, 478] *DIRECT FOOD ADDITIVES [R12] *Manufacturing of acetaldehyde, acetic acid, ethylacetate, ethylchloride, ethylether, butadiene, ethylene dibromide, plastics and plasticizers, soap and cleaning preparations, dyes, explosives [R13, 617] +MEDICATION (VET): +MEDICATION *In inks [R1, p. 13(81) 390] *For surgical suture packaging [R1, p. 22(83) 441] *Ethylene is manufactured by the vapor phase dehydration of ethanol [R1, p. 9(80) 369] *The addition of one mole of ethylene oxide to ethanol gives ethylene glycol monoethyl ether. Dilute soln of alcohol as fermented worts are oxidized by air at 30-40 deg C in the presence of various organisms to produce dilute acetic acid as vinegar. [R1, p. 9(80) 370] *Mono-, di-, and triethylamines, produced by catalytic reaction of ethanol with ammonia, are a significant outlet for ethanol. In the synthesis of ethyl acrylate, the esterification of acrylic acid is a major use for ethanol. [R1, p. 9(80) 371] *The addition of ethanol to acetylene gives ethyl vinyl ether. [R1, p. 9(80) 372] CPAT: *MOTOR FUEL SUPPLEMENT, 25%; SOLVENT FOR: TOILETRIES AND COSMETICS, 11%; COATINGS, INKS AND PROPRIETARY BLENDS, 11%; DETERGENTS, DISINFECTANTS AND FLAVORINGS, 7%; PROCESSING, 5%; PHARMACEUTICALS, 2%; OTHER SOLVENT USES, 2%; CHEM INTERMED FOR: GLYCOL ETHERS, 6%; ETHYL ACRYLATE, 6%; ETHYL AMINES, 5%; ETHYL ACETATE, 3%; ACETALDEHYDE, 3%; OTHER USES, 4% (1981 NON-BEVERAGE USE) [R14] *Chemicals manufacture, 40%; vinegar, 8%; solvents: coatings and inks, 15%; solvents: cosmetics and toiletries, 15%; solvents: foods flavors, and pharmaceuticals, 12%; other solvents, 5%; miscellaneous, 5% (1984 estimate) [R15] *CHEMICAL PROFILE: Synthetic ethanol: chemical intermediate (for ethyl acetate, ethyl acrylate, glycol ethers, ethylamines and other), 30%; toiletries and cosmetics, 20%; coatings solvent, 15%; vinegar, 10%; household cleaners, 7%; detergents, 5%; pharmaceuticals, 5%; printing inks, 3%; miscellaneous, 5%. Fermentation ethanol: fuel component, 90%; beverages, 8%; industrial (chemical and solvent) uses, 2% (1988). [R16] *CHEMICAL PROFILE: Ethanol. Demand: Synthetic/1987: 210 million gallons; 1988: 215 million gallons; 1992 /projected/: 230 million gallons. (Includes 15 to 20 million gallons of synthetic ethanol imports; exports are negligible). Fermentation/1987: 860 million gallons; 1988: 950 million gallons; 1992 /projected/: 1,150 million gallons (Foreign trade is minimal) (1988). [R16] PRIE: U.S. PRODUCTION: *(1977) 8.42X10+11 G (NOT INCL BEVERAGE) [R14] *(1982) 9.33X10+11 G (NOT INCL BEVERAGE) [R14] *(1984) 5.43X10+8 gal /estimate/ [R15] *(1985) 6.49X10+8 lb /Synthetic only for non-beverage purposes/ [R17] *(1986) 5.11X10+8 lb /Synthetic only/ [R18] *(1987) 5.74X10+8 lb [R9, p.15-5] U.S. IMPORTS: *(1977) 5.9X10+10 G (NOT INCL BEVERAGE) [R14] *(1982) 1.09X10+11 G (NOT INCL BEVERAGE) [R14] *(1985) 1.62X10+11 gal (for nonbeverage purposes) [R19] *(1986) 1.57X10+8 gal [R20] U.S. EXPORTS: *(1978) 2.18X10+10 G (NOT INCL BEVERAGE) [R14] *(1983) 7.53X10+9 G (NOT INCL BEVERAGE) [R14] *(1985) 3.24X10+6 gal [R21] *(1987) 1.04X10+6 gal [R22] *(1988) 4.59X10+5 gal [R23] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CLEAR, COLORLESS, VERY MOBILE LIQUID [R2, 35]; +Clear, colorless liquid. [R24] ODOR: *Mild, rather pleasant; like wine or whiskey [R6]; +Weak, ethereal, vinous odor. [R24] TAST: *Burning [R2, 35] BP: *78.5 DEG C [R2, 35] MP: *-114.1 DEG C [R2, 35] MW: *46.07 [R2, 34] CTP: *CRITICAL TEMPERATURE: 243 DEG C; CRITICAL PRESSURE: 63 ATM [R25, p. F-66] DEN: *0.789 @ 20 DEG C/4 DEG C [R2, 35] DSC: +pKa = 15.9 at 25 deg C [R26] HTC: *326.68 kg cal/g mol wt at 25 deg C [R25, p. D-276] HTV: *9673.9 G CAL/G MOLE [R25, p. C-672] OWPC: +log Kow= -0.31 [R27] SOL: *> 10% in water [R28]; *> 10% in ether [R28]; *> 10% in acetone [R28]; *> 10% in benzene [R28]; *MISCIBLE WITH WATER AND MANY ORG SOLVENTS [R2, 35]; +Water solubility = miscible [R26] SPEC: *INDEX OF REFRACTION: 1.361 @ 20 DEG C/D [R2, 35]; *MAX ABSORPTION (GAS): 181 NM (LOG E= 2.51); SADTLER REFERENCE NUMBER: 188 (IR, PRISM); 64 (IR, GRATING) [R29]; *IR: 6986 (Coblentz Society Spectral Collection) [R28]; *NMR: 14 (Varian Associates NMR Spectra Catalogue) [R28]; *MASS: 16 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R28]; *Intense mass spectral peaks: 31 m/z , 45 m/z, 46 m/z [R30] SURF: *22.75 dynes/cm in contact with vapor @ 20 deg C [R25, p. F-35] VAPD: *1.59 (AIR= 1) [R31, 1316] VAP: +59.3 mm Hg at 25 deg C /from experimentally derived coefficients/ [R32] VISC: *44.0 CP -98.11 deg C; 1.773 CP at 0 deg C; 1.200 CP at 20 deg C; 0.504 CP at 70 deg C [R25, p. F-42] OCPP: *% IN SATURATED AIR: 6.58 @ 25 DEG C; DENSITY OF SATURATED AIR: 1.04 (AIR= 1); EQUIVALENCES: 1 MG/L= 532 PPM; 1 PPM= 1.88 MG/CU M @ 25 DEG C AND 760 MM HG [R33, 4592] *RATIO OF SPECIFIC HEATS OF VAPOR: 1.128; HEAT OF SOLUTION: -55 CAL/G= -2.3X10+5 J/KG= -99 BTU/LB; REID VAPOR PRESSURE: 2.3 PSIA [R6] *Specific heat 0.618 cal/g @ 23 deg C [R3, 477] *Heat of Formation: -66.37 kcal/mol (liq); -56.19 kcal/mol (gas) at 25 deg C [R25, p. D-60] *Heat of Fusion: 26.05 cal/g= 108.99 J/g= 5,021 J/mol [R25, p. C-666] *Absorbs water rapidly [R2, 35] *SOLIDIFIES BELOW -130 DEG C [R2, 35] *Heat capacity: 113.0 J/mol-K (liquid) and 65.7 J/mol-K (gas) at 25 deg C AND 1 atm [R25, p. D-174] *VOLATILE [R34] *Dielectric constant: 25.00 at 20 deg C; 20.21 at 55 deg C; dipole moment: 1.69 (gas), 1.71 in benzene at 25 deg C [R35, p. 4-60] *Enthalpies of formation: -66.20 kcal/mole (liquid); -56.03 kcal/mole (gas); Gibbs (free) energies of formation: -41.63 kcal/mole (liquid); -40.13 kcal/mole (gas); Entropies: 38.49 cal/deg-mole (liquid); 67.54 cal/deg-mole (gas); Heat capacities: 26.76 cal/deg-mole (liquid); 15.64 cal/deg-mole (gas) [R35, p. 5-19] *Heat of melting: 1.198 kcal/mole; heat of sublimation: 10.11 kcal/mole at 298 K; specific heat: 19.36 cal/K.mol at 400 K [R35, p. 5-58] *Observed and estimated solubility of naphthalene in ethanol at 40 deg C: 0.073 mole fraction (observed) and 0.054 mole fraction (estimated) [R36, p. 3-21] *Observed and estimated solubility of anthracene in ethanol at 20 deg C: 0.0005 mole fraction (observed) and 0.0004 mole fraction (estimated) [R36, p. 3-22] *Observed and estimated solubility of phenanthrene in ethanol at 20 deg C: 0.0123 mole fraction (observed) and 0.0102 mole fraction (estimated) [R36, p. 3-23] *Rate constant for reaction of ethanol with OH radical at 300 K: 1.8X10+12 cu cm/mol-sec [R36, p. 10-23] *Electrical conductivity: 1.35X10-9/ohm cm at 25 deg C; heat of solution: 2.54 kcal/mole solute in water at 13 deg C; latent heat of fusion: 24.9 cal/g; specific tension: 22.1 dynes/cm at 25 deg C; wt/gal: 6.61 at 20 deg C [R5, 199] *Forms binary azeotropes with tert-amyl ethyl ether, benzene, 1-bromobutane, 2-bromobutane, cis-1-bromo-1-butene, trans-1-bromo-1-butene, cis-2-bromo-2-butene, trans-2-bromo-2-butene, 2-bromo-1-butene, 1-bromo-3-methylbutane, 1-bromo-1-methylpropane, 2-bromo-2-methylpropane, 1-bromopropane, 2-bromopropane, 2-bromopropane, trans-1-bromopropene, cis-1-bromopropene, tert-butyl ethyl ether, carbon disulfide, carbon tetrachloride, 1-chlorobutane, 2-chlorobutane, cis-1-chloro-1-butene, trans-1-chloro-1-butene, 2-chloro-1-butene, cis-2-chloro-2-butene, chloroform, 1-chloro-3-methylbutane, 1-chloro-2-methylpropane, 1-chloropropane, 2-chloropane, trans-1-chloropropene, 3-chloropropene, 1,3-cyclohexadiene, cyclohexane, cyclohexane, cyclopentane, 1,1-dichloropropane, 2,2-dichloropropane, 2,5-dimethylhexane, diethoxymethane, ethyl acetate, ethyl acrylate, ethyl propionate, ethyl propyl ether, ethyl sulfide, fluorobenzene, n-heptane, n-hexane, 2-iodobutane, 1-iodo-2-methylpropane, 1-iodopropane, 2-iodopropane, 3-iodopropene, isobutyl formate, isoprene, isopropyl acetate, methyl acetate, methyl acrylate, methyl borate, 2-methylbutane, methyl butyrate, methyl carbonate, methylcyclopentene, methylcyclopentene, methyl ethyl ketone, methyl propionate, octane, pentane, 2-pentanone, perchloroethylene, propanediol, propyl acetate, propyl ether, thiophene, toluene, trichloroethylene [R5, 219] *Forms ternary azeotropes with water, acetal; water, benzene; water, bromodichlormethane; water, 1-bromo-2-methylpropane; water, cis-1-bromopropane; water, trans-bromopropane; water, 1-bromopropane; water, 2-bromopropane; water, carbon disulfide; water, chloroform; water, 1-chloro-2-methylpropane; water, cyclohexene; water, 1,2-dichloroethane; water, cis-1,2-dichloroethylene; water, trans-1,2-dichloroethylene; water, dimethoxymethane; water, ethyl acetate; water, ethyl chloroacetate; water, trichloroethylene; water, triethylamine [R5, 219] *Saturated concn in air: 105 g/cu m at 20 deg C, 182 g/cu m at 30 deg C [R13, 617] *Liquid heat capacity: 0.583 BTU/lb-F @ 70 deg F; Liquid thermal conductivity: 1.159 BTU-in/hr-sq ft-F at 70 deg F; Saturated vapor density: 0.00716 lb/cu ft @ 70 deg F; Ideal gas heat capacity: 0.384 BTU/lb-F @ 75 deg F [R6] *Diffusion coefficient: 0.034 sq m/hr (calculated) and 0.037 sq m/hr (experiment) in air at 0 deg C and 1 atm [R1, p. 1(78) 87] *Magnetic susceptibility: 0.734X10-6 at 20 deg C [R1, p. 9(80) 339] +VAPOR PRESSURE= 40 MM HG @ 19 DEG C [R25, p. D-197] +Henry's Law constant = 5X10-6 atm-cu m/mol at 25 deg C [R37] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R38] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R38] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R38] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R38] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R38] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R38] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R38] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R38] FPOT: *DANGEROUS WHEN EXPOSED TO HEAT OR FLAME ... . [R31, 1317] NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R39, p. 325-48] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R39, p. 325-48] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R39, p. 325-48] FLMT: +LOWER 3.3%; UPPER 19% (BY VOL) [R39, p. 325-48] FLPT: +55 DEG F (13 DEG C) (CLOSED CUP) [R39, p. 325-48] *55 deg F (closed cup); 64 deg F (open cup) [R6] +63 deg F (17 deg C) (closed cup) /96%/ [R39, p. 325-48] +79 deg F (24 deg C) (closed cup) /50%/ [R39, p. 325-48] +144 deg F (62 deg C) (closed cup) /5%/ [R39, p. 325-48] AUTO: +685 DEG F (363 DEG C) [R39, p. 325-48] FIRP: *The most appropriate extinguishers are carbon dioxide and dust; Water may be used, provided it is /used/ in large amounts. [R40, 792] *Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical ... . [R41] EXPL: *VAPOR MAY EXPLODE IF IGNITED IN AN ENCLOSED AREA. [R6] REAC: *STRONG OXIDIZING AGENTS SUCH AS CHLORINE, PERMANGANATE, OR CHROMATE IN ACID SOLN REACT, IN SOME CASES VIOLENTLY, WITH ALCOHOL TO PRODUCE OXIDATION PRODUCTS. [R34] *A solution of permanganic acid (or its explosive anhydride dimanganese heptoxide) ... will explode on contact with ... ethanol ... . [R42, 1099] *Solid /ruthenium (VIII) oxide/ or its concentrated solutions or vapor, tends to oxidize ethanol, cellulose fibers ... explosively. [R43] *Bromine pentafluoride ... contact with ... ethanol is likely to cause fire or explosion ... . [R42, 93] *... Ethanol ignites then explodes /upon contact with nitrosyl perchlorate/. [R42, 935] *... Ethanol ... ignites on contact with /chromyl/ chloride ... . [R42, 963] *Uranium hexafluoride /reacts violently/ with ethanol ... . [R42, 1078] *... Ethanol ... ignites in contact with /iodine heptafluoride/ gas ... . [R42, 1080] *Attempted crystallization of ... /uranyl perchlorate/ from ethanol caused an explosion ... . [R42, 984] *Interaction ... /between/ water, methanol or ethanol /and acetyl bromide/ is violent, hydrogen bromide being evolved. [R42, 238] *Reclaimed silver nitrate crystals, damp with the alcohol used for washing, exploded violently when touched with a spatula ... . [R42, 13] *A 15% soln of nitric acid in ethanol was used to etch a bismuth crystal. After removing the metal, the mixture decomp vigorously. [R42, 1103] *Violent reaction on mixing /of disulfuryl difluoride and ethanol/ at ambient temp. [R42, 1066] *The desiccant /magnesium perchlorate/ in a drying tube, accidentally exposed to ethanol vapor, was left for several months. The explosion which occurred when the desiccant was scraped out was certainly due to formation of ethyl perchlorate. [R42, 973] *Addition of platinum black catalyst to ethanol caused ignition. Pre-reduction with hydrogen and/or nitrogen purging of air prevented this. [R42, 1386] *Contact of 1.5 g portions of the solid /potassium tert-butoxide/ ... with ... /ethanol vapor for 7 min/ caused ignition ... . [R42, 456] *Silver oxide and ammonia or hydrazine slowly form explosive silver nitride and, in presence of alcohol, silver fulminate may also be produced. [R42, 17] *Air must be excluded during exothermic interaction of ethanol with sodium finely dispersed in hydrocarbons to avoid the possibility of hydrogen air mixture explosions. [R42, 1317] *In the preparation of ethyl polysilicate by mixing tetrachlorosilane and industrial methylated spirit containing some water, failure of the agitator is thought to have led to layering of the alcohol over the dense chloride. Evolution of hydrogen chloride led to mixing of the layers, and a greatly incr rate of reaction and self-accelerating gas evolution which burst the reactor. [R42, 1005] +Acetyl chloride reacts violently with ethyl alcohol or water. [R39, p. 491-8] +A mixture of silver oxide plus ethyl alcohol and aq ammonia forms the very sensitive silver nitride. [R39, p. 491-171] +A little calcium hypochlorite added to ethyl alcohol or glycerol will result in a violent explosion after a short time. [R39, p. 491-42] +No really safe conditions exist under which ethyl alcohol and chlorine oxides can be handled. [R39, p. 491-57] +The addition of alcohols to highly concn hydrogen peroxide forms powerful explosives which can be detonated by shock. [R39, p. 491-80] +The Petrov method of preparing 1-iodo-2-ethoxy-3-butene calls for addition of 15 g of mercuric oxide to 0.11 molar ethyl alcohol in 25 ml of methyl alcohol, followed by 25 g of powdered iodine at -10 to -15 deg C, filtration, and dilution. A change in the procedure used 1 molar ethyl alcohol. While the alcohol was being distilled off under vacuum, a violent explosion occurred. [R39, p. 491-101] +A violent explosion occurred when manganese perchlorate, absolute alcohol and 2,2-dimethoxypropane were gently refluxed for about two hr under a stream of nitrogen. [R39, p. 491-80] +Alcohols should not be mixed with mercuric nitrate, as explosive mercury fulminate may be formed. [R39, p. 491-117] +Certain metal perchlorates recrystallized from benzene or ethyl alcohol can explode spontaneously. /Metal perchlorates/ [R39, p. 491-140] +In mineral analysis the potassium cation is sometimes identified by adding perchloric acid in the presence of ethyl alcohol concn. Explosions frequently occur that are due to the spontaneous decomp of ethyl perchlorate formed during concn and of residual perchloric acid. [R39, p. 491-141] +To dispose of a sodium-potassium waste, it was placed in a glove box, which was then purged with argon for 10 min. When 10 ml of alcohol was added to the waste, an immediate pressure rise caused the glove to burst and flame issued from the port. Also, a highly oxidized sphere of potassium was cut in two and one half was dropped into a dish of alcohol; an immediate explosion shattered the dish. Potassium superoxide was considered the cause of both incidents. [R39, p. 491-163] +Addition of air, or alcohol, or moisture to sodium hydrazide can produce an explosion. [R39, p. 491-179] +Strong oxidizers, potassium dioxide, bromine pentafluoride, acetyl bromide, acetyl chloride, platinum, sodium. [R44, 132] ODRT: *10 PPM [R6] *1.00X10-1 mg/l gas (detection in air, purity not specified) [R45, 61] *1.00X10+2 mg/l liquid (detection in water, purity not specified) [R45, 61] *9.23 ppm (detection in water, purity not specified) [R45, 61] *2.50X10-1 ppm (detection in water, purity not specified) [R45, 61] *5.75 ppm (detection in water, purity not specified) [R45, 61] *1.88X10-1 ppm (detection in water, purity not specified) [R45, 61] *1.00X10+2 ppm (detection in water, purity not specified) [R45, 61] *1.00X10+1 ppm (recognition in air, chemically pure) [R45, 61] *4.40X10+3 ppm (detection in air, purity not specified) [R45, 61] *2.40X10+13 molecules/cu cm (in air, purity not specified) [R45, 62] *3.30X10+13 molecules/cu cm (in air, purity not specified) [R45, 62] *Odor thresholds: 0.3420 mg/cu m (low) 9690.000 mg/cu m (high). [R46] EQUP: *ALL-PURPOSE CANISTER; SAFETY GOGGLES. [R6] *Personal protective equipment ... should be provided where there is ... prolonged skin contact. [R40, 792] *Protective clothing should be worn by persons who are exposed to ethanol and should be composed of natural rubber, neoprene, nitrile, or vitron as these compounds have breakthrough times (ie the time it takes for a compound to move from the outer surface of protective clothing to the inner surface) of at least an hour or more. [R47] *Breakthrough times geater than one hour reported by (normally, two or more testers for butyl rubber (butyl), natural rubber (nat.rub) neoprene (neop), nitrile rubber (nitrile) and viton. Breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for polyvinyl alcohol (PVA) and polyvinyl chloride (PVC). No data for neoprene/styrene-butadiene rubber (neop/SBR), nitrile rubber/polyvinyl chloride (nitrile/PVC), polyethylene (PE), polyurethane (PU), and styrene-butadiene rubber (SBR). [R47] +Wear appropriate personal protective clothing to prevent skin contact. [R44, 133] +Wear appropriate eye protection to prevent eye contact. [R44, 133] +Recommendations for respirator selection. Max concn for use: 3300 ppm. Respirator Class(es): Any supplied-air respirator. Any self-contained breathing apparatus with a full facepiece. [R44, 133] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R44, 133] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any appropriate escape-type, self-contained breathing apparatus. [R44, 133] OPRM: *Good ventilation will prevent the formation of harmful concentrations of alcohol vapors ... Arrangements should be made by the provision of sills and curbs and by the design of floors to limit the spread of escaping liquid and to conduct it to a safe place ... Precautions should be taken ... by the provision of flameproof electrical installations and equipment, to prevent sources of ignition where large quantities of ethyl alcohol are made or used /and/or stored/. [R40, 792] *If material /is/ not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R41] *Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R41] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R41] *Employees who handle liquid isobutyl alcohol should wash their hands before eating or smoking. /Isobutyl alcohol/ [R48, 1981.3] +The worker should immediately wash the skin when it becomes contaminated. [R44, 133] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R44, 133] +Contact lenses should not be worn when working with this chemical. [R44, 133] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R49] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R50] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R51] STRG: *Keep tightly closed, cool and away from flame. [R2, 35] *STORAGE TEMP: AMBIENT. VENTING: OPEN (FLAME ARRESTER) OR PRESSURE VACUUM. [R6] *Protect containers against physical damage. Underground storage tanks outside the building is preferred for use of large quantities. Small amt may be stored outside the building in the original shipping containers. ... Should not be stored with perchlorates, peroxides, chromic acid and nitric acid. [R52] CLUP: *Land spill: Apply appropriate foam to diminish vapor and fire hazard. [R41] *Water spill: Use natural barriers or oil spill control booms to limit spill travel. Allow to aerate. [R41] *Air spill: Apply water spray or mist to knock down vapors. [R41] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *The following wastewater treatment technologies have been investigated for ethanol: Biological Treatment. [R53] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R54, 2002.31] MEDS: *Look for chronic irritation of mucous membranes and signs of chronic alcoholism in regular physical exam. Ethyl alcohol can readily be determined in blood, urine, and expired air. [R55, 411] *The determination of ethanol in blood, breath or urine sampled during or just after the work period can provide a useful index to exposure. ... The blood alcohol concn should not exceed 200-300 mg/l in exposed workers. Pre-exposure specimens should be taken to rule out nonoccupational sources of ethanol. [R56, 141] *Employees should be screened for history of certain medical conditions ... /skin, liver, kidney, eye, or chronic respiratory diseases central and peripheral nervous systems/ which might place the employee at increased risk from butyl alcohol exposure. ... Any employee developing the ... conditions should be referred for further medical exam. [R48, 1981.1] HTOX: *At 20-99 mg ethyl alcohol/100 ml blood: Impaired sensory function: 1. Reduced visual acuity (flicker-fusion test). 2. Decr sense of smell and taste. 3. Elevated threshold for pain: a. Decr sensitivity of cornea of eye. b. Decr sensitivity to local heating of skin. B. Muscular incoordination: 1. Spontaneous and induced nystagmus. 2. Decr steadiness while standing (Romberg test). 3. Impaired performance on tests of skill (Ring test, finger-to-finger test, target practice, typing). 4. Impairment of ability to drive an automobile. C. Changes in mood, personality, and behavior: 1. Dizziness. 2. Reduced sense of fatigue. 3. Mild euphoria. 4. Self satisfaction. 5. Release of inhibitions. 6. Loud, profuse speech. D. Impaired mental activity: 1. Subtraction test. 2. Reading comprehension tests. [R57] *At 100-199 mg ethyl alcohol/100 ml/dl/ blood: A. Staggering gait. B. Marked impairment on mental tests. C. Marked impairment of driving ability. D. Lengthened reaction time. At 200-299 mg/100 ml/dl/: A. Nausea and vomiting. B. Diplopia. C. Marked ataxia. D. Extreme clumsiness. At 300-399 mg/100 ml/dl/: A. Hypothermia. Cold, clammy skin. B. Loss of ability to speak. C. Amnesia. D. Anesthesia. E. Heavy breathing. [R58] *The threshold level that impairs skill in automobile driving is about 35 mg/100 ml/dl/ ethyl alcohol in blood. Blood levels greater than 400 mg/100 ml/dl/ produce deep coma and possibly death. If the coma persists for 8 to 10 hr, shock and circulatory collapse may develop. [R59] *In severe acute intoxication pt is stuporous or comatose. Skin is cold and clammy, body temp is low, respirations ... slow and noisy, pupils may be normal or dilated ... heart rate accelerated. If this condition persists ... 8 or 10 hr, hypostatic pneumonia or incr intracranial pressure may ensue. [R60, 384] *... A splash on human eye causes immediate burning and stinging discomfort with reflex closure of the lids. [R61, 53] *Alcohol vapor exposure at sufficiently high concn may cause prompt stinging and watering of the eyes, but there appear to be no reports of eye injury from industrial exposure to alcohol vapors. Human volunteers exposed to alcohol vapor have observed at concn of 0.7 to 1% vapor in air the smell of alcohol was at first almost unbearable, although unpleasant later, and that the eyes began to burn with incr intensity after several min. ... A vapor concn of 0.25% had no notable effect on the eyes. [R61, 54] *... 4 cases of chronic alcoholic patients who developed oscillopsia (illusory movement of the environment) with downbeat nystagmus, associated with ataxia of gait and cerebellar atrophy /were reported/. [R61, 57] *... FETAL ALCOHOL SYNDROME ... THE ABNORMALITY CONSISTS IN CNS DYSFUNCTION (SUCH AS LOW IQ AND MICROCEPHALY), SLOWNESS IN GROWTH, A CHARACTERISTIC CLUSTER OF FACIAL ABNORMALITIES (SUCH AS SHORT PALPEBRAL FISSURES, HYPOPLASTIC UPPER LIP, AND SHORT NOSE), AND A VARIABLE SET OF MAJOR AND MINOR MALFORMATIONS. THESE FEATURES MAY BE DUE, AT LEAST IN PART, TO A DIRECT ACTION OF ETHANOL TO INHIBIT EMBRYONIC CELLULAR PROLIFERATION EARLY IN GESTATION. ... CHILDREN WITH THE FETAL ALCOHOL SYNDROME HAVE A GREATLY INCR SUSCEPTIBILITY TO BOTH LIFE THREATENING AND MINOR INFECTIOUS DISEASES. SUCH CHILDREN HAVE EXTENSIVE IMPAIRMENT OF THEIR IMMUNE SYSTEM ... . [R62, 375] *SURAL NERVES OF PT WITH DIFFERENT SIGNS OF ALCOHOLIC NEUROPATHY WERE STUDIED BY ELECTRON MICROSCOPY. MYELINATED AND UNMYELINATED FIBERS SHOWED DEGENERATIVE CHANGES OF THE WALLERIAN TYPE. IMBALANCE IN DEGENERATIVE AND REGENERATIVE PROCESSES SEEM TO BE THE BASIS OF CHRONIC PARTIAL DENERVATION. [R63] *... HEMATOLOGIC EFFECTS ... ALCOHOL INTERFERES WITH SEVERAL ASPECTS OF FOLATE METABOLISM AND TRANSPORT, AS WELL AS WITH ITS NORMAL PATTERN OF STORAGE AND RELEASE FROM THE LIVER. ... OTHER EFFECTS, SUCH AS THROMBOCYTOPENIA AND VACUOLIZATION OF PRECURSORS OF RED AND WHITE CELLS ... THERE IS ALSO A DEPRESSION OF LEUKOCYTE MIGRATION INTO INFLAMED AREAS WHICH MAY PARTLY ACCOUNT FOR POOR RESISTANCE OF ALCOHOLICS TO INFECTION. [R62, 377] *Alcohol ingestion impairs glottic reflexes, and alcoholics are predisposed to pneumonias and lung abscesses from aspiration of oropharyngeal bacteria. Alcohol intoxication also incr the frequency of sleep apnea and may result in respiratory failure from oversedation. [R64] *Acute alcohol ingestion can lead to alterations of either mechanical function or electrophysiologic properties of the heart, whereas chronic consumption can lead to progressive cardiac dysfunction and congestive cardiomyopathy. [R65] *Alcohol in modest doses has the potential of producing atrial or ventricular arrhythmias. Although many of the pt have underlying heart disease, there are reports of pt with no evident heart disease where acute alcohol ingestion has caused arrhythmias. This sequence of events, (ie, cause and effect), has been referred to as the "holiday heart" syndrome. [R66] *Pathologic effects of ethanol on hematopoietic tissue can result directly from alcohol ingestion or from secondary nutritional deficiencies or hepatic disease. The clinician will often confront an array of overlapping syndromes in the alcoholic pt which involve abnormalities of erythrocytes, leukocytes, and platelets. [R67] *The acute and chronic effects of ethanol on pancreatic structure and function are discussed. Acute necrotizing, acute edematous, acute relapsing, chronic relapsing, and painless pancreatitis have an established association with ethanol abuse. [R68] *A case control study involving interviews with the next of kin or close friends of 120 black males who recently died of esophageal cancer and 250 similarly aged black males who died of other causes was undertaken to discover reasons for the exceptionally high mortality from this cancer in Washington, DC. The major factor responsible for the excess was alcoholic beverage consumption, with an estimated 81% of the esophageal cancers attributed to its use; high use of alcoholic beverages was also found among the controls. The relative risk (RR) of esophageal cancer assoc with use of alcoholic beverages was 6.4 (95% confidence interval= 2.5, 16.4). The RR incr with amt of ethanol consumed and was highest among drinkers of hard liquor, although the risk was also elevated among consumers of wine and/or beer only. /Alcoholic beverages/ [R69] *Intestinal permeability was investigated with a (51)chromium-EDTA (edetic acid) absorption test in 36 non-intoxicated alcoholic pt without liver cirrhosis or overt clinical evidence of malabsorption or malnutrition. Pt abstaining from alcohol for less than 4 days almost invariably had higher intestinal permeability than controls, and in many the abnormality persisted for up to 2 wk after cessation of drinking. The site of altered permeability was the small bowel. The incr intestinal permeability to toxic "non-absorbable" cmpd of less than 5000 mol wt may account for some of the extraintestinal tissue damage common in alcoholic pt. [R70] *Although there is a dose response relationship between alcohol consumption and liver damage, less than one-third of alcoholics develop alcoholic liver disease (ALD). This individual susceptibility to the development of alcoholic liver disease may be explained by genetic and environmental factors. Of the genetic factors, female sex is clearly a significant risk factor, HLA status is probably important but further studies are needed, abnormalities in alcohol metabolism have not been shown to be of primary pathogenic importance and the plethora of immunological disturbances reported appear to be mere epiphenomena. Of the environmental factors, no consistent evidence attests to the significance of hepatitis B viral infection in the susceptibility to developing alcoholic liver disease. [R71] *Mortality from alcohol poisoning was studied by age, sex, marital status and occupation in Finland in 1978-1982. Of 1204 fatal alcohol poisonings, 76 were due to methanol, isopropanol, ethylene glycol, or combinations of these, the rest being due to ethanol. Males predominated: the percentage of females was 11%. Mortality was highest among persons aged 45-54 years. The risk of fatal poisoning differed by marital status and was inversely related to socio-economic level. Thus, among males aged 30-59 years, the age adjusted risk of death among divorced pensioners was 15 times that of married men in upper stratum occupations. If all males were at risk equal to that for married upper stratum men, the annual number of fatal alcohol poisonings among males would decrease by 67%. [R72] *Eighteen asymptomatic post menopausal women volunteered to ingest 2 ml of 100 proof vodka per kg of body weight in orange juice on one night and a placebo on another. Overnight sleep monitoring was performed immediately thereafter. Alcohol ingestion caused reduction in total sleep time from 329 to 281 min and a decrease in rapid eye movement sleep. There was no difference from placebo in the number of episodes of apnea or hypopnea, or in the frequency, length, or severity of oxygen desaturation. In contrast to the effects of alcohol ingestion in men, the effects on breathing and oxygenation are minimal during the sleep of women, if this amount of alcohol is ingested. [R73] *... ALCOHOL WITHDRAWAL IN PT WITH SEVERE PHYSICAL DEPENDENCE ... THREE SOMEWHAT DISTINCT WITHDRAWAL STATES THE TREMULOUS SYNDROME, ALCOHOL RELATED SEIZURE DISORDERS, AND DELIRIUM TREMORS ... MUCH OVERLAPPING ... TREMULOUSNESS, WHICH APPEARS WITHIN A FEW HOURS AFTER THE LAST DRINK, IS OFTEN ACCOMPANIED BY NAUSEA, WEAKNESS, ANXIETY, AND SWEATING. PURPOSIVE BEHAVIOR DIRECTED TOWARD OBTAINING ALCOHOL OR A SUITABLE SUBSTITUTE IS PROMINENT. THERE MAY BE CRAMPS AND VOMITING. HYPERREFLEXIA IS PROMINENT. TREMORS MAY BE MILD OR SO MARKED THAT PT MAY BE UNABLE TO LIFT A GLASS. SUBJECT MAY BEGIN TO "SEE THINGS," AT FIRST ONLY WHEN THE EYES ARE CLOSED BUT LATER EVEN WHILE THE EYES ARE OPEN. INSIGHT IS AT FIRST RETAINED, AND SUBJECT REMAINS ORIENTED. ... TONIC-CLONIC SEIZURES CAN OCCUR, BUT THEY ARE LESS COMMON IN ALCOHOL WITHDRAWAL THAN IN BARBITURATE WITHDRAWAL. THE SPONTANEOUS EEG SHOWS MILD BUT DEFINITE DYSRHYTHMIAS ... TREMULOUS STATE REACHES PEAK INTENSITY WITHIN 24 TO 48 HR, AND SEIZURES ARE MOST LIKELY TO OCCUR WITHIN FIRST 24 HR AFTER CESSATION OF DRINKING. IF THE SYNDROME PROGRESSES FURTHER, INSIGHT IS LOST; SUBJECT BECOMES WEAKER, MORE CONFUSED, DISORIENTED, AND AGITATED. ... AT THIS STAGE, WHICH APPEARS AROUND THE THIRD DAY OF WITHDRAWAL, PICTURE IS THAT OF TREMULOUS DELIRIUM ... HYPERTHERMIA IS COMMON, AND EXHAUSTION AND CARDIOVASCULAR COLLAPSE MAY OCCUR. ... IF PT DOES NOT DIE, RECOVERY USUALLY OCCURS WITHIN 5 TO 7 DAYS, WITHOUT TREATMENT. [R62, 549] *HEAVY DRINKER-HEAVY SMOKER HAS ABOUT 15 TIMES THE RISK OF THE NONSMOKER, NONDRINKER /OF DYING OF CANCER OF THE ORAL CAVITY/. [R74] *The effect of embryonic exposure to maternal drugs during cardiogenesis has been widely studied and the evidence suggests that maternal use of ethanol ... may increase the risk of congenital heart disease. [R75] *The metabolic effects of ethanol are due to a direct action of ethanol or its metabolites. Ethanol causes hyperglycemia or hypoglycemia depending on whether glycogen stores are adequate, inhibits protein synthesis and results in a fatty liver with elevations in serum triglyceride levels. Increases in high density lipoprotein cholesterol after ethanol ingestion may explain the lower risk of myocardial infarction and death from coronary disease after moderate drinking. Increases in serum lactate, resulting from the increased NADH/NAD+ ratio, and hyperurecemia, most likely the result of an increase in the turnover of adenine nucleotides, are common transient effects of ethanol ingestion. Causes of vitamin deficiencies in alcoholism are decreased dietary intake, decreased intestinal absorption, and alterations in vitamin metabolism. Ethanol decreases thiamine absorption and decreases the enterohepatic circulation of folate. Acetaldehyde increases the degradation of pyridoxal 5'-phosphate by displacing it from its binding protein and making it susceptible to hydrolysis by membrane bound alkaline phosphatase. Ethanol decreases hepatic vitamin A concn and its conversion to active retinal, and modifies retinal metabolism of vitamin D. [R76] *Amt that causes severe alcoholic intoxication (300 mg % /in blood/) does ... cause change in cerebral blood flow, metab, and vascular resistance. ... Cerebral oxygen uptake is much reduced. [R62, 374] *... Cirrhosis of liver that occurs in 8% of chronic alcoholics in contrast to 1% of abstainers and temporate drinkers may be, @ least in part, due to malnutrition ... . [R77] *In an experimental human study the effect of toluene and ethanol (alone or in combination) on psychophysiologic functions was studied in 12 men (22-44 yr of age). Each subject served as his own control. Ethanol was ingested at a dose equivalent to 15 mmol ethanol/kg body weight. Maximum blood levels of ethanol varied between 12-25 mmol/ml with a mean value of 16 mmol/ml (0.09%). Ethanol intake impaired performance on 2 of 4 tests and significantly increased heart rate during performance testing (2-6 beats/min, 0.05 > p > 0.01). No interaction between ethanol and toluene was observed. [R78] *MODERATE AMT OF ALCOHOL IN MAN MAY STIMULATE OR DEPRESS RESPIRATION; VENTILATORY RESPONSE TO CARBON DIOXIDE IS ... ALWAYS DEPRESSED. LARGE AMT ( ... BLOOD CONCN OF 400 MG/DL OR MORE) PRODUCE DANGEROUS OR LETHAL DEPRESSION OF RESP /USUALLY FATAL/. [R62, 373] *An analysis of the baseline data of the Paris Prospective Study 2 (3,348 middle-aged men) was done to assess the independent associations between the fatty acids of cholesterol esters and the main coronary heart disease risk factors. The association of alcohol consumption, a strong correlate of some fatty acids, was also examined. The alcohol consumption used in this study is a weighted sum of the different types of alcoholic beverages consumed by a subject during a typical week and is expressed in milliliters of alcohol per day. Palmitoleic acid was strongly associated with alcohol consumption (an increase of one standard deviation of the fatty acid with a mean increase of 15.6 ml/day alcohol consumption) and blood pressure. /Alcoholic beverages/ [R79] *Bone mineral density and various biochemical and hormonal values were measured in 28 patients currently drinking ethanol (drinkers), 12 patients claiming not to have consumed any ethanol for at least 6 mo (abstainers), and 35 non-alcoholic control subjects without clinical or biochemical evidence of liver disease. Iliac crest biopsies were taken under local anesthesia in the patients and under general anesthesia in the control subjects. Forearm bone mineral densities, spinal bone mineral densities, and iliac crest cancellous bone areas were significantly lower in the alcoholic patients compared with control subjects, but these values did not differ between the drinkers and the abstainers. The drinkers had significantly less osteoblastic activity than the abstainers, as assessed by dynamic bone histomorphometry. No differences were seen relating to histologic parameters of bone resorption, although the alcoholic patients who had lower serum free testosterone concentrations than the control subjects also had higher urinary hydroxyproline excretion rates. [R80] *The content of ethanol in the blood, tissues, and body fluid was measured at autopsy of a 25 yr old female who died from a suicidal overdose of imipramine, acetaminophen, codeine, diphenhydramine, and ethanol. The quantity of alcohol imbibed was not known. Blood samples were taken from at least 10 arterial and venous sites, and other samples were taken from 24 tissues, cerebrospinal fluid, vitreous humor and bile. Ethanol showed a narrow concentration range (151-175 mg/100 ml) in postmortem blood. [R81] *The influence of alcohol consumption and hepatic fibrosis on red blood cell membrane fatty acid composition and susceptibility to lipid peroxidation were investigated. Erythrocytes from chronic alcoholics with and without liver cirrhosis were analyzed. Erythrocytes from alcoholics without liver cirrhosis contained an increased proportion of saturated fatty acids over controls The cells contained less linoleic acid than controls, but exhibited a normal degree of lipid peroxidation upon oxidant stress induced by hydrogen peroxide. Erythrocytes from alcoholics with liver cirrhosis contained less arachidonic acid than controls, and were less susceptible to lipid peroxidation than controls. [R82] *A431 cells (ATTC), derived from human epidermoid carcinoma of the vulva, were grown to 80% confluence, using 4 ml of Dulbecco's minimum essential media supplemented with 1000 U/ml penicillin, 100 ug/ml streptomycin and 10% fetal calf serum. Binding media containing no ethanol, 25 mM ethanol or 100 mM ethanol were added to the appropriate dish and each dish was incubated 20 min at 37 C. Each dish was then brought to 1.6 nM epidermal growth factor and allowed to incubate at 37 C for 5 min. Three washes with ice cold Hank's plus 0.1% bovine serum albumin was followed by 3 addnl washes with Hank's minus bovine serum alburium to remove any remaining calf serum. The 1 N sodium hydroxide soln was counted in a gamma counter. Lowry protein detns were done and statistics were calculated using the Student's t-test. For each concn of ethanol tested, the rate of binding was 13 ng of epidermal growth factor/mg protein; showing that ethanol did not alter the ability of A431 cells to bind epidermal growth factor to its membrane receptor. /Alcoholic beverages/ [R83] *Twelve human social drinkers participated in a practice session plus four exptl sessions, each under a different ethanol dose and given in counterbalanced order. The task entailed forewarned, aimed transitive movements of the hand and arm, and entailed lifting a stylus from a central resting point and moving it to the left or right to contact a flanking target strip. A warning signal (light and tone) preceded the response signal by a period of 4 sec. Separate measures of reaction time (ie, time to lift stylus from central point) and MT (ie, subsequent time before contact with flanking strip) were obtained, as were measures of decision accuracy (ie, direction of response) and movement precision (ie, proportion of responses making contact with the target strip). In one condition (stimulus/response compatible), the correct response direction corresponded with stimulus location, whereas in a second condition (stimulus/response incompatible) the direction was opposite. Ethanol doses were 0 (placebo), 0.45 (low), 0.80 (medium) and 1.05 (high) g/kg lean body wt, mixed in a constant volume with orange juice and consumed over a half hr period. Additional maintenance doses of 0.12 g/kg were given at subsequent half hr intervals. Ethanol and stimulus/response compatibility both affected RT, but there was no suggestion of an interaction between the two variables. RTs were lengthened 31 msec by stimulus/response incompatibility, whereas at the highest dose, ethanol increased reaction time by about 30 msec. Simultaneously recorded movement-related brain potential disclosed decreased involvement of frontal and posterior brain areas. [R84] *The effect of alcohol (ethanol) abuse on muscarinic, cholinergic, and benzodiazepine receptors were studied in the hippocampus of histologically normal human brains obtained at autopsy in a general hospital population. Muscarinic, cholinergic synaptic receptor density determined with tritiated quinuclidinyl benzilate was decr by 30% in homogenates of the hippocampus of 25 alcohol abusers compared with 25 matched nonalcoholic controls. Densities of benzodiazepine receptors determined with (3)H flunitrazepam were also decr by approximately 30% in alcohol abusers. The affinities of both receptor types were not affected by alcohol abuse. Age and death to autopsy time interval had no significant effects on either wet tissue protein concentrations, yields of protein after centrifugation, or receptor binding. The contributions of age and time interval were each < 2% of the total variance of protein concn and receptor binding. When patients were excluded or incl who had received cholinergic, anticholinergic, or benzodiazepine medications before death, no significant effects on the final results were observed. Pneumonia (associated with acute hypoxia) and chronic obstructive pulmonary disease (associated with chronic hypoxia) were approximately equally distributed between the two groups and had no significant effects on the results. [R85] *Three polygraphic recordings of afternoon sleep related to the duration of one sleep cycle (90 min) were performed in 14 healthy adult volunteers (7 men and 7 women). Two reference polygraphic recordings were made on two consecutive days (before ingestion of alcohol) and only the second of these was retained. The third polygraphic recording was taken on day 3, 50 min after the start of a single slow oral ingestion of the equivalent of 0.25 g 95% ethanol/kg body wt. Alcohol was ingested as 40 proof whiskey, and the vol administered ranged from 34.5 to 66 ml. Analysis of polygraphic traces was carried out according to the criteria of Rechtschaffen and Kales, and results were presented using the parameters adopted by Gross et al. A single low dose of alcohol leading to a low mean blood alcohol level (< 30 mg/100 ml, range to 29 mg/100 ml), perturbed sleep in the normal nonalcohol dependent adult. The total duration of sleep, the percentage of delta sleep, and the duration (and percentage) of rapid eye movement sleep were decr. The number, duration, percentages of intrasleep awakenings, and the number of stage changes were incr. [R86] *The relationship of alcohol (ethanol) use to diet was examined in 2272 male and 2337 female adults aged 45 yr and older who provided a quantitative diet history during 1977-1979. Mean values for each dietary variable, adjusted for smoking, ethnicity, income, and education, were compared in each sex between abstainers and drinkers and by tertile of ethanol intake. Linear relationships with extent of drinking were also sought. Drinkers were found to be less obese than abstainers. Consumption of carbohydrate, vitamins, calcium, fruits, fruit juices, and raw vegetables was greater among abstainers whereas consumption of fat (particularly polyunsaturated fatty acids), cholesterol, zinc, meat, pickled vegetables, and dried fish was greater among drinkers. [R87] *Two hundred and seventeen visitors to a county show (age 16 to 73) were taught to use the unit system for estimates of alcohol (ethanol) consumption. All were tested on it until they successfully answered three simple questions about its use. Altogether 150 had heard of units of alcohol before, and 63 had counted their drinks in units. One hundred and four subjects were asked to examine the usual retail containers for 3 wines, 3 lagers, and 3 beers. The wines contained 0.05%, 7%, and 13% alcohol by vol; the lagers contained 0.9%, 3.4%, and 8.6%; and the beers contained 1%, 3.5%, and 10.9%. With one exception this was stated on the container, the strong lager being labeled only with its original gravity (1076 to 1082). Each subject was asked to estimate the number of units in one 150 ml glass of each wine and in one pint (0.57 l) of each lager and beer. The remaining 113 subjects underwent an identical procedure with larger amount of alcohol; the results were comparable. Sample glasses were used to illustrate the amounts in both cases. In the group of 104 subjects, between 80 and 88 correctly estimated the number of units in the standard strength drinks. Fewer correctly estimate the strength of the low alcohol drinks. Fewer still correctly estimated the strength of the extra strong drinks: mostly this was greatly underestimated, with 53 underestimating the strength of the wine, 103 the lager, and 93 the beer. After being told of the relative strengths of the drinks, 198 subjects agreed that it would be a good idea for bottles and cans of alcoholic drink to display their alcohol content in units. [R88] HTOX: *A pretested questionnaire was admin to 205 middle aged and elderly acute ischemic stroke patients and 410 outpatient controls matched by age, sex, race, and method of hospital payment. The frequency of hypertension (p < 0.001), transient ischemic attacks (p= 0.051) mean weekly alcohol consumption (p= 0.0286), and mean pack yr cigarette exposure (p= 0.0168) were higher among stroke index cases than controls. Mean weekly alcohol consumption was 173.47 g among stroke cases, and 119.92 g for controls. For weekly alcohol consumption, there was a highly significant dose response effect. 60.2% of stroke cases and 75.8% of controls consumed 0 ethanol/wk. 10.0% and 6.4% consumed 1 to 99 g; 14.9% and 9.6% consumed 100-299 g; and 14.9% and 8.1% consumed > 300 g, respectively. Analyses to assess the possibility of mutual confounding effects of independent variables, found hypertension and smoking to be independent risk factors for ischemic stroke, while alcohol consumption was not. Separate analyses by sex yielded similar results. [R89] *The relationship of oral cancer risk to types of alcoholic beverage consumed was investigated using data from a hospital based case control study (1976 to 1983) on 511 male and 226 female cancer cases, and 1057 male and 453 female controls. Drinkers were classified oral as consumers of predominantly beer, wine, or hard liquor (ie more than 50% of their whiskey equivalents of alcohol derived from a specific beverage). The number of predominantly wine drinkers was too small to permit analysis. Logistic regression was used to obtain estimates of oral cancer associate with each predominant beverage, with adjustment for other risk factors and confounding variables, including smoking, age, yr of education, and religion. In males, the odds ratio for predominantly beer drinkers increased with incr level of intake, reaching 4.87 (95% confidence interval: 2.51 to 9.46) in drinkers of 7+ oz of whiskey equivalents/day. The odds ratio for predominantly hard liquor drinkers showed a similar incr, reaching 5.74 (95% confidence interval: 2.94 to 11.22) in predominantly hard liquor drinkers consuming 7+ oz of whiskey equivalents/day. In females, all 3 levels of drinkers (1 to 3.9 oz/day, 4 to 6.9 oz/day and 7+ oz/day) had significantly elevated odds ratios, but there was no clear gradient. [R90] *A case control study comprising 216 cases of pancreatic cancer and 279 controls was conducted to investigate the relationship of pancreatic cancer with the consumption of alcoholic beverages. Cases and controls were stratified by sex and 10 yr age groups in the analysis. Cases drank significantly more beer than controls (p= 0.005). The relative risk associated with recent regular consumption of more than 7 pints of beer/wk, compared to nondrinkers, was 3.17 with a 95% confidence interval (1.16, 8.64). Regular consumption of 7 pints/wk in the past was associated with an estimated relative risk of 2.33, 95% confidence interval (0.92, 5.96). No significant difference was found between cases and controls in consumption of either wine or spirits and no differences between the sexes were observed. Smoking was a clear risk factor, but cases and controls were very similar with respect to tea and coffee drinking habits. The relative risks by the amount of alcohol consumed has a significant positive trend with past consumption (chi square= 3.88, df= 1, p= 0.05), but for recent consumption, the evidence was not significant (chi square= 3.00, df= 1, p= 0.08). The effect of alcohol appeared to be largely confined to the smokers, where the change in the relative risk (measured on a logarithmic scale) was 0.02 per unit of alcohol (p= 0.03). No significant trend with amount of alcohol consumed was found in non smokers. [R91] *The association between alcohol consumption and risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case control study conducted in Australia. The study involved 383 cases with biopsy confirmed benign proliferative epithelial disorders, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls individually matched (1:1) to cases on age and area of residence. When cases were compared with community controls, the unadjusted relative risk of benign proliferative epithelial disorders for drinkers versus nondrinkers was 0.9 (95% CI= 0.6-1.3), and the corresponding relative risk derived from comparing cases with biopsy controls was 1.0 (95% CI =0.6 - 1.4). These estimates did not change after adjustment for potential confounding. Variation in risk of benign proliferative epithelial disorders across levels defined in terms of daily total alcohol intake, and in terms of daily alcohol intake from individual beverages, was mostly insubstantial and not dose dependent. With community controls as the comparison group, risks for women who drank less than 1/4 of a glass, between 1/4 and 1 glass, and more than 1 glass of alcohol per day were 0.9 (95% CI= 0.6 - 1.3), 1.0 (95% CI= 0.7 - 1.5), and 0.7 (95% CI= 0.5 - 1.1) respectively, compared to a risk of unity for nondrinkers. Corresponding relative risks for cases versus biopsy controls were 0.8 (95% CI= 0.5-1.3), 0.9 (95% CI= 0.6-1.5), and 1.0 (95% CI= 0.6-1.7). Also, there was little variation in risk with age at first drink, or by current drinking status, and risk of benign proliferative epithelial disorders in association with alcohol consumption did not incr with severity of cytologic atypia. [R92] *The validity of self reported daily alcohol consumption was established by correlating concentration of ethanol in daily urine samples with number of reported standard alcoholic drinks. The relationship was linear between 4 and 10 reported drinks. Ethanol was detected in concentrations of less than 1.0 millimolar in 105 of the 287 urine samples from nondrinking days and at higher concentrations in 31 samples. Only 53% of the samples from reported days of abstinence were negative for ethanol. Only 94 of the 287 abstinent days were preceded by an abstinent day, and no ethanol was detected in the urine from 65% of those days, small quantities (0.05 to 0.999 millimolar) were detected in 31% of those days, higher concentrations were detected in only 4%. In addition to inaccurate reporting, other factors affected the correlation: the time between consumption of the reported drinks and urine sampling and the time span over which the drinks were consumed. By sampling 50% or fewer of the 84 days of a study for each subject, values of the correlation coefficients or the rank positions of subjects did not significantly change, but the 95% confidence intervals for the correlation coefficients did increase. [R93] *Four female subjects (21 to 39 years) were asked to discriminate between a stationary light signal and one that changed position in the center of a dark visual field before and during alcohol administration. These tests were designed to evaluate two processes involved in visual movement discrimination: visual sensitivity and decision making. Testing was conducted on a total of 15 days during a 5 week period. The dose of alcohol was 0.66 ml or 95% USP ethanol per kg body weight. Blood alcohol levels were determined 12 times during each session. Average peak blood alcohol levels ranged from 0.065% to 0.105%. The mean minutes to peak ranged from 20.5 + or - 9.3 to 50.3 + or - 8.6. Differences in performance of subjects before and after alcohol consumption were evaluated within the framework of a psychophysical model that characterized the problem of movement discrimination, producing independent estimates of visual sensitivity and decisional aspects of performance. Each subject made large and statistically reliable shifts in decisional criteria during the alcohol testing sessions even when visual sensitivity had adapted to alcohol intake effects. [R94] *Thirty eight subjects in the Colorado Alcohol Research on Twins and Adoptees study were retested between 3 and 39 months after their initial testing. Subjects were given a dose of ethanol (0.8 g/kg) calculated to bring their blood alcohol level to near 100 mg/dl, but no topping doses were given in the retests to maintain blood alcohol levels near peak for 3 hours as was done in the first test. Repeatability (test to retest correlation) was near zero for alcohol clearance rate, 0.36 for time to peak blood alcohol level, and 0.50 for peak blood alcohol level. Repeatabilities of prealcohol baseline scores were 0.55 (median) for the shortened battery of physiological, motor coordination, perceptual speed and reaction time measures. Repeatabilities were near zero for sensitivity scores and low (median, 0.02) for acute tolerance scores and perceived intoxication (median 0.27). [R95] *Topographic maps of brain electrical activity from scalp EEG electrodes were obtained from health adult female volunteers using a brain electrical activity mapping system. Each women received both ethanol (0.7 g/kg oral) and placebo in a counterbalanced order under double blind conditions at an interval of 1 to 6 days. Subjective reports of intoxication were obtained continuously via an instrumental joystick device. Subjects reported when they detected ethanol and qualitatively pleasant or unpleasant effects. All subjects reliably discriminated ethanol from placebo. Pronounced increases in EEG alpha activity occurred during ethanol induced intoxication in all subjects. The distribution of the high amplitude, fast frequency EEG alpha activity extended further frontally to the central sulcus and temporally during ethanol intoxication than during control sessions or after placebo administration. One woman with a positive family history of alcoholism experienced only a mild degree of intoxication. This behavioral response was accompanied by a slight decrease or no change in both slow and fast frequency alpha activity. [R96] *2002 randomly selected pregnant Australian women were recruited over a 3 yr period for a questionnaire survey covering demographic, lifestyle, health, dietary, and obstetric factors. 58% of the women were in their first trimester, 33% in their 2nd trimester, 8% in their third trimester at recruitment. Only 19 refused participation. When a stratified subsample of 665 women were followed, there were 42 miscarriages, 72 stillbirths, and 6 neonatal deaths. The subsample, selected on the basis of prepregnancy alcohol consumption, was followed through pregnancy. Data were collected on obstetric course and infant outcome. Results showed that beer, wine, and spirits drinkers differed significantly in maternal characteristics, nutrition, and other important variables such as smoking. Women who miscarried drank significantly higher volumes of beer (absolute ethanol intake from beer= 7 ml per day) than those with live births (3 ml) or stillbirths (3 ml). Beer drinkers were less likely to reduce their consumption in pregnancy than other drinkers if they also smoked more than 20 cigarettes per day. [R97] *Peripheral blood lymphocytes from 12 alcoholic patients in good nutritional status and without heavy liver damage and 15 healthy controls were used for studying the effects of chronic ethanol on lymphocyte membrane alpha 1-glycoprotein and immune response to various stimulating agents, including phytohemagglutinin, Ca ionophore A23187, and autologous non-T-cells in (autologous mixed lymphocyte reaction). Compared to controls, a significant impairment in AMLR was observed, but no difference was seen in the response to the other stimulating agents. While the percentage of alpha 1-glycoprotein bearing T-lymphocytes was significantly lower in alcoholics (14.4 + or - 8.6) than in controls (31.9 + or - 8.1; no differences were present in lymphocytes expressing other membrane glycoproteins, including CD5, CD4, and CD8. [R98] *Data from the Luebeck Blood Pressure Study, a cross-sectional study on a random sample (n = 3,100) of the 30 to 69 yr old population of Luebeck, were analyzed with regard to alcohol consumption and blood pressure. Men who consumed > 40 g/day alcohol had 5-6 mm Hg higher mean systolic and 4-5 mm Hg higher mean diastolic blood pressure than nondrinkers; there was a J-shaped relationship between alcohol consumption and systolic blood pressure. About 7% of hypertension among the men was due to alcohol consumption of > 40 g/day. Among women, there was a strong interaction between age and alcohol consumption. For women < 45 yr old, the alcohol blood pressure relationship was not pronounced. But for women > 45, a strong interaction between alcohol consumption and smoking was found. Compared to female nonsmokers, there were steep increases in the adjusted mean diastolic (5.2 mm Hg) and systolic (9.6 mm Hg) blood pressure of female smokers who consumed > 20 g/day alcohol. [R99] *ETHANOL AND CERTAIN SHORT CHAIN ARYL (BENZYL) AND ALIPHATIC (PROPYL, BUTYL) ALCOHOLS PRODUCED UP TO 10 FOLD INCR IN CYCLIC AMP CONCN IN PURIFIED HUMAN PERIPHERAL BLOOD LYMPHOCYTES. ETHANOL CONCN AS LOW AS 80 MG/DL PRODUCED SIGNIFICANT ELEVATIONS IN LYMPHOCYTE CYCLIC AMP. [R100] *Symptomatology (acute intoxication): 1. Early emotional lability: exhilaration, boastfulness, talkativeness, remorse, and belligerency. 2. Impaired motor coordination: slowed reaction time, slurred speech, ataxia. 3. Sensory disturbances: diplopia, vertigo. 4. Flushing of face, rapid pulse, sweating. 5. Nausea and vomiting. Eventual incontinence of urine and feces. 6. Drowsiness, stupor and finally coma, with impaired or absent tendon reflexes. Convulsive episodes may indicate hypoglycemia. 7. Pupils dilated or normal. 8. Peripheral vascular collapse (shock): hypotension, tachycardia, cold pale skin, hypothermia. 9. Slow stertorous respirations. 10. Death from respiratory or circulatory failure or from aspiration pneumonitis. 11. During convalescence: postalcoholic headache and gastritis; infections (for example, pneumonia, septicemia); alcoholic psychoses (for example, delirium tremens). [R10, p. III-169] *Acute alcohol admin has been shown to modify the ERG in ... human beings. [R61, 55] *Fetal alcohol syndrome is the name given to a collection of characteristic malformations that have been found in the infants and children of mothers who drank alcohol during pregnancy. Series of cases of eye abnormalities have been reported. ... Most common has been horizontal shortness of the palpebral fissure due principally to an abnormally large distance between the medial canthi. Also common are ptosis and strabismus, either convergent or divergent. High myopia, amblyopia, and pale optic discs have also been reported. These ocular abnormalities typically have been associated with facial anomalies, subnormal wt, delayed growth, and mental retardation. [R61, 57] *In ... human males ... acute exposure to alcohol primarily affects testicular synthesis and secretion of testosterone. ... Ethanol and acetaldehyde inhibit enzymes involved in gonadal testerone synthesis. ... Levels of estrogenic steroids incr as a result of altered hepatic metabolism and clearance of androgens. Women ... do not appear to be as sensitive to the direct gonadal effects of alcohol and may be less vulnerable to antifertility effects with chronic alcohol abuse. [R101] *Seven pt undergoing long term hemodialysis became addicted to vapor of denatured alcohol. Withdrawal symptoms occurred in 2 pt who tried unsuccessfully to stop the practice. ... The handling of motor vehicles was impaired by 100 mg/100 ml of alcohol in the blood, stupor might result from 300 mg/100 ml, and resp failure and sometimes death from 400 mg or more per 100 ml. The fatal dose was about 1 l of 50% vol/vol spirit ingested over a short period. In conjunction with other drugs, low concn of alcohol might provoke significant toxic effects. [R7, 35] *Analysis of 76 pt under 40 yr of age with ischemic infarction, indicated that alcohol intoxication incr the risk of brain infarction 2 to 3 times for men and 3 to 4 times for women. ... Alcohol caused brain damage which might be common. ... Intellectual impairment may be the earliest sign of alcohol abuse. A significant rise in blood-glucose concn and a significant delay in insulin secretion were observed in 12 healthy subjects 1 hr after drinking 50 ml of alcohol. ... Data from 83947 mem and women of various races indicated that regular intake of 3 or more alcoholic drinks daily was associated with raised blood pressure. ... Cancer of the mouth, pharynx, and esophygus, and primary cancer of the liver appeared to be definitely related to heavy consumption of alcohol in USA ... . [R7, 36] *Blood alcohol concn (% wt/vol): 0.03-0.12; stage of alcohol influence/intoxication in nontolerant individuals: euphoria; clinical sign/symptom: mild euphoria, sociability, talkativeness, incr self-confidence, decr inhibitions, diminution of attention, judgment, and control, loss of efficiency in fine performance tests /From table/ [R102, 793] *Blood alcohol concn (% wt/vol): 0.09-0.25 stage of alcohol influence/intoxication in nontolerant individuals: excitement; clinical sign/symptom: emotional instability, decr inhibitions, loss of critical judgment, impairment of memory and comprehension, decr sensory response, incr reaction time, some muscular incoordination /From table/ [R102, 793] *Blood alcohol concn (% wt/vol): 0.18-0.30; stage of alcohol influence/intoxication in nontolerant individuals: confusion; clinical sign/symptom: disorientation, mental confusion, dizziness, exaggerated emotional states (fear, anger, grief), disturbance of sensation (diplopia) and of perception of color, form, motion, dimensions, decr pain sense, impaired balance, muscular incoordination, staggering gait, slurred speech /From table/ [R102, 793] *Blood alcohol concn (% wt/vol): 0.27-0.40; stage of alcohol influence/intoxication in nontolerant individuals: stupor; clinical sign/symptom: apathy, general inertia, approaching paralysis, markedly decr response to stimuli, markedly muscular incoordination, inability to stand or walk, vomiting, incontinence of urine and feces, impaired consciousness, sleep or stupor /From table/ [R102, 793] *Blood alcohol concn (% wt/vol): 0.35-0.50; stage of alcohol influence/intoxication in nontolerant individuals: coma; clinical sign/symptom: complete unconsciousness, coma, anesthesia, depressed or abolished reflexes, subnormal temp, incontinence of urine and feces, embarrassment of circulation and respiration, possible death /From table/ [R102, 793] *Blood alcohol concn (% wt/vol): 0.45+; stage of alcohol influence/intoxication in nontolerant individuals: death; clinical sign/symptom: death from resp paralysis /From table/ [R102, 793] *Low doses result in behavioral disinhibition. As the dose incr, sexual response is impaired, resulting in failure of erection in males and reduced vaginal vasodilation and delayed orgasm in females. Chronic use has been associated with an 8% rate of impotence, one-half of which was irreversible despite abstinence from alcohol. The chronic effects are probably the result of both neurological and endocrine effects; alcohol has been shown to reduce testosterone levels and incr luteinizing hormone levels. The chronic effects are independent of liver disease. [R103, 113] *CUTANEOUS REACTIONS TO ETHANOL WAS EVALUATED IN A CONTROL GROUP AND IN PATIENTS BEFORE AND WHILE THEY WERE RECEIVING DISULFIRAM THERAPY. LOCAL CUTANEOUS ERYTHEMA WAS OBSERVED FROM PATCH TESTS WITH ETHANOL IN HYDRATED SKIN. SINCE REACTIONS NOTED FROM TOPICALLY APPLIED ALCOHOLS BEFORE AND WHILE THE PATIENTS WERE RECEIVING DISULFIRAM THERAPY WERE NOT STATISTICALLY DIFFERENT, A LOCALIZED DISULFIRAM-ALCOHOL REACTION IS UNLIKELY. ERYTHEMA RESULTING FROM TOPICALLY APPLIED ALCOHOLS OCCURRED IN A DOSE RELATED MANNER AND WAS CAUSED BY A DIRECT VASODILATORY EFFECT ON THE CUTANEOUS MICROVASCULATURE. [R104] *THE ACTIVITY Y PURIFIED HUMAN ERYTHROCYTE ACID PHOSPHATASE (EAPASE) WAS ENHANCED 2.6 FOLD BY ETHANOL. THE EXTENT OF HUMAN PROSTATIC ACID PHOSPHATASE (PAPASE) ACTIVATION BY ETHANOL WAS LOWER THAN THAT OF EAPASE. EAPASE AND PAPASE ACTIVATION BY ALIPHATIC ALCOHOLS, INCLUDING ETHANOL, WAS NONCOMPETITIVE. [R105] *Results of 2 case control studies of breast cancer which included questions on exposure to alcohol are reported. One study included 998 hospital cases (married women, ages 25-59 yr) and a like number of matched hospital controls while the other included 118 cases (women, ages 45-69 yr) diagnosed during mammographic screening and a like number of matched normal screenees. Compared to the relative risk of 1.0 in controls, the relative risks of breast cancer with alcohol consumption were 0.7 to 1.2, which were independent of the levels of alcohol consumed. [R106] *The relationship between dietary habits and prognostic factors for breast cancer was studied in 240 women (ages 50-65 yr) who had surgery for breast cancer between 1983 and 1986. A dietary history interview was conducted within the 4 mo following resection of the primary tumor. Bivariate analyses showed that the proportion of patients with estrogen receptor rich tumors increased significantly with age (p < 0.05). These patients reported higher absolute values for intake of fiber and retinol equivalents and lower absolute values for intake of alcohol. Estrogen receptor rich tumors were more common in patients in the lowest quartile for E% (percentage of total energy intake) from alcohol. [R107] *Exfoliated cells were collected from the cheek and tongue of 27 men aged 35 to 69 yr. DNA was extracted from the cells and analyzed by the enhanced (32)P-postlabeling technique using butanol extraction. A variety of adduct spots were detected but none was consistently associated with exposure to alcohol (ethanol). Some of the adducts detected had migration patterns in thin layer chromatography very similar to the major deoxyguanosine adducts formed by the diol epoxides of benzo(a)pyrene and 5-methylchrysene. Adduct spots with migration patterns similar to polynuclear hydrocarbon adducts accounted for only about one third of the total adduct spots observed. Relative adduct labeling values were determined for samples from 12 of the 27 men. Relative adduct labeling values ranged from 1.6X10-6 to 7.7X10-11 adducts/nucleotide. The relative adduct labeling values for adducts from the cheek or tongue were not significantly different. Adduct levels in drinkers (median relative adduct labeling of 9.1X10-10, n= 17) were significantly lower (p < 0.001) than adduct levels in non-drinkers (median relative adduct labeling of 3.7X10-8, n= 43). 4 of the subjects in this study have subsequently developed squamous cell carcinoma of the oral cavity. 3 of 4 consumed at least the equivalent of one ounce of hard liquor per day. (32)P-Postlabeling analysis of DNA from the oral cavity of these subjects did not demonstrate unique patterns or relative adduct labeling values. [R108] *In study 1, 92 subjects (12 to 42 yr old) with fetal alcohol syndrome (n = 58) or fetal alcohol effects (n = 34) were admin an IQ test, a test of academic achievement, a test of auditory receptive ability, and a test of adaptive and maladaptive behavior. Not all test data were available on all pt. Over a 10 yr period, the IQ scores of pt with fetal alcohol syndrome remained quite stable. IQ scores of adolescents and adults with fetal alcohol syndrome or fetal alcohol effects were 70 + or - 17). Pt with fetal alcohol syndrome had a significantly lower IQ than those with fetal alcohol effects (mean IQ of 65 vs 80). With a median age of 15 yr, the 70 pt tested for academic achievement were functioning at the 3rd to 4th grade levels for word recognition, spelling and arithmetic. 58% of the adults and adolescents were classified as having significant levels of maladaptive behavior. In study 2, 500 children were selected for participation in the study based on maternal reports of alcohol use during pregnancy or prior to pregnancy recognition. All children whose mothers were heavier ethanol drinkers were selected, along with a proportion of moderate, light, and infrequent drinkers and nondrinkers. Outcome (dependent) variables were assessed on days 1 and 2, at 8 and 18 mo, and at 4 and 7 yr of age. Follow-up of the cohort was 86% overall. Prenatal alcohol exposure was related to significantly lower IQ scores even though the mean IQ for the cohort was well within the normal range. When 6 to 8 yr olds were tested, both arithmetic and reading deficits were significantly associated with prenatal alcohol exposure, even though the mean scores were within the normal range for the age and grade of the subjects. On days 1 and 2 of life, significant neurobehavioral effects of prenatal alcohol exposure was seen. At 8 mo of age, prenatal alcohol exposure was associated with small decrements in mental and motor development. Neurobehavioral effects were also seen at 4 and 7 yr of age. [R109] HTOX: *Women in an antenatal clinic were screened for alcoholism. Women who were positive, and an equal number of non-alcoholic women matched on race, smoking, parity, date of recruitment, drug abuse, prepregnancy wt, and wk gestation at registration formed the study group. 1284 offspring were examined for fetal alcohol syndrome linked anomalies and 359 mother-infant pairs were recruited into a prospective child development cohort. At 4 yr, 10 mo, 239 mother-child pairs remained in the study. A tally of neonatal anomalies was used as a marker for fetal alcohol effects. Three different indicators of alcohol consumption (in-pregnancy, retrospective and estimated embryonic) were used to evaluate effects of the avg oz of alcohol per day (AA/day) consumed. Using the in pregnancy average oz alcohol per day data, the heaviest drinking group (> 0.5 oz alcohol/day) differed significantly from the abstaining group and from the low average oz alcohol per day groups (between 0 and 0.1 oz/day) in total fetal anomalies. Five yr later, using the retrospective index, no effect of ethanol on total fetal anomalies was seen for the abstention group and the low average oz alcohol per day groups. Notable and significant incr in total and craniofacial anomalies tallies were obtained at the 2 highest drinking levels (from 0.5 to > 1.5 oz alcohol/day). With the estimated embryonic average oz alcohol per day index, as well as the other 2, a clear breakpoint, or threshold was seen in comparisons of heavy drinking groups with low average oz alcohol per day groups (2.0 oz/day in the embryonic period). [R110] *A study of 400 infants born to members of a health maintenance organization were investigated to study the relation of the mother's use of alcohol (ethanol) during breast-feeding to the infant's development at 1-yr of age. Mental development, as measured by the Bayley Mental Development Index (MDI), was unrelated to maternal drinking during breast-feeding. However, motor development, as measured by the Psychomotor Development Index (PDI), was significantly lower in infants exposed regularly to alcohol in breast milk (after alcohol exposure during gestation was controlled for) with a dose-response relation (p for linear trend, 0.006). The infants of breast-feeding mothers who had at least one drink daily had a mean Psychomotor Development Index score of 98, whereas the infants exposed to less alcohol in breast milk had a mean Psychomotor Development Index score of 103 (95% confidence interval for the difference of the two means, 1.2 to 9.8). The effect was more pronounced when mothers who supplemented breast-feeding with formula were excluded from the analysis. [R111] *A cohort of 650 women was interviewed at each trimester of pregnancy about their level of alcohol (ethanol) intake. The mothers were classified as heavy alcohol users if they had an avg of > or = 1 drink/day, moderate users for an avg of 3 to 6 drinks/wk, and light users for an avg of < 2.9 drinks/wk. Data were reported for 595 live single births available for the followup study. A relationship was demonstrated between prenatal maternal alcohol use and growth and morphologic abnormalities in the offspring. Low birth wt, decr head circumference and length, and an incr rate of fetal alcohol effects were all found to be significantly correlated with exposure to alcohol during the first 2 mo of the first trimester. [R112] *Plasma luteinizing hormone, follicle stimulating hormone, prolactin, estradiol and progesterone were measured in 24 normal, adult women before and after iv admin of 100 ug luteinizing hormone releasing hormone (Factrel) and per os ingestion of an alcohol (0.694 g ethanol/kg body wt) or placebo soln. 12 subjects were studied during the early follicular phase of the menstrual cycle and 12 subjects were studied during the midluteal phase of the menstrual cycle. During each menstrual cycle phase, 6 subjects received placebo soln and 6 subjects received alcohol soln admin under double blind conditions. Mean peak blood alcohol levels of 113 to 122 mg/dl were measured 45 to 60 min after initiation of alcohol intake. During the follicular and the luteal phases of the menstrual cycle there were no significant differences in luteinizing hormone releasing hormone-stimulated follicle stimulating hormone or the prolactin response between the alcohol and placebo conditions. During the midluteal phase of the menstrual cycle, estradiol increments were also significantly higher after luteinizing hormone-releasing hormone and alcohol than after luteinizing hormone releasing hormone and placebo alcohol intake, but progesterone levels did not change. Acute alcohol intoxication induced a significant incr in plasma estradiol levels after luteinizing hormone releasing hormone admin during the follicular phase of the menstrual cycle and augmented the estradiol response to luteinizing hormone-releasing hormone stimulation during the luteal phase of the menstrual cycle. [R113] *ETHANOL AND CERTAIN SHORT CHAIN ARYL (BENZYL) AND ALIPHATIC (PROPYL, BUTYL) ALCOHOLS PRODUCED UP TO 10 FOLD INCR IN CYCLIC AMP CONCN IN PURIFIED HUMAN PERIPHERAL BLOOD LYMPHOCYTES. ETHANOL CONCN AS LOW AS 80 MG/DL PRODUCED SIGNIFICANT ELEVATIONS IN LYMPHOCYTE CYCLIC AMP. [R100] +Most epidemiologic studies of the relationship between alcohol consumption and breast cancer risk over the past decade have shown that persons who consume a moderate amount of alcohol are at 40-100% greater risk of breast cancer than those who do not consume alcohol. Dose-response effects have been observed, but no causal relationship has been established. This study examined the hypothesis that alcohol consumption affects levels of reproductive hormones. A controlled diet study lasting for six consecutive menstrual cycles was conducted. Participants were randomly assigned to two groups, and a crossover design was used. During the last thee menstrual cycles, alcohol consumption of the two groups was reversed. Thirty-four premenopausal women, aged 21-40 yr, with a history of regular menstrual cycles, consumed 30 g of ethanol (equivalent to approximately two avg drinks) per day for three menstrual cycles and no alcohol for the other three. All food and alcohol consumed were provided by the study. Caloric intake was monitored to ensure that each woman would maintain body weight at approximately the baseline level. Hormone assays were performed on pooled plasma or 24 hr urine specimens collected during the follicular (days 5-7), peri-ovulatory (days 12-15), and mid-luteal (days 21-23) phases of the third menstrual cycle for subjects on each diet. Alcohol consumption was associated with statistically significant increases in levels of several hormones. Plasma dehydroepiandrosterone sulfate levels were 7.0% higher in the follicular phase (p= .05). In the peri-ovulatory phase, there were increases of 21.2% (p= .01) in plasma estrone levels, 27.5% (p= .01) in plasma estradiol levels, and 31.9% (p= .009) in urinary estradiol levels. In the luteal phase, urinary estrone levels rose 15.2% (p= .05), estradiol levels incr 21.6% (p= .02), and estriol levels rose 29.1% (p= .03). No changes were found in the percent of bioavailable estradiol, defined by the sum of percent free estradiol and percent albumin-bound estradiol. However, incr total estradiol levels in the peri-ovulatory phase suggest elevated absolute amounts of bioavailable estradiol. This study has shown incr in total estrogen levels and the amount of bioavailable estrogens in association with alcohol consumption in premenopausal women. ... [R114] NTOX: *ANIMALS EXPOSED TO ETHYL ALCOHOL IN AIR MAY MANIFEST THE FOLLOWING SIGNS OF INTOXICATION: SLIGHT IRRITATION OF THE MUCOUS MEMBRANES, EXCITATION FOLLOWED BY ATAXIA, DROWSINESS, PROSTRATION ... /CNS DEPRESSION/, TWITCHING, GENERAL PARALYSIS, DYSPNEA, AND OCCASIONALLY DEATH ASSOCIATED WITH RESPIRATORY FAILURE. [R33, 4544] *IN LAB ANIMALS ... ANTICONVULSANT ACTION IS FOLLOWED BY PERIOD OF HYPEREXCITABILITY THAT LASTS FROM 12 HR (AFTER SINGLE DOSE) TO SEVERAL DAYS (AFTER CESSATION OF CHRONIC ADMIN). [R60, 377] *DIRECT DEPRESSION OF HEART BY ALCOHOL HAS BEEN OBSERVED FOLLOWING ITS ACUTE ADMIN TO EXPERIMENTAL ANIMALS; BOTH MYOCARDIAL CONTRACTILITY AND WORKING EFFICIENCY MAY BE ADVERSELY AFFECTED BY A BLOOD CONCN AS LOW AS 100 MG/DL. ELECTRON MICROSCOPIC OBSERVATIONS REVEAL CHARACTERISTIC INTRACELLULAR LESIONS IN THE MYOCARDIUM, ASSOC WITH CONGESTIVE HEART FAILURE; PROGNOSIS FOR RETURN OF MUSCLE FUNCTION IS GUARDED. [R60, 378] *CHRONIC ETHANOL INGESTION IN MALE RATS INCR CYTOCHROME P450 CONTENT AND ACTIVITY OF MICROSOMAL BENZO(A)PYRENE HYDROXYLASE IN THE UPPER INTESTINAL MUCOSA. INTESTINAL MICROSOMES FROM ETHANOL FED RATS ALSO EXHIBITED ENHANCED CAPACITY TO ACTIVATE BENZO(A)PYRENE TO A MUTAGEN. [R115] *ADMIN OF ETHANOL (500 ML/DAY IN FEED) TO PREGNANT DOGS FOR 20 WK FROM 1ST DAY OF PREGNANCY INDUCED SLIGHT, BUT MORPHOL AND BIOCHEM DISCERNABLE, CHANGES IN THE CNS OF THE PUPS. THESE CHANGES INCL NEURONAL DAMAGE WITHIN THE FRONTAL AND HIPPOCAMPAL CORTEX AND PURKINJE CELL LAYER, AND DECR IN LEVEL OF CHOLESTEROL ESTERS AS COMPARED TO CONTROL PUPS. [R116] *FEMALE RATS WERE PAIR-FED USING ISOCALORIC CONTROL OR 6.6% (VOL/VOL) ETHANOL LIQ DIETS FOR 1 MO PRIOR TO CONCEPTION AND THROUGHOUT GESTATION. ETHANOL PUPS SHOWED PREMATURE ONSET AND SLOW-DOWN OF ACTIVE MYELINATION. [R117] *24-HR LC50 VALUE FOR RAINBOW TROUT IN FLOW-THROUGH BIOASSAY SYSTEM @ 10 DEG C WAS 11200 MG/L. ETHANOL AT ABOUT O.26 OF THE FINGERLING LC50, AFFECTED CARDIOVASCULAR/RESP SYSTEMS IN ADULTS. SLIGHT VENTILATION RATE AND BUCCAL PRESSURE AMPLITUDE DEPRESSION OCCURRED IN INITIAL STAGES OF 24 HR EXPOSURE. Q-T INTERVAL DECREASED. [R118] *Treatment of CD-1 mice with 7 g/kg ethanol ip on one of gestational days 7, 8, 9, 10, or 11 significantly incr the percentage of malformed fetuses and decr fetal wt. [R119] *Ethanol ... is capable of breaking the physiological gastric mucosal barrier and may cause ultrastructural injury to the epithelial cells within several minutes of exposure. Ethanol at any pH, ... is lipid soluble and diffuses rapidly into surface epithelial cells. ... First, the nuclear chromatin becomes clumped and the density of the cytoplasmic ground substance decreases, followed by the mitochondria becoming swollen and the apical cell membrane distorted. Finally, the apical cell membrane ruptures and the cell disintegrates. Throughout this sequence, the tight junctions between cells appear morphologically intact. [R120] *The direct effects of ethanol on cardiac contractility are controversial, probably because of methodological reasons in relation to the choice of appropriate experimental models. The direct effects of 1, 2, 5 and 10 g/l ethanol on mycardial performance and metabolism in the isolated perfused working guinea pig heart was studied. In the normal heart ethanol induced a dose dependent, fully reversible depression of cardiac contractility without significant changes of heart rate or cardiac metabolism. In the post anoxic failing heart this effect was more pronounced. Ethanol had no arrhythmogenic effect even at high concentrations. It had no measurable effect on anoxic induced alterations or post anoxic recovery after a period of 20 min of anoxic perfusion. Anoxic induced lactate production was decreased in hearts pretreated with 10 g/l ethanol. The direct negative inotropic effect and the lack of chronotropic effect of ethanol was studied. They suggest the lack of effect on excitability. The mechanism of the negative inotropic effect does not seem to be metabolically related since cardiac O2 consumption and lactate production remain unaltered. [R121] *Ethanol (0.6 g/100 g) was administered orally to rats by means of an intragastric tube. This caused an accumulation of secretory vesicles laden with very low density lipoprotein (VLDL) particles which were seen 90 min after administration and later disappeared. Lysosomes and Golgi complex secretory vesicle (GCSV) fractions were isolated. The proteolytic and lipolytic activities of these fractions were measured in order to assess their possible role in the elimination of the initially retained secretory material. There was no change in proteolysis either in lysosomes or in the GCSV-fraction from ethanol-intoxicated rats when measured by the release of degradation products during incubation. Similarly, the activities of acid hydrolases were unaffected by acute ethanol intoxication. On the other hand, lipolysis increased by some 50-100% in the GCSV fraction, whereas the lysosomes displayed unchanged lipolytic levels compared with controls. Ultrastructurally, the GCSV-fraction from ethanol-intoxicated rat livers showed signs of disintegrated VLDL particles. It is concluded that acute ethanol intoxication causes an increase in lipolysis but not in proteolysis in the operationally defined GCSV fraction. Since triacylglycerol lipase activities did not change in the GCSV fraction, increased amounts of substrate seem to cause the enhanced lipolysis observed. [R122] *Luteinizing hormone (LH) secretory patterns were characterized in adult male and female rats exposed to ethanol during the last week of fetal life. Gonadectomized fetal alcohol exposed (FAE) males and females had significantly reduced plasma LH titers as compared with those of pair fed (PF) controls. The phasic afternoon LH secretory response to estrogen and progesterone priming was also significantly reduced in FAE females. These differences do not appear to be a result of altered pituitary sensitivity to luteinizing hormone releasing hormone (LHRH), since the infusion of LHRH resulted in an equal response in PF and FAE females. Subsequent characterization of the episodic pattern of LH secretion in FAE males revealed significantly reduced mean LH level, as well as, a decreased pulse amplitude and frequency when compared to PF males. Taken together, these data indicate that some of the central mechanisms controlling pituitary LH secretion are altered by prenatal exposure to alcohol. [R123] *In response to single ethanol administration orally, the catecholamine secretion from the adrenal medulla is enhanced as evaluated by urinary catecholamine excretion in rats. The threshold dose of 87 mmol/kg also produced a transient increase of blood sugar concn. Experiments with chronic ethanol treated rats showed that the increase of urinary catecholamine excretion following 87 mmol/kg disappeared occasionally, whereas the increase following repeated administration of 130 mmol/kg is permanent. Morphologic evaluation revealed enlargement of the adrenal medulla, changes of cells and nuclei as well as a distinct reduction of chromaffin reaction. [R124] *Pregnant Wistar rats (15/group) were exposed in inhalation chambers to 0, 10,000, or 16,000 ppm ethanol for 7 hr/day on gestation days 1-20. Groups of male Wistar rats (18/group) were exposed for 7 hr/day for six weeks. Exposed males were mated individually with unexposed virgin females for 5 days after completion of exposures. After parturition, pups from both maternally- and paternally-exposed groups were fostered to untreated females. Neither female or male rats exposed to 10,000 or 16,000 ppm ethanol showed any adverse effects. Offspring number (average of 14 pups/litter) was not affected at either concentration of ethanol. Behavioral testing revealed no differences from controls after maternal exposure to ethanol. [R125] *Twelve pregnant Sprague-Dawley rats were treated with a 12.5% v/v solution of ethanol in saline (0.015 ml/g body weight) administered ip on gestational days 6 thru 12. Control animals (12 rats) received an ip injection of saline. A third group of 22 rats were used as untreated controls. Embryos were removed on day 12 of gestation and studied. Of the 150 alcohol treated embryos, four embryos showed a delay in the development of cardiac primordia: instead of a differentiated heart, they had a beating "S" shaped cardiac tube. A distorted head shape and central nervous system defects were also present in some of the embryos. No alterations occurred in either the yolk sac circulatory system or the allantois in embryos of this group when compared to controls. [R126] *Pregnant Hartley guinea pigs averaging 57 days of gestation (3rd trimester) were given four 1 g/kg body weight doses of ethanol (ETH) administered orally at 1 hr intervals. Animals were sacrificed between 0.5-26 hr after treatment and the pharmacokinetics of ETH and acetaldehyde(AC) were determined. There was a bidirectional placental transfer of ETH between maternal fetal compartments with a peak concentration in blood and brain at 4.5 hr after administration and ETH accumulation in the amniotic fluid. AC concentration was at least 1000 fold less than the respective ETH concentration. Fetalethality was observed during the 9-26 interval after administration of ETH (55% at 23 hr). At this time interval, the AC concentration in maternal blood and fetal brain were 4 to 5 fold higher in the animals with dead fetuses when compared with animals with live litters. [R127] *The effects of glutathione (GSH) depletion on enhancing ethanol induced hepatotoxicity was investigated by measuring the serum concentrations of glutamic-pyruvic-transaminase (GPT) and sorbitol dehydrogenase (SDH) in rats. Male Wistar rats (7-8/group) were treated with phorone (250 mg/kg in 10 ml/kg olive oil ip) to deplete hepatic GSH, and 2 hr later with ethanol (1.6 g/kg iv). Controls received olive oil instead of phorone and saline instead of ethanol. In saline treated animals the GPT and SDH concentrations remained nearly constant during the test period (up to 25 hr), and no differences were seen between phorone pretreated rats and controls. In the normal rats treated with ethanol, there was a small but statistically significant increase in the GPT and SDH values 4 hr after treatment. However, in the phorone pretreated rats that also received ethanol, there was a several-fold statistically significant increase in both enzyme activities at 4 hr ; increases in enzyme activities were also seen at 2 hr (SDH), 3 hr (both enzymes), and 25 hr (GPT) after treatment. [R128] *Blood ethanol concn and reactive capacity of 10 young (8 months) and 5 old (24 months) male Fischer 344 rats were compared at 5, 10, 20, 45, 65, and 90 min following admin of ethanol (EtOH). Time dependent effects of intragastric intubation (3 g/kg) and ip injection (1.5 g/kg) of EtOH (20% w/v) were determined. Subsequent of IG delivery, blood ethanol concn rose most rapidly within the first 20 min, but did not reach peak levels until 90 min for both young (240 mg/dl) and old rats (250 mg/dl). Following ip injections, blood ethanol concn escalated within 5 min to 250 mg/dl in the young, to 175 mg/dl in the old, and declined gradually to a stabilized value of 150 mg/dl (young) and 130 mg/dl (old). The old rats never achieved the high blood ethanol concn seen in the young. Reactive capacity, a measure of auditory/visual reaction time, was inversely related to blood ethanol concn. As blood ethanol concn (ip) declined, performance improved at a similar rate in both age groups, although the old rats' performance was more impaired than that of the young. However, when ethanol was delivered by IG so that blood ethanol concn remained high for long periods of time, reactive capacity was far less impaired compared with ip delivery in which comparable blood ethanol concn were present for only a few minutes. [R129] *Twenty three 6-8 wk old male and female mice of various strains (Swiss, Balb/c, DBA/2, CBA, C57B1/6, and B6D2F1) received a topical application of a 95% solution of ethanol on both sides of the right ear on days 0 and 2, and a scapular sc injection of 0.05 ml of complete Freunds adjuvant on day 2. On day 9, left ear thickness was measured immediately before topical application of 95% ethanol (the maximal nonirritating concn), on both sides of the ear, and again 24 hr later (day 10). No statistically significant incr in ear thickness was seen. In another test procedure, anesthetized male (n=9) and female (n=10) Swiss mice received a sc injection of 0.05 ml of ethanol in complete Freunds adjuvant into the scapular region, together with a topical application of ethanol on the shaved abdomen. On days 3, 5, 7, 10, 12, and 14 they received a topical application on the shaved abdomen and a second scapular sc injection of 0.05 ml complete Freunds adjuvant on day 7. On day 26, left ear thickness was measured immediately before a topical application of ethanol on both sides of the ear. Left ear thickness was again measured on days 27 (24 hr after challenge) and 28 (48 hr later). No significant incr in ear thickness was seen. [R130] *Adult male Sprague Dawley rats were implanted with indwelling gastric cannula one wk prior to expt. Intragastric infusion of 4 g/kg ethanol into naive rats resulted in a rapid and substantial incr of release the stress hormones adrenocorticotropic hormone, corticosterone, epinephrine, and norepinephrine stress hormones. The mean SEM of the percent incr over basal levels (at 100) for adrenocorticotropic hormone was 572, 329, and 391 for 7.5, 15, and 60 min after ethanol admin, respectively; and for corticosterone values were 229, 202 and 368. For epinephrine, the incr after 15, 30, and 60 min was 550, 773, and 105, while that for norepinephrine was 229, 212, and 179, respectively. In another expt, rats were pretreated with either ganglion blocker (pentolinium, 5 mg/kg body wt) 5 min before ethanol admin, or were bilaterally adrenodemedullectomized two wk prior to the ethanol infusion. Neither procedure, which effectively eliminated the ethanol induced surge of catecholamines, resulted in a significant attenuation of the ethanol secretion of adrenocorticotropic hormone or corticosterone. [R131] *The effect of ethanol (10, 25, 50, 100, 200, and 400 mM) on muscarine stimulated release of (3)H-norepinephrine, (3)H-NE was studied using the rat pheochromocytoma cell line, PC12. At concn of 25 mM and above, ethanol produced a dose dependent inhibition of muscarine stimulated release of (3)H-NE (86.1-36.9% of control). The inhibition of muscarine stimulated transmitter release occurred in the absence of any effect of ethanol on (3)H-NE uptake, metabolism, or on muscarinic binding to the cells. However, ethanol produced an inhibition of muscarine stimulated elevation of intracellular free Ca(+2) which corresponded with the inhibition of transmitter release. At concn greater than 100 mM, ethanol produced both a stimulation of the release of (3)H-NE as well as an incr in intracellular free Ca(+2) > At 100 mM ethanol the incr in free Ca(+2) was 73.2% of control, and at 400 mM it was 50.8%. Ethanol (400 mM) causes approx a 20% incr in the basal rate of (3)H-NE release, accompanied by an elevation of the basal level of intracellular free Ca(+2) from 114 nM to 149 nM. The incr in basal transmitter release and intracellular free Ca(+2) occurred independent of the inhibition by ethanol of muscarine stimulated elevation in intracellular free CA(+2) or transmitter secretion. [R132] *C57BL mice were fed ethanol in a liquid diet for seven days and were withdrawn for various intervals. Chronic ethanol ingestion, leading to functional tolerance and physical dependence, significantly decreased the number of cerebellar antagonist binding sites, while the affinity was not affected. In cerebellar membranes, the proportion of high- and low-affinity ISO binding forms of BAR was not altered after chronic ethanol ingestion. The affinity for ISO of the high affinity ISO binding form of the receptor was significantly decreased. [R133] *Groups of NIH Swiss mice (n= 7) were admin 0, 10, or 20, mg/kg of one of three 5-hydroxytryptophan uptake inhibitors (fluoxetine), citalopram, or (fluvoxamine) or a noradrenaline uptake inhibitor (desipramine) ip 90 min prior to testing, followed by an ip injection of either 0 or 2.4 g/kg ethanol in distilled water vehicle 30 min prior to testing in the holeboard, followed by the elevated plusmaze test of anxiety. Ethanol increased activity in both tests, decreased both the number and duration of head dips in the holeboard, and increased both the percentage time and percentage entries on to the open arm of the plusmaze. None of the inhibitors significantly altered any of the behavioral measures. The only consistent interaction was seen with fluoxetine which reduced ethanol's anxiolytic effects at the 20 mg/kg dose without altering ethanol's effects on exploration or locomotion. [R134] *The influence of alcohol consumption and hepatic fibrosis on red blood cell membrane fatty acid composition and susceptibility to lipid peroxidation were studied using male Sprague Dawley rats. Cells from seven rats chronically treated with ethanol (20% ethanol in tap water for 14 wk (11 g ethanol/kg body wt)) or from 15 rats treated with thioacetamide (0.5 g/1 in tap water for 14 wk), an inducer of hepatic fibrosis, were analyzed. Red cells from the ethanol treated rats had minor changes in fatty acid composition compared with controls (n= 7). There was a slight decrease in the proportion of arachidonic acid and a slightly decreased susceptibility of the cells to lipid of peroxidation. Cells from rats with hepatic fibrosis had an increased proportion of linoleic acid and a decreased proportion of arachidonic acid compared to controls (n= 15). These cells were less susceptible to lipid peroxidation. [R82] *The substitution of drinking water in 26 male Wistar rats for a 10% ethanol solution for 4 wk in blood= 0.78 + or - 0.13 mM/l resulted in a decr of blood urea and citrulline synthesis in liver mitochondria; a slight inhibition in state 3 and state 4 respiration either with glutamate malate as substrates or succinate as substrate; no change in adversive diphosphate:oxygen ratio with succinate but slight incr with glutamate malate; a reduction of the cytochrome oxidase activity and cytochromes a + cytochrome a3 content; a 42% incr in the succinate dehydrogenase activity and a small but constant incr in the Vmax (no change in the Km) of the adenine nucleotide translocase activity in liver mitochondria. [R135] *The effect of ethanol (0.5 g/kg, iv) at different concn (30, 60, and 90%) was studied in male cats using radioactive microspheres on systemic hemodynamics and regional circulation. Ethanol produced a significant fall in systolic, diastolic and mean blood pressure. A significant reduction in heart rate, left ventricular work, cardiac output and total peripheral resistance was also observed. No change occurred in stroke volume. A significant decr in blood flow to left ventricle, right ventricle and interventricular septum was observed, but the vascular resistance of these regions was unaltered. Brain blood flow was not affected by various concn of ethanol. The vascular resistance significantly decr in spinal cord, medulla, pons, midbrain, hypothalamus, thalamus, caudate nucleus, cerebellum and cortex. The avg brain blood flow (ml/min/100 g) was 35.63 in control, 37.17 in 30%, 35.56 in 60% and 35.05 in 90% ethanol treated cats. Spleen, liver, pancreas, gastrointestinal tract, skin, muscle and bone did not show any significant change in the blood flow, while vascular resistance decr significantly in these organs. Kidneys and eyes showed decr blood flow and no change in vascular resistance following ethanol treatment. The blood passing through the arteriovenous shunts was significantly decr by ethanol. [R136] *Subcutaneous injection of neonatal gray opossums with 2 mg ethanol on day 2 and day 4 of life in the right or left hindquarter resulted in defects of the associated limb in 44% of the animals. The abnormalities, as recorded on day 21, were gait abnormalities, foot clubbing, moderately reduced limb size, fuse digits, missing digits, and in one case, a partially missing limb. Saline solution was administered to the control group, of which 16% had defects such as gait abnormalities, foot clubbing, and moderately reduced limb size. The opossums at birth were equivalent in development to a human fetus at 8 weeks and therefore useful for studying teratogenicity. [R137] *Ethanol (7.5 g/kg) was administered to neonatal rats in four consecutive feedings spaced two hours apart on either postnatal day 4, 5, or 6, via gastrostomy feeding tubes. Controls consisted of rats suckled in the normal manner and gastrostomy group fed formula. Ethanol exposures resulted in high peak blood alcohol concn (mean peak blood alcohol concn of 380, 439, and 460 mg/dl on days 4, 5, and 6, respectively). Whole brain weights as measured on the tenth postnatal day were greatest in the naturally suckled animals, slightly less in the gastrostomy controls, and significantly reduced in the ethanol fed rats. Ratios of whole brain to body weight were 3.703 in the suckle control, 3.423 in the gastrostomy control, 3.301 in day 4 ethanol group, 3.100 in day 5 ethanol group, and 3.102 in day 6 ethanol group. The cerebellum was affected more than the forebrain or brain stem, and cerebellar growth was more stunted by alcohol exposure on day 4 or 5 than on day 6. Small but significant delays in body growth occurred 1 to 2 days after the alcohol exposure for each group. [R138] *Groups of female mice were admin 5.8 g/kg (95% alcohol in saline intragastrically in a single intubation (0.3 mg/10 g body wt) on day 10 plus 4 hr of pregnancy. This dose of ethanol produced a blood ethanol concn of approx 450 mg % 60 min after injection. Control group animals were intubated with saline made isocaloric to the ethanol dose by addition of sucrose. On day 19 of gestation, fetal urogenital systems were examined by injection of indigo carmine into the bladder. 53 control and 116 ethanol treated fetuses were examined. Ethanol resulted in a significant decr in fetal wt. Malformed limbs, mostly in the form of fused digits (25 in all) were also seen in the ethanol treated animals but not in the controls. There was a significant increased incidence of hydronephrosis and hydroureter. In addition, there was a significant incr in reflux in the ethanol treated fetuses. The incidence of reflux appeared to be related to the severity of the hydronephrosis observed, though cases of hydronephrosis without reflux and reflux without hydronephrosis were found. Reflux occurred in only 7.1% of ethanol treated mice with a mild degree of hydronephrosis but in 46.1% of the mice with an extreme degree of hydronephrosis. [R139] *The effects of physical addiction to ethanol, withdrawal from ethanol addiction, and the genetic predisposition for drinking ethanol on the transport of enkephalins and Tyr-MIF-1 (Tyr-Pro-Leu-Gly-amide) across the blood brain barrier were studied in different strains of mice. In chronic oral ethanol exposure, 120 male ICR mice were fed 5% ethanol by vol via the diet for 10 days and half of the group was changed to sucrose mixture to constitute the withdrawal group. Male mice were genetically selected for predisposition to ethanol using strains C57BL/6J, C58/J, and DBA/2J (25 to 30 mice per strain). In acute ethanol exposure, mice received either 0.9% sodium chloride or 2.5 g/kg of ethanol ip in a vol of about 0.2 ml (20% ethanol) and transport was determined 0, 10 30, 45, 60, 90, or 120 min later. In other mice, the effect of incl ethanol in the ICV injections at concn of 0, 0.01, 0.05, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, 10, 15, 20 and 50% by vol was determined. During chronic exposure mice ingested an avg of 25 g/kg of ethanol/day. No statistically significant differences occurred among control mice with inhibitor, ethanol treated mice, or ethanol treated mice with inhibitor, indicating that ethanol primarily reduced the inhibitable portion of transport. Brain weights were different for genetically predisposed mice, as were half time disappearance rates and transport rates. Ethanol given in acute ip doses did not produce any differences in values for A or M of the transport equation or transport rate. In mice receiving ICV ethanol, values for A and the transport rate were statistically different from 0% at the 50% concn. [R140] NTOX: *The effect of cause associated with gastric infusion of ethanol on the free choice consumption of ethanol by male Sprague Dawley rats was assessed. Rats received a response independent conditioning experience with a distinctive drinking environment. Group RM-EtOH (n= 8) were given ethanol in a distinctive room and Group EtOH (n= 8) were given ethanol in their home cage after they had been returned from the distinctive room). Controls either received saline infusions either at the same time as Group RM-EtOH in the distinctive room or as Group EtOH (n= 4) in the home cage. On conditioning days 1 to 4, 2 g/kg ethanol was admin, and on days 5 to 10, 4 g/kg was admin. After training, rats were allowed daily free access to both an ethanol soln and tap water. In Expt 1, infusion of 20% ethanol reduced ethanol consumption on a choice test between 10% ethanol and tap water, compared with saline. The highest level of consumption was in controls, then Rm-EtOH, then EtOH. In Expt 2 the procedures were the same, except 2 g/kg ethanol was used, in a more palatable soln (0.1% saccharin + 10% ethanol) and was compared with consumption of tap water. Prior infusion with ethanol enhanced the consumption of the sweetened ethanol only when drug associated cues were present (group Rm-EtOH). In Expt 3, rats first received 10 24 hr periods of exposure to the sweetened 10% ethanol soln in their home cages. By the fourth exposure, animals had reached a stable level of consumption of about 40 ml of ethanol soln per day. Procedures were the same as the previous 2 expt. Levels of ethanol consumption were considerably higher than in Expt 1 and 2. [R141] *Two groups of 6 male Wistar rats were pair matched on a wt basis and fed a liquid diet containing either 18% of total calories as ethanol or pair fed isovolumetric amounts of the same diet in which the ethanol was substituted by isocaloric glucose (controls). After 3 to 7 days, the proportion of ethanol calories was increased to 36% with isocaloric incr of glucose in controls. Rats were sacrificed at 4 to 5 wk. Chronic ethanol consumption reduced the capacity for type II (anaerobic, fast twitch) fiber rich skeletal muscles to synthesize protein as reflected by a decr RNA/protein ratio. Type I (aerobic, slow twitch) fiber rich muscles were unaffected. A significant 12 to 190% reduction of skeletal muscle wt was seen, but ethanol feeding had no significant effect on cardiac output. The percentage of cardiac output to type I and type II fiber rich muscles, bone and tissue of the gastrointestinal tract was unaffected by ethanol consumption. Similarly, ethanol feeding had no effect on blood flow when it was calculated on the basis of tissue wt (ml/min/g). [R142] *The effect of ethanol (0.01-1%, v/v, or approx 1.74 to 174 mM) on single channel currents activated by N-methyl-D-aspartate (NMDA) in cultured hippocampal cells from Sprague Dawley rats were studied, using the outside out patch clamp technique. At low concn (1.74 to 8.65 mM) an incr in the probability of opening (p sub open) of the NMDA activated channel currents was seen without change in the mean channel open time. At higher concn (86.5 to 174 mM), a decr in p sub open (to 50% of controls) was seen with a concomitant decr in the mean open time. [R143] *Male Sprague Dawley rats (160-80 g) were pair fed liquid diets containing 36% calories as ethanol or an isocaloric mixture with maltose dextrin substituted for ethanol. Animals received progressive incr in ethanol during the first wk of feeding and were maintained on a reverse light dark cycle. Expt were started in overnight fasted animals, and all studies were performed between 6 and 8 wk of feeding unless otherwise noted. No incr of biliary hepatic glutathione (GSH) efflux in vivo was found in chronic ethanol fed hepatocytes. Hepatocytes from pair fed and ethanol fed rats were treated to obtain a wide range of cellular GSH concn. The relationship between cytosolic GSH and the rate of efflux was modeled by the Hill equation, revealing a similar sub max, 0.22 + or - 0.013 vs 0.20 + or - 0.014 nmol/min per 10+6 cells for ethanol fed and pair fed cells, respectively, whereas the Km was significantly decr (25.3 + or - 2.3 vs 33.5 + or - 1.4 nmol/10+6 cells) in ethanol fed cells. The difference in Km was larger when the data were corrected for the increased water content in ethanol fed cells. There was a direct correlation between mitochondria and cytosolic GSH, revealing that mitochondria from ethanol fed cells have less GSH at all cytosolic GSH values. The rate of resynthesis in depleted ethanol fed cells in the presence of methionine and serine was similar to control cells and gamma-glutamylcysteine synthetase remained unaffected by chronic ethanol. Levels of cytosolic and mitochondrial total GSH and the rate of GSH efflux were determined in pair fed and ethanol fed cells from rats at 2 and wk of treatment. At 2 wk, a selective 50% decr in mitochondrial GSH was observed (p < 0.01), without an effect on cytosolic total GSH or efflux. By 4 wk, the mitochondrial total GSH fell further, while a fall in cytosolic total GSH and increased efflux were evident in the ethanol fed group. [R144] *Cardiac membrane tissue from left ventricles of male rabbits was used to characterize the effects of ethanol on the activators of adenylate cyclase complex that act through the receptor site, the stimulatory guanine nucleotide binding regulatory protein, or the catalytic unit. Ethanol had no effect on adenylate cyclase activity stimulated by Mn +2, a selective activator of the catalytic unit, whereas high concentrations of ethanol (> 425 mM) inhibited both basal and isoproterenol stimulated adenylate cyclase. In contrast, in the presence of nonhydrolyzable GTP analogs, ethanol potentiated substantial increases in adenylate cyclase activity. In the presence of these GTP analogs, ethanol increased the Vmax without altering the affinity of adenylate cyclase for ATP. Ethanol also increased adenylate cyclase activity (4.5 fold) in membranes in which the guanine nucleotide binding regulatory protein had been preactivated with isoproterenol plus a nonhydrolyzable GTP analog. Beta adrenoreceptor density in rabbit heart membranes was 9.8 + or - 2.1 fmol/mg membrane protein with ethanol and 10.4 + or - 1.7 fmol/mg protein without ethanol. The ability of cholera toxin and NAD+ to augment adenylate cyclase activity through an effect on guanine nucleotide binding regulatory protein was attenuated by increasing concentrations of ethanol. [R145] *A brief exposure of recently ovulated mouse oocytes to a dilute solution (7%) of ethanol in vitro for 1, 3, or 5 min induced a uniform high incidence of parthenogenetic activation. The majority of parthenogenones developed a single haploid pronucleui after the extrusion of a second polar body. The proportionate incidence of this parthenogenetic class was significantly reduced as the duration of ethanol exposure increased from 1 min to 5 min. There was a concomitant increase in the incidence of parthenogenones that developed two haploid pronuclei following failure of extrusion of the second polar body. The ethanol induced single pronuclear haploid parthenogenones at metaphase of the first cleavage division were aneuploid. The incidence of aneuploidy was directly related to the duration of ethanol exposure (15.1% at 1 min, 15.5% at 3 min, and 25.7% at 5 min). G-band analysis of the aneuploid metaphases revealed that the chromosomes were not randomly involved in the malsegregation events. [R146] *Three female Macaque monkeys were trained to self administer alcohol intravenously during four daily sessions at noon, 4 PM, 8PM and midnight. Each session lasted 1 hour or until 20 alcohol injections of (0.12 g/kg) had been administered. In one amenorrheic alcohol dependent monkey, prolactin levels increased from 16.5 to 63 ng/ml during chronic, high dose alcohol self administration (3.4 g/kg/day); immunocytochemical examination of the anterior pituitary showed apparent hyperplasia of the lactotrophs. Four amenorrheic cycles (85 to 194 days) from two other alcohol female monkeys that self administered an average of 2.97 to 4.4 g/kg/day of alcohol were also studied. Each monkey became amenorrheic during the first menstrual cycle that alcohol was available. One monkey developed galactorrhea during a 97 day amenorrheic cycle when alcohol self administration averaged 3.35 g/kg/day. Although prolactin levels were intermittently elevated above 20 ng/ml, average levels during these amenorrheic cycles (14.7 + or - 1.8 to 19.6 + or - 1.5 ng/ml) did not differ significantly from prolactin levels during normal ovulatory menstrual cycles when no alcohol was available (19.7 + or - 0.36 ng/ml). Daily alcohol dose and prolactin levels were negatively correlated. High dose alcohol self administration was often associated with low normal prolactin levels, but a relative fall in alcohol dose was usually associated with elevated prolactin levels. Luteinizing hormone levels were significantly lower during amenorrheic cycles (16.9 + or - 1.2 to 24 + or - 1.4 ng/ml) than during nonalcohol control cycles (28 + or - 1.2 to 3 + or - 2.2 ng/ml). [R147] *The effects of ethanol and sulfhydryls on gastric mucosa were studied by dosing male rats with 1 ml of 50% ethanol by esophageal intubation. One hour after ethanol administration the animals were sacrificed and the gastric wall prepared for examination. Pretreatment with subcutaneous diethylmaleate (1 ml/kg), cysteamine (100 mg/kg) and 16,16-dimethyl prostaglandin E2 (10 ug/kg) significantly inhibited lesion formation. Pretreatment with N-ethylmaleimide (10 mg/kg) aggravated the lesions. Ethanol did not change the action of the other chemicals on glutathione levels in mucosa. N-Ethylmaleimide significantly enhanced the vascular permeability in the presence or absence of ethanol whereas the other agents significantly enhanced only the increased vascular permeability caused by ethanol. At doses which prevented ethanol induced mucosal injury, diethylmaleate, cysteamine and 16,16-dimethyl prostaglandin E2 potently inhibited gastric motility, whereas N-ethylmaleimide had no effect on motility. [R148] *The effects of ethanol in thyroid disease were studied in three groups of female rats. Group I was given L-thyroxine as subcutaneous pellets to induce hyperthyroidism, Group II was given propylthiouracil as subcutaneous pellets to induce hypothyroidism, Group III served as controls. Rats then received slow intravenous infusions of ethanol until they lost their righting reflex. The hypnotic dose of ethanol was increased significantly in the hyperthyroid rats (3.26 + or - 0.20 g/kg) and decreased in hypothyroidism (2.32 + or - 0.31 g/kg) (control 2.82 + or - 0.15). Ethanol concentrations in serum, brain, and cerebrospinal fluid at onset of effects were generally not affected by thyroid dysfunction except for a small increase of serum ethanol concentration in the hyperthyroid rats. [R149] *The effects of prenatal and postnatal exposure to ethanol on luteinizing hormone releasing hormone and luteinizing hormone were investigated in female rats and their offspring. Group 1 rats (control, no ethanol) were fed a liquid diet during gestation and lactation. Group 2 rats were fed ethanol in a liquid diet during gestation and the control diet during lactation. Group 3 rats were fed the control diet during gestation and ethanol in a liquid diet during lactation. Group 4 rats were fed the diet containing ethanol during both gestation and lactation. Female offspring were decapitated at 30 to 40 days. Hypothalamic luteinizing hormone releasing hormone contents in all the ethanol exposed groups (0.13 to 0.29 ng/hypothalamus) were less than that of the controls (0.80 and 1.05 ng/hypothalamus). Plasma luteinizing hormone concentrations of all ethanol exposed groups were less than those of controls (24.2 and 29.6 ng/ml): 18.9 an 17.8 ng/ml in animals from group 2 mothers (ethanol during gestation only), 5.7 and 6.8 ng/ml in animals from group 3 mothers (ethanol during lactation only) and 10.7 and 8.5 ng/ml in animals from group 4 mothers (ethanol during both gestation and lactation). [R150] *Blood glucose and rectal temperatures were monitored in genetically obese mice (C57 BL/6J ob/ob) prior to and following intragastric ethanol administration (12 mg/g body weight) in an attempt to relate the hypothermic response to ethanol to extracellular glucose concentration. Lean litter mates served as controls. Room temperature was controlled at 21.5 + or - 0.2 C, and animals were placed on a neutral surface, protected from drafts. In obese mice, ethanol administration was associated with hyperglycemia and hypothermia; however, the hypothermia was independent of blood glucose levels and of age. [R151] *Chinese hamster ovary cells exposed to 4% ethanol did not acquire any apparent chromosomal aberrations. However, posttreatment with ethanol potentiated the chromosomal aberrations induced by ultraviolet light, methyl methanesulfonate, mitomycin C or bleomycin. Chromatid exchanges were predominantly increased in cultures treated first with the ultraviolet light, methyl methanesulfonate, or mitomycin C and then with ethanol, whereas chromosome breaks and chromatid exchange were the major types of aberrations increased in the cultures treated with bleomycin and ethanol. [R152] *Cerebellar granule cells from excised cerebella of 8 day old Sprague Dawley rats were incubated with N-methyl-D-aspartate (10, 50, or 100 uM) in the presence of (0, 25, 50, or 100 mM) ethanol. Measurements of calcium uptake and cyclic guanosine monophosphate production demonstrated that ethanol preferentially inhibited N-methyl-D-aspartate receptor gated cation channel function. Concn of ethanol as low as 10 mM inhibited N-methyl-D-aspartate stimulated Ca(+2) uptake by > 30%. Ethanol also inhibited N-methyl-D-aspartate stimulated (Ca(+2)) dependent) cyclic guanosine monophosphate accumulation in a similar, dose dependent manner. The IC50 values for ethanol were 42.7 mM at 10 uM, 74.4 mM at 50 uM, and 156.7 mM at 100 uM N-methyl-D-aspartate. With 100 uM kainate, 100 mM ethanol did not significantly inhibit the cyclic guanosine monophosphate response: 16.0 + or - 9.4% inhibition (n= 4). [R153] *Groups of 6 adult male Sprague Dawley rats were admin saline or ethanol in saline ip daily for 7 days and killed 24 hr after the last dose. The doses of ethanol were 0.5, 1.0, and 3.0 ml/kg. Other groups of 6 rats were admin saline or ethanol (3 ml/kg ip) for 7 days. Carbon tetrachloride in corn oil (1.0 ml carbon tetrachloride/kg as a 50% solution in corn oil, ip) was admin on day 8, and measurements of butanol oxidase were made 24 hr later. 2-Butanol was incubated with microsomal lung and liver preparations from rats, and methyl ethyl ketone production was measured by gas chromatography. The rate was 6 to 8 times lower in lung than in liver. Admin of the two low doses of ethanol did not alter activity in the liver but was inhibitory in the lung. The high dose of 3.0 ml/kg caused a 41% inhibition in the liver and a 51% inhibition in the lung. The effects of ethanol and carbon tetrachloride were not additive. [R154] *Preimplantation two cell stage mouse embryos, obtained from superovulated CF-1 mice, were exposed to ethanol through the culture medium for 60 min followed by a 105 hr incubation period. Scoring was based on a system which recognized eight different stages of development, zero for dead cells of the two and four cell stage to 7 for hatching blastocyst. Control and ethanol exposed embryos survived equally well in ethanol concentrations as high as 800 ng/100 ml medium, the highest concentration tested. [R155] *The apparent pharmacological regulation of ethanol ingestion by rats was examined under the effects of wt restriction and enhanced palatability, two variables that have been shown to incr ethanol (alcohol) consumption when the alcohol is continuously available. Incr the palatability of the ethanol solution by the addition of a 0.25% saccharin solution enhanced consumption substantially such that the blood alcohol levels achieved in male Wistar rats were more than twice those of rats which had drunk unadulterated alcohol. Wt restriction to 80% of free feeding wt of male Wistar rats did not incr alcohol consumption under these conditions. [R156] *The effects of ethanol on the incidence and histology of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. Rats received alternate-day ip injections of 2.5 ml/kg body wt of 20% ethanol in 0.9% sodium chloride solution after 20 wk of oral treatment with N-methyl-N'-nitro-N-nitrosoguanidine. Prolonged administration of ethanol resulted in a significant incr in the incidence and number of gastric cancers of the glandular stomach in wk 52. However, it had no influence on the histological types of the gastric cancers. Furthermore, it caused a significant incr in the labelling index of the epithelial cells of the antrum in wk 52. [R157] *Length changes in dendritic networks of cerebellar Purkinje cells were studied in aging Fischer 344 rats after chronic ethanol treatment. Results showed that no significant metric changes in lengths of dendritic segments were detectable immediately following 24 wk of ethanol treatment. However, significant changes were observed after 8 wk of recovery from the ethanol treatment. The differences in lengths were restricted to terminal segments that were paired at the peripheral tips of the bifurcating networks. Unpaired terminal segments and internal segments did not show significant changes during the recovery period. [R158] *Effects of prenatal alcohol exposure during the last week of gestation on immune function and levels of brain corticotropin releasing factor (CRF) and ACTH were studied in Sprague-Dawley rats. Immune response was measured by T-lymphocyte proliferation in response to the T-cell mitogen concanavalin A in spleen and thymus cells of 21 day old male rats that had been exposed to alcohol in utero. The T-lymphocyte proliferative response was 8 fold less in spleen and twofold less in thymus cells from fetal alcohol exposed (FAE) animals as compared to controls. Thymus wt was significantly lower at birth in fetal alcohol exposed males but significantly higher at age 21 days, compared to controls. Both hypothalamic corticotropin releasing factor and pituitary ACTH contents were significantly decreased in fetal alcohol exposed males on postnatal day 1, but hypothalamic ACTH content was significantly elevated compared to controls. [R159] *Neonatal Camborough piglets were put under nitrous oxide anesthesia. In the first exptl series, piglets were given either ethanol (1.4 g/kg) in 5% dextrose in water infusion over 50 min via the femoral vein or an equal volume of vehicle only. In the second series, all piglets also received a 15 min iv infusion of 50 mg/kg 4-methylpyrazole 15 min before ethanol or vehicle infusion. Two hours after ethanol admin, blood pressure decr from 76 + or - 4 to 71 + or - 4 mm Hg and heart rate increased from 194 + or - 10 to 227 + or - 8 beats/min. By 5 hr, blood pressure dropped to 67.5 + or - 4 mm Hg and heart rate increased to 239 + or - 8 beats/min. In piglets pretreated with 4-methylpyrazole, an alcohol dehydrogenase inhibitor, there was a transient incr in blood pressure and a decr in heart rate immediately after the end of the ethanol infusion. However, the hemodynamic alterations observed 2 hr after ethanol treatment alone were prevented with 4-methylpyrazole. The mean ethanol metabolic rate derived from plasma data was 94 + or - 9 mg/l/hr. [R160] *The influence of ethanol on the activities of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA-reductase) and squalene-hopene-cyclase (SC) in hopanoid biosynthesis of Zymomonas mobilis subsp mobilis (ATCC 29191). By use of (14)C and (3)H-labelled substrates, the enzymes were detected with activities of 1.6 pmol/(min x mg protein) HMG-CoA-reductase and 2.3 pmol/(min x mg protein) for squalene-hopene-cyclase. Cells grown in the presence of 6% (v/v) ethanol did not show higher activities of these enzymes than cells grown in the presence of 1% (v/v) ethanol. Alcohol dependent induction of HMG-CoA-reductase in Z mobilis was examined by cultivation of cells at different ethanol concn and measurement of the corresponding enzyme activity. Cells grown in batch or continuous cultures at 47-74 g/l ethanol showed an even lower HMG-CoA-reductase activity than cells grown with 20 g/l glucose (producing ethanol concn < 1% v/v) without externally added ethanol. Squalene-hopene-cyclase activity was the same in crude extracts of Z mobilis cells grown in 2.5% or 8.5% ethanol. A significant incr of enzyme activity was caused by addition of ethanol to the assay. An ethanol concn of 60 g/l (7.6 v/v) led to enzyme activities of up to 5.8 pmol/(min x mg protein). [R161] *A CORRELATION BETWEEN HYPNOTIC POTENCY OF ALIPHATIC ALC AND ABILITIES TO DISRUPT STRUCTURE OF NEURONAL MEMBRANE IN VITRO WAS ESTABLISHED. SIGNIFICANT REDN IN ORDER PARAMETER WERE OBSERVED @ NERVE BLOCKING CONCN. THE FOLLOWING ALCOHOLS WERE INVESTIGATED: ETHANOL, PROPANOL, 2-PROPANOL, BUTANOL, 2-BUTANOL, 2-METHYL-1-PROPANOL, 2-METHYL-2-PROPANOL. DISORDERING POTENCY OF EACH ALCOHOL WAS CLOSELY RELATED TO ITS MEMBRANE SOLUBILITY, BASED ON OIL/WATER PARTITION COEFFICIENT. [R162] *RATS WHICH INGESTED A 2 MOLAR SOLN OF ETHANOL FOR 2 MO SHOWED MALLORY'S ALCOHOLIC HYALINE BODIES IN THE LIVER AND ALSO DECR IN FAT, GLYCOGEN, AND RNA OF THE LIVER. [R163] *IN THE RAT ... THE ORDER OF INCREASING LETHALITY BY SINGLE DOSE ORAL ADMIN IS AS FOLLOWS: ETHYL, ISOPROPYL AND SEC-BUTYL, N-BUTYL, TERT-BUTYL, ISOBUTYL, AND AMYL ALCOHOLS. [R10, p. III-12] *... About 50% inhibition of ammonia oxidation in Nitrosomonas at 4100 mg/l [R13, 618] *Guinea pig: inhalation: no signs of intoxication: 6400 ppm, 8 hr; 3000 ppm, 64X4 hr; Rat: inhalation: no signs of intoxication: 10,750 ppm, 0.5 hr; 3260 ppm, 6 hr [R13, 619] *A drop full-strength on rabbit eyes causes reversible injury graded only 3 on a scale of 10 after 24 hr. Application of 70% alcohol to rabbit corneas injures and temporarily loosens the corneal epithelium, but the recovery is complete. ... repeated applications (7 drops) of 40 to 80% alcohol to rabbit eyes over an unspecified but presumably longer time caused loss of corneal epithelium and endothelium, followed by hemorrhages in the conjunctiva, and infiltration and vascularizarion of the corneal stroma. [R61, 53] *Acute alcohol admin has been shown to modify the ERG in rabbits, monkeys ... . [R61, 55] *... The equivalent of 0.3 ml of ethanol /was injected/ into the chick air sac at 23 hr of incubation and produced neural tube and cerebral vesicle deformities along with some mesodermal defects. ... /1.0 to 2.0 g of ethanol per kg was injected to/ pregnant rats iv at 6 and 7 days of gestation ... and ... embryolethality but no defects in the surviving fetuses /were found/. ... Pregnant mice /were fed/ before and during pregnancy with a ... diet containing 15 to 30% ethanol derived calories. At the higher concn resorptions occurred frequently. Neural defects and cardiac malformations were found in a significant number of offspring. ... incr susceptibility to audiogenic seizures /was found/ in offspring of mice given alcohol. Learning is impaired in rats exposed during intrauterine life. [R164, 18] NTOX: *... The effects of binge drinking /were studied/ in three monkeys. ... 2.5 or 4.1 g/kg /was given/ by gavage once weekly from 40 days gestation to term. One nd facial exposed to the highest dose had neurologic, developmental a anomalies. ... One of the other two exposed to the lower dose had similar but less severe findings. [R164, 19] *Porcine pulmonary artery endothelial cells were cultured on micropore filters and the effect of ethanol on albumin transfer across cultured endothelial monolayers was studied. Chronic ethanol exposure resulted in a marked increase in albumin transfer compared with control cultures, and this difference in albumin transfer increased with increasing cell age. In contrast to its effects on endothelial barrier function, chronic ethanol exposure had little effect on endothelial cell growth characteristics. Even though thymidine incorporation into cell DNA was significantly less at passage 50 in ethanol treated cells compared with control cultures, the overall DNA and protein synthesis rate and the cell total DNA and protein content were not markedly affected by chronic ethanol exposure. [R165] *24 adult mongrel dogs were fed a diet (5 days per wk) mixed with 3 g/kg ethanol (ETOH) for 3 mo (group 1, n = 12) and 9 mo (group 2, n = 12); 12 dogs were fed a regular diet with no alcohol. Blood alcohol levels 2 to 3 hr after food consumption were 116 + or - 10 mg/100 ml. On the experimental day, both ETOH treated and ETOH free dogs were divided into two subgroups, one for hemorrhagic shock (mean arterial pressure of 30 mm Hg for 2 hr) and one for observation during anesthesia. Chronic ethanolism altered cardiocirculatory function (increased mean arterial pressure (p < 0.05), arterial lactate, and hematocrit (p < 0.05) and decr cardiac output (p < 0.05), stroke work, and pancreatic blood flow (p < 0.05)) regardless of the length of time ETOH was consumed. Hemorrhagic shock impaired cardiovascular performance regardless of ETOH consumption. However, coronary blood flow, myocardial oxygen delivery, extraction, and consumption were significantly higher (p < 0.05) in the ETOH treated compared with ETOH free dogs after 2 hr of shock. Cardiocirculatory dysfunction after fluid resuscitation from shock in the ETOH group was not related to inadequate coronary perfusion, metabolic acidosis, or cardiac hypertrophy. Examination of myocardial tissue by light microscopy showed no significant difference in myocyte size in any group regardless of chronic ethanol consumption. Hypercontraction lesions occurred in all shocked hearts, both intoxicated and nonintoxicated. There were not myocardial lesions in any nonhemorrhaged dog. There was increased total myocardial tissue calcium content in the ETOH group. [R166] *Young male Wistar rats (80 to 100 g body weight) were fed a nutritionally adequate liquid diet containing ethanol as 36% of total energy. Controls were fed the same diet in which ethanol was substituted by isoenergetic glucose. At the end of 6 wk, rats were killed and hearts were fractionated into sarcoplasmic, myofibrillar and stromal protein fractions by differential solubilization. The total myofibrillar protein content was significantly (p < 0.01) reduced by chronic ethanol feeding, though the contents of other fractions were relatively unaltered. The fractional and absolute rates of myofibrillar protein synthesis were significantly increased (p < 0.05), but the synthesis rates of sarcoplasmic and stromal protein fractions were unaffected by ethanol feeding. There was a statistically significant increase in the ratio of myofibrillar/stromal synthesis rates (p < 0.025) and a statistically significant decr in the ratio of sarcoplasmic/myofibrillar synthesis rates (p < 0.05). There was also significant incr in the ratio of myofibrillar/stromal absolute rates of protein synthesis. [R167] *Pregnant Sprague Dawley rats were placed into the following treatment groups: control (water and lab chow ad lib), 17% ethanol-derived calories (in liquid diet, 3.3% vol/vol), 35% ethanol derived calories (6.7% vol/vol), 17% pair fed, and 35% pair fed. Pair fed controls were fed the same volume of an isocaloric diet as was consumed by their respective ethanol treated groups, with maltose dextrin to replace ethanol. The pregnant female rats on the 17% ethanol diet consumed an avg of 10.8 g of ethanol/kg body wt/day and maintained a relatively constant blood alcohol concn of 40 mg% throughout gestation. 35% ethanol rats consumed an avg of 16.8 g ethanol/kg. Their blood ethanol rose steadily during gestation reaching a maximum of 170 mg% on the morning of day 18 of gestation. At birth, litters were culled to 6 and cross fostered to untreated surrogate mothers. Radial arm maze testing was initiated at 60 days of age and continued until the test criterion was satisfied (2 adjacent error free trials). One half of the rats in the 35% ethanol group did not reach criterion. The remainder of the 35% ethanol group and the 17% ethanol rats attained criterion but required twice as many trials as their respective pair fed controls. This difference was statistically significant for the 35% ethanol group (p < 0.05). The total number of errors committed prior to reaching the test criterion was elevated in both ethanol treated groups compared to their pair fed controls, but the avg time required to complete the maze per trial was reduced. Upon reaching criterion, there was very little difference in maze running times between pair fed control and ethanol treated groups. [R168] *Pregnant Sprague Dawley rats were placed into the following treatment groups: control (water and lab chow ad lib), pair fed, 10% ethanol derived calories, 20% ethanol derived calories, and 35% ethanol derived calories. The pair fed, 10% ethanol, 20% ethanol and 35% ethanol groups were fed a liquid diet containing either 0%, 2%, 4%, or 6.7% vol/vol ethanol, respectively. All the treatment groups received the same volume of an isocaloric diet that was consumed by the 35% ethanol derived calories group. Rats consumed an avg of 5.0, 10.0, and 16.8 g of ethanol/kg/day in the 10%, 20%,and 35% ethanol diets, respectively. Litters of alcohol treated mothers were smaller, had more still births and had a higher number of pups which died within 2 days of birth (6.6%, 11.5%, and 30%, versus 4.7% for pair fed, p < 0.05) than did the liters from the control mothers. At birth, litters were culled to six and cross fostered to untreated surrogate mothers. There was a significant effect of treatment on the body wt of pups at birth (p > 0.01). Pups in the 35% group were 4.13 g as compared to 6.27 g for the pair fed group. Pups were sacrificed at 30 days of age and brains dissected into 8 regions. Each brain region was homogenized and divided into soluble and membrane bound fractions by centrifugation and digestion with deoxycholic acid. Treatment of the mothers caused an incr in gamma-glutamyl transpeptidase activity associated with the membrane bound fraction in the brains of newborn pups only at the 20% and 35% ethanol levels. This incr was seen in all areas of brain examined (cerebellum, pons-medulla, hypothalamus, midbrain, striatum, hippocampus, cortex, and frontal cortex). In the midbrain and hypothalamus the activity was increased in a dose dependent manner. The incr in gamma-glutamyl transpeptidase activity in some areas of brain is maintained at least until the animals are 30 days old. Alcohol treatment had no effect on the activity associated with the soluble form of enzyme. [R169] *Long-Evans and Sprague-Dawley male rats were given liquid alcohol diets containing 35%, 17.5%, or 0% ethanol derived calories (EDC). The latter two groups were pair fed to the higher alcohol diet group. A fourth group received lab chow and water ad libitum to assess the role of paternal undernutrition associated with alcohol consumption. After 3 or 4 wk of diet consumption, these males were bred to females of the same strain. Pregnant females were divided into similarly treated alcohol groups and were fed these diets beginning on gestation day 8, thus creating a factorial study with strain, paternal, and maternal alcohol consumption as main factors. Paternal alcohol consumption was associated with decr litter size, decr testosterone levels, and a strain-related effect on offspring activity. Offspring activity decr for those sired by 35% and 17.5% ethanol derived calories Long Evans fathers. Activity also decr for offspring sired by 17.5% ethanol derived calories Sprague Dawley fathers but incr for those sired by 35% ethanol derived calories fathers. Paternal alcohol consumption did not affect postnatal mortality or passive avoidance learning of offspring. Maternal alcohol consumption was associated with lower birth wt, lower offspring wt at weaning, incr postnatal mortality, and poorer passive avoidance learning. However, offspring activity was not affected. In a separate study, levels of alcohol in the testes were found to be somewhat, but not significantly, lower than blood alcohol levels. DNA taken from sperm of Long Evans males consuming alcohol, migrated farther under pulsed field electrophoresis than DNA from control fathers, suggestive of an alcohol-related effect on sperm DNA. [R170] *To determine whether prenatal exposure to ethanol alters the response of the beta-endorphin system to stress, the effect of two types of stressful stimuli, ether and cold, was examined in the offspring of rats which during pregnancy were: fed with an ethanol containing diet (36% total calories of ethanol); pair-fed with an isocaloric sucrose diet; and fed ad libitum with standard lab chow (basic control group). The effect of stress on the content of beta-endorphin in the serum, pituitary gland and hypothalamus, as well as on the serum corticosterone and hypothalamic corticotropin-releasing factor (CRF) content was examined. Exposure to either stress on day 14 elicited no response by the beta-endorphin system of the ethanol exposed offspring. In contrast, the 22-day-old offspring of the ethanol treated rats exhibited greater elevations in serum beta-endorphin and corticosterone levels, following stress, than the offspring of the pair-fed and basic control groups. The elevations of serum beta-endorphin levels following stress were associated with small decr in the pituitary beta-endorphin and hypothalamic CRF contents. [R171] *Marine diatoms (Skeletonema costatum (Grev.) Cleve, 10,000 cells/ml) were exposed to a series of 5 or more concn of ethanol for 5 days (replicated 3 times). 11,619 mg/l ethanol caused a 50% reduction in the number of cells per ml, and 10,943 mg/l caused a 50% reduction in total cell volume. The no observed effect level (NOEL) was 5400 mg/l for total cell count and 3240 mg/l for total cell volume. [R172] *Hypothalami (from male Sprague- Dawley rats) maintained in short term culture was exposed to ethanol. After 90 min of preincubation, a 30-min incubation was conducted in low potassium medium without ethanol. Next, depolarizing high potassium Krebs Ringer's Phosphate buffer was used containing either no ethanol (n = 19) or ethanol at concn of 50 mg% (n = 6), 100 mg% (n = 14), 200 mg% (n = 8) or 400 mg% (n = 17). After 30 min the media was removed and analyzed for luteinizing hormone-releasing hormone. In separate expt, either no ethanol or one high dose of ethanol (400 mg%) was added to the initial, low potassium media. At the concn tested, ethanol failed to inhibit luteinizing hormone-releasing hormone release in vitro. [R173] *The acute (1 hr) effects of ip injections of 4 concn (10%, 30%, 45% and 60%) of a single dose (0.5 g/kg) of ethanol were investigated in groups of 10 unanesthetized male Wistar rats in an open circuit calorimeter. After baseline measurement in the test chamber and ip injection, rats were tested for an additional 60 min in the chamber. Every rat received ethanol and saline at 4-day intervals. Ethanol increased energy expenditure, with the greatest effect being produced by the two lowest concn. However even the 45 and 60% concn had an effect on energy expenditure when time after the injection was considered. In contrast, ethanol decr the respiratory quotient, with the greatest effect being produced by the two highest concn. The respiratory quotient of the control rats, after a small initial drop, quickly stabilized and remained very constant over time, whereas those of the ethanol treated rats declined progressively. Also, values for the 45% and 60% group were significantly lower than that following the 10% and 30% injections. Ethanol had only small and variable effects on motor activity. Treatment was significant only at the 60% concn. [R174] *Groups of 6 rats were fed alcohol (ethanol) for 6, 12 and 18 mo, while age matched controls were pair fed sucrose. Additional groups were alcohol fed for 6 and 12 mo and then withdrawn for 6 mo. The avg daily alcohol intake was 9 + or - 1.3 g/kg body wt, and no significant differences were found in the mean body wt of alcohol fed rats and controls. The numerical densities of the CA3 pyramidal cells and of the mossy fiber-CA3 synapses of the hippocampal formation were calculated applying the dissector method to adjacent sections of the CA3 pyramidal cell layer and the stratum lucidum respectively. Results showed a progressive loss of pyramidal cells in alcohol treated and withdrawal groups and a significant decr of mossy fiber-CA3 synapses after 18 mo of alcohol feeding. A significant reduction was found when the group alcohol fed for 12 mo and withdrawn for 6 mo was compared with the 18 mo control group. No differences were detected when the group alcohol fed for 6 mo and withdrawn for 6 mo was compared with age matched controls. The percentage of mossy fiber plasmalemma occupied by postsynaptic densities was significantly increased in the alcohol fed groups when compared with respective controls. These data show that mossy fiber-CA3 synapses display plastic and degenerative changes after chronic alcohol consumption and withdrawal. [R175] *Groups (n = 6) of male Sprague Dawley rats were given 10% ethanol (0.0, 1.0, 1.5, or 2.0 g/kg, ip, 15 min before testing) for 2 sessions of baseline and 18 sessions of acquisition in a radial maze. Each session consisted of 3 10-min trials of 8 rewards each. Emptied food wells were immediately rebaited so that an entry into any arm produced a reward of 2 food pellets. Ethanol produced a dose dependent reduction in the variability of arm choice, of angle of turn between arms, and of goal directed behavior. Correlations between these measures suggested they were not independent. [R176] *To define further the influence of ethanol on membranes, its effects on sodium ion (Na+) pump function were studied in monolayer cultures of fetal rat hepatocytes. The effects of ethanol (2 and 4 mg/ml) on total potassium ion (K+) influx, ouabain-sensitive K+ influx, Na+ pump density (from specific (3)H-ouabain binding), pump turnover rates and intracellular Na+ were measured following exposure of the cells to ethanol for 1-24 hr. In parallel studies, the effects of ethanol (2 mg/ml) on cell water content and membrane fluidity were measured. Ethanol had no immediate effect on K+ influx, but after 1 hr ethanol in concn of 2 and 4 mg/ml decr the total K+ influx (uM/100 billion cells/sec) from a control of 8.5 + or - 0.64 to 4.46 + or - 0.50 and 4.09 + or - 0.26 respectively (N = 6 for each experiment). This represented the max effect of ethanol since after 6 and 24 hr of ethanol treatment the K+ influx had incr towards control levels but remained significantly below that in control cells even at 24 hr. The decr in K+ influx reflected a decr in mean ouabain-sensitive K+ influx from a control of 5.87 to 3.24 and 2.70 (uM/100 billion cells/sec) after a 1-hr treatment with 2 and 4 mg ethanol/ml medium, respectively. Ethanol (2 mg/ml) treatment for 1 hr decr Na+ pump density (x 100,000 molecules ouabain per cell) from a control of 2.80 + or - 0.30 to 1.70 + or - 0.11 (p < 0.001). At 6 and 24 hr (3)H-ouabain binding showed a pattern similar to that seen with the K+ influx, tending to return to pretreatment levels. There was no change in individual pump turnover rates in the presence of ethanol. Following exposure to ethanol, cellular Na+ content steadily incr over the first 6 hr and then returned to control levels. When corrected for parallel changes in cell vol, intracellular Na+ concn incr by 17% (p < 0.01) after 1 hr and thereafter remained at this higher level throughout the 24 hr period. Measurements of membrane fluidity showed that it was incr markedly by ethanol at a concn of 2 mg/ml and that the effect bore a close temporal relationship to the changes in active K+ influx and Na+ pump density. [R177] *In a first expt, 11-day old pups received intragastric ethanol admin (1.5 g/kg). At different postabsorptive intervals, footshock was presented (0 to 30, 30 to 60, 60 to 90, or 90 to 120 min; n = 12 to 13 per group). An explicitly unpaired control group which experienced footshock prior to the state of intoxication was also employed. All animals were subsequently tested in terms of alcohol intake and ethanol locational odor preferences. Pups which suffered shock 1 to 30 or 30 to 60 min after ethanol intragastric admin exhibited lower ethanol intake scores than those recorded for the remaining groups. Mice which experienced shock 30 to 60 min after being inoculated with alcohol, also exhibited lower ethanol olfactory preference scores than those registered in the remaining groups. In a second expt, groups of 9 to 11 pups were exposed to footshock during the postabsorptive interval. 24 hr later, pups experienced ambient ethanol odor paired with soft (cotton) or rough (sandpaper) texture surfaces. Differential texture aversions were registered in exptl animals when compared with controls which suffered the state of intoxication explicitly unpaired with footshock, or unpaired presentations of ethanol odor and the tactile stimuli under consideration. Ethanol produced a decr in the value of a given texture when the 2 stimuli were paired. [R178] *Neonatal rats were exposed to 6.6 g/kg of alcohol (ethanol) each day between postnatal days 4 and 10 while artificial rearing procedures were used, in a manner which produced high peak and low trough blood alcohol concn each day. Gastrostomy controls were reared artificially with maltose/dextrin isocalorically substituted for alcohol in the milk formula, and suckle controls were reared normally by dams. The pups were sacrificed on day 10 and tissue sections (2 um thick were obtained in the sagittal plane through the cerebellum and in the horizontal plane through the hippocampal formation. Overall area measures were obtained for the hippocampus proper, area dentata, and cerebellum, along with areas of the cell layers of these regions. In the hippocampal formation, cell counts were made of the pyramidal cells of the hippocampus proper, the multiple cell types of the hilus, and the granule cells of the granular layer, granule cells of the external granular layer, and mitotic cells of the external granular layer were obtained from lobules I, V, VII, VIII, and IX. Alcohol selectively reduced areas and neuronal numbers in the cerebellum but had no significant effects on neuronal numbers in the hippocampal formation. Purkinje cells exhibited the greatest percent reductions, and cerebellar granule cells were significantly reduced in the granular layer but not in the external granular layer. All lobules showed these effects, but lobule I was significantly more affected than the other four lobules that were analyzed. [R179] *The specific activities of testicular postmeiotic enzyme markers such as sorbitol dehydrogenase (SDH), lactate dehydrogenase (LDH), and alpha-glycerophosphate dehydrogenase (GDH) that incr with age were used as a biochemical measure of testicular development in CFW mice treated with ethanol (3% vol/vol) via liquid diets from ages 20 to 55 days of life. Chronic ethanol treatment resulted in decr activities of sorbitol dehydrogenase and lactate dehydrogenase at ages 40 and 44 days, and of glycerophosphate dehydrogenase at ages 34, 40,and 44 days. These decr were consistent with an arrest in the developmental incr in sorbitol dehydrogenase, lactate dehydrogenase, and glycerophosphate dehydrogenase at ages 31 + or - 0.6, 31 + or - 2.6, and 25 + or - 0.5 days, respectively. After 29 days of ethanol treatment (age 50 days), testicular wt, epididymal sperm content, and sperm motility were reduced, relative to controls, by 37, 83, and 60%, respectively (p < 0.05). Light microscopic evaluation of testes revealed disorganization of spermatogenesis, germ cell degeneration, decr tubular luminal diameter, and vacuolation of Sertoli cells in ethanol-treated mice at age 50 days. Electron microscopic analysis showed that germ cell degeneration was not restricted to a specific cell type. Stage IX-XI tubules were observed in which spermatids had been retained and underwent phagocytosis within the Sertoli cell. Sertoli cells showed evidence of atypical nuclear invaginations. Sertoli cells underwent degenerative changes and were sloughed into the rete testis. [R180] *Twenty three 6-8 wk old male and female mice of various strains (Swiss, Balb/c, DBA/2, CBA, C57B1/6, and B6D2F1) received a topical application of a 95% solution of ethanol on both sides of the right ear on days 0 and 2, and a scapular sc injection of 0.05 ml of complete Freunds adjuvant on day 2. On day 9, left ear thickness was measured immediately before topical application of 95% ethanol (the maximal nonirritating concn), on both sides of the ear, and again 24 hr later (day 10). No statistically significant incr in ear thickness was seen. In another test procedure, anesthetized male (n= 9) and female (n= 10) Swiss mice received a sc injection of 0.05 ml of ethanol in complete Freunds adjuvant into the scapular region, together with a topical application of ethanol on the shaved abdomen. On days 3, 5, 7, 10, 12, and 14 they received a topical application on the shaved abdomen and a second scapular sc injection of 0.05 ml complete Freunds adjuvant on day 7. On day 26, left ear thickness was measured immediately before a topical application of ethanol on both sides of the ear. Left ear thickness was again measured on days 27 (24 hr after challenge) and 28 (48 hr later). No significant incr in ear thickness was seen. [R130] NTXV: *LD50 Rat oral 13.7 ml/kg; [R13, 619] *LD50 Rabbit oral 12.5 ml/kg; [R13, 619] ETXV: *LC50 PALAEMONETES > 250 MG/L/96 HR @ 21 DEG C, MATURE /STATIC BIOASSAY/; [R181] *LC50 SALMO GAIRDNERII (RAINBOW TROUT) 13000 MG/L/96 HR @ 12 DEG C (95% CONFIDENCE LIMIT 12000-16000 MG/L), WT 0.8 G /STATIC BIOASSAY/; [R181] *LC50 Pimephales promelas (fathead minnows) 15.3 g/l/96 hr (95% confidence limit 14.0-16.6 g/l); age 30 days old, water hardness 47.3 mg/l (CaCO3), temp 24.3 deg C, pH 7.60, dissolved oxygen 6.8 mg/l, alkalinity 43.7 mg/l (CaCO3); tank vol: 6.3 l; additions: 3.81 vol/day /Flow-through bioassay/; [R182, 1984.36] *EC50 Pimephales promelas (fathead minnows) 12.9 g/l/96 hr; age 30 days old, water hardness 47.3 mg/l (CaCO3), temp 24.3 deg C, pH 7.60, dissolved oxygen 6.8 mg/l, alkalinity 43.7 mg/l (CaCO3); tank vol: 6.3 l; additions: 3.81 vol/day /Flow-through bioassay/; [R182, 1984.36] *LC50 Pimephales promelas (fathead minnows) 14.2 g/l/96 hr (95% confidence limit 13.4-15.1 g/l); age 30 days old, water hardness 47.5 mg/l (CaCO3), temp 24.0 deg C, pH 7.56, dissolved oxygen 6.6 mg/l, alkalinity 40.9 mg/l (CaCO3); tank vol: 6.3 l; additions: 4.5 vol/day /Flow-through bioassay/; [R182, 1984.38] *Toxicity Threshold (Cell Multiplication Inhibition Test) Scenedesmus quadricauda (green algae) 5000 mg/l; [R13, 619] *Toxicity Threshold (Cell Multiplication Inhibition Test) Microcystis aeruginosa (algae) 1450 mg/l; [R13, 619] *Toxicity Threshold (Cell Multiplication Inhibition Test): Uronema parduczi Chatton-Lwoff (protozoa) 6120 mg/l; [R13, 619] *Toxicity Threshold (Cell Multiplication Inhibition Test) Entosiphon sulcatum (protozoa) 65 mg/l; [R13, 619] *Toxicity Threshold (Cell Multiplication Inhibition Test) Pseudomonas putida (bacteria) 6500 mg/l; [R13, 619] NTP: +Ethanol (EtOH) was evaluated as a known positive in the RACB protocol using CD-1 mice. A dose-range finding study provided data on water consumption, body weights, and clinical signs, which were used to select concns for the continuous cohabitation phase (Task 2) of 5, 10, and 15% w/v in distilled water. Water consumption was reduced at the middle and highest concns, by nearly equal to 9% and 25%, respectively. Interestingly, body weights remained unchanged during the course of Task 2. These concns, consumption, and body weight data produced calculated consumption estimates of nearly equal to 8.5, 16.0, and 20 g/kg/day. While the mean number of litters/pair was unchanged by EtOH consumption, the number of live pups/litter was reduced by nearly equal to 20% at the high dose. Viability, sex ratio, and pup body weight (absolute or adjusted for litter size) was unaffected by EtOH consumption. It was concluded that EtOH was causing no significant reproductive toxicity during Task 2, so a Task 3 crossover was not performed, and second generation effects (Task 4) were evaluated in the control and high dose groups only. The last litter from the control and 15% EtOH groups was nursed by the dam until weaning at /postnatal day/ 21, then provided with the same dosed water as their parents. While the viability of the F1 pups was unaffected by parental EtOH exposure, body weight was reduced by nearly equal to 25% at weaning. At the time of mating (nearly equal to /postnatal day/ 74), male and female body weights in the 15% EtOH group were 13% and 7% less than their respective controls. EtOH did not affect the proportion of F1 pairs mating or delivering live young, and the number and viability of those young were also unchanged. The weight of the F2 pups, adjusted for litter size, was reduced in the EtOH-exposed group by nearly equal to 7%. After the F2 pups were evaluated, all animals were killed, and the F1 parents were necropsied. For the EtOH-exposed group, male terminal body weight was 10% less than controls. Absolute testis weight was unchanged, while adjusted weights of liver and kidneys were increased in the EtOH-exposed mice by 11% and 12%, respectively. Epididymal sperm motility was reduced from a control value of 80% motile, to 55% in the EtOH-consuming group; there were no changes in epididymal sperm density or morphologic abnormalities. Female mice consuming 15% EtOH weighed 8% less than controls at sacrifice, while adjusted liver weight and kidney weight was increased by 13% and 11%, respectively. In summary, ethanol, at concns sufficient to affect water consumption more than body weight, had only modest reproductive effects (reduced sperm motility) in Swiss mice. These effects mirror those found in literature reports. [R183] ADE: *ALCOHOL IS RAPIDLY ABSORBED FROM STOMACH, SMALL INTESTINE, AND COLON. VAPORIZED ALCOHOL CAN BE ABSORBED THROUGH LUNG ... AND FROM SUBCUTANEOUS SITES ... ABSORPTION OF ALCOHOL THROUGH HUMAN SKIN IS NEGLIGIBLE. ... ALCOHOL IS FAIRLY UNIFORMLY DISTRIBUTED THROUGHOUT ALL TISSUES AND ALL FLUIDS OF THE BODY. PLASMA CONCN IS SOMEWHAT HIGHER THAN THAT IN ERYTHROCYTES. PLACENTA IS PERMEABLE TO ALCOHOL; THUS, ALCOHOL GAINS FREE ACCESS TO FETAL CIRCULATION ... AMT OF ALCOHOL IN BRAIN OF PERSONS DYING OF ALCOHOLIC INTOXICATION VARIES FROM 300 TO 600 MG/100 G /OF TISSUE/. ALCOHOL IS ALSO PRESENT IN CEREBROSPINAL FLUID, @ CONCN LOWER THAN THAT IN BLOOD WHEN THE BLOOD CONCN IS RISING AND HIGHER WHEN THE BLOOD CONCN IS FALLING. [R62, 378] *NORMALLY ABOUT 2% OF INGESTED ALCOHOL ESCAPES OXIDATION ... WHEN LARGE DOSES OF ALCOHOL HAVE BEEN CONSUMED THIS VALUE MAY BE AS HIGH AS 10%. ALTHOUGH SMALL AMT OF ALCOHOL CAN BE DETECTED IN VARIOUS SECRETIONS, MOST OF THE ALCOHOL THAT ESCAPES OXIDATION IS EXCRETED THROUGH THE KIDNEYS AND LUNGS. ... THE CONCN IN THE URINE IS SLIGHTLY GREATER THAN, AND THE CONCN IN THE ALVEOLAR AIR ONLY 0.05%, THAT OF THE BLOOD. [R62, 379] *The distribution of alcohol between alveolar air and blood depends on its speed of diffusion, and its vapor pressure at the prevailing temp and concn of alcohol in the lung capillaries. Empirical determinations have yielded rather different values for this distribution ratio, but a commonly accepted value is 1:2100. [R184] *Venous blood (orbital sinus) and brain ethanol levels were measured in long sleep and short sleep mice within the first 30 min following ethanol administration (2.5 to 6.0 g/kg). Ethanol was administered ip or intragastrically. For both lines of mice and for every dose, brain ethanol concentrations were significantly greater (as much as 100 mg/dl) than blood ethanol levels for the first 6 min, and peak blood and brain ethanol levels were reached 4 to 6 min after dosing. Approx 6 to 10 min (depending on dose and line of mouse) was required for blood and brain concn to reach equilibrium. At the time of loss of the righting response brain ethanol levels were significantly higher than blood ethanol levels. These results indicate that within the first 6 min after administration of ethanol, blood ethanol level is not suitable for the assessment of brain ethanol content. [R185] *The method of Pohorecky and Brick was modified for determination of ethanol concn in rebreathed air of rats. Female Sprague Dawley rats were injected with different doses (1 to 2 g/kg) of ethanol and both arterial blood and rebreathed air samples were collected at various time intervals (15 to 120 min) after administration. A good correlation (r= 0.96) was found between ethanol concn in arterial blood and in rebreathed air; the blood/breath conversion factor was 3241 + or - 55. Rats that were trained to discriminate between ip administered ethanol (1.2 g/kg) and the saline vehicle (12 mg/kg) were given different doses (0.5, 0.9 and 1.2 g/kg) of ethanol and were examined at various time intervals (1, 7.5, 15, 30, 60, 120 and 240 min) after administrations on certain test days. The results indicate a good correlation (r= 0.65) between the discriminative stimulus effects of ethanol and the concn measured in rebreathed air. The behavioral effects as well as the concn of ethanol in rebreathed air have a fast onset. The peak occurred 7.5 min after injection, and both the stimulus effects and concn of ethanol were time and dose dependent. [R186] *Delipidized stratum corneum was prepared from male human dorsal skin from skin banks. Previously weighed stratum corneum, delipidized stratum corneum, and hydrogels (prepared from polytetramethylene oxide and 2-hydroxyethylmethacrylate) were equilibrated with aqueous ethanol solutions of varying volume fractions of ethanol at 32 deg C for 24 hr. There is a broad maximum in the ethanol uptake into stratum corneum from 0.2 to 0.85 volume fraction of ethanol. The maximum ethanol uptake is roughly equivalent to the dry stratum corneum in wt. At an ethanol volume fraction of 1.0 there is a dramatic decr in ethanol uptake to 99 + or - 7 ug ethanol/mg stratum corneum. Dehydration and shrinkage of the stratum corneum largely reduces ethanol uptake in spite of the incr in ethanol driving force. Ethanol uptake into delipidized stratum corneum exhibits a sharp maximum at an ethanol volume fraction of 0.7. Using triolein as a simple lipid model, a linear cosolvency was observed with ethanol:triolein mixtures. There was no optimum for solubility in triolein. A model is proposed which qualitatively predicts the key features of ethanol enhanced skin permeation on the basis of these solubility phenomena and a constant diffusion coefficient. [R187] *The rate of ethanol elimination was studied in two groups of men by means of an Alcotest 7010(TM) breath analyzer. The exptl group consisted of 15 skid row alcoholics undergoing detoxification. Their median daily ethanol consumption was 211 (range 26 to 476) g pure ethanol during the last year. The control group was made up of 12 age matched healthy social drinkers consuming 9 (range 4 to 23) g/day pure ethanol during the last year. The median ethanol elimination rate in the elimination phase was 0.25 (range 0.13 to 0.31) g/l/hr during the detoxification period in the exptl group. This value was approximately 70% higher than in the control group (0.14 (0.12 to 0.17) g/l/hr. The alcoholic group had significantly higher values for gamma glutamyl transferase, alanine amino transferase, aspartate amino transferase, glutamate dehydrogenase, creatinine kinase, alkaline phosphatase, and HDL cholesterol, and lower urea, creatinine, and osmolality values in serum. Erythrocytes were lower and mean corpuscular volume was higher in the exptl group. Some correlation was found between reported ethanol intake, and the calculated ethanol elimination rate, as well as gamma glutamyl transferase, alanine amino transferase, aspartate amino transferase, glutamate dehydrogenase, mean corpuscular volume and HDL cholesterol. [R188] *Urine was analyzed immediately, 1, 2, 8, and 9 hr after drinking (during 2 hr) 3.75 ml/kg of beverages containing orange juice, 15 or 40% ethanol, and and 1 g/l of 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutyl alcohol or a mixture of 1-propanol and isobutyl alcohol. Maximum urine levels /in mg/l/ were found 1 hr after drinking ended: 1-propanol 5.04, 2-propanol 3.36, 1-butanol 0.43, 2-butanol 2.55, isobutyl alcohol ... 1.7-2.03 mg/l. Urine treatment with beta-glucuronidase before analysis indicated that significant amounts of the alcohols were excreted as glucuronides, esp isobutyl alcohol. 2-Propanol and 2-butanol were the slowest to be metabolized. When mixtures of alcohols were given, the concentrations of isobutyl alcohol glucuronides were high with the mixtures containing 5 and 15% ethanol, and decreased at 40% ethanol. [R189] *The small intestine extracts about 80% of an oral ethanol dose; the stomach absorbs the remainder. ... In healthy adults, 80%-90% of absorption occurs within 30-60 min, but food may delay complete absorption for 4-6 hr. [R102, 783] *Alcohol equilibrates rapidly between blood and milk; milk levels are about 90-95% of simultaneous blood levels. [R103, 177] *Ethanol is present as an endogenous substance in the blood of man, probably produced in the intestinal tract, at an avg level of 1.5 mg/l. Resting subjects developed blood concn of less than 100 mg/l when exposed to vapor concn of 7500-8500 ppm for 3 hr, while an exercising subject developed a blood level of 450 mg/l under the same conditions. A single oral dose of 0.5 ml/kg (35 ml/70 kg) of pure ethanol given to 4 fasting men produced an avg maximal blood concn of about 400 mg/l at 2 hr; a dose of 1.4 mg/l (98 ml/70 kg) produced a level of 1200 mg/l at 1 hr; and 2.0 ml/kg (140 ml/70 kg), a level of 2000 mg/l at 1 hr. The levels declined at a mean rate for the 21 subjects of 189 mg/l/hr. [R56, 140] *About 95% of a dose undergoes metabolism and the remainder is excreted unchanged in the breath, urine, sweat and feces. [R56, 140] *Pregnant Hartley guinea pigs were orally admin either 2 daily doses of 1 g ethanol/kg maternal body wt (n= 7) or isocaloric sucrose solution (n= 6) on days 1 through 59 of gestation (term= 66 days). The doses, given 2 hr apart, produced a maternal blood ethanol concn of 27.6 + or - 3.0 mM at 1 hr after the second ethanol dose, as assessed at 55 days of gestation. The activity of alcohol dehydrogenase, low K sub m aldehyde dehydrogenase, and high K sub m aldehyde dehydrogenase activities in the maternal liver, fetal liver, and placenta was determined spectrophotometrically at day 59 of gestation. None of these enzyme levels were statistically different for the 2 groups. This was also the case for the maternal blood and fetal blood ethanol and acetaldehyde concn, determined at 2 hr after maternal admin of 1 g ethanol/kg maternal body wt. There was no exptl evidence of ethanol induced malnutrition in the mother or growth retardation in the fetus. No statistical differences in the reproductive data, average daily food consumption, and maternal and fetal body and organ wt were found. There was a statistically significant incr (65%, p < 0.05) in the microsomal cytochrome p450 content of the maternal liver for the ethanol treatment compared with the sucrose treatment. [R190] *6 conscious and instrumented near-term pregnant ewes (135 to 140 days gestation) were given iv infusion of 3 g ethanol/kg total body wt admin as 6 doses of 0.5 g/kg over 8 hr. Maternal and fetal blood ethanol concn, determined in 2 animals, were maximal at 8 hr (3.74 and 3.82 mg/ml, respectively) and were virtually identical during the 24 hr study. Maternal and fetal blood gases (PO2, PCO2, or absolute base excess (ABE)) and acid-base balance (pH) were not significantly altered during and after ethanol admin compared with preinfusion values. There was also no change in fetal arterial blood HCO3 -1 or hemoglobin compared with control. Ethanol was not measurable in maternal and fetal blood 24 hr after the last ethanol dose. [R191] *Male human subjects (150, 19-30 yr of age) were given ethanol orally as vodka (0.55, 0.7, or 0.85 g/kg) followed by a second drink (0.3-0.4 g/kg) 3-4 hr later. After both doses, blood ethanol levels reached approx 100 mg/dl. Breath samples were taken every 20-30 min and rates of ethanol elimination were determined. In addition to the design described above, 100 subjects received 0.7 g/kg ethanol in 2 separate visits to the laboratory. In a third experimental design, ethanol was given iv to 12 subjects at an initial dose of 0.45 g/kg/30 min until breath ethanol levels reflected blood levels of approx 50 mg/dl. With the single-day experimental design, the frequency distribution of changes in rates of ethanol elimination between the first compared with the second administration of ethanol was not unimodal. Up to 20% of the subjects demonstrated rates more than 40% greater than basal values in response to ethanol. Based on these findings in humans, a Swift incr in Alcohol Metabolism (SIAM) was defined as an incr in the rate of ethanol elimination of at least 40% over the basal rate. Under these conditions, the frequency of Swift incr in Alcohol Metabolism was dose dependent (studied with 0.55, 0.7, and 0.85 g/kg); nearly 20% of the subjects demonstrated Swift incr in Alcohol Metabolism with a dose of ethanol of 0.85g/kg. In the 2-day experimental design, a Swift incr in Alcohol Metabolism response was also observed in about 10% of 49 well-fed subjects; however, none of 51 subjects tested exhibited a Swift incr in Alcohol Metabolism response following an overnight fast. In addition, a rapid and transient Swift incr in Alcohol Metabolism reflecting a 60% incr in the rate of ethanol elimination above basal values was observed when ethanol was given continuously for 5 hr iv. [R192] *Groups of 36 adult rats (18 males and 18 females) belonging to either UChA or UChB strains were exposed to either air (control group) or ethanol vapor (6 to 7 mg/l) during 46 hr in an inhalation chamber. Each group was further distributed into 4 subgroups according sex and strain (9 rats per each subgroup). Ethanol blood levels were measured during day 2 of exposure. 6 hr after exposure, rats from both groups received 60 mmoles/kg ethanol ip. Blood alcohol level data showed no significant difference by strain, but a marked difference according to sex. The mean blood alcohol level of females was 196 + or - 27 mg/dl and that of males was 114 + or - 22 mg/dl (p < 0.05). No significant difference in latency time (interval between injection and loss of righting reflex) was observed by treatment, sex or strain. The difference between /SRP: CNS depression/ time for control and exptl rats was significant for all groups, ie, 142 vs 42 min for female UChA (p < 0.001); 167 vs 51 for male UChA (p < 0.001); 91 vs 25 for female UChB (p < 0.005); 128 vs 55 for male UChB (p < 0.005). There was a significant difference of strain in the control group (p < 0.01) and of sex in the exptl group (p < 0.05). Data concerning blood alcohol at awakening after ip ethanol show a difference significant only at the 0.05 level, between exptl and control for males of the UChA strain. Data on the decr of rectal temp reveals no difference between treated and control rats, with the exception of the UChB males, which exhibited a slightly lower hypothermia, significant at the 0.05 level. [R193] *Groups of 12 selectively bred high alcohol drinking and low alcohol drinking adult male rats (S8 generation) were tested over a 4 wk period for the free choice consumption of 10% (v/v) ethanol in the presence of ad lib food and water. 12 rats from each line were also given food and water ad lib (controls). Rats of the high alcohol drinking line (n = 30) consumed 5.6 + or - 0.4 g ethanol/kg/day, and low alcohol drinking rats (n = 31) averaged 1.0 + or - 0.2 g/kg/day. Compared with the low alcohol drinking line, the contents of serotonin and/or 5-hydroxyindoleacetic acid were approx 10 to 20% lower in several brain regions of the high alcohol drinking line (cerebral cortex, striatum, nucleus accumbens, septal nuclei, hippocampus and hypothalamus). The levels of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid were also 10 to 20% lower in the nucleus accumbens and anterior striatum of the high alcohol drinking animals. [R194] *Rates of ethanol elimination (after iv admin of 0.6 g ethanol/kg) were determined in 4 hypogonadal pt at 1 wk and again at 8 wk after the admin of 1 dose of 200 mg of testosterone cypionate (Depo-testosterone). Ethanol elimination was unchanged in 2 pt, slightly decr in 1, and markedly increased in 1 pt at 8 wk as compared to 1 wk after testosterone admin. In the 3 pt with little or no change in ethanol elimination, initial high levels of plasma free testosterone, ranging from 445.0 to 3.8 ng/dl did not decr to abnormally low levels, but ranged between 1.6 and 7.7 ng/dl (normal = 1.20 to 2.10 ng/dl). In the fourth pt, an incr in ethanol elimination from 86.6 to 107.4 mg/kg body wt/hr was associated with a decr in plasma free testosterone from a high level of 4.7 to 0.8 ng/dl. Admin of testosterone had no effect on peak ethanol concn after ethanol infusion or on the apparent vol of distribution of ethanol. [R195] *The effects of 3 variations in meal composition (a solid and a liquid meal consumed together, a liquid meal consumed alone, and a liquid meal consumed 90 min after a solid meal) on the rates and patterns of solid and liquid gastric emptying were examined in 13 volunteers. By including alcohol (0.5 g/kg body wt) in the liquid meal, the relationship between alcohol absorption and gastric emptying was also assessed. The lag phase and the initial emptying phase of the solid meal were prolonged when the liquid meal was consumed with the solid meal, compared with when the liquid meal was consumed 90 min after the solid meal. In this latter situation, consumption of the liquid meal caused the cessation of emptying of solid food, and this second lag phase was followed by a slower than initial emptying phase. Gastric emptying of the liquid meal was slower when solid food was present and was slowest when liquid was consumed 90 min after the solid meal. Alcohol absorption was fastest when the liquid meal was consumed alone and slower when alcohol was consumed with or after the solid meal. For all three meals there was a close correlation ( r > or = 0.91) between alcohol absorption and liquid emptying. [R196] *A 30-mo old, 13-kg child reportedly ingested up to 16 oz of a wine containing 20% ethanol. The child was brought into the emergency department by paramedics, and upon arrival was found to be comatose and unresponsive to deep stimuli but breathing spontaneously. The pt remained unconscious and unresponsive for 3 hr after admission. The child was discovered at about 9 am by his mother. Blood ethanol and blood glucose levels were 98.78 and 22.14 mmol/l at 10:20 am; 84.45 and 24.31 at 1:40 pm; 52.10 and 23.88 at 6 pm, respectively. At 8:31 the next morning there was no detectable amount of ethanol in the blood. Recovery was complete without sequelae. Treatment consisted of prompt gastric decontamination and maintenance of adequate hydration and euglycemia. Elimination of ethanol was rapid and appeared to follow first order kinetics instead of the zero order kinetics usually observed. No significant metabolic or cardiorespiratory derangement occurred. [R197] *The distribution of maternally-derived glucose was determined in selected tissues of fetuses from ethanol-fed (EF) Sprague Dawley rats and from pair-fed (PF) and ad lib-fed (AF) controls. The ethanol-fed group was given unrestricted access to liquid diet, in which 30% of the calories were derived from ethanol. Maternal ethanol ingestion resulted in reduced fetal brain and liver wt and lower liver and lung glycogen levels compared to those of the pair-fed or ad lib-fed control groups. In addition, ethanol-fed fetuses exhibited reduced uptake of maternally-derived (3)H-2-deoxy-D-glucose (2DG) by placenta and fetal brain. Fetal body, liver, lung, and brain wt correlated with fetal plasma 3H activity and with the fetal:maternal plasma 3H ratio, an indicator of the rate of placental glucose transfer. Brain wt correlated with 2-deoxy-D-glucose content/g tissue wt. [R198] *Female Fischer 344 rats, aged 4, 14, and 25 mo, received 4.0 g/kg ethanol by ip injection. Blood alcohol concn after ethanol injection were 0.42, 0.50, and 0.52% at 2.5 hr, 0.40, 0.40, and 0.39% at 6 hr and < 0.0005 at 16 hr for 4, 14, and 25 month old rats, respectively. Hepatic glutathione levels were diminished 6 hr after ethanol injection and there were no age-dependent differences in the depleted levels (3.2 + or - 0.1, 3.5 + or - 0.2, and 3.0 + or - 0.5 ug glutathione/g liver). However, glutathione contents in livers of young-adult rats approached control levels after 16 hr, whereas they remained depressed in older rats. Serum levels of hepatic enzymes were significantly elevated 6 hr after ethanol admin. The incr were greater in middle-aged and old rats than in young-adult rats. [R199] METB: *NINETY TO 98% OF ALCOHOL THAT ENTERS THE BODY IS COMPLETELY OXIDIZED. ... AMT ... OXIDIZED PER UNIT OF TIME IS ROUGHLY PROPORTIONAL TO BODY WT AND PROBABLY TO LIVER WT. IN ADULT, AVG RATE AT WHICH ALCOHOL CAN BE METABOLIZED IS ABOUT 30 ML IN 3 HR. ... MAXIMAL DAILY METABOLISM OF ALCOHOL IS ABOUT 450 ML /IN MAN/. ... INITIAL OXIDATION OF ALCOHOL OCCURS CHIEFLY IN LIVER ... PRIMARY STEP IS OXIDATION ... TO ACETALDEHYDE BY ALCOHOL DEHYDROGENASE ... [R62, 378] *Male rats were given four consecutive hourly doses of ethanol at 1 g/kg to study the effects of ethanol on urinary excretion of folates. At 5 hours tritium labeled folic acid was administered and urine samples collected for 1 hour. At 6 hours rats were sacrificed with collection of plasma, liver, and kidney samples. A significant increase in the urinary excretion of endogenous folates occurred in ethanol treated rats at both the 4 to 5 hour and 5 to 6 hour periods, but no significant increase in tritium labeled derivatives was noted in ethanol treated rats. The predominant tritium labeled folic acid metabolites in urine were 5-formimimotetrahydrofolic acid and the formyl tetrahydrofolates whereas the major endogenous form was 5-methyltetrahydrofolic acid. Ethanol administration significantly increased the excretion of the methyl derivative, with minor effects on the other folate forms. The amount of endogenous folate present with each of the tissues (plasma, kidney, and liver) was not altered by ethanol treatment except for a significant increase in plasma folate in ethanol treated rats at 5 hours. The amount of tritium labeled folate derivatives within each of these tissues did not show any differences between ethanol and control treatments. In plasma, the major folate form was 5-methyltetrahydrofolic acid with a small amount of 5 and 10-formyltetrahydrofolic acid; the tritium labeled forms were predominantly 5-methyltetrahydrofolic acid and folic acid. In the kidney the predominant endogenous folate was 5-methyltetrahydrofolic acid (about 80% of total) with smaller amounts of the formyl and tetrahydrofolic acid derivatives; the major tritium labeled folate derivatives were 5-methyltetrahydrofolic acid and folic acid. In liver, endogenous folate levels were much higher than in kidney. Of the endogenousfolates in liver, 5-methyltetrahydrofolic acid represented the largest portion (about 50%) but tetrahydrofolic acid and the formyl derivatives also were present in large amounts; the major tritium labeled derivative was folic acid (60 to 80%). [R200] *METABOLISM OF ETHANOL, PROPANOL, ISOPROPANOL, BUTANOL, ISOBUTANOL, SEC-BUTANOL, AND TERT-BUTANOL WAS STUDIED AFTER ORAL ADMIN IN RABBITS. BLOOD PH WAS ON THE ACID SIDE WITH PROPANOL, BUTANOL, AND ISOBUTANOL, AND ON THE ALKALINE SIDE WITH ISOPROPANOL AND SEC-BUTANOL, BUT NO CHANGE WAS OBSERVED WITH ETHANOL AND TERT-BUTANOL. BUTANOL AND ISOBUTANOL HAD THE LOWEST RATE OF URINARY EXCRETION. ACETALDEHYDE AND ACETIC ACID WERE DETECTED AS THE URINARY METABOLITES OF ETHANOL AND PROAPNOL, WHEREAS ISOBUTYRALDEHYDE AND ISOVALERIC ACID WERE THE METABOLITES OF ISOBUTANOL. [R201] *The alcohol dehydrogenase pathway probably is the major pathway of ethanol oxidation in the body. Conversion of ethanol to acetaldehyde by alcohol dehydrogenase is the rate limiting step. Both alcohol and aldehyde dehydrogenase require NAD, which reduces the hepatic NAD/NADH ratio. The shift in this ratio changes the cytosol redox potential and causes profound metabolic abnormalities in chronic alcoholics. The final step is conversion of acetate to acetyl CoA and then carbon dioxide and water via the Krebs cycle. [R102, 784] *Results of research in alcoholism show great inter-individual, as well as racial, variability in metabolism of alcohol and acetaldehyde. The hypothesis is put forward that the individual and racial differences in alcohol metab are based on the genetically determined variability of the participating enzymes, alcohol dehydrogenase and aldehyde dehydrogenase. In Orientals lacking the mitochondrial low Km aldehyde dehydrogenase, acetaldehyde accumulates and produces symptoms of intoxication. [R202] *Blood concn of ethanol and acetaldehyde were determined in suckling Wistar rats after a single oral ethanol gavage. These results were compared with the hepatic activities of alcohol and aldehyde dehydrogenase. After intragastric administration of 3 g/kg body wt of ethanol, ethanol concn were much higher in suckling rats than in adult animals, especially at 90, 120, and 180 min after its administration. In addition, acetaldehyde concn were undetectable in suckling rats as opposed to adult rats, in whom micromolar concn were detected. Analysis of hepatic alcohol dehydrogenase activity revealed that it was very low at birth and it incr progressively with time attaining adult levels after 20 days of life. The alcohol dehydrogenase activity present in the liver of suckling rats presented similar Km values and sensitivity to pyrazole as adult rat liver. At birth, hepatic aldehyde dehydrogenase activity was low and it incr reaching adult levels during the suckling period. Adult levels for the component of low Km were attained earlier than for the component of high Km. The low affinity hepatic aldehyde dehydrogenase component in the newborn was different from that in the adult as assessed by kinetic studies and by its sensitivity to disulfiram. [R203] *Brain samples from rats genetically selected for high or low voluntary alcohol (ethanol) intake (AA and ANA strains) or for differences in alcohol induced motor incoordination (AT and ANT strains) were analyzed by histochemistry for aldehyde dehydrogenase (EC 1.2.1.3) activity in various CNS structures. All strains exhibited the highest aldehyde dehydrogenase activities in neurons of the mesencephalic tract of trigeminal nerve nucleus and in spinal cord motoneurons, while the lowest activities were observed in the somatosensory cortex. Although the general distribution pattern of aldehyde dehydrogenase activity was similar in the genetically selected strains, some potentially important differences were observed. AA rats with high voluntary alcohol consumption had lower aldehyde dehydrogenase activity (with acetaldehyde as substrate) in the neuropil of the olfactory tubercle but higher activity (with benzaldehyde as substrate) in the spinal cord motoneurons, Purkinje cells and capillary endothelium of the cerebellum as compared to the corresponding structures from the alcohol avoiding ANA rats. Alcohol resistant AT rats had higher aldehyde dehydrogenase activity, with benzaldehyde, in most CNS structures than did the alcohol sensitive ANT's, significantly so in the lamina II of the somatosensory cortex and the neurons of the lateral hypothalamic area. This relationship was also found with acetaldehyde as substrate in the neurons of the hypothalamic arcuate nuclei and in cerebellar capillaries, but the ANT's had the higher activity in the neurons of the cerebral cortex V lamina. [R204] *The activities of aldehyde dehydrogenase and alcohol dehydrogenase were measured in term placentas of 13 alcoholic women (avg ethanol consumption > 50 g/day) and 16 matched controls. With acetaldehyde 8 mM/l as substrate, the aldehyde dehydrogenase activity was 29.1 + or - 12.2 and 34.4 + or - 15.3 mU/g of wet wt (mean + or - SD) for alcoholics and controls, respectively. With 50 uM of acetaldehyde, aldehyde dehydrogenase activity was undetectable in both groups. No alcohol dehydrogenase activity could be detected in the placentas. The wt of placentas and newborns were significantly lower in the alcoholic group (placentas: 526 + or - 116 vs. 653 + or - 77 g, newborns 2,878 + or - 417 vs. 3,595 + or - 346 g). [R205] *Ethanol (2 g/kg) was administered via a liquid diet (36% ethanol) to fed Sprague-Dawley rats concomitantly with nutrients and to fasted rats without nutrients. When nutrients were intubated concomitantly with ethanol there was significant first-pass or presystemic ethanol metabolism by both the gastrointestinal mucosa and the liver. When ethanol was intubated without other nutrients first-pass metabolism was not detectable in fasted rats at this high ethanol dose. [R206] ACTN: *... ALCOHOL ... IS A PRIMARY AND CONTINUOUS DEPRESSANT OF THE CNS. THE APPARENT STIMULATION RESULTS FROM THE UNRESTRAINED ACTIVITY OF VARIOUS PARTS OF THE BRAIN THAT HAVE BEEN FREED FROM INHIBITION AS A RESULT OF THE DEPRESSION OF INHIBITORY CONTROL MECHANISMS. ALCOHOL DEPRESSES BOTH EXCITATORY AND INHIBITORY POSTSYNAPTIC POTENTIALS, IS MORE EFFECTIVE IN INHIBITING SYNAPTIC (PARTICULARLY POLYSYNAPTIC) FUNCTION THAN IMPULSE PROPAGATION, POTENTIATES PRESYNPTIC INHIBITION, AND HAS A VARIETY OF EFFECTS ON TRANSMITTER SYSTEMS. [R62, 372] *Acute alcoholic intoxication in man is probably not associated with any great change in hepatic function. Alcohol incr the rate at which isolated liver slices synthesize fat. It also causes mobilization of fat from peripheral tissue. Fat thus accumulates in the liver of normal individuals after the ingestion of relatively small amt of alcohol. Alcohol inhibits the secretion of protein from hepatic cells, and its prolonged use results in the accumulation of protein. The accumulation of fat and protein may be benign at first, and the associated hepatic disorders are reversible on abstinence. ... These processes can become irreversible and proceed eventually to the characteristic cirrhosis seen in many alcoholics. Malnutrition and vitamin deficiency may also contribute to the hepatic and gastrointestinal disorders in man, particularly if alcoholic liver disease is present. [R62, 375] *The ability of a number of metals and organic chemicals to induce metallothionein synthesis in primary cultures of rat hepatocytes was tested to determine whether metallothionein induction in vivo results from a direct effect of the agent on the liver or as a result of an indirect, physiological response to the agent. Hepatocytes were exposed to metals (zinc, cadmium, mercury, mangasese, lead, cobalt, nickel, and vanadium) or org cmpd. Ethanol, urethane, L-2-oxothiazolidine-4-carboxylate, or dexamethasonel were assayed for metallothionein by the cadmium/mercury radioassay. Cell viability was monitored by protein synthesis activity and cellular potassium ion concn. Increases in metallothionein concn were noted for zinc (22 fold), mercury (6.4 fold), cadmium (4.8 fold), cobalt (2.4 fold), nickel (22 fold), and dexamethasone (4.5 fold). However, even at max tolerated concn, manganese, lead, vanadium, ethanol, urethane, and L-2-oxothiazolidine-4-carboxylate did not increase metallothionein. Thus, zinc, cadmium, mercury, cobalt, nickel, and dexamethasone induce metallothionein in vitro and are direct inducers of metallothionein synthesis in hepatic tissue. In contrast, manganese, lead, ethanol, urethane, and L-2-oxothiazolidine-4- carboxylate, which did not increase the metallothionein content of hepatocytes, apparently do so in vivo by an indirect mechanism. [R207] *Implantation of permanent indwelling cannulas, aimed at the lateral cerebral ventricle, were made in male Charles River mice. The effect of intracerebroventricular dilazep (25, 50 and 75 ug), and its metabolites, 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine (15, 31 and 62 ug) and 1-(3-(3,4,5-trimethoxybenzoyloxy)propyl)perhydro-1,4-diazepine (62 and 125 ug) on 2 g/kg ethanol induced motor incoordination was studied. Mice were injected with ethanol 2 min after admin of the drug and evaluated for motor coordination at 15, 30, 45, and 60 min post-ethanol. Dose related potentiation of ethanol induced motor incoordination was noted with dilazep (p < 0.001) and its metabolites. The motor coordination was 1, 4, 11, and 27% of normal at 15, 30, 45 and 60 min post-ethanol respectively in 50 mg/kg dilazep group (p < 0.001). Whereas ip dilazep produced no apparent CNS effects, by the intracerebroventricular route it caused CNS excitation including tonic clonic seizures. Adenosine uptake inhibition, Ca2+ entry blockade or direct activation of adenosine receptors was ruled out as the possible mechanism of seizures because dipyridazole (50, 100 and 150 ug), verapamil (50, 75, and 100 ug) or N6-(2-phenylisopropyl)-adenosine admin intracerebroventricularly, while potentiating ip ethanol induced motor incoordination, did not produce seizures. The CNS excitation was minimal with 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine and none with 1-(3-(3,4,5-trimethoxybenzoyloxy)propyl)perhydro-1,4-diazepine. Theophylline pretreatment (50 mg/kg) partially blocked potentiation of ethanol induced motor incoordination by dilazep and 1,4-bis(3-hydroxypropyl)perhydro-1,4-diazepine but not by 1-(3-(3,4,5-trimethoxybenzoyloxy)propyl)perhydro-1,4-diazepine. [R208] *Guinea pig hippocampal pyramidal cells maintained in vitro were exposed to 50 or 100 mM ethanol. Ethanol consistently produced a suppression of neuronal firing, causing fewer spikes to be elicited upon stimulation by a 30 sec long depolarizing current pulse. No differences were found between cells impaled with either potassium chloride or potassium methyl sulfate-containing electrodes, between cells recorded at room or elevated temperatures (30 to 32 deg C), or between slices obtained from anesthetized or unanesthetized animals. The avg number of spikes (from neuronal firing) decr to 65% (n= 36) of the control value in ethanol (p < 0.0005). The ethanol effect was easily reversible, with spike frequencies recovering to control levels after washing out the drug. Also, the ethanol effect was blocked by treating the cell with cyclic 3',5'-adenosine monophosphate (200 mM) or cadmium ions (300 uM). 100 mM ethanol had no effect on the after-hyperpolarizing current. [R209] *Male Sprague Dawley rats were fed either a control liquid diet, or an isocaloric ethanol liquid diet of the Lieber type before being used in a study to elucidate the effects of ethanol on immunocompetent cells. There was a significant dose-related decr in lymphokine migration inhibitory factors (MIF) activity induced by phytohemagglutinin related to ethanol ingestion. In concanavalin A stimulated cells an apparent threshold effects was observed when ethanol was ingested at concn of 2 mg/kg/day or greater, with essentially all migration inhibitory factors activity abolished at these doses compared to 0 or 1 g/kg/day ethanol). The hypothesis of ethanol effects on sex steroid receptor or the receptor-hormone complex translocation to alter production of thymic stromal protein, hormone like substances was tested by evaluating thymic stromal estrogen receptors in rats pair-fed either the Lieber type ethanol or dextrose substituted control diet. Results (calculated from labelled steroid binding) indicate that the correlation coefficient, equilibrium association constant (KA) is unchanged between the two groups while estrogen receptors incr from 51 to 54 fm/ml. [R210] *Effects of ethanol on optokinetic, vestibular and caloric nystagmus were investigated in pigmented rabbits to determine whether or not it affects a specific site involved in the induction of various nystagmus. Optokinetic nystagmus was produced by rotation of the drum housing the rabbits with vertical stripes at an angular velocity of 0.85 deg/sec. Vestibular nystagmus was induced by horizontal rotation at an angular velocity of 30 deg/sec and caloric nystagmus by infusion of cold water into the external meatus. Cumulative injection of ethanol into the auricular vein to doses of 0.1, 0.2, 0.4, and 0.8 g/kg inhibited both vestibular and caloric nystagmus in a dose-dependent manner. [R211] *The effects of ethanol on serotonin (5-hydroxytryptamine) receptor binding in mouse brain were determined following 7 days of ethanol ingestion. Groups of 6 male C57BL/6NCR mice were fed either liquid diet or liquid diet in which ethanol (7% v/v) equicalorically replaced sucrose. Control diets were adjusted daily to match avg ethanol group amounts consumed. 5-HT(1A) receptor characteristics were measured utilizing the agonist (3)H-8-hydroxy-2-(di-n-propylamino)tetralin and 5HT2 receptor binding studies utilized the antagonist (3H)ketanserin. There was no change in either 5-HT(1A) or 5-HT2 receptor binding properties in any of the brain areas examined (cortex, hippocampus, striatum, diencephalon/midbrain, and pons/medulla). [R212] *To test the hypothesis that social ethanol consumption causes obesity by a hepatotoxic mechanism, the relationships between alcohol intake, cigarette smoking, serum gamma-glutamyl transpeptidase (GGT) and body build were investigated in 816 adult patients, 491 males and 325 females. A large part of the Broca index variance could be explained by hepatic damage as reflected by the gamma-glutamyl transpeptidase level. The higher the gamma-glutamyl transpeptidase, the more overweight were the subjects. Hyperinsulinemia may be the pathogenetic link; insulin is the strongest known blocker of lipolysis. Almost the total variation of obesity with gamma-glutamyl transpeptidase, occurred in the range of gamma-glutamyl transpeptidase up to 25 U/l, which is usually, but nevertheless erroneously, considered to be the normal range. This effect was independent of sex and age. Normal gamma-glutamyl transpeptidase is below 10 U/l, which is found on avg in females aged less than 20 yr. Females tolerate less alcohol than males. Although gamma-glutamyl transpeptidase is as high in females as in males around age 30, males drink about three times as much ethanol. For the same Gamma-glutamyl transpeptidase the Broca index is significantly higher in females than in males. Gamma-glutamyl transpeptidase generally incr with age; max gamma-glutamyl transpeptidase is reached in females in the age group 21-40 yr (due to the change in drinking habits around 1968), declining thereafter; in males at age 50. Obesity per se is not correlated with a high gamma-glutamyl transpeptidase. In the females there are hormonal factors influencing obesity. Although in the females gamma-glutamyl transpeptidase decr on avg after age 40, obesity incr (due to the decr in estrogens). After age 50 ethanol tolerance in males decr; they reduce their alcohol consumption, and yet the gamma-glutamyl transpeptidase remains high. Although people who smoke tend also to drink more alcohol, smokers are significantly leaner than nonsmokers. On avg males smoke about twice as heavily as females; this contributes to the fact that on avg males are leaner than females despite their higher alcohol consumption. Due to lower consumption the influence of ethanol and smoking on body build is smaller in females than in males. [R213] *A rat model of fetal alcohol syndrome was used by introducing pregnant Sprague-Dawley rats to a liquid diet containing 35% ethanol derived calories (Ethanol-fed, n = 6), while a second group was pair fed an isocaloric liquid diet without ethanol (Pair-fed, n = 6). A third group of pregnant dams received ad libitum lab chow (Control, n = 18). Daily maternal ethanol consumption averaged 12.7 g/kg body wt. No differences were observed in litter size among the groups, nor were gross dysmorphological features noted in any pups. At parturition, pups from the ethanol-fed and pair-fed groups were crossfostered by control mothers and all groups received lab chow. During adulthood (110 to 134 days old), male offspring were sacrificed and hippocampal and prefrontal cortical slices were prelabeled with (3)H-inositol. Phosphoinositide hydrolysis was determined by measuring the accumulation of (3)H-inositol phosphates in the presence of LiCl in response to activation of various excitatory amino acid receptors. In hippocampal slices, ibotenate- and quisqualate-induced phosphoinositide hydrolysis was reduced in ethanol-fed compared to pair-fed and control animals. Moreover the inhibitory effect of N-methyl-D-aspartate on carbachol-induced phosphoinositide hydrolysis, evident in pair-fed and control animals, was completely abolished in the hippocampus of ethanol-fed animals. In contrast, in the prefrontal cerebral cortex, the inhibitory effect of N-methyl-D-aspartate prevailed even in the ethanol-fed animals. [R214] *Electrophysiological studies were performed to determine whether or not ethanol potentiates the inhibitory effects of gamma-aminobutyric acid on medial vestibular nucleus neurons responding to horizontal sinusoidal rotation using alpha-chloralose anesthetized adult male cats. The medial vestibular nucleus neurons were classified into types I, II, III and IV neurons according to responses to horizontal rotation of the animal placed on the turntable in directions ipsilateral and contralateral to the recording site. Micro-osmotic application of ethanol up to 100 nA did not affect spontaneous firing or rotation induced incr in firing of type I neurons. However, inhibitory effects (25% inhibition at < 50 nA) of gamma-aminobutyric acid up to 50 nA on the rotation-induced incr in firing were potentiated during simultaneous application of ethanol up to 100 nA. The mean rotation-induced firing rate in the 15 neurons studied was significantly (p < 0.01) decr to 85.2% of the control value during simultaneous application of ethanol and gamma-aminobutyric acid, as compared with that by ethanol alone or gamma-aminobutyric acid alone. This potentiated inhibition was blocked by iontophoretic application of bicuculline (25 to 150 nA) and picrotoxin (45 to 150 nA). [R215] INTC: *CONCURRENT INGESTION OF CHLORAL HYDRATE AND ALCOHOL RESULTS IN GREATER CNS DEPRESSION ... CHLORAL BETAINE, TRICLOFOS, AND OTHER /RELATED/ PRODUCTS METABOLIZED TO YIELD TRICHLOROETHANOL WILL INTERACT WITH ALCOHOL. [R216, 20] *CONCURRENT INGESTION OF MEPROBAMATE AND ALCOHOL CAN LEAD TO ENHANCEMENT OF ... CNS DEPRESSANT EFFECTS. [R216, 145] *EFFECTS OF AMITRIPTYLINE AND RELATED TRICYCLIC ANTIDEPRESSANTS ON ALCOHOL ARE UNPREDICTABLE. [R216, 1] *... ALL BARBITURATES INTENSIFY DEPRESSANT EFFECTS OF ALCOHOL. [R216, 180] *CONCURRENT INGESTION OF ASPIRIN AND ALCOHOL MAY ENHANCE OCCULT BLOOD LOSS AND GASTRIC DAMAGE INDUCED BY ASPIRIN. ... MOST FORMS OF SALICYLATES MAY INTERACT WITH ALCOHOL ... . [R216, 16] *... PT TREATED WITH ORAL HYPOGLYCEMIC AGENTS MAY EXPERIENCE UNPLEASANT SYMPTOMS SIMILAR TO THOSE EXPERIENCED BY PT WHO TAKE DISULFIRAM AFTER INGESTION OF ALCOHOL. SIMILAR INTERACTIONS CAN OCCUR WITH METRONIDAZOLE OR CEPHALOSPORINS. ... THE HYPOGLYCEMIC EFFECT OF INSULIN MAY ALSO BE MARKEDLY INCR. ALCOHOL CAN INTERFERE WITH THE THERAPEUTIC ACTIONS OF A WIDE VARIETY OF DRUGS BY ALTERING THEIR METABOLISM. ... ACUTE INGESTION OF ETHANOL REDUCES THE CLEARANCE OF PHENYTOIN BECAUSE BOTH DRUGS COMPETE FOR THE SAME HEPATIC MICROSOMAL OXIDASE SYSTEM. [R62, 378] *ALCOHOL MAY ALSO INTERFERE WITH THERAPEUTIC ACTIONS OF ... COUMARIN TYPE OF ANTICOAGULANT ... . [R60, 382] *16 HEALTHY VOLUNTEERS TOOK PART IN A CROSSOVER STUDY EXAMINING THE EFFECT OF ETHYL ALCOHOL ON THE RATE OF SULFAMETHAZINE ACETYLATION. APPARENT HALF-LIFE OF DRUG DECR BY ABOUT 20% AFTER ETHANOL AND AMT OF DRUG ACETYLATED, MEASURED IN BLOOD AND URINE, INCREASED. [R217] *IN MICE AND RATS, METHAQUALONE DELAYED DISAPPEARANCE OF ETHANOL IN BLOOD AND BRAIN OVER A PERIOD OF 50 TO 200 MIN AFTER A LOADING DOSE OF 2.0 G/KG, IP OF ETHANOL. METHAQUALONE @ 140 AND 200 MG/KG INCR ETHANOL TOXICITY BY 11% AND 28%, RESPECTIVELY. CO-ADMIN OF ETHANOL USING 6.0, 7.0, AND 8.0 G/KG ALSO REDUCED THE LD50 OF METHAQUALONE BY 19, 24, AND 40%, RESPECTIVELY. CHRONIC ETHANOL ADMIN DECR METHAQUALONE TOXICITY. [R218] *COADMIN OF ALPHA-1-ACETYLMETHADOL @ 18 OR 36 MG/KG POTENTIATED ETHANOL TOXICITY; LD50 DUE TO ETHANOL WAS LOWERED BY 21 and 36%, RESPECTIVELY. ETHANOL (0.5 and 1 G/KG) DECR ALPHA-1-ACETYLMETHADOL TOXICITY; LD50 WAS INCR TO 76 AND 64 MG/KG, RESPECTIVELY, COMPARED WITH 56 MG/KG FOR ALPHA-1-ACETYLMETHADOL ALONE. AT 4 G/KG ETHANOL, LD50 WAS DECR TO 43.9 MG/KG, SHOWING POTENTIATION OF INTERACTION TOXICITY. [R219] *DIABETIC PT TREATED WITH PHENFORMIN SHOULD AVOID INGESTION OF ALCOHOLIC BEVERAGES BECAUSE CONCURRENT USE MAY CAUSE HYPOGLYCEMIC REACTIONS OR LEAD TO LIFE THREATENING LACTIC ACIDOSIS WITH SHOCK. [R216, 177] *In hamsters given ethanol in drinking water and also given the known pancreatic carcinogen N-nitrosobis(2-oxopropyl)amine (20 mg/kg, sc) no neoplastic lesions were observed at the end of the expt, whereas 11 of 14 hamsters given the carcinogen alone showed neoplastic lesions. Lipase activity was reduced in hamsters given the carcinogen but was normal in the ethanol + carcinogen treated animals. [R220] *A serious, relatively unrecognized occupational health problem involves the interaction of ethyl alcohol and chem agents used in industry. Workers who drink alcohol and are exposed to certain chem agents may experience adverse health effects such as nausea, dizziness, headache and liver damage. The synergistic interactions of ethanol with cmpd such as the thiurams, amides, oximes, halogenated hydrocarbons and metals were reviewed. [R221] *The influence of several neotropic drugs (piracetam, pyritinol, meclofenoxat, methylglucamine orotate (MGO) and dihydroergotoxine (DHET)) on both the ethanol preference and the enhanced seizure susceptibility after a single dose of ethanol was studied. Piracetam, MGO and DHET reduce the ethanol drinking in ethanol preferring mice. The enhanced seizure susceptibility after a single dose of ethanol was abolished by piracetam and MGO. [R222] *The ascending noradrenergic pathways from the locus coeruleus were lesioned bilaterally in 10 rats by intracerebral 6-hydroxydopamine injections. Ten rats were sham operated. All animals were subjected to a 4 day ethanol intoxication period using intragastric intubation. Intoxication and withdrawal assessments were performed blindly. The 6-hydroxydopamine lesions did not appear to affect tolerance to ethanol. During withdrawal, however, lesioned animals showed minor, but statistically significant changes in scores of certain non-convulsive withdrawal signs, but incidence and intensity of spontaneous and audiogenic convulsive seizures were not different between the groups. [R223] *A fatal case of multiple drug abuse in a 36 year old veterinarian involving injection of xylazine and ingestion of alcohol and clorazepate is presented. Quantitative analysis of xylazine was by gas liquid chromatography with a nitrogen detector. Xylazine concentrations (mg/l or mg/kg) were: blood, 0.2; brain, 0.4; kidney, 0.6; liver, 0.9; lung, 1.1; omentum adipose 0.05; and urine, 7.0. Blood ethanol and nordiazepam concentrations were 380 mg/dl and 2.5 mg/l, respectively. [R224] *A pharmacokinetic study was conducted to determine the effectiveness of lower doses of ethanol in the treatment of ethylene glycol (EG) poisoning. Four dogs were maintained at serum ethanol concentrations of 0, 35 and 140 mg/dl prior to EG (iv, 2 ml/kg) administration. The serum EG concentration-time data showed that the 35 mg/dl ethanol level provided as effective an inhibition of EG metabolism as did the 140 mg/dl level. The average urinary excretion rate of oxalic aid post EG administration was reduced to control levels by ethanol. The 35 mg/dl serum ethanol level reduced the total body clearance of EG from 93.9 to 50.0 ml/hr/kg and increased the effective half-life from 5.78 to 11.4 hr. Clinical testing was accomplished by giving the dogs 12 ml EG/kg body weight orally. One hour later, the dogs were either not treated or treated with a sodium bicarbonate-ethanol solution to obtain a serum ethanol concn of 50 mg/dl. The clinical test performed in the ethanol-treated dogs showed little change from normal limits. Urine calcium oxalate crystals were seldom found. The dogs given EG (12 ml/kg) but not treated with ethanol were in a coma at 13 hr and showed severe metabolic acidosis, dehydration, mild hepatocellular disease, and acute renal damage. Urine calcium oxalate crystals were found in high numbers. The rapid death associated with EG poisoning appeared to be due to metabolic acidosis in combination with dehydration. [R225] *Because alcoholism has adverse effects on Zn nutrition and many pregnant women consume less than the recommended dietary allowances of Zn, it was postulated that Zn deficiency acts as a co-teratogen with alcohol in the fetal alcohol syndrome. The effects of alcohol on progeny of pregnant mice fed a Zn deficient diet were compared to those fed a diet containing adequate Zn. Pregnant CBA mice (n= 66) were fed the Lieber-DeCarli liquid diet with 0, 15, or 20% ethanol derived calories containing 0.3 (low) or 8.5 (high) mug Zn/ml. Dams were sacrificed on day 18 of gestation. Resorptions, malformations, and individual fetal weights were recorded. Analysis of fetuses included assays for Zn, assessment of soft tissue malformations, and alizarin red staining for skeletal malformations. Fetal weights were lower in the groups fed the Zn-deficient diet for each concentration of alcohol (p < 0.005). The groups fed the combination of low Zn plus alcohol had 37-52% resorptions, while the animals on the Zn deficient diet without alcohol or the high Zn diet with alcohol diet had 0-2% resorptions. Skeletal malformations were related to alcohol concn but not Zn intake, while external malformations were higher in those maintained on the low Zn ethanol diet. These results suggest that Zn deficiency potentiated the teratogenic effects of alcohol and that nutritional intervention for alcoholic women during pregnancy might reduce the incidence or severity of fetal alcohol syndrome. [R226] *The interaction of ethanol with drugs and xenobiotics is complex because ethanol can affect any of the following steps; absorption, plasma protein binding, hepatic blood flow, distribution, hepatic uptake of drugs, and phase I and II hepatic metabolism. The ingestion of ethanol can lead to malabsorption of drugs. High concn of ethanol in conjunction with aspirin causes gastric mucosal damage. The principal effect of acute ethanol ingestion on drug metabolism is inhibition of microsomal drug metabolism. The synergistic effects of ethanol on central nervous system depressants can be explained by this mechanism. In contrast, chronic ethanol consumption increases mixed function oxidation and drug metabolism. The cross tolerance between ethanol and sedatives in chronic alcoholics may be due to this effect of alcohol. In addition, increased production of hepatotoxic products from certain drugs and xenobiotics and an increased activation of procarcinogens to carcinogens can result from this microsomal induction. The increased susceptibility to hepatotoxins and the enhanced carcinogenesis in the alcoholic may be explained by this fact. Other effects of the interaction between drugs and alcohol are the result of changes in organ susceptibility, best demonstrated for the central nervous system. Subsequently, the presence of liver disease has a great effect upon drug metabolism in alcoholics. [R227] *Pharmacokinetic interactions of ethanol with other drugs including its effects upon drug metabolite disposition, are reviewed in terms of clearance concepts. This approach is particularly useful in understanding the mechanisms of ethanol drug interactions (ie in separating the effects of ethanol upon drug clearance, volume of distribution and plasma protein binding.) The application of clearance concepts provides the basis for understanding the qualitative differences in ethanol interactions with low and high hepatic extraction ratio drugs. The effects of short and long term ethanol consumption upon different types of drug metabolism (oxidative, acetylation and glucuronidation) have been considered. Lomg term ethanol consumption may increase the clearance of a drug by induction of oxidative metabolism whereas short term consumption may decrease the clearance of such a drug. Clearance by N-acetylation appears to be increased in the presence of ethanol, while clearance by conjugation to glucuronic acid is decreased for some drugs by single dose consumption of ethanol. [R228] *Hepatocytes isolated from male Sprague-Dawley rats (Harlan, 200-275 g) were exposed to halogenated and non halogenated hydrocarbons. Leakage of cellular enzymes and inhibition of respiration were monitored as indicators of toxicity. Cell suspensions contained 2-3X10+6 cells/ml and were viable for 6 hr as indicated by a < 10% increment in the fractional release of aspartate aminotransferase (AST) activity. The hydrocarbons were added to the cell suspension as 20% solutions in ethanol. Only 3% of the AST activity was found in the medium at the beginning of the experiment, and there was no increase with time in cells treated with ethanol (n= 4). The relationship of the effects of cellular respiration to alteration in mitochondrial function was studied using dinitrophenol (DNP), an uncoupler of oxidative phosphorylation, and succinate, an NADH independent mitochondrial substrate. Ethanol caused a decrease in the DNP stimulated oxygen consumption (n= 5-8), but had essentially no effect on the succinate stimulated oxygen consumption. All parameters of mitochondrial function returned to control levels within one hr. [R229] *The effects of a combined high glucose diet and ethanol on chronic hexachlorobenzene (HCB) intoxication were examined using male Wistar rats. Treatments were: (1) glucose diet (63% glucose) (n= 10), (2) glucose diet plus 17.5 mmol HCB/kg food (n= 20), (3) glucose diet plus HCB plus 10% ethanol in the drinking water at an average of 0.104 mol ethanol/kg body weight daily (n= 20), (4) glucose diet plus ethanol (n= 10), (5) standard (control) diet (63% starch) (n= 30), and (6) standard diet plus HCB (n= 30). The treatment period lasted 60 days. HCB treatment produced clonic convulsions, tremors, and hyperexcitability with symptoms appearing earlier and more intensely in rats fed the standard diet. Ethanol itself affected only serum enzymes, increasing them significantly. The glucose diet and ethanol exerted contrasting effects so that the combination of glucose diet plus HCB plus ethanol produced similar results to those obtained with the standard diet plus HCB. [R230] *Drinking habits of rotogravure printers exposed to toluene were not found to influence performances on psychological examinations. Drinking habits were considered in grouping the workers. The test battery consisted of standardized tests for verbal and visual cognition and memory, perceptual motor speed, and psychomotor abilities. Within the rotogravure group, workers were divided into subgroups with (A) high toluene exposure (greater than 120 ppm) with heavy drinking, (B) high exposure with moderate drinking, (C) low exposure with heavy drinking, and (D) low exposure without heavy drinking. Mean test performances indicated that drinking habits did not explain the impairment of visual cognitive abilities. Heavy drinkers with high toluene exposure had intact performances. [R231] *The effects of a selective 5-hydroxytryptophan receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin on ethanol preference was studied in 34 male Wistar strain rats. The rats had access to a 6% (vol/vol) ethanol solution and water during baseline and treatment periods. Based on the baseline recordings, 2 groups of rats were formed: a high preference group (ethanol intake > 50% of total fluid intake) and a low preference group (ethanol intake < 30%). Both groups were treated sc with 0.125 mg/kg 8-hydroxy-2-(di-n-propylamino) tetralin twice daily for 3 days. The treatment caused a significant reduction of ethanol consumption in the high preference group, but no change in the low preference group. [R232] *Male and female long sleep and short sleep mice were pretreated with ethanol at varying doses (0 to 4 g/kg) 7.5 min prior to challenge with an ED80 dose of nicotine (long sleep: 4.25 mg/kg; short sleep: 6.25 mg/kg). Long sleep mice were more sensitive to the anticonvulsant effects of ethanol than were short sleep mice. To assess the effect of ethanol on the nicotine induced behavioral desensitization to nicotine observed previously in these mice, animals were pretreated with saline, nonanticonvulsant doses of ethanol (0.25 g/kg, 0.75 /kg or 1.5 g/kg), a subseizure producing dose of nicotine (2.0 mg/kg) or a combination of these two drugs 15 or 30 min prior to nicotine challenge. Ethanol enhanced the nicotine induced behavioral desensitization in both mouse lines; however, this effect was seen at lower ethanol doses and was more pronounced in long sleep mice. Ethanol pretreatment did not affect brain nicotine concn in either long sleep or short sleep mice. [R233] *The effect of acute (2.0 g/kg, intragastrically) and chronic (8.0 to 11.0 g/kg/day for 10 days, intragastrically) ethanol exposure on beta-endorphin in plasma, hypothalamus and pituitary, and on catecholamines in hypothalamus and plasma, and on corticosterone in plasma were examined in male Sprague Dawley rats. Plasma beta-endorphin, norepinephrine and corticosterone levels were significantly incr and dopamine was unchanged in acute and chronic ethanol treated rats. Compared to controls, plasma epinephrine levels were incr in acute ethanol treated rats but no significant change was observed in chronic ethanol treated rats. Plasma dopamine was significantly decr following chronic ethanol treatment while no significant change was observed after acute treatment. In the hypothalamus, beta-endorphin and dopamine contents were incr and norepinephrine levels were decr in response to ethanol exposure. Beta-endorphin levels were decr significantly in the anterior pituitary and the neurointermediate lobe of the pituitary in ethanol treated animals except in the neurointermediate lobe of the chronic ethanol treated animals. [R234] *Male albino Wistar rats trained to alternately shuttle between nose poke and lever operanda for rewarding stimulation to the medial forebrain bundle, were tested following intragastric intubations of ethanol (18%, 1.35 g/kg), the imidazobenzodiazepine, Ro 15-4513 (3 mg/kg in 18% ethanol), or vehicle. The duration of the alternation between operanda was significantly faster when the rats were intubated with ethanol. Ro 15-4513 treatment reversed ethanol enhanced effects on reinforced responses (p < 0.05). [R235] *One group (n= 21) of male Sprague-Dawley rats (310 to 360 g) were given gastric intubations of ethanol soln (10% w/v), while others (controls, n= 16) received isocaloric maltose-dextrin soln (17.5% w/v). Rats were given their soln every 8 hr for 24, 48, or 96 hr, alone or in combination with prazosin (1.0 mg/kg, every 8 hr, per os). The initial dose of ethanol was 5 g/kg, after which the criteria for subsequent doses were based on sign of intoxication displayed by individual animals just prior to the dose being given. Adrenal glands of rats receiving ethanol were larger (72.0 mg/pair after 48 hr) than those from control animal (57.4 mg); prazosin did not affect this (74.1 mg). In contrast, concurrent treatment with prazosin enhanced the loss of medullar catecholamines (by 60% at 24 hr) and noradrenaline (by 24% at 2 days) from hearts of rats given ethanol, while it had no such effects in controls. Excreted quantities of catecholamines were markedly increased in rats given ethanol and prazosin. Hearts of animals given the combined treatment of ethanol and prazosin showed cardiomegaly at 24 hr, when there was an incr of about 20 in proportional heart wt, an incr that persisted through the remaining 3 days of the study. At 48 hr, hearts of animals give prazosin and ethanol were heavier than those given ethanol alone. A significant correlation between catecholamine excretion and development of cardiac hypertrophy was identified. [R236] *Preincubation with 2 M ethanol inhibited L-alanine uptake, proton efflux and fermentation rates of exponential phase cultures of Auxotrophic strain Saccharomyces cerevisiae, KD115. Ethanol's inhibitory effect varied in yeast cells enriched with different fatty acyl residues. Ethanol's effect gradually decreased with incr unsaturation index. It was observed that cells enriched with polyunsaturated fatty acids acquired greater tolerance to ethanol as compared to monounsaturated fatty acids. By varying the degree of unsaturation of supplemented fatty acids a sequential insertion of double bonds in yeast membrane lipid was achieved. Incr concn of ethanol inhibited the efflux of H+ in palmitoleate and oleate enriched cells, but caused negligible effects of H+ efflux in linoleate and linolenate enriched cells. Percentage inhibition by ethanol of fermentative activity was reduced with incr unsaturation. As compared to palmitoleate, oleate and linoleate the inhibitory effect of ethanol on the fermentation rate of linolenate supplemented cells was the least. [R237] *Male rats (n= 40) were given a single ip injection of 30 mg azaserine/kg body wt at 19 days of age. The animals were fed a semipurified diet high in unsaturated fat (HF, 25% corn oil) either separately (n= 40) or in combination with ethanol (n= 40), which was provided in drinking water from day 25 onward at a concn of 10% (w/v). A separate group (control) was maintained on a diet low in unsaturated fat (LF, 5% corn oil). Rats were killed after 15 mo, and their pancreas, liver and kidneys were weighed. Dietary fat was found to enhance pancreatic carcinogenesis in rats. Ethanol slightly enhanced the multiplicity but not the incidence of malignant tumors (79 vs 86%). With ethanol, a nonsignificant incr in the number of atypical acinar cell nodules (AACN) with a diameter > mm was seen. In the high unsaturated fat + ethanol group the number of adenomas was lower than in the high unsaturated fat group (156 vs 176), which was accompanied by statistically nonsignificant, increase of malignant tumors (71 vs 57). [R238] *Male hamsters were injected sc with 20 mg N-nitrosobis(2-oxopropyl)amine (BOP)/kg body wt at 6 and 7 wk of age. The animals were fed a semi purified diet high in unsaturated fat (HF, 25% corn oil) either separately (n= 40) or in combination with ethanol (n= 40), which was provided in drinking water at a concn of 10% (w/v). Ethanol was introduced at 5% after the second carcinogen treatment, and gradually incr to 10% after 6 wk. A separate group (control) was maintained on a diet low in unsaturated fat (LF, 5% corn oil). Hamsters were killed 12 mo after the last BOP injection, and their pancreas, liver an kidneys were weighed. Dietary fat was found to enhance pancreatic carcinogenesis in hamsters. Ethanol did not influence the enhancing effect of high unsaturated fat on the development of ductular carcinomas in hamster pancreas. The number of tumor bearing hamsters was 25 for high unsaturated fat + ethanol and 29 for high unsaturated fat, while total adenocarcinomas were 35 and 37, respectively. [R238] *In urethane anesthetized albino Wistar rats, intracerebroventricular (ICV) microinjections of 1.61x10-6 and 7.82x10-4 mol of ethanol induced cardiac arrhythmias in 65.5% of the experiments. Cardiac disorders caused by ethanol (2.60x10-5 and 2.08x10-4 mol) were prevented by previous ICV admin of atropine (1.43x10-7 mol) and propranolol (3.86x10-7 mol). When toliprolol microinjections (3.38x 10-7 and 6.76x10-7) were associated with ethanol (1.04x10-4 and 4.69x10-4 mol) arrhythmias were evident in 4/6 expt, compared to toliprolol eliciting arrhythmia in 2/6 expt. IV injection of ethanol (1.46x10-5 and 6.26x10-3 mol/animal) induced cardiac arrhythmias in 85% (51 out of 60) of the expt. IV admin of atropine, toliprolol, propranolol, phentolamine, pheniramine, cimetidine, or aprotinin 20 min prior to ethanol failed to affect the arrhythmogenic properties of ethanol. Ethanol (3.26x10-4 mol/kg) had no effect on the cardiac arrhythmias induced by iv adrenaline (1.09x10-7 mol/kg. Ethanol also failed to antagonize the centrogenic arrhythmias elicited by ICV sodium L-glutamate. [R239] *6o o [Pampulha ME, Loureiro V; Biotechnol Lett 11 (4): 269-74 (1989)] Acetic acid inhibited fermentation in a respiratory deficient mutant of Saccharomyces cerevisiae (IGC 3507-111) in an exponential way. The undissociated form of the acid probably was the toxic agent. Ethanol potentiated this effect in a synergistic exponential way. Calculated values for inhibition constants of undissociated acetic acid (l/moles) in the presence of three concn of ethanol (0, 5, and 10 % vol/vol) at three pH values were: 34.0, 44.0, and 64.0, respectively at pH 3.5; 48.0 59.0, and 85.0, respectively at pH 4.5; and 65.0, 84.0, and 101.2, respectively at pH 5.5. *... Ethanol, isopropanol, n-butanol, sec-butanol, and tert-butanol ... exert a ... potentiating effect on the acute inhalation toxicity of carbon tetrachloride. ... Interaction between isopropanol and carbon tetrachloride was documented in an industrial accident ... where workers exposed to both agents exhibited hepatotoxicity. With ethanol the potentiation seems to be due to the presence of the unmetabolized alcohol; however, with isopropanol the effect seems to be caused by the presence of both unmetabolized alcohol and acetone. The results obtained with n-butanol resemble those of ethanol, whereas with 2-butanol they resemble those of isopropanol ... [R240, 303] *ADDING 1 G/L OF PROPAN-1-OL, PROPAN-2-OL, BUTAN-1-OL, BUTAN-2-OL, ISOBUTANOL TO 40% ETHANOL IN ORANGE JUICE LOWERED AND DELAYED BLOOD ETHANOL MAX IN TEN, 20-30 YR OLD MEN WHO DRANK 3.75 ML/KG OF SYNTHETIC BEVERAGE. [R241] INTC: *Adverse interactions with alcohol: interacting drug: acetaminophen; adverse effect: incr acute hepatotoxicity /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: anesthetics; adverse effect: decr effectiveness for induction of anesthesia /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: antihistamines; adverse effect: incr CNS depression with acute intoxication /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: benzodiazepines; adverse effect: incr CNS depression /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: bromocriptine (parlodel); adverse effect: nausea, abdominal pain /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: chloramphenicol (Chloromycetin); adverse effect: minor antabuselike symptoms /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: cycloserine (Seromycin); adverse effect: incr convulsions chronic abuse /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: disulfiram (Antabuse); adverse effect: abdominal cramps, flushing, vomiting, psychotic episodes, confusion /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: isoniazid (INH); adverse effect: incr incidence of hepatitis, decr isoniazid effect in some patients with chronic alcohol abuse /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: methisazone (Marboran); adverse effect: incr methisazone toxicity /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: metronidazole (Flagyl); adverse effect: mild antabuse like symptoms /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: narcotics; adverse effect: incr CNS depression with acute intoxication /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: phenothiazines; adverse effect: incr CNS depression /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: phenytoin (Dilantin); adverse effect: decr anticonvulsant effect with chronic alcohol abuse /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: propranolol (Inderal); adverse effect: masks tachycardia and tremor of alcoholic hypoglycemia /From table/ [R102, 785] *Adverse interactions with alcohol: interacting drug: quinacrine (Atabrine); adverse effect: minor antabuse like symptoms /From table/ [R102, 785] *Ethanol enhances the effects of coumarin anticoagulants ... insulin, monoamine oxidase inhibitors ... Disulfiram like intolerance to ethanol may occur from sulfonylureas, thiocarbamates, metronidazole, tolazoline, furazolidone, chloramphenicol, and quinacrine. [R242] *In a group of patients receiving aminosalicyclic acid for hyperlipidemia, the three pt who ingested ethanol developed a diminished hypolipidemic response. [R243, 200] *Chronic ethanol abuse can produce induction of hepatic microsomal enzymes resulting in enhanced antipyrine metabolism. ... It is proposed that the activity of alcohol dehydrogenase can be enhanced by incr ascorbic acid saturation. In healthy volunteers, the clearance of ethanol was slightly enhanced by ascorbic acid admin (1 g/day for 2 wk). [R243, 304] *It is proposed that prolonged intake of large amt of ethanol may enhace the metabolism of chloroform to hepatoxic metabolites. ... Cimetidine probably inhibits hepatic ethanol metabolism and/or incr the gastrointestinal absorption of ethanol. [R243, 307] *A case has been reported in which ethanol may have contributed to the psychotoxic reaction in an ethionamide treated patient. [R243, 212] *One would expect additive CNS depression with combined use of ethanol and glutethimide. Pharmacokinetic interaction has also been suggested. ... Acute intoxication with ethanol appears to inhibit meprobamate metabolism while chronic ethanol ingestion appears to induce hepatic microsomal enzymes resulting in enhanced meprobamate metabolism. ... Ethanol and metoclopramide may exhibit additive sedative effects. [R243, 309] *Ethanol produces vasodilation, which may enhance the orthostatic hypotension of guanethidine. [R243, 178] *It has been proposed that ethanol may enhance the possibility of methotrexate induced hepatotoxicity. [R243, 265] *Hypotension reportedly may occur following the combined use of ethanol and nitroglycerin. This is presumably due to the vasodilation which both agents may produce. [R243, 47] *Ingestion of alcohol reportedly enhances the degradation of "all penicillins" but no supporting clinical evidence is given. [R243, 225] *Ethanol appears to enhance the acetylation of procainamide in the liver. [R243, 15] *A disulfiram like reaction reportedly may occur following ethanol ingestion in pt receiving procarbazine. Additive CNS depression may also occur. [R243, 268] *Sulfonamides reportedly incr the adverse effects of ethanol and further impair driving ability. However, no supporting clinical data are given so that the clinical significance cannot be assessed. [R243, 236] *A small amt of admin tetrachloroethylene is absorbed from the gastrointestinal tract, resulting in CNS depression. This effect may be additive with that of alcohol. [R243, 312] *Chronic ingestion of large amt of ethanol may result in induction of hepatic microsomal enzymes. Since doxycycline is metabolized by the liver, its metabolism may be enhanced in alcoholic pt. [R243, 240] *Industrial exposure to trichloroethylene has been associated with ethanol intolerance ... [R243, 312] *CD 1 mice were treated ip on day 10 of gestation with 4, 6, or 7 g/kg ethanol. Ethanol rapidly crossed the placenta and appeared in the embryo 5 min after treatment. Acetaldehyde was detectable in maternal blood following all treatments and in maternal liver and embryos following treatment with 7 g/kg ethanol. Coadministration of 100 mg/kg 4-methylpyrazole, an alcohol dehydrogenase inhibitor, with 4 or 6 g/kg ethanol on day 10 of gestation significantly reduced the rate of ethanol elimination in all tissues examined. These data suggest that both ethanol and acetaldehyde are accessible to the embryo during a critical period of development. [R244] *IP ADMIN OF ETHANOL (0.7-1.8 MG/G/DAY FOR 7 DAYS) TO MICE DECR LEVEL OF HEPATIC MICROSOMAL CYTOCHROME P450, ARYLHYDROCARBON HYDROXYLASE, AND PROTEIN. ORAL ETHANOL (10% IN DRINKING WATER, 2-8 WK) DECR MICROSOMAL PROTEIN CONTENT, THEN INCR IT; P450 INCR, ARYLHYDROCARBON HYDROXYLASE DECR. IN MICE PRETREATED BOTH ORALLY AND IP WITH ETHANOL THE BINDING OF BENZO(A)PYRENE (B(A)P) TO DNA INCR. MORE TUMORS DEVELOPED IN PRETREATED MICE GIVEN B(A)P THAN IN CONTROLS GIVEN ONLY B(A)P. PRETREATED MICE HAD MUSCLE TUMORS, CONTROLS HAD MAMMARY TUMORS. [R245] *Ethanol, 25 to 50 mM added to cultured pineal glands in vitro, enhanced isoproterenol induced stimulation of cyclic AMP and melatonin production. Cells were obtained from rats decapitated during the light phase of a 14 hour light/10 hour dark cycle. The action of ethanol was observed only at doses of isoproterenol that produced a submaximal effect, and ethanol alone had no effect on cyclic AMP or melatonin release. The effects of ethanol on pineal cyclic AMP and melatonin release were reversible after a 15 min preincubation but not after a 2 hour preincubation. [R246] *THE METABOLISM IN VIVO OF ISOBUTANOL IN RATS LIVER, EVEN IN LOW CONCN, WAS MARKEDLY INHIBITED BY SIMULTANEOUS OXIDATION OF ETHANOL. [R247] *9 HR AFTER TERMINATION OF DRINKING 3.75 ML OF BEVERAGE CONTAINING 40% ETHANOL IN ORANGE JUICE @ 1.2 G ETHANOL/KG PLUS 1 G/L ISOBUTANOL, THE CONGENER ALC OR THEIR METABOLITES CAUSED INCR OF ERROR FIGURES AND SUBJECTIVE HANGOVER SYMPTOMS. [R248] *ETHANOL (LESS THAN 0.5 MMOLE), TERT-BUTANOL, AND N-PROPANOL INHIBITED N-NITROSODIMETHYLAMINE METABOLISM IN ISOLATED PERFUSED RAT LIVER. [R249] *The effects of prolonged infusions of ethanol on endothelium dependent vasorelaxation induced by acetylcholine and adenosine triphosphate (ATP) and on endothelium independent relaxation induced by papaverine were studied and compared in isolated perfused male Sprague Dawley rat mesenteric artery preparations. Infusion of ethanol over 60 min at concn of 1.6, 4.7, 6.3, and 7.9 mg/ml caused concn related inhibition of norepinephrine-induced vasoconstriction. In preparations infused with 6.3 and 7.9 mg/ml, this effect reached a maximum after 10-20 min but had vanished by the end of the infusion; 1 hr after the end of the infusion, the effects of norepinephrine were potentiated by 71% and 108%, respectively. Acetylcholine induced vasorelaxation (EC50 3.0 ng/ml in controls) was significantly reduced after 6.3 mg/ml ethanol infusion and totally abolished after 7.9 mg/ml ethanol infusion. ATP induced vasorelaxation (EC50 180 ng/ml in controls) was also abolished after 7.9 mg/ml of ethanol infusion. By contrast, the vasorelaxant effects of papaverine were not affected by 7.9 mg/ml ethanol infusion. Light-microscopic examination revealed that the endothelial cells were present in ethanol treated and in control mesenteric arterial beds. [R250] *Effects of silybin dihemisuccinate on the ethanol metabolizing systems of the rat liver were investigated using male Wistar rats. Fifteen min after intoxication with ethanol (2.0 g, 3.5 g or 5.0 g/kg; ip), the animals were treated with 20 mg, 30 mg or 50 mg/kg of silybin dihemisuccinate (iv via femoral vein), and blood ethanol concentrations were determined at hourly intervals after ethanol intoxication. Results showed that silybin dihemisuccinate increased blood ethanol only when intoxication was produced by doses of 3.5 g and 5.0 g/kg but not by 2 g/kg of ethanol. This effect is ascribed to an inhibition of the microsomal ethanol oxidizing system. Activities of alcohol dehydrogenase, catalase and NADPH-dependent cytochrome c reductase were not affected by silybin dihemisuccinate. [R251] *The relationship between lifetime alcohol (ethanol) consumption and respiratory symptoms in 195 subjects (including 111 alcoholics) and FEV1 pulmonary function level in 165 subjects (including 91 alcoholics) was examined. The mean ages for subjects from the Brockton VA Medical Center were 44.3 yr for pt (in an alcohol treatment program) and 41.0 yr for employees. Median duration of alcohol consumption was 21 yr, and the median alcohol consumption was 1527 kg-yr for the pt and was 72 kg-yr for employees. After adjustment for age and cigarette smoking status, using multiple logistic regression, lifetime alcohol consumption was a significant predictor of chronic cough and chronic phlegm, but not of any wheeze or persistent wheeze. Multiple linear regression analysis indicated that lifetime alcohol consumption was also a predictor of lower levels of FEV1 in a model that included age, pack-yr of cigarette smoking, and an interaction between alcohol consumption and pack-yr. For subjects with both heavy alcohol consumption and smoking, the level of pulmonary function was higher than expected compared to the effect of smoking alone. [R252] *The present study was undertaken to isolate and identify specific anatomical structures in the limbic-midbrain, limbic-forebrain which mediate changes in the ingestion of alcohol induced by tetrahydropapaveroline. In adult male Sprague Dawley rats, a 23 gauge guide tube was implanted stereotaxically either unilaterally or bilaterally in cerebral regions extending from coronal planes AP 1.0 to 10.0. Following recovery, each animal was tested by a standard screen for its self-selection of water versus an alcohol solution offered in 10 concn increased on each of 10 days from 3 to 30%. Tetrahydropapaveroline was dissolved in an artificial CSF vehicle containing Na2S2O5 or ascorbate and then microinjected in a volume of 1.5 to 2.0 ul at a depth 1.0 to 1.5 mm beneath the tip of the guide. After a set of 5 microinjections of tetrahydropapaveroline in a dose of 25, 50 or 250 ng was given over 3 days, the same lO day alcohol preference sequence was repeated. In nearly all rats, the microinjection series was repeated at either one or two depths 1.0 to 1.5 mm ventral to the first, after which the same alcohol test was repeated. The results showed that tetrahydropapaveroline induces or sustains significant incr in alcohol intake when the adduct was injected at 16 sites within caudal AP planes 1.0 to 5.0. Structures sensitive to tetrahydropapaveroline included the substantial nigra, reticular formation, medial lemniscus, zone incerta and medial forebrain bundle. When injected at 21 sites located more rostrally within AP planes 6.5 to 10.0, tetrahydropapaveroline also evoked significant increments in alcohol intake of a similar magnitude. The reactive loci included the N. accumbens, olfactory tubercle, lateral septum, preoptic area, stria terminalis, medial forebrain bundle and rostral hippocampus. In terms of the efficacy of the dose of tetrahydropapaveroline microinjected, 25, 50 and 250 ng induced alcohol self-selection in 81%, 5% and 14% of the sites, respectively. Repeated microinjections following identical procedures of two control solutions (0.9% saline or Na2S2O5) at 46 homologous sites within corresponding coronal planes from AP 1.5 to 10.0 produced no significant alterations in g/kg or proportional intakes of alcohol. For the rats, the mean intakes of maximally preferred concn of alcohol in g/kg were 3.83 after caudal injection of tetrahydropapaveroline (n= 15), 4.36 after rostral injection of tetrahydropapaveroline (n= 20), 0.53 after Na2S2O5 control (n= 18) , and 0.91 after saline control injection (n= 23). Composite anatomical maps of the tetrahydropapaveroline reactive sites revealed their integral overlap with dopaminergic pathways which originate in the ventral tegmentum and substantia nigra and project rostrally to structures within the limbic forebrain. [R253] *Sensitivity to bleomycin induced chromosome damage in 75 pt (53 men and 22 women) with previously untreated upper aerodigestive tract malignancies was compared with that in 62 healthy control subjects. Of the pt, 22 (29.3%) had carcinoma of the larynx, 20 (38.7%) had oral cavity lesions, and 23 (30.7%) had pharyngeal malignant tumors. Data on alcohol use were derived from a questionnaire. 45 pt and 13 controls were sensitive to bleomycin induced mutagenesis (age breaks/cell > 0.8). There were site specific differences in the elevated risks associated with ethanol consumption. The odds ratios for alcohol use were 6.7, 4.3, and 3.3 for the pharynx, larynx, and oral cavity, respectively. Analysis of alcohol use by consumption frequency showed incr risks with incr exposure. With the alcohol use (drinks/day) categories of 0, 1 to 2, 3 to 6, or > 6, the chromosome damage odds ratios were 1.0, 1.9, 5.0, and 44.5, respectively. [R254] *Groups of 10 male Swiss mice were admin either 2 g/kg ethanol or distilled water ip simultaneously with a contralateral ip injection of the selective alpha2-adrenoceptor antagonists atipamezole (1 or 3 mg/kg) or idazoxan (1 or 3 mg/kg), or distilled water. In expt 2, groups of 8 to 10 Swiss mice were admin ether 2 g/kg ethanol simultaneously with a contralateral ip injection of either 0.03, 0.1, 1.0 mg/kg atipamezole or distilled water. In expt 3, mice were admin either 2 g/kg ethanol or distilled water (ip) at the same time as a contralateral injection of Ro 15-4513 (3 or 10 mg/kg). Ethanol significantly reduced (p < 0.001) core temperature, while both a2-adrenoceptor antagonists were without effect when admin alone. However, both the 1 and 3 mg/kg doses of atipamezole significantly (p < 0.05) attenuated the ethanol induced reduction in body temperature 20 and 40 min after admin. The 3 mg/kg dose of idazoxan (but not the 1 mg/kg dose) also significantly (p < 0.05) attenuated ethanol's hypothermic effect 20 min after admin but this effect was not statistically significant at 40 min. In expt 2, using lower doses of atipamezole, attenuation of ethanol-induced hypothermia caused by atipamezole was found to be dose related. The benzodiazepine inverse agonist Ro 15-4513 possessed an intrinsic hypothermic action (p < 0.001) but neither attenuated nor enhanced the hypothermic effect of ethanol. [R255] *The effects of 6 wk of heavy ethanol (liquid diet of 36% ethanol) and moderate ethanol (liquid diet of 3.6% ethanol) feeding to male Wistar rats upon lipids and lipoprotein metabolism were determined. As compared to the control group (rats fed isocaloric amounts of dextrimaltose in place of ethanol), the heavy ethanol feeding resulted in the following changes: liver wt/kg body wt incr by 48% with a concomitant 52% incr in liver protein/kg body wt and a 2.75-fold incr in liver total lipids/kg body wt. In contrast, liver DNA/kg body wt or per liver was not affected significantly. Plasma cholesterol and triglycerides were higher by 53% and 77%, respectively. Liver cholesterol and triglycerides were 4.4-fold and 3.8-fold higher, respectively. Plasma total A1 was 1.72-fold higher 0.001), whereas there was no significant difference in plasma apo E levels between the two groups. However, plasma high density lipoproteins (HDL) apo E was 48% lower while the very low density lipoproteins (VLDL) E was 2.15-fold higher. Hepatic total protein synthetic rate in the ethanol group was not significantly different from the control group. In contrast, labeled leucine incorporation into the total secretory proteins was inhibited by 36% in the ethanol fed group. Specifically, inhibitions of the synthetic rates of various secretory proteins in the ethanol group compared to the control group were as follows: by 55% for total VLDL apoproteins, by 44% for apo A1 protein, by 55% for total apo E proteins, by 62% for VLDL apo E, by 52% for HDL apo E and by 50% for transferrin. In contrast, moderate ethanol feeding for six wk did not alter any of the above parameters. [R256] *The modifying effect of ethanol on aflatoxin B1 (AFB1)-induced hepatocarcinogenesis was examined in male ACI/N rats by chronic treatment at the post initiation phase. Rats received an ip injection of AFB1 (1.5 mg/kg) twice a wk for 10 wk (a total of 20 doses). Following a wk of acclimation, they were given 10% ethanol as drinking water for 56 wk. The effects of ethanol on hepatocarcinogenesis were evaluated in terms of the incidence of altered hepatocellular foci and neoplasms at the end of the experiment. Exposure to AFB1 alone induced a substantial number of altered foci (6.98 iron excluding foci/sq m) in rats. The number of altered liver cell foci in rats receiving AFB1 followed by ethanol was significantly incr (26.39 iron excluding foci/sq cm). In the rats given ethanol after AFB1, the total area and mean diameter of both iron excluding foci and altered foci identified in hematoxylin and eosin-stained sections were significantly higher than in the rats exposed to AFB1 alone. The incidence of liver cell tumors of the group given AFB1 and ethanol (3/15, 20%) was higher than that of the group treated with AFB1 alone (0/14, 0%). Treatment with ethanol alone for 56 wk did not induce either. [R257] *The effect of nicotine and nicotine/ethanol were examined using a 4-hr perfused human placental system and human placental vesicles. Placental systems and vesicles from nonsmokers were exposed to 'physiological' (0.2 uM) and large (about 20 uM) nicotine concn alone, as well as nicotine combined with 200 or 400 mg/ml ethanol, for 5 min, 24 hr, and 48 hr. Two nonmetabolizable amino acids, alpha-aminoisobutyric acid and cycloleucine were used as probes. The maternal compartment half-life of nicotine was 2.12 hr without ethanol and 2.65 hr with addition of ethanol. There was no statistically significant evidence of decr transport of these amino acids with exposure in either test system. There was no evidence of altered transport of antipyrine, nonspecific leakage of water or difference in lactate output, or glucose consumption with exposure of the perfused placenta to either nicotine or nicotine/ethanol. [R258] *Groups of 6 to 12 male CD-1 mice were given an ip injection of the anticonvulsive drug carbamazepine (10, 15, or 20 mg/kg) or propylene glycol (vehicle) 10 min before ip admin of 1.0, 1.5, 2.0, 2.5, or 4.0 g/kg ethanol in saline. Whereas mice that received 1.5 g/kg ethanol regained their normal motor coordination within 45 min of ethanol admin, only 85 and 75% of normal motor coordination was recorded in mice injected with 2 and 2.5 g/kg ethanol respectively, at 60 min post-ethanol. Carbamazepine significantly potentiated the motor incoordinating effect of 2 g/kg ethanol in a dose-dependent fashion. Motor coordination was only 35 and 20% of normal at 15 and 20 mg/kg carbamazepine, even at 60 min post-ethanol. Although carbamazepine did not alter the onset time, it significantly prolonged the duration of ethanol induced loss-of-righting reflex. 15 mg/kg carbamazepine significantly prolonged the duration of loss-of-righting reflex produced by 4 g/kg ethanol (hypnotic dose), compared to the saline + ethanol group, 102 vs 38.0 min, respectively. Pretreatment with theophylline (25 and 50 mg/kg) significantly attenuated the carbamazepine induced potentiation of both effects. 50 mg/kg theophylline markedly attenuated the potentiation on ethanol induced motor incoordination by carbamazepine (15 and 20 mg/kg) at all post-ethanol time periods. Results from a blood ethanol study indicated no effect of carbamazepine on the clearance of ethanol. [R259] *In Sprague-Dawley rats having relatively little experience in the open field, the actions of ethanol (0.75 g/kg ip), Ro15-4513, an imidazobenzodiazepine partial inverse antagonist, (1.25 mg/kg and 2.5 mg/kg, ip), and Ro15-4513 in combination with ethanol were measured on horizontal activity. Rats receiving ethanol showed a significant depression in horizontal activity. Doses of Ro15-4513 given alone (n = 14) produced no significant differences in activity from baseline levels. Rats (n = 8) pretreated with Ro15-4513 prior to receiving ethanol, however, showed a significant attenuation of the ethanol induced depression of activity. [R260] *The interactions of cocaine with ethanol in nontolerant and ethanol-hypnosis tolerant male Sprague-Dawley rats were examined. Cocaine pellets (12.5 mg) implanted sc in rats potentiated the hypnosis induced by ethanol (3.2 g/kg ip) and the implantation of the same type of pellets (12.5, 25 mg) in ethanol tolerant rats restored the ethanol hypnosis to levels observed in acutely treated animals. [R261] *Serotonin-stimulated activation of phospholipase C in primary astroglial cell cultures made from newborn Sprague-Dawley rats was studied as a mean of evaluating the effect of acute ethanol exposure on this signal transduction system. The addition of 50-150 mM ethanol prior to stimulation with 10-5 M serotonin led to a potentiation of the serotonin-induced (3H)-inositol phosphate formation and an incr incorporation of (3H)-inositol into the three phosphoinositides studied. The potentiating effect of ethanol was observed only when ethanol was added together with serotonin. Ethanol had no effect on arginine-vasopressin, bradykinin or phenylephrine-stimulated inositol lipid metabolism. [R262] *The effects of cadmium (100 ppm through drinking water) and ethanol (5 g/kg by gastric gavage) administration on biogenic amines, metal distribution and certain enzymes in male Wistar rat brain was investigated after 90 days of exposure. Co-exposure group revealed significant accumulation of cadmium and also incr in zinc levels compared to all the other groups. Ethanol alone decr monoamine oxidase activity and incr norepinephrine and 5-hydroxytryptamine levels, while in combination with Cd, these effects were more magnified. [R263] *Male CD-1 mice were given a series of tones paired with footshock in the closed arm of a Y maze. On a test session 8 days later the animals were tested for retention of the conditioned emotional response (CER). On the 2-min test session, the three arms of the maze were open and the number of entries into the arms was counted. Retention of the conditioned emotional response was measured by the decr in the number of entries in comparison with mice trained with no footshock. Starting 24 hr after training, and continuing for the 7 days between training and testing, the animals in different groups received a daily ip injection of saline, 3.6 g/kg of ethanol, 150 ug/kg of the cholinergic muscarinic agonist oxotremorine, or ethanol plus oxotremorine. Retention was evaluated 24 hr after the last injection. Ethanol reduced retention of the conditioned emotional response. This effect was attenuated by oxotremorine (150 ug/kg) given ip 6 min prior to testing, but not by the same dose of oxotremorine given daily together with the ethanol treatment. Oxotremorine injections administered prior to the retention test also enhanced the retention performance of the control group. Daily oxotremorine administration had no effect. [R264] INTC: *The effects of methyl n-butyl ketone (2.5, 3.75, and 5.0 mmol/kg ip), methyl isobutyl ketone (2.5 and 5 mmol/kg ip), methyl ethyl ketone (5, 10, and 15 mmol/kg ip) and acetone (10, 20, and 40 mmol/kg ip) on the duration of ethanol-induced loss of righting reflex and on ethanol elimination in male CD-1 mice were studied. The solvents were dissolved in corn oil and injected ip 30 min before ethanol 4 g/kg ip. The 4 solvents prolonged significantly the duration of ethanol induced loss of righting reflex when given in the following doses (mmol/kg): methyl n-butyl ketone, 3.75 and 5 (mean time = 11.5 min); methyl isobutyl ketone, 5: methyl ethyl ketone, 5 and 10, acetone, 20 and 40. This prolongation was dose related and increased as the dose of the solvent was increased. A dose of 40 mmol/kg acetone resulted in ataxia in all mice treated with this dose. The concn of ethanol in blood or brain (approx 2.5 to 3.5 mg/ml or mg/g, respectively) on return of the righting reflex were similar in solvent treated and control animals, with the exception of the group of mice treated with 40 mmol/kg acetone in which the ethanol concn were significantly lower than in control animals. The mean elimination rate of ethanol was markedly reduced (from 692 mg/hr/kg for controls) in mice treated with methyl n-butyl ketone 5 mmol/kg (523 mg/hr/kg), methyl ethyl ketone 15 mmol/kg (575 mg/hr/kg), and acetone 40 mmol/kg (386 mg/hr/kg). All 4 solvents reduced the activity of mouse liver alcohol dehydrogenase in vitro. The admin of 2,5 hexanedione (0.75 mmol/kg ip) did not alter the duration of ethanol induced loss of righting reflex, nor did it affect the concn of ethanol in the blood or brain on return of the righting reflex. Admin of 2-hexanol (2.5 mmol/kg ip) significantly prolonged the duration of ethanol induced loss of righting reflex but did not affect ethanol concn in the blood or brain on return of the righting reflex. [R265] *To determine whether or not the previously reported association between alcohol (ethanol) intake and high blood pressure is influenced by differential intake of calcium and potassium in drinkers compared with nondrinkers and to assess the magnitude of the independent contributions of alcohol, calcium, and potassium to blood pressure, these associations were evaluated in 7,011 men of Japanese descent. Alcohol consumption above a threshold of approx 20 ml/day was found to be positively, strongly, and independently correlated with systolic and diastolic pressures, and this effect was completely independent of the effects of calcium and potassium. Calcium and potassium intake were highly correlated and were inversely related to blood pressure, and their combined effect was greater than the effect of either alone. However, in the subgroup of moderate and heavier drinkers, only potassium was inversely related to blood pressure. This finding is compatible with previous reports of malabsorption and incr excretion of calcium at higher levels of alcohol intake, and it indicates that a small portion of the alcohol-induced blood pressure elevation may be mediated through calcium depletion. In the range of dietary intake in this cohort, the effect of alcohol on blood pressure was stronger than was either the separate or combined effects of calcium and potassium. [R266] *Groups of 8 male albino rats were given water ad lib and assigned to one of the following treatments, 6 days/wk for 4 mo: (Group 1) no treatment (control); (Groups 2 to 4) 1, 2, and 5 g/kg ethanol, once by gastric gavage; (Group 5) lead as lead acetate, 0.55 g/l in drinking water; (Groups 6 to 8) 1, 2, and 5 g/kg ethanol, once by gastric gavage plus lead as 0.55 g/l lead acetate in drinking water. Ethanol or lead when given alone inhibited the activity of blood gamma-aminolevulinic acid dehydratase (p < 0.05 compared to control for all levels after 2 mo treatment). Ethanol caused a dose-dependent incr in hepatic lipid peroxidation, which was more marked after 4 mo co-exposure to lead and ethanol. The co-administration of 5 but not 1 or 2 g/kg ethanol significantly enhanced the lead-induced inhibition of blood gamma-aminolevulinic acid dehydratase activity and the elevation of gamma-aminolevulinic acid excretion (p < 0.05). Exposure to lead and ethanol (5 g/kg) produced a more pronounced incr in hepatic lipid peroxidation and blood glucose level than either ethanol or lead alone. Co-exposure to ethanol did not affect the lead-induced incr in blood zinc protoporphyrin except at 5 g/kg after 4 mo exposure, when the level was significantly higher than in the lead group (p < 0.05). This combination also caused a significant incr in the dopamine contents of striatum, midbrain and pons medulla, norepinephrine contents in midbrain and 5-hydroxytryptamine contents of hypothalamus, striatum, midbrain and pons medulla over levels produced by lead alone. However, the level of norepinephrine in hypothalamus decr upon co-administration. The uptake and retention of lead was significantly (p < 0.05) higher in blood, liver, kidney and brain in animals co-exposed to lead and 5 g/kg ethanol. Blood and kidney lead was also increased by 2 g/kg ethanol (p < 0.05). [R267] *The effects of ethanol on releasable Ca stores were examined in microsomes isolated from ICR mouse whole brains. Ca release was monitored by detn of changes in the extra-microsomal Ca concn using Indo-1, a fluorescent Ca indicator. In the absence of ATP, ethanol released Ca from microsomes in a concn dependent manner, with a threshold for Ca release between 25 and 50 mM. A 50 mM concn of ethanol released about 0.5 nmol of Ca per mg of microsomal protein. The highest concn of ethanol (400 mM) released approx 5 nmol Ca/mg microsomal protein. Release was maximal within 10 sec. Ethanol induced release of microsomal Ca was reduced by approx 50% after ATP stimulated uptake of Ca, indicating that the ethanol releasable pool was diminished by ATP dependent uptake of Ca into an ethanol insensitive microsomal pool. Release of Ca produced by ethanol was linear with concn (25 to 400 mM). Ca release induced by ethanol was not altered by incr the temp from 15 to 25 C. However, incr the temp from 25 to 32 C and from 32 to 36 C produced a large incr in the ability of ethanol to release Ca. Simultaneous addition of ethanol and inositol 1,4,5-triphosphate produced additive responses. [R268] *Intranasal cocaine and oral ethanol (ETOH) were admin to nine male subjects (21-45 yr) during daily exptl sessions. In 3 hr sessions (5 days), a 14 min period of resting baseline was followed by the exptl session which consisted of 10 min of task performance, admin of ETOH (0, 19.4, 38.7, or 58.1 g), 35 min of ETOH baseline, admin of cocaine HCl (4, 48, 96 mg), 20 min of ETOH and intranasal cocaine baseline, 10 min of task performance, 40 min of resting, 10 min of task performance, and 6 min of resting. Intranasal cocaine increased resting heart rate and blood pressure, and oral ETOH increased resting heart rate and decreased resting blood pressure. [R269] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Local; Central Nervous System Depressants; Solvents [R270] *ALCOHOL IS FREQUENTLY EMPLOYED FOR MEDICINAL MIXTURES AS VEHICLE. ALCOHOL IS SOLVENT FOR THE TOXICODENDROL CAUSING IVY POISONING; EARLY AND THOROUGH WASHING OF THE AFFECTED PARTS WITH ALCOHOL MAY ABORT OR LESSEN SEVERITY OF DERMATITIS. IN PHENOL SKIN BURNS ALCOHOL SHOULD BE USED IMMEDIATELY AS A WASH IF CASTER OIL IS NOT AVAILABLE ... ALCOHOL COOLS THE SKIN WHEN IT IS ALLOWED TO EVAPORATE, AND ALCOHOL SPONGES ARE THEREFORE USED TO TREAT FEVER. IT IS ALSO RUBEFACIENT AND IS INCL IN LINIMENTS. ALCOHOL (50 TO 70% BY VOL) IS EMPLOYED AS A RUBBING AGENT ON THE SKIN OF BEDRIDDEN PT IN ORDER TO PREVENT DECUBITUS ULCERS. IT IS ALSO USED TO DECR SWEATING, AND IS AN INGREDIENT OF MANY ANHIDROTIC AND ASTRINGENT LOTIONS. ETHYL ALCOHOL STILL REMAINS THE MOST POPULAR SKIN DISINFECTANT. ... ALCOHOLIC BEVERAGES ... MAY BE GIVEN BEFORE MEALS AS STOMACHIC TO IMPROVE APPETITE AND DIGESTION, ESP IN CONVALESCENT AND DEBILITATED OR ELDERLY PT. ... ALCOHOL ACTS AS HYPNOTIC AND ANTIPYRETIC ... ALCOHOLIC BEVERAGES HAVE BEEN USED TO CHECK IMPENDING "HEAD COLDS". ... MAKES PT DROWSY AND SLEEPY ... . [R62, 380] *... IT HAS BEEN OCCASIONALLY ADMIN IV FOR PREOPERATIVE AND POSTOPERATIVE SEDATION IN PT IN WHOM OTHER MEASURES ARE INEFFECTIVE OR CONTRAINDICATED. DOSE EMPLOYED IS 1 TO 1.5 ML/KG. IV USE ... IS SPECIALIZED PROCEDURE AND SHOULD BE EMPLOYED ONLY BY ONE EXPERIENCED IN ... SUCH USE. [R34] *ETHANOL IN FORM OF 7% SOLN IS USED AS GASTRIC FUNCTION TEST. ... 50 ML OF 7% ETHANOL IS SWALLOWED WITH TUBE REMAINING IN PLACE. SEVERAL 10-15 ML SAMPLES OF GASTRIC CONTENTS WITHDRAWN ... AND SECRETORY CURVE IS PLOTTED. [R271] *ETHANOL IS AN IMPORTANT ADDN TO ... LOCAL ANTIINFECTIVE DRUGS BECAUSE OF ITS ABILITY TO SOLUBILIZE FAT AND EXERT SYNERGISTIC OR ADDITIVE EFFECT WHEN USED IN COMBINATION WITH OTHER ANTISEPTICS OR DISINFECTANTS. [R272] *ALCOHOL INJECTIONS /OF ETHANOL/ INTO ORBIT HAVE BEEN USED FOR MANY YEARS FOR LONG LASTING RELIEF OF SEVERE OCULAR OR NEURALGIC PAIN. MOSTLY RETROBULAR INJECTIONS HAVE BEEN USED AS AN ALTERNATIVE TO ENUCLEATION OF BLIND PAINFUL EYES, BUT WITH PROPER TECHNIQUE THEY CAN BE USED WITHOUT EXCESSIVE DANGER WITH SEEING EYES. [R61, 54] *DEHYDRATED ETHANOL MAY BE INJECTED IN CLOSE PROXIMITY OF NERVES OR SYMPATHETIC GANGLIA FOR RELIEF OF LONG LASTING PAIN THAT OCCURS IN TRIGEMINAL NEURALGIA, INOPERABLE CARCINOMA, AND OTHER CONDITIONS. EPIDURAL, SUBARACHNOID, AND LUMBAR PARAVERTEBRAL INJECTIONS OF ALCOHOL HAVE ALSO BEEN EMPLOYED ... . [R62, 381] +MEDICATION (VET): ANTISEPTIC, RUBEFACIENT, STOMACHIC, SEDATIVE, ANESTHETIC, NUTRIENT, VASODILATOR, SURFACTANT. ... IS ANTIDOTE OF CHOICE IN ETHYLENE GLYCOL (ANTIFREEZE) POISONING ... 70% SOLN ... TOPICAL ANTISEPTIC STRENGTH. 5% SOLN FOR IV USE. [R273] +MEDICATION (VET): ETHANOL HAS BEEN INJECTED FOR ALLEVIATION OF PAIN IN LAME HORSES, AND OCCASIONALLY IT HAS BEEN INJECTED EPIDURALLY IN CATTLE TO HELP CORRECT CHRONIC VAGINAL AND/OR RECTAL PROLAPSE. [R272] *THE COMMON BIOCHEMICAL PATHWAY OF OXIDATION OF BOTH METHANOL AND ETHANOL ... ACCOUNTS FOR THE CLINICAL OBSERVATIONS THAT SIMULTANEOUS ADMIN OF ETHANOL MAY AMELIORATE THE TOXIC SEQUELAE OF METHANOL POISONING. [R62, 381] *INTRAVENOUS ETHANOL, ONCE WIDELY USED TO INHIBIT PREMATURE LABOR, HAS BEEN REPLACED BY BETA-ADRENERGIC THERAPY. THE PROPOSED MECHANISM OF ALCOHOL INDUCED UTERINE RELAXATION INVOLVES THE INDIRECT INHIBITION OF THE /UTERINE/ MYOMETRIUM BY PREVENTING OXYTOCIN'S RELEASE FROM THE POSTERIOR PITUITARY GLAND. [R274] +MEDICATION (VET): TO DESTROY NERVE TISSUE [R2, 35] *The subarachnoid injection of alcohol in 322 pt with intractable pain from malignant disease gave long lasting marked relief in 187 and partial relief in 84. [R7, 38] *The equivalent of 50 ml of alcohol reduced intraocular pressure in glaucomatous pt by up to 30 mm Hg. ... This effect had been used prior to surgery in 2 pt unable to tolerate other agents. [R7, 38] WARN: *BRIEFLY APPLIED TO THE SKIN, 70% ALCOHOL DOES NO DAMAGE, BUT IT IS IRRITATING IF LEFT ON FOR LONG PERIODS OF TIME. AS THE RESULT OF REMOVAL OF CUTANEOUS LIPIDS, FREQUENT USE CAUSES DRY SKIN AND SCALINESS. IRRITATION IS SOMETIMES CAUSED BY DENATURANTS IN ETHANOL. APPLIED TO WOUNDS OR RAW SURFACES, ETHANOL NOT ONLY INCR INJURY BUT ALSO FORMS A COAGULUM UNDER WHICH BACTERIA MAY SUBSEQUENTLY THRIVE. IT IS THUS NOT USED TO DISINFECT OPEN WOUNDS. [R62, 962] *Ethanol potentiates the central nervous system effects of numerous sedative and depressant drugs. ... It should not be used by patients taking certain prescription drugs ... . [R34] +Maternal Medication usually Compatible with Breast-Feeding: alcohol (ethanol): Reported Sign or Symptom in Infant or Effect on Lactation: With large amounts drowsiness, diaphoresis, deep sleep, weakness, decrease in linear growth, abnormal weight gain; maternal ingestion of 1 g/kg daily decreases milk ejection reflex. /from Table 6/ [R275] TOLR: *CROSS TOLERANCE BETWEEN ALCOHOL AND OTHER DRUGS MAY BE DUE TO PHARMACODYNAMIC TOLERANCE IN THE CNS OR TO MORE RAPID METABOLISM, SINCE THE USE OF ALCOHOL INCR HEPATIC MICROSOMAL ENZYME ACTIVITY. [R62, 549] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethanol will enter the environment as emissions from its manufacture, use as a solvent and chemical intermediate, and release in fermentation and alcoholic beverage preparation. It naturally occurs as a plant volatile, microbial degradation product of animal wastes, and in natural fermentation of carbohydrates. When spilled on land it is apt to volatilize, biodegrade, and leach into the ground water, but no data on the rates of these processes could be found. Its fate in ground water is unknown. When released into water it will volatilize and probably biodegrade. It would not be expected to adsorb to sediment or bioconcentrate in fish. Although no data on its biodegradation in natural waters could be found, laboratory tests suggest that it may readily biodegrade and its detection in water systems may be due in part to its extensive use in industry with possible relatively steady and large levels of discharges. When released to the atmosphere it will photodegrade in hours (polluted urban atmosphere) to an estimated range of 4 to 6 days in less polluted areas. Rainout should be significant. Human exposure will be primarily in occupational atmospheres and consumption of products containing ethanol. Exposure will also occur from other contaminated atmospheres especially in proximity to industries and cities, and ingestion of contaminated drinking water, as well as proximity to sources of natural release(SRC). NATS: *Emissions from animal wastes, plants, insects, forest fires, microbes, and volcanoes(1). Emissions from natural fermentation of carbohydrates(2). [R276] ARTS: *Emissions from petroleum manufacture and storage, plastics, printing, refuse combustion, tobacco smoke, wood pulping, and whiskey manufacture(1). Leachate from landfills(2). Emissions and wastewater from its manufacture and use as a solvent and chemical intermediate(SRC,3). [R277] *In gasoline exhaust: 0.1 to 0.6 ppm; in workrooms: concn up to 5000 ppm have been reported; from whiskey fermentation vats: avg 182.2 g/cu m grain input [R13, 617] FATE: *TERRESTRIAL FATE: When spilled on soil, ethanol will both evaporate and leach into the ground due to the relatively high vapor pressure and low adsorption in soil. It will biodegrade in soil, probably to acetic acid and formaldehyde(1). If degradation is not rapid, it will leach into groundwater(SRC). [R278] *AQUATIC FATE: When released into water, ethanol will volatilize (estimated half life is 6 days) and biodegrade. It will not sorb to sediment or bioconcentrate in aquatic organisms. Although it readily biodegrades in laboratory tests, no data on its rate of degradation in natural waters could be found(SRC). *ATMOSPHERIC FATE: When released into the atmosphere, ethanol will photodegrade with a half-life ranging from hours in polluted urban atmospheres to approximately 6 days in cleaner atmospheres (based on a hydroxyl radical concn of 8X10+6 moles/cu cm). Due to its solubility in water, rainout may be an important process(SRC). BIOD: *Ethanol is biodegraded in aerobic systems using activated sludge, sewage (including filtered and settled), wastewater and soil inoculums(1-6). 5 day theoretical BOD values range from 37% - 86%(1,4). Biodegradation of 3, 7, and 10 mg/l with filtered sewage seed in fresh water resulted in 74% theoretical BOD in 5 days and 84% in 20 days; in salt water 45% theoretical BOD in 5 days and 75% in 20 days were observed(4). Formaldehyde and acetic acid are products of biodegradation by a soil inoculum(6). Anaerobic degradation (thermophilic digestion, 54 deg C) of ethanol (5 ml of a 5% aqueous ethanol solution) produced approx 1000 ml gas/g sample using seed which had been prepared in a synthetic medium(7). [R279] ABIO: *The estimated half-life of ethanol in the atmosphere ranges from 5.9 days(1) to 4 days (based on a hydroxyl radical concentration of 0.8X10+6 molec/cu cm(2,9)). The half-life for ethanol in hydrogen peroxide/nitrite/carbon monoxide mixtures (total pressure 100 torr; typical sunlit atmosphere) is 10 hrs at 19 degrees C(3). Photochemical smog chamber tests with 500 ppm ethanol and 500 ppm nitrite, sulfide, and/or water resulted in varying amounts of degradation: 50% degradation in 0.7 hr (nitrite/sulfide/water), 50% in 2.8hr (nitrite) and 25% in 6.3hr (sulfide)(5). A smog chamber test with 2 ppm ethanol and 1 ppm nitrogen resulted in 20% degradation in 5 hr(4). Ethanol is considered to have low reactivity (class 2 in a 5 class system (5 high)) in photochemical smog situations having ozone forming potential slightly higher than that of toluene(6). Reaction with hydroxyl radicals in aquatic media will not likely be a significant process(7,8). Alcohols are known to be resistant to hydrolysis(9). [R280] BIOC: *No information on the bioconcentration factor for ethanol could be found in the literature. However, its low octanol/water partition coefficient (log P -0.31; recommended value(1)) indicates that it will not bioconcentrate in fish(SRC). [R281] KOC: *No information on the adsorption of ethanol could be found in the literature. Its low octanol/water partition coefficient (log P -0.31; recommended value(1)) indicates that its adsorption to soil will be low(SRC). [R281] VWS: *The estimated half life for evaporation of ethanol from water 1m deep with a 1m/sec current and 3m/sec wind is 6.1 days and the gas exchange rate plays a more dominant role than the liquid exchange rate(1,SRC) based on the non dimensional Henry constant(0.257x10(-3) (2)). Ethanol is relatively volatile (vapor pressure 50 torr(3)) and would, therefore, readily evaporate from soil at the soil/air interface and solid surfaces(SRC). [R282] WATC: *DRINKING WATER: Detected (not quantified) in 5 city public supplies(1); detected (not quantified) in city public supplies(2-4). Philadelphia (1975-1976), identified, not quantified, in 1 of 3 water treatment plants and in drinking water of 1 of 1 hotel(5). [R283] *GROUNDWATER: Ethanol was found in groundwater suspected of leachate contamination (based on levels of inorganics) 190 ppb (1/13 sites pos), and detected at 58 ppb in landfill groundwater where inorganic levels indicated good or unknown water quality(2). Not detected in Miami, FL(1). [R284] *SURFACE WATER: Detected (not quantified) in 4 raw water sources - uncontaminated and contaminated with agricultural runoff, municipal or industrial wastes(1); Hayashida River (Jpn) highly polluted by leather industry, 4020 ppb(2). Detected at 58 ppb in landfill groundwater where inorganic levels indicated good or unknown water quality(3). [R285] *RAIN/SNOW: Santa Rita, AZ (rural), concn in precipitation, 15 ppb (by mass), ratio of concn in precipitation/condensate 0.31(1). [R286] EFFL: *Ethanol was detected in leachate from Minnesota landfills in the range of 23,000 ppb to 110,000 ppb (2/6 sites pos)(1). Traces found in 1 of 11 domestic wells near Granby, CT landfill, 1984(2). Concn in exhaust from simple hydrocarbon fuels (e.g. benzene, isooctane) < 0.1-0.6 ppm(3). [R287] ATMC: *RURAL/REMOTE: Pt. Barrow, AK, 1967, 24 hr avg is 0.77 ppb (upper limit methanol has same retention time; 17 of 25 samples pos)(1). URBAN: Chicago, IL: detected near 9% and in 46% homes tested (min 0.5 ppb; max < 100 ppb)(2). Urban: Leningrad, USSR 1976 - detected not quantified(3). Air pollution peak: Japan 29-57 ppb(4). Concn mean atmospheric (ppb by mass/volume): Tuscon, AZ, Feb-Sept 1982, 3.3 ppb (17 samples each); Santa Rita and Mt. Lemmon (rural), but influenced by anthropogenic contamination from the greater Tucson metropolitan area Aug-Sept 1982, 0.40 ppb (18 samples each)(5). [R288] *... In workrooms: concn up to 5000 ppm have been reported ... . [R13, 617] FOOD: *Identified, not quantified, as a volatile plant isolate in soy beans(1). Present at various concn in many beverages(2). Concn (ppb) in lima, common, mung, and soy beans (7, 5, 1 and 1 samples respectively): 1500-7900, 4200 avg; split peas, 3600; lentils 4400(3). Identified, not quantified, as a volatile flavor component in fried bacon(4) and mountain Beaufort cheese (French Alps, summer and winter)(5). [R289] *It is ... present to extent of 3-6% by vol in naturally fermented beers and ales, 10-12% in wines and 20-60% in distilled beverages. [R56, 140] RTEX: *Humans will be exposed to ethanol by ingestion of foods, flavorings, beverages, and pharmaceuticals (SRC). Workers will be exposed to ethanol in occupational settings associated with its manufacture, use as a solvent or use in synthesis(1), or when released as a product of fermentation, decomposition or combustion (including cigarette smoke)(2). [R290] *Inhalation of vapor and percutaneous absorption ... eye and skin contact. [R55, 410] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 3,240,470 workers are exposed to ethanol in the USA(1). Finnish furniture factory, 1975-84, 394 samples, 70% pos, 32 ppm avg of pos(2). [R291] *There is probably greater exposure to ethanol than to any other solvent with the exception of water. Not only is it used as a solvent in industry, but it is heavily consumed by large numbers of people as a component of potentially intoxicating beverages. As a result of the petroleum shortage, plans call for diluting gasoline with ethanol to form a combustible product termed "gasohol". At that point it is likely that ... /there will be/ universal exposure to ethanol. [R240, 648] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +3300 ppm [Based on 10% of the lower explosive limit for safety considerations even though the relevant toxicological data indicated that irreversible health effects or impairment of escape existed only at higher concentrations.] [R44, 132] ATOL: *Residues of ethyl alcohol are exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R292] *Ethyl alcohol is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R293] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1000 ppm (1900 mg/cu m). [R294] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1000 ppm (1900 mg/cu m). [R44, 132] TLV: +8 hr Time Weighted Avg (TWA): 1000 ppm. [R54, 2002.31] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R54, 2002.6] +A4; Not classifiable as a human carcinogen. [R54, 2002.31] OOPL: *MAXIMUM ACCEPTABLE CONCN (MAC) USSR 1000 mg/cu m [R40, 791] *Other recommendations: the USSR (1967) East Germany (1973) and Czechoslovakia (1969) limits are 500 ppm; West Germany (1974) and Sweden (1975) 1000 ppm. [R295] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethanol is produced, as an intermediate or final product, by process units covered under this subpart. [R296] FIFR: *Unless designated as an active ingredient /as determined by EPA/, this substance, when used in antimicrobial products as a solvent (except in textures or where sole or major active ingredients) is considered inert, having no independent pesticidal activity. The percentage of such an ingredient shall be included on the label in the total percentage of inert ingredients. [R297] *Residues of ethyl alcohol are exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R292] *Ethyl alcohol is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R293] FDA: *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R298] *Ethanol is an indirect food additive for use only as a component of adhesives. [R299] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 1400: Analyte: ethanol; Matrix: air; Sampler: solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.05 l/min; Vol: min: 0.1 l, max: 1 l; Stability: store in freezer; analyze as soon as possible /Alcohols I, ethanol/ [R300, p. V1 1400-1] *NIOSH 8002: Analytes: methyl ethyl ketone, ethanol, toluene (simultaneous); Specimen: venous blood, after 2 or more hr of exposure; Container: 5 ml heparin coated vacuum tube; Shipment: air express at 4 deg C; Sample stability: stable at 4 deg C for 3 wk; Controls: Pre-shift whole blood samples as well as whole blood samples from non exposed controls /2-Butanone, ethanol, and toluene in blood/ [R300, p. V1 8002-1] *A novel mouth cup device for sampling breath from unconscious subjects and analysis with a hand held breath alcohol instrument, the Alcolmeter SD-2 are described. The mouth cup device was made from a disposable polypropylene cup. The nasal tube is a polypropylene tube, 1.5 cm x 0.3 cm. [R301] ALAB: *Alcohol by vol in distilled liquors was determined by a Pycnometer method. Samples containing 60% or less alcohol by vol as well as samples containing more than 60% by vol were determined. [R302, p. 176 9.021] *Alcohol by vol in distilled liquors was determined by a hydrometer method. Applicable to spirits containing < or = 600 mg extract/100 ml. [R302, p. 176 9.024] *Alcohol in distilled liquors by a densitometric method. Mettler/Paar DMA 55D, with adapter No 5771 which permits continuous flow of sample through U-tube was used. [R302, p. 176 9.028] *Alcohol in distilled liquors by Williams Field Test. [R302, p. 176 9.035] *Alcohol by vol in liqueur-type and alcoholic dairy products by densitometer method. Applicable to products containing dissolved solids. [R302, p. 189 9.122] *Alcohol by vol in beer by a specific gravity method. [R302, p. 194 10.027] *Ethanol in beer a by gas chromatographic method. ... n-propanol internal standar is added to sample, and ethanol is determined by gas chromatography using flame ionization detection. [R302, p. 194 10.032] *Alcohol in wines by vol from refraction (rapid method). Determine immersion refractometer reading of distillate ... and find corresponding % alcohol ... . [R302, p. 220 11.006] *Alcohol in wines by dichromate oxidation. Sample is steam-distilled into acidified potassium dichromate soln. Oxidation of ethanol to ethyl acetate is completed by heating. Unreacted dichromate is determined by titration with standard ferric ammonium sulfate soln, using o-phenanthroline as indicator. Calculate % alcohol by vol ... . [R302, p. 220 11.008] *Alcohol in wines by a gas chromatographic method. [R302, p. 221 11.014] *Alcohol in vanilla extract by a pycnometer method. [R302, p. 353 19.004] *Alcohol in flavors /lemon, orange, lime, almond, cassia, cinnamon, and clove extracts/ by a gas chromatographic method. [R302, p. 353 19.002] *... Ethyl alcohol in cosmetics by a gas chromatographic method. [R302, p. 659 35.006] *... Alcohol in drugs by gas chromatographic method. Applicable to liquid preparations containing ethanol with isopropanol or acetone or individual cmpd. [R302, p. 668 36.012] *TRACE ODOR POLLUTANTS IN MODEL GARBAGE AND WASTE DISPOSAL PLANT WERE IDENTIFIED BY GC AND MASS SPECTROSCOPY. NEUTRAL AND AMINE CMPD WERE COLLECTED BY THE COLD TRAP METHOD IN THE SAMPLING HEAD SPACE GAS OF THE MODEL GARBAGE. ETHYL ALC WAS IDENTIFIED AS ONE OF THE NEUTRAL COMPONENTS. [R303] *A modified variant of the purge-and-trap gas chromatographic analysis of volatile organic carbon compounds in water was designed. Samples are purged in an ultrapure helium gas stream using an open loop arrangement. Volatile eluates are trapped onto selective adsorbents packed inside stainless steel tubes connected in series. After stripping, the adsorbent tubes are disconnected, fitted with analytical desorption caps and sequentially desorbed on a thermal desorber. The desorbed organics are trapped on a packed cold trap prior to flash volatilization of the volatiles across a fused silica transfer line onto a capillary column.Ethanol was among the 200 organic compounds separated using flame ionization and ion trap detection. The method is capable of quantitation down to 5 ng/l per component. The recoveries of ethanol from water at 30 and 60 C were 59 and 87%, respectively. [R304] CLAB: *RAPID VAPOR PHASE METHOD FOR DETERMINING ETHANOL IN BLOOD AND URINE BY GAS CHROMATOGRAPHY, AM J CLIN PATHOL, 46, 152, 1966. [R305, 149] *BLOOD OR URINE, SPECTROPHOTOMETRY AT 450 OR 350 NM; DUBOWSKI, K, TESTS FOR ALCOHOL ... COMMITTEE ON MEDICOLEGAL PROBLEMS, ED, US MEDICAL ASSOCIATION, CHICAGO, ILL, 1968, 61. [R305, 146] *AUTOMATED BLOOD ALCOHOL DETERMINATION (ADH-METHOD) USING THE LKB-SUBSTRATE ANALYZER 2074 WAS DISCUSSED. DEPROTEINATED SERUM OR BLOOD SAMPLES WERE INCUBATED WITH NAD AND ALCOHOL DEHYDROGENASE FOR 15 MIN AT 25 DEG C, EXTINCTION DETERMINED @ 340 NM. ACCURACY 96.76%, STANDARD DEVIATION 0.049. [R306] *NIOSH 8002: Analytes: methyl ethyl ketone, ethanol, toluene (simultaneous); Specimen: venous blood; Technique: gas chromatography, flame ionization detector; Carrier gas: helium, 25 ml/min; Column: glass, 3m X 2mm ID, 5% Carbowax 20 m on 100/120 mesh Chromosorb WHP; Range: 0.01 to 0.6 mg/ml; Precision (relative standard deviation): 0.056 (0.1 mg/ml blood) /2-Butanone, ethanol, and toluene in blood/ [R300, p. V1 8002-1] *A novel mouth cup device for sampling breath from unconscious subjects and analysis with a hand held breath alcohol instrument, the Alcolmeter SD-2 are described. The Alcolmeter SD-2 operates by means of an electrochemical detector and is calibrated to read directly in terms of blood alcohol content on the basis of a 2300:1 blood/breath ratio of ethanol. The mouth cup device was made from a disposable polypropylene cup. The nasal tube is a polypropylene tube, 1.5 cm x 0.3 cm. The equipment was evaluated in six healthy volunteers (three men and three women) 30 to 120 min after they drank a moderate dose of alcohol. Three kinds of breath were analyzed: end expired air from a conventional mouth tube; breath sampled from the mouth cup; and air from a nasal tube supplied with the breath analyzer. The ethanol concentration in breath from the mouth cup was slightly less than in end expired air but significantly greater than in nasal air. Results with mouth tube and mouth cup correlated highly with blood ethanol concentration as determined by gas chromatography; nasal tube air correlated less well. [R301] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Sato C et al; Alcohol Relat Dis Gastroenterol: p.172-84 (1985). A review with many references on the interactions of ethanol with drugs and xenobiotics. The effects of ethanol on absorption, plasma protein binding, hepatic blood flow, distribution, hepatic uptake, and phase I AND II hepatic metabolism are briefly summarized and the clinical relevance of the observed changes is discussed. Lieber CS, Leo MA; Falk Symp 39 Hepatology: 15-36 (1985). A review with 60 references on the direct effects of ethanol on vitamin A metabolism and resulting alterations of hepatic vitamin A levels even at early stages of alcohol liver injury. Implication with regard to vitamin A therapy in alcoholics and possible vitamin A toxicity were also discussed. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for ethanol is in progress. Route: dosed-water feed; Species: mice. [R307] SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R2: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R4: Estrin, N.F., Crosley, P.A. and Haynes, C.R. (eds.) CTFA Cosmetic Ingredient Dictionary. 3rd ed. Washington, D.C.: The Cosmetic, Toiletry and Fragrance Association, Inc. 1982. 1 R5: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. R6: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. 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Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. R306: MEBS D ET AL; BLUTALKOHOL 16 (1): 29-35 (1979) R307: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 325 Record 15 of 1119 in HSDB (through 2003/06) AN: 84 UD: 200303 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLBENZENE- SY: *AETHYLBENZOL- (GERMAN); *BENZENE,-ETHYL-; *EB-; *ETHYLBENZEEN- (DUTCH); *ETHYL-BENZENE-; *ETHYLBENZOL-; *ETILBENZENE- (ITALIAN); *ETYLOBENZEN- (POLISH); *NCI-C56393-; *PHENYLETHANE- RN: 100-41-4 MF: *C8-H10 SHPN: UN 1175; Ethylbenzene IMO 3.2; Ethylbenzene STCC: 49 091 63; Ethylbenzene HAZN: F003; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by dehydrogenation of naphthenes or from catalytic cyclization and aromatization. [R1, 1342] *ALKYLATION OF BENZENE WITH ETHYLENE IN LIQUID PHASE USING ALUMINUM CHLORIDE CATALYST OR IN VAPOR PHASE USING PHOSPHORIC ACID OR ALUMINA-SILICA CATALYST; RECOVERY FROM MIXED XYLENES VIA FRACTIONATION [R2] *Prepd from acetophenone [R3] *Produced by alkylation of benzene with ethylene using acidic catalysts and can be carried out in the liquid or vapor phase. [R4, p. V22 957] *Produced via the use of zeolite catalyst, ZSM-5, in a process called the Mobil-Badger vapor phase ethylbenzene process. [R4, p. V22 961] *(1) By heating benzene and ethylene in the presence of aluminum chloride, with subsequent distillation; (2) by fractionation directly from the mixed xylene stream in petroleum refining. [R5] FORM: *GRADE: TECHNICAL 99.0%; PURE 99.5%; RESEARCH 99.98%. [R6] *Grade: Technical, pure, research [R5] MFS: *Amoco Corporation, Hq, 200 East Randolph Drive, Chicago, IL 60601, (312) 856-6111; Subsidiary: Amoco Chemical Company (address same as Hq), (312) 856-3200; Chemical and Specialty Product Group; Production site: Texas City, TX 77592 [R7, 593] *ARCO Chemical Co., Hq, 3801 W. Chester Pk., Newtown Square, PA 19073; Production site: Channelview, TX 77530 [R7, 583] *Chevron Chemical Co., 6001 Bollinger Canyon Rd., San Ramon, CA 94583, (925) 842-5500; Production site: St. James, LA 70086 [R7, 593] *Cos-Mar, Inc., Hq, PO Box 11, Carville, LA 70721, (504) 642-5454; Production site: Carville, LA 70721 [R7, 593] *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 [R7, 593] *Huntsman Corp., 3040 Post Oak Blvd., Houston, TX 77056, (713) 235-6000; Production site: Odessa, TX 79760 [R7, 593] *Sterling Chemicals, Inc., Hq, 333 Clay St., Suite 3700, Houston, TX 77002, (713) 650-3700; Production site: Texas City, TX 77590 [R7, 593] *Westlake Styrene Corp., 2801 Post Oak Blvd., Suite 200, Houston, TX 77056, (713) 877-1924; Production site: Lake Charles, LA 70602-3089 [R7, 593] OMIN: *In most processes, ethylbenzene is not recovered because of high energy costs. [R8] *Ethylbenzene is recovered from benzene-toluene-xylene (BTX) processing. [R9] *19th-highest-volume chemical produced in the U.S. (1995). [R5] USE: *USED IN ... THE PRODUCTION OF SYNTHETIC RUBBER ... AS A SOLVENT OR DILUENT, A COMPONENT OF AUTOMOTIVE AND AVIATION FUELS; MFR OF CELLULOSE ACETATE [R10] *Ethylbenzene is mainly used as a precursor to styrene. [R4, p. V2 84] *... SOLVENT-EG, FOR ALKYD SURFACE COATINGS, CHEM INT FOR DIETHYLBENZENE AND ACETOPHENONE, FOR ETHYL ANTHRAQUINONE, FOR ETHYLBENZENE SULFONIC ACIDS (O-, M- AND P-), FOR PROPYLENE OXIDE AND ALPHA-METHYLBENZYL ALCOHOL, UNRECOVERED COMPONENT OF GASOLINE [R2] *Used as an intermediate for the manufacture of the styrene monomer and as a resin solvent. [R3] *Intermediate for the production of diethylbenzene and acetophenone. [R11] *Used as a component of automotive and aviation fuels. [R1, 1342] *Intermediate in production of styrene solvent. [R5] CPAT: *Intermediate for styrene monomer production, more than 99%; the remainder is exported or sold as solvent (1984). [R12] *Styrene, 97%; Miscellaneous, 3% (1983) /Estimate/ [R13] *CHEMICAL PROFILE: Ethylbenzene. Intermediate for styrene monomer production, over 99%. The remainder is used in solvent applications. [R14] *CHEMICAL PROFILE: Ethylbenzene. Demand: 1988: 9,935 million lb; 1989: 10,230 million lb; 1993 /projected/: 11,500 million lb. (Imports and exports are both minor, each one on the order of 200 million lb.) [R14] *Precursors for styrene production, more than 99 percent. The remainder is used in solvent applications. [R15] PRIE: U.S. PRODUCTION: *(1977) 8.3X10+9 lb [R16] *(1980) 3.5 x 10+12 g [R17] *(1981) 3.5 x 10+12 g [R17] *(1977) 3.77X10+12 G [R2] *(1982) 3.15X10+12 G [R2] *(1985) 3.35X10+12 g [R18] *(1988) 9.9X10+9 lb [R19] *(1990) 8.37 billion lb [R20] *(1991) 8.87 billion lb [R21] *(1992) 11.11 billion lb [R22] *(1993) 11.76 billion lb [R22] *(1993) 4,233,835 kg [R23] *1997: 12.9 billion pounds; 1998 13 billion pounds; 2002 15 billion pounds. (Includes exports, which amounted to 126 million pounds in 1996, but not imports which totaled 16 million pounds in that year). [R15] *Growth: Historical (1988-1997): 2.5 percent per year; future: 3 percent per year through 2002. [R15] U.S. IMPORTS: *(1978) 1.53X10+10 G [R2] *(1981) 2.09X10+10 G [R2] *US General Imports entered under schedule 4, pt 1B, of the TSUS (1983). Quantity of ethylbenzene: 87,201,615 lbs. [R24] *(1996) 16 million pounds [R15] U.S. EXPORTS: *(1978) 8.59X10+10 G [R2] *(1983) 4.84X10+10 G [R2] *(1985) 7.49X10+10 g [R25] *(1996) 126 million pounds [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R5] ODOR: *Aromatic odor [R5]; *Pungent odor [R1, 1342]; *SWEET, GASOLINE-LIKE ODOR [R6] BP: *136.1 deg C [R26] MP: *-94.9 deg C [R26] MW: *106.16 [R3] CTP: *Critical temperature = 617.15 K; critical pressure = 3.6X10+6 Pa [R27] DEN: *0.8670 @ 20 deg C/4 deg C [R26] HTC: *-17,780 BTU/lb= -9877 cal/g= -413.5x10+5 J/kg [R6] HTV: *4.8X10+7 J/kmol @ 178.20 K [R27] OWPC: *log Kow= 3.15 [R28] SOL: *SOL IN ALL PROPORTIONS IN ETHYL ALCOHOL AND ETHYL ETHER [R10]; *SOLUBILITY IN WATER @ 15 DEG C, 0.014 G/100 ML [R29, 1223]; *Miscible with the usual organic solvents. [R3]; *Soluble in alcohol, benzene, carbon tetrachloride, and ether. [R5]; *Slight soluble in chloroform; miscible in ethanol and ethyl ether. [R26]; *In water, 169 mg/l @ 25 deg C [R30]; *Insol in ammonia; sol in SO2. [R31] SPEC: *SADTLER REF NUMBER: 246 (IR, PRISM); 82 (IR, GRATING) [R32]; *IR: 4779 (Coblentz Society Spectral Collection) [R33]; *UV: 97 (Sadtler Research Laboratories Spectral Collection) [R33]; *NMR: 505 (Varian Associates NMR Spectra Catalogue) [R33]; *MASS: 322 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R33]; *Index of refraction: 1.4959 at 20 deg C/D [R26] SURF: *4.3 N/m @ 178.20 K [R27] VAPD: *3.66 (Air= 1) [R34] VAP: *9.6 mm Hg @ 25 deg C [R27] EVAP: *IT EVAPORATES ABOUT 94 TIMES MORE SLOWLY THAN ETHER [R1, 1342] VISC: *0.64 cP @ 25 deg C [R5] OCPP: *DENSITY OF SATURATED VAPOR-AIR MIXTURE AT 760 MM HG (AIR= 1): 1.03 (26 DEG C); SPECIFIC DISPERSION: 174.6 [R29, 1223] *CONVERSION FACTORS: 1 MG/L IS EQUIVALENT TO 230 PPM, 1 PPM IS EQUIVALENT TO 4.35 MG/CU M AT 25 DEG C, 760 MM HG [R29, 1231] *Specific heat: 0.41 cal/gal/K [R5] *Liquid-water interfacial tension: 35.48 dynes/cm= 0.03548 N/m @ 20 deg C [R6] *Ratio of Specific Heats of Vapor (gas): 1.071 [R6] *Heats of transition, J/(mol.K): fusion 9.164; formation @ 25 deg C: -12.456; entropy of formation 255.2 [R4, p. V5 833] *Cricital density: 2.67 mmol/cu m; critical volume: 374.0 cu m/mol [R4, p. V25 833] *Viscosity: 0.678 mPas (20 deg C) [R35] *Ionization potential: 8.76 eV [R35] *Flame speed: 0.35 m/s [R36] *Partition coefficients at 37 deg C for ethylbenzene into blood= 28.4; into oil= 3,790. [R37] *Henry's Law constant= 7.88X10-3 atm-cu m/mol @ 25 deg C [R30] *Hydroxyl radical rate constant= 7.10X10-12 cu m/molecule-sec @ 25 deg C [R38] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R39] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R39] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R39] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R39] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R39] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R39] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R39] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R39] FPOT: *A very dangerous fire ... hazard when exposed to heat or flame ... [R31] *Electrical ignition hazard: May be ignited by static discharge. [R40] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R41, p. 325-48] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R41, p. 325-48] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R41, p. 325-48] FLMT: *Lower flammable limit: 0.8% by volume; Upper flammable limit: 6.7% by volume [R41, p. 325-48] FLPT: *12.8 DEG C (55 DEG F) (CLOSED CUP) [R1, 1304] AUTO: *810 DEG F [R31] FIRP: *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R41, p. 49-65] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, carbon dioxide, or dry chemical. [R42] TOXC: *Irritating vapors are generated when heated. [R6] *The combustion products of ethylbenzene are water and carbon dioxide or carbon monoxide in limited oxygen atmospheres. [R43] *Compounds identified in tars produced by the pyrolysis of ethylbenzene include the following suspected carcinogens: 1-benzanthracene, benzene, benzofluoranthene, 10,11-benzofluoranthene, 12-benzofluoranthene, 1-benzofluoranthene, 1-benzopyrene, 3,4-benzopyrene, chrysene, and 1,2:5,6-dibenzanthracene. [R44] OFHZ: *Vapors are heavier than air and may travel to a source of ignition and flash back. Liquid floats on water and may travel to a source of ignition and spread fire. [R41, p. 49-65] EXPL: *Vapors form explosive mixtures with air. [R41, p. 49-65] *Lower explosive limit= 1.2%. Upper explosive limit= 6.8%. [R31] REAC: *Incompatibilities: Strong oxidizers. [R45, 4122] *... Can react vigorously with oxidizing materials. [R31] *Strong oxidizers. [R46, 132] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R31] ODRT: *140 ppm /Purity not specified/ [R6] *2-2.6 mg/cu m; detection: 0.4 mg/cu m /Purity not specified/ [R47, 944] *Odor Low: 8.7 mg/cu m, Odor High: 870.0 mg/cu m [R48] SERI: *... CHARACTERIZED ... AS MOST SEVERE IRRITANT OF THE BENZENE SERIES. [R49] *A concn of 200 ppm causes eye irritation. A concn of 100 ppm for 8 hr caused irritative effects in a human. [R50] *EXPOSURE TO CONCN OF 5000 PPM /24.6 MG/L/ ... CAUSES INTOLERABLE IRRITATION OF EYES, MUCOUS MEMBRANES AND NOSE. [R29, 1232] +HAZARD WARNING: ... exposure to 21.5 g/cu m (5000 ppm) ethylbenzene for a few seconds gives intolerable irritation of nose, eyes, and throat. [R51] EQUP: *Wear full protective clothing and positive pressure self-contained breathing apparatus. [R41, p. 49-65] *Rubber overclothing (including gloves) [R6] *Wear appropriate personal protective clothing to prevent skin contact. [R46, 132] *Wear appropriate eye protection to prevent eye contact. [R46, 132] *Recommendations for respirator selection. Max concn for use: 800 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R46, 132] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R46, 132] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R46, 132] OPRM: *Contact lenses should not be worn when working with this chemical. [R46, 132] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Employees should wash promptly when skin is wet or contaminated. Remove clothing immediately if wet or contaminated to avoid flammability hazard. [R45, 414] *BEFORE WORKERS ARE ALLOWED TO ENTER A REACTION VESSEL ... THE VESSEL SHOULD BE PURGED AND WELL VENTILATED. PERSONAL PROTECTIVE EQUIPMENT SHOULD BE SUPPLIED ... [R10] *... SUBSTITUTION OF LESS IRRITATING SUBSTANCES, ... REDESIGN OF OPERATIONS, ... PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, PROPER WORK CLOTHING AND STORAGE FACILITIES, PROTECTIVE CLOTHING, BARRIER CREAMS, AND MEDICAL CONTROL ... [R52] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R42] *COMBUSTION MAY BE IMPROVED BY MIXING WITH MORE FLAMMABLE LIQ. ... SHOULD NOT BE ALLOWED TO ENTER CONFINED SPACE, SUCH AS SEWER, BECAUSE OF POSSIBILITY OF EXPLOSION. [R53, 1981.2] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without hazard. Use water spray to knock-down vapors. [R42] *The worker should immediately wash the skin when it becomes contaminated. [R46, 132] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R46, 132] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R54] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R55] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R56] STRG: *Outside or detached storage is preferred. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Separate from oxidizing materials. [R41, p. 49-65] *Temp: ambient; Venting: open (flame arrester) or pressure-vacuum [R6] CLUP: *1) REMOVE ALL IGNITION SOURCES. 2) VENTILATE AREA OF SPILL OR LEAK. 3) FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ... BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER. [R53, 1981.1] *Land spills should be contained; skimming equipment and/or sorbent (polyurethane) foams can be used. Use of activated carbon is recommended. [R57] *Water spills should be contained; skimming equipment and/or sorbent (polyurethane) foams can be used to remove the slick. Universal gelling agent can be used to solidify a trapped mass. Use of activated carbon on dissolved portion is recommended. [R57] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, sawdust, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. [R42] *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. [R42] *Environmental considerations: Water spill: Use natural barriers or oil spill control booms to limit spill travel. Use surface active agent (e.g., detergent, soaps, alcohols), if approved by EPA. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R42] *ABSORB IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL [R53, 1981.2] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R58] *Ethylbenzene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R59] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R60] *The following wastewater treatment technologies have been investigated for ethylbenzene: Activated Carbon. [R61] *The following wastewater treatment technologies have been investigated for ethylbenzene: biological treatment. [R62] *The following wastewater treatment technologies have been investigated for ethylbenzene: stripping. [R63] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +The acute toxicity of ethylbenzene to algae, aquatic invertebrates and fish is moderate. ... No information is available regarding chronic exposure of aquatic organisms to ethylbenzene. There is limited information regarding the toxicity of ethylbenzene to bacteria ... There are no data for terrestrial plants, birds, or wild mammals. Human exposure to ethylbenzene occurs mainly by inhalation; 40-60% of inhaled ethylbenzene is retained in the lung. Ethylbenzene is extensively metabolized, mainly to mandelic and phenylglyoxylic acids. These urinary metabolites can be used to monitor human exposures. Ethylbenzene has low acute and chronic toxicity for both animals and humans. It is toxic to the central nervous system and is an irritant of mucous membranes and the eyes. ... Ethylbenzene is an inducer of liver microsomal enzymes. It is not mutagenic or teratogenic ... No information is available on reproductive toxicity or carcinogenicity of ethylbenzene. A guidance value of 22 mg/ cu m (5 ppm) has been calculated from animal studies. /This value would correspond to a weekly absorbed dose (daily ventilation of 20 cu m with 60% retention) of about 2000 mg./ The estimated exposure of the general population (even in the worst case situation) is below this guidance value. Long term occupational exposure to ethylbenzene concentrations estimated to be of this order of magnitude did not cause adverse health effects in workers. [R64] CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: nonclassifiable due to lack of animal bioassays and human studies. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: None. [R65] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R66, 2002.31] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R67, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatics hydrocarbons and related compounds/ [R67, 182] MEDS: *... EMPLOYMENT EXAMINATION SHOULD ENSURE THAT PERSONS WITH LIVER, KIDNEY, NERVOUS SYSTEM, BLOOD AND HEMOPOIETIC-ORGAN DISORDERS ARE /PROTECTED FROM EXPOSURE/ ... WOMEN WITH OVULATION AND MENSTRUAL CYCLE DISORDERS SHOULD ALSO BE /PROTECTED/. [R10] *Consider the points of attack (eyes, upper respiratory system, skin, central nervous system) in placement and periodic physical examinations. [R45, 413] HTOX: *PROLONGED EXPOSURE TO ... VAPORS MAY RESULT IN FUNCTIONAL DISORDERS, INCREASE IN DEEP REFLEXES, IRRITATION OF UPPER RESPIRATORY TRACT, HEMATOLOGICAL DISORDERS (LEUKOPENIA AND LYMPHOCYTOSIS, IN PARTICULAR) AND ... HEPATOBILIARY COMPLAINTS. [R10] *... ASPIRATION OF EVEN A SMALL AMT OF ETHYLBENZENE MAY CAUSE SEVERE INJURY, SINCE ITS LOW VISCOSITY AND SURFACE TENSION WILL CAUSE IT TO SPREAD OVER A LARGE SURFACE OF PULMONARY TISSUE. ... [R68, 92] *Produces an irritant effect from chronic inhalation at 100 ppm (0.492 mg/L)/8 hr. /From table/ [R1, 1344] *... /IT HAS BEEN/ SHOWN THAT CONCN OF 1 MG/L AND EVEN 0.1 MG/L MAY BE DANGEROUS AND MAY PRODUCE FUNCTIONAL AND ORGANIC DISTURBANCES (NERVOUS SYSTEM DISORDERS, TOXIC HEPATITIS AND UPPER RESP TRACT COMPLAINTS). CONCN AS LOW AS 0.01 MG/L MAY LEAD TO ... INFLAMMATION OF UPPER RESP TRACT MUCOSA. [R10] *Ethyl benzene vapor has a transient irritant effect on human eyes at 200 ppm in air. At 1000 ppm on the first exposure it is very irritating and causes tearing, but tolerance rapidly develops. At 2000 ppm eye irritation and lacrimation are immediate and severe; 5000 ppm causes intolerable irritation of the eyes and nose. [R69] *ETHYLBENZENE IS MORE VOLATILE THAN STYRENE AND ITS MANUFACTURE IS ACCOMPANIED BY A GREATER HAZARD OF ACUTE POISONING. ... [R10] NTOX: *... From ingestion of or exposure of skin or lung to high concns causes /CNS depression/ in animals. Although similar to benzene, ethylbenzene apparently does not cause bone marrow problems. [R70] *EXPOSURE OF GUINEA PIGS TO 1% CONCENTRATION HAS BEEN REPORTED AS CAUSING ATAXIA, LOSS OF CONSCIOUSNESS, TREMOR OF THE EXTREMITIES, AND FINALLY DEATH THROUGH RESPIRATORY FAILURE. THE PATHOLOGICAL FINDINGS WERE CONGESTION OF THE BRAIN AND LUNGS WITH EDEMA. [R31] *... CONCN ... OVER 2 MG/L MAY CAUSE ACUTE POISONING /IN LABORATORY ANIMALS/ ... INITIAL SYMPTOMS ... INCL IRRRTATION OF MUCOUS MEMBRANES ... FOLLOWED BY ... /CNS DEPRESSION/, CRAMPS AND DEATH ... DUE TO RESPIRATORY-CENTER PARALYSIS. MAIN PATHOLOGICAL FINDINGS ARE MARKED EDEMA OF BRAIN AND LUNG, FOCI OF EPITHELIAL NECROSIS IN RENAL TUBULES AND HEPATIC DYSTROPHY. [R10] *... /GUINEA PIGS/ THAT DIED FROM EXPOSURE /TO 10000 PPM FOR FEW MIN OR 5000 PPM FOR 30-60 MIN/ HAD INTENSE CONGESTION AND EDEMA OF LUNG AND GENERALIZED VISCERAL HYPEREMIA. [R68, 91] *IN GUINEA PIGS, 0.3% BY VOL IS MAX AMT FOR 1 HR WITHOUT SERIOUS SYMPTOMS; 0.1% BY VOL IS MAX AMT FOR SEVERAL HR WITHOUT SERIOUS DISTURBANCES. /FROM TABLE/ [R29, 1232] *REPEATED APPLICATIONS OF UNDILUTED ETHYLBENZENE TO THE SKIN OF RABBITS CAUSED ... BLISTERING. [R68, 92] *... RATS, RABBITS, GUINEA PIGS, AND MONKEYS /WERE EXPOSED/ TO CONCN OF ... 400-2200 PPM, 7 TO 8 HR/DAY, 5 DAYS A WK FOR AS LONG AS 6 MONTHS. THE GUINEA PIGS, RABBITS, AND MONKEYS WERE NOT AFFECTED ... SLIGHT INCREASE IN AVG WT OF KIDNEYS AND LIVERS WERE OBSERVED IN RATS EXPOSED TO 400 PPM FOR 186 DAYS. [R29, 1232] *... RATS /WERE INJECTED/ SUBCUTANEOUSLY WITH 1 ML ... PER KG OF BODY WT DAILY FOR 2 WEEKS AND ... NO DECREASE IN THE TOTAL FEMORAL MARROW NUCLEATED CELL COUNT /WAS OBSERVED/. THESE ANIMALS DEVELOPED A LEUCOCYTOSIS INSTEAD OF SEVERE LEUCOPENIAS FOUND IN BENZENE-DOSED ANIMALS WHICH SERVED AS POSITIVE CONTROLS. [R29, 1232] *EXPOSURE TO 2000 PPM FOR UP TO 375 MIN CAUSED IN SOME OF /GUINEA PIGS/ ... MOTOR ATAXIA AND APPARENT UNCONSCIOUSNESS; WITH 10,000 PPM THIS STAGE WAS REACHED IN 18 MIN. IT WAS PRECEDED BY VERTIGO, UNSTEADINESS AND ATAXIA. [R68, 92] *LIVER AND KIDNEY WT INCREASED IN RATS GIVEN SUBCHRONIC ORAL DOSES OF 408-680 MG/KG/DAY FOR 182 DAYS. /FROM TABLE/ [R1, 1345] *INHALATION @ 3050 PPM (15 MG/L) PRODUCED LOSS OF RIGHTING RESPONSE IN MICE AND DEATH IN 2 HR FROM 9150 PPM (45 MG/L). IN GUINEA PIGS 1000 PPM (4.92 MG/L)/3 MIN PRODUCED SLIGHT NASAL IRRITATION, @ 8 MIN EYE IRRITATION; 2000 PPM (9.84 MG/L)/1 MIN PRODUCED MODERATE EYE AND NASAL IRRITATION, UNCONSCIOUSNESS @ 345 MIN. /FROM TABLE/ [R1, 1344] *SUBACUTE EXPOSURE OF MALE RATS TO 2000 PPM PRODUCED INCREASES OF DOPAMINE AND NORADRENALINE LEVELS AND TURNOVER IN VARIOUS PARTS OF HYPOTHALAMUS AND MEDIAN EMINENCE 16-18 HR FOLLOWING LAST EXPOSURE. [R71] *Rats inhaling 600, 1200, or 2400 mg ethylbenzene/cu m for 24 hr/day from days 7-15 of pregnancy showed mild toxicity. The highest dose retarded skeletal development and weight gain in the fetuses and increased the incidence of extra ribs. Sacral displacement with abnormal development was observed in 2 instances. Thus, ethylbenzene, has some embryotoxic and teratogenic activity. [R72] *Ethylbenzene was investigated ... as a sensory irritant in mice. The concn necessary to depress the respiratory rate by 50% (RD 50) due to sensory irritation of the upper respiratory tract was 4060 ppm. ... A model for the sensory irritating action ... was proposed on the basis of ... physical interaction with a receptor protein. [R73] *Drop application to rabbit eyes caused slight irritation and no corneal injury demonstrable by fluorescein staining. Standard testing on rabbit eyes gave an injury grade of 2 on a scale of 10. [R69] *Rats were exposed for 3 days by inhalation to 2000 ppm of a xylene mixture, or ... ethylbenzene. All solvents increased hepatic cytochrome p450 concn and NADPH-cytochrome C reductase activity. The ability of ethylbenzene to modify the metabolism of other potentially toxic substances in liver, kidney, and lung microsomes suggested the possibility of synergistic toxic responses. [R74] *Concn of < 0.25 mg/l can cause tainting of fish flesh. [R50] *Neither maternal toxicity nor embryotoxicity was observed in gravid rabbits exposed to ethylbenzene /by inhalation/ at 100 or 1000 ppm. [R75] *Neither maternal toxicity nor embyrotoxicity was observed /in pregnant rats/ exposed to ethylbenzene /by inhalation/ at 100 ppm ... but /1000 ppm/ induced some indications of toxicity. ... A significant increase in the incidence of extra ribs was detected in rat fetuses exposed in utero to the high level. [R75] *Mice, B6C3F1 Fischer-344 rats, and /rabbits /New Zealand/ (five/sex/group) were exposed by inhalation to ethylbenzene vapors for 6 hr/day, 5 days/week for 4 weeks (20 exposures). Rats and mice received 0, 99, 382, or 782 ppm ethylbenzene while rabbits received 0, 382, 782, or 1610 ppm. No changes were evident in mortality patterns, clinical chemistries, urinalyses, or treatment-related gross/microscopic (including ophthalmologic) lesions. Rats exhibited sporadic lacrimation and salivation, as well as significantly increased liver weights at 382 and 782 ppm, and small increases in leukocyte counts at 782 ppm. Males at this exposure level also showed marginal elevations in platelet counts. In mice, females showed statistically increased absolute and relative liver weights at 382 and 782 ppm while males had statistically increased relative liver-to-brain weight ratios only at 782 ppm. Female rabbits at the high exposure level of 1610 ppm gained weight more slowly than controls (not statistically significant); males showed a similar transient downward trend after 1 week, but showed no differences from controls at study's end. A no observed adverse effect level (NOAEL) of 382 ppm appears appropriate for rats and mice with a lowest observed adverse effect level (LOAEL) of 782 ppm. A NOAEL of 782 ppm and LOAEL of 1610 ppm are appropriate for rabbits. [R76] *Repeated application of undiluted ethyl benzene to the ear and shaved abdominal area of rabbits (10-20 applications over a period of 2-4 wk) resulted in erthyema, edema, and superficial necrosis. ... Two drops of ethyl benzene into the conjunctival sac produced only a slight irritation of the conjunctival membranes but no corneal injury. [R77, 1991.581] *Inhalation of 2600 mg/cu m (600 ppm) ethyl benzene 7 hr/day, 5 days/wk for 186 days caused degeneration of the germinal epithelium in the testes of rabbits and monkeys but not of rats. Pregnant rats exposed at 100 or 1000 ppm 6 hr/day for 3 wk prior to mating and on days 1-19 of gestation had pups with a significant increase (p < 0.05) in extra rib formation; at the higher dose, maternal toxicity was indicated by increased liver, kidney, and spleen weights. [R77, 1991.582] *... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of ethylbenzene in male F344/N rats based on incr incidences of renal tubule neoplasms. The incidences of testicular adenoma were also incr. There was some evidence of carcinogenic activity of ethylbenzene in female F344/N rats based on incr incidences of renal tubule adenomas. There was some evidence of carcinogenic activity of ethylbenzene in male B6C3F1 mice based on incr incidences of alveolar/bronchiolar neoplasms. There was some evidence of carcinogenic activity of ethylbenzene in female B6C3F1 mice based on incr incidences of hepatocellular neoplasms. [R78] +Efforts were made to clarify the molecular basis of styrene toxicity on the dopaminergic systems and to evaluate whether the same mechanism was common to other solvents. Groups of male New Zealand rabbits were exposed to 750 ppm toluene, xylene, styrene, ethylbenzene, vinyltoluene, 7-methyl-styrene, or fresh air (control group). A significant depletion in both striatal and tubero infundibular dopamine was caused by styrene, ethylbenzene, and vinyltoluene. Methylation of the aromatic ring of styrene did not change its activity, whereas methylation of the side chain drastically reduced its effect on dopamine. Treatment carried out with the main metabolites of aromatic solvents indicated that acidic metabolites of some solvents caused striatal and tubero infundibular dopamine depletion. Present data suggested a chemical reaction between dopamine and some acidic metabolites. The active metabolites have an alpha-keto acid as the side chain or as a part of their molecule. These keto acids condense nonenzymatically with dopamine. [R79] NTXV: *LD50 Rat oral 5.46 g/kg; [R3] *LD50 Rat oral 3500 mg/kg; [R31] *LD50 Mouse ip 2272 mg/kg; [R31] *LD50 Rabbit skin 17,800 mg/kg; [R31] ETXV: *LC50 Lepomis macrochirus 32 mg/l/96 hr /Conditions of bioassay not specified/; [R80] *LC50 Carassius auratus 94.44 mg/l/96 hr /Conditions of bioassay not specified/; [R80] *LC50 Lebistes reticulatus 97.10 mg/l/96 hr /Conditions of bioassay not specified/; [R80] *LC50 Mysidopsis bahia (shrimp) 87.6 mg/l 96 hr in a static unmeasured bioassay; [R81] *LC50 Cyprinodon variegatus (sheepshead minnow) 275 mg/l 96 hr in a static unmeasured bioassay; [R81] *LC50 Pimephales promelas (fathead minnow) 42.3 (hardwater) to 48.5 (softwater) mg/l 96 hr /Conditions of bioassay not specified/; [R82] *LC50 Poecilla reticulata (guppy) 97.1 mg/l/96 hr /Conditions of bioassay not specified/; [R82] *Toxicity threshold (cell multiplication inhibition test): Microcystis aeruginosa (algae) 33 mg/l; Scenedesmus quadricauda (green algae) > 160 mg/l; [R47, 946] *Toxicity threshold (cell multiplication inhibition test): Entosiphon sulcatum (protozoa) 140 mg/l; Uronema parduczi Chatton-Lwoff (protozoa) > 110 mg/l; [R47, 946] *Toxicity threshold (cell multiplication inhibition test): Pseudomonas putida (bacteria) 12 mg/l; [R47, 946] *LC50 Palaemonetes pugio (grass shrimp, adult) 14,400 ug/l/24 hr in a static unmeasured bioassay; [R83] *LC50 Palaemonetes pugio (grass shrimp, larva) 10,200 ug/l/24 hr in a static unmeasured bioassay; [R83] *LC50 Pimephales promelas (fathead minnow) 12.1 mg/l/96 hr (confidence limit 11.5 - 12.7 mg/l), flow-through bioassay with measured concentrations, 26.1 deg C, dissolved oxygen 7.0 mg/l, hardness 45.6 mg/l calcium carbonate, alkalinity 43.0 mg/l calcium carbonate, and pH 7.39; [R84] NTP: +... 2 Yr Study in Rats: Groups of 50 male and 50 female F344/N rats were exposed to 0, 75, 250 or 750 ppm ethylbenzene 6 hr day, 5 days/wk for 104 wk. ... 2 Yr Study in Mice: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 75, 250 or 750 ppm ethylbenzene by inhalation, 6 hr/day, 5 days/wk for 103 wk. ... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of ethylbenzene in male F344/N rats based on incr incidences of renal tubule neoplasms. The incidences of testicular adenoma were also incr. There was some evidence of carcinogenic activity of ethylbenzene in female F344/N rats based on incr incidences of renal tubule adenomas. There was some evidence of carcinogenic activity of ethylbenzene in male B6C3F1 mice based on incr incidences of alveolar/bronchiolar neoplasms. There was some evidence of carcinogenic activity of ethylbenzene in female B6C3F1 mice based on incr incidences of hepatocellular neoplasms. [R78] TCAT: ?In a single generation reproduction study, 380 female and 60 male Wistar rats were exposed to ethylbenzene at average daily concentrations of 97 or 959 ppm 7 hours per day, 5 days per week for 3 weeks. They were then mated and exposed daily on gestation days (GD) 1-19 at concentrations of 96 (low) or 985 (high) ppm. Animals were sacrificed and examined on GD 21. No significant differences were observed between treatment groups and controls in food consumption, gestational body weights (of pregnant rats), organ weights (of male rats), histopathology of liver, kidney or lungs, percent pregnancy, no. of corpora lutea, no. of implants, total live or dead fetuses, no. of live or dead fetuses per litter, no. of resorptions per litter and percent litters with resorptions. A significant difference (ANOVA, Duncan's multiple range test) was observed in pregestational body weights in both treatment groups. Maternal toxicity was indicated in the high dose groups (dosed at the high level during both periods or dosed with air during pregestational and with the high level during gestation) by significant differences (ANOVA, Duncan's multiple range test) in liver, spleen and kidney weights. Statistically significant differences were seen in mean crown-rump length (in the group which was dosed at the high level during both periods), supernumerary ribs (in the 2 high dose groups and the group which was dosed with air pregestationally and with the low level during gestation) and rudimentary rib incidence (in the group dosed with air during pregestation and with the high level during gestation). [R85] ?In a single generation reproduction study 96 New Zealand White rabbits were artifically inseminated and exposed to ethylbenzene at average daily concentrations of 99 or 962 ppm 7 hours per day, through gestation day (GD) 24. Animals were sacrificed and examined on GD 30. Mortality was observed in 2 does, 1 from each dose group. No significant differences were observed between treatment groups and controls in the following: food consumption; body weight; weight gain; lung, kidney, and spleen mean weights; histopathology of liver, kidney, or lungs; percent pregnancy; no. of corpora lutea; no. of implants; total live or dead fetuses; no. of dead fetuses per litter; no. of resorptions per litter; percent litters with resorptions; and skeletal, visceral, or external parameters in fetuses. Significant differences (ANOVA, Duncan's multiple range test) relative to controls were observed in liver weights of the high dose group and in mean number of live fetuses per litter in both treatment groups. [R85] ?Ethylbenzene (CAS# 100-41-4) was evaluated for developmental toxicity in 89, 77, and 77 female Wistar rats exposed to 0, 100, and 1000 ppm of the test material respectively by inhalation for 7 hours per day, 5 days per week for 3 weeks. They were then mated and exposed daily through the 19th day of gestation. The rats were killed and examined at the 21st day of gestation. No significant differences were observed in food consumption and body weights during progestational and gestational exposure periods. At 1000 ppm relative and absolute liver, spleen, and kidney weights were significantly greater than controls and or the 100 ppm group. No treatment-related histological changes were observed. Body weights, placenta weights, and sex ratios were all within normal limits. There were no significant increases in major malformations or minor anomalies. Litters were examined for the presence of external, visceral, and skeletal defects as well as the incidence of growth retardation and intrauterine mortality. A statistically significant increased incidence of fetal supernumary ribs was observed at the 1000 ppm exposure. It was concluded that ethylbenzene caused maternal and developmental toxicity (significant increase in extra ribs) at 1000 ppm. [R86] ?Ethylbenzene (CAS# 100-41-4) was evaluated for developmental toxicity in 24, 23, and 22 New Zealand white rabbits artificially inseminated and exposed for 7 hours daily to 0, 100, and 1000 ppm of the test material respectively until the 24th day of gestation. Neither maternal toxicity nor embryotoxicity was observed in rabbits exposed to ethylbenzene at 100 or 1000 ppm. Rabbits had increased maternal liver weights at 1000 ppm and reduced mean number of live fetuses at 100 and 1000 ppm. No significant differences were observed in food consumption and weight gain. No treatment-related organ weight or histopathological changes were observed. Fetal size (weight and length), placenta weights, and sex ratios were all within normal limits. The sex ratios of the groups were not affected by treatment. No statistically significant incidences of major malformations, minor anomalies, or common variants were observed. It was concluded that the test material did not induce significant maternal toxicity, embryomortality, growth retardation, or teratogenicity at 1000 ppm. [R86] ?The frequency of chromosomal aberrations was evaluated in vitro by exposing rats liver (RL1) cells to 25, 50 or 100 ug of ethyl benzene/ml. No increases in the frequency of chromatid gaps, chromatid breaks or total chromosome aberrations was observed at any dose level. Ethyl benzene did not induce chromosome damage in this assay. [R87] ?The mutagenicity of ethyl benzene was evaluated in E. coli tester strains WP2 and WP2uvrA and in Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 (Ames test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on the results of preliminary bacterial toxicity determinations, ethyl benzene, in DMSO, was tested for mutagenicity at concentrations of 0.2, 2.0, 20.0, 200.0, and 2000.0 ug/plate using the direct plate incorporation method. Ethyl benzene did not cause a positive response in any of the tester strains with or without metabolic activation. [R87] ?The ability of ethyl benzene to induce conversion of differentially inactive alleles to wild-type alleles in Saccharomyces cervisiae was examined in the mitotic gene conversion assay. The cultures were dosed with solutions of 20 ul (in the absence of added metabolic action provided by Aroclor-induced rat liver S9 fraction) or 25 ul (with S9) of 1, 10, 50, 100 or 500 mg ethyl benzene/ml. Ethyl benzene did not produce an increase mitotic gene conversion, either with or without added metabolic activation, and was not considered to be mutagenic in the assay. [R87] POPL: *IN PERSONS WITH IMPAIRED PULMONARY FUNCTION, ESP THOSE WITH OBSTRUCTIVE AIRWAY DISEASES, BREATHING ETHYL BENZENE MIGHT CAUSE EXACERBATION OF SYMPTOMS DUE TO ITS IRRITANT PROPERTIES OR PSYCHIC REFLEX BRONCHOSPASM. [R53, 1981.] *PERSONS WITH ... EXISTING SKIN DISORDERS MAY BE MORE SUSCEPTIBLE TO EFFECTS. ... [R53, 1981.] *... PERSONS WITH LIVER, KIDNEY, NERVOUS SYSTEM, BLOOD AND HEMOPOIETIC-ORGAN DISORDERS. ... WOMEN WITH OVULATION AND MENSTRUAL CYCLE DISORDERS. ... [R10] ADE: *ABSORPTION IS CHIEFLY BY INHALATION. A SMALL PROPORTION ... THAT GETS INTO THE BLOOD STREAM IS EXHALED UNCHANGED, BUT MOST OF IT /70%/ IS FOUND IN THE URINE AS METABOLITES BECAUSE OF OXIDATION OF THE SIDE CHAIN. [R29, 1232] *IT IS ABSORBED ... THROUGH SKIN AT LOW RATE. ... HAS BEEN DETECTED IN SUBCUTANEOUS ADIPOSE TISSUE SAMPLES OF WORKERS 3 DAYS AFTER LOW TO HIGH EXPOSURE TO STYRENE AND RELATED RUBBER MFR COMPONENTS. ... HAS BEEN DETECTED IN CORD BLOOD SAMPLES, INDICATING ... TRANSPORT THROUGH PLACENTA. [R1, 1343] *Traces of ethylbenzene have been detected in exhaled air. It also occurs in the gas phase of smoke condensate and has been detected at 3.1 to 4.5 ppb in urban air. [R1, 1342] *THREE LAB TECHNICIANS EXPOSED TO 42 PPM AND 1 TO 34 PPM HAD AVG STEADY STATE BLOOD LEVELS OF 0.72 + OR - 0.11 MG/L. 30 MIN AFTER EXPOSURE CONCN HAD DROPPED TO APPROX 0.5% OF ORIGINAL VALUES. [R88] *After exposure to 112-156 mg/l (aq) the skin absorption rate in humans (n= 14) was 0.11 to 0.21 mg/sq m/hr. [R89] *When administered sc to 40 rats (2.5 ml, 1:1 v/v), ethylbenzene was detected in the blood within 2 hours, and the levels of ethylbenzene (10-15 ppm in blood) were maintained for at least 16 hours. [R90] *After exposure of rats to atmospheres of 50, 300, or 600 ppm ethylbenzene 6 hr/day, 5 days/wk, for maximum of 16 wk, the concn of ethylbenzene in perirenal fat and the urinary excretion of 1-phenylethanol, omega-hydroxyacetophenone, mandelic acid, phenylglyoxylic acid, hippuric acid, and phenaceturic acid were measured at the 2nd, 5th, and 9th weeks. Excretion of metabolites into urine increased in a dose-related manner, but less than linearly. The level of exposure, but not the duration of exposure, markedly affected the pattern of the metabolites in the urine. The concn of ethylbenzene in perirenal fat was low at 50 ppm, high at 300 ppm and higher still at 600 ppm, but not in proportion to the increased dose. [R91] *Percutaneous absorption of benzene, toluene, ethylbenzene, and aniline was investigated in male HRS/J hairless mice. Stainless steel skin depots containing 100 to 150 mg of solid sorbent were fixed to the backs of anesthetized mice and charged with about 5 ul of (14)C tagged test solution. Expired air samples were obtained until 4 hours after exposure, when mice were killed and samples for radioactivity were obtained from the skin depot, the skin under the depot, a wiping of the skin under the depot, the carcass, feces, urine, and cage washings. Physical constants were determined for each test compound, including octanol/water partition coefficient, solubility, vapor pressure, melting and boiling points, and absorption and evaporation rates. Solvent recovery exceeded 90% in all mice with highest recovery in the skin depot. Average administered doses were 3.94 mg benzene, of which 0.99% was absorbed; 3.89 mg toluene (2.31% absorbed), 4.10 mg ethylbenzene (3.61% absorbed), and 4.68 mg aniline (4.76% absorbed). Excretion rate in expired air was fastest during the first 15 minutes of exposure except in mice treated with toluene or ethylbenzene, which demonstrated maximal excretion rate during the second 15 minutes after exposure. A two compartment model was suggested by the initial rapid and subsequent gradual decay of expired breath excretion. Vapor pressure and boiling point were significantly correlated with the applied radioactive dose absorbed. Absorption rates were found to be 56, 49, 37, and 2.3 ug per square centimeter per minute for benzene, toluene, ethylbenzene, and aniline, respectively. [R92] METB: *ETHYL BENZENE IN MAN IS METABOLIZED 64% TO MANDELIC AND 25% TO PHENYLGLYOXYLIC ACID AND EXCRETED INTO URINE. [R93] *THE OXIDATION OF ETHYLBENZENE TO METHYLPHENYLCARBINOL IN ANIMALS ... WAS CONFIRMED ... WITH ADDITIONAL FINDING THAT BOTH ISOMERS OF METHYL PHENYL CARBINOL (THE + AND - FORMS) IN EQUAL AMT ARE RESULT OF ITS BIOLOGICAL HYDROXYLATION. [R68, 91] *In the rabbit, it is metabolized to a number of oxidation products and subsequently excreted. The major urinary metabolite is hippuric acid. The oxidation products are benzoic acid, phenylacetic acid, and mandelic acid, excreted as the glycine conjugate, and also methylphenylcarbinol, 1-phenylethanol, excreted as the glucuronide. [R1, 1343] *FROM A DOSE OF 100 MG/KG ADMIN ORALLY TO RATS ... THE URINARY METABOLITES, P-ETHYLPHENOL, ABOUT 0.3%, AND SMALLER QUANTITIES OF 1- and 2-PHENYLETHANOL /WERE IDENTIFIED/. [R94] *URINARY SULFATE RATIO DECREASES ARE NORMALLY A ROUGH EST OF DOSE-RELATED ALKYLBENZENE HYDROXYLATION DUE MAINLY TO SIDE CHAIN OXIDATION. ... THIS ... DOES NOT HOLD WITH DOSE-ACTION RELATIONSHIP FOR ETHYLBENZENE. ... AT HIGH DOSES, RING HYDROXYLATION INCREASES, ALTERING SULFATE RATIO. [R94] *PRODUCTS OF RING HYDROXYLATION ... DETECTED FOR 1ST TIME IN RABBIT URINE. ... IDENTIFICATION OF M- AND P-HYDROXYACETOPHENONE AND ... ACETOPHENONE REVEALS THAT FURTHER OXIDATION IN SIDE-CHAIN OF ACETOPHENONE TO PHENACYL ALCOHOL (AND THEN TO BENZOIC ACID) IS NOT ONLY PATHWAY. ... HOWEVER, RING-HYDROXYLATED PRODUCTS ARE ONLY MINOR ONES. [R95] *SINCE ... (1+) and (-1)METHYLPHENYL CARBINOL YIELDED (-1)MANDELIC ACID /IN RATS/, AS DID ACETOPHENONE AND OMEGA-HYDROXYACETOPHENONE, THE STEREOSELECTIVE STEP MUST OCCUR DURING OXIDATION AND/OR REDUCTION OF LATTER ... EITHER PATHWAY IS POSSIBLE, FOR ... PHENYLGLYOXAL AND ... PHENYLETHYLENE GLYCOL ... YIELDED (-)MANDELIC ACID STEREOSELECTIVELY. [R96] *BENZOYLFORMIC ACID WAS BY-PRODUCT IN ALL ... EXPT /IN WHICH RATS WERE FED POSSIBLE INTERMEDIATES/. HOWEVER, WHEN THIS CMPD WAS FED, NO MANDELIC ACID WAS FORMED, AND NEITHER WAS (-1)MANDELIC ACID CONVERTED INTO BENZOYLFORMIC ACID. [R96] *FEMALE ASSISTANTS USING MIXTURE OF XYLENES AND ETHYLBENZENE AS SOLVENT IN HISTOLOGY LAB WERE EXAM. AVG AIR CONCN OF (M + P)-XYLENE AND ETHYLBENZENE WAS BETWEEN 56-68 and 34-41 PPM. APPROX 1.1 TO 1.4% OF RETAINED ETHYLBENZENE WAS METABOLIZED TO 2-ETHYL-PHENOL. [R97] *IN 3 LAB TECHNICIANS OCCUPATIONALLY EXPOSED TO ETHYLBENZENE, THE URINARY METABOLITES WERE AMYGDALIC ACID, PHENYLGLYOXYLIC ACID AND 2-ETHYLPHENOL; WITHIN 24 HR MORE THAN 90% OF METABOLITES HAD BEEN EXCRETED. [R98] *After ip administration of /4.45 g/ ethylbenzene /to rabbits/ ... o-, p-, and m-hydroxyacetophenone were identified in urine. The above hydroxyacetophenones represented 0.11, 0.13, and 0.03% of the dose ... respectively. [R99] *WHEN ABSORBED THROUGH SKIN, MANDELIC ACID WAS EXCRETED AT 4.6%, WHEREAS AFTER LUNG ABSORPTION MAJORITY OF ETHYLBENZENE WAS CONVERTED TO MANDELIC ACID AND CONJUGATED WITH GLYCINE. [R1, 1343] *After 2 volunteers were exposed to 65 ppm ethylbenzene for 3 hr, the metabolites of ethylbenzene in their urine, mandelic acid, hippuric acid (HA), and phenylglyoxylic (PhGA) were analyzed. The metabolites were excreted in the urine in the order mandelic acid > hippuric acid > phenylglyoxylic. The highest value of excretion was observed 6-10 hr after the beginning of exposure. Mandelic acid/phenylglyoxylic and hippuric/phenylglyoxylic mol ratios of total excretion in urine were 3.5 and 2.6 respectively. [R100] *The purpose of this study was to clarify whether the blood concentration of inhaled toluene, ethylbenzene, m-xylene, or mesitylene can change after the concomitant pulmonary absorption of ethyl acetate. (Adult female Sprague-Dawley rats were exposed in a 20 liter glass chamber under dynamic conditions for 2 hours to various concentrations of the aromatics without or in combination with different concentrations of ethyl acetate (0, 1000, or 4000 ppm) in air. Concentration ranges were as follows: toluene, 140-690 ppm; ethylbenzene, 120-650 ppm; m-xylene, 100-560 ppm; mesitylene, 120-720 ppm; and ethyl acetate, 1000 or 4000 ppm. The coexposures with ethyl acetate lowered the blood concentrations of other inhaled aromatics. This reduction was statistically significant following a 2 hour exposure to 230 ppm toluene in combination with 1000 ppm ethyl acetate, 650 ppm ethylbenzene with 1000 ppm ethyl acetate, and 100 ppm m-xylene with 4000 ppm ethyl acetate.) Similarly a significant reduction of the blood level of the aromatics by ethyl acetate coinhalation was also observed at higher exposure concentrations with toluene and m-xylene. A metabolic interaction such as enhanced disposition of the aromatics, may be responsible for these effects. However, it is possible that the solubility of the solvents could be altered by the presence of ethyl acetate. It was concluded that coexposures to concentrations in the order of the threshold limit values (100 ppm for these solvents) with 400 ppm ethyl acetate should not be followed by a dangerous change of the blood levels of the aromatics. [R101] *Stereochemical considerations in the metabolism of ethylbenzene and styrene were investigated. Three alternative methods used to determine the enantiomeric composition of mandelic-acid in urine arising from exposure to styrene or ethylbenzene were described. Of the methods described, the direct gas chromatographic resolution of the enantiomers on a chiral stationary phase was the best approach. It was a simple analytical technique which avoids complex derivatization. An additional advantage was that it may be used as a gas liquid chromatography/mass spectrometry method and thus has advantages of sensitivity and specificity. F-19 nuclear magnetic resonance proved a useful alternative technique and was invaluable if standards of the pure isomers were not available. The major advantage of the nuclear magnetic resonance approach was that absolute configuration of the compound could be elucidated. (In experimental studies, rats were administered ethylbenzene or styrene at 100 mg/kg by the stomach tube; urine was collected over 96 hours. Male volunteers were exposed to ethylbenzene vapor in an exposure chamber at 435 mg/cu m for 4 hours; urine samples were collected before, during and after exposure. The results indicate that whereas only the R-enantiomer of mardelic acid was excreted after ethylbenzene exposure, the mandelic acid from styrene was essentially racemic. In three workers exposed occupationally to styrene, R/S ratios of 1.16, 1.27 and 1.14 were found. A synthetic R/S mixture of mandelic acid has a R/S ratio of 1.03.) [R102] *The principal metabolites of ethyl benzene in the rabbit are hippuric acid and methylphenylcarbinyl glucosiduronic acid (the glucuronide of methylphenylcarbinol), which were excreted in roughly the same amounts and accounts for 60-70% of the administered dose. Minor metabolites were pharmaceutic acid (10-20%) and mandelic acid (2%). [R77, 1991.583] ACTN: *The effect of styrene, toluene, ethylbenzene, alpha-methylstyrene, and butylbenzene on oxidative phosphorylation was studied using rat liver mitochondrial preparations. Rat liver mitochondria were prepared from male white Wistar rats and assessed for respiration rate, oxygen uptake, glutamate oxidation, succinate oxidation, ATPase activity, and proton permeability in the presence and absence of the alkyl benzene derivatives. Inclusion of the alkyl benzene derivatives in the incubation medium produced an initial acceleration of oxygen consumption followed by an inhibition of glutamate oxidation, and the stimulatory effect paralleled the aliphatic chain length. Glutamate oxidation was also inhibited by styrene, ethylbenzene, and alpha-methylstyrene but not by butylbenzene or toluene in 2,4-dinitrophenol uncoupled mitochondria. Styrene and the aliphatic benzene derivative stimulated succinate oxidation in rat liver mitochondria without effect on 2,4-dinitrophenol stimulated succinate oxidation. Similar stimulatory effects on ATPase activity were observed with maximal stimulation occurring at the same relative concentrations producing maximal succinate oxidation. ATPase stimulation required magnesium, was oligomycin sensitive, and showed an inverse relation to the hydrophobicity of the compounds tested. The inclusion of styrene in the incubation medium markedly increased the rate of passive entry of protons into rat liver mitochondria in a manner comparable to 2,4-dinitrophenol. It was concluded that styrene and other monosubstituted benzene derivatives act as mitochondrial uncoupling agents. [R103] *Effect of monocyclic aromatic hydrocarbons, their metabolites, and their structure on brain dopamine was studied. Adult male New Zealand rabbits were exposed to 750 ppm toluene, styrene, ethylbenzene, vinyltoluene, 7-methylstyrene, xylenes, and fresh air. Six groups of eight rabbits received 4 mM/kg ip for 3 days of hippuric acid, mandelic acid, methylhippuric acid, phenylglyoxylic acid, or 7-methylmandelic acid. Animals were killed 12 hours after inhalation exposure or 24 hours after the last dose of acid. The hypothalamus, striatum, hippocampus, tuberoinfundibular area, and part of the brain cortex were treated with 0.2 molar perchloric acid, homogenized, desorbed on alumina, and centrifuged. Supernatant was filtered and used to measure homovanillic acid. Styrene induced a marked dopamine depletion and a significant increase in homovanillic acid concentration. Ethylbenzene and vinyltoluene produced a smaller, but statistically significant effect. Toluene, xylenes, and 7-methylstyrene were ineffective. Phenylglyoxylic acid caused a decrease in dopamine levels and a consistent rise in homovanillic acid in striatal and tuberoinfundibular regions. Mandelic acid elicited the same effect, but to a lesser degree. 7-Methylmandelic, methylhippuric, and hippuric acids evoked no response. Neither solvents nor their metabolites affected norepinephrine contents of brain areas in which this neurotransmitter reaches high concentrations. It was concluded that the results indicate that the changes in brain dopamine depend on metabolic interferences of some metabolites of aromatic solvents with dopamine catabolism. Only metabolites whose side chain may be transformed into a alpha-keto acid caused dopamine depletion. [R104] *The effect of organic solvents on the CNS was discussed. The similarity of effects of different solvents is believed to be due to the formation of tetrahydroisoquinolines by nonenzymatic condensation of dopamine with metabolites of organic solvents having a reactive carbonyl group. The suspected metabolites are phenylglyoxylic- acid that is formed by metabolism of ethylbenzene, styrene, vinyltoluene; trichloroacetaldehyde, which derives from trichloroethylene, tetrachloroethylene; and trichloroethane; glyoxylic acid that is synthesized from ethyleneglycol and ethyleneglycolmonomethyl ether; formaldehyde that is metabolized from methanol; and acetaldehyde that is transformed from ethanol. The tuberoinfundibular dopaminergic system may represent a target for metabolites dissolved in the blood stream. The suggested mechanism implies a selective vulnerability of pituitary functions. The impairment of tuberoinfundibular activity may explain most of the behavioral changes observed with styrene and perhaps with other similar solvents. It appears that the majority of pathways that are affected in the hypothalamic control of gonadotropins in primates are adrenergic and dopaminergic. Occupational exposure to neurotoxins may cause repeated reversible CNS effects which are difficult to distinguish from the chronic effects. In workers exposed to styrene a relationship between recent exposure and measurable effects on CNS has been observed and prolonged exposure has failed to induce tolerance. It was concluded that although no excessive risk for Alzheimer disease and presenile dementia has been found, there is no indication that exposure to solvents does not cause irreversible or slowly reversible cognitive or neuropsychological impairment. [R105] *Efforts were made to clarify the molecular basis of styrene toxicity on the dopaminergic systems and to evaluate whether the same mechanism was common to other solvents. Groups of male New Zealand rabbits were exposed to 750 ppm toluene, xylene, styrene, ethylbenzene, vinyltoluene, 7-methyl-styrene, or fresh air (control group). A significant depletion in both striatal and tubero infundibular dopamine was caused styrene, ethylbenzene, and vinyltoluene. Methylation of the aromatic ring of styrene did not change its activity, whereas methylation of the side chain drastically reduced its effect on dopamine. Treatments carried out with the main metabolites of aromatic solvents indicated that acidic metabolites of some solvents cause striatal and tubero infundibular dopamine depletion. Present data suggested a chemical reaction between dopamine and some acidic metabolites. The active metabolites have an alpha-keto acid as the side chain or as a part of their molecule. These keto acids condense nonenzymatically with dopamine in both experimental models and in occupational exposed workers as evidenced by the direct measurements of dopamine in the brain. According to the authors, such a mechanism may account for neurobehavioral effects resulting from solvent exposure such as mood changes, or impaired attention spans and decreasing psychomotor performance factors. [R106] INTC: *IN LAB ASSISTANTS USING XYLENES AND ETHYLBENZENE, 2,4-DIMETHYLPHENOL, METAB OF M-XYLENE COULD NOT BE DETECTED. COMPETITIVE REACTION BETWEEN XYLENES AND ETHYLBENZENE PREVENTED M-XYLENE FROM OXIDATION. ... [R97] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethylbenzene's production and use as an intermediate for the production of styrene, its presence in automotive and aviation fuels, and its presence in crude oil may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 9.6 mm Hg at 25 deg C indicates ethylbenzene will exist solely as a vapor in the ambient atmosphere. Vapor-phase ethylbenzene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 55 hr. If released to soil, ethylbenzene is expected to have moderate mobility based upon an estimated Koc of 520. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 7.88X10-3 atm-cu m/mole. Ethylbenzene may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation in soil takes place via nitrate-reducing processes. If released into water, ethylbenzene may adsorb to suspended solids and sediment in water based upon the estimated Koc. Biodegradation in a gasoline contaminated aquifer ranged from 10-16 days under aerobic conditions. Ethylbenzene was degraded in 8 days in groundwater and 10 days in seawater as a component of gas oil. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.1 and 99 hrs, respectively. Measured BCFs of 0.67 to 15 suggest the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to ethylbenzene may occur through inhalation at municipal waste composting facilities and via inhalation and dermal contact with this compound at workplaces where ethylbenzene is produced or used. The general population may be exposed to ethylbenzene via inhalation of ambient air, drinking and eating contaminated foods and water, and by handling gasoline. Ethylbenzene is likely to be detected in groundwater. (SRC) NATS: *Ethylbenzene is a product of biomass combustion(1), and a component of crude oil(2). [R107] ARTS: *Ethylbenzene is present at 0.02 wt% in coke-oven tars. [R108] *Ethylbenzene's production and use as an intermediate for the manufacture of styrene and use as a resin solvent(1), intermediate for the production of diethylbenzene and acetophenone(2), and its use as a component of automotive and aviation fuels(3) may result in its release to the environment through various waste streams. [R109] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from a structure estimation method(2), indicates that ethylbenzene is expected to have moderate mobility in soil(SRC). Volatilization of ethylbenzene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 7.88X10-3 atm-cu m/mole(3). The potential for volatilization of ethylbenzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 9.6 mm Hg(4). Ethylbenzene was completely degraded in microcosms inoculated with the sediment material from a refinery pond or activated sludge from the refinery treatment facility under nitrate-reducing conditions(5). At Sleeping Bear Dunes National Lakeshore in Michigan, ethylbenzene was degraded at slow rates via anaerobic degradation under ambient subsurface conditions using ferric iron, sulfate and/or carbon dioxide as the terminal electron acceptors(6). [R110] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 520(SRC), determined from an estimation method(2), indicates that ethylbenzene may adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 7.88X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.1 and 99 hr, respectively(SRC). According to a classification scheme(5), an experimental log BCF of 1.19(7), which corresponds to a BCF of 15, suggests the potential for bioconcentration in aquatic organisms is low. In a shallow coastal plain aquifer contaminated with gasoline and diesel fuel in rural Sampson County in North Carolina, ethylbenzene was degraded in aerobic conditions within 10-16 days and in conditions of low initial oxygen, it was rapidly degraded in 21 days until the available oxygen was depleted(8). As a component of gas oil, ethylbenzene is completely degraded in groundwater in 8 days(9) and seawater in 10 days(10). In a mesocosm experiment using simulated Narragansett Bay conditions, complete biodegradation occurred in approximately 2 days after a 2 week lag in spring and a 2 day lag in summer(11). [R111] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethylbenzene, which has a vapor pressure of 9.6 mm Hg at 25 deg C(2), is expected to exist solely as a vapor. Vapor-phase ethylbenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is 55 hr(SRC), calculated from its rate constant of 7.1X10-12 cu cm/molecule-sec at 25 deg C(3). [R112] BIOD: *After a period of inocula adaptation, ethylbenzene is biodegraded fairly rapidly by sewage or activated sludge inoculua(1-3,9). As a component of gas oil, it is completely degraded in groundwater in 8 days(4) and seawater in 10 days(5). In a mesocosm experiment using simulated Narragansett Bay conditions, complete biodegradation occurred in approximately 2 days after a 2 week lag in spring and a 2 day lag in summer(6). Part of the attenuation in concn from a leaky gasoline storage tank in the chalk aquifer in England has been attributed to biodegradation(7). No degradation was observed in an anaerobic reactor even after 110 days acclimation(8) or at low concentrations in a batch reactor in 11 weeks under denitrifying conditions(10). Percent removal in an anaerobic, continuous-flow, laboratory bioflim column was 7% after a 2 day detention time(11); 99% removal was observed in a similar aerobic column following a 20 min detention time(11). [R113] *AEROBIC: A study was conducted using underground storage tanks containing gasoline and diesel fuel that contaminated a shallow coastal plain aquifer in rural Sampson County in North Carolina. Ethylbenzene was degraded in aerobic conditions within 10-16 days and in conditions of low initial oxygen, it was rapidly degraded in 21 days until the available oxygen was depleted(1). A combined culture experiment of Mycobacterium vaccae and Rhodococcus sp. strain R-22 showed M. vaccae alone and M. vaccae and R-22 together can oxidize ethylbenzene to 4-ethylphenol which is then degraded to 50 ppm within 72 hr(2). [R114] *ANAEROBIC: Anaerobic ethylbenzene transformation in Seal Beach Naval Weapons Station sediments in Southern California appeared to be strictly associated with nitrate-reducing processes(1). Ethylbenzene was completely degraded in microcosms inoculated with the sediment material from a refinery pond or activated sludge from the refinery treatment facility under nitrate-reducing conditions(2). At Sleeping Bear Dunes National Lakeshore in Michigan, ethylbenzene was degraded at slow rates via anaerobic degradation under ambient subsurface conditions using ferric iron, sulfate and/or carbon dioxide as the terminal electron acceptors(3). [R115] ABIO: *The rate constant for the vapor-phase reaction of ethylbenzene with photochemically-produced hydroxyl radicals is 7.1X10-12 cu cm/molecule-sec at 298 K(1) which corresponds to an atmospheric half-life of about 55 hr at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm. Ethylbenzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). Ethylbenzene photolysis occurs via photooxidation hydrogen abstraction from the alkyl group by photooxydatively formed hydroxyl radical which results in the formation of acetophenone, and eventually benzaldehyde with 2-butanedial, 4-oxo-2-hexenal, and 2-ethyl-2-butenedial being suggested as further end products(3). [R116] BIOC: *Experimental data on the bioconcentration of ethylbenzene include a log BCF of 1.9 in goldfish(2) and a log BCF of 0.67 for clams exposed to the water-soluble fraction of crude oil(1). Experimentally, a log BCF of 1.19 has also been reported(4) which corresponds to a BCF of 15. According to a classification scheme(3), these BCFs suggest the potential for bioconcentration in aquatic organisms is low. [R117] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for ethylbenzene can be estimated to be 520(SRC). According to a classification scheme(2), this estimated Koc value suggests that ethylbenzene is expected to have low mobility in soil. [R118] VWS: *The Henry's Law constant for ethylbenzene is 7.88X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that ethylbenzene will volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.1 hr(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 99 hr(SRC). Ethylbenzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of ethylbenzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 9.6 mm Hg(3). [R119] WATC: *DRINKING WATER: In surveys of representative US municipal water supplies, ethylbenzene has been detected in most cases(1,2,4-8,10). Values for 3 New Orleans finished drinking waters ranged 1.6 to 2.3 ppb(6). Chicago Central Water Works on Lake Michigan measured 4 ppb(8). It has been found in the water supply for Evansville, IN on the Ohio River(7). 6 of 10 US cities were found to be positive(1,4). One US city had 1 of 4 samples pos with a 1 ppb avg, while another reported no positive samples(5). Tap water from bank infiltrated Rhine River water in the Netherlands measured 30 ppb in one study(3). Zurich, Switzerland tap water - detected not quantified(9). 1982 US groundwater supply survey, random samples of finished water supplies using groundwater as a source, 466 random samples, 0.6%, pos (0.5 ppb detection limit), 0.8 ppb median, 1.1 ppb max(10). [R120] *GROUNDWATER: A well in Ames, IA measured 15 ppb 50 yr after tar residues were buried at a nearby coal gas plant(5). Concns of 82-400 ppb were detected in two aquifers near the Hoe Creek underground coal gasification site in Wyoming, 15 mo after gasification was complete(2). In a US survey, 1970-76, it was detected but not quantified in well waters(1). In Jackson Township, NJ, drinking water wells measured 2000 ppb(4). Chalk aquifer in East Anglia, England - 210 m from petroleum storage - 0.15 ppb, 10 m distance - 1110 ppb, and 100-200 m - < 250 ppb(3). [R121] *SURFACE WATER: Ethylbenzene has been detected but not quantified in a 1970-76 US survey(1,4). 14 heavily industrialized US river basins, 5 of 204 sites pos - 1-4 ppb; Chicago area and Illinois River Basin, 5 of 31 sites pos - 1-4 ppb(6). Two representative US cities, city A - 41% of 28 samples pos, 5.0 ppb avg, city B - 40% of 48 samples pos 3.2 ppb avg(2). Lower Tennessee River near Calvert City, KY reported 4.0 ppb(7). Lake Michigan, Chicago Sanitary and Ship Channel measured 1-2 ppb(3). River Glatt, Switzerland -detected, not quantified(5). USEPA STORET database, 1,101 data points, 10% pos, < 5.0 ppb median(8). [R122] *SEAWATER: Ethylbenzene concns were found to be 30-50 ng/l in an estuary in Brazos, US; between < 10-46.3 ng/l in UK; and 36.9 ng/l in Belgium(1). Ethylbenzene has been found in concns of 4.5-30 ng/l in Vineyard Sound; 0.4-4.5 ng/l in coastal and shelf sea water in the Gulf of Mexico; 5.5-22 ng/l in the coastal waters of Spain; 4.3-380 ng/l in Campeche Shelf; < 10 ng/l in shelf and bay waters in UK; and 9.4-18.7 ng/l in Belgian Continental Shelf(1). Ethylbenzene mean concn of 21.94 ng/l was found in the South Northern sea up to 60 km offshore in the Scheldt Estuary(2). In the coastal waters off the western Gulf of Mexico at the mouth of the Brazos River, TX, ethylbenzene concns range between 0.004-0.5 ug/l(3). In the Gulf of Mexico in unpolluted areas ethylbenzene concn is 0.4 to 5 ppb(4,6), while an area of anthropogenic influence ranged from 5 to 15 ppb(6). Cape Cod, MA measured ethylbenzene at 22 ppb(5,7) with 11 ppb being avg(5). In the coastal waters of the Dutch Northern Sea, 108 samples ranged from not detected to 20 parts per trillion and averaged 4 parts per trillion(8). [R123] *RAIN WATER: West Los Angeles, CA - 9 parts/trillion(1). Concn (parts/trillion) dissolved in rain, Portland, OR, Feb-April 1984, 7 rain events, 100% pos, 6.9-72, 34 avg(2). [R124] EFFL: *Industries with mean raw wastewater concentrations > 2000 ppb: gum and wood chemicals (11,000 ppb), pharmaceutical manufacturing (10,000 ppb), paint and ink formulation, and auto and other laundries(1). Effluents from representative water treatment plants in Southern California were variable < 10 ppb at San Diego City to 130 ppb at Los Angeles Co (both measurements following primary treatment)(2); < 10 ppb detected following secondary treatment(2). In a US city survey, 17% of 6 samples were positive, 6.0 ppb avg(3), Lake Michigan, North Side sewage treatment plant - 1 ppb(4). USEPA STORET database, 1,368 data points, 7.4% pos, < 3.0 ppb median(5). MN municipal solid waste landfills, leachates, 6 sites, 100% pos, 12-820 ppb, contaminated groundwater (by inorganic indices), 13 sites, 61.5% pos, 1.2-590 ppb, other groundwater (apparently not contaminated as indicated by inorganic indices), 7 sites, 14.3% pos, 9.4 ppb avg(6). 18.0 and 12.28 kilotons of ethylbenzene was emitted as part of gasoline exhaust emissions from motor vehicles in 1987 and 1990, respectively in UK(7). [R125] SEDS: *SOIL: Ethylbenzene concns found in three leachate samples taken from German hazardous waste sites where leachate samples A and B were both anaerobic and alkaline and leachate sample C was aerobic and slightly acidic, were 10, 3200, and 20,000 ug/l, respectively(1). SEDIMENTS: Sediments from the lower Tennessee River below Calvert City, KY measured 4.0 ppb for ethylbenzene(2). According to the USEPA STORET database, 350 data points were tested for ethylbenzene with 11% pos, 5.0 ppm median, dry weight(3). [R126] ATMC: *SOURCE DOMINATED: The ethylbenzene concn measured 0.5-2.6 ppb in the Allegheny Mt. Tunnel, with concns directly corresponding to the number of vehicles passing through the tunnel(1). Emissions testing from motor vehicle traffic in a Los Angeles roadway tunnel showed concns of 143 mg/l of ethylbenzene(2). The Maastunnel in the Netherlands measured an avg ethylbenzene concn of 6 ppb(3). Concn (ppb) a rural motorway in UK, May-Aug 1983, 184 samples, not detected-1.14, 0.17 avg(4); Aug 1982, not detected-0.70, 0.25 avg(5). Ethylbenzene ambient air concns at 2 landfill sites in Ireland were found to have a min and max of 0.03 and 5.9, median of 0.8 ug/cu m (site with no leachate collection), and 0.03 and 47.6, median of 5.3 ug/cu m (site with leachate collection), respectively(6). Houston, TX 21 individuals in urban sites reported a range of 2.5 to 154.2 ppb(8). A natural gas facility in Rio Blanco County, CO measured 3.6 ppb, and a Texaco refinery in Tulsa, OK ranged from 4.7 to 7.9 ppb(7). England - car park - 115 ppb, motorway - 92 ppb(9), while 6 sites at Gatwick airport ranged from 0.46 to 1.8 ppb, 1.4 ppb avg(10). 181 samples of US source dominated areas - 0.63 ppb avg(11). [R127] *URBAN/SUBURBAN: Values for major western US cities ranged from 0.1 to 27.7 ppb(1,5,6,7,13), with the avg being 2.68 ppb(SRC). Representative centers in New Jersey had a range of 0.17 to 0.33 ppb avg, 107 of 110 samples pos(4). Ethylbenzene was detected but not quantified in another New Jersey study(11). It has been detected in 6 USSR cities, including Lenningrad as well as New York and Paris(8-10). The Hague, Netherlands - 5 ppb(2); Sidney Australia - 1.3 ppb(12); Japan - 0.2 ppb and Frankfurt-am-Main, Germany - 1 ppb(14). 3 sites in England away from traffic - 16.1 to 18.8 parts/trillion avg, 2 sites with heavy traffic 28.7 to 33.9 parts/trillion avg(3). 8.7 ppb measured in the atmosphere of Zurich, Switzerland(17). 669 samples from the US had a median concn of 1.2 ppb(15). 36 Chicago metropolitan area homes tested - 36% in outdoor air(16). Gas-phase concn (ng/cu m) during 7 rain events, Portland, OR, Feb-Apri 1984, 7 rain events 100% pos, 780-2800, 1300 avg(20). Concn (ppb), Exhibition Road, London, May-Aug 1983, 267 samples, 100% pos, 0.05-2.17, 0.78 avg(18); June-July 1982, 256 samples, not detected-3.3, 0.88 avg(19). US 1979-1984, 15 cities, 1-2 weeks of sampling/site, overall range, not detected-31.5 ppb; range of avg, 0.6-4-6 ppb, avg of avg, 1.9 ppb(21). Ethylbenzene outdoor air concns in Rio de Janeiro, Brazil ranged from 3.1-7.4 ug/cu m(22). [R128] *RURAL/REMOTE: Concentration in air sampls from rural and remote areas in the continental US ranged between 0.5 to 2.2 ppb(1,6). Samples from the Jones State Forest north of Houston, TX ranged from 0.8 to 10.4 ppb(3). Air intake in fan rooms of the Allegheny Mt. tunnel measured 0.07 to 0.16 ppb(2). Air samples in England - 11.3 parts/trillion avg(4); the Netherlands - 0.8 ppb avg; and Belgium 0.01 to 15 ppb(5). Concn at rural site in the UK, May-Aug 1983, 204 samples, not detected-0.70, 0.14 ppb avg(7); July 1982, 175 samples, not detected-0.6, 0.12 ppb avg(8). [R129] *RURAL/REMOTE: Between May-Aug 1983, 204 samples of air were tested for ethylbenzene at a rural site in UK and it was found that the sample concn ranged between not detected to 0.70 ppb, with an avg of 0.14 ppb(1). In July 1982, 175 samples from rural UK ranged between not detected to 0.6 ppb, with an avg of 0.12 ppb(2). [R130] *INDOOR: Ethylbenzene indoor air concns in Rio de Janeiro, Brazil ranged from 9.3-13.1 ug/cu m. samples from 36 Chicago metropolitan area homes tested showed a 57% detection frequency in indoor air(2). [R131] FOOD: *Ethylbenzene concns in supermarket eggs packed in polystyrene, fresh unpacked eggs, and fresh eggs packed in polystyrene were found to be 28, 4, and 4 ng/g, respectively(1). Duck meat, duck fat, cantonese style roasted duck, and cantonese style roasted duck gravy had concns of 0.47, 2.55, 4.07, and 12.30 ppb ethylbenzene, respectively(2). Ethylbenzene was detected but not quantified in mountain Beaufort cheese(3). Ethylbenzene was detected in dried legumes such as beans with a 5 ppb avg concn, in split peas at 13 ppb, and in lentils at a 5 ppb concn(4). [R132] PFAC: FISH/SEAFOOD CONCENTRATIONS: *In 1982, bottomfish (sole and flounder species) from Commencement Bay and adjacent waterways in Tacoma, WA were found to have an avg concn of ethylbenzene of 0.01 ppm(1). 5 samples of oysters in Lake Pontchartrain, LA, had an avg concn of 0.8 ppb(2). [R133] MILK: *Ethylbenzene was detected, but not quantified, in 8 of 8 samples of mother's milk from 4 US urban areas(1). [R134] OEVC: *Detected in cigarette smoke(1). [R135] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 80,726 workers (21,785 of these are female) are potentially exposed to ethylbenzene in the US(1). Occupational exposure to ethylbenzene may occur via inhalation at municipal waste composting facilities where the air concn was found to be 78,000-178,000 ug/cu m(2),and through inhalation and dermal contact with this compound at worplaces where ethylbenzene is produced or used(SRC). The general population may be exposed to ethylbenzene via inhalation of ambient air, ingestion of foods and fish, and drinking contaminated water, and dermal contact with this compound and other products such as gasoline which contains ethylbenzene(SRC). [R136] AVDI: *AIR INTAKE: (assume air concn of 0.2-2.7 ppb)(2-6); 17-235 ug; WATER INTAKE: (assume water concn of 0-4 ppb(1)) 0-8 ug; FOOD INTAKE: insufficient data(SRC). [R137] BODY: *Ethylbenzene was detected, not quantified, in 8 of 8 samples of mother's milk from 4 US urban areas(1). 16.5% of 387 expired air samples taken from 54 normal, healthy, urban volunteers were positive for ethylbenzene concn with an avg of 1.8 ng/l expired air(2). Whole blood samples from 250 subjects ranged in ethylbenzene concns from not detected to 59 ppb, with an avg of 1.0 ppb(3). [R138] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *800 ppm [R46, 132] ADI: *Acceptable daily intake: 1.6 mg/day [R139] OSHA: *Permissible Exposure Limit: Table Z-1 8-Hr Time Weighted Avg: 100 ppm (435 mg/cu m). [R140] *Vacated 1989 OSHA PEL TWA 100 ppm (435 mg/cu m); STEL 125 ppm (545 mg/cu m) is still enforced in some states. [R46, 364] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 100 ppm (435 mg/cu m). [R46, 132] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 125 ppm (545 mg/cu m). [R46, 132] TLV: +8 hr Time Weighted Avg (TWA): 100 ppm; 15 min Short Term Exposure Limit (STEL): 125 ppm. [R66, 2002.31] +Biological Exposure Index (BEI): Determinant: mandelic acid in urine; Sampling Time: end of shift at end of workweek; BEI: 1.5 g/g creatinine. The determinant is nonspecific, since it is also observed after exposure to other chemicals. [R66, 2002.90] +Biological Exposure Index (BEI): Determinant: ethyl benzene in end-exhaled air. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. [R66, 2002.90] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R66, 2002.31] OOPL: *Australia: 100 ppm, STEL 125 ppm, substance under review (1990); Federal Republic of Germany: 100 ppm, short-term level 200 ppm, 5 min, 8 times per shift, skin (1990); Sweden: 80 ppm, short-term value 100 ppm, 15 min (1989); United Kingdom: 100 ppm, 10-min STEL 125 ppm (1991). [R77, 1991.584] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethylbenzene is produced, as an intermediate or a final product, by process units covered under this subpart. [R141] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Ethylbenzene is included on this list. [R142] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 700 ug/l [R143] FEDERAL DRINKING WATER GUIDELINES: +EPA 700 ug/l [R143] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 680 ug/l [R143] +(FL) FLORIDA 30 ug/l [R143] +(ME) MAINE 700 ug/l [R143] +(MN) MINNESOTA 700 ug/l [R143] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R144] +Ethylbenzene is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R145] +For the protection of human health from the toxic properties of ethylbenzene ... the ambient water criterion is determined to be 1.4 mg/l. [R146] +The maximum contaminant level (MCL) set forth by the National Revised Primary Drinking Water Regulations for the organic contaminant ethylbenzene in community and non-transient, non-community water systems is 0.7 mg/l. [R147] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R148] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Ethylbenzene is included on this list. [R149] RCRA: *F003; When ethylbenzene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F003), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R150] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *AIR SAMPLES WERE COLLECTED IN TEFLON LOOP (3.0 ML). [R151] *NIOSH Method 1501. Analyte: Ethylbenzene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: less or equal to 0.2 l/min. Sample Size: 10-24 liters. Shipment: no special specifications. Sample Stability: not determined. [R152] ALAB: *EPA Method 624. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the analysis of purgeable organics including ethylbenzene in the municipal and industrial discharges. Under the prescribed conditions, for ethylbenzene the method has a detection limit of 7.2 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R153] *EPA Method 1624. Isotope Dilution Purge-and-Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of volatile organic compounds in municpal and industrial discharges. By adding a known amount of a labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, for both the labeled, and unlabeled ethylbenzene the method has a minimum detection level 10 ug/l.The established acceptance performance criteria at 20 ug/l is 9.6 ug/l for the standard deviation of the recovery, with the average recovery of 15.6 to 28.5 ug/l and the labeled cmpd recovery ranging from below detection to 203%. [R153] *EPA Method 602. Purge-and-Trap Gas Chromatography with photoionization detection for the determination of purgeable aromatics including ethylbenzene in municipal and industrial discharges. Under the prescribed conditionss for ethylbenzene the detection limit is 0.2 ug/l. The method is applicable for use in the concentration range from the method detection limit to times that limit. Precision and method accuracy were found to be directly related to the concentration of the analyte essentially independent of the sample matrix. [R153] *EPA Method 524.2. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the determination of volatile aromatic compounds in water including finished drinking water, raw source water, and drinking water in any treatment stage. For ethylbenzene the method has a detection limit of 0.06 ug/l and a relative standard deviation of 8.6% with a wide bore capillary column, and a method detection limit of 0.03 ug/l and a relative standard deviation of 5.3% with a narrow bore capillary column. [R154] *EPA Method 503.1. Purge-and-Trap Gas Chromatography with a Photoionization Detector. The method is applicable for the determination of volatile aromatic and unsaturated organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For ethylbenzene the method has a detection limit of 0.002 ug/l and a relative standard deviation of 8.5%. Overall precision and method accuracy were found to be directly related to the concentration of the analyte essentially independent of sample matrix. [R155] *EPA Method 502.2: Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For ethylbenzene the method has a detection limit of 0.005 ug/l, a percent recovery of 101%, and a standard deviation of 1.4 using the photoionization detector; and there is no data given for the following: the method detection limit, a percent recovery, or the standard deviation of recovery using the electrolytic conductivity detector. [R156] *NIOSH Method 1501. Determination of Aromatic Hydrocarbons by Gas Chromatography with Flame Ionization Detection. [R157] *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile organics. This method can be used to quantify most volatile organic compounds including ethylbenzene that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R158] *EPA Method 8260. Gas Chromatography/Mass Spectrometry for the determination of volatile organic compounds. This method can be used to quantitate most volatile organic compounds including ethylbenzene that have boiling points below 200 deg C and are insoluble or slightly soluble in water. Under the prescribed conditions for ethylbenzene, the method has a detection limit of 0.06 ug/l, a percent recovery of 99%, and a percent relative standard deviation of 8.6% using a wide bore capillary column; and a detection limit of 0.03 ug/l, a percent recovery of 99%, and a percent relative standard deviation of 5.3% using a narrow bore capillary column. [R158] *OSW Method 8240B. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R159] *OSW Method 5021. Volatile Organic Compounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. [R159] *OSW Method 8020A. Determination of Aromatic Volatile Organics by Gas Chromatography. [R159] *OSW Method 8021A. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. [R159] *OSW Method 8021A. Halogenated and Aromatic Volatiles By Gas chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Technique. [R159] *OSW Method 8240B. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R159] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R159] *OSW Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R159] *OSW Method 5041. Analysis of Sorbent Cartridges From Volatile Organic Sampling Train by using the Wide-Bore Capillary Column Technique. [R159] *OSW Method 5041A. Protocol for Desorption of Sorbent Cartridges from Volatile Organic Sampling Train (VOST): Wide-Bore Capillary GC/MS Technique. [R159] *AOB Method OA-002-1. Volatile Organic Compounds by GC/MS Analysis of Tenax/CMS Cartridge and Summa Canister Samples. [R159] *AOB Method VA-001-1. Volatile Organic Compounds (VOCs) in Air Sampled by Sorbent Tubes and Analyzed by Purge and Trap GC. [R159] *AOB Method VA-003-1. Volatile Organic Compounds (VOCs) in Air by Portable GC/PID. [R159] *AOB Method VA-005-1. Volatile Organic Compounds (VOCs) in Ambient Air by Purge and Trap Gas Chromatography. [R159] *AOB Method VA-006-1. Volatile Organic Compounds (VOCs) in Ambient Air by Direct Portable GC/PID. [R159] *AOB Method VA-008-1. Volatile Organic Compounds (VOCs) in Ambient Air by Portable GC/PID with Direct Sampling via Pump and Sample Loop. [R159] *AOB Method VG-001-1. Volatile Organics in Soil Gas - Adsorbent Tube Method. [R159] *AOB Method VG-006-1. Volatile Organic Compounds (VOCs) in Ambient Air by Purge and Trap GC. [R159] *AOB Method VG-007-1. Halogenated and Aromatic Volatile Organic Compounds (VOCs) in Air and Soil Gas Sampled by Sorbent Tubes and Analyzed by Purge and Trap GC/ELCD/PID. [R159] *AOB Method VG-008-1. Volatile Organic Compounds (VOCs) in Soil Gas sampled by Tenax Tubes and Analyzed by Thermal Desorption GC/PID/ELCD. [R159] *AOB Method VG-010-1. Volatile Organic Compounds (VOCs) in Soil Gas by Direct Portable GC. [R159] *AOB Method VG-011-1. Halogenated and Aromatic Volatile Organic Compounds (VOCs) in Whole Gas Analyzed by Purge and Trap GC/ELCD/PID. [R159] *AOB Method VW-001-1. Volatile Organic Compounds (VOCs) in Water by Purge and Trap GC/PID/ELCD. [R159] *AOB Method VW-002-1. Volatile Organic Compounds (VOCs) in Water by Automated Headspace GC/PID/ELCD. [R159] *AOB Method VW-003-1. Volatile Organic Compounds (VOCs) in Water by Automated Headspace GC/PID/ELCD (Internal Standard). [R159] *AOB Method VW-004-1. Volatile Organic Compounds (VOCs) in Water by Manual Headspace Portable GC/PID. [R159] *AOB Method VW-008-1. Volatile Organic Compounds (VOCs) in Water by Purge and Trap GC. [R159] *AOB Method VW-010-1. Field Screening for Volatile Organic Compounds (VOCs) in Water and Soil by Headspace GC/PID (Photovac 10S10). [R159] *AOB Method VW-014-1. Volatile Organic Compounds (VOCs) in Water by Purge and Trap GC/PID/ELCD. [R159] *AOB Method VS-001-1. Volatile Organic Compounds (VOCs) in Soil by Purge and Trap GC/PID/ELC. [R159] *AOB Method VS-002-1. Volatile Organic Compounds (VOCs) in Soil and Sediment by Automated Headspace GC/PID/ELCD. [R159] *AOB Method VW-010-1. Field Screening for Volatile Organic Compounds (VOCs) in Water and Soil by Headspace GC/PID (Photovac 10S10). [R159] *CLP Method LC_VOA. Analysis of Water for Low concn Volatile Organic Compounds by Gas Chromatography/Mass Spectroscopy. [R159] *CLP Method MC_VOA. Analysis of Volatile Organics in Multi-Concentration Water Samples by Gas Chromatography with a Mass Spectrometer. [R159] *CLP Method MC_VOA. Analysis of Volatile Organics in Low concn Soil Samples by Gas Chromatography with a Mass Spectrometer. [R159] *CLP Method MC_VOA. Analysis of Volatile Organics in Medium concn Soil Samples by Gas Chromatography with a Mass Spectrometer. [R159] *DOE Method OS040. Rapid Determination Of Volatile Organic Contaminants in Water and Soils by Direct Purge Mass Spectrometry. [R159] *DOE Method OS040. Rapid Determination Of Volatile Organic Contaminants in Water and Soils by Direct Purge Mass Spectrometry. [R159] *DOE Method OS060. Immunoassay for Petroleum Fuel Hydrocarbons in Soil. [R159] *EAD Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. [R159] *EAD Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. [R159] *EMSLC Method 502.2. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. [R159] *EMSLC Method 503.1. Volatile Aromatic and Unsaturated Organic Compounds in Water by Purge and Trap Gas Chromatography. [R159] *EMSLC Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. [R159] *EMSLC Method 524.2 Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. [R159] *EMSLC Method 602. Purgeable Aromatics in Wastewater by Gas Chromatography with Photoionization Detection. [R159] *EMSLC Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. [R159] *EMSLC Method 624-S. Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. [R159] *SFSAS Method SFSAS_7. Determination of Purgeable Organics in Sediment. [R159] *AOB Method VS-006-1. Volatile Organic Compounds (VOCs) in Soil and Water by Purge and Trap GC. [R159] *AOB Method VW-011-1. Field Screening for Volatile Organic Compounds (VOCs) in Water and Soil by Purge and Trap GC/PID/ELCD. [R159] *CLP Method OHC. Organics Analysis, Multi-Media, High-Concentration. [R159] *SFSAS Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. [R159] *SFSAS Method SFSAS_5. Analysis of Fish for Volatile Organics by Purge and Trap Analysis. [R159] CLAB: *IN BLOOD BY ULTRAVIOLET-SPECTROPHOTOMETRIC METHOD. [R68, 91] *An automated high performance liquid chromatographic method for the direct determination of urinary concentrations of phenyl glyoxylic acid and mandelic acid, metabolites of styrene or ethylbenzene, is described. The method is simple and specific. Urine can be analyzed without solvent extraction. Analysis can be performed satisfactorily within 15 minutes for samples containing hippuric acid, o-, m- and p-methyl hippuric acids, phenyl glyoxylic acid, and mandelic acid, and within 15 minutes for those containing hippuric acid, phenyl glyoxylic acid and mandelic acid. 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Cincinnati, OH: ACGIH R78: Toxicology and Carcinogenesis Studies of Ethylbenzene in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 466 (1999) NIH Publication No. 99-3956 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R79: Mutti A; Toxicol 49 (1): 77-82 (1988) R80: Pickering QH, Henderson C; J Water Pollut Control Fed 38: 1419 (1966) R81: USEPA; In-depth Studies on Health Environmental Impacts of Selected Water Pollutants (1978) EPA No 68-01-4646 R82: Pickering OH, Henderson C; J Water Pollut Control Fed 38: 1419 (1966) R83: USEPA; Ambient Water Quality Criteria Doc: Ethylbenzene p.3-7 (1980) EPA 440/5-80-048 R84: Geiger D.L., Poirier S.H., Brooke L.T., Call D.J., eds. Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Vol. III. Superior, Wisconsin: University of Wisconsin-Superior, 1986.189 R85: Battelle Pacific Northwest Laboratories; Teratologic Assessment of Ethylbenzene and 2-Ethoxyethanol with Cover Letter Dated 061887, (1981), EPA Document No. 86870000402, Fiche No. OTS0513150 R86: SHELL OIL CO; Teratogenic assessment of ethylbenzene and 2-ethoxyethanol; EPA 88-920002072, 1/01/81, Fiche No. OTS0539167 R87: Shell Oil; In Vitro Genotoxicity Studies with Ethyl Benzene Hydroperoxide (EBHP) and Ethyl Benzene, (1981), EPA Doc. No. 86-870001656, Fiche No. OTS0515732 R88: HAGEMANN J ET AL, KREBSGEFAEHRDUNG ARBEITSPLATZ/ARBEITSMED KOLLOQ, BER JAHRESTAG DTSCH GES ARBEITSMED 19TH: 421 (1979) R89: Dutkiewicz T, Tyras H; Br J Ind Med 24 (4): 330-2 (1967) R90: USEPA; Ambient Water Quality Criteria Doc: Ethylbenzene p.C-6 (1980) EPA 440/5-80-048 R91: Engstroem K et al; Xenobiotica 15 (4): 281-6 (1985) R92: Susten AS et al; J Appl Toxicol 10 (3): 217-25 (1990) R93: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 126 R94: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3304 R95: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. 247 R96: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 505 R97: ANGERER J ET AL; INT ARCH OCCUP ENVIRON HEALTH 43 (2): 145 (1979) R98: HAGEMANN J ET AL; KREBSGEFAEHRDUNG ARBEITSPLATZ/ARBEITSMED KOLLOQ, BER JAHRESTAG DTSCH GES ARBEITSMED, 19TH: 421 (1979) R99: Kiese M, Lenk W; Xenobiotica 4: 337-43 (1974) R100: Yamasaki Y; Okayama Igakkai Zasshi 96 (5/6): 531-5 (1984) R101: Freundt KJ et al; Bull Environ Contam Toxicol 42 (4): 495-8 (1989) R102: Drummond L et al; Xenobiotica 19 (2): 199-207 (1989) R103: Mickiewicz W, Rzeczycki W; Biochem Pharmacol 37 (23): 4439-44 (1988) R104: Romanelli A et al; J Appl Toxicol 6 (6): 431-5 (1986) R105: Mutti A, Franchini I; Br J Ind Med 44 (11): 721-3 (1987) R106: Mutti A et al; Toxicol 49 (1, part 1): 77-82 (1988) R107: (1) Graedel TE; Atmospheric Chemical Compounds. New York NY Academic Press (1986) (2) Nunes P, Benville PE JR; Bull Environ Contam Toxicol 21: 71-24 (1979) R108: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V22 572 (1983) R109: (1) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 643 (1996) (2) Coty RR et al; Ullmann's Encycl Indust Chem. 5th ed. Deerfield Beach, FL: VCH Pub A 10: 35-43 (1985) (3) Clayton GB, Clayton FE; Patty's Industrial Hygiene and Toxicology. 2B: Toxicology. 4th ed. NY, NY: John Wiley and Sons Inc 2B: 1342 (1994) R110: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Sanemasa I et al; Bull Chem Soc Japan 55: 1054-62 (1982) (4) Daubert TE et al; Physical and Thermodynamic Properties of Pure Chemicals. NY, NY: Hemisphere Pub Corp (1989) (5) Ball HA et al; pp. 458-63 in In-Situ Bioreclamation. Hinchee RE, Olfenbuttel RF, eds. Boston, MA: Butterworth-Heinemann (1991) (6) Borden RC et al; Anaerobic biodegradation of BTEX in aquifer material. USEPA/600/S-97/003 pp. 9 (1997) R111: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Sanemasa I et al; Bull Chem Soc Japan 55: 1054-62 (1982) (5) France C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 43 (1995) (7) Park JH, Lee HJ; Chemosphere 26: 1905-16 (1993) (8) Borden RC et al; Water Resour Res 33: 1105-15 (1996) (9) Kappeler T, Wuhrmann K; Water Res 12: 327-33 (1978) (10) Van der Linden AC; Dev Biodegrad Hydrocarbons 1: 165-200 (1978) (11) Wakeham SG et al; Environ Sci Technol 17: 611-7 (1983) R112: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE et al; Physical and Thermodynamic Properties of Pure Chemicals NY, NY: Hemisphere Pub Corp (1989) (3) Atkinson R; J Phys Chem Ref Data Monograph No. 2 p. 48 (1994) R113: (1) Slave T et al; Rev Chim 25: 666-70 (1974) (2) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (3) Malaney GW, McKinney RE; Water Sewage Works 113: 302-9 (1966) (4) Kappeler T, Wuhrmann K; Water Res 12: 327-33 (1978) (5) Van der Linden AC; Dev Biodegrad Hydrocarbons 1: 165-200 (1978) (6) Wakeham SG et al; Environ Sci Technol 17: 611-7 (1983) (7) Tester DJ, Harker RJ; Water Pollut Control 80: 614-31 (1981) (8) Chou WL et al; Biotechnol Bioeng Symp 8: 391-414 (1979) (9) USEPA; Treatability Manual p 1.9.8-1 to 1.9.8-5 USEPA 600/2-82-001a (1981) (10) Bouwer EJ, McCarty PL; Appl Environ Microbiol 45: 1295-99 (1983) (11) Bouwer EJ, McCarthy PL; Ground Water 22: 433-40 (1984) R114: (1) Borden RC et al; Water Resour Res 33: 1105-15 (1996) (2) Fairlee JR et al; J Microbiol 43: 841-6 (1997) R115: (1) Ball HA, Reinhard M; Environ Toxicol Chem 15: 114-22 (1996) (2) Ball HA et al; pp. 458-63 in In-Situ Bioreclamation. Hinchee RE, Olfenbuttel RF, eds. Boston, MA: Butterworth-Heinemann (1991) (3) Borden RC et al; Anaerobic biodegradation of BTEX in aquifer material. USEPA/600/S-97/003 pp. 9 (1997) R116: (1) Atkinson R; J Phys Chem Ref Data Monograph No. 2 p. 48 (1994) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Forstner HJL et al; Environ Sci Technol 31: 1345-58 (1997) R117: (1) Nunes P, Benville PE Jr; Bull Environ Contam Toxicol 21: 719-24 (1979) (2) Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Park JH, Lee HJ; Chemosphere 26: 1905-16 (1993) R118: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R119: (1) Sanemasa I et al; Bull Chem Soc Jpn 55: 1054-62 (1982) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE et al; Physical and Thermodynamic Properties of Pure Chemicals NY, NY: Hemisphere Pub Corp (1989) R120: (1) NAS; The Alkylbenzenes p III-13 Contract 68-01-4655 (1980) (2) Shackelford WM, Keith, LH; Frequency of Organic Compounds in Surface Waters USEPA 600/4-76-062 (1976) (3) Piet GJ, Morra CF; p 31-42 in Artificial Groundwater Recharge; Huisman L, Olsthorn TN, eds (1983) (4) Bedding ND et al; Sci Total Environ 25: 143-67 (1982) (5) Callahan MA et al; p 55-61 in 8th Natl Conf Munic Sludge Manage Proc (1979) (6) Keith, LH et al; p 329-73 in Identification and Analysis of Organic Pollutants in Water. Keith LH ed (1976) (7) Kleopfer RD, Fairless BJ; Environ Sci Technol 6: 1036-7 (1972) (8) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in the Lakes Erie, Michigan, Huron and Superior Basins. Great Lakes Quality Review Board (1978) (9) Santodonato J et al; Investigation of selected potential environmental contaminants: styrene, ethylbenzene and related compounds 261 p USEPA 560/11-80-018 (1980) (10) Cotruvo JA; Sci Technol Environ 47: 7-26 (1985) R121: (1) Shackelford WM, Keith, LH; Frequency of Organic Compounds Identified in Water USEPA 600/4-76-062 (1976) (2) Stuermer DH et al; Environ Sci Technol 16: 582-7 (1982) (3) Tester DH, Harker RJ; Water Pollut Control 80: 614-31 (1981) (4) Burmaster DE; Environ 24: 6-13, 33-6 (1982) (5) Santodonato J et al; Investigation of Selected Potential Environmental Contaminants: Styrene, Ethylbenzene and Related Compounds 261 p USEPA 560/11-80-018 (1980) R122: (1) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Water USEPA 600/4-76-062 (1976) (2) Callahan MA et al; p 55-61 in 8th Natl Conf Munic Sludge Manage Proc (1979) (3) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in the Lakes Erie, Michigan, Huron and Superior Basins. Great Lakes Quality Review Board (1978) (4) Bertsch W et al; J Chromatogr 112: 701-18 (1975) (5) Zuercher F, Giger W; Vom Wasser 47: 37-55 (1976) (6) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters 75 p USEPA 560/6-77-015 (appendix USEPA 560/6-77-015a) (1977) (7) Goodley PG, Gordon M; Kentucky Acad Sci 37: 11-5 (1976) (8) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R123: (1) Dewulf J, Vanlangenhove H; Water Res 31: 1825-38 (1997) (2) Dewulf JP et al; Environ Sci Technol 32: 903-11 (1998) (3) Neff JM, Sauer TC Jr; Environ Sci Res 52: 163-75 (1996)(4) Sauer TC Jr et al; Mar Chem 7: 1-16 (1978) (5) Gschwend PM et al; Environ Sci Technol 16: 31-8 (1982) (6) Sauer TC Jr; Org Geochem 3: 91-101 (1981) (7) Mantoura RFC; Environ Sci Technol 16: 38-45 (1982) (8) Van de Meent D et al; Water Sci Technol 18: 73-81 (1986) R124: (1) Kawamura K, Kaplan IR; Environ Sci Technol 17: 497-501 (1983) (2) Ligocki MP; Atmos Environ 19: 1609-17 (1985) R125: (1) USEPA; Treatability Manual p.I.9.8-3 USEPA 600/2-82-001a (1981) (2) Young DR; 1978 Ann Rep Southern Calif Coastal Water Res Proj p 103-12 (1978) (3) Callahan MA et al; p 55-61 in 8th Natl Conf Munic Sludge Manage Proc (1979) (4) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in Lakes Erie, Michigan, Huron and Superior basins. Great Lakes Qual Board 373 p (1979) (5) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (6) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) (7) Field, RA et al; Atmos Environ 26A: 2983-96 (1992) R126: (1) Brack W et al; Environ Toxicol Chem 17: 1982-91 (1998) (2) Goodley PC, Gordon M; Kentucky Acad Sci 37: 11-5 (1976) (3) Staples CA et al; Environ Technol Chem 4: 131-42 (1985) R127: (1) Hampton CV et al; Environ Sci Technol 17: 699-708 (1983) (2) Fraser MP et al; Environ Sci Technol 32: 2051-60 (1998) (3) Bos R et al; Sci Total Environ 7: 269-81 (1977) (4) Clark AI et al; Sci Total Environ 39: 265-79 (1984) (5) Clark AI et al; Environ Pollut (Series B) 7: 141-58 (1984) (6) James KJ, Stack MA; Chemosphere 34: 1713-21 (1997) (7) Arnts RR, Meeks SA; Biogenic Hydrocarbon Contribution to the Ambient Air of Selected Areas 31 p USEPA 600/3-80-023 (1980) (8) Lonneman WA et al; Hydrocarbons in Houston air. USEPA 600/3-79-018 pp. 44 (1979) (9) Perry R, Twibell JD; Atmos Environ 7: 329-37 (1973) (10) Tsani-Bazaca E et al; Chemosphere 11: 11-23 (1982) (11) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. SRI Contract 68-02-3452 pp. 198 (1982) R128: (1) Arnts RR, Meeks SA; Biogenic Hydrocarbon Contribution to the Ambient Air of Selected Areas. pp. 31 USEPA 600/3-80-023 (1980) (2) Bos R et al; Sci Total Environ 7: 269-81 (1977) (3) Thornburn S, Colenutt BA; Int J Environ Stud 13: 265-71 (1979) (4) Harkov R et al; J Air Pollut Control Assoc 33: 1177-83 (1983) (5) Altshuller AP et al; Environ Sci Technol 5: 1009-16 (1971) (6) Lonneman WA et al; Environ Sci Technol 2: 1017-20 (1968) (7) Singh HB et al; Atmos Environ 15: 601-12 (1981) (8) Ioffe BV et al; Dokl Akad Nauk SSSR 243: 1186-9 (1978) (9) Ioffe BV et al; Environ Sci Technol 13: 864-8 (1979) (10) Ioffe BV et al; J Chromatogr 142: 787-95 (1977) (11) Lioy P et al; J Water Pollut Control Fed 33: 649-57 (1983) (12) Nelson PF, Quigley SM; Atmos Environ 17: 659-62 (1983) (13) Singh HB et al; Atmospheric Measurements of Selected Toxic Organic Chemicals. USEPA 600/3-80-072 (1980) (14) Santodonato J et al; Investigation of Selected Potential Environmental Contaminants; Styrene, Ethyl Benzene and Related Compounds. pp. 261 USEPA 560/11-80-018 (1980) (15) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data 198 p SRI Contract 68-02-3452 (1982) (16) Jarke FH et al; ASHRAE Trans 87: 153-66 (1981) (17) Grob K, Grob g; J Chromatogr 62: 1-13 (1971) (18) Clark AI et al; Sci Total Environ 39: 265-79 (1984) (19) Clark AI et al; Environ Pollut (Series B) 7: 141-58 (1984) (20) Ligocki MP et al; Atmos Environ 19: 1609-17 (1985) (21) Singh HB et al; Atmos Environ 19: 1911-9 (1985) (22) Brickus LSR et al; Environ Sci Technol 32: 3485-90 (1998) R129: (1) Arnts RR, Meeks SA; Biogenic Hydrocarbon Contribution to the Ambient Air of Selected Areas. USEPA 600/3-80-023 pp. 31 (1980) (2) Hampton CV et al; Environ Sci Technol 17: 699-708 (1983) (3) Seila RL; Non-Urban Hydrocarbon Concentrations in Ambient Air North of Houston, TX. USEPA 500/3-79-010 pp. 38 (1979) (4) Thornburn S, Colenutt BA; Int J Environ Stud 13: 265-71 (1979) (5) Termonia M; pp. 356-61 in Comm Eur Comm EUR7624 Phys Chem Behav Atmos Pollut (1982) (6) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. SRI Contract 68-02-3452 pp. 198 (1982) (7) Clark AI et al; Sci Total Environ 39: 265-79 (1984) (8) Clark AI et al; Environ Pollut (Series B) 7: 141-58 (1984) R130: (1) Clark AI et al; Sci Total Environ 39: 265-79 (1984) (2) Clark AI et al; Environ Pollut (Series B) 7: 141-58 (1984) R131: (1) Brickus LSR et al; Environ Sci Technol 32: 3485-90 (1998) (2) Jarke FH et al; ASHRAE Trans 87: 153-66 (1981) R132: (1) Matiella JE, Hsieh TCKY; J Food Sci 56: 387-90 (1991) (2) Wu CM, Liou SE; J Agric Food Chem 40: 838-41 (1992) (3) Dumont JP, Adda J; J Agric Food Chem 26: 364-7 (1978) (4) Lovegren NV et al; J Agric Food Chem 27: 851-3 (1979) R133: (1) Nicola RM; J Environ Health 49: 342-7 (1987) (2) Ferrario JB et al; Bull Environ Contam Toxicol 34: 246-55 (1985) R134: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R135: (1) NAS; The Alkylbenzenes USEPA Contract No. 68-01-4655 (1980) R136: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Eitzer BD; Environ Sci Technol 29: 896-902 (1995) R137: (1) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in the Lake Erie, Michigan, Huron and Superior Basins. Great Lakes Quality Review Board (1978) (2) Arnts RR, Meeks SA; Biogenic Hydrocarbon Contribution to the Ambient Air of Selected Areas p. 31 USEPA-600/3-80-023 (1980) (3) Atshuller AP et al; Environ Sci Technol 5: 1009-16 (1981) (4) Lonneman WA et al; Environ Sci Technol 2: 1017-20 (1968) (5) Singh HB et al; Atmos Environ 15: 601-12 (1981) (6) Singh HB et al; Atmospheric Measurements of Selected Toxic Organic Chemicals USEPA-600/3-80-072 (1980) R138: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Krotoszynski BK et al; J Anal Toxicol 3: 225-34 (1979) (3) Antoine SR et al; Bull Environ Contam Toxicol 36: 364-71 (1986) R139: USEPA; Ambient Water Quality Criteria Doc: Ethylbenzene p.C-22 (1980) EPA 440/5-80-048 R140: 29 CFR 1910.1000 (7/1/99) R141: 40 CFR 60.489 (7/1/99) R142: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R143: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R144: 40 CFR 401.15 (7/1/99) R145: 40 CFR 116.4 (7/1/99) R146: USEPA; Quality Criteria for Water 1986: Ethylbenzene (May 1,1986) EPA 440/5-86-001 R147: 40 CFR 141.61 (7/1/99) R148: 40 CFR 302.4 (7/1/99) R149: 40 CFR 716.120 (7/1/99) R150: 40 CFR 261.31 (7/1/99) R151: IMAMURA K ET AL; BUNSEKI KAGAKU 28 (9): 549 (1979) R152: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1501-1 R153: 40 CFR 136 (7/1/91) R154: USEPA; Methods for the Determinatioon of Organic Compounds in Finished Drinking Water and Raw Source Water (19860 R155: USEPA; Methods for the Determination of Organic Compouds in Finished Drinking Water and Raw Source Water (1986) R156: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R157: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R158: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R159: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC#4082. Rockville, MD: Government Institutes (1997) R160: Ogata M, Taguchi T; Int Arch Occup Environ Health 59 (3): 263-72 (1987) RS: 131 Record 16 of 1119 in HSDB (through 2003/06) AN: 88 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: FORMAMIDE- SY: *CARBAMALDEHYDE-; *Pesticide-Code:-122806-; *FORMIC-ACID,-AMIDE-; *METHANAMIDE-; *METHANOIC-ACID,-AMIDE- RN: 75-12-7 MF: *C-H3-N-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared on large scale from carbon monoxide and ammonia at high pressure and temp: Meyer, Orthner, Ber 54, 1705 (1921); 55, 857 (1922); Meyer, German patents 390,798 (1924); 392,409 (1924); 414,257 (1925 to BASF); Weitzel, Herbst, US patent 1,843,434 (1932 to IG Farben). [R1, 718] *Interaction of ethyl formate and ammonia with subsequent distillation. [R2] IMP: *Methanol, 0.1%; ammonium formate, 0.1%; water, 0.1%; iron, 0.0001% [R3, 964] FORM: *USEPA/OPP Pesticide Code 122806; Trade Names: MK-0244. [R4] MFS: *GFS Chemicals, Inc., P.O. Box 245, Powell, OH 43065, (800) 858-9682; Production site: Columbus, OH 43222 [R5] *Johnson Matthey, Inc., Alfa Aesar, 460 Swedeford Road, Wayne, PA 19087, (610) 971-3000; Production site: Ward Hill, MA 01835-8099 [R5] USE: *For Formamide (USEPA/OPP Pesticide Code: 122806) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R4] *Manufacture of formic esters and hydrocyanic acid by catalytic dehydration. [R1, 718] *Intermediate in organic synthesis. [R2] *Softener for paper, animal glues, water soluble glues. [R1, 718] *Important intermediate in the chemical industry; used for producing heterocyclic compounds, pharmaceuticals, crop protection agents, fungicides, and pesticides; used as a solvent in the manufacture and processing of plastics; to produce formic acid; used to remove coating from copper conductors; used in the spinning of acrylonitrile copolymers; employed in the antistatic finishing of plastics or formation of conductive coatings on plastic particles. [R3, 965] *Intermediate in the manufacture of cyanic acid, triazoles, vitamins, and dyes. [R6, p. V1 1174] *Formamide is used as a pharmaceutical solvent. [R7] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R8] *(1975) PROBABLY GREATER THAN 4.54X10+5 G [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Slightly viscous, colorless liquid [R1, 718]; *Oily liquid [R9, 148] ODOR: *Faint ammonia odor [R10]; *Odorless [R1, 148] BP: *210.5 deg C @ 760 mm Hg [R1, 718] MP: *2.55 deg C [R1, 718] MW: *45.04 [R1, 718] CORR: *Copper, brass and even lead are attacked. [R3, 963] DEN: *1.1334 @ 20 deg C/4 deg C [R1, 718] DSC: *pKa = - 0.48 @ 20 deg C [R11] HTC: *-568.2 kJ/mole [R3, 960] HTV: *64.98 kJ/mole [R3, 960] OWPC: *log Kow= -1.51 [R12] PH: *7.1 (0.5 molar aqueous soln) [R1, 718] SOL: *Sol in alcohol and acetone [R13]; *Miscible with methanol, phenol, dioxane, acetic acid, ethylene glycol, USP glycerol. [R1, 718]; *Insoluble in ethanol; very soluble in ethyl ether; miscible in chloroform, petroleum ether. [R14]; *In water, 1.0X10+6 mg/l @ 25 deg C. [R15] SPEC: *Index of refraction: 1.44911 @ 15 deg C/D; 1.4170 @ 110 deg C/D; 1.4095 @ 130 deg C/D; 1.44754 @ 20 deg C/D [R1, 718]; *SADTLER REFERENCE NUMBER: 2232 (IR, PRISM); MAX ABSORPTION (UNDILUTED): 205 NM (LOG E= 2.20) SHOULDER [R16]; *IR: 5670 (Coblentz Society Spectral Collection) [R14]; *NMR: 7220 (Sadtler Research Laboratories Spectral Collection) [R14]; *MASS: NIST 18879 (NIST/EPA/MCDC Mass Spectral Database 1990 version) [R14] SURF: *58.35 dyne/cm @ 20 deg C [R1, 718] VAPD: *1.56 (Air = 1) [R6, p. V1 1175] VAP: *6.10X10-2 mm Hg @ 25 deg C [R17] VISC: *nX10+5 @ 20 deg C= 4320; @ 30 deg C= 2926 [R1, 718] OCPP: *Dissolves casein, glucose, zein, tannins, starch, lignin, polyvinyl alcohol, cellulose acetate, nylon, chlorides of copper, lead, zinc, tin, iron, cobalt, aluminum, nickel, the acetates of the alkali metals, some inorganic sulfates and nitrates. [R1, 718] *Dielectric constant: epsilon= 84; industrial grades may have odor of ammonia [R1, 718] *Hygroscopic [R1, 148] *Hydrolyzes very slowly at room temperature, hydrolysis is accelerated by acids and bases at elevated temperatures. [R3, 960] *Saturated concentration in air: < 0.24 g/cu m @ 30 deg C [R6, p. V1 1175] *1 mg/cu m= 0.53 ppm, 1 ppm= 1.87 mg/cu m [R6, p. V1 1175] *Dielectric constant: 109 +/- 15 @ 20 deg C [R3, 960] *Dipole moment: 1.12X10-29 C-m @ 30 deg C [R3, 960] *BP: 200-212 deg C with partial decomposition beginning approximately 180 deg C [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat or flame. [R18] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R19] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R19] FLPT: *310 DEG F (OPEN CUP) [R19] EXPL: *Has exploded while in storage. [R18] REAC: *Incompatible with iodine, pyridine and sulfur trioxide. [R18] *Bottles containing a modified Karl Fischer reagent with formamide replacing methanol developed gas pressure during several months and burst. No reason was apparent, but slow absorption of moisture, formation of sulfuric acid and liberation of carbon monoxide from the formamide seems a likely sequence. [R20, 161] *A mixture containing 51% of calcium nitrate and 12% ammonium nitrate with 27% formamide and 10% water is detonable @ -20 deg C. [R20, 926] *Oxidizers, iodine pyridine, sulfur, trioxide, copper, brass, lead [Note: Hygroscopic (i.e., absorbs moisture from the air)]. [R9, 148] *Formamide is hydrolyzed very slowly at room temperature. Acids, bases and elevated temperatures accelerate the hydrolysis. [R21, 161] DCMP: *WHEN HEATED TO DECOMPOSITION, EMITS TOXIC FUMES OF /NITROGEN OXIDES/. [R18] *Decomposition products at the boiling point are ammonia, water, carbon monoxide and hydrogen cyanide [R22, p. 11(80) 258] ODRT: *Odor recognition in water: 1.00X10+2 (chemically pure) [R23] *150 mg/cu m (odor low) 150 mg/cu m (odor high) [R24] SERI: *Moderately irritating to skin, mucous membranes. [R25] *An irritant to skin, eyes, and mucous membranes. [R18] EQUP: *Wear rubber gloves, goggles and overalls. [R10] *Wear appropriate eye protection to prevent eye contact. [R9, 148] OPRM: *Women of childbearing potential should handle this substance only in a hood and should take precautions to avoid skin contact with the liquid because of the ease with which it passes through the skin. [R26] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Contact lenses should not be worn when working with this chemical. [R9, 148] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. STRG: *For storage ... tanks of stainless steel or aluminum are indicated. When small amounts of iron are permissible, mild steel can be used for tank cars and drums. Caffeine, adenine and other purines stabilize formamide in storage ... [R22, p. 11(80) 260] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *The following wastewater treatment technologies have been investigated for formamide: Concentration process: Biological treatment. [R27] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *Moderately irritating to skin, mucous membranes. [R25] *An irritant to skin, eyes, and mucous membranes. [R18] NTOX: *... IN ANIMALS ... FORMAMIDE AND MONOMETHYLFORMAMIDE HAVE BEEN SHOWN EXPERIMENTALLY TO BE TERATOGENS /ADMIN BY MOUTH OR PERCUTANEOUSLY/. [R28] *... APPLICATION OF FORMAMIDE TO SKIN OF PREGNANT MICE RESULTED IN INHIBITION OF FETAL GROWTH AND ... MALFORMATIONS; GROSS FETAL MALFORMATIONS WERE NOT OBSERVED /IN A LATER STUDY/. ... PREVIOUSLY REPORTED EFFECTS WERE PRODUCED UNDOUBTEDLY AT OVERWHELMING CONCENTRATIONS. [R29] *IN 2-WK FEEDING TEST ON 6 RATS, 4 DIED BEFORE 10TH TREATMENT OF 1.5 G FORMAMIDE/KG; OTHER 2 DIED WITHIN 2 DAYS AFTER 10TH DAY OF TREATMENT, INDICATING CUMULATIVE EFFECTS. ALL RATS SHOWED MARKED WEIGHT LOSS DURING TREATMENT, AND PATHOLOGIC EXAMINATION REVEALED ... GASTRITIS AND MALNUTRITION ... . [R29] *Skin tests on rabbits produced a LD50 of 6 g/kg. DuPont dermal toxicity studies reported the lethal dose to be approx 17 g/kg following application of formamide to the shaved backs of rabbits. Tests for primary skin irritation and allergic skin sensitization were carried out by applying undiluted formamide and a 50% aqueous soln of formamide to the shaved skin of guinea pigs. Both concns were strong irritants to the intact skin. Aqueous solns of formamide in concns of 50% and 33% were mildly to moderately irritating to the abraded skin of guinea pigs. Formamide did not produce skin sensitization. [R29] *... EYE IRRITATION TESTS IN RABBITS SHOWED ONLY MILD, TEMPORARY IRRITATION. [R29] *... NO SIGNS OF TOXICITY IN RATS WERE DETECTED IN SINGLE EXPOSURES FOR 6 HR @ 3900 PPM FORMAMIDE DISPERSED AS MIST, OR FOR EXPOSURES OF 10 DAYS' DURATION, 6 HR/DAY @ APPROX 1500 PPM ... VAPOR ... /THERE WAS/ NO INDICATION THAT ORGAN DAMAGE HAD OCCURRED UPON PATHOLOGICAL EXAM. [R29] *... 1 ML /FORMAMIDE ADMIN/ IP TO RATS ON GESTATIONAL DAYS 11-16 ... CAUSED 36% RESORPTION AND OF SURVIVORS 46% WERE STUNTED. DEFECTS OF PALATE AND EXTREMITIES ALSO OCCURRED. [R30] *YOUNG CHICK EMBRYOS WERE INCUBATED ON MEDIA CONTAINING FORMAMIDE AT CONCN OF 0.1 and 0.25 MOLAR. IN NEUROEPITHELIUM OF THESE EMBRYOS, IT WAS FOUND THAT THE 0.1 MOLAR CONCN HAD NO EFFECT; 0.25 MOLAR CONCN ONLY AFFECTED MITOSIS. [R31] *FORMAMIDE /AS LIQUID/ WAS APPLIED TO SKIN OF PREGNANT RATS DURING PERIOD OF FETAL ORGANOGENESIS. SLIGHT TERATOGENESIS AND EMBRYOMORTALITY WAS DEMONSTRATED. [R32] *ACUTE TOXICITY OF FORMAMIDES TO RATS AND MICE WAS IN INCR ORDER: FORMAMIDE, N-METHYLFORMAMIDE, N,N-DIMETHYLFORMAMIDE, N-ETHYLFORMAMIDE, AND N,N-DIETHYLFORMAMIDE. MICE WERE MORE SUSCEPTIBLE THAN RATS. THE COMPOUNDS INDUCED TESTICULAR LESIONS. [R33] *Formamide was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Formamide was tested at doses of 0.033, 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, AND TA100) in the presence and absence of rat or hamster liver S-9. Formamide was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 10 mg/plate. [R34] */Formamide/ rated 4 when tested on eyes of rabbits on a scale of 1 to 10 according to degree of injury observed after 24 hr, paying particular attention to condition of cornea. Most severe injuries have been rated 10. [R35] *FORMAMIDE IN AQUEOUS SOLN ADMIN BY STOMACH TUBE TO RABBITS FROM 6TH-18TH DAY PAST INSEMINATION SHOWED EMBRYOTOXIC AND WEAKLY TERATOGENIC EFFECTS AT CONCN NOT TOXIC TO MOTHER. [R36] *In the mouse, 0.1 ml of formamide (about one-fourth of the LD50 dose) dropped onto the skin on 1 or 2 days of embryogenesis was sufficient to cause death of half the embryos and malformation of all the survivors. [R37] *In the rat, cutaneous application of formamide, at doses of 600 mg/kg body weight (about one-twenty-eight of the average lethal dose), on 1 or 2 day during embryogenesis, was weakly emryotoxic, causing intrauterine deaths but not malformation. [R37] *In rats, one dose of formamide (2 g/kg) admin on the 7th day of gestation caused resorption of all implanted fetuses and three daily doses of 2 g/kg after day 7 destroyed the litter. The cutaneous application of 600 mg/kg in rats twice after day 10 of gestation was weakly embryotoxic and teratogenic. [R21, 163] *After ip application of 0.22 g/kg formamide to NMRI mice daily from the 6th to the 15th day post insemination, 27% of fetuses were lost and 25% showed malformations. [R21, 163] *In rabbits, 79 mg/kg formamide given daily from the 6th-18th day post insemination caused fetal malformations. [R21, 163] NTXV: *LD50 Rat oral 6 g/kg; [R29] *LD50 Rabbit dermal 6 g/kg; [R29] *LD50 Mouse oral 3.15 g/kg; [R21, 162] *LD50 Tumor bearing BDF1 mouse oral 400 mg/kg (given daily for 9 days); [R21, 162] *LD50 Tumor bearing BDF1 mouse oral 270 mg/kg (given daily for 17 days); [R21, 162] *LD50 Rat ip 5.6 g/kg; [R21, 162] *LD50 Mouse ip 2450 mg/kg; [R18] *LD50 Guinea pig ip 1.25 g/kg; [R21, 162] NTP: +Formamide (FORM) ... was evaluated for reproductive toxicity in CD-1 (Swiss) mice using the Reproductive Assessment by Continuous Breeding Protocol (RACB). Male and female mice were exposed to FORM in drinking water at doses of 0, 100, 350, and 750 ppm (/about/ 20-200 mg/kg/day). A Max Tolerated Dose (MTD) of FORM, based on indices of generalized toxicity, was not reached for F0 animals. However, reproductive toxicity, including reduced fertility and litter size, was observed at 750 ppm FORM. F0 females at 750 ppm FORM exhibited an incr in the avg days to litter, and tended to spend more time in diestrus than in another stage of the cycle. FORM caused no detectable change in the histopathology of kidney, liver, or reproductive organs. Estimated exposure for the F0 generation was 24, 80, and 195 mg/kg/day for the 100, 350, and 750 ppm FORM groups, respectively. Females tended to have higher relative exposure (mg/kg/day) compared to males. F1 postnatal survival was unaffected by treatment. The MTD for the F1 generation was 750 ppm FORM, based on reduced body weight. Mild reproductive toxicity, observed as reduction in litter size and increased days to litter, occurred at 750 ppm. No significant histopathologic changes were observed in either males or females. Estimated exposure to FORM was 26, 87, and 190 mg/kg/day for F1 animals. In summary, the MTD for generalized toxicity was not reached for the F0 generation, but was established at 750 ppm for the F1 generation. The No-Observed-Adverse-Effect-Level (NOAEL) for generalized toxicity was 750 ppm for the F0 generation and 350 ppm for the generation. Reproductive toxicity was observed at 750 ppm in both generations. [R38] +... This study was performed due to the lack of data from pregnant rats exposed during the entire embryo/fetal period. Dose selection was based on a screening study in which CD rats were treated by gavage with 0, 62, 125, 250, 500, or 1000 millgrams formamide per kilogram body weight per day on gestational days (gd) 6-19 ... . Maternal toxicity was noted at greater than or equal to 250 mg/kg/day, including morbidity, and reductions in water/food intake, body weight, and weight gain. Fetal body weight was reduced at greater than or equal to 125 mg/kg/day ... . In this study, female Sprague-Dawley-derived (CD(R) ) rats were dosed by gavage with formamide (50, 100, or 200 mg/kg/day) or its vehicle (deionized/distilled water) on gestational days 6-19. The dose volume was 5 ml/kg. Twenty-five timed-mated rats were assigned to each group. Dams were monitored at regular intervals throughout gestation for clinical signs, food and water intake, and body weight. At necropsy on gestational days 20, the following were recorded: maternal clinical condition; body, liver, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for external morphological anomalies. Approximately, one-half of the fetuses were examined for visceral anomalies, including internal head structures, and the remaining fetuses were examined for skeletal anomalies. Pregnancy was confirmed in 88-92% of females/group. No maternal deaths occurred, and there were no dose-related clinical signs. Maternal body weight exhibited significant decreasing trends (gestational days 15-20), with significant reductions at 200 mg/kg/day on gestational days 18, 19, and 20. Maternal body weight gain was also reduced at 200 mg/kg/day from gestational days 6 to 9, from gestational days 15 to 18, for the treatment period as a whole (gestational days 6 to 20), and for the gestational period as a whole (gestational days 0 to 20). However, maternal gestational weight gain, corrected for gravid uterine weight, was not affected. Maternal food and water intake were also unaffected Maternal liver weight (absolute or relative) was not affected by formamide exposure. Gravid uterine weight exhibited a significant decreasing trend (100, 94, and 87% of control weight), and the reduction was significant at 200 mg/kg/day. Prenatal mortality (resorptions and late fetal deaths), live litter size, and percent males/litter were not affected by formamide exposure. Average fetal body weight/litter exhibited a decreasing trend (98, 97, and 85% of average control weight), with significant reductions at greater than or equal to 100 mg/kg/day. No statistically significant differences were observed in the incidences of fetal morphological anomalies (malformations or variations). In summary, CD(R) rats were dosed by gavage with formamide (0, 50, 100, or 200 mg/kg/day) on gestational days 6-19. Minimal evidence of maternal toxicity was found at 200 mg/kg/day. Gravid uterine weight was reduced at 200 mg/kg/day, and fetal body weight was reduced at greater than or equal to 100 mg/kg/day. Thus, the maternal toxicity NOAEL was 100 mg/kg/day, and the LOAEL was 200 mg/kg/day. The developmental toxicity NOAEL was 50 mg/kg/day, and the LOAEL was 100 mg/kg/day. [R39] +... This study was performed due to the potential for human exposure to formamide and the lack of complete developmental toxicity data. Dose selection was based on a developmental toxicity screen in New Zealand White rabbits ... . Naturally-mated female New Zealand White (NZW) rabbits were dosed by gavage with formamide (10, 20, 40, 80 or 120 mg/kg body weight/day) or its vehicle (deionized/distilled water) on gestational days (gd) 6 through 29. Mild maternal toxicity and abortion or early delivery in 3 out of 7 pregnancies were found at 120 mg/kg/day. Although not statistically significant, the reduction in average fetal body weight at the high dose (83% of control weight) was considered to be a biologically relevant response to FORM exposure. In this study, female New Zealand White rabbits were dosed by gavage with formamide (35, 70, or 140 mg/kg/day) or its vehicle (deionized/distilled water) on gestational days 6 through 29. The dose volume was 1 ml/kg. The study was conducted in a two-replicate design. Twenty-four timed naturally-mated female rabbits (12 per replicate) were assigned to each group. Does were monitored at regular intervals throughout gestation for clinical signs, food intake, and body weight. At necropsy on gestational days 30, the following were recorded: maternal clinical condition; body, liver and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for morphological anomalies (external, visceral, and skeletal). Approximately one-half of the fetuses were examined for anomalies of the internal head structures. Abortions or early deliveries were noted in 0, 2, 2, and 8 females in the 0, 35, 70, and 140 mg/kg/day dose groups, respectively. At necropsy, confirmed pregnancy rates were 86-100% per group. One maternal death and four maternal deaths occurred in the low and high dose groups, respectively. Clinical signs associated with formamide exposure were minimal. Reduced or absent fecal output was more often recorded at the high dose (2-13 animals per day), presumably related to reduced feed consumption. A significant decreasing trend was noted for maternal body weight on gestational days 15, 18, 21, 24, 27, 29, and 30, maternal body weight change for gestational days 12 to 15, 15 to 18, 18 to 21 and 21 to 24, but not for weight change during treatment (gestational days 6 to 29) or gestation (0 to 30). Maternal body weight was significantly depressed in the high dose group on gestational days 21, 24, and 27. Maternal body weight change was significantly depressed at the high dose for gestational days 12 to 15, 18 to 21, and 21 to 24. In addition, maternal body weight change was depressed at the mid dose for gestational days 18 to 21. No significant treatment-related effects were observed for corrected maternal weight gain. Relative maternal food intake (g/kg/day) exhibited a decreasing trend during most of the treatment period treatment (gestational days 9 to 24), and was 34-59% of control intake in the high dose group from gestational days 12 through gestational days 24. Thereafter, no significant differences were noted among treatment groups for maternal relative feed consumption. Maternal liver weight (absolute and relative to body weight) was equivalent among groups. Gravid uterine weight exhibited a dose-related decreasing trend and was 71% of the control value at the high dose (significant). Formamide exposure decreased average litter size at 140 mg/kg/day that was 66% of the control mean. Mean fetal body weight per litter (males, females, and sexes combined) exhibited a decreasing trend. Mean fetal body weight per litter for males and the sexes combined was significantly decreased at the high dose. There was no effect of treatment on the incidence of external, visceral, or skeletal malformations or variations. In summary, maternal mortality and other indices of maternal toxicity were noted in this study at the high dose, and the maternal No Observed Adverse Effect Level (NOAEL) for formamide was 70 mg/kg/day. Formamide caused significant treatment-related developmental toxicity at 140 mg/kg/day, consisting of reduced mean live litter size and fetal body weight per litter. Thus, the developmental toxicity NOAEL was also 70 mg/kg/day. [R40] TCAT: ?Formamide was applied dermally to Wistar rats in a range finding study designed to determine the dosage levels for a 90 day dermal toxicity study. Groups of 10 rats (5 male and 5 female) received 0,100,300,1000 or 3,000 mg/kg formamide (> 99.5% purity) applied as an occluded dose 1X daily, 5 days a week for 2 weeks. Data were collected concerning body weights, food consumption, hematology (CBC and differential platelet, reticulocyte count) and gross necropsy (with special attention to spleen and testes). All treatment groups showed decreased body weight gain. No other toxic effects of formamide were found at any concentration up to 3000 mg/kg. An elevated reticulocyte count was observed in the high dose group which may have reflected an anemic condition. No clinical signs or behavioral abnormalities were detected. [R41] ADE: *FORMAMIDE IS ABSORBED DIRECTLY THROUGH GUINEA PIG SKIN ... . [R42] *After admin of 2-4 g/rabbit orally, 39% of the dose was recovered unchanged ... . [R21, 162] METB: *THERE APPEARS TO BE GOOD EVIDENCE FOR HYDROLYSIS /OF ALIPHATIC CARBOXYLIC AMIDES/ ... THE SITE OF HYDROLYSIS IS PROBABLY LIVER, WHERE THERE ARE RELATIVELY NONSPECIFIC AMIDASES. RATE OF HYDROLYSIS INCREASES RAPIDLY AS MOLECULAR WT INCREASES ... /EXCEPT/ ACETAMIDE WAS HYDROLYZED MORE SLOWLY THAN FORMAMIDE ... . [R42] *RELATIVE LACK OF IRRITANT EFFECTS /OF SIMPLE CARBOXYLIC AMIDES/ ON SKIN AND MUCOUS MEMBRANES INDICATES THAT HYDROLYSIS IS PROBABLY NOT OCCURRING THERE TO ANY EXTENT, OTHERWISE LOWER MOLECULAR WT ACIDS PRODUCED WOULD CAUSE LOCAL DAMAGE. [R42] *It is known that dimethylformamide is metabolized in man by sequential N-demethylation to methylformamide and formamide, which are largely eliminated in the urine. [R43] *In a study ... the hypothesis was tested that formamide undergoes metabolic hydrolysis in rabbits. Acidic substances were titrated after extraction by ether, before and after hydrolysis of urine samples. The ether-soluble acid determined in hydrolyzed urine was assumed to reflect the amount of formamide excreted unchanged. The difference between the amount of amide admin and the total amount excreted unchanged was considered to represent amide which was metabolically hydrolyzed. After admin of 2-4 g/rabbit orally, 39% of the dose was recovered unchanged using this method. [R21, 162] INTC: *FORMAMIDE (3 G/KG IV) HAD LITTLE EFFECT ON CAROTID SINUS REFLEX OR ON HYPERTENSION INDUCED BY EXOGENOUS CATECHOLAMINES, BUT FORMAMIDE DECR HYPERTENSION INDUCED BY INDIRECTLY ACTING AMINES TYRAMINE AND EPHEDRINE. [R44] *FORMAMIDE, WHEN ADMIN IP TO MICE IN SUBLETHAL DOSES (3.2, 0.77, 2, 1.2, AND 0.75 G/KG), LENGTHENED /CNS DEPRESSION/ ... INDUCED BY 100 MG HEXOBARBITAL, 350 MG CHLORAL, OR 1.4 G URETHANE/KG. [R45] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Formamide's production and use as an intermediate in the chemical industry; to produce heterocyclic compounds, pharmaceuticals, crop protection agents, fungicides, and pesticides; as a solvent in the manufacture and processing of plastics; to produce formic acid; to remove coating from copper conductors; in the spinning of acrylonitrile copolymers; in the antistatic finishing of plastics or formation of conductive coatings on plastic particles; may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 6.1X10-2 mm Hg at 25 deg C indicates formamide will exist solely as a vapor in the ambient atmosphere. Vapor-phase formamide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 8.0 days. If released to soil, formamide is expected to have very high mobility based upon a Koc of 3.6. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.4X10-9 atm-cu m/mole. If released into water, formamide is not expected to adsorb to suspended solids and sediment based upon the Koc. Several biodegradation screening studies have observed significant biodegradation of formamide which suggests that biodegradation may be important. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is expected to be slow. Occupational exposure to formamide may occur through inhalation and dermal contact with this compound at workplaces where formamide is produced or used. (SRC) ARTS: *Formamide's production and use as an intermediate in the chemical industry; to produce heterocyclic compounds, pharmaceuticals, crop protection agents, fungicides, and pesticides; as a solvent in the manufacture and processing of plastics; to produce formic acid; to remove coating from copper conductors; in the spinning of acrylonitrile copolymers; in the antistatic finishing of plastics or formation of conductive coatings on plastic particles(1) may result in its release to the environment through various waste streams(SRC). [R46] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 3.6(2), indicates that formamide is expected to have very high mobility in soil(SRC). Volatilization of formamide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-9 atm-cu m/mole(SRC), derived from its vapor pressure, 6.1X10-2 mm Hg(3), and water solubility, 1.0X10+6 mg/l(4). Formamide is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 6.1X10-2 mm Hg(3). Several biodegradation screening studies have observed significant biodegradation of formamide(5-8); although these screening studies are not specific to soil media, they suggest that biodegradation in soil may be important(SRC). [R47] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 3.6(2), indicates that formamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-9 atm-cu m/mole(SRC), derived from its vapor pressure, 6.1X10-2 mm Hg(4), and water solubility, 1.0X10+6 mg/l(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from a log Kow of -1.51(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Formamide is hydrolyzed very slowly at room temperature; the rate of hydrolysis increases rapidly in the presence of acid or bases and is further accelerated at elevated temperature(9). Biodegradation is an important fate process in water based on its biodegradability in aqueous screening tests(10-13). [R48] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), formamide, which has a vapor pressure of 6.1X10-2 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase formamide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 8 days(SRC), calculated from its rate constant of 2.0X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). [R49] BIOD: *AEROBIC: Theoretical BODs were measured for formamide of 1.6, 4.7, and 11.8% over 6-, 12-, and 24-hr inoculation periods(1), respectively. Theoretical BODs greater than 30% over a 2 week incubation period(2,3), and 22.6 and 57.7% over a 2 week incubation period(4) were noted using the Japanese MITI standard BOD test. [R50] ABIO: *The rate constant for the vapor-phase reaction of formamide with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 8 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Formamide is hydrolyzed very slowly at room temperature; the rate of hydrolysis increases rapidly in the presence of acid or bases and is further accelerated at elevated temperature(2). The rate constant for reaction of formamide with OH radicals in aqueous solution is < 5.0X10+8 cu dm/mol s(3). [R51] BIOC: *An estimated BCF of 3 was calculated for formamide(SRC), using a log Kow of -1.51(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R52] KOC: *The Koc of formamide is 3.6(1). According to a classification scheme(2), this Koc value suggests that formamide is expected to have very high mobility in soil(SRC). [R53] VWS: *The Henry's Law constant for formamide is estimated as 1.4X10-9 atm-cu m/mole(SRC) based upon its vapor pressure, 6.1X10-2 mm Hg(1), and water solubility, 1.0X10+6 mg/l(2). This Henry's Law constant indicates that formamide is expected to be essentially nonvolatile from water surfaces(3). Formamide is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 6.1X10-2 mm Hg(1). [R54] EFFL: *Formamide has been detected in wastewater from a polyamide production plant(1). Formamide was detected at 2.0 mg/l in gas condensate retort water in oil-shale retort, but was not detected in the processed retort water(2). [R55] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,724 workers (556 of these are female) are potentially exposed to formamide in the US(1). Occupational exposure to formamide may occur through inhalation and dermal contact with this compound at workplaces where formamide is produced or used(SRC). Formamide, a physiological product of N,N-dimethylformamide, was detected in the urine of synthetic leather factory workers(2). Urinary concns ranged from 7-69 mg/l for workers exposed to N,N-dimethylformamide in the workplace(2). [R56] BODY: *Formamide, a physiological product of N,N-dimethylformamide, was detected in the urine of synthetic leather factory workers(1). Urinary concns ranged from 7-69 mg/l for workers exposed to N,N-dimethylformamide in the workplace(1). [R57] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: *Vacated 1989 OSHA PEL TWA 20 ppm (30 mg/cu m); STEL 30 ppm (45 mg/cu m), is still enforced in some states. [R9, 364] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (15 mg/cu m)[skin]. [R9, 148] TLV: *8 hr Time Weighted Avg (TWA) 10 ppm,skin [R58, 2001.33] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R58, 2001.6] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Formamide is produced, as an intermediate or a final product, by process units covered under this subpart. [R59] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Formamide is included on this list. [R60] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R61] FDA: *Formamide is an indirect food additive for use only as a component of adhesives. [R62] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A HPLC method with UV detection was used for the determination of low mol wt amides in pharmaceutical matrixes. The method was based on Zorbax C8 or Alltech C18 column, mobile phase consisting of 3-5% MeCN in 0.1M phosphate buffer, and flow rate of 1-1.5 ml/min at the room temperature. By strongly retaining the sample matrix and allowing the amide analyte to elute, the method can be generally applied to many types of org matrix for pharmaceutical and agricultural products. /Amides/ [R63] *EPA Method 1666: Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by Isotope Dilution GC/MS. Detection limit = 1000 mg/l. [R64] *EPA Method 1671: Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by GC/FID. Detection limit = 100 mg/l. [R64] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for formamide. Route: gavage; Species: rats and mice. [R65] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 515 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V11 (1994) R4: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Formamide (75-12-7). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R5: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 650 R6: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley and Sons. New York, NY. 2001 R7: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 1454 R8: SRI R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R10: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 465 R11: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 654 R12: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 3 R13: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-166 R14: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V3 2809 R15: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 (1980) 258-63 R16: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-309 R17: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R18: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1690 R19: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-55 R20: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R21: Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990. R22: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R23: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 74 R24: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R25: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 605 R26: National Research Council. Prudent Practices for Handling Hazardous Chemicals in Laboratories. Washington, DC: National Academy Press, 1981. 34 R27: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-34 (1982) R28: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 137 R29: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.689 R30: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 70 R31: MESSIER P-E; J EMBRYOL EXP MORPHOL 35 (1): 197-212 (1976) R32: STULA EF, KRAUSS WC; TOXICOL APPL PHARMACOL 41 (1): 35-56 (1977) R33: PHAM HUU CHANH ET AL; THERAPIE 26 (3): 409-24 (1971) R34: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R35: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1036 R36: MERKLE J ET AL; ARZNEIM-FORSCH 30 (9): 1557-62 (1980) R37: Marzulli, F.N., H.I. Maibach. Dermatotoxicology 4th ed. New York, NY: Hemisphere Publishing Corp., 1991. 707 R38: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Formamide (FORM) (CAS No. 75-12-7) in CD-1 Swiss Mice, NTP Study No. RACB90005 (August 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R39: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity Evaluation of Formamide (CAS NO. 75-12-7) Administered by Gavage to Sprague-Dawley (CD(R)) Rats On Gestational Days 6 Through 19, NTP Study No. TER97002 (December 30, 1998) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R40: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity Evaluation Of Formamide (CAS No. 75-12-7) Administered By Gavage To New Zealand White Rabbits On Gestational Days 6 Through 29, NTP Study No. TER98002 (March 8, 2001) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R41: BASF Wyandotte corp.; Range Finding Study, Dermal Toxicity of Formamide in the Rat, Summary of Results. (1983), EPA Document No. 40-8357057, Fiche No. OTS0507216 R42: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1829 R43: Baselt, R.C. Biological Monitoring Methods for Industrial Chemicals. 2nd ed. Littleton, MA: PSG Publishing Co., Inc. 1988. 128 R44: PHAM-HUU CHANH ET AL; AGRESSOLOGIE 14 (4): 251-8 (1973) R45: PHAM-HUU CHANH ET AL; THERAPIE 27 (5): 873-80 (1972) R46: (1) Hohn A; Kirk-Othmer Encycl Chem Tech. 4th ed NY, NY: Wiley Interscience 11: 960 (1994) R47: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 4th ed. NY, NY: John Wiley and Sons 1: 1175 (2001) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (4) Eberling CL; Kirk-Othmer Encycl Chem Tech 3rd ed NY, NY: Wiley Interscience 11: 258-63 (1980) (5) Malaney GW, Gerhold RM; Eng Ext Ser (Purdue Univ) 112: 249-57 (1962) (6) Sasaki S; pp. 283-98 in Aquatic Pollutants. Hutzinger O et al, ed. Oxford, UK: Pergamon Press (1978) (7) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (8) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances, OECD Tokyo Meeting, Reference Book TSU-No. 3 (1978) R48: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 4th ed. NY, NY: John Wiley and Sons 1: 1175 (2001) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (5) Eberling CL; Kirk-Othmer Encycl Chem Tech 3rd ed NY, NY: Wiley Interscience 11: 258-63 (1980) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (9) Hohn A; Kirk-Othmer Encycl Chem Tech 4th ed NY, NY: Wiley Interscience 11: 959 (1994) (10) Malaney GW, Gerhold RM; Eng Ext Ser (Purdue Univ) 112: 249-57 (1962) (11) Sasaki S; pp. 283-98 in Aquatic Pollutants. Hutzinger O et al, ed. Oxford, UK: Pergamon Press (1978) (12) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (13) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances, OECD Tokyo Meeting, Reference Book TSU-No. 3 (1978) R49: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng New York, NY: Hemisphere Pub Corp (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R50: (1) Melaney GW, Gerhold RM; Ext Ser 112: 249-57 (1962) (2) Sasaki S; pp. 283-98 in Japan in Aquatic Pollutants. Hutzinger O et al, ed. Oxford, UK: Pergamon Press Oxford (1978) (3) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (4) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances, OECD Tokyo Meeting, Reference Book TSU-No. 3 (1978) R51: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Hohn A; Kirk-Othmer Encycl Chem Tech 4th ed NY, NY: Wiley Interscience 11: 959 (1994) (3) Fahartaziz, Ross AB; Selected Specific Rates of Reactions of Transients from Water in Aqueous Solution. III Hydroxyl radical and Perhydroxyl radical and their Ions. Washington DC: US Dept of Commerce, National Bureau of Standards NSRDS-NBS59, PB-263 (1977) R52: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R53: (1) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 4th ed. NY, NY: John Wiley and Sons 1: 1175 (2001) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R54: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (2) Eberling CL; Kirk-Othmer Encycl Chem Tech 3rd ed NY, NY: Wiley Interscience 11: 258-63 (1980) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R55: (1) USEPA Chemical Hazard Information Profile; Draft Report: Formamide Sept. 18, 1981. Washington, DC: Office of Toxic Substances (1981) (2) Leenheer JA et al; Environ Sci Technol 16: 714-23 (1982) R56: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Casal Lareo A, Perbellini L; Int Arch Occup Environ Health 67: 47-52 (1995) R57: (1) Casal Lareo A, Perbellini L; Int Arch Occup Enviroin Health 67: 47-52 (1995) R58: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R59: 40 CFR 60.489 (7/1/2000) R60: 40 CFR 716.120 (7/1/2000) R61: 40 CFR 712.30 (7/1/2000) R62: 21 CFR 175.105 (4/1/2000) R63: Snorek SV et al; J Chromatog; 458 : 287-93 (1988) R64: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R65: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 49 Record 17 of 1119 in HSDB (through 2003/06) AN: 89 UD: 200211 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: FURAN- SY: *AXOLE-; *DIVINYLENE-OXIDE-; *1,4-EPOXY-1,3-BUTADIENE-; *FURFURAN-; *NCI-C56202-; *OXACYCLOPENTADIENE-; *OXOLE-; *Tetrol-; *TETROLE- RN: 110-00-9 RELT: 125 [TETRAHYDROFURAN] (analog) MF: *C4-H4-O SHPN: UN 2389; Furan IMO 3.1; Furan STCC: 49 091 75; Furan HAZN: U124; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD BY DECARBOXYLATION OF 2-FURANCARBOXYLIC ACID. HAS BEEN PREPARED DIRECTLY FROM FURFURAL OVER HOT SODA-LIME OR BY DROPPING FURFURAL ON FUSED MIXTURE OF SODIUM AND POTASSIUM HYDROXIDES. [R1, 672] *DRY DISTILLATION OF FUROIC ACID FROM FURFURAL. [R2] *By heating furfural in the liquid phase in the presence of a palladium catalyst. [R3] *High yields of furan have been obtained when butanediol is oxidized by dichromate in acidic soln, followed by dehydration. [R3] FORM: *Industrial (99%) grade [R4] MFS: *International Chemical Group, Hq, P.O. Box 438000, San Ysidro, CA 92173 (619)274-7215. Production site: International Marketing Center, 4740 La Rueda Drive, La Mesa, CA 91941 (619)441-2739. [R5] USE: *CHEMICAL INTERMEDIATE FOR TETRAHYDROFURAN [R6] *ORGANIC SYNTHESIS, ESPECIALLY FOR PYRROLE, THIOPHENE [R2] *Used in production of pharmaceuticals, agricultural chemicals, stabilizers, and fine chemicals. [R7] CPAT: *PROBABLY 100% CONSUMED CAPTIVELY AS AN INT FOR TETRAHYDROFURAN (FURAN ITSELF IS NOT IMPORTANT COMMERCIALLY) (1975) [R6] *(1974) 3.63X10+10 G (EST-CAPTIVELY CONSUMED) [R6] PRIE: U.S. IMPORTS: *(1986) 9.66X10+6 lb /Furan (furfuryl type) resins/ [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid, turns brown upon standing [R2] ODOR: *Ethereal [R9] BP: *31.36 DEG C AT 760 MM HG [R1, 672] MP: *-85.6 deg C [R10] MW: *68.08 [R10] CTP: *Critical temp: 214 deg C [R9]; *Critical pressure: 5.32 mPa [R11] DEN: *0.9371 @ 19.4 DEG C/4 DEG C [R1, 672] HTC: *-500.1 kg cal/mole (at constant vol) [R9] HTV: *95.5 cal/g @ 31.2 deg C [R9] OWPC: *Log Kow= 1.34 [R12] SOL: *> 10% in acetone [R13]; *> 10% in benzene [R13]; *> 10% in ether [R13]; *> 10% in ethanol [R13]; *Water solubility = 1X10+4 mg/l at 25 deg C [R14] SPEC: *Index of refraction: 1.4214 @ 20 deg C/D [R9]; *MAX ABSORPTION (ALCOHOL): 208 NM (LOG E= 3.9) SHOULDER [R15]; *Furan, 99%, exhibits its two strongest infra red absorption bands at wavelengths of 10.1 and 13.5 microns. [R16]; *IR: 3664 (Sadtler Research Laboratories Prism Collection) [R13]; *UV: 3-15 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R13]; *NMR: 50 (Varian Associates NMR Spectra Catalogue) [R13]; *MASS: 51 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R13] VAPD: +2.3 (Air= 1) [R17] VAP: *Vapor pressure = 600 mm Hg at 25 deg C /from experimentally derived coefficients/ [R18] VISC: *0.38 cp @ 20 deg C [R11] OCPP: *Heat of formation @ 25 deg C= -14.9 kcal/mole [R9] *Dielectric constant @ 25 deg C: 2.95; dipole moment: 0.66 (gas), 0.67 in benzene @ 20 deg C (liquid) [R19, p. 4-62] *Enthalpy of formation: -8.23 kcal/mole; Gibbs (free) energy of formation: 0.21 kcal/mole; entropy: 63.86 cal/deg/mole; heat capacity: 15.64 cal/deg.mole [R19, p. 5-22] *Enthalpy of transition @ -123.2 deg C: 0.489 kcal/mole; enthalpy of sublimation @ 298 K: 6.61 kcal/mole; specific heat: 21.20 cal/K.mole @ 400 K, 29.31 cal/K/mole @ 600 K, 34.41 cal/K/mole @ 800 K, 37.39 cal/K/mole @ 1000 K [R19, p. 5-59] *Critical molar vol: 218 cu cm/mole [R19, p. 5-83] *STABLE TO ALKALIES, RESINIFIES ON EVAPORATION OR WHEN IN CONTACT WITH MINERAL ACIDS [R1, 672] *Slowly oxidizes in air to form peroxides. [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R20] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R20] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R20] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R20] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R20] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R20] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R20] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R20] FPOT: *Highly dangerous when exposed to heat or flame [R21] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R17] +Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R17] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R17] FLMT: +Lower 2.3%, upper 14.3% (% by vol) [R17] FLPT: *-32 deg F (-35 deg C) (Closed cup) [R1, 728] FIRP: *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. [R22] EXPL: *Moderate when exposed to flame. The low boiling point of this material makes it easy to obtain explosive concentrations of the vapor in inadequately ventilated areas. [R21] REAC: *Contact with acids can initiate a violent exothermic reaction. [R21] DCMP: *Furan is a heat-stable cmpd although, @ 670 deg C in the absence of catalyst, or @ 360 deg C in the presence of nickel, it decomposes to form a mixture consisting mainly of carbon monoxide, hydrogen, and hydrocarbons. [R23] EQUP: *Personnel protection: ... Wear appropriate chemical protective gloves, boots and goggles. [R22] *Breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for natural rubber (nat rub), neoprene (neop), neoprene/natural rubber (neop/nat rub), nitril rubber (nitril), chlorinated polyethylene (CPE), polyvinyl alcohol (PVA), and polyvinyl chloride (PVC). No data for butyl rubber (butyl), polyethlene (PE), polyurethane (PU), and viton. [R24] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R25, 1979.8] OPRM: *... Adequate ventilation /must/ be provided in areas handling this chemical. Contact with liq must be avoided since this chemical /furan/ can be absorbed through the skin. [R21] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R22] *Personnel Protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R22] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R25, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R25, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R25, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R25, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R25, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R25, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R25, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R25, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R25, 1979.11] SSL: */TURNS/ BROWN ON STANDING; COLOR CHANGE IS RETARDED IF SMALL AMT OF WATER ADDED [R26] *Unstabilized, it may form unstable peroxides on exposure to air and should always be tested before distillation. Washing with an aqueous solution of ferrous sulfate slightly acidified with sodium bisulfite will remove these peroxides. [R21] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R25, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R25, 1979.13] +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R25, 1979.13] CLUP: *PURIFICATION OF WASTEWATER CONTAINING FURAN COMPOUNDS WAS IMPROVED BY ADDING 5-500 MG/L ALKYLARYLPYRIDINIUM TO WASTEWATER. [R30] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R25, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U124, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R31] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. Also, good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. Also, a good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. /From table/ [R32] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R25, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R25, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R25, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R25, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R25, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of furan. There is sufficient evidence in experimental animals for the carcinogenicity of furan. Overall evaluation: Furan is possibly carcinogenic to humans (Group 2B). [R33] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R25, 1979.23] HTOX: *VAPORS ARE /CNS DEPRESSANT/. [R34] *Gastrointestinal congestion, liver damage, low blood pressure, fatigue, and headache are potential adverse effects following overexposure to furan. [R35] *A total of 39 molders and coreloakers exposed to furan resin sand and 27 unexposed local controls were examined by lung-function tests before and after a work shift. In all, 28 of the subjects exposed to furan resin sand and the control group were evaluated by dynamic spirometry and nitrogen washout. The remaining 11 subjects exposed to furan resin sand were studied using both static and dynamic spirometry and the CO single-breath technique. The time-weighted average exposure to furfuryl alcohol was about 7 mg/cu m, with peak values exceeding the present Swedish short-term exposure limit (40 mg/cu m). The exposure to respirable dust and formaldehyde as time-weighted over the shift was < 2 mg/cu m and 0.4 mg/cu m, respectively, in all groups. During the work shift studied, the 28 exposed subjects had more complaints of airway symptoms than did the controls, showing an average decrease of 0.21 in forced vital capacity but no fall in any other lung-function variable. The remaining 11 exposed subjects demonstrated a post-shift decrease in total lung capacity. The results indicate an acute restrictiveness induced by exposure to furan resin sand, but the underlying mechanism is unclear. Chronic impairment of lung function was not observed. [R36] NTOX: *FURAN IS ... HIGHLY TOXIC BY INHALATION IN ANIMALS ... SYMPTOMS OF INTOXICATION ... WITH INHALATION /ARE/ INCREASE IN RESPIRATORY RATE, FALL OF BLOOD PRESSURE, CONVULSIVE MOVEMENTS, COMPLETE ANESTHESIA, DEATH FROM ASPHYXIA DUE TO PARALYSIS OF THE MEDULLA. IT HAS BEEN SUGGESTED, ON BASIS OF ITS RESEMBLANCE TO DIVINYL ETHER, THAT IT MIGHT BE SUITABLE AS SURGICAL ANESTHETIC, BUT IT HAS MARKED TOXIC EFFECT ON CNS AND CAUSES MARKED FALL IN BLOOD PRESSURE AND INCREASE IN MUSCULAR TONUS AS ANESTHESIA DEEPENS. ... DOGS AND RABBITS COLLAPSED AND DIED AFTER 2 INHALATIONS FROM SATURATED COTTON WAD. [R37] *IT HAS A CORROSIVE EFFECT ON MUCOUS MEMBRANES OF MOUTH WHEN GIVEN ORALLY ... WITH ORAL ADMIN, A COPIOUS FLOW OF BLOODY SALIVA AND WATERY FLUID FROM NOSE /OCCURRED/. ... WITH IV INJECTION /IT/ CAUSES SYMPTOMS AND POST-MORTEM CHANGES SIMILAR TO THOSE OF ACUTE CYANIDE POISONING. ... CONVULSIONS /WERE/ FOLLOWED RAPIDLY BY DEATH. [R37] *CHANGES IN THE ORGANISM /ARE/ (1) GI TRACT HEMORRHAGES, WITH PARTIAL DESTRUCTION OF MUCOSA FOLLOWING ORAL ADMIN. (2) LUNGS MARKEDLY HYPEREMIC. (3) BLOOD VESSELS MUCH DILATED; BLOOD CHERRY RED. (4) KIDNEYS SOFT AND SWOLLEN. (5) LIVER RESEMBLED FIRST STAGES OF CHLOROFORM POISONING. [R37] *WHEN APPLIED IN 1-50% SOLUTIONS TO GUINEA PIG SKIN, FURAN WAS IRRITATING AND ALLERGENIC. [R38] *RESP TRACT RETENTION OF FURAN WAS STUDIED IN DOGS AS PART OF BROAD INVESTIGATION OF COMPOUNDS FOUND IN VAPOR PHASE OF CIGARETTE SMOKE. APPARENTLY, FURAN IS HIGHLY TOXIC AND IT IS READILY ABSORBED BY INHALATION ROUTE. [R39] *Serum transaminases (glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT) and ornithine carbamyltransferase) were determined in rats treated with subtoxic doses of furan. Only glutamic-oxalacetic transaminase increased in rats treated with furan. [R40] *Furan was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Furan was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9 fractions, at doses of 0.0333, 0.100, 0.3333, 1.000, and 3.3333 mg/plate. The highest ineffective dose tested in any S typhimurium strain was 3.3333 mg/plate. Precipitate was found in cultures containing the two highest doses. [R41] *... Male ICR Swiss mice ... were given a single ip injection of 5.1 mmol/kg of furan dissolved in sesame oil. Controls received an equivalent dose of sesame oil. Mice were sacrificed 24 hr postdosing. ... Furan induced massive centrilobular necrosis in the liver and slight proximal tubular necrosis in the kidneys. [R42] *... Male ddY mice, 7 wk of age, SPF-grade, received a single ip injection (0.2 mg/kg) of furan. ... Mice were sacrificed 24 hr after dosing. ... Severe coagulation necrosis of tubular cells of the kidney cortex, tubular precipitate, and slight atrophy of glomeruli were observed. Medullary cells appeared normal. The kidney lesions were accompanied by elevated levels of kidney calcium and plasma urea. The liver showed a massive coagulation necrosis of centrilobular parenchymal cells. /This was/ ... accompanied by elevated levels of liver calcium content and plasma glutamate pyruvate transaminase activity. The damaging effects ... on the kidneys and liver were prevented by pretreatment with inhibitors of microsomal enzymes, carbon disulfide, and diethyldithiocarbamate, admin orally 1 hr prior to furan admin. [R43] *... In male ICR mice ... furan caused lung damage at an ip dose of 5.15 mmol/kg in 5 ml sesame oil. Severe bronchiolar necrosis was observed in the lungs 24 hr postdosing. [R44] *Lethal concn for rats in air: 30400 ppm [R34] *Subchronic gavage studies /were conducted/ on furan and used F-344 rats and B6C3F1 mice for 13 weeks at doses ranging from 0-60 mg/kg furan in corn oil, 5 days/week. Groups of 10 male and 10 female rats and 10 female mice received doses of 60, 30, 15, 8, 4 and 0 mg/kg. Groups of 10 male mice received doses of 30, 15, 8, 4, 2 and 0 mg/kg. Gross necropsy was performed on all animals and data regarding mortality, body weight, organ weights, and clinical and histopathological signs of toxicity were evaluated. Complete histopathology was performed on all rats at the 60 and 30 mg/kg levels, all control rats and mice, female mice at the 60 mg/kg level and male mice at the 30 mg/kg level. Clinical signs of toxicity were mostly confined to male and female rats and female rats and female mice in the high-dose (60 mg/kg) group. Mortality occurred in 9/10 male and 4/10 female rats at the high-dose level. High-dose male and female rats and high-dose (30 mg/kg) male mice had treatment-related reduced rates of body weight gain. In rats, a dose-related increase in liver size was reported in all treated groups of males and in all but the low-dose group of females. Histopathological examination revealed a dose-related increased severity in liver lesions in the rats, with mild to minimal lesions observed at 4 mg/kg, the lowest level tested. Liver alterations associated with administration of furan included cytomegaly, degeneration, necrosis and nodular hyperplasia of the hepatocytes, cholangiofibrosis, hyperplasia of the bile duct epithelium and a pigment deposition in Kupffer cells. Additional lesions found only in high-dose animals that were considered treatment related were atrophy of the thymus and gonads, renal tubular dilatation and degeneration and necrosis of the renal tubular epithelium. In mice, treatment-related increases in liver weight were reported in males at a dose of greater than or equal to 15 mg/kg and in females at doses of greater than or equal to 30 mg/kg. The histopathological examination revealed a dose-related toxic hepatitis at greater or equal to 15 mg/kg in females and at greater than or equal to 8 mg/kg in males. Liver lesions were not found in male mice receiving doses of less than or equal to 8 mg/kg. In addition to the hepatic alterations reported above in rats, other liver changes reported in mice were focal fibrosis, focal cytological alteration, focal necrosis and focal supportive inflammation. [R45] *Furan ... produced incubation time and concn dependent decr in the glutathione (GSH) content and viability of freshly isolated F344 rat hepatocytes in vitro. Since furan itself did not significantly react with GSH, these data indicate the formation of a reactive metabolite of furan in hepatocyte suspensions. Treatment of the hepatocyte suspensions with the cytochrome p450 inhibitor 1-phenylimidazole delayed GSH depletion but did not alter furan induced (4-12 mM) cytolethality. The furan concentrations required to produce measurable hepatocyte lethality in vitro within 6 hr (4-12 mM) were several orders of magnitude greater than the predicted maximal liver concentrations of furan in vivo following hepatotoxic doses. In order to study the mechanisms involved in the cytolethality of furan toward hepatocytes in vitro at concentrations relevant to hepatotoxicity in vivo, a hepatocyte suspension culture system was developed that utilized furan concentrations and incubation times similar to hepatic dosimetry in vivo. Freshly isolated rat hepatocytes ... were incubated with furan (2-100 uM) for 1-4 hr and placed into culture, and viability was determined after 24 hr by lactate dehydrogenase release. Furan produced cytolethality (5-70%) and modest GSH depletion in an incubation time and concn dependent manner. Both GSH depletion and cytolethality induced by furan were prevented by 1-phenylimidazole and enhanced by acetone pretreatment in rats. /The results indicate/ that oxidation of furan by cytochrome p450 is required for GSH depletion and cytolethality, indicating that a reactive metabolite is involved in cell death. ... [R46] *Groups of 50 male and 50 female B6C3F1 mice, eight weeks of age, were administered 0, 8 or 15 mg/kg body weight furan (purity, > 99%) by gavage in corn oil on five days per week for 104 weeks. The numbers of surviving animals at the end of the study were reduced: 33/50 male controls, 17/50 at the low dose and 16/50 at the high dose (p= 0.009); and 29/50 female controls, 25/50 at the low dose and 2/50 at the high dose (p < 0.001). The incidence of hepatocellular adenomas was increased, with 20/50 among male controls, 33/50 at the low dose (p= 0.001, logistic regression analysis) and 42/50 at the high dose groups (p < 0.001). The incidence of hepatocellular carcinoma was also increased, occurring in 7/50 male controls, 32/50 at the low dose and 34/50 at the high dose (p < 0.001); and in 2/50 female controls, 7/50 at the low dose (p= 0.08) and 27/50 at the high dose (p < 0.001). All treated groups had high incidences of biliary hyperplasia, cholangiofibrosis, hepatocellular necrosis and focal hyperplasia. [R47] *Groups of 70 male and 70 female Fischer 344/N rats, seven to eight weeks of age, were administered 0, 2, 4 or 8 mg/kg body weight furan (purity, > 99%) dissolved in corn oil by gavage on fire days a week for 102 weeks. Interim evaluation were made on 10 rats from each group at 9 and 15 months. The numbers of animals still alive at the end of the study were 33/50 male controls, 28/50 at the low dose, 26/50 at the middle dose and 16/50 at the high dose (p < 0.001); and 24/50 female controls, 32/50 at the low dose, 28/50 at the middle dose and 19/50 at the high dose (p= 0.006). The incidence of hepatocellular adenomas was increased, and many rats had multiple adenomas; adenomas were found in 1/50 male controls, 4/50 at the low dose, 18/50 at the middle dose (p < 0.001, logistic regression analysis) and 27/50 at the high dose (p < 0.001); and in none of 50 female controls, 2/50 at the low dose, 4/50 at the middle dose (p= 0.048) and 7/50 at the high dose (p= 0.002). Hepatocellular carcinomas occurred only in males; 0/50 controls, 1/50 at the low dose, 6/50 at the middle dose (p= 0.009) and 18/50 at the high dose (p < 0.001). Cholangiocarcinomas were found in none of the control animals and in 43/50 males a the low dose, 48/50 at the middle dose and 49/50 at the high dose; and in 49/50 females a the low dose, 50/50 at the middle dose and 49/50 at the high dose (p < 0.001 for any group and either sex in comparison with controls). Biliary hyperplasia, cholangiofibrosis, hepatocellular necrosis and hyperplasia occurred in treated rats of each sex. The incidence of mononuclear-cell leukemia increased with does, occurring 8/50 male control, 11/50 at the low dos, 17/50 at the middle dose (p=0.022) and 21/50 at the high dose (p < 0.001). Cholangiocarcinomas, but no other tumors of the liver, were observed at 9 and 15 months, the incidence increasing with dose up to 100% at the high dose. In a 'stop-exposure' experiment, 50 males received 30 mg/kg body weight furan for 13 weeks, and 10 rats were killed and examined at 13 weeks and at 9 and 15 months; all animals were observed for two years. In addition to the lesions seen previously, cholangiocarcinomas were seen in all treated rats that survived for at least nine months, and 6/40 had hepatocellular carcinomas. [R47] *Repeated treatment of male Fischer 344 rats with furan by gavage at daily doses of 8 mg/kg body weight in corn oil, five days per week, resulted in a sustained, approximately 35 fold increase in the percentages of hepatocytes in S-phase over that in controls at weeks 1, 3 and 6. Northern blot analysis of mRNA expression in the livers showed up to a doubling of Ha-ras expression, but no measurable expression of fos, at weeks 1, 3 and 6. A the end of week 6, but not earlier, at approximately 10-fold increase in the expression of myc was observed. [R48] *Groups of 10 male and female Fischer 344/N rats and 10 female B6C3F1 mice received furan (purity, 99%) in corn oil at doses of 0, 4, 8, 15, 30 or 60 mg/kg body weight by gavage on five days per week for 13 weeks. Groups of 10 male mice received doses of 0, 2, 4, 8, 15 or 30 mg/kg body weight. In rats, dose-dependent bile-duct hyperplasia and cholangiofibrosis were observed, and animals at the high dose had renal tubular necrosis and dilatation and atrophy of the thymus, testes or ovaries. Mice had dose-dependent hepatic lesions with cytomegaly, degeneration, necrosis and bile-duct hyperplasia. [R48] *Furan administered by gavage to young adult male Fischer 344 rats at a dose of 60 mg/kg body weight per day five times per week for 10-14 days was highly toxic and induced marked atrophy of the right liver lobe. The cholangiolar-like structures that developed in this region consisted of biliary epithelial cells and ductular hepatocytes in various stages of maturation. Immunohistochemical and other phenotypic features of the cells were considered to be considered to be consistent with the development of rare bile ductular-like cell types from hepatocytes; in contrast, less severe treatment with furan led to the development of small intestinal-like glands. [R48] *Groups of male Fischer 344 rats were administered furan (purity, 99%) at 45 mg/kg body weight by gavage daily on five days per week for up to 32 days. Animals were killed on day 1, 3, 5, 7, 9, 12, 16, or 32. Severe hepatocellular necrosis was evident in the right and caudate lobes at the time of early sacrifices, and was followed by inflammatory cell infiltration, obvious bile-duct hyperplasia and then by development of metaplastic glands, ending with cholangiofibrosis by day 32. [R49] *Groups of five male Fischer 344 rats were administered furan (purity, 99%) in corn oil be gavage at does of 0, 15, 30, 45, or 60 mg/kg body weight daily on five days per week for three weeks; liver lesions were assessed by histology and histo- and immunochemistry. Animals at the two highest doses showed rapid development of severe cholangiofibrosis in the caudate liver lobe. Histologically, the lesion was characterized by well-differentiated hyperplastic bile ductules and numerous metaplastic intestinal glands supported by fibrous tissue. At the highest dose, cholangiolar-like structures were also observed. Phenotypic analysis of the hyperplastic ductular structures and of the metaplastic intestinal glands in the cholangiofibrotic areas suggested a precursor relationship between the ductular cells and the metaplastic cells. [R50] *In a study to characterize the histopathogenesis of intrahepatic cholangiocarcinomas induced by furan, groups of 10-12 young adult male Fischer 344 rats, weighing 160-190 g, were treated with 30 mg/kg body weight furan (purity, > 99%) in corn oil by gavage on five days a week for 6-13 weeks and observed up to 16 months. Lesions described as 'hepatic adenocarcinomas' occurred in the right caudate lobe of 4/9 rats treated for six weeks, 6/8 treated for nine weeks, 5/7 treated for 12 weeks and 9/10 treated for 13 weeks. Most of the tumors showed small intestinal differentiation, as reflected by the presence of goblet, Paneth and serotonin-positive cells. Two hepatocellular carcinomas were also found in the animals treated for 13 weeks. Cells from the adenocarcinoma cells did not contain TGF-alpha, but hepatocellular carcinoma cells did. [R51] *Furan was not mutagenic to Salmonella typhimurium after preincubation in the presence or absence of an exogenous metabolic activation system. It was reported in an abstract that furan was not mutagenic in a vapor-phase protocol. [R52] *Furna did not induce sex-linked recessive lethal mutations in Drosophila melanogaster when administered to adult flies by feeding or abdominal injection. [R52] *It was reported ... that furan did not induce unscheduled DNA synthesis in rat or mouse hepatocytes after treatment in vitro or in vivo. It induced gene mutation at the thymidine kinase locus of L5178Y mouse lymphoma cells in the absence of metabolic activation. Furan induced sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of metabolic activation. In another study, a positive response for the induction of chromosomal aberration was observed only at comparatively high dose in the presence of a live activation system from Arocolor 1254-pretreated male Swiss rats. [R52] *No sister chromatid exchanges or chromosomal aberrations were induced in bone-marrow cells of B6C3F1 male mice injected intraperitoneally with furan at doses up to 350 mg/kg body weight in vivo; however, chromosomal aberrations were induced at 250 mg/kg body weight in a extended protocol involving a late harvest time. [R52] *ras Proto-oncogene activation was studied in liver adenomas and carcinomas induced in B6C3F1 mice by furan. The frequency of activated H-ras and K-ras oncogenes was similar in hepatocellular tumors from 12/29 treated nice and in 15/27 vehicle controls, but the spectrum of activating mutations in the H-ras gene differed significantly. Although mutations occurred at codon 61 in tumors from both treated and untreated animals, mutations ... were observed in codon 117 only in animals treated with furan. [R52] *Groups of 10 Swiss albino mice (GP strain) given furan (purity not given) at a single dose of 300 mg/kg body weight in 0.9% sodium chloride intraperitoneally had centrilobular hepatic necrosis and coagulative necrosis of the proximal convoluted tubules of the outer renal cortex. Treatment of mice with the cytochrome p450 inhibitor piperonyl butoxide reduced the extent of liver necrosis and totally inhibited the renal necrosis. [R53] *The transplacental initiation-postnatal promotion model of mouse skin carcinogenesis is useful in studying the molecular and cellular mechanisms of perinatal carcinogenesis. Offspring transplacentally exposed to an initiating dose of a carcinogen typically do not produce any skin tumors in the absence of postnatal treatment; many skin tumors appear only when they are treated with tumor promoting agents postnatally. Tumor promoting agents alone produce no skin tumors or only a few. Thus, two stages of carcinogenesis, initiation and promotion, can be conveniently separated. Our results indicate that fetal c-Ha-ras can be transplacentally activated through a specific point mutation by a carcinogen. However, since postnatal promotion was essential for the production of tumors, they also suggest that a cell harboring such a mutation may remain dormant until it encounters a tumor promoting stimulus. Since a higher fraction of carcinomas than papillomas contained the specific mutation in Ha-ras, it is postulated that those papillomas with the point mutation have a selective advantage to progress towards carcinomas. [R54] *Preliminary results from the NTP bioassays of furan given by gavage indicate the induction of hepatocellular carcinomas in male F344 rats and in both sexes of B6C3F1 mice, and cholangiocarcinomas in both sexes of rats. To assess the genotoxicity of furan, chemically induced unscheduled DNA synthesis was evaluated in the in vivo hepatocyte DNA repair assay. Furan did not induce unscheduled DNA synthesis in hepatocytes isolated after single gavage treatment of male F344 rats (5, 30, and 100 mg/kg) or male B6C3F1 mice (10, 50, 100, and 200 mg/kg). Furan induced cytotoxicity and enhanced cell proliferation were evaluated in livers of rats and mice as events that also might give rise to mutations and/or drive tumor formation. The labeling index (LI, percentage of hepatocyte nuclei in S-phase) was measured histoautoradiographically following a single gavage administration of furan (30 mg/kg, male rats; 50 mg/kg, male mice) followed by an injection of 3H-thymidine 2 hr prior to sacrifice. Hepatocellular necrosis and a sharp increase in LI (23.9 for mice and 17.8 for rats versus less than 0.5 for controls) was observed 48 hr after treatment with furan, indicative of restorative cell proliferation secondary to cytotoxicity. Hepatocyte proliferation was evaluated also at the highest NTP bioassay dose (15 mg/kg/day for mice and 8 mg/kg/day for rats, 5 days/week) by labeling with 3H-thymidine administered via a 6 day osmotic pump implanted subcutaneously. Necrosis and inflammation were observed along the subcapsular visceral surface of the left or caudate liver lobes, likely due to diffusion of furan directly through the stomach to the liver. After 6 weeks of furan administration, male and female rats, but not mice, exhibited bile duct hyperplasia as well as metaplasia in the areas of fibrosis along the subcapsular visceral surface of the left or caudate liver lobes. The fold increase in hepatocyte LI in treated animals relative to the combined controls measured at weeks 1, 3, and 6 ranged from 39 to 5 for male mice, 18 to 51 for male rats, and 12 to 19 for female rats. Taken together, these data suggest that mechanisms other than direct DNA reactivity might explain the profile of oncogene mutations observed in the mouse liver tumors, including selective promotion of different subpopulations of preneoplastic cells and/or mutational events secondary to sustained cell proliferation or inflammation. The extensive amount of furan-induced cell proliferation subsequent to cytotoxicity likely had a significant impact on tumor development, and such data should be considered in risk evaluations for this compound. [R55] *The effect of nephrotoxic furans on urinary N-acetylglucosaminidase was examined in mice. ICR-mice were given: 100 mg/kg furan; 25, 50, or 100 mg/kg 2-ethylfuran; 250 mg/kg 3-ethylfuran; or 250 mg/kg 3-pentylfuran intraperitoneally. Sodium-salicylate, a known nephrotoxic, at 375 mg/kg and 3-methylthiopene, with no discernible nephrotoxic effects, at 500 mg/kg were given to similar mice. Results for each treated group were compared with an untreated group. Urine was collected for 24 hours after dosing and urinary N-acetylglucosaminidase was determined through absorbance of the p-nitrophenolate ion. Enzyme activity was expressed in units, representing 1 nanomole of substrate hydrolyzed per hour. Urinary N-acetylglucosaminidase was not affected by 3-methylthiopene and was increased by sodium-salicylate from 204 N-acetylglucosaminidase units to 428 N-acetylglucosaminidase units. All the furans caused a decrease in urinary N-acetylglucosaminidase. For furan, N-acetylglucosaminidase was 357 units for controls and 234 units for treated animals. Animals given 3-ethylfuran had urinary N-acetylglucosaminidase of 240 units. Those given 3-pentylfuran had 233 N-acetylglucosaminidase units in urine. Urinary N-acetylglucosaminidase was clearly dose related in animals given 2-ethylfuran. At 25 mg/kg N-acetylglucosaminidase was 187 units. At 50 mg/kg it dropped to 157 units. At 100 mg/kg it was only 60 units. The authors conclude that nephrotoxicity is associated with decreases in urinary N-acetylglucosaminidase although the mechanism is unclear. [R56] *Serum transaminases (GOT and GPT) and ornithincarbamyltransferase were determined in rats treated with subtoxic doses of furan, acetylfuran, and methylene chloride. Significant increases of all enzymes were observed in methylene chloride treated rats, while only GOT increased in rats treated with acetylfuran and with furan + methylene chloride. Calculation of the GOT/GPT ratios indicated a pattern of toxic hepatitis only for rats treated with acetylfuran and furan + methylene chloride. [R57] *Activated oncogenes in B6C3F1 mouse liver tumors and their relationship to carcinogenesis risk assessment were discussed. The usefulness of the B6C3F1 mouse liver bioassay in assessing potential hazards to humans was reviewed. The authors note that use of this assay is controversial because of the high incidence of liver tumors that occur with compounds that give negative results in other test systems, such as the Ames/Salmonella assay. Studies of activated oncogenes in chemically induced and spontaneously occurring B6C3F1 mouse liver tumors were reviewed. Studies with furan and furfural, two compounds that were positive in the mouse liver tumor bioassay but which gave negative results in the Ames/Salmonella assay, were described. These have indicated that the increased incidence of mouse liver tumors was due, at least in part, to the induction of weakly activating point mutations in ras oncogenes. Studies of activated oncogenes detected in hepatocellular tumors in B6C3F1 mice were discussed. These have resulted in detection of two activated raf genes and four nonras transforming genes as well as ras genes. Oligonucleotide analyses of activating mutations in ras oncogenes were considered. Mechanisms for oncogene activation in B6C3F1 mouse liver tumors were reviewed. Interpretation of mouse liver carcinogenesis data was discussed. The authors conclude that investigating patterns of oncogene activation in spontaneous and chemically induced mouse liver tumors not only provides insight into the mechanisms of tumor formation at the molecular level, but is useful for evaluating compounds, such as furan and furfural, that do not induce mutations in short term bacterial assays but give positive results in long term rodent carcinogenesis studies. [R58] NTOX: *Efforts were undertaken to determine 1 hour median lethal concentration data for furan, 2-methyl-furan, furfuryl-alcohol, and furfural in Sprague Dawley rats which could then be compared to the acute inhalation toxicity data as listed by the Department of Transportation under their rules for transporting Liquids Toxic by Inhalation. Each test material was administered as a vapor by using a bubbler for generation. The desired exposure level was achieved by controlling bubbler temperature and the flow rate of dilution air. Signs of toxicity observed during exposure included respiratory distress, increased secretory responses, and at higher concentrations, death. In many cases death did not result until the first or second week after exposure was completed. The median lethal dose obtained for 2-methyl-furan after 1 hour of exposure was 1,485 ppm; for furfuryl-alcohol, 592 ppm; for furfural, 1,037 ppm; and for furan, 3,464 ppm. Saturated vapor concentrations for each of the four materials at 20 deg C were as follows: furan, 650,000 ppm; 2-methyl-furan, 19,000 ppm; furfuryl-alcohol, 660 ppm; and furfural, l,400 ppm. [R59] *In a 2-yr carcinogenicity bioassay, 0, 2, 4, or 8 mg furan/kg body weight was administered to male and female Fischer (F344) rats and resulted in an 86-100% incidence of cholangiocarcinomas with occasional metastasis. In a separate but concurrent study, male F344 rats dosed with 30 mg furan/kg body weight for 90 days developed marked cholangiofibrosis and cholangiohepatitis and, when subsequently maintained without further treatment for an additional 6, 12, or 18 months, the cholangiofibrosis progressed to yield a 100% incidence of cholangiocarcinomas. Transplantation of 21 primary cholangiocarcinomas into syngeneic recipients resulted in growth from 4 donors. The 4 transplanted lines were successfully transferred through 8 serial passages and resulted in metastases in the recipients. The progressive growth of these proliferative hepatocholangial lesions over time, their transplantability, and the development of metastases in some of the cases provide biological evidence of the malignant potential of the furan-induced liver changes. [R60] *Furan, a rodent hepatotoxicant and hepatocarcinogen, produced incubation time- and concentration-dependent decreases in the glutathione (GSH) content and viability of freshly isolated F344 rat hepatocytes in vitro. Since furan itself did not significantly react with GSH, these data indicate the formation of a reactive metabolite of furan in hepatocyte suspensions. Treatment of the hepatocyte suspensions with the cytochrome P450 inhibitor l-phenylimidazole delayed GSH depletion but did not alter furan-induced (4 to 12 mM) cytolethality. The furan concentrations required to produce measurable hepatocyte cytolethality in vitro within 6 hr (4 to 12 mM) were several orders of magnitude greater than the predicted maximal liver concentrations of furan in vivo following hepatotoxic doses. In order to study the mechanisms involved in the cytolethality of furan toward hepatocytes in vitro at concentrations relevant to hepatotoxicity in vivo, a hepatocyte suspension/culture system was developed that utilized furan concentrations and incubation times similar to hepatic dosimetry in vivo. Freshly isolated rat hepatocytes in suspension (in Williams' Medium E) were incubated with furan (2 to 100 microM) for 1-4 hr and placed in culture, and viability was determined after 24 hr by lactate dehydrogenase release. Furan produced cytolethality (5 to 70%) and modest GSH depletion in an incubation time- and concentration-dependent manner. Both GSH depletion and cytolethality induced by furan were prevented by l-phenylimidazole and enhanced by acetone pretreatment of the rats. These data show that oxidation of furan by cytochrome P450 is required for GSH depletion and cytolethality, indicating that a reactive metabolite is involved in cell death. The results of this study underscore the importance of using in vivo toxicant concentrations and exposure times for in vitro mechanistic studies of chemically induced cytolethality. [R61] +... Conclusions: Under the conditions of these 2 yr gavage studies there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. [R62] ETXV: *LC50 Pimephales promelas (fathead minnow) 29-31 days 61 mg/l/96 hr, @ 23.2 deg C, pH 8.00, water hardness 44.5 mg/l CaCO3, flow-through bioassay; [R63] NTP: +... Toxicology and carcinogenesis studies were conducted by administering furan (purity > 99%) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... 2 Yr Studies: Groups of 70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in corn oil by gavage 5 days/wk for 2 yr. ... Groups of 50 mice of each sex received doses of 8 or 15 mg/kg furan 5 days per week for 2 yr. Conclusions: Under the conditions of these 2 yr gavage studies there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. [R62] ADE: *Absorbed ... by way of dermal route. [R21] *RESP UPTAKE IN DOGS WAS 90-95%, VARYING INVERSELY WITH VENTILATORY RATE. RETENTION WAS NOT AFFECTED BY TIDAL VOL CHANGES BUT WAS DIRECTLY RELATED TO CONCN INHALED FROM CIGARETTE SMOKE. FURAN IS READILY ABSORBED BY INHALATION ROUTE. [R64] *... The kinetics of furan biotransformation my male F344 rats were studied in vivo and in vitro in order to understand target tissue dosimetry. A physiologically based pharmacokinetic (PBPK) model for furan in rats was developed from gas uptake studies using the initial furan concn of 100, 500, 1050, and 3850 ppm. Tissue partition coefficients for furan were determined in vitro using vial equilibration techniques. Furan gas uptake kinetics in vivo were described by a single saturable process with a V(max) of 27.0 umol/hr/250 g rat and a K(m) of 2.0 uM. Furan metabolism in vivo was inhibited by pyrazole. The furan PBPK model adequately simulated blood and liver furan concn following 4 hr inhalation exposures to 52, 107, and 208 ppm furan. The biotransformation of furan was studied in freshly isolated rat hepatocytes exhibited a K(m) of 0.4 uM and a V(max) of 0.018 umol/hr/1x10(6) cells. Inhibition and induction studies indicated that cytochrome p450 was the catalyst of furan oxidation. ... /This data/ suggests that freshly isolated hepatocytes are a valuable in vitro system for predicting chemical pharmacokinetics in vivo. [R65] ACTN: *... Hepatic and renal injury produced by furan is the result of metabolic activation of the compound by cytochrome p450 oxygenases into chemically reactive metabolites. [R66] INTC: *Diethyldithiocarbamate and carbon disulfide prevented mice from renal injury induced by furan as evidenced by suppression of elevations in plasma urea nitrogen concn and kidney calcium content and by morphological alterations. In carbon tetrachloride-poisoned mice, furan nephrotoxicity was augmented. The augmented furan nephrotoxicity was also prevented by diethyldithiocarbamate or carbon disulfide. Thus, furan may exert nephrotoxicity through active metabolites formed in the kidney. Diethyldithiocarbamate and carbon disulfide also protected against hepatotoxicity induced by furan. As an extension of these studies, similar experiments were undertaken with furan, bromobenzene and cephaloridine, and other nephrotoxic agents that are also thought to require metabolic activation. Diethyldithiocarbamate or carbon disulfide prevented mice from suffering renal injury induced by furan and bromobenzene, as evidenced by suppression of elevations in plasma urea nitrogen concentration and kidney calcium content and of morphologic alterations. Cephaloridine nephrotoxicity, however, was not prevented. In carbon tetrachloride-poisoned mice, furan nephrotoxicity was augmented, whereas bromobenzene and cephaloridine nephrotoxicity was suppressed. The augumented furan nephrotoxicity was also prevented by diethyldithiocarbamate or carbon disulfide. These observations suggest that furan, like chloroform and 1,1-dichloroethylene, may exert nephrotoxicity through active metabolites formed in the kidney. For bromobenzene and cephaloridine nephrotoxicity, a renal bioactivation mechanism is suspected. Diethyldithiocarbamate and carbon disulfide also protected against hepatotoxicity induced by furan and thiophene. [R67] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Furan occurs in oils obtained by the distillation of pine wood containing rosin. Furan has been identified in volatile emissions from sorb trees and is a constituent of tobacco smoke. Furan's production and use in organic synthesis for pyrrole and thiophene, formation of lacquers, and as a solvent for resins, may result in its release to the environment through various waste streams. For example, energy related processes such as oil refining, coal mining, and coal gasification release furan in the effluent, and it is released to air as a gas phase component of cigarette smoke, wood smoke and exhaust gas from diesel and gasoline engines. Furan has been detected in samples of river water, effluents, household waste headspace, ambient air, in food such as roasted filbert, mutton, chicken, beef and mother's milk, and in expired human air. If released to soil, furan should have high mobility. Volatilization of furan may be important from moist and dry soil surfaces given an estimated Henry's Law constant of 5.4X10-3 atm-cu m/mole and an experimental vapor pressure of 600 mm Hg. According to biodegradation studies conducted in aquifer slurries, biodegradation of furan in soil and water will be slow, except for sulfate-reducing conditions where biodegradation may occur more quickly. If released to water, furan would not adsorb to suspended solids and sediment. Furan would volatilize from water surfaces with estimated half-lives for a model river and model lake of 2.5 hours and 3.3 days, respectively. Experimental BCF values of 0.9-1.5 and < 3.2-13 suggest that furan will not bioconcentrate in aquatic organisms. If released to the atmosphere, furan will exist as a vapor. Vapor-phase furan is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 9.5 hours. Particulate-phase furan may be physically removed from the air by wet deposition. The most probable route of exposure to furan by the general population and workers is inhalation. (SRC) NATS: *Furan occurs in oils obtained by the distillation of pine wood containing rosin(1). Furan has been identified in volatile emissions from sorb trees(2). [R68] ARTS: *Furan is a constituent of tobacco smoke. [R69] *Furan is discharged in municipal as well as industrial effluents. Energy related processes such as oil refining, coal mining, and coal gasification release furan in the effluent. [R70] *Furan is released to air as a gas phase component of cigarette smoke(1), wood smoke(2) and exhaust gas from diesel and gasoline engines(3). Furan's production and use in organic synthesis for pyrrole and thiophene(4), formation of lacquers(5), and as a solvent for resins(5), may result in its release to the environment through various waste streams(SRC). [R71] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 128(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that furan should have high mobility in soil(SRC). Volatilization of furan may be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 5.4X10-3 atm-cu m/mole(SRC), calculated from experimental values for vapor pressure(4) and water solubility(5). Volatilization from dry soil surfaces should also be important(SRC) based on an experimental vapor pressure of 600 mm Hg(SRC)(4). According to biodegradation studies conducted in aquifer slurries, biodegradation of furan in soil will be slow(6-10), except for sulfate-reducing conditions where biodegradation may occur more quickly(10). [R72] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 128(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(1), indicates that furan would not adsorb to suspended solids and sediment(SRC) in the water. Furan would volatilize from water surfaces based on an estimated Henry's Law constant of 5.4X10-3 atm-cu m/mole(SRC), calculated from experimental values for vapor pressure(3) and water solubility(4). Estimated half-lives for a model river and model lake are 2.5 hours and 3.3 days, respectively(1,SRC). Experimental BCF values of 0.9-1.5 and < 3.2-13(5) suggest that furan will not bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(6). According to biodegradation studies conducted in aquifer slurries, biodegradation of furan in water will be slow(5, 7-10), except for sulfate-reducing conditions where biodegradation may occur more quickly(10). [R73] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), furan, which has an experimental vapor pressure of 600 mm Hg at 25 deg C(2), will exist as a vapor in the ambient atmosphere. Vapor-phase furan is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 9.5 hours(3,SRC). Particulate-phase furan may be physically removed from the air by wet deposition(SRC). [R74] BIOD: *A four-week biodegradation study using 30 mg/l sludge and a furan concentration of 100 mg/l gave a theoretical BOD of 4%(1). In an anoxic aquifer slurry, furan did not mineralize and no transformation products were detected by HPLC(2). After 16 months incubation time, 80 percent of the initial furan remained(2). Adaptation (time to reach 5% reduction) and degradation (total time to reach < 1 ug/l) times for aerobic degradation of furan (initial concentrations 150-250 ug/l and 50 times dilution) in a mixture of aromatic hydrocarbons and nitrogen, sulfur, oxygen containing compounds were 390 and 160 hours and 530 and 340 hours, for the two concentrations, respectively(3). The theoretical gas production from anaerobic biodegradation of furan in diluted primary digesting sludge was - 22% with a lag period of > 70 days(4). The disappearance of furan in sulfate-reducing and methanogenic aquifer slurries after 1, 3, and 8 months are as follows: 11, 0, 0 and 102, 58, and < 3%(5). [R75] ABIO: *The rate constant for the vapor-phase reaction of furan with photochemically produced hydroxyl radicals has been experimentally determined to be 4.05X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 9.5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R76] *Furan is expected to be resistant to chemical hydrolysis under environmental conditions(1,SRC). The half-life for the reaction of furan with singlet oxygen in water has been estimated to be 1 hour based on a measured reaction rate constant of 1.4X10+8 L/mole-sec and assuming an ambient singlet oxygen concentration of 1X10-12 mole/l(2). The half-life for the reaction of furan vapor with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 6 hours using a experimentally derived rate constant of 4.0X10-11 cu cm/molecule-sec at 22 deg C and an average atmospheric hydroxyl radical concentration of 8.0X10+5 molecules/cu cm(3,SRC). The half-life for furan reacting with ozone in the atmosphere has been estimated to be approximately 6 days using an experimentally derived reaction rate constant of 2.4X10-18 cu cm/molecule-sec at room temperature and an average ambient hydroxyl radical concentration of 6.0X10+11 molecules/cu cm(3,SRC). The half-life for the night time reaction of furan with nitrate radicals has been estimated to be 34 minutes based on an experimentally derived reaction rate constant of 1.4X10-2 cu cm/molecule-sec at room temperature and an average night time nitrate radical concentration of 2.4X10+8 molecules/cu cm (nitrate radicals are unstable in sunlight)(3,SRC). [R77] *The half-life for the reaction of furan with photochemically generated hydroxyl radicals at 22 deg C has been calculated to be 6.0 and 2.3 hours, using experimentally devised rate constants of 4.0X10-11 and 1.05X10-10 mg/cu m/molecule-sec, respectively, and an average atmospheric hydroxyl radical concentration of 8.0X10-5 molecules/mg/cu m. The half-life for furan reaction with ozone in the atmosphere was estimated to be 3.3 days, using an experimentally derived reaction rate constant of 2.4X10-18 mg/cu m/molecule-sec at room temperature an average ambient ozone concentration of 1X10-12 molecules/mg/cu m. [R78] BIOC: *A six-week bioconcentration study using carp and furan concentrations of 1 and 0.1 mg/l gave BCF values of 0.9-1.5 and < 3.2-13, respectively(1). According to a recommended classification scheme(3), these BCF values suggest that bioconcentration in aquatic organisms will not be an important fate process(SRC). [R79] KOC: *The Koc of furan is estimated as approximately 128(SRC), using an experimental log Kow of 1.34(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that furan should have high mobility in soil(SRC). [R80] VWS: *The Henry's Law constant for furan is estimated as 5.4X10-3 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 600 mm Hg(1), and water solubility, 10,000 mg/l(2). This value indicates that furan will volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 2.5 hours(3,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 3.3 days(3,SRC). Furan's vapor pressure(1) and Henry's Law constant(1,2,SRC) indicate that volatilization from dry and moist soil surfaces may occur(SRC). [R81] WATC: *SURFACE WATER: Furan has been qualitatively identified in the Niagara River and 2 creeks in the Niagara River watershed(1,2). [R82] EFFL: *Furan has been detected in one of seven aqueous effluents from energy-related processes. In one site, it was found at a concn of 7 + or - 4 ppb in the effluent of the aqueous condensate from low-Btu gasification of Rosebud coal, Morgantown, WV. [R70] *Furan was detected in 1/63 industrial effluents at a concentration of < 10 ug/L(1). Furan was detected in aqueous condensate samples from low-Btu gasification of rosebud coal at a concentration of 7+/-4 ppb(2). It was not detected (detection limit 0.1 ppb) in groundwater or coal water prior to in situ coal gasification, product water samples obtained during in situ coal gasification, retort water from in situ oil shale processing or boiler blowdown water from in situ oil shale processing(2). [R83] *Furan was identified in the headspace above household waste in one out of 4 biodegradable (kitchen/biological) waste samples at < 0.01 mg/cu m(1). [R84] ATMC: *Furan has been detected at trace levels in the ambient air of the Kanawha Valley, WV at South Charleston (two different dates) and at St. Albans(1). [R85] FOOD: *Furan has been identified as a volatile component of roasted filberts(1). Furan has been identified in the volatile component of mutton, chicken, and beef(2). [R86] PFAC: PLANT CONCENTRATIONS: *Furan is identified in volatile emissions from arboreous plants (Genus: Sorbus)(1). [R87] MILK: *Furan has been qualitatively identified in mother's milk from Baton Rouge(1). [R88] RTEX: *Can be absorbed through the skin and resp tract. [R21] *The most probable route of exposure to furan by the general population and workers is inhalation(SRC). Detection of furan in 1 out of 12 samples of mother's milk suggests that a small number of breastfed infants may be exposed to this compound by ingestion (1,SRC). [R89] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 35 workers (7 of these are female) are potentially exposed to furan in the USA(1). [R90] BODY: *Furan was detected in the expired air of 2/3 male smokers and 4/5 male nonsmokers at the Brooks Air Force Base, TX with the rate of expiration ranging from 0.25-98 ug/hour for smokers and from 0.33-28 ug/hour for nonsmokers(1). This compound was also identified in 15/387 samples of expired air taken from 54 male and female nonsmokers from Chicago, IL mean concn 0.547 ng/L(2). Furan was qualitatively identified in 1/12 samples of mother's milk obtained from women in 4 different urban areas(3). [R91] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: +Workplace Environmental Exposure Level (WEEL): Worker exposure by all routes should be minimized to the fullest extent possible. [R92] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R93] +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Furan is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R94] RCRA: *U124; As stipulated in 40 CFR 261.33, when furan, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R95] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HAZARDOUS GASES FROM FIRES WERE ANALYZED BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY. [R96] *WASTE GASES FROM PLANT WERE ANALYZED BY GLC, MASS SPECTROMETRY, AND SECONDARY-ION MASS SPECTROMETRY. [R97] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Boyd MR; Adv Exp Med Biol 136B (Biol React Intermed - 2, Chem Mech Biol Eff, Pt B): 865-79 (1982). A review with 41 ref covering acute tissue lesions caused by furan derivatives, toxification and detoxification pathways, ultimate metabolites, effects of species, age, sex, and inducer treatment on liver and other target organ metabolism and toxicity, and the significance of cell-specific activation in target tissues. NTP; Executive Summary: Furan (Draft) (1986) ITC/USEPA; Information Review #201 (Draft) Furan (1980) Hasselriis F; APCA Annu, Meet 78 (6):85-76A (1985) Pankova VB; Zh Ushn Nos Gorl Bolezn 3: 42-7 (1981). Occupational allergies of the upper respiratory system Corsi GC et al; Boll Soc Ital Biol Sper 59 (8): 1049-52 (1983). Effect of subtoxic amounts of furan, acetylfuran and methylene chloride on some serum enzymes of rat. USEPA; Health and Environmental Effects Profile for Furan; (1987) ECAO-CIN-GO20 Lee A et al; Govt Reports Announcements and Index 05 (1987) DHHS/NTP; Toxicology and Carcinogenesis Studies of Furan in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 402 (1993) NIH Publication No. 93-2857 SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 545 R3: ITC/USEPA; Information Review #201 (Draft) Furan p.2 (1980) R4: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1994. 82 R5: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 655 R6: SRI R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA12 120 R8: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-539 R9: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 404 R10: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-167 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 502 (1980) R12: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 8 R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 647 R14: Valvani SC et al; J Pharm Sci 70: 502-7 (1981) R15: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-311 R16: Aldrich; The Aldrich Microfiche Library of Chemical Indices (1983) R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-55 R18: Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation; Design Inst Phys Prop Data, Amer Inst Chem Eng. Hemisphere Pub Corp, NY,NY 4 Vol (1989) R19: Dean, J.A. Handbook of Organic Chemistry. New York, NY: McGraw-Hill Book Co., 1987. R20: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-127 R21: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1462 R22: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 526 R23: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 516 (1980) R24: ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.55 (1983) R25: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R26: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 545 R27: 49 CFR 171.2 (7/1/96) R28: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 154 R29: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3034-2 (1988) R30: ARTEMEVA NA ET AL; USSR PATENT NUMBER 831744 (5/23/81) R31: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R32: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (1981) EPA 68-03-3025 R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 63 404 (1995) R34: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 613 R35: NTP; Executive Summary: Furan (Draft) p.7 (1986) R36: Ahman M et al; Int Arch Occup Environ Health 63 (3): 175-180 (1991) R37: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 699 R38: CHERNOUSOV AD; GIG SANIT 6: 28-32 (1974) R39: EGLE JL JR, GOCHBERG BJ; AM IND HYG ASSOC 40 (4): 310-4 (1979) R40: Corsi GC et al; Boll-Soc Ital Biol Sper 59 (8): 1049-52 (1983) R41: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R42: Wiley RA et al; Toxicol Appl Pharmacol 74: 1-9 (1984) as cited in NTP; Executive Summary: Furan (Draft) p.9 (1986) R43: Masuda Y et al; Jpn J Pharmacol 34: 221-9 (1984) as cited in NTP; Executive Summary: Furan (Draft) p.12 (1986) R44: Gammal LM et al; Toxicology 30: 177-84 (1984) as cited in NTP; Executive Summary: Furan (Draft) p.13 (1986) R45: SRI, Subchronic Toxicity Report on Furan (C56202) in Fischer-344 Fats and in B6C3F1 Mice (1982a and b) as cited in USEPA; Health and Environmental Effects Profile for Furan; p.15-16 (1987) ECAO-CIN-GO20 R46: Carfagna MA et al; Tox Appl Pharm 123 (2): 265-73 (1993) R47: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 396 (1995) R48: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 400 (1995) R49: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 399 (1995) R50: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V65 399 (1995) R51: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 397 (1995) R52: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 401 (1995) R53: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 398 (1995) R54: Yamasaki H et al; IARC Sci Publ (96): 221-37 (1989) R55: Wilson DM; Environ Mol Mutagen 19 (3): 209-222 (1992) R56: Wiley RA et al; Toxicology Letters 14 (No. 1-2): 93-96 (1982) R57: Corsi GC et al; Boll Soc Ital Biol Sper 59 (8): 1049-52 (1983) R58: Reynolds SH et al; Science 237 (4820): 1309-1316 (1987) R59: Terrill JB et al; American Industrial Hygiene Association Journal 50: A359-A361 (1989) R60: Maronpot RR et al; Toxicol Pathol 19 (4 Part 2): 561-570 (1991) R61: Carfagna MA et al; Toxicol Appl Pharmacol 123 (2): 265-73 (1993) R62: Toxicology and Carcinogenesis Studies of Furan in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 402 (1993) NIH Publication No. 93-2857 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R63: Brooke, L.T., D.J. Call, D.T. Geiger and C.E. Northcott (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Superior, WI: Center for Lake Superior Environmental Studies Univ. of Wisconsin Superior, 1984.85 R64: EGLE JL, GOCHBERG BJ; AM IND HYG ASSOC J 40 (4): 310-4 (1979) R65: Kedderis GL et al; Toxicol Appl Pharm 123 (2): 274-82 (1993) R66: NTP; Executive Summary: Furan (Draft) p.12 (1986) R67: Masuda Y et al; Jpn J Pharmacol 34 (2): 221-9 (1984) R68: (1) Windholz M ed; The Merck Index 10th ed. Merck Co. Rahway, NJ p. 613 (1983) (2) Isidorov VA et al; Atmos Environ 19: 1-8 (1985) R69: KIRK-OTHMER CONDENSED ENCYC CHEM TECH 1985 p.543 R70: ITC/USEPA; Information Review #201 (Draft) Furan p.8 (1980) R71: (1) Sakuma H et al; Nippon Sembai Kosha Chuo Kenkyusho Kenkyu Hokoku 117: 47-54 (1975) (2) Kleindienst TE et al; Environ Sci Tech 20: 493-501 (1986) (3) Hampton CV et al; Environ Sci Tech 16: 287-98 (1982) (4) Lewis RJSr; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Rheinhold Co pg 545 (1993) (5) Browning E; Toxicity and Metabolism of Industrial Solvents. NY,NY: American Elsevier pg 698 (1965) R72: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. ACS Profess Refer Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 8 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation; Design Inst Phys Prop Data, Amer Inst Chem Eng. NY,NY: Hemisphere Pub Corp, 4 Vol (1989) (5) Valvani SC et al; J Pharm Sci 70: 502- 7 (1981) (6) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (7) Adrian NR, Suflita JM; Environ Toxicol Chem 13: 1551-7 (1994) (8) Arvin E et al; Int Conf Physiochemical Biol Detox Hazard Wastes 2: 828-47 (1989) (9) Battersby NS, Wilson V; Appl Environ Microbiol 55: 433-9 (1989) (10) Kuhn EP, Suflita JM; Environ Toxicol Chem 8: 1149-58 (1989) R73: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Hansch C et al; Exploring QSAR. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 8 (1995) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation; Design Inst Phys Prop Data, Amer Inst Chem Eng. NY,NY: Hemisphere Pub Corp 4 Vol (1989) (4) Valvani SC et al; J Pharm Sci 70: 502-7 (1981) (5) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Adrian NR, Suflita JM; Environ Toxicol Chem 13: 1551-7 (1994) (8) Arvin E et al; Int Conf Physiochemical Biol Detox Hazard Wastes 2: 828-47 (1989) (9) Battersby NS, Wilson V; Appl Environ Microbiol 55: 433-9 (1989) (10) Kuhn EP, Suflita JM; Environ Toxicol Chem 8: 1149-58 (1989) R74: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation; Design Inst Phys Prop Data, Amer Inst Chem Eng. NY,NY: Hemisphere Pub Corp, 4 Vol (1989) (3) Atkinson R; J Phys Chem Ref Data. Monograph No. 1 (1989) R75: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Adrian NR, Suflita JM; Environ Toxicol Chem 13: 1551-7 (1994) (3) Arvin E et al; Int Conf Physiochemical Biol Detoxif Hazard Wastes 2: 828-47 (1989) (4) Battersby NS, Wilson V; Appl Environ Microbiol 55: 433-9 (1989) (5) Kuhn EP, Suflita JM; Environ Toxicol Chem 8: 1149-58 (1989) R76: (1) Atkinson R; J Phys Chem Ref Data. Monograph No. 1 (1989) R77: (1) Lyman WJ et al; Handbook of Chem Property Estimation Methods McGraw-Hill NY p. 7-4 (1982)) (2) Mill T, Mabey W; p. 221 in Environmental Exposure from Chemicals Vol 1 Neely WB, Blau GE eds CRC Press Boca Raton FL (1985) (3) GEMS; Graphical Exposure Modeling System. FAP. Fate of Atmos Pollut (1986) R78: USEPA, Fate of Atmosphenic Pollutants, Office of Toxic Substances, USEPA Washington DC. (1987) R79: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R80: (1) Hansch C et al; Exploring QSAR. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 8 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R81: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation; Design Inst Phys Prop Data, Amer Inst Chem Eng. NY,NY: Hemisphere Pub Corp, 4 Vol (1989) (2) Valvani, SC et al; J Pharm Sci 70: 502-7 (1981) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R82: (1) Elder VA et al; Environ Sci Tech 15: 1237-43 (1981) (2) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lake Ecosystem. Vol 1. p. 195 (1983) R83: (1) Perry DL et al; Identification of Organic Compounds in Industrial Effluent Discharges (1979) USEPA 600/4-79-016 NTIS PB-294794 (2) Pellizzari ED et al; ASTM Spec Tech Publ STP 686: 256-74 (1979) R84: (1) Wilkins K; Chemosphere 29: 47-53 (1994) R85: (1) Erickson MD, Pellizzari ED; Analysis of Organic Air Pollutants in the Kanawha Valley, WV and the Shenandoah Valley, VA USEPA-903/9-78-007 (1978) R86: (1) Kinlin TE et al; J Agric Food Chem 20: 1021 (1972) (2) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R87: (1) Singh HB, Zimmerman PB; Adv Environ Sci Technol 24: 177-243 (1992) R88: (1) Erickson MD et al; Acquisition and Chemical Analysis of Mother's Milk for Selected Toxic Substances. Office of Pesticides and Toxic Substances Washington, DC EPA-560/13-80-029 (1980) R89: (1) Pellizarri ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R90: (1) NIOSH; National Occupational Exposure Survey (NOES)(1983) R91: (1) Conkle JP et al; Arch Environ Health 30: 290-5 (1975) (2) Krotoszynski BK et al; J Anal Toxicol 3: 225-34 (1979) (3) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-6 (1982) R92: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R93: 40 CFR 302.4 (7/1/94) R94: 40 CFR 355 (7/1/97) R95: 40 CFR 261.33 (7/1/94) R96: BERG S ET AL; INT SYMP CONTROL AIR POLLUT WORK ENVIRON (PROC) PART 1: 309-21 (1978) R97: ABE K ET AL; TAIKI OSEN GAKKAISHI 15 (6): 262-6 (1980) RS: 95 Record 18 of 1119 in HSDB (through 2003/06) AN: 91 UD: 200211 RD: Reviewed by SRP on 03/16/1990 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N-HEXANE- SY: *DIPROPYL-; *ESANI- (ITALIAN); *HEKSAN- (POLISH); *HEXANE-; *HEXANEN- (DUTCH); *HEXYL-HYDRIDE-; *NCI-C60571-; *SKELLYSOLVE-B- RN: 110-54-3 MF: +C6-H14 SHPN: UN 1208; HEXANE IMO 3.1; Hexane STCC: 49 081 83; Hexane MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- IMP: *The isomers most commonly accompanying it are 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane and 2,2-dimethylbutane. [R1, 1042] USE: *DETERMINATION OF REFRACTIVE INDEX OF MINERALS, FILLING FOR THERMOMETERS [R2] *CALIBRATIONS, PAINT DILUENT [R3] *SOLVENT IN EXTRACTION OF SOYBEAN OIL, COTTONSEED OIL, FLAXSEED OIL, SAFFLOWER SEED OIL AND OTHER OIL SEEDS; REACTION MEDIUM IN MANUFACTURE OF POLYOLEFINS, ELASTOMERS, PHARMACEUTICALS; COMPONENT OF NUMEROUS FORMULATED PRODUCTS [R4] *AS DENATURANT FOR ALCOHOL (COMMERCIAL GRADES) [R5] *Cleaning agent for textile, furniture, and leather industries. [R6] *Laboratory reagent [R7] *Component of many products associated with the petroleum(1-3) and gasoline industries(3-5). [R8] CPAT: *APPROXIMATELY 30% OF ALL HEXANE IS USED FOR SOYBEAN EXTRACTION (1972) [R4] PRIE: U.S. IMPORTS: *(1972) NEGLIGIBLE [R4] U.S. EXPORTS: *(1972) NEGLIGIBLE [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R2]; +Colorless liquid. [R9] ODOR: +Gasoline-like odor. [R9] MW: *86.18 [R2] OWPC: +log Kow= 3.90 [R10] VAPD: *2.97 (AIR= 1) [R11, 3178] VAP: *150 MM HG @ 24.8 DEG C [R12] OCPP: *Wt/vol conversion: 3.52 mg/cu m= 1 ppm [R11, 3178] *VERY VOLATILE [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: +Strong oxidizers. [R13, 162] SERI: *MAY BE IRRITATING TO RESPIRATORY TRACT ... [R2] *Hexane is irritant to the skin. [R11, 3186] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R13, 162] +Wear appropriate eye protection to prevent eye contact. [R13, 162] +Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R13, 162] +Recommendations for respirator selection. Max concn for use: 1100 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R13, 162] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R13, 162] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R13, 162] OPRM: +Contact lenses should not be worn when working with this chemical. [R13, 162] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *BEFORE HEAT IS APPLIED FOR THE PURPOSE OF CUTTING OR WELDING A VESSEL THAT HAS CONTAINED ... ALL REMAINING RESIDUES MUST BE DRAINED ... /AND VESSEL/ PURGED WITH STEAM ... THIS PRECAUTION ... /ENSURES/ THAT EXPLOSIVE CONCN OF VAPOR AND AIR WILL NOT BE FORMED ... GOOD VENTILATION WILL PREVENT FORMATION OF HARMFUL CONCN OF THESE VAPORS IN NORMAL WORKPLACES. IN CONFINED SPACES LIKE A PROCESS OR STORAGE VESSEL OR A GARAGE INSPECTION PIT, HIGH CONCN CAPABLE OF CAUSING UNCONSCIOUSNESS OR DEATH HAVE BEEN KNOWN TO DEVELOP ... /HYDROCARBONS, ALIPHATIC/ [R1, 1072] *Products that have been treated with materials containing n-hexane may ... be dangerous during the evaporation stage. They must be left to dry in suitable places under a hood and not in the ordinary workplace. [R1, 1044] *Employees should wash promptly when skin is wet or contaminated. Remove clothing immediately if wet or contaminated to avoid flammability hazard. [R7] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock down vapors. If material leaking (not on fire) consider evacuation from downwind area based on amt of material spilled, location and weather conditions. [R14] *Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amt of water or soap and water. [R14] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R13, 162] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R13, 162] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Hexane may be disposed of by atomizing in a suitable combustion chamber. [R15] *Spray into the furnace. Incineration will become easier by mixing with a more flammable solvent. Recommendable methods: Incineration, open burning, use as a boiler fuel, and evaporation. Not recommendable method: Landfill. Peer review: Care. Highly flammable. Evaporate only small amt. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *IN MAN, 2000 PPM FOR 10 MIN RESULTED IN NO EFFECTS, BUT 5000 PPM CAUSED DIZZINESS AND ... GIDDINESS. ... SLIGHT NAUSEA, HEADACHE, EYE AND THROAT IRRITATION /OCCURRED/ TO 1400-1500 PPM. ... NO IRRITATION /WAS FOUND/ @ 500 PPM IN UNACCLIMATED SUBJECTS. [R5] *A ... MILD CENTRAL NERVOUS DEPRESSANT IN ACUTE EXPOSURES. ... VAPOR CAUSES ANESTHESIA OF SHORT DURATION WITHOUT SEQUELAE. ... IT TENDS TO VAPORIZE WHEN SWALLOWED OR ASPIRATED INTO TRACHEOBRONCHIAL TREE. THE RESULT CAN BE RAPID DILUTION OF ALVEOLAR AIR AND A MARKED FALL IN ITS OXYGEN CONTENT, WITH ASPHYXIA AND CONSEQUENT BRAIN DAMAGE OR CARDIAC ARREST. THE IRRITATIVE PULMONARY LESIONS OCCURRING AFTER THE ASPIRATION OF HIGHER HOMOLOGUES (EG OCTANE, NONANE, DECANE, ETC) AND OF MIXTURES THEREOF (EG KEROSENE) DO NOT APPEAR TO BE A PROBLEM WITH ... HEXANE. ... TOXIC NEUROPATHIES INCLUDING QUADRAPLEGIA HAVE OCCURRED AMONG JUVENILE GLUE SNIFFERS. [R17] *... SOLVENTS SUCH AS ... HEXANE ... MAY CONTACT THE EYE IN INDUSTRIAL OR LAB ACCIDENTS. THESE SUBSTANCES ... DISSOLVE FATS. ... THEY CAUSE PAIN ON CONTACTING THE EYE, AND EXAM AFTER GENEROUS SPLASH OF SOLVENT SHOWS DULLING OF THE CORNEA. ... DAMAGE APPEARS TO BE SCATTERED LOSS OF EPITHELIAL CELLS DUE TO SOLUTION OF SOME OF FATS THAT OCCUR IN THESE CELLS. [R18, 481] *EXPOSURE OF 78 SHOE FACTORY WORKERS (15 MEN, 63 WOMEN, AGES 17-38 YR (MEDIAN AGE 21.8 YR)) TO ALIPHATIC HYDROCARBONS IMPAIRED THE VESTIBULAR FUNCTION. IMPAIRMENT WAS CLASSIFIED AS TOXIC NUCLEO-RETICULAR SYNDROME. /ALIPHATIC HYDROCARBONS/ [R19] *3 CASES OF N-HEXANE NEUROPATHY IN SHOE INDUSTRY WERE REPORTED. IN MOST SEVERE CASES SYMPTOMS CONSISTED OF DYSARTHRIA, DISPROPORTIONATE ATAXIA OF GAIT, BLURRED VISION, AND SOMETIMES AFTER RECOVERY OF PERIPHERAL NEUROPATHY, APPEARANCE OF LEG SPASTICITY. [R20] *3 WOMEN HAD MOTOR POLYNEUROPATHY FOLLOWING INDUST EXPOSURE TO ADHESIVE AGENT CONTAINING 80.4% N-HEXANE. IN THE NERVE, THERE WERE POLYMORPHOUS CHANGES IN THE MYELIN SHEATHS AND AXONS OF LARGE DIAMETER FIBERS. MUSCLES SHOWED DENERVATION ATROPHY AND DEGENERATIVE CHANGES, WITH LYMPHOCYTIC INFILTRATES AND PHAGOCYTOSIS. [R21] *VISUAL EVOKED POTENTIALS AND AVERAGED EXTRAOCULAR ELECTRORETINOGRAMS WERE RECORDED FROM 15 WORKERS OCCUPATIONALLY EXPOSED TO N-HEXANE FOR 5-21 YR AND 10 CONTROLS. THE CHANGES IN EXPOSED SUBJECTS INDICATED CEREBRAL DYSFUNCTION. [R22] *93 OF 1662 WORKERS EXPOSED TO ORG SOLVENTS, WHICH CONSISTED MAINLY OF N-HEXANE AND A SMALL AMT OF TOLUENE, WERE FOUND TO HAVE SENSORY POLYNEUROPATHY (53), SENSORIMOTOR POLYNEUROPATHY (32), OR SENSORIMOTOR POLYNEUROPATHY WITH AMYOTROPHY (8). CRANIAL NERVE INVOLVEMENTS SUCH AS VISUAL DISORDERS AND FACIAL NUMBNESS WERE OBSERVED. ABOUT 50% SHOWED DENERVATION AND REINNERVATION OF THE NERVES. [R23] *Among 93 cases of n-hexane polyneuropathy during a large outbreak in 1968, 44 were studied. Over a few yr most of the cases completely recovered, except for a few with mild sensory impairment, after providing for 100 ppm as the maximal allowable concn of n-hexane and well equipped ventilation systems in individual houses. During the rescreening in 1981, before which there occurred only 2 pt, 21 cases with mild n-hexane polyneuropathy were observed, revealing mostly the same features as in the previous outbreak in 1968. From these data it may be suggested that, in spite of less than 50 ppm of n-hexane concn in a room, the sandal workers have suffered from neurotoxicity from this organic solvent. [R24] *In a cross-sectional study, nerve conduction velocities were determined in 59 workers employed in press proofing factories in Taipei. Workers were divided into exposure categories on the basis of air concentration of n-hexane (> 100 ppm, 50-99 ppm, < 50 ppm), and n-hexane concentration in the cleaning solvent used (> 50%, 49%-10%, < 10%). Fifteen (25%) of the study group were found to have polyneuropathy. ... In one factory where all 6 employees developed polyneuropathy, the air concentration of n-hexane was 190 ppm. /In other factories/ workers exposed to n-hexane at levels less than 100 ppm showed a significant ... decrease in motor nerve conduction velocities ... possibly explained by the common practice of working overtime. [R25] *NERVOUS SYSTEM DEGENERATION (DISTAL DYING-BACK AXONOPATHY) IS CAUSED BY HEXANE IN MAN. THE EFFECTS OF THIS CHEM ON THE PERIPHERAL AND CENTRAL NERVOUS SYSTEMS ARE DISCUSSED. 2,5-HEXANEDIONE IS PRINCIPAL METABOLITE OF THIS AND OTHER 6-CARBON COMPOUNDS AND IS PROBABLY RESPONSIBLE FOR THE AXONOPATHY ASSOCIATED WITH SOLVENT EXPOSURE. [R26] *Acute exposure to hexane causes central nervous system depression. Chronic exposure to an average air concn of 450-650 ppm for as little as 2 months may result in peripheral neuropathy, characterized by muscular weakness, loss of sensation, and impaired gait. [R27] *Hexane may be the most highly toxic member of the alkanes. ... When ingested, it causes nausea, vertigo, bronchial and general intestinal irritation, and CNS effects and presents an acute aspiration hazard. About 50 g may be fatal to humans. ... An exposure of 880 ppm for 15 min can cause eye and upper respiratory tract irritation in humans. ... exposure to 5000 ppm for 10 min causes marked vertigo. [R11, 3186] *"Blurred vision" ... has been mentioned in association with hexane polyneuropathy ... changes in the macula, particularly macular edema, may be produced by solvent vapors from shoemaker's cement, such as n-hexane. Fifteen people who were exposed industrially to hexane for a mean of 12 years ... had normal visual acuity and visual fields, but only 3 were thought to have normal color discrimination. ... There seemed to be vague disturbances in the appearance of the macula areas in 11 of the pt, and vague abnormalities were suspected in retinal fluoroangiograms in some pt. Visual evoked potentials in industrial workers are said to have been found abnormal. [R28] *... /It was/ concluded that n-hexane vapor levels of < 100 ppm for 8 hr/day were not likely to produce a clinical neuropathy, but mild subclinical changes in muscle strength and nerve conduction velocity may occur. ... Levels below 100 ppm may be neuropathic if extensive skin exposures also occur. [R29] NTOX: *HEXANE IS THREE TIMES AS ACUTELY TOXIC TO MICE AS IS PENTANE; CONCN OF 30000 PPM PRODUCED ... /CNS DEPRESSION/ WITHIN 30-60 MIN, AND CONVULSIONS AND DEATH RESULTED FROM 35000-40000 PPM. [R5] *WHEN MICE ARE EXPOSED TO ATMOSPHERE CONTAINING 2.5 TO 3% OF N-HEXANE FOR 4 DAYS, LIVER GROWTH IS OBSERVED AFTER 24 HR. [R30, 301] *... MICE /WERE EXPOSED/ TO COMMERCIAL HEXANE (65-70% N-HEXANE) FOR 24 HR A DAY, SIX DAYS A WEEK FOR ONE YEAR. EXPOSURE LEVELS RANGED FROM 100 TO 2000 PPM. ATROPHY AND DEGENERATION OF HIND LEG MUSCLE FIBERS WAS PRESENT IN ANIMALS EXPOSED TO 1000 and 2000 PPM. ... /TECHNICAL GRADE/ ... HEXANE (2000 PPM) ... EXPOSURES FOR ONE TO SIX MONTHS PRODUCED NEUROPHYSIOLOGIC EFFECTS IN WISTAR RATS AND RETRACTIONS OF THE MYELIN NERVE SHEATHS AND IN SOME INSTANCES RUPTURE OF SCHWANN CELL MEMBRANES. [R31] *PREGNANT FISCHER 344 RATS WERE EXPOSED FOR 6 HR/DAY TO 1000 PPM N-HEXANE ON DAYS 8-12, 12-16 OR 8-16 OF GESTATION. POSTNATAL GROWTH OF PUPS BORN TO DAMS EXPOSED TO 1000 PPM ON DAYS 8-16 OF GESTATION WAS SIGNIFICANTLY DEPRESSED COMPARED TO CONTROLS. [R32] *NEW ZEALAND RABBITS EXPOSED IN INHALATION CHAMBERS TO 3000 PPM 8 HR/DAY FOR 8 DAYS SHOWED CHANGES IN LUNGS, EMPHYSEMA, NECROTIC PHENOMENA IN BRONCHIOLAR EPITHELIUM AND ATELECTASIS. [R33] *EPICUTANEOUS ADMIN OF N-HEXANE TO GUINEA PIGS CAUSED PROGRESSING NUCLEAR PYKNOSIS AND JUNCTIONAL SEPARATION BETWEEN THE BASEMENT MEMBRANE AND THE BASAL CELLS OF THE SKIN. [R34] *EXPOSURE OF CHLAMYDOMONAS ANGULOSA AND CHLORELLA VULGARIS TO HEXANE RESULTED IN A WIDE RANGE OF TOXICITIES, WHEN DATA WERE EXPRESSED AS PERCENTAGE OF SATURATIONS CAUSING 50% REDN IN PHOTOSYNTHESIS. [R35] *STEROLOGENESIS FROM (14)C-ACETATE AND (3)H-MEVALONOLACTONE WAS STUDIED IN VITRO IN SCIATIC NERVES OF RATS. STEROLOGENESIS WAS NOT INHIBITED IN NERVES OF RATS WHO HAD INHALED 1000 PPM N-HEXANE FOR 6 HR. INCORPORATION OF (14)C ACETATE INTO TRIACYLGLYCEROLS OF NERVES FROM RATS EXPOSED TO N-HEXANE WAS INCREASED BY 50%. [R36] *Male rats were exposed by inhalation to several concn of hexane, admin continuously or intermittently. The 5th component of the brainstem auditory-evoked response (BAER) incr in latency and decr in amplitude in rats exposed to 1000 ppm hexane 24 hr/day, 5 days/wk, for 11 wk, reflecting a brainstem dysfunction. Latency returned to normal within 5 wk after termination of exposures, but amplitude did not. Latency of the cmpd action potential of the ventral caudal nerve of the tail of these rats was also incr, and this effect was still present 22 wk after termination of the exposure. [R37] *Adult rats were exposed to hexane at different concn. Lung tissue was then examined. The direct toxic effect to pneumocytes could be demonstrated as definite regressive alterations, such as fatty degeneration and change of lamellar bodies of type II pneumocytes as well as incr detachment of cells. After chronic inhalation of solvents conspicuous aggregation of lamellar discharge material of type II pneumocytes can be seen, and probably, as a result of an irritated fat metab, large lysosome like bodies with densely packed lipid material in type I pneumocytes. [R38] *The activity of lactate dehydrogenase, beta-glucuronidase, glucose-6-phosphate dehydrogenase, acid and alkaline phosphatase was studied in lung homogenate from New Zealand rabbits exposed to 3000 ppm of hexane 8 hr/day for 8 days or filtered air. In hexane treated animals, all enzymes examined, except alkaline phosphatase, were markedly incr. High values in lung lysosomal enzymes from treated rabbits reflect the acute inflammation while the incr in lung glucose-6-phosphate dehydrogenase may depend upon reparative process subsequent to hexane-induced lung damage. [R39] *In vitro toxicity of n-hexane using isolated perfused rabbit heart is reported. The force of cardiac contraction was significantly reduced following 1 hr perfusion with 9.6 mg/l n-hexane. [R40] *Male and female Fischer 344 rats were exposed to 0, 3000, 6500, or 10000 ppm n-hexane vapors 6 hr per day, 5 days per wk, for 13 wk. The mean body wt gain of male rats in the 10000 ppm group was significantly lower than for controls at 4 wk of exposure and thereafter. In addn to depression of body wt gain, the males exposed to 10000 ppm had slightly but significantly lower brain wt at necropsy. Axonopathy was observed in the tibial nerve in 4 of 5 male rats from the 10000 ppm group and one of five male rats in the 6500 ppm group and in the medulla from one male rat in the 10000 ppm group. These axonal changes were detectable only in teased nerve fiber preparations or in Epon embedded specimens. [R41] *Hexane was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology program (NTP). Hexane was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S9, at doses of 0.001, 0.0033, 0.010, 0.033, 0.100, and 0.333 mg/plate. The highest negative dose tested in any Salmonella typhimurium strain was 0.333 mg/plate. Some cultures exhibited slight clearing of the background bacterial lawn at the two highest doses tested. [R42] *Giant kelp (Macrocystis pyrifera): little or no effect on the photosynthetic activity: 10 mg/l. [R43, 733] *Young Coho salmon /Oncorhynchus kisutch/: no mortalities when applied in amt up to 100 ppm, after 96 hr in artificial seawater @ 8 deg C. [R43, 733] *... The injection of hexane in rabbits caused edema and hemorrhaging of the lungs and tissues, with polymorphonuclear leukocytic reactions. ... Dermal application of 2-5 ml/kg for 4 hr to rabbits has resulted in ataxia and restlessness. No deaths occurred @ 2 ml/kg, but some did @ 5 ml/kg. [R11, 3186] *Subchronic exposure of rats for 14 wk resulted in nervous system type disease, including cerebral peripheral distal axonopathy. ... Subchronic exposure of pigeons to 3000 ppm 5 hr/day, for 82 days over 17 wk has shown no pathological nerve tissue alterations. However, exposure of rats to 400-600 ppm, 5 days/wk has resulted in peripheral neuropathy in 45 days. Inhalation of 100 ppm hexane by mice gave no evidence of peripheral neuropathy in 7 months; however, 250 ppm resulted in peripheral nerve injury. Exposure of rats to 850 ppm for 143 days showed loss in wt and degeneration of myelin and axis cylinders in the sciatic nerve. [R11, 3187] *Concn of 100 ppm had an effect on the righting reflex in the white mouse. [R11, 3186] *... 0.2 ml of intratracheal n-hexane produces a fatal chemical pneumonitis in rats ... . [R6] *Studies in animals show the following decreasing order of neurotoxic potency: 2,5-hexanedione, /methyl n-butyl ketone (MBK)/, 2-hexanol, and n-hexane. ... The pronounced giant anoxal swelling of hexacarbon neuropathy is unique ... Swelling occurs initially in the proximal sides of the nodes of Ranvier in the distal portions of the nerve fiber and then progresses proximally. Nerve fibers may degenerate distal to the swellings, or secondary demyelination may occur distally. Myelin sheaths are inappropriately thin for their axon diameter. Long, distal nerve sections are the most vulnerable. The abnormally large fibers with swollen axons display abnormal accumulations of 10-nm neurofilaments that are involved in rapid protein transport. Studies in cats indicate widespread axonal degeneration in the mammillary body, lateral geniculate nucleus, and superior colliculus in experimental n-hexane neurotoxicity. Greater changes in the peripheral nervous system probably reflect the differential vulnerabilities of the shorter and smaller central nervous system fiber tracts. Prolonged low level exposure may cause premature deterioration of central nervous system areas responsible for visual perception and behavior. [R6] *Agents reported to affect male reproductive capacity: hexane. /From table/ [R18, 454] *Agents reported to affect female reproductive capacity: hexane. /From table/ [R18, 455] *Rats orally admin > or = 650 mg/kg for 90 days or more showed axonal degeneration in perpherial nerve. ... /In another study/ neuropathy /was produced/ in 101 days after giving 3.98 g/kg, 5 days/wk. [R44] NTXV: *LD50 Rat juvenile oral 24 ml/kg; [R17] *LD50 Rat adult oral 45 ml/kg; [R17] *LC50 Rat inhalation 48000 ppm/ < 4 hr; [R44] TCAT: ?Chronic toxicity was evaluated in male and female Sprague Dawley rats (6/sex/group) exposed to n-hexane via inhalation at 0, 6, 26 and 129 ppm for 6 hrs/day, 5 days/week for 6 months. There were significant differences between treated and control animals in the following: body weights (increased for males at 26 ppm), hemoglobin levels (decreased in all treated females), hematocrit levels (in females, decreased at 6 and 26 ppm, increased at 129 ppm), erythrocyte counts (decreased in all treated females at 3 months), clotting time (increased for females at 6 ppm at 3 months), and mean fasting glucose levels (increased in males at 129 ppm). All but the first and last observations appeared to be within normal biological limits and some were noted only at 3 months, suggesting that the effects were not treatment related. [R45] ?Chronic toxicity was evaluated in male and female Sprague Dawley rats (6/sex/group) exposed to n-hexane via inhalation at 0, 5, 27 and 126 ppm for 21 hrs/day, 7 days/week for 6 months. There were significant differences between treated and control animals in the following: hematocrit levels (increased in females at 126 ppm), blood urea nitrogen (decreased in females at 126 ppm). There were no significant differences between treated and control animals in mortality or body weight. [R46] ?Chronic toxicity was evaluated in male Sprague Dawley rats exposed to n-hexane via inhalation at 0 (24 rats), 125 (14 rats) or 500 ppm (34 rats) for approximately 22 hrs/day, 7 days/week for 6 months. There were significant differences between treated and control animals in the following: body weights (decreased at 125 and 500 ppm at weeks 13 and 11, respectively, and after), absolute and relative kidney weights and relative lung weights (increased at 500 ppm), relative spleen and brain weights (decreased at 125 ppm), relative lung weights (decreased at 500 ppm), axonal degeneration, myelin vacuolation and muscle atrophy (at 500 ppm), and microscopic renal changes including tubular epithelial desquamation, caste formation (degeneration), cytoplasmic basophilia, and decreased tubular diameter (regeneration) (at 500 ppm). [R47] ?Chronic toxicity was evaluated in male Sprague Dawley rats (10/group) exposed to n-hexane via inhalation at 0 or 500 ppm for approximately 22 hrs/day, 7 days/week for 6 months. There were significant differences between treated and control animals in the following: decreased absolute body, spleen, liver, heart, and brain weights; increased relative kidney, lung/trachea, testes, brain, and adrenal gland weights, neuronal atrophy and degeneration with secondary skeletal muscle atrophy, chronic nephritis, and peripheral nerve lesions. There were no differences between treated and control animals in mortality. [R48] ?The mutagenicity of n-hexane was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, n-hexane, diluted with 95% ethanol for strain TA1537 and with DMSO for the rest of the strains, was tested for mutagenicity at concentrations ranging from 194 - 33,000 ug/plate using the plate incorporation method. n-Hexane caused a reproducible increase in revertants in tester strain TA100 at all doses tested without activation. No dose-related effect was observed. n-Hexane did not cause a positive response in any of the other bacterial tester strains, either with or without metabolic activation. [R49] ?The ability of n-hexane to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenesis Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity tests, 8 nonactivated cultures were treated with 80, 90, 100, 110, 120, 130, 140, or 150 ug/ml which produced a range of 0 - 140% total growth. Eight activated cultures were treated with 40, 60, 80, 100, 120, 140, 160, or 180 ug/ml which produced a range of 0 - 22% total growth. None of the nonactivated or activated cultures produced mutant frequencies significantly greater than the solvent controls. [R50] ?The mutagenicity of n-hexane was evaluated in a dominant lethal assay using 3 groups of 12 male CD-1 mice receiving whole body exposures to nominal concentrations of 0, 100 or 400 ppm for 6 hrs/day, 5 days/week for 8 weeks. Following exposure, each male was mated for 5 days/week with 2 untreated females/week for 2 consecutive weeks. A small but statistically significant increase was observed in the fertility index of females mated to the high-dose group males in week two. A significant reduction in the average resorptions/pregnant female was observed for females mated to high-dose group males in week one. There were no differences between females mated to treated and control males with respect to average number of implantations/pregnant female, proportions of females with one or more resorptions, and proportions of females with two or more resorptions. [R51] ?The ability of n-hexane to cause chromosome aberrations was evaluated in the bone marrow cells of male Sprague-Dawley CD albino rats (5/group) exposed by inhalation to nominal concentrations of 0, 150, 300 or 600 ppm for 6 hrs/day, for 5 consecutive days. The rats were sacrificed on the day following the last administration of test substance and 50 cells/animal were scored for chromosome aberrations. All treated animals exhibited altered breathing and behavioral patterns following exposure to all test doses of n-hexane. There was a significant increase in frequency of chromosomal aberrations in the bone marrow cells of treated animals relative to controls including percent aberrant cells, and average aberrations/cell. Aberrations/cell were increased 3.3, 6.3, and 4.9 fold for the low-, mid-, and high-dose groups, respectively. The aberrations consisted mainly of chromatid breaks and markers, primarily fragments and dicentrics. [R52] ?The ability of n-hexane to cause chromosome aberrations was evaluated in the bone marrow cells of male Sprague-Dawley CD albino rats (5/group) exposed by inhalation to nominal concentrations of 0, 100 or 400 ppm for 6 hrs/day, for 5 days/week for 4 weeks for the control and low-dose groups, and for 1 week for the high-dose group. The rats were sacrificed on the day following the last administration of test substance and 50 cells/animal were scored for chromosome aberrations. Significant increases in treated animals relative to controls was observed in the percent total aberrations and percents of marker-type aberrations. There were no significant differences observed between treated and control animal body weights and mitotic indices. [R53] METB: *PHENOBARBITAL PRE-TREATMENT /OF LIVER MICROSOMES/ INDUCES 2- and 3-HYDROXYLATION /OF N-HEXANE/ SIX-FOLD; 3,4-BENZPYRENE SUPPRESSES 2- AND STIMULATES 3-HYDROXYLATION. [R30, 270] INTC: *Four separate groups of 5 rats each were exposed to 1000 ppm n-hexane, 1000 ppm n-hexane plus 1000 ppm toluene, 1000 ppm n-hexane plus 1000 ppm methyl ethyl ketone (MEK), or fresh air. Distributions of n-hexane metabolites in the mixed exposure group were almost similar to that of an n-hexane-alone group. The amt of metabolites decr to approx 1/6 of that in the n-hexane group by co-exposure with toluene and to approx 1/4 by co-exposure with MEK. Toluene decr the neurotoxicity of n-hexane by the inhibition of n-hexane metabolism. However, the reason the neurotoxicity of n-hexane is incr by co-exposure with MEK cannot be clearly explained. [R54] *Toluene @ 1000 ppm exerted an antagonistic effect on n-hexane neurotoxicity in rats exposed to 1000 ppm n-hexane 12 hr/day for 16 wk. While 1000 ppm n-hexane considerably impaired the function of peripheral nerves, as measured by nerve conduction velocities in the rat tail, the combined exposure resulted in only slight impairment. [R55] *n-Hexane ... potentiates chloroform toxicity. [R18, 304] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *n-Hexane is a highly volatile constituent in the paraffin fraction of crude oil and natural gas. n-Hexane is released to the environment via the manufacture, use, and disposal of many products associated with the petroleum and gasoline industries. Extensive data show release of n-hexane into the environment from printing pastes, paints, varnishes, adhesives and other coatings; hazardous waste disposal sites, landfills and waste incinerators; and the combustion of gasoline and diesel fueled engines. Photolysis, hydrolysis or bioconcentration of n-hexane are not expected to be an important environmental fate processes. Biodegradation of n-hexane may occur in soil and water; however, volatilization and adsorption are expected to be far more important fate processes. A Koc range of 1250 to 4100 indicates a low to slight mobility class in soil for n-hexane. In aquatic systems n-hexane may partition from the water column to organic matter contained in sediments and suspended materials. A Henry's Law constant of 1.81 atm-cu m/mole at 25 deg C suggests rapid volatilization of n-hexane from environmental waters. The volatilization half-lives from a model river and a model pond, the latter considers the effect of adsorption, have been estimated to be 2.7 hr and 6.8 days, respectively. n-Hexane is expected to exist entirely in the vapor-phase in ambient air. Reactions with photochemically produced hydroxyl radicals in the atmosphere have been shown to be important (average estimated half-life of 2.9 days). Data also suggests that nighttime reactions with nitrate radicals may contribute to the atmospheric transformation of n-hexane, especially in urban environments. The most probable route of human exposure to n-hexane is by inhalation. Extensive monitoring data indicate n-hexane is a widely occurring atmospheric pollutant. (SRC) NATS: *n-Hexane is a constituent in the paraffin fraction of crude oil and natural gas. [R56] ARTS: *Combustion Products of Polyvinyl Chloride: Hexane /From table/ [R11, 4288] *n-Hexane is released to the environment via the manufacture, use and disposal of many products associated with the petroleum(1-3) and gasoline industries(3-5). The combustion of gasoline and diesel fueled engines has been shown to release n-hexane into the atmosphere(6-8). Other well documented materials responsible for the release of n-hexane to the environment include printing pastes, paints, varnishes, adhesives and other coatings(9-11). Hazardous waste disposal sites(12-14), landfills(15-18) and waste incinerators(19) also release n-hexane into the environment. [R57] FATE: *TERRESTRIAL FATE: Photolysis or hydrolysis(1) of n-hexane are not expected to be important in soils. The biodegradation of n-hexane may occur in soils; however, volatilization and adsorption are expected to be far more important fate processes. A calculated Koc range for n-hexane of 1250 to 4100(2) indicates a low to slight soil mobility class(3). Based upon an estimated Henry's Law constant of 1.81 atm-cu m/mole(1), n-hexane is expected to rapidly volatilize from moist surface soils(2). [R58] *AQUATIC FATE: Photolysis or hydrolysis(1) of n-hexane in aquatic systems are not expected to be important. The log biodegradation of n-hexane may occur in aquatic environments; however, volatilization and adsorption are expected to be far more important fate processes. The log bioconcentration factor (log BCF) for n-hexane has been estimated to range from 2.24 to 2.89(1) suggesting bioconcentration is not an important factor in aquatic systems. An estimated range for Koc from 1250 to 4100(1) indicates n-hexane may absorb to carbon(2) and may partition from the water column to organic matter contained in sediments and suspended materials. An estimated Henry's Law constant of 1.81 atm-cu m/mole at 25 deg C(3) suggests rapid volatilization of n-hexane from environmental waters(1). Based on this Henry's Law constant, the volatilization half life from a model river (25 deg C; 1 meter deep flt(ing 1 m/{ec with a wind speed of 3 m/sec) has been estimated to be 2.7 hr(1,SRC). The volatilization half life from a model pond, which considers the effect of adsorption, can be estimated to be about 6.8 days(4,SRC). [R59] *ATMOSPHERIC FATE: Based on a vapor pressure of 151.5 mm Hg at 25 deg C(9), n-hexane is expected to exist entirely in the vapor phase in ambient air(10). n-Hexane does not absorb UV light in the environmentally signifcant range, > 290 nm(8) and probably will not undergo direct photolysis in the troposhere. Vapor phase reactions with photochemically produced hydroxyl radicals in the atmosphere have been shown to be important. The rate constants for n-hexane were measured to be 6.00X10-12, 5.31X10-12, 5.55X10-12, 5.61X10-12 and 5.50X10-12 cu cm/molecule-sec at 19(1), 22(2), 25(2), 26(3) and 32(4) deg C, respectively, which correspond to atmospheric half lives of about 2.7(1), 3.0(2) and 2.9(2-4) days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm. At 25 deg C the average rate constant for 8 well correlated experimental determinations was 5.58X10-12 cu cm/molecule-sec, which corresponds to an atmospheric half life of 2.9 days(5). Experimental data showed that 22.3% of the n-hexane fraction in a dark chamber reacted with NO3 to form the corresponding alkyl nitrate(6,7), suggesting nightime reactions with nitrate radicals may contribute to the atmospheric transformation of n-hexane, especially in urban environments(SRC). [R60] BIOD: *A variety of microorganisms degrade hexane by oxidn mechanisms similar to the lower homologues. Hexane is also utilized by various microorganisms, such as Mycobacterium vaccae and M. phlei. [R11, 3187] *The theoretical oxygen demand of benzene acclimated activated sludge for n-hexane was 4.1, 7.6, and 16.9% after 6, 24, and 72 hr, respectively(1). At intervals of 6, 12, and 24 hr endogenous respiration was greater than that of 3 preparations of n-hexane and activated sludge from differing aeration units of sewage treatment facilities(2). Within 24 hr, n-hexane was oxidized to its corresponding methyl ketone, 2-hexanone(3,5), and the corresponding alcohol, 2-hexanol(4,5), by cell suspensions of over 20 methyltrophic organisms isolated from lake water and soil samples(3-5). [R61] *Waste water treatment; Rotating disk contact aerator: influent 214.8 mg/l, effluent 0.3 mg/l; elimination: > 99% or 17,708 mg/sq m/24 hr or 4728 g/cu m/24 hr (includes evaporation and biodegradation). [R43, 732] *Incubation with natural flora in the groundwater, in presence of the other components of high octane gasoline (100 ul/l): biodegradation: 46% after 192 hr @ 13 deg C (initial concn 1.36 ul/l). [R43, 732] *The degradation of n-alkanes by microorganisms is similar to the degradation of fatty acids. The terminal methyl group is enzymatically oxidized by incorporation of a molecular oxygen by a monooxygenase producing a primary alcohol with further oxidation to an acid group, although involvement of a dioxygenase is also postulated. Once the fatty acid is produced, it is degraded into 2-carbon units via the beta-oxidation pathway. ... Another pathway for n-alkane degradation that is encountered less often is the oxidation of both terminal carbons to form a dioic acid with subsequent beta-oxidation. Subterminal oxidation of the 2-carbon atom is seen mainly in C3-C6 alkanes, although it does occur in longer chain alkanes also. ... A dehydrogenation of the n-alkane may also occur yielding an alkene which is then converted to an alcohol, although there is little evidence for this theory. Some microorganisms have been shown to have both terminal and subterminal oxidation, each having different rates of activity. The different chain lengths of n-alkanes are degraded to different extents ... . /In a study comparing/ ... growth on long an short chain alkanes by some bacteria ... the initial oxidase had a broad specificity and would oxidize C1-C8 alkanes ... /but/ cells grown on C4-C8 alkanes did not oxidize the shorter chain alkanes to a significant extent. ... /n-Alkanes/ [R62] ABIO: *Alkanes are generally resistant to hydrolysis(7) and n-hexane does not absorb UV light in the environmentally signifcant range, > 290 nm(8). Therefore n-hexane probably will not undergo hydrolysis or direct photolysis in the environment. The n-hexane concn of 82 ppbC in an air sampler was reduced by 29% within 6 hrs of irradiation by natural sunlight in downtown Los Angeles CA(6). The rate constants for vapor phase reactions of n-hexane with photochemically produced hydroxyl radicals were measured to be 6.00X10-12(1), 5.31X10-12(2), 5.55X10-12(2), 5.61X10-12(3), 5.50X10-12(4) and 6.8X10-12(5) cu cm/molecule-sec at 19(1), 22(2), 25(2), 26(3), 27(5), and 32(4) deg C, respectively, which correspond to atmospheric half lives of about 2.7(1), 3.0(2), 2.9(2-4) and 2.4(5) days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm. [R63] *At 25 deg C the average rate constant for 8 well correlated experimental determinations was 5.58X10-12 cu cm/molecule-sec, which corresponds to an atmospheric half life of 2.9 days(4). At 39 deg C the rate constant for the vapor phase reaction of n-hexane with photochemically produced hydroxyl radicals was determined to be 6.2X10-12 cu cm/molecule-sec, which corresponds to an atmospheric half life of 2.6 days(3). Experimental data showed that 22.3% of the n-hexane fraction in a dark chamber reacted with nitrate radical to form the corresponding alkyl nitrate(1,2), suggesting nightime reactions with nitrate radicals may contribute to the atmospheric transformation of n-hexane, especially in urban environments(SRC). [R64] *Est lifetime under photochemical smog conditions in SE England: 5.9 hr; photooxidation by ultraviolet light in aqueous medium @ 50 deg C: 50.51% degradation to carbon dioxide after 24 hr. [R43, 733] BIOC: *Based upon a water solubility of 9.5 mg/l(1) at 25 deg C and a log Kow of 4.11(2), the bioconcentration factor (log BCF) for n-hexane has been calculated to be 2.24 and 2.89, respectively, from recommended regression derived equations(3). These bioconcentration factor values are not indicative of important bioconcentration in aquatic organisms(SRC). [R65] KOC: *Based on a water solubility of 9.5 mg/l(1) and a log Kow of 4.11(2), the Koc of n-hexane has been calculated to range from 1250 and 4100 from various regression derived equations(3,SRC). These Koc values indicate a low to slight soil mobility class(4). [R66] VWS: *Based upon a water solubility of 9.5 mg/l(1) and a vapor pressure of 151.5 mm Hg at 25 deg C(1), the Henry's Law constant for n-hexane has been calculated to be 1.81 atm-cu m/mole(SRC). This value of Henry's Law constant indicates extremely rapid volatilization from environmental waters(2). The volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 2.7 hr(2,SRC). The volatilization half-life from an environmental pond, which considers the effect of adsorption, has been estimated to be 6.8 days(3,SRC). [R67] WATC: *DRINKING WATER: n-Hexane was reported as a compound identified in drinking water(1). n-Hexane was identified as a contaminant in well water from the Upper Potomac Aquifer which is used as a water supply for New Castle County, DE(2). Trace amounts of n-hexane were detected in water from the River Lee which is used as a water supply for North London England(3). [R68] *GROUND WATER: n-Hexane was identify in 1 of 7 groundwater samples taken near "The Valley of Drums", KY(1). [R69] *SEAWATER: n-Hexane was detected in 5 of 8 surface water samples in the Gulf of Mexico ranging in concn from 1.5 to 7.8 ng/l with an average concn of 4.62 ng/l(1). All 8 near surface sea water samples from the intertropical Indian Ocean contained small amounts of n-hexane(2). [R70] *SURFACE WATER: n-Hexane was listed as a contaminant present in the waters of Lakes Erie and Ontario(1). [R71] EFFL: *At a distance of 1 mile from its source, n-hexane was detected at a concn of 158.0 ug/cu m in the plume emitted from a General Motors plant located in Janesville, Wisconsin(1). n-Hexane was identified as a stack emission from waste incinerators(2). A refinery located in Tulsa, OK was attributed with emissions to the surrounding atmosphere where the n-hexane concn was measured to be 12.3 and 32.4 ppbC for two min before and after 1:33 pm(3). The n-hexane content of the air downwind of a Mobil natural gas facility in Rio Blanco, carbon monooxide was 58.8 ppbC(3). [R72] *Two of five hazardous waste sites listed on the Natural Priorities List emitted gaseous n-hexane with a 50 to 100% frequency of occurrence(1). Samples of hazardous waste material was reported to contain n-hexane(5). n-Hexane was also identified as a vapor emitted from landfills with an average and maximum concn of 1.8 and 28.9 ppm(2). A clay pit landfill in England that received municipal, industrial and liquid wastes emitted n-hexane gas at a concn of 96 mg/l(3). Landfill gas was found to contain n-hexane at a concn of 1.8 ppmv(4). [R73] *n-Hexane was detected in 3 of 63 industrial wastewater effluents at a concn ranging from 10 to 100 ug/l(1). Underwater hydrocarbon vents and formation waster discharges from offshore oil production platforms were found to contain n-hexane concn in the vapor-phase at 80 umol/l of gas and in the liquid state at 7520 ng/l, respectively(2). n-Hexane was identified as a contaminant in the leachate from the Army Creek Landfill 96 km (60 mi) southwest of Wilmington, DE(3). [R74] *Data from Sept 2 1979 identified n-hexane as a gaseous emission of the vehicle traffic through the Allegheny Mountain Tunnel of the Pennsylvania Turnpike(1). The average exhaust from 67 gasoline fueled vehicles was found to contain n-hexane at a concn 2.0% by weight(2). n-Hexane ranged in concn from 0.02 to 0.05 ppmv with an average from 8 samples of 0.02 ppmv(3). [R75] SEDS: *n-Hexane was detected in the soil surrounding an earthen disposal pit for produced water in the Duncan Oil Field, NM(1). [R76] ATMC: *URBAN: In a 1979 study of 5 sites in NJ, n-hexane was identified in the air over the cities of Rutherford and Newark(1). The ground level atmospheric concn of n-hexane at 1:25 PM was 3.4 ppb and 28.4 ppb at 8:00 AM for Huntington Park, CA(3). At 1500 ft the n-hexane concn was 2.0 ppb at 7:43 AM and at 8:07 AM at a height of 2,200 ft the n-hexane concn was 0.5 ppb(2). The n-hexane concn ranged from 5 to 20 ppbv at a downtown Los Angeles location for the Fall of 1981(3). From Aug 12, 1960 to Nov 18, 1960 the air of downtown Los Angeles ranged in n-hexane concn from 0.005 to 0.027 ppm with an average for 16 samples of 0.013 ppm(4). The ambient air of Riverside, CA was found to contain a n-hexane concn of 9.0 ppb at 7:30 AM Sept 24, 1968(5). At 8:05-8:25 AM on Mar 3, 1966 the n-hexane concn for a 2nd floor and roof top sample at the County Health and Finance Building in Riverside, CA were 7.2 and 6.6 ppb, respectively(5,6). The n-hexane concn for a 2nd floor sample at the County Health and Finance Building in Riverside, CA was 25.0 ppb at 7:40-8:00 AM, Dec 22, 1965(6). The n-hexane concn at 1100 ft just east of Antioch, CA was 3.5 ug/cu m(7). [R77] *URBAN: The atmospheric n-hexane concn ranged from 0.013 to 0.82 ppbv at Niwot Ridge Colorado(1). The n-hexane concn for 6 sites in Rio Blanco, n-hexane ranged from 1.0 to 58.8 ppbC with an average of 11.3 ppbC(2). The average n-hexane concn for 2 samples per 4 sites in Tulsa, OK was 14.2 ppbC with a range of 6.1 to 32.4 ppbC(2). The 1977 maximum and average concn of 675 points for n-hexane at a site in Houston, TX was 128 and 14 ppb of carbon, respectively(3). The average n-hexane concn from 6 to 9 am in Houston, TX was 24 ppb of Carbon(3). n-Hexane was detected in 15 of 16 air samples from Houston, TX ranging in concn from 6.4 to 273.4 ppm with an average of 88.4 ppm(4). [R78] *URBAN: In 1983-4 the respective minimum, maximum and average outdoor air concn of n-hexane in northern Italy were 2, 42 and 14 ug/l(1). The same study determined the respective minimum, maximum and average indoor air concn of n-hexane for 14 homes and an office building were 3, 590 and 71 ug/l(1). At Deuselbach, Hunsruck in Germany the atmospheric n-hexane concn was 0.051 ppb for October 23, 1983(2). n-Hexane was detected in the atmospheres of 6 industrialized cities of the USSR ranging in size of population from 0.4 to 4.5 million people(3-5). The average n-hexane concn (66 samples) in the air over Tokyo, Japan for 1980 was 1.0 ppb(6). n-Hexane was identified in the ambient air of Sydney, Australia(7) ranging in concn from 0.2 to 13.4 ppbv with an average concn of 2.1 ppbv(8). n-Hexane was detected in the atmosphere over the British Columbia Research Council Laboratory at the University of British Cloumbia(9). [R79] *RURAL: The respective median, minimum and maximum atmospheric concn of n-hexane for 5 rural locations in NC ranged from 0.2 to 7.5, 0.1 to 5.8, and 0.7 to 10.6 ppb(1). n-Hexane was detected in the atmospheres of downtown Tuscaloosa, AL and a rural site 35 miles away, the Talladega National Forest(2). The atmospheric concn of n-hexane at the Jones State Forest in rural TX was 4.1 ppbC(3). [R80] *REMOTE: The average n-hexane concn for samples taken at altitudes of 2000, 2500, and 300 ft over Lake Michigan on Aug 27, 1976 was 0.5 ppbV(1). The average n-hexane concn for samples taken at altitudes of 1000 and 1500 ft over Lake Michigan on Aug 28, 1976 was 0.4 ppbV(1). The air over the Norwegian Artic had an average n-hexane concn for 5 samples from Bear Island, 2 from Hopen and 2 from Spitsbergen of less than 20 parts per trillion/v in July 1982 and 172 parts per trillion/v in the spring of 1983(2). [R81] *SOURCE DOMINATED: At ground level, the atmospheric concn of n-hexane was 2.5 ug/cu m at 4, 7, 9, and 11 miles downwind of a General Motors plant in Janesville, Wisconsin(1). The n-hexane concn was 1.0 and 1.5 ug/cu m at 4 and 40 mi downwind of Janesville, WI 8-24-77(2). [R82] *INDOOR: n-Hexane occurred in 51% of the indoor air samples and 41% of the outdoor air samples taken in Chicago(1). The same study determined the respective minimum, maximum and average indoor air concn of n-hexane for 14 homes and an office building were 3, 590 and 71 ug/1(2). [R83] FOOD: *n-Hexane was identified as a volatile component of roasted filberts. [R84] MILK: *n-Hexane was detected in 8 of 12 samples of mothers breast milk from the cities of Bayonne NJ, Jersey City NJ, Bridgeville PA and Baton Rouge LA(1). [R85] OEVC: *An air sample taken near an oil fire was found to contain n-hexane and n-hexene at a combined concn of 1.21 mg/cu m(1). n-Hexane was also emitted from a Swedish floor finish 25 mo after its application(2). The concn of n-hexane vapors average 40.8 ppm at excavation sites for removing gasoline storage tanks(3). [R86] RTEX: *The most probable route of human exposure to n-hexane is by inhalation. Atmospheric workplace exposures have been documented(1-4). n-Hexane is a highly volatile compound and monitoring data indicates that it is a widely occuring atmospheric pollutant(SRC). [R87] *In the late 1960s and early 1970s attention was drawn to outbreaks of sensorimotor polyneuropathy among workers exposed to mixt of solvents containing n-hexane in concn ranging between 500 and 1000 ppm with higher peaks. Various working processes were involved such as glueing in sandal, shoe, belt and furniture mfg, polyethylene laminating, and cleaning tablets in pharmaceutical plant. [R1, 1072] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 1,996,557 workers are potentially exposed to n-hexane in the USA(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 354,754 workers are potentially exposed to n-hexane in the USA(2). n-Hexane was detected in the workplace atmospheres of 336 businesses in Belguim with a frequency of occurrence of 15% for those that utilize printing pastes; 7% where painting took place; 10% of the automobile repair shops and 6% for sites where various materials such as varnishes are employed(3). A 1984 study showed n-hexane was emitted from gasoline exposing outsider operators at the refineries to an average air concn of 0.473 mg/cu m; n-hexane was detected in 54 of 56 samples(4). Transport drivers were exposed to n-hexane at atmospheric concn of 1.019 mg/cu m and n-hexane was detected in 49 of 49 samples(4). Gas station attendants were exposed to n-hexane at atmospheric concn of 1.175 mg/cu m and n-hexane was detected in 48 of 49 samples(4). Tank contractors were exposed to vapors containing n-hexane at concn of 14.7 ppm at gasoline tank removal sites(5). A total of 89 employees who spray paints or glues on their jobs for 3 companies were exposed to n-hexane at an average concn of 1.1 ppm(6). [R88] BODY: *n-Hexane was detected in 8 to 12 samples of mothers breast milk from the cities of Bayonne NJ, Jersey City NJ, Bridgeville PA and Baton Rouge LA(1). The air expired from humans contained n-hexane in 6.9% of the 387 samples collected from 54 subjects(2). The average n-hexane concn of 4.7 ng/l was expressed as a the geometric mean with upper and lower limites of 13.5 and 1.63 respectively(2). [R89] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +1100 ppm (Based on 10% of the lower explosion limit for safety considerations even though the relevant toxicological data indicated that irreversible health efects or impairment of escape existed only at higher concentrations.) [R13, 162] ATOL: *Residues of hexane are exempted from the requirement of a tolerance when used as a solvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R90] *Hexane (incl hexane isomers) is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R91] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 500 ppm (1800 mg/cu m). [R92] +Vacated 1989 OSHA PEL TWA 50 ppm (180 mg/cu m) is still enforced in some states. [R13, 365] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 50 ppm (180 mg/cu m). [R13, 162] TLV: +8 hr Time Weighted Avg (TWA): 50 ppm, skin. [R93, 2002.35] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R93, 2002.6] +Biological Exposure Index (BEI): Determinant: 2,5-hexanedione in urine; Sampling Time: end of shift; BEI: 5 mg/g creatinine. The determinant is nonspecific, since it is also observed after exposure to other chemicals. [R93, 2002.90] +Biological Exposure Index (BEI): Determinant: n-hexane in end-exhaled air. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. [R93, 2002.90] +Notice of Intended Change for 2002: These biological exposure indices (BEIs), with their corresponding values, comprise those for which a limit has been proposed or for which retention on the Notice of Intent to Establish or Change has been proposed. In each case, the proposed indices should be considered trial values that will remain in the listing for the year following ratification by the ACGIH Board of Directors. If, during the year, no evidence comes to light that questions the appropriateness of the values herein, the values will be reconsidered for Adoption. Determinant: 2,5-hexanedione in urine; Sampling Time: end of shift at end of workweek; BEI: 0.4 mg/l. [R93, 2002.95] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Hexane is included on this list. [R94] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 4000 ug/l [R95] +(FL) FLORIDA 10 ug/l [R95] +(ME) MAINE 4000 ug/l [R95] +(MN) MINNESOTA 400 ug/l [R95] +(NC) NORTH CAROLINA 14300 ug/l [R95] +(NJ) NEW JERSEY 33 ug/l [R95] +(WI) WISCONSIN 600 ug/l [R95] FIFR: *Residues of hexane are exempted from the requirement of a tolerance when used as a solvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R90] *Hexane (incl hexane isomers) is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R91] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Couri D, Milks M; Annu Rev Pharmacol Toxicol 22: 145-66 (1982). This is a review and discussion with 93 references on the toxicity and metab of hexacarbons incl hexane. $null$ [R96] DHHS/NTP; Report on the Toxicity Studies of n-Hexane in B6C3F1 Mice (Inhalation Studies) NTP TOX2 (1991) NIH Pub No. 91-3121 SO: R1: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R2: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 678 R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 600 R4: SRI R5: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.305 R6: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 965 R7: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 498 R8: (1) Perry DL et al; Ident of Org Compounds in Ind Effluent discharges. USEPA- 600/4-79-016 (NTIS PB-294794) p. 230 (1979) (2) Sauer TC Jr; Org Geochem 7: 1-16 (1981) (3) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) (4) Rappaport SM et al; Appl Ind Hyg 2: 148-54 (1987) (5) Shamsky S, Samimi B; App Ind Hyg 2: 242-5 (1987) R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 162 R10: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 24 R11: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R12: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 633 R13: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R14: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.367 R15: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.4 R16: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 188 R17: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-150 R18: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. R19: D'ANDREA F ET AL; MED LAV 70 (1): 16-20 (1979) R20: RIZZUTO N ET AL; EUR NEUROL 19 (5): 308-15 (1980) R21: SCELSI R ET AL; J NEUROL SCI 47 (1): 7-20 (1980) R22: SEPPALAINEN AM ET AL; ELECTROENCEPHALOGR CLIN NEUROPHYSIOL 47 (4): 492-8 (1979) R23: SOBUE I ET AL; INT J NEUROL 11 (4): 317-30 (1978) R24: Iida M; Electroencephalogr Clin Neurophysiol (Suppl) 36: 671-81 (1982) R25: Wang J et al; Am J Ind Med 10: 111-18 (1986) R26: SCHAUMBURG HH, SPENCER PS; ANN NY ACAD SCI 329 (PUBLIC CONTROL ENVIRON HEALTH HAZARDS): 14-29 (1979) R27: Baselt, R.C. Biological Monitoring Methods for Industrial Chemicals. 2nd ed. Littleton, MA: PSG Publishing Co., Inc. 1988. 172 R28: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 482 R29: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume II. Boca Raton, FL: CRC Press, Inc., 1985. 63 R30: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. R31: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 469 R32: BUS JS ET AL; TOXICOL APPL PHARMACOL 51 (2): 295-302 (1979) R33: LUNGARELLA G ET AL; RES COMMUN CHEM PATHOL PHARMACOL 29 (1): 129-40 (1980) R34: KRONEVI T ET AL; ENVIRON RES 19 (1): 56-69 (1979) R35: HUTCHINSON TC ET AL; ENVIRON SCI RES 16 (HYDROCARBONS HALOGENATED HYDROCARBONS AQUAT ENVIRON): 577-86 (1980) R36: GILLIES PJ ET AL; TOXICOL APPL PHARMACOL 54 (2): 217-22 (1980) R37: Rebert CS et al; Neurobehav Toxicol Teratol 4 (1): 79-85 (1982) R38: Schnoy N et al; Respiration 43 (3): 221-31 (1982) R39: Barni-Comparini I et al; Agents Actions 12 (5): 737-42 (1982) R40: Raje RR; J Toxicol Environ Health 11 (4-6): 879-84 (1983) R41: Cavender FL et al; Fundam Appl Toxicol 4 (2 Pt 1): 191-201 (1984) R42: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R43: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R44: Snyder, R. (ed.) Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume 1: Hydrocarbons. Amsterdam - New York - Oxford: Elsevier, 1987. 330 R45: Bio/dynamics, Inc.; 26 Week Inhalation Toxicity Study of n-Hexane in the Rat. (1978), EPA Document No. FYI-AX-1081-0137, Fiche No. 0137-0 R46: Bio Dynamics, Inc.; 26 Week Inhalation Toxicity Study of n-Hexane in the Rat. (1978), EPA Document No. FYI-AX-1081-0137, Fiche No. 0137-0 R47: International Research and Development Corp.; Six Month Continuous Inhalation Exposures of Rats to Hexane Mixtures - Phase I. (1983), EPA Document No. FYI-AX-0282-0166, Fiche No. 0166-2 R48: International Research and Development Corp.; Six Month Continuous Inhalation Exposures of Rats to Hexane Mixtures - Phase II. (1983), EPA Document No. FYI-AX-0282-0166, Fiche No. 0166-2 R49: Hazelton Laboratories America, Inc.; In Vitro and In Vivo Mutagenicity Studies, Hexane, Final Report Draft. (1979), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 R50: Hazelton Laboratories America, Inc.; In Vivo and In Vitro Mutagenicity Studies, N-Hexane (Hexane UV), Final Report. (1980), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 R51: Litton Bionetics, Inc.; Mutagenicity Evaluation of n-Hexane in the Mouse Dominant Lethal Assay, Final Report. (1980), EPA Document No. FYI-AX-1081-0137, Fiche No. OTS0000137-0 R52: Hazelton Laboratories America Inc.; In Vivo and In Vitro Mutagenicity Studies, n-Hexane (Hexane UV), Final Report. (1980), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 R53: Hazelton Laboratories America Inc.; In Vitro and In Vivo Mutagenicity Studies, Hexane, Final Report. (1980), EPA Document No. FYI-OTS-0381-0106, Fiche No. OTS0000106-0 R54: Iwata M et al; Int Arch Occup Environ Health 53 (1): 1-8 (1983) R55: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985. 152 R56: USEPA; Drinking water Criteria Document for Gasoline. ECAO-CIN-D006, 8006-61-9 (1986) R57: (1) Perry DL et al; Ident of Org Compounds in Ind Effluent Discharges. USEPA-600/4-79-016 (NTIS PB-294794) p. 230 (1979) (2) Sauer TC Jr; Org Geochem 7: 1-16 (1981) (3) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) (4) Rappaport SM et al; Appl Ind Hyg 2: 148-54 (1987) (5) Shamsky S, Samimi B; App Ind Hyg 2: 242-5 (1987) (6) Neligan RE; Arch Environ Health 5: 581-91 (1962) (7) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (8) Nelson PF, Quigley SM; Atmos Environ 18: 79-87 (1984) (9) Vuelemans H et al; Am Indust Hyg Assoc J 48: 671-7 (1987) (10) Whitehead LW et al; Am Indust Hyg Assoc J 45: 767-72 (1984) (11) Van Netten et al; Bull Environ Contam Toxicol 40: 672-7 (1988) (12) LaRegina J et a; Environ Prog 5: 18-27 (1986) (13) Puskar MA et al; Environ Sci Technol 21: 90-6 (1987) (14) Stonebreaker RD, Smith AJ; p. 1-10 in Control Hazard Mater Spills. Proc Natl Conf Nashville,TN (1980) (15) Vogt WG, Walsh JJ; pp. 2-17 in Proc APCA Annu Meet 78th Vol. 6 (1985) (16) Young P, Parker A; ASTM Spec Tech Publ 851 (Hazard Ind Waster Manag): 24-41 (1984) (17) Zimmerman RE et al; p. 230-9 in Proc Int Gas Res Conf (1983) (18) DeWalle FB, Chian ESK; J Am Water Works Assoc 73: 206-11 (1981) (19) Junk GA, Ford CS; Chemosphere 9: 187-230 (1987) R58: (1) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9, 7-4 (1982) (3) Swann RL et al; Res Rev 85: 16-28 (1983) R59: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9, 5-4, 10, 7-4 (1982) (2) Swann RL et al; Res Rev 85: 16-28 (1983) (3) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) (4) USEPA; EXAMS II Computer Simulation (1987) R60: (1) Campbell IM et al; Chem Phys Lett 38: 362-4 (1976) (2) Atkinson R, Aschmann SM; Internat J Chem Kin 16: 1175-86 (1984) (3) Atkinson R et al; Internat J Chem Kin 14: 781-8 (1982) (4) Lloyd AC et al; J Physic Chem 80: 789-94 (1976) (5) Atkinson R, Chem Rev 85: 69-201 (1985) (6) Atkinson R et al; J Phys Chem 86: 4563-9 (1982) (7) Atkinson R et al; Preprints Amer Chem Soc Div Environ Chem 23: 173-6 (1983) (8) Silverstein RM, Bassler GC; Spectrometric Id of Org Cmpd, J Wiley and Sons Inc p. 148-169 (1963) (9) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) (10) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) R61: (1) Malaney GW, McKinney RE; Water Sewaage Works 113: 302-9 (1966) (2) Gerhold RM, Malaney GW; J Water Pollut Contr Fed 38: 562-79 (1966) (3) Patel RN et al; Appl Environ Microbiol 39: 727-33 (1980) (4) Patel RN et al; Appl Environ Microbiol 39: 720-6 (1980) (5) Hou CT et al; Appl Environ Microbiol 46: 178-84 (1983) R62: Parr, J.F., P.B. Marsh, and J.M. Kla (eds.). Land Treatment of Hazardous Wastes. Park Ridge, New Jersey: Noyes Data Corporation, 1983. 327 R63: (1) Campbell IM et al; Chem Phys Lett 38: 362-4 (1976) (2) Atkinson R, Aschmann SM; Internat J Chem Kin 16: 1175-86 (1984) (3) Atkinson R et al; Internat J Chem Kin 14: 781-8 (1982) (4) Lloyd AC et al; J Physic Chem 80: 789-94 (1976) (5) Klopffer W et al; Ecotox Environ Safety 15: 298-319 (1988) (6) Kopczynski SL et al; Environ Sci Technol 6: 342-7 (1972) (7) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 7-4 (1982) (8) Silverstein RM, Bassler GC; Spectrometric Id of Org Cmpd, J Wiley and Sons Inc p. 148-169 (1963) R64: (1) Atkinson R et al; J Phys Chem 86: 4563-9 (1982) (2) Atkinson R et al; Preprints Amer Chem Soc Div Environ Chem 23: 173-6 (1983) (3) Nolting F et al; J Atmos Chem 6: 47-59 (1988) (4) Atkinson R; Chem Rev 85; 69-201 (1985) R65: (1) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) (2) Hansch C, Leo AJ; Medchm Project Issue No. 26 Claremont CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 5-4, 5-10 (1982) R66: (1) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1982) (2) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (4) Swann RL et al; Res Rev 85: 16-28 (1983) R67: (1) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1982) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-15 to 15-29 (1982) (3) USEPA; EXAMS II Computer Simulation (1987) R68: (1) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982) (2) DeWalle FB, Chian ESK; J Am Water Works Assoc 73: 206-11 (1981) (3) Waggott A; Chem Water Reuse 2: 55-9 (1981) R69: (1) Stonebreaker RD, Smith AJ; p. 1-10 in Contr Haz Mater Spills, Proc Natl Conf Nashville, TN (1980) R70: (1) Sauer TC Jr et al; Mar Chem 7: 1-16 (1978) (2) Bonsang B et al; J Atmos Chem 6: 3-20 (1988) R71: (1) Great Lakes Water Quality Board; Inventory Chem Subst Id Great Lakes Ecos p. 195 (1983) R72: (1) Sexton K, Westberg H; Environ Sci Technol 14: 329-32 (1980) (2) Junk GA. Ford CS; Chemosphere 9: 187-230 (1980) (3) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) R73: (1) LaRegina J et al; Environ Prog 5: 18-27 (1986) (2) Vogt WG, Walsh JJ; pp. 2-17 in Proc APCA Annu Meet 78th Vol 6 (1985) (3) Young P, Parker A; ASTM Spec Tech Publ 851 (Hazard Ind Waste Manage Test): 24-41 (1984) (4) Zimmermn RE et al; pp. 230-9 in Proc Int Gas Res Conf (1983) (5) Puskar MA et al; Environ Sci Technol 21: 90-6 (1987) R74: (1) Perry DL et al; Ident of of Org Compounds in Ind Effluent Discharges USEPA-600/4-79-016 (NTIS PB-294794) p. 230 (1979) (2) Sauer TC Jr; Org Geochem 7: 1-1 (1981) (3) Dewalle FB, Chian ESK; J Am Water Works Assoc 73: 206-11 (1981) R75: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (2) Nelson PF, Quigley SM; Atmos Environ 18: 79-87 (1984) (3) Neligan RE; Arch Environ Health 5: 581-91 (1962) R76: (1) Eiceman GA et al: Intern J Environ Anal Chem 24: 143-62 (1986) R77: (1) Bozzelli JW et al; Analysis of Selected Toxic and Carcinogenic Substances in Ambient Air of NJ, State of NJ Dept Environ Protection (1980) (2) Scott Research Labs Inc; Atmospheric Reaction Studies in th Los Angeles Basin. NTIS PB-194-058 p. 86 (1969) (3) Groshean D, Fung K; J Air Pollut Control Assoc 34: 537-43 (1984) (4) Neligan RE; Arch Environ Health 5: 581-91 (1962) (5) Stephens ER; Hydrocarbons in Polluted Air NTIS PB-230 993/8 p.86 (1973) (6) Stephens ER, Burleson FR; J Air Pollut Control Assoc 17: 147-53 (1967) (7) Sexton K, Westberg H; Environ Sci Tech 14: 329-32 (1980) R78: (1) Roberts JM et al; Atmos Environ 19: 1945-50 (1985) (2) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) (3) Monson PR et al; Paper 78-50.4 in 71st Ann Meeting Air Pollut Contr Assoc (1978) (4) Lonneman WA et al; Hydrocarbons in Houston Air USEPA-600/3-79/018 p. 44 (1979) R79: (1) DeBortoli M et al; Environ Int 12: 343-50 (1986) (2) Rudolph J, Khedim A; Int J Environ Anal Chem 290: 265-82 (1985) (3) Ioffe BV et al; J Chromatogr 142: 787-95 (1977) (4) Ioffe BV et al; Dokl Akad Nauk Sssr 243: 1186-9 (1978) (5) Ioffe BV et al; Environ Sci Technol 13: 864-8 (1979) (6) Uno I et al; Atmos Environ 19: 1283-93 (1985) (7) Mulcahy MFR et al; Paper IV p.17 in Proc Symp Workshop Sess (1976) (8) Nelson PF, Quigley SM; Environ Sci Technol 18: 79-87 (1984) (9) Stump FD, Dropkin DL; Anal Chem 57: 2629-34 (1985) R80: (1) Seila RL et al; Atmospheric Volatile Hydrocarbon Composition at Five Remote Sites in NW NC. USEPA-600/D-84-092 (NTIS PB84-177930) (1984) (2) Holzer G et al; J Chromatog 142: 755-64 (1977) (3) Seila Rl; Non-urban Hydrocarbons Concn in Ambient Air North of Houston TX USEPA-500/3-79-010 p. 38 (1979) R81: (1) Miller MM, Alkezweeny AJ; Ann NY Acad Sci 338: 219-32 (1980) (2) Hov O et al; Geophys Res Lett 11: 425-8 (1984) R82: (1) Sexton K, Westberg H; Environ Sci Technol 14: 329-32 (1980) (2) Sexton K; Environ Sci Technol 17: 402-7 (1983) R83: (1) Jarke FH et al; Ashras Trans 87: 153-66 (1981) (2) DeBortoli M et al; Environ Int 12: 343-50 (1986) R84: Kinlin TE et al; J Agric Food Chem 20: 1021 (1972) R85: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R86: (1) Perry R; pp. 130-7 in Int Symp Ident Mass Environ Pollut (1971) (2) Van Notten et al; Bull Environ Contam Toxicol 40: 672-7 (1988) (3) Shamsky s, Samimi B; Appl Ind Hyg 2: 242-5 (1987) R87: (1) Vuelemans H et al; Am Indust Hyg Assoc J 48: 671-1 (1987) (2) Rapport SM et al; Appl Ind Hyg 2: 148-54 (1987) (3) Shamsky S, Samimi B; Appl Ind Hyg 2: 242-5 (1987) (4) Whitehead LW et al; Am Indust Hyg Assoc J 45: 767-72 (1984) R88: (1) NIOSH; National Occupational Hazard Survey (NOHS) (1974) (2) NIOSH; National Occupational Exposure Survey (NOES) (1983) (3) Vuelemans H et al; AM Indust Hyg Assoc J 48: 671-7 (1987) (4) Rappaport SM et al; Appl Ind Hyg 2: 148-54 (1987) (5) Shamsky S, Samimi B; App Ind Hyg 2: 242-5 (1987) (6) Whitehead LW et al; Am Indust Hyg Assoc J 45: 762-72 (1984) R89: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Krotoszynski BK et al; J Anal Toxicol 3: 225-34 (1979) R90: 40 CFR 180.1001(c) (7/1/88) R91: 40 CFR 180.1001(d) (7/1/88) R92: 29 CFR 1910.1000 (7/1/98) R93: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R94: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R95: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R96: WHO; Environmental Health Criteria 122: n-Hexane (1991) RS: 73 Record 19 of 1119 in HSDB (through 2003/06) AN: 97 UD: 200303 RD: Reviewed by SRP on 5/28/1986 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-METHOXYETHANOL- SY: *AETHYLENGLYKOL-MONOMETHYLAETHER- (GERMAN); *EGM-; *EGME-; *ETHANOL,-2-METHOXY-; *ETHER-MONOMETHYLIQUE-DE-L'ETHYLENE-GLYCOL- (FRENCH); *ETHYLENE-GLYCOL-METHYL-ETHER-; *ETHYLENE-GLYCOL,-MONOMETHYL-ETHER-; *GLYCOLMETHYL-ETHER-; *GLYCOL-MONOMETHYL-ETHER-; *1-HYDROXY-2-METHOXYETHANE-; *2-METHOXY-AETHANOL- (GERMAN); *Methoxyethanol-; *BETA-METHOXYETHANOL-; *2-METHOXY-1-ETHANOL-; *METHOXYHYDROXYETHANE-; *METHYL-CELLOSOLVE-; *Methyl-ethoxol-; *METHYLGLYKOL- (GERMAN); *METHYL-OXITOL-; *METIL-CELLOSOLVE- (ITALIAN); *METOKSYETYLOWY-ALKOHOL- (POLISH); *2-METOSSIETANOLO- (ITALIAN); *MONOMETHYL-ETHER-OF-ETHYLENE-GLYCOL- RN: 109-86-4 RELT: 54 [ETHYLENE GLYCOL MONOETHYL ETHER]; 538 [ETHYLENE GLYCOL MONOBUTYL ETHER] MF: *C3-H8-O2 SHPN: UN 1188; Ethylene glycol monomethyl ether IMO 3.3; Ethylene glycol monomethyl ether UN 1188; Methyl cellosolve MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM ETHYLENE OXIDE + METHANOL: FINCH, HAGEMEYER, US PATENT 2,748,171 (1956 TO KODAK); FROM ETHYLENE GLYCOL + DIAZOMETHANE: HESSE, MAJUMDAR, BER 93, 1129 (1960). [R1] *... BY REACTING ETHYLENE CHLOROHYDRIN OR ETHYLENE GLYCOL WITH NAOH AND A DIALKYL SULFATE ... [R2] *REACTION OF ETHYLENE OXIDE WITH EXCESS ANHYDROUS METHYL ALCOHOL [R3] FORM: *Grade or purity: Commercial [R4] *EKTASOLVE EM *GLYCOL ETHER EM [R5, p. 86/8512] *JEFFERSOL EM [R5, p. 86/8526] *MECS *POLY-SOLV EM *PRIST [R5, p. 86/8512] *DOWANOL EM MFS: *DOW CHEM U.S.A., MIDLAND, MI 48640 [R3] *EASTMAN KODAK CO, EASTMAN CHEM PRODUCTS, INC, SUBSID, TEXAS EASTMAN CO, LONGVIEW, TX 75601 [R3] *OLIN CORP, OLIN CHEMS GROUP, BRANDENBURG, KY 40108 [R3] *TEXACO INC, TEXACO CHEM CO, DIV, PORT NECHES, TX 77651 [R3] +UNION CARBIDE CORP, ETHYLENE OXIDE DERIVATIVES DIV, TAFT, LA 70057 [R3] +ICI Americas Inc, Chemicals Div, Wilmington, DE 19897, (302)575-3000 [R6, p.299] USE: *SOLVENT FOR LOW VISCOSITY CELLULOSE ACETATE, NATURAL RESINS, SOME SYNTHETIC RESINS AND SOME ALC SOL DYES; IN DYEING LEATHER; IN MODIFIED KARL FISCHER REAGENT; IN SEALING MOISTUREPROOF CELLOPHANE; IN QUICK DRYING VARNISHES, ENAMELS, NAIL POLISHES, WOOD STAINS [R1] *JET FUEL ANTIICING ADDITIVE; SOLVENT FOR RESINS USED IN THE ELECTRONICS INDUSTRY; CHEM INT FOR DI(2-METHOXYETHYL) PHTHALATE, A PLASTICIZER AND 2-METHOXYETHYL ACETATE AND OTHER DERIVATIVES; GENERAL PROCESS SOLVENT AND CARRIER FOR DYES; SOLVENT FOR COATINGS AND INKS [R3] *Solvent for nitro-cellulose, hydrocarbons [R7] *Perfume fixative [R8, 651] *In manufacture of photographic film [R9, p. II-182] +... Constituent of painting plasters, cleaning compounds, liquid soaps, cosmetics, nitrocellulose and hydraulic fluids [R10] +Solvent mixtures; lacquers; enamels; varnishes; ... perfume, fixative [R11] CPAT: *JET FUEL ANTIICING ADDITIVE (MILITARY AND GENERAL AVIATION AIRCRAFT ONLY), 47%; SOLVENT FOR RESINS USED IN THE ELECTRONICS INDUSTRY, 15%; CHEMICAL INTERMEDIATE, 12%; GENERAL SOLVENT AND CARRIER FOR DYES, 8%; SOLVENT FOR COATINGS AND INKS, 7%; EXPORTS, 11% (1983) [R3] PRIE: U.S. PRODUCTION: *(1978) 5.19X10+10 G [R3] *(1982) 4.05X10+10 G [R3] +(1985) 3.78X10+10 g [R6, p.267] U.S. IMPORTS: *(1978) 2.33X10+8 G [R3] *(1982) 2.29X10+8 G [R3] +(1985) 2.33X10+8 g [R12] U.S. EXPORTS: *(1978) 3.63X10+9 G [R3] *(1982) 3.47X10+9 G [R3] +(1985) 1.17X10+10 g [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQ [R14]; +Colorless liquid. [R15] ODOR: +MILD ETHEREAL ODOR [R16]; +Mild, ether-like odor. [R15] TAST: +BITTER [R16] BP: *125 DEG C @ 768 MM HG [R17, p. C-273] MP: *-85.1 DEG C [R17, p. C-273] MW: *76.09 [R1] CORR: *Methyl cellosolve will attack some forms of plastics, rubber, and coatings. [R18, 1981.] CTP: +CRITICAL TEMPERATURE: 292 DEG C; CRITICAL PRESSURE: 5.1 MEGANEWTONS/SQ M [R4] DEN: *0.9647 @ 20 DEG C/4 DEG C [R17, p. C-273] HTC: +-5250 CAL/G [R4] HTV: *9,893.8 gcal/gmole [R17, p. C-671] OWPC: +log Kow = -0.77 [R19] SOL: *MISCIBLE WITH WATER, ALC, ETHER, GLYCEROL, ACETONE, DIMETHYLFORMAMIDE [R1]; *MISCIBLE WITH BENZENE [R17, p. C-273] SPEC: *INDEX OF REFRACTION: 1.4028 @ 20 DEG C/D [R1]; +SADTLER REFERENCE NUMBER: 254 (IR, PRISM); 87 (IR, GRATING) [R20]; +IR: 4813 (Coblentz Society Spectral Collection) [R21]; +NMR: 32 (Sadtler Research Laboratories Spectral Collection) [R21]; +MASS: 95 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R21] SURF: +0.033 N/M @ 20 DEG C [R4] VAPD: +2.62 (AIR= 1) [R14] VAP: *6.2 MM HG @ 20 DEG C [R14] EVAP: *Approx 1 (Butyl acetate = 1) [R18, 1981.] OCPP: *PERCENT IN SATURATED AIR @ 25 DEG C: 1.28 [R22, 3912] *RATIO OF SPECIFIC HEATS OF VAPOR (GAS): 1.079; LATENT HEAT OF VAPORIZATION: 223 BTU/LB = 124 CAL/G = 5.19X10+3 J/KG [R4] *Sat concn 33 g/cu m at 20 deg C; 56 g/cu m at 30 deg C [R8, 651] *The lowest BP and greatest rate of evaporation of all avail glycol ether [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R23] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R23] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R23] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R23] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R23] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R23] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R23] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R23] FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME ... SPONTANEOUS HEATING: NO. [R14] FLMT: *LOWER 2.3, UPPER 24.5 (% BY VOL IN AIR) [R24] *2.5%-19.8% (in air) [R4] FLPT: *42 deg C cc [R18, 1981.] *120 deg C oc [R4] AUTO: *285 deg C [R18, 1981.] FIRP: *EXTINGUISH WITH DRY CHEMICAL, ALCOHOL FOAM, OR CARBON DIOXIDE. COOL EXPOSED CONTAINERS WITH WATER. [R4] TOXC: *Toxic gases and vapor (such as carbon monoxide) may be released in a fire involving methyl cellosolve. [R18, 1981.] EXPL: *... CAN REACT WITH OXIDIZING MATERIALS TO FORM EXPLOSIVE PEROXIDES. [R14] REAC: *Ethylene glycol monomethyl ether /in air/ forms peroxides that are highly explosive. [R25] *Contact with strong oxidizing agents may cause fires and explosions. Contact with strong caustics may cause decomposition. [R18, 1981.] +Strong oxidizers, caustics. [R26] ODRT: *... UNDER CONTROLLED CONDITIONS AND USING HUMAN VOLUNTEERS ... THE ODOR THRESHOLD FOR ETHYLENE GLYCOL METHYL ETHER WAS APPROX 60 PPM AND THE LEVEL OF STRONG ODOR 90 PPM. IN ANOTHER STUDY, HUMAN VOLUNTEERS WERE EXPOSED TO LEVELS OF 25 AND 115 PPM FOR A FULL WORKING DAY. THE 25-PPM LEVEL WAS CONSIDERED TO BE THE MAX TOLERATED ODOR LEVEL BY THREE OF FIVE PEOPLE, WHEREAS THE INTOLERABLE LEVEL APPEARED TO BE MORE THAN 115 PPM. [R22, 3919] *Detection: 9X10-2 ppm (air); Recognition: 2.2X10-1 ppm (air) [R27] SERI: *HAZARD WARNING: ... not appreciably irritating to skin, and mildly irritating to the eyes, may be absorbed through skin but is low in toxicity by this route, and is appreciably toxic when inhaled. Its vapors are irritating in acutely toxic concn, but concn that may cause serious systemic toxicity upon prolonged and repeated inhalation have negligible warning properties. [R22, 3911] EQUP: *CHEMICAL SAFETY GOGGLES; PROTECTIVE CLOTHING; SUPPLIED-AIR RESPIRATOR FOR HIGH CONCN; SAFETY SHOWER AND BATH. [R4] *Respirators ... used for operations which require entry into tanks or closed vessels, and in emergency situations. ... respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by NIOSH. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (8-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with liquid methyl cellosolve. ... Employees should be provided with and required to use splash-proof safety goggles where liquid methyl cellosolve may contact the eyes. [R18, 1981.] +Wear appropriate personal protective clothing to prevent skin contact. [R26] +Wear appropriate eye protection to prevent eye contact. [R26] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R26] +Recommendations for respirator selection. Max concn for use: 1 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R26] +Recommendations for respirator selection. Max concn for use: 2.5 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R26] +Recommendations for respirator selection. Max concn for use: 5 ppm. Respirator Class(es): Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R26] +Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator operated in a pressure-demand or other positive-pressure mode. May require eye protection. [R26] +Recommendations for respirator selection. Max concn for use: 200 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R26] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R26] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R26] OPRM: +Contact lenses should not be worn when working with this chemical. [R26] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *... a complete respiratory protection program should be instituted which incl regular training, maintenance, inspection, cleaning, and evaluation. ... Clothing contaminated with liquid methyl cellosolve should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of methyl cellosolve from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the methyl cellosolve, the person performing the operation should be informed of methyl cellosolve's hazardous properties. Where exposure of an employee's body to liquid methyl cellosolve may occur, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. Non-impervious clothing which becomes contaminated with liquid methyl cellosolve and any clothing which becomes wet with liquid methyl cellosolve should be removed immediately and such clothing should not be reworn until the methyl cellosolve is removed from the clothing. ... Skin that becomes contaminated with liquid methyl cellosolve should be immediately washed or showered with soap or mild detergent and water to remove any methyl cellosolve. Employees who handle liquid methyl cellosolve should wash their hands thoroughly before eating or smoking. [R18, 1981.] *If ... the materials are agitated or heated, or if skin contact is extensive and prolonged, it is advisable to protect the personnel by enclosing the process or providing local exhaust ventilation. /Glycols and derivatives/ [R28] +The worker should immediately wash the skin when it becomes contaminated. [R26] +Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R26] SSL: *VOLATILE [R16] *Heat /contributes to instability/ [R18, 1981.] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R29] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R30] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R31] STRG: *STORAGE TEMPERATURE: AMBIENT. VENTING: OPEN (FLAME ARRESTER). [R4] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN A SAFE PLACE (SUCH AS A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR THE HOOD DUCTWORK. BURN THE PAPER IN A SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER. METHYL CELLOSOLVE SHOULD NOT BE ALLOWED TO ENTER A CONFINED SPACE, SUCH AS A SEWER, BECAUSE OF THE POSSIBILITY OF AN EXPLOSION. [R18, 1981.] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *METHYL CELLOSOLVE MAY BE DISPOSED OF BY ATOMIZING IN A SUITABLE COMBUSTION CHAMBER. [R18, 1981.] +Concentrated waste containing no peroxides: discharge liquid at a controlled rate near a pilot flame. Concentrated waste containing peroxides: perforation of a container of the waste from a safe distance followed by open burning. Recommendable methods: Incineration and open burning. [R32, 175] +Ethylene glycol monomethyl ether should be atomized into an incinerator and combustion may be improved by mixing with a more flammable solvent. Recommendable methods: Incineration and open burning. Peer-review: Beware of peroxides in old material which may cause explosion or spontaneous combustion. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R32, 176] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: *Initial medical exam: ... Exam of the CNS should be stressed. ... A complete blood count should be performed incl a red cell count, a white cell count, a differential count of a stained smear ... hemoglobin and hematocrit. Urinalysis ... Periodic medical exam: The aforementioned medical exam should be repeated on an annual basis. [R18, 1981.] HTOX: *CHRONIC POISONINGS FROM VAPORS OF ... METHYL CELLOSOLVE ... HAVE OCCURRED IN THIS COUNTRY. TOXIC ENCEPHALOPATHY AND EVIDENCE OF BONE MARROW DEPRESSION WITHOUT HEMOLYSIS WERE KEY FINDINGS ... LUNG, KIDNEY AND LIVER CHANGES HAVE ALSO BEEN OBSERVED ... [R9, p. III-175] *MAY CAUSE ANEMIA, MACROCYTOSIS, APPEARANCE OF YOUNG GRANULOCYTES IN BLOOD ... [R1] *... A DEATH /WAS REPORTED/ AFTER INGESTION OF METHYL CELLOSOLVE, WITH POST-MORTEM FINDINGS OF HEMORRHAGIC GASTRITIS ... REPORTED TWO CASES OF ENCEPHALOPATHY IN WORKERS USING 2-METHOXYETHANOL AS A CLEANER. CONFUSION, DISORIENTATION, LETHARGY, AND ANOREXIA WERE PRESENT IN BOTH CASES. TREMORS, AGITATION, WEIGHT LOSS, BLURRED VISION, FEVER, HEADACHE, AND BED WETTING ... MARKED ANEMIA AND BONE MARROW DAMAGE ... WERE FOUND IN BOTH PATIENTS, AND ONE HAD PANCYTOPENIA. THE MORE SEVERELY AFFECTED WORKER HAD BEEN EXPOSED A FEW MONTHS, THE OTHER FOR ONLY ONE MONTH. [R33] *WHEN 2-METHOXYETHANOL WAS SUBJECTED TO THE UNSCHEDULED DNA SYNTHESIS (UDS) ASSAY IN HUMAN EMBRYO FIBROBLASTS, UDS WAS NOT INCR. [R34] *TO DETERMINE WHETHER EMPLOYEES POTENTIALLY EXPOSED TO ETHYLENE GLYCOL MONOMETHYL ETHER DURING MFG AND PACKAGING HAD A HIGHER PREVALENCE OF ANEMIA, LEUKOPENIA OR STERILITY THAN AN IN-PLANT COMPARISON GROUP, A CROSS-SECTIONAL STUDY WAS CONDUCTED AT THE MICHIGAN DIV OF DOW CHEM USA. BLOOD SAMPLES ON 65 OF 97 POTENTIALLY EXPOSED AND CONTROL WHITE MALES, AND SEMEN SAMPLES FROM A SUBSET OF 15 WERE ANALYZED. WITH THE POSSIBLE EXCEPTION OF SMALLER TESTICULAR SIZE, NO GROSS ABNORMALITIES OR CLINICALLY MEANINGFUL DIFFERENCES IN HEMATOLOGICAL OR FERTILITY INDICES WERE NOTED. RESULTS OF REGRESSION MODELING SUGGESTED THAT WHITE BLOOD CELLS AND HEMOGLOBIN HAVE BEEN DECR AT HIGHER EXPOSURE LEVELS. [R35] *... accidental ingestion of 1/2 pint of 2-methoxyethanol mixed with brandy led to coma and death within 5 hr. Autopsy revealed degeneration of kidney tubules, acute hemorrhagic gastritis, fatty degeneration of the liver, early necrosis of the pancreas, and brain edema. The total dose in this case was about 3 g/kg. [R9, p. II-182] *The response of a normal diploid human embryonal palatal mesenchymal (HEPM) cell line to glycol ethers was studied. These cells have gap junctions whose function in cell-cell communication was inhibited by a model teratogen. Potential HEPM donor cells were pulse labeled with (3H)uridine (10 muCi/ml for 3 hr) and then cocultured for 3 hr with 2x10+5 through 4x10+5 potential recipient cells in the absence or presence of 2-methoxyethanol (ME). Computer assisted quantative autoradiography was applied to assess the effects of metabolic cooperation. Although this phenomena was inhibited by ME the effect was not attributable to interference with gap junction-mediated transfer of labeled nucleotides but rather to the lack of formation of gap junctions resulting from cytotoxicity and poor physical contact between cells. [R36] *The first reported case of a possible toxic effecct of ethylene glycol monomethyl ether (EGME) exposure in the microfilm manufacturing industry was described. Reversible subjective CNS complaints and asymptomatic hematopoietic effects occurred following inhalation and skin exposure to EGME. [R37] *Overexposure to methyl cellosolve may cause irritation of the eyes, nose, and throat, drowsiness, weakness, and shaking. Swallowing methyl cellosolve may be fatal. ... Prolonged or repeated exposure may cause headache ... fatigue, staggering, personality change, and decr mental ability. Anemia and other blood changes may result. [R18, 1981.] NTOX: *EXPOSURE OF RATS AND MICE TO 1000 PPM /2-MEHTOXYETHANOL/ FOR 6 HR/DAY ON 9 DAYS DURING AN 11-DAY PERIOD CAUSED ADVERSE EFFECTS ON BODY WT GAIN, PERIPHERAL BLOOD COUNTS, BONE MARROW, TESTES, AND LYMPHOID TISSUES. SIMILAR BUT LESS PRONOUNCED CHANGES WERE ALSO SEEN IN SOME ANIMALS EXPOSED TO 300 PPM. ... DOSED MICE ORALLY 5 DAYS/WK FOR 5 WK. ... REDUCTIONS IN TESTES WEIGHTS WERE OBSERVED WITH DOSES OF 250 MG/KG/DAY OR GREATER OF 2-METHOXYETHANOL. [R33] *2-METHOXYETHANOL WAS SUBJECTED TO THE AMES' TEST, SEX-LINKED RECESSIVE LETHAL (SLRL) TEST IN DROSOPHILA, DOMINANT LETHAL TEST IN MALE RATS, BONE MARROW METAPHASE ANALYSIS IN MALE AND FEMALE RATS, AND THE SPERM ABNORMALITY TEST IN MICE. IN VIVO TEST ANIMALS WERE EXPOSED TO ATMOSPHERIC CONCN OF 25 OR 500 PPM. POINT MUTATIONS IN AMES' TEST WERE NOT INCR. THE SLRL TEST GAVE AMBIGUOUS RESULTS. CHROMOSOMAL ABERRATION FREQUENCIES WERE NOT INCR IN RAT BONE MARROW, BUT THERE WAS EVIDENCE FROM DOMINANT LETHAL TESTS THAT THE CMPD HAS PROFOUND EFFECTS UPON MALE RAT FERTILITY DURING THE MEIOTIC PHASE. PREGNANCY FREQUENCY WAS GREATLY REDUCED AND PREIMPLANTATION LOSSES WERE LARGE. THERE WAS EVIDENCE OF POSTIMPLANTATION LOSSES. SPERM ABNORMALITIES WERE INCR IN MICE. THESE EFFECTS ON MALE REPRODUCTIVE CELLS WERE CONFINED TO THE HIGHER CONCN OF THE CMPD. [R34] *ETHYLENE GLYCOL MONOMETHYL ETHER WAS ADMIN ORALLY TO RATS @ DOSES VARYING FROM 50 TO 500 MG/KG BODY WT/DAY FOR 11 DAYS. FIRST EVIDENCE OF TESTICULAR DAMAGE WAS OBSERVED 24 HR AFTER A SINGLE DOSE OF 100 MG/KG /AND WAS OBSERVED/ IN THE PRIMARY SPERMATOCYTES. AT 16 HR AFTER A SINGLE DOSE OF 500 MG/KG, MITOCHONDRIAL DAMAGE WAS ONE OF THE FIRST SUBCELLULAR CHANGES /OBSERVED/. AFTER DOSING ANIMALS WITH 500 MG/KG FOR 4 DAYS, THE TESTES RECOVERED WT, AND THE MAJORITY OF TUBULES RECOVERED THEIR SPERMATOGENIC POTENTIAL WITHIN ONE FULL MATURATION CYCLE. NO EFFECT LEVEL OVER THE 11-DAY TREATMENT PERIOD WAS 50 MG/KG/DAY. [R38] *THE DOSE DEPENDENT TOXICITY OF ETHYLENE GLYCOL MONOMETHYL ETHER VAPOR ON THE LIVER AND KIDNEYS WAS INVESTIGATED BY EXPOSING RATS TO /DOSE LEVELS OF/ 50, 100, OR 400 PPM FOR ONE OR 2 WK PERIODS. THE VAPOR CAUSED A SLIGHT DECR IN THE ACTIVITY OF LIVER ALDEHYDE DEHYDROGENASE AT 400 PPM. SERUM ALANINE AMINOTRANSFERASE ACTIVITY WAS NOT CHANGED. [R39] *GROUPS OF MALE AND FEMALE SPRAGUE-DAWLEY (CD) RATS WERE EXPOSED TO 0, 30, 100, OR 300 PPM ETHYLENE GLYCOL MONOMETHYL ETHER (EGME) VAPOR 6 HR/DAY, 5 DAYS/WK FOR 13 WK. FOLLOWING THE EXPOSURE PERIOD, MALES WERE BRED TO UNEXPOSED FEMALES TO EVALUATE REPRODUCTIVE CAPABILITY AND DOMINANT LETHALITY. RESULTS INDICATE A POTENTIAL FOR INHALED EGME TO COMPLETELY SUPPRESS FERTILITY IN MALE RATS AT THE 300 PPM LEVEL. FERTILITY OF THESE RATS WAS PARTIALLY RESTORED AT 13 WK POST-EXPOSURE. PATHOLOGIC ALTERATIONS WERE OBSERVED ONLY IN MALE RATS AT THE 300 PPM LEVEL, /AND INCLUDED/ DECR TESTICULAR SIZE AND ATROPHIC SEMINIFEROUS TUBULES. [R40] *MALE AND FEMALE SPRAGUE-DAWLEY RATS AND NEW ZEALAND WHITE RABBITS WERE EXPOSED TO 0, 30, 100, OR 300 PPM ETHYLENE GLYCOL MONOMETHYL ETHER VAPORS 6 HR/DAY, 5 DAYS/WK, FOR A TOTAL OF 13 WK. BODY WT AS WELL AS THYMUS AND TESTICULAR WT OF RATS AND RABBITS IN THE 300 PPM GROUP WERE REDUCED. HEMATOLOGIC CHANGES /WERE DETECTED/ IN RATS AND RABBITS EXPOSED TO 300 PPM. GROSS LESIONS /WERE OBSERVED/ IN RATS AND RABBITS EXPOSED TO 300 PPM INCL DECR SIZE OF THYMUS, DECR ABDOMINAL FAT, AND SMALL FLACCID TESTES IN MALES. IN ADDN, DECR LYMPHOID TISSUE IN SOME RABBITS, AS WELL AS A SLIGHT-TO-MODERATE DECR IN SIZE OF TESTES IN 4 OF 5 RABBITS IN THE 100 PPM GROUP AND 2 OF 5 RABBITS EXPOSED TO 30 PPM /WERE ALSO OBSERVED/. MICROSCOPIC LESIONS /OBSERVED/ INCL DEGENERATIVE CHANGES IN GERMINAL EPITHELIUM OF TESTES IN ALL MALE RATS AND RABBITS IN THE 300 PPM GROUP, AS WELL AS IN 3 OF 5 RABBITS IN THE 100 PPM GROUP AND 1 OF 5 MALE RABBITS IN THE 30 PPM GROUP. [R41] *RATS WERE EXPOSED TO ETHYLENE GLYCOL MONOMETHYL ETHER (EGME) BY INHALATION AT 100 AND 300 PPM FOR 6 HR/DAY. PREGNANT FEMALES WERE EXPOSED ON DAYS 6 TO 17 OF GESTATION. BODY WT GAIN WAS REDUCED IN BOTH EGME GROUPS. NO LITTERS WERE DELIVERED IN THE 300-PPM EGME GROUP AND ONLY 9/20 RATS IN THE 100-PPM EGME GROUP PRODUCED LITTERS WHERE THE NUMBER, WT, AND VIABILITY OF THE PUPS WERE REDUCED, BUT THE PUPS APPEARED NORMAL EXTERNALLY. WHEN MALE RATS WERE EXPOSED FOR 10 DAYS, 300 PPM EGME CAUSED SIGNIFICANT REDUCTIONS IN WHITE BLOOD CELL COUNT, RED BLOOD CELL COUNT, HEMOGLOBIN CONCN, HEMATOCRIT, AND MEAN CELL HEMOGLOBIN. [R42] *... /pregnant rats were/ exposed ... to 50 to 100 ppm /2-methoxyethanol/ for 7 hr daily on days 7 to 15 of gestation. An incr in skeletal and cardiac malformations were observed. [R43] *... found LD50 for mice to be 2.8 g/kg when given in oil soln. If given in water LD50 is slightly higher. In massive doses, material has a ... /CNS depressant/ action but @ lower dosage levels deaths are delayed and are accompanied by lung edema, slight liver injury, and marked kidney injury. Hematuria may occur from single doses. ... rabbits /were fed/ repeated daily doses ... and found that 7 doses of 0.1 ml/kg caused temporary hematuria. Larger doses caused exhaustion, tremors, albuminuria, hematuria, and death. Autopsy revealed severe kidney injury. [R22, 3912] *Eye irritation. When ethylene glycol monomethyl ether was introduced into the eyes of rabbits, it produced immediate pain, conjunctival irritation, and slight transitory cloudiness of the cornea, which cleared within 24 hr. [R22, 3913] *... 2 dogs /were exposed/ to vapor concn of 750 ppm ... 7 hr/day, 5 days/wk, for 12 wk ... hemoglobin concn, cell vol, and number of erythrocytes were decr. Red cells showed incr hypochromia, polychromatophilia, and microcytosis. ... white cells ... characterized by greater than normal number of immature forms. [R22, 3915] *... with guinea pig ... 5 /sc/ injections of either 0.5 or 1.0 ml/kg caused prostration, labored breathing, and death. ... 2 dogs /were injected (believed im)/ with 6 ml and 2 rabbits with 2 ml daily. 1 rabbit died after 2 injections and 1 dog was anuric after ... last ... injection. Clinical exam and autopsy of the animals ... revealed anuria, calcified casts in urine, irritation of bladder mucosa, hemorrhage in GI tract, lung edema, and liver and testicular injury. [R22, 3916] *Primary mixed cultures of Sertoli and germ cells were prepared from the testes of immature rats and their response to the known testicular toxicants ethylene glycol monomethyl ether (EGM) and ethylene glycol monoethyyl ether (EGE) was studied. EGM or EGE did not produce any morphological evidence of toxicity when added to the culture at up to 50 mM for 72 hr. Their metabolites methoxyacetic acid (MAA) and ethoxyacetic acid (EAA) at 2-10 mM for 24-72 hr caused degeneration of the pachytene and dividing spermatocytes, the target cells of the parent ethers in vivo. As in vivo earlier spermatocytes, spermatogonia and Sertoli cells appeared unaffected. [R44] *The effects of ethylene glycol monoethylether (EGME) on late stage and epididymal spermatids and spermatogonia /was studied/. Adult male rats of proven fertility were dosed orally with 0, 50, 100, or 200 mg/kg/day for 5 days. Each male was mated with two female/wk for 8 wk and the number of live and dead fetuses, resorption sites, and corpora lutea were noted. The fertility of males treated with 200 mg/kg EGME declined at week 4 and remained low for the rest of the study. [R45] *Propylene glycol monomethyl ether did not cause testicular atrophy or affect the development of rats at 600 ppm by inhalation, whereas ethylene glycol monomethyl ether (EGME) caused testicular atrophy at 300 ppm and showed teratogenic potential at 100 ppm. Diethylene glycol monomethyl ether showed no teratogenic potential when administered sc in rats at > 1000 mu l/kg, where as EGME had effects at 40 mu l/kg. EGME had effects on the testis in rats after a single exposure to 600 ppm for 4 hr. Ethylene glycol monoethyl ether also caused a reduction in testicular weight following a single exposure to saturated vapor for 3 hr (17 mg/l), but ethylene glycol monoisopropyl ether at 15 mg/l and ethylene glycol monoisopropyl ether at 4 mg/l showed no effects on the testis. [R46] *... At concentrations which were apparently not maternally toxic, 2-methoxyethanol was highly embryotoxic /in rats/, producing complete resorptions at 200 ppm, while increased resorptions, reduced fetal weights, and induced skeletal and cardiovascular defects occurred at both 50 and 100 ppm. [R47] *Studies were designed to define the target cell for ethylene glycol monomethyl ether (EGME) actions in rodent testes. ... Adult rats were treated with 150 mg/kg/day, 5 days/wk, and sacrificed 1, 2, 4, 7, or 10 days after the first dose. ... The most sensitive cells were the premeiotic and meiotic spermatocytes. [R48] *This study examined possible alterations in immune function and host resistance of B6C3F1 mice following exposure to ethylene glycol monomethyl ether (EGME) or its principal metabolite methoxyacetic acid (MOAA). EGME and MOAA were administered by gavage to mice in 10 doses over a 2 week period at 10 total doses of 250, 500, and 1,000 ug/g of body weight. A 48% reduction in thymus weight was observed at the intermediate and high doses of both chemicals. However no significant alterations in immune function or host resistance to L monocytogenes were observed in animals exposed to either EGME or MOAA. [R49] *These studies were performed to assess the effects of inhaled ethylene glycol monomethyl ether on the embryonal and fetal development of Fischer 344 rats, CF-1 mice, and New Zealand white rabbits. Rabbits and rats were exposed to vapor concn of 0, 3, 10, or 50 ppm for 6 hr/day on days 6-18 or days 6-15 of gestation, respectively. Mice were exposed to 0, 10, or 50 ppm on days 6-15 of gestation. Exposure of pregnant rabbits to 50 ppm produced significant increases in the incidence of malformations, minor variations and resorptions, as well as a decrease in fetal body weight. Rats and mice exposed to 50 ppm showed no evidence of a teratogenic effect. [R50] *... electrocardiography was used to evaluate heart function in day 20, rat (Sprague-Dawley) fetuses from mothers treated on gestation days 7-13 (sperm = 1) with 0, 25, or 50 mg/kg ethylene glycol monomethyl ether (EGME) by gavage in 10 ml water. The increased incidences of fetuses with cardiovascular malformations (primarily right ductus arteriosus and ventricular septal defect) and abnormal electrocardiograms (EKG) was dose dependent. The most prevalent EKG abnormality was a prolonged QRS wave. ... The enhanced duration and the appearance of the aberrant QRS's suggested the presence of an intraventricular conduction delay in these fetuses. [R51] *... exposure of paternal or maternal rats to 25 ppm 2-methoxyethanol (2ME) (the current USA permissible human occupational exposure limit) /was tested for/ detectable effects in the offspring. 18 young adult, male Sprague-Dawley rats were exposed to 25 ppm 2ME for 7 hr/day, 7 day/wk for 6 wk. They were then mated with untreated females which were allowed to deliver and rear their young. Groups of 15 rats were exposed 7hr/day on gestation days 7-13 or 14-20 and allowed to deliver and rear their young. At birth, litters were culled to 4 females and 4 males for behavioral testing of function activity and simple learning ability on days 10-90. Brains from newborn and 21 day old offspring were analyzed for neurochemical deviations from controls. No effects on paternal or maternal animals nor on the number or weight of live offspring were noted. Behavioral testing revealed significant differences from controls only in avoidance conditioning of offspring of mothers exposed on days 7-13. Neurochemical deviations were observed in brains from 21 day old offspring from the paternally exposed group as well as from both maternally exposed groups. Changes were numerous in the brainstem and cerebrum but were fewer in the cerebellum and midbrain. Apparently both maternal and paternal inhalation of 25 ppm 2ME produces some effect which is reflected in the offspring. [R52] *Male rats were given ethylene glycol monomethyl ether (EGM) ... po for 4 consecutive days at doses of 100 or 500 mg/kg/day. Animals were killed on days 1, 4, 8 and 22 after the final treatment. EGM produced thymic atrophy, lymphocytopenia and neutropenia and caused a slight reduction in the number of circulating red cells. EGM also abolished splenic extramedullary hemopoiesis which partially recovered on day 4, followed by a marked response on day 8 and a return to moderate control levels on day 22. Femoral bone marrow was hemorrhagic 1 day after treatment with EGM which appeared to be associated with sinus endothelial cell damage. By day 4 the histologic appearance of the marrow was normal. [R53] *The effects of a single inhalation exposure to the rat of the saturated vapors of ethylene glycol monomethyl ether (EGME) were investigated. Mature male albino rats were exposed to various levels of EGME for a single 4 hr period and killed 14 days later. Following this single exposure a dose related decrease in testis weight was observed in rats exposed to 5000, 2500, and 1000 ppm EGME. Histopathological examination revealed disordered spermatogenesis and tubular atrophy in these animals. Minimal degenerative changes were seen in the testis of rats exposed to 625 ppm EGME. [R54] *The effect of ethylene glycol monomethyl ether (EGME) on cell-mediated immunity was evaluated by an allograft rejection assay. Allogeneic B6C3F1 (C57BL/6 x C3H) mice were given oral doses of 300, 600, or 1200 mg/kg/administration EGME on days -12 through -8. Untreated controls were given oral doses of water on days -12 through -8 and -5 through -1. On day 0 mice were challenged with 1x10+2, 3x10+3, 1x10+5,or 3x10+6 L1210 cells by ip route. Syngeneic CD2F1 (Balb/c x DBA/2) mice were challenged with 1x10+5, L1210 cells on day 0 and were treated on days 1 to 5 and 8 to 12 with the same dosages of EGME used for the B6C3F1 mice. Water-treated syngeneic mice died with a median survival time (MST) of 8 days. There was no effect on the MST of syngeneic mice treated with EGME, indicating no direct antitumor effect of the compound. All allogenic mice recieving either water or Cy and challenged with 3x10+6 tumor cells, died with ascites. However when mice were treated with EGME and challenged with 3x10+6 tumor cells, no more than 1 animal per group died. This would indicate that there was either a prophylactic action of the compound or the immune system was stimulated. [R55] *Ethylene glycol monomethyl ether (EGM) was administered as a single dose of 250 mg/kg body wt and rats were examined at time periods after dosing. The number of spermatocytes and round spermatids in tubules at each stage of spermatogenesis was counted. A sharp transition in susceptibility was observed between zygotene spermatocytes in Stage XIV which showed no effect, and pachytene spermatocytes in stage I which showed death or depletion of 70% of its population after one day. A similar transition was seen between dividing spermatocytes and step I spermatids, the latter being unaffected. There was a gradual reduction in susceptibility toward midpachytene such that cells in stages VII-XI showed no effect. [R56] *The cytotoxicity of several glycol ethers including methoxy ethanol and some oxidation products, the corresponding alkoxy acetates, was compared in Chinese hamster ovary (Cho-K1) cells without metabolic activation. Cytotoxicity was measured in terms of cloning formation ability, and EC50 values (concentrations allowing 50% of the seeded cells to form colonies) were estimated. The results, in the case of unmetabolized glycol ethers tested, showed an increase in toxicity with increasing chain length. [R57] *Fifteen glycol ethers including ethylene glycol monomethyl ether were investigated for their potential to cause adverse reproductive toxic effects using in vivo mouse screening bioassay. Pregnant mice were orally dosed once/day on days 7-14 of gestation at 0-4% maternal mortality. Reproductive endpoints included pup survival in utero (percent of live litters/pregnant survivors), pup perinatal and postnatal survival (number of live pups/litter), number of dead pups/litter, and pup survival to 2.5 days of age), and pup body weight statistics (weight at birth and weight at 2.5 days of age). The study was conducted in 2 phases: a dose range-finding phase using nonpregnant female mice, and a definitive reproductive phase using time-mated mice. The range-finding phase sought to identify, for each chem, the maternal LD10 as the target dose. However, based upon reproductive phase results, such an exact dose was impractical to achieve. Thus, a range from LD5 to LD20 was considered a sufficient challenge dose that would not affect results due to high mortality. [R58] *Several structurally related alkyl glycol ethers were examined for their ability to block junction-mediated intercelluar communication. Interruption of intercellular communication was measured in vitro by an assay that depends on the transfer of metabolites via gap junctions, ie, metabolic cooperation. The potencies of the compounds were inversely related to the length of the aliph chain, the dose required for maximum blockage increasing as the aliph chain shortened. Cytotoxicity, as measured by cell survival, was also related to the structure of the compound, generally increasing with increased length of the aliph chain. [R59] *Past studies on the toxicological effects of ethylene glycol alkyl ethers as well as the recent data on these chemicals in Japan are reviewed. Studies on ethylene glycol alkyl ethers and related compounds administered to mice by oral gavage revealed the occurrence of testicular atrophy and decreased white blood cell count by EGM. [R60] *It is hypothesized that the known teratogen di(2-methoxyethyl) phthalate (DMEP) acts by in vivo hydrolysis to 2-methoxyethanol (2-ME), also a known teratogen, which in turn is metabolized to methoxyacetic acid (MAA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with the administration of these three agents on day 12 of gestation. On an equimolar dosage basis, DMEP, 2-ME, and MAA were equally potent, which is consistent with the hypothesis. There was a striking similarity in the defects produced by these agents, mainly hydronephrosis, heart defects, and short limbs and tails. In particular all three agents produced unusual heart defects (dilated ductus arteriosus and dilated aorti arch) not seen with other agents, as well as ventral polydactyly, a rarely seen defect, suggesting teratogenic action by a common mechanism or component; 4-methylpyrazole, an alcohol dehydrogenase inhibitor, provided significant protection against 2-ME. [R61] *Ethylene glycol monobutyl ether (EGBE) has been tested for its potential to produce adverse effects in laboratory animals by ingestion, vapor inhalation and skin penetration. The lowest dosage level at which effects were noted by ingestion was 200 mg/kg for 90 days, which produced testicular effects in rats, and 500 mg/kg for 5 weeks in mice where a decrease in erythrocyte count was noted. The significance of the testicular effect is uncertain because of the possibility that impurities were present in the test sample which are known to produce germinal epithelial cell damage. A no-observable effect level of 80 mg/kg was obtained in rats which received the EGBE in feed for 90 days. The lowest vapor exposure concentration at which effects were noted was 62 ppm (RBC fragility). Female rats exposed to 77 ppm for 13 weeks exhibited transient decreased weight gain and a transient decrease in erythrocyte count. An exposure concentration of 100 ppm produced increased erythrocyte fragility in mice. The no-observable effect level in rats exposed for 13 weeks was 25 ppm and in guinea pigs exposed for 6 weeks was 125 ppm. A dosage concentration of 180 mg/kg applied as a 50% aqueous dilution to the skin of female rabbits for nine applications produced hemoglobinuria. No observable systemic effects were noted when 150 mg/kg was applied to the skin of rabbits for 13 weeks. /Ethylene glycol monobutyl ether/ [R62] *Short-term and subchronic vapor inhalation studies have shown that there are pronounced differences in the toxicological properties of ethylene glycol monomethyl ether (EGME) ... Overexposure to EGME has resulted in adverse effects on testes, bone marrow and lymphoid tissues in laboratory animals. ... EGME is primarily oxidized to methoxyacetic acid in male rats ... Since methoxyacetic acid has been shown to have the same spectrum of toxicity as EGME in male rats, the observed ... toxicological properties of EGME ... are thought to be due to the fact that ... /EGME is/ biotransformed ... /to methoxyacetic acid/. [R63] *The behavioral teratogenic effects of ethylene glycol monomethyl ether (EGME) and ethylene glycol monoethyl ether (EGEE) were /studied/. Groups of 15 pregnant rats were exposed via inhalation to 25 ppm EGME or to 100 ppm EGEE on gestation days 7-13 or 14-20. An equal number of sham-exposed controls were included for both periods of gestation. The only effect noted in the maternal animals was a slightly prolonged gestation in the group exposed to 100 ppm EGEE on days 14-20. ... brains from 21-day-old offspring were removed and analyzed for ions of the neurotransmitters acetylcholine, dopamine, and 5-hydroxytryptamine. Both the behavioral testing and the chemical evaluations revealed functional alterations in litter groups experiencing prenatal exposure to EGME and EGEE at concentrations which produced no observable effects in the maternal animals. [R64] +The teratogenic potential of 2-Methoxyethanol (ME) was studied using the in vivo assay of Chernoff and Kavlock. ME was administered by dermal route to pregnant ALPK/AP rats on days 6 thru 17 of gestation, using 10 mg/kg body weight of a solution of 0, 3, 10, 30, or 100% ME in physiological saline. The rats were allowed to deliver and rear their litters until day 5 postpartum. A concentration of 100% of ME was lethal to all mothers, 30% was lethal to fetuses, and 10% caused a decrease in the litter size and a decrease in survival rate. A concentration of 3% had no adverse effects. Using this in vivo technique, it was estimated that a concentration of 10% ME is potentially teratogenic in the rat. [R65] +On gestation day 5, 160 Sprague-Dawley rats were assigned to 5 groups. Four groups were subdivided into 4 ethylene glycol monomethyl ether (EGME)-treatment groups of 8 dams each. On gestation days 6-12, dams were given 0, 25, 50, or 75 mg EGME/kg body weight by gavage. Dams were sacrificed on gestation days 9, 11, 13, or 15 and the embryos were analyzed. The fifth group of dams was allowed to deliver. None of the pregnant dams treated with 75 mg/kg EGME delivered pups. Gestation time was significantly prolonged and pup weight was reduced with increasing doses. On gestation day 11, exposure to 75 mg/kg EGME decreased ornithine decarboxylase activity per g of embryonic tissue by 60%. [R66] +The embryotoxic effects of 2-methoxyethanol (2-ME) were studied in macaques (Macaca fascicularis) receiving this chemical daily by gavage throughout the organogenetic phase of pregnancy (days 20 to 45). Dosages were 0.47, 0.32, or 0.16 mmole/kg, corresponding to 36, 24, or 12 mg/kg. Fetuses were collected at 100 days by Cesarean section. At the highest dose, all eight pregnancies ended in death of the embryo. One of these embryos was missing digit on each forelimb. Embryonic death occurred in 3 of 10 pregnancies at the middle dose and in 3 of 13 at the lowest dose. An additional spontaneous abortion occurred in both the middle and low dose groups. Anorexia and a dose related loss of maternal body weight were noted. In the high dose animals anorexia was severe, and the mean weight decreased from 4.25 to 3.88 kg over the course of the 25 day exposure. Distribution of the major metabolite, 2-methoxyacetic acid, indicated a half life of 20 hours, resulting in accumulation of metabolite in maternal serum after repeated daily dosing of 2-ME. Concentrations of 2-ME in embryo (37.50 to 162.93 ug/ml) and extraembryonic fluids (34.43 to 197.1 ug/ml) were similar to that of maternal serum (39.87 to 124.37 ug/ml). However, the yolk sac accumulated higher concentrations (109.87 to 319.35 ug/ml). [R67] NTOX: +Pregnant Crl:CD-1 ICR BR mice were admin 250 mg/kg (3.3 mmol/kg) 2-methoxyethanol (2-ME) on day 11 of gestation. Test groups were also given oral doses of serine (3.3 or 16.5 mmol/kg), sarcosine (3.3, 16.5, or 43 mmol/kg) and sodium acetate (43 mmol/kg) either concomitantly with 2-ME or after delays ranging from 4 to 18 hr. Animals were sacrificed on day 18 of gestation. The metabolism of 2-ME to 2-methoxyacetic acid occurred very rapidly. After 15 min, 55 and 51% of the 2-ME in maternal plasma and the embryo, respectively, had been converted to the alkoxy acid. 84% of 2-MA was transformed to 2-methoxyacetic acid by 30 min, and 95% by 45 min. Serine at 16.5 mmol/kg was as effective as formate in almost completely eliminating fetal digit malformations resulting from treatment with 2-ME (from 60 to 3% of fetuses). Unlike formate, serine was equally effective against 2-methoxyacetic acid induced dysmorphogenesis and the attenuating efficacy remained unchanged when serine admin was delayed for up to 8 hr after 2-ME or 2-methoxyacetic acid exposure. Both concomitant (43, 16.5, or 3.3 mmol/kg) and delayed (16.5 mmol/kg at 6 hr) sarcosine admin resulted in significantly less 2-ME induced paw dysmorphogenesis. Concurrent acetate treatment resulted in a reduction of 2-ME induced paw malformations from 47 to 5% of fetuses, and 83 to 40% of litters. Although the digit malformation incidence incr gradually to 15% of the fetuses being affected, acetate remained effective in ameliorating the paw dysmorphogenesis when admin was delayed for up to 12 hr. [R68] +Groups of 6 male Fischer 344 rats were dosed by gavage with a single dose of 6.6 mmol 2-methoxyethanol (2-ME)/kg (500 mg/kg). Serine (16.5 mmol/kg), sarcosine (16.5 mmol/kg), sodium acetate (43 mmol/kg), glycine (43 mmol/kg), and D-glucose (43 mmol/kg) were admin orally with 2-methoxyethanol. Animals were killed on day 24 post treatment. 2-Methoxyethanol treatment resulted in significant decr in daily sperm production on day 24 that were relatively consistent between the 5 treatment groups ranging from 57 to 59% of control values. Testicular wt declined 81 to 86%. Serine completely eliminated 2-methoxyethanol induced decr in daily sperm production, while glucose was without effect. Acetate, sarcosine, and glycine were of similar efficacy resulting in daily sperm production that was significantly greater than that observed in rats receiving 2-methoxyethanol alone. Sarcosine alone had no effect on daily sperm production, but when given concurrently with 2-methoxyethanol, it ameliorated testicular toxicity and lessened the severity of the decr in testicular wt. When glycine was admin with 2-methoxyethanol, daily sperm production was incr to 80% of control as opposed to 57% in animals receiving 2-methoxyethanol alone. Similar percentages for acetate were an incr of 75% of control as opposed to 59%. Histopathological studies revealed that 2-methoxyethanol treatment resulted in stage specific degeneration of late stage pachytene spermatocytes 24 hr after treatment. The cellular damage was characterized by a decr number of late stage pachytene spermatocytes, cellular shrinkage, and nuclear pyknosis or karyorrhexis. No apparent degenerative changes occurred 24 hr after concurrent treatment with serine. On day 24 following 2-methoxyethanol treatment, late stage elongated spermatids were decr in number or entirely missing in Stages V to VII of spermatogenesis. Similarly, serine prevented this decr in the number of spermatids in the lumina of the seminiferous tubules. [R69] +Groups of 10 Sprague Dawley rats were given 0-0.25% of 2-methoxyethanol in liquid diet on gestation days 7-18. Day 20 fetuses were examined for visceral or skeletal malformations. Concn above 0.025% 2-methoxyethanol (approx 73 mg/kg/day) produced total embryo mortality. Cardiovascular malformations were produced at lower levels. The teratogenic no-effect level was 0.006% 2-methoxyethanol (16 mg/kg). In a second experiment, groups of 12 Sprague Dawley rats were given 0, 0.006 and 0.012% of 2-methoxyethanol in liquid diet. Litters were culled to 8 pups, and tested for auditory and tactile startle and conditioned lick suppression, and for performance in figure-8 activity and the Cincinnati water maze on postnatal days 48-65. The high dose of 2-methoxyethanol produced approx 50% mortality in the offspring and incr the number of errors in the Cincinnati maze. An interaction study was conducted to determine if simultaneous exposure to 2-methoxyethanol and ethanol would reduce the teratogenicity of 2-methoxyethanol, but no reduction was observed. The hypothesis that 2-methoxyethanol acts by altering embryonic intracellular pH was tested by injecting 0.33 ml/kg of 2-methoxyethanol into rats on gestation day 13, and determining embryonic intracellular pH at 2, 4, 8, and 24 hr thereafter. There was an incr in pH at 4 hr, but not at later time points. Another group of rats was given 2-methoxyethanol along with amiloride, which blocks the sodium/hydrogen antiporter. The combined 2-methoxyethanol-amiloride exposure produced an incidence of cardiovascular malformations in fetuses twice that of 2-methoxyethanol alone. [R70] ETXV: *LD50 Goldfish greater than 5000 mg/l/24 hr; [R8, 651] *LC50 Lepomis macrochirus greater than 10,000 ppm/96 hr; Static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr; [R8, 651] *LC50 Menidia beryllina greater than 10,000 ppm/96 hr; Static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr; [R8, 651] *LC50 Guppy 17,400 ppm/7 day; [R8, 652] *LC50 Rainbow trout fingerlings 15,520 ppm/96 hr at 12 deg C; [R8, 652] NTP: +Ethylene Glycol Monomethyl Ether (EGME) ... was used to test the hypothesis that mouse strains of differing basal fertility would respond differently to a reproductive toxicant. This study used Swiss CD-1 mice in a modified RACB protocol. The design was modified to use 30 pairs of mice/group instead of the usual 40/control and 20/treated group. Neither Task 3, the crossover mating test, nor Task 1, normally used to set doses for the continuous cohabitation phase, were conducted, because sufficient data were already available on affected sex and the optimal doses to use. In all three studies, dose levels of EGME in drinking water for Task 2 were set at 0.03%, 0.1%, and 0.3% EGME, weight/volume. For this study, these concns produced calculated consumption estimates of nearly equal to 60, 200, and 550 mg/kg/d. Water consumption was not reduced by EGME addition. No males and 10 females died during Task 2: 1, 3, 3, and 3 in the control to high dose groups, respectively. All pairs had at least one litter in all groups except the high dose, where only 30% of the pairs had at least one litter. Only 2 high dose pairs produced 4 litters, and none produced 5. In the control and low dose litters, 93-94% of pups were born alive, while that was reduced to 87% in the middle dose, and to 14% in the high dose group. The number of live pups/litter was reduced in the high dose group, from a control mean of 11.7, to nearly equal to 0.5. There was no effect on live pup weight. The last litter was weaned for second-generation testing. Male and female pup survival in the middle dose group were reduced by 30-40%; there were no high-dose pups. Absolute pup weight in the middle dose group was reduced by nearly equal to 20% at weaning, but was not significantly different at earlier times. The F0 mice were killed and necropsied after the last litter was weaned. While female body weight was unchanged, female kidney weights were increased by 7% and 8% in the low and high dose groups, respectively. In males, body weight was also unchanged, and kidney weight was increased only at the low dose, by 10%. Male liver weights were increased by 6% and 7% in the middle and high dose groups, respectively. Testis weight and epididymis weight were reduced in the high dose group by nearly equal to 16% and nearly equal to 13%, respectively. Abnormal sperm forms were increased in the high dose group by nearly equal to 6-fold. The second generation mice were cohabited for a wk at 74 ± 10 days of age. There were no high dose offspring for this Task. Only 50% of the middle dose group mated, and a third of the 20 cohabited pairs delivered any pups at 0.1% EGME. While there was no reduction in litter size in this F1 mating, there was a 10% reduction in the proportion of live-born F2 pups at 0.1%, and a 10% reduction in their weight adjusted for litter size. After the F2 pups were delivered and assessed, all remaining animals were killed, and the F1 mice were necropsied. There were no adverse effects on female body or organ weights, or on male body weights. Liver weight (adjusted for body weight) was increased by nearly equal to 9% and 10%, and kidney weights (also adjusted) were increased by 9% and 7% in the low and middle dose groups, respectively. There was a 10% reduction in adjusted epididymis weight at the middle dose level. There were no changes in sperm parameters at either dose level. This study showed that the greatest effect produced by EGME at these doses was on the ability to become pregnant and deliver live pups. The top dose (0.3% EGME in the drinking water) was severely toxic to reproduction, with only 8/27 pairs delivering any litters of any pups, live or dead. The middle dose level (0.1% EGME) had few detectable effects on F0 reproduction, but significant adverse effects on F1 reproductive success, based on a reduced fertility index, a reduced proportion of liveborn pups, and reduced F2 pup weight. The lowest dose used in this study, 0.03% EGME, was without adverse reproductive effect in Swiss CD-1 mice. [R71] +Ethylene Glycol Monomethyl Ether (EGME) ... was used to test the hypothesis that mouse strains of differing basal fertility would respond differently to a reproductive toxicant. This study used C57Bl/6 mice in a modified RACB protocol. The design was modified to use 30 pairs of mice/group instead of the usual 40/control and 20/treated group. Neither Task 3, the crossover mating test, nor Task 1, normally used to set doses for the continuous cohabitation phase, were conducted, because sufficient data were already available on affected sex and the optimal doses to use. In all three studies, dose levels of EGME in drinking water for Task 2 were set at 0.03%, 0.1%, and 0.3% EGME, weight/volume. For this study, these concns produced estimated consumption values of nearly equal to 50, 170, and 500 mg/kg/day. Water consumption was not reduced by EGME addition. One male and two females died in the control group during Task 2, and 1 male, 1 female, and 2 males died in the low to high dose groups, respectively. These deaths were judged not to be treatment-related. While 23/27 control pairs delivered any pups, only 7/28 high dose pairs had any pups. Of those, 5 pairs delivered only 1 litter, and no high-dose pair delivered more than two litters. Thus, the mean number of litters/fertile pair declined from 3.57 (control) to 1.29 (high dose). Additionally, there were no live pups ever delivered at the high dose. The mean number of live pups/litter declined at the middle dose, from a control value of 8.0, to 6.9. A greater proportion of pups were born dead in the middle dose group (18%, vs. a control value of 8%). The mean pup weight adjusted for litter size increased at the low and middle doses by nearly equal to 2% and 4%, respectively. The pups from the last litter were reared by their dam until weaning. In control litters, 75% and 87% of male and female pups, respectively, survived until weaning. In the middle dose group, these values were reduced to 33% and 28%, respectively. Absolute female pup weight was reduced only at weaning by nearly equal to 35%.; male pup weight was not significantly decreased. After weaning the F1 mice, all remaining F0 mice were killed and necropsied. There were no changes in female body or organ weights. Male mice in the high dose group weighed 10% less than controls, and the adjusted liver weight for the middle dose males was increased by nearly equal to 6%. At the high dose, absolute testis weight was decreased by nearly equal to 30%, relative epididymis weight was decreased by nearly equal to 11%, the % of motile epididymal sperm and epididymal sperm density were decreased by nearly equal to 30% and nearly equal to 34%, respectively. The % abnormal sperm was increased at the middle and high doses, from a control value of 29%, to 37% and 96% abnormally-formed sperm, respectively. At 74 ± 10 days of age, F1 mice were cohabited for a wk within treatment groups. While there were sufficient F1's to make 20 non-sib pairs in the control and low-dose groups, there were sufficient middle-dose animals to form only 6 breeding pairs. Five of those 6 mated, but none delivered a litter of live pups (vs. 14/20 that delivered live young in the control group). Thus, F2 pups were available from only the low dose group and the controls. There were no differences between these groups in pup weight, mean pup number, viability, or proportion of males. After the F2 pups were delivered and assessed, all mice were killed, and the F1 mice were necropsied. While there was no effect on female body weight, there was a 50% reduction in ovary weight at the middle dose (n=6), and a 26% incr in adjusted kidney weight. In males, there were no changes in body weight, while middle dose males showed a 25% incr in relative kidney weight and a 34% reduction in prostate weight. Seminal vesicle weight was reduced in the low and middle dose groups by 6% and 15%. Abnormal sperm forms were increased in the middle dose group, from a control value of 25%, to a treated value of 43% abnormal. Epididymal sperm density in the low dose was reduced by 11%; the 23% reduction in the middle dose group was not significant due to the small number of mice. In summary, this strain had fewer pups/litter, and fewer litters/pair overall compared to the Swiss CD-1 strain, but more than the C3H strain. EGME completely inhibited successful reproduction at the top dose. The middle dose level (0.1%) was toxic, based on reductions in pup number and increases in abnormal sperm forms. In this strain, the low dose produced adverse effects in the second generation (reduced seminal vesicle weight and epididymal sperm count) that were not seen with the other strains at this dose. Compared to the Swiss mice, C57's had lower basal fertility, and were more affected by EGME exposure. This supports the hypothesis that strains of lower basal fecundity evidence greater reproductive toxicity than more robust and fertile strains when challenged with a toxicant. [R72] +EGMME severely affected fertility and reproduction in C3H mice when administered to adults at 0.3% in drinking water (none of the breeding pairs were fertile). At necropsy, body weights for both sexes, and seminal vesicles, right testis, right cauda and right epididymis weights in males were significantly decreased in the 0.3% dose group. The right ovary weight was relatively high. Sperm motility, sperm density and the incidence of abnormal sperm were also severely affected at 0.3% level. EGMME at 0.1% levels had less severe but still significant reproductive effects in the parental generation. These pairs showed decreased live pups/litter, proportion of pups born alive, and male pup weight during nursing. Furthermore, in the F0 females right ovary and liver weights were significantly higher than the control group. All second generation pairs receiving 0.1% EGMME were infertile. Thus, O.1% EGMME was shown to have greater effects on the second generation than on the parental generation. In the F1 male mice, the seminal vesicles, right cauda, right testis and right epididymis weights were significantly decreased. In the F1 females, terminal body liver and kidney weights were significantly decreased. There was no apparent effect on fertility or reproduction in F0 or F1 C3H mice at 0.03% level. Parental generation females in the 0.03% dose group showed slightly increased liver weights. In second generation animals, there was no effect with respect to terminal body or organ weights at the 0.03% level. [R73] +Dose levels selected were 0.006, 0.012, and 0.024% ethylene glycol monomethyl ether (EGMME), administered via drinking water. Male and female rats (20 pairs/treatment group, 40 pairs of control animals) were continuously exposed for a 7-day precohabitation period and 112-day cohabitation (Task 2). While there was no decr in avg litter size with increased dose, the number of live male pups/litter and the total number of pups/litter were decreased in the 0.024% group. Both absolute and adjusted live pup weight were increased in all EGMME groups, but this was not dose-related. During the cross-over mating to determine the affected sex, there were fewer live male pups born to the 0.024% male X control female pairs. During the mating trial for the second generation, fewer male and total pups were delivered in the high-dose group, and both absolute and adjusted pup weight were increased in the middle and high dose groups. Low control fertility (63% fertile) during the cross-over mating is a cause for concern, however suggested protocol changes should alleviate some of this problem. Thus the RACB protocol can successfully be adjusted for use in rats. [R74] +Dose levels selected were 0.01, 0.03, and 0.10% /ethylene glycol monomethyl ether (EGMME)/, administered via drinking water. In a modification of the standard protocol, male and female rats /about/ 20 pairs/treatment group, 40 pairs of control animals) were cohabited for approx 6 wks, separated to allow delivery, nursing and weaning of the second litter, then re-cohabited for approx 9 more wks. The weaned second litter was used for F1 reproductive testing. The control and 0.03% F0 pairs were also utilized for a crossover mating trial to determine the affected sex. Only one litter was born in the 0.10% dose group, and no pups were available for F1 testing. At 0.03% level of EGMME, number of live pups/litter and proportion of pups born alive decreased significantly, both in F0 AND F1 testing. In the crossover mating, proportion of pups born alive decreased significantly in the 0.03% male X control female group. Declining control F0 fertility and productivity noted in this study indicate that the standard RACB design (weaning last rather than second litter) is better suited to use with rats. [R75] +Ethylene Glycol Monomethyl Ether (EGME) ... was tested for reproductive toxicity in Swiss CD-1 mice using the RACB protocol. It was part of a series of glycol ethers and congeners evaluated for structure-activity correlations using this design. In a preliminary study using concns of 0.5%-2.0% EGME in drinking water, all treated mice were infertile. Thus follow-up study was designed to more accurately define the dose-response curve. Data from the previous study, plus body weights, clinical signs, and food/water consumption during the dose-range-finding segment (Task 1) were used to set concns for the main study (Task 2) at 0.1%, 0.2%, and 0.4% EGME in drinking water. These concns produced calculated consumption estimates of nearly equal to 159, 336, and 619 mg/kg/d. During Task 2, 1 male died in the control group, and 2, 2, 1, and 4 females died in the control-to-high-dose EGME groups, respectively. Only 1 of the remaining 16 high-dose pairs had a litter, while the fertility rate in the other groups was unchanged by EGME consumption. Female body weight during Task 2 was reduced, which reflects the lack of pregnancy-induced body weight increases. The number of litters/pair was reduced by 30% at 0.2% EGME, while the number of live pups/litter was reduced by 18% and 77% in the low dose and middle dose groups, respectively. No live pups were delivered at 0.4% EGME. Pup weight adjusted for litter size was reduced by 6% in the middle dose group. Cumulative days to litter was increased for all litters at all doses; for the 0.1% and 0.2% EGME groups, the last litter was delivered 8 and 11 days after the controls, respectively. The middle dose group was used in a Task 3 crossover to determine the affected sex. There was a 66% reduction in pups delivered to treated females, and the pup adjusted body weight was reduced by 6%. No adverse effects were seen in litters of treated males. After delivery and assessment of the litters, these F0 mice were killed and necropsied. Body and organ weights were unaffected by 0.2% EGME consumption, but estrous cycle length was increased from 4.8 days (controls) to 5.6 days. For a second generation mating, there were only sufficient mice from the 0.1% EGME group. Thus, F1 mice from the last litter of the control and 0.1% EGME groups were reared to mating at 74 ± 10 days of age. Only 5/20 EGME pairs mated and only 2/20 bore a litter (vs. 19/20 for controls for both endpoints). In those two litters, 75% of the pups were live-born (vs. 99% for controls). Other changes were not significant, probably due to the low number of animals involved. After litter delivery and subsequent vaginal lavage, the F1 mice were killed and necropsied. While female body weight was unchanged by 0.1% EGME consumption, adjusted liver weight was reduced by 11%. In males, no body weight difference was found, but EGME consumption reduced weights of seminal vesicles, epididymis and prostate by 11%, 12%, and 20% respectively. Epididymal sperm parameters and estrous cycle length were unchanged by 0.1% EGME exposure. In summary, these concns (0.1% to 0.4%) of EGME produced marked reductions in fertility and reproductive indices, while leaving body weights unchanged. Because of the reduced liver weight in the F1 females, it must be concluded that the reproductive effects seen in this study occurred in the presence of some somatic toxicity. [R76] TCAT: ?In preliminary studies, teratogenicity was evaluated in pregnant female monkeys (Macaca fascicularis, 1 monkey/dose level) orally exposed to 2-methoxyethanol by gavage at dose levels of 0.5 ml/kg (monkey-1), 0.25 ml/kg (monkey-2), or 0.1 ml/kg (monkey-3) on gestation days (GD) 26-27, 28-31, or 23-34, respectively. No toxic signs were observed in monkey-1 other than continuous vaginal bleeding from GD 17-48 and the fetus was aborted on day 48 (normal bleeding for species=7-14 days, bleeding believed to be contributing factor to abortion). Monkey-2 showed signs of maternal toxicity including regurgitation after 3rd dose and slight weakness after the 4th dose. Monkey-2's pregnancy progressed normally until the fetus was delivered by hysterotomy on GD 100. The fetus was small compared to mean fetal weight of controls and a severe kink was evident in the distal part of the tail, and further examination of the viscera and skeleton revealed no other malformations. Monkey-3 exhibited a 10% loss of maternal body weight and aborted her fetus on GD 27. Monkey-3 had carried two previous fetuses to termination (GD 100, no treatment) and aborted two other fetuses (treated with ethanol or sucrose). [R77] ?The effects of exposure to 2-methoxyethanol by inhalation on male New Zealand White rabbits (10/group), in particular the effects on the testes, were evaluated. Exposure was at nominal concentrations of 0, 3, 10 or 30 ppm for 6 hrs/day, 5 days/week, for a total of 13 weeks. There were no significant differences observed between treated and control animals in the following: appearance or demeanor of the rabbits, body weights, testes weights, gross pathology, and histopathological examination of the testes. [R78] ?The effect of 2-methoxyethanol was examined in a DNA repair assay with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article did not induce an increase in average net nuclear grain counts in whole cell autoradiography experiments, or a change in isolated DNA CsCL gradient profiles, following administration to cultured human embryonic intestinal cells at concentrations ranging from 76 to 9664 ug/ml in the presence or absence of activation. In a preliminary cytotoxicity test, 2-methoxyethanol was not toxic to cells at concentrations up to and including 9664 ug/ml. [R79] ?The in vitro absorption of 2-methoxyethanol through human skin was evaluated. The test substance as a neat liquid was left in contact with the skin for approximately 8 hours. There was an apparent lag phase in absorption, followed by attainment of a steady rate after approximately 2.75 hours. The mean steady rate of absorption was 1.66mg/cm(2)/hour for 2-methoxyethanol. No significant irreversible alterations to the barrier properties of the epidermal were observed. [R80] POPL: *Individuals who are occupationally exposed to methyl cellosolve and have hematologic and/or kidney disorders may be at increased risk. [R18, 1981.1] ADE: *THE MATERIAL /2-METHOXYETHANOL/ WAS DETECTED IN THE URINE OF RATS 30 MIN AFTER THE IP ADMIN OF 1.0 ML/KG AND CONTINUED TO BE PRESENT FOR A TOTAL OF 7 HR AFTER THE INJECTION, 3 HR AFTER IT WAS LAST SEEN IN THE BLOOD. ... IT APPEARS THAT ETHYLENE GLYCOL METHYL ETHER ... IS ELIMINATED MAINLY VIA EXPIRED AIR AND IN THE URINE. [R22, 3917] *MALE FISCHER 344 RATS WERE GIVEN A SINGLE ORAL DOSE OF APPROX 1 OR 8.7 MMOL/KG OF (14)C-ETHYLENE GLYCOL MONOMETHYL ETHER. APPROX 50 TO 60% OF THE ADMIN (14)C WAS EXCRETED IN URINE, AND ABOUT 12% WAS ELIMINATED AS (14)CO2 WITHIN 48 HR. [R81] *To assist evaluation of the hazards of skin contact with selected undiluted glycol ethers, their absorption across isolated human abdominal epidermis was measured in vitro. Epidermal membranes were set up in glass diffusion cells and, following an initial determination of permeability to tritiated water, excess undiluted glycol ether was applied to the outer surface for 8 hr. The appearance of glycol ether in an aqueous "receptor" phase bathing the underside of the epidermis was quantified by a gas chromatographic technique. A final determination of tritiated water permeability was compared with initial values to establish any irreversible alterations in epidermal barrier function induced by contact with the glycol ethers. 2-Methoxyethanol (EM) was most readily absorbed (mean steady rate 2.82 mg/sq cm/hr) ... There was a trend of reducing absorption rate with increasing molecular weight or reducing volatility for monoethylene glycol ethers ... . [R82] METB: *MALE FISCHER 344 RATS WERE GIVEN A SINGLE ORAL DOSE OF APPROX 1 OR 8.7 MMOL/KG OF (14)C-ETHYLENE GLYCOL MONOMETHYL ETHER. METHOXYACETIC ACID WAS IDENTIFIED AS THE PRIMARY URINARY METABOLITE, ACCOUNTING FOR 80-90% OF THE TOTAL (14)C IN URINE. [R81] *(14C) 2-Methoxyethanol (250 mg/kg, intraperitoneal) administered to Sprague-Dawley rats induced testicular toxicity. Radioactivity detected in the urine over 48 hr after treatment accounted for 55% of the dose. The major urinary metabolites were methoxyacetic acid and methoxyacetylglycine and they accounted for 50% to 60% and 18% to 25%, respectively, of urinary radioactivity. [R83] *Exposure to methoxyacetic acid (MA) (the major metabolite of 2-methoxyethanol) results in spermatocyte depletion and testicular atrophy in cultured rat Sertoli cells. Cell cultures were incubated with MA at 0, 3, or 10 mM for up to 12 hr and lactate concns and rates of lactate accumulation were impaired at the 3 and 10 mM concn. [R84] *The secondary metabolite of dimethoxyethyl phthalate (DMEP) methoxyacetic acid (MAA), but not the diester or its primary metabolites monomethoxyethyl phthalate and methoxyethyanol (ME) interferred with normal growth and development of organogenesis phase rat embryos in culture. These in vivo observations suggested that the teratogenicity of DMEP in vivo was due to enzymic cleavage of the diester to ME, followed by oxidation of the latter to MAA in the maternal compartment. [R85] *Intraperitoneal (ip) administration of methoxyacetic acid (MAA) to rats on day 8, 10, 12 or 14 of pregnancy was embryolethal and teratogenic. Skeletal anomalies, hydrocephalus and dilatation of the kidney pelvis were the most common malformations. Embryonic response to MAA varied with gestational age and with dosage (0.1-2.5 mmol/kg). These actions are similar to those previously reported for 2-methoxyethanol. [R86] *Short-term and subchronic vapor inhalation studies have shown that there are pronounced differences in the toxicological properties of ethylene glycol monomethyl ether (EGME) ... Overexposure to EGME has resulted in adverse effects on testes, bone marrow and lymphoid tissues in laboratory animals. ... EGME is primarily oxidized to methoxyacetic acid in male rats ... Since methoxyacetic acid has been shown to have the same spectrum of toxicity as EGME in male rats, the observed ... toxicological properties of EGME ... are thought to be due to the fact that ... /EGME is/ biotransformed ... /to methoxyacetic acid/. [R63] BHL: *... ETHYLENE GLYCOL METHYL ETHER WAS FOUND EQUALLY DISTRIBUTED IN BRAIN, PLASMA, LUNG, AND LIVER 1 HR AFTER ADMIN AND ... THE HALF-LIFE IN THE BODY WAS APPROX 1 TO 2 HR, UNLESS DOSES WERE NEAR THE LETHAL LEVEL. IN INHALATION STUDIES THE PLASMA LEVELS OF ETHYLENE GLYCOL METHYL ETHER INCR NEARLY LINEARLY 1, 2, 4, AND 6 HR /FOLLOWING/ EXPOSURES TO 3317 PPM. WHEN THE EXPOSURE WAS EXTENDED TO 8 HR THE CONCN IN THE PLASMA /LEVELS/ MORE THAN DOUBLED THAT FOUND AFTER THE 6-HR EXPOSURE, SUGGESTING THAT METABOLIC AND/OR EXCRETORY MECHANISMS WERE SATURATED. [R22, 3917] INTC: *... A SINGLE EXPOSURE OF MICE TO 125 PPM FOR 4 HR POTENTIATED THE HYPNOTIC EFFECTS OF BARBITURATES; AT 500 PPM FOR 4 HR, A DECR IN MOTOR ACTIVITY OCCURRED. [R22, 3916] *THE IV LD50 OF SERRATIA MARCESCENS ENDOTOXIN IN MICE WAS 17 MG/KG. HOWEVER, WHEN THE ENDOTOXIN WAS FOLLOWED IMMEDIATELY BY 950 MG IV METHYL CELLOSOLVE, THE LD50 DROPPED TO 0.25 MG/KG. IP METHYL CELLOSOLVE ALSO CAUSED POTENTIATION AS DID THE PREINCUBATION OF METHYL CELLOSOLVE AND ENDOTOXIN PRIOR TO INJECTION. [R87] *In adult female SPF Sprague-Dawley rats exposed for 2 hr to 1600 ppm 2-methoxyethanol (ME) the blood level of ME was considerably increased after pretreatment with ethanol (20 mmol/kg, ip). The blood level of ME remained nearly constant after the co-administration of ME (10 mm/kg, ip) with ethanol (20 mmol/kg), as long as ethanol levels in the blood remained above 3 mmol/l. Repeated ip dosing (five times one injection per hour) with ME (5mmol/kg) plus ethanol (8 or 10 mmol/kg) each resulted in an almost complete accumulation of ME. The prolonged retention of ME is due to an inhibition of its degradation via competition with ethanol for alcohol dehydrogenase. [R88] *Ethylene glycol monomethyl ether (EGME) was administered to young male rats at doses varying from 50 to 500 mg/kg/day for 11 days. At sequential times animals were killed and testicular histology examined. The initial and major site of damage was restricted to the primary spermatocytes undergoing post zygotene meiotic maturation and division. When animals were treated with inhibitors of alcohol metabolism followed by a testicular toxic dose of EGME (500 mg/kg) an inhibitor of alcohol dehydrogenase (pyrazole) offered complete protection. However pretreatment with aldehyde dehydrogenase inhibitors disulfiram or pargyline did not ameliorate the testicular toxicity of EGME. [R89] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Methoxyethanol is released to the environment as emissions from manufacture and use as a solvent, including volatilization from consumer products. In the atmosphere, it will photodegrade primarily by reaction with hydroxyl radicals in hours and rainout may be significant. Although no data on its rate of degradation in natural waters could be found, laboratory tests suggest that it will degrade in water. It will slowly volatilize, but will not sorb to sediment or bioconcentrate in aquatic organisms. Its fate when spilled on land is unknown, although volatilization from near-surface soil and leaching to groundwater are possible. Human exposure will be primarily in occupational atmospheres and from use of certain consumer products.(SRC) ARTS: *Volatilization losses and wastewaters from its use as a solvent for resins, dyes; Use in nail polishes, and quick drying varnishes, enamels and woodstains (1,SRC). [R90] FATE: *TERRESTRIAL FATE: When released on land 2-methoxyethanol is expected to volatilize from soil as well as leach rapidly into the ground. Its biodegradation in soils is unknown (SRC). *AQUATIC FATE: When released into water, 2-methoxyethanol will slowly volatilize and will not be expected to readily adsorb to sediment or bioconcentrate in fish. Although it is degradable in laboratory tests, no data on its rate of degradation in surface waters could be found. Its degradation in ground water is unknown(SRC). *ATMOSPHERIC FATE: When released into the atmosphere, 2-methoxyethanol will photodegrade with an estimated half-life of less than 1 day (SRC). Based on its miscibility with water, washout by rain may be significant. BIOD: *Biodegradation of 100-1000 mg/L 2-methoxyethanol with activated sludge at 20 degrees C for 10 days resulted in 64.7% theoretical BOD(1). Biodegradation of 3, 7, and 10 mg/L with filtered sewage seed in fresh water resulted in 30% theoretical BOD in 5 days and 88% theoretical BOD in 20 days; In salt water 6% theoretical BOD in 5 days and 39% theoretical BOD in 20 days was observed(2). Sewage seed degraded 2-methoxyethanol over 5 days resulting in 7% theoretical BOD using unadapted seed and 30% theoretical BOD using adapted seed.(3). No information is available on soil biodegradation. [R91] ABIO: *Ethers and alcohols are known to be resistant to hydrolysis(1). The estimated half-life of 2-methoxyethanol in the atmosphere is 17.54 hrs as a result of H atom abstraction by photochemically produced hydroxyl radicals (2). [R92] BIOC: *No information on the bioconcentration factor for 2-methoxyethanol could be found in the literature, however, its low octanol/water partition coefficient (log P of -0.77(1)) indicates that it will not bioconcentrate in fish (SRC). [R93] KOC: *No information concerning the adsorption of 2-methoxyethanol could be found in the literature. Its low octanol/water partition coefficient (log P of -0.77(1)) indicates that its adsorption to soil will be low (SRC). [R93] VWS: *Based on the vapor pressure and water solubility of 2-methoxyethanol, it is unlikely that volatilization will occur to a major extent in aquatic media (SRC). 2-Methoxyethanol is relatively volatile (vapor pressure 9.5 torr(1)) and would, therefore, evaporate from soil and other surfaces (SRC). [R94] RTEX: *Exposure to 2-methoxyethanol would be primarily occupational (SRC). *... FIVE CASES OF INDIVIDUALS EXPOSED TO METHYL CELLOSOLVE IN THE PRINTING DEPARTMENT OF A PLANT MAKING PLASTIC MATERIALS. THE METHYL CELLOSOLVE WAS THE COMMONLY USED CLEANING AGENT TO REMOVE PIGMENTS AND INK FROM THE FLOOR AND EQUIPMENT. [R95] *NIOSH estimates that 103,459 workers may be exposed to 2-methoxyethanol(1). [R96] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +200 ppm [R26] NREC: *NIOSH recommends that 2-methoxyethanol (2ME) ... be regarded in the workplace as having the potential to cause adverse reproductive effects in male and female workers. These recommendations are based on the results of several recent studies that have demonstrated dose related embryotoxicity and other reproductive effects in several species of animals exposed by different routes of administration. Appropriate controls should be instituted to minimize worker exposure to 2ME. NIOSH suggests that producers, distributors, and users of 2ME give this information to their workers and customers and that trade associations, and unions inform their members. [R97] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.1 ppm (0.3 mg/cu m) [skin]. [R26] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm, skin. [R98, 2002.39] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R98, 2002.6] +Biological Exposure Index (BEI): Determinant: 2-methoxyacetic acid in urine; Sampling Time: end of shift at end of workweek. Biological monitoring should be considered for this compound based on the review; however, a specific BEI could not be determined due to insufficient data. [R98, 2002.91] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Sampling ... may be performed by collection of methyl cellosolve vapors using an adsorption tube ... [R18, 1981.] *Air samples containing 2-methoxyethanol are taken with a glass tube, 7 cm x 4 mm ID, containing two sections of activated coconut shell charcoal (front=100 mg, back= 50 mg) separated by a 2 mm urethane foam plug. A silyated glass wool plug precedes the front section and a 3 mm urethane foam plug follows the back section. A sampling pump is connected to this tube and accurately calibrated at a flow rate of 0.01 to 0.05 l/min for a total sample size of 1 to 10 liters. Elution is performed with 1 ml of 5% methanol in CH2Cl2, and allowed to stand for 30 minutes. This technique has an overall precision of 0.068, over a studied range of 44 to 160 mg/cu m using 50 liter samples, and an average recovery of 93%. [R99, p. 1403-1] *Methods were developed and validated for personal monitoring of exposures to airborne glycol ethers. The silica gel tube method was used to monitor glycol ethers, but was affected by high humidity conditions, resulting in significant breakthough of the more volatile glycol ethers. The 3M organic vapor monitor accurately and conveniently determined exposure concentrations for DOWANOL EM, EE and PM glycol ethers, but sensitivities may be have been inadequate for sampling periods < 1 h. [R100] ALAB: *ANALYTE: METHYL CELLOSOLVE; MATRIX: AIR; PROCEDURE: ADSORPTION ON CHARCOAL, DESORPTION WITH 5% METHANOL IN METHYLENE CHLORIDE, GAS CHROMATOGRAPHY; RANGE: 44-160 MG/CU M. [R99, p. V2 S79] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: European Chemical Industry, Ecology and Toxicology Centre, Avenue, Bruxelles, Belgium, (1985) 68p. This report is an update of ECETOC Technical Report No. 4 Contents: haematological and testicular effects; teratological, embryotoxic and foetotoxic effects; neurologic and behavioural effects; genetic toxicity; carcinogenicity; skin absorption; metabolism; human exposure (exposure limits, environmental control, testing of effects on man); discussion; general conclusions. DHHS/NTP; NTP Technical Report on Toxicity Studies of Ethylene Glycol Ethers 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 26 NIH Publication No. 93-3349 (1993) For review see "The toxicology of glycol ether and its relevance to man: An up-dating of ECETOC Technical Report No. 4". 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Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.259 R34: MCGREGOR DB ET AL; GENETIC EFFECTS OF 2-METHOXYETHANOL AND BIS(2-METHOXYETHYL)ETHER; TOXICOL APPL PHARMACOL 70 (2): 303-16 (1983) R35: COOK RR ET AL; A CROSS-SECTIONAL STUDY OF ETHYLENE GLYCOL MONOMETHYL ETHER PROCESS EMPLOYEES; ARCH ENVIRON HEALTH 37 (6): 346-51 (1982) R36: Welsch F, Stedman DB; Environ Health Perspect 57: 125-33 (1984) R37: Cohen R; Am J Ind Med 6 (6): 441-6 (1984) R38: FOSTER PM ET AL; TESTICULAR TOXICITY OF ETHYLENE GLYCOL MONOMETHYL AND MONOETHYL ETHERS IN THE RAT; TOXICOL APPL PHARMACOL 69 (3): 385-99 (1983) R39: HEINONEN T, VAINIO H; DOSE DEPENDENT TOXICITY OF ETHYLENE GLYCOL MONOMETHYL ETHER VAPOR IN THE RAT; EUR J DRUG METAB PHARMACOKINET 6 (4): 275-80 (1981) R40: RAO KS ET AL; ETHYLENE GLYCOL MONOMETHYL ETHER II. REPRODUCTIVE AND DOMINANT LETHAL STUDIES IN RATS; FUNDAM APPL TOXICOL 3 (2): 80-5 (1983) R41: MILLER RR ET AL; ETHYLENE GLYCOL MONOMETHYL ETHER. I. SUBCHRONIC VAPOR INHALATION STUDY WITH RATS AND RABBITS; FUNDAM APPL TOXICOL 3 (1): 49-54 (1983) R42: DOE JE ET AL; COMPARATIVE ASPECTS OF THE REPRODUCTIVE TOXICOLOGY BY INHALATION IN RATS OF ETHYLENE GLYCOL MONOMETHYL ETHER AND PROPYLENE GLYCOL MONOMETHYL ETHER; TOXICOL APPL PHARMACOL 69 (1): 43-7 (1983) R43: Shepard, T.H. Catalog of Teratogenic Agents. 4th ed. Baltimore, MD: Johns Hopkins University Press, 1983. 831 R44: Gray JB et al; Toxicol Appl Pharmacol 79 (3): 490-501 (1985) R45: Chapin RE et al; Fundam Appl Toxicol 5 (1): 182-9 (1985) R46: Doe JE; Environ Health Perspect 57: 199-206 (1984) R47: Nelson BK et al; Environ Health Perspect 57: 261-71 (1984) R48: Chapin RE, Lamb JC; Environ Health Perspect 57: 219-24 (1984) R49: House RV et al; Toxicol Appl Pharmacol 77 (2): 358-6 (1985) R50: Hanley TR et al; Toxicol Appl Pharmacol 75 (3): 409-22 (1984) R51: Toraason M et al; Teratology 32 (1): 33-9 (1985) R52: Nelson BK et al; Pharmacol Biochem Behav 20 (2): 269-80 (1984) R53: Grant D et al; Toxicol Appl Pharmacol 77 (2): 187-200 (1985) R54: Samuels DM et al; Arch Toxicol Suppl 7: 167-70 (1984) R55: Houchens DP et al; Environ Health Perspect 57: 113-8 (1984) R56: Creasy DM et al; Exp Mol Pathol 43 (3): 321-36 (1985) R57: Jaeckh R et al; Toxicol Lett 26 (1): 73-8 (1985) R58: Schuler RL et al; Environ Health Perspect 57: 141-6 (1984) R59: Loch-Caruso R et al; Environ Health Perspect 57: 119-23 (1984) R60: Nagano K et al; Environ Health Perspect 57: 75-84 (1984) R61: Ritter EJ et al; Teratology 32 (1): 25-31 (1985) R62: Tyler TR; Environ Health Perspect 57: 185-91 (1984) R63: Miller RR et al; Environ Health Perspect 57: 233-9 (1984) R64: Nelson BK, Brightwell WS; Environ Health Perspect 57: 43-6 (1984) R65: Wickramaratne GADS; J Appl Toxicol 6:165-166 (1986) R66: Toraason M et al; Drug Chem Toxicol 9:191-203 (1986) R67: Scott WJ et al; Teratology 39 (4): 363-73 (1989) R68: Mebus CA, Welsch F; Toxicol Appl Pharmacol 99 (1): 98-109 (1989) R69: Mebus CA et al; Toxicol Appl Pharmacol 99 (1): 110-21 (1989) R70: Nelson BK et al; Neurotoxicol Teratol 11 (3); 273-84 (1989) R71: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Ethylene Glycol Monomethyl Ether (CAS #109-86-4): Reproduction and Fertility Assessment in CD-1 Mice When Administered in Drinking Water, NTP Study No. RACB86057 (March 1988) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R72: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Ethylene Glycol Monomethyl Ether (CAS #109-86-4): Reproduction and Fertility Assessment in C57Bl/6 Mice When Administered in Drinking Water, NTP Study No. RACB87058 (March 1988) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R73: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Ethylene Glycol Monomethyl Ether (CAS #109-86-4): Reproduction and Fertility Assessment in C3H Mice When Administered in Drinking Water, NTP Study No. RACB86099 (January 1989) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R74: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Ethylene Glycol Monomethyl Ether (CAS #109-86-4) in Sprague-Dawley Rats, Litter Five, NTP Study No. RACB88100 (June 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R75: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Ethylene Glycol Monomethyl Ether (CAS No. 109-86-4) in Sprague-Dawley Rats, Litter Two, NTP Study No. RACB89056 (June 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R76: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Ethylene Glycol Monomethyl Ether (CAS #109-86-4): Reproduction and Fertility Assessment in CD-1 Mice When Administered in Drinking Water, NTP Study No. RACB84055 (December 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R77: Children's Hospital Research Foundation; The Teratologic Potential of Methoxyethanol in Non-Human Primates. (1984), EPA Document No. FYI-OTS-1284-0370, Fiche No. 0000370-0 R78: Dow Chemical USA; Comments of the Chemical Manufacturers Association Glycol Ethers Program Panel on Chemical Hazard Information Profiles for Ethylene Glycol Monomethyl Ether (EGEE) and Ethylene Gylcol Monomethyl Ether (EGME). (1982), EPA Document No. FYI-OTS-0183-0225, Fiche No. 0000225 R79: Inveresk Research Intl. Ltd.; Tier II Mutagenic Screening of 13 NIOSH Priority Compounds (1980), EPA Document No. FYI-OTS-0981-0105, Fiche No. OTS0000105-0 R80: Imperial Chemical Industries, Central Toxicology Laboratory; 2-Methoxyethanol: Absorption Through Human Skin In Vitro, (1984), EPA Document No. FYI-AX-1084-0178, Fiche No. OTS0000178-2 R81: MILLER RR ET AL; COMPARATIVE METABOLISM AND DISPOSITION OF ETHYLENE GLYCOL MONOMETHYL ETHER AND PROPYLENE GLYCOL MONOMETHYL ETHER IN MALE RATS; TOXICOL APPL PHARMACOL 67 (2): 229-37 (1983) R82: Dugard PH et al; Environ Health Perspect 57: 193-7 (1984) R83: Moss EJ et al; Toxicol Appl Pharmacol 79 (3): 480-9 (1985) R84: Beattie PJ et al; Toxicol Appl Pharmacol 76 (1): 56-61 (1984) R85: Yonemoto J et al; Toxicol Lett 21 (1): 97-102 (1984) R86: Brown NA et al; Toxicol Lett 22 (1): 93-100 (1984) R87: GARTNER SL; METHYL CELLOSOLVE-INDUCED SENSITIZATION OF MICE TO BACTERIAL ENDOTOXIN; EXPERIENTIA 37 (2): 174-5 (1981) R88: Roemer KG et al; Drug Chem Toxicol 8 (4): 255-64 (1985) R89: Foster PM et al; Environ Health Perspect 57: 207-17 (1984) R90: (1)Merck Index; An Encyclopedia of Chemicals, Drugs, and Biologicals 10th Ed. pp.5905 (1983) R91: (1) Mills EJ JR, Stack VT JR; pp.492-517 in Proc Indust Waste Conf 8th Eng Bull Purdue Univ Eng Ext Ser (1954) (2) Price KS et al; J Water Pollut Contr Fed 46: 63-77 (1974) (3) Bridie AL et al; Water Res 13: 627-30 (1979) (4) Fincher EK, Payne WJ; Appl Microbiol 10: 542-7 (1962) (5) Verschueren K; Handbook of Environmental Data on Organic Chemicals 2nd ed Van Nostrand New York (1983) R92: (1) Lyman WJ et al; Handbook of Property Estimation Methods Environmental Behavior of Organic Compounds, New York, NY McGraw Hill pp.7-1 to 7-48 (1982) (2) GEMS. Graphical Environmental Modeling System. Fate of Atmospheric Pollutants (FAP) Data Base; USEPA Office of Toxic Substances (1985) R93: (1) Hansch C, Leo AJ; Medchem Project Pomona College Claremont, CA Issue No.26 (1985) R94: (1) Dow Chemical Company; The Glycol Ethers Handbook Midland, MI (1981) R95: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 484 R96: (1) NIOSH; RTECS (1984) R97: DHHS/NIOSH/Pub-83-112; Order No. PB84-155142 pp. 26 R98: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R99: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R100: Langhorst ML; AM IND HYG ASSOC J: 45 (6): p.416-424 (1984) RS: 100 Record 20 of 1119 in HSDB (through 2003/06) AN: 106 UD: 200302 RD: Reviewed by SRP on 2/28/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NITROMETHANE- SY: *METHANE,-NITRO-; *NITROCARBOL-; *NITROMETAN- (POLISH); +NMT- RN: 75-52-5 MF: *C-H3-N-O2 SHPN: UN 1261; Nitromethane IMO 3.3; Nitromethane STCC: 49 070 30; Nitromethane MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *VAPOR-PHASE NITRATION OF METHANE WITH NITRIC ACID [R1] *... BY INTERACTION OF SODIUM NITRITE AND SODIUM CHLOROACETATE. [R2] MFS: *ANGUS Chemical Co, Hq, 2211 Sanders Rd, Northbrook, IL 60062, (312) 498-6700; Production site: Sterlington, LA 71280 [R3] *W R Grace and Co, Hq, 1 Town Center Rd, Bocaraton, FL 33486-1010 (407) 362-2000; Organic Chemicals Division, 55 Hayden Ave, Lexington, MA 02173; Production site: Deer Park, TX 77536 [R3] USE: *ROCKET FUEL; SOLVENT FOR ZEIN; USED IN COATING INDUSTRY [R2] *RACING FUEL ADDITIVE; MILITARY PROPELLANT; SOLVENT FOR CELLULOSIC CMPD, POLYMERS AND WAXES; INT FOR NITRO AND AMINO ALCOHOLS [R1] CPAT: *ABOUT 4.54X10+8 GRAMS USED IN RACING FUELS (1975) [R1] PRIE: U.S. PRODUCTION: *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +COLORLESS LIQ [R4, p. 49-98]; *OILY LIQ [R2]; +Colorless, oily liquid. [R5] ODOR: *DISAGREEABLE ODOR [R2]; +Fruity odor [R4, p. 49-98]; +Disagreeable odor. [R5] BP: *101.2 DEG C AT 760 MM [R2] MP: *-29 DEG C [R2] MW: *61.04 [R2] CTP: *Critical temperature: 315 deg C, Critical pressure: 62.3 atm [R6] DEN: *1.1322 AT 25 DEG C/4 DEG C [R2] HTC: *2517 Cal/g [R6] HTV: *134 Cal/g [R6] OWPC: *low Kow= 0.17 [R7, 916] PH: *WATER SOLN ARE ACID TO LITMUS; PH OF 0.01 MOLAR AQ SOLN: 6.12 [R2] SOL: *9.5% BY VOL IN WATER AT 20 DEG C; SOL IN ALCOHOL, ETHER, DIMETHYL FORMAMIDE [R2]; *SOL IN ETHER AND ACETONE [R8]; +Water solubility: 1.11X10+5 mg/l [R9]; *11.1% in water @ 25 deg C [R10] SPEC: *INDEX OF REFRACTION: 1.38056 AT 22 DEG C/D [R2]; *SADTLER REF NUMBER: 61 (IR, PRISM); MAX ABSORPTION (ALCOHOL): 260 NM (LOG E= 1.59) [R11]; *IR: 25 (Sadtler Research Laboratories IR Grating Collection) [R12, p. V1 842]; *UV: 29 (Sadtler Research Laboratories Spectral Collection) [R12, p. V1 842]; *NMR: 9146 (Sadtler Research Laboratories Spectral Collection) [R12, p. V1 842]; *MASS: 41 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R12, p. V1 842]; *MASS: 10 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R12, p. V1 914] SURF: *37.0 dynes/cm @ 20 Deg C [R6] VAPD: *2.11 (Air= 1) [R13, 2029] VAP: *27.8 MM HG AT 20 DEG C [R14] VISC: *0.647 cP @ 20 deg C [R15] OCPP: */Bulk Density/ ( Wt/gal)=9.5 lb [R2] *Heat of solution: -5 cal/g; Ratio of specific heats of vapor (Gas): 1.172 [R6] *Solubility of water in nitromethane: 2.09% @ 25 deg C; coefficient of expansion 0.00115 cu m/deg C [R10] *Heat of formation (liq) @ 25 deg C= -113.1 kJ/mol [R16] +Henry's Law constant= 2.59X10-5 atm cu m/mol [R17] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R18] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R18] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R18] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R18] +Evacuation: Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R18] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R18] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R18] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R18] FPOT: *DANGEROUS, WHEN EXPOSED TO HEAT; OXIDIZERS OR FLAME [R13, 2030] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R4, p. 325-74] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R4, p. 325-74] +Reactivity: 4. 4= This degree includes those materials that, in themselves, are readily capable of detonation, explosive decomposition, or explosive reaction at normal temperatures and pressures. This includes materials that are sensitive to localized mechanical or thermal shock. If a material having this Reactivity Hazard Rating is involved in an advanced or massive fire, the area should be immediately evacuated. [R4, p. 325-74] FLMT: *LOWER FLAMMABLE LIMIT: 7.3%; UPPER FLAMMABLE LIMIT NOT DETERMINED [R19] FLPT: +95 deg F (35 deg C)(Closed Cup) [R4, p. 325-74] AUTO: +785 DEG F (418 DEG C) [R4, p. 325-74] FIRP: +FIGHT FIRES FROM PROTECTED LOCATION OR MAXIMUM POSSIBLE DISTANCE. USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE EXPOSED CONTAINERS COOL. [R4, p. 49-98] *If material /is/ on fire or involved in /a/ fire do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, or carbon dioxide. [R20] *If fire becomes uncontrollable or container is exposed to direct flame consider evacuation of one-third (1/3) mile radius. [R20] TOXC: +Combustion may produce oxides of nitrogen and other irritants and toxic gases. [R4, p. 49-98] OFHZ: +Vapors are heavier than air and may travel to a source of ignition and flash back. [R4, p. 49-98] EXPL: +Explosive decomposition begins at 599 deg F (315 deg C). May be detonated by nearby explosions. [R4, p. 49-98] +Nitromethane is made more sensitive to detonation by contamination with certain other materials such as amines and acids. [R4, p. 49-98] +/DURING REACTIONS OF/ ELECTRO-OXIDATION OF VARIOUS METHYL BENZENES /IN WHICH HEXAMETHYLBENZENE AND NITROMETHANE WERE USED/ VIOLENT EXPLOSIONS OCCURRED AT AUXILIARY ELECTRODE. [R4, p. 491-93] *Lower explosion limit 7.3% in air [R21] +Mixtures of nitromethane and aluminum chloride may explode when organic matter is present. [R4, p. 491-16] REAC: +Amines; strong acids, alkalis and oxidizers; hydrocarbons and other combustible materials; metallic oxides [Note: Slowly corrodes steel and copper when wet]. [R22] +Nitromethane, ether alone or in a mixture with methanol and caster oil (model airplane fuel) has a delayed but violent reaction with powdered calcium hypochlorite, especially when confined, as in a plastic bag. [R4, p. 419-42] ODRT: *ODOR AND SENSORY SYMPTOMS ARE NOT DEPENDABLE WARNING PROPERTIES. [R23, 4155] SERI: *Irritation of eyes, trachea, skin. [R24, 373] *MILDLY IRRITATING TO SKIN AND MUCOUS MEMBRANE. [R25] *Nitroparaffins, nitroderivatives of saturated aliphatic hydrocarbons, including nitromethane ... yield vapors which are irritating to the eyes. [R26] EQUP: *AIR MASK (DO NOT USE ORGANIC CANISTER); GOGGLES. [R27] +WEAR FULL PROTECTIVE CLOTHING AND POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. [R4, p. 49-98] *Wear neoprene gloves, plastic working clothes, self-contained breathing apparatus. [R24, 373] +Wear appropriate personal protective clothing to prevent skin contact. [R22] +Wear appropriate eye protection to prevent eye contact. [R22] +Recommendations for respirator selection. Max concn for use: 750 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R22] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R22] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any appropriate escape-type, self-contained breathing apparatus. [R22] OPRM: +Contact lenses should not be worn when working with this chemical. [R22] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material /is/ not on fire and not involved in /a/ fire keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R20] *Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R20] *If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R20] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R22] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R22] SSL: +Thermally unstable. [R4, p. 49-98] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R28] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R29] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R30] STRG: +Store in a cool, dry, well-ventilated location. Separate from amines, acids, bases, oxidizing materials, and metal oxides. Outside or detached storage is preferred. [R4, p. 49-98] CLUP: *1) REMOVE ALL IGNITION SOURCES. 2) VENTILATE AREA OF SPILL OR LEAK. 3) FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS AND BURN IN COMBUSTION CHAMBER WHICH ALLOWS BURNING IN UNCONFINED CONDITION AND IS EQUIPPED WITH EFFLUENT GAS CLEANING DEVICE. 4) LARGE QUANTITES CAN BE COLLECTED, DILUTED IN FUEL OIL AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. LIQ ... SHOULD NOT BE ALLOWED TO ENTER CONFINED SPACE, SUCH AS SEWER ... . [R31] *After covering the spills with soda ash, mix and spray with water. Scoop into a bucket of water and leave it stand for two hours. Neutralize with 6M-hydrogen chloride and pass into the drain with sufficient water. [R24, 374] +ELIMINATE ALL IGNITION SOURCES. STOP OR CONTROL THE LEAK, IF THIS CAN BE DONE WITHOUT UNDUE RISK. USE WATER SPRAY TO COOL AND DISPERSE VAPORS AND PROTECT PERSONNEL. [R4, p. 49-98] DISP: *Incineration. Large quantities of material may require nitrogen oxide removal by catalytic or scrubbing processes. [R32] *LIQ ... MAY BE DISPOSED ... BY DILUTING WITH FUEL OIL AND ATOMIZING IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH EFFLUENT CLEANING DEVICE. [R31] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A3; Confirmed animal carcinogen with unknown relevance to humans. [R33, 2002.45] ANTR: *Flush eyes copiously. Wash contaminated areas of body with soap and water. [R24, 374] HTOX: *NITROMETHANE CAN CAUSE ... CNS DEPRESSION. [R34] *MILDLY IRRITATING TO SKIN AND MUCOUS MEMBRANE. [R25] *Man: Severe toxic effects: 800 ppm= 2,028 mg/cu m/60 min; Symptoms of illness: 500 ppm= 1,268 mg/cu m [R7, 917] +May be harmful if inhaled. Irritating to skin, eye, and respiratory system. Causes dermatitis. [R4, p. 49-98] *Symptoms: Irritation of eyes, trachea, skin. [R24, 373] *Toxic by ingestion and inhalation. [R21] *A patient who ingested a methanol/nitromethane mixture (model airplane fuel) showed an apparent plasma creatinine concentration of 8.0 mmol/l by the Jaff'e reaction when the actual creatinine concentration, as measured by a specific enzymatic method, was 0.09 mmol/l. This effect was due to nitromethane in the plasma. Interference by nitromethane with the determination of creatinine by reaction with alkaline picrate (the Jaff'e reaction) has not previously been reported. When nitromethane was added to plasma, the apparent creatinine measured was linearly related to the amount of nitromethane added. Comparison of spectral changes occurring during creatinine/picrate and nitromethane/picrate reactions show substantial similarity, suggeting a similar structure for the products. Although the findings are of interest for both their toxicological and analytical implications, the main interest lies with their suggestion of a model system for future investigation of the Jaff'e reaction. [R35] NTOX: *CENTRAL NERVOUS DISTURBANCE ... PREDOMINANT EFFECT OF ACUTE /ORAL/ POISONING /IN RABBITS, 0.75-1 G/KG, DOGS, 20% EMULSION IN 0.3% METHYL CELLOSOLVE AND MICE, 5% AQ SOLN/ INCL CONVULSIONS, TWITCHING AND CEREBELLAR FITS ... /WEAKNESS/, ATAXIA AND ATHETOID MOVEMENTS. [R36] *ANIMALS EXPOSED TO 30,000 PPM IN AIR FOR LONGER THAN 1 HR DEVELOPED ... NERVOUS SYSTEM SYMPTOMS. ... DURING EXPOSURE TO LOWER CONCN /10000 PPM/ ... SLIGHT IRRITATION OF RESP TRACT ... FOLLOWED BY MILD ... /SRP: CNS DEPRESSION/ AND SALIVATION /IN RABBITS, GUINEA PIGS AND MONKEYS/. [R23, 4153] *... CONCN OF 100 PPM FOR 48 HR WAS LETHAL TO 1 EXPOSED MONKEY, BUT CONCN OF 5000 PPM FOR 3 HR WAS REQUIRED TO KILL GUINEA PIGS; LETHAL EXPOSURE ... FOR RABBITS ... 2500 PPM FOR 12 HR OR 5000 PPM FOR 6 HR. [R37] *THREE OF 10 RATS GIVEN 0.25% NITROMETHANE IN ... DRINKING WATER FOR 15 WK AND 4 OF 10 RATS GIVEN 0.1% DIED DURING COURSE OF EXPERIMENT. SURVIVING ANIMALS FAILED TO GAIN WT NORMALLY. ... EXAM SHOWED ... LIVER ABNORMALITIES. [R23, 4154] *HISTOPATHOLOGICAL CHANGES ... FOLLOWING ACUTE POISONING BY ALL ROUTES WERE CHIEFLY CONFINED TO LIVER AND KIDNEYS WITH LIVER SHOWING MOST PROMINENT INJURY. SUBCAPSULAR DAMAGE, FOCAL NECROSIS, ... FATTY INFILTRATION, CONGESTION, AND EDEMA ... OBSERVED /IN MONKEYS, GUINEA PIGS AND RABBITS/. [R23, 4154] *SKIN APPLICATION ... DOES NOT PRODUCE IRRITATION OR DEATH IN ANIMALS. [R23, 4154] *POSSIBILITY OF PRODUCING HISTIDINEMIA BY SC INJECTIONS WITH 0.4 ML (PER 100 G BODY WT) OF 1.2 MOLAR SOLN OF NITROMETHANE EVERY OTHER DAY WAS INVESTIGATED /IN RATS/. LIVER HISTIDASE ACTIVITY DECR ABOUT 80% WHEN INJECTED SC FOR 18 DAYS. HISTIDINE CONCN IN LIVER AND PLASMA WERE INCR TO PLATEAU OF 3-FOLD AND 4-FOLD OF CONTROLS AFTER 6 DAYS. [R38] *NO METHEMOGLOBIN WAS FORMED IN RATS GIVEN SINGLE OR REPEATED IP INJECTIONS AT 0.11 TO 1.5 G/KG, BUT TRACE AMT WAS FOUND IN ANIMALS EXPOSED TO ATMOSPHERE CONTAINING 13,000 PPM. NITROMETHANE IS APPROX AS TOXIC AS NITROETHANE. [R39] *The sulfhemoglobinemia and methemoglobinemia formation activities of similar drugs were studied in mice after admin of one or three ip doses. After admin of a single dose, nitromethane did not produce methemoglobinemia. Nitromethane produced sulfhemoglobinemia only after admin of three consecutive doses. /Dose and frequency of admin not given/ [R40] *FIFTY MALE RATS AND 15 MALE RABBITS WERE EXPOSED TO 98 OR 745 PPM, 5 DAYS/WK FOR APPROX 24 WK. 50 RATS AND 15 RABBITS EXPOSED TO FILTERED AIR FOR SIMILAR LENGTHS OF TIME SERVED AS CONTROLS. RATS WERE SACRIFICED AT 2 and 10 DAYS, 1, 3 and 6 MO FOLLOWING EXPOSURE; RABBITS AT 1, 3 and 6 MO. EFFECTS OBSERVED WERE DECR BODY WT GAIN IN RATS FOLLOWING 8 WK OF EXPOSURE TO 745 PPM, AND THYROID EFFECT EVIDENCED BY INCR THYROID WT AND DECR SERUM THYROXINE LEVELS, MOST NOTABLE IN RABBITS. [R41] *DURING 6 MONTHS OF EXPOSURE AT 98 OR 745 PPM OF NITROMETHANE, ONLY MILD TO MODERATE SYMPTOMS OF TOXICITY WERE OBSERVED IN RATS AND RABBITS. A REDUCTION IN BODY WEIGHT GAIN WAS OBSERVED IN RATS EXPOSED AT 745 PPM OF NITROMETHANE. HEMATOCRIT AND HEMOGLOBIN LEVELS IN RATS WERE SLIGHTLY DEPRESSED FROM 10 DAYS THROUGH 6 MONTHS OF EXPOSURE TO 745 PPM NITROMETHANE. RABBITS ALSO PROVIDED SUGGESTION OF DEPRESSION IN HEMOGLOBIN LEVELS. ... ORNITHINE CARBAMYL TRANSFERASE IN RABBITS WAS ELEVATED AFTER 1 AND 3 MONTHS, BUT NOT 6 MONTHS OF EXPOSURE AT 745 PPM OF NITROMETHANE. NO APPARENT EFFECTS ON GLUTAMIC-PYRUVIC TRANSAMINASE IN BOTH SPECIES OR SERUM T4 ACTIVITY IN RATS WERE OBSERVED. SERUM T4, HOWEVER, WAS STATISTICALLY SIGNIFICANTLY DEPRESSED IN RABBITS EXPOSED AT EITHER 98 OR 745 PPM NITROMETHANE AT 6 MONTH TESTING ... AS WELL AS AT 1 MONTH SACRAFICE FOR RABBITS EXPOSED AT 745 PPM. HISTOPATHOLOGIC EVALUATION INDICATED NO EXPOSURE-RELATED ABNORMALITIES IN RATS DUE TO EXPOSURE TO 98 OR 745 PPM FOR UP TO 6 MO. SOME EVIDENCE OF PULMONARY EDEMA AND OTHER PULMONARY ABNORMALITIES WAS OBSERVED IN RABBITS EXPOSED TO BOTH LEVELS OF NITROMETHANE FOR 1 MO. MOST IMPORTANT OBSERVATIONS ARE THAT INHALATION OF NITROMETHANE PRODUCES MILD IRRITATION AND TOXICITY BEFORE ... /CNS DEPRESSION/ OCCURS AND THAT LIVER DAMAGE CAN RESULT FROM REPEATED ADMIN AT LEVELS IN EXCESS OF 1000 PPM. [R23, 4155] *MALE 3 MO OLD WISTAR RATS DOSED IP WITH 200 MG/KG SHOWED INCR ACID PROTEINASE ACTIVITY IN BRAIN 4 HR AFTER INJECTION. CHANGE ACCOMPANIED BY MARGINAL INCR IN CEREBRAL GLUTATHIONE CONCN. HEPATIC EFFECTS RESTRICTED TO DECR CYTOCHROME C REDUCTASE ACTIVITY WITH PROLIFERATION OF SMOOTH ENDOPLASMIC RETICULUM. [R42] *SHEEP GIVEN ORALLY OR INTRARUMINALLY NITROMETHANE SHOWED ALTERED RUMINAL GASES. ACTIVITY WAS NOT INFLUENCED BY ROUTE. [R43] *TESTED FOR PHYTOTOXICITY IN WHEAT, ALFALFA, SOYBEAN, TOBACCO, CORN, WHITE OAK AND SCOTCH PINE. MAX DOSE WAS 25 MG/CU M. MINIMUM OR NO INJURY OBSERVED ON ANY OF PLANTS. [R44] *Nitromethane was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay. This reference reports on the testing of 270 chemicals, including nitromethane, using the standard protocol approved by the National Toxicology Program (NTP). The tests were performed by one or more of 3 different laboratories under contract to NTP. This test procedure includes testing of the chemical using a wide range of doses in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9. Nitromethane was tested at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. [R45] *Nineteen nitro compounds, including nitromethane, were evaluated for mutagenicity, using a modification of the standard Salmonella typhimurium mutagenicity assay. A preincubation protocol was used which incorporated flavin mononucleotide to facilitate nitro reduction. Nitromethane was negative in the modified preincubation assay with flavin mononucleotide despite extensive nitro reduction that occurred in the preincubation with flavin mononucleotide. [R46] *Nitroparaffins, nitroderivatives of saturated aliphatic hydrocarbons, including nitromethane ... yield vapors which are irritating to the eyes. [R26] *The tumorigenicity of automobile exhaust condensate was investigated in Syrian golden hamsters. Hamsters were given intratracheal instillations of automobile exhaust condensate containing nitromethane. The test substances were instilled in the animals at 2 week intervals until natural death. Histological examinations were performed on lungs and tracheas of all hamsters. In general, the treatment had little or no effect on body weight or survival time of the hamsters. Hyperplasia and metaplasia were seen in tracheal, bronchial, and alveolar epithelium, along with deposits of instilled condensate. The author concludes that intratracheal instillation of condensed products in hamsters is not a sensitive test. [R47] *The hepatotoxic and mutagenic potentials of 2-nitropropane, nitromethane, and nitroethane were compared. Hepatotoxicity was assessed biochemically and histopathologically in BALB/c mice. In male mice, plasma activities of the hepatic enzymes sorbitol dehydrogenase, alanine aminotransferase, and aspartate aminotransferase were significantly elevated 48, 72, and 96 hr after ip admin of 9 mmol/kg 2-nitropropane, but not at 24 hr and not after admin of smaller doses of 2-nitropropane nor after nitromethane or nitroethane (9 mol/kg). In female mice a dose of 6.7 mmol/kg of 2-nitropropane was sufficient to cause hepatotoxicity. The histopathological evaluation supported the biochemial results, and livers of mice that had received 2-nitropropane (9 mmol/kg) showed damage, particularly in the periportal region. Mutagenicity was tested in Salmonella typhimurium tester strains TA98, TA100, and TA102. Both 2-nitropropane and its anionic form, propane-2-nitronate, were mutagenic but the nitronate was the more powerful mutagen. Nitromethane, nitroethane, nor their nitronates caused an increase in the number of revertant colonies over those seen in control plates. The results suggest that the primary nitroalkanes are much less hepatotoxic and mutagenic than 2-nitropropane. [R48] +... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of nitromethane in male F344/N rats exposed to 94, 188, or 375 ppm. There was clear evidence of carcinogenic activity of nitromethane in female F344/N rats based on increased incidences of mammary gland fibroadenomas and carcinomas. There was clear evidence of carcinogenic activity of nitromethane in male B6C3F1, mice based on increased incidences of harderian gland adenomas and carcinomas. There was clear evidence of carcin ogenic activity in female B6C3F1, mice, based on increased incidences of liver neoplasms (primarily adenomas) and harderian gland adenomas and carcinomas. Increased incidences of alveolar/bronchiolar adenomas and carcinomas in male and female mice exposed to nitromethane were also considered to be related to chemical administration. [R49] NTXV: *LD50 Rat oral 940 mg/kg; [R24, 373] *LD50 Mouse oral 1440 mg/kg; [R24, 373] *LDLo Dog oral 125 mg/kg; [R24, 373] *LDLo Dog iv 750 mg/kg; [R24, 373] *LDLo Rabbit oral 750 mg/kg; [R24, 373] NTP: +... Male and female F344/N rats and B6C3F1, mice received nitromethane (purity 98% or greater) by inhalation for ... 2 yr. ... 2 YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 94, 188, or 375 ppm nitromethane by inhalation, 6 hr/day, 5 days/wk, for 103 wk. 2 YEAR STUDY lN MlCE: Groups of 50 male and 50 female mice were exposed to 0, 188, 375, or 750 ppm nitromethane by inhalation, 6 hr/day, 5 days/wk, for 103 wk. CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of nitromethane in male F344/N rats exposed to 94, 188, or 375 ppm. There was clear evidence of carcinogenic activity of nitromethane in female F344/N rats based on increased incidences of mammary gland fibroadenomas and carcinomas. There was clear evidence of carcinogenic activity of nitromethane in male B6C3F1, mice based on increased incidences of harderian gland adenomas and carcinomas. There was clear evidence of carcin ogenic activity in female B6C3F1, mice, based on increased incidences of liver neoplasms (primarily adenomas) and harderian gland adenomas and carcinomas. Increased incidences of alveolar/bronchiolar adenomas and carcinomas in male and female mice exposed to nitromethane were also considered to be related to chemical administration. [R49] ADE: *NITROPARAFFINS ARE ABSORBED THROUGH LUNG AND FROM GI TRACT. APPLICATIONS TO SKIN GIVE NO EVIDENCE OF SUFFICIENT ABSORPTION TO RESULT IN SYSTEMIC INJURY. /NITROPARAFFINS/ [R23, 4151] METB: *NITROMETHANE IS APPARENTLY METABOLIZED BY DIFFERENT MECHANISM THAN NITROETHANE AND NITROPROPANE IN THAT NEGLIGIBLE AMT OF NITRITES ARE FOUND IN BLOOD FOLLOWING IV INJECTION OF 1 MMOL IN RABBITS. [R23, 4154] *RABBIT LIVER HOMOGENATE YIELDS NITRITE AFTER INCUBATION WITH NITROMETHANE. [R50] *LIVER MICROSOMES FROM PHENOBARBITAL PRETREATED RATS CONVERT NITROMETHANE TO ACETONE AND NITRATE IN PRESENCE OF THE REDUCED FORM OF NICOTINAMIDE-ADENINE DINUCLEOTIDE PHOSPHATE AND OXYGEN. ADDITION OF NITROMETHANE TO OXIDIZED RAT LIVER MICROSOMAL SUSPENSION GAVE RISE TO SUBSTRATE BINDING DIFFERENCE SPECTRUM WITH PEAK AT 437 NM, INTERPRETED AS FORMATION OF CYTOCHROME P450 NO COMPLEX. PARALLEL TO COMPLEX FORMATION, OXIDIZED RAT LIVER MICROSOMES CATALYZED PRODN OF FORMALDEHYDE FROM NITROMETHANE IN THE REDUCED FORM OF NICOTINAMIDE-ADENINE DINUCLEOTIDE PHOSPHATE-DEPENDENT REACTION. [R51] INTC: *A patient who ingested a methanol/nitromethane mixture (model airplane fuel) showed an apparent plasma creatinine concentration of 8.0 mmol/l by the Jaff'e reaction when the actual creatinine concentration, as measured by a specific enzymatic method, was 0.09 mmol/l. This effect was due to nitromethane in the plasma. Interference by nitromethane with the determination of creatinine by reaction with alkaline picrate (the Jaff'e reaction) has not previously been reported. When nitromethane was added to plasma, the apparent creatinine measured was linearly related to the amount of nitromethane added. Comparison of spectral changes occurring during creatinine/picrate and nitromethane/picrate reactions show substantial similarity, suggeting a similar structure for the products. Although the findings are of interest for both their toxicological and analytical implications, the main interest lies with their suggestion of a model system for future investigation of the Jaff'e reaction. [R35] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Nitromethane may enter the environment in connection with its manufacture and use as a solvent, rocket fuel, and gasoline additive, as well as in vehicle exhaust and cigarette smoke. In addition it is a byproduct in the manufacture of the explosives RDX and HMX. If released on land or in water, nitromethane would be lost primarily by volatilization. Its volatilization half-life from a model river is 28.7 hr. Since it is not adsorbed appreciably by soil, it may leach in soil. The degradation rate in soil is low. Nitromethane does not bioconcentrate in fish. Humans are exposed to nitromethane in occupational settings via inhalation and dermal contact. The general population is exposed via inhalation primarily from auto exhaust and cigarette smoke. (SRC) ARTS: *Nitromethane may be released to the atmosphere or in water in conjunction with its use as a solvent for cellulosic compounds, polymers, waxes, and fats, rocket fuel, and gasoline additive(2). It is also released to the atmosphere in auto exhaust, cigarette smoke, and from turbine engines(3). Nitromethane is a byproduct in the manufacture of the munitions RDX and HMX and may therefore be released during their manufacture in wastewater and as air emissions(1). In 1984 in the U.S., these explosives were only manufactured in the Holston Army Ammunition Plant in Tennessee(1). [R52] FATE: *TERRESTRIAL FATE: If released on land nitromethane would be expected to volatilize rapidly due to its high vapor pressure, 35.8 mm Hg(1), high calculated Henry's Law constant, 2.59X10-5 atm cu m/mol(1-2,SRC), and low adsorptivity to soil(2-4). It also may leach into the soil where degradation should be low.(SRC) [R53] *AQUATIC FATE: If released in water, nitromethane will be lost by volatilization (half-lives 28.7 hr and 13 days in a model river and model pond, respectively(1-4)). Biodegradation in water may be important but only screening test data are available. It should not adsorb to sediment and particulate matter in the water column or bioconcentrate in fish. It may photodegrade in surface water, but no estimate of aqueous photodegradation rates is available(SRC). [R54] *ATMOSPHERIC FATE: In the atmosphere, nitromethane will degrade due to photolysis (half-life approximately 4-9 hr(1-2)). Reaction with photochemically produced hydroxyl radicals is very slow (half-life 100 days(3-4)). [R55] BIOD: *When incubated with activated sludges from 3 municipal treatment plants, nitromethane (500 mg/l) was oxidized to an insignificant amount by one of the three sludges and then only after a long acclimation period(1). At the concentration used, nitromethane appeared to be toxic to some sludges(1). When nitromethane was incubated with activated sludge, 36.2% mineralization occurred in 5 days(2). Degradation was low in a closed bottle biodegradability test, using a municipal sewage plant effluent innoculum, with 10% degradation occurring in 28 days(2). Aerobic and anaerobic degradation in soil is low; C14 studies performed with soil microorganisms resulted in 5.1% and 2.3% conversion to CO2, respectively in 35 days(2). During this time 23.7 and 59.3%, respectively, was lost as volatile products during the aerobic and anaerobic studies. [R56] ABIO: *Nitromethane absorbs UV radiation > 290 nm and undergoes primary dissociation to form free radicals(2). The half-life for photodissociation is 4.3 hr(1). Another study found the photodecomposition half-life for nitromethane in the presence of 5 ppm of NO to be 9.2 hr(4). Nitromethane was readily degradable in a solid surface photomineralization test with 4.4% mineralization to CO2 in 17 hr(3). Nitromethane reacts with photochemically-produced hydroxyl radicals with a rate constant at 22 deg C and 1 atmosphere pressure of 1.6X10-13 cu cm/molec-sec(5-6). The rate constant increases with increasing temperature and pressure which is consistent with the reaction proceeding by an addition mechanism(6). Assuming a hydroxyl radical concentration of 5X10+5 radicals/cu cm, the half-life of nitromethane in the atmosphere would be 100 days(SRC). [R57] BIOC: *In a 3-day experiment performed with C-14 labelled nitromethane, the bioconcentration factor in fish was 1.4(1). Therefore, the accumulation of nitromethane in aquatic organisms is negligible(SRC). Bioconcentration factors for nitromethane estimated from its water solubility, 1.11X10+5 mg/l(2), and log octanol/water partition coefficient, -0.35(3), range from 0.1 to 1.5 using six recommended regression equations(4). The bioconcentration factor in algae (Chorella fusca), as determined in a 24-hr experiment, was 960, indicating a slightly elevated bioaccumulation in algae(1,SRC). [R58] KOC: *Koc values for nitromethane estimated from its water solubility, 1.11X10+5 mg/l(2), and log octanol/water partition coefficient, -0.35(3), range from 0.28 to 15 using six recommended regression equations(4). Therefore nitromethane should exhibit high mobility in soil(1). [R59] VWS: *The Henry's Law constant for nitromethane, calclulated from its vapor pressure, 35.8 mm Hg(1), and water solubility, 1.11X10+5 mg/l(2), is 2.59X10-5 atm cu m/mol. Using this value of the Henry's Law constant, one estimates that the half-life for volatilization from a model river 1 m deep, flowing 1 m/sec and with a wind speed of 3 m/sec is 28.7 hr(3,SRC). The volatilization half-life in a model pond is 13 days(4). [R54] WATC: *DRINKING WATER: In an EPA survey designed to discover the source of pollutants in drinking water in five cities, nitromethane was identified, but not quantified, in the raw water source of drinking water in Philadelphia, PA and Cincinnati, OH(1). These supplies were contaminated with municipal waste and industrial discharges, respectively. [R60] EFFL: *The concentration of nitromethane in auto exhaust using nine hydrocarbon test fuels under simulated city driving conditions ranged from < 0.8 to 5.0 ppm(1). [R61] ATMC: *SOURCE DOMINATED: Maximum ground level concentrations of nitromethane at three sites on the boundary of an ammunition plant in Tennessee 0.21, 2, 2 ug/cu m(1). [R62] MILK: *Human milk from four urban areas: detected, but not quantified in 1 of 12 samples tested(1). [R63] RTEX: *The general population will be exposed to nitromethane by inhalation from motor vehicle exhaust and cigarette smoke. Workers may be exposed via inhalation and dermal contact associated with its use as a solvent or a component of rocket fuels. (SRC) *NIOSH (NOES Survey 1981-83) has statistically estimated that 70,467 workers may be exposed to nitromethane in the USA(1). [R64] BODY: *Human milk from four urban areas: detected, but not quantified in 1 of 12 samples tested(1). [R63] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +750 ppm [R22] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (250 mg/cu m). [R65] NREC: +NIOSH questioned whether the PEL proposed by OSHA for nitromethane was adequate to protect workers from recognized health hazards. [R22] TLV: +8 hr Time Weighted Avg (TWA): 20 ppm. [R33, 2002.45] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R33, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R33, 2002.45] OOPL: *USSR (1966): 9 ppm; West Germany (1974): 100 ppm; Romania (1975): 30 ppm. [R37] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Nitromethane is produced, as an intermediate or a final product, by process units covered under this subpart. [R66] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Nitromethane is included on this list. [R67] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R68] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2527. Analyte: Nitromethane. Matrix: Air. Sampler: Solid sorbent tube (chromosorb 106, 600 mg/300 mg). Flow Rate: 0.01 to 0.05 liters/min. Sample Size: 2 liters. Shipment: Separate front and back sorbent sections. Sample Stability: Stable 7 days @ 25 deg C. [R69] ALAB: *... SPECTROPHOTOMETRIC DETERMINATION OF PRIMARY NITROPARAFFINS /IN AIR/ UTILIZES COUPLING REACTION WITH P-DIAZOBENZENESULFONIC ACID ... NITROMETHANE CAN BE DETERMINED AT 440 MU ... . [R23, 4145] *MASS SPECTRA HAVE BEEN DETERMINED ON EIGHT C1-C4 MONONITROPARAFFINS /IN AIR/. NITROMETHANE ... ONLY MEMBER TO HAVE MAJOR PEAK AT ITS MASS WT, 61. [R23, 4147] *INFRARED ABSORPTION SPECTROSCOPY ... USED TO MONITOR ANIMAL INHALATION CHAMBER CONCN ... . [R23, 4147] *DETERMINATION OF ORGANIC POLLUTANTS FROM AMBIENT AIR USING GAS CHROMATOGRAPHY/MASS SPECTROMETRY/COMPUTER TECHNIQUES. [R70] *NIOSH Method 2527. Analyte: Nitromethane. Matrix: Air. Procedure: Gas chromatography, nitrogen-specific detector. For nitromethane this method has no estimated detection limit. The overall precision/RSD is 0.042 @ 0.34 to 1.34 mg/sample and the recovery is not given. Applicability: The working range is 60 to 360 ppm (150 to 900 mg/cu m) for a 2-liter air sample. Interferences: None. [R69] CLAB: *USE OF PURGE AND TRAP TECHNIQUE WITH CAPILLARY GAS CHROMATOGRAPHY/MASS SPECTROMETRY/COMPUTER ANALYSIS FOR VOLATILE ORGANICS INCL NITROMETHANE IN LACTATING WOMEN AND COW MILK WAS SUCCESSFUL. [R71] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: MATTHEWS RD; ESTIMATED PERMISSIBLE LEVELS, AMBIENT CONCENTRATIONS, AND ADVERSE EFFECTS OF THE NITROGENOUS PRODUCTS OF COMBUSTION: THE CYANIDES, NITROOLEFINS, AND NITROPARAFFINS; J COMBUST TOXICOL 7 (AUG): 157 (1980). REVIEW WITH 51 REFERENCES INCLUDES EST OF MAX PERMISSIBLE LEVELS. Toxicology and Carcinogenesis Studies of Nitromethane in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 461 (1997) NIH Publication No. 97-3377 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that a pathology working group is reviewing data from a two year study on nitromethane. Route: aqueous exposure; Species: fish project 1, fish. [R72] SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1046 R3: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 810 R4: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R5: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 230 R6: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R7: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R8: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-320 R9: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. R10: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V21 387 (1983) R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-374 R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R13: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R14: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 647 R15: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V21 390 (1983) R16: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V15 971 (1981) R17: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R18: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-129 R19: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982.,p. 49-129 R20: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.499 R21: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 830 R22: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 230 R23: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R24: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. R25: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-213 R26: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 669 R27: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R28: 49 CFR 171.2 (7/1/96) R29: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 187 R30: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3149 (1988) R31: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R32: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-8 (1981) EPA 68-03-3025 R33: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R34: Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987. 144 R35: De Leacy EA et al; Clin Chem 35 (8): 1772-4 (1989) R36: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 282 R37: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.439 R38: WANG ML, LEE SC; J CHIN BIOCHEM SOC 2 (1): 25 (1973) R39: DEQUIDT J ET AL; BULL SOC PHARM LILLE (1): 29 (1973) R40: Nomura A; Nippon Yakurigaku Zasshi; 71 (4): 351-365 (1975) R41: LEWIS TR ET AL; J ENVIRON PATHOL TOXICOL 2 (5): 233 (1979) R42: ZITTING A ET AL; TOXICOL LETT 13 (3-4): 189 (1982) R43: ZALUCKI G, ZAWADZII W; MED WETER 37 (2): 121 (1981) R44: THOMPSON CR ET AL; ENVIRON SCI TECHNOL 13 (10): 1263 (1979) R45: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R46: Dellarco VL, Prival MJ; Environ Mol Mutagen 13 (2): 116-27 (1989) R47: Kunstler K; Cancer Letters 18 (1): 105-8 (1983) R48: Dayal R et al; Fundam Appl Toxicol 13 (2): 341-8 (1989) R49: Toxicology and Carcinogenesis Studies of Nitromethane in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 461 (1997) NIH Publication No. 97-3377 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R50: SCOTT EW; J IND HYG TOXICOL 25: 20 (1943) R51: SAKURAI H ET AL; BIOCHEM PHARMACOL 29 (3): 341 (1980) R52: (1) Ryon MG et al; Database Assessment of the Health and Environmental Effects of Munition Production Waste Products Oak Ridge,TN: Oak Ridge Natl Lab ORNL-6018, NITS DE84-016512 (1984) (2) Hawley CG; The Condensed Chemical Dictionary 10th ed. NY: Van Nostrand Reinhold Co (1981) (3) Graedel TE et al; Atmospheric Chemical Compounds NY: Academic Press (1986) R53: (1) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (2) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 4 (1982) (4) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) R54: (1) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds. NY: Amer Inst for Phys Prop Data (1989) (2) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 15 (1982) (4) USEPA; EXAMS II (1987) R55: (1) Ryon MG et al; Database Assessment of the Health and Environmental Effects of Munition Production Waste Products Oak Ridge, TN: Oak Ridge Natl Lab ORNL-6018, NITS DE84-016512 (1984) (2) Dilling WL et al; Environ Sci Technol 10: 351-6 (1976) (3) Nielson OJ et al; Chem Phys Letters 156: 312-8 (1989) (4) Liu R et al; Chem Phys Letters 167: 519-23 (1990) R56: (1) Gerhold RM, Malaney GW; J Water Pollut Contr Fed 38: 562-79 (1966) (2) Freitag D et al; Ecotoxicological Profile Analysis of Nitroparaffins according to OECD Guidelines with C14-Labelled Compounds. In TSCA 8D Submissions to EPA for Nitromethane (Fiche No. OTS516767 (1988) R57: (1) Ryon MG et al; Database Assessment of the Health and Environmental Effects of Munition Production Waste Products Oak Ridge,TN: Oak Ridge Natl Lab ORNL-6018, NITS DE84-016512 (1984) (2) Calvert JG, Pitts JN Jr; Photochemistry NY, NY: Wiley pp. 454-5, 477-9 (1966) (3) Freitag D et al; Ecotoxicological Profile Analysis of Nitroparaffins according to OECD Guidelines with C14- Labelled Compounds. In TSCA 8D Submissions to EPA for Nitromethane (Fiche No. OTS516767 (1988) (4) Dilling WL et al; Environ Sci Technol 10: 351-6 (1976) (5) Nielson OJ et al; Chem Phys Letters 156: 312-8 (1989) (6) Liu R et al; Chem Phys Letters 167: 519-23 (1990) R58: (1) Freitag D et al; Ecotoxicological Profile Analysis of Nitroparaffins according to OECD Guidelines with C14-Labelled Compounds. In TSCA 8D Submissions to EPA for Nitromethane (Fiche No. OTS516767 (1988) (2) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) (3) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 5 (1982) R59: (1) Swann RL et al; Res Rev 85:17-28 (1983) (2) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) (3) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 4 (1982) R60: (1) USEPA; Preliminary Assessment of Suspected Carcinogens in Drinking Water Interim Report to Congress (1975) R61: (1) Seizinger DE, Dimitriades B; JAPCA 22: 47-51 (1972) R62: (1) Ryon MG et al; Database Assessment of the Health and Environmental Effects of Munition Production Waste Products Oak Ridge,TN: Oak Ridge Natl Lab ORNL-6018, NITS DE84-016512 (1984) R63: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R64: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) R65: 29 CFR 1910.1000 (7/1/98) R66: 40 CFR 60.489 (7/1/90) R67: 40 CFR 716.120 (7/1/90) R68: 40 CFR 712.30 (7/1/90) R69: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2527-1 R70: KROST KJ ET AL; ANAL CHEM 54 (4): 810 (1982) R71: PELLIZZARI ED ET AL; BULL ENVIRON CONTAM TOXICOL 28 (3): 322 (1982) R72: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 53 Record 21 of 1119 in HSDB (through 2003/06) AN: 123 UD: 200303 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,1,2,2-TETRACHLOROETHANE- SY: *A13-04597-; *Acetosal-; *Acetylene-tetrachloride-; *Bonoform-; *Cellon-; *1,1,2,2-CZTEROCHLOROETAN- (POLISH); *1,1-DICHLORO-2,2-DICHLOROETHANE-; *DICHLORO-2,2-DICHLOROETHANE-; +Pesticide-Code:-078601-; *EPA-Pesticide-Chemical-Code-078601-; *ETHANE,-1,1,2,2-TETRACHLORO-; *NCI-C03554-; *1,1,2,2-TETRACHLOORETHAAN- (DUTCH); *1,1,2,2-TETRACHLORAETHAN- (GERMAN); *1,1,2,2-TETRACHLORETHANE- (FRENCH); *TETRACHLOROETHANE-; *S-TETRACHLOROETHANE-; *SYM-TETRACHLOROETHANE-; *TETRACHLORURE-D'ACETYLENE- (FRENCH); *1,1,2,2-TETRACLOROETANO- (ITALIAN); *WESTRON- RN: 79-34-5 RELT: 4148 [1,1,1,2-TETRACHLOROETHANE] (ISOMER); 2034 [PENTACHLOROETHANE] (METABOLIC PRECURSOR) MF: *C2-H2-Cl4 SHPN: UN 1702; Tetrachloroethane IMO 6.1; Tetrachloroethane STCC: 49 403 54; Tetrachloroethane HAZN: U209; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *MFR BY CATALYTIC ADDITION OF CHLORINE TO ACETYLENE; BY CHLORINATION OF ETHYLENE; BY CATALYTIC CHLORINATION OF ETHANE; BY CHLORINATION OF 1,2-DICHLOROETHANE. [R1] *CHLORINATION OR OXYCHLORINATION OF ETHYLENE. [R2] *Produced by direct chlorination or oxychlorination utilizing ethylene as feedstock ... in most cases, 1,1,2,2-tetrachloroethane is not isolated, but immediately thermally cracked at 454 deg C to give the desired trichloroethylene and tetrachloroethylene products ... high purity 1,1,2,2- tetrachloroethane is made by chlorinating acetylene. [R3, p. V6 26] IMP: */SRP/: 1,1,1,2-Tetrachloroethane is an impurity found in technical grade 1,1,2,2-tetrachloroethane. FORM: *Grades or purity: Technical, 98% [R4] *98+%; Neat standard for EPA methods [R5] OMIN: *DUE TO ITS TOXICITY AND AVAILABILITY OF LESS TOXIC SOLVENTS AND TO NEW PROCESSES FOR MANUFACTURING CHLORINATED ETHYLENES, THE MANUFACTURE AND USE OF TETRACHLOROETHANE IS NOW VERY LIMITED. [R6, 1986.561] *1,1,2,2-Tetrachloroethane is also an incidental byproduct of other production processes for chlorinated hydrocarbons, such as the production of 1,1,1- and 1,1,2-trichloroethane [R7, p. VA6 279] *It is rarely used as a solvent because of its high toxicity. [R7, p. VA6 280] *The only significant use of 1,1,2,2-tetrachloroethane is as a feedstock in the manufacture of trichloroethylene, tetrachloroethylene and 1,2-dichloroethylene. [R3, p. V6 28] USE: +For 1,1,2,2-Tetrachloroethane (USEPA/OPP Pesticide Code: 078601) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R8] *NONFLAMMABLE SOLVENT FOR FATS, OILS, WAXES, RESINS, CELLULOSE ACETATE, COPAL, PHOSPHORUS, SULFUR, RUBBER; SOLVENT IN CERTAIN TYPES OF FRIEDEL-CRAFTS REACTIONS, PHTHALIC ANHYDRIDE CONDENSATIONS; IN MFR OF PAINTS, VARNISH, RUST REMOVERS; IN SOIL STERILIZATION AND WEED KILLER, INSECTICIDE FORMULATIONS; IN DETERMINATION OF THEOBROMINE IN CACAO; AS IMMERSION FLUID IN CRYSTALLOGRAPHY; IN THE BIOLOGICAL LABORATORY TO PRODUCE PATHOLOGICAL CHANGES IN GI TRACT, LIVER AND KIDNEYS. INTERMEDIATE IN MFR OF TRICHLOROETHYLENE AND OTHER CHLORINATED HYDROCARBONS HAVING TWO CARBON ATOMS. [R1] *FOR CLEANSING AND DEGREASING METALS; ... PAINT REMOVERS, ... LACQUERS, PHOTOGRAPHIC FILM; ... ALCOHOL DENATURANT ... . [R9] *CHEM INT FOR TRICHLOROETHYLENE AND TETRACHLOROETHYLENE; CHEM INT FOR 1,2- and 1,1-DICHLOROETHYLENE; SOLVENT EG, FOR POLYESTERS AND EXTRACTIONS; MOTH-PROOFING AGENT FOR TEXTILES. [R2] *Use in manufacture of cyanogen chloride, polymers, and tetrachloro-alkylphenol; use as a solvent in preparation of adhesives. [R10, 1981.3] *Bleach manufacturing [R11, 1075] *Used in cement, lacquers; in manufacture of artificial silk, and artificial pearls. Recently, it has also been used in the estimation of water content in tobacco and many drugs, and as a solvent for chromium chloride impregnation of furs. [R12] PRIE: U.S. PRODUCTION: *Production figures for 1,1,2,2-tetrachloroethane cannot be estimated [R7, p. VA6 280] U.S. IMPORTS: *(1985) 6.11X10+7 g [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS /PURE/ TO PALE-YELLOW LIQUID /TECHNICAL/ [R4]; +Colorless to pale-yellow liquid. [R14] ODOR: *SWEETISH, SUFFOCATING, CHLOROFORM-LIKE ODOR [R1]; +Pungent, chloroform-like odor. [R14] BP: *46.5 DEG C [R15] MP: *-43.8 deg C [R15] MW: *167.85 [R15] CORR: *CORROSIVE LIQUID [R9] *Liquid will attack some forms of plastics, rubber and coatings. [R10, 1981.2] CTP: *Critical temperature = 388 deg C; Critical pressure = 3.99 mPa [R3, p. V6 27] DEN: *1.5953 g/cu cm @ 20 deg C [R15] HTC: *-8.3464E+08 J/kmol [R16] HTV: *230.5 J/g @ 20 deg C [R3, p. V6 27] OWPC: +log Kow = 2.39 [R17] SOL: *1.0 G/350 ML WATER AT 25 DEG C [R1]; *Sol in alcohol, ether, acetone, and benzene. [R18]; *2,900 mg/l water at 20 deg C. [R11, 1075]; *MISCIBLE WITH METHANOL, ETHANOL, PETROLEUM ETHER, CARBON TETRACHLORIDE, CHLOROFORM, CARBON DISULFIDE, DIMETHYLFORMAMIDE, AND OILS. [R1]; *2962 mg/l in water at 25 deg C [R19] SPEC: *SADTLER REFERENCE NUMBER: 1465 (IR, PRISM); 247 (IR, GRATING) [R20]; *INDEX OF REFRACTION: 1.49410 AT 20 DEG C/D [R15]; *IR: 660 (Sadtler Research Laboratories IR Grating Collection) [R21]; *NMR: 10209 (Sadtler Research Laboratories Spectral Collection) [R21]; *MASS: 1073 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R21] SURF: *34.72 dynes/cm @ 20 deg C [R3, p. V6 27] VAPD: *5.79 (air= 1) [R22] VAP: *9 MM HG @ 30 DEG C [R23] EVAP: *0.65 (Butyl acetate= 1) [R10, 1981.2] VISC: *1.77 cP @ 20 deg C [R3, p. V6 27] OCPP: *Average evaporative half-life of 55.2 min for concn of 0.92 mg/l in water. [R24] *RATIO OF SPECIFIC HEATS OF VAPOR (GAS): 1.090 @ 25 DEG C; LATENT HEAT OF VAPORIZATION: 55.1 CAL/G [R4] *WEIGHT 13.25 LB/GAL @ 25 DEG C [R9] *Sat concn in air = 46 g/cu m at 20 deg C, 75 g/cu m at 30 deg C [R11, 1075] *0.79% IN SATURATED AIR @ 25 DEG C [R25, 3513] *Solubility of water in solvent @ 20 deg C= 0.03% by weight; Water- no cloud @ -10 deg C= 0.032% by weight; freezing point -43 deg C; Residues on evaporation 0.00062% by weight [R23] *Partition coefficients at 37 deg C for 1,1,2,2-tetrachloroethane into blood= 121; into oil= 13,200. [R26] *Vapor pressure= 6.1 mm Hg at 25 deg C [R27] *Vapor pressure = 4.62 mm Hg at 25 deg C (calculated from experimentally derived coefficients); Liquid molar volume = 0.105754 cu m/kmol; Heat of fusion at melting pt = 9.172E+06 J/kmol [R16] *Vapor pressure = 5.95 mm Hg at 25 deg C; Heat of vaporization = 10.94 kcal/mol at 25 deg C; surface tension = 36.04 dyne/cm at 20 deg C [R28] *HEAVY, MOBILE LIQUID [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R29] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R29] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R29] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R29] +Evacuation: Spill: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R29] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R29] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R29] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R29] FPOT: *NOT FLAMMABLE [R4] FLPT: *No flash point, nonflammable. [R30] FIRP: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam dry chemical or carbon dioxide. Apply water from as far a distance as possible Keep run-off water out of sewers and water sources. [R31, 1992.887] TOXC: *IRRITATING HYDROGEN CHLORIDE VAPOR MAY FORM IN FIRE. [R4] EXPL: +An explosion may occur when the solvent symmetrical tetrachloroethane is almost removed in the chlorinolysis of 2,4-dinitrophenyl disulfide. [R32, p. 491-77] REAC: *UNAFFECTED BY STRONG ACIDS @ ORDINARY AND MODERATE TEMP, BUT CONVERTED TO GLYOXAL SULFATE BY FUMING SULFURIC ACID; IN WEAK ALKALI TRICHLOROETHYLENE IS PRODUCED, AND IN STRONG ALKALI, EXPLOSIVE DICHLOROACETYLENE; METALS, IN PRESENCE OF STEAM, CONVERT IT TO 1,2-DICHLOROETHYLENE. [R33] *1,1,2,2-Tetrachloroethane is not an inert solvent, and on heating with solid potassium hydroxide or other base, hydrogen chloride is eliminated and chloro- or dichloroacetylene /are formed/ which ignite in air. [R34, 238] *Mixtures of potassium with tetra- and pentachloroethane will often explode spontaneously after a short delay during which a voluminous solid separates out. [R34, 1289] +Tetrachloroethane may explode with potassium or sodium. [R32, p. 491-176] +Mixtures of sodium-potassium alloy and bromoform, tetrachloroethane, or pentachloroethane can explode on standing at room temperature. They are especially sensitive to impact. [R32, p. 491-183] +Chemically-active metals, strong caustics, fuming sulfuric acid [Note: degrades slowly when exposed to air]. [R35, 300] DCMP: *WHEN EXPOSED TO AIR, IT DEGRADES SLOWLY TO TRICHLOROETHYLENE AND TRACES OF PHOSGENE. [R33] *In presence of moisture the compound gradually decomposed with evolution of hydrochloric acid. [R30] *When exposed to ultraviolet radiation, tetrachloroethane decomp to form ... 2,2-dichloroacetyl chloride ... . [R36, 2162] *... When in contact with flame, incandescent material, or red hot metal surfaces, it decomp to form hydrochloric acid, carbon dioxide and carbon monoxide. [R36, 2162] *When heated to decomp it emits toxic fumes of /hydrogen chloride/. [R37] ODRT: *ODOR THRESHOLD OF LESS THAN 3 PPM. [R6, 1986.561] *Detection Limit: 0.5 mg/l (water) [R38] *Low: 21.0 mg/cu m; High: 35.0 mg/cu m. [R39] SERI: *Irritating to eyes, nose, and throat. Contact with eyes causes irritation and lacrimation. ... [R4] EQUP: *CHEM SAFETY GOGGLES; PLASTIC FACE SHIELD; AIR- OR OXYGEN-SUPPLIED MASK; SAFETY HAT WITH BRIM; SOLVENT-PROOF APRON; SYNTHETIC RUBBER GLOVES. [R4] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (8-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with liquid 1,1,2,2-tetrachloroethane. ... Employees should be provided with and required to use splash-proof safety goggles where there is possibility of liquid 1,1,2,2-tetrachloroethane contact /with/ the eyes. Where there is any possibility that employees' eyes may be exposed to liquid 1,1,2,2-tetrachloroethane, an eye-wash fountain should be provided within the immediate work area for emergency use. [R10, 1981.2] *... Neoprene or PVC hand protection ... . Where it is necessary to enter tanks ... that have contained tetrachloroethane, workers should wear a safety harness and lifeline together with other protective equipment and should be under constant observation by a person in the open. [R36, 2163] +Wear appropriate personal protective clothing to prevent skin contact. [R35, 300] +Wear appropriate eye protection to prevent eye contact. [R35, 300] +Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R35, 300] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R35, 300] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R35, 300] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R35, 300] OPRM: *Clothing contaminated with liquid 1,1,2,2-tetrachloroethane should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of 1,1,2,2-tetrachloroethane from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the 1,1,2,2-tetrachloroethane, the person performing the operation should be informed of 1,1,2,2-tetrachloroethane's hazardous properties. ... Skin that becomes contaminated with liquid 1,1,2,2-chloroethane should be immediately washed or showered with soap or mild detergent and water to remove any 1,1,2,2-tetrachloroethane. Eating and smoking should not be permitted in areas where liquid 1,1,2,2-tetrachloroethane is handled, processed, or stored. Employees who handle liquid 1,1,2,2-tetrachloroethane should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. [R10, 1981.3] *Due to its high toxicity, tetrachloroethane is used less and less in industry. Wherever technically possible its use should be abandoned and a less toxic substance should be substituted. ... Where its use cannot be avoided it should, if possible, be contained in a closed circuit or any sources of atmospheric contamination should be controlled by effective local exhaust ventilation, backed up by general workshop ventilation. Workplaces should have impermeable floors and any spilled tetrachloroethane should be cleaned up immediately. Porous materials contaminated with the solvent should be kept in airtight metal containers while awaiting disposal. The solvent should not be heated above 120 deg C and it should not be allowed to come into contact with open flames or very hot surfaces. [R36, 2162] +Contact lenses should not be worn when working with this chemical. [R35, 300] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. [R35, 300] +Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R35, 300] *If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. [R31, 1992.887] *Personnel protection: Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. [R31, 1992.888] SSL: *STABLE IN ABSENCE OF AIR, MOISTURE AND LIGHT, EVEN @ HIGH TEMP [R33] *Heat /contributes to instability/ [R10, 1981.2] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R40] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R41] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R42] STRG: *Keep containers closed. Store in cool and dark place. [R43] *STORAGE TEMP: AMBIENT; VENTING: OPEN. [R4] *... Should be stored in closed, clearly labelled containers in ... ventilated area, sheltered from sunlight. [R36, 2163] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. COLLECT FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR MATERIAL. [R10, 1981.4] *Avoid contact with liquid and vapor. Keep people away. Issue warning-poison, air contaminant. Stop discharge if possible. Isolate and remove discharged material Notify local health and pollution control agencies. Notify operators of nearby water intakes. [R4] *Absorb the spills with paper towels or the like materials. Place in a hood to evaporate. Dispose by burning the towel. [R43] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U209, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R44] *Tetrachloroethane is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Incineration, preferably after mixing with another combustible fuel, care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R45] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R46] *1,1,2,2-Tetrachloroethane is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Incineration is done, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R45] *This compound should be susceptible to removal from waste water by air stripping. [R47] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. Recommendable methods: Incineration and evaporation. Not recommendable method: Discharge to sewer. Peer-review: Dilute with kerosene or fuel oil due to high chlorine content. Evaporate small amt only. (Peer review conclusions of an IRPTC expert consultation (May 1985)) [R48] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: 1,1,2,2-Tetrachloroethane is a volatile synthetic chemical that is used as intermediate in the synthesis of other chlorinated hydrocarbons. HUMAN EXPOSURE: Human exposure to this chemical is primarily via inhalation. Very few data are available on the effects of exposure to 1,1,2,2-tetrachloroethane. ANIMAL/PLANT STUDIES: The toxicological profile of this chemical has also not been well characterized; because of its declining use, available data are confined to early limited studies. The acute toxicity of 1,1,2,2-tetrachloroethane in experimental animals is slight to moderate. Based on the results of principally limited short term and subchronic studies, the liver appears to be the most sensitive target organ. Although most of the available studies are inadequate to allow a no or lowest observed effect level (NO(A)EL or LO(A)EL for hepatotoxicity to be determined with confidence, minimal effects on the liver (reversible increase in lipid content) and other endpoints (an increase in levels of adrenocorticotropic hormone and reversible alteration in hematological parameters) have been observed in rats exposed to 13.3 mg/cu m for up to nine months. Based on limited, primary range finding studies and early investigations, reproductive and developmental effects have been observed in experimental animals only at doses that caused reductions in body weight. Long term ingestion of this chemical resulted in increased incidences of liver tumors in both male and female B6C3F1 mice. However, similar exposure was not associated with a significant increase in tumors at any site in Osborne-Mendel rats, although both species were exposed only for up to 78 wk. Based on the results of available in vivo and in vitro assays, 1,1,2,2-tetrachloroethane has, at most, weak genotoxic potential. 1,1,2,2-Tetrachloroethane was a potent promoter, but not an initiator, of gamma-glutamyltranspeptidase positive foci in the liver of rats. The profile for tumor induction by 1,1,2,2-tetrachloroethane is similar to that of dichloroacetic acid, its primary metabolite. Information on the mechanism of tumor induction by this compound is incomplete; for several of its metabolites, it has been suggested that tumors are likely induced by mechanisms for which there is a threshold. Exposure to 1,1,2,2-tetrachloroethane has been demonstrated to inhibit the activities of environmental bacteria (lowest reported IC50 was 1.4 mg/l) and cause immobilization of Daphnia magna (48 hr EC50 values of 23 mg/l and above). In fresh water fish species, the lowest LC50 (96 hr) was 18.5 mg/l in flagfish (Jordanella floridae), where the lowest observed effect concentration (LOEC) for longer term exposure was 7.2 mg/l, which resulted in reduced larval survival in the same species. No data were identified on the effects of this substance on terrestrial organisms. [R49] CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1,1,2,2-tetrachloroethane. There is limited evidence in experimental animals for the carcinogenicity of 1,1,2,2-tetrachloroethane. Overall evaluation: 1,1,2,2-Tetrachloroethane is not classifiable as to its carcinogenicity to humans (Group 3). [R50] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Increased incidence of hepatocellular carcinomas in mice. HUMAN CARCINOGENICITY DATA: None. [R51] *A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R52, 66] ANTR: *Irrigate eyes with water. Wash contaminated areas of body with soap and water. Gastric lavage, if swallowed, followed by saline catharsis. Diet with high contents of fat, liver extract. [R43] MEDS: */Protect/ from exposure those individuals with diseases of central nervous system, liver and kidneys. Annual physical examinations of exposed personnel with complete blood counts and studies of liver and kidney functions. [R43] *... Preplacement medical exam /should/ incl at least: 1) Comprehensive medical and work histories with special emphasis directed to symptoms related to the liver, kidneys, and nervous system. Information about exposure to other chemicals should be recorded, as should episodes of nausea, vomiting, dizziness or headaches; 2) A physical exam; 3) Liver function tests, such as serum transaminase determinations, shall be performed, and screening tests of nervous system function should be considered by the responsible physician; 4) Judgment of the worker's ability to use positive or negative pressure respirators. [R36, 2163] HTOX: *THIS COMPOUND ALSO CAUSES SOME CENTRAL NERVOUS SYSTEM DEPRESSION, ... NERVOUSNESS AND INCOORDINATION ... IN VERY SEVERE ACUTE EXPOSURES, UNCONSCIOUSNESS AND DEATH FROM RESPIRATORY FAILURE MAY BE SEEN. [R25, 3514] *Chronic intoxication by tetrachloroethane can take two forms: Central nervous system effects, such as tremor, vertigo and headache. And gastrointestinal and hepatic symptoms incl nausea, vomiting, gastric pain, jaundice, and enlargement of the liver. In 9 cases observed in the artificial silk industry, nearly all complained of general discontent, ... insomnia, loss of appetite, constipation, and fatigue. ... In 7 cases, 1 fatal, observed in a war industry ... anorexia ... was noted ... . In an artificial leather plant, 2 workers died from liver disease and other workers complained of ... impaired mental processes; Leucopenia and other blood changes were also noted. ... A death from toxic jaundice, after 2 months on a process involving ... tetrachloroethane has ... been reported ... . /Tetrachloroethane/ [R36, 2162] */1,1,2,2-TETRACHLOROETHANE/ ... CAUSED /NEUROPATHY/ ... AND PARALYSIS ... . [R53] *Eight humans, each of whom ingested 3 ml by mistake, became comatose and areflexic, but recovered without sequelae. [R54] *THE SLOW ELIMINATION OF TETRACHLOROETHANE FROM THE BODY MAY BE A REASON FOR ITS HIGH TOXICITY. ... TETRACHLOROETHANE IS A POWERFUL ... /CNS DEPRESSANT/, BEING TWO TO THREE TIMES AS EFFECTIVE AS CHLOROFORM. ... FATAL CASES ... HAVE RESULTED FROM INGESTION ... WITH DEATH OCCURRING WITHIN 12 HOURS. [R36, 2162] *Compound is a powerful /CNS depressant/ and liver poison. May also cause changes in blood composition and neurological disturbances. Repeat exposure by inhalation can be fatal. [R4] *If the exposure was severe, within a few hr a deep dusky coloration of the skin may appear. ... If the vapor or liquid ... gets into the eyes, it may cause watering and burning. It may cause serious eye damage. ... [R10, 1981.1] *Acute and chronic exposures produce jaundice, liver enlargement, fatty degeneration, hepatic necrosis, and cirrhosis. Resp irritation and pulmonary edema may follow inhalation exposures. Dermal exposure leads to dryness, scaling, inflammation, and a purpuric rash. [R54] *Acute poisoning results in depression of the central nervous system, which can cause death within 12 hr. Chronic poisonings can take two forms. The hepatotoxic effect is one of major concern and is often accompanied by gastrointestinal disturbances. [R55, 1991.1507] *Numerous deaths due to its ingestion, inhalation and cutaneous absorption have been recorded. The solvent affects primarily the central nervous system and the liver and caused polyneuritis and paralysis. Of 380 workers exposed to the solvent 133 (35%) exhibited tremor and other nervous symptoms. Accidental and occupational exposure produced liver damage, ranging from severe fatty degeneration to necrosis and acute atrophy, which was frequently fatal, and gastrointestinal disorders; toxic effects were also observed in the hematopoietic system. [R56] NTOX: *... RATS WERE FOUND TO SURVIVE 4 HR EXPOSURE @ 500 PPM BUT DID NOT SURVIVE 4 HR @ 1000 PPM. [R25, 3514] *DOGS EXPOSED TO VAPORS OF TETRACHLOROETHANE HAVE DEVELOPED NO CORNEAL INJURY EVEN THOUGH THEY UNDERWENT REPEATED /CNS DEPRESSION/ ... . /TETRACHLOROETHANE/ [R57] *... RABBITS /EXPOSED/ @ 0.3, 1.5, and 14.6 PPM OF TETRACHLOROETHANE, 3 TO 4 HR DAILY FOR 7 TO 11 MO. ... MORPHOLOGIC CHANGES WERE REPORTED IN LIVER AND KIDNEYS OF RABBITS EXPOSED AT BOTH 1.5 PPM AND 14.6 PPM, AS WELL AS, SEVERAL CHANGES ASSOCIATED WITH SUPPRESSION OF IMMUNORESPONSE SYSTEM. /TETRACHLOROETHANE/ [R55, 1991.1506] *MICE EXPOSED TO 600 PPM TETRACHLOROETHANE FOR 3 HR. AFTER 8 HR HEPATIC TOTAL LIPIDS AND TRIGLYCERIDES INCR TO 216 and 518 (CONTROLS- 100). DECR IN HEPATIC ATP LEVELS PARALLELED INCR IN LIPIDS. THUS, EXPOSURE INDUCED FATTY LIVER IN MICE AND WAS EQUIPOTENT TO CARBON TETRACHLORIDE. [R58] *CELLS OF SACCHAROMYCES CEREVISIAE CONTAIN CYTOCHROME P450 AND ARE CAPABLE OF METABOLIZING PROMUTAGENS TO GENETICALLY ACTIVE PRODUCTS. TETRACHLOROETHANE INDUCED MITOTIC GENE CONVERTANTS AND RECOMBINANTS AND TO LESSER EXTENT GENE REVERTANTS IN YEAST SYSTEM. [R59] *AN IP INJECTION OF 25 MG TETRACHLOROETHANE/KG INHIBITED HOLE BOARD AND ORIENTATIONAL REACTIONS IN RATS; 50 MG INJECTION INHIBITED ORIENTATIONAL REACTION AND SPONTANEOUS LOCOMOTOR ACTIVITY IN MICE, AND BLOCKED PASSIVE AVOIDANCE LEARNING. INHALATION OF 450 MG TETRACHLOROETHANE/CU M FOR 4 HR INHIBITED SUMMING-UP OF SUBTHRESHOLD ELECTRICAL IMPULSES AND ORIENTATIONAL REACTION IN RATS. INHALATION OF 1000 MG/CU M ALSO STIMULATED HOLE BOARD REACTION. [R60] *BIOASSAY FOR CARCINOGENICITY WAS CONDUCTED IN OSBORNE-MENDEL RATS. TIME-WEIGHTED AVG DOSES IN MG/KG/DAY WERE 108 and 62 (MALE RATS), 76 and 43 (FEMALE RATS) FOR 78 WK ORALLY. NO CONCLUSIVE EVIDENCE FOR CARCINOGENICITY IN RATS. [R61] *RATS WERE EXPOSED FOR SEVERAL HR/DAY, 5 DAYS/WK FOR 15 WK TO TETRACHLOROETHANE. INCORPORATION OF (3)H-THYMIDINE INTO LIVER DNA INCR BY 313% AFTER 4 EXPOSURES AND SUBSEQUENTLY LEVELED TO CONTROL VALUES. PATHOLOGICAL CHANGES IN LIVER AFTER 9 EXPOSURES. [R62] *EPOXIDE HYDRATASE ACTIVITY IN RAT LIVER DECLINED SIGNIFICANTLY AFTER 1,1,2,2-TETRACHLOROETHANE ADMIN INTRAGASTRICALLY. [R63] *RATS WERE ADMINISTERED 0.015 MG/L TETRACHLOROETHANE BY INHALATION FOR 10 DAYS. PRIMARY REACTIONS DETECTED IN RATS WERE INCR ACTH-CONTENT IN HYPOPHYSIS, CHANGES IN SERUM PROTEIN FRACTIONS AND TOTAL LIPID CONTENT OF LIVER AND KIDNEY. [R64] *TETRACHLOROETHANE WAS MORE HARMFUL TO TOTAL ANTIBODY FORMATION THAN ITS PENTACHLORO OR DICHLORO ANALOGS AFTER INHALATION @ 2 MG/CU M 3 HR DAILY FOR 8-10 MO BY RABBITS. [R65] *IN RABBITS EXPOSURE TO 10 MG TETRACHLOROETHANE/CU M FOR 3 HR/DAY 6 DAYS/WK FOR 7-8.5 MO DECR BLOOD ACETYLCHOLINE LEVELS TO GREATER EXTENT THAN DID SIMILAR TREATMENT WITH DICHLOROETHANE. ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE ACTIVITIES OF BLOOD WERE INCR THEN DECR BY CMPD. [R66] *IN ALL RABBITS EXPOSED TO 100 MG/CU M TETRACHLOROETHANE 3-4 HR DAILY FOR 7-11 MO, AGGLUTININ FORMATION WAS DEPRESSED AFTER 1-1.5 MO OF TREATMENT. [R67] *GROUPS OF 50 MALE AND 50 FEMALE 5 WK OLD B6C3F1 HYBRID MICE WERE ADMIN TECHNICAL-GRADE 1,1,2,2-TETRACHLOROETHANE IN CORN OIL BY GAVAGE ON 5 DAYS/WK. /FOR 78 WK/ ... THE MEASURED, TIME-WEIGHTED AVG DOSES WERE 142 (LOW-DOSE) AND 284 (HIGH-DOSE) MG/KG BODY WT/DAY. ... IN MALES, HEPATOCELLULAR CARCINOMAS OCCURRED IN 2/19 UNTREATED CONTROLS, 1/18 VEHICLE-TREATED CONTROLS, IN 13/50 LOW-DOSE ANIMALS AND IN 44/49 HIGH-DOSE ANIMALS; IN FEMALES, THE RESPECTIVE INCIDENCES WERE 0/19, 0/20, 30/48, AND 43/47. [R68] *TREATMENT OF AB-JENA AND DBA MICE WITH 300-400 MG/KG BODY WT/DAY TETRACHLOROETHANE DURING ORGANOGENESIS PRODUCED EMBRYOTOXIC EFFECTS AND A LOW INCIDENCE OF MALFORMATIONS (EXENCEPHALY, CLEFT PALATE, ANOPHTHALMIA, FUSED RIBS AND VERTEBRAE). THE EFFECTS WERE RELATED TO DOSE AND PERIOD OF TREATMENT ... . [R69] *1,1,2,2-TETRACHLOROETHANE WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM STRAINS TA1530 AND TA1535, SHOWING A LINEAR INCR IN REVERSION FREQUENCY WITH INCREASING CONCN; NEGATIVE RESULTS WERE OBTAINED IN STRAIN TA1538. /1,1,2,2-TETRACHLOROETHANE/ ... INHIBITED THE GROWTH OF DNA POLYMERASE-DEFICIENT (POL A-) ESCHERICHIA COLI; THE RATIO OF THE AREAS OF INHIBITION OF POL A-:POL A+ WAS 1.88 WITH A CONCN OF 10 UL/PLATE ... . [R69] *1,1,2,2-TETRACHLOROETHANE WAS NON-MUTAGENIC IN THE SALMONELLA/MAMMALIAN MICROSOME ASSAY AS SHOWN BY NO INCR IN HIS+ REVERSIONS ... . [R70] *IN RATS EXPOSED TO 1,1,2,2-TETRACHLOROETHANE IN AIR FOR 4 HR, 5 TIMES/WK, FOR 1-1.5 MO, IT WAS OBSERVED THAT CONTINUOUS EXPOSURE CAN BE REPLACED BY INTERMITTENT EXPOSURE WITHOUT AFFECTING THE ADAPTATION REACTIONS OF THE ORGANISM. [R71] *1,1,2,2-Tetrachloroethane was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of 1,1,2,2-tetrachloroethane that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of 1,1,2,2-tetrachloroethane tested by injection (800 ppm) or feeding (1500 ppm) were negative in this assay. [R72] *In monkeys exposed to 1,000 ppm or 4,000 ppm 2 hr/day for 190 days, marked vacuolation of the liver was observed. [R73] *Rats /exposed by inhalation/ of 1.94 ppm /1,1,2,2-tetrachloroethylene/ 4 hr/day up to 265 days, increased the number of white blood cells, pituitary adrenocorticotropic hormone, and the total fat content of the liver. [R74] NTXV: *LD50 Rat oral 200 mg/kg; [R4] *LD50 Rat oral 0.20 ml/kg; [R1] *Toxic dose Dog oral 0.7 g/kg; [R11, 1076] ETXV: *LC50 Daphnia magna 9,320 ug/l/48 hr; in a static unmeasured bioassay; [R75] *LC50 Pimephales promelas (fathead minnow) 20,300 ug/l/96 hr; in a flow-through measured bioassay; [R76] *LC50 Lepomis macrochirus (bluegill) 21,300 ug/l/96 hr; in a static unmeasured bioassay; [R77] *LC50 Mysiodopsis bahia (Mysid shrimp) 9,020 ug/l/96 hr; in a static unmeasured bioassay; [R78] *LC50 Cyprinodon variegatus (sheepshead minnow) 12,300 ug/l/96 hr; in a static unmeasured bioassay; [R78] *LC50 Selenastrum capricornutum 136,000-146,000 ug/l/96 hr /Conditions of bioassay not specified/; [R79, 440/5-89-0269] *LC50 Skeletonema costatum (alga) 6,230-6,440 ug/l/96 hr /Conditions of bioassay not specified/; [R79, 440/5-80-0269] *LC50 Poecilia reticulata (guppy) 37 ppm/7 day /Conditions of bioassay not specified/; [R11, 1076] *LC50 Daphnia magna 62 mg/l/48 hr /Conditions of bioassay not specified/; [R80] *EC50 Daphnia magna 14 mg/l/28 day; toxic effect: Reproductive impairment /Conditions of bioassay not specified/; [R81] *EC50 Selenastrum capricornutum (alga) 136,000 ug/l/96 hr; Toxic effect: Chlorophyll a /Conditions of bioassay not specified/; [R82] *EC50 Selenastrum capricornutum (alga) 146,000 ug/l/96 hr; Toxic effect: Cell numbers. /Conditions of bioassay not specified/; [R83] *EC50 Skeletonema costatum (alga) 6,440 ug/l/96 hr; Toxic effect: Chlorophyll a. /Conditions of bioassay not specified/; [R83] *EC50 Skeletonema costatum (alga) 6,230 ug/l/96 hr; Toxic effect: Cell count. /Conditions of bioassay not specified/; [R83] *LC50 Pimephales promelas (fathead minnow) 20.3 mg/l/96 hr (confidence limit 19.9 - 20.7 mg/l), flow-through bioassay with measured concentrations, 25.6 deg C, dissolved oxygen 7.8 mg/l, hardness 45.2 mg/l calcium carbonate alkalinity 43.4 mg/l calcium carbonate and pH 7.28; [R84] NTP: +A bioassay for possible carcinogenicity of technical grade 1,1,2,2-tetrachloroethane was conducted using Osborne-Mendel rats and B6C3F1 mice. ... 1,1,2,2-Tetrachloroethane in corn oil was administered by gavage at either of two dosages, to groups of 50 male and 50 female animals of each species 5 days/wk. Treatment was over a period of 78 wk, followed by an observation periods of 32 wk for the rats and 12 wk for the mice. The high and low time weighted avg dosages were, respectively, 108 and 62 mg/kg/day for male rats, 76 and 43 mg/kg/day for female rats, and 282 and 142 mg/kg/day for the mice of both sexes. Dor each species, 20 animals of each sex were placed on test as vehicle controls. These animals were intubated with corn oil at the same rate as the high dose animals. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. Among mice, hepatocellular carcinomas were observed in 2/16 (13%) male untreated controls, 1/18 (6%) male vehicle controls, 13/50 (26%) low dose males, 44/49 (90%) high dose males, 0/18 female untreated controls, 0/20 female vehicle controls, 30/48 (63%) low dose females, and 43/47 (91%) of the high dose females. The incidence of hepatocellular carcinoma indicated a highly significant (p < 0.001) positive dose related trend in mice of both sexes. No statistically significant incidence of neoplastic lesions was observed in male or female rats. However, two hepatocellular carcinomas and one neoplastic nodule, which are rare tumors in the male Osborne-Mendel rat, were observed in the high dose males. Under the conditions of this study, orally administered 1,1,2,2-tetrachloroethane is a liver carcinogen in B6C3F1 mice of both sexes. The results do not provide conclusive evidence for the carcinogenicity of 1,1,2,2-tetrachloroethane in Osborne-Mendel rats. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal; Female Rats: Negative; Male Mice: Positive; Female Mice: Positive. [R85] TCAT: ?The ability of 1,1,2,2-tetrachloroethane to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary toxicity tests, concentrations of 1, 10, 100 and 250 ug/ml were used with corresponding survival rates ranging from 104% to 60% of controls. The test compound did not induce any statistically significant transformation. [R86] ?The mutagenicity of 1,1,2,2-tetrachloroethane (TCE) was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat or mouse (male or female) liver S9 fraction. Based on the results of preliminary bacterial toxicity determinations, TCE was not mutagenic in any of the tests, either with or without activation. The tests were conducted using a protocol in which the chemical is tested over a minimum of 6 dose levels, the highest nontoxic dose level being 10 mg/plate unless solubility, mutagenicity, or toxicity dictates a lower upper limit. [R87] ?The effects of 1,1,2,2-tetrachloroethane (TCE) in dimethylsulfoxide were examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, TCE was tested at concentrations of 1% to 1x10-7%. Concentrations of 1x10-2% and above were both cytotoxic and genotoxic. Lower concentrations were neither cytotoxic nor genotoxic. [R88] ?The effects of 1,1,2,2-tetrachloroethane (TCE) in dimethylsulfoxide solvent were examined in the mouse hepatocyte primary culture/DNA repair assay using hepatocytes from male B3C3F1 mice. Based on preliminary toxicity tests, concentrations of 1% to 1x10(-7)% TCE were tested. The 1% and 0.1% levels were toxic and genotoxic. Lower levels tested were neither toxic nor genotoxic. [R89] POPL: *WORKERS WITH A TENDENCY TO LIVER DISEASE, ESP HABITUAL DRINKERS OF ALCOHOLIC BEVERAGES, ... AND OBESE INDIVIDUALS ALSO APPEAR ABNORMALLY SUSCEPTIBLE TO TETRACHLOROETHANE. [R36, 2163] ADE: *... Readily absorbed through ... skin. [R54] *... IS READILY ABSORBED VIA THE LUNG OR GASTROINTESTINAL TRACT. ... IT IS APPARENTLY READILY EXCRETED BY THE LUNGS. [R25, 3515] *HALF OF A DOSE OF (14)C-LABELED 1,1,2,2-TETRACHLOROETHANE (0.21-0.32 G/KG, IP) WAS EXPIRED FROM MOUSE AS LABELED CO2 WITHIN 3 DAYS AND 28% EXCRETED IN URINE. [R90] *ABOUT 97% OF INHALED 1,1,2,2-TETRACHLOROETHANE WAS RETAINED IN THE LUNG 1 HR AFTER EXPOSURE ... . [R53] METB: *PENTACHLOROETHANE WAS METABOLIZED TO TRICHLOROETHENE AND TETRACHLOROETHANE (96 AND 4%, RESPECTIVELY) BY RAT LIVER MICROSOMAL FRACTIONS UNDER ANAEROBIC CONDITIONS. [R91] *WHEN ADMINISTERED IP TO MICE, ONE-HALF OF A DOSE OF 1,1,2,2-TETRACHLOROETHANE WAS EXPIRED AS CO2. DICHLOROACETIC ACID, TRICHLOROACETIC ACID, TRICHLOROETHANOL, OXALIC ACID, AND GLYOXYLIC ACID ACCOUNTED FOR ABOUT ONE-HALF OF THAT PROPORTION OF DOSE EXCRETED IN THE URINE. MUCH OF THE REMAINDER WAS ACCOUNTED FOR AS GLYCINE BY SIMULTANEOUS INJECTION OF BENZOATE AND RECOVERY OF HIPPURIC ACID. [R92] *TETRACHLOROETHANE WHEN ADMIN FOR 8 HR AS VAPOR @ 200 PPM TO RATS AND MICE, PRODUCED FUJIWARA REACTION-POS URINARY METABOLITES, TRICHLOROACETIC ACID, TRICHLOROETHANOL AND TOTAL TRICHLORO CMPD IN YIELDS CONSISTENT WITH THEIR VAPOR PRESSURE AND EASE OF METABOLIC CONVERSION. [R93] *INCUBATION OF 1,2-(14)C-LABELED 1,1,2,2-TETRACHLOROETHANE WITH A RECONSTITUTED MONOOXYGENASE SYSTEM OR WITH INTACT RAT LIVER MICROSOMES LED TO THE FORMATION OF A METABOLITE CAPABLE OF BINDING COVALENTLY TO PROTEINS AND OTHER NUCLEOPHILES. THE ENZYME SYSTEM RESPONSIBLE FOR METABOLIZING TETRACHLOROETHANE TO BOTH SOLUBLE AND COVALENTLY BOUND METABOLITES WAS INDUCED BY PHENOBARBITAL OR XYLENE BUT NOT BY BETA-NAPHTHOFLAVONE TREATMENT. THE RESULTS ARE CONSISTENT WITH A SCHEME WHEREBY 1,1,2,2-TETRACHLOROETHANE IS METABOLIZED BY CYTOCHROME P450 TO DICHLOROACETYL CHLORIDE, WHICH CAN BIND COVALENTLY TO VARIOUS NUCLEOPHILES OR HYDROLYZE TO DICHLOROACETIC ACID. [R94] *... 1,1,2,2-Tetrachloroethane appears to be metabolized by hepatic nuclear cytochrome p450, and ... converted to chlorinated metabolites after incubation with hepatic nuclei and an NADPH-generating system plus EDTA, with the omission of any component eliminating metabolite production. [R95] ACTN: *TETRACHLOROETHANE METABOLISM APPARENTLY TOOK PLACE MAINLY VIA A STAGEWISE HYDROLYTIC FISSION OF CARBON-CHLORIDE BONDS AND OXIDATION. WITH PART OF TETRACHLOROETHANE, A NONENZYMIC DEHYDROCHLORINATION OCCURRED WITH FORMATION OF TRICHLOROETHYLENE. [R90] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Most of the released 1,1,2,2-tetrachloroethane enters the atmosphere where it is extremely stable (half-life > 2 years). Some of the chemical will eventually diffuse into the stratosphere where it will rapidly photodegrade. 1,1,2,2-Tetrachloroethane which is released into water will primarily be lost by volatilization in a matter of days to weeks. The volatilization half-lives from a model river and a model pond have been estimated to be 6.3 hr and 3.5 days, respectively. 1,1,2,2-Tetrachloroethane is not expected to partition from the water column to organic matter contained in sediments and suspended solids. A measured Koc of 79 in a silt loam indicates 1,1,2,2-tetrachloroethane will be highly mobile in soil. When disposed of on soil, part of the 1,1,2,2-tetrachloroethane may leach into groundwater. There is evidence that 1,1,2,2-tetrachloroethane slowly biodegrades. A product of biodegradation under anaerobic conditions is 1,1,2-trichloroethane, a chemical which is resistant to further biodegradation. Under alkaline conditions, 1,1,2,2-tetrachloroethane may be expected to hydrolyze. A measured aqueous hydrolysis rate constant, KB of 2.3X10+7 L/moles-yr, corresponds to hydrolytic half-lives of 1.1,11.1, and and 111 days at pH 9, 8, and 7, respectively. 1,1,2,2-Tetrachloroethane will not be expected to bioconcentrate into the food chain. The major source of human exposure is from ambient air near industrial sources.(SRC) NATS: *1,1,2,2-Tetrachloroethane is not known to occur as a natural product(1). [R96] ARTS: *1,1,2,2-Tetrachloroethane may be released into the atmosphere as a result of its use as a metal degreasing agent, paint, varnish and rust remover, extractant, solvent, as a chemical intermediate, etc.(1,3). 1,1,2,2-Tetrachloroethane can be emitted from hazardous waste landfills(2). [R97] *... Byproducts obtained from vinyl chloride, allyl chloride, and epichlorohydrin manufacturing facilities ... included ... 1,1,2,2-tetrachloroethane ... . [R98] FATE: *TERRESTRIAL FATE: 1,1,2,2-Tetrachloroethane may undergo hydrolysis in alkaline soil. A measured aqueous hydrolysis rate constant, KB of 2.3X10+7 L/moles-yr, corresponds to a half-life of 1.1 days at pH of 9(1). A measured Koc of 79 in a silt loam(2), suggests 1,1,2,2-tetrachloroethane will be highly mobile in soil(3) and therefore can leach into groundwater. A calculated Henry's Law constant of 4.55X10-4 atm-cu m/mole at 25 deg C(SRC) suggests volatilization of 1,1,2,2,-tetrachloroethane from moist soils should be important. [R99] *AQUATIC FATE: Under alkaline conditions, 1,1,2,2-tetrachloroethane may be expected to hydrolyze. A measured aqueous hydrolysis rate constant, KB of 2.3X10+7 L/moles-yr, corresponds to half-lives of 1.1 and 111 days at pH of 9 and 7(1). The primary loss of 1,1,2,2-tetrachloroethane from the aquatic compartment will be by evaporation which should have a half-life of days to weeks depending on the body of water in question. Based upon a calculated Henry's Law constant of 1.55X10-4 atm-cu m/mole at 25 deg C(SRC), the volatilization half-life from a model river has been estimated to be 6.3 hr(2,SRC). Adsorption to sediment would not be a significant loss mechanism. The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be about 3.5 days(3,SRC). Some biodegradation may occur in situations where evaporation is extremely slow and the body of water is rich in microorganisms such as a eutrophic lake. Biodegradation in groundwater is possible but the biodegradation product 1,1,2-trichloroethane is resistant to further biodegradation(SRC). [R100] *ATMOSPHERIC FATE: Based upon a vapor pressure of 6.1 mm Hg at 25 deg C(1), 1,1,2,2-tetrachloroethane is expected to exist entirely in the vapor phase in ambient air(2). 1,1,2,2-Tetrachloroethane is practically inert in the troposphere with a half-life exceeding 800 days. As such it will be transported long distances with some of it returning to earth in rain. It can be expected to diffuse slowly into the stratosphere where it will degrade rapidly by photodissociation. With continual release, one might expect to find increasing atmospheric concentration(SRC). [R101] BIOD: *One investigator who incubated the tetrachloroethane with sewage seed for 7 days and followed that with three successive 7-day subcultures found no significant degradation under these conditions(1). These results are in conflict with those of another investigator who obtained 41% degradation in 24 days in a modified shake flask biodegradability test using an unacclimated inoculum and 19% degradation in a river die-away test while 5 other chlorinated ethanes and ethenes tested were undegraded(2). A continuous flow biofilm column operating under anaerobic conditions with a sewage inoculum achieved 97% steady state removal during 4 months of operation(3). A product of the biodegradation was 1,1,2-trichloroethane(3). The most commonly found products of microbial degradation of these compounds evidently come from reductive dehalogenation, while nonmicrobial degradations tend to involve hydrolysis and/or oxidation(4). [R102] ABIO: *1,1,2,2-Tetrachloroethane is virtually inert in the troposphere. The half-life for the reaction with photochemically produced hydroxyl radicals is > 800 days or < 0.1% loss per 12 hr sunlit day(1). In the stratosphere it may photolyze(2) or degrade rapidly by reaction with chlorine radicals(3). A measured aqueous hydrolysis rate constant of KB = 2.3X107 M-1 yr-1 at pH of 9 and 25 deg C corresponds to half-lives of 1.1 and 111 days at pH of 9 and 7(4). [R103] BIOC: *1,1,2,2-Tetrachloroethane would not be expected to bioconcentrate in fish. The log of the bioconcentration factor in fish is reported to be 0.9-1(1,2). After 14 days exposure to an average water concn of 9.62 ug/L, the log bioconcentration factor of 1,1,2,2-tetrachloroethane in the tissue of bluegill sunfish (Lepomis macrochirus) was 0.9(1-3). [R104] KOC: *A measured Koc of 79 in a silt loam(1), suggests 1,1,2,2-tetrachloroethane will be highly mobile in soil(2). [R105] VWS: *Laboratory measurements of the rate of evaporation of 1,1,2,2-tetrachloroethane from water gave a half-life of 32-56 minutes(1,2). In natural waters one would expect a half-life for volatilization in the order of days to weeks depending on mixing conditions(SRC). Based upon a water solubility of 2962 ppm at 25 deg C(3) and a vapor pressure of 6.1 mm Hg at 25 deg C(4), a Henry's Law Constant of 4.55X10-4 atm-cu m/mole has been calculated(SRC). This value indicates volatilization of 1,1,2,2-tetrachloroethane from environmental waters should be important(5). The volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 6.3 hr(5,SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be 3.5 days(6,SRC). Due to its moderate vapor pressure, volatilization from dry soil will be fairly rapid(SRC). [R106] WATC: *DRINKING WATER: Detected in 2 of 3 investigations of US drinking water(1,3,4). In treated water from 30 Canadian treatment facilities - 1 site positive (1 ppb) in Aug/Sept, not detected in Nov/Dec(2). Also found in 1 of 13 drinking water wells in Tacona,WA(5). 1,1,2,2-Tetrachloroethane was listed as a contaminant found in drinking water(6) for a survey of US cities including Pomona, Escondido, Lake Tahoe and Orange Co, CA and Dallas, Washington, DC, Cincinnati, Philadelphia, Miami, New Orleans, Ottumwa, IA, and Seattle(7). [R107] *SURFACE WATER: Detected not quantified - River Glatt, Switzerland(1). Trace to < 1 ppb measured samples from the Ohio River(3,4); 1 ppb detected in the Detroit R(5). Trace to 1.9 ppb in the Schuylkill R at Philadelphia, PA(4); 67 of 608 samples pos in representative New Jersey surface waters, max of 3 ppb measured(2). Not detected in raw water for 30 Canadian potable drinking facilities in Aug/Sept and only one facility had detectable amounts in Nov/Dec - 12 ppb(6). Only 12 of 204 sites near heavily industralized areas across US were positive, positive sites ranged from 1 to 9 ppb(7). 1,1,2,2-Tetrachloroethane is listed as a contaminant of Great Lakes Erie, Ontario, and the St Lawrence River(8). [R108] *GROUNDWATER: New Jersey - 64 of 1072 representative groundwater sources positive, 2.7 max(1). Detected, not quantified, in 10 most polluted wells from a 408 well survey in New Jersey, with the wells being located under urban land use areas(2). Groundwater samples from near the Hooker Chemical and Plastics Corp disposal site at Love Canal, NY contained 1,1,2,2-tetrachloroethane(3). Six of 7 ground water sample from near the "Valley of Drums", KY contained 1,1,2,2-tetrachloroethane at a concn of 6.4, 18, 12, 5.7, 0.2 and 6.2 ug/L(4). [R109] EFFL: *Only the metal finishing industry has mean water effluents exceeding 20 ppb, the mean effluent level of 1,1,2,2-tetrachloroethane for this industry is 290 ppb and the maximum observed level is 570 ppb(1). Detected in samples of effluents from 3 US chemical plants and a US sewage treatment plant(2). Unidentified isomer from industrial effluent South Clair R Sarnia, Ontario detected at 5 sites(3). The biotreatment and final effluents of a Class A oil refinery contained 1,1,2,2-tetrachloroethane at a concn of greater than 50 and less than 10 ug/L, respectively(4). Wastewater from the gaseous diffusion plant operated by Union Carbide at Oak Ridge, TN contained 1,1,2,2-tetrachloroethane in the volatile fraction(5). Leachate from Hooker Chemical and Plastics Corp disposal site at Love Canal, NY contained 1,1,2,2-tetrachloroethane(6). An unspecified isomer of tetrachloroethane was identified as a product of coal combustion(7). [R110] SEDS: *Sediment samples from nearby the Hooker Chemical and Plastics Corp disposal site at Love Canal, NY contained 1,1,2,2-tetrachloroethane(1). [R111] ATMC: *RURAL: Not detected in 2 US samples(5). URBAN/SUBURBAN: 853 US sites: 5.4 parts/trillion median, 25% of samples exceed 8.9 ppt, max 4800 ppt, not detected in > 25% of samples(5). 0.01-9.4 ppb in urban atmospheres in Japan(8). Trace to 57 ppb avg measured in studies covering major US cities(1,2,3,4,6). INDUSTRIAL: 0 to .25 ppb in 5 industrial sites in US 3 of 5 pos, 2.70 ppb, 3 max with 1 site detected, not quantified(7). US - source dominated areas (60 samples) 0 parts/trillion median, 25% of samples exceed 27 parts/trillion, max 700 parts/trillion(5). 1,1,2,2-Tetrachlorethane was detected in the ambient air at Love Canal, Niagara Falls, NY(9). [R112] FOOD: *Unspecified isomers of tetrachloroethane had been detected, concn not reported, in volatile flavor constituents of broiled beef(1). The Food and Drug Administration's "market basket" collections were demarcated as fatty and non-fatty fractions at the 20% lipid point(2). The high, low and average 1,1,2,2-tetachloroethane concn of the fatty and non-fatty food groups according to the extracted procedure were 118, 50 and 70 ng/g, and 122, 49 and 84 ng/g, respectively(2). The high, low and average 1,1,2,2-tetrachloroethane concn for the fatty and non-fatty food groups according to the cleaned up procedure were 85, 24 and 58 ng/g, and 89, 8 and 57 ng/g, respectively(2). [R113] OEVC: *The adsorption isotherms of halogenated aliphatic hydrocarbons by various selected types of inactive microbial biomass were determined. The isotherms were shown to be independent on the initial organic solution concn and could be described by a modified Freundlich adsorption equation. Biosorptive uptake capacities varied among the biomass species. The water solubility and the octanol/water partition coefficient of the tested organics affected the biomass uptake capacity. In general, the least water sooluble component showed the greatest tendency to be accumulated by the microbial biomass. The results also suggest that structural differences among the various microbial biomass types and possibly the fragmentation of the microbial cells, also affect the biomass uptake capacity for both single and mixed-solute systems. [R114] RTEX: *Humans are primarily exposed to 1,1,2,2-tetrachloroethane from ambient air or from contaminated drinking water. (SRC) *1,1,2,2-Tetrachloroethane can affect the body if it is inhaled, if it comes in contact with the eyes or skin, or if it is swallowed. It may be absorbed through the skin. [R10, 1981.1] *1974 National Occupational Hazard Survey concluded that workers most likely to be exposed are those in industrial controls, toiletry preparations, and electric service industries, the latter exposure stemming from use of commercial solvent cleaners(1). NIOSH has estimated that approximately 11,000 persons have occupational contact with 1,1,2,2-tetrachloroethane(5). NIOSH (NOHS Survey 1972-1974) has statistically estimated that 7201 workers are exposed to 1,1,2,2-tetrachloroethane in the USA(2). NIOSH (NOES Survey as of 3-29-89) has statistically estimated that 4,143 workers are potentially exposed to 1,1,2,2-tetrachloroethane in the USA(3). The average indoor air concn of 1,1,2,2-tetrachloroethane equaled the outdoor concn at 0.03 for an office building and 0.02 for a school(4). [R115] AVDI: *AIR INTAKE (assume 5.4 parts per trillion)(1) 0.74 ug; WATER INTAKE (assume 0-1 ppb) 0-2 ug(SRC). [R116] BODY: *1,1,2,2-Tetrachloroethane was detected in the adipose tissue, liver and lungs of humans(1). [R117] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH has recommended that 1,1,2,2-tetrachloroethane be treated as a potential human carcinogen. [R35, 300] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (35 mg/cu m). Skin Designation. [R118] +Vacated 1989 OSHA PEL TWA 1 ppm (7 mg/cu m), skin designation, is still enforced in some states. [R35, 372] NREC: +NIOSH has recommended that 1,1,2,2-tetrachloroethane be treated as a potential human carcinogen. [R35, 300] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R35, 300] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 ppm (7 mg/cu m), skin. [R35, 300] +NIOSH considers ethylene chloride; hexachloroethane; 1,1,2,2-tetrachloroethane; and 1,1,2-trichloroethane; to be potential occupational carcinogens. Additionally, NIOSH recommends that the other five chloroethane compounds: 1,1-dichloroethane; ethyl chloride; methyl chloroform; pentachloroethane; and 1,1,1,2-tetrachloroethane be treated in the workplace with caution because of their structural similarity to the four chloroethanes shown to be carcinogenic in animals. [R35, 300] TLV: +8 hr Time Weighted Avg (TWA) 1 ppm, skin [R52, 66] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R52, 6] +A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R52, 66] OOPL: *USSR (1967): 0.7 ppm; Federal Republic of Germany (1967): 1 ppm; Rumania (1967): 1.5 ppm; Yugoslavia (1967): 1 ppm. [R6, 1986.563] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Tetrachloroethanes are produced, a intermediates or final products, by process units covered under this subpart. /Tetrachloroethanes/ [R119] +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,1,2,2-Tetrachloroethane is included on this list. [R120] WSTD: STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 1 ug/l [R121] +(NJ) NEW JERSEY 1 ug/l [R121] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.17 ug/l [R121] +(FL) FLORIDA 0.2 ug/l [R121] +(MN) MINNESOTA 2 ug/l [R121] +(WI) WISCONSIN 0.2 ug/l [R121] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Chlorinated ethanes/ [R122] +The levels which may result in incremental increase of cancer risk over the lifetime are estimated at 10-5, 10-6, and 10-7. The corresponding recommended criteria are 1.7 ug/l, 0.17 ug/l, and 0.017 ug/l, respectively. [R123] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R124] TSCA: *EPA has issued a final rule, under section 4 of the Toxic Substances Control Act (TSCA), requiring manufacturers and processors to test /this cmpd/ for certain health effects. Oral 14 day repeated dose and oral 90 day subchronic toxicity studies are required. ... [R125] RCRA: *U209; As stipulated in 40 CFR 261.33, when 1,1,2,2-tetrachloroethane as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R126] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1019. Analyte: 1,1,2,2-Tetrachloroethane. Matrix: Air. Sampler: A solid sorbent tube (petroleum charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/m: Sample Size: 10 liters. Shipment: Routine. Sample Stability: Not determined. [R127] ALAB: *DETERMINATION OF FREE AND TOTAL POTENTIAL HALOFORMS IN DRINKING WATER. GAS CHROMATOGRAPHY/ELECTRON CAPTURE DETECTION. LIMIT OF DETECTION: 7 UG/L. [R128] *1,1,2,2-TETRACHLOROETHANE WAS DETERMINED IN WASTE-CONTAMINATED SOIL AND CHEMICAL STILL BOTTOM EXTRACTS BY GAS CHROMATOGRAPHY. [R129] *DETERMINATION OF 1,1,2,2-TETRACHLOROETHANE IN AQUEOUS INDUSTRIAL EFFLUENTS BY ISOTOPE DILUTION GAS CHROMATOGRAPHY/MASS SPECTROMETRY IS DESCRIBED. [R130] *VACUUM EXTRACTION AND CONDENSATION IN PURGING TRAP COOLED BY LIQUID NITROGEN; DETERMINATION OF 1,1,2,2-TETRACHLOROETHANE IN FISH AND SEDIMENT. [R131] *NIOSH Method 1019. Analyte: 1,1,2,2-Tetrachlorethane. Matrix: Air. Procedure: Gas chromatography, hydrogen air flame ionization detector. For 1,1,2,2-tetrachloroethane this method has an estimated detection limit of 0.010 mg/sample. The overall precision/RSD is 0.016 @ 0.16-0.64 mg/sample. Applicability: The working range is 1.5 to 15 ppm (10 to 100 mg/cu m) for a 10 liter air sample. Interferences: None known. [R127] *EPA Method 8010. Direct Injection of Purge-and-Trap Gas Chromatography with halogenspecific detector for the analysis of halogenated volatile organics including 1,1,2,2-tetrachloroethane in solid waste. Under the prescribed conditions, for 1,1,2,2-tetrachloroethane the method has a detection limit of 0.03 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R132] *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile organics. This method can be used to quantify most volatile organic compounds including 1,1,2,2-tetrachloroethane that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R132] *EPA Method 502.2: Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For 1,1,2,2-tetrachloroethane the method has a detection limit of 0.01 ug/l, a percent recovery of 99%, and a standard deviation of 6.8 using the photoionization detector; and a method detection limit of 0.01 ug/l, percent recovery and standard deviation of recovery were not given for the electrolytic conductivity detector. [R133] *EPA Method 502.1. Purge-and-Trap Gas Chromatography with halogen-specific detector for the determination of halogenated volatile compounds including 1,1,2,2-tetrachloroethane in finished drinking water, raw source water, or drinking water in any treatment stage. Under the prescribed conditions, for 1,1,2,2-tetrachloroethane the method detection limit is 0.01 ug/l. [R133] *EPA Method 524.1. Purge-and-Trap Gas Chromatography/Mass Spectrometry. The method is applicable for the determination of volatile organic compounds in water, finished drinking water, raw source water, or drinking water in any treatment stage. For 1,1,2,2-tetrachloroethane the method has a detection limit of 0.14 ug/l and a standard deviation of 12.8%. [R133] *EPA Method 601. Purge-and-Trap Gas Chromatography with electrolytic conductivity detection for the analysis of purgeable halocarbons including 1,1,2,2-tetrachloroethane in municipal and industrial discharges. Under the prescribed conditions, the method detection limit for 1,1,2,2-tetrachloroethane is 0.03 ug/l. The method is recommended for use in the concentration range from the method detection limit to 1000 times that limit. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R134] *EPA Method 624. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the analysis of purgeable organics including 1,1,2,2-tetrachloroethane in municipal and industrial discharges. Under the prescribed conditions, for 1,1,2,2-tetrachloroethane the method has a detection limit of 6.9 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R134] *EPA Method 1624. Isotope Dilution Purge-and-Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of volatile organic compounds in municipal and industrial discharges. By adding a known amount of a labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, for both labeled and unlabeled 1,1,2,2-tetrachloroethane the method has a minimum detection level of 10 ug/l. The established acceptance performance criterion at 20 ug/l is 9.6 ug/l for the standard deviation of the recovery, with the average recovery of 10.7 to 30.0 ug/l and the labeled cmpd recovery ranging from 5 to 199 %. [R134] *OSW Method 8260; Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique; Capillary Gas Chromatography/Mass Spectrometry; detection limit = 0.040 ug/L [R132] *OSW Method 8021; Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Technique; Capillary Gas Chromatography Electrolytic Conductivity Detector; detection limit = 0.010 ug/L [R132] *AREAL Method IP-1B, Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbent Tubes; Capillary Gas Chromatography/Mass Spectrometry; detection limit = 6.5 ng per sample [R135] CLAB: *VACUUM EXTRACTION AND CONDENSATION IN PURGING TRAP COOLED BY LIQUID NITROGEN; DETERMINATION OF 1,1,2,2-TETRACHLOROETHANE IN FISH. [R131] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: PARKER JC ET AL; CHLOROETHANES: REVIEW OF TOXICITY; AM IND HYG ASSOC J 40 (3): A-46, A-48, A-50, A-52-A-60 (1979). REVIEW OF CHLOROETHANE HEALTH HAZARD WITH 5 REFERENCES. Harkov R et al; J Environ Sci Health Part A A20 (5): 491-501 (1985) TSCA CHIPs present a preliminary assessment of 1,1,2,2-Tetrachloroethane's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404. USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes (1980) EPA 440/5-80-0269 USEPA/ECAO; Health Effects Assessment for 1,1,2,2-Tetrachloroethane (1986) EPA 540/1-86-032 DHHS/ATSDR; Toxicological Profile for 1,1,2,2-Tetrachloroethane (1989) ATSDR/TP-89/22 DHEW/NCI; Bioassay of 1,1,2,2-Tetrachloroethane for Possible Carcinogenicity (1978) Technical Rpt Series No. 27 DHEW Pub No. (NIH) 78-827 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for 1,1,2,2-tetrachloroethane is completed, and the chemical is in review for further evaluation. Route: gavage; Species: rats and mice. [R136] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for 1,1,2,2-tetrachloroethane is completed, and the chemical is in review for further evaluation. Route: microencapsulation in feed; Species: rats and mice. [R136] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1449 R2: SRI R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: The Aldrich Catalog/Handbook of Fine Chemicals 1994-95, Aldrich Chem Co, Milwaukee, WI, pp 1306 (1994) R6: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. 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Windsor, Ontario, Great Lakes Quality Board 373 p. (1978) (4) Snider EH, Manning FS; Environ Int 7: 237-58 (1982) (5) McMahon LW; Organic Priority Pollutants in Wastewater. NTIS DE83010817 Gatinburg, TN p. 220-49 (1983) (6) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) (7) Junk GA et al; Organic Compounds from Coal Combustion. In: ACS Symp Ser 319 (Fossil Fuels Util): 109-23 (1986) R111: (1) Hauser TR, Bromberg SM; Environ Monit Asses 2: 249-72 (1982) R112: (1) Singh HB et al; Atmos Environ 15: 601-12 (1981) (2) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) (3) Harkov R et al; Toxic and Carcinogenic Air Pollutants in New Jersey - Volatile Organic Substances. Unpublished work Trenton, NJ: Off Cancer Toxic Sub (1981) (4) Harkov R et al; J Air Pollut Control Assoc 33: 1177-83 (1983) (5) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. SRI Contract 68-02-3452 198 p (1982) (6) Lioy PJ et al; J Water Pollut Control Fed 33: 649-57 (1983) (7) Pellizzari ED; Environ Sci Technol 16: 781-5 (1982) (8) IARC; Monograph. Some Halogenated Hydrocarbons 20: 477-89 (1979) (9) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) R113: (1) IARC; Monograph. Some Halogenated Hydrocarbons 20: 477-89 (1979) (2) Daft JL; J Agric Food Chem 37: 560-4 (1989) R114: Tsezos M, Seto W; Water Res 20 (7): 851-858 (1986) R115: (1) IARC; Monograph. Some halogenated hydrocarbons 20: 477-89 (1979) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1974) (3) NIOSH; National Occupational Exposure Survey (NOES) (1989) (4) Sheldon LS et al; Indoor Air in Public Buildings Vol 1 p. 163 EPA/600 6-88 009a PB89-102503 (1988) (5) Konietzko H; Hazard Asses Chem Dev 3: 401-48 (1984) R116: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere SRI Contract 68-02-3452 p. 198 (1982) R117: (1) Geyer HJ et al; Regul Toxicol Pharmacol 6: 313-47 (1986) R118: 29 CFR 1910.1000 (7/1/98) R119: 40 CFR 60.489 (7/1/92) R120: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R121: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R122: 40 CFR 401.15 (7/1/91) R123: USEPA; Quality Criteria for Water 1986: Chlorinated Ethanes (May 1,1986) EPA 440/5-86-001 R124: 40 CFR 302.4 (7/1/92) R125: 58 FR 59667 (11/10/93) R126: 40 CFR 261.33 (7/1/92) R127: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1019-1 R128: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 482 (1979) R129: GURKA DF, BETOWSKI LD; ANAL CHEM 54: 1819-24 (1982) R130: COLBY BN ET AL; INTERNATIONAL ENVIRONMENT AND SAFETY FEB: 8-13 (1982) R131: HIATT MH; ANAL CHEM 53: 1541-3 (1981) R132: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R133: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water 500 Series Methods (1988) EPA/600/4-88/039 R134: 40 CFR 136 (7/1/91) R135: USEPA/Atmospheric Research and Exposure Assessment Laboratory (AREAL); Compendium of Methods for the Determination of Air Pollutants in Indoor Air, Engineering Science, One Harrison Park, Suite 305, 401 Harrison Oaks Blvd, Cary, NC 27513 as cited in USEPA; EMMI. Environmental Monitoring Index Database Version 1.02 (1992) EPA/871-B-92-001 (NTIS Document No. PB92-503093) R136: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 94 Record 22 of 1119 in HSDB (through 2003/06) AN: 124 UD: 200302 RD: Reviewed by SRP on 1/20/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRACHLOROETHYLENE- SY: *AI3-01860-; *Ankilostin-; *Antisal-1-; *Antisol-1-; *Caswell-no-827-; *CZTEROCHLOROETYLEN- (POLISH); *Didakene-; *Dow-Per-; *ENT-1,860-; *EPA-pesticide-chemical-code-078501-; *ETHENE,-TETRACHLORO-; *ETHYLENE-TETRACHLORIDE-; *Ethylene,-tetrachloro-; *Fedal-Un-; *NCI-C04580-; *Nema-; *PCE-; *Per-; *Perawin-; *Perc-; *PERCHLOORETHYLEEN,-PER- (DUTCH); *Perchlor-; *PERCHLORAETHYLEN,-PER- (GERMAN); *PERCHLORETHYLENE-; *PERCHLORETHYLENE,-PER- (FRENCH); *PERCHLOROETHYLENE-; *Perclene-; *PERCLOROETILENE- (ITALIAN); *Percosolv-; *Perk-; *Perklone-; *Persec-; *Tetlen-; *Tetracap-; *TETRACHLOORETHEEN- (DUTCH); *TETRACHLORAETHEN- (GERMAN); *TETRACHLORETHYLENE-; *TETRACHLOROETHENE-; *1,1,2,2-TETRACHLOROETHYLENE-; *TETRACLOROETENE- (ITALIAN); *Tetraguer-; *Tetraleno-; *Tetralex-; *Tetravec-; *Tetroguer-; *Tetropil- RN: 127-18-4 MF: *C2-Cl4 SHPN: UN 1897; Tetrachloroethylene; Perchloroethylene IMO 6.1; Tetrachloroethylene STCC: 49 403 55; Tetrachloroethylene HAZN: U210; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. F002; A hazardous waste from nonspecific sources when a spent halogenated solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Manufactured by catalytic oxidn of 1,1,2,2-tetrachloroethane: Ellsworth, vancamp, US patent 2,951,103 (1960 to Columbia-Southern Chem); Feathers, Rogerson, US patent 3,040,109 (1962 to Pittsburgh Plate Glass) ... by catalytic chlorination of acetylene: Thermet, Parvi, US patent 2,938,931 (1960 to Societe d'electrochimie, d'electrometallurgie et des acieries electriques d'Ugine). [R1] *Prepared primarily by two processes: (1) The Huels method whereby direct chlorination of ethylene yields 70% perchloroethylene, 20% carbon tetrachloride, and 10% other chlorinated products; (2) Hydrocarbons such as methane, ethane, or propane are simultaneously chlorinated and pyrolyzed to yield over 95% perchloroethylene plus carbon tetrachloride and hydrochloric acid. [R2] *Tetrachloroethylene is produced mainly by oxyhydrochlorination, perchlorination, and/or dehydrochlorination of hydrocarbons or chlorinated hydrocarbons such as 1,2 dichloroethane, propylene, propylene dichloride, and 1,1,2-trichloroethane. [R3] FORM: *Available in the United States ... in veterinary preparations (eg, Nema Worm Capsules (Parke-Davis)). These capsules contain pure tetrachloroethylene. Avail sizes are 0.2, 0.5, 1.0, 2.5 and 5 ml. [R4] *Tetrachloroethylene is avail in the USA in the following grades: purified, technical, USP, spectrophotometric, and dry-cleaning. The technical and dry-cleaning grades both meet specifications for technical grade and differ only in the amount of stabilizer added to prevent decomposition. Stabilizers ... incl amines or mixtures of epoxides and esters. Typical analysis of the commercial grade is ... nonvolatile residue, 0.0003%; free chlorine, none; moisture, no cloud at -5 deg C ... USP grade contains not less than 99.0% and no more than 99.5% tetrachloroethylene, the remainder consisting of ethanol. ... [R5] *Food Grade [R6] */Tetrachloroethylene (BP) may/ ... contain thymol 0.01% wt/wt as a preservative. [R7, 106] *Tetrachloroethylene Capsules (USP, BP, 1973) [R7, 107] *Tetrachloroethylene Draught (BNF, 1966): tetrachloroethylene 2.5 ml, acacia 2 g, peppermint emulsion 0.3 ml, chloroform water to 50 ml. [R7, 107] *Perklone (ICI Mond, UK): a brand of tetrachloroethylene for dry-cleaning purposes. [R7, 107] MFS: *Dow Chemical USA, Hq 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Plaquemine, LA 70764 [R8] *PPG Industries, Inc, Hq One PPG Place, Pittsburgh, PA 15272, (412) 434-3131; Production site: Chemicals Group, Lake Charles, LA 70601 [R8] *Vulcan Materials Company, Metal Division, Hq, PO Box 530930, Birmingham, AL 35253, (205) 877-3000; Vulcan Chemicals, division, PO Box 7689, Birmingham, AL 35253; Production site: Geismar, LA 70734 [R8] OMIN: *Method of purification: distillation [R9] USE: *For Tetrachloroethylene (USEPA/OPP Pesticide Code: 078501) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R10] *Used in the textile industry for dry-cleaning and for processing and finishing; used in both cold cleaning and vapor degreasing of metals; it is used as a chem intermediate in the synthesis of fluorocarbon 113, 114, 115, and 116; it is used as a heat-exchange fluid [R11] *SCOURING, SIZING AND DESIZING AGENT IN TEXTILE MANUFACTURE [R12] *COMPONENT OF AEROSOL LAUNDRY-TREATMENT PRODUCTS [R12] *SOLVENT, EG, FOR SILICONES [R12] *Insulating fluid and cooling gas in electric transformers [R1] *In typewriter correction fluids (eg, Liquid Paper, Wite-Out, Snopake, etc) [R13] *Formerly used, but no longer approved, in mixtures with grain protectants and certain liquid grain fumigants [R14] *MEDICATION (VET): After the advent of phenothiazine ... little use has been made of the chlorinated hydrocarbons ... /as a ruminant anthelmintic/. Tetrachloroethylene has continued to be used in small animals over the years but has been largely replaced by drugs that are less toxic and easier to admin. [R15] CPAT: *The consumption pattern in the USA in 1974 is est to have been as follows: Textile and dry cleaning industries, 69%; Metal cleaning, 16%; Chemical intermediate (eg, prepn of trichloroacetic acid in some fluorocarbons), 12%; Miscellaneous uses, 3%. [R16] *Demand: (1982), 545 million lb; (1983), 679 million lb; (1987), 625 million lb [R17] *(1974) Dry cleaning and textile processing, 59%; Industrial metal cleaning, 21%; Exports, 11%; Chemical intermed (mostly fluorocarbons), 6%; Other, 3%. [R17] *SOLVENT IN DRY CLEANING, 46%; DEGREASING SOLVENT, 21%; CHEM INTERMED FOR FLUOROCARBONS, 12%; AGENT IN TEXTILE MFR, 7%; COMPONENT OF AEROSOL PRODUCTS, 2%; OTHER, 12% (1980, EST) [R12] *CHEMICAL PROFILE: Perchloroethylene. Demand: 1988: 495 million lb; 1989: 495 million lb; 1993 /projected/: 495 million lb. (Includes exports, but not imports, which totaled 121 million lb last yr). [R18] *CHEMICAL PROFILE: Perchloroethylene. Dry cleaning and textile processing, 50%; chemical intermediate (mostly fluorocarbon F-113), 28%; industrial metal cleaning, 9%; exports, 10%; other, 3%. [R18] *Demand: (1996) 280 million pounds; (1997) 290 million pounds; (2001, projected) 335 million pounds [R19] *(1998) 312 million pounds; (1999) 318 million pounds; (2003) /projected/ 340 million pounds [R20] *Chemical precursor, 50 percent; dry cleaning, 21 percent; metal cleaning and vapor degreasing, 18 percent; other, 11 percent. [R20] PRIE: U.S. PRODUCTION: *(1981) 3.16X10+11 GRAMS [R21] *(1976) 121x10+6 lb [R22] *(1978) 3.34X10+11 G [R12] *(1983) 2.40X10+11 G [R12] *(1985) 3.08X10+11 g [R23] *(1986) 4.05X10+8 LB [R24] *(1987) 4.70X10+8 LB [R24] *(1982) 550 million lb [R25] *(1974) 333,100 tons; (1976) 303,400 tons; (1978) 333,400 tons; (1980) 347,100 tons; (1982) 265,300 tons; (1984) 260,000 tons; (1986) 187,800 tons; (1988) 225,800 tons; (1989) 218,300 tons; (1990) 132,300 tons. [R19] U.S. IMPORTS: *(1977) 5.98X10+10 G [R12] *(1982) 1.70X10+10 G [R12] *(1985) 6.36X10+10 g [R26] *(1986) 1.83X10+5 LB [R27] *61 million pounds in 1996. [R19] U.S. EXPORTS: *(1978) 2.90X10+10 G [R12] *(1983) 2.47X10+10 G [R12] *(1985) 9.84X10+9 g [R28] *48 million pounds in 1996. [R19] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid. [R29, 300] ODOR: *Ether-like odor [R9]; *Mildly sweet, chloroform-like odor [R30]; *Chlorinated solvent odor [R31] BP: *121.3 deg C [R32] MP: *-22.3 deg C [R32] MW: *165.83 [R32] CORR: *Corrosion of aluminum, iron, and zinc, which is negligible unless water is present, can be inhibited by the addition of stabilizers [R33, 52] CTP: *347.1 deg C; 9.74 MPa (to convert MPa to atm, divide by 0.101) [R33, 52] DEN: *1.6227 @ 20 deg C/4 deg C [R32] HTC: *679.9 kJ/mol (constant pressure with formation of aq hydrochloric acid; 831.8 kJ/mol (constant volume at 18.7 deg C) (to convert J to cal, divide by 4.184) [R33, 51] HTV: *90.2 BTU/lb= 50.1 cal/g= 2.10X10+5 J/kg [R30] OWPC: *log Kow= 3.40 [R34] SOL: *Miscible with alcohol, ether, chloroform, benzene [R1]; *Miscible with solvent hexane; dissolves in most of the fixed and volatile oils [R35, 1184]; *0.015 G/100 ML WATER AT 25 DEG C [R5] SPEC: *SADTLER REF NUMBER: 237 (IR, PRISM); 79 (IR, GRATING) [R36]; *Index of Refraction: 1.5053 at 20 deg C/D [R32]; *IR: 4786 (Coblentz Society Spectral Collection) [R37]; *MASS: 1053 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R37] SURF: *31.74 dynes/cm at 20 deg C in contact with vapor [R38] VAPD: *5.7 (AIR= 1) [R39] VAP: *18.5 mm Hg @ 25 deg C [R40] EVAP: *EVAPORATION RATE SLOWER THAN THAT FOR TRICHLOROETHYLENE, ABOUT 3-1. [R39] VISC: *Liquid: 0.932, 0.839, 0.657 and 0.534 CP at 15, 25, 50 and 75 deg C, respectively; Vapor: 9900 CP at 60 deg C [R33, 51] OCPP: *Liquid-water interfacial tension: 44.4 dynes/cm= 0.0444 N/m at 25 deg C [R30] *Conversion factors: 1 mg/l equals 147.4 ppm and 1 ppm equals 6.78 mg/cu m at 25 deg C, 760 mm Hg [R41, 4208] *Partition coefficients at 37 deg C for tetrachloroethylene into blood= 13.1; into oil= 1,920 [R42] *Sat concn in air: 126 g/cu m at 20 deg C, 210 g/cu m at 30 deg C [R43] *DECOMP SLOWLY IN WATER TO YIELD TRICHLOROACETIC AND HYDROCHLORIC ACIDS; OXIDIZED BY STRONG OXIDIZING AGENTS [R5] *Henry's law constant = 0.0177 atm-cu m/mole @ 25 deg C [R44] *Hydroxyl radical rate constant = 1.67X10-13 cu cm/molecule-sec @ 25 deg C [R45] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of tetrachloroethylene stem from its toxicologic properties. Exposure to this colorless liquid may occur from its use as a solvent and as an intermediate in chemical syntheses. In addition to eye and skin inflammation from contacting liquid tetrachloroethylene, inhalation of its vapor can cause central nervous system depression, liver necrosis, and effects on the lung, heart, and kidney. The ACGIH recommends a workplace limit (TLV) of 50 ppm as an 8 hr time-weighted average (TWA) with a note to prevent skin contact. Tetrachloroethylene's sweet chloroform-like odor may warn of its presence at a sub-TLV level of 4.68 ppm; however, to assure against exposure, it is recommended that self-contained breathing apparatus and full protective clothing be worn, especially in fire or spill situations. Although considered nonflammable, containers of tetrachloroethylene may explode in the heat of a fire and its vapor will decompose in contact with open flames or red-heated materials to yield the poisonous gas, phosgene. For small fires involving tetrachloroethylene, extinguish with dry chemical or CO2, and for large fires, use water spray, fog, or foam. Cool containers with water. If the fire involves a tank car or truck, isolate the area for 1/2 mile in all directions. Tetrachloroethylene should be stored in a cool, dry, well-ventilated location, away from strong oxidizers, potential fire hazards, caustic soda, potash, and chemically active metals such as barium, lithium, and beryllium. For small spills of tetrachloroethylene, ventilate the area then take up with vermiculite, dry sand, or earth. Large spills should be diked for later disposal. Prior to implementing land disposal of waste residues (including waste sludge), consult environmental regulatory agencies for guidance. DOT: +Health: Vapors may cause dizziness or suffocation. Exposure in an enclosed area may be very harmful. Contact may irritate or burn skin and eyes. Fire may produce irritating and/or toxic gases. Runoff from fire control or dilution water may cause pollution. [R46] +Fire or explosion: Some of these materials may burn, but none ignite readily. Most vapors are heavier than air. Air/vapor mixtures may explode when ignited. Container may explode in heat of fire. [R46] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. Ventilate closed spaces before entering. [R46] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R46] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R46] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R46] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Stop leak if you can do it without risk. Small liquid spills: Take up with sand, earth or other noncombustible absorbent material. Large spills: Dike far ahead of liquid spill for later disposal. Prevent entry into waterways, sewers, basements or confined areas. [R46] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R46] FLPT: *No flash point in conventional closed tester. [R47] FIRP: *Approach from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray to keep fire-exposed containers cool. Use flooding quantities of water as fog or spray. Extinguish fire using agent suitable for surrounding fire. [R47] TOXC: *Combustion by-products may include hydrogen chloride and phosgene. [R47] EXPL: *Mixtures with lithium shavings ... are impact-sensitive and will explode, sometimes violently. [R48, 1315] *The presence of 0.5% of trichloroethylene as impurity in tetrachloroethylene during unheated drying over solid sodium hydroxide caused the generation of dichloroacetylene. After subsequent fractional distillation, the volatile fore-run exploded. [R48, 211] *Mixtures of /dinitrogen/ tetraoxide with ... tetrachloroethylene are explosive when subjected to shock of 25 g TNT equivalent or less. [R48, 1352] REAC: *Granular barium in contact with ... tetrachloroethylene ... is susceptible to detonation. [R48, 78] *Reacts with metals to form explosive mixtures; Sodium hydroxide, possible explosion. [R49, 696] *Several cases of violent reaction between aluminum and ... tetrachloroethylene in vapor degreasers have been noted. [R48, 26] *Strong oxidizers; chemically-active metals such as lithium, beryllium, and barium; caustic soda; sodium hydroxide; potash. [R29, 300] *Strong oxidizers; chemically active metals such as lithium, beryllium and barium; caustic soda; sodium hydroxide; potash. [R29, 300] DCMP: *When in contact with activated charcoal decomposes to form hexachloroethane and hexachlorobenzene at 700 deg C. [R50] *... decomposes slowly in contact with moisture to yield trichloroacetic acid and hydrochloric acid [R51] *It affords various decomp products depending on conditions, but mostly hydrogen chloride and phosgene. [R52, p. 5(79) 754] *... If involved in a fire decomposes to produce hydrogen chloride and phosgene. [R47] ODRT: *The distinctive odor of tetrachloroethylene does not necessarily provide adequate warning. Because tetrachloroethylene quickly desensitizes olfactory responses, persons can suffer exposure to vapor concentrations in excess of TLV limits without smelling it. [R52, p. 5(79) 761] *Recognition in air: 4.68 ppm (chemically pure) [R53] *Perchloroethylene has a not unpleasant etheral or aromatic odor. ... 50 ppm, odor threshold (very faint) to unacclimated; no physiological effects (8 hr). 100 ppm, odor (faint) definitely apparent to unacclimated; very faint to not perceptible during exposure; no physiological effects (8 hr). 200 ppm, odor (definite) moderate to faint upon exposure; faint to moderate eye irritation; minimal light-headedness; (eye irritation threshold 100-200 ppm). 400 ppm, odor (strong) unpleasant; definite eye irritation, slight nasal irritation; definite incoordination (2 hr). 600 ppm, odor (strong) very unpleasant but tolerable; definite eye and nasal irritation; dizziness, loss of inhibitions (10 min). 1000 ppm, odor (very strong) intense, irritating; markedly irritating to eyes and resp tract; considerable dizziness (2 min). 1500 ppm, odor (almost intolerable) "gagging"; irritation almost intolerable to eyes and nose; complete incoordination within minutes to unconsciousness within 30 min. [R41, 4240] SERI: *Eye exposure can lead to conjunctivitis; Skin exposure can lead to inflamation; Inhalation can lead to respiratory tract irritation. [R49, 507] *Tetrachloroethylene vapor is a mucous membrane and upper resp irritant at levels above 75 to 100 ppm. [R54, 986] EQUP: *FOR HIGH VAPOR CONCN USE APPROVED CANISTER OR AIR-SUPPLIED MASK; CHEMICAL GOGGLES OR FACE SHIELD; PLASTIC GLOVES. [R30] *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R55, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R29, 300] *Wear appropriate eye protection to prevent eye contact. [R29, 300] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R29, 300] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R29, 300] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full face piece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R29, 300] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R29, 300] OPRM: *Contact lenses should not be worn when working with this chemical. [R29, 300] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R29, 301] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R55, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R55, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R55, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R55, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R55, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R55, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres for chem such as nitrosamines. Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R55, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R55, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R55, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R29, 300] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R29, 300] SSL: *RAPIDLY DETERIORATES IN WARM CLIMATES [R56, 1031] *Tetrachloroethylene is stable up to 500 deg C in the absence of catalysts, moisture, and oxygen. [R51] *THE MATERIAL IS EXTREMELY STABLE AND RESISTS HYDROLYSIS [R57] *PURE CMPD IS SLOWLY DECOMP BY VARIOUS METALS IN PRESENCE OF MOISTURE [R35, 1177] *The physical stability of emulsions of tetrachloroethylene can be enhanced by diluting the tetrachloroethylene with arachis oil before emulsification. This practice may be harmful because the oil increases the absorption, and thus the toxicity, of the drug. [R7, 107] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R55, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R55, 1979.13] *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R58] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R59] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R60] STRG: *STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM ACTIVE METALS. ISOLATE FROM OPEN FLAMES, AND COMBUSTIBLES. [R47] *It is stored in mild steel tanks equipped with breathing vents and chemical driers. It can be transferred through seamless black iron pipes, with gasketing materials of compressed asbestos, asbestos reinforced with metal, or asbestos impregnated with Teflon or Viton, employing centrifugal or positive displacement pumps of cast iron or steel construction. Small quantities ... may be stored safely in green or amber glass containers. [R52, p. 5(79) 759] *TEMPERATURE: AMBIENT. VENTING: PRESSURE-VACUUM. [R30] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R55, 1979.13] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. COLLECT FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR MATERIAL. [R61, 1981.4] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R55, 1979.15] *Approach release from upwind. Stop or control the leak, if this can be done without undue risk. Control runoff and isolate discharged material for proper disposal. [R47] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F002; U210, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R62] *TETRACHLOROETHYLENE MAY BE DISPOSED OF BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL AND DISPOSING IN A SECURED SANITARY LANDFILL /SRP: MORE DESIRABLE METHODS OF DISPOSAL ARE AVAILABLE/ [R61, 1981.5] *... Tower aeration is the most cost-effective technique for removing volatile organic chlorine chemicals from drinking water. /Volatile organic chlorine chemicals/ [R63] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R55, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": Total destruction ... by incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose.The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R55, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R55, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R55, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating, or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols, and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R55, 1979.17] *Chemical Treatability of Tetrachloroethylene; Concentration Process: Activated carbon; Chemical Classification: Halocarbon; Scale of Study: Laboratory scale; Type of Wastewater Used: Well water; Results of Study: Performance for treatment of water containing several halogens. Virgin: 5100 BV to 33 ppb compound leakage; 13.3 days; gal treated/cu ft sorbent, 38,250. Regenerated: 4000 BV to 33 ppb compound leakage; 10.4 days; gal treated/cu ft sorbent, 30.0; (column studies 14 mm diameter glass tubes, height 4 in (15 cu cm absorbent) Flow-2 gpm/cu ft (16 BV/hr) regenerated at 37 lb steam/cu ft @ 5 psig). [R64] *Chemical Treatability of Tetrachloroethylene; Concentration Process: Resin Adsorption; Chemical Classification: Halocarbon; Scale of Study: Laboratory Scale; Type of Wastewater Used: Well Water; Comments: Column studies: 14 mm diameter glass tubes, height 4 in (15 cu cm adsorbent) Flow-2 gpm/cu ft (16 BV/hr) regenerated at 37 lb steam/cu ft @ 5 psig. [R65] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R66] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. Alternatively, it may be recovered from waste gases and reused. Recommendable method: Incineration. [R67] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is limited evidence in humans for the carcinogenicity of tetrachloroethylene. There is sufficient evidence in experimental animals for the carcinogenicity of tetrachloroethylene. Overall evaluation: Tetrachloroethylene is probably carcinogenic to humans (Group 2A). In making the overall evaluation, the working group considered the following evidence: (1) Although tetrachloroethylene is known to induce peroxisome proliferation in mouse liver, a poor quantitative correlation was seen between peroxisome proliferation and tumor formation in the liver after administration of tetrachloroethylene by inhalation. The spectrum of mutations in proto-oncogenes in liver tumors from mice treated with tetrachloroethylene is different from that in liver tumors from mice treated with trichloroethylene. (2) The cmpd induced leukemia in rats. (3) Several epidemiological studies showed elevated risks for esophageal cancer, non-Hodgkin's lymphoma and cervical cancer. [R68] *A3. A3= Animal carcinogen. [R69] ANTR: *Basic treatment: .Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with sterile dressings after decontamination ... . /Carbon tetrachloride and related compounds/ [R70, p. 194-5] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of myocardial irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Carbon tetrachloride and related compounds/ [R70, 195] MEDS: *Periodical exam of the liver and kidneys. [R49, 508] *Exhaled air was analyzed for tetrachloroethene in teachers and 4-5 year old pupils of a kindergarten situated near a factory, and in residents of an old folks home situated near a former chemical waste dump. The tetrachloroethene concentrations were higher in the exhaled air of children living near the factory (mean 24 ug/cu m, n= 6) than in control children (mean 2.8 ug/cu m, n= 11). In the old folks home, the tetrachloroethene concentrations in the exhaled air of people living on the first floor were higher (mean 7.8 ug/cu m, n= 10) than in the exhaled air of the people living on the second floor and higher (mean 1.8 ug/cu m, n= 19). From the results of this study, it is clear that in environmental exposure to tetrachloroethene, biological monitoring of exhaled air is a simple, efficient, effective, and convenient method of assessing total ambient exposure of both young and aged subjects. [R71] *PRECAUTIONS FOR "CARCINOGENS": ... in relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may precede them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical Carcinogens/ [R55, 1979.23] HTOX: *... acute hepatic necrosis and oliguric uremia have followed human exposure. [R72] */CNS depressant/ ... in high concentrations. Defatting action on skin can lead to dermatitis. [R73] *Excessive exposure ... has resulted in effects on the central nervous system, mucous membranes, eyes, and skin, and to a lesser extent the lungs, liver, kidneys. The effects most frequently noted have been on the nervous system. Unconsciousness, dizziness, headache, vertigo or light ... /CNS depression/ have occurred in many instances after occupational exposures. [R74] *Perchloroethylene has been reported to produce effects on the liver in humans. The concn ... generally appeared to be in excess of 100 ppm. [R75] *Several studies of the effects of prolonged exposure to perchloroethylene vapors on human volunteers are avail. ... Prolonged exposure to 200 ppm results in early signs of CNS depression, while there was no response in men or women repeatedly exposed to 100 ppm for 7 hr/day. Clinical chemical studies indicate no liver or kidney effects at these levels but massive exposure to concentrations causing unconsciousness have resulted in proteinuria and hematuria. [R74] *A CASE OF CNS DEPRESSION AND 2 CASES OF ACUTE OLIGURIC UREMIA AFTER INHALATION OF PERCHLORETHYLENE VAPORS FROM NEWLY CLEANED CLOTHES IN A SELF-SERVICE DRY-CLEANING MACHINE ARE REPORTED. [R76] *A PT IS REPORTED WHO HAD A CONNECTIVE TISSUE TYPE OF DISEASE CLINICALLY SIMILAR TO VINYL CHLORIDE DISEASE, POSSIBLY CAUSED BY ABNORMAL SENSITIVITY TO PERCHLORETHYLENE TO WHICH HE WAS EXPOSED IN HIS OCCUPATION. [R77] *CHANGES IN NEUROLOGICAL NATURE OF WORKERS EXPOSED TO TETRACHLOROETHYLENE AT GREATER THAN MAC (MAXIMUM PERMISSIBLE CONCENTRATION) WERE RELATED TO DEFECTIVE ACTION OF LIVER AND SUPRARENAL GLAND CORTEX. INCR IN AMINOTRANSFERASE IN BLOOD SERUM AND SLIGHT SHIFTS IN PROTEINOGRAMS OBSERVED. [R78] *SIX WK OLD BREAST-FED INFANT HAD OBSTRUCTIVE JAUNDICE AND HEPATOMEGALY. TETRACHLOROETHYLENE WAS DETECTED IN MILK AND BLOOD. AFTER DISCONTINUANCE OF BREAST-FEEDING RAPID CLINICAL AND BIOCHEM IMPROVEMENT WERE NOTED. [R79] *LYMPHOCYTES FROM 10 FACTORY WORKERS EXPOSED TO TETRACHLOROETHYLENE FOR 3 MO TO 18 YR SHOWED NO SIGNIFICANT DOSE-RELATED CHANGES IN CHROMOSOME ABERRATIONS, SISTER CHROMATID EXCHANGE RATE, PROPORTION OF M2+M3 METAPHASES OR MITOTIC INDEX, COMPARED WITH CONTROLS. [R80] *A new form of substance abuse in adolescents is the inhalation of fumes from typewriter correction fluids (Liquid Paper, Wite-Out, Snopake, etc), which are composed of various chlorinated solvents, /including tetrachloroethylene/, to induce euphoria. Medical complications of such abuse and medical management of acute toxic episodes are discussed herein, along with suggestions for controlling this substance abuse. [R13] *After ingestion of 12-16 g tetrachloroethylene, a 6 year old boy was admitted to the clinic in coma. In view of the high initial tetrachloroethylene blood level, hyperventilation therapy was performed. Under this therapeutic regimen, the clinical condition of the patient improved considerably. The tetrachloroethylene blood level profile which was determined under hyperventilation therapy could be computer fitted to a two compartment model. Elimination of tetrachloroethylene from the blood compartment occurred via a rapid and a slow process with half-lives of 30 min and 35 hours, respectively. These values compared favorably with the half-lives of 160 min and 33 hours under normal respiratory conditions. During hyperventilation therapy, the relative contribution to the fast elimination process increased from 70% for physiological minute volume to 99.9%. A minor fraction of the ingested dose was excreted with the urine (integral of 1% during the first 3 days). In contrast to previous results, trace amounts of unchanged tetrachloroethylene were detected in the urine besides trichloroacetic acid and trichloroethanol. [R81] *Pulmonary edema occurred in a laundry worker who was found unconscious after exposure to tetrachloroethylene vapor. ... Multiple premature ventricular contractions in otherwise healthy workers have been reported in occupational tetrachloroethylene exposures, but no direct link with sudden death has been made. Chronic exposure has not produced cardiovascular toxicity. [R54, p. 986-7] *A 68 year old launderette worker was anesthetised and suffered erythema and 30% superficial burns after spilling a container of tetrachloroethylene over his clothes. The defatting property of tetrachloroethylene would lead to cracking of damaged skin. [R7, 107] *A 21 year old man who had been exposed to fumes of tetrachloroethylene developed acute pulmonary edema and became comatose. He received isoprenaline 800 ug in 1 l of dextrose injection iv, furosemide 40 mg, aminophylline 250 mg, and dexamethasone 10 mg iv. Oxygen was admin. After 6 hr, improvement was noted. No evidence of liver or kidney damage was seen. [R7, 107] *... Residual organ damage is not commonly observed in humans who have been exposed to large quantities of the compound. Tetrachloroethylene was formerly used widely as an intestinal anthelminthic. ... Oral doses of 2.8 to 4.0 ml given for this purpose were quite effective and safe. Inebriation was the only troublesome side effect that was noted in 46,000 treated patients. Inhalation of tetrachloroethylene sufficient to produce inebriation and unconsciousness has failed to elicit hepatic, renal, or hematological abnormalities in some individuals. However, in other cases, mild to severe hepatotoxicity has been diagnosed. In most such instances, liver injury was not manifest until several days after exposure. Recovery was uneventful, but sometimes prolonged, particularly in the more severe cases. Tetrachloroethylene was quite slowly eliminated, in that approx 1 ppm tetrachloroethylene was measured in the breath of victims as long as 11 to 12 days after exposure. Little evidence of kidney injury or damage of any other organ was noted in any of the aforementioned cases. ... [R82, 136] *Acute exposure to tetrachloroethylene by inhalation results in central nervous system depression. Liver and kidney toxicity have been reported as effects of acute exposures to very high doses. In dry cleaners chronically exposed to tetrachloroethylene, incr levels of markers of early renal damage and/or dysfunction were attributed to the exposure. [R83] *To evaluate the risk of cancer and other diseases among workers engaged in aircraft manufacturing and potentially exposed to cmpds containing chromate, trichloroethylene (TCE), perchloroethylene (PCE), and mixed solvents. A retrospective cohort mortality study was conducted of workers employed for at least 1 year at a large aircraft manufacturing facility in California on or after 1 January 1960. The mortality experience of these workers was determined by exam of national, state, and company records to the end of 1996. Standardised mortality ratios (SMRs) were evaluated comparing the observed numbers of deaths among workers with those expected in the general population adjusting for age, sex, race, and calendar year. The SMRs for 40 cause of death categories were computed for the total cohort and for subgroups defined by sex, race, position in the factory, work duration, yr of first employment, latency, and broad occupational groups. Factory job titles were classified as to likely use of chemicals, and internal Poisson regression analyses were used to compute mortality risk ratios for categories of yr of exposure to chromate, TCE, PCE, and mixed solvents, with unexposed factory workers serving as referents. RESULTS: The study cohort comprised 77,965 workers who accrued nearly 1.9 million person-years of follow up (mean 24.2 yr). Mortality follow up, estimated as 99% complete, showed that 20,236 workers had died by 31 December 1996, with cause of death obtained for 98%. Workers experienced low overall mortality (all causes of death SMR 0.83) and low cancer mortality (SMR 0.90). No significant increases in risk were found for any of the 40 specific cause of death categories, whereas for several causes the numbers of deaths were significantly below expectation. Analyses by occupational group and specific job titles showed no remarkable mortality patterns. Factory workers estimated to have been routinely exposed to chromate were not at increased risk of total cancer (SMR 0.93) or of lung cancer (SMR 1.02). Workers routinely exposed to TCE, PCE, or a mixture of solvents also were not at increased risk of total cancer (SMRs 0.86, 1.07, and 0.89, respectively), and the numbers of deaths for specific cancer sites were close to expected values. Slight to moderately increased rates of non-Hodgkin's lymphoma were found among workers exposed to TCE or PCE, but none was significant. A significant incr in testicular cancer was found among those with exposure to mixed solvents, but the excess was based on only six deaths and could not be linked to any particular solvent or job activity. Internal cohort analyses showed no significant trends of increased risk for any cancer with increasing years of exposure to chromate or solvents. The results from this large scale cohort study of workers followed up for over 3 decades provide no clear evidence that occupational exposures at the aircraft manufacturing factory resulted in increases in the risk of death from cancer or other diseases. Our findings support previous studies of aircraft workers in which cancer risks were generally at or below expected levels. [R84] NTOX: *UNCONSCIOUSNESS WAS OBSERVED IN RATS WITHIN FEW MIN @ CONCN OF 6000 PPM OR MORE AND AFTER SERVERAL HOURS AT 3000 PPM, BUT UNCONSCIOUSNESS WAS NOT OBSERVED AT 2000 PPM. AT THESE HIGH-LEVEL SINGLE EXPOSURES, THE PREDOMINANT RESPONSE WAS ... DEPRESSION OF NERVOUS SYSTEM. THERE WERE SLIGHT CHANGES IN LIVER, CHARACTERIZED BY SLIGHT INCR IN WT, SLIGHT INCR IN TOTAL LIPID, AND SLIGHT CLOUDY SWELLING. [R85] *EXCESSIVE ABSORPTION OF DRUG WILL RESULT IN DIZZINESS AND INCOORDINATION ... AND EVEN DEATH. [R86] *IN HOST MEDIATED ASSAY IN MICE, USING SALMONELLA TYPHIMURIUM TA1950, TA1951 AND TA1952, THERE WAS A SIGNIFICANT INCR IN NUMBER OF REVERTANTS WITH DOSES EQUIV TO LD50 AND HALF THE LD50, BUT THIS WAS NOT DOSE RELATED. ... THERE WAS NO INDUCTION OF CHROMOSOMAL ABERRATIONS IN BONE MARROW CELLS OF MICE THAT HAD RECEIVED EITHER SINGLE (HALF LD50) OR 5 DAILY IP INJECTIONS (1/6 LD50) OF ... /TETRACHLOROETHYLENE/. [R87] *... pregnant mice and rats /were exposed/ to concn of 300 ppm. Both species were exposed for /periods of/ 7 hours daily, on days 6 through 15 of gestation. No fetal toxicity or teratogenicity was detected. [R88] *... behavioral tests /were performed/ on the offspring of rats exposed to 100 ppm for 7 hr daily on days 14-20 of gestation ... no changes ... /were observed in/ the control pups. At exposure levels of 900 ppm the maternal animals gained less weight and the offspring performed less well on neuromotor tests and had lower levels of brain acetylcholine and dopamine. Pair fed controls were not used. [R88] *GROUPS OF 50 MALE AND 50 FEMALE B6C3F1 MICE, APPROX 5 WK OLD ... WERE ADMIN TETRACHLOROETHYLENE IN CORN OIL BY GAVAGE ON 5 CONSECUTIVE DAYS/WK FOR 78 WK. ... TIME-WEIGHTED AVG DOSES WERE 536 AND 1072 MG/KG BODY WT/DAY IN MALES AND 386 AND 772 MG/KG BODY WT/DAY IN FEMALES. GROUPS OF 20 MALE AND 20 FEMALE MICE WERE EITHER UNTREATED OR RECEIVED CORN OIL ALONE. ... THE SHORTER LIFESPAN IN TREATED ANIMALS WAS DUE TO EARLY TOXICITY AND HIGH INCIDENCES OF HEPATOCELLULAR CARCINOMAS IN ANIMALS OF BOTH SEXES ... [R89] *... ONLY A NEARLY LETHAL /ORAL/ DOSE (4 G/KG BODY WT) CAUSED SWELLING OF THE CONVOLUTED /KIDNEY/ TUBULES AND HYDROPIC DEGENERATION IN MALE MICE ... IP DOSES OF 1.6-2.3 G/KG BODY WT ... CAUSED SLIGHT CALCIFICATION OF THE TUBULES OF THE KIDNEY IN DOGS ... [R90] *MALE RATS WERE EXPOSED FOR 4 HR TO VARIOUS CONCN OF TETRACHLOROETHYLENE. THE ENZYMES SGOT, SGPT, AND OCT WERE MARKEDLY ELEVATED AS A RESULT OF EXPOSURE. [R91] *Rats inhalation: No pathological effects @ 70 ppm, 8 hr/day, 5 days/wk, 7 mo; Some pathological changes in liver and kidneys @ 230 ppm, 8 hr/day, 5 days/wk, 7 mo. [R92] */Tetrachloroethylene was not/ mutagenic ... in 2 strains of Salmonella typhimurium in the presence of a postmitochondrial mouse liver supernatant, following exposure to vapors ... [R93] *The cardiac effects of tetrachloroethylene ... were studied in several species. To standardize the dosimetry, tetrachloroethylene was prepared for iv injection in soln of Tween 80, which had no demonstratable cardiotoxicity. In rabbits under urethane anesthesia and in cats and dogs under pentobarbital anesthesia, tetrachloroethylene increased the vulnerability of the ventricles to epinephrine induced extrasystoles, bigeminal rhythms, and tachycardia. The mean threshold doses of tetrachloroethylene were 10 mg/kg in rabbits, 24 mg/kg in cats, and 13 mg/kg in dogs. In rabbits this threshold dose for cardiac arrhythmias corresponded to blood levels between 2.2 and 3.6 ug/ml. Animals demonstrating a reflex bradycardia to vasopressor doses of epinephrine were relatively resistant to the arrhythmogenic action of tetrachloroethylene. Ventricular arrhythmias occurred in less than 30% of the animals after tetrachloroethylene alone. In cats higher doses of tetrachloroethylene (40 mg/kg) produced acute pulmonary edema. Tetrachloroethylene (30-40 mg/kg) decreased left intraventricular dP/dt (max) in dogs, without significantly increasing left intraventricular end diastolic pressure, although there was a transient decrease in arterial blood pressure that accompanied the early phase of myocardial depression. [R94] *A study was designed to determine the effects of tetrachloroethylene on the phyto- and zooplankton community at initial concentrations of 1.2 and 0.44 mg/l in separated compartments of an experimental pond. Measurements in the surrounding water were made simultaneously to detect possible effects of compartmentalization. Residues as low as 0.1 mg/l could be analyzed 5 days (low dose) and 38 days (high dose) post-application. In all applied biotopes, a lethal effect on the Daphnia population was detected. The phytoplankton community showed an increase of relative abundance and a decrease in species diversity. Studies of the frequency distribution of 6 selected phytoplankton species. (Spirogyra species, Microcystis flos-aquae, Stichococcus bacillaris, Nitzschia acicularis, Chilomonas parameium, Actinophrys species) demonstrated the total elimination of at least 4 species from the treated compartments. In spite of different dosing, only weak differences were found in toxic effects between the low and high dosed compartments. No significant chemically induced effect was observed on the physicochemical properties of the treated water. [R95] *Exptl momentary spraying of rabbits eyes with tetrachloroethylene from a pressurized fire extinguisher from a distance of 1 foot caused immediate pain and blepharospasm. The corneal epithelium became granular and optically irregular, and patches of epithelium were lost, but the eyes recovered completely within 2 days. [R96] *Results of the mutagenicity test using L5178Y mouse lymphoma cells were positive for tetrachlorethylene. [R97] *Oxidative DNA damage is emerging as an biomarker of effect in studies assessing the health risks of occupational chemicals. Trichloroethylene (TCE) and perchloroethylene (PERC) are used in the dry cleaning industry and their metab can produce reactive oxygen cmpds. The present study examined the potential for TCE AND PERC to induce oxidative DNA damage in rats that was detectable as increased urinary excretion of 8-hydroxydeoxyguanosine (8OHdG). Thiobarbaturic acid reactive substances (TBARS) and 8-epiprostaglandin F2alpha (8epiPGF) were also measured as biomarkers of increased oxidative stress. Male Fischer rats were admin a single i.p. injection of 0, 100, 500, or 1000 mg/kg of PERC or TCE. Control rats received only vehicle (1:4 v/v of Alkamuls/water). A positive control group received 100 mg/kg 2-nitropropane (2NP). Rats were sacrificed 24 hr after dosing. In rats receiving 2NP or TCE but not PERC, TBARS and the 8OHdG/dG ratios were significantly elevated in liver. Lymphocyte 8OHdG/dG was not affected significantly by 2NP, TCE or PERC. In rats receiving 2NP, urinary excretion of 8OHdG AND 8epiPGF2 were significantly increased. In rats receiving TCE or PERC, significant increases in 8epiPGF2 or 8OHdG were not evident. Results indicate that a single high dose of TCE, but not PERC, can induce an increase in oxidative DNA damage in rat liver. However, the usefulness of 8OHdG as a biomarker of TCE-induced oxidative DNA damage is questionable. [R98] *Rats, rabbits, and monkeys withstood 7 hr exposures to 400 ppm tetrachloroethylene vapor 5 days/week for 6 months without apparent adverse effects on mortality, growth, body and organ weights, and periodic clinical chemistry determinations. However, guinea pigs could tolerate repeated 7 hr exposures at concentrations no higher than 100 ppm. [R99] *Rats died within a few minutes of inhaling a vapor concentration of 30,000 ppm tetrachloroethylene and in about 30 min at 19,000 ppm. Death was narcotic in nature. A series of essentially straight lines was obtained when log concentration was plotted against log time for exposures to tetrachloroethylene that were just sufficient to cause lethality in rats, just small enough to be survived by all rats, and just small enough to cause no organic injury. A concentration of 2000 ppm was tolerated for up to 14 hr, and 3000 ppm was tolerated for 4 hr with no deaths. Unconsciousness was produced in rats within a few minutes at concentrations of 6000 ppm or greater and after several hr at 3000 ppm was tolerated for 4 hr with no deaths. Unconsciousness was produced in rats within a few minutes at concentrations of 6000 ppm or greater and after several hours at 3000 ppm, but unconsciousness was not observed at 2000 ppm. [R99] NTXV: *LD50 Oral Mouse 6000-8571 mg/kg body weight LD50 Oral Rat 2400-13000 mg/kg bw; [R83] *LC50 Rat inhalation 4100 ppm/6 hr LC50 Rat inhalation 5000 ppm/8 hr LC50 Mouse inhalation 5200 ppm/4 hr LC50 Mouse inhalation 2978 ppm/6 hr; [R83] ETXV: *LC50 Poecilia reticulata (guppy) 18 ppm/7 days /Conditions of bioassay not specified/; [R92] *LC50 Pimephales promelas (fathead minnow) 18.4 mg/l/96 hr (flow-through bioassay); [R92] *LC50 Pimephales promelas (fathead minnow) 21.4 mg/l/96 hr (static bioassay); [R92] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL SUNFISH) 46 MG/L/24 HR AT 21-23 DEG C (95% CONFIDENCE LIMIT 11-15 MG/L) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R100] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL SUNFISH) 13 MG/L/96 HR AT 21-23 DEG C (95% CONFIDENCE LIMIT 11-15 MG/L) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R100] *LC50 Daphnia magna (water flea) 18 mg/l/48 hr, static bioassay, at 22 deg C; [R101] *LC50 Salmo gairdneri (rainbow trout) 5 mg/l/96 hr, static bioassay at 12 deg C; [R102] *LC50 Limanda limanda (dab) 5 mg/l/96 hr, flow-through bioassay; [R103] *LC50 Tanytarsus dissimilis (midge) 30, 840 ug/l/48 hr, static bioassay; [R104] *LC50 Lepomis macrochirus (bluegill sunfish) 12,900 ug/l/96 hr, static bioassay; [R105] NTP: *The bioassay of USP grade tetrachloroethylene for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Tetrachloroethylene in corn oil was admin by gavage at either of two dosages to groups of 50 male and 50 female animals of each species, 5 days/wk, over a period of 78 wk followed by an observation period of 32 wk for rats and 12 wk for mice. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The high and low time weighted avg dosages of tetrachloroethylene in the chronic study were 941 and 471 mg/kg/day for the male rats, 949 and 474 mg/kg/day for the female rats, 1072 and 536 mg/kg/day for the male mice, and 772 and 386 mg/kg/day for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same time that dosed animals were gavaged with tetrachloroethylene mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage treatments. No significant incr incidence of neoplastic lesions was observed in treated rats. ... In both male and female mice, admin of tetrachloroethylene was associated with a significantly incr incidence of hepatocellular carcinoma. Hepatocellular carcinomas were observed in 2/17 (12%) untreated control males, 2/20 (10%) untreated control females, 0/20 vehicle control females, 19/48 (40%) low dose females, and 19/48 (40%) high dose females. Hepatocellular carcinomas metastasized to the kidney in one untreated control male and to the lung in three low dose males, one low dose female, and one high dose female. ... The results of the bioassay of tetrachloroethylene in Osborne-Mendel rats do not allow an evaluation of the carcinogenicity of this cmpd due to the high rate of early death among the treated animals. However, under the condition of this study, tetrachloroethylene was a liver carcinogen in B6C3F1 mice of both sexes. Levels of Evidence of Carcinogenicity: Male Rats: Inadequate study; Female Rats: Inadequate study; Male Mice: Positive; Female Mice: Positive. [R106] *Toxicology and carcinogenesis studies of tetrachloroethylene (99.9%) pure were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hr/day 5 days/wk for 103 wk. The exposure concn used (0, 200 or 400 ppm for rats and 0, 100 or 200 ppm for mice) were selected on the basis of results from a 13 wk inhalation study. ... During the 2 yr studies, exposure to tetrachloroethylene did not consistently affect body wt gains in either rats or mice. ... Both concns of tetrachloroethylene were associated with incr incidences of mononuclear cell leukemia in male rats (28/50; 37/50; 37/50). In female rats, tetrachloroethylene incr the incidence of leukemia (18/50; 30/50; 29/50) and decr the time to occurrence of the disease. Tetrachloroethylene produced renal tubular cell karyomegaly in male and female rats, renal tubular cell hyperplasia in male rats, and renal tubular cell adenomas and adenocarcinomas (combined) in male rats (1/49; 3/49; 4/50). The incidence of renal tubular cell tumors was statistically significant; these uncommon tumors have been consistently found at low incidences in male rats in other 2 yr studies of chlorinated ethanes and ethylenes. One low dose male rat had a kidney lipoma, and another had a nephroblastoma. Four high dose male and two high dose female rats had gliomas of the brain, whereas one control male and one control female had this tumor. In male and female mice, tetrachloroethylene caused dose related incr in the incidences of hepatocellular neoplasms. In males, tetrachloroethylene at 200 ppm incr the incidence of hepatocellular adenomas (11/49; 8/49; 18/50) and at both concn incr the incidence of hepatocellular carcinomas (7/49; 25/49; 26/50). In female mice, tetrachloroethylene at both concn incr the incidences of hepatocellular carcinoma (1/48; 13/50; 36/50). Tetrachloroethylene also produced renal cell karomegaly in both sexes of mice, and one low dose male mouse had a tubular cell adenocarcinoma. In these inhalation studies, there was no neoplastic changes in the respiratory tracts of either species, but there was an incr in the incidence of squamous metaplasia in the nasal cavities in dosed male rats (0/50; 5/50; 5/50). ... Under the conditions of these 2 yr inhalation bioassays, there was clear evidence of the carcinogenicity of tetrachloroethylene for male F344/N rats as shown by incr incidence of mononuclear cell leukemia and uncommon renal tubular cell neoplasms. There was some evidence of carcinogenicity of tetrachloroethylene for female F344/N rats as shown by incr incidences of mononuclear cell leukemia. There was clear evidence of carcinogenicity for B6C3F1 mice as shown by incr incidences of both hepatocellular adenomas and carcinomas in males and of hepatocellular carcinomas in females. [R107] TCAT: ?The ability of tetrachloroethylene to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation assay) was evaluated. Based on preliminary toxicity test determinations (exposure time=3 days), tetrachloroethylene was tested at 0, 2, 10, 50 and 250 ug/ml, with cell survival ranging from 100% to 51% relative to untreated controls. None of the tested concentrations produced significantly greater transformation frequencies relative to untreated controls. [R108] ?The mutagenicity of tetrachloroethylene was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Tetrachloroethylene did not cause a positive response in any of the tester strains with or without added metabolic activation. Tetrachloroethylene was evaluated using a protocol in which the test article was usually tested over a minimum of 6 dose levels, the highest nontoxic dose level being 10 mg/plate unless solubility, mutagenicity or toxicity dictated a lower upper limit. [R109] ?The ability of tetrachloroethylene to induce DNA repair in the hepatocyte primary culture (HPC) system was evaluated using hepatocytes from male B6C3F1 mice and Osborne-Mendel rats. In both the mouse and rat HPC/DNA repair assays, tetrachloroethylene was cytotoxic from 0.01% to 0.1% and was not genotoxic from 0.001% to 0.00001%. [R110] POPL: *... individuals with diseases of the heart, liver, kidneys, and lung. [R49, 508] ADE: *... READILY ABSORBED THROUGH THE LUNG AND TO A MUCH SMALLER DEGREE THROUGH SKIN OR MUCOUS MEMBRANES OR FOLLOWING INGESTION. [R111] *METABOLISM ... IS RELATIVELY SLOW WITH ONLY FEW PERCENT OF DOSE BEING EXCRETED AS METABOLITES, MAJOR ONE BEING TRICHLOROACETIC ACID ... [R112] *(36)CL-TETRACHLOROETHYLENE FED TO RATS IS EXCRETED LARGELY UNCHANGED IN EXPIRED AIR (98% OF DOSE IN 2 DAYS), AND IS METABOLIZED, TO ONLY SLIGHT EXTENT, INTO TRICHLOROACETIC ACID (2%) WHICH IS EXCRETED IN URINE. [R113] *Concn curves of perchloroethylene in blood and exhaled air after exposure showed that it was eliminated from the body at three different rates with corresponding half-life. [R114] *Personal monitoring of exposure to tetrachloroethylene ... and analyses of urine for total trichloro-compounds were carried out in two groups of workers ... one group (20 males and 19 females) in dry-cleaning workshops and the other (16 males and 6 females) engaged in the removal of glue from silk cloth. Comparison of the urinary trichloro-compounds levels with tetrachloroethylene in the environment revealed that, while the metabolite levels increased essentially linear to tetrachloroethylene concn up to 100 ppm, leveling off was apparent in the metabolite excretion when the exposure to tetrachloroethylene was more intense (eg more than 100 ppm), indicating that the capacity of humans to metabolize tetrachloroethylene is rather limited. A tentative calculation ... indicated that, at the end of an 8 hr shift with exposure to tetrachloroethylene at 50 ppm (TWA), 38% of the tetrachloroethylene absorbed through the lung would be exhaled unchanged and less than 2% would be metabolized to be excreted into the urine, while the rest would remain in the body to be eliminated later. [R115] *Tetrachloroethylene was still detectable in the breath of rats 16 hr after a single exposure to levels of 339-3390 mg/cu m for 1-40 hr. [R116] *Male Sprague-Dawley rats exposed to (14)C-tetrachloroethylene by either gavage (1.0 mg/kg) or inhalation (10 ppm, 10.4 mg/kg) excreted 70% of the dose unchanged in expired air. Approximately 3% was excreted as carbon dioxide, and approximately 23% was excreted in the urine and feces as nonvolatile metabolites. [R117] *Once in the bloodstream, tetrachloroethylene tends to distribute to body fat. In human tissue at autopsy, ratios of fat to liver concentrations are greater than 6:1 [R118] *An autopsy after a fatal tetrachloroethylene exposure revealed an 8 times greater concn in brain compared with blood ... [R54, 986] *Tetrachloroethylene (PCE) is eliminated primarily via the lung. The respiratory half-life for PCE elimination has been estimated at 65 to 70 hours. [R119] *Tetrachloroethylene reached near steady-state levels in blood of human volunteers with two hours of continuous exposure. [R120] *Absorption of tetrachloroethylene (PCE) through the skin by immersing the thumbs of volunteers in PCE for 40 minutes and measuring the PCE in the exhaled air. High concentrations of PCE in exhaled breath (160 to 260 ug/cu m) were measurable five hours after exposure. [R121] *Tetrachloroethylene excretion in breast milk has been associated with obstructive jaundice in newborn infants. [R54, 986] *Nine unrelated groups (659 males) working in plastic boat, chemical, plastic button, paint, and shoe factories were studied. Urine samples were collected at the beginning of the workshift and at the end of the first half of the shift. A close relationship (correlation coefficient always above 0.85) between the average environmental solvent concentration (mg/cu m) measured in the breathing zone and the urinary concentration of unchanged solvent (ug/L) was observed. The authors recommended a biological equivalent exposure limit of 101 ug/L. biological exposure data for urine collected over 4 hr during random sampling for at least 1 yr could be used to evaluate long-term exposure and probability of non-compliance for individual or groups of workers. [R122] *Objective: The present study was initiated to examine a quantitative relationship between tetrachloroethene (TETRA) in blood and urine with TETRA in air, and to compare TETRA in blood or urine with trichloroacetic acid (TCA) in urine as exposure markers. Methods: In total, 44 workers (exposed to TETRA during automated, continuous cloth-degreasing operations), and ten non-exposed subjects volunteered to participate in the study. The exposure to vapor was monitored by diffusive sampling. The amounts of TETRA AND TCA in end-of-shift blood and urine samples were measured by either head-space gas chromatography (HS-GC) or automated methylation followed by HS-GC. The correlation was examined by regression analysis. Results: The maximum time-weighted average (TWA) concn for TETRA-exposure was 46 ppm. Regression analysis for correlation of TETRA in blood, TETRA in urine and TCA in urine, with TETRA in air, showed that the coefficient was largest for the correlation between TETRA in air and TETRA in blood. The TETRA in blood, in urine and in air correlated mutually, whereas TCA in urine correlated more closely with TETRA in blood than with TETRA in urine. ... The biological marker levels at a hypothetical exposure of 25 ppm TETRA were substantially higher in the present study than were the levels reported in the literature. ... Conclusions: Blood TETRA is the best marker of occupational exposure to TETRA, being superior to the traditional marker, urinary TCA. [R123] *In vitro dermal absorption was measured for 3 volatile organic cmpds in dilute aqueous soln through freshly prepared and previously frozen human skin. The permeability coefficients at 26 deg C for chloroform (0.14 cm/h) and trichloroethylene (0.12 cm/h) were similar but much larger than that for tetrachloroethylene (0.018 cm/h). Storage of the skin at -20 deg C did not significantly affect the penetration of these chemicals. The dermal absorption of chloroform through freshly prepared human skin was not changed significantly by pretreatment of the skin with commonly used consumer products (moisturizer, baby oil, insect repellent, sunscreen); however, the permeability coefficient was found to incr from 0.071 cm/h at 11 deg C to 0.19 cm/h at 50 deg C. These data suggest that exposure estimates for chloroform and other contaminants in water should consider the appropriate exposure scenario to properly assess the dermal dose. [R124] *During hyperventilation therapy, the relative contribution to the fast elimination process increased from 70% for physiological minute volume to 99.9%. A minor fraction of the ingested dose was excreted with the urine (integral of 1% during the first 3 days). In contrast to previous results, trace amounts of unchanged tetrachloroethylene were detected in the urine besides trichloroacetic acid and trichloroethanol. [R81] METB: *METABOLITES: TRICHLOROACETIC ACID; TRICHLOROETHANOL; INORG CHLORIDE; TRANS-1,2-DICHLOROETHYLENE IN EXPIRED AIR. /FROM TABLE/ [R125] *IN TETRACHLOROETHYLENE EXPOSURE, URINARY METABOLITE LEVELS OF TRICHLOROETHANOL, TOTAL TRICHLORO COMPOUNDS, AND TRICHLOROACETIC ACID INCREASED UNTIL THE ATMOSPHERIC CONCN OF THE SOLVENT REACHED 50 TO 100 PPM; LITTLE INCR IN THESE METABOLITES OCCURRED AT HIGHER SOLVENT CONCN. [R126] *The relationship among dose, metabolism and hepatotoxicity in mice which resulted from subchronic exposure to the chlorinated solvents trihloroethylene and perchloroethylene were examined. Male Swiss-Cox mice received either trichloroethylene (0 to 3200 mg/kg/day) or perchlorothylene (0 to 2000 mg/kg/day) in corn oil by gavage for 6 weeks. Urinary metabolites from individual mice were quantified to estimate the extent to which each compound was metabolized. Four parameters of hepatotoxicity were assessed: liver weight, triglycerides, glucose-6-phophatase activity, and serum glutamic-pyruvic transaminase (SGPT) activity. Trichloroethylene sigificantly affected liver weight and glucose-6-phosphatase activity; perchloroethylene affected all four parameters. The metabolism of trichloroethylene was linearly related to dose through 1600 mg/kg, but then became saturated. The metabolism of perchloroethylene was saturable. The dose-effect curves of the affected hepatotoxicity parameters of both compounds were nonlinear and resembled the dose-metabolism graph of the corresponding solvent. Plots of the hepatotoxicity data of each compound against total urinary metabolites were linear in all cases, suggesting that the hepatotoxicity of both perchloroethylene and trichloroethylene in mice is directly related to the extent of their metabolism. This pattern is consistent with formation of the toxic intermediate in the primary metabolic pathway of each compound. [R127] *Toxicokinetic modeling of the uptake and elimination of tetrachloroethylene showed that human metabolic parameters could be predicted by scaling rat metabolic parameters for tetrachloroethylene as a function of body weight. Trichloroacetic acid and trichloroethanol have been reported as urinary metabolites of tetrachloroethylene in both humans and experimental animals. [R128] BHL: *The elimination of tetrachloroethylene in expired air ranged from 50 to 150 ppm (339 to 1,017 mg/cu m) for up to 8 hr. Biological half-life for fat stores was 71.5 hr. [R129] *The biological half-life of tetrachloroethylene metabolites (as measured as total trichloro-compounds) is 144 hours. [R130] *Elimination is slow (biological half-life of 65 hours for exhaled perchloroethylene) because of continuing release of perchloroethylene from fat stores. [R54, 986] ACTN: *... /TETRACHLOROETHYLENE HAS BEEN/ SHOWN ... TO RELEASE LYSOSOMAL ENZYMES FROM GRANULAR FRACTIONS PREPARED FROM NEMATODES. SINCE GUT OF NEMATODES SEEMS TO BE SPECIALIZED FOR LYSOSOMAL INTRACELLULAR DIGESTION OF NUTRIENTS, INTERFERENCE WITH THIS PROCESS MAY WELL EXPLAIN ACTION OF TETRACHLOROETHYLENE ... IT HAS BEEN ASSUMED THAT AFFECTED WORMS ARE PARALYZED SUFFICIENTLY TO RELEASE THEIR ATTACHMENT TO INTESTINAL WALL ... [R56, 1031] INTC: */When formerly used/ ... alcohol must be avoided before and for 24 hours after use of tetrachloroethylene. ... No laxative should be given, since this increases the toxic effects and decreases the effectiveness of the drug. [R4] *Intubation of rats with mixtures of benzene and tetrachloroethylene yielded a combined toxicity which was only slightly less than additive. Mixtures of toluene with tetrachloroethylene resulted in LD50 values of less than than predicted for simple additivity, indicating synergistic effects. [R131] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): After the advent of phenothiazine ... little use has been made of the chlorinated hydrocarbons ... /as a ruminant anthelmintic/. Tetrachloroethylene has continued to be used in small animals over the years but has been largely replaced by drugs that are less toxic and easier to admin. [R15] *... /IT/ IS USEFUL ONLY AGAINST HOOKWORM INFESTATIONS IN MAN. TREATMENT WITH THIS AGENT IS MORE EFFECTIVE AGAINST NECATOR AMERICANUS THAN AGAINST ANCYLOSTOMA DUODENALE ... /FORMER USE/ [R56, 1032] *... SINGLE DOSE /ORAL/ OF 0.12 ML/KG ... MAX OF 5 ML. ... DIET BEFORE ADMIN ... SHOULD BE LOW IN FAT AND PT SHOULD EAT ONLY LIGHT MEAL PREVIOUS EVENING. NEXT MORNING ... /DRUG/ INGESTED ON EMPTY STOMACH ... SINGLE TREATMENT ... GENERALLY REMOVE ... WORMS, BUT TWO OR MORE TREATMENTS @ 4-DAY INTERVALS ... TO CLEAR INFESTATION. /FORMER USE/ [R56, 1031] *TETRACHLOROETHYLENE, USP ... AVAILABLE IN SOFT GELATIN CAPSULES CONTAINING 0.2, 1.0, OR 2.5 ML OF DRUG. IT MAY BE DIFFICULT TO OBTAIN DRUG IN CAPSULE FORM FOR HUMAN USE. /FORMER USE/ [R56, 1031] WARN: *VET: AT ONE TIME IT WAS USED FAIRLY EXTENSIVELY AGAINST GI PARASITES OF RUMINANTS. ITS DISADVANTAGE IN RUMINANTS IS NECESSITY OF STIMULATING CLOSURE OF ESOPHAGEAL GROOVE SO THAT MEDICATION IS DELIVERED DIRECTLY TO ABOMASUM RATHER THAN PASSING INTO RUMEN WHICH ... REDUCES EFFECTIVENESS OF DRUG. ... NO FOOD OR WATER SHOULD BE ALLOWED FOR 12-18 HR BEFORE AND FOR 4 HR AFTER DOSING. ... /IT/ IS CONTRAINDICATED IN TAPEWORM-INFECTED ANIMALS SINCE IRRITATION OF THESE WORMS MAY RESULT IN THEIR BALLING UP AND OCCLUDING DIGESTIVE PASSAGE. IT IS ... CONTRAINDICATED IN ANIMALS WITH DISTEMPER ... AND SHOULD NOT BE ADMIN TO NURSING ANIMALS OR THOSE WEIGHING LESS THAN 2 LB (APPROX 1 KG). [R15] *VET: RESTRICT DIETARY FAT WITHIN 2 DAYS BEFORE AND AFTER USE TO AVOID ENHANCED ABSORPTION OF THIS FAT SOL LIVER TOXICANT. CONTRAINDICATED IN FEBRILE DISEASES OR IN DEBILITATED ANIMALS. STRONG MUCOSAL IRRITANT. BREAKING CAPSULES IN MOUTH HAS PRODUCED ATAXIA, CONVULSIONS, AND ANESTHESIA. [R132] *Food and Environmental Agents: Effect on Breast-Feeding: Tetrachloroethylene-cleaning fluid (perchloroethylene): Obstructive jaundice, dark urine. /from Table 7/ [R133] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Tetrachloroethylene's production and use as a dry cleaning agent, degreasing agent and as a chemical intermediate in the production of fluorocarbons will result in its release to the environment through various waste streams. If released to air, a vapor pressure of 18.5 mm Hg at 25 deg C indicates tetrachloroethylene will exist solely as a vapor in the ambient atmosphere. Vapor-phase tetrachloroethylene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 96 days. Direct photolysis is not expected to be an important environmental fate process since this compound only absorbs light weakly in the environmental UV spectrum. If released to soil, tetrachloroethylene is expected to have moderate mobility based upon Koc values in the range of 200-237 and tetrachloroethylene has often been detected in groundwater. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 0.0177 atm-cu m/mole. Tetrachloroethylene may volatilize from dry soil surfaces based upon its vapor pressure. Volatilization half-lives in the range of 1.2-5.4 hrs were measured for tetrachloroethylene from a sandy loam soil surface and volatilization half-lives of 1.9-5.2 hrs were measured from an organic topsoil. Biodegradation is expected to occur slowly in soils under both aerobic and anaerobic conditions. If released into water, tetrachloroethylene is not expected to adsorb to suspended solids and sediment in water based upon the Koc data. The biodegradation half-lives of tetrachloroethylene in aerobic and anaerobic waters were reported as 180 and 98 days, respectively. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hour and 5 days, respectively. Measured BCF values of 26-77 in fish suggest bioconcentration in aquatic organisms is low to moderate. Hydrolysis is not expected to be an important environmental fate process based on a hydrolysis half-life of 9 months. Tetrachloroethylene may undergo indirect photolysis in natural waters when photosensitizers such as humic material are present. Occupational exposure to tetrachloroethylene may occur through inhalation and dermal contact with this compound at workplaces where tetrachloroethylene is produced or used. The general population may be exposed to tetrachloroethylene via inhalation of ambient air, ingestion of food and drinking water. (SRC) ARTS: *Water pollution by tetrachloroethylene leaching from vinyl liners in asbestos-cement water pipelines for water distribution. [R134] *During chlorination water treatment, it can be formed in small quantities. [R135] *Tetrachloroethylene's production and use as a dry cleaning agent, degreasing agent and as a chemical intermediate in the production of fluorocarbons(1) may result in its release to the environment through various waste streams(SRC). Tetrachloroethylene is released through vaporization losses from dry cleaning and industrial metal cleaning(2), and in wastewater, particularly from metal finishing, laundries, aluminum forming, organic chemical/plastics manufacturing and municipal treatment plants(3). [R136] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values in the range of 200-237(2-4), indicates that tetrachloroethylene is expected to have moderate mobility in soil(SRC). Volatilization of tetrachloroethylene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 0.0177 atm-cu m/mole(5). Tetrachloroethylene may volatilize from dry soil surfaces based on a vapor pressure of 18.5 mm Hg at 25 deg C(6). Volatilization half-lives in the range of 1.2-5.4 hrs were measured for tetrachloroethylene from a sandy loam soil surface and volatilization half-lives of 1.9-5.2 hrs were measured from an organic topsoil(7). Tetrachloroethylene, reached 11% of its theoretical BOD in 4 weeks using an activated sludge inoculum in the Japanese MITI test(8), suggesting biodegradation will be slow under aerobic conditions(SRC). Biodegradation under anaerobic conditions occurs slowly with acclimated microorganisms(9,10). [R137] *AQUATIC FATE: Based on a classification scheme(1), Koc values in the range of 200-237(2-4) indicate that tetrachloroethylene is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(5) based upon a Henry's Law constant of 0.0177 atm-cu m/mole(6). Using this Henry's Law constant and an estimation method(5), volatilization half-lives for a model river and model lake are 1 hour and 5 days, respectively(SRC). According to a classification scheme(7), BCF values in the range of 26-77 measured in fish(8-10), suggests bioconcentration in aquatic organisms is low to moderate(SRC). The biodegradation half-lives of tetrachloroethylene in aerobic and anaerobic waters were reported as 180 and 98 days, respectively(11). Hydrolysis is not expected to be an important environmental fate process for tetrachloroethylene based on a hydrolysis half-life of 9 months in purified, de-ionized water(12). Tetrachloroethylene may undergo indirect photolysis in natural waters when photosensitizers such as humic acids are present(13). This process is only expected to be important in sunlit surface waters containing humic material. [R138] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tetrachloroethylene, which has a vapor pressure of 18.5 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase tetrachloroethylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 96 days(SRC), calculated from its rate constant of 1.67X10-13 cu cm/molecule-sec at 25 deg C(3). Tetrachloroethylene may also be degraded in the atmosphere by reaction with ozone, but the rate of this reaction is too slow to be environmentally important(4). Direct photolysis is not expected to be an important environmental fate process since this compound only absorbs light weakly in the environmental UV spectrum(5). [R139] BIOD: *No degradation occurred in 21 days in 3 biodegradability tests with acclimated or unacclimated inocula or in a river die-away test(4). Microbial degradation did not contribute to the removal of tetrachloroethylene (PCE) in a mesocosm experiment which simulated Narraganset Bay, RI(5). Under aerobic conditions there was no degradation in 25 weeks in a batch experiment with a sewage inoculum(1) or when low concentrations of PCE (16 ug/l) were circulated through an acclimated aerobic biofilm column over a period of 1 year(2). While only 3.75% of the PCE treated by conventional, extended and 2-stage activated-sludge pilot plants appeared in the effluent, most of the PCE was discharged to the air from the extended aeration(3). [R140] *ANAEROBIC: There is evidence that slow biodegradation of tetrachloroethylene (PCE) occurs under anaerobic conditions when the microorganisms have been acclimated, yielding trichloroethylene (TCE) as a product(1,2). An experiment in a continuous-flow laboratory methanogenic column using well acclimated mixed culture and a 2-day detention time had an average PCE removal rate of 76%(3). In a continuous-flow mixed-film methanogenic column with a liquid detention time of 4 days, mineralization of 24% of the PCE present occurred; TCE was the major intermediate formed (72%), but traces of dichloroethylene isomers and vinyl chloride were also found(4). In other column studies under a different set of methanogenic conditions, nearly quantitative conversion of PCE to VC was found in 10 days(4). Removal of 86% PCE occurred in a methanogenic biofilm column (8 weeks of activation followed by 9-12 weeks of acclimation(5)). [R141] *A large reduction of tetrachloroethylene which had been recirculated through a soil column for 14 days was attributed to adsorption and volatilization(2). In a microcosm containing muck from an aquifer recharge basin, 72.8% loss was observed in 21 days against 12-17% in controls, and the metabolites trichloroethylene, cis- and trans-1,2-dichloroethylene, dichloromethane, and chloroethene were identified(3). However, when subsurface samples were aseptically removed from above and below the water table and incubated in the laboratory, no degradation occurred in 16 weeks(4). In one field groundwater recharge project, degradation was observed in the 50 day recharge period(1). [R142] *Tetrachloroethylene, present at 30 mg/l, reached 11% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 100 mg/l and the Japanese MITI test(1), suggesting biodegradation will be slow under aerobic conditions(SRC). The biodegradation half-life of tetrachloroethylene in aerobic and anaerobic waters was reported as 180 and 98 days, respectively(2). The first-order anaerobic biodegradation rate constant of tetrachloroethylene was reported in the range of 0.00042-0.0071 day-1(3), corresponding to half-lives of 98-1,650 days(SRC). Tetrachloroethylene was degraded to trichloroethene, 1,2-dichloroethene and ultimately vinyl chloride during a 6 day incubation period using a groundwater and sediment microcosm obtained from a contaminated site in Toronto, Canada(4). [R143] ABIO: *The rate constant for the vapor-phase reaction of tetrachloroethylene with photochemically-produced hydroxyl radicals is 1.67X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 96 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Tetrachloroethylene may also be degraded in the atmosphere by reaction with ozone, but the rate of this reaction is too slow to be environmentally important(2). Direct photolysis is not expected to be an important environmental fate process since this compound only absorbs light weakly in the environmental UV spectrum(3). Tetrachloroethylene may undergo indirect photolysis in natural waters when photosensitizers such as humic material are present(4). When tetrachloroethylene in aqueous solution was irradiated with light greater than 290 nm in wavelength, 75% degradation was observed over the course of one year, while 59-65% degradation was observed for dark controls(5). Hydrolysis is not expected to be an important environmental fate process for tetrachloroethylene based on a hydrolysis half-life of 9 months in purified, de-ionized water(5). [R144] *Photodegradation in the stratosphere is rapid(1). When PCE adsorbed to silica gel is irradiated through a pyrex filter, 50-90% is lost in 6 days(2). [R145] BIOC: *The BCF value of tetrachloroethylene in fathead minnows was 39(1) and the BCF value for bluegill sunfish was 49(2). BCF values of 26-77 were observed for carp exposed to 0.1 mg/l of tetrachloroethylene and values of 28-76 were observed for carp exposed to 0.01 mg/l over an 8 week incubation period(3). According to a classification scheme(4), these BCF data suggest that bioconcentration in aquatic organisms is low to moderate(SRC). [R146] KOC: *The Koc value of tetrachloroethylene in a silt loam was measured as 210(1) and the Koc in a Lincoln fine sandy soil was 200(2). An average Koc of 237 was calculated for tetrachloroethylene in 6 soils (acid peat, acid humic, calcareous humic, iron-oxide rich subsurface soil, clay subsurface soil, and sandy subsurface soil)(3). According to a classification scheme(4) these Koc data suggest that tetrachloroethylene is expected to have moderate mobility in soil(SRC). [R147] VWS: *The Henry's Law constant for tetrachloroethylene is 0.0177 atm-cu m/mole(1). This Henry's Law constant indicates that tetrachloroethylene expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1 hour(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5 days(SRC). The volatilization half-life of tetrachloroethylene was reported as 3.2 minutes in laboratory experiments using distilled water(3). Tetrachloroethylene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). Tetrachloroethylene is expected to volatilize from dry soil surfaces based on a vapor pressure of 18.5 mm Hg at 25 deg C(4). Volatilization half-lives in the range of 1.2-5.4 hrs were measured for tetrachloroethylene from a sandy loam soil surface and volatilization half-lives of 1.9-5.2 hrs were measured from an organic topsoil(5). [R148] WATC: *Samples for analysis of volatile organic compounds were collected from 315 wells in the Potomac-Raritan-Magothy aquifer system in southwestern New Jersey and a small adjacent area in Pennsylvania (USA) during 1980-1982. Volatile organic compounds were detected in all 3 aquifer units of the Potomac-Raritan-Magothy aquifer system. Most of the contamination appeared to be confined to the outcrop area. Low levels of contamination were found away from the outcrop area in the upper and middle aquifer. Trichloroethylene, tetrachloroethylene and benzene were the most frequently detected compounds. Differences in the distributions of light chlorinated hydrocarbons, /(including tetrachloroethylene)/, trichloroethylene, and aromatic hydrocarbons, ie, benzene, were noted and were probably due to differences in the uses of the compounds and the distribution patterns of potential contamination sources. The distribution patterns of volatile organic compounds differed greatly among the 3 aquifer units. The upper aquifer, which cropped out mostly in less-developed areas, had the lowest percentage of wells with volatile organic compounds detected (10% of wells sampled). The concentrations in most wells in the upper aquifer which had detectable levels were < 10 ug/l. In the middle aquifer, which cropped out beneath much of the urban and industrial area adjacent to the Delaware River, detectable levels of volatile organic compounds were found in 22% of wells sampled, and several wells contained concentrations > 100 ug/l. The lower aquifer, which was confined beneath much of the outcrop area of the aquifer system, had the highest percentage of wells (28%) with detectable levels. This was probably due to vertical leakage of contamination from the middle aquifer and the high percentage of wells tapping the lower aquifer in the most heavily developed areas of the outcrop. [R149] *The National Health Department (Italy) had promoted and supported a preliminary survey on the presence of some chlorinated organic compounds in the drinking water. The drinking water of some cities of northern Italy was analyzed for the presence of trichloroethylene, tetrachloroethylene, methylchloroform, carbon tetrachloride, trihalomethanes, polychlorinated biphenyls, and the most common chlorinated pesticides. From March, 1981 to June, 1982, 8 controls were done for 11 sampling points. All water underwent different treatments with carbon. In the raw water, trichloroethylene (47/48) and tetrachloroethylene (34/48) showed the highest frequency of positivity. One well had the highest concentrations of these compounds (trichloroethylene 81-158 ug/l; tetrachloroethylene 15-32 ug/l). In the finished waters, carbon trichloride the most abundant trihalomethane formed during chlorination, was detected in 80% of the 39 samples, against 31% in the 48 raw water samples. No polychlorinated biphenyls and chlorinated pesticides were found at the chosen detection limit (0.05 ug/l). [R150] *DRINKING WATER: In a survey of 180 US cities with finished surface water, the median concn of tetrachloroethylene in drinking water was reported as 0.3 ppb with a max concn of 21 ppb(1). In survey of 36 US cities with finished groundwater, the median concn of tetrachloroethylene was 3 ppb(1). Tetrachloroethylene was detected at a max conc of 1.5 ppm in contaminated drinking wells in the US(2,3). The avg concn of tetrachloroethylene from 30 Canadian potable water facilities was reported as 1 ppb(4). A survey of drinking water sources in the Netherlands showed that 64 sources had tetrachloroethylene concns greater than 10 ppb, 12 sources had concns greater than 100 ppb, 4 sources had concns greater than 1 ppm and 2 sources had concns greater than 100 ppm(5). Drinking water obtained from the Rhine River, Netherlands had a max concn of 50 parts per trillion tetrachloroethylene(6). Drinking water in Niagra Falls, NY had tetrachloroethylene concns of 0.35-2.9 ppb(7). A survey of drinking water for individual states in the US reported that 220 of 1,569 samples contained tetrachloroethylene at concns of trace to 3,000 ppb(8). Tetrachloroethylene was detected in 264 drinking water wells in California at a max concn of 166 ug/l(9). [R151] *GROUNDWATER: The median concn of tetrachloroethylene in groundwater from 27 US cities was 0.6 ppb(1). The max concn of tetrachloroethylene in groundwater wells from San Fernando Valley, CA was 130 ppb(2). Groundwater from Britain contained less than 2 ppb of tetrachloroethylene in 8 out of 10 samples analyzed(3). Groundwater underlying 2 rapid infiltration sites in the US contained tetrachloroethylene at concns of 0.07 and 0.63 ppb(4). Shallow groundwater wells in Japan contained tetrachloroethylene at concns of 0.2-23,000 ppb and deep wells contained 0.2-150 ppb(5). Tetrachloroethylene was identified, not quantified in 27% of groundwater samples obtained from shallow wells in southern New Jersey(6). [R152] *SURFACE WATER: The median concn of tetrachloroethylene in surface water from 154 US cities was 2 ppb(1). Tetrachloroethylene was identified, not quantified, in 2,346 out of 4,972 samples of water from the Ohio River(2). The avg concn of tetrachloroethylene in Lake Ontario water was reported as 0.009 ppb(3). The concn of tetrachloroethylene in the Rhine River, Netherlands was reported as 0.12-0.62 ppb from 1976-1982(4). The concn of tetrachloroethylene in Lake Zurich, Switzerland was reported as 0.025-0.14 ppb(5,6). The STORET Database of US surface water reported that tetrachloroethylene was identified in 3,543 out of 9,323 surface water samples(7). Tetrachloroethylene was detected in the Elbe River near Hamburg Germany at concns of 16-163 ng/l from 1992-1993(8). [R153] *SEAWATER: Tetrachloroethylene has been detected in seawater at concns of 0.1 to 0.8 parts per trillion(1,2). Tetrachloroethylene was detected in the Gulf of Mexico at concns of 0-40 parts per trillion(3). Surface water from the Eastern Pacific Ocean contained tetrachloroethylene at concns of 0.1-2.8 parts per trillion(4). [R154] *RAIN/SNOW: Tetrachloroetheylene was detected in rain from an industrial city in England at 150 parts per trillion(1). West Los Angeles (3/26/82) tetrachloroethylene was detected in rain at a concn of 21 parts per trillion(2). Tetrachloroethylene was detected in rain from La Jolla, California at 5.7 parts per trillion(3) and central and southern California at 1.4 and 2.3 parts per trillion, respectively(3). [R155] EFFL: *Tetrachloroethylene was detected in industrial effluent at concns of 1-20 ppb and in the effluent of municipal treatment plants at concns of 1-10 ppb(1). Tetrachloroethylene was released from the Baltimore Municipal Treatment Plant at concns of 8-129 ppb(2). Maximum concns of tetrachloroethylene were reported in wastewater from the following industries: auto and laundry facilities, 93 ppm; aluminum forming facilities, 4 ppm; metal finishing plants; 110 ppm; organic chemical/plastic manufacturing plants, 5.1 ppm (mean value); paint and ink plants, 4.9 ppm(3). Tetrachloroethylene was detected in landfill gas from 7 waste sites in the United Kingdom at concns of 0.1-255 ng/cu m(4). Tetrachloroethylene was detected in the effluent of a municipal waste incinerator in Germany at 0.16 ug/cu m(5). Tetrachloroethylene was identified, not quantified, in water samples at 279 hazardous waste sites in the US(6). [R156] SEDS: *SOIL: Tetrachloroethylene was detected in soil samples from rural areas of the Netherlands at concns of 0.2-1.0 ug/kg(1). Tetrachloroethylene was identified, not quantified, in soil samples from a photocopier refurbishing plant in NY(2). Tetrachloroethylene was detected in soil from an industrial waste disposal site in Denmark at a concn of 19 mg/kg(3). [R157] *SEDIMENT: Tetrachloroethylene was detected in sediment from 172 stations in Liverpool Bay, England at an avg concn of 4.8 parts per trillion(1). Tetrachloroethylene was detected in 25 of 359 sediment samples from the US at a median concn of less than 0.050 ppb(2). Tetrachloroethylene was detected in sediment from Ijmeer, Netherlands at concns of 0.02 and 0.07 mg/kg(3). [R158] ATMC: *URBAN/SUBURBAN: The concentration of tetrachloroethylene at various US cities ranged from less than 0.2 to 9.75 ppb(1). Tetrachloroethylene mean concentrations from seven U.S. cities (1980-1981) ranged from 0.290-0.590 ppb with a max concn of 7.60 ppb(2). [R159] *INDOOR: The median concn of tetrachloroethylene inside 9 homes near Old Love Canal, Niagara, NY was reported as 71 parts per trillion(1). Tetrachloroethylene was detected in a classroom near a dry cleaning facility in the Netherlands at 1.9 ppb,(2) and a nursing home situated near a former chemical waste dump at 1.2 and 0.2 ppb on first and second floors, respectively(3). [R160] *RURAL/REMOTE: Tetrachloroethylene was detected in White Face Mountains, NY at concns of less than 0.02 to 0.19 ppb from September 16-19 1974(1). Tetrachloroethylene was detected in Barrows, Alaska at concns of 56-128 parts per trillion(2). The average concn of tetrachloroethylene in the northern hemisphere was reported as 40 parts per trillion(3). [R161] *SOURCE DOMINATED: Typical concns of tetrachloroethylene in source dominated and industrial areas have been reported in the range of 0.3-1.5 ppb, with max concns of 10 ppb(1-5). Tetrachloroethylene was detected in Old Love Canal, Niagara, NY at a median concn of 109 parts per trillion(6). Tetrachloroethylene was detected around a playground near a dry cleaning facility in the Netherlands at 0.15 ppb(7). Tetrachloroethylene was detected in industrialized regions of Tsubame, Japan (0.019-0.23 ppb), Tokamachi, Japan (0.20-2.8 ppb) and Kubiki, Japan (0.024-0.63 ppb)(8). [R162] FOOD: *Tetrachloroethylene concentrations in foods ranged from non-detectable amounts (< 0.01 ug/kg) in orange juice to 13 ug/kg in English butter. [R163] *Tetrachloroethylene was detected in Chinese style sauce (2 ppb), quince jelly (2.2 ppb), crab apple jelly (2.5 ppb), grape jelly (1.6 ppb) and chocolate sauce (3.6 ppb)(1). Tetrachloroethylene was detected in various food from England at concns of 0.01-0.13 ppb(2). Tetrachloroethylene was detected in 2 of 10 wheat samples at 1.8 and 2.1 ppb and 2 corn samples at 0.45 and 0.54 ppb(3). Tetrachloroethylene was detected in butter and margarine at concns of 0.7-18 ug/kg and peanut butter at concns of 0.6-9.7 ug/kg(4). [R164] PFAC: PLANT CONCENTRATIONS: *Tetrachloroethylene was detected in marine algae at concns of 13-23 ppb(1). [R165] FISH/SEAFOOD CONCENTRATIONS: *Tetrachloroethylene was detected at concns of 0.3-43 ppb in marine fish, 0.5-176 ppb in marine invertebrates in England(1), 250 ppb in American eel (Delaware River), 1,050 ppb in American eel (Newark Bay), 77 ppb in carp (Delaware River), 108 ppb in striped bass (Raritan River), 88 ppb in spot fish (Houston Ship Channel)(2). Tetrachloroethylene was detected in fish from the Rhine River and Lake Constance Germany at concns of 25-100 ppb(3). Tetrachloroethylene was detected in clams from the Ariho River, Japan at 0.6 ug/kg(4). [R166] ANIMAL CONCENTRATIONS: *Tetrachloroethylene was detected at concns of 0.6-19 ppb in grey seal blubber (NE Coast of England) and at concns of 1.4-39 ppb in marine and freshwater birds (coast of England)(1). [R167] MILK: *Tetrachloroethylene was detected in 7 of 8 samples in mother's milk from 4 urban areas in the US(1). One hour after a visit to a dry cleaning plant, one sample of mother's milk contained 10 ppm tetrachloroethylene. This decreased to 3 ppm after 24 hr(2). [R168] RTEX: *Currently at risk of exposure are more than 500,000 workers, primarily in the dry cleaning and textile industries, which use more than 2/3 of the domestically produced tetrachloroethylene. [R54, 986] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 536,688 workers (139,308 of these are female) are potentially exposed to tetrachloroethylene in the US(1). Occupational exposure to tetrachloroethylene may occur through inhalation and dermal contact with this compound at workplaces where tetrachloroethylene is produced or used(SRC). The mean concn of tetrachloroethylene in alveolar air in 18 workers at 12 dry cleaning stores was 73 mg/cu m(2). The general population may be exposed to tetrachloroethylene via inhalation of ambient air, ingestion of food and drinking water(SRC). [R169] AVDI: *The AVDI of tetrachloroethylene measured in 8 urban areas of Japan was reported as 21 ug (inhalation) and 0.84 ug (ingestion)(1). [R170] BODY: *Tetrachloroethylene was detected in 7 of 8 samples in mother's milk from 4 urban areas in the US(1). One hour after a visit to a dry cleaning plant, one sample of mother's milk contained 10 ppm tetrachloroethylene. This decreased to 3 ppm after 24 hr(2). Tetrachloroethylene was detected in expired breath and blood from 9 individuals living in Love Canal, NY at 600-4,500 ng/cu m and 0.35-260 ng/ml, respectively(3). Tetrachloroethylene was detected in human body fat (8 subjects) 0.4-29.2 ppb and various human organs less than 6 ng/g(4). The mean concn of tetrachloroethylene in alveolar air in 136 residents living near 12 dry-cleaning stores were: living equal to or < 5 floors above the stores 5 mg/cu m, adjacent houses 1 mg/cu m, one house away 0.2 mg/cu m, across street < .1 mg/cu m, whereas the mean concn in 18 workers from these stores was 73 mg/cu m(5). [R171] *Whole blood, USA survey of 250 (121 males, 129 females), 0.7-23 ppb, 2.4 ppb avg(1). Breath samples (ug/cu m, weighted statistics), Elizabeth and Bayonne, NJ, 1981, 295-339 samples, 93% pos, 280 max, 13.0 avg, 6.8 median(2). Alveolar air in children and teachers in school situated near factory were 24 ug/cu m avg for children and 11 and 47 ug/cu m for the teachers(3). The mean concentration of tetrachloroethylene in the classroom was 13 ug/cu m(3). Alveolar air of residents of a nursing home situated near a former chemical waste dump averaged 7.8 ug/cu m first floor and 1.8 ug/cu m on the second floor, where ambient concentrations averaged 8.2 and 1.6 ug/cu m, respectively(3). USA FY82 National Human Adipose Tissue Survey specimens, 46 composites, 61% pos (> 3 ppb, wet tissue concn), 94 ppb max(4). [R172] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH has recommended that tetrachloroethylene be treated as a potential human carcinogen. [R29, 300] ADI: *Suggested No-Adverse-Response Level (SNARL): In light of the lack of definitive information regarding the quantitiy of tetrachloroethylene that must be ingested to depress psychophysiological function, it seems appropriate that calculations for a SNARL be based upon quantities of the chemical that are required to produce tissue injury. ... the 0.3 ml/kg (0.49 g/kg) dose appears to be a reasonable "minimum toxic dose" from which to calculate a 24-hr SNARL for contamination of drinking water, assuming that the sole source of tetrachloroethylene during this period will be from 2 l/day of drinking water consumed by a 70 kg human. A safety factor of 100 is applied: 490 mg/kg times 70 kg/100 times 2 l= 172 mg/l. The above considerations ignore the possibility that tetrachloroethylene may be carcinogenic. ... a 7-day standard for drinking water contamination, which was obtained by dividing the 24-hr standard by 7 (172 mg/l/7 days= 24.5 mg/l), should protect against adverse effects by the chemical. [R82, 140] OSHA: *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 100 ppm. [R173] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 200 ppm. [R173] *Permissible Exposure Limit: Table Z-2 Acceptable maximum peak above the acceptable ceiling concentration for an 8-hour shift. Concentration: 300 ppm. Maximum Duration: 5 minutes in any 3 hours. [R173] *Vacated 1989 OSHA PEL TWA 25 ppm (170 mg/cu m) is still enforced in some states. [R29, 372] NREC: *NIOSH recommends that tetrachloroethylene be regulated as a potential human carcinogen. [R29, 300] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R29, 300] *Minimize workplace exposure concentrations; limit number of workers exposed. [R29, 300] TLV: *8 hr Time Weighted Avg (TWA) 25 ppm; Short Term Exposure Limit (STEL) 100 ppm [R174, 55] *BEI (Biological Exposure Index) for Perchloroethylene: Perchloroethylene in end-exhaled air prior to the last shift of workweek is 5 ppm. (1997 adoption) [R174, 101] *BEI (Biological Exposure Index) for Perchloroethylene: Perchloroethylene in blood prior to the last shift of workweek is 0.5 mg/l. (1997 adoption) [R174, 101] *BEI (Biological Exposure Index) for Perchloroethylene: Trichloroacetic acid in urine at end of shift at end of workweek is 3.5 mg/l. The determinant is nonspecific, since it is observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. (1997 Adoption) [R174, 101] *A3: Confirmed animal carcinogen with unknown relevance to humans. [R174, 55] OOPL: *Maximum allowable concentrations range from 10 mg/cu m (1.5 ppm, ceiling value) in the USSR, 140 mg/cu m (20 ppm, TWA) in Sweden, and 250 mg/cu m (37 ppm) in Czechoslovakia to 340 mg/cu m (50 ppm) in the Federal Republic of Germany, Japan. Short-term exposure limits range from 340 mg/cu m (50 ppm) in Sweden to 1250 mg/cu m (183 ppm) in Czechoslovakia and 1340 mg/cu m (200 ppm) in the USA. The acceptable limit in Brazil is 525 mg/cu m (78 ppm) for 48 hr per week. [R175] *Maximum allowable concentrations are 1.0 mg/cu m average per day or 4.0 mg/cu m average per 0.5 hr in Czechoslovakia and 0.06 mg/cu m average per day in the USSR. [R175] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 100 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 200 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 1000 ppm (not life threatening) up to 1 hr exposure. [R176] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Tetrachloroethylene is included on this list. [R177] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l [R178] STATE DRINKING WATER STANDARDS: +(FL) FLORIDA 3 ug/l [R178] +(NJ) NEW JERSEY 1 ug/l [R178] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.67 ug/l [R178] +(CT) CONNECTICUT 5 ug/l [R178] +(ME) MAINE 3 ug/l [R178] +(MN) MINNESOTA 7 ug/l [R178] +(WA) WASHINGTON 4 ug/l [R178] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R179] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Tetrachloroethylene is included on this list. [R180] RCRA: *D039; A solid waste containing tetrachloroethylene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R181] *F002; When tetrachloroethylene is a spent halogenated solvent, it is classified as a hazardous waste from a nonspecific source (F002), as stated in 40 CFR 261.31, and must be managed according to state and/or federal hazardous waste regulations. [R182] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Volatile organic compounds pose a challenge to ground-water sampling protocols, since they can be lost as a water sample degasses or lost due to sorption on tubing or pump materials. Laboratory sorption experiments were conducted with 5 common flexible tubing materials to determine the impact of sorptive bias for chloroform, trichloroethylene, trichloroethane and tetrachloroethylene. Tubes made of Teflon, polyethylene, polypropylene, polyvinyl chloride and silicone rubber were all found to sorb the test compounds in short exposure periods. Virgin tubing materials introduce substantial amounts of leachable organic matter in similar exposures. Tubing made of Teflon showed the least absorption and leaching problems and should be the tubing material of choice for detailed organic sampling purposes. Absorption into the polymer matrix is the likely mechanism for the errors. [R183] *Analyte: Tetrachloroethylene; Matrix: Air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01-0.2 l/min; Vol: min: 0.2 @ 100 ppm, max: 40; Stability: not determined [R184, p. V2 1003-1] ALAB: *A freeze-out concn method is used to determine trace levels of tetrachloroethylene in the presence of other cmpd. Detection limit is 0.2 ppt (1.36X10-6 mg/cu m) for 500 ml aliquots of ambient air samples. Samples are measured by gas chromatography coupled with electron capture configuration. When freeze-out is completed, tetrachloroethylene remains behind; While oxygen and nitrogen gasses are passed through as the freeze-out loop is heated. Carrier gas sweeps the contents onto the column. [R185] *DETERMINATION OF TRACE AMT OF 136 C1-C13 ORG CMPD (INCL TETRACHLOROETHYLENE) IN AIR SAMPLES COLLECTED FROM THE ATMOSPHERE OF STREETS BY GC IS DISCUSSED. [R186] *TETRACHLOROETHYLENE IN DRINKING WATER IS ANALYZED DIRECTLY WITH GAS CHROMATOGRAPHY EQUIPPED WITH ELECTRON CAPTURE DETECTION. THE LIMIT OF DETECTION IS 0.5 UG/L (NICHOLSON AA ET AL; ANAL CHEM 49: 814-9 (1977)). [R187] *TETRACHLOROETHYLENE WAS DETERMINED IN WASTE-CONTAMINATED SOIL AND CHEMICAL STILL BOTTOM EXTRACTS BY GAS CHROMATOGRAPHY. [R188] *DETERMINATION OF TETRACHLOROETHYLENE IN FISH BY GAS CHROMATOGRAPHY; DETECTION LIMITS IN 0.1-1.0 PPB RANGE. [R189] *NIOSH Method 1003. Analyte: Tetrachloroethylene; Matrix: air; Procedure: Gas chromatography, flame ionization detector; Desorption: 1 ml CS2, stand 30 min; Range: 0.4 to 12 mg/sample; Precision: 0.052; Est LOD: 0.01 mg/sample; Interferences: none [R184] *EPA Method 8010: Halogenated Volatile Organics. For the analysis of solid waste ... Under the prescribed conditions, tetrachloroethylene has a detection limit of 0.03 ug/l, an average recovery range of four measurements of 8.1-29.6 ug/l, and a limit for the standard deviation of 5.4 ug/l. [R190] *EPA Method 8240B: Gas Chromatography/Mass Spectrometry for Volatile Organics Method 8240 can be used to quantify most volatile organic commpounds that have boiling points below 200 deg C and that are insoluble or slightly soluble in water, including the title compound. ... Under the prescribed conditions, tetrachloroethylene has an average recovery range for four samples of 17.0-26.6 ug/l with a limit for the standard deviation of 5.0 ug/l and a retention time of 22.2 min. [R190] *EPA Method 601 A purge and trap gas chromatography method for the analysis of tetrachloroethylene in municipal and industrial discharges, consists of a stainless steel column, 8 ft x 0.1 in ID, packed with Carbopack B (60/80 mesh) coated with SP-1000, with electrolytic conductivity detection, and helium as the carrier gas at a flow rate of 40 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 45 deg C for 3 minutes then programmed at 8 deg/min to final temperature of 220 deg C. This method has a detection limit of 0.03 ug/l and an overall precision of 0.18 times the average recovery +2.21, over a working range of 8.0 to 500 ug/l. [R191] *EPA Method 624: A purge and trap gas chromatography/mass spectrometry method for the analysis of tetrachloroethylene in municipal and industrial discharges, consists of a glass column, 6 ft x 0.1 in, packed with Carbopack B (60/80 mesh) coated with 1% SP-1000, with the detection performed by the mass spectrometer, and helium as the carrier gas at a flow rate of 30 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 45 deg C for 3 minutes and then programmed at 8 deg/min to a final temperature of 220 deg C. This method has a detection limit of 4.1 ug/l and an overall precision of 0.16 times the average recovery - 0.45, over a working range of 5 to 600 ug/l. [R191] *EPA Method 1624: An isotope dilution gas chromatography/ mass spectrometry method for the determination of volatile organic compounds in municipal and industrial discharges is described. This method is designed to meet the survey requirements of Effluent Guidelines Division (EGD) and the National Pollution Discharge Elimination System (NPDES). Under the prescribed conditions, unlabeled tetrachloroethylene has a minimum level of 10 ug/l and a mean retention time of 1528 sec. The labeled compound has a characteristic primary m/z of 166/172. This method has an initial precision of 6.6 ug/l, an accuracy of 15.1-28.5 ug/l, and a labeled compound recovery of 31-181%. [R191] *AOB Method VA-005-1. Volatile Organic Compounds (VOCs) in Ambient Air by Purge and Trap Gas Chromatography. No detection limit. [R192] *AOB Method VA-006-1. Volatile Organic Compounds (VOCs) in Ambient Air by Direct Portable GC/PID. No detection limit. [R192] *AOB Method VA-008-1. Volatile Organic Compounds (VOCs) in Ambient Air by Portable GC/PID with Direct Sampling via Pump and Sample Loop. No detection limit. [R192] *APHA Method 6210-D. Volatile Organics in Water by Gas Chromatographic/ Mass Spectrometric Purge and Trap Capillary-Column Technique. No detection limit [R192] *APHA Method 6220-C. Volatile Aromatic Organics in Water by Purge and Trap Gas Chromatography. Detection limit = 0.05 ug/l. [R192] *APHA Method 6230-C. Volatile Aromatic Organics in Water by Purge and Trap Gas Chromatography. Detection limit = 0.03 ug/l. [R192] *AOB Method VS-001-1. Volatile Organic Compounds (VOCs) in Soil by Purge and Trap GC/PID/ELCD. Detection limit = 10 ug/kg. [R192] *AOB Method VS-001-1. Volatile Organic Compounds (VOCs) in Soil and Sediment by Automated Headspace GC/PID/ELCD. Detection limit = 100 ug/kg. [R192] CLAB: *DETERMINATION OF TETRACHLOROETHYLENE IN FISH BY GAS CHROMATOGRAPHY; DETECTION LIMITS IN 0.1-1.0 PPB RANGE. [R189] *The expired breath of subjects, exposed for periods of approx 90 min to atmospheres artificially contaminated with low levels ... tetrachloroethylene (approx 50 ppm), was monitored during and after the exposure period using an atm pressure ionization mass spectrometer (API/MS), fitted with a direct breath analysis system. The retention of solvent by the subjects estimated from steady state levels in the expired breath, averaged 87%. The elimination of unchanged solvent via respiration during the post exposure period followed first order kinetics a with mean half-life value of 79 min. [R193] *NIOSH Method 3704. Perchloroethylene in exhaled breath and air. Portable GC/PID. [R184] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: IKEDA M; IGAKU NO AYUMI 102 (6-7): 453-9 (1977). REVIEW OF INDUCTION OF LIVER ANGIOSARCOMA, HEPATOCELLULAR CARCINOMA, NEPHROBLASTOMA, PULMONARY TUMOR, KIDNEY ADENOCARCINOMA, AND MAMMARY CARCINOMA BY CHLORINATED ETHYLENES IN RATS AND MICE INCL CORRELATION OF EFFECTS TO DOSE, AGE AND SEX. UTZINGER R, SCHLATTER C; CHEMOSPHERE 6 (9): 517-24 (1977). A REVIEW ON THE TOXICITY OF TRACE AMT OF TETRACHLOROETHYLENE IN WATER WITH EMPHASIS ON MUTAGENICITY, CARCINOGENICITY AND MIXED FUNCTION OXIDASE. HAKE CL, STEWART RD; ENVIRON HEALTH PERSPECT 21: 231-8 (1977). REVIEW OF ACCIDENTAL AND CONTROLLED EXPOSURE OF HUMANS TO TETRACHLOROETHYLENE. WALTER P ET AL; CHLORINATED HYDROCARBON TOXICITY (1,1,1-TRICHLOROETHANE, TRICHLOROETHYLENE, AND TETRACHLOROETHYLENE): A MONOGRAPH. US NTIS, PB REP; ISS PB-257185, 178 PP (1976). REVIEW WITH 91 REFERENCES. RESULTS OF A STUDY OF THE 1920-1975 LITERATURE ON TOXICITY OF TETRACHLOROETHYLENE. 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National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) HIST: *On September 28, 1982, an Illinois Gulf Railroad freight train derailed 43 cars in Livingston, Louisiana. Thirty-six cars were tank cars, of which 27 contained various regulated hazardous or toxic chemical commodities, 2 contained nonregulated hazardous materials, and 5 contained flammable petroleum products. Fires resulted and toxic gases were released into the atmosphere. Residents within a 5 mile radius of the derailment were evacuated for up to two weeks. More than 200,000 gal of toxic chemical products were spilled and absorbed into the ground. Extensive excavation of the contaminated soil and its transportation to a distant dump site were required. Property damage was estimated to be greater than 14 million dollars and long-term closure of the railroad line and adjacent highway resulted. ... 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New York, NY: Academic Press, Inc., 1991. 697 R100: BUCCAFUSCO RJ ET AL; BULL ENVIRONM CONTAM TOXICOL 26: 446 (1981) R101: Le Blanc GA; Bull Environ Contam Toxicol 24: 684-91 (1980) as cited in WHO; Environ Health Criteria: Tetrachloroethylene p.15 (1984) R102: Shubat PJ et al; Bull Environ Contam Toxicol 28: 7-10 (1982) as cited in WHO; Environ Health Criteria: Tetrachloroethylene p.24 (1984) R103: Pearson CR, McConnell G; Proc R Soc Land B 189: 305-32 (1975) as cited in WHO; Environ Health Criteria: Tetrachloroethylene p.24 (1984) R104: USEPA; Task 11, Contract No 68-01-3887 (1980) as cited in USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.B-1 (1980) EPA 440/5-80-073 R105: USEPA; Contract No 68-01-4646 (1978) as cited in USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.B-2 (1980) EPA 440/5-80-073 R106: DHEW/NCI; Bioassay of Tetrachloroethylene for Possible Carcinogenicity (1977) Technical Rpt Series No. 13 DHEW Pub No. (NIH) 77-813 R107: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tetrachloroethylene in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 311 (1986) NIH Publication No. 86-2567 R108: Arthur D. Little, Inc.; Cell Transformation Assays of 11 Chlorinated Hydrocarbon Analogs. (1983), EPA Document No. 40-8324457, Fiche No. OTS0509392 R109: SRI International; Investigations of the Species Sensitivity and Mechanism of Carcinogenicity of Halogenated Hydrocarbons. (1984), EPA Document No. 40-8424225, Fiche No. OTS0509408 R110: Naylor Dana Institute; DNA Repair Tests of 11 Chlorinated Hydrocarbon Analogs, Final Report. (1983), EPA Document No. 40-8324292, Fiche No. OTS0509403 R111: Arena, J.M. and Drew, R.H. (eds.) Poisoning-Toxicology, Symptoms, Treatments. 5th ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 257 R112: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 476 R113: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 213 R114: Monster AC, Houtkooper JM; Int Arch Occup Env Health 42: 319 (1979) R115: Ohtsuki T et al; Int Arch Occup Environ Health 51: 381-90 (1983) R116: WHO; Environ Health Criteria: Tetrachloroethylene p.21 (1984) R117: NTP; Toxicology and Carcinogenesis Studies of Tetrachloroethylene p.19 Report #311 (1986) NIH Pub# 86-2567 R118: McConnell G et al; Endeavor 34: 13-8 (1975) as cited in USEPA; Health Advisories for 25 Organics: Tetrachloroethylene p.307 (1987) PB 87-235578 R119: Stewart RD et al; Arch Environ Health 20: 224-9 (1970) as cited in USEPA; Health Advisories for 25 Organics: Tetrachloroethylene p.307 (1987) PB 87-235578 R120: Stewart RD et al; Arch Environ Health 2: 516 (1961) as cited in USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.C-3 (1980) EPA 440/5-80-073 R121: Stewart RD and Dodd HC; Am Ind Hug Assoc Jour 25: 439 (1964) as cited in USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.C-4 (1980) EPA 440/5-80-073 R122: Ghittori S et al; Am Ind Hyg Assoc J 48 (9): 786-90 (1987) R123: FURUKI K et al; INTERNATIONAL ARCHIVES OF OCCUPATIONAL AND ENVIRONMENTAL HEALTH 73 (4): 221-227 (2000) R124: Nakai JS et al; J Toxicol Environ Health 58 (3): 157-170 (1999) R125: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 381 R126: IKEDA M ET AL; BRIT J IND MED 29 (3): 328-33 (1972) R127: Buben JA, O'Flaherty EJ; Toxicol Appl Pharmacol 78 (1): 105-22 (1985) R128: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 190 (1995) R129: Gruberan E, Fernandez J; Brit J Ind Med 31: 159 (1974) R130: Ikeda M and Imamura T; Int Arch Arbeitsmed 31: 209 (1973) as cited in USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.C-4 (1980) EPA 440/5-80-073 R131: USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.C-17 (1980) EPA 440/5-80-073 R132: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 587 R133: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 142 (1994) R134: Yuskus LR; J Am Water Works Assoc 76 (2): 76-81 (1984) R135: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 769 R136: (1) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: VanNostrand Reinhold Co., p. 850 (1997) (2) Chemical Marketing Reporter; Chemical Profile Tetrachloroethylene. December 15, 1997. NY, NY: Schnell Pub Co (1997) (3) US EPA; Treatability Manual. p. I.12.26-1 to I.12.26-5 USEPA-600/2-82-001A (1981) R137: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Choiu CT et al; Science 206: 831-2 (1979) (3) Wilson JT et al; Environ Qual 10: 501-506 (1981) (4) Friesel P et al; Fresenius Z Anal Chem 319: 160-64(1984) (5) Gossett JM; Environ Sci Technol 21: 202-206 (1987) (6) Riddick JA et al; Organic Solvents: Physical Properties and Methods of Purification 4th ed NY, NY: Wiley Interscience (1986) (7) Zytner RG et al; pp. 101-8 in 43rd Purdue Indust Waste Conf (1989) (8) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center.ISBN 4-89074-101-1 (1992) (9) Bouwer EJ, McCarty PL; Appl Environ Micribiol 45: 1286-94 (1983) (10) Wilson JT et al; Devel Indust Microbiol 24: 225-33 (1983) R138: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Choiu CT et al; Science 206:831-2 (1979) (3) Wilson JT et al; Environ Qual 10: 501-506 (1981) (4) Friesel P et al; Fresenius Z Anal Chem 319: 160-64(1984) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (6) Gossett JM; Environ Sci Technol 21: 202-206 (1987) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Neely WB et al; Environ Sci Technol 8: 1113-15 (1974) (9) Barrows ME et al; Dyn Exposure Hazzard Assess Toxic Chem Ann Arbor, MI: Ann Arbor Sci p. 379-92 (1980) (10) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (11) Capel PD, Larson SJ; Chemosphere 30: 1097-1106 (1995) (12) Dilling WL et al; Environ Sci Technol 9: 833-88 (1975) (13) Mill T; Chemosphere 38: 1379-90 (1999) R139: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Riddick JA et al; Organic Solvents: Physical Properties and Methods of Purification 4th ed NY, NY: Wiley Interscience (1986) (3) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (4) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (5) Crutzen PJ et al; J Geophys Res 83: 345-63 (1978) R140: (1) Bouwer EJ et al; Environ Sci Technol 15: 596-9 (1981) (2) Bouwer EJ, McCarty PL; Environ Sci Technol 16: 836-43 (1982) (3) Watanabe H; Gesuido Kyokaiski 20: 29-37 (1983) (4) Mudder TI; Amer Chem Soc Div Env Chem Conf p. 52-3 (1982) (5) Wakeham SG; Environ Sci Technol 17: 611-7 (1983) R141: (1) Bouwer EJ, McCarty PL; Appl Environ Micribiol 45: 1286-94 (1983) (2) Wilson JT et al; Devel Indust Microbiol 24: 225-33 (1983) (3) Bouwer EJ, McCarty PL; Ground Water 22: 433-40 (1984) (4) Vogel TM, McCarty PL; Appl Environ Microbiol 49: 1080-3 (1985) (5) Bouwer EJ, Wright JP; Am Chem Soc Div Environ Chem. 191st Natl Meet 26: 42-5 (1986) R142: (1) Bouwer EJ et al; Environ Sci Technol 15: 596-99 (1981) (2) Bouwer EJ et al; Water Res 15: 151-59 (1981) (3) Parsons F et al; J Amer Wat Works Assoc 76: 56-9 (1984) (4) Wilson JT et al; Ground Water 21: 134-42 (1983) R143: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center.ISBN 4-89074-101-1 (1992) (2) Capel PD, Larson SJ; Chemosphere 30: 1097-1106 (1995) (3) Rathbun RE; US Geol Surv Prof Pap 1589: 1-151 (1998) (4) Hunkeler D et al; Environ Sci Technol 33: 2733-38 (1999) R144: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (3) Crutzen PJ et al; J Geophys Res 83: 345-63 (1978) (4) Mill T; Chemosphere 38: 1379-90 (1999) (5) Dilling WL et al; Environ Sci Technol 9: 833-88 (1975) R145: (1) Mueller JPH Korte F; Chemosphere 3: 195-8 (1977) (2) Gaeb S et al; Nature 270: 331-3 (1977) R146: (1) Neely WB et al; Environ Sci Technol 8: 1113-15 (1974) (2) Barrows ME et al; Dyn Exposure Hazzard Assess Toxic Chem Ann Arbor, MI: Ann Arbor Sci pp. 379-92 (1980) (3) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center.ISBN 4-89074-101-1 (1992) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) R147: (1) Choiu CT et al; Science 206: 831-2 (1979) (2) Wilson JT et al; Environ Qual 10: 501-506 (1981) (3) Friesel P et al; Fresenius Z Anal Chem 319: 160-64 (1984) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R148: (1) Gossett JM; Environ Sci Technol 21: 202-206 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Chiou CT et al; Environ Int 3: 231-4 (1980) (4) Riddick JA et al; Organic Solvents: Physical Properties and Methods of Purification 4th ed NY, NY: Wiley Interscience (1986) (5) Zytner RG et al; pp. 101-8 in 43rd Purdue Indust Waste Conf (1989) R149: Fusillo TV et al; Ground Water 23 (3): 354-60 (1985) R150: Ziglio G et al; Ig Mod 82 (3): 419-35 (1984) R151: (1) Coniglio WA et al; Occurrence of Volatile Organics in Drinking Water. p. 7 Unpublished EPA report (1980) (2) Burmaster DE; Environ 24: 6-13, 33-6 (1982) (3) Giger W, Molnar-Kubica E; Bull Environ Contam Toxicol 19: 475-80 (1978) (4) Otson R et al; J Assoc Off Anal Chem 65: 1370-4 (1982) (5) Trouwborst T; Sci Total Environ 21: 41-6 (1981) (6) Piet GJ, Morra CF; pp. 31-42 in Artificial Groundwater recharge; Huismon L, Olsthorn TN, eds, Pitman Pub (1983) (7) Barkley J et al; Biomed Mass Spectrum 7: 139-47 (1980) (8) Cotruvo JA et al; pp. 511-30 in Organic Carcinogens in Drinking Water (1986) (9) Lam RHF et al; pp. 15-44 in Water Contamination and Health. Wang RGM, ed, NY, NY: Marcel Dekker, Inc (1994) R152: (1) Coniglio WA et al; Occurrence of Volatile Organics in Drinking Water. p. 7 Unpublished EPA report (1980) (2) Chemical Engineering 90: 35 (1983) (3) Fielding M et al; Environ Technol Lett 2: 545-50 (1981) (4) Hutchins SR et al; Environ Toxicol Chem 2: 195-216 (1983) (5) Magara Y, Furuichi T; pp. 231-43 in New Concepts and Development in Toxicol. Chambers PL et al, eds. Elsevier Sci Publ (1986) (6) Baehr L et al; Water Resour Res 35: 127-36 (1999) R153: (1) Coniglio WA et al; Occurrence of Volatile Organics in Drinking Water. p. 7 Unpublished EPA report (1980) (2) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Water. USEPA-560/6-77-015 and USEPA-560/6-77-015A (1977) (3) Kaiser KLE et al; J Great Lakes Res 9: 212-23 (1983) (4) Malle KG; Z Wasser Abwasser Forsch 17: 75-81 (1984) (5) Grob K, Grob G; J Chrom 90: 303-13 (1974) (6) Schwarzenbach RP et al; Environ Sci Technol 13: 1367-73 (1979) (7) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (8) Gotz R et al; Chemosphere 36: 2085-2101 (1998) R154: (1) Murray AJ, Riley JP; Nature 242: 37-8 (1973) (2) Pearson CR, McConnell G; Proc Roy Soc London Ser B 189: 305-32 (1975) (3)Sauer TC Jr; Org Geochem 3: 91-101 (1981) (4) Singh HB et al; J Geophys Res 88: 3675-83 (1983) R155: (1) Pearson CR, McConnell G; Proc Roy Soc London Ser B 189: 305-32 (1975) (2) Kawamura K, Kaplan IR; Environ Sci Technol 17: 497-501 (1983) (3) Su C, Goldberg ED; Mar Poll Transfer 1976: 353-74 (1976) R156: (1) STORET Data Base (2) Helz GR, Hsu RY; Limnol Oceanogr 23: 858-69 (1978) (3) US EPA; Treatability Manual. p.I.12.26-1 to I.12.26-5 USEPA-600/2-82-001A (1981) (4) Allen MR Environ Sci Technol 31: 1054-61 (1997) (5) Jay K, Stieglitz L; Chemosphere 30: 1249-60 (1995) (6) Johnson BL; Chemosphere 31: 2415-28 (1995) R157: (1) Hoekstra EJ et al; Chemosphere 38: 2875-83 (1999) (2) Pavlostathis SG, Zhuang P; Chemosphere 27: 586-96 (1993) (3) Broholm K et al; Environ Technol 12: 279-89 (1991) R158: (1) Pearson CR, McConnell G; Proc Roy Soc London Ser B 189: 305-32 (1975) (2) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (3) Heida H; Contam Soil Int Conf 909-912 (1986) R159: (1) Lillian D et al; Amer Chem Soc Symp Ser 17: 152-8 (1975) (2) Andelman JB; Environ Health Persp 62: 313-8 (1985) R160: (1) Barkley J et al; Biomed Mass Spectron 7: 139-47 (1980) (2) Monster AC, Smolders JFJ; Int Arch Occup Environ Health 53: 331-6 (1984) (3) Herbert P et al; Chem Ind 24: 861-9 (1986) R161: (1) Lillian D et al; Amer Chem Soc Symp Ser 17: 152-8 (1975) (2) Khalil MAK, Rasmussen RA; Environ Sci Technol 17: 157-64 (1983) (3) Singh HB et al; Atmospheric Distrbutions, Sources and Sinks of Selected Halocarbons, Hydrocarbons, SF6 and N20. USEPA-600/3-79-107 p. 88,117-8 (1979) R162: (1) Lillian D et al; Amer Chem Soc Symp Ser 17: 152-8 (1975) (2) Pellizzari ED; Quantation of Chlorinated Hydrocarbons in Previously Collected Air Samples. USEPA-450/3-78-112 (1978) (3) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) (4) Su C, Goldberg ED; Mar Pollut Transfer pp. 353-74 (1976) (5) Leoy PJ et al; Atmos Environ 17: 2321-30 (1983) (6) Barkley J et al; Biomed Mass Spectron 7: 139-47 (1980) (7) Monster AC, Smolders JFJ; Int Arch Occup Environ Health 53: 331-6 (1984) (8) Kawata K et al; Bull Environ Contam Toxicol 57: 1-7 (1996) R163: McConnell G et al; Endeavour 34: 13 as cited in USEPA; Ambient Water Quality Criteria Doc: Tetrachloroethylene p.C-1 (1980) EPA 440/5-80-073 R164: (1) Entz RC, Hollifield HC; J Agric Food Chem 30: 84-88 (1982) (2) McConnell G et al; Endeavour 34: 13-18 (1975) (3) Heikes DL, Hopper ML; J Assoc Anal Chem 69: 990-98 (1986) (4) Page BD, Lacroix GM; J AOAC Int 78: 1416-28 (1995) R165: (1) Pearson CR, McConnell G; Proc Roy Soc London Ser B 189: 305-22 (1975) R166: (1) Pearson CR, McConnell G; Proc Roy Soc London Ser B 189: 305-32 (1975) (2) Dickson AG, Riley JP; Mar Pollut Bull 7: 167-9 (1976) (3) Binnemann PH et al; A Lebensm - Unters Forsch 176: 253-61 (1983) (4) Gotoh M et al; Bull Environ Contam Toxicol 60: 74-80 (1998) R167: (1) Pearson CR, McConnell G; Proc Roy Soc London Ser B 189: 305-32 (1975) R168: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Jensen AA; Res Rev 89: 1-128 (1983) R169: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Verberk MM, Scheffers TML; Environ Res 21: 432-7 (1980) R170: (1) Yoshida K; Chemosphere 27: 621-30 (1993) R171: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Jensen AA; Res Rev 89: 1-128 (1983) (3) Barkley J et al; Biomed Mass Spectrom 7: 139-47 (1980) (4) McConnell G et al; Endeavour 34: 13-8 (1975) (5) Verberk MM, Scheffers TML; Environ Res 21: 432-7 (1980) R172: (1) Antoine SR et al; Bull Environ Contam Toxicol 36: 364-71 (1986) (2) Wallace L et al; J Occup Med 28: 603-7 (1986) (3) Monster AC, Smolders JFJ; Int Arch Environ Health 53: 331-6 (1984) (4) Stanley JS; Broad Scan Analysis of the FY82 National Human Adipose Tissue Survey Specimens Vol. I Executive Summary p. 5 USEPA-560/5-86-035 (1986) R173: 29 CFR 1910.1000 (7/1/2000) R174: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R175: WHO; Environ Health Criteria: Tetrachloroethylene p.35 (1984) R176: American Industrial Hygiene Association. The AIHA 2000 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. AIHA Press, Fairfax, VA. 2000. 27 R177: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R178: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R179: 40 CFR 401.15 (7/1/2000) R180: 40 CFR 716.120 (7/1/2000) R181: 40 CFR 261.24 (7/1/2000) R182: 40 CFR 261.31 (7/1/2000) R183: Barcelona MJ et al; Anal Chem 27 (2): 460-4 (1985) R184: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R185: Rasmussen RA et al; J Air Poll Cont Assoc 27: 579 (1977) R186: IOFFE BV ET AL; J CHROMATOGR 142: 787-95 (1977) R187: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 498 (1979) R188: GURKA DF, BETOWSKI LD; ANAL CHEM 54: 1819 (1982) R189: OFSTAD EB ET AL; THE SCIENCE OF THE TOTAL ENVIRONMENT 20: 205-16 (1981) R190: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R191: 40 CFR 136 (7/1/87) R192: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R193: Benoit FM et al; Int Arch Occup Health 55 (2): 113-20 (1985) R194: Nat Transp Safety Board; Railroad Accident Report: Derailment of Illinois Central Gulf Railroad Freight Train Extra 9629 East and Release of Hazardous Materials at Livingston, LA on September 28, 1982 80 pp. (1983) NTSB/RAR-83105 RS: 156 Record 23 of 1119 in HSDB (through 2003/06) AN: 125 UD: 200303 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRAHYDROFURAN- SY: *BUTANE,-1,4-EPOXY-; *BUTANE-ALPHA,-DELTA-OXIDE-; *BUTYLENE-OXIDE-; *CYCLOTETRAMETHYLENE-OXIDE-; *DIETHYLENE-OXIDE-; *1,4-EPOXYBUTANE-; *FURANIDINE-; *FURAN,-TETRAHYDRO-; *HYDROFURAN-; *NCI-C60560-; *OXACYCLOPENTANE-; *OXOLANE-; *TETRAHYDROFURAAN- (DUTCH); *TETRAHYDROFURANNE- (FRENCH); *TETRAIDROFURANO- (ITALIAN); *TETRAMETHYLENE-OXIDE-; *THF- RN: 109-99-9 RELT: 89 [FURAN] (Analog) MF: *C4-H8-O SHPN: UN 2056; Tetrahydrofuran IMO 3.1; Tetrahydrofuran STCC: 49 082 90; Tetrahydrofuran HAZN: U213; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Manufactured by catalytic hydrogenation of maleic anhydride. [R1] *(1) Catalytic hydrogenation of furan with nickel catalyst. (2) Acid-catalyzed dehydration of 1,4-butanediol. [R2, 1087] *Decarboxylation of furfural with zinc-chromium-molybdenum catalyst with hydroxylation to THF. [R3] *Reaction of acetylene and formaldehyde under high pressure and copper catalysis to yield butanediol which is then dehydrated to THF. [R3] *DuPont announced the commercialization of a moving-bed recycle-based technology for the oxidation of butane to maleic anhydride... for hydrogenation to tetrahydrofuran [R4] IMP: *Stabilized to prevent excess peroxide formation on storage: with 0.05-1.0% p-cresol, 0.05-0.1% hydroquinone, or less than 0.01-0.1% 4,4'-thiobis(6-tert-butyl-m-cresol): Bordner, Hinegardner, and Campbell, US patents 2,489,260, 2,525,410 and 3,029,257 (1949, 1950, and 1962, all to Du Pont). [R1] *Peroxide (as hydrogen peroxide): 0.015%, water: 0.02% [R5] FORM: *Grades: technical, spectrophotometric. [R2, 1574] *Liquid, industrial, 99.5% grades [R6, 123] *99.9%, HPLC, spectrophotometric, anhydrous, UV, nonspectro reagent grades [R6, 324] MFS: *BASF Corp., Chemical Div., Chemical Intermediates, 3000 Continental Dr - North, Mount Olive, NJ 07828-1234, (973) 426-2600; Production site: Geismar, LA 70734 [R7] *DuPont, DuPont Specialty Chemicals, 1007 Market St., Wilmington, DE 19898, (800) 441-7515. DuPont Performance, Specialty and Fine Chemicals; Production site: La Porte, TX 77571 [R7] *Lyondell Chemical Co., 1221 McKinney St., Suite 700, Houston, TX 77010, (713) 652-7200; Production site: Channelview, TX 77530 [R7] *Penn Specialty Chemicals, Inc., Six Tower Bridge, 181 Washington St., Suite 450, Conshohocken, PA 19428, (877) 895-PENN; Production site: Memphis, TN 38108 [R7] OMIN: *0.025% BUTYLATED HYDROXYTOLUENE (BHT) PRESENT TO PREVENT PEROXIDE FORMATION. [R8] *Commercial material is supplied stabilized with a phenolic antioxidant which is effective under normal closed storage conditions in preventing the formation and accumulation of peroxide. ... Copper chloride /is used/ for removal of trace amt of peroxides. ... The use of lithium tetrahydroaluminum is only recommended for drying tetrahydrofuran which is peroxide-free and is not grossly wet. ... Peroxides in THF may be destroyed by passing through activated carbon at 20-66 deg C with contact time > 2 min. [R9, 448] USE: *Solvent for high polymers, esp. polyvinyl chloride. As reaction medium for Grignard and metal hydride reactions. In the synthesis of butyrolactone, succinic acid, 1,4-butanediol diacetate. Solvent in histological techniques. [R1] *SOLVENT FOR FAT OILS, UNVULCANIZED RUBBER; FOR MAKING ADIPIC ACID [R10] *Solvent in preparation of printing inks, adhesives, lacquers, and other coatings; Grignard reagent in synthesis of motor fuels, vitamins, hormones, pharmaceuticals, synthetic perfumes, organometallic cmpds, and insecticides. [R11, 1981.3] *Solvent for natural and synthetic resins, particularly vinyls, in topcoating solutions, polymer coating, cellophane, protective coatings, adhesives, magnetic tapes, printing inks, etc., Grignard reactions, lithium aluminum hydride reductions, and polymerizations; chemical intermediate and monomer. [R2, 1087] *Solvent for production of tetraethyl and tetramethyl lead. [R12, 643] *Polyacetal resin comonomer; solvent (Grignard reagents, tetraethylead production, solution styrene-butadiene rubber production, magnetic tape production, polyvinyl chloride/rubber bonding, printing plates); vinylidene copolymer solvent (cellophane coatings). [R13] CPAT: *Resin solvent 40%, Chemical Int 40%, Grignard reaction solvent 20%. [R14] *SOLVENT FOR RESINS, 40%; CHEMICAL INTERMEDIATE, 40%; REACTION SOLVENT, 20% (1977) [R15] *Polytetrahydrofuran, 68%; coating solvent, 23%; other (reaction solvent, thiophane), 9% (1983) [R16] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 2.72X10+10 G [R15] *(1982) 4.85X10+10 G [R15] *(1985) 5.46X10+10 g [R17] *(1987) 1.42X10+8 lb [R18] *(1988) 9.38X10+7 lb [R19] *94,353,000 kg in 1993 [R20] U.S. IMPORTS: *(1974) 4.2X10+5 lb/yr [R21] *(1975) 8.2X10+4 lb/yr [R21] *(1985) 1.24X10+8 g [R22] *(1986) 8.12X10+4 lb [R23] U.S. EXPORTS: *(1978) 4.99X10+9 G [R15] *(1983) 6.73X10+9 G [R15] *(1985) 1.71X10+8 g [R24] *(1987) 9.50X10+6 lb [R25] *(1988) 1.01X10+7 lb [R26] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, mobile liquid [R27]; *Water-white liquid [R2, 1087]; *Colorless liquid [R28, 302] ODOR: *Ether-like odor [R1]; *FAINT FRUITY ODOR [R8] TAST: *PUNGENT TASTE [R29] BP: *65 deg C @ 760 mm Hg [R30] MP: *-108.3 deg C [R30] MW: *72.11 [R30] CORR: *Tetrahydrofuran will attack some forms of plastics, rubber, and coatings. [R11, 1981.2] CTP: *Critical temperature: 268.0 deg C; critical pressure: 51.2 atm [R31, 536] DEN: *0.8892 @ 20 deg C [R30] HTC: *-14,990 BTU/lb= -8330 cal/g= -348.8X10+5 J/kg [R8] HTV: *180 BTU/lb= 98.1 cal/g= 4.1X10+5 J/kg [R31, 546] OWPC: *Log Kow= 0.46 [R32] SOL: *30% IN WATER @ 25 DEG C [R29]; *Miscible with alcohols, ketones, esters, hydrocarbons, and ethers. [R1]; *Very soluble in acetone, benzene, ether, ethanol, and chloroform [R33]; *Miscible in water at 25 deg C [R34] SPEC: *Index of refraction: 1.4050 @ 20 deg C/D [R30]; *UV cutoff for spectro grade: 220 NM [R1]; *Tetrahydrofuran, 99.5%, exhibits its two strongest infrared absorption bands at wavelengths of 9.4 and 11.0 microns. [R35]; *UV Absorbance, maximum: 1.00 at 225 nm, 0.50 at 240 nm, 0.25 at 250 nm, 0.08 at 270 nm, 0.02 at 290 nm, 0.01 at 320-400 ppm /'Photrex' Reagent, for spectrometry, 1.00 cm path length vs distilled water/ [R5]; *IR: 74 (Sadtler Research Laboratories Prism Collection) [R33]; *1H-NMR: 77 (Varian Associates NMR Spectra Catalogue) [R33]; *MASS: 61288 (NIST/EPA/MSDC Mass Spectral Database 1990 Version) [R33]; *13C-NMR: 73 (Johnson and Jankowski: Carbon-13 NMR Spectra, J Wiley and Sons, NY) [R33] SURF: *26.4 dynes/cm @ 25 deg C [R31, 536] VAPD: *2.56 (Air= 1) [R31, 536] VAP: *1.62X10+2 mm Hg @ 25 deg C [R36] EVAP: *8 (Butyl acetate= 1) [R31, 536] VISC: *0.53 cP @ 20 deg C [R31, 536] OCPP: *CONVERSION FACTOR: 1 PPM= 2.94 MG/CU M; 1 MG/L= 340 PPM [R37, 700] *RATIO OF SPECIFIC HEATS OF VAPOR (GAS): (EST) 1.083 [R8] *Saturated liquid density: 55.230 lb/cu ft; saturated vapor pressure: 2.913 lb/sq in; saturated vapor density: 0.03660 lb/cu ft (all at 75 deg F) [R8] *Liquid heat capacity: 0.401 BTU/lb-F at 70 deg F [R8] *Ideal gas heat capacity: 0.375 BTU/lb-F at 100 deg F [R8] *Dielectric constant: 7.4 at 25 deg C [R31, 536] *Electrical conductivity: 1.5X10-8 mohm/cm @ 25 deg C [R31, 536] *Dipole moment: 1.75 debyes @ 25 deg C [R31, 536] *Enthalpy of formation: -51.67 kcal/mole (liquid) [R38, p. 5-38] *Enthalpy of sublimation @ 298 K: 7.65 kcal/mole [R38, p. 5-72] *Critical volume: 224 cu cm/mole [R38, p. 5-88] *Vapor pressure = 0.06 atm at 0 deg C, 0.11 atm at 10 deg C, 0.173 atm at 20 deg C, 0.26 atm at 30 deg C [R39] *Henry's law constant: 7.05X10-5 atm-cu m/mole @ 25 deg C [R40] *Hydroxyl radical reaction rate constant: 1.61X10-11 cu cm/molecule-sec @ 25 deg C [R41] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *Tetrahydrofuran (THF) is a very hazardous substance due primarily to its flammable and explosive properties. Toxicity is also of concern and must be considered in the safe handling and storage of THF. Irritation from dermal contact with THF warrants the wearing of neoprene gloves and safety glasses for protection during the routine handling of this substance. Toxic, as well as flammable, concentrations of THF in air can be avoided by compliance with the TLV of 200 ppm. However, in emergency situations, such as fires involving THF or when the Short Term Exposure Limit (STEL) of 250 ppm is exceeded, a self-contained breathing apparatus and an approved organic vapor cannister, respectively, are needed. THF is highly volatile with a low flash point (1 deg F) and flammability limit of 2%. Its heavier-than-air vapors can travel at low profile for considerable distances and flash back to the point of origin. Further, unstabilized THF forms peroxides upon exposure to air or light, which, if allowed to accumulate above 1% become thermally explosive. THF also reacts explosively with lithium-aluminum alloys. In consideration of the above, THF should be contained in tightly sealed dark glass bottles or steel drums affixed with the DOT-required label, "Flammable Liquid". Should THF leak from containment vessels, its faint, fruity smell, is detectable at 50 ppm and may serve as a warning. Containers should be stored in cool, dark, well-ventilated areas, away from ignition sources and oxidizing materials. Should a THF fire occur, it may be combated with dry chemical or CO2 extinguishants. Water may be ineffective in firefighting. However, if a leak or spill has not ignited, it may be flushed with water for cooling and diluting if conditions of ignition threaten. Knock down vapors with water spray. Spills or leaks should be absorbed with paper or dissolved in petroleum ether or alcohol (of a higher molecular weight than butyl alcohol); then collected and removed for outdoor evaporation or safe incineration. DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R42] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R42] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R42] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R42] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R42] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R42] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R42] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R42] FPOT: *Flammable, dangerous fire risk. [R43] *A very dangerous fire hazard when exposed to heat, flame, oxidizers. [R44] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R45, p. 325-85] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R45, p. 325-85] *Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R45, p. 325-85] FLMT: *LOWER: 2% UPPER: 11.8% (% BY VOL) [R45, p. 49-126] FLPT: *6 deg F (closed cup); -4 deg F (open cup) [R8] *-14.5 deg C (closed cup) [R46, 1991.1415] AUTO: *321 DEG C (610 DEG F) [R45, p. 49-126] FIRP: *Approach fire from upwind to avoid hazardous vapors and toxic decompositions. Use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R45, p. 49-126] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R47, 1040] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame--consider evacuation of one-third (1/3) mile radius. [R47, 1040] *Closed containers may rupture violently when heated. [R45, p. 49-126] TOXC: *When heated, an irritating vapor is generated. [R8] OFHZ: *Vapor is heavier than air and may travel considerable distance to source of ignition and flash back. [R45, p. 49-126] EXPL: *Explosive in the form of vapor when exposed to heat or flame. In common with ethers, unstabilized tetrahydrofuran forms thermally explosive peroxides on exposure to air. [R44] *Explosive reaction with /potassium hydroxide; sodium aluminum hydride; sodium hydroxide/; sodium tetrahydroaluminate. Reacts with 2-aminophenol + potassium dioxide to form an explosive product. Reacts with lithium tetrahydroaluminate or borane to form explosive hydrogen gas. [R44] REAC: *UNSTABILIZED TETRAHYDROFURAN FORMS THERMALLY EXPLOSIVE PEROXIDES ON EXPOSURE TO AIR. STORED THF MUST ALWAYS BE TESTED FOR PEROXIDES PRIOR TO DISTILLATION. PEROXIDES CAN BE REMOVED BY TREATMENT WITH STRONG FERROUS SULFATE SOLN MADE SLIGHTLY ACIDIC WITH SODIUM BISULFATE. [R44] *An attempt to remove peroxides /from tetrahydrofuran/ by shaking with solid ferrous sulfate before distillation did not prevent explosion of the distillation residue. Alkali treatment to destroy peroxides appears not to be safe. [R48, 467] *Peroxidized material /tetrahydrofuran/ should not be dried with sodium or potassium hydroxide, as explosions may occur. [R48, 467] *Tetrahydrofuran had been dried over the aluminate and then stored over calcium hydride for 2 yr to prevent peroxide formation. Subsequent addition of more aluminate caused a strong exotherm and ignition of liberated hydrogen. [R48, 45] *During synthesis of sodium tetrahydroaluminate from its elements in tetrahydrofuran, a violent explosion occurred when absorption of hydrogen had stopped. This was attributed to deposition of solid above the liquid level, overheating and reaction with solvent to give butoxyaluminohydrides. Vigorous stirring and avoiding overheating are essential. [R48, 46] *Rapid addition of bromine to the dried solvent /tetrahydrofuran/ to make a 10% solution caused a vigorous reaction with gas evolution. ... Photocatalyzed bromination of the solvent may have been involved. ... [R48, 102] *Addition of anhydrous chlorides (hafnium tetrachloride, titanium tetrachloride, and zirconium tetrachloride) directly to tetrahydrofuran caused a violent exothermic reaction. [R48, 1049] *2-Aminophenol was being oxidized in tetrahydrofuran solution at 65 deg C using a larger than normal proportion of potassium dioxide. When stirring was stopped after 6 hr, a violent explosion occurred. ... attributed to formation of tetrahydrofuranyl hydroperoxide by the excess dioxide. [R48, 1305] *EXPLOSIONS MAY ... OCCUR WHEN /TETRAHYDROFURAN/ IS BROUGHT INTO CONTACT WITH LITHIUM-ALUMINUM ALLOYS. [R29] *SAFETY IN HANDLING TETRAHYDROFURAN IN LAB IS DISCUSSED IN RELATION TO AN EXPLOSION WHICH OCCURRED IN A UNIVERSITY LAB DURING REFLUXING OF TETRAHYDROFURAN WITH CALCIUM HYDRIDE. [R49] *A glass bottle containing a 1 m solution /which is stabilized with 5 mol% of sodium tetrahydroborate/ of the complex /borane-tetrahydrofuran/ in THF exploded after 2 wk in undisturbed lab storage out of direct sunlight at 15 deg C. ... Tetrahydroborate content may in fact have destabilized the borane-THF reagent, with generation of hydrogen pressure in the closed bottle. [R9, 61] *A violent explosion during reflux of the solvent /tetrahydrofuran/ with calcium hydride was attributed to cleavage of the cyclic ether by overheated excess hydride. [R48, 467] *Using potassium hydroxide /or sodium hydroxide/ to dry impure tetrahydrofuran, which can contain peroxides, is hazardous. Serious explosions can occur. [R45, p. 491-194] *Strong oxidizers, lithium-alluminum alloys [Note: Peroxides may accumulate upon prolonged storage in presence of air]. [R28, 302] DCMP: *When heated to decomp it emits acrid smoke and irritating fumes. [R44] *Upon contact with air, THF may decompose into explosive peroxides and carbon monoxide. [R46, 1991.1517] ODRT: *20-50 ppm [R8] *7.3-10.2 mg/cu m (recognition in air) [R50, 1089] *Low: 7.37 mg/cu m; High: 177.0 mg/cu m /From table/ [R51] SERI: *Strong irritant to skin and mucous membranes ... [R52] *Vapor: Irritating to eyes, nose and throat. ... Liquid: Irritating to skin and eyes. [R8] EQUP: *THE WEARING OF PERSONAL PROTECTIVE EQUIPMENT IS RECOMMENDED FOR WORKERS WHO ARE DIRECTLY EXPOSED TO ... /TETRAHYDROFURAN/. [R29] *Wear special protective clothing and positive pressure self-contained breathing apparatus. [R45, p. 49-126] *Employees should be provided with and required to use impervious clothing, gloves, face-shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with tetrahydrofuran. Employees should be provided with and required to use splash-proof goggles where there is any possibility of liquid tetrahydrofuran contacting the eyes. [R11, 1981.3] *Personnel protection: ... Wear appropriate chemical protective gloves, boots, and goggles. [R47, 1040] *Breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for natural rubber (Nat. rub), neoprene (Neop), neoprene/natural rubber (neop/nat rub), nitrile rubber (nitrile), polyethylene (PE), chlorinated polyethylene (CPE), polyvinyl alcohol (PVA) and polyvinyl chloride (PVC). No data for butyl rubber (butyl), nitrile rubber/polyvinyl chloride (nitrile/PVC), polyurethane (PU) and viton. [R53] *Wear appropriate personal protective clothing to prevent skin contact. [R28, 302] *Wear appropriate eye protection to prevent eye contact. [R28, 302] *Recommendations for respirator selection. Max concn for use: 2000 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R28, 302] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R28, 302] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R28, 302] OPRM: *Avoid long contact with skin. [R54] *Contact lenses should not be worn when working with this chemical. [R28, 302] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *TETRAHYDROFURAN SHOULD BE USED WITH GREAT CARE AND SHOULD BE TESTED FOR ABSENCE OF PEROXIDES WITH POTASSIUM IODIDE-STARCH PAPER EVERY TIME IT IS USED. [R55] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R11, 1981.2] *Clothing wet with liquid tetrahydrofuran should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of tetrahydrofuran from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the tetrahydrofuran the person performing the operation should be informed of tetrahydrofuran's hazardous properties. Any clothing which becomes contaminated with liquid tetrahydrofuran should be removed immediately and not reworn until the tetrahydrofuran is removed from the clothing. [R11, 1981.3] *Skin that becomes wet with liquid tetrahydrofuran should be promptly washed or showered to remove any tetrahydrofuran. [R11, 1981.3] *Persons not wearing protective equipment and clothing should be restricted from areas of spills or leaks until cleanup has been completed. [R11, 1981.3] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R47, 1041] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R47, 1041] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R47, 1041] *The worker should immediately wash the skin when it becomes contaminated. [R28, 302] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R28, 302] SSL: *Tetrahydrofuran will auto-oxidize in the presence of light and O2 to form resinous products that color water from pink to brown at conc above 100-250 mg/l. [R56] *May form, organic peroxides when exposed to air or light but usually inhibited against peroxide formation. [R57] *Upon contact with air, THF may decompose into explosive peroxides and carbon monoxide. [R46, 1991.1517] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R58] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R59] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R60] STRG: *Store in a cool, dry, well-ventilated location. Store away from heat, oxidizing materials, and sunlight. Outside or detached storage is preferred. Inside storage should be a standard flammable liquids storage warehouse, room, or cabinet. [R45, p. 49-126] *STORAGE TEMPERATURE: AMBIENT. [R8] *Distillation or alkali treatment of stabilized tetrahyrofuran removes the involatile anti-oxidant, and the solvent must be restabilized or stored under nitrogen to prevent formation during storage, which should not exceed a few days duration in the absence of stabilizer. [R48, 467] CLUP: *Absorb with paper. Evaporate completely all spilled surface. Dispose by burning the paper after complete ventilation of vapor. [R57] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U213, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R61] *A good candidate for liquid injection incineration at a temperture range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. Also, a good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. Also, a good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R62] *Tetrahydrofuran is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. In controlled waste containing peroxides, perforation of a container of the waste form a safe distance is followed by open burning. [R63] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *HUMAN TOXICITY: Data pertaining to the toxicity of tetrahydrofuran (THF) in humans is quite limited. The probable oral lethal dose in humans is 50-500 mg/kg. Severe occipital headaches were reported in the testing for pharmacological properties of THF and among technicians performing animal experiments. Toxicity (TCLo) is expected following exposure to a 2.5% concn of THF. ANIMAL TOXICITY: Animal studies indicate that THF is only "MODERATELY TOXIC" from acute exposure with the lowest reported LD50's of 1900-2900 mg/kg by oral route. Median lethal concns by inhalation varied with the duration of exposure but were > 20,000 ppm with all species for exposures of 1 hr or less. Reports of animal studies document irritation of the skin and mucous membranes, including the eyes, nose, and upper respiratory tract, as the predominant effect from lower exposures (about 100-200 ppm). High acute doses (about 25,000 ppm) produced anesthesia with delayed induction and recovery periods, accompanied by a fall in blood pressure and strong respiratory stimulation. The margin of safety between anesthesia and death is small. Other effects recorded are those of damage to liver, kidneys, and lung after prolonged exposures to levels of THF > 1000 ppm. Toxic manifestations varied somewhat with the route of exposure with irritation of upper respiratory tract observed with inhaled THF and inflammation of the GI tract following oral ingestion. The only report on carcinogenicity is that of a test for skin tumors in which THF was applied to the skin of mice twice/wk for 25 exposures with an observation period of 17.5 months. No carcinogenic effect was observed. THF was negative when tested for mutagenicity using the Ames test; however, it would appear to enhance the mutagenicity of certain tryptophan-pyrolysate substances. No information is presented on metabolism, absorption, and distribution. The only report on excretion is the finding of THF in mother's milk. ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Provide a low-stimulus environment. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Treat frostbite by rapid rewarming ... . /Ethers and related compounds/ [R64, 224] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Ethers and related compounds/ [R64, 225] +Inhalation Developmental Toxicology Studies: Teratology Study of Tetrahydrofuran (CAS No. 109-99-9) in Mice and Rats NTP Study: TER88047 ABSTRACT Tetrahydrofuran (THF), a four-carbon cyclic ether, is widely used as an industrial solvent. Although it has been used in large quantities for many years, few long-term toxicology studies, and no reproductive or developmental studies, have been conducted on THF. This study addresses the potential for THF to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1(R) ) mice to 0, 600, 1800, or 5000 ppm tetrahydrofuran (THF) vapors, 6 hours per day, 7 days per week. Each treatment group consisted of 10 virgin females (for comparison), and 33 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. The only overt symptom exhibited by pregnant rats was a reduction in body weight gain for the 5000-ppm group and there were no maternal deaths. However, mean body weights of virgin females were not affected, thus indicating that pregnancy was a factor in the toxicological response. The pregnancy rate was 93%. The mean gravid uterine weight and the extragestational weight gain (EGWG; sacrifice body weight minus gravid uterine weight minus 0 dg weight) were reduced for the 5000-ppm group relative to the control, but the difference was not significant. There were no treatment-related effects on the number of implantations, the mean percent of live pups/litter and resorptions/litter, or on the fetal sex ratio. Fetal weights were significantly reduced for the 5000-ppm exposure group relative to controls. The mean percent affected fetuses per litter was not significantly different among treatment groups for any individual malformation or variation or for combined totals. Mice exhibited overt symptoms of toxicity at the 1800- and 5000-ppm THF concentrations. Approximately 30% of the animals in the 1800-ppm group, and all in the 5000-ppm group, were subject to narcosis. Approximately 27% of the pregnant animals and 30% virgins in the 5000-ppm group died during the first six days of exposure; consequently, this group was removed from exposure to prevent further mortality. There were no maternal deaths in either the 600 or 1800-ppm exposure groups. As in rats, the mean body weights of virgin mice at sacrifice were not significantly affected by exposure to THF. Mean body weights of pregnant mice and uterine weights were significantly less than controls for the 5000- and 1800-ppm groups at sacrifice. The EGWG was also significantly reduced for the 5000-ppm group. There was no effect on the number of implantations per dam, and the mean pregnancy rate for all mated mice was 86%. There was a significant reduction in the mean percent of live pups/litter for the 1800- and 5000-ppm groups and a corresponding increase in the percent of resorptions/litter. Pregnant females in the 5000-ppm exposure group that survived to the scheduled sacrifice had litters with a 95% incidence of resorption. Neither fetal weight nor the sex ratio was affected in the 600- or 1800-ppm groups. The mean percent affected fetuses per litter was not significantly different among treatment groups for any individual malformation or for combined totals. There was an exposure-correlated increase in the incidence of reduced sternebral ossifications; however differences between groups were not significant. Swiss (CD-1(R) ) mice appeared to be much more susceptible to the toxic effects of THF, manifested as narcosis, mortality, and intrauterine death, than were the rats. The rats appeared unaffected by THF exposure except for a slight, but significant, decrease in maternal and fetal weight at the 5000-ppm level. Interestingly, in mice the reduction in maternal weight gain and the increase in intrauterine death at the 1800-ppm level were not accompanied by a treatment-associated decline in live fetal weight, nor by an increase in the incidence of fetal malformations. These facts suggest that in mice, if the conceptus survives, development as assessed by this experimental design, continues in a normal fashion. Report Date: August 1988 [R65] MEDS: *Consider the points of attack /eyes, skin, resp system, CNS/ in preplacement and periodic physical exam. [R12, 848] *The following medical procedures should be made available to each employee who is exposed to tetrahydrofuran at potentially hazardous levels: (1) Initial Medical Screening: Employees should be screened for history of certain medical conditions (listed below) which might place the employee at increased risk from tetrahydrofuran exposure. These are skin, liver, kidney, and chronic respiratory diseases. (2) Periodic Medical Examination: Any employee developing the above listed conditions should be referred for further medical examination. [R11, 1981.1] *The assessment of tetrahydrofuran can be accomplished through measurement of tetrahydrofuran where airborne exposure levels were found to correlate with urinary tetrahydrofuran levels, when measured at a specified time post tetrahydrofuran exposure. However, no information was located which demonstrated a correlation between urinary tetrahydrofuran levels and the onset of adverse health effects. Urine Reference Ranges: Normal - Not established; Exposed - BEI (sampling time is end of shift, measured as tetrahydrofuran: 8 mg/l (Notice of intent to establish); Toxic - not established. [R66, 1124] *Chest Radiography: Chest radiographs are widely used to assess pulmonary diesase. They are useful for detecting early lung early lung cancer in asymptomatic people, and especially for detecting of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, experts' views on the risk-to-benefit ratio in detection of pulmonary disease conflict, so routine annual chest x-rays are not recommended for all people. [R66, 1125] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. [R66, 1125] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. [R66, 1126] HTOX: *... SEVERE OCCIPITAL HEADACHE REPORTED IN INVESTIGATORS TESTING ITS PHARMACOLOGICAL PROPERTIES. [R52] *Signs and symptoms accompanied by a marked decrease in the number of white blood cells were observed in researchers engaged in experimental spinning of synthetic fibers. These effects were suspected to be due to poisoning by tetrahydrofuran which was used as a solvent for polyvinyl chloride. ... [R67] *Tetrahydrofuran can cause dermatitis on prolonged exposure. [R11, 1981.1] *Exposure to THF has been reported to be irritating to the skin, eyes, and mucous membranes; no specific concn for irritation has been described. Individuals exposed to high concn of THF have elevated circulating enzymes and have complained of nausea, tinnitus, and occipital headache. [R46, 1991.1518] *Liver biopsy confirmed fatty degeneration and siderosis along with elevated gamma glutamyl transferase and alanine aminotransferase occurred in one adult male occupationally exposed to THF. [R46, 1991.1518] */Case study:/ A polyvinyl chloride pipe insulator ... /was exposed/ to THF ... /for/ 2 wks in a poorly ventilated, confined space. After hospitalization for acute appendicitis with enflurane anesthesia, the patient developed cerebral convulsions. ... /It was/ suggested that the interaction of the anesthetic and occupational exposure to THF may have contributed to the onset of the convulsions. [R46, 1991.1518] *Two cases of occupational exposure to THF were reported ... The symptoms included irritation of mucous membranes, nausea, headache, dizziness, and possible cytolytic hepatitis. The effects on mucous membranes and the central nervous system resolved within a few hours after cessation of exposure. [R46, 1991.1518] *This study /was conducted/ in a video tape manufacturing facility in Singapore where workers were exposed to mixed solvents consisting of methyl ethyl ketone (MEK), cyclohexanone (CHE), tetrahydrofuran (THF), and toluene (TOL). The objectives were to quantify workers' exposure to the various solvents and to evaluate if there were any neurobehavioral changes among workers compared to controls. Nineteen exposed workers out of a workforce of 45 were studied. Twenty six workers (with no exposure) matched for ethnic group, age, years of education served as controls. Eight hr personal environmental samples were analyzed for the 19 workers along with symptom questionnaires, clinical exam, and neurobehavioral tests including the Santa Ana Dexterity, Finger Tapping, Digit Span, and Visual Reproduction tests. The mean TWA concn /for the cmpds/ were all below the threshold limit values (TLVs). However, the total solvents concn index exceeded unity in one of the work areas. Significant differences were /noted/ for prevalence of headache, and eye and nose irritation among the exposed workers. There were also significant differences for the Santa Ana test for both hands, Digit Span test and Visual Reproduction test. ... No dose effect relation between behavioral scores and airborne solvent exposure was noted. ... [R68] NTOX: *A single 4 hr inhalation of THF in rabbits in the range of 100 to 12,000 ppm resulted in a transient dose related decrease of tracheal ciliary activity. Single or repeated exposures have been associated with cytolytic hepatitis and fatty degeneration of the liver. [R46, 1991.1517] *... Concentrations of THF > 25,000 ppm were required to produce anesthesia. The anesthetic properties were rather poor in that onset was delayed and recovery poor; this was accompanied by pronounced hypotension and marked respiratory hyperpnea. There was a narrow margin of safety between anesthesia and death in dogs and mice. [R46, 1991.1517] *... When dogs inhaled 200 ppm THF 6 hr/day for 3 to 4 weeks, an observable effect on pulse pressure was recorded; however, no demonstrable histopathologic changes were found despite extended exposure of 9 weeks, followed by an additional 3 week exposure at up to 400 ppm. [R46, 1991.1517] *ACUTE ORAL ADMIN /OF TETRAHYDROFURAN TO CATS/ WAS FOUND ... TO CAUSE INFLAMMATION, NECROSIS AND HEMORRHAGE OF GASTROINTESTINAL TRACT. KIDNEYS SHOWED INJURY TO TUBULES. ... INFLAMMATION /OF LIVER/ AND CONGESTION AND EDEMA /OF LUNGS, WERE OBSERVED/. [R37, 701] *THF was irritating to rabbits when applied topically in aq soln exceeding 20% concn. [R46, 1991.1517] *Male rats that inhaled more than 5000 ppm THF for 12 weeks at 4 hr/day showed signs of systemic intoxication, skin and respiratory tract irritation, liver function disturbance, and abnormalities in glucose metabolism. Although systemic effects were not observed after similar exposures at lower concn, slight respiratory tract irritation occurred in some rats that inhaled concn less than 200 ppm. [R46, 1991.1517] */CNS DEPRESSANT/ ... DOSE /OF TETRAHYDROFURAN/. BY INHALATION, FOR MICE, 6.7 VOL % IN 5 MIN; 1.1 VOL % IN 43 MIN; FOR DOGS, 5.6 VOL % (OXYGEN MIXT) FOR 2 HR. [R37, 701] *RABBITS EXPOSED TO TETRAHYDROFURAN (THF) @ 12,000 PPM FOR 4 HR HAD PARALYSIS OF THE NASAL CILIARY FUNCTION DUE TO THE ABSENCE OF CILIARY BEATING, WHILE MORPHOLOGICAL DAMAGE OF CILIATED CELLS WAS NOT SO SEVERE. MODERATE DESTRUCTIVE CASES, PARTIAL DESTRUCTION OF THE OUTER CELLULAR MEMBRANE WAS RECOGNIZED. THE FALLING OFF OR ABSENCE OF CILIATED CELLS WAS NEVER OBSERVED. [R69] *RATS WERE EXPOSED TO TETRAHYDROFURAN AT 200 OR 1000 PPM, 4 HR/WK FROM 12 TO 24 WK OF AGE. THE LOWER CONCN CAUSED SLIGHT DAMAGE WHEREAS THE HIGHER CONCN CAUSED SEVERE DAMAGE TO THE NASAL AND TRACHEAL EPITHELIUM. THE DEGREE INCL DECR NUMBER OF CILIA, VACUOLIZATION AND INCR DENSE GRANULES OF THE CYTOPLASM. [R70] *2.2 vol % Tetrahydrofuran killed 50% of exposed mice in less than 2 hr. Anesthesia was marked by prolonged induction, profuse salivation, poor muscular relaxation, fall in blood pressure, respiratory stimulation, and a narrow margin of safety. [R71] *Tetrahydrofuran tested negative for sex-linked recessive lethal heritable genetic effects in Drosophila in FY 1983. /No additional data given/ [R72] *In test results for cytogenetic effects in Chinese hamster ovary cells, tetrahydrofuran tested positive for chromosomal aberrations and negative for sister chromatid exchanges. /No additional data given/ [R73] *Oral lethal dose of a 20% solution in rabbits 2.5 g/kg. ... A vapor concn of 2.2 vol % killed 50% of exposed mice in less than 2 hr. [R52] *Tetrahydrofuran (THF) was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. THF was tested at doses of 0.1, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Tetrahydrofuran was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 10 mg/plate. [R74] *Rats were exposed to 100, 200, 1000 or 5000 ppm tetrahydrofuran for 4 hr/day for 12 weeks. 100 and 200 ppm had no significant effects except for slight mucosal irritation. 1000 ppm affected liver function as indicated by serum chemistry tests. 5000 ppm caused marked local irritant symptoms and morphological damage of the respiratory mucosae, and affected white blood cell counts, blood sugar levels and liver functions. [R75] *The LD50 of tetrahydrofuran dissolved in olive oil was approximately 2500 mg/kg in mice and dissolved in saline was 1900 and 2900 mg/kg in mice and rats, respectively. The median lethal concentration was approximately 21000 ppm in rats when tetrahydrofuran was inhaled for 3 hr. Rats exposed to 100-200 ppm of tetrahydrofuran showed no significant effects, except for slight local irritant symptoms such as redness of the nose and eyelids. Almost all rats exposed to > 5000 ppm of tetrahydrofuran displayed marked local irritant symptoms, such as edema or opacity of the cornea, salivation, and discharge or bleeding in nasal mucosa. A cataleptoid posture, coma, and clonic muscle spasms indicating irritant symptoms of the central nervous system were also observed. [R76] *Muscle acetylcholinesterase activity increased in a concentration dependent manner in male rats that inhaled 200, 1000, or 2000 ppm for 18 weeks at 6 hr/day. THF concentrations in brain and peripheral fat appeared to decrease after 2 weeks. At 200 ppm, hepatic protein and mixed function oxidase activity were increased. At 2000 ppm, liver function was inhibited. Increased skeletal muscle succinate dehydrogenase activity was noted. In a 13 week study inhalation study, ataxia was reported in rats at 5000 ppm and ... /CNS depression/ was reported in mice at 1800 ppm. Hepatocytomegaly developed in mice of both sexes at 5000 ppm; uterine atrophy and degeneration of the adrenal cortex occurred in the female mice. [R46, 1991.1517] *High concn (1x10-2 M) of THF inhibited the in vitro activity of rat hepatic cytochrome p-450 by 80%. [R46, 1991.1518] *Sensory irritation in mice exposed to chemical emissions was investigated using a modification of an ASTM standard protocol. Samples of carpet, ceiling tile, wallcovering, resilient flooring, and veneer were tested as typical indoor products. Sensory irritation during head only animal exposure was assessed by monitoring changes in respiratory frequency and waveform when test products were continuously ventilated at either 23 or 70 deg C. Animals /were exposed/ to 1 hr exposures to product emissions, corresponding to 1, 4, 24 and 27 elapsed hr of product exposure. Sensory irritation was generally not observed when products were tested at 23 deg C, but could be induced during at least one exposure period from all products except the carpet sample at 70 deg C. Although the total volatile organic cmpd emissions from a given product tested at elevated temperature incr between 5 and 30 fold from the emissions at ambient temperature, gas chemicals showed differences in the relative chemical compositions of the test atmospheres. ... Incr the temperature to 70 deg C may incr the total chemical concn of product emissions, it may not produce a chemical exposure comparable to that at ambient conditions. Since most human exposure to product emissions occurs at ambient conditions, the significance of irritation at elevated temperatures is ... questionable. [R77] *Sprague-Dawley rats and Swiss CD-1 mice were exposed to 0, 600, 1,800 or 5,000 ppm tetrahydrofuran ... vapors 6 hr/day, 7 days/wk (6-19 days of gestation) for rats; 6-17 days of gestation for mice). Body weights of pregnant rats in the 5,000 ppm group were reduced at /sacrifice/. There were no effects on the percentage of live rat fetuses/litter or on the fetal sex ratio. Fetal body weight was significantly reduced in the 5,000 ppm group, but the incidence of abnormalities was not incr. Mice in the 1,800 ppm and 5,000 ppm group were sedated during exposure; approx 27% of the mice in the 5,000 ppm group died. Mean body and uterine weights of mice were reduced for the 1,800 and 5,000 ppm groups at /sacrifice/ (18 days of gestation), but adjusted maternal weight gain was not affected at 1,800 ppm. There was a reduction in the percentage of live fetuses/litter for the mice in the 1,800 and 5,000 ppm groups (95% resorptions in the 5,000 ppm group). Fetal weight and sex ratio in mice were not affected. An incr in the incidence of reduced sternebral ossifications was correlated to tetrahydrofuran concn, although differences between groups were not statistically significant. There were no incr in the incidences of any other malformations or variations. These results suggest that tetrahydrofuran may be embryotoxic in mice, but if the conceptus survives, development as assessed by this experimental design continues in a normal fashion. The no observable adverse effect level (NOAEL) for maternal toxicity was 1,800 ppm in both rats and mice. The NOAEL for developmental toxicity was 1,800 ppm in rats and 600 ppm in mice. [R78] *... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of tetrahydrofuran in male F344/N rats based on incr incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of tetrahydrofuran in female F344/N rats exposed to 200, 600 or 1,800 ppm or male B6C3F1 mice exposed to 200, 600 or 1,800 ppm. There was clear evidence of carcinogenic activity of tetrahydrofuran in female B6C3F1 mice based on incr incidences of hepatocellular neoplasms. [R79] NTXV: *Toxicity threshold (cell multiplication inhibition test) Pseudomonas putida (bacteria) 580 mg/l; [R50, 1087] *LD50 Mouse inhalation 6.7%/30 min; [R37, 701] *LC50 Rat inhalation 80,975 ppm/1 hr; [R50, 1088] *LC50 Rat inhalation 62,000 ppm/2 hr; [R50, 1088] *LC50 Rat inhalation 18,000-22,000 ppm/4 hr; [R50, 1088] *LC50 Rat inhalation 21,000 ppm/3 hr; [R44] *Growth inhibition Microcystis (blue green algae) 225 mg/l (pH 7.0); [R80] *Toxicity threshold (cell multiplication inhibition test) Uronema parduczi Chatton-Lwoff (protozoa) 858 mg/l; [R50, 1087] *Toxicity threshold (cell multiplication inhibition test) Microcystis aeruginosa (algae) 225 mg/l; [R50, 1088] *LD50 Rat oral 3.2 ml/kg, older rats; [R46, 1991.1517] *LD50 Rat oral 2.3 ml/kg, 14 day old males; [R46, 1991.1517] *LD50 Rat oral 3.6 ml/kg, young adults; [R46, 1991.1517] *LD50 Rat oral 1650 mg/kg; [R44] *LD50 Rat ip 2900 mg/kg; [R44] *LD50 Mouse ip 1900 mg/kg; [R44] ETXV: *LC50 Pimephales promelas (fathead minnow) 2160 mg/l 96 hr flow-through bioassay, wt 0.12 g, water hardness 45.5 mg/l CaCO3, temp: 25 + or - 1 deg C, pH 7.5, dissolved oxygen greater than 60% of saturation; [R81] NTP: *... Groups of 50 male and 50 female F344/N rats were exposed to 0, 200, 600 or 1,800 ppm tetrahydrofuran by inhalation 6 hr/day, 5 days/wk for 105 wk. ... Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 200, 600 or 1,800 ppm tetrahydrofuran by inhalation, 6 hr/day, 5 days/wk for 105 wk. ... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of tetrahydrofuran in male F344/N rats based on incr incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of tetrahydrofuran in female F344/N rats exposed to 200, 600 or 1,800 ppm or male B6C3F1 mice exposed to 200, 600 or 1,800 ppm. There was clear evidence of carcinogenic activity of tetrahydrofuran in female B6C3F1 mice based on incr incidences of hepatocellular neoplasms. [R79] +... This study addresses the potential for /Tetrahydrofuran/ (THF) to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1) mice to 0, 600, 1,800, or 5,000 ppm tetrahydrofuran (THF) vapors, 6 hr/day, 7 days/wk. Each treatment group consisted of 10 virgin females (for comparison), and 33 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation (dg), and rats on 6-19 /day of gestation/. The day of plug or sperm detection was designated as 0 /day of gestation/. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 /day of gestation; mice, 18 /day of gestation/). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects. The only overt symptom exhibited by pregnant rats was a reduction in body weight gain for the 5,000-ppm group and there were no maternal deaths. However, mean body weights of virgin females were not affected, thus indicating that pregnancy was a factor in the toxicological response. The pregnancy rate was 93%. The mean gravid uterine weight and the extragestational weight gain (EGWG; sacrifice body weight minus gravid uterine weight minus 0 /day of gestation/ weight) were reduced for the 5000-ppm group relative to the control, but the difference was not significant. There were no treatment-related effects on the number of implantations, the mean % of live pups/litter and resorptions/litter, or on the fetal sex ratio. Fetal weights were significantly reduced for the 5,000-ppm exposure group relative to controls. The mean % affected fetuses/litter was not significantly different among treatment groups for any individual malformation or variation or for combined totals. Mice exhibited overt symptoms of toxicity at the 1,800- and 5,000-ppm THF concns. Approx 30% of the animals in the 1,800-ppm group, and all in the 5,000-ppm group, were subject to narcosis. Approx 27% of the pregnant animals and 30% virgins in the 5,000-ppm group died during the first 6 days of exposure; consequently, this group was removed from exposure to prevent further mortality. There were no maternal deaths in either the 600 or 1,800-ppm exposure groups. As in rats, the mean body weights of virgin mice at sacrifice were not significantly affected by exposure to THF. Mean body weights of pregnant mice and uterine weights were significantly less than controls for the 5,000- and 1,800-ppm groups at sacrifice. The EGWG was also significantly reduced for the 5,000-ppm group. There was no effect on the number of implantations/dam, and the mean pregnancy rate for all mated mice was 86%. There was a significant reduction in the mean % of live pups/litter for the 1,800- and 5,000-ppm groups and a corresponding incr in the % of resorptions/litter. Pregnant females in the 5,000-ppm exposure group that survived to the scheduled sacrifice had litters with a 95% incidence of resorption. Neither fetal weight nor the sex ratio was affected in the 600- or 1,800-ppm groups. The mean % affected fetuses/litter was not significantly different among treatment groups for any individual malformation or for combined totals. There was an exposure-correlated incr in the incidence of reduced sternebral ossifications; however differences between groups were not significant. Swiss (CD-1) mice appeared to be much more susceptible to the toxic effects of THF, manifested as narcosis, mortality, and intrauterine death, than were the rats. The rats appeared unaffected by THF exposure except for a slight, but significant, decr in maternal and fetal weight at the 5,000-ppm level. Interestingly, in mice the reduction in maternal weight gain and the incr in intrauterine death at the 1,800-ppm level were not accompanied by a treatment-associated decline in live fetal weight, nor by an incr in the incidence of fetal malformations. These facts suggest that in mice, if the conceptus survives, development as assessed by this experimental design, continues in a normal fashion. [R82] TCAT: ?Tetrahydrofuran (CAS# 109-99-9) was evaluated for the effect on cell proliferation. F344/N rats and B6C3F1 mice were exposed to tetrahydrofuran at concentrations of 0, 200, 600, and 1800 ppm in a 13-week inhalation toxicity study sponsored by NTP (NTP TR475). The kidneys of male rats and the livers of female mice (10/species/exposure group) were embedded in paraplast, then processed and stained for the Proliferating Cell Nuclear Antigen (PCNA). There was a slight increase in PCNA in the liver of mice from the high dose group with a minimal decrease in the other groups. The rat kidneys showed a minimal decrease in all tubular compartments, being most pronounced in the low dose group. Because the study was based on a single time point observation and there was no clear increase in cell proliferation, no conclusions could be drawn concerning the tumorigenicity potential of tetrahydrofuran. [R83] ?Tetrahydrofuran (CAS# 109-99-9) was evaluated for developmental toxicity. In part I of the experiment the test material was administered to 14, 7, 7, 7, and 7 CD rats by inhalation at exposure levels of 0, 200, 500, 2500, and 5000 ppm, respectively on gestational days 6-15. In part II, 29, 87, and 38 CD rats were administered the test material by inhalation at exposure levels of 0, 1000, and 5000 ppm, respectively from days 6-15 of gestation. In both parts I and II, no maternal deaths occurred but the 5000 ppm exposure induced significant decreases in feed consumption (p < 0.05) and body weight gain (p < 0.05) along with absence of response to noise stimulus during the exposure period, followed by lethargy and incoordination for 1 hour post-exposure. No toxic responses were observed at 200 or 500 ppm (part I). At 1000 ppm (part II) and 2500 ppm (part I) only a reduced response to a noise stimulus was observed in comparison to controls. The mean number of implantations per dam and the incidence of malformed fetuses were not exposure related (among part I or part II). At 5000 ppm, the fetal variations of reduced weight and less ossified sternae were significantly different (p < 0.05) from controls (for both part I and part II). Embryotoxicity expressed as developmental delay occurred at 5000 ppm. [R84] ?Tetrahydrofuran (CAS #109-99-9) was evaluated for subchronic toxicity in dogs (breed not specified). Four dogs were exposed (6 hrs./5 days/9 wks.) to the test material at 200 ppm (average weekly concentration) followed by 366 ppm (average weekly exposure) for 3 additional weeks at 6 hrs./5 days/week for a total of 12 weeks. Two of the four dogs were then exposed an additional two successive days to 2,100 ppm (approximate). Blood pressure measurements were taken morning and afternoon four weeks preceding exposure period (control period) and before and after daily exposures. A decrease in pulse pressure was noted in 3 dogs after 3 to 4 weeks' exposure at 200 ppm accompanied by a decrease in systolic pressure in 2 dogs (153-B AND 153-C), while the third (153-A) experienced an increase in diastolic pressure. In general, two dogs (153-A AND 153-D) showed an increase in diastolic and systolic pressure, dog# 153-B showed an increase in diastolic pressure, and dog# 153-C showed a steady drop in systolic and diastolic pressure. At 366 ppm, blood pressure was decreased in 3 of 4 dogs. When exposed to 2,100 ppm (dogs #153-A AND 153-C), the diastolic, systolic, and pulse pressure dropped sharply on the second day. Dog #153-C showed a steady drop in hemoglobin count and a considerably higher than control level white blood count. There were no other significant gross or microscopic effects observed in the heart, lungs, spleen, pancreas, or kidney. [R85] POPL: *Persons with existing skin disorders may be more susceptible to the effects /of tetrahydrofuran exposure/. [R11, 1981.1] ADE: *EXCRETION OF TETRAHYDROFURAN IN MOTHER'S MILK REPORTED IN 1 OF 12 SAMPLES COLLECTED IN 4 URBAN AREAS IN NEW JERSEY, PENNSYLVANIA, AND LOUISIANA. [R86] *Adult male rats exposed to tetrahydrofuran vapor at 8.2 (200 ppm), 41 (1,000 ppm) or 82 mumol/l (2,000 ppm) for 2 to 18 weeks, five days a week, 6 hrs daily, showed dose-dependent brain and perirenal fat solvent burden linearly correlated to each other. After two weeks of exposure, the body burden of tetrahydrofuran seems to decrease. This might have been caused by increased oxidative metabolism as enhanced 7-ethoxycoumarin-O-deethylase activity was detected in liver and kidneys in the second week and onwards. The exposure also caused inhibition of alcohol and formaldehyde dehydrogenase activities in liver at the highest dose. Biochemical effects in the cerebellum were not detected, while gluteal muscle specimens showed increased succinate dehydrogenase activity in a dose-related manner. This points to effects on the energy metabolism. Muscle acetylcholine esterase activity was also increased showing possible effects on the myoneural junctions. [R87] *When healthy volunteers were exposed at 100 or 400 ppm THF in air, the percentage of expired THF was 35% in males with normal breathing, 25% in males with deep breathing, and 19% in females with deep breathing. Three hour exposures at 50 ppm THF resulted in 40% expiration of THF in males with normal breathing and 27% in males with deep breathing. The elimination half life of THF was 30 minutes. In subjects exposed at 50 ppm THF in air for 6 hours, traces of THF were present at 3 hours after the end of exposure. In individuals exposed at 200 ppm THF for 3 hours, THF blood concn were higher at 1 hour after the end of exposure than immediately after cessation of exposure. [R46, 1991.1518] METB: *In vitro studies indicated that THF was first hydroxylated by the microsomal enzymes and further cleaved to the straight chain fatty acid in the presence of cytosol. [R46, 1991.1518] BHL: *When healthy volunteers were exposed at 100 or 400 ppm THF in air, ... the elimination half life of THF was 30 minutes. [R46, 1991.1518] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Tetrahydrofuran's production and use as a solvent for natural and synthetic resins and in organic synthesis may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 162 mm Hg at 25 deg C indicates tetrahydrofuran will exist solely as a vapor in the ambient atmosphere. Vapor-phase tetrahydrofuran will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl and nitrate radicals; the half-life for these reactions in air are about 1 and 3 days, respectively. If released to soil, tetrahydrofuran is expected to have very high mobility based upon Koc values of 23 and 18. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 7.1X10-5 atm-cu m/mole. Tetrahydrofuran may volatilize from dry soil surfaces based upon its vapor pressure. Tetrahydrofuran added to surface soil had an abiotic half-life of 5.7 days. If released into water, tetrahydrofuran is not expected to adsorb to suspended solids and sediment based upon the Koc. Tetrahydrofuran is expected to biodegrade under aerobic conditions but may be resistant to biodegradation in anaerobic environments. In the modified MITI screening test, tetrahydrofuran at 30 mg/l was completely biodegraded in 14 days using an activated sludge inoculum. Tetrahydrofuran at 50 mg C/l was resistant to anaerobic biodegradation with a lag period of greater than 60 days using a primary digesting sludge as an inoculum. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 13.1 hrs and 6.6 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to tetrahydrofuran may occur through inhalation and dermal contact with this compound at workplaces where tetrahydrofuran is produced or used. (SRC) ARTS: *Tetrahydrofuran's production and use as a solvent for natural and synthetic resins (e.g., vinyls), in top-coating solutions, and in organic synthesis(1) may result in its release to the environment through various waste streams(SRC). [R88] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 23 and 18(2), indicates that tetrahydrofuran is expected to have very high mobility in soil(SRC). Volatilization of tetrahydrofuran from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 7.1X10-5 atm-cu m/mole(3). The potential for volatilization of tetrahydrofuran from dry soil surfaces may exist(SRC) based upon a vapor pressure of 162 mm Hg(4). Tetrahydrofuran is expected to biodegrade under aerobic conditions but may be resistant to biodegradation in anaerobic environments(SRC). In the modified MITI screening test, tetrahydrofuran at 30 mg/l was completely biodegraded in 14 days using an activated sludge inoculum(5); however, the EEC manometric respirometric method, tested in 22 different laboratories, gave a mean of 34% of the theoretical BOD within 28 days(6). Tetrahydrofuran at 50 mg C/l was resistant to anaerobic biodegradation with a lag period of greater than 60 days (the incubation period) using a primary digesting sludge as an inoculum; no gas production was seen during this time(7). Tetrahydrofuran, added to the surface of 2 different soil samples which had been sterilized to prevent microbial degradation, had a disappearance half-life of 5.7 days(8). [R89] *AQUATIC FATE: Based on a classification scheme(1), Koc values of 23 and 18(2) indicates that tetrahydrofuran should not adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 7.1X10-5 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 13.1 hrs and 6.6 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow of 0.46(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Tetrahydrofuran is expected to biodegrade under aerobic conditions but may be resistant to biodegradation in anaerobic environments(SRC). In the modified MITI screening test, tetrahydrofuran at 30 mg/l was completely biodegraded in 14 days using an activated sludge inoculum(8); however, the EEC manometric respirometric method, tested in 22 different laboratories, gave a mean of 34% of the theoretical BOD within 28 days(9). Tetrahydrofuran at 50 mg C/l was resistant to anaerobic biodegradation with a lag period of greater than 60 days (the incubation period) using a primary digesting sludge as an inoculum; no gas production was seen during this time(10). [R90] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tetrahydrofuran, which has a vapor pressure of 162 mm Hg at 25 deg C(2), will exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase tetrahydrofuran is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and nitrate radicals(SRC); the half-lives for these reactions in air are about 1 day(3) and 3 days(4), respectively. Butyrolactone and alpha-hydroxytetrahydrofuran were formed as products during the photooxidation of tetrahydrofuran(5). [R91] BIOD: *At concns of 0.5, 5 and 10 mg/l, THF was detected in distilled water for 1-2, 6-8 and 10 days, respectively. In presence of microbial contamination degradation took 2-3 days less. The chemical and biochemical oxidation of THF is accompanied by considerable consumption of dissolved O2. [R92] *Tetrahydrofuran at 50 mg C/l was resistant to anaerobic biodegradation with a lag period of greater than 60 days (the incubation period) using a primary digesting sludge as an inoculum; no gas production was seen during this time(1). In the prolonged Closed Bottle Test, using an activated sludge inoculum, tetrahydrofuran reached 39, 57 and 61 % of the theoretical BOD in 28, 42, and 56 days, respectively(2). Using the EEC manometric respirometric method in 22 different laboratories, tetrahydrofuran reached a mean of 34% of the theoretical BOD within 28 days(3). In the modified MITI screening test, tetrahydrofuran at 30 mg/l was completely biodegraded in 14 days using an activated sludge inoculum(4). [R93] *Greater than 90% removal of tetrahydrofuran, at an initial concentration of 1.082 mg/l, was seen following activated sludge treatment; using a biological aerated filter reactor, tetrahydrofuran, at 496 ug/l, had a removal of 54%(1). A pilot-scale activated sludge system, operated at a hydraulic retention time of 7.5 hours and a flow rate of 35 gpm gave an average removal of 76.4% for tetrahydrofuran; an average of 10.2% of this was due to stripping, 1.2% was due to sludge adsorption(2). Biodegradation increased during this test(2) indicating some acclimation of the microbial population(SRC). Pilot-scale extended aeration wastewater treatment plants with dual media secondary effluent filters were able to completely remove tetrahydrofuran (initial concentrations between 50-100 ug/l) under both acclimated and non-acclimated conditions(3). [R94] ABIO: *The rate constant for the vapor-phase reaction of tetrahydrofuran with photochemically-produced hydroxyl radicals has been estimated as 1.6X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 1 day at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). Butyrolactone and alpha-hydroxytetrahydrofuran were formed as products during the photooxidation of tetrahydrofuran(2). A rate constant for the vapor-phase reaction of tetrahydrofuran with nitrate radicals was measured as 4.88X10-15 cu cm/molecule sec(3). This corresponds to an atmospheric half-life of about 3 days(SRC) at an atmospheric concentration of 5X10+8 nitrate radicals per cu cm(4). Tetrahydrofuran is moderately reactive in photochemical smog conditions where nitrogen oxides are present; reactions occur in time scales of hours(5-7). Acrolein and formaldehyde have been reported as reaction products(6). Tetrahydrofuran is stable to photooxidation in water(8,9). Tetrahydrofuran is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(10). [R95] BIOC: *An estimated BCF of 3 was calculated for tetrahydrofuran(SRC), using a log Kow of 0.46(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R96] KOC: *Koc values of 23 and 18 were determined for tetrahydrofuran using a zero headspace extractor vessel in Captina silt loam (pH = 4.97, organic carbon = 1.49%) and McLaurin sandy loam (pH = 4.43, organic carbon=0.66%), respectively(1). According to a classification scheme(2), this estimated Koc value suggests that tetrahydrofuran is expected to have very high mobility in soil(SRC). A retardation factor of 1.0 was measured for tetrahydrofuran in a ground water system in Indiana(3). A retardation factor of 2.2, based on plume length, was measured for tetrahydrofuran in an aquifer beneath a landfill in Ottawa, Ontario(4). A column packed with aquifer material was used to measure a retardation factor of 1.2 for tetrahydrofuran(5). [R97] VWS: *The Henry's Law constant for tetrahydrofuran is 7.1X10-5 atm-cu m/mole(1). This Henry's Law constant indicates that tetrahydrofuran is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 13.1 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 6.6 days(SRC). Tetrahydrofuran's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of tetrahydrofuran from dry soil surfaces may exist(SRC) based upon a vapor pressure of 162 mm Hg(3). [R98] WATC: *SURFACE WATER: The avg concn of tetrahydrofuran in 14 heavily industrialized river basins in the US (201 sites) was > 1 ppb (29 sites positive; range, 1-318 ppb)(1). Tetrahydrofuran was identified in water samples taken from the Puerto Rico offshore industrial waste dumpsite in 1978 at unreported concentrations(2). Tetrahydrofuran was detected in the Dutch surface waters at concns ranging from 1.1 to 6.4 ug/l (detection limit = 0.03 ug/l)(3). [R99] *DRINKING WATER: Tetrahydrofuran was detected in treated drinking water at levels ranging from 0.2-0.8 ug/l in the Niagara River area(1). Tetrahydrofuran was detected in drinking water at unreported concentrations(2). [R100] *GROUND WATER: Tetrahydrofuran was detected in 3 groundwater wells (maximum concn = 560 ug/l) in a study measuring VOCs in 51 Wisconsin solid waste landfills(1). Tetrahydrofuran was detected at unreported concentrations in groundwater on one Department of Energy research and defense production facility(2) and in groundwater from the Biscayne Aquifer Study area in Florida at a maximum concentration of 400 ug/l(3). Tetrahydrofuran was detected in an aquifer beneath the Gloucester Landfill near Ottawa, Canada where organic chemicals were disposed of between 1969 and 1980(4). Groundwater sampled under two waste disposal sites in Minnesota contained tetrahydrofuran at concentrations from 24-3900 ug/l(5). Leachates from 3 of 5 landfill sites in Connecticut contained tetrahydrofuran; Cheshire site = 60 ug/l, Norwich site = 20 ug/l, Danbury site = 330 ug/l(6). Tetrahydrofuran was detected in contaminated ground water in The Netherlands with a maximum concentration of 3 ug/l(7). [R101] EFFL: *30 samples taken between 1973-1976 ranged from 0 ug/l (Olin Corp, Brandenbury, KY, Ohio River/Wabash River) to 450,000 ug/l (General Electric, Mt Vernon, IN, Ohio River). Other notably high concn were 1000 ug/l (M/T Chem, Carrloton, KY, Ohio River), 850 ug/l (Olin Corp, IN, Ohio River/ Wabash River), and 318 ug/l (Ashtabula, OH). [R102] *Leachate from the Rochester Municipal Landfill contained tetrahydrofuran at 0.43 mg/l(1). Effluent samples taken from a plant that finished polyester fabrics contained tetrahydrofuran at unreported concentrations(2). Tetrahydrofuran was reported in the vehicle exhaust gases from a gasoline engine at unreported concentrations(3). Effluent from a sewage treatment plant in Barceloneta, Puerto Rico, receiving waste from several pharmaceutical industries contained tetrahydrofuran at unreported concentrations(4). Ambient air samples from 2 of 5 hazardous waste sites in New Jersey contained tetrahydrofuran at unreported concentrations(5). [R103] *20 of 1043 common household compounds contained tetrahydrofuran at unreported concentrations(1). Tetrahydrofuran was identified but not quantified as a volatile organic compound released from textile floor coverings(2). Tetrahydrofuran was identified as a major constituent of PVC primer and adhesive and was found to be leached into the water surrounding bonded joints at concentrations ranging from 215-63,000 ug/l (concentrations given for the first wash for 7 different products)(3); 6 and 8 months following PVC pipe installation tetrahydrofuran concentrations in the surrounding water were 13 and 7.5 ppm, respectively(5). Volatile organic compounds measured from a sludge landfill simulator contained tetrahydrofuran at unreported concentrations(4). The concn of tetrahydrofuran in landfill leachate ranges from 18 to 1,400 ug/l(6). [R104] SEDS: *Tetrahydrofuran was detected at unreported concentrations in soil on one Department of Energy research and defense production facility(1). [R105] ATMC: *Atmospheric air 500 m from a furan factory contained 0.173 mg/m3 tetrahydrofuran. [R106] *URBAN: Urban air samples, reported in the VOCs database update, from an unreported location(s) contained tetrahydrofuran at a median concentration of 0.283 ppbv(1). [R107] *INDOOR AIR: Tetrahydrofuran was detected at an average concentration of 1058 ug/cu m in new and recently renovated buildings(1). [R108] FOOD: *THF has been identified in coffee aroma. [R109] *Tetrahydrofuran was detected as a volatile compound, isolated from floured chickpea seed(1). This compound was identified in the volatile component of cooked chicken(2). [R110] MILK: *In 4 urban areas, tetrahydrofuran was detected in Mother's milk in 1 of 12 samples(1). [R111] RTEX: *Tetrahydrofuran can affect the body if it is inhaled, swallowed, or comes in contact with the eyes or skin. [R11, 1981.1] *90,000 workers in 3,000 plants are exposed from the following industries: special trade contractors, chem and allied products, electric gas and sanitary services. Occupations with potential exposure are electricians, agriculture and biological technicians, and electric power linemen and cablemen. [R112] *Worker exposure during application of coatings to cellophane film by an open process was evaluated. Maximum THF vapor concn was 20 ppm. During rethreading operation 10-46 ppm (TWA) were reported and exposure of hands to liquid THF occurred. [R113] *Workers were exposed to THF while joining PVC casing to PVC pipe with cement containing THF. Of 4 conc measured, 1 registered 20 ppm for a 20 min period. [R114] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 303,049 workers (24,842 of these are female) are potentially exposed to tetrahydrofuran in the US(1). Occupational exposure to tetrahydrofuran may occur through inhalation and dermal contact with this compound at workplaces where tetrahydrofuran is produced or used(SRC). Occupational exposure to tetrahydrofuran was studied in the air, blood, and urine of 58 male workers in a video tape manufacturing plant; exposure was through inhalation of tetrahydrofuran vapors and direct dermal contact(2). [R115] BODY: *In 4 urban areas, tetrahydrofuran was detected in Mother's milk in 1 of 12 samples(1). [R111] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *2000 ppm (Based on 10% of the lower explosion limit for safety considerations even though the relevant toxicological data indicated that irreversible health efects or impairment of escape existed only at higher concentrations.) [R28, 302] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 200 ppm (590 mg/cu m). [R116] *Vacated 1989 OSHA PEL TWA 200 ppm (590 mg/cu m); STEL 250 ppm (735 mg/cu m) is still enforced in some states. [R28, 372] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 200 ppm (590 mg/cu m). [R28, 302] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 250 ppm (735 mg/cu m). [R28, 302] TLV: *8 hr Time Weighted Avg (TWA): 200 ppm; 15 min Short Term Exposure Limit (STEL): 250 ppm. [R117, 2002.56] *Biological Exposure Index (BEI): Determinant: tetrahydrofuran in urine; Sampling Time: end of shift; BEI: 8 mg/l. [R117, 2002.93] OOPL: *Recommended occupational exposure level /(Netherlands)/ Time-weighted average (TWA) 300 mg/cu m (100 ppm)/8 hr [R118] WSTD: STATE DRINKING WATER GUIDELINES: +(MA) MASSACHUSETTS 1300 ug/l [R119] +(MI) MICHIGAN 230 ug/l [R119] +(NH) NEW HAMPSHIRE 154 ug/l [R119] +(WI) WISCONSIN 50 ug/l [R119] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R120] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. [R121] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Tetrahydrofuran is included on this list. [R122] *A testing consent order is in effect for tetrahydrofuran for health effects testing. FR citation: 1/23/95. [R123] RCRA: *U213; As stipulated in 40 CFR 261.33, when tetrahydrofuran, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R124] FDA: *Tetrahydrofuran is an indirect food additive for use only as a component of adhesives. [R125] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1609. Analyte: tetrahydrofuran; Matrix: air; Sampler: solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Vol: min 1 l, max 9 l; Sample stability: not determined [R126] ALAB: *NIOSH Method 1609. Analyte: tetrahydrofuran; Matrix: air; Technique: gas chromatography, flame ionization detector; Desorption: 0.5 ml carbon disulfide, stand 30 min; Range: 0.5 to 13 mg/sample; Precision (relative standard deviation): 0.16 @ 3 to 11.8 mg/sample; Est limit of detection: 0.05 mg/sample; Interferences: high humidity may reduce the breakthrough volume of the charcoal tube. [R126] *Method outlines the use of gas chromatography/microwave-induced plasma for the detection of organic oxygenated compounds in simple mixtures. Tetrahydrofuran had 99% recovery, with a detection limit of 40 ng oxygen in a complex system. [R127] */Determination of tetrahydrofuran by/ use of solvent optimization software for rapid selection of conditions for reversed phase high performance liquid chromatography. [R128] *AREAL Method IP-1B. Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbent Tubes. This method is applicable to the sampling and analysis of volatile organic compounds in indoor air. Detection limit = 1.2 ng. [R129] *EMSLC Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. This method is applicable to surface water, ground water, and drinking water in any treatment stage. Detection limit = 1.6 ug/l. [R129] *EAD Method 1666. Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by Isotope Dilution GC/MS. The method contains two options for the analysis of volatile organic compounds in waters, soils, and municipal sludges by isotope dilution GC/MS. Detection limit = 20 ug/l. [R129] CLAB: *Tetrahydrofuran can be separated from biological fluids after injection onto packed gas chromatography columns with flame ionization detector or in a closed vessel or by controlled temp diffusion from the liquid phase into the air above the sample (head space). Tetrahydrofuran has a relative retention time of 0.78 min (ethanol= 1.9 min). [R130] *Occupational exposure to tetrahydrofuran was studied by analysis of environmental air, blood, alveolar air, and urine from 58 workers in a video tape manufacturing plant /by using/ head space gas chromatography with a FID detector. [R131] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Chemical Selection Working Group Profile No. 446, Tetrahydrofuran (1979). USEPA; Chemical Hazard Information Profile: Tetrahydrofuran (1979). Health and Safety Executive; Criteria Document Summaries-Synopses of the Data Used in Setting Occupational Exposure Limits. 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Comm Eur Communities, Eur 9962 (1985) (10) Battersby NS, Wilson V; Appl Environ Microbiol 55: 433-39 (1989) R91: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation, NY: Hemisphere Pub Corp (1989) (3) Atkinson R; J Phys Chem Ref Data. Monograph 1 (1989) (4) Atkinson R et al; J Phys Chem 92: 3454-57 (1988) (5) Stenberg VI et al; J Org Chem 35: 1774-77 (1970) R92: Pozdnyakova AG; Gig Sanit 34 (9): 114 (1969) as cited in USEPA; Chem Hazard Info Profile: THF p. 258 (1979) R93: (1) Battersby NS, Wilson V; Appl Environ Microbiol 55: 433-39 (1989) (2) Van Ginkel CG, Stroo CA; Ecotoxicol Environ Safety 24: 319-27 (1992) (3) Painter HA, King EF; Ring Test Program 1983-84. Assessment of Biodegradability of Chemicals in Water by Manometric Respirometry. Comm Eur Communities, Eur 9962 (1985) (4) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R94: (1) Clapp LW et al; Water Environ Res 66: 153-60 (1994) (2) Dobbs RA, Bhattacharya SK; pp 68-81 in USEPA 600/9-90-037. Proc 16th Ann Haz Waste Res Symp. Cincinnati, OH (1990) (3) Safferman SI, Bhattacharya SK; Treatability of RCRA Compounds in a BOD/Nitrification Wastewater Treatment System with Dual Media Filtration. Risk Reduction Engineering Laboratory Cincinnati, OH. USEPA/600/S2-90/013 (1990) R95: (1) Atkinson R; J Phys Chem Red Data. Monograph 1 (1989) (2) Stenberg VI et al; J Org Chem 35:1774-77 (1970) (3) Atkinson R et al; J Phys Chem 92: 3454-57 (1988) (4) Kwok ESC et al; Environ Sci Technol 30: 329-334 (1996) (5) Levy A; Adv Chem Ser 124: 70-94 (1973) (6) Popav VA; Gig Sanit 36: 7-10 (1971) (7) Farley FF; pp. 713-27 in Inter Conf Photochem Oxidant Pollut Control. Wahsington, DC: USEPA-560/6/77-015A (1977) (8) Anbar M, Neta P; Int J Appl Radiation and Isotopes 18: 493-523 (1967) (9) Hendry DG et al; J Phys Chem Ref Data 3: 944-78 (1974) (10) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R96: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 9 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R97: (1) Walton BT et al; J Environ Qual 21: 552-58 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) (3) Nyer EK et al; Ground Water Monitoring Rev 11: 80-82 (1991) (4) Patterson RJ et al; Wat Sci Tech 17: 57-69 (1985) (5) Priddle MW, Jackson RE; Ground Water 29: 260-66 (1991) R98: (1) Cabani S et al; Trans Faraday Soc 67: 1943-50 (1971) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation, NY: Hemisphere Pub Corp (1989) R99: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Water USEPA-560/6-77-015 p. 74 (1977) (2) Brooks JM et al; pp. 171-98 in Wastes Ocean V1 Duedall, IW ed. NY, NY: Wiley (1983) (3) Miermans CJH et al; Chemosphere 40: 39-48 (2000) R100: (1) Komsta E et al; Bull Environ Contam Toxicol 41: 515-22 (1988) (2) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982) R101: (1) Battista JR, Connelly JP; VOC Contamination at Selected Wisconsin Landfills-Sampling Results and Policy Implications. Wisconsin Dept of Natural Resources, Madison, WI 53707. Publ-SW-094-89 (1989) (2) Riley RG, Zachara JM; Chemical Contaminants of DOE Lands and Selection of Contaminant Mixtures for Subsurface Science Research. DOE/ER-05471 (NTIS DE92014826). Richland WA: Pac Northwest Lab (1993) (3) Canter LW, Sabatini DA; Intern J Environ Studies 46: 35-57 (1994) (4) Patterson RJ et al; Wat Sci Tech 17: 57-69 (1985) (5) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) (6) Sawhney BL, Lozloski RP; J Environ Qual 13: 349-52 (1984) (7) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) R102: EPA Storet data storage system as cited in Hazard Profile: Exposure Info on Tetrahydrofuran p.4-5 (1979) R103: (1) Brown KW, Donnelly KC; Haz Waste Haz Mater 5: 1-26 (1988) (2) Gordon AW, Gordon M; Trans Ky Acad Sci 42: 149-57 (1981) (3) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (4) Kennicutt MCII et al; Chemosphere 13: 535-48 (1984) (5) LaRegina J, Bozzelli JW; Environ Prog 5: 18-26 (1986) R104: (1) Sack TM et al; Atmos Environ 26A: 1063-70 (1992) (2) Sollinger S et al; Atmos Environ 28: 2369-78 (1994) (3) Sosebee JBJR et al; Contamination of Groundwater Samples with Poly(Vinyl Chloride) Adhesives and Poly(Vinyl Chloride) Primer from Monitor Wells. ASTM Spec Tech Publ 805. (Hazar Ind Solid Waste Test): 38-50 (1983) (4) Vogt WG, Walsh JJ; in Proc - APCA Annu Meet. 78th. 6: 1-17 (1985) (5) Wang TC, Bricker JL; Bull Environ Contam Toxicol 23: 620-23 (1979) (6) Roy WR; p. 418 in Contam Groundwaters. Adriano DC et al, eds. Northwood, England: Sci Rev (1994) R105: (1) Riley RG, Zachara JM; Chemical Contaminants of DOE Lands and Selection of Contaminant Mixtures for Subsurface Science Research. DOE/ER-05471 (NTIS DE92014826). Richland WA: Pac Northwest Lab (1993) R106: Makeicheva; Inst Saint Gig Profzabol 8: 52 (1974) as cited in Hazard Profile: Exposure Information on THF p.9 (1979) R107: (1) Shah JJ, Heyerdahl EK; National Ambient Volatile Organic Compounds (VOCs) Database Update. USEPA/600/3-88/010 (1988) R108: (1) Rothweiler H et al; Atmos Environ 26A: 2219-25 (1992) R109: Fenarali's Handbook of Flavor Ingredients, 2nd ed p.664 (1975) as cited in Chemical Selection Working Groups Profile #446: Tetrahydrofuran (1979) R110: (1) Rembold H et al; J Agric Food Chem 37: 659-62 (1989) (2) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R111: (1) Pellizzari ED et al; Bull Environ Toxicol 28: 322-8 (1982) R112: NIOSH. 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R118: Directorate of Labor; Expert Committee for Occupational Standards. 35 pp. (1991) R119: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R120: 40 CFR 302.4 (7/1/2001) R121: 40 CFR 712.30 (7/1/2001) R122: 40 CFR 716.120 (7/1/2001) R123: 40 CFR 799.5000 (7/1/2001) R124: 40 CFR 261.33 (7/1/2001) R125: 21 CFR 175.105 (4/1/2001) R126: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R127: Bradley C, Carnahan JW; Anal Chem 60:858-863 (1988) R128: Pichini S et al; J Chromat 697 (1-2): 383-8 (1995) R129: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R130: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 407 R131: Ong CN, et al; Br J Ind Med 48 (9): 616-21 (1991) RS: 107 Record 24 of 1119 in HSDB (through 2003/06) AN: 127 UD: 200302 RD: Reviewed by SRP on 3/2/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRALIN- SY: *BENZOCYCLOHEXANE-; *NAPHTHALENE-1,2,3,4-TETRAHYDRIDE-; *NAPHTHALENE,-1,2,3,4-TETRAHYDRO-; *DELTA(SUP 5,7,9)-NAPHTHANTRIENE; *TETRAHYDRONAPHTHALENE-; *1,2,3,4-TETRAHYDRONAPHTHALENE-; *1,2,3,4-TETRAHYDRONAPHTHALIN-; *TETRALINA-; *TETRALINE-; *TETRANAP- RN: 119-64-2 MF: *C10-H12 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY CATALYTIC HYDROGENATION OF PURIFIED NAPHTHALENE. [R1] *... FORMED DURING ACIDIC, CATALYTIC HYDROCRACKING OF PHENANTHRENE. [R2, 3241] *ISOLATED FROM MIDDLE FRACTION OF COAL OIL. [R3] *Hydrogenation of naphthalene in the presence of a catalyst at 150 deg C. [R4] IMP: *DECAHYDRONAPHTHALENE AND NAPHTHALENE ARE THE PRINCIPAL IMPURITIES. [R5] FORM: *"ESSENCE OF TETRALIN" IS COMMERCIAL MIXTURE OF TETRALIN AND HEXALIN, PALE YELLOW LIQUID WHICH IS BETTER SOLVENT OF RESINS THAN TETRALIN ALONE ... . [R6, 119] *GRADES OR PURITY: 90+% [R7] *THE COMMERCIAL PRODUCT TYPICALLY HAS A TETRAHYDRONAPTHALENE CONTENT OF > 97 wt%. [R5] *Grade: Technical [R4] MFS: *Du Pont Co, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000, (800) 441-7515; Du Pont Chemicals, Rt 130, Deepwater, NJ 08023; Production site: Deepwater, NJ 08023 [R8] OMIN: *PEROXIDE FORMATION /FROM CONTACT WITH AIR/ IS PREVENTED BY THE ADDITION OF AN ANTIOXIDANT, SUCH AS HYDROQUINONE. [R1] *Compatible with natural and synthetic vehicles. [R4] *The germicidal action of quaternary ammonium cmpd was increased by a factor of 3 with the addition of tetralin. [R9] *Tetralin ring used in a group of new fungicidal phenols, which have lower phyto and mammalian toxicity as compared to known phenolic fungicides. [R10] *Used as a chemical intermediary in the formation of acylisopropyltetramethylindans which have a musk aroma and enhance the aroma of perfume cmpd and colognes. [R11] USE: *SOLVENT FOR CAMPHOR, SULFUR AND IODINE; IN PAINT THINNERS; AS PAINT REMOVER WHEN MIXED WITH DECALIN OR WHITE SPIRIT; AS INSECTICIDE FOR CLOTHES MOTH; AS SUBSTITUTE FOR TURPENTINE AND PETROL IN GERMANY. [R6, 119] *SOLVENT FOR NAPHTHALENE, FATS, RESINS, OILS, WAXES, USED INSTEAD OF TURPENTINE IN LACQUERS, SHOE POLISHES, FLOOR WAXES; DEGREASING AGENT. [R1] *IN PLANT PATHOLOGY, TETRALIN HAS BEEN SUCCESSFUL IN TOTAL DESTRUCTION OF CROWN GALL AND OLIVE KNOT NEOPLASMS. [R2, 3242] *A COMBINATION OF 31% TETRAHYDRONAPHTHALENE AND 0.03% CUPRIC OLEATE (CUPREX) IS PROMOTED AS A PEDICULICIDE AND MITICIDE, BUT ITS TRUE EFFICACY REMAINS TO BE DETERMINED. [R12] PRIE: U.S. PRODUCTION: *(1975) GREATER THAN 9.08X10+5 G [R13] *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R13] U.S. IMPORTS: *(1983) 3.17X10+7 g [R14] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R6, 119] ODOR: *ODOR RESEMBLING MIXTURE OF BENZENE AND MENTHOL [R1]; *MOLDY, TURPENTINE ODOR [R7]; *Pungent odor [R4] BP: *207.6 DEG C @ 760 MM HG [R15, p. 3-478] MP: *-35.8 DEG C [R15, p. 3-478] MW: *132.20 [R1] DEN: *0.9702 G/ML @ 20 DEG C/4 DEG C [R16, 143] HTC: *-10,200 CAL/G [R7] HTV: *76.5 CAL/G [R7] PH: *ACIDITY NEUTRAL [R4] SOL: *MISCIBLE WITH ETHANOL, BUTANOL, ACETONE, BENZENE, PETROLEUM ETHER, CHLOROFORM, and PETROLEUM ETHER, DECALIN; SOL IN METHANOL: 50.6% WT/WT; INSOL IN WATER. [R1]; *SOL IN ANILINE [R17]; *SOL IN ETHER [R15, p. 3-478] SPEC: *INDEX OF REFRACTION: 1.54135 @ 20 DEG C/D; 1.53919 @ 25 DEG C/D [R1]; *MAX ABSORPTION (ALCOHOL): 259 NM (LOG E= 2.69); 266 NM (LOG E= 2.84); 274 NM (LOG E= 2.90); 286 NM (LOG E= 2.28) [R17]; *Intense mass spectral peaks: 104 m/z (100%), 132 m/z (53%), 91 m/z (43%), 51 m/z (17%) [R18]; *IR: 4776 (Coblentz Society Spectral Collection) [R19, p. V2 330]; *UV: 3-250 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R19, p. V2 330]; *NMR: 557 (Varian Associates NMR Spectra Catalogue) [R19, p. V2 330]; *MASS: 631 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R19, p. V2 330]; *MASS: 288 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R19, p. V1 874] SURF: *35.5 DYNES/CM @ 20 DEG C [R7] VAPD: *4.6 (AIR= 1) [R6, 119] VAP: +0.368 mm Hg at 25 deg C, from experimentally derived coefficients [R20] VISC: *2.012 cP @ 25 deg C [R21] OCPP: *MOISTURE CONTENT NONE; RESIDUE ON EVAPORATION NONE; BULK DENSITY 8 LB/GAL [R4] *Heat capacity at 25 deg C: 217.5 J/mol K [R15, p. 6-124] *Henry's Law constant= 1.7X10-3 atm-cu m/mol at 25 deg C [R22] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME; CAN REACT WITH OXIDIZING MATERIALS. SPONTANEOUS HEATING: NO. [R23] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R24] +Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R24] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R24] FLMT: +UPPER FLAMMABLE LIMIT: 5.0% BY VOL @ 302 DEG F; LOWER FLAMMABLE LIMIT 0.8% BY VOL @ 212 DEG F [R24] FLPT: *171 DEG F (77 DEG C) (OPEN CUP); 180 DEG F (82 DEG C) (CLOSED CUP) [R1] +160 DEG F (71 DEG C) (CLOSED CUP) [R24] *176 deg C (Closed cup); 190 deg F (Open cup) [R7] AUTO: +725 DEG F (385 DEG C) [R24] FIRP: *WATER MAY BE INEFFECTIVE ON FIRE. COOL EXPOSED CONTAINERS WITH WATER. [R7] EXPL: *... OXIDIZES ON EXPOSURE TO AIR, LEAVING EXPLOSIVE RESINOUS RESIDUES. [R6, 119] REAC: *Prolonged, close contact with air may cause an explosion. [R25] DCMP: *UNDER ... PYROLYSIS AT 700 DEG C, TETRALIN ... YIELDS TARS THAT CONTAIN APPRECIABLE QUANTITIES OF 3,4-BENZOPYRENE. [R2, 3241] ODRT: *Detection threshold 18 ppm in water, purity not specified. [R26] SERI: *... VAPORS ARE KNOWN TO PRODUCE ... IRRITATION OF CONJUNCTIVA AND RESPIRATORY TRACT MUCOSA. [R27] *Irritant to eyes and skin. [R4] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *PROLONGED, INTIMATE CONTACT WITH AIR MAY CAUSE THE FORMATION OF TETRALIN PEROXIDE; VOLATILE WITH STEAM [R1] STRG: *IN GENERAL MATERIALS ... TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS ... SHOULD BE STORED IN COOL ... VENTILATED PLACE, OUT OF ... SUN, AWAY FROM ... FIRE HAZARD ... BE PERIODICALLY INSPECTED AND MONITORED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED. [R23] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *... IN HIGH CONCENTRATIONS, /SRP: CNS DEPRESSANT/ ... . [R1] *... VAPORS ARE KNOWN TO PRODUCE HEADACHE, NAUSEA, VOMITING, AND IRRITATION OF CONJUNCTIVA AND OF RESPIRATORY TRACT MUCOSA. HIGH CONCENTRATIONS PRODUCE /CNS DEPRESSION/. [R27] *Dermal exposure to tetralin has caused eczematous dermatitis, but only rarely, and exposure to tetralin fumes in poorly ventilated places has produced /CNS depressant/ effects including marked restless, eye irritation, headache, malaise, asthenia, nausea, and vomiting. [R28, 123] *A hallmark for tetralin exposure in man is the production of green colored urine. ... Green urine /was reported/ from a man who had ingested 5.7 g of a pigment called di-tetralin. ... Two cases of "tetralin urine" /were reported/ in painters who used tetralin-containing varnishes in a poorly ventilated area; these workers also showed intense irritation of the mucous membranes, profuse lacrimation , headache, and stupor. [R16, 149] *A skin condition similar to turpentine induced dermatitis that was eczematous in nature was reported in painters using tetralin or mixtures of tetralin and other compounds. [R16, 149] *Neurological disturbances due to tetralin have been reported in humans. The marked degree of restlessness shown by babies sleeping in a room recently treated with a tetralin-based varnish was attributed to a direct effect of tetralin on the CNS. [R16, 149] *Asthenia was observed in subjects sleeping in rooms which had been waxed with a polish later found to contain a substance corresponding in odor and properties to crude tetralin. [R16, 149] *Tetralin use in a factory was reported to have caused severe headache, malaise, and vomiting to the extent that workers had to be removed from the site. [R16, 149] *Hospital patients on a ward whose floor was recently waxed with a tetralin-based polish and whose windows were closed due to cold weather experienced eye irritation, headache, nausea, diarrhea, and green urine. [R16, 149] *In an episode of self-poisoning, a woman ingested approx 250 ml of Cuprex, an ectoparasiticide which contains 31.5% tetralin, 0.03% copper oleate, 52.7% paraffin oil, and 15.7% acetone. The patient experienced nausea, vomiting, intragastric discomfort, had one episode of melena, and noticed her urine was green in color. Upon admission to the hospital, the patient had proteinuria and casts in her, elevated serum levels of bilirubin, creatinine, alkaline phosphatase, lactic dehydrogenase, and glutamic oxaloacetic transaminase. A total of 1900 ml of green-gray urine was collected during the 24 hr period after admission and analyzed. Nonconjugated 1,2,3,4-tetrahydro-1-naphthol (alpha-tetralol), unchanged tetralin, and an unidentified metabolite were found in the urine along with the glucuronides of 1,2,3,4-tetrahydro-1-naphthol and 1,2,3,4-tetrahydro-2-naphthol (beta-tetralol). At the time of discharge on the 14th hospital day, all laboratory values had returned to normal. [R16, 149] *Tetralin (100 ppm) induced cellular injury which progressed over 5 hr until the entire Ehrlich-Landschuts diploid population was irreversibly injured. Tetralin appeared to be more cytotoxic in the short term incubations than classic hepatotoxic agents, such as carbon tetrachloride and carbon disulfide, suggesting that the cytotoxic effect was due to the parent compound per se and not to metabolites of tetralin. [R16, 150] *Tetrahydronaphthalene ... vapor is said to cause sensation of irritation of the eyes and respiratory tract, but test applications of the liquid to rabbit eyes caused no injury detectable twenty four hours later. [R29] NTOX: *OXIDATION PROCESSES IN RATS GIVEN TETRALIN, BOTH PURE AND CONTAINING PEROXIDES, BY MOUTH AND BY SC AND IV INJECTION, WERE EXAMINED ... FOUND BOTH CAUSED AN INITIAL FALL IN BODY TEMPERATURE FOLLOWED BY A RISE, AND ... THOUGH TETRALIN SCARCELY ALTERED OXYGEN CONSUMPTION, IT DID CAUSE AN ALTERATION IN THE RESP QUOTIENT, THE CARBON DIOXIDE ELIMINATION BEING DECREASED. ... OBSERVED AN INCR IN URINARY NITROGEN AFTER PROLONGED ADMIN OF TETRALIN. [R6, 120] *IN EXPERIMENTS ... WITH MICE, IT WAS ADMIN ON A MASK; EVEN WHEN SOAKED THIS PRODUCED ONLY /SEMI-CNS DEPRESSION/ AFTER INITIAL SHORT PERIOD OF EXCITATION UNLESS MASK WAS HEATED TO INCREASE VAPOR. ... /GUINEA PIGS WERE GIVEN/ BY MOUTH (0.25 ML DAILY), CUTANEOUS APPLICATION (TO 6 SQ CM OF SHAVED SKIN) AND INHALATION (1.42 UG/L FOR 8 HR DAILY). ... LOSS OF WT AND TREMORS WERE NOTED ... ALSO PARALYSIS OF THE HIND QUARTERS AND DIFFICULT RESPIRATION AND ... AFTER A WK OF APPARENT WELL-BEING, RESTLESSNESS OR APATHY, ROUGHENING OF SKIN, ANOREXIA AND SOMETIMES TORPOR. WITH ORAL ADMIN THERE WAS INTENSE DIARRHEA AND WITH SKIN APPLICATION ECZEMA. [R6, 121] *... DEFINITE SIGNS OF CATARACT /WERE OBSERVED IN GUINEA PIGS/ AFTER 6 DAYS OF INHALATION OF ... VAPOR ... SIMILAR OBSERVATION IN RABBITS FOLLOWING ORAL ADMIN. ... CATARACTS /WERE NOT PRODUCED/ IN RATS FED ON DIET CONTAINING 2% TETRALIN FOR 2 MONTHS. CHANGES IN THE BLOOD PICTURE WERE NOT ... SIGNIFICANT- SLIGHT NORMOCHROMIC ANEMIA, A TENDENCY TO LEUKOPENIA WITH LONG EXPOSURE, AND RELATIVE LYMPHOCYTOSIS. ... AN INCREASE OF POLYNUCLEAR LEUKOCYTES AND ERYTHROCYTES /WERE OBSERVED/. [R6, 122] *... THE URINE OF THE /GUINEA PIGS/ RECEIVING TETRALIN BY MOUTH BECAME SCANTY AND DARK COLORED, WITH A GREENISH-BROWN TINGE, BUT NOT A CLEAR GREEN. ... ALL STAGES OF INJURY TO LIVER, FROM HYPEREMIA TO FATTY DEGENERATION AND CENTRILOBULAR ATROPHY /ALSO NOTED IN GUINEA PIGS EXPOSED TO TETRALIN/. ... THE KIDNEYS SHOWED ALL STAGES OF A TOXIC EFFECT, INCLUDING SEVERE NECROTIZING NEPHROSIS ESPECIALLY OF THE CONVOLUTED TUBULES, WHILE ... THERE WAS EVIDENCE OF EPITHELIAL NEPHRITIS, AND THE URINE CONTAINED ALBUMIN, CYLINDERS AND RED BLOOD CELLS. ... FOUND ... DARK COLORATION OF /RAT/ URINE WAS PRODUCED ONLY AFTER ADMIN OF SEVERAL DOSES OF PURE TETRALIN, BUT AFTER ONE DOSE OF TETRALIN WHICH CONTAINED PEROXIDES. [R6, 122] *... DIRECT CONTACT OF LIQUID TETRALIN WITH LUNG TISSUE BY ASPIRATION CAUSES PULMONARY EDEMA AND HEMORRHAGE AT SITE OF CONTACT /IN SMALL RODENTS/. [R6, 123] *Inhalation of saturated vapor for 8 hr is fatal in rats. ... Aspiration of tetralin causes pulmonary edema and hemorrhage at the point of contact. [R28, 122] *Cataract formation and nephritic lesions are seen in guinea pigs after vapor exposure. [R27] *The most disturbing feature of animal experiments is the report of cataract following respiratory exposure or oral intubation. /Researchers/ were unable to produce cataracts in rats fed tetralin at a dietary level of 20,000 ppm for 2 months; alpha-tetralol was also ineffective, but beta-tetralol was a powerful cataractogen. Because alpha-tetralol and beta-tetralol have been shown to be matabolites of tetralin, it may be that reported differences in the susceptibility of different species to the cataractogenic effects of tetralin depend on differences in their metabolism of the compound. [R30, 642] *Dermal exposure to tetralin has caused eczematous dermatitis, but only rarely, and exposure to tetralin fumes in poorly ventilated places has produced /CNS depressant/ effects including marked restlessness, eye irritation, headache, malaise, asthenia, nausea, and vomiting. [R30, 643] *Administered orally to rabbits and guinea pigs, ... /tetrahydronaphthalene/ has been found to cataracts even more readily than naphthalene itself, but not in rats. In guinea pigs, opacities appear in the cortex of the lens at the equator ina few days, and proceed posteriorly. Also, round gray spots develop in the fundus, and the retina has a turbid appearance. [R29] *The metabolism and nephrotoxicity of tetralin were studied in rats. Male Fischer 344 rats were given 0.5 ml/kg tetralin intragastrically every other day for 14 days. Urine samples were collected for 48 hr and analyzed for metabolites. The rats were killed at the end of the exposure period and the kidneys were removed. One kidney was taken for histopathological examination. The other was homogenized and the homogenates were analyzed for metabolites. Six urinary metabolites were identified; no metabolites were detected in the kidney homogenates. Histopathological changes included increased amounts of cytoplasmic hyaline droplets in proximal convoluted tubular epithelial cells and cellular degeneration in the proximal convoluted tubules. No intratubular cellular casts, overt glomerular changes, or significant inflammation was observed. It was concluded that with the exception of 2-tetralol, all of the urinary tetralin metabolites show that oxidation has occurred on the carbon atoms of the saturated ring closest to the aromatic ring. Tetralin induces the classical lesions of hydrocarbon induced nephropathy. [R31] NTXV: *LD50 Rat oral 2860 mg/kg; [R28, 122] *LD50 Rabbit dermal 17,300 mg/kg; [R28, 122] ADE: *ABSORBED VAPOR IS EXCRETED BY KIDNEYS AS ALPHA- AND BETA-TETRAHYDRONAPHTHOLS ANDTHEIR GLUCURONIDES ... . [R27] *RADIOACTIVE TETRALIN, WHEN ADMIN TO RABBIT, WAS EXCRETED IN URINE AS GLUCURONIDEAT 87-99% AND IN FECES AT 0.6-1.8% OF ORIGINAL DOSE. ... WAS ABSORBED BY MUSSEL BUT NOT METABOLIZED; ... UP TO 80% WAS RELEASED IN UNCHANGED FORM WHEN THE ORGANISM WAS TRANSFERRED TO FRESH SEAWATER. [R2, 3242] *When radioactive tetralin was fed to rabbits, 87-90% of the activity was excreted in the urine in 2 days and 0.5-3.7% on the third day. The feces contained only 0.6-1.8%. No radioactivity was found in the breath, and negligible amounts were retained in the tissues. About 90-99% of the dose was accounted for. [R30, 643] METB: *(1-(14)C)-TETRALIN IS METABOLIZED IN RABBITS BY HYDROXYLATION OF ALICYCLIC RING TO YIELD CONJUGATES OF AC-ALPHA-TETRALOL (60% OF DOSE), AC-BETA-TETRALOL (20%) AND TETRALIN-1,2-DIOL (2.5%), AND HYDROXYLATION OF AROMATIC RING ... YIELDING AR-BETA-TETRALOL (5,6,7,8-TETRAHYDRO-2-NAPHTHOL, 0.1%). [R32] *YIELDS 2-HYDROXYTETRALYLMERCAPTURIC ACID, 1,2,3,4-TETRAHYDRO-1-NAPHTHOL, 1,2,3,4-TETRAHYDRO-2-NAPHTHOL IN RABBIT. YIELDS 1,2,3,4-TETRAHYDRO-1,2-DIHYDROXYNAPHTHALENE, 5,6,7,8-TETRAHYDRO-2-NAPHTHOL IN RABBIT. /FROM TABLE/ [R33] *In rabbits, the main urinary metabolite was the glucuronide of alpha-tetralol (52.4%). Other conjugated metabolites were beta-tetralol (25.3%), 4-hydroxy-alpha-tetralone (6.1%), and cis-tetralin-1,2-diol (0.4%). Using rat liver homogenates, it was shown that conversion of tetralin to tetralol requires reduced nicotinamide adenine dinucleotide phosphate and that tetralin hydroperoxide is a probable intermediate. Further study confirmed this possibility and indicated that tetralin hydroxylation proceeds via a radical mechanism similar to that of lipid peroxidation. [R30, 643] *Tetralin, a component of fuels, solvents, and varnishes, is metabolized in male Fischer 344 rats to 1-tetralol, 2-tetralol, 2-hydroxyl-1-tetralone, 4-hydroxyl-1-tetralone, 1,2-tetralindiol, and 1,4-tetralindiol. [R31] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Tetralin is released to the atmosphere in emissions from automobile and diesel engines, incinerators, and kerosene space heaters. It is also released to the environment in effluents from several industrial sources. If released to the atmosphere, tetralin will exist in the vapor phase. Vapor phase tetralin is rapidly degraded by photochemically produced hydroxyl radicals (estimated half-life of 11 hrs) during the day-time and nitrate radicals (half-life of 3.6 days) during the night-time. If released to soil, tetralin may adsorb strongly (estimated Koc of about 1,800). If released to water, it will adsorb to sediment and suspended matter and will partition from the water column to sediment. Tetralin will bioconcentrate in aquatic organisms that cannot metabolize it. Volatilization from water is fast (estimated half life of 4 hours from a model river) when adsorption does not take place. Some biodegradation studies suggest that biodegradation may be fast with half-lives of 4-13 days. Exposure of the general population may occur through dermal contact and inhalation of contaminated air and may occur during its use as a replacement for turpentine especially in shoe polish and floor wax. Workers may also be exposed to tetralin via inhalation and dermal contact. (SRC) ARTS: *Tetralin is released to the environment in emissions from automobile and diesel engines(1), incinerators(2), kerosene space heaters(3), and from automobile assembly plants during painting processes(4). Tetralin is released in effluents from paper-mills(5), petroleum refineries(6), and in advanced waste treatment effluents(7). Tetralin may also be released to surface waters via runoff from land(8). [R34] FATE: *TERRESTRIAL FATE: If released to soil, adsorption is expected to take place. However, it has been detected in groundwater beneath a municipal landfill(4) and the annual loadings of tetralin in runoff from land in the Canadian Ontario and Great Lakes water basins are estimated to be 1,053 and 2,270 kg/yr, respectively(5). Based on biodegradation half-lives of 4-13 days in aquatic systems(1-3), biodegradation in soil will be important(SRC). [R35] *AQUATIC FATE: Based on the estimated Henry's Law constant of 1.7X10-3 atm-cu m/mol at 25 deg C(2), volatilization half-lives from a model river (1 m deep flowing 1 m/sec and wind velocity of 3 m/sec) and lake (1 m deep) can be estimated to be 4 hours and 5 days, respectively(1,SRC). An estimated Koc value of 1,800(3) suggests a high adsorption potential; furthermore, tetralin was detected in suspended solids from St. Louis Bay(4). Screening and grab sample tests indicate a biodegradation half-life of 4-13 days in seawater, groundwater, and river water(5-7). Bioconcentration in fish may be important in organisms that cannot metabolize tetralin(8). [R36] *ATMOSPHERIC FATE: Based on the experimental vapor pressure of 0.368 mm Hg at 25 deg C(1), tetralin is expected to exist almost entirely in the vapor phase in the ambient atmosphere(2). Vapor phase tetralin will degrade rapidly in the ambient atmosphere by reaction with photochemically produced hydroxyl radicals with a half-life of about 11 hours(3,SRC). Vapor phase tetralin will also degrade in the ambient atmosphere at night-time by reaction with nitrate radicals with a half-life of about 3.6 days(4-5,SRC). [R37] BIOD: *DEGRADATION IN SEA WATER BY OIL OXIDIZING MICROORGANISMS: 31% BREAKDOWN AFTER 21 DAYS AT 22 DEG C IN STOPPERED BOTTLES CONTAINING A 1000 PPM MIXTURES OF ALKANES, CYCLOALKANES, AND AROMATICS. [R38] *One screening test using sewage seed suggests that tetralin (initial concn of 3-10 ppm) biodegrades slowly in synthetic seawater; 3, 3, 2, and 3 percent theoretical BOD in 5, 10, 15, and 20 days, respectively(1). However, 0.0124 ppm tetralin was not detected after 10 days of incubation in artificial seawater at 25 deg C indicating that tetralin is moderately oxidized(2). An initial concn of 0.0112 ppm tetralin was observed to degrade 100% in 8 days in a groundwater grab sample at 10 deg C and pH 8(3). Tetralin (20.1 ppm initial concn) exhibited 18, 40, 58, 65, 70, and 75 percent theoretical CO2 production after 5, 10, 15, 20, 25, and 35 days, respectively, in water from the Ohio River at 22-25 deg C and pH 7.2; the half-life in this study was 13 days and, after redosing, a half-life of 9 days was observed under the same conditions(4). [R39] ABIO: *The rate constant for the vapor phase reaction of tetralin with photochemically produced hydroxyl radicals is measured to be 3.43X10-11 cu cm/molecule-sec at 25 deg C(1) which corresponds to an atmospheric half-life of about 11 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The rate constant for the vapor phase reaction of tetralin with nitrate radicals (NO3) is measured to be 1.1X10-14 cu cm/molecule-sec at 25 deg C(2) which corresponds to a half-life of about 3.6 days at an atmospheric concn of 2X10+8 NO3 radicals per cu cm(3,SRC). [R40] BIOC: *A measured BCF in fish was reported to be about 200(1); this experimental BCF suggests that bioconcentration in aquatic organisms will be important environmentally(SRC). [R41] KOC: *A Koc for tetralin of about 1,800 can be estimated using a structure activity relationship(1). Based on a suggested classification scheme(2), this Koc value suggests that tetralin has low mobility in soil. [R42] VWS: *The Henry's Law constant for tetralin can be estimated to be approximately 1.7X10-3 atm-cu m/mole at 25 deg C using a chemical structure estimation method(2). According to a suggested classification scheme(1), volatilization from water will be significant. Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 4 hours(1,SRC). The volatilization half-life from a model lake (1 meter deep) can be estimated to be about 5 days(1,SRC). Tetralin exhibited a half-life attributed to volatilization of 8.5 days in a mesocosm containing 13 cu-m Narragansett seawater poisoned with HgCl2 to retard biological activity(3). [R43] WATC: *SURFACE WATER: Tetralin was qualitatively identified in water from the River Lee, United Kingdom, in which several sewage treatment plants discharge their effluents(1). Tetralin was quantified at a concn range of 1.3-60.6 ng/L in water from the Rainy River which forms an international boundary between the U.S. and Canada(2). Tetralin was detected at a concn of 31 ng/L in water from the Sava River, Northern Croatia, Yugoslavia(3). [R44] *GROUNDWATER: In 1984, tetralin was qualitatively identified in groundwater near Falmouth, MA(1). Tetralin was identified in groundwater at a concn of 13 and 300 ng/L from wells 120 and 30 m, respectively, from a municipal landfill near Zegreb in Northern Croatia, Yugoslavia; groundwater 0 m from the municipal landfill contained 560 ng/L tetralin(2). [R45] *DRINKING WATER: Tetralin was quantitatively identified at a concn of 25 ng/L in drinking water from Cincinnati, OH in February 1980(1). Tetralin was qualitatively identified in drinking water from Poplarville, MS, New Orleans, LA, Philadelphia, PA, Ottumwa, IA, and Seattle, WA from January, 1976-March, 1979(2). [R46] EFFL: *Tetralin was identified at a concn range of 13.3-154.3 ng/L in paper-mill effluents being discharged into the Rainy River(1). Tetralin was qualitatively identified in advanced waste treatment water from Lake Tahoe, CA in October of 1974(2). Tetralin was detected at a concn range of 2-58 ug/mL in 5 incinerator effluent extracts(3). Tetralin was detected 1 km from a Volvo assembly plant in Goteborg, Sweden at a concn of 4.6 ug/cu-m on January 14, 1981; regional Goteburg air contains less than 0.01 ug/cu-m tetralin(4). Also, 30 ug/cu-m tetralin was detected in air nearby a Saab assembly plant in Sweden on January 19, 1981(4). These data suggest tetralin is released from automobile assembly plants in emissions from solvents used during painting processes(4). Tetralin emission rates from well-tuned radiant and maltuned convective kerosene space heaters ranged from 100-240 ng/kJ(5). [R47] *Based upon monitoring data of runoff from land, approximately 1,053 and 2,271 kg tetralin/yr are input to the Canadian Lake Ontario and Canadian Great Lakes water basins, respectively(1). Tetralin was detected at a concn of 11 ng/g in wastewater from the petroleum refining industry after dissolved air flotation(2). [R48] SEDS: *Tetralin was qualitatively identified in suspended solids from St. Louis Bay in the Duluth harbor in 1983(1). [R49] ATMC: *INDOOR AIR: Tetralin was detected at concns of 10 and 20 ug/cu-m in 2 of 6 indoor air samples taken mostly from homes in northern Italy(1). [R50] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Tetralin was detected in small mouth bass (Micropterus dolomieui) at a concn of 75.3 ng/g and yellow perch (Perca flavescens) at concns of 73.2 and 34.5 ng/g from the Rainy River which forms an international boundary between the U.S. and Canada(1). [R51] RTEX: *During its use in shoe polish and floor wax(1), the general population may be exposed to tetralin via inhalation and dermal contact(SRC). Workers may be exposed to tetralin via inhalation of contaminated air and dermalcontact(SRC). [R52] *... MAY OCCUR IN THE PAINT, SOLVENT, AND VARNISH INDUSTRIES. [R2, 3242] *Tetralin was identified at a concn range of 0-1 ug/cu-m in personal air samples taken from the vulcanization area of a tire retreading factory(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 503 workers are potentially exposed to tetralin in the USA(2). [R53] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *A method /has been described/ for the quantification of tetralin in the presenceof petroleum-type hydrocarbons in avian tissues which involves pentane extraction followed by GLC and GLC-MS ... . [R16, 145] *A procedure /has been described/ for the determination of tetralin in the presence of a number of other organic compounds in fish samples by vacuum distillation and fused silica capillary GC/MS ... . [R16, 145] *Metabolites of tetralin in human urine have been quantitated by GLC equipped with a flame ionization detector. [R16, 145] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: BEAUMONT D, WAIGH RD; THE BETA-ADRENOMIMETIC ACTIVITY OF TETRAHYDROISOQUINOLINESAND TETRAHYDRONAPHTHALENES. PROG MED CHEM 18: 45-86 (1981). A REVIEW WITH 155 REFERENCES ON THE BETA-ADRENOMIMETIC ACTIVITY OF 1,2,3,4-TETRAHYDROISOQUINOLINE AND 1,2,3,4-TETRAHYDRONAPHTHALENE DERIVATIVES. Nelson NA et al; Solvent Nephrotoxicity in Humans and Experimental Animals. Am J Nephrol 10 (1): 10-20 (1990). Evidence from human case reports, epidemiologic studies and animal experiments have suggested that exposure to organic solvents is associated with a wide spectrum of renal disorders, including tubular necrosis, interstitial disease, glomerulonephritis and neoplasia. This review summarizes what is known about solvent induced renal damage in humans and experimental animals, with emphasis on hypothesized mechanisms by which this broad range of disorders may occur. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on tetralin is scheduled for peer review. Route: inhalation; Species: rats and mice. [R54] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1453 R2: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R3: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT SUPPL p.223 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1132 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 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Vol.1 pp. 45,46,142,179 USEPA-600/1-84-020A (1984) (8) Great Lakes Water Quality Board; 1987 Report on the Great Lakes Water Quality Appendix B Vol 1 Report Inter Joint Comm p. 2.5-4 (1989) R35: (1) Vanderlinden AC; Dev Biodeg Hydrocarbons 1: 165-200 (1978) (2) Kappeler T, Wuhrmann K; Water Res 12: 327-33 (1978) (3) Ludzack FJ, Ettinger MB; Eng Bull Ext Ser No.115 pp. 278-82 (1963) (4) Ahel M; Bull Environ Contam 47: 586-93 (1991) (5) Great Lakes Water Quality Board; 1987 Report on the Great Lakes Water Quality Appendix B Vol.1 Report Inter Joint Comm p. 2.5-4 (1989) R36: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 15-15 to 15-32 (1990) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Meylan WM et al; Environ Sci Technol 26: 1560-7 (1992) (4) Bahnick DA, Markee TP; J Great Lakes Res 11: 143-55 (1985) (5) Vanderlinden AC; Dev Biodeg Hydrocarbons 1: 165-200 (1978) (6) Kappeler T, Wuhrmann K; Water Res 12: 327-33 (1978) (7) Ludzack FJ, Ettinger MB; Eng Bull Ext Ser No.115 pp. 278-82 (1963) (8) Santadonato J et al; Health and Ecological Assessment of Polynuclear Aromatic Hydrocarbons. Park Forest South,IL: Pathotox Publ pp. 160-1 (1981) R37: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals NY: Hemisphere Pub Corp (1989) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; Atmos Environ 24A: 1-41 (1990) (4) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (5) Sabljic A, Guesten H; Atmos Environ 24A: 73-8 (1990) R38: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 1089 R39: (1) Price KS et al; J Water Pollut Contr Fed 46: 63-77 (1974) (2) Vanderlinden AC; Dev Biodeg Hydrocarbons 1: 165-200 (1978) (3) Kappeler T, Wuhrmann K; Water Res 12: 327-33 (1978) (4) Ludzack FJ, Ettinger MB; Eng Bull Ext Ser No.115 pp. 278-82 (1963) R40: (1) Atkinson R; Atmos Environ 24A: 1-41 (1990) (2) Sabljic A, Guesten H; Atmos Environ 24A: 73-8 (1990) (3) Atkinson R et al; Environ Sci Technol 21: 1123-6 (1987) R41: (1) Sabljic A; Z Gesamte Hyg Ihre Grenzgeb 33: 493-6 (1987) R42: (1) Meylan WM et al; Environ Sci Technol 26: 1560-7 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R43: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Wakeham SG et al; Environ Sci Technol 17: 611-7 (1983) R44: (1) Waggott A; Chem Water Reuse 2: 55-9 (1981) (2) Merriman JC et al; Chemosphere 23: 1605-15 (1991) (3) Ahel M; Bull Environ Contam 47: 586-93 (1991) R45: (1) Barber LBII et al; Environ Sci Technol 22: 205-11 (1988) (2) Ahel M; Bull Environ Contam 47: 586-93 (1991) R46: (1) Coleman WE et al; Arch Environ Contam Toxicol 13: 171-8 (1984) (2) Lucas SVet al; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol.1 pp. 45,46,142,179 USEPA-600/1-84-020A (1984) R47: (1) Merriman JC et al; Chemosphere 23: 1605-15 (1991) (2) Lucas SV et al; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol.1 pp. 45,46,142,179 USEPA-600/1-84-020A (1984) (3) James RH et al; Proc APCA 77th Ann Mtg 84-18.5 pp. 1-25 (1984) (4) Petersson G; Environ Pollut 4: 207-17 (1982) (5) Traynor GW et al; Environ Sci Technol 24: 1265-70 (1990) R48: (1) Great Lakes Water Quality Board; 1987 Report on the Great Lakes Water Quality Appendix B Vol.1 Report to the International Joint Commission p. 2.5-4 (1989) (2) Snider EH, Manning FS; Environ Int 7: 237-58 (1982) R49: (1) Bahnick DA, Markee TP; J Great Lakes Res 11: 143-55 (1985) R50: (1) DeBortoli M et al; Environ Internat 12: 343-50 (1986) R51: (1) Merriman JC et al; Chemosphere 23: 1605-15 (1991) R52: (1) Budavari S et al; The Merck Index 11th ed. Rahway,NJ: Merck and Co Inc p. 9154 (1989) R53: (1) Cocheo V et al; Am Ind Hyg Assoc 44: 521-7 (1983) (2) NIOSH National Occupational Exposure Survey (NOES) (1983) R54: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 39 Record 25 of 1119 in HSDB (through 2003/06) AN: 131 UD: 200302 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TOLUENE- SY: *ANTISAL-1A-; *BENZENE,-METHYL-; *Caswell-no-859-; *CP-25-; *METHACIDE-; *METHANE,-PHENYL-; *METHYLBENZENE-; *METHYLBENZOL-; *NCI-C07272-; *PHENYLMETHANE-; *TOLUEEN- (DUTCH); *TOLUEN- (CZECH); *TOLUOL-; *TOLUOLO- (ITALIAN) RN: 108-88-3 MF: *C7-H8 SHPN: UN 1294; Toluene IMO 3.2; Toluene STCC: 49 093 05; Toluene 49 093 56; Toluene (toluol), reclaimed solvents, derived from the use of printing inks, consisting of 70% recycled toluol and not more than 30% lactol spirits, textile spirits and mineral spirits 49 060 10; Toluene (toluol), mixed with aluminum alkyls, not to exceed 20% (aluminum alkyl) HAZN: U220; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. F005; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *UNRECOVERED COMPONENT OF GASOLINE [R1] *Catalytic reforming of petroleum steams accounts for 87% of total toluene production. An additional 9% is separated from pyrolysis gasoline produced in steam crackers during manufacture of ethylene and propylene ... coal-tar separation from coke ovens produces 1% of total toluene ... up to 2% of the toluene produced is obtained as a by-product from styrene manufacture. [R2] *(1) By catalytic reforming of petroleum. (2) By fractional distillation of coal tar light oil. [R3] IMP: *... Commercial grades /of toluene/ usually contain small amounts of benzene as an impurity. [R4] *Technical grades (90-120 deg C boiling range) are less pure and may contain up to 25% benzene as well as other hydrocarbons. [R5] *Commercial grades /of toluene/ can ... contain polynuclear aromatic hydrocarbons (PAH), including pyrene, fluoranthrene, and benzo[ghi]perylene. [R6, 1991.1568] FORM: *Research, reagent, nitration - all 99.8+%; Industrial: Contains 94+%, with 5% xylene and small amounts of benzene and nonaromatic hydrocarbons; 90/120: Less pure than industrial. [R7] *Grades: Research 99.99%; Pure 99.98% [R8] *Grades: 1st degree nitration; 2nd degree commercial; 90% solvent [R9] *Grade: (Usually defined in terms of boiling ranges) Pure, commercial, straw-colored, nitration, scintilation, industrial. [R3] MFS: *Amoco Corp., 200 East Randolph Drive, Chicago, IL 60601, (312)856-6111; Production site: Texas City, TX 77590 [R10] *BP America, 200 Public Square, Cleveland OH 44114-2375. (216) 586-4141; Production sites: Alliance, LA 70037; Lima, OH 45804 [R10] *CITGO Petrochemical Co., 6130 S. Yale Ave., Tulsa, OK 74136, (918)495-4000; Production sites: Corpus Christi, TX 78469; Lake Charles, LA 70601; Lemont, IL 60439-3659 [R10] *Coastal Refining and Marketing, 9 Greenway Plaza, Houston, TX 77046, (713)877-6559; Production site: Corpus Christi, TX 78403 [R10] *Coastal Eagle Point Co., 9 PO Box 1000, US Route 130AND I295 Westville, NJ 08093, (609)853-3100; Production site: Westville, NJ 08093 [R10] *Chevron Chemical Corp., 6001 Bollinger Canyon Rd., San Ramon, CA 94583, (925)842-5500; Production site: Port Arthur, TX 77460 [R10] *Dow Chemical USA, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Plaquemine, LA 70765 [R10] *Equistar Chemicals LP., One Houston Center, 1221 McKinney St., Suite 1600, Houston, TX 77010, (713)652-7300; Production sites: Alvin, TX 77511; Channelview, TX 77530; Corpus Christi, TX 78410 [R10] *Exxon Chemical Co., 13501 Katy Freeway, Houston, TX 77079, (281)871-6000; Production site: Baton Rouge, LA 70821 [R10] *Fina Oil and Chemical Co., PO Box 2159, Dallas, TX 75221-2159, (214) 750-2400; Production site: Port Arthur, TX 77460 [R10] *Hess Oil Virgin Islands Corp., Kings Hill Rd., P.O. Box 127 Kingshill, VI 00851-0127, (340)778-4000; Production site: St. Croix, VI 00850 [R10] *Koch Refining Co., PO Box 2256, Wichita, KS 67201, (316)828-5500; Production site: Corpus Christi, TX 78403 [R10] *Lyondell-CITGO Refining Co., 1200 Lawndale, Houston, TX 77017, (713)321-4111; Production site: Houston, TX 77252 [R10] *Marathon Ashland Petroleum LLC., 539 South Main St., Findlay, OH 45840-3295, (419) 422-2121; Production sites: Catlettsburg, KY 41129; Texas City, TX 77592-1191 [R10] *Mobil Chemical Co., 3225 Gallows Rd., Fairfax, VA 22037-0001, (703)846-3000; Production sites: Chalmette, LA 70043; Beaumont, TX 77704-3868 [R10] *Phillips Petroleum Co., Phillips Building, Bartlesville, OK 74004, (918)661-6600; Production site: Sweeney, TX 77480 [R10] *Phillips Puerto Rico Core Inc., Road 3 Route 710, Barrio Las Mareas Guayama PR 00785, (787)864-1515; Production site: Guayama, PR 00785 [R10] *Shell Chemical Co., One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713)241-6161; Production site: Deer Park, TX 77536 [R10] *Sun Company Inc., 1801 Market St., Philadelphia, PA 19103, (800) 825-3535; Production sites: Marcus Hook, PA 19061; Toledo, OH 43693; Tulsa, OK 74102 [R10] *Texaco Refining and Marketing Inc., 10 Universal City Plaza, Universal City, CA 91608-1097, (818)505-2000; Production site: El Dorada, KS 67042 [R10] *Ultramar Diamond Corp., 6000 N. Loop 1604, W. San Antonio, TX 78249-1112, (210)592-2000; Production site: Three Rivers, TX 78071 [R10] *Valero Energy Corp., San Antonio Valero Tower, W 1H 10, San Antonio, TX 78229-4718, (210)370-2000; Production site: Houston, TX 77012-2408 [R10] OMIN: *28th Highest-volume chemical produced in the USA (1995). [R3] USE: *In manufacture benzoic acid, benzaldehyde, explosives, dyes, and many other organic compounds; as a solvent for paints, lacquers, gums, resins, in the extraction of various principles from plants; as gasoline additive. [R11] *DILUENT FOR PHOTOGRAVURE INKS [R12, 2184] *IN FABRIC AND PAPER COATING, MFR ARTIFICIAL LEATHER [R13, 67] *Used in cements, solvents, spot removers, cosmetics, antifreezes, and inks. [R14] *Asphalt and naphtha constituent. Detergent manufacture. [R15] *Mfg benzene derivatives, caprolactam, saccharin, medicines, dyes, perfumes, TNT; solvent recovery plants; component of gasoline; solvent for paints and coatings, gums, resins, rubber and vinyl organosol; diluent and thinner in nitrocellulose lacquers; adhesive solvent in plastic toys and model airplanes; detergent mfg; gasoline and naphtha constituent. [R16, 1722] *Fuel blending [R17, 525] *DENATURANT [R1] *The largest chemical use for toluene is the production of benzene and urethane via hydrodealkylation. [R18] *Used in production of drugs of abuse. [R4] CPAT: *CHEM INT FOR BENZENE, 55.3%; SOLVENT, 25.7%; CHEM INT FOR TOLUENE DIISOCYANATE, 7.3%; CHEM INT FOR BENZOIC ACID, 2.5%; CHEM INT FOR BENZYL CHLORIDE, 1.5%; OTHER, 7.7% (1981 NON-GASOLINE USE) [R1] *Benzene, 46%; gasoline blending, 37%; solvent, 8%; toluene diisocyanate, 7%; miscellaneous chemicals, 2% (1985) /estimate/ [R18] *In the USA in 1981, the use of toluene as a solvent was second only to its use in benzene production via hydrodemethylation and accounted for about 26% of nonfuel consumption. [R19] *Of the estimated 3.3 million tons of toluene produced in the USA in 1980, 44% was used to make benzene, 34% to make gasoline, 10% in solvents, 6% to make toluene diisocyanate, and 6% for miscellaneous use. [R19] PRIE: U.S. PRODUCTION: *(1981) 4.68X10+12 G (ALL USES, 93% CHEM GRADE) [R20] *(1977) 1.50X10+12 G [R1] *(1982) 1.54X10+12 G [R1] *(1985) 2.30X10+12 g [R21] *(1990) 6.21 billion lb [R22] *(1991) 6.30 billion lb [R23] *(1992) 5.81 billion lb [R24] *(1993) 6.38 billion lb [R24] *(1993) 2.276572X10+9 kg [R25] U.S. IMPORTS: *(1978) 1.92X10+11 G [R1] *(1983) 2.73X10+11 G [R1] *(1985) 1.57X10+8 gal [R26] U.S. EXPORTS: *(1978) 3.65X10+11 G [R1] *(1983) 1.15X10+11 G [R1] *(1985) 2.82X10+7 gal [R27] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid. [R28, 310] ODOR: *Sweet, pungent, benezene-like odor. [R28, 310] BP: *110.6 deg C [R29, p. 3-55] MP: *-94.9 deg C [R29, p. 3-55] MW: *92.14 [R29, p. 3-55] CORR: *Noncorrosive liquid. [R30] CTP: *Critical temperature: 591.75 K; Critical pressure: 4.108 MPa [R29, p. 6-54] DEN: *0.8636 @ 20 deg C/4 deg C [R29, p. 3-55] HTC: *3910.3 KJ/mol [R29, p. 6-111] HTV: *38.01 KJ/mol @ 25 deg C [R29, p. 6-111] OWPC: *log Kow= 2.73 [R31] SOL: *Miscible with alcohol, chloroform, ether, acetone, glacial acetic acid, carbon disulfide [R11]; *Soluble in ethanol, benzene, diethyl ether, acetone, chloroform, glacial acetic acid and carbon disulfide; insoluble in water. [R32]; *In water, 526 mg/l @ 25 deg C [R33] SPEC: *SADTLER REF NUMBER: 419 (IR, PRISM); 119 (IR, GRATING); MAX ABSORPTION (ALCOHOL): 207 NM (LOG E= 3.97); 260 NM LOG E= 2.48) [R34]; *Index of refraction: 1.4967 @ 20 deg C/D [R29, p. 3-55]; *IR: 3574 (Coblentz Society Spectral Collection) [R35]; *UV: 155 (Sadtler Research Laboratories Spectral Collection) [R35]; *NMR: 157 (Varian Associates NMR Spectra Catalogue) [R35]; *MASS: 189 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R35]; *Intense mass spectral peaks: 65 m/z, 91 m/z, 92 m/z [R36] SURF: *29.71 dyne/cm @ 10 deg C; 28.93 dyne/cm @ 20 deg C; 24.96 dyne/cm @ 50 deg C; 21.98 dyne/cm @ 75 deg C; 19.01 dyne/cm @ 100 deg C [R29, p. 6-137] VAPD: *3.1 (Air=1) [R37, p. 1304-5] VAP: *28.4 mm Hg @ 25 deg C [R38] VISC: *0.778 cP @ 0 deg C; 0.560 cP @ 25 deg C; 0.424 cP @ 50 deg C; 0.333 cP @ 75 deg C; 0.270 cP @ 100 deg C [R29, p. 6-173] OCPP: *CONVERSION FACTORS: 1 PPM= 3.76/CU M; 1 MG/L= 226 PPM. [R13, 66] *Ratio of Specific Heats of Vapor (Gas): 1.089; floats on water [R7] *Partition coefficients at 37 deg C for toluene into blood= 15.6; into oil= 1,470. [R39] *Henry's Law constant = 6.64X10-3 atm-cu m/mole @ 25 deg C [R40] *Hydroxyl radical rate constant = 5.96X10-12 cu cm/molecule-sec @ 25 deg C [R41] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R42] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R42] +Public safety: Call Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R42] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R42] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R42] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R42] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R42] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R42] FPOT: *Flammable liquid. A very dangerous fire hazard when exposed to heat, flame, or oxidizers. [R4] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R43, p. 325-87] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R43, p. 325-87] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R43, p. 325-87] FLMT: *Lower flammable limit: 1.1% by volume; Upper flammable limit: 7.1% by volume [R43, p. 325-87] FLPT: *40 deg F (4 deg C) (Closed cup) [R43, p. 325-87] *16 deg C (Open cup) [R7] AUTO: *896 DEG F (480 DEG C) [R43, p. 325-87] FIRP: *TO FIGHT FIRE, USE FOAM, CO2, DRY CHEMICAL. [R4] *Approach fire from upwind to avoid hazardous vapors and toxic decomposition [R43, p. 49-127] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. [R44] TOXC: *MODERATELY DANGEROUS; WHEN HEATED, EMITS TOXIC FUMES /WHICH/ CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R45] OFHZ: *Vapor is heavier than air and may travel a considerable distance to a source of ignition and flash back. [R7] *Flame speed equals 37 cm/sec. [R46] EXPL: *LEL: 1.27%; UEL: 7%. [R4] REAC: *Frozen bromine trifluoride reacts violently with toluene at -80 deg C. [R47, 91] *A mixture of /dinitrogen/ tetraoxide and toluene exploded, possibly initiated by impurities. [R47, 1353] *Lack of proper control in nitration of toluene with mixed acids /nitric/ may lead to runaway or explosive reaction. A contributory factor is the oxidative formation, and subsequent nitration and decomposition of nitrocresols. [R47, 1165] *When /tetranitromethane is/ mixed with hydrocarbons in approximately stoichiometric proportions, a sensitive highly explosive mixture is produced which needs careful handling ... . Explosion of only 10 g of a mixture with toluene caused 10 deaths and 20 severe injuries. The mixture contained excess toluene in error.8 [R47, 189] *Interaction /of uranium hexafluoride/ with ... toluene ... is very vigorous, with separation of carbon, and violent with ethanol or water. [R47, 1126] *Incompatible with strong oxidizers. [R48, 869] *Strong oxidizers. [R28, 310] *Reacts photochemically with nitrogen oxides or halogens to form nitrotoluene, nitrobenzene and nitrophenol and halogenated products, respectively. [R32] *Explosive reaction with 1,3-dichloro-5,5-dimethyl-2,4-imidazolididione; dinitrogen tetraoxide; concentrated nitric acid, sulfuric acid + nitric acid; N2O4; AgClO4; BrF3; Uranium hexafluoride; sulfur dichloride. Forms an explosive mixture with tetranitromethane. [R4] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R4] ODRT: *2.14 ppm (8 mg/cu m). Odor recognition level is reported as 1.03 to 140 ug/cu m. [R49] *Odor in air= 1.30x10+11 mol/cu cm [R50] SERI: *A human eye irritant. An experimental skin and severe eye irritant. [R4] EQUP: *Protective clothing should include gloves, barrier creams, eye goggles or face shields, and a cartridge-type or self-contained breathing apparatus. [R37, 1332] +WEAR SELF-CONTAINED BREATHING APPARATUS; WEAR GOGGLES IF EYE PROTECTION NOT PROVIDED. [R43, p. 49-127] *Eye protection: Glasses having shatter-resistant glass or equivalent lenses and side shields to protect the eyes from toluene splashes. [R51] *If, for the purpose of maintenance or cleaning, a person is required to enter a vessel or similar area which has contained toluene, all suitable precautions for work in confined spaces should be adopted. Respiratory protection of the airline or self-contained type is essential; Reliance should not be placed on a canister respirator for such work. Workers whose hands may be exposed to toluene should wear suitable gloves or barrier creams. A thick layer of barrier cream should be applied. Under certain circumstances the use of a mask may be necessary for this type of work. [R12, 2185] *Respirator selection: 500 ppm: Chemical cartridge respirator with organic vapor cartridge/supplied-air respirator/self-contained breathing apparatus; 1000 ppm: Chemical cartridge respirator with organic vapor cartridge with full facepiece; 2000 ppm: Gas mask with organic vapor canister/supplied-air respirator with full facepiece, helmet, or hood/self-contained breathing apparatus with full facepiece; Escape: gas mask with organic vapor canister/self-contained breathing apparatus. [R48, 870] *Wear appropriate personal protective clothing to prevent skin contact. [R28, 310] *Wear appropriate eye protection to prevent eye contact. [R28, 310] *Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R28, 310] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R28, 310] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R28, 310] OPRM: *Drench-type showers, eye-wash fountains should be installed and maintained to provide prompt, immediate access. [R52] *Open lights or other agencies liable to ignite the vapor should be excluded from areas where the liquid is liable to be exposed in use or by accident. [R12, 2185] *A major concern in the painting studio is solvents, /including toluene/. ... Precautions include ... use of dilution and local exhaust ventilation, control of storage areas, disposal of solvent soaked rags in covered containers, minimizing skin exposure and the use of respirators and other personal protective equipment. The control of fire hazards is also important, since many of the solvents are highly flammable. [R53] *Contact lenses should not be worn when working with this chemical. [R28, 310] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R44] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R44] *If material leaking (not on fire): Consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R44] *The worker should immediately wash the skin when it becomes contaminated. [R28, 310] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R28, 310] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R54] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R55] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R56] STRG: *Outside or detached storage is preferred. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Separate from oxidizing materials. [R43, p. 49-127] *Use ambient storage temperature. [R7] CLUP: *Eliminate all ignition sources. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors and protect personnel. Absorb in noncombustible material for proper disposal. Control runoff and isolate discharged material for proper disposal. [R43, p. 49-197] *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. [R57] *Fluorocarbon water foam may be used to diminish vapors and provide wet down. [R58] *Cellosive and hycar absorbent materials, may be used for vapor suppression and/or containment of toluene. [R58] *Treat contaminated water by gravity separation of solids, followed by skimming of surface. Pass through dual media filtration and carbon adsorption units (carbon ratio 1.0 kg to 10.0 kg soluble material). Return waste water from backwash to gravity separator. [R58] *Environmental considerations - Land Spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder,or commercial sorbents. Apply "universal" gelling agent to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. [R44] *Environmental considerations - Water Spill: Use natural barriers or oil spill control boom to limit spill travel. Use surface active agent (eg Detergent, soaps, alcohols), if approved by EPA. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R44] *Environmental considerations - Air Spill: Apply water spray or mist to knock down vapors. [R44] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers U220, and F005 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R59] *Toluene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R60] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R61] *Additional flammable solvent may be added to increase incineration efficiency. Following treatment at a spill site or waste management facility, the resultant sludge can be disposed of to a secure landfill. [R62] *LARGE QUANTITIES CAN BE RECLAIMED OR COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER. TOLUENE SHOULD NOT BE ALLOWED TO ENTER A CONFINED SPACE, SUCH AS SEWER, BECAUSE OF POSSIBILITY OF EXPLOSION. ... DISPOSAL METHODS: TOLUENE MAY BE DISPOSED OF BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER. [R57] *The following wastewater treatment technologies have been investigated for toluene: biological treatment. [R63] *The following wastewater treatment technologies have been investigated for toluene: stripping. [R64] *The following wastewater treatment technologies have been investigated for toluene: solvent extraction. [R65] *The following wastewater treatment technologies have been investigated for toluene: activated carbon. [R66] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence for the carcinogenicity of toluene in humans. There is evidence suggesting lack of carcinogenicity of toluene in experimental animals. Overall evaluation: Toluene is not classifiable as to its carcinogenicity to humans (Group 3). [R67] *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: No human data and inadequate animal data. Toluene did not produce positive results in the majority of genotoxic assays. HUMAN CARCINOGENICITY DATA: None. [R68] +A4. A4= Not classifiable as a human carcinogen. [R69, 67] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R70, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatics hydrocarbons and related compounds/ [R70, 182] MEDS: *Yearly physical examinations of exposed personnel, with special attention to the eyes and central nervous system, including complete blood count and liver function tests. [R17, 526] *The clinical examination should include hemocytometric testing and a thrombocyte (platelet) count in view of the possibility that toluene may contain a certain proportion of benzene. [R12, 2185] *Hippuric acid levels above 5 g/l of urine may result from exposure greater than 200 ppm determined as a time weighted average. [R48, 870] HTOX: *Among 61 painters inhaling 100-1100 ppm toluene for 2 wk to 5 yr, depressed erythrocyte counts with elevated hemoglobin, mean corpuscular volumes, and elevated mean corpuscular hemoglobin were found in 5% to 30% compared with groups of 73-395 workers not known to be exposed to toluene; differential leukocyte counts were not significantly different between the toluene-exposed and the reference workers. [R6, 1991.1573] *... TOLUENE CAUSES DEFATTING OF SKIN WITH SUBSEQUENT DANGER OF DRYNESS, FISSURING AND SECONDARY INFECTION. [R71] *... SUDDEN DEATH AMONG "SNIFFERS" MAY BE ATTRIBUTED TO LETHAL CARDIAC ARRHYTHMIAS FOLLOWING SENSITIZATION OF THE MYOCARDIUM. [R72] *... PERMANENT ENCEPHALOPATHY ... /IN/ MAN WHO INHALED TOLUENE REGULARLY FOR OVER 14 YR /WAS DESCRIBED/. [R73] *VAPORS OF TOLUENE CAUSE NOTICEABLE SENSATION OF IRRITATION TO HUMAN EYES AT 300-400 PPM IN AIR, BUT EVEN AT 800 PPM IRRITATION IS SLIGHT. ... IN HUMAN VOLUNTEERS EXPOSED TO CONCN AS HIGH AS 800 PPM ... DILATION OF PUPILS AND IMPAIRMENT OF REACTION IN ASSOCIATION WITH FATIGUE AT END OF 8 HR, ALSO SLIGHT PALLOR OF FUNDI. [R74] *Metabolic acidosis with a high "anion gap" in 2 patients who had been sniffing toluene. [R75] *A report of 2 children who sniffed glue containing toluene. One of the children became comatose after an episode of "sniffing" which lasted for several hours. Adverse effects included reduced appetite, nightmares, vertical nystagmus, and incoordination. [R75] *WORKERS IN PHARMACEUTICAL PLANT IN FRANCE EXPOSED TO TOLUENE DEVELOPED LEUKOPENIA, AND NEUTROPENIA. WITHIN 6 MO, THOSE AFFECTED SHOWED INCR IN CLOTTING TIME AND DECR IN PROTHROMBIN LEVEL ... [R37, 1329] *PERIPHERAL BLOOD LYMPHOCYTES FROM 32 MALE ROTOGRAVURE WORKERS SHOWED NO SIGNIFICANT DIFFERENCE FROM CONTROLS IN FREQUENCY OF CHROMOSOME ABERRATIONS AND SISTER CHROMATID EXCHANGES. [R76] *Patients (3) with history of recurrent toluene abuse were hospitalized and severe metabolic acidosis, electrolyte abnormalities, hypoalkemia, and muscular weakness were present. Distal renal tubular acidosis was believed to be present in 2/3 patients. [R77] *Child of a mother with a 14 year history of solvent abuse showed symptoms of fetal alcohol syndrome. [R78] *A 27-year-old male developed cerebral and cerebellar atrophy over a period of five years of extensive glue sniffing. He also developed bilateral optic atrophy with blindness and severe sensorineural hearing loss. [R79] *Toluene appears to produce reversible effects upon liver, renal, and nervous systems. ... The nervous system appears to be the most sensitive to the effects of toluene. ... High level toluene exposures produced incoordination, ataxia, unconsciousness and eventually, death. Lower level acute exposures in man produce dizziness, exhilaration and confusion. Activity level has been inadequately studied. Schedule controlled behaviors have been reported to produce inverted U-shaped concentration-effect curves on response rate measures. Alterations at levels as low as 150 ppm have been reported when appetitive contingencies are used. Very few studies of the nervous system have been performed at levels below 1000 ppm and most of the results were inconclusive. ... [R80] *Lethal levels 1.0 mg%; 10.0 ug/ml [R81] *IN EXPERIMENTS IN VITRO, TOLUENE DID NOT CHANGE NUMBER OF SISTER-CHROMATID EXCHANGES OR THE NUMBER OF CHROMOSOMAL ABERRATIONS IN HUMAN LYMPHOCYTES. [R82] *A 28 yr old painter who was believed to be a habitual toluene sniffer was admitted to Chiba Emergency Medical Center on several occasions. Symptoms included: Tremors of the upper extremeties, staggering of gait, slurred speech, slight mental deterioration, pendular nystagmus, bradycardia, mild tremor of the leg, action myoclonus, and head and trunchal titubation. There was no dysmetria. The involuntary movements were classified as hyperkinesie volitionnelle. Muscle tone was hypotonic. Muscle weakness and atrophy were not seen. Deep tendon reflexes were all exaggerated, but there was no pathological reflex. He showed wide-based ataxic gait. Sensory and autonomic functions were normal. Blood, urine and cerebrospinal fluid analysis appeared normal. Electroencephalography showed 40-50 uV, 9-10 c/s alpha waves with a few fast waves. Brain CT scan revealed a moderate enlargement of the lateral and third ventricles. Surface electromyography was performed on the proximal musculature of the arm. 3 c/s reciprocal rhythmical grouping discharges were found at the terminal phase of the elbow bending. The tremor was diminished by 20 minutes ischemic compression test of the arm. With respect to therapy, clonazepam was useful for hyperkinesie volitionnelle. He became able to drink a cup of water without spilling it by his own hands, and was discharged from hospital on April 3rd, 1981. It was believed that he was a habitual sniffer to toluene. On June 30th, 1983 he was found comatose. On admission to Chiba Emergency Medical Center, his breath smelt of toluene. His blood toluene level was 7.53 ppm, and urinary hippuric acid concentration was 9,500 mg/l. He died on July 9th, 1983, because of disseminated intravascular coagulation, multiple organ failure and perforation of the terminal ileum. Autopsy was performed and neuropathological findings were as follows. 1) Diffuse demyelination and gliosis of the cerebral and cerebella white matter. 2) Marked loss of Purkinje cells of the cerebellum. 3) Astrocytic proliferation of the dentate fugal system and inferior olivary nucleus of medulla. ... [R83] *Autopsy findings on a man who fell from a height due to acute toluene poisoning while painting are described. Gas chromatographic examination revealed that the toluene concentrations of his blood, lung, liver and brain were 48, 35, 65 and 80 ug/g, respectively. These toluene levels were not enough to be definitely lethal, but were enough to anesthetize the central nervous system. [R84] *The psychological performance of 43 rotogravure printers exposed to a mean time- weighted average of 117 ppm toluene for a mean time period of 21.7 yr was compared to that of 31 offset printers with a mean working period of 23 yr. The offset printers were exposed to mixtures of aliphatic hydrocarbons or ethyl acetate (amounts not given) for a total of 10 to 60 min daily. Drinking habits were considered in grouping the workers. The test battery consisted of standardized tests for verbal and visual cognition and memory, perceptual motor speed, and psychomotor abilities. Performances of the two printer groups were similar with rotogravure printers having statistically significant lower scores on tests measuring visual cognitive abilities. Mean test performances indicated that drinking habits did not explain the impairment of visual cognitive abilities. [R85] *Acute poisoning may result from exposure to high concn of toluene; A /CNS depressant/ effect is produced. Human death has resulted from exposure to 10,000 ppm. Toluene is more acutely toxic than benzene; however, severe blood disorders of the type associated with benzene are not reported. Inhalation of 200 ppm has affected the CNS in humans. [R49] *Vapors irritate eyes and upper respiratory tract; Cause dizziness, headache, anesthesia, and respiratory arrest. Liquid irritates eyes. If aspirated, causes coughing, gagging, distress, and rapidly developing pulmonary edema. If ingested causes vomiting, griping, diarrhea, and depressed respiration. Kidney and liver damage may follow ingestion. [R7] *In recent years some youngsters have been indulging in what is called thinner inhalation, posing a serious social problem. Organic solvents have also been widely used industrially as adhesives or degreasing and rinsing agents, generating a kind of occupational disease which has become a medical problem. Some school children who refuse to go to school complaining of headache, head heaviness, blurred vision, diplopia, or dizziness, may actually have toluene toxicosis caused by the adhesive they use in constructing plastic models. /An examination of/ 35 such patients neurogically, found some impairment in the cerebellar cortex, cerebellar nuclei, or efferent pathways. This report is presented to invite comments from other researchers. [R86] *Severe, acute toluene intoxication in two workers was described. Special attention was paid to the metabolism of toluene in man and to the choice of reference parameters to monitor intoxication. The men had tiled a small swimming pool to be used for exercise programs in a rehabilitation clinic. They had used a special glue to make the joints of cement between the tiles resistant to bleaching solution; the next day they removed the excess glue using toluene. One worker was exposed for 2 hours and the other for 3 hours. Both were overcome with the fumes, and were found lying at the bottom of the pool. Symptoms included stupefaction, paresis, and amnesia. Patient-A had mucosal irritation of the eyes and slurred speech. He was stuporose and unable to walk or sit. His amnesia lasted for about 3 hours. Patient-B had mucosal irritation of the eyes, was drowsy, and was just able to walk. He had normal speech and complained of headache. The duration of his amnesia was about 2.5 hours. Solid evidence for toluene exposure was provided by the blood toluene concentration. The concentration 2 hours after exposure was 4.1 mg/l in patient-A and 2.2 mg/l in patient-B. [R87] *The memory sequelae for a group of female workers accidentally exposed to organic solvents were examined retrospectively to evaluate complaints of residual memory impairment. The subjects included seven employees (mean age 32.1 years) who agreed to retesting and who had been severely intoxicated by exposure to toluene and aliphatic hydrocarbons found in adhesives used in the manufacture of tennis balls. They were compared to eight workers (mean age 33.7 years) who were solvent exposed but not affected by the accident and ten workers (mean age 36.6 years) who had no exposure. Acute symptoms included faintness, nausea, vomiting, and headache. Complaints of impaired memory, personality changes, and loss of confidence persisted 8 months after exposure. Memory testing was first performed 2 months after exposure, with the follow up 6 months later to assess recovery. The three memory tasks included paired associate task, serial position task, and Brown-Peterson task. The subjects showed normal patterns of performance on tests of learning and short term and long term memory, but demonstrated marked difficulties when attention had to be divided between two resource competing tasks. The clearest evidence of impairment was observed in the Brown-Peterson task, where the acute group showed a significantly greater increase in word recall omission after periods of counting backwards in threes. The magnitude of the memory sequelae was not correlated with scores of self rated depression. It was concluded that solvent intoxication can cause neuropsychological sequelae lasting more than 8 months; memory tasks could prove useful in identifying memory impairment in other occupationally exposed groups. [R88] *In a cross-sectional study of 181 male workers of a rotogravure printing plant, most of whom were exposed to toluene levels well above the GDR threshold limit values, 55 subjects revealed pathological liver screening values (activities of serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase; liver size). The differential diagnostic examination showed in 51 of these 55 subjects an association with competing factors such as alcohol abuse (78%) and overweight (40%), to a slight extent disorders of fat and carbohydrate metabolism and of the gallbladder. Drug intake did not play any role. The variance and regression analyses of the biochemical data have shown that alcohol significantly and considerably increases the activities of all three enzymes tested. Bodyweight had a similar, but less pronounced, significant effect. On the other hand, in subjects with a higher alcohol intake the activities of liver enzymes in highly toluene exposed subgroups were significantly and clearly lower than among slightly toluene exposed workers. [R89] *General health effects include lethality, growth, morbidity, liver and kidney damage and miscellaneous effects. Neurobehavioral effects include epidemiological and clinical findings, activity and sleep, performance and learning, electrophysiological effects. Evaluation and synthesis of data is included. It was concluded that low level exposure to toluene has its primary effect on the CNS. From a systematic or general point of view it is not clear what this effect is. Both depressant and excitatory effects (possibly concentration dependent) were reported as well as other kinds of results. Other health effects were not life threatening at any exposure level short of that producing lethality. Effects were reversible even at extremely high exposure levels for very long durations. [R90] *Toluene embryopathy is characterized by microcephaly, central nervous system dysfunction, attentional deficits and hyperactivity, developmental delay with greater language deficits, minor craniofacial and limb anomalies, and variable growth deficiency. Previously, three affected children, born to women who inhaled toluene regularly throughout pregnancy, have been reported. Two more cases are described emphasizing the importance of toluene as a potential human teratogen. [R91] *Neurobehavioral tests were undertaken by 30 female workers exposed to toluene and matched controls with low occupational exposure to toluene. The environmental air levels (TWA) of toluene was 88 ppm for the exposed workers and 13 ppm for the controls. The toluene in blood concentrations for the exposed workers was 1.25 mg/l and for the controls 0.16 mg/l. Statistically significant differences between workers exposed to toluene and controls in neurobehavioral tests measuring manual dexterity (grooved peg board), a visual scanning (trail making, visual reproduction, Benton visual retention, and digit symbol), and verbal memory (digit span) were observed. Further, the performance at each of these tests was related to time weighted average exposure concentrations of air toluene. The workers exposed to toluene had no clinical symptoms or signs. The question arises as to whether these impairments in neurobehavioral tests are reversible or whether they could be a forerunner of more severe damage. [R92] *When compared with benzene, toluene has little to no effect on immunocompetence. However, it should be noted that toluene exposure effectively attenuates the immunotoxic effects of benzene (probably because of competition for metabolic enzymes). [R93, 380] *Neutral organic solvents such as ... toluene ... cause pain on contacting the eye, and examination after a generous splash of solvent shows dulling of the cornea. The epithelium will show punctate staining with fluorescein. The damage appears to be scattered loss of epithelial cells due to solution of some of the fats that occur in these cells. [R93, 586] *Toxicities associated with toluene: CNS depression, syncope, coma, cardiac arrhythmias and sudden death, ataxia, convulsions, rhabdomyolysis, increased creatine phosphokinase, abdominal pain, nausea, vomiting, hematemesis, peripheral neuropathy, paresthesias, encephalopathy, optic neuropathy, cerebella ataxia, distal renal tubular acidosis, hyperchloremia, hypokalemia, azotemia, hypophosphatemia, hematuria, proteinuria, pyruria, normalities, decreased cognitive function, fatal overdose. /From table/ [R94, 1494] *Women workers exposed to high air concentrations of toluene (50-150 ppm) appeared to have a higher incidence of spontaneous abortion than a similar group of women with no occupational exposure to toluene. [R94, 166] *Maternal spray paint or glue sniffing leads to maternal complications including renal tubular acidosis, hypokalemia, hypocalcemia, cardiac arrhythmias, rhabdomyolysis, and premature labor. Premature toluene exposure leads to a characteristic pattern of anomalies similar to findings in infants exposed to alcohol in utero, consisting of an increased incidence of malformations, poor growth, and developmental delays. [R94, 166] *Eye and upper airway irritation occurred after a 6.5 hr exposure to an air level of 100 ppm (377 mg/cu m) toluene, and lachrymation was seen at 500 mg/cu m. [R95] *Volunteers exposed to 100 ppm (377 mg/cu m) toluene for 6 hr/day for four days suffered from subjective complaints of headache, dizziness and a sensation of intoxication. In subjects exposed to 750 mg/cu m for 8 hr, fatigue, muscular weakness, confusion, impaired coordination, enlarged pupils and accommodation disturbances were experienced; at about 3000 mg/cu m, severe fatigue, pronounced nausea, mental confusion, considerable incoordination with staggering gait and strongly affected pupillary light reflexes were observed. After exposure at the high level, muscular fatigue, nervousness and insomnia lasted for several days. Heavy accidental exposure leads to coma. [R95] *Humans exposed to concentrations of toluene of between 200-800 ppm may experience respiratory and ocular irritation. [R96, 1090] *Children with microcephaly, minor craniofacial and limb anomalies, central nervous system defects, attention disorders, developmental delay, learning disorders, and language deficits were born to mothers who abuse toluene by inhalation during pregnancy. [R96, 1091] *Controlled exposure effects on volunteers were studied at toluene concentrations ranging from 40, 60, or 100 ppm. ... Psychologic measurements indicated decrements in vigilance, visual perception, motor performance, and ability to carry out functions at 100 ppm. [R96, 1092] *Acute effects in humans following exposure to toluene: 50-100 ppm: subjective complaints (fatigue or headache), but probably no observable impairment of reaction time or coordination; 200 ppm: mild throat and eye irritation; 100-300 ppm: detectable signs of incoordination may be expected during exposure periods up to 8 hr; 400 ppm: lacrimation and irritation to the eyes and throat; 300-800 ppm: gross signs of incoordination may be expected during exposure periods up to 8 hr; 1500 ppm: probably not lethal for exposure periods of up to 8 hr; 4000 ppm: would probably cause rapid impairment of reaction time and coordination, exposures of one hr or longer might lead to /CNS depression/ and possibly death; 10,000-30,000 ppm: onset of /CNS depression/ within a few minutes, longer exposures may be lethal. /From table/ [R97, 724] *Studies of women exposed to solvents such as benzene, toluene, and xylene have shown menstrual disturbances, principally associated with abnormal bleeding. [R98, 155] *FROM THE STANDPOINT OF CHRONIC EXPOSURE, IT IS CLEAR THAT TOLUENE DOES NOT CAUSE THE SEVERE INJURY TO THE BONE MARROW THAT IS CHARACTERISTIC OF BENZENE POISONING. [R6, 1991.1571] *Toluene abuse (to 10,000 ppm) has been linked with kidney disease as evidenced by blood (hematuria), protein (proteinuria), albumin (albuminuria), and pus (pyuria) in the urine, accompanied by elevated serum creatinine, decreased urinary output, and metabolic and renal tubular acidosis. [R6, 1991.1573] *... The highest toluene concentrations in air that could be tolerated for 3.5-6 hr without measurable decrements on behavioral test performance were 80 ppm to 100 ppm. [R6, 1991.1574] *The pregnancies of four of five women associated with gross toluene abuse (0.5 to 2 cans of spray paint/day for 6 mos to 11 yr) resulted in evidence of renal toxicity (as evidenced by severe renal tubular acidosis), fetal toxicity (manifest as intrauterine growth retardation), and teratogenicity (deformed external ears, ventricular septal defect, micrognathia, hydronephrosis) with facial features reminiscent of the FAS (short palpebral fissures, epicanthal folds, maxillary hypoplasia). [R6, 1991.1575] *In a case study of two adult white males who suffered from toluene intoxication while removing glue from tiles in a swimming pool, cardiac arrhythmias were noted. Response seemed to be highly variable among individuals. One person exposed for 2 hr to less than 1890 ppm toluene exhibited a rapid heartbeat (sinus tachycardia), while the second person, exposed for 3 hr, exhibited a slow heartbeat (bradycardia). [R99] *Severe renal tubular acidosis was observed in five pregnant women who were chronic abusers of paints containing toluene. [R100] *Exposure of students to 75 or 150 ppm toluene for 7 hr caused a dose-related impairment of function on digit span, pattern recognition, the one hole test, and pattern memory. There was an effect on the results of the symbol digit test but the effect was not dose related. Subjects served as their own controls. ... There were no differences in the results on simple reaction time, POMS mood scale, visual memory, hand-eye coordination, Sternberg test, finger tapping, reaction time, continuous performance test, and critical tracking test. [R101] *A group of 95-104 workers exposed to TWA of 41-46 ppm toluene during shoemaking, printing, and audio equipment production were evaluated for symptoms and signs of exposure when compared to 130 control subjects. The incidence of health-related complaints among the toluene exposed workers was two to three times that of the controls. Dizziness was reported by about two-thirds of the toluene exposed respondents. These subjects also complained of headaches, sore throats, eye irritation, and difficulty with sleep. When the exposed subjects were divided into two groups, one with TWA exposures of less than 40 ppm and the other with exposures greater than or equal to 40 ppm, the incidence of headache and sore throat, but not dizziness, showed a dose-response pattern. [R102] *Children born to toluene abusers have exhibited renal tubular acidosis immediately after birth due to hyperchloremia. In each incident the acidosis was resolved within 3 days of birth. [R103] *Several case series have demonstrated that high exposure to toluene through sniffing during pregnancy induces a syndrome that closely resembles the fetal alcohol syndrome, with pre- and postnatal growth deficiency, microcephaly and developmental delay, typical craniofacial features including micrognathia, small palpebral fissures, and ear anomalies. [R104] *Renal tubular acidosis is one of a number of human complications reported in the offspring of mothers inhaling toluene during pregnancy. This article reports a case of a premature newborn with renal tubular acidosis probably due to maternal sniffing of paint containing toluene. Characteristics of this condition are described as well as its medical management. [R105] NTOX: *A TEMPORARY INCOORDINATION WITH MUSCULAR TREMORS HAS BEEN OBSERVED IN PUPPIES AND KITTENS AND IN DOGS AT TWICE THERAPEUTIC DOSE LEVEL. CALVES IN POOR CONDITION SHOWED STAGGERING GAIT AND SOME COLLAPSED BUT RECOVERY WAS COMPLETE AFTER UP TO 4 HOURS. FOUR TIMES THERAPEUTIC DOSE RATE PRODUCED NO OBSERVABLE CHANGES IN ... ORGANS. [R106] *... /CNS DEPRESSANT/ EFFECT OF TOLUENE ... IS EXERTED IN 2 PHASES--A PRELIMINARY ... /CNS DEPRESSION/ FOLLOWED BY STAGE OF EXCITEMENT, MANIFESTED BY TREMOR, MUSCULAR CRAMPS AND DISTURBANCES IN BEHAVIOR ... [R13, 70] *... SWELLING OF GLOMERULI, CYLINDERS AND ALBUMIN IN URINE IN 2 ... DOGS. BUT ... /INVESTIGATORS/ NOTE THAT THE DOGS WERE OF BREED WHICH FREQUENTLY DEVELOP INTERSTITIAL NEPHRITIS. ... HEMORRHAGIC AND DEGENERATIVE LESIONS IN GOATS. [R13, 72] *IN DOGS ... CONGESTION AND HEMORRHAGIC FOCI WERE PRESENT IN LIVER; THESE LESIONS ... ALSO PRESENT IN GOATS ... CONGESTION AND SOME ALVEOLAR INFLAMMATION /OF LUNG ALSO/ ... IN DOGS AND ... GOATS. SPLEEN ... SHOWED SOME DIMINUTION OF LYMPHOID FOLLICLES AND PLAQUES OF HEMOSIDEROSIS. [R13, 71] *EFFECTS IN CATS EXPOSED TO 7800 PPM (31.0 MG/L)/6 HR: CNS EFFECTS, MYDRIASIS, MILD TREMORS, PROSTRATION IN 80 MIN, LIGHT ANESTHESIA IN 2 HR. /FROM TABLE/ [R37, 1327] *INTRATRACHEAL ADMIN /TO CATS/ WITH CHRONICALLY IMPLANTED ELECTRODES INDUCED SEIZURES ALONG WITH BEHAVIORAL DISTURBANCES SUCH AS NODDING, TWITCHING AND APPARENT HALLUCINATIONS. [R107] *... RATS /EXPOSED/ TO 1500 MG/CU M OF AIR FROM DAY 1 THROUGH 8 OR 1000 MG/CU M FOR 8 HR DAILY FROM DAY 1 THROUGH DAY 21 /OF GESTATION/ ... /WITH/ NO TERATOGENIC EFFECT. SOME FETAL GROWTH RETARDATION ... @ HIGHER DOSE ... MICE WERE EXPOSED DURING DAYS 6-13 TO 1500 MG/CU M OF AIR WITH SIMILAR RESULTS. [R108] */GAVAGING/ MICE /WITH/ 1.0 MG/KG ON DAYS 6 THROUGH 15 /OF GESTATION/ ... INCR CLEFT PALATE IN THE OFF-SPRING. [R108] *TOLUENE WAS UNABLE TO REVERT SALMONELLA TYPHIMURIUM STRAINS TA1535, TA1537, TA1538, TA98 AND TA100 IN THE AMES SALMONELLA/MICROSOME ASSAY, EITHER WITH OR WITHOUT METABOLIC ACTIVATION BY S9 MIX FROM LIVERS OF RATS EITHER UNTREATED OR INDUCED WITH AROCLOR 1254. [R109] *FOLLOWING IP ADMIN OF 1 ML TOLUENE/KG DAILY FOR 21 DAYS TO RATS, MIXED-FUNCTION OXYGENASE ACTIVITY INCREASED 33.8% IN LIVER BUT WAS UNCHANGED IN BRAIN. [R110] *TOLUENE AND M-XYLENE CAUSED MUSCULAR WEAKNESS AND EQUILIBRIUM DISTURBANCES IN THE RAT FOLLOWING IP ADMIN. THE LOCOMOTOR (OPEN-FIELD BEHAVIOR) AND RUNNING ACTIVITY (WHEEL-RUNNING) IN THE RAT WAS MOST AFFECTED BY TOLUENE. THESE DIFFERENCES WERE RELATED TO THE DIFFERENCES IN THE STIMULATORY EFFECTS OF THE SOLVENTS ON THE CNS. [R111] *RATS WERE EXPOSED TO TOLUENE OR N-HEXANE OR A MIXT OF THE 2 CMPD AT 1000-8000 PPM FOR 8 HR. ACETYLCHOLINE WAS INCR AT LOW CONCN OF THE SOLVENTS, BUT WAS GREATLY DECR AT HIGH CONCN. CHOLINE ACETYLTRANSFERASE WAS DECR SIGNIFICANTLY AT HIGH CONCN OF THE MIXT. ACETYLCHOLINE ESTERASE ACTIVITY WAS INCR BY THE SOLVENTS. [R112] *In skin painting studies with CF1, CH, and BaH strains of mice, 0.05 to 0.1 ml/mouse was applied to 25 mice/sex/strain for 52 weeks. Results were negative for tumor development. [R113] *Intraperitoneal admin of 250, 500, or 1,000 mg/kg at 0 and 24 hr failed to give positive results in micronucleus test with Swiss mice. [R114] *... Groups of rats were trained on the conditioned avoidance response task during the last week of a 5 week exposure to 1400 or 1200 ppm toluene (14 hr/day, 7 days/week) or during the first or third weeks after the exposure ended. None of the three groups ... were able to acquire the auditory condition avoidance response ... . Subsequent tests ... revealed that hearing with these rats was unimpaired at 4 KHz, slightly impaired at 8 KHz, and markedly impaired at 12 KHz and above. [R115] *Pregnant CD-1 mice were housed singly in multicompartment cages in inhalation chambers and exposed to toluene at a concentration of 0, 750, or 1500 mg/cu m (0, 200, or 400 ppm) for 7 hrs/day from day 7 through day 16 of gestation. The mice were killed on day 17 of gestation and the fetuses were removed and examined. Maternal weight gain was not affected by toluene exposure but the liver to body weight ratio was significantly reduced. The treated dams showed no significant differences in the average number of implantation sites, number of live fetuses, fetal mortality, or fetal body weight at either toluene concentration compared to control values. The incidence of enlarged renal pelvis was significantly greater in fetuses exposed to 200 ppm than in the fetuses exposed to 400 ppm or in the controls. A shift in rib profile (number of fetuses with 13 ribs) was observed in the higher toluene concentration group, and this shift was significantly different from the rib profile of controls. There was an increase in the total activity of lactic dehydrogenase activity in the brain of the dams from the 400 ppm group. The total activity of lactic dehydrogenase in the toluene exposed pups did not differ significantly from the controls for liver, heart, lung, or kidney, but the brain lactic dehydrogenase activity of the treated group was slightly greater than the control value. [R116] *Behavioral toxicity of toluene was assessed in mice confined in a 20 liter hermetically sealed chamber for several hours. Toluene was introduced through a port and volatilized by a hot plate. Samples of chamber air for analysis were taken through another port. A smaller mesh cage held the mouse within the larger chamber. Schedule-controlled responding was developed by arranging that a response, breaking a beam of light, was followed by mild (under an F1 60 sec) schedule. Responding was much more rapid in the presence of stimuli correlated with the F1 schedule than when the schedule was not operating. Standard sessions consisted of alternating series of 8 consecutive F1 60 sec and inter-series 30 min time-outs. Concentration-effect curves were determined by exposing a mouse to incremental additions of toluene at 30 min intervals. Toluene increased the rate of responding in most mice at levels of about 700 ppm. Higher concentrations progressively reduced responding. The ED50 (the concentration reducing responding by 50%) averaged 1657 ppm in 10 mice. It is estimated that there is a 1/1000 chance /ED001/ of the responding of a mouse being reduced by as much as 10% by a concentration of toluene of 69 ppm. [R117] *Sixteen rats were chronically implanted with bipolar electrodes in the hipocampal regions containing cells generating electric theta-activity. The animals were divided into 4 groups of which 2 were exposed to 500 ppm of toluene in inhalation chambers, for 8 or 16 hours per day for 5 days per week in 12 weeks respectively, and 2 served as controls. The hippocampal electric activity was recorded 48 hours after each weekly exposure. Frequencies of theta-activity in the exposed groups were found to differ from their respective control group by variance analysis. Each point on the frequency versus time plot were further analysed by Student's t-test. Compared to the non-exposed group the eight hours daily exposed showed an initial period of increased frequency of the regular theta-waves together with an increased incidence of theta-activity after 1-2 weeks of exposure. In the sixteen hours daily exposed rats two weeks of toluene inhalation produced a significant reduction in the theta-wave frequency. This change was also reached after either weeks of exposure in the eight hours daily exposed group. At this moment the theta-activity was frequency disrupted by short amplitude irregular waves, a phenomen which increased gradually throughout the rest of the exposure period. The average blood concentration of toluene was 16.7 ug/ml and 17.7 ug/ml and not significantly different for the eight and sixteen hours exposed groups respectively. [R118] *The effects of toluene vapors on brain lipid changes were investigated in male Sprague-Dawley rats. The animals (8/group) were continuously exposed to 320 ppm toluene for 30 days. Controls were exposed to air. Exposed animals showed decreased body weight (p < 0.01), decreased brain weight (p < 0.01), and a decrease in the weight of the cerebral cortex (p < 0.05) when compared to controls. In the cerebral cortex of exposed rats, total phospholipids was reduced (p < 0.001), there was an increase in phosphatidic acid (p < 0.05) and a decrease in a minor fatty acid of ethanolamine phosphoglyceride (p < 0.05). No changes in lipids were found in the brain stem. [R119] *With the intention of investigating possible morphological alterations effected by toluene in the developing CNS, rat pups were exposed to 100 ppm and 500 ppm of atmospheric toluene from postnatal day 1 until sacrifice at postnatal day 28, when the hippocampal region (area dentata, Ammon's horn, subiculum) was examined by light microscope and alterations in the volumes of the layers of the subdivisions were determined. The layers of Ammon's horn and the subiculum were not affected qualitatively or quantitatively by the 500 ppm exposure. Within the area dentata, the volume of the granule cell layer was 6% smaller in animals exposed to 100 ppm and 13% smaller in animals exposed to 500 ppm than they were in controls. The volumes of the hilus, which is a terminal field of granule cell axons, and the commissural-association zone of the dentate molecular layer, which is the terminal field of the hilar projection to the granule cells, were smaller (12% and 19%) in animals exposed to 500 ppm than they were in controls. Argyrophilic cells were found in the granule cell layer of all animals exposed to 500 ppm. Pronounced granule cell degeneration was found in one animal exposed to 500 ppm. The granule cell layer of animals exposed to 100 ppm appeared qualitatively normal. The alterations reported here support the few earlier reports of morphological alterations in the CNS of adult laboratory animals. Effects of toluene similar to those described, that is alterations in specific neuron populations and their afferent and efferent terminal fields may complement changes in neurophysiology and behavior that have been observed in prenatally and perinatally exposed rodent pups. Causal relationships, however, remain to be elucidated. [R120] *The aim of the present study was to investigate the effects of toluene on fetal development in well nourished and malnourished rats. Long-term behavioral consequences after in utero exposure were also studied. Toluene (1.2 g/kg sc) was administered daily to well nourished and to malnourished (food restricted to 50% of ad libitum intake) pregnant rats, during the second (8-15 days) or the third week of pregnancy (14-20 days). Offspring were evaluated for malformation, development of the skeleton, prenatal growth of the brain and liver, postnatal growth and long lasting behavioral effects. In utero exposure to toluene during the third week of pregnancy resulted in low body weight at birth, which persisted in the male offspring into adulthood. Malnutrition increased fetal susceptibility to the effects of toluene as indicated by evaluation of the development of the skeleton. Behavioral tests performed when the pups were 30 and 90 days old showed effects of in utero malnutrition (increased ambulation and worse performance in a shuttle box), but no behavioral effects related to toluene exposure were detected. These data indicate that in utero exposure to toluene can have long lasting effects on body growth and that maternal malnutrition increases the risk for toluene fetotoxicity. [R121] *Toluene did not induce gene mutations in Salmonella typhimiurium strain TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In the mouse lymphoma assay, toluene gave an equivocal response with and without exogenous metabolic activation. Toluene did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation. [R122] *... Toluene can alter learned behavior at concentrations below anesthetic levels but, in general, above 1000 ppm. [R93, 747] *Toluene was injected into the yolk sac of fresh fertile chicken eggs prior to incubation. Hatchability of the eggs was 85%, 25%, and 0 with exposures of 4.3, 8.7, and 17.4 mg/egg, respectively. [R123] *Toluene was reported to induce chromosomal aberrations in the bone marrow cells of male albino rats after chronic inhalation exposure to 5.4 or 50.7 mg/cu m on 4 hr/day, five days/wk for four months or after sc injection of 0.8 g/kg bw. Chromosomal aberrations in bone marrow cells were reported following sc injection of 1 g/kg bw daily for 12 days to male albino rats. [R124] *Toluene and benzene administered concurrently were reported to have an additive effect on induction of chromosomal aberrations. Toluene reduced the number of sister chromatid exchanges induced by benzene when both compounds were administered intraperitoneally to DBA/2 mice and reduced the clastogenic activity of benzene when the two compounds were simultaneously administered orally to CD-1 mice, intraperitoneally to Sprague-Dawley rats, or subcutaneously to NMRI mice. [R125] *Animal studies in mice exposed to toluene at concentrations of 2.5-500 ppm demonstrated decreased host defense to respiratory infections. [R96, 1092] *The cardiovascular response of 25 mongrel dogs following exposure to 30,000 ppm toluene for 9-10 min was complex. For most of the animals, there was no change in electrocardiogram readings for the first 3-4 min of exposure. The heartbeat then became rapid for several minutes, and was followed by a period of bradycardia. Immediately before death ventricular fibrillation was noted. ... Four of the dogs were particularly sensitive, their ventricular arrhythmias were transient and accompanied by fluctuations of blood pressure. The authors suggested that toluene had a direct effect on the septal and ventricular muscles of the heart which permitted the development of fatal arrhythmias in sensitive dogs. [R126] *Mice exposed for 3 hr to toluene at concentrations of 2.5-500 ppm exhibited increased, but not dose-related, susceptibility to respiratory infections when challenged by Streptococcus zooepidemicus. Pulmonary bactericidal activity was decreased at concentrations of 2.5 ppm and 100-500 ppm but not at concentrations of 5-50 ppm. There was no effect on susceptibility to infection with a toluene exposure of 1 ppm for 3 hr, 5 days (3 hr/day) or 4 wk (3 hr/day). The bactericidal activity of the lung was decreased during the 5-day treatment but not with the 4-wk treatment. The authors hypothesized that toluene exerted an adverse effect on alveolar macrophage function, thereby decreasing disease resistance. [R127] *Studies have demonstrated that toluene can produce subtle changes in the auditory system. Intermediate exposure to toluene produced a permanent loss of hearing in the high frequency range (approximately 16 kHz) in rats exposed to 1200 ppm for 5-9 wk or 1000 ppm for 2 wk. [R128] *In 3-day-old rats, daily 15 min exposures to toluene resulted in a dose-related increase in righting-reflex latency time. At each dose the righting-reflex latency decreased over the first 4 wk of exposure indicating that the animals had developed at least partial tolerance to the toluene. During the second 4-wk period, latencies increased again at the higher doses but were never as great as they were for the initial toluene exposure. The results for the second 4-wk period showed that there were limitations to the adaptive response at the higher toluene doses and that there were cumulative effects of exposure at these doses. Tolerance was probably the result of induction of toluene metabolizing enzymes. [R129] *Concentrations of 480 ppm and above decreased the ability of trained rats to perform a sequence of lever press actions associated with a reward (milk). During training, the rats were divided into two groups. The reward presentation for one group was not accompanied by any noticeable external events. For the second group, the reward presentation was accompanied by light and sound stimuli. The effects of toluene on performance were less severe with the rats trained using the light and sound reinforcement. This suggests that behavior associated with external signals is less subject to disruption by toluene than behavior that is not accompanied by external reinforcement. [R130] *Age ... influences neurological response after exposure to toluene. Young rats (50 days old) were affected by toluene to a lesser extent than older rats (120 days old) based on several measurements of escape latency 30 days after exposure to 30,000-40,000 ppm for 15 min/day. [R131] *Toluene exposure ... changes sleep patterns in animals. Both single episodes of toluene exposure (about 1000 ppm) and subchronic 8 hr/day exposures for 3 wk (about 600 ppm), changed patterns of sleep and wakefulness in rats. After the single exposures, there was a decrease in wakefulness and an increase in slow-wave sleep; a prolonged sleep latency was apparent for the 2 days following exposure. Latency was defined as the time interval between the end of the exposure period and the beginning of a particular phase of the sleep cycle. Following the 3 wk exposures, there was an increase in wakefulness during the dark period on the 2 days after exposure and a decrease in slow wave sleep on the first day. [R132] *Brain levels of norepinephrine, dopamine, serotonin, vanillylmandelic acid, homovanillic acid, and 5-hydroxyindolacetic acid were altered in six areas of the brain in male CD-1 mice administered toluene (5-105 mg/kg/day) in their drinking water for a 28-day period. Significant increases of norepinephrine, dopamine, and serotonin were present in the hypothalamus at all dose levels. The maximum increase occurred with the 22 mg/kg/day dose and there were lesser increases for both the 5 and 105 mg/kg/day doses, giving biphasic response. Roughly similar fluctuations were seen in the concentrations of vanillylmandelic acid and homovanillic acid, which are metabolites of dopamine and norepinephrine and 5-hydroxyindolacetic acid, a serotonin metabolite. In corpus striatum, the levels of dopamine and serotonin were significantly increased at the two highest doses. The level of vanillylmandelic acid was also increased significantly at the same doses. In the medulla oblongata, the concentrations of norepinephrine, vanillylmandelic acid, and 5-hydroxyindolacetic acid were significantly increased at the 22 mg/kg/day dose, but not at the other doses, while the levels of serotonin were significantly increased at the 22 and 105 mg/kg/day doses. Norepinephrine concentrations were elevated in the midbrain. ... [R133] *To identify the frequency range most sensitive to toluene-induced auditory damage, the auditory function of adult Long-Evans rats exposed to 1750 ppm of toluene (6 h/day, 5 days/week, 4 weeks), was tested by recording auditory-evoked potentials directly from the round window of the cochlea. The present electrocochleographic findings do not support a specific mid- to high-frequency loss of auditory sensitivity. On the contrary, the electrophysiologic data, obtained for audiometric frequencies ranging from 2 to 32 kHz, showed a hearing deficit not only in the mid-frequency region (12-16 kHz), but also in the mid-low-frequency region (3-4 kHz). Actually, the effect of toluene was independent of the frequency in our experimental conditions. Histological analysis was consistent with electrophysiologic data because a broad loss of outer hair cells occurred in both mid- and mid-apical coil of the organ of Corti. [R134] NTXV: *LD50 Rat oral 2.6 to 7.5 g/kg; [R135] *LD50 Rabbit dermal 14.1 ml/kg; [R135] *LD50 Rat (female) ip 1.64 g/kg; [R136] *LD50 MOUSE IP 1.15 G/KG; [R137] *LD50 Rat oral 5000 mg/kg; [R4] *LD50 Rat ip 1332 mg/kg; [R4] *LD50 Rat iv 1960 mg/kg; [R4] *LC50 Mouse ihl 400 ppm/24 hr; [R4] *LD50 Mouse ip 59 mg/kg; [R4] *LD50 Mouse sc 2250 mg/kg; [R4] *LD50 Mouse ip 640 mg/kg; [R4] *LD50 Rabbit skin 12,124 mg/kg; [R4] *... The LC50 for toluene in mice is 5320 ppm/8 hr /via inhalation/ ..; [R93, 746] *As the duration of toluene inhalation exposure increased, the LC50 in rats decreased from 26,700 ppm for 1 hr, to 12,200 ppm for 2-2.5 hr, to 8000 ppm for 4 hr; [R6, 1991.1568] ETXV: *LC50 FOR BLUEGILL WAS 17 MG/L/24 HR AND 13 MG/L/96 HR (95% CONFIDENCE LIMIT 11-15 MG/L) @ 21-23 DEG C AFTER EXPOSURE TO TOLUENE. /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R138] *LC50 Palaemonetes pugio (grass shrimp) 9.5 mg/l/96 hr /Conditions of bioassay not specified/; [R16, 1727] *LC50 Cancer magister (crab larvae stage I) 28 mg/l/96 hr /Conditions of bioassay not specified/; [R16, 1727] *LC50 Crangon franciscorum (shrimp) 4.3 mg/l/96 hr /Conditions of bioassay not specified/; [R16, 1728] *LC50 Pimephales promelas (fathead minnow) 56-34 mg/l/24-96 hr /Conditions of bioassay not specified/; [R16, 1728] *LC50 Lebistes reticulatus (guppy) 63-59 mg/l/24-96 hr /Conditions of bioassay not specified/; [R16, 1729] *LC50 Channel catfish 240 mg/l 96 hr /Conditions of bioassay not specified/; [R139] *LC50 Pimephales promelas (fathead minnow) 34.27 mg/l 96 hr (95% Confidence Limits= 22.83-45.86 mg/l) /Conditions of bioassay not specified/; [R140] *LC50 Carassius auratus (goldfish) 57.68 mg/l 96 hr (95% Confidence Limits= 48.87-68.75 mg/l) /Conditions of bioassay not specified/; [R140] *LC50 Lebistes reticulatus (guppy) 59.30 mg/l 96 hr (95% Confidence Limits= 50.87-70.34 mg/l) /Conditions of bioassay not specified/; [R140] *LC50 Daphnia magna, (water flea) 313 mg/l 48 hr /Conditions of bioassay not specified/; [R141] *LC50 Nitocra spinipes (copepod) 24.2-74.2 mg/l 24 hr /Conditions of bioassay not specified/; [R142] *LC50 Artemia salina (brine shrimp) 33 mg/l 24 hr /Conditions of bioassay not specified/; [R143] *LC50 Morone saxatilis (striped bass) 7.3 mg/l 96 hr /Conditions of bioassay not specified/; [R144] *LC50 Cyprinodon variegatus (sheepshead minnow) 277-485 mg/l 96 hr /Conditions of bioassay not specified/; [R145] *LC50 Aedes aegypti-4th instar (mosquito larvae) 22 mg/l /Conditions of bioassay not specified/; [R146] *LC50 Calandra granaria (grain weevil) 210 mg/l /in air/; [R147] *LC50 Pimephales promelas (fathead minnows) 55-72 mg/l (embryos), 25-36 mg/l (1-day posthatch protolarvae), and 26-31 mg/l (30-day-old minnows)/ 96 hour /Conditions of bioassay not specified/; [R148] *EC50 Pimephales promelas (fathead minnow) 14.6 mg/l/96 hr (confidence limit 14.0 to 15.1 mg/l), flow-through bioassay with measured concentrations, 24.7 deg C, dissolved oxygen 6.9 mg/l, hardness 45.4 mg/l calcium carbonate, alkalinity 43.4 mg/l calcium carbonate, and pH 7.89. Effect: loss of equilibrium; [R149] *LC50 Pimephales promelas (fathead minnow) 36.2 mg/l/96 hr (confidence limit 29.4 to 44.6 mg/l), flow-through bioassay with measured concentrations, 24.7 deg C, dissolved oxygen 6.9 mg/l, hardness 45.4 mg/l calcium carbonate, alkalinity 43.4 mg/l calcium carbonate, and pH 7.89; [R149] NTP: *Long-term studies were conducted by exposing groups of 60 rats /F344/N/ of each sex to 0, 600, or 1,200 ppm toluene by inhalation, 6.5 hours per day, 5 days per week. Groups of 60 /B6C3F1/ mice of each sex were exposed at 0, 120, 600, or 1,200 ppm on the same schedule. ... Animals were exposed to toluene for 103 weeks. Nephropathy was seen in almost all rats, and the severity was somewhat increased in exposed rats. A rare renal tubular cell carcinoma in a female rat and an equally uncommon sarcoma of the kidney in another female rat were seen in the 1,200 ppm exposure group. Erosion of the olfactory epithelium and degeneration of the respiratory epithelium were increased in exposed rats. Inflammation of the nasal mucosa and metaplasia of the olfactory epithelium were increased in exposed female rats. A rare squamous cell carcinoma of the nasal mucosa was seen in one female rat at 1,200 ppm. A squamous cell papilloma of the forestomach was observed in one female rat at 1,200 ppm, and a squamous cell carcinoma was observed in a second female rat at 1,200 ppm. No chemically related neoplasms were found in male rats, and the one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with inhalation exposure to toluene. For mice, no biological important increases were observed for any nonneoplastic or neoplastic lesions. [R150] TCAT: ?Neurotoxicity was determined in groups of rats (4 male and 4 female, strain not reported) exposed by inhalation to 0,100, or 1500 ppm toluene (purity not reported) 6 hrs/day, 5 days/week for periods up to 27 weeks. Histological sections of selected areas of the brainstem were made for the upper medulla oblongata (including dorsal and ventral cochlear and vestibular nuclei), lower metencephalon (including superior olivary nuclei, trapezoid body and ventral cochlear nuclei), upper metencephalon (including the lateral lemniscus, superior olivary nuclei, cochlear and vestibular nuclei, and inferior colliculus) and the mesencephalon-diencephalon junction (including the medial geniculate). The investigators reported that the "vast majority" of sections from animals exposed to toluene were indistinguishable from controls. Shrunken and darkly stained neurons were observed in the corpus trapezoid of one animal exposed to 100 ppm and another exposed to 1500 ppm toluene; these were present in only one section and not in sufficient quantity to be considered a positive response by the investigators. Statistical analysis of the results was not reported. [R151] ?Chronic toxicity was evaluated in male and female Sprague Dawley rats (15/sex/group) exposed to toluene via inhalation at 0, 100 and 1500 ppm for 6 hrs/day, 5 days/week for 26 weeks. There were significant increases in the hematocrit and hemoglobin levels in females at 1500 ppm in the 13th week. There were significant differences in females at week 26 in the following: decreased mean blood clotting time and increased mean serum glutamic pyruvic transaminase at 100 ppm level, and decreases in glucose levels at 1500 ppm. There were no significant differences between treated and control animals in urinalysis. [R152] ?Teratogenicity was evaluated in mated female CRL:COBS CD (SD) BR rats (27/group) exposed to toluene by inhalation at nominal concentrations of 0, 100 or 400 ppm on gestation days (GD) 6-15 for 6 hrs/day. The adult female rats were sacrificed on GD 20 and examined. There were no significant differences observed between treated and control animals in the following: maternal mortality, body weights, food consumption, examination of tissues and organs at necropsy (except an insignificant number of observations of mottled lungs in 4 high-dose group rats), pregnancy rate, live litters, implantation sites, resorptions, litters with resorptions, dead pups, litters with dead pups, live pups/implantation site, mean live litter size, average pup weights, fetal sex ratio, examination of soft tissues of the head, thoracic and visceral organs, and skeletal abnormalities. [R153] ?The ability of toluene to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenesis Assay) was evaluated in the presence and absence of mouse liver S9 metabolic activation. Based on preliminary toxicity tests, both nonactivated and S9-activated cultures were treated with 0.30, 0.20, 0.15, 0.10, or 0.050 ul/ml produced a range of 7 - 78% total growth for nonactivated cultures and from 60 - 138% total growth for S9-activated cultures. None of the nonactivated or activated cultures produced mutant frequencies significantly greater than the solvent (DMSO) controls. [R154] ?The mutagenicity of toluene was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538, and the yeast Saccharomyces cerevisiae tester strain D4, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, toluene, diluted with acetone, was tested for mutagenicity at concentrations up to 5.0 ul/plate using both the plate and suspension assay methods. Toluene did not cause a positive response in any of the bacterial or yeast tester strains, either with or without metabolic activation. [R154] ?The mutagenicity of toluene was evaluated in a dominant lethal assay using three groups of male CD-1 mice (12/group) receiving whole body exposures to nominal concentrations of test material at 0, 100 or 400 ppm for 6 hrs/day, 5 days/week for 8 weeks. Following exposure, each male was mated with two untreated females/week for two consecutive weeks. Females were sacrificed 14 days after the midweek of mating. There was no effect of treatment for all dosed male mice as indicated by mortality, body weight and in-life physical observations. There were no significant differences between treated and control females with respect to fertility indices, average number of implants/pregnant female, average number of dead implants/pregnant female, and proportions of female with one or more dead implants. [R155] ?The ability of toluene to cause chromosome aberrations in the bone marrow cells of male Charles River rats exposed by intraperitoneal injection at dose levels of 0, 0.025, 0.082 or 0.247 cc/kg (in DMSO solvent, 0.65 cc/rat/day), either once in an acute study (15 rats/group) or once each day for 5 days in a subchronic study (5 rats/group) was evaluated. Five rats/group in the acute study were sacrificed 6, 24 or 48 hrs following dosing and the rats in the subchronic study were sacrificed 6 hrs after administration of the last dose. 50 cells/animal were scored for chromosome aberrations. None of the cells from any of the treated animals exhibited a significant increase in the frequency of chromosome aberrations. [R154, ] ?The percutaneous absorption of toluene was evaluated in six human volunteers. A glass ring having an area of 13cm(2) was placed against the palm and 2ml of 14C-toluene was applied. After one minute the ring was removed and adherent liquid allowed to evaporate. All urine was collected and analyzed for radioactive content until background levels of activity were approached. Toluene absorption was very low, averaging .022ul/cm(2) for the six human subjects. [R156] POPL: *Preclude individuals from exposure to toluene who have central nervous system or liver diseases. [R17, 526] ADE: *TOLUENE VAPOR IS READILY ABSORBED BY INHALATION AND THE LIQUID BY THE GI TRACT, BUT POORLY FROM THE SKIN. [R13, 68] *IN DOGS SUBJECTED TO INHALATION ... HIGHEST CONCENTRATIONS WERE FOUND IN THE ADRENALS (20 UG/G), BRAIN (19 UG/G IN CEREBELLUM AND 18 UG/G IN CEREBRUM), AND BONE MARROW (18 UG/G). [R13, 69] *ALTHOUGH SOME ABSORBED TOLUENE MAY BE REEXHALED BY LUNG, MAJOR EXCRETORY PATHWAY IS RAPID OXIDATION OF TOLUENE TO BENZOIC ACID, WHICH IS CONJUGATED WITH GLYCINE AND EXCRETED AS HIPPURIC ACID IN URINE. ... WITHIN REASONABLE LIMITS, EXCRETION OF HIPPURIC ACID IN URINE IS PROPORTIONAL TO EXPOSURE. AN EXPOSURE OF 200 PPM OF TOLUENE RESULTED IN EXCRETION OF 3.5 G HIPPURIC ACID PER LITER OF URINE (SPECIFIC GRAVITY 1.016). [R157] *SIX SUBJECTS EXPOSED TO TOLUENE IN INSPIRED AIR (50, 100, 150 PPM) SHOWED LITTLE DIFFERENCE IN RATE OF RESP SOLVENT UPTAKE. NO SIMPLE RELATION EXISTED BETWEEN UPTAKE RATE AND PERIPHERAL VENOUS CONCN, INDICATING THAT NO CALCULATION COULD BE MADE FOR TOXIC DOSE OF INNER ORGANS. DIFFERENCES IN RESP EXCRETION WAS EXPLAINED BY RESP MINUTE VOL IN POST-EXPOSURE PERIOD, and , AFTER EXPOSURE AT REST, THE AMT OF BODY FAT. [R158] *FOLLOWING SINGLE IP ADMIN OF (14)C-LABELED TOLUENE (290 UG/KG) TO MICE, HIGHEST LEVEL OF RADIOACTIVITY WAS FOUND IN ADIPOSE TISSUE, FOLLOWED IN DESCENDING ORDER BY KIDNEY, LIVER AND LUNG. LOWEST ACTIVITY WAS IN BRAIN TISSUE AND BLOOD/BRAIN RATIO WAS ABOUT 0.4. [R159] *The blood/gas partition coefficient ranges from 12.4 to 15.6. [R160] *At equilibrium, the avg toluene concn per liter of blood is 2.4 mg for each 100 ppm toluene in the envir air. [R49] *... Whole body autoradiography has been modified and applied to distribution studies of ... toluene. ... [R161] *The urinary excretion of hippuric acid and o-cresol in humans was measured after a 7 hr exposure to toluene at a constant concn of 100 ppm but with a time-weighted avg of 100 ppm. In study A, 4 men were exposed to clean air and to constant and varying concns of toluene in combination with rest and with 100 W exercise for 140 min exercise increased the end-exposure excretion rate of hippuric acid and o-cresol by 47 and 114%, respectively. After exposure, all excess hippuric acid was excreted within 4 hr, while o-cresol was eliminated with a half-life of approx 3 hr. Alveolar air concn of toluene was 21-31 ppm during constant exposure and 13-57 ppm during varying exposure, but no difference in mean alveolar toluene concn or in metabolite excretion was seen between the exposure schedules. In study B, 32 men and 39 women aged between 31 and 50 yr were exposed once to either clean air or ... or varying concns of toluene. The background excretion rate of hippuric acid was 0.97 mg/min (1.25 g/g creatinine) and rose to 3.74 mg/min (3.90 g/g creatinine) during the last 3 hr of exposure to 100 pmm toluene. The corresponding figures for o-cresol were 0.05 ug/min (0.08 mg/g creatinine ), and 2.04 ug/min (2.05 mg/g creatinine). The individual creatinine excretion rate was considerably influenced by sex, body wt, and smoking habits, thus influencing the metabolite concn standardized in relation to creatinine. Thus, both metabolites are estimates of toluene exposure; o-cresol is more specific than hippuric acid, but the individual variation in excretion of both metabolites is large, and when implementing either of them as biological exposure indexes, the influence of sex, body size, age as well as consumption of tobacco and alcohol has to be considered. [R162] *The distribution of radioactivity in pregnant mice was registered at different time intervals (0-24 hr) after a 10 min period of inhalation of toluene. ... Autoradiographic and liq scintillation methods were used to make possible the distinction between volatile, water sol, and firmly tissue bound radioactivity. Toluene reached high concns immediately after inhalation in lipid rich tissues (brain and fat) and well perfused organs (liver and kidney) but were rapidly eliminated resulting in low concns at 1 hr in all maternal tissues, except fat. Metabolites reached peak levels around 30 min to 1 hr after inhalation, but were also relatively rapidly eliminated. ... One exception was the very strong accumulation of water sol metabolites at 4 and 24 hr in the nasal mucosa and olfactory bulb after inhalation of toluene. Volatile radioactivity was observed in the placenta and fetuses immediately and up to 1 hr after inhalation of solvent at all stages of gestation. The fetal levels were, however, much lower than in maternal tissues. In early gestation, an even distribution pattern was observed, while the fetal liver reached a higher concn than other fetal tissues in late gestation. In similarity with maternal tissues, fetal tissues reached the highest levels of metabolites 30 min to 1 hr after inhalation. A retention in uterine fluid was seen at 4 hr. Otherwise no retention of metabolites was observed in the fetoplacental unit. No firmly tissue bound metabolites of the studied solvents were observed in the fetal tissues in late gestation, indicating no fetal capacity for formation of reactive metabolites. [R163] *A study was instituted to determine whether gavage dosing and inhalation exposure resulted in similar blood levels of toluene. Groups of male Sprague-Dawley rats were dosed with toluene either by gavage with 0.10, 0.25, 0.50, or 1.0 mg/kg/body weight or through exposure to atmospheres containing 200 to 1000 ppm toluene. Blood samples were taken at 0.5, 1.0, 2.0, 4.0, 6.0, and 24.0 hours following dosing. Steady state blood concentrations were reached for both inhaled doses within 30 minutes of the exposure. After 6 hours the steady state toluene blood concentrations for the 200 and 1000 ppm dose levels were 2.89 and 37.23 ppm, respectively. For the oral doses, the peak blood toluene concentration increased with increasing dosage. Blood profiles from higher oral doses more closely approximated the steady state inhalation blood profiles. At 24 hours following dosing, blood toluene levels from all doses by either route were below detectable levels, suggesting minimal carry over of toluene concentrations from one day to the next. An equation was derived which will allow the gavage dose of toluene to be made equivalent to an inhalation dose. Based on results of other studies, it was suggested that blood toluene levels following sc injection more closely resemble those obtained following inhalation than do blood levels after gavage. However, it is possible to obtain blood concentrations of toluene similar to those generated by a 6 hour inhalation exposure to 1000 ppm through gavage dosing. [R164] *An investigation was carried out to quantitate the effect of pulmonary ventilation on uptake and biological concentrations of six organic solvents. Tested solvents were acetone, styrene, toluene, xylenes, methylchloroform, and tetrachloroethylene. Lung uptake and urinary concentration (Cu) were measured in 15 volunteers, 24 to 52 years old, exposed in a chamber for 2 or 4 hours at rest, 2 hours with three alternations of light exercise, 1 hour of light exercise, or 30 minutes or more strenuous exercise. Environmental levels and urinary concentration were measured in 528 occupationally exposed workers before and after 4 hours of work at a light task (pulmonary ventilation 12 to 18 liters per minute). For volunteers, uptake and urinary concentration values were significantly correlated. Environmental levels and urinary concentration showed a close relationship for occupational exposure. Biological equivalent exposure limits corresponding to threshold limit value (TLV) time weighted averages were derived from urinary concentration values. For acetone, styrene, and xylenes, uptake for a given time and exposure level was dependent only on ventilation. The toluene retention index was slightly lower for exercise than for rest, and uptake was ventilation dependent during rest and ventilation and retention index dependent during exercise. Retention indices decreased with increasing ventilation at rest and during exercise for tetrachloroethylene and methylchloroform. Their urinary concentration values were ventilation and retention index dependent. Methylchloroform uptake was higher during light versus heavy exercise. It was concluded that work load profoundly affects the absorbed amount of chemical and should be a factor in implementation of biological exposure indices and TLVs. [R165] *Animal studies indicate that toluene readily crosses the placenta. [R94, 166] *When dogs were exposed to 0.4-0.6 ug/ml toluene vapor, 91-94% was taken up in the lungs. Absorption was complete when toluene was given orally to dogs; the blood level in rats increased more slowly after oral administration than after inhalation. Absorption through the skin of mice in vivo was 4.50 ug/sq cm per hour. Toluene penetrated rat skin excised three days after clipping and depilation with cream at a rate one-tenth that of benzene and ten times that of ortho-xylene. [R166] *Toluene levels in brain and blood were linearly related to toluene levels in inhaled air after rats were exposed to 50, 100, 500, or 1000 ppm (189, 377, 1885, or 3770 mg/cu m) toluene for 3 hr. [R166] *When rabbits were given a single oral dose of 350 mg/kg bw toluene, 19% was exhaled unchanged within 12 hr. [R167, 91989)] *Pregnant C57B1 mice were exposed by inhalation to 14C-toluene (theoretical concentration, 2000 ppm (7540 mg/cu m)) for 10 min on days 11, 14 or 17 of gestation, and distribution of the label was determined 0, 0.5, 1, 4 and 24 hr after exposure. The label quickly entered the embryo, but uptake was low relative to that in maternal tissues. All fetal activity was extractable, indicating that no firmly bound metabolite was present. [R167, (1989)] *In humans, up to 75% of inhaled toluene is metabolized to hippuric acid and excreted in the urine within 12 hr of exposure. The remainder of the toluene is mainly excreted unchanged with a small percent being excreted as a sulfate or glucuronide of cresol. [R96, 1091] *The uptake of toluene in the blood is doubled during physical activity compared to the uptake at rest. [R97, 723] *In nude mice exposure to 300, 1000, or 3000 ppm toluene under conditions where there was no respiratory intake of toluene, led to a dose-related and duration-related increase in whole body toluene levels. The calculated skin absorption coefficient was 1.24 cm/hr. The skin absorption rate for the 300 ppm concentration was 0.0009 mg/sq cm/hr; for the 1000 ppm concentration , it was 0.0046 mg/sq cm/hr; and for the 3000 ppm concentration, it was 0.0144 mg/sq cm/hr. [R168] *In humans, the toluene is distributed between the plasma and red blood cells at approximately a 1:1 ratio according to in vitro data; in rats, the ratio is 1:2 based on in vivo data. [R169] *In one human who died 30 min after ingestion of 625 mg/kg toluene, the liver was found to have the highest concentration of toluene (133.5 ug/g) followed by the pancreas (88.2 ug/g), brain (85.3 ug/g), heart (62.6 ug/g), blood (12.2 ug/g), body fat (12.2 ug/g), and cerebrospinal fluid (11.1 ug/g). [R170] METB: *Toluene is extensively metabolized via oxidation to benzyl alcohol then to benzaldehyde by alcohol dehydrogenase. Further oxidation then forms benzoic acid. Conjugation with glycine produces the major metabolite, hippuric acid, which is excreted in the urine. Benzyl glucuronide is formed in smaller amounts by conjugation with glucuronic acid. [R171] *IN PRINTERS EXPOSED TO AIR CONTAINING TOLUENE (AVG CONCN 23 PPM), URINARY EXCRETION OF O-CRESOL, WHICH IS NOT A NORMAL CONSTITUENT OF URINE, WAS OBSERVED. APPARENTLY, TOLUENE WAS OXIDIZED AT AROMATIC NUCLEUS FORMING CRESOLS, BESIDES HIPPURIC ACID. [R172] *In rats, approx 0.5%-1.1% of the dose is converted to o-cresol and p-cresol and is excreted as glucuronide and sulfate conjugates. [R173] *In mammalian species, acidic metabolites are conjugated with glycine to form hippuric acid and phenylacetic acid. In humans, the phenylacetic acid metabolite is also conjugated with glutamine to form phenacetylglutamine. [R174] *The association between occupational toluene exposure and blood and adipose tissue toluene concentrations was examined. Breathing zone samples were monitored for toluene in two Swedish rotogravure printing facilities. Sc adipose tissues were taken from 37 workers after work on Thursday or Friday and analyzed for toluene. Venous blood samples were taken from 11 workers after work on Friday and at various times over the following weekend and assayed for toluene. Blood and adipose tissue samples were obtained from 11 other workers immediately after work and after 63 and 135 hours nonexposure and analyzed for toluene. Blood samples were also taken from 21 unexposed workers and analyzed for toluene. Attempts were made to fit the blood toluene data to various pharmacokinetics models. Airborne toluene concentrations in the printing factories ranged from 8 to 416 mg/cu m, median 75 mg/cu m. Blood toluene concentrations in the unexposed workers were below the detection limit, 0.01 umole/l. Blood samples obtained immediately after work contained 0.22 to 21.4 umole/l toluene. Elimination of toluene from the blood could be described by a three compartment model having median halftimes of 9 minutes, 2 hours, and 79 hours. Toluene was eliminated from adipose tissue with a median halftime of 79 hours. Adipose tissue concentrations were significantly associated with the workers' exposure to airborne toluene during the previous week. Adipose tissue toluene concentrations were significantly correlated with blood toluene concentrations after 70 hours exposure. It was concluded that the prolonged presence of toluene in the blood means that there is an endogenous exposure from adipose tissue depots that continues long after occupational exposure has ended. [R175] *Evidence has suggested that there is an ethnic related difference in organic solvent metabolism in humans; analyses were thus made to obtain evidence of strain differences in animals to assist in consolidating the observation in workers. Female Donryu, Fischer, Sprague-Dawley, and Wistar rats were exposed to toluene at dose levels of 5, 45, 500, 2500, and 3500 ppm for 8 hours in a dynamic flow type exposure system. Urine samples were collected for 24 hours from the start of exposure. While the variation in free p-cresol excretion was wide among the rats of the same strain exposed to toluene at the same concentration, it was also noted that the four strains tested could be classified into two groups depending on the free p-cresol levels at toluene concentrations up to 500 ppm. No significant differences were noted between Sprague-Dawley and Wistar strains nor between Donryu and Fischer strains at the 45 and 500 ppm levels. However, there were significant differences between these two groups. At higher concentrations of 2500 and 3500 ppm, the increase in the free p-cresol levels was remarkable only in Donryu rats, reaching the levels of Sprague-Dawley and Wistar rats, while the level in Fischer rats remained unchanged. [R176] *The mutual metabolic suppression between benzene and toluene was studied. The subjects, 190 male Chinese workers employed in shoe manufacturing, printing, audio equipment manufacture, and automobile industries, were divided into four groups based on occupational exposure: 65 were exposed to benzene, 35 to toluene, 55 to both compounds, and 35 served as comparisons. The arithmetic mean exposure level of benzene was 31.9 and of toluene 44.7 ppm. The mixture contained benzene at 17.9 +/29.3 and toluene at 20.5 +/25.8 ppm. The exposure levels were measured using individuals diffusive samplers. The geometric mean levels of the metabolites, phenol, catechol, hydroquinone, hippuric acid, and o-cresol, in unexposed workers were 6.9, 9.4, 4.8, 72.5, and 0.066 mg per liter, respectively. Values corrected for creatinine and specific gravity were different from the values cited above. Multiple correlation coefficients for benzene exposure versus its three metabolites were for phenol, 0.740; for catechol, 0.629; and for hydroquinone, 0.726. Multiple correlation coefficients for toluene and its two metabolites were 0.649 for hippuric acid and 0.583 for o-cresol. The slopes of regression lines for the exposure to benzene in the presence of toluene were less than half of those obtained when the workers were exposed to benzene alone; however, the regression lines for benzene in mixture versus catechol were about 80% or higher than the lines observed with benzene as the sole pollutant. The regression lines for toluene in the mixture and excretion level of hippuric acid and o-cresol showed reduced metabolic conversion compared to when exposure was limited to toluene alone. It was concluded that simultaneous exposure to benzene and toluene results in mutual suppression of metabolism yielding the urinary metabolites phenol, hydroquinone, hippuric acid, and o-cresol. [R177] BHL: *0.083 days (Inhaled as environmental air) [R49] ACTN: *... Toluene at low concn /less than 100 ppm/ may produce disturbances in dopaminergic mechanisms of the basal ganglia probably leading to functional changes in sensory-motor integration. ... [R178] *Exposure to toluene causes both reversible and irreversible changes in the central nervous system. The effects of toluene inhalation on some specific enzymes and glutamate and GABA receptor binding in defined parts of the rat brain were studied following several exposure schemes. The activities of the transmitter synthesizing enzymes glutamic acid decarboxylase (GAD), choline acetyltransferase (ChAT) and aromatic amino-acid decarboxylase (AAD) were used as markers for permanent loss of neuronal activity. Catecholaminergic neurons showed a 50% reduction in the brain stem after 4 weeks exposure to 250 and 1000 ppm toluene. Following 500 ppm of toluene, 16 hr/day for 3 months, a general increase in the activities was seen. This is most probably due to a reduction in total protein content, to which the activities were related. The neurotransmitters glutamate and GABA had their specific receptor binding increased in most of the brain areas studied, but decreased in some areas. The glial enzyme, glutamine synthetase, has its activity increased in the cerebellar hemisphere following 4 weeks exposure to 1000 ppm. This suggests that glial cells in the area may have proliferated, a frequent phenomenon following CNS damage. [R179] *The effect of styrene, toluene, ethylbenzene, alpha-methylstyrene, and butylbenzene on oxidative phosphorylation was studied using rat liver mitochondrial preparations. Rat liver mitochondria were prepared from male white Wistar rats and assessed for respiration rate, oxygen uptake, glutamate oxidation, succinate oxidation, ATPase activity, and proton permeability in the presence and absence of the alkyl benzene derivatives. Inclusion of the alkyl benzene derivatives in the incubation medium produced an initial acceleration of oxygen consumption followed by an inhibition of glutamate oxidation, and the stimulatory effect paralleled the aliphatic chain length. Glutamate oxidation was also inhibited by styrene, ethylbenzene, and alpha-methylstyrene but not by butylbenzene or toluene in 2,4-dinitrophenol uncoupled mitochondria. Styrene and the aliphatic benzene derivative stimulated succinate oxidation in rat liver mitochondria without effect on 2,4-dinitrophenol stimulated succinate oxidation. Similar stimulatory effects on ATPase activity were observed with maximal stimulation occurring at the same relative concentrations producing maximal succinate oxidation. ATPase stimulation required magnesium, was oligomycin sensitive, and showed an inverse relation to the hydrophobicity of the compounds tested. The inclusion of styrene in the incubation medium markedly increased the rate of passive entry of protons into rat liver mitochondria in a manner comparable to 2,4-dinitrophenol. It was concluded that styrene and other monosubstituted benzene derivatives act as mitochondrial uncoupling agents. [R180] INTC: *IP LD50 OF TOLUENE FOR MALE MICE WAS 1.15 G/KG. PRETREATMENT WITH PHENOBARBITAL, PRODUCED MARKED DECR IN SLEEP INDUCED BY TEST DOSE (0.96 G/KG IP) OF TOLUENE. PRETREATMENT WITH HEPATIC ENZYME INHIBITORS SUCH AS CARBON TETRACHLORIDE, 2-DIETHYLAMINOETHYL-2,2-DIPHENYLATE HYDROCHLORIDE, PYRAZOLE AND CYANAMIDE PRODUCED INCR IN SLEEP AND DEATH ASSOC WITH PROLONGATION OF SLEEPING TIME. [R137] *TOLUENE WITH ASPHALT FUMES OR CHLORINATED HYDROCARBONS, SUCH AS TRICHLOROETHYLENE AND TETRACHLOROETHENE, CAUSES DEPRESSION OF HYDROXYLATION AND URINARY CONJUGATE EXCRETIONS. ... COMBINED EXPOSURE TO TOLUENE, XYLENE, FORMALDEHYDE, AND ANILINE DYES DECR GRANULOCYTIC PHOSPHATASE ACTIVITY. CONVERSELY, HYDROGEN PEROXIDE ADMIN TO RATS INCR THE BLOOD PEROXIDE ACTIVITY AND INCR THE TOLERANCE TO TOLUENE, AS DID PHENOBARBITAL IN SPECIFIC QUANTITIES. [R181] *SPRAGUE-DAWLEY RATS WERE EXPOSED BY INHALATION TO TOLUENE (500, 1500, and 3000 PPM) FOR 3 DAYS. TOLUENE INCR CONCN OF LIVER MICROSOMAL CYTOCHROME P-450. A DOSE-DEPENDENT INCR IN THE IN VITRO LIVER MICROSOMAL FORMATION OF SEVERAL METABOLITES OF BIPHENYL AND BENZO(A)PYRENE WAS OBSERVED FOR TOLUENE. TOLUENE MODIFIED THE METABOLISM AND TOXICITY OF OTHER ENVIRONMENTAL CONTAMINANTS. [R182] *Perchloroethylene enhances toxicity of toluene admin orally in rats. [R183] *Toluene and trichloroethylene seem to exhibit competitive inhibition. [R184] *CFY rats ... on day 12 of pregnancy ... dams were given: 0, 125, 250, 500 and 3,600 mg/cu m ... and 250 mg/kg acetylsalicylic acid by gavage; two subgroups ... treated with 250 mg/kg acetylsalicylic acid in combination with 3,600 mg/cu m toluene inhalation were given 0, 2.5, or 5 gm/kg glycine 2 hours before the acetylsalicylic acid dose. ... Toluene was found to potentiate the toxic effect of acetylsalicylic acid and to increase both maternal and embryonic toxicity ... increasing acetylsalicylic acid embryotoxicity caused by toluene can be warded off by glycine administration. [R185] *The metabolic interaction of toluene and ethanol was studied in male rabbits having received ethanol (26.0 mmol/kg po), toluene (5.4 mmol/kg po) or both. Compared with ethanol alone, toluene given 2 hr after ethanol caused a significantly higher and more prolonged concentration of blood alcohol. A similar trend of blood alcohol was observed at the later stage with toluene given prior to ethanol. On the other hand, with simultaneous doses of the two substances, the blood toluene concentration was higher for the first 15-30 min than the ethanol control and the urinary excretion of hippuric acid, a main metabolite of toluene, was markedly decreased for the first 2 hr. The blood ethanol in this group, on the contrary, was reduced until 1 hr after administration. These results indicate that toluene and ethanol act reciprocally as competitive inhibitors in their metabolism after single administrations. [R186] *In an experimental human study, the effect of toluene and ethanol (alone or in combination) on psychophysiologic functions was studied in 12 men (22-44 yr of age). Each subject served as his own control. Subjects were exposed to toluene by inhalation at a concentration of 300 mg toluene/cu m air for 4.5 hr. Ethanol was ingested at a dose equivalent to 15 mmol ethanol/kg body weight. Toluene had no significant effect on the 4 performance tests. A significant but weak depression of heart rate was observed during sleep latency tests (1-2.5 beats/min, 0.001 < p < 0.01). There was a significant increase in reporting of headache (p < 0.05) and in reporting for all symptoms (nausea, headache, irritation) combined (p < 0.05). No interaction between ethanol and toluene was observed. [R187] *Male Sprague-Dawley rats were used to study the renal toxicity potential of subchronic exposure to non-toxic doses of a combination of styrene and toluene. Four groups (n= 6) of rats were injected ip with: (1) 4 mmol styrene 2 times/day at 4 hr intervals; (2) 10 mmol toluene/kg once a day; (3) 4 mmol styrene/kg 2 times/day plus 10 mmol toluene/kg once/day; (4) All treatments were given 5 days/wk for 4 consecutive wk. By the fourth wk, there was a significant increase (p < 0.05) in urinary excretion of gamma-glutamyl transpeptidase, protein, and glucose by the group receiving combined treatment versus those receiving treatment with either chemical alone. There was an increase in excretion of hippuric acid in the mixture treatment group, but no increase in mandelic and phenylglyoxylic acids or thioethers. Blood urinary nitrogen was not modified by the individual chemicals or the mixture. Electron microscopic examination of the kidney showed an increase of single membrane vacuoles in the proximal convoluted tubules of rats treated with a mixture of chemicals, but not with toluene or styrene alone. [R188] *... Toluene has been shown to be a competitive inhibitor of the metabolism of benzene. This competitive interaction alleviates the metabolite-mediated toxicity of benzene ... [R93, 741] *Xenobiotic competitors for the same metabolic route, such as benzene and xylene, would ... have an impact on toluene metabolism. [R189] *... A single alcoholic drink has a very strong, acute inhibitory effect on the hepatic elimination of toluene. [R190] *The aim of this study was to examine if the drug chlorzoxazone has any influence on the toxicokinetics of acetone and toluene. Chlorzoxazone is mainly metabolized by the same enzyme (Cytochrome P450 2E1) as ethanol and many other organic solvents. Ten male volunteers were exposed to solvent vapor (2 hr, 50 watt) in an exposure chamber. Each subject was exposed to acetone only (250 ppm), acetone + chlorzoxazone, toluene (50 ppm) only, toluene + chlorzoxazone, and chlorzoxazone only. Chlorzoxazone (500 mg) was taken as two tablets 1 h prior to solvent exposure. Samples of blood, urine and exhaled air were collected before, during and until 20 h post exposure. The time-concentration curves of acetone and toluene in blood were fitted to one- and four-compartment toxicokinetic models, respectively. Except for a delayed excretion of hippuric acid in urine, no effects on the toluene toxicokinetics were seen after chlorzoxazone treatment. Small increases in chlorzoxazone plasma levels were seen after exposure compared to chlorzoxazone alone. These interactions, although statistically significant, seem to be small compared to the interindividual variability on metabolism and toxicokinetics. [R191] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *Ingestion of approximately 60 ml (625 mg/kg) of toluene proved fatal for a while male mental patient. [R192] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Toluene is released into the atmosphere principally from the volatilization of petroleum fuels and toluene-based solvents and thinners and from motor vehicle exhaust. Toluene's production and use as an intermediate in the production of benzoic acid, benzaldehyde, benzene, explosives, dyes and many other organic compounds may also result in its release to the environment through various waste streams. Toluene has been detected in emissions from volcanos, forest fires and crude oil. If released to air, a vapor pressure of 28.4 mm Hg at 25 deg C indicates toluene will exist solely as a vapor in the ambient atmosphere. Vapor-phase toluene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3 days. Toluene may also be degraded in the atmosphere by reaction with nitrate radicals and ozone molecules, but these reactions are too slow to be environmentally important. If released to soil, toluene is expected to have high to moderate mobility based upon Koc values in the range of 37-178. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 6.64X10-3 atm-cu m/mole. Toluene may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation is expected to occur rapidly in soil surfaces, with half-lives in the range of several hours to 71 days. If released into water, toluene is not expected to adsorb to suspended solids and sediment based upon a Koc of 166 measured in lake sediment. Biodegradation is expected to occur rapidly in water, with reported half-lives of 4 and 56 days in aerobic and anaerobic water, respectively. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hour and 4 days, respectively. Measured BCF values of 13 and 90 in fish suggest bioconcentration in aquatic organisms is low to moderate. Hydrolysis is not expected to be an important environmental fate process for toluene due to lack of hydrolyzable functional groups. Exposure to toluene may occur occupationally during its production or subsequent use, particularly as a solvent or in gasoline, via dermal and respiratory routes. The main route of exposure for the general population will be through inhalation from contaminated air and handling of gasoline as well as ingestion of contaminated drinking water and food, and exposure to some consumer products. (SRC) NATS: *Toluene occurs in nature in ... natural gas deposits ... [R19] *Toluene has been detected in emissions from volcanos, forest fires and crude oil(1). [R193] ARTS: *Toluene is a major constituent (20-60 ug/cigarette) of the gas phase of the mainstream smoke of unfiltered cigarettes. /From table/ [R98, 1212] *Toluene is released into the atmosphere principally from the volatilization of petroleum fuels and toluene-based solvents and thinners and from motor vehicle exhaust(1,2). Toluene's production and use as an intermediate in the production of benzoic acid, benzaldehyde, explosives, dyes and many other organic compounds(3) may also result in its release to the environment through various waste streams(SRC). [R194] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 37-178 measured in soil(2,3), indicates that toluene is expected to have high to moderate mobility in soil(SRC). Volatilization of toluene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 6.64X10-3 atm-cu m/mole(4). Toluene may volatilize from dry soil surfaces based on a vapor pressure of 28.4 mm Hg at 25 deg C(5). Complete biodegradation of toluene was observed in lab microcosm tests during a 40 hour incubation period using soils previously exposed to toluene(6). The biodegradation half-life in various soils was reported as several hours to 71 days(7). [R195] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 166 measured in lake sediment(2) indicates that toluene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 6.64X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1 hour and 4 days, respectively(SRC). According to a classification scheme(5), BCF values of 13(6) and 90(7) measured in fish, suggest bioconcentration in aquatic organisms is low to moderate. The half-life of toluene in aerobic and anaerobic water was reported as 4 and 56 days, respectively(8). [R196] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), toluene, which has a vapor pressure of 28.4 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase toluene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, nitrate radicals and ozone molecules(SRC). The half-life for the reaction with hydroxyl radicals is estimated to be 3 days(SRC), calculated from its rate constant of 5.96X10-12 cu cm/molecule-sec at 25 deg C(3). The half-life for the nighttime reaction with nitrate radicals is estimated as 491 days(SRC) calculated from its rate constant of 6.8X10-17 cu cm/molecule-sec at 25 deg C(3). The half-life for the reaction with ozone is estimated as 27,950 days(SRC) calculated from its rate constant of 4.1X10-22 cu cm/molecule-sec at 25 deg C(3). [R197] BIOD: *Toluene is readily degradable in a variety of standard biodegradability tests using sewage seed or sludge inoculums(1-7). Degradation has been observed in several die-away tests using seawater or estuarine water(9-12). The degradation rate is much faster in systems which have been contaminated by oil(9,10). Complete degradation has been observed in 4 days and 22 days in a marine mesocosm with summer and spring conditions, respectively(12), and 10 days in a 1% gas oil mixture in a North Sea coast water inoculum(8). A 90 day half-life in uncontaminated estuarine water was reduced to 30 days in oil-polluted water(10). The half-life in water collected near Port Valdez, Alaska was 12 days(9). 1.5 mM and 3 mM Ring-labeled toluene added to a methanogenic inoculum originally enriched from sewage sludge and incubated at 35 deg C for 60 days resulted in 3.6 and 4.5% 14-C final activity respectively(13). [R198] *Toluene completely degraded in groundwater in 8 days including a lag of 3-4 days while microbial populations became acclimated(1). Other investigators found that only 1-2% of toluene degraded in the subsurface environment(2) and > 90% degraded in 4 weeks in soil cores at various depths both above and below the water table(3,5). Microbial attack proceeds via immediate hydroxylation of the benzene ring followed by ring-cleavage or oxidation of the side chain followed by hydroxylation and ring-cleavage(4). [R199] *Complete biodegradation of toluene was observed in lab microcosm tests during a 40 hour incubation period using soils previously exposed to toluene(1). Toluene was rapidly degraded in soil column experiments using acclimated soil at a rate of 8-35 mg/kg-day, and the rate followed zero-order kinetics(2). First-order degradation rate constants of 0.0005 to 0.0063 day-1 were measured for toluene in a gasoline-contaminated aquifer zone(3). These rate constants correspond to half-lives of 100-1,386 days(3). A first-order biodegradation rate constant of 0.045 day-1 was reported for toluene in an anaerobic petroleum contaminated aquifer, corresponding to a biodegradation half-life of 15 days(4). Toluene was rapidly biodegraded by indigenous mixed cultures in sandy aquifer material and pure cultures isolated from the aquifer(5). The zero-order rate constant for the aquifer material was 23 mg/l-day and had a lag period of 2 days(5). The half-life of toluene in aerobic and anaerobic water was reported as 4 and 56 days, respectively(6). The biodegradation half-life in various soils was reported as several hours to 71 days(7). [R200] ABIO: *The rate constant for the vapor-phase reaction of toluene with photochemically-produced hydroxyl radicals has been measured as 5.96X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 3 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of toluene with nitrate radicals has been measured as 6.8X10-17 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 491 days at an atmospheric concentration of 2.4X10+8 nitrate radicals per cu cm(2). The rate constant for the vapor-phase reaction of toluene with ozone has been measured as 4.1X10-22 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 27,950 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). Toluene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(4) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum. [R201] BIOC: *The BCF of toluene in eels was reported as 13(1) and the BCF in golden ide was reported as 90(2). According to a classification scheme(3), this BCF data suggests bioconcentration in aquatic organisms is low to moderate. [R202] KOC: *In association with clay minerals, toluene's adsorption is inversely proportional to the pH of the soil. Approximately 40-70% of toluene applied to the surface of sandy soils is volatilized. [R203] *The Koc of toluene was reported as 178 in a sandy soil(1) and as 37 (Wendover silty loam), 160 (Grimsby silt loam), 160 (Vaudreil sandy loam) and 46 (sandy soil)(2). The Koc of toluene in lake sediment was measured as 166(3). According to a classification scheme(4), this Koc data suggests that toluene is expected to have high to moderate mobility in soil. [R204] VWS: *The Henry's Law constant for toluene is 6.64X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that toluene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1 hour(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). Toluene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). Toluene may volatilize from dry soil surfaces based upon a vapor pressure of 28.4 mm Hg at 25 deg C(3). [R205] WATC: *Toluene is detected in 28% of National Priority List (NPL) sites in groundwater. Average concentration: 5.18 ppm; Maximum concentration: 1100 ppm. /From table/ [R96, 304] *GROUNDWATER: Toluene was detected in groundwater near contaminated wells from gasoline storage tanks at concns of 0.55-6400 ppb(1,2) and groundwater underlying 2 rapid infiltration sites at 0.2 ppb(3). Groundwater under a gasification site 15 months after gasification contained toluene at 170-740 ppb(4). In a cluster well study under an old industrial site, mean levels of toluene in bedrock wells were 90 ppb while shallow and deep glacial wells were 10 ppb(5). Toluene was detected in 1.3% of the samples in the US Ground Water Supply Survey, 1982, at a max concn of 2.9 ppb and a median concn of 0.8 ppb(6). [R206] *DRINKING WATER: Toluene was detected in 33% of the samples from 30 Canadian treatment facilities at an avg concn of 2 ppb (14 ppb max) in summer months and in 53% of the samples at an avg concn of < 1 ppb (13 ppb max), during winter(1). Toluene was detected at concns of 0-2 ppb in drinking water of cities supplied by the Great Lakes(2). Toluene was detected in 14% of the samples of drinking water in the US at concns of less than 1 part per trillion(3). In a federal survey of finished drinking water from groundwater sources toluene was detected in less than 5% of the samples(4). Toluene was detected in 3 New Orleans area water supplies at 0-10 ppb(5). Toluene was identified, not quantified, in 60% of drinking water tested in the National Organics Reconnaissance Survey(6). The max concn of toluene in tapwater derived from bank-filtered Rhine River water was 1 ppb(7). Toluene was detected in 3 contaminated drinking water wells in New Jersey at 55, 260, 6400 ppb whereas the highest concn in drinking water from surface water sources was 6.1 ppb(8). Drinking water supplied from groundwater in England 210 m from a gasoline storage tank contained 0.15 ppb of toluene(9). In a 5-city survey in which the water supplies came from different types of sources with various sources of pollution, 2 contained toluene, one 0.1 ppb and the other 0.7 ppb(10). Toluene was detected in 20 of 182 bottled water samples at an avg concn of 6.92 ug/kg and a range of 0.5-63 ug/kg(11). [R207] *SURFACE WATER: Toluene was detected in 31 of 204 sites at concns of 1-5 ppb in 14 heavily industrialized river basins in the US(1). Toluene was identified, not quantified, in various rivers(2-5). Toluene was detected in the Gulf of Mexico at 3-376 parts per trillion(6,7) and the Vineland Sound, MA at 10-54 parts per trillion(8). Toluene was detected in the Elbe River, Germany at concns of 30-243 ng/l(9). [R208] *RAIN WATER: Toluene was detected in rain in west Los Angeles at 76 parts per trillion(1). Toluene was detected in 71.4% of the rain samples from 7 rain events in Portland, OR, Feb-Apr 1984, at concns of 40-220 parts per trillion(2). [R209] EFFL: *Industries in which the mean effluent levels exceed 1000 ppb are: auto and other laundries, iron and steel manufacturing, gum and wood chemicals, pharmaceuticals, organic chemicals/plastics manufacturing, paint and ink formulation. The highest mean value is 52 ppm for pharmaceuticals and the highest maximum values are 230 and 260 ppm for pharmaceuticals and organic chemicals/plastics manufacturing(1). Toluene was detected in a plume from General Motors Paint Plant, Janesville, WI at 156 ppb(2). Auto exhaust contained toluene at concns of 196-718 mg/cu m(3). [R210] *Toluene was detected in landfill gas emissions at concns of 20,400 ppb, 34,907 ppb and 76,700 ppb(1). Toluene was detected in the gas emissions of 7 waste disposal sites in the UK at concns of 10-287 mg/cu m(2). Toluene was identified, not quantified, in the exhaust of a moped(3) and 4-stroke lawn mower(4). Toluene was detected in car exhaust under normal operating conditions at concns of 3.31-4.52 ppm and an avg of 3.83 ppm(5). The mean emission rate of toluene is 89-453 mg/km, with the lowest emission rates occurring at higher driving speeds(5). Toluene was detected in the effluent of a hazardous waste incinerator in Germany at a concn of 34 ug/cu m(6). [R211] SEDS: *SEDIMENT: Toluene was identified, not quantified in sediment from rivers near industrial facilities in the US(1,2). USEPA STORET DATABASE: Toluene was detected in 67 of 397 sediment samples at a median concn of 5.0 ppb dry weight(3). Toluene was detected in 33% of the sediment samples from Lake Pontchartrain, LA at an avg concn of 0.7 ppb wet weight(4). Toluene was detected at concns of less than 0.1 ng/g to 1.2 ng/g in sediment from rivers near Niigata, Japan(5). Toluene was detected in sediment of the Passaic River, NJ at concns of 3-250 ug/kg(6). [R212] ATMC: *URBAN/SUBURBAN: In a survey of 3,195 samples obtained from urban areas in the US, toluene was detected at concns of 0-85 ppb (11 ppb median)(1). Average toluene concns in US cities range from 0.8-37 ppb with max values ranging from 6.5-1,110 ppb(2-9). Daily variations in concentrations and ratios of toluene to benzene indicate that auto traffic is the most common source of atmospheric toluene(10,11,12). Toluene was detected in Middelsbrough, UK and London, UK at 1.55 and 7.475 ppb, respectively(13). The avg concn of toluene inside buses and cars in Taipei, Taiwan was reported as 367 and 599 ug/cu m(14). Toluene was detected in various streets in Europe at concns of 87-127 ug/cu m(15). The concn of toluene inside automobiles in Paris, France was 178-258 ug/cu m(16). [R213] *INDOOR AIR: Toluene was detected at mean concns of 4.8 ug/cu m in telephone communications offices, 10.1 ug/cu m in data center offices and 5.7 ug/cu m in administrative offices in the US(1). Toluene was detected in the volatile emissions of newly installed carpet cushions at an emission rate of 4-79 ug/sq m-hr during the first 6 hours after installation(2). Toluene was detected in hairdresser salons in Norway at concns of 0.04-0.11 mg/cu m(3). [R214] *RURAL/REMOTE: Toluene was detected in the atmosphere of 115 remote samples taken in the US at concns of 0.057-30 ppb, (0.66 ppb median)(1). Toluene was identified, not quantified, in a forest in Germany(2). Toluene was detected in Langenbrugge, Germany and West Beckham, UK at concns of 0.441 and 0.999 ppb, respectively(3). Toluene was detected at a concn of 0.04 ppb in Izana, Canaries(3) [R215] *SOURCE DOMINATED: In a survey of 188 source dominated samples from the US, toluene was detected at concns of 0.037-5,500 ppb (4.6 ppb median)(1). Toluene was detected in the air of the Lipari and BFI landfills in NJ at 0.40 and 310 ppb(2). Toluene was detected at concns of 14-22 ppb 4 miles downwind from a General Motors paint plant(3). The avg concn of toluene around gasoline pumps during fueling was in the range of 0.14-1.2 mg/cu m and the fenceline concns at the filling stations were in the range of 0.005-0.02 ppm(4). Toluene was detected in the Fort McHenry Tunnel, MD at concns of 79-90 ppb(5). [R216] FOOD: *Toluene was identified, not quantified, in baked potatoes(1), mountain cheese(2), fried bacon(3), fried chicken(4), peanut oil(5) and raw beef(6). [R217] PFAC: PLANT CONCENTRATIONS: *Toluene was identified, not quantified, in the Korean Chamachwi plant(1). [R218] FISH/SEAFOOD CONCENTRATIONS: *Flesh of fish from petroleum contaminated harbor in Japan contained toluene at 5 ppm(1). Toluene was detected in oysters from Lake Pontchartrain, LA at an avg concn of 3.4 ppb and clams at concns of 18 and 11 ppb(2). Toluene was identified, not quantified, in boiled shrimp and crab(3). [R219] MILK: *Toluene was identified, not quantified, in 8 samples of mothers' milk from 4 urban areas(1). [R220] OEVC: *Light oil from coal 12-20% toluene; crude oil 1.2-2.4% auto fuel 8-12%(1). [R221] *Evaporation from gasoline tank: 0.3 - 0.9 vol % of total evaporated hydrocarbons; evaporation from carburetor: 0.5 - 2.4 vol % of total evaporated hydrocarbons. [R16, 1723] *In exhaust of gasoline engines: 3-8 vol% of total exhaust hydrocarbons; in exhaust of diesel engine: 3% of emitted hydrocarbons; in exhaust of rotary gasoline engine: 16% of emitted hydrocarbons; in exhaust of gasoline engine: 0.1-7.0 ppm (partly crotonaldehyde); in 4 municipal landfill gases in S. Finland (1989-1990): avg 0.23-137, max 143 mg/cu m. [R16, 1723] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,625,598 workers (288,299 of these are female) are potentially exposed to toluene in the US(1). Occupational exposure to toluene may occur through inhalation and dermal contact with this compound at workplaces where toluene is produced or used(SRC). The general population may be exposed to toluene via inhalation of ambient air, ingestion of food and drinking water, handling of gasoline, and exposure to some consumer products where toluene is used as a solvent(SRC). [R222] *Toluene was detected in hairdresser salons in Norway at concns of 0.04-0.11 mg/cu m(1). The time weighted average (TWA) of toluene in the workplace air of a municipal waste composting facility was reported as 188,000 ug/cu m(2). In a 1989 Danish survey on chemical exposures(3), the number of worker exposure events for toluene were documented: manufacturing of metals, 420; manufacturing of metal fabricated products 64,000; electrical machinery and apparatus, 1,500; manufacture of transport equipment 2,700; painters and carpenters 15,000; construction workers, 5,400; publishing and printing, 6,300; wholesale trades, 5,000; textile and leather manufacturing, 4,400; wood and furniture manufacturing, 5,900; manufacture of chemicals, 8,700; manufacture of paints and petroleum, 1,400; manufacture of non-metallic mineral products, 2,300; manufacture of optical instruments, 2,500 manufacture of plastic and boat building, 1,100; sewage and refuse disposal, 99; agriculture and forestry, 11,000; health services, 2,600. The total number of work related exposure events was 140,000(3). Toluene was detected in the workplace air of glass fiber manufacturing plants and high temperature sealing component and clutch lining plants at a mean concn of 65 ppm(4). [R223] AVDI: *AIR INTAKE (assume median concn 11 ppb(1)) 843 ug; WATER INTAKE (assume 2 ppb(2)) 4 ug; FOOD INTAKE - insufficient data. [R224] BODY: *Toluene was identified, not quantified, in 8 samples of mothers' milk from 4 urban areas(1). Toluene was detected in 250 of 250 specimens of human blood at concns of 0.2-38 ppb (1.5 ppb avg)(2). Toluene was detected in 91% of the samples of the National Human Adipose Tissue Survey at a max concn of 250 ppb(3). Toluene was identified, not quantified, in expired breath of people at service stations during fueling(4). The mean concn of toluene in the blood of non-occupationally exposed individuals in the US was 0.52 ppb(5). The avg concn of toluene in the blood and urine of workers in glass fiber and clutch lining plants were 911 ug/l and 2.9 mg/l, respectively(6). [R225] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *500 ppm [R28, 310] ATOL: *Toluene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R226] OSHA: *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 200 ppm. [R227] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 300 ppm. [R227] *Permissible Exposure Limit: Table Z-2 Acceptable maximum peak above the acceptable ceiling concentration for an 8-hour shift. Concentration: 500 ppm. Maximum Duration: 10 minutes. [R227] *Vacated 1989 OSHA PEL TWA 100 ppm (375 mg/cu m); STEL 150 ppm (560 mg/cu m) is still enforced in some states. [R28, 372] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 100 ppm (375 mg/cu m). [R28, 310] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 150 ppm (560 mg/cu m). [R28, 310] TLV: +8 Hr Time Weighted Avg (TWA) 50 ppm, skin [R69, 67] +Biological Exposure Index (BEI): Hippuric acid in urine at end of shift is 1.65 g/g creatinine. The determinant is usually present in a significant amt in biological specimens collected from subjects who have not been occupationally exposed. Such background levels are incl in the BEI value. The determinant is nonspecific, since it is observed after exposure to some other chemicals. These nonspecific tests are preferred because they are easy to use and usually offer a better correlation with exposure than specific tests. In such instances, a BEI for a specific, less quantitative biological determinant is recommended as a confirmatory test. [R69, 101] +Biological Exposure Index (BEI) adoption (1998): Toluene in venous blood prior to last shift of workweek is 0.5 mg/l. [R69, 101] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R69, 6] +Biological Exposure Index (BEI): Determinant: o-Cresol in urine; Sampling Time: end of shift; BEI:0.5 mg/L. The determinant is usually present in a significant amt in biological specimens collected from subjects who have not been occupationally exposed. Such background levels are incl in the BEI value. [R69, 101] +A4. A4= Not classifiable as a human carcinogen. [R69, 67] OOPL: *Australia: 100 ppm, STEL 150 ppm (substance under review) (1990); Federal Republic of Germany: 100 ppm, short-term level 500 ppm, 30 min, twice per shift, Pregnancy group B, a risk of damage to the developing embryo or fetus must be considered to be probable (1992); Sweden: 80 ppm, short-term value 100 ppm, 15 min, planning of new plants or alterations of old ones, 50 ppm (1990); United Kingdom: 50 ppm, 10-min STEL 150 ppm, skin (1991). [R6, 1991.1577] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 50 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 300 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 1000 ppm (not life threatening) up to 1 hr exposure. [R228] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Toluene is produced, as an intermediate or a final product, by process units covered under this subpart. [R229] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Toluene is included on this list. [R230] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 1000 ug/l [R231] FEDERAL DRINKING WATER GUIDELINES: +EPA 1000 ug/l [R231] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 150 ug/l [R231] +(WI) WISCONSIN 1000 ug/l [R231] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 2000 ug/l [R231] +(CT) CONNECTICUT 1000 ug/l [R231] +(FL) FLORIDA 40 ug/l [R231] +(ME) MAINE 1400 ug/l [R231] +(MN) MINNESOTA 1000 ug/l [R231] +(WA) WASHINGTON 800 ug/l [R231] +(WI) WISCONSIN 343 ug/l [R231] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R232] +Toluene is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R233] +For the protection of human health from the toxic properties of toluene ... the ambient water criterion is determined to be 14.3 mg/l. [R234] +The maximum contaminant level (MCL) set forth by the National Revised Primary Drinking Water Regulations for the organic contaminant toluene in community and non-transient, non-community water systems is 1 mg/l. [R235] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R236] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Toluene is included on this list. [R237] RCRA: *U220; As stipulated in 40 CFR 261.33, when toluene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R238] *F005; When toluene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F005), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R239] FIFR: *Toluene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R226] FDA: *Toluene is an indirect food additive for use only as a component of adhesives. [R240] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *... Personal dosimeter type badge monitor collects organic vapors ... /for analysis/ using gas chromatographic techniques ... sampled over the range of 0.5 ppm-1100 ppm /organic vapors/ [R241] *NIOSH Method 1500. Analyte: Toluene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.20 l/min. Sample Size: 8 liters. Shipment: No special precautions. Sample Stability: At least 2 weeks. [R242, p. 1500-1] *NIOSH Method 4000. Analyte: Toluene. Sampler: Passive (activated carbon). Shipment: Transfer sorbent to septum-capped vial; otherwise routine. Sample Stability: At least 2 weeks @ 25 deg C if stored in septum-capped vial. [R242, p. 4000-1] *NIOSH Method 8002. Analyte: Toluene. Specimen: Venous blood, after 2 or more hrs of exposure. Shipment: Air express @ 4 deg C. Sample Stability: Stable @ 4 deg C for 3 weeks. [R242, p. 8002-1] *NIOSH Method 1501. Analyte: Toluene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: Less or equal to 0.20. Sample Size: 8-liters. Shipment: No special precautions. Sample Stability: Not determined. [R242, p. 1501-1] ALAB: *Quantitative determination of 4 to 40 ppm toluene in water with precision of 10% using IR spectroscopy. [R243] *Quantitative method for detection of toluene in water by gas chromatography. Levels over 1 ppm can be detected. [R243] *TOLUENE WAS IDENTIFIED IN WASTE-CONTAMINATED SOIL AND CHEMICAL STILL BOTTOM EXTRACTS BY GC/FOURIER TRANSFORM INFRARED SPECTROMETRY. [R244] *TWENTY AQ INDUST EFFLUENTS CONTAINING POLLUTANTS WERE ANALYZED USING ISOTOPE DILN AND GC/MASS SPECTROMETRY. TOLUENE WAS ONE OF THE POLLUTANTS. [R245] *NIOSH Method 1500. Analyte: Toluene. Matrix: Air. Procedure: Gas chromatography hydrogen-air flame ionization detector. For toluene this method has an estimated detection limit of 0.001 to 0.01 mg/sample with capillary column/sample. The overall precision/RSD is 0.011. Applicability: This method is intended for determining the OSHA-regulated hydrocarbons included within the boiling point range of n-pentane through n-octane. Interferences: At high humidity, breakthrough volumes may be reduced by as much as 50%. [R242, p. 1500-1] *NIOSH Method 4000. Analyte: Toluene. Procedure: Gas chromatography, hydrogen-air flame ionization detector. For toluene this method has an estimated detection limit of 0.01 mg/sample. The overall precision/RSD is 0.022. Applicability: The working range is 13 to 660 ppm (50 to 2500 mg/cu m) for a 4 hr sample. Interferences: None identified. [R242, p. 4000-1] *NIOSH Method 1501. Analyte: Toluene. Matrix: Air. Procedure: Gas chromatography, hydrogen-air flame ionization detector. For toluene this method has an estimated detection limit of 0.001 to 0.01 mg/sample with capillary column/sample. The overall precision/RSD is 0.011. Applicability: This method is for peak, ceiling and TWA determinations of aromatic hydrocarbons. Interferences: Use of the recommended column will prevent interferences by alkanes (less or equal to C10). [R242, p. 1501-1] *EPA Method 524.1. Purge-and-Trap Gas Chromatography/Mass Spectrometry. The method is applicable for the determination of volatile organic compounds in water, finished drinking water, raw source water, or drinking water in any treatment stage. For toluene the method has a detection limit of 0.08 ug/l and a standard deviation of 4.1%. [R246] *EPA Method 524.2. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the determination of volatile aromatic compounds in water including finished drinking water, raw source water, and drinking water in any treatment stage. For toluene the method has a detection limit of 0.11 ug/l and a relative standard deviation of 8.0% with a wide bore capillary column, and a method detection limit of 0.08 ug/l and a relative standard deviation of 5.9% with a narrow bore capillary column. [R247] *EPA Method 602. Purge-and-Trap Gas Chromatography with photoionization detection for the determination of purgeable aromatics including toluene in municipal and industrial discharges. Under the prescribed conditions for toluene the detection limit is 0.2 ug/l. The method is applicable for use in the concentration range from the method detection limit to 100 times that limit. Precision and method accuracy were found to be directly related to the concentration of the analyte essentially independent of the sample matrix. [R248, 97/1/91)] *EPA Method 624. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the analysis of purgeable organics including toluene in the municipal and industrial discharges. Under the prescribed conditions, for toluene the method has a detection limit of 6.0 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R248, (7/1/91)] *EPA Method 1624. Isotope Dilution Purge-and-Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of volatile organic compounds in municipal and industrial discharges. By adding a known amount of a labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, for both the labeled, and unlabeled ethylbenzene the method has a minimum detection level 10 ug/l.The established acceptance performance criteria at 20 ug/l is 6.2 ug/l for the standard deviation of the recovery, with the average recovery of 14.5 to 28.7 ug/l and the labeled cmpd recovery ranging from 4 to 193%. [R248, (7/1/91)] *EPA Method 8020. Direct Injection or Purge-and-Trap Gas Chromatograpy with photoionization detection for the determination of aromatic volatile organics including toluene in solid waste. Under the prescribed conditions, for toluene the method has a detection limit of 0.2 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R249] *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile Organics. This method can be used to quantify most volatile organic compounds including toluene that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R249] *EPA Method 502.2: Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For toluene the method has a detection limit of 0.01 ug/l, a percent recovery of 99%, and a standard deviation of 1.9 using the photoionization detector. [R246] *EPA Method 502.1. Purge and Trap Gas Chromatography with a halogen-specific detector for the determination of halogenated volatile compounds including toluene in finished drinking water, raw source water, or drinking water in any treatment stage. Under the prescribed conditions for toluene, the method detection limit is 0.02 ug/l. [R246] *AOB Method OA-002-1. Volatile Organic Compounds by GC/MS Analysis of Tenax/CMS Cartridge and Summa Canister Samples. No detection limit. [R250] *AOB Method VA-001-1. Volatile Organic Compounds (VOCs) in Air Sampled by Sorbent Tubes and Analyzed by Purge and Trap GC. No detection limit. [R250] *AOB Method VA-003-1. Volatile Organic Compounds (VOCs) in Air by Portable GC/PID. No detection limit. [R250] *AOB Method VA-005-1. Volatile Organic Compounds (VOCs) in Ambient Air by Purge and Trap Gas Chromatography. No detection limit. [R250] *AOB Method VA-006-1. Volatile Organic Compounds (VOCs) in Ambient Air by Direct Portable GC/PID. No detection limit. [R250] *AOB Method VA-007-1. Volatile Organic Compounds (VOCs) in Ambient Air by GC/PID, GC/PID/FID, or GC/FID. No detection limit. [R250] *AOB Method VA-008-1. Volatile Organic Compounds (VOCs) in Ambient Air by Portable GC/PID with Direct Sampling via Pump and Sample Loop. No detection limit. [R250] *AOB Method VG-001-1. Volatile Organics in Soil Gas - Adsorbent Tube Method. No detection limit. [R250] *AOB Method VG-006-1. Volatile Organic Compounds (VOCs) in Ambient Air by Purge and Trap GC. No detection limit. [R250] *AOB Method VG-007-1. Halogenated and Aromatic Volatile Organic Compounds (VOCs) in Air and Soil Gas Sampled by Sorbent Tubes and Analyzed by Purge and Trap GC/ELCD/PID. No detection limit. [R250] *AOB Method VG-008-1 . Volatile Organic Compounds (VOCs) in Soil Gas sampled by Tenax Tubes and Analyzed by Thermal Desorption GC/PID/ELCD. No detection limit. [R250] *AOB Method VG-010-1. Volatile Organic Compounds (VOCs) in Soil Gas by Direct Portable GC. No detection limit. [R250] *AREAL Method IP-1A . Determination of Volatile Organic Compounds (VOCs) in Indoor Air Using Stainless Steel Canisters. No detection limit. [R250] *AREAL Method IP-1B . Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbent Tubes. No detection limit. [R250] *AREAL Method TO-1 . Determination of Volatile Organic Compounds in Ambient Air using Tenax Adsorption and Gas Chromatography/Mass Spectrometry (GC/MS). No detection limit. [R250] *AREAL Method TO-2 . Determination of Volatile Organic Compounds In Ambient Air by Carbon Molecular Sieve Adsorption and Gas Chromatography/Mass Spectrometry (GC/MS). No detection limit. [R250] *AREAL Method TO-14. Determination of Volatile Organic Compounds (VOCs) in Ambient Air using SUMMA Passivated Canister Sampling and Gas Chromatographic Analysis. No detection limit. [R250] CLAB: *NIOSH Method: 8002. Analyte: Toluene. Specimen: Venous blood, after 2 or more hours of exposure. Procedure: Gas chromatography, hydrogen-air flame ionization detector. The precision/RSD is 0.098 (1 ug/ml blood) and the recovery is 0.93 @ 2 ug/ml blood. The working range is 1 to 600 ug/ml. Applicability: Toluene is commonly found in trace amounts in humans working in the paint spray industry. Interferences: Ethanol in excess of the stated range increased blood toluene concentration. When substances other than the analytes are present in the blood, record their identities to determine possible interferences. [R242, p. 8002-1] *A procedure for the determination of toluene in blood by the purge and trap method is described ... has a linear range which extends up to at least 1500 ug/l ... detection limit ... is estimated to be less than 7.5 ug/l ... [R251] *An automated high performance liquid chromatographic method for the direct determination of urinary concentrations of p-methylhippuric acids, and metabolites of toluene is described. A mixed solution of 5 mM potassium phosphate monobasic/acetonitrile (90/10) was used as a mobile phase . The method is simple and specific. Urine can be analyzed without solvent extraction. [R252] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: REVIEW: BENIGNUS VA; NEUROTOXICOLOGY (PARK FOREST SOUTH, ILL) 2 (3): 567 (1981). REVIEW ON HEALTH EFFECTS OF TOLUENE, PARTICULARLY WITH RESPECT TO ITS NEUROTOXIC EFFECTS IN HUMANS AND LAB ANIMALS. NIOSH; Criteria Document: Toluene (1973) DHEW Pub. 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Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R243: Amer Water Works Assoc; Standard Methods for the Examination of Water and Waste Water 14th Ed (1976) R244: GURKA DF, BETOWSKI LD; ANAL CHEM 54: 1819 (1982) R245: COLBY BN ET AL; INTERNATIONAL ENVIRONMENT AND SAFETY FEB: 8 (1982) R246: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R247: USEPA; Methods for the Determinatioon of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R248: 40 CFR 136 R249: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R250: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R251: Cocheo V et al; Am Ind Hyg Assoc 43 (12): 938-41 (1982) R252: Ogata M, Taguchi T; Int Arch Occup Environ Health 59 (3): 263-72 (1987) R253: Heare SF et al; 1986 Hazard Matl Spill Conf p.12-18 (1986) RS: 191 Record 26 of 1119 in HSDB (through 2003/06) AN: 133 UD: 200303 RD: Reviewed by SRP on 1/20/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRICHLOROETHYLENE- SY: *ACETYLENE-TRICHLORIDE-; *AI3-00052-; *ALGYLEN-; *ANAMENTH-; *BENZINOL-; *Caswell-No-876-; *CECOLENE-; *CHLORILEN-; *1-CHLORO-2,2-DICHLOROETHYLENE-; *Chlorylea, Chorylen, CirCosolv, Crawhaspol, Dow-Tri, Dukeron, Per-A-Clor, Triad, Trial, TRI-Plus M, Vitran; *DENSINFLUAT-; *1,1-Dichloro-2-chloroethylene-; +Pesticide-Code:-081202-; *EPA-Pesticide-Chemical-Code-081202-; *ETHENE,-TRICHLORO-; *ETHINYL-TRICHLORIDE-; *ETHYLENE-TRICHLORIDE-; *ETHYLENE,-TRICHLORO-; *FLECK-FLIP-; *FLOCK-FLIP-; *FLUATE-; *GERMALGENE-; *LANADIN-; *LETHURIN-; *NARCOGEN-; *NARKOSOID-; *NCI-C04546-; *NIALK-; *NSC-389-; *PERM-A-CHLOR-; *PETZINOL-; *PHILEX-; *THRETHYLEN-; *THRETHYLENE-; *TRETHYLENE-; *TRI-; *TRIASOL-; *Trichloraethen- (German); *Trichloraethylen,-tri- (German); *TRICHLORAN-; *TRICHLOREN-; *Trichlorethene- (French); *TRICHLORETHYLENE-; *Trichlorethylene,-tri- (French); *TRICHLOROETHENE-; *1,1,2-TRICHLOROETHYLENE-; *TRICLENE-; *Tricloretene- (Italian); *Tricloroetilene- (Italian); *Trielin-; *Trielina- (Italian); *TRIKLONE-; *TRILENE-; *TRIMAR-; *TRI-PLUS-; *VESTROL- RN: 79-01-6 MF: *C2-H-Cl3 SHPN: UN 1710; Trichloroethylene IMO 6.1; Trichloroethylene STCC: 49 411 71; Trichloroethylene HAZN: U228; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. F002; A hazardous waste from nonspecific sources when a spent solvent. D040; A waste containing trichloroethylene may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Until 1968, about 85% of United States production capacity of trichloroethylene was based on acetylene. The acetylene-based process consists of two steps: acetylene is first chlorinated to 1,1,2,2-tetrachloroethane, with a ferric chloride, phosphorus chloride or antimony chloride catalyst, and the product is then dehydrohalogenated to trichloroethylene. The current method of manufacture is from ethylene or 1,2-dichloroethane. In a process used by one plant in the United States, trichloroethylene is produced by noncatalytic chlorination of ethylene dichloride and other C2 hydrocarbons with a mixture of oxygen and chlorine or hydrogen chloride. [R1, 79] *Ethylene dichloride + chlorine (chlorination; coproduced with perchloroethylene) [R2] *Ethylene dichloride + chlorine + oxygen (oxychlorination/dehydrochlorination; coproduced with perchloroethylene) [R2] IMP: *Acidity (as hydrochloric acid), 0.0005% max; alkalinity (as sodium hydroxide), 0.001% max; residue on evaporation, 0.005% max; antioxidants, such as amine (0.001-0.01% or more) or combinations of epoxides such as epichlorohydrin and esters (0.2-2% total) [R3] *Apart from added stabilizers, commercial grades of trichloroethylene should not contain more than the following amounts of impurities: water, 100 ppm; acidity (as HCl), 5 ppm; insoluble residue, 10 ppm. Free chlorine should not be detectable. [R1, 76] *Impurities that have been found in commercial trichloroethylene products include: carbon tetrachloride, chloroform, 1,2-dichloroethane, trans-1,2-dichloroethylene, cis-1,2-dichloroethylene, pentachloroethane, 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethylene, tetrachloroethylene, bromodichloromethane, bromodichloroethylene, and benzene. [R1, 76] FORM: *Trichloroethylene for medicinal purposes may contain thymol as a preservative. Industrial grades ... may contain stabilizers, such as triethanolamine. [R4] *Grades: USP; technical; high purity; electronic; metal degreasing; extraction. [R5] *Trichloroethylene is available in the USA in high-purity, electronic USP, technical, metal degreasing and extraction grades [R6] *Commercial grades of trichloroethylene, formulated to meet use requirements, differ in the amount and type of added inhibitor. Typical grades contain > 99% trichloroethylene; they include a neutrally inhibited vapor-degreasing grade and a technical grade for use in formulations. [R1, 76] *Stabilizers that have been used in formulations of trichloroethylene include neutral inhibitors and free-radical scavengers, amyl alcohol, n-propanol, isobutanol, 2-pentanol, diethylamine, triethylamine, dipropylamine, diisopropylamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, aniline, acetone, ethyl acetate, borate esters, ethylene oxide, propylene oxide, 1,2-epoxybutane, cyclohexene oxide, butadiene dioxide, styrene oxide, pentene oxide, 2,3-epoxy-1-propenol, 3-methoxy-1,2-epoxypropane, stearates, 2,2,4-trimethyl-1-pentene, 2-methyl-1,2-epoxypropanol, epoxycyclopentanol, epichlorohydrin, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, dioxalane, trioxane, alkoxyaldehyde hydrazones, methyl ethyl ketone, nitromethanes, nitropropanes, phenol, ortho-cresol, thymol, para-tert-butylphenol, para-tert-amylphenol, isoeugenol, pyrrole, N-methylpyrrole, N-ethylpyrrole, (2-pyrryl)trimethylsilane, glycidyl acetate, isocyanates and thiazoles. [R1, 76] MFS: *Dow Chemical USA, Hq, 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 [R7] *PPG Industries, Inc., Hq, One PPG Place, 36 East, Pittsburgh, PA 15272, (412) 434-3131; Chemicals Group; Production site: Lake Charles, LA 70602 [R7] OMIN: *Since there are now only two producers (Dow and PPG), the USITC stopped publicly reporting production and other statistics at the end of 1982 [R8] *Depending on the condition, dissociation of HCl at elevated temperatures in the presence of carbon in a chemical plasma will produce 1,1,2-trichloroethane, 1,2-dichloroethane, trichloroethylene, and perchloroethylene. [R9] *Cancelled for use in fumigant mixture or as a solvent with other ingredient on grains. [R10] USE: +For Trichloroethylene (USEPA/OPP Pesticide Code: 081202) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R11] *Therap cat: anesthetic (inhalation)/former use/; Therap cat (vet): anesthetic (inhalation) [R4] *IN GAS PURIFICATION, AS A SOLVENT OF SULFUR AND PHOSPHORUS [R12, 190] *Aerospace operations (flushing liquid oxygen) [R5] *AGENT IN REMOVAL OF BASTING THREADS IN TEXTILE PROCESSING [R13] *CHEM INT FOR 1,1,2,2-TETRACHLOROETHYL SULFENYL CHLORIDE [R13] *SOLVENT BASE FOR METAL PHOSPHATIZING SYSTEMS [R13] *SOLVENT IN CHARACTERIZATION TEST FOR ASPHALT [R13] *ENTRAINER FOR RECOVERY OF FORMIC ACID [R13] *Used as household cleaner; with trichloroethane it is used in most typewriter correction fluid. /SRP: Former use/ [R14] *Used in wool-fabric scouring [R15] *Intermediate in the production of pentachloroethane. [R16] *Carrier solvent for the active ingredients of insecticides, and fungicides. [R16] *MEDICATION *MEDICATION (VET) *Used in the preparation of insecticidal fumigants. [R17, 690] *Trichloroethylene was used earlier as an extraction solvent for natural fats and oils, such as palm, coconut and soya bean oils. It was also an extraction solvent for spices, hops and the decaffeination of coffee. The United States Food and Drug Administration banned these uses of trichloroethylene...its use in cosmetic and drug products was also discontinued...It was used as both an anesthetic and an analgesic in obstetrics. /Former uses/ [R1, 80] *Trichloroethylene has been used, in limited quantities, to control relative molecular mass in the manufacture of polyvinyl chloride. It has also been used as a solvent in the rubber industry, some adhesive formulations and in research laboratories. In the textile industry, it is used as a carrier solvent for spotting fluids and as a solvent in dyeing and finishing. It is also used as a solvent in printing inks, paint, lacquers, varnishes, adhesives and paint strippers. [R1, 80] *The major use of trichloroethylene is in metal cleaning or degreasing. Trichloroethylene is used in degreasing operations in five main industrial groups: furniture and fixtures, fabricated metal products, electric and electronic equipment, transport equipment and miscellaneous manufacturing industries. It is also used in plastics, appliances, jewellery, automobile, plumbing fixtures, textiles, paper, glass and printing industries. [R1, 80] *Used as a chemical intermediate in the synthesis of captafol; chloroacetic acid; 1-chloro-2,2,2-trifluoroethane [R2] *Stabilized grades are produced for vapor cleaning applications [R2] *Use of trichloroethylene in fluorocarbon production and as a metal cleaning and degreasing solvent are both increasing. In vapor degreasing, trichloroethylene has regained some market share as a result of the phaseout of 1,1,1-trichloroethane for emissive uses. Growth prospects for trichloroethylene as a fluorocarbon feedstock hold more potential, however, particularly its use as a precursor for the workhorse hydrofluorocarbon product, HFC-134a. [R18] CPAT: *Demand: (1982): 240 million pounds; (1983): Est 235 million pounds; 1987: Est 215 million pounds. [R19] *Vapor degreasing of fabricated metal parts, 80%; chemical intermediate, 5%; miscellaneous used, 5%; exports, 10% (1985) [R20] *Vapor degreasing of fabricated metal parts, 66%; chemical intermediates, miscellaneous domestic uses, 5%; exports, 22%. [R19] *Vapor degreasing of fabricated metal parts, 65%; chemical intermediates and miscellaneous uses, 35%. [R18] *Demand: 1996: 180 million pounds; 1997: 190 million pounds; 2001: 230 million pounds (includes exports) [R18] PRIE: U.S. PRODUCTION: *USA production: (1981): 258,182 pounds. [R21] *Production quantities (1976): 610X10+6 pounds. [R22] *(1985) 7.72X10+10 g /Estimated/ [R8] *(1991) 320 million lb [R23] U.S. IMPORTS: *(1985) 1.98X10+10 g [R24] *Imports last year totaled approximately 10 million pounds, averaging 12 million pounds during the period. [R18] U.S. EXPORTS: *(1985) 1.06X10+10 g [R25] *Exports were 65 million pounds during 1996, but averaged 83 million pounds per year in the 1992-1996 period. [R18] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CLEAR, COLORLESS, OR BLUE MOBILE LIQUID [R26, 986]; *Colorless liquid (unless dyed blue). [R27, 316] ODOR: *Ethereal odor [R28, 1784]; *Sweet smelling [R29]; *Characteristic odor resembling that of chloroform [R4] BP: *87.2 deg C [R30] MP: *-84.7 deg C [R30] MW: *131.39 [R30] CORR: *Non-corrosive [R31, 883] CTP: *Critical temperature: 300.2 deg C; Critical pressure: 4.986 MPa [R32] DEN: *1.4642 @ 20 deg C/4 deg C [R4] HTC: *-6.56 kJ/g [R32] HTV: *8,314.7 gcal/gmole [R33] OWPC: *log Kow= 2.61 [R34] SOL: *Soluble in ethanol, diethyl ether, acetone, and chloroform [R1, 75]; *Miscible in oil. [R35]; *In water, 1,280 mg/l @ 25 deg C [R36] SPEC: *SADTLER REF NUMBER: 185 (IR, PRISM); MAX ABSORPTION: LESS THAN 200 NM (VAPOR) [R37]; *Index of refraction: 1.4773 @ 20 deg C/D [R30]; *IR: 62 (Sadtler Research Laboratories IR Grating Collection) [R38]; *NMR: 9266 (Sadtler Research Laboratories Spectral Collection) [R38]; *MASS: 583 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R38]; *Intense mass spectral peaks: 60 m/z, 95 m/z, 130 m/z [R39] SURF: *29.3 dynes/cm = 0.0293 N/m at 20 deg C [R40] VAPD: *4.53 /Air=1/ [R4] VAP: *69 mm Hg @ 25 deg C [R41] VISC: *0.00550 poise at 25 deg C [R42] OCPP: *Percent in saturated air: 10.2 (25 DEG C); Equivalencies: 1 mg/l= 185.8 ppm and 1 ppm= 5.38 mg/cu m @ 25 deg C, 760 mm Hg) [R43, 4194] *Ratio of Specific Heats of Vapor (gas) : 1.116 [R40] *Olive oil/water partition coefficient 522:1 at 37 deg C. [R44] *Liquid heat capacity: 0.231 Btu/lb-F; saturated vapor pressure: 1.166 lb/sq in; saturated vapor density: 0.02695 lb/cu ft (all at 70 deg F) [R40] *Saturated liquid density: 90.770 lb/cu ft; ideal gas heat capacity: 0.146 Btu/lb-F (All at 75 deg F) [R40] *Weight per gallon @ 20 deg C: 12.20 lb. [R42] *Partition coefficients at 37 deg C for trichloroethylene into blood = 9.5; into oil = 718. [R45] *Dielectric constant: @ 16 deg C 3.42; coefficient of cubic expansion: 0.00119 (at 0-40 deg C); heat of formation: -42.3 kJ/mol (liquid), -7.78 kJ/mol (vapor); latent heat of vaporization: 238 kJ/kg (at boiling point) [R32] *Henry's Law Constant=9.85X10-3 atm-cu m/mol @ 25 deg C [R46] *Hydroxyl radical rate constant = 2.36X10-12 cu cm/molecule-sec at 25 deg C [R47] *Slowly dec (with formation of HCl) by light in the presence of moisture [R4] *Will not attack the common metals even in the presence of moisture [R5] *Photo-oxidized in air by sunlight (half-time, five days) giving phosgene and dichloroacetyl chloride [R1, 76] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *Trichloroethylene (TCE) is a hazardous substance due primarily to its toxicity. Effects result from both high-level, acute and lower-level, chronic exposures. Protection must be afforded against both dermal contact and inhalation. Dermal protection is accomplished by routinely wearing neoprene constructed gloves, worksuit, apron, and shoes. Safety goggles or a face shield is necessary to protect against splash potential. The TLV for TCE is 50 ppm with a short term exposure limit (STEL) of 200 ppm. These levels should be attained through local exhaust (pressure/vacuum) ventilation. If the STEL is exceeded, an organic vapor-acid canister respirator or air-supplied, self-contained breathing apparatus (in emergencies) is recommended. The ethereal, chloroform-like odor of TCE is detectable at 50 ppm, with levels above 200 ppm becoming disagreeable. Its clear, colorless appearance and liquid form do not serve similarly as warnings against dermal contact. The potential fire hazard from TCE alone is low. However, TCE, when exposed to flames or an electric arc in the presence of iron, copper, zinc, or aluminum, can form phosgene, a highly toxic gas. Also, TCE in the presence of heat and strong oxidizers (eg, tetraoxide) reacts violently. Even without a heat source, TCE can react with strong alkali (eg, sodium hydroxide) to form the dangerously toxic, flammable and explosive dichloroacetylene. Perchloric acid also reacts violently with TCE. Further TCE forms impact-explosive mixtures with finely divided aluminum, beryllium, lithium, magnesium or titanium. TCE should be packaged in steel drums. These drums should be stored in a cool, dry, well-ventilated area because TCE will slowly decompose to corrosive HCL when exposed to light and moisture. Should a TCE fire occur, it may be combated with water, fog, dry chemical, carbon dioxide or foam extinguisher. Spills of TCE should be isolated by flushing with water to an impoundment. Density stratification will cause the formation of a bottom TCE layer which can be pumped and containerized. DOT: +Health: Vapors may cause dizziness or suffocation. Exposure in an enclosed area may be very harmful. Contact may irritate or burn skin and eyes. Fire may produce irritating and/or toxic gases. Runoff from fire control or dilution water may cause pollution. [R48] +Fire or explosion: Some of these materials may burn, but none ignite readily. Most vapors are heavier than air. Air/vapor mixtures may explode when ignited. Container may explode in heat of fire. [R48] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. Ventilate closed spaces before entering. [R48] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R48] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R48] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R48] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Stop leak if you can do it without risk. Small liquid spills: Take up with sand, earth or other noncombustible absorbent material. Large spills: Dike far ahead of liquid spill for later disposal. Prevent entry into waterways, sewers, basements or confined areas. [R48] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R48] FPOT: *FIRE HAZARD: LOW, WHEN EXPOSED TO HEAT. HIGH CONCN OF TRICHLOROETHYLENE VAPOR IN HIGH TEMP AIR CAN BE MADE TO BURN MILDLY IF APPLIED WITH STRONG FLAME. THOUGH SUCH CONDITION IS DIFFICULT TO PRODUCE, FLAMES OR ARCS SHOULD NOT BE USED IN CLOSED EQUIPMENT WHICH CONTAINS ANY SOLVENT RESIDUE OR VAPOR. [R49] *At normal handling temperatures, trichloroethylene behaves as a non-flammable, non-burnable substance. [R50] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R51, p. 325-88] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R51, p. 325-88] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R51, p. 325-88] FLMT: *Lower flammable limit: 8% by volume at 25 deg C; Upper flammable limit: 10.5% by volume at 25 deg C [R51, p. 325-88] *Lower flammable limit: 7.8% by volume at 100 deg C; Upper flammable limit: 52% by volume at 100 deg C [R51, p. 325-88] AUTO: *420 DEG C (788 DEG F) [R51, p. 325-88] FIRP: *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray to keep fire-exposed containers cool. Use water spray, dry chemical, foam, or carbon dioxide. Extinguish fire using agent suitable for surrounding fire. [R51, p. 49-130] *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) [R52, 1073] TOXC: *Combustion may produce irritants and toxic gas including hydrogen chloride. [R51, p. 49-130] EXPL: *UPPER (77 DEG F) 10.5% VOL; LOWER (77 DEG F) 8% VOL [R27, 316] *UPPER 90% VOL; LOWER 12.5% VOL [R49] *... Under ordinary conditions of use, trichloroethylene is non-flammable and non-explosive... . [R53, p. 104.244] REAC: *Strong caustics and alkalis; chemically-active metals (such as barium, lithium, sodium, magnesium, titanium, and berylium). [R27, 316] *1-Chloro-2,3-epoxypropane, the mono- and di-2,3-epoxypropyl ethers of 1,4-butanediol, and 2,2-bis-4(2',3'-epoxypropoxy)-phenyl-propane can, in presence of catalytic quantities of halide ions, cause dehydrochlorination of trichloroethylene to dichloroacetylene, which causes minor explosions when the mixture is boiled under reflux. [R54, 223] *Granular barium in contact with trichloroethylene is susceptible to detonation. [R54, 78] *Mixtures of powdered beryllium with trichloroethylene will flash on heavy impact. [R54, 85] *Mixtures of lithium shavings and trichloroethylene are impact-sensitive and willexplode, sometimes violently. [R54, 1315] *Mixtures of powdered magnesium with trichloroethylene will flash on heavy impact. [R54, 1322] *Mixtures of powdered titanium and trichloroethylene flash or spark under heavy impact. [R54, 1464] *Trichloroethylene reacts violently with the anhydrous perchloric acid. [R54, 963] *Mixtures of dinitrogen tetraoxide with trichloroethylene react violently on heating to 150 deg C. [R54, 1352] *Mixture of liquid oxygen with dichloromethane, 1,1,1-trichloroethane, trichloroethylene, and chlorinated dye penetrants 1 and 2 exploded violently when initiated with a blasting cap. [R54, 1408] *In the presence of strong alkali (eg, sodium hydroxide), trichloroethylene can decompose into dichloroacetylene, an explosive, flammable, and highly toxic compound. [R55] *Formation of phosgene, a highly toxic gas, was observed when trichloroethylene came into contact with iron, copper, zinc, or aluminum over the temperature range 250 deg C to 600 deg C. [R56] *Mixtures of trichloroethylene and oxygen will ignite at temperatures above 25.5 deg C when the trichloroethylene concentration is between 10.3 and 64.5%. [R57] *PHOTOREACTIVE LIQUID; WILL NOT ATTACK COMMON METALS EVEN IN PRESENCE OF MOISTURE [R58] *An emulsion, formed during extraction of a strongly alkaline liquor with trichloroethylene, decomposed with the evolution of the spontaneously flammable gas, dichloroacetylene. This reaction could also occur if alkaline metal-stripping preparations were used in conjunction with trichloroethylene degreasing preparations, some of which also contain amine inhibitors which could cause the same reaction. [R54, 223] *Mixtures of dinitrogen tetraoxide with trichloroethylene are explosive when subjected to shock of 25 g TNT equivalent or less. [R54, 1352] *Aluminum powder reaction when /exposed/ to trichloroethylene. [R54, 25] *Incompatibilities: Strong caustics; when acidic reacts with aluminum; chemical active metals-barium, lithium, sodium, magnesium, titanium. [R31, 883] DCMP: *SLOWLY DECOMPOSED WITH FORMATION OF HYDROCHLORIC ACID BY LIGHT IN PRESENCE OF MOISTURE [R59] *Autoxidation products, such as phosgene and dichloroacetylene, added stabilizers, such as epichlorohydrin, and decomp products, such as chlorine and hydrochloric acid, may be responsible for some of the toxic and carcinogenic effects reported for trichloroethylene. [R60] ODRT: *10 mg/l (in water) /Purity not specified/ [R61, 1133] *5.00X10-1 mg/l (liquid) (detection in water) [R62] *2.14X10+1 ppm (recognition in air) (chemically pure) [R62] SERI: *Exposure to trichloroethylene vapor may cause irritation of the eyes, nose, and throat. [R31, 884] *Liquid: irritating to skin and eyes. [R40] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R27, 317] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R27, 317] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R27, 317] *Wear appropriate eye protection to prevent eye contact. [R27, 317] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R27, 317] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R27, 317] *ORGANIC VAPOR-ACID CANISTER; SELF-CONTAINED BREATHING APPARATUS FOR EMERGENCIES; NEOPRENE OR VINYL GLOVES; CHEMICAL SAFETY GOGGLES; FACE-SHIELD; NEOPRENE SAFETY SHOES; NEOPRENE SUIT OR APRON FOR SPLASH PROTECTION. [R40] */Wear/ positive-pressure hose masks, airline masks or an industrial canister-type gas mask fitted with an appropriate canister for absorbing trichloroethylene vapor are acceptable. [R63, 2215] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R64, 1979.8] *Cleaning of confined spaces presents serious hazards: the gas should be dispelled by mobile ventilators before workers are permitted to enter, safety belts and lifelines and respiratory protective equipment of the self-contained or supplied-air type should be avail, and another worker should be posted outside for supervision and rescue, if necessary. [R53, p. 65.13] OPRM: *Recommended ventilation design concentrations: 100 ppm; dilution rate: 30,000 cu ft air/lb solvent flow. [R61, 608] *PVC and natural rubber should not be used when cleaning up a TCE spill. Equipment should not be iron or metal, or be susceptible to hydrogen chloride. [R65] *Processes employing trichloroethylene should be designed so that the operator is not exposed to direct contact with the solvent or its vapor. Open electric heaters, high-temp processes, arc welding or open flames should not be used in environments with trichloroethylene vapor. ... Workers should be given instruction in the safe handling ... and be well acquainted with the hazards that may result from improper use. ... Adequate sanitary facilities should be provided and workers encouraged to wash before eating and at the end of the shift. [R63, 2215] *Trichloroethylene should not be stored near foodstuffs, strong acids, alkalis, or oxidizing agents. [R66] *Stop discharge if possible. Keep people away. Avoid contact with liquid and vapor. Call fire department. Isolate and remove discharged material. Notify local health and pollution control agencies. [R40] *Avoid long contact with skin. [R67] *Contact lenses should not be worn when working with this chemical. [R27, 317] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R27, 317] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R27, 317] *If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. [R52, 1074] *Personnel protection: Keep upwind. ... Avoid breathing vapors or dusts. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R52, 1074] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R64, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R64, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R64, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R64, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R64, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R64, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R64, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R64, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R64, 1979.11] SSL: *RELATIVELY STABLE IN AIR [R12, 189] *UNSTABLE IN LIGHT AND MOISTURE [R26, 985] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R64, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R64, 1979.13] *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R68] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R69] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R70] STRG: *STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM ACTIVE METALS. ISOLATE FROM OPEN FLAMES AND COMBUSTIBLES. [R51, p. 49-130] *Store trichloroethylene in cans or in dark glass bottles to minimize decomposition. [R71] *All containers for trichloroethylene should bear a label giving the following or similar information: TRICHLOROETHYLENE-WARNING Vapor harmful. Use only with adequate ventilation. /safe handling and storage of chemicals/ [R53, p. 61.10] *... May be stored satisfactorily in galvanized iron, black iron, or steel containers. [R63, 2155] *Preserve trichloroethylene in sealed, light-resistant ampules or in frangible, light-resistant glass tubes. [R59] *Storage temp: ambient [R40] *Storage areas should be cool, well-ventilated, flame-proof, and shielded from direct sunlight, high-temperature surfaces, or sparks. [R66] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R64, 1979.13] CLUP: *Contain and isolate spill by using clay/bentonite dams, interceptor trenches, or impoundments. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Construct swale to divert uncontaminated portion of watershed around contaminated portion. ... Density stratification and impoundment -- remove product from bottom layer by pumping through manifold or polyethylene rope mop collection or remove clarified upper portion by skimmers or siphon. Treatment is required for both clarified and concentrated fractions. Treatment alternatives include powdered activated carbon, granular activated carbon, and biodegradation. /Other/ treatment alternatives for contaminated soils include well point collection and treatment of leachates as for contaminated waters, bentonite/cement injection to immobilize spill. [R65, p. 8-1] *Waste water treatment: evaporation from water at 25 deg C of 1 ppm solution: 50% after 19-24 min, 90% after 63-80 min [R61, 1134] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash or cement powder. [R52, 1074] *Environmental consideration: Water spill: If dissolved, in region of 10 ppm or greater concentations, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R52, 1074] *Environmental considerations: Air spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. [R52, 1074] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R64, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers U228, D040, and F002 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R72] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. An alternative to disposal for trichloroethylene is recovery and recycling. [R31, 885] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R73] *This compound should be susceptible to removal from wastewater by air stripping. [R74] *Chemical Treatability of Trichloroethylene; Concentration Process: Activated Carbon; Chemical Classification: Halogens; Scale of Study: Pilot Scale/Continuous Flow; Type of Wastewater Used: Hazardous Material Spill; Influent Concentration: 21 ppb; Results of Study: 98.6% removal with 0.3 ppb detected in effluent after 8.5 min contact time (250,000 gal spilled materials treated with EPA mobile treatment trailer). [R75] *The following wastewater treatment technology has been investigated for trichloroethylene: Concentration process: Biological treatment. [R76] *The following wastewater treatment technology has been investigated for trichloroethylene: Concentration process: Chemical precipitation. [R77] *The following wastewater treatment technology has been investigated for trichloroethylene: Concentration process: Stripping. [R78] *The following wastewater treatment technology has been investigated for trichloroethylene: Concentration process: Solvent extraction. [R79] *The following wastewater treatment technology has been investigated for trichloroethylene: Concentration process: Activated carbon. [R80] *Trichloroethylene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Incineration, preferably after mixing with another combustible fuel; care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R81] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R82] *Recovering: Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. An alternative to disposal for TCE /trichloroethylene/ is recovery and recycling. Recommendable method: Incineration. Not recommendable method: Discharge to sewer. [R83] *Incineration and evaporation: Small quantities may be poured onto a 10% soda ash and sand mixture, then placed in a paper container and incinerated. Wastes from cleaning operations should be stored in a well ventilated area until they can be incinerated or chemically treated to reduce the toxicity. Residues may be poured on sand, soil or ashes, at a safe distance from occupied areas and allowed to evaporate in the atmosphere. [R83] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R64, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R64, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R64, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R64, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R64, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *There is limited evidence in humans for the carcinogenicity of trichloroethylene. There is sufficient evidence in experimental animals for the carcinogenicity of trichloroethylene. OVERALL EVALUATION: Trichloroethylene is probably carcinogenic to humans Group 2A. In making the overall evaluation, the working group considered the following evidence: (1) Although the hypothesis linking the formation of mouse liver tumors with peroxisome proliferation is plausible, trichloroethylene also induced tumors at other sites in mice and rats. [R84] *A5. A5= Not suspected as a human carcinogen. (1993) ... The substance has been demonstrated by well-controlled epidemiological studies not to be associated with any increased risk of cancer in exposed humans. [R85] ANTR: *Most mild exposures respond to removal from the source and supportive care. Serious toxicity most often results from hypoxemia or cardiac dysrhythmias so that oxygen, intubation, intravenous lines, and cardiac monitoring should be started initially as the clinical situation dictates. ... Syrup of ipecac should be given to the alert patient who ingests more than a minor amount (eg, more than several swallows in a 2-year-old) and presents within 2 hours of ingestion. Activated charcoal and cathartics may be given, although their efficacy has not been studied. [R86, 992] *Basic treatment: .Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with sterile dressings after decontamination ... . /Carbon tetrachloride and related compounds/ [R87, p. 194-5] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of myocardial irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Carbon tetrachloride and related compounds/ [R87, 195] *Skin decontamination. Flush contaminating fumigants from the skin and eyes with copious amounts of water or saline for at least 15 minutes. Some fumigants are corrosive to the cornea and may cause blindness. Specialized medical treatment should be obtained promptly following decontamination. Skin contamination may cause blistering and deep chemical burns. Absorption of some fumigants across the skin may be sufficient to cause systemic poisoning in the absence of fumigant inhalation. For all these reasons, decontamination of eyes and skin must be immediate and thorough. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare162] *Physical placement. Remove victims of fumigant inhalation to fresh air immediately. Even thought initial symptoms and signs are mild, keep the victim quiet, in a semi-reclining position. Minimum physical activity limits the likelihood of pulmonary edema. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare162] *Respiration. If victim is not breathing, clear the airway of secretions and resuscitate with positive pressure oxygen apparatus. If this is not available, use chest compression to sustain respiration. If victim is pulseless, employ cardiac resuscitation. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare163] *Pulmonary edema. If pulmonary edema is evident, there are several measures available to sustain life. Medical judgment must be relied upon, however, in the management of each case. The following procedures are generally recommended: Put the victim in a sitting position with a backrest. Use intermittent and/or continuous positive pressure oxygen to relieve hypoxemia. (Do not give oxygen at greater concentrations or longer periods than necessary, because it may exaggerate the fumigant injury to long tissue. Monitor arterial pO2.) slowly administer furosemide ... to reduce venous load by inducing diuresis. Consult package insert for additional directions and warnings. Some patients may benefit from careful administration of anxiolytic drugs. Whenever possible, such patients should be managed by intensivists in an intensive care center. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare163] *Shock. Combat shock by placing victim in the Trendelenburg position and administering plasma, whole blood, and/or electrolyte and glucose solutions intravenously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continuously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare163] *Control convulsions. Seizures are most likely to occur in poisonings by methyl bromide, hydrogen cyanide, acrylonitrile, phosphine, and carbon disulfide. /Lorazepam is increasingly being recognized as the drug of choice for status epilepticus, although there are few reports of its use with certain pesticides. One must be prepared to assist ventilation with lorazepam and any other medication used to control seizures. ... Phenobarbital is an additional treatment for seizure control. ... For seizure management, most patients respond well to usual management consisting of benzodiazepines, or phenytoin and phenobarbital./ /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare163] *Gastrointestinal decontamination. If a fumigant liquid or solid has been ingested less than an hour prior to treatment, consider gastric emptying, followed by activated charcoal, ... . /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare163] *Fluid balance should be monitored, and urine sediment should be checked regularly for indications of tubular injury. Measure serum alkaline phosphatase, LDH, ALT, AST, and bilirubin to assess liver injury. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare163] *Extracorporeal hemodialysis may be needed to regulate extracellular fluid composition if renal failure supervenes. It is probably not very effective in removing lipophilic fumigant compounds from blood, but it is, of course, effective in controlling extracellular fluid composition if renal failure occurs. /Fumigants/ [R88, http://www.epa.gov/pesticides/safety/healthcare164] MEDS: *Preplacement and periodic exam should incl the skin, resp, cardiac, central, and peripheral nervous systems, as well as liver and kidney function. Alcohol intake should be evaluated. [R31, 884] *Effective medical supervision requires an adequate assessment of the level of exposure. This should be achieved by environmental monitoring ... as well as by biological monitoring. [R63, 2216] */Protect/ from exposure those individuals with diseases of central nervous system, lung, liver, and kidneys. [R89] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R64, 1979.23] *... Changes in EKG waves have been observed among persons with exposure to trichloroethylene. [R53, p. 7.22] *The assessment of trichloroethylene exposure can be accomplished through measurement of either trichloroethylene or the metabolite, trichloroethanol. The most reliable biological monitoring test appears to be measurement of trichloroethanol, which has been found to correlate with exposure levels. ... Whole Blood Reference Ranges: Normal - none detected (trichloroethylene, trichloroethanol); Exposed - BEI (sampling time is end of shift at end of workweek, measured as free trichloroethanol) 4.0 mg/l, BAT (sampling time is end of exposure or end of shift, or for long-term exposure sampling time is after several shifts: both measured as the metabolite, trichloroethanol) 5 mg/l; Toxic - levels greater than 1500 ug/l have been associated with onset of coma. [R90, 2209] *The assessment of trichloroethylene exposure can be accomplished through measurement of either trichloroacetic acid or trichloroethanol. These levels have been found to correlate well with exposure levels. ... Urine Reference Ranges: Normal - none detected (trichloroacetic acid or trichloroethanol); Exposed - BEI (sampling time is end of workweek, measured as the metabolite, trichloroacetic acid) 100 mg/g creatinine, BEI (sampling time is end of workweek, measured as the metabolites trichloroacetic acid and trichloroethanol) 300 mg/g creatinine, BAT (sampling time is end of exposure or end of shift, or for long-term exposures sampling time is after several shifts: both measured as the metabolite, trichloroacetic acid) 100 mg/l; Toxic - not established. [R90, 2209] *Liver Function Tests: ... Biochemical tests - Enzymes that reflect cholestasis: alkaline phosphatase (AP), 5'-nucleotidase (5'-NT) /and/ leucine aminopeptidase (LAP); ... Enzymes that detect direct hepatic damage: aspartate aminotransferase (AST) /and/ alanine aminotransferase (ALT). ... Clearance tests - indocyanine green ... antipyrine test ... /and/ serum bile acids. [R90, 2211] HTOX: *IN ACUTE INHALATION EXPOSURES RAPID COMA MAY ENSUE WITH EVENTUAL DEATH FROM HEPATIC OR RENAL FAILURE. AN OCCASIONAL SUDDEN DEATH SUGGESTS VENTRICULAR FIBRILLATION. SEQUELAE, WHICH MAY BE MORE COMMON AFTER INHALATION THAN AFTER INGESTION, INCLUDE LIVER AND KIDNEY LESIONS, REVERSIBLE TRIGEMINAL (OR OTHER NERVE) DEGENERATION AND PSYCHIC DISTURBANCES. [R91] *... Workers exposed @ concn avg about 10 ppm ... complained of headache, dizziness and sleepiness. ... An epidemiology study on the hepatic tumor incidence in subjects working with trichloroethylene ... failed to show a correlation between liver /cancer/ and occupational exposure. ... Another ... study looked at the mortality of 2117 workers exposed to trichloroethylene ... found no correlation between cancer and occupational exposure. [R92] *Trichloroethylene is only mildly irritating to the skin if allowed to evaporate. From continued use of the material in contact with the skin, defatting can take place. [R43, 4196] *Fatal hepatic failure has been observed following the use of trichloroethylene as an anesthetic. This effect has occurred in patients with complicating conditions such as malnutrition, toxemias, burns, or those who have received transfusions. [R93] *Prolonged occupational exposure to trichloroethylene has been associated with impairment of peripheral nervous system function, persistent neuritis and temporary loss of tactile sense and paralysis of the fingers after direct contact with the solvent. [R94] *A case of severe liver necrosis following a prolonged (4-1/2 hour) use of trichloroethylene as an anesthetic has been reported. [R95] *Following chronic and acute overexposure to trichloroethylene during operation of a dry cleaning unit, symptoms included symmetrical bilateral VIIIth cranial nerve deafness as well as cerebral cortical dysrhythmia and alterations in the electroencephalogram. The patient recovered after the exposure stopped. [R96] *Acute overexposure to trichloroethylene resulted in chronic involvement of the bulbar cranial nerves and esophageal and pharyngeal motility impairment. [R97] *Autopsy findings in a 16 yr old boy who died while sniffing plastic cement containing TCE indicated severe heart failure. ... Liver failure is not the usual cause of death among solvent sniffers, but liver biopsies often reveal toxic centrilobular necrosis. [R60] *The behavioral effects of exposure to trichloroethylene /indicate that/ laboratory /and work-place/ exposure to 540 or 1080 mg/cu m for 70 min, has no effect on reaction time or short-term memory. [R98] *Chromosome analyses of cultured lymphocytes from 28 workers aged 23-67 who had been employed on degreasing unit using trichloroethylene for 1-21 years showed high rates of hypodiploid cells (9 of 28). [R99] *Evoked trigeminal potentials were studied in 104 subjects occupationally exposed to trichloroethylene. Subjects had an average exposure time of 8.23 yr and an average daily exposure of 7 hr (exposure levels were not given). Controls were 52 healthy nonexposed subjects. Symptoms suffered by 49 of the exposed subjects included dizziness, headache, asthenia, insommnia, mood perturbation, and sexual problems. Eighteen subjects had trigeminal nerve symptoms. These subjects were significantly older (p < 0.001) than asymptomatic subjects. Forty subjects had a pathological trigeminal somatosensory evoked potential. Of these, 28 had a normal trigeminal examination and 12 an abnormal one. For those with trigeminal symptoms, an abnormal trigeminal somatosensory evoked potential was observed in subjects who had the longest and most intense exposure periods. [R100] *Estimated human lifetime carcinogenic risk: 3.77X10-7 for male and 6.84X10-8 for female /From table, assuming a daily consumption of 1 liter of water containing trichloroethylene in a concn of 1 ug/l/ [R101, 84] *... Eye irritation: 160 ppm; supportable during 30 min: 379-372 ppm; full /SRP: CNS depression/: 2,500-6,000 ppm; severe toxic effects: 2,000 ppm= 10,940 mg/cu m, 60 min; symptoms of illness: 800 ppm= 4,376 mg/cu m; unsatisfactory /exposure level/: > 400 ppm= 2,188 mg/cu m [R61, 1135] *... The estimated fatal oral dose in humans is 3-5 ml/kg. The lowest concn produce unconsciousness in adult humans is 16 mg/l (3,000 ppm); the equivalent oral dose is 40-150 ml. [R60] *77 of 104 trichloroethylene workers showed abnormal electrocardiographic tracings, which may precede permanent heart damage. [R102] *Adverse psychological and behavioral abnormalities have been reported in industrial overexposures and include symptoms of headache, fatigue, lightheadedness, depression, insomnia, irritability, and confusion. Cranial and peripheral neuropathies have been associated with industrial and medical use. Selective trigeminal neuralgia has been diagnosed in one study in 20% of trichloroethylene workers by demonstrating electrophysiological abnormalities. [R86, 992] *Skin: defatting action /of trichloroethylene/ can cause dermatitis. [R40] *In anesthetic concn, trichloroethylene causes little or no irritation to the respiratory tract. Trichloroethylene causes increased respiratory rate (tachypnea) but decreased alveolar ventilatory amplitude, which is associated with decreased blood oxygen tension and increased carbon dioxide tension. [R103] *... In almost all cases where a xenobiotic /incl trichloroethylene/ has a terminal carbon with two halides attached, side-chain oxidation mediated by cytochrome p450 will produce a toxic, reactive intermediate. [R104, 121] *Eight men inhaled trichloroethylene at concentrations of 0, 100, 300, and 1000 ppm for 2 hr. Each man received the different concentrations in random order. Five tests of visualmotor performance were administered to each volunteer three times during each 2 hr session, and one additional test was administered immediately before and immediately after exposure. At a concentration of 1000 ppm, the compound adversely affected performance in tests of depth perception, steadiness, and manual skill but had no statistically significant effect on performance in three other standard tests. The small increase in errors associated with 100 and 300 ppm were not statistically significant. [R17, 694] *Six naive volunteers were exposed to trichloroethylene aerosol and vapor for 8 hr in one day (two 4 hr exposures separated by a 1.5 hr interval); the concentration varied from 90 to 130 ppm. A slight sense of dizziness and transient eye irritation occurred during maximal fractuations in concentration. Although there was no objective disturbance of motor function, coordination, equilibrium, or behavior, there was a statistically significant decrement in performance of standard tests of perception, memory, complex reaction time, and manual dexterity. Similar results were obtained when the study was repeated with six workers who were accustomed to the odor of the compound. [R17, 694] *Three volunteers each placed one thumb in trichloroethylene for 30 min. They experienced a burning sensation on the dorsum of their thumbs within 3-18 min, and this burning became moderately severe within 5 min after onset in two persons but remained mild in one. The pain became more intense for several minutes just after the thumbs were removed from the solvent, and tingling persisted for 30 min. Erythema subsided within 2 hr. The compound was measurable in the breath of some volunteers within 10 min after exposure started and in all within 20 min. The mean peak breath concentration was 0.5 ppm. [R17, 694] *Vapors of trichloroethylene are only slightly irritating to the respiratory tract. Premedication with atropine or scopolamine hydrobromide is recommended to eliminate possible mucus secretions. The anesthetic typically accelerates respiratory rate. As the tachypnea progresses, respiratory activity becomes more rapid and shallower. Sudden bursts of tachypnea are sometimes associated directly with surgical stimulation. [R105] *A retrospective cohort study of 14,457 workers at an aircraft maintenance facility was undertaken to evaluate mortality associated with exposures in their workplace. The purpose was to determine whether working with solvents, particularly trichloroethylene, posed any excess risk of mortality. The study group consisted of all civilian employees who worked for at least one year at Hill Air Force Base, Utah, between 1 January 1952 and 31 December 1956. Work histories were obtained from /official records/ ... and the cohort was followed up for ascertainment of vital state until 31 December 1982. Observed deaths among white people were compared with the expected numbers of deaths, based on the Utah white population, and adjusted for age, sex and calendar period. Significant deficits occurred for mortality from all causes (SMR 92, 95% CI 90-95), all malignant neoplasms (SMR 90, CI 83-97), ischemic heart disease (SMR 93, 95% CI 88-98), nonmalignant respiratory disease (SMR 87, 95% CI 76-98) and accidents (SMR 61, 95% CI 52-70). Mortality was raised for multiple myeloma in white women (SMR 236, 95% CI 87-514), non-Hodgkin's lymphoma in white women (SMR 212, 95% CI 102-390), and cancer of the biliary passages and liver of white men dying after 1980 (SMR 358, 95% CI 116-836). Detailed analysis of 6929 employees occupationally exposed to trichloroethylene, the most widely used solvent at the base during the 1950s and 1960s, did not show any significant or persuasive association between several measures of exposure to trichloroethylene and any excess of cancer. Women employed in departments in which fabric cleaning and parachute repair operations were performed had more deaths than expected from multiple myeloma and non-Hodgkin's lymphoma. The inconsistent mortality patterns by sex, multiple and overlapping exposures, and small numbers made it difficult to ascribe these excesses to any particular substance. ... [R106] *Human subjects with high repeated, but non-occupational, exposure may exhibit toxic effects on the liver (e.g., elevated aspartate and alanine aminotransferase), renal insufficiency, and abnormal EEG patterns. [R107] *Acute effects on the CNS are characterized by two sequential phases (i.e., excitation and depression), and are usually reversible. ... In the early phase of excitation, euphoria and inebriation are present. The subsequent phase of CNS depression is characterized by various degrees of narcosis culminating in coma. Muscular hypotomy, muscular spasms, reduced tendon reflexes, and loss of coordination may occur. [R107] *Childhood leukemia in a community in Massachusetts, USA, where water from two wells was contaminated with trichloroethylene /was studied/. Measurements made in 1979 showed a concentration of 267 ppb (ug/l) trichloroethylene in the well water. Twenty cases of childhood leukemia were diagnosed in the community in 1964-83, and these were associated with a significantly higher estimated cumulative exposure to water from the two contaminated wells than a random sample of children from the community (observed cumulative exposure, 21.1; expected cumulative exposure, 10.6; p= 0.03). [R108] *A study conducted in New Jersey, USA, during 1979-87 included 75 towns, of which 27 were included in a /previous/ study. Trichloroethylene concentrations were measured during 1984-85, and an average level was assigned to each town. The highest level assigned was 67 ug/l. The water supply of six towns contained > 5 ug/l trichloroethylene (average, 23.4 ug/l). Women in these towns had a significantly higher total incidence of leukemia than the inhabitants of towns were the concentration of trichloroethylene in drinking water was < 0.1 ug/l (relative risk, 1.4; 95% CI, 1.1-1.9); no such effect was seen for men (1.1, 0.84-1.4). The risk among women was particularly elevated for acute lymphocytic leukemia, chronic lymphocytic leukemia in childhood was also significantly increased, in girls but not in boys. Increased risks for non-Hodgkin's lymphoma were apparent in towns in the highest category of trichloroethylene contamination (0.2; 0.94-1.5 for men and 1.4; 1.1-1.7 for women) and was particularly elevated for high-grade lymphomas. [R109] *Trichloroethylene (Tri) caused modest cytotoxicity in freshly isolated human proximal tubular (hPT) cells, as assessed by significant decreases in lactate dehydrogenase (LDH) activity after 1 hr of exposure to 500 muM Tri. Oxidative metabolism of Tri by cytochrome p450 to form chloral hydrate (CH) was only detectable in kidney microsomes from one patient out of four tested and was not detected in hPT cells. In contrast, GSH conjugation of Tri was detected in cells from every patient tested. The kinetics of Tri metab to its GSH conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) followed biphasic kinetics, with apparent Km and Vmax values of 0.51 and 24.9 mM AND 0.10 and 1.0 nmol/min/mg protein, respectively. S-(1,2-dichlorovinyl)-L-cysteine (DCVC), the cysteine conjugate metabolite of Tri that is considered the penultimate nephrotoxic species, caused both time- and concn-dependent increases in LDH release in freshly isolated hPT cells. Preincubation of hPT cells with 0.1 mM aminooxyacetic acid did not protect hPT cells from DCVC-induced cellular injury, suggesting that another enzyme besides the cysteine conjugate beta-lyase may be important in DCVC bioactivation. ... These data indicate that the pathway involved in the cytotoxicity and metab of Tri in hPT cells is the GSH conjugation pathway and that the cytochrome p450-dependent pathway has little direct role in renal Tri metabolism in humans. [R110] *Trichloroethylene (TCE) is both acutely toxic and carcinogenic to the mouse lung following exposure by inhalation. In contrast, it is not carcinogenic in the rat lung and is markedly less toxic following acute exposure. Toxicity to the mouse lung is confined almost exclusively to the nonciliated Clara cell and is characterized by vacuolation and incr in cell replication. Chloral, a metabolite of TCE that accumulates in Clara cells and has been shown to be the cause of the toxicity, also causes aneuploidy in some test systems. Cytotoxicity, increased cell division, and aneuploidy are known risk factors in the development of cancer and provide a plausible mode of action for TCE as a mouse lung carcinogen. All acute and chronic effects of TCE on the mouse lung are believed to be a direct consequence of high cytochrome P450 activity and impaired metab of chloral in Clara cells. Comparisons between species suggest that the ability of the human lung to metabolize TCE is approx 600-fold < that in the mouse. In addtn, the human lung differs markedly from the mouse lung in the number and morphology of its Clara cells. Thus, the large quantitative differences between the metabolic capacity of the mouse lung and the human lung, together with the species differences in the number and morphology of lung Clara cells, suggest that the risks to humans are minimal and that other tumor sites should take precedent over the lung when assessing the potential risks to humans exposed to TCE. [R111] *An ecological epidemiological study was conducted with data obtained from an environmental dose-reconstruction study and the Arizona Birth Information Tapes. Before 1981, a portion of the city of Tucson water-distribution system was contaminated with trichloroethylene (i.e., < 5 ug/l of water to 107 ug/l of water). Target and comparison populations were selected with a Geographic Information System. Logistical-regression analysis revealed an association between maternal exposure to trichloroethylene via drinking water and very-low-birth-weight babies (i.e., < 1,501 grams) (odds ratio = 3.3; 95% confidence interval = 0.5, 20.6; AND Wald chi-square p value = 0.2). No association was found between maternal exposure to trichloroethylene via drinking water and low birth weight or full-term low-birth-weight infants (gestational period > 35 wk and < 46 wk). [R112] *... Changes in EKG waves have been observed among persons with exposure to trichloroethylene. [R53, p. 7.22] NTOX: *MUTAGENICITY: MUTATION RESEARCH 86: 355 (1981). MOUSE IN VIVO SOMATIC MUTATION ASSAY (SPOT TEST) - COAT COLOR MUTANTS: POSITIVE. [R113] *... REPORTED SYMPTOMS OF CHRONIC INTOXICATION IN DOGS IN 3-8 WEEKS AFTER INHALATION OF 500 TO 750 PPM FOR 4-8 HOURS DAILY, 5-6 DAYS PER WEEK. THE SYMPTOMS CONSISTED OF LETHARGY, ANOREXIA, NAUSEA, VOMITING AND LOSS OF WEIGHT. LIVER DYSFUNCTION WAS ALSO SHOWN IN THESE DOGS. [R114] *... REPEATED EXPOSURE TO 3000 PPM (27 EXPOSURES DURING 36 DAYS) ... CAUSED DISTURBANCES OF EQUILIBRIUM AND COORDINATION ... AFTER ... 1ST WEEK SALIVATION, RESTLESSNESS AND HYPEREXCITABILITY, THEY RECOVERED ... ONLY HISTOLOGICAL ABNORMALITY ... FAT VACUOLES IN ... LIVER OF FEMALE RATS. [R12, 197] *WHEN SOYA-BEAN MEAL IS EXTRACTED WITH TRICHLOROETHYLENE IT WAS TOXIC TO CATTLE ... THE SYNDROME IN CATTLE IS KNOWN VARIOUSLY AS STOCKMAN DISEASE, DUREN DISEASE AND BARBANT DISEASE. [R115] *CATS AND GUINEA PIGS EXPOSED TO 1000 PPM DAILY FOR 1 1/2 HR ... FROM 10 DAYS TO 10 MONTHS ... IN THOSE WHICH SURVIVED SEVERAL MONTHS, CIRRHOSIS AND BILIARY HYPERPLASIA ... LATTER PROGRESSING IN SOME ANIMALS TO PROLIFERATIVE 'BILIARY ADENOMATOSIS'. [R12, 198] *GASTRIC INTUBATION OF 2.4 OR 1.2 G/KG BODY WT TRICHLOROETHYLENE 5 TIMES WEEKLY IN MALE B6C3F1 MICE (AGE NOT SPECIFIED) AND OF 1.8 OR 0.9 G/KG BODY WT IN FEMALES INDUCED HEPATOCELLULAR CARCINOMAS IN 30/98 MICE GIVEN LOW DOSE AND IN 41/95 (43.2%) MICE GIVEN HIGHER DOSE. HEPATOCELLULAR CARCINOMAS ... IN 1/40 (2.5%) CONTROL MICE. [R116] *FEMALE RATS EXPOSED TO VAPORS OF 200 TO 1800 PPM FOR 2 WK SHOWED NO EFFECTS INDICATIVE OF TREATMENT-RELATED MATERNAL TOXICITY, EMBRYOTOXICITY, ... TERATOGENICITY OR BEHAVIORAL DEFECTS. ... /SRP: EVIDENCE OF DEVELOPMENTAL DELAY WAS SEEN/. [R117] *PURE TRICHLOROETHYLENE STABILIZED BY AMINE BASE, ADMIN BY INHALATION @ 0, 100 and 500 PPM FOR 6 HR/DAY, 5 DAY/WK FOR 18 MO TO /NMRI/ MICE, RATS AND SYRIAN HAMSTERS. ONLY FEMALE MICE SHOWED INCR IN MALIGNANT LYMPHOMAS. [R118] *EXPOSURE OF MALE MICE TO TRICHLOROETHYLENE VAPORS DURING 24 HR @ LEVELS OF 50, 202 and 450 PPM DID NOT REVEAL MUTAGENIC EFFECTS IN DOMINANT LETHAL ASSAY. [R119] *TRICHLOROETHYLENE WAS AMONG HALOGENATED HYDROCARBONS TESTED FOR CARCINOGENICITY BY CHRONIC ADMIN BY 1 OR MORE ROUTES IN HA:ICR SWISS MICE. TCE INACTIVE BY CRITERIA USED. [R120] *... 50 MALE AND 50 FEMALE B6C3F1 HYBRID MICE, 5 WK OLD, WERE ADMIN 99% PURE TRICHLOROETHYLENE, CONTAINING 0.19% 1,2-EPOXYBUTANE AND 0.09% EPICHLOROHYDRIN IN CORN OIL BY GAVAGE ON 5 DAYS A WK FOR 78 WK. HIGH DOSE MALES RECEIVED 2000-2400 MG/KG BODY WT/DAY, AND FEMALE 1400-1800 MG/KG BODY WT/DAY; LOW DOSE MALE AND FEMALES RECEIVED 1000-1200 MG/KG BODY WT/DAY AND 700-900 MG/KG BODY WT. ALL SURVIVING ANIMALS WERE OBSERVED UNTIL ... 95 WK OF AGE. ... HEPATOCELLULAR CARCINOMA OCCURRED IN 1/20 CONTROL MALES AND 0/20 CONTROL FEMALES, IN 26/50 LOW DOSE MALES AND 4/50 LOW DOSE FEMALES, AND IN 31/48 HIGH DOSE MALES, 11/47 HIGH DOSE FEMALES. METASTASES OF THE LIVER CELL TUMORS TO THE LUNG WAS FOUND IN 7/98 TREATED MALES AND IN 1 CONTROL MALE. LUNG TUMORS OCCURRED IN TREATED ANIMALS OF BOTH SEXES ... ONLY ONE LUNG ADENOMA IN FEMALE. [R121] *A single 1000 mg/kg body wt dose ... in corn oil was admin by gavage to 50 mice of each sex, and doses of 1000 and 500 mg/kg body wt were given in the same manner to 50 rats of each sex 5 days/wk for 2 yr. For each group of test animals there were corresponding groups of controls composed of 50 animals of each sex. The trichloroethylene was stabilized with an amine antioxidant (diisopropylamine) and contained no detectable traces of 1,2-epoxybutane or epichlorohydrin. ... The results observed in the mice support the previous NCI (1976) findings that trichloroethylene significantly incr the incidence of hepatocellular carcinomas in B6C3F1 mice of both sexes. [R101, 82] *IN VIVO AND IN VITRO METHODOLOGIES THAT HAVE EMPLOYED THE YEAST SCHIZOSACCHAROMYCES POMBE AS GENETIC INDICATOR HAVE BEEN UTILIZED TO INVESTIGATE THE MUTAGENICITY OF TWO TRICHLOROETHYLENE (TCE) SAMPLES OF PURE AND TECHNICAL GRADE. BOTH TCE SAMPLES GAVE NEGATIVE RESULTS FOR IN VIVO AND IN VITRO ASSAYS, WHEREAS THE 2 CONTAMINANTS WERE FOUND MUTAGENIC ONLY IN VITRO. [R122] *No liver lesions or hepatomas were found in NLC mice which had received oral doses of 0.1 ml of a 40% solution of trichloroethylene in oil twice weekly for an unspecified period. [R123] *Trichloroethylene (3.3 mM) in the presence of a metabolic activating microsomal system induced reverse mutations in Escherichia coli strain K12. It has also been shown to induce frame-shift as well as base substitution mutations in Saccharomyces cerevisiae strain XV185-14C in the presence of mouse liver homogenate. [R123] *In rabbits, blood levels of greater than 30 mg/l (following continuous iv infusion of 1-5 mg/kg/min, trichloroethylene) induced positional nystagmus /SRP: rapid movement of the eyeball when the head is held in various positions/. [R124] *ACS purity trichloroethylene induced both point mutation and gene conversion at the ilv and trp loci of the D7 strains of Saccharomyces cerevisiae in the presence of a mouse liver 10,000 g supernatant metabolizing system. A dose response was observed in both instances over the range of 10-40 mM. [R125] *Application of 0.1 ml of trichloroethylene directly applied to the eye of a rabbit produced a mild-moderate conjunctivitis with some epithelial abrasions being noted on examination with fluorescein. Microscopic examination on day 7 indicated epithelial keratosis in the process of healing. The eye returned to normal in two weeks. [R126] *Concentration of 1 mM trichloroethylene induced transformation of rat embryo cells (Fischer rat embryo cell system F1706) in vitro which appeared as a progressively growing foci of cells lacking contact inhibition and by the growth of macroscopic foci when inoculated in semi-solid agar. The transformed cells grew as undifferentiated fibrosarcomas at the site of inoculation in 100% of newborn Fischer rats between 27 and 68 days post-inoculation. [R127] *Chronic administration /by gavage/ of 2400 mg/kg per day of trichloroethylene to male B6C3F1 mice, induced localized cell necrosis, enhanced DNA synthesis, and centrilobular hepatocellular swelling. Prolonged exposure (3 weeks), the primary response was dose-related centrilobular hepatocellular swelling and the occurrence of mineralized (calcified) cells. [R128] *Trichloroethylene was non-mutagenic in the Ames Salmonella assay when tested with TA100 in a 10 liter desicator. Exposure levels were as high as 20% in air (v/v) for up to 16 hr. The assay was performed in the presence and absence of a phenobarbital-induced liver S9 fraction from male mice. Chloral hydrate, a metabolite of trichloroethylene, was found to be mutagenic in strain TA100 in the Salmonella standard plate incorporation assay in doses ranging from 0.5 to 10.0 mg/plate. The mutagenic activity was enhanced in the presence of rat liver S9 mix. [R101, 81] *Sperm exam from mice exposed to 0.3% for 4 hr daily for 5 days revealed incr abnormalities after 28 days. [R129] *Rats exposed to 37,000, 42,000, and 56,000 mg/cu m of trichloroethylene vapor for two hours exhibited elevated activities of serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and isocitrate dehydrogenase. Hepatotoxicity (indicated by the increased levels of these hepatic enzymes in the serum) was greatly enhanced by pretreatment with 3-methylcholanthrene. [R130] *Trichloroethylene was neither embryotoxic nor teratogenic in Sprague-Dawley rats and Swiss Webster mice inhaling trichloroethylene. These results have been confirmed in two other studies in female rats exposed in one case to 500 ppm and in other to 1800 ppm. Trichloroethylene was found to be weakly mutagenic in Escherichia coli in the presence of a metabolizing system ... or in extensive studies in Drosophila. Positive effects in some studies may be due to epoxy stabilizers sometimes present in trichloroethylene. [R92] *Female Sprague-Dawley rats were given trichloroethylene (TCE) in distilled drinking water at concentrations of 312, 625, and 1250 mg/l. Dams received TCE from 14 days prior to breeding, throughout gestation, and until the pups were weaned at 21 days of age. Control dams received untreated distilled water. Male offspring of experimental and control dams were used to study exploratory behavior either 28, 60, or 90 days of age. Wheel-running, feeding, and drinking behavior tests in rat pups were conducted for 24 hr/day from 55-60 days of age. At 28 days of age, no difference in exploratory activity was seen among treatment groups. At 60 and 90 days of age, rat pups exposed to /SRP: even the lowest concentrations/ of TCE exibited increased levels of exploration. Rats exposed to 1250 mg/l TCE were more active on the wheel than controls or those exposed to 625 mg/l TCE. No significant differences were detected among treatment groups for the levels or timing of feeding or drinking activities. [R131] *Trichloroethylene was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Trichloroethylene was tested doses at doses of 0.01, 0.033, 0.10, 0.333, and 1.0 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Trichloroethylene was negative in these tests and the highest ineffective dose tested in any S typhimurium strain was 1.0 mg/plate. Slight clearing of the background bacterial lawn occurred in all cultures at the high dose. [R132] *Affected fathead minnows, 31 days old, in toxicant concentrations ranging from 8.43-77.3 mg/l, lost schooling behavior, swam in a corkscrew/spiral pattern near the surface, were hyperactive and hemorrhaging. Equilibrium loss was not observed prior to death. No effect data were recorded. Individual lengths and weights were not recorded; however, the measured mean weight was 0.109 g. Spike recovery data were not available, but the mean recovery was likely > 90%. [R133] *Trichloroethylene /0.5 ml/ (purity 99.5%) applied to the shaved non-abraded skin of rabbits for 24 hours under an occlusive dressing, produced severe skin irritation. [R134] *Trichloroethylene (1.0 ml) /purity not specified/ was applied, occluded in a skin depot, to the clipped skin of a guinea pig. Histological examinations performed at 15 minutes, 1, 4, and 16 hour /indicated/ degenerative changes (pyknotic nuclei) were observed in the epidermis after 15 minutes, and were progressive (pyknosis, karyolysis, junctional separation of the epidermis) up to the end of the study. [R135] *Groups of 49-50 female ICR mice 4 weeks of age ... exposed by inhalation to trichloroethylene (purity = 99.8%, with 0.128% carbon tetrachloride, 0.019% benzene, 0.019% epichlorohydrin, and 0.01% 1,1,2-trichlorethane) at 0.270, 810, or 2430 mg/cu m 7 hr/day for 5 days/wk, for 104 weeks. The surviving animals were /sacrificed/ 107 weeks after the start of the study. Mortality was similar in control and treated groups. Lung adenomas were found in 5, 2, 5, and 4 mice in the control, low-dose, mid-dose and high-dose groups, respectively. Adenocarcinomas occurred in 1/49, 3/50, 8/50, and 7/46 mice in the control, low-dose, mid-dose and high-dose groups, respectively; increased incidences in the mid- and high-dose groups were statistically significant compared with controls. [R136] *A pure sample of trichloroethylene, stabilized with thymol /concentration not specified/ did not induce forward mutations at the HGPRT locus of a Chinese hamster V-79 cell line treated in vitro, with or without S9 mix metabolic activation. [R137] *Gelatinsorbitol microcapsules containing 44.1% trichloroethylene (TCE) were prepared and mixed in NIH-07 rodent meal diet and provided at microcapsule concentrations of 0 (untreated control group), 1.25, 2.5, 5.0, or 10% (equivalent to 0, 0.55, 1.10, 2.21, or 4.41% TCE in the diet, respectively) to groups of 10 male F344 rats for 14 days. An additional control group received diets containing 5% empty capsules. For comparisions, TCE dissolved in corn oil was administered by gavage to different groups of 10 male rats for 14 consecutive days at dose levels adjusted to correspond to those in the feed study. Treatment-related deaths occurred only in the highest dose group of the gavage study. Body weight gain and feed consumption were reduced in high-dose groups of both the feed and gavage studies. ... Dose-related increases in organ (liver and kidney) weight/body weight ratios, individual cell necrosis in the liver, and hepatic microsomal NADPH cytochrome-c reductase and peroxisomal palmitoyl-CoA oxidase and catalase activities were found in both the dosed-feed and gavage groups. Induction of cytochrome p450 occurred only in the dosed-feed study. [R138] *... MAJOR CONSIDERATION MUST BE GIVEN TO CUMULATIVE EFFECTS OF THIS COMPOUND. ... IN LONG-TERM FEEDING STUDIES CARRIED OUT BY THE NATIONAL CANCER INSTITUTE (1976b), ... MICE (BOTH SEXES, AT BOTH LOW AND HIGH DOSE LEVELS) EXPERIENCED A HIGHLY SIGNIFICANT INCREASE IN HEPATOCELLULAR CARCINOMAS. ... MIKISKOVA AND MIKISKA (1966) DEMONSTRATED THAT TRICHLOROETHANOL HAD A PRONOUNCED DEPRESSANT EFFECT ON THE CENTRAL NERVOUS SYSTEM. [R139] *When fed in drinking water to mice for 4 to 6 months at concentrations of 0, 0.1, 1.0, and 2.5, and 5.0 mg/ml of water, "There was a decreased body weight gain at the highest dose, which could be attributed to a decrease in fluid consumption. The most significant effects attributable to TCE were an increase in liver weight in both sexes accompanied by increased nonprotein sulfhydryl levels in the males, and an increase in kidney weight in both sexes accompanied by increases in protein and ketones in the urine. ... The 6 months average daily doses were 0, 144, 217, 393, and 660 mg/kg body weight for the male mice. Female mice averaged 0, 18, 193, 437, and 793 mg/kg/day. [R43, 4197] *... Several species of animals /were exposed/ 7 hr/day, 5 days/week for approximately 6 months. At 3000 ppm by volume in air, rats and rabbits both showed an increase in liver and kidney weight. At 400 ppm rats showed an increase in liver and kidney weights and the male rats also showed significantly less growth. Guinea pigs had increased liver weights and the growth of the exposed males was less than the controls. Rabbits showed a slight increase in liver weight. An exposed monkey showed no response at 400 ppm. At 200 ppm, the only effect was depressed growth in guinea pigs. Rats, rabbits, and monkeys showed no response. At a concentration of 100 ppm, none of the species showed any significant response. The maximum concentrations tolerated without adverse effect for the 6 month period were as follows: monkeys, 400 ppm; rats and rabbits, 200 ppm; and guinea pigs, 100 ppm. [R43, 4197] *... Rats, guinea pigs, dogs, rabbits, and monkeys /were exposed/ 24 hr/day for 90 days to 35 ppm with no effect except slight growth depression. Repeated 8 hr daily exposures to 700 ppm for 90 days were also without effect. [R43, 4197] *Pregnant /rats and mice and their offsprings/ were exposed for 7 hr to 300 ppm on days 6 to 15 of pregnancy with no evidence of adverse effect on the dams, on reproduction, or on the offspring by any of the usual criteria of a teratogenic study. [R43, 4198] *In a teratology reproduction study, the NTP fed microencapsulated trichloroethylene to rats and mice at doses as high as 300 mg/kg/day to rats and 750 mg/kg/day to mice with little effect. Sperm motility was reduced 45% in F0, males and 18% in F1, male mice. There is no ready explanation for less response in the F1-generation male mice. [R43, 4198] *When fed to B6D2F1 mice by gavage on days 1 to 5, 6 to 10, or 10 to 15 (day 1, vaginal plug) trichloroethylene in corn oil cause no reproductive, maternal, or foal effects. Daily dosages were 0, 1/10, or 1/100 of the oral LD50 (2402 mg/kg used as LD50 value). Weanlings were kept for 21 days or 42 days. Trichloroethylene also had no effect on in vitro fertilization. [R43, 4198] *Apart from two reports in which trichloroethylene weakly induced mutation in Salmonella typhimurium TA1535, purified trichloroethylene did not induce gene mutation in various strains of Salmonella in the absence of metabolic activation; however, trichloroethylene containing directly mutagenic epoxide stabilizers did. [R140] *Previous epidemiological studies with humans and laboratory studies with chickens and rats linked trichloroethylene (TCE) exposure to cardiac defects. Although the cardiac defects in humans and laboratory animals produced by TCE are diverse, a majority of them involves valvular and septal structures. Progenitors of the valves and septa are formed by an epithelial-mesenchymal cell transformation of endothelial cells in the atrioventricular (AV) canal and outflow tract areas of the heart. Based on these studies, we hypothesized that TCE might cause cardiac valve and septa defects by specifically perturbing epithelial-mesenchymal cell transformation. We tested this hypothesis using an in vitro chick-AV canal culture model. This study shows that TCE affected several elements of epithelial-mesenchymal cell transformation. In particular, TCE blocked the endothelial cell-cell separation process that is associated with endothelial activation. Moreover, TCE inhibited mesenchymal cell formation throughout the concn range tested (50-250 ppm). In contrast, TCE had no effect on the cell migration rate of the fully formed mesenchymal cells. Finally, the expression of 3 proteins (selected as molecular markers of epithelial-mesenchymal cell transformation) was analyzed in untreated and TCE-treated cultures. TCE inhibited the expression of the transcription factor Mox-1 and extracellular matrix (ECM) protein fibrillin 2. In contrast, TCE had no effect on the expression of alpha-smooth muscle actin. These data suggest that TCE may cause cardiac valvular and septal malformations by inhibiting endothelial separation and early events of mesenchymal cell formation in the heart. [R141] *Strategies are needed for assessing the risks of exposures to airborne toxicants that vary over concns and durations. The goal of this project was to describe the relationship between the concn and duration of exposure to inhaled trichloroethylene (TCE), a representative volatile organic chemical, tissue dose as predicted by a physiologically based pharmacokinetic model, and neurotoxicity. Three measures of neurotoxicity were studied: hearing loss, signal detection behavior, and visual function. The null hypothesis was that exposure scenarios having an equivalent product of concn and duration would produce equal toxic effects, according to the classic linear form of Haber's Rule ... . All experiments used adult male, Long-Evans rats. Acute and repeated exposure to TCE increased hearing thresholds, and acute exposure to TCE impaired signal detection behavior and visual function. Examination of all three measures of neurotoxicity showed that if Haber's Rule were used to predict outcomes across exposure durations, the risk would be overestimated when extrapolating from shorter to longer duration exposures, and underestimated when extrapolating from longer to shorter duration exposures. For the acute effects of TCE on behavior and visual function, the estimated concn of TCE in blood at the time of testing correlated well with outcomes, whereas cumulative exposure, measured as the area under the blood TCE concn curve, did not. ... Models incorporating dosimetry can account for differing exposure scenarios and will therefore improve risk assessments over models considering only parameters of external exposure. [R142] *Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH AND TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concns of TCA in blood required to induce liver cancer approach the mM range. Concns of DCA in blood associated with carcinogenesis are in the sub-muM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA AND/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPARalpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPARalpha that are observed in rodents. This may be attributed to lower levels of expressed PPARalpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA AND TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis. [R143] *The possibility that the acute neurotoxic effects of organic solvents change with repeated exposure will affect risk assessment of these pollutants. ... Rats inhaling trichloroethylene (TCE) showed a progressive attenuation of impairment of signal detection behavior across several wk of intermittent exposure, suggesting the development of tolerance. Here, we explored the development of tolerance to TCE during 2 wk of daily exposures, and the degree to which learned behavioral modifications ("behavioral tolerance") could account for the effect. Adult Long-Evans rats were trained to perform a visual signal detection task (SDT) in which a press on one lever yielded food if a visual stimulus (a "signal") had occurred on that trial, and a press on a second lever produced food if no signal had been presented. In two experiments, with 2000 and 2400 ppm of TCE res pectively, trained rats were divided into two groups (n = 8/group) with equivalent accuracy and then exposed to TCE in two-phase studies. In Phase 1, one group of rats received daily SDT tests paired with 70-min TCE exposures, followed by 70-min exposures to clean air after testing. The other group received daily SDT tests in clean air, followed by 70-min exposures to TCE (unpaired exposure and testing). All rats thus received the same number and daily sequence of exposures to TCE that differed only in the pairing with SDT testing. Both concns of TCE disrupted performance of the paired groups and this disruption abated over the 9 days of exposure. In Phase 2, the pairing of exposure and test conditions were reversed for the two groups. The groups that were shifted from unpaired to paired exposures (Unpaired-Paired groups) showed qualitatively similar patterns of deficit and recovery as did the rats whose tests were initially paired with TCE (Paired-Unpaired groups), indicating that task-specific learning was involved in the development of tolerance. Quantitative differences in the magnitude and duration of the effects of TCE in the two groups indicated that other factors, not specific to the SDT, also contributed to the development tolerance to TCE. [R144] *Exposure of rats to trichloroethylene induces a sustained excretion of large amounts of formic acid in urine. Both of the major metabolites, trichloroethanol and trichloroacetic acid, were found to induce this response, but not the minor metabolite S-(1, 2-dichlorovinyl) cysteine. Other polychlorinated solvents, including carbon tetrachloride and chloroform, also increased urinary formate excretion. Addition of folic acid either to diet or drinking water modulated the response indicating that these rats were folate deficient. Two markers of vitamin B(12) deficiency, methylmalonic acid and 5-methyltetrahydrofolate, were also markedly incr in urine and plasma respectively. The incr in 5-methyltetrahydrofolate is consistent with a folate deficiency caused by an inhibition of the vitamin B(12) dependent methionine salvage pathway. Since both vitamin B(12) and chemicals containing polychlorinated carbon atoms readily form free radicals, it is suggested that trichloroacetic acid and trichloroethanol interact with vitamin B(12) through a free radical mechanism inducing a B(12) deficiency and, as a consequence, a folate deficiency. As a result of the folate deficiency, excess formic acid, which is normally utilised through this pathway, is excreted in urine. [R145] NTOX: *... There is increasing evidence relating exposure to trichloroethylene /(1,1,2-trichloroethene)/ with autoimmunity. To investigate potential mechanisms, we treated the autoimmune-prone MRL + / + mice with trichloroethylene in the drinking water at 0, 2.5 or 5.0 mg/ml ... . As early as 4 wk of treatment. Western blot analysis showed a dose-dependent incr in the level of trichloroethylene-modified proteins, indicating that a reactive metabolite of trichloroethylene was formed. Significant increases in antinuclear antibodies (ANA) and total serum immunoglobulins were found following 4-8 wk of trichloroethylene treatment, indicating that trichloroethylene was accelerating an autoimmune response. Investigation into possible mechanisms of this autoimmune response revealed that trichloroethylene tre atment dramatically increased the expression of the activation marker CD44 on splenic CD4+ T cells at 4 wk. In addtn, splenic T cells from mice treated for 4 wk with trichloroethylene secreted more IFN-gamma and less IL-4 than control T cells, consistent of a T-helper type 1 (Th1) type immune or inflammatory response. A specific immune response directed against dichloroacetylated proteins was found at 22 wk of trichloroethylene treatment. ... The results suggest that trichloroethylene treatment accelerated an autoimmune response characteristic of MRL + / + mice in association with nonspecific activation of Th1 cells. In addtn, long-term treatment with trichloroethylene led to the initiation of a trichloroethylene-specific immune response. [R146] *The mechanism of trichloroethylene-induced liver peroxisome proliferation and the sex difference in response was investigated using wild-type Sv/129 and peroxisome proliferator-activated receptor alpha (PPARalpha)-null mice. Trichloroethylene treatment (0.75 g/kg for 2 wk by gavage) resulted in liver peroxisome proliferation in wild-type mice, but not in PPARalpha-null mice, suggesting that trichloroethylene-induced peroxisome proliferation is primarily mediated by PPARalpha. No remarkable sex difference was observed in induction of peroxisome proliferation, as measured morphologically, but a markedly higher induction of several enzymes and PPARalpha protein and mRNA was found in males. On the other hand, trichloroethylene induced liver cytochrome P450 2E1, the principal enzyme responsible for metabolizing trichloroethylene to chloral hydrate, only in males, which resulted in similar expression levels in both sexes after the treatment. Trichloroethylene influenced neither the level of catalase, an enzyme involved in the reduction of oxidative stress, nor aldehyde dehydrogenase, the main enzyme catalyzing the conversion to trichloroacetic acid. These results suggest that trichloroethylene treatment causes a male-specific PPARalpha-dependent increase in cellular oxidative stress. [R147] *Trichloroethylene (TCE), dichloroacetic acid (DCA), and trichloroacetic acid (TCA) are environmental contaminants that are carcinogenic in mouse liver. 5-Methylcytosine (5-MeC) in DNA is a mechanism that controls the transcription of mRNA, including the protooncogenes, c-jun and c-myc. ... TCE decreased methylation of the c-jun and c-myc genes and increased the level of their mRNAs. Decreased methylation of the protooncogenes could be a result of a deficiency in S-adenosylmethionine (SAM), so that methionine, by increasing the level of SAM, would prevent hypomethylation of the genes. For 5 days, female B6C3F1 mice were admin, daily by oral gavage, either 1000 mg/kg bw of TCE or 500 mg/kg DCA or TCA. At 30 min after each dose of carcinogen, the mice received, by ip injection, 0, 30, 100, or 450 mg/kg methionine. Mice were euthanized at 100 min after the last dose of DCA, TCA, or TCE. Decreased methylation in the promoter regions of the c-jun and c-myc genes and increased levels of their mRNA and proteins were found in livers of mice exposed to TCE, DCA, AND TCA. Methionine prevented both the decreased methylation and the increased levels of the mRNA and proteins of the two protooncogenes. The prevention by methionine of DCA- TCA-, AND TCE-induced DNA hypomethylation supports the hypothesis that these carcinogenes act by depleting the availability of SAM. Hence, methionine would prevent DNA hypomethylation by maintaining the level of SAM. Furthermore, the results suggest that the dose of DCA, TCA, or TCE must be sufficient to decrease the level of SAM in order for these carcinogens to be active. [R148] HTXV: *Estimated fatal oral dose 3 to 5 mg/kg [R86, 990] NTXV: *LC50 Rat inhalation 26,000 ppm/1 hr; [R149] *LC50 Rat inhalation 12,000 ppm/4 hr; [R150] *LC50 Mouse inhalation 8450 ppm/4 hr; [R151] *LD50 Rabbit percutaneous 29 g/kg; [R152] *LD10 Female CD-1 Mouse gavage 1161 mg/kg; male CD-1 mouse gavage 1347 mg/kg; [R153] *LD50 Female CD-1 Mouse gavage 2443 mg/kg; male CD-1 mouse gavage 2402 mg/kg; [R153] *LD90 Female CD-1 Mouse gavage 2443 mg/kg; male CD-1 mouse gavage 4253 mg/kg; [R153] *LD100 Female CD-1 Mouse gavage 5500 mg/kg; male CD-1 mouse gavage 6000 mg/kg; [R154] *LD50 Mouse inhalation 49,000 ppm/30 min; [R61, 1135] *Rat inhalation 100 ppm/8 hr, no effect; [R61, 1135] *Rabbit inhalation 1,200 ppm/473 hr, no effect; [R61, 1135] *Rabbit, ape, rat, guinea pig inhalation 730 ppm/8 hr/day, 6 weeks, no effects; [R61, 1135] *LD50 Mouse inhalation 5,500 ppm/10 hr; [R61, 1135] *LD50 Dog oral 5680 mg/kg; [R155] *LD50 Dog ip 2,800 mg/kg; [R155] *LD50 Rabbit dermal 20 ml/kg; [R155] *LD50 Rat oral 4920 mg/kg; [R17, 690] *LD50 Mouse (female) oral 2443 mg/kg; [R17, 690] *LD50 Mice (male) oral 2402 mg/kg; [R17, 690] *LD50 Mouse ip 3222 mg/kg; [R17, 690] *LD50 Dog ip 2783 mg/kg; [R17, 690] ETXV: *LC50 Sheepshead minnow 20 mg/l/96 hr. /Conditions of bioassay not specified/; [R156] *LC50 Bluegill sunfish 44,700 ug/l/96 hr. /Static bioassay/; [R157] *LC50 Grass shrimp 2 mg/l/96 hr. /Conditions of bioassay not specified/; [R158] *Toxicity Threshold (Cell Multiplication Inhibition Test) Entosiphon sulcatum (protozoa) 1200 mg/l /Time not specified, conditions of bioassay not specified/; [R61, 1135] *Toxicity Threshold (Cell Multiplication Inhibition Test) Uronema parduczi Chatton-Lwoff (protozoa) > 960 mg/l /Time not specified, conditions of bioassay not specified/; [R61, 1135] *Toxicity Threshold (Cell Multiplication Inhibition Test) Scenedesmus quadricauda(green algae) > 1000 mg/l /Time not specified, conditions of bioassay not specified/; [R61, 1135] *Toxicity Threshold (Cell Multiplication Inhibition Test) Microcystis aeruginosa (algae) 63 mg/l /Time not specified, conditions of bioassay not specified/; [R61, 1134] *LC50 Mexican axolotl (3-4 wk after hatching) 48 mg/l/48 hr /Conditions of bioassay not specified/; [R61, 1135] *LC50 Clawed toad (3-4 wk after hatching) 45 mg/l/48 hr /Conditions of bioassay not specified/; [R61, 1135] *LC50 Pimephales promelas (fathead minnow) 40.7 mg/l/96 hr (95% confidence limits 31.4-71.8 mg/l) /Flow-through test/; [R61, 1135] *LC50 Pimephales promelas (fathead minnow) 66.8 mg/l/96 hr (95% confidence limits 59.6-74.7 mg/l) /Static test/; [R61, 1135] *EC10 Pimephales promelas (fathead minnow) 15.2 mg/l/24 hr; 16.9 mg/l/48 hr; 15.5 mg/l/72 hr; 13.7 mg/l/96 hr; Toxic effect for all concentrations specified: loss of equilibrium. /Flow-through bioassay/; [R61, 1135] *EC50 Pimephales promelas (fathead minnow) 23.0 mg/l/24 hr; 22.7 mg/l/48 hr; 22.2 mg/l/72 hr; 21.9 mg/l/96 hr; Toxic effect for all concentrations specified: loss of equilibrium. /Flow-through bioassay/; [R61, 1135] *EC90 Pimephales promelas (fathead minnow) 36.2 mg/l/24 hr; 30.6 mg/l/48 hr; 31.8 mg/l/72 hr; 34.9 mg/l/96 hr; Toxic effect for all concentrations specified: loss of equilibrium. /Flow-through bioassay/; [R61, 1135] *Toxicity Threshold (Cell Multiplication Inhibition Test) Pseudomonas putida (bacteria) 65 mg/l; [R61, 1134] NTP: *Toxicology and carcinogenesis studies of trichloroethylene (more than 99% pure, stabilized with 8 ppm diisopropylamine) were conducted by administering the chemical in corn oil by gavage at doses of 0, 500, or 1000 mg/kg/day 5 days/wk for 103 wk to groups of 50 male and 50 female ACI, August, Marshall, and Osborne-Mendel rats. ... Under the conditions of these two yr gavage studies of trichloroethylene in male and female ACI, August, Marshall, and Osborne-Mendel rats, trichloroethylene administration caused renal tubular cytomegaly and toxic nephropathy in both sexes of the four strains. However, these are considered to be inadequate studies of carcinogenic activity because of chemically induced toxicity, reduced survival, and deficiencies in the conduct of these studies. Despite these limitations, tubular cell neoplasms of the kidney were observed in rats exposed to trichloroethylene and interstitial cell neoplasms of the testis were observed in Marshall rats exposed to trichloroethylene. /Trichloroethylene stabilized with 8 ppm diisopropylamine/ [R159] *Carcinogenesis studies of epichlorohydrin-free trichloroethylene (TCE) was conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Dosage levels were 500 and 1,000 mg/kg for rats and 1,000 mg/kg for mice. Trichloroethylene was administered five times per week for 103 weeks, and surviving animals were killed between weeks 103 and 107. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Groups of 50 male and 50 female rats were used as untreated controls. Epichlorohydrin-free trichloroethylene caused renal tubular-cell neoplasms in male F344/N rats, produced toxic nephrosis in both sexes, and shortened the survival time of males. This experiment in male F344/N rats was considered to be inadequate to evaluate the presence or absence of a carcinogenic response to trichloroethylene. For female F344/N rats receiving trichloroethylene, containing no epichlorohydrin, there was no evidence of carcinogenicity. Trichloroethylene (without epichlorohydrin) was carcinogenic for B6C3F1 mice, causing increased incidences of hepatocellular carcinomas in males and females and of hepatocellular adenomas in females. [R160] +Trichloroethylene (TCE), a common industrial solvent and dry cleaning agent, was tested for its effects on reproduction and fertility in Fisher 344 rats using the RACB protocol. TCE was microencapsulated in a gelatin/sorbitol shell, and added to the diet. Data from a 2 wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation study at 0.15, 0.30, and 0.60% w/w. Based on the results of the analysis of feed formulations and measures of feed consumption, the daily TCE dosages were nearly equal to 76, 156, and 289 mg/kg/day. In the F0 animals, there were no clinical signs of toxicity, and no animals died during the Task 2 phase. Dam postpartum body weights were reduced at all dose levels during Task 2: from 4-6% at the low dose to nearly equal to 8% at the high dose. There was a monotonic trend to fewer litters/pair (from 3.5 in controls to 2.9 in the high dose group), and the middle and high dose groups had 9% and 16% fewer pups/litter than the controls. Pup weight and viability were unchanged at any dose level. The last litter was reared by the dam. During this 21 day nursing period, viability was not affected by TCE exposure, but body weights were depressed for pups from all treated groups. The decr was not dose-related, and ranged from 9%-20% compared to controls. At 21 and 45 days post-partum, the F1 rats from all groups were tested for behavioral alterations in an open-field test. At 21 days there were no differences across groups, while at 45 days, mice at the high dose crossed the field fewer times, each trip was quicker than controls, and there were fewer rearing episodes, and more time spent grooming. The changes in fertility and pup number seen in Task 2 prompted the conduct of a Task 3 crossover to determine the affected sex using the control and top dose groups. While 100% of the control x control pairs mated, only 75% of the groups containing a treated animal did. There were no differences across groups in terms of the number of pups/litter, or the viability or weight of those pups. An affected sex could not be determined for this compound. After the delivery and assessment of the Task 3 litters, the control and high dose F0 adults were killed and necropsied. The body weight of high-dose treated males was reduced by nearly equal to 4%, while relative liver weight and kidney weight was increased by nearly equal to 24% and 12%, respectively, compared to controls. There were no changes in sperm indices. For females, body weight was reduced by nearly equal to 10%, while relative liver weight was increased by nearly equal to 19% and kidney weight was increased by nearly equal to 7%. The fertility of the second generation was evaluated for all dose groups. There was no treatment-related effect on the proportion of pairs mating or delivering litters, nor were there any differences between the groups in terms of number of pups/litter, or pup viability or weight. After delivery and evaluation of the F2 pups, the F1 adults were killed and necropsied. Male body weights were reduced by 5%, 7%, and 9% (low to high dose groups, respectively). Absolute testis weight was also reduced, by 6-8% in all dosed groups. Adjusted liver weights were increased by 6%, 9%, and 16%, respectively. Seminal vesicle weight was increased by nearly equal to 18% at the middle dose only. Treated female body weights were reduced by 4%, 3%, and 11%, respectively, from low to high dose groups, while adjusted liver weight was increased by 10% at both the middle and high dose levels. Abnormal sperm forms were more numerous at the low dose, approx doubled from 0.54% to 1.13%. No other sperm changes were noted. No vaginal cyclicity data were collected. In sum, these data indicate that TCE produced some general toxicity (reduced body weight gain, increased relative liver and kidney weights) at all doses, while reducing reproductive indices only in the F1 rats at the middle and high dose levels. Thus, TCE was not found to be a selective reproductive toxicant in rats. [R161] +Trichloroethylene (TCE), a common industrial solvent and dry cleaning agent, was tested for its effects on reproduction and fertility in Swiss CD-1 mice using the RACB protocol. TCE was microencapsulated in a gelatin/sorbitol shell, and added to the diet. Data from a 2 wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation study at 0.15, 0.30, and 0.60% w/w. Based on the results of the analysis of feed formulations and an avg daily feed consumption of nearly equal to 5.0g, the daily TCE dosages were nearly equal to 100, 300, and 700 mg/kg/day. TCE exposure was associated with no adverse clinical signs, and post-partum dam weights during the Task 2 cohabitation phase were not reduced by TCE. The only adverse reproductive change noted during Task 2 was a 4% reduction in pup weight adjusted for litter size at the high dose. The last litter from the control and high dose groups was reared to weaning, for subsequent evaluation of second generation fertility. Maternal TCE exposure during lactation was associated with a significant incr in perinatal mortality: the 28% mortality rate in control litters is significantly less than the 61% mortality rats in the high dose TCE group. After weaning, mortality rates were comparable between the two groups. After the F1 pups were weaned, the F0 control and high dose mice were killed and necropsied. Male body weight was not changed, while absolute testis weight was reduced by 4%, adjusted liver weight was increased by nearly equal to 34%, and adjusted prostate weight was reduced by nearly equal to 16%. Sperm motility was reduced by nearly equal to 45% in the high dose TCE treated animals; no other sperm or reproductive changes were noted. In females, body weight was unchanged while adjusted liver weight was increased by nearly equal to 30%. No histologically-visible changes in vaginal epithelium were noted. Treated mice had a greater incidence of centrilobular hypertrophy, and renal tubular degeneration and corticomedullary epithelial karyomegaly. Males were generally more affected than females. The second generation mice from the control and high dose groups were cohabited at nearly equal to /postnatal day/ 74. No reproductive endpoint was altered by TCE exposure. After evaluation of the F2 pups, the F1 adults were killed and necropsied. Male body weight was unchanged, but adjusted liver weight was increased by nearly equal to 60%, adjusted kidney weight was increased by nearly equal to 9%, and adjusted epididymis weight increased by nearly equal to 9%. The % motile sperm was reduced by nearly equal to 20%, while the proportion of abnormal sperm was increased from a control value of 8%, to 10% in the treated mice. TCE-treated female body weights were not different from controls, while adjusted liver weight and kidney weight were increased by nearly equal to 30% and 16%, respectively. Hepatic and renal microscopic lesions were similar to those noted for the F0 mice. Histologic evaluation of the vaginal epithelium indicated cycling in both groups, but cycles were not assessed in vivo. In summary, TCE exposure to mice via the diet produced significant hepatic and renal toxicity (increased weights and microscopic lesions), reduced sperm motility in both generations, and produced greater lactational mortality in the high dose group. These data suggest that the hepatic/renal/lactational toxicities were more severe than the relatively moderate reductions in sperm motility. [R162] +... The purpose of this time course study was to determine the potential effects of trichloroethylene to induce autoimmunity in the Brown Norway Rat model and to determine the time of maximum effect. The studies were conducted in female Brown Norway Rat. The animals were administered trichloroethylene (500 mg/kg) five days a week for an 8-week period by oral gavage. Trichloroethylene was prepared weekly in a 10% Alkamus-deionized water solution. Additional groups of vehicle- and trichloroethylene-exposed animals also received mercuric chloride (1 mg/kg) three times per week by subcutaneous injection for 2 additional weeks. Various parameters of autoimmunity were evaluated weekly, at the time of sacrifice following trichloroethylene treatment, and at time of sacrifice following challenge with mercuric chloride. ... The results of the time course study demonstrate that female Brown Norway rats have a strong aversion to being exposed to trichloroethylene by oral gavage. Furthermore, during the study 3 deaths directly related to chemical exposure were observed in the trichloroethylene exposure group which consisted of 15 animals. Animals exposed to trichloroethylene had decreased body weights compared to the vehicle control animals during the first two weeks of the study and a decrease in body weight gain over the course of the study period. While no effect was observed on spleen, lungs, thymus or adrenal weights, increases were observed in relative kidney (8%) and liver (14%) weights compared to the vehicle controls. When parameters indicative of autoimmune responses were evaluated, no effect was observed on serum IgE levels evaluated weekly, at the time of sacrifice or following challenge with mercuric chloride. No effect was observed on total serum IgG levels at the time of sacrifice; however, a decreased total IgG response was observed in the trichloroethylene-exposed animals following challenge with mercuric chloride. No effect was observed on serum IgG antibody titers to dinitrophenol-human serum albumin (DNP-HSA) evaluated weekly or at the time of sacrifice. Decreased serum IgG antibody titers to DNP-HSA response were observed in the trichloroethylene-exposed animals following challenge with mercuric chloride. While no effect was observed on serum IgG antibody titers to sheep erythrocytes at the time of sacrifice, a decrease in serum IgG antibody titers to sheep erythrocytes was observed in the trichloroethylene-exposed animals following challenge with mercuric chloride. When parameters related to autoimmune disease were evaluated, no effects were observed in blood urea nitrogen (BUN) levels at the time of sacrifice or following challenge with mercuric chloride. No effect was observed on urinalysis parameters which included glucose, protein, pH, and blood in the urine as measured using Hema-Combistix. No effect was observed on serum IgG antibody titers to laminin evaluated weekly or at the time of sacrifice. A decrease in serum IgG antibody titers to laminin was observed in the trichloroethylene-exposed animals following challenge with mercuric chloride; however, the decrease did not reach the level of statistical significance. No effects were observed in serum IgG antibody titers to double stranded DNA (dsDNA) at the time of sacrifice or following challenge with mercuric chloride. In conclusion, this time course study demonstrates that exposure to trichloroethylene at a dose level of 500 mg/kg for eight weeks results in significant changes in parameters of autoimmunity and that the time of maximum effect on IgG responses occurred 6 weeks after initiation of trichloroethylene exposure. Although no effects were observed on IgE responses, significant changes were observed in IgG antibody-mediated parameters following mercuric chloride challenge. Trichloroethylene, at a dose level of 500 mg/kg, produced no significant effect on any of the indicators of autoimmune disease. Due to the exposure-related loss of animals at the 500 mg/kg dose level, future studies using the Brown Norway rat should be conducted at lower doses. [R163] +... Trichloroethylene ... had previously been shown to suppress immune function. Trichloroethylene was selected for study with the intent of performing an interaction study with ethanol with the immune system being the target system. Previous studies were performed by the investigators showing that trichloroethylene, administered in the drinking water to CD-mice for 120 days, suppressed selected parameters of the immune system. The purpose of this range-finding study was to select doses for use in the interaction study. In order for the study to be performed within the confines of an interaction study, the period of exposure was set at 14 days and higher doses than were previously reported were used. The route of administration was by gavage. Corn oil was selected as the vehicle ... . Toxicological parameters assessed were body weight, selected organ weights and selected hematological indicators. The two immunological assays used to assess immune status were the IgM spleen antibody-forming cell (AFC) response to sheep erythrocytes (sRBC) and the cytotoxic T lymphocyte (CTL) response. Tricloroethylene, in doses between and including 50 and 800 mg/kg administered for 14 days, did not alter body weight or body weight gain or change the hematological parameters examined. Trichlorethylene, in doses including and between 100 and 800 mg/kg, caused a dose-related increase in liver weight but no changes in kidney, spleen or thymus weight. Tricloroethylene, in doses between and including 50 and 800 mg/kg administered for 14 days, did not affect the spleen IgM antibody-forming cell response to sheep erythrocytes. Trichlorethylene, in doses including and between 100 and 800 mg/kg, did not affect the cytotoxic T lymphocyte response. ... [R164] TCAT: ?The ability of trichloroethylene to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary toxicity determinations (exposure time=1 day), trichloroethylene was tested at 0, 4, 20, 100 and 250 ug/ml, with cell survival ranging from 125% to 96% relative to untreated controls. The test compound did not produce significantly greater transformation frequencies than untreated controls. [R165] ?The effects of trichloroethylene were examined in the mouse hepatocyte primary culture DNA repair assay. Based on preliminary toxicity tests, trichloroethylene was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4), 1x10(-5) and 1x10(-6)% in DMSO solvent vehicle. The highest two concentrations were too cytotoxic to evaluate in the assay. The lower levels were not cytotoxic but the 0.01 and 0.001% levels caused a significant increase in the unscheduled DNA synthesis over the solvent control (DMSO). [R166] ?The effects of trichloroethylene were examined in the rat hepatocyte primary culture DNA repair assay. Based on preliminary toxicity tests, trichloroethylene was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4) and 1x10(-5)% in DMSO solvent vehicle. The higher two levels were too cytotoxic to be evaluated in the assay. The concentrations at 0.01% or lower were not cytotoxic and did not cause a significant increase in the unscheduled DNA synthesis over the solvent control. [R166] ?The mutagenicity of trichloroethane was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Trichloroethylene caused a positive response in strains TA100 and TA1535, both with and without added metabolic activation. Trichloroethylene did not cause a positive response in strains TA98 or TA1537 in any of the test. Trichloroethylene was evaluated using a protocol in which the test article was usually tested over a minimum of 6 dose levels, the highest nontoxic dose level being 10 mg/plate unless solubility, mutagenicity or toxicity dictated a lower limit. [R167] ?The pharmacokinetics of 1,1,2-trichloroethylene (TRI) was evaluated in male B6C3F1 mice (4/exposure) and male Osborne-Mendel rats (4/exposure) receiving nominal concentrations of 14C-TRI at 10ppm or 600ppm for 6 hours in a dynamic airflow chamber. Mice and rats were placed in Roth-type metabolism cages for collection of feces, urine and expired air for 50 hours post exposure. Within 50 hours, 98-99% of the total radioactivity observed in all exposed male mice was metabolized. The primary route of elimination (approximately, 75% of total body burden) for all mice was via the urine. Approximately 9% of 14C-TRI body burden in mice was biotransformed to the 14C-carbon dioxide. No indication of saturation of 14C-TRI metabolites in the high dose mice was observed. In contrast, rats metabolism of 14C-TRI appeared to show characteristics of saturation at the high dose level. Total metabolism of 14C-TRI in rats at the high dose level (79% of absorbed dose) was decreased relative to the low dose rats (98% of the absorbed dose). Also, exhalation of 14C-TRI increased 10-fold with increased exposure in rats. The primary route of elimination of 14C-TRI in the rat was via the urine which accounted for approximately 62% and 55% of the 14C-TRI body burden in low and high doses, respectively. Mice metabolized 2.2 fold and 3.6 fold more TRI on a per kg body weight basis than rats at 10ppm and 600ppm, respectively. [R168] ?The ability of 1,1,2-trichloroethylene to alkylate hepatic DNA was evaluated in four male B6C3F1 mice receiving a carcinogenic dose (1200mg/kg) of 14C-TRI orally by gavage. Mice were sacrificed 5 hours post exposure, and liver were excised. 1,1,2-Trichloroethylene alkylated hepatic DNA in mice to a very small degree, with the maximum estimate average DNA alkylation of 0.62 (+/-0.42) alkylations/10(6) nucleotides for three mice and no 14C-associated bases were detected in the fourth mouse. [R169] ?The ability of trichloroethylene (TCE) to cause unscheduled DNA synthesis was evaluated in 3 sets of male B6C3F1 mice (10-12/group) exposed by gavage using 3 regimes: Set 1, 0 or 2400 mg/kg/day for 3 days; Set 2, 0 or 2400 mg/kg/day for 5 days/week for 3 weeks; and Set 3, 0 , 250, 500, 1200 or 2400 mg/kg/day for 5 days/week for 3 weeks. Mice were injected subcutaneously with radiolabelled thymidine, Set 1 daily, and Sets 2 and 3 on the last 5 and 4 days of TCE treatment, respectively. The animals were sacrificed upon termination of treatment and the kidneys (Set 1 only) and livers examined. There were statistically significant differences noted between treated and control mice in the following: Sets 1 and 2 (p < 0.01, Dunnett's or Student's t-test), increased liver/body weight ratio and hepatic DNA synthesis, and decreased ug DNA/g tissue; Set 3, dose-related increase in liver/body weight ratio (500 mg/kg/day and above, p < 0.01), and a dose-related decrease in hepatic DNA synthesis (500 mg/kg/day and above, p < 0.01). No significant differences were observed between the kidneys of treated and control mice of Set 2. Histopathological changes in hepatic tissue were observed in all treated animals (dose-related in Set 3 animals). Five mice treated with 1200 mg radiolabelled TCE/kg by gavage and sacrificed 3 hrs later indicated that TCE alkylated hepatic DNA only to a small degree. [R170] ?The ability of trichloroethylene (TCE) to cause unscheduled DNA synthesis was evaluated in 2 sets of male Osborne-Mendel rats (4/group) exposed by gavage using 2 regimes: Set 1, 0 or 1100 mg/kg/day for 3 days, and Set 2, 0 or 1100 mg/kg/day for 5 days/week for 3 weeks. The rats were injected subcutaneously with radiolabelled thymidine, Set 1 daily, and Set 2 on the last 5 days of TCE treatment. The animals were sacrificed upon termination of treatment and the kidneys (Set 1 only) and livers examined. There were statistically significant differences noted between treated and control rats in the following: Set 2 (p < 0.01, Dunnett's or Student's t-test), increased liver/body weight ratio and hepatic DNA synthesis. No significant differences were observed between the kidneys of treated and control rats of Set 2 or the livers of treated and control rats of Set 1. No significant histopathological changes in hepatic tissue were observed in any of the groups of animals. [R170] ?The macromolecular binding of 1,1,2-trichloroethylene (TRI) was evaluated in male B6C3F1 mice (12/exposure) and male Osborne-Mendel rats (12/exposure) receiving nominal concentrations of 14C-TRI at 10ppm or 600ppm for 6 hours in a dynamic air flow chamber. Four rats and four mice were sacrificed at 0, 6 and 24 hours post exposure, and liver and kidneys were excised. Additional mice and rats were sacrificed at 50 hour post exposure from a previous study under the same conditions. The mice had greater binding of radiolabel from TRI than the rat after exposure to 10 or 600ppm of 14C-TRI. Macromolecular binding as measured by pmole Eq C14-TRI per ug protein was three to four times greater in both hepatic and renal tissue in mice following 600ppm exposure than rats. Only a modest increase was observed in hepatic tissue of the mouse following 10ppm exposure relative to the rat. Maximum binding in the liver for both species was observed immediately following exposure (3 hours for the kidneys) and decreased steadily over the next 48 hours. [R168] ADE: *... It can penetrate intact human skin. [R60] *PLACENTAL TRANSMISSION DATA: TIME TO APPEAR IN FETUS--2 MIN; TIME TO FETAL/MATERNAL CONCN EQUILIBRIUM--6 MIN; FETAL/MATERNAL CONCENTRATION RATIO--1.0 /FROM TABLE/ [R171] *... A DAILY EXPOSURE LEVEL OF APPROXIMATELY 100 PPM, ONLY ONE-THIRD OF THE RETAINED TRICHLOROETHYLENE (CALCULATED) IS EXCRETED AS METABOLITES IN THE URINE DURING THE WORK DAY. [R139] *BINDING OF TCE TO LIVER MICROSOMAL PROTEINS OF MALE B6C3 HYBRID MICE WAS 46% HIGHER THAN /BINDING OF/ (14)C-TCE TO MICROSOMAL PROTEINS FROM MALE OSBORNE-MENDEL RATS. [R172] *10 VOLUNTEER STUDENTS WERE EXPOSED TO 250-380 PPM OF TRICHLOROETHYLENE FOR 160 MIN. RETENTION AMOUNTED TO 36%. 16% OF THE RETAINED AMT WAS ELIMINATED THROUGH RESPIRATION AFTER EXPOSURE. TRICHLOROACETIC ACID EXCRETION IN FEMALES WAS 2-3 TIMES MORE THAN THAT IN MALES FOR THE 1ST 24 HR AFTER EXPOSURE. TWICE AS MUCH TRICHLOROETHANOL WAS EXCRETED IN MALES THAN IN FEMALES FOR THE 1ST 12 HR. THESE FINDINGS SUGGEST A SEX DIFFERENCE IN HUMAN METABOLISM OF TRICHLOROETHYLENE. [R173] *The blood concn of trichloroethylene during inhalation and elimination /in humans/ closely parallels alveolar gas concn. Trichloroethylene most rapidly attains equilibrium by passive diffusion into the vessel rich group of tissues (VRG) (brain, heart, kidneys, liver, endocrine and digestive systems), more slowly with lean mass (MG) (muscle and skin) and lastly with adipose tissue (FG). As determined from elimination kinetics following exposure, trichloroethylene distributes from blood into these 3 major compartments at approx rate constants of VRG: 17 hr(-1) (half-life, 2.4 min), MG: 1.7 hr(-1) (t/2, 25 min) and FG: 0.2 hr(-1) (half-life, 3.5 hr). While MG is 50% of the body vol versus 20% for FG, saturation and desaturation proceeds more rapidly from the MG compartment than the FG compartment because of the considerably greater solubility of trichloroethylene in lipids. Thus, variations in trichloroethylene uptake between individuals is influenced first by lean body mass and second by adipose tissue mass. [R174] *Careful balance studies using GC methodology show, that after single or repeated daily exposures to trichloroethylene concentrations between 50 and 380 ppm, an average of 11% of /absorbed/ trichloroethylene is eliminated unchanged by the lung (half-life= 5 hr), 2% of the dose is eliminated as trichloroethanol by the lung (half-life 10 to 12 hr) and 58% is eliminated as urinary metabolites. The remaining 30% of the dose has been postulated to be metabolized by additional pathways or routes of elimination of one or more unknown metabolites. [R175] *The ratio between trichloroethylene exposure and urinary trichloroacetic acid excretion appears to decrease with age. [R176] *Pure trichloroethylene is absorbed through mouse abdominal skin at a rate of 55 nmol/sq cm/min. [R177] *When (14)C-trichloroethylene was administered by im injection at a dose of 50 mg/kg, the radioactivity excreted in the urine and feces ranged from 40-60% of the dose in chimpanzees, 11-28% in baboons, and 7-40% in rhesus monkeys. [R178] *When 18 mg/kg of trichloroethylene in 5 ml of water or corn oil was intragastrically administered to fasting rats (400 g), the peak blood concn (5.6 minutes for aqueous solution) averaged 15 times higher for water than for corn oil solution (14.7 vs < 1.0 ug/ml). The peak blood concn was reached faster for water than for oil solution, which exhibited a second delayed peak 80 minutes post-absorption. [R179] *In humans, the blood/air partition coefficient ranges from 9 to 15. Daily body uptake has been estimated to be approximately 6 mg/kg body weight, for an exposure of 4 hr at 378 mg/cu m and /is not influenced/ by the quantity of adipose tissue. [R180] *Trichloroethylene retention varies according to physical activity. Under laboratory conditions, human volunteers at rest exposed to concentrations of 540 or 1080 mg/cu m for 30 minutes, 50% of the quantity inhaled was retained. The percentage retained decreased from 50% to 25% when activity rose from rest to a 150 watt workload, but, because of increased ventilation, the absolute amount absorbed still increased. [R181] *Trichlororethylene is expired from the lungs for 2 days after exposure, and traces may be present on the 3rd day. About 8% of the retained material is excreted as metabolites in the feces, but most is excreted in the urine. /It was/ found that an average of 73% of the trichloroethylene retained by men and women after inhalation could be recovered in the urine as follows: monochloroacetic acid, 4%; trichloroacetic acid, 19%; and trichloroethanol, 50%. In humans, excretion of the metabolites of trichloroethylene is fastest for monochloroacetic acid, intermediate for trichloroethanol, and slowest for trichloroacetic acid. Following the use of trichloroethylene as an anesthetic, trichloroacetic acid may be detected in the urine for 5-12 days. Following accidental ingestion of trichloroethylene, trichloroacetic acid was found in the serum and urine for 27 days. [R182] *Trichloroethylene and its metabolites appear to cross the placenta readily in many species. In mice, inhalation of trichloroethylene resulted in accumulation of its metabolite, trichloroacetic acid, in amniotic fluid. [R183] *A physiologically based pharmacokinetic (PBPK) model was developed that provides a comprehensive description of the kinetics of trichloroethylene (TCE) and its metabolites, trichloroethanol (TCOH), trichloroacetic acid (TCA), and dichloroacetic acid (DCA), in the mouse, rat, and human for both oral and inhalation exposure. The model includes descriptions of the three principal target tissues for cancer identified in animal bioassays: liver, lung, and kidney. Cancer dose metrics provided in the model include the area under the concn curve (AUC) for TCA AND DCA in the plasma, the peak concn and AUC for chloral in the tracheobronchial region of the lung, and the production of a thioacetylating intermediate from dichlorovinylcysteine in the kidney. Addtl dose metrics provided for noncancer risk assessment include the peak concns and AUCs for TCE AND TCOH in the blood, as well as the total metab of TCE divided by the body weight. Sensitivity and uncertainty analyses were performed on the model to evaluate its suitability for use in a pharmacokinetic risk assessment for TCE. Model predictions of TCE, TCA, DCA, AND TCOH concns in rodents and humans are in good agreement with a variety of experimental data, suggesting that the model should provide a useful basis for evaluating cross-species differences in pharmacokinetics for these chemicals. In the case of the lung and kidney target tissues, however, only limited data are available for establishing cross-species pharmacokinetics. As a result, PBPK model calculations of target tissue dose for lung and kidney should be used with caution. [R184] *Trichloroethylene (TCE) pharmacokinetics have been studied in experimental animals and humans for over 30 yr. Compartmental and physiologically based pharmacokinetic (PBPK) models have been developed for the uptake, distribution, and metab of TCE and the production, distribution, metab, and elimination of P450-mediated metabolites of TCE. TCE is readily taken up into systemic circulation by oral and inhalation routes of exposure and is rapidly metabolized by the hepatic P450 system and to a much lesser degree, by direct conjugation with glutathione. Recent PBPK models for TCE and its metabolites have focused on the major metabolic pathway for metab of TCE (P450-mediated metabolic pathway). This article briefly reviews selected published compartmental and PBPK models for TCE. Trichloroacetic acid (TCA) is considered a principal metabolite responsible for TCE-induced live r cancer in mice. Liver cancer in mice was considered a critical effect by the U.S. EPA for deriving the current maximum contaminant level for TCE in water. In the literature both whole blood and plasma measurements of TCA are reported in mice and humans. To reduce confusion about disparately measured and model-predicted levels of TCA in plasma and whole blood, model-predicted outcomes are compared for first-generation (plasma) and second-generation (whole blood) PBPK models published by Fisher and colleagues. Qualitatively, animals and humans metabolize TCE in a similar fashion, producing the same metabolites. Quantitatively, PBPK models for TCE and its metabolites are important tools for providing dosimetry comparisons between experimental animals and humans. TCE PBPK models can be used today to aid in crafting scientifically sound public health decisions for TCE. [R185] *Trichloroethylene (TCE) ... is oxidized by high-affinity, low-capacity cytochrome P450 isozymes and subsequently converted to metabolites, some of which are carcinogenic in mice and rats. Although the initial oxidation step is known to be rate-limiting and saturable, the oral dosage-range over which saturation materializes is unclear. One objective of this study was to characterize the dose-dependency of GI absorption of TCE and its kinetics over a wide range of oral bolus doses. A related objective was to investigate cause(s) of the apparent saturation kinetics observed. ... /TCE was/ given in doses of 2 to 1200 mg/kg bw via the stomach tube. ... The rate of GI absorption of TCE diminished as the dosage increased. Pharmacokinetic analysis indicated that TCE was eliminated by capacity-limited hepatic metab, with incursion into nonlinear kinetics with bolus doses :8 to 16 mg/kg. Effects of p-nitrophenol, a competitive metabolic inhibitor, were manifest at a high, but not at a low TCE dose. Gavage bolus doses as high as 1200 mg/kg did not cause rapid elevation of serum enzyme levels, typical of the solvation of hepatocellular membranes observed after portal vein admin of TCE ... . No evidence of cytochrome P4502E1 (CYP2E1) destruction was seen with oral doses up to 1000 mg/kg. Instead, CYP2E1 activity was induced as early as 1 h postdosing. Induction was maximal at 12 hr, then returned toward controls during the next 12 h. Pretreatment with cycloheximide did not reduce CYP2E1 activity in rats given 432 or 1000 mg TCE/kg, suggesting that binding of TCE to CYP2E1 may stabilize the isozyme. Metabolic saturation, in concert with relatively slow GI absorption, are responsible for the prolonged elevation of blood TCE levels in rats given high TCE doses, while suicidal inactivation of CYP2E1 and hepatocellular injury apparently play little role. [R186] *... To assess the dermal bioavailability of trichloroethylene (TCE), exhaled breath was monitored ... using an ion trap mass spectrometer (MS/MS) to track the uptake and elimination of TCE from dermal exposures in rats and humans. A physiologically based pharmacokinetic (PBPK) model was used to estimate total bioavailability. Male F344 rats were exposed to TCE in water or soil under occluded or nonoccluded conditions by applying a patch to a clipper-shaved area of the back. Rats were placed in off-gassing chambers and chamber air TCE concn was quantified for 3-5 h post-dosing using the MS/MS. Human volunteers were exposed either by whole-hand immersion or by attaching patches containing TCE in soil or water on each forearm. Volunteers were provided breathing air via a face mask to eliminate inhalation exposure, and exhaled breath was analyzed using the MS/MS. The total TCE absorbed and the dermal permeability coefficient (KP) were estimated for each individual by optimization of the PBPK model to the exhaled breath data and the changing media and/or dermal patch concns. Rat skin was significantly more permeable than human skin. Estimates for KP in a water matrix were 0.31 : 0.01 cm/h and 0.015 : 0.003 cm/hr in rats and humans, respectively. KP estimates were more than three times higher from water than soil matrices in both species. KP values calculated using the standard Fick's Law equation were strongly affected by exposure length and volatilization of TCE. In comparison, KP values estimated using noninvasive real-time breath analysis coupled with the PBPK model were consistent, regardless of volatilization, exposure concentration, or duration. [R187] *In lifetime bioassays, trichloroethylene (TCE, CAS No. 79-01-6) causes liver tumors in mice following gavage, liver and lung tumors in mice following inhalation, and kidney tumors in rats following gavage or inhalation. Recently developed pharmacokinetic models provide estimates of internal, target-organ doses of the TCE metabolites thought responsible for these tumor responses. Dose-response analyses following recently proposed methods for carcinogen risk assessment from the U.S. EPA are conducted on the animal tumor data using the pharmacokinetic dosimeters to derive a series of alternative projections of the potential carcinogenic potency of TCE in humans exposed to low environmental concns. Although mechanistic considerations suggest action of possibly nonlinear processes, dose-response shapes in the observable range of tumor incidence evince little sign of such patterns. Results depend on which of several alternative pharmacokinetic analyses are used to define target-organ doses. Human potency projections under the U.S. EPA linear method based on mouse liver tumors and internal dosimetry equal or somewhat exceed calculations based on admin dose, and projections based on mouse liver tumors exceed those from mouse lung or rat kidney tumors. Estimates of the carcinogenic potency of the two primary oxidative metabolites of TCE--trichloroacetic acid and dichloroacetic acid, which are mouse liver carcinogens in their own right--are also made, but it is not clear whether the carcinogenic potency of TCE can be quantitatively ascribed to metabolic generation of these metabolites. [R188] *Regulatory agencies are challenged to conduct risk assessments on chemical mixtures without full information on toxicological interactions that may occur at real-world, low-dose exposure levels. The present study was undertaken to investigate the pharmacokinetic impact of low-dose coexposures to toluene and trichloroethylene in vivo in male F344 rats using a real-time breath analysis system coupled with physiologically based pharmacokinetic (PBPK) modeling. Rats were exposed to compounds alone or as a binary mixture, at low (5 to 25 mg/kg) or high (240 to 800 mg/kg) dose levels. Exhaled breath from the exposed animals was monitored for the parent cmpds and a PBPK model was used to analyze the data. At low doses, exhaled breath kinetics from the binary mixture exposure compared with those obtained during single exposures, thus indicating that no metabolic interaction occurred with the se low doses. In contract, at higher doses the binary PBPK model simulating independent metab was found to under predict the exhaled breath concn, suggesting an inhibition of metab. Therefore the binary mixture PBPK model was used to compare the measured exhaled breath levels from high- and low-dose exposures with the predicted levels under various metabolic interaction simulations (competitive, noncompetitive, or uncompetitive inhibition). Of these simulations, the optimized competitive metabolic interaction description yielded a Ki value closest to the Km of the inhibitor solvent, indicating that competitive inhibition is the most plausible type of metabolic interaction between these two solvents. [R189] METB: *RATS EXCRETE 5-7 TIMES MORE TRICHLOROETHANOL THAN TRICHLOROACETIC ACID AFTER EXPOSURE TO TRICHLOROETHYLENE. [R190] *EXCRETION OF METABOLITES HAS BEEN STATED TO AMT TO 56% OF TRICHLOROETHYLENE INHALED-7-27% TRICHLOROACETIC ACID, 22.2-22.5% TRICHLOROETHANOL, FREE OR CONJUGATED, 22.5-45.5% UROCHLORALIC ACID AND SMALL AMT ... OF MONOCHLOROACETIC ACID AND CHLOROFORM. ... [R12, 194] *METAB OF TCE PROCEEDED THROUGH FORMATION OF A COMPLEX WITH OXYGENATED CYTOCHROME P450 WHICH, BY REARRANGEMENT, CAN LEAD TO: (A) SUICIDAL HEME DESTRUCTION; (B) FORMATION OF CHLORAL, WHICH COULD BE REDUCED TO TRICHLOROETHANOL AND CONJUGATED TO FORM A GLUCURONIDE OR OXIDIZED TO TRICHLOROACETIC ACID; (C) FORMATION OF TCE OXIDE, WHICH DECOMP TO CO AND GLYOXYLIC ACID; AND (D) METABOLITES WHICH BIND IRREVERSIBLY TO PROTEIN, DNA, AND RNA. [R191] *Hepatic microsomes from rats fed for 3 weeks on an isocaloric diet deficient in carbohydrate (sucrose) had an increased capacity (2-1/2-fold) to metabolize trichloroethylene. [R192] *IN VITRO ADDITION OF TCE TO INCUBATION MIXTURE DECR METAB OF ETHYLMORPHINE AND HEXOBARBITAL BY HEPATIC MICROSOMES IN RATS. INHIBITION OF HEXOBARBITAL METAB WAS COMPETITIVE. REPEATED ADMIN TO RATS DECR MICROSOMAL CYTOCHROME P450; INCR LIVER/BODY WT RATIO, MICROSOMAL PROTEINS, NADPH-CYTOCHROME C REDUCTASE ACTIVITY, ANILINE HYDROXYLASE ACTIVITY. [R193] *The metabolism of TCE in rats involves oxidation by the liver /SRP: post-mitochondrial supernatant/ mixed function oxidase system to an epoxide intermediate, which binds covalantly to proteins and causes centrilobular damage in the liver. ... [R60] *Rats and mice metabolize trichloroethylene in a qualitatively similar fashion; however, the greater rate of metabolism in mice resulted in (a) a 4-fold greater burden of metabolized trichloroethylene per kilogram of body weight (600 ppm/hr and 2000 mg/kg oral dose) and (b) 4- and 7-fold higher blood concentrations of trichloroethanol and trichloroacetic acid in mice versus rats (1000 mg/kg oral dose), respectively. Humans metabolize trichloroethylene to trichloroethanol and trichloroacetic acid, but more slowly than either mice or rats, which is thought to have important implications with respect to the greater sensitivity of the mouse to toxic effects of trichloroethylene. Trichloroethylene is metabolized by the cytochrome p450 mixed-function oxidase system to chloral (trichloroacetaldehyde), which is subsequently oxidized to trichloroacetic acid or reduced to trichloroethanol (free and conjugated). [R17, 691] *Trichloroethylene is converted to trichloroethanol, free and conjugated with glucuronic acid. The initial conversion of the solvent is to chloral hydrate. Trichloroacetic and the monochloroacetic acid and trichloroethanol are found in the urine. Urinary metabolites can be used for assessment of exposure. [R102] *The toxicity and metab of trichloroethylene (TRI) were studied in renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. TRI was slightly toxic to both PT and DT cells, and inhibition of cytochrome P450 (P450; substrate, reduced-flavoprotein:oxygen oxidoreductase (RH-hydroxylating or -epoxidizing); EC 1.14.14.1) increased TRI toxicity only in DT cells. In untreated cells, glutathione (GSH) conjugation of TRI to form S-(1,2-dichlorovinyl)glutathione (DCVG) was detected only in PT cells. Inhibition of P450 transiently increased DCVG formation in PT cells and resulted in detection of DCVG formation in DT cells. Formation of DCVG in PT cells was described by a two-component model (apparent Vmax values of 0.65 and 0.47 nmol/min per mg protein and Km values of 2.91 and 0.46 mM). Cytosol isolated from rat renal cortical, PT, AND DT cells expressed high levels of GSH S-transferase (GST; RX:glutathione R-transferase; EC 2.5.1.18) alpha (GSTalpha) but not GSTpi. Low levels of GSTmu were detected in cortical and DT cells. Purified rat GSTalpha2-2 exhibited markedly higher affinity for TRI than did GSTalpha1-1 or GSTalpha1-2, but each isoform exhibited similar Vmax values. Triethyltinbromide (TETB) (9 muM) inhibited DCVG formation by purified GSTalpha1-1 AND GSTalpha2-2, but not GSTalpha1-2. Bromosulfophthalein (BSP) (4 muM) only inhibited DCVG formation by GSTalpha2-2. TETB AND BSP inhibited approximately 90% of DCVG formation in PT cytosol but had no effect in DT cytosol. This suggests that GSTalpha1-1 is the primary isoform in rat renal PT cells responsible for GSH conjugation of TRI. These data ... describe the metab of TRI by individual GST isoforms and suggest that DCVG feedback inhibits TRI metab by GSTs. [R194] *A major focus in the study of metab and disposition of trichloroethylene (TCE) is to identify metabolites that can be used reliably to assess flux through the various pathways of TCE metab and to identify those metabolites that are causally associated with toxic responses. ... Sex- and species-dependent differences in biotransformation pathways ... can play an important role in the utility of laboratory animal data for understanding the pharmacokinetics and pharmacodynamics of TCE in humans. Sex-, species-, and strain-dependent differences in absorption and distribution of TCE may play some role in explaining differences in metab and susceptibility to toxicity from TCE exposure. The majority of differences in susceptibility, however, are likely due to sex-, species-, and strain-dependent differences in activities of the various enzymes that can metabolize TCE and its subsequent metabolites. An addtl factor that plays a role in human health risk assessment for TCE is the high degree of variability in the activity of certain enzymes. TCE undergoes metab by two major pathways, cytochrome P450 (P450)-dependent oxidation and conjugation with glutathione (GSH). Key P450-derived metabolites of TCE that have been associated with specific target organs, such as the liver and lungs, include chloral hydrate, trichloroacetate, and dichloroacetate. Metabolites derived from the GSH conjugate of TCE, in contrast, have been associated with the kidney as a target organ. Specifically, metab of the cysteine conjugate of TCE by the cysteine conjugate beta-lyase generates a reactive metabolite that is nephrotoxic and may be nephrocarcinogenic. Although the P450 pathway is a higher activity and higher affinity pathway than the GSH conjugation pathway, one should not automatically conclude that the latter pathway is only important at very high doses. [R195] *Metabolites of toluene (hippuric acid) and trichloroethylene (total trichloro cmpds) have been estimated in labotratory rats after microsomal induction by phenobarbital. Phenobarbital pretreatment accelerated the removal of total trichloro cmpds, however, excretion of hippuric acid was moderately diminished. Results on cytochrome P450 suggest that microsomal induction by phenobarbital was higher in trichloroethylene treated rats than toluene treated rats. It is concluded that in addition to distinct substrate specificity of CYP450 isozymes several other factors like Vmax/Km and QH determine the metab of organic solvents. [R196] *A ... study investigated the possible differences in metabolism and pharmacokinetics between mice and rats exposed to trichloroethylene. A comparison of metabolized trichloroethylene on a wt basis indicates that the mouse metabolizes 2.2 times more than the rat at 10 ppm and 3.6 times at 600 ppm. Hepatic macromolecular binding was greater in the mouse than in the rat. The binding data suggest that tumor formation in the mouse exposed to trichloroethylene occurred via a nongenetic mechanism and tumors are not expected if liver injury does not occur. [R92] BHL: *THE BIOL HALF-LIVES OF THE URINARY METABOLITES OF HUMANS OCCUPATIONALLY EXPOSED TO TRICHLOROETHYLENE WAS APPROX 41 HR. [R197] *The half-life of trichloroethylene in exhaled air and in the blood depends on the length of exposure and on the time of sampling after exposure. ... Maximum concn /of trichloroethanol/ in blood and urine /is reached/ almost directly after exposure. ... concn decr with a half-life of about 10-15 hr. ... Concn of trichloroacetic acid in both the blood and urine incr for up to 20-40 hr after /a single/ exposure. ... concn decr with a half-life of about 70-100 hr. [R198] ACTN: *TCE WAS INCUBATED WITH RAT LIVER MICROSOME, NADPH AND RNA (FROM YEAST). THE METABOLITES WERE IRREVERSIBLY BOUND TO MICROSOMAL PROTEINS. HYDROLYSIS OF RNA AND SEPARATION OF NUCLEOSIDES SHOWED DIFFERENT ALKYLATION PRODUCTS ARISING FROM TCE AND VINYL CHLORIDE. ... NEWBORN RATS WERE EXPOSED FOR 10 WEEKS TO 2000 PPM VINYL CHLORIDE OR TRICHLOROETHYLENE (8H/DAY; 5 DAYS/WEEK). AFTER THIS PERIOD LIVERS OF THE ANIMALS WERE STAINED FOR NUCLEOSIDE-5-TRIPHOSPHATASE. WHEREAS THE VINYL CHLORIDE EXPOSED RATS SHOWED FOCAL HEPATOCELLULAR DEFICIENCIES IN THIS ENZYME, WHICH ARE SUPPOSED TO REPRESENT AN EARLY SIGN OF MALIGNANCY, NO SUCH CHANGES WERE INDUCED BY TRICHLOROETHYLENE EXPOSURE. [R199] *BINDING CONSTANTS (KS) FOR INTERACTION WITH RAT LIVER MICROSOMAL P450 FOR ITS METAB TO CHLORAL HYDRATE WERE NOT ALTERED BY INDUCTION WITH PHENOBARBITAL, 3-METHYLCHOLANTHRENE OR SPIRONOLACTONE. TCE APPEARED TO BE ACTIVATED BY CYTOCHROME TO ACTIVELY ALTER HEME MOIETY OF THE CYTOCHROME P450. [R200] INTC: *DISULFIRAM IS SAID TO INHIBIT THE OXIDATION /OF TRICHLOROETHYLENE/ IN MAN TO THE MORE TOXIC TRICHLOROETHANOL (AND THENCE TO TRICHLOROACETIC ACID) ... [R91] *IN VITRO, ADDITION OF TCE DECR METAB OF ETHYLMORPHINE AND HEXOBARBITAL BY RAT HEPATIC MICROSOMES. IN VIVO, TCE INHIBITED HEXOBARBITAL METABOLISM IN RATS. [R193] *BIOCHEM AND TOXICOLOGICAL EFFECTS OF COMBINED EXPOSURE TO 1,1,1-TRICHLOROETHANE (500 PPM) AND TCE (200 PPM) FOR 4 DAYS 6 HR DAILY CAUSED ACCUM OF 1,1,1-TRICHLOROETHANE IN PERIRENAL FAT. FURTHER EXPOSURE ON DAY 5 CAUSED RAPID INCR IN VARIOUS ORGAN CONTENTS OF BOTH SOLVENTS WITH DEPRESSION OF BRAIN RNA. [R201] *Rabbits were given 10 mg/kg doses of caffeine 30 minutes prior to exposure to 6000 ppm (32,280 mg/cu m) of trichloroethylene under dynamic airflow conditions. Epinephrine was infused until arrhythmias occurred after 7.5, 15, 30, 45, and 60 minutes of exposure and 15 and 30 minutes post-exposure. An increase in epinephrine-induced arrhythmias in trichloroethylene-exposed rabbits was observed when the animals were treated with caffeine and challenged with doses of epinephrine as low as 0.5 ug/kg. [R202] *Phenobarbital administration to rats or hamsters in vivo increases the oxidation of trichloroethylene. This results in an incr in the conversion of trichloroethylene to trichloroacetaldehyde. [R203] *Compared to chloral hydrate alone, ingestion of ethanol 30 minutes after chloral hydrate resulted in higher and more prolonged concentrations of plasma trichloroethanol and in lower plasma trichloroacetic acid levels and in urinary trichloroethanol glucuronide. ... [R204] *Disulfiram (1.35 mmol/kg) was administered perorally to rabbits 24 and 6 hr prior to a 1 hr exposure (6000 ppm 32,280 mg/cu m) of trichloroethylene. When challenged with 0.5-3.0 ug/kg epinephrine, disulfiram prevented epinephrine-induced arrhythmias. [R205] *Isopropanol and acetone ... cause enhanced hepatotoxicity with ... trichloroethylene. [R104, 348] *Studies /conducted/ with rats /indicate/ that the effects of trichloroethylene were more pronounced in the animals that were fed a high carbohydrate diet than those on a high protein diet. /Concentration of trichloroethylene not specified/ [R206] *Rats exposed to 37,000, 42,000, and 56,000 mg/cu m of trichloroethylene vapor for two hours exhibited elevated activities of serum glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, and isocitrate dehydrogenase. Hepatotoxicity (indicated by the increased levels of these hepatic enzymes in the serum) was greatly enhanced by pretreatment with 3-methylcholanthrene. [R130] *To elicit the "degreaser's flush," ethanol was administered to seven male volunteers who were repeatedly exposed to trichloroethylene (TCE) vapor. In six exposed subjects, transient vasodilatation of superficial skin vessels occured after the ingestion of small amounts of ethanol (< 0.5 ml/kg body weight). The dermal response reached maximum intensity 30 minutes after its onset and then faded completely within 60 minutes. Two factors appear necessary before the dermal response can be elicited: (1) repeated exposures to TCE and (2) ingestion of alcohol. [R207] *... The induction of the hepatic microsomal mixed-function oxidase system by drugs, taken for therapeutic reasons, or by exposure to certain environmental chemicals (e.g., phenobarbital, toluene, PCBs) can bring about an incr rate of trichloroethylene metabolism. [R208] *Elimination of trichloroacetic acid and trichloroethanol was studied in rats exposed to trichloroethylene alone, or in combination with xylene, at 4.5 mmol/cu m air for five consecutive days. Prior to each inhalation, the rats were pretreated per os with ethyl alcohol at 1366 mg/kg bw or 2732 mg/kg bw. Both xylene and ethanol given separately, dependent on the dose, decreased urine elimination of trichloroacetic acid and trichloroethanol by about 34% (1366 mg/kg) and 45% (2732 mg/kg), respectively. Under conditions of the combined ethanol/xylene exposure, the xenobiotics reduced the elimination of trichloroethylene and trichloroethanol by about 80% and 20% respectively. [R209] *Neonatal male B6C3F1 (CRL, MI) mice were injected ip at 15 days of age with either 2.5 or 10 ug/g body weight ethylnitrosourea (ENU) (26-33/group) or 2 ul/g body weight of 0.1M sodium acetate (32/group) as the solvent control. At 28 days of age, the mice were placed on drinking water containing 3 or 40 mg/l trichloroethylene and they were killed after 61 weeks exposure to trichloroethylene. Controls (22-23/group) were given 0, 2.5, or 10 ug/g body weight ethylnitrosourea + sodium chloride (2 g/l). Trichloroethylene resulted in a significant increase in liver weight (p < 0.001) when given at 40 mg/l to mice pretreated with 2.5 ug/g body weight of ethylnitrosourea. Trichloroethylene alone, however, did not increase the incidence of adenomas or hepatocellular carcinomas above control levels. [R210] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Anesthetics, Inhalation; Solvents [R211] *Trichloroethylene ... is no longer used /as anesthetic agent/. [R212] *MEDICATION (VET): INHALATION ANESTHETIC [R59] *Dental anesthetic. /Former use in USA/ [R50] *INHALATION ANALGESIC. /Former use in USA/ [R59] WARN: *TRICHLOROETHYLENE HAS BEEN REPORTED TO CAUSE CONVULSIONS IN CHILDREN; THEREFORE, IT SHOULD NOT BE USED IN PATIENTS WITH CONVULSIVE DISORDERS. [R26, 986] *Patients exposed to trichloroethylene should be warned of the potential adverse effects of ethanol ingestion. [R213] *Isopropanol and acetone ... cause enhanced hepatotoxicity with ... trichloroethylene. [R104, 348] *...Its anesthetic action is weak. Its low volatility appears in part to be responsible for this effect. ... Apparatus that employs bubbling oxygen assists in accelarating the volatility of the anesthetic to increase its potency. Because of its inherent weakness as an anesthetic, induction of anesthesia is slow. Cardiac arrhythmias produced by the anesthetic are unfavorable. Trichloroethylene cannot be used in a closed circuit with soda lime because of formation of a toxic product. [R105] *Relaxation of abdominal musculature is poor during trichloroethylene anesthesia.This effect is similar to other agents (eg, ketamine, alpha-chloralose) that do not induce Stage III anesthesia. Trichloroethylene is considered unsatisfactory for this type of surgery unless it is used in conjunction with a skeletal muscle relaxant. It has very little if any effect upon uterine function. It readly crosses the placenta to reach the fetal circulation of sheep, goats, and probably other species. [R105] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Trichloroethylene's production and use in degreasing operations as well as in plastics, appliances, jewellery, automobile, plumbing fixtures, textiles, paper, glass and printing industries may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 69 mm Hg at 25 deg C indicates trichloroethylene will exist solely as a vapor in the ambient atmosphere. Vapor-phase trichloroethylene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 7 hours. If released to soil, trichloroethylene is expected to have high mobility based upon an average Koc of 101, measured in 32 soils. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 9.85X10-3 atm-cu m/mole. Trichloroethylene is expected to volatilize from dry soil surfaces based upon its vapor pressure. Cometabolic biodegradation of trichloroethylene has been reported under aerobic conditions where additional nutrients have been added. Under anaerobic conditions, as might be seen in flooded soils, sediments or aquifer environments, trichloroethylene is slowly biodegraded via reductive dechlorination; the extent and rate of degradation is dependent upon the strength of the reducing environment. Trichloroethylene half-lives in the field for aquifer studies range from 35 days to over 6 years. If released into water, trichloroethylene is not expected to adsorb to suspended solids and sediment based on an average Koc value of 101. Volatilization from water surfaces will be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3.5 hours and 5 days, respectively. Volatilization half-lives in an experimental field mesocosm ranged from 10.7 to 28 days. BCF values in fish ranging from 4 to 39 suggest bioconcentration in aquatic organisms is moderate to low. Occupational exposure to trichloroethylene has been shown to occur through inhalation and dermal contact with this compound at workplaces where trichloroethylene is produced or used. Extensive monitoring data indicate that the general population may be exposed to trichloroethylene via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and other consumer products containing trichloroethylene. Trichloroethylene is widely detected in groundwater. (SRC) NATS: *Trichloroethylene is not known to occur as a natural product. [R214] ARTS: *Trichloroethylene's production and use in degreasing operations in five main industrial groups (furniture and fixtures, fabricated metal products, electric and electronic equipment, transport equipment and miscellaneous manufacturing industries)(1) may result in its release to the environment through various waste streams(SRC). It is also used in plastics, appliances, jewellery, automobile, plumbing fixtures, textiles, paper, glass and printing industries(1). Air emissions from metal degreasing plants contain trichloroethylene(2); it has also been reported in wastewater from metal finishing, paint and ink formulation, electrical/electronic components, and rubber processing industries(3). [R215] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an average Koc value of 101, based on measurements in 32 soils(2), indicates that trichloroethylene is expected to have high mobility in soil(SRC). Volatilization of trichloroethylene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 9.85X10-3 atm-cu m/mole(3). The potential for volatilization of trichloroethylene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 69 mm Hg(4). The initial percentage of trichloroethylene in the gas (24, 52, 57%), liquid (5, 3, 4%) and adsorbed (71, 45, 39%) phases was determined in three soils, respectively (Rindge, 11.2% organic matter, 35.4% moisture; Yolo, 2.2% organic matter, 11.7% moisture; Reiff, 1.4% organic matter, 13.9% moisture)(5). Trichloroethylene is resistant to aerobic biodegradation although biodegradation may proceed cometabolically(5,6). Under anaerobic conditions, as might be seen in soil microsites, flooded soils or aquifer sites, trichloroethylene is slowly biodegraded via reductive dechlorination; the extent and rate of degradation is dependent upon the strength of the reducing environment(7). [R216] *AQUATIC FATE: Based on a classification scheme(1), an average Koc value of 101, based on measurements in 32 soils(2), indicates that trichloroethylene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected to be a major fate process for this compound in water(3) based upon a Henry's Law constant of 9.85X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3.5 hours and 5 days, respectively(SRC). Trichloroethylene volatilization half-lives from a mesocosm field experiment in Narragansett Bay ranged from 10.7 to 28 days(5). Trichloroethylene is not degraded under aerobic conditions although cometabolic biodegradation has been reported under conditions where additional nutrients have been added(6-8). Under anaerobic conditions, as might be seen in sediments or groundwater, trichloroethylene is slowly biodegraded via reductive dechlorination; the extent and rate of degradation is dependent upon the strength of the reducing environment(9). According to a classification scheme(10), BCF values ranging from 4.0 in carp(11) to 39 in rainbow trout(12), suggests the potential for bioconcentration in aquatic organisms is low to moderate. [R217] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trichloroethylene, which has a vapor pressure of 69 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase trichloroethylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7 days(SRC), calculated from its rate constant of 2.36X10-12 cu cm/molecule-sec at 25 deg C(3). Phosgene, dichloroacetyl chloride, chloroform and formyl chloride are formed from the reaction of trichloroethylene with hydroxyl radicals(4-6). [R218] BIOD: *AEROBIC: Under aerobic conditions, trichloroethylene is biodegraded only in the presence of another compound that can support microbial growth in a process called cometabolism; biodegradation is generally complete and vinyl chloride is not produced(2). Indigenous sources of carbon associated with soil organic matter did not support cometabolic degradation of trichloroethylene in a soil study(3). Trichloroethylene was aerobically degraded in a column composed of aquifer sediments by 9 and 87% during the first 6.5 months and the following 3.5 months, respectively; the initial loss of 9% may have been due to abiotic losses such as adsorption or volatilization(1). cis-1,2-Dichloroethylene was reported as the major product of trichloroethylene degradation in this experiment(1). Trichloroethylene was mineralized by up to 30% in microcosms containing soil and vegetation from a former trichloroethylene-contaminated site (4). Microcosms which were either non-vegetated or sterile showed mineralization of trichloroethylene, measured as CO2 production, of 10 to 15% and 5 to 10%, respectively(4). [R219] *AEROBIC: In a municipal activated sludge plant, 47.3, 47.8, and 0.0% of the influent trichloroethylene concn (at 40.7 ug/l) was biodegraded, stripped and found in the waste sludge, respectively (effluent concn of 2.0 ug/l)(1). Two laboratory scale activated sludge reactors (AS-L, AS-H) and 2 biological aerated filter reactors (BAF-L, BAF-H) under high- and low-loaded conditions were used to study the removal of trichloroethylene during wastewater treatment(2). The average influent concn was 32.1 ug /l; effluent concns for AS-L, AS-H, BAF-L, and BAF-H were 5.3, 6.1, 2.3, and 9.7 ug/l, respectively(2). Loss due to biodegradation was 0, 0, 58, and 3% influent loadings, respectively, while loss due to stripping was 66, 85, 34, and 67% influent loadings, respectively(2). [R220] *ANAEROBIC: 90% of trichloroethylene initially added to contaminated bed sediments from a freshwater lake and incubated under methanogenic conditions for 60 days was degraded; ethene (46%), methane(9%) and carbon dioxide (12%) were produced during its degradation(1). Biodegradation rates for trichloroethylene in anaerobic groundwater field studies were reported as follows: Dover Air Force Base, DE (half-life of 2.8 years; methanogenic, redox > 50 mV)(2); Vejen Landfill, Denmark (4 in situ microcosms, methanogenic, no biodegradation over 180 days(5), Grindsted Landfill, Denmark (methanogenic/iron- and sulfate-reducing conditions, 924 day monitoring period, half-lives=533-2310 days)(6), Plattsburgh Air Force Base, NY (3 transects, half-lives of 0.56 years, 1.82 years, and no degradation)(7), Tibbetts Road Superfund site, NH (3 transects, half-lives=1.17 to 1.69 years)(8), St. Joseph, MI (half-lives of 1.82, 0.53, 0.745, 0.495 years)(9,10), St. Joseph, MI (half-lives of 113, 124, and 433 days for 3 different transects)(3), Picatinny Arsenal, NJ (half- life of 0.578 years(10); half-life of 2.2 years(11)), Sacramento, CA (half-life of 0.63 years)(10), Necco Park, NY (half-life of 1 year)(10), Plattsburgh Air Force Base, NY (half-lives of 0.53 years, 3.01 years and no biodegradation)(10), San Francisco, CA (half-life of 0.16 years)(10), Cecil Field, FL (half-lives of 0.095 to 0.21 years)(10), Eielson Air Force Base, Alaska (half-life of 3.8 years), and Cape Canaveral Air Station, Florida (half-life of 2.4 years)(12). Trichloroethylene was degraded under methanogenic and sulfate-reducing conditions in a fractured bedrock aquifer to ethene(4). [R221] *Biodegradation rates for trichloroethylene in anaerobic aquifer microcosm studies were reported as follows: Wilder's Grove, NC landfill (methanogenic, lag phase of < 41 to > 300 days; degradation complete within 40 to 110 days once started)(1), Dover Air Force Base, DE(methanogenic, half-lives of 57 and 267 days for 2 locations at site)(2), Picatinny Arsenal, NJ (first-order rate constant of 0.001 to 0.02 per week)(3), Picatinny Arsenal, NJ (half-lives of 1.1, 1.65, and 3.3 years)(6), Picatinny Arsenal, NJ (first-order rate constant of 0.004 to 0.035 per week)(7), Vejen Landfill, Denmark(4 microcosms, methanogenic, no degradation over 140-180 days)(4), Tibbetts Road Superfund site, NH (half-lives of 0.188 years(5), 0.144 years(6)), St. Joseph, MI (half-lives of 0.385 and 0.58 years), and Traverse City, MI (half-life of 0.385 years)(6). In situ microcosm studies were conducted in both polluted aerobic and anaerobic and in unpolluted aerobic aquifer conditions in the Vejen City landfill; trichloroethylene was not degraded under either oxygen condition over a 90-day period(9). Trichloroethylene is reductively dechlorinated forming cis-1,2-dichloroethylene initially, then vinyl chloride and possibly ethene and ethane depending on the strength of the reducing environment(8). Under iron or sulfate-reducing conditions, cis-1,2-dichloroethylene is the major metabolite of trichloroethylene biodegradation while ethene is the major metabolite under methanogenic conditions(10). [R222] *ANAEROBIC: Mass balance analysis of the loss of trichloroethylene from an aquifer beneath Picatinny Arsenal showed that 78, 11, and 11% of the trichloroethylene annually removed was due to biodegradation, advective transport to a local water body, and advection-driven volatilization, respectively(1). [R223] ABIO: *The rate constant for the vapor-phase reaction of trichloroethylene with photochemically-produced hydroxyl radicals has been measured as 2.36X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 7 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Atmospheric residence time based upon reaction with hydroxyl radical is 5 to 6 days(2-4) with the production of phosgene, dichloroacetyl chloride, chloroform and formyl chloride(3,6,7). The rate constant for the vapor-phase reaction of trichloroethylene with nitrate radicals has been measured as 2.93X10-16 cu cm/molecule-sec at 25 deg C(13). This corresponds to an atmospheric half-life of about 114 days at an atmospheric concn of 2.4X10+8 nitrate radicals per cu cm(14). Ozone depletion potential values for trichloroethylene range from 0.083 to 0.13 relative to CFC-11(8). The mean value for the gas scavenging ratio for trichloroethylene is 3.7 at 8 deg C(9). Trichloroethylene is relatively reactive under smog conditions(12) with 60% degradation in 140 min(6) and 50% degradation in 1 to 3.5 hours(11) reported. Trichloroethylene is not hydrolyzed by water under normal conditions(10). Trichloroethylene absorbs light greater than 290 nm weakly; therefore, direct photolysis is not expected to be an important fate prcoess(10). However, slow photooxidation in water has been noted (half-life of l0.7 months)(11). [R224] *Two pilot-scale activated sludge systems (flow rate 35 gpm; hydraulic retention time 7.5 hours; SRT of 4 days) fed municipal wastewater were spiked with 0.25 mg/l trichloroethylene in combination with 46 other compounds; 103% removal of trichloroethylene was obtained through stripping(1). [R225] BIOC: *BCF values of 17 and 39(1) were measured in bluegill sunfish and rainbow trout, respectively. In carp, BCF values of 4.3 to 17 and 4.0 to 16.0 were reported for trichloroethylene at 70 and 7 ug/l, respectively(2). A BCF of 302 was measured in a green alga(4). According to a classification scheme(3), these BCF values suggest the potential for bioconcentration in aquatic organisms is moderate to low. Marine monitoring data suggest only moderate bioconcentration (2-25 times) of trichloroethylene(5,6). [R226] KOC: *Measured Koc values of 100(1), 110(2), 72 to 180 (organic matter of < 1.0 to 5%(3), 66(8), 49 (peat soil)(10), 72, 96, 142(5) and 58 (peat soil)(5). The average Kd value for trichloroethylene, applied with a mixture of organic compounds to low organic, subsurface soils (average foc=0.00017), was 0.093(4). Kp values of 1.06 (coarse sand), 0.67 (silty-clay loam), 0.17 (fine sand), 6.0 (podzolic sand, % organic content=0.90), 4.2 (sandy soil, % organic content=6.07), 32 (peat soil, % organic content=59.3) and 1.24 (Bandelier tuff, % organic content=0.11) have been reported for trichloroethylene(11). A study of 32 soils(foc range of 0.0012 to 0.31) reported an average Koc of 101(5). Koc values for trichloroethylene in a loess sand, weathered shale, and unweathered shale were 123, 363, and 2691, respectively(6). In nine different soils (foc ranging from 0.13 to 1.2%), Koc values ranged from 69 to 209(7). Trichloroethylene from soil samples which had been contaminated for 18 years was found to be resistant to desorption, requiring extended periods of time for equilibration(9). According to a classification scheme(12), these Koc values generally suggest that trichloroethylene is expected to have moderate to high mobility in soil. Trichloroethylene partitioned from an aqueous solution of Bandelier tuff under equilibrium conditions to 64-81% in water, 16-23% in vapor phase, and 2-20% in the tuff(13). [R227] *In a field groundwater test, no sorption of trichloroethylene onto organic carbon or mineral surfaces present in the sand aquifer was observed(1). Two field studies, both of shallow confined aquifers, reported retardation factors from 5 to 9 (foc=0.11%) and 11.4 (foc=0.11%)(2). In undisturbed rock cores from the Coventry sandstone aquifer system (foc=0.7 to 0.8%), trichloroethylene had a retardation factor of less than 3 indicating that it should migrate readily with water(2). Other column studies using sand aquifer material reported retardation factors from 1.1 to 4.7(2). A retardation factor of 1.1 was reported for trichloroethylene in the aquifer underlying the Canadian Forces Base in Borden, Ontario(3). The initial percentage of trichloroethylene in the gas (24, 52, 57%), liquid (5, 3, 4%) and adsorbed (71, 45, 39%) phases was determined in three soils, respectively (Rindge, 11.2% organic matter, 35.4% moisture; Yolo, 2.2% organic matter, 11.7% moisture; Reiff, 1.4% organic matter, 13.9% moisture)(9). Sorption in these soils followed reversible, linear sorption isotherms(9). Sorption of trichloroethylene vapor to soil is possible; linear sorption coefficients of trichloroethylene from the vapor phase were about one to four orders of magnitude greater than those from the aqueous phase based on studies using six different US EPA soils and sediments under varying moisture contents(10). [R228] VWS: *The Henry's Law constant for trichloroethylene is 9.85X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that trichloroethylene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 3.5 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5 days(SRC). Half-lives of evaporation from laboratory water surfaces (distilled water) have been reported to be on the order of several minutes to hours, depending upon the turbulence(4,5). Half-lives of trichloroethylene from an experimental marine ecosystem (MERL) under field conditions and during periods when volatilization appeared to dominate ranged from 10.7 to 28 days; turbulence is expected to be greater in open water resulting in even faster half-lives(6). The potential for volatilization of trichloroethylene from dry soil surfaces exists(SRC) based upon a vapor pressure of 69 mm Hg(3). [R229] *The transport behavior of trichloroethylene vapor in a section of unsaturated sands and silts at a field site in Borden, Ontario was studied(1). Movement of trichloroethylene vapor through unsaturated layers was shown to be lateral based on the density-induced advective flow of the contaminated soil gas(1). Gas-phase diffusion coefficients for trichloroethylene in tuff soils with varying moisture content were measured(2). Under wet conditions (12-15% moisture), diffusion coefficients of 0.0022-0.0067 and 0.0067-0.0070 sq cm/sec were determined for trichloroethylene; under dry conditions (1-3% moisture, diffusion coefficients of 0.0211-0.0230 and 0.0237-0.0292 sq cm/sec were determined(2). Soil diffusion coefficients were measured for trichloroethylene at 3 different soil porosities (0.29 to 0.43); values ranged from 0.254X10-3 to 1.986X10-3 sq cm/sec, with the larger values associated with higher soil porosity levels(4). The total amount of trichloroethylene that volatilizes in 100 days may be reduced from 84.6% volatilized without vapor sorption to 73.2% in a soil with increasing water content with depth, based on a flexible finite element transport model(3). Using the same model, vapor sorption enhanced the rate of volatilization in 100 days for a soil with low water content at depth from 72.4% without vapor sorption to 90.3% with vapor sorption(3). Very dry soil conditions combined with a soil type having strong vapor sorption characteristics may significantly retard the transport of trichloroethylene (in the vapor phase)(3). [R230] WATC: *GROUNDWATER: Trichloroethylene was the most frequently detected organic chemical and in highest concentration; 28% of wells from 8 states sampled positive with a max conc reported at 35,000 ppb(2); 38.5% of 13 US cities tested positive with a mean concn 29.72 ppb, range 0.2-125 ppb(1). A study in New Jersey of 670 wells showed that 1.8% and 4.0% of wells had concn > 100 ppb and > 10 ppb, respectively(3). Groundwater samples in the Netherlands collected from 1976-78, at 232 pumping stations, showed that 67% were positive (> 0.01 ppb) for trichloroethylene(4). [R231] *GROUNDWATER: Trichloroethylene concns measured at 6 landfill sites in southern Ontario ranged from below the method detection limit (not given)(3 of 6 sites) to 21 ug/l(1). 10 of 27 groundwater sites in Kanagawa Prefecture, Japan (samples collected 1995-1998), contained trichloroethylene at concns from < 0.1 to 220 ug/l(2). In a study of groundwater beneath 27 Swedish landfills, median and maximum concns of < 0.1 and 5.0 ug/l trichloroethylene were reported(3). 13% of groundwater alluvial wells monitored in Denver metropolitan in 1993 contained trichloroethylene (max concn 2 ug/l)(4). Trichloroethylene was detected in 10.1% (n=208 wells) of groundwater samples collected in urban areas by the National Water-Quality Assessment Program at a maximum concn of 230 ug/l (reporting limit=0.2 ug/l; 3 wells exceeded MCL or health advisory level)(5). An assessment of untreated ambient groundwater in the US from 1985 to 1995 was conducted as part of the National Water-Quality Assessment Program; trichloroethylene was detected in 11.6% of urban wells (n=406) and 1.6% of rural wells (n=2542)(6). 26 of 1,083 shallow wells and 14 of 277 deep wells sampled in 15 cities in Japan in 1983 contained measurable concns of trichloroethylene(7). Of 210 urban wells and springs sampled during the USGS National water-Quality Assessment Program, 10% contained trichloroethylene(8). [R232] *DRINKING WATER: 28 of 113 US public water supplies tested positive for trichloroethylene, mean 2.1 ppb(1). Trichloroethylene was found in finished groundwater in 36% of 25 US cities at a mean concn of 6.76 ppb, range 0.11-53.0 ppb(2). Samples from the Love Canal, Niagara Falls, NY showed that 7 of 9 samples tested positive, with a concn range of 10-250 parts/trillion(3). 466 random samples of finished groundwater showed that 6.4% pos, 1 ppb median concn, 78 ppb max concn(4). State data, 2894 samples, showed that 28.0% tested positive for trichloroethylene from a trace to 35,000 ppb; in the US National Screening Program, of 142 samples, 25.4% tested positive with a trace to 53 ppb and in a Community Water Supply Survey, 3.3% of 452 samples were positive, with a concn range of 0.5-210 ppb(5). [R233] *DRINKING WATER: Trichloroethylene was detected in drinking water from Zagreb, Croatia at concns ranging from < 0.05 to 22.93 ug/l(1). Trichloroethylene tap water concns ranged from 0.03 to 2.1 ug/l according to the EPA's National Organics Monitoring Survey, published in 1977(2). Concns of trichloroethylene in groundwater before and after treatment from June 1995 to May 1996 at a water-pumping station in Zagreb, Croatia, ranged from 5.05-12.90 ug/l (mean=8.55 ug/l) and 2.16 to 15.29 ug/l (mean=8.53 ug/l), respectively(3). The Eau Clair Municipal Well field, WI, supplies drinking water to 57,600 residents; concns of trichloroethylene in water samples at this site ranged from 0.02 to 13 ug/l(4). This is currently listed as a Superfund site(4). Trichloroethylene was measurable in 8, 12, and 66% of collected drinking water samples in Los Angeles (Jan/Feb 1984), Los Angeles (May 1984), and Contra Costa (June 1984), respectively(5). [R234] *SURFACE WATER: Trichloroethylene concns of 1-24 ppb were measured in industrial rivers in US, with Lake Erie - 188 ppb, 88 of 204 samples pos(1). It is the third most frequently detected compound in Ohio River - 2427 of 4972 samples pos, 86% 0.1-1.0 ppb(2). Samples from Zurich, Switzerland lake surface contained 38 ppb, and at a 30 m depth - 65 ppb(3). Results reported in the USEPA STORET database of 9,295 data points, showed that 28.0% were positive for trichloroethylene, 0.10 ppb median(4). [R235] *SURFACE WATER: Trichloroethylene was present in water samples from Jackfish Bay, Lake Superior, at concns from 4.1 to 120 ng/l; Jackfish Bay receives 94,000 cu m/d of bleached-kraft mill effluent(1). Estuarine waters containing trichloroethylene were collected from sites in the UK (Humber, < 10-40.6 ng/l; Tees, < 10-269; Tyne, < 10-43.7; Wear, < 10-132; Tweed, < 10; Mersey, 250-4200), The Netherlands/Belgium (Scheldt in 1987-1989, < 10-1570; Scheldt in 1993, 54.7), Germany (Elbe, < 700), and the US (Back River, < 132-30,000 and 260-13800; Brazos river, 6-280)(2). Seawaters (beach, bay, fjord, coastal and shelf seawaters) containing trichloroethylene were collected from the following sites: Liverpool Bay, UK (< 3600 ng/l), Swansea Bay, UK (< 10), Byfjorden, Sweden(0.28 ng/l), Skagerrak (< 2.6 to < 5.8), Firth of Forth, UK (< 10), Moray Forth, UK(< 10), North Minch, UK (< 10), Bristol Channel, UK (< 10), Belgian continental shelf (4.9- 7.3)(2). Open seawaters containing trichloroethylene were collected from the following sites: the NE Atlantic Ocean (5-11 ng/l), Antarctica in 1990 (3.8 ng/l), Sea of Japan in 1991 (< 10 ng/l), and the East Pacific Ocean in 1981 (0.1 to 0.7 ng/l)(2). Trichloroethylene was measured in two sites in the River Elbe near Hamburg in 1992/1993; at Zollenspieker, upstream of Hamburg, concns ranged from 20-132 ng/l (median=57 ng/l) and at Seemannshoft, downstream of Hamburg, concns ranged from 13-117 ng/l (median=39 ng/l)(3). Trichloroethylene was found in water samples collected from 30 sites within the urban rivers and estuaries of Osaka, Japan; a median concn of 0.39 ug/l (78 of 136 samples positive, range=0.31-45 ug/l) was reported(4). The average concn of trichloroethylene in marine water samples was 0.3 ppb, max 3.6 ppb(6). A mean concn of 14.93 ng/l was reported for trichloroethylene based on data collected in the southern North Sea from Sept 1994 to December 1995(5). [R236] *RAIN/SNOW/FOG: Concns of trichloroethylene in rainwater from La Jolla, California cnotained 5 parts/trillion, and from an industrial area in England 150 parts/trillion(4). Samples from 7 rain events in Portland, OR, Feb-Apr 1984 showed were 100% pos, concns ranging from 0.78-16 parts/trillion, 5.6 avg(5). 117 rain samples collected over 1991 in Kobe, Japan contained unmeasurable concns of trichloroethylene (< 0.001 mg/l)(1). Cloud water samples were collected during 1987 and 1988 at Mt. Mitchell State Park, NC; concns of trichloroethylene ranged from 0-6.7 ng/ml with an average concn of 1.38 ng/ml(2). Surface snow, snow collected from 0.5 m depth and surface ice sampled in the Terranova Bay area in Antarctica, 1991-1992, contained trichloroethylene at 14, 8.5, and 11 ng/l, respectively(3). Snow collected from a snow pit at 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 m contained trichloroethylene at concns of 5.7, 2.9, 8.3, 8.9, 3.9, 8.0, and 9.0 ng /l, respectively (Terranova Bay area, Antarctica, 1992-1993)(3). Snow samples from Southern California contained 30 parts/trillion, central California 1.5 parts/trillion, and Alaska 39 parts/trillion(4). [R237] EFFL: *Landfill gas at seven U.K. waste disposal sites contained trichloroethylene at < 0.1 (4 sites) to 152 mg/cu m(1). Gas samples from 3 old and 1 active municipal landfills in Southern Finland contained trichloroethylene at average concns of 0.1 to 5.25 mg/cu m and a maximum concn of 13 mg/cu m(2). Average trichloroethylene concns of 710 and 2079 ppbV were measured in samples of landfill gas(3). 6% of urban runoff samples (n=86) from 4 of 19 different cities contained trichloroethylene at concns from 0.3 to 10 ug/l(4). Emissions of trichloroethylene from hazardous waste incinerators in the US were estimated as 81.8 ng/l or 0.7 tons/yr(5). Primary sludge from seven US publicly owned treatment works contained trichloroethylene at 35-284 ug/l(6). Stationary source emissions of 2640 tons/yr trichloroethylene were reported for The Netherlands in 1980(7). Landfill gas from 6 abandoned hazardous waste sites and 1 sanitary landfill contained trichloroethylene at mean concns of 0.08 to 2.43 ppbV and an overall maximum value of 12.3 ppbV(8). Emissions from a municipal waste incineration plant contained trichloroethylene at 4.0 ug/cu m(9). Bleaching effluent from 3 different kraft pulp mills in Finland contained trichloroethylene at concns of 0.1 to 0.7 ug/l(10). Trichloroethylene has been identified in spent chlorination and alkali extraction liquors from pulp bleaching(11). Effluent from 4 wastewater treatment plants in the Great Lakes basin contained trichloroethylene at concns of < 1 to 1 ppb(12). Trichloroethylene was reported in the flue gas from the combustion of pulverized coal at minimum and maximum concns of 4.747X10-7 and 5.685X10-7 lb/10+6 Btu, respectively(13). The combustion of waste plastics containing vinyl chloride polymer in an incinerator resulted in concns of trichloroethylene in the exhaust gas of 47-82 ug/cu m, depending on the combustion and exit chamber temperatures(14). Concn of trichloroethylene in sewage sludge generally ranges from 1 to 10 mg/kg dry weight(15). Pyrolysis of military HC smokepots resulted in the production of trichloroethylene(16). Leachate samples from 5 hazardous waste landfills and 4 sanitary landfills contained trichloroethylene at concns of 30 to 9500 ug/l and 2.3 to 7.9 ug/l, respectively(17). Emissions from coal-fired power stations contained trichloroethylene at concns of 5.7 ug/N-cu m; the concn in coal is 0.02 ug/g(18). Diesel engines are reported to emit 4.5 ug/N-cu m(18). [R238] *Trichloroethylene was detected not quantified in wastewater in vicinity of a specialty chemicals plant(1). Industries with mean trichloroethylene concns greater than 75 ppb: paint and ink formulation, electrical/electronic components, and rubber processing mean range, 7-530 ppb, max range 3-1600 ppb(2). Concn results of trichloroethylene reported in the USEPA STORET database are as follows: 1,480 data points, 19.6% pos, 5.0 ppb median(3). Groundwater samples at 178 CERCLA hazardous waste disposal sites were 51.3% pos(4). Trichloroethylene was detected in MN municipal solid waste landfills: leachates from 6 sites, 83.3% pos, 0.7-125 ppb; contaminated groundwater (by inorganic indices), 13 sites, 69.2% pos, 0.2-144 ppb; other groundwater (apparently not contaminated as indicated by inorganic indices), 7 sites, 28.6% pos, 0.2-6.8 ppb(5). [R239] *Off-gas from a conventional activated sludge treatment facility contained trichloroethylene at average concns of 175, 86, and 242 mg/cu m for three different weeks of operation in 1995/1996 (1). Trichloroethylene represented 1.1% of the total mass distribution of different species emitted in 1990 from the United Kingdom(2). Influent and effluent samples collected from the 14 water pollution control plants (11 with full secondary treatment)in New York city between 1989 and 1993 contained trichloroethylene at concn ranges of 1 to 46 ug /l (27% positive, n=84) and 2 to 3 ug /l (7% positive, n=84), respectively(3). Groundwater samples collected from beneath an active landfill in Orange County, Florida, in 1989/1990 and 1992/1993 contained trichloroethylene at concns ranging from below detection to 9.21 ug/l and 0.09 to 0.54 ug/l, respectively(4). 30 of 49 Superfund sites citing municipal well contamination, distributed in 21 US states, contained trichloroethylene in groundwater samples(5). Emissions of trichloroethylene from wastewater treatment plants in Los Angeles, CA were 366, 12, 3, and 5 kg/yr for Hyperion, Terminal Island, Tillman, and LA-Glendale plants, respectively(6). Trichloroethylene was emitted during coal combustion at concns ranging from 4.747X10-7 to 5.685X10-7 lb/10+6 Btu(7). Concns of trichloroethylene in municipal landfill leachate ranged from 1 to 15 mg /l; concns in landfill gases ranged from 1.2 to 175 mg/cu m (median 0.66 mg/cu m)(8). Trichloroethylene was emitted from 8 municipal solid waste composting facilities at a maximum concn of 1300 ug/cu m; fresh, mid-aged, old, and curing compost contained trichloroethylene at average concns of 98, 3, 3, and 2 ug/cu m, respectively(9). Global atmospheric emission fluxes of trichloroethylene were reported in 1988 to 1992; values ranged from 197 to 241 kt/year(10). [R240] SEDS: *SEDIMENT: Trichloroethylene was not detected in sediment in the vicinity of a specialty chemicals plant(1). The compound was detected in marine sediments from Liverpool Bay, England at a max of 9.9 ppb(2). It has been reported in the USEPA STORET database, based on 338 data points where 6.0% were reported positive, at < 5.0 ppb median concn(3). Trichloroethylene was detected in sediment from Lake Pontchartrain at Passes; from 3 sites, 66.7% were positive at a concn of 0.1-0.2 ppb, wet weight(4). [R241] *SOIL: Average concns of trichloroethylene in a pine and agricultural soil ranged from 0.08 to 0.8 and < 0.01 to 0.06 ug/kg dry weight, respectively(1). [R242] ATMC: *Global concn of trichloroethylene has been reported as follows: avg 8 parts/trillion, Northern hemisphere 15-16 parts/trillion, Southern hemisphere < 3 parts/trillion(1,2). Concns in major USA cities have been reported at a mean concn of 96-483 parts/trillion, with a max of 236-3097 parts/trillion, and a min of 5-36 parts/trillion(3,4). Sampling studies conducted in Portland, OR, from Feb-Apr 1984, showed a concn in air (ng/cu m) during 7 rain envents as follows: 100% pos, 240-3900, 1537 avg(11). Industrial area concns have been reported at a 1.2 ppb mean; urban/suburban- 0.25 ppb mean, and rural- trace-0.10 ppb(5-7). Results from a study based in England are as follows: industrial 40-60 ppb, suburban 1-20 ppb, rural 5 ppb(8). Air samples taken from the Love Canal region, Niagara Falls, NY resulted in 2 of 3 samples being pos (1.6 and 3.4 ppb), and home basement levels estimated at 0.83 ppb(9). Waste disposal site in Edison, NJ showed trichloroethylene concns ranging from a trace-61 ppb(10). [R243] *URBAN/SUBURBAN: Air samples collected in Bilbao, Spain in March 1996 contained trichloroethylene at a mean concn of 0.7 ppbV(1). 14.6% of air samples collected outside 50 homes in the Los Angeles area contained trichloroethylene(2). Mean concns of 1.0 (n=103) and 2.1 (n=83) ug/cu m were reported in air samples collected from 1986 to 1990 in Southeast Chicago and East St. Louis, respectively(3). Air samples collected as part of the Urban Baseline VOC Measurement Program in the District of Columbia from March 1990 to March 1991 contained trichloroethylene in 66.07% of the samples at a mean concn of 0.33 ppbv (range=0.17-2.83 ppbv)(4). A maximum outdoor air concn of < 2 ug/cu m was reported in a study of 300 Dutch homes(5). Trichloroethylene was measured in air samples collected from urban and suburban locations in Chicago at average concns of 0.82-1.16 and 0.52 ug/cu m, respectively(6). The national VOC database, representing 300 cities from 42 states, reports outdoor air samples (n=3021) contained trichloroethylene at average and median concns of 0.495 and 0.158 ppbv, respectively (data reported up to 1985)(7). [R244] *URBAN/SUBURBAN: Trichloroethylene was detected in air samples set up by the North Rhine-Westphalia State Centre for Air Quality Control and Noise Abatement (76 stationary stations and 8 mobile monitoring stations); annual average concns in 1990 ranged from 0.17 to 0.62 ug/cu m(1). Air samples collected in Porto Alegre, Brazil from March 1996 to April 1997 contained trichloroethylene at an average concn of 0.367 ppb (range=0.1-1.2 ppb, n=23, 6 samples at detection limit of 0.1 ppb)(2). 32% of air samples collected at 10 different locations in Boston, Chicago, Houston and the Seattle/Tacoma area in 1988/1989 as part of the Toxic Air Monitoring System network contained trichloroethylene at concns greater than 0.10 ppbv(3). Yearly mean concns of trichloroethylene across several Canadian cities in 1990 and in the US were 0.28 (maximum=20 ug/cu m) and 6.0 ug/cu m, respectively(4). Air samples collected between 1994 and 1996 at a site in Phoenix, AZ and at Tucson, AZ contained trichloroethylene at average concns of 0.05 (range 0.00 to 0.26 ppbv) and 0.04 ppbv (range 0.00 to 0.25 ppbv), respectively(5). [R245] *INDOOR: Indoor air samples, collected from 12 Canadian homes in November/December 1986 contained trichloroethylene at concns from below detection (detection limit not stated) to 2 ug/cu m (average concn of 0.5 ug/cu m, average concn in Feb/March of 1.6 ug/cu m); ambient air collected outside each home contained trichloroethylene at below detection to 2 ug/cu m with an average of 0.2 ug/cu m in November/December and 0.8 in Feb/March(1). A WHO summary of indoor air studies from homes in Italy, The Netherlands, USA, and Germany reported that the average home in these studies contained 5 ug/cu m trichloroethylene(2). 50% of air samples collected from the kitchens of 50 homes in the Los Angeles area contained trichloroethylene(3). Indoor air samples from nonsmoking and smoking homes contained trichloroethylene at mean concns of 1.84 (range of 0.00 to 9.08 ug/cu m) and 0.66 (range of 0.00 to 3.41 ug/cu m) ug/cu m, respectively(4). Air samples collected from a newly constructed office facility in 1987/1988 contained trichloroethylene at concns of 16.4, 7.2, 58.2, and 14.8 ug/cu m at four different sampling events; air samples collected from the roof contained this compound at 0.9 ug/cu m(5). 27% of indoor air samples from 26 "sick" houses contained trichloroethylene at concns ranging from not detected to 4.30 ug/cu m; 50 "normal" houses contained trichloroethylene at mean and median concns of 0.97 and 0.25 ug/cu m (max= 20.38 ug/cu m)(6). [R246] *INDOOR AIR: An emission rate of 3.6 ug/sq m/hr was measured for the release of trichloroethylene from linoleum tile(1). A summary of US studies monitoring VOCs in indoor air reports that trichloroethylene has been measured at an average concn of 1.347 ppb in 2134 measurements(1). A maximum indoor air concn of 106 ug/cu m was reported in a study of 300 Dutch homes(1). Trichloroethylene was reported in air samples during a study of West German homes with a concn range of < 1.0 to 1200 ug/cu m (mean concn of 13 ug/cu m)(1). Air samples collected from 757 randomly selected Canadian homes in 1992 contained trichloroethylene at unreported concns(2). [R247] *RURAL/REMOTE: Mean concns of trichloroethylene in air samples collected from Talladega National Forest were 0.2 ppb(1). Air samples collected from 4 forests in southwest Germany between 1986 and 1988 contained trichloroethylene at mean concns of 0.45, 0.55, 0.5, and 0.45 ug/cu m(2). A mean concn of 0.6 ug/cu m (n=23) was reported in air samples collected from 1987 to 1990 from a rural site near Champaign, IL(3). Concns of trichloroethylene were measured in air samples collected above the Pacific Ocean (1977, mean=0.07 ug/cu m), Panama Canal Zone (1977, 0.08 ug/cu m), and in the northern hemisphere (1985, 0.06-0.09 ug/cu m) and southern hemisphere (1981, < 0.02 ug/cu m). Air samples from rural locations contained trichloroethylene: Badger Pass, CA (1977, mean=0.06 ug/cu m, range=0.005-0.09 ug/cu m), Whiteface Mountains, NY (1974, mean=0.5 ug/cu, range= < 0.3-1.9 ug/cu m), Reese River, NV (1977, mean=0.06 ug/cu m, range=0.005-0.09 ug/cu m), Jetmar, KS (1978, mean=0.07 ug/cu m, range=0.04-0.11 ug/cu m)(4). Trichloroethylene was measured in marine air masses surveyed over an area in the western Pacific between 43 deg N, 150 deg E and 4 deg N, 113 deg E in September 1994 at mean and median concns of 3.52 and 0.32 parts/trillion volume, respectively (range=0.03-141.2 parts/trillion volume)(5). Ambient concns of trichloroethylene in air samples from the western Pacific, 1991 to 1994, ranged from 0.36 to 70 parts/trillion volume with mean concns from 3 different cruises of 1.90 to 9.5 parts/trillion volume(6). The national VOC database reports remote and rural median concns of 0.013 (n=14) and 0.010 (n=84) ppbv for trichloroethylene(7). [R248] *RURAL/REMOTE: Air samples from the Antarctic from April 1985 to February 1986 contained trichloroethylene at 3.1X10-11 mol/cu m(1). Trichloroethylene concns in Arctic air samples peaked in December and January and declined to almost zero in June/July(2). A mean concn of 141.1 parts/trillion volume was measured for trichloroethylene in the air above the southern North Sea during cruises from Sept 1994 to Dec 1995(3). Air samples collected between 1994 and 1996 at a site in Payson, AZ and at Casa Grande, AZ contained trichloroethylene at avg concns of 0.10 (range 0.00 to 1.13 ppbv) and 0.09 ppbv (range 0.00 to 1.46 ppbv), respectively(4). [R249] FOOD: *Trichloroethylene was detected in the following food samples: intermediates grain-based food (1984): 9 varieties, 44.4% pos, 0.77-2.7 ppb, 1.9 ppb (max concn in yellow corn meal; wheat, corn, oats (1984)), 10, 2, and 1 samples, respectively: not detected(1). Sampling table-ready foods showed trichloroethylene concns as follows: 19 varieties, 47% pos, 1.7-8.0 ppb, 1.5 ppb avg, max concn in plain granola; butter, 7 samples, 100% pos; 1.6-20 ppb, 9.7 ppb avg; margarine, 7 samples, 100% pos, 3.7-980 ppb, 4.3 ppb avg of pos, max concn in Mozzarella cheese(2). Trace amounts of trichloroethylene were detected in extracted edible oils(1). It was also detected in meat, beverages, dairy products, fruits and vegetables, oil and fats, range 0.02-60 ug/kg(1). Concns of trichloroethylene in food samples were as follows: Cheshire cheese: 3 mg/kg; English butter: 10 mg/kg; eggs: 0.6 mg/kg; shin of beef: 16 mg/kg; beef fat: 12 mg/kg; pig liver: 22 mg/kg; margarine: 6 mg/kg; olive oil (Spanish): 9 mg/kg; cod liver oil: 19 mg/kg; vegetable oil for frying: 7 mg/kg; fruit juices: 5 mg/kg; light beer: 0.7 mg/kg; freeze-dried coffee: 4 mg/kg; tea in bags: 60 mg/kg; Yugoslavian wine: 0.02; potatoes: 3 mg/kg; apples: 5 mg/kg; pears: 5 mg/kg; fresh bread: 7 mg/kg(3). [R250] *5 of 372 samples of food, obtained from the Food and Drug Administration's "market basket" collections, contained trichloroethylene at concns ranging from 2 to 94 ng/g (mean=49 ng/g)(1). Trichloroethylene was present in samples of butter from not detected to 0.3 ug/kg, in margarine at concns from not detected to 0.4 ug/kg, in peanut butter at concns from not detected to 0.7 ug/kg, and in pastry mix at a concn of 0.2 ug/kg(2). Floured chickpeas contained trichloroethylene at unreported concns(3). Trichloroethylene has been reported as a component of chicken meat volatiles(4). [R251] PFAC: PLANT CONCENTRATIONS: *Tree cores obtained from bald cypress, tupelo, sweet gum, oak, sycamore, and loblolly pine growing over shallow groundwater contaminated with trichloroethylene contained this compound at concns from < 50 to 35,040 nmol /l (n=138, sampled January-February 1998, Savannah River Site, SC)(1). [R252] FISH/SEAFOOD CONCENTRATIONS: *Conger conger (eel): gill, gut: 29 ng/g; brain, muscle: 62-70 ng/g; Gaddus morhua (cod): stomach, muscle: 7-8 ng/g; brain, liver: 56-66 ng/g; Pollachius birens (coal fish): muscle: 8 ng/g; alimentary canal: 306 ng/g; Scylliorhinus canicula (dog fish): muscle, gut, brain: 40-41 ng/g; liver: 479 ng/g; Trisopterus luscus (bib): gill: 40 ng/g; muscle, skeletal tissue: 185-187 ng/g. [R28, 1788] *Trichloroethylene has been reported in marine fish at the following concns: flesh - 0.04-1.1 ppm, liver - 0.66-20.0 ppb, mussels - 50 day exposure 1.37 ppm(1). Shelfish from Lake Pontachartrain at Passes contained the following concns: oysters, 5 samples, 2.2 ppb avg; clams, composite samples from 2 sites, 5.7 and 0.8 ppb(2). [R253] ANIMAL CONCENTRATIONS: *Clams collected in 1995/1996 from the Ariho, Koe and Okita Rivers, Japan, did not contain measurable quantities of trichloroethylene (detection limit < 0.5 ug/kg)(1). Earthworms collected from a forest site adjacent to a former landfill site and chemical plant in West Germany during 1989 contained trichloroethylene at concns below detection (detection limit not reported) to 170 ng/g wet weight(2). In a sampling study conducted near Liverpool Bay, UK, trichloroethylene concns in Alca torda (Razorbill Auk), Uria aalge (Guillemot), and Rissa tridactyla (Kittiwake) sea bird eggs were 23-33 mg/kg. Levels of 2.4 mg/kg for Phalacrocrax aristotelis (Shag) were also noted(3). [R254] MILK: *Trichloroethylene has been detected in dairy products(1). In mother's milk samples from 4 U.S. urban areas, 8 of 8 samples tested positive for the compound(2). The concn of trichloroethylene in fresh milk was 0.3 mg/kg(3). [R255] OEVC: *Trichloroethylene was found in 2.2% of 1159 household products; automotive products (0.1% weight/weight, 1.2% positive hits in category), household cleaner/polishes (0.0%, 0.9%), paint-related products (3.0%, 1.1%), fabric and leather treatments (0.0%, 2.2%), cleaners for electronic equipment (0.3%, 1.4%), oils, greases and lubricants (0.3%, 1.8%), adhesive-related products (34.7%, 2.6%) and miscellaneous products (33.9%, 14.1%)(1). Household cleaning agents and pesticides contained trichloroethylene at an average concn of 7 ug/cu m (2). Trichloroethylene was identified in 3 of 26 samples of hobby glue at 0.007 to 0.15 weight percent(3). In the European Community, trichloroethylene is used by some producers during the decaffeinating of coffee(4). [R256] RTEX: *TRICHLOROETHYLENE WHEN PRESENT IN AIR NEAR OPEN ARC WELDING MAY BE DECOMP TO LEVELS OF PHOSGENE DANGEROUS TO HEALTH, WHEREAS THE HCL AND CL2 FORMED SIMULTANEOUSLY MAY NOT ALWAYS PROVIDE AN ADEQUATE WARNING AGAINST THE PRESENCE OF PHOSGENE. [R257] *Many industrial workers, operating room personnel and dentists are regularly exposed to TCE, some to large doses. The general public encounters trichloroethylene in cleaning fluids, some decaffeinated coffees and spice extracts. [R60] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 392,805 workers (169,851 of these are female) are potentially exposed to trichloroethylene in the US(1). Occupational exposure to trichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where trichloroethylene is produced or used(SRC). Extensive monitoring data indicate that the general population may be exposed to trichloroethylene via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and other products containing trichloroethylene(SRC). [R258] *An open-top and an enclosed conveyor-loaded production trichloroethylene vapor degreasers had average emission factors of 2.6 g TCE/min and 0.67 g TCE/min, respectively(1). Waste gases from aluminum plasma-etching processes (using chlorine containing etchants) during semiconductor production contained trichloroethylene at an average concn of 315.70 ng /l(2). The number of US workers exposed to TCE is estimated to be 283,000(3). Operating room levels range from 0.3-103 ppm, with an estimated 5000 medical, dental and hospital personnel being routinely exposed(1). Air levels at a dial assembly workshop in Japan measured 25-100 ppm; degreasing room levels, 150-250 ppm(3). Trichloroethylene was detected in 6% of 7705 solvent air samples reported from different industries in Norway and stored in the EXPO occupational exposure database(4). [R259] *23-41% of trichloroethylene in feed water to showers was lost with a water temperature of 23 to 40 deg C(1). Trichloroethylene was detected in chlorinated swimming pool water from a pool in Gdansk, Poland at concns of not detected (detection limit, on average, 0.01 ug/cu dm) to 13.3 ug/cu dm for 4 different dates in 1991(2). [R260] BODY: *Therapeutic or normal blood level 0.1-9 mg% [R261] *PERSONAL AIR: The exhaled breath of 73% of 26 smokers and 81% of 43 nonsmokers contained trichloroethylene at unreported concns(1). Breath of 12.5% of 50 individuals living in the Los Angeles area contained trichloroethylene(2). 51.2% of personal air samples collected from these 50 individuals contained trichloroethylene(2). Increased personal air exposures were reported following solvent use, household cleaning, furniture stripping, visiting a dry cleaning shop, photo developing and using paint remover of up to 220 ug/cu m from a baseline of < 2 ug/cu m(3). Personal air samples of Los Angeles and Contra Costa residents contained trichloroethylene at concns of 7.8 (n=110, Los Angeles residents, February 1984), 6.4(n=50, Los Angeles residents, May 1984) and 3.8 (n=67, Contra Costa residents, June 1984)(4). [R262] *Blood samples from 179 of 277 people from the general population contained trichloroethylene at a mean concn of 458 ng/l; a mean blood concn of 763 ng/l was reported from 63 of 113 urban workers as compared to 180 ng/l from 82 of 127 workers(1). Blood samples collected from workers exposed to trichloroethylene in 4 dry-cleaning shops (air concns ranged from 25-40 ppm) contained this compound (median=3.39 umol /l after work (range=0.46-12.71), 0.38 umol /l before work (range=0.15-3.58)(2). Urine samples from the same workers contained the trichloroethylene metabolite, trichloroethanol (median=54.89 umol/mol creatinine, range=5.30-177.67 after work; median=9.70 umol/mol creatinine, range=0.38-35.65 before work)(2). Kidney (n=9), lung (n=13), and muscle (n=16) tissues collected from humans in Turku, Finland in 1987 contained trichloroethylene at 0.7, 0.02, and 0.2 ug/kg, respectively(3). 20% of composite adipose tissue samples collected in FY82 (n=46 composite samples) contained trichloroethylene(4). Breathing air samples from 30 residents of Tokyo, Japan had a mean concn of 2.0 ug/cu m trichloroethylene with a calculated daily intake due to breathing ambient air of 40 ug/person (men 24.9 ug/person; women 51.5 ug/person)(5). Breath samples of Los Angeles and Contra Costa residents contained trichloroethylene at concns of 1.6 (n=110, Los Angeles residents, February 1984), 1.0 (n=50, Los Angeles residents, May 1984) and 0.6 (n=67, Contra Costa residents, June 1984)(6). [R263] *Trichloroethylene was detected in mother's milk samples from 4 US urban areas, with 8 of 8 samples testing pos(1). Concns in post-mortem wet tissue samples were 1-32 ppb(2). Breath samples Love Canal residents, Niagara Falls, NY contained a trace of trichloroethylene with 4 of 9 samples pos; blood - 0.09.50 ppb, 6 of 9 samples pos; and urine - 40-550 parts/trillion, 9 of 9 samples pos(3). Concns in whole blood specimens from 250 subjects ranged from not detected to 1.5 ppb, with a 0.4 ppb avg(4). [R264] *Trichloroethylene was detected in the blood of 13 of 677 samples taken from non-occupationally exposed Americans (detection limit= 0.010 ppb(1). Trichloroethylene was measured in blood samples collected from 79 humans at concns ranging from < 0.015 to 0.090 ug/l(2). Exhaled breath from humans following both inhalation and dermal exposures during showering or dermal exposure following bathing using normal tap water contained trichloroethylene at concns up to 0.32 ug/cu m/ug/l(3). [R265] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers trichloroethylene to be a potential occupational carcinogen. [R27, 316] ATOL: *Tolerances are established for residues of trichloroethylene resulting from its use as a solvent in the manufacture of foods as follows: decaffeinated ground coffee 25 ppm; decaffeinated soluble (instant) coffee extract 10 ppm; and spice oleoresins 30 ppm (provided that if residues of other chlorinated solvents are also present, the total of all residues of such solvents in spice oleoresins shall not exceed 30 ppm). [R266] OSHA: *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 100 ppm. [R267] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 200 ppm. [R267] *Permissible Exposure Limit: Table Z-2 Acceptable maximum peak above the acceptable ceiling concentration for an 8-hour shift. Concentration: 300 ppm. Maximum Duration: 5 minutes in any 2 hours. [R267] *Vacated 1989 OSHA PEL TWA 50 ppm (270 mg/cu m); STEL 200 ppm (1080 mg/cu m) is still enforced in some states. [R27, 372] NREC: *NIOSH considers trichloroethylene to be a potential occupational carcinogen. [R27, 316] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R27, 316] *Recommended Exposure Limit: 60 Min Ceiling Value: 2 ppm. /During the usage of trichloroethylene as an anesthetic agent/ [R27, 316] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 25 ppm. /During exposures to trichloroethylene other than as an anesthetic agent/ [R27, 316] TLV: *8 hr Time Weighted Avg (TWA) 50 ppm; Short Term Exposure Limit (STEL) 100 ppm [R268, 68] *BEI (Biological Exposure Index) for Trichloroethylene: Trichloroacetic acid in urine at end of workweek is 100 mg/g creatinine. The determinant is nonspecific, since it is observed after exposure to other chemicals. (1986 Adoption) [R268, 102] *BEI (Biological Exposure Index) for Trichloroethylene: Trichloroacetic acid and trichloroethanol in urine at end of shift at end of workweek is 300 mg/g creatinine. The determinant is nonspecific, since it is observed after exposure to other chemicals. (1986 adoption) [R268, 102] *BEI (Biological Exposure Index) for Trichloroethylene: Trichloroethylene in end-exhaled air. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. [R268, 102] *A5: Not suspected as a human carcinogen. [R268, 68] *BEI (Biological Exposure Index) for Trichloroethylene: Free trichloroethanol in blood at end of shift at end of workweek is 4 mg/l. The determinant is nonspecific, since it is observed after exposure to other chemicals. (1986 adoption) [R268, 102] *BEI (Biological Exposure Index) for Trichloroethylene: Trichloroethylene in blood. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. (1993 adoption) /No value specified in text/ [R268, 102] OOPL: *Occupational exposure limits used in various countries are as follows: (time-weighted values) Australia: 535 mg/cu m; Austria: 260 mg/cu m; Belgium: 535 mg/cu m; Bulgaria: 10 mg/cu m; Czechoslovakia: 250 mg/cu m, ceiling value 1250 mg/cu m; Egypt: 267; Finland: 260 mg/cu m; France: 405 mg/cu m, ceiling value 1080 mg/cu m; German Democratic Republic: 250 mg/cu m, ceiling limit: 750 mg/cu m; Germany, Federal Republic: 260 mg/cu m; Hungary: 50 mg/cu m; Italy: 400 mg/cu m, skin irritation 1000 mg/cu m; Japan: 268 mg/cu m; Netherlands: 190 mg/cu m; Poland: 50 mg/cu m (ceiling value); Romania: 200 mg/cu m, 300 mg/cu m (ceiling value); Spain: 535 mg/cu m; Sweden: 110 mg/cu m, short-term exposure limit 250 mg/cu m; Switzerland: 260 mg/cu m; United Kingdom: 535 mg/cu m; USSR: 10 mg/cu m (ceiling value); Yugoslavia: 200 mg/cu m. [R269] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 100 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 500 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 5000 ppm (not life threatening) up to 1 hr exposure. [R270] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Trichloroethylene is produced, as an intermediate or a final product, by process units covered under this subpart. [R271] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Trichloroethylene is included on this list. [R272] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l [R273] STATE DRINKING WATER STANDARDS: +(FL) FLORIDA 3 ug/l [R273] +(NJ) NEW JERSEY 1 ug/l [R273] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 3.2 ug/l [R273] +(CT) CONNECTICUT 5 ug/l [R273] +(ME) MAINE 5 ug/l [R273] +(MN) MINNESOTA 30 ug/l [R273] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R274] +Trichloroethylene is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R275] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R276] RCRA: *U228; As stipulated in 40 CFR 261.33, when trichloroethylene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R277] *D040; A solid waste containing trichloroethylene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R278] *F002; When trichloroethylene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F002), as stated in 40 CFR 261.31, and must be managed according to state and/or federal hazardous waste regulations. [R279] FDA: *Trichloroethylene is an indirect food additive for use as a component of adhesives. [R280] *Tolerances are established for residues of trichloroethylene resulting from its use as a solvent in the manufacture of foods as follows: decaffeinated ground coffee 25 ppm; decaffeinated soluble (instant) coffee extract 10 ppm; and spice oleoresins 30 ppm (provided that if residues of other chlorinated solvents are also present, the total of all residues of such solvents in spice oleoresins shall not exceed 30 ppm). [R266] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Water samples were collected in 125 ml serum vial that had been cleaned by detergent wash, distilled water rinse, dichromic acid wash, and oven-drying at 150 deg C. Vials were completely filled and stored at 4 deg C. Minimum loss occurred during storage at 4 deg C up to 28 days. [R281] *Sampling ... /is conducted by utilizing/ activated carbon felt badges. [R282] *Sampling ... /is conducted by utilizing/ activated carbon tubes. [R283] *EPA Method 8010. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40-ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R284] *NIOSH Method: 3701. Analyte: Trichloroethylene. Matrix: Air. Sampler: Air bag (Tedlar). Flow Rate: 0.02 to 0.05 l/min or higher; fill bag to equal to or greater than 80% of capacity; spot samples possible. Sample Stability: Bags should be analyzed as soon after collection as possible (equal to or greater than 4 hrs). [R285] *NIOSH Method: 1022. Analyte: Trichloroethylene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min. Sample Size: 3.4 liters. Shipment: Routine. Sample Stability: Not determined. [R285] ALAB: *RECOVERIES WERE FROM FORTIFIED WHEAT SAMPLES, USING GAS LIQUID CHROMATOGRAPHIC COLUMN AND ELECTRON CAPTURE DETECTOR. [R286] *Trichloroethylene in grain is analyzed by gas chromatography with source-heated electron capture detector and glass-lined injection block. Construct calibration curve daily of peak heights against ng fumigant/125 ml acetone for suitable range. [R287, p. VI 290-1] *Trichloroethylene in spice oleoresins is analyzed by gas chromatographic method. [R287, p. VII 1175] *Fujiwara Test: Trichloroethylene is treated with pyridine in an alkaline environment. Solution absorbance is then determined at 535 or 470 nm (absorptivity: 18-32 l/g/cm with a sensitivity of about 1 mg/kg. [R288] *Infra-red spectroscopy: In the gaseous phase, quantities are determined by measuring the optical density at the selected wavelength of 11.8 um. ... This corresponds to a detection sensitivity of not less than 0.5 ug/l. [R289] *High-resolution gas chromatography with electron capture detector/mass spectrophotometry...for determination of trichloroethylene in soil /has been utilized/ as a confirmatory technique with a detection threshold of approximately 10 mg/kg (10 ppm). [R290] *EPA Method 8010. Direct Injection or Purge and Trap Gas Chromatography with halogen-specific detector for the analysis of halogenated volatile organics including trichloroethylene in solid waste. Under the prescribed conditions for trichloroethylene, the method has a detection limit of 0.12 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R284] *EPA Method 502.1. Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography. Revision 2.0. Analysis by GC with electrolytic conductivity detection. Detection limit= 0.001 ug/l in drinking water. [R291] *EPA Method 502.2. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. Detection limit= 0.01 ug/l in drinking water. [R291] *EPA Method 503.1. Volatile Aromatic and Unsaturated Organic Compounds in Water by Purge and Trap Gas Chromatography" Revision 2.0 Analysis by gas chromatography with photoionization detection. Detection limit= 0.01 ug/l in drinking water. [R291] *EPA Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. Detection limit= 0.4 ug/l in drinking water. [R291] *EPA Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. Revision 4.0. Detection limit= 0.19 ug/l in drinking water. [R291] *EPA Method 551. Determination of Chlorination Disinfection Byproducts and Chlorinated Solvents in Drinking Water by Liquid-Liquid Extraction and Gas Chromatography with Electron-Capture Detection. Detection limit= 0.002 ug/l in drinking water. [R291] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. Detection limit= 0.120 ug/l in drinking water. [R291] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. Detection limit= 1.9 ug/l in wastewater. [R291] *EPA Method 8240. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Estimated quantitation limit= 5 ug/l. [R291] *EPA Method 8021. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. Detection limit= 0.01-0.02 ug/l. [R291] *EPA Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R291] *EPA Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. Detection limit= 2 ug/kg in soil. [R291] *NIOSH Method: 3701. Analtye: Trichloroethylene. Matrix: Air. Procedure: Gas chromatography (portable), photoionization detector. For trichloroethylene this method has an estimated detection limit of 0.25 ng/injection/sample. The precision/RSD is 0.078 and the recovery is not given. Applicability: The working range is 10 to 1000 ppm (54 to 5100 mg/cu m) in relatively non-complex atmospheres where trichloroethylene is known to be present. Interferences: None found. [R285] *NIOSH Method: 1022. Analyte: Trichloroethylene. Matrix: Air. Procedure: Gas chromatography, flame ionization detector. For trichloroethylene this method has an estimated detection limit of 0.01 mg/sample. The precision/RSD is 0.038 @ 1.6 to 6.4 mg/sample and the recovery is not given. Applicability: The working range is 27 to 875 ppm (150 to 4700 mg/cu m for a 3.4 liter air sample. Interferences: None studied. [R285] *Gas chromatograph/mass spectrometric analysis of volatiles including trichloroethylene. The Contract Required Quantitation Limits are 5.0 ug/kg in solids at low level, 500 ug/kg in solids at medium level, and 5 ug/l in water as used in EPA Contract Laboratory Program. [R292] *EPA Method 0-3115. Purge and trap gas chromatography/mass spectrometric method for the determination of organic substances including trichloroethylene in water and fluvial sediments. The estimated detection limit is 3 ug/l as used in US Geological Survey Techniques of Water Resources. [R292] CLAB: *GAS CHROMATOGRAPHY USED TO DETERMINE HUMAN SERUM AND ADIPOSE TISSUE LEVELS OF VOLATILE PURGEABLE HALOGENATED HYDROCARBONS. [R293] *Practical recommendation for the biologic monitoring of exposure to trichloroethylene is as following: Biological parameter: trichloroethanol. Biological material: Urine. /SRP: Permissable/ value: 150 mg/g creatinine /From table/ [R294] *Practical recommendation for the biologic monitoring of exposure to trichloroethylene is as following: Biological parameter: trichloroacetic acid. Biological material: plasma. Permissable value: 5 mg/100 ml /After 5-day exposure, from table/ [R294] *Practical recommendation for the biologic monitoring of exposure to trichloroethylene is as following: Biological parameter: trichloroethanol. Biological material: plasma. Permissable value: 0.25 mg/100 ml /After 5-day exposure, from table/ [R294] *Matrix: breath; conventional reference range: < 1 ppm; international recommended reference range: < 8 umolar [R295] *A method is presented which is suitable for the analysis of certain halocarbons in blood and tissue samples. Among these halocarbons is ... trichloroethylene. ... Blood samples are warmed and an inert gas is passed through the sample to extract the volatile halocarbons. Treated samples are macerated in water, then treated the same as for blood samples. A Tenax gas chromatography cartridge is used to trap the vapors which are then recovered by thermal desorption and analyzed on gas chromatography/mass spectrometry. The limits of detection of this method are approximately 3 ng/ml for a 10 ml blood sample and 6 ng/g for 5 g tissue samples. [R296] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Health and Safety Executive Monograph: Trichloroethylene #6 (1982). USEPA; Ambient Water Quality Criteria Document: Trichloroethylene (1980) EPA-440/5/80-007. NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.27. NTP TR No 002; Route: oral, gavage; Species: rats and mice. NTIS No PB264122/AS. WHO; Environ Health Criteria 50: Trichloroethylene (1985). Municipal Environmental Research Laboratory; USEPA, Survey of Two Municipal Wastewater Treatment Plants for Toxic Substances, March (1977) DHHS/ATSDR; Toxicological Profile for Trichloroethylene (Update) TP-92/19 (1993) NTP TR No 243; Route: gavage; Species: rats and mice. NTIS No PB91111815/AS. [R297] Bruening T; Bolt HM; Critical Reviews in Toxicology 30 (3): 253-285 (2000). Renal toxicity and carcinogenicity of trichloroethylene: Key results, mechanisms, and controversies. Lash LH; Parker JC; Scott CS; Environ Health Perspect 108 (2): 225-240 (2000). Modes of action of trichloroethylene for kidney tumorigenesis. Moore MM; Harrington-Brock K; Environmental Health Perspectives 108 (2): 215-223 (2000). Mutagenicity of trichloroethylene and its metabolites: implications for the risk assessment of trichloroethylene. Wartenberg D; Reyner D; Scott C; Environmental Health Perspectives 108 (2): 161-176 (2000). Trichloroethylene is an organic chemical that has been used in dry cleaning, for metal degreasing, and as a solvent for oils and resins. It has been shown to cause liver and kidney cancer in experimental animals. This article reviews over 80 published papers and letters on the cancer epidemiology of people exposed to trichloroethylene. SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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Rockville, MD: Government Institutes (1997) R292: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.510 (1991) OST Pub 21W-4005 R293: PEOPLES AJ ET AL; PREPR PAP NATL MEET--AM CHEM SOC DIV ENVIRON CHEM 18 (2): 485-6 (1978) R294: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 1000 R295: Tietz, N.W. (ed.). Clinical Guide to Laboratory Tests. Philadelphia, PA: W.B. Saunders Co., 1983. 112 R296: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 435-44 (1985) R297: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.272 RS: 286 Record 27 of 1119 in HSDB (through 2003/06) AN: 136 UD: 200302 RD: Reviewed by SRP on 1/23/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-XYLENE- SY: *AI3-52255-; *BENZENE,-1,4-DIMETHYL-; *p-DIMETHYLBENZENE-; *1,4-DIMETHYLBENZENE-; *p-Methyltoluene-; *Scintillar-; *p-xylene-; *1,4-XYLENE-; *p-XYLOL- RN: 106-42-3 RELT: 4500 [XYLENES] (Mixture) MF: *C8-H10 SHPN: UN 1307; Xylenes IMO 3.2; Xylenes IMO 3.3; Xylenes STCC: 49 093 51; Xylenes HAZN: U239; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. /Xylenes/ F003; A hazardous waste from nonspecific sources when a spent solvent. /Xylenes/ MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Selective crystallization or solvent extraction of meta-para mixt; sepn from mixed-xylene feedstocks by adsorption (Parex process). [R1] *4-Xylene is separated by continuous crystallization or adsorption from the mixed xylenes or isomerized from the 3-xylene/4-xylene distillate. [R2] IMP: *Commercial xylenes may contain small amounts of toluene, trimethylbenzene, phenol, thiophene, pyridine, and nonaromatic hydrocarbons. /Xylenes/ [R3] FORM: *Research, 99.99%; Pure, 99.8%; Technical, 99.0%. [R4] MFS: *Amoco Corporation, Hq, 200 East Randolph Drive, Chicago, IL 60601, (312) 856-6111; Production site: Texas City, TX 77592-0568 [R5] *Chevron Chemical Company, 6001 Bollinger Canyon Road, San Ramon, CA 94853 (510) 842-5500. Aromatics and Derivatives Division, 1301 McKinney Street, PO Box 3766, Houston, TX 77253 (713) 754-2000. Production Site: Pascagoula, MS 39567 [R5] *Exxon Chemical Company, 13501 Katy Freeway, Houston, TX 77079 (713) 870-6000. Exxon Chemical Americas, PO Box 3272, Houston, TX 77253-3272 (713) 870-6000. Production Site: 5000 Bayway Drive PO Box 4004, Baytown, TX 77520 [R5] *Koch Refining Co, PO Box 2256, Wichita, KS 67201, (316) 832-5500; Production site: Corpus Christi, TX 78403 [R5] *Lyondell-Citgo Refining Company Ltd, 12000 Lawndale, Houston, TX 77017. (713) 321-4111. Production Site: Houston, TX 77052 [R5] *Mobil Chemical Company,3225 Gallows Road, Fairfax, VA 22037-0001 (703) 846-3000. Petrochemicals Division, Hdqtrs: Intercontinental Center, Suite 906, 15600 JF Kennedy Boulevard, Houston, TX 77032-2343 (713) 590-7700. Production Site: Chalmette, LA 70043 (504) 279-9481 [R5] *Phillips Puerto Rico Core Inc, Street No. 3, Route 710, Barrio Las Mareas, PO Box 10003, Guayama, PR 00784 (809) 864-1515. Production Site: Guayama, PR 00784 [R5] OMIN: *The commercial product "mixed xylenes" is a technical product generally containing approximately 40% m-xylene and 20% each of o-xylene, p-xylene, and ethylbenzene, as well as small quantities of toluene. [R6] USE: *Synthesis of terephthalic acid for polyester resins and fibers ("Dacron," "Mylar," "Terylene"); pharmaceutical synthesis; insecticides [R1] *CHEM INTERMED FOR DIMETHYL TEREPHTHALATE AND TEREPHTHALIC ACID [R7] *CHEM INTERMED FOR DIMETHYL TETRACHLOROTEREPHTHALATE-HERBICIDE [R7] *SOLVENT [R7] *p-Xylene ... frequently ... used for paints or in the printing trade. [R8] *Used as a chemical intermediate for the synthesis of 1,4-bis(chloromethyl)benzene; dimethyl terephthalate; poly-p-xylylene; terephthalic acid; 4-(tri-fluoromethyl)benzaldehyde; 4-(trifluoromethyl)benzyl alcohol; 2,5-xylidine. [R9] CPAT: *Dimethyl terephthalate and terephthalic acid for saturated polyester production, 100% (except negligible amounts used as solvents, coating or pesticides) (1985) [R10] *CHEMICAL PROFILE: Paraxylene. Dimethyl Terephthalate and terephthalic acid for saturated polyester production, 100% (except negligible amounts) for use as solvents, coating or pesticides. This includes 75% for domestic consumption and 25% for export. [R11] *CHEMICAL PROFILE: Paraxylene. Demand: 1985: 4.5 billion lb; 1986: 4.7 billion lb; 1990 /projected/: 5.23 billion lb. [R11] *CHEMICAL PROFILE: Paraxylene. Dimethyl terephthalate and terephthalic acid, 85%; exports, 15%. (Domestically, negligible amounts are used in solvents, coatings and pesticides). [R12] *Chemical Profile: Paraxylene. Demand: 1994: 6000 million lb; 1995: 6250 million lb; 1999:/projected/: 7500 million lbs (includes exports, which were 640 million lbs in 1994, but not imports which were 30 million lbs). [R13] *Chemical Profile: Paraxylene. Virtually all p-xylene recovered in the US is consumed in the manufacture of terphthalic acid. A small amount is used as a solvent and in the manufacture of herbicides. [R13] PRIE: U.S. PRODUCTION: *(1980) 1.9X10+12 G [R14] *(1981) 2.06x10+12 g [R15] *(1976) 1.32x10+12 g [R16] *(1977) 1.44X10+12 G [R7] *(1982) 1.54X10+12 G [R7] *(1985) 2.17X10+12 g [R17] *(1993) 1.45X10+9 kg [R18] *(1990) 5.20 billion lb [R19] *(1991) 5.35 billion lb [R20] *(1992) 5.66 billion lb [R21] *(1993) 5.76 billion lb [R21] *6.34 billion lb [R22] U.S. IMPORTS: *(1978) 9.53X10+9 G [R7] *(1983) 3.18X10+10 G [R7] *(1985) 6.53X10+10 g [R23] *(1986) 3.71X10+7 gal [R24] *Chemical Profile: 30 million lbs in 1994 [R13] *Chemical Profile: 640 million lbs in 1994 [R13] U.S. EXPORTS: *19.7% of total 1980 xylene market. [R25] *(1978) 3.19X10+11 G [R7] *(1983) 3.23X10+11 G [R7] *(1985) 5.03X10+11 g [R26] *(1987) 9.68X10+7 gal [R27] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless plates or prisms at low temp [R28]; *Colorless liquid [R1]; *Color: Saybolt units +30 (research, pure and technical grades) [R29]; +Colorless liquid (Note: A solid below 56 degrees F). [R30, 336] ODOR: *Sweet [R4]; +... Aromatic odor. [R30, 336] BP: *138.35 deg C [R31] MP: *13.2 deg C [R32] MW: *106.16 [R32] CTP: *Critical temp: 359 deg C; Critical pressure at 35.7 atm [R33, p. F-66] DEN: *0.86104 @ 20 deg C/4 deg C [R28] HTC: *-4559.8 kJ/mol [R31] HTV: *9809.9 cal/mole [R33, p. C-673] OWPC: *log Kow= 3.15 [R34] SOL: *Insol in water [R28]; *Miscible in alcohol, ether, acetone [R32]; *water solubility = 198 mg/l @ 25 deg C [R35] SPEC: *Index of refraction: 1.49575 @ 20 deg C/D [R28]; *IR: 3575 (Coblentz Society Spectral Collection) [R36]; *UV: 609 (Sadtler Research Laboratories Spectral Collection) [R36]; *NMR: 203 (Varian Associates NMR Spectra Catalogue) [R36]; *MASS: 326 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R36] SURF: *28.3 dynes/cm @ 20 deg C in contact with vapor [R33, p. F-37] VAPD: *3.7 (air= 1) [R37, 1193] VAP: *8.84 mm Hg at 25 deg C [R38] EVAP: *Evaporation rate: 9.9 (ether= 1) [R39, 3291] VISC: *0.648 centipoise @ 20 deg C [R33, p. F-44] OCPP: *Conversion factor: 4.34 mg/cu m= 1 ppm [R39, 3256] *Liquid-water interfacial tension: 0.0378 n/m at 20 deg C [R4] *Taste threshold in air: 0.47 ppm [R40] *Dielectric constant 2.27 @ 25 deg C [R41] *Critical density: 2.64 mmol/cu m [R41] *Critical volume: 379.0 cu m/mol [R41] *Heat of fusion 17.112 J/mole deg K [R41] *Heat of formation: (endothermal) @ 25 deg C= -24.43 J/mole deg K [R41] *Entropy of formation 247.4 J/mole deg K [R41] *... Combustion characteristics: critical compression ratio 14.2; research octane value 116.4 and motor octane number is 6 units lower. [R42] *p-Xylene and m-xylene cannot be separated by distillation because their boiling points are too close. [R42] *Partition coefficients at 37 deg C for p-xylene into blood= 37.6; into oil= 3,690. [R43] *Oxidation of p-xylene can form terephthalic acid or dimethyl terephthalate. [R44] *Xylene can be easily chlorinated, sulfonated, or nitrated. /Xylenes/ [R45] *Henry's Law constant = 0.0069 atm-cu m/mol @ 25 deg C [R46] *hydroxyl radical rate constant = 1.43X10-11 cu m/molc-sec @ 25 deg C [R47] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 4-xylene stem from its toxicologic properties and flammability. Exposure to this colorless sweet-smelling liquid (solid, below 13 deg C) may occur from its use as a solvent, as a component of gasoline, and as a chemical intermediate. Toxic by all routes of exposure (ie, dermal, ingestion, and inhalation), 4-xylene can cause effects including headache, dizziness, skin and eye irritation, kidney and liver damage, pulmonary edema, coma, and death. The ACGIH recommends a workplace exposure limit (TLV) of 100 ppm an 8-hr time-weighted average (TWA); however, to assure protection, wear an approved canister or air-supplied mask, face shield, plastic gloves, and boots. In emergency situations, a self-contained breathing apparatus and full protective clothing are recommended. If contact does occur, immediately flush exposed eyes with running water, wash exposed skin with soap and water, and remove contaminated clothing. Individuals with diseases of the central nervous system, liver, kidneys, and blood should be protected from exposure. 4-Xylene is easily ignitable by heat, sparks, or flame (flash point: 25 deg C, closed cup), and may do so explosively in an enclosed area. Also, vapor may travel a considerable distance to a source of ignition and flash back. The heat of a fire may cause containers to explode and/or cause thermal degradation of 4-xylene, producing irritating and poisonous gases. Fires involving 4-xylene may be extinguished with dry chemical, CO2, water spray, fog, or foam. For massive fires in enclosed areas, use unmanned hose holders or monitor nozzles. If a 4-xylene tank car or truck is involved in a fire, isolate 1/2 mile in all directions. Runoff from fire control water may cause pollution and, upon entering a sewer, may create an explosion hazard. 4-Xylene should be stored in closed containers, in cool, well ventilated areas (outdoor or detached areas are preferable), away from sources of ignition, oxidizing agents, and any activity that could cause physical damage to containers. For small spills of 4-xylene, take up with sand or other non-combustible absorbent and place in containers for later disposal, or absorb on paper and evaporate in an appropriate exhaust hood. For large spills, isolate the area, dike far ahead of the spill, and collect the material for disposal. 4-Xylene is a good candidate for the Belliot process of oxidative destruction, as well as liquid injection, rotary kiln, and fluidized bed incineration. 4-Xylene may be sent to a solvent disposal company, but prior to implementing any land disposal of waste residue (including waste sludge), consult regulatory agencies for guidance. DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Xylenes/ [R48] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Xylenes/ [R48] +Public safety: Call Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Xylenes/ [R48] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Xylenes/ [R48] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Xylenes/ [R48] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Xylenes/ [R48] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Xylenes/ [R48] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Xylenes/ [R48] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R49] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R49] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R49] FLMT: +% by vol: lower 1.1; upper 7.0 [R49] FLPT: +25 deg C (Closed cup) [R49] AUTO: +528 deg C [R49] FIRP: *Foam, dry chemical or carbon dioxide. Water may be ineffective. Cool exposed containers with water. [R4] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. /Xylenes/ [R50] OFHZ: +Vapors are heavier than air and may travel to a source of ignition and flashback. /Xylenes/ [R49] EXPL: *Moderate, in form of vapor, when exposed to heat or flame. [R51] REAC: *In liquid phase aerobic oxidation of p-xylene in acetic acid to terephthalic acid, it is important to eliminate the inherent hazards of this fuel-air mixture. Effects of temp, pressure and presence of steam on explosive limits of the mixture have been investigated. [R52, 713] *Oxidation of p-xylene with nitric acid under pressure in manufacture of terephthalic acid is an explosion hazard in autoclaves and condensing systems. [R52, p. 1165-66] *Can react with oxidizing materials. [R51] *An attempt to chlorinate xylene with 1,3-dichloro-5,5-dimethyl-2,4-imidazolidindione (dichlorohydrantoin) caused a violent explosion. The haloimide undergoes immediate self accelerating decomp in the presence of solvents. /Xylenes/ [R52, 524] +Strong oxidizers, strong acids. [R30, 336] ODRT: *Detection in air at 0.05 ppm. [R4] SERI: *Xylene vapor may cause irritation of the eyes, nose, and throat. At high concentrations, xylene vapor may cause severe breathing difficulties which may be delayed in onset. Repeated or prolonged exposure ... may cause a skin rash. /Xylenes/ [R53, 1981.1] *Vapor irritates eyes and mucous membranes and may cause dizziness, headache, nausea, and mental confusion. Liquid irritates eyes and mucous membranes. /Xylenes/ [R54] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum) ... to prevent repeated or prolonged skin contact with liquid or solid xylene. Clothing contaminated with xylene should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of xylene from the clothing. If the clothing is to be laundered ... the person performing the operation should be informed of xylene's hazardous properties. /Xylenes/ [R53, 1981.2] *Approved canister or air-supplied mask; goggles or face shield; plastic gloves and boots. [R4] *Breakthrough times /for natural rubber, neoprene, and polyvinyl chloride/ less (usually significantly less) than one hr reported by (normally) two or more testers. Breakthrough times /for polyvinyl alcohol/ greater than one hr reported by (normally) two or more testers. Some date suggesting breakthrough times /for nitrile rubber/ of approx an hour or more. /Xylenes/ [R55] +Wear appropriate personal protective clothing to prevent skin contact. [R30, 337] +Wear appropriate eye protection to prevent eye contact. [R30, 337] +Recommendations for respirator selection. Max concn for use: 900 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R30, 337] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R30, 337] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R30, 337] OPRM: +Contact lenses should not be worn when working with this chemical. [R30, 337] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Skin that becomes contaminated with xylene should be promptly washed with soap or mild detergent and water to remove any xylene. Employees who handle liquid or solid xylene should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. /Xylenes/ [R53, 1981.3] *A major concern in the painting studio is solvents, /including xylene/. ... Precautions include ... use of dilution and local exhaust ventilation, control of storage areas, disposal of solvent soaked rags in covered containers, minimizing skin exposure and the use of respirators and other personal protective equipment. The control of fire hazards is also important, since many of the solvents are highly flammable. /Xylenes/ [R56] +The worker should immediately wash the skin when it becomes contaminated. [R30, 337] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R30, 337] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. /Xylenes/ [R50] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. ... /Xylenes/ [R50] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R57] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R58] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R59] STRG: *Protect against physical damage. Store in well ventilated, cool places. Detached or outdoor storage is preferred. Separate from oxidizing agents and source of ignition. [R60, 559] *Ambient storage temp and open (flame arrester), or pressure-vacuum. [R4] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE RECLAIMED OR COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER. XYLENE SHOULD NOT BE ALLOWED TO ENTER CONFINED SPACE, SUCH AS SEWER ... /XYLENES/ [R53, 1981.4] *For spills on land, absorb remaining xylene with sand or vermiculite and put in metal containers for disposal. Activated carbon may be used on undissolved portion. /Xylenes/ [R61] *For spills on water, contain and apply a universal gelling agent to solidify trapped mass then remove it. /Xylenes/ [R61] *Soil: construct barriers to contain spill or divert to impermeable holding area. Remove material with pumps or vacuum equipment. Absorb residual liquid with natural or synthetic sorbents, shovel into containers with covers. /Xylenes/ [R62] *Water: contain with booms, weirs, or natural barriers. Use (oil) skimming equipment or suction hoses to remove slick, followed by application of sorbents. /Xylenes/ [R62] *Air: use water spray to control flammable vapor. Control runoff for later treatment and/or disposal. /Xylenes/ [R62] *Spillage Disposal: Shut off all possible sources of ignition. Wear face shield, goggles, laboratory coat, and nitrile rubber gloves. Cover spill with a 1:1:1 mixture by weight of sodium carbonate or calcium carbonate, clay cat litter (bentonite) and sand, then shovel into bucket and transport to fume hood for atmospheric evaporation. Ventilate site of spillage well to evaporate remaining liquid and dispel vapor. /Xylenes/ [R54] *Environmental considerations - air spill: Apply water spray or mist to knock down vapors. /Xylenes/ [R50] *Environmental considerations - water spill: Use natural barriers or oil spill control booms to limit spill travel. Use surface active agent (eg, detergent, soaps, alcohols), if approved by EPA. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Xylenes/ [R50] *Environmental considerations - land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. /Xylenes/ [R50] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U239 and F003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. /Xylenes/ [R63] *p-Xylene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R64] *A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. /Xylenes/ [R65] *Recommendable methods: Incineration, use as a boiler fuel, and evaporation. [R66] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of xylenes. There is inadequate evidence in experimental animals for the carcinogenicity of xylenes. Overall classification: Xylenes are not classifiable as to their carcinogenicity to humans (Group 3)./Xylenes, o,m,p isomers/ [R67] +CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Orally administered technical xylene mixtures did not result in significant increases in incidences in tumor responses in rats or mice of both sexes. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate. [R68] +A4. Not classifiable as a human carcinogen. /Xylene, o, m, p isomers/ [R69, 74] MEDS: *Physical examinations of exposed personnel annually, with special attention to eyes and central nervous system, and include complete blood count and studies of liver and kidney function. [R60, 557] HTOX: *Symptoms: Conjunctivitis, dermatitis, irritation to respiratory tract, dyspnea, anorexia, nausea, vomiting, fatigue, headache, vertigo (dizziness), incoordination, irritation, gangrene, anemia. [R60, 559] *Symptoms: Inflammation of the skin and mucous membranes; irritation of respiratory tract; hard to breath, lack of appetite, nausea, vomiting, fatigue, headache, dizziness, incoordination, irritability, CNS depression, anemia; partial paralysis of hands and feet. [R60, 557] *The concentration of xylene present in the blood, its serum or plasma, that has been reported to cause death, or is so far above reported therapeutic or toxic concentrations that one can judge that it might cause death in humans is 3-40 ug/ml. /Xylenes/ [R70] *Disturbances of memory, mood, equilibrium and sleep that occurred simultaneously with headache and indigestion, were experienced more frequently among women working in histology who had daily exposure to formaldehyde, xylene and toluene than in unexposed female clerical workers in the same hospitals. Neurobehavioral symptoms were accompanied by irritation of the eyes, upper air ways and trachea. Formaldehyde exposure correlated better with neurobehavioral symptoms and with respiratory and mucous membrane symptoms than did exposure to xylene/toluene or to other agents. /Xylenes/ [R71] *Vapor irritates eyes and mucous membranes and may cause dizziness, headache, nausea, and mental confusion. Liquid irritates eyes and mucous membranes. Swallowing or absorption through skin would cause poisoning. Prolonged exposure to skin contact may result in dermatitis. [R54] *All of the six volunteers were able to detect the odor of mixed xylenes at a concentration of 60 mg/cu m; four could detect 6 mg/cu m, but none could detect 0.6 mg/cu m. The odor threshold was calculated as 4.5 mg/cu m or about 1 ppm for a 10-sec exposure. In a 15-min exposure period, the only common sign of discomfort at 2000 mg/cu m (460 ppm) was eye irritation in four of six subjects. Some transitory olfactory fatigue occurred, with recovery in 10 min. /Xylenes/ [R72, 644] *Serum concentrations of liver enzymes were determined for Swedish paint industry workers exposed to a mixture of organic solvents including xylene. Mean xylene exposure for 44 individuals was 82 mg/cu m (19 ppm) with a range of 1 to 6070 mg/cu m; five workers were exposed to a mean concentration of 865 mg/cu m (199 ppm). Serum alanine aminotransferase, aspartate aminotransferase, ornithine carbamoyltransferase, and gamma-glutamyltransferase activities were not elevated by these exposures. /Xylenes/ [R72, 644] *... Sixteen male subjects /were exposed/ at 70 ppm p-xylene for 4 hours. Performance in tests of simple reaction time, short term memory, and choice reaction time remained unchanged after inhaling xylene. [R73, 1991.1736] *The quantitative relationship between exposure to xylene vapor and urinary excretion in methylhippuric acid isomers were studied in the second half of a working wk. The participants in the study were 121 male workers engaged in dip-coating of metal parts who were predominantly exposed to three xylene isomers. The intensity of exposure measured by diffusive sampling during an 8-hr shift was such that the geometric mean vapor concn was 3.8 ppm for xylenes (0.8 ppm for o-xylene, 2.1 ppm for m-xylene, and 0.9 ppm for p-xylene), 0.8 ppm for toluene, and 0.9 ppm for ethylbenzene. Urine samples were collected at the end of the shift and analyzed for metabolites by HPLC. The statistical analysis showed that there is a linear relationship between the intensity of exposure to xylenes and the concn of methylhippuric acid in urine, that the regression line passes very close to the origin, and that the increment in observed (i.e., noncorrected) methylhippuric acid concn as a function of incr xylene concn was 17.8 mg/ppm. Further exam on the basis on individual xylene isomers showed that the slopes of the regression lines for o- and m-isomers were similar (i.e., 17.1 and 16.6 mg/L/ppm, respectively), whereas that for p-xylene was larger (21.3 mg/L/ppm). [R74] NTOX: *Unlike benzene, chronic inhalation exposure to p-xylene, did not cause leukopenia in rats. [R75] *THE ACUTE IP LD50 OF P-XYLENE IN FEMALE RATS WAS 3.8 MG/KG. DOSAGES OF 0.1 MG/KG/DAY FOR 3 DAYS CAUSED MODERATE FATTY INFILTRATION OF THE LIVER. [R76, 180] *SUBACUTE EXPOSURE OF MALE SPRAGUE-DAWLEY RATS TO 2000 PPM P-XYLENE INCREASED DOPAMINE AND NORADRENALINE LEVELS AND TURNOVER IN VARIOUS PARTS OF THE HYPOTHALAMUS AND MEDIAN EMINENCE 16-18 HR FOLLOWING THE LAST EXPOSURE. [R77] *Increased hepatic cytochrome p450 concn and reduced nicotinamide adenine dinucleotide cytochrome C reductase activity occurred in rats exposed 3 days to 2000 ppm of p-xylene. In lung microsomes, cytochrome p450 content was decreased. [R78] *CFY mice were exposed to p-xylene at 150, 1500, or 3000 mg/cu m, 24 hr/day from days 7-14 of gestation. Toxic effects were decr wt of fetuses, incr incidence of skeletal retardation, and decr in activity of enzymes, succinic dehydrogenase, alkaline and acid phosphatase and glucose 6-phosphatase and changed characteristic features of functional maturity of the nephron, retardation of fetus was dose related. [R79] *CFY RATS WERE EXPOSED TO 3000 MG/CU M P-XYLENE ON 10TH, and 9TH AND 10TH DAYS OF GESTATION. EXPOSURE TO P-XYLENE DECR WT OF FETUSES AND PROGESTERONE AND 17 BETA-ESTRADIOL LEVELS OF PERIPHERAL BLOOD. IT WAS CONCLUDED THAT P-XYLENE, BY INDUCING THE HEPATIC MONOOXYGENASE SYSTEM, FACILITATES THE BIOTRANSFORMATION OF PROGESTERONE AND 17 BETA-ESTRADIOL, WHICH IS METABOLIZED BY THIS SYSTEM. THE DECR IN SEX HORMONE LEVEL OF PERIPHERAL BLOOD IS SUPPOSED TO PLAY A ROLE IN EMBRYOTOXICITY. [R80] *p-Xylene was nonmutagenic using the Ames assay. It did not revert Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, AND TA100 either with or without metabolic activation by S9 mix derived from livers of treated or untreated rats. [R81] *COD EGGS WERE EXPOSED TO SEAWATER SOLUTIONS OF XYLENES. TREATMENT DURING FERTILIZATION WITH M-XYLENE OR P-XYLENE INDUCED SIGNIFICANT DECR IN FERTILIZATION RATE AT CONCENTRATIONS GREATER THAN 10 PPM. FERTILIZED EGGS WERE EXPOSED 3 HR OR 6 HR BEFORE 1ST CLEAVAGE. EFFECTS UPON THE EARLY CLEAVAGE PATTERN WERE SIGNIFICANT FROM A CONCN INTERVAL OF 2-7 PPM. CHARACTERISTIC EFFECTS INCL INHIBITION OF FORMATION OF CLEAVAGE FURROW. SMALL CELLS OR TOTAL ABSENCE OF CLEAVAGE OCCURRED IN HIGHEST CONCENTRATIONS (16-35 PPM), WHILE AT 8-15 PPM, INCOMPLETE OR UNEVEN CLEAVAGE WAS USUAL. EXPOSURE TO LOWER CONCENTRATIONS COULD GIVE A VERY WRINKLED CLEAVAGE MEMBRANE. [R82] *Xylene was administered to CD-1 mice by gavage as the m-, o-, or p-isomer from days 6-15 of gestation at 0.30, 0.75, and 1.00 mg/kg body weight/dose, and from days 12-15 of gestation at 1.00 mg/kg body weight/dose ... overt maternal toxicity and a significantly incr incidence of resorptions among the offspring were noted only at the high dose level of m-xylene, these adverse effects and an incr incidence of cleft palate ... were noted at both the middle and high dose levels of o- and p-xylene. After exposure from days 12-15 of gestation to any isomer of xylene maternal toxicity was significantly increased; ... incr ... incidence of malformations ... mostly cleft palates, were observed only with m- or p-xylene. [R83] *... The effects of p-xylene on uterine and ovarian blood flow and on the peripheral blood levels of progesterone and 17-beta-estradiol in pregnant CFY rats /were studied/. Inhalation esposures to 3,000 mg/cu m for 24 or 48 hr (gestational day 10 or gestational days 9 and 10, respectively) did not alter the blood flow of gravid uteri in anesthetized animals; however, 48 hr exposures were associated with slight (nonsignificant) decreases in ovarian venous flow and significant reductions in blood levles of progesterone and 17-beta-estradiol. These effects were associated with significant reductions in fetal body weight; however, maternal body weights or body weight changes were not reported. [R80] *Genotoxic effects of 5 widely used aromatic industrial solvents, ethylbenzene, toluene, o-xylene, m-xylene and p-xylene, on bone marrow cells of male NMRI mice were studied using the micronucleus test. Each cmpd was given to animals by ip administration of 2 similar doses 24 hr apart. Increased formation of micronuclei within polychromatic erythrocytes of femoral bone marrow 30 hr after the first injection was conducted was apparently due to the clastogenic effect of the test cmpd. Of the chem tested, only toluene gave a dose-dependent increase in the frequency of micronucleated polychromatic erythrocytes. This genotoxic activity of toluene was confirmed in male B6C3Fl mice. [R84] *Two laboratories tested multiple forms of xylene for their developmental toxicity hazard potential (A/D ratio) by means of the hydra assay. The three isomers, as well as a solution of mixed xylenes, all interfered with development (D) at or near to concn that also were toxic to adult (A) hydra. The development/adult ratios ranged from 1 to 2 in hydra as they had in conventional tests made in pregnant laboratory animals. Each testing laboratory concluded that xylenes were not primary development hazards but coeffective agents capable of disrupting development only at or near to concn also toxic to adults. In each instance every xylene tested interfered with the same stage or developmental sequence and in a concn related manner. /Xylenes/ [R85] *Xylene, a widely used industrial solvent, is a mixture of the o-, m- and p- isomers. The effects of each individual isomer, and a commercial-grade mixture of xylenes on 2 behavioral measures: operant performance of 15 mice trained to lever-press under a DRL (different reinforcement of low rates) 10 sec schedule, and motor performance of mice on an inverted screen test were studied. The 15 min operant sessions immediately followed 30 min exposures to solvent vapors (500-7000 ppm), or air, in static inhalation chambers. o-, m-, p- and Mixed xylenes produced similar biphasic effects on response rates, and concentration dependent decreases in reinforcement rates. The lowest significantly effective concentration for each isomer on any variable was 1400 ppm, where increases in response rates occurred. Half-maximal response rate decreases /ranged from/ 5179 ppm (o-xylene) to 6176 ppm (m-xylene). The temporal distribution of responses was only moderately disrupted, even at high concentrations. In other groups of mice, motor coordination was also disrupted by the xylenes in a concentration dependent manner. Half-maximal effective concentrations /ranged from/ 2676 ppm (p-xylene) to 3790 ppm (m-xylene). [R86] *PRETREATMENT OF RATS WITH PHENOBARBITAL INCR THE LD50 OF PARA-XYLENE MORE THAN 20%. [R75] *Data obtained from rodents indicates that maternal exposure to mixed xylenes or individual xylene isomers can have adverse effects on the conceptus. Fetotoxic effects were reported following maternal inhalation exposure to mixed xylenes; altered enzyme activities were also found in rat pups. Dermal application resulted in apparent changes in fetal enzyme activities, while oral treatment was followed by prenatal mortality, growth inhibition, and malformations, primarily cleft palate. Maternal inhalation of individual isomers was associated with all the above mentioned effects, with the exception of cleft palate. The o- and p- isomers appeared more hazardous to the offspring than did the m-isomer. Malformations (ie cleft palate) associated with mixed or individual isomers were primarily reported at maternally toxic doses. Thus, a clear case for a selective teratogenic effect due to the exposure to xylene has yet to be presented. [R87] *... Mixed xylenes (60% m-, 14% p-, and 9% o-xylene and 17% ethylbenzene) in corn oil were administered by gavage to mice and rats 5 days/week for 103 weeks. Mice received daily doses of 500 or 1000 mg/kg; rats received 250 or 500 mg/kg. No gross or histopathological lesions were related to these treatments; tumor incidence was similar for treated and control groups of either species. There was no evidence for carcinogenicity. When tested for mutagenicity, o-, m-, and p-xylene were negative by assay in the Ames system using Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, and TA100 with or without metabolic activation by S9 fraction derived from livers of rats either untreated or induced with Aroclor 1254. Xylene did not change the number of sister chromatid exchanges or the number of chromosomal aberrations in human lymphocytes in vitro. /Xylenes/ [R72, 644] *Teratogenicity has been evaluated for a xylene mixture (9.1% o, 60.2% m, 13.6% p, and 17.0% ethylbenzene) in pregnant albino CD-I mice given the mixture at dosages of 2.4, 3.0, and 3.6 mL/kg/day by gavage on days 6-15 of gestation. ... xylene produced a significant increase in malformations, with cleft palate being the major malformation observed. Exposure of CFY rats to 1000 mg/cu m (230 ppm) xylene for 24 hr/day from day 9 to 14 of gestation was not teratogenic, although there was an increase in skeletal anomalies consisting of extra ribs and fused sternebrae. [R72, 644] *In rats exposed to 1000, 1500, and 2000 ppm p-xylene in 4 hr, dosage-dependent increases were measured in serum concentrations of glutamic-pyruvic transaminase (GPT), glutamic-oxaloacetic transaminase (GOT), glucose-6-phosphate (dehydrogenase (G-6-PDH), isocitrate dehydrogenase (ICD), lactate dehydrogenase (LDH), glutathione reductase, and 5'-nucleotidase. Glutamic-pyruvic transaminase, and glutamic-oxaloacetic transaminase were elevated by even the lowest exposure. Surprisingly, serum cholinesterase was increased by all exposure concentrations at the termination of the exposure, although there was no increase after 24 hr. [R72, 644] *Rats exposed 6 hr/day for 3 days to 2000 ppm of a xylene mixture of the o, m, and p isomers showed an increase in hepatic cytochrome p450 and NADPH-cytochrome c reductase. The p isomer was less potent in inducing this effect that the other isomers or the mixture. Microsomes from lung and kidney also showed increases in cytochrome p450 for the xylene mixture and isomers except the p isomer failed to induce cytochrome p450 in microsomes from kidney. [R72, 644] *Mixed xylenes or the individual isomers were not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537 either in the presence or absence of induced rat or hamster hepatic (S9) activation. [R73, 1991.1735] *When rats inhaled p-xylene at 1000, 1500, or 2000 ppm for 4 hours, serum enzyme activities increased; these changes were indicative of acute hepatocellular damage. [R73, 1991.1732] *When rats were exposed orally to 2.5 ml/kg p-xylene 6 of 10 animals died. /From table/ [R39, 3292] *p-Xylene was lethal to rats exposed to 4912 ppm (21.1 mg/l)/24 hr. /From table/ [R39, 3293] *p-Xylene produces ... /CNS depression/ in mouse at 2300 ppm (10 mg/l). /From table/ [R39, 3293] *Groups of 25 Sprague Dawley rats were exposed by inhalation to 0, 3500, or 7000 mg/cu m para-xylene (purity, 99%) for 6 hours per day on days 7-16 of gestation, and the offspring were evaluated for growth, viability and neurobehavioral development. The high dose level reduced maternal weight gain during the exposure period, but growth, viability, locomotor activity and the acoustic startle response of the offspring were not affected. [R88] *This study assessed effects of exposure to p-xylene ... on mice infected with murine cytomegalovirus, a mouse model for a common human virus. It was postulated that adverse health effects could occur as a results of (1) enhanced infection due to xylene-induced immune suppression, (2) incr p-xylene toxicity due to viral suppression of cytochrome P-450, and/or (3) additive or synergistic effects on liver function due to tissue injury by both p-xylene and murine cytomegalovirus. Mice were exposed to filtered air, 600 or 1200 ppm p-xylene 6 hr/day for 4 day and infected with a sublethal dose of murine cytomegalovirus after the first exposure. No deaths occurred among uninfected, p-xylene-exposed mice or infected, air-exposed mice; 34% and 0% mortality occurred respectively in infected mice exposed to 1200 and 600 ppm p-xylene. Virus titers in the liver and splenic natural killer cell activity were unaffected by exposure to 1200 ppm p-xylene. Small but significant incr in serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase activities ... were observed at 4 days postinfection. p-Xylene exposure had no effect on these serum enzyme activities in uninfected mice, but 1200 ppm potentiated this effect in infected mice. Murine cytomegalovirus significantly suppressed and p-xylene significantly incr total P-450 levels in the liver, but there was no significant interaction between the two. Isozymes 1A1, 2B1/B2, and 2E1 were decr to a similar degree, suggesting that the virus does not target specific isozymes. Enhanced mortality was not due to immune suppression. While p-xylene-potentiated liver damage was caused by the virus, the magnitude of serum enzyme activities indicates that this damage was not a likely cause of death. The cause of deaths is unclear, results were consistent with the hypothesis that enhanced mortality was related to enhanced xylene toxicity due to suppression of P-450, although additive or synergistic damage to tissues other than liver cannot be ruled out. [R89] *Pregnant Sprague-Dawley rats were exposed to either 3500 or 7000 mg/cu m p-xylene from days 7-16 of gestation. Dams were allowed to give birth, and litters were counted, weighed, and observed for external malformations on postnatal days 1 and 3. Litters were normalized to 8 pups (4/sex) on postnatal day 4. On postnatal day 21 animals were weaned and littermates housed by sex. Body weights were recorded weekly until weaning and once every 2 wk thereafter. CNS development was evaluated by acoustic startle response on postnatal days 13, 17, 21, and 63 as well as figure-8 maze activity on days 22 and 65. Maternal weight gain during the treatment period was significantly less in the high-dose group. No effects were seen on litter size or weight at birth or on postnatal day 3. There were no effects of p-xylene exposure on growth rate. There were no treatment-related effects on acoustic startle response or figure-8 maze activity. Thus, p-xylene as admin in this study does not appear to be a selective developmental toxicant in the rat. [R90] *The time and dose dependency of visual evoked potential changes following oral admin of p-xylene and toluene were examined using adult male Long-Evans-hooded-rat. Both these chemicals affected the processing of visual data at exposures far below those assoc with lethality. The most evident effect was a depression in peak N3 amplitude. P2 amplitude was incr in the toluene study and in one of the p-xylene studies. The lowest concn of either chemical to cause an observable effect was 250 mg/kg for p-xylene and 125 mg/kg for toluene. A depressed amplitude of FEP peak N3 occurred following either oral or inhalation exposures to p-xylene and following oral exposure to toluene. The studies indicated a greater depression of peak N3 amplitude at 500 mg/kg, an inconsistent incr in peak P2 amplitude, and no change in peak N1 amplitude. A difference in the potency of the two cmpd was suggested, along with a difference in mechanism from that by which ethanol or sulfolane exert their effects. Both p-xylene and toluene appear to influence the manner in which the brain processes visual info. The possibility that this alteration may result from changes in arousal or excitability was noted. [R91] *To evaluate the possibility that p-xylene affects cognitive behavior, male Long-Evans hooded rats inhaled p-xylene at concn of 0 or 1600 ppm, 4 hr per day for 1 to 5 days, and were evaluated after exposure on two learning tasks and a test of motor activity. Autoshaping was carried out across 5 successive days with p-xylene exposure in the morning followed by testing in the afternoon. For this test, the retraction of single response lever on a variable-time 35-sec schedule was followed by delivery of a food pellet. When the force required to depress the lever was low (0.10 N), response acquisition was faster in animals having inhaled 1600 ppm p-xylene than in air-exposed controls, When the force was incr to 0.20 N, however, p-xylene-exposed rats acquired the response no faster than controls. In contrast, inhaled p-xylene at 1600 ppm suppressed response rates in an automaintained reversal learning paradigm without affecting reversal rate. Studied of motor activity showed that while vertically-directed activity was unaffected by p-xylene, horizontally-directed activity was incr by about 30% for the first 15 min of each daily 25-min test. [R92] *RATS GIVEN SINGLE IP INJECTION OF P-XYLENE SUFFERED 65% LOSS OF PULMONARY MICROSOMAL P-XYLENE HYDROXYLASE ACTIVITY. PRETREATMENT WITH PHENOBARBITAL INCR HEPATIC P-XYLENE HYDROXYLASE AND CYTOSOLIC ALDEHYDE DEHYDROGENASE ACTIVITIES BUT HAD NO EFFECT ON ALC DEHYDROGENASE ACTIVITY IN HEPATIC CYTOSOL. EXPERIMENTS IN VITRO SHOWED THAT INACTIVATION OF CYTOCHROME P450 BY P-XYLENE REQUIRED METABOLIC CONVERSION OF P-XYLENE TO P-TOLUALDEHYDE. IN AS MUCH AS LUNG TISSUE CANNOT FORM P-TOLUALDEHYDE (BECAUSE OF LOW ACTIVITY OF P-METHYLBENZYL ALC DEHYDROGENASE), IT IS ASSUMED THAT INACTIVATION OF LUNG ENZYMES IN VIVO FOLLOWING EXPOSURE TO P-XYLENE WAS DUE TO THE ALDEHYDE INTERMEDIATE WHICH IS FORMED IN THE LIVER AND TRANSPORTED TO THE LUNG. [R93] *IN VITRO ACTIVATION EXPT DEMONSTRATED THAT ... RABBIT HEPATIC BUT NOT PULMONARY MICROSOMAL ENZYME SYSTEMS WERE AFFECTED BY PHENOBARBITAL PRETREATMENT. /IN RABBITS/ PHENOBARBITAL, 3-METHYLCHOLANTHRENE, AND CHLORPROMAZINE RAISE LC50 OF INHALED P-XYLENE, BUT ONLY 3-METHYLCHOLANTHRENE HAD ANY EFFECT ON INJECTED SOLVENT. [R39, 3298] NTXV: *LD50 Rat oral 4.3 g/kg /Xylene/; [R72, 643] *LD50 Rat oral 10 mL/kg /Xylene/; [R72, 643] *LD50 Mouse oral 1590 mg/kg /Xylene/; [R72, 643] *LC50 Rat oral 29,000 mg/cu m (6670 ppm) /Xylene/; [R72, 644] *LC50 Mouse inhalation 3900 ppm for 6 hr exposure; [R73, 1991.1732] ETXV: *LC100 Tetrahymena pyriformis (ciliate) 3.77 mmole/l/24 hr /Conditions of bioassay not specified/; [R37, 1194] *LC50 Crangon franciscorum (shrimp) 2.0 ppm/96 hr /Conditions of bioassay not specified/; [R37, 1194] *LC50 Poecilia reticulata (guppy) 35 ppm/7 day /Conditions of bioassay not specified/; [R37, 1194] *TLm Bluegill fresh water 22 ppm/96 hr /Conditions of bioassay not specified/; [R94] *LC50 Morone saxatilis (bass) 2.0 ppm/96 hr /Conditions of bioassay not specified/; [R37, 1194] *LD50 Goldfish 18 mg/l/24 hr /Modified ASTM D 1345 method/; [R37, 1194] *TLm Fathead minnow 27-29 mg/l/24-96 hr. /Conditions of bioassay not specified/; [R37, 1194] TCAT: ?In an acute toxicity study, male Charles River rats (5/group) were given single gavage exposures to p-xylene. The animals were observed for up to 14 days following exposure. Exposure levels of 2.025, 3.038, 4.556, and 6.834 g/kg resulted in the following mortality results (number of deaths): 0, 0, 2, and 4, respectively. Most of the deaths occurred within 2 days. The LD50 is 5.145 g/kg. Gross pathological examination of the animals which died during the study revealed gastroenteritis and pale, discolored kidneys whereas examination of the survivors did not reveal any pathologic alterations. Reactions observed at all dose levels included hypoactivity and rhinitis. At 3.038 g/kg and above, the animals also exhibited ruffed fur, muscular weakness, salivation, and tremors. At 4.556 g/kg and above, the animals also exhibited prostration and hemorrhagic lacrimation. [R95] ?In an acute toxicity study, male and female albino rabbits (2/sex/group, strain not reported) were given single dermal exposures on abraded skin to p-xylene at dose levels of 200 and 3,160 mg/kg. The animals were observed for 14 days following exposure. None of the animals died during the study. The test material was severely irritating to the skin with the skin changes at 24 hours being characterized by red, well-defined erythema, mild edema, and second degree burns. Escharosis was noted at 7 and 14 days. No gross tissue pathology except for the local skin changes was observed at autopsy which could be attributed to the test material. [R96] ?In an acute toxicity study, male and female Charles River rats (3 males and 2 females/control group, 5/sex/treated group) were given single inhalation exposures to p-xylene at a nominal concentration of 34.7 mg/liter for 6 hours. The animals were observed for 14 days following exposure. The exposure atmospheres were produced by passing a stream of clean, dry air through undiluted test material at ambient temperature. None of the animals died during the study and 14-day body weight gains were comparable for the treated and control animals. The treated animals exhibited tremors and exophthalmos during the study. No gross tissue pathology was observed at autopsy which could be attributed to the test material. [R97] ?In an acute toxicity study, male and female Charles River mice (3 males and 2 females/control group, 5/sex/treated group) were given single inhalation exposures to p-xylene at a nominal concentration of 34.7 mg/liter for 6 hours. The animals were observed for 14 days following exposure. The exposure atmospheres were produced by passing a stream of clean, dry air through undiluted test material at ambient temperature. One of the treated female animals died during the study and advanced autolysis was found in this mouse during gross pathological examination. No gross tissue pathology was observed in the surviving animals at autopsy which could be attributed to the test material. The 14-day body weight gains were comparable for the treated and control animals. The treated animals exhibited tremors during the study. [R97] ?In an acute toxicity study, male and female Charles River guinea pigs (3 males and 2 females/control group, 5/sex/treated group) were given single inhalation exposures to p-xylene at a nominal concentration of 34.7 mg/liter for 6 hours. The animals were observed for 14 days following exposure. The exposure atmospheres were produced by passing a stream of clean, dry air through undiluted test material at ambient temperature. None of the animals died during the study and 14-day body weight gains were comparable for the treated and control animals. The treated animals exhibited tremors during the study. No gross tissue pathology was observed at autopsy which could be attributed to the test material. [R97] ?An acute inhalation toxicity study was conducted with groups of male and female albino Wistar rats (3/sex/group) receiving whole body exposure to the vapors of p-xylene in a dynamic air flow chamber. The vapor was generated in a glass flask containing the test substance maintained at 20 +/- 1 degrees celsius. Maximum exposure was for 7 hours, but if deaths occurred during either the exposure period or observation period, exposures were repeated at shorter intervals. During the 7 hour exposure, all the animals died during the exposure. Therefore the test was repeated, and two additional test were preformed at exposure times of 1 hour and 30 minutes. No deaths were reported for the 30 minute group rats. For the 1 hour exposed animals, 2 males died on the day 1 and 1 female died on day 6 of the observation period. During all exposures animals were observed with body tremors, lachrymation, salivation, agitation, semi-comatose, comatose, Cheyne-Stokes breathing, facial and eye twitching, involuntary muscle spasms and hind leg paddling action. One hour group survivors appeared to recover by day 1-3 and 30 minute animals recovered rapidly after exposure. The theoretical saturated concentration of p-xylene at 20 degrees celsius was calculated to be 8560ppm and the concentrations by weight loss estimation was calculated to be 8800, 9100 and 9000ppm for the 7, 1 and 0.5 hour exposure, respectively. [R98] ?p-Xylene (CAS# 106-42-3) was evaluated for carcinogenicity. The test substance was painted on the hairless skin of the backs of C3H/HeJ male mice (40/group), 3 times a week, until death ensued (25-months). One brushful of test material undiluted was applied at each painting. The brush delivered between 0.01 and 0.02 grams per mouse per application. It was concluded that tumorigenicity was negative with only 1 tumor (papilloma) detected. [R99] POPL: *... Those individuals with diseases of the central nervous system, liver, kidneys, or blood. [R60, 557] ADE: *For exposure to xylene at concn averaging 100 ppm, the mean methyl hippuric acid concn should average 1.5 to 2 g/g creatinine (range 1.0-3.0) in a sample collected during the second part of the exposure period. Almost total urinary excretion of xylene occurs by 24 hours. The rapid xylene clearance from blood (plasma half-life of 4 hours) prevents adequate biological monitoring of serum samples. /Xylenes/ [R100] *XYLENES HAVE BEEN REPORTED TO CROSS THE HUMAN PLACENTA. /XYLENES/ [R76, 180] *XYLENE, WHEN INGESTED, IS READILY ABSORBED BY THE HUMAN SYSTEM, AS HAS BEEN SHOWN IN ACCIDENTAL INGESTIONS. ABSORPTION THROUGH INTACT AND BROKEN SKIN OCCURS READILY. ... XYLENE IS ABSORBED MAINLY THROUGH MUCOUS MEMBRANES AND PULMONARY SYSTEM. ... ABSORBED XYLENE IS TRANSLOCATED THROUGH THE VASCULAR SYSTEM. ... /XYLENES/ [R39, 3296] *Humans exposed to 46 or 92 ppm of o-, m-, p-xylene or a mixture (1:1:1) of the three for 8 hr absorbed approx 64% of the inhaled xylene. No difference in the absorption rate was reported due to level of exposure, length of exposure, or the type and/or mixture of the xylene isomers. The absorption of xylene appeared to vary among individuals due to differences in ventilation rate. ... Individuals with an incr ventilation rate retained less xylene. [R101] *Male Wister rats exposed to xylene in air (80% m-xylene, 12% p-xylene) for 6 hr/day, 5 days/week for 2 weeks accumulated 64.8 mg xylene/g of perirenal fat after five exposures and 127.0 mg xylene/g of perirenal fat after 10 exposures to xylene. [R102] *That vapors may ... be absorbed through the skin of male human volunteers aged 20 to 35 years wearing supplied air respirators and light pajamas and socks was demonstrated for exposures of 600 ppm of xylene ... at 25 deg C at 50% RH for 3.5 hr. The estimated dermal exposure compared with inhalation exposure over the same exposure time frame, assuming inhalation and skin to be the only two absorption routes ... /was/ 1.4% ... The dermal exposure absorption uptake for xylene was calculated to be 6 nmol/sq cm/hr even though liquid xylene can penetrate skin quickly at 1.13 umol/sq cm/hr. /Xylene/ [R103] *In a ... study with 20 ppm xylene, the uptake from inhalation alone was 57.7% ... but with much interindividual variability. Dermally absorbed xylene in the form of urinary methylhippuric acid was excreted 2 to 4 hr later than absorbed xylene from inhalation. ... Delays of several minutes occurred in the percutaneous absorption of liquid ... xylene, but these delays increased to about 1 hr for xylene ... to achieve a steady state. /Xylene/ [R103] *In rats exposed to 208 mg/cu m methyl-(14)C para-xylene for 1 hour, distribution of radioactivity immediately after termination of the exposure was highest in the kidneys, followed by subcutaneous fat, ischiatic nerve, blood, liver and lungs. Activity was 1/5 to 1/30 of these levels 6 hours after the end of exposure. [R104] *Pregnant mice were exposed by inhalation to (14)C para-xylene (theoretical concentration, 2000 ppm (8680 mg/cu m)) for 10 min on days 11, 14 or 17 of gestation, and distribution of the label was determined 0, 0.5, 1 and 4 hours after exposure. The label quickly entered the embryo, but uptake was low relative to maternal tissues. All fetal activity was extractable, indicating that no firmly bound metabolite was present. [R105] *Most of the xylene that is absorbed is excreted rapidly into the urine as metabolites. When rabbits were given oral doses of up to 1.8 g each of the three isomers, separately, well over 50% of the radioactivity was recovered in urine within 24 hours. [R104] *When 3 mmol/kg ortho-, meta-, or para-xylene were given intraperitoneally to rats, urinary excretion of thiocompounds was highest with ortho-xylene and much lower with meta-xylene and para-xylene. [R104] *Following exposure of rabbits to an atmosphere of about 3000 mg/cu m (690 ppm) for 3 hr/day, 6 days/week for 130 days, xylene /9.1% ortho, 60.2% meta, and 13.6% para isomers/ was found at slightly higher average concentration in the adrenal (148 ppm), bone marrow (130 ppm), spleen (115 ppm), and brain (100 ppm) than in blood (91 ppm) or in other organs. [R72, 644] METB: */WHEN ADMIN TO RABBIT, RAT AND GUINEA PIG/ P-XYLENE WAS EXCRETED AS P-TOLUIC ACID DERIV, BUT ALSO A 2,5-DIMETHYLPHENOL GLUCURONIDE WAS ISOLATED ... ACCORDING TO ONE REPORT, O-, M-, AND P-XYLENE, IN DECREASING ORDER, ARE DEMETHYLATED TO PHENOL. GENERALLY, THE XYLENES ARE METABOLIZED TO CORRESPONDING O-, M-, P-TOLUIC ACIDS ... AND EXCRETED IN URINE FREE OR CONJUGATED WITH GLYCINE AS METHYLHIPPURIC ACID. [R39, 3298] *IN HUMANS ... EXPOSED TO APPROX 0.2-0.4 MG/L XYLENE ISOMERS (O-, M-, P-XYLENE) OR 1:1:1 MIXT FOR UP TO 8 HR ... PULMONARY RETENTION WAS 64%, WHICH WAS ... INDEPENDENT OF DOSAGE OR DURATION OF EXPOSURE. AFTER EXPOSURE, ONLY 5% OF RETAINED XYLENES WERE ELIM IN EXPIRED AIR. MORE THAN 95% ... EXCRETED BY HUMANS INTO URINE IN FORM OF METHYLHIPPURIC ACIDS. ... SMALL PORTION ... EXCRETED INTO URINE AS CORRESPONDING XYLENOLS. [R76, 179] *PSEUDOMONAS AERUGINOSA CONVERTS P-XYLENE INTO P-METHYLBENZYL ALCOHOL AND POSSIBLY FURTHER TO METHYLBENZOIC ACID. [R39, 3298] *METAB OF P-XYLENE (100 UMOL) STUDIED IN ISOLATED, PERFUSED RABBIT LIVERS AND LUNGS. RELEASE OF P-TOLUALDEHYDE INTO CIRCULATION DID NOT OCCUR IN PERFUSED RABBIT LIVERS. P-TOLURIC ACID (N-P-TOLUYLGLYCINE) WAS MAJOR HEPATIC METABOLITE, WITH SMALLER AMT OF TOLUIC ACID AND P-METHYLBENZYL ALCOHOL. RABBIT LIVERS DID NOT PRODUCE DETECTABLE AMT OF P-TOLUALDEHYDE, 2,5-DIMETHYLPHENOL OR ANY GLUCURONIDE CONJUGATES. ONE MAJOR PULMONARY METAB WAS P-METHYLBENZYL ALC. PREDOMINANCE OF THIS METAB REFLECTS DEFICIENCY OF LUNG TISSUE IN ALC DEHYDROGENASE. PERFUSED LUNG ALSO PRODUCED 2,5-DIMETHYLPHENOL A DERIVATIVE NOT PRODUCED IN THE LIVER. DURING P-XYLENE METAB IN PERFUSED LUNGS, DERIVATIVES WHICH BECAME COVALENTLY BOUND TO LUNG PROTEINS WERE FORMED WHICH SUGGESTS THAT P-XYLENE METAB MIGHT PROCEED AT LEAST PARTIALLY THROUGH REACTIVE INTERMEDIATE(S) CAUSING DESTRUCTION OF PULMONARY CYTOCHROME P450. METAB WAS ALSO CHARACTERIZED USING RECONSTITUTED MONOOXYGENASE SYSTEMS CONTAINING PURIFIED RABBIT PULMONARY LUNG CYTOCHROME P450 (I) and (II). [R106] *THE INVOLVEMENT OF SEQUENTIAL SIDE-CHAIN OXIDN, SULFATION, AND GLUTATHIONE CONJUGATION IN FORMATION OF MERCAPTURIC ACIDS FROM XYLENES WAS INVESTIGATED. THE POSITION OF METHYL GROUPS ATTACHED TO THE AROMATIC NUCLEUS AFFECTED METABOLISM. FACTORS THAT ARE INVOLVED IN HIGH YIELD OF MERCAPTURIC ACIDS AFTER ADMIN OF O-XYLENE AS COMPARED TO M-XYLENE AND P-XYLENE INCL RELATIVELY LOW APPARENT AFFINITY OF O-METHYLBENZYL ALCOHOL FOR CYTOSOLIC ALCOHOL DEHYDROGENASE, THE RELATIVELY HIGH APPARENT AFFINITY OF O-METHYLBENZYL ALC FOR CYTOSOLIC SULFOTRANSFERASE, AND THE HIGH ELECTROPHILIC REACTIVITY OF THE O-METHYLBENZYL SULFATE. [R107] *META AND PARA ISOMERS ARE ... EXTENSIVELY OXIDIZED TO TOLUIC ACIDS (ABOUT 90% OF THE DOSE), AND THESE ARE CONJUGATED MOSTLY WITH GLYCINE. HYDROXYLATION TO CORRESPONDING XYLENOLS ALSO OCCURS TO A SMALL EXTENT. [R108] *GENERALLY, THE XYLENES ARE METABOLIZED TO CORRESPONDING O-, M-, P-TOLUIC ACIDS ... AND EXCRETED IN URINE FREE OR CONJUGATED WITH GLYCINE AS METHYLHIPPURIC ACID. ... A LINEAR RELATIONSHIP WAS FOUND BETWEEN ATMOSPHERIC XYLENE CONCN AND EXCRETED TOLUIC ACID. /XYLENE/ [R39, 3296] *Xylenes are metabolized both in the liver and lungs, primarily at a side-chain, to form methylhippuric acid and toluic acid (methylbenzoic acid) glucuronide as major metabolites and methylbenzyl mercapturic acid as a minor metabolite. They are metabolized to a lesser extent at the aromatic ring to form dimethylphenol. The ratio among the metabolites varies depending on the isomer and the species of animal. [R104] *In rats, guinea pigs, and rabbits, all three isomers /ortho-, meta-, and para-xylene/ are oxidized on the methyl group to form the corresponding toluic acid or on the ring to form phenols. There was no evidence that both methyl groups were oxidized; unconjugated 3,5-dimethylphenol and its glucuronide were isolated from urine. In rats exposed to atmospheres of m-xylene and ethylbenzene, methylhippuric acid, dimethylphenol, and methylbenzene alcohol were identified in urine as metabolites of m-xylene. [R72, 644] INTC: *Sixteen men were studied in an exposure chamber to assess the effect of four hr exposure to toluene (3.25 mmole/cu m), p-xylene (2.84 mmole/cu m) a mixture of toluene and p-xylene (2.20 + 0.94 mmol/cu m) and a control condition. With the aid of microcomputers subjects performed tests of simple reaction time, short term memory, and choice reaction time immediately after entering the chamber, after two, and after four hours of exposure. The results indicate that the performance on the tests was unaffected by exposure. In the light of this result, the risk of an acute effect on central nervous functions after exposure for four hours at these concn was considered to be minimal. [R109] *Eight male subjects were exptl exposed to toluene, p-xylene, and a combination of toluene and p-xylene to study the influence of coexposure and exposure to different levels of each solvent on their uptake and elimination. The exposures were performed for 4 hr at exposure levels equiv to or lower than the Swedish threshold limit value for toluene, 300 mg/cu m (3.2 mmol/cu m). During and after the exposure, solvent concn were measured in blood and in expired air. In addition, the pulmonary ventilation rate was measured during the exposure. Decreases in the blood/end exhaled air concn ratio were found for both toluene and p-xylene when given in combination compared with separate exposure. The total solvent uptake relative to the exposure level was decreased after exposure to the higher solvent concn, and the apparent clearance was also decreased after exposure to the higher concn of solvent. Finally, the blood solvent concn were lower at the end of the exposure compared with the maximal concn during each exposure condition. In the kinetics of toluene and p-xylene, the total amt of toluene or p-xylene, or both, seems to be of major importance. The change in blood/end exhaled air concn ratio may indicate an effect of coexposure. [R110] *... When consumed prior to exposure, ethanol decreases the metabolic clearance of xylene by approximately one-half. /Xylenes/ [R100] *It is unclear whether the pneumotoxicity observed with bromobenzene in phenobarbital-induced rats is related to bromobenzene bioactivation in lung, liver or both. To help differentiate pulmonary from hepatic bioactivation, bromobenzene was admin alone and in combo with p-xylene, which inhibits pulmonary but induces hepatic cytochrome P450. Exposure to p-xylene alone (3400 ppm for 4 hr) produced no changes in bronchoalveolar lavage fluid measurements ... or serum sorbitol dehydrogenase. p-Xylene incr hepatic microsomal benzyloxy-, pentoxy-, and ethoxy-resorufin O-dealkylase activities but decr pulmonary microsomal benzyloxy- and pentoxy-resorufin O-dealkylase activities. Immunoblot analysis revealed an induction of hepatic but not pulmonary microsomal P450IIB apoprotein. When rats were exposed to p-xylene (2800 ppm) or room air for 4 hr, treated 12 hr later with bromobenzene (0.5 mL/kg, ip) or corn oil, and killed after 12 hr, p-xylene incr hepatic P450IIIB (27-fold) concomitant with a similar incr in benzyloxy-resorufin O-dealkylase activity. p-Xylene also incr hepatic P450IA apoprotein (3 to 4-fold) with a complimentary incr in ethoxy-resorufin O-dealkylase activity. p-Xylene potentiated bromobenzene-induced hepatotoxicity. In pulmonary microsomes p-xylene and bromobenzene each produced similar decr in both ethoxy- and benzyloxy-resorufin O-dealkylase activities. The combination of p-xylene and bromobenzene had an additive effect on pulmonary P450IA1 reduction. Bronchoalveolar lavage fluid analysis and histopathology revealed no pneumotoxicity with any treatment. p-Xylene potentiation of bromobenzene-induced hepatotoxicity without pneumotoxicity suggests that the liver does not produced metabolites of bromobenzene which are directly involved in pulmonary damage. [R111] *The effects of p-xylene and ethanol on the lung metabolism of benzo(a)pyrene were studied. p-Xylene was admin by ip injection at doses ranging from 0.1 to 1.0 g/kg (1:1 in soybean oil). Ethanol was admin po at 5 g/kg (40% w/v). Rats given p-xylene, ethanol, or p-xylene and ethanol were sacrificed 1 hr after treatment. Additional time points of 15 min, 30 min, 4 hr, and 24 hr after p-xylene (1 g/kg) were examined. 3-Hydroxy-benzo(a)pyrene (3-OH) formation was measured fluorometrically as aryl hydrocarbon hydroxylase activity in lung microsomes. p-Xylene (1 g/kg) inhibited the formation of 3-OH benzo(a)pyrene 40% at 15 min, 27% at 30 min, 43% at 1 hr, and 39% at 4 hr after treatment. Inhibition of aryl hydrocarbon hydroxylase activity was still present 24 hr after dosing (41%). Aryl hydrocarbon hydroxylase activity was inhibited 27% and 46% at 0.5 mg/kg and 1.0 mg/kg p-xylene (1 hr), respectively, while the lowest dose (0.1 mg/kg) did not change activity. Analysis of the major metabolites of benzo(a)pyrene by HPLC demonstrated that the formation of 3-OH and 4,5-diol benzo(a)pyrene were inhibited 32% and 50%, respectively, in lung microsomes prepared 24 hr after a single injection of p-xylene (1 g/kg). None of the other metabolites analyzed were changed by p-xylene. Ethanol had no effect on 3-OH benzo(a)pyrene formation during a 1-hr treatment. A combined dose of ethanol and p-xylene moderately inhibited 3-OH benzo(a)pyrene formation. These findings indicate that benzo(a)pyrene detoxication (i.e., 3-OH formation) in rat lung is selectively inhibited by p-xylene but not ethanol. Ethanol appears to modify the inhibitory effect of p-xylene. [R112] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4-Xylene's production and use in petroleum products, as a chemical solvent and intermediate, and for the manufacture of terephthalic acid and herbicides may result in its release to the environment through various wastestreams. Naturally occurring sources of 4-xylene such as petroleum, forest fires and the volatiles of plants may also account for this compounds presence in the environment. 4-Xylene will enter the atmosphere primarily from fuel emissions and exhausts linked with its use in gasoline. Based upon an experimental vapor pressure of 8.84 mm Hg at 25 deg C, it is expected to exist solely in the vapor phase in the ambient atmosphere. Vapor-phase 4-xylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an atmospheric half-life of about 27 hours. 4-Xylene is expected to have moderate mobility in soils based upon experimental Koc values obtained for a variety of soils at differing pH values and organic carbon content. Volatilization from dry soil surfaces is expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is expected based on an experimental Henry's Law constant of 6.9X10-3 atm-cu m/mole. Biodegradation is an important environmental fate process for 4-xylene. In general, it has been found that 4-xylene is biodegraded in soil and groundwater samples under aerobic conditions and may be degraded under anaerobic denitrifying conditions. In water, 4-xylene is expected to adsorb somewhat to sediment or particulate matter based on its measured Koc values of 246 and 540 in silt and sandy loams respectively. This compound is expected to volatilize from water surfaces given its experimental Henry's Law constant. estimated half-lives for a model river and model lake are 3 and 99 hours, respectively. The potential for bioconcentration in aquatic organisms is expected to be low based on an experimental BCF value of 15, measured in fish. Exposure to 4-xylene may occur occupationally during its production or subsequent use, particularly as a solvent or in gasoline, via dermal and respiratory routes. The main route of exposure for the general population will be through inhalation of contaminated air as well as ingestion of contaminated drinking water and food. Dermal contact with household products containing 4-xylene is also expected to be significant. (SRC) NATS: *Naturally occurring sources of xylenes are petroleum(1), forest fires and volatiles from plants(2). [R113] ARTS: *Present in exhaust of gasoline engines at 1.9 vol% of emitted HC /m- and p-xylenes/; exhaust of diesel engines at 1.9% emitted HC /m- and p-xylene/; reciprocating gasoline engine at 1.3% of emitted HC; rotary gasoline engine at 5.6% of emitted HC /m- and p-xylene/ [R37, 119] *4-Xylene's production and use in petroleum products, as a chemical solvent and intermediate, and for the manufacture of terephthalic acid and herbicides(1-4) may result in its release to the environment through various wastestreams(SRC). [R114] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1) and experimentally determined Koc values of 246 and 540 in silt and sandy loams respectively(2), 4-xylene is expected to have moderate mobility in soil(SRC). Volatilization from dry soil surfaces is expected based on the experimental vapor pressure of 8.44 mm Hg at 25 deg C(3). Volatilization from moist soil surfaces is expected based on an experimentally determined Henry's Law constant of 6.9X10-3 atm-cu m/mole(4). Biodegradation is an important environmental fate process for 4-xylene(SRC) in dry and moist soils as indicated by aquatic screening studies(5-7). [R115] *AQUATIC FATE: Based on a recommended classification scheme(1) and experimentally determined Koc values of 246 and 540 in silt and sandy loams respectively(2), 4-xylene can be expected to adsorb somewhat to suspended solids and sediment in water(SRC). 4-Xylene is expected to volatilize from water surfaces(1,SRC) based on an experimental Henry's Law constant of 6.9X10-3 atm-cu m/mole(3). Estimated half-lives for a model river and model lake are 3 and 99 hours, respectively(1,SRC). Biodegradation in aquatic systems under aerobic and anaerobic conditions is also suggested from a variety of groundwater and aquifer studies(4-10). [R116] *According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-xylene, which has an experimental vapor pressure of 8.84 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-xylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the atmospheric half-life of this compound is about 27 hours(3,4,SRC). Ambient levels of 4-xylene are detected in the atmosphere due to large emissions of this compound(SRC). [R117] BIOD: *In general, it has been found that 4-xylene is biodegraded in soil and groundwater samples under aerobic conditions and may be degraded under anaerobic denitrifying conditions(SRC). Using a standard BOD dilution technique and a sewage inoculum, a theoretical BOD of 44% was observed over a 5 day incubation period(1). Over 88% of an unspecified initial concentration of 4-xylene was biodegraded by an activated sludge inoculum obtained from a municipal wastewater treatment facility(2) during a 5 day incubation period. A jet fuel acclimated aquifer mineralized 70-80% of a 4-xylene sample under denitrifying conditions over a 55 day incubation period(3). A coarse sand aquifer removed 52-100% of 4-xylene from contaminated groundwater under natural aerobic conditions over a 13 day incubation period(4). Biodegradation of 4-xylene was observed under anaerobic denitrifying conditions(4). A 0.15 mM sample of 4-xylene was completely degraded in a diesel fuel acclimated aquifer during an 11 day incubation period(5). Complete biodegradation of a groundwater sample of 4-xylene, 85 ug/l, in an activated sand aquifer was observed within 110 days(6). The degradation rate constant for 4-xylene in an activated sand aquifer was measured as 0.038 days-1(6). The degradation rate constant of 4-xylene measured in the Columbus Air Force Base aquifer, Columbus, MS was 0.0107 days-1(7). [R118] *An activated sludge inoculum obtained from a Wisconsin wastewater treatment facility biodegraded a 5.53 ug/l sample of 3-and 4-xylene(1). Aerobic flow-through aquifer column studies resulted in 80% removal of combined 3- and 4-xylene(2). Combined 3- and 4-xylene concentrations were not significantly reduced within 42 days following the addition of nitrate to this column; however, anaerobic conditions in the nitrate-amended column resulted in about 50% removal of 3- and 4-xylene after several months(2). Leachate containing 3- and 4-xylene at 100 ug/l was significantly biodegraded under denitrifying conditions but not under either iron-reducing or methanogenic conditions(3). Anaerobic microcosms were constructed using aquifer sediment and groundwater from the Seal Beach Naval Weapons Station in CA which had been contaminated with gasoline(4). Following the loss of toluene, 3- and 4-xylenes were biodegraded completely by day 39 with a maximum rate of 4.1 ug/l-hr(4). Following the addition of nitrate, there was less complete removal of 3- and 4-xylene however, the maximum removal rate was increased to 5.4 ug/l-hr(4). Groundwater contaminated with combined 3- and 4-xylenes (at 1,300 ug/l) was treated with both upflow aerated columns and rotating biological contactors with 98% removal in 37 days and 96% removal in 146 days, respectively(5). 98.1% of the combined 3- and 4-xylenes present initially were biodegraded in an activated sludge treatment plant(6). [R119] ABIO: *The rate constant for the vapor-phase reaction of 4-xylene with photochemically-produced hydroxyl radicals has been measured as 14.3X10-12 cu cm/molecule-sec at 25 deg C(1,2). This corresponds to an atmospheric half-life of about 27 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,2). The rate constant for the vapor-phase reaction of 4-xylene with nitrate radicals has been measured as 1.4X10-16 cu cm/molecule-sec at 25 deg C(3). This corresponds to an atmospheric half-life of about 115 days at an atmospheric concentration of 5X10+8 nitrate radicals per cu cm(3,SRC). Products from the gas-phase reaction of nitrate with 4-xylene were 4-methylbenzaldehyde and 4-methylbenzyl nitrate(4). The rate constant for the vapor-phase reaction of 4-xylene with ozone has been measured as 4X10-22 cu cm/molecule-sec at 24 deg C(5). This corresponds to an atmospheric half-life of about 78 years at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(5,SRC). Ambient levels of 4-xylene are detected in the atmosphere due to large emissions of this compound(SRC). [R120] *The photolysis of jet fuel JP-4 in water resulted in the degradation of 3- and 4-xylene, combined, from 1.46 to 1.38 to 1.34 to 1.20 mg/L in 0, 7, 14, and 21 days, respectively, in pond water(1). 4-Xylene is not expected to undergo hydrolysis in the environment due to the lack of functional groups to hydrolyze(SRC). [R121] BIOC: *An experimental BCF value of 15 has been determined for fish(1,2). According to a classification scheme(3), this BCF value suggests that bioconcentration of 4-xylene in aquatic organisms is low(SRC). [R122] KOC: *Based on a recommended classification scheme(1) and experimentally determined Koc values of 246 and 540 in silt and sandy loams respectively(2), 4-xylene is expected to have moderate mobility in soil(SRC). [R123] VWS: *The experimental Henry's Law constant for 4-xylene is measured as 6.9X10-3 atm-cu m/mole(1). This value indicates that 4-xylene will volatilize rapidly from water surfaces(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 3 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 99 hours(2,SRC). Volatilization from moist soil surfaces is expected based on 4-xylene's Henry's Law constant(1,SRC). Based on 4-xylene's experimental vapor pressure of 8.84 mm Hg at 25 deg C, volatilization from dry soil surfaces is expected(3,SRC). [R124] WATC: *DRINKING WATER: In a survey of 30 Canadian water treatment facilities, the average value of 4-xylene combined with ethyl benzene was 1 ppb with a maximum value of 10 ppb(1). 4-Xylene has been qualitatively detected in the municipal drinking water supplies of Cleveland, OH(2), Philadelphia, PA(3), Washington, DC(4), Tuscaloosa, AL and Houston, TX(5). In a survey of organics in drinking water derived from groundwater sources, 4- and 2-xylene combined were found in 2.1% of 280 sample sites supplying < 10,000 persons and 1.1% of 186 sites supplying > 10,000 persons. The maximum combined concns were 0.59 and 0.91 ppb, respectively(6). Combined 3- and 4-xylene was detected at a concn of 0.1 ppb in bank filtered Rhine river drinking water in the Netherlands(7). 4-Xylene was detected in 6 drinking water wells near a landfill, at concns in the range of 0.3-2.1 ppb(8). 4-Xylene was detected in 14 drinking water studies in Great Britain, 10 from surface water sources and 4 from ground supplies(9). Combined 3- and 4-xylene was detected in the drinking water produced by offshore installations in Norway at concns between 130-15,000 ng/l(10). [R125] *GROUNDWATER: 4-Xylene was detected in groundwater under a landfill in Norman, OK (0.9 ppb)(1), under a rapid infiltration site in Phoenix, AZ (0.10-49 ppb)(2), under a coal gasification site in Wyoming 15 months after gasification completed (240-830 ppb)(3). 4-Xylene was detected in a recovery well from a landfill 7 years after closing (2.9 ppb)(4). [R126] *SURFACE WATER: 4-Xylene was detected in the raw water supplies for 30 Canadian treatment facilities, 23% contained a combination of p-xylene and ethyl benzene which averaged < 1 ppb and whose maximum value was < 1 ppb in summer and 2 ppb in winter(1). 4-Xylene was detected, not quantified in the Black Warrior River in Tuscaloosa, AL(2) and the Glatt River in Switzerland(3). 4-Xylene was detected in the Adige River, Italy (0.1-0.6 ug/l)(4). 4-Xylene was detected in the Morava River, Slovakia (0.16-0.97 ug/l)(5). [R127] *SEAWATER: Samples obtained from Vineland Sound, MA, contained 3- and 4-xylene (4.5-66.0 parts per trillion)(1). Combined 3- and 4-xylene was detected in coastal sections of the Gulf of Mexico, (2.7-24.4 parts per trillion)(2). Combined 3- and 4-xylene was detected in the northern Gulf of Mexico, (1-30 ng/l)(3). [R128] *RAIN/SNOW: 4-Xylene was detected in the rainfall in West Los Angeles, CA, at a concn of 9 parts per trillion(1). Combined 3- and 4-xylene was detected in antarctic snow at concns of 12 to 198 ng/l(2). Combined 3- and 4-xylene was quantified during seven rain events in Portland, OR in 1984, and concns ranged from 34 to 260 ng/l(3). [R129] EFFL: *4-Xylene was detected (33.2 ug/g) in the leachate from a petroleum refinery plant(1). 4-Xylene was detected (1.97 mg/l) in the leachate near a landfill in Virginia(2). 4-Xylene was detected, not quantified in the leachate of a Florida landfill(3). 4-Xylene was detected (0.46-2.97 ppm) in the tail pipe emissions from automobiles in the UK(4). 4-Xylene was detected (61.5-427.4 mg/km) in the emissions of automobiles under various driving conditions in the UK(5). Emissions of 3- and 4-xylene from an outboard boat motor (71 mg for 10 minutes of operation), into a freshwater lake in Germany were measured(6). Unspecified concns of 4-xylene were detected in the effluent of coal power plants in the US(7). [R130] *Woodsmoke samples collected from residential chimneys contained 3- and 4-xylene, combined, reported as the ratio 3- and 4-xylene/CO2 from 0.009 for a softwood, hot burn to 0.235 for a softwood, cool burn(1). Tailpipe emissions of 3- and 4-xylene for 9 vehicles at 75, 90, and 105 deg F were measured as 3.28-3.80, 2.52-3.73, and 3.20-3.27 wgt%, respectively(2). Hot soak evaporative emissions of 3- and 4-xylene for 9 vehicles at 75, 90, and 105 deg F were measured as 5.20-5.34, 5.23-6.01, and 5.11-7.49 wgt%, respectively(3). Evaporative emissions of 3- and 4-xylene for 9 vehicles at 60-84, 72-96, and 84-108 deg F were measured as 2.57-3.22, 2.83-2.94, and 0.25-1.29 wgt%, respectively(3). The mean concn of 3- and 4-xylene in exhaust from 6 cars was 12322 ppb(3). Air samples taken along an urban road (in 1982) in London, England, contained 3- and 4-xylene, combined, at a mean concn of 2.76 ppm (n=256)(4). Air samples collected along a motorway in Toddington, England (in the countryside), contained 3- and 4-xylene, combined, at a mean concn of 0.85 ppm (n=198)(4). Exhaust air from the Elbtunnel, Germany, contained 3-and 4-xylene, combined, at concns from 150.9 to 169.8 ug/cu m(5). [R131] SEDS: *4-Xylene was detected in the soil near a pulp mill at a concn of 0.9 g/ton(1). Sediment collected from the River Morava, Slovakia, contained 3- and 4-xylene, combined, at concns from 0.21 to 1.53 ug/kg wet weight(2). Sediment samples from the River Tees estuary, England, contained 3- and 4-xylene, combined, at concns from 3.4 to 250 ppb(3). [R132] ATMC: *RURAL/REMOTE: 4-Xylene was detected in Atlantic Ocean air, 0.01-0.02 ppb(1), Pacific Ocean air, 0.02-0.04 ppb(2) and Indian Ocean air, 0.003-0.005 ppb(3). 4-Xylene was detected at concns between 26-1187 ng/cu m in German forests(4). Air samples from Silwood Park, England, contained 3- and 4-xylene at a mean concn of 0.49 ppm(5). Air samples collected from Whitaker's Forest, Sierra Navada Mountains, CA, contained 3- and 4-xylene, combined, at unreported concns(6). Median air concns of 3- and 4-xylene, combined, at several rural locations in northwestern North Caroline were 0.6 (Roan Mountain), 1.0 (Grandfather Mountain), 0.7 (Linville Gorge), 0.7 (Rich Mountain), 15.3 (Boone center), and 3.3 (Boone outskirts) ppb(7). [R133] *URBAN/SUBURBAN: 4-Xylene was detected at concns of about 0.10-0.15 ppb at a roadside in the Atlanta, GA metropolitan area(1). 4-Xylene was detected at a mean concn of 14.8 ug/cu m in 102 areas sampled in the US(2). Average concns in the range of 0.6-10.0 ppb were measured for 3- and 4-xylene in 12 US cities(3). Combined 3- and 4-xylene was detected at an average concn of 18.1 ppb in 39 US cities(4). 4-Xylene was detected in the Lincoln Tunnel, NY at a concn of 49 ppb(5). Combined 3- and 4-xylene was detected in the passenger areas of vehicles in Boston, MA (20.9 ug/cu m), Raleigh, NC (30.5 ug/cu m) and Los Angeles, CA (153.9 ug/cu m)(6). Ambient levels of 4-xylene were reported for several locations in the US and Europe(7). [R134] *SOURCE DOMINATED AREAS: Combined 3-and 4-xylene was detected at concns between 0.2-99.0 ppb near two landfills in New Jersey(1), and at concns between 3-5 ppb downwind from an automobile painting plant in Janesville, WI(2). [R135] *INDOOR AIR: 4 of 9 indoor air samples taken from the living rooms of houses situated above screen printing plants in Amsterdam, The Netherlands, contained 3- and 4-xylene, combined, at median concns of < 0.04 to < 0.05 mg/cu m (detection limit= < 0.01 mg/cu m)(1). At a building facility with a history of occupant complaints characteristic of sick building syndrome, indoor air samples from building 2, building 3, building 3 exhaust, and outdoor air contained 3- and 4-xylene, combined, at 12, 22, 15, and 3.9 ug/cu m, respectively(2). Indoor air samples from 31 residences in the Kanawha Valley, WV (the center of a heavily industrialized area) contained 3- and 4-xylene, combined, at a mean concn of 17.73 ug/cu m (median=7.27 ug/cu m)(3). Indoor air concns of 3- and 4-xylene, combined, in 12 homes in Canada ranged from 7-104 ug/cu m (average=31.1 ug/cu m; Nov/Dec collection)(4). Indoor air samples collected from 5 apartments and 9 houses in Italy during 1983-1984 contained 3- and 4-xylene at a mean concn of 89 ug/cu m (mean outdoor concn of 24 ug/cu m)(5). Indoor air from an office building, a school, and two elderly homes contained 3- and 4-xylene, combined, at median concns of 8.2-150 (outdoor=0.96-3.3 ug/cu m), 7.9 (outdoor=13 ug/cu m), and 8.1-9.5 (outdoor=8.1-13 ug/cu m) ug/cu m, respectively(6). 4-Xylene was detected in the emissions of freshly glued wallpaper and freshly glued carpet at concns of 26 ug/cu m and 150 ug/cu m respectively(7). [R136] FOOD: *Combined 3- and 4-xylene was detected in the volatiles of several table ready foods at concns of 10-114 ppb(1). 4-Xylene was detected in the volatiles of roasted duck at concns of 0.7-21.2 ppb(2). Unspecified concns of 4-xylene were detected in California nectarines(3). Unspecified concns of 4-xylene were detected in eggs from the US(4). Unspecified concns of 4-xylene were detected in the volatiles of meat products in the US(5). [R137] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Combined 3- and 4-xylene was detected in rainbow trout from the Colorado river and carp obtained from Las Vegas Wash, NV at concns of 50 and 120 ppb respectively(1). [R138] OEVC: *Composite gasoline samples from Los Angeles m- and p-xylene combined are 6.73 wt%(1). [R139] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 5723 workers (3320 of these are female) are potentially exposed to 4-xylene in the US(1). 4-Xylene was detected at an average concn of 1.7 ppm in the urine of 121 metal coatings workers in the US(2). 4-Xylene was detected in air samples obtained from the vulcanization areas of rubber manufacturing plants in Italy, at concns between 0-120 u g/cu m(3). Combined 3- and 4-xylene was detected at concns between 1-158 mg/cu m in the breathing zones of automobile paint shops sampled in the US(4). Workers using a thinner containing 32.8% 3- and 4-xylene in spray painting operations at a shipbuilding yard had measured concns of methyl hippuric acid in their urine(5). The 8 hour TWA for worker exposure to combined 3- and 4-xylene in a German histology laboratory and a US histology laboratory was measured as 243-295 mg/cu m and 11-315 mg/cu m respectively(5). The 8 hour TWA for worker exposure to combined 3- and 4-xylene in a US hospital laboratory was measured as 2.6-1700 mg/cu m(5). Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where 4-xylene is produced or used(SRC). The general population will be exposed to 4-xylene largely via inhalation of ambient air, particularly in areas with heavy traffic, near filling stations and near industrial sources such as refineries(SRC). Exposure may also arise from consuming contaminated drinking water(SRC). An average concn of 0.37 ppb of combined 3- and 4-xylene was measured in blood samples collected from 60 persons in the US that are not occupationally exposed to 3- and 4-xylene(6). [R140] *Humans are exposed to 4-xylene primarily from air, particularly in areas with heavy traffic, near filling stations, near industrial sources such as refineries or where 4-xylene is used as a solvent. Exposure may also arise from drinking contaminated well water near leaking underground gasoline storage tanks or from spills of petroleum products. (SRC) *Benzene and xylenes are components of gasoline. The US population exposed to xylenes from petroleum related sources can be assumed to be the same as for benzene, namely: people choosing self-service at gasoline service stations 37,000,000; people living in the vicinity of gasoline service stations 118,000,000; petroleum refineries 6,597,000; urban exposure (auto emissions) 113,690,000(1). /Xylenes/ [R141] AVDI: *AIR INTAKE: (assume typical concn of 0.8 ppb which is the median urban/suburban concn for m- and p-xylene combined multiplied by the fraction of p-xylene in the m- plus p-xylene component of gasoline) 71 ug. WATER INTAKE: (assume typical concn of 0-1 ppb) 0-2 ug. FOOD INTAKE: - insufficient data. (SRC) BODY: *4-Xylene was detected in expired breath samples from Bayonne, NJ (3.0-3.2 ug/cu m), Los Angeles, CA (1.4-2.3 ug/cu m), and Pittsburgh, PA (1.1 ug/cu m)(1). 4-Xylene was detected in expired breath samples in Los Angeles, CA (2.43-3.46 ug/cu m)(2). Combined 3- and 4-xylene was detected in expired breath samples in Bayonne, NJ at average concns of 4.7-10 ug/cu m(3). Based on a sample of 355 persons, it was determined that 95% of the population of Bayonne and Elizabeth, NJ had detectable levels of combined 3- and 4-xylene in expired breath(4). [R142] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +900 ppm [R30, 336] ATOL: *Xylene is exempted from the requirement of a tolerance when used as an aquatic herbicide applied to irrigation conveyance systems in accordance with the following conditions: (a) It is to be used only in programs of the Bureau of Reclamation, US Department of Interior and cooperating water user organizations. (b) It is to be applied as an emulsion at an initial concn not to exceed 750 ppm. (c) It is not to be applied when there is any likelihood that the irrigation water will be used as a source of raw water for a potable water system or where return flows of such treated irrigation water into receiving rivers and streams would contain residues of xylene in excess of 10 ppm. (d) Xylene to be used as an aquatic herbicide shall meet the requirement limiting the presence of a polynuclear aromatic hydrocarbons as listed in 172.250 of title 21, Code of Federal Regulations. /Xylene/ [R143] *Residues of xylene are exempted from the requirement of a tolerance when used as a solvent and cosolvent (limits: pesticide formulations for grain storage only) in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. /Xylene/ [R144] *Xylene is exempted from the requirement of a tolerance when used as a solvent and cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. /Xylene/ [R145] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (435 mg/cu m). /Xylenes (o-, m-, p-isomers)/ [R146] +Vacated 1989 OSHA PEL TWA 100 ppm (435 mg/cu m); STEL 150 ppm (655 mg/cu m) is still enforced in some states. /Xylene (o-, m-, p-isomers)/ [R30, 374] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 100 ppm (435 mg/cu m). [R30, 336] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 150 ppm (655 mg/cu m). [R30, 336] TLV: +8 hr Time Weighted Avg (TWA) 100 ppm; 15 min Short Term Exposure Limit (STEL) 150 ppm /Xylene (o-, m-, p-isomers)/ [R69, 72] +BEI (Biological Exposure Index): Methylhippuric acids in urine at end of shift is 1.5 g/g creatinine. /Xylenes, technical grade/ [R69, 104] +A4. A4= Not classifiable as a human carcinogen. /Xylene (o-,m-, and p- isomers)/ [R69, 72] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 4-Xylene is included on this list. [R147] WSTD: STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 1750 ug/l [R148] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R149] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R150] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Xylene is included on this list. [R151] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R152] RCRA: *F003; When xylene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F003), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. /Xylenes/ [R153] *U239; As stipulated in 40 CFR 261.33, when xylene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /Xylenes/ [R154] FIFR: *Xylene is exempted from the requirement of a tolerance when used as an aquatic herbicide applied to irrigation conveyance systems in accordance with the following conditions: (a) It is to be used only in programs of the Bureau of Reclamation, US Department of Interior and cooperating water user organizations. (b) It is to be applied as an emulsion at an initial concn not to exceed 750 ppm. (c) It is not to be applied when there is any likelihood that the irrigation water will be used as a source of raw water for a potable water system or where return flows of such treated irrigation water into receiving rivers and streams would contain residues of xylene in excess of 10 ppm. (d) Xylene to be used as an aquatic herbicide shall meet the requirement limiting the presence of a polynuclear aromatic hydrocarbons as listed in 172.250 of title 21, Code of Federal Regulations. /Xylene/ [R143] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Xylene is found on List C. Case No: 3020; Pesticide type: insecticide; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Xylene; AI Status: Registrants of the pesticide have not made or honored a commitment to seek reregistration, conduct the necessary studies, or pay the requisite fees, or they have asked EPA to cancel their product registrations. Unless some other interested party supports them, products containing the pesticide will be cancelled. /Xylene/ [R155] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *GASES EMITTED BY MOTOR VEHICLES WERE COLLECTED ON TENAX GC POLYMER ADSORBENT ... APPROX 400 COMPOUNDS WERE DETECTED ONE OF WHICH WAS P-XYLENE. [R156] *Xylene vapor trapped on charcoal from a known vol of air is desorbed with carbon disulfide. /Xylenes/ [R157] ALAB: *Xylene vapor trapped on charcoal from a known vol of air is desorbed with carbon disulfide and injected into a gas chromatograph with a flame ionization detector. Limit of detection was found to be < 12 ug/sample. /Xylenes/ [R157] *DETERMINATION OF WATER POLLUTANTS BY GAS CHROMATOGRAPHY. DETECTION LIMITS OF LESS THAN 1 UG/L WERE OBTAINED FOR 32 COMPOUNDS ONE OF WHICH WAS P-XYLENE. [R158] *ATMOSPHERIC HYDROCARBONS WERE DETECTED USING GAS CHROMATOGRAPHY DETECTORS AND MASS SPECTROMETRY IN SELECTED ION MONITORING MODE. [R159] *GASES EMITTED BY MOTOR VEHICLES WERE COLLECTED ON TENAX GC POLYMER ADSORBENT AND ANALYZED BY GLASS-CAPILLARY GAS CHROMATOGRAPHY-MASS SPECTROMETRY. APPROX 400 COMPOUNDS WERE DETECTED ONE OF WHICH WAS P-XYLENE. [R156] *EPA Method 524.1- Volatile Organic Compounds in Water By Purge-and-Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of various volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. Using this method, 4-xylene has a method detection limit of 0.13 ug/l and a standard deviation of 4.2%. [R160] *EPA Method 502.2 Volatile Organic Compounds in Water by Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. This method is applicable for the determination of various volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. Using this method, 4-xylene has a method detection limit (MDL) of 0.01 ug/l, a percent recovery of 99%, and a standard deviation of recovery of 0.9 on a photoionization detector. [R160] *EPA Method 524.2- Volatile Aromatic Compounds in Water by Purge-and-Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of various volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. Using this method, 4-xylene has a method detection limit (MDL) of 0.13 ug/l and a relative standard deviation of 7.7% with a wide bore capillary column, and a MDL of 0.06 ug/l and a relative standard deviation of 6.3% with a narrow bore capillary column. [R160] *EPA Method 503.1- Volatile Aromatic and Unsaturated Organic Compounds in Water By Purge-and-Trap Gas Chromatography. This method is applicable for the determination of various volatile aromatic and unsaturated compounds in finished drinking water, raw source water, or drinking water in any treatment stage. Using this method, 4-xylene has a method detection limit of 0.002 ug/l and a relative standard deviation of 8.7%. Overall precision and method accuracy were found to be directly related to the concentration of the analyte. [R160] *ANALYTE: XYLENE; MATRIX: AIR; PROCEDURE: ADSORPTION ON CHARCOAL, DESORPTION WITH CARBON DISULFIDE, GAS CHROMATOGRAPHY; RANGE: 218-870 MG/CU M; PRECISION: COEFFICIENT OF VARIATION 0.060. /XYLENES/ [R161] *ORGANIC GASES WERE COLLECTED IN TUBE FILLED WITH SOLID SORBENT. XYLENE WAS ONE OF THE GASES IDENTIFIED BY GAS CHROMATOGRAPHY/MASS SPECTROMETRY. /XYLENES/ [R162] *Commercial heterogeneous solvent products (eg paints, inks, and adhesives) were collected nationwide in Japan in 1980. The vapor phase of the product containers were analyzed for volatile organic solvent constituents by means of FID-gas chromatography on two FS-WCOT (OV-101 and PEG-600) capillary columns. ... Organic solvent components identified, ... /included/ xylenes /which were/ predominantly the m- (66%) and p- isomers. (61%) /Xylenes/ [R163] *The results of a successful test of remote fluorescence analysis of ground water contaminants by using uv lasers and fiber optics /is described/. Several priority pollutants /including/ xylenes were detected using this technique. /Xylenes/ [R164] *Method TO-14 : A sample of indoor air is drawn through a sampling train comprised of components that regulate the rate and duration of the sampling into a pre-evacuated SUMMA(R) passivated cannister. Upon receipt at the laboratory the canister is attached to the analytical system. During analysis, water vapor is reduced in the gas stream by a Nafion(R) dryer, and the VOCs are then concentrated by collection in a cryogenically-cooled trap. The cryogen is then removed and the temperature of the trap is raised. The VOCs originally collected in the trap are revolatilized, separated on a GC column, then detected by one or more detectors for identification and quanititation. Interferences can occur in a sample analysis if moisture accumulates in the dryer. Because GC/MS analytical systems employ Nafion permeable membrane dryer to remove water vapor selectively from the sample stream, polar organic compounds may permeate concurrent with the moisture molecule. [R165] *Method IP-1A: Note: The only detection limit data given in this method are for selected analytes using a portable GCPID. Therefore, detection limits are not given in this index for this method. A sample of indoor air is drawn through a sampling train comprised of components that regulate the rate and duration of the sampling into a pre-evacuated SUMMA(R) passivated cannister. Upon receipt at the laboratory the canister is attached to the analytical system. During analysis, water vapor is reduced in the gas stream by a Nafion(R) dryer, and the VOCs are then concentrated by collection in a cryogenically-cooled trap. The cryogen is then removed and the temperature of the trap is raised. The VOCs originally collected in the trap are revolatilized, separated on a GC column, then detected by one or more detectors for identification and quanititation. The analytical strategy of this method involves using a high resolution GC coupled to one or more appropriate GC detectors,either being nonspecific detectors (eg NPD, FID, PID) or specific detectors such as a mass spectrometer operating in either selected ion monitoring (SIM) or in the SCAN mode. [R165] *Method 8021: Method 8021 provides chromatographic conditions for the detection of halogenated and aromatic volatile compounds. Samples can be analyzed using direct injection or purge-and-trap (Method 5030). Ground water samples must be determined using method 5030. A temperature program is used in the GC to separate the organic compounds. Detection is achieved by an electrolytic conductivity detector and photoionization detector. Tentative identifications are obtained by analyzing standards under the same conditions used for samples and comparing resultant GC retention times. Confirmatory information can be gained by comparing the relative response of the 2 detectors. Concentrations of the identified components are measured by relating the response produced for that compound to the response produced by a compound that is used as an internal standard. [R166] *Method 8260: The volatile compounds are introduced into the gas chromatograph by the purge-and-trap method or by direct injection (in limited applications). Purged sample components are trapped in a tube containing suitable sorbent materials. When purging is complete, the sorbent tube is heated and backflushed with helium to desorb trapped sample components. The analytes are desorbed directly to large bore capillary or cryofocused on a capillary precolumn before being flash evaporated to a narrow bore column for analysis. The column is temperature programmed to separate the analytes which are then detected with a mass spectrometer interfaced to the GC. Wide capillary columns require a jet separator, whereas narrow bore columns can be directly interfaced to the ion source. If the above sample introduction techniques are not applicable, a portion of the sample is dispersed in solvent to dissolve the volatile organic constituents. A portion of the solution is combined with organic-free reagent water in a specially designed purging chamber. It is then analyzed by purge and trap GC/MS following the normal water method. Qualitative identifications are obtained by analyzing standards under the same conditions used for samples and comparing resultant GC retention times. Each identified component is quantified by relating the MS response for an appropriate selected ion produced by that compound to the MS response for another ion produced by an internal standard. [R166] CLAB: *Quantitative determination of urinary metabolites exposed to xylene using colorimetric determination is widely used. The metabolites of ... xylene are measured as ... methyl hippuric acid (MHA), paper chromatography and thin-layer chromatography are necessary as pretreatments of samples. The addition of pyridine, p-dimethylaminobenzaldehyde (DAB) and acetic anhydride to glycine conjugates gives the most stable color development. Excellect analytical sensitivity and specificity with gas chromatographic methods requires pretreatment with diazomethane for methylesterification of MHA. High performance liquid chromatography has been widely used for analysis of organic solvents. Non-volatile metabolites in urine can be assayed by this method without pretreatment. /Xylenes/ [R167] *... phenolic metabolites /of xylene/ were quantitatively estimated in hydrolyzed urine samples by gas chromatography. /Xylenes/ [R168] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Von Burg R; J Appl Toxicol 2: 269-71 (1982). A review article on the toxicity of xylene and its isomers. National Academy of Sciences; The Alkyl Benzenes (1981) Toxicology Review; Mutation Research 47 (2): 75 (1978) NIOSH; Criteria Document: Xylene (1975) DHEW Pub. NIOSH 75-168 Fishbein L; Sci Total Environ 43 (1-2): 165-83 (1985). A review article on the toxicology of xylenes. 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NTIS PB 86-233 939/AS. Washington, DC: USEPA (1986) (2) Cozzarelli IM et al; Environ Sci Technol 29: 458-69 (1995)(3) Chen CS, Zoltek JJR; Chemosphere 31: 3455-64 (1995) (4) Bailey JC et al; Atmos Environ 24: 43-52 (1990) (5) Bailey JC et al; Sci Tot Environ 93: 199-206 (1990) (6) Juettner F; Chemosphere 29: 191-200 (1994) (7) Junk GA et al; ACS Symp Ser 319: 109-23 (1986) R131: (1) Edgerton SA et al; Environ Sci Technol 20: 803-07 (1986) (2) Stump FD et al; J Air Waste Manage Assoc 42: 1328-35 (1992) (3) Blake NJ et al; J Geophys Res 98: 2851-64 (1993) (4) Clark AI; Environ Pollut 7: 141-58 (1984) (5) Dannecker W et al; Sci Total Environ 93: 293-300 (1990) R132: (1) Kookana RS, Rogers SL; Rev Environ Contam Toxicol 142: 13-64 (1995) (2) Al-Rekabi H et al; Bull Environ Contam Toxicol 56: 90-97 (1996) (3) Harland BJ et al; Intern J Environ Anal Chem 20: 295-311 (1985) R133: (1) Bozzelli JW et al; Analysis of selected toxic and carcinogenic substances in ambient air in New Jersey. New Jersey Dept Environ Prot (1980) (2) Sexton K, Westberg H; Environ Sci Technol 14: 329-32 (1980) (3) Singh HB et al; Atmos Environ 19: 1911-9 (1985) (4) Juttner F; Chemosphere 17: 309-17 (1988) (5) Clark AI et al; Environ Pollut 7: 141-58 (1984) (6) Helmig D, Arey J; Sci Total Environ 112: 233-50 (1992) (7) Seila RL et al; Atmospheric Volatile Hydrocarbon Composition at Five Remote Sites in Northwestern North Caroline. USEPA-600/D-84-092. (NTIS PB84-177930). Research Triangel Park, NC: USEPA (1984) R134: (1) Bernardo-Bricker A; J Air Waste Manage Assoc 45: 591-603 (1995) (2) Kelly TJ et al; Ambient Concn Summaries For Clean Air Act. Title III. Hazardous Air Pollutants. US EPA Contract No 68-D80082, USEPA/600/R-94/090, Final Report. Research Triangle Park (1993) (3) Singh HB et al; Atmos Environ 19: 1911-9 (1985) (4) Seila RL et al; Determination of C2 to C12 Ambient Air Hydrocarbons in 39 US Cities From 1984 Through 1986. USEPA/600/S3-89/058 Atmos Res Expos Assess Lab, Research Triangle Park NC (1989) (5) Lonneman WA et al; Environ Sci Technol 20: 790-796 (1986) (6) Chan CC et al; J Air Waste Manage Assoc 41: 1594-1600 (1994) (7) Grosjean D et al; Sci Tot Environ 100: 367-414 (1991) R135: (1) Bozzelli JW et al; Analysis of selected toxic and carcinogenic substances in ambient air in New Jersey. New Jersey Dept Environ Prot (1980) (2) Sexton K, Westberg H; Environ Sci Technol 14: 329-32 (1980) R136: (1) Verhoeff AP et al; Int Arch Occup Environ Hlth 60: 201-09 (1988) (2) Weschler CJ et al; Amer Ind Hyg Assoc J 51: 261-68 (1990) (3) Cohen MA et al; J Air and Waste Manage Assoc 39: 1086-93 (1989) (4) Chan CC et al; J Air Waste Manage Assoc 40: 62-67 (1990) (5) DeBortoli M et al; Environ Internat 12: 343-50 (1986) (6) Hartwell TD et al; Proc APCA Annu Meet 78th Vol. 3. 85-30B.3 (1985) (7) Wallace LA et al; Atmos Environ 21: 385-93 (1987) R137: (1) Heikes DL et al; J Agric Food Chem 43: 2869-75 (1995) (2) Wu CM, Liou SE; J Agric Food Chem 40: 838-41 (1992) (3) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) (4) Matiella JE, Hsieh TCY; J Food Sci 56: 387-90 (1991) (5) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R138: (1) Hiatt MH; Anal Chem 55: 506-516 (1983) R139: (1) NAS; The Alkyl Benzenes page I-1 to I-99 (1980) R140: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Kawai T et al; Int Arch Occup Environ Health 63: 69-75 (1991) (3) Cocheo V et al; Am Ind Hyg Assoc J 44: 521-527 (1983) (4) Medinilla J, Espigares M; Ann Occup Hyg 32: 509-513 (1988) (5) Ashley DL et al; Clin Chem 40: 1401-1404 (1994) (5) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-Present. Xylenes. 47: 129 (1989) (6) Ashley DL et al; Clin Chem 40: 1401-1404 (1994) R141: (1) Mara SJ, Lee SS; Human Exposure to Atmos Benzene, Center for Resource Environ Studies Rep No.30 pp 3 Menlo Park CA: SRI (1977) R142: (1) Hartwell TD et al; Atmos Environ 21: 2413-24 (1987) (2) Hartwell TD et al; Atmos Environ 26A: 1519-27 (1992) (3) Wallace LA et al; Toxicol Environ Chem 12: 215-36 (1986) (4) Wallace LA et al; Atmos Environ 19: 1651-61 (1985) R143: 40 CFR 180.1025 (7/1/95) R144: 40 CFR 180.1001(c) (7/1/95) R145: 40 CFR 180.1001(d) (7/1/95) R146: 29 CFR 1910.1000 (7/1/98) R147: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R148: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R149: 40 CFR 116.4 (7/1/88) R150: 40 CFR 302.4 (7/1/95) R151: 40 CFR 716.120 (7/1/95) R152: 40 CFR 712.30 (7/1/92) R153: 40 CFR 261.31 (7/1/95) R154: 40 CFR 261.33 (7/1/95) R155: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.235 (Spring, 1998) EPA 738-R-98-002 R156: HAMPTON CV ET AL; ENVIRON SCI TECHNOL 16: 287-96 (1982) R157: NIOSH; Criteria Document: Xylene p.82, 84 (1975) DHEW Pub. NIOSH 75-168 R158: OTSON R, WILLIAMS DT; ANAL CHEM 54: 942-6 (1982) R159: POSSANZINI M ET AL; COMM EUR COMMUNITIES, (REP) EUR; (EUR 7624, PHYS-CHEM BEHAV ATOMS POLLUT) 76-81 (1982) R160: USEPA; EMMI. Environmental Monitoring Methods Index. Version 2.0. NTIS PB-95-502415 (1995) R161: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V3 S318 R162: RIGBY LJ; ANN OCCUP HYG 24 (4): 331-46 (1981) R163: Kumai M et al; Indust Health 21: 185-97 (1983) R164: Chudyk WA et al; Anal Chem 57 (7): 1237-42 (1985) R165: USEPA/Atmospheric Research and Exposure Laboratory (AREAL); Compendium of Methods for the Determination of Toxic Organic Compounds in Ambient Air (1988) EPA/600/4-89/017 R166: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R167: Ogata M; Acta Med Okayama 35 (6): 385-94 (1981) R168: Bakke OM, Scheline BR; Toxicol Appl Pharmacol 16: 691-700 (1970) as cited in NIOSH; Criteria Document: Xylene p.55 (1975) DHEW Pub. NIOSH 75-168 RS: 137 Record 28 of 1119 in HSDB (through 2003/06) AN: 148 UD: 200210 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-ISOBUTYL-KETONE- SY: *AI3-01229-; *Caswell-No.-574AA-; *EPA-Pesticide-Chemical-Code-044105-; *FEMA-NUMBER-2731-; *HEXON- (CZECH); *HEXONE-; *ISOBUTYL-METHYLKETON- (CZECH); *ISOBUTYL-METHYL-KETONE-; *Isopropyl-acetone-; *KETONE,-ISOBUTYL-METHYL-; *METHYL-ISOBUTYL-CETONE- (FRENCH); *METHYLISOBUTYLKETON- (DUTCH,GERMAN); *4-METHYL-2-OXOPENTANE-; *4-METHYL-2-PENTANON- (CZECH); *4-METHYL-PENTAN-2-ON- (DUTCH, GERMAN); *2-METHYL-4-PENTANONE-; *4-METHYLPENTANONE-2-; *2-METHYLPROPYL-METHYL-KETONE-; *METILISOBUTILCHETONE- (ITALIAN); *4-METILPENTAN-2-ONE- (ITALIAN); *METYLOIZOBUTYLOKETON- (POLISH); *MIBK-; *MIK-; *2-PENTANONE,-4-METHYL-; *SHELL-MIBK- RN: 108-10-1 MF: *C6-H12-O SHPN: UN 1245; Methyl isobutyl ketone IMO 3.2; Methyl isobutyl ketone STCC: 49 092 45; Methyl isobutyl ketone (flammable liquid) HAZN: U161; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. F003; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY HYDROGENATION OF MESITYL OXIDE OVER NICKEL AT 160-190 DEG C, DARZENS, CR SEANCES ACAD SCI PARIS, 140, 152, 1905; ALSO BY OXIDATION OF METHYL ISOBUTYL CARBINOL. [R1] *ACETONE IS TREATED WITH BARIUM HYDROXIDE TO YIELD DIACETONE ALCOHOL; THIS IS DEHYDRATED TO MESITYL OXIDE WHICH CAN BE HYDROGENATED TO SATURATE THE DOUBLE BOND AND PRODUCE METHYL ISOBUTYL KETONE. [R2, 750] */Methyl isobutyl ketone is prepared/ by reacting sodium acetoacetic ester with isopropyl bromide and treating the resulting 2-isopropyl-acetoacetic ester with dilute acid to saponify the ester and decarboxylate the resulting keto acid. [R3] FORM: *Grades: technical, 98.5%. [R4] */The NF grade/ ... contains not less than 99% of methyl isobutyl ketone. [R3] *MIBK IS FREQUENTLY BLENDED WITH METHYL ETHYL KETONE IN HIGH SOLIDS LACQUERS [R5] MFS: *Eastman Kodak Company, Hq, 343 State Street, Rochester, NY 14650, (716) 724-4000, Eastman Chemical Division, PO Box 431, Kingsport, TN 37662; Production site: Texas Eastman Company, Longview, TX 75607 [R6, 747] *Shell Oil Company, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Shell Chemical Company Division; Production site: Deer Park, TX 77536 (Houston plant) [R6, 747] *Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817, (203) 794-2000, Chemicals and Plastics Business Group, Solvents and Coatings Materials Division; Production site: Institute, WV 25103 [R6, 747] OMIN: */IT IS USED/ IN NON-ALCOHOL BEVERAGES; ICE CREAM, ICES, ETC; CANDY; AND BAKED GOODS AT 6.3 PPM. [R1] USE: *Solvent for vinyl, epoxy, acrylic and natural resins. Solvent for nitrocellulose and dyes. [R7, p. VA15 79-80] *Denaturant for rubbing alcohol [R3] *SOLVENT FOR PAINTS, VARNISHES, NITROCELLULOSE, LACQUERS, MFR OF METHYL AMYL ALCOHOL; ORGANIC SYNTHESIS, EXTRACTION PROCESSES, INCL EXTRACTION OF URANIUM FROM FISSION PRODUCTS, ORGANIC SYNTHESIS [R4] *SOLVENT FOR PROTECTIVE COATINGS AND IN RARE METALS EXTRACTION, DEWAXING OF MINERAL OILS AND IN MFR OF ANTIBIOTICS [R8] *USED IN DRYCLEANING PREPARATIONS, SYNTHESIS OF METHYL ISOBUTYL CARBIONOL (MIBC) [R5] *SYNTHETIC FLAVORING ADJUVANT: FLAVOR USEFUL IN FRUIT FLAVORS, RUM CHEESE. [R9] CPAT: *65% AS SOLVENT FOR PROTECTIVE COATINGS, 5% AS SOLVENT FOR RARE METAL EXTRACTION; 5% EXPORTED; 25% FOR MISC APPLICATIONS INCLUDING DEWAXING OF MINERAL OILS AND IN THE MANUFACTURE OF ANTIBIOTICS (1971) [R8] *NITROCELLULOSE LACQUERS, 25%; OTHER COATINGS, INKS, LACQUERS, 30%; SOLVENT EXTRACTION, 10%; MIBC, 10%; METALURGICAL, 5%; EXPORT, 15%; MISC, 5% (1980) [R5] *CHEMICAL PROFILE: Methyl isobutyl ketone. Demand: 1986: 145 million lb; 1987: 148 million lb; 1991 /projected/: 155 million lb. (Includes exports; in addition, 12.5 million lb were imported in 1986). [R10] PRIE: U.S. PRODUCTION: *(1984) 6.50X10+10 g [R11] *(1987) 1.51X10+8 lb [R12] *(1988) 2.0X10+8 lb [R13] *In 1987, US production was 70,000 tons. [R7, p. VA15 80] *US Production (1993): 6.806X10+7 kg [R14] *Demand: 1995: 175 million pounds; 2000: 175 million pounds. [R15] U.S. IMPORTS: *(1984) 9.31X10+9 g [R16] *(1986) 1.25X10+7 lb [R17] U.S. EXPORTS: *(1984) 7.22X10+9 g [R18] *(1987) 5.90X10+5 lb [R19] *(1988) 1.92X10+6 lb [R20] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R4] ODOR: *PLEASANT ODOR [R4]; *HAS FAINT, KETONIC AND CAMPHOR ODOR [R21] BP: *115.8 DEG C AT 760 MM HG [R4] MP: *-85 DEG C [R4] MW: *100.16 [R21] CTP: *Critical temp: 568.9 deg F = 298.3 deg C = 571.5 K; critical pressure: 475 psia = 32.3 atm = 3.27 MN/sq m [R22] DEN: *0.8042 AT 20 DEG C [R4] HTC: *3,740 kJ/mol [R7, p. VA15 79] HTV: *36.15 kJ/mol [R7, p. VA15 70] OWPC: *log Kow= 1.31 [R23] SOL: *19,000 mg/l in water @ 25 deg C [R24]; *Sol in alcohol, ether, acetone, benzene, and chloroform. [R6, p. 3-246]; *Miscible with most organic solvents [R4] SPEC: *INDEX OF REFRACTION: 1.3962 AT 20 DEG C/D; SADTLER REF NUMBER: 23 (IR, GRATING) [R25]; *IR: 44 (Sadtler Research Laboratories Prism Collection) [R26]; *UV: 21 (Sadtler Research Laboratories Prism Collection) [R26]; *NMR: 139 (Varian Associates NMR Spectra Catalogue) [R26]; *MASS: 252 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R26] SURF: *23.6 dynes/cm= 0.0236 N/m @ 20.0 deg C [R22] VAPD: +3.5 (air= 1) [R27, p. 325-70] VAP: *19.9 mm Hg at 25 deg C /from experimentally derived coefficients/ [R28] EVAP: *5.6 (ether= 1) [R29] OCPP: *Percent in saturated air 1.0; 1 ppm is equivalent to 4.10 mg/cu m; and 1 mg/l is equivalent to 244 ppm at 25 deg C, 760 mm Hg [R29] *Mobile, liquid; distills between 114 and 117 deg C /NF Grade/ [R3] *WEIGHT PER GALLON @ 20 DEG C IS 6.68 LB [R4] *Liq-water interfacial tension: 15.7 dynes/cm= 0.0157 N/m at 22.7 deg C [R22] *Water/air, blood/air, oil (olive oil)/air, oil/water, and oil/blood partition (or solubility) coefficients of methyl isobutyl ketone were measured by vial-equilibration in combination with gas chromatography. Partition coefficients for methyl isobutyl ketone: water/air: 79; blood/air: 90; oil/air: 926. The blood/air partition coefficients for ketones are almost in the same range as the water/air, irrespective of the oil/air partition coefficients. [R30] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R31] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. [R31] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R31] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R31] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R31] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R31] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R31] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R31] FPOT: *Flammable liquid when exposed to heat, flame, or oxidizers. [R32] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R27, p. 325-70] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R27, p. 325-70] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R27, p. 325-70] FLMT: +Lower: 1.4% by vol @ 200 deg F; Upper: 7.5% @ 200 deg F [R27, p. 325-70] FLPT: *75 deg F (open cup) [R22] *73 deg F (23 deg C); (closed cup) [R21] AUTO: +840 deg F (448 deg C) [R27, p. 325-70] FIRP: *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R33] *Flammable. Flashback along vapor trail may occur. Vapor may explode if ignited in an enclosed area. Wear goggles and self-contained breathing apparatus. Extinguish with dry chemical, alcohol foam, or carbon dioxide. Water may be ineffective on fire. Cool exposed containers with water. [R34] OFHZ: +VAPOR IS HEAVIER THAN AIR (VAPOR-AIR DENSITY AT 100 DEG F, 1:1) AND MAY TRAVEL CONSIDERABLE DISTANCE TO SOURCE OF IGNITION AND FLASH BACK. [R27, p. 49-89] EXPL: +Vapors form explosive mixtures with air. [R27, p. 49-89] +Upper explosive limit= 8.0%; Lower= 12% [R35, 164] *Moderately explosive in the form of vapor when exposed to heat or flame. [R32] REAC: *Ignites on contact with potassium-t-butoxide ... May form explosive peroxides upon exposure to air. Can react vigorously with reducing material. [R32] +Strong oxidizers, potassium tert-butoxide. [R35, 164] *4-Methyl-2-pentanone had not been considered prone to autoxidation, but an explosion during prolonged and repeated aerobic hot evaporation of the solvent was attributed to formation and explosion of a peroxide. [R36] ODRT: *0.10 ppm [R37, 4747] *Air: 0.68 ul/l; water: 1.3 mg/l; odor safety class B; B= 50-90% of distracted persons perceive warning of TLV [R38] *0.47 ppm [R22] *Odor detection limit in air: 9.70x10-6 g/l (gas). [R39] *0.410 mg/cu m (odor low) 192.7 mg/cu m (odor high). [R40] SERI: *The MIBK odor was objectionable and the vapor was irritating to the eyes at 200 ppm. [R41, 1991.1020] *... /AT 100 PPM/ METHYL ISOBUTYL KETONE MAY IRRITATE EYES OF MORE SENSITIVE PERSON. [R42] *Vapors cause irritation of ... nose ... . [R22] EQUP: *Personnel protection: ... Wear appropriate chemical protective gloves, boots and goggles. [R33] *Breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for natural rubber. Breakthrough times greater than one hour reported by (normally two or more testers for polyvinyl alcohol (PVA). No data for butyl rubber, neoprene (Neop), nitrile rubber, nitrile rubber/polyvinyl chloride, polyethylene (PE), chlorinated polyethylene (CPE), polyurethane (PU), polyvinyl chloride (PVC), styrene-butadiene rubber (SBR), and viton. [R43] +Wear appropriate personal protective clothing to prevent skin contact. [R35, 165] +Wear appropriate eye protection to prevent eye contact. [R35, 165] +Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R35, 165] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R35, 165] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R35, 165] OPRM: +Contact lenses should not be worn when working with this chemical. [R35, 165] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Work practices and industrial hygiene techniques should minimize the volatilization of ketones in the workroom air in order to ensure that the exposure limits are not exceeded. /Ketones/ [R44, 1173] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R33] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R33] +The worker should immediately wash the skin when it becomes contaminated. [R35, 165] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R35, 165] SSL: *STABLE LIQUID [R45] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R46] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R47] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R48] STRG: *... OPEN LIGHTS OR OTHER AGENCIES LIABLE TO IGNITE THE VAPOR SHOULD BE EXCLUDED FROM THOSE AREAS WHERE LIQUID IS BEING STORED OR USED. /KETONES/ [R2, 751] +Protect against physical damage. Separate from oxidizing materials. Outside or detached storage is preferred. Inside storage should be in a standard flammable liquids storage room. [R27, p. 49-89] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U161 and F003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R49] *A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R50] *Spray into the furnace. Incineration will become easier by mixing with a more flammable solvent. Recommendable methods: Incineration, open burning, and use as a boiler fuel. [R51] *Methyl isobutyl ketone is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R52] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *For immediate first aid: ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Ketones and related compounds/ [R53] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary. ... For contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport. ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Ketones and related compounds/ [R53] HTOX: *... The sensory threshold of MIBK /was studied/ in 12 men and women subjected to various concentrations of MIBK for 15-minute periods. Vapor pressure data were used to calculate the quantity of vapors added from saturators maintained at constant temperature. The highest concentration that most subjects evaluated as satisfactory for 8 hr continuous exposure was 100 ppm. The MIBK odor was objectionable and the vapor was irritating to the eyes at 200 ppm. [R41, 1991.1020] *Exposure to 50-105 ppm for 15-30 min provoked gastrointestinal disturbances and central nervous system impairment in a few workers. /Ketones/ [R44, 1171] *One group of workers exposed to 100 ppm methyl isobutyl ketone developed headache and nausea, whereas another group complained only of respiratory tract irritation. Tolerance to methyl isobutyl ketone seemed to develop during the work week but was lost over the weekend and most of these effects were not seen at 20 ppm. [R54] *Possible exposure to organic solvents in the manufacture of athletic equipment at /manufacturer facility in/ Leesburg, Florida was investigated. The study was requested by employees and was conducted on February 17-18, 1982. The facility employs about 120 workers. Environmental sampling and employee interviews were conducted. Two dip room workers were overexposed to total solvant vapor mixtures. These mixtures were composed of methyl ethyl ketone (MEK) at concentrations of 720 and 580 mg/cu m (NIOSH standard: 590 mg/cu m); toluene at concentrations of 230 and 130 mg/cu m (below NIOSH standard); and methyl isobutyl ketone (MIBK) at concentrations of 110 and 60 mg/cu m (also below NIOSH standard). All 32 workers interviewed reported at least one work related symptom. Complaints included dryness, itching and skin irritation, eye irritation, headaches, and dizziness. /Results of the study conclude that dip room workers/ were exposed to a health hazard from mixutures of MEK, MIBK, and toluene. The /study recommends/ that until the dip room process can become fully automated, workers must strictly observe the respirator program. [R55] *Worker exposures to epoxy resins, curing agents, and other chemicals were investigated in April, June, July and September, 1982, and May 1983 at Bowing Vertol Company in Philadelphia, Pennsylvania. The evaluation was requested by Local 1069, United Auto Workers, on behalf of about 4600 workers concerned about skin problems and a potential cancer risk. Air samples were collected for dust, methylenedianiline (MDA), ethylenediamine (EDA), methylisobutyl ketone (MBK), toluene, cyclohexanone, and butyl glycidyl ether (BGE). Medical interviews were conducted with 20 exposed and 20 unexposed workers, and skin examinations were completed. A proportional mortality ratio study for cancer was also completed for workers who died between 1968 and 1980. Concentrations of BGE, dust, MBK, and toluene were below respective OSHA tandards of 270, 15, 410, and 750 mg/cu m. No EDA or cyclohexanone was detected. MDA concentrations ranged up to 0.46 mg/cu m, below the American Conference of Governmental Industrial Hygienists Threshold Limit Value of 0.8 mg/cu m. Twice as many exposed as unexposed workers reported skin problems such as redness, itching, and cracking. The problems were reportedly exacerbated by hot weather and continued use of epoxy materials. An excess rate of cancer of the bladder was identified for workers expsed to epoxy resins and amine hardeners. /Data suggests/ that exposures to epoxy resins and amine hardeners present a health risk for skin problems. MDA is a suspected carcinogen and may be responsible for the high incidence of bladder cancer. Improved ventilation, use of protective clothing and equipment, and further evaluation of the MDA cancer association /was recommended/. [R56] *Irritative effects and CNS symptoms of methyl isobutyl ketone (MIBK) were studied in human volunteers during inhalation exposure. The volunteers were exposed (2 hr, 50 W) in an exposure chamber on four different occasions to about 10, 100 and 200 mg/cu m MIBK and to a combination of about 100 mg/cu m MIBK and 150 mg/cu m toluene. Irritative and CNS symptoms occurred during exposure. The degree of both irritative and CNS symptoms increased during exposure to 100 and 200 mg/cu m compared with 10 mg/cu m, but combination exposure with toluene exhibited the most pronounced effect. There were no significant effects from exposure on the performance of a simple reaction time task or a test of mental arithmetic. [R57] *After an 8 month period of sniffing a lacquer thinner containing toluene, ethyl acetate, methyl isobutyl ketone (MIBK), Isopropyl alcohol, and butyl acetate in a plastic bag in which solvent concentrations were 12,000 ppm toluene, 11,500 ppm ethyl acetate, 6,000 ppm isopropyl alcohol, and 2,000 ppm MIBK, cerebral dysfunction was evidenced by blurred vision, dysarthria, nystagmus, slight intention tremor, staggering gait and an abnormal electroencephalogram. Inhalation of relatively high concentrations of toluene apprears to result in impairment of the vermis followed by the cerebral hemispheres and the cerebrum. These effects are important in connection with the occupational use of toluene containing solvents. [R58] NTOX: *... Guinea pigs /were exposed/ to concn of 1000, 16,800, and 28,000 ppm methyl isobutyl ketone. The 1000 ppm level caused little or no irritation of eyes and nose of the animals. Guinea pigs showed a decr respiratory rate during the first 6 hr of exposure ... attributed to a low grade ... /central nervous system depression/. The 16,800 ppm level caused immediate signs of eye and nose irritation followed by salivation, lacrimation, ataxia, and death. Nine of 10 ... died within 6 hr of exposure. The highest concn used (28,000 ppm) killed 50 percent of the animals within 45 min. Only a few guinea pigs survived 60 min of exposure. ... Fatty livers and congestion of the brain, lungs and spleen were noted. [R59, 1790] *Undiluted ... methyl isobutyl ketone (0.1 ml) produced some irritation within 10 min when instilled in the rabbit eye. Inflammation and swelling occurred in 8 hr, and inflammation, swelling, and exudate were present at 24 hr. A single application ... to the skin of rabbits produced only transient erythema, but daily applications of 10 ml for 7 days caused drying and flaking of the skin. ... 500 mg ... produced moderate irritation of rabbit skin after 24 hr. [R59, 1789] *Exposure to 19,500 ppm ... methyl isobutyl ketone produced anesthesia in 7 of 10 mice within 30 min. ... Concn above 20,000 ppm produced anesthesia within 30 min with subsequent death of most of the animals. Gross examination at necropsy revealed congestion of the lungs. [R37, 4749] *... Rats exposed to 25 ppm ... methyl isobutyl ketone showed a minimal statistical increase in pressor lever response, but the discriminatory behavior of baboons was not impaired by exposures of 20-40 ppm. ... Reported delayed behavioral response times in baboons exposed to 50 ppm of methyl isobutyl ketone alone, but no alteration of response was seen when methyl isobutyl ketone was combined with methyl ethyl ketone (100 ppm). ... Reported subtle behavior alterations in rats exposed to 100 ppm methyl isobutyl ketone continuously for 2 wk. Kidney and liver wt and the organ/body wt ratios were also incr after exposure to 200 ppm for 2 wk and to 100 ppm for 90 days. ... Kidney damage at 2 wk after 100 ppm /described/ as droplet tubular nephrosis. This damage was reversible, even after 90 days of exposure. ... [R37, 4750] *A 90 day continuous inhalation study using Rhesus monkeys, dogs, and rats exposed at 100 ppm of MIBK produced no significant changes in clinical parameters or hematology; rat liver and kidney weights increased. All exposed rats showed hyaline droplet degeneration of the proximal renal tubules with occasional focal tubular necrosis. The tubular damage was considered transient and reversible. [R41, 1991.1019] *METHYL ISOBUTYL KETONE (98.79%) FAILED TO PRODUCE DETECTABLE NERVOUS SYSTEM DAMAGE IN CATS SC INJECTED TWICE/WK, 5 DAYS/WK FOR 8.5 MO. [R60] *When given orally to mice and rats, the lethal doses of methyl isobutyl ketone were 2.85 and 4.6 g/kg, respectively. Exposure of rats to solvent at 86-127 mg/cu m 4 hr daily for 4.5 months caused disturbances in the conditioned reflexes and in the detoxifying function of the liver; a decr of the eosinophil count in the blood was also observed. [R61] *Rats, dogs, and monkeys were exposed to methyl isobutyl ketone vapor (410 mg/cu m). Rats developed hyaline droplet nephrosis within 2 wk of exposure, but this was reversed by removal from the methyl isobutyl ketone, even after a 90 day exposure. The 60 min emergency exposure limit of 100 ppm and the 90 and 100 day provisional limits had a wide margin of safety. [R62] *Rat kidney wt and kidney/body wt ratio were significantly incr after continuous exposure of the rats to 410 mg methyl isobutyl ketone/cu m for 2 wk, and kidney and liver organ wt and organ/body wt ratio were incr after exposure to 820 mg/cu m for 2 wk and to 410 mg/cu m for 90 days. [R63] *Lesions from exposure to methyl isobutyl ketone were found only in the rat, and were limited to the first and second sections of the proximal convoluted tubule of the nephron of the kidney. The lesion was designated hyaline droplet toxic tubular nephrosis, and the lesion was present at 14 days of exposure and continued with a variable decr in severity throughout the exposure. [R64] *Methyl isobutyl ketone was evaluated for effects on a delayed match-to-sample discrimination task in the juvenile baboon. The animals were exposed to 1/2 the threshold limit value of each gas for 24 hr per day during a 7 day period. Each exposure condition affected accuracy of performance minimally but resulted in incr and decr extra responses during the delay intervals. Response times were slowed under methyl isobutyl ketone. [R65] *A decr in respiratory rate and a decr in duration of immobility occurred in mice during and following short-term inhalation exposures to some commonly used aliphatic ketones. Linear concn effect relationships were obtained that allowed 2 different median active levels (MALs) to be calculated. Median active levels that produced a 50% decr in immobility were determined for methyl isobutyl ketone. The systematic determination of median active levels permits classification of ketones in terms of their relative potencies for eliciting a given effect. [R66] *Six male and six female Fischer 344 rats and B6C3F1 mice were exposed to 0, 100, 500, and 2000 ppm methyl isobutyl ketone. The animals were exposed to methyl isobutyl ketone vapor for 6 hr/day for 5 days with 2 days off and exposure for 4 more consecutive days. No deaths occurred in the animals during this study. Absolute and relative liver weight (p < 0.01) and absolute (p < 0.05) and relative (p < 0.01) kidney weight of male rats increased significantly after exposure to 2000 ppm. In female mice exposed to 2000 ppm, there was a significant (p < 0.05) increase in absolute and relative (p < 0.01) liver weight and absolute kidney weight. An increased incidence of hyaline droplets and epithelial regeneration in proximal tubules was noted in male rats exposed to 2000 ppm. No other histological changes were noted. In a subchronic study, animals were exposed to 0, 50, 250, or 1000 ppm methyl isobutyl ketone 6 hr/day, 5 days/wk for 14 wk. Body weights of rats and mice were similar to the controls throughout the 14 wk. In male rats the absolute and relative liver weights after exposure to 1000 ppm were significantly (p < 0.001) larger than the controls. In female rats absolute, but not relative, kidney weight was increased by exposure to 250 ppm. A statistically significant (p < 0.01) increase in absolute liver weight in male mice exposed to 250 or 1000 ppm, and an increase in relative liver weight in males exposed to 1000 ppm /were noted/. After exposure to 1000 ppm methyl isobutyl ketone, male rat platelet numbers increased significantly (p < 0.01) whereas eosinophils decreased significantly (p < 0.05) in female rats. Serum cholesterol increased significantly (p < 0.01) in male rats exposed to 250 or 1000 ppm. An increase in urine glucose was observed in male and female rats exposed to 1000 ppm methyl isobutyl ketone. Histopathologic observation showed an increase in hyaline droplets in the kidneys of male rats exposed to 250 and 1000 ppm methyl isobutyl ketone. [R67] *Methyl isobutyl ketone (MiBK) ... /was/ tested for potential genotoxicity. The assays ... of MiBK included the Salmonella/microsome (Ames) assay, L5178Y/TK+/- mouse lymphoma assay, BALB/3T3 cell transformation assay, unscheduled DNA synthesis assay, and micronucleus assay. ... The presence of a marginal response only at the highest cytotoxic concentration tested in the L5178Y/TK+/- mouse lymphoma assay, the lack of reproducibility in the BALB/3T3 cell transformation assay, and clearly negative results in the Ames assay, unscheduled DNA synthesis and micronucleus assays, suggest that MiBK is unlikely to be genotoxic in mammalian systems. [R68] NTXV: *LD50 Rat oral 2.08 g/kg; [R21] ETXV: *LD50 Angelaius phoeniceus (Redwinged blackbird) oral 100 mg/kg; [R69] *LC50 Carassius auratus (goldfish) 460 mg/l/24 hr /Conditions of bioassay not specified/; [R70] *LC50 Pimephales promelas (fathead minnow) 505 mg/l 96 hr flow-through bioassay, wt 0.12 g, water hardness 45.5 mg/l CaCO3, temp: 25 + or - 1 deg C, pH 7.5, dissolved oxygen greater than 60% of saturation; [R71] *EC50 photobacterium 80 mg/l 5 min /OECD209 closed system inhibition/; [R72] *EC50 Selenastrum capricornutum (algae) 400 mg/l 96-hr /Conditions of bioassay not specified/; [R72] *EC50 Scenedesmus subspicatus (algae) 980 mg/l 48-hr /Conditions of bioassay not specified/; [R72] *LC50 Daphnia magna (water flea) 240; 4,300 mg/l 24-hr /Conditions of bioassay not specified/; [R72] *EC50 Daphnia magna (water flea) 170; > 1,000 mg/l 48-hr /Conditions of bioassay not specified/; [R72] *EC50 Daphnia magna (water flea) 1,550; 3,682; 4,280 mg/l 24-hr /Conditions of bioassays not specified/; [R72] *EC100 Daphnia magna (water flea) 5,000 mg/l 24-hr /Conditions of bioassay not specified/; [R72] *LC50 Artemia salina (brine shrimp) 862; 1,230; 1,250 mg/l 24-hr /Conditions of bioassays not specified/; [R72] *LC50 Goldfish 460 mg/l 24-hr /Conditions of bioassay not specified/; [R72] *LC50 Leuciscus idus melanotus (fish) 675-890 mg/l 48-hr /Conditions of bioassay not specified/; [R72] *LC50 Salmo gairdneri (fish) 600 mg/l 96-hr /Conditions of bioassay not specified/; [R72] *LC50 Pimephales promelas (fish) 505-540 mg/l 96-hr /Conditions of bioassay not specified/; [R72] TCAT: ?The ability of methyl isobutyl ketone (MIBK) to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction was evaluated. Based on preliminary clonal toxicity determinations (exposure time=2 hrs), MIBK was tested at 2.4, 3.6 and 4.8 ul/ml in the absence of activation (cell survival ranging from 86.7-51.1%, and at 1, and 4 ul/ml in the presence of activation (cell survival ranging from 83.7-65.3%). MIBK in the absence of added metabolic activation induced a statistically significant increase in transformation when compared with controls, whereas MIBK in the presence of activation was negative in this test. In repeat tests, MIBK was tested at 7, 6, 5 and 4 ul/ml in the absence of added activation and at 5, 4, 3 and 2 ul/ml in the presence of activation. Repeat test results were negative in both cases. The results of the first tests were not reproducible. [R73] ?An inhalation teratology study was conducted with pregnant Fischer 344 rats and CD-1 mice receiving whole body exposures to methyl isobutyl ketone at a nominal concentration of 0, 300, 1000 or 3000 ppm. At each concentration, 35 rats and 30 mice were exposed for 6hrs/day on days 6-15 of gestation. Increases in mortality, gross pathology, or uterine implantation rates were not observed at any dose in rats. In 3000 ppm group rats, maternal toxicity was evident by statistical differences in: mean body weight, body weight gain, food consumption values and kidney weights. Increases in body weight, gross pathology or uterine implantation rates were not observed at any dose in mice. In 3000 ppm mice, maternal toxicity was evident by statistical differences in: mortality (3000ppm group, 3 deaths out of 25 compared to control group, 0 deaths) and absolute and relative liver weights. Fetal toxicity was indicated by reduced fetal body weights (3000 ppm and 300 ppm group rats and 3000 ppm group mice) and number of dead fetuses (3000 ppm group mice) relative to controls. The predominant malformations observed were skeletal (3000 ppm group, rats and mice) and visceral (3000 ppm group, mice). No statistically significant differences between control and treatment groups were found for any of the fetal external, visceral or skeletal parameters. [R74] ADE: *Ketones are readily absorbed through the intact skin. Usually they are rapidly excreted ... in the expired air. /Ketones/ [R44, 1170] *The toxicokinetics of methyl isobutyl ketone ... /was/ studied in human volunteers during inhalation exposure. The volunteers were exposed (2 hr, 50 W) in an exposure chamber on four different occasions to about 10, 100 and 200 mg/cu m MIBK and to a combination of about 100 mg/cu m MIBK and 150 mg/cu m toluene. The relative pulmonary uptake of MIBK was about 60% and the total uptake increased linearly with increasing exposure concentration. The concentration of MIBK in blood rose rapidly after the onset of exposure and no plateau level was reached during exposure. No tendency for saturation kinetics could be observed within the dose interval and the apparent blood clearance was 1.61/hr/kg at all exposure levels. The concentration of unchanged MIBK in the urine after exposure was proportional with the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 hr post exposure. The concn of the metabolites 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol were below the detection limit (5 nmol/1). [R57] METB: *... METHYL ISOBUTYL KETONE ... /WAS/ METABOLIZED IN GUINEA PIG BY OMEGA-1 OXIDATION TO ... /4-HYDROXY-4-METHYL, 2-PENTANONE, AND IT IS NOT NEUROTOXIC/ ... DUE PRESUMABLY TO LACK OF FORMATION OF 2,5-DIKETONE. [R75] *GUINEA PIGS WERE GIVEN SINGLE 450 MG/KG (IP) DOSES OF METHYL N-BUTYL KETONE WHICH WAS METAB TO METHYL ISOBUTYL KETONE (MIBK) AND OTHER METABOLITES. METHYL ISOBUTYL KETONE WAS CONVERTED TO 4-HYDROXY-2-METHYL-PENTANONE AND 4-METHYL-2-PENTANOL. [R76] BHL: *IN GUINEA PIGS SERUM HALF-LIVES AND CLEARANCE TIMES FOR METHYL ISOBUTYL KETONE WAS 66 MIN AND 6 HR RESPECTIVELY. [R76] INTC: *An experiment /was conducted/ to investigate the mechanism of methyl isobutyl ketone synergism of n-hexane neurotoxicity ... The results suggest that the synergistic action of methyl isobutyl ketone on n-hexane neurotoxicity may be related to its ability to induce liver microsomal cytochrome p450, resulting in increased metabolic activation of n-hexane to more potent neurotoxic metabolites. [R77] *The potentiating properties of methyl isobutyl ketone (MIBK) ... on the acute cholestatic response induced by taurolithocholate (TLC) were investigated in male Sprague Dawley rats. Animals were pretreated with 3.75 to 15.0 nmol ... by gavage administration daily for 3 or 7 days. Intravenous injections of taurolithocholate were 5, 10, 15, 20, or 25 mg/kg. Bile was collected over 15 or 30 minute periods to measure bile flow. Daily ketone pretreatment resulted in an enhancement of the diminution in bile flow observed after taurolithocholate challenge. When the ... /ketone was/ administered without taurolithocholate chellenge, cholestasis was not observed. Slight increases in bile flow did occur. [R78] *Pharmacological and metabolic ... /interaction between methyl isobutyl ketone/ ... and ethanol ... /was/ explored in male Charles-River-CD-1-mice. The animals were exposed to ... methyl isobutyl ketone (MiBK) at 2.5 and 5 mmol/kg, ip. ... All mice were injected ip with 4 g ethanol/kg at 30 min after pretreatment. The duration of ethanol induced loss of righting reflex was prolonged significantly by ... /MiBK at 5 mmol per kg/. As the dose of solvent increased, the prolongation also increased. Similar concentrations of ethanol were found in the blood and brain on the return of the righting reflex in both solvent treated and control animals. ... The activity of mouse liver alcohol-dehydrogenase in vitro was reduced /by MiBK/ . ... /Data suggests/ that the solvents enhanced the loss of righting reflex caused by ethanol exposure by reducing the rate at which ethanol was eliminated from the body. [R79] *The potentiating properties of two metablites of methyl isobutyl ketone (MIBK), 4-methyl-2-pentanol (4MPOL) and 4-hydroxymethyl isobutyl ketone (4-OHMIBK), on the acute cholestatic response induced by manganese (Mn) alone or in combination with bilirubin (Mn/BR) were studied in the rat. Male Sprague-Dwley-rats were catheterized in the common bile duct and in a femoral vein. Bile flow was expressed as a percentage of the flow in control animals. 4-Methyl-2-pentanol or 4-hydroxymethyl isobutyl ketone 1.88 to 15 mmol/kg, was dissolved in corn oil and administered by gavage, either as a single treatment or once a day for 3 days. Manganese 4.5 or 6.0 mg/kg as the sulfate, was injected iv 18 hr later. In experiments using manganese/bilirubin, bilirubin, 15 mg/kg, was injected iv 15 min after the manganese injection. Administration of 4-methyl-2-pentanol or 4-hydroxymethyl isobutyl ketone alone caused an observable increase in bile flow. Administration of 4-methyl-2-pentanol or 4-hydroxymethyl isobutyl ketone 18 hr before a single dose cholestatic challenge enhanced the cholestatic effect of manganese/bilirubin in a dose related fashion. After repetitive administration of 4-hydroxymethyl isobutyl ketone a significant reduction in bile flow was observed with either dosage for 15 to 135 minutes. After repetitive administration of 4-methyl-2-pentanol the difference was found only with the lower dosage of Mn and only at 15 minutes after its administration. /Results indicate/ that MIBK and its two major metabolites enhance the cholestasis following administration of manganese/bilirubin, manganese. The results are important because they illustrate that cholestasis can be enhanced by ketone compounds or ketogenic substances. [R80] *Potentiation of haloalkane hepatotoxicity by ketones and ketogenic agents is a well known phenomenon. The importance of the CCl4 dosage in these combinations, however, has not been explored. Its influence was investigated in male Sprague-Dawley rats. Dose-effect curves for potentiation were generated using 1,3-butanediol, methyl n-butyl ketone or methyl isobutyl ketone as potentiation agents. Animals were orally treated with these compounds prior to a challenge of CCl4 (0 to 0.5 ml/kg, ip). Liver injury was assessed by monitoring plasma alanine-aminotransferase activity and bilirubin concentrations after CCl4 treatment. The minimal effective dosage (MED) for each potentiator was used as the criterion of comparison for each combination. The minimal effective dosage values were determined from the plasma alanine-aminotransferase data. Results showed that when the CCl4 dosage was increased from 0.01 to 0.10 ml/kg, the minimal effective dosage of each potentiator decreased ten-fold. ... [R81] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl isobutyl ketone's (MIBK) production and use as a solvent for vinyl, epoxy, acrylic, and natural resins and as a solvent for nitocellulose and dyes may result in its release to the environment through various waste streams. Its use as an extracting agent for the production of antibiotics, or the removal of paraffins from mineral oil for the production of lubricating oils will also lead to its release to the environment. Methyl isobutyl ketone occurs naturally in oranges and grapes, but the amount released by artificial sources is assumed to be much greater. Based on an experimental vapor pressure of 19.9 mm Hg at 25 deg C, MIBK is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase MIBK is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of about 27 hours. Methyl isobutyl ketone is expected to have high mobility in soils based upon an estimated Koc value of 123. Volatilization from dry soil surfaces is expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is also expected based upon an estimated Henry's Law constant of 1.38X10-4 atm-cu m/mol. This compound is expected to biodegrade under aerobic and anaerobic conditions. In water, MIBK is not expected to adsorb to suspended solids or sediment based upon its estimated Koc value. Volatilization from water surfaces is expected to be an important environmental fate process given its estimated Henry's Law constant. Estimated half-lives for a model river and model lake are 9 and 141 hours, respectively. Bioconcentration in aquatic organisms is considered low based upon an estimated BCF value of 6. Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where MIBK is produced or used. The general population may be exposed to MIBK primarily through the use of commercially available products containing this compound such as paints, adhesives, pesticides (pyrethrins) and rubber cements. Exposure may also arise from inhalation and ingestion of drinking water and food that contains MIBK. (SRC) NATS: *IN ORANGES AND GRAPES; IN VINEGAR [R1] ARTS: *Methyl isobutyl ketone's (MIBK) production and use as a solvent for vinyl, epoxy, acrylic, and natural resins and as a solvent for nitocellulose and dyes(1) will result in its release to the environment through various waste streams(SRC). Its use as an extracting agent for the production of antibiotics, or the removal of paraffins from mineral oil for the production of lubricating oils(1) will also lead to its release to the environment(SRC). [R82] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 123(SRC), determined from an experimental log Kow of 1.31(2), and a recommended regression-derived equation(3), indicates that MIBK is expected to have high mobility in soil(SRC). Volatilization of MIBK from moist soil surfaces(SRC) is expected given an estimated Henry's Law constant of 1.38X10-4 atm-cu m/mole(SRC), determined from an experimental vapor pressure of 19.9 mm Hg at 25 deg C(4) and water solubility of 19,000 mg/l at 25 deg C(5). Volatilization from dry soil surfaces is expected based upon the vapor pressure of this compound(4,SRC). Biodegradation is expected to be an important fate process for this compound(SRC). MIBK was shown to biodegrade under both aerobic and anaerobic conditions(6-9). [R83] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 123(SRC), determined from an experimental log Kow of 1.31(2), and a recommended regression-derived equation(3), indicates that MIBK is not expected to adsorb to suspended solids and sediment in water(SRC). MIBK is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 1.38X10-4 atm-cu m/mole(SRC), determined from an experimental vapor pressure of 19.9 mm Hg at 25 deg C(4) and water solubility of 19,000 mg/l at 25 deg C(5). Estimated half-lives for a model river and model lake are 9 and 141, hours respectively(6,SRC). Biodegradation of this compound occurs in both freshwater and seawater(7-10). According to a classification scheme(11), an estimated BCF value of 6(3,SRC), from an experimental log Kow(2,SRC), suggests that bioconcentration in aquatic organisms is low(SRC). [R84] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), MIBK, which has an experimental vapor pressure of 19.9 mm Hg at 25 deg C(2), will exist solely as a vapor in the ambient atmosphere. Vapor-phase MIBK is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 27(3,SRC) hours. [R85] BIOD: *In a wastewater stream the concn of chemical products can be measured or characterized by analyses such as Biochemical or Chemical Oxygen Demand (BOD or COD). The BOD and COD of industrial chemicals were found. BOD: 2.06 g of oxygen/g of methyl isobutyl ketone; COD: 2.16 g of oxygen/g of methyl isobutyl ketone. [R86] *The theoretical BOD of MIBK (5 ppm) in seawater was measured as 27.6% and 30.6% over a 5 day incubation period(1). The theoretical BOD of MIBK in freshwaters seeded with settled domestic sewage was 56%, 66%, 69% and 69%, over 5, 10, 15 and 20 day incubation periods(2). The theoretical BOD of MIBK in synthetic seeded seawaters with settled domestic sewage was 15%, 46%, 50% and 53%, over 5, 10, 15 and 20 day incubation periods(2). The theoretical BOD of a 100 mg/l sample of MIBK in an activated sludge inoculum was 84% over a 2 week incubation period(3). The theoretical methane recovery of MIBK in an anaerobic aquifer was 46% over a 3 week incubation period(4). [R87] ABIO: *The rate constant for the vapor-phase reaction of MIBK with photochemically-produced hydroxyl radicals has been measured as 1.41X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 27 hours at an atmospheric concn of 5.0X10+5 hydroxyl radicals per cu cm(1,SRC). The photochemical degradation products of MIBK with hydroxyl radicals are acetone and 2-methylpropanal(2). Methyl isobutyl ketone in cyclohexane exhibits strong absorption of UV light > 290nm(3), suggesting that MIBK has the potential to undergo direct photolysis in the environment. The half-life for direct photolysis of MIBK in the atmosphere is predicted to be on the order of 15 hours based on an overlap of the solar spectrum with the absorption spectrum at a solar zenith angle of 30 deg(4). MIBK is not expected to undergo hydrolysis in the environment due to the lack of functional groups to hydrolyze(SRC). [R88] BIOC: *An estimated BCF value of 6 was calculated for MIBK(SRC), using an experimental log Kow of 1.31(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R89] KOC: *The Koc of MIBK is estimated as approximately 123(SRC), using an experimental log Kow of 1.31(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that MIBK is expected to have high mobility in soil(SRC). [R90] VWS: *The Henry's Law constant for MIBK is estimated as 1.38X10-4 atm-cu m/mole(SRC) from its experimental value for vapor pressure, 19.9 mm Hg(1), and experimental water solubility, 19,000 mg/l(2). This value indicates that MIBK will volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 9 hours(3,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 141 hours(3,SRC). MIBK is expected to volatilize from dry soil surfaces given its experimental vapor pressure(1,SRC). [R91] WATC: *SURFACE WATER: Methyl isobutyl ketone was identified, not quantified, in Cuyahoga River(1) and in 1 out of 204 samples of surface water collected near heavily industrialized areas across the US(2). Methyl isobutyl ketone was identified, not quantified, in 1 out of 17 samples of Delaware River(3). Methyl isobutyl ketone was detected at mean concns of 57.1 ug/l (range, 2.8-332 ug/l) and 1.2 ug/l (range, 0.01-5.60 ug/l) in the Adige River, Italy(4). Methyl isobutyl ketone was detected at a concn of less than 10 ug/l in the Potomac River(5). [R92] *DRINKING WATER: Methyl isobutyl ketone was identified, not quantified, in 4 out of 14 drinking water supplies sampled in England(1) and in drinking water in the Netherlands(2). [R93] *GROUNDWATER: Methyl isobutyl ketone was detected in the Biscayne Aquifer groundwater at a maximum concn of 90 ug/l(1). Methyl isobutyl ketone was detected at a concn of 10 ug/l near a waste disposal facility in Kansas(2). Methyl isobutyl ketone was detected at a concn of 62,000 ug/l in the vicinity of a coal strip-mine in Ohio(3). [R94] EFFL: *Leachate collected from the Southington, CT municipal landfill contained MIBK at a concn of 172-263 ug/l(1). Methyl isobutyl ketone was detected in leachate from Granby, CT municipal landfill at a concn of 25-150 ppb(2). Methyl isobutyl ketone was identified, not quantified in leachate from Maxy Flats, KY low-level radioactive waste disposal site(3). Methyl isobutyl ketone was detected in the soil of a Michigan waste disposal facility at a concn of 4 ug/kg(4). Methyl isobutyl ketone was detected in the effluent from a pharmaceutical plant at a concn of 0.4-0.8 kg/cu m(5). Methyl isobutyl ketone was detected in the effluent from a solid waste composting plant at concns of 43 ug/cu m (field), 28 ug/cu m (tipping area), 1,500 ug/cu m (shredder), 62 ug/cu m (indoor air), 900 ug/cu m (fresh compost), 1,100 ug/cu m (middle age compost), 830 ug/cu m (old compost) and 60 ug/cu m (curing region)(6). Detected at a concn of 190 ug/l in formation water discharged from an offshore (Shell Oil) production operation in the Gulf of Mexico(7). Methyl isobutyl ketone has been identified in the final effluent from at least one plant in each of the following industries: printing and publishing, coal mining, electronic, and organic chemicals(8) and has been found in gasoline engine exhaust(9). [R95] ATMC: *OUTDOOR AIR: Methyl isobutyl ketone was identified, not quantified, in a West German forest(1) and in 1 of 8 air samples taken in New Jersey(2). Methyl isobutyl ketone was detected at mean concns of 0-6 ug/cu m in air samples across the US(3,4). INDOOR AIR: Methyl isobutyl ketone was identified, not quantified, in 2 classrooms at a school located in France(5). [R96] FOOD: *Methyl isobutyl ketone was identified, not quantified, in the volatile component of baked potatoes(1). Methyl isobutyl ketone was detected in the volatiles of scrambled eggs (3 ng/g)(2), cured beef (0.03 mg/kg)(3) and cured chicken (0.06 mg/kg)(3). Methyl isobutyl ketone was detected at concns of 43.6 ng/g and 93.6 ng/g in salt-fermented anchovies and shrimp, respectively(4). [R97] OEVC: *MIBK has been found in gasoline engine exhaust gas(1). During 1979 methyl isobutyl ketone was found in waste material from pharmaceutical production, which was later disposed of by discharge into the ocean at a dumpsite north of Puerto Rico(2). Identified in water from drum storage area in the "Valley of the Drums" hazardous waste site near Louisville, KY, concn range 880-1600 ug/l(3). [R98] RTEX: *The most likely exposures ... in the workplace are by inhalation of the vapors and by skin and eye contact. [R37, 4751] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 467,763 workers (82,337 of these are female) are potentially exposed to MIBK in the US(1). Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where MIBK is produced or used(SRC). Methyl isobutyl ketone was detected in the breathing zones in 1 of 11 automobile paint shops in Spain at a concn of 29.9 mg/cu m(2). concns of 0.5-58 ppm were detected in the breathing zones at 47 paint manufacturing and finishing shops across the US(3). Methyl isobutylketone was identified, not quantified, in 89 automobile paint shops in South Africa(4). Methyl isobutylketone was detected in 4 of 70 spray paint shops in Australia at an average concn of 6.8 mg/cu m(5). The general population will be exposed to MIBK primarily through the use of commercially available products containing this compound such as paints, adhesives, pesticides (pyrethrins and pyrethroids) and rubber cement(6,7,SRC). Exposure may also arise from inhalation of ambient air, ingestion of drinking water, and food that contains MIBK(SRC). [R99] BODY: *Methyl isobutyl ketone has been identified in the expired air from a non-smoking heterogenous study population(1). [R100] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +500 ppm [R35, 164] ATOL: *Residues of methyl isobutyl ketone are exempted from the requirement of a tolerance when used as a solvent, cosolvent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R101] *Methyl isobutyl ketone is exempted from the requirement of a tolerance when used as a solvent, cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R102] *Methyl isobutyl ketone is exempted from the requirement of a tolerance when used as a solvent, cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R103] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (410 mg/cu m). [R104] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 50 ppm (205 mg/cu m). [R35, 164] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 75 ppm (300 mg/cu m). [R35, 164] TLV: +8 hr Time Weighted Avg (TWA): 50 ppm; 15 min Short Term Exposure Limit (STEL): 75 ppm. [R105, 2002.42] +Biological Exposure Index (BEI): Determinant: methyl isobutyl ketone in urine; Sampling Time: end of shift; BEI: 2 mg/l. [R105, 2002.92] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Methyl isobutyl ketone is produced, as an intermediate or final product, by process units covered under this subpart. [R106] +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Methyl isobutyl ketone is included on this list. [R107] WSTD: STATE DRINKING WATER GUIDELINES: +(CA) CALIFORNIA 40 ug/l [R108] +(FL) FLORIDA 350 ug/l [R108] +(MA) MASSACHUSETTS 350 ug/l [R108] +(MI) MICHIGAN 350 ug/l [R108] +(MN) MINNESOTA 300 ug/l [R108] +(NH) NEW HAMPSHIRE 350 ug/l [R108] +(WI) WISCONSIN 500 ug/l [R108] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R109] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Methyl isobutyl ketone is included on this list. [R110] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R111] *A testing consent order is in effect for methyl isobutyl ketone for health effects testing. FR citation: 1/23/95. [R112] RCRA: *U161; As stipulated in 40 CFR 261.33, when methyl isobutyl ketone, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R113] *F003; When methyl isobutyl ketone is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F003), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R114] FDA: *Methyl isobutyl ketone is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. Synthetic flavoring substances and adjuvants consist of one or more of the following /including methyl isobutyl ketone/, used alone or in combination with flavoring substances and adjuvants generally recoginized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. [R115] *Methyl isobutyl ketone is an indirect food additive for use only as a component of adhesives. [R116] *Methyl isobutyl ketone is an indirect food additive polymer for use as a basic component of single and repeated use food contact surfaces. Polysulfide polymer-polyepoxy resins may be safely used as the food contact surfacce of articles intended for packaging, transporting, holding, or otherwise contacting dry food in accordance with precribed conditions. Optional substances may include methyl isobutyl ketone. [R117] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 1300: Analyte: methyl isobutyl ketone; Sampler: Solid Sorbent Tube, (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01-0.2 l/min; Vol: min: 1 l, max: 25 l; sample stability: unknown. [R118, p. V2 1300-2] *Activated charcoal, Ambersorb XE-348, and Amberlites XAD-2, XAD-4, and XAD-7 were evaluated as solid adsorbents for work-room air sampling of selected ketones including methyl isobutyl ketone. Activated charcoal had good capacity for the compounds investigated, but most ketones decomposed on this adsorbent during storage. Ambersorb XE-348 also showed good capacity for most of the ketones and decomposition was insignificant. [R119] ALAB: *AN AUTOMATED ECG 900 GAS CHROMATOGRAPHY SYSTEM WAS USED TO MEASURE SOLVENT EXPOSURE IN PAINT FACTORY FOR 20 DAYS. SAMPLING WAS PERFORMED AUTOMATICALLY EVERY 15 MIN AT EACH OF SEVERAL FIXED STATIONS IN 2 DEPT, AND FED DIRECTLY TO GAS CHROMATOGRAPH. [R120] *NIOSH 1300: Analyte: Methyl isobutyl ketone; Matrix: air; Prodedure: Gas chromatography, hydrogen flame ionization detector; Estimated limit of detection: 0.02 mg/sample; desorption:1 ml carbon disulfide, stand 30 min; injection volume: 5 ul; column: glass (12 ft x 1/4 in); temperature: injector: 250 deg C, detector: 300 deg C, column: 50 deg C to 170 deg C @ 10 deg/min; carrier gas: nitrogen or helium, 30 ml/min; interferences: none reported. [R118, p. V2 1300-1] *The vapor of methyl isobutyl ketone is collected in water and the soln allowed to react with acidic 2,4-dinitrophenylhydrazine soln. The addition of methanolic potassium hydroxide results in the formation of red coloration, which is compared visually with standards after 10 min. [R121] *Purge-and-trap analysis of methyl isobutyl ketone using fused silica capillary column gas chromatography/mass spectrometry was evaluated for the analysis of priority pollutant organics. Preliminary tests of a 30-m SE54 capillary column systems indicated satisfactory precision (8.5%) and excellent accuracy (98.5% and 102% recoveries). Not only was the capillary column much faster than the packed column (13 min compared to 33 min), it also overcame difficulties normally encountered with samples having excessive complexity, very large concn spread among components, or high concn of high-boiling components. [R122] *EPA Method 8015: Nonhalogenated Volatile Organics. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the collected sample with air, must be avoided. Two VOA vials are filled per sample location, then placed in separate plastic bags for shipment and storage. Samples can be analyzed by direct injection or purge-and trap gas chromatography. A temperature program is used in the gas chromatograph to separate the organic compounds. Column 1 is an 8-ft by 0.1-in I.D. stainless steel or glass column packed with 1% SP-1000 on Carbopack-B 60/80 mesh or equivalent. Column 2 is a 6-ft by 0.1-in I.D. stainless steel or glass column packed with n-octane on Porasil-C 100/120 mesh (Durapak) or equivalent. Detection is achieved by a flame ionization detector (FID). Under the prescribed conditions, methyl isobutyl ketone can be detected using this method. No statistical analysis was determined; specific method performance information will be provided as it becomes available. [R123] *EPA Method 8015A: Non-halogenated Organic. Provides gas chromatographic conditions for the dectection of certain non-halogenated volatile organic compounds. [R123] *EPA Method 8240A: Volatile Organics by Gas Chromatography/Mass Spectrometry GC/MS. Method to separate and analyze complex volatile organic compounds by GC/MS. [R123] CLAB: *Methyl isobutyl ketone was detected in brain, liver, lung, vitreous fluid, kidney, and blood of 2 individuals who died from exposure to painting sprays, by packed and open tubular gas chromatographic column and mass spectroscopy. [R124] *A GAS CHROMATOGRAPHY PROCEDURE FOR DETECTING SOLVENTS IN BIOLOGICAL FLUIDS IS DESCRIBED. METHOD REQUIRES 0.05 ML OF SAMPLE AND N-PENTANE AS SOLVENT. METHYL ISOBUTYL KETONE WAS DETECTED IN BLOOD BY THIS PROCEDURE. SENSITIVITY WAS 0.04 TO 0.24 NG. [R125] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Istituto Superiore di Sanita; Rapp Istisan, Iss 85/26: 122 (1985) Toxicological file of organic solvents use in industrial technological areas. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for methyl isobutyl ketone. Route: inhalation; Species: rats and mice. [R126] HIST: *The wreck of the MV Ariadne, a Panamanian flag container ship, is examined as a case study of a hazardous substance emergency response in a third world country. /The ship/, carrying a cargo of heavy fuel oil, tetraethyl lead, xylene, toluene, methyl isobutyl ketone, butyl acetate, ethyl acetate, and acetone was grounded while departing the harbor of Mogadishu, Somalia. The Somalian government requested a team of technical advisors to help respond appropriately to the emergency. The major issues addressed by the advisory team were the need for additional salvage equipment and expertise, the danger of toxic fumes from the fire and explosions aboard the ship, the presence and possible release of tetraethyl lead, possible port blockage by the wreck, recovery of the chemical drums, and the extent of environmental damage caused by the release of oil, pesticides, and tetraethyl lead into the harbor. ... [R127] SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 391 R2: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R3: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. 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New York: Van Nostrand Reinhold Co., 1987. 772 R46: 49 CFR 171.2 (7/1/96) R47: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 179 R48: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3089 (1988) R49: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R50: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-14 (1981) EPA 68-03-3025 R51: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 220 R52: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-8 (1981) EPA 68-03-3025 R53: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 237 R54: Elkins HB; The Chemistry of Industrial Toxicology 2nd ed. Wiley New York (1959) R55: Lee S, Murphy D; NIOSH; Health Hazard Evaluation Report p.16 (1982) No. HETA-82-30-1184 R56: Liss GM, Chrostek W; NIOSH; Health Hazard Evaluation Report p.28 (1983) No. HETA-82-146-1388 R57: Hjelm EW et al; Int Arch Occup Environ Health 62 (1): 19-26 (1990) R58: Takeuchi Y et al; Industrial Health 19 (3): 163-69 (1981) R59: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R60: SPENCER PS, SCHAUMBURG HH; TOXICOL APPL PHARMACOL 37 (2): 301-11 (1976) R61: Batyrova TF; Gig Tr Prof Zabol 11: 52-3 (1973) R62: MacEwen JD et al; US Nat Tech Inform Serv AD Rep 29 (1971) Iss No 730291 R63: Vernot EH et al; US Nat Tech Inform Serv AD Rep: 11 (1971) Iss No 751443 R64: MacKenzie WF; US Nat Tech Inform Serv, AD Rep: 13 (1971) Iss No 751444 R65: Geller I et al; Pharmacol Biochem Behav 11 (4): 401-6 (1979) R66: De Ceaurriz J et al; Food Chem Toxicol 22 (7): 545-9 (1984) R67: Phillips RD et al; Fundam Appl Toxicol 9 (3): 380-8 (1987) R68: O'Donoghue et al; Mutat Res 206 (2): 149-61 (1988) R69: Schafer EW; Toxicol Appl Pharm 21: 315-30 (1972) R70: Bridie AL et al; Water Res 13 (7): 623-6 (1979) R71: Veith GD et al; Canadian J Fisheries Aquat Sci 40 (6): 743-8 (1983) R72: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1294 R73: Microbiological Assoc., Inc.; Activity of Methyl Isobutyl Ketone in the Morphological Transformation Assay Using BALB/3T3 Mouse Embryo Cells. (1984), EPA DOocument No. FYI-OTS-1084-0355, Fiche No. 0355-0 R74: Bushy Run Research Center; A Teratologic Evaluation of Methyl Isobutyl Ketone in Fischer 344 Rats and CD-1 Mice Following Inhalation Exposure, Final Report. (1984), EPA Document No. 40-8444071, Fiche No. OTS0507469 R75: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 496 R76: DIVINCENZO GD ET AL; TOXICOL APPL PHARMACOL 36 (3): 511-22 (1976) R77: Abou-donia MB, et al; Toxicol Appl Pharmacol 81 (1): 1-16 (1985) R78: Plaa GL, Ayotte P; Toxicol Appl Pharm 80 (2): 228-34 (1985) R79: Cunningham J et al; Fund Appl Toxicol 13 (1): 102-9 (1989) R80: Vezina M, Plaa GL; Toxicol Appl Pharmacol 92 (3): 419-27 (1988) R81: Pilon D et al; Toxicol Appl Pharmacol 94 (2): 183-90 (1988) R82: (1) Siegel H, Eggersdorfer M; Ullmann's Encycl of Indust Chem 5th ed Deerfield, FL: VCH Publ A15: 79-80 (1990) R83: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR Hydrophobic, Electronic and Stearic Constants Washington,DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. NY,NY: Hemisphere Pub Corp (1989) (5) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992)(6) Takemoto S et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) (7) Price KS et al; J Water Pollut Control Fed 46: 63-77 (1974) (8) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (9) Suflita JM, Mormile MR; Environ Sci Technol 27: 976-78 (1993) R84: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR Hydrophobic, Electronic and Stearic Constants Washington,DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. NY,NY: Hemisphere Pub Corp (1989) (5) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (7)Takemoto S et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) (8) Price KS et al; J Water Pollut Control Fed 46: 63-77 (1974) (9) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (10) Suflita JM, Mormile MR; Environ Sci Technol 27: 976-78 (1993) (11) Franke C et al; Chemosphere 29: 1501-14 (1994) R85: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. NY,NY: Hemisphere Pub Corp (1989) (3) Atkinson R; J Phys Chem Ref Data (1989) R86: Bridie AL et al; Water Res 13 (7): 627-30 (1979) R87: (1) Takemoto S et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) (2) Price KS et al; J Water Pollut Control Fed 46: 63-77 (1974) (3) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (4) Suflita JM, Mormile MR; Environ Sci Technol 27: 976-78 (1993) R88: (1) Atkinson R; J Phys Chem Ref Data (1989) (2) Atkinson R, Aschmann SM; Int J Chem Kinetics 27: 261-75 (1995) (3) Sadlter; Standard UV Spectra No. 21; Philadelphia: Sadlter Res Lab (1961) (4) Cox RA et al; Environ Sci Tech 15: 587-92 (1981) R89: (1) Hansch C et al; Exploring QSAR Hydrophobic, Electronic and Stearic Constants Washington,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R90: (1) Hansch C et al; Exploring QSAR Hydrophobic, Electronic and Stearic Constants Washington DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R91: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. NY,NY: Hemisphere Pub Corp (1989) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility Ver 5. Univ Ariz Tucson AR (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R92: (1) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem Vol.1 - Summary; Windsor Ontario, Canada (1983) (2) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters. Appendix: Organic Analysis Data USEPA-560/6-77-015 (1977) (3) Sheldon LS, Hites RA; Environ Sci Tech 12: 1188-94 (1978) (4) Benfenati E et al; Chemosphere 25: 1665-74 (1992) (5) Hall LW JR et al; Aquat Toxicol 10: 73-99 (1987) R93: (1) Fielding M et al; Organic Pollutants in Drinking Water. Medmenham England: Water Res Center pp. 17-28 (1981) Vanbeek CGEM; Proc Info Comm Hydrol Res 38: 193-205 (1987) R94: (1) Canter LW, Sabatini DA; Int J Environ Stud 46: 35-57 (1994) (2) USEPA; Superfund Record of Decision USEPA/ROD/RO7-89/032 (1989) (3) USEPA; Superfund Record of Decision USEPA/ROD/R85-88/068 (1988) R95: (1) Sawhney BL, Kozlosku RP; J Environ Qual 13: 349-52 (1984) (2) Sawhney BL, Raabe JA; The Connecticut Agric Experiment Bull 833: 1-9 (1986) (3) Francis AJ et al; Nuclear Tech 50: 158-63 (1980) (4) USEPA; Superfund Record of Decision USEPA/ROD/RO5-86/034 (1986) (5) Brorson T et al; Environ Toxicol Chem 13: 543-52 (1994) (6) Eitzer BD; Environ Sci Technol 29: 896-902 (1995) (7) Sauer TC; Environ Sci Tech 16: 287-98 (1982) (8) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater of Organic Pollutants in Consent Survey USEPA Contract No. 68-03-2867 (1982) (9) Hampton CV et al; Environ Sci Tech 16: 287-98 (1982) R96: (1) Helmig D et al; Chemosphere 19: 1399-1412 (1989) (2) Wallace LA et al; Environ Res 35: 293-319 (1984) (3) Kelly TJ et al; USEPA Contract No 68-D800082, EPA/600/R-94/090 (1993) (4) Kelly TJ et al; Environ Sci Technol 28: 378-387 (1994) (5) Cailleux A et al; Chromatographia 37: 57-59 (1993) R97: (1) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (2) Matiella JE, Hsieh TCY; J Food Sci 56: 387-90 (1991) (3) Ramarathnam N et al; J Agric Food Chem 39: 1839-47 (1991) (4) Cha YJ, Cadwallader KR; J Food Sci 60: 19-24 (1995) R98: (1) Hampton CV et al; Environ Sci Tech 16: 287-98 (1982) (2) Brooks JM et al; pp. 171-98 in Waste Ocean Vol.1 NY,NY: Wiley (1983) (3) Stonebraker RD, Smith AJ; pp. 1-10 in Control Hazard Mater Spills Nashville,TN: Proc Natl Conf (1980) R99: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Medinilla J, Espigares M; Ann Occup Hyg 32: 509-13 (1988) (3) Myer HE et al; Am Ind Hyg Assoc J 54: 663-70 (1993) (4) Rees D et al; Scand J Work Environ Health 19: 236-44 (1993) (5) Winder C, Turner PJ; Ann Occup Hyg 36: 385-94 (1992) (6) Hampton CV et al; Environ Sci Tech 16: 287-98 (1982) (7) Brooks JM et al; pp. 171-98 in Waste Ocean Vol.1 NY,NY: Wiley (1983) R100: (1) Sauer TC; Environ Sci Technol 15: 917-23 (1981) R101: 40 CFR 180.1001(c) (7/1/96) R102: 40 CFR 180.1001(d) (7/1/96) R103: 40 CFR 180.1001(e) (7/1/96) R104: 29 CFR 1910.1000 (7/1/98) R105: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R106: 40 CFR 60.489 (7/1/96) R107: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R108: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R109: 40 CFR 302.4 (7/1/96) R110: 40 CFR 716.120 (7/1/96) R111: 40 CFR 712.30 (7/1/96) R112: 40 CFR 799.5000 (7/1/96) R113: 40 CFR 261.33 (7/1/96) R114: 40 CFR 261.31 (7/1/96) R115: 21 CFR 172.515 (4/1/96) R116: 21 CFR 175.105 (4/1/96) R117: 21 CFR 177.1650 (4/1/96) R118: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R119: Levin JO, Carleborg L; Ann Occup Hyg 31 (1): 31-8 (1987) R120: GAZZANIGA G ET AL; MED LAV 69 (3): 232-48 (1978) R121: Smith AF, Wood R; Analyst 97 (1154): 363-7 (1972) R122: Dreisch FA, Munson TO; J Chromatogr Sci 21 (3): 111-8 (1983) R123: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R124: Bellanca JA et al; J Anal Toxicol 6 (5): 238-40 (1982) R125: GHIMENTI G ET AL; ANN 1ST SUPER SANITA 14 (3): 583-87 (1978) R126: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 R127: Heare SF et al; 1986 Hazard Matl Spill Conf p.12-18 (1986) RS: 87 Record 29 of 1119 in HSDB (through 2003/06) AN: 149 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-DICHLOROETHYLENE- SY: *ACETYLENE-DICHLORIDE-; *1,2-DCE-; *1,2-DICHLOR-AETHEN- (GERMAN); *Dichloroacetylene-; *1,2-DICHLOROETHENE-; *SYM-DICHLOROETHYLENE-; *DICHLORO-1,2-ETHYLENE- (FRENCH); *DIOFORM-; *ETHENE,-1,2-DICHLORO-; *ETHYLENE,-1,2-DICHLORO-; *NCI-C56031- RN: 540-59-0 RELT: 5656 [CIS-1,2-DICHLOROETHYLENE] (Mixture Component); 6361 [TRANS-1,2-DICHLOROETHYLENE] (Mixture Component); 6878 [DICHLOROETHYLENE] (Mixture) MF: *C2-H2-Cl2 SHPN: UN 1150; Dichloroethylene IMO 3.2; Dichloroethylene STCC: 49 091 45; Dichloroethylene HAZN: U079; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF 1,1,2,2-TETRACHLOROETHANE WITH STEAM OVER AN IRON CATALYST [R1] *By partial chlorination of acetylene [R2] *1,1,2-trichloroethane is dehydrochlorinated at 500 deg C to produce cis- and trans-dichloroethylene [R3] *Bordner, US patent 2,504,919 (1950 to Du Pont). Prepn of trans-form: Adler, US patent 2,440,997 (1948 to Stockholms Superfosfot Fabriks Aktiebolag). Separation of cis- and trans- forms by fractional distillation: ... Truce, Barney, J Org Chem 27, 128 (1962). [R4] *Manufactured by the direct chlorination of acetylene at 40 deg C [R5, 37] *Other routes use liquid-phase acetylene oxychlorination or synthesis from 1,1,2,2-tetrachloroethylene... [R6, 298] FORM: *Grades: technical; as cis, trans, and mixture of both. [R2] *Grades or Purity: Commercial [R7] *97% pure [R8] */TECHNICAL/ 1,2-DICHLOROETHYLENE /CONSISTS OF/ 60%, 40% CIS-, TRANS-ISOMERS. [R9] MFS: *Schumacher, 1969 Palomar Oaks Way, Carlsbad, CA 92009-1307, (800) 545-9242; Production site: Carlsbad, CA 92009 /trans-1,2-Dichloroethylene/ [R10] OMIN: *Trans isomer is more widely used in industry than either the cis isomer or the commercial mixture [R11, p. II-62] *Occur as a byproduct in the production of vinyl chloride and trichloroethylene [R6, 298] USE: *Used as a solvent for waxes, resins, and acetylcellulose. It is also used in the extraction of rubber, as a refrigerant, in the manufacture of pharmaceuticals and artificial pearls and in the extraction of oils and fats from fish and meat. /1,2-Dichloroethylene/ [R12] *Solvent for fats, phenol, camphor [R4] *SOLVENT FOR NATURAL RUBBER; COOLANT IN REFRIGERATION PLANTS; LOW TEMP SOLVENT; SPECIAL-PURPOSE SOLVENT [R1] *Cis and trans isomers of 1,2-dichloroethylene have had use as solvents and chem intermediate. Neither of isomers has developed wide industrial usage in the USA partly because of their flammability. [R13] *General solvent for dye extraction; perfumes; lacquers; thermoplastics; organic synth [R2] *... IS USED AS LOW TEMP EXTRACTING AGENT FOR HEAT SENSITIVE SUBSTANCES SUCH AS PERFUME OILS AND CAFFEINE IN COFFEE. [R14] *Used as feed stock for the synthesis of tri- and perchloroethylene. [R6, 299] *1,2-DCE is used as a direct solvent for perfumes, dyes, gums and waxes, oils, lacquers, thermoplastics, phenols, and camphor; as a chemical intermediate for chlorinated compds; and as an agent in retarding fermentation. 1,2-DCE is used as a low-temperature solvent for heat-sensitive substances in the extraction of caffeine, fats, and natural rubber. It is also used in organic synthesis for polymers and telomers, in addn to miscellaneous application as a dry cleaning solvent, cleaning soln for printed circuit boards, food packaging adhesives, and germicidal fumigants. [R15, 1991.429] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Mobile liquid [R5, 36]; *Colorless liquid (usually a mixture of the cis and trans isomers) ... [R16, 98] ODOR: *Ethereal, slightly acrid [R4]; *Pleasant [R2]; *Sweet, slightly irritating chloroform-like odor [R5, 36]; *... Slightly acrid, chloroform-like odor. [R16, 98] BP: *Approx 55 deg C [R4] MP: *-50 deg C [R17] MW: *96.95 [R4] CORR: *1,2-Dichloroethylene will attack some forms of plastics, rubber, and coatings. [R18, 1981.2] DEN: *Approx 1.28 [R4] HTC: *-4847.2 Btu/lb= -2692.9 cal/g= -112.67X10+5 J/kg [R7] HTV: *130 Btu/lb= 72 cal/g= 3.0X10+5 J/kg [R7] OWPC: *log Kow = 2.00 /avg cis and trans-isomers/ [R19] SOL: *Soluble in alcohol, ether, and most other organic solvents [R4]; *In water, 3.50X10+3 mg/l @ 25 deg C. [R20] SPEC: *IR: 3645 (Sadtler Research Laboratories Prism Collection) [R21]; *MASS: 203 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R21] SURF: *24 dynes/cm= 0.024 N/m @ 20 deg C [R7] VAPD: *3.4 (Air = 1) /cis- and trans-isomers/ [R22] VAP: *2.01X10+2 mm Hg @ 25 deg C [R23] OCPP: *Evaporation from water at 25 deg C of 1 ppm solution: 50% after 24 min, 90% after 83 min. [R24] *Henry's Law constant = 4.08X10-3 atm cu m/mol @ 25 deg C [R25] *Hydroxyl radical reaction rate constant = 2.09x10-12 cu cm/molecule-sec @ 25 deg C [R26] *Colorless /1,2-Dichloroethylene/ [R27] *Sweet pleasant odor /1,2-Dichloroethylene/ [R7] *Heat of combustion: -4,847.2 Btu/lb= -2,692.9 cal/g /1,2-Dichloroethylene/ [R7] *Latent heat of vaporization: 130 Btu/lb= 72 cal/g /1,2-Dichloroethylene/ [R7] *Liquid-Water Interfacial Tension: (est) 30 dynes/cm= 0.030 N/m @ 20 deg C; Vapor (Gas) Specific Gravity: 3.34 [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R28] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R28] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R28] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. [R28] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R28] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R28] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R28] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R28] FPOT: *FLAMMABLE LIQUID [R29, p. 49-51] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R29, p. 325-34] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R29, p. 325-34] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R29, p. 325-34] FLMT: *Lower flammable limit: 5.6% by volume; Upper flammable limit: 12.8% by volume [R29, p. 325-34] FLPT: *36 DEG F (2 DEG C) [R29, p. 325-34] AUTO: *860 deg F (460 deg C) [R29, p. 325-34] FIRP: *Use dry chemical, foam, carbon dioxide, or water spray. Use flooding quantities of water to blanket the fire. Water may be ineffective. Use water spray to keep fire-exposed containers cool. Fight fire from protected location or maximum possible distance. [R29, p. 49-51] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Keep run-off water out of sewers and water sources. [R30] TOXC: *Combustion by-products may include hydrogen chloride and phosgene. [R29, p. 49-51] OFHZ: *Vapors are heavier than air and may travel to a source of ignition and flash back. [R29, p. 49-51] EXPL: *Lower 9.7%; upper 12.8% [R31] *Containers may explode in fire. [R7] REAC: *The reaction /of 1,2-dichloroethylene and potassium hydroxide/ produces chloroacetylene, which is explosive and spontaneously flammable in air. It is highly toxic. The addn of sodium, caustic, or caustic soln to 1,2-dichloroethylene ... may form monochloroacetylene ... which ... is spontaneously flammable in air. [R29, p. 491-160] *May release explosive chloroacetylene by the contact with copper or copper alloys. [R32] *Addition of a hot liquid to the cold solvent caused sudden emission of sufficient vapor to cause a flame to flash back 12 m from a fire. Although the bulk of the solvent did not ignite, various items of paper and wood in the room were ignited by the transient flame. [R33] *Incompatible with alkalies, difluoromethylene dihypofluorite, and nitrogen tetraoxide. [R34] *Strong oxidizers, strong alkalis, potassium hydroxide, copper [Note: Usually contains inhibitors to prevent polymerization]. [R16, 98] DCMP: *Gradually decomposed by light, air, and moisture to form hydrogen chloride. [R15, 1991.429] *When heated to decomposition it emits highly toxic fumes of /hydrogen chloride/. [R35] POLY: *Polymerization will not occur under ordinary conditions of shipment. [R7] *Hazardous polymerization may occur. Polymerization may be caused by elevated temperature, oxidizing materials, peroxides, or sunlight. [R29, p. 49-51] SERI: *Contact with liquid causes irritation of eyes and (on prolonged contact) skin. [R7] *Irritating to skin, eyes, and respiratory system. [R29, p. 49-51] EQUP: *Rubber gloves; safety goggles; air supply mask or self-contained breathing apparatus. [R7] *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any reasonable probability of eye contact. [R12] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with 1,2-dichloroethylene. Employees should be provided with and required to use splash proof goggles where there is any possibility of liquid 1,2-dichloroethylene contacting the eyes. [R18, 1981.2] *Wear appropriate personal protective clothing to prevent skin contact. [R16, 99] *Wear appropriate eye protection to prevent eye contact. [R16, 99] *Recommendations for respirator selection. Max concn for use: 1000 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection needed. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R16, 99] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R16, 99] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R16, 99] OPRM: *If this chemical gets into the eyes, irrigate immediately. If this chemical contacts the skin, wash with soap promptly. If a person breathes in large amounts of this chemical, move the exposed person to fresh air at once and perform artificial respiration. ... Employees should wash promptly when skin is wet or contaminated. Remove clothing promptly if wet or contaminated to avoid flammability hazard. [R12] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. [R18, 1981.2] *In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R18, 1981.2] *Clothing contaminated with liquid 1,2-dichloroethylene should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of 1,2-dichloroethylene from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the 1,2-dichloroethylene, the person performing the operation should be informed of 1,2-dichloroethylene's hazardous properties. Non-impervious clothing which becomes contaminated with liquid 1,2-dichloroethylene should be removed immediately and not reworn until the 1,2-dichloroethylene is removed from the clothing. [R18, 1981.2] *Skin that becomes contaminated with liquid 1,2-dichloroethylene should be immediately washed or showered with soap or mild detergent and water to remove any 1,2-dichloroethylene. [R18, 1981.2] *Contact lenses should not be worn when working with this chemical. [R16, 99] *It material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. [R30] *Personnel protection: Keep upwind. Avoid breathing vapors. ... Do not handle broken packages unless wearing appropriate personal protective equipment. [R30] *Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. [R36] *The worker should immediately wash the skin when it becomes contaminated. [R16, 99] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16, 99] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *GRADUALLY DECOMPOSED BY AIR, LIGHT, AND MOISTURE, FORMING HCL [R37] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R38] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R39] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R40] STRG: *Store in a cool, dry, well-ventilated location. Separate from air, light, heat, strong oxidizing materials. [R29, p. 49-51] CLUP: *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be reclaimed or collected and atomized in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. [R18, 1981.2] *Absorb on paper. Evaporate on a glass or iron dish in hood. Burn the paper. [R32] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U079, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R41] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. Also, a potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. Also a potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. /Trans-1,2-Dichloroethylene/ [R42] *This compound should be susceptible to removal from wastewater by air stripping. [R43] *Removal of chlorinated hydrocarbons from wastewater is discussed. /Chlorinated hydrocarbons/ [R44] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. Recommendable method: Incineration. Not recommendable method: Discharge to sewer. [R45] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations as needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Minimize physical activity and provide a quiet atmosphere. Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. Rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Treat frostbite with rapid rewarming techniques ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R46] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R46] *Stabilization: Treatment is largely supportive. Watch for respiratory depression and arrhythmias. Obtain arterial blood gases. Administer oxygen if there is evidence of altered mental status or dyspnea. Treat hypotension with volume expansion and vasopression. Use lidocaine or beta-blockers for ventricular arrhythmias. Skin: Remove contaminated clothing. Wash affected area with soap and copious amounts or water. Eye: Irrigate the eye for 15-20 min. Obtain a consultation if symptoms persist. Oral: Most of the halogenated solvents ingested in quantities of 1-2 swallows may be partially removed by ipecac-induces emesis if admin within a few hr to a patient who has not lost the gag reflex, is not seizing, is not markedly lethargic, or is not in coma. Observe the patient in the upright position to lessen the possibility of aspiration. Activated charcoal is probably ineffective. Inhalation: Move from the contaminated area. Provide a source of oxygen and prepare for mechanical ventilation. If the patient is unconscious and the pulse is absent, initiate CPR measures. Enhancement of Elimination: Maintain good ventilation. Hemodialysis or hemoperfusion are not likely to be useful because of the high lipophilic properties of these solvents. Antidote: N-acetylcysteine may restore depleted glutathione stores, but no adequate clinical studies are available to validate this possible treatment. Supportive Care: Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encephalopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, EKG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. /Halogenated hydrocarbons/ [R47] MEDS: *The following medical procedures should be made available to each employee who is exposed to 1,2-dichloroethylene at potentially hazardous levels; Initial Medical Screening: Employees should be screened for history of certain medical conditions which might place the employee at an increased risk from 1,2-dichloroethylene. /Such conditions include/: liver and chronic respiratory disease. ... Periodic Medical Examination: Any employee developing the above-listed conditions should be referred for further medical conditions. [R18, 1981.1] HTOX: *VAPOR EXPOSURE MAY PRODUCE CENTRAL NERVOUS DEPRESSION OR, IN MILDER EXPOSURES NAUSEA, VOMITING, WEAKNESS, TREMOR, AND EPIGASTRIC CRAMPS. ... REVERSIBLE CORNEAL CLOUDING IS DESCRIBED. [R11, p. II-162] *Based on a few cases of human poisoning and animal data, this solvent is considered to have toxic potential equivalent to that of trichloroethylene. Exposure limit: TLV= 790 mg/cu m. [R48] *IT IS ... A LESS POTENT /SRP: CNS DEPRESSANT/ ... THAN CHLOROFORM. ... THE ACUTE TOXICITY OF THE CIS ISOMER APPEARS TO BE SOMEWHAT GREATER THAN THAT OF THE TRANS FORM. [R15, 1991.429] *ASIDE FROM /SRP: CNS DEPRESSANT/ ... PROPERTIES OF THIS SOLVENT, TOXIC EFFECTS HAVE NOT BEEN PROMINENT IN RATHER SMALL-SCALE INDUSTRIAL USAGE. [R14] *All of the halogenated solvents are central nervous system depressants that produce dose-related changes in mental function and consciousness depending on the individual chemical and the duration of exposure. /Halogenated solvents/ [R49, 736] *Halogenated solvents tested during the 1800s for use as an anesthetic and discarded included ... 1,2-dichloroethane (/caused/ excessive salivation, convulsive movements, postoperative blue-gray corneal opacities)... . [R49, 732] NTOX: *THE NO EFFECT LEVEL IN ANIMALS UPON PROLONGED INHALATION EXPOSURE IS @ LEAST 1000 PPM, AND THE SUPPORTING INFORMATION BY OTHER ROUTES OF ADMINISTRATION, THE TIME WEIGHTED AVERAGE TLV OF 200 PPM MAY BE TOO CONSERVATIVE FOR 1,2-DICHLOROETHYLENE. THE MOST IMPORTANT EFFECTS OF DICHLOROETHYLENE ARE /SRP: CNS DEPRESSION/ AND IRRITATION OF THE CNS; LIVER AND KIDNEY INJURY DO NOT APPEAR TO BE IMPORTANT RESPONSES ALTHOUGH SOME GERMAN INVESTIGATORS REPORTED FATTY DEGENERATION OF LIVER UPON REPEATED /CNS DEPRESSANT/ DOSES. [R50] *A group of Fischer 344 rats received 2.0 millimoles of diethylnitrosamine by gavage. Another group received 2-acetyl-aminofluorene for 2 weeks with 2 ml/kg carbon tetrachloride by gavage in addition to diethylnitrosamine. At 14 days after termination of the treatment, hepatocytes were isolated and cultured in the presence of chloroform, 1,2-dibromoethane, 1,1-dichloroethane, 1,2-dichloroethene, 1,1,1- trichloroethane and 1,1,2-trichloroethane. Cells were evaluated for survival and for expression of gamma-glutamyl-transpeptidase. Pretreatment with diethylnitrosamine and 2-acetyl-aminofluorene produced many gamma-glutamyl-transpeptidase containing hepatocytes. 1,2-Dibromoethane was the most toxic, followed in order by 1,2-dichloroethylene; 1,1,2-trichloroethylene; 1,1,1-trichloroethylene; chloroform, and 1,1-dichloroethylene. [R51] *... RATS, RABBITS, GUINEA PIGS, AND DOGS EXPOSED 7 HR DAILY, 5 DAYS EACH WK FOR 6 MO SHOWED NO CHANGES ATTRIBUTABLE TO 1,2-DICHLOROETHYLENE @ EITHER 500 OR 1000 PPM. PARAMETERS STUDIED WERE GROWTH, MORTALITY, ORGAN AND BODY WT, HEMATOLOGY, CLINICAL CHEMISTRY, AND GROSS AND MICROSCOPIC PATHOLOGY. ... NO EFFECTS WERE SEEN IN RATS DOSED EITHER SC, PERCUTANEOUSLY, OR BY ACUTE OR CHRONIC INGESTION. [R15, 1991.430] *ONE DOG NARCOTIZED WITH ... VAPOR WHILE EYES WERE PROTECTED FROM DIRECT CONTACT WAS FOUND TO HAVE NO GROSS CORNEAL TURBIDITY, BUT SLIGHT DISTURBANCE OF CORNEAL ENDOTHELIUM AND SLIGHT STROMAL EDEMA WERE FOUND MICROSCOPICALLY. [R52] *THE MUTAGENICITY OF SEVERAL CHLORINATED ETHYLENES WAS TESTED ON ESCHERICHIA COLI STRAIN K-12 IN CULTURE MEDIUM CONTAINING MOUSE LIVER MICROSOMES METABOLIC ACTIVATION SYSTEM. 1,2-TRANS-DICHLOROETHYLENE WAS NOT MUTAGENIC. /1,2-TRANS-DICHLOROETHYLENE/ [R53] *Mice were exposed during 4 hr to various concentrations of 13 aliphatic or aromatic solvents, incl 1,2-dichloroethylene. After exposure, measurements were made to see whether these neurotoxicants would decrease the immobility developed in a behavioral despair swimming test. Each chemical reduced the total duration of immobility measured over 3 min in a concentration-related manner. The systematic determination of the atmospheric concentrations responsible for a 50% decrease in immobility (ID50) permitted classification of the solvents in terms of their potencies. [R54] *1,2-Dichloroethane produced a significant reduction in antibody forming cells, while 1,2-dichloroethylene and 1,1,2-trichloroethylene produced trends towards suppression. Mice exposed to 1,2-dichloroethane for 90 days showed no alteration in the antibody forming cells, serum antibody titers, or response to B-lymphocyte mitogen, lipopolysaccharide. There was a marked dose dependent reduction in delayed hypersensitivity response to sheep erythrocytes in the presence of a hyper-responsiveness to the T-lymphocyte mitogen concanavalin A. 1,2-Dichloroethane did not alter the functional activity of the reticuloendothelial system. [R55] *Some but not all dogs /CNS depressed/ by inhaling the vapor have been observed to develop delicate superficial corneal turbidity. The first observation of corneal disturbance was made on three dogs repeatedly exposed to dichloroethylene by evaporation of 10-15 cc in a chamber of 0.115 cu m volume. Haziness was observed in both corneas of one dog after the second exposure and slight haziness of one eye of another dog after fourteen exposures, but no ocular disturbance was found in the third dog. A more detailed study subsequently showed that the corneal haziness occuring in dogs was attributable to many fine gray flecks in the endothelium, and that this usually cleared in twenty-four hours, or forty-eight hours at the most. [R52] *... Volatile organic contaminants of water were evaluated for acute oral toxicity, 14-day repeated-dosing toxicity, taste aversion, 90-day subchronic toxicity, and multigeneration effects in mice. The cmpd studied were primarily halomethanes and chlorophenols, including 1,2-dichloroethylene. Acute toxicity was low, and there were no teratological or dominant lethal effects. All cmpd caused apparent central nervous system depression and behavior changes. The liver and possibly the immune system were sensitive target organs, and male mice were more sensitive than females. [R56] *Cis,trans-1,2-dichloroethylene was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Cis-, trans-1,2-dichloroethylene was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.0333, 0.100, 0.3333, 1.000, and 3.3333 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strains was 3.3333 mg/plate. Slight clearing of the background bacterial lawn occurred at this dose. /Cis,trans-1,2-dichloroethylene/ [R57] *Cis- and trans-1,2-dichloroethylene were tested for mutagenic effects in a diploid strain (D7) of yeast Saccharomyces cerevisiae in suspension tests with and without a mammalian microsomal activation system, a S9 mouse liver fraction, and by an in vivo intrasanguineous host-mediated assay. The effects of the same agents on aminopyrine N-demethylase activity and cytochrome p450 level in liver were studied in nonpretreated and in phenolbarbital + beta-naphthoflavone-pretreated mice. In the suspension test, both isomers exhibited dose dependent toxicity, and survival was lower with metabolic activation than without. In the host mediated assay, only the cis-isomer showed evidence of mutagenic activity with significant increases in convertants at the trp locus and reverants at the ilv locus. Such mutagenic activity was found after acute and chronic doses and in the liver, kidney, and lung tissue. ... The cis-isomer tended to inhibit activity or destroy the enzyme. [R58] NTXV: *LD50 Rat oral 770 mg/kg; [R35] *LD50 Mouse ip 2 g/kg; [R35] POPL: *Individuals with conditions of the liver and chronic respiratory disease may be at an increased risk from exposure to 1,2-dichloroethylene. [R18, 1981.1] ADE: *1,2-DCE IS LARGELY EXCRETED THROUGH THE LUNGS. [R15, 1991.429] *Once absorbed, halogenated solvents distribute rapidly to tissue based on their lipid content and individual tissue/blood partition coefficients. Generally the highest concentrations appear in the fat, brain, and blood. Peak blood levels occur soon after exposure ceases following inhalation, whereas peak levels following oral administration occur 1-2 hours after administration. Animal and human studies indicate that accumulation of these chemicals in fat generally is not substantial following chronic exposure unless concentrations are high. /Halogenated solvents/ [R49, 738] METB: *Using an isolated, perfused rat liver prepn, /investigators/ ... found that both isomers /cis and trans/ were metabolized to the same metabolites dichloroacetic acid and dichloroethanol. In this system, the cis isomer was metabolized to a greater extent than was the trans isomer. These metabolites are apparently formed via an epoxide intermediate. In studies of rats exposed to 1,2-dichloroethylene vapor, trans-1,2-dichloroethylene was found to be metabolized more slowly than was the cis isomer. Studies with rat liver microsomes demonstrated a type 1 difference spectra with these substances, implicating the involvement of cytochrome p450. [R59] *Incubation of rat liver microsomes with 1,2-dichloroethylene caused a fall in microsomal cytochrome p450 content (as determined by measuring the oxidation of reduced nicotinamide adenine dinucleotide at 340 nm), without affecting other microsomal enzymes. The decrease in cytochrome p450 occurred only in the presence of reduced nicotinamide adenine dinucleotide, suggesting that the dichloroethylene must be metabolized to exert its destructive action. The loss of cytochrome p450 was probably due to destruction of heme, since the fall in cytochrome p450 was always accompanied by a parallel decrease in microsomal heme content. [R60] ACTN: *Numerous xenobiotics are known to be bioactivated and to covalently bind to proteins, but the resulting amino acid adducts are unknown. In this study, the amino acid adducts of 12 (14)C-labeled aliphatic halides were examined after formation in an in vitro rat hepatic microsomal system. After exhaustive solvent extraction of the polypeptide microsomal protein, the amino acid adducts were isolated by Pronase digestion, followed by filtration through a 500 mol-wt exclusion membrane. 1,2-Dichloroethylene had a single major amino acid adducts. The single amino acid adducts formed following incubation of iodoform with microsomes was identified as S-methylcysteine. Thus, this method appears capable of resolving binding sites and is the initial isolation step for identifying specific adducts to proteins. [R61] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Dichloroethylene's production and use as a solvent may result in its release to the environment through various waste streams. Under anaerobic conditions that may exist in landfills or sediment, 1,2-dichloroethylene may be formed as a breakdown product from the reductive dehalogenation of trichloroethylene facilitated by microorganisms. If released to air, a vapor pressure of 201 mm Hg at 25 deg C indicates 1,2-dichloroethylene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichloroethylene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 31 hrs. If released to soil, 1,2-dichloroethylene is expected to have moderate mobility based upon an estimated Koc of 290. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 7.3X10-3 atm-cu m/mole. 1,2-Dichloroethylene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 1,2-dichloroethylene is expected to adsorb to suspended solids and sediment based upon the estimated Koc. 1,2-Dichloroethylene biodegrades in environment under anaerobic conditions. Field degradation half-lives range from 0.14 to 9.9 yrs for cis-1,2-dichloroethylene. 1,2-Dichloroethylene is not expected to biodegrade under aerobic conditions. cis- and trans-1,2-Dichloroethylene, present at 2.6 and 2.3 mg/l, respectively, reached 0% of their theoretical BOD in 4 weeks using an activated sludge inoculum and the Japanese MITI test. No biodegradation of trans-1,2-Dichloroethylene occurred in a river die-away test. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.1 and 94 hrs, respectively. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected since chlorinated ethylenes hydrolyze very slowly at environmental conditions. Occupational exposure to 1,2-dichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloroethylene is produced or used. Monitoring data indicate that the general population may be exposed to 1,2-dichloroethylene via drinking water with this compound. (SRC) ARTS: *1,2-Dichloroethylene's production and use as a solvent(1) may result in its release to the environment through various waste streams(SRC). Under anaerobic conditions, that may exist in landfills or sediment, 1,2-dichloroethylene may be formed by reductive dehalogenation of trichloroethylene facilitated by microorganisms(2). [R62] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 290(SRC), determined from a log Kow of 2.0(2) and a regression-derived equation(3), indicates that 1,2-dichloroethylene is expected to have moderate mobility in soil(SRC). Volatilization of 1,2-dichloroethylene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.3X10-3 atm-cu m/mole(SRC), derived from a vapor pressure of 201 mm Hg(4), and water solubility of 3.5X10+3 mg/l(5). The potential for volatilization of 1,2-dichloroethylene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 201 mm Hg(4). 1,2-Dichloroethylene biodegrades in soil under anaerobic conditions(SRC). The field scale estimate of the apparent loss coefficient for cis-1,2-dichloroethylene under anaerobic (reducing) conditions ranges from 0.07 to 5.11 yr-1(6), which corresponds to half-lives ranging from 0.14 to 9.9 yrs(SRC). 1,2-dichloroethylene is not expected to biodegrade under aerobic conditions(SRC). cis- and trans-1,2-Dichloroethylene, present at 2.6 and 2.3 mg/l, respectively, reached 0% of their theoretical BOD in 4 weeks using an activated sludge inoculum and the Japanese MITI test(7). trans-1,2-Dichloroethylene was recalcitrant in shake flask tests modified to accommodate volatile chemicals(8,9); the concns examined in these studies ranged from 0.80 to 25 ppm, and a 21 day acclimation period and the addition of a lactose cometabolite did not alter the biodegradability. Similarly, no biodegradation occurred in a river die-away test(9). [R63] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 290(SRC), determined from a log Kow of 2.0(2) and a regression-derived equation(3), indicates that 1,2-dichloroethylene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 7.3X10-3 atm-cu m/mole(SRC), derived from a vapor pressure of 201 mm Hg(4), and water solubility of 3.5X10+3 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.1 and 94 hours, respectively(SRC). According to a classification scheme(6), an estimated BCF of 7(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). 1,2-Dichloroethylene biodegrades in water under anaerobic conditions(SRC). The field scale estimate of the apparent loss coefficient for cis-1,2-dichloroethylene under anaerobic (reducing) conditions ranges from 0.07 to 5.11 yr-1(8), which corresponds to half-lives ranging from 0.14 to 9.9 yrs(SRC). 1,2-dichloroethylene is not expected to biodegrade under aerobic conditions(SRC). cis- and trans-1,2-Dichloroethylene, present at 2.6 and 2.3 mg/l, respectively, reached 0% of their theoretical BOD in 4 weeks using an activated sludge inoculum and the Japanese MITI test(9). trans-1,2-Dichloroethylene was recalcitrant in shake flask tests modified to accommodate volatile chemicals(10,11); the concns examined in these studies ranged from 0.80 to 25 ppm, and a 21 day acclimation period and the addition of a lactose cometabolite did not alter the biodegradability. Similarly, no biodegradation occurred in a river die-away test(11). [R64] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-dichloroethylene, which has a vapor pressure of 201 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase 1,2-dichloroethylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 31 hours(SRC) calculated from a isomer avg rate constant of 2.1X10-12 cu cm/molecule-sec at 25 deg C(3). [R65] BIOD: *AEROBIC: cis- and trans-1,2-Dichloroethylene, present at 2.6 and 2.3 mg/l, respectively, reached 0% of their theoretical BOD in 4 weeks using an activated sludge inoculum and the Japanese MITI test(1). trans-1,2-Dichloroethylene was recalcitrant in shake flask tests modified to accommodate volatile chemicals(2,3); the concns examined in these studies ranged from 0.80 to 25 ppm, and a 21 day acclimation period and the addition of a lactose cometabolite did not alter the biodegradability. Similarly, no biodegradation occurred in a river die-away test(3). Other studies under aerobic conditions showed similar results of limited degradation under aerobic conditions for 1,2-dichloroethylene(4). However, mineralization of C14-labeled 1,2-dichloroethylene (mixture of 20% trans and 71% cis isomers) was observed under aerobic conditions in streambed sediments characterized by a high content of natural organic matter (2.5% dry mass organic content) and saturated with humic acid-laden black water(5); 67% of C14-labeled CO2 was recovered in 50 days under aerobic conditions(5) which corresponds to a first-order half-life of 31 days(SRC). [R66] *ANAEROBIC: When trans-1,2-dichloroethylene was incubated under anaerobic conditions with methanogenic aquifer material obtained adjacent to a landfill site in a serum bottle at 17 deg C, at least 16 wk of incubation were required before disappearance began relative to autoclaved controls whereas the concn of the cis isomer was reduced to < 2% of controls during the same period(1). Vinyl chloride was identified as a degradation product after 1-2 weeks(1). After 40 wk, the average concn of the trans isomer was reduced to 18% of controls, only traces of the cis isomer remained, and no vinyl chloride or other degradation product were found(1). Another investigator found that when cis- or trans-1,2-dichloroethylene were incubated anaerobically using an inoculum from a municipal waste digester in order to simulate conditions in a landfill, vinyl chloride appeared within 6 weeks(2). Biodegradation of 1,2-dichloroethylene was studied in microcosms prepared from uncontaminated organic sediment from the Everglades and allowed to sit to insure oxygen depletion(3). Under these anoxic conditions, 50% and 73% of the cis and trans isomer were lost in 6 months with accompanying formation of vinyl chloride(3). Ethyl chloride was formed in the case of the cis but not the trans isomer, indicating that there is at least one pathway other than the reductive dechlorination for the cis isomer(3). Mineralization of C14-labeled 1,2-dichloroethylene (mixture of 20% trans and 71% cis isomers) was observed under anaerobic conditions in streambed sediments characterized by a high content of natural organic matter (2.5% dry mass organic content) and saturated with humic acid-laden black water(4). 7% of C14-labeled CO2 was recovered in 50 days for unamended sediments(4) which corresponds to a first-order half-life of 478 days(SRC); 25% of C14-labeled CO2 was recovered in 50 days for sediments amended with 2 mg humic acid/l(4) which corresponds to a first-order half-life of 121 days(SRC); humic acids are believed to serve as electron acceptors in the anaerobic oxidation 1,2-dichloroethylene(4). [R67] ABIO: *The rate constant for the vapor-phase reaction of 1,2-dichloroethylene (isomer avg) with photochemically-produced hydroxyl radicals is 2.1X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 31 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2). The rate constant for the vapor-phase reaction of 1,2-dichloroethylene (isomer avg) with ozone has been estimated as 2.7X10-20 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(2). This corresponds to an atmospheric half-life of about 430 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3) suggesting that this reaction is too slow to be environmentally significant(SRC). Hydrolysis is not expected since chlorinated ethylenes hydrolyze very slowly at environmental conditions(4). 1,2-Dichloroethylene is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm)(5,6). [R68] BIOC: *An estimated BCF of 7 was calculated for 1,2-dichloroethylene(SRC), using a log Kow of 2.0(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R69] KOC: *The Koc of 1,2-dichloroethylene is estimated as 290(SRC), using an isomer avg log Kow of 2.0(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1,2-dichloroethylene is expected to have moderate mobility in soil(SRC). [R70] VWS: *Evaporation from water at 25 deg C of 1 ppm solution: 50% after 18 min (cis); 90% after 83 min (trans) [R71] *The Henry's Law constant for 1,2-dichloroethylene is estimated as 7.3X10-3 atm-cu m/mole(SRC), derived from a vapor pressure of 201 mm Hg(1), and water solubility of 3.5X10+3 mg/l(2). This estimated Henry's Law constant indicates that 1,2-dichloroethylene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 1.1 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 94 hours(SRC). 1,2-Dichloroethylene's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,2-dichloroethylene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 201 mm Hg(1). [R72] WATC: *DRINKING WATER: In a 1982 USA groundwater supply survey, 16 supplies from a random sample of 466 were positive for 1,2-dichloroethylene (isomers not specified) at a quantitation limit of 0.2 ppb(1). The median and max concn were 1.1 and 2 ppb, respectively(1). 1,2-Dichloroethylene (isomers not specified) was detected in samples collected from 16 of 466 randomly selected sites using groundwater as a raw water source (detection limit 0.2 ug/l); the max concn was 2.0 ppb(2). From July 1982 to 1983, 1,2-dichloroethylene (isomers not specified) was positively identified in 3 raw and 3 treated water samples (detection limit not reported) from 10 potable water treatment plants in Canada at a trace concn(3). A survey of 30 Canadian potable water treatment facilities showed that between 1 and 6 of the supplies contained 1,2-dichloroethylene (isomers not specified) in their finished drinking water(4). The highest level measured was 32 ppb(4). Of the 14 UK water supplies surveyed, two contained detectable quantities of 1,2-dichloroethylene (isomers not specified)(5). Two contaminated drinking water wells in Massachusetts and one in New York contained 323, 294 and 91 ppb of 1,2-dichloroethylene (isomers not specified), respectively(6). Nationally, the highest reported concn in drinking water derived from surface sources was 9.8 ppb(6). A Vero Beach, FL production well located 268 m from a leaking underground storage tank containing trichloroethylene contained 12 ppm of 1,2-dichloroethylene (isomers not specified)(7). [R73] *GROUNDWATER: Groundwater 1 mile from the site of an abandoned industrial landfill contained 138 ppb of 1,2-dichloroethylene (isomers not specified)(1). At a Connecticut solvent recovery site, the concentration of 1,2-dichloroethylene (isomers not specified) was 30 and 2.7 ppm on-site and not detected and 4.3 ppm 80 m down gradient at the water table and from a deep well, respectively(2). Similar results were obtained at a solvent recovery site in Wisconsin(2). Here the analogous concn were 30 and 8.7 ppm on-site and ND and 47 ppm 80 m down gradient(2). An explanation offered for these results is that 1,2-dichloroethylene (isomers not specified) is a degradation product and that degradation is faster closer to the surface where cometabolites are more abundant(2). The Biscayne aquifer, that supplies drinking water to residents of Dade County, in the vicinity of the Miami Drum site contained 0-26 ppb of 1,2-dichloroethylene(3). 1,2-Dichloroethylene (isomers not specified) was detected in 3 of 63 samples collected from private well Nebraska during the summer of 1982 (detection limit = 0.2 ug/l) at max and median concns of 0.50 and 2.1 ug/l, respectively(4). During 1983-1984, 1,2-dichloroethylene (isomers not specified) was detected in 7 of 9 monitoring wells at a concn of 2.9 ug/l in Nebraska(4). In the Biscayne aquifer in the vicinity of a Miami drum site, 1,2-dichloroethylene (isomers not specified) was detected in 2 of 3 samples (detection limit not reported) at a mean concn of 19 ug/l(5). The mean concn of 1,2-dichloroethylene (isomers not specified) at site of a leaking subsurface trichloroethylene storage tank in Vero Beach, FL ranged from 1,000 to 4,000 ppb (sampling period Apr 1981 to Dec 1983)(6). [R74] *SURFACE WATER: 6% of the 1144 stations in the USEPA STORET data base has detectable quantities of 1,2-dichloroethylene (isomers not specified) in the water(1). The median concn was < 5 ppb(1). 1,2-Dichloroethylene (isomers not specified) was absent from samples taken from the Niagara River and open waters of Lake Ontario(2). The concn of 1,2-dichloroethylene (isomers not specified) in the Hylebos Waterway in the Puget Sound, WA ranged from 0.8 to 2.4 ppb in 1979(3). 1,2-Dichloroethylene (isomers not specified) was detected in 23 of 39 samples (detection limit 4.0 ug/l) from a drainage discharging into the Indian River in Vero Beach, FL; the mean and range of concns were 15.7 ppb and 4.0-48.1 ppb, respectively, from samples collected between May 1981 to May 1982(4). The max concn of 1,2-dichloroethylene (isomers not specified) in Wilson Creek, which is adjacent to a hazardous waste site in Bullit County, KY, was 75 ppb(5). [R75] *RAIN/SNOW: Rain water from a rain event in west Los Angeles contained 230 ng/l of 1,2-dichloroethylene(1). [R76] EFFL: *7.0% of the 1369 stations in the EPA STORET data base had detectable quantities of 1,2-dichloroethylene in effluent(1). The median concn was < 2.5 ppb(2). Final effluent from the Los Angeles County wastewater treatment plant contained 5.2 ppb of 1,2-dichloroethylene (isomers not specified)(3). 1,2-Dichloroethylene (isomers not specified) was detected emanating from a simulated landfill made from municipal waste and sewage sludge 8 months after preparation(4). 4 of 5 leachate samples from a landfill site that accepted both municipal and industrial wastes contained 1,2-dichloroethylene (isomers not specified) ranging from 150 to 3200 ppb(2). Based on site records of waste accepted, this is thought to be a breakdown product of more highly chlorinated compounds(2). The average concn of 1,2-dichloroethylene (isomers not specified) in gas emerging from the surface of 9 landfills used for methane recovery was 200 ppb(5). [R77] SEDS: *4% of the 361 stations in the USEPA STORET data base had detectable quantities of 1,2-dichloroethylene in sediment(3). The median concn was < 5 ppb(3). Surficial sediment taken 6 km northwest of the discharge from the Los Angeles County wastewater treatment plant at a depth of 60 m contained < 0.5 ppb (dry weight) of 1,2-dichloroethylene(1). 1,2-Dichloroethylene has been detected, but not quantitated in sediment/soil/water samples at the Love Canal(2). [R78] ATMC: *URBAN/SUBURBAN: The mean concn of 1,2-dichloroethylene (isomers not specified) was measured in the urban atmosphere of the following cites (in ppb): Tulsa, OK (< 0.1), Kanawha Valley, WV (0.08), Front Royal, VA (0.1), S Charleston, WV (< 0.08), Birmingham, AL (< 0.1), Baton Rouge, LA (< 0.1), Upland, CA (< 0.1), Magna, VT (0.08), Grand Canyon, AZ (0.065), and Geismer, LA (max concn, 2.6)(1). The concn of 1,2-dichloroethylene (isomers not specified) in air outside of 3 of 9 homes in Old Love Canal (Niagara Falls, NY) hazardous waste site in 1978 was a trace (detection limit unspecified)(2). [R79] *INDOOR AIR: The concn of 1,2-dichloroethylene (isomers not specified) in indoor air from a basement of a home in Old Love Canal (Niagara Falls, NY) was 0.015 ppb(sampling date, 1978)(1). 1,2-Dichloroethylene (isomers not specified) was detected in 16 of 16 indoor air samples (detection limit not specified) from homes in Knoxville, TN (sampling date, Winter 1982); the mean concn was 8.1 ppb(2). [R80] *SOURCE DOMINATED: At the Kin-Buc disposal facility in Edison, NJ, max concn of 1,2-dichloroethylene (isomers not specified) was 1.3 ppb (sampling date unspecified)(1). The mean and max concn of 1,2-dichloroethylene (isomers not specified) detected in landfill gas at selected US landfills was 70 and 3,600 ppb, respectively(2). 1,2-Dichloroethylene (isomers not specified) was detected in air from Newark, Elizabeth, and Camden, NJ from Jan 18 to Feb 26, 1982; the mean concns were 0.01 ppb (8 of 30 samples), 0.01 ppb (10 of 38 samples), and 0.01 ppb (10 of 37 samples), respectively(3). [R81] *RURAL/REMOTE: 1,2-Dichloroethylene (isomers not specified) was not detected (detection limit 5 parts per trillion) in rural air near Pullman, WA between Dec 1974 and Feb 1975(1). [R82] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Samples of fish livers, shrimp muscle and invertebrates collected 6 km northwest of the discharge from the Los Angeles County wastewater treatment plant contained < 0.3 ppb (wet weight) of 1,2-dichloroethylene(1). None of the 95 stations in the USEPA STORET data base had detectable quantities of 1,2-dichloroethylene in fish(2). The median concn was < 5 ppb(2). [R83] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 216 workers (10 of these are female) are potentially exposed to 1,2-dichloroethylene in the US(1). Occupational exposure to 1,2-dichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloroethylene is produced or used(SRC). Monitoring data indicate that the general population may be exposed to 1,2-dichloroethylene via inhalation of drinking water containing this compound(SRC). [R84] AVDI: *WATER INTAKE: Assume 1.1 ppb(1), 2.2 ug 1,2-dichloroethylene(SRC). [R85] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *1000 ppm [R16, 98] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 200 ppm (790 mg/cu m). [R86] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 200 ppm (790 mg/cu m). [R16, 98] TLV: *8 hr Time Weighted Avg (TWA) 200 ppm [R87, 2001.26] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R87, 2001.6] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 70 ug/l [R88] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Dichloroethylenes (1,1-, and 1,2-dichloroethylene)/ [R89] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R90] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2-Dichloroethylene is included on this list. [R91] RCRA: *U079; As stipulated in 40 CFR 261.33, when 1,2-dichloroethylene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R92] FDA: *1,2-Dichloroethylene is an indirect food additive for use only as a component of adhesives. [R93] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1003. Calibrate each personal sampling pump with sampler in line. Break ends of sampler (solid sorbent tube) and attach sampler to personal sampling pump with flexible tubing. Sample at flow rate of 0.01 to 0.2 l/min for total sample of 3 l. [R94] ALAB: *NIOSH Method 1003. Gas Chromatography/Flame ionization detector. Detection limit 475 mg/cu-m. [R94] *EPA Method OHC. Organics Analysis, Multi-Media, High-Concentration. Gas Chromatography/Mass Spectrometry. Detection limit = 2.5 mg/kg. [R95] *EPA Method 624-S. Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. This method is used for qualitative and quantitative analysis of purgeable (volatile) organic compounds in municipal and industrial wastewater treatment sludges. Gas Chromatography/Mass Spectrometry, Detection limit was not reported. [R95] *EPA Method MC_VOA-W. Analysis of Volatile Organics in Multi-Concentration Water Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to water from hazardous waste sites. Detection limit = 10 ug/l. [R95] *EPA Method MC_VOA-LS. Analysis of Volatile Organics in Low Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to soil and sediment from hazardous waste sites. Detection limit = 10 ug/kg. [R95] *EPA Method MC_VOA-MS. Analysis of Volatile Organics in Low Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to soil and sediment from hazardous waste sites. Detection limit = 1200 ug/kg. [R95] *EPA Method MC_VOA-W. Analysis of Volatile Organics in Multi-Concentration Water Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to water from hazardous waste sites. Detection limit = 10 ug/l. [R95] CLAB: *... The purged 1,1- and 1,2-dichloroethylene were retained on Tenax gas chromatogtaphy (80-100 mesh), then desorbed by heating and vented into a Tracor 560 gas chromatograph. The detection limit of the Hall electrolytic conductivity detector operated in the halogen mode was 50 pg. Recoveries of 1,1- and 1,2-dichloroethylene from various animal tissues spiked in vitro were greater than 50%. This purge-and-trap technique appears well suited for studies of the uptake and disposition of volatile organics in body tissues. [R96] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Dichloroethylenes (1980) EPA 440/5-80-041 Ahrenholz SH; NIOSH, US Dept Health No. HETA-83-375-1521 (1984). Area and breathing zone samples were analyzed for carbon disulfide, carbon monoxide, carbon tetrachloride, chloroform, 1,2-dichloroethylene, ethylene dibromide, ethylene dichloride, methyl-bromide, and grain dust at the US Dept of Agriculture Federal Grain Inspection Service field office, Portland, Oregon in November, 1983 and April, 1984. DHHS/ATSDR; Toxicological Profile for 1,2-Dichloroethene (1990) ATSDR/TP-90/13 SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 364 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. 733 R4: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 17 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 (1993) R6: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 (1986) R7: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. 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Boca Raton, FL: Lewis Pub (1994) R63: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Pub p. 96 (1984) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (6) Wilson JT et al; pp. 124-7 in Symp Nat Atten Chlorin Org Ground Water (1996) (7) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. trans-1,2-Dichloroethylene (156-60-5) and cis-1,2-Dichloroethylene (156-59-2). Available from the Database Query page at http://www.citi.or.jp/citi/owa/search_cas as of Apr 18, 2001. (8) Mudder TI; Diss Abstr Int B 42: 1804 (1981) (9) Mudder TI, Musterman JL; Preprint. Div Environ Chem Amer Chem Soc Kansas City, MO. Sept 1982 pp. 52-3 (1982) R64: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Pub p. 96 (1984) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Wilson JT et al; pp. 124-7 in Symp Nat Atten Chlorin Org Ground Water (1996) (9) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. trans-1,2-Dichloroethylene (156-60-5) and cis-1,2-Dichloroethylene (156-59-2). Available from the Database Query page at http://www.citi.or.jp/citi/owa/search_cas as of Apr 18, 2001. (10) Mudder TI; Diss Abstr Int B 42: 1804 (1981) (11) Mudder TI, Musterman JL; Preprint. Div Environ Chem Amer Chem Soc Kansas City, MO. Sept 1982 pp. 52-3 (1982) R65: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Pub p. 96 (1984) (3) Atkinson R; J Phys Chem Ref Data. Monograph 1 (1989) R66: (1) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. trans-1,2-Dichloroethylene (156-60-5) and cis-1,2-Dichloroethylene (156-59-2). Available from the Database Query page at http://www.citi.or.jp/citi/owa/search_cas as of Apr 18, 2001. (2) Mudder TI; Diss Abstr Int B 42: 1804 (1981) (3) Mudder TI, Musterman JL; Preprint. Div Environ Chem Amer Chem Soc Kansas City, MO. Sept 1982 pp. 52-3 (1982) (4) Fogel MM et al; Appli Environ Microbiol 51:720-4 (1986) (5) Bradley PM et al; Appl Environ Micro 64:3102-5 (1998) R67: (1) Wilson BH et al; Environ Sci Technol 20: 997-1002 (1986) (2) Hallen RT et al; ACS Div Environ Chem 192nd Natl Mtg 26: 344-6 (1986) (3) Barrio-Lage G et al; Environ Sci Technol 20: 96-9 (1986) (4) Bradley PM et al; Appl Environ Micro 64: 3102-5 (1998) R68: (1) Atkinson R; J Phys Chem Ref Data. Monograph 1 (1989) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (4) Callahan MA et al; Water related fate of 129 priority pollutants. Vol II. Washington DC: USEPA, Off Plan Strds, Off Water Waste Manage. USEPA 440/4-79-029b (1979) (5) Ausbel R, Wijnen MHJ; Int J Chem Kinetics 75: 739-51 (1975) (6) Dahlberg JA; Acta Chemica Scandinavica 23: 3081-90 (1969) R69: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R70: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R71: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley and Sons. New York, NY. 2001,p. V1 756 R72: (1) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Pub p. 96 (1984) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R73: (1) Cotruvo JA; Sci Total Environ 47: 7-26 (1985) (2) Westrick JJ et al; J Amer Water Works Assoc 76: 52-59 (1984) (3) Otson R; Int J Environ Anal Chem 31: 41-53 (1987) (4) Otson R et al; J Assoc Off Analyt Chem 65: 1370-4 (1982) (5) Fielding M et al; Organic Micropollutants In Drinking Water Tr-159 Medmenham, Eng Water Res Cent 49 pp. (1981) (6) Burmaster DE; Environ 24: 6-13, 33-36 (1982) (7) Wang TC et al; Arch Environ Contam Toxicol 14: 719-23 (1985) R74: (1) Lao RC et al; pp. 107-18 in Analytical Techniques In Environmental Chemistry II. Albaiges J, ed. NY, NY: Pergamon Press Ltd (1982) (2) Cline PV, Viste DR; Waste Manage Res 3: 351-60 (1985) (3) Myers VB; pp. 354-7 in Florida Natl Conf Manage Uncontrolled Hazard Waste Sites (1983) (4) Goodebjauf O, Atkinsin JC; Ground Water 24: 231-233 (1986) (5) ATSDR; Toxicological Profile for 1,2-Dichloroethen (Update). p. 101 (1996) (6) Wang T et al; Arch Environ Contam Toxicol 14: 719-23 (1985) R75: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Great Lakes Water Quality Board; pp. 195 in An Inventory Of Chemical Substances Identified In The Great Lakes Ecosystem Volume 1 - Summary Report To The Great Lakes Water Quality Board Windson Ontarion, Canada (1983) (3) Riley RG et al; Quanitition of pollutants in suspended matter and water from Puget Sound. Richland, WA: Battelle Pacific Northwest Lab, NOAA-80061003 p. 110 (1980) (4) Wang T et al; Arch Environ Contam Toxicol 14: 719-23 (1985) (5) Stonebraker RD, Smith AJ Jr; pp. 1-10 in Control Hazard Mater Spills, Proc Nat Conf Nashville, TN (1980) R76: (1) Kawamura K, Kaplan IR; Environ Sci Tech 17: 497-501 (1983) R77: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Cline PV, Viste DR; Waste Manage Res 3: 351-60 (1985) (3) Gossett RW et al; Mar Pollut Bull 14: 387-92 (1983) (4) Vogt WG, Walsh JJ; Volatile Organic Compounds In Gases From Landfill Simulators Proc -APAC Annu Meet 78th (vol6) pp. 17 (1985) (5) Zimmerman RE et al; pp. 230-9 in Proc Int Gas Res Conf (1983) R78: (1) Gossett RW et al; Mar Pollut Bull 14: 387-92 (1983) (2) Hauser TR et al; EPA's Monitoring Program AT Love Canal 1980 Env Monit Assess 2: 249-72 (1982) (3) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R79: (1) Pellizzari ED; Gov Rep Announce 79: 68 (1978) (2) Barkley J et al; Biomed Mass Spectrometry 7: 139-47 (1980) R80: (1) Barkley J et al; Biomed Mass Spectrometry 7: 139-47 (1980) (2) Gupta KC et al; Proc - APCA Annual Meeting 1977, 84: 1.3-3.1 (1984) R81: (1) Pellizzari ED; Quantification of chlorinated hydrocarbons in previously collected air samples. Gov Rep Announce 79: 68 (1978) (2) USEPA; Volatile Organic Compounds in Gases from Landfill Simulators. Washington, DC: USEPA NTIS PB85-113454/GAR (1984) (3) Harkov R et al; pp. 69-90 in Toxic Air Pollution, A Comprehensive Study of Non-Criteria Air Pollutants. Lioy PJ, Daisey JM, eds. Chelsea, MI: Lewis Pubs, Inc (1987) R82: (1) Grimsrud EP, Rasmussen RA; Atmos Environ 9: 1014-17 (1975) R83: (1) Gossett RW et al; Mar Pollut Bull 14:387-92 (1983) (2) Staples CA et al; Environ Toxicol Chem 4:131-42 (1985) R84: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R85: (1) Cotruvo JA; Sci Total Environ 47: 7-26 (1985) R86: 29 CFR 1910.1000 (7/1/2000) R87: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R88: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R89: 40 CFR 401.15 (7/1/2000) R90: 40 CFR 712.30 (7/1/2000) R91: 40 CFR 716.120 (7/1/2000) R92: 40 CFR 261.33 (7/1/2000) R93: 21 CFR 175.105 (4/1/2000) R94: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R95: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R96: Lin SN et al; J Chromatogr 244 (2): 311-20 (1982) RS: 80 Record 30 of 1119 in HSDB (through 2003/06) AN: 170 UD: 200303 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLENE-OXIDE- SY: *E-O-; *AETHYLENOXID- (GERMAN); *AI3-26263-; *Amprolene-; *ANPROLENE-; *Anproline-; *Caswell-no-443-; *DIHYDROOXIRENE-; *DIMETHYLENE-OXIDE-; *ENT-26263-; +Pesticide-Code:-042301-; *EPA-pesticide-chemical-code-042301-; *Epoxyethane-; *1,2-EPOXYETHANE-; *ETO-; *ETYLENU-TLENEK- (POLISH); *Fema-no-2433-; *T-GAS-; *NCI-C50088-; *OXACYCLOPROPANE-; *OXANE-; *OXIDOETHANE-; *ALPHA,BETA-OXIDOETHANE-; *OXIRAAN- (DUTCH); *OXIRAN-; *OXIRANE-; *OXIRENE,-DIHYDRO-; *OXYFUME-; *OXYFUME-12- RN: 75-21-8 RELT: 168 [ETHYLENE] (Metabolic Precursor) MF: *C2-H4-O SHPN: UN 1040; Ethylene oxide IMO 2.3; Ethylene oxide STCC: 49 201 08; Ethylene oxide HAZN: U115; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CATALYTIC OXIDATION OF ETHYLENE; PREPARED FROM ETHYLENE CHLOROHYDRIN AND POTASSIUM HYDROXIDE. [R1, 599] *Direct oxidation ... utilizes the catalytic oxidation of ethylene with oxygen over a silver-based catalyst ... . [R2, p. V9 924] *The process involves the reaction of ethylene with hypochlorous acid followed by dehydrochlorination of the resulting chlorohydrin with lime .... . /Chlorohydrin process/ [R2, p. V9 923] FORM: */ETHYLENE OXIDE/ IS MIXED WITH EITHER CARBON DIOXIDE OR FLUOROCARBON 12 ... TO ELIMINATE FLAMMABILITY ... . CARBOXIDE IS NONFLAMMABLE MIXTURE OF 10% BY WT ETHYLENE OXIDE IN CARBON DIOXIDE ... STERILANT 12 IS NONFLAMMABLE MIXT OF 12% BY WT ... IN FLUOROCARBON 12 ... . [R3] *Grades or purity: commercial: 100% must contain no acetylene. [R4] *GRADES: TECHNICAL; PURE (99.7%). [R5] *Specifications: 0.002 wt % acidity, max (calculated as acetic acid), 0.003 wt % aldehydes, max (calculated as acetaldehyde), 0.03 wt % water, max. [R2, p. V9 945] MFS: *BASF Corp, Hq, 8 Campus Drive, Parsippany, NJ 07054, (201) 397-2700; Consumer Products and Life Science Division, 100 Cherry Hill Road, Parsippany, NJ 07054, (201) 316-3000; Automotive Products; Industrial Organics Business; Production site: Geismar, LA 70734 [R6] *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Plaquemine, LA 70764 [R6] *Eastman Chemical Co, Hq, PO Box 511, Kingsport, TN 37662, (615) 229-2000; Texas Eastman Div; Production site: Longview, TX 75607 [R6] *Hoechst Celanese Corp, Hq, Route 202-206 N, Somerville, NJ 08876, (908) 231-2000; Chemical Group, Commodity Chemicals, 1601 West LBJ Freeway, Dallas, TX 75381-9005, (214) 277-4000; Production site: Clear Lake, TX 77058 [R6] *Occidental Petroleum Corp, Hq, 10889 Wilshire Blvd, Suite 1500, Los Angeles, CA 90024, (213) 879-1700; Petrochemicals, Ethylene oxide % Derivatives Division; Production site: Bayport, TX 77000 [R6] *PD Glycol, Hq, Gulf States Rd, Beaumont, TX 77707, (409) 838-4521; Production site: Beaumont, TX 77704 [R6] *Shell Chemical Co, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production site: Geismar, LA 70734 [R6] *Sun Company Inc (R and M), Hq, 1801 Market Street, Philadelphia, PA 19103, (215) 977-3451; Production site: Bradenburg, KY 40108 [R6] *Union Carbide Corp, Hq, Old Ridgeway Road, Danbury, CT 06817, (203) 794-2000; Industrial Chemicals Division; Production sites: Seadrift, TX 77983; Taft, LA 70057 [R6] *Texaco Chemical Co, Hq, 3040 Post Oak Blvd, P.O. Box 27707, Houston, TX 77056, (713) 961-3711; Production site: Port Neches, TX 77651 [R6] *Formosa Plastics Corporation U.S.A., Hq, 9 Peach Tree Road, Livingston, NJ 07039, (201) 992-2090; Production site: Point Comfort, TX 77978 [R6] OMIN: *A variety of new process concepts for ethylene oxide-ethylene glycol are being developed based on such raw materials as synthesis gas and ethanol. [R7] *The compatibility of polycarbonate with ethylene oxide was studied. The polycarbonate devices can be safely exposed to 3 ethylene oxide cycles. Polycarbonates are compatible with ethanol at 73-158 deg F. [R8] *The chlorohydrin process is not economically competitive, and was quickly replaced by the direct oxidation process as the dominant technology. At the present time, all ethylene oxide production in the world is achieved by the direct oxidation process. [R2, p. V9 923] USE: +For Ethylene oxide (USEPA/OPP Pesticide Code: 042301) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R9] *RIPENING AGENT FOR FRUITS, FUNGISTAT [R10] *INACTIVATES KREB'S ASCITES TUMOR CELLS [R11] *ROCKET PROPELLANT [R5] *FUMIGANT FOR FOODSTUFFS AND TEXTILES; IN ORGANIC SYNTHESIS; STERILIZE SURGICAL INSTRUMENTS; AGRICULTURAL FUNGICIDE [R1, 559] *STARTING MATERIAL FOR MFR OF ACRYLONITRILE AND NONIONIC SURFACTANTS. [R1, 559] *... USEFUL FOR FUMIGATING INSECTS IN PACKAGED CEREALS, BAGGED RICE, TOBACCO, AND CLOTHING AND FURS IN VAULTS. ... IT IS ALSO USED IN VAULTS FOR FUMIGATING VALUABLE PACKAGED DOCUMENTS. [R12] *... FOR TREATMENT BY FUMIGATION OF BOOKS; DENTAL, PHARMACEUTICAL, MEDICAL AND SCIENTIFIC EQUIPMENT AND SUPPLIES, ... DRUGS; LEATHER; MOTOR OIL; PAPER; SOIL; BEDDING FOR EXPERIMENTAL ANIMALS; ... FURNITURE; AND TRANSPORTATION VEHICLES ... . [R13] *Formation of diethylene glycol, the cellosolves and carbitols, dioxane, ethylene chlorohydrin and polymer (carbowax); intermediate for polyethylene terephthalate polyester fiber. [R14] *STERILANT AND SPOROCIDE-EG, IN HEALTH CARE INDUST [R15] *Used as a fumigation agent on ... beehives (empty and diseased), beekeeping equipment ... . [R16] *Used on hospital equipment including: hypodermic needles/syringes, surgical prosthetic parts, heart and lung machines, dental, hospital and laboratory instruments, heat labile materials, moisture labile materials, oral and inhalation equipment, diagnostic instruments/equipment, hospital critical rubber, plastic items, hospital critical equipment, thermometers, laboratory equipment, pharmaceutical equipment, stainless steel surfaces; and on hospital fabrics, materials, paper products, sheeting, grooming instruments. [R16] *Chemical intermediate for ethylene glycols, ethanolamines, glycol ethers and surfactants. [R17] +MEDICATION (VET) CPAT: *CHEM INT FOR ETHYLENE GLYCOL, 60.5%; CHEM INT FOR NONIONIC SURFACTANTS (ACYCLIC), 7.1%; CHEM INT FOR NONIONIC SURFACTANTS (CYCLIC), 4.6%; CHEM INT FOR GLYCOL ETHERS, 7.2%; CHEM INT FOR ETHANOLAMINES, 7.1%; CHEM INT FOR DIETHYLENE GLYCOL, 5.1%; CHEM INT FOR TRIETHYLENE GLYCOL, 2.1%; CHEM INT FOR POLYETHYLENE GLYCOL, 1.6%; OTHER, 4.7% (1981) [R15] *Monoethylene glycol, 59%; higher glycols, 15%; ethoxylates, 10%; ethanolamines, 6%; glycol ethers, 5%; miscellaneous, 5% (1984) [R7] *CHEMICAL PROFILE: Ethylene oxide. Ethylene glycol, 59%; nonionic surfactants, 14%; ethanolamines, 8%; glycol ethers, 6%; diethylene glycol, 6%, triethylene glycol, 2%; miscellaneous, including polyethylene glycol, urethane polyols and exports, 5%. [R18] *CHEMICAL PROFILE: Ethylene oxide. Demand: 1986: 5.7 billion lb; 1987: 5.8 billion lb; 1991 /projected/: 6.4 billion lb. [R18] *CHEMICAL PROFILE: Ethylene oxide. Ethylene glycol, 59%; nonionic surfactants, 13%; ethanolamines, 8%; glycol ethers, 6%; diethylene glycol, 6%, triethylene glycol, 2%; miscellaneous, including polyethylene glycol, urethane polyols and exports, 6%. [R19] *CHEMICAL PROFILE: Ethylene oxide. Demand: 1989: 5.8 billion lb; 1990 /projected/: 5.9 billion lb; 1994 /projected/: 6.4 billion lb. (Imports and exports are negligible, each on the order of 25 million lb per year.) [R19] PRIE: U.S. PRODUCTION: *(1977) 2.03X10+12 G [R15] *(1982) 2.26X10+12 G [R15] *(1986) 2.49X10+12 g /Estimated/ [R7] *(1985) 2.58X10+12 g [R20] *(1988) 5.95X10+9 lb [R21] *(1986) 2.49x10+12 g [R20] *(1990) 5.36 billion lb [R22] *(1991) 5.25 billion lb [R23] *(1992) 5.83 billion lb [R24] *(1993) 5.68 billion lb [R24] *1992 Production: 2,643,813,000 kg; 1992 Sales: 254,452,000 kg [R25] U.S. IMPORTS: *(1977) 1.15X10+10 G [R15] *(1982) 4.30X10+9 G [R15] *(1985) 1.03X10+10 g [R26] U.S. EXPORTS: *(1978) 3.46X10+10 G [R15] *(1983) 6.27X10+9 G [R15] *(1985) 2.82X10+10 g [R27] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS GAS @ ORDINARY ROOM TEMP AND PRESSURE; LIQUID BELOW 12 DEG C [R1, 559]; +Colorless gas or liquid (below 51 degrees F) ... [R28, 138] ODOR: *Sweet [R4]; +ETHER-LIKE ODOR [R29, p. 49-68]; *Reminiscent of bruised apples [R30]; +... Ether-like odor. [R28, 138] BP: *10.7 DEG C @ 760 MM HG [R1, 599] MP: *-111 DEG C [R1, 599] MW: *44.06 [R31] CTP: *Critical temperature = 469.15 K; Critical pressure = 7.1941X10+6 Pa [R32] DEN: *0.882 @ 10 DEG C/10 DEG C [R1, 599] HTC: *1280.9 kJ/mol (liquid); 1306.1 kJ/mol (gas) [R33, p. 5-76] HTV: *24.75 kJ/mol @ 25 deg C [R33, p. 6-114] OWPC: +log Kow= -0.30 [R34] SOL: *... Miscible in all proportions with water, alcohol, ethers, and most organic solvents [R2, 916]; *SOL IN BENZENE, ACETONE [R35]; *MISCIBLE WITH CARBON TETRACHLORIDE [R36, 2167] SPEC: *MAX ABSORPTION (GAS): 169 NM (LOG E= 3.58); 171 NM (LOG E= 3.57) [R37]; *INDEX OF REFRACTION: 1.3597 @ 7 DEG C/D [R1, 599]; *IR: 1109 (Sadtler Research Laboratories Prism Collection) [R38]; *MASS: 12 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R38] SURF: *Liquid: 24.3 dynes/cm= 0.0243 N/m at 20 deg C. [R4] VAPD: *1.49 [R39] VAP: *1314 MM HG AT 25 DEG C (calculated from experimentally derived coefficients) [R32] VISC: *9.45x10-3 mPa.s (25 deg C, gas) and 0.254 mPa.s (10 deg C, liquid) [R40] OCPP: +LIQ IS LIGHTER THAN WATER, VAPOR IS HEAVIER THAN AIR [R29, p. 49-68] *Heat of solution in water: 142.57 kJ/kg @ 25 deg C [R41] *CAN REACT WITH OXIDIZING MATERIALS [R42] *Ratio of specific heats of vapor (gas): 1.212 [R4] *Chemical oxygen demand: 1.74 Nederlands norm (dutch standard test method) 3235 - 5.3 sublimation: 24.9 K/mole at 25 deg C [R43, 654] *Heat of fusion: 28.07 cal/g [R44] *Ionization potential: 10.56 eV [R45] *Standard Enthalpy of Formation: -77.8 kJ/mol /liquid/; -52.6 kJ/mol (gas) [R33, p. 5-28] *Heat of fusion: 5.1714 J/k mol [R32] *Coefficient of thermal expansion: 1.51x10-3/deg C [R46] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; may be fatal if inhaled or absorbed through skin. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control may cause pollution. [R47, p. G-119] +Fire or explosion: Flammable; may be ignited by heat, sparks or flames. May form explosive mixtures with air. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Vapors from liquefied gas are initially heavier than air and spread along ground. Vapors may travel to source of ignition and flash back. Some of these materials may react violently with water. Containers may explode when heated. Ruptured cylinders may rocket. Runoff may create fire or explosion hazard. [R47, p. G-119] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. Ventilate closed spaces before entering. [R47, p. G-119] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R47, p. G-119] +Evacuation: Spill: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 1600 meters (1 mile) in all directions; also, consider initial evacuation for 1600 meters (1 mile) in all directions. [R47, p. G-119] +Fire: DO NOT EXTINGUISH A LEAKING GAS FIRE UNLESS LEAK CAN BE STOPPED. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. FOR CHLOROSILANES, DO NOT USE WATER; use AFFF alcohol-resistant medium expansion foam. Move containers from fire area if you can do it without risk. Damaged cylinders should be handled only by specialists. Fire involving tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R47, p. G-119] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Do not direct water at spill or source of leak. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. FOR CHLOROSILANES, use AFFF alcohol-resistant medium expansion foam to reduce vapors. If possible, turn leaking containers so that gas escapes rather than liquid. Prevent entry into waterways, sewers, basements or confined areas. Isolate area until gas has dispersed. [R47, p. G-119] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. In case of contact with liquefied gas, thaw frosted parts with lukewarm water. Keep victim warm and quiet. Keep victim under observation. Effects of contact or inhalation may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R47, p. G-119] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 60 meters (200 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.3 kilometers (0.2 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 125 meters (400 feet); then, PROTECT persons Downwind during DAY 0.3 kilometers (0.2 miles) and NIGHT 1.0 kilometers (0.6 miles). /Ethylene oxide; Ethylene oxide with nitrogen/ [R47, p. TABLE] FPOT: +Flammable liquid [R29, p. 49-68] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R29, p. 325-51] +Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R29, p. 325-51] +Reactivity: 3. 3= This degree includes materials that, in themselves, are capable of detonation, explosive decomposition, or explosive reaction, but require a strong initiating source or heating under confinement. This includes materials that are sensitive to thermal and mechanical shock at elevated temperatures and pressures and materials that react explosively with water. Fires involving these materials should be fought from a protected location. [R29, p. 325-51] FLMT: *Lower flammable limit: 3%; Upper flammable limit: 100% [R48, 237] FLPT: *< 0 deg F (Open cup) [R4] AUTO: *804 DEG F [R49] FIRP: *Fire extinguishing agents: water. [R4] *Stop flow of gas if possible. Combat fires from behind barrier, with unmanned hose holder or monitor nozzle. Flood discharge area with water. Cool exposed containers and protect men effecting shut off with water. [R4] *Carbon dioxide and dry-chemical extinguishers are useful against small fire. [R48, 238] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R50] *Evacuation: If fire is prolonged and material is confined in the container consider evacuation of one (1) mile radius. If fire becomes uncontrollable or container is exposed to direct flame, consider evacuation of one (1) mile radius. [R50] TOXC: *Irritating vapors generated when heated. [R4] OFHZ: *Vapor is heavier than air and may travel considerable distance to a source of ignition and flash back. [R4] EXPL: *LOWER EXPLOSIVE LIMIT: 3.0%, UPPER EXPLOSIVE LIMIT: 100%. EXPLOSION HAZARD: SEVERE, WHEN EXPOSED TO FLAME. [R49] *GAS IS EXPLOSIVE IN CONCN ABOVE 3% AND MUST BE MIXED WITH CARBON DIOXIDE OR FLUOROCARBONS. [R51] *Decompostion products are explosive. [R48, 666] +VAPOR FORMS EXPLOSIVE MIXTURES WITH AIR OVER A WIDE RANGE. [R29, p. 49-68] REAC: *Metal fittings containing copper, silver, mercury, or magnesium should not be used in ethylene oxide service, since traces of acetylene could produce explosive acetylides capable of detonating ethylene oxide vapor. [R52, 272] *INCOMPATIBILITIES: BECAUSE OF HIGH CHEMICAL REACTIVITY ... IT REACTS WITH MANY PHARMACEUTICAL SUBSTANCES AND WITH VITAMINS, AMINO ACIDS, AND OTHER FOOD CONSTITUENTS. ... [R53] *Accidental contamination of a large ethylene oxide feed-cylinder by reaction liquor containing trimethylamine caused the cylinder to explode 18 hr later. Contamination was possible because of a faulty pressure gauge and suck-back of froth above the liquid level. [R52, 276] +Highly reactive! Hazardous polymerization may occur especially if contaminated. Reacts with acids, alkalies, salts, combustible materials. Ethylene oxide and water may form stratified layers. May undergo runaway reaction with water. Many materials may accelerate this reaction. [R29, p. 49-68] *It reacts with chloride and water to produce two active germicides, 2-chloroethanol and ethylene glycol. [R54] +Strong acids, alkalis and oxidizers; chlorides of iron, aluminum and tin; oxides of iron and aluminum; water. [R28, 138] DCMP: *Liquid ethylene oxide is not detonable, but the vapor may be readily initiated into explosive decomposition. [R52, 272] POLY: *Precautions designed to prevent explosive polymerization of ethylene oxide are discussed, including rigid exclusion of acids, covalent halides such as aluminium, iron (III), and tin (IV) chloride, basic materials like alkali hydroxides, ammonia, amines, metallic potassium, and catalytically active solids such as aluminium or iron oxides or rust. [R52, 274] *POLYMERIZATION IS CATALYZED BY A NUMBER OF MATERIALS, SUCH AS ACIDS, ALKALIS, SOME CARBONATES, OXIDES OF IRON AND ALUMINUM, AND CHLORIDES OF IRON, TIN, ALUMINUM, AND BORON. NO ACETYLIDE-FORMING METALS SUCH AS COPPER OR COPPER ALLOYS SHOULD BE IN CONTACT WITH ETHYLENE OXIDE. [R36, 2166] *Accidental contamination of an ethylene oxide feed tank by ammonia caused violently explosive polymerization. [R52, 273] ODRT: *50 ppm [R4] *Recognition: 1.5 mg/cu m= 0.8 ppm, mean detection concn: 700 ppm; absolute perception limit: 260 ppm; 50% recognition: 500 ppm; 100% recognition: 500 ppm [R43, 654] *Low: 520 mg/cu m; High: 1400 mg/cu m [R55] *300 ppm in air [R56, 663] SERI: *Ethylene oxide is irritating to the eyes, respiratory tract, and skin. [R57] *Aqueous solutions of ethylene oxide or solutions formed when the anhydrous cmpd comes in contact with moist skin are irritating and may lead to a severe dermatitis with blisters, blebs and burns. It is also absorbed by leather and rubber and may produce burns or irritation. Allergic eczematous dermatitis has also been reported. Exposure to the vapor in high concn leads to irritation of the eyes. Severe eye damage may result if the liquid is splashed in the eyes. Large amounts of ethylene oxide evaporating from the skin may cause frostbite. [R58] EQUP: *AIR-SUPPLIED MASK; GOGGLES OR FACE SHIELD; RUBBER SHOES AND COVERALLS. [R4] *Wear neoprene gloves, safety glasses, plastic protective clothing and self-contained breathing apparatus. [R48, 237] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R59, 1979.8] *A study was conducted to evaluate protective clothing garment materials used by emergency response personnel and to determine their effectiveness when combating ammonia or ethylene oxide in gaseous form. Data were collected using an automated permeation test system for 13 garment materials representing 11 types of total encapsulating suit materials and two glove materials. For the study neat (100%) and 2000 ppm (0.2%) gas were chosen as challenge concentrations. A closed loop test system was chosen for the study using an infrared detector. Breakthrough times and steady state permeation rates were determined. The results indicated suitable garment materials were found to protect workers against 100% anhydrous ammonia for an extended time period and there was also a large selection of materials for 0.2% ammonia. Surgical latex was not recommened for protection against ammonia. While several materials offered resonable working time protection against 100% ethylene oxide, only two of the 17 materials were useful for extended time periods. The semiautomated test system expedited chemical permeation resistance testing and proved to be effective in securing the needed data. [R60] +Wear appropriate personal protective clothing to prevent skin contact. /Liquid/ [R28, 139] +Wear appropriate eye protection to prevent eye contact. /Liquid/ [R28, 139] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] /Liquid/ [R28, 139] +Recommendations for respirator selection. Max concn for use: 5 ppm. Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. End of service life indicator (ESLI) required. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R28, 139] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R28, 139] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. End of service life indicator (ESLI) required. Any appropriate escape-type, self-contained breathing apparatus. [R28, 139] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R50] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R50] +Contact lenses should not be worn when working with this chemical. [R28, 139] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R59, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R59, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R59, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R59, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R59, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R59, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R59, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R59, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R59, 1979.11] *Substantial quantities of ethylene oxide may remain in treated materials after gas sterilization. Consequently,, safe use of ethylene oxide in hospitals and health instrument manufacture requires an aeration phase, the length of which depends on the material being treated. [R57] +The worker should immediately wash the skin when it becomes contaminated. /Liquid/ [R28, 139] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R28, 139] SSL: *HYDROLYZES SLOWLY IN AQ SOLN [R61] *STABLE IN WATER [R62] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R63] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R64] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R65] STRG: *Temperature: ambient [R4] *Protect containers against physical damage, check for leakage intermittently. Store in distant outdoor tank or container protected from direct sunlight, lined with insulating material, equipped with an adequate refrigeration and water system. Indoor storage should be restricted to small quantities. Place material in a combustible liquid cabinet which is fireproof in conformity with regulations. [R48, 237] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R59, 1979.13] CLUP: *Shut off ignition sources and call fire dept. Stop /flow/ if possible. Stay upwind and use water spray to "knock down" vapor. Isolate and remove discharged material. Notify local health and pollution control agencies. [R4] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R59, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U115, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R66] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R67] *Evaporation and open burning: A) Place on ground in an open area. Evaporate or burn by igniting from a safe distance. B) Dissolve in benzene, petroleum ether or higher alcohol such as butanol. Dispose by burning the soln. Recommendable method: Incineration. Peer review: Ethylene oxide boils @ 11 deg C, therefore burning in an incinerator can cause difficulties unless a gas feed can be arranged. It is soluble in water or alcohol and these soln can be burned. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R68] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R59, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R59, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R59, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R59, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R59, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A2; Suspected human carcinogen. [R69] *Evaluation: There is limited evidence in humans for the carcinogenicity of ethylene oxide. There is sufficient evidence in experimental animals for the carcinogenicity of ethylene oxide. In making the overall evaluation, the Working Group took into consideration the following supporting evidence. Ethylene oxide is a directly acting alkylating agent that: (1) induces a sensitive, persistent dose-related increase in the frequency of chromosomal aberrations and sister chromatid exchange in peripheral lymphocytes and micronuclei in bone marrow cells of exposed workers; (2) has been associated with malignancies of the lymphatic and hematopoietic system in both humans and experimental animals; (3) induces a dose related increase in the frequency of hemoglobin adducts in exposed humans and dose related increases in the numbers of adducts in DNA and hemoglobin in exposed rodents; (4) induces gene mutations and heritable translocations in germ cells of exposed rodents; and (5) is a powerful mutagen and clastogen at all phylogenetic levels. Overall evaluation: Ethylene oxide is carcinogenic to humans (Group 1). [R70] ANTR: *Treatment consists of general supportive care. [R71, 997] MEDS: *Biological monitoring of ethylene oxide exposure by analysis of alveolar air and blood was studied in 10 workers employed in a hospital sterilizer unit. Environmemtal air, alveolar air, and venous blood were sampled during and at the end of an 8 hr workshift. The mean environmental concentration of ethylene oxide was 5.4 mg/cu m air and the mean alveolar ethylene oxide concentration was 1.2 mg/cu m alveolar air. Regression analysis showed that blood ethylene oxide concentrations were higher than environmental ethylene oxide concentrations by a mean ratio of 3 and higher than alveolar ethylene oxide concentrations by a mean ratio of 12. [R72] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R59, 1979.23] *The 1984 OSHA standard for ethylene oxide (EtO) mandates medical surveillance under various circumstances. When performed medical surveillance for EtO must include a complete blood count (CBC) with differential leukocyte count. This requirement is based on reports of EtO associated absolute lymphocytosis and other hematologic effects. This paper describes experiences in providing EtO medical surveillance for a 300 bed hospital over a 6 year period. An apparent relative lymphocytosis which persisted over 3-4 years in sterilization workers with documented TWA personal EtO exposures averaging 0.07 ppm /was observed/. In addition three workers had a history of acutely toxic overexposure to EtO as a result of a sterilizer malfunction. These workers became symptomatic following the high accidental overexposure but did not show absolute lymphocytosis or altered patterns in the relative lymphocytosis. Finally a cross-sectional comparison of the CBC data from the EtO exposed workers to data from non-EtO exposed hospital workers showed no significant differences ruling out an association of the relative lymphocytosis with EtO exposure. These observations led us to review the basis for the inclusion of the CBC in routine EtO medical surveillance. /Such/ experience, review of the literature on EtO associated lymphocytosis and anemia, and review of the literature on the use of the CBC with differential as screening test suggest that the leukocyte differential may not be useful in routine medical surveillance for EtO exposure. [R73] *In a study on workers in a chemical plant where ethylene oxide (EtO) is manufactured and partly used for ethylene glycol production, exposure to EtO was monitored during annual periodic health assessments In January 1988, December 1988, and March 1990 by the determination of the level of 2-hydroxyethylvaline in hemoglobin. The 2-hydroxyethylvaline levels in workers corresponded with the potential EtO exposures. The highest level was found in December 1988, in blood samples collected 1-2 months after a shut down, maintenance, and start up program. The range of adduct levels found in the three examinations indicated that average EtO exposures during the 4 months preceding blood sampling were below 0.5 ppm. It was demonstrated that the method allows for the accurate monitoring of low levels of EtO exposure and provides personalized time integrated exposure data with great discriminative power. In addition, the method may serve to identify unexpected personal exposures, which may lead to targeted exposure control measures. [R74] HTOX: *INHALATION CAUSES NAUSEA, VOMITING, NEUROLOGICAL DISORDERS, AND EVEN DEATH. TRACES OF GAS IN GLOVES OR CLOTHING MAY CAUSE BURNS. ... RESIDUES IN VASCULAR CATHETERS CAN CAUSE THROMBOPHLEBITIS; IN ENDOTRACHEAL TUBES, TRACHEITIS. [R51] *... A pulmonary irritant if inhaled [R75] *... MAY BE DESCRIBED AS A CENTRAL DEPRESSANT, AN IRRITANT ... CONTACT WITH ... DILUTE SOLN MAY CAUSE IRRITATION AND NECROSIS OF EYES ... BLISTERING ... AND NECROSIS OF SKIN. EXCESSIVE EXPOSURE MAY CAUSE IRRITATION OF ... LUNGS, AND CENTRAL DEPRESSION. [R36, 2167] *Conjunctivitis, dyspnea, cough, vertigo, nausea and vomiting, abdominal pain, parasystole, arrhythmia, pulmonary edema, and paralysis. [R48, 237] *The incidence of spontaneous abortions among hospital staff who used ethylene oxide, glutaral (glutaraldehyde) and formaldehyde for the chemical sterilization of instruments was studied using data from a questionnaire and a hospital discharge register. Results showed that the frequency of spontaneous abortions was 11.3% for the sterilizing staff and 10.6% for the nursing auxiliaries (controls). When the staff were concerned in sterilizing during their pregnancy the frequency was 16.7% compared with 5.6% for the nonexposed pregnancies. The incr frequency ... correlated with exposure to ethylene oxide but not with exposure to glutaral or formaldehyde. [R76] *Accidental exposure of a person to an estimated concn of 500 ppm in air for 2-3 min was enough to cause temporary unconsciousness and seizures, but apparently did not produce ocular symptoms. [R77, 419] *A report of 1st to 3rd degree burns occurring postoperatively or postpartum in 19 women. The gowns and sheets used were found to contain 16-50 times the safe residual concn of ethylene oxide. [R30] *Workers who had been employed for more than one year by a company producing ethylene oxide had been studied from 1960-1961. No significant differences had been found between workers permanently working in the ethylene oxide manufacturing area, those who had previously worked in this area, those working there intermittently and a further group who had never worked in ethylene oxide production. However, a subgroup of individuals with high exposure had decreased hemoglobin concn and signficant lymphocytosis. When workers were followed up from 1961-1977, those who had been exposed full-time to ethylene oxide production showed a considerably excess mortality, this being mainly due to an increased incidence of leukemia, stomach cancer and diseases of the circulatory system. Although malignancies could not be linked to any particular chemical associated with ethylene oxide production it was considered that ethylene oxide and ethylene dichloride, possibly together with ethylene chlorohydrin or ethylene, were the causative agents. [R30] *The permeation of ethylene oxide through human skin was determined in vitro. Permeation studies were performed with excised skin in diffusion cells. Ethylene oxide shows that it permeated quickly. The health hazard involved in the use of ethylene oxide in sterilization of medical goods is discussed. [R78] *Chronic ethylene oxide poisoning occurred collectively in four sterilizing workers of a factory manufacturing medical appliances in Izumo, Japan. All the patients presented with symptoms of multiple neuropathy, of which the chief complaints were sensory disturbance of the lower limbs and gait disturbance. One of the patients presented with delirium and visual hallucinations. ... Clinical observations of the poisoning /were analyzed/ and the causal factors from the standpoint of industrial epidemiology and safety measures for the future /were discussed/. [R79] *Chromosome aberration frequencies in 61 employees potentially exposed to ethylene oxide were compared with those in unexposed control groups. Three worksites /were studied/ with differing historical ambient levels of ethylene oxide. Within worksites, groups were classified as high potential exposed, low potential exposed, or controls. Further control groups including an off-site community control group were added to give a total of 304 control individuals. Blood samples were drawn several times over a 24-month period. Aberrations were analyzed in 100 cells per sample after culture for 48-51 hours. Worksites I, II, and III respectively represented increasing levels of potential ethylene oxide exposure. At worksites I and II, no consistent differences in aberration frequencies were found among groups. At worksite III aberration frequencies in potentially exposed individuals were significantly increased compared with controls. The frequencies of cells with aberrations were 5.6% for the 2 individuals in the high potential exposure category and 2.6% for 23 persons in the low potential exposure group. The overall frequency of cells with aberrations in the matched control individuals was 1.4%. In the total control group of 304 individuals, ... significant increases in aberrations associated with smoking and increasing age /were found/. [R80] *A retrospective cohort study was performed on a group of 664 male workers employed for at least one month during the period 1942-1979 in a chemical factory. Both established and suspected carcinogens had been handled in the plant, primarily piperazine, but also urethane, ethylene oxide, formaldehyde, and organic solvents. A significantly increased mortality, compared with the regional death rate, was observed in the cohort. The increase was mainly due to violent deaths and cardiovascular diseases. A statistically significant increase in cancer morbidity was observed for malignant lymphoma/myelomatosis when an induction latency time /minimum/ of 10 years was used. Furthermore, an increase in bronchial cancer was noted, but it was statistically significant only when an induction-latency time /minimum of/ 15 years was used. [R81] *Samples of blood were collected from a group of plant workers engaged in the manufacture of ethylene oxide for periods of up to 14 yr, and also from a group of control personnel matched by age and smoking habits. Peripheral blood lymphocytes were cultured for cytogenetic analysis. Selected immune and hematological parameters were also investigated. The results of these studies showed no statistically significant difference between the group of plant workers and the control group in respect to any of the biological parameters investigated in this study. Nevertheless, duration of employment in ethylene oxide manufacturing was positively correlated (p < 0.05) with the frequency of chromosome breaks and with the percentage of neutrophils in a differential white blood cell count, and negatively correlated (p < 0.05) with the percentage of lymphocytes. As the values of these parameters remained within the normal limits of control populations, the correlations were considered to have no significance for health. The amount of alkylation (2-hydroxyethyl groups) of the Nt atom of histidinyl residues in hemoglobin was also measured in an attempt to gauge recent individual exposures to ethylene oxide. Variable but, in most instances, readily measurable amounts of Nt- (2'-hydroxyethyl)-L-histidine (Nt represents the N3 atom of histidine) were found in the hemoglobin of plant workers and in the control group who had not knowingly been exposed to an exogenous source of ethylene oxide. There was no statistically significant difference between the results obtained in the control group and in the group of plant workers. [R82] *A study was made of the effects of ethylene oxide on the health of sterilizer workers and other personnel exposed while using ethylene oxide for sterilization of disposable medical devices. The only significant findings were obtained by chromosomal analysis of cultured lymphocytes harvested from the workers. There were significant differences in the numbers and types of chromosomal aberrations between the exposed workers and the nonexposed controls. Quadriradial and triradial chromosomal forms, which were rarely found in nonexposed populations, were increased in exposed workers. Increased numbers of sister chromatid exchanges was found in the cultured lymphocytes of some, but not all, exposed persons during the 2 yr of study. Workers (13) were removed from exposure in 1979 because of increased numbers of aberrant cells. Follow-up over 4 yr did not show a significant improvement, except for a moderate reduction in sister chromatid exchanges. Recommendations were given for a surveillance of persons working with or exposed to ethylene oxide. [R83] *... Dialyzer hypersensitivity syndrome presents as an acute anaphylactoid reaction, the symptoms of which may range from mild to life threatening in severity. The cause of this syndrome is unknown, but affected patients appear to have a high incidence of positive radioallergosorbent tests to a conjugate of human serum albumin and ethylene oxide, suggesting that ethylene oxide, a substance used to dry sterilize artificial kidneys, may be an offending allergen. [R84] *Samples of peripheral blood were collected from 33 men who were employed in the manufacture of ethylene oxide for between 1 and 14 yr, and from 32 men from other parts of the same plant who were used as controls. Their lymphocytes were analyzed for chromosome damage. There were low frequencies of polyploidy, chromatid aberrations and chromosome breaks in the cells of the 65 men. A slightly higher frequency of chromatid aberrations was observed in the cells of the ethylene oxide workers than in those of the controls. There was a positive correlation between length of employment in the ethylene oxide group and the numbers of aberrations in the cultures of each individual. This trend was not solely attributable to the age of the men. The levels of chromatid and chromosome damage observed in this study are consistent with those in humans who were not recently exposed to known chromosome-breaking agents. [R85] *EXPOSURE TO LOW VAPOR CONCN OFTEN RESULTS IN DELAYED NAUSEA AND VOMITING. HIGHER CONCN PRODUCE IRRITATION OF EYES, NOSE, AND THROAT; HIGH CONCN MAY CAUSE EDEMA OF LUNGS. CONTACT WITH SKIN CAUSES BLISTERING AND BURNS. [R4] *Concern about the possible adverse influence of the workplace environemnt on reproduction now extends to women health professionals. ... A postal survey of all women who graduated from US veterinary schools during the period 1970-1980 (n = 2,997; response rate = 90.2%) /was conducted/. Occupational and reproductive histories were obtained, and spontaneous abortion risks were estimated with respect to self-reported exposure to radiation, ethylene oxide, halothane and other anesthetic gases, and pesticides. Of the 2,174 pregnancies among cohort members who had one veterinary job at the time of conception, 83.3% of the conceptions occurred while the veterinarian held a job that involved exposure to pesticides, 63.2% involved exposure to radiation, 61.9% to anesthetic gases other than halothane, 50.7% to halothane, and 14.0% to ethylene oxide. Agent-specific spontaneous abortion risks were estimated for the exposed/unexposed pregnancies, and risk ratios adjusted for gravidity, history of spontaneous abortion, age and alcohol and tobacco use were derived by means of logistic regression. Estimated risk ratios were close to 1.0, and no effect was seen for hours worked per week, a measure of exposure intensity. Despite no apparent influence of the exposures on spontaneous abortion risk, caution must be exercised in interpretation of these results because of potential exposure misclassification. Importantly, the results emphasize the extent to which women veterinarians may be exposed to reproductive hazards while pregnant. [R86] *Eight hospital workers with chronic ethylene oxide exposure were age-sex matched with eight nonexposed controls with no significant differences in educational backgrounds and vocabulary scores. The exposed group performed more poorly on all eight measures of cognition, memory, attention, and coordination, with 71.3% less accuracy on the Hand-Eye Coordination Test. There was a dose-response relationship between exposure and the following: Continuous Performance Test and sural velocity. These findings suggest that neurologic dysfunction may result from long-term low-dose exposure to ethylene oxide, and that these effects may occur at exposure levels common in hosptial sterilizer operations. [R87] *Ethylene oxide is an alkylating agent and a model direct-acting mutagen and carcinogen. This study has evaluated a panel of biologic markers including ethylene oxide-hemoglobin adducts, sister-chromatid exchanges, micronuclei, chromosomal aberrations, DNA single-strand breaks and an index of DNA repair (ratio of unscheduled DNA synthesis to NA-AF-DNA binding) in the peripheral blood cells of 34 workers at a sterilization unit of a large university hospital and 23 controls working in the univer library. Comprehensive environmental histories were obtained on each subject including detailed occupational and smoking histories. Industrial hygiene data obtained prior to the study and personal monitoring during the 8 years preceding the study showed that workers were subject to low level exposure near or below the current Occupational Safety and Health Administration (OSHA) standard of 1 ppm (TWA). Personal monitoring data obtained during 2 weeks prior to blood sampling were uniformly less than 0.3 ppm (TWA). After adjusting for smoking, ethylene oxide workplace exposure was significantly (p < 0.001) associated with ethylene oxide hemoglobin (a carcinogen protein adduct) and 2 measures of sister chromatid (the average number of sister chromatid exchanges/cell (SCE50) and the number of high frequency cells (SCEHFC). There was an apparent suppression of DNA repair capacity in ethylene oxide exposed individuals as measured by the DNA repair index; ie, the ratio of unscheduled DNA synthesis and NA-AAF-DNA binding (p < 0.01). No association of DNA repair index with smoking was found. Another important finding of this study is the highly significant correlation between ethylene oxide-hemoglobin adduct levels and SCEHFC (p < 0.01) and sister-chromatid exchanges (p < 0.02) which provides evidence of a direct link between a marker of biologically effective dose and markers of genotoxic response. In contrast, micronuclei, chromosomal aberrations and single-strand breaks were not significantly elevated in the workers. The activity of the u-isoenzyme of glutathione-S-transferase was measured as a possible genetic marker of susceptibility and a modulator of biomarker formation. However, possibly because of confounding by age, no significant relationships were found between glutathione-S-transferase and any of the exposure-related markers by ANOVA or among other independent variables by regression. [R88] *A multicenter cohort study was carried out to study the possible association between exposure to ethylene oxide and cancer mortality. The cohort consisted of 2658 men from eight chemical plants of six chemical companies in the Federal Republic of Germany who had been exposed to ethylene oxide for at least one year between 1928 and 1981. The number of subjects in the separate plants varied from 98 to 604. By the closing date of the study (31 December 1982) 268 had died, 68 from malignant neoplasms. For 63 employees who had left the plant (2.4%) the vital status remained unknown. The standardized mortality ratio for all causes of death was 0.87 and for all malignancies 0.97 compared with national rates. When local state rates were used the standardized mortality ratio were slightly lower. Two deaths from leukemia were observed compared with 2.35 expected standardized = 0.85). Standardized mortality ratios for carcinoma of the esophagus (2.0) and carcinoma of the stomach (1.38) were raised but not significantly. In one plant an internal "control group" was selected matched for age, sex, and date of entry into the factory and compared with the exposed group. In both groups a "healthy worker effect" was observed. The total mortality and mortality from malignant neoplasms was higher in the exposed than in the control group; the differences were not statistically significant. There were no deaths from leukemia in the exposed group and one in the control group. [R89] *We have applied the micronucleus assay to exfoliated cells of buccal and nasal cavities to monitor the genotoxic risk in a group of workers exposed to chromic acid and in another group exposed to ethylene oxide. The first group comprised 16 subjects working in a hard type chrome plating factory showing increased chromium absorption and chromium induced rhinopathy. The second group comprised 9 subjects working in a sterilization unit, exposed to ethylene oxide concentrations lower than 0.38 ppm as timed weighted average for a working shift; 3 of them were involved in a acute exposure too. The frequency of micronucleus in buccal mucosa was within the norm for exposure both to chromium and to ethylene oxide. The micronucleus frequency in nasal mucosa was not altered in chromium platers, whereas a significant increase (p less than 0.01) in micronucleus was found in 2 out of 3 subjects involved in the accidental ethylene oxide leakage and a non-significant increase in micronucleus was found in the group chronically exposed to ethylene oxide. [R90] *Work practices as well as personal and environmental exposure levels were reported among ethylene oxide sterilizer operators in health care facilities in the province of Alberta, Canada. A survey was undertaken between October of 1985 and September of 1986 concerning the use of and exposure to ethylene oxide in 174 hospitals. The first part of the survey considered all hospitals with ethylene oxide sterilizers, inquiring about their use at the facility. The second part of the survey queries workers (14 men and 151 women) concerning their work history and health status. While no detectable levels of ethylene oxide were found in environmental samples, over half of the respondents stated they could smell ethylene oxide at work. While sampling results never indicated concentrations above the provincial 15 minute time weighted average short term exposure limit of 50 ppm, personal exposure concentrations and the use of portable sterilizers were positively associated with short term symptoms such as irritations of the mucous membranes and skin. Life style behavior and exposure to other chemical irritants were not considered in the course of this study. [R91] +A retrospective cohort study was conducted to examine the mortality experience of 2174 men employed between 1940 and 1978 by a large chemical company and who had been assigned to a chemical production department that used or produced ethylene oxide. Comparisons were made with the general United States population, the regional population, and with a group of 26,965 unexposed men from the same plants. Comparisons with general United States death rates showed fewer deaths than expected in the ethylene oxide group due to all causes and for total cancers. There was no statistically significant excess of deaths due to any cause. Seven deaths each due to leukemia and pancreatic cancer were observed with 3.0 and 4.1 deaths expected. Among the subcohort of men who worked where both average and peak exposure levels were probably highest, however, one death due to pancreatic cancer (0.9 expected) and no deaths due to leukemia were observed. Four of the seven who died from leukemia and six of the seven died from pancreatic cancer had been assigned to the chlorohydrin department where the potential for exposure to ethylene oxide is judged to have been low. The relative risk of death due to each disease was strongly related to duration of assignments to that department. When men who worked in the chlorohydrin department were excluded, there was no evidence for an association of exposure to ethylene oxide with pancreatic cancer or leukemia. Together with the failure to show independent ethylene oxide associations, the chlorohydrin department results suggest that leukemia and pancreatic cancer may have been associated primarily with production of ethylene chlorohydrin or propylene chlorohydrin, or both. These results emphasize the importance of examing additional concurrent asynchronous exposures among human populations exposed to ethylene oxide. [R92] *An epidemiological study was conducted in 55 subjects (mean age: 41) in hospitals to determine the prevalence of lens opacities and cataracts in workers exposed to ethylene oxide in six sterilization units. The relation between occupational exposure to ethylene oxide and white blood cell concentrations was also investigated. Lens opacities were observed in 19 of the 55 exposed. No link was found between the characteristics of the lens opacities and the characteristics of exposure. For cataracts, their prevalence differed significantly between the exposed (six of 21) and the non-exposed (0 of 16); there was no relation between their existence and overexposures. The risk of lens opacifications by ethylene oxide could also exist during chronic exposure to low concentrations. Linear relations were found between the logarithm of the cumulative exposure index and the logarithms of blood concentrations of polymorphoneutrophils. [R93] *A cohort study was carried out of mortality among 2876 men and women exposed to ethylene oxide during its manufacture and use in England and Wales. The study cohort included employees from three companies producing ethylene oxide and derivative compounds such as polyethylene glycols and ethoxylates, from one company that manufactured alkoxides from ethylene oxide and from eight hospitals with ethylene oxide sterilizing units. While industrial hygiene data were not available before 1977, since then the time weighted average exposures have been less than 5 ppm in almost all jobs and less than 1 ppm in many. Past exposures were probably somewhat higher. In contrast to other studies, no clear excess of leukemia was noted (three deaths occurred versus 2.09 expected), and no increase in the incidence of stomach cancer (five deaths occurred versus 5.95 expected) was observed. This lack of consistency with the results of earlier studies may be due to differences in exposure levels. Total cancer mortality was similar to that expected from national and local death rates from this disease. Small excesses were noted in some specific cancers, but their relevance to ethylene oxide exposure was doubtful. No excess of cardiovascular disease was found. While the results of this study did not exclude the possibility that ethylene oxide is a human carcinogen, they suggested that any risk of cancer from currently permitted occupational exposures is small. [R94] *Ethylene oxide is widely used to sterilize heat-sensitive materials. Acute and chronic neurogenic effects to the central and peripheral nervous system in man and animals have been described. A cross-sectional study of 25 hospital central supply workers exposed to low levels of ethylene oxide and 24 unexposed control workers was conducted. Subjects were tested with a neuropsychological screening battery by examiners blinded to exposure status. Results were reviewed independently by 2 neuropsychologists without knowledge of exposure. Subject status was categorized as normal, impaired, or disagreement (between the two neuropsychologists). There were more subjects concordantly judged as impaired in the exposed group than in the control group. Although limited by the cross-sectional study design and the global categorization, these findings suggest that central nervous system dysfunction and cognitive impairment may result from chronic ethylene oxide exposure in hospital central supply units. [R95] *Ethylene oxide is used to chemically sterilize heat-sensitive materials in hospitals. Neurotoxic effects of ethylene oxide have been described in animals and humans; cognitive deficits may be associated with chronic low level ethylene oxide exposure. In this study, hospital workers with chronic ethylene oxide exposure were compared with a non-exposed control group to detect neurological and neuropsychological abnormalities. Ethylene oxide breathing zone levels of up to 250 ppm in exposed subjects were reported. The exposed group had lower P300 amplitude in electroencephalographic (EEG) tests, bilaterally hypoactive distal deep tendon reflexes and poorer performance on neuropsychological tests involving psychomotor speed. Exposed subjects acknowledge more symptoms and higher levels of depression and anxiety. Nerve conduction velocities and EEG spectral analysis were simialr in both exposed and control groups as were scores on most psychological tests. [R96] HTOX: *A 43 yr old female licensed practical nurse, while sterilizing heat sensitive medical items, accidentally dropped and broke an ampule containing 17 gm epoxyethane. While disposing of the broken ampule, she began to experience nausea and stomach spasms. The exposure was estimated to have been of 2-3 min duration and not to have exceeded 500 ppm. Upon leaving the contaminated room, she became pale, lightheaded, and passed out for approximately 3-4 min. Convulsive movements of her arms and legs were noted during a 1-min period of apnea. She was given oxygen, began breathing, and awoke instantly without confusion or nausea. Approximately 3 min later she again felt nausea, stomach spasms, and lightheadedness and became apneic and passed out. Twitching of the extremities occurred and she was given oxygen again. Arterial blood gases, chest X rays, and routine laboratory measurements performed at that time were normal. During the 24 hr following discharge she continued to complain of random muscle twitches, nausea, and malaise. [R56, 666] *The presence of ethylene oxide in dialysis tubing has been suggested as a possible cause of allergic reactions in some patients. Ethylene oxide also is a pulmonary irritant when inhaled. It is too toxic to be applied topically as an antiseptic. [R54] *Three cases of hematopoietic cancer that had occurred been 1972 and 1977 /were reported/ in workers at a Swedish factory where 50% ethylene oxide and 50% methyl formate had been used since 1968 to sterilize hospital equipment. Attention had been drawn to the case cluster by the factory safety committee. One woman with chronic myeloid leukaemia and another with acute myelogenous leukaemia had worked in a storage hall where they were exposed for 8 hr per day to an estimated 20 plus or minus 10 (SD) ppm (36 plus or minus 18 mg/cu m) ethylene oxide. The third case was that of a man with primary macroglobulinemia (morbus Waldenstrom) who had been manager of the plant since 1965 and had been exposed to ethylene oxide for an estimated 3 hr per week. (The Working Group noted that Waldenstrom's macroglobulinemia is classified in ICD /International Classification of Diseases codes/ 10 as a malignant immunoproliferative disease.) [R97] *Two hundred and three workers employed for at least one year at /a Swedish factory where 50% ethylene oxide and 50% methyl formate had been used since 1968 to sterilize hospital equipment/ were subsequently followed up for mortality. During 1978-82, five deaths occurred (4.9 expected), of which four were from cancer (1.6 expected). Two of the deaths were from lymphatic and hematopoietic cancer (0.13 expected), but one of these decedents had been part of the original case cluster that had prompted the study. [R97] *A retrospective cohort study /was reported/ of 767 men employed at a chemical plant in eastern Texas, USA, between 1955 and 1977 where ethylene oxide was produced. All of the men had worked at the factory for at least five years and were potentially exposed to the compound. Potential exposure to ethylene oxide was determined by personnel at the company on the basis of work histories. In an industrial hygiene survey in all samples taken in the ethylene oxide production area contained less than 10 ppm (18 mg/cu m). Vital status was ascertained for more than 95% of cohort members from a combination of plant records, personal knowledge and telephone follow-up. Altogether, 46 deaths were recorded, whereas 80 were expected on the basis of US vital statistics. Death certificates were obtained for 42 of the 46 deceased subjects. Eleven deaths were from cancer (15.2 expected), and nonsignificant excesses were seen of cancers of the pancreas (3/0.8) and brain and central nervous system (2/0.7) and of Hodgkin's disease (2/0.4); no death from leukaemia was found. [R98] *18,254 employees at 14 US industrial plants where ethylene oxide had been used to sterilize medical supplies or spices or in the testing sterilizing equipment /were followed/. The plants were selected because they held adequate records on personnel and exposure and their workers had accumulated at least 400 person-years at risk before 1978. Only workers with at least three months of exposure to ethylene oxide were included in the cohort. Forty five percent of the cohort were male, 79% were white, 1,222 were sterilizer operators and 15,750 were employed before 1978. Analysis of 627 8 hr personal samples indicated that average exposure during 1976-85 was 4.3 ppm (7.7 mg/cu m) for sterilizer operators; the average level for other exposed workers, on the basis of 1,888 personal samples, was 2.0 ppm (3.6 mg/cu m). Many companies began to install engineering controls in 1978, and exposures before that year were thought to have been higher. There was no evidence of confounding exposure to other occupational carcinogens. The cohort was followed to 1987 through the national death index and records of the Social Security Administration, the Internal Revenue Service and the US Postal Service, and 95.5% were traced successfully. The expected numbers of deaths were calculated from rates in the US population, stratified according to age, race, sex and calendar year. In total, 1,177 cohort members had died (1,454.3 expected), including 40 for whom no death certificate was available. There were 343 deaths from cancer (380.3 expected). The observed and expect numbers of deaths were 36/33.8 from all lymphatic and hematopoietic cancer, including 8/5.3 from lymphosarcoma-reticulosarcoma (ICD9 200), 4/3.5 from Hodgkin's disease, 13/13.5 from leukaemia, 8/6.7 from non-Hodgkin's lymphoma (ICD9 202) and 3/5.1 from myeloma; 6/11.6 from cancer of the brain and nervous system; 11/11.6 from cancer of the stomach; 16/16-9 from cancer of the pancreas; 8/7.7 from cancer of the oesophagus; and 13/7.2 from cancer of the kidney. Mortality ratios for subjects first exposed before 1978 were virtually identical to those for the full cohort. No significant trend in mortality was observed in relation to duration of exposure, but the mortality ratios for leukaemia (1.79 based on five deaths) and non-Hodgkin's Lymphoma (1.92 based on five deaths) were higher after allowance for a latency of more than 20 years. Among the sterilizer operators, mortality ratios (and observed numbers of deaths) were 2.78 (two) for leukaemia and 6.68 (two) for lymphosarcoma/reticulosarcoma; no death from stomach cancer was seen. [R99] *Repeat plasma donors were studied to determine whether there was a relationship between allergic-type reactions during plasmapheresis and IgE-dependent sensitization to ethylene oxide gas used for sterilization of disposable fluid administration sets. Serums from 32 donors with allergic-type reactions and 84 donors who had no reactions but were exposed to the same materials and served as controls were tested for IgE antibodies to ethylene oxide. The results, expressed as an IgE ethylene oxide index, were greater than 2 in 78% of serums from donors with allergic and 12% of serums from controls. This association was significant (p < 0.0001). Reactivity of the antibodies was directed against an ethylene oxide-human serum albumin conjugate and not against human serum albumin carrier protein. IgG antibodies with ethylene oxide specificity also were present in the serums of repeat plasmapheresis donors. Each of seven rabbits immunized with an ethylene oxide-protein conjugate responded with a high serum level of antibody with ethylene oxide specificity. It was concluded that the residual ethylene oxide in fluid administration sets is immunogenic and may cause allergic reactions in plasma donors. [R100] *Chromosomal aberrations and micronuclei in lymphocytes were measured in workers exposed to propylene oxide in a factory producing alkylated starch, and in workers exposed to ethylene oxide in connection with sterilization of medical equipment. Adduct levels in hemoglobin were determined as a measure of in vivo doses of the two compounds. The levels of hydroxypropylvaline in propylene oxide exposed workers were correlated in estimated exposure doses. The levels of this adduct in the unexposed group were close to the detection limit of the method. The levels of hydroxyethylvaline, recorded in the propylene oxide-exposed group were consistent with earlier data on hemoglobin alkylation in occupationally unexposed subjects. The adduct measurements revealed increased levels of hydroxyethylvaline in the two subgroups of ethylene oxide-exposed workers, ie, assemblers with a low and sterilizers with a high exposure. According to expectation the subgroups differed in adduct levels. The results of the cytogenetic study showed that the clastogenic potency of propylene oxide was lower than that of ethylene oxide, since the propylene oxide-exposed individuals had lower frequencies of micronuclei and chromosomal breaks compared to the assemblers despite a lower adduct level in the last group. [R101] *Cases of human ethylene oxide (EtO) neuropathy were reviewed and the clinical features characterized. ... The 12 patients with EtO toxicity selected for review were each engaged ln sterilizing work with EtO in the factory or hospital. Sensorimotor neuropathy developed in two patients within 3 and 5 months of exposure. They had been repeatedly exposed to EtO for up to several hundred ppm. Complaints included muscle weakness hypesthesia and a tingling sensation in distal lower limbs although distal upper limbs were also sometimes involved. Ten of the 12 demonstrated muscle weakness in neurological examinations. Needle EMG revealed neurogenic changes in eight. Histological studies of the sural nerve biopsied in three patients demonstrated mild abnormalities. Cerebrospinal fluid studies showed elevated protein in two of six patients. ... [R102] *Mortality from cancer among workers exposed to ethylene oxide (EtO) has been studied in 10 distinct cohorts that include about 29800 workers and 2540 deaths. This paper presents a review and meta-analysis of these studies, primarily for leukemia, nonHodgkin's lymphoma, stomach cancer, pancreatic cancer, and cancer of the brain and nervous system. The magnitude and consistency of the standardized mortality ratios (SMRs) were evaluated for the individual and combined studies, as well as trends by intensity or frequency of exposure, by duration of exposure, and by latency (time since first exposure). Exposures to other workplace chemicals were examined as possible confounder variables. Three small studies ... initially suggested an association between EtO and leukemia, but ln seven subsequent studies the SMRs for leukemia have been much lower. For the combined studies the SMR = 1.06 (95% confidence interval (95% CI) 0.73-1.48). There was a slight suggestion of a trend by duration of exposure (p = 0-19) and a suggested incr with longer latency (p = 0.07), but there was no overall trend in risk of leukemia by intensity or frequency of exposure; nor did a cumulative exposure analysis in the largest study indicate a quantitative association. There was also an indication that ln two studies with Increased risks the workers had been exposed to other potential carcinogens. For non-Hodgkin's lymphoma there was a suggestive risk overall (SMR = 1.35, 95% CI 0.93-1.90). Breakdowns by exposure intensity or frequency, exposure duration, or latency did not indicate an association, but a positive trend by cumulative exposure (p = 0.05) was seen In the largest study. There was a suggested incr ln the overall SMR for stomach cancer (SMR = 1.28, 95% CI 0.98-1.65 (CI 0.73-2.26 when heterogeneity among the risk estimates was taken Into account)), but analyses by intensity or duration of exposure or cumulative exposure did not support a causal association for stomach cancer. The overall SMRs and exposure-response analyses did not indicate a risk from EtO for pancreatic cancer (SMR = 0.98), brain and nervous system cancer (SMR = 0.89), or total cancer (SMR = 0.94). Although the current data do not provide consistent and convincing evidence that EtO causes leukemia or non-Hodgkin's lymphoma, the issues are not resolved and await further studies of exposed populations. [R103] *Ethylene oxide (EtO) induced mutations in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene were characterized in 28 independently derived 6-thioguanine resistant human diploid fibroblast clones using polymerase chain reaction based techniques and Southern blot analysis. Sequence analysis revealed one single base pair deletion and 13 base substitutions nine of which were transversions: five AT-TA three GC-TA and one GC-CG. Four mutants were found to have GC-AT transitions. Seven of the point mutations caused splicing errors. Six occurred in splice site sequences and one created a new splice acceptor site 16 bp upstream of exon 9. Three splice mutations were localized at the same site in the splice donor sequence of intron 8. Fourteen mutants had large HPRT gene deletions. In seven mutants the entire HPRT gene was deleted. The remaining deletion mutants had a truncated HPRT gene where one or several exons were lost. These results show that EtO induces many different kinds of HPRT mutations, among which as many as 50% are large deletions. [R104] *A cohort of 1971 chemical workers licensed to handle ethylene oxide was followed up retrospectively from 1940 to 1984 and the vital status of each subject was ascertained. No quantitative information on exposure was available and therefore cohort members were considered as presumably exposed to ethylene oxide. The cohort comprised 637 subjects allowed to handle only ethylene oxide and 1334 subjects who obtained a license valid for ethylene oxide as well as other toxic gases. Potential confounding arising from the exposure to these other chemical agents was taken into consideration. Causes of death were found from death certificates and comparisons of mortality were made with the general population of the region where cohort members were resident. Seventy six deaths were reported whereas 98.8 were expected; the difference was statistically significant. The number of malignancies for any site exceeded the expected number (standardized mortality ratio (SMR) = 130; 43 observed deaths; 95% confidence interval (95% CI) 94-175) and approached statistical significance. For all considered cancer sites the SMRs were higher than 100 but the excess was only significant p < 0.05, two sided test for lymphosarcoma and reticulosarcoma ICD-9 = 200; SMR = 682; four observed deaths; (95% CI 186-1745) The excess of cases for all cancers of hematopoietic tissue (ICD-9)= 200-208) also approached statistical significance (SMR = 250; six observed deaths; 95% CI 91-544). [R105] NTOX: *Perturbations in bone marrow and peripherial blood elements of mice exposed to ethylene oxide were evaluated. Mice exposed to 225 ppm ethylene oxide for 6 hr/day were removed for analysis 1, 2, 4, 8, and 14 days and 4, 6, 8, and 10 wk (5 day/week). Blood analysis included blood cell counts, hemoglobin determination, and hematocrit. Bone marrow evaluation included stem-cell assay (CFU-S) or flow cytometry analysis, cell cycle and B-cell analysis. Perturbations of peripheral leukocytes occurred after one exposure. After multiple exposures, hematocrit, red cell number, and hemoglobin were generally depressed, with transient compensatory bursts, and bone marrow cellularity and CFU-S were below normal. White cell numbers fluctuated dramatically during the exposure period. There was a shift in the numbers of granulocytes in the bone marrow followed by replacement and relative lymphocyte deficit, especially pronounced at 10 wk. [R106] *Female mice of hybrid stocks (C3H x C57BL)F1 and (SEC x C57BL)F1 were exposed to 300, 1200, or 1800 ppm of ethylene oxide for various exposure periods. Exposed females were either mated before or after treatment to male mice (C3H x C57BL)F1 and killed on the 17th day after observation of a vaginal plug. Fetal abnormalities and mortality were observed in both treatment groups. Early developmental stages of the zygote appears to be more sensitive to the action of ethylene oxide than later stages. [R107] *... REPEATED EXPOSURES OF RATS @ 400 PPM CAUSED RESP IRRITATION, WT LOSS, WEAKNESS AND DEATH. ... REPEATED EXPOSURES OF DOGS, RATS AND MICE @ 100 PPM FOR SIX MONTHS CAUSED NO SIGNIFICANT EFFECTS; HOWEVER, THERE WAS A SLIGHT ANEMIA IN DOGS. [R108, 1986.256] *... THERE WAS IRRITATION OF RESP PASSAGES, INCLUDING THE LUNGS, IN ANIMALS REPEATEDLY EXPOSED TO 204, 357 and 841 PPM ... IN ADDITION THERE WERE GROWTH DEPRESSIONS, ORGAN WT CHANGES AND ORGANIC INJURY TO THE LIVERS, KIDNEYS, ADRENALS, AND TESTES OF RATS AND GUINEA PIGS. [R108, 1986.256] *Exposure of animals to high concn of the gas has caused lacrimation in cats, and inflammation of the conjunctiva and clouding of the cornea in dogs, cats, rabbits, and especially guinea pigs. [R77, 419] *30 8-WK OLD FEMALE ICR/HA SWISS MICE WERE PAINTED THRICE WEEKLY ON CLIPPED DORSAL SKIN WITH APPROX 0.1 ML OF 10% SOLN ... IN ACETONE FOR LIFE. MEDIAN SURVIVAL TIME WAS 493 DAYS; NO SKIN TUMORS WERE OBSERVED. [R109] *12 RATS RECEIVED MAX TOTAL DOSES OF 1 G/KG BODY WT ... IN ARACHIS OIL BY SC INJECTION ... PERIOD OF TREATMENT WAS 94 DAYS. ANIMALS WERE OBSERVED FOR LIFETIME; NO LOCAL SARCOMAS WERE OBSERVED. [R109] *... 86 FEMALE SWISS-WEBSTER MICE, GERM-FREE AND INBRED, WERE EXPOSED TO ... ETHYLENE OXIDE TREATED GROUND-CORNCOB BEDDING FOR 150 DAYS AND THEN TO UNTREATED BEDDING FOR LIFESPAN (MAXIMAL, 900 DAYS); 63 MICE DEVELOPED TUMORS @ VARIOUS SITES. NO TUMORS WERE REPORTED IN 83 FEMALE MICE, 100-600 DAYS OLD, WHICH WERE NOT EXPOSED TO TREATED BEDDING ... (THIS OBSERVATION DOES NOT ALLOW AN EVALUATION OF THE CARCINOGENICITY OF ETHYLENE OXIDE). [R109] *EXPOSURE OF MALE LONG-EVANS RATS FOR 4 HR TO 1.83 G/CU M (1000 PPM) ETHYLENE OXIDE PRODUCED DOMINANT LETHAL MUTATIONS; CHROMOSOME ABERRATIONS WERE OBSERVED IN BONE-MARROW CELLS OF MALE LONG-EVANS RATS EXPOSED TO 0.45 G/CU M (250 PPM) ETHYLENE OXIDE FOR 7 HR PER DAY FOR 3 DAYS. [R110] *TERATOGENIC POTENTIAL OF IV ADMIN WAS ASSESSED IN CD-1 MOUSE @ DOSE 0, 75, and 150 MG/KG @ 4 PERIODS DURING GESTATION. RESULTS INDICATE TERATOGENICITY @ LEVELS 500-5000 TIMES ABOVE EXPOSURE LIMITS CURRENTLY PROPOSED BY FDA FOR ETO RESIDUES IN MEDICAL DEVICES. [R111] *Ethylene oxide was reported positive for mutagenicity test performed on bacteria, Neurospora, Drosophila, mammalian cells. [R112] *Statistically significant increases in mononuclear cell leukemia in female Fischer rats increased linearly with dose. Among male Fischer 344 rats in the same experiment, ethylene oxide induced peritoneal mesothelioma which originated in the testicular mesothelium. [R113] *Rats and mice exposed to ethylene oxide had significantly increased numbers of polychromatic erythrocytes containing micronuclei. [R114] */Ethylene oxide/ was injected iv on several days during organogenesis in the mouse. Skeletal malformations occurred in fetuses whose mother received 150 mg/kg which produced maternal toxicity. Doses of 75 mg/kg caused no defects. Rats /were/ exposed on days 6-15 of gestation for 6 hr daily to 10-100 ppm. At the highest dose, fetal growth retardation occurred but there was no increase in congenital defects. [R115] *Ethylene oxide was administered intragastrically by gavage at 2 dosages, 30 and 7.5 mg/kg body weight to groups of 50 female Sprague-Dawley rats twice weekly for a period of nearly 3 years using salad oil as the solvent. It induced local tumors, mainly squamous cell carcinomas of the forestomach, dependent on the dosage. The first tumor occurred in the 79th week. The following tumor rates resulted 62 and 16%. In addition carcinomata in situ, papillomas and reactive changes of the squamous epithelium of the forestomach were observed in other animals, but ethylene oxide did not induce tumors at sites away from the point of administration. [R116] *Groups of F344 rats of each sex were exposed to either ethylene oxide vapor (concentrations of 100, 33 or 10 ppm) or to room air 6 hr daily, 5 days/wk, for up to 2 yr. Three representative sections of the brain from each rat were evaluated. Of 23 primary brain tumors which were found, 2 were in control animals. Increased numbers of brain tumors were seen in 100 ppm and 33 ppm ethylene oxide exposed male and female rats. Significant trend analyses were found for both males and females, indicating that ethylene exposure > 10 ppm was related to the development of these brain tumors. [R117] *In a dose-response study, male mice were exposed to inhalation of ethylene oxide for 4 consecutive days. Mice were exposed for 6 hr per day to 300 ppm, 400 ppm, or 500 ppm ethylene oxide for a daily total of 1,800, 2,400, or 3,000 ppm per hr, respectively. In the dose-rate study, mice were given a total exposure of 1,800 ppm per hr per day delivered either at 300 ppm in 6 hr, 600 ppm in 3 hr, or 1,200 ppm in 1.5 hr. Quantitation of dominant-lethal responses was made on matings involving sperm exposed as late spermatids and early spermatozoa, the most sensitive stages to ethylene oxide. In the dose-response study, a dose related increase in dominant-lethal mutations were observed, the dose-response curve proved to be nonlinear. In the dose-rate study, increasing the exposure concentrations resulted in increased dominant-lethal responses. [R118] *The offspring of DBA/2J male mice exposed to ethylene oxide (ETO) by inhalation had an increased incidence of both dominant visible and electrophoretically detected mutations over that found in control populations. The progeny at risk were obtained from matings during the exposure period and were the products of germ cells that were exposed throughout the entire spermatogenic process. Apparently, male germ cells repeatedly exposed to ethylene oxide during spermatogenesis are susceptible to ethylene oxide induced transmissible damage. [R119] *Ethylene oxide at 357 ppm 35 hr/week for 12 weeks produced a sensorimotor neuropathy in rats, rabbits, and monkeys, but not guinea pigs or mice. Continued exposure resulted in paralysis and muscle atrophy of the hindlimbs. At 204 ppm, 35 hr/wk for 32 weeks, rabbits and monkeys, but not guinea pigs, rats, or mice, developed a clinical neuropathy. The monkeys had decreased tendon reflexes, loss of withdrawal from superficial pain over the hindquarters, partial paralysis, and muscle atrophy indicative of toxic axonopathy. A positive Babinski reflex in these monkeys indicated that upper motor neurons or their axons were also affected. Dogs showed occasional tremors, transient weakness, atrophy and fatty replacement of skeletal muscle following ethylene oxide exposures of 292 ppm, 30 hr/week for 6 weeks. Levels of about 100 ppm repeatedly were without neurotoxicity in rats, rabbits, guinea pigs, mice, dogs, and monkeys. [R120, 87] *The results of efforts to identify and quantify macromolecular adducts of ethylene oxide, to determine the source and significance of background levels of these adducts, and to generate molecular dosimetry data on these adducts are reviewed. A time-course study was conducted to investigated the formation and persistence of 7-(2-hydroxyethyl) guanine in various tissues of rats exposed to ethylene oxide by inhalation, providing information necessary for designing investigations on the molecular dosimetry of adducts of ethylene oxide. Male F344 rats were exposed 6 hr/day for up to 4 weeks (5 days/wk) to 300 ppm ethylene oxide by inhalation. Another set of rats was exposed for 4 weeks to 300 ppm ethylene oxide, and then killed 1-10 days cessation of exposures. DNA samples from control and treated rats were analyzed for 7-(2-hydroxyethyl)guanine using neutral thermal hydrolysis, HPLC separation, and fluorescence detection. The adduct was detectable in all tissues of treated rats following 1 day of ethylene oxide exposure and increased approximately linearly for 3-5 days before the rate of increase began to level off. Concentrations of 7-(2-hydroxyethyl)guanine was greatest in brain, but the extent of formation was similar in all tissues studied. The adduct disappeared slowly from DNA, with an apparent half-life of approx 7 days. The shape of the formation curve and the in vivo half-life indicate that 7-(2-hydroxyethyl)guanine will approach steady-state concentrations in rat DNA by 28 days of ethylene oxide exposure. The similarity in 7-(2-hydroxyethyl)guanine formation in target and nontarget tissues indicates that the tissue specificity for tumor induction is due to factors in addition to DNA-adduct. [R121] *The utility of hemoglobin as a DNA monitor in cases of exposure to ethylene oxide was investigated in rats via use of an inhalation system with dynamically generated test atmospheres. Animals were exposed to atmospheres containing 1, 10, or 33 ppm radiolabeled ethylene oxide for 6 hours. After exposure, the animals were sacrificed and the organs removed for isolation of DNA. DNA hydrolysates and adducts were further analyzed by high pressure liquid chromatography. Globin was isolated from pooled erythrocytes. The relationship between inhalation doses of ethylene oxide and alkylation DNA and globin was described in terms of moles of adduct per gram of DNA or globin. Linear relationships were observed between formation of hydroxyethyl adducts in both DNA and hemoglobin and the exposure concentration of radiolabeled ethylene oxide. Alkylation frequencies of DNA were similar in all tissues studied with exception of testis; corresponding alkylation in hemoglobin was not significantly different. Results indicate that the results support the suggestion that, in the case of ethylene oxide exposure, determination of the hemoglobin dose in vivo is a valid indicator of the dose delivered to DNA. [R122] *Exposure of female mice to ethylene oxide by inhalation 1 or 6 hr after mating produced not only multitemporal death of conceptuses but also high rates of abnormalities among surviving fetuses. In contrast, only marginal effects were observed when females were exposed 9 or 25 hr after mating. The abnormalities found among 17 day gestation live fetuses were predominated by hydrops and eye defects, which, together, constitute 54% of all anomalies. Most of the remaining anomalies were distributed among 5 other types: small size, cleft palate, and cardiac, abdominal wall, or extremity and/or tail defects. In a follow-up study the fetuses of females treated 6 hr postmating were examined at 11-15 days gestation and the progression of fetal death and of malformations was studied. Results indicate that the expression of most fetal anomalies does not become apparent until late in gestation. Several of these induced anomalies are similar to common human sporadic birth defects. This new class of experimentally induced fetal anomalies provides a new avenue for investigating zygotic biology and a system for studying the progression of aberrant development. [R123] *Wistar male and female rats were exposed to ethylene oxide at a concentration of 250 ppm, 6 hours a day, 5 days a week for 17 weeks simultaneously, and the sex difference of anemia induced by ethylene oxide was investigated. Hemoglobin concentrations of both the male and female exposed groups were decreased when compared with each control group, and the anemia in the female exposed group was more severe than that in the male exposed group. Absolute spleen weight increased only in the female exposed group. We have already reported that a decrease of the glutathione reductase activity in the erythrocyte plays an important role in the ethylene oxide induced anemia. In the present study, the activity in both male and female exposed groups decreased when compared with each control group, and there was no sex difference in the degree of the decrease. From these observations, /it was/ concluded that there was a sex difference in the ethylene oxide induced anemia. [R124] *The effect of chronic inhalation of ethylene oxide on urinary coproporphyrin and delta- aminolevulinic acid were studies. When Wistar male rats were exposed to 500 ppm ethylene oxide three times a week, daily urine volume was increased by 200-300% from the first week to the fifth week of the experimental period. After exposure, daily coproprorphyrin excretion and urinary coproporphyrin per mg of creatinine increased by 250% and 141%, respectively. On the other hand, daily excretion of delta-aminolevulinic acid in urine tended to increase but did not increase significantly by creatinine correction. This /may be/ the first report of ethylene oxide induced experimental porphyria. [R125] *Male Wistar rats were exposed to ethylene oxide at concentrations of 50, 100, or 250 ppm for six hours a day, on five days a week for 13 weeks. Dose effect relations of inhaled ethylene oxide on spermatogenesis were evaluated from testicular and epididymal weights, histopathological changes and lactate dehydrogenase X (LDH X) activity in the testis, and sperm counts and sperm head abnormalities in the epididymis. At 250 ppm, a decrease in epididymal weights, slight degenerations in the seminiferous tubules, decreased sperm counts, and increased numbers of abnormal sperm heads in the tail of the epididymis were found; these were not seen at lower doses. When the abnormal sperm heads were classified into immature types and teratic types, the number of immature heads increased only at 250 ppm. On the other hand, the teratic type had increased at doses of 50 and 100 ppm ethylene oxide when compared with the control group. Hence, subchronic inhalation of ethylene oxide at low concentrations affects spermatogenesis in rats. [R126] *The effects of systemic toxicity including reproductive toxicity of ethylene oxide on female rats were studied. When Wistar female rats were exposed to 250 ppm of ethylene oxide for six hours a day, five days a week for ten weeks, they showed inhibition of body weight gain and paralysis of the hindlegs. Hematogological examination revealed macrocytic and normochromic anemia with high reticulocyte counts. The estrus cycle of the exposed group was prolonged and the percentage of the diestrus stage increased. There was no atrophy in the ovary or the uterus. However, the activity of glutathione reductase in the ovary decreased by 18% and that of glutathione-S-transferase increased by 30%. These results indicate that ethylene oxide has a similar effect on both female and male rats and that the female reproductive system is also affected. [R127] *The toxic effects of residual ethylene oxide, a frequently used gas-sterilant, on embryos either frozen for long-term purposes or stored acutely for 30 min to 9 hr in a fresh condition in 0.25 ml straw containers were evaluated. In Experiment 1, fresh embryos were frozen (using conventional technology) in straws previously aerated for 0 hr to 8 mo after ethylene oxide sterilization. With the exception of the 8 mo group in which survival and quality ratings were depressed, embryo viability was not affected significantly by short-term prefreeze and post-thaw exposure to ethylene oxide residues. Experiment 2 was conducted to analyze the influence of prefreeze exposure to ethylene oxide residues on embryo development in vitro for embryos temporarily stored in previously sterilized straws aerated for different intervals. Compared to non-ethylene oxide sterilized control straws, the development, quality, and viability of embryos exposed to ethylene oxide-treated straws were compromised (p less than 0.05) as the aeration interval decreased and the exposure interval increased. The combined results of both experiments indicate that ethylene oxide-treated straws can be used to cryopreserve gametes efficiently, but only if the aeration interval is greater than or equal to 72 hr and the prefreeze duration of exposure is less than or equal to 3 hr. [R128] *Thirty B6C3F1 mice of both sexes that were exposed at ethylene oxide vapor concentrations of 1, 10, 50, 100, or 250 ppm, 6 hours/day, 5 days/week for 10 to 11 weeks showed no effects on survival, body weight, or histologic sections of various organs. Neuromuscular toxicity was observed at the three highest exposure levels, and both sexes in the 250 ppm exposure group had a statistically significant increase in hunched posture, reduced locomotion, and righting reflex. These symptoms were also observed in some animals of both sexes exposed at 50 or 100 ppm. Neuromuscular effects appeared to be the most sensitive indicator of exposure to ethylene oxide in this study. [R129, 1991.618] *When ethylene oxide/saline solutions of varied concentrations (0.1% to > 20%) were applied repeatedly over a 6-hour period to the eyes of rabbits, a dose-dependent increase in congestion, swelling, discharge, iritis, and corneal cloudiness was observed. These effects were an indication of the irritating effect of ethylene oxide on mucous membranes and corneal epithelium. The 0.1% ethylene oxide concentration was the maximum, nondamaging concentration of this chemical for the 6 hour exposure period. [R129, 1991.618] *Infusion of ethylene oxide into the aorta of rats caused a significant decrease (approximately 30%) in kidney glomerular filtration rates, resulting in kidney dysfunction. [R129, 1991.617] *Pathological examination of tissues from mice, rats, and guinea pigs that died after lethal exposure to ethylene oxide revealed adverse effects that included lung congestion, hyperemia of the liver and kidneys, and gray discoloration of the liver. Animals that experienced delayed death had emphysema of the lungs, fatty degeneration of the liver, cloudy swelling of the kidney tubules, and congestion of the spleen and brain, all believed to be a cause or contributing to these deaths. [R129, 1991.617] *Mice, rats, guinea pigs, rabbits, and dogs exposed to lethal concentrations of ethylene oxide had symptoms of mucous membrane irritation, central nervous system (CNS) depression, lacrimation, nasal discharge, salivation, nausea, vomiting, diarrhea, respiratory irritation, incoordination, and convulsions. Surviving animals showed subsequent bronchitis, pneumonia, and loss of appetite with delayed symptoms of apathy, dyspnea, vomiting, paralysis (particularly of the hindquarters), and periodic convulsions, followed eventually by death. Rapid deaths were usually associated with lung edema; delayed deaths frequently resulted from secondary infections in the lungs, although general systemic intoxication is also believed to be associated with these delayed deaths. [R129, 1991.617] *... Fischer 344 rats, 120 rats/sex/group, /were exposed/ at 10, 30, or 100 ppm ethylene oxide vapor, 6 hours/day, 5 days/week for 2 years. Two groups of controls were exposed to untreated air under similar conditions. Ten animals each at 6 and 12 months and 20 animals at 18 months were sacrificed to determine possible treatment-related effects. Both interim and terminal evaluations included hematology, serum clinical chemistry, urinalysis, body weight, organ weight, bone marrow cytogenicity studies, and gross and histologic examinations. Histopathologic examinations of rat tissue from the 100 ppm ethylene oxide exposed animals and the control group were performed at 6, 12, and 18 month necropsy intervals. At the 24 month sacrifice, histopathologic examination was made on all tissues of the 100 ppm exposed rats as well as controls and on potential target tissues, other selected tissues, and tissues with gross lesions in the 10 and 33 ppm exposed animals. The six types of tumors found in the ethylene oxide exposed rats that appear to be treatment related are subcutaneous fibroma, peritoneal mesothelioma, pancreatic adenoma, pituitary adenoma, brain neoplasm, and mononuclear cell leukemia. In this 2-year study, a dose-related increased incidence of mononuclear cell leukemia was found in both sexes. It was significant in the 100 and 33 ppm exposed females from the 18th or 19th month onward. A trend test revealed a treatment-related response in both sexes. An increased incidence of peritoneal mesotheliomas originating from the testicular mesothelium was found in males exposed at 33 and 100 ppm from the 23rd month onwards and an increased incidence of subcutaneous fibroma in males surviving the 24-month, 100 ppm exposures. There was no increased incidence of pituitary tumors, although they appeared earlier in the 100 ppm exposed group. [R129, 1991.618] *No specific testicular damage was seen in test animals exposed at nontoxic doses of ethylene oxide. When maternally toxic doses of ethylene oxide were administered intravenously in mice, embryo and fetal toxicity were found. Pregnant rats inhaling ethylene oxide had a reduction in fetal weight but no teratogenic effects. [R129, 1991.619] *Earlier studies ... revealed that ethylene oxide or ethyl methanesulfonate induced high frequencies of midgestation and late fetal deaths and of malformations among some of the surviving fetuses when female mice were exposed at the time of fertilization of their eggs or during the early pronuclear stage of the zygote. Effects of the two mutagens are virtually identical. Thus ln investigating the mechanisms responsible for the dramatic effects ln the early pronuclear zygotes the two compounds were used interchangeably in the experiments. First a reciprocal zygote-transfer study was conducted in order to determine whether the effect is directly on the zygotes or Indirectly through maternal toxicity. And second cytogenetic analyses of pronuclear metaphases early cleavage embryos and midgestation fetuses were carried out. The zygote transplantation experiment rules out maternal toxicity as a factor ln the fetal maldevelopment. Together with the strict stage specifically observed in the earlier studies this result points to a genetic cause for the abnormalities. However the cytogenetic studies failed to show structural or numerical chromosome aberrations. Since intragenic base changes and deletions may also be ruled out it appears that the lesions in question induced In zygotes by the two mutagens are different from conventional ones and therefore could be a novel one ln experimental mammalian mutagenesis. [R130] *A ... 2-year carcinogenic study involved male Fischer 344 rats (80 in each group) and 12 Cynomolgus-monkeys per group exposed at either 50 or 100 ppm ethylene oxide 7 hours/day, 5 days/week for 24 months. Rats exposed at 50 ppm had a significantly increased incidence of mononuclear cell leukemia. The absence of a dose-response relationship was attributed to an increased mortality rate for the rats exposed at 100 ppm. Peritoneal mesotheliomas originating from the testicular mesothelium and mixed cell gliomas in the brain were found in a dose related increased incidence that was statistically significant for the 100 ppm exposure group. Exposures at the 50 and 100 ppm concentrations also reduced body weight gain and had an adverse effect upon the survival rate of the rats compared to the controls. Mortality was dose-dependent. Peritoneal mesotheliomas and gliomas are tumor types that can be found in humans. The 50 or 100 ppm exposed monkeys did not show any significant changes in hematological, clinical or urine chemistry, or ophthalmological parameters. At 100 ppm, nerve conduction velocities were decreased, and evidence of neurotoxicity and demyelination was noted in the 50 ppm and 100 ppm exposure groups. Sperm counts and motility were also reduced, and both exposure concentrations caused significant increases in the incidence of sister-chromatid exchanges (SCE) and chromosomal aberrations. [R129, 1991.618] NTOX: *... Monkeys /were exposed/ at 50 or 100 ppm ethylene oxide for 7 hours/day, 5 days/week for 2 years. ... Data /were collected/ in 1987 for sister chromatid exchanges (SCE) in peripheral blood lymphocytes and compared these data with those generated immediately prior to cessation of the 2 year exposure in 1981. Ethylene oxide induced SCE persisted at levels significantly higher than those of the nonexposed controls. These findings indicate that long lived lymphocytes may not be efficient with repair of the ethylene oxide induced lesions which produce SCE. [R129, 1991.619] *Male mice were exposed to ethylene oxide for 6 hours/day on 4 consecutive days at 300, 400, or 500 ppm for a daily total of 1800, 2400, or 3000 ppm hours (total exposures of 7200, 9600, and 12,000 ppm hours), respectively. A dose related increase in dominant-lethal mutations was observed; the dose response curve proved to be nonlinear. In a dose rate study, mice were given a total exposure of 1800 ppm hours per day for 4 consecutive days. This exposure was delivered at 300 ppm for 6 hours, 600 ppm for 3 hours, or 1200 ppm for 1.5 hours. Increasing the exposure concentrations resulted in increased dominant lethal responses even when the total dose was the same. [R129, 1991.619] *When freshly prepared aqueous solutions (2 to 5 percent) were injected intravenously into dogs, the LD50 was found to be about 125 mg/kg. A dose of 30 mg/kg or more usually caused vomiting and defecation for about 2 hr, followed by weakness and flaccidity, usually apparent in the hind limbs first. Doses up to 100 mg/kg in dogs under barbiturate anesthesia caused no apparent changes in blood pressure or cardiac rate. Respiration is adequate until terminal stages, when it becomes labored and cyanosis develops. Tonic extensor spasm may precede respiratory cessation. Since the heart usually beats after all reflexes disappear, death is believed due to respiratory failure . [R36, 2172] *... In aqueous solution the maximum concentration that could be applied externally to the ... /eyes of rabbits/, one drop every 10 minutes for 6 hours, without causing damage to the conjunctiva was 0.1%, to the cornea was 1%, and to the lens or retina was 20%. ... /Also/ if the aqueous humor was replaced once with an aqueous solution of ethylene oxide the maximum nondamaging concentration for the iris and lens was 0.1%, and for the cornea was 1%. At higher concentrations, damage consisted of irreversible opacities of cornea and lens. [R77, 100] *Ethylene oxide is a classical mutagen and a carcinogen based on evidence from studies in experimental animals. Chinese hamster V79 cells were treated for 2 hr with gaseous ethylene oxide, in sealed treatment chambers, and assayed for survival and mutagenic response by analysis of induced resistance to 6-thioguanine or ouabain. Significant numbers of mutants were produced at both genetic markers by 1,250-7,500 ppm ethylene oxide. Similarly, primary Syrian hamster embryo cells were treated for 2 or 20 hr with gaseous ethylene oxide in sealed treatment chambers and subsequently assayed for survival and increased sensitivity to SA7 virus transformation. Treatment concentrations extended from toxic to several nontoxic concentrations. After 2 hr ethylene oxide treatment at 625-2,500 ppm a significant enhancement of virus transformation was observed. At 20 hr after treatment no enhancement was observed. Treatment of hamster cells with ethylene oxide in both bioassay systems yielded concentration-related, quantitative results. [R131] *In mice exposed by inhalation for 5 hr/day, 5 days/week, for 10 weeks to 250, 100, 50, 10, or 0 ppm epoxyethane in air, clinical significant pathological findings were limited to the group exposed to 250 ppm. These findings included minimal decreases in red blood cell count, packed cell volume, and hemoglobin; decreased testicular and spleen weights; and increased liver weight. Abnormal pinch and righting reflexes, posture, and locomotion were also observed in mice exposed to 250 ppm. However, histological sections of the liver, testis, bone marrow, brain, and spleen taken from these mice were normal. [R56, 664] *Groups of 120 male and 120 female Fischer 344 rats, eight weeks of age, were exposed by inhalation to ethylene oxide (purity, > 99.9%) vapor at 10, 33 or 100 ppm (18, 59 or 180 mg/cu m) for 6 hr per day on five days per week for two years. Two control groups, each of 120 male and 120 female rats, were exposed in inhalation chambers to room air. All animals that died or were killed when moribund and those killed at scheduled intervals of 6, 12, 18 an 24-25 months were examined. During month 15 of exposure, mortality increased in both treated and control groups due to a viral sialodacryoadenitis. Mortality was higher in the groups inhaling 33 and 100 ppm ethylene oxide than in the other groups and was more frequent in females than in males near the fifteenth month. Up to 18 months of exposure, no significant increase in tumor incidence was observed. In treated rats killed after 18 months, the incidence of tumors in the brain classified as gliomas, malignant reticulosis and granular-cell tumors was increased for animals of each sex. The incidences of glioma among rats killed at 18 and 24-25 months were: males: 1/181 (controls), 0/92 (10 ppm), 3/86 (33 ppm) and 6/87 (100 ppm) (p < 0.05, trend analysis and Fisher's exact test for high dose versus control); and females: 0/187 (controls), 1/94 (10 ppm), 2/90 (33 ppm) and 2/78 (100 ppm) (p < 0.05, trend analysis). In females killed after 24 months of exposure mononuclear-cell leukaemia was found in 5/60 (control I), 6/56 (control II), 11/54 (10 ppm), 14/48 (33 ppm) and 15/26 (100 ppm) animals; the incidence of leukaemia was reported ... to be significantly increased in the 100 ppm group (p < 0.001) and in a mortality adjusted trend test (p < 0.005). In males, mononuclear-cell leukaemia was found in 5/48 (control I), 8/49 (control II), 9/51 (10 ppm), 12/39 (33 ppm) and 9/30 (100 ppm) animal (p < 0.05 in a mortality adjusted trend test). Peritoneal mesotheliomas originating in the testicular serosa were found in 1/48 (control I), 1/49 (control II), 2/51 (10 ppm), 4/39 (33 ppm) and 4/30 (100 ppm) males (p < 0.005 trend test). The incidence of subcutaneous fibromas in male rats of the high-dose group was also significantly increased: 1/48 (control I) 2/49 (control II), 9/51 (10 ppm), 1/39 (33 ppm) and 11/30 (100 ppm) (p < 0.001). [R132] *The effects of repeated exposure to ethylene oxide on lipid peroxidation and glutathione metabolism in both rat liver and brain were examined. Increased levels of malondialdehyde in the liver were observed after 6 and 13 weeks of exposure to ethylene oxide. The increased level of malondialdehyde observed in the hepatic homogenates of the treated rats reflected that of the microsomal fraction. On the other hand, no change in the level of malondialdehyde was detected in the brain of rats either at a 6- or 13-week treatment. Glutathione reductase activity was found to decrease at 6 or 13 weeks in liver and brain of treated rats. Both reduced and oxidized forms of glutathione in homogenates of liver and brain obtained from treated rats were, however, similar to those of the control at 40 hr after the last exposure in individual experiments. To elucidate the cause of lipid peroxidation, the time course of glutathione content after exposure with ethylene oxide were studied in more detail. Significant decreases in both GSH and GSSG content in these organs were detected shortly after exposure to ethylene oxide and their levels recovered gradually with time and reached the control values at 40 hr in the liver, although the changes were less significant in the brain as compared with those in the liver. These results suggest that enhancement of lipid peroxidation in the microsomal fraction of the liver after repeated exposure to ethylene oxide may possibly arise from repeated depletions of glutathione to certain critical levels and less removal of lipid peroxidation. [R133] *This paper describes a dominant neurological mutation identified among the progeny of a male parent treated with ethylene oxide. The defects observed in the heterozygous mutant include: head tossing, poor limb coordination, and corneal clouding. Both the behavior and ocular manifestations of the mutant syndrome worsen progressively as the affected animals grow older. The mutant animals swim poorly, although they do orient themselves in reference to the surface of the water. Breeding in general is poor. Very small litter sizes result when heterozygous animals of either sex are mated to normal mice. Many male carriers are functionally sterile. All mutant animals had abnormal karyotypes. The original carrier mouse had a translocation between chromosomes 4 and 17, which was also present in all but one mutant animal. The exceptional animal, which showed all mutant behavior characteristics, had 41 chromosomes, which included two normal 4 and 17 homologs and the small 417 translocation chromosome. Karyotypes of unaffected siblings of mutants were normal. ... [R134] *Male Fischer and B6C3Fl mice (10/species/group) were exposed to ethylene 6 hr/day, 5 days/week, for 4 weeks. The ethylene target concentrations were 0, 40, 1000, and 3000 ppm. An ethylene oxide (EO) control group for each species was exposed under the same conditions at a target concentration of 200 ppm. Bone marrow was collected approximately 24 hr after the final exposure. Polychromatic erythrocyte (PCE) to normochromatic erythrocyte (NCE) ratios were determined and 2000 PCE/animal were scored for the presence of micronuclei. Ethylene did not produce statistically significant, exposure-related increases in the frequency of micronucleated PCE (MNPCE) in the bone marrow of either rats or mice when compared to air exposed control animals. As expected, EO exposure resulted in significant increases in the frequencies of MNPCE in both species. [R135] +... Conclusions: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity for B6C3F1 mice as indicated by dose related incr incidences of benign or malignant neoplasms of the lung and benign neoplasms of the harderian gland in both male and female B6C3F1 mice following exposure to ethylene oxide vapors at 50 and 100 ppm. In female mice, ethylene oxide caused additional malignant neoplasms of the uterus, mammary gland, and hematopoietic system (lymphoma). [R136] HTXV: *No effect level: 5-10 ppm, during 10 yr; severe toxic effects: 60 min 250 ppm= 450 mg/cu m; symptoms of illness: 100 ppm= 180 mg/cu m; unsatisfactory > 10 ppm= 18 mg/cu m [R43, p. 654-655] NTXV: *LC50 Rat 1460 ppm (Exposure: 882-2298 ppm/4 hr). Effects were ocular and respiratory irritation, diarrhea, increased activity. /From table/; [R120, 88] *LC50 Mouse 835 ppm (Exposure: 533-1365 ppm/4 hr). Effects were ocular and respiratory irritation, increased activity. /From table/; [R120, 88] *LD50 Rat oral 330 mg/kg; [R48, 237] *LC50 Rat inhalation 1462 ppm/4 hr; [R48, 237] *LC50 Mouse inhalation 836 ppm/4 hr; [R48, 237] *LC50 Dog inhalation 973 ppm/4 hr; [R48, 237] *LD50 Guinea pig oral 270 mg/kg; [R48, 237] ETXV: *LC50 Goldfish 90 mg/l/24 hr modified ASTM D 1345; [R43, 654] NTP: +... Toxicology and carcinogenesis studies of ethylene oxide (greater than 99% pure) were conducted by exposing groups of 50 B6C3F1 mice of each sex to air containing 0, 50, or 100 ppm ethylene oxide, 6 hours per day, 5 days per week for 102 wk. ... Conclusions: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity for B6C3F1 mice as indicated by dose related incr incidences of benign or malignant neoplasms of the lung and benign neoplasms of the harderian gland in both male and female B6C3F1 mice following exposure to ethylene oxide vapors at 50 and 100 ppm. In female mice, ethylene oxide caused additional malignant neoplasms of the uterus, mammary gland, and hematopoietic system (lymphoma). [R136] +Ethylene oxide (ETO) ... was evaluated for toxic and teratogenic effects in artificially inseminated New Zealand white (NZW) rabbits which were matched for body weight across treatment groups on gestational day (gd) 0. Ethylene oxide in 5% dextrose was administered daily in a volume of 1 ml/kg of body weight on gestational day 6 through 14 at dosages of 0, 9, 18 or 36 mg/kg/day, iv, or on gestational day 6 through 9 at dosages of 0, 18 or 36 mg/kg/day, iv. ... Administration of ethylene oxide (0, 9, 18 or 36 mg/kg/day, iv) on gestational days 6-14 resulted in mortality rates of 0% (0/27), 8.3% (2/24), 4.2% (1/24) and 22.2% (6/27), for the control through high-dose groups, respectively. Measures of maternal body weight (gestational days 14 and 30), maternal weight gain (i.e., weight gain during gestation, weight gain during treatment and absolute weight gain) and gravid uterine weight were each decreased in a dose-related manner. Examination of uterine contents on gestational day 30 revealed significant dose-related increases in the percentage of resorptions, nonlive and affected fetuses per litter. Average live litter size was decreased in a dose-related manner, as was the percentage of males per litter. No evidence of a treatment-related teratogenic effect observed, even at dosages which produced maternal and fetal toxicity. Maternal toxicity related to ethylene oxide (0, 18 or 36 mg/kg/day, iv) administered on gestational days 6-9 was limited to localized inflammation at the injection site for 1/23 confirmed-pregnant females in the high-dose group. Maternal weight gain during treatment and during gestation were reduced in a dose-related manner, but absolute maternal weight gain was not affected. At sacrifice on gestational day 30, examination of the uterine contents failed to reveal any evidence of a fetotoxic or teratogenic effect. In conclusion, no evidence for a teratogenic effect of ethylene oxide was observed when the compound was administered intravenously to NZW rabbits on gestational days 6-14 or gestational days 6-9 of gestation. [R137] TCAT: ?Chronic toxicity was evaluated in rats from the Army Chemical Center's Chemical Corps Medical Laboratories colony (20 animals) exposed to 100 ppm ethylene oxide via inhalation for 6 hrs/day for 6 months. The exposed animals showed no toxic signs. No significant effects were observed in weight gain, rectal temperature, EKG's, blood calcium and urea, or bilirubin. Mortalities for exposed and control rats were 3 out of 20 and 3 out of 20, respectively. [R138] ?Chronic toxicity was evaluated in mice from the Army Chemical Center's Chemical Corps Medical Laboratories colony (30 animals) exposed to 100 ppm ethylene oxide via inhalation for 6 hrs/day for 6 months. The exposed animals showed no toxic signs. No significant effects were observed in weight gain, rectal temperature, EKG's, blood calcium and urea, or bilirubin. Mortalities for exposed and control mice were 8 out of 30 and 4 out of 30, respectively. [R138] ?In a one-generation teratology study, pregnant female Fischer 344 rats (21-22/group) were exposed to ethylene oxide by inhalation at nominal concentrations of 0, 10, 33 or 100 ppm for 6 hrs on gestation days (GD) 6-15. The only treatment-related effect noted was a significant decrease in male and female fetal body weight relative to fetuses in control groups. No significant differences between treated and control animals were observed in the following: maternal and fetal survival, number of implantation and resorption sites, number of preimplantation losses, crown-to-rump length, the results of examination of all the fetuses for gross external abnormalities and half of each litter for visceral abnormalities and the other half for skeletal abnormalities. [R139] ?Chronic toxicity and oncogenicity were evaluated in groups of male and female Fischer 344 rats (120/sex/group) exposed to ethylene oxide via inhalation at 0, 10, 33 and 100 ppm for 6 hrs/day, 5 days/week for approximately 2 yrs. There was a statistically significant difference between treated animals and controls in the following: mortality (increased for both sexes at 100 ppm), body weight (decreased in males at 100 ppm and females at 100 and 33 ppm), mononuclear cell leukemia (increased in all treated female groups), peritoneal mesothelioma (increased in males at 100 and 33 ppm), cumulative percentage of pituitary adenoma (increased in females at 100 ppm), number of neoplasms/neoplasm bearing rats (increased for all treated rats, especially females), and number of rats with malignant neoplasms (increased in females at 100 and 33 ppm). There were no statistically significant differences in the following: chromosomal aberrations, ophthalmic lesions, urinalysis, hematology, serum clinical chemistry, or histopathology of the testes in males. [R140] ?As part of a chronic inhalation study, the ability of ethylene oxide to cause chromosome aberrations was evaluated in bone marrow cells of Fischer 344 rats receiving nominal concentrations of the test material at 0 or 100ppm in a dynamic air flow chamber for 6hours/day, 5days/week for 12 months [also see OTS0206201; final report]. After exposure, a minimum of 5 animals/sex/group were sacrificed and at least 50 bone marrow cells/animal were collected. No statistically significant (Wilcoxon Sum of Ranks Test) increase in the frequency of chromosome aberrations was observed in bone marrow cells of rats exposed to 100ppm of ethylene oxide compared to the controls [R141] ?The fate of ethylene oxide (EO) was evaluated in preexposed male Fischer 344 rats and their respective controls (2 preexposed to 100ppm EO for 8 weeks plus 2 controls/ 2 preexposed to 100ppm EO for 10 weeks plus two controls) receiving a nominal concentration of 14C-EO at 100ppm for six hours in a closed cycle, recirculating inhalation chamber. Urine, feces and expired air were collected during and 18 hours after exposure to 14C-EO. There were no significant differences between the non-preexposed or preexposed animals in the routes of elimination or in metabolic profiles. There were no significant differences in the concentration of radioactivity in either group of animals, except that the radioactivity associated with the RBC was 1.3 times greater in the non-preexposed animals. The data indicates that prolonged exposure of rats to EO has little effect on the metabolism of the chemical. [R142] ?The disposition of ethylene oxide (EO) was evaluated in male Fischer 344 rats (4/exposure) receiving nominal concentrations of 14C-EO at 10, 100 or 1000ppm for six hours in a closed cycle, recirculating, inhalation metabolism chamber. Urine, feces and carbon dioxide was collected during exposure and in Roth metabolism cages for 18 hours following exposure. The mean estimated absorbed dose was 2.7, 20.2 and 106.8mg EO/kg body weight for the 10, 100 and 1000ppm exposure, respectively. For all exposures the primary route of elimination was urine (mean value of 59% recovered 14C-activity), followed by CO2 (12%), feces (4.5%), and expired EO (1%). The highest concentrations of 14C-activity was found in the urinary bladder, liver, packed blood cells and adrenal glands, with the lowest concentration found in the fat. The increase in radioactivity concentration in tissue associated with increased exposure level of EO appeared to have a non-linear component. Analysis of urine obtained 18 hours post exposure was characterized by four radioactive metabolites. A significant increase in radioactivity was observed in two metabolites, a significant decrease in one and no difference in the fourth metabolite at 1000ppm relative to urinary metabolites in the other exposed rats. [R143] POPL: *Ethylene oxide is a suspected occupational toxicant of the male reproductive system indigenous to the occupation of hospital sterilizers. /From table/ [R71, 144] *Industrial and occupational exposure is generally the result of inhalation of ethylene oxide vapor released from leaking or faulty equipment, valves, or fittings. [R120, 86] */Hospital workers/ operating a defective ethylene oxide sterilizer. [R120, 86] ADE: *AFTER EXPOSURE OF MICE TO MIXT OF 1,2-(3)H-ETHYLENE OXIDE VAPOR IN AIR FOR 75 MIN, 90-95% OF RADIOACTIVITY WAS ELIMINATED IN 24 HR. HIGHEST CONCN OF RESIDUAL RADIOACTIVITY WERE FOUND IN PROTEIN FRACTIONS OF SPLEEN; SMALLER AMT OCCURRED IN LIVER, KIDNEY, LUNG AND TESTIS. [R144] *Iv injection of (14)C-labeled ethylene oxide indicated that (14)C concn in the testicle, epididymis and other organs were higher than those in the blood when measured 20 min to 4 hr after exposure. Radioactivity was still present in the epididymis 24 hr after exposure had ended. [R145] *Biological monitoring of ethylene oxide exposure by analysis of alveolar air and blood was studied in 10 workers employed in a hospital sterilizer unit. Environmental air, alveolar air, and venous blood were sampled during and at the end of an 8-hr workshift. The mean environmental concentration of ethylene oxide was 5.4 mg/cu m air and the mean alveolar ethylene oxide concentration was 1.2 mg/cu m alveolar air. Regression analysis showed that blood ethylene oxide concentrations were higher than environmental ethylene oxide concentrations by a mean ratio of 3 and higher than alveolar ethylene oxide concentrations by a mean ratio of 12. [R72] *... Rats /were exposed/ for 6 hours at airborne concentrations of 1800, 180, or 18 ug/l of (14)C labeled ethylene oxide. The assimilated doses of ethylene oxide were 107 20, and 2.7 mg/kg, respectively. [R129, 1991.619] *The distribution of radioactivity following the incubation of human blood with radio-labelled ethylene oxides was investigated in vitro. After incubation, the individual blood samples were separated into lymphocytes and high (Mr greater than 10,000) and low (Mr less than 10,000) molecular fractions of erythrocyte cytoplasm and blood plasma. The radioactivity was determined in each sample by liquid scintillation counting. In erythrocyte cytoplasm, the distribution of radioactivity showed marked interindividual differences and two distinct groups could be distinguished. The coincidence of these groups with conjugators and non-conjugators, in terms of the enzymatic conjugation of methyl halides to glutathione in erythrocytes, suggests a common principle, such as enzyme polymorphism. Such polymorphism has been described for glutathione S-transferase mu in the human liver, an enzyme that efficiently conjugates epoxides. In the other blood compartments, the interindividual differences were either less significant or were not detectable. Binding products with various macromolecules in blood, such as hemoglobin or lymphocyte DNA, are being discussed as biological monitors for occupational exposure to ethylene oxide. The observation that erythrocytes exhibit interindividual differences as described above make binding products with hemoglobin less suitable for biological monitoring of ethylene oxide exposure than, for example, DNA adducts in lymphocytes. [R146] *Inhaled epoxyethane is well absorbed. The absorption of inhaled epoxyethane was limited by alveolar ventilation in resting rats and mice. In mice, the highest concn of radioactivity were found in the liver and kidneys following a 75-min inhalation exposure to 2.2 ppm 14(C) epoxyethane. Concentrations of radioactivity in the testes, spleen, lungs, and brain were approximately equal to level expected if 14(C) epoxyethane was evenly distributed in the body. The radioactivity was rapidly cleared from the tissue and eliminated in the urine. [R56, 664] *Ethylene oxide is readily taken up by the lungs. A study on workers exposed to ethylene oxide revealed an alveolar retention of 75-80%, calculated from hourly determinations of ethylene oxide concentrations in environmental air ranging from 0.2 to 22.5 mg/cu m (0.11-12.3 ppm) and in alveolar air from 0.05 to 7 mg/cu m (0.03-3.8 ppm). At steady state, therefore, 20-25% of inhaled ethylene oxide reaching the alveolar space is exhaled as unchanged compound and 75-80% is taken up by the body and metabolized. Blood samples taken from workers 4 hours after the work shift and later gave venous blood:alveolar air coefficients of 12-17 and venous blood:environmental air coefficients of 2.5-3.3. The difference from the value of 90 determined from the blood:air partition coefficient in vitro was explained by incomplete saturation of tissues and limitation of the metabolic rate by the lung uptake rate. [R147] METB: *... ABSORBED INTO THE CELL WHERE IT UNDERGOES HYDROLYSIS TO ETHYLENE GLYCOL ... [R36, 2179] *In adult male Sprague-Dawley rats, male Swiss CD-1 mice, and male rabbits, 20 or 60 mg/kg ethylene oxide as a solution in distilled water was injected into the caudal vein in rats and mice or in the marginal vein in rabbits. Some animals were exposed to 200 ppm ethylene oxide in inhalation chambers. The animals were housed in metabolism cages, and urine samples were collected at 0-6 hr and 6-24 hr. The urine samples were analyzed for 2-hydroxyethylmercapturic acid, N-acetyl-S-carboxy-methyl-L cysteine, S-(2-hydroxyethyl)-L-cysteine, S-carboxymethyl-L-cysteine, and ethylene glycol. Species-related differences in the metabolic disposition of ethylene oxide were observed. Excretion product patterns did not differ significantly between injected doses. Rats (n= 5) eliminated 37% of ethylene oxide as 2-hydroxyethylmercapturic acid (31%) and ethylene glycol (6%); mice (n= 10) converted 19.3% of the ethylene oxide to 2-hydroxyethylmercapturic acid (8.3%), S-2-hydroxyethyl-L-cysteine (5.8%), S-carboxymethyl-L-cysteine (1.9%), and ethylene glycol (3.3%). The rabbits (n= 3) excreted only 2% of the ethylene oxide, primarily as ethylene glycol. In rats, larger amounts of 2-hydroxyethylmercapturic acid were excreted in the 6-24 hr period, and larger amounts of ethylene glycol were excreted in the 0-6 hr period. In mice, equal amounts of 3-hydroxyethylmercapturic acid were excreted in the two collection periods and larger amounts of ethylene glycol were excreted in the 6-24 hr period. No urine was voided by the rabbits in the 0-6 hr period. No qualitative differences in urinary metabolite excretion of ethylene oxide were observed relative to the method of exposure. [R148] *After fumigation of coca powder with ethylene oxide, several derivatives were isolated. Using IR and MS, these compounds have been identified as N,N-bis-(di-ethoxy-O-hydroxyethyl)isoleucylalanyl-cysteine, and N-(ethoxy-O-hydroxyethyl)tyrosine. [R149] ACTN: *Ethylene oxide is a carcinogenic compound which is also an ethylene metabolite. Ethylene oxide forms macromolecular adducts with proteins and nucleic acids. Targets in proteins are the amino acids cysteine, histidine and valine (if N-terminal, as in hemoglobin). The major DNA adduct is 7-(2-hydroxyethyl)-guanine. [R150] *Mechanisms underlying the production of fetal anomalies subsequent to exposure of zygotes to ethylene oxide or ethyl methanesulfonate were investigated in (C3HxC57BL)F1-mice. Female mice were injected with ethyl methanesulfonate ip at 250 mg/kg, 6 hours after mating, or were exposed to ethylene oxide at 1,200 ppm for 1.5 hours, starting 6 hours after mating. A reciprocal zygote transfer study was conducted to determine if the induced response was direct property of exposed zygotes or an indirect effect due to maternal toxicity. Cytogenetic analyses of pronuclear metaphases, early cleavage embryos, and midgestation fetuses were also carried out to explore the nature of the genetic damage. The zygote transplantation experiment ruled out maternal toxicity as a factor in fetal maldevelopment and pointed to a genetic cause for the abnormalities. The cytogenetic studies, however, failed to uncover structural or numerical chromosome aberrations. The authors conclude that while the lesions induced in zygotes by the two mutagenic compounds are likely to be genetic in nature, they are different from conventional ones; they could be novel lesions in experimental mammalian mutagenesis, or the mechanisms responsible for their production could involve a nonmutational imprinting process that causes changes in gene expression. [R130] INTC: *Cell transformation in vitro of C3H/10T1/2 cells, using gamma-radiation and ethylene oxide, in both the absence and presence of the cancer promoter, 12-O-tetradecanoylphorbol-13- acetate, was studied. 12-O-tetradecanoylphorbol-13-acetate promotes transformation of C3H/10T1/2 cells to the same extent. In the dose ranges studied the average enhancement of the transformation frequency was 2.4 and 2.5 for ethylene oxide and gamma-radiation, respectively. The rad-equivalence of ethylene oxide in the presence of 12-O-tetradecanoylphorbol-13-acetate was calculated to be 75 + or - 52 rad/mMh (95% confidence interval) which is consistent with the value 78 + or - 14 rad/mMh (95% confidence interval) obtained without 12-O-teradecanoylphorbol-13-acetate treatment. [R151] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +MEDICATION (VET): SPORICIDAL, VIRUCIDAL [R11] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethylene oxide will primarily enter the atmosphere in association with its production and use as a chemical intermediate as well as its relatively minor use as a sterilant and fumigant. From its industrial use, some ethylene oxide will be discharged into water. Once in the atmosphere it will degrade very slowly by reaction with hydroxyl-radicals (estimated half-life 211 days). Releases into water will be removed by volatilzation, hydrolysis and to a lesser extent, biodegradation. The volatilization half-lives for its removal from a model river and model lake are 5.9 hr and 3.8 days, respectively. Ethylene oxide will not adsorb strongly to soil or bioconcentrate in fish, although its presence in some food items may result from its use as a fumigant and sterilant. Major human exposure will be from occupational atmospheres. (SRC) NATS: *Since ethylene oxide is a product of combustion of hydrocarbon fuels, it is likely that ethylene oxide would be produced during the combustion of naturally-occurring hydrocarbons.(SRC) ARTS: *In vent gas and fugitive emission from its production and use as a chemical intermediate in the manufacture of ethylene glycol, ethoxylates, glycol ethers and ethanolamines(1). Aqueous effluent associated with its production and use as a chemical intermediate. Fugitive emissions from its use as a fumigant and sterilant of food, cosmetics and hospital supplies(1,3-4); auto and diesel exhaust - combustion product of hydrocarbon fuels(1,2); tobacco smoke(1). While its use as a fumigant and sterilant constitute only 2% of its use, emissions from these uses are proportionately higher than other uses and result in greater exposure(3,4). [R152] FATE: *TERRESTRIAL FATE: When released on land, ethylene oxide would tend to volatilize rapidly. It is miscible in water and poorly adsorbed to soil so leaching is likely to occur. Although experimental data are lacking, hydrolysis in soil is probable. (SRC) *AQUATIC FATE: When released into water ethylene oxide will primarily be lost by three processes: volatilization, hydrolysis and biodegradation in that order of importance. Volatilization will depend on wind and mixing conditions and would be expected to occur in hours to days. The volatilization half-lives of ethylene oxide in a model river and lake are 5.9 hr and 3.8 days, respectively. The half-life for hydrolysis is 9-14 days leading to biodegradable products. Because of the limited data, it is difficult to estimate the rate of biodegradation; the available data would suggest that the biodegradation rate is slower than the volatilization and hyrdrolysis rates. Ethylene oxide would not tend to adsorb to sediment. In groundwater, ethylene oxide will degrade due to hydrolysis. (SRC) *ATMOSPHERIC FATE: Ethylene oxide will degrade in the atmosphere primarily by reaction with photochemically produced hydroxyl radicals. Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of ethylene oxide in the atmosphere will be 211 days(1,SRC). Data suggests that neither rain out nor adsorption into aqueous aerosols in the air should remove much of this compound(2). [R153] BIOD: *Based on limited data, ethylene oxide biodegrades at a reasonable rate after a period of acclimation. In a dilution bottle test, there was 3-5% degradation after 5 days and 52% degradation after 20 days(1,2). Since ethylene oxide hydrolyzes to ethylene glycol which is readily biodegraded, there is a fair amount of uncertainty in the biodegradability measurements(2). In a river die-away test, the rate of degradation was not significantly different than for hydrolysis(2). Ethylene oxide biodegradation rate constants measured at a full-scale wastewater treatment plant were 0.38 and 0.59 ug/min-g biomass(3). These rate constants would imply that a system with a 6 day residence time operated with mixed liquor suspended solids of 2500 mg/L would effectively biodegrade 8.2 and 12.7 mg/L of ethylene oxide, respectively(SRC). [R154] ABIO: *Ethylene oxide hydrolyzes slowly in fresh and salt water to give ethylene glycol and ethylene chlorohydrin(1). The half-life for this reaction is 12-14 days for pH's between 5-7 in fresh water(1,2,3) and 9-11 days in salt water(1). The ratio of chlorohydrin to glycol formed was found to be 0.11 and 0.23 in 1% and 3% sodium chloride solutions respectively(1). The hydrolysis rate is increased considerably in acidic or basic solutions(2). In the atmosphere, ethylene oxide reacts with photochemically-produced hydroxyl radicals with a rate constant of 7.6X10-14 cu cm/molecule-s at(1). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of ethylene oxide in the atmosphere would be 211 days(SRC). Earlier smog chamber experiments with both natural and artificial illumination are consistent with a slowly degrading compound(6). In one of these, 20% of the ethylene oxide degraded in 5.3 hr(4). [R155] BIOC: *Although no studies of bioconcentration for ethylene oxide were found in the literature, one would not expect it to bioconcentrate due to its low octanol/water partition coefficient (log Kow= -0.3)(1).(SRC) [R156] KOC: *No data could be found concerning the adsorption of ethylene oxide to soil. One would not expect a very high adsorptivity due to its low octanol/water partition coefficient (log Kow = -0.3)(1). Based on a regression analysis with the log octanol/water partition coefficient(2), one would calculate a KOC of 16(SRC). [R157] VWS: *The half-life for evaporation of ethylene oxide from water is 1 hr with no wind and 0.8 hr with a 5 m/sec wind as determined in a laboratory experiment(1). The Henry's law constant for ethylene oxide is 1.48X10-4 atm-cu m/mole(1). Using this value of the Henry's Law constant, one would estimate a volatilization half-life of 5.9 hr for ethylene oxide from a model river 1 m deep with a 1 m/s current and a 3 m/s wind(3,SRC). Similarly, its half-life from a model lake 1 m deep with a 0.05 m/s current and 0.5 m/s wind is 3.8 days. Although no data on the volatilization of ethylene oxide from soil could be found, a study of the dissipation of ethylene oxide from fumigated commodities gave half-life values of 4 hr to 17.5 days(2). [R158] EFFL: *Detected, not quantified in an effluent sample in Brandenburg, KY in Feb 1974, at a production facility(1,2). It is estimated that in ethylene oxide production, between 0.25 and 47.5 kg of ethylene oxide is emitted to the air for each kg produced(3). [R159] FOOD: *1970-76 FDA Monitoring Program - detected, not quantified in 1 out of 2372 samples of eggs in 1975(1). [R160] PFAC: FISH/SEAFOOD CONCENTRATIONS: *1970-1976 FDA Food Monitoring Program - detected, not quantified in 1 out of 3262 samples of fish (1975), not found in 443 samples of shellfish for this period(1). [R161] RTEX: *Exposure to ethylene oxide is primarily occupational via inhalation. (SRC) *OSHA estimates that approximately 80,000 and 144,000 workers are directly and indirectly exposed to ethylene oxide in ethylene oxide production, chemical synthesis by ethoxylation, health care facilities (sterilization), medical products (sterilization) and miscellaneous manufacturers (e.g., spice sterilization)(1). The number of workers exposed directly (indirectly) in the various industries are: production and synthesis 3676; sterilization - health care facilities 62,370 (25,000); sterilization - medical products manufacture 14,000 (116,900); sterilization - spice manufacturers 160(1). Typical exposures are usually high during short periods in which sterilizer doors are opened, typically 5-10 ppm for 20 minutes(1). Some typical survey results are: Medical products manufactures 0.1.1-2.0 ppm 8 hr TWA; Hospital sterilizer chamber operators 2.5 ppm TWA; 121 use sites in Southern California < 5 ppm (TWA) in 114/121 sites; 2 hospitals 3-6 ppm and < 5 ppm resp; survey of 27 hospitals TWA exposures less than or equal to 1, < 4 and > 10 ppm in 9/27, 16/27 and 5/27, respectively(1). Union Carbide production plant in Texas City 5-33 ppm and 7.25 and 10.25 ppm avg in 2 control rooms and 0-56 ppm, 11.6 ppm avg throughout plant(2). In-depth survey of 2 Union Carbide production facilities in West Virginia- 2 of 48 and 4 of 41 samples positive, TWA exposure of positive samples 1.5-82 ppm(4,5). Production and maintenance workers in the 1960's avg exposure levels 0.6-60 ppm(3). [R162] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 50,132 workers are exposed to ethylene oxide in the USA(2). The personal 8-hr TWA exposure in 12 hospitals ranged from ND to 6.3 ppm for sterilizer operators and ND to 6.7 ppm for folders and packers. Short term (2 to 30 min) exposure levels for sterilizer operators ranged from ND to 103 ppm(1). Lower exposure levels were correlated with effective engineering controls and good work practices, rather than with the size of the hospital, or number or location of sterilizers. [R163] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers ethylene oxide to be a potential occupational carcinogen. [R28, 138] ATOL: *A tolerance of 50 ppm is established for residues of the antimicrobial agent and insecticide ethylene oxide, when used as a postharvest fumigant in or on the following raw agricultural commodities: Black walnut meats, copra, whole spices. [R164] *Residues of ethylene oxide in ground spices from both postharvest application to the raw agricultural commodity whole spices and application to the ground spices shall not exceed the established tolerance of 50 ppm for residues in whole spices. [R165] OSHA: +The employer shall ensure that no employee is exposed to an airborne concentration of ethylene oxide in excess of 1 ppm as an 8-hr TWA. The employer shall ensure that no employee is exposed to an airborne concentration of ethylene oxide in excess of 5 ppm as averaged over a sampling period of 15 min. [R166] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: < 0.1 ppm (< 0.18 mg/cu m). [R28, 138] +Recommended Exposure Limit: 10 min/day ceiling value: 5 ppm (9 mg/cu m). [R28, 138] +NIOSH considers ethylene oxide to be a potential occupational carcinogen. [R28, 138] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R28, 138] TLV: +8 hr Time Weighted Avg (TWA): 1 ppm. [R69] +A2; Suspected human carcinogen. [R69] OOPL: *Germany: 5 ppm; USSR: 0.5 ppm. [R108, 1986.257] +Emergency Response Planning Guidelines (ERPG): ERPG(1) Not appropriate; ERPG(2) 50 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 500 ppm (not life threatening) up to 1 hr exposure. [R167] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethylene oxide is produced, as an intermediate or a final product, by process units covered under this subpart. [R168] +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Ethylene oxide is included on this list. [R169] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 10 ug/l [R170] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R171] +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Ethylene Oxide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 1,000 lbs. [R172] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Oxirane is included on this list. [R173] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R174] RCRA: *U115; As stipulated in 40 CFR 261.33, when ethylene oxide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R175] FIFR: *A tolerance is established for residues of the antimicrobial agent and insecticide ethylene oxide, when used as a postharvest fumigant in or on the following raw agricultural commodities: black walnut meats, copra, whole spices. [R164] *Ethylene oxide may be safely used as a fumigant for the control of microorganisms and insect infestation in ground spices and other processed natural seasoning materials, except mixt to which salt has been added ... Tolerances are established for residues of ethylene oxide in ground spices from both postharvest application to the raw agricultural commodity whole spices and application to the ground spices. [R176] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Ethylene oxide is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 2275; Pesticide type: insecticide, fungicide, rodenticide, antimicrobial; Case Status:In Pre-Special Review. The pesticide is in or has completed the reregistration process and, meanwhile, is also the subject of an in-depth Special Review.; Active ingredient (AI): Ethylene oxide; Data Call-in (DCI) Date(s): 05/24/91; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R177] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 3702. Analyte: Ethylene oxide. Sampler: Ambient air or bag sample. Flow Rate: Greater or equal to 0.07 l/min; spot samples possible. Shipment: Calibration and carrier gas shipment must comply with hazardous materials shipment regulations. Sample Stability: Bag samples stable 24 hrs @ 25 deg C. [R178, p. 3702-1] *NIOSH Method 1614. Analyte: Ethylene oxide. Matrix: Air. Sampler: Solid sorbent tube (hydrogen bromide-coated petroleum charcoal, 100 mg/50 mg) Flow Rate: 0.05 to 0.15 l/min: Sample Size: 24 liters. Shipment: Routine. Sample Stability: 90% recovery after 17 days @ 25 deg C in the dark. [R178, p. 1614-1] *Analyte: Ethylene oxide. Procedure: Trapping on solid adsorber. Sample flow: 0.05 to 1.15 l/min. Sample Size: 11 (at 5 ppm) to 24 liters. [R179] *The method uses a hydrobromic acid-coated charcoal tube to collect ethylene oxide as its 2-bromoethanol reaction product. Similar high recoveries were obtained for 4 hr samples collected at a sampling rate of 0.1 l/min from test atmospheres in the concentration range of 0.1 to 16 ppm ethylene oxide at high humidity (80%) and ambient temperature (22 deg to 25 deg C). Samples collected under these same conditions and stored for a minimum of 2 weeks resulted in average recoveries that ranged from 84% to 101%. Average recoveries of 97% were obtained for 2 ppm air samples collected at low humidity with no storage; however, storage of these samples at 22 deg C to 25 deg C resulted in an approximated loss of 5% per week. [R180] ALAB: *NIOSH Method 3702. Analyte: Ethylene oxide. Procedure: Gas chromatography (portable) with photoionization detector. For ethylene oxide this method has an estimated detection limit of 2.5 pg/injection @ .001 ppm/ml injection. The precision/RSD is less than 0.07 @ 0.05 to 0.02 ppm. Applicability: The working range is 0.001 to 1000 ppm in relatively non-complex atmospheres (eg, sterilization facilities). Interferences: Freon 12, carbon dioxide and alcohols do not interfere. [R178, p. 3702-1] *NIOSH Method 1614. Analyte: Ethylene oxide. Matrix: Air. Procedure: Gas chromatography electron capture detector. For ethylene oxide this method has an estimated detection limit of 1 ug ethanol/sample. The precision/RSD is 0.028 @ 18 to 71 ug ethanol/sample. Applicability: The working range is 0.05 to 4.6 ppm (0.08 to 8.3 mg/cu m) for a 24 liter air sample. Interferences: 2-Bromoethanol, if present in the sample, interferes. [R178, p. 1614-1] *Analyte: Ethylene oxide. Procedure: Gas chromatography/Electron capture detector. Carrier gas flow: 25 ml/min. Sample size: 1 ml. The working range is 0.04 to 0.98 ppm (24 liter sample). Overall precision: 0.13 and detection limit of 1 ug/sample. Interference: 2-Bromoethanol. [R179] *Ethylene oxide can be determined by spectrophotometry and by colorimetry or volumetrically. Gas chromatography of air samples and residues from fumigated materials has been used for foodstuffs, pharmaceuticals and surgical equipment. It can also be found in cigarette smoke by gas chromatography or mass spectrometry ... and also in mixtures of lower olefin oxides and aldehydes. Limits of detection by spectrophotometry and gas chromatography were generally of the order of 1 mg/kg. [R181] *A field evaluation study was conducted to determine the effectiveness of 12 commercially available monitoring devices designed to detect exposure levels to ethylene oxide. These passive dosimeters were exposed to four different ethylene oxide concentration levels. [R182] *OSHA Method 49. Gas chromatography using an electron capture detector, target concn 1 ppm (1.8 mg/cu m), reliable quantitation limit 0.7 ppb (1.3 ug/cu m). [R183] *OSHA Method 50. Gas chromatography using an electron capture detector, target concn 1 ppm (1.8 mg/cu m), reliable quantitation limit 3.0 ppb (5.4 ug/cu m). [R184] *OSHA Method 30. Gas chromatography using an electron capture detector, target concn 1 ppm (1.8 mg/cu m), reliable quantitation limit 52.2 ppb (94.0 ug/cu m) [R185] *OSW Method 8240A. Volatilie organics by gas chromatography/mass spectroscopy (GC/MS): Packed column technique. No detection limit. [R186] CLAB: *... Methods were developed using capillary gas chromatography. Gas chromatography with mass spectrometry for determining S-methylcysteine, N(r)(2-hydroxyethyl)histidine and N(r)(2-hydroxypropyl)histidine in hemoglobin, allowing the monitoring of in vivo exposure of laboratory animals and humans to methylating agents, ethylene oxide and propylene oxide, respectively. ... An alternative method of dose monitoring of some methylating agents by the measurement of the urinary N-7-methylated guanine derived from alkylated DNA break-down products was also investigated. [R187] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: TSCA CHIPs present a preliminary assessment of ethylene oxide's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404 Kercher et at; Appl Ind Hyg 2 (1): 7-12 (1987). Before and after an evaluation of engineering controls for ethylene oxide sterilization in hospitals. USEPA; Office of Air Quality and Planning Standards EPA-450/4-84-007L (1986). DHHS/ATSDR; Toxicological Profile for Ethylene Oxide (1990) ATSDR/TP-90/16 DHHS/NTP; Toxicology and Carcinogenesis Studies of Ethylene Oxide in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 326 (1987) NIH Publication No. 88-2582 Kimmel GL et al; Toxicologist 10 (1): (1990) ... Reproductive and developmental toxicity risk assessment for ethylene oxide. Florack EIM, Zielhuis GA; 62 (4): 273-77 (1990). This review /details/ the evidence for reproductive toxicity of ethylene oxide gathered through animal studies and epidemiological /data/. Govt Reports Announcements and Index (GRA and I) 13: (1994). Hazards of ethylene oxide exposure. NTIS/PB94-878576. A bibliography is available that contains abstracts concerning ethylene oxide exposure. Dellarco VL et al; Environ Mol Mutagen 16 (2): 85-103 (1990). Review of the mutagenicity of ethylene oxide. USEPA/OPP; Pesticide Fact Sheet Number 234: Ethylene Oxide (EtO) EPA/540/FS-92/195 (1992). This document contains current information on ethylene oxide which includes regulatory data. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) HIST: *A Chessie System freight train derailed in a wooded, rural area near Woodland Park, Michigan in February 1978. Four tank cars were damaged, spilling approx 300,000 lb of vinylidene chloride, 330,000 lb of phenol, and 125,000 lb of ethylene oxide. Most of the phenol, which had solidified on the surface, was removed by a cleanup contractor although residual phenol remained in the soil. The ethylene oxide vaporized, posing no groundwater contamination problems. The vinylidene chloride percolated through the sandy soils into the groundwater about 50 ft below the ground surface. Vinylidene chloride concentrations as high as 300 mg/l were found in monitoring wells near the derailment site. The groundwater cleanup program was completed over a three yr period. ... [R188] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R3: Farm Chemicals Handbook 1981. Willoughby, Ohio: Meister, 1981.,p. C-141 R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 490 R6: SRI. 1994 Directory of Chemical Producers -United States of America. 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(Multivolume work).p. V60 102 (1994) R133: Katoh T et al; Toxicol 58 (1): 1-9 (1989) R134: Lewis SE et al; Mutat Res 229 (2): 135-40 (1990) R135: Vergnes JS, Pritts IM; Mutat Res 324 (3): 87-91 (1994) R136: Toxicology and Carcinogenesis Studies of Ethylene Oxide in B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 326 (1987) NIH Publication No. 88-2582 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R137: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Ethylene oxide (CAS No. 75-21-8) in New Zealand White Rabbits, NTP Study No. TER82078 (April 18, 1983) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R138: Army Chemical Center; The Chronic Toxicity of Inhaled Ethylene Oxide. (1955), EPA Document No. 878211697, Fiche No. 205856 R139: Carnegie-Mellon University; Ethylene Oxide Teratology Study. (1979), EPA Document No. 878213864, Fiche No. OTS0206333 R140: Bushy Run Research Center; Ethylene Oxide Two-Year Inhalation Study on Rats, Final Report. (1981), EPA Document No. 878212152, Fiche No. 206028 R141: Bushy Run Research Center; Report on Cytogenetic Studies of Bone Marrow Cells: 12-Month Sacrifice Interval, (1980), EPA Document No. 878212057, Fiche No. OTS0206060 R142: Carnegie-Mellon Institute of Research; Metabolism Study on Ethylene Oxide (EO) in Rats, (1978), EPA Document No. 878212054, Fiche No. OTS0206060 R143: Bushy Run Research Center; Dose Dependent Disposition of 14-Labeled Ethylene Oxide in Rats, (1982), EPA Document No. 878212056, Fiche No. OT0206060 R144: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 162 (1976) R145: Appelgren LE et al; Europ Soc Toxicol 18: 315 (1977) R146: Fost U et al; Hum Exp Toxicol 10 (1): 25-31 (1991) R147: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 104 (1994) R148: Tardif R et al; Fundam Appl Toxicol 9 (3): 448-53 (1987) R149: Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 292 R150: Bolt HM et al; Int Arch Occup Environ Health 60 (3): 141-4 (1988) R151: Kolman A et al; Toxicol Lett 53 (3): 307-13 (1990) R152: (1) Bogyo DA et al; Investigations of Selected Potential Environmental Contaminants. Epoxides USEPA-560/11-80-005 p. 60-9 (1980) (2) Graedel TE; Chemical Compounds in the Atmosphere Academic Press, NY p. 272 (1978) (3) Chemical and Engineering News p. 12 (1983) (4) Cawse JN et al; in Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: Wiley-Interscience 9: 432-71 (1980) R153: (1) Atkinson R; J Chem Phys Ref Data Monograph 1 (1989) (2) Cupitt LT; Atmospheric persistence of eight air tosics. USEPA-600/S3-87/004 (1987) R154: (1) Bridie AL et al; Water Res 13:627-30 (1979) (2) Conway RA et al; Environ Sci Technol 17:107-12 (1983) (3) Green D, Eklund B; Field assessment of the fate of volatile organics in aerated wastewater systems. pp. 478-86 in USEPA/9-87-015. (1987) R155: (1)Conway RA et al; Environ Sci Technol 17:107-12 (1983) (2) Bogyo DA et al; Investigation of selected environmental contaminants: Epoxides. USEPA-560/11-80-005 p 69-96 (1980) (3) Mabey W, Mill T; J Phys Chem Ref Data 7:383-415 (1978) (4) Joshi SB et al; Atmos Environ 16: 1301-10 (1979) (5)Atkinson R; J Chem Phys Ref Data Monograph 1 (1989) (6) Cupitt LT; Atmospheric persistence of Eight Air Toxics. USEPA-600/S3-87/004 (1987) R156: (1) Hansch C, Leo AJ; Substituent Constants for Correlation Analysis in Chemistry and Biology. NY: John Wiley and Sons p. 339 (1979) R157: (1) Hansch C, Leo AJ; Substituted Constants for Correlation Analysis in Chemistry and Biology. NY: John Wiley and Sons p. 339 (1979) (2) Kenaga EE, Going CAI; Aquatic Toxicology, Proceedings of the Third Annual Symp on Aquatic Toxicology, ASTM, Philadelphia, PA (1980) R158: (1) Conway RA et al; Environ Sci Technol 17:107-112 (1983) (2) Bogyo DA et al; Investigations of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p 70-90 (1980) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) R159: (1) Shalkelford WM, Keith LH; Frequency of Organic Compounds Identified in Water. USEPA-600/4-76-062 p 129 (1976) (2) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p 17 (1980) (3) Carpenter CE et al; Toxic Subst J 10: 323-71 (1990) R160: (1) Duggan RE et al; Pesticide residue levels in foods in the US from July 1 to June 30, 1976. Food and Drug Admin. page 10-18 (1983) R161: (1) Duggan RE et al; Pesticide Residue Levels in Foods in the US from July 1 to June 30, 1976. Food and Drug Administration p 10-18 (1983) R162: (1) OSHA; Occupational Exposure to Ethylene Oxide; Proposed Rule. 48 FR 17283-17319 4,21 (1983) (2) Joyner RE; Arch Environ Health 8:700-10 (1964) (3) Hogstedt C et al; Brit J Ind Med 36:276-80 (1979) (4) Oser JL; In-depth Industrial Hygiene Report of Ethylene Oxide Exposure at Union Carbide Corp., WV NIOSH IWS-67.17B 47 p (1978) (5) Oser JL; In-depth Industrial Hygiene Report of Ethylene Oxide Exposure at Union Carbide Corp., South Charleston, WV NIOSH IWS-67.10 25 p (1979) R163: (1) Elliot LJ et al; Appl Ind Hyg 3: 141-5 (1988) (2) NIOSH; National Occupational Exposure Survey (1989) R164: 40 CFR 180.151 (7/1/92) R165: 40 CFR 185.2850(c) (7/1/92) R166: 29 CFR 1910.1047(c) (7/1/98) R167: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.25 R168: 40 CFR 60.489 (7/1/92) R169: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R170: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R171: 40 CFR 302.4 (7/1/92) R172: 40 CFR 355 (7/1/97) R173: 40 CFR 716.120 (7/1/92) R174: 40 CFR 712.30 (7/1/92) R175: 40 CFR 261.33 (7/1/92) R176: 40 CFR 185.2850 (7/1/92) R177: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.182 (Spring, 1998) EPA 738-R-98-002 R178: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R179: Royal Society of Chemistry. Measurement Techniques for Carcinogenic Agents in Workplace Air. Publ. No. EUR 11897, Commission of the European Communities/Scientific and Technical Communication Unit, Luxembourg. Great Britian: St. Edmundsbury Press Ltd, 1989.21 R180: Cummins KJ et al: Am Ind Hyg Assoc J 48 (6): 563-73 (1987) R181: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 160 (1976) R182: Puskar MA, Hecker LH; Am Ind Hyg Assoc J 50 (1): 30-6 (1989) R183: OSHA Method 49, Ethylene oxide, issued 11/84 R184: OSHA Method 50, Ethylene oxide, issued 1/85 R185: OSHA Method 30, Ethylene oxide, issued 8/81 R186: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R187: Bailey E et al; Arch Toxicol 60 (1-3): 187-91 (1987) R188: Posthuma AR et al; 1983 Nat Conf Environ Engin p.775-82 (1983) RS: 186 Record 31 of 1119 in HSDB (through 2003/06) AN: 172 UD: 200210 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CUMENE- SY: *BENZENE,-ISOPROPYL-; *BENZENE, (1-METHYLETHYL)-; *CUMEEN- (DUTCH); *CUMOL-; *2-FENILPROPANO- (ITALIAN); *2-FENYL-PROPAAN- (DUTCH); *ISOPROPILBENZENE- (ITALIAN); *ISOPROPYLBENZEEN- (DUTCH); *ISOPROPYLBENZENE-; *ISOPROPYLBENZOL-; *ISOPROPYL-BENZOL- (GERMAN); *2-PHENYLPROPANE-; *PROPANE,-2-PHENYL- RN: 98-82-8 MF: *C9-H12 SHPN: UN 1918; Isopropylbenzene IMO 3.3; Isopropylbenzene STCC: 49 131 25; Cumene HAZN: U055; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... distillation from coal tar naptha fractions or from petroleum, alkylation of benzene with propylene (phosphoric acid catalyst) [R1] *Manufactured from propylene and benzene utilizing an acidic catalyst, eg, solid phosphoric acid. [R2, p. V7 286] *High purity cumene can be easily produced from either refining or steam cracker-derived propylene. [R2, p. V7 287] IMP: *Sulfur compounds 2 ppm, Max; Olefinic materials 200-700 ppm [R2, p. V7 287] FORM: *Grades: Technical; research; pure [R1] *0.16% wt in gasoline [R3, 1170] *99.9% MIN ASSAY [R2, p. V7 289] MFS: *Amoco Corporation, Hq, 200 East Randolph Drive, Chicago, IL 60601, (312) 856-6111; Production site: Texas City, TX 77592-0568 [R4, 533] *Chevron Chemical Company, 6001 Bollinger Canyon Rd, San Ramon, CA 94583, (925) 842-5500; U.S. Chemicals Division, 1301 McKinney St., PO Box 3766, Houston, TX 77253, (713) 754-2000; Production site: Port Arthur, TX 77640 [R4, 533] *CITGO Petroleum Corp., 6130 S Yale Ave, Tulsa, OK 74136, (918) 495-4000; Production site: Corpus Christi, TX 78469 [R4, 533] *Champlin Refining and Chemicals Inc, Hq, PO Box 160066, Irving, TX 75016-0066, (214) 402-7000; Production site: Corpus Christi, TX 78469 [R4, 543] *Coastal Eagle Point Oil Co., PO Box 1000, US Route 130 and I-295, Westville, NJ 08093, (609) 853-3100; Production site: Westville, NJ 08093 [R4, 533] *Georgia Gulf Corp., 400 Perimeter Center Terrace, Suite 595, PO Box 105197, Atlanta, GA 30346, (770)395-4500; Production site: Pasadena, TX 77501 [R4, 533] *JLM Chemicals, Inc., 3350 West 131st St., PO Box 598, Blue Island, IL 60406, (708) 388-9373; Production site: Blue Island, IL 60406 [R4, 533] *Koch Industries, Inc., Hq, PO Box 2256, Wichita, KS 67201, (316)828-5500; Production site: Corpus Cristi, TX 78403 [R4, 533] *Marathon Ashland Petroleum LLC, 539 South Main St., Findlay, OH 45840-3295, (419)422-2121; Production site: Catlettsburg, KY 41129 [R4, 533] *Shell Chemical Co., One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713)241-6161; Production site: Deer Park, TX 77536 (Houston Plant) [R4, 533] *Sun Company, Inc, 1801 Market St., Philadelphia, PA 19103, (800) 825-3535; Production site: Philadelphia, PA 19145 [R4, 533] *Texaco Refining and Marketing Inc, 10 Universal City Plaza, Universal City, CA 91608-1097, (818)505-2000; Production Site: El Dorado, KS 67042 [R4, 533] OMIN: *UNION CARBIDE'S 640 MILLION LB PER YR PENUELAS, PR AND MARATHON OIL'S 210 MILLION LB PER YR TEXAS CITY, TX PLANT ARE ON STANDBY; MONSANTO CLOSED ITS ALVIN, TX PLANT IN 1983 [R5] *Cumene forms a charge-transfer complex with ozone in a number of solvents. When this charge-transfer complex was photolyzed at -75 deg C or warmed greater than -40 deg C, reactions formed cumyl hydrotrioxide and ring-ozonated products (in a ratio of 70/30). [R6] *Thirty-second highest-volume chemical produced in U.S. (1991). [R7, 328] USE: *Used as a thinner for paints, enamels, and lacquers and as a solvent for fats and resins and as such has been suggested as a replacement for benzene. [R8, 735] *Component of high octane aviation fuel; in prodn of styrene [R9] *In manuf of acetophenone, phenol, acetone, and 2-methylstyrene [R10] *In the manufacturing of ... polymerization catalysts, diisopropylbenzene, catalyst for acrylic and polyester type resins; naptha constituent and asphalt ... [R3, 1170] *Minor amounts are used in gasoline blending. [R8, 735] *RAW MATERIAL FOR PEROXIDES AND OXIDATION CATALYSTS [R11] *CHEM INTERMEDIATE FOR DICUMYL PEROXIDE. [R12] *Virtually all cumene produced is oxidized to cumene hydroperoxide which is then cleaved catalytically to phenol and acetone. [R13] CPAT: *65% FOR PHENOL; 34% FOR ACETONE; 1% FOR ALPHA-METHYLSTYRENE AND MISC APPLICATIONS (1972) [R12] *98% OXIDATION FOR PHENOL/ACETONE PRODUCTION; 1.8% POLYMERIZATION FOR ALPHA-METHYLSTYRENE; 0.2% EXPORTS (1985) [R5] *CHEMICAL PROFILE: Cumene. Demand: 1986: 3.7 billion lb; 1987: 4.0 billion lb; 1991 /projected/: 4.3 billion lb. (Includes exports; in addition, 328 billion lb were imported in 1986). [R14] *More than 95% of the cumene produced is used as feedstock for the production of phenol and acetone. [R8, 734] *Demand: 1998, 6.7 billion lbs; 1999, 6.9 billion lbs; 2003, 8.0 billion lbs [R13] PRIE: U.S. PRODUCTION: *(1972) 1.04X10+12 GRAMS [R12] *(1975) 9.09X10+11 GRAMS [R12] *(1984) 1.70X10+12 g [R15] *(1988) 4.5X10+9 lb [R16] *(1990) 4.31 billion lb [R17] *(1992) 4.67 billion lb [R18] *(1991) 4.57 billion lb [R19] *(1993) 4.49 billion lb [R18] *U.S. Production in 1977 was 1.2 million metric tons while in 1987 it grew to 1.8 million metric tons. [R8, 735] U.S. IMPORTS: *(1972) 2.02X10+11 GRAMS [R12] *(1975) 9.50X10+10 GRAMS [R12] *(1980) 1.38X10+11 g (EST) [R20] U.S. EXPORTS: *(1972) NEGLIGIBLE [R12] *(1975) 2.07X10+10 GRAMS [R12] *(1984) 2.24X10+9 g [R21] *Exports totaled 465 million lbs in 1998. [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R10]; *Colorless liquid ... [R22, 80] ODOR: *Gasoline-like odor. [R23]; *... Sharp, penetrating, aromatic odor. [R22, 80] BP: *152.4 deg C @ 760 torr [R24, p. 3-55] MP: *-96.0 deg C [R24, p. 3-55] MW: *120.19 [R24, p. 3-55] CTP: *Critical temperature: 358 deg C; critical pressure: 31.7 atm [R24, p. 3-55] DEN: *Specific gravity: 0.862 @ 20 deg C/4 deg C [R10] HTC: *45.13 KJ/mol [R24, p. 6-113] HTV: *10,335.3 gcal/gmol [R25, p. C-677] OWPC: *log Kow= 3.66 [R26] SOL: *Sol in acetone, ether, ethanol [R24, p. 3-55]; *In water, 50 mg/l at 20 deg C [R3, 1170]; *Soluble in most organic solvents; insoluble in water. [R27, 1991.346]; *Soluble in many organic solvents [R10]; *In water, 61.3 mg/l @ 25 deg C. [R28] SPEC: *INDEX OF REFRACTION: 1.4915 @ 20 DEG C/D; MAX ABSORPTION (HEXANE): 254 NM (LOG E= 2.3), 251 NM (LOG E= 2.4), 267 NM (LOG E= 2.3); SADTLER REFERENCE NUMBER: 242 (IR, PRISM), 8023 (IR, GRATING) [R25, p. C-221]; *SPECIFIC DISPERSION: 166.2 [R29]; *IR: 4781 (Coblentz Society Spectral Collection) [R30]; *UV: 95 (Sadtler Research Laboratories Spectral Collection) [R30]; *NMR: 240 (Varian Associates NMR Spectra Catalogue) [R30]; *MASS: 483 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R30] SURF: *27.69 mN/m @ 25 deg C [R24, p. 6-113] VAPD: *4.1 (Air= 1) [R31, 1305] VAP: *4.5 mm Hg @ 25 deg C [R32] VISC: *0.737 mPa.sec @ 25 deg C [R24, p. 6-174] OCPP: *% IN SATURATED AIR @ 38.3 DEG C AND 760 MM HG: 1.32; DENSITY OF SATURATED VAPOR-AIR MIXT @ 38 DEG C AND 760 MM HG (AIR= 1): 1.03 [R29] *Liquid-water interfacial tension: 54.6 dynes/cm= 0.0546 N/m at 22.7 deg C [R33] *Ratio of specific heat vapor (gas) = 1.059 [R33] *Control methods: calculated half life time based on evaporative loss for a water depth of 1 m at 25 deg C: 5.8 hr [R3, 1171] *Henry's Law constant= 1.15X10-2 atm-cu m/mol @ 25 deg C [R28] *Hydroxyl radical rate constant= 6.50X10-12 cu cm/molecule-sec @ 25 deg C [R34] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R35] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R35] +Public safety: Call Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R35] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R35] +Evacuation: Spill: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R35] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R35] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R35] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R35] FPOT: *Flammable liquid when exposed to heat or flame ... [R36] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R37, p. 325-29] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R37, p. 325-29] *Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R37, p. 325-29] FLMT: *Lower flammable limit: 0.9% by volume; Upper flammable limit: 6.5% by volume [R37, p. 325-29] FLPT: *102 deg F (39 deg C) (Closed cup) [R10] AUTO: *795 deg F [R36] FIRP: *To fight fire, use foam, carbon dioxide, dry chemical. [R36] *Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R37, p. 49-45] EXPL: *IF SOLN OR COATINGS CONTAINING CUMENE ARE HEATED ... IN DRYING OVEN ... EXPLOSION, READILY ... /OCCURS UNDER CERTAIN CONDITIONS/. [R38, 572] *LEL: 0.9%; UEL: 6.5% [R36] REAC: *Mixing cumene /with chlorosulfonic acid, nitric acid, or oleum/ in a closed container caused the temperature and pressure to increase. [R37, p. 491-66] *Incompatible with oxidizers. [R39] *Oxidizers, nitric acid, sulfuric acid [Note: Forms cumene hydroperoxide upon long exposure to air.] [R22, 80] DCMP: *Hazardous decomposition products: Toxic gases and vapors (such as carbon monoxide) may be released. [R40, 1981.2] ODRT: *Human odor perception: 0.06 mg/cu m= 0.012 ppm. [R3, 1170] *Detection of cumene in air 0.008 ppm. [R41] *Recognition of cumene in air 0.047 ppm. [R41] SERI: *CUMENE IS CONSIDERED A PRIMARY SKIN AND EYE IRRITANT ... [R42] EQUP: *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any reasonable probability of eye contact. ... Remove nonimpervious clothing promptly if contaminated or wet. [R43, 268] *... Enclosure, local ventilation or general ventilation should be arranged to maintain atmospheric concn below safe limits. [R38, 573] *If concentration in air is greater than 1000 ppm, use self-contained breathing apparatus. [R33] *500 ppm: Chemical cartridge respirator with an organic vapor cartridge(s); Supplied-air respirator; Self-contained breathing apparatus. 8000 ppm: type-C supplied-air respirator with a full facepiece operated in pressure-demand or other positive pressure mode or a full facepiece, helmet, or hood operated in continuous-flow mode. Escape: gas mask with an organic vapor canister (chin-style or front- or back-mounted canister); self-contained breathing apparatus. [R39] *Data indicate that cumene breaks through CPE protective materials in approximately an hour or more. [R44] *Wear appropriate personal protective clothing to prevent skin contact. [R22, 81] *Wear appropriate eye protection to prevent eye contact. [R22, 81] *Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. [R22, 81] *Recommendations for respirator selection. Max concn for use: 900 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R22, 81] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R22, 81] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R22, 81] OPRM: *Notify local health and pollution control officials, and operators of nearby water intakes. [R33] *Contact lenses should not be worn when working with this chemical. [R22, 81] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R22, 81] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R22, 81] SSL: *Volatile [R45, 94] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R46] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R47] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R48] STRG: *... PRECAUTIONS ... SUCH AS MOUNDS AROUND STORAGE TANKS, SILLS AT DOORWAYS OR ESPECIALLY DESIGNED FLOORS /ARE NEEDED/ TO LIMIT SPREAD OF ESCAPING LIQ. OPEN FLAMES AND OTHER SOURCES OF IGNITION SHOULD BE EXCLUDED WHERE CUMENE IS STORED. [R38, 573] *Outside or detached storage is preferred. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Separate from oxidizing materials, nitric acid, sulfuric acid. [R37, p. 49-45] *Storage temperature: Ambient. [R33] CLUP: *ISOPROPYLBENZENE, ISOPROPYLBENZENE PEROXIDE, AND ISOPROPYL PEROXIDE WERE REMOVED FROM WASTE GASES BY ABSORPTION IN AN AQ SOLN OF SODIUM SULFITE. [R49] *Remove all ignition sources; ventilate /the/ area of spill or leak. For small quantities absorb on paper towels /and/ evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. [R40, 1981.3] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U055, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R50] *Cumene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R51] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R52] *... Large quantities can be collected and atomized in a suitable combustion chamber. Combustion may be improved by mixing with a flammable liquid. Cumene liquid should not be allowed to enter a confined space, such as a sewer, because of the possibility of an explosion. [R40, 1981.] *The following wastewater treatment technologies have been investigated for cumene: Concentration process: Activated carbon. [R53] *The following wastewater treatment technologies have been investigated for cumene: Concentration process: Resin adsorption. [R54] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: Cumene is a water insoluble petrochemical used in the manufacture of several chemicals, including phenol and acetone. HUMAN EXPOSURE: In humans, cumene is metabolized primarily to the secondary alcohol. 2-phenyl-2-propranol. This alcohol and its conjugates are readily excreted by humans. No data are available with which to quantify human exposure. It is not possible to assess its potential for carcinogenicity in humans, because long term carcinogenicity studies with the chemical have not been performed. ANIMAL/PLANT STUDIES: Cumene is metabolized primarily to the secondary alcohol, 2-phenyl-2-propanol in animals. This alcohol and its conjugates are readily excreted by rodents. Increases in organ weights, primarily the kidney weughts are the most prominent effects observed in rodents readily exposed to cumene by either the oral or inhalation route. No adverse effects were observed in rat or rabbit fetuses whose mothers had been exposed to cumene during fetal development. Although no multigenerational reproductive studies have been performed using cumene, the rapid metabolism and excretion, coupled with the lack of effects on sperm morphology in a subchronic study, suggest that it has a low potential for reproductive toxicity. Most genotoxicity test data with cumene are negative. Inadequate data, especially measured exposure information, exist to allow a quantitative evaluation of the risk to populations of aquatic ot terrestrial organisms from exposure to cumene. Values indicate a slight potential for bioconcentration in fish. There are no data on the bioaccumulation in fish. [R55] CARC: *WEIGHT OF EVIDENCE CHARACTERIZATION: Classification - D; not classifiable as to human carcinogenicity. Basis -- Under the current Risk Assessment Guidelines, cumene is assigned category D, not classifiable, indicating no or inadequate human or animal data. Under the Proposed Guidelines for Carcinogen Risk Assessment, it is concluded that the carcinogenic potential of cumene cannot be determined because no adequate data, such as well-conducted long-term animal studies or reliable human epidemiological studies, are available for any assessment. Concern for the carcinogenic potential of cumene is judged to be limited from several standpoints. The metabolic pathways of this compound are, for the most part, known for both rats and humans and do not involve any suspect reactive species. Cumene has been examined in a relatively complete battery of in vivo and in vitro mutagenicity tests, including gene mutation, chromosomal aberration, and primary DNA damage. Only a single test, a micronucleus assay, was mildly positive, and then at a dose that resulted in mortality in some animals. Trends in structure-activity relationships are unclear for cumene. It is, however, clear with respect to metabolism that cumene is more analogous to methyl benzene (toluene) than to ethyl benzene, and that toluene showed no evidence of carcinogenic activity in rats or mice in a 2-year inhalation study /by NTP, 1990/. In summary, there is not much suspicion that cumene would pose a significant carcinogenic hazard. HUMAN CARCINOGENICITY DATA: Inadequate; none are available. ANIMAL CARCINOGENICITY DATA: Inadequate; none are available. [R56] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R57, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatics hydrocarbons and related compounds/ [R57, 182] MEDS: *Consider points of attack /(eyes, upper respiratory system, skin, central nervous system)/ in preplacement and periodic physical examinations. [R43, 267] *Employees should be screened for history of: kidney disease; chronic respiratory disease; liver disease; and skin disease, which might place the employee at increased risk from cumene exposure. [R40, 1981.1] HTOX: *FORTY-EIGHT PERCENT OF 102 WORKERS EXPOSED 7-10 YR TO ISOPROPYLBENZENE VAPORS HAD INCR BILIRUBIN CONCN, ALTERATION OF ENZYMATIC ACTIVITY, CHANGED LIPID METAB, LIVER AND HEPATOBILIARY FUNCTIONS, AND DYSKINESIA. [R58] *A high degree of cell membrane damage (measured as increased permeability) was observed when human lung fibroblasts were incubated in the presence of 25 mM cumene. [R59] *Short-term exposure: Cumene may cause dizziness, drowsiness, slight incoordination, and unconsciousness. [R40, 1981.1] *Potential CNS action. CNS depressant. [R36] *TOXIC BY INGESTION, INHALATION, AND SKIN ABSORPTION ... [R7, 329] *Cumene is considered a primary skin and eye irritant ... . [R42] *The action of the alkylbenzenes under conditions of acute exposure resembles those of the general anesthetics. /Alkylbenzenes/ [R60] NTOX: *Exposure of rats at 500 ppm cumene daily for 5 mos resulted in no significant changes in the peripheral blood; however, hyperemia and congestion were noted in the lungs, liver, and kidneys of exposed animals. When animals were dosed by repeated gastric intubation of 154 mg cumene/kg body weight for 194 days, no evidence of injury was found. At a higher dosage (462 mg/kg), an increase in the weight of kidneys was observed. Subcutaneous application of 1 ml cumene/kg daily for 2 wk did not lower the femoral marrow cell population. [R27, 1991.346] *Mice exposed to the vapors of cumene showed dilatation of cutaneous blood vessels, and grades of CNS depression, depression of respiration, and death, depending on the concentration and duration of exposure. [R27, 1991.346] *BY INHALATION ... EXPOSURE OF DOGS, CATS, RABBITS TO 60 MG/L (12200 PPM) DID NOT PRODUCE ANY SIGN OF INTOXICATION. ... IN MICE, BY INHALATION ... /PRC: CNS DEPRESSIVE/ DOSE /WAS FOUND/ TO BE BETWEEN 20 AND 25 MG/L (4000-5000 PPM) REPRESENTING LOWER TOXICITY ... THAN EITHER BENZENE OR TOLUENE. ... INHALATION EXPT ON RATS USING CONCN OF 6.5 MG/L (2000 PPM) 8 HR/DAY FOR 130-180 DAYS. RATS PROVED ... MORE SENSITIVE THAN THE RABBIT, SHOWING ... SYMPTOMS OF INTOXICATION, FOLLOWED BY DEATH AFTER 6-16 HR. EVEN 4 MG/L PROVED FATAL AFTER 16 HR, BUT AT 2.5 MG/L (500 PPM) NO SYMPTOMS OF DISTURBANCE OF HEALTH WERE OBSERVED. ... REPEATED INHALATION OF 2000 PPM CAUSED SYMPTOMS OF INTOXICATION IN RABBITS AND RATS. THESE INCLUDED SOMNOLENCE, MOTOR DISTURBANCE, AND LOSS OF EQUILIBRIUM. [R45, 96] *RATS, GUINEA PIGS, SQUIRREL MONKEYS, AND DOGS EXPOSED REPEATEDLY TO CUMENE VAPORS 8 HR/DAY, 5 DAYS/WK FOR 6 WK OR CONTINUOUSLY 90-127 DAYS. NO TOXIC EFFECTS WERE NOTED ON HEART, LUNG, LIVER, SPLEEN, KIDNEY, BRAIN, AND SPINAL CORD. [R61] *EXPOSURE OF RABBITS TO CUMENE, DOSE OF 0.5 MG/L FOR 4 HR/DAY FOR 4 MONTHS CAUSED CHANGES IN IMMUNOLOGICAL INDICATORS ONLY AT END OF EXPERIMENT. [R62] *CHRONIC INTOXICATION OF RATS AND RABBITS WITH ISOPROPYLBENZENE DECR OSMOTIC RESISTANCE OF LEUKOCYTES, DECR GLYCOGEN AND PEROXIDASE CONTENT OF NEUTROPHILS AND ACCUMULATED LIPIDS IN NEUTROPHILS. [R63] *Noradrenaline-induced respiration of isolated brown fat cells was 73% inhibited by 1 mM cumene. Brown fat cells respond to noradrenaline if every function, from the receptor at the cell membrane to mitochondrial cytochrome oxidase, is intact. [R64] *Cell multiplication of ascites sarcoma BP8 cells was inhibited 3% when ... /the/ cells were incubated in the presence of 0.1 mM cumene. 100% Inhibition /was/ noted /at/ 1 mM levels of the compound. [R65] *One-day exposure to cumene at 0.05 and 0.1% caused 100% death of Radix peregra and Lymnea stagnalis, respectively. ... Water temperature, pH, and total hardness had no effect on the toxic effect of the compound. The only important factor was oxygen, so the water was aerated during the experiments. [R66] *The influence of different kinds of industrial solvents on the vestibular function in rats /was/ studied by recording nystagmus, induced by accelerated rotation. The effect was related to the blood levels of the solvents. ... /Cumene caused an/ excitation of the vestibulo-oculomotor reflex. ... /It is suggested/ that the excitation of the vestibulo-oculomotor reflex is caused by interaction of cumene with central pathways in the reticular formation and the cerebellum. [R67] *The alkylbenzenes, incl isopropyl benzene, were investigated for their property as sensory irritants in mice. The concn of isopropyl benzene necessary to depress the respiratory rate by 50% due to sensory irritation of the upper respiratory tract was 2490 ppm. Minimal or no pulmonary irritation was observed with these alkybenzenes. [R68] *Cumene at 0.5 ml/l within 24 hr caused 100% mortality of both crabs Asellus aquaticus L and Gammarus fossarum Koch (Isopoda, Amphipoda). [R69] *An LC50 of 10.0 mg/l in mice exposed for 7 hr to a "relatively pure" cumene. In a repeat study in somewhat older mice (27 g vs 21 g), the LC50 was 11.5 mg/l, suggesting possible resistance with age. A technical grade cumene (> 95%) produced similar effects. The mice were described as manifesting slight lack of coordination followed by /SRP: CNS depression/ complete relaxation, loss of reflexes, decreased respiration, and death. /SRP: CNS depression/ lasted up to 36 hr in surviving animals. Pathological findings were notable for slight fatty infiltration of the liver, particularly in centrilobular areas, and some fatty droplets in renal cells. There was no evidence of pulmonary irritation. [R70] *Female rats were given 139 oral doses of cumene over 194 days at 154, 462, or 769 mg/kg body weight per dose. No effects on weight or on hematological or histopathological indices were noted at 154 mg/kg/day. At the two higher concn, only a dose-related increase in kidney weight was observed. [R70] *Contact of /cumene/ with the skin causes erythema and irritation. Eye contamination may produce conjunctival irritation. [R27, 1991.346] *Studies were conducted to evaluate the subchronic inhalation toxicity, neurotoxicity and ototoxicity of cumene in rats. Fischer-344-rats were exposed to cumene vapor at concentrations of 0, 100, 500 and 1,200 ppm for 6 hours per day, 5 days a week, for 13 weeks. A separate group received one 6 hour exposure. A second study tested similar exposure regimens for cumene concentrations of 0, 50, 100, 500 and 1,200 ppm. Blood samples from the rats in each group were collected for the measurement of hematological and serum chemistry parameters. The rats were killed during week 14 of the first study, or following a 4 week postexposure in the second study, and nervous system tissues were analyzed via light microscopy. Remaining rats in the subchronic study underwent complete necropsy after death. Male rats exposed to 500 and 1,200 ppm in the first study exhibited decreases in motor activity, but such effects were not observed in the second study. Male rats in the 500 and 1,200 ppm exposure groups demonstrated renal proximal tubular hypertrophy, hyperplasia, and hyaline drop formation as well. No exposure related ophthalmologic results or effects on spermatogenesis were found. Rats of both sexes from these groups also demonstrated decreased body weight and food consumption and altered hematological and clinical chemistry parameters. It was concluded that cumene produces mild to moderate toxic effects in rats at concentrations between 500 to 1,200 ppm, and that cumene vapor produces no appreciable neurotoxic or ototoxic effects at these concentrations. [R71] HTXV: *Human reflex response: adverse response: 0.028 mg/cu m. [R3, 1170] NTXV: *LC50 Mouse inhalation 2,000 ppm/7 hr; [R72] *LD50 Rat oral 2.91 g/kg; [R10] *LC50 Rat /inhalation/ 8000 ppm/4 hr; [R73] *LD50 Rat oral 1400 mg/kg; [R36] *LC50 Mouse inhalation 24,700 mg/cu m/2 hr; [R36] ETXV: *LC50 Daphnia magna 0.6 ppm/48 hr /Conditions of bioassay not specified/; [R74] *LD50 Agelaius phoeniceus (red-winged blackbird) oral 98 mg/kg; [R75] *Mytilus edulis (mussel larvae): no significant alteration of growth rate at concentrations of 1 to 50 ppm; [R3, 1171] *LC50 Pimephales promelas (fathead minnow) 6.32 mg/l/96 hr (confidence limit 6.04 - 6.61 mg/l), flow-through bioassay with measured concentrations, 25.4 deg C, dissolves oxygen 6.6 mg/l, hardness 44.3 mg/l calcium carbonate, alkalinity 42.1 mg/l calcium carbonate, and pH 7.58; [R76] *EC50 Pimephales promelas (fathead minnow) 6.32 mg/l/96 hr (confidence limit 6.04 - 6.61 mg/l), flow-through bioassay with measured concentrations, 25.4 deg C, dissolved oxygen 6.6 mg/l, hardness 44.3 mg/l calcium carbonate, alkalinity 42.1 mg/l calcium carbonate, and pH 7.58. Effect: loss of equilibrium. Affected fish lost schooling behavior and swam in a corkscrew/spiral pattern. They were hyperactive and darkly colored, had increased respiration, and lost equilibrium prior to death. Samples were not taken for the A, B, and C tanks at 96 hours for determination of toxicant concentrations; [R76] TCAT: ?The ability of cumene to induce morphological transformation was evaluated in the BALB/3T3 mouse embryo cell line (Cell Transformation Assay). Based on preliminary toxicity determinations (exposure time = 2 days), cumene was tested at concentrations of 5, 20 and 60ug/ml, resulting in colony forming efficiency ranging from 69.0% to 22.0%. Only at the 60ug/ml level was a positive response observed (six - Type III foci). Both positive and negative controls elicited expected results. [R77] ?The effect of cumene was examined in the rat hepatocyte primary culture/DNA repair assay. Primary hepatocytes were isolated from Fischer 344 rats and exposed to test article at 8, 16, 32, 64 or 128 ug/ml for 19 hours. A statistically significant (test type not reported, p < 0.01) increase in mean net nuclear grain counts, and percentage of cells in repair was observed at 16 and 32 ug/ml. Cytotoxicity was observed during the test at the 128 ug/ml dose level. [R78] ?The metabolic disposition of cumene was studied in Fischer 344 rats (4/sex/dose group) after oral gavage administration of a single dose of 33 or 1350 mg 14C- cumene/kg bw/day in Emulphor-saline vehicle. Another group of rats was administered a dose of 33 mg non-radioactive cumene/kg bw/day for 7 consecutive days, followed by a single dose of labeled cumene on the eighth day. Similar results were obtained between the single and repeated dose experiments. The urine was the major route of excretion of 14C. Approximately 80% of the administered radioactivity had been excreted in the urine 72 hours after dosing with radioactive cumene. After the high dose, exhaled volatile organics more than doubled the amount exhaled after the low dose of cumene, (14% of the administered dose compared with 5%, respectively). Relatively little radioactivity was found in tissues 72 hours after dosing. Liver, kidney, and adipose tissue contained 2-3 times more 14C than other tissues after the low and repeated dose exposures; 14C was concentrated in the femur and adipose tissue after the high dose of cumene. Distribution of cumene after low-, high-, and repeated-dose exposures could be fitted to one-compartment models with elimination half-lives from blood of 16, 9.2, and 5.7 hours, respectively. Six metabolites were identified in the urine, two of them were major components. [R79] ?The metabolic disposition of cumene was studied in Fischer 344 rats (4/sex/dose group) after nose-only exposure to nominal concentrations of 100, 500, or 1200 ppm of 14C-cumene vapors for 6 hours. Over 80% of the administered radioactivity was recovered in the urine 72 hours following exposure to any of the 3 cumene concentrations. Females in the 500 ppm group exhaled 7% of the radioactivity as volatile organics in 72 hours, compared with < 7% in the other 2 treated groups. 14C in adipose tissue was 0.04, 0.08, and 0.05% of the dose inthe 100, 500, and 1200 ppm groups, respectively. At each exposure level, the percentage of 14C in adipose tissue was higher thatn in any other tissue. 14C was also concentrated in liver, kidney, bone, heart, ovaries, and skeletal muscle, but differences were observed between male and female rats. The blood concentration of 14C peaked at 1.9 ug-eg/g blood 6 hours after initiation of exposure and rapidly declined thereafter. Half-life elimination of 14C from blood after exposure to 100, 500, or 1200 ppm cumene were 3.9, 4.5, and 6.6 hours, respectively. Six metabolites detected in the urine were the same as those detected after oral or i.v. dosing with cumene. Experiments with unlabeled cumene gave terminal half-life estimates of 17-30 hours for cumene itself and were generated from a two-compartment model constructed using blood concentration versus time data. [R79] ?The metabolic disposition of cumene was studied in Fischer 344 rats (4/sex/dose group) after a single intravenous injection of 33 mg 14C-radiolabeled compound/kg bw/day. The vehicle was Emulphor in buffered saline. The principal route of excretion of radioactivity was the urine (75% recovered radioactivity at 72 hours after dosing). Volatile hydrocarbons accounted for a total of approximately 8.5% of the injected radioactivity 72 hours after dosing. Fecal excretion, or excretion of 14C-CO2 was minimal. Maximal urinary excretion occurred 16 hours after dosing. Only small traces of radioactivity were found in the carcasses. There were no significant differences between male and female rats with respect to toxicological parameters. 14C concentration in blood was maximal (approximately 7000 ug-eg/g blood) 15 minutes after dosing and decreased to 1/3 maximal levels after 1 hour. Twenty-four hours after dosing, the blood concentration of 14C had decreased to approximately 1/40 of the peak value. Elimination of radioactivity from blood were best fit to a two-compartment model described by a biexponential equation; the terminal half- lives were determined to be 0.24 and 8.0 hours. At least six radiolabeled metabolite peaks were detected in urine and in exhaled air; two of these six peaks accounted for more than 90% of the radioactivity in urine. The six major peaks found in urine after i.v. dosing were the same as those found in urine after oral and inhalation exposure to cumene. [R79] ?The ability of cumene to induce micronuclei in bone marrow polychromatic erythrocytes of groups of 10 male and 10 female Crl:CDR-1(ICR)BR Swiss mice was evaluated at dose levels of 0.25, 0.50, 1.00 (2 doses), and 1.00 (1 dose, 15 animals) g/kg administered in paraffin oil by gavage once daily for two days using bone smears prepared, half on day 3 and half on day 4, following onset of dosing. Dose levels were based on preliminary toxicity studies. No significant (p < =0.05) increase occurred in any cumene dose group relative to controls, although the positive control, administered 75 mg/kg cyclophosphamide intraperitoneally, did show a difference (p < =0.05). [R80] ?The ability of cumene to induce mutations at the gene locus coding for hypoxanthine-guanine phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was evaluated in the presence and absence of metabolic activation from Aroclor-induced rat liver S9 fraction. Based on preliminary cytotoxicity tests, nonactivated cultures were treated with cumene at concentrations of 8, 16, 32, 64, and 128 mcg/ml producing cell survivals relative to the vehicle control (Pluronic F127) of 122.9, 92.8, 104.7, 124.6, and 89.2% respectively. Activated cultures treated with cumene concentrations of 64, 128, 150, and 175 mcg/ml produced relative cell survivals ranging from 91.0 - 7.6%. A significant mutagenic response was not observed in either activated or nonactivated trials. [R81] ?The effect of cumene was examined in the rat hepatocyte primary culture/DNA repair assay. Primary hepatocytes were isolated from Fischer 344 rats and exposed to test article at 8, 16, 32, 64 or 128 ug/ml for 19 hours. A statistically significant (test type not reported, p < 0.01) increase in mean net nuclear grain counts, and percentage of cells in repair was observed at 16 and 32 ug/ml. Cytotoxicity was observed during the test at the 128 ug/ml dose level. [R82] ?Cumene was tested for genotoxicity in vitro in cultured adult male Fischer 344 rat hepatocytes exposed to concentrations of 0, 1, 2, 4, 8, 16, 24, 32, 48, 64, 80, 96, 112, or 128 ug/ml culture medium, in the presence of 10 uCi/ml 3H-thymidine. The rate of unscheduled DNA synthesis in hepatocytes was determined by measuring the extent of incorporation of labeled thymidine into DNA, using autoradiography. Concentrations ranging from 32 to 120 ug/ml were excessively toxic to cell cultures and unscheduled DNA synthesis could not be measured at these concentrations. The treatment did not increase the rate of unscheduled DNA synthesis, indicating that the test compound was not genotoxic in rat hepatocytes under the conditions of this assay. [R83] ?The mutagenicity of cumene was evaluated in Salmonella tester strains TA98, TA100, TA1535, and TA1537, both in the presence and absence of added metabolic activaiton provided by Aroclor-induced rat liver S9 fraction. After bacterial toxicity determinations, cumene was tested for mutagenicity at concentrations of up to 0.2 ul/plate using the plate incorporation technique, and concentrations of 20 ul/spot in the spot test. Cumene did not induce a positive response in any bacterial tester strain, either with or without metabolic activation. [R84] ?Cumene (CAS No. 98-82-8) was evaluated for neurotoxicity in a functional test of auditory brainstem responses to tone pips. The test substance was administered by inhalation to rats (10/sex/group) at 0, 50, 100, 500, and 1,200 ppm 6 hours/day, 5 days/week for 13 weeks. There were no effects on the auditory function of rats after exposure to cumene. [R85] POPL: *Employees /with kidney, chronic respiratory, liver, or skin disease/ are at increased risk from cumene exposure. [R40, 1981.1] ADE: *CUMENE IS STATED TO BE ABSORBED THROUGH THE INTACT SKIN MORE RAPIDLY THAN TOLUENE, XYLENE, OR ETHYLBENZENE. A SMALL QUANTITY ... ABSORBED IN THE BLOOD IS EXHALED UNCHANGED, BUT THE MAJOR PORTION IS ... EXCRETED IN THE URINE AS CONJUGATED ALCOHOLS OR ACIDS. [R27, 1991.346] *VAPOR IS READILY ABSORBED INTO BLOOD STREAM AND SMALL PART (LESS THAN 5% ...) IS EXHALED UNCHANGED. ... AMT OF CUMENE /WERE FOUND/ VARYING FROM 8 UG/G IN LIVER TO 29 UG/G IN BLOOD OF RATS 48 HR AFTER LAST EXPOSURE (REPEATED FOR TWO MONTHS) TO CONCN OF 500 PPM. ... ISOPROPYLBENZENE APPEARS TO BE LOCALIZED SELECTIVELY AND ESP IN ENDOCRINE GLANDS, CENTRAL NERVOUS SYSTEM, SPLEEN AND LIVER AND ... IT DISAPPEARS MORE RAPIDLY IN RABBIT THAN IN RAT. ... BLOOD RETAINS A CERTAIN AMT LONGER THAN INTERNAL ORGANS. [R45, 95] *ABSORPTION OF CUMENE LEADS TO A DEFINITE INCREASE IN URINARY EXCRETION OF GLUCURONIDES OF COMPOUNDS FORMED BY PARTIAL OXIDATION OF ALKYL RADICAL. MAIN METABOLIC PATHWAY ... DOES NOT INVOLVE PRODN OF PHENOL, WHICH EXPLAINS LACK OF AGGRESSIVENESS OF CUMENE TO BONE MARROW. [R38, 572] *IV ADMIN TO RAT SHOWED HIGHEST CONCN IN ADIPOSE TISSUES, KIDNEY, BRAIN, ADRENAL GLANDS, HEART, AND LUNG, 2-3 HR LATER INCR CONCN IN BRAIN, PITUITARY AND BONE MARROW. [R86] *EXPT MADE ON 10 HEALTHY VOLUNTEERS, EXPOSED TO VAPORS OF 240, 480 OR 720 MG/L, SHOWED RETENTION OF ABOUT 50% CUMENE. [R87] *90% of an oral dose of cumene /was recovered as metabolites/ from rabbit urine. [R88] */A study was conducted/ to determine the tissue distribution of cumene in rats exposed to the cmpd by inhalation. In one series of experiments, the animals were exposed to cumene at levels of 2.5 mg/l for two months. The duration of each daily exposure ... was not specified. 24 hr after the last exposure cumene levels in various tissues were analyzed. ... The highest levels of cumene were observed in the thyroid, and adrenal glands, and the lowest levels in the kidney, heart, lung, and stomach. Intermediate levels were found in components of the central nervous system. [R89] *Cumene was measured in the breath and blood of two groups of individuals; one group belonging to a hospital staff, and the other included chemical workers who were not exposed to cumene (workplace air concn < 0.1 ug/l). Chemical workers were examined in the morning before the start of work in the plant infirmary, and the hospital staff in the hospital infirmaries. At the time of biological sampling for each individual, one environmental sample was also taken of the air. Environmental concn of cumene were not significantly different in the plant and in the hospital infirmaries. Blood cumene concn was significantly higher in chemical workers. A correlation between alveolar and environmental concn was found for cumene. [R90] METB: *Cumene is absorbed readily by the mammalian system and oxidized at the side chain, one of the metabolites being the dimethylphenylcarbinol glucuronide. [R31, 1347] *HYDROXYLATION OF AROMATIC HYDROCARBONS FOLLOWING THEIR ORAL ADMIN TO RATS ALSO RECEIVING PURIFIED DIET WITH NEOMYCIN TO REDUCE LEVELS OF NORMALLY OCCURRING PHENOLS, YIELDED URINARY METABOLITE 2-PHENYL-2-PROPYL ALCOHOL AND 2-PHENYL-1-PROPYL ALCOHOL. [R91] *A VARIETY OF BACTERIAL STRAINS, SUCH AS PSEUDOMONAS DESMOLYTICA, PSEUDOMONAS CONVEXA, AND PSEUDOMONAS OVALIS ARE CAPABLE OF GROWING ON CUMENE. OXIDATION PRODUCTS WERE IDENTIFIED AS 3-ISOPROPYLCATECHOL AND (+)-2-HYDROXY-7-METHYL-6-OXOOCTANOIC ACID. [R31, 1347] *In rabbits, 90% of a 2 ml oral dose was accounted for as side-chain oxidation products of cumene, which were excreted as glucuronide conjugates. About 40% of the dose was excreted as the glucuronide of 2-phenyl-2-propanol, 25% as the glucuronide of 2-phenyl-1-propanol, and 25% as the ester-glucuronide of 2-phenyl-propionic acid. [R92] *... The major portion /of the cumene absorbed in the blood/ is metabolized in the liver ... [R27, 1991.346] *MAJOR PORTION /AFTER DERMAL EXPOSURE/ IS ... EXCRETED IN THE URINE AS CONJUGATED ALCOHOLS OR ACIDS. [R27, 1991.346] *ABSORPTION OF CUMENE LEADS TO A DEFINITE INCREASE IN URINARY EXCRETION OF GLUCURONIDES OF COMPOUNDS FORMED BY PARTIAL OXIDATION OF ALKYL RADICAL. MAIN METABOLIC PATHWAY ... DOES NOT INVOLVE PRODN OF PHENOL, WHICH EXPLAINS LACK OF AGGRESSIVENESS OF CUMENE TO BONE MARROW. [R38, 572] *90% of an oral dose of cumene /was recovered as metabolites/ from rabbit urine. [R88] ACTN: *The alkylbenzenes, incl isopropyl benzene, were investigated for their property as sensory irritants in mice. A model for the sensory irritating action of alkylbenzenes was proposed on the basis of their physical interaction with a receptor protein in a lipid layer. [R68] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Cumene's production and use in the production of phenol and acetone may result in its release to the environment through various waste streams. Cumene occurs in a variety of natural substances including essential oils from plants and foodstuffs. If released to air, a vapor pressure of 4.5 mm Hg at 25 deg C indicates cumene will exist solely as a vapor in the ambient atmosphere. Vapor-phase cumene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2.5 days. Cumene is also known to react with ozone radical found in the atmosphere but not at an environmentally important rate. If released to soil, cumene is expected to have low mobility based upon an estimated Koc of 820. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 0.0115 atm-cu m/mole. Cumene may volatilize from dry soil surfaces based upon its vapor pressure. However, adsorption to soil is expected to attenuate volatilization. After a 10 and 20 day exposure of cumene to wastewater inoculum, a theoretical BOD of 62% and 70% was observed, respectively. Based on these results, cumene is expected to undergo considerable biodegradation in soil environments. If released into water, cumene is expected to adsorb to sediment and suspended solids in water based upon the estimated Koc. Using river water and sediment, the aerobic biodegradation of cumene was studied in a closed system. The disappearance rate of cumene (avg concn 2.5 mg/l) via mineralization was 0.02/day; this equates to a half-life of 34.6 days. Based on the results of this experiment, residence time of cumene in aquatic ecosystems will likely be brief. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.2 hrs and 4.4 days, respectively. However, volatilization from water surfaces is expected to be attenuated by adsorption to sediment and suspended solids in the water column. A BCF of 35 suggests bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to cumene may occur through inhalation and dermal contact with this compound at workplaces where cumene is produced or used. The general population may be exposed to cumene via inhalation of ambient air, ingestion of food, and vapors from gasoline products containing cumene. Cumene is widely detected in the atmosphere mainly due to its presence in gasoline and as a natural component in plants. (SRC) NATS: *Cumene occurs in a variety of natural substances including essential oils from plants(1), marsh grasses(2,3), and a variety of foodstuffs(4-12). [R93] ARTS: *About 98% of cumene produced in the U.S. is used to produce acetone and phenol(1). Cumene is released by manufacturing and processing plants and during the transport of cumene. Cumene is also a constituent of crude oil and finished fuels(2). It is, therefore, released to the environment by oil spills and the incomplete combustion of fossil fuels by land transportation vehicles. It is also released during the transportation and distribution of motor fuels and by evaporative loss from gasoline stations. Cigarette tobacco also releases cumene during consumption(3). Cumene release from all these sources was estimated to be 21 million pounds annually(4). Other, unquantifiable anthropogenic cumene releases include operations involving vulcanization of rubber(5), building materials(6), jet engine exhaust(7), outboard motor operation(8), solvent uses(9), paint manufacture(10), pharmaceutical production(11), and textile plants(12). Cumene is also released to the environment from leather tanning, iron and steel manufacturing, paving and roofing, paint and ink formulation, printing and publishing, ore mining, coal mining, organics and plastics manufacturing, pesticide manufacturing, electroplating and pulp and paper production(13). [R94] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 820(SRC), determined from a structure estimation method(2), indicates that cumene is expected to have low mobility in soil(SRC). Volatilization of cumene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 0.0115 atm-cu m/mole(3). The potential for volatilization of cumene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 4.5 mm Hg(4). However, adsorption to soil is expected to attenuate volatilization(SRC). After a 10 and 20 day exposure of wastewater inoculum to cumene, a theoretical BOD of 62% and 70% was observed, respectively(5). Based on these results, cumene is expected to undergo considerable biodegradation in soil environments(SRC). [R95] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 820(SRC), determined from an estimation method(2), indicates that cumene is expected to adsorb to sediment and suspended solids in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 0.0115 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.2 hrs and 4.4 days, respectively(SRC). In natural waters, cumene is degraded by reaction with hydroxyl radicals(SRC); the half-life for this reaction in water is estimated to be 107 days(SRC), calculated from its rate constant of 7.5X10+9 L/mol sec at pH 7(5). In another study of the abiotic degradation of cumene in aquatic systems, photooxidation of cumene by alkylperoxy radicals and hydroxyl radicals was found to occur with half-lives of 2.2 and 0.7 yrs, respectively(6). According to a classification scheme(7), a BCF of 35(8) suggests the potential for bioconcentration in aquatic organisms is moderate. Using river water and sediment, the aerobic biodegradation of cumene was studied in a closed system(9). The disappearance rate of cumene (avg concn 2.5 mg/l) via mineralization was 0.02/day; this equates to a half-life of 34.6 days(9). Based on the results of this experiment, residence time of cumene in aquatic ecosystems will likely be brief(9). In an experiment to study the disappearance of organic compounds found in crude oil during an oil spill, cumene was found to disappear (combination of evaporation and dissolution) within 90 mins of being spilled into seawater(10). In a similar experiment, water samples taken from an oil spill in the Canadian Arctic waters in the Ragged Channel revealed that after 6 hours, cumene could not be detected in the aromatic fraction(11). Cumene has a reported volatilizaiton half-life in water ranging form 3.2 to 5.8 hrs(12). [R96] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cumene, which has a vapor pressure of 4.5 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase cumene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.5 days(SRC), calculated from its rate constant of 6.5X10-12 cu cm/molecule-sec at 25 deg C(3). Vapor-phase cumene is also degraded in the atmosphere by reaction with ozone radicals(SRC); the half-life for this reaction in air is estimated to be 3 yrs(SRC), calculated from its estimated rate constant of 1.0X10-20 cu cm/molecule-sec at 25 deg C(4). Cumene has an absorption maximum at 258 nm in cyclohexane(5) and has been theoretically estimated to have a direct photolysis half-life of about 1500 years(6). Consequently, direct photolysis degradation is not expected to be significant in the atmosphere(SRC). [R97] BIOD: *Cumene was added to uncontaminated groundwater and this solution was continuously percolated through a column containing homogeneous sand(1). No additional nutrients were added to the system and it was assumed to be aerobic throughout. Biodegradation occurred following 5 days of acclimation and the cumene degraded to non-detectable levels within 48 h(1). Cumene biodegradation in batch reactors proceeded following about 144 hr of acclimation and after 120 hr, cumene was non-detectable(2). In unacclimated cultures, the half-life of cumene was 206 hr (62 hr after acclimation)(2). Mixed cultures from contaminated and uncontaminated estuarine sediments were capable of degrading cumene with the higher rate observed in the culture from the contaminated sediment(2). Cumene incubated with mixed cultures taken from various depths in the Atlantic Ocean at 15 deg C were all capable of biodegrading cumene(3). When cumene was incubated with an activated sludge acclimated to benzene, the theoretical BOD was reduced by 37.8% after 192 hr(4). A 20-day biological oxygen demand study was conducted using unacclimated, settled, domestic wastewater as the inoculum(5). After 10 and 20 days, the theoretical BOD was 62% and 70%, respectively(5). Activated sludge acclimated to aniline degraded cumene following an acclimation period of about 30 hr(6). Activated sludge samples from three different communities were able to degrade 50 mg/l cumene(7). Incubation with a pure culture of Pseudomonas putida resulted in the degradation of cumene to an orthodihydroxy compound in which the isopropyl side chain of cumene was intact(8). Incubation of cumene with Pseudomonas desmolytica and Pseudomonas convexa resulted in the formation of (+)-2-hydroxy-7-methyl-6-oxo-octanoic acid via 3-isopropylcatechol(9). [R98] *AEROBIC: Using river water and sediment in a test system, the aerobic biodegradation of cumene was studied in a closed system(1). The disappearance rate constant of cumene (avg concn 2.5 mg/l) for total mineralization was 0.02/day; this equates to a half-life of 34.6 days. However, when volatilization was considered coupled with biodegradation, the half-life for cumene became 2.5 days(1). Cumene biodegradation experienced a lag time of approximately 5 days(1). Based on the results of this experiment, residence time of cumene in aquatic ecosystems will likely be brief(1). [R99] *ANAEROBIC: In an in-situ anaerobic biodegradation study of various alkyl benzene compounds, cumene was found to undergo considerable biodegradation(1). Biodegradation proceeded via methanogenic and fermentative bacteria(1). [R100] ABIO: *The rate constant for the vapor-phase reaction of cumene with photochemically-produced hydroxyl radicals is 6.5X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 2.5 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The major product of the reaction of cumene with hydroxyl radicals is likely to be isopropylphenols with minor compounds resulting from side chain attack(2). Vapor-phase cumene is also degraded in the atmosphere by reaction with ozone radicals(SRC); the half-life for this reaction in air is estimated to be 3 yrs(SRC), calculated from its rate constant of 1.0X10-20 cu cm/molecule-sec at 25 deg C(2). Cumene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3) nor to directly photolyze in the environment at a significant rate based upon a UV absorption of 258 nm in cyclohexane(4). In aqueous solution, cumene will react with hydroxyl radical (avg concn = 1.0X10-17 molec/cu cm) at a reaction rate of 7.5X10+9 L/mol sec at pH 7; resulting in an estimated half-life of 107 days(5). In another study of the abiotic degradation of cumene in aquatic systems, photooxidation of cuemene by alkylperoxy radicals and hydroxyl radicals was found to occur with half-lives of 2.2 and 0.7 yrs, respectively(6). [R101] BIOC: *A BCF of 35 for cumene was determined in fish(1). A BCF of about 35.5 was measured in goldfish which were exposed to cumene at 1 mg/l(2). According to a classification scheme(3), these BCF values suggest the potential for bioconcentration in aquatic organisms is moderate. [R102] KOC: *Cumene is expected to partition to soil and sediment since it has an olive oil/water partition coeffecient of 4316, and an olive oil/air partition coefficient of 1.44. [R103] *Recovery of 100 ml samples of ... cumene was in most cases > 99%, after percolation through black soil, red soil, clayish loam, potter's clay, and alluvium soil columns 75 cm high and 3 cm in diameter. ... The petrochem changed pH in acidic soils more than in buffered soils. [R104] *Using a structure estimation method based on molecular connectivity indices(1), the Koc for cumene can be estimated to be 820(SRC). According to a classification scheme(2), this estimated Koc value suggests that cumene is expected to have low mobility in soil. [R105] VWS: *The Henry's Law constant for cumene is 0.0115 atm-cu m/mole(1). This Henry's Law constant indicates that cumene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.2 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4.4 days(SRC). Cumene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of cumene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 4.5 mm Hg(3). [R106] WATC: *SURFACE WATER: Cumene was found in the River Lee, UK at < 0.1 and > 0.1 ug/l at two separate sampling points(1). Cumene was detected but not quantified in surface water samples from Narraganset Bay, RI(2) and Japan(3). [R107] *GROUNDWATER: Cumene was detected in three ground water samples from Hoe Creek, WV near an underground coal gasification site at 19, 27 and 59 ug/l (mean 35 ug/l)(1). Cumene was found in groundwater throughout the US (including Puerto Rico) at less then 0.5 ug/l(2). Cumene was detected in 5 groundwater samples from Great Ouse Basin, UK (near a gasoline storage tank) ranging from 0.01-30 ug/l (mean 9.8 ug/l(3). Cumene was also detected but not quantified in groundwater from Ames, IA(4), New York state(5), Melbourne, Australia (near a dump site)(6) and Milan, Italy (near underground storage tanks)(7). [R108] *DRINKING WATER: Ten drinking water samples taken for each of 13 US cities reported that 7.7% of samples tested positive for cumene at an avg concn of 0.01 ug/l(1). Cumene was detected in drinking water samples from Cincinnati, OH at 0.014 ug/l(2). Cumene was found in drinking water throughout the US (including Puerto Rico) at less then 0.5 ug/l(3). Cumene was detected but not quantified in drinking water from New York State(4) and in tap water from Japan(5). [R109] *GROUNDWATER: Cumene was detected in groundwater at two out of three sites studied in Denmark; these sites had been contaminated by creosote and in one case gasoline as well(1). Three groundwater samples from a shallow sandy aquifer in Holte, Denmark contained cumene concns ranging from 2 to 22 ug/l while five groundwater samples from Fredericia (Jutland) Denmark contained cumene concns ranging from none detected to 3 ug/l(1). [R110] *RAIN/SNOW/FOG: Eight surface snow samples taken during the 1987/88, 1988/89, and 1990/91 Italian Antarctic Expeditions and six samples collected at different depths from two dissimilar sites during the 1990/91 expedition, were analyzed for organic content(1). Cumene was found at an avg value of 8 ng/l in the 1987/88 expedition, 16 ng/l in the 1988/89 expedition, and was not detected in the 1990/91 expedition(1). Cumene was not detected in deep snow samples collected during the 1990/91 expedition either(1). [R111] EFFL: *Cumene was determined to be a volatile organic compound released by photocopying machines during operation at an emission rate ranging from 140-220 ug/hr(1). Headspace samples from toner cartridges were also studied and found to contain cumene at 6.6 ng/ml(1). A study to evaluate the benefits of various vehicles with and without a catalytic converter was conducted on cars manufactured from 1991-93(2). Cumene emission rates from a 1991 Toyota with and without a catalytic converter were 0.0003 and 0.002 g/km, respectively(2). The emission rate from a 1991 Ford with a catalytic converter was 0.0004 g/km while cumene emission rates from a 1993 vehicle on a cold and hot start (both using catalytic converter) were 0.0009 and 0.0002 g/km, respectively(2). Catalytic converters were found to reduce emissions of cumene anywhere from 57.4-91.7%(2). Regionwide cumene emission rates in Los Angeles, CA from August 27-28, 1987 were measured at 2.3X10+3 kg/day(3). In a study to identify VOCs from biodegradable municipal mixed waste, cumene was detected (concn not specified) in 1 out of 7 mixed waste samples(1). [R112] SEDS: *SEDIMENT: Cumene was detected in sediment samples from Puget Sound, WA and Strait of Juan de Fuca, WA; in 23 samples, 16% were positive, with a concn ranging from 0.02 to 19 ug/g, averaging 2.3 ug/g(1). Cumene was detected but not quantified in Puget Sound, WA(2). [R113] *SOIL: Soil samples taken from beneath an old building in Germany contained cumene at a concn of 24 mg/kg(1). [R114] ATMC: *Samples collected from the Milwaukee plume over Lake Michigan on August 27 and 28, 1976 contained 0.1 ppb (v/v) of isopropylbenzene. [R115] *Measurements of Los Angeles air (126 samples) in 1966 yielded cumene concentrations averaging 3 ppb with a maximum of 12 ppb. [R116] *URBAN/SUBURBAN: In 17 air samples taken from Los Angeles, CA, 94% tested positive for cumene with concns ranging from none detected-9.8 ug/cu m(1). In another study of Los Angeles air, cumene tested positive in 100% of 136 samples taken at a mean concn of 14.7 ug/cu m (144 ug/cu m max)(2). Cumene tested positive in 8 out of 10 air samples taken from Los Angeles at concns ranging from < 2.45-36 ug/cu m (16.66 ug/cu m mean)(3). In 21 air samples taken from Houston, TX, cumene tested positive in 88% of them at concns ranging from none detected-24.89 ug/cu m (12.15 ug/cu m mean)(4). Two air samples taken above Lake Michigan (1000-3000 ft) contained cumene at 0.49 ug/cu m(5). In 15 air samples taken from Jones State Forest, TX (near Houston), cumene tested positive in 100% of them at concns ranging from 0.108-9.8 ug/cu m(2.45 ug/cu m mean)(6). In 9 air samples taken near campfires from the Smokey Mountains National Park, TN, cumene tested positive in 44% of them at concns ranging from < 0.049-0.392 ug/cu m (0.245 ug/cu m mean)(7). Air samples taken from Deer Park, TX near the Shell Oil Refinery contained cumene at 29.4 ug/cu m (downwind) and 53.9 ug/cu m(upwind)(8). Air samples taken from Delft, Netherlands contained cumene ranging from < 0.49-1.96 ug/cu m(9). Cumene was detected but not quantified in air samples taken in Elizabeth, Newark, Batsoto and South Amboy, NY(10), Pullman, WA(11), Allegheny Mountain Tunnel, PA(12), Leningrad, USSR(13), and Gatwick, UK(14). [R117] *URBAN/SUBURBAN: In a literature review, conducted in 1986, of indoor and outdoor atmospheric levels of cumene in both residential and commercial environments, it was found that cumene reached a daily avg concn of 0.177 ppbv in the United States(1). Avg ambient urban concns of cumene measured in Porte Alegre, Brazil from March 20, 1996 to April 16, 1997 were 0.9 mg/cu m(2). Air pollution measurements were conducted in the Antwerp, Belgium Craeybeckx tunnel in 1991(3). Cumene had an avg concn of 0.003 and 0.009 g/kg carbon (g/kg carbon signifies cumene's concn in relation to the total amount of carbon based pollutants) in the tunnel during normal traffic and congested traffic conditions, respectively(3). Emission rates from motor vehicles were studied for vapor-phase, semivolatile, and particle-phase organics inside and outside a Los Angeles roadway tunnel in 1993(4). Cumene was emitted at a rate of 11 mg/l of gasoline consumed(4). [R118] *RURAL/REMOTE: Cumene was detected(concentration not specified) in ambient air samples taken from Witaker's Forest/Sierra Nevada Mountains, California from June 20-June 22, 1990(1). Measurements were performed in midsummer at high ambient temperatures and under stable meteorological conditions with high solar radiation(1). Although the area was very remote, the air samples could have been influenced by emissions from California's Central Valley and even from the San Francisco Bay area(1). [R119] FOOD: *Trace quantities of cumene have been detected in papaya(1), Sapodilla fruit(2) and Australian honey(3). Cumene has been detected but not quantified in fried chicken(4), tomatoes(5), Concord grapes(6), cooked rice(7), oat groats(8), baked potatoes(9), Beaufort cheese(10), fried bacon(11), dried legumes (beans, split peas and lentils)(12), southern pea seeds(13), and Zinfandel wine(6). [R120] *Cumene has been detected as one of several volatile hydrocarbons found in chicken and pork(1). [R121] PFAC: PLANT CONCENTRATIONS: *Cumene occurred in a variety of marsh grass species at 6.0X10-5 to 5.0X10-4% of the total fresh plant(1-3). Cumene has been detected but not quantified in curly parsley(4), and oakmoss(5,6). [R122] FISH/SEAFOOD CONCENTRATIONS: *Approximate concentration causing adverse taste in fish: 0.25 mg/l. [R3, 1171] RTEX: *The most probable route of human exposure to cumene is exposure to air contaminated with the chemical from evaporation of petroleum products (ie in individuals engaged in pumping gas or due to combustion of petroleum products or tobacco(1). Additional exposure may result from food consumption. Little exposure is expected to result from water intake. (SRC) [R123] *Work area monitoring samples from cumene producers and processors were as follows. Distillation - 0.0001-3.35 ppm, 0.45 ppm mean; oxidation - 0.0001-5.58 ppm, 0.93 ppm mean; laboratory - 0.34-0.44 ppm, 0.39 ppm mean; repair - 0.16-2.50 ppm, 1.33 ppm mean; recovery - 0.001-1.20 ppm, 0.31 ppm mean; cumene unit - 0.078-0.620 ppm, 0.189 ppm mean(1). Gasoline delivery truck drivers are exposed to air containing from < 0.01-0.04 ppm cumene(2). Cumene levels were 60-250 ug/cu m in shoe factory air and 2-200 ug/cu m in the vulcanization area and not detected-10 ug/cu m in the extrusion area of tire retreading plant(3). [R124] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 14,268 workers (2,760 of these are female) are potentially exposed to cumene in the US(1). Occupational exposure to cumene may occur through inhalation and dermal contact with this compound at workplaces where cumene is produced or used(SRC). The general population may be exposed to cumene via inhalation of ambient air(2-4), ingestion of food(5), and vapors from gasoline products(6) containing cumene(SRC). [R125] BODY: *Cumene has been detected at 0.13 ug/hour(1) and detected but not quantified(2) in human expired air from non-smoking individuals. [R126] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *900 ppm [IDLH based on 10% of the lower explosive limit for safety considerations even though the relevant toxicological data indicated that irreversible health effects or impairment of escape existed only at higher concentrations.] [R22, 81] ATOL: *Cumene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R127] *Isopropylbenzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R128] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 50 ppm (245 mg/cu m). Skin Designation. [R129] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 50 ppm (245 mg/cu m). Skin. [R22, 80] TLV: +8 Hr Time Weighted Avg (TWA): 50 ppm. [R130, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R130, 2002.6] OOPL: *Australia: 50 ppm, skin (1990); Federal Republic of Germany: 50 ppm, skin (1990); Sweden: 25 ppm, 15-min short-term value 35 ppm, skin (1984); United Kingdom: 50 ppm, 10-min STEL 75 ppm, skin (1991). [R27, 1991.347] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Cumene is produced, as an intermediate or a final product, by process units covered under this subpart. [R131] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Cumene is included on this list. [R132] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 0.8 ug/l [R133] +(MN) MINNESOTA 300 ug/l [R133] +(NH) NEW HAMPSHIRE 280 ug/l [R133] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R134] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Cumene is included on this list. [R135] RCRA: *U055; As stipulated in 40 CFR 261.33, when cumene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R136] FIFR: *Isopropylbenzene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R128] *Cumene is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R127] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Adsorption on activated charcoal is the preferred method of sampling for cumene. A known volume of air is drawn through a charcoal tube to trap the organic vapors. The charcoal in the tube is then transferred to a small, stoppered container, and the sample is desorbed with carbon disulfide. [R137] *Principle: Collection and concentration on activated charcoal; Sampling flow: 10-200 ml/min. [R138] *NIOSH Method S23. Analyte: Cumene. Matrix: Air. Procedure: Adsorption on charcoal, desorption with carbon disulfide. Flow Rate: 0.20 l/min. Sample Size: 10 l. [R139, p. V2 S23-1] *NIOSH Method 1501. Analyte: Cumene. Matrix: Air. Sampler: Solid sorbent tube, (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.20 l/min. Sample Size: 10 to 30 l. Shipment: No special precautions. Sample Stability: Not determined. [R140] ALAB: *LIQUID PHASES AND OPTIMAL CONDITIONS ARE RECOMMENDED FOR CONDUCTING A GAS-LIQUID CHROMATOGRAPHIC ANALYSIS OF ISOPROPYLBENZENE. [R141] *THE MINIMUM DETERMINABLE CONCN OF ISOPROPYLBENZENE BY CHROMATOGRAPHY WAS 10 UG. [R142] *EPA Method 524.2. Purge-and-Trap Gas Chromatography/Mass Spectrometry. The method is applicable for the determination of volatile aromatic compounds in water, finished drinking water, raw source water or drinking water in any treatment stage. For isopropylbenzene the method has a detection limit of 0.10 ug/l and a relative standard deviation of 7.7 % ug/l with a wide bore capillary column. [R143] *EPA Method 503.1. Purge-and-Trap Gas Chromatography with a Photoionization Detector. The method is applicable for the determination of volatile aromatic and unsaturated organic compounds in finished drinking water, raw Source water, or drinking water in any treatment stage. For isopropylbenzene the method has a detection limit of 0.005 ug/l and a relative Standard deviation of 8.7%. Overall precision and method accuracy were found to be directly related to the concentration of the analyte, and essentially independent of sample matrix. [R143] *EPA Method 502.2. Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For isopropylbenzene the method has a detection limit of 0.05 ug/l, a percent recovery of 98%, and a standard deviation of 0.9 using the photoionization detector. [R143] *NIOSH Method S23. Analyte: Cumene. Matrix: Air. Procedure: Gas chromatography. Method evaluation: Method was validated over the range 120 to 480 mg/cu m using a 10 liter sample. Precision (CVt): 0.059. Applicability: Under the conditions of sample size (10 l) the useful range is 2.5 to 750 mg/cu m. [R139, p. V2 S23] *Technique: Gas chromatography, flame ionization detection; Carrier gas: Nitrogen or hellium; Limit of detection 0.001 mg per sample. [R138] *NIOSH Method 1501. Analyte: Cumene. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. For cumene, this method has an estimated detection limit of 0.001 to 0.01 mg. Sample size is 10 to 30 liters. The precision/RSD is 0.010 and the recovery is not given. Applicability: This method is for peak ceiling and TWA determinations of aromatic hydrocarbons. It may be used for simultaneous measurements. [R140] CLAB: *CUMENE, IN SOLN TO GIVE 0.43-17.2 UG CUMENE/ML N-HEXANE WAS DETERMINED IN BLOOD EXTRACTS USING GAS-LIQUID CHROMATOGRAPHY. DETECTION LIMIT WAS 0.4 MG CUMENE/L SERUM. [R144] *CUMENE IN URINE WAS ANALYZED BY GAS-CHROMATOGRAPHY AND FLAME IONIZATION DETECTION. [R145] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: ITC/USEPA; Information Review #464 (Draft) Cumene (1984) National Research Council; The Alkyl Benzenes (1981) U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) for Cumene (98-82-8) Toxicological Review in Adobe PDF. Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of August, 1997. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for cumene. Route: inhalation; Species: rats and mice. [R146] SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 315 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. R4: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. R5: CHEMICAL PROFILE: CUMENE, 1985 R6: Pryor WA et al; J Am Chem Soc 105 (11): 3614-22 (1983) R7: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R8: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V7 (93) R9: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V and (93) 735 R10: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 443 R11: ITI. TOX AND HAZARD INDUSTRY CHEM SAFETY MANUAL 1979 p.139 R12: SRI R13: Chemical Marketing Reporter; Chemical Profile Cumene. March 22, 1999. p. 45 NY,NY: Schnell Pub Co (1999) R14: Kavaler AR; Chemical Marketing Reporter 232 (10): 54 (1987) R15: USITC. SYN ORG CHEM-USA PROD/SALES 1984 p.25 R16: USITC. 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Washington, DC: American Chemical Society., 1995. 60 R27: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R28: Sanemasa I et al; Bull Chem Soc Japan 55: 1054-62 (1982) R29: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3257 R30: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 461 R31: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R32: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. 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Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) R107: (1) Waggot A; pp. 55-99 in Chem Water Reuse Vol. 2 Cooper WJ, ed Ann Arbor, MI (1981) (2) Wakeham SG et al; Can J Fish Aquatic Sci 40: 304-21 (1983) (3) Akiyama T et al; J UOEH 2: 285-300 (1980) R108: (1) Steurmer DH et al; Environ Sci Technol 16: 582-87 (1982) (2) Westrick JJ et al; J Am Water Works Assoc 76: 52-9(1984) (3) Tester DJ, Harker RJ; Water Pollut Cont 80: 614-31 (1981) (4) Burnham AK et al; Anal Chem 44: 139-42 (1972) (5) Burmaster DE; Environ 24: 6-36 (1982) (6) Stepan S et al; Aust Water Res Coun Conf Ser 1: 415-24 (1981) (7) Botta D et al; pp. 261-75 in Anal Org Micropollut Water Comm Eur Communities (Rep) EUR, EUR 8518 (1984) R109: (1) Keith LH et al; pp. 329-63 in Identification and Analysis of Org Pollut in Water Keith LH ed Ann Arbor, MI (1976) (2) Coleman WE et al; Arch Environ Contam Toxicol 13: 171-8 (1984) (3) Westrick JJ et al; J Am Works Assoc 76: 52-9 (1984) (4) Burmaster DE; Environment 24: 6-36 (1982) (5) Shiraishi H et al; Environ Sci Technol 19: 585-9 (1985) R110: (1) Johansen SS et al; Ground Water Monit Rev 17: 106-15 (1997) R111: (1) Desideri PG et al; J Environ Anal Chem 55: 33-46 (1994) R112: (1) Leovic K et al; J Air Waste Manag Assoc 48: 915-923 (1998) (2) Chan CC et al; J Air Waste Manage Assoc 45: 116-24 (1995) (3) Harley RA, Cass GR; Environ Sci Technol 28: 88-98 (1994) (4) Wilkins K; Chemosphere 29: 47-53 (1994) R113: (1) Brown JM et al; Investigation of petroleum in the marine environs of the Strait of Juan de Fuca and northern Puget Sound, USEPA-600/7-79-164 (1979) (2) Malins DC et al; Environ Sci Technol 18: 705-13 (1984) R114: (1) Bachhausen P; Contaminated Soil 90: 983-988 (1990) R115: Miller DF, Alkezweeny AJ; Annals New York Acad Sci 338: 219-32 (1980) as cited in ITC/USEPA; Information Review #464 (Draft) Cumene p.20 (1984) R116: Lonneman WA et al; Environ Sci and Tech 2 (11): 1017-20 (1968) as cited in ITC/USEPA; Information Review #464 (Draft) Cumene p.20 (1984) R117: (1) Grosjean D, Fung k; J Air Pollut Cont Assoc 34 537-43 (184) (2) Lonneman WA et al; Environ Sci Technol 2: 1017-20 (1968) (3) Neligan RE et al; pp. 118-21 in ACS Nat Meeting (1965) (4) Lonneman WA et al; Hydrocarbons in Houston air, USEPA-600/3-79-018 (1979) (5) Miller DF, Alkezweeny AJ; Ann NY Acad Sci 338: 219-32 (1980) (6) Seila RL; Non-urban Hydrocarbon concns in Ambient Air North of Houston, TX USEPA-600/3-79-010 (7) Arnts RR, Meels SA; Biogenic Hydrocarbon Contribution to the Ambient Air of Selected Areas. Tulsa, Great Smokey Mountains, Rioblanco County, CO USEPA-600/3-80-023 (1980) (8) Oldham RG et al; in Proc Spec Conf cont Specific (Toxic) Pollut, Frederick ER ed, Air Poll Control Assoc Pittsburgh, PA (1979) (9) Bos R et al; Sci Total Environ 7: 269-81 (1977) (10) Bozzelli JW et al; Analysis of Selected Toxic and Carcinogenic Substances in Ambient Air in New Jersey, Off Cancer Toxic Subst Res, NJ Dept Environ Protect (1980) (11) Nutmagul W et al; Anal chem 55: 2160-64 (1983) (12) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (13) Ioffe BV et al; Environ Sci Technol 13: 864-8 (1979) (14) Tsani-Bazaca E et al; Chemosphere 11: 11-23 (1982) R118: (1) Shah JJ, Singh HB; Environ Sci Technol 22: 1381-8 (1988) (2) Grosjean E et al; Environ Sci Technol 32: 2061-9 (1998) (3) DeFre R et al; Environ Health Perspect 4: 31-31 (1994) (4) Fraser MP et al; Environ Sci Technol 32: 2051-60 (1998) R119: (1) Helmig D, Arey J; Sci Tot Env 112: 233-250 (1992) R120: (1) Flath RA, Forrey RR; J Agric Food Chem 25: 103-9 (1977) (2) Macleod AJ, Gonzales de Troconis N; J Agric Food Chem 30: 515-7 (1982) (3) Graddon AD et al; J Agric Food Chem 27: 832-7 (1979) (4) Tang J et al; J Agric Food Chem 31: 1287-92 (1983) (5) Schormueller J, Kochmann HJ; Z Lebensm Unters Forsch 141: 1-9 (1969) (6) Stern DJ et al; J Agric Food Chem 15: 1100-3 (1967) (7) Yajima I et al; Agric Biol Chem 42: 1229-33 (1978) (8) Heydanek MG, McGorrin RJ; J Agric Food Chem 29: 950-4 (1981) (9) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (10) Dumont JP, Adda J; J Agric Food Chem 26: 364-7 (1978) (11) Ho CT et al; J Agric Food Chem 31: 336-42 (1983) (12) Lovegren NV et al; J Agric Food Chem 27: 851-3 (1979) (13) Fisher GS et al; J Agric Food Chem 27: 7-11 (1977) R121: (1) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R122: (1) Mody NV et al; Phytochem 13: 2027-9 (1974) (2) Mody NV et al; Phytochem 13: 1175-8 (1974) (3) Mody NV et al; Phytochem 14: 599-601 (1975) (4) Vernon F, Richard HMJ; Lebensum-Wiss Technol 16: 32-5 (1983) (5) Gavin J et al; Helv Chim Acta 61: 352-7 (1978) (6) Tabacchi R, Nicollier G; Int Cong Essen Oils Oct 7-11, 1977 Kyoto, Japan (1979) R123: (1) Jackson J et al; Test Rule Support Document Cumene Syracuse Res Corp pp 170 SRC-TR-85-098 (1985) R124: (1) Chemical Manufacturers Association; Cumene Program Panel: Industrial Hygiene survey (1985) (2) American Petroleum Institute; Letter to TSCA Interagency Testing Committee USEPA (1984) (3) Cocheo V et al; Amer Ind Hyg Assoc J 44: 521-7 (1983) R125: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Shah JJ, Singh HB; Environ Sci Technol 22: 1381-8 (1988) (3) Grosjean E et al; Environ Sci Technol 32: 2061-9 (1998) (4) DeFre R et al; Environ Health Perspect 4: 31-31 (1994) (5) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) (6) Schulz RC et al;, Kirk-Othmer Encycl Chem Technol. 4th ed. NY, NY: John Wiley and Sons 7: 735 (1993) R126: (1) Conkle JP et al; Arch Environ Health 30: 290-5 (1975) (2) Krotoszynski BK, O'Neill HJ; J Environ Sci Health Part A Environ Sci Eng 17: 855-83 (1982) R127: 40 CFR 180.1001(e) (7/1/99) R128: 40 CFR 180.1001(d) (7/1/99) R129: 29 CFR 1910.1000 (7/1/99) R130: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R131: 40 CFR 60.489 (7/1/99) R132: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R133: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R134: 40 CFR 302.4 (7/1/99) R135: 40 CFR 716.120 (7/1/99) R136: 40 CFR 261.33 (7/1/97) R137: National Research Council; The Alkyl Benzenes p.126 (1981) R138: Royal Society of Chemistry. Measurement Techniques for Carcinogenic Agents in Workplace Air. Publ. No. EUR 11897, Commission of the European Communities/Scientific and Technical Communication Unit, Luxembourg. Great Britian: St. Edmundsbury Press Ltd, 1989.40 R139: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R140: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1501-1 R141: MALYAROVA LK, NESTEROVA NE; GIG TR PROF ZABOL 16 (4): 58-9 (1972) R142: BOLDINA ZN; GIG SANIT 36 (9): 69-70 (1971) R143: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R144: GOENECHEA S ET AL; MIKROCHIM ACTA 2 (5-6): 391-4 (1980) R145: SENCZUK W, LITEWKA B; BROMATOL CHEM TOKSYKOL 7 (1): 93-7 (1974) R146: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 106 Record 32 of 1119 in HSDB (through 2003/06) AN: 173 UD: 200211 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-PROPYLENE-OXIDE- SY: *AD-6- (Suspendingagent); *AI3-07541-; *Caswell-No-713A-; *Pesticide-Code:-042501.-; *EPA-Pesticide-Chemical-Code-042501-; *EPOXYPROPANE-; *1,2-Epoxypropane-; *ETHYLENE-OXIDE,-METHYL-; *METHYL-ETHYLENE-OXIDE-; *Methyloxirane-; *NCI-C50099-; *OXIRANE,-METHYL-; *OXYDE-DE-PROPYLENE- (FRENCH); *PROPANE,-EPOXY-; *PROPANE,-1,2-EPOXY-; *PROPENE-OXIDE-; *PROPYLENE-EPOXIDE-; *PROPYLENEOXIDE- RN: 75-56-9 MF: *C3-H6-O SHPN: IMO 3.1; Propylene oxide UN 1280; Propylene oxide STCC: 49 066 20; Propylene oxide MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Propylene oxide was 1st prepared in 1860 ... by the reaction of propylene chlorohydrin with potassium hydroxide. Until 1969, essentially all the propylene oxide produced in USA was made by the so-called chlorohydrin process in which propylene is treated with hypochlorous acid (chlorine and water) to produce propylene chlorohydrin; this is converted to propylene oxide using calcium hydroxide or sodium hydroxide. A plant using a version of the peroxidation process was started in USA in 1969. Peroxidation processes use an oxidant such as an organic hydroperoxide (tert-butyl hydroperoxide or ethylbenzene hydroperoxide) or peracetic acid to convert propylene to propylene oxide. Currently, about 1/2 of USA propylene oxide-production capacity is based on the chlorohydrin process, and the other half is based on the peroxidation process ... [R1] *Arco produces propylene oxide ... with propylene and isobutane. The first step is isobutane hydroperoxidation to t-butyl hydroperoxide. The second is epoxidation of propylene with t-butyl hydroperoxide, forming propylene oxide and tert-butyl alcohol. [R2] *Results from the action of KOH (aq) on propylene chlorohydrin. [R3] *(1) Chlorohydration of propylene followed by saponification with lime, (2) peroxidation of propylene, (3) epoxidation of propylene by a hydroperoxide complex with molybdenum catalyst. [R4] IMP: *Acetaldehyde and propionaldehyde are produced in small amt as by-products of the peroxidation processes. [R1] FORM: */IT IS/ OFTEN MIXED WITH CARBON DIOXIDE TO REDUCE FLAMMABILITY AS WELL AS ABSORPTION OF OXIDE BY FUMIGATED MATERIALS. [R5] *PROPYLENE OXIDE IS AVAIL ... AS PRODUCT OF 99.99% PURITY /BY ONE PRODUCER/. ANOTHER ... GIVES FOLLOWING SPECIFICATIONS: ACETIC ACID, 0.005%; WATER, 0.01%; PROPIONALDEHYDE, 0.05% ... [R6] *Propylene oxide is avail in USA with following specifications: water, 500 mg/kg max; total aldehydes, 100 mg/kg max; chlorides (as chlorine), 40 mg/kg max ... [R1] *Propylene oxide is avail in western Europe with following specifications: purity, 99.9% min; water, 200 mg/kg max; aldehydes (as propionaldehyde), 100 mg/kg max; and chlorine, 50 mg/kg max. [R1] *A ready to use soln from Jefferson Chemical Co Inc, has 99.9999% active ingredient propylene oxide. /Former/ [R7] *Pressurized gas, from Union Carbide Corp, has 8.00% active ingredient propylene oxide. A ready to use soln available from Union Carbide Corp Chemicals and Plastics has 99.99% active ingredient propylene oxide. [R7] *A ready to use soln available from Aberco, Inc has 99.99% active ingredient propylene oxide. [R7] MFS: *Dow Chemical U.S.A., 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production sites: Freeport, TX 77541; Plaquemine, LA 70765 [R8] *Huntsman ICI Chemicals LLC, 500 Huntsman Way, Salt Lake City, UT 84108, (801) 584-5700. Huntsman Polyurethanes; Production site: Port Neches, TX 77651 [R8] *Lyondell Chemical Co., 1221 McKinney St., Suite 700, Houston, TX 77010, (713) 652-7200; Production sites: Bayport, TX 77062; Channelview, TX 77530 [R8] OMIN: *FUMIGATION IS EFFECTIVE AT LOW TEMP BECAUSE OF LOW BOILING POINT. [R5] *UNDER CONDITION USED FOR FUMIGATION OF FOODSTUFF PROPYLENE OXIDE CAN COMBINE WITH MOISTURE TO FORM GLYCOL; IN PRESENCE OF INORGANIC CHLORIDE FROM FOODSTUFFS, CORRESPONDING CHLOROHYDRINS WERE FORMED. [R9] *Propylene oxide was 1st produced commercially in USA in 1925. ... /It was being/ produced by 6 companies /in USA in 1979/. ... /It is/ produced by 1 company in Canada and 1 in Brazil. It is produced by 4 companies in Federal Republic of Germany, 2 in the Netherlands and 1 each in France, Italy and Spain. ... Propylene oxide is also produced at 2 plants in Romania and at 1 plant each in Bulgaria, the German Democratic Republic, Poland, the USSR AND Yugoslavia. Commercial prodn started in Japan in 1959. Five Japanese companies currently mfr it at 6 plants. ... /It is also/ produced by 1 company in Taiwan and at 1 plant in India. [R10] *... DESTRUCTION OF 90% OR MORE OF BACTERIA, YEAST AND MOLDS IN COCOA /WAS NOTED/. TOTAL COUNTS AS HIGH AS 200,000-300,000/G COULD BE REDUCED TO 10,000. IN DRIED EGG YOLK ORIGINAL COUNT OF 20,000/G WERE REDUCED TO 200. ... WITH DRIED WHOLE EGG SOLIDS ... BUT REFRACTIVE ANAEROBES AND SALMONELLAE WERE REDUCED BELOW DETECTION LEVELS. IN SPLIT GREEN PEAS COUNTS OF 11,000-16,000 WERE REDUCED TO 40 OR LESS. FINAL COUNTS WERE MADE FOR YEASTS, MOLDS, FLAT SOURS AND THERMOPHILES. IN DRIED YEAST, PROPYLENE OXIDE AFFECTED TOTAL COUNT, AEROBIC SPORE FORMERS AND COLIFORMS. ... [R11, 159] *Commercial production is from chlorine and propylene using a chlorohydrin process or from alternate raw materials using peroxidation processes. [R12] *Propylene oxide has been found as a trace level impurity in poly(propylene oxide)(1). [R13] USE: *For 1,2-propylene oxide (USEPA/OPP Pesticide Code: 042501) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R14] *Chemical intermediate in prepn of polyethers to form polyurethanes; in prepn of urethane polyols and propylene and dipropylene glycols; in prepn of lubricants, surfactants, oil demulsifiers. Also as a solvent; fumigant; soil sterilant. [R3] *Isopropanol amines, synthetic elastomer (homopolymer) [R4] *STERILIZATION OF PACKAGED FOOD PRODUCTS IN FUMIGATION CHAMBERS. [R5] *HERBICIDE [R15, 2187] *FDA has approved use of propylene oxide as a direct and indirect food additive for 1) use as an etherifying agent in prodn of modified food starch (at use levels of 25% max or less); and 2) use as a package fumigant for certain fruit products and as a fumigant for bulk quantities of several food products, provided residues of propylene oxide and propylene glycol do not exceed specified limits [R16] *In detergent manufacture and as a component in brake fluids [R17] *Microbicide, insecticide and miticide. ... Bacteriostat, fungicide. [R7] CPAT: *CHEM INTERMED FOR POLYURETHANE POLYOLS, 64%; PROPYLENE GLYCOL, 19%; DIPROPYLENE GLYCOL, 2%; GLYCOL ETHERS, 2%; OTHER USES (INCL MINOR QUANTITIES USED IN NONINTERMEDIATE APPLICATIONS), 13% (1982) [R18] *Polyurethane- flexible foams, 40%; - rigid foams, 7%; - non-cellular, 10%; - coatings and adhesives, 7%; polyols for specialty surfactants, 4%; propylene glycol, 22%; detergents, 4%; other, 6% (1984) [R2] *CHEMICAL PROFILE: Propylene Oxide. Urethane polyether polyols (75% for flexible foams, 15% for rigid foams, 10% for non-foam uses), 60%; propylene glycol, 20%; glycol ethers, 3%; dipropylene glycol, 2%; miscellaneous, including industrial polyglycols, surfactants and isopropanolamines, 6%; exports, 9%. [R19] *CHEMICAL PROFILE: Propylene oxide. Demand: 1986: 2.2 billion lb; 1987: 2.3 million lb; 1991 /projected/: 2.6 million lb. [R19] *CHEMICAL PROFILE: Propylene oxide. Urethane polyether polyols, 60% (75% for flexible foams, 15% for rigid foams, 10% for non-foam uses); propylene glycol, 20%; glycol ethers, 3%; miscellaneous, including industrial polyglycols, surfactants and isopropanolamines, 5%; exports, 12%. [R20] *CHEMICAL PROFILE: Propylene oxide. Demand: 1989: 2,655 million lb; 1990 /projected/: 2,700 million lb; 1994 /projected/: 3,100 million lb. (Includes exports, but not imports, which are negligible.) [R20] *Urethane polyether polyols, 60 % (flexible foams, 53 %; rigid foams, 6 %; non-foam use, 1 %); propylene glycols, 25 %; P-series glycol ethers, 4 %; miscellaneous, including polyalkylene glycols, allyl alcohol and isopropanolamines, 11 %. [R12] PRIE: U.S. PRODUCTION: *(1977) 8.62X10+11 G [R18] *(1982) 7.62X10+11 G (EST) [R18] *(1983) 8.35X10+11 g [R2] *(1990) 3.20 billion lb [R21] *(1991) 2.50 billion lb [R22] *(1992) 2.70 billion lb [R23] *(1993) 2.73 billion lb [R23] *(1995) 35th highest-volume chemical produced in U.S. [R4] *(1997) 3.1 million pounds; (1998) 3.2 million pounds; (2002) 3.5 million pounds. [R12] U.S. IMPORTS: *(1977) 1.60X10+10 G [R18] *(1982) 2.31X10+10 G [R18] *(1983) 1.45X10+10 g [R2] *(1985) 1.08X10+10 g [R24] *Imports are negligible. [R12] U.S. EXPORTS: *(1977) 4.50X10+10 G [R18] *(1982) 6.64X10+10 G [R18] *(1983) 7.53X10+10 g [R2] *(1985) 6.13X10+9 g [R25] *Exports of major PO derivatives, primarily urethane polyether polyols and propylene glycols, are significant. [R12] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid ... [Note: A gas above 94 degrees F.] [R26, 270] ODOR: *ODOR IS SWEET, ALCOHOLIC, AND LIKE ETHER OR BENZENE [R15, 2190]; *In foods, propylene oxide has no residual odor. [R5]; *Ethereal odor [R4]; *... Benzene-like odor ... [R26, 270] TAST: *In foods, propylene oxide has no residual taste. [R5] BP: *34.23 deg C [R3] MP: *-112.13 deg C [R3] MW: *58.08 [R3] CORR: *NONCORROSIVE TO METALS [R5] CTP: *Critical temperature: 209.1 deg C at 48.6 atm [R27] DEN: *0.8304 @ 20/20 deg C [R4] HTC: *-13,000 BTU/LB = -7,221 CAL/G = -302.3X10+5 JOULES/KG [R27] HTV: *LATENT HEAT OF VAPORIZATION: 205 BTU/LB+ 114 CAL/G+ 4.77X10+5 JOULES/KG [R27] OWPC: *log Kow= 0.03. [R28] SOL: *40.5 wt% water @ 20 deg C [R3]; *MISCIBLE WITH ACETONE, BENZENE, CARBON TETRACHLORIDE, METHANOL, AND ETHER [R15, 2187]; *Soluble in alcohol and ether. [R4]; *In water, 590,000 mg/l @ 25 deg C [R29] SPEC: *IR: 15270 (Sadtler Research Laboratories IR Grating Collection) [R30, p. V2 146]; *NMR: 32 (Varian Associates NMR Spectra Catalogue) [R30, p. V2 146]; *MASS: 31 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R30, p. V2 146]; *MASS: 3980 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R30, p. V2 183]; *Index of refraction: 1.3670 @ 20 degrees C/D [R31] SURF: *24.5 dynes/cm [R27] VAPD: *2.0 (Air= 1) [R15, 2187] VAP: *538 mm Hg @ 25 deg C [R32] VISC: *0.28 centipoise at 25 deg C [R1] OCPP: *Solubility of water in propylene oxide is 12.8% by wt at 20 deg C. [R3] *LIQ SURFACE TENSION: 24.5 DYNES/CM= 0.0245 NEWTON/M @ 15 DEG C; HEAT OF SOLN (EST): -19 BTU/LB= -11 CAL/G= -0.45X10+5 JOULES/KG [R27] *Ratio of Specific Heats of Vapor (gas): 1.113 [R27] *SADTLER REFERENCE NUMBER: 387, 2211, 2212 (IR, PRISM) INDEX OF REFRACTION: 1.3607 AT 20 DEG C/D /DL-FORM/ [R33] *Hydroxyl radical reaction rate constant= 5.20X10-13 cu cm/molecule-sec @ 25 deg C [R34] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Propylene oxide/ [R35] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. /Propylene oxide/ [R35] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Propylene oxide/ [R35] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Propylene oxide/ [R35] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Propylene oxide/ [R35] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Propylene oxide/ [R35] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Propylene oxide/ [R35] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Propylene oxide/ [R35] FPOT: *FLAMMABLE, DANGEROUS FIRE RISK [R36] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R37, p. 325-82] *Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R37, p. 325-82] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R37, p. 325-82] FLMT: *Lower flammable limit: 2.3% by volume; Upper flammable limit: 36% by volume [R38, p. 325-82] FLPT: *-35 deg F (closed cup); -20 deg F (open cup) [R27] AUTO: *Ignition temp 449 deg C, 840 deg F [R37, p. 325-82] FIRP: *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as a fog. Solid streams of water may be ineffective. Cool all effective containers with flooding quantities of water. Apply water from as far away as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R39] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame, evacuate for a radius of 1 mile. [R39] *Use flooding quantities of water as fog. May use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire exposed containers cool. Fight fire from protected location or maximum possible distance. [R37, p. 49-114] EXPL: *A VERY DANGEROUS FIRE AND EXPLOSION HAZARD WHEN EXPOSED TO HEAT OR FLAME. [R40] *LOWER 2.1%; UPPER 38.5% [R41, 1991.1316] *Explosive reaction with epoxy resin and sodium hydroxide. Forms explosive mixtures with oxygen. Reacts with ethylene oxide + polyhydric alcohol to form the thermally unstable polyether alcohol. [R40] REAC: *No acetylide-forming metals such as copper or copper alloys should be in contact with propylene oxide. [R42, p. 348-9] *A polyether-alcohol, prepared by co-condensation of ethylene oxide and propylene oxide with a polyhydric alcohol, was stored at above 100 deg C and exposed to air via a vent line. After 10-15 hr, violent decompostion occurred, rupturing the vessel. [R38, 275] *... PROPYLENE OXIDE MAY REACT WITH INORG CHLORIDES PRESENT IN FOODSTUFFS TO FORM TOXIC CHLOROHYDRINS. [R11, 157] *Mixing propylene oxide and epoxy resin in a waste bottle led to an explosion, probably owing to the polymerization of the oxide catalysed by the amine accelerator in the resin. [R38, 379] *The transition of deflagration to detonation in /propylene oxide and oxygen/ mixtures was studied with respect to mixing ratio, pressure, and spark energy. [R38, 380] *A drum of crude product containing unreacted propylene oxide and sodium hydroxide catalyst exploded and ignited, probably owing to base-catalyzed exothermic polymerization of the oxide. [R38, 380] *Anhydrous metal chlorides; iron; strong acids, caustics and peroxides. [Note: polymerization may occur due to high temperatures or contamination with alkalis, aqueous acids, amines and acidic alcohols.] [R26, 270] *Can react vigorously with oxidizing materials. [R40] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R40] POLY: *An investigation into the hazards associated with the base catalyzed polymerization reactions to which ethylene oxide and propylene oxide are subjected was conducted. The overall goal was to determine if propylene oxide undergoes a polymerization process which is as exothermic as that of ethylene oxide. In particular, the temperature dependence of these polymerizations, along with the contaminant initiations were compared for the two monomers. The polymerization studies were performed in an accelerating rate calorimeter. Both monomers were reacted in this vessel with varying amounts of an aqueous sodium hydroxide catalyst. The energy required to initiate the polymerization of propylene oxidee was higher. The activation energy for the polymerization of ethylene oxide was 81.1 kj/mol while that of propylene oxide was 83.6 kJ/mol. This meant that ethylene-oxide is about 10 to 20 times easier to polymerize at 20 degrees C. Ethylene oxide was much more likely to autoignite, with an ignition temperature of 429 degrees compared to 550 degrees for propylene oxide. The authors conclude that ethylene oxide is significantly more reactive than propylene oxide to alkali catalyzed polymerizations. The controls required for ethylene oxide handling and storage are probably too severe for propylene oxide. [R43] *Polymerizes in the presence of aqueous sodium hydroxide. [R41, 1991.1316] *Hazardous polymerization may occur when in contact with highly active catalytic surfaces, acids, and bases. [R37, p. 49-114] ODRT: *Inasmuch as the detectable odor concn of propylene oxide is reported to be as high as 200 ppm, its odor cannot be reliably used as a warning. [R41, 1991.1318] *Odor detection in air= 9.90x10+0 ppm /Purity not specified/ [R44] *Odor recognition in air= 3.50x10+1 ppm /Purity not specified/ [R44] *Low: 24.7500 mg/cu m; High: 500.000 mg/cu m [R45] *Odor thresholds of 35 ppm, 44 ppm, and 200 ppm have been reported. [R41, 1991.1316] SERI: *... WHEN CONFINED TO THE SKIN ... EVEN DILUTE CONCN (10%) MAY CAUSE IRRITATION ... HIGHLY DILUTE SOLUTIONS (LESS THAN 10%) MAY BE MORE IRRITATING TO THE SKIN THAN UNDILUTED PROPYLENE OXIDE. [R46] *Propylene oxide vapors are irritating to the skin, eyes and respiratory system. [R47] *The major adverse effects ... demonstrated in humans involve burning or blistering of the skin when prolonged contact with non-volatilized chemical has occurred. This has been shown to occur even with low concentrations of propylene oxide. Corneal burns ... have also been reported. [R48, p. 104.148] *Irritating to skin, eyes, and respiratory system. [R37, p. 49-114] EQUP: */When handling/ wear rubber gloves, large and heavy face shields (body shields are also recommendable) and self-contained breathing apparatus. [R49] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R50, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R26, 271] *Wear appropriate eye protection to prevent eye contact. [R26, 271] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R26, 271] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R26, 271] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Any appropriate escape-type, self-contained breathing apparatus. [R26, 271] *Wear special protective clothing and positive pressure self-contained breathing apparatus. [R37, p. 49-114] OPRM: *Employees should be provided with and required to use splash-proof safety goggles where liquid propylene oxide may contact the eyes. Where there is any possibility of exposure of an employee's body to liquid propylene oxide, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. Any clothing which becomes contaminated with liquid propylene oxide should be removed immediately and such clothing should not be reworn until the propylene oxide is removed from the clothing. Clothing wet with liquid propylene oxide should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of the propylene oxide. If the clothing is to be laundered or otherwise cleaned to remove the propylene oxide, the person performing the operation should be informed of propylene oxide's hazardous properties. [R51, 1981.3] *Smoking, eating, and drinking before washing should be absolutely prohibited when any pesticide ... is being handled or used. /Pesticides/ [R48, p. 62.16] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R39] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R39] *Contact lenses should not be worn when working with this chemical. [R26, 271] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R50, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R50, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R50, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R50, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R50, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R50, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R50, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R50, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R50, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R26, 271] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R26, 271] SSL: *It polymerizes exothermically. [R42, 348] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R52] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R53] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R54] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R50, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R50, 1979.13] STRG: *Use glass or metal containers sealed with nitrogen. [R49] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R50, 1979.13] *Store in a cool, dry, well-ventilated location. Outside or detached storage is preferred. Separate from acids, alkalies, salts, combustible material, clay-based absorbents. [R37, p. 49-114] CLUP: *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R39] *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN A SAFE PLACE (SUCH AS A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR THE HOOD DUCTWORK. BURN THE PAPER IN A SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES MAY BE COLLECTED, DISSOLVED IN ALC OF GREATER MOL WT THAN BUTYL ALC, AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER. [R55] *Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, sawdust, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. [R39] *Water spill: Use natural barriers or oil spill control booms to limit spill. Use surface active agent (eg detergent, soaps, alcohols) to compress and thicken spilled material. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, apply activated carbon at ten times the spilled amount in region of 10 ppm or greater concentration. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R39] *Air spill: Apply water spray or mist to knock down vapors. [R39] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R50, 1979.15] *Eliminate all ignition sources. Approach release from upwind. Stop or control the leak, if it can be done without undue risk. Use water spray to cool and disperse vapors, protect personnel, and dilute spills to form nonflammable mixtures. Do not use clay-based absorbents. Control runoff and isolate discharged material for proper disposal. [R37, p. 49-114] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Propylene oxide is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Concentrated waste containing no peroxides; discharge liquid at a controlled rate near a pilot flame. Concentrated waste containing peroxides; perforation of a container of waste from a safe distance followed by open burning. [R56] *PROPYLENE OXIDE MAY BE DISPOSED OF BY DISSOLVING IN PENTYL OR HIGHER CARBON NUMBER ALC AND ATOMIZING IN A SUITABLE COMBUSTION CHAMBER. [R51, 1981.4] *Concentrated waste containing no peroxides-discharge liquid at a controlled rate near a pilot flame. Concentrated waste containing peroxides-perforation of a container of the waste from a safe distance followed by open burning. Recommendable methods: Incineration, open burning and evaporation. Peer review: Very volatile (bp 33 deg C) may make it difficult to feed to incinerator with safety. Open burning and evaporation are recommendable for small amounts. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R57] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R50, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R50, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R50, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R50, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R50, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on inadequate human data and an increased incidence of benign and malignant tumors at the site of exposure in two species of animals, when exposed by subcutaneous injection, by inhalation, and by gavage. There was also evidence of mutagenicity in a variety of test systems. Propylene oxide is structurally similar to other chemicals that demonstrate carcinogenic activity in animals.HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R58] *Evaluation: There is inadequate evidence in humans for the carcinogenicity of propylene oxide. There is sufficient evidence in experimental animals for the carcinogenicity of propylene oxide. Overall evaluation: Propylene oxide is possibly carcinogenic to humans (Group 2B). [R59] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Provide a low-stimulus environment. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Treat frostbite by rapid rewarming ... . /Ethers and related compounds/ [R60, 224] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Ethers and related compounds/ [R60, 225] MEDS: *The following medical procedures should be made available to each employee who is exposed to propylene oxide at potentially hazardous levels. Employees should be screened for history of certain medical conditions which might place them at an increased risk from propylene oxide exposure. Skin disease: Propylene oxide can cause dermatitis. Persons with existing skin disorders may be more susceptible to the effects of this agent. Liver disease: Although propylene oxide is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Kidney disease: Although propylene oxide is not known as a kidney toxin in humans, the importance of this organ in the elimination of toxic substances justifies special consideration in persons with impaired renal function. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of propylene oxide may cause exacerbation of symptoms due to its irritant properties. Periodic Medical Examination: Any employee developing the above-listed conditions should be referred for further medical examination. [R51, 1981.1] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R50, 1979.23] *Monitoring propylene oxide exposure by analyzing N-gamma-(2-hydroxypropyl)histidine in hemoglobin from a group of exposed workers was investigated. N-gamma-(2-hydroxypropyl)histidine values were assayed in blood samples from workers in different departments of a facility where propylene oxide was used for producing hydroxypropylated starch, from four comparisons employed at an ethylene oxide sterilization factory, and from nine comparisons from the same geographic area. Personal and stationary air concentrations of propylene oxide were also monitored during 5 work days and exposures classified as high, intermediate, or low on the basis of propylene oxide concentration and duration of worker exposure. The four workers whose propylene oxide exposure was rated high had hemoglobin alkylation ranging from 4.5 to 8.6 nanomoles N-gamma-(2-hydroxypropyl)histidine per gram hemoglobin (nmol/G). The two workers with intermediate exposure had hemoglobin alkylation of 1.0 and 1.2 nmol/g. The workers with low exposure had values of 0.85 and 0.2 nmol/g. The second worker had not been exposed over the previous year and could be considered a referent. Hemoiglobin alkylation in employees of an ethylene oxide sterilization ranged from less than 0.1 to 0.38 nmol/g. In all other comparisons hemoglobin alkylation values were less than 0.1 nmol/g. /It was/ concluded that the method is sensitive enough for dosimetry to be carried out at current exposure concentrations in some work environments. The degree of alkylation of hemoglobin gives a measure of the in vivo propylene oxide dose obtained during a period of about 4 months, the lifespan of red cells. [R61] HTOX: *Propylene oxide is a strong irritant of the eyes, mucous membranes, ... and high concn have shown a mild CNS depression. Corneal burns and dermatitis have been reported ... . [R41, 1991.1318] *EFFECTS OF OVEREXPOSURE: MILD DEPRESSION OF CNS, EYE, NASAL AND LUNG IRRITATION, NAUSEA, VOMITING AND DRUNKENNESS. [R62] *One case of human poisoning reported in Russia resulted from vapor exposure to 1500 ppm wt/vol for 10 min. Initial symptoms included lung ... irritation, headache, general asthenia and diarrhea. After 2 hr, the patient became cyanotic and collapsed. After admin of oxygen and antihistamines and treatment for shock, he regained consciousness and vomited but remained confused and weak. The pulse rate and blood pressure returned to normal in 2 hr ... recovery was complete on the following day. [R63] *A 26 YR OLD FEMALE ANALYST DEVELOPED HAND ECZEMA FROM EXPOSURE TO PROPYLENE OXIDE IN DEHYDRATION OF ANIMAL SPECIMENS FOR ELECTRON MICROSCOPY. [R64] *TWO LAB ASSISTANTS DEVELOPED CONTACT DERMATITIS FROM A DISPOSABLE SWAB FOR PREINJECTION USE, CONTAINING ISOPROPYL ALCOHOL 70% AND PROPYLENE OXIDE 1%. PATCH TESTING GAVE POSITIVE ALLERGIC REACTION TO PROPYLENE OXIDE IN BOTH PATIENTS. [R65] *PROPYLENE OXIDE CAUSED INHIBITION OF UNSCHEDULED DNA SYNTHESIS AFTER OCCUPATIONAL EXPOSURE. [R66] *THE MEAN CHROMOSOME ABERRATION RATE IN WORKERS WITH GREATER THAN 20 YR EXPOSURE TO ALKYLENE OXIDES INCL ETHYLENE AND PROPYLENE OXIDES SHOWED A SIGNIFICANT INCR WITH 5.7-6.4% INCL GAPS AND 2.7-3.5% EXCLUDING GAPS, AS COMPARED TO 1.4 and 4% RESPECTIVELY IN THE CONTROLS. [R67] *A method for quantifying alkylated amino acids in hemoglobin involved specific splitting off of the N-terminal amino acid while not touching the rest of the protein. Ethylene oxide, propylene oxide and styrene oxide were the alkylating agents used in this study. Tests with spiked globin samples indicated that concentrations as low as 1 nanomole N-(2-hydroxyethyl)valine per gram hemoglobin were quantifiable with this method. This would be equivalent to an average exposure to 1 ppm ethylene oxide for 40 hours per week, for the lifetime of the hemoglobin. This is of sufficient detail for determining exposure to alkylating agents in occupational settings and differentiating them from the background levels found in human blood. [R68] *In humans, propylene oxide has produced corneal burns, elevated blood alkylhistidine, and chromosomal aberrations. [R69] *A technique was described which used sister chromatid exchanges in human peripheral blood lymphocyte cultures to assess the genotoxic potential of vapors. The compounds tested were methyl bromide, ethylene oxide, propylene oxide, and diesel exhaust. Heparinized human whole blood was obtained from healthy nonsmokers. Whole blood was cultured under standard conditions, with the addition of phytohemagglutinin to stimulate lymphocyte division. After 22 to 26 hours, cultures were exposed to 4.3 percent methyl bromide, 4.0 percent ethylene oxide, 2.5 percent propylene oxide, or direct diesel exhaust. Propylene oxide increased sister chromatid exchanges from 8.74 to 22.74 per cell. This system is useful for detecting volatile genotoxic agents and may have application for monitoring of workplaces where airborne genotoxic agents may exist. [R70] *ADVERSE ... EFFECTS CAN FOLLOW INHALATION OF VAPORS AND FROM EYE AND SKIN CONTACT WITH LIQUID OR WITH SOLN AS DILUTE AS 1%. [R15, 2187] *Commercially avail mixtures /of propylene oxide/ with carbon dioxide ... may be asphyxiant and vesicant. [R38, 379] *Exposure of man to propylene oxide mainly occurs through inhalation at the workplace. Because of the alkylating nature of propylene oxide, the formation of DNA adducts, the positive response in vitro mutagenesis assays, the carcinogenic effects in animals at the sites of entry into the body, and the absence of adequate data on cancer in human beings - propylene oxide should be regarded as if it presented a carcinogenic risk for man, and levels in the environment should be kept as low as feasible. [R71] *Chromosomal aberrations and micronuclei in lymphocytes were measured in workers exposed to propylene oxide in a alkylated starch factory, and in workers exposed to ethylene oxide in connection with sterilization of medical equipment. Adduct levels in hemoglobin were determined as a measure of in vivo doses of the two compounds. The levels of hydroxypropylvaline in propylene oxide exposed workers were correlated in estimated exposure doses. The levels of this adduct in the unexposed group were close to the detection limit of the method. The levels of hydroxyethylvaline, recorded in the propylene oxide exposed group were consistent with earlier data on hemoglobin alkylation in occupationally unexposed subjects. The adduct measurements revealed increased levels of hydroxyethylvaline in the two subgroups of ethylene oxide exposed workers, ie, assemblers with a low and sterilizers with a high exposure. According to expectation the subgroups differed in adduct levels. The results of cytogenetic study showed that the clastogenic potency of propylene oxide was lower than that of ethylene oxide, since the propylene oxide exposed individuals had lower frequencies of micronuclei and chromosomal breaks compared to the assemblers despite a lower adduct level in the last group. [R72] *Employees of plants where alkylene oxide is manufactured or processed were subjected to mutagenicity studies carried out on lymphocyte cultures in accordance with the methods of Moorhead at al, de Jong and Anders. The employees were divided into four groups, according to their periods of exposure: (1) Long-term exposure for more than 20 years; (2) exposure for less than 20 years; (3) long-term exposure and accident (ethylene oxide inhalation or skin contact); and (4) accident, ie, brief high exposure to ethylene oxide. Measurement of the concentrations in various sections of the plant yielded values of up to 3 ppm under conditions of normal operation. However, this figure rose briefly to 1900 ppm under plant breakdown hat workers were subjected to higher exposure in the past. One hundred metaphases per person were analyzed for chromosome aberrations. The results are given in Tables 1 through 4. A significant increase in the aberration rate was found only in employees in Group 1. This was confirmed by a control examination carried out one year later. The employees of groups 2, 3 and 4 displayed no significant increases. However, in evaluating these findings, it should be noted that the employees had been in contact with a wide range of substances and products in the course of their occupation, which means that the increased aberrations rate found cannot be attributed unequivocally to exposure to a particular substance. [R67] *1,2-epoxypropane has been shown to act as a direct alkylating agent in various tissues, and thus the possibility of carcinogenic potential is raised. [R48, p. 104.148] NTOX: *... IN ACUTE /INHALATION/ EXPOSURES OF RATS, SURVIVORS EXHIBITED FOLLOWING SYMPTOMS: IRRITATION OF THE EYE AND NOSE, DIFFICULTY IN BREATHING, DROWSINESS, WEAKNESS, AND OCCASIONALLY SOME INCOORDINATION. SINGLE 4 HR EXPOSURE TO 4000 PPM RESULTED IN DEATH IN 4 OF 6 RATS. [R73] *Liquid propylene oxide dropped on rabbit eyes has caused reversible injury similar to that caused by acetone, graded 5 on scale of 1 to 10 after 24 hr. Exposure of monkeys and rabbits to 457 ppm vapor in air for 7 hr daily had no adverse effect, but in rats and guinea pigs it irritated eyes and induced lung edema. In guinea pigs and rabbits no disturbance of corneas ... was detectable by slit-lamp biomicroscope after exposure to vapor concn high enough to cause death of guinea pigs and rabbits from respiratory ... /injury/ in the course of several days, except possibly ... the incr in normal punctate staining of corneal epithelium with fluorescein. [R74] *MATCHED GROUPS OF 5 YOUNG ADULT FEMALE WHITE RATS EACH WERE FED OLIVE OIL SOLN OF PROPYLENE OXIDE BY INTUBATION 5 TIMES A WK UNTIL A TOTAL OF 18 DOSES HAD BEEN GIVEN AT LEVELS OF 0.1, 0.2, and 0.3 G/KG/DAY. ANIMALS RECEIVING A DOSAGE LEVEL OF 0.2 G/KG AND 0.1 G/KG SHOWED NO EFFECT AS JUDGED BY GROSS APPEARANCE, GROWTH, BLOOD UREA NITROGEN DETERMINATIONS, ORGAN WT, AND MICROPATHOLOGY OF THE VARIOUS ORGANS IN COMPARISON WITH CONTROLS RECEIVING OLIVE OIL. A DOSAGE LEVEL OF 0.3 G/KG CAUSED LOSS OF BODY WT, GASTRIC IRRITATION, AND SLIGHT LIVER INJURY. [R15, 2190] *EARLY SYMPTOMS /OF ACUTE VAPOR POISONING/ INCLUDE LACRIMATION, NASAL DISCHARGE, AND SALIVATION FOLLOWED BY GASPING AND LABORED BREATHING IN ALL SPECIES, AND VOMITING IN DOGS. SEVERE IRRITATION IN THE LUNGS MAY PERSIST FOR SEVERAL DAYS AND, IN SOME CASES, LEAD TO PNEUMONIA. ... PROPYLENE OXIDE HAS ONLY A RELATIVELY WEAK ANESTHETIC ACTION WHICH BECAME APPARENT WHEN ANIMALS WERE EXPOSED TO CONCN OF 4000 PPM OR MORE. [R15, 2190] *UPON REPEATED 7-HR EXPOSURE TO 457 PPM /BY INHALATION, THERE WAS/ ONLY ... SLIGHT DEPRESSION OF GROWTH IN GUINEA PIGS EXPOSED FOR 15-17 DAYS. NO EFFECTS WERE NOTED IN RATS. AFTER 37-39 DAYS ... DEPRESSION OF GROWTH WAS NOTED IN BOTH GUINEA PIGS AND RATS. ADDITIONAL EFFECTS WERE MODERATE AND INCLUDED ALVEOLAR HEMORRHAGE AND EDEMA ... WITH INTERSTITIAL EDEMA AND CONGESTION OF LUNGS OF RATS AND GUINEA PIGS. ... SLIGHT FATTY DEGENERATION OF LIVER IN MALE GUINEA PIGS WAS OBSERVED. [R73] *OF 12 RATS ... GIVEN TOTAL DOSES OF 1500 MG/KG BODY WT ... IN ARACHIS OIL BY SC INJECTION WITHIN 325 DAYS (DOSING SCHEDULE NOT SPECIFIED), 8 DEVELOPED LOCAL SARCOMAS AFTER 507-739 DAYS. IN SIMILAR EXPT IN WHICH TOTAL DOSES OF 1500 MG/KG BODY WT PROPYLENE OXIDE IN WATER WERE INJECTED SC, 1/12 RATS DEVELOPED LOCAL SARCOMA AFTER 158 DAYS AND 2 DEVELOPED LOCAL SARCOMAS AFTER 737 DAYS. [R75, 1976)] *PROPYLENE OXIDE INDUCED DOSE-DEPENDENT INCREASE IN NUMBER OF REVERTANT MUTATIONS IN HISTIDINE-DEPENDENT SALMONELLA TYPHIMURIUM STRAINS TA1535 AND TA100, BUT NOT IN STRAINS TA1537 OR TA98. [R76] *INDUCTION OF BASE-SUBSTITUTION MUTATIONS WAS DEMONSTRATED IN SPOT TESTS WITH STRAINS OF S TYPHIMURIUM (TA100 AND TA1535) AND E COLI AT 700 UG/PLATE OF PROPYLENE OXIDE; RAT-LIVER MICROSOMES AND COFACTORS (S9 MIX) WAS WITHOUT SIGNIFICANT EFFECT ON THIS RESPONSE. A MALE MOUSE DOMINANT LETHAL TEST EMPLOYING ORAL DOSES OF 50 OR 250 MG/KG/DAY FOR 14 DAYS GAVE NO EVIDENCE OF MUTAGENIC ACTION ON SPERM. [R77] *1,2-PROPYLENE OXIDE WAS ADMIN TO NMRI FEMALE MICE AT 2.5, 1.0, 0.3 and 0.1 MG IN SINGLE SC INJECTIONS ONCE/WK USING TRICAPRYLIN AS VEHICLE FOR 95 WK. TOTAL DOSE/MOUSE WAS 165.4, 72.8, 21.7 and 6.8 MG. LOCAL TUMORS DEPENDING ON DOSAGE WERE MOSTLY FIBROSARCOMAS WITH FREQUENCY BETWEEN 16 and 2%. [R78] *1,2-PROPYLENE OXIDE ADMIN INTRAGASTRICALLY BY GAVAGE AT 2 DOSAGES (60 and 15 MG/KG BODY WT) TO GROUPS OF 50 FEMALE SPRAGUE-DAWLEY RATS TWICE WEEKLY FOR A PERIOD OF NEARLY 3 YR INDUCED LOCAL TUMORS, MAINLY SQUAMOUS-CELL CARCINOMAS OF THE FORESTOMACH. [R79] *PROPYLENE OXIDE TESTED FOR MUTAGENIC ACTIVITY FOLLOWING VAPOR EXPOSURE USING 3 IN VIVO TEST SYSTEMS. RAT DOMINANT LETHAL AND MOUSE SPERM-HEAD MORPHOLOGY ASSAYS WERE CONDUCTED USING MALES EXPOSED @ 300 PPM FOR 7 HR/DAY ON 5 CONSECUTIVE DAYS. A SEX-LINKED RECESSIVE LETHAL TEST IN DROSOPHILA MELANOGASTER EMPLOYED A 24 HR STATIC EXPOSURE @ 645 PPM. EVALUATION OF SPERM-HEAD MORPHOLOGY DID NOT RESULT IN AN INCR IN ABNORMAL FORMS. STATISTICALLY SIGNIFICANT INCR IN PREIMPLANTATION LOSSES AND REDUCTION IN THE NUMBER OF LIVING IMPLANTS WAS OBSERVED IN RATS. A HIGHLY SIGNIFICANT INCR IN SEX-LINKED RECESSIVE LETHAL MUTATION WAS OBSERVED IN TWO GERM STAGES IN DROSOPHILA. [R80] *MALE MONKEYS WERE EXPOSED TO 0, 100, and 300 PPM PROPYLENE OXIDE FOR 6 HR/DAY, 5 DAYS/WK FOR 2 YR. BRAIN, ULNAR AND SCIATIC NERVES, AND SPINAL CORD TISSUE WERE EXAM HISTOLOGICALLY. NO DIFFERENCES WERE FOUND BETWEEN CONTROLS AND CHEM TREATED ANIMALS. IN THE MEDULLA OBLONGATA OF THE BRAIN, PROPYLENE OXIDE EXPOSED MONKEYS HAD SIGNS OF AXONAL DYSTROPHY. [R81] *THE MUTAGENIC ACTION OF 45 EPOXIDES WAS INVESTIGATED IN LURIA AND DELBRUCK'S FLUCTUATION TEST WITH KLEBSIELLA PNEUMONIAE AS THE TEST ORGANISM. IN THIS TEST 36 OF THE 45 EPOXIDES APPEARED TO BE MUTAGENIC. THE MUTAGENICITY OF 1,2-EPOXIDES DECR WITH INCR LENGTH OF C CHAIN. GENERALLY, 1,2-EPOXIDE CMPD WITH ELECTRONEGATIVE GROUPS WERE MORE MUTAGENIC THAN 1,2-EPOXYPROPANE. [R82] *AT RELATIVE HUMIDITY OF 25% and 37 DEG C, 90% OF B SUBTILIS SPORES WERE KILLED IN 40 MIN (1250 MG PROPYLENE OXIDE/L). IN COCOA POWDER, BACTERIAL COUNTS WERE REDUCED 5-70% AND MOLD COUNTS 90-99%. ... IN WHEAT OF 13% MOISTURE INITIAL BACTERIAL COUNT OF 1,000,000/G WAS REDUCED TO 500/G AT 118 DEG F BY VAPOR SYSTEM CONTAINING 1.5 G/L OF PROPYLENE OXIDE. [R11, 159] *The ability of long term exposures to inhaled propylene oxide to induce sister chromatid exchanges and chromosome aberrations in the peripheral lymphocytes of monkeys was investigated. Five groups of adult male cynomolgus monkeys were exposed to 100 or 300 ppm propylene oxide (7 hr/day, 5 days/wk) for 2 years. ... Lymphocytes from these /animals/ manifested no group differences from controls for any variable-chromatid, or chromosome type aberrations, gaps or sister chromatid exchanges (metaphase). [R83] *The chronic inhalation toxicity and carcinogenicity of ethylene oxide and propylene oxide were evaluated in a 2 yr inhalation bioassay. Five groups of male weanling Fischer 344 rats, 80/group, were exposed at 0 ppm (shared control; filtered air), 50 ppm ethylene oxide, 100 ppm ethylene oxide, 100 ppm propylene oxide, or 300 ppm propylene oxide (7 hr/day, 5 days/wk) for 104 wk. Among rats exposed to propylene oxide there was a dose-dependent increase in the incidence of complex epithelial hyperplasia in the nasal passages, and 2 adenomas were detected in the nasal passages of rats exposed at 300 ppm propylene oxide. The incidence of adrenal phenochromocytomas was elevated in both propylene oxide exposure groups, but not in a dose-related manner. All rat groups were affected by an outbreak of Mycoplasma pulmonis infection which occurred in combination with the epoxide exposures and affected the survival of rats in this study, and influenced the development of the proliferative lesions in the nasal mucosa of the propylene oxide-exposed rats. No treatment related changes in any clinical chemistry or urinalysis indices were detected. Adrenal pheochromocytomas and proliferative lesions of the nasal cavity were increased in rats exposed to propylene oxide. [R84] *The SOS umu-test has been used for the detection of DNA-damaging agents. In this system the plasmid pSK1002 carrying a fused gene umuC-lacZ was introduced into Salmonella typhimurium TA1535. The SOS function induced by genotoxic agents is detected by a colorimetric measurement of beta-galactosidase activity encoded by the lacZ gene, which is regulated by the Umu operon. This system was used with modifications to study the SOS function inducibility of volatile chemicals (propylene oxide, methyl bromide, and ethylene dibromide) and air pollutants (diesel emission, welding fumes, and cigarette smoke). Tester cells were exposed directly to the test material. The enzyme activity of the treatment cells was measured according to the established procedure. Results of the study showed that all chemicals and pollutants tested induced SOS function in a dose-related manner. [R85] *A short-term microbial method using Bacillus subtilis infected with bacteriophage phi 105 DNA was described. Wild-type bacteriophage phi 105 DNA was reacted with potential mutagens and then transfected into Bacillus subtilis carrying a mutated bacteriophage phi 105 DNA. After plating, an increase in frequency of clear plaques signified that the tested cmpd was mutagenic. Propylene oxide was mutagenic. [R86] *Sprague-Dawley rats receiving propylene oxide by stomach tube in doses of 15 or 60 mg/kg of body weight twice weekly for 109.5 weeks exhibited a dose dependent increase in forestomach tumors. ... NMRI-mice receiving 0.1, 0.3, 1.0, or 2.5 mg of propylene oxide by sc or im injection once a week for 95 weeks developed tumors at the site of injection. ... Propylene oxide has induced mutations in Salmonella typhimurium, Escherichia coli, Klebsiella pneumoniae, Neurospora crassa, Schizosaccharomyces pombe, Drosophila melanogaster, rat hepatocytes and human lymphocytes in vitro, and male CD 1 mice. [R87] *Propylene oxide inhalation by B6C3F1-mice at concentrations of 200 or 400 ppm 6 hours a day, 5 days a week, for 103 weeks caused an increase in nasal turbinate respiratory epithelium inflammation, in hemangiomas among both sexes, and in hemangiosarcomas among males. Exposure of Fischer 344 rats caused increases in inflammation, epithelial hyperplasia, and squamous metaplasia of the nasal turbinate respiratory epithelium, as well as in C-cell adenomas and carcinomas among females. Propylene oxide inhalation by Fischer 344 rats at 100 or 300 ppm 7 hours a day, 5 days a week for 104 weeks, resulted in a dose-dependent increase in inflammatory respiratory system lesions and complex nasal cavity epithelial hyperplasia, as well as in pheochromocytomas and peritoneal mesotheliomas. ... [R87] *Propylene oxide inhalation by New Zealand white rabbits at 500 ppm 7 hours a day from gestation days 1 or 7 to 19 caused a 2.8 percent resorption rate increase. Exposure of Sprague-Dawley-rats from 3 weeks before gestation to gestation day 16, from gestation day 1 to 16, or from gestation day 7 to 16 caused reduced maternal weights, copora lutea populations, implantation site numbers, live fetus counts, and fetal growth, while increasing rib dysmorphology. [R87] *The possible use of the degree of inhibition of glutathione-S-transferase activity as a biological marker for determining exposure to chemicals such as acrolein, styrene oxide, propylene oxide, ethylene dibromide, and ethylene dichloride was explored. A dose-dependent inhibition was evident in each case not only for inactivation of erythrocyte glutathione-S-tranferase in situ but for inhibition of purified erythrocyte glutathione-S-transferase as well. Concentrations inhibiting 50% of the activity ranged from around 10-3 to 10-4 molar. [R88] *The potential of vapor phase chemicals to alter susceptibility to induced respiratory infection was examined in mice. Female CD1 mice were simultaneously exposed to Streptococcus zooepidemicus aerosols and threshold limit value of ... propylene oxide. ... A pulmonary bactericidal activity assay was performed after mice inhaled aerosols of viable radioactive bacteria to determine bacterial clearance from the lung. Changes in pulmonary bactericidal activity were significant after single and multiple exposures of some compounds, but there was no consistent pattern of effects with the mortality studies. [R89] *A battery of short term tests was performed. Bacterial mutation assays conducted were: plate incorporation assay, preincubation assay, spot test, and treat and plate method. Saccharomyces gene conversion assays conducted involved treatment of stationary phase cells and treatment of log phase cells. Rat liver chromosome assays included cytotoxicity and chromosome assays. Specific compounds which indicated mutations in bacteria, gene conversion in yeast, or chromosome damage /included/ propylene oxide ... . [R90] *Propylene oxide, glycidol, epichlorohydrin, and trichloropropylene oxide were reacted with deoxyguanosine as well as deoxyadenosine and, except for the trichloro compound, with DNA. Reactivity with the purine deoxynucleosides as well as the four deoxynucleosides in DNA were quantitated by HPLC methods. Correlations for reactivity of the propylene oxides with the individual deoxynucleosides in solution and in DNA, except for deoxythymidine, were indicated for mutagenicity in TA100 in the liquid-preincubation Ames test. [R91] *37 aliphatic epoxides were tested for mutagenicity in Salmonella strains TA98, TA100, TA1535 and TA1537 and/or TA97 with and without metabolic activation using a standardized protocol. 3 of the 8 unsubstituted aliphatic epoxides and 11 of the 12 glycidyl ethers were mutagenic. /Propylene oxide was mutagenic/ in TA100 without activation and was mutagenic in TA1535 without activation. [R92] *Inhalation exposures were conducted with five water-reactive compounds: beta-propiolactone, methylmethane sulfonate, ethylchloroformate, dichloroacetyl chloride, and propylene oxide on male Sprague-Dawley rats. The hydrolysis rates of these compounds span 6 orders of magnitude. The compounds were administered for 30 days (6 hr/day X 5 days/wk) with the use of exposure concentrations that were inversely proportional to the respective hydrolysis rates. With this protocol, all compounds except propylene oxide (the slowest reacting compound) produced nasal cancer in rats. [R93] *Propylene oxide is a highly reactive, electrophilic substance, which reacts with cellular macromolecules such as RNA, DNA and proteins, by alkylating nucleophilic centers. Propylene oxide is a mutagen. It induces local tumors when inhaled or administered by subcutaneous and intragastric routes and has an adverse effect on male and female reproduction in animals (mice and rats). Propylene oxide is an allergic sensitiser. [R94] *Twenty-seven chemicals (including 1,2-propylene oxide) previously tested in rodent carcinogenicity assays were tested for induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells as part of a larger analysis of the correlation between results of in vitro genetic toxicity assays and carcinogenicity bioassays. Chemicals were tested up to toxic doses with and without exogenous metabolic activation. 1,2-Propylene oxide was shown to be a potent inducer of sister chromatid exchanges and chromosomal aberrations both with and without S9. [R95] *Reproductive parameters in Fischer 344 rats were evaluated following inhalation of propylene oxide for two successive generations. Thirty male and 30 female rats were exposed to 0, 30, 100, or 300 ppm propylene oxide for 6 hr/day, 5 days/week for 14 weeks and then mated to produce the f1 litters. After weaning, 30 randomly selected f1 pups/sex/group were exposed to propylene oxide for 17 weeks and subsequently mated to produce the f2 litters. Reproductive parameters examined included fertility, litter size neonatal growth, and survival. All adults and selected weanlings were examined for gross and histologic lesions. Toxicity due to propylene oxide was demonstrated by decreased body weights of parental f0 and f1 rats at 300 ppm. No treatment-related effects on fertility (mating or conception) were observed in either f0 or f1 matings. Neonatal surival indices for f1 or f2 litters revealed no treatment-related effects. Litter size was decreased in the f1 rats exposed to 100 ppm propylene oxide. However, the litter size in the 300 ppm group was comparable to the control group, and no effect on litter size was shown in propylene oxide exposed f2 litters. Pup weights were unaffected by parental exposure to propylene oxide in either generation. Pathologic examination of adults and weanlings revealed no changes considered due to propylene oxide. Based on these results, it is concluded that inhalation exposure to propylene oxide at levels up to 300 ppm over two generations did not produce any adverse effects on reproductive function. [R96] *The developmental toxicity potential of propylene oxide was evaluated in Fischer 344 rats following inhalation exposure. Four groups of 25 mated female rats were exposed to 0, 100, 300, and 500 ppm of propylene oxide for 6 hr per day on Gestation Days 6 through 15, inclusive. Cesarean sections were performed on all females on Gestation Day 20 and the fetuses removed for morphological evaluation. Exposure to propylene oxide did not adversely affect survival, appearance, or behavior at any of the exposure levels tested. Maternal body weight gain and food consumption were reduced significantly among the females at the 500 ppm level during the exposure period. No exposure-related effects were noted with respect to maternal water consumption, organ weights, cesarean section, or fetal morphological observations with the sole excretion of increased frequency of seventh cervical ribs in fetuses at the maternally toxic exposure level of 500 ppm. In summation, the no-observable-adverse-effect level of propylene oxide, when administered to Fischer 344 rats via whole-body inhalation exposure, was considered to be 300 ppm. [R97] *Propylene oxide was tested for mutagenic activity following vapor exposure using 3 in vivo test systems. Rat dominant lethal and mouse sperm-head morphology assays were conducted using males exposed to propylene oxide at 300 ppm in a dynamic exposure chamber for 7 hr/day on 5 consecutive days. A sex linked recessive lethal test in Drosophila melanogaster employed a 24 hr static exposure to propylene oxide at 645 ppm. Male mice were killed 1, 3, 5, 7 and 9 wk post exposure for evaluation of sperm-head morphology. Propylene oxide exposure did not result in an increase in abnormal forms. Male rats were mated with 2 virgin females/wk for 6 wk following exposure. A statistically significant increase in preimplantation losses and a statistically significant reduction in the number of living implants in the 1st post exposure wk did not appear to be treatment related. A highly significant increase in sex linked recessive lethal mutations was observed in 2 germ cell stages (mature sperm and developing spermatocytes). These results warrant continued caution in potential human exposure to propylene oxide. [R80] *The ethylene oxide/propylene oxide polymers evaluated in this study have previously been shown to have a low order of toxicity and/or irritancy by ocular, dermal, or oral routes of administration. These studies evaluated the acute inhalation toxicity of respirable aerosols of three ethylene oxide/propylene oxide compounds (U-660, U-2000, and U-5100) that differ in chain length, molecular weight, and viscosity. The respective 4 hr LC50 values (95% confidence limits) for U-660, U-2000, and U-5100 in Wistar albino rats were 4670 (4090-5320), 330 (227-480), and 106 (45-245) mg/cu m. Occasionally, slight increase in respiration rate and slight hyperactivity were observed during the postexposure period. All deaths were delayed for 2-5 days postexposure. Body weight gains were transiently depresed in rats exposed to U-2000 and U-5100. Discolored lungs and livers occurred in animals which died during the 14 day postexposure period. Subsequently, a repeated-exposure study was conducted on U-5100 in F-344 rats exposed for 6 hr/day, 5 days/week, for 9 exposures at mean concentrations of 0, alveolar epithelial cells. Lung weights remained elevated after the 2 wk at concentrations as low as 5 mg/cu m. [R98] *A new protocol for testing vapors and gases in the L5178Y mouse lymphoma assay is presented. Four chemicals, propylene, 1,2-propylene oxide, 1,3-butadiene, and vinylidene chloride, were tested for their mutagenic potential. Cultures were exposed to the chemicals, which were delivered as vapors or gases, for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine, 3 ug/ml. Each chemical was tested at least twice. Significant responses were obtained with 1,2-propylene oxide and vinylidene chloride, but neither cytotoxicity nor mutagenicity was induced by 1,3-butadiene; propylene could not be classified as either mutagenic or non-mutagenic in the assay. Rat liver S9 mix was not a requirement for the mutagenic activity of 1,2-propylene oxide, whereas the liver preparation markedly enhanced both the cytotoxicity and mutagenicity of vinylidene chloride. [R99] *In Wistar rats subjected daily to 6 hr exposure of propylene oxide at a concentration of 1,500 ppm (5 times a wk for 7 wk). ataxia developed in the hindlegs. Myelinated fibers in hindleg nerves and in the fasciculus gracilis showed axonal degeneration, sparing the nerve cell body of the first sacral dorsal root ganglion ad myelinated fibers of the first sacral dorsal and ventral roots. These pathologic findings are compatible with central-peripheral distal axonopathy. This is apparently the first animal model of propylene oxide neuropathy to be verified histologically. [R100] *The carcinogenicity of proplene oxide was investigated because of its extensive production, its potential for exposure of humans in the workplace or for exposure through food, the positive results in short term genetic assays, and the inadequacy of available animal carcinogenesis data on the material. Groups of 50 F344/N rats and (C57BL/6x3H) F1 mice were exposed to 0, 200, or 400 ppm propylene oxide for 6 hours/day, 5 days/week, for up to 103 weeks. Mean body weight decreased during the second year of exposure in mice rats exposed at the higher level. There was a decrease in survival in mice exposed to 400 ppm. Neoplastic lesions were observed in the nasal cavity of rats and mice exposed to 400 ppm. In male and female rats there was in increased incidence of papillary adenomas of the nasal epithelium, while in male and female mice there were increased incidences of hemoglomas and hemangiosarcomas of the nasal mucosa. Exposure also caused suppurative inflammation, hyperplasia, and squamous metaplasia in the nasal epithelium of rats and inflammation in mice. [R101] *Four groups of 100 Wistar rats of each sex were exposed by inhalation to 0, 30, 100 or 300 ppm propylene oxide for 6 hr/day, 5 days/wk for 28 months. After 12, 18 and 24 months ten rats/sex/group were killed to provide interim hematological, biochemical and urinary data. Mortality was increased by wk 115 in both sexes in the 300 ppm group and by wk 119 in females of the 100 ppm group. Body weights were lower than those of the controls throughout the study in males of the 300 ppm group and in females of the 300 ppm group during the first year of the study. Increased incidences of degenerative and hyperplastic changes of the nasal mucosa were observed in all exposed groups. Exposure to 300 ppm propylene oxide was associated with an increased incidence of both benign and malignant mammary tumors in females. There was no increase in the incidence of any particular type of tumor other than mammary tumors. The total number of rats bearing malignant tumors at sites other than the mamamry glands was increased in both sexes in the 300 ppm group compared with the controls. [R102] *1,2-Propylene oxide ... test results for mutagenicity in Salmonella assays ... proved positive. [R103] *Under the conditions of these studies, there was some evidence of carcinogenicity for F344/N rats, as indicated by increased incidences of papillary adenomas of the nasal turbinates in male and female rats exposed to propylene oxide at 400 ppm. For male and female B6C3Fl mice, there was clear evidence of carcinogenicity, as indicated by increased incidences of hemangiomas or hemangiosarcomas of the nasal turbinates at 400 ppm. In the respiratory epithelium of the nasal turbinates, propylene oxide also caused suppurative inflammation, hyperplasia, and squamous metaplasia in rats and inflammation in mice. [R104] NTOX: *Hyperemia and edema resulted from application of 10% or 20% aqueous soln of propylene oxide to the shaved intact skin of rabbits under an occluding plastic cover when the duration of exposure was 6 min or longer. The most severe exposures resulted in scar formation. [R41, 1991.1316] *... Propylene oxide /is/ 1/2 to 1/3 as potent as ethylene oxide based on single-exposure data. Secondary pulmonary infection followed acute inhalation exposure to propylene oxide. [R41, 1991.1316] *When gavaged as a 10% olive oil solution, rats survived 0.3 g/kg and died at 1.0 g/kg. The dermal LD50 in rabbits was 1.3 g/kg. Four-hour inhalation LC50 of propylene oxide were 4126 mg/cu m (1740 ppm) in mice and 9486 mg/cu m (4000 ppm) in rats. At 7200 ppm in rats, deaths were 0/10, 2/10, and 5/10 after exposures of 0.25, 0.5, and 1.0 hr, respectively. [R42, 349] *Propylene oxide is a direct-acting mutagen and rodent carcinogen. We have studied how propylene oxide modifies 2'deoxynucleosides at pH 7.0-7.5 and 37 deg C for 10 hr. Propylene oxide reacts as an SN2 alkylating agent by forming the following 2-hydroxypropyl adducts: N6-2-hydroxypropyl-dAdo (7% yield), 7-2-hydroxypropyl-Gua (37%) and 3-2-hydroxypropyl-dThd (4%). Alkylation at N-3 of dCvd resulted in conversion of the adjacent exocylic imino group at C-4 to an oxygen (hydrolytic deamination) with the formation of a dUrd adduct, 3-2-hydroxypropyl-dUrd (14%). Ultraviolet spectroscopy and mass spectrometry were used for the structural determination of these adducts. Confirmation of the unexpected 3-2-hydroxypropyl-dUrd adduct was provided by an accurate mass measurement technique where diagnostic ions in the mass spectra of 3-2-hydroxypropyl-dUrd were measured to within 0.0005 atomic mass units of the predicted mass. Propylene oxide was reacted in vitro with calf thymus DNA (pH 7.0-7.5, 37 deg C, 10 hr) and yielded N6-2-hydroxypropyl-dAdo (1 nmol/mg DNA), 3-2-hydroxypropyl-Ade (14 nmol/mg DNA), 7-2-hydroxypropyl-Gua (133 nmol/mg DNA) and 3-2-hydroxypropyl-dUrd (13 nmol/mg DNA). A mechanism for the hydrolytic deamination of 3-2-hydroxpropyl-dCyd to 3-2-hydroxypropyl-dUrd involving the hydroxide on the 2-hydroxypropyl side chain is proposed. This cytosine to uracil conversion may play a role in the mutagenic and carcinogenic activity of this epoxide. [R105] *Irritating to the eyes of animals, and liquid caused severe eye irritation in rabbits. [R42, 350] NTXV: *LD50 Guinea pig /oral/ 0.69 g/kg; [R106] *LC50 Mouse inhalation 1740 ppm/4 hr; [R49] *LD50 Rabbit skin 1245 mg/kg; [R40] *LC50 Rat inhalation 4000 ppm/ 4 hr; [R41, 1991.1316] *LD50 Rabbit percutaneous 1.5 ml/kg; [R41, 1991.1316] *LD50 Rat ip 150 mg/kg; [R40] *LD50 Rat oral 380 mg/kg; [R40] *LD50 Mouse ip 175 mg/kg; [R40] *LD50 Guinea pig oral 660 mg/kg; [R40] ETXV: *LC50 Goldfish 170 mg/l/24 hr /Conditions of bioassay not specified/; [R107] *LC50 Mullet 89 ppm/96 hr /Conditions of bioassay not specified/; [R107] *TLm Gambusia affinis (mosquito fish) 141 mg/l/96 hr at 24 deg C, static bioassay; [R106] *TLm Bluegill 215 mg/l/96 hr at 24 deg C, static bioassasy; [R106] NTP: +The 2 year carcinogenesis studies of propylene oxide (greater than 99.9% pure) were conducted by exposing groups of 50 F344/N rats and 50 B6C3Fl mice of each sex to air containing propylene oxide at concentrations of O (chamber control), 200, or 400 ppm for 6 hours per day, 5 days per week, for 103 weeks. Under the conditions of these studies, there was some evidence of carcinogenicity for F344/N rats, as indicated by increased incidences of papillary adenomas of the nasal turbinates in male and female rats exposed to propylene oxide at 400 ppm. For male and female B6C3Fl mice, there was clear evidence of carcinogenicity, as indicated by increased incidences of hemangiomas or hemangiosarcomas of the nasal turbinates at 400 ppm. In the respiratory epithelium of the nasal turbinates, propylene oxide also caused suppurative inflammation, hyperplasia, and squamous metaplasia in rats and inflammation in mice. [R108] TCAT: ?Chronic toxicity and oncogenicity were evaluated in male and female SPF-reared albino rats (100/sex/group) exposed via inhalation to 0, 30, 100 and 300 ppm propylene oxide for 6 hrs/day, 5 days/week for 123 weeks (females) or 124 weeks (males). Significant increases were observed in treated animals compared to controls in the following: palpable subcutaneous masses (females at 300 ppm), mortality (both sexes at 300 ppm, females at 100 ppm), degenerative and hyperplastic changes in the nasal mucosa (all treated rats), incidence and multiplicity of mammary gland masses and benign mammary tumors (females at 300 ppm), number of mammary fibroadenomas per fibroadenoma-bearing females (all treated females), malignant mammary tumors (females at 300 ppm), and malignant non-mammary tumors (both sexes at 30 ppm). Significant decreases for treated animals was observed for the following: body weights (both sexes at 300 ppm, females only in first year of study) and incidence of pale exorbital lachrymal glands (males at 300 ppm). No significant effects were observed in the following: food intake, biochemistry or urinalysis. [R109] ?The mutagenicity of propylene oxide was evaluated in Salmonella tester strain 1538 (Ames Test) and also in E. coli strains WP2 and WP2uvrA, both in the presence and absence of Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, propylene oxide was tested for mutagenicity at concentrations of 0, 0.2, 2.0, 20.0 and 500 ug/ml in two sets of tests, one set preincubated the chemical and cells for 1 hr (both with and without activation) and the other set preincubated for 4 hrs (without activation only). Tryptophan was used as the selection agent for the E coli mutants. Propylene oxide did not cause a reproducible positive response in the Salmonella tester strain TA1538. Propylene oxide did cause a reproducible positive response without metabolic activation at exposures of 1 and 4 hrs when tested at 20 ug/ml with strain WP2uvrA. With metabolic activation, a positive response occurred with WP2uvrA at 500 ug/ml after a 1 hr exposure. The lack of a positive response in WP2 at the 500 ug/ml concentration with activation was attributed to the considerable cell toxicity observed in those tests. [R110] ?The ability of propylene oxide to cause chromosome aberrations was evaluated in an liver epithelial-type cell line of Carworth Farm E (CFE) rat. Cultures were treated with propylene oxide at 0, 25, 50, 75 and 100ug/ml and incubated for 24 hours, after which colcemid was added. Chromosome changes were analyzed in 100 cells from each culture. All of the treated cells exhibited increases (no statistics reported) in the frequency of chromosome aberrations relative to the controls, and a dose-response relationship was also observed. [R111] ?The effect of propylene oxide (PO) on liver non-protein sulfhydryls was evaluated in male Wistar/Lewis rats (9/exposure) receiving nominal concentrations of PO at 75 (TWA 80ppm), 150 (TWA 143ppm), 225 (TWA 217ppm), 300 (TWA 284ppm) or 600ppm (TWA 904ppm) for six hours in a dynamic air flow chamber. All animals were sacrificed at the end of exposure, and blood and livers were collected for analysis. Hepatic non-protein sulfhydryls were significantly depressed in livers of animals exposed at 300ppm or greater relative to the controls, and a dose-response relation was observed. The concentration of PO in the blood was proportional to exposure concentrations, except for exposures ranging from 150ppm to 300ppm were there was a disproportionate increase concentration of PO in the blood. [R112] ?A subchronic inhalation toxicity study was conducted with group of male and female Wistar rats receiving whole body exposure to propylene oxide at nominal concentration of 0, 75, 150, 300 or 600ppm in a dynamic air flow chamber. At each concentration, groups of 20 rats (10 male and 10 female) were exposed 6 hours a day, 5 days a week, for 13 weeks. The treatment produced no signs of toxicity in any of the animals as indicated by mortality, hematological values, major biochemical and urinary values, gross and histopathologic observations relative to controls. There was a depression in body weight gain in males and females at the high dose level. [R113] ?As part of a two-generation reproduction study, the neurotoxic potential of propylene oxide was evaluated in male Fischer 344 rats (F0 generation). Thirty animals per group received whole body exposure to propylene oxide at nominal concentrations of 0, 30, 100 or 300ppm for 6 hours per day, 5 days per week, for approximately 24 weeks. Observational battery tests were performed on all rats from each dose level at approximately 8, 16 and 24 weeks of exposure. Also preformed prior to sacrifice were hindlimb grip strength test and an open-field activity test. After sacrifice an extensive histopathologic examination of the central and peripheral nervous system was conducted. There were no differences in the test results between the treated groups and control groups. Mild neuroaxonal dystrophy (eosinophilic spheroids) in the region of the nucleus gracilis was present in the majority of control and treated animals, however, the incidence and severity of the condition was more prevalent in the controls than the high dose animals. [R114] POPL: *Persons with existing skin disorders or liver, kidney or chronic respiratory diseases may be more susceptible to the effects of propylene oxide. [R51, 1981.1] ADE: *THE RESPIRATORY SYSTEM IS THE PRIMARY ROUTE OF ABSORPTION, ALTHOUGH THE SKIN ALSO REPRESENTS A ROUTE BY WHICH PHYSIOLOGICALLY SIGNIFICANT AMT ... MAY ENTER THE BODY ... . [R73] METB: *PROPYLENE OXIDE REACTS WITH DNA AT NEUTRAL PH TO YIELD TWO PRINCIPAL PRODUCTS, N-7-(2-HYDROXYPROPYL)GUANINE AND N-3-(2-HYDROXYPROPYL)ADENINE. [R115] *Chromosomal aberrations and micronuclei in lymphocytes were measured in workers exposed to propylene oxide in a factory alkylated starch, and in workers exposed to ethylene oxide in connection with sterilization of medical equipment. Adduct levels in hemoglobin were determined as a measure of in vivo doses of the two compounds. The levels of hydroxypropylvaline in propylene oxide-exposed workers were correlated in estimated exposure doses. The levels of this adduct in the unexposed group were close to the detection limit of the method. The levels of hydroxyethylvaline, recorded in the propylene oxide-exposed group were consistent with earlier data on hemoglobin alkylation in occupationally unexposed subjects. The adduct measurements revealed increased levels of hydroxyethylvaline in the two subgroups of ethylene oxide-exposed workers, ie, assemblers with a low and sterilizers with a high exposure. According to expectation the subgroups differed in adduct levels. The results of cytogenetic study showed that the clastogenic potency of propylene oxide was lower than that of ethylene oxide, since the propylene oxide-exposed individuals had lower frequencies of micronuclei and chromosomal breaks compared to the assemblers despite a lower adduct level in the last group. [R72] *The pharmacokinetics of propylene and its reactive metabolite, propylene oxide, were assessed in rats to examine purported differences in carcinogenicity between the two compounds. Groups of Sprague-Dawley rats were exposed in closed exposure systems to propylene or propylene oxide. Pharmacokinetic parameters were determined by a two compartment model which was used to calculate the body burden of propylene oxide resulting from inhaled propylene. The thermodynamic equilibrium constant for the whole body to air ratio was dependent on the physical properties of the substances and was determined to be 1.6 for propylene and 45 for propylene oxide. Saturation kinetics according to the Michaelis Menten constant were found for propylene; in contrast, no saturation kinetics were observed for propylene oxide up to initial concentrations of 3000 ppm in the atmosphere of the exposure chambers. By means of pharmacokinetic parameters, the body burden of propylene oxide was calculated for different conditions of continous exposure either to propylene oxide or to propylene. The maximum body burden of propylene oxide did not exceed a concentration of 71 nanoliters propylene oxide gas per milliter tissue if rats were exposed to propylene even at very high concentrations. [R116] BHL: *... The half-life of inhaled propylene oxide in rats is 40 min. [R41, 1991.1318] ACTN: *Thymidine was reacted in methanol with 4 epoxides of varying mutagenicities: propylene oxide, glycidol, epichlorohydrin, and trichloropropylene oxide. A single product was detected with each epoxide, and these products had the same retention times on silica HPLC. UV spectra of the products identified them as 3-alkylthymidines, and this was confirmed by IR and NMR spectra. Mass spectra analysis showed that the attachment was at the least substituted C of the epoxide. Formation of alkylthymidines correlated to Taft sigma electron withdrawing values for the substituents on the epoxides and mutagenicities in strain TA100 of the Ames assay. [R117] INTC: *WHEN ... /IT IS MIXED WITH CARBON DIOXIDE/ SMALL DOSES ARE MORE EFFECTIVE AND A QUICKER KILL IS EFFECTED THROUGH STIMULATION OF INSECT RESP. [R5] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Propylene oxide's production and its use as a chemical intermediate in polymer synthesis and as a food additive (fumigant), may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 538 mm Hg at 25 deg C indicates 1,2-propylene oxide will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-propylene oxide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 30 days. If released to soil, 1,2-propylene oxide is expected to have very high mobility based upon an estimated Koc of 25. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 6.96X10-5 atm-cu m/mole. 1,2-Propylene oxide may volatilize from dry soil surfaces based upon its vapor pressure. 1,2-Propylene oxide, present at 100 mg/l, reached 95% of its theoretical BOD in 3 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test, suggesting biodegradation will be an important fate process. If released into water, 1,2-propylene oxide is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 12 hours and 6 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Propylene oxide will hydrolyze at half-life rates of 11.6 days (at pH's 7-9) and 6.6 days (at pH 5) at 25 deg C. The presence of chloride ion accelerates the degradation in water and the chemical degradation half-lives in seawater are estimated to be 4.1 days (at pH's 7-9) and 1.5 days (at pH 5) at 25 deg C. Reaction of propylene oxide with Cl ion in water yields approximately 90% 1-chloro-2-propanol and 10% 2-chloro-1-propanol as products under neutral pH conditions. Occupational exposure to 1,2-propylene oxide may occur through inhalation and dermal contact with this compound at workplaces where 1,2-propylene oxide is produced or used. Propylene oxide has been detected in 6.2% of 1,159 consumer products that are used indoors; products found to containing the highest concentration of propylene oxide were automotive and paint products. (SRC) NATS: *Propylene oxide is not known to occur as a natural product. [R69] ARTS: *1,2-Propylene oxide's production and its use as a chemical intermediate in polymer synthesis(1) and as a food additive (fumigant)(1,2), may result in its release to the environment through various waste streams(SRC). [R118] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 25(SRC), determined from an measured log Kow of 0.03(2) and a regression-derived equation(3), indicates that 1,2-propylene oxide is expected to have very high mobility in soil(SRC). Volatilization of 1,2-propylene oxide from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.96X10-5 atm-cu m/mole(SRC), calculated from its vapor pressure, 538 mm Hg(4), and water solubility, 5.9X10+5 mg/l(5). The potential for volatilization of 1,2-propylene oxide from dry soil surfaces may exist (SRC) based upon a vapor pressure of 538 mm Hg(4). The aqueous hydrolysis of propylene oxide occurs at an environmentally important rate; therefore, hydrolysis in moist soil is likely to be important (5). 1,2-Propylene oxide, present at 100 mg/l, reached 95% of its theoretical BOD in 3 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(6), suggesting biodegradation will be an important fate process(SRC). [R119] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 25(SRC), determined from an measured log Kow of 0.03 and a regression-derived equation(3), indicates that 1,2-propylene oxide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 6.96X10-5 atm-cu m/mole (SRC), based upon its vapor pressure, 538 mm Hg(4), and water solubility, 5.9X10+5 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 12 hours and 6 days, respectively(SRC). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression- derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). In freshwater, propylene oxide will hydrolyze with estimated half-lives of 11.6 days (pH's 7-9) and 6.6 days (pH 5) at 25 deg C(5). 1,2-Propylene oxide, present at 100 mg/l, reached 95% of its theoretical BOD in 3 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(8), suggesting biodegradation will be an important fate process(SRC). [R120] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-propylene oxide, which has a vapor pressure of 538 mm Hg at 25 deg C(2) is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-propylene oxide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 30 days(SRC), calculated from its rate constant of 5.2X10-12 cu cm/molecule-sec at 25 deg C(3). [R121] BIOD: *AEROBIC: 1,2-Propylene oxide, present at 100 mg/l, reached 95% of its theoretical BOD in 3 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1); therefore, this compound is expected to biodegrade rapidly. In another study, using the standard dilution method, a 5 day theoretical BOD of 8% was measured for propylene oxide using a filtered effluent seed from a biological sanitary waste treatment plant while a 5 day theoretical BOD of 9% was measured using an adapted seed(2). [R122] ABIO: *The rate constant for the gas-phase reaction of propylene oxide with photochemically produced hydroxyl radicals in the atmosphere has been experimentally determined to be 5.2X10-13 cu cm/molecule-sec at 25 deg C(1); assuming an average atmospheric hydroxyl radical concn of 5X10+5 molecules/cu cm, a half-life of 30 days can be calculated for this reaction(SRC). The anticipated products of the atmospheric reaction with hydroxyl radicals have been cited as oxomethyl acetate, propanedial, formaldehdye, and diformyl ether(2). Ozone is not expected to react with propylene oxide in the atmosphere(3). The hydrolysis half-life of propylene oxide in fresh water at 25 deg C has been estimated to be 11.6 days at pH 7-9 and 6.6 days at pH 5(4). The half-life of propylene oxide in seawater (3% NaCl concn) at 25 deg C has been estimated to be 4.1 days at pH 7-9 and 1.5 days at pH 5(4) with the formation of chloropropanols. The rate constant for the reaction of propylene oxide with photochemically produced hydroxyl radicals in water at room temperature has been experimentally determined to be 2.4X10+8/m-sec(5); assuming an average hydroxyl radical concentration of 1X10-17M in natural water(6), a half-life of 9.15 years can be calculated indicating no environmental significance(SRC). [R123] BIOC: *An estimated BCF of 3 was calculated for 1,2-propylene oxide(SRC), using a log Kow of 0.03(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R124] KOC: *The Koc of 1,2-propylene oxide is estimated as 25(SRC), using a measured log Kow of 0.03(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1,2-propylene oxide is expected to have very high mobility in soil(SRC). [R125] VWS: *The Henry's Law constant for 1,2-propylene oxide is estimated as 6.96X10-5 atm-cu m/mole(SRC) based upon its vapor pressure, 538 mm Hg(1), and water solubility, 5.9X10+5 mg/l(2). This Henry's Law constant indicates that 1,2-propylene oxide is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 12 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 6 days(SRC). The potential for volatilization of 1,2-propylene oxide from dry soil surfaces may exist(SRC) based upon a vapor pressure of 538 mm Hg(1). [R126] EFFL: *A propylene oxide concentration of 0.047 mg/l was detected in a water effluent from Olin Corporation's Brandenberg, KY chemical production facility on Feb 2, 1974(1). Atmospheric emissions of propylene oxide from propylene oxide manufacturing processes during 1978 were estimated to be about 1.16 million lb(2). Atmospheric emissions resulting from the use of propylene oxide in the production of urethane polyols, propylene glycol, surfactant polyols, di- and tripropylene glycols, glycol ethers and miscellaneous applications during 1978 were estimated to be about 147.7, 13.9, 15.8, 2.9, 1.2 and 3.8 thousand lb, respectively(2). It has been suggested that proplyene oxide may be emitted to the atmosphere from automobile exhaust and from combustion exhausts of stationary sources that burn hydrocarbons(3). [R127] ATMC: *SOURCE DOMINATED: Propylene oxide has been detected in 6.2% of 1,159 consumer products that are used indoors. Products containing the highest concentration of propylene oxide were automotive (0.3% w/w) and paint products (0.3% w/w)(1). Propylene oxide was tentatively identified in unspecified atmospheric air samples in the US(2). [R128] FOOD: *TREATED WHEAT HAD EPOXIDE RESIDUE OF 300 PPM, BUT AFTER IT WAS MILLED FLOUR CONTAINED LESS. /PROPYLENE OXIDE/ [R11, 159] *WHEN FOODS WERE TREATED WITH PROPYLENE OXIDE, 1-CHLOR-2-PROPANOL WAS FORMED. [R129] RTEX: *Exposure of man to propylene oxide mainly occurs through inhalation at the workplace. [R71] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 421,140 workers (317,309 of these are female) are potentially exposed to 1,2-propylene oxide in the US(1). Occupational exposure to 1,2-propylene oxide may occur through inhalation and dermal contact with this compound at workplaces where 1,2-propylene oxide is produced or used(SRC). In a 1979 study by one USA manufacturer, the typical average daily exposure of workers to propylene oxide were 0.5-5 mg/cu m with worst-case peak exposures of 59-9000 mg/cu m (highest exposure being that of maintenance workers cleaning pumps)(2). Levels of worker exposure were reported to be 0.5 to 5.9 mg/cu m in a polymer polyol unit, not detectable to 1.2 mg/cu m in an oxide adducts unit, and not detectable in a flexible polyol unit of a large chemical manufacturing facility producing many chemical products including propylene oxide derivatives(2). A propylene oxide concn of 3.6 mg/cu m was found near an operator at a flexible polyol unit in another large chemical manufacturing facility(2). Propylene oxide has been detected in 6.2% of 1,159 consumer products that are used indoors; products found to containing the highest concentration of propylene oxide were automotive and paint products(SRC). [R130] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers propylene oxide to be a potential occupational carcinogen. /SRP: No IDLH value specified/. [R26, 270] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (240 mg/cu m). [R131] *Vacated 1989 OSHA PEL TWA 20 ppm (50 mg/cu m) is still enforced in some states. [R26, 370] NREC: *NIOSH considers propylene oxide to be a potential occupational carcinogen. [R26, 270] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R26, 270] TLV: *8 hr Time Weighted Avg (TWA) 20 ppm [R132, 59] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R132, 6] *A3: Confirmed animal carcinogen with unknown relevance to humans. [R132, 59] *Notice of Intended Change for 2000: These substances, with their corresponding values and notations, comprise those for which a limit has been proposed for the first time or for which a change in the Adopted listing has been proposed. In each case, the proposed values should be considered trial values for the year following ratification by the ACGIH Board of Directors. If, during the year, no evidence comes to light that questions the appropriateness of these proposals, the value will be reconsidered for adoption as TLVs. Time Weighted Avg (TWA): 2 ppm; Carcinogenicity, A3; Sensitizer. [R132, 75] OOPL: *Emergency Response Planning Guidelines (ERPG): ERPG(1) 50 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 250 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 750 ppm (not life threatening) up to 1 hr exposure. [R133] *Australia: 20 ppm, Category 2, probable human carcinogen, substance under review; Federal Republic of Germany: no MAK, Group A2 unmistakable carcinogenic in animal experimentation only, Technical Exposure Limits (TRK) 2.5 ppm; Sweden: 5 ppm, short-term value 10 ppm, 15 min; United Kingdom: 20 ppm, 10 min STEL 100 ppm. [R41, 1991.1319] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Propylene oxide is produced, as an intermediate or a final product, by process units covered under this subpart. [R134] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,2-Propylene oxide is included on this list. [R135] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 5,000 ug/l [R136] CWA: +Propylene oxide is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R137] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R138] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Propylene oxide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 10,000 lbs. Extremely hazardous substances that are solids are subject to either of two threshold planning quantities ... The lower quantity applies only if the solid exists in powdered for and has a particle size less than 100 microns; or is handled in solution or in molten form; or meets the criteria for a National Fire Protection Association (NFPA) rating of 2, 3 or 4 for reactivity. If the solid does not meet any of these criteria, it is subject to the upper ... threshold planning quantity ... . [R139] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Oxirane, methyl is included on this list. [R140] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Propylene oxide is found on List B. Case No: 2560; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Propylene oxide; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R141] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *... Sampling tubes are packed with a porous polymer gas chromatographic adsorbent (Porapak N) to collect the propylene oxide. [R142] *NIOSH Method 1612. Analyte: Propylene oxide. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min: Sample Size: 5 liters. Shipment: Refrigerated. Sample Stability: Not determined. [R143] ALAB: *Analytical methods include spectrophotometry, gas chromatography, electron impact spectroscopy, and colorimetric methods. A multigas analyzer utilizing microwave spectroscopy has also been developed to monitor propylene oxide in air. [R144] *The method is based on the hydrolysis of propylene oxide to form propylene glycol, which is then oxidized to formaldehyde with periodic acid and determined photometrically following reaction with chromotropic acid. The detection limit of the method is 1 ug, and the minimum measurable concentration is 0.5 mg/cu m. [R145] *Gas chromatography may be used to determine the levels of propylene oxide in food, cellulose, and plastic products. [R75, (1976)] *NIOSH Method 1612. Analyte: Propylene oxide. Matrix: Air. Procedure: Gas chromatography, hydrogen-air flame ionization detector. For propylene oxide this method has an estimated detection limit of 0.01 mg/sample. The precision/RSD is 0.029 @ 0.6 to 2.4 mg/sample. Applicability: The working range is 8 to 295 ppm (20 to 700 mg/cu m) for a 5 liter air sample. Interferences: None found. [R143] *Propylene oxide is analysed by gas chromatograph for analysis. Recovery is 100 + or - 3 percent for samples analyzed up to 3 weeks after collection. This technique is most appropriate for concentrations of less than 100 ppm in a 1 liter air sample, and has a sensitivity of approximately 1 ppb. [R142] CLAB: *A GAS CHROMATOGRAPHY-MASS SPECTROMETRIC METHOD IS DESCRIBED FOR DETERMINATION IN HEMOGLOBIN OF S-METHYLCYSTEINE IN FOLLOWING EXPOSURE TO PROPYLENE OXIDE. 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Fairfax, VA 1999.26 R134: 40 CFR 60.489 (7/1/2000) R135: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R136: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R137: 40 CFR 116.4 (7/1/2000) R138: 40 CFR 302.4 (7/1/2000) R139: 40 CFR 355 (7/1/2000) R140: 40 CFR 716.120 (7/1/2000) R141: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.204 (Spring, 1998) EPA 738-R-98-002 R142: Russell JW; Environ Sci Technol 9: 1175-8 (1975) as cited in USEPA/ECAO; Summary Health Assessment Document For 1,2-Propylene oxide (Draft) p.1-4 (1985) EPA Contract No 68-02-4030 R143: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R144: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 246-274 R145: Gronsberg ES; Gig Tr Prof Zabol 4: 48-49 (1981) as cited in USEPA/ECAO; Summary Health Assessment Document For 1,2-Propylene oxide (Draft) (1985) EPA Contract No 68-02-4030 R146: BAILEY E ET AL; ANAL PROC (LONDON) 19 (5): 239 (1982) RS: 137 Record 33 of 1119 in HSDB (through 2003/06) AN: 175 UD: 200302 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PROPYLENE- SY: *R-1270-; *METHYLETHENE-; *METHYLETHYLENE-; *NCI-C50077-; *PROPENE-; *1-PROPENE-; *1-PROPYLENE- RN: 115-07-1 MF: *C3-H6 SHPN: UN 1077; Propylene UN 1075; Propylene or liquified petroleum gas IMO 2.1; Propylene STCC: 49 057 82; Propylene MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OBTAINED FROM PETROLEUM OILS DURING REFINING OF GASOLINE. CATALYTIC OR THERMAL CRACKING OF HYDROCARBONS ALWAYS YIELDS PROPYLENE. IF NECESSARY, IT CAN BE OBTAINED BY CATALYTIC DEHYDROGENATION OF PROPANE. [R1] IMP: *CONTAMINANTS ARE PROPANE, ETHANE, CARBON DIOXIDE. [R1] *Polymerization grade propylene typically contains the following impurities (ppm max): saturates (200), butylene (20), ethylene (20), methylacetylene (10), oxygen (10), butadiene (5), propadiene (5), carbon monoxide (5), carbon dioxide (5), water (5), hydrogen (5), and methanol (5). [R2] FORM: *Grades: chemical 92+%; polymerization 99+%; research 99+%; propylene concentrate 80+%. [R3] MFS: *Amoco Corporation, Hq, 200 East Randolph Drive, Chicago, IL 60601, (312) 856-6111; Subsidiaries: Amoco Chemical Company (address same as Hq), (312) 856-3200; Chemical and Specialty Products Group; Production sites: Alvin, TX 77511; Texas City, TX 77590; Amoco Oil Co, 200 East Randolph Dr, Chicago, IL 60601, (312) 856-5111; Production site: Whiting, IN 46394 [R4, 919] *Ashland Oil, Inc, Hq, 1401 Winchester Avenue, Ashland, KY 41101, (606) 329-3333; Ashland Petroleum Company, Production site: Catlettsburg, KY 41129 [R4, 919] *BP America, Inc, Hq, 200 Public Square, Cleveland, OH 44114-2375, (216) 586-4141; Production site: Lima, OH 45804; Subsidiary: BP Chemicals America, Inc [R4, 919] *Chevron Corp, Hq, 225 Bush St, San Francisco, CA 94104, (415) 894-7700; Subsidiary: Chevron Chemical Co; Aromatics and Derivatives Division, 1301 McKinney Street, PO Box 3766, Houston, TX 77253; Production sites: El Segundo, CA 90245; Philadelphia, PA 19101; Richmond, CA 94802; Olefins and Derivatives Division, 1301 McKinney Street PO Box 3766, Houston, TX 77253; Production sites: Cedar Bayou, TX 77520; Port Arthur, TX 77640 [R4, 919] *CITGO Petroleum Corp, Hq, 6130 S Yale Ave, Tulsa, OK 74136, (918) 495-4000; Production site: Lake Charles, LA 70601; Subsidiary: Champlin Refining and Chemicals, Inc; Production site: Corpus Christi, TX 78409-9176 [R4, 919] *The Coastal Corp, Hq, Coastal Tower 9 Greenway Plaza, Houston, TX 77046, (713) 877-1400; Subsidiaries: Coastal Eagle Point Oil Co (address same as Hq), (713) 877-6553; Production site: Westville, NJ 08093; Coastal Refining and Marketing, Inc (address same as Hq); Production site: Corpus Christi, TX 78403 [R4, 919] *Diamond Shamrock R and M Inc, Hq, PO Box 696000, San Antonio, TX 78269-6000, (512) 641-6800; Production sites: Dumas, TX 79086; Mont Belvieu, TX 77580 [R4, 919] *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production sites: Freeport, TX 77541; Plaquemine, LA 70764 [R4, 919] *Du Pont Company, Inc, Hq, 1007 Market St, Wilmington, DE 19898, (302) 774-1000; Dupont Chemicals, (800) 441-9442; Production site: Orange, TX 77630 [R4, 919] *Eastman Kodak Co, Hq, 343 State St, Rochester, NY 14650, (716) 724-4000; Eastman Chemical Company; Texas Eastman Division; PO Box 7444, Longview, TX 75607; Production site: Longview, TX 75607 [R4, 919] *Exxon Corp, Hq, 225 E John W Carpenter Freeway, Irving, TX 75062-2298, (214) 444-1000; Exxon Chemical Co, division; Exxon Chemical Americas, PO Box 3272, Houston, TX 77001; Production sites: Baton Rouge, LA 70821; Baytown, TX 77520; Bayway, NJ 07202 [R4, 919] *The BFGoodrich Co, Hq, 3925 Embassy Parkway, Akron, OH 44313, (216) 374-2000; BFGoodrich Chemical Group; Production site: Calvert City, KY 42029 [R4, 919] *Koch Industries, Inc, Hq, PO Box 2256, Wichita, KS 67201, (316) 832-5500; Subsidiaries: Koch Refining Co; Production site: Corpus Christi, TX 78403 [R4, 919] *Mobil Corp, Mobil Oil Corp, Hq, 3225 Gallows Rd, Fairfax, VA 22037-0001, (703) 846-3000; Mobil Chemical Company, division, 100 First Stamford Place, PO Box 10070, Stamford, CT 06904-2070; Petrochemicals Division, Intercontinental Center, Suite 906, 15600 JF Kennedy Boulevard, Houston, TX 77032-2343; Production sites: Beaumont, TX 77704; Houston, TX 77017 [R4, 920] *Occidental Petroleum Corporation, Hq, 10889 Wilshire Blvd, Suite 1500, Los Angeles, CA 90024, (213) 879-1700; Petrochemicals; Olefins and Aromatics Division; Production sites: Chocolate Bayou, TX 77511; Corpus Christi, TX 78410; Lake Charles, LA 70629 [R4, 920] *Phillips Petroleum Co, Hq, Phillips Bldg, Bartlesville, OK 74004, (918) 661-6600; Chemicals Division; Olefins and Cyclics Branch; Production site: Sweeny, TX 77480 [R4, 920] *Quantum Chemical Corp, Hq, 99 Park Ave, New York, NY 10016, (212) 949-5000; USI Division, 11500 Northlake Dr PO Box 429550, Cincinnati, OH 45249; Production sites: Clinton, IA 52732; Morris, IL 60450; Deer Park, TX 77536 [R4, 920] *Rexene Products Co, Hq, 5005 LBJ Freeway, Occidental Tower, Dallas, TX 75244, (214) 450-9000; Production site: Odessa, TX 79760 [R4, 920] *Salomon Inc, Hq, World Trade Center, New York, NY 10048, (212) 783-7000; Phibro Energy, Inc, 600 Steamboat Rd, Greenwich, CT 06830; Phibro Refining, Inc; Production sites: Houston, TX 77012; Texas City, TX 77590 [R4, 920] *Shell Oil Co, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Shell Chemical Co, division (address same as Hq); Production sites: Deer Park, TX 77536; Norco, LA 70079; Wood River, IL 62095 [R4, 920] *Sun Company, Inc, Hq, 100 Matsonford Road, Radner, PA 19087, (215) 293-6000; Subsidiary: Sun Refining and Marketing Company; Production sites: Marcus Hook, PA 19061; Toledo, OH 43693; Tulsa, OK 74102 [R4, 920] *Texaco Inc, Hq, 2000 Westchester Ave, White Plains, NY 10650, (914) 253-4000; Subsidiary: Texaco Chemical Co; Production sites: Delaware City, DE 19706; El Dorado, KS 67042; Port Arthur, TX 77640; Port Neches, TX 77651 [R4, 920] *Union Carbide Corporation, Hq, Old Ridgeway Road, Danbury, CT 06817, (203) 794-2000; Subsidiary: Union Carbide Chemicals and Plastics Co, Inc; Industrial Chemicals Division; Production sites: Seadrift, TX 77983; Taft, LA 70057; Texas City, TX 77590 [R4, 920] *Union Texas Petroleum/BASF Corp/GE Petrochemicals, Inc, Hq, PO Box 470, Geismar, LA, 70734; Production site: Geismar, LA 70734 [R4, 920] *USX Corp, 600 Grant St, Pittsburgh, PA 15219-4776, (412) 433-1121; Subsidiary: Marathon Oil Co; Production sites: Detroit, MI 48217; Garyville, LA 70051; Texas City, TX 77592 [R4, 921] *Vista Chemical Co, Hq, 900 Treadneedle, Houston, TX 77079, (713) 588-3000; Production site: Lake Charles, LA 70669 [R4, 921] *Clark Oil and Refining Corp, Hq, 8182 Maryland Ave, St Louis, MO 63105-3721, (314) 854-9696; Production site: Hartford, IL 62048 [R4, 919] *EPC Partners Ltd/HIMONT Inc, Hq, PO Box 4324, Houston, TX 77210, (713) 880-6500; Production site: Mont Belvieu, TX 77580 [R4, 919] *Lyondell Petrochemical Co, Hq, One Houston Center, 1221 McKinney, Suite 1600, PO Box 3646, Houston, TX 77253-3646; Production site: Channelview, TX 77530 [R4, 920] *Fina, Inc, Hq, PO Box 2159, Dallas, TX 75221, (214) 750-2400; Subsidiary: Fina Oil and Chemical Company; Production sites: Big Spring, TX 79720; Port Arthur, TX 77640 [R4, 920] *Javelina Gas Processing, Hq, 5314 I-37 Frontage Road, Corpus Christi, TX 78407, (512) 289-4900; Production site: Corpus Christi, TX 78407 [R4, 920] *Kerr-McGee Corp, Hq, Kerr-McGee Center, PO Box 25861, Oklahoma City, OK 73125, (405) 270-1313; Subsidiary: Kerr-McGee Refining Corp; Southwestern Refining Company, Inc; Production site: Corpus Christi, TX 78469 [R4, 920] *Westlake Petrochemicals Corp, Hq, Westlake Center, 2801 Post Oak Blvd, Houston, TX 77056, (713) 960-9111; Production site: Sulfur, LA 70664-2449 [R4, 920] *Crown Central Petroleum Corp, Hq, I North Charles St, Baltimore, MD 21203, (301) 539-7400 [R5, p. 2-4] *Oxy Petrochemicals, Inc, Hq, S Greenway Plaza, Suite 2500, Houston, TX 77046, (713) 623-2246 [R5, p. 2-4] *General Electric Co, Hq, Specialty Chemicals Group, Parkersburg Center, 5th and Avery, Parkersburg, WV 26102, (413) 448-6394 [R5, p. 2-4] *Marathon Petroleum Co, Hq, Texas Refining Division, 539 S Main St, Findlay, OH 45840, (419) 422-2121 [R5, p. 2-4] *EPC Partners, Ltd, Hq, PO Box 4324, Houston, TX 77210, (713) 880-6500 [R5, p. 2-4] *Hill Petroleum Co, Hq, PO Box 5038, Houston, TX 77262-5038, (203) 246-2000 [R5, p. 2-4] *Valero Refining and Marketing Co, Hq, 530 McCullough, San Antonio, TX 78292, (512) 246-2000 [R5, p. 2-4] USE: *IN POLYMERIZED FORM AS POLYPROPYLENE PLASTIC; RAW MATERIAL IN MANUFACTURE OF ACETONE, ISOPROPYLBENZENE, ISOPROPYL HALIDES [R1] *MONOMER FOR POLYPROPYLENE; COMONOMER FOR ETHYLENE-PROPYLENE ELASTOMERS; MONOMER IN POLYMER GASOLINE; AS FUEL; CHEM INTERMED FOR ACRYLONITRILE, PROPYLENE OXIDE, ISOPROPYL ALC, CUMENE, BUTRALDEHYDES, NONENE, DODECENE, HEPTENE, ALLYL CHLORIDE, ACROLEIN, OTHER ORG CHEM; COMPONENT OF ALKYLATE GASOLINE, LIQUIFIED REFINERY GASES [R6] */Mfr/ isopropyl alcohol, polypropylene, synthetic glycerol, acrylonitrile, propylene oxide, heptene, cumene, polymer gasoline, acrylic acid, vinyl resins, oxo chemicals. [R7, 973] *In prodn of synthetic rubber; as aerosol propellant and component. [R8, 3200] *In /mfr of/ n-butanol [R9] +MEDICATION CPAT: *50% FOR ORGANIC CHEMICALS (INCLUDING 11% FOR POLYPROPYLENE; 8% FOR ACRYLONITRILE; 7% FOR PROPYLENE OXIDE; 7% FOR ISOPROPYL ALCOHOL; 5% FOR CUMENE; 4% FOR BUTYRALDEHYDES; 2% FOR NONENE; 1.5% FOR DODECENE; 1% FOR HEPTENE; 1% FOR ALLYL CHLORIDE; 0.5% FOR ETHYLENE-PROPYLENE ELASTOMER; 0.5% FOR ACROLEIN; 1.5% FOR OTHER CHEMICALS); 46% FOR GASOLINES (INCLUDING 36% FOR ALKYLATE GASOLINE; 10% FOR POLYMER GASOLINE); 4% FOR MISC APPLICATIONS (INCLUDING USE AS FUEL AND IN LIQUIFIED REFINERY GASES) (1974) [R6] *Polypropylene, 34%; Acrylonitrile, 17%; Propylene oxide, 11%; Cumene, 9%; Oxo chemicals, 8%; Isopropanol, 6%; Acrylic acid and esters, 5%; Miscellaneous, 10% (1984) [R10] *CHEMICAL PROFILE: Propylene. Polypropylene, 36%; acrylonitrile; 16%; propylene oxide, 11%; cumene, 8%; isopropanol, 6%; oligimers, 6%; acrylic acid, 3%; export, 1%; other, 5%. [R11] *CHEMICAL PROFILE: Propylene. Demand: 1985: 14.7 billion lb; 1986: 15.1 billion lb; 1990 /projected/: 17 billion lb. [R11] *CHEMICAL PROFILE: Propylene. Polypropylene, 38%; acrylonitrile, 14%; propylene oxide, 11%; cumene, 10%; oxo alcohols, 8%; isopropanol, 6%; oligomers, 5%; acrylic acid, 3%; export, 1%; other 4%. [R12] *CHEMICAL PROFILE: Propylene. Demand: 1988: 19.0 billion lb; 1989: 19.4 billion lb; 1993 /projected/: 22.5 billion lb. (Includes exports, but not imports, which totaled 635 million lb last year.) [R12] PRIE: U.S. PRODUCTION: *(1972) 3.9X10+12 G [R6] *(1975) 4.0X10+12 G [R6] *(1985) 6.78X10+12 g [R13] *(1989) 9.3 X 10+12 g [R5, p. 2-2] *(1990) 21.85 billion lb [R14] *(1991) 27.71 billion lb [R4, 921] *(1991) 21.55 billion lb [R15] *(1992) 23.43 billion lb [R16] *(1993) 22.40 billion lb [R16] U.S. IMPORTS: *(1972) NEGLIGIBLE [R6] *(1975) NEGLIGIBLE [R6] *(1984) 2.40X10+11 g (est) [R17] U.S. EXPORTS: *(1972) NEGLIGIBLE [R6] *(1975) NEGLIGIBLE [R6] *(1984) 4.13X10+10 g (est) [R17] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS GAS [R7, 972] ODOR: *Practically odorless [R8, 3199] BP: *-48 DEG C @ 760 MM HG [R1] MP: *-185 DEG C (TRIPLE POINT) [R1] MW: *42.08 [R1] CTP: *CRITICAL TEMPERATURE: 91.8 DEG C; CRITICAL PRESSURE: 45.6 ATM [R1] DEN: *LIQ: 0.5139 @ 20 DEG C/4 DEG C [R1] HTC: *-19,692 Btu/lb= -10,940 cal/g= -458.04x10+5 J/kg [R18] HTV: *104.62 CAL/G @ BP [R1] OWPC: +log Kow = 1.77 (measured) [R19] SOL: *Sol in water (44.6 ml/100 ml), ethanol (1250 ml/100 ml), acetic acid (524.5 ml/100 ml) [R20]; *Sol in alcohol and ether [R7, 972] SPEC: *INDEX OF REFRACTION: 1.3567 @ -40 DEG C/D [R1]; *IR: 6403 (Sadtler Research Laboratories Prism Collection) [R21]; *MASS: 10 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R21] SURF: *16.7 DYNES/CM @ 90 DEG C [R1] VAPD: *1.49 (air= 1.0) [R1] VAP: +vapor pressure = 8.69X10+3 mm Hg at 25 deg C (from experimentally derived coefficients) [R22] VISC: *83.4 micropoises @ 16.7 deg C [R23] OCPP: *HEAT OF FUSION: 717.6 CAL/MOL; BURNS WITH YELLOW SOOTY FLAME; LIQUEFIES @ 7-8 ATM; DIPOLE MOMENT: 0.35 [R1] *Ratio of specific heats of vapor (gas): 1.152; Floats and boils on water [R18] *Henry's Law constant: 1.96X10-1 atm-cu m/mole at 25 deg C. [R24] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: EXTREMELY FLAMMABLE. Will be easily ignited by heat, sparks or flames. Will form explosive mixtures with air. Vapors from liquefied gas are initially heavier than air and spread along ground. Vapors may travel to source of ignition and flash back. Containers may explode when heated. Ruptured cylinders may rocket. [R25] +Health: Vapors may cause dizziness or asphyxiation without warning. Some may be irritating if inhaled at high concentrations. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Fire may produce irritating and/or toxic gases. [R25] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. [R25] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. Always wear thermal protective clothing when handling refrigerated/cryogenic liquids. [R25] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for l600 meters (1 mile) in all directions; also, consider initial evacuation for 1600 meters (1 mile) in all directions. [R25] +Fire: DO NOT EXTINGUISH A LEAKING GAS FIRE UNLESS LEAK CAN BE STOPPED. Small fires: Dry chemical or CO2. Large fires: Water spray or fog. Move containers from fire area if you can do it without risk. Fire involving Tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R25] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. If possible, turn leaking containers so that gas escapes rather than liquid. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Do not direct water at spill or source of leak. Prevent spreading of vapors through sewers, ventilation systems and confined areas. Isolate area until gas has dispersed. CAUTION: When in contact with refrigerated/cryogenic liquids, many materials become brittle and are likely to break without warning. [R25] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. Clothing frozen to the skin should be thawed before being removed. In case of contact with liquefied gas, thaw frosted parts with lukewarm water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R25] FPOT: *DANGEROUS FIRE RISK. [R18, 864] *... Highly flammable ... when mixed with air or oxygen. [R26, 1073] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R27] +Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R27] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R27] FLMT: *LOWER 2.4%, UPPER 10.3% BY VOLUME IN AIR. [R1] FLPT: *-162 DEG F (-108 DEG C) [R7, 972] AUTO: *927 DEG F (497 DEG C) [R7, 972] FIRP: *Do not extinguish fire unless flow can be stopped. If possible use foam, carbon dioxide, or dry chemical to extinguish fire. If none of these compounds are available use water in flooding quantities as a fog, being sure to cool all affected containers. Apply water from as far a distance as possible, and do not use solid streams of water since they may be ineffective. Keep material out of water sources and sewers and build dikes as necessary to contain flow. Wear self contained breathing apparatus, boots, protective gloves and goggles and be sure to wash away any material which may have contacted the body with copious amounts of water or soap and water. Do not handle damaged packages without protective equipment. If fire becomes uncontrollable or a container is exposed to direct flame, evacuate for a radius of 2500 feet. If material leaking (and is not on fire), downwind evacuation must be considered. [R28] TOXC: *Combustion products of propylene ... include carbon dioxide and carbon monoxide. [R29] OFHZ: *Vapor is heavier than air and may travel considerable distance to a source of ignition and flash back. [R18] EXPL: *EXPLOSION HAZARD MODERATE, WHEN EXPOSED TO HEAT OR FLAME. UNDER UNUSUAL CONDITIONS, IE, 955 ATM PRESSURE AND 327 DEG C, IT HAS BEEN KNOWN TO EXPLODE. [R30, 2296] *EXPLOSIVE LIMITS: LOWER 2.4%; UPPER 10.1% [R30, 2295] REAC: *Propylene reacts vigorously with oxidizing materials and with nitrogen dioxide (NO2), dinitrogen tetraoxide (N2O4), and dinitrogen oxide (N2O). Furthermore, liquid propylene will explode on contact with water at 42-75 deg C. [R31] *... Explosive when mixed with air or oxygen. [R26, 1073] POLY: *Polymerizes only at elevated temperature and pressure in the presence of a catalyst. [R2] OHAZ: *REACTS VIOLENTLY WITH OXIDIZING AGENTS. [R2] ODRT: *17.3 mg/cu m [R8, 3201] *Propylene has odor thresholds of 10-50 mg/cu m (detection) and about 100 mg/cu m (recognition), and an organoleptic limit of 0.5 mg/l [R32] EQUP: *Organic vapor canister or air supplied mask; goggles or face shield (for liquid) protective clothing (for liquid). [R18] *Plastic or neoprene coated canvas gloves should be worn where liquid propylene is handled. [R33] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R34] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R35] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R36] STRG: *Protect cylinder against physical damage and from excessive temperature rise by storing away from sources of heat. No part of a cylinder should be subjected to a temperature above 52 deg C. Store cylinders in an upright position and firmly secured. Segregate full and empty cylinders. Isolate from oxygen and other oxidizers. Avoid exposure to areas where salt or other corrosive chemicals are present. Ground and bond all lines and equipment used with propylene. Do not use near sparking motors or other non explosion proof equipment. [R33] CLUP: *Spills in Water: Contain contaminated water if possible by using natural barriers or oil spill control booms to limit spreading. A universal gelling agent may be applied to solidify trapped mass and to increase effectiveness of the booms. If solubilized, application of activated carbon at 10% spill amount over region occupied by 10 mg/l or greater concentrations is recommended. Spills on Land: Contain if possible by forming mechanical and/or chemical barriers to prevent spreading. Apply universal gelling agent to immobilize spill or use fly ash or cement powder to absorb the liquid. Leaking containers should be removed to an isolated well-ventilated area and if possible, the contents transferred to other suitable containers. Safety goggles, impervious clothing and positive pressure self-contained breathing apparatus should be worn. Plastic or neoprene-coated canvas gloves should be worn when liquid propylene is handled. [R37] DISP: *Propylene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R38] *Waste propylene must never be discharged directly into sewers or surface waters. Return all unused quantities to manufacturing company for disposal. Propylene may be burned but do not allow the flame to go out since the release of a cloud of propylene to the environment poses a major fire/explosion hazard. [R37] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of propylene. There is inadequate evidence in experimental animals for the carcinogenicity of propylene. Overall evaluation: Propylene is not classifiable as to its carcinogenicity to humans (Group 3). [R39] +A4; Not classifiable as a human carcinogen. [R40, 2002.50] ANTR: *If splashes of liquid propylene cause freezing of the skin, never rinse the affected area with hot or tepid water. If liquid propylene contacts the eyes flush eyes with water for 15 minutes. [R41] HTOX: *Propylene is usually handled commercially in liquid form and will cause freezing burns when in contact with skin or eyes. Gross inhalation may cause reduced blood pressure and disordered heart rhythm. [R26, 1764] *At a concn of 6.4% for 2.25 min, mild intoxication, paresthesias, and inability to concentrate were noted. However, memory was not impaired. At 12.8% in 1 min, the same symptoms were markedly accentuated and at 24 and 33%, unconsciousness followed in 3 min. Human exposure to 23% propylene for 3 to 4 min however did not produce unconsciousness. Two subjects exposed to 35 and 40% propylene vomited during or after the experiment, and one complained of severe vertigo. Exposure to 40, 50, and 75% for a few min caused initial reddening of eyelids, flushing of face, lacrimation, coughing, and sometimes flexing of legs. No variation in respiratory or pulse rates or electrocardiograms were noted. A concn of 50% prompted anesthesia in 2 min, followed by complete recovery without any physiological indications. [R8, 3200] NTOX: *In a research project ... propylene was admin by inhalation to rats and mice of both sexes in doses of 200, 1000 and 5000 ppm for 7 hr/day, 5 days/wk. The experiment included suitable control groups and was continued during 24 months for the rats and 18 months for the mice. Statistical analysis of the results obtained did not reveal any carcinogenic effects for rats or mice. [R26, 1766] *Animal experiments with cats have shown no toxic signs when anesthesia was induced with propylene concn of 20 to 31%, some subtle effects from 40 to 50%, blood pressure decrease and rapid pulse at 70%, and the unusual ventricular ectopic beat from 50 to 80%. A concn of 40% produced light anesthesia in rats, with no toxic symptoms within 6 hr, and an exposure to 55% for 3 to 6 min, 65% for 2 to 5 min, and 70% for 1 to 3 min resulted in deep anesthesia with no CNS signs or symptoms. However ... propylene was found to be a cardiac sensitizer in the dog. Chronic exposure of mice to minimal /SRP: CNS depressant/ ... concn caused moderate to very slight fatty degeneration of the liver, but somewhat less than ethylene. [R8, 3200] *Propylene is not mutagenic when tested in Escherichia coli, but conversely, protects against mutation. [R8, 3200] *Similar to ethylene, propylene also has a stimulating effect on plant growth at low concn, but is inhibitory at high levels. [R8, 3201] *Chronic toxicity studies ... were conducted by exposing groups of 50 F344/N rats and 50 B6C3F1 mice of both sexes to either 5,000 or 10,000 ppm concn of propylene for 6 hr/day, 5 days/wk for 103 wk. Controls, (groups of 50 rats and 50 mice of each sex in similar chambers) received only clean air on a similar schedule. Survival and mean body weights of exposed and control male and female rats and mice were similar. In exposed rats, increased incidences of non-neoplastic lesions were observed in the nasal cavity. These consisted of epithelial hyperplasia in female rats exposed to the high concentrations and squamous metaplasia in female rats exposed to both concentrations and in male rats exposed to the low concn. In addition inflammatory changes characterized by an influx of lymphocytes, macrophages, and granulocytes into the submucosa and granulocytes into the lumen occurred in male rats of both exposure groups. [R42] *The mutagenic potential of 1,2-propylene oxide, 1,3-butadiene, propylene, and vinylidene chloride was evaluated in a version of the L51784 mouse lymphoma assay modified for gases and volatile liquids. Butadiene and propylene were selected as examples of gases and 1,2-propylene oxide and vinylidene chloride as examples of volatile liquids. Cultures of the 3.7.2 heterozygote of L5178Y mouse lymphoma cells were exposed to 1,2-propylene oxide, butadiene, propylene, or vinylidene chloride vapor at concentrations up to 30% for 4 hours in the presence or absence of liver S9 mix using a specially designed vapor transfer system that prevented the loss of vapor from the culture medium. The cells were then cultured for 2 days after which they were plated in soft agar containing 3 ug/ml trifluorothymidine. Cytotoxicity was evaluated by determining decreases in cell population growth or cloning efficiency. Mutagenicity was assessed by determining the frequency of forward mutations at the thymidine kinase locus. Propylene was not cytotoxic or mutagenic in the absence of S9 mix. In the presence of S9 mix, propylene showed inconsistent, nonreproducible mutagenic responses. [R43] *Propylene was administered by inhalation, 7 hours daily, 5 days weekly, at a concentration of 5000, 1000, 200 and 0 ppm, to Sprague-Dawley rats and Swiss mice. Groups of 120 male and 120 female rats (high-dose and controls) or 100 male and 100 female rats (mid- and low-dose) were treated for 104 weeks, and groups of 100 male and 100 female mice (each dose and controls) for 78 weeks. The animals were kept under observation until spontaneous death. Under the tested experimental conditions, the monomer was not shown to be carcinogenic. [R44] NTP: *Toxicology and carcinogenesis studies of propylene (greater than 99% pure) were conducted by exposing groups of 50 F344/N rats and 49 or 50 B6C3F1 mice of each sex to propylene in air by inhalation at concentrations of 5,000 or 10,000 ppm, 6 hr/day, 5 days/wk, for 103 wk. Other groups of 50 rats and 50 mice of each sex in chambers received air only on the same schedule and served as chamber controls. The highest concn of propylene that was considered safe for these studies was 10,000 ppm because of risk of explosion, that can occur at higher concentrations. ... Hemangiosarcomas were found in one low dose male mouse (liver), two high dose male mice (spleen), and three high dose female mice (subcutis, spleen, and uterus). Hemangiomas were found in one low dose and in one high dose female mouse (liver). ... Under the conditions of these studies, there was no evidence of carcinogenicity in male and female F344/N rats or in male and female B6C3F1 mice exposed to propylene by inhalation at concentrations of 5,000 or 10,000 ppm for 103 wk. In the nasal cavity, propylene induced squamous metaplasia of the respiratory epithelium in male and female rats and epithelial hyperplasia in female rats. [R45] TCAT: ?Oncogenicity was evaluated in male and female Sprague Dawley rats (at least 100/sex/group) exposed to propene via inhalation at 0, 200, 1000 or 5000 ppm for 7 hrs/day, 5 days/week for 2 yrs. Propene did not show any carcinogenic effects in the rats. [R46] ?Oncogenicity was evaluated in male and female Swiss mice (at least 100/sex/group) exposed to propene via inhalation at 0, 200, 1000 or 5000 ppm for 7 hrs/day, 5 days/week for 18 months. Propene did not show any statistically significant carcinogenic effects in the mice. [R46] METB: *... propylene is expected to undergo various addition reactions, such as hydration to the alcohol, and excretion as the conjugated alcohol or propionic acid. These reactions may progress in a similar manner as recorded for an enzyme system of Pseudomonas oleovorans, which hydroxylates but does not epoxidize propylene. [R8, 3200] ACTN: *In an in vitro study of the mechanism of action of ethylene as a plant growth inhibitor, the effects of ethylene and some of its analogs, including propylene, on the oxidation of indole-3-acetic acid were examined. Ethylene and its analogs inhibited the oxidation of indole-3-acetic acid by peroxidase under conditions where the iron complex (compound III, an oxy-ferrous complex of peroxidase) shuttle was activated. Inhibition occurred only in the presence of the superoxide anion radical 02(-). Spectral and kinetic data indicated that ethylene and its analogs enhanced the rate of reaction of 02(-) with peroxidase; ie, the iron complex (compound III) shuttle, resulting in the formation of compound III. Propylene was a less effective inhibitor than ethylene. [R47] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: */Formerly/ in dental surgery as temporary anesthetic. [R8, 3200] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Some sources of propylene are biological in origin; it is a component of garlic essential oils, European fir, Scots pine, natural gases, and it is released by germinating beans, corn, cotton, and pea seeds. Propylene's release to the environment is wide spread since it is an ubiquitous product of incomplete combustion. Propylene is released to the atmosphere in emissions from the combustion of gasoline, coal, wood and refuse. If released to the atmosphere, propylene will exist in the vapor-phase. Vapor-phase propylene may be degraded by ozone (half-life of 24 hr), nitrate radicals (half-life of 4 days), or photochemically produced hydroxyl radicals (estimated half-life of 14.6 hr). Hydrolysis, bioconcentration, adsorption, and biodegradation are not expected to be important fate processes of propylene in soil or aquatic ecosystems. In soil and water, propylene may oxidize to its corresponding 1,2-epoxide. The high vapor pressure suggests that the gas may permeate through soil and sediment. Volatilization is expected to be the primary environmental fate process in soil and water. Volatilization half-lives from a model river and a model environmental pond have been estimated to be 1.9 and 23 hr, respectively. The most probable route of human exposure to propylene is by inhalation of contaminated air. (SRC) NATS: *PROPYLENE HAS BEEN FOUND IN GASEOUS METABOLITES RELEASED BY GERMINATING BEANS, CORN, COTTON AND PEA SEEDS. ... IT HAS BEEN DETECTED IN GASES DESORBED FROM COAL SAMPLES. ... [R48, p. V19 216] *... Occurs naturally in fruits, such as bananas and apples, but also in ocean sediments as a microbiological degradation product. [R8, 3200] *Propylene is a volatile component of garlic essential oils with a reported concn range of 0.01-5.99 ug/g garlic bulb(1); it has been found in the gaseous metabolites released by germinating beans, corn, cotton, and pea seeds(4). Propylene is released to the environment in forests as a volatile component of European fir and Scotch pine(2) and it is released to the atmosphere in emissions from biomass combustion, natural gas, volcanos, and microbes(3). [R49] ARTS: *Propylene is also expected to be released to the environment in the combustion gases of hydrocarbon fuels, wood, cigarettes, and synthetic polymers such as polyethylene, polyamides, and polyacrylonitrile which have been found to contain it. Propylene was present at a concn of approximately 10.7 ppm in the combustion gases following the burning of 5 kg of polypropylene in a 27 cu m room. Propylene has also been detected in the exhaust gases of jet engines at maximum concn of approximately 130-143 ppm as well as in the flue gases of a municipal incinerator at levels of < 0.4 - < 1.5 ppm. [R50] *The propylene content of the exhaust gases of automobiles burning leaded and unleaded gasoline was lower in late-model cars equipped with oxidative catalytic converters (2.9 percent as carbon) than earlier models without converters (6.5 percent as carbon). [R51] *A survey on the concn of compounds emitted from various trades and industries in Hong Kong was performed to indicate the level of pollutants occurring in the stacks of selected industries. Sampling from 2 stacks in a gas works revealed a mean propylene concn of 0.257 ul/cu m (range= 0.182 to 0.332). [R52] *Propylene occurs in cigarette smoke(1). Propylene is released to the atmosphere in emissions from burning gasoline, diesel and turbine engines(3); it is also released in emissions from the combustion of polyethylene(2), wood(4), coal(5), tobacco, and refuse(3); veneer drying, wood pulping, petroleum and acrylonitrile manufacturing discharge propylene to the atmosphere(3). [R53] FATE: *Atmospheric Fate: The atmospheric fate and photochemical reactions of propylene ... indicate that the principal reactant is the hydroxyl radical. Reactions of propylene with ozone occur predominantly in the evening, while reactions of propylene with atomic oxygen or sulfur dioxide (SO2) are reported to be insignificant ... because of their relatively low /atmospheric/ concn. ... The atmospheric half-life of propylene was 7.7 hr (calc). [R54] *TERRESTRIAL FATE: Volatilization is expected to be the primary fate process of propylene in soil(SRC) based on a measured vapor pressure of 8.69X10+3 mm Hg at 25 deg C(1) and a Henry's Law constant of 1.96X10-1 atm-cu m/mole at 25 deg C(2). A calculated Koc range of 219-237(3,SRC) indicates a medium mobility class for propylene in soils(4); however, its high vapor pressure would suggest that the gas may permeate through soil(SRC). Propylene may oxidize to its corresponding 1,2-epoxide(5-6). Pure culture studies suggest that propylene may be susceptible to microbial degradation; however, it is unknown whether propylene will biodegrade in the environment(SRC). [R55] *AQUATIC FATE: Pure culture studies suggest that propylene may biodegrade; however, it is unknown whether biodegradation in the aquatic environment will occur(SRC). Propylene may oxidize to its corresponding 1,2-epoxide(5-6). Hydrolysis of propylene is not expected to be an important fate process in aquatic environments because of the lack of hydroxyable functional groups(3,SRC). An estimated Koc range of 219-237(3,SRC) and high vapor pressure of 8.69X10+3 mm Hg at 25 deg C(1) indicate that the gas may permeate through organic matter contained in sediments and suspended materials(SRC). The experimental Henry's Law constant of 1.96X10-1 atm-cu m/mole at 25 deg C(2) suggests rapid volatilization of propylene from environmental waters(3). Based on this Henry's Law constant, the volatilization half-life from a model river has been estimated to be 1.9 hr(3,SRC). The volatilization half-life from a model environmental pond can be estimated to be 23 hr(4,SRC). [R56] *ATMOSPHERIC FATE: Based on the experimental vapor pressure of 8.69X10+3 mm Hg at 25 deg C(1), propylene is expected to exist almost entirely in the vapor phase in the ambient atmosphere(2). Vapor-phase propylene will degrade rapidly in the ambient atmosphere by reaction with photochemically produced hydroxyl radicals with a half-life of about 14.6 hours(3,SRC). Vapor-phase propylene will also degrade in the ambient atmosphere by reaction with ozone and nitrate radicals with respective half-lives of 1 and 4 days(4-5,SRC). [R57] BIOD: *In water bodies, propylene is readily degraded by microorganisms and is therefore not expected to bioaccumulate or bioconcentrate in organisms and food chains. [R58] *... PL-1 (an axenic culture isolated from marine soil) in the presence or absence of arsenite (an inhibitor of pyruvate metabolism) metabolised propylene ... into two products, the first containing one carbon atom and the second containing two. Isocitrate lyase activity and fatty acid profile determination further indicated that ... PL-1 oxidized propylene via attack at the double bond, resulting in cleavage of the molecule. [R58] *Pure culture studies suggest that propylene may be susceptible to microbial degradation(1-4). Based on cell free suspensions of several propane and methane-grown microbes, propylene is expected to oxidize to its corresponding 1,2-epoxide which may accumulate in the environment(1,3-4). [R59] *Radiolabeled experiments with (14)C propylene and (14)CO2 in PL-1 (an axenic culture isolated from marine soil) in the presence or absence of arsenite (an inhibitor of pyruvate metabolism) indicated that propylene was not metabolized into pyruvate, but rather was cleaved into two products, the first containing one carbon atom and the second containing two. Isocitrate lyase activity and fatty acid profile determination further indicated that ... PL-1 oxidized propylene via attack at the double bond, resulting in cleavage of the molecule. [R58] ABIO: *Data on the diurnal rates of several groups of reactions between atmospheric components and propylene indicated that the principal source of attack was the hydroxyl radical (OH), which accounted for more than 75 percent of the total propylene removed. The reactions of propylene with ozone were predominant during the evening. The reactions of propylene with atomic oxygen or excited sulfur dioxide (SO2) were reported to be insignificant in the environment because of their relatively low concentration. [R60] *Water vapor (< 11,000 ppm) had no effect on the photooxidation rate of propylene by NOx or on the yield of nitrogen dioxide (NO2) and ozone (O3). Carbon monoxide (< 200 ppm), on the other hand, increased the rate of propylene photooxidation and product formation. [R61] *Propylene glycol dinitrate was the major product in the gas-phase reaction of dinitrogen pentoxide with propylene in dry air in an evacuable smog chamber. Other products were acetaldehyde, propylene oxide, nitrogen dioxide, and nitric acid. The ratio of propylene glycol dinitrate, acetaldehyde, and propylene oxide appeared to be independent of the dinitrogen pentoxide concentration. The formation of propylene glycol dinitrate in the propylene-NO-air photo-oxidation system may result from the reaction of propylene with generated dinitrogen pentoxide or nitric oxide radical. [R62] *The rate constant for the vapor-phase reaction of propylene with photochemically produced hydroxyl radicals is measured to be 2.63X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 14.6 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The rate constant for the vapor-phase reaction of propylene with ozone in the troposphere is measured to be 1.13X10-17 cu cm/molecule-sec at 25 deg C which corresponds to a half-life of about 24 hrs at an atmospheric concn of 7X10+11 molecules per cu cm(2,SRC). The rate constant for the vapor-phase reaction of propylene with nitrate radicals (NO3) is measured to be 1X10-14 cu cm/molecule-sec at 25 deg C(3) which corresponds to a half-life of about 4 days at an atmospheric concn of 2X10+8 NO3 radicals per cu cm(4,SRC). Alkenes are generally resistent to environmental hydrolysis(5); therefore, hydrolysis is not expected to be an important aquatic fate process of propylene(SRC). [R63] BIOC: *In water bodies, propylene is readily degraded by microorganisms and is therefore not expected to bioaccumulate or bioconcentrate in organisms and food chains. [R58] *Based upon a measured water solubility of 200 mg/L at 25 deg C(1) and a measured log Kow of 1.77(2), the BCF range for propylene can be estimated to be 13 to 31 from regression derived equations(3). This BCF range indicates that bioconcentration in aquatic organisms will not be important. [R64] KOC: *Based upon a measured water solubility of 200 mg/L at 25 deg C(1) and a measured log Kow of 1.77(2), the Koc range for propylene can be estimated to be 219 to 237 from regression derived equations(3). According to a suggested classification scheme(4), propylene may have medium mobility in soil and sediment. However, the high vapor pressure suggests that the gas may permeate through soil(SRC). [R65] VWS: *Upon release to surface waters, a small amount of propylene may dissolve in water, but most of the released material is expected to volatilize to the atmosphere. [R58] *Based on a measured Henry's Law constant of 0.196 atm-cu m/mole at 25 deg C(1), the volatilization half-life of propylene from a model river 1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec has been estimated to be approximately 1.9 hrs(2,SRC). The volatilization half-life from a model environmental pond has been estimated to be about 23 hrs(3). [R66] WATC: *CONCN OF PROPYLENE HAVE BEEN MEASURED IN GULF OF MEXICO (0.1-16 NL/L), CARIBBEAN SEA (0.2-5.8 NL/L), ATLANTIC OCEAN (TRACE-11.0 NL/L) AND PACIFIC OCEAN (0.6-3.6 NL/L). [R48, p. V19 217] *Propylene has been detected in marine and fresh waters in trace amounts. Propylene surface levels in the Gulf of Mexico have been determined at 9.3x10-7 ml/l and in the North Atlantic at 5.9x10-7 ml/l water. Fresh water levels in Russia have been determined at 0.5 mg/l propylene in 1965. [R67] *MARINE WATER: In April of 1985, propylene was detected in several water samples taken from the Indian Ocean along the coast of Madagascar and Africa at a concn range of 2.5-15 ppbV(1). In June of 1976, propylene was found in South Texas Coastal waters at a concn range of 0.22-1.86 nl/l; the major source of propylene in this area is expected to be offshore petroleum operations(2). In August of 1974, propylene concns were 0.09-8.69 nl/l in the Southern Baeufort Sea; concns were 0.14-3.55 nl/l in August of 1975(3). High concns of propylene (67.1 and 91.9 nl/l) were detected in the Gulf of Mexico near the outflow of the Mississippi River and the discharge of formation waters and hydrocarbon venting from offshore oil production; other concns ranged from 1.0-1.5 nl/l(4). From 1966-1972, average propylene concns ranged 0.1-16, 0.2-5.8, 0.6-11, 0.6-1.9, 0.6-3.6 nl/l in open waters from the Gulf of Mexico, Caribbean Sea, Atlantic Ocean, Greenland Sea, and the Pacific Ocean, respectively; furthermore, propylene concns decrease with increasing depth in the water column, reaching trace levels at 150-200m(5). [R68] EFFL: *Emissions of propylene from automobile exhaust ranged from 2.09 to 3.24% TNMHC (total non-methane hydrocarbon) at 6 sites on U.S. Highway 70, Raleigh, NC,(1). Emissions of propylene from various gasoline fueled engines ranged from 45-80 mg/km driven(5). In another study, emissions of propylene from various gasoline fueled engines averaged 95.29 mg/km driven in an urban area, 61.32 mg/km driven in a suburban area, 46.79 mg/km driven in a rural area, and 44.44-50.46 mg/km driven on a motorway(3). Furthermore, emissions of propylene increased from about 2.8 to about 6.5% of total hydrocarbon content (THC) when the speed increased from 20 km/hr to about 115 km/hr(3). Propylene concns ranged from 0.038-0.19 ppm in air containing automotive emissions(4). Propylene was qualitatively identified in emissions from burning polyethylene(5) and samples of volcanic gases from Kunashir Island, U.S.S.R(6). The average concn of propylene in the Lincoln Tunnel (connecting Weehawhen, NJ with Manhattan Island, NY) was 630.1 ppbC in 1970 and 122.4 ppbC in 1982(7). [R69] *Propylene was detected in 9 jet engine emission samples at a concn range of 0.03-430.3 ppmC(1). Propylene was detected at a concn range of 92-126 ppb in 3 wood combustion emissions(2). Propylene was qualitatively identified in stack emissions from waste incineration(3). Emissions of propylene from various gasoline fueled cars were: 1.42-2.92% of total hydrocarbon content (THC) in a 1987 Toyota Camry, 0.99-4.10% THC in a 1986 GM Grand Am, 1.14-3.16% THC in a 1986 Ford Mustang, 1.36-2.49% THC in a 1984 GM Cavalier, 0.73-1.47% THC in a 1986 Chrysler Omni, 1.57-2.76% THC in a 1987 Nissan Sentra, 2.80-4.79% THC in a 1985 Honda Accord, 0.66-1.77% THC in a 1987 Toyota Corolla, and 1.75-3.12% THC in a 1987 Dodge Caravelle(4). Emissions of propylene from GM's first variable-fuel vehicle using methanol/gasoline mixtures were 0.8 mg/mi (100% methanol), 2.5 mg/mi (85% methanol), 7.8 mg/mi (50% methanol), 10.0 mg/mi (15% methanol), and 10.7 mg/mi (0% methanol)(5). [R70] SEDS: *In 1977, respective propylene concns in core samples taken from the Bering shelf, Bering slope, and Aleutian basin were: 9-77, 7-87, and 6-40 ml/l interstitial water(1). [R71] ATMC: *Propylene concentrations in ambient air samples have been found to vary diurnally and with wind direction. Ground-level concentrations of propylene in urban air samples collected in several US cities ranged from 4 to 17 ppb (geometric mean), whereas concentrations in rural surface air samples from six domestic sites ranged from < 0.5 to 3.0 ppb (geometric mean). [R72] *In the United Kingdom propylene concn in the air of a rural area over a two year period varied from 0.17-8.2 ug/cu m, with a mean concn of 1.19 ug/cu m. [R20] *IN JAPAN, AIR CONCN OF PROPYLENE IN AN INDUSTRIAL AREA NEAR PETROCHEMICAL PLANT WERE 17-170 UG/CU M (10-100 PPB). [R48, p. V19 216] *INDOOR AIR: On April 24, 1987 and May 1, 1987 the average indoor concn of propylene was determined to be 70 and 33 ug/cu-m, respectively, in a tavern during normal smoking conditions(1). [R73] *On April 24, 1987 and May 1, 1987 the average outdoor concn of propylene was determined to be 6 and 7 ug/cu-m, respectively, outside a tavern during normal smoking conditions(1). Propylene was detected in Tulsa, OK air on July 27, 1978 at avg concn ranges of 4.2-5.6, 2.8-3.2, and 27.5-109.9 ppbC downwind from the health department, post office, and the Texaco refinery, respectively; it was detected at 1.9 ppbC in Liberty Mounds air, a rural location outside of Tulsa(2). Propylene concns ranged from 0.5-2.8 ppbC in Rio Blanco county, CO air on July 24 and 25, 1978 and 0.5-8 ppbC in Smoky Mountain air on September 25 and 26, 1978(2). During February and March 1978, propylene concns in northwest England were: 1-17 ppb in air around the Castner-Kellner petrochemical Works, < 1-41 ppb in air downwind from the Stanlow oil Refinery, 2 ppb downwind from an ammonium nitrate fertiliser works, 2-10 ppb in populated background areas, and 1-11 ppb in rural background areas(3). The average ambient concn of propylene in the Houston, TX ship channel industrial complex was 10.7 ppbV during Sept 1987-Sept 1988(4). [R74] *In April of 1985, propylene was detected in several samples of air above the Indian Ocean along the coast of Madagascar and Africa at a concn range of 0.22-11.19 ppbV(1). Average propylene concns in urban air were 22.2 ppbC in Sydney, Australia during Sept 1979-June 1980(2), 14.0 ppbC in Upland, CA, USA during June-Sept 1975(4), 17.0 ppbC in Houston, TX, USA during July 1976(3), 8.0 ppbC in Washington D.C., USA during July-August 1980(3), and 5.1 ppbC in Lancaster, England during June-July 1983(6). Average propylene concns in rural air were 1.0 ppbC in Elkton, MO, USA during August-Sept 1975(4), 0.5 ppbC in Belfast, ME during June-July 1975(3), and 2.1 ppbC in Harwell, England during 1973(5). In May of 1976, propylene was detected at a concn range of 0.3-1.0 ppbC at 6 of 7 sites in St. Petersburg/Tampa, the Everglades, and Miami, FL(7). [R75] *Propylene was detected at a concn range of 7-32 ppbV in Los Angeles, CA air during Sept 29-Nov 13, 1981(1). Average monthly concns of propylene ranged from 1.1 to 15.3 ppbV for 1985 in atmospheric samples taken at Deonar, India(2). [R76] FOOD: *Propylene is a volatile component of garlic essential oils with a reported concn range of 0.01-5.99 ug/g garlic bulb(1). Propylene has been qualitatively detected in the gaseous metabolites released by germinating beans, corn, and pea seeds(2). [R77] PFAC: PLANT CONCENTRATIONS: *Propylene was qualitatively detected in emissions from European fir(1), Scotch pine(1), and the gaseous metabolites released by cotton seeds(2). [R78] MILK: *In a pilot study of pollutants in the breast milk of women living in 4 urban industrial areas in the USA, propylene was qualitatively detected in 2 of 12 samples(1). [R79] OEVC: *Propylene has been identified in cigarette smoke. ... Thus it may occur in the ambient air of metropolitan areas, and has been detected in smog samples of various cities. ... [R8, 3200] *A DIESEL-POWERED PASSENGER CAR WAS FOUND TO EMIT PROPYLENE IN ITS EXHAUST AT A RATE OF 0.0207 G/MILE (12.9 MG/KM) WHEN BURNING COMMERCIAL DIESEL FUEL. ... [R80] *The average airborne yield of propylene was measured to be 1300 ug/cigarette(1). [R73] RTEX: *Under environmental conditions, propylene is a gas; therefore, the most probable route of human exposure to propylene is by inhalation. (SRC) *Estimates of occupational exposures to propylene have been reported in industrial hygiene surveys performed by the National Institute for Occupational Safety and Health. 10,274 workers were potentially exposed to propylene in domestic workplace environments in 1970. [R72] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 10,274 workers are potentially exposed to propylene in the USA(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 7,305 workers are potentially exposed to propylene in the USA(2). [R81] BODY: *In a pilot study of pollutants in the breast milk of women living in 4 urban industrial areas in the USA, propylene was detected in 2 of 12 samples(1). [R79] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: +Simple asphyxiant - inert gas or vapor. A TLV may not be recommended for each simple asphyxiant because the limiting factor is the available oxygen. [R40, 2002.50] +A4; Not classifiable as a human carcinogen. [R40, 2002.50] +Notice of Intended Change for 2002: These substances, with their corresponding values and notations, comprise those for which a limit has been proposed for the first time or for which a change in the Adopted value is proposed. In each case, the proposed values should be considered trial values for the year following ratification by the ACGIH Board of Directors. If, during the year, no evidence comes to light that questions the appropriateness of these proposals, the values will be reconsidered for adoption as TLVs. 8 hr Time Weighted Avg (TWA): 200 ppm. [R40, 2002.64] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Propylene is produced, as an intermediate or a final product, by process units covered under this subpart. [R82] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *INFRA-RED SPECTROPHOTOMETRY OF CRYOGENICALLY COOLED GASEOUS MIXTURES CAN BE USED TO DETECT PROPYLENE. GAS CHROMATOGRAPHY DETECTION IN SEAWATER. [R80] *Gas chromatography combined with mass spectrometry has been used to determine propylene in gaseous mixtures and hydrocarbon oils, with a limit of detection of approximately of 0.1 ppm. [R20] *Propylene has been detected by measuring the chemiluminescence of a reaction of the hydrocarbon with ozone or with active nitrogen. [R80] *Automatic unattended sampling and analysis of background levels of C2-C5 hydrocarbons. [R83] *Estimation of C2-C5 hydrocarbons in air by pre-concentration on silica gel at dry ice temperature. [R84] CLAB: *A method for monitoring exposure to simple epoxides and alkenes through gas chromatographic determination with electron-capture detection of hemoglobin adducts. [R85] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Summary Health Assessment Document For Propylene (Draft) (1986) EPA Contract No. 68-02-4030 Environment Canada; Tech Info for Problem Spills: Propylene (Draft) (1981) DHHS/NTP; Toxicology and Carcinogenesis Studies of Propylene in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 272 (1985) NIH Publication No. 86-2528 HIST: *Safety Promotion in the Process Industries: Vol. 1 Safety in Operations and Processes, Symposium Series No. 80 pL9-L14 (1983) The events contributing to uncontrolled release of propylene from a polypropylene plant in Norway were reported. The exit valves in a polypropylene reactor at the Saga Petrokjemi factory became plugged with the polymer. The factory was shut down, propylene was boiled off, and the reactor was purged with nitrogen six times. The top manholes were open. The temperature at the bottom of the reactor was 0 deg C at the time the reactor started to be filled with water, then it dropped to minus 50 deg C. Injection of steam into reactor jacket increased the temperature to minus 30 deg C. The gas emission increased and propylene leaked into the control room around cable ducts. The filling of the reactor with water continued for about 3 hours at which point a concentrated release of propylene and nitrogen occurred with a bang. One hour later the reactor was closed, the contents were heated to 10 deg C, and again purged with nitrogen. The major factors contributing to the release of the gaseous mixture from the reactor were believed to be the presence of gaseous and liquid propylene pockets dispersed in a high volume of the polymer powder, lower temperatures in the reactor, and malfunctioning of the ventilator system. [R86] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1247 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 214 (1979) R3: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R4: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. R5: United States International Trade Commission. Synthetic Organic Chemicals-United States Production and Sales, 1989. USITC Publication 2338, 1990. Washington, DC: United States International Trade Commission, 1990. R6: SRI R7: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R8: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R9: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 480 R10: CHEMICAL PRODUCTS SYNOPSIS: Propylene, 1984 R11: Kavaler AR; Chemical Marketing Reporter 230 (18): 66 (1986) R12: Kavaler AR; Chemical Marketing Reporter 236 (20): 58 (1989) R13: Chem Eng News 64(16): 13 (1986) R14: Chem and Engineering News 70 (15): 17 (4/13/92) R15: Chem and Engineering News 71 (15): 11 (4/12/93) R16: Chem and Engineering News 72 (15): 13 (4/11/94) R17: CHEMICAL PRODUCTS SYNOPSIS: Propylene, 1984 R18: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R19: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 6 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 213 (1979) R21: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 159 R22: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R23: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. F-60 R24: Wasik SP, Tsang W; J Phys Chem 74: 2970-6 (1970) R25: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-115 R26: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R27: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-82 R28: Bureau of Explosives; Emergency Handling of Haz Matl in Surface Trans p.438 (1981) R29: Environment Canada; Tech Info for Problem Spills: Propylene (Draft) p.59 (1981) R30: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R31: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 228-246 R32: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983.,p. 1027-1028 R33: Environment Canada; Tech Info for Problem Spills: Propylene (Draft) p.63 (1981) R34: 49 CFR 171.2 (7/1/96) R35: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 204 R36: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.2070 (1988) R37: Environment Canada; Tech Info for Problem Spills: Propylene (Draft) p.62 (1981) R38: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-9 (1981) EPA 68-03-3025 R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 60 176 (1994) R40: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R41: Environment Canada; Tech Info for Problem Spills: Propylene (Draft) p.58 (1981) R42: Quest JA et al; Toxicol Appl Pharmacol 76 (2): 288-95 (1984) R43: McGregor D et al; Environ Mol Mutagen 17 (2): 122-9 (1991) R44: Ciliberti A et al; Ann N Y Acad Sci 534: 235-45 (1988) R45: DHHS/NTP; Toxicology and Carcinogenesis Studies of Propylene (Inhalation Studies) in F344/N Rats and B6C3F1 Mice Technical Report Series No. 272 (1985) NIH Publication No. 86-2528 R46: Bolonga Tumour Center and Institute of Oncology; Final Statement to International Joint Study on the Long-Term Effects of Propylene. (1981), EPA Document No. FYI-OTS-0681-0116, Fiche No. 0116-0 R47: Smith AM, et al; Biochemistry 22: 1645-50 (1983) as cited in USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-13 (1986) EPA Contract No 68-02-4030 R48: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R49: (1) Yu TH et al; J Agric Food Chem 37: 725-30 (1989) (2) Isidorov VA et al; Atmos Environ 19: 1-8 (1985) (3) Graedel TE et al; Atmospheric Chemical Compounds. Sources, Occurrence, and Bioassay. Orlando, FL: Academic Press Inc p. 142 (1986) (4) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 19: 213-17 (1979) R50: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-2 (1986) EPA Contract No 68-02-4030 R51: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-2 (1986) EPA Contract No. 68-02-4030 R52: Fung YS; Environ Int 14 (6) 501-9 (1989) R53: (1) Lofroth G et al; Environ Sci Technol 23: 610-14 (1989) (2) Hodgkin JH et al; J Macromol Sci-Chem A17: 35-44 (1982) (3) Graedel TE et al; Atmospheric Chemical Compounds. Sources, Occurrence, and Bioassay. Orlando, FL: Academic Press Inc p. 142 (1986) (4) Kleindienst TE et al; Environ Sci Technol 20: 493-501 (1986) (5) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 19: 213-17 (1979) R54: Graedel TE, et al; Atmos Environ 10 1095-1116 (1976) as cited in USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-6 (1986) EPA Contract No 68-02-4030 R55: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals NY: Hemisphere Pub Corp (1989) (2) Wasik SP, Tsang W; J Phys Chem 74: 2970-6 (1970) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) Hou CT et al; Appl Environ Microbiol 46: 171-7 (1983) (6) Hou CT et al; Appl Environ Microbiol 38: 127-34 (1979) R56: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals NY: Hemisphere Pub Corp (1989) (2) Wasik SP, Tsang W; J Phys Chem 74: 2970-6 (1970) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (4) USEPA; EXAMS II computer simulation (1987) (5) Hou CT et al; Appl Environ Microbiol 46: 171-7 (1983) (6) Hou CT et al; Appl Environ Microbiol 38: 127-34 (1979) R57: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals NY: Hemisphere Pub Corp (1989) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; J Chem Phys Ref Data Monograph 1 p. 103 (1989) (4) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (5) Sabljic A, Guesten H; Atmos Environ 24A: 73-8 (1990) R58: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-12 (1986) EPA Contract No. 68-02-4030 R59: (1) Hou CT et al; Appl Environ Microbiol 46: 171-7 (1983) (2) Perry JJ; The Role of Co-oxidation and Commensalism in the Biodegradation of Recalcitrant Molecules (NTIS PB-80-28-034) U.S. Army Research Office (1980) (3) Hou CT et al; Appl Environ Microbiol 38: 127-34 (1979) (4) Patel RN et al; Div Ind Microbial 23: 187-205 (1982) R60: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-6 (1986) EPA Contract No. 68-02-4030 R61: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-11 (1986) EPA Contract No. 68-02-4030 R62: Hoshino M et al; Chem Lett 12 1367-70 (1978) as cited in USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-12 (1986) EPA Contract No. 68-02-4030 R63: (1) Atkinson R; J Chem Phys Ref Data Monograph 1 p. 103 (1989) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (3) Sabljic A, Guesten H; Atmos Environ 24A: 73-8 (1990) (4) Atkinson R et al; Environ Sci Technol 21: 1123-6 (1987) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R64: (1) McAuliffe C; J Phys Chem 70: 1267-75 (1966) (2) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) R65: (1) McAuliffe C; J Phys Chem 70: 1267-75 (1966) (2) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R66: (1) Wasik SP, Tsang W; J Phys Chem 74: 2970-6 (1970) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (3) USEPA; EXAMS II computer simulation (1987) R67: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-12 (1986) EPA Contract No 68-02-4030 R68: (1) Bonsang B et al; J Atmos Chem 6: 3-20 (1988) (2) Brooks JM et al; Fate and Effects of Petroleum Hydrocarbons in Marine Organisms and Ecosystems DA Wolfe ed. NY: pp. 373-83 (1977) (3) MacDonald RW; Environ Sci Technol 10: 1241-46 (1976) (4) Sauer TCJR; Limnol Oceanogr 25: 338-51 (1980) (5) Swinnerton JW, Lamontagne RA; Environ Sci Technol 8: 657-63 (1974) R69: (1) Zweidinger RB et al; Environ Sci Technol 22: 956-62 (1988) (2) Westerholm RN et al; Environ Sci Technol 22: 925-30 (1988) (3) Bailey JC et al; Atmos Environ 24A: 43-52 (1990) (4) Bellar T et al; Anal Chem 34: 763-5 (1962) (5) Hodgkin JH et al; J Macromol Sci-Chem A17: 35-44 (1982) (6) Isidorov VA et al; J Atmos Chem 10: 329-40 (1990) (7) Lonneman WA et al; Environ Sci Technol 20: 790-6 (1986) R70: (1) Katzman H, Libby WF; Atmos Environ 9: 839-42 (1975) (2) Kleindienst TE et al; Environ Sci Technol 20: 493-501 (1986) (3) Junk GA, Ford CS; Chemosphere 9: 187-230 (1980) (4) Stump F et al; Atmos Environ 23: 307-20 (1989) (5) Williams RL et al; J Air Waste Manage Assoc 40: 747-56 (1990) R71: (1) Kvenvolden KA, Redden GD; Geochim Cosmochim ACTA 44: 1145-50 (1980) R72: USEPA/ECAO; Summary Health Assessment Document For Propylene (Draft) p.2-3 (1986) EPA Contract No. 68-02-4030 R73: (1) Lofroth G et al; Environ Sci Technol 23: 610-14 (1989) R74: (1) Lofroth G et al; Environ Sci Technol 23: 610-14 (1989) (2) Arnts RR, Meeks SA; Atmos Environ 15: 1643-51 (1981) (3) Harrison RM, Holman CD; Environ Tech Let 1: 345-54 (1980) (4) LaGrone FS; Environ Sci Technol 25: 366-8 (1991) R75: (1) Bonsang B et al; J Atmos Chem 6: 3-20 (1988) (2) Nelson PF, Quigley SM; Environ Sci Technol 16: 650-5 (1982) (3) Sexton K, Westberg H; Environ Sci Technol 14: 329-32 (1980) (4) Singh HB et al; Atmospheric Measurements of Selected Hazardous Organic Chemicals USEPA-600/S3-81-032 (1981) (5) Cox RA et al; United Kingdom Atomic Energy Authority Harwell, Oxfordshire (1976) (6) Colbeck I, Harrison RM; Atmos Environ 19: 1899-904 (1985) (7) Lonneman WA et al; Environ Sci Technol 12: 459-63 (1978) R76: (1) Grosjean D, Fung K; J Air Pollut Control Assoc 34: 537-43 (1984) (2) Mohan Rao AM, Pandit GG; Atmospheric Environ 22: 395-401 (1988) R77: (1) Yu TH et al; J Agric Food Chem 37: 725-30 (1989) (2) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 19: 213-17 (1979) R78: (1) Isidorov VA et al; Atmos Environ 19: 1-8 (1985) (2) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 19: 213-17 (1979) R79: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-28 (1982) R80: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 217 (1979) R81: (1) NIOSH National Occupational Hazard Survey (NOHS) (1974) (2) NIOSH National Occupational Exposure Survey (NOES) (1983) R82: 40 CFR 60.489 (7/1/91) R83: Mowrer J, Lindskog A; Atmos Environ Part A 25A (9): 1971-9 (1991) R84: Netravalkar AJ, Rao AM Mo; Chromatographia 22 (1-6): 183-6 (1986) R85: Kautiainen A, Toernqvist M; Int Arch Occup Environ Health 63 (1): 27-31 (1991) R86: Christiansen JH, Jorgensen LE; Proceedings of the Fourth International Symposium on Loss Prevention and RS: 70 Record 34 of 1119 in HSDB (through 2003/06) AN: 176 UD: 200303 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACRYLONITRILE- SY: *ACRITET-; *ACRYLNITRIL- (GERMAN,DUTCH); *ACRYLON-; *ACRYLONITRILE- (DOT); *ACRYLONITRILE-MONOMER-; *AI3-00054-; *AKRYLONITRYL- (POLISH); *Carbacryl-; *Caswell-No.-010-; *CIANURO-DI-VINILE- (ITALIAN); *CYANOETHYLENE-; *CYANURE-DE-VINYLE- (FRENCH); *ENT-54-; *Pesticide-Code:-000601-; *FUMIGRAIN-; *MILLER'S-FUMIGRAIN-; *NCI-C50215-; *NITRILE-ACRILICO- (ITALIAN); *NITRILE-ACRYLIQUE- (FRENCH); *PROPENENITRILE-; *2-PROPENENITRILE-; *TL-314-; *VCN-; *VENTOX-; *VINYL-CYANIDE-; *VINYLKYANID- RN: 107-13-1 MF: *C3-H3-N SHPN: UN 1093; Acrylonitrile, inhibited and uninhibited IMO 3.2; Acrylonitrile, inhibited STCC: 49 064 20; Acrylonitrile HAZN: U009; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *(a) From propylene, oxygen, and ammonia with either bismuth phosphomolybdate or uranium-based cmpd as catalysts (b) Addition of hydrogen cyanide to acetylene with cuprous chloride catalyst (c) Dehydration of ethylene cyanohydrin. [R1] IMP: *Polymerization grade acrylonitrile contains a number of impurities and additives, namely, dimethylformamide, hydrogen peroxide, hydroxyanisole, methyl acrylate, phenyl ether-biphenyl mixture, sodium metabisulfite, sulfur dioxide, sulfuric acid, and titanium dioxide. [R2] *Acetone, 300 ppm max; acetonitrile, 500 ppm max; aldehydes, 100 ppm max; hydrogen cyanide, 10 ppm max; hydroquinone monomethyl ether (inhibitor), 35-50 ppm; iron, 0.10 ppm max; nonvolatile matter, 100 ppm max; peroxides, 0.5 ppm max; water, 1.3882-1.3892 wt% max. [R3, 363] FORM: *USEPA/OPP Pesticide Code 000601; Trade Names: Acritet, component of (with 016501), Ventox, component of (with 016501), Acrylon, component of (with 016501), Carbacryl, component of (with 016501), Acrylofume, component of (with 016501), 020701 and 081501). [R4] *Technical grade acrylonitrile with greater than 99% purity. [R5] *Acritet = 34% acrylonitrile, 60% CCl4; ventox = acritet; carbacryl: equal volumes of acrylonitrile and CCl4; acrylofume: 39.5% acrylonitrile, 30% CCl4, 30% chloroform, 0.5% chloropicrin. [R6, 133] MFS: *BP Amoco Corp., 200 E. Randolph Dr., Chicago, IL 60601, (312) 856-6111; Production sites: Green Lake, TX 77031; Lima, OH 45802 [R7] *Cytec Industries Inc., Building Block Chemicals, Five Garret Mountain Plaza, W. Patterson, NJ 07424, (973) 357-3100; Production site: Waggaman, LA 70094 [R7] *Dupont, Dupont Specialty Chemicals, 1007 Market St., Wilmington, DE 19898, (800) 441-7515; Production site: Beaumont, TX 77704 [R7] *Solutia Inc., 575 Maryville Centre Dr., P.O. Box 66760, St. Louis, MO 63166-6760, (314) 674-1000; Production site: Alvin, TX 77511 [R7] *Sterling Chemicals Inc., 1200 Smith St., Suite 1900, Houston, TX 77002-4312, (713) 650-3700; Production site: Texas City, TX 77590 [R7] OMIN: *Fumigant formulations containing acrylonitrile with names Acrylon, Carbacryl, Fumigrain, Ventox, and ENT-54 are no longer manufactured in the United States. [R8] *Commercial acrylonitrile is stabilized against self-polymerization by ... methylhydroquinone (35-50 ppm). [R3, 355-63] *Acrylic fibers marketed under tradenames including Acrilan, Creslan, Orlon, and Zefran ... tradenames for modacrylic fibers include Acrylan, Elura, SEF, and Verel. Acrylic and/or modacrylic fibers are manufactured from acrylonitrile. [R9] USE: *For Acrylonitrile (USEPA/OPP Pesticide Code: 000601) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R4] *In the plastics, surface coatings, and adhesives industries. As chem int in synthesis of antioxidants, pharmaceuticals, dyes, surface-active agents, extra. In org synth to introduce cyanoethyl group. As modifier for natural polymers. [R10] *As a pesticide fumigant for stored grain /srp: former use/ [R11] *IN CO-POLYMERS WITH STYRENE AND BUTADIENE; NITRILE RUBBER; CYANOETHYLATION OF COTTON; BOTTLES FOR SOFT DRINKS /SRP: DISCONTINUED BY FDA/ [R12, 1991.30] *COMONOMER FOR BARRIER RESINS [R13] *COMONOMER WITH STYRENE FOR URETHANE POLYETHER POLYOLS [R13] *COMONOMER FOR ALKYD/ACRYLONITRILE COPOLYMERS [R13] *Monomer for acrylic and modacrylic fibers and high-strength whiskers; acrylonitrile butadiene styrene copolymer and acrylonitrile styrene copolymers; nitrile rubber; cyanoethylation of cotton; synthetic soil blocks (acrylonitrile polymerized in wood pulp); organic synthesis; adiponitrile; grain fumigant; monomer for a semiconductive polymer that can be used like inorganic oxide catalysts in dehydrogenation of tert-butanol to isobutylene and water. [R14, 19] *1. Acrylic fibers. More than half of acrylonitrile production goes into acrylic fibers used mainly in textile and clothing industries. 2. Copolymer resins of plastics, such as the acrylonitrile-butadiene-styrene (ABS) and styrene-acrylonitrile (SAN) resins. These are used for pipes and fitting, automotive parts, appliances, furniture, and building components, among other products. 3. Nitrile rubbers, which are resistant to chemicals, oils, solvents, heat, aging, and abrasion, are employed mainly for industrial purposes. 4. Miscellaneous uses include production of acrylamide, acrylic esters, adhesives, adiponitrile, alkyd resins, antioxidants, coatings, cyanoethylated natural fibers and paper, dielectric paper, dyes, electrically conductive rubber, emulsifying agents, insecticides, latex paints, photographic emulsions, plasticizers, synthetic leathers, wire insulation, floor polish, and inks. [R15, 949] *In the production of arylic and modacrylic fibers by copolymerization with methylacrylate, methylmethacrylate, vinylacetate, vinylchloride, or vinylidenechloride; the manufacture of acrylonitrile-butadiene-styrene (ABS) and styrene acrylonitrile (SAN) resins; fumigant. [R6, 133] *Manufacture of adiponitrile, nitrile rubbers, elastomers, acrylic fibers; acrylic fibers used for apparel (e.g., sweaters, fleece wear, and sportswear), home furnishings (e.g., carpets, upholstery, draperies); manufacture of carbon fibers used in aircraft, defense, and aerospace industries; production of fatty amines, ion exchange resins, fatty amine amides used in cosmetics, adhesives, corrosion inhibitors, and water treatment resins. [R3, 364] CPAT: *COMONOMER FOR ACRYLIC AND MODACRYLIC FIBERS, 51%; COMONOMER FOR ACRYLONITRILE-BUTADIENE-STYRENE RESINS, 18%; CHEM INT FOR ADIPONITRILE, 13%; CHEM INT FOR ACRYLAMIDE, 6%; COMONOMER FOR NITRILE ELASTOMERS, 3%; COMONOMER FOR STYRENE-ACRYLONITRILE RESINS, 2%; OTHER USES, 7% (1983) [R13] *In 1976, 282 million kg were used to make acrylic and modacrylic fibers. [R16] *Acrylic and modacrylic fibers, 45%; acrylonitrile butadiene styrene copolymer resins, 20%; styrene acrylonitrile polymer resins, 9%; adiponitrile, 13%; acrylamide, 6%; miscellaneous, 7% (1984) [R17] *CHEMICAL PROFILE: Acrylonitrile. Exports, 43%; acrylic and modacrylic fibers, 28%; acrylonitrile-butadiene-styrene and styrene-acrylonitrile resins, 15%; adiponitrile, 7%; acrylamide, 4%; miscellaneous, including nitrile rubber and barrier resins, 3%. [R18] *CHEMICAL PROFILE: Acrylonitrile. Demand: 1988: 2.580 million lb; 1989: 2.660 million lb; 1993 /projected/: 3.025 million lb. (Includes exports but not imports, which are negligible.) [R18] *Worldwide consumption of acrylonitrile increased 52% between 1976 and 1988, from 2.5X10+6 to 3.8X10+6 tons/yr; Consumption (worldwide): acrylic fibers (65%), 2.52X10+6 tons (1988), 2.41X10+6 tons (1985), 2.04X10+6 tons (1980), 1.76X10+6 tons (1976); ABS resins, 5.5X10+5 tons (1988), 4.35X10+5 tons (1985), 3.0X10+5 tons (1980), 2.7X10+5 tons (1976); adiponitrile, 3.1X10+5 tons (1988), 2.35X10+5 tons (1985), 1.6X10+5 tons (1980), 9.0X10+4 tons (1976); other (including nitrile rubber, SAN resin, acrylamide, and barrier resins), 4.6X10+5 tons (1988), 3.9X10+5 tons (1985), 2.4X10+5 tons (1980), 4.2X10+5 tons (1976). [R19, 364] *Adiponitrile (33%); acrylic fibers (25%); ABS/SAN resins (23%); acrylamide (9%); nitrile elastomers (3%); miscellaneous, including polymers, polyols, barrier resins and carbon fibers (7%). [R20] *U.S. Demand (which equals production minus exports): 1997) 1.753X10+9 lbs; (1998) 2.186X10+9 lbs; (2002) 1.95X10+9 lbs (est) [R20] PRIE: U.S. PRODUCTION: *(1983) 9.53X10+11 G [R13] *(1978) 7.95X10+11 G [R13] *(1977): 745,000 million tons [R21] *(1985) 1.06X10+12 g [R22] *38th highest-volume chemical produced in USA (1985) [R23] *(1990) 2.68 billion lb [R24] *(1991) 2.65 billion lb [R25] *(1991) 3,055 million lb [R26] *(1992)2.83 billion lb [R27] *(1993) 2.51 billion lb [R27] *1.17X10+6 tons (1988) [R19, 362] *(1997) 3.29X10+9 lbs; (1998) 3.12 X10+9 lbs [R20] U.S. IMPORTS: *(1977) 8.54X10+7 G [R13] *(1982) 1.00X10+6 G [R13] *(1985) 2.00X10+5 g [R28] *Negligible [R20] U.S. EXPORTS: *(1978) 1.09X10+11 G [R13] *(1983) 3.88X10+11 G [R13] *(1977) 109,000 million tons [R29] *(1985) 4.28X10+11 g [R30] *Total: (1988) 5.1X10+5 tons, (1987) 6.10X10+5 tons [R3, 362] *(1997) 1.538 X10+9 lbs; (1998) 9.34 X10+8 lbs [R31] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear, colorless liquid [R19, 353]; *Colorless to pale-yellow liquid [R32, 8] ODOR: *PRACTICALLY ODORLESS, OR WITH A VERY SLIGHT ODOR OF PEACH KERNELS [R33, 71]; *Sweet odor [R34]; *Irritating odor [R35]; *Unpleasant odor. [R32, 8]; *Onion, garlic, pungent [R6, 133] BP: *77.3 deg C @ 760 mm Hg [R10] MP: *-82 deg C [R14, 18] MW: *53.06 [R10] CORR: *Attacks copper and copper alloys ... attacks aluminum in high conc. [R35] CTP: *Critical temperature: 246 deg C; critical pressure: 3.54 MPa [R3, 353] DEN: *0.8004 @ 25 deg C/4 deg C [R10] HTC: *1761.5 kJ/mol @ 25 deg C (liquid) [R3, 354] HTV: *32.65 kJ/mol @ 25 deg C [R3, 354] OWPC: *log Kow= 0.25 [R36] PH: *6.0-7.5 (5% aqueous solution) [R3, 353] SOL: *SOL IN ISOPROPYL ALCOHOL [R37]; *Sol in ethanol [R38]; *Acrylonitrile is ... miscible with ethanol, carbon tetrachloride, ethyl acetate, ethylene cyanohydrin, liquid carbon dioxide, ... toluene, petroleum ether, and xylene. [R39]; *In water, 7.45X10+4 mg/l @ 25 deg C [R40] SPEC: *Index of refraction: 1.3888 @ 25 deg C/D [R10]; *MAX ABSORPTION (ALCOHOL): 203 NM (LOG E= 3.79); SADTLER REF NUMBER: 386 (IR, PRISM); V15 (NMR) [R41] SURF: *26.6 dyn/cm @ 25 deg C [R3, 353] VAPD: *1.8 (Air =1) [R3, 353] VAP: *109 mm Hg @ 25 deg C [R42] EVAP: *4.54 (Butyl Acetate= 1) [R43] VISC: *0.34 cP at 25 deg C [R3, 354] OCPP: *... Yellowing upon exposure to light indicates photo-alteration to saturated derivatives. [R5] *Solubility of water in acrylonitrile: 3.1 parts water/100 parts acrylonitrile [R10] *Henry's Law constant = 1.38X10-4 atm cu m/mole @ 25 deg C [R44] *Hydroxyl radical rate constant = 4.10X10-12 cu cm/molecule-sec at 25 deg C [R45] *Saturated concn = 257 g/cu m @ 20 deg C, 383 g/cu m @ 30 deg C [R6] *Dielectric constant @ 33.5 MHz = 38; dipole moment = 1.17X10-29 C-m (liquid phase), 1.924X10-29 C-m (vapor phase); molar refractivity (D line) = 15.67; molar heat of fusion = 6.61 kJ/mol; ionization potential = 10.75 eV; free energy of formation = 195 kJ/mol @ 25 deg C; enthalpy of formation (@ 25 deg C): 185 kJ/mol (gas), 150 kJ/mol (liquid); molar heat capacity: 2.09 kJ/kg K (liquid), 1.204 kJ/kg K (gas @ 50 deg C and 1 atm); entropy (gas @ 25 deg C, 1 atm) = 274 kJ/mol K [R3, 353-4] *Forms azeotropes with tetrachlorosilane, water, isopropyl alcohol, benzene, methanol, carbon tetrachloride, chlorotrimethylsilane. [R3, 354] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Acrylonitrile, inhibited/ [R46] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Acrylonitrile, inhibited/ [R46] +Public safety: Call Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Acrylonitrile, inhibited/ [R46] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Acrylonitrile, inhibited/ [R46] +Evacuation: Spill: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Acrylonitrile, inhibited/ [R46] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Acrylonitrile, inhibited/ [R46] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Acrylonitrile, inhibited/ [R46] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Acrylonitrile, inhibited/ [R46] FPOT: *Highly ignitable and flammable. [R47, 16] *Dangerous fire hazard when exposed to heat, flame, or oxidizers. [R48] NFPA: *Health: 4. 4= Materials that, on very short exposure, could cause death or major residual injury, including those that are too dangerous to be approached without specialized protective equipment. A few whiffs of the vapor or gas can cause death, or contact with the vapor or liquid may be fatal, if it penetrates the fire fighter's normal protective gear. The normal full protective clothing and breathing apparatus available to the typical fire fighter will not provide adequate protection against inhalation or skin contact with these materials. [R49, p. 325-11] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R49, p. 325-11] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R49, p. 325-11] FLMT: *Lower flammable limit: 3%; upper flammable limit: 17% [R49, p. 325-11] FLPT: *30 deg F (Closed cup) [R32, 8] *0 deg C (Open cup) [R47, 16] AUTO: *898 DEG F; 481 DEG C [R49, p. 49-11] FIRP: *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. Fight fire from protected location or maximum possible distance. [R49, p. 49-13] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R50] *Fire fighting phases: use dry chemical, "alcohol foam", or carbon dioxide. ... Do not use water because it causes frothing. [R51] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame - consider evacuation of one-half (1/2) mile radius. [R50] TOXC: *Combustion by-products include hydrogen cyanide and oxides of nitrogens. [R49, p. 49-12] *Lopac, an acrylonitrile polymer, produces ammonia at pyrolysis temp of 188 deg C and above. At temp 500-740 deg C products are carbon monoxide, carbon dioxide, acetylene, ammonia, hydrogen cyanide, acetonitrile, acrylonitrile, propionitrile and pyrrole. [R52] *1 kg of polyacrylonitrile plastic produces 15 g hydrogen cyanide upon heating; so in a 30 cu m room 100-200 g polyacrylonitrile fibers yields 10-15 times the Maximum Acceptable Concentration value. [R53] OFHZ: *VAPORS ARE HEAVIER THAN AIR AND MAY TRAVEL TO A SOURCE OF IGNITION AND FLASH BACK. [R49, p. 49-12] EXPL: *MODERATE EXPLOSION HAZARD WHEN EXPOSED TO FLAME. [R48] *LOWER LIMIT 3.05%, UPPER LIMIT 17.0%, IN AIR @ 25 DEG C [R54] *Explosive polymerization may occur on storage with silver nitrate. Potentially explosive reactions with benzyltrimethylammonium hydroxide + pyrrole, tetrahydrocarbazole + benzyltrimethylammonium hydroxide. [R48] REAC: *Strong oxidizers, acids and alkalis; bromine; amines. [Note: Unless inhibited (usually with methylhydroquinone) may polymerize spontaneously or when heated or in presence of strong alkali. Attacks copper.] [R32, 8] *Explosive polymerization may occur on storage with silver nitrate. Potentially explosive reactions with benzyltrimethylammonium hydroxide + pyrrole, tetrahydrocarbozole + benzyltrimethylammonium hydroxide. Violent reactions with strong acids (e.g., nitric or sulfuric), strong bases, azoisobutyronitrile, dibenzoyl peroxide, di-tert-butylperoxide, or bromine. [R48] *... Very reactive and polymerizes violently in the presence of strong bases. ... May polymerize spontaneously, particularly in the absence of oxygen or on exposure to light. [R15, 949] *Incompatible with AgNO3 /silver nitrates/ and amines. [R48] *Contact of strong acids (nitric or sulfuric) with acrylonitrile may lead to vigorous reactions. ... Contamination of a drum of acrylonitrile by nitric acid residue in the filling hose led to a slowly accelerating polymerisation reaction which burst the drum after 10 days. [R55, p. 348-9] *Acrylonitrile polymerises violently in contact with strong bases, whether stabilised or unstabilised. Alkaline hydrolysis of acrylonitrile is exothermic and violent, especially when the temperature is above 60 deg C, the pressure is above atmospheric, and when heating at 60 deg C is prolonged above 10 mins. Polymerisation does not induce a violent reaction at 40-50 deg C at a concentration of 3% of sodium hydroxide in water. [R55, 349] *Bromine was being added in portions to acrylonitrile with ice cooling, with intermediate warming to 20 deg C between portions. After half the bromine was added, the temperature increased to 70 deg C; then the flask exploded. [R55, 349] *Acrylonitrile containing undissolved solid silver nitrate is liable, on long standing, to polymerise explosively and ignite. This was attributed to the slow deposition of a thermally insulating layer of polymer on the solid nitrate, which gradually gets hotter and catalyses rapid polymcrisation. [R55, 350] DCMP: *... When burned may decompose to free cyanide. [R15, 948] *When heated to decomposition it emits toxic fumes of NOx and CN- /nitrogen oxides and cyanides/. [R48] POLY: *Hazardous polymerization may occur. Polymerization may be caused by elevated temperature or alkalies. Uninhibited monomer vapor may form polymer in vents and other confined spaces. [R49, p. 49-12] *It may polymerize if contaminated with strong bases or if the container is subject to heat as in fire conditions. [R56] *Tends to polymerize violently so it must never be stored uninhibited, in light or close to bases. Violent polymerization in contact with bases. Violent polymerization in the presence of bromine, possibly due to catalysis by hydrogen bromide. Free radical polymerization initiated by azoisobutyronitrile, benzoyl peroxide or di-tert-butyl epoxide may be explosive. May polymerize violently in the presence of silver nitrate. [R57, 17] ODRT: *21.4 PPM [R35] *Detection of acrylonitrile in water is 1.86x10+1 ppm; chemically pure [R58] *Low= 8.1000 mg/cu m; High= 78.7500 mg/cu m [R59] SERI: *ACRYLONITRILE SPILLED ON HUMAN SKIN RESULTS IN ERYTHEMA AND BLISTERS. [R60, p. II-215] *Prolonged skin contact with liquid acrylonitrile can result in systemic toxicity and the formation of large dermal vesicles after a latent period of several hours. The affected skin area may resemble a second degree, thermal burn. [R12, 1991.31] *Acrylonitrile vapor is ... a potent eye, mucous membrane, and skin irritant ... . [R61] EQUP: *... PERSONAL RESPIRATORY PROTECTION PREFERABLY OF POSITIVE PRESSURE TYPE AND IMPERMEABLE PROTECTIVE CLOTHING IS NECESSARY WHEN THERE IS POSSIBILITY OF EXPOSURE RESULTING FROM NORMAL BUT NONROUTINE OPERATION SUCH AS PUMP REPLACEMENT. RESPIRATORY PROTECTIVE EQUIPMENT, PROTECTIVE CLOTHING AND FIRE FIGHTING EQUIPMENT MUST BE AVAILABLE FOR EMERGENCY USE. [R62, 56] *AIR-SUPPLIED MASK, INDUSTRIAL CHEMICAL TYPE, WITH APPROVED CANISTER FOR ACRYLONITRILE IN LOW (LESS THAN 2%) CONCENTRATIONS; RUBBER OR PLASTIC GLOVES; COVER GOGGLES OR FACE MASK; RUBBER BOOTS; SLICKER SUIT; SAFETY HELMET. [R35] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R63, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R32, 9] *Wear appropriate eye protection to prevent eye contact. [R32, 9] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R32, 9] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R32, 9] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R32, 9] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R32, 9] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *WORK AREAS SHOULD BE ... FREE FROM OPEN LIGHTS, FLAMES, AND EQUIPMENT THAT IS NOT EXPLOSION-PROOF. [R64] *BECAUSE OF TOXIC, AS WELL AS FLAMMABLE, NATURE OF VAPOR, PRECAUTIONS MUST BE TAKEN BY ENCLOSURE OF PLANT AND BY MEANS OF EXHAUST VENTILATION TO PREVENT VAPORS ESCAPING INTO WORKPLACE AIR. [R62, 56] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ...Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R50] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R50] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R50] *... Treatment kits available to medical personnel should contain amyl nitrate, sterile sodium nitrite, sterile sodium thiosulfate, syringes, needles, tourniquet, and a gastric tube. [R65] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R63, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R63, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R63, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R63, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R63, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R63, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R63, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R63, 1979.11] *Workers not wearing protective equipment and clothing should be restricted from areas of spills or leaks until cleanup has been completed. [R66] *Workers who handle acrylonitrile should wash their faces, hands, and forearms thoroughly with soap and water before eating, smoking, or using toilet facilities. [R66] *Skin that becomes contaminated with acrylonitrile should be promptly washed with soap and water. [R66] *Workers should be required to shower following a workshift and prior to putting on street clothes. Clean work clothes should be provided daily. [R66] *The storage, preparation, dispensing, or consumption of food or beverages, the storage or application of cosmetics, the storage or smoking of tobacco or other materials, or the storage or use of products for chewing should be prohibited in work areas. [R66] *Clothing which is contaminated with acrylonitrile should be removed immediately and placed in sealed containers for storage until it can be discarded or until provision is made for the removal of acrylonitrile from the clothing. If the clothing is to be laundered or cleaned, the person performing the operation should be informed of acrylonitrile's hazardous properties. Reusable clothing and equipment should be checked for residual contamination before reuse or storage. [R66] *Chemical protective clothing should be selected after utilizing available performance data, consulting with the manufacturer, and then evaluating the clothing under actual use conditions. Workers should be provided with and required to use chemical protective clothing, gloves, and other appropriate protective clothing necessary to prevent skin contact with acrylonitrile. [R66] *Penetrates leather, so contaminated leather shoes and gloves should be destroyed. [R35] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *All nitriles should be handled under carefully controlled conditions and only by personnel having a thorough understanding and knowledge of safe handling techniques. Because of the nature of nitrile cmpd and the lack of complete toxicity data on many nitriles, care should be exercised in handling these cmpd to avoid inhalation of the vapors, ingestion, and contact with the skin. /Nitriles/ [R62, 1447] *The worker should immediately wash the skin when it becomes contaminated. [R32, 9] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R32, 9] *Contact lenses should not be worn when working with this chemical. [R32, 9] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R67] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R68] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R69] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R63, 1979.13] *Separate from any sources of ignition and combustible materials. Outdoor or detached storage is preferred. For indoor storage, standard combustible materials storage room should be used. Protect from alkalis and oxidizing agents. Protect containers against physical damage. Do not store uninhibited acrylonitrile under any conditions. Preferably seal with inert gas such as nitrogen. Store drums on end with bungs up, no more than two layers. [R47, 17] *Isolate from alkalies and oxidizing materials. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Outside or detached storage is preferred. Do not store uninhibited acrylonitrile. [R49, p. 49-13] CLUP: *Remove solutions containing acrylonitrile by vacuum cleaning to prevent an increase in airborne concentrations. [R70] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, sawdust, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. [R50] *Environmental considerations: Air spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. [R50] *Environmental considerations: Water spill: Use natural barriers or oil spill control booms to limit spill travel. Use surface active agent (eg, detergent, soaps, or alcohols) if approved by EPA. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. Add calcium hypochlorite. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R50] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R63, 1979.15] *Shut off all possible sources of ignition. Instruct others to keep at a safe distance. ... Cover the spill with a 1:1:1 mixture by weight of sodium carbonate or calcium carbonate, clay cat litter (bentonite) and sand. When the acrylonitrile has been absorbed, scoop the mixture into a plastic container and package for disposal by burning. Ventilate area well to evaporate remaining acrylonitrile and dispel vapor. [R57, 18] *If acrylonitrile is spilled or leaked, the following steps should be taken: 1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities of liquids containing acrylonitrile, absorb on paper towels and place in an appropriate container. 4. Large quantities of liquids containing acrylonitrile may be absorbed in vermiculite, dry sand, earth, or a similar material and placed in an appropriate container. 5. Liquids containing acrylonitrile may be collected by vacuuming with an appropriate system. If a vacuum system is used, there should be no sources of ignition in the vicinity of the spill, and flashback prevention devices should be provided. [R66] *Releases may require isolation or evacuation. Eliminate all ignition sources. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors, and protect personnel. Control runoff and isolate discharged material for proper disposal. [R49, p. 49-12] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U009, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R71] *Acrylonitrile is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Nitrogen oxides removed from effluent gas by scrubbers and/or thermal devices. [R72] *Recovering: Incineration with provision for nitrogen oxides removal from effluent gases by scrubbers or afterburners. Recovery of acrylonitrile from acrylonitrile process effluent is an alternative to disposal. Recommendable method: Incineration. Not recommendable methods: Landfill, evaporation. [R73] *A good candidate for rotary kiln incineration, with a temperature range of 820 to 1,600 deg C and a residence time of seconds. A good candidate for fluidized bed incineration, with a temp range of 450 to 980 deg C and a residence time of seconds. A good candidate for liquid injection incineration, with a temp range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R74] */Incineration using/ ... a two stage combustion process to dispose of /acrylonitrile which/, when oxidized (one stage process), produces a flue gas containing excessive amounts of nitrogen oxides . It consists of a reduction furnace in which a high temperature reducing environment (less than stoichiometric air) converts the nitrogen oxides present into nitrogen, quench section which cools the water gas by directly contacting it with cool recycle gas, an incinerator which converts the hydrogen to water and carbon monoxide to carbon dioxide, heat recovery boiler which produces steam in cooling the flue gas and an unlined vent stack. Recycle gas cooling in lieu of air, steam, or water is an integral part of this process to minimize nitrogen oxides formation and maximize heat recovery. [R75] *The following wastewater treatment technology has been investigated for acrylonitrile: Concentration process: Activated carbon. [R76] *The following wastewater treatment technology has been investigated for acrylonitrile: Concentration process: Solvent exraction. [R77] *The following wastewater treatment technology has been investigated for acrylonitrile: Concentration process: Stripping. [R78] *The following wastewater treatment technology has been investigated for acrylonitrile: Concentration process: Biological treatment. [R79] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R63, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R63, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R63, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R63, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R63, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: B1; probable human carcinogen. BASIS FOR CLASSIFICATION: The observation of a statistically statistically significant increase in the incidence of lung cancer in exposed workers and observation of tumors, generally astrocytomas in the brain, in studies in two rat strains exposed by various routes (drinking water, gavage, and inhalation) forms the basis for this classification. [R80] +A3. Confirmed animal carcinogen with unknown relevance to humans. [R81, 2002.13] +Evaluation: There is inadequate evidence in humans for the carcinogenicity of acrylonitrile. There is sufficient evidence in experimental animals for the carcinogenicity of acrylonitrile. Overall evaluation: Acrylonitrile is possibly carcinogenic to humans (Group 2B). [R82] ANTR: *Severe acute inhalations should be treated like cyanide poisoning. The first priority is to establish adequate ventilation (100% oxygen) and circulation, since cyanide antidotes are theoretically useful but clinically unproven in acrylonitrile poisoning. [R83, 1487] *Sodium nitrite and sodium thiosulfate have been recommended as antidotes, although their efficacy in human toxicity is unproven. Most exposures will not require an antidote, but the Lilly cyanide kit theoretically may be useful in severe exposures. [R83, 1487] *The usual decontamination measures (..., lavage, charcoal) may be effective within the first 1 to 2 hours postingestion, but should not delay the use of nitrites and thiosulfate in significantly symptomatic patients. [R83, 1487] *Symptomatic management especially of respiration is the mainstay of treatment. Moderately to severely exposed patients should have an evaluation of liver function. [R83, 1487] *Rapid support of respiration and circulation is essential to successful treatment of cyanide intoxication. Massive cyanide overdoses have survived with only good supportive care. Immediate attention should be directed toward assisted ventilation, administration of 100% oxygen, insertion of intravenous lines, and institution of cardiac monitoring. Obtain an arterial blood gas immediately and correct any severe metabolic acidosis (pH below 7.15). Oxygen (100%) should be used routinely in moderate or severely symptomatic patients even in the presence of a normal pO2, since 100% O2 increases O2 delivery, may reactivate cyanide-inhibited mitochondrial enzymes, and potentiates the effect of thiosulfate. Avoid mouth to mouth resuscitation during CPR in order to prevent self-poisoning. /Cyanides/ [R83, 1480] *Amyl nitrite perles are designed to produce 3% to 5% methemoglobinemia while an iv line is established for iv sodium nitrite. As a temporizing measure, the patient inhales the vapors until the sodium nitrite is ready. Because of the variability in methemoglobin production and the potential for cardiovascular collapse, this step may be omitted if sodium nitrite is readily available and the patient is not in extremis. Adequate ventilation and oxygenation are more important than administration of amyl nitrite. One perle ... is crushed and inhaled ... until iv nitrite is given. Sodium nitrite ... is administered iv slowly ... to produce a 20% methemoglobin level in adults. ... Administer sodium nitrite doses to children on the basis of body weight, since fatal methemoglobinemia has occurred in children. /Cyanides/ [R83, 1481] *... Acute poisoning should be managed with amyl nitrate or sodium thiosulfate. [R61] *... The first aid for acute overexposure is still the same as the treatment for cyanide poisoning (i.e., sodium nitrite and thiosulfate or cobalt EDTA, in selected cases). Experimental studies have shown that antidote effectiveness differs in various species; however, the use of cysteine hydrochloride was most effective. [R15, 951] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Administer amyl nitrite ampules as per protocol and physician order ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mI/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Cyanide and related compounds/ [R84] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer cyanide antidote kit as per protocol and physician order ... . Monitor and treat cardiac arrhythmias if necessary ... . Consider vasopressors to treat hypotension without signs of hypovolemia ... . Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Cyanide and related compounds/ [R84] MEDS: *EXAMINATION OF SKIN, CNS, HEPATIC, AND RENAL FUNCTION. [R85] *Determination of acrylonitrile - derived mercapturic acids in urine may prove to be of value for the biological monitoring of exposure. [R86] *Suggested /monitoring/ tests include determination of cyanide in blood and cyanomethemoglobin in blood. [R87] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R63, 1979.23] *A nonspecific medical surveillance program should include a preplacement exam and periodic follow-up. a history of fainting spells or convulsive disorders may incr the risk of acrylonitrile work. A medical exam with special emphasis on skin, respiratory tract, heart, CNS, kidney, and liver function is recommended. A baseline health status determination will enable the detection of toxic or carcinogenic changes during periodic exams. The periodic exam should be similar to the pre-placement exam. Symptoms related to the exposure should be included in the medical history. The periodic exam should be done at least every year. [R15, 950] HTOX: *SEVERAL CASES OF MILD JAUNDICE ACCOMPANIED BY MILD ANEMIA AND LEUKOCYTOSIS HAVE BEEN REPORTED. [R48] *WHEN POISONING CASES DO OCCUR, SYMPTOMS DERIVE FROM TISSUE ANOXIA AND ARE IN ORDER OF ONSET: LIMB WEAKNESS, DYSPNEA, BURNING SENSATION IN THROAT, DIZZINESS, AND IMPAIRED JUDGEMENT, CYANOSIS AND NAUSEA, COLLAPSE, IRREGULAR BREATHING, CONVULSIONS AND DEATH. IN LATTER STAGES COLLAPSE, IRREGULAR BREATHING OR CONVULSIONS AND CARDIAC ARREST MAY OCCUR WITHOUT WARNING. SOME PATIENTS APPEAR HYSTERICAL OR MAY EVEN BE VIOLENT. [R62, 55] *EXAMINATION OF 18 WORKERS WHO HAD BEEN EXPOSED TO ACRYLONITRILE FOR AVERAGE OF 15.3 YR AND 18 WORKERS WHO HAD NOT BEEN EXPOSED TO ACRYLONITRILE SHOWED NO DIFFERENCE IN INCIDENCE OF CHROMOSOME ABERRATIONS. [R88] *IN AN ANALYSIS OF MORTALITY AMONG 327 EMPLOYEES OF RUBBER CHEMICAL PLANT WHO HAD POTENTIAL EXPOSURE TO ACRYLONITRILE, 9 DEATHS FROM LUNG CANCER WERE FOUND IN COMPARISON TO 5.9 EXPECTED BASED ON MORTALITY RATES FOR USA WHITE MALES AND 4.7 EXPECTED BASED ON MORTALITY RATES FOR OTHER RUBBER WORKERS FROM THE SAME CITY. THE EXCESS WAS GREATER AMONG MEN WHO WORKED 5 THROUGH 14 YR AND WHO DIED 15 OR MORE YR AFTER STARTING WORK IN THE PLANT (4 DEATHS OBSERVED, 0.8 EXPECTED). [R89] *Four cases of toxic epidermal necrosis developed 11-21 days after patients were exposed to a fumigant containing 2:1 carbon tetrachloride and acrylonitrile. Blisters of the skin and mucous membranes were followed 3-4 weeks later by death from septic shock and gastrointestinal hemorrhage in 3 patients. The fourth, a 10 yr old male, survived with topical and parenteral corticosteroid application. [R90] *576 Japanese workers exposed to 5-20 ppm over 10 yr showed headache, fatigue, nausea, and weakness with symptoms of anemia, jaundice, conjunctivitis, and abnormal whole blood and serum specific gravity, cholinesterase, urobilinogen, bilirubin, urinary protein, and sugar values, indicative of liver injury and a general toxic effect. [R91] *Smokers may have incr thiocyanate in blood and urine confusing the possible incr of thiocyanate levels due to acrylonitrile exposure. [R92] *... An occupational epidemiologic study that involved workers exposed to acrylonitrile at a DuPont textile fibers plant in Camden, SC was conducted. ... The study cohort was 1,345 male employees "identified as having had potential exposure to acrylonitrile at one time between start-up in 1950 and 1966". The cut-off -up through the end of 1976. ... The severity of exposure levels were designated as high, medium, and DuPont representatives agreed that 20 ppm, 10 ppm, and 5 ppm might be used to action of high, medium, and low exposure levels. ... A trend toward increased risks was seen not only with increased follow-up time but also with severity of exposure. In wage roll workers with at least moderate exposure and probable latent period of at least 15 yr, the observed and numbers of cancer cases were 13 and 5.5, respectively. Furthermore, half of this excess cancer was respiratory cancer, 5 /observed/ versus 1.4 /expected/ (p < 0.05). [R93] *A cohort mortality study of 1,469 workers from 12 factories located in the Federal Republic of Germany was conducted. ... These 12 factories are part of the BASF Company. ... Not only did an excessive significant risk remain with respect to lung cancer (9 observed versus 4.37 expected based on Federal Republic of Germany rates, p < 0.05), but also a significant excess risk of cancer of the lymphatic system was seen (4 observed versus 1.38 expected, p < 0.05). These results are questionable. The members of this cohort were apparently exposed to a number of different carcinogens ie, vinyl chloride, distillation residues containing polycyclic hydrocarbons, cadmium, B-napthylamine, dimethylsulfate, and epichlorohydrin. ... /There was an/ incomplete follow-up on foreign workers. Although, there are many limitations to this study, it is possible that exposure to acrylonitrile may indeed be related to an excessive risk of lung cancer and cancer of the lymph system. [R94] *A cohort mortality study of 327 white male employees of a rubber manufacturing plant in Akron, Ohio was conducted ... . The levels of acrylonitrile that these workers were exposed to while on the job were not reported. ... The risk of death due to cancer was somewhat elevated, with 22 observed versus 17.9 expected. Most of this excess was due to lung cancer deaths which were nonsignificantly higher, with 9 observed versus 5.9 expected. Only workers employed for 5 to 14 yr and followed for at least 15 yr, had a significantly elevated risk of lung cancer (4 observed versus 0.8 expected p < 0.01). However, if workers who were employed for more than 14 yr and followed for at least 15 yr were added to the latter group, ... the risk of lung cancer was actually reduced but still significant (4 observed versus 1.4 expected, P < 0.05). The excessive risk of lung cancer in this group may not be entirely due to exposure to acrylonitrile, but may be partially reflective of exposures to other substances within the same environment. [R95] *A cohort mortality study of 934 men who worked on the polymerization of acrylonitrile and spinning of acrylic fiber at six different factories was conducted. ... Two of the six factories were located in Scotland and Northern Ireland; the remainder were located in England and Wales. ... Deaths from cancer of the stomach were statistically significantly elevated over all age groups (5 observed versus 1.9 expected p < 0.05) with deaths to persons in the 55-64 age group contributing the largest portion (3 observed versus 0.7 expected, p < 0.05). On the other hand, a statistically significant elevated risk of cancer of the lung, trachea, and bronchus appeared only in the age group 15-44 (3 observed versus 0.7 expected, p < 0.05) but not in any other age group. [R96] *SYMPTOMATOLOGY: 1. Massive doses may produce, without warning, sudden loss of consciousness and prompt death from respiratory arrest. With smaller but still lethal doses, the illness may be prolonged for 1 or more hours. 2. Upon ingestion, a bitter, acrid, burning taste is sometimes noted, followed by a feeling of constriction or numbness in the throat. Salivation, nausea and vomiting are not unusual ... . 3. Anxiety, confusion, vertigo, giddiness, and often a sensation of stiffness in the lower jaw. 4. Hyperpnea and dyspnea. Respiration become very rapid and then slow and irregular. Inspiration is characteristically short while expiration is greatly prolonged. 5. The odor of bitter almonds may be noted on the breath or vomitus ... . 6. In the early phases of poisoning, an incr in vasoconstrictor tone causes a rise in blood pressure and reflex slowing of the heart rate. Thereafter, the pulse becomes rapid, weak, and sometimes irregular ... . A bright pink coloration of the skin due to high concn of oxyhemoglobin in the venous return may be confused with that of carbon monoxide poisoning. 7. Unconsciousness, followed promptly by violent convulsions, epileptiform or tonic, sometimes localized but usually generalized. Opisthotonos and trismus may develop. Involuntary micturition and defecation occur. 8. Paralysis follows the convulsive stage. The skin is covered with sweat. The eyeballs protrude, and the pupils are dilated and unreactive. The mouth is covered with foam, which is sometimes bloodstained ... . The skin color may be brick red. Cyanosis is not prominent in spite of weak and irregular gasping. In the unconscious patient, bradycardia and the absence of cyanosis may be key diagnostic signs. 9. Death from respiratory arrest. As long as the heart beat continues, prompt and vigorous treatment offers some promise of survival. /Cyanide/ [R60, p. III-126] *It has long been known to possess a high degree of toxicity and to possess many of the characteristics of poisoning by cyanide ion. ... Level of cyanide ion in blood appears to be correlated with the degree of poisoning ... . [R97] *A study population composed of 2,671 men who had worked at either of 2 facilities of the American Cyanamid Company was studied for mortality experiences resulting from exposure to acrylonitrile. The employment period considered ranged from 1951 for the facility in Fortier, LA AND 1957 for the Santa Rose, FL facility and extended through December 31, 1979. Social Security Administration records and the National Death Index were used to determine the vital status of the cohort as of 1983. There were 237 deaths by the end of the study, and 61 men were lost to follow up. Death certificates were used to determine the cause of death; death certificates were not found for 15 men. Industrial hygiene monitoring was begun in 1977 but this was before any major operational changes were made and so the conditions prevailing in 1977 were taken as representative of the conditions back to the beginning of each facility. No statistically significant excess of all cause or cause specific mortality was noted among these workers. No trend was found for respiratory cancer mortality in relation to acrylonitrile exposure. Men who had been exposed to high levels of acrylonitrile had respiratory cancer rates similar to men who had not been exposed in the workplace to this chemical and similar to the rate in the general US male population. This study does not support the contention that acrylonitrile is a carcinogen for humans. [R98] *The ability of acrylonitrile to induce cytotoxicity, sister chromatid exchanges and DNA single strand breaks was studied in cultured human bronchial epithelial cells. The toxic effect as determined by cloning efficiency was observed at a dose of 600 ug/ml but not at doses of both 150 and 300 ug/ml. The frequency of sister chromatid exchange in untreated cells was 3.7 + or - 1.3 per cell. In contrast, cells treated with acrylonitrile at 150 and 300 ug/ml exhibited 6.6 + or - 1.3 and 10.7 + or - 1.7 sister chromatid exchanges per metaphase, respectively. DNA single strand breaks were induced by acrylonitrile at dose levels of 200 and 500 ug/ml. The genotoxic effects on human bronchial epithelial cells that were directly exposed to acrylonitrile are of interest in relation to evidence for the higher lung cancer incidence of acrylonitrile workers in epidemiological studies. [R99] *This study was to determine whether exposure to dimethylformamide and acrylonitrile separately or in combination, was assoc with incr cancer incidence. Workers exposed to dimethylformamide and/or acrylonitrile were observed from 1956 through 1984 for cancer incidence. The workers exposed to dimethylformamide but not acrylonitrile showed significant excesses in incidence for buccal cavity and pharynx cancer and malignant melanoma. A significant excess of prostate cancer incidence was observed among workers exposed to dimethylformamide and acrylonitrile. No dose-response relationships were observed between dimethylformamide or acrylonitrile exposure and cancer incidence. The significant excesses in cancer incidence among employees exposed to dimethylformamide and/or acrylonitrile could be due to statistical chance or other factors, such as tobacco and alcohol consumption. [R100] *Prolonged skin contact with liquid acrylonitrile can result in systemic toxicity and the formation of large dermal vesicles after a latent period of several hours. The affected skin area may resemble a second degree, thermal burn. [R12, 1991.31] *Acrylonitrile closely resembles hydrocyanic acid in its toxic action. by inhibiting the respiratory enzymes of tissues, it renders the tissue cells incapable of oxygen absorption. Poisoning is acute; there is little evidence of cumulative action on repeated exposure. Exposure to low concn is followed by flushing of the face and incr salivation; further exposure results in irritation of the eyes and nose, photophobia, deepened respiration. If exposure continues, shallow respiration, nausea, vomiting, weakness, an oppressive feeling in the chest, and occasionally headache and diarrhea are other complaints. [R48] *In humans, breathing acrylonitrile at a concn of 16 /ppm/ causes headaches, nausea, and disorientation. This concn is close to that at which acrylonitrile can be smelled in air (about 21 ppm). Breathing acrylonitrile in air for long periods of time and at high concn can cause death. The actual concn of acrylonitrile and breathing times which cause death have not been measured. ... Acrylonitrile can be smelled at a concn of 19 ppm when dissolved in water. [R101] NTOX: *ESCHERICHIA COLI WP2, UVRA - REVERSE MUTATION STUDIES: POSITIVE; ESCHERICHIA COLI WP2 - REVERSE MUTATION STUDIES: POSITIVE. [R102] *RATS INGESTING 0.1% IN WATER FOR A PERIOD OF 13 WK SHOWED RETARDED GROWTH AND EMACIATION; SOME EFFECTS WERE ALSO NOTED WITH AS LOW AS 0.05% IN WATER IN 2-YR FEEDING STUDIES. [R103] *... ORAL STUDIES ... IN /SPRAGUE-DAWLEY/ RATS ... /INDICATE/ THAT IN SMALL NUMBER OF ... RATS ADMIN 0, 35, 100, OR 300 MG/L ... IN DRINKING WATER, AND KILLED AFTER 12 MO, SQUAMOUS-CELL PAPILLOMAS OF FORESTOMACH, MICROGLIOMAS OF CNS AND ZYMBAL GLAND CARCINOMAS OCCURRED. ... NO SUCH TUMORS WERE SEEN IN CONTROLS. [R104] *... 40 MALE AND 40 FEMALE SPRAGUE-DAWLEY RATS, 4-5 WK OF AGE, WERE GIVEN 5 MG/KG BODY WT ... IN OLIVE OIL BY GAVAGE 3 TIMES/WK FOR 52 WK. AT 131 WK ... 4 TREATED FEMALES, 1 TREATED MALE AND 1 FEMALE CONTROL HAD FORESTOMACH PAPILLOMAS AND ACANTHOMAS; NO INCR ... SEEN IN INCIDENCE OF CNS GLIOMAS. [R105] *GROUPS OF 30 MALE AND 30 FEMALE SPRAGUE-DAWLEY RATS 4-5 WK OF AGE, WERE EXPOSED TO 88, 44, 22 OR 11 MG/CU M (40, 20, 10, OR 5 PPM) ... BY INHALATION FOR 4 HR A DAY ON 5 DAYS/WK FOR 52 WK. AFTER 136 WK, 13-23% TREATED RATS HAD MAMMARY TUMORS (VERSUS 10% IN CONTROLS); 1 FEMALE EXPOSED TO 20 PPM AND 1 MALE AND 1 FEMALE EXPOSED TO 10 PPM HAD ZYMBAL GLAND CARCINOMA (NONE IN CONTROLS); 1.6-6.6% TREATED ANIMALS HAD FORESTOMACH PAPILLOMAS AND ACANTHOMAS (NONE IN CONTROLS); 2 MALES EXPOSED TO 40 PPM AND 1 MALE EXPOSED TO 20 PPM HAD CNS GLIOMAS (NONE IN CONTROLS). [R105] *IP INJECTION OF 50 MG/KG BODY WT ACRYLONITRILE DAILY FOR 3 WK TO ADULT RATS RESULTED IN LOSS OF BODY WT, LEUKOCYTOSIS, FUNCTIONAL DISTURBANCES IN LIVER AND KIDNEYS, SLIGHT DAMAGE TO NEURONAL CELLS OF BRAIN STEM AND CORTEX AND PARENCHYMAL DEGENERATION OF LIVER AND KIDNEYS. SINGLE IV DOSE OF 150 MG/KG BODY WT (15 MG/ANIMAL) ACRYLONITRILE ADMIN TO RATS PRODUCED BILATERAL ADRENOCORTICAL HEMORRHAGE AND NECROSIS. [R105] *DOGS EXPOSED TO CONCN OF 30-40 PPM FOR TEN WK (5 DAYS A WK, 6.5 HR A DAY) SUFFERED 50% MORTALITY. KIDNEYS AND LIVER WERE ONLY SLIGHTLY AFFECTED, AND IN HALF THE CASES LUNGS SHOWED INCOMPLETE EXPANSION (ATELECTASIA). [R33, 72] *ACRYLONITRILE APPLIED TO THE SKIN OF RATS AT DOSES OF 28 OR 14 MG/KG BODY WT FOR 2 MONTHS, OR 2.8, 0.56 OR 0.11 MG/KG BODY WT FOR 4.5 MONTHS, HAD A GENERAL TOXIC EFFECT; THE DOMINANT CHANGES WERE IN THE BLOOD VESSELS (CONGESTIVE PLETHORA AND HEMORRHAGES). [R106] *ACRYLONITRILE, IN AQ OR GAS PHASES, INDUCED REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA1530, TA1535, TA1950, TA100, TA1538, TA98 AND TA1978 IN PRESENCE OF 9000XG SUPERNATANT OF LIVER FROM MICE OR RATS. IT WAS ... MUTAGENIC TO SALMONELLA TYPHIMURIUM TA1530 IN FLUCTUATION TEST IN PRESENCE OF 9000XG SUPERNATANT OF RAT LIVER. [R107] *ACRYLONITRILE IN SOLN PRODUCED REVERSE MUTATIONS IN PLATE INCORPORATION ASSAY USING ESCHERICHIA COLI WP2, WP2 UVRA AND WP2 UVRAPOLA WITHOUT METABOLIC ACTIVATION SYSTEM. ACRYLONITRILE WAS ALSO MUTAGENIC IN FLUCTUATION TEST IN ESCHERICHIA COLI WP2 AND WP2 UVRAPOLA @ CONCN 20-40-FOLD LESS THAN THAT USED IN PLATE ASSAY. [R107] *In a rat whole embryo culture system, depletion of glutathione aggravated the embryo-toxic and teratogenic effects of acrylonitrile. [R108] *Exposure of Sprague Dawley rats to acrylonitrile by inhalation in the range of 12-100 ppm (26-220 mg/cu m) for six hours per day on days 6-20 of gestation resulted in fetotoxicity accompanied by overt signs of maternal toxicity at 25 ppm (54 mg/cu m) and higher concentrations. No significant teratogenicity was observed. [R108] *After a single oral dose of 46.5 mg/kg body weight acrylonitrile, moderate to marked hyperplasia of the Clara cells lining the bronchioles was observed in male Sprague Dawley rats. [R109] *PREGNANT SPRAGUE DAWLEY RATS WERE GIVEN 0, 10, 25 OR 65 MG/KG/DAY BY GAVAGE FROM DAY 6-15 OF GESTATION. ADDITIONAL RATS WERE EXPOSED FOR 6 HR/DAY TO 0, 40 OR 80 PPM BY INHALATION FROM DAY 6-15 OF GESTATION. ORAL ADMINISTRATION OF 65 MG/KG/DAY, A MATERNALLY TOXIC LEVEL, RESULTED IN EMBRYOTOXICITY. FINDINGS SUGGESTIVE OF TERATOGENIC EFFECT WERE NOTED @ 25 MG/KG/DAY BY GAVAGE AND @ 80 PPM BY INHALATION. NO EMBRYOTOXICITY OR TERATOGENICITY @ 10 MG ORALLY OR INHALATION OF 40 PPM IN RATS /WAS OBSERVED/. [R110] *GLUTATHIONE ENHANCED THE MICROSOMAL MEDIATED MUTAGENICITY OF ACRYLONITRILE IN SALMONELLA TYPHIMURIUM STRAIN TA1530. [R111] *THE PRESENCE OF LIVER HOMOGENATES WAS NECESSARY FOR GASEOUS ACRYLONITRILE TO INDUCE MUTATIONS IN SALMONELLA TYPHIMURIUM TA1530. [R112] *THE POSSIBILITY WAS STUDIED THAT LIVER METABOLISM OF ACRYLONITRILE COULD PRODUCE STABLE TRANSPORTABLE MUTAGENIC METABOLITES IN CULTURED CHINESE HAMSTER OVARY CELLS. ACRYLONITRILE DID NOT PRODUCE SISTER CHROMATID EXCHANGES IN CHINESE HAMSTER OVARY CELLS, HOWEVER, SIGNIFICANT INCR WAS PRODUCED WHEN CHINESE HAMSTER OVARY CELLS WERE CO-CULTURED WITH FRESHLY ISOLATED RAT HEPATOCYTES. THIS SUGGESTS THAT THE LIVER CELLS METABOLIZE ACRYLONITRILE AND THE REACTIVE METABOLITE IS TRANSPORTED FROM THEM TO CHINESE HAMSTER OVARY CELLS. [R113] *RATS PRETREATED WITH PHENOBARBITAL OR AROCLOR WERE ADMIN ACRYLONITRILE (50, 75, 100, OR 150 MG/KG) ORALLY FOR 1, 2, OR 3 DAYS. FOCAL SUPERFICIAL NECROSIS OF LIVER ASSOCIATED WITH HEMORRHAGIC GASTRITIS OF DISTENDED FORESTOMACH WAS FOUND IN RATS NECROPSIED 24 HR AFTER ADMIN OF 150 MG/KG. [R114] *PRIOR EXPOSURE OF RATS TO SUBLETHAL CONCN OF ACRYLONITRILE PROVIDED PROTECTION AGAINST EXPOSURES TO NORMALLY LETHAL CONCN OF ACRYLONITRILE . HOWEVER, THIS TOLERANCE TO ACRYLONITRILE DOES NOT PROTECT AGAINST SUBSEQUENT POISONING BY CYANIDE AND PROTECTION AGAINST ACRYLONITRILE TOXICITY IS NOT PROVIDED BY PRETREATMENT WITH COMPOUNDS WHICH HAVE STRUCTURAL SIMILARITY TO ACRYLONITRILE, EG, ACRYLAMIDE OR ETHYLENE. AROCLOR 1254 DOES NOT PROTECT AGAINST ACRYLONITRILE TOXICITY WHICH SUGGESTS THAT THE TOLERANCE RESULTING FROM ACRYLONITRILE PRETREATMENT IS NOT THE RESULT OF ENZYME INDUCTION. [R115] *Rats given 20 mg/kg/day for 6 wk or 40 mg/kg/day for 4 wk misperformed in a labyrinth test, and showed impaired food conditioned reflexes and depressed learning ability which indicates central nervous system disturbances. [R116] *Chronic whole life cycle: Exposure of Daphnia magna to 3.6 mg/l produced no adverse effects. [R117] *Acrylonitrile failed to show mutagenic activity in the mouse lymphoma L5178Y kinase mouse lymphoma cell assay. [R118] *The ovicidal effects of acrylonitrile ... on the eggs of the yellow-fever mosquito (Aedes aegypti) were studied. Mature eggs were exposed for 24 hr to the vapor of 5 or 10 ul added acrylonitrile in sealed one quart jars (21 to 32 deg C, 100% humidity) and then placed in deoxygenated water to determine hatchability. The percent mortality at the two treatment levels (4.2 or 8.4 mg/l, by calculation) was 60 and 92%, respectively. [R119] *The effects of acrylonitrile on cultured seagrass, Ruppia maritima were studied. Acrylonitrile was added to the water column to give concn ranging from 10 ug/l to 10 g/l. Concn greater than 100 mg/l totally inhibited photosynthesis and respiration, as measured by dissolved oxygen changes. Lower concn had no effect on these processes. ... All concn reduced the growth rate of shoots. [R120] *Acrylonitrile was administered in the drinking water to Sprague-Dawley rats for 2 yr at dose levels of 35, 100, and 300 ppm. A statistically significant incidence of tumors was observed in the brain (astrocytomas), ear canal (Zymbal gland), stomach (nonglandular portion), mammary gland (females only), tongue, pituitary gland, pancreas (males only), and uterus. [R121] *A three-generation reproductive study was conducted using Charles River rats. These rats and their offspring ingested water containing 100 or 500 ppm acrylonitrile starting approximately 15 days post-weaning and were mated after 100 days. Female rats were maintained on water containing acrylonitrile for 20 weeks; following delivery of the second litter, the animals were exposed to acrylonitrile for approximately 45 weeks. Following exposure, the animals in the three generations were sacrificed. ... The tumor incidence was low; only rats of the second generation at the high-dose level showed a significant increase in the number of tumors. /These tumors were found in the brain (astrocytomas) and ear canal (zymbal gland)/. [R122] *... Acrylonitrile was administered in the drinking water to 100 Fischer 344 rats of each sex at dose levels of 1, 3, 10, 30, and 100 ppm, and the control group contained 200 animals/sex. ... All females were sacrificed at 23 months due to low survival. The males were continued on test until the 26th month when similar survival levels were reached. Mortality in the males and females receiving 100 ppm was markedly greater than in controls, while mortality in the 10 ppm males and females receiving 3 and 30 ppm was also somewhat greater than controls. ... Slight, but generally consistent reductions in hemoglobin, hematocrit, and erythrocyte counts were noted for the females receiving 100 ppm throughout the study. Histopathological evaluation revealed an increased incidence of malignant tumor-bearing animals in the groups recieving 10, 30, and 100 ppm. The observed tumors were astrocytomas of the central nervous system (brain and/or spinal cord) and squamous cell carcinomas of the ear canal, as well as mammary gland carcinomas in the females receiving 100 ppm. [R123] *A carcinogenicity bioassay was conducted using 40 Sprague Dawley rats of each sex in both the treated and control groups which were exposed to a single dose of 5 mg/kg acrylonitrile by gavage dissolved in olive oil, 3 times a week, for 52 weeks. On spontaneous death, a moderate increase in tumors of the mammary gland region and forestomach of female rats was described. [R124] *In this study, acrylonitrile was administered by intubation to Sprague Dawley (Spartan) rats (100/sex/group) at three dose levels of 0, 0.10, and 10.0 mg/kg/day, 5 days/wk. ... All surviving animals in all groups were terminated during the 20th month to ensure at least 10 animals/sex for histopathological evaluation. The body weights of high-dose group males were consistently slightly lower than controls. Histopathological evalutions showed that there were statistically signifcant increased incidences in tumors of the brain (astrocytomas) and ear canal (zymbal gland) in both high-dose males and females. Stomach and intestinal tumors were observed only in high-dose males, and mammary gland tumors were observed in high-dose females. Statistically significant tumor incidences were not observed in low-dose groups either in males or females. [R124] *Sprague Dawley rats were exposed to atmospheres containing 5, 10, 20, and 40 ppm acrylonitrile 4 hr/day, 5 days/wk, for 12 months. The rats were maintained for their entire lifetime. Histological examination of the selected tissues were made. ... Slight increases were observed in mammary gland tumors of males and females, the forestomach of males, and the skin of females. [R125] *In this study, 100 male and female Sprague Dawley rats (Spartan substrain) were exposed /by inhalation/ to 0, 20, or 80 ppm of acrylonitrile 6 hr/day, 5 days/wk, for 2 yr, except during weekends or holidays. ... During the first 6 mo of the study, the exposed rats drank more water and appeared to excrete a lower specific gravity urine than control rats. In lifetime observations of male and female rats exposed to acrylonitrile vapors, toxic effects, characterized by decrease in body weight and early mortality, were observed. Microscopic examination of tissues revealed a treatment-related statistically significant incidence of tumors in the central nervous system, ear canal gland (zymbal gland), tongue, small intestine, and mammary gland. In male and female rats, statistically significant increased incidences were observed only at the 80 ppm dose levels with the exception of glial cell tumors of the central nervous system which were also increased in female rats at 20 ppm. [R125] *Acrylonitrile was administered in the drinking water to 100 Sprague Dawley (Spartan) rats of each sex at dose levels of 0, 1, and 100 ppm. The study was terminated early due to low survival rates; females were sacrificed at 19 mo and males were sacrificed at 22 mo. ... Histopathology evaluation revealed an increased incidence of astrocytomas of the brain and spinal cord, carcinomas and adenomas of the zymbal gland or ear canal, and squamous cell carcinomas and papillomas of the forestomach in the high-dose males and females. [R126] *The teratogenicity of acrylonitrile has been investigated using Sprague Dawley rats exposed to the compound by inhalation or by gavage on days 6 to 15 of gestation. Acrylonitrile was administered /by gavage/ at doses of 10, 25, and 65 mg/kg/day per os or by exposing the animals to an atmosphere of 40 or 80 ppm (87 or 147 mg/cu m) acrylonitrile for 6 hr/day. ... Rats exposed by inhalation to 40 or 80 ppm of acrylonitrile had no statistically significant changes in reproductive success or fetal development. Only the pups of rats administered acrylonitrile per os (65 mg/kg) for days 6 to 15 of gestration had an increase in malformations. At the high dose level ... there was a significant increase in acaudate or short-tailed fetuses. The majority of other abnormalities including short trunk, anteriorly displaced ovaries, missing ribs, and imperforate anus were observed in the acaudate and short-tailed fetuses whether these animals were from the control or experimental group. The only anomaly that occurred solely in treated animals was a right-sided aortic arch, which appeared in one fetus from the 25 mg/kg/day group and one fetus from the 65 mg/kg/day group. [R127] *When applied as a single drop to a rabbit cornea, it has caused only a transient disturbance without corneal opacification. [R128] *2,3-(14C)ACRYLONITRILE WAS INCUBATED WITH RAT LIVER MICROSOMES, NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE, REDUCED AND DNA, RNA OR BOVINE SERUM ALBUMIN. IRREVERSIBLE BINDING OCCURRED TO THE MACROMOLECULAR TARGETS. MOST OF (14)C BOUND TO DNA, RNA OR POLYNUCLEOTIDES. [R129] *... This compound found in plastic and fibers /was administered/ to rats on days 6 through 15 of gestation at doses of 25 mg per kg by mouth. Some maternal toxicity occurred and trunk and aortic anomalies were produced. Inhalation of 80 ppm produced teratogenic effects. Inhalation of 40 ppm or oral doses of 20 mg per kg caused no fetal effects. [R130] *The interaction of acrylonitrile with rat blood was investigated at the molecular level in an attempt to understand the possible mechanism of its toxicity. The results obtained were compared to those with potassium cyanide, a compound known to liberate cyanide in biologic conditions. ... 90% of the radioactivity from potassium cyanide in erythrocytes was found in the heme fraction of hemoglobin. Potassium cyanide interacts mainly through cyanide liberation and binding to heme, whereas acrylonitrile, which binds to cytoplasmic and membrane proteins, may damage red cells by mechanisms other than release of cyanide. [R131] *ACRYLONITRILE SHOWED SPECTRAL INTERACTION WITH HEPATIC MICROSOMES FROM MOUSE, RAT, AND MAN. IN HUMAN AND RAT LIVER, MICROSOMES RESULTED IN LIGAND ACRYLONITRILE-BINDING SPECTRA BUT NOT IN MOUSE LIVER MICROSOMES. HEPATIC MICROSOMES FROM PHENOBARBITAL-TREATED MICE WITH ACRYLONITRILE SHOWED A TYPE I SUBSTRATE BINDING. LIGAND SPECTRA WERE RECORDED WITH MICROSOMES FROM BENZ(A)PYRENE-TREATED MICE. MICROSOMES FROM UNTREATED CONTROL MICE SHOWED A MIXED TYPE BEHAVIOR. [R132] *QUANTITATIVELY, ACRYLONITRILE-INDUCED GI HEMORRHAGE IS TIME AND DOSE DEPENDENT AND IS NOT THE RESULT OF A DIRECT IRRITATING ACTION ON GASTRIC TISSUES. THE EFFECT OF CYTOCHROME P450 ENZYME INDUCERS ON THIS EFFECT WAS STUDIED. PRETREATMENT WITH PHENOBARBITAL DECREASED GI BLOOD LOSS (55%) WHILE AROCLOR 1254 GREATLY INCREASED IT BY 240%. ADMIN OF ACRYLONITRILE TO RATS TREATED WITH COBALT CHLORIDE OR SKF 525A (CYTOCHROME P450 ENZYME INHIBITORS) RESULTED IN SIGNIFICANT PROTECTION AGAINST GI BLEEDING. PRETREATMENT WITH DIETHYLMALEATE (A KNOWN DEPLETOR OF REDUCED GLUTATHIONE) DID NOT CAUSE A SIGNIFICANT CHANGE IN ACRYLONITRILE-INDUCED GI BLEEDING. [R133] *Pre-treatment with cyanide was found to greatly enhance the toxicity of acrylonitrile, and to cause a three-fold incr in the cyanide level in the blood of treated rats. [R134] *URINE FROM ACRYLONITRILE TREATED RATS AND MICE WAS MUTAGENIC TO SALMONELLA TYPHIMURIUM STRAIN TA1530 IN ABSENCE OF A METABOLIC ACTIVATION SYSTEM. BETA-GLUCURONIDASE ADDED TO INCUBATION MIXT ENHANCED MUTAGENICITY OF URINE FROM PHENOBARBITAL TREATED AND UNTREATED RATS AND MICE INJECTED WITH ACRYLONITRILE. [R135] *An assessment was undertaken of whether acute and subacute administration of acrylonitrile to male Sprague Dawley rats could induce a lipoperoxidation process. The study monitored ethane in expired air as the most specific noninvasive indicator of lipoperoxidation. In the acute experiment, acrylonitrile was given by the ip route at doses ranging from 10 to 100 mg/kg. Carbon tetrachloride was used as a positive control and was given ip at a dose of 1 ml/kg. Sodium cyanide was given at a dose of 2.5 mg/kg. Phenobarbital pretreatment consisted of a single ip injection at 100 mg/kg followed by 3 day oral administration in drinking water. The microsomal enzyme inhibitor SKF-525A was injected ip at 50 mg/kg 45 minutes prior to acrylonitrile. In the acute studies, the exhalation of ethane in animals receiving ip injections of 50 mg/kg acrylonitrile increased during the first 2 hours and then leveled off. Pretreatment with vitamin-E and SKF-525A prevented this response. The response, however, was exacerbated by pretreatment with phenobarbital. In a subacute experiment acrylonitrile was given ip, once a day, 5 days a week for 4 weeks at a dose of 5, 10, or 40 mg/kg. The subacute study indicated increased ethane production and serum sorbitol-dehydrogenase activity. Several morphological changes were noted in mitotic activity, increased nucleolar size and myelinic figures in mitochondria. The growth of subacute study. [R136] *Daily oral administration of acrylonitrile (10 mg/kg body weight) to mice for a period of 60 days caused a significant decrease in the activity of testicular sorbitol dehydrogenase and acid phosphatase, and an increase in that of lactate dehydrogenase and beta-glucuronidase. Histopathological studies revealed degeneration of the seminiferous tubules. A decrease in the sperm counts of the epididymal spermatozoa was also observed. [R137] *A study was made of the chronic effects of ingestion of low doses of acrylonitrile on tumor incidence in rats. Male Sprague Dawley rats were exposed to 0, 20, 100, or 500 ppm acrylonitrile in drinking water for 2 years. Complete necrospy was performed on rats that died and on surviving rats killed at the end of 2 years. Accelerated mortality was noted at 500 ppm acrylonitrile. This group showed a trend toward decreased water consumption. Body weights in 100 ppm and 500 ppm groups increased more slowly in the first year and decreased more in the second year relative to controls. Dose related neoplastic changes noted were increased Zymbal's gland carcinomas and forestomach papillomatous proliferations and decreased benign adenomas of the pituitary. Pituitary adenomas were age related in control rats and contained immunoreactive prolactin. Most Zymbal's gland tumors were histologically poorly differentiated squamous carcinomas and were locally destructive. One produced a metastatic lung lesion. Forestomach papillomatous changes were only noted in the 500 ppm group. Mortality is not increased in rats ingesting up to 100 ppm acrylonitrile, Zymbal's gland tumors increase and pituitary adenomas decrease in a dose related manner with acrylonitrile, and there is a tendency to increased forestomach papillomas. [R138] *The biochemical and developmental effects of acrylonitrile in rats exposed in utero were examined. Pregnant Charles-Wistar rats received 0 or 5 mg/kg/day acrylonitrile orally from day 5 to day 21 of gestation. Acrylonitrile had no effect on maternal body weight, weight of the offspring, length of gestation, number of offspring delivered, sex within the litters, the onset of pinna detachment, eye opening, incisor eruption, or fur appearance. Pups had no abnormalities in the development of righting reflex, cliff avoidance, grip strength, spontaneous motor activity or learning ability. Two weeks post partum, 5-hydroxytryptamine was decreased in the corpus striatum and hypothalamus and increased in the pons/medulla while sodium concentrations were slightly increased in the hippocampus and significantly reduced in the pons/medulla. Monoamine-oxidase levels were decreased from 88 to 45 nanomoles benzaldehyde formed per minute per milligram protein in the 3 week old gestationally treated pups compared to the untreated controls. At 3 weeks there were no significant differences in acetylcholinesterase concentrations or sodium/potassium/ATPase activity between treated and control pups. Although exposure to low levels of acrylonitrile does not affect functional development of pups, there are changes in biogenic amines that can lead to future neurological effects. [R139] *STRUCTURE-ACTIVITY RELATIONSHIPS WERE QUALITATIVELY AND QUANTITIVELY EXAMINED FOR 56 COMPOUNDS (EG DERIVATIVES OF PROPIONITRILE, ACRYLONITRILE, AND CYSTEAMINE) WHICH CAUSED DUODENAL ULCER AND/OR ADRENOCORTICAL NECROSIS IN RATS. ULCEROGENIC ACTIVITY WAS MOST INTENSE IN THE CARBONITRILES ATTACHED TO 2 OR 3-C BACKBONES. [R140] *ACRYLONITRILE IS MUTAGENIC IN SALMONELLA TYPHIMURIUM. THE COMPARATIVELY WEAK ACTIVATING EFFECT OF MICROSOMAL FRACTION AND INABILITY OF BOTH SKF525A AND COBALT TO INHIBIT (RAT AND MOUSE) S9 MEDIATED MUTAGENICITY OF ACRYLONITRILE SUGGEST THAT CYTOCHROME P450-DEPENDENT MONOOXYGENASES DO NOT PLAY MAJOR ROLE IN METABOLIC ACTIVATION INTO MUTAGENIC INTERMEDIATE(S). [R141] *When injected sc at 0.5 mg/rat/day for 10 days, acrylonitrile decreased the rate of oxygen uptake and increased that of glycolysis in brain. [R142] NTXV: *LD50 Rat sc 80 mg/kg; [R143] *LD50 Rat oral 93 mg/kg; [R64] *LD50 Rat oral 78 mg/kg; [R144] *LD50 Guinea pig oral 90 mg/kg; [R144] *LD50 Rabbit oral 93 mg/kg; [R145] *LD50 Rabbit dermal 280 mg/kg; [R145] *LD50 Guinea pig dermal 250 mg/kg; [R145] *LC50 Rat inhalation 425 ppm/4 hr; [R48] *LD50 Rat skin 148 mg/kg; [R48] *LD50 Mouse ip 46 mg/kg; [R48] *LD50 Mouse subcutaneous 35 mg/kg; [R48] ETXV: *LC50 Pimephales promelas (fathead minnow) 2600 ug/l/30 days /Static bioassay/; [R146, p. 2-3] *LC50 Pinfish 24,500 ug/l/24 hr (saltwater) /Static bioassay/; [R146, p. 2-3] *LC50 Lepomis macrochirus (bluegill) 11,800 ug/l/96 hr /Static bioassay/; [R147] *LC50 Pimephales promelas (fathead minnow) 10,100 ug/l/96 hr /Flow-through bioassay/; [R147] *LC50 Poecilia reticulata (guppy) 33,500 ug/l/96 hr, /Static bioassay/; [R147] *LC50 Crangon crangon 10-33 mg/l/24 hr /Conditions of bioassay not specified/; [R148] *LC50 Lepomis macrochirus (bluegill) 28 mg/l/24 hr, 10 mg/l/96 hr /Conditions of bioassay not specified/; [R149] *LC50 Daphnia magna (water flea) 13 mg/l/24 hr; 7.6 mg/l/48 hr; no discernible effect = 0.78 mg/l. /Conditions of bioassay not specified/; [R150] TCAT: ?Chronic toxicity and oncogenicity were evaluated in male and female Sprague-Dawley rats (10/sex/group) exposed orally to acrylonitrile in drinking water for 2 years at concentrations of 0, 35, 85 or 210 ppm for the first 21 days and 0, 35, 100 or 300 ppm thereafter. There were significant differences between treated animals and controls in the following: water and food consumption and body weight (decreased in all treated groups), endocardial fibrosis (males at 300 ppm), and mortality (increased for all treated female groups and males at 300 ppm). There was a significant decrease in treated animals in the incidence of tumors which usually occur with increasing frequency in old age in the pituitary gland, thyroid gland, adrenal glands, pancreas and uterus. There was a significant increase of tumors in treated animals in the following organs: central nervous system (all treated groups), Zymbal gland (all treated females and males at 300 ppm), nonglandular portion of stomach (both sexes at 100 and 300 ppm), tongue (both sexes at 300 ppm), carcinoma of small intestine (males at 35 and 300 ppm, females at 100 and 300 ppm), malignant mammary tumors (females at 300 ppm), and number of animals with any mammary tumors (females at 35 and 100 ppm). There were no significant differences between treated animals and controls in hematology, urinalysis or clinical chemistry. [R151] ?Oncogenicity was evaluated in male and female Fischer 344 rats (200/sex/group) orally exposed to acrylonitrile in drinking water for 2 yrs. at concentrations of 0, 1, 3, 10, 30 or 100 ppm. There were statistically significant increases in treated animals relative to controls in the following: brain astrocytomas, combined ear canal papillomas/adenomas and carcinomas and malignant tumors (both sexes at 30 and 100 ppm, females also at 10 ppm), combined tumors (females at 300 and 100 ppm), detectable mammary masses (females at 100 ppm and males at 10 ppm), grossly detectable masses of the head (both sexes at 100 ppm and females also at 30 ppm), and squamous cell papillomas (both sexes at 30 ppm and males also at 3 and 10 ppm; there was no dose-related trend in this latter category and the overall incidence was low, 4%). There were no significant differences between treated animals and controls in the following: total mammary tumors (all female groups) and squamous cell carcinoma of the stomach (observed in only one high-level male). [R152] ?Teratogenicity was evaluated in pregnant female Sprague Dawley rats (29-39/group) orally exposed to acrylonitrile by gavage at dose levels of 0, 10, 25 or 65 mg/kg/day on gestation days 6-15. There were significant differences observed between high-dose group and control animals in the following: increased hyperexcitability and salivation, thickening of the non-glandular portion of the stomach, decreased body weight gain, increased absolute and relative liver weight, increased water intake, decreased fetal body weight and crown-rump length, increased frequency of acaudate fetuses and acaudate and short-tailed fetuses, increase in fetuses missing more than a single thoracic and lumbar vertebra (up to a maximum of missing 11 thoracic, all lumbar and all lumbar vertebrae), increase in incidence of fetuses missing more than one pair of ribs, delayed ossification of the 5th sternebrae, split 2nd sternebrae, and missing centra of cervical vertebrae. There were no significant differences observed between treated and control animals in the following: maternal mortality, pregnancy rates, litter size, fetal sex ratio, incidence or distribution of resorptions, and ossification of the skulls of fetuses. [R153] ?The mutagenicity of acrylonitrile was evaluated in bacterial Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 and yeast Saccharomyces cerevisiae tester strain D4, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Acrylonitrile was tested for mutagenicity at concentrations of 0.1, 1.0, 10, and 100 ul/plate using the overlay method. Acrylonitrile did not cause a reproducible positive response in any of the bacterial or yeast tester strains, either with or without metabolic activation. [R154] ?The ability of acrylonitrile to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced mouse liver S9 fraction. Based on preliminary toxicity tests, both nonactivated and S9-activated cultures were treated at 0.01, 0.005, 0.001, or 0.0005% which produced ranges of 88-101% and 83-103% total growth for nonactivated and S9-activated cultures, respectively, relative to negative controls. None of the nonactivated or activated cultures produced mutant frequencies significantly greater than the solvent controls. [R155] ?The mutagenicity of acrylonitrile was evaluated in bacterial Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 and in yeast S. cerevisiae D3 tester strain, both in the presence and absence of added metabolic activation by Aroclor-induced mouse liver S9 fraction. Acrylonitrile was tested at concentrations up to 5000 ug/plate using the plate incorporation method. Acrylonitrile did not cause a positive response in any of the bacterial or yeast tester strains, either with or without metabolic activation. [R156] ?The mutagenicity of acrylonitrile was evaluated in Salmonella tester strains TA1535, TA1537 and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Acrylonitrile, diluted with ethanol, was tested for mutagenicity at concentrations up to 10,000 ug/plate using the plate incorporation method. Acrylonitrile did not cause a positive response in any of the bacterial tester strains, either with or without metabolic activation. [R157] ?The fate of 14C-acrylonitrile (AC) was studied using male albino Sprague-Dawley rats (Spartan substrain, 4 and 5 rats at low- and high-dose levels, respectively) exposed by gavage to single doses of 0.1 or 10 mg AC/kg. Excreta were collected for 72 hrs, the animals sacrificed, and samples of excreta, skin, carcass, and cage wash were analyzed for radioactivity. The primary route of excretion was the urine. The percentages of the low/high dose excreted in the urine (34/67%) remaining in the body was total, 37/27%; carcass, 24/16%, skin, 13/11%. Additional AC was excreted in the feces (5/5%) and expired air as 14CO2 (5/4%) of low- and high-dose animals, respectively. Expired air of both groups contained < 0.1% H14CN. The highest tissue to plasma ratios of AC and metabolites were found in the stomach (14.3/11.3, low/high dose), red blood cells (2.2/5.2) and skin (2.1/2.7). The elimination of plasma radioactivity was biphasic by inspection and the alpha and beta phase half-lives ranged from 3.5 to 5.8 hrs and 50 to 77 hrs, respectively. At least 5 different metabolites of AC were resolvable by HPLC with 3 of these comprising > 95% of the total radioactivity. The individual proportions of these urinary metabolites were dependent on the time after dosing. The urinary metabolites were not identified, but were shown not to be acrylamide. [R158] ?The fate of 14C-acrylonitrile (AC) was studied using male albino Sprague-Dawley rats (Spartan substrain, 4/group) exposed by inhalation to nominal concentrations of 5 or 100 ppm in a "nose-only" inhalation chamber. Animals were placed in glass metabolism cages and excreta were collected for 220 hrs, the animals sacrificed, and samples of excreta, carcass, and cage wash were analyzed for radioactivity. The primary route of excretion was the urine. The percentages of the low/high dose excreted in the urine (69/82%) as well as the percentages remaining in the body (total, 19/11%) were dose dependent. Additional AC was excreted in the feces (4/3%) and expired air as 14CO2 (6/3%) of low/high-dose animals, respectively. The plasma clearance was biphasic by inspection and the alpha and beta phase half-lives for low/high doses were 1.9/3.6 hrs and 64/57 hrs, respectively. At least 5 different metabolites of AC were resolvable by HPLC with 3 of these comprising > 99% of the total radioactivity. The individual proportions of these urinary metabolites were dependent on the time after dosing. The urinary metabolites were not identified, but were shown not to be acrylamide. [R158] ?The fate of 14C-acrylonitrile (AC) was studied using male albino Sprague-Dawley rats (Spartan substrain, 1 low-dose rat each sacrificed at 2 hrs and 24 hrs after dosing, 1 high-dose rat each sacrificed at 5 and 20 min and 24 hr) dosed intravenously with single doses of 1 or 10 mg AC/kg. In the low-dose rats, the highest tissue to plasma ratios of AC and metabolites were found in the stomach (8.11 at 2 hrs after dosing and 7.36 at 24 hrs, respectively), red blood cells (3.33 and 7.16 at 2 and 24 hrs), skin (1.91 and 2.85 at 2 and 24 hrs), and kidneys (1.33 and 3.15 at 2 and 24 hrs). The concentration of radioactivity in the plasma at the 2 and 24 hr sacrifice times were 0.727 and 0.220 ugEq/ml, respectively. The stomachs of the high-dose rats were removed, dissected into glandular and nonglandular portions, and the portions analyzed for radioactivity. The amount of radioactivity in the entire stomach increased from 30.33 to 68.64 ugEq from 5 min to 24 hrs, and the percentage of radioactivity in the contents of the stomach increased from 35 to 88% over this time period. The concentration of radioactivity in the adrenal glands of the high-dose rats was high initially (53.69 ugEq/g) but decreased 13 fold by 24 hrs (4.13 ugEq/g). [R158] POPL: */Protect/ from exposure those individuals with pulmonary and liver diseases. [R47, 17] ADE: *Acrylonitrile can be readily absorbed by mouth, through intact skin, or by inhalation. [R97] *ACRYLONITRILE ... CAN BE ABSORBED THROUGH ... LUNG AND INTESTINAL MUCOSA. [R159] *AFTER ... LETHAL DOSE ... (75 MG/KG BODY WT /IV/) IN RABBITS, HYDROGEN CYANIDE CONCN IN BLOOD ROSE STEADILY UNTIL DEATH OF ANIMALS; THE THIOCYANATE CONCN IN BLOOD INCR SLIGHTLY ... AFTER SINGLE IV INJECTION OF 15 MG/KG ... ABOUT 3% OF DOSE WAS EXPIRED FOR ABOUT 1 HR AND APPROX 10% OF TOTAL DOSE WAS EXCRETED IN URINE FOR MORE THAN 48 HR AFTER ITS INJECTION. [R106] *IN GUINEA PIGS, ELIMINATION OF ACRYLONITRILE IN URINE WAS DEMONSTRATED WITHIN 24 HR AND 30 HR AFTER ORAL AND SC ADMIN, RESPECTIVELY. ... IN RATS GIVEN DOSES OF 26-40 MG/KG BODY WT, ELIMINATION OF THIOCYANATE IN URINE WAS OVER 20% OF DOSE AFTER ORAL ADMIN, 2-5% AFTER IP OR SC INJECTION AND 1% AFTER IV ADMIN. GREATER AMT OF ACRYLONITRILE IS TRANSFORMED INTO THIOCYANATE AFTER ORAL THAN AFTER IP ADMIN IN HAMSTERS AND MICE. [R107] *DISTRIBUTION OF (14)C-ACRYLONITRILE IN RAT AND CYNOMOLGUS MONKEY HAS BEEN STUDIED BY WHOLE-BODY AUTORADIOGRAPHY. RADIOACTIVITY WAS SEEN IN BLOOD, LIVER, KIDNEY, LUNG, ADRENAL CORTEX AND STOMACH MUCOSA OF RATS RECEIVING ORAL OR IV ADMIN AND MONKEYS RECEIVING ORAL ADMIN. [R160] *RATS ORALLY ADMIN 46.5 MG/KG OF LABELED ACRYLONITRILE (AN) EXCRETED 40% OF (14)C IN URINE, 2% IN FECES, 9% IN EXPIRED AIR AS (14)CO2, 0.5% AS (14)HCN, and 4.8% UNCHANGED IN 24 HR. BILE FLOW INCR 3 TIMES AFTER ADMIN AND OVER 6 HR, 27% OF THE (14)C WAS RECOVERED IN BILE. RED BLOOD CELLS RETAINED SIGNIFICANT AMOUNTS OF RADIOACTIVITY FOR MORE THAN 10 DAYS AFTER TREATMENT, WHEREAS THE (14)C ACTIVITY DECLINED SHARPLY IN PLASMA. INITIALLY, THE HIGHEST LEVELS OF RADIOACTIVITY OCCURRED IN STOMACH AND STOMACH CONTENT FOLLOWED BY INTESTINE. IN LIVER, KIDNEY, BRAIN, SPLEEN, ADRENAL, LUNG, AND HEART TISSUES, THE RADIOACTIVITY OF THE ACID SOL FRACTIONS DECLINED WHILE COVALENT BINDING TO MACROMOLECULES REMAINED UNCHANGED. IN SUBCELLULAR FRACTIONS OF LIVER, KIDNEY, SPLEEN, BRAIN, LUNG, AND HEART, 20-40% OF THE TOTAL RADIOACTIVITY WAS BOUND TO NUCLEAR, MITOCHONDRIAL, AND MICROSOMAL FRACTIONS WHEREAS IN CYTOSOL ONLY 6-14% WAS BOUND OVER 6 HR. [R161] *PHARMACOKINETICS OF 2,3-(14)C- AND 1-(14)C-ACRYLONITRILE (VCN) WAS STUDIED IN MALE SPRAGUE-DAWLEY RATS GIVEN AN ORAL DOSE OF 46.5 MG/KG. IN RATS GIVEN 2,3-(14)C-VCN ONLY 2% OF THE (14)C ACTIVITY WAS EXHALED AS (14)CO2 AND NONE WAS RECOVERED AS (14)HCN, WHEREAS RATS GIVEN (14)C-VCN EXHALED ABOUT 12% OF (14)C ACTIVITY AS (14)CO2 and 0.5% AS (14)HCN. IN THE INITIAL 24 HR, 40% OF RADIOACTIVITY FROM (14)C-VCN APPEARED IN URINE, WHILE 60% WAS RECOVERED IN THE URINE OF RATS GIVEN 2,3-(14)C-VCN. THE RED BLOOD CELLS RETAINED SIGNIFICANT AMOUNTS OF RADIOACTIVITY FROM BOTH COMPOUNDS FOR MORE THAN 10 DAYS, WHEREAS THE (14)C ACTIVITY IN PLASMA DECLINED SHARPLY. HIGHEST LEVEL OF RADIOACTIVITY FOR BOTH COMPOUNDS WAS RECOVERED IN GI. IN LIVER, KIDNEY, BRAIN, SPLEEN, ADRENAL, LUNG, AND HEART TISSUES THE UNBOUND PERCENT OF ACTIVITY DECREASED, WHILE IRREVERSIBLE PERCENT COVALENT BINDING TO MACROMOLECULES IN RELATION TO TOTAL INCREASED CONCOMITANTLY. SUBCELLULAR FRACTIONATION OF TISSUES SHOWED THAT MOST OF THE COVALENTLY BOUND RADIOACTIVITY WAS DISTRIBUTED IN NON-CYTOSOLIC FRACTIONS. COMPARED TO 1-(14)C-VCN ADMINISTERED ANIMALS, THE PERCENTAGE OF COVALENT BINDING OF 2,3-(14)C-VCN WAS SIGNIFICANTLY HIGHER EVEN 72 HR AFTER DOSING. [R162] *15 mg/kg administered by gavage to guinea pigs, 3% of dose detected in urine 24 hr after dosing and in expired air, 10% of the dose. Urinary thiocyanate accounted for 14% of dose. [R163] *Workers absorbed 0.6 mg/sq cm/hr of acrylonitrile applied to the skin of forearm. [R164] *Six groups (n= 4/group) of male Wistar rats were used to study the excretion of acrylonitrile and its metabolites after exposure to 1, 5, 10, 50, or 100 ppm acrylonitrile for 8 hr. One additional group was used as a control and was not exposed to acrylonitrile. ... Unmetabolized acrylonitrile was significantly higher during the exposure to 10 ppm than to 5 ppm (0.970 umol; 0.148 umol, respectively) and exhibited a dose dependent increase to 25.798 umol at 100 ppm. The excretion pattern of thiodiglycolic acid was similar to that of acrylonitrile. Exposures of 1 or 5 ppm acrylonitrile resulted in excretion of hydroxyethyl mercapturic acid and S-carboxymethyl cysteine. The latter metabolite was excreted in higher concentrations during acrylonitrile exposure (2.43 + or - 0.38 umol) than during the following 24 hr (1.17 + or - 0.43 umol), and excretion of cyanoethyl mercapturic acid was similar. Excretion of cyanoethyl mercapturic acid was significant, during 8 hr exposure, at 5 ppm (1.04 + or - 0.52 umol) compared to 1 ppm (0.18 + or - 0.01 umol) exposure. [R165] *When volunteers were exposed to an atmosphere containing 20 mg/cu m acrylonitrile for up to 4 hours, retention in the respiratory tract was 46 + or - 1.6%, which did not change significantly during the experimental period. [R166] *Workers exposed to 0.13 ppm (0.3 mg/cu m) acrylonitrile vapor in a factory excreted unchanged acrylonitrile in their urine, the amounts being greater at the end of the exposure period, declining rapidly thereafter until the beginning of the next workday. The amounts excreted in samples taken during the working week or on the following two days off ranged from 2 to 152 ug acrylonitrile/g creatinine. [R166] METB: *ACRYLONITRILE IS METABOLIZED BY MAMMALS (MOUSE, RAT, HAMSTER, GUINEA PIG, RABBIT, DOG, MONKEY) TO CYANIDE, WHICH IS THEN TRANSFORMED TO THIOCYANATE AND ELIMINATED AS SUCH IN URINE. THERE IS MARKED DISAGREEMENT AS TO WHAT PERCENTAGE IS THUS METABOLIZED, AND VALUES FROM 4-30% HAVE BEEN REPORTED. [R107] *TWO MAJOR METABOLITES IDENTIFIED IN THE URINE OF RATS WERE THIOCYANATE AND N-ACETYL-S-(2-CYANOETHYL)CYSTEINE. A THIRD WAS TENTATIVELY IDENTIFIED AS 4-ACETYL-3-CARBOXY-5-CYANOTETRAHYDRO-1,4-2H-THIAZINE. ACRYLONITRILE WAS NOT FOUND IN THE URINE. [R167] *TWO TYPES OF MERCAPTURIC ACIDS IDENTIFIED IN URINE OF RATS WERE N-ACETYL-S-(2-HYDROXYETHYL)-L-CYSTEINE AND N-ACETYL-S-(2-CYANOETHYL)-L-CYSTEINE. FORMATION OF MERCAPTURIC ACIDS IS BY DIRECT CONJUGATION AND VIA INTERMEDIATE OXIDN PROCESS. [R168] *IN BRAIN AND LIVER, THE ENZYMES INVOLVED IN THE METABOLISM OF ACRYLONITRILE WERE LOCALIZED IN THE MICROSOMAL FRACTIONS. DUE TO LIMITED RATE OF METABOLISM IN THE BRAIN, HEPATIC ENZYMES WERE MOSTLY USED. INDUCTION OF ACRYLONITRILE MICROSOMAL METABOLISM WAS OBSERVED WITH 3-METHYLCHOLANTHRENE TREATMENT, BUT WAS NOT AS SUBSTANTIAL AS THAT FROM PHENOBARBITAL OR AROCLOR 1254. DECREASING THE HEPATIC CYTOCHROME P450 CONTENT WITH CARBONYL CHLORIDE RESULTED IN PARALLEL DECR IN THE RATE OF ACRYLONITRILE METABOLISM. [R169] *METABOLISM OF ACRYLONITRILE USING SUBCELLULAR FRACTIONS ISOLATED FROM RATS AND HUMANS WAS STUDIED. RAT LIVER MICROSOMES OR RECONSTITUTED CYTOCHROME P450 SYSTEM CATALYZED THE MIXED-FUNCTION OXIDATION OF ACRYLONITRILE TO 2-CYANOETHYLENE OXIDE. THIS EPOXIDE WAS FOUND TO SERVE AS A SUBSTRATE FOR MICROSOMAL EPOXIDE HYDROLASE. HYDROGEN CYANIDE WAS RELEASED DURING HYDROLYSIS OF 2-CYANOETHYLENE OXIDE OR THE REACTION OF THE EPOXIDE WITH REDUCED GLUTATHIONE. RAT LIVER CYTOSOL PREPN CONTAINED GLUTATHIONE S-TRANSFERASE ACTIVITY TOWARDS ACRYLONITRILE AND GREATER ACTIVITY WITH 2-CYANOETHYLENE OXIDE AS SUBSTRATE. CYTOSOL PREPN FROM RAT BRAIN AND HUMAN LIVER HAS NO DETECTABLE GLUTATHIONE S-TRANSFERASE ACTIVITY TOWARDS ACRYLONITRILE BUT DID EXHIBIT SOME ACTIVITY TOWARDS 2-CYANOETHYLENE OXIDE. [R170] *Acrylonitrile was metabolized to thiocyanate more effectively by mice than by rats following oral, ip, and iv administration. [R134] */A study was conducted to determine/ the effect of administration of vitamins B1 or B2 plus cysteine to rats exposed to acrylonitrile vapor over a long period. ... Urinary excretion of thiocyanate decreased with ... treatment. ... A decline of alcohol dehydrogenase activity /was noted/ upon administration of vitamin B1 or B2 plus cysteine. [R171] *Quantitative and qualitative data were obtained for thiocyanate, 2-cyanoethylmercapturic acid, and 2-hydroxyethylmercapturic acid formation following ip, iv, or inhalation exposure of acrylonitrile at varied doses. Deacetylation of mercapturic acid and HPLC measurement of the resultant cysteine conjugate was used to assess 2-cyanoethylmercapturic acid and 2-hydroxyethylmercapturic acid. For ip and iv administration, four groups of male Sprague-Dawley rats (5/group) were given acrylonitrile in saline at doses of 0, 0.6, 3.0, or 15.0 mg/kg. For inhalation studies, rats were exposed to target concentrations of 0, 4, 20, or 100 ppm for 6 hr. For all experiments, urine was collected 24 hr after exposure and analyzed for acrylonitrile metabolites. Following ip administration, 2-cyanoethylmercapturic acid, 2-hydroxyethylmercapturic acid, and thiocyanate represented 50-54% of administered acrylonitrile with 2-cyanoethylmercapturic acid representing the major metabolite. The metabolism of acrylonitrile following iv administration was quantitatively and qualitatively similar to ip administration with the exception that no measurable urinary metabolites were detected for the 0.6 mg/kg dose level. For both ip and iv routes the proportion of urinary 2-cyanoethylmercapturic acid increased with dose. A qualitative difference in acrylonitrile disposition following inhalation exposure was demonstrated by thiocyanate representing the major metabolite in rats exposed to 20 or 200 ppm. [R172] *Forty-seven percent of a single oral dose of acrylonitrile (30 mg/kg) was excreted as seven urinary metabolites. The three major metabolites in order of excretion are thiocyanate, N-acetyl-S-(2-cyanoethyl)cysteine, and a thiazine. Eight-hour exposure to 4.2 ppm of acrylonitrile produced a mean urinary thiocyanate excretion of 11.4 mg/l. However, the presence of hydrogen cyanide in smoke indicates that plasma levels of thiocyanate and cyanide are higher in smokers than in nonsmokers (ie, 1.5 mg/ml versus 0.58 mg/ml, respectively). [R83, 1486] *Acrylonitrile is metabolized to the reactive cyanoethylene oxide (CEO) (also called glycidonitrile), mainly by CYP2E1, but also by other forms of human cytochrome p450. [R166] BHL: */Acrylonitrile has a/ half-life in /bluegill/ tissue between 4 and 7 days. [R173] ACTN: *ACRYLONITRILE-INDUCED ADRENAL NECROSIS IS ASSOCIATED WITH THE EARLY DEPLETION OF ADRENAL GLUTATHIONE AND ELEVATION OF ADRENAL DOPAMINE. THESE BIOCHEMICAL EVENTS COULD RESULT IN INCR SUSCEPTIBILITY TO FREE RADICAL-MEDIATED LIPID PEROXIDATION WHICH MAY PLAY A ROLE IN PATHOGENESIS OF ADRENAL INJURY CAUSED BY ACRYLONITRILE. [R174] *Acrylonitrile has been shown to cyanoethylate ring nitrogen atoms of certain minor tRNA nucleosides, ribothymidine, and thymidine. [R175] *ADMIN IP TO RATS @ DOSE OF 100 MG/KG BODY WT ... /IT/ INHIBITS NON-COMPETITIVELY ACTIVITY OF BRAIN, KIDNEY, AND LIVER CYTOCHROME OXIDASE; WHEN INJECTED SC AT DOSE OF 100-120 MG/KG BODY WT IT DECR RATIO BETWEEN OXIDIZED AND REDUCED NUCLEOTIDES IN BRAIN AND BLOOD; WHEN GIVEN ... IV DOSE OF 150 MG/KG ... REDUCES ... GLUTATHIONE IN LIVER, LUNG, KIDNEYS, ADRENALS, AND BRAIN OF RATS. [R106] INTC: *Hydrogen cyanide and carbon monoxide enhance acrylonitrile toxicity in experimental animals. [R176] *WHEN SODIUM THIOSULFATE WAS GIVEN IN MULTIPLE INJECTIONS, IT PROTECTED MICE AGAINST DEATH BY PROPIONITRILE. [R177] *The toxic mechanism of nitriles and the effect of metabolic modifiers in mice were studied in relation to their physicochemical properties. All the test nitriles liberated cyanide both in vivo and in vitro, with the exception of benzonitrile, although the extent of liberation and the effect of carbon tetrachloride pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into 3 groups. In group 1, acute toxicity was greatly reduced by carbon tetrachloride pretreatment, in group 2, toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher at death in the brains of mice given group 1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. The relation between log (1/LD50) and log p for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear. For most nitriles, the in vitro metabolism was inhibited when the incubation mixture contained either SKF-525A, carbon monoxide, or microsomes from mice treated with carbon tetrachloride. When mice were closed with ethyl alcohol, metabolic enhancement of nitriles was seen compared with the control. However, ethyl alcohol, when added to the incubation mixture, inhibited the in vitro metabolism of nitriles. /Nitriles/ [R178] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Acrylonitrile's production and use in acrylonitrile-butadiene-styrene/styrene-acrylonitrile resins, acrylamide, nitrile elastomers, polymers, polyols, barrier resins, and carbon fibers may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 109 mm Hg at 25 deg C indicates acrylonitrile will exist solely as a vapor in the ambient atmosphere. Vapor-phase acrylonitrile will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone; the half-lives for these reactions in air are estimated to be 4 and 83 days, respectively. Acrylonitrile does not absorb light > 290 nm and is therefore not susceptible to direct photolysis. If released to soil, acrylonitrile is expected to have very high mobility based upon an estimated Koc of 33. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 1.38X10-4 atm-cu m/mole. Acrylonitrile may volatilize from dry soil surfaces based upon its vapor pressure. At concn up to 100 ppm, complete degradation of acrylonitrile occurred in < 2 days in soil. If released into water, acrylonitrile is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Acrylonitrile completely degraded in river water in 6 days and degraded completely in 20 days in another study, requiring less time for degradation with acclimation. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4 hours and 4 days, respectively. A BCF of 48 for bluegills suggests the potential for bioconcentration in aquatic organisms is moderate. Acrylonitrile was stable at pH 4 to 10 for 23 days indicating that hydrolysis is negligible under these conditions. Occupational exposure to acrylonitrile may occur through inhalation and dermal contact with this compound at workplaces where acrylonitrile is produced or used. Monitoring data indicate that the general population may be exposed to acrylonitrile via inhalation of ambient air and dermal contact with products containing acrylonitrile. (SRC) ARTS: *Acrylonitrile's production and use in acrylonitrile-butadiene-styrene/styrene-acrylonitrile resins, acrylamide, nitrile elastomers, polymers, polyols, barrier resins, and carbon fibers(1) may result in its release to the environment through various waste streams(SRC). Acrylonitrile is found in auto exhaust(2). Residual amounts are reported to be released from clothing, furniture made with polyacrylic fibers and to leach from polyacrylonitrile packaging material(3). Acrylonitrile monomer is released during the burning of polyacrylonitrile plastic and cigarette smoke(3). [R179] *... Only people living near chemical factories or work sites are likely to be exposed to measurable amounts of acrylonitrile in air and water. ... Member of the general population may also be potentially exposed to acrylonitrile through the consumption of acrylonitrile-contaminated food. [R180] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 33(SRC), determined from a log Kow of 0.25(2) and a regression-derived equation(3), indicates that acrylonitrile is expected to have very high mobility in soil(SRC). Volatilization of acrylonitrile from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 1.38X10-4 atm-cu m/mole(4). The potential for volatilization of acrylonitrile from dry soil surfaces may exist(SRC) based upon a vapor pressure of 109 mm Hg(5). At concn up to 100 ppm, complete degradation of 14C-acrylonitrile occurred in < 2 days in a Londo soil(6). Greater than 50% of the radioactivity was recovered as 14C-carbon dioxide following 6 days of incubation. Transient formation of acrylamide and acrylic acid as intermediates of degradation were observed(6). Similar results were obtained in studies conducted with Tappan loam and sand(6). Acclimation of the microorganisms was required before degradation of 100 ppm acrylonitrile in sand(6). Degradation of higher concn (500 and 1,000 ppm in Londo soil) was relatively slow and may be due to inhibitory effects of the parent compound(6). [R181] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 33(SRC), determined from a log Kow of 0.25(2) and a regression-derived equation(3), indicates that acrylonitrile is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1.38X10-4 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 4 hours and 4 days, respectively(SRC). According to a classification scheme(4), a BCF of 48 for bluegills(5) suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Biodegradation of acrylonitrile has been demonstrated in wastewater, activated sludge, and various microbial cultures free from other living organisms(6). Acrylonitrile completely degraded in Mississippi river water in 6 days(7) and degraded completely in 20 days in another study using river water, requiring less time for degradation with acclimation(8). [R182] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acrylonitrile, which has a vapor pressure of 109 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase acrylonitrile is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC); the half-life for reaction with hydroxyl radicals in air is estimated to be 4 days(SRC), calculated from its rate constant of 4.10X10-12 cu cm/molecule-sec at 25 deg C(3); the half-life for reaction with ozone in air is estimated to be 83 days(SRC), calculated from its rate constant of 1.38X10-19 cu cm/molecule-sec at 25 deg C(4). Acrylonitrile (10 ppm) was stable at pH 4 to 10 for 23 days indicating that hydrolysis is negligible under these conditions(5). Acrylonitrile does not absorb light > 290 nm and is therefore not susceptible to direct photolysis(6). [R183] BIOD: *AEROBIC: Biodegradation of acrylonitrile has been demonstrated in wastewater, activated sludge, and various microbial cultures free from other living organisms(1). Enzyme-catalyzed hydrolysis of nitriles, such as acetonitrile, has been shown to proceed by two distinct routes(2,3); a nitrilase transforms the nitriles directly into acids plus ammonium ion, or a nitrile hydratase forms the amide which is hydrolyzed to acid plus ammonium ion by amidase(2,3). Acrylonitrile concns of 5 and 10 ppm in wastewater were completely degraded within 7 days in static-culture flask screening studies(4). In studies using activated sludge inocula, > 95% degradation of acrylonitrile and > 70% of theoretical BOD removal was reported after 21 days of acclimation in a screening study(5). In a waste water treatment plant, 30% of theoretical BOD removal of acrylonitrile was reported after 10 days(6). Using a bench-scale continuous flow reactor, > 99% degradation of acrylonitrile and 30% of theoretical BOD removal was reported(7). Other studies, report 0 and 38% of theoretical BOD removal after 5 and 20 days respectively(8). Acrylonitrile completely degraded in Mississippi river water in 6 days(9) and degraded completely in 20 days in another study using river water, requiring less time for degradation with acclimation(10). In river water, 65% theoretical BOD was removed in 5 days after 27 days acclimation(11). At concn up to 100 ppm, complete degradation of 14C-acrylonitrile occurred in < 2 days in a Londo soil(1). Greater than 50% of the radioactivity was recovered as 14C-carbon dioxide following 6 days of incubation. Transient formation of acrylamide and acrylic acid as intermediates of degradation were observed(1). Similar results were obtained in studies conducted with Tappan loam and sand(1). Acclimation of the microorganisms was required before degradation of 100 ppm acrylonitrile in sand(1). Degradation of higher concn (500 and 1,000 ppm in Londo soil) was relatively slow and may be due to inhibitory effects of the parent compound(1). [R184] *ANAEROBIC: The biodegradation of acrylonitrile is reported to occur readily at concns < 20 mg/l during anaerobic digestion processes operated in municipal sewage treatment facilities(1). A Pseudomonas-containing sludge, used for the treatment of industrial acrylonitrile wastes, could degrade up to 35% of the pollutant at concentration levels of 500 mg/l(1). In another study, acrylonitrile was poorly degraded in a reactor under anaerobic conditions with a 2-10 day retention time; only 17% utilization was reported after 110 days of acclimation(2). [R185] ABIO: *The rate constant for the vapor-phase reaction of acrylonitrile with photochemically-produced hydroxyl radicals is 4.10X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 4 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). The rate constant for the vapor-phase reaction of acrylonitrile with photochemically-produced ozone is 1.38X10-19 cu cm/molecule-sec at 25 deg C(2). This corresponds to an atmospheric half-life of about 83 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(SRC). Acrylonitrile (10 ppm) was stable at pH 4 to 10 for 23 days indicating that hydrolysis is negligible under these conditions(3). Acrylonitrile does not absorb light > 290 nm and is therefore not susceptible to direct photolysis(4). [R186] BIOC: *The whole body BCF for bluegills exposed to acrylonitrile for 28 days (or until equilibrium was obtained) in a flowing water system was 48(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). [R187] KOC: *The Koc of acrylonitrile is estimated as 33(SRC), using a measured log Kow of 0.25(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that acrylonitrile is expected to have very high mobility in soil(SRC). [R188] VWS: *The Henry's Law constant for acrylonitrile is 1.38X10-4 atm-cu m/mole(1). This Henry's Law constant indicates that acrylonitrile is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 4 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). Acrylonitrile's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of acrylonitrile from dry soil surfaces may exist(SRC) based upon a vapor pressure of 109 mm Hg(3). The evaporation half-life for acrylonitrile is about 13 hours(4). [R189] WATC: *DRINKING WATER: Acrylonitrile was detected but not quantified in one or more water supplies in a 5 city survey of US drinking water with known sources of contamination(1). [R190] *SURFACE WATER: Only 5% of samples had detectable quantities of acrylonitrile in EPA's Water Quality Database (US-914 STORET)(1). Acrylonitrile was not detected at 298 of 298 surface water stations in the United States(2). [R191] *GROUNDWATER: Screening of 1174 community wells and 617 private wells in Wisconsin during the early 1980's did not detect any acrylonitrile(1). Acrylonitrile was not detected at 1,401 of 1,401 groundwater stations in the United States(2). [R192] EFFL: *1.6% of samples from 1,278 STORET stations (EPA Water quality data base) had detectable quantities of acrylonitrile(1). Acrylonitrile was detected in the treated wastewater from the following industries (mean concn): iron and steel manufacturing (1,600 ppb), foundries (23 ppb), organic chemicals/plastics manufacture (93 ppb), and rubber processing (10 ppb)(2). In Rio Blanco, CO, the concn of acrylonitrile in oil shale retort outgas was 0.5-2 ppm(3). At acrylic fiber manufacturing plant in the United States, the concn of acrylonitrile in the effluent was 0.1 g/l(4). At a chemical and latex manufacturing plant in Louisville, KY, acrylonitrile was detected but not quantified in effluents(4). Sources of atmospheric emissions of acrylonitrile from production facilities include absorber vents (0.44 g/kg), flare stacks (0.5 g/kg), product loading (0.14 g/kg), fugitive emissions (0.26 g/kg), storage tanks (0.81 g/kg), deep well ponds (0.10 g/kg), and incinerators (negligible)(5). [R193] SEDS: *Soil samples from LA, NJ, TX, AL, SC, VA, and WV analyzed for acrylonitrile had concns ranging from 0-50 ug/kg(1). Acrylonitrile was not detected in all but one soil sample at 11 industrial sites and in sediment at 4 industrial sites in the US(2). The one positive soil sample was at the detection limit of 0.5 ppb(2). Acrylonitrile was not detected in 351 samples from EPA Water Quality database (STORET) in the United States(3). [R194] ATMC: *Annual average atmospheric concn of acrylonitrile ranged up to 20.0 ug/cu m. [R146, p. 4-1] *Atmospheric acrylonitrile concn was sampled at 11 industrial sites, ranging from an average of 0.1-249 ug/cu m, with the highest reading at 325 ug/cu m. [R195] *URBAN/SUBURBAN: Air samples collected from LA, NJ, TX, AL, SC, VA, and WV were found to contain acrylonitrile at concns ranging from 1.1-325 ug/cu m(1). As part of EPA's VOC-AMBI database, the avg outdoor concn of acrylonitrile was determined to be 4.016 ppb in the United States(2) [R196] *SOURCE DOMINATED: At 12 sites in the United States (43 samples), the mean concn of acrylonitrile was 970 parts per trillion (range, 46-110,000 parts per trillion)(1). [R197] RTEX: *INHALATION IS ... MOST IMPORTANT ROUTE OF ABSORPTION IN THE INDUSTRIAL CONTEXT. SKIN ABSORPTION CAN ALSO TAKE PLACE BUT IS SLOWER TO CAUSE EFFECTS. LEATHER GLOVES AND FOOTWEAR READILY ABSORB ACRYLONITRILE AND CAN LEAD TO SKIN ABSORPTION ... . [R62, 55] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 81,691 workers (27,358 of these are female) are potentially exposed to acrylonitrile in the US(1). Occupational exposure to acrylonitrile may occur through inhalation and dermal contact with this compound at workplaces where acrylonitrile is produced or used(SRC). Monitoring data indicate that the general population may be exposed to acrylonitrile via inhalation of ambient air and dermal contact with products containing acrylonitrile(SRC). Workplace air at an acrylic fiber plant, where large fraction of workers complained of symptoms of illness, had an acrylonitrile concn of 3-20 mg/cu m(2). Air in old thermosetting plastics molding plant where workers had adverse symptoms had an acrylonitrile concn of 1.4 mg/ cu m(2). Several steps in production of acrylonitrile-butadiene-styrene copolymer have been identified as potential employee exposure sources to acrylonitrile(3). Between the years 1980-1983, the range of avg exposures to acrylonitrile ranged from 0.01 to 1.85 ppm for workers at 8 acrylonitrile production facilities located in Virginia, Ohio, Texas, Louisiana, Florida, and Alabama(4). The general population living within 30 km of an industrial plant which manufactures or uses acrylonitrile may be exposed to atmospheric levels as high as 20 ug/cu m(5). [R198] AVDI: *Average intake of acrylonitrile in the United Kingdom during 1982 was 0.3 ug/person per day. [R199] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers acrylonitrile to be a potential occupational carcinogen. /SRP: No IDLH specified/ [R32, 8] OSHA: *The employer shall assure that no employee is exposed to an airborne concentration of acrylonitrile in excess of two (2) parts acrylonitrile per million parts of air (2 ppm) as an eight (8)-hr TWA. [R200] *The employer shall assure that no employee is exposed to an airborne concentration of acrylonitrile in excess of ten (10) ppm as averaged over any fifteen (15)-min period during the working day. [R201] *The employer shall assure that no employee is exposed to skin contact or eye contact with liquid acrylonitrile. [R202] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 ppm. [R32, 8] *Recommended Exposure Limit: 15 Min Ceiling Value: 10 ppm. Skin. [R32, 8] *NIOSH considers acrylonitrile to be a potential occupational carcinogen. [R32, 8] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R32, 8] TLV: +8 hr Time Weighted Avg (TWA) 2 ppm, skin. [R81, 2002.13] +A3: Confirmed animal carcinogen with unknown relevance to humans. [R81, 2002.13] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R81, 2002.6] OOPL: *France: 9 mg/cu m TWA, 34 mg/cu m STEL; Hungary: 0.5 mg/cu m TWA, 0.5 mg/cu m STEL; Japan: 45 mg/cu m TWA; Sweden: 4 mg/cu m TWA, 13 mg/cu m STEL; USSR: 0.5 mg/cu m STEL. /From table/ [R203] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 10 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 35 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 75 ppm (not life threatening) up to 1 hr exposure. [R204] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Acrylonitrile is produced, as an intermediate or a final product, by process units covered under this subpart. [R205] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Acrylonitrile is included on this list. [R206] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.15 ug/l [R207] +(FL) FLORIDA 8 ug/l [R207] +(NH) NEW HAMPSHIRE 0.06 ug/l [R207] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Cyanides/ [R208] +Acrylonitrile is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R209] +The levels for acrylonitrile through ingestion of contaminated water and contaminated aquatic organisms ... which may result in incremental increase of cancer risk over the lifetime are estimated at 1X10-5, 1X10-6, and 1X10-7. The corresponding criteria are 0.58 ug/l, 0.058 ug/l, and 0.006 ug/l, respectively. For consumption of aquatic organisms only, excluding consumption of water, the levels are 6.5 ug/l, 0.65 ug/l, and 0.065 ug/l, respectively. [R210] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R211] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Acrylonitrile is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 10,000 lbs. [R212] RCRA: *U009; As stipulated in 40 CFR 261.33, when acrylonitrile, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R213] FIFR: *Classified for restricted use, limited to use by or under the direct supervision of a certified applicator. Acrylonitrile used in combination with carbon tetrachloride, not as the sole active ingredient. All uses restricted. Criteria based on accident history of both acrylonitrile and carbon tetrachloride products. [R214] *Criteria Possibly Met or Exceeded: Carcinogenicity, developmental toxicity, and neurotoxicity. Voluntary cancellation of three products only. [R215] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Samples of natural, waste, and drinking water are collected in narrow-mouth bottles filled to overflowing to prevent aeration and stored head-space free at 4 deg C. If free or combined chlorine is present (up to 5 ppm) add 10 mg thiosulfate/40 ml sample. Analyze samples within 14 days. [R146, p. 9-2] *NIOSH Method 1604. Analyte: Acrylonitrile. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min. Sample Size: 10 liters. Shipment: Routine. Sample Stability: At least 7 days at 25 deg C. [R216] *OSW Method 31. Sampling Method for Volatile Organic Compounds. This method is used to determine volatile organic compounds in gaseous emissions from a wide variety of stationary sources including hazardous waste incinerators to an upper concentration limit of 1.5 ppm. [R217] *OSW Method 5031: Volatile, Nonpurgeable, Water-Soluble Compounds by Azeotropic Distillation. This method describes a procedure for separation of nonpurgeable, water soluble, and volatile organic compounds in aqueous samples or leachates from solid matrices using azeotropic distillation. [R217] ALAB: *Solid wastes can be analyzed for acrylonitrile using GC/MS analysis of 100 ppb with 8% precision and 89% recovery. [R146, p. 9-3] *NIOSH Method 1604. Analyte: Acrylonitrile. Matrix: Air. Procedure: GC, flame ionization detection. For acrylonitrile this method has an estimated detection limit of 0.001 mg for 20 liter sample. The precision/RSD is 0.06 at 0.016 mg/sample and the recovery is 94%. Applicability: The working range is 0.7 to 46 ppm (1.5 to 100 mg/cu m) for a 10 liter air sample. Interferences: None known. [R216] *Gas chromatographic method is used for determination of acrylonitrile in food including cold pack cheese, peanut butter, honey butter, and margarine at equal to or greater than 15 ppb. [R218] *EPA Method 603. Purge and Trap Gas Chromatography Method with flame ionization detection for the determination of acrolein and acrylonitrile in municipal and industrial discharges. Under the prescribed conditions for acrylonitrile, the method has a detection limit of 0.5 ug/l and an average recovery of 104.0 ug/l for industrial wastewater at a spike concentration of 100 ug/l. [R219] *EPA Method 1624. Isotope Dilution Purge and Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of volatile organic compounds in municipal and industrial discharges. By adding a known amount of an isotopically labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If isotopically labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, acrylonitrile has a minimum detection limit of 9 ug/kg in solids at high level and a minimum level of 10 ug/l in water with no interferences present. [R220] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). This method is applicable to various type of samples, regardless of water content, including ground water, aqueous sludge, caustic liquors, acid liquors, waste solvents, and oily waste. Detection limit unspecified. [R217] *OSW Method 8316. Determination of Acrylamide, Acrylonitrile and Acrolein by High Performance Liquid Chromatography (HPLC). Detection limit unspecified. Detection limit = 20 ug/l. [R217] *OSW Method 8015B. Nonhalogenated Organics Using GC/FID. Detection limit unspecified. [R217] *OSW Method 8030A. Acrolein and Acrylonitrile By Gas Chromatography. This method is used to determine the concentration of acrolein and acrylonitrile in water. Detection limit = 0.50 ug/l. [R217] *OSW Method 8031: Determination of Acrylonitrile in Water by Gas Chromatography. This Method is used to determine the concentration of acrylonitrile in water and other matrices. Detection limit = 10 ug/l. [R217] *OSW Method 8240B-S: Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). This method is applicable to various types of samples regardless of water content. Detection limit unspecified. [R217] *OSW Method 8260A: Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit unspecified. [R217] *OSW Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. This method is used to determine volatile organic compounds in a variety of solid waste matrices. Detection limit unspecified. [R217] *OSW Method 5041. Analysis of Sorbent Cartridges From Volatile Organic Sampling Train by using the Wide-Bore Capillary Column Technique. Detection limit = 13 ng. [R217] CLAB: *A GC METHOD FOR DETERMINING ACRYLONITRILE IN RAT PLASMA AT NG LEVELS IS DESCRIBED. [R221] *ACRYLONITRILE WAS DETERMINED IN BLOOD AND URINE OF WORKERS BY HEADSPACE GC ON CHROMOSORB 102 WITH NITROGEN AS CARRIER GAS. DETECTION LIMIT WAS 0.05 UG/ML; STD DEVIATION WAS 5%. [R222] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Health Assessment Document: Acrylonitrile (1983) EPA 600/8-82-007F. USEPA; Ambient Water Quality Criteria Doc: Acrylonitrile (Draft) (1980). NIOSH; Recommended Standard for Occupational Exposure to Acrylonitrile DHEW Pub No 78-116 (1978). WHO; Environ Health Criteria: Acrylonitrile (1983). Homan ER; Clinical and Experimental Toxicol of Cyanides, Bristol, UK 1-21 pages (1987). Reactions, industrial processes, and materials with potential for exposure to cyanide compounds were discussed in this overview on the toxicology of cyanides. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC (2000) DHHS/ATSDR; Toxicological Profile for Acrylonitrile TP-90/02 (1990) The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that acrylonitrile is on the list of post peer review technical reports in progress. Route: gavage; Species: mice. NTP TR No 506. [R223] HIST: *Concentration of acrylonitrile in the ground water increased when it rained several months after an accidental spillage occurred. The persistence of acrylonitrile in the water of wells located within 30 m of a spill of 91,000 l of acrylonitrile from a tank car was followed for about 1 year. No attempt was made to contain or clean up the spill for 108 days and water from 5 wells showed acrylonitrile concentrations ranging from 46 up to 3520 mg/l during this time. On day 108, contaminated soil was removed, but levels of acrylonitrile actually increased in some wells. Levels decreased after about 170 days, when contaminated groundwater was pumped away; a sample of this groundwater contained an acrylonitrile concentration of 144 mg/l. It is possible that the high concentration of acrylonitrile caused by the spill was lethal to bacteria, precluding biological degradation. However, no quantitative measurements of soil or water organisms were made. [R224] SO: R1: Weiss, G.; Hazardous Chemicals Handbook. 1986, Noyes Data Corporation, Park Ridge, NJ 1986. 18 R2: USEPA; Ambient Water Quality Criteria Doc: Acrylonitrile (Draft) p.C-1 (1980) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V1 (1991) R4: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Acrylonitrile (107-13-1). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of February 5, 2001. R5: USEPA; Health Assessment Document: Acrylonitrile p.3-6 (1983) EPA 600/8-82-007F R6: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. R7: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 441 R8: USEPA; Health Assessment Document: Acrylonitrile p.3-1 (1983) EPA 600/8-82-007F R9: USEPA; Ambient Water Quality Criteria Doc: Acrylonitrile (Draft) p.C-2 (1980) R10: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 24 R11: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 24 R12: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R13: SRI R14: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. R15: Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 73 (1979) R17: CHEMICAL PRODUCTS SYNOPSIS: Acrylonitrile, 1985 R18: Kavaler AR; Chemical Marketing Reporter 235 (10): 50 (1989) R19: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V1 (91) R20: ChemExpo; Chemical profile for Acrylonitrile (107-13-1). May 8, 2000. Available from the Database Query page http://www.chemexpo.com/news/PROFILE000508.cfm as of Dec 27, 2000. R21: Suta BE; Assessment of Human Exposures to Atmospheric Acrylonitrile, EPA Contract No 68-02-2835 p.2 (1979) R22: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.264 R23: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 19 R24: Chem and Engineering News 70 (26): 36 (6/29/92) R25: Chem and Engineering News 71 (15): 11 (4/12/93) R26: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 443 R27: Chem and Engineering News 72 (15): 13 (4/11/94) R28: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1985 p.1-574 R29: Suta BE; Assessment of Human Exposures to Atmospheric Acrylonitrile, EPA Contract No. 68-02-2835, p.13 (1979) R30: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1985 p.2-80 R31: ChemExpo; Chemical profile for Acrylonitrile(107-13-1). May 8, 2000. Available from the Database Query page http://www.chemexpo.com/news/PROFILE000508.cfm as of Dec 27, 2000. R32: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R33: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R34: WHO; Environ Health Criteria: Acrylonitrile p.15 (1983) R35: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R36: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 5 R37: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. 4864 R38: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-289 R39: Miller LM, Villaume JE; Investigation of Selected Potential Environmental Contaminants EPA 560/2-78-003 (1978) as cited in USEPA; Health Assessment Document: Acrylonitrile p.3-2 (1983) EPA 600/8-82-007F R40: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R41: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-465 R42: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R43: 29 CFR 1910.1045 (7/1/85) R44: Bocek K; Experientia Suppl 23: 231-40 (1976) R45: Kwok ESC, Atkinson R: Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. 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New York: Van Nostrand Rheinhold, 1987. 3 R52: USEPA; Ambient Water Quality Criteria Doc: Acrylonitrile (DRAFT) p.C-15 (1980) R53: USEPA; Ambient Water Quality Criteria Doc: Acrylonitrile (DRAFT) p.C-103 (1980) R54: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V1 415 R55: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R56: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.12 R57: Armour, M.A. Hazardous Laboratory Chemicals Disposal Guide. Boca Raton, FL: CRC Press Inc., 1991. R58: ASTM; Compilation of Odor and Taste Threshold Values Data p.8 (1978) R59: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R60: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. 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Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 1181 R219: 40 CFR 136, App. A (7/1/91) R220: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.15 (1991) OST Pub 21W-4005 R221: FRESHOUR NL, MELCHER RG; J ANAL TOXICOL 7 (2): 103-5 (1983) R222: BENCHEV K ET AL; KHIG ZDRAVEOPAZ 25 (1): 87-9 (1982) R223: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 R224: WHO; Environ Health Criteria: Acrylonitrile p.29-30 (1983) RS: 175 Record 35 of 1119 in HSDB (through 2003/06) AN: 177 UD: 200211 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACROLEIN- SY: *Acquinite-; *ACRALDEHYDE-; *ACROLEINA- (ITALIAN); *ACROLEINE- (DUTCH,FRENCH); *ACRYLALDEHYDE-; *ACRYLALDEHYD- (GERMAN); *ACRYLIC-ALDEHYDE-; *AI3-24160-; *AKROLEINA- (POLISH); *AKROLEIN- (CZECH); *ALDEHYDE-ACRYLIQUE- (FRENCH); *ALDEIDE-ACRILICA- (ITALIAN); *Allyl-aldehyde-; *Caswell-No-009-; *Crolean-; *EPA-Pesticide-Chemical-Code-000701-; *NSC-8819-; *Papite-; *PROPENAL-; *2-PROPENAL-; *PROP-2-EN-1-AL-; *PROPENAL- (CZECH); *2-PROPEN-1-ONE- RN: 107-02-8 MF: *C3-H4-O SHPN: UN 1092; Acrolein, inhibited IMO 3.1; Acrolein, inhibited STCC: 49 064 10; Acrolein, inhibited HAZN: P003; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *It was produced commercially starting in 1938 by the vapor-phase condensation of acetaldehyde and formaldehyde. In 1959, the direct oxidation of propylene in presence of a catalyst became the preferred commercial process, and variations of this process are the only methods currently used commercially. The acetaldehyde-formaldehyde route was last used in the USA in 1970. [R1] *Prepared ... by passing glycerol vapors over magnesium sulfate heated to 330-340 deg C. [R2] *... /Oxidation of/ propylene with bismuth-phosphorus-molybdenum catalyst. [R3, 17] *Lab prepn by heating mixt of anhydrous glycerol, acid potassium sulfate and potassium sulfate in presence of ... hydroquinone and distilling in dark. [R2] IMP: *Impurities include water, 4.0% max, and small amounts of acetaldehyde and propionaldehyde. [R4] *Propionaldehyde and acetone are the principal carbonyl impurities in freshly distilled acrolein. [R5] FORM: *USEPA/OPP PC Code 000701; Trade Names: Aqualin, Crolean, Magnacide H, Acquinite, NSC 8819. [R6] *MAGNACIDE H LIQUID HERBICIDE--92% ACROLEIN. AQUALINE HERBICIDE (SHELL)--85% ACROLEIN. [R7] *Grade: Technical. [R3, 17] *Acrolein is available in the USA as a commercial grade with minimum purity of 92% and contains 0.1-0.25% hydroquinone as an inhibitor. [R4] *Technical grade is 92-97%. [R8, 18] MFS: *Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817; (203) 794-2000; Production site: Taft, LA 70057 [R9] *Degussa-Huls Corp., 65 Challenger Rd., Ridgefield Park, NJ 07660, (201)641-6100; Chemical Group; Production site: Theodore, AL 36590 [R9] OMIN: *IT WAS INTRODUCED AS AN AQUATIC HERBICIDE AND ALGICIDE BY THE SHELL CHEMICAL CO UNDER THE TRADE NAME "AQUALIN" OR "AQUALINE" (A NAME NO LONGER USED FOR THIS PRODUCT IN SOME COUNTRIES) AND PROTECTED BY US PATENTS 2,042,220; 2,959,476; 2,978,475. [R10] *AQUALIN /HAS BEEN/ ... DISCONTINUED BY SHELL CHEMICAL CO. [R11] *The commercial production of acrolein started in Japan in 1960. Three Japanese companies currently mfr it for sale ... one of these companies and three others produce acrolein as an intermediate in the synthesis of acrylic acid and its esters. [R12] *NOT PHYTOTOXIC TO COMMON FIELD CROPS WHEN USED AS DIRECTED BY PRODUCT LABEL. [R13, 8] *Formation from glycerol by the action of B. amaracrylus: Boisenet, Compt. Rend. 199, 941, 1271 (1929) [R2] *The commercial product contains a polymerization inhibitor such as hydroquinone. When used as a reagent in fine chemical applications, acrolein is usually produced in situ from acetaldehyde and aqueous formaldehyde. [R14] *Must be stored in the dark, under nitrogen. [R8, 18] *Method of Purification: Rectification [R3, 17] USE: *For Acrolein (USEPA/OPP PC Code: 000701) active products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R6] *Mfr colloidal forms of metals; making plastics, perfumes; warning agent in methyl chloride refrigerant; has been used in military poison gas mixtures. Used in organic synthesis. Aquatic herbicide. [R2] *CHEMICAL INT IN SYNTH OF GLYCERIN, ... ACRYLIC ACID, AND ESTERS; PESTICIDE [R15] *Intermediate for glycerol, polyurethane, polyester resins, and pharmaceuticals [R3, 17] *Aquatic herbicide, rodenticide [R16] *Applied to control the growth of aquatic weeds in irrigation waterways or of algae and mollusks in recirculating water systems. [R17, 156] *FOR CONTROL OF SUBMERGED WEEDS (POTAMOGETON, NAJAS, ZANNICHELLIA, CERATOPHYLLUM, SPIROGYRA, AND OTHERS) AND FLOATING WEEDS (WATER CRESS, WATER HYACINTH AND WATER PRIMROSE) IN IRRIGATION CANALS, DITCHES. ... ALSO AN ALGICIDE. [R13, 8] *Used as a liquid fuel [R18, 39] *Chemical intermediate for DL-methionine, its hydroxy analog, and their salts; as a microbiocide in oil wells; Used to make modified food starch [R12] *Direct uses of acrolein are as a tissue fixative, which when coupled with a freeze substitution technique is valuable for preserving enzyme activity in histochemical investigations, a leather tanning agent, and recently, in tests, as a fumigant for ground squirrel burrows. [R19] *In world War I, it was used as a tear gas under the name Papite. [R19] *Cellulose fibre crosslinking agent [R14] *It is used in the manufacture of pharmaceuticals, perfumes, food supplements, and resins. It is also used as a biocide and fungicide. [R20, 982] CPAT: *The largest market for acrolein is for methionine manufacture (1978) [R21, 232] *In the production of D,L-methionine by Rhone-Poulenc in France, approximately 2,000 tons/annually of acrolein are produced and consumed. [R17, 157] *More than 80% of the refined acrolein that is produced today goes into the synthesis of methionine. Much larger quantities of crude acrolein are produced as an intermediate in the production of acrylic acid. More than 85% of the acrylic acid produced worldwide is by the captive oxidation of acrolein. [R21, 232] *In Australia, over 66 tons were used annually for control of submersed plants in more than 4000 km of irrigation canals. [R19] PRIE: U.S. PRODUCTION: *(1972) 2.72X10+10 G [R15] *(1974) 2.77X10+10 G [R15] *(1991) 900 million lb [R22, 284] U.S. IMPORTS: *(1972) NEGLIGIBLE [R15] U.S. EXPORTS: *(1972) NEGLIGIBLE [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless or yellowish liquid [R3, 17]; *Colorless or yellow liquid ... [R23, 6] ODOR: *Extremely sharp; extremely acrid, pungent, burnt sweet; hot fat [R24]; *... Piercing, disagreeable odor. [R23, 6] BP: *52.5 deg C @ 760 mm Hg [R2] MP: *-88 deg C [R2] MW: *56.06 [R2] CORR: *Non-corrosive to iron and steel at room temperature [R7] DEN: *0.8389 @ 20 deg C; 0.8621 @ 0 deg C; 0.8075 @ 50 deg C [R2] HTC: *-12,500 BTU/lb= -6,950 cal/g= -290X10+5 J/kg [R3, 52] HTV: *216 BTU/lb= 120 cal/g= 5.02X10+5 J/kg [R3, 52] OWPC: *log Kow= -0.01 [R25] PH: *pH 6.0 (max); a 10% solution in water at 25 deg C. [R21, 237] SOL: *SOL IN PETROLEUM ETHER [R26]; *Sol in alc, ether [R2]; *Soluble in oxygenated solvents [R14]; *Miscible with lower alcohols, ketones, benzene, diethyl ether ... [R8, 18]; *In water, 208 g/kg @ 20 deg C [R8, 18]; *In water, 2.12X10+5 mg/l @ 25 deg C [R27] SPEC: *Index of refraction: 1.4022 @ 19 deg C/D [R2]; *INDEX OF REFRACTION: 1.4017 @ 20 DEG C/D [R28]; *SADTLER REF NUMBER: 6645 (IR, PRISM) [R29]; *MAX ABSORPTION (ETHYL ALCOHOL): 207 NM (LOG E = 4.05) [R29]; *Acrolein has a moderate UV absorption in the solar spectral region. For acrolein in hexane, the extinction coefficients at wavelengths of 303 nm, 328 nm, 336 nm, 360 nm, and 386 nm, are 9.7 M-1 cm-1, 18.5 M-1 cm-1, 21.0 M-1 cm-1, 13.5 M-1 cm-1, and 5.0 M-1 cm-1, respectively. [R30, p. 20-2]; *IR: 6646 (Sadtler Research Laboratories Prism Collection) [R31]; *UV: 5-8 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R31]; *NMR: 9153 (Sadtler Research Laboratories Spectral Collection) [R31]; *MASS: 22 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R31] SURF: *24 DYNES/CM = 0.024 N/M AT 20 DEG C [R32] VAPD: *1.94 (Air= 1) [R33] VAP: *274 mm Hg @ 25 deg C [R34] VISC: *0.35 cP @ 20 deg C [R21, 233] OCPP: *Conversion factors: 1 mg/l = 437 ppm; 1 ppm = 2.3 mg/cu m [R22, 287] *HEAT OF POLYMERIZATION: -50 BTU/LB = -28 CAL/G = -1.2X10+5 J/KG (EST); LIQ-WATER INTERFACIAL TENSION: 35 DYNES/CM = 0.035 N/M @ 20 DEG C (EST); RATIO OF SPECIFIC HEATS OF VAPOR (GAS): 1.1487 [R32] *BP: 17.5 deg C @ 200 mm Hg; 2.5 deg C @ 100 mm Hg; -7.5 deg C @ 60 mm Hg; -64.5 deg C @ 1.0 mm Hg [R2] *VP: 210 MM HG @ 20 DEG C; 135.71 MM HG @ 10 DEG C; 325.70 MM HG @ 30 DEG C; 692.15 MM HG @ 50 DEG C [R13, 8] *Unstable, polymerizes (especially under light or in the presence of alkali or strong acid) forming diacryl, a plastic solid. [R2] *Henry's Law constant= 1.22X10-4 atm-cu m/mol @ 25 deg C [R35] *Hydroxyl radical rate constant= 1.22X10-11 cu cm/molecule-sec @ 25 deg C [R36] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Acrolein, inhibited/ [R37] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Acrolein, inhibited/ [R37] +Public safety: Call Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Acrolein, inhibited/ [R37] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Acrolein, inhibited/ [R37] +Evacuation: Spill: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Acrolein, inhibited/ [R37] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Acrolein, inhibited/ [R37] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Acrolein, inhibited/ [R37] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Acrolein, inhibited/ [R37] FPOT: +Flammable liquid [R38, p. 49-11] NFPA: *Health: 4. 4= Materials that, on very short exposure, could cause death or major residual injury, including those that are too dangerous to be approached without specialized protective equipment. A few whiffs of the vapor or gas can cause death, or contact with the vapor or liquid may be fatal, if it penetrates the fire fighter's normal protective gear. The normal full protective clothing and breathing apparatus available to the typical fire fighter will not provide adequate protection against inhalation or skin contact with these materials. [R38, p. 325-11] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R38, p. 325-11] *Reactivity: 3. 3= This degree includes materials that, in themselves, are capable of detonation, explosive decomposition, or explosive reaction, but require a strong initiating source or heating under confinement. This includes materials that are sensitive to thermal and mechanical shock at elevated temperatures and pressures and materials that react explosively with water. Fires involving these materials should be fought from a protected location. [R38, p. 325-11] FLMT: *Lower flammable limit: 2.8% by volume; Upper flammable limit: 31% by volume [R38, p. 325-11] FLPT: *-15 DEG F (CLOSED CUP); -26 DEG C (CLOSED CUP) [R38, p. 325-11] *LESS THAN 0 DEG F (OPEN CUP); -18 DEG C (OPEN CUP) [R39] AUTO: *428 DEG F (220 DEG C) UNSTABLE [R38, p. 325-11] FIRP: *Fire fighting procedure: In advanced or massive fires, fire fighting should be done from a safe distance, or from a protected location. Use dry chemical, alcohol foam, or carbon dioxide. water may be ineffective but water should be used to keep fire exposed containers cool. If a leak or spill has not ignited, use water spray to disperse vapors. If it is necessary to stop a leak, use water spray to protect personnel attempting to do so. Water spray may be used to flush spills away from exposures and to dilute spills to nonflammable mixtures. Acrolein vapors are uninhibited and may form polymers in vents or flame arrestors of storage tanks, resulting in stoppage of vents. [R40, 100] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam dry chemical or carbon dioxide. /Acrolein, inhibited/ [R41] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame, consider evacuation of one mile radius. /Acrolein, inhibited/ [R41] *The high toxicity and volatility of acrolein require use of air packs or air breathing equipment for any significant /fire involving acrolein/. [R42] *Use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Fight fire from protected location or maximum possible distance. /Acrolein, inhibited/ [R38, p. 49-11] TOXC: *Toxic gases and vapors (such as carbon monoxide and peroxides) may be released in a fire involving acrolein. [R43, 1981.] OFHZ: +VAPOR IS HEAVIER THAN AIR ... AND MAY TRAVEL A CONSIDERABLE DISTANCE TO A SOURCE OF IGNITION AND FLASH BACK. [R38, p. 49-11] EXPL: *LOWER 2.8%; UPPER 31% [R39] REAC: *Mixing acrolein and oleum in a closed container caused the temperature and pressure to increase. [R38, p. 491-10] *Mixing acrolein and oleum in a closed container caused the temperature and pressure to increase. [R38, p. 491-10] *Mixing acrolein and 70% nitric acid in a closed container caused the temperature and pressure to increase. [R38, p. 491-9] *Mixing acrolein and ethyleneimine in a closed container caused the temperature and pressure to increase. [R38, p. 491-9] *Mixing acrolein and chlorosulfonic acid in a closed container caused the temperature and pressure to increase. [R38, p. 491-9] *Mixing acrolein and 28% ammonium hydroxide in a closed container caused the temperature and pressure to increase. [R38, p. 491-9] *Mixing acrolein and 2-aminoethanol in a closed container caused the temperature and pressure to increase. [R38, p. 491-9] *In the presence of alkaline or strong acid contamination, which acts as a catalyst, acrolein undergoes a condensation reaction liberating around 300 kJ/kg acrolein reacted. This reaction may be very rapid and violent. [R44] *Water initiates exothermic reactions catalyzed by mineral acids and possibly some metallic salts. An interference between acrolein and water appears to promote the reaction and it is not prevented by the usual acrolein polymerization inhibitors, eg, hydroquinone or 4-methoxyphenol. The reaction can be avoided by scrupulously eliminating ionic contaminants and water layers, and maintaining reasonably low temp. To dispose of acrolein or arrest a runaway reaction, 20 or more volumes of water must be added to completely solubilize the acrolein ... . [R45] *Oxidizers, acids, alkalis, ammonia, amines [Note: polymerizes readily unless inhibited -- usually with hydroquinone. May form shock sensitive peroxides overtime]. [R23, 6] DCMP: *DANGEROUS; WHEN HEATED TO DECOMPOSITION, EMITS HIGHLY TOXIC FUMES ... [R46] POLY: *Polymerizes (especially under light or in the presence of alkali or strong acid) forming disacryl, a plastic solid. [R39] *POLYMERIZES SLOWLY IN PRESENCE OF AIR [R13, 8] *Acrylaldehyde is very reactive and will polymerize rapidly, accelerating to violence, in contact with strong acid or basic catalysts. [R47] *A 2 yr old sample stored in a refrigerator close to a bottle of dimethylamine exploded violently, presumably after absorbing enough volatile amine (which penetrates plastics closures) to initiate polymerization. [R47] *May polymerize in the presence of light and explosively in the presence of concentrated acids forming disacryl, a white plastic solid. [R48, 3] *Acrolein polymerizes with release of heat on contact with minor amounts of acids (including sulfur dioxide), alkalis, volatile amines, salts, thiourea, oxidants (air) and on exposure to light and heat. [R38, p. 491-10] ODRT: *0.21 PPM /PURITY NOT SPECIFIED/ [R32] *Air: 0.16 ul/l; Water: 0.11 mg/l; Odor safety class D; D= 10-50% of attentive persons can detect TLV concn in the air [R49] *Low= 0.0525 mg/cu m; High= 37.5000 mg/cu m; Irritating concn= 1.25 mg/cu m. [R50] SERI: *Acrolein produces intense irritation to the eye and mucous membranes of the respiratory tract. [R18, 40] *Intense lacrimation and nasal irritation ... [R51] *The general sequence of acrolein irritation is concentration-time dependent eg, 1 ppm for 1 min gives slight nasal irritation; 1 ppm for 5 min gives intolerable eye irritation; 5.5 ppm for 5 seconds gives moderate eye irritation; and 5.5 ppm for 1 min produces marked lacrimation. ... [R52] *Severe irritation of the eyes, skin, mucous membranes; ... . [R48, p. 3-4] *Acrolein is intensely irritating to the eyes ... . ... Skin irritation ... can be produced from prolonged or repeated contact. [R53] EQUP: *CHEMICAL SAFETY GOGGLES AND FACE SHIELD; SELF-CONTAINED BREATHING APPARATUS, POSITIVE-PRESSURE HOSE MASK, AIRLINE MASK OR INDUSTRIAL CANISTER-TYPE GAS MASK; RUBBER SAFETY SHOES; CLOTHING MADE OF RUBBER OR OTHER IMPERVIOUS MATERIAL. [R32] *Recommendations for respirator selection. Max concn for use: 2 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R23, 7] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R23, 7] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R23, 7] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R23, 7] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R23, 7] *Wear appropriate eye protection to prevent eye contact. [R23, 7] *Wear appropriate personal protective clothing to prevent skin contact. [R23, 7] OPRM: *WHEREVER POSSIBLE, ACROLEIN SHOULD BE STORED, HANDLED AND PROCESSED IN THE OPEN OR IN ROOFED AREAS WITH OPEN SIDES. ... PROCESSING EQUIPMENT SHOULD BE OF TOTALLY ENCLOSED TYPE WITH AN OXYGEN-FREE ATMOSPHERE. WHERE ACROLEIN IS HANDLED, EXHAUST AND/OR GENERAL VENTILATION SHOULD BE FITTED. ... BEFORE A TANK HAVING CONTAINED ACROLEIN IS ENTERED, IT SHOULD BE PURGED WITH NITROGEN /VENTILATED WITH AIR/ AND PRECAUTIONS RELEVANT TO ENTERING CONFINED SPACES SHOULD BE OBSERVED. [R44] *All tanks, processing vessels, pumps, reactors, heat exchangers, and similar equipment should be protected by adequate emergency vent-relief devices. Acrolein vapors are not inhibited and can form polymers in vent lines, valves, and flame arresters with subsequent stoppage of the vent. [R42] *In case of /acrolein/ contamination with mineral acids or alkalis, depending on the amt involved, the temp rise may be slow enough to permit control injection of a buffer solution /of acetic acid, glacial or hydroquinone, photo-grade or sodium acetate, anhydrous/. An emergency supply should be available at all times in areas where acrolein is handled. The effectiveness of stored buffer is unchanged by discoloration. [R45] *Hazardous situations are most likely to occur when it is necessary to deviate from standard operating procedures. The acrolein system should be a dedicated system and almost completely isolated, so that the possibility of contamination can only occur when temporary tie-ins are made. No hoses or lines should be used in blowing lines, washing equipment ... unless the past history of the hose is known and the hose is thoroughly cleaned. [R42] *Contact lenses should not be worn when working with this chemical. [R23, 7] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Air packs or fresh air breathing masks should be available in an area where acrolein is handled. Safety showers and eye baths must be avail in the area. [R52] *Evacuation: If material leaking (not on fire), consider evacuation from downwind area based on amount of material spilled, location and weather conditions. /Acrolein, inhibited/ [R41] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Acrolein, inhibited/ [R41] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. /Acrolein, inhibited/ [R41] *Eating and smoking should not be permitted in areas where liquid acrolein is handled, processed, or stored. [R43, 1981.] *The worker should immediately wash the skin when it becomes contaminated. [R23, 7] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R23, 7] SSL: *UNSTABLE [R39] *The stability of acrolein is very dependent on pH. [R54] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R55] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R56] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R57] STRG: *Separate from oxidizing materials, peroxides, acids, and alkalies. Store in a cool, dry, well-ventilated location, protected from sunlight. Outside or detached storage is preferred. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Do not store uninhibited acrolein. [R38, p. 49-11] *For storage, the pH of acrolein is adjusted to 5-6 by the addition of acetic acid. [R54] *... Can be stored under oxygen-free nitrogen in dark glass bottles, in cylinders, or in black iron drums. [R13, 9] *Should be handled in a fume hood or closed system with exhaust ventilation of adequate scrubbing facilities. Should be stored in air-tight containers with nitrogen gas filled in a cool, well-ventilated place away from sources of possible ignition or fire. Do not store uninhibited acrolein under any circumstances. When filled drums or other containers are stored in separate storage rooms, trapped door drains should be provided and floors pitched to the drains. The storage areas should be provided with automatic sprinkler or other adequate extinguishing system. Acids, alkalis or oxidants should not be stored nearby. Outdoors or isolated storage place is preferable. [R58] CLUP: *1. Remove all ignition sources. 2. Ventilate the area of spill or leak. 3. for small quantities, absorb on paper towels. evaporate in safe place (such as fume hood). Allow sufficient time for evaporating vapors to completely clear hood ductwork. Burn paper in suitable location away from combustible materials. For large quantities, cover with sodium bisulfite add small amount of water, and mix. Then, after 1 hr, flush with large amt of water, and wash site with soap solution. Liquid should not be allowed to enter confined space, such as sewer, because of possibility of explosion. [R40, 101] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyur or foamed concrete. Neutralize with sodium bisulfate. /Acrolein, inhibited/ [R41] *Environmental considerations: Air spill: Apply water or mist to knock down vapors. Combustion products include corrosive or toxic vapors. /Acrolein, inhibited/ [R41] *Environmental considerations: Water spill: Use natural barriers or oil spill control booms to limit spill motion. Add sodium bisulfate. If dissolved, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Acrolein, inhibited/ [R41] *Spills of liquid acrolein are handled by covering the acrolein with 6 inches of National 99 Aero-O-Foam to suppress evaporation; Polymerization of the spilled acrolein by adding a dilute, 5-10% aqueous sodium carbonate solution should then be ... /applied/. Dilute aqueous sodium bisulfite may be used on small spills. [R42] *Releases may require isolation or evacuation. Eliminate all ignition sources. Use water spray to cool and disperse vapors, protect personnel, and dilute spills to form nonflammable mixtures. /Acrolein, inhibited/ [R38, p. 49-11] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R59] *Aqueous wastes with low concn of acrolein are usually neutralized with sodium hydroxide and fed to a sewage treatment plant for biological secondary treatment. Concentrated wastes are reprocessed whenever possible or burned in special waste incinerators. Recommendable methods: Neutralization, incineration. Not recommendable methods: Discharge to sewer, landfill. Peer-review: Old acrolein may be explosive as a result of very fast self-polymerization reaction. Handle with care. Dissolve in water, add excess 10% sodium bisulfate soln. ... (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R60] *Incineration: Dissolve in a combustible solvent, then spray the soln into the furnace with afterburner. [R60] *Acrolein is a waste chemical stream constituent which may be subject to ultimate disposal by controlled incineration. (1500 deg F, 0.5 sec minimum for primary combustion; 2000 deg F, 1.0 sec for secondary combustion) [R61] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R62] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R63] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R64] *The following wastewater treatment technologies have been investigated for acrolein: Biological treatment. [R65] *The following wastewater treatment technologies have been investigated for acrolein: Activated carbon. [R65] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *Acrolein is very toxic to aquatic organisms. Acute EC50 and LC50 values for bacteria, algae, crustacea, and fish are between 0.02 and 2.5 mg/liter, bacteria being the most sensitive species. ... In animals and humans the reactivity of acrolein effectively confines the substance to the site of exposure, and pathological findings are also limited to these sites. ... Acrolein reacts directly with protein and non-protein sulfhydryl groups and with primary and secondary amines. It may also be metabolized to mercapturic acids, acrylic acide, glycidaldehyde or glyceraldehyde. Evidence for the last three metabolites has only been obtained in vitro. Acrolein is a cytotoxic agent. In vitro cytotoxicity has been observed as low as 0.1 mg/liter. The substance is highly toxic to experimental animals and humans following a single exposure via different routes. The vapor is irritating to the eyes and respiratory tract. Liquid acrolein is a corrosive substance. ... At higher single exposure levels, degeneration of the respiratory epithelium, inflammatory sequelae, and perturbation of respiratory function develop. ... In general, body weight gain reduction, decrement of pulmonary function, and pathological changes in nose, upper airways, and lungs have been documented in most species exposed to concentrations of 1.6 mg/cu m or more for 8 hr/day. Pathological changes include inflammation, metaplasia, and hyperplasia of the respiratory tract. Significant mortality has been observed following repeated exposures to acrolein vapor at concentrations above 9.7 mg/ cu m. In experimental animals acrolein has been shown to deplete tissue glutathione and in in vitro studies, to inhibit enzymes by reacting with sulfhydryl groups at active sites. There is limited evidence that acrolein can depress pulmonary host defenses in mice and rats. Acrolein can induce teratogenic and embryotoxic effects if administered directly into the amnion. ... Acrolein has been shown to interact with nucleic acids in vitro and to inhibit their synthesis both in vitro and in vivo. Without activation it induced gene mutations in bacteria and fungi and caused sister chromatid exchanges in mammalian cells. ... The threshold levels of acrolein causing irritation and health effects are 0.7 mg/ cu m for odor perception, 0.13 mg/cu m for eye irritation, 0.3 mg/ cu m for nasal irritation and eye blinking, and 0.7 mg/ cu m for decreased respiratory rate. ... In view of the high toxicity of acrolein to aquatic organisms, the substance presents a risk to aquatic life at or near sites of industrial discharges, spills and biocidal use. [R66] CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Classification is based on increased incidence of adrenal cortical adenomas to female rats and carcinogenic potential of an acrolein metabolite. Acrolein is mutagenic in bacteria and is structurally related to probable or known human carcinogens. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R67] *Evaluation: There is inadequate evidence in humans for the carcinogenicity of acrolein. There is inadequate evidence in experimental animals for the carcinogenicity of acrolein. Overall evaluation: Acrolein is not classifiable as to its carcinogenicity to humans (Group 3). [R68] ANTR: *Flush eyes with abundant water, also wash thoroughly contaminated skin using soap. Treat skin burns as usual. Supply oxygen with use of intermittent positive-pressure breathing apparatus. ... Contaminated clothing should be promptly removed ... . [R58] *Exposure should be treated with copious irrigation; ... [R20, 419] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin bums with dry sterile dressings after decontamination ... . /Acrolein and related compounds/ [R69, 290] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema .... Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Use proparacaine hydrochloride to assist eye irrigation ... . /Acrolein and related compounds/ [R69, p. 290-91] MEDS: *The monitoring of acrolein in the urine can be accomplished through measurement of acrolein. This test may be useful for identification of exposure. However, no information was located which showed a correlation between urine levels and environmental exposure levels or the onset of adverse health effects. [R70, 108] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. [R70, 109] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. [R70, 109] *Sputum Cytology: Sputum cytology along with chest radiographs have been the standard procedures for detecting early lung cancer in asymptomatic patients. Sputum cytology has been found to be useful for detection of central tumors, especially squamous carcinomas. [R70, 109] *Initial Medical Examination: A complete medical history and physical examination with emphasis on the heart and lungs: The purpose is to detect existing medical conditions which might place the exposed employee at increased risk from reported effects of acrolein, and to establish a baseline for future health monitoring. Examination of the heart and lungs should be stressed. 14"x17" Chest roentgenogram: Acrolein may cause lung damage. Surveillance of the lungs is indicated. Forced Vital Capacity and Forced Expiratory Volume (1 sec): Acrolein is reported to cause decreased pulmonary function. Periodic surveillance is indicated. Periodic Medical Examination: The aforementioned medical examination should be repeated on an annual basis, except that an x-ray is considered necessary only when indicated by the results of the pulmonary function tests. [R43, 1981.1] HTOX: *IT IRRITATES SKIN, MUCOUS MEMBRANES. VAPORS CAUSE LACRIMATION. WEAK SENSITIZER; INHALATION MAY CAUSE ASTHMATIC REACTION. [R39] *... /INHALATION CAUSES/ IRRITATION OF NOSE AND THROAT, TIGHTNESS OF CHEST, AND SHORTNESS OF BREATH, NAUSEA AND VOMITING. BRONCHOPULMONARY EFFECT IS VERY SEVERE; EVEN IF VICTIM RECOVERS FROM ACUTE EXPOSURE, THERE WILL BE PERMANENT RADIOLOGICAL AND FUNCTIONAL DAMAGE. [R44] *Exposure to 1 ppm (2.3 mg/cu m) acrolein vapor in air causes lacrimation and marked eye, nose and throat irritation within a period of 5 min. Acrolein is a severe pulmonary irritant and powerful lachrymogen at a concn of 3 ppm (7 mg/cu m) and greatly irritates the conjunctiva and mucous membranes of upper resp tract. At higher concn it ... causes injury to lung; Resp insufficiency may persist for at least 18 mo after exposure. A 10 min exposure to 350 mg/cu m was lethal. [R71] *... Skin contact with liquid acrolein /has been described/ as causing irritation, erythema, and edema, and a splash in the eye as causing blepharoconjunctivitis, lid edema, fibrinous or purulent discharge, and corneal injury, which ... may be deep and long-lasting. ... Severe damage is possible as from alkali burns ... . [R72] *INHALATION OF AIR CONTAINING 10 PPM ACROLEIN MAY BE FATAL IN A FEW MIN. [R73] *Acrolein ... is a well-established respiratory irritant. [R74] *Intense lacrimation and nasal irritation ordinarily give adequate warning of inhalation, but exposed patients should be observed for 24 hr for a slowly developing pulmonary edema. [R51] *Acrolein increases airway resistance and tidal volume and decreases respiratory frequency. [R75] *Aldehydes increase airflow at concentrations below those that decrease respiratory frequency. /Aldehydes/ [R75] *The ability of the highly reactive aldehyde acrolein to affect growth, membrane integrity, differentiation, and thiol status and to cause DNA damage has been studied at serum and thiol free conditions using cultured human bronchial epithelial cells. Acrolein markedly decreases colony survival at 3 uM whereas about 10 fold higher concentrations are required to increase membrane permeability, measured as uptake of trypan blue dye. Acrolein at uM concentrations also causes epithelial cells to undergo squamous differentiation as indicated by decreased clonal growth rate, dose dependent increased formation of cross linked envelopes, and increased cell planar surface area. Acrolein causes a marked and dose dependent cellular depletion of total and specific free low molecular weight thiols as well as protein thiols. Exposure to acrolein did not cause oxidation of glutathione indicating that thiol depletion occurred by direct conjugation of reduced glutathione to acrolein without concomitant generation of active oxygen species. Furthermore, acrolein is genotoxic and causes both DNA single strand breaks and DNA protein cross-links in human bronchial epithelial cells. The results indicate that acrolein causes several cytopathic effects that relate to multistage carcinogenesis in the human bronchial epithelium. [R76] *... The purpose of this study was to: (a) compare the relative abilities of phosphoramide mustard and acrolein to induce cytogenetic damage and cytotoxicity in cultured human lymphocytes; (b) assess the efficacy of 2-mercaptoethanesulfonic acid to attenuate the cytogenetic damage and cytotoxicity induced by cyclophosphamide, acrolein, phosphoramide mustard, and diethyl-4'-hydroperoxycyclophosphamide, an activated acrolein generating compound; and (c) determine if concanavalin A stimulated T-lymphocytes, which differentiate into suppressor cells upon lectin activation, exhibit any heightened cytogenetic sensitivity compared to a variety of cultured mammalian cells during exposure to phosphoramide mustard or acrolein as reported by other investigators. Purified mononuclear leukocytes were stimulated with concanavalin A and exposed to cyclophosphamide (0.5-2.0 mM) without and exogenous activation system, acrolein (0.001-40.0 uM), phosphoramide mustard (0.0014-27.1 uM), or diethyl-4'-hydroperoxycyclophosphamide (0.1-100.0 uM) in the presence or absence of 2-mercaptoethansulfonic acid (1, 5, or 10 mM). All four compounds induced significant concentration related increases in the sister chromatid exchange frequency, but only phosphoramide mustard was clastogenic. On an induced sister chromatid exchange/uM basis, phosphoramide mustard was 130 and 193 times more potent than were diethyl-4'-hydroperoxycyclophosphamide and acrolein respectively. 2-Mercaptoethanesulfonic acid protected against the cytogenetic damage and cytotoxicity induced by the four compounds, but it was particularly effective against acrolein and diethyl-4'-hydroperoxycyclophosphamide by abolishing sister chromatid exchange induction completely. Sister chromatid exchanges and chromosome aberrations differed considerably in their induction kinetics in lymphocytes exposed to phosphoramide mustard, and these disparities suggested an uncoupling of the two phenomena. Although sister chromatid exchange induction was not consistently associated with cytotoxicity with the four agents, chromosome aberration induction coincided with an inhibition of cell cycle kinetics in phosphoramide mustard treated cells. The exceptionally high sister chromatid exchange frequency of up to 21 times baseline in cells exposed to phosphoramide mustard indicates that T-supressor lymphocytes stimulated with concanavalin A may be particularly sensitive to the DNA-damaging effects of phosphoramide mustard. Finally, these data suggest that the anticarcinogenicity of 2-mercaptoethanesulfonic acid correlates with its ability to attenuate cytogenetic damage and cytotoxicity induced by reactive cyclophosphamide metabolites. [R77] *The possible use of the degree of inhibition of glutathione-S-transferase activity as a biological marker for determining exposure to chemicals such as acrolein, styrene oxide, propylene oxide, ethylene dibromide, and ethylene dichloride was explored. Glutathione-S-transferase activity was studied in vitro in human erythrocytes or as the purified enzyme. While glutathione-S-transferase activity was inhibited by all these compounds, acrolein was the most inhibitory. A dose dependent inhibition was evident in each case not only for inactivation of erythrocyte glutathione-S-transferase in situ but for inhibition of purified erythrocyte glutathione-S-transferase as well. Concentrations inhibiting 50% of the activity (I50) ranged from around 10(-3) to 10(-4) M. Some of the I50 values for the compounds used in this study were relatively high. It was stated that the concentrations of these chemicals in the blood of chronically exposed industrial workers may not reach these levels. It is suggested that further studies be made to evaluate the usefulness of inhibition of erythrocyte glutathione-S-transferase by these agents. [R78] *... Is a severe pulmonary irritant and lacrimating agent with a piercing, disagreeable, acrid odor. It is ciliastatic and capable of causing direct tissue damage ... [R20, 982] *... Toxic effects of acrolein exposure include sensory irritation, enzymatic inhibition, elevated liver alkaline phosphatase, protein synthesis inhibition, weight loss, and death. Acrolein is a suspected carcinogen ... May possess immunotoxic potential... Can induce pulmonary edema. [R20, 982] *Severe irritation of the eyes, skin, mucous membranes; abnormal pulmonary function; delayed pulmonary edema, chronic respiratory disease. [R48, p. 3-4] *Acrolein is a major contributor to the irritative quality of cigarette smoke ... [R75] NTOX: *When swallowed, /acrolein/ produces severe gastrointestinal distress with pulmonary congestion and edema. [R51] *SUBACUTE INHALATION TOXICITY OF ACROLEIN WAS EXAM IN 4 GROUPS OF 20 HAMSTERS, 12 RATS, and 4 RABBITS EACH EXPOSED 6 HR/DAY, 5 DAYS/WK FOR 13 WK AT CONCENTRATIONS OF 0, 0.4, 1.4, and 4.9 PPM. THE HIGHEST CONCENTRATION CAUSED DEATH IN RATS, OCULAR AND NASAL IRRITATION, GROWTH DEPRESSION AND METAPLASIA AND HYPERPLASIA OF THE LINING OF THE RESP TRACT IN ALL SPECIES. THE LOWEST EXPOSURE LEVEL (0.4 PPM) PRODUCED NO TOXIC EFFECTS IN RABBITS OR HAMSTERS. [R79] *Groups of pure bred beagle dogs, squirrel monkeys (Saimiri sciurea), guinea pigs, AND Sprague-Dawley derived rats were exposed to 0.7 and 3.7 ppm (1.6 and 8.5 mg/cu m) acrolein vapor for 8 hr/day on 5 days/wk for 6 consecutive weeks; squamous metaplasia and basal cell hyperplasia in the trachea were observed in dogs and monkeys, and squamous metaplasia of the lung in 7/9 monkeys. [R80] *ANIMAL EXPT INDICATE THAT ACROLEIN ... /DESTROYS/ RESPIRATORY TRACT MUCOUS MEMBRANES TO SUCH AN EXTENT THAT RESPIRATORY FUNCTION IS FULLY INHIBITED WITHIN 2-8 DAYS. [R44] */ACROLEIN/ ... AFFECTS ALKALINE PHOSPHATASE AND TYROSINE-ALPHA-KETOGLUTARATE TRANSAMINASE ACTIVITIES IN RATS 5-12 HR AFTER INJECTION (3 MG/KG 20 HR BEFORE SACRIFICE) OR INHALATION. ... DATA SUGGESTED ... ACROLEIN STIMULATES PITUITARY-ADRENAL SYSTEM, LEADING TO HYPERSECRETION OF GLUCOCORTICOIDS ... /WHICH STIMULATE SYNTH OF ENZYME PROTEINS/. [R81] *Acrolein has ... been reported to cause alterations in lung and liver biochemistry, incl significant reduction in microsomal mixed-function oxidase activity, in rats given 2 ip injections of 5 mg/kg body wt acrolein. A single ip injection of 3 mg/kg body wt acrolein to male Holtzman rats ... caused a prolongation of ... pentobarbital and hexobarbital sleeping time. In vitro studies ... total destruction of liver and lung microsomal the reduced form of nicotinamide-adenine dinucleotide phosphate cytochrome c reductase by 1.5 to 6 mM (0.084 to 3.3 mg/ml) acrolein, total loss of nonprotein sulfhydryl content and partial loss of protein sulfhydryl content in these organs /have been observed/. Depletion of sulfhydryl (21-63%) in the resp mucosa of male Fisher 344 rats after inhalation of 0.1 to 5 ppm (0.23 to 11.5 mg/cu m) acrolein vapor has ... been reported. [R80] *Two groups of 18 male and female Syrian golden hamsters, 6 wk old, were exposed to 0 or 4 ppm (0 or 9.2 mg/cu m) acrolein vapor (purity unspecified) for 7 hr/day on 5 days/wk for 52 weeks. Six animals per group were killed at 52 wk and the remainder at 81 wk. Survival was similar in treated and control animals. No tumor of resp tract was found in any group. [R82] *... ACROLEIN INDUCED MUTATIONS IN DROSOPHILA MELANOGASTER (2.23% COMPARED TO 0.19% IN CONTROLS). ... RESULTS REPORTED ... INDICATE THAT ACROLEIN IS MUTAGENIC IN AN ESCHERICHIA COLI STRAIN DEFICIENT IN DNA POLYMERASE WITHOUT METABOLIC ACTIVATION. [R83] *IT WAS ... NEGATIVE IN BACK-MUTATION TEST (SPOT TEST) WITH 2 YEAST STRAINS, 1 SENSITIVE TO BASE SUBSTITUTION (S211) and 1 TO FRAMESHIFT MUTATION (S128). [R84] *... /Acrolein/ added ... to an in vitro rat embryo culture at 5 ug/ml (equimolar to a teratogenic dose of cyclophosphamide) ... /produced/ no growth retardation or increase in defects. At twice the dose the cmpd was lethal. ... Growth retardation but no structural defects at 100 and 150 uM concentrations /were observed/ when rat embryos were exposed in vitro. ... [R85] *Acrolein (practical grade), stabilized with 0.2% hydroquinone ... and dissolved in 25 ul of 0.9% sodium chloride, was injected at doses of 0.001, 0.01, 0.1, 1.0 and 10 umol/egg (0.006 to 56 ug/egg) into ... air space or the yolk sac of 3-day-old White Leghorn SK 12 strain chick embryos. On day 14 of incubation, the embryos were examined for ... viability and malformations. Dose-related lethality was observed ... . No clear evidence of teratogenic potential was found. [R86] *Dose-related incr in embryolethality, but not in malformations (4/69 fetuses at high dose, compared to 2/121 in control group were malformed, but this difference was not significant), was found when groups of New Zealand white rabbits were injected iv on day 9 of gestation with 3, 4.5 or 6 mg/kg body wt acrolein (stabilized with 0.2% hydroquinone). The high dose killed 6/16 rabbits, compared to 0/13 controls. ... Direct injections into yolk sac of 10, 20 or 40 ul of a 0.84% soln of acrolein in physiological saline into day-9 embryos resulted in a dose-related incr in ... resorptions (63% in high-dose group compared to 21.2% in controls) and malformations (23.3% in high-dose group compared to 3% in controls). The defects in high-dose group incl hypoplastic and asymmetrical cervical and thoracic vertebrae, shortened extremities and a ventricular septal defect. [R86] *Signs of ... /toxicity in mallard ducks given oral LD50 doses of acrolein/. Regurgitation, reluctance to leave the swimming pond, slow responses, ataxia, geotaxia, imbalance, phonation, wing tremors, running and falling, asthenia, myasthenia, and withdrawal. Treatment levels as low as 3.33 mg/kg /orally/ produced /these/ signs /in mallards/. Signs appeared as soon as 10 min and persisted up to 36 days after treatment. Mortalities occurred as soon as 32 min; However, several mortalities occurred several days after treatment. /Sample purity: 92%/ [R87] *Repeated inhalation by chickens of 50 and 200 ppm (115 and 450 mg/cu m) acrolein vapor for 5 min/day for 1 to 27 days produced concentration-dependent decreases in the numbers of ciliated and goblet cells and mucous glands in the trachea, and lymphocytic inflammatory lesions in the tracheal mucosa. [R80] *Lesions occurring in the respiratory tract of mice after exposure to 10 sensory irritants, incl acrolein, at a concn which elicited a respiratory rate decr of 50% (RD50 of acrolein= 1.7 ppm), were compared with respect to type and severity. After exposure of mice for 6 hr/day for 5 days, the respiratory tract was examined for histopathological changes. All irritants produced lesions in the nasal cavity with a distinct anterior-posterior severity gradient. The lesions ranged from slight epithelial hypertrophy or hyperplasia to epithelial erosion, ulceration, and necrosis with variable inflammation of the subepithelial tissues. [R88] *Groups of Fischer 344 rats were exposed to either filtered air, 0.4, 1.4, or 4.0 ppm acrolein for 62 days (6 hr/day, 5 days/wk). Mortality was observed only in the 4.0 ppm chamber, where 32 of 57 male rats died, but none of the 8 exposed females died. The lungs of the 4.0 ppm group were heavier than those of the larger control animals. Relative to controls, there was a 20% incr in total dry lung wt while the percent dry wt decr 1.5% in the high dose group. Lung connective tissue content was incr as a result of subchronic acrolein exposure. The amount of elastin per unit dry wt was 173% of control values in the animals exposed to 4.0 ppm acrolein. Collagen levels were elevated in both the 1.4 and 4.0 ppm groups, 113 and 137%, respectively, of control values. Histologically, the 4.0 ppm animals demonstrated bronchiolar epithelial necrosis and sloughing, bronchiolar edema with macrophages, and focal pulmonary edema. Exposure related lesions were observed in only 3 of the 31 rats examined from the 1.4 ppm chamber and in none of the animals exposed to 0.4 ppm acrolein. [R89] *Continuous 90 day exposure at 0.22 ppm caused inflammation in liver, lung, kidneys, and heart of monkeys, guinea pigs, and dogs. Exposure to 1.8 ppm caused squamous cell metaplasia and basal cell hyperplasia of the trachea in monkeys. [R90] *Inhibition of cell multiplication starts at 0.44 mg/l in protozoa (Uronema parduczi Chatton-Lwoff); At 0.21 mg/l in bacteria (Pseudomonas putida); And at 0.04 mg/l in algae (Microcystis aeruginosa). The lowest observed avoidance concn in insects was above 0.1 mg/l for mayfly nymphs (Ephemerella walkeri); 0.1 mg/l for rainbow trout (Salmo gairdneri). The incipient Median Threshold Limit (TLm) for fathead minnow was 84 ug/l in a flow through bioassay; The maximum acceptable toxicant concentration was 11.4 ug/l. [R91] *The pathologic and immunotoxic effects of acrolein were studied using 4 groups of male Sprague-Dawley rats. Rats were exposed to 0, 0.17, 1.07, or 2.98 ppm of acrolein for 6 hr/day, 5 days/wk for 3 wk. From each treatment group (N= 40), 12 rats were used for spleen and lung associated lymph node blastogenesis using the T-cell mitogen, phytohemaglutinin P, and the B-cell mitogen, Salmonella typhimurium. Ten additional rats received an intratracheal challenge of sheep erythrocytes after which lung associated lymph node cells were assayed for plaque formation. The remaining 18 rats were evaluated for host resistance to Listeria monocytogenes. Histological examination of nasal turbinates of the rats exposed to 2.98 ppm revealed exfoliation, erosion and necrosis of respiratory epithelium, and squamous metaplasia. The lung did not demonstrate significant histopathology. A decrease in body weight gain was observed only for rats exposed to 2.98 ppm. In vitro pulmonary immune response as determined by the hemolytic plaque assay, and lymphocyte response to phytohemaglutinin P and Salmonella typhimurium were not affected by any of the acrolein exposures. Acrolein exposure did not affect resistance to Listeria. [R92] *Acrolein is formed when fat is overheated and has the typical smell of "burning fat". ... A poodle, shut up for half an hour in a small unventilated kitchen with a chip pan of boiling fat, was seen next day to have swollen tonsils, blood from the nostrils and a temperature of 39.4 deg C. 24 hr later there was slight dyspnea, the pulse was faint, the tongue cyanosed and the eyes congested and discharging pus. It collapsed and died soon afterwards. [R93] *Embryologic and teratogenic effects of acrolein over a narrow concentration range in cultured rat embryos were assessed. On the tenth day of gestation, pregnant Sprague-Dawley rats were etherized and the uterus was removed. Embryos were dissected free of maternal tissue and cultured in either a serum or serum free medium; dissolved acrolein was added. After 42 hours of culture time, embryos were examined for viability and morphology. For embryos cultured in serum, 100% mortality was observed at 140 uM acrolein. Significance in number of embryo deaths was reached at 120 uM; median effective concentration (EC50) for embryo deaths was 115 uM. Significant increases in embryo malformations were detected with doses as low as 80 uM; the EC50 for malformations was 137 uM. Malformations of the brain, heart, somites, facial area, and forelimb buds occurred most frequently. Doses of 80 uM acrolein and greater produced significant decreases in embryo growth and development. Yolk sac diameter, crown rump length, head length, number of somites, protein content, and total morphological score decreased significantly at 120 uM compared to controls. In embryos cultured in a serum free medium, acrolein was totally embryolethal at 20 uM; EC50 for acrolein induced mortality was 8.3 uM. Malformations occurred in 67, 80, and 100% of the embryos in the 5, 10, and 15 uM dose groups, respectively. The EC50 for acrolein induced malformations was 2.8 uM. Malformations included reduced left forelimb bud, blebs of the maxillary, nasal or optic region, protrusions of the body, hindlimbs or head area, cardiac malformations, head abnormalities, incomplete turning, and irregular somites. At 5 and 10 uM acrolein, there was a significant decrease in yolk sac diameter, crown rump and head length, somite number, and morphological score. [R94] *The mutagenic potential of acrolein has been studied with a wide range of in vitro and in vivo genetic toxicity assays. The data often have been conflicting, especially with the Ames assay. This study was undertaken to assess the mutagenic potential of acrolein using the CHO/HGPRT assay, both with and without metabolic activation. This assay system was chosen because it provides eukaryotic DNA as the target and is capable of detecting a range of mutational events. Because of its considerable toxicity, acrolein was tested over a very narrow dose range of 0.2-2 nl/ml without exogenous activation and 0.5-8 nl/ml with rat S-9 activation. Multiple assays were performed under both conditions. The results indicated that while acrolein was clearly very cytotoxic, it did not induce a significant mutagenic response in the presence or absence of metabolic activation. [R95] *The effect of systemic administration of acrolein, a constituent of cigarette smoke and a metabolite of cyclophosphamide, on the urinary bladder epithelium of 8 week old male F344 rats was investigated. The animals were injected with single dose of acrolein at 25 mg/kg by intragastric intubation or ip injection. The 25 mg/kg dose level proved extremely toxic. The mortality rate was 42% for both groups. Rats administered acrolein intragastrically had severe erosive hemorrhagic gastritis. Rats treated ip had severe localized peritonitis. Surviving animals were sacrificed at 24 or 48 hours after administration and shown to have focal simple hyperplasia of the urinary bladder after 2 days. In a second set of studies groups of 10 week old male F344 rats were given acrolein via intraperitoneal injection at doses of 0.5, 1, 2, 4, or 6 mg/kg divided into up to three doses. Rats were injected with tritiated thymidine 7 days after the first treatment, and bladders were processed for autoradiographic evaluation. Sufficient acrolein reached the urinary bladder to induce a proliferative response following ip administration as determined by autoradiography. [R96] *The carcinogenic effects of chronic exposure to acrolein, acrolein diethylacetal, acrolein oxime, and allyl alcohol were tested in rats and hamsters. Each compound was administered at various doses up to near the maximum tolerated dose in drinking water to groups of 20 male or female F344 rats for up to 2 years. Acrolein was not given to hamsters because it proved to be too toxic for administration in an adequate dose. The other compounds were given at doses of 2 mg/wk by gavage to male Syrian golden hamsters. One group of each species was maintained as untreated controls, and a group of rats was given acetaldoxine as a control for possible carcinogenicity of oximes. Animals that survived the treatments were allowed to die naturally or were killed when moribund, and they were necropsied and lesions examined histologically. There was little or no effect of any of the treatments on mortality of the rats compared with the controls. The only suggestion of a possible carcinogenic effect was an unusually high incidence of five adenomas and two hyperplastic nodules of the adrenal cortex in the group of 20 rats treated with the highest concentration (625 ppm) of acrolein. The incidence of common neoplasms was very similar to the incidence in the controls. Three hamsters had adenomas of the pancreatic ducts, which were not seen in untreated hamsters. Approximately half of the hamsters treated with acrolein diethylacetal or acrolein oxime that survived early toxicity died with neoplasms. It was concluded that, considering the relatively small size of the test groups, it is not certain that acrolein and its derivatives are not carcinogenic, although it appears that any carcinogenic effect of these compounds will be weak. [R97] *Acrolein has been shown to form cyclic deoxyguanosine adducts when it reacts with DNA in vitro. In this study, a recently developed immunoassay for these adducts to study their formation in DNA from Salmonella typhimurium exposed to acrolein /was utilized/. Acrolein deoxyguanosine adducts were formed in a dose dependent fashion in Salmonella tester strains TA100 and TA104, reaching levels as high as 5 umol adduct/mol deoxyguanosine. Using the liquid preincubation assay, acrolein induced mutations were also found in strains TA100 and TA104. The correlation between acrolein deoxyguanosine adduct concentration and acrolein induced mutations in TA100, which contains GC base pairs at the site of reversion, suggests that the acrolein deoxyguanosine adduct is a promutagenic lesion. That mutations are also seen in TA104 which contains AT base pairs at the site of reversion suggest that adducts of bases other than deoxyguanosine may also be important in the mutagenic activity of acrolein. [R98] *The effects of acrolein were studied on the chick embryos of 48 and 72 hr of incubation. Acrolein was dissolved in physiological saline and injected into the air sacs of the eggs at doses ranging from 0.001 to 0.1 mg per egg. The controls received an equal amount of saline only (0.1 ml per egg). All the embryos including controls were examined at day 13. In all, 600 eggs were utilized for this investigation. At 48 hr incubation, the percentage survival ranged from 80 to 0 as the dosage of acrolein was increased. Embryonic mortality following 72 hr incubation did not increase significantly at any dose level. Gross malformations such as short and twisted limbs, everted viscera, microphthalmia, short and twisted neck, and hemorrhage over the body were observed. The frequency and the type of gross abnormalities did not vary much in the 48 or 72 hr treated groups. The incidence of malformation in the controls was low. The results of this study indicate that acrolein is embryotoxic at higher doses and moderately teratogenic to chick embryogenesis. [R99] *An animal model was used to study the effects of early administration of intramuscular corticosteroids on mortality and lung histopathology induced by a component of smoke. Thirty-six rabbits (mean weight, 2.7 kg) were exposed to acrolein vapor for 15 min; 30 min later the animals were divided into 3 treatment groups. One group received saline placebo intramuscularly at 12 hr intervals, a second group was treated intramuscularly with 100 mg methylprednisolone at 12 hr intervals, and a third group was treated with a single 100 mg dose of methylprednisolone followed by doses of saline at 12 hr intervals. The animals were studied for a 72 hr period. There was a significantly lower mortality in the 2 steroid-treated groups than in the nontreated group. A scoring system was developed for evaluating observed histologic changes in the lung. No correlation was seen between survival and histologic score or between score and treatment. High scores for particular histologic features did not explain mortality nor did they predominate in untreated animals; vascular congestion was found to be greater in the steroid-treated group. The beneficial effects of steroids in reducing mortality after inhalation of a common smoke constituent was not associated with any evidence of attenuation of lung damage. [R100] *... Acrolein at concn of 1x10-4 to 1x10-10 M was phytotoxic to tobacco tissue cultures. [R101] *Acrolein is a direct-acting mutagen in prokaryotic and eukaryotic systems... [R53] HTXV: *TCLo Man inhalation 1 ppm [R58] NTXV: *LD50 Rat oral 46 mg/kg; [R58] *LD50 Rat sc 50 mg/kg; [R58] *LD50 Mouse sc 30 mg/kg; [R58] *LD50 Rabbit oral 7 mg/kg; [R58] *LD50 Rabbit skin 562 mg/kg; [R58] *LC50 Sprague-Dawley rat (combined sexes) 26 ppm/1 hr; [R102] *LC50 Sprague-Dawley rat (combined sexes) 8.3 ppm/4 hr; [R102] *LD50 Cat inhalation 11 ppm/3-10 hr; [R22, 308] *LD50 Cat inhalation 18-92 ppm/3-4 hr; [R22, 308] *LD50 Cat inhalation 690-1150 ppm/2 hr; [R22, 308] *LD50 Rat inhalation 130 ppm/30 min; [R22, 310] ETXV: *LD50 Mallard Duck (male, 3-5 mo old) oral 9.11 mg/kg (95% confidence limit 6.32 mg/kg) /Sample purity 92%/; [R87] *LD50 Carassius auratus (goldfish) < 0.08 mg/l/24 hr (modified ASTM D 1345) /Conditions of bioassay not specified/; [R91] *LC50 Lepomis macrochirus (bluegill sunfish) 79 ug/l/24 hr /Conditions of bioassay not specified/; [R91] *LC50 Salmo trutta (brown trout) 46 ug/l/24 hr /Conditions of bioassay not specified/; [R91] *LC50 Lepomis macrochirus 0.10 mg/l/24 hr ; 0.09 mg/l/96 hr /Conditions of bioassay not specified/; [R103] *LC50 Daphnia magna 0.23 mg/l/24 hr; 0.083 mg/l/48 hr; No discernible effect conc= 0.034 mg/l. /Conditions of bioassay not specified/; [R104] *CARP AND THREAD-FIN SHAD ARE PARTICULARLY SENSITIVE, BEING KILLED @ 1 TO 2 PPM. BLACK BASS, BLUE GILL, AND LAMPREY EEL LARVAE APPEAR TO TOLERATE UP TO 5 PPM. /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R13, 8] *Inhibition of cell multiplication starts at 0.44 mg/l in Uronema parduczi (protozoa). ..; [R91] *The lowest observed avoidance concn in insects was above 0.1 mg/l for Ephemerella walkeri (mayfly nymphs) ... ; [R91] *... The incipient Median Threshold Limit (TLm) for Pimephales promelas (fathead minnow) was 84 ug/l in a flow through bioassay; The maximum acceptable toxicant concentration was 11.4 ug/l; [R91] *LC50 Pimephales promelas (fathead minnow) 14.0 ug/1/96 hr (confidence limit not reliable), flow-through bioassay with measured concentrations, 17.4 deg C, dissolved oxygen 9.3 mg/l, hardness 45.2 mg/l calcium carbonate, alkalinity 42.9 mg/l calcium carbonate, and pH 7.4; [R105] *LC50 Pimephales promelas (fathead minnow) 19.5 ug/1/96 hr (confidence limit 17.3-22.0 ug/l), flow-through bioassay with measured concentrations, 24.9 deg C, dissolved oxygen 7.3 mg/l, hardness 45.0 mg/l calcium carbonate, alkalinity 44.1 mg/l calcium carbonate, and pH 7.9; [R106] *EC50 Pimephales promelas (fathead minnow) 19.5 ug/l/96 hr (confidence limit 17.3-22.0 ug/l), flow-through bioassay with measured concentrations, 24.9 deg C, dissolved oxygen 7.3 mg/l, hardness 45.0 mg/l calcium carbonate, alkalinity 44.1 mg/l calcium carbonate, and pH 7.9. Effect: Affected fish lost schooling behavior, were hyperactive and overreactive to external stimuli, and had increased respiration. Equilibrium loss was not observed prior to death; [R106] *Inhibition of cell multiplication starts at ... 0.21 mg/l in bacteria (Pseudomonas putida) ..; [R91] *Inhibition of cell multiplication starts at ... 0.04 mg/l in algae (Microcystis aeruginosa). ..; [R91] TCAT: ?Acrolein (CAS # 107-02-8) was evaluated for acute oral toxicity in groups of 10 male CD-1 mice administered single doses of 0.0, 11.0, 13.2, 15.84, and 19.0 mg/kg by oral gavage (10 ml/kg in deionized water). Treatment was associated with lethargy, squinting of eyes, rough coats, hunching, and piloerection. Several survivors of 14-day post-gavage observation also had blackening, necrosis, and breakage of nails. Reduced weight gains (-11.6% - 28.6%) persisted at all dose levels to 14th-day end of study. All treatment-related mortality (22/50) occurred within 2 days of dosing and was consistent with an oral LD50 (by Karber probit analysis) in male mice of 13.9 (95% confidence limit, 12.8 - 15.1) mg/kg. Upon necropsy, the study lethalities exhibited reddened lungs and hemorrhagic stomachs and intestines. Other than 1 male of a 13.2 mg/kg dose with reddened lungs, the study survivors showed minimal pathological changes on terminal sacrifice. [R107] ?Acrolein (CAS # 107-02-8) was evaluated for mutagenicity in the Salmonella Liquid Suspension Mutant Fraction Assay. Relative to negative control, concentrations of 1, 3, 10, 20, and 40 ug/ml induced no concentration-related mutagenicity (increased mutant fraction, or number of mutants/viable cell) in duplicate assays with 5 Salmonella strains, either with or without rat liver metabolic activation. [R108] ?Acrolein (CAS # 107-02-8) was evaluated for acute oral toxicity in groups of 10 nonfasted male rats albino administered doses of 0, 31.6, 39.8, 50, and 63 mg/kg by oral gavage. Based on a method of Thompson, treatment was associated with an oral LD50 for male rats of 46 (39 - 56) mg/kg. Doses of 46 mg/kg administered to rats in a 0.05% aqueous dilution (instead of 0.5%) killed only 1/10 rats in a subsequent trial. Study lethalities had congested and mottled livers, hemorrhagic peritoneums, and hemorrhagic and injected stomachs. [R109] ?Acrolein (CAS # 107/02-8) was evaluated for acute oral toxicity in groups of 5 male New Zealand albino rabbits fed single doses of 3.16, 6.3, 12.6, and 25.2 mg/kg (1% in water). Treatment was associated with mortality consistent with an oral LD50 in rabbits of 7.1 (3.1 to 16.7) mg/kg. No further information was provided. Study lethalities had pale and mottled livers, injected, congested and hemorrhagic stomachs, and pale and friable kidneys. [R109] ?Acrolein (CAS # 107-02-8) was evaluated for repeated dose oral toxicity in groups of 10 Sherman strain rats exposed to concentrations of 0, 1, and 10 ppm in the drinking water (approximate doses of 0, 0.17, and 1.5 mg/kg/day) for 30 days. Treatment was associated with decreased fluid ingestion, reduced mean weight gain in surviving rats, and increased relative kidney weights (10 ppm), with no increased toxic mortality or pathology. Histopathological evaluation of small intestine, kidney, and liver revealed no treatment-related changes. Two day trial with exposures to 0, 30, 100, 300, and 1000 ppm in the drinking water versus fluid imbibed in groups of 10 rats revealed that reduced fluid intake is significantly related to acrolein concentrations. [R109] ?Acrolein (CAS # 107-02-8) was evaluated for acute inhalation toxicity in Sprague-Dawley rats (5/sex/group) administered single dynamically-generated exposures to mean vapor concentrations of 0, 14, 22, 24, 31, and 81 ppm for 1 hour or 0, 4.8, 7.0, 9.1, and 12.1 ppm for 4 hours. Exposures were associated with clinical signs of toxicity at all exposure levels, including lacrimation, periocular, perinasal, and perioral wetness and encrustation, unkempt fur, labored breathing, lethargy, and stomach distention. Body weights or bodyweight gains were universally depressed during post-exposure Week 1 and, during Week 2, in 22 and 24 ppm groups of 1-hour exposures and 12.1, 9.1, and 7.0 ppm groups of 4-hour exposures. Treatment-related mortality occurred primarily from Day 1 through Day 6 and, based on a Thompson moving average method, was consistent with all-sex inhalation 1-hour and 4-hour LC50s (with 95% confidence limits), respectively, of 26 (24-27) ppm and 8.3 (7.0-9.9) ppm. Upon necropsy, gross lesions were identified only in study lethalities and included perinasal and perioral encrustation, mottled discoloration of lungs and liver, clear fluid-filled trachea and thoracic cavity, reddened submandibular lymph nodes, gas-filled stomach and intestines, and opaque or cloudy eyes. [R110] ?Acrolein (CAS # 107-02-8) was evaluated for mutagenicity in the Chinese Hamster Ovary (CHO) Mutation test. Selected based on preliminary cytotoxicity tests, concentrations of 0.0 (ethanol solvent control), 0.2, 0.5, 1.0, 2.0, and 4.0 x 10(-5)% (v/v), both in the presence and the absence of S9 metabolic activation, produced statistically significant (Student's t-test, p < 0.01) mutagenicity (mutants/10(6) cells/viable cells). Significantly increased CHO mutagenicity, ranging from 56.2 (2.0 x 10(-5)%) to 200.00 (0.5 x 10(-5)%) mutants/10(6) viable cells without metabolic activation and 18.6 (0.2 x 10(-5)%) to 190.9 (2.0 x 10(-5)% mutants/10(6) viable cells, did not correlate to concentrations, however, and positive results were not obtained in either Sister Chromatid Exchange or Unscheduled DNA Synthesis tests. While acrolein mutagenicity was statistically indicated in the CHO Mutation test, a dose-response relationship was not demonstrated. [R111] ?Acrolein (CAS # 107-02-8) was evaluated for clastogenicity in the Sister Chromatid Exchange (SCE) test. Selected based on preliminary cytotoxicity tests, 6 staggered acrolein concentrations between 0.0% (negative culture, ethanol solvent, and positive controls) and 3.0 x 10(-5)% (v/v) without S9 metabolic activation and between 0.0% and 10.0 x 10(-5)% with metabolic activation, respectively, induced no statistically significant (Student's t-test) dose-related increments in Chinese Hamster ovary (CHO) cell SCE frequency (SCE/cell, mean SCE/chromosome of 20 cells/culture) after 5-hour and 2-hour incubations. Statistically significant increases in SCE were observed at doses of 0.8 x 10(- 5)% (p < 0.05) and 5.0 x 10(-5)% (p < 0.01), respectively, in cultures without and with S9 metabolic activation; however, based on a lack of a dose-response relationship, study authors concluded that acrolein does not induce SCE-derived mutagenicity in vitro. [R111] ?Acrolein (CAS # 107-02-8) was evaluated for mutagenicity in an Unscheduled DNA Synthesis (UDS) Assay with rat hepatocytes. Selected based on preliminary cytotoxicity tests, 12 acrolein concentrations from 0.00 (ethanol solvent control, 2 positive controls) to 30.0 x 10(-5)% added to rat liver cells cultured in the presence of 3H-thymidine and hydroxyurea for 2 hours were associated a statistically significant (p < 0.05, Duncan's Multiple Range Analysis) increase in nuclear-bound label per 10(6) viable hepatocytes at a dose of 0.6 x 10(5)%. Further, both nuclear-bound label and DNA-bound label from DNA precipitated per 10(6) viable hepatocytes/dose exposed at toxicity levels allowing at least 50% survival were consistently numerically greater than values obtained from historical and solvent controls. A lack of dose-related statistically significant increases in either nuclear- and/or DNA-bound label led authors to conclude this study was inconclusive regarding acrolein-induced unscheduled DNA synthesis in rat hepatocytes in vitro. [R111] ?Acrolein (CAS # 107-02-8) with several other chemicals was evaluated for sensory (upper airway) irritation in a modified Alarie Mouse Sensory Irritation Test. Four each male Swiss Albino CD-1 mice were administered dynamic head only exposures to vapor concentrations of 0.0 to 8.7 ppm in air over 10 minutes to characterize type response as either immediate and persisting, immediate with accommodation (ameliorated with time), or immediate and progressive during exposures. Concentrations below 2 ppm produced a linear response (breaths/minute/animal) curve, while maximal responses (decreased respiration rate) occurred after 10 minutes' exposure, thus indicating a progressive response to exposure without physiological accommodation or compensation; an RD50 (linear regression determination of that concentration causing 50% reduction of respiratory rate) was 1.27 ppm (R=0.89; 95% CL 1.07-1.52 ppm). Response data were not provided. [R112] ?Acrolein (CAS # 107-02-8) was evaluated for acute inhalation toxicity in groups of 5 each male and female Syrian golden hamsters administered low dynamic whole-body exposures to vapor concentrations of 11.2, 23.3, 30.0, and 30.4 ppm in air for 4 hours. During all exposures, the animals kept their eyes shut and exhibited lachrymation, dyspnea, nasal secretion, and, late in the exposure, inflating of cheek pouches. Treatment was also associated with significantly dose-related mortality between 24 hours and 12 days post exposure, consistent with an LC50 (by a method of Litchfield and Wilcoxon) of 25.4 ppm (58 mg/m3 air) with a calculated LCt50 of 101 ppm-hour. [R113] ?Acrolein (CAS # 107-02-8) was evaluated for acute inhalation toxicity in male Sprague-Dawley Spartan rats (7/exposure group) administered single dynamically generated whole-body exposures to average analytic vapor concentrations of 14.5, 41.5, 93.5, and 251 ppm for up to 30 minutes. During exposures and a 15-minute post-exposure venting period, the animals were observed continuously for behavioral anomalies and sensory irritation, including altered reflexes, eye and/or nasal irritation, and or respiratory irregularities. Treatment was associated with clinical signs of toxicity including teary and squinted eyes, nasal discharge, labored breathing, gasping, and prostration at all levels of exposure; treatment also dampened righting, blink, and pain reflexes at exposures of 41.5 ppm or greater. Bodyweights were low normal based on comparison with historical controls, and mortality was consistent with a 30-minute LC50 of 60 ppm. Additionally, severity, time to onset, progression, and duration of the toxic response were each correlated with dose. Immediate necropsy of study lethalities upon their discovery revealed treatment-related gross pathology including congestion of nasal turbinates (41.5 ppm), failure of lungs to collapse on incision with a dark mottled and congested appearance of apical and cardiac regions of the lungs (41.5 ppm, 1/7), accumulations of exudate around nose and mouth (93.5 ppm, 7/7; 251 ppm, 7/7), mucopurulent or mucohemorrhagic rhinitis (93.5 ppm, 7/7; 251 ppm, 7/7), pulmonary congestion and hemorrhage (93.5 ppm, 7/7; 251 ppm, 7/7), gaseous distention of the stomach (93.5 ppm, 7/7; 251 ppm, 7/7), congestion of liver and kidneys (93.5 ppm, 7/7; 251 ppm, 1/7), pulmonary edema (251 ppm), and hydrothorax (251 ppm). None of 7/7 terminally sacrificed survivors of a 14.5 ppm exposure exhibited any treatment-related gross pathology, while survivors of 41.5 ppm exposures had catarrhal rhinitis on Day 15 terminal necropsy. [R114] ?Acrolein (CAS # 107-02-8) was evaluated for subchronic inhalation toxicity in Syrian golden hamsters (10/sex/group) administered dynamic whole-body exposures to vapor concentrations of 0, 0.4, 1.4, and 4.9 ppm in air for 6 hours/day, 5 days/week over 13 weeks. Treatment with high and mid-level exposures was associated with clinical signs of toxicity, including restlessness, insomnia, eye irritation, nasal discharge, salivation, and statistically significant (p < 0.05, Student's t-test) and persistent reductions in bodyweight (4.9 ppm). Treatment-related mortality consisted of a solitary 4.9 ppm male killed in moribund condition in Week 12. Elevations in hemoglobin and hematocrit values, as well as erythrocyte and lymphocyte counts, were statistically significant (p < 0.05, Wilcoxon analysis) in 4.9 ppm females, while the high-exposure female neutrophil count was significantly depressed. Serum biochemistry values appeared unaffected in both males and females, as urinalyses were unremarkable relative to controls. Increased relative kidney, brain, gonad, and lung weights reached statistical significance in high dose animals of both sexes, while relative heart weights were significantly increased in 4.9 ppm females only. Examination of major organs on terminal necropsy (on the day following a final exposure) revealed no gross changes attributable to treatment, other than subcutaneous edema, ascites, epididymal abscesses, gastric ulcer, and pale kidneys and liver of the high-exposure male lethality. Histological evaluation of head, larynx, trachea, and pulmonary lobes of each animal revealed cellular changes of the nasal cavity, larynx, and trachea, including moderate rhinitis, necrosis, and hyper- and metaplasia of respiratory and olfactory epithelium, primarily in the 4.9 ppm group. Females of 4.9 ppm exposures also exhibited slight hyperplastic appearance of the vocal cords and surrounding tissues and near universal focal hyper- and metaplasia of the tracheal epithelium. A few males also showed tracheal hyper- and metaplasia. No histopathological changes attributable to acrolein exposure were identified in the bronchi or lungs, and, among the 4.9 ppm males and females examined, no other organ systems showed histological manifestation of acrolein vapor toxicity. Only the premature high exposure study lethality exhibited amyloidosis of the kidneys, liver, and adrenals, testicular atrophy, as well as inflammatory changes in many organs. [R115] ?Acrolein (CAS # 107-02-8) was evaluated for mutagenicity in the Reverse Mutation Test using 5 strains of Salmonella typhimurium cultured both in the presence and the absence of mammalian metabolic activation with acrolein concentrations of 0 (negative and positive controls), 0.001, 0.01, 0.1, and 1.0 ug/plate (a dose of 10 ug was toxic in preliminary screening tests) for 48 hours. None of the 5 Salmonella typhimurium strains produced sufficiently increased revertants/plate over negative control to indicate a acrolein mutagenicity and no dose-related response was demonstrated. [R116] ?Acrolein (CAS # 107-02-8) was evaluated for mutagenicity in a quantitative overlay assay using 5 strains of Salmonella typhimurium cultured both in the presence and the absence of Aroclor-induced rat liver microsomal enzyme with acrolein concentrations of 0 (solvent and positive controls), 1, 3, 5, 10, 20, 30, and 50 ug/plate for 48 hours. None of the 5 Salmonella typhimurium strains produced sufficiently increased revertants/plate over negative control, either with or without mammalian metabolic activation, to indicate a acrolein mutagenicity. No toxicity was observed under these test conditions, although preliminary screening had shown toxicity associated with exposures to 25 to 39 ug/plate. [R117] POPL: *Since acrolein has been shown to suppress pulmonary antibacterial defenses, individuals with or prone to pulmonary infections may also be at a greater risk /from exposure to this cmpd/. [R118] ADE: *IT CAN ... BE ABSORBED PERCUTANEOUSLY ... [R51] *In goat and hen, no acrolein was detected in tissues or excreta, or in goat milk or hen eggs following administration of high doses. [R8, 19] METB: *... The excretion of acrolein metabolites in urine of adult female Wistar rats /was observed/ after a single oral admin of 10 mg/kg body wt acrolein in corn oil. S-carboxyethyl-N-acetylcysteine (S-carboxyethylmercapturic acid) AND S-(propionic acid methyl ester) mercapturic acid were reported to be the major metabolites. [R119] *MALE CFE ALBINO RATS METABOLIZED 10.5% OF A SC DOSE OF 1 ML OF A 1% SOLN OF ACROLEIN IN ARACHIS OIL TO N-ACETYL-S-(3-HYDROXYPROPYL)-L-CYSTEINE, WHICH WAS ISOLATED FROM THE URINE. [R119] *Acrolein is metabolized in vitro by liver and lung microsomes to glycidaldehyde. [R82] *Acrolein is a suspected carcinogen because of its 2,3-epoxy metabolite ... [R20, 982] ACTN: *ACROLEIN IS A GENERAL CELL TOXICANT, AND KILLS THROUGH ITS SULFHYDRYL REACTIVITY, WHICH DESTROYS VITAL ENZYME SYSTEMS IN PLANT CELLS. [R13, 10] *CARDIOVASCULAR ACTIONS OF ACROLEIN ADMIN IV ARE SIMILAR TO ACETALDEHYDE AND PROPIONALDEHYDE. PRESSOR RESPONSE APPEARS TO RESULT FROM RELEASE OF CATECHOLAMINES FROM SYMPATHETIC NERVE ENDINGS AND FROM ADRENAL MEDULLA OF ANESTHETIZED RATS. THESE ALDEHYDES ALSO EXERT CARDIOINHIBITORY EFFECT WHICH IS MEDIATED BY VAGUS NERVE. INHALATION STUDIES WITH ACROLEIN REVEALED THAT THIS ALDEHYDE HAS SIGNIFICANT CARDIOVASCULAR ACTIVITY AT CONCENTRATIONS BELOW THOSE WHICH MIGHT BE ENCOUNTERED IN CIGARETTE SMOKE. PREDOMINANT EFFECT OF INHALED ACROLEIN AT THESE DOSES WAS AN INCREASE IN BLOOD PRESSURE AND HEART RATE. [R120] *Resting rat pulmonary alveolar macrophages exposed to acrolein were stimulated to synthesize and release thromboxane B2 and prostaglandin E2 in a dose-dependent manner. Although phagocytosis was also inhibited in a dose-dependent manner, the reduction in prostaglandin E2 appeared to be partially independent of particle ingestion since thromboxane B2 synthesis was not affected by low doses of acrolein. In fact, high doses induced a slight enhancement in thromboxane B2 synthesis. Therefore, acrolein selectively inhibited the enzyme, prostaglandin endoperoxide E isomerase, necessary for the conversion of the endoperoxide to prostaglandin E2. The possible involvement of acrolein's sulfhydryl reactivity in the inhibition of the isomerase enzyme was indicated. Pulmonary macrophages were unable to reverse the acrolein effects on arachidonate metabolite synthesis after 6 hr in an acrolein-free environment. [R121] *EXPOSURE OF RABBIT LUNG ALVEOLAR MACROPHAGES TO ACROLEIN INHIBITED PHAGOCYTOSIS, ADHESIVENESS, CALCIUM(2+)-DEPENDENT ATPASE, BUT NOT MAGNESIUM(2+)-DEPENDENT ATPASE. [R122] *IN MICE EXPOSED TO ACROLEIN-FORMALDEHYDE ATMOSPHERES, MEASUREMENT OF RESP RESPONSE SHOWED THAT ACROLEIN AND FORMALDEHYDE ACT AT SAME RECEPTOR SITE. COMPETITIVE ANTAGONISM OCCURS WHEN PRESENT TOGETHER. [R123] *The inhibition of DNA-methylase activity by acrolein was studied in vitro. DNA-methylase isolated from the urothelium or liver of rats was incubated with acrolein and the extent of methylase inhibition was determined. Acrolein at 10 umol/l inhibited liver DNA-methylase activity by about 50% and urothelium activity by approximately 26%. A Line weaver-Burk plot showed that acrolein inhibited liver DNA-methylase activity in a competitive manner with an inhibition constant at 6.7 uM. Liver DNA-methylase was incubated with 10 uM acrolein and 0 to 200 uM dithiothreitol or 0 to 50 uM glutathione and the effects on DNA-methylase activity were determined. Glutathione and dithiothreitol protected against acrolein induced inhibition of DNA-methylase activity. Glutathione showed a much greater protective effect than dithiothreitol. Hepatic DNA-methylase was incubated with acrolein in the presence or absence of added DNA or methylase protein and the effects on DNA-methylase activity were determined. Increasing the methylase protein concentration protected against inhibition whereas increasing the concentration of DNA had no effect. DNA/acrolein adducts from Micrococcus lysodeikticus were added to hepatic DNA-methylase and the effect on DNA-methylase activity was investigated. As the concentration of DNA adducts from Micrococcus lysodeikticus increased, DNA-methylase activity decreased. The authors conclude that acrolein is similar to N-methyl-N'-nitro-N-nitrosoguanidine in its ability to react with both DNA and DNA-methylase protein. [R124] *Acrolein, a genotoxic aldehyde released in the metabolic activation of the cytostatic drug cyclophosphamide, is inactivated by glutathione transferases either by conjugation with reduced glutathione or by covalent binding to the enzymes in the absence of glutathione or by covalent binding to the enzymes in the absence of glutathione. The catalytic efficiency (kcat/Km) with acrolein as a substrate was determined for representatives of the three classes Alpha, Mu, and Pi of human glutathione transferases. Transferase pi exhibited the highest and transferase epsilon the lowest catalytic efficiencies, respectively. As measured by the kcat/Km value, acrolein ranks among the most active substrates known for transferase Pi. The irreversible binding of acrolein to the enzymes was monitored as the inactivation of the enzyme activity. Transferase Pi reacted significantly more rapidly with acrolein than did transferases Mu and epsilon. [R125] *An examination was conducted of the effects of allylamine and acrolein on electron transport and oxidative phosphorylation in mitochondria isolated from hearts of male Sprague-Dawley rats. Both acrolein and allylamine inhibited State III, State IV, and uncoupler stimulated respiration in a concentration dependent fashion when added to mitochondria respiring on glutamate, malate, and malonate as substrate. While the concentration dependent inhibitory effect was statistically greater for acrolein than allylamine for State III and uncoupler stimulated oxygen uptake, the concentrations necessary to produce these effects were in the millimolar range for both compounds. Allylamine and acrolein also displayed concentration dependent effects on respiratory enzyme activities in mitochondria actively respiring on succinate as substrate. State III, State IV, and uncoupler stimulated oxygen uptake were significantly inhibited by increasing concentration of all allylamine or acrolein. In contrast to the results obtained with glutamate, malate, and malonate, with succinate as substrate no significant differences between allylamine and acrolein in concentration effect slopes were noted for State III, State IV and uncoupler stimulated activities, indicating site selectivity between the two compounds. Respiratory control ratios were significantly decreased by allylamine and acrolein with glutamate, malate, and malonate substrate. When succinate was used as substrate, the respiratory control ratio was significantly reduced only by acrolein, again suggesting the site selective nature of this compound. [R126] *Acrolein was evaluated in vitro as a potential substrate or inhibitor of rat liver mitochondrial and cytosolic aldehyde-dehydrogenases. Subcellular fractions, cytosolic and mitochondrial, were prepared from male Sprague-Dawley rat livers without pretreatment and were used on the same day they were prepared. Oxidation of acrolein by aldehyde dehydrogenases in subcellular fractions and enzyme inhibition by acrolein were assayed spectrophotometrically and chromatographically. It was found that acrolein was not oxidized by either mitochondrial or cytosolic aldehyde dehydrogenases, but rather was a potent inhibitor of these enzymes in a dose dependent manner. In the presence of 2-mercaptoethanol, an adduct with acrolein was formed and enzyme activity was detected. Particularly susceptible to the inhibitory effects of acrolein was the mitochondrial high affinity aldehyde dehydrogenase. Inhibition was rapid with an 88% reduction in control aldehyde dehydrogenase activity within 5 seconds of addition of 10 uM acrolein. It was suggested that at the aldehyde binding site an irreversible inhibition occurs and at the cofactor binding site of the enzyme a reversible noncompetitive inhibition occurs. Inhibition of cytosolic high affinity aldehyde dehydrogenase was also rapid, with a 54% inhibition being reached in 5 seconds after addition of 50 uM acrolein. It was concluded that acrolein may cause irreversible inhibition of the isozymes by covalently binding to the sulfhydryl group through a Michael addition to form a thioether at the active site of the enzyme. This aldehyde dehydrogenase inhibitory effect of acrolein may be important in the toxicity of aldehyde compounds liberated by lipid peroxidation. Acrolein inhibition of aldehyde dehydrogenases may also be important in toxicities associated with cyclophosphamide chemotherapy. [R127] *Acrolein is believed to cause tissue damage by the mechanism of release of toxic /Oxygen/ radicals via activation of arachidonic acid cascade, by binding to sulfhydryl groups, and by protein damage. [R20, 982] INTC: *The interaction of the antihypertensive agent guanethidine and two aldehydes possessing sympathomimetic activity on the pressure of spontaneously hypertensive rats was studied. Acrolein (0.05-0.5 mg/kg) produced a pressor response at low doses and a depressor response at high doses in acutely and chronically guanethidine pretreated spontaneously hypertensive rats. Depressor responses to high doses of aldehydes may have been attributed to vagal stimulation or direct vasodilation. There was a significant interaction between the aldehydes and guanethidine, which may have implication for someone undergoing treatment with guanethidine for hypertension while being exposed to acetaldehyde and related cmpd from ethanol and tobacco smoke. [R128] *Muramyl dipeptide protection from acrolein toxicity was tested using isolated rat hepatocytes. Incubation of hepatocyte suspensions with acrolein (143 umol/ml) for 15 min reduced viability to 62%. Pretreatment of hepatocytes in incubation media with muramyl dipeptide (20.6 nmol/ml) incr viability significantly to 83% p < 0.05). It is suggested that muramyl dipeptide in certain dosages may produce nonspecific stabilization of cytoplasmic membranes towards acrolein. [R129] *The protective effect of n-acetylcysteine against the toxicity of ... acrolein ... was investigated using isolated rat hepatocytes as the experimental system. ... n-Acetylcysteine protected against acrolein toxicity by providing a source of SH groups, and was effective without prior conversion. [R130] *Groups of 30 male and 30 female Syrian golden hamsters were exposed to 0 or 4 ppm (0 or 9.2 mg/cu m) acrolein vapor (purity unspecified) for 7 hr/day on 5 days/wk for 52 weeks, and were given, at the same time and also for 52 wk, weekly intratracheal instillations of 2 dose levels of benzo(a)pyrene or sc injections of n-nitrosodiethylamine (once every 3 wk). All surviving animals were killed at 81 wk. Addnl exposure to acrolein did not significantly incr the tumor incidence produced by benzo(a)pyrene or N-nitrosodiethylamine. [R82] */Male Sprague-Dawley albino/ rats were exposed to experimental atmospheres of carbon monoxide in air, acrolein in air, and to mixtures of carbon monoxide and acrolein in air. The toxic potency of each ... was evaluated ... by measurement of time to incapacitation as a function of toxic gas concentrations. ... There was no evidence of synergistic action. ... An inhibitory or antagonistic effect of undefined mechanism /existed/ when acrolein was present in the mixture at concentrations of lesser toxic potency that of carbon monoxide. [R131] *Incubation of isolated hepatocytes with allyl alcohol results in GSH depletion and subsequent cytotoxicity which is prevented by pyrazole, an inhibitor of alcohol dehydrogenase. Both GSH depletion and cytotoxicity were much more rapid when hepatocytes were incubated with acrolein, the reactive metabolite, and were not affected by pyrazole. However, cytotoxicity of both allyl alcohol and acrolein was enhanced by the aldehyde dehydrogenase inhibitors cyanamide and disulfiram. Malondialdehyde, a lipid peroxidation product, was also formed when hepatocytes were incubated with either agent, and treatment of hepatocytes with a ferric iron chelator, desferrioxamine, or an antioxidant delayed the cytotoxicity without affecting GSH depletion. ... [R132] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *INHALATION OF AIR CONTAINING 10 PPM ACROLEIN MAY BE FATAL IN A FEW MIN. [R73] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Acrolein is released to the environment through manufacturing processes and its use as an intermediate for glycerine, methionine, glutaraldehyde and other organic chemicals. It is also released into the environment through exhaust gas from combustion processes including tobacco smoke, emissions from forest fires, and auto exhaust. Acrolein has also been detected in sugar cane molasses, souring salted pork, the fish odor of cooked horse mackerel, the volatiles from white bread, the volatile components of chicken-breast muscle, the aroma volatiles of ripe arctic bramble berries and the products from heating animal fats and vegetable oils. If released to air, a vapor pressure of 274 mm Hg at 25 deg C indicates acrolein will exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase acrolein will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, ozone, and nitrate radicals; the half-lives for these reactions in air are estimated to be 20 hrs, 15 days, and 28 days, respectively. Acrolein in hexane solvent show moderate absorption of UV light > 290 nm, which indicated potential for photolytic transformation under environmental conditions. If released to soil, acrolein is expected to have very high mobility based upon an estimated Koc of 3. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 1.22X10-4 atm-cu m/mole. Acrolein may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, acrolein is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. The half-life of acrolein in natural unsterilized water was 29 hours compared with 43 hours in sterilized (thymol-treated) water. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4.4 hrs and 4.6 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to acrolein may occur through inhalation and dermal contact with this compound at workplaces where acrolein is produced or used. Exposure of the general population occurs primarily through atmospheric contact. (SRC) NATS: *Aldehydes are reported to be common products of a variety of microbial and vegetative processes(1). Acrolein has been identified as a volatile component of essential oil extracted from the wood of oak trees(2). Acrolein has been detected in sugar cane molasses, souring salted pork, the fish odor of cooked horse mackerel, the volatiles from white bread, the volatile components of chicken-breast muscle, the aroma volatiles of ripe arctic bramble berries and the products from heating animal fats and vegetable oils(2). Small amounts of acrolein have been detected in tomatoes(3) and in chicken and beef volatiles(4). [R133] ARTS: *An estimated 46.7 tons of acrolein were emitted into the USA atmosphere during 1978. Acrolein has been identified as an emission from plants mfr acrylic acid. Acrolein emissions have ... been reported from coffee-roasting operations (none detected to 0.6 mg/cu m), from a lithographic plate coater (less than 0.23 to 3.9 mg/cu m) and from an automobile-spray booth (1.1 to 1.6 mg/cu m). Addnl sources of atmospheric acrolein that have been identified incl turbine engines, the mfr of fish oils, lacquers, plastics and synthetic rubber, forest fires and spray painting. [R134] *It has been estimated that acrolein, acetone and low-molecular-wt fatty acids are emitted at the rate of 1 million kg/year during the mfr of oxidation-hardening enamels in the Netherlands. Acrolein was detected in the USSR in air samples from populated areas located in the vicinity of 3 enamelled wire mfr plants. It has ... been detected in ventilation gases from paint and varnish preparation and distributing shops in USSR. [R134] *Acrolein was detected among other trace odors in air in Japan: (1) in exhaust gas from a metal paint drier (6.1 mg/cu m); (2) in exhaust gas from 2 poultry-manure dryers (3.1-4.2 mg/cu m); and (3) in exhaust gas from a corn-starch mfr works (1.8 mg/cu m). [R134] *Acrolein is released to the environment through manufacturing processes and its use as an intermediate for glycerine, methionine, glutaraldehyde and other organic chemicals. It is also released into the environment through exhaust gas from combustion processes including tobacco smoke, emissions from forest fires, and auto exhaust. Direct application to water and wastewater during use as an aquatic herbicide and slimicide and from formation in the atmosphere as a photooxidation product of various hydrocarbon pollutants including 1,3-butadiene are potential sources of acrolein in the environment(1-5). [R135] *The main source of acrolein is incomplete organic combustion(1). Specific point sources include residential fireplaces, burning of coal, oil, and natural gas in power plants, automobile exhaust, overheated vegetable and animal fats, tobacco and marijuana smoke, and structural and vegetative fire smoke(1). [R136] FATE: *AQUATIC FATE: EXPTL DATA FOR DECAY OF ACROLEIN IN WATER INDICATE APPROX 1ST ORDER KINETICS. THE REACTION CONTINUED TO COMPLETION IN NATURAL WATER. DATA ON EFFECTS OF PH ON DECAY OF ACROLEIN MAY BE USED AS A CONSERVATIVE ESTIMATE OF DISSIPATION RATE. IN WATER FLOWING IN 2 CHANNELS, AN 8 TO 10 FOLD DISCREPANCY BETWEEN OBSERVED AND PREDICTED RATES OF DISSIPATION WAS ATTRIBUTED TO MAJOR LOSSES IN VOLATILIZATION AND ADSORPTION. A RELATIVELY NONVOLATILE REACTION PRODUCT (WHICH GAVE A POSITIVE REACTION WITH DINITROPHENYLHYDRAZINE) ACCUMULATED INITIALLY BUT DISSIPATED. [R137] *TERRESTRIAL FATE: In the terrestrial environment, it is estimated that acrolein would have a low tendency to adsorb on soil and would probably volatilize into the air or be leached from the soil by water. [R138, (1984)] *AQUATIC FATE: Half-life in water at pH 5, 150 hr; at pH 7, 120-180 hr; at pH 9, 5 to 40 hr. [R8, 19] *AQUATIC FATE: Acrolein is removed from aqueous environments, with half-lives usually on the order of less than a day. The primary loss process appears to be an initial hydration (and possibly some biotransformation) to beta-hydroxypropionaldehyde, which is then further biotransformed. [R30, p. 20-1a] *Due to its high vapor pressure and water solubility, acrolein is expected to be highly mobile when released into the environment, although degradative processes are likely to limit its transport. [R138, (1980)] *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3(SRC), determined from a structure estimation method(2), indicates that acrolein is expected to have very high mobility in soil(SRC). Volatilization of acrolein from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 1.22X10-4 atm-cu m/mole(3). The potential for volatilization of acrolein from dry soil surfaces may exist(SRC) based upon a vapor pressure of 274 mm Hg(4). Results of biodegradation screening studies indicate that acrolein would be readily degraded by mixed microbial populations(5-7). The half-life of acrolein in natural unsterilized water was 29 hours compared with 43 hours in sterilized (thymol-treated) water(8). [R139] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3(SRC), determined from an estimation method(2), indicates that acrolein is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1.22X10-4 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 4.4 hrs and 4.6 days, respectively(SRC). The decay of acrolein and its hydration product 3- hydroxypropanal displayed first order kinetics in agricultural canals when applied at the recommended rate for aquatic weed control(5); the half-life for this reaction is 21 days. The dissipation half-life of acrolein was 10.2 and 7.3 hours in weedy and non-weedy canals, respectively. In the weedy canal, 91.5% of acrolein had dissipated within 33.0 hours and in the non-weedy canal, 48% had dissipated within 7.9 hours(5). The half-life of acrolein in natural unsterilized water was 29 hours compared with 43 hours in sterilized (thymol-treated) water(6). In another experiment, acrolein added to irrigation channels at initial concentrations of 6.1, 17.5 and 50.5 ppm underwent 100% loss in 12.5 days(7). Removal rate constants ranging from 0.27-0.34 1/days were calculated by linear regression. These values correspond to half-lives of 2.0-2.5 days(8). According to a classification scheme(9), an estimated BCF of 3(SRC), from a log Kow of -0.01(10) and a regression-derived equation(11), suggests the potential for bioconcentration in aquatic organisms is low. Reaction with singlet oxygen or alkylperoxy radicals, and photolysis are not expected to be important fate processes. [R140] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acrolein, which has a vapor pressure of 274 mm Hg at 25 deg C(2), is expected to exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase acrolein is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 20 hrs(SRC), calculated from its rate constant of 1.99X10-11 cu cm/molecule-sec at 25 deg C(3). Products of the reaction of acrolein with hydroxyl radicals include: carbon dioxide, formaldehyde, glycoaldehyde, ketene, and peroxypropenyl nitrate(4). The half-life for acrolein reacting with ozone in the atmosphere has been estimated to be 15 days based on an experimentally determined reaction rate constant of 7.4X10-19 cu cm/molecule-sec at room temperature(5) and assuming an average ambient ozone concentration of 7X10+11 molecules/cu cm(5). The half-life for acrolein reacting with nitrate radical in the atmosphere has been estimated to be 28 days based on an experimentally determined reaction rate constant of 1.20X10-15 cu cm/molecule-sec at room temperature(6) and assuming an average ambient ozone concentration of 2.4X10+8 molecules/cu cm(7). Acrolein in hexane solvent show moderate absorption of UV light > 290 nm(8), which indicated potential for photolytic transformation under environmental conditions(SRC). [R141] BIOD: *AEROBIC: The half-life of acrolein in natural unsterilized water was 29 hours compared with 43 hours in sterilized (thymol-treated) water(1). These results suggest that biodegradation may be partially responsible for the degradation of acrolein in the environment. 100% loss was observed when 5 and 10 mg/l acrolein underwent a static incubation in the dark at 25 deg C with sewage inoculum for 7 days(2). In another experiment, acrolein reached 30% of its BOD in river water after 100 hrs(3). Results of other biodegradation screening studies also indicate that acrolein would be readily degraded by mixed microbial populations(4-6). In contrast, no BOD removal was observed during a 5-day BOD dilution test in which effluent from a biological waste treatment plant was used(7). [R142] *ANAEROBIC: Acrolein, at an initial concentration of 50 mg/l as organic carbon, gave no evidence of degradation when incubated for 8 weeks in a 10% anaerobic sludge inoculum(1). [R143] ABIO: *Acrolein has been determined to be one product of the photooxidation of 1,3-butadiene in air. This photooxidation reaction may contribute to significant ambient atmospheric levels of acrolein because of the occurrence of 1,3-butadiene at concn of approx 4.6 ug/cu m in urban ambient air. [R134] *Acrolein contains no functional groups which would be suspectible to chemical hydrolysis under environmental conditions(1,2). Arcolein will be susceptible to formation of beta-hydroxypropionaldehyde by hydration in water. Hydration is a reversible reaction with an equilibrium constant of 21.2. The half-life for hydration of acrolein has been calculated to be 21 days based on a pseudo-first order reaction rate constant of 0.032 day-1(1). Half-lives for acrolein reacting with singlet oxygen and alkyl peroxy radicals in natural sunlit water have been estimated to be 8 and 23 years, respectively. These values are based on reaction rate constants of 1X10+7 and 3.4X10+3 l/mole-hr, respectively, a singlet oxygen concentration of 1X10-12 mole/l and an alklyl peroxy radical concentration of 1X10-9 mole/l(2). Acrolein in hexane solvent show moderate absorption of UV light > 290 nm(2), which indicated potential for photolytic transformation under environmental conditions(SRC). However, hydration of acrolein in water would destroy the chromophores which absorb light. As a result, the potential for direct photolysis would be slight(2). [R144] *The rate constant for the vapor-phase reaction of acrolein with photochemically-produced hydroxyl radicals is 1.99X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of approximately 20 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2). Products of the reaction of acrolein with hydroxyl radicals include: carbon dioxide, fomaldehyde, and glycolaldhyde. In the presence of nitrogen oxides, products include peroxyacetylnitrate and nitric acid(3). The half-life for acrolein reacting with ozone in the atmosphere has been estimated to be 15 days based on an experimentally determined reaction rate constant of 7.4X10-19 cu cm/molecule-sec at room temperature(4) and assuming an average ambient ozone concentration of 7X10+11 molecules/cu cm(4). The rate constant for the vapor-phase reaction of acrolein with nitrate radicals is 1.20X10-15 cu cm/molecule-sec at 25 deg C(5). This corresponds to an atmospheric half-life of approximately 28 days at an atmospheric concentration of 2.4X10+8 nitrate radicals per cu cm(6). Based on these values, reaction with hydroxyl radical is expected to be the most important fate process for acrolein in the ambient atmosphere(SRC). The half-life for photodissociation of acrolein in the atmosphere has been estimated to be approximately 3.5 days based on measured quantum yields(7). [R145] BIOC: *A BCF of 344 has been measured for acrolein in bluegill sunfish(1). However, this value may be an overestimate since total (14)C was measured and may have included acrolein metabolites. An estimated BCF of 3 was calculated for acrolein(SRC), using a log Kow of -0.01(2) and a regression-derived equation(3). According to a classification scheme(4), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R146] KOC: *Koc = 5.0 (calculated from water solubility by regression equations). [R147] *Using a structure estimation method based on molecular connectivity indices(1), the Koc for acrolein can be estimated to be 3(SRC). According to a classification scheme(2), this estimated Koc value suggests that acrolein is expected to have very high mobility in soil. [R148] VWS: *The Henry's Law constant for acrolein is 1.22X10-4 atm-cu m/mole(1). This Henry's Law constant indicates that acrolein is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 4.4 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4.6 days(SRC). Acrolein's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of acrolein from dry soil surfaces may exist(SRC) based upon a vapor pressure of 274 mm Hg(3). [R149] WATC: *SURFACE WATER: Acrolein concn in surface water was reported as follows: USEPA STORET Data Base - 798 water samples, 0.25% pos., median concn < 14 ug/l(1). [R150] *RAIN/SNOW: Levels of acetone and acrolein in rainwater samples obtained in CA ranged from not detected-0.05 mg/l (detection limit not reported)(1). Levels of acetone-acrolein-propanal in cloud, mist and fog samples obtained in CA ranged from not detected-0.86 mg/l (detection limit not reported)(1). [R151] EFFL: *Present in 6 out of 11 samples of municipal effluent from Dayton, OH, concn range 20-200 ug/l(1). Detected in raw sewage in 2 sewage treatment plants in Chicago at concn ranging from 216-825 ug/l; although concn in final effluents were below 100 ug/l(2). USEPA STORET Data Base - 1265 effluent samples, 1.5% pos., median concn < 10.0 ug/l(3). Acrolein has been identified in emissions from: plants manufacturing acrylic acid, not quantified; coffee roasting operations, not detected-0.6 mg/cu m (detection limit not reported); from a lithographic plate coater, < 0.23-3.9 mg/cu m; and from an automobile spray booth, 1.1-1.6 mg/cu m(1). Detected in 1 out of 5 leachate samples from a Wisconsin municipal solid waste landfill(4). [R152] *In the Netherlands, total emissions in 1980 were estimated at 701 tons/yr from mobile sources and 31 tons/yr from stationary sources(1). Acrolein has been detected in gasoline exhaust ranging from 0.2-5.3 ppm(2). Acrolein comprises 2.6-9.8 % volume of total gasoline exhaust aldehydes. It has been reported that acrolein accounts for 5% of the total aldehydes present in diluted car exhaust(2). In the United States, it is estimated that emission of aldehydes from fireplaces is 14-54 Gg/yr; total acrolein emissions (representing 3.5%-5.7% of total aldehydes) are roughly 0.5-3.1 Gg/yr(1). Production loss estimates by way of fugitive emissions and equipment leakage were 76,300 lbs in 1978(1). Tobacco and marijuana smoke represent another significant source of atmospheric acrolein for both smokers and nonsmokers(1). Cigarettes contribute 3-228 ug acrolein/cigarette while marijuana cigarettes (joints) contribute 92-162 ug. The concentration of acrolein emitted from wood furniture coatings was measured(3). Twenty days after a wood finishing product had been applied to a piece of wood furniture, the acrolein concentration was 1280 ug/cu m(3). [R153] SEDS: *Acrolein was detected in sediment/soil/water samples collected from Love Canal in Niagara Falls, NY during 1980(1). USEPA STORET Data Base - 331 sediment samples, 0% pos.(2). [R154] ATMC: *Levels between less than 1 and 20 mg/cu m are considered representative of concn present in urban air. [R155] *Acrolein has been found at very low concn (0.44 to 32 ug/cu m) in ambient air in urban and suburban areas. Air-monitoring data obtained between 1961 and 1976 show that this compound occurred at mean ambient levels of 16 ug/cu m in Los Angeles, CA (urban atmosphere, 42 data points) and at mean levels of 0.7 ug/cu m in Edison, NJ (near emissions source, 19 data points). [R156] *URBAN/SUBURBAN: Air samples collected in Claremont, CA during Aug-Sept 1979 contained acrolein at a max concn of 34 mg/cu m(1). Acrolein accounts for about 1-13% of total atmospheric aldehydes and occurs at approximately 8-26% of the formaldehyde concentration in urban air. Urban air from Tokyo, Japan had an average acrolein concentration of 7.2 ppb, while in the Netherlands mean concentrations of 0.5 ppb in ambient air have been reported(2). Levels up to 32 ug/cu m (13.9 ppb) were measured in outdoor urban air in Japan, Sweden, and the United States, with extremely high levels associated within or near structural and vegetation fires(2). The average concentration of acrolein in urban air from Los Angeles from 1961 to 1968 ranged from 4-7 ppb with max concentrations reaching 14 ppb(3). The average concentration of acrolein in Sao Paulo and Salvador, Brazil in 1988 was 0.56 and 0.13 ppb, respectively(3). [R157] *SOURCE DOMINATED: During June-July 1976, in air of Edison, NJ (near emission sources), 19 samples, mean concn 0.71 ng/cu m(1). During a 12 month period in 1968, acrolein was detected in air of the Los Angeles Basin at levels ranging from not detected to 0.04 mg/cu m (detection limit not reported), although most measurements were between 0.002-0.02 mg/cu m(2). Acrolein was detected at a level of 0.14 mg/cu m in an atmospheric grab sample obtained near an oil fire(3). Acrolein was detected at 0.057 to 0.085 ppm (detection limit not stated) at the Portsmouth Naval Shipyard in New Hampshire(4). [R158] FOOD: *Alcoholic beverages often contain trace amounts of acrolein. It is sometimes a problem since it causes an organoleptic condition called "pepper" by the alcohol fermentation industry ... acrolein is detectable in low-proof whiskey at concn as low as 10 mg/l. This value probably represents the upper limit for acrolein, since industry has adapted corrective procedures to reduce "pepper" by reducing acrolein concn. [R159] *... Acrolein is a component of many foods, and processing can increase the acrolein content. [R160] *... Acrolein was identified in raw turkey. [R161] *Acrolein has been detected in sugar cane molasses, souring salted pork, the fish odor of cooked horse mackerel, the volatiles from white bread, the volatile components of chicken-breast muscle, the aroma volatiles of ripe arctic bramble berries and the products from heating animal fats and vegetable oils(1). This compound has also been detected in fresh lager beer at levels of 1.11-2.00 ug/l, mean concn 1.6 ug/l(1). [R162] *Small amounts of acrolein have been detected in tomatoes, cooked potatoes, beer, wine, rums, whiskey, and raw chicken(1). Glycerol dehydration is a main source of acrolein in foods. Since glycerides are the main constituent of lipids, foods containing a high fat content will be potential sources of acrolein, principally during cooking. Significant amounts of acrolein are produced from heated oils(1). The amount of acrolein formed from oil heated above 300 deg C in lard, corn oil, cottonseed oil, and sunflower oil were 109, 164, 5.1, and 163 ug/l, respectively(1). However, some oils, such as olive, peanut, rapeseed, and sesame, can undergo auto oxidation at temperatures as low as 80 deg C. This suggests that kitchen workers using these oils may be exposed to acrolein since they use temperatures as high as 200 deg C(1). Olive oil, the most unsaturated, produced the highest amounts of acrolein while soybean oil, the most saturated, produced the lowest. Acrolein has been detected in chicken and beef volatiles(concentrations not specified)(2). [R163] PFAC: PLANT CONCENTRATIONS: *... Measured the unsaturated aldehyde fraction in raw cocoa beans and chocolate liquor. ... They measured 2-enol concn of 0.6 to 2.0 umol/100 g fat in raw cocoa beans and 1.3 to 5.3 umol/100 g in the chocolate liquor. [R164] *No acrolein was detected 1 day following high application rates to lettuce. [R165] FISH/SEAFOOD CONCENTRATIONS: *Acrolein was detected in fish at the following concn: USEPA STORET Data Base - 87 samples, 1% pos., median concn < 1.0 ug/kg wet basis(1). [R150] OEVC: *Found in: tobacco smoke, 3-141 ug/cigarette; diesel engine exhaust gas, 0.06-19.6 mg/cu m; gasoline engine exhaust gas, 0.46-12.2 mg/cu m; rotary gasoline engine exhaust gas, 0.46 mg/cu m; combustion products of hydraulic fluid; smoke from the combustion of wood, 115 mg/cu m, kerosene, < 2.3 mg/cu m and cotton, 138 mg/cu m; combustion products of cellophane used to seal meat packages; and decomposition products of overheated wax(1). Acrolein emissions from a wood burning fireplace ranged from 21-132 mg/kg of wood burned(1). [R166] *Acrolein is formed by photochemical degradation of hydrocarbons, particularly 1,3-butadiene; the irradiation of 1,3-butadiene in the presence of NO and air gave a 55% yield(1). Acrolein may also be produced in higher organisms as a metabolite of allylamine and allyl alcohol, the anticancer drug cyclophosphamide, and spermine or spermidine, or through UV irradiation of skin lipids(1). [R136] RTEX: */In a 1974 report/, acrolein was detected in a truck-maintenance shop in USA at a mean concn of 4.6 ug/cu m. The following exposures to acrolein in workplace air have been reported: (1) levels of 0.44-1.5 mg/cu m ... in a Russian rubber vulcanization plant producing styrene-butadiene rubber footwear components /from a 1969 report/; (2) 0.11-1.04 mg/cu (0.04-0.4 ppm) during the welding of metals coated with anti-corrosion primers /from a 1973 report/; (3) 0.22-0.32 mg/cu m in pitch-coking plants, 0.004-0.014 in coal-coking plants /from a 1972 report/; and (4) less than 0.1 mg/cu m (0.04 ppm) from diesel train engine exhaust during repair and servicing /from a 1973 report/. Acrolein was found at quarries in exhaust gases from diesel engines and in workplace air at levels of 2.1-7.2 mg/cu m /from a 1981 report/. [R156] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 65 workers are exposed to acrolein in the USA(1). However, this estimate does not include exposure to tradename compounds which contain acrolein. Occupational exposure to acrolein may occur through inhalation and dermal contact with this compound at workplaces where acrolein is produced or used(SRC). Exposure of the general population occurs primarily through atmospheric contact(1). The variety of outdoor and indoor sources includes incomplete combustion of fuels and other organic compounds, production and manufacturing processes, photochemical oxidation of airborne hydrocarbons, and cigarette smoke (both first- and secondhand)(2). Despite different sources, typical atmospheric concentrations (1- 20 ppb) usually differ little between indoor and outdoor air(2). [R167] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *2 ppm [R23, 6] ADI: */The National Academy of Sciences/ estimated the ADI for man to be 15.6 ug/kg or 1.09 mg/man, assuming a 70 kg body weight. [R168] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.1 ppm (0.25 mg/cu m). [R169] *Vacated 1989 OSHA PEL TWA 0.1 ppm (0.25 mg/cu m); STEL 0.3 ppm (0.8 mg/cu m) is still enforced in some states. [R23, 359] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.1 ppm (0.25 mg/cu m). [R23, 6] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 0.3 ppm (0.8 mg/cu m). [R23, 6] TLV: *Ceiling limit: 0.1 ppm, skin [R170] *A4. A4= Not classifiable as a human carcinogen. [R170] OOPL: *USSR (1966): 0.3 ppm; Czechoslavakia (1969): 0.2 ppm. *Emergency Response Planning Guidelines (ERPG): ERPG(1) 0.1 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 0.5 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 3 ppm (not life threatening) up to 1 hr exposure. [R171] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Acrolein is produced, as an intermediate or a final product, by process units covered under this subpart. [R172] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Acrolein is included on this list. [R173] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 320 ug/l [R174] +(FL) FLORIDA 110 ug/l [R174] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R175] +Acrolein is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R176] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R177] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Acrolein is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R178] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R179] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2-Propenal is included on this list. [R180] RCRA: *P003; As stipulated in 40 CFR 261.33, when acrolein, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R181] FIFR: *Classified for restricted use, limited to use by or under the direct supervision of a certified applicator. Acrolein as sole active ingredient in a formulation is classified as restricted for all uses based on inhalation hazard to humans and residue effects on avian species and aquatic organisms. No mixtures are registered. [R182] *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Acrolein is found on List B. Case No: 2005; Pesticide type: Fungicide, herbicide, antimicribial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Acrolein; Data Call-in (DCI) Date(s): 05/06/91; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R183] FDA: *Food starch may be esterified and etherified by treatment with one of the following: Acrolein, not to exceed 0.6% and vinyl acetate, not to exceed 7.5%. Limitations: Acetyl groups in food starch-modified not to exceed 2.5%. [R184] *Food starch may be etherified by treatment with one of the following: Acrolein, not to exceed 0.6%. [R185] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A personal air sampling method for acrolein has been developed based on the use of the solid sorbent Amberlite XAO-2 coated with 2,4-dinitrophenyl-hydrazine. Using this method, acrolein in the range of 0.02-0.52 ppm can be analyzed in 5 liter samples with a recovery of 80-100%. [R186] *Personal air sampling method: Use of hydroquinone-treated carbon as the solid sorbent. [R187] *A personal air sampling method /for acrolein has been developed/ using a Porapak N adsorption tube to trap acrolein with subsequent thermal desorption. With this method, acrolein concentrations below 1 ppm can be determined with recovery efficiencies approaching 100%. [R188] *NIOSH Method 2539. Analyte: Acrolein. Sampler: Solid sorbent tube (10% 2-(hydroxymethyl)piperidine on XAD-2, 120 mg/60 mg). Flow Rate: 0.01 to 0.05 l/min: Sample Size: 5 liters. Shipment: @ 25 deg C or lower. Sample Stability: Stable greater or equal to 1 week @ 25 deg C. [R189, p. 2539-1] *NIOSH Method 2501. Analyte: Acrolein. Sampler: Solid sorbent tube 2-(hydroxymethyl)piperidine on XAD-2, 120 mg/60 mg. Flow Rate: 0.01 to 0.1 l/min: Sample Size: 48 liters. Shipment: Routine. Sample Stability: At least 4 weeks @ 25 deg C. [R189, p. 2501-1] *NIOSH Method 211. Analyte: Acrolein. Matrix: Air. Procedure: Collection in midget impinger with 1% aqueous sodium sulfite, reaction with 4-hexyl resorcinol. Flow Rate: 2.0 l/min. Sample Size: 50 liters. [R190] ALAB: *NIOSH Method 2539. Analyte: Acrolein. Procedure: Gas chromatography, flame ionization detector and gas chromatography/mass spectrometry. For acrolein this method has an estimated detection limit of 2 ug aldehyde/sample. The precision/RSD is not determined. Applicability: This is a screening technique to determine the presence of aldehydes and should not be used for quantitation. Interferences: High boiling naphtha mixtures, may have components with retention times similar to the acrolein and may be interferences in the gas chromatographic analysis. [R189, p. 2539-1] *NIOSH Method 2501. Analyte: Acrolein. Procedure: Gas chromatography, nitrogen-specific detector. For acrolein this method has an estimated detection limit of 2 ug/sample. The precision/RSD is not determined. Applicability: The method has sufficient sensitivity for personnal monitoring below the PEL of 0.1 ppm with an 8 hr sample collected at 0.01 l/min. Interferences: None known. [R189, p. 2501-1] *Acrolein has been ... determined as its 2,4-dinitrophenylhydrazone derivative using gas chromatography with flame-ionization detection in (1) diesel automobile engine exhaust; (2) automobile engine exhaust; and (3) the aroma volatiles of ripe arctic bramble berries, using thin-layer and gas chromatography with mass spectrometry confirmation. Gas chromatography with flame-ionization detection has also been used to determine the content of acrolein in waste-water, with a limit of detection of 0.5 mg/l. ... A microwave spectrophotometric method has been used to determine acrolein in automobile exhaust. [R191] *Acrolein in air (0.13-1.5 mg/cu m) reacted with 10% (wt/wt) 2-(hydroxymethyl)piperidine coated on XAD-2 (16/50 mesh) sorbent to produce a bicyclic oxazolidine, 9-vinyl-1-aza-8-oxabicyclo(4.3.0)nonane. This cmpd was desorbed from the sorbent with toluene and determined by gas chromatography with nitrogen-specific detection. [R192] *Differential Pulse Polarography is used to determine acrolein in natural water. Prepare sample by buffering with phosphate; add ethylenediaminetetraacetic acid. Range of detection is 0.05 to 0.5 mg/l. [R193] *Liquid Chromatography/Electrochemistry is used to determine acrolein in aqueous solution. Prepare sample by derivatizing with 2,4-dinitrophenylhydrazine. Limit of detection is 99 pg. [R193] *High Pressure Liquid Chromatography equipped with flame ionization detector is used to determine acrolein in automobile exhaust. Sample is prepared by diluting and then bubbling through impingers containing 2-diphenylacetyl-1,3-indandione-1-hydrazone in acetonitrile and hydrochloric acid catalyst. Limit of detection is 1.4 ug/cu m (20 l samples). High pressure liquid chromatography equipped with ultraviolet detection has a detection limit of 11 ug/cu m (20 liter samples). [R193] *NIOSH Method: 211. Analyte: Acrolein. Matrix: Air. Procedure: Colorimetry. Method Evaluation: Method was validated over the range of 1 to 30 ug/10 ml using a 50 l sample. Precision (CVt): + or - 5% for standards, unknown for air samples. Interferences: There is no interferences from sulfur dioxide, nitrogen dioxide, ozone and most organic air pollutants. A slight interference occurs from dienes: 1.5% for 1,3-butadiene and 2% for 1,3-pentadiene. [R190] *EPA Method 8030. Gas Chromatographic analysis of acrolein, acrylonitrile, and acetronitrile. Detection is achieved by a flame ionization detector. For acrolein the method detection limit is 0.7 ug/l, the average recovery range for four samples is 42.9 to 60.1 ug/l, and the limit for the standard deviation is 4.6 ug/l. [R194] *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile Organics. This method can be used to quantify most volatile organic compounds including acrolein that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R194] *EPA Method 603. Purge-and-Trap Gas Chromatography Method with electrolytic conductivity detection for the determination of acrolein and acrylonitrile in municipal and industrial discharges. Under the prescribed conditions for acrolein the method has a detection limit of 0.7 ug/l and an average recovery of 9.3 ug/l for industrial water at a spike concentration of 100 ug/l. [R195] *NIOSH Method 5031. Detection of Volatile, Nonpurgeable, Water-Soluble Compounds by Azeotropic Distillation. [R196] *NIOSH Method 8316. Determination of Acrylamide, Acrylonitrile and Acrolein by High Performance Liquid Chromatography (HPLC). [R196] *NIOSH Method 8315. Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC). [R196] CLAB: *An accurate and sensitive high-performance liquid chromatographic method is described for estimation of acrolein at 1 ng level in biological tissues (kidney and liver) using a ultra violet detector. The method was based on the reaction of acrolein with 2,4-dinitrophenylhydrazine. The recovery of the acrolein-1,2-dinitrophenyl- hydrazine adduct from tissue homogenates under simulated conditions by 3 different methods was fair to poor (5-44%). The recovered material consistently had shorter retention times than acrolein standards. [R197] *Fluorescence spectroscopy has been used to determine the acrolein present in biological systems. [R191] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: GENERAL REVIEW OF ACROLEIN AND OTHER ALDEHYDES IS FOUND IN FORMALDEHYDE AND OTHER ALDEHYDES, NAS/NRC (1981). FOLMAR LC; ACROLEIN, DALAPON, DICHLOBENIL, DIQUAT, AND ENDOTHAL: BIBLIOGRAPHY OF TOXICITY TO AQUATIC ORGANISMS; US FISH WILD L SERV TECH PAP (88): 1-16 (1977). TOXICITY TABLES LIST TEST ORGANISMS (PLANTS, INVERTEBRATES and o VERTEBRATES), TYPES OF TESTS, EXPTL CONDITIONS AND TEST RESULTS FOR ACROLEIN AND OTHER CHEMICALS. EACH TABLE IS FOLLOWED BY REFERENCES. Toxicology Review: Environmental Health Perspectives, DHEW Publication 11: 163 (1975) Toxicology Review: Cahiers de Medecine du Travail 10 (3): 49 (1973) Toxicology Review: Mutation Research 47: 115 (1977) USEPA; Chemical Hazard Information Profile: Acrolein (1980) EPA 560/11-80-011 USEPA; Ambient Water Quality Criteria Doc: Acrolein (1980) EPA 440/5-80-016 DHHS/ATSDR; Toxicological Profile for Acrolein (1990) ATSDR/TP-90/01, NTIS PB91-180307 WHO; Environmental Health Criteria 127: Acrolein (1992) USEPA/ECAO; Ambient Water Quality Criteria Document: Addendum for Acrolein. Final Draft (9/89) ECAO Pub. ECAO-CIN-614 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on acrolein is scheduled for peer review. Route: gavage; Species: rats and mice. NTP TR No 48. [R198] SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 134 (1985) R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 23 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 1676 R76: Grafstrom RC et al; Cancer Res 48(7): 1717-21 (1988) R77: Wilmer JL et al; Cancer Res 46(1): 203-10 (1986) R78: Ansari GAS et al; Toxicol Lett 37 (1): 57-62 (1987) R79: FERON VJ ET AL; TOXICOLOGY 9 (1-2): 47-58 (1978) R80: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 144 (1985) R81: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 555 R82: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 142 (1985) R83: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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Superior Wisconsin: University of Wisconsin-Superior, 1988.41 R107: SRI Intl; Acute Oral LD50 of Acrolein in Male Mice; BSC Project Number 11479; 12/30/82; EPA Document No. 88-920000355; Fiche No. OTS0534806 R108: SRI Intl; Salmonella Liquid Suspension Mutant Fraction Assay, BSC Project Number 10258; 12/30/80; EPA Document No. 88-920000355; Fiche No. OTS0534806 R109: Union Carbide Chem and Plas Co; Acute and Subacute Oral Toxicity of Acrolein; 11/08/49; EPA Document No. 86-920000742; Fiche No. OTS0535072 R110: Union Carbide Chem and Plas Co; Acute Inhalation Toxicity of Acrolein Vapor by One and Four Hour Exposures; 02/02/87; EPA Document No. 86-920000742; Fiche No. OTS0535072 R111: Union Carbide Chem and Plas Co; Acrolein (inhibitor-free) In Vitro Mutagenesis Studies -3-Test Battery; 06/29/81; EPA Document No. 86-920000742; Fiche No. OTS0535072 R112: E I Dupont De Nemours and Co Inc; Mouse Sensory Irritation Method Verification, Haskell Laboratory Report No. 209-80; 04/19/80; EPA Document No. 86-870001049; Fiche No. OTS0514951 R113: Dow Chem Co; Acute Inhalation Toxicity of Acrolein in Hamsters (Final Report); 08/01/71; EPA Document No. 88-920001468S; Fiche No. OTS0536144 R114: Dow Chem Co; A Study of the Inhalation Toxicity of Acrolein (Final Report); 01/12/76; EPA Document No. 88-920001478S; Fiche No. OTS0536154 R115: Dow Chem Co; Sub-chronic (90-Day) Inhalation Toxicity Study with Acrolein in Hamsters; 10/01/74; EPA Document No. 86-920000855S; Fiche No. OTS0535413 R116: Goodyear Tire and Rubber Co; Mutagenicity Evaluation of Acrolein; 10/26/79; EPA Document No. 86-920001016; Fiche No. OTS0533562 R117: Monsanto Co; Mutagenicity Plate Assay - Acrolein (Final Report); 06/13/77; EPA Document No. 86-920000169; Fiche No. OTS0534374 R118: USEPA; Ambient Water Quality Criteria Doc: Acrolein p.C-51 (1980) EPA 440/5-80-016 R119: IARC. 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Monograph No. 1 (1989) (4) Ghilarducci DP, Tjeerdema RS; Rev Environ Contam Toxicol 144: 95-146 (1995) (5) Atkinson R, Carter WP; Chem Rev 84: 437-70 (1984) (6) Harley RA, Cass GR; Environ Sci Technol 28: 88- 98 (1994) (7) Atkinson R et al; Atmos Env 24: 2647-54 (1990) (8) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants. pp. 53-4 USEPA-440/4-81-014 (1981) R142: (1) Bowmer KH, Higgins ML; Arch Environ Contam Toxicol 5: 87-96 (1976) (2) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (3) Ghilarducci DP, Tjeerdema RS; Rev Environ Contam Toxicol 144: 95-146 (1995) (4) Stover EL, Kincannon DF; J Water Poll Control Fed 55: 97-109 (1983) (5) Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants. USEPA-440/4-79-029A pp. 20-1 to 20-11 (1979) (6) Hultman B; Water Sci Tech 14: 79-86 (1982) (7) Bridie AL et al; Water Res 13: 627-30 (1979) R143: (1) Shelton DR, Tiedje JM; Development of Tests for Determining Anaerobic Biodegradation Potential. USEPA 560/5-81-013 NTIS PB84-166495 (1981) R144: (1) Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants. USEPA-400/4-79-029A pp. 20-1 to 20-11 (1979) (2) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants. pp. 53-4 USEPA-440/4-81-014 (1981) R145: (1) Atkinson R; J Phys Chem Ref Data. Monograph No. 1 (1989) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Edney E et al; Atmospheric Chemistry of Several Toxic Compounds. USEPA-600/53-82-092 (1983) (4) Atkinson R, Carter WP; Chem Rev 84: 437-70 (1984) (5) Harley RA, Cass GR; Environ Sci Technol 28: 88-98 (1994) (6) Atkinson R et al; Atmos Env 24: 2647-54 (1990) (7) Gardner EP et al; Project Summary: The Primary Photochemical Processes of Acrolein p. 3.1 USEPA-600/S3-86-005 (1986) R146: (1) Barrows ME et al; in Dynamics, Exposure Hazard Assess Toxic Chem. Ann Arbor, IM: Ann Arbor Science pp. 279-92 (1980) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, And Steric Constants. ACS Professional Reference Book. Washington, DC: Amer Chem Soc p. 5 (1995) (3) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) R147: Kenaga EE; Ecotoxicology and Environmental Safety 4: 32 (1980) R148: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R149: (1) Gaffney JS et al; Environ Sci Technol 21: 519-23 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Compounds. NY, NY: Lewis Publ p. 177 (1997) R150: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R151: (1) Grosjean D, Wright B; Atmos Environ 17: 2093-6 (1983) R152: (1) IARC; Acrolein; Inter Agency for Research on Cancer 36: 133-61 (1985) (2) Lue-Hing C et al; AICHE Symp Ser 77: 144-50 (1981) (3) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (4) Sabels GV, Clarke, TP; Waste Manag Res 2: 119-30 (1984) R153: (1) Ghilarducci DP, Tjeerdema RS; Rev Environ Contam Toxicol 144: 95-146 (1995) (2) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold Co., p. 128 (1996) (3) Salthammer T; Indoor Air 7: 189-97 (1989) R154: (1) Hauser TR, Bomberger SM; Environ Monit Assess 2:249-72 (1982) (2) Staples CA et al; Environ Toxicol Chem 4:131-42 (1985) R155: Carson BL et al; Acrolein Health Effects, Ann Arbor, MI: U.S. Environ Protection Agency (1981) EPA 460/3-81-034 R156: IARC. 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Menlo Park, CA: SRI International (1982) (2) IARC; Acrolein; Inter Agency for Research on Cancer 36: 133-61 (1985) (3) Perry R; Mass Spectrometry in the Detection and Identification of Air Pollutants Int Symp Ident Meas Environ Pollut pp. 130-37 (1971) (4) Tharr DG, Singal M; Health Hazard Report No. HETA-83-376-1556, Portsmouth Naval Shipyard, NH pp. 14 (1985) R159: USEPA; Ambient Water Quality Criteria Doc: Acrolein p.C-11 (1980) EPA 440/5-80-016 R160: USEPA; Ambient Water Quality Criteria Doc: Acrolein p.C-12 (1980) EPA 440/5-11-016 R161: Hrdlicka J, Kuca J; Poultry Sci 44: 27 (1965) as cited in USEPA; Ambient Water Quality Criteria Doc: Acrolein p.C-10 (1980) EPA 440/5-80-016 R162: (1) IARC; Acrolein; Inter Agency for Research on Cancer 36: 133-61 (1985) R163: (1) Ghilarducci DP, Tjeerdema RS; Rev Environ Contam Toxicol 144: 95-146 (1995) (2) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R164: Boyd EN et al; J Food Sci 30: 854 (1965) as cited in USEPA; Ambient Water Quality Criteria Doc: Acrolein p.C-11 (1980) EPA 440/5-80-016 R165: (1) Tomlin CDS, ed; The Pesticide Manual World Compendium. 11th ed., Surrey, England: British Crop Protection Council. p. 19 (1997) R166: (1) IARC; Acrolein; Inter Agency for Research on Cancer 36:133-61 (1985) R167: (1) NIOSH; National Occupational Exposure Survey (NOES) (1984) (2) Ghilarducci DP, Tjeerdema RS; rev Environ Contam Toxicol 144: 95-146 (1995) R168: USEPA; Ambient Water Quality Criteria Doc: Acrolein p.C-53 (1980) EPA 440/5-80-016 R169: 29 CFR 1910.1000 (7/1/99) R170: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 15 R171: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.25 R172: 40 CFR 60.489 (7/1/99) R173: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R174: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R175: 40 CFR 401.15 (7/1/99) R176: 40 CFR 116.4 (7/1/99) R177: 40 CFR 302.4 (7/1/99) R178: 40 CFR 355 (7/1/99) R179: 40 CFR 712.30 (7/1/99) R180: 40 CFR 716.120 (7/1/99) R181: 40 CFR 261.33 (7/1/99) R182: 40 CFR 152.175 (7/1/99) R183: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.159 (Spring, 1998) EPA 738-R-98-002 R184: 21 CFR 172.892(f) (4/1/99) R185: 21 CFR 172.892(e) (4/1/99) R186: Anderson K et al; Chemosphere 10: 275-80 (1981) R187: Hurley GF, Ketcham NH; Am Ind Hyg Assoc J 39: 615-619 (1978) R188: Campbell DN, Moore RH, J Am Ind Hyg Assoc 40: 904-9 (1979) R189: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R190: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. 211-1 R191: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 483 (1979) R192: Kennedy ER et al; Anal Chem 56 (12): 2110-23 (1984) R193: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 141 (1985) R194: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R195: 40 CFR 136 97/1/90) R196: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R197: Boor PJ, Ansari GA S; J Chromatogr 375 (1): 159-64 (1986) R198: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 169 Record 36 of 1119 in HSDB (through 2003/06) AN: 181 UD: 200303 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,3-BUTADIENE- SY: *BUTADIEEN- (DUTCH); *BUTA-1,3-DIEEN- (DUTCH); *BUTADIENE-; *Butadiene-monomer-; *ALPHA-BUTADIENE-; *ALPHA,-GAMMA-BUTADIENE-; *BUTA-1,3-DIENE-; *BUTADIENE-1,3-UNINHIBITED-; *BUTA-1,3-DIEN- (GERMAN); *BUTADIEN- (POLISH); *Methylallene-; *1-METHYLALLENE-; *NCI-C50602-; *VINYLETHYLENE- RN: 106-99-0 MF: *C4-H6 SHPN: UN 1010; Butadiene (inhibited) IMO 2.0; Butadiene (inhibited) STCC: 49 057 03; Butadiene, inhibited (butadiene, impure, for further refining) 49 057 04; Butadiene, inhibited (butadiene from petroleum) 49 057 05; Butadiene, inhibited (butadiene from alcohol) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *STEAM CRACKING OF HYDROCARBONS (COPRODUCT WITH ETHYLENE); REACTION OF ACETALDEHYDE WITH ETHYL ALCOHOL (NON USA METHOD); ISOLATION FROM GASEOUS EXHAUST OF PETROLEUM DISTILLATES COKING (FORMER METHOD). [R1] *Produced by converting acetaldehyde to aldol, followed by hydrogenation and dehydration. It is also produced by reacting acetylene with formaldehyde, hydrogenating the product 2-butyne-1,4-diol, followed by dehydration and reduction to 1,4-butanediol. [R2] *Catalytic dehydrogenation of butenes or butanes; oxidative dehydrogenation of butenes [R3] *From cracked products of heavy petroleum oils; dehydrogenation of isopentene; pyrolysis of methyl pentene or of isobutyleneformaldehyde condensation products; dehydration of methyl butenol. [R4, 659] *Oxidative dehydrogenation is the primary butadine process. It is an exothermic, autoregenerative, heterogeneous catalyzed reaction, in which the steam serves as a heat sink to moderate the temperature. [R5, p. 19(82) 908] IMP: *Acetylene is an impurity in the ppm range [R6] *1,2-Butadiene is a by-product in the production of 1,3-butadiene [R7] FORM: *Technical 98.0%; chemically pure 99.8%. [R3] *RESEARCH GRADE 99.86 MOLE %; SPECIAL PURITY 99.5 MOLE %; RUBBER GRADE 99.0 MOLE %; COMMERCIAL 98%. [R8] MFS: *BP Amoco Corp., Hq, 200 East Randolph Dr., Chicago, IL 60601, (312) 856-6111; Production site: Alvin, TX 77512-1488 [R9] *Equistar Chemicals, LP, One Houston Center, 1221 McKinney St., Suite 700 Houston, TX 77010, (713) 652-4000; Production sites: Alvin, TX 77512; Channelview, TX 77530; Corpus Christi, TX 78460 [R9] *Exxon Mobile Corp., 13501 Katy Freeway, Houston, TX 77079, (281) 870-6000; Production sites: Baton Rouge, LA 70821; Baytown, TX 77520 [R9] *Huntsman Corp., Houston Office: 3040 Post Oak Blvd., Houston, TX 77056, (713) 235-6000; Utah Office: 500 Huntsman Way, Salt Lake City, UT 84108, (801) 854-5700; Production site: Port Neches, TX 77651 [R9] *Shell Chemical Co., Hq, One Shell Plaza, P.O. Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production sites: Norco, LA 70079; Deer Park, TX 77536 [R9] *Texas Petrochemicals Corp., 3 Riverway, Suite 1500, Houston, TX 77045, (713) 627-7474; Production site: Houston, TX 77017 [R9] OMIN: *Methods of purification /incl/ extractive distillation in presence of furfural, absorption in aq cuprous ammonium acetate, or use of acetonitrile. [R3] *tert-Butylcatechol (0.01-0.02%) /is added to inhibit/ polymerization. [R10] *The polymerization inhibitor tert-butyl catechol can be removed from 1,3-butadiene gas ... by distillation or by washing with dilute caustic soda solution. [R11] *STABILIZATION WITH O-DIHYDROXYBENZENE: BRITISH PATENT 569,412; WITH ALIPHATIC MERCAPTANS: US PATENT 2,373,754. [R12] *(1995) 36th highest volume chemical produced in the USA [R3] USE: *Polymers such as synthetic rubber, plastics, and resins. [R13] *CHEM INT FOR ADIPONITRILE, POLYCHLOROPRENE VIA CHLOROPRENE, 1,5,9-CYCLODODECATRIENE AND 1,4-HEXADIENE, CAPTAN AND CAPTOFOL FUNGICIDES, ETHYLIDENE NORBORNENE AND SULFOLANE, BORON ALKYLS, HEXACHLOROBUTADIENE, BUTANEDIOL (NON-US USE), AND FOR 1,5-CYCLOOCTADIENE (FORMER USE). [R1] *Increasing usage in the formation of rocket fuels, plastics and resins. [R14] *Synthetic elastomers (styrene-butadiene, polybutadiene, neoprene, nitriles), acrylonitrile-butadiene-styrene (ABS) resins. [R3] *Many commercially significant latex paints are based on styrene-butadiene copolymers. ... [R15] *Initiators /including butadiene/ are used widely in the polymer industry /and/ for ... other chemical reations, eg, oxidation and autoxidation, chlorination, bromination, and nonpolymeric addition to double bonds. [R5, p. 13(81) 356] CPAT: *COMONOMER FOR STYRENE-BUTADIENE RUBBER (SBR), 40%; MONOMER FOR POLYBUTADIENE, 20%; CHEM INT FOR ADIPONITRILE, 12%; COMONOMER FOR STYRENE-BUTADIENE LATEXES, 8%; CHEM INT FOR POLYCHLOROPRENE, 7%; COMONOMER FOR ACRYLONITRILE-BUTADIENE-STYRENE RESINS, 5%; COMONOMER FOR NITRILE RUBBER, 3%; OTHER POLYMER OR COPOLYMER USES, 3%; OTHER USES, 2% (1981) [R1] *Comonomer for SBR, 50%; monomer for polybutadiene, 22%; chloroprene /neoprene rubber, 6%; / nitrile rubber, 3%; hexamethylenediamine, 9%; acrylonitrile-butadiene-styrene, 5%; miscellaneous, 5% (1983) [R16] *Styrene-butadiene rubber, 45%; polybutadiene rubber, 20%; hexamethylene diamine, 10%; styrene-butadiene latex, 7%; ABS resins, 7%; chloroprene rubber, 5%; nitrile rubber, 3%; miscellaneous, 3% (1984) [R17] *Demand (1998): 5.3 billion lbs; (1999) 5.4 billion lbs; (2003) 5.8 billion lbs (projected) [R18] PRIE: U.S. PRODUCTION: *(1977) 1.48X10+12 g [R1] *(1982) 8.69X10+11 g [R1] *(1977) 2.1 - 7.3 billion lb (produced/imported) [R19] *Production declined about 2.7% between 1974 and 1979, from 3.68 to 3.58 billion lb [R20] *(1980) 2.89 billion lb [R20] *(1985) 1.06X10+12 g (grade for rubber elastomers) [R21] *(1989) 3,094 million lbs (Rubber grade) [R22] *(1990) 3.09 billion lb [R23] *(1991) 3.05 billion lb [R24] *(1992) 3.23 billion lb [R25] *(1993) 3.09 billion lb [R25] U.S. IMPORTS: *(1978) 2.82X10+11 G [R1] *(1983) 4.01X10+11 G [R1] *(1977) 2.1 - 7.3 billion lb (produced/imported) [R19] *(1984) 3.96X10+11 g /estimate/ [R17] *1.2 billion lbs in 1998 and 1999 [R18] U.S. EXPORTS: *(1978) 4.25X10+10 G [R1] *(1983) 4.38X10+10 G [R1] *(1984) 6.58X10+10 g /estimate/ [R17] *U.S. exports were negligible in 1998 and 1999. [R18] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless gas ... [Note: A liquid below 24 degrees F. Shipped as a liquefied compressed gas]. [R26, 34] ODOR: *MILDLY AROMATIC ODOR [R27, 1991.156]; *GASOLINE-LIKE ODOR [R10]; *... Mild aromatic or gasoline-like odor ... [R26, 34] BP: *-4.5 deg C @ 760 mm Hg [R13] MP: *-108.966 deg C [R13] MW: *54.09 [R13] CORR: *Non-corrosive [R28, 347] CTP: *Critical temperature: 161.8 deg C; Critical pressure: 42.6 atm [R13] DEN: *0.6149 g/cu cm @ 25 deg C [R29] HTV: *389 J/g @ 25 deg C [R7] OWPC: *log Kow= 1.99 [R30] SOL: *Sol in org solvents; alcohol dissolves about 40 vol at room temp [R13]; *Sol in ether and ethanol; very sol in acetone [R31]; *water solubility = 735 mg/l at 20 deg C [R32] SPEC: *Index of refraction: 1.4292 @ 25 deg C [R29]; *IR: SADP 893 (Sadtler Research Laboratories Prism Collection) [R33]; *UV: OES 5-18 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R33]; *MS: NIST 61294 (NIST/EPA/MCDC Mass Spectral Database 1990 version) [R33] SURF: *13.4 dynes/cm at 20 deg C [R8] VAPD: *1.87 (Air = 1) [R34, 1242] VAP: *2,110 mm Hg @ 25 deg C [R35] EVAP: *Greater than 25 (butyl acetate = 1) [R36, 1981.1] VISC: *Gas at 101.325 kPa at 20 deg C: 0.00754 cP; Liquid at -40 deg C: 0.33 cP [R37] OCPP: *Dimerizes to 4-vinylcyclohexane [R34, 1251] *LIQUID SURFACE TENSION: 13.4 DYNES/CM AT 20 DEG C; LIQUID-WATER INTERFACIAL TENSION: (EST) 67 DYNES/CM AT 22 DEG C; VAPOR (GAS) SPECIFIC GRAVITY: 1.9 AT 20 DEG C; RATIO OF SPECIFIC HEATS OF VAPOR (GAS): 1.1; LATENT HEAT OF VAPORIZATION: 100 CAL/G; HEAT OF COMBUSTION: -10560 CAL/G; HEAT OF POLYMERIZATION: -305 CAL/G [R8] *1 mg/cu m = 0.45 ppm; 1 ppm = 2.25 mg/cu m [R38, 296] *Specific volume at 21.1 deg C, 101.325 kPa: 430.6 cu d/kg; 6.9 cu ft/lb [R37] *Absolute density, gas at 101.325 kPa at 0 deg C: 2.428 kg/cu m; Relative density, gas at 101.325 kPa at 0 deg C (air = 1): 1.878; Density, liquid at saturation pressure at 20 deg C: 0.621 kg/l; Critical density: 0.245 kg/cu m [R37] *Critical compressibility factor: 0.270 [R37] *Molar specific heat, gas at 101.325 kPa at 25 deg C: Constant pressure: 82.132 j/(mol X K); 0.363 kcal/(kg X K); Constant volume: 73.803 J/(mol X K); 0.326 kcal/(kg X K) [R37] *Heat of fusion: 40.80 cal/g [R39] *LIQUEFIED COMPRESSED GAS [R8] *Colorless liquid at -4.7 deg C [R36, 1981.1] *Hydroxyl radical reaction rate constant = 6.66X10-11 cu cm/molecule-sec @ 25 deg C [R40] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: EXTREMELY FLAMMABLE. Will be easily ignited by heat, sparks or flames. Will form explosive mixtures with air. Silane will ignite spontaneously in air. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Vapors from liquefied gas are initially heavier than air and spread along ground. Vapors may travel to source of ignition and flash back. Containers may explode when heated. Ruptured cylinders may rocket. /Butadienes, inhibited/ [R41] +Health: Vapors may cause dizziness or asphyxiation without warning. Some may be toxic if inhaled at high concentrations. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Fire may produce irritating and/or toxic gases. /Butadienes, inhibited/ [R41] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 100 meters (330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. /Butadienes, inhibited/ [R41] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Butadienes, inhibited/ [R41] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 1600 meters (1 mile) in all directions; also, consider initial evacuation for 1600 meters (1 mile) in all directions. /Butadienes, inhibited/ [R41] +Fire: DO NOT EXTINGUISH A LEAKING GAS FIRE UNLESS LEAK CAN BE STOPPED. Small fires: Dry chemical or CO2. Large Fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Fire involving tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles, if this is impossible withdraw from area and let fire burn. /Butadienes, inhibited/ [R41] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Stop leak if you can do it without risk. Do not touch or walk through spilled material. Do not direct water at spill or source of leak. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. If possible, turn leaking containers so that gas escapes rather than liquid. Prevent entry into waterways, sewers, basements or confined areas. Isolate area until gas has dispersed. /Butadienes, inhibited/ [R41] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with liquefied gas, thaw frosted parts with lukewarm water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Butadienes, inhibited/ [R41] FPOT: *Flammable gas ... [R42, p. 49-30] *DANGEROUS FIRE HAZARD WHEN EXPOSED TO HEAT, FLAME, OR POWERFUL OXIDIZERS. ... REACTION WITH SODIUM NITRITE FORMS A SPONTANEOUSLY FLAMMABLE PRODUCT. EXOTHERMIC REACTION WITH BORON TRIFLUORIDE ETHERATE + PHENOL. [R43, 540] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R42, p. 325-19] *Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R42, p. 325-19] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R42, p. 325-19] FLMT: *Lower flammable limit: 2.0% by volume; Upper flammable limit: 12% by volume [R42, p. 325-19] FLPT: *-105 DEG F [R43, 539] AUTO: *788 DEG F [R43, 539] FIRP: *STOP FLOW OF GAS. USE WATER TO KEEP FIRE-EXPOSED CONTAINERS COOL AND TO PROTECT INDIVIDUALS EFFECTING THE SHUT-OFF. BUTADIENE VAPORS ARE UNINHIBITED AND MAY FORM POLYMERS IN VENTS OR FLAME ARRESTERS OF STORAGE TANKS, RESULTING IN STOPPAGE OF VENTS. [R44] *If a fire involving 1,3-butadiene becomes uncontrollable or container is exposed to direct flame, evacuate from a radius of 2500 feet. [R45] *If 1,3-butadiene is on fire or involved in fire: Do not extinguish fire unless flow can be stopped; Use water in flooding quantities as fog; Cool all affected containers with flooding quantities of water and apply water from as far a distance as possible. [R45] *Respiratory protection for fire fighting: A self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode. [R36, 1981.4] OFHZ: *1,3-Butadiene vapors are heavier than air and a flame can flash back to the source of leakage. [R45] *FLOATS AND BOILS ON WATER. FLAMMABLE VISIBLE VAPOR CLOUD IS PRODUCED. [R10] EXPL: *UPON EXPOSURE TO AIR IT FORMS EXPLOSIVE PEROXIDES SENSITIVE TO HEAT, SHOCK, OR HEATING ABOVE 27 DEG C. MAY DECOMPOSE EXPLOSIVELY WHEN HEATED ABOVE 200 DEG C/ 1 KBAR. EXPLODES ON CONTACT WITH ALUMINUM TETRAHYDROBORATE. POTENTIALLY EXPLOSIVE REACTION WITH /NITROGEN OXIDES/ NOx + O2, ETHANOL + IODINE + MERCURY OXIDE (AT 35 DEG C), CLO2 /CHLORINE DIOXIDE/, CROTONALDEHYDE (ABOVE 180 DEG C), BUTEN-3-YNE (WITH HEAT AND PRESSURE). [R43, 540] *Butadiene will decompose explosively if heated under pressure at 30-40 deg C/min to exceed critical temperatures of 200-340 deg C and pressures of 1-1.2 kbar, simultaneously. [R46, 435] REAC: *Solid butadiene at below -113 deg C will absorb enough oxygen at subatmospheric pressure to explode violently when allowed to melt. [R46, 434] *An explosion and fire occurred in the pipework of a vessel in which dilute butadiene was stored under an "inert gas" atmosphere generated by combustion of fuel gas in a limited supply of air. The "inert gas" containing up to 1.8% oxygen and traces of nitrogen, reacted over an extended period in the vapor phase to produce concentrations of a gummy material containing up to 64% butadiene peroxide and 4.2% of a butadiene-nitrogen complex. The deposits decomposed explosively. [R46, 436] *Phenol, chlorine dioxide, copper, crotonaldehyde [Note: May contain inhibitors (such as tributylcatechol) to prevent self-polymerization. May form explosive peroxides upon exposure to air]. [R26, 34] *When mixed with air, it forms potentially explosive peroxides. [R27, 1991.156] *REACTION WITH SODIUM NITRITE FORMS A SPONTANEOUSLY FLAMMABLE PRODUCT. EXOTHERMIC REACTION WITH BORON TRIFLUORIDE ETHERATE + PHENOL. [R43, 540] *UPON EXPOSURE TO AIR IT FORMS EXPLOSIVE PEROXIDES SENSITIVE TO HEAT, SHOCK, OR HEATING ABOVE 27 DEG C. ... EXPLODES ON CONTACT WITH ALUMINUM TETRAHYDROBORATE. POTENTIALLY EXPLOSIVE REACTION WITH /NITROGEN OXIDES/ NOx + O2, ETHANOL + IODINE + MERCURY OXIDE (AT 35 DEG C), CLO2 /CHLORINE DIOXIDE/, CROTONALDEHYDE (ABOVE 180 DEG C), BUTEN-3-YNE (WITH HEAT AND PRESSURE). [R43, 540] DCMP: *May decompose explosively when heated above 200 deg C/ 1 kbar. ... When heated to decomposition it emits acrid smoke and fumes. [R43, 540] POLY: *POLYMERIZES AND COPOLYMERIZES EASILY, EG,UNDER INFLUENCE OF SODIUM ... [R12] +Hazardous polymerization may occur. Usually contain inhibitors to prevent polymerization. Uninhibited monomer vapor may form polymer in vents and other confined spaces. [R42, p. 49-30] *Butadiene vapor in contact with cobalt metal will initiate "popcorn" polymerization of the diene. [R47] *In prolonged storage, butadiene will (even when very poor and in sealed glass containers) produce 'popcorn' polymer. [R46, 435] OHAZ: *MODERATELY DANGEROUS WHEN HEATED, IT EMITS ACRID FUMES. ... [R48] ODRT: *4 MG/CU M [R10] *Detection: 4.50x10-1 ppm, purity not specified. [R49] *0.35 mg/cu m (odor low) 2.86 mg/cu m (odor high) [R50] SERI: *Irritation of the human respiratory system: 10,000 ppm for 1 min; Slight irritation of the eyes and upper respiratory tract, no other effects: 8,000 ppm/8 hr. [R38, 297] *MAY BE IRRITATING TO SKIN, MUCOUS MEMBRANES [R12] *Skin contact with liquid 1,3-butadiene will cause irritation. Cooling due to its evaporation from the skin surface may cause frostbite. [R27, 1991.157] *It causes slight irritation to the skin and eyes. [R34, 1251] EQUP: *CHEMICAL-TYPE SAFETY GOGGLES; RESCUE HARNESS AND LIFE LINE FOR THOSE ENTERING A TANK OR ENCLOSED STORAGE SPACE; HOSE MASK WITH HOSE INLET IN A VAPOR-FREE ATMOSPHERE; SELF-CONTAINED BREATHING APPARATUS; RUBBER SUIT. [R44] *Respiratory protection for butadiene is as follows: Vapor concentration 5000 ppm or less: A gas mask with a chin-style canister providing protection against butadiene; 8000 ppm or less: Any supplied-air respirator, or any self-contained breathing apparatus; 20,000 ppm or less: A gas mask with a front-or back-mounted canister providing protection against butadiene, or any supplied-air respirator with a full facepiece; Greater than 20,000 ppm or entry and escape from unknown concentrations: Self-contained breathing apparatus with a full facepiece respirator which includes a type-C supplied-air respirator with a full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and an auxillary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode; Escape: Any gas mask providing protection against butadiene, or any escape self-contained breathing apparatus. [R36, 1981.4] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R51, 1979.8] *Wear appropriate personal protective clothing to prevent the skin from becoming frozen from contact with the liquid or from contact with vessels containing the liquid. [R26, 35] *Wear appropriate eye protection to prevent eye contact with the liquid that could result in burns or tissue damage from frostbite. [R26, 35] *Quick drench facilities and/or eyewash fountains should be provided within the immediate work area for emergency use where there is any possibility of exposure to liquids that are extremely cold or rapidly evaporating. [R26, 35] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R26, 35] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Any appropriate escape-type, self-contained breathing apparatus. [R26, 35] OPRM: *Leak detection: Areas suspected of leaks should be painted with a soap solution; Leaks will be evident by the formation of small bubbles. Under no circumstances should a match or flame be used to detect butadiene leaks. [R52] *Leaks of flammable gases require special handling. All sources of ignition should be eliminated at once. If practical, the cylinder should be removed to a safe, out-of-doors area, and plainly tagged as defective. If the gas is also toxic, proper breathing equipment should be /worn/ before transporting the cylinder to the disposal area. Warnings should be posted in the area to prevent persons from approaching the cylinder with lit cigarettes or open flames. Attach an appropriate control valve to the cylinder valve outlet and adjust the gas discharge to a moderate discharge rate. When the cylinder is empty, close the cylinder valve and follow the supplier's directions for cylinder return, after informing the supplier of the defect. The local fire department may be of help in removing the leaking cylinder to the disposal area. [R52] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Notify operators of nearby water intakes /when 1,3-butadiene is involved in a spill/. [R10] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R51, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R51, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R51, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R51, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R51, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R51, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R51, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R51, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R51, 1979.11] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R26, 35] SSL: *... Polymerizes readily, particularly if oxygen is present ... the commercial material contains an inhibitor to prevent spontaneous polymerization during shipment or storage. [R4, 177] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R53] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R54] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R55] STRG: +Outside or detached storage is preferred. Store in a cool, dry, well-ventilated location. Isolate from oxidizing materials. [R42, p. 49-30] *STORAGE TEMPERATURE: AMBIENT. VENTING: SAFETY RELIEF. [R10] *MUST BE KEPT INHIBITED DURING STORAGE ... STORAGE IS USUALLY UNDER PRESSURE OR IN INSULATED TANKS BELOW 35 DEG F. [R4, 177] *Since butadiene is heavier than air and any leaking gas will tend to collect in the depressions, storage in pits and basements should be avoided. ... Cylinders should be ... handled so as to avoid shock. A safety relief valve is usually incorporated in the cylinder valve. ... Leaks are best detected by painting the suspected area with a soap soln, so that any escaping gas will form visible bubbles ... [R28, 348] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R51, 1979.13] *Exposure to butadiene can be reduced by ensuring that fittings on closed-loop systems are not worn or incorrectly connected. Further measures to control potential exposures include: use of closed-loop systems for cylinder sampling, use of dual mechanical seals to control release from leaking pumps, use of magnetic gauges to monitor rail-car filling operations and use of a laboratory hood for cylinder voiding. [R56] *In prolonged storage, butadiene will (even when very poor and in sealed glass containers) produce 'popcorn' polymer. [R46, 435] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. IF IN LIQUID FORM, FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN A SAFE PLACE (SUCH AS A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR THE HOOD DUCTWORK. BURN THE PAPER IN A SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER. 4. IF IN GASEOUS FORM, STOP FLOW OF GAS. IF SOURCE OF LEAK IS A CYLINDER AND THE LEAK CANNOT BE STOPPED IN PLACE, REMOVE THE LEAKING CYLINDER TO A SAFE PLACE IN THE OPEN AIR AND REPAIR THE LEAK OR ALLOW THE CYLINDER TO EMPTY. [R44] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R51, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Butadiene may be disposed of: 1) If in liquid form, by atomizing in a suitable combustion chamber. 2) If in gaseous form, by burning in a safe location or in a suitable combustion chamber. Recommendable methods: Incineration, open burning. Butadiene is a gas at normal temp and pressures and incineration may be difficult to arrange. Butadiene may potentially be polymerized. Small amt can be released and burned. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R44] *Butadiene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R57] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R51, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R51, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R51, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R51, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R51, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is limited evidence in humans for the carcinogenicity of 1,3-butadiene. There is sufficient evidence in experimental animals for the carcinogenicity of 1,3-butadiene. Studies in vitro suggest that the metab of 1,3-butadiene is qualitatively similar in humans and experimental animals. There is sufficient evidence in experimental animals for the carcinogenicity of 1,2:3,4-diepoxybutane. Overall evaluation: 1,3-Butadiene is probably carcinogenic to humans (Group 2A). [R58] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Inadequate human data and sufficient rodent (mouse and rat) studies in which exposure to airborne concentrations of 1,3-butadiene caused multiple tumors and tumor types form the basis for this classification. Related compounds are carcinogenic and mutagenic. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R59] +A2. Suspected human carcinogen. [R60, 2002.18] ANTR: *If contact of the liquid form of 1,3-butadiene with the skin occurs, frostbite may develop. If frostbite develops, cover the frostbitten part with a warm hand or woolen material. If the fingers or hand are frostbitten, have the victim hold his hand in his armpit next to his body. Then place the frostbitten part in warm water, about 42 deg C (108 deg F). If warm water is not available, or is impractical to use, wrap the affected part gently in blankets. Let the circulation re-establish itself naturally. Encourage the victim to exercise the affected part while it is being warmed. [R11] *In the event of an emergency, institute first aid procedures and send for first aid or medical assistance. If liquid butadiene gets into the eyes, wash eyes immediately with large amounts of water, lifting the lower and upper lids occasionally. If irritation persists after washing, get medical attention. Contact lenses should not be worn when working with this chemical. If liquid butadiene gets on the skin, immediately flush the contaminated skin with water. If liquid butadiene soaks through the clothing, remove the clothing immediately and flush the skin with water. Do not use hot water for flushing. If irritation persists after washing, get medical attention. If a person breathes in large amounts of butadiene, move the exposed person to fresh air at once. If breathing has stopped, perform artificial respiration. Keep the affected person warm and allow person to rest. Get medical attention as soon as possible. Move the affected person from the hazardous exposure. If the exposed person has been overcome, notify someone else and put into effect the established emergency rescue procedure. Do not become a casualty. Understand the facility's emergency rescue procedures and know the locations of rescue equipment before the need arises. [R36, 1981.3] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aliphatic hydrocarbons and related compounds/ [R61, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory rest. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aliphatic hydrocarbons and related compounds/ [R61, 207] MEDS: *Routine medical examinations should be provided to each employee who is exposed to butadiene at potentially hazardous levels. [R36, 1981.1] */Health effects to consider/ Cancer; teratogenicity; reproductive effects ... . Appropriate engineering and work-practice controls. [R62, 1386] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R51, 1979.23] *Aside from annual medical approval for use of a respirator that includes pulmonary function testing, the medical surveillance exam currently includes occupational and medical histories, a physical exam , and exam of peripheral blood cells. The purpose of these exams is to detect persons who exhibit blood alterations characteristic of anemia or leukemia and to detect, by physical exam, non-Hodgkin's lymphoma. The proposed frequency is every year. [R63, 1009] HTOX: *A historic prospective cohort of 6,678 hourly paid male workers in a rubber tire manufacturing plant in Akron, Ohio /were studied/. The cohort was composed of all active and retired male employees aged 40-84 yr as of January 1, 1964. During the 9 yr follow-up period from 1964-1972, 1,783 workers died. Death certificates were obtained for 99.5% of these workers. ... Statistically significant excesses were observed for stomach cancer, ... lymphosarcoma, and leukemia ... in the active age range of 40-64. For the full age range of 40-48, significant standard mortality rate (SMR) incr were observed for cancers of the stomach, prostate, lymphosarcoma, diabetes mellitus, and arteriosclerosis. ... /An evaluation of/ the relationship of these mortality excesses to specific jobs within this plant /was accomplished/ by designing a nested case-control study. Out of a total of 1,983 deaths observed during the 10 yr follow-up period of 1964-1973, 455 individuals who had died from certain specific causes were selected as subjects. The specific causes of death incl stomach, colorectal, respiratory, prostate, and bladder cancers; Cancers of the lymphatic and hematopoietic systems; Lymphatic leukemias; Ischemic heart disease; and diabetes mellitus. Out of these 455 cases, 353 deaths were attributed to cancers and 102 to noncancer causes. ... For all of the causes of death under investigation, there were statistically significant (p < 0.001) assoc with many areas in which workers had at least 5 years of exposure. In the ... plant area, the significant (p < 0.001) risk ratios were 6.2 for lymphatic and hematopoietic cancer, 3.9 for lymphatic leukemia, 3.0 for ischemic heart disease, and 2.2 for stomach cancer. ... /Rubber tire manufacturing/ [R64] *WHEN EXPOSED TO PHOTO-OXIDATION WITH OZONE AND NITROGEN DIOXIDE, AS IN FORMATION OF SMOG, 1,3-BUTADIENE IS ... A POTENT PRECURSOR OF PRODUCTS THAT ARE IRRITATING TO HUMAN EYE, PRODUCING BOTH FORMALDEHYDE AND ACROLEIN. ... [R65] */INHALATION/ AT VERY HIGH CONCN ... /EG 25% IN AIR/ CAN RESULT IN DEATH WITHIN 23 MIN [R66] *1,3-Butadiene can asphyxiate by the displacement of air. [R45] *A 1982 mortality study of 13,920 workers employed during the period 1943-1979 in the styrene-butadiene rubber polymer manufacturing industry indicated that the overall mortality of workers (production, utilities, maintenance, and other work groups) was low compared to the general population. Several cancer sites with high statistically significant mortality ratios were identified. These include cancer of the testes in the maintenance group; cancers of the digestive system (esophagus, stomach, large intestine) and larynx in the utilities and maintenance groups; AND Hodgkin's disease in all 4 work groups. Analysis by work group indicated specific findings which may warrant further investigation. No attempt was made to include work environment exposure levels (1,3-butadiene, styrene) in the data analysis because information was not available. /Styrene-butadiene/ [R27, 1991.157] *Little acute toxicity occurs from human industrial exposure, with mild mucous membrane irritation reported between 2,000 and 18,000 ppm and coughing, drowsiness, and fatigue at higher concentrations. Butadiene appears much less toxic acutely than styrene. Inhalation exposures between 600 and 8,000 ppm in animal models produce malignant lymphomas, reproductive cancers, and thyroid carcinoma as well as teratogenic effects in pregnant rats. Epidemiological studies of workers indicate a definite, but not statistically significant, increase in leukemia and lymphomas. NIOSH recommends that 1,3-butadiene be considered a potential occupational carcinogen and teratogen. [R62, 968] *Workers should be instructed that smarting of the eyes, respiratory irritation, headache and vertigo may indicate that the concentration in the atmosphere is unsafe. [R28, 348] *Overexposure to butadiene may cause irritation of the eyes, nose, and throat. It may also cause drowsiness and /SRP: > 10,000 ppm/ lightheadedness. Exposure to very high concentrations may cause unconsciousness and death. Spilled on the skin, it may cause frostbite and irritation. [R36, 1981.1] *Some combinations /with butadiene/ have shown added irritancy. For example, children playing with butadiene-mineral or clay mixt developed dermatitis or specific rashes a few days post-contact. [R34, p. 1251-2] *Volunteers exposed to 8000 ppm for 8 hr also showed no effect other than mild irritation of the eyes and upper respiratory tract, and 10,000 ppm for 5 min showed no effects on blood pressure or respiration. [R34, 1251] */Human volunteers exposed/ at 2000, 4000, or 8000 ppm of 1,3-butadiene for 6-8 hr, resulting in slight smarting of the eyes, difficulty in focusing on instrument scales, and a transient objection to the 1,3-butadiene odor. [R27, 1991.157] *Human systemic effects by inhalation: cough, hallucination, distorted perceptions, changes in the visual field and other unspecified eye effects. The vapors are irritating to eyes and mucous membranes. If spilled on skin or clothing, it can cause burns or frostbite (due to rapid vaporization). [R43, 540] *Human signs and symptoms from overexposure to 1,3-butadiene... include blurred vision, nausea, and irritating of the respiratory tract, progressing to a feeling of fatigue, headache, vertigo, nausea, decr blood pressure and pulse rate, unconsciousness, respiratory paralysis, and death. [R67, 381] *Inhalation of 1,3 butadiene is mildly /CNS depressant/ in humans at low concentrations (not otherwise specified) and may result in a feeling of lethargy and drowsiness ... . At very high concentrations, 1,3 butadiene causes /CNS depression/ leading to respiratory paralysis and death. The first signs observed in humans are blurred vision, nausea, paresthesia and dryness of the mouth, throat, and nose, followed by fatigue, headache, vertigo, decreased blood pressure and pulse rate, and unconsciousness. Respiratory paralysis is likely to occur only after exposure to high concentrations of 1,3 butadiene such as after spills or leaks. [R68] *Psychomotor responses of two men inhaling 2,000, 4,000 or 8,000 ppm 1,3 butadiene for 6 to 8 hours/day on different days were evaluated by ... . At the two higher concentrations, the subjects performed a steadiness test; at the highest concentration, a tapping rate test was also performed. Results after 1,3 butadiene exposure were identical to those obtained before exposure. [R69] NTOX: *Deep anesthesia was induced in rabbits in 8-10 min at 200,000-250,000 ppm. Death due to respiratory paralysis occurred within 25-35 min at 250,000 ppm. Recovery from brief periods of anesthesia occurred within 2 min of terminating the exposure. [R27, 1991.156] *RABBITS EXPOSED TO CONCN RANGING FROM 200000 TO 250000 PPM ONCE A DAY FOR 15 TO 21 DAYS HAD NO DELETERIOUS EFFECTS FROM THESE EXPOSURES. DURING ACTUAL INHALATION OF THESE HIGH CONCN ... ANIMALS WERE LIGHTLY ANESTHETIZED ... LOSS OF PUPILLARY REFLEX ... AND RALES WERE NOTED. [R70] *DOGS AND RABBITS EXPOSED EXPTL TO AS MUCH AS 6700 PPM 7.5 HR A DAY FOR 8 MO HAVE DEVELOPED NO HISTOLOGICALLY DEMONSTRABLE ABNORMALITY IN ANY PART OF EYES. ... [R65] *INCUBATION OF SALMONELLA TYPHIMURIUM STRAINS TA1530 AND TA1535 IN PRESENCE OF GASEOUS BUTADIENE INCR NUMBER OF HIS+ REVERTANTS/PLATE IN ABSENCE OF FORTIFIED S-9 RAT LIVER FRACTION. [R71] *In mice exposed to concn of 10%, butadiene caused no symptoms, of 15% light CNS depression, of 20% some excitement and CNS depression in 6 to 12 min, and of 30 to 40% of excitement with twitching in 1 to 1.2 min and 40 to 60 sec, respectively. ... Rats gavaged with 100 mg/kg butadiene for 2.5 months showed some lymphohistocytic infiltration in the heart, liver, and kidney. [R34, 1251] *THREE MONTH TOXICITY AND 2 YR CARCINOGENICITY STUDIES WERE INITIATED TO IDENTIFY ANY POTENTIAL HAZARD TO OCCUPATIONALLY EXPOSED PERSONNEL. FIVE GROUPS OF SPRAGUE-DAWLEY RATS WERE EXPOSED TO 1,3-BUTADIENE GAS AT ATMOSPHERIC CONCN OF 0, 1000, 2000, 4000 and 8000 PPM VOL/VOL, RESPECTIVELY, 6 HR/DAY, 5 DAYS/WK FOR 13 WK. FORTY MALE AND 40 FEMALE ANIMALS WERE USED IN EACH GROUP, OF WHICH 10 OF EACH SEX WERE KILLED AT 2 and 6 WK. NO UNTOWARD EFFECTS ATTRIBUTABLE TO EXPOSURE WERE OBSERVED, EXCEPT A MODERATELY INCREASED SALIVATION, PARTICULARLY IN FEMALE ANIMALS DURING THE LAST 6-8 WK OF EXPOSURE, AT HIGHER CONCN OF BUTADIENE. MACROSCOPIC AND HISTOPATHOLOGIC EXAMINATION AFTER 2, 6, and 13 WK OF EXPOSURE SHOWED NO UNTOWARD CHANGES RELATED TO BUTADIENE GAS. RESULTS OF THE CARCINOGENICITY STUDY WERE NOT GIVEN. [R72] *National Toxicology Program (NTP) concluded that 1,3-butadiene was carcinogenic in rats and mice of both sexes. 1,3-butadiene caused incr incidences of hemangiosarcomas of the heart, malignant lymphomas, alveola/ bronchiolar adenomas and carcinomas, and papillomas of the forestomach were caused in mice of both sexes. In female mice, the cmpd caused acinar cell carcinomas of the mammary gland, granulosa cell tumors of the ovary, and hepatocellular adenomas and carcinomas. 1,3-Butadiene caused mammary fibroadenomas/carcinomas, thyroid follicullar cell adenomas, and uterine sarcomas in female rats when admin by inhalation. It also caused Leydig cell adenomas of the testes, exocrine tumors of the pancreas, AND Zymbal gland carcinomas in male rats. [R73] *... Groups of mated Sprague-Dawley rats were exposed to 0, 200, 1,000 or 8,000 ppm of 1,3-butadiene via inhalation for 6 hours/day from days 6-15 of gestation. ... Effects included embryonic growth retardation and slight embryolethality at all dose levels (200-8,000 ppm). Effects were dose-related. Exposure of rats to the 8,000 ppm /level/ during days 6-15 of gestation resulted in a significant increase in major skeletal abnormalities. [R74] *Bean plants exposed to 1,3-butadiene at 10,000 ppm exhibited an 18% increase in petiole abscission as compared to controls. No effect was observed at a concn of 1 ppm, and while exposure to 10, 100, and 1000 ppm doses increased abscissions 2, 5, and 8%, respectively. [R75] *Male and female B6C3F1 mice were exposed 6 hr/day, 5 days/wk, for 60-61 wk to air containing 0, 625, or 1250 ppm 1,3-butadiene. These concn are somewhat below or slightly above the OSHA standard of 1000 ppm for butadiene. The study was designed for 104 wk exposures, but had to be ended early due to cancer related mortality in both sexes at both exposure concn. There were early induction and incr incidences of hemangiosarcomas of the heart, malignant lymphomas, aleolar-bronchiolar neoplasms, squamous cell neoplasms of the forestomach in males and females and acinar cell carcinomas of the mammary gland, granulosa cell neoplasms of the ovary, and hepatocellular neoplasms in females. [R76] *Groups of 110 female rats were exposed to atmospheres containing 0 (control), or 1000 or 8000 ppm (vol/ vol) butadiene for 6 hr/day, 5 days/wk. Ten of each sex from each group were killed at 52 wk. The study was terminated when it was predicted that survival would drop to 20-25% (105 wk for females and 111 wk for males). High-dose rats had wet, ruffled fur and showed slight incoordination during the first exposure each week. During the second year, mortality in both treated female groups was accompanied by an increase of the severity of nephropathy. Body wt was slightly lower than controls in both sexes at the high dose over the first 12 wk. Liver weights at both doses were increased in both sexes with no associated. pathological change. Kidney wt was increased in males at the high dose, together with an increase in the severity of nephrosis. There were increases in the incidences of pancreatic exocrine adenoma (high dose, male); uterine sarcoma (both doses, female); Zymbal gland carcinoma (high dose, female); mammary tumors (both doses, female); thyroid follicular cell tumors; and testis Leydig cell tumors (high dose). Apparently, the butadiene is a weak oncogen to the rat under the conditions of exposure used in this study. [R77] *Whether butadiene or isoprene administration would result in the formation of adducts with blood hemoglobin and whether such adducts can be used as a measure of previous exposure(s) were studied. Male B6C3F1 mice and male Sprague-Dawley rats were injected with 1, 10, 100, or 1000 umol (14)C butadiene or 0.3, 3.0, 300, or 3000 umol (14)C isoprene/kg. Animals were killed 24 hr later. Globin was isolated from blood samples and was analyzed for (14)C by liquid scintillation spectroscopy. Hemoglobin adduct formation was linearly related to admin doses up to 100 umol (14)C butadiene or 500 umol (14)C isoprene/kg for mice and rats, resp. For (14)C butadiene, the efficiency of hemoglobin adduct formation in mice and rats within the linear response range was 0.177 and 0.407 (pmol of (14)C-adducts/mg globin)/(umol of retained (14)C butadiene/kg), resp. For (14)C isoprene, these values for mice and rats were 0.158 and 0.079 (pmol of (14)C-adducts/mg globin)/ (umol of retained (14)C isoprene/kg), respectively. Hemoglobin adducts also accumulated linearly after repeated daily admin of 100 umol (14)C butadiene or 500 umol (14)C isoprene/kg to mice and rats, respectively, for 3 days. (14)C Butadiene-derived hemoglobin adducts in blood showed lifetimes of approx 24 ppm and approx 65 days for mice and rats, respectively, which correlate with the reported lifetimes for red blood cell in these rodent species. Thus, levels of butadiene- or isoprene-derived adducts on hemoglobin in circulating blood may be a useful measure of prior exposures to these cmpds. [R78] *Mice were exposed to 1250 ppm 1,3-butadiene by inhalation 6 hr/day, 5 days/wk for 6 or 12 wk. Immune function asays were selected to evaluate specific humoral and cell- mediated immunity and spontaneous cytotoxicity; lymphoid organ histopathology was also evaluated. A slight decr in antibody plaque-forming cells/spleen was observed in exposed mice, although plaque-forming cells/106 splenic lymphocytes was normal. Significant extramedullary hematopoiesis and erythroid hyperplasia was observed in spleens from exposed mice, and correlated with a 2-fold incr in thymidine incorporation in spontaneusly proliferating splenocytes. No differences in proliferation to alloantigens were demonstrable between control and 1,3-butadiene-exposed splenocytes. Mitogenesis by phytohemaglutinin, concanavalin A, and lipopolysaccharide was suppressed in splenocytes from exposed mice, but may have been due to the cellular dilution effect of hematopoietic activity. Cytotoxic T-lymphocyte generation was suppressed afer a 6-wk exposure to 1,3-butadiene, but was comparable to controls after 12 wk of exposure. No differences in spontaneous cytotoxicity were observed between control and exposed mice. Overall, no persistent immunology defects were detectable after inhalation exposure to this tumorigenic agent. [R79] *Groups of male B6C3F1 mice were exposed to ambient air or to gaseous 1,3-butadiene (at 6.25, 62.5, and 625 ppm for 10 exposure days (6 hr/day). Exposure to 1,3-butadiene induced in bone marrow: a significant incr in the frequency of chromosomal aberrations; a significant elevation in the frequency of sister chromatid exchanges, a significant lengthening of the average generation time (AGT); a significant depression in the mitotic index(MI); and , as measured in the peripheral blood, a significant incr in the proportion of circulating polychromatic erythrocytes, and a significant incr in the level of micronucleated polychromatic erythrocytes and micronucleated normochromatic erythrocytes. The most sensitive indicator of genotoxic damage was the frequency of sister chromatid (significant at 6.25 ppm), followed by micronucleated-polychromatic erythrocytes levels (significant at 62.5 ppm). The most sensitive measure of cytotoxic damage ... (significant at 62.5 ppm), followed by % polychromatic erythrocytes (significant by trend test only). Because each cytogenetic endpoint was evaluated in every animal, a correlation analysis was conducted to evaluate the degree of concordance among the various indicators of genotoxic and cytotoxic damage. The extent of concordance ranged from a very good correlation between the induction of micronucleated-polychromatic erythrocytes and the induction of sister chromatid exchanges to the lack of a significant correlation between the depression in the mitotic index and any other endpoint. [R80] *1,2-Epoxybutene was mutagenic to Salmonella typhimurium TA1530, TA1535 and TA100, but not to TA1537, TA1538 or TA98. It was reported to be mutagenic to Escherichia coli WP2 uvrA in the absence of an exogenous metabolic system. 1,2:3,4-Diepoxybutane /SRP: metabolite/ induced prophage in Bacillus megaterium, Pseudomonas pyocyanea and Escherichia coli k-12. It was mutagenic to S. typhimurium TA1535 (0.01-0.1 ul/plate) and TA100 (2-15 mM) in the absence of a metabolic system. At concentrations of 0.05-1 mM, 1,2:3,4-diepoxybutane /SRP: metabolite/ induced streptomycin resistance in fluctuation test with Klebsiella pneumoniae, in the absence of a metabolic system. [R81] *... Under the conditions of these studies, there was clear evidence of carcinogenicity for 1,3-butadiene in male and female B6C3F1 mice as shown by incr incidences and early induction of hemangiosarcomas of the heart, lymphomas, alevolar/bronchiolar adenomas and carcinomas, and papillomas of the stomach in males and females; and of acinar cell carcinomas of the mammary gland, granulosa cell tumors of the ovary, and hepatocellular adenomas and adenomas or carcinomas (combined) in females. ... [R82] *... Conclusions: The previous inhalation studies of 1,3-butadiene in male and female B6C3F1 mice provided clear evidence of carcinogenicity at exposure concn of 625 or 1,250 ppm. The present inhalation studies, 2 yr exposures of 6.25, 20, 62.5, 200, or 625 ppm or shorter duration exposures of 200, 312, or 625 ppm, provide a better characterization of the concn dependent responses for 1,3-butadiene induced neoplasms and nonneoplastic lesions. The present studies confirmed the clear evidence of carcinogenicity of 1,3-butadiene in male B6C3F1 mice based on incr incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, preputial gland, and in female B6C3F1 mice based on incr incidences of neoplasms in the hematopoetic system, heart, lung, forestomach, liver, harderian gland, ovary, and mammary gland. [R83] *The diepoxide of 1,3-butadiene (1,2:3,4-diepoxybutane), a probable metabolite, has been reported to be a mild skin tumorigen when topically applied to the dorsal skin of mice. Results from a long-term study completed in 1979 of the inhalation toxicity and carcinogenicity of 1,3-butadiene to rats indicate that 1,3-butadiene is carcinogenic in experimental animals. Rats (110 per sex per exposure group) were exposed 105 weeks and males for 111 weeks at 1,3-butadiene concentrations of 0, 1000, or 8000 ppm. [R27, 1991.156] *Rats and guinea pigs /were exposed/ to 6700 ppm 1,3-butadiene daily for 8 months. The only observed effect was a slight decr in weight gain ... . [R63, 1005] *1,3-Butadiene is mutagenic following activation by liver microsomes in bacterial species. Ip admin of 1,3-butadiene monoxide induced sister chromatid exchanges and chromosome abnormalities in B6C3F1 mice, as did 10 days' inhalation at levels of 6.25, 62.5, and 625 ppm. [R63, 1007] *Groups of 60 male B6C3F and 60 male NIH Swiss mice, 4-6 weeks of age, were exposed to 0 or 1250 ppm (2760 mg/cu m) butadiene (> 99.5% pure) by whole-body inhalation for 6 hr/day on 5 days/wk for 52 wk. An additional group of 50 male B6C3F mice was exposed similarly to butadiene for 12 wk and held until termination of the experiment at 52 wk. The incidence of thymic lymphomas in B6C3f mice was 1/60 control, 10/48 exposed for 12 wk 7 34/60 exposed for 52 wk and, in NIH Swiss mice, 8/57 exposed for 52 wk. Hemangiosarcomas of the heart were observed in 5/60 B6C3f mice and 1/57 NIH Swiss mice. [R84] *Groups of 70-90 male and 70-90 female B6C3F mice, 6.5 weeks of age, were exposed to butadiene (purity, > 99%) at concentrations of 1, 6.25, 20, 62.5, 200 or 625 ppm (0, 14, 44, 138, 440 or 1380 mg/cu m) for 6 hours per day of five days per week for up to two years. Ten animals per group were killed and evaluated after 40 and 65 weeks of exposure. Survival was significantly reduced (p < 0.05) in all groups of mice exposed at 20 ppm or higher; terminal survivors were: males: 35/70 control, 39/70 at 6.25 ppm, 24/70 at 20 ppm, 22/70 at 62.5 ppm, 3/70 at 200 ppm and 0/90 at 625 ppm; females: 37/70 controls, 33/70 at 6.25 ppm, 24/70 at 20 ppm; 11/70 at 62.5 ppm; 0/70 at 200 ppm and 0/90 at 625 ppm. Exposure to butadiene produced increases in the incidences in both sexes of lymphomas, heart hemangiosarcomas, lung alveolar/bronchiolar adenomas and carcinomas, forestomach papillomas and carcinomas, Harderian gland adenomas and adenocarcinomas and hepatocellular adenomas and carcinomas. The incidences of mammary gland adenocarcinomas and benign and malignant ovarian granulosa-cell tumors were increased in females. [R85] *Groups of 60 male and 60 female B6C3F mice, 8-10 weeks old, were exposed to butadiene (purity unspecified) by whole-body inhalation for a single 2 hour period at concentrations of 0, 1000, 5000, or 10000 ppm (0, 2200, 11000 or 22000 mg/cu m). The mice were then held for two years, at which time all survivors were killed and tissues and organs examined histopathologically. Survival, weight gains and tumor incidences of exposed mice were not affected by butadiene exposure (survival: males - 28/60 control, 34/60 low-dose, 44/60 mid-dose, 34/60 high-dose; females - 45/60, 36/60, 38/60, 45/60). [R85] *Butadiene increased the frequency of sister chromatid exchanges and micronuclei in mouse but not rat bone marrow. Micronucleus frequency also increased in peripheral erythrocytes and splenocytes. Butadiene also induced chromosomal aberrations in mouse bone marrow, and dominant lethal mutations, heritable translocations and spermhead abnormalities in mice. It did not induce aneuploidy in bone marrow cells in vivo. [R86] *Mutations were induced at the hprt locus in mice exposed to butadiene for 6 hours per day on five days per week at 625 ppm (1380 mg/cu m) for two weeks or at 1300 ppm (2760 mg/cu m) for one week. Butadiene was mutagenic in the mouse spot test (500 ppm (1100 mg/cu m) 6 hours per day for five days) and in two transgenic mouse models. Exposure to 62.5 or 1250 ppm (138 or 2760 mg/cu m) butadiene for 6 hours per day on five days per week for four weeks increased the frequency of mutation induced at A:T base pairs in bone marrow of lacI mice, while exposure to 625 ppm for 6 hours per day for five days increased the lacZ mutation frequency in lung but not liver or bone marrow of the MutaMouse. [R86] *Groups of 70 male and female B6C3F1 mice were exposed to 0, 6.25, 62.5, 200 or 625 ppm (0, 14, 44, 138, 440 or 1380 mg/cu m) butadiene for 6 hours per day on five days per week for up to 103 weeks. Groups of 10 males and 10 females were killed at 40 and 65 weeks. Ovarian atrophy was noted in female mice at 65 weeks of exposure (after completion of the reproductive life of this species) at 20 ppm and higher. Testicular atrophy occurred after 65 weeks in the male mice at 625 ppm. [R87] *Enhanced susceptibility to butadiene induced leukemogenesis as a result of an ability to express the retrovirus was suggested by the finding that exposure to 1250 ppm butadiene for one year resulted in a 57% incidence of thymic lymphoma in B6C3F1 mice (with expression of the virus) and a 14% incidence in NIH Swiss (without viral expression). [R87] *In female rats exposed to 1-30 mg/cu m butadiene for 81 days, morphological changes were observed in liver, kidney, spleen, nasopharynx and heart. In gourps of 24 rats exposed to 600-6700 ppm (1300-14800 mg/cu m) butadiene for 7.5 hr/day on 6 days/wk for eight months, no adverse effect was noted, except for a slight retardation in growth at the highest concn. Rats exposed to 2200-17600 mg/cu m butadiene for 6 hr/day on 5 days/wk for 3 months showed no treatment-related effect other than incr salivation in females. [R88] *Rabbits exposed to 25% (250,000 ppm) butadiene exhibited light, relaxed anesthesia in 1.6 min, followed by loss of various reflexes, CNS effects, and death in 23 min. [R34, 1251] *In animals exposed to 6,700 ppm or less 1,3 butadiene, no impairment of fertility was noted when groups of male and female rats, rabbits, or guinea pigs were housed together and allowed to mate freely ... . In intermediate duration studies, no histopathological evidence of treatment related effects in reproductive organs of rats ... or mice (NTP 1984) was found, but reproductive function was not assessed in these studies. [R69] *A concentration related increase in the incidence of sperm head abnormalities occurred in B6C3Fl mice after exposure to 1,000 and 5,000 ppm of 1,3 butadiene for 6 hours/day for 5 days ... . Dominant lethality in CD 1 mice was also observed during the first 2 postexposure weeks after the males were exposed to 200, 1,000 but not 5,000 ppm ... . The study was considered to be inconclusive because of the lack of dose response. [R69] *In a chronic study, exposure of mice to 6.25 ppm or more of 1,3 butadiene resulted in an increased incidence of ovarian atrophy in females ..., while a corresponding increase in testicular atrophy was observed in males only after exposure to 625 ppm ... . The data indicated high susceptibility of female mice to 1,3 butadiene induced effects in reproductive organs. Malignant tumors in reproductive tissues were found after chronic exposure in rats, but reproductive functions were not evaluated ... . [R69] *B6C3Fl mice were exposed to 1,3 butadiene at concentrations up to 10,000 ppm for 6 hours/day for 2 days ... . A statistically significant dose related increase in micronucleus induction was observed in mice beginning at 100 ppm. The frequency of micronucleated polychromatic erythrocytes was also significantly increased in B6C3Fl mice exposed 6 hours/day, 5 days/week for 13 weeks to concentrations of 62.5 and 625 ppm of 1,3-butadiene. [R89] NTXV: *LD50 Rat oral 5.48 g/kg; [R90] *LD50 Mouse oral 3.21 g/kg; [R90] *LC50 Rat inhalation 285,000 mg/cu m/4 hr; [R91] *LC50 Mouse inhalation 270,000 mg/cu m/2 hr; [R91] ETXV: *TLm Pinperch 71.5 mg/l/24 hr /Conditions of bioassay not specified/; [R38, 297] NTP: *... Inhalation carcinogenesis studies of 1,3-butadiene were conducted by exposing groups of 50 male and 50 female B6C3F1 mice 6 hr/day 5 days/wk to air containing the test chemical at concentrations of 0 (chamber controls), 625, or 1,250 ppm. These studies were planned for 103 wk exposures but were terminated at wk 60 for male mice and wk 61 for female mice because of the rapidly declining survival, primarily due to neoplasia. ... Under the conditions of these studies, there was clear evidence of carcinogenicity for 1,3-butadiene in male and female B6C3F1 mice as shown by increased incidences and early induction of hemangiosarcomas of the heart, lymphomas, alevolar/bronchiolar adenomas and carcinomas, and papillomas of the stomach in males and females; and of acinar cell carcinomas of the mammary gland, granulosa cell tumors of the ovary, and hepatocellular adenomas and adenomas or carcinomas (combined) in females. ... [R82] *... Toxicology and carcinogenesis studies were conducted by exposing groups of male and female B6C3F1 mice to air containing 1,3-butadiene (greater than 99% pure) for up to 2 yr. ... 2 Year Studies: Groups of 70 male and 70 female mice were exposed to air containing 0, 6.25, 20, 62.5, or 200 ppm 1,3-butadiene for 6 hr /day, 5 days/wk for up to 2 yr; groups of 90 male and 90 female mice were exposed to 625 ppm 1,3-butadiene on the same schedule. .... Conclusions: The previous inhalation studies of 1,3-butadiene in male and female B6C3F1 mice provided clear evidence of carcinogenicity at exposure concentrations of 625 or 1,250 ppm. The present inhalation studies, 2 yr exposures of 6.25, 20, 62.5, 200, or 625 ppm or shorter duration exposures of 200, 312, or 625 ppm, provide a better characterization of the concentration dependent responses for 1,3-butadiene induced neoplasms and nonneoplastic lesions. The present studies confirmed the clear evidence of carcinogenicity of 1,3-butadiene in male B6C3F1 mice based on increased incidences of neoplasms in the hematopoietic system, heart, lung, forestomach, liver, harderian gland, preputial gland, based on increased incidences of neoplasms in the hematopoetic system, heart, lung, forestomach, liver, harderian gland, ovary, and mammary gland. [R83] +Maternal toxicity, reproductive performance and developmental toxicology were evaluated in Sprague-Dawley-derived rats during and following 6 hours/day, whole-body, inhalation exposures to 0 (filtered air), 40, 200 and 1000 ppm of 1,3-butadiene. The female rats (Ns = 24 to 28), which had mated with unexposed males (day of sperm detection = 0 days of gestation; dg), were exposed to the chemical from 6 through 15 dg and sacrificed on 20 days of gestation. Maternal animals were weighed prior to mating and on 0, 6, 11, 16 and 20 days of gestation; the rats were observed for mortality, morbidity and signs of toxicity during exposure and examined for gross tissue abnormalities at necropsy. ... There were no significant differences among treatment groups in maternal body weights or extragestational weights of rats exposed to 1,3-butadiene concentrations of 40 or 200 ppm, but, in animals exposed to 1,000 ppm, significantly depressed body weight gains were observed during the first 5 days of exposure and extragestational weight gains tended to be lower than control values. These results, and the absence of clinical signs of toxicity, were considered to indicate that there was no maternal toxicity at exposure levels of 200 ppm or lower. The percentage of pregnant animals and the number of litters with live fetuses were unaffected by treatment. Placental weights, fetal body weights and sex ratios were unaffected by treatment. There were no significant differences among groups in incidences of fetal malformations. However, in the 200-ppm exposure group, a significant increase in the incidence of reduced sternebral ossification was detected when the analyses were based on the number of affected fetuses but not on the number of affected litters. This difference could not be correlated with fetal body weights or exposure regimens and was not considered to be treatment-related. There were also irregularities in the thoracic vertebrae, but the incidence of reduced ossification in fetuses of the control group was significantly higher than in fetuses of the 200- and 1000-ppm exposure groups. Under the conditions of this exposure regimen, there was no evidence for a teratogenic response to 1,3-butadiene exposure. [R92] +Maternal toxicity, reproductive performance and developmental toxicology were evaluated in CD-1(R) mice following whole-body, inhalation exposures to 0 (filtered air), 40, 200 and 1000 ppm of 1,3-butadiene. The female mice, which had mated with unexposed males (day of detection of a copulation plug = 0 days of gestation; dg), were exposed to the chemical for 6 hours/day on 6 through 15 dg and sacrificed on 18 dg. ... For unknown reasons, the overall percentage of pregnant mice was low (60%), but no differences among treatments were detected in the number of pregnancies or implantation sites/dam. The incidence of early resorptions was higher in control mice than in animals exposed to 200 ppm, but no effect was observed on the percentage of total resorptions and live fetuses/litter. Significant concentration-related decreases were detected in a number of maternal body weight measures (weight gains during the intervals encompassing the last 5 days of exposure and from the end of exposure to sacrifice, body weight at sacrifice, extragestational weight and weight gain, and weight of the gravid uterus). There was a significant concentration-related depression of fetal body weights and placental weights. Body weights of male fetuses of all exposed groups were significantly lower than values for control fetuses; weights of female fetuses were significantly depressed in the mice exposed to 200 and 1000 ppm. In the 200- and 1000-ppm exposure groups, weights of placentas of male fetuses were significantly decreased, but placental weights of female fetuses were significantly affected only in litters exposed to the highest 1,3-butadiene concentration. There were no significant differences among groups in the incidences of malformations. However, incidences of fetal variations (supernumerary ribs and reduced ossification of the sternebrae) were significantly increased in litters from mice exposed to 200 and 1000 ppm. This exposure regimen produced significant signs of maternal toxicity at concentrations of 200 and 1000 ppm 1,3-butadiene. Fetal growth retardation, decreased placental weights, and increased incidences of morphologic variations were observed to occur in a concentration-related manner. Body weights of male fetuses of mice exposed to the lowest concentration of 1,3-butadiene (40 ppm) were significantly depressed, although no other signs of retarded fetal development or significant alterations in maternal indices were noted at this exposure level. These results may indicate that the fetus is more susceptible than the dam to 1,3-butadiene toxicity, but no evidence of teratogenicity was found in the offspring of dams exposed to 1,3-butadiene vapors on 6 through 15 days of gestation. [R93] TCAT: ?Chronic toxicity and oncogenicity were evaluated in male and female CD strain Sprague Dawley rats (110/sex/group) exposed to 1,3-butadiene via inhalation at 0, 1000 and 8000 ppm for 6 hrs/day, 5 days/week for 105 and 111 weeks for females and males, respectively. There were significant differences between treated animals and controls in the following: subcutaneous masses (increased and with earlier onset for both sexes at both levels), body weight (decreased 1st 12 weeks for both sexes at both levels), mortality (increased mortality at 8000 ppm for both sexes), relative and absolute liver weight (increased for males at both doses and for females at 1000 ppm), and adrenal weight (increased for low dose males). There were significant increases in both common and uncommon tumor types at both treatment levels, including these types of tumors: mammary, thyroid follicular, and uterus/vaginal stromal (females), and tumors of the Zymbal gland (both sexes). There were no significant differences between treated animals and controls in the following: hematology, blood chemistry, urinalysis and pathology. [R94] ?Teratogenicity was evaluated in mated female Sprague Dawley rats (24/treated group, 40 in control group) exposed by inhalation to 1,3-butadiene at nominal concentrations of 0, 200, 1000 or 8000 ppm for 6 hrs/day on gestation days 6-15. There were significant differences observed between treated and control animals in the following: decreased maternal body weights and body weight gain (high-dose level for entire exposure period, mid-dose group early in exposure period, low dose group, but "less marked" than at higher doses), decreased mean fetal weight and crown/rump length (high-dose group), and increased incidence of wavy ribs (fetuses of all treated groups). A variety of defects were reportedly observed in fetuses of high-dose group, but they were not reported on this microfiche. There were no significant differences observed between treated and control animals in the following: mortality, clinical changes, pregnancy incidence, implantation or implantation losses, gravid uterine weight, post-implantation losses, and fetal sex distribution. [R95] ADE: *Blood concentrations in the femoral artery and femoral vein of rabbits nine minutes after exposure to an airborne concn of 250,000 ppm of 1,3-butadiene were 0.26 mg/ml and 0.18 mg/ml, respectively. [R96] *Rats exposed to 1,3-butadiene for 2 hours at an airborne concn of 130,000 ppm butadiene had the highest concentrations of the chemical in the perirenal fat (152 mg%); Lower concentrations (36-51 mg%) were found in the liver, brain, spleen, and kidney. Ninety minutes after exposure to 130,000 ppm for one hour, the tissue concentrations were minimal. [R96] *Following an ip injection of radiolabeled 1,3-butadiene, male B6C3F1 mice exhaled most of the dose unchanged. Exhaled carbon dioxide was the next largest pool for the (14)C label. Lesser amounts were detected in the urine and feces and little remained in the carcass 65 hours after the ... injection. [R96] *Male Sprague Dawley rats and B6C3F1 mice were exposed by inhalation (nose-only) for 3.4 hr to 1220 and 121 ug (14)C-1,3-butadiene/l of air, respectively. For rats and mice, elimination of butadiene was rapid with 77 to 99% of the initial tissue burden being eliminated with half-times of 2 to 10 hr. [R97] *Male Sprague Dawley rats and B6C3F1 mice were exposed by inhalation (nose-only) for 3.4 hr to 1220 and 121 ug (14)C-1,3-butadiene/l of air, respectively. In both species, high concentrations of radioactivity were distributed to respiratory tract tissue (lung, trachea, nasal turbinates), gastrointestinal tract (small and large intestine), liver, kidneys, urinary bladder, and pancreas within 1 hr after exposure. Tissues of mice contained 15 to 100 times more (14)C-butadiene equivalents/umole of butadiene inhaled than rat tissues. One hr after exposure all rat tissues retained a substantial amount of (14)C that was associated with volatile material, probably butadiene and/or metabolites; this was also true for mouse liver (the only tissue studied at this time). There were no differences in rats and mice in terms of specific tissue accumulation or rate of elimination from tissues. The tissues of mice contained significantly higher concentrations of (14)C-butadiene per umole inhaled apparently due to the higher minute volume/kg of body weight of mice. The large amounts of nonvolatile material in tissues within one hr of exposure indicate that butadiene is rapidly metabolized following inhalation. [R97] *The distribution coefficient found when 1,3-butadiene was equilibrated with fresh blood samples (0.603) was quite similar to that calculated from measurements in animals breathing a 25% concn of 1,3-butadiene (0.645). ... The movement of inspired air into the blood is a process of simple diffusion form alveoli and solution into blood. [R67, 376] */Exposure to the vapor concn for 50% lethality in rats indicates/ that body fat may be a depot for 1,3-butadiene, since perinephric fat contained 3-4 times more 1,3-butadiene than did brain, liver, kidney, or spleen. [R67, 377] METB: *IN RAT LIVER MICROSOMES, 1,3-BUTADIENE WAS METABOLIZED TO BUTADIENE MONOXIDE, WHICH WAS SUBSEQUENTLY TRANSFORMED INTO 3-BUTENE-1,2-DIOL BY MICROSOMAL EPOXIDE HYDROLASE. IN THE METABOLISM OF BUTADIENE OXIDE IN MICROSOMES, 4 METABOLITES WERE DETECTED, NAMELY 2 STEREOISOMERS OF DL-DIEPOXYBUTANE (A SUSPECTED CARCINOGEN) and 2 STEREOISOMERS OF 3,4-EPOXY-1,2-BUTANEDIOL. NO MESO-DIEPOXYBUTANE WAS DETECTED. [R98] *1,3-BUTADIENE WAS INCUBATED IN THE PRESENCE OF RAT LIVER MICROSOMES SUPPLEMENTED WITH AN NADPH-GENERATING SYSTEM. ONE OF THE MAJOR METABOLITES OF BUTADIENE WAS 1,2-EPOXYBUTENE-3. [R99] *The pharmacokinetics of ... 1,3-butadiene ... were studied in male Spraque-Dawley rats by of a closed inhalation chamber system. 1,3-Butadiene showed saturable metabolism when untreated rats were used. Linear pharmacokinetics applied at exposure concn below ... 1500 ppm. Pretreatment with arochlor 1254 (polychlorinated biphenyls) increased Vmax. ... No saturation of metabolic capacity was observed with exposure concn up to 12,000 ppm when rats were pretreated with arochlor 1254. A comparison with previous studies on ethane and n-pentane suggested that introduction of a double bond into a saturated aliphatic hydrocarbon increased the rate of metabolism under conditions in vivo. [R100] *The diepoxide of 1,3-butadiene (1,2:3,4-diepoxybutane), a probable metabolite, has been reported to be a mild skin tumorigen when topically applied to the dorsal skin of mice. Results from a long-term study completed in 1979 of the inhalation toxicity and carcinogenicity of 1,3-butadiene to rats indicate that 1,3-butadiene is carcinogenic in experimental animals. Rats (110 per sex per exposure group) were exposed 105 weeks and males for 111 weeks at 1,3-butadiene concentrations of 0, 1000, or 8000 ppm. [R27, 1991.156] *Comparative investigations of inhalation pharmacokinetics of 1,2-epoxybutene-3, the primary reactive intermediate of butadiene, revealed major differences in metab of this cmpd between rats and mice. Whereas in rats no indication of saturation kinetics of epoxybutene metab could be observed up to exposure concns of 5000 ppm, in mice saturation of epoxybutene metab becomes apparent at atmospheric concn of approx 500 ppm. The estimated maximal metabolic rate in mice for epoxybutene was only 350 umol/hr/kg (rats: > 2600 umol/hr/kg). In the lower concn range where first-order metab applied (up to about 500 ppm) epoxybutene is metabolized by mice at higher rates compared to rats (metabolic clearance/kg bw, mice: 24,900 ml/hr, rats: 13,400 ml/hr). Under these condition the steady state concn of expoxybutene in the mouse is approx 10 times that in the rat. When mice are exposed to high concns of butadiene (> 2000 ppm; conditions of saturation of butadiene metab; closed exposure system) epoxybutene is exhaled by the animals; and its concn in the gas phase increases with exposure time. At approx 10 ppm epoxybutene signs of acute toxicity are observed. When rats are exposed to butadiene under similar conditions, the epoxybutene concn reaches a plateau at approx 4 ppm. Under these conditions hepatic nonprotein sulfhydryl cmpd are virtually depleted in mice but not in rats. Evidently in addn to the higher rate of metab of butadiene in mice, limited detoxification and consequently accumulation of its primary reactive intermediate epoxybutene may be a major determinant for the higher susceptibility of mice to butadiene-induced carcinogenesis. [R101] *1,3-Butadiene is converted to 1,2-epoxybutene (vinyl oxirane) by mixed-function oxidases in rat liver microsomes in vitro. Pretreatment of rats with phenobarbital increased enzyme activity. 1,2-Expoxybutene is further metabolized to 1,2:3,4-diepoxybutane and 3-butene-1,2 diol; the latter product is metabolized by mixed-function oxidases to 3,4-epoxy-1,2-butanediol. [R102] *N-(2-Hydroxy-3-butenyl)valine as a reaction product of epoxybutene with N-terminal valine in hemoglobin has been found in workers exposed to butadiene. [R103] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,3-Butadiene's production and use in the manufacture of polymers such as synthetic rubber, plastics and resins may result in its release to the environment through various waste streams. 1,3-Butadiene is also released in emissions from motor vehicles and tobacco smoke. If released to air a vapor pressure of 2,110 mm Hg at 25 deg C indicates 1,3-butadiene will exist solely as a gas in the ambient atmosphere. Gas-phase 1,3-butadiene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, ozone molecules and nitrate radicals. The half-life for the reaction in air with hydroxyl radicals, ozone and nitrate radicals is estimated to be 6 hours, 37 hours and 14 hours, respectively. If released to soil, 1,3-butadiene is expected to have moderate mobility based upon an estimated Koc of 288. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 0.074 atm-cu m/mole. 1,3-Butadiene may volatilize from dry soil surfaces based upon its vapor pressure. Laboratory studies employing pure bacterial cultures isolated from lake and soil samples were shown to degrade 1,3-butadiene to 1,2-epoxybutene, however it is not clear what the rate of degradation is under environmental conditions. If released into water, 1,3-butadiene is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is expected to be an important environmental fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 and 70 hours, respectively. The biodegradation half-life of 1,3-butadiene in aerobic waters has been reported as 7 days and the half-life in anaerobic waters was reported as 28 days. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to 1,3-butadiene may occur through inhalation and dermal contact with this compound at workplaces where 1,3-butadiene is produced or used. The general population is exposed to 1,3-butadiene via inhalation of ambient air, particularly in areas of heavy vehicular traffic and dermal contact with this compound from consumer products containing 1,3-butadiene. (SRC) ARTS: *1,3-Butadiene's production and use in the manufacture of polymers such as synthetic rubber, plastics and resins(1) may result in its release to the environment through various waste streams(SRC). 1,3-Butadiene is also released in emissions from motor vehicles and tobacco smoke(2). [R104] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 288(SRC), determined from a log Kow of 1.99(2) and a regression-derived equation(3), indicates that 1,3-butadiene will have moderate mobility in soil(SRC). Volatilization of 1,3-butadiene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 0.074 atm-cu m/mole(SRC),calculated from its vapor pressure of 2,110 mm Hg(4) and water solubility of 735 mg/l(5). The potential for volatilization of 1,3-butadiene from dry soil surfaces may exist(SRC) based upon its vapor pressure(4). Laboratory studies employing pure bacterial cultures isolated from lake and soil samples were shown to degrade 1,3-butadiene to 1,2-epoxybutene(6,7), however it is not clear what the rate of degradation is under environmental conditions(SRC). [R105] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 288(SRC), determined from a log Kow of 1.99(2) and a regression-derived equation(3), indicates that 1,3-butadiene is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 0.074 atm-cu m/mole(SRC), calculated from its vapor pressure of 2,110 mm Hg(4) and water solubility of 735 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1 and 70 hours, respectively(SRC). According to a classification scheme(6), an estimated BCF of 7(SRC), from its log Kow(2)and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis is not expected to be an important environmental fate process for 1,3-butadiene(8). The biodegradation half-life in aerobic waters has been reported as 7 days and the half-life in anaerobic waters was reported as 28 days(8). [R106] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,3-butadiene, which has a vapor pressure of 2,110 mm Hg at 25 deg C(2), is expected to exist solely as a gas in the ambient atmosphere. Gas-phase 1,3-butadiene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, ozone molecules and nitrate radicals(SRC). The half-life for the reaction in air with hydroxyl radicals is estimated to be 6 hours(SRC), calculated from its rate constant of 6.66X10-11 cu cm/molecule-sec(3). The half-life for the reaction in air with ozone is estimated to be 37 hours(SRC), calculated from its rate constant of 7.5X10-18 cu cm/molecule-sec(4). The half-life for the reaction in air with nitrate radicals is estimated to be 14 hours(SRC), calculated from its rate constant of 5.6X10-14 cu cm/molecule-sec(5). [R107] BIOD: *Pure bacterial cultures isolated from lake and soil samples in NJ were shown to degrade 1,3-butadiene to 1,2-epoxybutene(1,2). 1,3-Butadiene was listed in a group of chemicals which should be biodegraded by biological sewage treatment as long as suitable acclimatization is achieved(3). The biodegradation half-life in aerobic waters has been reported as 7 days and the half-life in anaerobic waters was reported as 28 days(4). [R108] ABIO: *The rate constant for the gas-phase reaction of 1,3-butadiene with photochemically-produced hydroxyl radicals has been measured as 6.66X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the gas-phase reaction of 1,3-butadiene with ozone molecules has been measured as 7.5X10-18 cu cm/molecule-sec at 25 deg C(2). This corresponds to an atmospheric half-life of about 37 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). The reaction with nitrate radicals has been recognized as an important night time sink for 1,3-butadiene(4,5). The rate constant for the gas-phase reaction of 1,3-butadiene with nitrate radicals has been measured as 5.6X10-14 cu cm/molecule-sec at 25 deg C(4). This corresponds to an atmospheric half-life of about 14 hours at a nighttime atmospheric concentration of 2.4X10+8 nitrate radicals per cu cm(5). 1,3-Butadiene is not expected to undergo hydrolysis in the environment due to a lack of hydrolyzable functional groups(6,7). [R109] BIOC: *An estimated BCF of 7 was calculated for 1,3-butadiene(SRC), using a log Kow of 1.99(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R110] KOC: *The Koc of 1,3-butadiene is estimated as 288(SRC), using a log Kow of 1.99(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1,3-butadiene is expected to have moderate mobility in soil(SRC). [R111] VWS: *The Henry's Law constant for 1,3-butadiene is estimated as 0.074 atm-cu m/mole(SRC) from its vapor pressure, 2,110 mm Hg(1), and water solubility, 735 mg/l(2). This Henry's Law constant indicates that butadiene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 1 hour(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 70 hours(SRC). 1,3-Butadiene's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,3-butadiene from dry soil surfaces may exist based upon the vapor pressure(1). [R112] WATC: *DRINKING WATER: 1,3-Butadiene was identified, but not quantified in US drinking water(1). [R113] *SURFACE WATER: 1,3-Butadiene was detected in 1 of 204 samples of 14 Heavily industrialized river basins in the US (1975-76) at a concn of 2 ppb(1). [R114] EFFL: *1,3-Butadiene was emitted at a mean rate of 20.7 mg/km in 6 motor vehicles without catalytic converters and at a mean rate of 2.1 mg/km in the exhaust of vehicles with catalytic converters(1). The emission rate (40 deg F) of 1,3-butadiene in a vehicle using an oxygenated fuel was 3.10 mg/mi and the emission rate in the same vehicle using a non-oxygenated fuel was 5.75 mg/mi(2). It was also shown that vehicles equipped with oxidation catalysts significantly decreased the emissions of 1,3-butadiene(2). 1,3-Butadiene was emitted at rates of 0-1.5 mg/mi in vehicles using 8 different fuels including alternative fuels containing mixtures of alcohol and gasoline(3). The mean emission rate of 10 4-stroke lawnmower engines using a standard gasoline was 0.25 g/kW-hr, and the mean emission rate from the same engines using an oxygenated fuel containing 12% methyl tertiary butyl ether (MTBE) was 0.22 g/kW-hr(4). The avg concn of 1,3-butadiene in landfill gas from the Fresh Kills landfill, NY was 3.98 ppm(5). [R115] ATMC: *RURAL/REMOTE: 1,3-Butadiene was detected at concns of 0.1 to 6.5 ppb in Jones State Forest, TX (Jan 1978)(1). [R116] *SUBURBAN/URBAN: 1,3-Butadiene was detected in Riverside, CA at concns of 0 to 0.7 ppb (6 samples, afternoons with heavy haze; Aug-Nov 1965); 2.0 ppb (moderately heavy haze and clear sky, March 1966) to 9.0 ppb (light haze and partly cloudy, Dec 1965)(1). 1,3-Butadiene was detected in Los Angeles central business district at concns of 0 to 9 ppb(2). The avg concn of 1,3-butadiene in urban air samples in the US was 1.5 ppb for 1977-1978(3). The concn of 1,3-butadiene in London, England ranged from 0.4-2.4 ppb from July 1991 to September 1992(4). 1,3-Butadiene was detected at concns of 0-2.5 ug/cu m (avg concn of 0.81 ug/cu m) in Los Angeles, CA during the summer of 1993(5). The mean concn of 1,3-butadiene in downtown Porto Alere, Brazil (March 20 1996 to April 16 1997) was 2.7 mg/cu m(6). [R117] *SOURCE DOMINATED: 1,3-Butadiene was detected in industrial areas of Houston, including tunnels at concns of 0-33.3 ppb (avg 24.8 ppb)(1). The avg concn of 1,3-butadiene in source dominated areas of the US was 1.9 ppb (1977-1980)(2). 1,3-Butadiene was identified, not quantified, in Homebush Bay, Australia (industrial area), June 3, 1975(3). [R118] *INDOOR AIR: 1,3-Butadiene was detected in 1 of 14 samples of indoor air in Arizona at a concn of 0.38 ug/cu m(1). [R119] FOOD: *1,3-Butadiene was detected in 6 out of 6 vegetable oils packaged in a butadiene based plastic container at concns of 8-9 ppb(1). [R120] OEVC: *The avg concn of 1,3-butadiene in cigarette smoke was 14 ug/cu m(1). 1,3-Butadiene was identified, not quantified, in polybutadiene film food wrapping products(2). [R121] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 9,456 workers (286 of these are female) are potentially exposed to 1,3-butadiene in the US(1). The time-weighted average exposure in a rubber production plant: 0.22-59 ppm (over 1 month in 1977); Air in petrochemical workplace in USSR: 4.1-4.2 ppm (2). The general population may be exposed to 1,3-butadiene via inhalation of ambient air, particularly near areas of heavy vehicular traffic and dermal contact with this compound and other consumer products containing 1,3-butadiene(SRC). [R122] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers 1,3-butadiene to be a potential occupational carcinogen. [R26, 34] OSHA: *The employer shall ensure that no employee is exposed to an airborne concentration of 1,3-Butadiene in excess of 1 ppm measured as an 8-hr TWA. The employer shall ensure that no employee is exposed to an airborne concentration of 1,3-Butadiene in excess of 5 ppm as determined over a sampling period of 15 min. [R123] NREC: *NIOSH considers 1,3-butadiene to be a potential occupational carcinogen. /SRP: No IDLH specified/. [R26, 34] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R26, 34] TLV: +8 hr Time Weighted Avg (TWA) 2 ppm [R60, 2002.18] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R60, 2002.6] +A2: Suspected human carcinogen. [R60, 2002.18] OOPL: *International occupational limits for butadiene are as follows: United Kingdom: 1000 ppm or 2200 mg/cu m; Bulgaria: 45 ppm or 100 mg/cu m; Czechoslovakia: 230 ppm or 500 mg/cu m; Finland: 1000 ppm or 2200 mg/cu m; East and West Germany: 1000 ppm or 2200 mg/cu m; Poland: 45 ppm or 100 mg/cu m; Rumania: 682 ppm or 1500 mg/cu m; Yugoslavia: 1000 ppm or 2200 mg/cu m. [R124] *Russia: 100 mg/cu m. [R28, 347] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 10 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 200 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 5000 ppm (not life threatening) up to 1 hr exposure. [R125] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Butadiene is produced, as an intermediate or a final product, by process units covered under this subpart. [R126] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,3-butadiene is included on this list. [R127] *... Substances for which a Federal Register notice has been published that included consideration of the serious health effects, including cancer, from ambient air exposure to the substance. 1,3-Butadiene is included on this list. [R128] WSTD: STATE DRINKING WATER GUIDELINES: +(NH) NEW HAMPSHIRE 0.019 ug/l [R129] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R130] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *ANALYTE: BUTADIENE. MATRIX: AIR. PROCEDURE: ADSORPTION ON CHARCOAL, DESORPTION WITH CARBON DISULFIDE, GAS CHROMATOGRAPHY. RANGE: 1065-4590 MG/CU M. COEFFICIENT OF VARIATION 0.058 FOR TOTAL ANAL AND SAMPLING METHOD IN RANGE ... /INDICATED/. THIS VALUE CORRESPONDS TO 130 MG/CU M STD DEVIATION AT OSHA STD LEVEL OF 1000 PPM (2200 MG/CU M). [R131] *Sampling may be performed by collection of butadiene vapors using an adsorption tube with subsequent desorption with carbon disulfide gas chromatographic analysis. [R36, 1981.1] ALAB: *INFRARED AND GAS CHROMATOGRAPHIC ANALYTICAL METHODS WERE ADAPTED FOR MONITORING THE CONCN AND DISTRIBUTION OF BUTADIENE IN EXPOSURE CHAMBERS, AND FOR ANALYSIS OF KNOWN IMPURITIES, PARTICULARLY, T-BUTYL CATECHOL AND 4-VINYL-1-CYCLOHEXENE, IN ATMOSPHERES GENERATED FOR INHALATION TESTS. [R132] *A modified variant of the purge-and-trap gas chromatographic analysis of volatile organic carbon compounds in water was designed. Samples collected in 1 L glass bottles are purged at 60 deg C for 1 hr in an ultrapure helium gas stream using an open loop arrangement. Volatile eluates are trapped onto selective adsorbents packed inside stainless steel tubes connected in series. After stripping at a flow rate of 100 mg/min for 60 min, the adsorbent tubes are disconnected, fitted with analytical desorption caps and sequentially desorbed for 10 min on a thermal desorber. The desorbed organics are trapped at 30 deg C on a packed cold trap prior to flash volatilization of the volatiles across a fused silica transfer line onto a capillary column. The method separated over 200 organic compounds within 40 min using flame ionization and ion trap detection and is capable of quantitation down to 5 ng/l per component. The recoveries of 1,3-butadiene from water at 30 and 60 deg C were 100 and 103%, respectively. Improvement was made of compound recovery by substituting a second Tenax-TA tube with Chromosorb 106 and a third Tenax-TA tube with Spherocarb. Percentage recoveries of 1,3-butadiene with the two series of tubes (all Tenax-TA or 3 different kinds) were 17.2, 28.7, and 18.5%, and 17.7, 43.3, and 39.0% for tubes 1, 2, and 3, respectively. [R133] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: SERENBETZ H; 1,3-BUTADIENE. ITS TOXICITY PROFILE, RISK IN THE WORKPLACE, AND REGULATORY CONSIDERATIONS; ANNU MEET PROC INT INST SYNTH RUBBER PROD 24 (6): 1-25 (1983). REVIEW OF 1,3-BUTADIENE, ITS TOXICITY PROFILE, RISK IN THE WORKPLACE, AND REGULATORY CONSIDERATIONS. 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V39 167 (1986) R82: Toxicology and Carcinogenesis Studies of 1,3-Butadiene in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 288 (1984) NIH Publication No. 84-2544 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R83: Toxicology and Carcinogenesis Studies of 1,3-Butadiene in B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 434 (1993) NIH Publication No. 93-1365 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R84: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 132 (1999) R85: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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V71 163 (1999) R89: DHHS/ATSDR; Toxicological Profile for 1,3 butadiene p.19 TP-91/07 (1992) R90: USEPA; Health Assessment Document: 1,3-Butadiene p.27 (1985) EPA-600/8-85-004A R91: USEPA; Chemical Hazard Information Profile: 1,3-Butadiene p.10 (1981) R92: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Inhalation Developmental Toxicology Studies of 1,3-Butadiene (CAS No. 106-99-0) in the Rat, NTP Study No. TER89041 (November 1987 ) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R93: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Inhalation Developmental Toxicology Studies: Teratology Study of 1,3-Butadiene (CAS No. 106-99-0) in Mice, NTP Study No. TER85144 (November 1987) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R94: The Toxicity and Carcinogenicity of Butadiene Gas Administered to Rats by Inhalation for Approximately 24 Months, Final Report, Volume 1. (1981), EPA Document No. 45-8101002, Fiche No. OTS0504853 R95: Hazelton Laboratories, Inc.; 1,3-Butadiene: Inhalation Teratogenicity Study in the Rat, Final Report. (1981), EPA Document No. 88-8200415, Fiche No. OTS0505459 R96: USEPA; Health Assessment Document: 1,3-Butadiene p.29 (1985) EPA-600/8-85-004A R97: Bond JA et al; Am Ind Hyg Assoc J 48 (10): 867-72 (1987) R98: MALVOISIN E, ROBERFROID M; XENOBIOTICA 12 (2): 137-44 (1982) R99: MALVOISIN E ET AL; J CHROMATOGR 178 (2): 419-26 (1979) R100: Bolt HM et al; Arch Toxicol 55 (4): 213-8 (1984) R101: Kneiling R et al; Arch Toxicol 61 (1): 7-11 (1987) R102: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 166 (1986) R103: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 137 (1999) R104: (1) Budvari S, ed; Merck Index, 12th ed, NJ: Whitehouse Station, Merck and Co. p 248 (1996) (2) Graedel TE; Chemical Compounds in the Atmosphere, NY, NY: Academic Press p.76 (1978) R105: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 8 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (5) McAuliffe C; J Phys Chem 70:1267-75 (1966) (6) Hou CT et al; Appl Environ Microbiol 38: 127-134 (1979) (7) Hou CT et al; Appl Environ Microbiol 46: 171-177 (1983) R106: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 8 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (5) McAuliffe C; J Phys Chem 70: 1267-75 (1966) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Capel PD, Larson SJ; Chemosphere 30: 1097-1107 (1995) R107: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (3) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (4) Atkinson R; Atmos Environ 24A: 1-41 (1983) (5) Andersson Y, Ljungstroem E; Atmos Environ 23: 1153-55 (1989) R108: (1) Hou CT et al; Appl Environ Microbiol 38: 127-134 (1979) (2) Hou CT et al; Appl Environ Microbiol 46: 171-177 (1983) (3) Thom NS, Agg AR; Proc Roy Soc Lond B 189: 347-57 (1975) (4) Capel PD, Larson SJ; Chemosphere 30: 1097-1107 (1995) R109: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Atkinson R; Atmos Environ 24A: 1-41 (1983) (3) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (4) Andersson Y, Ljungstroem E; Atmos Environ 23: 1153-55 (1989) (5) Atkinson R et al; Environ Sci Technol 18: 370-5 (1984) (6) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (7) Capel PD, Larson SJ; Chemosphere 30: 1097-1107 (1995) R110: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 8 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R111: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 8 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R112: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (2) McAuliffe C; J Phys Chem 70: 1267-75 (1966) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R113: (1) USEPA; CHIP (Draft) 1,3-butadiene p. 20 (1981) R114: (1) Ewing BB et al; Monitoring to detect previously unrecognized pollutants in surface waters. Appendix: organic analysis data pp. 75 USEPA-560/6-77-015 (1977) R115: (1) Ye Y et al; Atmos Environ 31: 1157-68 (1997) (2) Stump FD et al; J Air Waste Manage Assoc 44: 781-786 (1994) (3) Gabele P; J Air Waste Manage Assoc 45: 770-77 (1995) (4) Gabele P; J Air Waste Manage Assoc 47: 945-52 (1997) (5) Eklund B; Environ Sci Technol 32: 2233-37 (1998) R116: (1) Seila RL; Nonurban Hydrocarbon Concentrations in Ambient Air North of Houston. USEPA-500/3-79-010 p.38 (1979) R117: (1) Stephens ER, Burleson FR; J Air Pollut Control Assoc 17: 147-53 (1967) (2) Neligan RE; Arch Environ Health 5: 581-91 (1962) (3) Brodzinsky R, Singh HB; Volatile Organic Compounds in the Atmosphere: An Assessment of Available Data p.198 SRI Inter contract 68-02-3452 (1982) (4) Field RA et al; Environ Technol 15: 931-44 (1994) (5) Fraser MP et al; Environ Sci Technol 31: 2356-67 (1997) (6) Grosjean E et al; Environ Sci Technol 32: 2061-69 (1998) R118: (1) Lonneman WA et al; Hydrocarbons in Houston air. USEPA-600/3-79-018 p.44 (1979) (2) Brodzinsky R, Singh HB; Volatile Organic Compounds in the Atmosphere: An Assessment of Available Data p.198 SRI Inter contract 68-02-3452 (1982) (3) Mulcahy MFR et al; Occurrence Control Phtochem Pollut, Proc Symp Workshop Session, Paper No IV, pp. 17 (1976) R119: (1) Gordon SM et al; J Expo Anal Environ Epidem 9: 456-470 (1999) R120: (1) McNeal TP, Breder CV; J Assoc Off Anal Chem 70: 18-21 (1987) R121: (1) Lofroth G et al; Environ Sci Technol 23: 610-14 (1989) (2) Tan S, Okada T; Shokuhin Eiseigaku Zasshi 22:150-4 (1981) R122: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) USEPA; CHIP (Draft) 1,3-Butadiene p.6 (1981) R123: 29 CFR 1910.1051(c) (7/1/2000) R124: USEPA; Chemical Hazard Information Profile (Draft) 1,3-Butadiene p.17 (1981) R125: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.25 R126: 40 CFR 60.489 (7/1/2000) R127: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R128: 40 CFR 61.01(b) (7/1/2000) R129: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R130: 40 CFR 302.4 (7/1/2000) R131: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V2 S91 R132: PULLINGER DH ET AL; AM IND HYG ASSOC J 40 (9): 789-95 (1979) R133: Bianchi A et al; J Chromatogr 467 (1): 111-28 (1989) RS: 128 Record 37 of 1119 in HSDB (through 2003/06) AN: 184 UD: 200303 RD: Reviewed by SRP on 11/07/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NAPHTHALENE- SY: *ALBOCARBON-; *DEZODORATOR-; +Pesticide-Code-055801-; *MOTH-BALLS-; *MOTH-FLAKES-; *NAFTALEN- (POLISH); *NAPHTHALIN-; *NAPHTHALINE-; *NAPHTHENE-; *NCI-C52904-; *TAR-CAMPHOR-; *WHITE-TAR- RN: 91-20-3 MF: *C10-H8 SHPN: UN 1334; Naphthalene (crude or refined) UN 2304; Naphthalene, molten IMO 4.1; Naphthalene (crude or refined); naphthalene, molten STCC: 49 403 60; Naphthalene or naphthalin, crude (tar camphor) 49 403 61; Naphthalene or naphthalin, other than crude (tar camphor) HAZN: U165; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN: MOST ABUNDANT SINGLE CONSTITUENT OF COAL TAR. DRY COAL TAR CONTAINS ABOUT 11%. CRYSTALLIZES FROM MIDDLE OR "CARBOLIC OIL" FRACTION OF DISTILLED TAR. PURIFIED BY HOT PRESSING, WHICH MAY BE FOLLOWED BY WASHING WITH SULFURIC ACID, SODIUM HYDROXIDE, AND WATER, THEN BY FRACTIONAL DISTILLATION OR BY SUBLIMATION. [R1] IMP: *The main impurity in crude 78 deg C coal tar naphthalene is sulfur which is present in the form of thionaphthalene (1-3%). Methyl- and dimethylnaphthalenes also are present (1-2 wt %) with lesser amounts of indene, methylindenes, tar acids, and tar bases. [R2] FORM: +USEPA/OPP Pesticide Code 055801; Trade Names: Naphthalin, Tar camphor. [R3] *GRADES: BY MELTING POINT, 74 DEG C MIN (CRUDE) TO ABOVE 79 DEG C (REFINED); SCINTILLATION (80-81 DEG C) [R4] *Produced in several grades characterized by solidification point ... petroleum naphthalene ... one grade ... 79.0 deg C minimum. Coal tar naphthalene ... 78 deg crude, 77.5 deg low sulfur, and an 80 deg refined material with a purity of 99.6% [R5] MFS: *Allied-Signal Inc, Hq, Columbia Road and Park Ave, Morristown, NJ 07960, (201) 455-2000; Engineered Materials Sector; Production site: 3330 S 3rd St, Ironton, OH 45638 [R6] *Chemical Exchange Industries, Inc, Hq, 3813 Buffalo Speedway, Houston, TX 77006, (713) 526-8291; Subsidiary: Advanced Aromatics Chemical Company; Production site: Baytown, TX 77520 [R6] *Koppers Industries, Inc, Hq, 436 7th Ave, Pittsburgh, PA 15219, (412) 227-2001; Production sites: Follansbee, WV 26037 [R6] *Texaco Inc, Hq, 2000 Westchester Ave, White Plains, NY 10650, (914) 253-4000; Subsidiary: Texaco Chemical Company, 4800 Fournace Place, PO Box 430, Bellaire, TX 77401, (713) 666-8000; Production site: Delaware City, DE 19706 [R6] OMIN: *Naphthalene usually is sold commercially according to its freezing or solidification point because there is a correlation between the freezing point and the naphthalene content of the product. The correlation depends on the type and relative amount of impurities present. Because the freezing point can be changed appreciably by the presence of water, values and specifications are listed on a dry, wet, or as-received basis using an appropriate method agreed upon between buyer and seller. [R7] *ONLY PURE GRADES, FREE FROM DUST SHOULD BE USED FOR FUMIGATION [R8] *USE OF NAPHTHALENE AS MOTH REPELLENT AND INSECTICIDE IS DECR DUE TO INTRODUCTION OF CHLORINATED CMPD SUCH AS PARA-DICHLOROBENZENE. [R1] *Naphthalene, anthracene, and biphenyl were individually adsorbed on fly ash from a coal-fired powder plant and treated with hydrogen chloride (g) in nitrogen at 150 deg C. Products from the reaction included mono- and poly-chlorinated cogeners of parent polyaromatic hydrocarbon at total yields of ca 9-15% for all products. Brominated aromatic products, observed in indentical studies using municipal incinerator fly ash, were not detected in significant amounts. The results suggest that the absence of chlorinated compounds in coal combustion effluent can not be attributed to chemical properties of fly ash surfaces involved in heterogeneous gas-solid phase reactions. Alternate explanations should be sought in the low levels of hydrogen chloride in the effluent stream or the chemistry of the combustion event. [R9] USE: +For Naphthalene (USEPA/OPP Pesticide Code: 055801) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R3] *MFR OF PHTHALIC AND ANTHRANILIC ACIDS, ... NAPHTHOLS, ... NAPHTHYLAMINES, SULFONIC ACID, ... SYNTHETIC RESINS, CELLULOID, LAMPBLACK, SMOKELESS POWDER, ... HYDRONAPHTHALENES. [R1] *Is used in the preparation of anthraquinone. [R10] *Is used for the manufacturing of indigo. [R11] *Is used in the formation of perylene via the intermolecular Scholl reaction. [R12] *A high yielding (98%) process from the oxidn by microrganisms, has been developed in Japan for the production of salicylic acid from naphthalene. [R13] *CHEM INT FOR PHTHALIC ANHYDRIDE [R14] *CHEM INT FOR 1-NAPHTHYL-N-METHYLCARBAMATE INSECTICIDE [R14] *CHEM INT FOR BETA-NAPHTHOL AND SYNTHETIC TANNING CHEMS [R14] *CHEM INT FOR SURFACTANTS-EG, NAPHTHALENE SULFONATES [R14] *CHEM INT FOR 1-NAPHTHYLAMINE (FORMER USE) [R14] +MEDICIATION (VET) *Ingredient of some moth repellants and toilet bowl deodorants. [R15, p. III-307] *Sulfonation of naphthalene with sulfuric acid produces mono-, di-, tri-, and tetranaphthalenesulfuric acids. [R16] *Intestinal vermifuge and wood preservative. /Former use/ [R15, p. III-307] CPAT: *CHEM INT FOR PHTHALIC ANHYDRIDE, 58%; CHEM INT FOR 1-NAPHTHYL-N-METHYLCARBAMATE, 21%; CHEM INT FOR BETA-NAPHTHOL, 8%; CHEM INT FOR SYNTHETIC TANNING AGENTS, 6%; MOTH REPELLANT, 3%; CHEM INT FOR SURFACTANTS, 3%; OTHER, 1% (1980 EST) [R14] *Chem intermediate for phthalic anhydride, 50%; chem intermediate for carbamate insecticides, 20%; chemical intermediate for naphthalene sulfonic acids, 20%; miscellaneous, 10% (1984) [R5] *Phthalic anhydride, 60%; exports, 15%; 1-naphthol, tetralin, 1-naphthyl methyl carbamate insecticide, 10%; tanning agents, 8%; surfactants and other uses, 7% (1985) [R17] *CHEMICAL PROFILE: Naphthalene. Phthalic anhydride, 60%; 1-naphthyl methyl carbamate insecticide and related products (tetralin and 1-naphthol), 10%; dispersant chemicals, 10%; moth repellent, 6%; synthetic tanning agents, 5%; miscellaneous uses, 5%; exports, 4%. [R18] *CHEMICAL PROFILE: Naphthalene. Demand: 1986: 250 million lb; 1987: 255 million lb; 1991 /projected/: 270 million lb (Includes exports, imports are negligible). [R18] PRIE: U.S. PRODUCTION: *(1974) 2.9X10+11 metric tons. [R19] *(1979) 3.24X10+11 g [R20] *(1980) 3.16X10+11 g [R21] *(1982) 3.17X10+11 g [R14] *Primary products from petroleum and natural gas, thousands of metric tons: naphthalene, 1977: 151. [R22] *(1977) 2.27X10+11 G [R14] *(1980) 2.04X10+11 G [R14] *Naphthalene production will grow at about GNP rate over the next five years. Coal-tar naphthalene production remained static from 1973-1977 at about 1.36X10+11 g. Little change is seen. [R23] *The total naphthalene capacity for all USA producers in 1979 was 324,000 metric tons with 206,000+ produced from coal tar and 118,000+ from petroleum. [R24] *(1984) 1.27X10+11 g [R5] U.S. IMPORTS: *Naphthalene imports provided about 10-20% of the material consumed in the USA until ca 1963 when that percentage dropped to and leveled at less than 5%. [R25] *(1977) 4.1X10+9 G [R14] *(1982) 4.7X10+9 G [R14] *(1985) 2.22X10+7 g /Naphthalene solidifying under 79 deg C/ [R26, p.1-546] *(1985) 4.79X10+7 g /Naphthalene solidifying at 79 deg C and over/ [R26, p.1-547] U.S. EXPORTS: *(1981) 2.0X10+9 G [R14] *(1985) 5.92X10+9 g [R27] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +WHITE, CRYSTALLINE FLAKES OR SOLID [R28, p. 49-94]; *WHITE SCALES, BALLS, POWDER OR CAKES [R29]; *MONOCLINIC PLATES FROM ALCOHOL [R30]; +Colorless to brown solid ... [Note: Shipped as a molten solid]. [R31, 220] ODOR: *AROMATIC ODOR [R32]; *ODOR OF ... MOTH BALLS [R33]; +... Odor of mothballs ... [R31, 220] BP: *217.9 DEG C @ 760 MM HG [R1] MP: *80.2 DEG C [R1] MW: *128.16 [R1] CORR: *Melted naphthalene will attack some forms of plastics, rubber, and coatings. [R34] CTP: *CRIT TEMP: 887.4 DEG F= 475.2 DEG C= 748.4 DEG K [R33]; *CRIT PRESSURE: 588 PSI= 40.0 ATM= 4.05 MEGANEWTONS/SQ M [R33] HTC: *-16,720 BTU/LB= -9287 CAL/G= -388.8X10+5 JOULES/KG [R33] HTV: *43.5 kJ/mol [R35] OWPC: +log Kow= 3.30 [R36] SOL: *Soluble in alcohol, acetate [R30]; *1 G/3.5 ML BENZENE OR TOLUENE [R1]; *1 G/8 ML OLIVE OIL OR TURPENTINE [R1]; *1 G/2 ML CHLOROFORM OR CARBON TETRACHLORIDE [R1]; *1 G/1.2 ML CARBON DISULFIDE [R1]; *VERY SOL IN ETHER, HYDRONAPHTHALENES [R1]; *VERY SOL IN FIXED AND VOLATILE OILS [R1]; *30 MG/L IN WATER; ... VERY SOL IN 1,2-DICHLOROMETHANE [R37]; *SOL IN ETHYLENE DICHLORIDE [R38] SPEC: *MAX ABSORPTION (ALCOHOL): 221 NM (LOG E= 5.04); 275.5 NM (LOG E= 3.76); 286 NM (LOG E= 3.59); 311 NM (LOG E= 2.38) [R39]; *SADTLER REF NUMBER: 865 (IR, PRISM): 169 (IR, GRATING) [R39]; *ULTRAVIOLET ABSORPTION: SEVERAL CHARACTERISTIC BANDS BETWEEN 217.5 and 320 NM IN HEXANE [R1]; *PURPLE FLUORESCENCE IN HG LIGHT (PETROLEUM ETHER SOLN) [R1]; *INDEX OF REFRACTION: 1.58212 AT 100 DEG C/D [R1]; *INDEX OF REFRACTION: 1.4003 @ 24 DEG C/D; 1.5898 @ 85 DEG C/D [R30]; *Intense mass spectral peaks: 128 m/z (100%), 51 m/z (13%), 129 m/z (11%), 64 m/z (11%) [R40]; *IR: 5547 (Coblentz Society Spectral Collection) [R41]; *UV: 265 (Sadtler Research Laboratories Spectral Collection) [R41]; *NMR: 62 (Sadtler Research Laboratories Prism Collection) [R41]; *MASS: 553 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R41] SURF: *LIQUID SURFACE TENSION: 31.8 DYNES/CM= 0.0318 NEWTONS/M AT 100 DEG C [R33] VAPD: *4.42 [R32] VAP: *0.01 kPa [R42] EVAP: *Much less than 1. (Butyl acetate= 1) [R34] OCPP: *SUBLIMES APPRECIABLY @ TEMP ABOVE MELTING POINT [R1] *LATENT HEAT OF VAPORIZATION: 145 BTU/LB= 80.7 CAL/G= 3.38X10+5 JOULES/KG [R33] *Naphthalene carries two nonequivalent sets of hydrogen atoms. Therefore, two isomers of every monosubstituted naphthalene are known. [R43] *Triple point, deg C: 80.28. Heat of fusion at triple point, kJ/mol: 18.979. [R35] *Heat capacity (at 15.5 deg C and 101.3 kPa), J/(molxK): 159.28. Heat of formation (at 25 deg C), kJ/mol: Solid: 78.53; gas: 150.58. [R35] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible material. May be ignited by friction, heat, sparks or flames. Some may burn rapidly with flare burning effect. Powders, dusts, shavings, borings, turnings or cuttings may explode or burn with explosive violence. Substance may be transported in a molten form. May re-ignite after fire is extinguished. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +Health: Fire may produce irritating and/or toxic gases. Contact may cause burns to skin and eyes. Contact with molten substance may cause severe burns to skin and eyes. Runoff from fire control may cause pollution. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +Protection clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +Fire: Small fires: Dry chemical, CO2, sand, earth, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Cool containers with flooding quantities of water until well after fire is out. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch or walk through spilled material. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Large spills: Wet down with water and dike for later disposal. Prevent entry into waterways, sewers, basements or confined areas. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Removal of solidified molten material from skin requires medical assistance. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Naphthalene, crude; Naphthalene, molten; Naphthalene, refined/ [R44] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R28, p. 325-73] +Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R28, p. 325-73] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R28, p. 325-73] FLMT: +LOWER 0.9%; UPPER 5.9%. [R28, p. 325-73] FLPT: +174 DEG F (OPEN CUP); 79 DEG C (CLOSED CUP) [R28, p. 325-73] AUTO: *526 deg C [R35] FIRP: +USE WATER, CARBON DIOXIDE, DRY CHEMICAL, OR FOAM. FOAM OR DIRECT WATER SPRAY ON MOLTEN NAPHTHALENE MAY CAUSE EXTENSIVE FOAMING. [R28, p. 49-93] *If material is on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Solid streams of water may be ineffective. Use alcohol foam, carbon dioxide, or dry chemical. [R45] TOXC: *Toxic gases and vapors (such as dense acrid smoke and carbon monoxide) may be released in a fire involving naphthalene. [R34] OFHZ: *Molten naphthalene spatters and foams in contact with water. [R33] EXPL: *MODERATE, IN FORM OF DUST, WHEN EXPOSED TO HEAT OR FLAME. [R32] REAC: +NAPHTHALENE ... WILL REACT VIOLENTLY WITH CHROMIC ANHYDRIDE. [R28, p. 491-62] +Strong oxidizers, chromic anhydride. [R31, 220] ODRT: *Odor detection in water 6.80 ppm (purity not specified) [R46] *At least as low as 0.3 ppm. [R34] *Odor threshold (water) 0.021 mg/l (w/v); odor threshold (air) 0.084 ppm (v/v) [R47] SERI: *Irritating to skin ... does occur. Vapors can cause eye irritation at concn of 15 ppm in air. ... [R48] *Upon direct skin contact, naphthalene is a primary irritant. [R49] EQUP: *USA BUREAU OF MINES APPROVED ORGANIC VAPOR CANISTER UNIT (USBM TYPE B), RUBBER GLOVES, CHEMICAL SAFETY GOGGLES; FACE SHIELD, COVERALLS AND/OR RUBBER APRON, RUBBER SHOES OR BOOTS. [R33] *Respiratory protection for napthalene: Minimum respiratory protection required above 10 ppm: Particulate and vapor concentration: 500 ppm or less: Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a dust filter, or gas mask with an organic vapor canister (chin-style front- or back-mounted canister) with a dust filter, or any supplied-air respirator with a full facepiece, helmet, or hood, or any self-contained breathing apparatus with a full facepiece. Greater than 500 ppm or entry and escape from unknown concentrations: Any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode, or a combination respirator which includes a Type C supplied-air respirator with a full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and an auxillary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode; Escape: Any gas mask providing protection against organic vapors and particulates, or any escape self-contained breathing apparatus. [R34] *Employees should be provided with and required to use impervious clothing, gloves, face-shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with naphthalene. [R34] */IN/ EXPOSURE OF WORKMEN TO HIGH NAPHTHALENE CONCN, THE USE OF RESP PROTECTIVE EQUIPMENT AND CHEM-TYPE PLASTIC GOGGLES IS ESSENTIAL. PLASTIC FOOTWEAR AND HANDWEAR MAY BE REQUIRED TO PROTECT SKIN. EMERGENCY SHOWERS AND EYE FOUNTAINS SHOULD BE INSTALLED AT WORKPLACES WHERE THERE IS A DANGER OF EYE OR SKIN CONTAMINATION. SAFETY CLOTHING INCL APRONS AND FACE SHIELDS ARE A NECESSARY PRECAUTION FOR PERSONS HANDLING LIQUID NAPHTHALENE THAT MAY COME IN CONTACT WITH WATER. [R50] +Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust and mist filter. May require eye protection. Any supplied-air respirator. May require eye protection. [R31, 221] +Recommendations for respirator selection. Max concn for use: 250 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R31, 221] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R31, 221] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R31, 221] +Wear appropriate personal protective clothing to prevent skin contact. [R31, 221] +Wear appropriate eye protection to prevent eye contact. [R31, 221] OPRM: +Contact lenses should not be worn when working with this chemical. [R31, 221] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Heat only in specifically-designed lamps. /Moth repellents/ [R8] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Skin that becomes contaminated with liquid naphthalene should be immediately washed or showered with soap or mild detergent and water to remove any naphthalene. [R34] *Eating and smoking should not be permitted in areas where liquid naphthalene is handled, processed, or stored. [R34] *If an employees' clothing becomes contaminated with solid naphthalene, employees should change into uncontaminated clothing before leaving the work area. Clothing contaminated with naphthalene should be placed into closed containers for storage until it can be discarded or until provision is made for the removal of the naphthalene from the clothing. If the clothing is to be laundered or cleaned to remove the naphthalene, the person performing the operation should be informed of naphthalene's hazardous properties. Non-impervious clothing which becomes contaminated with naphthalene should be removed promptly and not reworn until the naphthalene is removed from the clothing. [R34] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R34] *If material is not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. [R51] *Molten naphthalene tank vents must be adequately heated and insulated to prevent the accumulation of sublimed and solidified naphthalene. A collapsed tank can result easily from pumping from a tank with a plugged vent. [R48] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *In case of aquatic contamination notify local health and wildlife officials and operators of nearby water intakes. [R33] +The worker should immediately wash the skin when it becomes contaminated. [R31, 221] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R31, 221] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R31, 221] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R52] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R53] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R54] STRG: *Without inert-gas blanketing and at the temperature normally used for the storage of molten naphthalene, ie, 90 deg C, the vapors above the liquid are within the flammability limits. Thus, storage tanks containing molten naphthalene have a combustible mixture in the vapor space and care must be taken to eliminate all sources of ignition around such systems. Naphthalene dust can form explosive mixtures with air which necessitates the design and operation of solid handling systems. [R48] +Store in a cool, dry, well-ventilated location. Separate from oxidizing materials. May be stored under nitrogen gas. [R28, p. 49-93] CLUP: *If naphthalene is spilled, the following steps should be taken: 1) Ventilate area of spill. 2) For small quantities, sweep onto paper or other suitable material, place in an appropriate container and burn in a safe place (such as a fume hood). [R34] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. [R55] *Environmental considerations: Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, apply activated charcoal at ten times the spilled amount in the region of 10 ppm or greater concn. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R55] *The particle-bound portion of polycyclic aromatic hydrocarbons (PAH) can be removed by sedimentation, flocculation, and filtration processes. The remaining one-third dissolved PAH usually requires oxidation for partial removal/transformation. /Polynuclear aromatic hydrocarbons/ [R56] *Data on the solubilization of p-dichlorobenzene, naphthalene, and biphenyl in aqueous solutions of sodium dodecylsulfate (0-100 nM concentration) indicate increases in effective solubilities of these hydrophobic compounds by factors of roughly 20 to 100. p-Dichlorobenzene is effectively removed from spiked clay-sand mixtures by leaching with sodium dodecylsulfate solutions in laboratory columns. Surfactant solutions loaded with p-dichlorobenzene are satisfactorily treated by gentle extraction with hexane, and the recovered surfactant solution satisfactorily solubilizes biphenyl. A simple model for predicting the solubilization behavior of surfactants is developed and tested experimentally. [R57] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U165, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R58] *A GOOD CANDIDATE FOR ROTARY KILN INCINERATION AT A TEMPERATURE RANGE OF 820 TO 1,600 DEG C AND RESIDENCE TIMES OF SECONDS FOR LIQUIDS AND GASES, AND HOURS FOR SOLIDS. A GOOD CANDIDATE FOR FLUIDIZED BED INCINERATION AT A TEMPERATURE RANGE OF 450 TO 980 DEG C AND RESIDENCE TIMES OF SECONDS FOR LIQUIDS AND GASES, AND LONGER FOR SOLIDS. [R59] *The following wastewater treatment technologies have been investigated for naphthalene: biological treatment. [R60] *The following wastewater treatment technologies have been investigated for naphthalene: chemical precipitation. [R61] *The following wastewater treatment technologies have been investigated for naphthalene: solvent extraction. [R62] *The following wastewater treatment technologies have been investigated for naphthalene: activated carbon. [R63] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +WEIGHT OF EVIDENCE CHARACTERIZATION: Using criteria of the 1986 Guidelines for Carcinogen Risk Assessment, naphthalene is classified in group C, a possible human carcinogen. This is based on the inadequate data of carcinogenicity in humans exposed to naphthalene via the oral and inhalation routes, and the limited evidence of carcinogenicity in animals via the inhalation route. Using the 1996 Proposed Guidelines for Carcinogen Risk Assessment, the human carcinogenic potential of naphthalene via the oral or inhalation routes "cannot be determined" at this time based on human and animal data; however, there is suggestive evidence (observations of benign respiratory tumors and one carcinoma in female mice only exposed to naphthalene by inhalation). Additional support includes increase in respiratory tumors associated with exposure to 1-methylnaphthalene. At the present time the mechanism whereby naphthalene produces benign respiratory tract tumors are not fully understood, but are hypothesized to involve oxygenated reactive metabolites produced via the cytochrome P-450 monooxygenase system. However, based on the many negative results obtained in genotoxicity tests, a genotoxic mechanism appears unlikely. HUMAN CARCINOGENICITY DATA: Available data are inadequate to establish a causal association between exposure to naphthalene and cancer in humans. Adequately scaled epidemiological studies designed to examine a possible association between naphthalene exposure and cancer were not located. Overall, no data are available to evaluate the carcinogenic potential in exposed human populations. [R64] +A4; Not classifiable as a human carcinogen. [R65] ANTR: *Gastric lavage (stomach wash), if swallowed, followed by saline catharsis. Maintain an alkaline urine. Blood transfusion if indicated. [R66] MEDS: *Physical examinations of exposed personnel annually, with special attention to the eyes, complete blood count, and urinalysis. [R66] *Recommended medical surveillance: The following medical procedures should be made available to each employee who is exposed to naphthalene at potentially hazardous levels: Initial Medical Examination: A complete history and physical examination: The purpose is to detect existing conditions ... that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the eyes, blood, liver, and kidneys should be stressed. The skin should be examined for evidence of chronic disorders. Naphthalene has been shown to cause red cell hemolysis. A complete blood count should be performed, including a red cell count, white cell count, and a differential count of a stained smear, as well as hemoglobin and hematocrit. ... A urinalysis should be performed, including at a minimum: specific gravity, albumin, glucose, and a microscopic /examination/ on centrifuged sediment. Periodic Medical Examination: The aforementioned medical examinations should be repeated on an annual basis. [R34] HTOX: *Symptomatology: A. Surface contact: 1. Naphthalene cataracts and ocular irritation. 2. skin irritation and, in the case of a sensitized person, severe dermatitis. Lesions clear spontaneously, as soon as the exposure is terminated. 3. Percutaneous absorption ... inadequate to produce acute systemic reactions except in newborns. B. Inhalation of vapor: 1. Headache, confusion, and excitement. 2. Nausea and sometimes vomiting, and extensive sweating. 3. Dysuria, hematuria, and the acute hemolytic reaction described below. 4. Rarely optic neuritis is encountered. [R15, p. III-309] *Symptomatology: C. Ingestion: 1. Abdominal cramps with nausea, vomiting, and diarrhea. 2. Headache, profuse perspiration, listlessness, confusion. 3. In severe poisoning, coma with or without convulsions. 4. Irritation of the urinary bladder ... Signs and symptoms: urgency, dysuria, and the passage of a brown or black urine with or without albumin and casts. ... 5. Acute intravascular hemolysis is the most characteristic sign. ... It begins on the 3rd day and is accompanied by anemia, leukocytosis, fever, hemoglobinuria, jaundice, renal insufficiency, and sometimes, disturbances in liver function. 6. In the absence of adequate supportive treatment, death may result from acute renal failure in adults or kernicterus in young infants. [R15, p. III-309] *Naphthalene ingestion or inhalation can result in massive hemolysis in glucose-6-phosphate dehydrogenase deficient subjects; hemolysis in normal individuals occurs only with exposure to very high levels. [R67] *Rare cases of corneal epithelium damage in humans have been reported. [R48] *Conjunctivitis, swelling of parotid glands, hepatomegaly, splenomegaly, tenesmus, and lenticular opacities in peripheral portions. [R66] *Six cases of malignant tumors occurred among 15 workers exposed to vapors of naphthalene and coal tar for a period of up to 32 years at a coal tar naphthalene production facility: 4 individuals contracted laryngeal carcinoma and all were smokers; the other 2 workers developed neoplasms of the pylorus and cecum. No control group was examined. [R68] *A 36 yr old pharmacist was given 5 g of unpurified naphthalene in an emulsion of castor oil in divided doses in the course of thirteen hr. On awakening eight to nine hr later he had severe pain in the bladder, and found that he was nearly blind, although previously he had had good vision. ... A yr later /examination showed/ the vision to be reduced to finger counting at 1.5 meters, unimproved by glasses, and the visual fields were constricted to 30-50 degrees. In both lenses were seen countless fine whitish opacities arranged as a zonular cataract about the nucleus with a narrow clear zone at the equator. ... Fundi could not be seen clearly ... the retinas appeared pale and turbid, the vessels were narrowed, ... the temporal portions of the papillas seemed pale. [R69, 651] *A 69 yr old black female exposed to naphthalene and paradichlorobenzene developed aplastic anemia two months after exposure. [R70] *POISONING MAY OCCUR BY INGESTION OF LARGE DOSES, INHALATION, OR SKIN ABSORPTION. [R1] *Toxicity and death /have been reported/ in newborn infants exposed to naphthalene vapors from clothes or blankets that had been stored in or near the infant's room. [R71] *The development of cataracts and retinal hemorrhage in a 44 yr old man occupationally exposed to powdered naphthalene /were reported/. Unilateral chorioretinitis /developed/ in a coworker. ... /Cataracts developed/ in 8/21 workers exposed to naphthalene fumes or dust for < or = 5 years in a manufacturing setting. [R49, ] *Toxic effects in infants have been associated with naphthalene exposure (level not reported) of the mother during gestation. [R49] *Hemolysis following accidental ingestion of naphthalene in black females deficient in glucose-6-phosphate dehydrogenase has not been previously reported. A 20 mo old black female is presented and the literature reviewed. Although glucose-6-phosphate dehydrogenase deficiency is X-linked, health care providers must be aware that hemolysis may occur in females who are deficient in glucose-6-phosphate dehydrogenase after exposure to naphthalene. [R72] *Diapers or clothes stored with mothballs and used directly on infants have caused skin rashes and systemic poisoning. [R49] NTOX: *ORAL ADMIN OF 1 G/KG/DAY TO RABBITS LEADS TO LENTICULAR CHANGES, INITIALLY OBSERVED AS SWELLING IN PERIPHERAL PORTION OF LENS. ... WITHIN 2 WK THE WHOLE LENS IS AFFECTED WITH MATURE CATARACT. ... BIOCHEMICAL BASIS FOR CATARACT ... SHOWN TO BE RELATED TO LIVER METABOLITE OF NAPHTHALENE, 1,2-DIHYDRO-1,2-DIHYDROXYNAPHTHALENE. [R73] *SELECTIVE LUNG DAMAGE AND NECROSIS OCCURRED IN CLARA CELLS OF MOUSE ADMIN NAPHTHALENE. IT PRODUCED SELECTIVE DEPRESSION OF PULMONARY MONOOXYGENASE ACTIVITIES WITHOUT ACCOMPANYING CHANGES IN HEPATIC MONOOXYGENASE. A DOSE-DEPENDENT ALTERATION OF CLARA CELLS WAS NOTED. [R74] *AFTER ORAL ADMIN OF NAPHTHALENE FOR 10 DAYS TO RATS BIOCHEMICAL ALTERATIONS OCCURRED. CHANGES WERE SIGNIFICANT IN THE LIVER WHERE INCR IN LIVER WT, LIPID PEROXIDATION AND ANILINE HYDROXYLASE ACTIVITY WERE NOTED. [R75] *THE CRAB CHANGED ANTENNULAR ORIENTATION AND FLICKING RATE, WHEN PRESENTED WITH NAPHTHALENE OR WATER SOL FRACTIONS OF CRUDE OIL. [R76] *DECR IN CELLULAR MANGANESE AND POTASSIUM WAS FOUND WITHIN A VERY SHORT TIME OF EXPOSURE TO NAPHTHALENE AND AQ EXTRACTS OF CRUDE OIL IN CHLAMYDOMONAS ANGULOSA. THIS MAY BE DUE TO HYDROCARBON-INDUCED MEMBRANE DAMAGE. [R77] *ENZYME ACTIVITIES OF LIVER MICROSOMAL PREPN FROM SEAWATER ADAPTED MALLARD DUCKS EXPOSED 50 DAYS TO CRUDE OIL (5 TYPES) CONTAMINATED FOOD ASSESSED IN TERM OF THEIR ABILITY IN VITRO TO METAB NAPHTHALENE. A DOSE-DEPENDENT INCR IN ACTIVITY NOTED WITH 3 PATTERNS OF RESPONSE APPARENT. [R78] *LARVAL MUD CRABS WERE EXPOSED CONTINUOUSLY FROM HATCHING THROUGH 1ST STAGE TO SUBLETHAL CONCN OF NAPHTHALENE (0, 75, 150 OR 300 MUG/L). SALINITY AND TEMPERATURE WERE VARIED. AT OPTIMAL SALINITY NO CONSISTENT EFFECT OF NAPHTHALENE ON GROWTH WAS APPARENT. [R79] *No carcinogenic activity was observed in an in vitro rat embryo cell/Rauscher leukemia virus test system at doses up to 0.1 g/l. [R80] *225 Mg/kg ip injection of naphthalene to C57BL/6J mice produced significant (30-70%) and prolonged (8-15 days) impairment in pulmonary microsomal monooxygenase activities without altering these activities in liver microsomes. [R81] *Naphthalene (0.05-2.0 mmol/kg) was administered in corn oil ip to C57B1/6J mice. Lung tissue from interim sacrificed animals was rapidly fixed and examined by electron microscopy. Mice in the higher dosage groups developed necrosis of secretory nonciliated bronchiolar cells. Epithelial structure returned to normal within seven days in all cases. No changes were noted in either untreated or corn oil-treated control group. [R82] *... Exposure of the 4th instar larvae of the freshwater dipteran Chironomus attenuatus to 1 mg/l for 1 hr resulted in ... the loss of ionic regulation. ... /This was/ due to inhibition of specific enzyme systems and not to a general alteration of membrane integrity. [R83] *Ip injection of channel catfish (Ictalurus punctatus) with 100 ug benzo(a)pyrene, Aroclor 1254, or naphthalene, singly and in combinations, affected the levels of the brain neurotransmitters norepinephrine, dopamine, and 5-hydroxytryptamine, but the effect showed no discernible pattern. The effects of combinations of the chemicals did not appear to be predictable from the effects of individual chemicals. In several instances, the change in the level of neurotransmitter in fish receiving a combination of chemicals was greater than in fish receiving either chemical alone. [R84] *SELECTIVELY PHYTOTOXIC ... [R38] *Pregnant rabbits were gavaged with 16 mg/kg of metabolite of naphthalene on days 20, 22, and 24 of gestation. Cataracts and retinal damage were found in the offspring. [R85] *Detoxification of naphthalene in rabbits by conjugation with glucuronic acid may have a protective influence against development of naphthalene cataract. [R69, 653] *Inhibition of photosynthesis of a freshwater, non-axenic unialgal culture of Selenastrum capricornutum at: 1% saturation: 110% (14)C fixation (vs controls); 10% saturation: 89% (14)C fixation (vs controls); 100% saturation: 15% (14)C fixation (vs controls). [R86, 897] *The toxic effect of aromatic hydrocarbons, benzene, toluene, naphthalene, 1-methylnaphthalene, anthracene, 9-methylanthracene, phenanthrene, on the productivity of various marine planktonic algae (Dunaliela biocula, Phaeodactylum tricornutum, and Isochysis galbaya) increased with increasing number of aromatic rings. The methylated compounds were most toxic. Taxonomic differences in sensitivity to aromatic hydrocarbons /was investigated/. [R87] *The effect of 10 organic chemicals on the growth and reproduction of the marine red alga was investigated. The test measured vegetative growth, formation of tetrasporangia (site of meiosis-asexual spore production), and production of cystocarps (evidence of sexual reproduction). The procedure was used to test the effects of ... naphthalene. Chronic values were determined for vegetative growth and formation of reproductive structures based on significant decreases from control levels. Absence of reproductive structures was also used to determine chronic values. No endpoint was consistently more sensitive than any other, and the ranking of the compounds from most to least toxic was similar regardless of the endpoint used. [R88] *Following the intraperitoneal administration of naphthalene (200 mg/kg) to mice, the lung, in comparison with other organs, was selectively damaged. Histological examination of the lung showed that it was the non-ciliated, bronchiolar epithelial cells (Clara cells) which were damaged. At higher doses (400 mg/kg and 600 mg/kg, ip), there was also damage to the cells in the proximal tubules of the kidney. In contrast to the effect in mice, doses of naphthalene as high as 1600 mg/kg (ip) caused no detectable pulmonary or renal damage in the rat. This difference in toxicity between the mouse and rat was reflected by the ability of naphthalene to more severely deplete the non-protein sulfhydryls in the mouse lung and kidney than in the rat. In order to investigate the species difference in toxicity, the metabolism of naphthalene by lung and liver microsomes of the mouse and rat was studied. In all cases, naphthalene was metabolized to a covalently bound product(s) and to two major methanol-soluble products, which co-chromatographed with 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene. However, both the covalent binding and metabolism were approximately 10-fold greater in microsomes prepared from mouse lung compared with those from the rat. [R89] *The effect of exposure to naphthalene and aqueous extracts of crude oil on contents of manganese and potassium in cells of Chlamydomonas angulosa was measured simultaneously by neutron activation analysis. [R90] *The mutagenic activity from Cunninghamella elegans incubated 72 hr with various polycyclic aromatic hydrocarbons was evaluated in the Salmonella typhimurium reversion assay. All of the polycyclic aromatic hydrocarbons extracts were assayed in tester strains TA98 and TA100 both with and without metabolic activation using a liver fraction from Aroclor 1254 treated rats. None of the extracts from fungal incubations with the mutagenic polycyclic aromatic hydrocarbons ... naphthalene, ... displayed any appreciable mutagenic activity ... [R91] *Naphthalene was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Naphthalene was tested at doses of 0.3, 1.0, 3.3, 10, 33, and 100 ug/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Naphthalene was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 100 ug/plate. Slight clearing of the background bacterial lawn occurred at /the highest/ dose in some cultures. [R92] *Necropsy findings /in Sprague Dawley rats/ (study deaths): Multiple lesions of the stomach mucosa; and discolored lungs, adrenals, and intestines. [R93] */Dermal sensitization/ study /was/ conducted /in Hartley guinea pigs/. ... Results: Induced and challenged at 100%. Challenge scores: incidence = 0/20; severity = 0.0 @ 48 hours. Naphthalene is considered to be non-sensitizing. [R93] */Dogs/ administered 420 and 1530 mg/kg naphthalene (in a solid form) in a single oral dose /showed/ decreases of 29 and 33%, respectively, in blood hemoglobin concentrations. [R94] *Short-term exposure: Adverse effects, associated ... with 267 mg/kg/day /for 14 days/ included increased mortality and decreased terminal body weights in male and female /CD-1/ mice, decreased absolute thymus weight (30%) in males, and increased bilirubin and decreased absolute and relative spleen and lung weights in females. There were no effects on hexobarbital sleeping time or on various immunological screening tests, with the exception that high-dose females had decreased response to concanavalin A in lymphocytes. A NOAEL of 53 mg/kg was identified. [R95] *A NOAEL /in F344 rats/ was observed to be 50 mg/kg /5 days/week for 13 weeks by gavage/. [R95] *A NOAEL /in B6C3F1 mice/ of 200 mg/kg/day /5 days /week for 13 weeks by gavage/ was ... identified. [R96, ] *A NOAEL /in BDI and BDIII rats/ was found to be 41 mg/kg/day (10 g/0.35 kg/700 days assuming a body weight of 0.35 kg). /Naphthalene was administered in the diet/. [R96] *Treatment /of mated female CD-1 mice with 300 mg/kg/day of naphthalene by gavage/ began on gestation day 7 and continued for 8 consecutive days. Vehicle (corn oil) treated controls were maintained. Treatment was associated with maternal toxicity (increased mortality and reduced body weight gain) and fetotoxicity manifested as a reduced number of live young at birth. ... Offspring were not examined for malformations. ... There was no evidence of fetal or maternal toxicity /after ip administration of 395 mg/kg naphthalene to adult female Sprague Dawley rats/. [R97] *The administration to pregnant rabbits of 2-naphthol, a metabolite of naphthalene, has been associated with cataracts and evidence of retinal damage in the offspring. [R97] *Naphthalene was not active in reverse mutation assays in ... Salmonella typhimurium with or without metabolic activation. Naphthalene was also not mutagenic in a Salmonella forward mutation assay with TM677. Negative results were reported for the Rec /Recombinational DNA Repair/ assay in Escherichia coli in the presence or absence of an exogenous mammalian metabolism system. ... No enhancement of /cell/ transformation was observed /in rat and mouse embryo cells infected with leukemia virus or in murine mammary gland organ cultures/. [R97] *Naphthalene did not cause DNA damage in a rat hepatocyte alkaline elution assay. [R97] *No carcinogenic response was observed ... in rats given oral doses of 10 to 20 mg/day naphthalene, 6 days/week from day 100 to day 800 of age, or in rats given either sc or ip injections of 20 mg naphthalene, 1 day/week for 40 weeks, and observed for the remainder of their lives. [R98] *Increased incidence of lymphosarcomas /was reported/ in rats injected with 500 mg/kg coal tar naphthalene in sesame oil every 2 weeks for seven treatments; however, the injection site was painted with a carcinogen (carbolfuchsin) and the naphthalene was known to contain impurities. In another study, ... an increased incidence of lympathic leukemia /was reported in mice painted with a 0.5% solution of coal tar naphthalene in benzene/. [R99] *In a pulmonary adenoma induction test, inhalation of 0, 10 or 30 ppm (0, 52, 157 mg/cu m) naphthalene by groups of 30 female strain A/J mice (6 to 8 weeks old) for 6 hours/day, 5 days/week for 6 months, did not produce a significant adenoma response. [R99] *The glutathione conjugate (14)C-propachlor was perfusd through a calf kidney in situ; 23% of the dose was excreted in the perfused kidney urine as the cysteine conjugate, no mercapturic acid was detected. A 5 day old calf dosed orally with (14)C-propachlor excreted 70% dose in the urine as the cysteine conjugate; no mercapturic acid was detected. Rumen microflora were established in the calf (5 weeks older) and the experiment was repeated with the same results. When the same calf was dosed 1 week later with (14)C-naphthalene, 99% dose was excreted in the urine, mostly as the dihydrodiol glucuronide (34%) and the dihydrohydroxy cysteine conjugate (47%); no mercapturate was detected. A 9 day old calf dosed orally with (14)C- dichlobenil) excreted 67% dose in the urine as cysteine conjugates (34%), and products of cysteine conjugate beta-lyase cleavage of cysteine conjugates (30%); no mercapturates were detected. Cysteine S-conjugate N-acetyltransferase activity in calf kidney and liver was about 10% of that in the corresponding rat tissues. [R100] *It was noted that although data on the metabolism of 70 xenobiotic compounds in fish and enzyme activities in 80 fish exist, there are very few data that enable one to predict the metabolism of a given compound from a knowledge of enzyme activity. Existing data on the rates of metabolism of xenobiotic compounds in fish were reviewed. Only five studies that relate metabolism reactions to enzyme activity existed: the oxidation of benzo(a)pyrene, fenitrothion, carbaryl, and naphthalene, and the glucuronidation of phenol. These have shown that in a few cases the metabolic rates can be correlated with enzyme activity. For example, in some fish the rates of oxidation of benzo(a)pyrene, fenitrothion, and carbaryl can be correlated with increases in aryl hydrocarbon hydroxylase activity. This correlation was not seen in studies of the rates of oxidation of naphthalene. The /data suggest/ that there are very few data that relate in vivo metabolism rates of xenobiotic compounds in fish to the in vivo enzyme activity. In many cases where such data exist the in vivo metabolism data do not correlate well with the enzyme activity data. Additional studies that focus on identifying the role of steric hinderance in metabolism reactions, identifying which enzymes catalyze a given reaction, and evaluating the roles of nonhepatic organs in in vivo metabolism should be conducted. [R101] *Naphthalene produces selective injury to Clara cells in the mouse in vivo and in the isolated perfused lung. To investigate the role of circulating reactive metabolites in lung injury, the stability, metabolism and cytotoxicity of naphthalene oxide, a reactive intermediate, were examined in the perfused mouse lung. The t1/2 of naphthalene oxide is 4 min in Waymouth's medium. Addition of 5% bovine serum albumin of the medium increased the half-life of the epoxide to 11 min. Perfusion of the lung with 0.2 or 2 umol of naphthalene oxide decreased pulmonary reduced glutathione levels of 62 and 42% of control, respectively. 1,4-Naphthoquinone and naphthol glucuronide represented 36 and 25% of the total polar metabolites isolated after infusion of naphthalene oxide, whereas dihydrodiol and thioether conjugates were minor metabolites. In comparison, thioethers and dihydrodiol were the primary metabolites isolated from lungs perfused with (14)C naphthalene. Histologic examination of the lungs fixed 4 hr after infusion of naphthalene oxide (0.25-1.0 umol/60 min) revealed selective vacuolation and necrosis of Clara cells, significant decreases in the mass of bronchiolar Clara cells and increases in the mass of vacuolated cells. Injury to lungs perfused with naphthalene or secondary metabolites such as naphthoquinones, 1-naphthol and 1,2-dihydroxynaphthalene was less dramatic. In contrast to other studies implicating quinones as mediators of aromatic hydrocarbon toxicity, the current work suggests that epoxides play a significant role in naphthalene-induced lung injury. This investigation also demonstrates that circulating epoxides are capable of eliciting selective Clara cell injury. [R102] *Pulmonary toxicities of naphthalene, 2-methylnaphthalene, 2-isopropylnaphthalene and 2,6-diisopropylnaphthalene were studied in mice. Twenty four hr after ip administration of naphthalene (200 mg/kg (1.6 mmol)) or 2-methylnapthalene (400 mg/kg (2.8 mmol)), pulmonary damage was detected. Prior treatment with diethyl maleate resulted in enhancement of naphthalene and 2-methylnaphthalene induced bronchiolar damage. In contrast to the effects of naphthalene and 2-methylnaphthalene, injections of 2-isopropylnaphthalene (3000 mg (17.6 mmol)/kg) and 2,6-diisopropylnaphthalene (3000 mg (14.2 mmol)/kg) did not cause detectable pulmonary damage. Injections of naphthalene and 2-methylnaphthalene caused considerable depletion of pulmonary reduced glutathione, while injections of 2-isopropylnaphthalene and 2,6-diisopropylnapthalene caused only a slight depletion. There were general decreases in the binding of the compounds to lung slices with increasing number of carbons of the alkyl substituent. Pretreatment with a cytochrome p450 inducer (beta-naphthoflavone) increased the binding of naphthalene, 2-methylnaphthalene, and 2-isopropylnaphthalene to lung slices. Treatments with naphthalene, 2-methylnaphthalene, 2-isopropylnaphthalene and 2,6-diisopropylnaphthalene did not affect the lipid peroxidation or phospholipid contents in the lung. These results suggest that the differences in pulmonary toxicity among naphthalene, 2-methylnaphthalene, 2-isopropylnaphthalene and 2,6-diisopropylnaphthalene may be dependent on the ability of these compounds to irreversibly bind to lung tissue. [R103] *Developmental toxicity and clastogenicity of naphthalene /was compared/ within an in vitro preimplantation mouse embryo culture system. Whole mouse embryos were collected 72 hr after conception and co-cultured in serum supplemented NCTC 109 medium containing 0.16 mM naphthalene. Embryos were harvested and karyotyped as a function of time over 48 hr post treatment. Chromosomal damage was greatest at 24 hr after exposure with a 10-fold incr observed in embryos exposed to naphthalene compared to untreated controls; a 30-fold incr in chromosomal damage was observed comparing untreated controls with cultures containing naphthalene and rodent hepatic S-9. These findings suggest that while naphthalene is minimally embryotoxic in the absence of exogenous biotransformation it is clastogenic; these observations indirectly indicate the presence of embryonic enzyme activity competent to metabolically activate naphthalene. Further, naphthalene clastogenicity markedly decr at 48 hr implicating the involvement of embryonic DNA repair. [R104] *The in vitro developmental toxicity of the bicyclic aromatic hydrocarbon naphthalene was characterized with a preimplantation mouse embryo culture system. Day 3 ICR mouse blastocysts were co-cultured with naphthalene for 1 hr either alone or in media supplemented with an Aroclor induced rat S-9 preparation and cofactors. Toxin treated blastocysts were subsequently cultured in NCTC 109 media with 10% fetal bovine serum for 72 hr to observe the developmental effects of exposure. Developmental parameters observed included viability, hatching, culture dish attachment and trophoblastic outgrowth with the presence of a distinct inner cell mass. At media concentrations up to 0.78 mM, naphthalene alone exhibited negligible toxic effects in culture; however naphthalene co-cultured with Aroclor induced rat hepatic S-9 fractions exhibited concn dependent embryolethality with an approximate LC50 of 0.18 mM in media. Naphthalene also induced concn dependent embryotoxicity at all observed parameters in S-9 supplemental media at concn ranging from 0.20 to 0.78 mM. These findings document the role of biotransformation in naphthalene's embryotoxicity to early mouse blastocysts and implicate naphthalene as a potentially embryotoxic and abortifacient component polycyclic aromatic hydrocarbon mixtures. [R105] *In vitro embryotoxic effects of naphthalene /were monitored/ subsequent to in vivo exposure. Female ICR mice were injected on day 2 of gestation with naphthalene ip at either 14 mg/kg or 56 mg/kg. Embryos were collected on gestation day 3.5 and cultured in serum supplemented NCTC 109 medium for 72 hr. Embryos were examined during culture for viability, hatching, attachment and the presence of a distinct inner cell mass with trophoblastic outgrowth. Maternal napthalene doses at levels below the naphthalene LD50 inhibited the viability and implanation capability of fertilized embryos. Maternal exposure to naphthalene at 56 mg/kg and 14 mg/kg caused marked decreased in vitro attachment and embryonic growth; at the higher dose, delays in development were observed within 48 hr of culture. These findings support previous in vitro observations of naphthalene embryotoxicity and confirm the prenatal toxicity of this compound subsequent to in vivo exposure. [R106] *Maximum /dermal/ irritation score (erythema) was 2 (days 1 to 4); considered to be slightly irritating. /Dermal scoring was according to Draize/. No edema was observed. Slight fissuring of the skin was noted. All scores returned to normal by day 6. [R93] *Draize ocular irritation scores = 0 of 110 (rinsed) and 3.8/110 (unrinsed); considered minimally irritating. All scores returned to normal by 72 hours. [R93] HTXV: *A fatal /human/ dose from oral exposure /was reported/ to be approximately 2 g. [R49] NTXV: *LD50 Sprague Dawley rat oral 2.6 g/kg; [R93] *LD50 New Zealand White rabbit dermal > 2.0 g/kg; [R107] *LD50 Male CD-1 mouse gavage 533 mg/kg; [R108] *LD50 Female CD-1 mouse gavage 710 mg/kg; [R108] *LD50 Male Sherman rat oral 2200 mg/kg; [R49] *LD50 Female Sherman rat oral 2400 mg/kg; [R49] ETXV: *TLm Oncorhynchus gorbuscha (pink salmon) 1.37 ppm/96 hr at 4 deg C; 1.84 ppm/96 hr at 8 deg C; 1.24 ppm/96 hr at 12 deg C /Static bioassay/; [R86, 897] *TLm Pandalus goniurus (shrimp) 2.16 ppm/96 hr at 4 deg C; 1.02 ppm/96 hr at 8 deg C; 0.971 ppm/96 hr at 12 deg C /Static bioassay/; [R86, 897] *LC50 Parhyale hawaiensis (amphipod) 15 ppm/24 hr open bowl; 6.5 ppm/24 hr closed bottle in a static bioassay; [R86, 897] *LC50 Pimephales promelas (fathead minnow) 7.76 (7.39-8.14) mg/l 24 hr, wt 116 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R109] *LC50 Pimephales promelas (fathead minnow) 6.35 (5.95-6.77) mg/l 48 hr, wt 116 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R109] *LC50 Pimephales promelas (fathead minnow) 6.08 (5.74-6.44) mg/l 72 and 96 hr, wt 116 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R109] NTP: *... The 2 yr studies were conducted by exposing groups of male and female B6C3F1 mice to naphthalene (> 99% pure) vapor for 6 hr day for 5 days/wk, for 104 wk. ... Groups of male and female mice were exposed to atmospheres containing 0 (75 mice per group), 10 (75 mice per group), or 30 ppm (150 mice per group) napthalene. ... Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of naphthalene in male B6C3F1 mice exposed to 10 or 30 ppm. There was some evidence of carcinogenic activity of naphthalene in female B6C3F1 mice, based on increased incidences of pulmonary alveolar/bronchiolar adenomas. [R110] +... Naphthalene (0, 50, 150, or 450 mg/kg/day) was administered by gavage to pregnant rats during the major period of organogenesis (gestational days 6-15). Dams and fetuses were examined for signs of toxicity and teratogenicity. Each group contained 25-26 pregnant dams. Naphthalene admin produced clinical signs of toxicity. All doses of naphthalene caused lethargy, slow breathing, prone body posture, and rooting, but the effects subsided in the 50 and 150 mg/kg/day groups before the end of the treatment period. Clinical toxicity persisted throughout dosing in rats treated with 450 mg/kg/day naphthalene. Maternal mortality was low and limited to 2 animals in the 50 mg/kg/day group. Based upon the absence of maternal deaths at the higher doses, the association between naphthalene toxicity and maternal deaths at the 50 mg/kg/day dose is equivocal. Pregnancy rate, gravid uterine weight and liver weight (absolute and relative) were unaffected by naphthalene treatment. Naphthalene caused significant deficits in maternal body weight gain during the treatment period. Relative to the control group, the 150 mg/kg/day group showed a 31% reduction in weight gain during treatment as compared to a 53% reduction in the 450 mg/kg/day group. Post-treatment weight gain from gestational day 15 through sacrifice on gestational day 20 also remained significantly below controls in these two groups. Body weights were correspondingly reduced from gestational days 9-20. Maternal body weights and weight gains were unaffected by 50 mg/kg/day naphthalene. Maternal food and water consumption (absolute and relative) in the two highest dose groups were initially suppressed on gestational days 6-9. But unlike the effects on weight, the deficits in food and water intake were transient and confined to gestational days 6-9. Water consumption also displayed a transient incr on gestational days 9-12. Naphthalene was not fetotoxic or teratogenic. The avg number of corpora lutea/dam, implantation sites/litter, and live fetuses/litter were within 95-102% of controls in all treatment groups. Average fetal body weight was similarly unaffected by naphthalene. The results from this study indicate that naphthalene causes maternal toxicity expressed as CNS depression, decreased body weight, and altered food and water consumption. The maternal NOAEL was < 50 mg/kg/day. Fetal growth, viability, and morphological development were not significantly affected by naphthalene, even at doses which caused significant maternal toxicity. However, statistically significant trends toward decreased fetal weight and increased malformation incidence suggest that the high dose (450 mg/kg/day) may be just below a significant LOAEL for developmental effects. [R111] +... Naphthalene (0, 20, 80, or 120 mg/kg/day) was administered in corn oil by gavage to pregnant rabbits during the major period of organogenesis (gestational days 6-19). ... There was no maternal mortality in the control or naphthalene groups and each group contained 20-23 pregnant does at necropsy. Maternal body weights in the naphthalene-treated groups were comparable to controls at all gestational ages. Maternal corrected gestational weight gain and food consumption in all three naphthalene groups was also comparable to controls throughout gestation. Exam of the uterine contents revealed that naphthalene was not fetotoxic. Avg live litter size and average fetal body weight in the naphthalene-treated groups were normal. There was no effect of naphthalene on the incidence of malformations (external, visceral, or skeletal). The incidence of variations or defects (fetuses with one or more malformation or variation) on a per fetus or litter basis was similarly unaffected in the naphthalene-treated groups. The results from this study provide no definitive evidence for naphthalene being toxic to the fetus or doe at doses as high as 120 mg/kg/day. Higher doses were not examined in this study due to the reported incidence of 40% maternal mortality following admin of 150 mg/kg/day naphthalene to pregnant rabbits in a range-finding study ... . [R112] POPL: *Individuals with glucose-6-phosphate-dehydrogenase deficiency would be susceptible to hemolytic anemia /induced by naphthalene/. [R113] */Protect/ from exposure individuals with diseases of the blood, liver, and kidneys. [R66] *Pregnant women may be especially susceptible to exposure effects associated with coal tar pitch volatiles. /Coal tar pitch volatiles/ [R34] *Persons with existing skin disorders may be more susceptible to the effects of /coal tar pitch volatiles/. /Coal tar pitch volatiles/ [R34] ADE: *CUTANEOUS ABSORPTION OF NAPHTHALENE IN INFANTS IS INCR BY BABY OIL. [R114] *... READILY ABSORBED WHEN INHALED. [R115, 3340] *... EXCRETED IN URINE AS 1-NAPHTHYLMERCAPTURIC ACID (15% DOSE) AND AS CONJUGATES OF 1,2-DIHYDRONAPHTHALENE-1,2-DIOL (10%), 1- and 2-NAPHTHOLS AND 1,2-DIHYDROXYNAPHTHALENE. [R116, 219] *At 100 mg/kg intraperitoneally, 20 to 30% was excreted in the rat urine 85 to 90% of these in the form of conjugates /which are acidic/; 5 to 10% was excreted in the bile, of these also 70 to 80% as acid conjugates, with the major metabolite naphthalene-1,2-dihydrodiol. [R115, 3341] *IN SMALL OYSTERS TRANSPORT OF NAPHTHALENE BETWEEN TISSUES IS PRIMARILY BY DIFFUSION. IN INTACT OYSTERS, ACCUM IN ADDUCTOR MUSCLE AND BODY FOLLOWED ACCUM IN GILLS AFTER A LARGE LAG-TIME. IN ISOLATED TISSUES WITH NO SHELL TO IMPEDE WATER, THERE WAS NO TIME LAG. [R117] *THE GILLS OF DOLLY VARDEN CHAR (SALVELINUS MALMA) WERE THE MOST IMPORTANT PATHWAY FOR EXCRETION OF (14)C FROM (14)C-LABELED NAPHTHALENE. IN GENERAL, FISH EXPOSED TO TOLUENE EXCRETED MORE (14)C THAN FISH EXPOSED TO NAPHTHALENE. [R118] *ENGLISH SOLE EXPOSED TO (3)H-BENZO(A)PYRENE AND (14)C-NAPHTHALENE IN SEDIMENT CONTAINING PRUDHOE BAY CRUDE OIL. BIOCONCENTRATION VALUE FOR (14)C NAPHTHALENE WAS GREATER THAN VALUES FOR (3)H-BENZO(A)PYRENE IN TISSUES OF FISH EXPOSED FOR 24 HR. [R119] *THE PATTERN OF NAPHTHALENE UPTAKE AND ACCUM FROM A FLOW-THROUGH SYSTEM INTO OYSTER TISSUES WAS RELATIVELY CONSTANT AFTER ONLY A FEW HR OF EXPOSURE. ACCUM WAS INFLUENCED BY NUTRITIONAL STATE, LIPID CONCN, LENGTH OF EXPOSURE TO NAPHTHALENE AND EXTERNAL NAPHTHALENE CONCN. [R120] *THE MECHANISM OF TRANSPORT BY POLYNUCLEAR AROMATIC HYDROCARBONS (PAH) INTO CELLS AND BETWEEN INTRACELLULAR MEMBRANES IS DISCUSSED. FROM THE PARTITIONING PARAMETERS, THE RATE LIMITING STEP /IN THE TRANSPORT OF PAH'S CELLS AND ACROSS INTRAELLULAR MEMBRANE/ INVOLVES SOLVATION OF TRANSFER SPECIES IN THE INTERFACIAL WATER AT PHOSPHOLIPID SURFACE. [R121] *Polynuclear aromatic hydrocarbons are highly soluble in adipose tissue and lipids. /Polynuclear aromatic hydrocarbons/ [R122] *Naphthalene was readily taken up by tissue of laying pullets, swine, and dairy cattle after oral administration of a single dose or on a daily basis for 31 days. Adipose tissue, kidneys, livers, and lungs of pullets had the highest naphthalene levels after acute treatment; kidneys had high levels after chronic treatment. In swine, adipose tissues had high levels of naphthalene after acute treatment; lungs were highest with chronic treatment. In cattle, livers had the highest levels of naphthalene after both treatments. [R123] *CONJUGATES OF GLUTATHIONE, CYSTEINYLGLYCINE AND CYSTEINE, INTERMEDIATES IN FORMATION OF MERCAPTURIC ACIDS, ARE EXCRETED, PARTICULARLY IN BILE, AS METABOLITES OF ... NAPHTHALENE. ... [R124] *Cutaneous and gastrointestinal absorption are facilitated when naphthalene is administered with oil or fat, respectively. [R71] *Humans most absorb naphthalene by the inhalation route. [R71] *Naphthalene and its metabolites have been reported to cross the human placenta in amounts sufficient to cause fetal toxicity. [R125] *Single gavage doses of naphthalene of 0, 30, 75 or 200 mg/kg /were administered/ to two male and two female yearling chimpanzees and five adult male SPF Wistar rats, and urinary excretion of thioether /was determined/. At 0, 30, 75 and 200 mg/kg, thioether excretion in rats was 94.4, 185.6, 279.6 and 502.0 umol/24 hr/kg, respectively. Thioether excretion by chimpanzees (measured at 0 and 200 mg/kg) did not increase as a result of exposure to naphthalene. [R126, PB90-259821] *Reactive metabolites bind irreversibly with eye lens proteins and are associated with cataract formation. They also bind covalently with macromolecules in the lungs and may be associated with damage to the bronchiolar epithelium. [R127] METB: *... METABOLIZED VIA 1,2-EPOXIDE INTO 1,2-DIHYDRONAPHTHALENE-1,2-DIOL, 1,2-DIHYDRO-1-NAPHTHOL AND N-ACETYL-S-(2-HYDROXY-1,2-DIHYDRONAPHTHYL)-CYSTEINE, WHICH AFTER FURTHER METABOLISM ... EXCRETED IN URINE AS 1-NAPHTHYLMERCAPTURIC ACID ... AND CONJUGATES OF 1,2-DIHYDRONAPHTHALENE-1,2-DIOL ... 1- and 2-NAPHTHOLS, and 1,2-DIHYDROXYNAPHTHALENE. [R116, 219] *... NAPHTHALENE 1,2-OXIDE IS INTERMEDIATE IN MICROSOMAL HYDROXYLATION OF NAPHTHALENE. [R128] *... NAPHTHALENE ... AND MONOHALOGENATED BENZENES ARE METABOLIZED INTO MERCAPTURIC ACIDS, CONJUGATES IN WHICH N-ACETYLCYSTEINE MOIETY REPLACES A HYDROGEN ATOM. [R116, 92] *NAPHTHALENE YIELDS S-(1-NAPHTHYL)GLUTATHIONE IN RABBIT. NAPHTHALENE YIELDS S-(1-NAPHTHYL)GLUTATHIONE IN RAT, IN MOUSE AND IN GUINEA PIGS. /FROM TABLE/ [R129] *NAPHTHALENE YIELDS CIS-1,2-DIHYDRO-1,2-DIHYDROXYNAPHTHALENE IN PSEUDOMONAS. /FROM TABLE/ [R129] *FISH WERE EXPOSED TO ... NAPHTHALENE IN SEDIMENT CONTAINING PRUDHOE BAY CRUDE OIL. NAPHTHALENE WAS METAB TO 1,2-DIHYDRO-1,2-DIHYDROXYNAPHTHALENE GLUCURONIDE. [R119] *Cunninghamella elegans (a filamentous fungus) is capable of oxidizing naphthalene to trans-1,2-dihydroxy-1,2-dihydronaphthalene. Other metabolites were identified as 1-napthol, 2-napthol and 4-hydroxy-1-tetralone. [R130] *Ringed seals (Phoca hispida) were exposed experimentally to oil contamination by feeding of a (14)C naphthalene crude oil in fish for up to 4 days at a rate of 5 ml/day. Mixed function oxygenase activity, measured as aryl hydrocarbon hydroxylase in liver and kidney, was found to be induced; in particular, /activity in the kidney was induced 3-fold/ mixed function oxygenase induction correlated with a high degree of conversion of crude oil hydrocarbons to water-soluble metabolites. Most of the radioactivity was found in the polar fraction of the plasma and urine. [R131] *Naphthalene is first metabolized by hepatic mixed function oxidases to the epoxide, naphthalene-1,2-oxide. The epoxide can be enzymatically converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydronaphthalene or conjugated with glutathione. The dihydrodiol can then be conjugated to form a polar compound with glucuronic acid or sulfate or be further dehydrogenated to form the highly reactive 1,2-dihydroxynaphthalene. This too can be enzymatically conjugated with sulfate or glucuronic acid or spontaneously oxidized to form 1,2-naphthoquinone. [R132] *The urinary excretion of mercapturic acids was considered as an indicator for human exposure. [R133] *... In rabbits 1,2-dihydroxynaphthalene ... is produced enzymatically and by autoxidation, and /it is/ the metabolic intermediate responsible for naphthalene cataractogenesis. [R69, 653] *CONJUGATES OF GLUTATHIONE, CYSTEINYLGLYCINE AND CYSTEINE, INTERMEDIATES IN FORMATION OF MERCAPTURIC ACIDS, ARE EXCRETED, PARTICULARLY IN BILE, AS METABOLITES OF ... NAPHTHALENE. ... [R116, 92] *In the presence of glutathione and glutathione transferases, microsomal fractions prepared from fresh samples of human lung tissue obtained at resection metabolized naphthalene to naphthalene dihydrodiol and 3 glutathione conjugates at easily measurable rates. Addition of varying amounts of human lung microsomal protein markedly inhibited mouse liver microsome-catalyzed naphthalene metabolism in one sample but not the other. These studies suggest that there may be an inhibitor, potential released during tissue homogenization, that makes measurement of human lung xenobiotic metabolism difficult. [R134] *Naphthalene and 2-methylnaphthalene cause a highly organo and species selective lesion of the pulmonary bronchiolar epithelium in mice. Naphthalene but not 2-methylnaphthalene induced pulmonary bronchiolar injury is blocked by prior administration of the cytochrome p450 monooxygenase inhibitor piperonyl butoxide, thus suggesting that metabolism by enzyme other than the p450 monooxygenases may be important in 2-methylnaphthalene induced injury. Since many of the polycyclic aromatic hydrocarbons are metabolized by the prostaglandin endoperoxide synthetase system and because detectable xenobiotic metabolizing activity has been associated with the prostaglandin synathetases in the Clara cell, the studies reported here were done to compare reduced nicotinamide adenine dinucleotide phosphate versus arachidonate dependent metabolism of naphthalene in vitro and to determine whether indomethacin, a potent inhibitor of prostaglandin biosythesis, was capable of blocking the in vivo toxicity of these two aromatic hydrocarbons. The NADPH-dependent metabolism of naphthalene and 2-methylnaphthalene to covalently bound metabolites in lung or liver microsomal incubations occurred at easily measurable rates. Renal microsomal NADPH-dependent metabolism of either substrate was not detected. The formation of covalently bound naphthalene or 2-methylnaphthalene metabolites was dependent upon NADPH and was inhibited by the addition of reduced glutathione, piperonyl butoxide, and SKF-525A. Covalent binding of radioactivity from (14)C 2-methylnaphthalene also was strongly inhibited by incubation in a nitrogen atmosphere . ... The arachidonic acid-dependent formation of reactive metabolites from naphthalene or 2-methylnaphthalene was undetectable in microsomal incubations from lung, liver or kidney. Indomethacin, 1 hr before and 6 hr after the administration of 300 mg/kg naphthalene or 2-methylnaphthalene, failed to block the pulmonary bronchiolar injury induced by these organisms. These studies suggest that the major enzymes involved in the metabolic activation of naphthalene or 2-methylnaphthalene in vitro are cytochrome p450 monooxygenases and that cooxidative metabolism by the prostaglandin synthetases appears to play little role in the formation of reactive metabolites in vitro. [R135] *In an experimental animal study, doses of naphthalene ranging from 1 ug to 1 g were administered in the feed to 3 young pigs and their urine was collected in 2 sequential 24 hr specimens. The major urinary metabolite, conjugated 1-naphthol, was separated by gas chromatography and detected by electron capture. Most 1-naphthol excretion occurred during the first 24 hr period following dosing. Metabolic 1-naphthol could be detected after administration of as little as 100 ug naphthalene. A linear relationship was observed between urinary 1-naphthol and oral dose (both expressed on the log scale) in 24 hr specimen (r squared = 0.961, p < 0.05) and 48 hr specimens (r squared = 0.906, p < 0.05). [R136] *In vitro studies of naphthalene indicate that oxidation to the epoxide, naphthalene 1,2-oxide, is the initial biotransformation reaction in rats. This intermediate may then be converted to a number of other oxidation products (eg, phenols, dihydrodiols) or be conjugated with glutathione. [R137] *Urinary radioactivity /of a single 100 mg/kg ip dose of (14)C-naphthalene/ (collected for 72 hours) accounted for 60% of the administered dose. The ether extractable portion of the urine accounted for 6% of the administered dose and consisted primarily of 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene at 60 and 28%, respectively, of the ether extractable radioactivity. Water soluble metabolites included 1-naphthol; 1,2-dihydro-1,2-dihydroxy-1-naphthyl sulfate; 1,2-dihydro-2-hydroxy-1-naphthyl glucuronide and N-acetyl-S-(1,2-dihydro-2-hydroxy-1-naphthyl)cysteine at 5.0, 8.0, 16.8 and 65.0% of the nonether-extractable urinary radioactivity, respectively. ... Glutathione and mercapturic acid conjugation are major detoxification pathways in rats. [R126, 259821] *Following the ip administration of naphthalene (200 mg/kg) to mice, the lung, in comparison with other organs, was selectively damaged. Histological examination of the lung showed that it was the non-ciliated, bronchiolar epithelial cells (Clara cells) which were damaged. At higher doses (400 mg/kg and 600 mg/kg, ip), there was also damage to the cells in the proximal tubules of the kidney. In contrast to the effect in mice, doses of naphthalene as high as 1600 mg/kg ip caused no detectable pulmonary or renal damage in the rat. This difference in toxicity between the mouse and rat was reflected by the ability of naphthalene to more severely deplete the non-protein sulfhydryls in the mouse lung and kidney than in the rat. In order to investigate the species difference in toxicity, the metabolism of naphthalene by lung and liver microsomes of the mouse and rat was studied. In all cases, naphthalene was metabolized to a covalently bound product(s) and to two major methanol soluble products, which co-chromatographed with 1-naphthol and 1,2-dihydro-1,2-dihydroxynaphthalene. However, both the covalent binding and metabolism were approximately 10-fold greater in microsomes prepared from mouse lung compared with those from the rat. [R89] *Oral median lethal doses naphthalene ranged from around 350 mg/kg in mice to 2200 mg/kg in rats. The toxicity of naphthalene and 2-methylnaphthalene is due to a bronchiolar necrosis that develops rapidly after inhalation exposure. Clara cells in the bronchiolar epithelium are the primary target for low doses of naphthalene and 2-methylnaphthalene. When given in multiple doses to mice the bronchiolar epithelium appears to develop a tolerance to naphthalene. 2-Methylnaphthalene is less acutely toxic than naphthalene. Mice have tolerated intraperitoneal doses of 2-methylnaphthalene as high as 800 mg/kg. Both naphthalene and 2-methylnaphthalene must be metabolically activated to form enantiomeric epoxides and diol epoxides to express their toxicity. Stereochemical investigations in the case of naphthalene conducted in mice have shown that a major reason for the selective injury to the bronchiolar epithelium may be the high degree to which it is epoxidated. No specific naphthalene or 2-methylnaphthalene metabolite that can damage Clara cells has been identified nor has a close relationship between the metabolic binding and toxicity been established. The Clara cell toxicity of naphthalene and 2-methylnaphthalene may be due to circulating metabolites. [R138] *The fate of glutathione conjugates derived from naphthalene metabolism at various dose levels (5-80 mg/kg) were examined in an effort to explore the potential use of urinary mercapturic acids as biomarkers of exposure to naphthalene and as indicators of the activity and stereoselectivity of cytochrome p450 dependent naphthalene epoxidation. This approach extends previous studies which demonstrated a high degree of stereoselectivity in the formation of (+)-1R,2S-naphthalene oxide from naphthalene in target tissue microsomes (mouse lung), but not in microsomal preparations isolated from nontarget tissues such as mouse liver. To validate the use of mercapturic acids as indicators of epoxide formation in vivo, individual naphthalene oxide glutathione adduct isomers were administered iv to mice, and urinary metabolites were identified and quantified. Mercapturates accounted for 69-75% of the administered dose in the 8 hr urines of animals treated with trans-1-(S)-hydroxy-2-(S)-glutathionyl-1,2-dihydronaphthalene (adduct 1) and 76-84% for trans-1-(R)-hydroxy-2-(R)-glutathionyl-1,2-dihydronaphthalene (adduct 2). Only 39-57% of the dose of trans-1-(R)-glutathionyl-2-(R)-hydroxy-1,2-dihydronaphthalene (adduct 3) administered to mice was excreted as the mercapturic acid derivative; however, two additional metabolites were detected which were not present in the urine of animals treated with adducts 1 or 2. The first metabolite, accounting for 2-4% of the dose of adduct 3, was not identified. The second metabolite, isolated by HPLC and identified by mass spectrometry as (hydroxy-1,2-dihydronaphthalenylthio)pyruvic acid, accounted for 14-25% of the administered dose of adduct 3. [R139] *Naphthalene induced pulmonary and renal toxicity and polycyclic aromatic hydrocarbon induced carcinogenesis are known to be mediated by their reactive metabolites. Subchronic exposure (90 days) of mice to naphthalene does not alter humoral and cellular mediated immune responses, whereas polycyclic aromatic hydrocarbons, such as benzo(a)pyrene and 7,12-dimethylbenzanthracene, are known to be immunosuppressive. To understand these differences, the antibody forming cell responses of splenocyte cultures exposed to naphthalene (2, 20, and 200 uM) were evaluated. At these concentrations, the antibody forming cell response to sheep red blood cells (RBC) was not affected. To determine if reactive metabolites of naphthalene were immunosuppressive, splenocytes were exposed to naphthalene metabolites by direct addition or through the use of a metabolic activation system. The addition of 1-naphthol (70 and 200 uM) and 1,4-naphthoquinone (2, 7, and 20 uM) resulted in a decreased antibody forming cell response. Suppression of antibody forming cell responses was also obtained by culturing splenocytes with liver S9 and naphthalene. Since splenic metabolism of naphthalene to nonimmunosuppressive metabolites may account for the absence of immunotoxicity, the types of naphthalene metabolites generated by splenic microsomes were determined. It was observed that splenic microsomes were unable to generate any detectable naphthalene metabolites, whereas liver microsomes were able to generate both 1,2-naphthalene diol and 1-naphthol. Thus, the absence of an immunosuppressive effect by naphthalene exposure may be related to the inability of splenocytes to metabolize naphthalene. Moreover, the concentration of naphthalene metabolites generated within the liver that may diffuse to the spleen may be inadequate to produce immunotoxicity. [R140] ACTN: *1,2-Dihydroxynaphthalene or 1,2-naphthoquinone /metabolites of naphthalene/ combined with amino acids or irreversibly with the thiol groups of lens protein to form a brown precipitate. ... Hydroperoxide formed in the oxidation of 1,2-dihydroxynaphthalene and ascorbic acid can act with high levels of glutathione peroxidase in the eye to oxidize glutathione. [R141] *... One or more metabolic products of naphthalene reaches the eye by way of the bloodstream, reacts with the constituents of the lens and thus disrupts its integrity and transparency. [R69, 653] *Mitochondrial respiration is inhibited 50% by 10 ppm (78 uM) nicotinamide adenine dinucleotide oxidase, nicotinamide adenine dinucleotide-cytochrome c reductase, ubiquinone-50 oxidase, and nicotinamide adenine dinucleotide-ubiquinone reductase are inhibited; while succinate oxidase, nicotinamide adenine dinucleotide-ferricyanide reductase, nicotinamide adenine dinucleotide -indophenol reductase, and ATPase activities are not inhibited. ... Exposure at concentrations > 7.5 ppm causes cultured cells to round up ... with eventual death the result. The effects of naphthalene on morphology and respiration are very similar, suggesting that mitochondrial inhibition plays a significant role in the effects of naphthalene on intact cells. [R142] *The renal epithelium of the marine prosobranch gastropod Littorina littorea consists of two cell types, namely, vacuolated excretory cells and ciliated cells. The present work investigates the fine structure of the kidney of winkles after experimental exposure to low levels (30 ug/liter) of naphthalene in sea water. Ultrastructural changes within excretory cells consisted of increased formation or accumulation of lipid droplets, increased occurrence of membrane bound dark bodies which became enlarged after 96 hr of exposure to naphthalene, distortion of the Golgi complex, and altered mitochondrial structure. An increase in the numbers of residual bodies was observed in napthalene-exposed ciliated cells, together with numerous lipid droplets. In addtion, hemocytes were seen to infiltrate the renal tissue of treated female winkles. [R143] INTC: *Ip injection of channel catfish (Ictalurus punctatus) with 100 ug benzo(a)pyrene, Aroclor 1254, or naphthalene, singly and in combinations, affected the levels of the brain neurotransmitters norepinephrine, dopamine, and 5 hydroxytryptamine, but the effect showed no discernible pattern. The effects of combinations of the chemicals did not appear to be predictable from the effects of individual chemicals. In several instances, the change in the level of neurotransmitter in fish receiving a combination of chemicals was greater than in fish receiving either chemical alone. [R84] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +MEDICATION (VET): 0.2% ... USED IN COMBINATION-TYPE ANTISEPTIC FOR IRRIGATING WOUNDS AND 1% ... ON NEGLECTED INFECTED WOUNDS. [R29] +MEDICATION (VET): EXTERNALLY, ON LIVESTOCK AND POULTRY ... TO CONTROL LICE ... POWDER USUALLY CONTAINS 15-35% CONCN ALTHOUGH 100% ... OCCASIONALLY USED ... LOWER CONCN ... USED WITH OTHER INSECTICIDES. [R29] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Naphthalene enters the atmosphere primarily from fugitive emissions and exhaust connected with its presence in fuel oil and gasoline. In addition, there are discharges on land and into water from spills during the storage, transport and disposal of fuel oil, coal tar, etc. Once in the atmosphere, naphthalene rapidly photodegrades (half-life 3-8 hr). Releases into water are lost due to volatilization, photolysis, adsorption, and biodegradation. The principal loss processes will depend on local conditions but half-lives can be expected to range from a couple of days to a few months. When adsorbed to sediment, biodegradation occurs much more rapidly than in the overlying water column. When spilled on land, naphthalene is adsorbed moderately to soil and undergoes biodegradation. However, in some cases it will appear in the groundwater where biodegradation still may occur if conditions are aerobic. Bioconcentration occurs to a moderate extent but since depuration and metabolism readily proceed in aquatic organisms, this is a short term problem. The primary source of exposure is from air, especially in areas of heavy traffic or where fumes from evaporating gasoline or fuel oil exist or in the vicinity of petroleum refineries and coal coaking operations. (SRC) NATS: *Component of crude oil; since naphthalene is a natural combustion product, forest fires, etc may be a source of naphthalene. (SRC) ARTS: *Emissions from its production from petroleum refining and coal tar distillation(1); Emissions and wastewater from its use as a chemical intermediate(2); Motor vehicle emissions; tobacco smoke(3); coal tar pitch fumes(1); unvented kerosene space heaters(4); smoke from tire fire(5). Oil spills and leaking underground petroleum storage tanks and leaks and spills of othe petroleum products(6,SRC). [R144] *Naphthalene has been identified in cigarette smoke condensate(1). [R145] FATE: *TERRESTRIAL FATE: The sorption of napthalene to soil will be low to moderate depending on its organic carbon content. Its passage through sandy soil will be rapid. It will undergo biodegradation which may be rapid when the soil has been contaminated with PAHs (half-life a few hours to days) but slow otherwise (half-life > 80 days). Evaporation of naphthalene from the top soil layer will be important but the importance of the process will gradually decrease as the soil depth increases. Laboratory experiments conducted to observe the fate of naphthalene in soil columns under moderate and high flow conditions for 90 days found a decay rate of 0.1 1/day under moderate flow conditions and much lower decay rate, 0.0147 1/day, under high flow conditions(1). The napthalene therefore degraded rapidly under moderate flow conditions and had completely disappeared from the soil column at the end of 90 days. At this time the napthalene had advected downward approximately 1.2 m. Higher flow rates may reduce the diffusion of oxygen into the soil causing a reduction in degradation rates. When naphthalene was incubated in two sandy loam soils, at concentrations typical of those in waste disposal sites, for 48 hrs, 30% of the naphthalene was lost by volatilization(2). The biodegradation rates and half-lives for the two soils were 0.3370 and 0.3080 1/day and 2.1 and 2.2 days, respectively(2,SRC). [R146] *AQUATIC FATE: Photolysis, volatilization, biodegradation, and adsorption may all be important loss mechanisms for naphthalene disharged into water. In the Rhine River the half-life has been determined as 2.3 days based upon monitoring data(1). Moderate adsorption to sediment and particulate matter occurs. In surface layers of water, photolysis may be dominant (half-life 3 days). Volatilization is an important loss mechanism especially in rapid streams since the half-life for a river may be a couple of days. In a mesocosm experiment which simulated Narragansett Bay, the half-life in winter was 12 days; loss being primarily due to evaporation(2). These investigators did not mention any photolytic loss which would certainly have been noticed since they used sterile controls(2). In oil contaminated water which is not exposed to sunlight because the water is murky or the water depth is great, biodegradation can be important with half-lives of 7 days in oil polluted streams to a few months in coastal waters. (SRC) [R147] *ATMOSPHERIC FATE: Naphthalene reacts with photochemically produced hydroxyl radicals and degrades with a half-life of 3-8 hr(2-4). Although photolysis should occur, no data could be found to assess its importance. In polluted urban air, reaction with NO3 radicals may be an additional sink for night time loss. An analysis of PAH concentrations and the origins of the air masses reaching the sampling site over a two week period (14 sampling events) indicates that the concentration is determined by the origin of the air mass (long distant transport)(1). Short terms phenoma, such as rain events, appear to be without effect. [R148] *AQUATIC FATE: Ground water in the immediate vicinity of an area previously used for the disposal of charcoal manufacturing wastes has been shown to contain low levels of phenolic and polycyclic compounds. Based on the analysis of samples obtained from monitoring wells, the levels of the organic contaminants are reduced to near or below the detection limit within a distance of 100 meters downgradient of the fill. Examination of the ground water chemistry indicated that the aquifer is essentially aerobic across the site, except in the immediate vicinity of the fill. At this point, dissolved oxygen is apparently depleted due to the biodegradation of organic contaminants introduced into the ground water, with a concomitant increase in the inorganic carbon concentration. Laboratory microcosm experiments demonstrated that the naturally occurring microorganisms can readily degrade a mixture of the predominant organic contaminants. Half-lives for biodegradation were in the range of 3 to 8 days for phenolic substrates, and 11 to 18 days for naphthalene. Computer model simulations indicated that the attenuation observed in the aquifer cannot be explained in terms of physical processes such as adsorption or dispersion, but is consistent with biological degradation. [R149] BIOD: *Polycyclic aromatic hydrocarbons with 4 or less aromatic rings are degraded by microbes and are readily metabolized by multicellular organisms ... . /Polycyclic aromatic hydrocarbons/ [R150, p. 97-17] *Biodegradation is probably slower in the aquatic system than in the soil, and biodegradation may be much more important in those aquatic systems which are chronically affected by contamination. /Polycyclic aromatic hydrocarbons/ [R150, p. 95-11] *There is a moderate amount of data concerning the biodegradability of naphthalene both in standard biodegradability tests and in natural systems. Although there is some conflicting data, the preponderance of data suggests that naphthalene degrades after a relatively short period of acclimation and that degradation can be rapi in oil polluted water, slow in unpolluted water and that the rate of degradation increases with the concentration of naphthalene(5). In laboratory tests with sewage or sludge inoculums, 100% degradation was obtained in 7 days(1-2) while others got 0% BOD in 5 days(3-4). The lag period for naphthalene degradation decreased as groundwater was more polluted with fuel oil; the lag period was 1.2 and 1.9 days in heavily polluted and slightly polluted water, respectively versus 12 days for unpolluted water(8). Approximately 70% was lost in a pilot-scale municipal wastewater treatment plant due to biodegradation(6). In water, bacteria can utilize naphthalene only when it is in the dissolved state(7). [R151] *Twenty percent of naphthalene was degraded to CO2 when incubated in water from an oil polluted creek(1) and rapid degradation, sometimes as fast as 95% degradation in 1.5 hr(3), have been reported in other experiments with inoculums from oil contaminated water or sediment(2). In die-away tests, reported half-lives include 70 hr in water with high PAH levels(4); 7, 24, 63, and 1700 days in an oil polluted estuarine stream, clean estuarine stream, coastal waters and in the Gulf Stream respectively(5); 9 days in water near a coal-coking wastewater discharge(6). Highest rates of mineralization in a relatively unpolluted station in Long Island Sound and the Hudson River Estuary, corrected for volatilization, were 118%/day (5.8 ug/L-day)) and 172%/day (1.72 ug/L-day), respectively(10). In water from the Alaskan Continental Shelf degradation rates avg 0.5%/week; however, when nutrient levels are lower as in late spring-early summer (after algae blooms), the degradation rate is reduced(7). In a mesocosm experiment using Narragansett Bay seawater, the half-life in late summer was 0.8 days and is principally due to biodegradation(8). Biodegradation half-life 43 days in microbe-supplemented filtered Lake Superior Harbor water and 39 days in nutrient and microbe-supplemented water(9). [R152] *Degradation rates in sediment are much higher than in water, being 8-20 fold higher than in the water column above the sediment(3). Half-lives in sediment include 4.9 hr and > 88 days in oil contaminated and uncontaminated sediment, resp(3), 9 days in sediment near a coal coaking discharge(2); and 3, 5, and > 2,000 hours in sediments with high, medium and low PAH levels respectively(1). When incubated in a slurry with sediment from an uncontaminated pond, the mineralization rate increases, reaching a peak after 6-12 days corresponding to a half life of 78 days(4). Biodegradation half-life ranged from 2.4 weeks in sediments chronically exposed to petroleum hydrocarbons to 4.4 weeks in sediment from a pristine enviornment(5). Naphthalene disappeared rapidly from an unacclimated agricultural soil during a 60 day period(6). Naphthalene (concn 7 mg/L) degradation was studied under various redox conditions in soil-water systems(7). It degraded to undectectable levels in 45 days, 2 wk lag, under denitrifying conditions (anaerobic with 75 mg nitrate/L(7). No significant degradation occurred in 50 days under anaerobic conditions(7). [R153] *No degradation under anaerobic conditions was observed in 6 and 11 weeks in a lab reactor with seed from a well near a source of contamination(1), or with sewage seed(2), resp, but complete degradation occurred in 8 days in gas-oil saturated groundwater which was circulated through under aerobic conditions(3). The latter case indicates that some species of ubiquitous microflora present in clean groundwater is capable of degrading naphthalene. Biodegradation occurred in groundwater contaminated with creosote(4). [R154] *This study explores the potential for a bacterial monooxygenase to remove polynuclear aromatic hydrocarbons from aqueous solutions at high rates. This is part of a larger effort to test the versatility of the cytochrome p450cam monooxygenase enzyme system for detoxification of industrial process wastewaters that contain trace quantities of hazardous compounds like PAHs or halocarbons. The intracellular concentration of p450cam in washed, resting cells suspensions of Pseudomonaoas putida PpG 786 that were cultured on camphor was measured by adapting a spectrophotometric method used to measure p450 concentration in extracts of mammalian tissue. Naphthalene removal in the suspensions was measured as a function of incubation time, biomass concentration, starting naphthalene concentration, starting naphthalene concentraton ((3-180 umol/l) and in the presence of known p450 inhibitors. Involvement of the p450cam system in the measured naphthalene disappearance was established by showing that while significant naphthalene removal occurred in camphor-grown biomass, no disappearance was observed in glutamate-grown biomass and that removal was turned off in the presence of the p450 inhibitor metyrapone. The half-live of napthalene removed decreased rapidly as initial naphthalene concentration increased, and essentially no naphthalene was removed when the starting concentration exceeded 189 umol/l (23 ppm). [R155] +The mineralization of (14)C-labelled naphthalene was studied in pristine and oil-contaminated soil slurry (30% solids) under denitryfying conditions using a range of concentrations from below to above the aqueous phase saturation level. Results from sorption-desorption experiments indicated that naphthalene desorption was highly irreversible and decreased with an increase in the soil organic content, thus influencing the availability for microbial consumption. Under denitrifying conditions, the mineralization of naphthalene to CO2 occurred in parallel with the consumption of nitrate and an increase in pH from 7.0 to 8.6. When the initial substrate concentration was 50 ppm (ie close to the aqueous phase saturation level), about 90% of the total naphthalene was mineralized within 50 days, and a maximum mineralization rate of 1.3 ppm/day was achieved after a lag period of approx 18 days. When added at concentrations higher than the aqueous phase saturation level (200 and 500 ppm), similar mineralization rates (1.8 ppm/day) occurred until about 50 ppm of the naphthalene was mineralized. After that the mineralization rates decreased logarithmically to a minimum of 0.24 ppm/day for the rest of the 160 days of the experiments. For both of these higher concentrations, the reaction kinetics were independent of the concentration, indicating that desorption of the substrate governs the mineralization rate. Other results indicated that pre-exposure of soil to oil contamination did not improve the degradation rates nor reduce the lag periods. This study clearly shows the potential of denitrifying conditions for the biodegradation of low molecular weight polyaromatic hydrocarbons. [R156] ABIO: *Naphthalene absorbs light with a wavelength greater than 290 nm and will photolyze in water(1,3). Photolysis should also occur in air but no experimental data could be found(SRC). The half-life in surface waters is calculated to be 71 hours(1,2) and longer in deeper or murky water(1). When a mixture of jet fuel was added to filtered deionized water, salt water or pond water and exposed to sunlight, 44-77% of the naphthalene in the fuel was lost in 7 days(6). The presence of algae in the water can increase the rate of photolysis of naphthalene by a factor of 1.3 to 2.7(5). If nitrite is present in the water, mutagenic products are formed during photolysis(4). Reaction with oxidizing species in natural waters as well as hydrolysis will not be significant(3). [R157] *Naphthalene in air reacts with photochemically generated hydroxyl radicals, the rate constant being 2.16X10-11 cu cm/molec-sec(1-2,5). Its half-life is about 8 hr in clean air and 3 hr in moderately polluted air(1-3). The loss of naphthalene due to reaction with N2O5 and O3 in air is neglible(1,3,6). In polluted urban air, reaction with NO3 radicals may be an additional sink for night time loss(4). [R158] BIOC: *Naphthalene bioconcentrates to a moderate amount in fish and aquatic invertebrates (log BCF 1.6-3.0)(1-6). However, at least for invertebrates, depuration is rapid when the organism is placed in water free of the pollutant(6-7) and naphthalene is also readily metabolized in fish(8). [R159] *... Some marine organisms have no detectable aryl hydrocarbons hydroxylase enzyme systems, namely: phytoplankton, certain zooplankton, mussels (Mytilus edulis), scallops (Placopecten sp), and snails (Litternia littorea). ... Those organisms which lack a metabolic detoxification enzyme system, tend to accumulate polycyclic aromatic hydrocarbons. /Polycyclic aromatic hydrocarbons/ [R160] *Bioaccumulation, especially in vertebrate organisms, is considered to be short-term, and is not considered an important fate process. /Polycyclic aromatic hydrocarbons/ [R150, p. 95-9] *POLYCYCLIC AROMATIC HYDROCARBONS (PAH) WERE ANALYZED IN SURFACIAL SEDIMENTS AND BENTHIC ORGANISMS IN SOUTHEASTERN LAKE ERIE, NEAR A LARGE COAL-FIRED POWER PLANT. SEDIMENT CONCN (530-770 PPB PAH) WERE RELATIVELY HOMOGENOUS THROUGHOUT MOST OF THE 150 SQUARE KM AREA, ALTHOUGH RIVER AND NEARSHORE CONCENTRATIONS REACHED 4 PPM. OLIGOCHAETE WORMS DID NOT BIOCONCENTRATE (ON WET WT BASIS) ANY OF THE PAH. CHIRONOMIDE MIDGES COLLECTED 1 KM OFFSHORE EXHIBITED BIOCONCENTRATION OF 5 PAH ONE OF WHICH WAS PYRENE. FURTHER OFFSHORE, THESE APPARENT BIOCONCENTRATIONS DISAPPEARED, WITH MIDGES AT NEAR EQUILIBRIUM WITH SEDIMENTS. [R161] KOC: *Naphthalene is adsorbed moderately by soil and sediment. 17 soils and sediment had a mean Koc of 871(1) and soils from Switzerland had a Koc of 812(3). A mean Koc of 2400 was measured for 4 silt loams and a sandy loam soil(2), a mean Koc of 594 (range 420-830) for 5 soils of different clay and organic carbon content(14), and a Koc of 4100 was measured for natural estuarine colloids(12). After a release of petroleum derived fuels or solvents, nonaqueous phase liquids are retained in the pore space of soils or as a thin film. Soils contaminated with residual hydrocarbons adsorb napthalene to a much greater extent, (nearly 2 orders of magnititude greater in Lincoln sand) than in natural soil(13). Partitioning to the residual hydrocarbons occurred independently of that to the soil organic carbon. While sorption decreased somewhat as a result of weathering, high retention persisted after extensive weathering. Although it adsorbs to aquifer material(10), in simulations of groundwater transport systems and rapid infiltration sites, and in field studies, naphthalene frequently appears to infiltrate(4-9). Partitioning to dissolved organic matter can reduce the apparent partitioning to soil and facilitate transport in soil(15). A half-life of 65 hr due to sediment adsorption in a flowing river of 1 m depth and 0.5 m/sec has been predicted(11). In a variety of surface waters only 0.1-0.8% of the napthalene was sorbed to particulate matter(11). [R162] VWS: *The laboratory determined half-life for the evaporation of naphthalene from water 1 m deep with a 1 m/sec current velocity and a 3 m/sec wind speed is 4.1-5 hr(1,2). In the case of naphthalene the rate of volatilization is much more sensitive to the current velocity and a 10 fold decrease in current to 0.1 m/sec will increase the half-life to 32 hours whereas 10 fold decrease in wind speed to 0.3 m/sec will increase the half-life to 11 hr(1). The rate of evaporation of naphthalene in jet fuel from water relative to the oxygen reaeration rate ranged from 0.2 to 0.5 which when combined with typical reaeration rates for natural bodies of water(4) give a half-life for evaporation of 50 and 200 hr in a river and lake respectively(3). Estimated volatilization half-lives from a soil containing 1.25% organic carbon were 1.1 day from 1 cm soil depth and 14.0 days from 10 cm soil depth(5). In moisture-saturated soil as in the case of flooded soil, volatilization may not be important(6). [R163] WATC: *DRINKING WATER: Napthalene measured as follows: Washington DC tap water - 1 ppb(1). 3 New Orleans area drinking water plants sampled - detected but not quantified(2). 12 Great Lake municipalities drinking water supplies - 0.9 to 1271 ppb, with levels being generally higher in winter(3). Cincinnnati, OH, Feb 1980 - 5 parts/trillion(5). Drinking waters - up to 1.4 ppb(4). 2 representative US cities, tap water - not detected, 14% frequency in source for city A - 7.8 ppb avg, 23% frequency in source for City B - 23.0 ppb avg(6). [R164] *DRINKING WATER: Naphthalene measured as follows: Rhine River water, the Netherlands, bank-filtered tap water - 100 parts/trillion(1). Kitakyushu area Japan - 2.2 ppb(2). Zurich Switzerland, tap water - 8 parts/trillion(3,6). Ottawa, Ontario - January, 1978 - 4.8 parts/trillion, February, 1978 - 6.8 parts/trillion(4). 4 of 5 Nordic tap water, - 1.2 to 8.8 parts/trillion(5). [R165] *GROUNDWATER: Naphthalene was detected as follows: Hoe Creek, NY, underground coal gasification site, 2 aquifers sampled 15 months after gasification complete - 380 to 1800 ppb(1). Samples from East Anglica, England chalk aquifer 10, 100-120, and 210 m distance from gasoline storage - 150, 30, and 0.1 ppb resp(2). 3 of 4 rapid infiltration sites, Fort Polk, LA - 0.03 to 0.22 ppb, 1 of 4 sites not quantified(3). Zurich, Switzerland - not detected(4). Gas Works Park, Seattle, WA - sites of coal and oil gasification plant that ceased operation in 1956: 9 of 15 wells positive for napthalene above the 0.005 mg/L detection limit, 0.02-12 mg/L(5). Representive, highly impacted groundwater at five sanitary landfill sites in southern Ontario: < 0.2, 19, 21, 60, and 61 ppb(6). Detected in groundwater near Falmouth, MA in infiltration site for secondary effluent used since 1936(7). [R166] *SURFACE WATER: Lake Michigan - a trace detected at 5 of 9 sites(7). Delaware River studies ranged from a trace to 0.9 ppb(1,5). Ohio River between Wheeling and Evansville (5 samples) and 3 tributaries - detected at a detection limit of 0.1 ppb(3). Charles River, Boston - detected at a detection limit of 0.1 ppb(4). Lower Tennessee R, Calvert City, KY - 30.4 ppb (water and sediment)(6). Unspecified US river near industrial sites - 6 to 10 ppb(2). Natural waters - up to 2 ppb(8). MacKenzie River, Canada - six sites along 1200 km length sediment(10). 0.67 mi downstream from site of a tire fire 27 ppb(9). [R167] *SURFACE WATER: Lake Zurich, Switzerland - surface water - 8 parts/trillion: water at 30 m depth - 52 parts/trillion(2-3). Kitakyusku area, Japan - detected, not quantified in river water(1). River Glatt, Switzerland - detected, not quantified(4). Mississippi River during summer 1980 - 4 - 34 ppb(5). [R168] *SEAWATER: Napthalene measured as follows: Gulf of Mexico - unpolluted (anthropogenic influence) 0.2 parts/trillion mean(2). Cape Cod, MA - Vineyard Sound - 0.5/35 parts/trillion, 12 parts/trillion avg and results displayed a strong seasonal pattern, highest concentrations noted in winter which suggests a source from heating fuels(4). Chemotaxis Dock, Vineyard Sound MA, Dec 78 to Mar 79 - 0 to 27 parts/trillion, with low levels reported in Dec and Jan; high level reported in February, correlating with a late heavy snowfall, indicating runoff or atmospheric inputs(5). Dohkai Bay, Japan - area polluted by domestic and industrial waste as well as airborne particulates - detected, not quantified(3). Kitakyusku area, Japan - detected, not quantified(1). Estuary sites in Texas adjacent to offshore shallow water multiwell platform 2.1 ppb; 10 m from platform 54.7 ppb(6). [R169] EFFL: *Industrial effluents- up to 3200 ppb, discharges from sewage treatment plants - up to 22 ppb(1). Water sample from a stream running through an oil tank farm, Knoxville TN - 8 ppb(2) tire manufacturing plant wastewaters - 100 ppb(2,4). Spent chlorination liquors from bleaching of sulfite pulp - 0.8 - 2.0 g/ ton pulp(9). Bekkelaget Sewage treatment plant, Oslo, Norway, secondary sewage water effluent - 88 parts/trillion (dry period, Nov, 1979), 303 parts/trillion (dry period, spring, 1980), 1504 parts/trillion (after rainfall, summer, 1980)(3). Gas phase emission rates, diesel trucks - 7.4 mg/km (filtered), 9.2 mg/km (nonfiltered), gasoline-powered vehicles - 8.6 mg/km (filtered), 8.1 mg/km (unfiltered)(5). 2 representative USA cities, sewage treatment plant influent, city A - 33% frequency, 13 ppb avg, city B - 67% frequency, 14.8 ppb avg; city B effluent - not detected(6). Industries with mean treated wastewater concentrations greater than 200 ppb - paint and ink formulation, electrical/electronic components, auto and other laundries, iron and steel manufacturing ( < 920 ppb)(7). Maxey Flats, KY and West Valley, NY - trench leachate - 0.12 to 0.28 ppm (3 of 3 trenches pos) and 0.46 to 1.7 ppm (2 of 3 pos)(8). [R170] SEDS: *Detected in only 1 sediment sample from an industrial location on an unspecified USA river(1). Royal Botanical Gardens, Hamilton, Ontario - 2.0 ppb in pond sediment(2). Lower Tennessee River, Calvert, KY - 30.4 ppb water and sediment(3) Kitakyusku area, Japan - detected in sediment, not quantified(4). Dohkai Bay, Japan, area polluted by domestic and industrial waste and airborne particulates - detected in sediment, not quantified(5). Saudafjord, Norway, suggested sources - ferro alloy smelter, sediment from 6 sites, station 1 closest to smelter - 483.8 ppb (0-2 cm), 685.9 ppb (2-4 cm), 278.7 ppb (4-6 cm), 328.3 pb (6-8 cm), station 2,2479.5 ppb (0-2 cm), station 3,48.3 ppb (0-2 cm), station 4,10.9 ppb (4-6 cm), not detected stations 5 and 6 (furthest away)(6). South Texas coast, samples taken following the blowout of an exploratory oil well (Ixtoc-1) - detected at trace amount in 3 of 3 samples(7). Cascoe Bay Maine, detected in 1 of 30 samples at 113 ppb(8). Windsor Cove, Buzzards Bay, MA, 0-6 cm - 9.2 ppm (Oct 74), 0.63 ppm (May 75), 0.11 ppm (June 1977), oil spill occurred October 1974(9). Wild Harbor, Buzzards Bay, MA - detected not quantified immediately following September 1969 oil spill, not detected from 1971 to 1976(9). Sediments from various fjords in Norway, 0-5 cm samples: Saudafjord, 800 m from ferro alloy plant - 2,870 ppb; Sorfjord, Tyssedal, 500 m from aluminum plant 3 and 5 km from zinc and calcium carbide plants resp - 220 ppb; Sorfjord, Hovland, 15, 18 and 20 km from above industries - 41.5 ppb. Brofjord, 800 m from petroleum refinery - 70.0 ppb; Oslofjord, Bunnefjord, close to city of Oslo - 53.6 ppb; Oslofjord, Lysakerkilen, close to city of Oslo 45.8 ppb; North Sea 500 m from oil field - 31.6 ppb; North Sea, 10 km from oil field - 4.32 ppb, and Framvaren, a permanent anoxic fjord with no potential local pollution but high PAH values - 292 ppb (0-10 cm), 272 ppb (14-20 cm)(10). March Point, Strait of Juan de Fuca and Northern Puget Sound, unpolluted area, baseline study - not detected in two week sampling intervals(11). Soil near aluminum reduction plant - 48.3 ppn; unpolluted soil - 46.2 ppb; soil under a March - 57.7 ppb(12). Northwest region of Arabian Gulf, region with many oil refineries and heavy oil tanker traffic (29 stations) 0.01 - 7.14 ppb(13). [R171] ATMC: *RURAL: Narragansett Bay, RI coastal area - 3.18 pg/cu m (particulates > 1.0 um), 49.10 pg/cu m (very fine particulates < 1.0 um)(1). Remote site in the Mediterranean Sea at Corsica (14-24 hrs samples) 11.69-38.94 ug/cu m(18). URBAN/SUBURBAN: 11 US samples 180 parts/trillion median, 11-480 parts/trillion range(5). Kingston RI - 31.1 pg/cu m (particulates > 1.0 um), 27.90 pg/cu m (very fine particulates < 1.0 um)(1). USSR industrial cities and Leningrad - detected not quantified(2,3). Providence, RI, industrialized urban - 248.0 pg/cu m (particulates > 1.0 um), 100.70 pg/cu m (very fine particulates < 1.0 um)(1). Lillestrom and Oslo Norway - detected, not quantified(4). Air in residential areas near aluminum reduction plant - 11.3 - 117 ng/cu m(14-15). Three large South African cities - detected not quantified(6). Paris, France - 730-2100 parts/trillion, Zurich Switzerland - 320 parts/trillion(8). Torrance, CA during a pollution episode - 2.9 - 3.3 ug/cu m(10). Glendora, CA during air pollution episode - 3.1 ug/cu m av daytime, 4.3 ug/cu m av nighttime(17). Chicago area homes - 43% frequency in indoor air, 21% frequency of occurrence in outdoor air(9). Northern Italy - indoor air, 11 ug/cu m (mean), 70 ug/cu m (max); outdoor air, 2 ug/cu m (mean), 11 ug/cu m (max)(11). SOURCE DOMINATED: US source dominated areas; 95 samples 400 parts/trillion median, 16000 parts/trillion max.(5). Allegheny Mt Tunnel, Pennsylvania Tpk. - 3.1 to 10.0 ug/cu m (592-1910 parts/trillion)(filtered), 3.5 to 10.1 ug/cu m (nonfiltered), low values correspond to low traffic volume(7). Air near hazardous sites - 0.1 - 0.88 ppb (mean), 5.2 ppb (max), near landfill, 0.08 ppb (mean), 0.31 ppb (max)(12). Gaseous effluents from coal-fired power plants under near-ideal conditions - 0.01 - 1.8 ug/cu m(13). INDOOR AIR: 12 Canadian homes 1-77 ug/cu m, 13.9 ug/cu m, mean, whereas ambient air was ND-5 ug/cu m, 2.0 ug/cu m, mean(16). [R172] *Providence, RI: Air levels of naphthalene: vapor: 0.0001 ug/cu m, particulate: 0.0025 ug/cu m; Kingston, RI: vapor: 0.0003 ug/cu m, particulate: 0.0003 ug/cu m; Narragansett Bay, RI: vapor: 0.00005 ug/cu m, particulate: 0.000003 ug/cu m. [R173] *PARTICLE-SIZE DISTRIBUTION STUDIES OF POLYCYCLIC AROMATIC HYDROCARBONS, MANY OF WHICH ARE CARCINOGENIC, IN CITY AND SUBURBAN ATMOSPHERES INDICATE THAT THESE COMPOUNDS ARE ASSOCIATED WITH PARTICLES HAVING MASS MEDIAN EQUIVILANT DIAMETER VALUES OF ABOUT 0.5 UM. [R174] FOOD: *Of 27,065 samples of foods collected and analyzed in 10 state laboratories in 1988 and 1989, only 2 contained naphthalene and neither of these was of regulatory significance(1). [R175] PFAC: PLANT CONCENTRATIONS: *Southern Norway area, various species marine algae - not detected to 2109 ppb(1). [R176] *Occurs naturally in the essential oils of the roots of Radix and Herba ononidis [R115, 3333] FISH/SEAFOOD CONCENTRATIONS: *Pike from Detroit River, and Carp and Pike from Hamilton Harbor - detected, not quantified, Lake Trout from Lake Superior - detected, not quantified, estimated conc range detected - 0.01 to 5 ppm(1). Cepangopaludina chinensis, Royal Botanical Gardens, Hamilton Ontario - < 0.01 ppb(2). Polycheates 4.2 to 5.5 ppm, clam 0.43 ppm(3). Mussels, Saudalfjord, Norway suggested source - ferro alloy smelter, 4 stations - not detected(4). Mussels sampled near the Bekkelaget sewage treatment plant, Oslo, Norway - not detected(5). Southern Norway Coast, mussels, 7 of 9 samples pos, trace to 516 ppb; various invertebrates ND to 241 ppb, results not separable from methyl naphthalene(6). Mussels and oysters from more than 100 US east, west, gulf coast sites, Woods Hole - 2.8 ppb avg, USEPA Natl Res Lab, Narragansett - 4.8 ppb avg Univ New Orleans, Center for Bio-organic Studies 96 ppb avg(7). Several species Nigerian freshwater fish species, traditionally smoked - 1.75 to 7.88 ppb, traditionally solar dried - 0.96 to 7.38 ppb, oven dried - 0.19 to 4.42 ppb(8). March Point mussels, Strait of Juan de Fuca and Northern Puget Sound, unpolluted area baseline study, 3 of 6 two week interval samples pos, 3.3 to 13 ppb(9). Commencement Bay in Puget Sound, WA, 1982 survey - highest level in bottom fish 0.51 ppm(10). Not detected in composite samples of fish from Great Lakes harbors and tributary mouths in 1980-1981 survey(11). [R177] MILK: *Mother's milk from 4 USA urban areas - detected in 6 of 8 samples quantified. [R178] OEVC: *Coke oven: concentrations of naphthalene in vapor: 11.35-1,120 ug/cu m, in particulate 0-4.40 ug/cu m. [R179] *Five municipal refuse incinerator fly ashes; ND to 460 ppb; 3 municipal refuse incinerator mixed fly ash-bottom ash 1300 - 28,000 ppb(1). [R180] RTEX: *Coal tar pitch volatiles ... may contact the eyes. /Coal tar pitch volatiles/ [R34] *Exposure of up to 220 ppm (vapor) and 4.4 ug/cu m (particulates) are possible in industrial situations(1). Naphthalene exposed workers include those who make beta naphthol, celluloid, dye chemicals, fungicide, hydronaphthalene, lampblack, phthalic anhydride, smokeless powder as well as those who work with/in coal tar, moth repellants, tanneries, textile chemicals, aluminum reduction plants(1). Air levels of naphthalene in an aluminum reduction plant - 0.72-311.3 ug/cu m (0.1-59.5 ppb)(vapor), 0.090-4.00 ug/cu m (particulate); coke oven 11.35-1,120 ug/cu m (2-214 ppb)(vapor), 0-4.40 ug/cu m (particulate)(1). Air conc in different work areas of silcon carbide plant - 1.3 - 58 ug/cu m(2). Results of field trials on average exposure to particulate (vapor phase) naphthalene in specified operation in certain industries in ug/cu m: paving/ roofing/ steel/ silicon carbide 11.43 (0.08); refractory brick 16.30 (-); silicon carbide 75.40 (0.01); aluminum refinery 1111.4 (0.52)(3). NIOSH (NOES Survey 1981-1983) has statistically estimated that 23,092 workers may be exposed to naphthalene in the USA(4). [R181] *Individuals with potential exposure to naphthalene include: beta-naphthol makers; celluloid makers; coal tar workers; dye chemical makers; fungicide makers; hydronaphthalene makers; lampblack makers; moth repellant workers; phthalic anhydride makers; smokeless powder makers; tannery workers; textile chemical workers; aluminum reduction plant workers. /From table/ [R182] *Perhaps the greatest hazard to the worker is the potential for operating or maintenance personnel to be accidentally splashed with hot molten naphthalene while taking samples or disassembling process lines. [R48] *Humans are primarily exposed to naphthalene from ambient air particularly in areas with heavy traffic, near petroleum refineries, coal tar distillation facilities or where evaporative losses from the storage, transport, transfer or disposal of fuel oil occurs. Another source of exposure is from tobacco smoke. Although data is scanty, moderate exposure may occur from some supplies of drinking water. (SRC) *POLYCYCLIC AROMATIC HYDROCARBON (PAH) CONTENT IN AIR OF 10 FERROUS AND NONFERROUS FOUNDRIES WAS STUDIED. CERTAIN OCCUPATIONS REPORTED TO HAVE A HIGH RISK OF LUNG CANCER, SUCH AS MOLDERS, CASTERS AND CRANE MEN, WERE ASSOCIATED WITH HIGH CONCENTRATIONS OF PAH EXPRESSED AS PERCENTAGE OF TOTAL SUSPENDED PARTICULATE. THIS RESULT WAS NOT STATISTICALLY SIGNIFICANT. [R183] *GLASS CAPILLARY GAS CHROMATOGRAPHY SHOWED THAT WORKERS IN COKE PLANT WERE EXPOSED TO 5 TO 1000 MG POLYCYCLIC AROMATIC HYDROCARBONS (PAH)/CU M AIR (INCL ACENAPHTHYLENE). PARTICULATE MATTER CONTAINS 98% RESPIRABLE PAH. [R184] *Workers ... exposed to coal tar, mineral oil, and petroleum waxes. /Polynuclear aromatic hydrocarbons/ [R185] AVDI: *AIR INTAKE: (assume 0.18 ppb vapor) 19 ug; WATER INTAKE: (assume 0.001-2 ppb) 0.002-4 ug(SRC). BODY: *Mother's milk from 4 USA urban areas - detected in 6 of 8 samples positive(1). [R178] *HUMAN ADIPOSE TISSUE CONCENTRATIONS: A National Human Adipose Tissue Survey (NHATS) by EPA for fiscal year 1982 detected naphthalene in wet adipose tissue with a frequency of 40% and conc range < 9 ppb - 63 ppb(1). [R186] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +250 ppm [R31, 220] ADI: *The Ten-day Health Advisory (HA) for the 10 kg child is calculated as ... 0.53 mg/l (rounded to 0.5 mg/l). [R187] *The Longer-term Health Advisory (HA) for a 10 kg child is calculated as ... 0.357 mg/l (rounded to 0.4 mg/l). ... The Longer-term Health Advisory for a 70 kg adult is calculated as ... 1.249 mg/l (rounded to 1 mg/l). [R188] *The Reference Dose (RfD), formerly called the Acceptable Daily Intake (ADI), /was determined to be/ 0.00357 mg/kg/day (rounded to 0.004 mg/kg/day). ... The Drinking Water Equivalent Level (DWEL) /was determined to be/ 0.1249 mg/l (rounded to 0.1 mg/l). ... The Lifetime Health Advisory for a 70 kg adult /was calculated as/ 0.02498 mg/l (rounded to 0.02 mg/l). [R189] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 10 ppm (50 mg/cu m). [R190] +Vacated 1989 OSHA PEL TWA 10 ppm (50 mg/cu m); STEL 15 ppm (75 mg/cu m) is still enforced in some states. [R31, 368] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (50 mg/cu m). [R31, 220] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 15 ppm (75 mg/cu m). [R31, 220] TLV: +8 hr Time Weighted Avg (TWA): 10 ppm; 15 min Short Term Exposure Limit (STEL): 15 ppm, skin. [R65] +A4; Not classifiable as a human carcinogen. [R65] OOPL: *West Germany: 10 ppm; East Germany and USSR: 4 ppm [R191] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Naphthalene is included on this list. [R192] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 20 ug/l [R193] STATE DRINKING WATER STANDARDS: +(NJ) NEW JERSEY 300 ug/l [R193] STATE DRINKING WATER GUIDELINES: +(ME) MAINE 25 ug/l [R193] +(MN) MINNESOTA 300 ug/l [R193] +(WA) WASHINGTON 14 ug/l [R193] +(WI) WISCONSIN 40 ug/l [R193] +(FL) FLORIDA 6.8 ug/l [R193] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. [R194] +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R195] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R196] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Naphthalene is included on this list. [R197] RCRA: *U165; As stipulated in 40 CFR 261.33, when naphthalene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R198] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Naphthalene is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0022; Pesticide type: Insecticide; Registration Standard Date: 09/01/81; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Naphthalene; Data Call-in (DCI) Date(s): 05/06/91, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R199] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Macro-reticular resins. XAD- 2 and XAD- 7. [R86, 896] *NIOSH Method 5506. Analyte: Napthalene. Matrix: Air. Sampler. Filter plus sorbent (2 um, 37 mm polytetrafluoroethylene plus washed XAD-2,100 mg/50 mg). Flow Rate: 2 l/min: Sample Size: 400 liter. Shipment: Transfer filters to culture tubes; wrap sorbent and culture tubes in aluminum foil, ship @ 0 deg C. Sample Stability: Unknown; protect from heat and UV radiation. [R200, p. 5506-1] *NIOSH Method 5515. Analyte: Naphthalene. Matrix: Air. Sampler: Filter plus sorbent (2 um, 37 mm PTFE and washed XAD-2, 100 mg/50 mg). Flow Rate: 2 l/min: Sample Size: 400-liters. Shipment: Transfer filters to culture tubes; wrap sorbent and culture tubes in aluminum foil; ship @ 0 deg C. Sample Stability: Unknown, protect from heat and UV radiation. [R200, p. 5515-1] *NIOSH Method S292. Analyte: Naphthalene. Matrix: Air. Procedure: Adsorption on charcoal and description with carbon disulfide. Flow Rate: 1 l/min. Sample Size: 200 liters. [R201] ALAB: *Gas-Liquid chromatography is used extensively to determine the naphthalene content of mixtures. Naphthalene can be separated easily from thionaphthene, the methyl- and dimethylnaphthalenes, and other aromatics. Analysis of the various other impurities may require the use of high resolution capillary columns. Other tests that are routinely performed on commercial grades of naphthalene include: evaporation residues (ASTM D 2232), APHA color (ASTM D 1686), water (ASTM D 95), and acid-wash color (ASTM D 2279). Methods to measure sulfur content are the oxygen-bomb combustion method (ASTM D 129), the lamp combustion method (ASTM D 1266), and the Raney nickel reduction technique. [R48] *EPA Method 610: A high performance liquid chromatography method for the analysis of naphthalene in municipal and industrial discharges, consists of a stainless steel column, 25 cm x 2.6 mm ID, with reverse phase HC-ODS Sil-X, 5 micron size. with a fluorescence or UV detector. Isocratic elution is done for 5 min using acetonitrile/water (4:6), then linear gradient elution to 100% acetonitrile over 25 min at 0.5 ml/min flow rate. Inject 5 to 25 ul of the sample extract or std into the HPLC using a high pressure syringe or a constant volume sample injection loop. This method has a detection limit of 1.8 ug/l and an overall precision of 0.41 times the average recovery + 0.74, over a working range of 0.1 to 425 ug/l. [R202, (7/1/91)] *EPA Method 1625. Isotope Dilution Capillary Column Gas Chromatography/Mass Spectrometry method for the determination of semivolatile organic compounds in municipal and the industrial discharges. By adding a known amount of a labeled compound to every sample prior to purging, a correction for recovery of the pollutant can be made. If labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, for the labeled, unlabeled naphthalene the method has a minimum detection level of 10 ug/l, and 10 ug/l, respectively and an initial precision of 20 ug/l, and 39 ug/l, respectively. The accuracy ranges for the labled, unlabeled compound are 80 to 139 ug/l, and 28 to 157 ug/l, respectively. The labeled compound recovery is 14 to 305%. [R202, (7/1/91)] *AN ANALYTICAL METHOD INVOLVING A SINGLE TLC SEPARATION OF THE CYCLOHEXANE-SOLUBLE FRACTION OF AIRBORNE PARTICULATE MATTER INTO 3 POLYCYCLIC AROMATIC HYDROCARBON FRACTIONS AND 1 ALIPHATIC HYDROCARBON FRACTION SUITABLE FOR GLC ANALYSIS IS DEVELOPED AND APPLIED. THE METHOD IS SIMPLE, RAPID AND SUITABLE FOR ROUTINE ANALYSIS OF THESE COMPOUNDS IN AIRBORNE PARTICULATE MATTER. /POLYCYCLIC AROMATIC HYDROCARBONS/ [R203] *A TLC/HPLC (HIGH PRESSURE LIQUID CHROMATOGRAPHY) PROCEDURE FOR DETERMINATION OF POLYCYCLIC AROMATIC HYDROCARBONS (PAH) OCCURRING IN ASPHALT FUMES (ADSORBED ON A PARTICULATE MATTER) IS DESCRIBED. THE METHOD IS BASED ON THE EXTRACTION OF ASPHALT FUME PARTICLES, COLLECTED ON GLASS-FIBER FILTERS, USING CARBON TETRACHLORIDE. A CLEAN UP STEP IS AIDED BY A TLC PROCEDURE ON ALUMINUM TRIOXIDE THINLAYER PLATES, USING A MIXTURE OF CYCLOHEXANE/ACETONE/ETHER AS THE MOBILE PHASE. UNDER UV-LIGHT, THE PAH ARE INDICATED AS FLUORESCENT SPOTS. SEPARATION OF THE COLLECTED PAH INTO INDIVIDUAL COMPONENTS AND THEIR IDENTIFICATION IS PERFORMED BY THE AID OF A HPLC PROCEDURE. /POLYCYCLIC AROMATIC HYDROCARBONS/ [R204] *AN INTEGRATED APPROACH COMPRISING A COMBINATION OF GLASS CAPILLARY GC, MASS SPECTROMETRY, LIQ CHROMATOGRAPHY AND UV SPECTROMETRY WAS USED FOR UNAMBIGUOUS IDENTIFICATION OF POLYNUCLEAR AROMATIC HYDROCARBON IN AIRBORNE PARTICULATES. LIQUID CHROMATOGRAPHY WITH ON-LINE UV SPECTRAL SCANNING WAS VALUABLE FOR DIFFERENTIATION OF ISOMERIC AND COELUTING PAH. THE ADVANTAGES OF THIS APPROACH OVER GC/MS ALONE WERE ILLUSTRATED. A SIMPLE, 1-STEP PROCEDURE FOR ISOLATION OF PAH BY PREPARATIVE TLC IS ALSO REPORTED. /POLYNUCLEAR AROMATIC HYDROCARBONS/ [R205] *A 4-STEP METHOD FOR THE REPRODUCIBLE ANALYSIS OF POLYNUCLEAR AROMATIC HYDROCARBONS IN SMALL QUANTITIES OF CIGARETTE SMOKE CONDENSATE (CSC) IS PRESENTED. PAH WERE ISOLATED FROM AS LITTLE AS 1 G OF CIGARETTE SMOKE CONDENSATE BY SOLVENT PARTITION, COLUMN CHROMATOGRAPHY, AND ANALYSIS GEL FILTRATION (GF). THE GEL FILTRATION ISOLATE WAS ANALYZED BY GAS CHROMATOGRAPHY. /POLYNUCLEAR AROMATIC HYDROCARBONS/ [R206] *EPA 8270. Capillary Column Gas Chromatography/Mass Spectrophotometry. This method is applicable for the determination of semivolatile organic compounds in extracts prepared from all types of solid wastes matrices, soils, and groundwater. This method is applicable to quantify most acidic, basic, and neutral organic compounds that are soluble in methylene chloride and are capable of being eluted without derivatization as sharp peaks from a capillary column (DB-5 or equivalent). Under the prescribed conditions, for naphthalene the method detection limit is 30.1 ug/l. The precision and a method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R207] *NIOSH Method 5506. Analyte: Naphthalene. Matrix: Air. Procedure: High performance liquid chromotography fluoresence/ultra violet detection. For naphthalene this method has an estimated detection of 0.25 ng/sample. The overall precision/RSD is 0.125. Applicability: The working range for naphthalene is 1 to 50 ug/cu m for a 400 liter air sample. Interferences: Any compound which elutes at the same high performance liquid chromatography retention time may interefere. [R200, p. 5506-1] *NIOSH Method 5515. Analyte: Naphthalene. Matrix: Air. Procedure: Gas chromatography, capillary column, flame ionization detector. For naphthalene this method has an estimated detection limit of 0.3 to 0.5 ug/sample. Applicability: The working range for naphthalene is 3 to 150 ug/cu m for a 400 liter air sample by high performance liquid chromatography. Interferences: Any compound which elutes at the same gas chromatography, retention time may interfere. [R200, p. 5515-1] *NIOSH Method S292. Analyte: Naphthalene. Matrix: Air. Procedure: Gas chromatography. Method Evaluation: Method was validated over the range of 19.3 to 83 mg/cu m using a 200 liter sample. Precision (CVt): 0.055. Applicability: Under the conditions of sample size (200 l) the useful range is 15 to 150 mg/cu m. Interferences: A compound with the same retention time as the analyte is an interference. [R201] *EPA Method 8100. Gas Chromatography Method for the detection of ppb levels of certain polynuclear aromatic hydrocarbons including naphthalene in solid waste. (Note: The gas chromatographic method described here cannot adequately resolve the following four pairs of compounds: anthracene and phenanthrene; chrysene and benzo(a)anthracene; benzo(b)fluoranthene and benzo(k)fluoranthene; and dibenzo(a,h)anthracene and indeno(1,2,3-cd)pyrene). Appropriate sample extraction techniques must be used prior to analysis. Detection is achieved with a flame ionization detector. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R207] *EPA Method 8250. Packed Column Gas Chromatography/Mass Spectrometry Technique for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soil, and groundwater. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride and capable of being eluted wtih derivatization as sharp peaks from a gas chromatographic packed column. Under the prescribed conditions, naphthalene has a detection limit of 1.6 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R207] *EPA Method 8310. High Performance Liquid Chromatography with UV/flame ionization detection for the determination of polynuclear aromatic hydrocarbons. Under the prescribed conditions, naphthalene has a detection limit of 1.8 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R207] *EPA Method 502.2: Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For naphthalene the method has a detection limit of 0.06 ug/l, a percent recovery of 102%, and a standard deviation of 6.3 using the photoionization detector; no results were given for the electrolytic conductivity detector. [R208] *EPA Method 503.1. Purge-and-Trap Gas Chromatography with a Photoionization Detector. The method is applicable for the determination of volatile aromatic and unsaturated organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For naphthalene the method has a detection limit of 0.04 ug/l and a relative standard deviation of 14.8%. Overall precision and method accuracy were found to be directly related to the concentration of the analyte essentially independent of sample matrix. [R209] *EPA Method 625. Gas Chromatography/Mass Spectrometry Method for the analysis of acid/base/neutral extractables including naphthalene in municipal and industrial discharges. Under the prescribed conditions for naphthalene the method has a detection limit of 1.6 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R202, (7/1/90)] CLAB: *HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (REVERSE PHASE) ANALYSIS OF POLYCYCLIC AROMATIC HYDROCARBONS IN SKIN LIPIDS. /POLYCYCLIC AROMATIC HYDROCARBONS/ [R210] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: REVIEW AND BIBLIOGRAPHY (175 PAGES): RODD ET AL, THORPE'S DICTIONARY OF APPLIED CHEMISTRY 8, 263 (1947). 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R151: (1) Fochtman EG, Eisenberg W; Treatability of Carcinogenic and Other Hazardous Organic Compounds; pp.61 USEPA-600/2-79-097 (1979) (2) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (3) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (4) Heukelekian H, Rand MC; J Water Pollut Control Assoc 23: 1040-53 (1955) (5) Van der Linden AC; Dev Biodegrad Hydrocarbons 1: 165-200 (1978) (6) Petrasek AC et al; J Water Pollut Control Fed 55: 1286-96 (1983) (7) Thomas JM et al; Appl Environ Microbiol 52: 290-6 (1986) (8) Aamand J et al; J Contam Hydrology 4: 299-312 (1989) R152: (1) Walker JD, Colwell RR; Appl Environ Microbiol 31: 189-97 (1976) (2) Van der Linden AC; Dev Biodegrad Hydrocarbons 1: 165-200 (1978) (3) Herbes SE et al; Appl Environ Microbiol 32: 244-6 (1977) (4) Herbes SE et al; pp. 113-28 in The Scientific Basis of Toxicity Assessment; Witschi H ed; Elseveir/North Holland Biomed Press (1980) (5) Lee RF; 1977 Oil Spill Conf; Amer Petrol Inst pp. 611-6 (1977) (6) Herbes SE; Appl Environ Microbiol 41: 20-8 (1981) (7) Roubal G, Atlas RM; Appl Environ Microbiol 35: 897-905 (1978) (8) Wakeham SG et al; Environ Sci Technol 17: 611-7 (1983) (9) Vaishnaw DD AND Babeu L; Bull Environ Contam Toxicol 39: 237-44 (1987) (10) Hudak JP et al; Mar Ecol Prog Ser 47: 97-102 (1988) R153: (1) Herbes SE et al; pp. 113-28 in The Scientific Basis of Toxicity Assessment; Witschi H ed; Elseveir/North Holland Biomed Press (1980) (2) Herbes SE; Appl Environ Microbiol 41: 20-8 (1981) (3) Herbes SE, Schwall LR; Appl Environ Microbiol 35: 306-16 (1978) (4) Saylor GS, Sherrill TW; Bacterial Degradation of Coal Conversion Byproducts (Polycyclic Aromatic Hydrocarbons) in Aquatic Environments; Knoxville TN pp. 90 Tenn Elnev Report No. 39535 (1981) (5) Heitkamp MA et al; Appl Environ Microbiol 53: 129-36 (1987) (6) Coover MP, Sims RC; Haz Waste Haz Mater 4: 69-82 (1987) (7) Mihelcic JR, Luthy RG; Appl Environ Microbiol 54: 1182-7 (1988) R154: (1) Ehrlich GG et al; Ground Water 20: 703-10 (1982) (2) Bouwer EJ, McCarty PL; Appl Environ Microbiol 45: 1295-9 (1983) (3) Kappeler T, Wuhrmann K; Water Res 12: 327-33 (1978) (4) Thomas JM et al; Environ Toxicol Chem 6: 607-14 (1987) R155: Kulisch GP, Vilker VL; Biotechnical Prog 7 (2): 93-8 (1991) R156: Al-Bashir B et al; Appl Microbiol Biotechnol 34 (3): 414-9 (1990) R157: (1) Zepp RG, Schlotzhauer PF; pp. 141-58 in Polynuclear Aromatic Hydrocarbons; Jones PW, Leber P ed. Ann Arbor Press Ann Arbor MI (1979) (2) Herbes SE et al; pp. 113-28 in Scientific Basis of Toxicity Assessment; Witachi H ed; Elseveir/North Holland Biomed Press (1980) (3) Callahan MA et al; Water-related Environmental Fate of 129 Priority Pollutants; pp. 95-1 to 95-20 USEPA-440/4-79-029b (1979) (4) Suzuki J et al; Bull Environ Contam Toxicol 31: 79-84 (1983) (5) Zepp RG, Scholzhauer PF; Environ Sci Technol 17: 462-8 (1983) (6) Smith JH, Harper JC; 12th Conf on Environ Toxicol; pp. 336-53 (1982) R158: (1) Atkinson R et al; Environ Sci Technol 18: 110-3 (1984a) (2) Kloepffer W et al; Chim Zig 110: 57-61 (1986) (3) Atkinson R et al; Environ Sci Technol 21: 1014-22 (1987) (4) Atkinson R et al; J Phys Chem 88: 1210-5 (1984b) (5) Atkinson R; J Phys Chem Ref Data, Monograph 1 (1989) (6) Atkinson R; Aschmann SM; Atmos Environ 21: 2323-6 (1987) R159: (1) Roubal WT et al; Arch Environ Contam Toxicol 7: 237-44 (1978) (2) Veith GD et al; J Fish Res Board Canada 36: 1040-8 (1979) (3) Southworth GR et al; Water Res 12: 973-7 (1978) (4) Geyer H et al; Chemosphere 11: 1121-34 (1982) (5) Lee RF; pp. 60-70 in Fate and Effects of Petroleum Hydrocarbons in Marine Organisms and Ecosystems Vol 6. Wolfe DA ed; (1977) (6) Eastmond DA et al; Arch Environ Contam Toxicol 13: 105-11 (1984) (7) Tarshis IB; Arch Environ Contam Toxicol 10: 79-86 (1981) (8) Callahan MA et al; Water-related Environmental Fate of 129 Priority Pollutants; pp. 95-1 to 95-20 USEPA-440/4-79-029b (1979) R160: Malins DC; Ann NY Acad Sci 298: 482-496 (1977) as cited in: Health and Welfare Canada; Polycyclic Aromatic Hydrocarbons p.37 (1979) Report No. 80-EHD-50 R161: EADIE BJ ET AL; CHEMOSPHERE 11 (2): 185-92 (1982) R162: (1) Karickhoff SW; Chemosphere 10: 833-46 (1981) (2) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (3) Schwarzenbach RP, Westall J; Environ Sci Technol 15: 1360-7 (1981) (4) Goerlitz DF; Bull Environ Contam Toxicol 32: 37-44 (1984) (5) Hutchins SR et al; Environ Toxicol Chem 2: 195-216 (1983) (6) Roberts PV et al; J Water Pollut Control Fed 52: 161-71 (1980) (7) Schwarzenbach RP et al; Environ Sci Technol 17: 472-9 (1983) (8) Piet GJ et al; Int Symp Quality of Groundwater Studies in Environ Sci 17: 557-64 (1981) (9) Rittmann BE et al; Ground Water 18: 236-43 (1980) (10) Ehrlich GG et al; Ground Water 20: 703-10 (1982) (11) Herbes SE et al; pp. 113-28 in Scientific Basis of Toxicity Assesment; Witschi H ed; Elsevier/North Holland Biomed Press (1980) (12) Wijayaratne RD, Means JC; Mar Environ Res 11: 77-89 (1984) (13) Bouchard DC et al; Chemosphere 21: 975-89 (1990) (14) Kishi H et al; Chemosphere 21: 975-89 (1990) (15) Khan AT, Tomson MB; Environ Toxicol Chem 9: 253-63 (1990) R163: (1) Southworth GR; Bull Environ Contam Toxicol 21: 507-14 (1979) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Environmental behavior of organic chemicals; McGraw Hill New York NY p. 960 (1982) (3) Smith JH, Harper JC; 12th Conf on Environ Toxicol; pp. 336-53 (1982) (4) Mill T et al; Laboratory Protocols for Evaluating the Fate of Organic Chemicals in Air and Water; p. 255 USEPA-600/3-82-022 (1982) (5) Jury WA et al; J Environ Qual 13: 573-9 (1984) (6) Bouwer EJ et al; Water Res 18: 463-72 (1984) R164: (1) Scheiman MA et al; Biomed Mass Spectrom 4: 209-11 (1974) (2) Keith LH et al; pp. 329-73 in Identification and Analysis of Organic Pollutants in Water; Keith LH ed; Ann Arbor MI Ann Arbor Press (1976) (3) Williams DT et al; Chemosphere 11: 263-76 (1982) (4) USEPA; Ambient Water Quality Criteria; Naphthalene, NTIS PB81-117707, Springfield, VA (1980) (5) Coleman WE et al; Arch Environ Contam Toxicol 13: 171-8 (1984) (6) Callahan MA et al; 8th Natl Conf Munic Sludge Manag Proc; p. 55 (1979) R165: (1) Piet GJ, Morra CF; pp.31-42 in Artificial Groundwater Recharge (Water Res Eng Ser); Huisman L, Olsthorn TN eds; Pitman Pub (1983) (2) Akiyama T et al; J UOEH 2: 285-300 (1980) (3) Grob K, Grob G; J Chromatogr 90: 303-13 (1974) (4) Benoit FM et al; Int J Environ Anal Chem 6: 227-87 (1979) (5) Kveseth K et al; Chemosphere 11: 623-39 (1982) (6) Korte F, Klein W; Ecotox Environ Safety 6: 311-27 (1982) R166: (1) Stuermer DH et al; Environ Sci Technol 16: 582-7 (1982) (2) Tester DJ, Harker RJ; Water Pollut Control 80: 614-31 (1981) (3) Hutchins SR et al; Environ Toxicol Chem 2: 195-16 (1983) (4) Korte F, Klein W; Ecotox Environ Safety 6: 311-27 (1982) (5) Turnery GL, Goerlitz DF; Ground Wat Monit Rev 10: 187-98 (1990) (6) Barker JF; Water Poll Res J Canada 22: 33-48 (1987) (7) Barber LB II et al; Environ Sci Technol 22: 205-11 (1988) R167: (1) Sheldon LS, Hites RA; Environ Sci Technol 12: 1188-94 (1978) (2) Junglclaus GA et al; Environ Sci Technol 12: 88-96 (1978) (3) Ohio R Valley Water Sanit Comm; Assessment of Water Qaulity Condition Ohio R Mainstreams 1978-9 Cincinnati OH (1980) (4) Hites RA, Biemann K; Science 178: 158-60 (1972) (5) Sheldon LS, Hites RA; Environ Sci Technol 13: 574-9 (1979) (6) Goodley PC, Gordon M; Kentucky Acad Sci 37: 11-5 (1976) (7) Konasewich D et al; States Report on Organic and Heavy Metal Contaminants in the Lake Erie, Michigan, Huron, and Superior Basins. Great Lakes Quality Board; pp. 273 (1978) (8) USEPA; Ambient Water Quality Criteria: Napthalene USEPA-440/5-80-059 (1980) (9) Peterson JC et al; Anal Chem 58: 70A-74A (1986) (10) Carey JH et al; Sci Toto Environ 97-98: 69-88 (1990) R168: (1) Akiyama T et al; J UOEH 2: 285-300 (1980) (2) Grob K, Grob G; J Chromatogr 90: 303-13 (1974) (3) Korte F, Klein W; Ecotox Environ Safety 6: 311-27 (1982) (4) Zuercher F, Giger W; Vom Wasser 47: 37-55 (1976) (5) DeLeon IR et al; Chemosphere 15: 795-805 (1986) R169: (1) Akiyama T et al; J UOEH 2: 285-300 (1980) (2) Sauer TC Jr; Org Geochem 3: 91-101 (1981) (3) Shinohara R et al; Environ Int 4: 163-74 (1980) (4) Gschwend PM et al; Environ Sci Technol 16: 31-8 (1982) (5) Mantoura RFC et al; Environ Sci Technol 16: 39-45 (1982) (6) Brooks JM et al; Environ Sci Technol 24: 1079-85 (1990) R170: (1) USEPA; Ambient Water Quality Criteria: Naphthalene; USEPA 440/5-80-059 (1980) (2) Carlson RM et al; Implications to the Aquatic Environment of Polynuclear Aromatic Hydrocarbons Liberated from Northern Great Plains Coal; pp. 156 USEPA 600/3-79-093 (1979) (3) Kveseth K et al; Chemosphere 11: 623-39 (1982) (4) Jungclaus GA et al; Anal Chem 48: 1894-6 (1976) (5) Hampton CV et al; Environ Sci Technol 17: 699-708 (1983) (6) Callahan MA et al; 8th Natl Conf Munic Sludge Manag Proc; p.55 (1979) (7) USEPA; Treatability Manual; p.I.10.15-1 to 15-5 USEPA 600/2-82-001a (1981) (8) Francis AJ et al; Nuclear Tech 50: 158-63 (1980) (9) Carlberg GE et al; Sci Total Environ 48: 157-67 (1986) R171: (1) Jungclaus GA et al; Environ Sci Technol 12: 88-96 (1978) (2) Kalas L et al; pp. 567-76 in Hydrocarbons and Halogenated Hydrocarbons in the Aquatic Environment; Afghan BK, Mackay D eds; New York Plenum Press (1980) (3) Goodley PC, Gordon M; Kentucky Acad Sci 37: 11-5 (1976) (4) Akiyama T et al; J UOEH 2: 285-300 (1980) (5) Shinohara R et al; Environ Int 4: 163-74 (1980) (6) Bjoerseth A et al; Sci Total Environ 13: 71-86 (1979) (7) Bedinger CA Jr, Nulton CP; Bull Environ Contam Toxicol 28: 166-71 (1982) (8) Larsen PF et al; Bull Environ Contam Toxicol 30: 530-5 (1983) (9) Teal JM et al; J Fish Res Board Canada 35: 510-20 (1978) (10) Sporstal S et al; Environ Sci Technol 17: 282-6 (1983) (11) Brown DW et al; Investigation of Petroleum in the Marine Environs of the Strait of Juan de Fuca and Northern Puget Sound; p. 33 USEPA-600/7-79-164 (1979) (12) Vogt NB et al; Environ Sci Technol 21: 35-44 (1987) (13) Al-Saad HT; Mar Pollut Bull 18: 248-51 (1987) R172: (1) Krstulovic AM et al; Am Lab 9: 11-8 (1977) (2) Ioffe BV et al; J Chromatogr 142: 787-95 (1977) (3) Ioffe BV et al; Environ Sci Technol 13: 864-8 (1979) (4) Thrane KE, Mikalsen A; Atmos Environ 15: 909-18 (1981) (5) Brodzinsky R, Singh HB; Volatile Organics in the Atmosphere: An Assessment of Available Data; pp. 198 SRI 68-02-3452 (1982) (6) Louw CW et al; Atmos Environ 11: 703-17 (1977) (7) Hampton CV et al; Environ Sci Technol 17: 699-708 (1983) (8) Raymond A, Guiochon G; Environ Sci Technol 8: 143-8 (1974) (9) Jarke FH et al; ASHRAE Trans 87: 153-66 (1981) (10) Arey J et al; Atmos Environ 21: 1437-45 (1987) (11) DeBortoli M et al; Environ Int 12: 343-50 (1986) (12) LaRegina J et al; Environ Prog 5: 18-27 (1986) (13) Junk GA et al; ACS Symp Ser 319 (Fossil Fuels Utilize) 109-23 (1986) (14) Vogt NB et al; Environ Sci Technol 21: 35-44 (1987) (15) Thrane KE; Atmos Environ 21: 617-28 (1987) (16) Chan CC et al; J Air Waste Manage Assoc 40: 62-7 (1990) (17) Arey J et al; Environ Sci Technol 23: 321-7 (1989) (18) Masclet P et al; Atmos Environ 22: 639-50 (1988) R173: Krstulovic AM et al; Am Lab 9:11 (1977) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene p.C-4 (Draft) (1980) R174: BUTLER JD, CROSSLEY P; SCI TOTAL ENVIRON 11 (1): 53 (1979) R175: (1) Minyard JP Jr, Roberts WE; J Off Anal Chem 74: 438-52 (1991) R176: (1) Knutzen J, Sortland B; Water Res 16: 421-8 (1982) R177: (1) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in the Lakes Erie, Michigan, Huron and Superior Basins Great Lakes Qual Board (1978) (2) Kalas L et al; pp. 567-76 in Hydrocarbons and Halogenated Hydrocarbons in the Aquatic Environment; Afghan BK, Mackay D eds; New York Plenum Press (1980) (3) Carlson RM et al; Implications to the Aquatic Environment of Polynuclear Aromatic Hydrocarbons Liberated from Northern Great Plains Coal; pp. 156 USEPA 600/3-79-093 (1979) (4) Bjorseth A et al; Sci Total Environ 13: 71-86 (1979) (5) Kveseth K et al; Chemosphere 11: 623-39 (1982) (6) Knutzen J, Sortland B; Water Res 16: 421-8 (1982) (7) Galloway WB et al; Environ Toxicol Chem 2: 395-410 (1983) (8) Afolabi OA et al; J Agric Food Chem 31: 1083-90 (1983) (9) Brown DW et al; Investigation of Petroleum in te Marine Environs of the Strait of Juan de Fuca and Northern Puget Sound; p. 34 USEPA-600/7-79-164 (1979) (10) Nicola RM et al; J Environ Health 49: 342-7 (1987) (11) DeVault DS; Arch Environ Contam Toxicol 14: 587-94 (1985) R178: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R179: Bjorseth A et al; Scand Jour Work Environ Health 4: 224 (1978) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene p.C-4 (Draft) (1980) R180: (1) Shane BS et al; Arch Environ Contam Toxicol 19: 665-73 (1990) R181: (1) USEPA; Ambient Water Quality Criteria: Naphthalene; USEPA 440/5-80-059 (1980) (2) Dufresna A et al; Am Ind Hyg Assoc J 48: 160-6 (1987) (3) Lesage J et al; Am Ind Hyg Assoc 48: 753-9 (1987) (4) NIOSH; National Occupational Exposure Survey (1989) R182: USEPA; Ambient Water Quality Criteria Doc: Naphthalene p.C-5 (Draft) (1980) R183: VERMA DK ET AL; ANN OCCUP HYG 25 (1): 17-26 (1982) R184: BJOERSETH A ET AL; SCAND J WORK, ENVIRON HEALTH 4 (3): 224 (1978) R185: USEPA; Ambient Water Quality Criteria Doc: Polynuclear Aromatic Hydrocarbons (Draft) p.C-37 (1980) R186: (1) Stanely JS; Broad Scan Analysis of the FY82 National Human Adipose Tissue Survey Speciments Vol III. Semi-volatile Organic Compounds EPA-560/5-860-037, Washington, DC USEPA pp. 148 (1986) R187: USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-13 (1990) NTIS No. PB90-259821 R188: USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-14 (1990) NTIS No. PB90-259821 R189: USEPA/ODW; Drinking Water Health Advisories for 15 Volatile Organic Chemicals p. I-16 (1990) NTIS No. PB90-259821 R190: 29 CFR 1910.1000 (7/1/98) R191: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.420 R192: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R193: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R194: 40 CFR 401.15 (7/1/90) R195: 40 CFR 116.4 (7/1/90) R196: 40 CFR 302.4 (7/1/90) R197: 40 CFR 716.120 (7/1/90) R198: 40 CFR 261.33 (7/1/90) R199: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.135 (Spring, 1998) EPA 738-R-98-002 R200: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R201: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. S292-1 R202: 40 CFR 136 R203: DAISEY JM, LEYKO MA; ANAL CHEM 51 (1): 24-6 (1979) R204: RIETZ EB; ANAL LETT 12 (12): 143-54 (1979) R205: CHOUDHURY DR, BUSH B; ANAL CHEM 53 (9): 1351-6 (1981) R206: SEVERSON RF ET AL; ANAL CHEM 48 (13): 1866 (1976) R207: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R208: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R209: USEPA; Methods for the Determination of Organic Compouds in Finished Drinking Water and Raw Source Water (1986) R210: WOLFF MS ET AL; CHEMOSPHERE 11 (6): 595 (1982) RS: 170 Record 38 of 1119 in HSDB (through 2003/06) AN: 187 UD: 200302 RD: Reviewed by SRP on 5/6/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CAPROLACTAM- SY: *AMINOCAPROIC-LACTAM-; *2-AZACYCLOHEPTANONE-; *2H-AZEPIN-2-ONE,-HEXAHYDRO-; *2H-AZEPIN-7-ONE,-HEXAHYDRO-; *EPSILON-CAPROLACTAM-; *OMEGA-CAPROLACTAM-; *6-CAPROLACTAN-; *CAPROLATTAME- (FRENCH); *CYCLOHEXANONE-ISO-OXIME-; *EPSYLON-KAPROLAKTAM- (POLISH); *HEXAHYDRO-2-AZEPINONE-; *HEXAHYDRO-2H-AZEPIN-2-ONE-; *HEXAMETHYLENIMINE,-2-OXO-; *6-HEXANELACTAM-; *HEXANOIC-ACID,-6-AMINO-,-CYCLIC-LACTAM-; *HEXANOIC-ACID,-6-AMINO-,-LACTAM-; *1,6-HEXOLACTAM-; *E-KAPROLAKTAM- (CZECH); *2-KETOHEXAMETHYLENIMINE-; *NCI-C50646-; *2-OXOHEXAMETHYLENIMINE-; *2-PERHYDROAZEPINONE- RN: 105-60-2 MF: *C6-H11-N-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... Catalytic hydrogenation of phenol to cyclohexanone, reaction with ammonia to cyclohexanone oxime with ammonia to cyclohexanone with Beckmann rearrangement with sulfuric acid catalyst; catalytic oxidation of cyclohexane with cyclohexanone, reaction with hydroxylamine sulfate and ammonia to cyclohexanone oxime followed by sulfuric acid catalyzed Beckmann rearrangement ... . [R1] *UV-catalyzed reaction of cyclohexane with nitrosyl chloride to cyclohexanone oxime hydrochloride, followed by Beckmann rearrangement [R1] *Catalytic oxidation of cyclohexane to cyclohexanol, reacting with peracetic acid to form caprolactone, and further reaction with ammonia. [R1] *... BY MELTING EPSILON-AMINO-N-CAPRYLIC ACID FOLLOWED BY VACUUM DISTILLATION ... FROM TOLUENE BY OXIDATION ... FOLLOWED BY HYDROGENATION /IN ITALY/ ... BY PHOTOCHEMICAL NITROSATION OF CYCLOHEXANE /IN JAPAN/ ... [R2] IMP: *Moisture-0.10% max; iron (as Fe) 0.5 ppm max; volatile bases (as ammonia 5 ppm max; cyclohexanone oxime 10 ppm max [R3, p. V4 205] FORM: *Flake; molten [R1] MFS: *Allied-Signal, Inc., Hq, 101 Columbia Rd., Morristown, NJ 07962-1057, (973)455-2000; AlliedSignal Polymers; Production site: Hopewell, VA 23860 [R4] *BASF Corp, Hq, 3000 Continental Drive - North, Mount Olive, NJ 07828-1234; Chemicals Division, 3000 Continental Drive - North, Mount Olive, NJ 07828-1234, (973) 426-2600; Fiber intermediates; Production site: Freeport, TX 77541 [R4] *DSM Chemicals North America, Inc., Hq, 1 Columbia Nitrogen Road, P.O. Box 2451, Augusta GA 30903, (706) 849-6600; Production site: Augusta, GA 30903 [R4] OMIN: *MISC APPLICATIONS FOR CAPROLACTAM ARE AS REACTIVE ADDITIVE FOR FLOOR POLISHES AND IN SPECIAL COATINGS, BRUSH BRISTLES AND TEXTILE STIFFENERS. [R5] *ALLIED'S PRODUCTION IS PHENOL-BASED. OTHERS USE CYCLOHEXANE AS FEEDSTOCK; NIPRO IS 100% MERCHANT; BADISCHE AND ALLIED USE A PORTION OF OUTPUT FOR NYLON-6 PRODUCTION [R6] USE: *Mfr synthetic fibers of the polyamide type (Perlon); solvent for high mol wt polymers [R7] *Manufacture of synthetic fibers (especially nylon 6), plastics, bristles, film, coatings, synthetic leather, plasticizers and paint vehicles, cross-linking agent for polyurethanes, synthesis of amino acid lysine. [R1] *US FDA PERMITS USE OF CAPROLACTAM ETHYLENE-ETHYL ACRYLATE GRAFT POLYMERS AS COMPONENT OF SIDE SEAM CEMENTS INTENDED FOR USE IN CONTACT WITH FOOD ... [R5] CPAT: *93% FOR NYLON 6 FIBERS; 7% FOR NYLON 6 PLASTICS AND FILMS (1973) [R8] *86.4% NYLON-6 FIBERS, INCL MONO-FILAMENT; 9.6% NYLON-6 RESINS AND FILM; 3.7% EXPORTS; 0.3% MISC (1984) [R6] *CHEMICAL PROFILE: Caprolactam. Nylon 6 fibers, including monofilament, 87%; nylon 6 resins and film, 10%; exports, 3%. [R9] *CHEMICAL PROFILE: Caprolactam. Demand: 1985: 1,021 million lb; 1986: 1,070 million lb; 1990 /projected/: 1,200 million lb. [R9] *CHEMICAL PROFILE: Caprolactam. Nylon 6 fibers, including monofilament, 87%; nylon 6 resins and film, 7%; exports, 1%. [R10] *CHEMICAL PROFILE: Caprolactam. Demand: 1988: 1,260 million lb; 1989: 1,265 million lb; 1993 /projected/: 1,460 million lb. (Includes exports, but not imports, which totaled 24 million lb of crude material last year.) [R10] *(1997) 1.57X10+9 lbs; (1998) 1.60X10+9 lbs; (2002) 1.76X10+9 lbs (includes exports) [R11] *Nylon 6 fibers, including monofilament, 80 percent; engineering resins and film, 20 percent. [R11] PRIE: U.S. PRODUCTION: *(1972) 2.91X10+11 GRAMS [R8] *(1984) 4.68X10+11 g [R12] *(1988) 1.3X10+0 LBS [R13] *(1990) 1.38 billion lb [R14] *(1991) 1.28 billion lb [R15] *(1992) 1.38 billion lb [R16] *(1993) 1.36 billion lb [R16] *(1998) 1.72X10+9 lbs/yr capacity [R11] U.S. IMPORTS: *(1972) 2.74X10+10 GRAMS [R8] *(1983) 8.63X10+8 g [R17] *(1996) 5.6X10+7 lbs [R11] U.S. EXPORTS: *(1972) 9.13X10+9 GRAMS [R8] *(1984) 2.68X10+10 g [R18] *(1996) 1.83X10+8 lbs; averaged 184 million pounds annually in the 1992-1996 period. [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Hygroscopic leaflets from petroleum ether [R7]; *White, crystalline solid or flakes ... [Note: Significant vapor concentrations would be expected only at elevated temperatures]. [R19, 50]; *White flakes or fused [R1] ODOR: *... Unpleasant odor ... [R19, 50] TAST: *UNPLEASANT [R20, 1979)293] BP: *270 deg C [R21] MP: *69.3 deg C [R21] MW: *113.16 [R7] DEN: *Specific gravity: 1.02 at 75 deg C/4 deg C (liq) [R7] HTC: *-31,900 J/g (liquid @ 25 deg C) [R3, p. V4 828] HTV: *116 cal/g [R1] SOL: *Soluble in chlorinated solvents, petroleum distillate, and cyclohexene. [R1]; *Freely sol in methanol, ethanol,tetrahydrofurfuryl alc; ether, dimethylformamide, sol in chlorinated hydrocarbons, cyclohexene, petroleum fractions [R7]; *Soluble in benzene, ethanol, and chloroform [R21]; *In water, 5.25X10+6 mg/l @ 25 deg C. [R22] SPEC: *MAX ABSORPTION: 198 NM (E= 686, 1%, 1 CM) [R23]; *IR: 1228 (Coblentz Society Spectral Collection) [R24]; *UV: 6-91 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R24]; *NMR: 6492 (Sadtler Research Laboratories Spectral Collection) [R24]; *MASS: 145 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R24] VAPD: *3.91 (air=1) [R25] VAP: *1.9X10-3 mm Hg at 25 deg C [R26] VISC: *9 cP @ 78 deg C [R7] OCPP: *HEAT OF FUSION: 29 CAL/G; HYGROSCOPIC [R27] *Density: 1.05 @ 25 deg C/4 deg C /70% aq soln/ [R7] *HYDROLYSED BY STRONG MINERAL ACIDS, GIVING AMINO ACIDS [R28, 91] *Index of refraction: 1.4965 @ 31 deg C/D; 1.4935 @ 40 deg C/D /70% aq soln/ [R7] *Vapor pressure: 6 mm Hg @ 120 deg C [R29] *BP: 180 deg C @ 50 mm Hg [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Strong oxidizers, (acetic acid + dinitrogen trioxide). [R19, 50] *During preparation of the N-nitroso derivative from the lactam in acetic acid solution, the treatment with dinitrogen trioxide must be very effectively cooled to prevent explosive decomposition. [R30] DCMP: *When heated to decomposition it emits toxic fumes /nitrogen oxides/. [R31] SERI: *On direct contact, vapors irritate eyes, nasal passages, and skin. [R32] *A skin and eye irritant. [R31] EQUP: *WORKERS SHOULD BE SUPPLIED WITH SUITABLE PROTECTIVE CLOTHING INCL ... GLOVES AND EYE-WEAR; RESP PROTECTIVE EQUIPMENT MAY BE NECESSARY. [R33, 1094] *Wear appropriate personal protective clothing to prevent skin contact. [R19, 51] *Wear appropriate eye protection to prevent eye contact. [R19, 51] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *ALL VESSELS AND PIPING SHOULD BE REGULARLY CHECKED FOR LEAKS ... EXHAUST VENTILATION SHOULD BE INSTALLED. [R33, 1094] *CONCN OF.../60 MG/CU M SHOULD/ BE AVOIDED, AND HENCE WORKSHOPS SHOULD BE EFFECTIVELY VENTILATED. [R28, 92] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R19, 51] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R19, 51] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R19, 51] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Controlled incineration (oxides of nitrogen are removed from the effluent gas by scrubbers and/or thermal devices). Also caprolactam may be recovered from caprolactam still bottoms or nylon waste. Recommendable method: Incineration. [R34] *The following wastewater treatment technologies have been investigated for caprolactam: biological treatment. [R35] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of caprolactam were available. There is evidence suggesting a lack of carcinogenicity of caprolactam in experimental animals. Overall evaluation: Caprolactam is probably not carcinogenic to humans (Group 4). [R36] +A4. Not classifiable as a human carcinogen. [R37] ANTR: *Basic Treatment: Establish a patent airway. Suction if necessary. Encourage patient to take deep breaths. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Irritating materials/ [R38, 137] *Advanced Treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Early intubation at the first sign of upper airway obstruction may be necessary. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Irritating materials/ [R38, 137] *Basic Treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/in. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/ [R38, 139] *Advanced Treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/ [R38, 139] MEDS: *... PERSONS SUBJECT TO PROLONGED EXPOSURE TO EPSILON-CAPROLACTAM SHOULD BE MEDICALLY EXAMINED, ESP THEIR RESP, CIRCULATORY AND NERVOUS SYSTEMS /SRP: SKIN, GENITOURINARY TRACT/. [R28, 92] HTOX: *... WORKERS ... EXPOSED TO 61 MG/CU M ... and ... TO 16-17 MG/CU M OF /EPSILON-CAPROLACTAM/ ... COMPLAINED OF APPREHENSION AND NERVOUS IRRITABILITY ... OTHER SYMPTOMS INCL BLEEDING FROM NOSE, DRYNESS OF NOSE, INFLAMMATION OF THROAT, PAINFUL LIPS, HEARTBURN, FLATULENCE AND A BITTER TASTE IN MOUTH ... . [R33, p. V2 1093] *... WORKERS EXPOSED TO CONCN OF LESS THAN 17.5 MG/CU M ... COMPLAIN OF HEADACHES AND MALAISE, DRY GLOSSY SKIN, LOSS OF NORMAL TOUCH SENSATION IN FINGERTIPS AND NAIL DEFORMATIONS. [R33, 1093] *... LOSS OF CONTROL AND SOME CONFUSION WERE REPORTED TO OCCUR IN WORKERS EXPOSED TO CAPROLACTAM ... NERVOUS SYSTEM, GENITO-URINARY TRACT AND CARDIOVASCULAR SYSTEM DISORDERS WERE OBSERVED IN FEMALE WORKERS EXPOSED TO CAPROLACTAM DURING MFR OF NYLON 6. [R39] *LIGHT SENSITIVITY OF EYE WAS PRODUCED BY INHALATION OF CAPROLACTAM @ 0.11 MG/CU M AND HIGHER. [R40] *... DERMATOSES AMONG WORKERS IN CAPROLACTAM MFR PLANT SHOWED THAT CONTACT DERMATITIS AND ECZEMA OF HANDS WERE MOST PREVALENT. DRY ERYTHEMATOUS SQUAMOUS FOCI ON SMOOTH SKIN ... . [R40] *... EXPOSED DELIBERATELY TO SEVERAL CONCN OF CAPROLACTAM VAPOR RANGING FROM 53 MG/CU M TO 521 MG/CU M CONFIRM THAT EYE IRRITATION ... /IS/ EXPERIENCED BY EVERY ONE @ THESE RELATIVELY HIGH CONCN. [R41, p. 96.1] *ORAL DOSE OF 3-6 G WAS GIVEN DAILY FOR 3-5 YR FOR TREATMENT OF OBESITY IN 90 SUBJECTS. NO TOXIC EFFECTS WERE OBSERVED. THERE WAS NO EFFECT ON APPETITE, AND ONLY 1 PERSON DEVELOPED ALLERGY TO CAPROLACTUM ... . [R40] *Caprolactam causes dermal irritation and sensitization. Functional disorders of the nervous system, genito-urinary tract and cardiovascular system have been reported among exposed female workers. [R42] *Women exposed occupationally to caprolactam were reported to have an increased frequency of variety of complications during pregnancy. [R42] *... WORKERS WERE EXPOSED UP TO 17 YR TO VAPOR CONCN AS HIGH AS 5-10 PPM WITHOUT ANY EVIDENCE OF DAMAGE TO HEALTH. MEDICAL RECORDS DO NOT INDICATE ANY ILLNESS ATTRIBUTABLE TO VAPOR INHALATION, ALTHOUGH SEVERAL CASES OF SKIN IRRITATION DUE TO DIRECT CONTACT WITH SOLID ARE REPORTED. [R41, p. 96.1 (89)] *Agents reported to affect female reproductivity capacity ... Industrial chemicals ... Plastic monomers-caprolactam /from table/ [R43] *Spirometric lung functions of 173 workers engaged in various sections of a caprolactam plant were performed in March 1989, along with 60 non-exposed healthy volunteers. FVC, FEW, PEFR and FEF-25-75 were used for multiple regression analysis of lung functions of this group. After allowing for age, height and smoking habits the exposed group did not show any significant difference from the non-exposed group. These findings are consistent with the view that organic chemicals like benzene, cyclohexane, cyclohexanone, cyclohexanol, hydroxylamine and lactum do not have chronic effects on lung functions of exposed workers. [R44] NTOX: *IN LARGE PARENTERAL DOSES, EPSILON-CAPROLACTAM IS A POWERFUL RESPIRATORY STIMULANT AND MILD CIRCULATORY DEPRESSANT; IN SMALLER DOSES ... /IT/ PRODUCES MILD PRESSOR EFFECT ON CIRCULATION. [R45, 1986.95] *... ANIMALS WERE ADMIN DAILY 50-100 MG EPSILON-CAPROLACTAM/KG ... WHICH INHIBITED GROWTH, INCR MORTALITY, MODIFIED BLOOD PICTURE, CAUSED A RELATIVE INCR IN SERUM GAMMAGLOBULIN AND AFFECTED LIVER AND KIDNEYS ... . [R45, 1986.96] *... AIR CONCN RANGING FROM 118 TO 261 MG/CU M WERE TOLERATED /BY GUINEA PIGS/ WITHOUT MANIFEST ADVERSE EFFECTS, EXCEPT FOR ... COUGH ... EXPOSED IN 7 DAILY 7 HR EXPOSURES ... @ AIR CONCN OF 51 MG/CU M FROM 180 DEG C MELT, FOR 5 TO 8 HR/DAY FOR 26 TO 30 DAYS ... SLIGHT EVIDENCE OF NASAL IRRITATION. [R45, 1986.95] *DOSES OVER 900 MG/KG BODY WT LED TO DEATH OF ANIMALS THROUGH RESP PARALYSIS. RATS AND RABBITS EXHIBITED VIOLENT INTERMITTENT EPILEPTIFORM-TYPE CONVULSIONS. [R28, 327] *... (5 MG FOR 40 DAYS, 10 MG FOR 30 DAYS, 25 MG FOR 30 DAYS, 50 MG FOR 60 DAYS, TOTAL 4.25 G) WERE GIVEN TO 8 GUINEA-PIGS ... SC. NO DEATH ... POISONING IS SHOWN BY ANEMIA AND LEUCOCYTOSIS ... MARKED EOSINOPHILIA. SPINAL CORD SHOWED INCR IN EOSINOPHILS AND ORTHOCHROMATIC ERYTHROBLASTS. [R28, 327] *... (5 MG FOR 40 DAYS, 10 MG FOR 30 DAYS, 25 MG FOR 30 DAYS, 50 MG FOR 60 DAYS, TOTAL 4.25 G) WERE GIVEN TO 8 GUINEA-PIGS ... SC. ... BLOOD SHOWED LOWER THAN NORMAL CALCIUM CONTENT ... INCR IN UREA LEVEL. AUTOPSY SHOWED CONGESTION OF ALL ORGANS, LIVER AND KIDNEY LESIONS, AND HYPERTROPHY OF SPLEEN. [R28, 327] *... ACTION ON SKIN ... EPSILON-CAPROLACTAM HAD NO IRRITANT EFFECT WHEN APPLIED TO SHAVED SKIN OF RATS AND RABBITS TWICE DAILY FOR 4 DAYS. [R28, 91] *DOSES OF 350-600 MG/KG BODY WT ADMIN IP TO RATS PRODUCED ... TREMORS, CONVULSIONS, CHROMODACRYORRHEA (BLOODY EYE DISCHARGE) AND TEMP DEPRESSION. IV INJECTIONS OF 100-300 MG/KG BODY WT TO RABBITS PRODUCED TREMORS, CONVULSIONS, MYDRIASIS (DILATATION OF PUPIL) AND OPISTHOTONOS (TETANIC SPASM). [R39, (1979)] *IN RATS, CONCN OF 120-150 MG/CU M CAPROLACTAM IN AIR REDUCED FERTILITY AND CAUSED DEATH OF EMBRYOS. [R39, (1979)] *IN DOGS IV INJECTION OF 0.002 G/KG INCR ARTERIAL PRESSURE; 0.1 G/KG CAUSED BRIEF CARDIAC ARREST AND SHARP DECR IN ARTERIAL PRESSURE, AND THEN AN INCR ... ADDITIONAL ... EFFECT ON PERIPHERAL, AS WELL AS CENTRAL, NERVOUS SYSTEM ... . [R40] *... CHANGES IN CONDITIONED-REFLEX ACTIVITIES /IN RATS/ WERE SEEN @ DAILY ORAL DOSE OF 15 MG/KG FOR 2 MO. ... GUINEA PIGS ... EXPOSED TO VAPORS OF CAPROLACTAM (0.01-0.03 MG/L) ONCE EVERY 2 DAYS. ON DAY 14 ... CIRCULATORY ANTIBODIES ... APPEARED. BY DAY 30, SERUM ANTIBODIES ... IN LUNG TISSUES ... SUGGESTED ... SELF-IMMUNIZING PROCESS. [R40] *Twenty-seven chemicals (including caprolactam) previously tested in rodent carcinogenicity assays were tested for induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells as part of a larger analysis of the correlation between results of in vitro genetic toxicity assays and carcinogenicity bioassays. Chemicals were tested up to toxic doses with and without exogenous metabolic activation. Results showed that treatment of the Chinese hamster ovary cells with up to 5 mg/ml caprolactam in the presence or absence of S9 did not increase the frequency of chromosomal aberrations or sister chromatid exchanges. [R46] *Caprolactam gave negative results in a wide range of in vitro short-term tests. It did not induce mutation in Salmonella typhimurium in the presence or absence of an exogenous metabolic system, recombination or aneuploidy in fungi, or DNA damage, DNA repair, point mutation, sister chromatid exchange, micronuclei, aneuploidy or polyploidy in cultured mammalian cells. Results of borderline positivity were obtained in tests for gene conversion in yeast and for morphological transformation in cultured mammalian cells. Caprolactam inducecd somatic-cell mutations in Drosophila melanogaster. There is some evidence that it induced point mutations in yeast and chromosomal aberrations in cultured human cells. [R47] *In male rats exposed for 4 hr per day to 125 mg/cu m (27 ppm) caprolactam dusts, spermatogenesis was reduced after 2.5 months. No effect was seen in animals exposed to 11 mg/cu m (2.4 ppm). [R48] *Groups of 50 male and 50 female Fischer 344/N rats, six weeks of age, were fed a diet containing 3750 or 7500 mg/kg (ppm) caprolactam (minimum purity, > 99.5%) for 103 weeks. An equal number of untreated rats of each sex served a untreated controls. All surviving animals (> 64%) were killed at 105 weeks. Slight decrease in body-weight gains were observed in animals of each sex. No treatment-related tumour was observed. [R49] *Groups of 50 male and 50 female B6C3F mice, six weeks of age, were fed a diet containing 7500 or 15,000 mg/kg (ppm) caprolactam (minimum purity, > 99.5%) for 103 weeks. An equal number of untreated mice of each sex served as controls. All surviving animals (> 76%) were killed at 105 weeks. Slight decreases in body-weight gains were noted in animals of each sex. No treatment-related tumor was observed. [R49] *When male rats were exposed for 4 hr per day to 125 mg/cu m (27 ppm) caprolactam dust or 2.5 months, disturbances in nervous system function (increasing excitability), gonads (changes in spermatogenesis), respiratory system (decreased respiratory rate) and urinary function (decreased excretion of chloride) were observed. No adverse effect was noted in rats exposed to 11 mg/cu m. [R49] *Exposure of female rats to concentrations of 140 and 475 mg/cu m (30 or 100 ppm) caprolactam dust disrupted the estrous cycle and reduced the proportion of inseminated rats that became pregnant. ... /Exposure of/ rats to these concentrations for 4 hr daily on gestation days 1-5, 6-12 or on day 13 after parturition ... increased pre- and post-implantation intrauterine deaths and reduced fetal body weight. [R48] *Adult female rats were orally dosed with 1/5 the LD50 of either an initiator of carcinogens (1,2-dibromo-3-chloropropane, promoters or putative promoters of carcinogenesis (hexachlorobenzene, alpha-hexachlorocyclohexane, kepone and toxaphene) or noncarcinogens (coumaphos, EDTA, caprolactam, 8-hydroxyquinoline, titanium(IV)oxide, sodium diethyldithiocarbamate, and sucrose) at 21 and 4 hr before sacrifice. The initiator and promoters selected in the study were all of the halogenated hydrocarbon class. 1,2-Dibromo-3-chloropropane caused a large degree of hepatic DNA damage and an increase in hepatic ornithine decarboxylase activity. At doses ranging between 1/5 to 3/5 the LD50, all four promoters or putative promoters induced rat hepatic ornithine decarboxylase activity. The seven noncarcinogens produced several biochemical effects at doses of 1/5 the LD50: serum alanine aminotransferase increase (caprolactam and diethyldithiocarbamate, decreased hepatic cytochrome p450 (sucrose and diethyldithiocarbamate and increased hepatic ornithine decarboxylase (8-hydroxyquinoline and diethyldithiocarbamate. None of the seven noncarcinogens caused hepatic DNA damage or coordinate induction of hepatic ornithine decarboxylase and cytochrome p450. [R50] *Caprolactam was evaluated for developmental toxicity potential in both rats and rabbits by the oral route. In rats dosed on days 6-15 of gestation with 100, 500 or 1000 mg/kg/day of caprolactam, the maternal survival rate was significantly lower in the high dose group and implantation efficiencies were slightly lower in the 100 and 1000 mg/groups (but not the 500 mg/kg) than in the control. The incidence of fetal death was comparable for all groups, and the incidence of fetal viability was considerably lower in the high dose group (but not the mid or low) than in the control group. Visceral anomalies and one visceral variant were observed in one 100 mg/kg and one 500 mg/kg pup, respectively. The anomalies included exencephaly, an incomplete left eyelid, microphthalmia (right), and a protruding tongue. No skeletal anomalies were observed. It was concluded that caprolactam at levels up to at least 500 mg/kg of body weight produced no teratogenic effects in the Fischer 344 rats. In rabbits receiving 50, 150 or 250 mg/kg caprolactam on days 6-28 of gestation, the pregnancy rate in all groups was at least 80%. The numbers of corpora lutea, live and dead fetuses, resorptions, the sex ratio and the pre- and post-implantation losses were not significantly different among the test and control groups. The incidence of major malformations and of minor skeletal anomalies was unaffected by treatment with caprolactam. Maternal weights were depressed in the group receiving 250 mg/kg. Treatment of a separate group with a positive control substance (6-aminonicotinamide) resulted in significantly (p less than 0.001) increased incidences of major malformations, minor visceral anomalies and minor skeletal anomalies. Maternal toxicity in terms of mortality was observed in pregnant rabbits treated with caprolactam at a dose of 250 mg/kg/day. Fetotoxicity was evidenced by lower fetal weights at the 150 and 250 mg/kg/day levels, and an increased incidence of thirteenth ribs was observed at the 250 mg/kg/day dose level. Neither embryotoxicity nor teratogenicity occurred at any dose level. [R51] *Fischer 344 albino rats were exposed to caprolactam in their diets at concentrations of 0, 1000, 5000, or 10,000 ppm as part of a three generation reproductive study. Considering mortality, clinical signs, reproductive performance or gross pathological findings, no treatment related effects were observed in the parental animals. In the P2 and P3 middle and high dose males and females there were consistently lower body weights. The P2 and P3 middle and high dosed males and the high dosed females demonstrated consistently lower mean food consumption values. A slight increase in the severity of spontaneous nephropathies, occasionally accompanied by granular casts were noted on histopathologic studies of the high dose P1 males. No treatment related effects were noted among the offspring with regard to gross appearance, gross pathology, survival, number of pups, percentage of male pups or kidney weight. On days 1, 7, and 21 of lactation, analysis of offspring body weights revealed consistently significant lower mean values in the high dose male and female animals of all filial generations. [R52] *An experiment was conducted to examine the induction of chromosomal aberrations in bone marrow of male and female 1C3F1 mice caused by a single dose of 100 mg caprolactam caprolactam/kg body weight, delivered by oral intubation. Caprolactam was given in an aqueous solution at a volume of 0.1 ml/10 g of body weight. At 24, 30, and 48 hr after treatment, bone marrow was sampled from groups of ten animals each. The animals were dosed with 2 mg/kg of colchicine exactly 1 hour prior to sacrifice. No chromosomal aberrations were produced under these experimental conditions by caprolactam. The frequency of cells with breaks and gaps remained at the control level in all three sampling groups. The mitotic indices were reduced at the 30 and 48 hr intervals indicating a cytotoxic effect. Under similar conditions, benzo(a)pyrene, which served as a positive control, significantly increased the aberrations rates at a dose of 63 mg/kg. The sampling time for benzo(a)pyrene treated animals was 30 hr after treatment. [R53] *A carcinogenesis bioassay of caprolactam ... was conducted by feeding diets containing 3,750 or 7,500 ppm caprolactam to groups of 50 male or female F344 rats and 7,500 or 15,000 ppm to groups of 50 male or female B6C3F1 mice for 103 wk. Control groups consisted of 50 undosed rats and 50 undosed mice of each sex. ... Under the conditions of this bioassay, caprolactam was not carcinogenic for F344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R54] *This study was designed to assess the potential subchronic inhalation toxicity of caprolactam when administered as a 3 micron aerosol from an aqueous solution to Sprague Dawley CD rats (10/sex/group) via whole body exposure. The study was enhanced with the inclusion of motor activity measurements and a functional observational battery to assess the neurotoxic potential of caprolactam. The rats were exposed at least 65 times over a 13 week period for 6 hr per day, 5 days per week, to target concentrations (3 microns, mass median aerodynamic diameter) of 0, 25, 75, and 250 mg/cu m. An additional 10 animals/sex/group were similarly exposed and then held for a 4 week recovery period. Exposure levels were determined gravimetrically six times daily; one daily sample was analyzed by high pressure liquid chromatography. No deaths were observed in the study during the exposure or recovery periods. Treatment related responses such as labored breathing and nasal discharge were seen during many of the exposures. Similar responses as well as moist rales were seen during the nonexposure periods during the 13 weeks of exposure. However, these responses abated during the 4 week recovery period. There were no clearly treatment related responses observed with ophthalmoscopic examinations body weight measurements, food consumption measurements, neurobehavioral evaluations, clinical pathology evaluations, organ weight measurements, or macroscopic pathology examinations. Microscopic findings that were considered related to exposure to the test material were seen in the nasoturbinal tissues (hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the olfactory mucosa) of the two higher exposure group animals and in the laryngeal tissues (squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland) of all three exposure group animals. These changes were considered to be adaptive responses to an irritant (caprolactam). The keratinization of the metaplastic epithelium in the larynx was considered to be an adverse effect. By the end of the 4 week recovery period, there was complete regression of the keratinization in the larynx, but recovery of the adaptive nasoturbinal effects had not completely resolved. In conclusion, the whole body exposure of Sprague Dawley rats to caprolactam as a respirable aerosol for 6 hr/day, 5 days/week, for 15 weeks at gravimetrically determined levels of 24, 70, and 243 mg/cu m resulted in respiratory tract effects (laryngeal) at the highest exposure level with complete recovery within 4 weeks postexposure. The results indicate that the no observed adverse effect level for caprolactam is 70 mg/cu m, based on upper respiratory effects, with 243 mg/cu m representing a no observed effect level for systemic toxicity, neurotoxicity, and lower respiratory tract effects. [R55] NTXV: *LD50 Mouse (male) oral 2.1 g/kg; [R49] *LD50 Mouse (female) oral 2.5 g/kg; [R49] *LD50 Rat (male) oral 1.6 g/kg; [R49] *LD50 Rat (female) oral 1.2 g/kg; [R49] *LC50 Mouse inhalation 450 mg/cu m/2 hr; [R49] *LC50 Rat inhalation 300 mg/cu m/2 hr; [R49] *LD50 Mouse sc 0.75 g/kg; [R49] *LD50 Mouse ip 0.57 g/kg; [R49] *LD50 Mouse iv 0.48 g/kg; [R49] *LD50 Rat oral 1210 mg/kg; [R31] *LD50 Mouse oral 930 mg/kg; [R31] *LD50 Mouse ip 650 mg/kg; [R31] NTP: *A carcinogenesis bioassay of caprolactam ... was conducted by feeding diets containing 3,750 or 7,500 ppm caprolactam to groups of 50 male or female F344 rats and 7,500 or 15,000 ppm to groups of 50 male or female B6C3F1 mice for 103 wk. Control groups consisted of 50 undosed rats and 50 undosed mice of each sex. ... Under the conditions of this bioassay, caprolactam was not carcinogenic for F344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R54] TCAT: ?Acute dermal toxicity was evaluated in groups of 4 male albino New Zealand strain rabbits receiving single occluded applications of undiluted E-caprolactam at dose levels of 0.5, 1.0 and 2.0 gm/kg of body weight. The test material was held in contact with the intact skin for a 24 hour period. Mortality was observed in 1 animal in the 0.5 gm/kg dose group and in all animals in the 2.0 gm/kg dose group (period of observation not reported); the LD50 was calculated to be 1.41 gm/kg of body weight. Clinical observation were not reported. Gross necropsy revealed mottled livers, congested and hemorrhagic lungs and congested kidneys. [R56] ?Caprolactam (CAS # 105-60-2) was evaluated for acute inhalation toxicity in SPF1-Wistar/Chbb rats (10/sex/group) administered single nose-only exposures to the aerosol (MMAD 50% = 2.69 um; 86.6% capable of alveolar exposure) in air at mean analytical concentrations of 0, 5.25, 8.35, and 10.12 mg/l for 4 hours. During exposures, the animals exhibited eyelid closure, shallow to spasmodic respiration, and mild to marked defense reactions; steppage gait, bloody nasal exudate, spasmodic respiration, bloody lacrimation, squatting, bristling fur, and severe tremor were noted during 14-day post-exposure recovery. No change in bodyweights or bodyweight gains after exposures could be attributed to substance exposure. Mortality was dose-related, occurred before Day 2 following exposures, and was consistent with LD50's of 9.6 and 7.08 mg/l (p < 0.05 based on a probit analysis of D.J. Finney), respectively, for male and female rats. Among study lethalities, gross pathology on necropsy included general circulatory congestion, elevated hyperemia of the lung, and moderate to severe fatty degeneration of the liver. Histologic evaluation revealed fine-droplet fatty degeneration of peripheral acini in the liver and ischemic tubular nephrosis of the renal cortex in a solitary lethality of a 10.12 mg/l exposure. [R57] ?The effect of subchronic dietary treatments on renal function was evaluated in groups of 6 male and 6 female Fischer 344, Sprague-Dawley and Wistar strain rats administered caprolactam at dietary levels of 0. 0.01, 0.05, 0.1, and 0.5%, available ad libitum, for 90 days. Mortality was observed in one Sprague-Dawley male from the 0.01% feeding level. Clinical observations revealed no treatment-related effects. Body weight were significantly lower (p < = 0.05) than controls in: Fischer 344 females at the 0.50% level; in Sprague-Dawley males at the 0.1% and 0.5% levels; in Sprague-Dawley females at the 0.01%, 0.05% and 0.50% levels; in Wistar males at 0.05% and 0.50%; and in Wistar females at 0.50%. Serum chemistry analysis revealed significant increases (p < = 0.05) in BUN, serum chloride levels and decreases in BUN, serum creatine levels, serum chloride levels, serum sodium levels, and serum hematocrit levels; these results, however, appear to be random and not related to the test material. Urinalysis data revealed dose-related increases in urine volume in Fischer 344 males and females at the 3 highest doses. Dose related increases in the kidney/body weight ratio were observed in Sprague-Dawley males at 0.10 and 0.50% and in Wistar males at 0.50%. Gross necropsy revealed no compound-related incipient nephrosis, chronic inflammation, cytomegalic and chromophobic epithelial cells, protenaceous deposits, increased cytoplasmic vacuolization int eh tubules, increased hyalin droplets, and tubular epithelial hyperplasia and basophilia. In a similar study also evaluating the effects of caprolactam, the only compound-related effect was the altering renal function (fractional reabsorption of water) at the highest dose level (0.50%). [R58] ?Caprolactam (CAS # 105-60-2) was evaluated for subchronic oral toxicity specific to the kidney in groups (100/sex/strain) of Fischer 344, Sprague-Dawley, and Wistar rats randomized to nominal dietary exposures (ad libitum) of 0, 0.01, 0.05, 0.10, and 0.50% for a minimum 84 of 90 consecutive days. Dietary exposures were continued as rats of each strain (2 x 6, 2 x 8 and 2 x 6/sex/dose group) participated in Phases I and II of 3 distinct analyses of previously documented or implied renal toxicity: Phase 1 employed non-invasive techniques to establish the locale of renal toxicity, dose-response correlation, and sex and/or strain specificity by (Part A) measurement of biological markers of degenerative effects on the renal early proximal tubule (PT) and PT reabsorptive processes and (Parts B AND C) determination of relative sensitivity and expression of toxicity in stressed (dehydrated or extracellular volume expansion) kidneys. Phase II used invasive procedures on anesthetized animals to (Part A) monitor proteinaceous material in Bowman space and/or the proximal tubule, and (Part B) directly measure glomerular filtration, urine clearance or reabsorption of free water and electrolytes, and blood and urine osmolality. Recovery from (Part A) any nephrotoxic effects (functional and/or histological) and, (Part B, per protocol amendment) specifically those effects documented in Phase 1 was examined in Phase III animals allowed 90-day recovery following cessation of 90 days' dietary exposure. Only all-strain lethalities and those strains demonstrating histological renal toxicity in Phase 1 high dose groups were terminated by pathology in Phase II (for light microscopy evaluation of changes in function and structure per protocol amendment) and Phase III (for evidence of recovery from toxic effects). Results of Phase I revealed functional nephrotoxicity in the stressed kidney only, including inhibited natriuresis upon volume expansion and diminished urine concentrating capacity during water deprivation, suggesting a distal tubule target of toxic action. Treated rats showed no gross pathology, but had increased kidney weights and increased incidence of hyalin droplets within renal tubules, more pronounced in males than females, and in Fischer 344 and Sprague-Dawley than in Wistar rats. Additionally, colloidal iron staining of glomeruli did not correlate with either level of exposure or with occurrence of tubular eosinophilic hyalin droplets. In Phase II, kidney weights were also increased and only fractional reabsorption of water in Fischer 344 or Sprague-Dawley high dose rats was altered, again supporting a distal tubule site of nephrotoxic effects in these strains. Based on urine concentrating capacity, the function of kidneys is fully reclaimed during 90-day recovery, which was verified on histological assessment concluding Phase III of study. [R59] ?Caprolactam (CAS # 105-60-2) was evaluated for subchronic inhalation toxicity in Sprague-Dawley CD rats (10/sex/group) administered whole-body exposures to the liquid aerosol (MMAD = 2.9 um) from an aqueous mixture (1:1) at analytical concentrations of 0, 23, 66, and 244 mg/cu m, 6 hours per day, 5 days/week for 13 weeks. Duplicate groups received identical exposure regimens for toxicological assessment following a 4-week post-treatment recovery period. Additionally, functional observational batteries and motor activity assessments examined signs of neurotoxicity pre-exposure, at staggered intervals during treatment and after the recovery period. Terminal sacrifice of 10 rats/sex/group at 13 and 17 weeks included histopathological examination of lungs, liver, kidneys, nasopharyngeal tissue, and larynx in all animals. Treatment was associated with labored breathing and nasal discharge during and after the exposures, moist rales following exposures that abated during recovery, and no mortality throughout the study. No distinct treatment-related ophthalmic, bodyweight, food consumption, neurobehavioral, clinical pathology, organ weight, or gross pathological changes were observed pre- or post- recovery. Exposure-related histopathology included hypertrophy/hyperplasia of goblet cells in the respiratory mucosa and intracytoplasmic eosinophilic material in epithelial cells of the nasoturbinal olfactory mucosa (66, 244 mg/cu m) and squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium covering the ventral seromucous gland of the larynx (all exposure levels). A small number of 243 mg/cu m rats also exhibited minimal keratinization of the metaplastic epithelium of the larynx. Recovery from laryngeal and nasoturbinal effects was apparent but incomplete following 4-week recovery. The study authors, however, attributed all but laryngeal keratinization (243 mg/cu m) to a typical physiological response to inhaled foreign particulate matter and not specific aerosol caprolactam toxicity, assigning an upper respiratory tract no observed effect level (NOEL) of 70 mg/cu m, while the study NOEL was 243 mg/cu m for lower respiratory tract, systemic, and neuro-toxicity. [R60] ?Caprolactam (CAS # 105-60-2) was evaluated for carcinogenicity in F344 rats (50/sex/group) exposed ad libitum to dietary concentrations of 0 (basal diet control), 3750, and 7500 ppm for 103 weeks. The exposure regimens were established based on range- finding single, repeated-dose (14-day), and subchronic studies. In subchronic study, dietary exposures up to 7500 ppm for 13 weeks produced reductions in food consumption with no other signs of clinical toxicity and no histopathologic changes. Both diminutions in bodyweight gains and food consumption in treated rats of the chronic study were inversely related to dose. Neither survival, frequency of neoplastic and non-neoplastic lesions, nor nature of lesions appeared statistically significantly (one-tailed Fisher exact test) affected by dietary caprolactam exposure, upon microscopic examination of major tissues and organs in surviving animals following terminal necropsy and of select tissues and organs of the study lethalities. No toxic lesions were encountered in any tissue, and histological evaluation revealed no significant toxic or carcinogenic effects of oral caprolactam under the conditions of this bioassay. A Cochran-Armitage test for linear trend of increased incidence of specific lesions among treated groups was statistically significant in the positive direction for interstitial-cell tumors of the testes (p = 0.038) and carcinomas of the pituitary in males (p = 0.037), while statistically significant in the negative direction for papillary adenocarcinomas of the mammary gland (p = 0.24) and fibromas of the subcutaneous tissue in males (p = 0.028). While no statistically significant evidence was established, calculation of relative risk indicated a positive trend for some lesions suggesting the theoretical possibility of tumor induction undetectable in this bioassay. [R61] ?The ability of caprolactam to enhance the transformation of secondary hamster embryo cells (strain not reported) was evaluated at test article concentrations of 0, 2,000, 2,991, 4,472, 6,687, and 10,000 microgram/ml. Survival frequencies ranged from 0% to 83%. The transformation frequency was equal to 0 at all concentrations except the 10,000 microgram/ml concentration which was completely toxic. [R62] ?Caprolactam (CAS # 105-60-2) was evaluated for effects on amino acid metabolism (tyrosine and tryptophan) in male Fisher 344 rats by measurement of liver enzyme activity (uMoles Product/Hr./gm Liver), tyrosine aminotransferase (TAT) and tryptophan oxygenase (TPO) after peroral or intraperitoneal exposure. Caprolactam, following acute oral gavage (0, 300, 600, 900, 1200, and 1500 g/kg), repeated intraperitoneal injection (500 mg/kg), and 7-day dietary administration (0%, 0.5%, 1.0%, and 5.0%) to male rats (numbers unspecified) markedly induced both enzymes. The spiked enzyme activities relative to controls peaked early (3-6 hours), in a dose-related manner, and reflected diminished effects over time and upon repeated intraperitoneal injections. Conversely, caprolactam dampened the activity of glucose-6-phosphatase post-gavage while fructose-1,6-diphosphatase appeared unaffected, and cytochrome P-450 levels fell following early intraperitoneal injections as TAT and TPO activities were maximized. No response in glucose-1-phosphatase or fructose-1,6-diphosphatase activity was noted from either repeated intraperitoneal injections or dietary exposures. On comparison to pair-fed control rats whose diets were adjusted to correspond to the diminished intakes of the caprolactam-exposed rats in the 7-day dietary inclusion study, the increased activity of these liver enzymes became insignificant. Further, food restriction increased leucine-3H incorporation into protein, while caprolactam-induced food restriction did not, suggesting that caprolactam suppressed the stimulation of protein synthesis prompted by attrition. Consequently, food efficiencies associated with a 7-day 5% diet of caprolactam and the pair-fed control, respectively, were -146 and -33 (g weight gain/g diet consumed) relative to the negative (basal diet) control. Neither adrenalectomy nor concurrent administration of actinomycin D diminished the caprolactam-induced increase in enzyme activity and, in fact, both potentiated the toxicity of oral caprolactam. With the additional observation that caprolactam and actinomycin D-induced enzyme activity exceeded that due to actinomycin D alone, these results suggest neither endogenous steroid nor RNA synthesis is required for caprolactam-mediated enzyme induction. Aflatoxin B1, by contrast and paradoxically, appeared to block caprolactam induction of TPO. [R63] ?A three generation study was performed in groups of 10 males and 20 female albino Fischer 344 (CD) rats administered caprolactam in the diet at levels of 1000, 5000, and 10,000 ppm for 10 weeks prior to mating. Treatment-related effects were not observed in the parental animals with respect to mortality, clinical observations, reproductive indices or gross pathology. Significant reductions in body weight were observed in the second and third parental generations in the high-dose groups while slight reductions were observed in the mid-dose groups. Significant reductions in food consumption were observed in high-dose groups of the second and third parental generation. Histomorphologic findings noted in high-dose males of the first generation included slightly increased severity of spontaneous nephropathy with granular casts. Body weights of pups from high-dose groups from all generations were significantly reduced while pup body weights from mid-dose groups were generally lower. Otherwise, no treatment-related effects with respect to gross appearance, gross pathology, survival, or percentage of male pups, were observed in offspring. [R64] ?Teratogenicity of caprolactam was evaluated in groups of 20 pregnant Fischer 344 rats dosed 0, 100, 500, and 1000 mg/kg/day by gavage gestation days (GD) 6-15. In the highest dose group, 9 died, 3 not pregnant. Clinical signs of maternal toxicity were urine stains (high dose), rough coat (mid and high dose), red vaginal discharge (all doses), bloody crust on or near facial orifices (high dose), thin or hunched appearance (mid and high dose), and depression (high dose). Food consumption was decreased GD 6-11 (mid and high dose), GD 11-15 (mid dose), and GD 0-20 (mid dose). Maternal weight gain was significantly depressed GD 6-15 for mid and high dose groups. Mean number of corporal lutea and implantations per group were comparable among all groups. Pregnancy rates and implantation efficiencies were slightly lower in the mid and high dose groups than in controls, and the incidence of resorption significantly higher in the high dose group. Incidence of fetal death was unchanged, but fetal viability was reduced in the high dose group. Male fetal weight was slightly reduced in all treated groups, but that for females, only in the mid and high dose groups. Fetal lengths were slightly lower in the high dose group. Uterine weights were slightly lower in all treated groups; ovarian weights were higher in high dose rats. Visceral and skeletal anomalies and variants were similar in treated and control groups. [R65] ?Reproductive toxicity of caprolactam (Clm) was evaluated in groups of 25 inseminated New Zealand white rabbits dosed by gavage with 0, 40, 150, or 250 mg/kg per day Clm gestation days (GD) 6-28 or 3 mg/kg 6-aminonicotinamide (6-AN, a positive control) GD9. Maternal mortalities (GD of death) in the above groups were 1 (GD 29), 0, 0, 4 (GD 6,6,6,28), respectively. Abortions, respectively, were 1, 2, 1, 2, and 0. Clinical symptoms prior to death of treated animals included convulsions, red staining of fur around mouth and nares, and in the dam which died GD 28, abortion (GD 27), hypothermia, and decreased food consumption from GD 9. Of those which lived till sacrifice and cesarian section GD 29, convulsions and rapid breathing was seen at 250 mg/kg, but no adverse clinical effects on the dams in the other groups. Weight decreased in 150 (GD 6-9) and 250 (GD 6-12) mg/kg Clm and 6AN (GD 9-12) dams. Weight gain GD 6-29 decreased significantly (p < 0.05) in 250 mg/kg dams, and in 150 mg/kg dams when corrected for uterine weight. Necropsies of dams that died early showed reddening of lungs and tracheal mucosa with frothy fluid; necropsies of dams surviving to sacrifice were normal. Numbers of corpora lutea, live and dead fetuses, resorptions, sex ratio, and pre- and post-implantation losses were un-affected. Fetal weights were decreased in 150 and 250 mg/kg Cln and 6AN groups. Major malformations were not induced by Cln, but 6AN caused significant (p < 0.001) increases. Minor visceral and skeletal Cln effects on fetuses were absence of posterior azygos lobe in the lungs at 50 mg/kg and increased incidence of 13th ribs at 250 mg/kg. [R66] ?Caprolactam (CAS # 105-60-2) was evaluated for tissue affinity and disposition in adult Swiss-Webster mice administered carbonyl-14C-caprolactam: Two males receiving 6.4- 6.9 mg/kg by intravenous injection were anesthetized and frozen after 0.33 and 9 hours, and 1 nonpregnant and 5 pregnant female mice (GD 14.5), respectively, gavaged with doses of 6.5-6.7 mg/kg were anesthetized and frozen at 3 hours, 20 minutes, 1, 3, 9 and 24 hours after treatment, thus precluding translocation or removal of soluble compounds from their sites of residence in vivo. Only kidneys and nasal epithelia showed early tissue affinity within the first hour, although notable increases of radioactivity occurred in the fetuses and brain of pregnant dams. At 1 hour post-treatment, the bile ducts in the liver reflected marked hepatic secretion of caprolactam and its metabolites. Fetal exceeded maternal radioactivity at 3 hours, due to the more rapid clearance by the mothers. By 24 hours, most of the radioactivity was cleared from the maternal-fetal unit, although small residues remained in umbilical cords, amnion, yolk sac, maternal lens, maternal Harder's gland, and maternal liver. There was also a significant amount of radioactivity retained in the olfactory lobe of the brain, although this was thought to be an artifact of the freezing procedure. The solitary nonpregnant female showed a similar deposition of radioactivity to that in the pregnant mouse frozen after 3 hours. Although distribution was somewhat more equilibrated at 20 minutes, renal and hepatic elimination, and tissue affinities in the male at 9 hours were very similar to those of the 9-hour pregnant female. [R67] ADE: *... STUDY IN WHICH ANIMALS WERE ADMIN DAILY 50-100 MG EPSILON-CAPROLACTAM/KG ... RESULTED IN NO ACCUMULATION ... . [R20, 1979)294] *DETOXICATION RATE OF EPSILON-CAPROLACTAM WAS DETERMINED TO BE BETWEEN 60-70 MG/KG/HR FOR RATS. ... RAPID RATE OF ELIMINATION ... FROM BODY PREVENT ACCUM @ LEVEL CONSIDERABLY GREATER THAN RECOMMENDED TLV. [R20, 1979)294] *The distribution of (14)C caprolactam was studied by whole body autoradiography in male and female mice 3 hr after oral administration of 6.4-6.9 mg/kg body weight. Radioactivity was rapidly absorbed from the stomach and distributed throughout the entire animal; there was efficient elimination by the kidneys and liver. Material secreted by the liver into bile and intestinal contents did not appear to be reabsorbed via the enterohepatic circulation. [R48] *When pregnant Swiss-Webster mice were treated by oral intubation with 6.5-6.7 mg/k body weight (14)C caprolactam, rapid transfer of the radioactivity across the placenta was demonstrated by whole body autoradiography, with near complete elimination from the fetal and maternal compartments 24 hr after treatment. [R48] *When pregnant Swiss-Webster mice were treated by oral intubation with 6.5-6.7 mg/k body weight (14)C caprolactam, rapid transfer of the radioactivity across the placenta was demonstrated by whole-body autoradiography, with near-complete elimination from the fetal and maternal compartments 24 h after treatment. [R48] METB: *METAB STUDIES OF CAPROLACTAM IN RAT AND RABBIT PRODUCED EQUIVOCAL RESULTS AS FAR AS THEIR APPLICATION TO MAN IS CONCERNED; RABBIT APPEARED TO METABOLIZE CAPROLACTAM COMPLETELY, WHEREAS RAT EXCRETED CAPROLACTAM ONLY IN PART AS METABOLITE EPSILON-AMINO ACID. [R45, 1986.96] *EPSILON-CAPROLACTAM IS EXCRETED BY RATS PARTLY AS LACTAM AND PARTLY AS EPSILON-AMINO ACID. [R40] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Caprolactam's production and use in the manufacture of synthetic fibers of the polyamide type and as a solvent for high molecular weight polymers may result in its release to the environment through various waste streams. Caprolactam is produced in small quantities by some plants (i.e. sunflowers) as a secondary metabolite. If released to air, a vapor pressure of 1.9X10-3 mm Hg at 25 deg C indicates caprolactam will exist solely in the vapor phase in the ambient atmosphere. Vapor-phase caprolactam will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 21 hours. If released to soil, caprolactam is expected to have high mobility based upon an estimated Koc of 57. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.4X10-11 atm-cu m/mole. Caprolactam biodegradation in soil has not been reported, but it has a relatively short half life (5 to 14 days) in both aerobic waste water treatment systems and other aquatic systems (lakes and rivers). This suggests that it will be degraded in most aerobic soils. Based on very slow hydrolysis rates of other aliphatic acid amides, hydrolysis would not be expected to be an important fate process. However, experiments conducted with sterile natural waters demonstrated that caprolactam is abiotically degraded. Since the product of this degradation was not identified, it is not known if the primary product of this abiotic degradation is aminocaproic acid, a product of the hydrolysis of caprolactam. If released into water, caprolactam is not expected to adsorb to suspended solids or to sediments in water based upon its estimated Koc of 57. Volatilization from water surfaces is not expected to be an important fate process based upon its estimated Henry's Law constant. An estimated BCF of 3.2 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to caprolactam may occur through inhalation and dermal contact with this compound at workplaces (carpet and polymer mills) where caprolactam is produced or used. (SRC) NATS: *Caprolactam was not thought to occur naturally in the environment(1), but it has been found as a secondary metabolite of the sunflower(2). It is thought to act as a growth regulator in these plants and inhibits the growth of other dicot seedlings (cress)(2). [R68] ARTS: *Caprolactam's production and use in the manufacture of synthetic fibers of the polyamide type and as a solvent for high molecular weight polymers(1) may result in its release to the environment through various waste streams(SRC). [R69] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 57(SRC), determined from a structure estimation method(2), indicates that caprolactam is expected to have high mobility in soil(SRC). Volatilization of caprolactam from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.4X10-11 atm-cu m/mole from its vapor pressure, 1.9X10-3 mm Hg at 25 deg C(5), and water solubility, 5.25X10+6 mg/l(6). Caprolactam is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 1.9X10-3 mm Hg at 25 deg C(5). Caprolactam is degraded in aquatic environments with a half life of 5 to 15 days, and is expected to be degraded in aerobic soils in a similar timeframe(6). [R70] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 57(SRC), determined from an estimation method(2), indicates that caprolactam is not expected to adsorb to suspended solids or to sediments in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.4X10-11 atm-cu m/mole(SRC) calculated from its vapor pressure, 1.9X10-3 mm Hg at 25 deg C(4), and water solubility, 5.25X10+6 mg/l(5). According to a classification scheme(6), an estimated BCF of 3.1(SRC), from an estimated log Kow of 0.66(7) suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation in aquatic environments is expected to be extensive; complete degradation of 50-100 ug/ml caprolactam was observed in nutrient-amended or sediment-associated lake water in 21 days(8). Slightly less caprolactam was degraded (36-85%) after 21 days if higher concentrations (1000 to 2000 ug/ml) were used. However, in none of these control cases was any complete degradation (mineralization) of the caprolactam observed. Based on very slow hydrolysis rates of other aliphatic acid amides, hydrolysis is not expected to be an important fate process(5). Experiments conducted with sterile natural waters, however, demonstrated that caprolactam is abiotically degraded. It is not known whether or not the product of this abiotic degradation is the product of hydrolysis, aminocaproic acid(5). [R71] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), caprolactam, which has a vapor pressure of 1.9X10-3 mm Hg at 25 deg C(4), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase caprolactam is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 21 hours(SRC), calculated from its rate constant of 18X10-12 cu cm/molecule-sec at 25 deg C(3). Caprolactam does not absorb light in the environmental spectrum (> 290 nm), indicating there is little potential for direct photolysis. [R72] BIOD: *The activated sludge treatment of wastewater containing caprolactam from a Nylon 6 manufacturing plant was investigated by basic studies and by operating a full scale treatment plant. Activated sludges were obtained from municipal and industrial wastewater sources or were prepared by mixing caprolactam utilizing bacteria (Bacillus and Achromobacter) with municipal activated sludge. Bulking phenomena were observed in the acclimatization of ordinary activated sludges even when started from very low concentrations of caprolactam. The activated sludge synthesized from caprolactam utilizing bacteria showed better results with respect to sludge volume index, biochemical oxygen demand removal, and transparency of treated water. Wastewater from the Nylon 6 manufacturing plant, which contained caprolactam, was treated by this synthesized activated sludge in a bench scale apparatus consisting of a 4 cu m aeration basin and a 1.4 cu m sedimentation basin. The optimum biochemical oxygen demand loading was estimated to be 0.35 to 0.40 kg/kg of mixed liquor sludge solids/day. Production of excess activated sludge was 10% of the biochemical oxygen demand load. A wastewater treatment facility consisting of a 2500 cu m aeration basin and 1250 cu m sedimentation basin was constructed near the nylon 6 manufacturing plant to process 5000 cu m of wastewater (biochemical oxygen demand of 300 to 400 mg/l) per day. The treatment plant produces effluent with a biochemical oxygen demand below 10 mg/l. [R73] *Caprolactam (50 ug/ml) was biologically degraded in grab samples in 21 days(1). In sterilized stream and lake water samples 35-50% of the caprolactam underwent primary degradation(1) to aminocaproic acid, achieved by hydrolysis(2). In natural (not sterilized) waters, 75-100% of the chemical underwent primary degradation. Mineralization (complete degradation, as measured by %CO2 evolution) of caprolactam was not observed in any sterile water samples, but was observed in all non-sterile samples. After a 21 day incubation, grab samples at initial concentrations of 40.4 ug/ml were degraded as follows (as measured by %CO2 evolution): sterilized stream water: < 5%; unsupplemented stream water: < 5%; stream water plus sediment: 8%; stream water with yeast extract: 36%; sterilized lake water: < 5%; unsupplemented lake water: 5%; lake water plus sediment: 10%; lake water with yeast extract: 50%. In grab samples of lake water amended with yeast extract at an initial concentration caprolactam at 50 ug/ml, when incubated at 10, 20, and 25 deg C for 7 days, 17, 72, and 90% degradation was observed, respectively. After 21 days, nearly all the caprolactam at all temperatures was degraded. With lake water grab samples amended with yeast extract and a caprolactam concentration of 40.4 ppm, 8, 72, and 79% CO2 evolution was observed when incubated at 10, 20, and 25 deg C, respectively. For a grab sample amended with caprolactam at concentrations of 100, 1000 and 2000 ug/ml, primary degradation of 100, 85 and 36%, respectively, was observed after 21 days. Grab samples amended with initial concentrations of 100, 1000, and 2000 ug/ml caprolactam showed 80, 32 and 8% CO2 evolution, respectively, in lake water supplemented with yeast extract(1). [R74] *BOD dilution water, 2 day 90% TOC removal, activated sludge inocula(1). BOD dilution water, initial concn corresponding to 200 mg/L C, 5 day 94.3% COD removal, acclimated activated sludge inocula (vigorous system)(2). OECD method, initial concn corresponding to 40 ppm C, 10 day acclimation, 19 day 93% COD removal(3). Zahn-Wellens, initial concn equivalent to 1000 mg/L COD, 6 days > 90% degradation, 3.5 day lag period, non-adapted acclimated sludge inocula(4). Zahn-Wellens, 5 day 88% COD removal; Sapromat respirometer, 5 day 82% COD removal; Closed bottle test, 5 day 10% Theoretical Biochemical Oxygen Demand (5). A proposed mechanism for metabolism: caprolactam to epsilon-aminocaproic acid adipic semialdehyde to adipic acid(6). [R75] *AEROBIC: Several bacterial strains can degrade caprolactam(1) and it is degraded in activated sludge treatment plants and natural waters(1). Caprolactam, present at 100 mg/l, reached 100% of its theoretical degradation in 1 week using a carbon-supplemented lake water as the environmental medium, incubated at 20 deg C. At higher concentrations (1000-2000 mg/l), caprolactam was degraded (80 and 60%, respectively) within three weeks in carbon supplemented lake water(1). These test levels are higher than predicted environmental spill concentrations of > =50 mg/l, or of continuous release concentrations of < = 10 mg/l(1). Caprolactam, present at 100 mg/l, reached 82% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(2). [R76] ABIO: *The rate constant for the vapor-phase reaction of caprolactam with photochemically-produced hydroxyl radicals has been estimated nas 1.8X10+13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 21 hrs(SRC) at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Caprolactam is reported to have an atmospheric lifetime of less than one day, based on the lack of reaction product data(2). It has been reported that aliphatic acid amides are resistant to hydrolysis(3). Conversely, it has also been reported that amides undergo chemical hydrolysis(4). Based on experimental evidence(5), caprolactam underwent primary degradation in sterile water, which may have been due to chemical hydrolysis, however, no identification of the reaction product was performed. Caprolactam is not expected to photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R77] BIOC: *An estimated BCF of 3.2 was calculated for caprolactam(SRC), using an estimated log Kow of 0.66(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R78] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for caprolactam is estimated to be 57(SRC). According to a classification scheme(2), this estimated Koc value suggests that caprolactam is expected to have high mobility in soil. [R79] VWS: *The Henry's Law constant for caprolactam is estimated as 5.4X10-11 atm-cu m/mole(SRC), calculated from its vapor pressure, 1.9X10-3 mm Hg at 25 deg C(1), and water solubility, 5.25X10+6 mg/l(2). This Henry's Law constant indicates that caprolactam is expected to be essentially nonvolatile from water surfaces(3). Caprolactam's estimated Henry's Law constant indicates that volatilization from moist soil surfaces will not occur(SRC). Caprolactam is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R80] WATC: *CAPROLACTAM ... REPORTED TO BE PRESENT ... IN WASTE WATERS FROM NYLON 6 PLANTS IN JAPAN AND RUSSIA ... DETECTED IN (1) FINISHED DRINKING-WATER IN US...(2) EFFLUENT WATER FROM LANDFILL LEACHATE IN DELAWARE ... (3) FINAL EFFLUENT WASTE-WATER FROM DYE MFR PLANT, @ LEVELS OF 36-150 UG/L. [R39, (1979)] *GROUND WATER: June 1975 qualitatively identified in well water(1). April 1974 qualitatively identified in landfill leachate from sites in Dover, DE and Newcastle County, DE(1). A series of montoring wells installed at the Wilder's Grove landfill, Raleigh, NC showed concns of caprolactam at 995, 95, < 5.0, 133 ug/l (outflow from sedimentation basin) and 78, 88, < 5.0, and < 5.0 ug/l, inflow from surrounding waste deposit sites to sedimentation basin(2). [R81] *DRINKING WATER: July 1975 and Jan 1976 qualitatively identified in drinking water in the US(1). Caprolactam was qualitatively identified in drinking water in Germany(2). [R82] *SURFACE WATER: Stream water samples collected Dec 1983, downstream from tire fire which broke out in Winchester, VA during Oct 1983, 9700 ug/l - 0.67 km downstream, 250 ug/l - 1.1 km downstream, and 44 ug/l - 9 km downstream(1). Caprolactam was identified at Lobith, Germany on the Rhine River at a concn of 0.88 ug/l(2). [R83] EFFL: *July 1976, dye manufacturing plant in MA, concn range 36-150 ug/L(1). Qualitatively identified in water samples taken from advance waste treatment plants in Lake Tahoe, CA Oct 1974 and Washington D.C. Sept 1974(2). Present in trace amounts in the waste waters from nylon 6 manufacturing plants in Japan and Russia(3). [R84] ATMC: *URBAN/SUBURBAN: A survey of ambient atmospheric sampling data in populated areas of the United States was conducted for the compounds in the 189 Hazardous Air Pollutant List (HAP), one of which is caprolactam(1). No ambient measurement data for caprolactam was located(1). [R85] OEVC: *Residual monomers and oligomers were determined in nylon food packing following oven cooking with food oil(1). The average content of caprolactam in an oven roasting bag is 0.438 mg/g; the average amount of caprolactam migrating to oil after heating was 0.98 ug/g(1). [R86] RTEX: *VALUES OF 20-40 MG/CU M ... IN POLYMERISATION SHOP AND IN WEAVING WORKSHOPS. FOR 8 HR WORKING PERIOD THIS REPRESENTS TOTAL AMT OF LACTAM BREATHED EQUAL TO AVG VALUE OF 0.1-0.2 G. [R28, 91] *NIOSH has statistically estimated that 8661 workers (4209 of these are female) workers are potentially exposed to caprolactam in the US(1). Occupational exposure to caprolactam may occur through inhalation and dermal contact with this compound at workplaces where caprolactam is produced or used(SRC). The general population may be exposed to caprolactam via inhalation of ambient air, especially around new carpet installations(2,3). [R87] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: *Vacated 1989 OSHA PEL TWA 1 mg/cu m; STEl 3 mg/cu m is still enforced in some states. /Dust/ [R19, 361] *Vacated 1989 OSHA PEL TWA 5 ppm (20 mg/cu m); STEL 10 ppm (40 mg/cu m) is still enforced in some states. [R19, 361] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 mg/cu m. /Dust/ [R19, 50] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 3 mg/cu m. /Dust/ [R19, 50] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.22 ppm (1 mg/cu m). /Vapor/ [R19, 50] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 0.66 ppm (3 mg/cu m). /Vapor/ [R19, 50] TLV: +8 hr Time Weighted Avg (TWA) 1 mg/cu m; Short Term Exposure Limit (STEL) 3 mg/cu m /Particulate/ [R37] +8 hr Time Weighted Avg (TWA) 5 ppm; Short Term Exposure Limit (STEL) 10 ppm /Vapor/ [R37] +A4. A4= Not classifiable as a human carcinogen. /Particulate and vapor/ [R37] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Caprolactam is produced, as an intermediate or a final product, by process units covered under this subpart. [R88] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Caprolactam is included on this list. [R89] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2H-Azepin-2-one, hexahydro- is included on this list. [R90] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *... DETERMINED IN WASTE-WATER BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY, WITH LIMIT OF DETECTION OF CA 1 UG/L (PPB) ... COMPOSITION, TREATMENT EFFICIENCY, AND ENVIRONMENTAL SIGNIFICANCE OF DYE MFR PLANT EFFLUENTS. [R91] *COLORIMETRY @ 500 NM OF IRON (III)-HYDROXAMIC ACID COMPLEX HAS BEEN USED TO DETERMINE CAPROLACTAM IN AIR, WITH LIMIT OF DETECTION OF 50 UG/SAMPLE ... DETERMINATION OF CAPROLACTAM IN AIR. [R91] *Visual comparison with standard solution. [R92, 46] *Photometric method: The absorbance of a 1 wt% caprolactam solution (50 ml or 100 ml aqueous solution) is measured 250 or 600 s after the addition of 0.01 N potassium permanganate (1 ml or 2 ml) at a specific wavelength and compared to water treated with permanganate. [R92, 47] CLAB: *THIN-LAYER CHROMATOGRAPHY HAS BEEN USED TO DETERMINE CAPROLACTAM IN BLOOD AND TISSUE. [R91] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Caprolactam Technical Report Series No. 214 (1981) NIH Publication No. 81-1770 SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 205 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 116 (1979) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 508 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 117 (1979) R6: CHEMICAL PROFILE: CAPROLACTAM, 1984 R7: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 287 R8: SRI R9: Kavaler AR; Chemical Marketing Reporter 230 (15): 58 (1986) R10: Kavaler AR; Chemical Marketing Reporter 236 (16): 58 (1989) R11: Chemical Marketing Reporter; Chemical Profile Caprolactam. March 2, 1998. p. 33. NY, NY: Schnell Pub Co (1998) R12: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.253 R13: United States International Trade Commission. Synthetic Organic Chemicals- United States Production and Sales, 1988. USITC Publication 1989. Washington, DC: United States International Trade Commission, 1989.p. 15-3 R14: Chem and Engineering News 70 (15): 17 (4/13/92) R15: Chem and Engineering News 71 (15): 11 (4/12/93) R16: Chem and Engineering News 72 (15): 13 (4/11/94) R17: USITC. IMPORTS OF BENZENOID CHEMICALS AND PRODUCTS 1983 p.12 R18: BUREAU OF THE CENSUS. U.S. EXPORTS 1984 p.2-73 R19: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R20: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to R21: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-16 R22: Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study, Arlington, VA: Marriott-Crystal Gateway (1984) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 115 (1979) R24: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 388 R25: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 407 R26: Jones AH; J Chem Eng Data 5: 196-200 (1960) R27: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 224 R28: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R29: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1515 R30: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 646 R31: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 647 R32: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1577 R33: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R34: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 98 R35: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-31 (1982) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 71 395 (1999) R37: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 23 R38: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 119 R40: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 699 R41: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986. R42: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 262 (1986) R43: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 566 R44: Patel MB; Indian J Ind Med 36 (2): 76-81 (1990) R45: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists R46: Gulati DK et al; Environ Mol Mutagen 13 (2): 133-93 (1989) R47: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 263 (1986) R48: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 254 (1986) R49: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 253 (1986) R50: Kitchin KT, Brown JL; Terat Carcinogen Mutagen 9 (5): 273-85 (1989) R51: Grad SC et al; J Appl Toxicol 7 (5): 317-26 (1987) R52: Serota DG et al; J Apple Toxicol 84 (4): 285-93 (1988) R53: Adler ID, Ingwersen I; Mutation Research 224 (3): 343-5 (1989) R54: Carcinogenesis Bioassay of Caprolactam in F344 Rats and B6C3F1 Mice Technical Report Series No. 214 (1981) NIH Publication No. 81-1770 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R55: Reinhold RH et al; Toxicol Sci 44 (2): 197-205 (1998) R56: Union Carbide Corp.; Range Finding Tests on E-Caprolactam, (1965), EPA Doc No. 86-870001440, Fiche No. OTS0515602 R57: BASF Corp; Acute Inhalation Toxicity LC50 (4 Hours) of Caprolactam in Rats; 08/19/85; EPA Document No. 86-910000133; Fiche No. OTS0528365 R58: Allied Chemical Corp.; Effects of Subchronic Dietary Caprolactam Treatment on Specific Renal Functional Parameters in Adult Rats (Vol 1 of 3), (1983), EPA Doc. No. 86-870000741, Fiche No. OTS0514848 R59: Allied Chem Corp; Effects of Subchronic Dietary Caprolactam Treatment of Specific Renal Functional Parameters in Adult Rats Study (Volume 3 of 3); 10/03/83; EPA Document No. 86-870000743; Fiche No. OTS0514850 R60: Industrial Health Foundation; A 13-Week Inhalation Toxicity Study (With a 4-Week Recovery) of Caprolactam (494-95A) in the Rat Via Whole-Body Exposures; 03/27/97; EPA Document No. 87970000006; Fiche No. OTS0572866-1 R61: Bayer Corp; Carcinogenesis Bioassay of Caprolactam in Rats; 07/01/95; EPA Document No. 86950000195; Fiche No. OTS0557707 R62: Allied Chemical Corporation, In Vitro Mutagenicity and Cell Transformation Screening of Caprolactam, (1979), EPA Document No. 86-870000708, Fiche No. OTS0514815 R63: Allied Signal Inc; Influence of Caprolactam on Rat Liver Tyrosine Aminotransferase and Tryptophan Oxygenase; 03/01/79; EPA Document No. 86-870001706; Fiche No. OTS0515782 R64: Hazelton Labs.; A Three Generation Reproduction Study in Rats with Caprolactam (Final Report), (1981), Doc. No. 86-870000735, Fiche No. OTS0514842 R65: Hazleton Laboratories. Teratology Study in Rats with Caprolactam (Final Report). (1980) EPA No. 86-870000737, Fiche No. OTS0514844 R66: Bio-Research Laboratories, Ltd. A Teratology Study of Caprolactam in Rabbits with Attachments. (1983) EPA No. 86-870000744, Fiche No. OTS0514851 R67: Indus Hlth Foundation Inc; Proceedings of a Symposium on an Industry Approach to Chemical Risk Assessment - Caprolactam and Related Compounds as a Case Study; EPA Document No. 86950000199; Fiche No. OTS0557711 R68: (1) Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study, Arlington, VA: Marriott-Crystal Gateway (1984) (2) Duke SO; Rev Weed Sci 2: 15- 44 (1986) R69: (1) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co., Inc. p. 287 (1996) R70: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (5) Jones AM; J Chem Eng Data 5: 196-200 (1960) (6) Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study, Arlington, VA: Marriott-Crystal Gateway (1984) R71: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Jones AM; J Chem Eng Data 5: 196-200 (1960) (5) Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study. Pittsburgh, PA: Ind Health Found (1984) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (8) Fortmann L, Rosenberg A; Chemosphere 13: 53-65 (1984) R72: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Jones AM; J Chem Eng Data 5: 196-200 (1960) R73: Kageyama M, Tomita, K; Water Sci Technol 20 (10): 49-55 (1988) R74: (1) Fortmann L, Rosenberg A; Chemosphere 13: 53-65 (1984) (2) Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study. Pittsburgh, PA: Ind Health Found (1984) R75: (1) Pagga U, Guenthner W; pp 498-504 in Comm Eur Communities Eur 7549 Environ Qual Life (1982) (2) Pitter P; Water Res 10: 231-5 (1976) (3) Zahn R; Huber W; Tenside Deterg 12: 266-70 (1975) (4) Zahn R, Wellens H; Z Wasser Abwasser Forsch 13: 1-7 (1980) (5) Zahn R, Wellens H; Chemker Z 98: 228-32 (1974) (6) Shama G, Wase DAJ; Int Biodeterior Bull 17: 1-9 (1981) R76: (1) Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study, Arlington, VA: Marriott-Crystal Gateway (1984) (2) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101- 1 (1992) R77: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Kao AS; J Air Waste Managa Assoc 44: 683-96 (1994) (3) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (4) Lyman WJ et al; p. 7-5 in Handbook of Chemical Property Estimation Methods. NY, NY: McGraw-Hill (1982) (5) Fortmann L, Rosenberg A; Chemosphere 13: 53-65 (1984) R78: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R79: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R80: (1) Jones AM; J Chem Eng Data 5: 196-200 (1960) (2) Loewengart G; pp. 36-52 in Proc Symp Ind Approach Chem Risk Assess: Caprolactam Relat Compd Case Study, Arlington, VA: Marriott-Crystal Gateway (1984) (2) Duke SO; Rev. Weed Sci 2:15-44 (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R81: (1) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Water USEPA-600/4/76-062 p. 96-7 (1976) (2) Johnston JJ et al; Anaerobic biodegradation of hazardous organics in groundwater down gradient of a sanitary landfill. USGS Project No. 08 (Fy 1992) UNC-WRRI-94-287 (1994) R82: (1) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Water USEPA-600/4/76-062 p. 96-7 (1976) (2) Kool HS et al; Crit Rev Env Control 12: 307-57 (1982) R83: (1) Peterson JC et al; Anal Chem 58: 70A-74A (1985) (2) Hendriks AJ et al; Wat Res 28: 581-98 (1994) R84: (1) Games LM, Hites RA; Anal Chem 49: 1433-40 (1977) (2) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol 2 p. 145 USEPA-600/1-84-020B NTIS PB85-128239 (1984) (3) IARC; Caprolactam and Nylon 6; Inter Agency for Research on Cancer 19: 115-8 (1979) R85: (1) Kelly TJ et al; Environ Sci Technol 28: 378-87 (1994) R86: (1) Begley TH et al; Food Add Contam 12: 671-6 (1995) R87: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) (2) Pleile JD, Whiton RS; Appl Occup Environ Hyg 5: 693-699 (1990) (3) Hodgson AT et al; p. 19 in Proc Annu Meet - Air Waste Manage Assoc, 85th (vol 5) 92/79.15 (1992) R88: 40 CFR 60.489 (7/1/99) R89: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R90: 40 CFR 716.120 (7/1/99) R91: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 118 R92: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA5 (86) RS: 87 Record 39 of 1119 in HSDB (through 2003/06) AN: 189 UD: 200302 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HEXAMETHYLENE-DIAMINE- SY: *1,6-DIAMINO-N-HEXANE-; *1,6-DIAMINOHEXANE-; *HEXAMETHYLENEDIAMINE-; *1,6-HEXAMETHYLENEDIAMINE-; *1,6-HEXANEDIAMINE-; *HEXANE,-1,6-DIAMINO-; *1,6-HEXYLENEDIAMINE-; *HMDA-; *NCI-C61405- RN: 124-09-4 MF: *C6-H16-N2 SHPN: UN 1783; HEXAMETHYLENE DIAMINE, SOLID UN 2280; HEXAMETHYLENE DIAMINE, SOLUTION IMO 8.0 ASCH: 1,6-Hexanediamine dihydrochloride; 6055-52-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPARED BY REDUCING ADIPONITRILE WITH SODIUM AND ALCOHOL: SLOTTA, TSCHESCHE, BER 62, 1404 (1929). MFR: FAITH, KEYES AND CLARK'S INDUSTRIAL CHEMICALS, FA LOWENHEIM, MK MORAN, EDS (WILEY INTERSCIENCE, NEW YORK, 4TH ED, 1975) PP 442-4. [R1, 678] *1) REACTION ADIPIC ACID AND AMMONIA (CATALYTIC VAPOR-PHASE) TO YIELD ADIPONITRILE, FOLLOWED BY LIQ-PHASE CATALYTIC HYDROGENATION. 2) CHLORINATION OF BUTADIENE FOLLOWED BY REACTION WITH SODIUM CYANIDE (CUPROUS CHLORIDE CATALYST) TO 1,4-DICYANOBUTYLENE, AND HYDROGENATION. [R2] FORM: *Grade or purity: Anhydrous: 99.8%; 70% soln [R3] MFS: *E I du Pont de Nemours and Company, Inc, Hq, 1007 Market St, Wilmington, DE 19898, (302) 774-1000; Production sites: Orange, TX 77630; Victoria, TX 77901 [R4] *Monsanto Co, Hq, 800 North Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Production sites: Decatur, AL 35602; Pensacola, FL 32575 [R4] OMIN: +/NYLON/ MANUFACTURING PROCESS STARTS WITH HIGH-PRESSURE SYNTHESIS OF ADIPIC ACID AND HEXAMETHYLENE DIAMINE WHICH ARE HEATED...IN ABSENCE OF AIR TO FORM AMIDE LINKAGES... WATER IS REMOVED AND MOLTEN NYLON (...NYLON 66) IS EXTRUDED IN RIBBON-LIKE FORM.../TO BE MELTED AND FILAMENTS FORMED/. /POLYAMIDES/ [R5, 1750] USE: *CHEM INT FOR NYLON-TYPE POLYAMIDE RESINS [R6, 802] *Used to prepare hexamethylene diisocyanate. [R7] CPAT: *88% USED IN PRODN OF NYLON 66; 12% USED IN OTHER APPLICATIONS INCLUDING THE PRODN OF NYLON 610 AND 612 (1972) [R8] PRIE: U.S. PRODUCTION: *(1972) 3.88X10+11 GRAMS [R8] *(1975) 3.40X10+11 GRAMS [R8] *Capacity (Jan 1, 1996): Total capacity 1330 million lbs. 930 million lbs (adiponitrile from butadiene); 200 million lbs (adiponitrlie from acrylonitrile); 200 million lbs (transferred adiponitrile). [R4] U.S. IMPORTS: *(1972) 1.68X10+8 GRAMS [R8] *(1975) 7.31X10+6 GRAMS [R8] *(1984) 7.78x10+7 g [R9] U.S. EXPORTS: *(1972) NEGLIGIBLE [R8] *(1984) 9.99X10+9 g [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LEAFLETS [R2]; *RHOMBIC BIPYRAMIDAL PLATES [R11] ODOR: *ODOR OF PIPERIDINE [R6, 802]; *Weak, fishy [R3] BP: *205 DEG C [R6, 802] MP: *42 DEG C [R6, 802] MW: *116.21 [R6, 802] DEN: *(anhyd) 0.799 at 60 deg C (liquid) [R3] DSC: *pKb= 3.3, pKa= 10.7 [R12, 3137]; *pKa = 11.02 [R13] HTC: *(est) -12,200 Btu/lb= -6,790 cal/g= -284X10+5 J/kg [R3] HTV: *203 BTU/LB= 113 CAL/G= 4.73X10+4 J/KG [R3] SOL: *FREELY SOL IN WATER; SLIGHTLY SOL IN ALC, BENZENE [R6, 802]; *SOMEWHAT SOL IN ETHER [R2]; *Water solubility = 2,460,000 mg/l at 4.5 deg C [R14] SPEC: *IR: 1392 (Coblentz Society Spectral Collection) [R15]; *NMR: 16074 (Sadtler Research Laboratories Spectral Collection) [R15]; *MASS: 440 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R15] SURF: *34.6 DYNES/CM= 0.0346 N/M AT 60 DEG C [R3] VAPD: *4.01 (AIR= 1) [R12, 3140] OCPP: *SUBLIMES AS LONG NEEDLES [R6, 802] *CONVERSION FACTOR: 1 MG/L= 210 PPM; 1 PPM= 4.75 MG/CU M [R12, 3140] *ABSORBS WATER AND CARBON DIOXIDE FROM AIR [R6, 862] *NEEDLES FROM WATER OR ALCOHOL; FREELY SOL IN WATER; MP: 248 DEG C /HEXAMETHYLENE DIAMINE DIHYDROCHLORIDE/ [R1, 679] *HEAT OF SOLUTION (EST): -9 BTU/LB= -5 CAL/G= -0.2X10+5 J/KG [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +Public safety: CALL Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Hexamethylene diamine; Hexamethylene diamine, solution/ [R16] FPOT: *COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME... [R17] FLMT: *0.7-6.3% in air [R3] FLPT: *160 deg F OC [R3] FIRP: *Extinguish with water, foam, dry chemical, or carbon dioxide. [R3] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Solid streams of water may be ineffective. Use "alcohol" foam, dry chemical or carbon dioxide. /Hexamethylene diamine solution/ [R18] *If material on fire or involved in fire: Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Solid streams of water may be ineffective. Use "alcohol" foam, dry chemical or carbon dioxide. /Hexamethylene diamine, solid/ [R18] REAC: *...can react with oxidizing materials. [R17] ODRT: *0.0041 mg/cu m [R3] *0.0032 mg/cu m [R19] SERI: *DIAMINES ARE STRONG BASES AND EXHIBIT SKIN AND EYE IRRITANT PROPERTIES SIMILAR TO MONOAMINES. /DIAMINES/ [R12, 3162] *THE SOLID MAY BE EXPECTED TO BE STRONGLY IRRITATING OR CAUSTIC TO THE EYES ON ACCOUNT OF ITS ALKALINITY. [R20] EQUP: *Protective clothing; eye protection. [R3] *Personnel protection: ... Wear appropriate protective gloves, boots and goggles. ... Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. /Hexamethylene diamine solution; hexamethylene diamine, solid/ [R18] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. /Hexamethylene diamine solution/ [R18] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. /Hexamethylene diamine, solid/ [R18] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. ... If contact with the material anticipated, wear appropriate chemical protective clothing. /Hexamethylene diamine solution; hexamethylene diamine, solid/ [R18] SSL: *VAPORIZES READILY [R21] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R22] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R23] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R24] CLUP: *TREATMENT OF WASTE WATER CONTAINING HEXAMETHYLENEDIAMINE FROM POLYAMIDE MFG IN REVERSE OSMOSIS APPARATUS WITH CELLULOSE ACETATE MEMBRANES WAS STUDIED TO DETERMINE THE EFFECT OF HCL ADDITION ON TRANSPORT OF COMPONENTS OF THE SOLN THROUGH A MEMBRANE AND TO ASSESS THE POSSIBILITY OF CHANGING THE PH OF THE CONCN FORMED IN THE APPARATUS. [R25] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *FEASIBILITY OF MICROBIAL DECOMP OF ORGANIC WASTES UNDER CONDITIONS EXISTING IN DEEP WELLS WAS INVESTIGATED. UNDER AEROBIC CONDITIONS TEMP IS NOT A CONSTRAINT; THERMOPHILIC BACTERIA DECOMP A WIDE VARIETY OF COMPOUNDS. GROWTH OF THERMOPHILIC BACTERIA IS POSSIBLE WITH HEXAMETHYLENEDIAMINE. [R26] *(1) Add to layer of sodium bisulfite. Spray with water and neutralize. ... [R27] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Organic bases\amines and related compounds/ [R28] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... Anticipate seizures and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... Cover skin burns with sterile dressings after decontamination ... . /Organic bases\amines and related compounds/ [R28] HTOX: *CONJUNCTIVAL AND UPPER RESPIRATORY TRACT IRRITATION HAS BEEN OBSERVED IN WORKERS HANDLING HEXAMETHYLENEDIAMINE. ONE WORKER, OUT OF 20 STUDIED, DEVELOPED ACUTE HEPATITIS FOLLOWED BY DERMATITIS WHICH WAS ATTRIBUTED TO HEXAMETHYLENEDIAMINE. NO ANEMIA WAS OBSERVED. [R29] *...CASE...DESCRIBED IN ITALY IN WHICH 20 WORKERS WERE EXPOSED TO HEXAMETHYLENE DIAMINE AND 8 SUFFERED FROM IRRITATION TO EYES AND UPPER RESPIRATORY TRACT, WHILE ONE CONTRACTED DERMATITIS, AND ANOTHER, ACUTE LIVER DISEASE. DERMATITIS HAS...BEEN DESCRIBED IN FRANCE... [R30] *Workers involved in the production of condensers were examined. Their contact with hexamethylenediamine, capon lacquer, and epoxide tar results in development of allergic diseases, such as atopic forms of bronchial asthma, allergic rhinitis and dermatitis. [R31] NTOX: *Hexamethylenediamine causes anemia, weight loss, and degenerative microscopic changes in the kidneys and liver and to a lesser degree in the myocardium of guinea pigs after repeated doses. [R29] *...ANIMAL EXPERIMENTS HAVE SHOWN THAT INHALATION OF HIGH CONCN...MAY CAUSE ANEMIA, LEUKOPENIA, IRRITATION OF THE MUCOUS MEMBRANES, AND INFLAMMATION OF LUNGS AND KIDNEYS. [R5, 1752] *SIX GUINEA PIGS TO WHICH 0.02 G OF SUBSTANCE WAS ADMIN ORALLY DAILY FOR 20-95 DAYS WERE SLOWLY POISONED. THE SAME DOSE.../0.02 G/ WHEN ADMIN SC, KILLED 3 OTHER GUINEA PIGS IN 5-7 DAYS. MAIN SYMPTOMS WERE LOSS OF WT AND ANEMIA OF HEMOLYTIC TYPE ACCOMPANIED BY LEUKOPENIA. ...KIDNEY AND LIVER...DEGENERATION. [R32] *SKIN CORROSION WAS TESTED USING RABBITS THAT HAD BEEN CLIPPED OF HAIR ON BACKS AND FLANKS. 1,6-HEXANEDIAMINE APPLIED IN AMT OF 0.5 G. AFTER 4 HR, WRAP AND PATCHES WERE REMOVED, DAMAGE OCCURRED IN @ LEAST 2 OF 6 RABBITS. THE CMPD WAS CLASSIFIED AS CORROSIVE. [R33] *EXPOSURE OF RATS 4 HR/DAY FOR 8 DAYS TO ATMOSPHERE CONTAINING 1.25 MG/CU M, DECR THRESHOLD OF NEUROMUSCULAR EXCITABILITY, INCR BLOOD LEUKOCYTE AND LIVER GLYCOGEN LEVELS, CAUSED DISORDERS OF RENAL EXCRETORY CAPACITY, AND ALTERED PHAGOCYTIC ACTIVITY OF NEUTROPHILS. [R34] *CHRONIC INHALATION OF 1 MG HEXAMETHYLENE DIAMINE INDUCED LEUKOCYTOLYSIS AND LEUKERGY WITH AND WITHOUT ANTIGEN STIMULATION, AND ALTERED HEMOGLOBIN AND LEUKOCYTE LEVELS IN RATS SENSITIZED BY ORAL ADMINISTRATION OF DICHLOROMETHYLBENZENE OR ORAL AND IM ADMINISTRATION OF BENZYLPENICILLIN @ 4-10 MG/KG FOR 15 DAYS, BUT NOT IN INTACT RATS. [R35] *1,6-diaminohexane (DAH) was administered to pregnant female mice during the time of maximal fetal ornithine decarboxylase (ODC) activity, days 10-14 of gestation. Such treatment resulted in an inhibition of fetal ODC activity, as measured 2 hours later, and a proportional decrease in fetal weight, as measured on day 18 of gestation. [R36] *1,6-Diaminohexane was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 1,6-Diaminohexane was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.100, 0.333, 1.000, 3.333, 6.666, and 10.000 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 10.000 mg/plate. Slight to total clearing of the background bacterial lawn occurred in most cultures at the highest dose. [R37] *A study was conducted as part of a program designed to assess risk associated with occupational exposure to hexamethylenediamine. Sprague-Dawley rats were divided into four groups each containing 26 males and 26 females. The rats were given daily doses of 0, 50, 150, or 500 mg/kg hexamethylenediamine. After a minimum of 56 days of treatment, the F0 rats were mated to produce the Fl offspring. Pregnant F0 females were allowed to give birth to Fl pups. After a minimum of 98 days of treatment the Fl parents were mated to produce the F2 offspring. The F2 pups were sacrificed on lactation day 21. No treatment related mortality was noted. Judging by weight gain, males were more sensitive to the dietary administration of hexamethylenediamine than females. Greater than 90% of the target concn of hexamethylenediamine were fed to rats in all groups. The actual doses consumed, however, averaged between 123 and 132% of the target doses in these groups. Fertility was not adversely affected by the dietary administration of hexamethylenediamine over two generations. Pup survival was not significantly reduced in any of the treated groups. At birth pup body weights were not adversely affected by treatment, but during lactation reduced weights were apparent in both sexes from the high dose group. No meaningful differences were noted between the control rats and the treated rats of either generation in regard to antemortem observations, copulatory interval, gestation length, nesting and nursing behavior, and appearance of the pups. No treatment related effects were noted on testes weights and no effects were noted by macroscopic or microscopic examination of tissues evaluated. [R38] *1,6-Hexanediamine (HDA) is a high production volume chemical which is used as an intermediate in the synthesis of paints, resins, inks, and textiles and as a corrosion inhibitor in lubricants. Two and 13 week studies of the toxicity of the dihydrochloride salt of HDA (HDDC) were conducted in male and female Fischer 344/N rats and B6C3F1 mice using whole body inhalation exposure. Both species were evaluated for histopathologic and reproductive effects, and rats were examined for clinical chemistry and hematologic changes. In the 2 week inhalation studies, animals were exposed to 10-800 mg HDDC/cu m, 6 hr/day. All rats, all female mice, and two of five male mice in the high exposure group died before the end of the study. Surviving mice in this group had a dose dependent depression in body weight gain. Clinical signs were primarily related to upper respiratory tract irritation and included dyspnea and nasal discharge in both species. Treatment related histopathologic lesions included inflammation and necrosis of the laryngeal epithelium of both species and the tracheal epithelium of mice, as well as focal inflammation and ulceration of the respiratory and olfactory nasal mucosa. In the 13 wk inhalation studies, animals were exposed to HDDC at concentrations of 1.6-160 mg/cu m for 6 hr/day, 5 days/week. In addition to the base study groups, a supplemental group of rats at each exposure level was included to assess the effect of HDDC on reproduction. No treatment related changes in organ weights or organ to body weight ratios occurred in rats, and no treatment related clinical signs or gross lesions were seen in either species. Chemical related microscopic lesions were limited to the upper respiratory tract (larynx and nasal passages) in the two highest exposure groups and were similar in both species. These lesions included minimal to mild focal erosion, ulceration, inflammation, and hyperplasia of the laryngeal epithelium, in addition to degeneration of the olfactory and respiratory nasal epithelium. HDDC caused no significant changes in sperm morphology or vaginal cytology and no significant adverse effects on reproduction in rats or nice. Hematologic and clinical chemistry changes in rats were minor and sporadic and were not accompanied by related histologic findings. HDDC did not increase the frequency of micronucleated erythrocytes in mice. /1,6-Hexanediamine dihydrochloride/ [R39] *The effects of hexamethylenediamine ... (HMDA) on mitogen induced proliferative responses and stimulation of ornithine-decarboxylase (ODC) activity were examined in splenic lymphocytes from female C57BL/6J mice. Addition of 0.1 to 16 millimolar HMDA at the start of culture or after 24 or 48 hr of culture decr the proliferative response to T-cell and B-cell mitogens. The concn of HMDA required to cause suppression incr with incubation time. Removal of the diamine after 24 hours allowed cells to proliferate normally upon reculture with mitogen. Mitogenic responses of cultures containing the ODC inhibitor alpha-difluoromethylornithine (DFMO) were also inhibited in a time and dose dependent manner. ODC activity was markedly decr by inclusion of diamine or DFMO in the culture medium. Putrescine did not reverse the suppressive effects of diamine on proliferation, but did restore DFMO containing cultures to control levels of activity. The /results suggest/ ... conclude that HMDA suppresses lymphocyte proliferation in vitro by alteration of ODC and polyamine activity; comparison of results obtained with DFMO and HMDA suggests that HMDA may act via multiple pathways, only one of which involves inhibition of ODC activity . [R40] *Four groups of 15 male and 15 female Sprague-Dawley derived (CD) rats were exposed to aqueous hexamethylenediamine (HMD) aerosols for 6 hr/day, 5 days/wk for 13 wk at mean analytical concn of 0, 12.8, or 51 mg/cu m. Because of exposure related deaths in a group of male and female rats similarly exposed to 215 mg/cu m HMD, this group was terminated during the seventh week of the study. Signs of respiratory and conjunctival irritation were observed in rats at both the 51 and 215 mg/cu m HMD test levels. Body weight gain was significantly reduced in both sexes exposed to 215 mg/cu m HMD. At the 5 wk study interval, slight hemopoietic stimulation of peripheral blood parameters was observed in rats of both sexes exposed to 215 mg/cu m HMD. Treatment related microscopic lesions were seen only in rats exposed to 215 mg/cu m HMD and were confined to the trachea, nasal passages, and lungs. The no effect level in this study is considered to be 12.8 mg/cu m HMD. [R41] *... Dietary admin of hexamethylenediamine (HMD) to groups of rats for 3 months at dosages of 0, 50, 150, and 500 mg/kg resulted in a modest retardation in weight gain at the two higher test levels. No other obvious signs of toxicity or changes in the peripheral blood picture or selected clinical pathology parameters were found at any test level throughout the study. Evaluation of absolute and relative weights of 10 selected organs, as well as complete necropsies and microscopic evaluation of over 30 selected tissues and organs, revealed no changes considered related to treatment. The admin of HMD by gavage to pregnant rats at 0, 112, 184 and 300 mg/kg/day 1 on days 6-15 of pregnancy (day 1 = day sperm detected) did not induce any teratogenic effects. Signs of maternal toxicity were observed only at 300 mg/kg/day. Embryotoxicity was observed at both the 300 and 184 mg HMD kg/day dosage levels. No treatment related effects were observed at 112 mg HMD kg/day. [R42] TCAT: ?1,6-Hexanediamine (CAS # 124-09-4) was evaluated for acute oral toxicity in Long Evans rats (5/sex/group) administered single gavage (free base) doses of 485, 679, 950, 1,330, and 1,960 mg/kg bodyweight and in additional groups given gavage doses of 950, 1,330, 1,860, 2,600, and 3,640 mg/kg. Treatment was associated with progressively more serious signs of toxicity with greater dosages. Pharmacotoxic signs upon oral administration of hexanediamine at doses of 485-1860 mg/kg bodyweight included immediate hypokinesis, hyperventilation, coarse body tremors, and abdominal grip. At doses of 1860 mg/kg and above, the adverse responses were profound and all animals were dead within 24 hours of dosing. An LD50 was 830 mg/kg with 95% confidence limits of 730 and 950 mg/kg. Necropsy of study lethalities revealed severe irritation of the mucous membranes and extensive gastrointestinal hemorrhaging. [R43] ?Hexamethylene Diamine, (CAS # 124-09-4) was evaluated in Charles River COBS CD rats (26/sex/group) administered measured dietary doses of 0, 50, 150, and 500 mg/kg bodyweight at 78.02% concentration in two successive generations (F0 and F1). A control group received the basal laboratory diet with an ethanol (solvent) concentration equivalent to that in the high-dose diet. F0 and F1 were mated once to produce F1 and F2 progeny, respectively. Treatment was associated with reduced bodyweight gains in high- and mid-dose F0 and F1 males and in high-dose F1 females. Food consumption was reduced in F0 and F1 females. High-dose F0 and F1 females demonstrated significantly lower weight gains during gestational periods. Fertility indices of dams and sires and the testes weights of males without litters did not reveal an adverse effect of treatment. Copulation, gestation, weaning intervals, and dynamics of dams were comparable to controls at all treatment levels in both generations. A 500 mg/kg high dose was associated with significant (p < 0.05) reductions in both F1 and F2 progeny numbers as well as pup weights on lactation days 14 and 21. Smaller viable litter sizes did not correlate with increased numbers of dead pups. Survival through weaning was comparable in the progeny of control and all treated rats of both generations. Antemortem pathology on terminal necropsy of all high-dose and control parents revealed no gross lesions and no microscopic changes related to treatment. A dietary "no effect" level was 150 mg/kg day and researchers concluded that fetal developmental toxicity was produced only at levels associated with significant maternal toxicity. [R44] ?Hexamethylene diamine (1,6-diaminohexane, CAS# 124-09-4) was administered in the diet to groups of 52 rats (26 males and 26 females) at doses of 50, 150, and 500 mg/kg/day for two generations. A control group received the basal laboratory diet. The F0 and F1 generations were each mated once to produce F1 and F2 generations. Treatment related changes included reduction in weight in F0 males and F1 males and females and reduced food consumption among F0 and F1 males and females in the high dose group. The high dose group also showed reduced litter size, and decreased pup weight on lactation days 14 and 21 for both generations. No other treatment effects were noted with regard to lactation, female body weights, fertility indices, copulatory interval, gestation length, pup survival or appearance, or testes weight or appearance. The authors conclude that the 150 mg/kg/day level can be considered the dietary "no effect" level. This EPA status report only includes a summary of this study. [R45] ADE: *.../HEXAMETHYLENE IS/ ABSORBED THROUGH THE SKIN. [R46, 2059] *Following oral administration of (14)C-labeled 1,6-diaminohexane to male rats, approx 20% of the administered dose was recovered as (14)CO2 after 72 hr. Urinary and fecal excretion accounted for 47 and 27% of the administered radioactivity, respectively. Of several tissues examined, the highest concn of residual radioactivity were found in the prostate at 24 and 72 hr post-administration. [R47] *An isocyanate generation apparatus was developed and stable isocyanate atmospheres were obtained. At a concn of 5 ug 1,6-hexamethylene diisocyanate (HD) per cu m the precision was found to be 7% (n = 5). Three volunteers were each exposed to the different concn of HI (11.9, 20.5, and 22.1 micrograms/ cu m) and three concns of isophorone diisocyanate (IPDI) (12.1, 17.7, and 50.7 micrograms/cu m), in an exposure chamber. The duration of the exposure was 2 hr. Urine and blood samples were collected, and hydrolyzed under alkaline conditions to the HI and IPDI corresponding amines, 1,6-hexamethylene diamine (HDA) and isophorone diamine (IPDA), determined as their pentafluoropropionic anhydride amides (HDA-PFPA and IPDA-PFPA). The HDA- and IPDA-PFPA derivatives were analyzed using liquid chromatography mass spectrometry with thermospray monitoring negative ions. When working up samples from the exposed persons without hydrolysis, no HDA or IPDA was seen. The average urinary excretion of the corresponding amine was 39% for HI and 27% for IPDI . An association between the estimated inhaled dose and the total excreted amount was seen. The average urinary elimination half-time for HDA was 2.5 hr and for IPDA, 2.8 hr. The hydrolysis condition giving the highest yield of HDA and IPDA in urine was found to be hydrolysis wi the 3 M sodium hydroxide during 4 hr. No HDA or IPDA could be found in hydrolyzed plasma (< ca 0.1 micrograms/l) . [R48] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Hexamethylene diamine's production and use as a chemical intermediate in the production of nylon-type polyimide resins may result in its release to the environment through a variety of waste streams. Based on an extrapolated vapor pressure of 0.12 mm Hg at 25 deg C, hexamethylene diamine is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase hexamethylene diamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of about 6 hours. If released to soil, hexamethylene diamine is expected to have moderate mobility based on an estimated Koc value of 286. Volatilization from dry soil surfaces is not expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is not expected based on an estimated Henry's Law constant of 3.2X10-9 atm-cu m/mol. Biodegradation in soils is expected to be an important environmental fate process for this compound. Standard BOD dilution techniques indicate that hexamethylene diamine biodegrades under aerobic conditions. In water, hexamethylene diamine is expected to adsorb to sediment or particulate matter based on the estimated Koc value of this compound. This compound is not expected to volatilize from water surfaces given its estimated Henry's Law constant. A measured pKa value of 11 indicates that hexamethylene diamine will not dissociate significantly at environmentally important pH values. Biodegradation is expected to occur slowly in aqueous environments. The potential for bioconcentration in aquatic organisms is low based on an estimated BCF value of 1. Occupational exposure may occur through inhalation and dermal contact with this compound at workplaces where hexamethylene diamine is produced or used to synthesize nylon-type resins. (SRC) ARTS: *Hexamethylene diamine's production and use as a chemical intermediate in the production of nylon-type polyimide resins(1) may result in its release to the environment through a variety of waste streams(SRC). [R49] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 286(SRC), determined from a structure estimation method(2), indicates that hexamethylene diamine is expected to have moderate mobility in soil(SRC). Volatilization of hexamethylene diamine is not expected from moist soil surfaces(SRC) given an estimated Henry's Law constant of 3.2X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Volatilization of hexamethylene diamine from dry soil surfaces is not expected(SRC) based on an extrapolated vapor pressure of 0.12 mm Hg(SRC) at 25 deg C(4). Biodegradation is expected to be an important environmental fate process for this compound(SRC). Standard BOD dilution techniques with activated sludge indicate that hexamethylene diamine biodegrades under aerobic conditions(5-7). [R50] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 286(SRC), determined from a structure estimation method(2), indicates that hexamethylene diamine is expected to adsorb to suspended solids and sediment in water(SRC). Hexamethylene diamine is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 3.2X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). An experimental pKa value of 11(5), indicates that hexamethylene diamine will not dissociate significantly at environmentally important pH values(SRC). Biodegradation is expected to occur slowly in aqueous environments(SRC). Degradation rates of 4% and 10% were observed for hexamethylene diamine (50 ppm) incubated in water from the Mino River, Japan and seawater off the coast of Japan over a 3 day incubation period(6). According to a classification scheme(7), an estimated BCF value of 1(3,SRC), from an estimated log Kow of 0.35(8,SRC), suggests that bioconcentration in aquatic organisms is low(SRC). [R51] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), hexamethylene diamine, which has an extrapolated vapor pressure of 0.12 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase hexamethylene diamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 6 hours(3,SRC). [R52] BIOD: *Biodegradation is expected to be an important environmental fate for this compound(SRC). Using a standard BOD dilution technique and an activated sludge inoculum, a theoretical BOD of 56% was observed during a 14 day incubation period(1). Using standard BOD dilution techniques and activated sludge inocula, theoretical BOD values of 41% to 56% were observed during a 14 day incubation period following a 6 day acclimation period(2). Based on 14 day BOD data, hexamethylene diamine is considered biodegradable(3). Following a 3 day acclimation period, 90% biodegradation of hexamethylene diamine in an activated sludge inoculum was observed during a 6 day incubation period, with an average COD of 26% per day(4). Degradation rates of 4% and 10% were observed for hexamethylene diamine (50 ppm) incubated in water from the Mino River, Japan and seawater off the coast of Japan over a 3 day incubation period(5). A theoretical oxygen demand between 20 and 60% was observed for hexamethylene diamine in a Warburg apparatus during a 5 day incubation period(6). [R53] ABIO: *The rate constant for the vapor-phase reaction of hexamethylene diamine with photochemically-produced hydroxyl radicals has been estimated as 6.9X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). An experimental pKa value of 11(2), indicates that hexamethylene diamine will not dissociate significantly at environmentally important pH values(SRC). Hexamethylene diamine is not expected to undergo hydrolysis or direct photolysis in the environment due to the lack of functional groups to hydrolyze or absorb UV radiation at environmentally significant wavelengths(SRC). [R54] BIOC: *An estimated BCF value of 1 was calculated for hexamethylene diamine(SRC), using an estimated log Kow of 0.35(1,SRC) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R55] KOC: *Based on a recommended classification scheme(1), an estimated Koc value of 286(SRC), determined from a structure estimation method(2), indicates that hexamethylene diamine is expected to have moderate mobility in soil(SRC). [R56] VWS: *The Henry's Law constant for hexamethylene diamine is estimated as 3.2X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that hexamethylene diamine will be essentially nonvolatile from water surfaces(2,SRC). Hexamethylene diamine is not expected to volatilize from dry soil surfaces based on an extrapolated vapor pressure of 0.12 mm Hg at 25 deg C(3). [R57] RTEX: *CONJUNCTIVAL AND UPPER RESPIRATORY TRACT IRRITATION HAVE BEEN OBSERVED IN WORKERS HANDLING HEXAMETHYLENEDIAMINE. ... AIR CONCN VARIED FROM 2 and 5.5 MG/CU M DURING NORMAL OPERATIONS TO 32.7 AND 131.5 MG/CU M DURING AUTOCLAVE OPERATIONS IN 2 PLANTS. [R12, 3163] *.../1 REPORT INDICATES/ THAT HEXAMETHYLENEDIAMINE MAY HAVE BEEN THE CAUSE OF HEMOLYTIC ANEMIA PREVIOUSLY REPORTED IN NYLON WORKERS EXPOSED TO CRUDE ADIPONITRILE. HOWEVER THIS WAS NOT FOUND...IN A /LATER/ STUDY OF WORKERS EXPOSED TO HEXAMETHYLENEDIAMINE. [R46, 2023] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 11,005 workers (1,701 of these are female) are potentially exposed to hexamethylene diamine in the US(1). Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where hexamethylene diamine is produced or used(2,SRC). [R58] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: +8 hr Time Weighted Avg (TWA): 0.5 ppm. [R59, 2002.35] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R59, 2002.6] OOPL: +Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 5 mg/cu m. [R60] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *THIN-LAYER CHROMATOGRAPHY WAS USED TO DETERMINE HEXAMETHYLENEDIAMINE IN SANITARY-CHEM STUDIES OF POLYMERS. [R61] *Gas chromatographic determination of aliphatic and alicyclic amines as perfluoro fatty acid amides using electron-capture and nitrogen-selective detection is discussed. [R62] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of 1,6-Hexanediamine Dihydrochloride Administered by Drinking Water and Inhalation to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 24 NIH Publication No. 93-3347 (1993) SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 598 R3: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R4: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 656 R5: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R6: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA12 630 R8: SRI R9: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-356 R10: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-81 R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-334 R12: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R13: Perrin DD; Dissociation constants of organic bases in aqueous solution. IUPAC Chem Data Ser: Suppl 1972. Buttersworth, London. (1972) R14: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 708 R16: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R17: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1800 R18: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 565 R19: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1100 R20: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 529 R21: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 547 R22: 49 CFR 171.2 (7/1/96) R23: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 159 R24: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.8171 (1988) R25: EMAN MI ET AL; KHIM PROM-ST, SER; PROIZVOD PERERAB PLASTMASS SINT SMOL 10: 17-9 (1980) R26: GRULA MM, GRULA EA; REPORT: 1-61 (1976) ISS BERC-RI-76-6 R27: Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995. 733 R28: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 168 R29: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 1146 R30: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 1093 R31: Engibaryan LA, Frangulyan RA; Zh Eksp Klin Med 0 (2): 596-9 (1984) R32: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 329 R33: VERNOT EH ET AL; TOXICOL APPL PHARMACOL 42 (2): 417-24 (1977) R34: TKACHENKO AE; GIG TR PROF ZABOL 12: 51 (1976) R35: IZRAILET LI, LAIVINA E; GIG PROF ZABOL 123-6 (1980) R36: Manen CA et al; Teratology 28 (2): 237-42 (1983) R37: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R38: Short RD, et al; Fund Appl Toxicol 16 (3): 490-494 (1991) R39: Hebert CD, et al; Fundam Appl Toxicol 20 (3): 348-59 (1993) R40: Lueke RW, et al; Toxicology 56 (3): 301-13 (1989) R41: Johannsen FR, et al; Fundam Appl Toxicol 9 (3): 504-11 (1987) R42: Johannsen FR, Levinskas GJ; J Appl Toxicol 7 (4): 259-63 (1987) R43: PROCTER AND GAMBLE CO; The Acute Toxicity (LD50) of 1,6-Hexanediamine; 3/8/77; EPA Doc. No. 88-920004935; Fiche No. OTS0542112 R44: MONSANTO CO; Hexamethylene Diamine, Two Generation Rat Reproduction Study; 9/20/85; EPA Doc. No. 88-900000152; Fiche No. OTS0526381 R45: MONSANTO COMPANY; USEPA Status Report: Hexamethylene Diamine (1990), EPA Document No. 8EHQ-0590-0979, Fiche No. OTS0526381-1 R46: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R47: David RM, Heck HD; Localization of 1,6-(14)C diaminohexane (HMDA) in the prostate and the effects of HMDA on early gestation in Fischer-344 rats; Toxicol Lett 17 (1-2): 49-55 (1983) R48: Tinnerberg H, et al; Int Arch Occup Environ Health 67 (6): 367-74 (1995) R49: (1) Budavari S; Merck Index, 12th ed. Whitehouse Station, NJ: Merck and Co. p 902 (1996) R50: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Yaws CL; Handbook of Vapor Pressure Vol 2 C5 to C7 Compounds. Houston, TX: Gulf Publ Co (1994) (5) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Urano K, Kato Z; J Haz Mat 13: 147-59 (1986) (7) Sasaki S; pp. 283-298 in Aquatic Pollutants: Transformation and Biological effects. Hutzinger O, Von Letyold LH, Zoeteman BC, eds Oxford: Pergamon Press (1978) R51: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chemical Series: Supplement. Buttersworth, London (1972) (6) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) R52: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yaws CL; Handbook of Vapor Pressure Vol 2 C5 to C7 Compounds. Houston,TX: Gulf Publ Co (1994) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R53: (1) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Urano K, Kato Z; J Haz Mat 13: 147-59 (1986) (3) Sasaki S; pp. 283-298 in Aquatic Pollutants: Transformation and Biological effects. Hutzinger O, Von Letyold LH, Zoeteman BC, eds Oxford: Pergamon Press (1978) (5) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (6) Wotzka J et al; Dtsc Gewaesserkd Mitt 37: 106-113 (1993) R54: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chemical Series: Supplement. Buttersworth, London (1972) R55: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995)(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R56: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) R57: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Yaws CL; Handbook of Vapor Pressure Vol 2 C5 to C7 Compounds. Gulf Publ Co: Houston, TX (1994) R58: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Leung HW, Paustenbach DJ; Am J Ind Med 18: 717-35 (1990) R59: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R60: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R61: DUKHOVNAYA IS; CHROMATOGRAPHIC DETERMINATION OF HEXAMETHYLENEDIAMINE IN SANITARY-CHEMICAL STUDIES OF POLYMERS; GIG SANIT 8: 49-50 (1980) R62: Skarping G et al; Trace analysis of amines and isocyanates using glass capillary gas chromatography and selective detection. III. Determination of aliphatic and alicyclic amines as perfluoro fatty acid amides using electron-capture and nitrogen-selective detection; J Chromatogr 303 (1): 89-98 (1984) RS: 49 Record 40 of 1119 in HSDB (through 2003/06) AN: 192 UD: 200211 RD: Reviewed by SRP on 03/16/1990 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALLYL-ALCOHOL- SY: *ALCOOL-ALLILCO- (ITALIAN); *ALCOOL-ALLYLIQUE- (FRENCH); *ALLILOWY-ALKOHOL- (POLISH); *ALLYL-AL-; *ALLYLALKOHOL- (GERMAN); *ALLYLIC-ALCOHOL-; *3-HYDROXYPROPENE-; *ORVINYLCARBINOL-; *1-Propene-3-ol-; *2-Propene-1-ol-; *PROPENOL-; *PROPEN-1-OL-3-; *2-PROPENOL-; *2-PROPEN-1-OL-; *PROPENYL-ALCOHOL-; *2-PROPENYL-ALCOHOL-; *SHELL-UNKRAUTTOD-A-; *Vinyl-carbinol-; *WEED-DRENCH- RN: 107-18-6 MF: *C3-H6-O SHPN: UN 1098; Allyl alcohol IMO 3.2; Allyl alcohol STCC: 49 074 25; Allyl alcohol HAZN: P005; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DEHYDRATION OF PROPYLENE GLYCOL [R1] *PREPARED BY HEATING GLYCEROL WITH FORMIC ACID: KAMM, MARVEL, ORG SYN VOL 1, 15 (1921); CF DELABY, DUBOIS, COMPT REND 188, 710 (1929). [R2] *The first commercial process ... employs the alkaline hydrolysis of allyl chloride. Reaction conditions involve steam injection and temp of about 150 deg C ... . Caustic concn is kept low during hydrolysis to minimize diallyl ether by-product formation. The pH is maintained at 10-12. ... A more recent commercial process employs oxidation of propylene to acrolein, which in turn reacts with a secondary alcohol to yield allyl alcohol and a ketone. [R3, p. 2(78) 103] *THE SHELL GLYCEROL PROCESS /CONSISTS OF/ THE REACTION OF ACROLEIN WITH ISOPROPYL ALCOHOL IN THE PRESENCE OF MAGNESIUM AND ZINC OXIDES YIELDING 77% ALLYL ALCOHOL. [R3, p. 1(78) 184] *HYDROGENATION /OF PROPARGYL ALCOHOL/ GIVES ALLYL ALCOHOL ... . [R3, p. 1(78) 247] *Vapor phase hydrogenation /of acrolein/ in the presence of a cadmium-silver catalyst gives allyl alcohol in high yield. [R3, p. 1(78) 284] *Propylene oxide isomerizes to allyl alcohol, propionaldehyde, and acetone. A 95% yield of allyl alcohol from epoxide may be obtained with a supported lithium phosphate catalyst. [R3, p. 19(82) 252] FORM: *INDUSTRIAL GRADE [R4] *Grades of purity: 98% [R5] *A Weed Seed Killer [R6] *Soluble concentrate from Shell Chemical Company [R6] *Hopkins Allyl Alcohol Weed Seed Killer [R6] MFS: *Arco Chemical Co, Hq, 3801 W Chester Pike, Newtown Square, PA 19073; Production site: Bayport, TX 77062 [R7] OMIN: *ALLYL ALCOHOL APPLIED AT 150-200 L/40,000 L WATER/HA WAS MOST EFFECTIVE HERBICIDE WHEN APPLIED 2 WK BEFORE PINE AND BEECH SEED SEEDING ON LIGHT SOIL. [R8] *DISCONTINUED BY DOW CHEMICAL CO. [R9] USE: *MANUFACTURE OF FLAVORINGS, PERFUMES; TO DENATURE ALCOHOL [R10, 377] *MANUFACTURE OF RESINS, PLASTICIZERS, ALLYL CMPD [R2] *Manufacture of fire retardants [R11, 20] *USED IN THE MANUFACTURE OF GLYCEROL [R3, p. 2(78) 103] *USED TO REACT WITH GLYCOL FORMATE TO PRODUCE A LIQUID COATING RESIN, CR-39 (PITTSBURGH PLATE GLASS CO) [R3, p. 18(82) 479] *USED WITHOUT FORMULATION FOR CONTROL OF GRASS SEED, AND APPLIED AS DRENCH TO TOBACCO SEED BEDS. ALSO USED ON NURSERY, VEGETABLE. PLANTING CAN BE ACCOMPLISHED FROM ABOUT 3 TO 10 DAYS AFTER APPLICATION [R12] *CONTACT PESTICIDE FOR WEED SEEDS AND CERTAIN FUNGI [R13, 176] *PRODUCTION OF VARIOUS ALLYL ESTERS OF WHICH THE MOST IMPORTANT ARE DIALLYL PHTHALATE AND DIALLYL ISOPHTHALATE WHICH SERVE AS MONOMERS AND PREPOLYMERS [R14] *Allyl alcohol is oxidized to prepare acrolein [R15] *Herbicide, unspecified, restricted; herbicide, terrestrial, restricted. Used on celery, seed bed; ornamental plants as soil treatment; ornamental nursery plants, uncultivated agricultural areas as soil treatment. [R6] *Intermediate for pharmaceuticals and other organic chemicals, military poison. [R1] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 4.54X10+5 G [R16] *(1975) GREATER THAN 9.08X10+5 G [R16] *(1984) 8.5X10+11 g /ALLYL ALCOHOL, N-PENTYL ALCOHOL, 2-METHYL-1-BUTANOL/ [R17] U.S. IMPORTS: *(1972) NEGLIGIBLE [R16] *(1984) 4.35X10+8 g [R18] *(1986) 2.16X10+6 lb [R19] U.S. EXPORTS: *(1972) NEGLIGIBLE [R16] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MOBILE LIQUID [R20]; *COLORLESS LIQUID [R2]; +Colorless liquid ... [R21, 10] ODOR: *PUNGENT, MUSTARD-LIKE [R2]; +... Pungent, mustard-like odor. [R21, 10] BP: *96-97 DEG C [R2] MP: *-129 DEG C [R22] MW: *58.08 [R22] CORR: *Non corrosive to metals [R23] *Attack some forms of plastics, rubber, and coatings. [R24, 1981.2] CTP: *Critical temp: 272 deg C; critical pressure: 55.5 atm [R25, p. F-66] DEN: *0.8540 @ 20 DEG C/4 DEG C [R2] HTC: *442.4 kg cal/g mol wt at 20 deg C [R25, p. D-274] HTV: *10,577.7 g cal/g mole [R25, p. C-637] OWPC: +log Kow= 0.17 [R26] SOL: *> 10% in water [R22]; *> 10% in alcohol [R22]; *> 10% in ether [R22]; *> 10% in chloroform [R22]; *MISCIBLE WITH PETROLEUM ETHER [R2] SPEC: *INDEX OF REFRACTION: 1.4135 @ 20 DEG C/D [R25, p. C-61]; *SADTLER REFERENCE NUMBER: 284 (IR, PRISM); MAX ABSORPTION (98% SULFURIC ACID): 273 NM (LOG E= 3.67) [R27]; *Allyl alcohol, 99%, exhibits its two strongest infrared absorption bands at wavelengths of 3.0 and 9.7 microns. [R28]; *IR: 97 (Sadtler Research Laboratories IR Grating Collection) [R22]; *UV: 5-10 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R22]; *NMR: 34 (Varian Associates NMR Spectra Catalogue) [R22]; *MASS: 29 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R22] SURF: *25.8 dynes/cm @ 20 deg C in contact with air or vapor [R25, p. F-35] VAPD: *2.00 (AIR= 1) [R29] VAP: *23.8 MM HG @ 25 DEG C [R30, 602] VISC: *2.145 CP at 0 deg C; 1.49 CP at 15 deg C; 1.363 CP at 20 deg C; 1.07 CP at 30 deg C; 0.914 CP at 40 deg C; 0.553 CP at 70 deg C [R25, p. F-41] OCPP: *72.3% ALLYL ALCOHOL AND 27.7% WATER FORMS A CONSTANT BOILING MIXTURE, BP @ 87.5 DEG C [R2] *1 MG/L= 422 PPM; 1 PPM= 2.37 MG/CU M @ 25 DEG C, 760 MM HG; DENSITY OF SATURATED AIR: 1.031 @ 25 DEG C (AIR= 1); PERCENT IN SATURATED AIR: 3.13% @ 25 DEG C [R31, 4663] *WT/GAL 7.11 LB @ 20 DEG C [R1] *Becomes a glass at -190 deg C [R32] *Saturated concn in air: 57 g/cu m at 20 deg C; 98 g/cu m at 30 deg C [R13, 176] *Ratio of specific heats of vapor: 1.12; heat of soln: negligible (est); Reid vapor pressure: 1.0 psia [R5] *Liquid heat capacity= 0.493 BTU/lb-F @ 70 deg F; Liquid thermal conductivity= 1.123 BTU-in/hr-sq ft-F at 77.09 deg F; Saturated vapor density= 0.00375 lb/cu ft @ 70 deg F; Ideal gas heat capacity= 0.327 BTU/lb-F @ 70 deg F [R5] *Coefficient of expansion: 0.00101/deg C at 20 deg C; specific heat: 0.665 g cal/g deg C at 20-95 deg C (liquid) [R32] *Forms binary azeotropes with allyl ether, benzene, 1-bromobutane, 1-bromopropane, chlorobenzene, 1-chlorobutane, 1-chloro-3-methylbutane, 1-chloro-2-methylpropane, cyclohexane, cyclohexene, diethoxymethane, ethyl propionate, ethyl sulfide, heptane, hexane, isobutyl formate, 3-methyl-2-butanone, methyl butyrate, methyl carbonate, methylcyclohexane, methyl isobutyrate, octane, 2-pentanone, 3-pentanone, propyl acetate, propyl alcohol, propyl ether, toluene [R32] *MOBILE LIQUID [R20] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R33] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R33] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R33] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R33] +Evacuation: Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R33] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R33] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R33] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R33] FPOT: *AT 22 DEG C, LIQUID GIVES OFF FLAMMABLE CONCN OF VAPOR IN AIR. [R34] NFPA: +Health: 4. 4= Materials that, on very short exposure, could cause death or major residual injury, including those that are too dangerous to be approached without specialized protective equipment. A few whiffs of the vapor or gas can cause death, or contact with the vapor or liquid may be fatal, if it penetrates the fire fighter's normal protective gear. The normal full protective clothing and breathing apparatus available to the typical fire fighter will not provide adequate protection against inhalation or skin contact with these materials. [R35, p. 325-12] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R35, p. 325-12] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R35, p. 325-12] FLMT: *LOWER 2.5%; UPPER 18.0% (IN AIR) [R30, 603] FLPT: +72 deg F (22 deg C) (closed cup) [R35, p. 325-12] *90 deg F (open cup) [R32] AUTO: *443 deg C (in air); 348 deg C (in oxygen) [R32] FIRP: +USE DRY CHEM, ALCOHOL FOAM, OR CARBON DIOXIDE; WATER MAY BE INEFFECTIVE. BUT WATER SHOULD BE USED TO KEEP FIRE EXPOSED CONTAINERS COOL. IF LEAK OR SPILL HAS NOT IGNITED, USE WATER SPRAY TO DISPERSE VAPORS AND TO PROTECT MEN ATTEMPTING TO STOP LEAK. WATER SPRAY MAY BE USED TO FLUSH SPILLS AWAY FROM EXPOSURES AND TO DILUTE SPILLS TO NONFLAMMABLE MIXTURES. [R35, p. 49-13] *Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. [R36] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame consider evacuation of one-third (1/3) mile radius. [R36] TOXC: +WHEN HEATED, IT EMITS TOXIC FUMES. [R35, p. 49-13] *Toxic gases and vapors (such as carbon monoxide) may be released in a fire involving allyl alcohol. [R24, 1981.2] OFHZ: +VAPOR FORMS EXPLOSIVE MIXTURES WITH AIR. VAPOR HEAVIER THAN AIR (VAPOR-AIR DENSITY @ 100 DEG F, 1.1) AND MAY TRAVEL A CONSIDERABLE DISTANCE TO A SOURCE OF IGNITION AND FLASH BACK. [R35, p. 49-13] EXPL: *LOWER 2.5%; UPPER 18% (IN AIR) ... EXPLOSION HAZARD: MODERATE, WHEN EXPOSED TO FLAME. [R29] REAC: +A reaction between allyl alcohol and carbon tetrachloride produced trichlorobutylene epoxide (oxide) and dichlorobutylene epoxide (oxide), a mixture which during distillation proved to be unstable and detonated in the still. [R35, p. 491-12] *When aqueous sodium hydroxide was added to a mixture of /2,4,6-trichlorotriazine/ and /allyl/ alcohol at 28 deg C instead of the normal 5 deg C, a rapidly accelerating reaction led to the rupture of the bursting disc and a gasket, and subsequently to a flash fire and explosion. [R37] +Mixing allyl alcohol and chlorosulfonic acid in a closed container caused the temperature and pressure to increase. [R35, p. 491-12] +Mixing allyl alcohol and 70% nitric acid in a closed container caused the temperature and pressure to increase. [R35, p. 491-12] +Mixing allyl alcohol and oleum in a closed container caused the temperature and pressure to increase. [R35, p. 491-12] +Allyl alcohol and tri-n-bromomelamine exploded fifteen minutes after mixing at room temperature. [R35, p. 491-12] +As a benzene extract of allyl benzenesulfonate was prepared from allyl alcohol and benzene sulfonyl chloride in the presence of aqueous sodium hydroxide, under vacuum distillation two fractions came off, then the temperature rose to 135 deg C, when the residue darkened and exploded. [R35, p. 491-12] +Mixing allyl alcohol and 96% sulfuric acid in a closed container caused the temperature and pressure to increase. [R35, p. 491-12] +Diallyl phosphite is made from allyl alcohol and phosphorus trichloride. When the product is distilled in vacuo in a carbon dioxide stream, explosions usually occur after about two-thirds is distilled. [R35, p. 491-12] +Strong oxidizers, acids, carbon tetrachloride [Note: Polymerization may be caused by elevated temperatures, oxidizers, or peroxides]. [R21, 10] ODRT: *1.70X10-2 mg/l (gas) (odor detection in water, chemically pure) [R38] *150.0 mg/cu m [R39] *0.78 ppm [R5] *Odor thresholds 1.9500 mg/cu m (low) 5.0000 mg/cu m (high). [R39] SERI: *... CONCN LIKELY TO BE INJURIOUS, IN SHORT PERIOD OF TIME WILL BE PAINFUL TO EYES AND NOSE. [R10, 381] *Severe eye irritation results from exposure to 25 ppm ... 5 ppm is slightly irritating to some individuals. [R40] *... Irritation of the nose begins at 10-15 ppm ... . [R41] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with allyl alcohol. Employees should be provided with and required to use splash proof goggles where there is any possibility of liquid allyl alcohol contacting the eyes. [R24, 1981.2] *Breakthrough times greater than one hour reported by (normally) two or more testers for butyl rubber and chlorinated polyethylene. Breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers neoprene and polyvinyl alcohol. No data for polyurethene, polyvinyl chloride, and rubber. [R42] +Wear appropriate personal protective clothing to prevent skin contact. [R21, 11] +Wear appropriate eye protection to prevent eye contact. [R21, 11] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R21, 11] +Recommendations for respirator selection. Max concn for use: 20 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R21, 11] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R21, 11] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R21, 11] OPRM: *PREVENTIVE MEASURES ... INCLUDE PROVISION OF CLOSED SYSTEMS, IF THIS IS NOT FEASIBLE, RESPIRATORY PROTECTION BY EXHAUST VENTILATION ... . [R10, 381] *STORAGE TANKS OUTSIDE BUILDING SHOULD BE BUNDED TO PREVENT SPREAD OF ACCIDENTALLY ESCAPING LIQUID, AND RAMPED SILL SHOULD BE CONSTRUCTED AT DOORWAYS OF STOREROOMS TO RETAIN FLAMMABLE LIQ THAT MAY ESCAPE FROM STORAGE VESSELS INSIDE. [R34] *BEFORE HEAT IS APPLIED FOR PURPOSE OF WELDING OR CUTTING VESSEL WHICH HAS CONTAINED ALLYL ALCOHOL, VESSEL SHOULD BE EMPTIED AND PURGED WITH STEAM AND AIR TO REMOVE EVERY TRACE OF FLAMMABLE LIQ AND VAPOR. [R34] *Clothing contaminated with liquid allyl alcohol should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of allyl alcohol from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the allyl alcohol, the person performing the operation should be informed of allyl alcohol's hazardous properties. [R24, 1981.3] *Skin that becomes contaminated with liquid allyl alcohol should be immediately washed or showered to remove any allyl alcohol. Eating and smoking should not be permitted in areas where liquid allyl alcohol is handled, processed, or stored. Employees who handle liquid allyl alcohol should wash their hands thoroughly before eating, smoking, or using toilet facilities. [R24, 1981.3] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R24, 1981.2] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R36] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. Do not handle broken packages unless wearing appropriate personal protective equipment. [R36] *Evacuation: If material leaking, not on fire, consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R36] +Contact lenses should not be worn when working with this chemical. [R21, 11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Where there is any possibility of exposure of an employee's body to liquid allyl alcohol, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. [R24, 1981.3] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Employees who handle liquid isobutyl alcohol should wash their hands before eating or smoking. /Isobutyl alcohol/ [R24, 1981.3] +The worker should immediately wash the skin when it becomes contaminated. [R21, 11] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R21, 11] SSL: *UPON SEVERAL YEARS STORAGE, IT POLYMERIZES TO THICK SYRUP WHICH BECOMES BRITTLE RESINOID MASS WHEN TREATED WITH ETHER [R2] *Stable in UV light [R23] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R43] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R44] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R45] STRG: +Separate from oxidizing materials. Store in a dry, cool, well-ventilated location. [R35, p. 49-13] *KEEP TIGHTLY CLOSED. [R2] *Storage temp: ambient; venting: pressure-vacuum [R5] CLUP: *Spills and leakage: absorb on paper. Evaporate on a glass or iron dish in hood. Burn the paper. [R11, 21] *If allyl alcohol is spilled or leaked, the following steps should be taken: remove all ignition sources, ventilate area of spill or leak, and for small quantities absorb on paper towels. Evaporate in a safe place, such as a fume hood. Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be collected and atomized in a suitable combustible chamber. Allyl alcohol should not be allowed to enter a confined space, such as a sewer, because of the possibility of an explosion. [R24, 1981.3] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquids with fly ash, cement powder, sawdust, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. [R36] *Environmental considerations: Water spill: If dissolved, in region of 10 ppm or greater concentration apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R36] *Environmental considerations: Air spill: Apply water spray or mist to knock down vapors. [R36] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P005, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R46] *Prior to incineration, dilution of this highly toxic liquid with a flammable solvent is recommended. It is miscible with water and most organic solvents. The cmpd is hazardous to wildlife and is toxic to plants and seeds. It has no lasting effect on soil although temporary sterilization occurs. Recommendable methods: Incineration, adsorption, landfill, discharge to sewer. Peer-review: Adsorb on inorganic adsorbent before landfill. Dilute small amounts with much water and discharge to sewer. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R47] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R48] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R48] *Allyl alcohol is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R49] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R50] *Chemical Treatability of Allyl Alcohol; Concentration Process: Activated Carbon; Chemical Classification: Alcohols; Scale of Study: Isotherm Test; Type of Wastewater Used: Pure Compound; Influent Concentration: 1000 ppm; Results of Study: 21.9% reduction; final concn of 789 ppm; capacity was 0.024 g/g of carbon. Adsorbability found to increase with molecular weight. For compounds of < 4 carbons, the order of decreasing adsorption was: undissociated organic acids, aldehydes, esters, ketones, alcohols (when > 4 carbons, alcohols moved ahead of esters), and glycols. Aromatics had greatest adsorption. Results of two component isotherm tests could be predicted from single compound tests; however, in four component tests, only about 60% of predicted adsorption occurred. Continuous columns produced 60-80% of theoretical isotherm capacity. Carbon dose was 5 g/l Westvaco Nuchar. [R51] *Alyl alcohol may be disposed of 1. By absorbing it in vermiculite, dry sand, earth or a similar material and disposing in a secured sanitary landfill. 2. By atomizing in a suitable combustion chamber. [R24, 1981.4] *The following wastewater treatment technology has been investigated for allyl alcohol: Activated carbon. [R52] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R53, 2002.14] MEDS: */Monitor/ hepatic, renal, and respiratory function. [R54] *The following medical procedures should be made available to each employee who is exposed to allyl alcohol at potentially hazardous levels: Initial Medical Screening: Employees should be screened for history of certain medical conditions (listed below) which might place the employee at increased risk from allyl alcohol exposure. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of allyl alcohol might cause exacerbation of symptoms due to its irritant properties. Skin disease: Allyl alcohol can cause skin burns. Persons with existing skin disorders may be more susceptible to the effects of this agent. Liver disease: the importance of the liver in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Kidney disease: the importance of the kidney in the elimination of toxic substances justifies special consideration in those with impaired renal function. Eye disease: Because allyl alcohol is reported to cause eye injury, those with existing eye diseases may be at increased risk from exposure. Any employee developing the above-listed conditions should be referred for further screening. /SRP: Allyl alcohol is the most commonly used experimental model for a hepatic periportal toxicant. The possibility of hepatic disease should be considered in humans exposed to allyl alcohol because of its extreme periportal toxicity in experimental animals./ [R24, 1981.1] HTOX: *... ABSORBED THROUGH INTACT SKIN IN TOXIC AND EVEN LETHAL CONCN. DERMATITIS OF VARIABLE TYPES AND DEGREES RESULTS, IN ADDITION TO FIRST AND SECOND-DEGREE BURNS WITH VESICULATION. [R55] *... LIQUID MAY PRODUCE ... SUPERFICIAL NECROSIS. ... INHALED VAPOR MAY LEAD TO PULMONARY EDEMA WITH SLOWLY DEVELOPING DISTRESS. [R56] *SEVERE EYE IRRITATION RESULTS FROM EXPOSURE TO 25 PPM ... 5 PPM IS SLIGHTLY IRRITATING TO SOME INDIVIDUALS. CORNEAL NECROSIS HAS BEEN REPORTED TO RESULT IN TEMPORARY BLINDNESS ... SKIN PENETRATION MAY LEAD TO SERIOUS SYSTEMIC INJURY (VISCERAL CONGESTION, PERIPORTAL CONGESTION OF THE LIVER, HEMATURIA, AND NEPHRITIS) ... /ALLYL ALCOHOL/ PRODUCES A SYNDROME OF LACRIMATION, PHOTOPHOBIA, BLURRED VISION, AND RETROBULBAR PAIN. ALTHOUGH THESE SYMPTOMS PERSIST FOR SOME HOURS FOLLOWING EXPOSURE, NEITHER INCREASED SENSITIVITY NOR TOLERANCE APPEAR TO DEVELOP. [R40] *ETHANOL AND CERTAIN SHORT CHAIN ARYL (BENZYL) AND ALIPHATIC (PROPYL, BUTYL) ALCOHOLS PRODUCED UP TO 10 FOLD INCR IN CYCLIC AMP CONCN IN PURIFIED HUMAN PERIPHERAL BLOOD LYMPHOCYTES. ETHANOL CONCN AS LOW AS 80 MG/DL PRODUCED SIGNIFICANT ELEVATIONS IN LYMPHOCYTE CYCLIC AMP. [R57] NTOX: *BY INHALATION, REPEATED EXPOSURE OF RATS TO 40, 60 and 100 PPM CAUSED GASPING, SEVERE DEPRESSION AND NASAL DISCHARGE, AND AT HIGHEST LEVELS SOME ANIMALS DIED BY 10TH EXPOSURE. ... /RATS, RABBITS, GUINEA PIGS AND DOGS WERE/ EXPOSED TO ... 7 PPM 7 HR A DAY FOR 6 MONTHS. ... LIVER SHOWED CLOUDY SWELLING AND FOCAL NECROSIS, AND KIDNEY NECROSIS OF CONVOLUTED TUBULES AND PROLIFERATION OF INTERSTITIAL TISSUE; THESE CHANGES WERE MILD AND REVERSIBLE. [R10, 379] *APPLICATION TO EYES CAUSES ERYTHEMA OF CONJUNCTIVA AND SWELLING OF CORNEA, SOMETIMES WITH OPACITY, BUT NO PERMANENT INJURY. [R10, 380] *RAPID DROP IN CAROTID BLOOD PRESSURE, DEFINITE REDUCTION IN RESPIRATORY RATE AND AMPLITUDE, AND INCREASE IN HEMOCONCENTRATION (HEMATOCRIT), BUT NO INCREASE IN CONCN OF HISTAMINE IN PLASMA, FOLLOWED IV INJECTION OF 40 MG/KG INTO A DOG. [R58] *ALLYL ALCOHOL IS HIGHLY PHYTOTOXIC. [R20] *THE LIVERS OF RATS SHOWED PERIPORTAL NECROSIS AND ELEVATION OF HEPATIC GLUTATHIONE WITHIN 24 HR FOLLOWING THE ADMIN OF ALLYL ALCOHOL. [R59] *0, 1, 3, 24, and 72 HR AFTER ORAL ADMIN TO RATS OF 1 ML/100 G BODY WT OF 1% ALLYL ALCOHOL, LIVERS CONTAINED 1.05, 1.088, 1.37, 1.21, AND 1.51 (ARBITRARY) UNITS OF MALONIC ALDEHYDE AND 4.30, 5.68, 10.97, 6.67, AND 7.13 (ARBITRARY) UNITS OF CONJUGATED DIENES. ALANINE AMINOTRANSFERASE ACTIVITY WAS VERY HIGH DURING THIS PERIOD. NECROSIS IN THE HEPATOCYTE AND KUPFFER CELL CYTOPLASM WAS OBSERVED FROM THE 4TH HR AFTER ADMIN WHICH SHOWS THAT THE ONSET OF LIPID PEROXIDATION PRECEDES NECROSIS. [R60] *30 MG/KG ORALLY IN RATS CAUSE MARKED PERIPORTAL NECROSIS WHICH WAS ASSOC WITH LOSSES OF ALCOHOL DEHYDROGENASE AND SUCCINATE DEHYDROGENASE ACTIVITIES IN LIVER. BENZO(A)PYRENE HYDROXYLASE AND HEPATIC CONTENT OF CYTOCHROME P450 WERE DECR SHOWING INHIBITION OF XENOBIOTIC METABOLISM. [R61] *96 HR AFTER SINGLE ADMIN OF ALLYL ALCOHOL, ACIDOPHILIA, NECROSIS AND VACUOLATION OF PANCREATIC ACINAR CELLS OF RATS WERE NOTED. ELECTRON MICROSCOPY REVEALED CYTOPLASMIC LIPID DROPLETS, MITOCHONDRIAL DEGENERATION AND NECROSIS IN ACINAR CELLS. [R62] *MUTAGENICITY OF VINYL COMPOUNDS WERE TESTED IN 5 STRAINS OF SALMONELLA TYPHIMURIUM. ALLYL ALCOHOL WAS MUTAGENIC IN MORE THAN 1 STRAIN. [R63] *THREE HR AFTER ORAL ADMIN TO RATS OF 1 ML/100 G BODY WT OF ALLYL ALCOHOL, CYTOCHROME P450 WAS INCR BY 33% IN LIVER MICROSOMES. AMINOPYRINE DEMETHYLASE AND DIMETHYLANILINE DEMETHYLASE WERE STIMULATED. ACTIVITY OF MICROSOMAL HYDROXYLATION SYSTEM GRADUALLY DECREASED. [R64] *0.05 ML/KG OF ALLYL ALCOHOL ADMIN ORALLY TO MICE CAUSED DEPLETION OF HEPATIC GLUTATHIONE ACTIVITY. THE EXTENT OF DEPLETION WAS 44.5% OF CONTROL VALUES. [R65] *ALLYL ALCOHOL WAS ADMIN TO RATS IN DRINKING WATER FOR 15 WK. DOSE-RELATED REDN IN FLUID INTAKE WAS OBSERVED. GROWTH AND FOOD CONSUMPTION DECR IN BOTH SEXES GIVEN 800 PPM AND IN MALES ADMIN 200 PPM. LESS URINE WAS PRODUCED IN MALES ADMIN 100 PPM OR MORE AND IN FEMALES ADMIN 200 OR 800 PPM. LIVER, SPLEEN, AND KIDNEY WT INCR. [R66] *CYCLIC(C)AMP WAS STUDIED IN MALE SPRAGUE-DAWLEY RATS ADMIN A SINGLE DOSE OF ALLYL ALCOHOL. ADRENAL (C)AMP CONCN INCR 10 HR AFTER INTOXICATION COMPARED TO CONTROLS. IN FINAL STAGE OF EXPERIMENT (30-39 HR AFTER APPLICATION) ALL INTOXICATION WAS ASSOC WITH SIGNIFICANT INCR IN ADRENAL (C)AMP CONCN. [R67] *ALLYL ALC (20 MG/KG) ENHANCED MITOTIC ACTIVITY OF ADRENOCORTICAL CELLS IN RATS AFTER 24 HR BUT ACTIVITY RETURNED TO NORMAL VALUES WITHIN FOLLOWING 12 HR. [R68] *The effects of allyl alcohol administration were evaluated in male rats at 4-5, 14-15, and 24-25 months of age to determine if susceptibility to hepatotoxic injury is modified as a consequence of aging. Parameters measured were severity of hepatocellular necrosis as judged by light microscopy of liver sections, activity of alanine aminotransferase and aspartate aminotransferase in serum, and hepatic microsomal cytochrome p450 content and NADPH-cytochrome p450 reductase activity. Allyl alcohol toxicity was more severe in middle-aged and old rats than in young-adult rats. [R69] *Single necrogenic doses of allyl alcohol admin to Fischer 344 rats were used to produce cell specific injury in centrilobular hepatocytes, periportal hepatocytes, and bile duct cells, respectively. Allyl alcohol administration increased serum alanine aminotransferase activity but had no effect on serum gamma-glutamyl transferase activity. [R70] *Allyl alcohol was investigated for its property as sensory irritant in Ssc:CF-1 mice. The concentration of the chemical necessary to depress the respiratory rate by 50% (RD50) due to sensory irritation of the upper respiratory tract was 3.9 ppm. No pulmonary irritation was found at the concn causing a 50% decrease in respiratory rate. [R71] *Several alpha-, beta-unsaturated carbonylic cmpd and their corresponding allylic alcohols were tested in a modified Salmonella typhimurium assay with and without metabolic activation by S9 mix. Allyl alcohol exerted a significant direct mutagenic activity (750 revertants/umol). [R72] *The effect of acute exposure of rats to allyl alcohol (0.05 ml/kg, ip) on the activity of enzymes of hepatic phase I (cytochrome p450-linked microsomal monooxygenases, epoxide hydrolase) and phase II (glucuronyl-, glutathione-, acetyl- and sulfotransferases) biotransformation were studied in rats. Allyl alcohol reduced hepatic cytochrome p450 in liver, and the activities of ethylmorphine demethylase, benzphetamine demethylase, benzo[a]pyrene hydroxylase, and ethoxyresorufin deethylase. No significant decrease in epoxide hydrolase or glucuronyltransferase activities were observed. The activities of cytosolic conjugating enzymes (glutathione-, sulfo- and acetyltransferases) also were minimally affected by toxic liver injury. [R73] *Five industrial and agricultural chemicals incl allyl alcohol were tested for their ability to induce reverse mutations in Salmonella typhimurium and forward mutations in Streptomyces coelicolor and Aspergillus nidulans. Allyl alcohol was completely negative in all test systems. [R74] *In rats a single dose of allyl alcohol (100 mul/kg) was given to produce periportal liver damage. The prothrombin index was reduced to a minimum after 12 hr and reestablished after 24 hr. The galactose elimination capacity was not changed. Hepatic glutathione content was unchanged for the first 24 hr but was then elevated two-fold. Microsomal D-nitroanisole demethylase showed a slight initial increase and a subsequent reduction. Thus, in chemical liver damage ribosomal function is more vulnerable than cytosolic phosphorylation of carbohydrate. [R75] *Male NMRI mice were fed a sucrose diet for 48 hr in order to reduce the hepatic glutathione content and to level off its diurnal variation. After administration of allyl alcohol (AA: 1.1 mmol/kg), hepatic glutathione (24.3 +/- 7.0 nmol GSH/mg protein) was almost totally lost within the first 15 min (less than 0.5 nmol GSH/mg protein). Subsequently, a massive lipid peroxidation was observed, ie, the animals exhaled 414 +/- 186 nmol ethane/kg/hr compared to 0.9 +/- 0.8 of controls, and the hepatic TBA-reactive compounds had increased from 55 +/- 16 pmol/mg protein in controls to 317 +/- 163 after 1 hr. Concomitantly, a 40-45% loss of the polyunsaturated fatty acids (arachidonic and docosahexaenoic acid) in the liver lipids was observed. About 80% of the cytosolic alcohol dehydrogenase activity and about 50% of the microsomal p450-content were destroyed. In vivo-inhibition of alcohol dehydrogenase by pyrazole or induction of aldehyde dehydrogenase by phenobarbital abolished allyl alcohol-induced liver damage as well as glutathione depletion and lipid peroxidation, while inhibition of aldehyde dehydrogenase by cyanamide made a subtoxic dose of allyl alcohol (0.60 mmol/kg) highly toxic. In vitro, acrolein alone failed to initiate lipid peroxidation in soy bean phospholipid liposomes or in mouse liver microsomes. Thus, acrolein not only impairs the glutathione defense system but also directly destroys cellular proteins and evokes lipid peroxidation by an indirect iron-dependant mechanism. [R76] *The possible involvement of thiols and adenine nucleotides in the selective toxicity to periportal regions by allyl alcohol was evaluated in isolated perfused rat livers. Infusion of allyl alcohol (350 microM) for 20 min depleted hepatic glutathione content by 95% in both regions of the liver lobule yet damage was undetectable as indexed by release of lactate dehydrogenase or uptake of trypan blue. Perfusion for an additional 40 min in the absence of allyl alcohol resulted in lactate dehydrogenase release (2400 U/l) and uptake of trypan blue by 75% of hepatocytes in periportal regions of the liver lobule; however dye was not taken up by cells in pericentral areas. Because the content was depleted in the undamaged pericentral area, it was concluded that thiol depletion alone cannot explain local toxicity to periportal regions by allyl alcohol. [R77] *Two well known hepatotoxicants, allyl alcohol and bromobenzene, were studied using an in vitro system of cultured liver slices from control and phenobarbital-treated rats, respectively. Dose- and time-dependent increases in media lactate dehydrogenase (LDH), and decreases in slice K+ content and in protein synthesis were observed in rat liver slices incubated with either compound at concentrations between 0.1 and 1 mM over a period of 6 hr. Additionally, the toxicity of either bromobenzene or allyl alcohol, evaluated at 4 hr, was inhibited when slices were preincubated for 30 min with beta-ethyl-2,2-diphenylvalerate hydrochloride (SKF 525-A) (0.1 mM) or pyrazole (1.0 mM), respectively. [R78] *The role of calcium in allyl alcohol-induced hepatotoxicity was investigated in the isolated hemoglobin-free perfused rat liver. At a Ca2+ concentration of 2.5 mmol/l in the perfusate, allyl alcohol (initial concentration 1.17 mmol/l) produced an enhanced release of SGPT and sorbitol dehydrogenase (SDH) from the liver, an increase in the lactate/pyruvate ratio of the perfusate, a decrease in hepatic oxygen consumption and an increase of both hepatic calcium and malondialdehyde content. In the absence of Ca2+ in the perfusate, no hepatic calcium accumulation occurred with allyl alcohol, but all other signs of hepatic damage were as severe as with 2.5 mmol/l Ca2+. On the other hand, high extracellular Ca2+ (5 mmol/l) alone led to a threefold increase of liver calcium but produced only marginal hepatotoxicity and only slightly enhanced the hepatotoxic effects of allyl alcohol. The concentrations of allyl alcohol in the perfusate were not altered at different Ca2+ concentrations. [R79] *The toxicity of allyl alcohol was studied in freshly isolated renal epithelial cells prepared from male and female rats. Cells from female rats demonstrated a greater susceptibility to allyl alcohol toxicity as assessed by glutathione depletion and loss of cell viability. The sensitivity of female rat renal cells appears to relate to the higher activity of alcohol dehydrogenase found in the female rat kidney, which metabolizes allyl alcohol to the highly reactive aldehyde, acrolein. Pyrazole, an inhibitor of alcohol dehydrogenase, abolished the cytotoxic effects of allyl alcohol whereas inhibition of aldehyde dehydrogenase by disulfiram treatment was found to increase the sensitivity of renal cells to the effects of allyl alcohol. These results indicate that acrolein is the toxic metabolite responsible for the renal cell injury following eposure to allyl alcohol, and unless immediately inactivated acrolein interacts with critical nucleophilic sites of the cell and initiates cell injury. [R80] *Male CD-1 mice were tested with carbon tetrachloride (1 ml/kg, ip), or allyl alcohol (0.05 ml/ kg, ip) or both 24 h prior to sacrifice. The livers were removed, homogenized and mitochondrial preparations were fractionated. The mitochondrial pellet from allyl alcohol-treated livers was characterized by a preponderance of condensed mitochondria whether carbon tetrachloride was given also or not. The mitochondrial fraction from carbon tetrachloride-treated mice failed to utilize oxygen whereas that fraction from mice given allyl alcohol did not differ from control in either its basal oxygen consumption (state 4) or oxygen utilization after the addition of adenosine diphosphate (state 3). State 4 respiration differed slightly but significantly from control in mitochondria from mice given both allyl alcohol and carbon tetrachloride whereas state 3 respiration was greatly and significantly decreased from that of control values. Electron micrographs of liver slices from mice given allyl alcohol or the combination of allyl alcohol and carbon tetrachloride showed normal mitochondrial morphology. [R81] *The influence of aging on the toxicity of allyl alcohol was studied in hepatocytes isolated from male Fischer 344 rats. Initial values for trypan blue uptake, lactate dehydrogenase (LDH) release, alanine aminotransferase release, and glutathione content were similar in cells isolated from rats aged 5, 15, or 26 months. Incubation with 0.1 to 0.8 mM allyl alcohol resulted in a dose- and time-dependent loss of viability. Inhibition by pyrazole of allyl alcohol-induced lactic dehydrogenase (LDH) release from hepatocytes also was affected by age. Total protection was observed for cells from young rats whereas no protection was found for those of old rats. Cells from middle-aged rats were between the extremes. [R82] *Male CD1 mice and male CD rats were administered allyl alcohol, 0.05 ml/kg in corn oil, ip, 24 hr prior to sacrifice. Pentobarbital sleeping time, serum glutamic pyruvic transaminase (SGPT), histologic evidence of liver necrosis, and respiratory activity of liver mitochondria were used as indices of hepatotoxicity. Allyl alcohol treatment resulted in a significant decrease in pentobarbital sleeping time in mice (p < 0.05), but significantly prolonged the sleeping time in rats (p < 0.005). SGPT was significantly elevated in treated mice (3-fold, p < 0.05) and rats (20-fold). There was no visible liver necrosis in mice; livers from treated rats showed variable necrosis. Micrographs of mitochondria from treated rats showed flocculent densities in the matrix compartment. Mitochondria from control mice and rats and treated mice had normal state 3 respiratory activity and normal respiratory control. In treated rats state 3 respiratory activity was depressed relative to the control value and respiratory control was absent, indicating inability to carry out oxidative phosphorylation. [R83] NTXV: *LD50 Rabbit percutaneous 89 mg/kg; [R84] *LD50 Mouse oral 85 mg/kg; [R85] *LD50 Rat oral 64 mg/kg; [R2] *LC50 Rat inhalation 165 ppm/4 hr; [R86] *LC50 Rat inhalation 76 ppm/1 hr; [R86] *LD50 Mouse intraperitoneal 60 mg/kg; [R87] ETXV: *LD50 Goldfish 1 mg/l/24 hr modified ASTM 1345 bioassay; [R13, 177] POPL: *Persons with pre existing skin disorders may be more susceptible to the effects of this agent. ... In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of allyl alcohol might cause exacerbation of symptoms due to its irritant properties. [R24, 1981.1] ADE: *ALLYL ALCOHOL IS READILY ABSORBED THROUGH INTACT SKIN. [R55] *ALLYL ALCOHOL IS APPARENTLY OXIDIZED READILY SINCE WITHIN FEW MIN AFTER IV INJECTION OF RATS WITH THE DOSAGE OF 30 MG/KG, VENA CAVA BLOOD CONTAINED AVG CONCN OF ABOUT 24 UG/ML; WITHIN 15 MIN CONCN WAS ABOUT 4 UG/ML AND WITHIN 1 HR THE ALCOHOL HAD ALMOST DISAPPEARED FROM THE BLOOD. DURING CONSTANT IV INFUSION THE ALLYL ALCOHOL DISAPPEARED AT RATE OF ABOUT 23 MG/HR. DURING THE PERIOD OF 15-120 MIN AFTER ADMIN OF SINGLE ORAL DOSE OF ALLYL ALCOHOL (120 MG/KG) TO RATS, MEAN CONCN OF THIS ALCOHOL IN THE PORTAL VEIN WAS BETWEEN 9 AND 15 UG/ML. [R31, 4668] *... ABSORBED THROUGH INTACT SKIN IN TOXIC AND EVEN LETHAL CONCN. [R55] *ABSORPTION THROUGH THE SKIN LEADS TO DEEP MUSCLE PAIN, PRESUMABLY DUE TO SPASM. [R88] METB: *THE BIOTRANSFORMATION OF ALLYL ALCOHOL WAS STUDIED IN RAT LIVER AND LUNG PREPN. ACRYLIC ACID WAS FORMED FROM ALLYL ALCOHOL. LUNG AND LIVER MICROSOMAL EPOXIDATION PRODUCTS WERE ALSO IDENTIFIED. [R89] *Rats treated with single ip doses (0.05 ml/kg) of allyl alcohol showed significantly greater hepatic necrosis and elevation of plasma glutamic-pyruvic transaminase (GPT) levels 24 hr later than rats given the same dose of deuterium-labeled allyl alcohol (d2-allyl alcohol). The covalent binding of radiolabel to hepatic proteins of rats treated with (14)C allyl alcohol was three-fold greater than that in rats given the same dose of d2-(14)C allyl alcohol. The formation of acrolein and acrylic acid by hepatic 9000X g and cytosol fractions from d2-allyl alcohol was significantly less than that from allyl alcohol. The relationship of rate of formation of reactive metabolite (acrolein) to toxicity of allyl alcohol and d2-allyl alcohol is demonstrated. [R90] *A linear incr in NADH fluorescence was observed when 25-150 uM allyl alcohol was infused into livers of rats; however, when allyl alcohol /concn/ exceeded 200 umol, oxygen uptake by the liver was inhibited 30-40%, and a large increase in NADH fluorescence occurred. Allyl alcohol (350 uM) inhibited oxygen uptake only in periportal regions. The maximal increase in NADH fluorescence due to allyl alcohol infusion (100 umol) was greater in pericentral than in periportal region. 4-Methylpyrazole (80 umol), an inhibitor of alcohol dehydrogenase, prevented the fluorescence incr due to allyl alcohol in both regions, indicating that the changes were due entirely to NADH generated from alcohol dehydrogenase-dependent allyl alcohol metabolism. Local rates of allyl alcohol metabolism were 23 and 31 mumol/g/hr in periportal and pericentral regions, respectively. Thirty min after the ip injection of a necrogenic dose of allyl alcohol in vivo in the portal vein and vena cava the concn were 1210 and 530 um, respectively. Since allyl alcohol is metabolized in both regions of the liver lobule, the hypothesis that the zone-specific hepatotoxicity results from its exclusive metabolism to acrolein in periportal regions seems unlikely. [R91] *Rates of allyl alcohol metabolism in periportal and pericentral regions of the liver lobule were measured to determine whether the zonal toxicity due to allyl alcohol results from its selective metabolism in periportal regions. Infusion of allyl alcohol into perfused livers from fed, phenobarbital-treated rats caused an increase in nicotinamide adenine dinucleotide, reduced form (NADH) fluorescence (366 leads to 450 nm) measured with a large-tipped (2 mm) light guide placed on the surface of the liver. A linear increase in NADH fluorescence was observed when 25-150 uM allyl alcohol was infused; however, when allyl alcohol exceeded 200 uM, oxygen uptake by the liver was inhibited 30-40%, and a large increase in NADH fluorescence occurred. Using the correlation (r= 0.91) between rates of allyl alcohol uptake and the increase in NADH fluorescence established for the whole organ, local rates of allyl alcohol metabolism were 23 and 31 mumoles/g/hr in periportal and pericentral regions, respectively. Since allyl alcohol is metabolized in both regions of the liver lobule, the hypothesis that the zone specific hepatotoxicity results from its exclusive metabolism to acrolein in periportal regions seems unlikely. [R91] ACTN: *... THE PRIMARY CAUSE OF DEATH FROM ALLYL ALCOHOL IS PROBABLY CARDIOVASCULAR FAILURE, WHICH PROBABLY FOLLOWS DEPRESSION OF RESPIRATORY AND VASOMOTOR CENTERS AND DECREASE IN EFFECTIVE BLOOD PRESSURE. [R31, 4668] INTC: *BOTH PHENOXYBENZAMINE AND HEXAMETHONIUM, WHEN GIVEN TO RATS PRIOR TO ORAL ADMIN OF 120 MG/KG OF ALLYL ALCOHOL, AFFORDED PARTIAL PROTECTION TO THE LIVER AGAINST INHIBITION OF OXYGEN UPTAKE BY THE LIVER AND INCREASE IN WATER CONTENT. PHENOXYBENZAMINE MORE THAN DOUBLED MEAN TIME OF DEATH FOR RATS GIVEN ALLYL ALCOHOL ORALLY, BUT IT DID NOT ALTER MORTALITY. [R31, 4668] *PRETREATMENT OF MICE WITH DIETHYLMALEATE, A GLUTATHIONE INHIBITOR, INCR HEPATOTOXICITY OF ALLYL ALCOHOL. [R65] *THE EFFECT OF DIETHYL MALEATE TREATMENT, FASTING, AND TIME OF ADMIN ON ALLYL ALCOHOL INDUCED HEPATOTOXICITY WAS STUDIED IN ANIMALS. ALLYL ALC FED TO ANIMALS AT 21 HR INCR PLASMA ENZYMES. FASTING PROTECTED ANIMALS WHILE DIETHYLMALEATE TREATMENT ENHANCED TOXICITY OF ALLYL ALCOHOL. [R92] *PRETREATMENT OF MICE WITH 4.8 G/KG OF ETHANOL ENHANCED HEPATOTOXICITY OF ALLYL ALCOHOL AS EVIDENT BY INCR IN SERUM ENZYME ACTIVITIES. [R93] *PRETREATMENT OF MICE WITH 175 MG/KG OF OMEGA-HYDROXYHEXYL-2-PYRIDONE ALMOST COMPLETELY ABOLISHED THE EFFECTS OF ALLYL ALCOHOL, A RETINAL POISON. [R94] *Dihydroxydibutylether (DHBE), a hepatotropic drug possessing choleretic properties, was tested against several kinds of chemical-induced liver intoxication in rodents. DHBE appears to protect the rats from increases in plasma SGOT and SGPT levels when admin 1 and 7 hr after admin of hepatotoxic quantities of allyl alcohol. [R95] *In male Wistar rats the hepatoprotective effect of pollen extracts (Cernitins) against orally introduced 1% allyl alcohol (0.4 ml per 100 g body weight) was investigated. Cernitins were applied orally at 0.6, 24 and 30 hr after allyl alcohol administration. After 48 hr an autopsy was performed and blood was collected for biochemical tests. Liver damage was evaluated by measurement of aminotransferases (AspAT) and alkaline phosphatase activity, total bilirubin level in the blood serum as well as by histological examination of the livers. Cernitins significantly reduced the serum enzymes elevations induced by allyl alcohol. The hepatoprotective properties of Cernitins were confirmed by histopathological studies. [R96] *The time course of allyl alcohol induced toxicity was studied in freshly isolated rat hepatocytes incubated with 0.4 and 0.8 mM allyl alcohol. The sequence of events was as follows: an initial rapid decrease of 65 to 75% in glutathione concentration within 10 min, a subsequent increase in malondialdehyde (final concentration 60 times greater than initial values) and decrease in protein sulfhydryl groups (at 20 min with 0.8 mM and at 0.4 m of allyl alcohol), and the eventual loss of membrane integrity a 30 min with the higher dose and at 45 min with the lower dose. The sulfhydryl compounds, N-acetylcysteine and dithiothreitol, markedly delayed the depletion of glutathione, prevented significant loss of protein sulfhydryl groups, and protected the cells against viability loss. The antioxidants, butylated hydroxytoluene and Tolox C, and the iron chelator deferoxamine suppressed allyl alcohol induced malondialdehyde production without affecting the depletion of cellular thiols or the loss of viability. [R97] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Allyl alcohol is used as intermediate in the preparation of a variety of substances and has been used as a contact herbicide. When released to water allyl alcohol is not expected to volatilize, photooxidize or directly photolyze. Biodegradation is expected to be the predominant fate of allyl alcohol in water. Release of allyl alcohol to soil is expected to result in biodegradation and possible migration to groundwater. Volatilization from wet soil, direct photolysis, and bioconcentration are not expected to be significant. Volatilization from dry surfaces or soil should be significant. Release of allyl alcohol to the atmosphere is expected to result mainly in reaction with photochemically generated hydroxyl radicals with estimated half-lives of 6.03-14.7 hr. Direct photolysis is not expected to be significant. Due to the high water solubility of allyl alcohol, rainout may also occur. Allyl alcohol has been detected in human breath. Human exposure is expected to result mainly from the presence of allyl alcohol in exhaust from internal combustion engines, but some may result from use of the compound as a herbicide. (SRC) ARTS: *Allyl alcohol is used in the preparation of esters for use in resins and plasticizers, as an intermediate in the production of pharmaceuticals and other organic chemicals, in the manufacture of glycerol and acrolein, and in the production of military poison gas and herbicides(1,2). Allyl alcohol has also been used as a contact pesticide for weed seeds and certain fungi(3). Dow Chemical Company, however, has discontinued production of allyl alcohol, presumably for this pesticide purpose(4). When used as a herbicide, allyl alcohol is used as 98% active ingredient(6). These applications and uses could result in occupational exposure. Allyl alcohol has been detected but not quantified in exhaust gases from internal combustion engines(5). [R98] *... ALLYL ALCOHOL IS PRESENT AS AN IMPURITY IN METHYL ALCOHOL, IN QUANTITIES SUFFICIENT TO CAUSE TOXIC EFFECTS. IT WAS FOUND TO THE EXTENT OF 0.5% IN A SAMPLE LABELED PURE METHYL ALCOHOL. [R10, 377] FATE: *Terrestrial Fate: Residue disappearance and leaching of (14)C-allyl alcohol from different soils was studied in laboratory experiments. Residue disappearance and leaching from soils was correlated negatively to the organic matter content. [R99] *TERRESTRIAL FATE: Migration to groundwater and biodegradation are expected to be the predominant fates of allyl alcohol released to soil. Volatilization and direct photolysis are not expected to be significant(SRC). *AQUATIC FATE: The most likely fate of allyl alcohol is expected to be biodegradation. Volatilization, direct photolysis and photooxidation are all expected to be slow processes. (SRC) *ATMOSPHERIC FATE: Using a 2nd order rate constant of 25.9 +/- 3.3 cu cm/molecule sec(1) and an average hydroxyl radical concentration of 5X10-5 molecules/cu cm(2), a pseudo first order rate constant of 1.3X10-5 sec was estimated(SRC). An estimated half-life of 14.7 hr was calculated using an experimental rate constant(1) and an average hydroxyl radical concentration(2,SRC). Using the Fate of Atmospheric Pollutants portion of GEMS, a half-life for the reaction of allyl alcohol with photochemically generated hydroxyl radicals of 6.03 hr was estimated(SRC,3). The predominant fate of allyl alcohol in the atmosphere is, therefore, expected to be reaction with hydroxyl radicals. Due to the miscibility of allyl alcohol with water(4), rainout may also occur. Direct photolysis is not expected to be important as allyl alcohol may not absorb significant amounts of radiation at > 290 nm(SRC). [R100] BIOD: *Following incubation of 20 deg C with settled sewage seed, 2.5 ppm of allyl alcohol had degraded to 9.1%, 55.0%, 78.2% and 81.8% of the theoretical BOD after 5, 10, 15, and 20 days, respectively(1). After 10 days exposure to a sewage seed at 20 deg C, a BOD of 1.60 (ppm oxygen/ppm allyl alcohol) was observed. The theoretical BOD was 2.2 ppm (oxygen/ppm allyl alcohol)(2). In a 5 day BOD test, 81% of the ThOD was observed following incubation of allyl alcohol at 20 deg C with a sewage seed(3). Allyl alcohol has been confirmed to be easily biodegradable in the 14 day Japanese MITI screening biodegradability test(4). [R101] ABIO: *Photo-oxidation by UV light in aqueous medium at 50 deg C: 13.9% degradation of carbon dioxide after 24 hr. [R13, 177] *When a 13.5 mg/l aqueous solution of allyl alcohol reacted with hydroxyl radicals formed by the photolysis of hydrogen peroxide by light at > 290 nm at a pH of 5.9 for 3 hr, 14.85% of the allyl alcohol degraded(1). The bimolecular rate constant for the reaction between allyl alcohol and hydroxyl radicals in water is 1.2X10+9/m-sec at pH 7(2). Using 1X10-17 M for an average aqueous concentration of the hydroxyl radical, a pseudo first order rate constant of 1.2X10-8/sec was estimated(SRC). A half-life of 1.8 years was calculated from this rate constant(SRC). Upon exposure to UV light (< 290 nm) for 24 hr, 13.9% of the 171.0 mg allyl alcohol intially present in the vapor phase was degraded(3). The allyl alcohol was placed into a 1 l flask in which it was allowed to volatilize before being passed to a 20 l flask in which it was irradiated with UV light. The temperature of the water circulating through the system reached 50 deg C about six hours after the irradiation began(3). Using a 2nd order rate constant measured of 25.9 +/- 3.3 cu cm/molecule sec at 440 K (167 C)(4), and an average hydroxyl radical concentration of 5X10-5 molecules/cu cm(5), a pseudo first order rate constant of 1.3X10-5 1/s was estimated (SRC). From this value, a half-life of 14.7 hr was estimated, but the reaction at ambient temperatures would be expected to be slower(SRC). Using the fate from Atmospheric Pollutants portion of GEMS, a half-life for the reaction of allyl alcohol with photochemically generated hydroxyl radicals of 6.03 hr was estimated(SRC,6). [R102] BIOC: *Allyl alcohol is not expected to bioconcentrate based on its measured log octanol/water partition coefficient of 0.17(1). [R103] *The uptake of (14)C-allyl alcohol residues by lettuce and carrots was investigated in the greenhouse. Uptake of residues was higher by carrots than by lettuce, and higher by lettuce roots than by lettuce tops. No bioaccumulation was observed. [R99] KOC: *Using a measured log octanol/water partition coefficient of 0.17 (1), a soil sorption coefficient of 1.47 was estimated (SRC,2). A soil sorption coefficient of this magnitude suggests that allyl alcohol will not adsorb strongly to soil and may, therefore, be mobile in soil(3). [R104] VWS: *The measured Henry's Law constant of allyl alcohol at 25 deg C is 4.9X10-6 atm cu m/mol(1). Based on this value only slow volatilization of allyl alcohol is expected to occur from water or moist soil(SRC). [R105] EFFL: *Allyl alcohol has been detected but not quantified in exhaust gases from internal combustion engines(1). [R106] RTEX: *Allyl alcohol can affect the body if it is swallowed, is inhaled, or comes in contact with the skin or eyes. [R24, 1981.1] *Rapidly absorbed through skin. [R84] *The following list includes some common operations in which exposure to allyl alcohol may occur ... Use in preparation of various allyl esters ... use in preparation of chemical derivatives used in perfumes, flavorings, and pharmaceuticals; use as a fungicide, herbicide, and nematocide; use in refining and dewaxing of mineral oil [R24, 1981.3] *A probable route of exposure to allyl alcohol in humans is the release of the compound from internal combustion vehicles in the exhaust(1). Other exposure may result from the use of allyl alcohol as a contact pesticide for weed seeds and certain fungi(2). [R107] BODY: *Allyl alcohol was found at 0.52 and 9.5 ug/hr in expired air from a smoker and a non-smoker, respectively(1). [R108] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +20 ppm [R21, 10] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 2 ppm (5 mg/cu m). Skin Designation. [R109] +Vacated 1989 OSHA PEL TWA 2 ppm (5 mg/cu m); STEL 4 ppm (10 mg/cu m), skin designation, is still enforced in some states. [R21, 359] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2 ppm (5 mg/cu m). [R21, 10] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 4 ppm ( 10 mg/cu m). Skin. [R21, 10] TLV: +8 hr Time Weighted Avg (TWA): 0.5 ppm, skin. [R53, 2002.14] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R53, 2002.6] +A4; Not classifiable as a human carcinogen. [R53, 2002.14] OOPL: *Other recommendations: 2 ppm as reported in 1980 for Australia, Belgium, Netherlands, Sweden and Switzerland (1978), Finland (1975), and in 1984 for West Germany. [R40] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Allyl alcohol is produced, as an intermediate or final product, by process units covered under this subpart. [R110] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 250 ug/l [R111] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R112] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R113] +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Allyl Alcohol is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 1,000 lbs. [R114] RCRA: *As stipulated in 40 CFR 261.33, when allyl alcohol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R115] FIFR: *Classified for restricted use, limited to use by or under the direct supervision of a certified applicator. ... Applies to all formulations and uses, allyl alcohol is restricted due to acute dermal toxicity. [R116] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 1402: Analyte: allyl alcohol; Matrix: air; Sampler: solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Vol: min: 1 l, max: 10 l; Stability: store in freezer; analyze as soon as possible /Alcohols III, ally alcohol/ [R117] *Allyl alcohol in air samples was absorbed on activated carbon and extracted with a 5% solution of isopropyl alcohol in carbon disulfide. [R118] ALAB: *NIOSH 1402: Analyte: allyl alcohol; Matrix: air; Technique: gas chromatography, flame ionization detector; Est limit of detection: 0.01 mg/sample; Overall precision (relative standard deviation): 0.111; Range studied: 0.02 to 0.1 mg/sample; Interferences: High humidity reduces sampling capacity. Less volatile cmpd may displace more volatile cmpd on the charcoal. [R117] *PRODUCT ANALYSIS ... BY MEASURING THE ADDITION OF BROMINE OR ACETYLATION OF THE HYDROXY GROUP. IT MAY BE DETECTED BY TRAPPING IN WATER OR SULFURIC ACID AND OXIDIZING TO ACRYLALDEHYDE BY CHROMIC-SULFURIC ACID. [R85] CLAB: *A simple gas chromatographic method is described for the simultaneous detection of lower alcohols, eg, butyl alcohol, propyl alcohol, pentanol, and allyl alcohol in human stool specimens and rat blood in the presence of large quantities of ethanol. A fused silica capillary column coated with carbowax 20 M was used. The apparent recovery of these alcohols was 98.1-100.7%. [R119] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Chemical Profile: Allyl Alcohol (1985). USEPA; Health and Environmental Effects Profile for Allyl alcohol (1985) ECAO-CIN-P121 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on allyl alcohol is scheduled for peer review. Route: gavage; Species: rats and mice. NTP TR No 48. [R120] SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 39 R2: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 44 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R4: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 46 R5: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R6: Purdue University; National Pesticide Information Retrieval System (1987) R7: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 448 R8: GORZELAK A; SYLWAN 123 (2): 33 (1979) R9: Farm Chemicals Handbook 88. Willoughby, Ohio: Meister Publishing Co., 1988.,p. C-16 R10: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R11: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. R12: Farm Chemicals Handbook 1981. Willoughby, Ohio: Meister, 1981.,p. C-14 R13: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R14: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 128 R15: Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975. 817 R16: SRI R17: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.256 R18: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-359 R19: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-526 R20: Martin, H. and C.R. Worthing (eds.). Pesticide Manual. 4th ed. Worcestershire, England: British Crop Protection Council, 1974. 9 R21: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R22: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 54 R23: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. Old Woking, Surrey, United Kingdom: Royal Society of Chemistry/Unwin Brothers Ltd., 1983.,p. A011/Oct 83 R24: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R25: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R26: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 6 R27: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-466 R28: Aldrich; The Aldrich Microfiche Library of Chemical Indices (1983) R29: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 159 R30: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R31: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R32: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 260 R33: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-131 R34: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 85 R35: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R36: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.22 R37: Bretherick, L. Handbook of Reactive Chemical Hazards. 3rd ed. Boston, MA: Butterworths, 1985. 366 R38: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 10 R39: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R40: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.18 R41: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 68 R42: ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.61 (1983) R43: 49 CFR 171.2 (7/1/96) R44: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 94 R45: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3055 (1988) R46: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R47: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 81 R48: 40 CFR 165 (7/1/88) R49: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-4 (1981) EPA 68-03-3025 R50: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-8 (1981) EPA 68-03-3025 R51: Giusti DM et al; J Water Pollution Control Federation 46 (5): 947-65 (1974) as cited in USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-125 (1982) R52: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-3-E-22 (1982) R53: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R54: Fuscaldo, A., B. J. Erlick, and B. Hindman. (eds.). Laboratory Safety-Theory and Practice. New York: Academic Press, 1980. 253 R55: Arena, J.M. and Drew, R.H. (eds.) Poisoning-Toxicology, Symptoms, Treatments. 5th ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 275 R56: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-98 R57: ATKINSON JP ET AL; J CLIN INVEST 60 (2): 284-94 (1977) R58: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1487 R59: ATZORI L ET AL; BOLL SOC ITAL BIOL SPER 56 (21): 2218-22 (1980) R60: KOPYLOVA TN, VICUPE Z; EKSP MED (RIGA) 3: 58-61 (1978) R61: LAKE BG ET AL; BIOCHEM SOC TRANS 6 (1): 145-7 (1978) R62: NIZZE H ET AL; DIGESTION 19 (6): 359-69 (1979) R63: LIJINSKY W, ANDREWS AW; TERATOG, CARCINOG, MUTAGEN 1 (3): 259-67 (1980) R64: GORSHTEIN ES ET AL; EKSP MED (RIGA) 3: 15-20 (1978) R65: SIEGERS CP ET AL; PROC EUR SOC TOXICOL 18 (CLIN TOXICOL): 160-2 (1977) R66: CARPANINI F MB ET AL; TOXICOLOGY 9 (1-2): 29-46 (1978) R67: DANZ M, KITTLICK P-D; EXP PATHOL 13 (2-3): 139-44 (1977) R68: DANZ M ET AL; EXP PATHOL 12: 301-8 (1976) R69: Rikans LE; Toxicol Appl Pharmacol 73 (2): 243-9 (1984) R70: Leonard TB et al; Am J Pathol 116 (2): 262-9 (1984) R71: Nielsen GD et al; Acta Pharmacol Toxicol 54 (4): 292-8 (1984) R72: Lutz D et al; Mutat Res 93 (2): 305-15 (1982) R73: Gregus Z et al; J Pharmacol Exp Ther 222 (2): 471-9 (1982) R74: Principe P et al; J Sci Food Agric 32 (8): 826-32 (1981) R75: Poulsen HE, Korsholm B; Acta Pharmacol Toxicol 54 (2): 120-3 (1984) R76: Jaeschke H et al; Biochem Pharmacol 36 (1): 51-7 (1987) R77: Belinsky SA et al; J Pharmacol Exp Ther 238 (3): 1132-7 (1986) R78: Smith PF et al; Toxicol Appl Pharmacol 87 (3): 509-22 (1987) R79: Strubelt O et al; Acta Pharmacol Toxicol 59 (1): 47-52 (1986) R80: Ohio Y et al; Chem Biol Interact 52 (3): 289-99 (1985) R81: Rutkowski JV et al; Toxicology 40 (1): 25-30 (1986) R82: Rikans LE, Hornbrook KR; Toxicol Appl Pharmacol 84 (3): 634-9 (1986) R83: Jacobs JM et al; Toxicol Lett 38 (3): 257-64 (1987) R84: Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989.,p. C-16 R85: Worthing, C. R. (ed.). Pesticide Manual. 6th ed. Worcestershire, England: British Crop Protection Council, l979. 9 R86: USEPA; Health and Environmental Effects Profile for Allyl alcohol p.36 (1985) ECAO-CIN-P121 R87: Dunlap MK et al; AMA Arch Ind Health 18: 303-11 (1958) as cited in USEPA; Health and Environmental Effects Profile for Allyl alcohol p.36 (1985) ECAO-CIN-P121 R88: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 299 R89: PATEL JM ET AL; DRUG METAB DISPOS 8 (5): 305-8 (1980) R90: Patel JM et al; Drug Metab Dispos 11 (2): 164-6 (1983) R91: Belinsky SA et al; Mol Pharmacol 25 (1): 158-64 (1984) R92: HANSON SK, ANDERS MW; TOXICOL LETT 1 (5-6): 301-5 (1978) R93: STRUBELT O ET AL; ACTA PHARMACOL TOXICOL 43 (3): 211-8 (1978) R94: GAURI KK ET AL; DOC OPHTHALMOL PROC SER 13: (ERG, VER PSYCHOPHYS) 335-40 (1977) R95: Fregnan CB et al; Acta Ther 8 (3): 189-99 (1982) R96: W'ojcicki J et al; Arch Immunol Ther Exp 33 (6): 841-9 (1985) R97: Hormann VA et al; Toxicol Appl Pharmacol 98 (3): 375-84 (1989) R98: (1) Merck Index; An Encyclopedia of Chemicals, Drugs and Biologicals 10th ed. p. 44 (1983) (2) Hawley GG; Condensed Chem Dictionary 10th ed. Van Nostrand Reinhold NY p. 34 (1981) (3) Verschueren K; Handbook of Environ Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY p. 176 (1983) (4) Meister RT, ed; Farm Chemicals Handbook p. C-13 (1987) (5) Hampton CV, et al.; Environ Sci Technol 16: 287-98 (1982) (6) National Pesticide Information Retrieval System (accessed 5-12-87) R99: Scheunert I et al; J Environ Sci Health, Part B Pestic Food Contam Agric Wastes 16 (6): 719-42 (1981) R100: (1) Atkinson R, et al; Adv Photochem 11: 375-488 (1979) (2) Neely WB Chemicals in the Environment Marcel Dekker, Inc. New York (1980) (3) Graphical Exposure Modeling System. FAP. Fate of Atmos Pollut (1986) (4) Riddick JA et al; Organic Solvents John Wiley, New York p. 256 (1986) R101: (1) Lamb CB, Jenkins GF; Proc 8th Indus Waste Conf Purdue Univ pp. 329-9 (1952) (2) Mills EJ, Stack VT; Proc 8th Indus Waste Conf Purdue Univ Extension Series 83: 492-517 (1954) (3) Bridie Al, et al; Water Res 13: 627 (1979) (4) Sasaki S; pp. 283-98 in Aquatic Pollut Transformation and Biological Effects (1978) Biological Effects. (5) Hutzinger O, et al; eds., Oxford Pergamon Press pp. 283-98 (1978) R102: (1) Mansour M; Bull Environ Contam Toxicol 34: 89-95 (1985) (2) Anbar M, Neta P; Int J Appl Rad Isot 18: 493-523 (1967) (3) Knoevenagal K, Himmelreich R; Arch Environ Contam 4: 324-33 (1976) (4) Atkinson R, et al; Adv Photochem 11: 375-488 (1979) (5) Neely WB; Chemicals in the Environment Marcel Dekker, Inc New York (1980) (6) Graphical Exposure Modeling System. FAP. Fate of Atmos Pollut (1986) R103: (1) Hansch C, et al; Medchem Project Issue No. 19 (1985) R104: (1) Hansch C, Leo AJ; Medchem Project Issue No. 19 (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY pp. 4-9 (1982) (3) Kenaga EE; Ecotox Environ Safety 4: 26-38(1980) R105: (1) Hine J, Mookerjee PK; J Org Chem 40: 292 (1975) R106: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) R107: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (2) Verschueren K; Handbook of Environ Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY p. 176 (1983) R108: (1) Conkle JP, et al; Arch Environ Health 30: 290-5 (1975) R109: 29 CFR 1910.1000 (7/1/98) R110: 40 CFR 60.489 (7/1/89) R111: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R112: 40 CFR 116.4 (7/1/88) R113: 54 FR 33418 (8/14/89) R114: 40 CFR 355 (7/1/97) R115: 40 CFR 261.33 (7/1/88) R116: 40 CFR 152.175 (7/1/88) R117: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V1 1402-1 R118: Kacpura B; Prace Centralnego Instytutu Ochrony Pracy 33 (117): 111-20 (1983) R119: Doizaki WM, Levitt MD; J Chromat 276 (1): 11-8 (1983) R120: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 83 Record 41 of 1119 in HSDB (through 2003/06) AN: 193 UD: 200211 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYL-ACRYLATE- SY: *ACRYLATE-D'ETHYLE- (FRENCH); *ACRYLIC-ACID,-ETHYL-ESTER-; *ACRYLSAEUREAETHYLESTER- (GERMAN); *AETHYLACRYLAT- (GERMAN); *ETHOXYCARBONYLETHYLENE-; *ETHYLACRYLAAT- (DUTCH); *ETHYLAKRYLAT- (CZECH); *ETHYL-PROPENOATE-; *ETHYL-2-PROPENOATE-; *ETIL-ACRILATO- (ITALIAN); *Etilacrilatului- (Roumanian); *FEMA-NUMBER-2418-; *NCI-C50384-; *2-PROPENOIC-ACID-ETHYL-ESTER- RN: 140-88-5 MF: *C5-H8-O2 SHPN: UN 1917; Ethyl acrylate, inhibited IMO 3.2; Ethyl acrylate, inhibited STCC: 49 072 15; Ethyl acrylate, inhibited, polymerizable 49 091 67; Ethyl acrylate, inhibited HAZN: U113; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF NICKEL CARBONYL AND ACETYLENE WITH ETHYL ALCOHOL IN THE PRESENCE OF AN ACID; OR ESTERIFICATION OF ACRYLIC ACID WITH ETHYL ALCOHOL (MODIFIED REPP PROCESS) [R1] *Prepd from ethylene chlorohydrin or acrylonitrile, ethanol, and sulfuric acid ... [R2, 3806] *Vinyl chloride reacts at 270 deg C at > 6895 kPa (68 atm) with ethanol in the presence of a cobalt and palladium catalyst to give ethyl acrylate in 17% yield ... . [R3] *Oxo reaction of acetylene, carbon monoxide, and ethyl alcohol in the presence of nickel or cobalt catalyst. [R4] *In ... propylene oxidation process acrolein is first formed by the catalytic oxidation of propylene vapor at high temp in the presence of steam. The acrolein is then oxidized to acrylic acid. ... The acrylic acid is esterified with alcohol to the ... acrylic ester in a separate process. /Acrylic ester monomers/ [R5] IMP: *WATER: 0.10% BY WT, MAX; ACIDITY, AS ACRYLIC ACID: 0.009% BY WT, MAX [R6] *WATER: 0.05% BY WT (MAX), ACRYLIC ACID: 0.005% BY WT (MAX) [R7] FORM: *Latol 28-tall oil fatty acid [R8] *TYPICAL PROPERTIES FOR COMMERCIAL GRADE ETHYL ACRYLATE AVAIL IN US ARE ... PURITY 99.0%; ACIDITY (AS ACRYLIC ACID), 0.0008%; WATER, 0.03%; INHIBITORS, 15 OR 200 MG/KG (PPM) HYDROQUINONE MONOMETHYL ETHER OR 1000 MG/KG (PPM) HYDROQUINONE. [R9] *99.5% BY WT (MIN) INHIBITED WITH 15-20 PPM HYDROQUINONE [R6] *99.5% BY WT (MIN) INHIBITED WITH HYDROQUINONE OR MONOMETHYL ETHER OF HYDROQUINONE [R10] *Grades: Technical (inhibited, usually with hydroquinone or its monomethyl ether); Pure uninhibited [R4] MFS: *BASF Corporation; HQ: 3000 Continental Drive - North, Mount Olive, NJ 07828-1234 (800) 669-BASF; Chemicals Division, 3000 Continental Drive - North, Mount Olive, NJ 07828-1234 (973) 426-2600; Industrial Organics; Production site: Freeport, TX 77541 [R11] *Celanese Ltd.; Hq: 1601 West LBJ Freeway Dallas, TX 75234 (972) 443-4000; Chemicals Division; Production site: 9502 Bayport Road, Clear Lake, TX 77507-1498 (PO Box 58009 Houston, TX 77258-8009) [R11] *Rohm and Haas Company; Hq: 100 Independence Mall West, Philadelphia, PA 19106-2399 (215) 592-3000; Production site: Deer Park, TX 77536 [R11] *Union Carbide Corporation; Hq: Old Ridgebury Road Danbury, CT 06817 (203) 794-2000; Production site: Taft, LA 70057 (PO Box 110 Hahnville, LA 70057) [R11] OMIN: *THE COUNCIL OF EUROPE (1974) LISTED ETHYL ACRYLATE IN THE LIST OF ARTIFICIAL FLAVORING SUBSTANCES THAT MAY BE ADDED TO FOODSTUFFS WITHOUT HAZARD TO PUBLIC HEALTH, @ LEVEL OF 1 PPM. [R12] *... POLYMERIZED ESTERS ... ESP METHYL, ETHYL AND BUTYL ESTERS, ARE KNOWN UNDER TRADE NAMES OF "LUCITE", "PLEXIGLAS", and "PERSPEX", AND ARE OF CONSIDERABLE COMMERCIAL IMPORTANCE. THEY ARE WIDELY USED AS SUBSTITUTES FOR GLASS AND IN CERTAIN SITUATIONS ARE PREFERRED TO IT SINCE THEY ARE ALMOST AS TRANSPARENT AS GLASS BUT WEIGH ONLY HALF AS MUCH. ... WHERE HIGH OPTICAL ACCURACY IS NOT REQUIRED THEY CAN ALSO BE MADE INTO LENSES. THIS ORGANIC GLASS HAS PROPERTY OF TOTAL INTERNAL REFLECTION AND CAN "PIPE" LIGHT ... USEFUL FOR SURGICAL RETRACTORS AND THROAT LIGHTS. ... WIDELY USED FOR DENTURES, ARTIFICIAL EYES AND SURGICAL PROSTHESES. THE POLYMERS MAY BE CAST INTO SHEETS OR MOULDED ... . [R13] USE: *ETHYL ACRYLATE IS A MAJOR COMPONENT OF STRAIGHT ACRYLIC EMULSION POLYMERS USED IN LATEX PAINTS, A MAJOR MONOMER USED IN STRAIGHT ACRYLIC EMULSION FOR TEXTILE APPLICATIONS, INCL BACKCOATINGS, FABRIC FINISHES, PIGMENT BINDERS, DIRT RELEASE AGENTS AND THICKENERS. USED TO MAKE EMULSION POLYMERS FOR PAPER COATING; AS PULP ADDITIVES IN FLOOR POLISHES AND SEALANTS; IN SHOE POLISHES; IN BASE COATINGS AND SURFACE IMPREGNATION OF LEATHER IN ADHESIVES, SEALANTS, CAULKING CMPD AND BINDERS. [R14] *PERMITTED AS COMPONENTS OF PRODUCTS INTENDED FOR USE IN CONTACT WITH FOOD: (1) ADHESIVES, (2) RESINOUS AND POLYMERIC COATINGS, (3) PAPER AND PAPERBOARD FOR AQ AND FATTY FOOD, (4) RIGID AND SEMI-RIGID ACRYLIC PLASTICS, (5) CROSS-LINKED POLYESTER RESINS, and (6) RIGID AND SEMI-RIGID VINYL CHLORIDE PLASTIC MODIFIERS. [R15] *Formerly used as an additive in food as flavoring and fragrance [R16, 3004] CPAT: *(ALL ACRYLIC ESTERS) 47% FOR SURFACE COATINGS; 22% FOR TEXTILES; 7% FOR PAPER; 7% FOR POLISHES; 3% FOR LEATHER; 9% FOR ACRYLIC FIBERS; 5% FOR MISC APPLICATIONS (1969) [R1] *45% FOR COATINGS, 16% FOR TEXTILES AND LEATHER FINISHES, 9% FOR PAPER COATINGS, 8% FOR ADHESIVES, 6% FOR POLYACRYLATES, 5% FOR POLISHES, 5% FOR ACRYLIC FIBERS, 6% OTHER (1983 EST) /ACRYLATES AND ACRYLIC ACID/ [R17] PRIE: U.S. PRODUCTION: *(1972) 1.25X10+11 G [R1] *(1975) 1.09X10+11 G [R1] *(1983) 1.39X10+11 g [R18] *Annual production of ethyl acrylate in 1976 was reported to be over 295 million pounds. [R19] *1993: 1.60X10+8 kg (1.60X10+11 g) [R20] U.S. IMPORTS: *(1972) NEGLIGIBLE [R1] *(1975) 3.50X10+9 G [R1] *(1983) 1.36X10+9 g (EST) /ACRYLATES AND ACRYLIC ACID/ [R17] U.S. EXPORTS: *(1972) 9.03X10+9 G [R1] *(1975) 1.84X10+10 G [R1] *(1984) 3.97X10+10 g [R21] *(1987) 5.58X10+6 lb [R22] *(1988) 7.22X10+6 lb [R23] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear liquid. [R16, 3003] ODOR: *Acrid penetrating odor [R16, 3003]; *Sour, pungent, hot plastic odor [R24]; *Acrid odor. [R25] BP: *99.4 deg C [R26] MP: *-71.2 deg C [R26] MW: *100.12 [R26] CTP: *CRITICAL TEMP: 534 DEG F= 279 DEG C= 552 K; CRITICAL PRESSURE: 544 PSI= 37 ATM= 3.7 MN/SQ M [R27] DEN: *0.9234 @ 20 deg C/4 deg C [R26] HTC: *655.49 Kcal/mol [R2, 641] HTV: *8.27 Kcal/mol [R2, 641] OWPC: *log Kow= 1.32 [R28] SOL: *> 10% in chloroform [R29]; *> 10% in alcohol [R29]; *> 10% in ether [R29]; *2% (wt/vol) in water at 20 deg C [R30, 1991.571]; *1.5 parts by wt (of the formula wt)/100 parts by wt of water [R31, p. 1-228]; *1.50 g/100 g water at 25 deg C (15,000 mg/l) [R32] SPEC: *Index of refraction: 1.4068 @ 20 deg C/D [R26]; *MAX ABSORPTION (ALCOHOL): 208 NM (LOG E= 3.84) [R33]; *Sadtler Ref Number: 29702 (IR, grating) [R34]; *Ethyl Acrylate, 99%, exhibits its two strongest infra red absorption bands at wavelengths of 5.8 and 8.3 microns. [R35]; *IR: 4305 (Coblentz Society Spectral Collection) [R29]; *NMR: 7951 (Sadtler Research Laboratories Spectral Collection) [R29]; *MASS: 247 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R29] SURF: *0.025 DYNES/CM= 0.025 N/M @ 20 DEG C [R27] VAPD: *3.45 (air= 1) [R16, 3001] VAP: *38.6 mm Hg @ 25 deg C [R36] EVAP: *3.3 (butyl acetate= 1) [R37, 1981.2] OCPP: *Specific heat @ -60 deg C: 0.442 Cal/g/deg C; polymerizes on distillation; azeotropes: 45% water= BP 81 deg C; 56.8% Ethanol= BP 76 deg C [R2, 641] *Conversion factor: 4.09 mg/cu m is equiv to 1 ppm [R16, 3001] *Ratio of specific heats of vapor: 1.080; latent heat of vaporization: 149 BTU/lb= 82.9 cal/g= 3.47X10+5 J/kg; liquid-water interfacial tension: (est) 40 dynes/cm= 0.04 N/m at 20 deg C [R27] *Saturation concentration /in air/ 158 g/cu m @ 20 deg C [R34] *SATURATED AIR CONTAINS 38,500 PPM BY VOL OF VAPOR @ 20 DEG C, 760 MM HG [R30, 1991.571] *Liquid heat capacity= 0.453 BTU/lb-F @ 70 deg F; Liquid thermal conductivity= 10149 BTU-in/hr-sq ft-F at 70 deg C; Saturated vapor density= 0.01011 lb/cu ft @ 70 deg F; Ideal gas heat capacity= 0.272 BTU/lb-F @ 75 deg F [R27] *Critical volume 320 cu cm/mole [R31, p. 5-82] *Bulk density: 7.6 lb/gal at 20 deg C [R4] *Heat of polymerization: -335 BTU/lb= -186 cal/g= -7.79X10+5 J/kg [R27] *Saturation concn: /in air/ 258 g/cu m at 30 deg C [R24] *Heat of evaporation: 347 J/g; specific heat: 1.97 J/g-K [R38, p. 1(78) 392] *React readily with electrophilic, free-radical, and nucleophilic agent /Acrylic acid and esters/ [R39] *Polymerizes exothermically in the presence of light, heat, and peroxides above 10 deg C, unless inhibited. [R16, 3003] *The monomer polymerizes to a transparent, elastic substance that is practically odorless and insoluble in conventional solvents. [R16, 3003] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Ethyl acrylate, inhibited/ [R40] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Ethyl acrylate, inhibited/ [R40] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Ethyl acrylate, inhibited/ [R40] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Ethyl acrylate, inhibited/ [R40] +Evacuation: Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Ethyl acrylate, inhibited/ [R40] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Ethyl acrylate, inhibited/ [R40] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Ethyl acrylate, inhibited/ [R40] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Ethyl acrylate, inhibited/ [R40] FPOT: *... Flammable and is a potentially dangerous fire and explosion hazard. [R30, 1991.571] *A very dangerous fire hazard when exposed to heat or flame. [R41] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R42, p. 325-47] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R42, p. 325-47] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R42, p. 325-47] FLMT: *Lower 1.4%, upper 14% by vol /Ethyl acrylate, inhibited/ [R42, p. 49-64] FLPT: *50 deg F (10 deg C) (open cup) [R42, p. 325-47] *60 deg F (open cup) [R41] AUTO: *702 deg F (372 deg C) [R42, p. 325-47] FIRP: *Use water spray to keep fire-exposed containers cool. Use fine spray or fog to control fire by preventing its spread and absorbing some of its heat. Solid streams of water may be ineffective or may cause frothing. Use water spray, dry chemical, foam, or carbon dioxide. Fight fire from protected location or maximum possible distance. /Ethyl acrylate, inhibited/ [R42, p. 49-63] *If material on fire of involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid stream of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical or carbon dioxide. /Ethyl acrylate, inhibited/ [R43, 440] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame, consider evacuation of one-half (1/2) mile radius. If material leaking (not on fire) consider evacuation from downwind area based on amt of material spilled, location and weather conditions. /Ethyl acrylate, inhibited, polymerizable/ [R43, p. 440-1] TOXC: *TOXIC AND IRRITATING VAPORS GENERATED WHEN HEATED. [R27] *Toxic gases and vapors (such as carbon monoxide) may be released in a fire involving ethyl acrylate. [R37, 1981.2] OFHZ: *VAPOR IS HEAVIER THAN AIR AND MAY TRAVEL A CONSIDERABLE DISTANCE TO A SOURCE OF IGNITION AND FLASH BACK. /ETHYL ACRYLATE, INHIBITED/ [R42, p. 49-64] EXPL: *Low explosive limit 1.8% [R41] REAC: *Mixing ethyl acrylate and chlorosulfonic acid in a closed container caused the temperature and pressure to increase. [R42, p. 491-80] *Oxidizers, peroxides, polymerizers, strong alkalis, moisture, chlorosulfonic acid [Note: Polymerizes readily unless an inhibitor such as hydroquinone is added]. [R44, 132] *... Can react vigorously with oxidizing materials. [R41] DCMP: *When heated to decomp it emits acrid smoke and irritating fumes. [R41] POLY: *Hazardous polymerization may occur. Polymerization may be caused by elevated temperature, oxidizers, peroxides. /Ethyl acrylate, inhibited/ [R42, p. 49-64] *POLYMERIZES ON DISTILLATION; POLYMERIZATION PROCESS SPEEDED UP BY HEAT, LIGHT, AND PEROXIDES [R45, 546] *Inhibited monomer was transferred from a steel drum into a 4l clear glass bottle exposed to sunlight in a laboratory in which the ambient temp was temporarily higher than usual. Exothermic polymerization set in and caused the bottle to burst. Precautions recommended included increase inhibitor concn tenfold (to 200 ppm) for laboratory-stored samples, and use of metal or brown glass containers. [R46] ODRT: *1 ppb (4 ug/cu m) [R8] *Water: 0.0012 mg/l; Air: 0.00038 ul/l; odor safety class A; A= More than 90% of distracted persons perceive warning of TLV concn in the air. [R47] *2.00x10-4 ppm (odor recognition in air, purity not specified) [R48, 64] *3.00x10-4 ppm (odor recognition in air, purity not specified) [R48, 64] *3.60x10-4 ppm (odor recognition in air, purity not specified) [R48, 64] *6.70x10-2 ppm (odor detection in water, chemically pure) [R48, 63] *4.70x10-4 ppm (odor recognition in water, chemically pure) [R48, 63] *Odor thresholds are 0.0008 (low) and 32.0000 (high) mg/cu m [R49] SERI: *THE MONOMER IS HIGHLY IRRITATING TO EYES, SKIN, MUCOUS MEMBRANES. [R45, 546] *Ethyl acrylate is a strong irritant to the skin, eyes, mucous membranes, ... and respiratory system. [R16, 3004] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face-shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with ethyl acrylate. Employees should be provided with and required to use splash-proof goggles where there is any possibility of liquid ethyl acrylate contacting the eyes. [R37, 1981.3] */NIOSH APPROVED/ ORGANIC CANISTER OR AIR-SUPPLIED MASK ... IMPERVIOUS GLOVES [R27] *HANDLING PROCEDURES RECOMMEND WEARING RUBBER GLOVES, FACE SHIELD, AND PROTECTIVE CLOTHING. ... FOR SPILLS AND EXPOSURES ABOVE THE TLV, ALL-PURPOSE CANISTER MASKS SHOULD BE AVAILABLE. [R50] +Wear full protective clothing and positive pressure self contained breathing apparatus. [R42, p. 49-63] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R51, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R44, 132] *Wear appropriate eye protection to prevent eye contact. [R44, 132] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R44, 132] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities should provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R44, 132] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R44, 133] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R44, 133] OPRM: *Clothing contaminated with liquid ethyl acrylate should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of ethyl acrylate from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the ethyl acrylate, the person performing the operation should be informed of ethyl acrylate's hazardous properties. Non-impervious clothing which becomes contaminated with liquid ethyl acrylate should be removed immediately and not reworn until the ethyl acrylate is removed from the clothing. [R37, 1981.3] *Where there is any possibility of exposure of an employee's body to liquid ethyl acrylate, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. [R37, 1981.3] *Skin that becomes contaminated with liquid ethyl acrylate should be immediately washed or showered with soap or mild detergent and water to remove any ethyl acrylate. [R37, 1981.3] *Remove all ignition sources. Do not allow to enter confined spaces. [R37, 1981.3] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R51, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R51, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R51, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R51, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R51, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R51, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R51, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R51, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R51, 1979.11] *In material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak of without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. /Ethyl acrylate, inhibited/ [R43, 440] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amt of water or soap and water. /Ethyl acrylate, inhibited/ [R43, 440] *INHALATION OF ETHYL ACRYLATE DUST SHOULD BE AVOIDED. [R50] *The worker should immediately wash the skin when it becomes contaminated. [R44, 132] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R44, 132] SSL: *EASILY POLYMERIZES ON STANDING. IF PURE, THE MONOMER CAN BE STORED BELOW +10 DEG C WITHOUT INCURRING POLYMERIZATION. [R45, 546] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R52] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R53] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R54] STRG: +Store in away from heat, oxidizers, and sunlight. Outside or detached storage is preferred. Separate from any oxidizers, peroxides, or other initiators. [R42, p. 49-64] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R51, 1979.13] *The effectiveness of phenolic inhibitors is dependent on the presence of oxygen and the monomers must be stored under air rather than an inert atmosphere. Temp must be kept low to minimize formation of peroxides and other products. ... The acrylic esters may be stored in mild or stainless steel, or aluminum. /Acrylic acid and derivatives/ [R38, p. 1(78) 349] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. BURN PAPER IN A SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIAL. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER. ETHYL ACRYLATE SHOULD NOT BE ALLOWED TO ENTER A CONFINED SPACE, SUCH AS SEWER, BECAUSE OF THE POSSIBILITY OF AN EXPLOSION. [R37, 1981.3] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R51, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U113, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R55] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. Also, a good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. Also, a good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R56] *Ethyl Acrylate is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. /From table/ [R57] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R51, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R51, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R51, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R51, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R51, 1979.17] *The following wastewater treatment technology has been investigated for ethyl acrylate: Biological treatment. [R58] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4. Not classifiable as a human carcinogen. [R59] +Evaluation: No epidimiological data relevant to the carcinogenicity of ethyl acrylate were available. There is sufficient evidence in experimental animals for the carcinogenicity of ethyl acrylate. Overall evaluation: Ethyl acrylate is possibly carcinogenic to humans (Group 2B). [R60] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to lS L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R61, 221] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the paticnt who is unconscious. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Esters and related compounds/ [R61, p. 221-2] MEDS: *The following medical procedures should be made available to each employee who is exposed to ethyl acrylate at potentially hazardous levels: Initial Medical Screening: Employees should be screened for history of certain medical conditions (listed below) which might place the employee at increased risk from ethyl acrylate exposure. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of ethyl acrylate might cause exacerbation of symptoms due to its irritant properties. Skin disease: Ethyl acrylate is absorbed through the skin. It also is a defatting agent and may cause dryness or cracking. Persons with preexisting skin disorders may be more susceptible to the effects of this agent. Liver disease: Although ethyl acrylate is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Kidney disease: Although ethyl acrylate is not known as a kidney toxin in humans, the importance of this organ in the excretion of certain chemicals and their metabolites should be considered before exposing persons with impaired kidney function. [R37, 1981.1] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R51, 1979.23] HTOX: *LACRIMATOR. ... LETHARGY AND CONVULSIONS MAY OCCUR IF VAPORS OF THE MONOMER ARE INHALED IN HIGH CONCN. [R45, 862] *... /ETHYL ACRYLATE HAS/ AN EXTREMELY IRRITATING ACTION ON THE ENTIRE /RESP/ TRACT. RESP ... RAPID, THE LIPS BLUE, AND CONVULSIVE MOVEMENTS ... DEATH /SRP: CAN OCCUR/ FOLLOWING PULMONARY EDEMA. ... CAUSES SERIOUS BURNS OF THE CORNEA AND MAKES IT OPAQUE. [R62] *ETHYL ACRYLATE TESTED @ 4% IN PETROLEUM PRODUCED NO IRRITATION AFTER 48-HR CLOSED PATCH TEST ON HUMAN SUBJECTS. A MAXIMIZATION TEST WAS CARRIED OUT ON 24 VOLUNTEERS. MATERIAL WAS TESTED @ CONCN OF 4% IN PETROLEUM AND PRODUCED SENSITIZATION REACTIONS IN 10 OF THE 24. [R12] *Ethyl acrylate is irritating to the ... mucous membranes of the gastrointestinal tract and respiratory system. ... Prolonged exposure to 205-308 mg/cu m (50-75 ppm) ethyl acrylate produced drowsiness, headache and nausea. 14 of 33 workers exposed over an average period of five years to 4-58 mg/cu m ethyl acrylate (and 50 mg/cu m butyl acrylate) complained of autonomic and neurotic symptoms, eletroencephalographic examination showed no organic dysfunction. [R63] *ONE CASE REPORT INDICATED THAT A WORKER EXPOSED TO DUST OF A POLYMER OF ETHYL ACRYLATE WAS HOSPITALIZED FOR THE INVESTIGATION OF A RESP COUGH; ITCHING OF SKIN OF THE FACE AND EARS ALSO OCCURRED. /POLYMER/ [R64] *WHEN COMPARING STRAIGHT WITH BRANCHED CHAIN ACRYLATES, ETHYL ACRYLATE BY ORAL ROUTE MAY BE ONLY HALF AS TOXIC AS METHYL ACRYLATE, BUT EIGHT TIMES AS TOXIC AS METHYL METHACRYLATE, and 13 TIMES AS TOXIC AS ETHYL METHACRYLATE. [R16, 3000] *SENSITIZATION OF WORKERS, PRESUMABLY BY SKIN CONTACT WITH THE LIQ, HAS BEEN REPORTED BY TWO MANUFACTURERS ... . [R65] *... 3934 employees of ... Bristol, Virginia, plant who were exposed to ethyl acrylate prior to 1946 /were evaluated/. The study found an excess of colon or rectal cancers in the exposed worker group (p= 0.0001). However, these findings are confounded by the fact that employees were exposed to a variety of other chemicals in addition to ethyl acrylate. No quantification of these exposure concentrations was available. The company stated that, of all products manufactured at this plant, ethyl acrylate accounted for about 10%. Thus, there is inadequate evidence from this study to link carcinogenicity to exposure of humans to ethyl acrylate. [R30, 1991.572] *The vapor of ethyl acrylates can be very irritating at 4-5 ppm. /From table/ [R66] *Acrylates may be polymerized to stable surface coatings (paints, lacquers, inks, etc.) by alkylation via the Michaelis-type addition reaction. Thus, acrylates have an inherent potential as electrophiles to be genotoxic, limited in their biological activity by their physicochemical properties. To evaluate their systemic genotoxicity, ethyl acrylate, tripropylene glycol diacrylate, or Lacquer A, an ultraviolet radiation curable lacquer containing tripropylene glycol diacrylate as the active ingredient, were applied dermally to Tg.AC mice (3 times a week for 20 weeks). Peripheral blood leukocytes were evaluated for DNA damage (single-strand breaks, alkali labile sites, DNA crosslinking) at weeks 4, 8, 12, 16, and 20 by using the alkaline (pH: 13) single cell gel assay. Peripheral blood polychromatic erythrocytes and normochromatic erythrocytes were evaluated for the presence of micronuclei at week 20. The extent of DNA migration in leukocytes and the frequency of micronucleated erythrocytes was not significantly altered by treatment with tripropylene glycol diacrylate when administered alone or in Lacquer A or with ethyl acrylate, at doses that induced cell proliferation in keratinocytes. The absence of genotoxicity in these two cell populations suggests that these acrylates are not genotoxic or that they are not absorbed systemically when applied dermally. However, a significant, dose-dependent increase in the percentage of polychromatic erythrocytes relative to the vehicle control was present in mice treated with tripropylene glycol diacrylate, while a dose-dependent, but nonsignificant, increase in the percentage of polychromatic erythrocytes was observed in mice treated with Lacquer A. This observed increase in the rate of erythropoiesis may reflect bone marrow/blood toxicity, a homeostatic mechanism in response to the treatment-induced tumor burden, and/or a hematopoietic response to epidermal keratinocyte cytokines induced by tissue injury. [R67] NTOX: *THE LIQUID MONOMER APPLIED IN QUANTITY OF 0.1 TO 0.5 ML TO RABBIT CORNEAS CAUSES INJURY ... LIMITED TO DAMAGE OF THE CORNEAL EPITHELIUM. [R68] *Groups of 50 male and 50 female Fischer 344/N rats, 7 wks of age, received 100 or 200 mg/kg body wt ethyl acrylate (purity, 99-99.5%, stabilized with 15 mg/kg of the monomethyl ether of hydroquinone) in 5 mL/kg corn oil by gavage 5 times per wk for 103 wk. /Control groups received corn oil only/. Experiment was terminated at 104-l05 wk. Survival in the control, low-dose and high-dose groups was: males, 82%, 64% and 68%; females, 72%, 72% and 84%. The incidences of squamous cell carcinomas of the forestomach in the control, low-dose and high-dose male rats were: 0/50, 5/50 and 12/50 (p < 0.001, Fishers exact test, high-dose versus control, AND Cochran Armitage test for trend); females, 1/50, 6/50 and 11/50 (p= 0.002, Fishers exact test, high-dose versus control, AND Cochran Armitage test for trend), respectively. Dose-related incr were observed in the incidence of non-neoplastic lesions (hyperkeratosis, hyperplasia and inflammation) in the forestomach in animals of each sex (National Toxicology Program, 1983). [R69] *Groups of 105 female and 105 male B6C3F1 mice, seven to nine weeks of age, were exposed to vapors of ethyl acrylate (purity, > 99.5%) at concn of 100, 310 or 920 mg/cu m (25, 75 or 225 ppm) for 6 hr per day on five days per wk. The treatment with the low and medium doses lasted 27 months ... high-dose treatment was discontinued after 6 mo due to a significant decr in body-wt gain. ... approximately 75 animals per sex in the exposed group and 60 animals per sex in the control groups were available for the full study. ... Survival in all groups was adequate for evaluation of late-appearing tumors. ... Treatment-related incr in the incidence of tumors observed. ... Thyroid follicular adenomas were incr in high-dose male mice when compared to concurrent but not historical controls (2/121 in concurrent controls; 16% in historical controls; and 7/69 in high-dose males). Dose-related incr were observed in the incidence of nonneoplastic lesions of the olfactory mucosa (glandular hyperplasia and metaplasia) in animals of each sex. [R70] *Male and female Fischer 344 rats and B6C3F1 mice were given 100, 200, 400, 600, or 800 mg/body wt ethyl acrylate in corn oil by gavage. After 14 days, rats developed abdominal adhesions (@ 600 and 800 mg/kg) and tissue lesions of the forestomach (@ 400 mg/kg), characterized histologically as hyperkeratosis, hyperplasia and inflammation. Inflammation of the forestomach was seen in mice at 400 and 600 mg/kg. Such lesions were not found at doses of 100 and 200 mg/kg. /Control data not given/ [R71] *Early studies of the inhalation toxicity of ethyl acrylate vapors in small numbers of rats, rabbits, guinea pigs, and monkeys reported signs of acute irritation in the lung and upper respiratory tract at concentrations of 1230 and 2200 mg/cu m (300 and 540 ppm) or 4940 mg/cu m (1204 ppm). [R71] *In an inhalation study ... pregnant Sprague-Dawley rats /were exposed/ to 0, 205, or 615 mg/cu m (0, 50 or 150 ppm) ethyl acrylate vapor for 6 hr/day on gestation days 6-15. Maternal toxicity at 615 mg/cu m (150 ppm) was reflected in reduced food consumption and body-wt gain. In the fetuses, no significant incr was seen in gross, visceral or skeletal malformations at either exposure level, although 3 fetuses in 3 litters (10% of litters) in the 615 mg/cu m (150 ppm) group had hypoplastic tail and associated skeletal defects. Historically, this defect had been noted in 1% of over 800 control litters, and the highest incidence in one control group was 7% of litters. [R72] *When undiluted ethyl acrylate was applied to the skin of 40 male C3H/HeJ mice at a dose of 25 ul (23 mg/mouse per application) three times weekly for life, histological skin changes were observed, including epidermal necrosis (four animals), keratin necrosis (six animals), dermal fibrosis (six animals), hyperkeratosis (12 animals) and dermatitis (five animals). [R72] *Inhalation exposure of rats to 70, 300, and 540 ppm of ethyl acrylate for up to 30 days produced mortality and pathologic changes in lung, liver, and kidneys in the high and middle concentration groups. High mortality forced termination after 19 days of exposure at the 540 ppm air concn. Eighteen of 30 rats exposed at the 300 ppm concentration died prior to completion of the 30-day exposure regimen, while all 30 rats exposed at 70 ppm survived until termination of the study. Histopathologic changes consisting of pulmonary congestion, cloudy swelling and congestion of the liver, cloudy swelling of renal tubules, and excessive pigmentation of the spleen were observed in the rats that had died prior to termination of the 30-day exposure period. In a second phase of the study, rats, rabbits, and guinea pigs were subjected to 50 inhalation exposures of 7 hr each at 75 ppm ethyl acrylate. There were no indications of toxicity. Higher concn produced mortality ... Pulmonary edema and toxicity-related degenerative changes in the heart, liver, and kidneys were noted. [R30, 1991.571] *LOCAL REACTION ON SKIN CLASSIFIED ... AS MILD TO MODERATE IRRITANT DEPENDING ON TYPE AND LENGTH OF CONTACT; WHEN PAINTED ON UNBROKEN RABBIT SKIN AND LEFT UNCOVERED, NO SIGNS OF IRRITATION WERE FOUND. ... CHRONIC ANIMAL INHALATION TOXICITY STUDIES /WITH RATS/ SHOWED ... THAT 300 PPM SEVEN HR DAILY, FIVE DAYS PER WK FOR 30 DAYS ... PRODUCED IRRITATION OF MUCOUS MEMBRANES OF EYES, NOSE AND MOUTH AS WELL AS LETHARGY, DYSPNEA AND CONVULSIVE MOVEMENTS. MICROSCOPICALLY, PULMONARY CONGESTION AND EDEMA, AND DEGENERATIVE CHANGES IN LIVER, KIDNEYS, AND HEART MUSCLE WERE SEEN. [R65] *ETHYL ACRYLATE ... IS A STRONG IRRITANT TO ... GI TRACT ... /IT/ IS ABSORBED BY SKIN, CAUSES LOCAL IRRITATION AND SYSTEMIC DEGENERATE CARDIAC, HEPATIC, SPLENIC, AND NEPHRIC CHANGES. AT HIGHER DOSES, SUCH AS ABOVE THE LD50, EFFECTS IN RABBITS IN THE TERMINAL STAGES WERE CHARACTERIZED BY DYSPNEA, CYANOSIS, AND CONVULSIVE MOVEMENTS. [R16, p. 3004-5] *IN RATS ADMIN ETHYL ACRYLATE (25-400 MG/KG) FROM 7TH TO 16TH DAY OF PREGNANCY DECR MEAN WT INCR AND PLACENTA WT WERE OBSERVED. INCR NUMBER OF FETAL RESORPTIONS AND SKELETAL ANOMALIES WERE ALSO NOTED. NUMBER AND SIZE OF LIVE FETUSES WERE NOT SIGNIFICANTLY DIFFERENT FROM CONTROLS. [R73] *The micronucleus test was used to study the mutagenic effects of ethyl acrylate. The chemical was administered to Balb/C male mice by ip injection in two doses, separated by a period of 24 hours. At doses of 225-1800 mg/kg, ethyl acrylate significantly induced chromosome damage resulting in micronuclei formation in bone marrow polychromatic erythrocytes. It also significantly decr the ratio of polychromatic to normochromatic erythrocytes. Positive results provided evidence of clastogenic activity. [R74] *Ethyl acrylate (7.5-15 ug/mL) induced a dose-related increase in the incidence of chromosomal aberrations in cultured Chinese hamster lung cells in the absence of a metabolic system. [R63] *Male C3H/HeJ mice (40/group) were treated with 25 uL undiluted ethyl acrylate, 1% acrylic acid or 1% butyl acrylate on the dorsal skin 3 times/wk for their lifetime. A positive control group received 0.1% 3-methylcholanthrene (MC). No epidermal tumors were observed in the animals that received any test substance. In the positive control group, 39 animals had skin tumors, including 33 with confirmed squamous-cell carcinomas. Nonneoplastic skin changes, ie, dermatitis, dermal fibrosis, epidermal necrosis and hyperkeratosis, were observed in several mice that received ethyl acrylate. No statistically significant effects on survival were seen. There was no evidence for local carcinogenic activity of acrylic acid, ethyl acrylate or butyl acrylate under the conditions of these studies. [R75] *Acute exposure studies were conducted using adult male Spraque-Dawley rats to obtain LC50/24 hr concentrations for the common esters of acrylic and methacrylic acids. The order of acute toxicity was determined to be methyl acrylate > ethyl acrylate > butyl acrylate > butyl methacrylate > methyl methacrylate > ethyl methacrylate. 4 hr daily exposures (excluding weekends) of young adult male rats to 110 ppm methyl acrylate in air over a period of 32 days failed to produce significant differences in body or tissue weights, blood chemistries, gross metabolic performance, and spontaneous small intestinal motor activities when compared with a sham-exposed group. [R76] *A number of chemicals have been shown to cause malignant neoplasms in the forestomach of Fischer 344 rats when administered chronically by gavage. The present study was designed to identify early forestomach lesions following 2 wk repeated gavage administration of some of these forestomach carcinogens. Groups of 8 or more male F344 rats received ethyl acrylate, a reported forestomach carcinogen, 5 days/weeks for 2 weeks. Histopathologic examination of forestomachs of rats killed 24 hr after the last dose indicated no significant difference in the incidence or severity of epithelial cell proliferation in the rat forestomach between the vehicle control group and the 2 negative control groups. The incidence and severity of epithelial cell proliferation of the rat forestomach in every group treated with a forestomach carcinogen was significantly higher than the incidence in the vehicle or negative control groups. Early epithelial cell proliferation of the forestomach may be associated with at least some chemicals that induce forestomach neoplasia following chronic administration by gavage. [R77] *Forestomachs of rats which received 100 mg/kg ethyl acrylate for 14 days were recovered to normal within 2 weeks following the last dose. Forestomachs of rats receiving 200 mg/kg ethyl acrylate still exhibited numerous lesions 2 weeks following the last dose, and mucosal hyperplasia was present in the forestomachs at 4 weeks postexposure. Two lesions, submucosal fibrosis and foreign body reaction, became more prevalent in high-dose animals with time. Foreign body reaction, which was present in the forestomachs 4 weeks postexposure, appeared to have resulted from entrapment of hair and/or feed particles in forestomach lesions in the course of healing. It is speculated that the increased cell proliferation and the induced foreign body reactions may contribute to the previously demonstrated carcinogenic effect of ethyl acrylate on the rat forestomach. [R78] *The toxicologic effects and carcinogenic potential of inhaled ethyl acrylate vapors were assessed in mice and rats for periods of up to 27 months. Histopathologic changes in olfactory portions of the nasal mucosa were present in groups exposed to 0, 25 and 75 ppm of the vapors 6 hr/day, 5 days a week. The changes were concentration dependent and were confined generally to those areas normally lined by olfactory epithelium. No oncogenic response was noted in either animal species. [R79] *LC50 VALUES FOR ETHYL ACRYLATE ARE 16,200 MG/CU M FOR MICE AND 7500 MG/CU M FOR RATS. TOPICAL APPLICATION CAUSED HYPEREMIA, HEMORRHAGES, AND SORES. [R80] *The minimum lethal oral dose for rabbits was 280-420 mg/cu m. ... The lowest lethal dermal dose for rats has been reported to be 1800 mg/kg. [R30, 1991.571] *STRUCTURE-TOXICITY RELATIONSHIPS OF ACRYLATES, INCL ETHYL ACRYLATE, AND METHACRYLATES WERE ANALYZED IN MICE. ACUTE ORAL LD50, PARTITION COEFFICIENT (P), and 2ND ORDER RATE CONSTANT (K) MEASURED EXPTL. TOXICITIES FOUND TO BE DEPENDENT UPON LOG P OR LOG K, ESPECIALLY UPON LOG P. [R81] *Contact sensitivity was produced in Guinea pigs with mono-, di-, and tri- acrylate compounds. /Mono-, di-, and tri- acrylate compounds/ [R82] *... NO EFFECT INHALATION CONCN FOR MONKEYS AND THREE RODENT SPECIES WAS APPROX 30 PPM ... PROLONGED CONTACT OF SKIN OR EYE TO LIQ MAY CAUSE SEVERE DAMAGE ... METHYL ACRYLATE /WAS FOUND/ TO BE APPROX TWICE AS TOXIC AS ETHYL ACRYLATE IN SINGLE INHALATION EXPOSURES. [R83] *F344 rats and B6C3F1 mice were exposed by inhalation to 25, 75, and 225 ppm of ethyl acrylate 6 hr/day during 30 days. Decreased body weight, inflammation, and degenerative and metaplastic alterations were found in the nasal mucous membrane of animals exposed at the two highest concentrations. At all concentration levels, dose-dependent changes of the olfactory epithelium were found. The changes were ascribed to the irritative effect of ethyl acrylate. [R84, 757] *In a study on ethyl acrylate with monkeys (24.5, 26.2, 272, and 1024 ppm or 100, 107, 1115, and 4200 mg/cu m, one animal/dose level, 7 hr/day, 130 days), the animal exposed to the highest dose level died after 2 days, and the animal exposed to the second highest concentration was prostrated and had symptoms of mucous membrane irritation after 28 days of exposure. In animals exposed to the two lowest concentrations, no toxic effects were observed. [R84, 757] NTXV: *LD50 Rat oral 760-1020 mg/kg; [R38, p. 1(78) 350] *LC50 Rat inhalation 1000-2000 ppm/4 hr; [R30, 1991.571] *LD50 Rabbit percutaneous 1800 mg/kg; [R38, p. 1(78) 350] *LD50 Rabbit oral 280-420 mg/kg; [R38, p. 1(78) 350] *LD50 Mouse intraperitoneal 600 mg/kg; [R38, p. 1(78) 350] *LD50 Mouse oral 1800 mg/kg; [R38, p. 1(78) 350] *LD50 Rat ip 450 mg/kg; [R41] *LD50 Rat oral 14.8 g/kg; [R16, 3004] *LD50 Rabbit oral 3.63 g/kg; [R16, 3004] *LD50 Rat ip 1.22 g/kg; [R16, 3004] *LD50 Mouse ip 1.25 g/kg; [R16, 3004] ETXV: *Bacteria: Pseudomonas putida: inhibition of cell multiplication starts at 270 mg/l; [R85] *Algae: Microcystis aeruginosa: inhibition of cell multiplication starts at 14 mg/l; [R85] NTP: *Carcinogenesis studies of ethyl acrylate were conducted by administering this test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 100 or 200 mg/kg. Ethyl acrylate was administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Survival of dosed male and female rats and mice was comparable with that of the corresponding vehicle controls. There was no evidence of systemic toxicity in the prechronic or in the 2-year studies. Compound-related increased incidences of hyperkeratosis, inflammation, and hyperplasia of the forestomach were observed in rats and mice in the prechronic as well as 2-year studies. In the 2-year studies, squamous cell papillomas and squamous cell carcinomas of the forestomach occurred at the site of chemical deposition with significant positive trends and increased incidences in dosed groups versus vehicle controls for both sexes of rats and mice. Nonneoplastic and neoplastic forestomach lesion frequencies were related to the concentration of ethyl acrylate in dosing solutions used. Significant negative trends for several common rodent tumors were found in treated animals in the 2-year studies. Under the conditions of these studies, ethyl acrylate was carcinogenic for the forestomach of F344/N rats and B6C3F1 mice, causing squamous cell carcinomas in male rats and male mice, squamous cell papillomas in male and female rats and male mice, and squamous cell papillomas or carcinomas (combined) in male and female rats and mice. Evidence for carcinogenicity was greater in males than in females. Ethyl acrylate also caused irritation of the forestomach mucosa in male and female rats and mice. [R86] TCAT: ?Chronic toxicity was evaluated in male and female Fischer 344 rats (115/sex/group) receiving whole body exposures to ethyl acrylate at nominal concentrations of 0, 25 or 75ppm in a dynamic air flow chamber. Animals were exposed 6 hours per day, 5 days per week, for 12 months beginning at age 7 to 9 weeks. Two male animals died spontaneously, one in the control group and one in the low dose group. Palpable masses were identified in one control group male and in two high dose females. Mean body weight gains of high dose groups were significantly lower than controls. There was no effect of treatment for all dosed rats as indicated by: absolute or relative organ weights, hematologic values, clinical chemistry values, urinalysis values or gross necropsy observations. Nasal lesions were observed in both exposure groups and exhibited a dose-response relationship. [R87] ?The ability of ethyl acrylate to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity tests, nonactivated cultures were treated in duplicate with concentrations ranging from 10nl/ml to 60nl/ml. Five of the nonactivated cultures from 10nl/ml to 40nl/ml produced total relative growth ranging from 49.5% to 1.5% and one of the 40nl/ml treatments and higher concentrations were too toxic evaluate. Two of the 30nl/ml and one 40nl/ml treatments produced mutant frequencies significantly greater than the solvent control (DMSO). These results and confirmatory testing revealed a dose-related mutagenic activity under nonactivated conditions. Based on preliminary toxicity tests and mutation, four activated cultures per treatment were tested with concentrations ranging from 50nl/ml to 400nl/ml. Activated cultures ranging from 50nl/ml to 300nl/ml produced relative growth ranging from 54.5% to 2.2% and two of the 300nl/ml treatments and higher were too toxic to evaluate. Treatments at or above 100nl/ml produced mutant frequencies significantly greater than the solvent control (DMSO), and a dose-response was observed. [R88] POPL: *... Certain medical conditions /chronic respiratory disease, skin disease, liver disease, kidney disease/ ... might place the employee at increased risk from ethyl acrylate exposure. [R37, 1981.1] ADE: *Ethyl acrylate is absorbed through the skin. [R37, 1981.1] *Absorption of ethyl acrylate vapors by the isolated upper respiratory tract was compared to the isolated lower respiratory tract and intact animal. 30-70% of ethyl acrylate was absorbed when passed through the upper respiratory tract. Similar levels were absorbed by the isolated lower respiratory tract and intact animal. It was estimated that intact animals received 50% of ethyl acrylate via the upper respiratory tract. [R89] *The fate of ethyl acrylate was studied in F344 rats indicating that ethyl acrylate was readily absorbed from the stomach (90% of the dose in 4 hours, distributed to all tissues examined, and rapidly excreted in the expired air and in the urine). Ethyl acrylate did not bind to DNA in rat liver but did bind covalently to the protein of the forestomach and liver. The covalently bound radioactivity in the liver proteins declined significantly between 4 and 24 hours while no significant decline was seen in the covalent binding of radioactivity to forestomach proteins. The major urinary metabolites of ethyl acrylate were the mercapturic acids of ethyl acrylate and acrylic acid. [R90] *Organ damage was observed in test animals when they were exposed to methyl and ethyl acrylate and methyl methacrylate vapors. This shows that acrylate compounds are absorbed from the lungs. Ethyl acrylate vapor was efficiently absorbed from the lungs of the rat (63% on an average); the proportion retained was the same at different concentration levels up to 1000 mg/cu m. [R84, 756] *After a single oral dose of (2,3-14C) ethyl acrylate, the label was widely distributed in rat tissues. Highest radioactivity was detected in the gastrointestinal tract, the liver, and the kidneys. In the liver, irreversibly bound radioactivity was found in lipids and in proteins; in the mucous membrane of the forestomach, radioactivity was mainly bound to proteins. [R91] *Dosing rats orally with labeled (2,3-14C) ethyl acrylate was followed by approximately 70% of the dose being eliminated as carbon dioxide in the expired air in 24 hours. In the same period, 9% and 4% of the dose were excreted as mercapturic acid metabolites, in the urine and feces, respectively. At the dose levels of 100, 200, and 400 mg/kg of ethyl acrylate, the amounts of carbon dioxide produced were directly dependent on the dose, and no signs of saturation of the metabolic pathways were observed. [R84, 757] METB: *ETHYL ACRYLATE WAS HYDROLYZED TO ACRYLIC ACID IN RAT LIVER, KIDNEY, AND LUNG HOMOGENATES. ITS DISAPPEARANCE IN BLOOD IN VITRO IS IN PART DUE TO BINDING WITH NONPROTEIN SULFHYDRYLS OF RBC RATHER THAN TO HYDROLYSIS. [R92] *WHEN ADMIN ORALLY TO RATS AT 1/10 OF THE LD50, THE MATERIAL APPEARED TO BE METABOLIZED PROMPTLY ... . [R16, 3004] *Ethyl acrylate binds to glutathione in vitro both spontaneously and after catalysis by liver glutathione-S-transferase. [R63] *The fate of ethyl acrylate was studied in F344 rats. The major urinary metabolites of ethyl acrylate were the mercapturic acids of ethyl acrylate and acrylic acid. [R90] *Nonenzymatic and enzymatic hydrolysis of ethyl acrylate to acrylic acid was demonstrated to occur in vitro in plasma and homogenates of rat forestomach, glandular stomach, stomach contents, liver, lung and kidney. [R63] *FOUR TO 14 DAYS AFTER A SINGLE ORAL ADMIN OF 400 MG ETHYL ACRYLATE/KG (0.5 LD50), URINARY EXCRETION OF 4-HYDROXY-3-METHOXYMANDELIC ACID (I) BY RATS WAS DECREASED. AN ADMIN OF 200 MG ETHYL ACRYLATE/KG ONLY TRANSIENTLY DECR THE (I) EXCRETION. CATECHOLAMINE METABOLISM IN ETHYL ACRYLATE TOXICITY IS DISCUSSED. [R93] ACTN: *Quantitative hemolysis assays of acrylate and methacrylate esters provided estimates of the intrinsic hemolytic activity (Hi, the slope of the concentration-response curve) and the concentrations effecting 5% (H5) and 50% (H50) hemolysis. The dependence of hemolytic activity and LD50 (mice) on physical properties (lipophilicity, molar refraction, and molecular volume of the esters was detected by multiple regression analysis. The observed correlations were: Hi, R2 = 0.94; H5, R2 = 0.95; H50, R2 = 0.94; and LD50, R2 (all compounds) = 0.80, R2 (all compounds less the methyl esters) = 0.94. The difference of the methyl esters was associated with the smaller steric volume of the methyl ester substituent and the presence (methacrylates) or absence (acrylates) of the branched Methyl group. Associative steric contributions of the branched methyl group and the ester substituents were probably responsible for greater variability in the methyacrylate series. ... /It was concluded that/ the mechanism of the action of the esters is membrane-mediated and relatively nonspecific and that in vivo biotransformation was not a significant factor. Also, long-term toxic liability of the esters may be more closely related to intrinsic toxicity than acute toxicity. [R94] INTC: *PRETREATMENT OF RATS WITH TRIORTHOTOLYL PHOSPHATE POTENTIATED THE LETHAL ACTION OF INHALED METHYL AND ETHYL ACRYLATE. CARBOXYLESTERASES ARE IMPORTANT IN DETOXIFICATION OF METHYL AND ETHYL ACRYLATE AND THE EXPOSURE TO INHIBITORS OF CARBOXYLESTERASE MAY POTENTIATE ADVERSE EFFECTS OF ACRYLATE ESTERS. [R95] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethyl acrylate's production and use in the manufacture of emulsion polymers used in surface coatings, textile, paper, polishes, and leather, in solution polymers for surface coatings, and in acrylic fibers may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 38.6 mm Hg at 25 deg C indicates ethyl acrylate will exist solely as a vapor in the ambient atmosphere. Vapor-phase ethyl acrylate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 1.5 days. Reaction with ozone is expected to be an important removal process of atmospheric ethyl acrylate; the half-life for this reaction is estimated to be 2 days. Major transformation products include glyoxylic acid, ethyl glyoxylate, ethyl formate and epoxides. Ethyl acrylate does not absorb light in the environmental UV spectrum (> 290 nm), and is not expected to directly photolyze. If released to soil, ethyl acrylate is expected to have very high mobility based upon a Koc of 42. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 3.4X10-4 atm-cu m/mole. Based upon its vapor pressure, ethyl acrylate may volatilize from dry soil surfaces. If released into water, ethyl acrylate is not expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Ethyl acrylate readily biodegrades in screening tests using sewage seed both in fresh and salt water; it reached 52% of its theoretical BOD in 2 weeks using an activated sludge inoculum. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 6 hours and 5 days, respectively. An estimated BCF of 6 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis half-lives at pH 7, 8, and 11 were estimated to be 3 years, 103 days, and 2.5 hours, respectively. Occupational exposure to ethyl acrylate may occur through inhalation and dermal contact with this compound at workplaces where ethyl acrylate is produced or used. The general population may be exposed to ethyl acrylate via inhalation of air, ingestion of food, and dermal contact with this compound and other products containing ethyl acrylate. (SRC) ARTS: *Ethyl acrylate's production and use in the manufacture of emulsion polymers used in surface coatings, textile, paper, polishes, and leather, in solution polymers for surface coatings, and in acrylic fibers(1) may result in its release to the environment through various waste streams(SRC). [R96] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 42(2) indicates that ethyl acrylate is expected to have very high mobility in soil(SRC). Volatilization of ethyl acrylate from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.4X10-4 atm-cu m/mole(SRC), from its vapor pressure of 38.6 mm Hg(3) and water solubility of 15,000 mg/l(4). The potential for volatilization of ethyl acrylate from dry soil surfaces may exist(SRC) based upon its vapor pressure(3). Hydrolysis of ethyl acrylate is expected to occur in alkaline soils; a half-life of 2.5 hours was determined at pH 11(5,SRC). Screening tests indicate that ethyl acrylate is readily biodegradable(6-8). [R97] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 42(2) indicates that ethyl acrylate is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 3.4X10-4 atm-cu m/mole(SRC), from its vapor pressure of 38.6 mm Hg(4) and water solubility of 15,000 mg/l(5). Volatilization half-lives for a model river and model lake are 6 hours and 5 days, respectively(SRC), using an estimation method(3). Hydrolysis of ethyl acrylate is expected to occur. A base-catalyzed second-order hydrolysis rate constant of 7.8X10-2 L/mol-sec was determined(6); this corresponds to half-lives of 3 years, 103 days, and 2.5 hours at pH values of 7, 8 and 11, respectively(SRC). According to a classification scheme(7), an estimated BCF of 6(3,SRC), from a log Kow of 1.32(8), suggests the potential for bioconcentration in aquatic organisms is low. Ethyl acrylate readily biodegrades in screening tests using sewage seed both in fresh and salt water(9); it reached 52% of its theoretical BOD in 2 weeks using an activated sludge inoculum(10). [R98] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethyl acrylate, which has a vapor pressure of 38.6 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase ethyl acrylate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.5 days(SRC) from its estimated rate constant of 1.1X10-12(3). A major removal process of ethyl acrylate from the atmosphere is reaction with ozone; major transformation products include glyoxylic acid, ethyl glyoxylate, ethyl formate and epoxides(4). The rate constant for the reaction of ethyl acrylate with ozone is 5.7X10-18 cu cm/molc-sec, corresponding to a half-life of 2 days(5). Because ethyl acrylate does not absorb in the environmental UV spectrum (> 290 nm), it is not expected to directly photolyze(5). [R99] BIOD: *AEROBIC: Ethyl acrylate readily biodegrades in screening tests using sewage seed both in fresh and salt water(1). The percent of theoretical BOD is 28 and 11%, respectively, after 5 days; after acclimation, the BOD after 5 days increased to 66% of theoretical(1). Ethyl acrylate, present at 100 mg/l, reached 52% of its BOD in 2 weeks using an activated sludge inoculum and the Japanese MITI test(2). In three separate Zahn-Wellens tests, 60, 100, and > 60% Total Organic Carbon was removed in 3 hours, 7 days, and 11 days, respectively(4). The BOD5/COD ratio for ethyl acrylate was determined to be 0.77, which is indicative of significant potential for biodegradability(4). [R100] *ANAEROBIC: After 110 days of acclimation, ethyl acrylate was degraded in an anaerobic reactor employing acetate-enriched cultures and a 2-10 day hydraulic retention time with 95% utilization(1). [R101] ABIO: *The rate constant for the vapor-phase reaction of ethyl acrylate with photochemically-produced hydroxyl radicals has been estimated as 1.1X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.5 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Another major removal process of ethyl acrylate from the atmosphere is reaction with ozone; major transformation products include glyoxylic acid, ethyl glyoxylate, ethyl formate and epoxides(2). The rate constant for the reaction of ethyl acrylate with ozone was determined to be 5.7X10-18 cu cm/molecule-sec, corresponding to a half-life of 2 days(4). A base-catalyzed second-order hydrolysis rate constant of 7.8X10-2 L/mol-sec was determined for ethyl acrylate(3); this corresponds to half-lives of 3 years, 103 days, and 2.5 hours at pH values of 7,8 and 11, respectively(SRC). Ethyl acrylate is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum(4). [R102] BIOC: *An estimated BCF of 6 was calculated for ethyl acrylate(SRC), using a log Kow of 1.32(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. Ethyl acrylate is highly soluble in water and, therefore, is not expected to significantly bioconcentrate in aquatic organisms(4). [R103] KOC: *The Koc of ethyl acrylate is 42(1). According to a classification scheme(2), this estimated Koc value suggests that ethyl acrylate is expected to have very high mobility in soil. Ethyl acrylate is highly soluble in water and, therefore, is not expected to significantly partition to sediments(1). [R104] VWS: *The Henry's Law constant for ethyl acrylate is estimated as 3.4X10-4 atm-cu m/mole(SRC) from its vapor pressure, 38.6 mm Hg(1), and water solubility, 15,000 mg/l(2). This Henry's Law constant indicates that ethyl acrylate is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as approximately 6 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as approximately 5 days(SRC). Ethyl acrylate's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of ethyl acrylate from dry soil surfaces may exist(SRC) based upon a vapor pressure of 38.6 mm Hg(1). [R105] EFFL: *In a comprehensive survey of wastewater from 4000 industrial and publicly owned treatment works sponsored by the Effluent Guidelines Division of the U.S. EPA, ethyl acrylate was identified in discharges of the following industrial category (frequency of occurrence; median concn in ppb): paint and ink (6; 27.3), publicly owned treatment works (2; 79.9),unspecified (1; 846.7)(1). It was found in stack emissions from a company involved in painting and printing in Japan(2). A plastic material (Acronal 80D) used in building constructions in the U.S.S.R. emitted ethyl acrylate(3). The following industrial categories have been identified as sources of emission of ethyl acrylate in a screening of toxic air pollutants: plastics materials and resins, medicinals and botanicals, pharmaceutical preparations, paints and allied products, industrial organic chemicals, industrial furnaces and ovens, petroleum bulk stations and terminals, and nonresidential building operations; no quantitative data were reported(4). [R106] ATMC: *SOURCE DOMINATED: Mean TWA ethyl acrylate concns of < 1-55 ppb were detected in the breathing zone of workers near 4 polymerization reactors in a polystyrene production plant; breathing zone mean TWA concns at the unloading dock of the same plant was 211 ppb(1). Ethyl acrylate concns of 0.7-21 mg/cu m were reported in the air at the unwoven fabrics division of a textile plant in Poland(2). [R107] *URBAN/SUBURBAN: In a survey conducted at various sites across the United States, ethyl acrylate was detected in the ambient air of 8 samples collected from 1 unspecified location, concn not reported(1). [R108] FOOD: *FOUND IN THE FRUIT OF ANANAS SATIVUS L. [R12] *Ethyl acrylate has been reported to be a volatile component of pineapple concentrate(1). It is also a volatile component of Beaufort cheese, a Gruyere type cheese manufactured in a limited area of the French Alps(2). [R109] OEVC: *Ethyl acrylate has been found as a residual monomer in polyethyl acrylate at a concn of 50 ppm and in aqueous polymer latexes used in the paper textile industries(1). [R96] RTEX: *The toxicologically important routes of entry for ethyl acrylate are inhalation, ingestion, and skin and/or eye contact. [R110] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 34,070 workers (6,627 of these are female) are potentially exposed to ethyl acrylate in the US(1). Occupational exposure to ethyl acrylate may occur through inhalation and dermal contact with this compound at workplaces where ethyl acrylate is produced or used(SRC). The general population may be exposed to ethyl acrylate via inhalation of air(2), ingestion of food(3), and dermal contact with this compound in numerous paper products(4) and latex paints(4) containing ethyl acrylate(SRC). [R111] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH has recommended that ethyl acrylate be treated as a potential human carcinogen. [R44, 132] ATOL: */Polymers of Acrylic Acid Esters/ are exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R112] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 25 ppm (100 mg/cu m). Skin Designation. [R113] *Vacated 1989 OSHA PEL TWA 5 ppm (20 mg/cu m); STEL 25 ppm (100 mg/cu m), skin designation, is still enforced in some states. [R44, 364] NREC: *NIOSH recommends that ethyl acrylate be regulated as a potential human carcinogen. [R44, 132] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R44, 132] TLV: +8 hr Time Weighted Avg (TWA) 5 ppm; 15 min Short Term Exposure Limit (STEL) 15 ppm [R59] +A4. A4= Not classifiable as a human carcinogen. [R59] OOPL: *Australia: 5 ppm, peak limitation, sensitizer ... (1990); Federal Republic of Germany: 5 ppm, short-term level 10 ppm, 5 min, 8 times per shift, sensitizer (1990); Sweden: 10 ppm, 15 min short-term value 15 ppm, skin, sensitizer (1989); United Kingdom: 5 ppm , 10 min STEL 15 ppm, skin (1991). [R30, 1991.573] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethyl acrylate is produced, as an intermediate or a final product, by process units covered under this subpart. [R114] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 5,000 ug/l [R115] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R116] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Ethyl acrylate is included on this list. [R117] RCRA: *U113; As stipulated in 40 CFR 261.33, when ethyl acrylate, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R118] FIFR: */Polymers of acrylic acid esters/ are exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R119] FDA: *Ethyl acrylate is a food additive permitted for direct addition to food for human consumption in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and b) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. [R120] *Homopolymers and copolymers of Ethyl acrylate are an indirect food additive for use only as a component of adhesives. [R121] *Substances used in the manufacture of paper and paperboard products used in food packaging shall include /ethyl acrylate copolymers of itaconic acid or methacrylic acid/ for use only on paper and paperboard which is waxed. Under the conditions of normal use, these substances would not reasonably be expected to migrate to food, based on available scientific information and data. [R122] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 1450: Analyte: ethyl acrylate; Matrix: air; Sampler: solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Vol: min: 1 l at OSHA standard; max: 10 l; Sample stability: not determined /Esters I, ethyl acrylate/ [R123] ALAB: *The electron-impact and methane chemical-ionization mass spectra of selected methacrylate and acrylate monomers, incl ethyl acrylate, commonly used in dental materials are reported and discussed. The 2 ionization modes complement each other, and together the mass spectra offer adequate information for identification purposes. The application of the mass spectral methods is demonstrated on resin-based dental materials with identification of the monomer content. [R124] *RETENTION TIMES FOR ACRYLATES WERE MEASURED WITH 2 DIFFERENT COLUMNS (C18 CORASIL AND C8 LICHROSORB) USING REVERSE-PHASE HIGH PRESSURE LIQ CHROMATOGRAPHY IN ORDER TO OBTAIN THE PARTITION COEFFICIENTS OF ACRYLATES BETWEEN 1-OCTANOL AND WATER (LOG P). /ACRYLATES/ [R125] *Air sampling is conducted using charcoal adsorbent. Samples are desorbed using carbon disulfide and analyzed using a gas chromatograph. [R16, 3006] *NIOSH Method 1450: Esters I by GC/FID; GC with flame ionization detection, workplace air, detection limit of 2.0 mg/cu m. [R126] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: TSCA Chemical Hazard Information Profile (CHIPs) present a preliminary assessment of ethyl acrylate's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404 Scientific Basis for Swedish Occupational Standards VI p.1-133 (1985). It is compilation of consensus reports on the physical, chemical and toxicological properties and methods of determination of potentially hazardous substances. DHHS/NTP; Toxicology and Carcinogenesis Studies of Ethyl Acrylate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 259 (1986) NIH Publication No. 87-2515 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1-B2 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting Ethyl acrylate (140-88-5); Reason: ... The majority opinion of the Report on Carcinogens review groups was to recommend that ethyl acrylate be removed from the Report on Carcinogens. This was based on the facts that 1) the forestomach tumors induced in animal studies were seen only when ethyl acrylate was admin by gavage at high concn that induced marked local irritation and cellular proliferation, 2) animal studies by other routes of administration including inhalation were negative, and 3) because significant chronic human oral exposure to high concn of ethyl acrylate monomer is unlikely. Therefore ethyl acrylate does not meet the criteria to be listed in the Report on Carcinogens as reasonably anticipated to be a human carcinogen. SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. 9 (94) 847 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 478 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. 1 (91) 320 R6: CELANESE CHEM CO. ETHYL ACRYLATE SALES SPECIFICATION, 1984 R7: UNION CARBIDE. ETHYL, BUTYL, AND 2-ETHYLHEXYL ACRYLATES, TECHNICAL BULLETIN, (UNDATED) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 81 (1986) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 58 (1979) R10: UNION CARBIDE. ETHYL, BUTYL AND 2-ETHYLHEXYL ACRYLATES, TECHNICAL BULLETIN, UNDATED R11: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 591 R12: Opdyke, D.L.J. 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RS: 110 Record 42 of 1119 in HSDB (through 2003/06) AN: 195 UD: 200210 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-METHACRYLATE- SY: *Acrylic-acid,-2-methyl-,-methyl-ester-; *DIAKON-; *METAKRYLAN-METYLU- (POLISH); *METHACRYLATE-DE-METHYLE- (FRENCH); *METHACRYLIC-ACID,-METHYL-ESTER-; *METHACRYLSAEUREMETHYL-ESTER- (GERMAN); *METHYLMETHACRYLAAT- (DUTCH); *METHYL-METHACRYLAT- (GERMAN); *METHYL-METHYLACRYLATE-; *METHYL-ALPHA-METHYLACRYLATE-; *METHYL-2-METHYLPROPENOATE-; *METHYL-2-METHYL-2-PROPENOATE-; *METIL-METACRILATO- (ITALIAN); *MMA-; *MME-; *MONOCITE-METHACRYLATE-MONOMER-; *NCI-C50680-; *PEGALAN-; *2-PROPENOIC-ACID,-2-METHYL-,-METHYL-ESTER- RN: 80-62-6 RELT: 2649 [METHACRYLIC ACID]; 1332 [METHACRYLIC ACID, ETHYL ESTER] MF: *C5-H8-O2 SHPN: UN 1247; Methyl methacrylate monomer, inhibited NA 1247; Methyl methacrylate monomer, uninhibited IMO 3.2; Methyl methacrylate monomer, inhibited STCC: 49 072 50; Methyl methacrylate monomer, inhibited 49 072 55; Methyl methacrylate monomer, uninhibited HAZN: U162; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Oxidation of tert-butyl alcohol to methacrolein and then to methacrylic acid, followed by reaction with methanol. [R1, 773] *... Acetone cyanohydrin is treated with concentrated sulfuric acid at 100 deg C, affording the corresponding methacrylamide sulfate which is esterified with methanol at 90 deg C. After purification, methyl methacrylate (99.8% purity) is obtained in a yield of about 85%. [R2] *Ashland Chemical ... has unveiled a new route /to produce methyl methacrylate/ based on propylene and carbon monoxide feedstocks. [R3] *Some quantities of methyl methacrylate monomer are also made available by "cracking" polymethyl methacrylate scrap. [R4] *Certain esters, particularly those of disubstituted acetic acids, maybe dehydrogenated to corresponding alpha, beta-unsaturated esters. Methyl isobutyrate ... gives methyl methacrylate ... . [R5, p. 9(80) 319] *The methacrylates can be synthesized by catalytic oxidation of isobutylene and subsequent esterification with the appropriate alcohol, or by reacting acetone with hydrocyanic acid and subsequent esterification in sulfuric acid with the appropriate alcohol. /Methacrylic esters/ [R6, 3008] FORM: *99.8% purity [R2] *Grade: Technical (inhibited). [R1, 773] *METHYL METHACRYLATE IS ONE OF NINE COMPOUNDS COMPRISING TUN, A RESIN BINDER, WHICH IS USED IN A DENTAL FILLING COMPOSITION. [R7] *Supplied commercially as the polymers. /Methacrylate ester/ [R1, 749] *Inhibitors of polymerization: hydroquinone, 22-65 ppm; hydroquinone methyl ether, 22-120 ppm; dimethyl tert-butylphenol, 45-65 ppm. [R8] *Commercial products contain hydroquinone methyl ether or similar polymerization inhibitors [R9, 588] MFS: *CYRO Industries, Hq: 100 Enterprise Dr., Rockaway, NJ 07866 (973) 442-6000. Production site: Westwego, LA 70094 (Fortier Plant) [R10] *ICI Americas Inc., Hq: Concord Plaza, 3411 Silverside Road, PO Box 15391, Wilmington, DE 19850 (302) 887-3000; ICI Acrylics Inc., 7275 Goodlett Farms Parkway, Cordova, TN 38018 (901) 381-2000. Production sites: Beaumont, TX 77704; Memphis, TN 38127 [R10] *Rohm and Haas Company, Hq: 100 Independence Mall West, Philadelphia, PA 19106-2399 (215) 592-3000; Production site: Deer Park, TX 77536 [R10] OMIN: *METHYL METHACRYLATE, AND IN GENERAL THE METHACRYLIC ESTERS, POLYMERIZE MUCH LESS READILY THAN THE CORRESPONDING ORDINARY ACRYLATES. NONE THE LESS, THEY ARE STABILIZED BY ADDING HYDROQUINONE OR PYROGALLOL, PARTICULARLY IN THE PRESENCE OF METALLIC COPPER. [R11, 88] *Acrylics such as plexiglas and lucite contain methyl methacrylate and peroxide catalysts. Methyl methacrylate ... can be liberated if the acrylic material is heated. [R12] USE: *Monomer for polymethacrylate resins, impregnation of concrete [R1, 773] *COMONOMER FOR COPOLYMERS-EG, WITH ACRYLIC ESTERS [R13] *CHEM INT FOR HIGHER METHACRYLATE ESTERS-EG, STEARYL [R13] *Used in the production of polymers such as surface coating resins, plastics (Plexiglas and Lucite), ion exchange resins and plastic dentures. [R14] *The methyl methacrylate monomer and polymers have wide applicability in medical technology as bone cement, but have been partially replaced by bucrylate and similar synthetics. Also serves as medicinal spray adhesive or nonirritant bandage solvent, and in dental technology as ceramic filler of cement; can also be used as a water-repellent on concrete surfaces. [R6, 3009] *Hard contact lenses with wettable surfaces were prepared from copolymers of hydroxyethyl methacrylate (5-15 wt%) with methyl methacrylate (85-95 wt%). [R5, p. 6(79) 723] *Co-polymerization of methyl methacrylate (80-90%) with acrylic acid (10-20%), and diverse cross-linking agents, followed by neutralization of the polymerized acrylic acid with a basic substance, such as ammonium hydroxide or ethylenimine, /produce/ hydrogels used for contact lenses. /Acrylic Acid/ [R5, p. 6(79) 735] *Poly(methyl methacrylate) block binding agent; marble-like surfaces/basins/panels (kitchens, bathrooms); nitrile rubber comonomer; engineering adhesives; industrial flooring compositions; precast concrete composites; reactive diluent (unsaturated polyester resins); resin mortars (self-leveling floors, jointless floor/wall coatings [R9, 589] CPAT: *MONOMER IN POLYMERS USED FOR ACRYLIC SHEET, 28%; FOR SURFACE COATING RESINS, 25%; FOR MOULDING AND EXTRUSION COMPOUNDS, 21%; AS POLYMER PROCESSING AIDS AND IMPACT MODIFIERS 6%; MONOMER IN EMULSION POLYMERS, 10%; IN UNSATURATED POLYESTER RESINS, 4%; CHEM INT FOR HIGHER METHACRYLATE ESTERS, 2%; OTHER USES (MOSTLY AS A MONOMER), 4% (1982). [R13] *Surface coatings, 33%; cast and extruded sheet, 30%; molding and extrusion compounds, 25%; misc, 2%; exports, 10% (1984). [R15] *CHEMICAL PROFILE: Methyl methacrylate. Cast and extruded heat, 25%; molding powders and resins, 25%; surface coatings, 20%; impact modifiers, 10%; exports, 8%; other emulsion polymers, 6%; polyester modifiers, 4%; higher methacrylates, 2%. [R16] *CHEMICAL PROFILE: Methyl methacrylate. Demand: 1987: 1,028 million pounds; 1988: 1,055 million pounds; Trend: 1992: 1,164 million pounds (includes exports, but excludes monomer imports, which were one quarter of exports last year.) [R16] *Acrylic plastic and resins ,47% (cast and extruded sheet, 32%; molding powders and resins, 15%); surface coatings, 24%; impact modifiers, 13%; emulsion polymers, 8%; mineral-based sheet, 3%; higher methacrylates, 2%; polyester modifiers, 2%; misc, 1% [R17] *Demand - 1995: 1.37 billion pounds; 1996: 1.18 billion pounds; 2000: 1.58 billion pounds [R17] PRIE: U.S. PRODUCTION: *(1977) 3.38X10+11 G (INCL CAPTIVE PRODN) [R13] *(1982) 3.27X10+11 G (INCL CAPTIVE PRODN) [R13] *3.90X10+11 g [R18] *(1986) 9.41X10+8 lb [R19] *1987) 1.03X10+9 lb [R20] *1988) 1.10X10+9 lb [R20] *(1993) 5.21X10+8 kg (5.21X10+11 g) [R21] U.S. IMPORTS: *(1978) 1.58X10+9 G [R13] *(1982) 5.62X10+7 G [R13] *(1985) 1.31X10+10 g [R22] *(1986) 2.01X10+7 lb [R23] U.S. EXPORTS: *(1978) 3.14X10+10 G [R13] *(1983) 3.82X10+10 G [R13] *(1985) 3.71x10+9 [R24] *(1987) 6.77X10+6 lb [R25] *(1988) 6.83X10+6 lb [R26] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless volatile liquid. [R1, 773] ODOR: *Characteristic quality: sulfur-like, sweet, sharp; hedonic tone: unpleasant [R27]; *Acrid, fruity odor. [R28] BP: *100.5 deg C @ 760 mm Hg [R29] MP: *-48 deg C [R29] MW: *100.12 [R29] CTP: *CRITICAL TEMP: 561 DEG F= 294 DEG C= 567 K; CRITICAL PRESSURE: 485 PSIA= 33 ATM= 3.3 MEGANEWTONS/SQUARE M [R8] DEN: *0.9440 @ 20 deg C/4 deg C [R29] HTC: *-11,400 BTU/lb= 6,310 cal/g= -264X10+5 J/kg (estimated) [R8] HTV: *8,974.9 g cal/g mole [R30] OWPC: *log Kow= 1.38 [R31] SOL: *Sol in methyl ethyl ketone, tetrahydrofuran, esters, aromatic and chlorinated hydrocarbons [R32]; *SLIGHTLY SOL IN GLYCOL [R33]; *> 10% in alcohol [R34]; *> 10% in ether [R34]; *> 10% in acetone [R34]; *1.500 lb/100 lb water at 68.02 deg F [R8]; *Sol in chloroform [R35]; *1.6 parts by wt/100 parts by wt of water at room temp [R35]; *1.5 g/100 g water at 30 deg C [R5, p. 14(81) 83]; *Soluble in most organic solvents [R1, 773]; *In water, 1.59X10+4 mg/l @ 25 deg C [R36] SPEC: *Index of refraction: 1.4142 at 20 deg C [R29]; *IR: 2226 (Sadtler Research Laboratories Prism Collection) [R34]; *UV: 2-37 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R34]; *NMR: 113 (Varian Associates NMR Spectra Catalogue) [R34]; *MASS: 245 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R34] SURF: *0.028 N/m at 20 deg C. VAPD: *3.45 (Air= 1) [R6, 3001] VAP: *38.5 mm Hg @ 25 deg C [R37] EVAP: *3.1 (Butyl acetate= 1) [R38, 1981.2] OCPP: *CONVERSION FACTOR: 1 PPM IN AIR= 4.1 MG/CU M [R39] *Water chemistry; methyl methacrylate will float in a slick and dissolve slowly. [R40] *Weight: 7.8 lb per gallon [R41] *Saturated concn in air: 164 g/cu m at 20 deg C, 258 g/cu m at 30 deg C [R27] *Liquid water interfacial tension: 14.3 dynes= 0.0143 N/m at 22.7 deg C; Ratio of specific heats of vapor: 1.059; Heat of polymerization: -248 BTU/lb= -138 cal/g= -5.78X10+5 J/kg; Reid vapor pressure: 0.5 psia (approx) [R8] *Liquid heat capacity: 0.448 BTU/lb-F @ 70 deg F; Liquid thermal conductivity: 1.023 BTU-in/hr-sq ft-F at 70 deg F; Saturated vapor density: 0.01119 lb/cu ft @ 70 deg F; Ideal gas heat capacity: 0.361 BTU/lb-F @ 75 deg F [R8] *Readily polymerized by light, heat, ionizing radiation, and catalysts; can be copolymerized with other methacrylate esters and many other monomers [R1, 773] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Methyl methacrylate monomer, inhibited; Methyl methacrylate monomer, uninhibited/ [R42] FPOT: *A very dangerous fire hazard when exposed to heat or flame ... . [R43] *May ignite on contact with benzoyl peroxide. [R43] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R44, p. 325-70] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R44, p. 325-70] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R44, p. 325-70] FLMT: *LOWER 1.7%; UPPER 8.2% (BY VOLUME) [R44, p. 325-70] FLPT: *50 DEG F; 10 DEG C (OPEN CUP) [R44, p. 325-70] *55 deg F (Tag open cup) [R45] FIRP: *Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. Fight fire from protected location or maximum possible distance. /Methyl methacrylate, monomer, inhibited/ [R44, p. 49-91] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, 713] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame-consider evacuation of one-half (1/2) mile radius. /Methyl methacrylate monomer, inhibited/ [R46, 713] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame-consider evacuation of one-third (1/3) mile radius. /Methyl methacrylate monomer, uninhibited/ [R46, 713] TOXC: *Toxic gases and vapors (such as carbon monoxide) may be released in a fire involving methyl methacrylate. [R38, 1981.2] OFHZ: *Vapor is heavier than air and may travel a considerable distance to a source of ignition and flash back. [R8] EXPL: *EXPLOSIVE IN THE FORM OF VAPOR WHEN EXPOSED TO HEAT OR FLAME. [R43] *LOWER 2.1%; UPPER 12.5% BY VOLUME IN AIR. [R47, 1991.1029] *The monomer may undergo spontaneous, explosive polymerization. Reacts in air to form a heat-sensitive explosive product (explodes on evaporation at 60 deg C). [R43] REAC: *... Can react with oxidizing materials. [R43] *Benzoyl peroxide was weighed into a stainless steel beaker that had been rinsed previously with methyl methacrylate. The peroxide catalyzed polymerization of the methacrylate and the build-up of heat was sufficient to ignite the remainder of the peroxide. [R44, p. 491-29] *Incompatibilities: nitrates, oxidizers, peroxides, polymerizers, strong alkalies, moisture. [R14] *Following an incident in which a drum containing bulked drainings (from other drums awaiting reconditioning) fumed and later exploded after sealing, it was found that methyl methacrylate and propionaldehyde can, under certain conditions of mixing, lead to a rapid exothermic reaction. [R48, p. 533-4] *Nitrates, oxidizers, peroxides, strong alkalis, moisture [Note: May polymerize if subjected to heat, oxidizers, or ultraviolet light. Usually contains an inhibitor such as hydroquinone.] [R49, 214] *Potentially violent reaction with the polymerization initiators azoisobutyronitrile; dibenzoyl peroxide; di-tert-butyl peroxide; propionaldehyde. [R43] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R43] POLY: *The monomer tends to self-polymerize and this may become explosive. ... Exposure of the purified (unstabilized) monomer to air at room temp for 2 months generated an ester-oxygen interpolymer, which exploded on evaporation of the surplus monomer at 60 deg C (but not at 40 deg C). [R48, 533] *If the material becomes contaminated or the chilled material warms up, it may polymerize. If the polymerization takes place inside a container, the container is subject to violent rupture. /Methyl methacrylate monomer, uninhibited/ [R46, 714] *If the polymerization takes place inside a container, the container is subject to violent rupture. /Methyl methacrylate monomer, inhibited/ [R46, 713] *This substance readily polymerizes to a clear plastic known variously as Lucite, Plexiglas and Perspex. [R50] *METHYL METHACRYLATE, AND IN GENERAL THE METHACRYLIC ESTERS, POLYMERIZE MUCH LESS READILY THAN THE CORRESPONDING ORDINARY ACRYLATES. NONE THE LESS, THEY ARE STABILIZED BY ADDING HYDROQUINONE OR PYROGALLOL, PARTICULARLY IN THE PRESENCE OF METALLIC COPPER. /METHACRYLATES/ [R11, 88] *Hazardous polymerization may occur. Usually contains inhibitors to prevent polymerization. Polymerization may be caused by elevated temperature, oxidizers, peroxides, or sunlight. ... Uninhibited monomer vapor may form polymer in vents and other confined spaces. /Methyl methacrylate monomer, inhibited/ [R44, p. 49-91] ODRT: *0.05 ppm [R8] *0.21 ppm [R38, 1981.2] SERI: *The vapors are irritating to the eyes and resp system. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, p. 713-4] *Irritating to ... skin. [R51] EQUP: *Wear appropriate chemical protective gloves, boots and goggles. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, p. 713-4] *SUITABLE PROTECTIVE CLOTHING AND SELF-CONTAINED RESP PROTECTIVE APPARATUS SHOULD BE AVAILABLE FOR USE OF THOSE WHO MAY HAVE TO RESCUE PERSONS OVERCOME BY FUMES. /ACRYLIC ACID AND DERIVATIVES/ [R52, 53] *Wear appropriate personal protective clothing to prevent skin contact. [R49, 214] *Wear appropriate eye protection to prevent eye contact. [R49, 214] *Recommendations for respirator selection. Max concn for use: 1000 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R49, 215] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R49, 215] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R49, 215] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Contact lenses should not be worn when working with this chemical. [R53] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water to knock-down vapors. Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, 713] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, 713] *Evacuation: ... If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, 713] *Inhibitors do not function in absence of air, so inert gas blankets should not be used. [R38, 1981.2] *Remove clothing immediately if wet or contaminated to avoid flammability hazard. [R14] *Adequate exhaust ventilation should be provided to protect the workers from the inhalation of fumes. ... Maintenance and good housekeeping should be ensured. [R52, 54] *... Hazard is the generation of considerable exothermic heat in some of the reactions, so that high pressures and temp may develop. This danger ... should be borne in mind when designing plant. Awareness of the dangers and of good engineering design are essential to safety. Employees should be instructed about the necessity of cleansing the skin if it is contaminated by materials which are irritants or skin-absorbed. With careful design, however, and complete enclosure of those processes where toxic chemicals or intermediates occur, dangerous exposures can be avoided. /Acrylic acid and derivatives/ [R52, 53] *The worker should immediately wash the skin when it becomes contaminated. [R49, 214] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R49, 214] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R54] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R55] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R56] STRG: *Separate from oxidizing materials, peroxides, or other initiators. Store in cool, dry, well-ventilated place. /Methyl methacrylate monomer, inhibited/ [R44, p. 49-91] *Use standard combustible liquid storage room for indoor storage. [R57] *Keep container in a well-ventilated place. Keep away from sources of ignition. ... Take precautionary measures against static discharges. [R51] *Temp during storage must be kept low to minimize formation of peroxides and other oxidation products. ... Storage temp below 30 deg C are recommended for the polyfunctional methacrylates. ... the methacrylate monomers should not be stored for longer than one year. Shorter storage times are recommended for the aminomethacrylates, ie, three months, and the polyfunctional methacrylates, ie, six months. Many of these cmpd are sensitive to UV light and should, therefore, be stored in the dark. The methacrylic esters may be stored in mild steel, stainless steel, or aluminum. /Methacrylic acid and derivatives/ [R5, p. 15(81) 370] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER. METHYL METHACRYLATE SHOULD NOT BE ALLOWED TO ENTER CONFINED SPACE, SUCH AS SEWER, BECAUSE OF POSSIBILITY OF AN EXPLOSION. [R38, 1981.4] *Environmental considerations: Air spill: Apply water spray or mist to knock down vapors. /Methyl methacrylate monomer, inhibited and uninhibited/ [R46, 714] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Apply "universal" gelling agent to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. /Methyl methacrylate monomer, uninhibited and inhibited/ [R46, p. 713-4] *Environmental consideration: Water spill: Use natural barriers or oil spill control boons to limit spill travel. Use surface active agent (e.g. detergent, soaps, alcohols), if approved by EPA. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Methyl methacrylate monomer, uninhibited and inhibited/ [R46, p. 713-4] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U162, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R58] *1. BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL ... . 2. BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER. [R38, 1981.4] *Do not empty into drains. [R51] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: Methyl methacrylate is a volatile synthetic chemical that is used principally in the production of cast acrylic sheet, acrylic emulsions, and molding and extrusion resins. HUMAN EXPOSURE: Data on absorption following dermal exposure are limited. In humans, methyl methacrylate is rapidly metabolized to methacrylic acid. This compound us a mild skin irritant in humans and has the potential to induce skin sensitization in susceptible individuals. Although occupational asthma associated with methyl methacrylate has also been reported, there is no conclusive evidence that this compound is a respiratory sensitizer. Epidemiological studies do not provide strong or consistent evidence of a carcinogenic effect of methyl methacrylate on any target organ in humans, nor can it be inferred with any degree of confidence that the posibility of an increased risk has been disaproved. ANIMAL/ PLANT STUDIES: Methyl methacrylate is rapidly absorbed and distributed following inhalation or oral administration to experimental animals. Data on absorption following dermal exposure are limited. In experimental animals, methyl methacrylate is rapidly metabolized to methacrylic acid. Following inhalation, 16-20% of the chemical is deposited in the upper respiratory tract of rats, where it is primarily metabolized by local tissue esterases. The acute toxicity of this compound is low. Irritation of the skin, eye and nasal cavity has been observed in rodents and rabbits exposed to relatively high concentrations of methyl methacrylate. The chemical is a mild skin sensitizer in animals. The effect observed most frequently at the lowest concentration after repeated inhalation exposure to this compound is irritation of the nasal cavity. Effects on the kidney and liver at higher concentrations have been reported. The lowest reported effect level for irritation was 410 mg/cu m in rats exposed to this material for 2 yr (based upon inflammatory degeneration of the nasal epithelium); the no observed effect level (NOEL) in this investigation was approximately 100 mg/cu m. In a study in rats, there were no developmental effects, although there were decreases in maternal body weight following inhalation of concentrations up to 8,315 mg/cu m. There was no reduction in fertility in a dominant lethal assay in mice exposed to this compound at concentrations up to 36,900 mg/cu m and no adverse effects on reproductive organs in repeated dose studies conducted to date. Available data pn the neurotoxicity of methyl methacrylate are limited; impairment of locomotor activity and learning and behavioral effects on the brain were observed in rats exposed orally to 500 mg/kg bw/day for 21 days. Methyl methacrylate was not carcinogenic in an extensive well documented 2 yr bioassay in rats and mice exposed by inhalation and in additional chronic inhalation studies in rats and hamsters. This substance is not mutagenic in vitro bacterial systems, this compound is mutagenic and clastogenic in mammalian cells in vitro. In in vivo studies (primarily by the inhalation route) in which there has been clear evidence of toxicity within the target tissue, there has been limited evidence of the genotoxicity of methyl methacrylate. The toxicity of methyl methacrylate to aquatic organisms is low. No chronic studies on aquatic organisms were identified. Acute tests have been conducted on fish, Daphnia magna and algae. The most sensitive effect was the onset of inhibition of cell multiplication by the green alga Scenedesmus quadricauda at 37 mg/l following an 8 day exposure period. The lowest EC50 for immobilization in Daphnia was 720 mg/l. The 96 hr LC50 for juvenile bluegill sunfish (Lepomis macrochirus) under flow through conditions was 191 mg/l, whereas LC50 values for durations 1-24 hr ranged from 420-356 mg/l, respectively. The 96 hr LC50 for rainbow trout (Oncorhynchus mykiss) under flow through conditions was > 79 mg/l, the highest concentration tested. Sublethal/behavioral responses were noted among the fish at 40 mg/l. [R59] CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of methyl methacrylate. There is evidence suggesting lack of carcinogenicity of methyl methacrylate in experimental animals. Overall evaluation: Methyl methacrylate is not classifiable as to its carcinogenicity to humans (Group3). [R60] *WEIGHT OF EVIDENCE CHARACTERIZATION: Under EPA's 1986 Guidelines for Carcinogen Risk Assessment, MMA would be classified as evidence of non-carcinogenicity for humans or a Group E chemical. Under the Proposed Guidelines for Carcinogenic Risk Assessment, MMA is considered not likely to be carcinogenic to humans by any route of exposure because it has been evaluated in four well-conducted chronic inhalation studies in three appropriate animal species without demonstrating carcinogenic effects. Basis - The results of the 2-year inhalation studies conducted for NTP showed no evidence of carcinogenicity of MMA for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for female B6C3F1 mice exposed at 500 or 1,000 ppm. In addition, no increase was seen in the number or type of tumors in either rats or hamsters from the chronic inhalation study performed by Hazelton Laboratories /in 1979/. No carcinogenic activity was reported in a chronic oral study. Fewer animals were used and the experimental protocol and results of this oral study were not as well documented as for the inhalation study. However, acute oral exposure studies and structure-activity relationship comparisons with other acrylates suggest that the introduction of a methyl group to the acrylate moiety (e.g., EC to MMA) negates carcinogenic activity. Epidemiology studies show no clear excess of cancer. Though a report suggesting increased colon cancer among ethyl acrylate/MMA-exposed workers exists, a high background for this effect has been documented for the location and time of this study, the effects were not reproduced in other similar and more recent studies, a clear relationship between exposure and effect was not demonstrated, and the extent that ethyl acrylate concurrent exposure confounded results could not be determined. Given these structure-activity relationship considerations, the low potential for cancer from MMA exposure indicated in genotoxicity, laboratory animal and epidemiology studies suggests that MMA does not represent a carcinogenic hazard to humans. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: No evidence. [R61] +A4; Not classifiable as a human carcinogen. [R62] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R63, 221] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Esters and related compounds/ [R63, p. 221-2] MEDS: *Employees should be screened for history of certain medical conditions /chronic resp, skin, kidney, and liver diseases/ which might place the employee at incr risk from methyl methacrylate exposure. [R38, 1981.1] HTOX: *... VAPOR IS ... /CNS DEPRESSANT/. [R52, 54] *... /IRRITATES/ THE ALIMENTARY CANAL WHEN INGESTED ORALLY. ... CAUSE KIDNEY AND LIVER LESIONS. [R11, 324] *... Small amounts of methyl methacrylate vapor found in casting plants was found to induce functional abnormalities in the nervous system of plant workers. In another series of experiments, exposure to methacrylate glue in the placement of bone prostheses was also found to induce severe hypotension and in some cases cause death. The studies did not determine, however, whether the adverse reactions were the result of the methacrylate or bone marrow embolism. [R64, 746] *TESTS WERE MADE ON SKIN OF 50 VOLUNTEERS, WHO DEVELOPED SLIGHT ERYTHEMA AFTER 48 HR, WHILE TESTS CARRIED OUT 10 DAYS LATER SHOWED THAT SOME HAD BECOME SENSITIVE TO MONOMER. [R11, 159] *TOTAL PLASMA CONCN OF LACTATE DEHYDROGENASE AND ISOENZYMES 3, 4, and 5 WERE ELEVATED 3 HR AFTER INSERTION OF SECOND ARTIFICIAL HIP USING METHYL METHACRYLATE CEMENT. RESULTS INDICATED THAT LUNG DAMAGE OCCURRED. [R65] *EFFECT OF METHYLMETHACRYLATE ON CHEMOTAXIS OF POLYMORPHONUCLEAR LEUKOCYTES EVALUATED BY IN VITRO METHOD. CHEMOTACTIC FACTORS REMAINED CHEMOTACTICALLY ACTIVE AT CONCN OF 1.25%. WHEN ADDED TO SERUM PRIOR TO ZYMOSAN ACTIVATION CONCN ABOVE 0.312% ABOLISHED CHEMOTACTIC ACTIVITY. [R66] *METHYL METHACRYLATE VAPOR IS ACUTE IRRITANT CAUSING EYE AND MUCOUS MEMBRANE IRRITATION AT CONCN OF 125 PPM. AT HIGHER CONCN, DEATH FROM PULMONARY EDEMA OCCURRED. IT HAS BEEN LINKED TO CARDIAC ARREST AND OTHER CARDIOVASCULAR EFFECTS RESULTING FROM ITS HYPOTENSIVE PROPERTIES. [R67] *ONE REPORT ON 152 WORKERS EXPOSED TO 2-200 MG/CU M ... METHYL METHACRYLATE STATES THAT 119 COMPLAINED OF HEADACHES, 45 NOTED PAIN IN EXTREMITIES, 32 SHOWED EXCESSIVE FATIGUE, 32 HAD SLEEP DISTURBANCE, 30 HAD LOSS OF MEMORY, and 25 SHOWED IRRITABILITY. [R68] *IT IS MILD IRRITANT TO RESP MUCOUS MEMBRANES, AND GIVES RISE TO SOME DERMATOSES ... . [R11, 88] *Inhalation of vapor at concn of 150 mg/cu m is said to produce central nervous effects in humans. ... Both the monomer and the polymerizing catalyst, benzoyl peroxide, may cause contact dermatitis. Such cases have been reported among dental technicians who make dentures from the resins and among surgeons who use methyl methacrylate as orthopedic cement. The skin and oral mucosa of some denture wearers have become sensitized. [R50] *Neurotoxic effect: Asthenia; autonomic dystonia; encephalopathy [R69] *IN 45 PATIENTS UNDERGOING HIP REPLACEMENT, EFFECT OF METHYL METHACRYLATE CEMENT ON SYSTOLIC BLOOD PRESSURE WAS INFLUENCED BY STATE OF BLOOD PRESSURE BEFORE IMPLANTATION AND CHANGES IN CONCN OF HALOTHANE IN ANESTHETIC GASES. A DANGEROUS FALL IN BLOOD PRESSURE WAS AVOIDED BY USING NEUROLEPTANALGESIA. [R70] *A case of systemic sensitivity reaction to bone cement (97% methyl methacrylate monomer) in a female operating room nurse was reported. The subject reported two previous episodes of nausea, sore throat and chest congestion with exposure to bone cement. Upon third exposure the subject reacted within minutes of mixing of the cement with headache and lethargy. She was noted to have diffuse erythroderma, a blood pressure of 180/100 and respiratory rate of 26. These eased after she was given subcutaneous epinephrine and her symptoms completely resolved after three days. Air samples taken on another day showed methyl methacrylate (MMA) concentrations of 0.4 ppm to 1.5 ppm. [R71] *Methylmethacrylate resin powder may cause interstitial pneumonitis with vacuolated alveolar macrophages observed in BAL fluid. [R72] *Allergic contact dermatitis from methyl methacrylates in artificial nails has caused painful paronychia, nail dystrophy, onycholysis, paresthesia of the finger tips, and dermatitis of the eyelids and face. [R73] *From 1987 to 1989 the North American Contact Dermatitis Group found 18 of 228 patients (1.3%) to be allergic to methyl methacrylate and 15 of 228 patients (1.1%) to be allergic to ethyl methacrylate. [R73] *Between 3 to 5% of methylmethacrylate is unreacted monomer, posing an occupational hazard among dental technicians who experience feelings of numbness, coldness, and pain in the dominantly exposed hand. Sensory conduction velocities in finger nerves are slowed in conjunction with the numbness. Urine output of methylmethacrylate in such dental technicians reflects a percutaneous absorption. [R74, 1668] *An operating room nurse developed a sensitivity reaction to the odor of orthopedic cement characterized by hypertension, dyspnea, and generalized erythroderma. She recovered. Methylmethacrylate air concentrations were 0.4 ppm, 1.0 ppm, and 1.5 ppm monitored over 15-minute periods. Operating room personnel are exposed for about 30 min for each orthopedic procedure. ... Increased complaints of respiratory, cutaneous, and genitourinary problems have been observed in workers exposed to methylmethacrylate at concentrations of 4-49 ppm over an 8 hr time-weighted average. [R74, 1667] *FIVE WORKERS IN CONTACT WITH CHLOROPRENE (2-2.2 MG/CU M; 0.56-0.61 PPM) AND METHYL METHACRYLATE (0.5-2 MG/CU M; 0.1-0.5 PPM) WERE FOUND TO HAVE STATISTICALLY SIGNIFICANT INCR IN CHROMOSOMAL ABERRATIONS IN THEIR LYMPHOCYTES. [R75] NTOX: *IN CHRONIC STUDIES, RATS AND DOGS WERE GIVEN DRINKING WATER CONTAINING 16, 60, and 2,000 PPM AND 10, 100, and 1,000 PPM METHYL METHACRYLATE, RESPECTIVELY, FOR 2 YR. NO CLINICAL, LAB OR PATHOLOGICAL EVIDENCE OF TOXICITY WAS OBSERVED ... . [R64, 746] *... SC IMPLANTS OF FRESHLY POLYMERIZED METHYL METHACRYLATE FOR UP TO 39 MO INCR INCIDENCE OF LOCAL FIBROSARCOMA COMPARED TO GLASS IMPLANT CONTROL IN RATS. IN ANOTHER STUDY ... SC IMPLANTS OF POLYMERIZED METHYL METHACRYLATE INDUCED LOCAL FIBROSARCOMAS IN MICE. DOSES OF 0.13-0.44 ML/KG METHYL METHACRYLATE INJECTED INTO PREGNANT RATS ON DAY 5, 10 and 15 OF GESTATION WERE FOUND TO AFFECT ABSORPTIONS, FETAL SURVIVAL AND FETAL SIZE @ ALL DOSES. HEMANGIOMAS WERE ALSO OBSERVED IN SOME FETUSES FROM HIGHEST DOSE GROUP. NO SKELETAL ABNORMALITIES OBSERVED AT ANY DOSE. [R64, 746] *MONOMERIC FORM IS REPORTEDLY LETHAL @ ORAL DOSES FROM 6 TO 9 G/KG IN LAB ANIMALS. POISONED ANIMALS EXHIBIT RESP DEPRESSION, AND COMA; ALSO IRRITATION OF SKIN, EYES AND RESPIRATORY TRACT. [R50] *INSERTION OF 3 DROPS OF THIS MONOMER IN EYE OF RABBIT PRODUCES IMMEDIATE IRRITATION ACCOMPANIED BY INFLAMMATION AND SUBSEQUENT EDEMA, WHICH CLEARS UP IN 3 DAYS. TOXICITY OF METHYL METHACRYLATE WHEN INHALED AND WHEN ADMIN SC AND IP HAS ... BEEN STUDIED. ... KIDNEY AND LIVER LESIONS RESEMBLING THOSE CAUSED BY CARBON TETRACHLORIDE /WERE FOUND/. LIVER INJURY WAS ALSO FOUND, BUT SOMETIMES IT APPEARED TO BE REVERSIBLE, AND HEALED SUBSEQUENTLY. ... /IN OTHER STUDIES IT WAS/ FOUND THAT WHEN ANIMALS ARE MADE TO BREATHE TOXIC AMT OF THE VAPOR OF THE MONOMER THERE IS GREAT EXHAUSTION, DYSPNEA, AND DIMINUTION OF THE REFLEXES, THE ANIMALS FINDING INCR DIFFICULTY IN BREATHING, AND FINALLY DYING THROUGH RESP FAILURE. [R11, 89] *... SINGLE 8-HR EXPOSURES TO ... CONCN OF 4400 PPM WERE FATAL TO RATS AND RABBITS, BUT NOT GUINEA PIGS. ... EXPOSURES OF 10,000 to 11,000 PPM FOR ONE-HALF HR TO 3 HR DAILY FOR 15 DAYS CAUSED DEATHS AMONG MICE AND DOGS, BUT GUINEA PIGS SURVIVED. [R47, 1991.1029] *TREATMENT OF RATS WITH METHYL METHACRYLATE CAUSED DECR IN HEPATIC BETA-GLUCURONIDASE LEVELS WITHIN 24 HR. SERUM ENZYMIC ACTIVITY GRADUALLY INCR UPON TREATMENT. [R76] *MONOMERIC METHYL METHACRYLATE VAPOR IN AIR WAS DELIVERED INTO THE BREATHING AIR OF DOGS. 2000 PPM RESULTED IN TRANSIENT DROP IN ARTERIAL BLOOD PRESSURE AND MARKED INHIBITION OF ONGOING GI MOTOR ACTIVITIES. [R77] *EXPOSURE OF RATS TO 116 PPM METHYL METHACRYLATE VAPOR FOR 8 HR/DAY FOR 3-6 MO DECR SC FAT DEPOSITS, BODY, LUNG AND SPLEEN WT, AFFECTED INTESTINAL TRANSIT PERFORMANCE, AND ALTERED BLOOD CHEMISTRY. [R78] *THE CARDIOVASCULAR EFFECTS OF METHYL METHACRYLATE MONOMER IV INJECTIONS WERE STUDIED IN DOGS. IV 0.1 ML/KG RESULTED IN SIGNIFICANT VARIATIONS IN CARDIAC OUTPUT (+20%), PULMONARY PRESSURE (+30%) AND DIASTOLIC SYSTEMIC PRESSURE (-25%) IN DOGS. [R79] *PREGNANT MICE WERE EXPOSED TO 1330 PPM METHYL METHACRYLATE FOR 2 HR TWICE DAILY DURING 6TH-15TH DAY OF PREGNANCY. SLIGHT INCR IN WT OF FETUS WAS OBSERVED BUT THERE WAS NO EVIDENCE OF TERATOLOGICAL EFFECTS. [R80] *GROUPS OF 25 MALE AND 25 FEMALE WISTAR RATS WERE ADMIN 0, 6, 60 OR 2000 MG/L (PPM) METHYL METHACRYLATE IN THEIR DRINKING-WATER FOR 2 YR; NO TREATMENT-RELATED TUMORS WERE FOUND. /WORKING GROUP NOTED THAT INSUFFICIENT DETAILS ON SURVIVAL AND PATHOLOGICAL EXAM WERE GIVEN/. [R81] *TEN WISTAR RATS WERE PAINTED ON THE BACK OF THE NECK WITH METHYL METHACRYLATE 3 TIMES A WK FOR 4 MO AND THEN KEPT FOR LIFESPAN. NO LOCAL TUMORS WERE OBSERVED (THE WORKING GROUP NOTED THAT THE STUDY WAS INADEQUATE DUE TO THE INSUFFICIENT NUMBER OF ANIMALS AT RISK AND THE SHORT DURATION OF TREATMENT). [R82] *ISOLATED GUINEA PIG ILEUM WAS EXPOSED TO 755 PPM METHYL METHACRYLATE. SPONTANEOUS MOTOR ACTIVITIES AND CONTRACTILE RESPONSES TO ELECTRICAL FIELD STIMULATION DECR. PERSISTENCE OF THIS INHIBITORY RESPONSE INDICATES THAT EFFECT IS PARTLY DUE TO DIRECT ACTION UPON CONTRACTILE MECHANISM OF INTESTINE. [R83] *INHALATION EXPOSURES CAUSED A DEPRESSION OF MULTIPLE-UNIT ELECTRICAL ACTIVITY IN LATERAL HYPOTHALAMUS AND VENTRAL HIPPOCAMPUS OF MATURE MALE RATS WHICH WERE EXPOSED TO 400 PPM OF METHYL METHACRYLATE IN AIR FOR 60 MINUTES. [R84] *THE TOXICITY OF 6 ACRYLATES AND 6 METHACRYLATES, INCLUDING METHYL METHACRYLATE, WAS DETERMINED IN RATS AND FISH. ALL THE ESTERS WERE LESS TOXIC THAN ACRYLAMIDE AND ACRYLONITRILE. METHACRYLATES WERE APPROXIMATELY 5-FOLD LESS TOXIC THAN ACRYLATES. FOR A GIVEN SERIES, TOXICITY DECREASED WITH INCREASING LENGTH OF THE CARBON CHAIN. [R85] *METHACRYLATE ESTER MONOMER AND METHACRYLIC ACID DECR THE HEART RATE AND FORCE OF CONTRACTION OF THE ISOLATED, PERFUSED RABBIT HEART WHEN ADDED TO THE PERFUSING LIQUID AT CONCN OF 1:1000, 1:10,000 OR 1:100,000 (VOL/VOL), AND MOST OF THE CMPD DECR THE CORONARY FLOW RATE. METHACRYLIC ACID, METHYL METHACRYLATE, ETHYL METHACRYLATE, AND DIMETHYLAMINOETHYL METHACRYLATE PRODUCED AN IRREVERSIBLE EFFECT ON THE ISOLATED HEART AT ALL 3 CONCN, WHILE 1,3-BUTYLENE DIMETHACRYLATE, 2-ETHYLHEXYL METHACRYLATE, ISODECYL METHACRYLATE, AND LAURYL METHACRYLATE PRODUCED ONLY A REVERSIBLE EFFECT AT ALL 3 CONCN. [R86] *METHACRYLIC ACID ADMIN IV INCR RESPIRATORY RATE, DECR HEART RATE, AND PRODUCED ELECTROCARDIOGRAM CHANGES IN ANESTHETIZED DOGS. METHACRYLIC ACID, METHYL, N-PROPYL, N-BUTYL, ISOBUTYL, AND HYDROXYETHYL METHACRYLATES PRODUCED A BIPHASIC RESPONSE, AN ABRUPT FALL IN BLOOD PRESSURE FOLLOWED BY A SECONDARY RISE. 2-ETHYLHEXYL, ISODECYL, LAURYL, AND TERT-BUTYLAMINOETHYL METHACRYLATES PRODUCED ONLY A HYPOTENSIVE EFFECT. DIMETHYLAMINOETHYLMETHACRYLATE PRODUCED ONLY A HYPERTENSIVE EFFECT. [R87] *TWENTY-ONE DIFFERENT ACRYLATE AND METHACRYLATE COMPOUNDS, INCLUDING METHYL METHACRYLATE, WERE SCANNED FOR THEIR ABILITY TO INDUCE CONTACT SENSITIVITY, USING 5 DIFFERENT SENSITIZATION PROTOCOLS. CONTACT REACTIONS OF VARYING INTENSITIES WERE PRODUCED TO ALL THE MONO-, DI-, AND TRIACRYLATES TESTED. METHACRYLATES DID NOT SENSITIZE GUINEA PIGS. [R88] *MONOMERIC METHYL METHACRYLATE @ CONCN APPROX 10 MMOL DECR AMPLITUDE OF ACTION POTENTIAL OF DESHEATHED AMPHIBIAN SCIATIC NERVE AND PRODUCED HYPERPOLARIZATION OF RESTING POTENTIAL. THE ETHYL, ALLYL, AND BUTYL ESTERS WERE MORE ACTIVE THAN METHYL METHACRYLATE. ISOBUTYL METHACRYLATE WAS LESS ACTIVE, AND SODIUM METHACRYLATE HAD NO EFFECT. SODIUM AND POTASSIUM CURRENTS ACROSS THE NERVE MEMBRANE AT THE NODE OF RANVIER WERE DECR BY METHYL METHACRYLATE. [R89] *... EMBRYOFETAL TOXICITY AND TERATOGENIC EFFECTS OF A GROUP OF METHACRYLIC ESTERS IN RATS /WERE STUDIED/. THE ESTERS STUDIED INCLUDED METHYL METHACRYLATE, ETHYL METHACRYLATE, BUTYL METHACRYLATE, ISOBUTYL METHACRYLATE, AND ISODECYL METHACRYLATE. ESTERS WERE ADMIN @ 1/10, 1/5 and 1/3 LD50 DOSE ON 5TH, 10TH, 15TH DAYS OF GESTATION. ... EACH ESTER PRODUCED SOME OR ALL OF THE FOLLOWING EFFECTS: RESORPTIONS, GROSS AND SKELETAL MALFORMATIONS, FETAL DEATH OR DECREASED SIZE. SINCE THE CHEMICAL WAS ADMIN IP, IT IS POSSIBLE THAT THE TOXIC EFFECTS WERE DUE DIRECTLY TO THE CHEMICAL'S PASSING INTO THE EMBRYO, RATHER THAN THROUGH SYSTEMIC ABSORPTION. [R90] *GUINEA PIGS COULD BE STRONGLY SENSITIZED TO METHYL, ETHYL, AND N-BUTYL METHACRYLATES IN ETHANOL OR OLIVE OIL BY TOPICAL ROUTE, OR IN SALINE BY INTRADERMAL ROUTE. [R91] *... SIX TYPES OF METHACRYLATE ESTERS /WERE ADMIN/ TO PREGNANT RATS ON DAYS 5, 10 AND 15 OF GESTATION IN DOSES UP TO ONE-THIRD THE ACUTE INTRAPERITONEAL LD50. THE MAXIMUM DOSES USED WERE 0.44, 0.40, 0.78, 0.46 AND 0.82 ML/KG FOR THE METHYL, ETHYL, N-BUTYL, ISOBUTYL, ISODECYL METHACRYLATE RESPECTIVELY. HEMANGIOMAS WERE INCR AT THE HIGHEST DOSES AS WERE RESORPTIONS. THE FETAL WT WAS REDUCED BY TREATMENT. ACRYLIC ACID WAS INJECTED IN VOL OF UP TO 0.0075 ML/KG AND THIS WAS ASSOCIATED WITH RESORPTIONS AND HEMANGIOMAS. FETAL MORTALITY AND AN INCIDENCE OF UP TO 16% MALFORMATIONS WERE REPORTED ... . [R92] *... Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenicity of methyl methacrylate for male F344/N rats exposed at 500 or l,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for male and female B6C3Fl mice exposed at 500 or 1,000 ppm. ... [R93] *In a 3-month study with mice and rats, the animals were exposed to methyl methacrylate via inhalation at 4 concentrations ranging from 500 ppm (2080 mg/cu m) to 3000 ppm (12,480 mg/cu m). In female and male rats 2000 ppm and 3000 ppm, respectively, caused inflammation in the nasal cavity and necrosis of the olfactory epithelium. The mice showed metaplastic changes of the nasal epithelium even at the lowest level of 500 ppm. Apart from the local airway injuries, there were rather few observations concerning systemic toxicity: female rats showed dose-related malacia and gliosis of the brain at and above 1000 ppm; at 2000 ppm and higher concentrations, male mice showed a dose-related increase in renal cortical necrosis and tubular degeneration. [R94, 757] *In an inhalation carcinogenicity study, B6C3F1 mice (both sexes) and F344/N male rats were exposed to methyl methacrylate vapor at 500 or 1000 ppm (2080 or 4160 mg/cu m), 6 hr/day, 5 days/wk for 103 weeks. Female F344/N rats were exposed to 250 or 500 ppm of methyl methacrylate. The exposures did not affect the longevity of the animals, and the occurrence of tumors was not exposure related in mice or rats of either sex. In high dose female rats, mononuclear cell leukemias occurred at a higher incidence but without statistical significance. Methyl methacrylate exposures caused inflammation of the nasal cavity and degeneration of the olfactory epithelium in all groups of mice and rats, including the lowest level of 250 ppm. [R94, 759] *When a rhesus monkey was exposed to methyl methacrylate for 22 hr, the animal died from acute pulmonary edema; centrilobular necrosis was recorded at autopsy. [R47, 1991.1029] *Rats and mice inhaled 500, 1000, 2000, 3000, or 5000 ppm methyl methacrylate for 6 hr/day, 5 days/wk for 14 wk. Concentration-dependent mortality was recorded; all rats exposed at 5000 ppm died, and cerebellar congestion and hemorrhage into the cerebellar pedoncles, malacia, and gliosis were found in early and late deaths, respectively. There was a dose-dependent increase in olfactory epithelial necrosis and sloughing; metaplasia and inflammation in the nasal turbinates occurred in the mice. Renal cortical necrosis, tubular degeneration with focal mineralization and hepatic necrosis were seen in the male mice. No deaths occurred in groups of rats or mice that inhaled 500 or 1000 ppm methyl methacrylate, but body weights were reduced. [R47, 1991.1029] *Methyl methacrylate has been applied externally on rabbit eye and caused irritation requiring several days of recovery. [R95] NTXV: *LD50 Rat oral 9400 mg/kg; [R96] *LD50 Rat oral 7800 mg/kg; [R47, 1991.1029] *LD50 Rabbit oral 6000 mg/kg; [R47, 1991.1029] *LC50 Rat inhalation 3750 ppm/8hr; [R97] *LD50 MOUSE ORAL 5.5 ML/KG; [R98] *LD50 Rat ip 1328 mg/kg; [R43] *LD50 Rat sc 7500 mg/kg; [R43] *LC50 Mouse ihl 18,500 mg/cu m/2 hr; [R43] *LD50 Mouse ip 1000 mg/kg; [R43] *LD50 Mouse sc 6300 mg/kg; [R43] *LD50 Dog sc 4500 mg/kg; [R43] ETXV: *TLm Pimephales promelas (fathead minnow) 499-159 mg/l/24-96 hr /Conditions of bioassay not specified/; [R97] *TLm Lepomis macrochirus (bluegill) 368-232 mg/l/24-96 hr /Conditions of bioassay not specified/; [R97] *TLm Carassius auratus (goldfish) 423-277 mg/l/24-96 hr /Conditions of bioassay not specified/; [R97] *TLm Lebistes reticulatus (guppies) 368 mg/l/24-96 hr /Conditions of bioassay not specified/; [R97] *Toxicity threshold (cell multiplication inhibition test): Pseudomonas putida (bacteria): 100 mg/l; [R97] *Toxicity threshold (cell multiplication inhibition test): Microcystis aeruginosa (alga) 120 mg/l; [R97] *Toxicity threshold (cell multiplication inhibition test): Scenedesmus quadricauda (green alga) 37 mg/l; [R97] *Toxicity threshold (cell multiplication inhibition test): Entosiphon sulcatum (protozoa) 450 mg/l; [R97] *Toxicity threshold (cell multiplication inhibition test): protozoa (Uronema parduczi Chatton-Lwoff) 556 mg/l; [R97] NTP: *Toxicology and carcinogenesis studies of methyl methacrylate ... were conducted by exposing groups of F344/N rats and B6C3Fl mice by inhalation for 14 wk and 2 years. Based on these results, 2 yr inhalation toxicology and carcinogenesis studies were conducted in which groups of 50 male rats were exposed to methyl methacrylate at 0, 500, or 1,000 ppm; female rats at 0. 250, 500 ppm; and male and female mice at 0, 500, or l,000 ppm. Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenicity of methyl methacrylate for male F344/N rats exposed at 500 or l,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for male and female B6C3Fl mice exposed at 500 or 1,000 ppm. ... [R99] TCAT: ?Chronic toxicity and oncogenicity were evaluated in male and female Fischer 344 rats (70/sex/group) exposed via inhalation to methyl methacrylate at 0, 25, 100 or 400 ppm for 6 hrs/day, 5 days/week for 2 years. An exposure related mild rhinitis of the nasal mucosa lining of the turbinates was diagnosed by 1 of 3 pathologists who examined the slides of the tissues. No other significant differences were noted in clinical signs, mortality, body weights, clinical chemistries, hemograms, and gross and microscopic pathology, including type or number of tumors. The mean body weight of females at 400 ppm were slightly lower than controls (by 5-8% after 1 year). [R100] ?Chronic toxicity and oncogenicity were evaluated in male and female Fischer 344 rats (number of animals not reported) exposed via inhalation to methyl methacrylate at 0, 25, 100 or 400 ppm for 6 hrs/day, 5 days/week for 2 years. No significant differences between treated animals and controls were noted in clinical signs, body weights, clinical chemistries, hemograms, and gross and microscopic pathology, including type or number of tumors. At 400 ppm, the body weights of both sexes were consistently lower than controls and the cumulative mortality at week 78 was substantially higher as compared to controls. [R100] ?The ability of methyl methacrylate to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S-9 metabolic activation. Based on preliminary toxicity tests, nonactivated cultures tested at concentrations up to 100nl/ml were highly toxic without inducing significant increases in the mutant frequency. S-9 activated cultures tested at concentrations ranging from 100 to 200nl/ml induced moderate to high toxicity and dose dependant increases in the mutant frequency. [R101] POPL: *... Certain medical conditions /chronic resp, skin, kidney, and liver diseases/ ... might place the employee at incr risk from methyl methacrylate exposure. [R38, 1981.1] *A history of skin disease during childhood or allergic conjunctivitis or rhinitis may predispose an individual to the dermatologic effects caused by methyl methacrylate. [R74, 1668] *Patients who acquire an allergic contact dermatitis to ethyl methacrylate and butyl methacrylate may also have a positive patch-test reaction to methyl methacrylate monomer. [R74, 1668] ADE: *SPEED WITH WHICH METHYL METHACRYALTE MONOMER APPEARS IN EXPIRED GASES IN ANIMALS AND RATIO BETWEEN QUANTITY EXPIRED AND QUANTITY ADMIN IN CASE OF IV INJECTION WERE STUDIED. [R102] *Up to 88% of a single dose of methyl (14)C-methacrylate in rats was expired as (14)C-carbon dioxide in 10 days (65% in 2 hr), irrespective of the route of admin and of the specific labeling of the propylene residue of the molecule. [R103] *Intravenous or oral administration of 5.7 mg/kg of methyl (14C) methacrylate to rats resulted in excretion of 65% of the dose in the expired air in 2 hr and 84% to 88% in 10 days. Approximately 5% of the dose was retained in the body, and the remaining part was excreted in the urine and feces. It was found that the pattern of excretion was similar when a relatively large dose of methyl methacrylate (120 mg/kg) was given orally to rats. [R94, 757] METB: *Methyl methacrylate is metabolized in rat liver slices via the citric acid cycle. It undergoes hydroxylation to a primary alcohol followed by oxidation to an aldehyde; finally the compound is deformylated to pyruvic acid. [R64, 745] *UP TO 88% OF SINGLE DOSE OF METHYL(14)C-METHACRYLATE IN RATS IS EXPIRED AS (14)C-CARBON DIOXIDE IN 10 DAYS (65% IN 2 HR). IMPLICATIONS ARE THAT THE METABOLIC PATHWAY CONCERNED INVOLVES INTERMEDIARY METABOLISM AND RELATES TO MITOCHONDRIAL FUNCTION. [R104] *AFTER ADMIN OF METHYL METHACRYLATE TO RATS, URINARY MERCAPTURIC ACID WAS ISOLATED AND IDENTIFIED AS THE DICARBOXYLIC ACID N-ACETYL-S-(2-CARBOXYPROPYL)CYSTEINE, AND TO A LESSER EXTENT AS THE MONOMETHYL ESTER. [R105] *METHYL METHACRYLATE, THE MONOMER COMPONENT OF POLY(METHYL METHACRYLATE) CEMENT USED IN ORTHOPEDIC SURGERY, UNDERWENT HYDROLYSIS TO METHACRYLIC ACID DURING HIP REPLACEMENT OPERATIONS. CIRCULATING LEVELS OF METHACRYLIC ACID WERE COMPARABLE TO THOSE OF METHYL METHACRYLATE, THE CONCENTRATIONS BEING 0-15 UG/CC. [R106] INTC: *SOME COMPOUNDS, SUCH AS THE METHYL, ETHYL, N-PROPYL, OR BUTYL METHACRYLATES CAN PRODUCE INHIBITION OF BARIUM CHLORIDE-INDUCED CONTRACTION OF THE ISOLATED GUINEA PIG ILEUM. [R6, 3008] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl methacrylate's production and use in polymethacrylate resins, in medicinal adhesives, dental technology, bone cements, and as a water-repellent on concrete surfaces may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 38.5 mm Hg at 25 deg C indicates methyl methacrylate will exist solely as a vapor in the ambient atmosphere. Vapor-phase methyl methacrylate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 7.4 hours. Because methyl methacrylate does not absorb light in the environmental UV spectrum (> 290 nm), it is not expected to directly photolyze. If released to soil, methyl methacrylate is expected to have high mobility based upon a Koc of 95. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 3.2X10-4 atm-cu m/mole. Methyl methacrylate may potentially volatilize from dry soil surfaces based upon its vapor pressure. If released into water, methyl methacrylate is not expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Screening studies support rapid biodegradation of methyl methacrylate; it reached 94% of its theoretical BOD in 2 weeks using an activated sludge inoculum. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 6 hours and 5 days, respectively. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis of methyl methacrylate may be a significant process under basic conditions based upon a hydrolytic half-life of 3.4 hours at pH 11; half-lives at pH 7, 8, and 9 were 4 years, 140 days, and 14 days respectively. Occupational exposure to methyl methacrylate may occur through inhalation and dermal contact with this compound at workplaces where methyl methacrylate is produced or used. The general population may be exposed to methyl methacrylate via ingestion of drinking water and inhalation or dermal contact with resins, dental products, or artificial nail products containing methyl methacrylate. (SRC) NATS: *Methyl methacrylate is not known to occur naturally(1). [R107] ARTS: *Methyl methacrylate's production and use in polymethacrylate resins(1), in medicinal adhesives, dental technology, bone cements, and as a water-repellent on concrete surfaces(2) may result in its release to the environment through various waste streams(SRC). [R108] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 95(2) indicates that methyl methacrylate is expected to have high mobility in soil(SRC). Volatilization of methyl methacrylate from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.2X10-4 atm-cu m/mole(SRC), from its vapor pressure of 38.5 mm Hg(3) and water solubility of 1.6X10+4(4). The potential for volatilization of methyl methacrylate from dry soil surfaces may exist(SRC) based upon its vapor pressure(3). Screening tests indicate that methyl methacrylate is readily biodegradable(5-7); it reached 94% of its theoretical BOD in 2 weeks using an activated sludge inoculum(5). [R109] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 95(2) indicates that methyl methacrylate is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 3.2X10-4 atm-cu m/mole(SRC), from its vapor pressure of 38.5 mm Hg(4) and water solubility of 1.6X10+4(5). Volatilization half-lives for a model river and model lake are 6 hours and 5 days, respectively(SRC), using an estimation method(3). Hydrolysis of methyl methacrylate may be a significant process under basic conditions based upon a hydrolytic half-life of 3.4 hours at pH 11; half-lives of 4 years, 140 days, and 14 days were determined at pH 7, 8, and 9, respectively(6). According to a classification scheme(7), an estimated BCF of 7(3), from a log Kow of 1.38(8), suggests the potential for bioconcentration in aquatic organisms is low. Screening tests indicate that methyl methacrylate is readily biodegradable(9,10,11); it reached 94% of its theoretical BOD in 2 weeks using an activated sludge inoculum(9). [R110] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methyl methacrylate, which has a vapor pressure of 38.5 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase methyl methacrylate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7.4 hours(SRC) from its rate constant of 5.2X10-11 cu cm/molecule-sec at 25 deg C(3). The rate constant for the reaction of methyl methacrylate with ozone is 1.1X10-17 cu cm/molc-sec, corresponding to a half-life of 1 day at an atmospheric concn of 7X10+11 molecules/cu cm(4). Because methyl methacrylate does not absorb light in the environmental spectrum above 290 nm(5), direct photolysis is not expected to occur(SRC). [R111] BIOD: *AEROBIC: Methyl methacrylate, present at 100 mg/l, reached 94% of its theoretical BOD in 2 weeks using an activated sludge inoculum and the Japanese MITI test(1). In the modified Japanese MITI test, methyl methacrylate reached 32% of its theoretical BOD after 28 days; in a closed bottle test, methyl methacrylate released 88% of carbon dioxide evolution after 28 days; and > 95% methyl methacrylate was degraded in the Zahn-Wellens test, time not specified(2). Methyl methacrylate was reported to be completely degraded by activated sludge in approximately 20 hr(3). In a standard biodegradability test using sewage seed, 42% of the theoretical BOD was consumed in 19 days, including a 3-4 day lag period; with acclimated seed, 66% of the theoretical BOD was consumed in 22 days(4). The biodegradation rate for methyl methacrylate at 75 ppm starting concentration, treated using a mixed microbial population immobilized in calcium alginate gel, was 9.3 ppm/hr; this corresponded to 89% removal due to biodegradation(5). [R112] ABIO: *The rate constant for the vapor-phase reaction of methyl methacrylate with photochemically-produced hydroxyl radicals is 5.2X10-11 cu cm/molecule-sec at 25 deg C(1); this corresponds to an atmospheric half-life of about 7.4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). A major removal process of methyl methacrylate from the atmosphere is reaction with hydroxyl radicals; the atmospheric lifetime was reported to be < 1 day to 1.5 days(2). Reaction products include pyruvic acid, methyl pyruvate, and epoxides(3). The rate constant for the aqueous-phase reaction with photochemically-produced hydroxyl radicals has been determined to be 1.2X10+10 L/mol-sec at pH 7(4); this corresponds to an aqueous half-life of approximately 67 days at an aqueous hydroxyl radical concentration of 1.0X10-17 mol/l(SRC). The rate constant for the vapor-phase reaction of methyl methacrylate with ozone has been estimated as 1.1X10-17 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(5); this corresponds to an atmospheric half-life of about 1 day at an atmospheric concentration of 7X10+11 molecules/cu cm(SRC). A base-catalyzed second-order hydrolysis rate constant of 5.6X10-2 L/mol-sec was determined for methyl methacrylate(6); this corresponds to half- lives of 4 years, 140 days, 14 days, and 3.4 hours at pH values of 7, 8, 9 and 11, respectively(SRC). Methyl methacrylate is not expected to directly photolyze in sunlight(SRC) based upon the lack of absorption of light at wavelengths > 290 nm (wavelength max = 239 nm)(7). [R113] BIOC: *An estimated BCF of 7 was calculated for methyl methacrylate(SRC), using a log Kow of 1.38(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low. Methyl methacrylate is highly soluble in water and, therefore, is not expected to significantly bioconcentrate in aquatic organisms(3). [R114] KOC: *The Koc in soil of methyl methacrylate is 95(1). According to a classification scheme(2), this estimated Koc value suggests that methyl methacrylate is expected to have high mobility in soil. Methyl methacrylate is highly soluble in water and, therefore, is not expected to significantly partition to sediments(1). [R115] VWS: *The Henry's Law constant for methyl methacrylate is estimated as 3.2X10-4 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 38.5 mm Hg(1), and water solubility, 1.6X10+4 mg/l(2). This Henry's Law constant indicates that methyl methacrylate is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as approximately 6 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as approximately 5 days(SRC). Methyl methacrylate's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of methyl methacrylate from dry soil surfaces may exist(SRC) based upon its vapor pressure(1). [R116] WATC: *DRINKING WATER: Methyl methacrylate was identified in commercial deionized charcoal-filtered water in New Orleans, LA, concn not specified(1). Grab samples of raw and treated water were taken at waterworks treating lowland river water in the UK between March and December 1976; methyl methacrylate was identified in the survey of treated water, concn unknown(2). Methyl methacrylate was listed as one of the many organic chemicals identified in drinking water in the US and Europe as of 1974(3). Methyl methacrylate was identified, but not quantified, in USA drinking water(4) and in finished drinking water at levels < 1 ppb(5). [R117] *SURFACE WATER: In a survey conducted at 14 heavily industrialized river basins in the U.S., methyl methacrylate was detected in the Chicago area (204 sites sampled), 10 ppb(1) and in Lake Michigan (91 sites sampled), 10 ppb(2). [R118] EFFL: *Methyl methacrylate was detected in exhaust stacks from a plant where acrylic resin based paints were dried, concn ranging from 5-20 ppm(1). Methyl methacrylate is a gaseous product of the combustion of polymethyl methacrylate(1). [R119] ATMC: *INDOOR: Methyl methacrylate was identified in Norwegian dental workroom air following finishing and polishing of a denture base resin, at a concn of approximately 100 ppm(1). [R120] FOOD: *No data on methyl methacrylate levels in food could be located. However, polymethyl methacrylate can be used for food wrap and methyl methacrylate monomer can migrate from the plastic into ethanolic solutions at room temperature or into water at elevated temperatures; therefore, these methacrylates may migrate into food from the packaging material(1). [R121] OEVC: *Methyl methacrylate has been identified as a volatile component of furniture surface coatings, concn not specified(1). Methyl methacrylate was identified as a volatile component of paint-coated steel plates heated to 350 deg C, concn of 100 mg/cu m(2). Residual methyl methacrylate monomer has been detected in commercial polystyrene plastics at 36 ppm(3). Residual methyl methacrylate in 5 commercial acrylic bone cements has been reported to have migrated into prepared tissue medium; concns as high as 0.7-5.1 wt% were detected in fatty components of bone marrow(3). [R122] RTEX: *The following list includes some common operations in which exposure to methyl methacrylate may occur ... . Use during casting of acrylic sheets, use during molding of acrylic sheets or polymethacrylate powders, use during spray application of unsaturated polyester resins (surface coatings or structural components), use during brush or roller applications of unsaturated polyester resins (surface coatings or structural components), liberation during manufacture of methyl methacrylate resins for surface coatings, during polymerization to produce molding and extruding powders, liberation during production of synthetic fibers, during manufacture of unsaturated polyester resins, liberation during dye molding of articles from polyester resins, during production of emulsion polymers for use in adhesives, sealants, fabrics, sizes, leather finishes, paper coatings, polishes, during machining of articles from resins (acrylic plastics). [R38, 1981.3] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 120,778 workers (55,667 of these are female) are potentially exposed to methyl methacrylate in the US(1). Occupational exposure to methyl methacrylate may occur through inhalation and dermal contact with this compound at workplaces where methyl methacrylate is produced or used. The general population may be exposed to methyl methacrylate via ingestion of drinking water(2,3) and inhalation or dermal contact with resins(4), dental products(5), or artificial nail products(6) containing methyl methacrylate. In a national survey conducted in 1989 at 1,448 Danish businesses, methyl methacrylate was identified in approximately 43,000 exposure events in 19 industry groups(7). Mean TWA methyl methacrylate concns of 18-103 ppb were detected in the breathing zone of workers near 4 polymerization reactors and a loading dock in a polystyrene production plant(8). The individual TWA concn detected in the breathing zone of workers ranged from < 1 ppb to 378 ppb, with the max concn detected at reactor A(5). Methyl methacrylate vapors were detected in the personal air space of nail sculptors in Springdale, OH, concns ranging from 0.8 to 3.6 ppm, well below the NIOSH recommended exposure limit criteria of 100 ppm(6). [R123] *NIOSH estimated that 30,000 workers in the U.S. had been exposed to methyl methacrylate(1). A study of 91 exposed and 43 non-exposed workers at five plants manufacturing polymethyl methacrylate sheets reported a 4-49 ppm/8hr TWA exposure(1). Methyl methacrylate was detected in the atmospheres above surfaces freshly painted with commercial acrylic latexes, concns ranging from 0.001-0.075 ppm, in studies conducted in the USSR(1). Methyl methacrylate was detected at concns below the hygienic threshold limit in dental work rooms and in operating rooms during total hip replacement surgery(2,3). [R124] BODY: *Methyl methacrylate was identified in the urine of 11 dental technicians in Switzerland, concn ranging from 16-373 nmol/mmol creatinine(1). [R125] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *1000 ppm [R49, 214] ADI: *AN ADI /ACCEPTABLE DAILY INTAKE/ OF 0.1 MG/KG/DAY WAS CALCULATED ON BASIS OF AVAILABLE CHRONIC TOXICITY DATA. [R64, 747] ATOL: *Methyl methacrylate is exempted from the requirement of a tolerance when used as a surfactant or a related adjuvant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R126] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (410 mg/cu m). [R127] NREC: *Recommended Exposure Limit: 10 hr Time-Weighted avg: 100 ppm (410 mg/cu m). [R49, 214] TLV: +8 hr Time Weighted Avg (TWA): 50 ppm; 15 min Short Term Exposure Limit (STEL): 100 ppm, sensitizer. [R62] +A4; Not classifiable as a human carcinogen. [R62] OOPL: *Australia: 100 ppm, sensitizer (1990); Federal Republic of Germany: 50 ppm, short-term level 100 ppm, 5 min, 8 times per shift, sensitizer, Pregnancy group C, no reason to fear a risk of damage to the developing embryo or fetus when MAK and BAT values are adhered to (1992); Sweden: 50 ppm, short-term value 150 ppm, 15 min, skin, sensitizer (1990); United Kingdom: 100 ppm, 10-min STEL 125 ppm (1991). [R47, 1991.1031] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Methyl methacrylate is produced, as an intermediate or a final product, by process units covered under this subpart. [R128] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Methyl methacrylate is included on this list. [R129] WSTD: STATE DRINKING WATER GUIDELINES: +(ME) MAINE 200 ug/l [R130] +(FL) FLORIDA 25 ug/l [R130] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R131] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R132] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Methyl methacrylate is included on this list. [R133] RCRA: *U162; As stipulated in 40 CFR 261.33, when methyl methacrylate, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R134] FIFR: *Methyl methacrylate is exempted from the requirement of a tolerance when used as a surfactant or a related adjuvant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R126] FDA: *Homopolymers and copolymers of Methyl methacrylate are an indirect food additive for use only as a component of adhesives. [R135] *Substances used in the manufacture of paper and paperboard products used in food packaging shall incl methyl methacrylate copolymers of itaconic acid ... for use only on paper and paperboard which is waxed. Under the conditions of normal use, these substances would not reasonably be expected to migrate to food, based on available scientific information and data. /Methyl methacrylate copolymers/ [R136] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH S43: ANALYTE: METHYL METHACRYALTE; MATRIX: AIR; PROCEDURE: ADSORPTION ON XAD-2 [R137] ALAB: *NIOSH S43: ANALYTE: METHYL METHACRYLATE MATRIX: AIR; PROCEDURE: DESORPTION WITH CARBON DISULFIDE; GAS CHROMATOGRAPHY/FLAME IONIZATION DETECTOR; RANGE: 193-725 MG/CU M; PRECISION (COEFFICIENT OF VARIATION): 0.063 [R137] *NIOSH Method 2537: Methyl Methacrylate by GC/FID; GC with flame ionization detection, workplace air, detection limit of 1.0 mg/cu m. [R138] *METHYL METHACRYLATE CAN BE DETERMINED BY POLAROGRAPHY IN EFFLUENT WATERS ... . [R81] *MIGRATION OF METHYL METHACRYLATE FROM POLYMETHY METHACRYLATE CONTAINERS TO FOOD-SIMULATED SOLVENTS WAS INVESTIGATED BY GAS CHROMATOGRAPHY. DETECTION LIMIT WAS 0.05 PPM BY DIRECT METHOD. RESIDUAL AMT FOUND IN COMMERCIAL WARES WAS 0.03-1.00%. [R139] *MONOMERS IN 24 BRANDS OF DENTAL RESTORATIVE RESINS WERE ANALYZED BY 90 MHR NMR. SPECTRA WERE TAKEN OF CDCL3 SOLN OF ORGANIC PART OF THE FILLING MATERIALS AND COMPARED WITH PURE MONOMERS. [R140] *METHOD WAS DEVELOPED FOR GAS CHROMATOGRAPHY DETERMINATION OF METHYL ACRYLATE, METHYL METHACRYLATE, BUTYL ACRYLATE, AND BUTYL METHACRYLATE IN AIR IN PRESENCE OF SOME OTHER CMPD. THE METHOD CONSISTS OF THE DETERMINATION OF METHYL AND BUTYL ESTERS IN PAIRS FROM DIFFERENT SAMPLES UNDER DIFFERENT CONDITIONS OF SEPARATION ON COLUMNS CONTAINING 10% PMS-100 ON CELYTE-545, 10% KEE 60 ON CHROMOSORB-W, AND 7% DDF ON CHROMOSORB-W. THE SENSITIVITY OF THE METHOD IS 0.003 MG/CU M FOR METHYL ACRYLATE AND METHYL METHACRYLATE. [R141] *THE ELECTRON-IMPACT AND METHANE CHEM-IONIZATION MASS SPECTRA OF SELECTED ACRYLATE AND METHACRYLATE MONOMERS, INCLUDING METHYL METHACRYLATE, COMMONLY USED IN DENTAL MATERIALS ARE REPORTED AND DISCUSSED. THE TWO IONIZATION MODES COMPLEMENT EACH OTHER, AND TOGETHER THE MASS SPECTRA OFFER ADEQUATE INFORMATION FOR IDENTIFICATION PURPOSES. THE APPLICATION OF THE MASS SPECTRAL METHOD IS DEMONSTRATED ON RESIN-BASED DENTAL MATERIALS WITH IDENTIFICATION OF THE MONOMER CONTENT. [R142] *Thin-layer chromatography, polarography, and spectrometry are used for soln measurements. Methacrylates in air have been analyzed by TlC, polarography, and colorimetry. Polarography has been used for determination of any residual monomer in the polymer. A variety of spectroscopic techniques, eg, NMR, IR, and Raman spectroscopy also have been used, particularly for analysis of surgical cements and dental restorative resins. /Methacrylic acid and derivatives/ [R5, p. 15(81) 368] *Air samples can be adsorbed on XAD-2 media; the analyte is desorbed from sampling media using carbon disulfide and analyzed using a gas chromatography equipped with a flame ionization detector. [R6, 30009] *EAD Method 1624: Volatiles by Isotope Dilution - Water: Volatile Organic Compounds by Isotope Dilution GCMS; Gas chromatography with low resolution mass spectrometry, water, detection limit of 10.0 ug/l. [R143] *SFSAS Method SFSAS_29: Organics in Biological Tissue: Extraction and Analysis of Organics in Biological Tissue; Capillary gas chromatography with low resolution mass spectrometry, tissue, detection limit of 0.050 mg/kg. [R143] *EAD Method 1624: Volatiles by Isotope Dilution - Soil: Volatile Organic Compounds by Isotope Dilution GCMS; Gas chromatography with low resolution mass spectrometry, soil, detection limit not specified. [R143] CLAB: *Liquid chromatography, liquid scintillation counting, and NMR spectroscopy were used to determine methyl methacrylate and methacrylic acid blood levels in vitro. [R144] *GAS CHROMATOGRAPHIC METHOD IS DESCRIBED WHICH PERMITS THE QUANTITATIVE DETERMINATION OF MONOMERIC METHYL METHACRYLATE (MMA) IN HUMAN BLOOD AFTER BONE CEMENT IMPLANTATIONS. THE HEADSPACE METHOD WAS APPLIED IN ORDER TO MINIMIZE THE PROPORTION OF BLOOD COMPONENTS WHICH UPSET THE DETERMINATION. THE EVALUATION WAS FROM CALIBRATION CURVES WITH N-BUTYL ACETATE AS AN INTERNAL STANDARD. IN CASE OF HIP-JOINT OPERATIONS, MMA CONCN IN THE BLOOD OF THE PT WERE MEASURED IN SAMPLE TAKEN IMMEDIATELY AFTER THE IMPLANTATION OF THE BONE CEMENT. THIS METHOD PERMITS THE ELUCIDATIONS OF THE CONNECTION BETWEEN SERIOUS CARDIOVASCULAR COMPLICATIONS AND THE UPTAKE OF MMA BY THE CIRCULATORY SYSTEM. [R145] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Methyl Methacrylate in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 314 (1986) NIH Publication No. 87-2570 U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) for Methyl Methacrylate (80-62-6) Toxicological Review in Adobe PDF. Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March, 1998. SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. 9 (94) 770 R3: Chem Week 137 (17): 10 (1985) R4: CHEMICAL PRODUCTS SYNOPSIS: Methyl Methacrylate, 1985 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R6: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R7: PLYMALE RW; COMPOSITION AND METHOD FOR TREATING TEETH; US PATENT NUMBER 3997504, 12/14/76 R8: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R9: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. R10: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 754 R11: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R12: Hart C; Journal of Environmental Health 49 (5): 282-86 (1987) R13: SRI R14: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 612 R15: CHEMICAL PROFILE: Methyl Methacrylate, 1985 R16: Kavaler AR; Chemical Marketing Reporter 233 (13): 62 (1988) R17: Chemical Marketing Reporter; Chemical Profile: Methyl Methacrylate; December 30: p. 33 (1996) R18: USITC. SYN ORG CHEM-U.S. PROD/SALES p. 267 (1985) R19: USITC. SYN ORG CHEM-U.S. PROD. PRELIMINARY FEBRUARY SERRIES C/P-87-5 (1988) R20: USITC. SYN ORG CHEM-U.S. PROD/SALES p.15-6 (1988) R21: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-87 R22: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS p.1-582 (1985) R23: BUREAU OF THE CENSUS. 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Rockville, MD: Government Institutes (1997) R144: Corkill JA, Crout DHG; J Chromatogr Bio Appl 233: 404-9 (1982) R145: RUHNKE J ET AL, CHROMATOGRAPHIA 7 (2): 55-8 (1974) RS: 108 Record 43 of 1119 in HSDB (through 2003/06) AN: 196 UD: 200211 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALPHA-METHYL-STYRENE- SY: *AS-METHYLPHENYLETHYLENE-; *BENZENE, (1-METHYLETHENYL)-; *ISOPROPENIL-BENZOLO- (ITALIAN); *ISOPROPENYL-BENZEEN- (DUTCH); *ISOPROPENYLBENZENE-; *ISOPROPENYL-BENZOL- (GERMAN); *1-Methylethenyl-Benzine-; *1-Methylethylenebenzene-; *1-Methyl-1-phenylethene-; *ALPHA-METHYLSTYREEN- (DUTCH); *ALPHA-METHYLSTYRENE-; *ALPHA-METHYLSTYROL-; *ALPHA-METHYL-STYROL- (GERMAN); *ALPHA-METIL-STIROLO- (ITALIAN); *1-PHENYL-1-METHYLETHYLENE-; *BETA-PHENYLPROPENE-; *2-PHENYLPROPENE-; *2-PHENYL-1-PROPENE-; *BETA-PHENYLPROPYLENE-; *2-PHENYLPROPYLENE-; *1-PROPENE,-2-PHENYL- RN: 98-83-9 MF: *C9-H10 SHPN: UN 2303; Isopropenylbenzene IMO 3.3; Isopropenylbenzene MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... Primarily produced as a by-product of cumene-phenol operations ... . Alkylation of benzene with propylene followed by dehydrogenation of isopropylbenzene to alpha-methylstyrene was practiced commercially by Dow until 1977. [R1, 990] *Cumene hydroperoxide (acid-catalyzed hydrolysis; by product of phenol acetone production); cumene (dehydrogenation) IMP: *Contaminated by (max concn) cumene (0.15%), n-propylbenzene (0.20%), sec-butylbenzene (0.40%), tert-butylbenzene (0.40%), trans-2-phenylbutane-2 (0.05%), 2-phenylbutene-1 (0.01%), dimers (0.01%), polymers(0.01%), phenol (0.005%), and p-tert-butylcatechol (as stabilizer; 0.005%). [R2] *beta-Methylstyrene is an impurity contained in alpha-methylstyrene at a concn of about 0.5% by weight(1). [R3] FORM: *Typical chemical analysis of alpha-methylstyrene: purity, 99.3% by wt; aldehydes as CHO, 10 ppm; peroxides as hydrogen peroxide, 3 ppm; tert-butylcatechol, 15 ppm; alpha-methylstyrene, 0.5% by wt; isopropylbenzene, 0.2% by wt. [R4] *97.5% GRADE [R5] MFS: *Aristech Chemical Corp., Chemicals Div., 210 Sixth Ave., Pittsburgh, PA 15222- 2611, (412) 316-2747; Production site: Ironton, OH 45636 [R6] *Frontier El Dorado Refining Co., 1401 South Douglas Rd., El Dorado, KS 67042, (316) 321-2200; Production site: El Dorado, KS 67042 [R6] *Georgia Gulf Corp., 400 Perimeter Center Terrace, Suite 595, Atlanta, GA 30346, (770) 395-4500; Production sites: Pasadena, TX 77501, Plaquemine, LA 70765-0629 [R6] *JLM Chemicals, Incm, 350 West 131st Street, Blue Island, IL 60406, (708) 388- 9373; Production site: Blue Island, IL 60406 [R6] *Sunoco, Inc., Ten Penn Center, 1801 Market St., Philadelphia, PA 19103-1699, (215) 246-8920; Production site: Philadelphia, PA 19145 [R6] OMIN: *A polymerization inhibitor such as tert-butyl catechol is usually present in commercial quantities. [R7] *AMOCO IN TEXAS CITY, TX PRODUCES APPROXIMATELY 40 MILLION POUNDS/YR /FOR CAPTIVE USE/ FOR MANUFACTURE OF THE COMPANY'S PROPRIETARY POLYMER, RESIN 18. THIS CAPTIVE PRODUCTION IS NOT REPORTED TO THE USA INTERNATIONAL TRADE COMMISSION. [R8] USE: *Polymerization monomer, especially for polyesters [R7] *USED AS A THIRD MONOMER TO RAISE THE GLASS TRANSITION TEMPERATURE IN ACRYLONITRILE-BUTADIENE-STYRENE RUBBER-THERMOPLASTIC RESIN. [R9] *Polyvinyl chloride/high temperature ABS comonomer; reactive diluent (unsaturated polyester resins) [R10] *USED AS A UV DEGRADATION INHIBITOR IN ACRYLONITRILE-BUTADIENE-STYRENE RESINS [R11] *THE DOMINANT MERCHANT MARKET APPLICATION IS AS A COMONOMER IN ACRYLONITRILE-BUTADIENE-STYRENE RESINS [R11] CPAT: *62.5% AS A MONOMER FOR POLY(ALPHA-METHYL STYRENE); 37.5% FOR STYRENATED OILS FOR SURFACE COATINGS (1971) [R12] *ACRYLONITRILE-BUTADIENE-STYRENE RESINS, 34%; COATINGS, INCLUDING ADHESIVES, 14%; POLYESTER RESINS, 4%; MISCELLANEOUS, 8%; EXPORTS, 40% (1984) [R13] */END USE PATTERN MERCHANT MARKET ONLY/ ACRYLONITRILE-BUTADIENE-STYRENE RESINS, 70%; HYDROCARBON RESINS, 15%; UNSATURATED POLYESTER AND ALKYD RESINS, 10%; MISCELLANEOUS, 5% (1983) [R11] *CHEMICAL PROFILE: alpha-Methylstyrene. Demand: 1985: 48 million lb; 1986: 49 million lb; 1990 /projected/: 54.5 million lb. [R14] *CHEMICAL PROFILE: alpha-Methylstyrene. ABS resins, 45%; exports, 40%; adhesives and waxes, 10%; polyester resins and miscellaneous, 5%. [R15] *CHEMICAL PROFILE: alpha-Methylstyrene. Demand: 1988: 90 million lb; 1989: 92 million lb; 1993 /projected/: 102 million lb. (Includes exports, but not imports, which are negligible). [R15] PRIE: U.S. PRODUCTION: *(1972) 1.7X10+10 G (1983) 45.537x10+6 lb (USITC, 1984). [R12] *(1975) 1.36X10+10 G [R12] *(1988) 131 million lb (est as of Jan 1, 1988) [R16] *(1993) 2.25X10+10 g [R17] U.S. IMPORTS: *(1975) 4.63X10+6 G (PRINCIPLE CUSTOMERS DISTRICTS) [R12] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid ... [R18, 216] ODOR: *... Characteristic odor. [R18, 216]; *Sharp aromatic odor [R19] BP: *165.4 deg C [R20] MP: *-23.2 deg C [R20] MW: *118.18 [R20] CTP: *Critical temperature: 384 deg C; Critical pressure: 4.36 MPa [R1, 991] DEN: *0.9106 [R20] HTC: *4863.73 kJ/mol at 25 deg C (gas at constant pressure) [R1, 991] HTV: *404.55 J/g at 25 deg C; 326.35 J/g at boiling point [R1, 991] OWPC: *log Kow= 3.48 [R21] SOL: *SOL IN ALC; SOL IN ALL PROPORTIONS IN ACETONE, CARBON TETRACHLORIDE [R22]; *Sol in benzene, chloroform [R23]; *Sol in ether [R20]; *Sol in n-heptane, ethanol [R24]; *In water, 116 mg/l @ 25 deg C [R25] SPEC: *Index of refraction: 1.5386 @ 20 deg C/D [R20]; *MAX ABSORPTION (PETROLEUM ETHER): 242.5 NM (LOG E= 4.04), 277 NM (LOG E= 2.44) [R22]; *IR: 329 (American Petroleum Institute Collection) [R26]; *UV: 6-224 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R26]; *MASS: 61890 (NIST/EPA/MSDC Mass Spec Database, 1990 version); 1015 (Atlas of Mass Spectral Data, John Wiley and Sons, NY) [R26] SURF: *32.40 dynes/cm @ 20 deg C [R1, 991] VAP: *1.9 mm Hg @ 25 deg C [R27] VISC: *0.940 cP @ 20 deg C [R7] OCPP: *Ionization potential: 8.35 electron volts (eV) [R18, 216] *Critical volume, 3.26 ml/g; critical density, 0.29 g/ml; specific heat of liquid, 2.0460 J/g deg K at 40 deg C, and 2.1757 J/g deg K at 100 deg C; specific heat of vapor, 1.2357 J/g deg K at 25 deg C; heat of formation of liquid, 112.97 kJ/mol at 25 deg C; heat of polymerization, 39.75 kJ/mol; cubical coefficient of expansion, 9.774X10-4 at 20 deg C [R1, 991] *Hydroxyl radical reaction rate constant = 5.2X10-11 cu cm/molecule-sec @ 25 deg C [R28] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of alpha-methyl styrene stem from its toxicologic properties and flammability. Toxic by all routes (ie, inhalation, ingestion, and dermal contact), exposure to this sweet-smelling, colorless liquid may occur from its use in the manufacture of acrylonitrile-butadiene-styrene resins, adhesives, waxes, and polyester resins. Effects from exposure may include irritation of the eyes, skin, and upper respiratory tract, dermatitis, and central nervous system depression. OSHA has established a 100 ppm Ceiling limit for workplace exposure until the final rule (establishing a 50 ppm time weighted average (TWA) limit) becomes effective on December 31, 1992. Engineering controls should be used to maintain airborne levels of alpha-methyl styrene to at or below the permissible limit. In activities and situations where over-exposure may occur, wear chemical protective clothing and a self-contained breathing apparatus. If contact should occur, irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes, and wash exposed skin thoroughly with soap and water. Contaminatedclothing should be removed and left at the worksite for cleaning. Alpha-methyl styrene is easily ignited by heat, sparks, or flames. Its heavier-than-air vapor may travel considerable distances to a source of ignition and flash back, or form explosive concentrations in enclosed spaces such as sewers. Also, containers of alpha-methyl styrene may explode in the heat of a fire. For fires involving alpha-methyl styrene, extinguish with dry chemical, CO2, Halon, water spray or standard foam. Consider evacuation of one half mile radius, especially if a tank car or truck is involved. Alpha-methyl styrene should be stored away from heat, oxidizers, peroxides, halogens, catalysts for vinyl or ionic polymers, aluminum, and iron chloride. For small spills of alpha-methyl styrene, take up with sand or other noncombustible absorbent and place into containers for later disposal. Dike far ahead of large spills to prevent runoff. Before implementing land disposal of alpha-methyl styrene waste, consult with environmental regulatory agencies for guidance. DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. Substances may be transported hot. [R29] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R29] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R29] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R29] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R29] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R29] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R29] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R29] FPOT: *Moderate fire risk. [R30, 782] *Readily ignites on slight heating. [R31] *Flammable [R32] NFPA: *Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R33, p. 325-8] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R33, p. 325-8] *Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R33, p. 325-9] FLMT: *1.9% (lower flammable limit) ; 6.1% (upper flammable limit) [R34] FLPT: *83.89 DEG C (CLOSED CUP) [R35] *57.8 deg C (Cleveland open-cup) [R36] AUTO: *1066 deg F (574 deg C) [R33, p. 325-72] TOXC: *When heated to decomposition, it emits acrid smoke and fumes. [R37] EXPL: *In air, 1.9% (lower); 6.1% (upper) [R30, 782] *In air, 0.7% (lower); 3.4% (upper) [R24] REAC: *Oxidizers, peroxides, halogens, catalysts for vinyl or ionic polymers; aluminum, iron chloride, copper [Note: Usually contains an inhibitor such as tert-butyl catechol]. [R18, 216] DCMP: *When heated to decomposition, it emits acrid smoke and fumes. [R37] POLY: *... Subject to polymerization by heat or catalysts ... [R30, 781] ODRT: *Odor detection in air, 5.20X10-2 ppm (purity not specified) [R38] *Odor recognition in air, 1.60X10-1 ppm (purity not specified) [R38] *Odor (low) 0.2496 mg/cu m; Odor (high) 960.0 mg/cu m; Irritating concn 960.0 mg/cu m. [R39] SERI: *Generally, alpha-methyl styrene is an irritant to the eyes, skin, and upper respiratory tract. [R40] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R18, 217] *Wear appropriate eye protection to prevent eye contact. [R18, 217] *Recommendations for respirator selection. Max concn for use: 500 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. [R18, 217] *Recommendations for respirator selection. Max concn for use: 700 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R18, 217] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R18, 217] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R18, 217] OPRM: *Contact lenses should not be worn when working with this chemical. [R18, 217] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Avoid inhalation and skin contact. [R30, 782] *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any ... eye contact. Employees should wash promptly when skin is wet or contaminated. Remove nonimpervious clothing promptly if wet or contaminated. [R41] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *The worker should immediately wash the skin when it becomes contaminated. [R18, 217] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R18, 217] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R42] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R43] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R44] STRG: *DURING STORAGE IT IS FREQUENTLY STABILIZED WITH TERT-BUTYL CATECHOL AS INHIBITOR. [R35] CLUP: *For spills and leakage absorb on paper. Evaporate on a glass or iron dish in hood. Burn the paper. [R31] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R45, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatic hydrocarbons and related compounds/ [R45, 182] *If alpha-methyl styrene gets into the eyes, wash eyes immediately with large amounts of water, lifting the lower and upper lids occasionally. Get medical attention as soon as possible. Contact lenses should not be worn when working with this chemical. [R46] *If alpha-methyl styrene gets in the skin, promptly flush the contaminated skin with water. If alpha-methyl styrene soaks through the clothing, remove the clothing immediately and flush the skin with water when there is skin irritation, get medical attention. [R46] *If a person breathes in large amounts of alpha-methyl styrene, move the exposed person to fresh air at once. If breathing has stopped, perform artificial respiration. Keep the affected person warm and at rest. Get medical attention as soon as possible. [R46] *If alpha-methyl styrene has been swallowed, do not induce vomiting. Get medical attention immediately. [R46] MEDS: *OCCUPATIONAL EXPOSURE TO ALPHA-METHYL STYRENE WAS MONITORED BY MEASURING THE ATROLACTIC ACID (2-PHENYL-2-HYDROXYPROPIONIC ACID) CONTENT OF THE URINE. DETERMINATION WAS SPECTROPHOTOMETRIC. [R47] *Employees should be screened for history of certain medical conditions which might place the employee at increased risk from alpha-methyl styrene exposure. Skin disease: alpha-Methyl styrene can cause dermatitis on prolonged exposure. Persons with pre-existing skin disorders may be more susceptible to the effects of this agent. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of alpha-methyl styrene might cause exacerbation of symptoms due to its irritant properties or psychic reflex bronchospasm. Kidney disease: Although alpha-methyl styrene is not known as a kidney toxin in humans, the importance of this organ in the elimination of toxic substances justifies special consideration in those with possible impairment of renal function. Liver disease: Although alpha-methyl styrene is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. [R46] HTOX: *Prolonged skin contact may cause dermatitis, and repeated inhalation may result in CNS depression. [R40] *... FOUR HUMAN SUBJECTS EXPOSED TO A CONCENTRATION OF 200 PPM OF ALPHA-METHYL STYRENE REPORTED ... UNPLEASANT ODOR AND SLIGHT EYE IRRITATION AFTER ... 2 MINUTES /OF EXPOSURE/. [R35] *Overall, alpha-methyl styrene appears to be somewhat less toxic than styrene and vinyltoluene. [R40] *Overexposure to alpha-methyl styrene causes slight irritation of the eyes, upper respiratory tract, and skin. With prolonged and repeated contact, there may be depression of the central nervous system. [R46] NTOX: *GROUPS OF RATS, GUINEA PIGS, RABBITS, MICE AND MONKEYS WERE GIVEN REPEATED EXPOSURES 7 HR DAILY, 5 DAYS/WK AT A CONCN OF 200 PPM OF ALPHA-METHYLSTYRENE VAPOR FOR ... ABOUT 6 MO. AS JUDGED BY GROWTH, MORTALITY, GROSS APPEARANCE AND BEHAVIOR, ORGAN WT STUDIES AND GROSS AND MICROSCOPIC EXAM OF TISSUES, THIS VAPOR CONCN HAD NO ADVERSE EFFECT UPON ANY OF THE SPECIES STUDIED. ... [R35] *ALPHA-METHYL STYRENE ... HAS BEEN TESTED BY APPLICATION OF A DROP TO RABBIT EYES AND HAS BEEN FOUND TO CAUSE ONLY SLIGHT TRANSIENT EVIDENCE OF CONJUNCTIVAL IRRITATION AND NO CORNEAL DAMAGE DEMONSTRATED WITH FLUORESCEIN. [R48] *CHRONIC INTOXICATION OF ISOPROPYLBENZENE OR ALPHA-METHYLSTYRENE UPON RATS AND RABBITS DECREASED THE OSMOTIC RESISTANCE OF THE LEUKOCYTES, DECREASED THE GLYCOGEN AND PEROXIDASE CONTENT OF THE NEUTROPHILS, AND ACCUMULATED LIPIDS IN THE NEUTROPHILS. [R49] *AT 1 DAY AFTER ACUTE INTOXICATION BY ALPHA-METHYLSTYRENE (3-5 MG/L AIR, 6 HR/DAY FOR 6 DAYS TO RATS) BRAIN LEVELS OF GAMMA-AMINOBUTYRIC ACID, LYSINE, HISTIDINE AND ASPARTATE INCREASED; AND VALINE, METHIONINE AND TYROSINE DECREASED. FOLLOWING CHRONIC, 4-MONTHS ADMINISTRATION (0.05 MG/L, 6 HR/DAY), CHANGES WERE OBSERVED IN ALL EXCEPT 2 OF THE 15 CEREBRAL AMINO ACIDS EXAMINED. [R50] *A 4 MO INHALATION OF MAX PERMISSIBLE CONCN OF ALPHA-METHYLSTYRENE BY FEMALE RATS INCR EMBRYONAL MORTALITY FROM 7.5 (CONTROL VALUE) TO 33.3%. TERATOGENESIS FREQUENCY WAS INCR FROM 3.0 (CONTROL VALUE) TO 21.0%. [R51] *ALPHA-METHYLSTYRENE, IN A CONCN OF 30%, APPLIED TO RABBIT SKIN DAILY FOR 20 DAYS CAUSED INFLAMMATION, HYPEREMIA, EDEMA, AND DESQUAMATION. THE PREPN HAD IRRITATING AND SENSITIZING PROPERTIES. THICKENING OF THE EPIDERMAL LAYER AND HYPERKERATOSIS WERE ALSO OBSERVED. [R52] *THE INHALATION OF ALPHA-METHYLSTYRENE INDUCED CHANGES IN EPIDERMIS, CONNECTIVE TISSUE, HAIR, GLANDS, AND NEURON FIBERS OF RAT SKIN. THESE CHANGES DISAPPEARED 30-60 DAYS AFTER TREATMENT STOPPED. [R53] *SINGLE INHALATION OF ALPHA-METHYLSTYRENE (3-5 MG/L) DECREASED THE ACETYLCHOLINE LEVEL OF THE BLOOD, KIDNEYS, AND LIVER, BUT WAS SIMILAR TO ACRYLONITRILE IN ITS EFFECTS ON ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE ACTIVITY IN RATS. ACRYLONITRILE INCREASED THE ACETYLCHOLINESTERASE ACTIVITY OF THE BRAIN AND DECREASED ACETYLCHOLINESTERASE IN THE KIDNEYS; INCREASED BUTYRYLCHOLINESTERASE IN THE LIVER AND KIDNEYS AND DECR BUTYRYLCHOLINESTERASE IN THE BRAIN AND SPLEEN, WHILE INCR ACETYLCHOLINE ONLY IN THE SPLEEN OF RATS. [R54] *EXPERIMENTAL EFFECTS OF THE COMBINED ACTION OF 1,3-BUTADIENE AND ALPHA-METHYLSTYRENE WERE INVESTIGATED IN ANIMALS. THE INHALATION BY RATS OF A MIXTURE OF 1,3-BUTADIENE (99.8 MG/CU M) AND ALPHA-METHYLSTYRENE (5.2 MG/CU M) RESULTED IN A DECREASE IN THE LEVEL OF LEUKOCYTES AND THEIR PHAGOCYTIC ACTIVITY, RESPIRATION OF THE LIVER, THE ASCORBIC ACID LEVEL IN BLOOD, LIVER, AND BRAIN, THE THIAMINE LEVEL IN THE LIVER AND URINE, AND URINARY EXCRETION OF RIBOFLAVINE. [R55] *Phenobarbital admin with alpha-methylstyrene increased oxidative metabolism with the excretion of atrolactic acid amounting to approx 30%. Sulfur containing antioxidants cysteine and methionine, decreased the excretion 40-60%. Activation and inhibition of the microsomal enzymes under the influence of phenobarbital and the antioxidants, respectively, indicate that alpha-methylstyrene oxidizing enzymes are primarily located in the liver. The oxidative metabolites of alpha-methylstyrene, alpha-phenyl-alpha-hydroxypropanol and atrolactate, were more toxic than alpha-methylstyrene. [R56] NTXV: *LD50 Rat oral 4900 mg/kg; [R31] TCAT: ?alpha-Methyl styrene (CAS # 98-83-9) was evaluated for developmental toxicity in female Sprague-Dawley rats (10-13/treatment group) administered intraperitoneal injections of 0 (corn oil solvent control) or 250 mg/kg bodyweight (the maximum tolerated dose in a previous range-finding study) on Gestational Days (GD) 1 though 15. On GD 21, all animals were sacrificed for examination of treatment-related maternal toxicity, defined as a statistically significant (p < 0.05) change in at least 2 organ weights on necropsy, or fetal developmental toxicity, defined as statistically significant delay in fetal development. Treatment was associated with reproductive anomalies in treated dams relative to negative controls, including significant elevation in resorptions and a significant decrement in the fetal female sex ratio. No significant maternal gross or histologic tissue changes and no fetal visceral or skeletal malformations were attributable to treatment. Summary data only were provided. [R57] ?alpha-Methyl styrene (CAS # 98-83-9, 99%) was evaluated for mutagenicity in Chinese hamster ovary cells exposed in vitro for 5 hours to concentrations of 0 (DMSO solvent control), 0.05, 0.075, 0.1, 0.125, and 0.15 uL/mL/plate with and without added Aroclor-induced rat liver S-9 mix. Concentrations were chosen from levels in a cytotoxicity study that were associated with cloning efficiencies of 108 to 0% of solvent control. A significant positive result was defined as a dose-dependent increase in mean replicate values with at least 2 consecutive doses of mutant frequencies rates in excess of 40 mutants per 10(6) clonable cells. The concurrent cytotoxicity ranging from 0 to 92% in the initial selective assay, no significant substance-related mutagenicity relative to control was observed, either in the presence or absence of metabolic activation. A confirmation assay employing concentrations of 0, 0.05, 0.075, 0.1, 0.125, and 0.135 uL/mL/plate (associated with cloning efficiencies ranging from 96 to 4%) with or without metabolic activation also failed to demonstrate significantly increased rates of mutation relative to solvent control. [R58] POPL: *Employees should be screened for history of certain medical conditions which might place the employee at increased risk from alpha-methyl styrene exposure. Skin disease: alpha-Methyl styrene can cause dermatitis on prolonged exposure. Persons with pre-existing skin disorders may be more susceptible to the effects of this agent. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of alpha-methyl styrene might cause exacerbation of symptoms due to its irritant properties or psychic reflex bronchospasm. Kidney disease: Although alpha-methyl styrene is not known as a kidney toxin in humans, the importance of this organ in the elimination of toxic substances justifies special consideration in those with possible impairment of renal function. Liver disease: Although alpha-methyl styrene is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. [R46] ADE: *ALPHA-METHYLSTYRENE AT 0.1 ML ON A WATCH GLASS WAS PUT IN CONTACT WITH HUMAN SKIN AND AFTER 10 MIN THE REMAINING AMOUNT WAS DISSOLVED WITH ETHYL ALC AND DETERMINED BY SPECTROPHOTOMETER. THE ABSORPTION RATE OF PURE ALPHA-METHYLSTYRENE WAS 19.5 MG/SQ CM, AND AQ SOLN VARIED FROM 0.048-0.256 MG/SQ CM DEPENDING ON THE TEMP AND CONCN. THE EXCRETION KINETICS OF ALPHA-METHYLSTYRENE METABOLITES IS A FIRST-ORDER PROCESS. [R59] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *alpha-Methylstyrene's production and use as a monomer in the production of polymers and as a reactive diluent may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 1.9 mm Hg at 25 deg C indicates alpha-methylstyrene will exist solely as a vapor in the ambient atmosphere. Vapor-phase alpha-methylstyrene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone; the half-life for these reactions in air are estimated to be 7 and 2 hrs, respectively. alpha-Methylstyrene absorbs light in the environmental UV spectrum and has the potential for direct photolysis. If released to soil, alpha-methylstyrene is expected to have low mobility based upon an estimated Koc of 1,900. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 2.6X10-3 atm-cu m/mole. alpha-Methylstyrene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, alpha-methylstyrene is expected to adsorb to suspended solids and sediment based upon the estimated Koc. A 0% theoretical BOD obtained using the Japanese MITI test indicates that this compound is not expected to biodegrade. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4 hrs and 4 days, respectively. A BCF of 30 for goldfish suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to alpha-methylstyrene may occur through inhalation and dermal contact with this compound at workplaces where alpha-methylstyrene is produced or used. Monitoring data indicate that the general population may be exposed to alpha-methylstyrene via inhalation of indoor air containing alpha-methylstyrene. (SRC) ARTS: *alpha-Methylstyrene's production and use as a monomer in the production of polymers and as a reactive diluent(1) may result in its release to the environment through various waste streams(SRC). In automotive products, alpha-methylstyrene is added to acrylonitrile-butadiene-styrene in order to create less heavy, more fuel efficient cars(2). alpha-Methylstyrene is also used in modified polyester and alkyd resins(2). As a copolymer with methylmethacrylate, alpha-methylstyrene is resistent to distortion at high temperatures and is used in food applications(2). Polymers of alpha-methylstyrene possess low molecular weights and are viscous liquids that are employed as plasticizers in plastics, paints, waxes and adhesives(2). [R60] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,900(SRC), determined from a log Kow of 3.48(2) and a regression-derived equation(3), indicates that alpha-methylstyrene is expected to have low mobility in soil(SRC). Volatilization of alpha-methylstyrene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.6X10-3 atm-cu m/mole(SRC), derived from its vapor pressure, 1.9 mm Hg(4), and water solubility, 116 mg/l(5). The potential for volatilization of alpha-methylstyrene from dry soil surfaces may exist(SRC) based upon its vapor pressure(4). alpha-Methylstyrene, present at 100 mg/l, reached 0% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(6). Therefore this compound is not expected to biodegrade in soil(SRC). [R61] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,900(SRC), determined from a log Kow of 3.48(2) and a regression-derived equation(3), indicates that alpha-methylstyrene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 2.6x10-3 atm-cu m/mole(SRC), derived from its vapor pressure, 1.9 mm Hg(4), and water solubility, 116 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 4 hrs and 4 days, respectively(SRC). According to a classification scheme(6), a BCF of 30 for goldfish(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). alpha-Methylstyrene, present at 100 mg/l, reached 0% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(6). Therefore this compound is not expected to biodegrade in water(SRC). [R62] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), alpha-methylstyrene, which has a vapor pressure of 1.9 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase alpha-methylstyrene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC); the half-life for these reactions in air are estimated to be 7 and 2 hrs, respectively(SRC), calculated from rate constants of 5.2X10-11 cu cm/molecule-sec at 25 deg C(3) and 1.4X10-16 cu cm/molecule-sec(4), respectively. [R63] BIOD: *AEROBIC: alpha-Methylstyrene, present at 100 mg/l, reached 0% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(6). Therefore this compound is not expected to biodegrade(SRC). However, several microorganisms are able to grow using alpha-methylstyrene as a carbon source(2). [R64] ABIO: *The rate constant for the vapor-phase reaction of alpha-methylstyrene with photochemically-produced hydroxyl radicals has been estimated as 5.2X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 7 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). The rate constant for the vapor-phase reaction of alpha-methylstyrene with ozone has been estimated as 1.4X10-16 cu cm/molecule-sec at 25 deg C(SRC) derived using a structure estimation method(2). This corresponds to an atmospheric half-life of about 2 hrs at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). alpha-Methylstyrene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(4). In cyclohexane, alpha-methylstyrene weakly absorbs UV light in the environmentally significant range (wavelengths > 290 nm)(5). Hence, the potential for direct photolysis of alpha-methylstyrene in the environment exists(SRC). [R65] BIOC: *A BCF of 30 in goldfish was measured for alpha-methylstyrene(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R66] KOC: *The Koc of alpha-methylstyrene is estimated as 1,900(SRC), using a log Kow of 3.48(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that alpha-methylstyrene is expected to have low mobility in soil(SRC). [R67] VWS: *The Henry's Law constant for alpha-methylstyrene is estimated as 2.6X10-3 atm-cu m/mole(SRC) derived from its vapor pressure, 1.9 mm Hg(1), and water solubility, 116 mg/l(2). This Henry's Law constant indicates that alpha-methylstyrene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 4 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4 days(SRC). alpha- Methylstyrene's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of alpha-methylstyrene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 1.9 mm Hg(1). [R68] WATC: *DRINKING WATER: Alpha-methylstyrene was identified in 2 of 14 treated water supplies in England(2). Alpha-methylstyrene was detected in the analysis of volatiles in Delaware River water, which is used as a drinking water supply for Philadelphia, PA; however, it was not detected in 11 samples that were solvent extracted(1). Alpha-methylstyrene was detected in a groundwater aquifer which serves as the drinking water supply for Milan, Italy, at a depth of 30 m beneath a paint factory where organics were stored in leaking tanks(3). [R69] *GROUND WATER: alpha-Methylstyrene was identified at 2 of 7 groundwater sample-sites taken near "The Valley of Drums", KY at concentrations of 0.48 and 9 ug/l(1). [R70] SEDS: *Alpha-methylstyrene was detected in the sediments at 1 of 7 sample sites taken near "The Valley of Drums", KY at concn ranging from 10 to 1000 ug/kg(1). A sediment sample dredged from the Calcasieu River, LA in Nov 1979 was found to contain alpha-methylstyrene; no concn was reported(2). [R71] ATMC: *From 1970 to 1987, the national average daily ambient air concn of alpha-methylstyrene for 176 points representing remote, rural, suburban and urban sites was 0.050 ppbV(1). Alpha-methylstyrene was detected in the atmospheres of 6 industrialized cities of the USSR ranging in size of population from 0.4 to 4.5 million people(2-4). [R72] *INDOOR AIR: alpha-Methylstyrene was detected, not quantified, in the indoor air of 8 of 26 houses located in Finland at relatively low concentrations(1). [R73] MILK: *An unidentified isomer of alpha-methylstyrene was detected in 2 of 12 samples of human breast milk taken from women in 4 USA cities(1). [R74] OEVC: *The headspace concn of alpha-methylstyrene from copier toner cartridges ranged from 22-33 ng/ml in the air taken from emission test chambers(1). The emission rate of alpha-methylstyrene from dry-process photocopiers ranged from < 10-24 ug/hr per copier while idle and < 50-330 ug/hr per copier during operation(2). [R75] RTEX: *WASHINGS FROM THE HANDS OF WORKERS IN SYNTHETIC RUBBER PRODN CONTAINED 0.024 TO 4.05 MG OF ALPHA-METHYLSTYRENE. THE SKIN ROUTE IS MORE IMPORTANT THAN INHALATION IN CONDITIONS WHERE HANDS ARE GREATLY EXPOSED. [R59] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,214 workers are potentially exposed to alpha-methylstyrene in the US(1). Occupational exposure to alpha-methylstyrene may occur through inhalation and dermal contact with this compound at workplaces where alpha-methylstyrene is produced or used(SRC). Workers at a polystyrene production plant were exposed to alpha-methylstyrene in the atmosphere at time weighted average concn 8, 15, 23, 98, and 116 ppb for 13, 1, 6, 11, and 9 samples at 5 separate locations with maximum concns of 56, 40, 52, 360, and 583 ppb respectively(2). The atmospheric concn of alpha-methylstyrene ranged from 0 to 5 ug/cu m for the extrusion area of an electrical insulation manufacturing plant(3). Monitoring data indicate that the general population may be exposed to alpha-methylstyrene via inhalation of indoor air containing alpha-methylstyrene(SRC). [R76] BODY: *An unidentified isomer of alpha-methylstyrene was detected in 2 of 12 samples of human breast milk taken from women in 4 USA cities(1). [R74] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *700 ppm [R18, 217] OSHA: *Permissible Exposure Limit: Table Z-1 Ceiling value: 100 ppm (480 mg/cu m). [R77] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 50 ppm (240 mg/cu m). [R18, 216] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 100 ppm (485 mg/cu m). [R18, 216] TLV: *8 hr Time-Weighted Avg: (TWA) 50 ppm; 15 min Short Term Exposure Limit (STEL): 100 ppm. [R78] OOPL: *West Germany: 100 ppm; USSR: 1 ppm. [R79] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. alpha-Methylstyrene is produced, as an intermediate or a final product, by process units covered under this subpart. [R80] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Benzene, (1-methylethenyl)- is included on this list. [R81] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1501. Analyte: alpha-Methyl styrene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.20 l/min. Sample Size: 3 to 30 liters. Shipment: No special precautions. Sample Stability: Not given. [R82] ALAB: *NIOSH Method 1501. Analyte: alpha-Methyl styrene. Matrix: Air. Procedure: Gas Chromatography, flame ionization detection. For alpha-methyl styrene this method has an estimated detection limit of 0.001 to 0.01 mg/sample. The precision/RSD is 0.011. Applicability: This method is for peak, ceiling and time-weighted average determination of aromatic hydrocarbons. The working range is 236-943 mg/cu m for a 30-liter air sample. Interferences: Alcohols, ketones, ethers, and halogenated hydrocarbons are possible interferences. 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Nashville, TN (1980) (2) Steinheimer TR et al; Anal Chim Acta 129: 57-67 (1981) R72: (1) Shah JJ, Heyerdahl EK; National Ambient VOC Database Update USEPA 600/3- 88/010 (1988) (2) Ioffe BV et al; J Chromatogr 142: 787-95 (1977) (3) Ioffe BV et al; Dokl Akad Nauk Sssr 243: 1186-9 (1978) (4) Ioffe BV et al; Environ Sci Technol 13: 864-8 (1979) R73: (1) Kostiainen R; Atmos Environ 29: 693-702 (1995) R74: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R75: (1) Leovic K et al; Air Waste Manage 48: 915-23 (1998) (2) Leovic KW et al; Air Waste Manage 46: 821-9 (1996) R76: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Samini B, Falbo L; Am Ind Hyg Assoc J 43: 858-62 (1982) (3) Cocheo V et al; Am Ind Hyg Assoc J 44: 521-7 (1983) R77: 29 CFR 1910.1000 (7/1/2001) R78: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.42 R79: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.410 R80: 40 CFR 60.489 (7/1/2001) R81: 40 CFR 716.120 (7/1/2001) R82: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R83: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 58 Record 44 of 1119 in HSDB (through 2003/06) AN: 202 UD: 200302 RD: Reviewed by SRP on 5/11/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,4-D- SY: *Silvaprop-1-; *U-46-D-; *U-46-; *U-46DP-; *ACETIC ACID, (2,4-DICHLOROPHENOXY)-; *ACIDE-2,4-DICHLORO-PHENOXYACETIQUE- (FRENCH); *Acido(2,4-Dicloro-Fenossi)-Acetico (Italian); *Acme-LV-4-; *Acme-LV-6-; *Agricorn-D-; *Agroxone-; *Bladex-B-; *Brush-Killer-64-; *Croprider-; *2,4-D-ACID-; *D50-; *Dacamine-; *De-Pester-Ded-Weed-LV-2-; *Desormone-; *2,4-DICHLOOR-FENOXY-AZIJNZUUR- (DUTCH); *DICHLOROPHENOXYACETIC-ACID-; *2,4-DICHLOROPHENOXYACETIC-ACID-; *2,4-DICHLOR-PHENOXY-ESSIGSAEURE- (GERMAN); *Dicopur-; *Dioweed-; *DMA-4-; *Dormon-; *Dormone-; *2,4-Dwuchlorofenoksyoctowy-kwas- (Polish); *Dymec-; *Emulsamine-; *Emulsamine-E-3-; *Emulsamine-BK-; *Weedone-100-Emulsifiable- (Canada); *ENVERT-171-; *ENVERT-DT-; *ESTERON-; *ESTERON-99-; *ESTERON-76-BE-; *ESTERON-BRUSH-KILLER-; *ESTERON-99-CONCENTRATE-; *ESTERONE-FOUR-; *ESTERON-44-WEED-KILLER-; *ESTONE-; *FARMCO-; *Fernesta-; *FERNIMINE-; *Fernoxone-; *Ferxone-; *FOREDEX-75-; *For-ester-; *FORMOLA-40-; *Green Cross Weed-No-More "80"; *HEDONAL- (Theherbicide); *HERBIDAL-; *HIVOL-44-; *Ipaner-; *KROTILINE-; *KWASU-2,4-DWUCHLOROFENOKSYOCTOWY-; *KYSELINA-2,4-DICHLORFENOXYOCTOVA-; *Lawn-Keep-; *Butoxy-D 3: 1 Liquid emulsifiable Brushkiller LV96 (Canada); *Macondray-; *MACRONDRAY-; *MIRACLE-; *MONOSAN-; *Mota-Maskros-; *Moxon-; *Netagrone-; *NETAGRONE-600-; *Novermone-; *2,4-PA-; *Palormone-; *PENNAMINE-; *Pennamine-D-; *PHENOX-; *Phenoxyacetic-acid,-2,4-dichloro-; *Pielik-; *PLANOTOX-; *Plantgard-; *Red-Devil-Dry-Weed-Killer-; *RHODIA-; *Salvo-; *Scott's-4-XD-Weed-Control-; *B-Selektonon-; *Spritz-Hormin-; *SUPERORMONE-CONCENTRE-; *SUPER-D-WEEDONE-; *TRANSAMINE-; *Tributon-; *TRINOXOL-; *VERGEMASTER-; *VERTON-D-; *Verton-38-; *VERTON-2D-; *VERTRON-2D-; *VIDON-638-; *VISKO-RHAP-DRIFT-HERBICIDES-; *VISKO-RHAP-LOW-VOLATILE-4L-; *WEED-AG-BAR-; *Weedar-; *WEEDAR-64-; *Weedatul-; *WEEDEZ-WONDER-BAR-; *Weed-B-Gon-; *Weedone-; *WEEDONE-LV4-; *Weed-Rhap-; *Weed-Rhap-A-4-; *Weed-Rhap-B-4-; *Weed-Rhap-B-266-; *Weed-Rhap I-3.34; *R-H-Weed-Rhap-20-; *Weed-Rhap-LV-4-0-; *WEED-TOX-; *WEEDTROL- RN: 94-75-7 MF: *C8-H6-Cl2-O3 SHPN: UN 3082; Environmentally hazardous substance, liquid,nos UN 3077; Environmentally hazardous substance, solid, nos IMO 9.0; Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos STCC: 49 411 26; 2,4-Dichlorophenoxyacetic acid (or) 2,4-D HAZN: D016; A waste containing 2,4-D may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. U240; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. ASCH: Agent orange; 39277-47-9 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *By chlorination of molten phenoxyacetic acid; from 2,4-dichlorophenol, sodium and ethyl chloroacetate followed by hydrolysis of ester. [R1] *2,4-D is produced commercially by chlorination of phenol to form 2,4-dichlorophenol, which reacts with monochloroacetic acid to form 2,4-D. [R2, 493] IMP: *Major impurities /found/ in technical 2,4-D: 2,6-Dichlorophenoxyacetic acid, 0.5-1.5%; 2-Monochlorophenoxyacetic acid, 0.1-0.5%; 4-Monochlorophenoxyacetic acid, 0.2-0.8%; Bis(2,4-dichlorophenoxy) acetic acid, 0.1-2.0%; ... 2-Chlorophenol, 0.0004-0.04%; 4-Chlorophenol, 0.0004-0.005%; Water, 0.1-0.8%. [R3] *2,4-Dichlorophenol; Chlorinated diphenyl ethers; Bis-2,4-dichlorophenoxymethane; Non-toxic di- and tri-chlorodibenzofurans and chlorodibenzo-p-dioxins. [R4] *Analysis of 28 samples of technical 2,4-D by gas chromatography showed that hexachlorodioxins were present in only one sample, at less than 10 ppm. The dioxin most likely to be formed (2,7-dichlorodibenzo-p-dioxin) was not found. The major impurity in technical 2,4-D was identified as bis-(2,4-dichlorophenoxy)methane, at 30 ppm. [R2, 493] *Wastes from 2,4-D production may contain a number of constituents, including 2,4-dichlorophenol, 2,6-dichlorophenol, 2,4,6-trichlorophenol, and chlorophenol polymers. [R5] *Predioxins (non-toxic), and hydroxydiphenylethers. [R6] *SIXTEEN SAMPLES OF 2,4-D, AS ESTERS AND AMINE SALTS, WERE ANALYZED FOR CHLORINATED DIBENZO-P-DIOXINS. DI-, TRI-, AND TETRA-CHLORODIBENZO-P-DIOXINS WERE IDENTIFIED. ESTER FORMULATIONS SHOWED MUCH HIGHER LEVELS OF CONTAMINATION THAN AMINE. /2,4-D ESTERS AND AMINE SALTS/ [R7] *Various esters, salts and mixtures with other herbicides have been marketed by many companies over the past 40 years. ... A sequestering agent is included in commercial formulations to prevent precipitation of calcium or magnesium salts by hard water. [R8, 220] *2,4-D was found at about a 50% concn in the defoliant Agent Orange, which was used extensively throughout Vietnam. However the controversies associated with the use of Agent Orange were associated with the contaminant (dioxin) in the 2,4,5-T component of the defoliant mixture, and not 2,4-D. [R9] FORM: *USEPA/OPP Pesticide Code 030001; Trade Names: Weed-broom (Use 3 code Nos. 012301, 013803 and 030001). [R10] *Emulsifiable concentrate, soluble concentrate, water-soluble powder, granules [R11] *95% technical, technical esters, and formulated product grades [R12] *Brush-rhap LV 2D-2T Rhodia Low Volatile Brush Killer No 2 [R13] *2,4-D and 2,4,5-T mixed with Banvel /Former/ [R13] *2,4-D with Benazolin [R13] *Types of formulations: Granular; amine and ester liquids; Dust; and Aerosol spray (foam). [R14] *Forms available: sodium salt (60-85% acid), amine salts (10-60% acid), esters (10-45% acid) [R15] *Acme Super Brush Killer (with dicamba); Acme Brush Killer 875 (with dicamba + MCPP); U 46 DP (dichlorprop); Duplosan DP-D ... (dichlorprop-P); Actril DS ... (ioxynil); U 46 Combi-Fluid (MCPA); Chipco Turf Kleen; 2 Plus 2 (MCPP); U 46 KV-Combi-Fluid ( mecoprop); Duplosan KV-Combi ...(mecoprop-P); Gordon's Vegemec Vegetation Killer (prometon); Gordon's Phenomee (MCPP) Lentemul. [R16] *Gesapax H (2,4-D + ametryn (1.4 : 1)); Gesaprim D (2,4-D + atrazine (1 : 2.5)); Hytrol (2,4-D + amitrole + diuron + simazine); Klinopalm (2,4-D + ametryn + sodium hydrogen methylarsonate (1.4 : 1 : 3)); Modown DG (2,4-D + bifenox); Rilof H (2,4-D + piperophos (about 1 : 2 to 2 : 3)); 2,4-D + amitrole + atrazine; 2,4-D + amitrole + TCA; 2,4-D + atrazine + sodium chlorate; 2,4-D + chlorfenac; 2,4-D + dichlorprop + picloram; 2,4-D + maleic hydrazide; 2,4-D + monuron-TCA; 2,4-D + picloram + tebuthiuron; 2,4-D + triclopyr. [R8, 222] *Brush Killer 170 (butoxyethanol esters of 2,4-dichlorophenoxypropionic acid and 2,4-D) [R17] *Acme Vegetation Killer (2,4-D + Prometone) [R18] *Allied Chemical Low Volatile 1-1/3-2/3 Brush Killer (2,4-D + 2,4,5-T + isooctyl esters of 2,4-D AND 2,4,5-T) /Former/ [R19] *Brush-Rhap B-2-2 (2,4-D + 2,4,5-T) /Former/ [R20] *Brush-Rhap LV-2-2-0 (2,4-D + 2,4,5-T) /Former/ [R21] *Chempar Low Volatile Brush Killer No 2 (2,4-D + 2,4,5-T) /Former/ [R21] *De-Pester Ded-Weed for Lawns (2,4-D + 2,4,5-T + kerosene) /Former/ [R22] *Emulsavert 248 (2,4-D + 2,4,5-T + N,N-dimethyloleylamine salts of 2,4-D AND 2,4,5-T) /Former/ [R23] *Jet-Weed Killer Power Pellets (2,4-D + silvex) [R24] *Kansel (2,4-D + dicamba) [R24] *Limit (chloro-N,N-diallylacetamide + 2,4-D) [R25] *Nutro Dandelion and Turf Weed Killer (2,4-D + dicamba) [R26] *Nutro Weed Bomb (2,4-D + MCPP) [R26] *Pill Kill Kartridges for Dandelions and Broadleaf Weeds (2,4-D + silvex) [R27] *Pratt Lawn Weed Killer (2,4-D + 2,4,5-TP) [R28] *Pratt's Crabgrass and Broadleaf Weed Killer (octyl ammonium methyl arsonate + 2,4-D) [R28] *Proturf Broad Spectrum Weedicide (2,4-D + dicamba) [R28] *Proturf Broad Spectrum Weedicide II (2,4-D + 2-(2-methyl-4-chlorophenoxy)propionic acid) [R28] *Proturf Fertilizer Plus Dicot Weed Control (2,4-D + dicamba) [R28] *Proturf Fertilizer Plus Dicot Weed Control II (2,4-D + 2-(2-methyl-4-chlorophenoxy)propionic acid) [R28] *Reasor-Hill Brush Rhap (2,4-D + 2,4,5-T) /Former/ [R28] *Rhodia Low Volatile Brush Killer No 2 (2,4-D + 2,4,5-T) /Former/ [R28] *Robot Gardener Weed and Crabgrass Killer (potassium cyanate + 2,4-D) [R28] *Turf Builder Plus 2 (2,4-D + 2-(2-methyl-4-chlorophenoxy)-propionic acid) [R29] MFS: *Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268, (317) 337-3000; Production site: Midland, MI 48667 [R30] *Nufarm, Inc., 317 Florence Rd., St. Joseph, MO 64504, (800) 852-5234; Production site: St. Joseph, MO 64504 [R30] *Riverdale Chemical Co., 1333 Burr Ridge Parkway, Suite 125A, Burr Ridge, IL 60521-0866, (708) 754-3330; Production site: Chicago Heights, IL 60411 [R30] OMIN: *2,4-D was prepared in 1941 Pokorny R. [R31] */2,4-D AS FREE/ ACID IS NOT USED CUSTOMARILY BY ITSELF; /IT IS/ USUALLY /USED/ AS /ITS/ AMINE /SALT/, /METALLIC/ SALT, OR ESTER. [R16] *There are approximately 1500 registered products containing 2,4-D. [R14] *Technical grade 2,4-D is avail in USA as free acid (98% purity), as salts (dimethylamine, mixed ethanolamine and isopropanolamine, lithium and sodium) and as esters of the following alcohols: isopropyl; n-butyl; sec-butyl; iso-octyl; 2-butoxyethyl, and butoxypolypropylene glycol. [R31] *Chlorophenoxy herbicides are applied alone or as mixtures with other herbicides, in solutions, dispersions, or emulsions in water and/or oil, using equipment that produces large droplets to avoid spray drift. /Chlorophenoxy herbicides/ [R32] *New Zealand: The spraying of phenoxyherbicides is restricted within prescribed distances of vineyards. /Phenoxyherbicides/ [R33] *Hard water leads to precipitation of the calcium and magnesium salts, but a sequestering agent is included in formulations to prevent this. [R34] *The following plants are resistant (plants are not killed with foliage applications): Ash; Ash, mountain; Basswood; Beech; Blackberry; Cedar, western red; Cedar, yellow; Currants; Fir, balsam; Fir, Douglas; Gorse; Hawthorn; Hemlock, western; Hickory; Hornbean; Lilac; Maple; Maple, mountain; Maple, red; Maple, vine; Oak; Pine; Prickly-ash; Raspberries, wild; Rhododendron; Rose; Salmonberry; Spruce, black; Spruce, white. /From table/ [R35] USE: *For 2,4-D (USEPA/OPP Pesticide Code: 030001) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R10] *Herbicide used on grasses, wheat, barley, oats, sorghum, corn, sugarcane, and noncrop areas /pasture and range land; lawns and turf/ for post-emergent control of canada thistle, dandelion, annual mustards, ragweed, lambsquarters and others. Some formulations for pine release, water hyacinth control and prevention of seed formation; double-gee, wild radish, turnip and other broadleaf weeds in cereals. [R36] *Registered for use on rice in the Philipines. [R36] *2,4-D when applied properly, will increase the red color in potatos. It is used on tomatos to cause all fruits to ripen at the same time for machine harvesting. [R37] */2,4-D free/ acid serves as the basic material from which the soluble esters and salts are produced. [R38, p. III-130] *Used in forest management: Brush control; Conifer release; Tree injection. [R14] *To increase latex output of old rubber trees. [R1] *HERBICIDE FOR PASTURE AND RANGELANDS; AGRICULTURAL USE-EG, WHEAT, CORN, GRAIN SORGHUM, RICE AND OTHER GRAINS; INDUSTRIAL/COMMERCIAL USES; LAWNS, TURF, AND AQUATIC USE; OTHER FIELD CROPS-EG, NUTS; COMPONENT OF HERBICIDE FOR JUNGLE DEFOLIATION-FORMER USE. [R39] *2,4-D, its salts and esters are systemic herbicides, widely used for weed control in cereals and other crops at 0.28-2.3 kg/ha. [R40, 325] *Chlorophenoxy compounds including acids, salts, amines and esters are ... /used/ in agriculture for control of broad-leaf weeds and in control of woody plants along roadside, railways and utilities rights of way. /Chlorophenoxy compounds/ [R41] *2,4-D is used as a ... plant growth regulator. It is a component of Agent Orange, a military defoliant. [R42, 1991.375] CPAT: *HERBICIDE FOR PASTURE AND RANGELAND, 26%; FOR WHEAT, 26%; FOR CORN, 14%; FOR OTHER GRAINS EXCEPT SORGHUM, 12%; FOR INDUSTRIAL/COMMERCIAL USES, 11%; FOR LAWNS AND TURF, 3%; FOR AQUATIC USES, 3%: FOR GRAIN SORGHUM, 3%; FOR OTHER FIELD CROPS-EG, CITRUS, FRUITS, NUTS, AND VEGETABLES, 2%; (1982) [R39] *75% AS A SELECTIVE HERBICIDE FOR BROADLEAF WEEDS AND BRUSH, ON SMALL GRAINS, CORN, SORGHUM, RICE, OTHER MINOR CROPS, AND GRAZING LAND; 13% FOR INDUSTRIAL AND COMMERCIAL USE ON NON-CROPLAND; 6% BY GOVERNMENT AGENCIES ON NON-CROPLAND; 6% FOR HOME AND GARDEN USE ON TURF (1972). [R39] *PASTURE AND RANGELANDS, 26%; WHEAT, 26%; CORN, 14%; INDUSTRIAL/COMMERCIAL USES, 11%; LAWNS AND TURF, 4%; AQUATIC USES, 3%; GRAIN SORGHUM, 3%; RICE, 1%; OTHER GRAINS, 11%; OTHER FIELD CROPS-EG, DECIDUOUS NUTS AND FRUITS, CITRUS, AND VEGETABLES, 2% (1982). [R39] PRIE: U.S. PRODUCTION: *(1978) 2.19X10+10 G-DEMAND (2,4-D INCL ESTERS AND SALTS) [R39] *(1982) 2.05X10+10 G-DEMAND (2,4-D INCL ESTERS AND SALTS) [R39] *(1991) Exceeded 5000 lb or US $5000 in value [R43] *(1946) 5.5 million lbs; (1950) 14 million lbs; (1960) 36 million lbs; (1964) 54 million lbs; (1990) 52-67 million lbs; (2001) 47 million lbs. [R44, p. V4 490] U.S. IMPORTS: *(1977) 1.14X10+9 G [R39] *(1982) 3.24X10+9 G [R39] *(1983) 9.89X10+6 lb [R45] U.S. EXPORTS: *(1972) 3.18X10+9 G (2,4-D AND SALTS AND ESTERS) [R39] *(1978) 2.97X10+9 G (2,4-D INCL ESTERS AND SALTS) [R39] *(1983) 4.65X10+9 G (2,4-D INCL ESTERS AND SALTS) [R39] *(1985) 1.60X10+9 g [R46] *(1987) 8.74X10+6 lb [R47] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White to yellow crystalline powder /SRP: yellow color is phenolic impurities/ [R15]; *Colorless powder [R40, 323]; *White to yellow, crystalline ... powder. [R48]; *Crystals from benzene [R1] ODOR: *ODORLESS WHEN PURE [R49]; *A slight phenolic odor [R50] BP: *160 deg C @ 0.4 mm Hg [R1] MP: *138 deg C [R1] MW: *221.04 [R1] CORR: *Free acid is corrosive to metals. [R11] *Most formulations are noncorrosive to spray equipment although some concentrates may be deleterious to painted surfaces. [R51] DEN: *1.42 @ 25 deg C [R52] DSC: *pKa= 2.73 [R40, 323] HTC: *-7700 BTU/lb= -4300 cal/g= -180X10+5 J/kg [R53] OWPC: *log Kow= 2.81 [R54] SOL: *67.3 g/400 ml acetone at 25 deg C; 0.94 g/100 ml benzene at 28 deg C; 0.63 g/100 ml carbon disulfide at 29 deg C; 0.16 g/100 ml carbon tetrachloride at 25 deg C; 0.08 g/100 ml diesel oil and kerosene at 25 deg C; 78.5 g/100 ml dioxane at 31 deg C; 10.3 g/100 ml ethanol (50%) at 25 deg C; 100 g/100 ml ethyl alcohol (95%) at 25 deg C; 27.0 g/100 ml ethyl ether at 25 deg C; 24.8 g/100 ml isopropanol at 31 deg C; 25 g/100 ml methyl isobutyl ketone at 25 deg C; 0.52 g/100 ml ortho-dichlorobenzene at 25 deg C; 0.058 g/100 ml toluene at 25 deg C [R51]; *INSOL IN PETROLEUM OILS [R55]; *1.1 g/kg n-heptane at 20 deg C [R11]; *540 PPM IN WATER AT 20 DEG C [R2, 493]; *In water, 677 ppm @ 25 deg C. [R56] SPEC: *SADTLER REF NUMBER: 13141 (IR, PRISM); 8174 (IR, GRATING); MAX ABSORPTION (WATER, 0.1 N HCL): 282 NM (LOG E= 3.26); 289 NM (LOG E= 3.20) SHOULDER [R57]; *The undissociated molecule in 0.1 M hydrochloric acid has a molar absorptivity of 1820 molar/cm at 282 nm; the anion in 0.01 M phosphate buffer is 2070 at 283.5 nm. [R58]; *IR: 2221 (Coblentz Society Spectral Collection) [R59]; *UV: 3427 (Sadtler Research Laboratories Spectral Collection) [R59]; *1H-NMR: 10803 (Sadtler Research Laboratories Spectral Collection) [R59]; *MASS: 52494 (NIST/EPA/MSDC Mass Spectral Database 1990 Version) [R59]; *Intense mass spectral peaks: 162 m/z (100%), 164 m/z (69%), 220 m/z (61%), 222 m/z (39%) [R60]; *Intense mass spectral peaks: 111 m/z, 133 m/z, 175 m/z [R61] SURF: *66.5 dyne/cm at 25 deg C and pH 1.4 [R62] VAP: *8.25X10-8 mm Hg @ 20 deg C (1.1X10-2 mPa @ 20 deg C) [R40, 323] OCPP: *Percent adsorbed by 10 mg activated carbon from 1X10-4 M aqueous solution @ pH 3.0: 60.1%; @ pH 7.0: 18.8%; at pH 11.0: 14.3%. [R63] *NON-HYGROSCOPIC [R55] *polarizability= 227.4; Latent heat of fusion= 5.6 kcal/mol; Dipole moment= 3.33 debye [R64] *Proton NMR: Free 2,4-D in CD3OD shows no free H downfield of the aromatic absorptions, but shows an exchange peak with CD3OD at 5.13 ppm relative to TMS. The CH2 group absorbs at 4.72 ppm, H-3 /of the ring/ at 7.35, H-5 at 7.12, and H-6 at 6.90 ppm. [R65] *Henry's Law constant = 8.6X10-6 atm-cu m/mole @ 20 deg C [R66] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: *Fire or explosion: Some may burn but none ignite readily. Those substance designated with a "P" may polymerize explosively when heated or involved in a fire. Containers may explode when heated. Some may be transported hot. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *Health: Inhalation of material may be harmful. Contact may cause burns to skin and eyes. Inhalation of asbestos dust may have a damaging effect on the lungs. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control may cause pollution. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *Evacuation: Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *Fire: Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Do not scatter spilled material with high pressure water streams. Dike fire-control water for later disposal. Fire involving tanks: Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from engulfed in fire tanks. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *Spill or leak: Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent dust cloud. Avoid inhalation of asbestos dust. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Small spills: Take up with sand or other noncombustible absorbent material and place into containers for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Cover powder spill with plastic sheet or tarp to minimize spreading. Prevent entry into waterways, sewers, basements or confined areas. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] *First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Environmentally hazardous substance, solid, nos; Environmentally hazardous substance, liquid, nos/ [R67] FPOT: *Material itself does not burn or burns with difficulty. [R68] FLPT: *THE ACID AND SALTS ARE NONFLAMMABLE. HOWEVER, COMMERCIAL FORMULATIONS OF /2,4-D FREE/ ACID MAY HAVE FLASH POINT MINIMUM OF 88 DEG C (CLEVELAND OPEN CUP) ... /SRP: INERT COMPONENTS OF FORMULATION/ [R69, 132] FIRP: *Extinguishant: Carbon dioxide, dry chemical, foam, and water. [R70, 1981.2] *Extinguish fire using agent suitable for type of surrounding fire. [R68] TOXC: *Toxic gases and vapors (such as hydrogen chloride and carbon monoxide) may be released in a fire involving 2,4-D. lo [R70, 1981.2] *Toxic and irritating ... phosgene gas may form. [R53] REAC: *Contact with strong oxidizers may cause fires or explosions. [R70, 1981.2] *Strong oxidizers. [R48] *2,4-D is a strong acid, and forms water-soluble salts with alkali metals and amines. [R34] DCMP: *When heated to decomposition it emits toxic fumes of /chlorides/. [R71] *Decomposition products: toxic gases and vapors (such as hydrogen chloride and carbon monoxide) may be released in a fire involving 2,4-D. [R42, 1991.375] ODRT: *Detection: 3.13 mg/kg /SRP: Technical grade/ [R72, 496] SERI: *Dust may irritate eyes. [R53] *Acute eye or skin irritation ... has been reported in agricultural and forestry workers following occupational exposure. [R73] *Irritates eyes, causes gastrointestinal disturbances. [R74, 32] EQUP: *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with 2,4-D or liquids containing 2,4-D. ... Employees should be provided with and required to use dust- and splash-proof safety goggles where 2,4-D or liquids containing 2,4-D may contact the eyes. [R74, 31] *Wear appropriate personal protective clothing to prevent skin contact. [R48] *Wear appropriate eye protection to prevent eye contact. [R48] *Respirator Recommendations: Up to 100 mg/cu m: (APF = 10) Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust, mist, and fume filter/(APF = 50) Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter/(APF = 25) Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust, mist, and fume filter/(APF = 10) Any supplied-air respirator/(APF = 50) Any self-contained breathing apparatus with a full facepiece. [R48] *Respirator Recommendations: Emergency or planned entry into unknown concentrations or IDLH conditions: (APF = 10,000) Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode/(APF = 10,000) Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained positive-pressure breathing apparatus. [R48] *Respirator Recommendations: Escape: (APF = 50) Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter/Any appropriate escape-type, self-contained breathing apparatus. [R48] OPRM: *Handle carefully. Do not contaminate water, food or feed by product storage or disposal. ... Do not use spray equipment contaminated with this product for any other purposes unless thoroughly cleaned with a suitable cleaner. ... Do not apply where irrigation water may be contaminated. [R16] *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... If employees' clothing ... becomes contaminated with 2,4-D, employees should change into uncontaminated clothing before leaving the work premises. Clothing contaminated with 2,4-D should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of 2,4-D from the clothing. If the clothing is to be laundered or otherwise cleaned to remove 2,4-D, the person performing the operation should be informed of 2,4-D's hazardous properties. Non-impervious clothing which becomes contaminated with 2,4-D should be removed promptly and not reworn until the 2,4-D is removed from the clothing. [R70, 1981.2] *Eating and smoking should not be permitted in areas where solid 2,4-D is handled, processed, or stored. Employees who handle 2,4-D or liquids containing 2,4-D should wash their hands thoroughly with soap or mild detergent before eating, smoking, or using toilet facilities. [R70, 1981.3] */Individuals/ not wearing protective equipment and clothing should be restricted from areas of spills until cleanup has been completed. [R70, 1981.3] *In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation /of equipment/. [R70, 1981.2] *Contact lenses should not be worn when working with this chemical. [R48] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material /is/ not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Keep upwind. ... Avoid breathing vapors or dusts. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R68] *Smoking, eating, and drinking before washing should be absolutely prohibited when any pesticide ... is being handled or used. /Pesticides/ [R75, 1619] */When/ cleaning glassware and spray equipment: wash thoroughly with water and detergent soln. Alcohol or ketone type solvents may be used with ester formulations. Preferably, equipment should not be used for application of other pesticides or fertilizers. [R69, 132] *The worker should immediately wash the skin when it becomes contaminated. [R48] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R48] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R48] *Handle carefully. Do not contaminate water, food, or feed by product storage or disposal. Do not use spray equipment contaminated with this product for any other purposes unless thoroughly cleaned with a suitable cleaner. Do not apply where irrigation water may be contaminated. [R74, 31] SSL: *Stable under normal conditions of storage. [R74, 31] *Stable up to 50 deg C for at least 2 yr. [R76] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R77] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R78] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R79] STRG: *DO NOT STORE NEAR OTHER AGROCHEMICALS OR SEEDS. [R16] CLUP: *1) Ventilate area of spill. 2) For small quantities, sweep onto paper or other suitable material, place in an appropriate container and burn in a safe place (such as a fume hood). Large quantities may be reclaimed. [R74, p. 31-2] *Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid, or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. [R68] *Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the amount spilled. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R68] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers D016 and U240, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R80] *Landfill: Recommendable method: Incineration. Not recommendable method: Discharge to sewer. Peer-review: Incinerate at high temp or PCDDs may be formed. [R81, 70] *Incineration and landfill: 2,4-D /2,4-dichlorophenoxyacetic acid/ is known to be readily detoxified by soil microorganisms and at low dosages is normally decomposed in one to four weeks. The detection of 2,4-dichlorophenol, 4-chlorocatechol, chloromuconic and succinic acids from either soil or pure culture studies suggests a sequence of reactions involving ring hydroxylation and cleavage and further metabolism of the open chain structure to carbon dioxide. The non-persistence and detoxification of 2,4-D in soil indicate that burial in non-crop areas away from water supplies would be an acceptable method for the disposal of small quantities of 2,4-D. Incineration at high temperatures with sufficient residence time leads to complete detoxification of 2,4-D and is the most environmentally acceptable method for 2,4-D disposal. For the decontamination of 2,4-D containers-drums: triple rinse and drain procedure ("triple rinse" means the flushing of containers three times of the normal diluent equal to approximately 10% of the container's capacity and adding the rinse liquid to the spray mixture or disposing of it by the method prescribed for disposing of the pesticide). Small containers should be punched full of holes, crushed and taken to a landfill. [R81, 71] *Chemical treatment: Detoxification requires treatment with chloride of lime or sodium carbonate. Rinse containers with a 5% soln of caustic soda. Farms are allowed to destroy if necessary up to 10 kg of the pesticide. Removal of 17% of 2,4-D /(2,4-dichlorophenoxy)acetic acid/ from water is achieved by coagulation and complete water treatment by ozonation; the use of activated charcoal is an effective treatment technique. [R81, 71] *Herbicide orange /was incinerated/ by the use of two identical refractory lined furnaces on board the Mt Vulcanus while at sea. The average wall temperature was 1273 deg C and average flame was 1500 deg C. A residence time of 1.0 second was used. Combustion efficiency was > 99.98%. Destruction efficiency was: 2,4-D > 99.9%; 2,4,5-T > 99.9%; Total hydrocarbon 99.982 to 99.992%; Herbicide orange > 99.999%; 2,3,7,8-tetrachlorodibenzo-p-dioxin > 99.93 to > 99.99%; Chlorinated hydrocarbons > 99.999%. /From table/ [R82] *The following wastewater treatment technology have been investigated for 2,4-D and related herbicides: Concentration process: Resin adsorption. [R83] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *A4; Not classifiable as a human carcinogen. [R84, 2002.25] *Classification of carcinogenicity: 1) evidence in humans: limited; overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /SRP: The older literature indicated that these compounds were carcinogenic. It was discovered that this was due to contamination, including dioxin./ /Chlorophenoxy herbicides; From table/ [R85] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Monitor body temperature and treat if necessary. /Chlorophenoxy herbicides and related compounds/ [R86, p. 293-4] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's /SRP: "To keep open", minimal flow rate/. Titrate to maintain adequate urine flow. Watch for signs of fluid overload. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive without signs of hypovolemia ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Chlorophenoxy herbicides and related compounds/ [R86, 294] *Alkaline diuresis should be used to treat acute poisoning with chlorophenoxy herbicides or ioxynil in the presence of coma or other poor prognostic indicators, such as acidemia, or if plasma total chlorophenoxy concentrations are 0.5 g/l or more. [R87] *For acute 2,4-D ... /exposure/ the usual measures of gut and skin decontamination ... are recommended within the first several hours. On the basis of pharmacokinetic data, alkaline diuresis has been suggested in severe overdose as a method to enhance elimination of 2,4-D, but this procedure should be used cautiously in the presence of renal dysfunction. Alkalinization of the urine and generous fluid replacement have the added benefit of treating any myoglobinuria present. Watch for the development of metabolic acidosis, hyperthermia, hyperkalemia, myoglobinuria, and hepatic and/or renal dysfunction. [R88, 1096] *Bath and shampoo with soap and water to remove chemicals from skin and hair. Obtain medical treatment if irritation persists. Individuals with chronic skin disease or known sensitivity to these herbicides should either avoid using them or take strict precautions to avoid contact (respirator, gloves, etc). FLUSH contaminating chemicals from eyes with copious amounts of clean water for 10-15 min. If irritation persists, obtain medical treatment. /Chlorophenoxy compounds/ [R89] *If substantial amounts of chlorophenoxy compounds have been ingested, spontaneous emesis may occur. If vigorous emesis has not occurred, /SRP: consider GI contamination/ endotracheal tube. Repeated admin of charcoal at half or more the original dosage every 2-4 hr may be beneficial. If gastric aspiration and lavage is not performed due to delay in treatment, and if the patient is fully alert, administer charcoal and laxative orally. Administer iv fluids to accelerate excretion of the chlorophenoxy cmpd, and to limit concn of the toxicant in the kidney. A urine flow of 4-6 ml/min is desirable. Iv saline/dextrose has sufficed to rescue comatose patients who drank 2,4-D and mecoprop several hours before hospital admission. Caution: Monitor urine protein and cells, BUN, serum creatinine, serum electrolytes, and fluid intake/output carefully to insure that renal function remains unimpaired and that fluid overload does not occur. Forced alkaline diuresis has been used successfully in management of suicidal ingestions of chlorophenoxy cmpds. Alkalinizing the urine by including sodium bicarbonate in the iv soln apparently accelerates excretion of 2,4-D dramatically and mecoprop excretion substantially. Urine pH should be maintained in the 7.5-8.8 range. Include potassium chloride as needed to offset increased potassium losses: add potassium chloride to each liter of iv soln. Monitor serum electrolytes carefully. There may possibly be some hazard to the kidneys when urine concns of toxicant are very high, so integrity of renal function and fluid balance should be monitored carefully as the chlorophenoxy cmpd is excreted. [R90] *With one exception, treatment is entirely symptomatic. the exception involves quinidine sulfate, which may be of value not only for preventing cardiac arrhythmia but also for treating the dysfunction of skeletal muscle. [R91, 1325] MEDS: *Recommended medical surveillance: The following medical procedures should be made available to each employee who is exposed to 2,4-D at potentially hazardous levels: 1) Initial Medical Screening: Employees should be screened for a history of certain medical conditions which might place the employee at increased risk from 2,4-D exposure. /Such conditions include:/ liver, kidney, cardiovascular diseases, or convulsive disorder or neuropathy. Periodic medical examination: Any employee developing the above-listed conditions should be referred for further medical examination. [R70, 1981.1] *Because dermal absorption is an important route of exposure to chlorophenoxy herbicides, biological monitoring is useful in estimating the absorbed dose. Urine concn provides the most accurate estimate of body burden ... . /Chlorophenoxy herbicides/ [R92] HTOX: *The free acid has a somewhat higher toxicity than the sodium salt, the amine salts or the esters. [R38, p. III-130] *A male suicide victim weighing 55 kg ingested an unknown quantity of pure 2,4-D acid in kerosene. Symptomatology included: coma; myotonia; fever; pulmonary emphysema and edema; liver necrosis; degeneration of kidney tubules; and death in 6 days. 2,4-D concentration in tissues was 57.6-407.9 mg/kg. [R93] *Symptomatology (partly inferential): 1. Fatigue, weakness, anorexia, perhaps nausea, vomiting and diarrhea. 2. Hyporeflexia and lethargy progressing to coma, with constricted pupils (miosis). 3. Flaccid paralysis has been described in one comatose patient, grand mal convulsions with opisthotonus in another, hypertonia with areflexia in a third, and twitching and jerking in a fourth. ... 5. Progressive decline in blood pressure with death in deep coma. The possibility that hyperpyrexia and hypermetabolism may have contributed to the fatal outcome does not appear to have been ruled out (one comatose patient was described as sweating profusely). A terminal pneumonia is likely. 6. Disturbance in body temp regulation may be encountered. Perhaps severe reduction of body temp in cool or cold environments. More probably, febrile responses in warm environments or during exercise. 7. Progressive hypotension with death in peripheral vascular collapse, perhaps associated with acidosis due to lactic acidemia and other products of hypermetabolism. 8. In nonfatal poisonings, severe and protracted neuritis with pain, paresthesias and weakness. ... Humans have experienced muscle fasciculations as well as myotonia. Chronic exposure may lead to central nervous system defects in the control of motor function. [R38, p. III-323] *The induction of sister chromatid exchanges /was studied/ ... in peripheral lymphocytes of workers spraying foliage ... with 2,4-D. ... The concn of 2,4-D ... in the urine samples after exposure varied from 0.00 to 10.99 mg/l. ... Results ... indicate that 2,4-D ... /does/ not act as a direct DNA damaging agent. /SRP: Formulation not specified/ [R94] *A case report of accidental inhalation exposure to a toxic dose of 2,4-D is described. A 57 yr old man sprayed a 40% aq soln of 2,4-D by a manual pump under windy conditions. During the evening and day after the work was performed, the farmer experienced generalized asthenia, profuse perspiration, vomiting and oliguria and was admitted to the hospital. Central and peripheral effects that were experienced in the early phase of illness included dizziness, change of reflexes and uncertain walking. The only alterations in routine lab test results was a transitory albuminuria. The clinical condition of the patient gradually improved, until 18 days after the accident, when symptoms related to the nervous system worsened and a serious form of hemorrhagic enterocolitis developed. Neural effects included uncertain walking, sluggish patellar and achilles tendon reflexes, positive Romberg sign and dysmetria. Lab tests did not provide addnl information at this stage. By 5 months, all symptoms except hyporeflexia had receded. [R95] *A case report is presented of polyneuritis which developed in a man after he sprayed 2,4-D. Two solutions, containing 235 g/l and 410 g/l of 2,4-D had been applied over several days from a sprayer, towed by a tractor. ... The 52 year old male worker experienced pain on the right side of the face that developed into paresthesia and anesthesia and on the next day developed hypoesthesia of the right leg. Two weeks later, symptoms of the right leg improved while anesthesia and weakness of the left leg developed and the facial symptoms remained. The patient presented at a clinic after an additional 2 weeks, at which time Achilles reflex and all but deep sensations were found to be absent. No disorders of the arms or of other organ systems were detected. Polyneuritis and disorders of the right trigeminal nerve were treated with vitamin B and in 6 weeks the patient was discharged. The condition of his face and left leg had improved and responses to electrodiagnostic stimulation were normal. Neurological impairment of the muscle still remained and the Achilles reflex was still absent, but atrophy did not develop. [R96] *Of 6 volunteers, none experienced any ill effect either subjectively or as measured by clinical and lab tests after ingesting one dose of 2,4-D at the rate of 5 mg/kg. ... /It/ appeared in the blood within 1 hr, and reached its max level of 25-50 ppm in 7-12 hr in different men. [R91, 1322] *In a suicide involving ingestion of 50 g of 2,4-D, the patient was conscious but dazed ... 1 hr after ingestion. 9 hr after /ingestion/ ... the patient was in deep coma with generalized muscle hypotonia, relaxation of sphincters, loss of reflexes, and hypotension. He also exhibited pendular eye movements. Despite symptomatic care and diuresis, respiration became rapid and superficial, mydriasis appeared, and the patient died 12 hr after ingestion. [R91, 1322] *A male suicide victim ingested 125 ml of 2,4-D (400 mg active ingredient/l) symptomology included: loss of consciousness, coma, generalized muscular hypotonia, loss of all reflexes, hypotension, hyperglycemia, proteinuria, and death in 12 hr. 2,4-D concentration in tissues < 400 mg/kg. [R97] *A 46 yr old farmer accidentally ingested 2,4-D. His symptoms included a badly burned tongue and throat, nausea, vomiting, profuse sweating, and a burning sensation in his mouth, chest, and the lower part of his abdomen. Gastric lavage was performed in hospital about 1 hr after ingestion. 12 hr after admission his face was still flushed and he vomited frequently despite antiemetic therapy. He began to complain of aching and tender muscles. 24 hours after admission difficult respiration and cyanosis was evident. He had lost the use of his intercostal muscles and was breathing with his diaphragm; his arm muscles showed fibrillary twitching. ... 30 hr after admission, respiration became noticeably less labored, although X-rays revealed patchy, basilar pneumonitis, for which he received penicillin. Lab findings reflected muscle injury. 11 days after admission the patient was still complaining of muscle soreness, fatigue, and insomnia, and he was moderately depressed. 2 wks after admission, the patient was discharged. Loss of sexual potency was discovered and lasted about 4 months. During 36 mo of follow-up, there was no sign or symptom of polyneuropathy. [R91, 1322] *Some recent epidemiologic studies have suggested that chlorinated phenoxy acid herbicides are human carcinogens. The mortality experience in a cohort of 1,926 men who had sprayed 2,4-dichlorophenoxyacetic acid (2,4,-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) during 1955-1971 has been followed prospectively from 1972 to 1980. The total phenoxy acid exposure was generally rather low because the duration of work had mostly been less than two months. In 1972-1976 mortality from all natural causes in the cohort was only 54% of the expected value (based on age-specific rates for the general population), and in the succeeding 4 yr period 81% of the expected value. In the assessment of cancer, mortality allowance was made for 10- and 15-yr periods of latency between the first exposure and the start of the recording of vital status during the follow-up. No increase in cancer mortality was detected, and the distribution of cancer types was unremarkable. No cases of death from lymphomas or soft tissue sarcomas were found. The study results must, however, be viewed with great caution owing to the small size of the cohort, the low past exposure, and the brief follow-up period. [R98] *A population based case control study of soft-tissue sarcoma, Hodgkin's disease, non-Hodgkin's lymphoma in Kansas found farm herbicide use to be associated with non-Hodgkin's lymphoma (odds ratio, 1.6; 95% confidence interval, 0.9, 2.6). Relative risk to non-Hodgkin's lymphoma increased significantly with number of days of herbicide exposure/yr and latency. Men exposed to herbicides more than 20 days/yr had a sixfold increased risk of non-Hodgkin's lymphoma (odds ratio 6.0; 95% confidence interval, 1.9, 19.5) relative to nonfarmers. Frequent users who mixed or applied the herbicides themselves had an odds ratio of 8.0 (95% confidence interval, 2.3, 27.9) for non-Hodgkin's lymphoma. Excesses were associated with use of phenoxyacetic acid herbicides specifically 2,4-dichlorophenoxyacetic acid. Neither soft-tissue sarcoma nor Hodgkin's disease associated with pesticide exposure. This study confirms the reports from Sweden and several US states that non-Hodgkin's lymphoma is associated with farm herbicide use, especially phenoxyacetic acids. It does not confirm the case-control studies or the cohort studies of pesticide manufacturers and Vietnam veterans linking herbicides to soft-tissue sarcoma or Hodgkin's disease. [R99] *A 5 year old male child involved in an accidental ingestion of 2,4-D (Deherban A) (amount unspecified) /exhibited/ symptomatology /which/ included: drowsiness; unsteadiness; difficulties with speech; dilated pupils. On /the/ fourth day, toxic myocarditis with abnormal ECG, kidney damage indicated by increased blood urea levels but no liver damage /were noted/. Complete recovery /occurred/ within about one month. [R100] *A female suicide victim (age not specified or body weight) ingested an unknown quantity of 2,4-D. Symptomatology included: Loss of consciousness; vomiting; uterine bleeding; tachycardia and circulatory failure. Death occurred in about 30 hr. Edema and congestion of brain, fatty liver cell changes, fatty changes in kidney tubules pulmonary hyperemia and edema with isolated hemorrhages /were noted/. 2,4-D concentration in tissues was 20-116 mg/kg. [R101] *... /There is a report of a man who/ had no ill effect from oral doses of 500 mg/day (about 7 mg/kg/day) for 21 days ... /2,4-D form or formulation not specified/. [R91, 1324] *MAMMALIAN CYTOGENETICS - IN VITRO LEUKOCYTE OR LYMPHOCYTE STUDIES, HUMAN: POSITIVE. [R102] *The results of some epidemiological studies have suggested an association between exposure to phenoxy herbicides and increased incidences of malignant tumors and tumor mortality. It is not clear, at present, whether this represents a true association, and if so, whether it is specifically related to 2,4-D. [R103] *The ... human fibroblast cell line /VA-4/ ... /was treated with/ 2,4-D ... at 1, 10, 100, or 1000 uM for 1, 3, 5, 8, or 12 hr. Unscheduled DNA synthesis measured by (3H)-TdR incorporation and autoradiographic analysis was determined in cell cultures with and without rat (S9) metabolic activation. ... 2,4-D treated cultures had statistically significant increases ... at all concn tested. No metabolic activation was necessary for this effect. In addition ... at 1, 10, and 100 uM, 2,4-D induced 0.7, 1.1, and 1.3 breaks per 1X10+8 daltons DNA, respectively. ... /SRP: Formulation not specified/ [R104] *During the field application of 2,4-D, several cases of illness were reported. Symptoms included burning sensation in the throat and chest, weakness, loss of appetite and weight, and slight albuminuria. [R42, 1991.377] *A patient receiving a single iv dose of 2000 mg 2,4-D sodium showed no clinical signs of toxicity, whereas 3600 mg was definitely toxic. [R105] *Short-term exposure: Contact of the material with the skin may cause a rash. ... 2,4-D can cause dermatitis on prolonged exposure. [R70, 1981.1] *The risk of soft tissue sarcoma following possible exposure to phenoxy acid herbicides was studied in 354,620 Swedish men, who were employed in agriculture or forestry according to a national census in 1960. This cohort was further divided into six subcohorts. The reference cohort encompassed 1,725,845 Swedish men employed in other industries. All persons were followed up in the cancer-environment register during the period 1961-79. A total of 331 cases of soft tissue sarcomas was observed in the study cohort and there were 1,508 cases in the reference group (relative risk 0.9; 95% confidence interval, 0.8-1.0). No subcohort of agricultural or forestry workers showed any significantly increased relative risk, nor was there any significant difference in relative risk between the subcohorts. Despite the greatly increased use of phenoxy acid herbicides from 1947 to 1970, no time related increase in the relative risk of soft tissue sarcoma was found in the total cohort or in any of the subcohorts. /Phenoxy acid herbicides/ [R106] *A number of men with malignant lymphoma of the histiocytic type and previous exposure to phenoxy acids or chlorophenols were observed and reported in 1979. A matched case-control study has therefore been performed with cases of malignant lymphoma (Hodgkin's disease and non-Hodgkin's lymphoma). This included 169 cases and 338 controls. The results indicate that exposure to phenoxy acids, chlorophenols, and organic solvents may be a causative factor for malignant lymphoma. Combined exposure of these chemicals seemed to increase the risk. Exposure to various other agents was not obviously different in cases and in controls. /Phenoxy acids and chlorophenols/ [R107] *A previous case-control study which used the occupational information available on the New Zealand Cancer Registry found that agricultural workers were at increased risk of developing non-Hodgkin's lymphoma. The findings are now presented for the second phase of the study which entailed interviewing 83 cases of non-Hodgkin's lymphoma registered under code 202 of the International Classification of Diseases together with 168 controls with other types of cancer and 228 general population controls. The findings for the two control groups were similar, and there were no significant differences between cases and controls regarding potential exposure to phenoxyherbicides (odds ratio= 1.4, 90% confidence limits 0.7-2.5, p= 0.26) or chlorophenols (odds ratio= 1.3, 90% confidence limits 0.6-2.7, p= 0.39). The odds ratio for fencing work, necessitating exposure to several potential risk factors including arsenic and sodium pentachlorophenate was 2.0 (90% confidence limits 1.3-3.0, p= 0.01). The odds ratio for employment in a meat works, necessitating potential exposure to 2,4,6-trichlorophenol and zoonotic viruses, was 1.8 (90% confidence limits 1.1-3.1, p= 0.04). There was a significant statistical interaction between the risks associated with these two activities, the odds ratio for involvement in both activities compared with involvement in neither being 5.7 (90% confidence limits 2.3-14.3, p= 0.03). /Phenoxyherbicides, chlorophenols, arsenic, and sodium pentachlorophenate/ [R108] *Phenoxyherbicides ... have been widely used in New Zealand for over 30 years. In the light of the Swedish studies reporting an association between exposure to phenoxyherbicides or chlorophenols and soft tissue sarcoma, a case-control study was undertaken that involved interviewing 82 subjects (cases) with soft tissue sarcoma and 92 controls with other types of cancer. For those potentially exposed to phenoxyherbicides for more than one day not in the five years before cancer registration, the estimate of relative risk was 1.3, with 90% confidence limits of 0.6-2.5. The comparable relative risk estimate for chlorophenol exposure was 1.5 with 90% confidence limits of 0.5-4.5. The discovery of cases in trichlorophenol manufacturing plants in the United States lended support to the Swedish findings, but further studies are needed to conclude whether human exposure to these chemicals truly increases the risk of soft tissue sarcoma. /Phenoxyherbicides or chlorophenols/ [R109] *In 1977 several patients were seen with soft-tissue sarcomas and previous exposure to phenoxy acids. This clinical observation resulted in a case referent (case control) study being undertaken which showed that exposure to phenoxy acids or chlorophenols, which are chemically related, gave a roughly six fold increase in the risk for this type of tumor. A further case referent study of soft tissue sarcomas has now been performed to confirm these earlier findings and also to obtain further information on the effects of different phenoxy acids. This new investigation gave an increase of the same magnitude in the risk for soft tissue sarcomas after exposure to phenoxy acids or chlorophenols, but this risk related also to exposure to phenoxy acids free from impurities, such as polychlorinated dibenzodioxins and dibenzofurans. /Phenoxy acids/ [R110] *The purpose of this cohort study is to shed further light on the potential carcinogenic effect indicated by a Swedish case control study of the 2,4-dichlorophenol and 4-chloro-ortho-cresol based phenoxy herbicides, unlikely to be contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. In the present study it was the intention to include all persons in manufacture of phenoxy herbicides in Denmark before 1982. The predominant product was MCPA and only a very limited /quantity/ of 2,4,5-T was processed in one of the two factories included in the study. ... 99% of the registered employees could be followed-up. ... Five cases of soft tissue sarcomas (STS) were observed among male employees in contrast to 1.84 expected cases. This result supports the Swedish observation of an increased risk of soft tissue sarcomas following exposure to phenoxy herbicides unlikely to be contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin. ... Seven cases of malignant lymphomas were observed among male employees in contrast to 5.37 expected does not support the Swedish observation of an excess risk. ... Among males thus employed 11 lung cancer cases were observed in contrast to 5.33 expected. /Phenoxy herbicides or 4-chloro-ortho-cresol/ [R111] *An earlier cohort study of Swedish railroad workers indicated a possible relationship between exposure to herbicides and an increased overall tumor morbidity and mortality. The cohort of 348 individuals has now been followed through October 1978. In this updated analysis of the causes of death among railroad workers, the observed number of tumor deaths was higher than expected, especially among individuals exposed in the earlier years of the study to both amitrol and phenoxy acids. No specific type of tumor predominated although there were three stomach and 3 lung cancers. ... /Amitrol and Phenoxy acids/ [R112] *A cohort of herbicide applicators was formed in 1972 from the personnel records of four main Finnish employers involved in chemical brushwood control. ... The cohort included 1971 male workers who had been exposed to chlorinated phenoxyacids for at least two weeks during 1955-1971. Forty-five individuals had died during the same period. Thus there were 1926 persons alive in the beginning of 1972 through 1980, and for cancer morbidity from 1972 through 1978. ... During the nine year prospective follow-up period ... 105 persons had died from natural causes versus 155 expected (observed/expected 0.68). ... The ... most common types of tumor ... lung and stomach ... cancers closely corresponded to the expected figures. ... When the ten year period of latency was taken into account there were no significant differences between the observed and expected figures although for some tumors greater numbers were found than expected: 9 cases of lung cancer (6.6 expected), 2 bladder tumors (0.9 expected) and 2 lip cancers (0.5 expected). ... After making allowance for 10 and 15 year periods of latency which restricted the relatively small number of person years even more, no incr of cancer mortality was uncovered. ... This study /did not/ ... allow any assessment of the soft tissue sarcoma risk because the number of persons having a sufficiently long latency period is too small. /Chlorinated phenoxyacids/ [R113] *WHEN INGESTED, HIGH CONCENTRATIONS OF CHLOROPHENOXY COMPOUNDS MAY IRRITATE THE MOUTH AND THROAT, AND GI TRACT. ... CHEST PAIN (FROM ESOPHAGITIS), ABDOMINAL PAIN AND DIARRHEA COMMONLY ENSUE. ... ABSORBED CHLOROPHENOXY COMPOUNDS HAVE CAUSED FIBRILLARY MUSCLE TWITCHING, SKELETAL MUSCLE TENDERNESS, AND MYOTONIA ... INGESTION OF VERY LARGE AMOUNTS HAS PRODUCED METABOLIC ACIDOSIS, FEVER, TACHYCARDIA, HYPERVENTILATION, VASODILATATION AND SWEATING. PARTICULAR CASES HAVE BEEN CHARACTERIZED BY COMA AND CONVULSIONS. /CHLOROPHENOXY COMPOUNDS/ [R114] *IN THREE HUMAN BEINGS, ABSORPTION OF AN UNSPECIFIED ESTER OF DICHLOROPHENOXYACETIC ACID THROUGH SKIN CAUSED POLYNEURITIS, BUT WITH NO DISTURBANCE OF EYES OR VISION. [R115] *SUBJECTIVE CLINICAL SYMPTOMS REPORTED AMONG WORKERS USING VARIOUS ESTERS AND SALTS OF 2,4-D INCL RAPID FATIGUE, HEADACHE, LOSS OF APPETITE AND PAIN IN THE REGION OF THE LIVER AND STOMACH. SENSITIVITY TO TASTE AND SMELL WAS LOWERED. /2,4-D ESTERS AND SALTS/ [R116] *The chlorophenoxy herbicides have produced contact dermatitis in man ... . /Chlorophenoxy compounds/ [R117] *IN THE BODY, THE ... ESTERS OF CHLOROPHENOXY COMPOUNDS ARE HYDROLYZED FAIRLY RAPIDLY SO THAT THE MAMMALIAN TOXICITY OF EACH COMPOUND DEPENDS MAINLY ON THE ACID INVOLVED. /CHLOROPHENOXY HERBICIDES/ [R118, 521] *RESULTS OF SINGLE COHORT STUDY OF SMALL NUMBER OF WORKERS EXPOSED TO VARIOUS HERBICIDES, INCL 2,4-D ... ARE NOT SUFFICIENT TO EVALUATE CARCINOGENICITY OF 2,4-D TO MAN ... EPIDEMIOLOGICAL STUDIES ARE GENERALLY CONFOUNDED BECAUSE OF THE COEXPOSURE TO OTHER CHEMICALS EG 2,4,5-T WHICH ALSO HAS 2,3,7,8-TCDD AS A CONTAMINANT. /SRP: SPECIFIC SALT OR ESTER NOT SPECIFIED/ [R119] *The possibility that exposure to Agent Orange or phenoxy herbicides may have increased risk of soft tissue arcomas has been of genuine concern to Vietnam veterans and their families. A hospital-based case comparison group study was undertaken to examine, through a comprehensive review of medical records and military personnel records the association between previous military service in Vietnam and soft tissue sarcomas. The case group comprised 234 Vietnam-era veteran patients who served in the US military between 1964 and 1975 and were treated in one of the 172 VA hospitals between 1969 and 1983 with a diagnosis of soft tissue sarcomas. The comparison group consisted of 13,496 patients who were systematically sampled from the same Vietnam-era veteran patient population from which the cases were drawn. Military service information, in particular Vietnam service status, for each case and control patient was obtained from a review of the patient's military personnel records archived at the National Personnel Records center in St Louis, Missouri. No significant association of soft tissue sarcomas and previous military service in Vietnam was observed: odds ratio was 0.83 with a 95% confidence interval of 0.63 to 1.09. [R120] *Vietnam veteran risks for fathering babies with major structural birth defects were assessed using a case-control study. Information regarding military service in Vietnam was obtained from interviews with mothers and fathers of babies in case and control groups and from review of military records. Vietnam veterans, in general, did not have an increased risk of fathering babies with defects (all types combined; relative risk estimate, 0.97). Vietnam veterans who had greater estimated opportunities for Agent Orange exposure did not seem to be at greater risk for fathering babies with all types of defects combined. However, for a few specific types of defects the estimated risks were higher for subgroups of Vietnam veterans that may have had a greater likelihood of exposure to Agent Orange. These seemingly higher risks could be chance events, the result of some experience in the Vietnam service of the father, or the result of some other unidentified risk factor. [R121] *A suicide attempt by a 30.2 kg female (age not specified) who had ingested 100 ml herbicide (13.6 g 2,4-D) ... excretion of 2,4-D initially slowed by competitive excretion of dicamba, small amounts of 2,4-D still excreted 3 weeks after ingestion, only 52% of ingested 2,4-D excreted in urine, rest assumed to have been excreted by fecal route; Plasma clearance half-life = 59.2 hr initially, and 16.7 hr after most of the dicamba was excreted. [R122] HTOX: *A male suicide victim 26 years of age ingested a mixture of 360 ml 2,4-D and mecoprop amine salt (10.6%, 11.6% ai) and 360 ml chlorpyrifos in kerosene (6.7% ai) plus few granules of warfarin (0.025% ai, 2,4-D= 600 mg/kg bw; Mecoprop= 600 mg/kg) symptomalogy included: Coma with pin-point pupils; tachycardia; hypertension; myoclonus; diarrhea; then hypotension; cardiac arhythmias; asystole; and death after 30 hr. Plasma 2,4-D concentrations were 321 mg/kg at 1.6 hr, 540.9 mg/kg at 21 hr, 480.8 mg/kg at 30 hr. Urinary concentration (on admission) was 230.3 mg/kg, gastric content (on admission) was 108.2 mg/kg, tissue (post-mortem) was: brain, 186.4 mg/kg; blood, 389.5 mg/kg; liver, 293.5 mg/kg; heart, 301.2 mg/kg; and kidney: 315.0 mg/kg. /2,4-D, mecoprop amine salt, chloropyrifos and warfarin/ [R123] *This study group included 57 male subjects, 32 being farmers who were exposed to 2,4-dichlorophenoxyacetic acid, and 25 nonexposed referents. Contact with the herbicide was either by the oral route, by inhalation or by skin contact. The mean value of 2,4-dichlorophenoxyacetic acid in the urine samples of exposed farmers was 9.02 mg/l. In the unexposed group the subjects had no detectable concns of 2,4-dichlorophenoxyacetic acid in their urine samples. Significant differences were demonstrated in spermatozoon anomalies among the individuals exposed to the chemical. The % of asthenospermia, mobility, necrospermia and teratospermia were greater in the exposed group than in the referents. There was no significant difference between the sperm volume of the exposed subjects and that of the referents. Following a short recovery period asthenospermia, motility and necrospermia disappeared while teratospermia remained. [R124] *In light of findings suggesting an increase in the risk for non-Hodgkin's lymphoma among men exposed to phenoxyherbicides and concerns among veterans over Agent Orange exposure, a hospital based case-control study was undertaken to examine the association between military service in Vietnam and non-Hodgkin's lymphoma. The cases consisted of 201 Vietnam era veteran patients who were treated in one of 172 Department of Veterans Affairs hospitals from 1969 through 1985 with a diagnosis of non-Hodgkin's lymphoma. 358 Vietnam era veteran patients with a diagnosis other than malignant lymphoma served as a comparison group. Military service information was obtained from a review of the veteran's military personnel records. Service in Vietnam did not increase the risk of non-Hodgkin's lymphoma either in general (branch adjusted odds ratio = 1.03, 95% confidence interval = 0.70-1.50) or with increased latency period as defined as the duration in years from first service in Vietnam to hospital discharge. Surrogate measures of potential Agent Orange exposure such as service in a specific military branch, in a certain region within Vietnam, or in a combat role as determined by military occupational speciality were not associated with any increased risk of non-Hodgkin's lymphoma. [R125] *The incidence of non-Hodgkin's lymphoma was examined in a cohort of 18,313 United States Army veterans from the Vietnam era. Diagnoses were confirmed through a review of hospital records. Among veterans who had died after discharge or who had participated in a telephone interview (8170 Vietnam veterans and 7564 non-Vietnam veterans), seven Vietnam veterans and one non-Vietnam veteran had developed non-Hodgkin's lymphoma (p = 0.07). As none of the non-Hodgkin's lymphoma cases had military job titles which suggest that they were occupationally exposed to herbicides while in Vietnam, the reasons for the excess are unclear. [R126] *Consideration of the combined cohort studies of workers exposed to the phenoxy herbicides per se provides little or no evidence of carcinogenicity. Thus, the total weight of evidence currently available does not support a conclusion that the phenoxy herbicides present a carcinogenic hazard to humans. [R127] *The occurrence of malignant lymphomas and soft tissue sarcomas were investigated in an Italian community where phenoxy herbicides have been extensively used. Some of the herbicides employed included 2,4-dichlorophenoxyacetic acid, and 2,4,5-trichlorophenoxyacetic acid, and their propionic derivatives along with 4-chloro-2-methylphenoxyacetic acid. Phenoxy herbicides have been used in rice weeding in the area since 1950. Thorough searching revealed 43 cases of Hodgkin's disease, 141 cases of non-Hodgkin's lymphoma, and 30 cases of soft tissue sarcoma in men and 20 cases of Hodgkin's disease, 112 cases of non-Hodgkin's lymphoma and 19 cases of soft tissue sarcoma in women. Soil and water analysis in 1974 and 1975 revealed contamination with 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid the propionic derivative of it. Repeat analyses for the current study were conducted. The incidence rate of the disease was clearly increased among males living in areas where phenoxy herbicides were measurable as environmental contaminants. The incidence of disease was markedly greater in municipalities along the canal with higher levels of contamination. /2,4-D and 2,4,5-T and 4-Chloro-2-methylphenoxyacetic acid/ [R128] *Isolated case reports have circumstantially linked the use of the herbicide 2,4-dichlorophenoxyacetic acid to polyneuropathy. However, a critical review of the literature reveals numerous reasons for doubting a relationship of 2,4-dichlorophenoxyacetic acid to polyneuropathy: (1) too few cases given the wide use of the chemical; (2) no valid toxicologic or epidemiologic evidence; (3) the diversity of antecedent illness; (4) an unlikely time sequence of antecedent illness to exposure (pharmacokinetics); (5) the lack of polyneuropathy in medical patients given repetitive doses of 2,4-dichlorophenoxyacetic acid; (6) the lack of polyneuropathy in heavily exposed military personnel involved in operation Ranch Hand; (7) the biological properties of 2,4-dichlorophenoxyacetic acid which minimize penetration of 2,4-dichlorophenoxyacetic acid into the nervous system under normal exposure conditions; and (8) the lack of polyneuropathy in a variety of experimental animal species given 2,4-dichlorophenoxyacetic acid by several routes of exposure and at dose levels and durations of exposure many times greater than human applicator exposure. Thus, the weight of evidence indicates that 2,4-dichlorophenoxyacetic acid is an unlikely cause of polyneuropathy. [R129] *One case of acute poisoning from accidental inhalation has been reported. It involved transient loss of consciousness, urinary incontinence, and vomiting followed by myalgia, muscular hypertonia, fever, headache, and constipation. the most interesting feature was intermittent nodal tachycardia, which, along with the muscular hypertonia, gradually subsided during the admin of quinidine. [R91, 1323] *A 39-yr old male farmer who sustained excessive exposure to 2,4-D while spraying crops developed a primary sensory peripheral neuropathy 4 days after exposure. Electromyographic and peroneal nerve conduction studies were within normal limits. Symptoms improved, but the patient continued to complain of intermittent numbness of the hands after prolonged use. [R130, 1065] *Cohort members were male employees of The Dow Chemical Company who manufactured or formulated 2,4-D any time from 1945 to the end of 1994. Their mortality experience was compared with national rates and with more than 40 000 other company employees who worked at the same location. 330 Deaths were observed among 1517 people compared with 365 expected (standardised mortality ratio (SMR)=0.90, 95% confidence interval (95% CI) 0.81 to 1.01). There were no significantly increased SMRs for any of the causes of death analyzed. When compared with the United States rates, the SMR for non-Hodgkin's lymphoma (NHL) was 1.00 (95% CI 0.21 to 2.92). The internal comparison with other Dow employees showed a non-significant relative risk of 2.63, (95% CI 0.85 to 8.33). Death was attributed to amyotrophic lateral sclerosis (ALS) for three cohort members. Compared with the other company employees, the relative risk was 3.45 (95% CI 1.10 to 11.11). The cases were employed in the manufacture or formulation of 2,4-D at different periods (1947-9, 1950-1, and 1968-86), and for varying durations of time (1.3, 1.8, and 12.5 years). [R131] *The effects of exposure to different concns of phenoxyherbicides and their metabolites were studied in human erythrocytes, with particular attention to catalase (CAT-EC. 1.11.1. 6- hydrogen peroxide: hydrogen peroxide oxidoreductase). 4-chloro-2-methylphenoxyacetic acid (MCPA), 2,4-dimethylphenol (2, 4-DMP) and 2,4-dichlorophenoxyacetic acid (2,4-D) did not affect CAT activity, but 2,4-dichlorophenol (2,4-DCP) and 2,4,5-trichlorophenol (2,4,5-TCP) decr its activity, the latter being the more inhibitory. [R132] *These studies further indicated that this crop growing area used more chlorophenoxy herbicides and fungicides than elsewhere in Minnesota. Based on frequency of use and known biology, certain herbicides, pesticide additives, fungicides, and mycotoxins are suspect agents. To define whether these agents affect developmental endpoints in vitro, 16 selected agrochemicals were examined using the MCF-7 breast cancer cell line. In the flow cytometric assay, cell proliferation in this estrogen-responsive cell line indicates xenobiotic-mediated estrogenic effects. Cell viability, morphology, ploidy, and apoptosis were incorporated in this assay. Data showed that the adjuvants X-77 and Activate Plus induced significant cell proliferation at 0.1 and 1 microg/ml. The commercial-grade herbicides 2,4-D LV4 and 2,4-D amine induced cell proliferation at 1 and 10 microg/ml. The reagent-grade 2,4-D products failed to induce proliferation over the same concentration range, suggesting that other ingredients in the commercial products, presumably adjuvants, could be a factor in these results. The fungicides triphenyltin and mancozeb induced apoptosis at concentrations of 4.1 microg/ml (10(-5) M) and 50 microg/ml, respectively. Triphenyltin also induced aneuploidy (C2/M arrest) at 0.41 microg/ml (10(-6) M). [R133] *Adjuvants in the formulations may have contributed to some of the features observed. Vomiting, abdominal pain, diarrhea, and, occasionally, gastrointestinal hemorrhage were early effects. When present, hypotension was predominantly due to intravascular volume loss, although vasodilation and direct myocardial toxicity may have contributed in some cases. Neurotoxic features included coma, hypertonia, hyperreflexia, ataxia, nystagmus, miosis, hallucinations, convulsions, fasciculation, and paralysis. Hypoventilation occurred not infrequently, usually in association with central nervous system depression, but respiratory muscle weakness was a factor in the development of respiratory failure in some patients. Myopathic symptoms including limb muscle weakness, loss of tendon reflexes, and myotonia were observed and increased creatine kinase activity was noted in some cases. Other clinical features reported included metabolic acidosis, rhabdomyolysis, renal failure, increased aminotransferase activities, pyrexia, and hyperventilation. Twenty-two of 66 patients died. [R134] *A first patient, aged 51 years, had attempted to commit suicide by taking orally 400 ml of a 40% solution of 2,4-D. He was admitted in a coma, 6.5 h after poisoning. Extracorporal hemodialysis was performed and the course of the illness was satisfactory. The second patient, aged 80 years, had accidentally drunk 100 ml of a 40% solution of 2,4-D. He was admitted in a coma a few hours after poisoning. Hemodialysis and resin hemoperfusion were performed and the course of the illness was satisfactory. Prior to the above therapy the patient had a 2,4-D serum concentration of 177 mg/100 ml. 2,4-D clearance was 56.3 ml/min during this therapy. The third patient, aged 24 years, had drunk 200 ml of a 40% solution of 2,4-D in a suicide attempt, and paraquat poisoning was also suspected. He was admitted 10 h after poisoning and immediately hemodialysis and hemoperfusion were carried out: the course of the illness was satisfactory. On admittance the concentration of 2,4-D in serum was 122.5 mg/100 ml, and clearance was 72.9 ml/min during treatment. The fourth patient, aged 50 years, had accidentally drunk 100-200 ml of a 40% solution of 2,4-D. He was admitted in a coma 3 h after poisoning. Hemodialysis was performed and the course of the illness was satisfactory. On admittance the concentration of 2,4-D in serum was 37 mg/100 ml and clearance was 68.7 ml/min. [R135] NTOX: */2,4-D FREE/ ACID WAS ORALLY ADMIN TO 2 MULE DEER DOES DAILY FOR 30 DAYS. ONE SURVIVED 80 MG/KG/DAY AND THE OTHER 240 MG/KG/DAY; THEY SHOWED ONLY SLIGHT TOXIC EFFECTS, BUT NO WT LOSS. ... GASTROINTESTINAL AND ENDOCARDIAL HEMORRHAGES WERE SEEN AT NECROPSY. LC50 RAT FISCHER-344 MALE ORAL 443 MG/KG (95% CONFIDENCE LIMITS 270-1103 MG/KG) (2,4-D ACID IN CORN OIL). [R136] *Monkeys tolerated 214 mg/kg without serious effect. ... Large doses of 2,4-D quickly kill animals, apparently through ventricular fibrillation. At lower doses, when death is slow, various signs of muscular involvement, including myotonia, stiffness of the extremities, ataxia, paralysis, and coma, are seen; this is accompanied by a reduction in body temperature and metabolic rate. Repeated admin at levels that may or may not lead to death results in anorexia, loss of weight, vomiting, depression, roughness of coat, and general tenseness and muscular weakness. ... Repeat admin at dietary levels of 3000 ppm or more was found lethal to rats, whereas 1000 ppm was tolerated longer. A level of 1000 ppm for 113 days caused depressed growth, incr mortality, and slight incr in liver weight. A dietary level of 300 ppm (about 15 mg/kg/day) for 113 days caused no clinical, lab, or histological changes. [R91, 1319] *YOUNG ADULT FEMALE RATS WERE GIVEN ORAL DOSES OF 2,4-D IN OLIVE OIL AT 0, 3, 10, 30, 100 and 300 MG/KG 5 TIMES A WK FOR 4 WK. ... DEPRESSED GROWTH RATES, LIVER PATHOLOGY, AND GI IRRITATION OCCURRED AT 300 MG/KG. [R2, 496] *IN DOGS, TOXIC SYMPTOMS WERE OFTEN NOT PRESENT UNTIL 6 HR AFTER ORAL ADMIN OF LETHAL DOSE OF 2,4-D; THE ANIMALS BECAME ATAXIC WITH PROGRESSIVE INCR SPASM. DEATH APPEARED TO BE DUE ... TO HEPATIC CONGESTION OR ... PNEUMONIA. PATHOLOGICAL CHANGES, LIMITED TO THE GI TRACT, LUNG AND LIVER, FOLLOWED BY DEVELOPMENT OF ANOREXIA, WT LOSS AND MYOTONIA. DOGS EXHIBITED EVIDENCE OF LIVER DAMAGE MORE FREQUENTLY THAN OTHER ANIMALS STUDIED. [R137] */ORAL ADMIN OF LD50 DOSE OF TECHNICAL GRADE 2,4-D ACID (> 99%) TO MALLARD DUCKS, JAPANESE QUAIL, PHEASANTS, CHUKAR AND ROCK DOVES PRODUCED THE FOLLOWING/ SIGNS OF INTOXICATION: POLYDIPSIA; ATAXIA; IMBALANCE; SLOWNESS; FLUFFED FEATHERS; TACHYPNEA; TREMORS; PROSTRATION; PTOSIS; AND SALIVATION. [R136] *... In rats ... /given/ doses of 0.5-1.0 mg/kg ... /2,4-D was observed to be/ highly embryotoxic. ... /When/ rats /were injected/ with one-twentieth LD50 on the 4, 5, 6, 9, 11, 12, 13, 14 and 15th day of pregnancy ... strong embryotoxic effects /were observed/. [R138, 194] *... RATS /WERE GIVEN/ UP TO 87.5 MG/KG ON DAYS 6 THROUGH 15 OF GESTATION. WITH DOSES ABOVE 25 MG/KG SC EDEMA, WAVY RIBS, DELAYED OSSIFICATION AND LUMBAR RIBS WERE OBSERVED. [R138, 193] *ADMIN OF 2,4-D ... ORALLY OR SC DURING DAYS 6-14 OF PREGNANCY INCR INCIDENCE OF FETAL ANOMALIES AMONG BL6, AKR AND/OR C3H STRAINS OF MICE, BUT NOT AMONG B6AK AND A/Ha STRAINS. PURITY OF CMPD ... 90%, MP 136-140 DEG C ... [R139] *... 2,4-D AT 221 MG/KG/DAY INCR FETAL MORTALITY, BUT PRODUCED NO CLEFT PALATES /IN CD-1 MICE/. ... /IN ANOTHER STUDY/ ... TERATOGENIC AND EMBRYOTOXIC EFFECTS IN NMRI MICE THAT RECEIVED 50 OR 110 MG/KG INJECTIONS OF 2,4-D ON DAYS 6-14 OF GESTATION /WERE OBSERVED/. [R2, 497] *WHEN 2,4-D WAS ADMIN AT CONCN OF 500 MG/KG OF DIET DURING ENTIRE PREGNANCY OF A SOW, ANOREXIA WAS NOTED; NEWBORN PIGLETS WERE UNDERDEVELOPED AND APATHETIC AND 10/15 DIED WITHIN 24 HR. CONTINUED FEEDING OF 50 MG/KG OF DIET TO SURVIVORS UNTIL ... 8 MO OF AGE CAUSED GROWTH DEPRESSION, PERSISTENT ANEMIA, AND MODERATE DEGENERATIVE CHANGES OF LIVER AND KIDNEYS. [R139] *GROUPS OF 25 MALE AND 25 FEMALE 3 WK OLD OSBORNE-MENDEL RATS WERE FOR 2 YR FED ON DIETS CONTAINING 0, 5, 25, 125, 625 OR 1250 MG/KG OF DIET 2,4-D. 2,4-D WAS 96.7% PURE AND CONTAINED NO DETECTABLE LEVELS OF 2,7-DICHLORO- OR 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ... . NUMBERS OF MALE AND FEMALE RATS WITH MALIGNANT TUMORS WERE 6 IN CONTROLS AND 8, 7, 7, 8 and 14 IN THE TREATED GROUPS, RESPECTIVELY. TUMORS WERE RANDOMLY DISTRIBUTED AND WERE ALSO FOUND IN AGING RATS OF THIS STRAIN. ... A STATISTICAL INCR (P < 0.05) IN NUMBER OF TREATED RATS WITH MALIGNANT TUMORS OVER CONTROLS WERE FOUND ONLY IN MALES RECEIVING ... 1250 MG/KG. [R140] *2,4-D INDUCED CHROMOSOME ABERRATIONS IN NUMBER OF CULTIVATED PLANTS AND WEEDS. CYTOLOGICAL ABNORMALITIES INCL CHROMOSOME BRIDGES, FRAGMENTS, LAGGING CHROMOSOMES, C-MITOSES AND CHROMATIN BODIES. [R141] *SACCHAROMYCES CEREVISIAE STRAIN D4 5 X 10(+6) WAS TREATED WITH 2 ML OF AQUEOUS 2,4-D SUSPENSION (TRADE NAME, U46D-FLUID). THE MITOTIC GENE CONVERSION FREQUENCY OF THE ADE 2 LOCUS WAS INCR 5-FOLD ABOVE CONTROL VALUES; THAT OF THE TRP 5 LOCUS WAS INCR 6-FOLD ABOVE CONTROL VALUES. [R2, 496] *IN RECESSIVE LETHAL TEST, ADULT MALE DROSOPHILA WERE TREATED WITH 2,4-D IN SUBSTRATE FOR 2 WK AND THEN MATED WITH UNTREATED FEMALES. RECESSIVE LETHALS WERE PRESENT AT RATE OF 0.25% OF COMBINED F1 AND F2 GENERATIONS. [R142] *2,4-D does not appear to be a cumulative toxicant in most species, although low doses may be cumulative in the dog. Oral doses of 100 mg/kg were lethal in the rat when admin for 10 consecutive days, but not when admin 5 days per week for 4 weeks. Daily doses of 75 mg/kg or lower produced no toxic effects. [R143] *The effects of 2,4-D treatment in vitro on bovine fetal muscle cells were examined histologically. Limb muscles from 2.5-4.5 month fetuses were cultured as cell suspensions for 1 day and then aliquots of cells were cultured in the presence of 2 or 20 mg/l 2,4-D (99.6% purity). After a 24-96 hr culture, cell counts were taken. ... The numbers of metaphase cells, polyploid cells and degenerating cells were higher in cells treated with either concn of 2,4-D than in control cells. Abnormalities of treated cells included unipolar and tripolar spindles of mitotic cells, malorientation of the mitotic apparatus and mitosis of myoblasts undergoing myogenesis. /It was/ concluded that 2,4-D exerted a mitostatic effect on dividing cells and a mitogenic effect on postmitotic myogenic cells. [R144] *The effects of 2,4-D on egg hatching and early development through the prezoeal stage /of the Dungeness crab/ were measured in a 24 hr toxicity test. Duplicate beakers of 3,300, 10,000, 33,000, 100,000 or 330,000 ug/l 2,4-D each received 30 eggs. At the highest dose tested, 2,4-D inhibited egg hatching (1/58 eggs hatched). At 100,000 ug/l less than 20% of the hatching prezoeae developed into the first zoeae stage and motility was inhibited. ... In 80 day long term toxicity assays, 2,4-D decreased survival of larvae ... at the highest dose tested, 10,000 ug/l. ... Exposure to ... 2,4-D increased the duration of larval stages. In juvenile crabs and in adults, no effects of 2,4-D were observed up to doses of 10,000 ug/l. ... The larval stage was most sensitive to 2,4-D. ... The maximum acceptable toxicant concentration (MATC) was below 1,000 ug/l for 2,4-D free acid. [R145] *... Effects of acute and sub-acute admin of 2,4-D on the electroencephalographic activity and conditioned reflex responses of 24 rats, 4 cats and 2 dogs. ... Administration of /200 mg/kg/ ip only once in the acute experiments and once daily until death in the sub-acute experiments /were investigated/. ... Response to a previously learned and reinforced conditioned reflex (sound and electric shock) was measured in animals treated with 2,4-D for 5 consecutive days. In acute experiments, EEG recordings revealed an inhibition of desynchronization within 15 min of admin. ... In the sub-acute experiments, EEG measurements revealed a gradual decrease in the frequency of spontaneous electrical activity. In addition, the duration of desynchronization decreased as the 2,4-D treatment continued. By the fifth day no desynchronization was evident. Response to a previously learned conditioned reflex also decreased steadily with continued 2,4-D treatment. All response to the conditioned reflex was lost by the fifth day of treatment. Histologic examination of the spinal cord showed demyelinization of the pyramidal tract. [R146] *... Male Sprague-Dawley rats were admin subcutaneous doses of 2,4-D in aqueous solution daily. Body weights, organ weights, and thyroid function tests were carried out. Statistically significant effects of 7 daily doses of 80 mg/kg 2,4-D on thyroid function included increased (131)Iodine uptake over 24 hr and decreased serum protein-bound iodine levels. ... [R147] *Alterations in several enzymes involved in energy production were measured in muscles of rats after 2,4-D admin. Doses of 100 mg/kg of 2,4-D in aqueous sodium bicarbonate solution were admin ip to rats daily for 14 days. Controls were given sodium acetate. Myocardium, soleus (red muscle), and semimembranous (white muscle) samples were removed, homogenized, and the supernatent after centrifugation (separated by polyacrylamide gel electrophoresis) and the stained bands were quantitated by densitometry. The total lactate dehydrogenase activity was not altered in any muscles by 2,4-D treatment. The density of the isoenzyme band, lactate dehydrogenase 5 was elevated significantly in the semimembranous of treated rats while lactate dehydrogenase 4 was decreased. The lactate dehydrogenase 5 band for the M soleus muscle was increased in density while the lactate dehydrogenase 1, 3, and 4 bands were decreased after treatment. Myocardial lactate dehydrogenase 4 and 5 decreased while lactate dehydrogenase 1 increased after trH subunits, calculated from the proportions of each lactate dehydrogenase isoenzyme were significantly elevated in myocardium and decreased in the other two muscles after 2,4-D treatment. Malate dehydrogenase activity decreased in all three myotonic muscles, with the largest change in myocardium. [R148] *The cytogenetic effects of 2,4-D in mice were examined. Male outbred white mice (18-20 g; 6 mice per dose level) received a single oral dose of 10, 50, 100 or 300 mg 2,4-D/kg body weight. Ten control mice were also included in the study. Mice were killed 20 hr after admin of the herbicide. Chromosome spreads were prepared and 200 metaphases per animal were scored. Increased chromosome aberrations were observed only at the toxic doses of 100 and 300 mg/kg. Single acentric fragments were the most common form of chromosome damage; Paired fragments occurred much less frequently; And translocations were rare. From these results the /it was/ concluded that 2,4-D is a weak mutagen in mice. [R149] *The acute and chronic toxicity of 2,4-D was studied in sheep. Single doses of 200-900 mg/kg 2,4-D sodium salt were admin per-orally to sheep. Other sheep were admin 120 daily doses of 18 mg/kg 2,4-D amine salt orally. Mortality and clinical signs were recorded and hematological and biochemical blood tests were performed. A dose of 900 mg/kg killed all sheep. Clinical signs of intoxication occurred after doses of 500 mg/kg or greater and included general weakness, ataxia, immobility, muscular paralysis of the hind legs, difficulty in breathing, sensitivity to light, and lack of appetite. Death occurred 2-4 days after exposure. Fluctuations in both directions occurred during the first month for the erythrocyte count, leukocyte counts, hemoglobin levels, blood nitrogen levels, and "alkaline reserve" (no further explanation given for this parameter). No traces of 2,4-D, admin as a single dose of 300-400 mg/kg of the amine or sodium salt, were detected 12 days after exposure (no other methodology was reported for this experiment). /It was/ concluded that meat from sheep was safe for human consumption 12 days after sheep had ingested 2,4-D and that 2,4-D was a compound of moderate toxicity. /SRP: Sodium salt/ [R150] *... 2,4-D is carcinogenic in male and female rats. ... Ingesting 2,4-D developed incr incidences of malignant neoplasms. Lymphosarcomas were incr in rats of both sexes, and /also/ neoplasms of the mammary gland in female rats. Male rats also had carcinomas of the endocrine organs ... also ... promotes neoplasms of the skin in mice. ... Also mutagenic and teratogenic in animals ... . [R151] *Complete mortality was observed within 31 hr among Bacillus calyciflorus exposed to 5.0 ppm, 2,4-D. Higher concn of 2,4-D were lethal to Daphnia lumholtzi, the entire /fish food organism/ population dying in 20 ppm concn at 31 hr. [R152] *... 2,4-D acid (20-80 mg/kg) when given by gavage twice weekly for 5 weeks /in male Fischer-344 rats/ ... produced a significant incr in fore- and hindlimb grip strength. Other neurological measurements such as ... motor activity and startle responsiveness were not affected. [R153] *... 2,4-D at a dosage of 500 mg/l stimulated the proliferation of the heterotrophic bacterial community present in the water of three fish ponds over a period of one yr. [R154] *DNA REPAIR-DEFICIENT BACTERIAL TESTS: POSITIVE. [R155] *ESCHERICHIA COLI WP2 - REVERSE MUTATION STUDIES WITH METABOLIC ACTIVATION: NEGATIVE. [R155] *CHINESE HAMSTER LUNG (V79) CELLS IN CULTURE - GENE MUTATION, HPRT LOCUS STUDIES: POSITIVE. [R155] *MAMMALIAN CYTOGENETICS - IN VIVO BONE MARROW STUDIES, NON-HUMAN: POSITIVE. [R155] *INTRODUCTION OF SATURATION LEVELS OF ... ARTIFICIAL AUXINS /INCLUDING 2,4-D/ INTO DELICATE HORMONAL BALANCE OF GROWING PLANT CAUSES PROFOUND CHANGES IN NORMAL GROWTH PATTERN. [R156] *PURE 2,4-D ACID AT 100 PPM CAUSED SLIGHT MORTALITY FOR FINGERLING BREAM AND LARGEMOUTH BASS. SOME FORMULATIONS OF 2,4-D ARE RELATIVELY TOXIC TO FISH AND SHOULD NOT BE INTRODUCED INTO AQUATIC ENVIRONMENTS UNLESS SPECIFICALLY RECOMMENDED ON LABEL. ACUTE TOXICITY: ACUTE ORAL LD50 OF VARIOUS FORMULATIONS FALL IN RANGE OF 300-1000 MG/KG FOR RATS, GUINEA PIGS, AND RABBITS ON WT BASIS. TOXICITY TO CATTLE APPEARS TO BE QUITE SIMILAR TO THAT OF LABORATORY ANIMALS. CHRONIC TOXICITY: RATS (2-YR) 1250 PPM IN DIET--NO EFFECT. DOGS (2 YR) 500 PPM IN DIET--NO EFFECT. [R69, 133] *Teratogenic and reproductive effects: The no-observed-adverse-effect /level/ of 2,4-D in mammals and birds appears to be about 10 mg/kg bw/day. [R157] *Mutagenic effects: Studies available at present are not adequate for the quantitive evaluation of the mutagenic effects of 2,4-D and its derivatives in short-term tests. However, the evidence does not suggest that 2,4-D derivatives are potent mutagens. [R157] *2,4-D was evaluated using the Chernoff/Kavlock in vivo teratology screen procedure. End points analyzed as part of this assay were maternal toxicity and early postnatal growth/viability of offspring. Thirty pregnant CD-1 mice were given 87.5 mg/kg/day 2,4-D on days 8-12 of gestation and allowed to deliver. Forty vehicle treated animals served as controls. 2,4-D caused 7% mortality among the treated females and reduced the birth weights of pups born to surviving animals when compared with controls. [R158] *2,4-Dichlorophenoxyacetic acid (2,4-D) was injected intraperitoneally into adult male Fischer rats for 3-12 weeks. During the period of study gait and toe spreading reflexes remained normal and distal motor latencies, motor and mixed nerve conduction velocities, and amplitudes remained similar (p > 0.05) in animals receiving 2,4-D or vehicle which suggests that 2,4-D is not toxic to peripheral nerves in the rat. [R159] *Experimentally, 2,4-D affects cerebral electrical activity. ... 200 mg/kg of 2,4-D ip either in single or repetitive daily doses to rats, cats, and dogs ... /produced/ changes in the electroencephalogram pattern and in conditioned reflexes. ... 2,4-D protects mice genetically predisposed to audiogenic seizures. The effective dose (ED50) for seizure protection is 75 mg/kg or about half the dose producing myotonia. [R160] *The percent of fathead minnows that survived a particular concn of 2,4-D increased with increasing pH. At a concn of 7.43 mg/l, 60% of the fish survived in 192 hr at pH 7.6, whereas 100% survived at pH 9.8. Normal schooling behavior was completely disrupted and the equilibrium was lost after 24 hr exposure to 7.43 mg/l at pH 7.6, whereas neither character was affected even after 192 hr exposure to this concn at a higher pH (8.68 or 9.08). The reduction in toxicity of 2,4-D is due to a greater amt of dissociation in higher pH. [R161, p. V2 18] *The hematocrit values in bluegills from ponds treated with 10 mg/l 2,4-D were above normal for 3 days, but returned to normal 7 days after spraying. [R161, p. V2 76] *Testicular DNA synthesis inhibition mice 29% at 200 mg/kg /SRP: Unspecified salt or ester of 2,4-D/ [R72, 497] *GROUPS OF MALE C57BL/6 MICE WERE GIVEN FEED CONTAINING VARIOUS CONCN OF 2,4-D, 2,4,5-TRICHLOROPHENOXYACETIC ACID, and 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN TO PROVIDE DAILY DOSES OF APPROX 40 MG/KG 2,4-D, 40 MG/KG 2,4,5-TRICHLOROPHENOXYACETIC ACID , and 2.4 MG/KG 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (GROUP II); 40 MG/KG 2,4-D, 40 MG/KG 2,4,5-TRICHLOROPHENOXYACETIC ACID , and 1.2 MG/KG 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (GROUP III); and 20 MG/KG 2,4-D, 20 MG/KG 2,4,5-TRICHLOROPHENOXYACETIC ACID AND 1.2 MG/KG 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN (GROUP IV). THE CHEMICAL MIXTURES WERE CHOSEN TO APPROXIMATE THE CONCENTRATIONS OF THE COMPONENTS OF THE HERBICIDE AGENT ORANGE. CONTROLS (GROUP I) WERE ADMIN A DIET WITH ONLY THE CORN OIL VEHICLE ADDED TO THE FEED. IN TREATED ANIMALS, LIVER ENLARGEMENTS, HEPATOCELLULAR TOXICITY, AND REDUCED THYMUS SIZE WERE FOUND AND BODY WEIGHT GAIN WAS SIGNIFICANTLY LESS THAN CONTROLS. SIGNIFICANT OR COMPLETE RECOVERY FROM LIVER AND THYMUS EFFECTS WERE OBSERVED ON RETURN TO NORMAL DIET. ALL EFFECTS ATTRIBUTED TO THE MIXTURE WERE ELICITED BY INDIVIDUAL COMPOUNDS IN THE MIXTURE IN PREVIOUS STUDIES. [R162] *Chinese hamster V79 were used to measure intercellular communication, 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and several mixtures of these compounds were tested for their ability to inhibit this biological process. The ability of these chemicals to inhibit colony-forming ability of these cells was tested prior to the studies to measure intercellular communication. 2,4-D was less cytotoxic than 2,4,5-T. Both 2,4,5-T and 2,4-D were able to inhibit intercellular communication at their respective non-cytotoxic dose ranges. Various mixtures of both chemicals were also able to inhibit intercellular communication, showing some kind of activity. No-effect levels were also noted in the intercellular communication assay. These results were interpreted as being consistent with the hypothesis that these compounds might be teratogenic by their ability to inhibit intercellular communication during development. [R163] *2,4-D at dosages of 10 or 20 mg/kg has an insignificant effect on acetate metabolism. ... At a dosage of 400 mg/kg reduced the oxidation of acetate to carbon dioxide, and this effect lasted at least 24 hr. Blood cholesterol levels of rats and rabbits are reduced by repeated, tolerated admin of 2,4-D. ... In vitro cholesterol synthesis can be inhibited by 2,4-D. [R118, 522] *NO SIGNIFICANT INCR IN INCIDENCE OF TUMORS IN VARIOUS MOUSE STRAINS ... GIVEN 2,4-D OR ITS ESTERS AT 46.4 MG/KG/DAY ORALLY ON DAYS 7-28 FOLLOWED BY ... 323 PPM FOR 18 MO. [R2, 496] *The herbicides 2,4,5-T and 2,4-D induced fetopathy and an increased incidence of skeletal anomalies following single daily oral doses of 100-150 mg/kg to pregnant rats on days 6-15 of gestation. The observed skeletal defects were not incompatible with postnatal survival, weight gain and viability of the offspring from treated dams being within control limits. [R164] *IN STUDIES OF CD-1 MICE ... 2,4-D ESTERS (ISOPROPYL ESTER AT 147 MG/KG/DAY, N-BUTYL ESTER AT 155 MG/KG/DAY, AND ISOOCTYL ESTER AT 186 MG/KG/DAY) HAD NO EFFECT ON INCIDENCE OF CLEFT PALATE OR FETAL MORTALITY, BUT DID AFFECT FETAL WEIGHT. STATISTICALLY SIGNIFICANT INCR IN PROPORTION OF ABNORMAL FETUSES WAS REPORTED IN MICE THAT RECEIVED MAXIMALLY TOLERATED SUBCUTANEOUS DOSES OF ... 2 ISOPROPYL ESTERS OF 2,4-D (... 100 and 94 UG/KG, RESPECTIVELY), IN DIMETHYL SULFOXIDE (DMSO) SOLN. [R2, 497] *ADMIN OF 2,4-D OR ITS ISOPROPYL, BUTYL, OR ISOOCTYL ESTERS ORALLY OR SC DURING DAYS 6-14 OF PREGNANCY INCREASED THE INCIDENCE OF FETAL ANOMALIES AMONG BL6, AKR AND/OR C3H STRAINS OF MICE ... THE PURITY OF THE COMPOUNDS WAS ... ISOPROPYL AND BUTYL ESTERS, 99%; ISOOCTYL ESTER, 97%. [R139] *THE MAXIMUM TOLERATED ORAL DOSE OF 2,4-D (98.7% PURITY, NO CHLORINATED DIBENZO-PARA-DIOXINS FOUND WITHIN THE LIMIT OF DETECTION OF 0.2 MG/KG) OR AN EQUIMOLAR DOSE OF 2,4-D PROPYLENE GLYCOL BUTYL ETHER ESTER OR OF THE ISOOCTYL ESTER OF 2,4-D HAD EMBRYOLETHAL AND GROWTH RETARDING EFFECTS BUT NO TERATOGENICITY WHEN GIVEN TO PREGNANT SPRAGUE-DAWLEY (SPARTAN STRAIN) RATS ON DAYS 6-15 OF GESTATION. OTHER SIGNS OF FETOTOXICITY WERE SC EDEMA, DELAYED OSSIFICATION AND WAVY RIBS. 2,4-D DID NOT AFFECT FERTILITY, GESTATION, LACTATION OR VIABILITY OF THE NEWBORN; THE PROPYLENE GLYCOL BUTYL ETHER AND ISOOCTYL ESTERS DECR VIABILITY OF THE NEWBORN AND LACTATION INDICES. [R165] *IN STUDIES OF CD-1 MICE ... ISOOCTYL ESTER AT 186 MG/KG/DAY HAD NO EFFECT ON INCIDENCE OF CLEFT PALATE OR FETAL MORTALITY, BUT DID AFFECT FETAL WT. ... PREGNANT RATS WERE TREATED ORALLY WITH ... ISOOCTYL ESTER OF 2,4-D UP TO 131 MG/KG/DAY ON DAYS 6-15 OF GESTATION. FETOTOXIC RESPONSES WERE SEEN @ HIGH DOSAGES, BUT TERATOGENIC EFFECTS WERE NOT SEEN AT ANY DOSAGE. ... NO-ADVERSE-EFFECT DOSAGE OF 2,4-D (OR THE MOLAR EQUIVALENT, IN CASE OF ESTERS) WAS 25 MG/KG/DAY. A STATISTICALLY SIGNIFICANT INCR IN PROPORTION OF ABNORMAL FETUSES WAS REPORTED IN MICE THAT RECEIVED MAX TOLERATED SC DOSES OF THE ISOOCTYL ESTER ... (130 UG/KG ...) IN DIMETHYL SULFOXIDE SOLN. DIMETHYL SULFOXIDE ITSELF, HOWEVER, IS A TERATOGEN. [R2, 497] *ADMIN OF 2,4-D OR ITS ISOPROPYL, BUTYL, OR ISOOCTYL ESTER /97%/ ORALLY OR SUBCUTANEOUSLY DURING DAYS 6-14 OF PREGNANCY INCREASED INCIDENCE OF FETAL ANOMALIES AMONG BL6, AKR AND/OR C3H STRAINS OF MICE BUT NOT AMONG BGAK AND A/HA STRAINS. [R139] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF)F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR)F1 MICE WERE GIVEN SINGLE SC INJECTIONS OF 215 MG/KG BODY WT 2,4-D (90% PURE, MP 136-140 DEG C) IN DIMETHYL SULFOXIDE ON THE 28TH DAY OF LIFE AND OBSERVED UP TO 78 WEEKS OF AGE ... TUMOR INCIDENCES WERE COMPARED WITH ... CONTROLS THAT WERE EITHER UNTREATED OR WERE INJECTED WITH DIMETHYL SULFOXIDE, 0.5% AQ GELATIN OR CORN OIL. THE TUMOR INCIDENCE IN ANY GROUP OR COMBINATION OF GROUPS WAS NOT SIGNIFICANTLY DIFFERENT FROM THAT IN CONTROLS (P > 0.05). [R166] *6XC3H/ANF) F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR)F1 MICE RECEIVED COMMERCIAL 2,4-D (90%, MP 136-140 DEG C) ACCORDING TO THE FOLLOWING DOSE SCHEDULE: 46.4 MG/KG BODY WT IN 0.5% GELATIN BY STOMACH TUBE AT 7 DAYS OF AGE AND THE SAME AMOUNT (NOT ADJUSTED FOR INCR BODY WT) DAILY UP TO 28 DAYS OF AGE; SUBSEQUENTLY, THE MICE WERE GIVEN 149 MG/KG OF DIET /FEED/. ... THE EXPT WAS TERMINATED WHEN THE MICE WERE ABOUT 78 WEEKS OF AGE ... TUMOR INCIDENCES WERE COMPARED WITH THOSE OBSERVED AMONG GROUPS OF ... CONTROL MICE, WHICH HAD BEEN UNTREATED OR HAD RECEIVED GELATIN ONLY: THE INCIDENCES WERE NOT SIGNIFICANTLY GREATER (P > 0.05) WHEN ANY GROUP OR COMBINATION OF GROUPS WERE CONSIDERED. SIMILAR RESULTS WERE OBTAINED IN GROUPS OF MICE GIVEN 2,4-D ISOPROPYL, BUTYL, OR ISOOCTYL ESTERS (99%, 99%, AND 97% PURE) AT DOSES OF 46.6 MG/KG BODY WT FROM 7-28 DAYS OF AGE AND, SUBSEQUENTLY 111, 149, and 130 MG/KG OF DIET /FEED/ RESPECTIVELY UP TO 78 WEEKS OF AGE. [R140] *The mammalian pharmacology is not well characterized. ... Both acute and chronic toxicities in laboratory mammals are low. All species ... tested react similarly, and there seems to be only minor differences in potency between various salts and esters of 2,4-D, either as pure chemical or as commercial preparations. [R38, p. III-130] *Mutagenicity tests were performed for components of the defoliant Agent-Orange with the Salmonella arabinose resistant assay system. These components included 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid along with butyl, isobutyl and isooctyl esters and the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin. Arabinose sensitive S typhimurium strain SV50 was used as the tester strain. Rat and hamster liver S9 homogenate and S9 mix were used for metabolic activation. No mutagenic response to the test compounds was observed under any of the assay conditions used. With the use of activation, neither hamster nor rat S9 induced any mutagenic response. /It appears that the cmpd tested/ do not cause point mutations. [R167] NTOX: *The acute effects of 2,4-dichlorophenoxyacetic acid (2,4-D) administered orally to female mongrel dogs in doses of 25, 50, 75, 100 or 125 mg/kg were investigated by means of neurological examinations, electromyography and motor nerve conduction velocity tests carried out at various times following treatment. On day one after treatment with 125 mg/kg, one of four dogs was lethargic but recovered by day three. Also on day one, myotonic dimpling was evident in one dog each in the groups treated with 50, 100, 125 mg/kg. Dogs treated with more than 50 mg/kg had generalized myotonic discharges which increased according to the dose and were resolved by day 14 but not day seven. Treatment failed to affect motor nerve conduction velocity. Pathologic changes in teased nerve fibers involved occasional fiber degeneration, paranodal demyelination and intercalated internodes. Transverse semi-thin sections showed mild focal fiber degeneration and eventual medial plantar nerve depletion in five dogs treated with 25, 100 and 125 mg/kg and in lateral plantar nerve of two dogs treated with 125 mg/kg and one control. A single exposure to sublethal oral doses of 2,4-D is not associated with evidence of polyneuropathy. [R168] *Male Han/Wistar rats were exposed for 2 weeks to 2,4-D at 100 mg/kg/day. Significant increases were noted in the peroxisomes in liver cells following exposure to 2,4-D but no affect was noted on the average size of peroxisomes. [R169] *The effects of some common rice field herbicides, such as 2,4-dichlorophenoxyacetic acid (2,4-D), Machete, and Saturn, on the paddy field nitrogen-fixing cyanobacteria Nostoc linckia, Nostoc calcicola, Nostoc sp and Anabaena doliolum were studied. These cyanobacteria were found to be more tolerant to 2,4-D (lethal doses 1500-2000 ug/ml) than to Machete and Saturn (lethal doses 6-8 ug/ml). The effects ... on some physiological processes of Nostoc linckia were studied. 2,4-D stimulated the growth and nitrogen fixation up to 100 ug/ml concentration (a dose higher than the field dose, ie, about 40 ug/ml), recommended for field application. ... 100 ug/ml 2,4-D stimulated the uptake of nitrate but not of ammonium; higher doses of 2,4-D inhibited the uptake of both nutrients. ... Lower pH enhanced the toxicity of all three herbicides, whereas higher pH (up to 9.0) lowered it. Glucose and acetate (each 500 ug/ml) protected against the toxicity of 2,4-D and Saturn, but not against Machete. Whereas glutamine, arginine, serine, and tryptophan conferred protection against the toxicity of all three herbicides, methionine did not, and the presence of methionine with herbicide in the culture medium resulted in greater toxicity to Nostoc linckia than that in the presence of the herbicide alone. [R170] *The effects of p-chlorophenoxyacetic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), and 2,4,5-trichlorophenoxyacetic acid on hepatic peroxisomes and xenobiotic metabolizing enzymes were studied in mice. Male C57B1/6 mice were administered 0 to 0.125% p-chlorophenoxyacetic acid, 2,4-D, or 2,4,5-Trichlorophenoxyacetic acid in their diet for 4 days. ... The liver somatic index, ... carnitine acetyl transferase, cyanide insensitive palmitoyl cobalamine oxidation, catalase, cytochrome oxidases, glutathione transferase, and cytosolic, microsomal, and mitochondrial epoxide hydrolase were evaluated. The liver somatic index was significantly increased by 2,4-D and 2,4,5-trichlorophenoxyacetic acid . 2,4-D signiicantly increased microsomal protein and 2,4,5-trichlorophenoxyacetic acid significantly increased mitochondrial protein. 2,4-D and 2,4,5-trichlorophenoxyacetic acid significantly increased, palmitoyl cobalamine oxidation, catalase and total cytochrome oxidase activity. p-Chlorophenoxyacetic acid significantly increased cytochrome oxidase, but had not effect on any of the other parameters. 2,4-D and 2,4,5-trichlorophenoxyacetic acid significantly increased cytosolic and microsomal epoxide hydroxylase activities. Cytosolic glutathione transferase activity was increased to a smaller extent. /There were/ marked differences in proliferation of peroxisomes and induction of xenobiotic metabolizing enzymes seen with compounds differing only slightly in structure. [R171] *The mutagenic activity of 2,4-D was assessed utilizing cytogenetic, chlorophyll mutation, specific-locus and pollen viability endpoints in Allium cepa and Oryza sativa. In the Allium root tip assay onion bulbs with roots were treated with 25, 50, 75 or 100 ppm 2,4-D for 4 hr and the frequency of aberrations was estimated. With an increase in concentration there was rise in frequency of aberrant cells. In the case of mutation assays, presoaked rice seeds were treated wih 100, 200 or 300 ppm 2,4-D for 4 hr and sown in the field. Mutation frequency was estimated on M1 plant, spike and M2 seedling basis. With increasing concentration, there was a concomitant increase in mutation frequency. Highly significant chlorophyll-deficient and waxy mutants besides sterile pollen were observed. ... 2,4-D has genotoxic potential. [R172] *The effects of chlorinated phenols and phenates on biochemical parameters were investigated in liver and white blood cells of 90 day old female Sprague-Dawley rats in an effort to understand why 2,4,6-trichlorophenol (2,4,6-T) causes cancer in rodents while 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenol (2,4,5-T), which are structurally similar compounds, do not. Two oral doses of each of these compound were given to separate groups of rats 21 and 4 hours prior to sacrifice. Each dose was 1/5 of the median lethal dose. No DNA damage in rat liver or white blood cells was noted. No changes were found in serum alanine-aminotransferase activity or hepatic glutathione. [R173] *Mutagenic properties of the plant growth regulating hormones indole-3-acetic acid (IAA) and indole-3-butyric acid (IBA) were studied along with those of the herbicides 2,4-(dichlorophenoxy)acetic acid (2,4-D), 2,4-(dichlorophenoxy)butyric acid (2,4-DB), 4-chloro-2-methylphenoxyacetic acid (MCPA), using the Ames test. Strains of Salmonella typhimurium used included TA-97a, TA-98, TA-100, TA-1535, TA-1537, and TA-1538. Recombinogenicity was also studied for the herbicides in Aspergillus nidulans. Indole-3-acetic acid and indole-3-butyric acid did not induce any point mutations in six different strains of S typhimurium. Both 2,4-D and 4-chloro-2-methylphenoxyacetic acid increased point mutations in Salmonella and mitotic segregation in Aspergillus. Frameshift mutation occurred only when an S9 metabolic system was used and only in the strain TA-97a. A somewhat weak mutagenic effect was noted strain TA 97a which may be due to a particularly high sensitivity to mutagens in this strain. Mitotic segregation was increased by 2,4-D with S9 4-chloro-2-methylphenoxyacetic acid alone in A nidulans mainly through mitotic crossing over. [R174] *Results were reported for the embryotoxicity of 42 environmental contaminants applied externally to mallard eggs. The LC50 of herbicides and insecticides in aqueous emulsion were measured by egg immersion. 2,4-D, glyphosate, atrazine, carbaryl, dalapon, dicamba, methomyl and phosmet were only slightly toxic or not toxic (LC50 of 178 to greater than 500 lb/acre; 199-560 kg/ha). [R175] *Female CD-1 mice were exposed to Tordon 202c (a picloram and 2,4-D combination herbicide) in the drinking water at concentrations of 0.21, 0.42, and 0.84% for 60 days prior to mating with untreated males. One-half of the pregnant females subsequently continued treatment thorughout gestation while the remaining females were maintained on distilled water. Fetal weight, crown-rump length, placental weight, and maternal gestational weight gain were reduced in a dose dependent manner following combined preconceptional and gestational exposure. The incidence of malformed fetuses (cleft palate, renal agenesis, hydronephrosis, unilateral testicular agenesis, and umbilical hernia) and fetuses with variants (especially incomplete ossification of the skeleton) were increased in a dose-dependent manner following combined exposure. Increased maternal mortality and decreased preconception weight gain were observed in the highest dosage group. Relative maternal liver weight was increased in a dose-dependent manner. The results suggest that combined preconceptional and gestational exposure to Tordon 202c is required for teratogenesis and fetal growth depression. Preconceptional exposure alone is not effective in increasing the risk for embryotoxicity. [R176] *The effects of ethyl 4-chloro-2-methylphenoxyacetate and other phenoxyacid compounds on hepatic xenobiotic metabolizing enzymes were studied in male rats. ... A marked increase in the activity of aniline hydroxylase was noted in the 2,4-dichlorophenoxyacetic acid treated group, whereas the aminopyrine N-demethylase activity significantly decreased in the same group. [R177] *The effects of 2,4-dichlorophenoxyacetic acid on brain and CSF biogenic amines and their acidic metabolites were studied in rats. Male Wistar rats were injected sc with 10, 30, 100, or 200 mg/kg sodium 2,4-dichlorophenoxyacetate, and then observed for clinical signs of toxicity. Rats were killed 0.5, 3.5, 7.5, 15.5, or 31.5 hours later and the CSF and brains were taken and assayed for dopamine, noradrenaline, 5-hydroxytryptamine, homovanillic acid, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, and tryptophan. In rats injected with 200 mg/kg sodium 2,4-dichlorophenoxyacetate, brain 5-hydroxytryptamine was slightly increased after 3.5 hours and 5-hydroxyindoleacetic acid was increased by 3.2 times the control value 0.5 to 7.5 hours after dosing. Dopamine concentrations were slightly increased. CSF 5- hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentrations were significantly increased between 0.5 and 7.5 hours after dosing. The increases in CSF 5- hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid, and homovanillic acid concentration correlated well with the appearance of symptoms such as myotonia and lethargy. The 30 and 100 mg/kg doses caused significant increases in brain 5-hydroxyindoleacetic acid and CSF 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, and homovanillic acid concentrations after 1.5 hours. The 100 mg/kg dose caused a significant increase in brain homovanillic acid concentration at the same time point. The 10 mg/kg dose did not induce any increases in concentration of any of the amines or their metabolites. The 10 and 30 mg/kg doses did not induce any clinical signs of intoxication. [R178] *A hospital based case control study of companion dogs examined the risk of developing canine malignant lymphoma associated with the use of chemicals in and about the home. Information from a self-administered owner questionnaire and/or a telephone interview of about 491 cases, 466 nontumor controls, and 479 tumor controls indicated that owners in households with dogs that developed malignant lymphoma applied 2,4-dichlorophenoxyacetic acid herbicides to their lawn and/or employed commercial lawn care companies to treat their yard significantly more frequently than control owners (odds ratio = 1.3). In addition, the risk of canine malignant lymphoma rose to a twofold excess with four or more yearly owner applications of 2,4-dichlorophenoxyacetic acid. [R179] *The reproductive toxicity of 2,4-D has been studied at dietary doses of 0, 5, 20, and 80 mg/kg/day in a two generation reproductive study in Fischer 344 rats. The parental Fo group was treated with 2,4-D for 15 weeks prior to mating. No adverse effects on fertility were observed in the 5 and 20 mg/kg daily dose groups, although reduced pup weights were noted in the 20 mg/kg F2a litters. A daily NOAEL of 5 mg/kg for reproductive toxicity was established from this study. In addition to this reproduction study, recent subchronic and chronic studies in rats, mice and dogs produced no evidence of treatment related histopathological changes in the testes at any of the dose levels ... . [R44, p. V4 493] *The aim of this investigation was to determine whether the herbicide increases the frequency of sister chromatid exchanges (SCEs) in bone marrow and spermatogonial cells of mice exposed in vivo. The experiment included an oral administration of 2,4-D to three groups of mice (50,100 and 200 mg/kg), as well as to a control group of animals administered with distilled water, pH 10.5 and another group injected with cyclophosphamide (50 mg/kg). In somatic cells, the results showed a significant SCE increase with the two high doses tested, a response that was manifested in a dose-dependent manner. With regard to the mitotic index and the cell proliferation kinetics, there were no modifications exerted by 2,4-D; however, cyclophosphamide induced cytotoxic damage and a cell-cycle delay. With respect to the germ cells, the genotoxic results were similar to those described earlier; that is, there was a significant SCE increase induced by the two high 2,4-D doses tested and a higher genotoxic damage was observed in the animals treated with cyclophosphamide. [R180] *The cytogenetic effect of 2,4-dichlorophenoxy acetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (2,4-DCP) was studied in bone-marrow, germ cells and sperm head abnormalities in the treated mice. Swiss mice were treated orally by gavage with 2,4-D at 1.7, 3.3 and 33 mg kg(-1)BW (1/200, 1/100 and 1/10 of LD(50)). 2,4-DCP was intraperitoneally (i.p.) injected at 36, 72 and 180 mg kg(-1)BW (1/10, 1/5, 1/2 of LD(50)). A significant increase in the percentage of chromosome aberrations in bone-marrow and spermatocyte cells was observed after oral administration of 2,4-D at 3.3 mg kg(-1)BW for three and five consecutive days. This percentage increased and reached 10.8+/-0.87 (P < 0.01) in bone-marrow and 9.8+/-0.45 (P < 0.01) in spermatocyte cells after oral administration of 2,4-D at 33 mg kg(-1)BW for 24 h. This percentage was, however, lower than that induced in bone-marrow and spermatocyte cells by mitomycin C (positive control). 2,4-D induced a dose-dependent increase in the percentage of sperm head abnormalities. The genotoxic effect of 2,4-DCP is weaker than that of 2,4-D, as indicated by the lower percentage of the induced chromosome aberrations (in bone-marrow and spermatocyte cells) and sperm head abnormalities. [R181] *2,4-D-injected into one striatum (100 microg/rat) produced a marked depression in locomotor activity and elicited a moderate circling towards the ipsilateral side at 6 and 24 h postinjection. These behavioral changes were accompanied by a decrease and an increase of serotonin (5-HT) and homovanillic acid (HVA) levels, respectively. 2,4-D administration (100 microg/rat) into the nucleus accumbens, induced similar behavioral and neurochemical patterns to the intrastriatal 2,4-D injection, although rats did not present notorious turning. When 2,4-D was injected into one medial forebrain bundle (MFB, 50 microg/rat), animals presented ipsilateral circling, while locomotor activity was unchanged at 3 and 7 days post-injection. These last rats also exhibited diminished levels of striatal 5-HT, dopamine (DA) and their metabolites without changes in the substantia nigra (SN). Animals sacrificed 3 and 7 days after a 6-OHDA injection into one of the MFB, presented progressive depletion of dopamine in striatum and SN. 2,4-D as well as 6-OHDA-treated rats into one of the MFB were challenged with low dose (0.05 mg/kg s.c.) of apomorphine (only at 7 days post-injection) to evaluate a possible DA-receptor supersensitivity. Only 6-OHDA treated rats showing a vigorous contralateral rotation activity. These results indicate that 2,4-D induced a regionally-specific neurotoxicity in the basal ganglia of rats. The neurotoxic effects of 2,4-D on basal ganglia by interacting with the monoaminergic system depended not only on the exact location of the 2,4-D injection, but also on the dose and time period of post-injection. [R182] *We observed that a single exposure to 1 mM 2,4-D diminished growth and total protein content in all E. coli strains tested in vitro. In addition, successive exposures to 0.01 mM 2,4-D had a toxic effect decreasing growth up to early stationary phase. Uropathogenic E. coli adhere to epithelial cells mediated by fimbriae, adhesins, and hydrophobic properties. 2,4-D exposure of uropathogenic E. coli demonstrated altered hydrophobicity and fimbriation. Hydrophobicity index values obtained by partition in p-xylene/water were 300-420% higher in exposed cells than in control ones. Furthermore, values of hemagglutination titer, protein contents in fimbrial crude extract, and electron microscopy demonstrated a significant diminution of fimbriation in treated cells. Other envelope alterations could be detected, such as lipoperoxidation, evidenced by decreased polyunsaturated fatty acids and increased lipid degradation products (malonaldehyde), and motility diminution. [R183] *... We studied the influence of 6 concns viz. 0 (control), 100, 200, 300, 400 and 500 mg l-1 of 2,4-D on the population growth of the rotifer Brachionus patulus under two algal (Chlorella) food levels (0.5 x 10(6) and 1.5 x 10(6) cells ml-1). Regardless of herbicide concn, the population growth of B. patulus was dependent on the algal food levels, in that an incr in algal food level supported a better population growth. Similarly at any Chlorella density, the herbicide had a negative influence on the population growth of B. patulus. Herbicide level of 500 mg l-1 inhibited population growth of B. patulus beyond 5 days. Rotifers grown under low food density and high herbicide concn (300 mg l-1 or above) were completely eliminated after day 15. The rate of population incr (r) (mean + or - standard error) in the controls varied from 0.46 + or - 0.002 and 0.55 + or - 0.004 under 0.5 x 10(6) and 1.5 x 10(6) cells ml-1 of Chlorella, respectively. The r values became negative under both, low and high food levels, at or beyond 300 mg l-1 of 2,4-D. The maximal population abundance (ind. ml-1) in controls varied from 294 + or - 9 to 503 + or - 21 under low and high food levels of Chlorella, respectively. [R184] *The potential for 2,4-D and its salts and esters to induce developmental toxicity was investigated in rats (8 studies) and rabbits (7 studies). Maternal toxicity associated with exposure was dependent on the dose level expressed as 2,4-D acid equivalents. The severity of the maternal effect was correlated to the 2,4-D acid-equivalent dose, with increasing dose levels that exceeded renal clearance causing increasingly more severe maternal effects. In both species, maternal body weight effects began to be manifested at dose levels of 30 mg 2,4-D acid equivalent/kg/day. At higher dose levels (50-75 mg/kg/day in rats and 75-90 mg/kg/day in rabbits), body weights and feed consumption were more severely affected. [R185] *The results obtained demonstrated that 2,4-dichlorophenoxyacetic acid has cytotoxic and mutagenic effects. The positive response of yeast and transformed hematopoietic cells was verified in kinetics and dose-response experiments. [R186] *The influence of sublethal doses of 2,4-dichlorophenoxyacetic acid (2,4-D) on serum T3 AND T4 concns in Hsd Cpb: Wistar rats of both sexes was studied. The trial was performed on 24 males and females respectively, each divided into three groups of 8 animals (control, groups 1 and 2). Aqueous soln of the compound (11 mg/kg bw--group 1 and 110 mg/kg bw--group 2) or clean tap water (control group) was used. Aliquots of 2.4 ml/kg bw were administered with a stomach tube from the 1st-10th day of the experiment. Three days before the first treatment and on the 6th and 13th day of the experiment the serum T3 AND T4 concns were determined by commercial radioimmunoassay kits (Byk-Sangtec Diagnostica), validated for rats. A significant decr of serum T4 (P < 0.01) AND T3 (P < 0.001) was determined in males of groups 1 and 2 during the experiment. On the 6th day of experiment serum T4 AND T3 values were significantly lower (P < 0.001 and 0.01 respectively) in group 2 than in the controls and group 1 of both males and females. During the whole experiment serum T4 levels were lower in females than in males (P < 0.05). [R187] *Animals were administered a single dose of the LD(50) of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD) (25 microg/kg), 2, 4-dichlorophenoxyacetic acid (2,4-D) (375 mg/kg) and dieldrin (DED) (38 mg/kg) by gavage. Seventy-two hours after treatment, increased expression of CYP1A1, CYP1A2 and CYP1B1 was observed in the liver, kidney and mammary tissue. Since CYP1A and CYP1B1 are the major enzymes catalyzing 2- and 4-hydroxylation of E(2), respectively, the effect of these CHCs on the metabolism of E(2) was investigated in rat tissues. Formation of 2- and 4-catechol estrogens was increased in a tissue-specific manner in response to treatment. TCDD was the most potent inducer for CYP1 enzyme mRNA and for the 2- and 4-hydroxylation of E(2). 2,4-D and DED induced similar responses, but less than that of TCDD. [R188] *Female CD-1 mice were exposed to a commercial amine formulation of 2,4-dichlorophenoxyacetic acid (2,4-D) on days 6-16 of gestation in drinking water at concentrations ranging from 0 to 1.0% of the formulated product, equivalent to approximately 0-650 mg/kg/d expressed as the amine derivative. The effect of 2,4-D on urethan-induced pulmonary adenoma formation was evaluated in female offspring 19 w after birth. Urethan-induced sleeping times observed following ip injection of 1.5 mg urethan/g bw 7 w after birth were not altered by 2,4-D (p = 0.10), indicating that 2,4-D did not affect the rate of urethan elimination. 2,4-D exposure did not affect the number of tumors produced (p = 0.58), but did reduce the mean tumor diameter in the highest dose group (p < 0.01). This minor antineoplastic activity of 2,4-D may be related, in part, to inhibitory effects of 2,4-D on various enzymatic or metabolic pathways, essential for cellular growth and tissue development. Since exposure to 2,4-D during pregnancy had little impact of tumor production, it is unlikely that persistent alteration to developing immune cells involved in the cell-mediated immunosurveillance mechanisms occurred. [R189] *We studied offspring of dams which had received 50, 70 or 700 mg/kg of 2,4-Dichlorophenoxyacetic acid (2,4-D) during nursing. Neonatal tissues and the stomach content (milk) were examined up to 16 post natal days to detect body and organs weight alterations and 2,4-D residues after 2,4-D maternal dosing every-other-day, from post natal day 1. We detected 2,4-D residues in stomach content, blood, brain and kidney of 4-day-old neonates breast-fed by 2,4-D exposed mothers and onward. 2,4-D residues were dose- and exposure-time-dependent. The highest dose impaired body growth, as well as low tissue weights and diminished stomach contents. Levels of 2,4-D residues in stomach content, blood, kidney and brain of post natal rats (age PD 4-PD 16) fed through lactation from dams treated with 2,4-D demonstrated that 2,4-D was transferred to the neonates and the diminished body and tissues weight during this developmental period could be due to a diminished milk intake or/and to the direct 2,4-D toxic effect. Besides, when the herbicide treatment (100 mg 2,4-D/kg) was withdrawn from the dams, 2,4-D residues remained in the stomach content of neonates for at least one week. [R190] NTOX: *2,4-dichlorophenoxyacetic acid and its derivatives (collectively known as 2,4-D) are herbicides used to control a wide variety of broadleaf and woody plants. The genetic toxicity of an ester (2,4-D 2-butoxyethylester) and two salts (2,4-D isopropylamine and 2,4-D triisopropanolamine) was investigated in cultured mammalian cells. The end points used were the induction of chromosomal aberrations in primary cultures of rat lymphocytes and forward mutations at the HGPRT locus of Chinese hamster ovary cells. There was no evidence of genotoxicity for the test materials in the experimental systems used. These results were consistent with the general lack of genotoxic potential for 2,4-D in a number of other test systems. [R191] *2,4-dichlorophenoxyacetic acid and several of its derivatives are herbicides used to control a wide variety of broadleaf and woody plants. The genetic toxicity in vitro of 2,4-D AND 7 of its salts and esters were examined by employing gene mutation in bacteria (Ames test) and induction of DNA damage and repair in rat hepatocytes. In addn, an in vivo unscheduled DNA synthesis (UDS) assay was performed on 2,4-D. There were no indications of genotoxic potential for 2,4-D acid, or any of its derivatives, in these assays. [R192] *Pregnant rats were daily orally exposed to 70 mg/kg/day of 2,4-D from gestation day (GD) 16 to postnatal day (PND) 23. After weaning, the pups were assigned to one of the two subgroups: T1 (fed with untreated diet until PND 90) and T2 (maintained with 2,4-D diet until PND 90). Effects on offsprings were evaluated with a neurotoxicological test battery. Neuromotor reflexes, spontaneous motor activity, serotonin syndrome, circling, and catalepsy were analyzed during various postnatal ages. 2,4-D neonatal exposure induced delay of the ontogeny of righting reflex and negative geotaxis accompanied by motor abnormalities, stereotypic behaviors (excessive grooming and vertical head movements), and hyperactivity in the open field. Adult rats of both sexes (T2 group) showed a diminution of ambulation and rearing, while excessive grooming responses were only observed in T2 males. Besides, these animals manifested serotonin syndrome behaviors, catalepsy, and right-turning preference. Some behaviors were reversible, but others were permanent, and some were only expressed after pharmacological challenges. [R193] *An independent scientific review panel had concerns involving study design, analysis and interpretation of results in a case-control study investigating the relationship between canine malignant lymphoma (CML) and the use of 2,4-D herbicide. To address these concerns, a re-analysis was done to examine 2,4-D use and its association with CML. This case-control study re-analyzed the data using the exposure definition used in the original study, re-analyzed the data using a redefinition of exposure, and conducted a dose-response analysis with the redefined exposure criteria. ... A dose-response relationship between 2,4-D use and CML was confirmed. Additionally, the occurrence of CML was not found significantly associated with the use of 2,4-D. [R194] *The fetotoxic effect of 2,4-dichlorophenoxyacetic acid (2,4-D) was investigated. Histological and histochemical changes in the liver of newborn, young and adult rats exposed to the herbicide from the prenatal period to the end of an experiment were evaluated. The experiment used 90 male and female, Wistar, aged to 10 wks rats, divided into 2 groups: I-control-30 AND II-60 animals which received the water soln of 2,4-D acid sodium salt in a daily dose of 250 mg/kg b.w. It was given with drinking water every day. The animals were sacrificed after 24 hrs, 4, 6, and 10 wks of the experiment. The results obtained showed that the admin of 2,4-D acid to rats in the prenatal and postnatal period, in a dose inducing subacute intoxication leads to histological and histochemical changes in the liver. The observed changes indicate disorders in energetic processes in hepatocytes and are morphological exponents of detoxicative processes there. They are most intensified with newborn rats. It suggests also, that pregnants ought not to work with 2,4-D and should avoid any contact with herbicides belonging to the 2,4-dichlorophenoxyacetic acid group. [R195] *An experimental model was designed to study the acute lesions caused by a continuous exposure to 2,4-dichlorophenoxyacetic acid (2,4-D) disolved in water (400 mg/L) in hematopoietic kidney tissue in tench (Tinca tinca L). Fifty fish were used in this study, 15 for calculating 96 hr LC50 and 35 were euthanized 1, 2, 5, 8, and 12 days postpoisoning (five treated and two controls each time). Tissue samples, fixed in 5% glutaraldehyde in 0.1 M phosphate buffer (pH 7. 2) for histopathological examination, revealed marked alteration of hematopoietic tissue, characterized by progressive swelling and cell necrosis, activation of the phagocyte system, and subsequent formation of myelin figures. Variations recorded in hematocrit and hemoglobin levels in blood samples indicated changes in membrane permeability, complementing the findings on hematopoietic tissue. The lethal dose (LC50) at 96 hr demonstrated the importance of the species and chemical form used as factors in calculating a product's toxicity. [R196] *The acute toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D), a herbicide, was studied in chicks dosed with 100, 300, 500, or 600 mg 2,4-D/kg BW, by the oral route. Clinical, laboratory, and histopathological methods were used as indicators of toxicity. After acute exposure, the herbicide decreased motor activity and induced muscular weakness and motor incoordination; decreased weight gain; increased serum creatine kinase (CK) and alkaline phosphatase (AP) activities and serum uric acid (UA), creatinine (CR), and total proteins (TP) levels; and did not change serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) activities. These changes were time- and dose-dependent and reversible. The LD50 (lethal dose 50%) calculated for oral 2,4-D in chicks was 420 mg/kg BW (385 to 483). Chromatographic analysis of the serum of the intoxicated chicks showed the presence of the herbicide; the amount found was dose- and time-dependent, increasing from 2 to 8 h after exposure and decreasing afterwards. Histopathological post-mortem studies conducted on intoxicated chicks showed hepatic (vacuolar degeneration of the hepatocytes), renal (tubular nephrosis), and intestinal (hemorrhagic) lesions. T [R197] *Dermatotoxicity of agricultural chemicals (ACs) with or without ultraviolet (UV) irradiation was histologically examined using hairless descendants of Mexican hairless dogs. ACs examined were pentachlorophenol sodium salt, 2,4-dichlorophenoxyacetic acid (DCPAA), Maneb, and Zineb. One day after cessation of the 7-day AC treatment, the skin treated with DCPPA and Maneb indicated only slight histological changes. The UV + AC-treated sites had as much pigmentation as the control sites. Fourteen days after cessation of treatment, dogs treated with Maneb showed marked reactions such as epidermal degeneration, vasodilation, and intradermal infiltration of inflammatory cells. These histological changes were more severe in the UV + AC-treated sites. Zineb induced comedones with well-developed pilosebaceous glands. [R198] *Forms of 2,4-dichlorophenoxyacetic acid ... are herbicides used to control a wide variety of broadleaf and woody plants. Single-dose acute and 1-year chronic neurotoxicity screening studies in male and female Fischer 344 rats (10/sex/dose) were conducted on 2,4-D according to the U.S. EPA 1991 guidelines. The studies emphasized a Functional Observational Battery (which included grip performance and hindlimb splay tests), automated motor activity testing, and comprehensive neurohistopathology of perfused tissues. Dosages were up to 250 mg/kg by gavage for the single-dose study, and up to 150 mg/kg/day in the diet for 52 weeks in the repeated-dose study. In the acute study, gavage with 250 mg/kg test material caused slight transient gait and coordination changes and clearly decreased motor activity at the time of maximal effect on the day of treatment (day 1). Mild locomotor effects occurred in one mid-dose rat (75 mg/kg), on Day 1 only. No gait, coordination, or motor activity effects were noted by day 8. In the chronic study, the only finding of neurotoxicologic significance was retinal degeneration in females in the high-dose group (150 mg/kg/day). Body weights of both sexes were slightly less than controls in the mid-dose group, and 10% less than controls in the high-dose group. [R199] *The effect of 2,4-dichlorophenoxyacetic acid (2,4-D) on the in vitro synthesis of proteins was studied in Chinese hamster ovary cells. A remarkable inhibition of the synthesis of proteins was observed when cells grew for 24 h in presence of 1 mM 2,4-D. This effect was reversed by adding 0.1 mM of the three polyamines (putrescine, spermidine and spermine) to the cultured cells. [R200] *Eighteen English pointer dogs were randomly assigned to 3 outdoor grass-plot enclosures (6/enclosure) uniformly sprayed once with either the 2,4-dichlorophenoxyacetic acid (2,4-D) or to dimethylamine formulation (DMA-4) at the maximum recommended application rate, DMA-4 at 4 times the maximum recommended application rate, or the DMA-4 vehicle alone at 4 times the maximum recommended application rate. A heavy rain shower occurred 24 h after application. The dogs were observed for clinical signs and evaluated using an electroencephalograph, electrocardiograph (lead I), and electromyograph prior to exposure, and either 1 or 7 d after continuous exposure. Clinical examination, hematologic and serum biochemical data were obtained, and serum, urine and kidney 2,4-D were quantified. Half of the dogs from each group were killed after 1 d of continuous exposure, while the other half were killed after 7 d. Gross postmortem and histologic examinations were conducted on each dog. No obvious 2,4-D effects were detected in any of the dogs. [R201] *English pointer dogs dosed po with encapsulated 2,4-dichlorophenoxyacetic acid (2,4-D) at 1.3, 8.8, 43.7, 175 or 220 mg/kg body weight failed to exhibit abnormalities in hematologic, serum biochemical, urinalysis, or electrocardiographic parameters. At the 3 lowest doses, no changes were noted in electro-encephalograms (EEGs). In the dog given 175 mg/kg, at 24 h postdosing mild sedation was accompanied by excessive slowing in the EEG with loss of low voltage fast activity. In the dog given 220 mg/kg, nonspecific alterations in the EEG suggestive of irritation and mild seizure activity was detected 7 h, but the EEG returned to normal by 24 h. A maximum 2,4-D concentration in serum of 1075 ppm was detected 5 h after a po dose of 220 mg/kg. A maximum 2,4-D, concentration in urine of 1792 ppm was detected 2 h after a po dose of 175 mg/kg, while 25 h after that dose kidney tissue contained 271 ppm. [R202] *English Pointer dogs dosed po with encapsulated 2,4-dichlorophenoxyacetic acid (2,4-D) or 2-methoxy-3,6-dichlorobenzoic acid (dicamba) developed varying degrees of myotonia. Dogs given 175 or 220 mg of 2,4-D/kg body weight rapidly developed clinical and electromyographic (EMG) manifestations consistent with a diagnosis of myotonia or pseudomyotonia. Dogs given 2,4-D at 86.7, 43.7 or 8.8 mg/kg body weight developed subclinical manifestations of myotonia detectable only with an electromyograph. The administration of 2,4-D at 1.3 or 1.0 mg/kg body weight failed to produce detectable EMG changes. One dog given dicamba at 86.7 mg/kg body weight developed clinical and EMG manifestations of myotonia similar to those induced by the highest doses of 2,4-D. [R203] *Chick embryos were treated on day 0 of incubation with two phenoxy herbicides, 2-methyl-4-chlorophenoxyacetic acid (MCPA) (0.4, 2 mg/egg) and 2,4-dichlorophenoxyacetic acid (2, 4-D) (1, 2, 4 mg/egg). Both herbicides seemed to exert toxic effects mainly on the liver of 19-day-old embryos. Specific histological analysis indicated biliary stasis. Ethoxycoumarin O-deethylase was depressed by MCPA but raised by 2, 4-D. Other hepatic monooxygenase activities were unaffected by the herbicides and no significant changes were found in cytochromes. The higher dose of MCPA increased NADPH-cytochrome P450 reductase. 2,4-D treatment increased by activity of glutathione-S-transferases in the hepatic post-microsomal fraction while MCPA increased them at the lower dose and significantly reduced them at the higher. [R204] *Pregnant animals (Sprague-Dawley strain) were dosed by oral gavage with one of a series of compounds on days 6-15 of gestation. These chemicals were diquat (DIQ), ethylene-bis-isothiocyanate (EBIS), toxaphene (TOX), styrene (STY), 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenol (2,4,5-Tr), triphenyl tin hydroxide (TPTH), and cacodylic acid (CAC). The compounds were chosen because they exhibited little or no developmental toxicity in previous studies. Dosage levels producing maternal weight loss and/or lethality were determined from preliminary toxicity studies. Significant maternal weight reductions were noted during the course of treatment with all compounds except CAC and 2,4,5-Tr. Maternal lethality was produced by EBIS, TOX, 2,4,-D, and 2,4,5-Tr. The main treatment-related developmental toxicity noted in litters at term consisted of increased lethality (EBIS, TPTH) and decreased fetal weight (EBIS and CAC). Treatment-related anomalies were seen in litters treated with 2,4-D and TOX (supernumerary ribs) and with EBIS and STY (enlarged renal pelvis). No significant developmental effects were produced with DIQ, or 2,4,5-Tr. [R205] *Female crabs of Chasmagnathus granulata, sampled at the external zone of the Rio de la Plata estuary, were chronically exposed to the pesticides parathion and 2,4-D, both of which have been extensively applied to crops in Argentina for a decade and have been detected several times above permissible levels in the estuary. After 2 months of female exposure to the pesticides during the reproductive season, the crabs' ovaries were dissected and fixed in Bouin's solution, to assess the possible effects of pesticides at the histological level. Parathion caused a significant increase in both previtellogenic and vitellogenic oocyte size, as well as a loss of the normal spherical shape of the oocytes. With 2,4-D, a significant decrease in vitellogenic oocyte size was noted, whereas the number of atretic follicles increased as a result of exposure to this herbicide. [R206] *The acute toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) was studied in cattle. Steers were orally treated with 100, 300 or 600 mg 2,4-D/kg. Behavioral alterations, heart and respiratory functions, rectal temperature and ruminal movements were observed at 2, 4, 8, 12, 24, 48, 72 and 96 hr after treatment. At these moments, blood and urine samples were collected and serum 2,4-D levels were determined. Results show that animals' vital function and hematocrit were not modified by the herbicide. Other signs were doses and time-dependent and included motor alterations (weakness, lethargy, decreased general activity) and decreased ruminal movements and proteinuria. The herbicide was rapidly excreted and the intoxication signs were completely reversed. [R207] *Brain uptake is membrane-limited via a blood-brain barrier with saturable clearance from the CSF into the venous blood by the choroid plexus. The body has both a central and a deep compartment with saturable renal clearance from the central compartment. The model was used to examine venous plasma time course curves with experimental data from rats given 2,4-D by i.v. (5 or 90 mg/kg) or by oral ingestion (10, 50, or 150 mg/kg). The model was then extended to examine studies in which rabbit plasma, brain, and CSF concentrations were measured at 2 h after i.p. injection (40 mg/kg). In the rat, elimination was saturable (Vmax2 = 3.45 mg/h; Km2 = 86 mg/l) and the deep-compartment transfer coefficients were K12 (0.013 l/h) and K21 (0.048 l/h) between body and deep tissue compartment. Both oral and i.v. data were well described with these values. Limited single time point brain data from rabbits were analyzed with a lumped brain model assuming the generic model for 2,4-D in rat applies to the rabbit. [R208] *The acute, subchronic and chronic toxicities of 2,4-dichlorophenoxyacetic acid (2,4-D) were studied ir rats. Animals were exposed acutely (600 mg/kg), subchronically (200 ppm for 30 d) and chronically (200 ppm for 180 d) to 2,4-D by the oral route. Clinical, laboratory and histopathological methods were used as indicators of toxicity. After acute exposure, the herbicide decreased locomotor activity and induced ataxia, sedation, muscular weakness (mainly of the hind quarters) and gasping for breath; increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (AP), amylase activities and creatinine levels; decreased total protein (TP) and glucose levels; and increased hematocrit values. Subchronic and chronic 2,4-D exposures did not induce overt clinical signs or symptoms of intoxication. However, subchronic herbicide exposure increased AST activity and albumin and hematocrit values, and chronic exposure increased AST, AP and LDH activities, decreased amylase and glucose levels, but did not change hematocrit values. Chromatographic analysis of the serum of chronically exposed rats showed the presence of the herbicide; the amount found (3.76 + or - 1.16 ug/ml) suggested the absence of 2,4-D accumulation within the body. Although macroscopic or histopathological lesions were not observed in acutely, subchronically or chronically 2,4-D exposed rats, the laboratory data obtained suggest tissue injuries after dosing, since the results are considered early indicators of primarily hepatic and muscle tissue damage. [R209] *The acute toxicity of 2,4-dichlorophenoxyacetic acid (2,4-D) was studied in cattle. Steers were dosed po with 100, 300 or 600 mg 2,4-D/kg bw. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), O-glutamyl transferase (O-GT), creatine kinase (CK), lactate dehydrogenase (LDH) activities and urea, creatinine, glucose, total proteins and albumin levels were determined at intervals after dosing. The lowest 2,4-D dose did not change the biochemical parameters studied; the 300 mg/kg dose decreased AST, O-GT and CK activities and increased urea and glucose levels; the highest dose of 2,4-D increased LDH and CK activities and protein, urea, creatinine and glucose levels. These changes were time and dose-dependent and completely reversible. Acute 2,4-D intoxication disrupted the serum levels of several enzymes and blood components which mainly reflect kidney and muscle damage induced by the herbicide. [R210] *Forms of 2,4-dichlorophenoxyacetic acid (collectively known as 2,4-D) are herbicides used to control a wide variety of broadleaf and woody plants. Subchronic toxicity studies in rats were conducted on three forms of 2,4-D: the parent form, 2,4-D acid; 2,4-D dimethylamine salt (DMA); and 2,4-D 2-ethylhexyl ester (2-EHE). Doses in the subchronic studies (on an acid equivalent basis) were 0, 1, 15, 100, and 300 mg/kg/day. Major treatment related findings in the three studies included decreases in red cell mass, decreases in T3 and T4 levels, decreases in ovary and testes weights, increases in liver, kidney, and thyroid weights, and cataracts and retinal degeneration (high-dose females). These data demonstrated the comparable toxicities of 2,4-D acid, DMA, and 2-EHE and support a subchronic no-observed-effect level of 15 mg/kg/day for all three forms. [R211] *Forms of 2,4-dichlorophenoxyacetic acid ... are herbicides used to control a wide variety of broadleaf and woody plants. Doses in the 2-year chronic/oncogenicity rat study were 0, 5, 75, and 150 mg/kg/day. The chronic toxicity paralleled subchronic findings, and a NOEL of 5 mg/kg/day was established. A slight increase in astrocytomas observed (in males only) at 45 mg/kg/day in a previously conducted chronic rat study was not confirmed in the present study at the high dose of 150 mg/kg/ day. Doses in the 2-year mouse oncogenicity studies were 0, 5, 150, and 300 mg/kg/day for females and 0, 5, 62.5, and 125 mg/ kg/day for males. No oncogenic effect was noted in the study. [R212] *Male CD-1 mice were exposed to a commercial formulation of 2,4-dichlorophenoxyacetic acid (2,4-D), the amine derivative, in the drinking water at concentrations ranging from 0 to 0.163% of the formulated product, equivalent to approximately 0-50 mg kg-1 day-1 2,4-D content. The effect of 2,4-D on urethan-induced pulmonary adenoma formation was evaluated following a 105-day exposure. Urethan-induced sleeping times observed following an i.p. injection of urethan (1.5 mg g-1) after 3 weeks of 2,4-D exposure were not altered by 2,4-D, indicating that 2,4-D did not influence urethan elimination. Pulmonary adenoma production, which was evaluated 84 days after urethan injection, was enhanced by 2,4-D exposure but had no effect on tumor size. The effect of 2,4-D on the incidence of spontaneous murine lymphocytic leukemia was evaluated during the 365-day treatment period. Mortality associated with the leukemia virus was not altered by 2,4-D treatment. Exposure to this commercial 2,4-D product at moderately high levels of exposure may modify the development or expression of certain tumors in CD-1 mice. The mechanism of the co-carcinogenic or tumor-promoting activity associated with 2,4-D exposure remains to be determined. [R213] *The following plants are susceptible (plants are usually killed by one application at 2-3 kg of herbicide in 1000 liters of water, sufficient quantity, 200-1400 liters/ha, should be applied to thoroughly wet the foliage): Alder; Birch, Blueberry; Broom, scotch; Brush-honeysuckle; Caragana, common; Cherry; Chokecherry; Creeper, Virginia; Elderberry; Grape; Hazelnut; Maple, Manitoba; Sagebrush, big; Saskatoon; Sumac; Thimbleberry; Willow. /From table/ [R35] *The following plants are of intermediate sensitivity (more than one application at 2-3 kg of herbicide in 1000 liters of water, sufficient quantity, 200-1400 liters/ha should be applied to thoroughly wet the foliage): Barbarry, common; Buckthorn, European; Bush-cranberry; Cottonwood, black; Dogwood, red-osier; Elm; Hardhack; Locust, black; Meadowsweet; Plum; Poison ivy; Poplar, aspen; Poplar, balsam; Sheep-laurel; Snowberry, western; Sweet-fern. /From table/ [R35] *OBJECTIVE: To investigate the clinical effects and to determine the 2,4-dichlorophenoxyacetic acid plasma concns after a dose of twice the reported LD50 (100 mg/kg) was admin orally to dogs. Investigation included electromyographic evaluations and biochemical parameter determinations, as well as observable clinical signs. METHODS: Six beagle dogs were admin 2,4-dichlorophenoxyacetic acid 200 mg/kg orally. Dogs were monitored for the development of clinical signs and were anesthetized at 24 hr for needle electromyography. Blood was collected pre- and 24-hr postadmin. Plasma was analyzed for total and unbound 2,4-dichlorophenoxyacetic acid by high-performance liquid chromatography with fluorescence detection. Serum was submitted for clinical chemistry parameter analysis. Statistical analyses of the chemistry parameters were performed using paired t-tests. RESULTS: All 6 dogs survived after oral admin of twice the reported LD50. Clinical signs observed were vomiting in 33% and diarrhea in 100% of the dogs. No gait abnormalities were seen in awake dogs. Electromyographic findings revealed predominantly insertional myotonia with 1 dog having spontaneous fibrillations. Decreases from baseline measurements were seen in serum calcium, potassium, and total bilirubin. The mean total and unbound plasma 2,4-dichlorophenoxyacetic acid concns were 511 mg/L AND 129 mg/L, respectively. CONCLUSIONS: This study demonstrates that the beagle dog is less sensitive to the acute effects of 2,4-dichlorophenoxyacetic acid than previously reported. The main clinical effects seen after oral admin of twice the reported LD50 were vomiting and diarrhea. Total and unbound plasma 2,4-dichlorophenoxyacetic acid concns may be a useful indicator of toxicity. [R214] NTOX: *The effects of mixtures of parathion (PA; 5 mg kg-1), toxaphene (TOX; 50 mg kg-1)and/or 2,4-dichlorophenoxyacetic acid (2,4-D; 50 mg kg-1) on the hepatic mixed-function oxygenase (MFO) system were studied in ICR male mice (21-24 g) by oral intubation daily for 7 days. In general, TOX and TOX-containing mixtures were found to induce the metabolism of amidopyrine (21-52%), aniline (58-72%), phenacetin (239-307%), pentobarbital (104-148%) and benzo[a]pyrene (143-304%) in the 9000 g liver supernatants and to increase the hepatic cytochrome P-450 contents (57-80%). Furthermore, the TOX pretreatment was effective in enhancing the biotransformation of PA or paraoxon (PO) in the supernatants. This enhancement was not altered significantly by 5 mM EDTA. Although TOX increased the aliesterase activity in the serum and liver homogenates and supernatants by 31-158%, the activity of paraoxonase was not affected in these preparations. The TOX-induced increase in the metabolism of PA or PO was, at least in part, associated with the MFO system, and paraoxonase did not have significant involvement in the increase. These findings suggest that the toxicity of the PA + TOX mixture would be lower than that of PA, as TOX has the ability to increase the biotransformation of PA, as well as of PO, and the levels of aliesterase, thereby providing a pool of noncritical enzymes for the binding of PO. Because of these properties of TOX, it is anticipated that the toxicity of the PA + TOX + 2,4-D mixture also would be lower than that of PA. [R215] *This paper reviews the properties of the Alcaligenes eutrophus JMP134 tfdA gene product, the enzyme responsible for the first step in 2,4-dichlorophenoxyacetic acid (2,4-D) biodegradation. The gene was overexpressed in Escherichia coli and several of its enzymatic properties were characterized. Although this enzyme catalyzes a hydroxylation reaction, it is not a monooxygenase. Rather, TfdA is an Fe(II) and alpha-ketoglutarate-dependent dioxygenase that metabolizes the latter cosubstrate to succinate and carbon dioxide. A variety of other phenoxyacetates and alpha-ketoacids can be used by the enzyme, but the greatest catalytic efficiencies were found using 2,4-D and alpha-ketoglutarate. The enzyme possesses multiple essential histidine residues, whereas catalytically essential cysteine and lysine groups do not appear to be present. [R216] */In rats exposed for/ 90 days, ... 2,4-D (100 ppm/day) leads to circadium rhythm alterations in the thyroid and the adrenal and to a much lesser degree in the testis. /SRP: Unspecified salt or ester of 2,4-D/ [R217] */In/ ... studies with rats, cats, and dogs ... 2,4-D crystals caused reversible EEG changes. The chronic experiments involved ip injection of 2,4-D at a dose of 200 mg/kg of body weight daily until the death of the animal (usually on the sixth day). Based on these experiments ... it is very likely that 2,4-D accumulates in the organism and in the cerebral tissue causing an increasingly more severe paralysis in the function of these tissues ... Myelopathy manifested as demyelinization was detectable in the dorsal portion of the spinal cord. [R218] HTXV: *The mean adult estimated lethal dose of 2,4-D is 28 g. [R130, 1065] NTXV: *LD50 Mouse ingestion 521 mg/kg /SRP: Unspecified salt or ester of 2,4-D/; [R72, 497] *LD50 Rabbit skin 1400 mg/kg; [R71] *LD50 Guinea pig oral 469 mg/kg; [R91, 1320] *LD50 Hamster oral 500 mg/kg; [R42, 1991.375] *LD50 RAT FISCHER-344 MALE ORAL 443 MG/KG (95% CONFIDENCE LIMITS 270-1103 MG/KG) (2,4-D ACID IN CORN OIL); [R136] *LD50 for 3 week old chicks (M, F) by oral administration of undiluted 2,4-D/2,4,5-T (1:1) was 4000 mg/kg (2700-5900 mg/kg). Acid equivalent was not specified. /From table/; [R219] *The mean adult /oral/ lethal dose of 2,4-D is estimated to be 28 g; [R88, 1093] *LD50 Rabbit oral 800 mg/kg /from table/; [R91, 1320] *LD50 Rat oral 275 mg/kg; [R74, 33] *LD50 Rat (male and female) dermal 2,000 mg/kg; [R74, 33] *LD50 Mouse oral 300 mg/kg; [R74, 33] *LD50 Dog oral 100 mg/kg; [R74, 33] ETXV: *LC50 Salvelinus namaycush (lake trout) 45 mg/l/96 hr (95% confidence limit 35-56 mg/l) /2,4-D acid, granular 100%/ wt 0.3 g, Static bioassay at 10 deg C, without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l; [R220, 1980.59] *LC50 Salmo clarki (cutthroat trout) 64 mg/l/96 hr (95% confidence limit 57-72 mg/l) /2,4-D acid, granular 100%/ wt 0.3 g, Static bioassay at 10 deg C, without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l; [R220, 1980.59] *LD50 ODOCOILEUS HEMIONUS HEMIONUS (MULE DEER) MALE AND FEMALE 8-11 MO OLD ORAL 400-800 MG/KG /TECHNICAL GRADE ACID (> 99%)/; [R136] *LD50 PHASIANUS COLCHICUS (PHEASANT) FEMALE 3-4 MO OLD ORAL 472 MG/KG (95% CONFIDENCE LIMIT 340-654 MG/KG) /TECHNICAL GRADE ACID (> 99%)/; [R136] *LD50 MALLARD (ANAS PLATYRHYNCHOS) FEMALE 3-5 MO OLD ORAL GREATER THAN 1000 MG/KG /TECHNICAL GRADE ACID (> 99%)/; [R136] *TLm Crassostrea virginica (American oyster), egg: 8X10+3 ppb/48 hr; larvae: 740 ppb/14 day; Static lab bioassay /2,4-D Unspecified ester/; [R72, 497] *TLm Crassostrea virginica (American oyster), egg: 2.044X10+4 ppb/48 hr; larvae: 6.429X10+4 ppb/14 day; Static lab bioassay /Unspecified 2,4-D salt/; [R72, 497] *LC50 Lepomis macrochirus (bluegill fish) 0.9 ppm/48 hr /Conditions of bioassay not specified/; [R72, 497] *LC50 Salmo gairdneri (rainbow trout) 1.1 ppm/48 hr /Conditions of bioassay not specified/; [R72, 497] *LC50 Morone saxatilis (striped bass) 70.1 mg/l/96 hr static bioassay; [R72, 497] *LC50 Banded killifish 26.7 mg/l/96 hr static bioassay; [R72, 497] *LC50 Lepomis gibbosus (pumpkinseed fish) 94.6 mg/l/96 hr static bioassay; [R72, 497] *LC50 Morone americana (white perch) 40.0 mg/l/96 hr static bioassay; [R72, 497] *LC50 Anguilla rostrata (American eel) 300.6 mg/l/96 hr static bioassay; [R72, 497] *LC50 Cyprinus carpio (carp) 96.5 mg/l/96 hr static bioassay; [R72, 497] *LC50 Lebistes reticulatus (guppy) 70.7 mg/l/96 hr static bioassay; [R72, 497] *LC50 Alburnus alburnus (bleak) embryo 159 mg/l/12 hr /Conditions of bioassay not specified; sodium salt/; [R72, 497] *LC50 Alburnus alburnus (bleak) embryo 129 mg/l/24 hr /Conditions of bioassay not specified; sodium salt/; [R72, 497] *LC50 Alburnus alburnus (bleak) embryo 64 mg/l/36 hr /Conditions of bioassay not specified; sodium salt/; [R72, 497] *LC50 Alburnus alburnus (bleak) embryo 13 mg/l/48 hr /Conditions of bioassay not specified; sodium salt/; [R72, 497] *LC50 Lebistes reticulatis (guppy) 3758.4 mg/l/24 hr /Conditions of bioassay not specified; SRP: Unspecified salt or ester of 2,4-D/; [R221] *LC50 Daphnia magna (water flea) 363-389 mg/l/48 hr /Conditions of bioassay not specified, SRP: Unspecified salt or ester of 2,4-D/; [R221] *LD50 Columba livia (rock dove) male and female oral 668 mg/kg (95% confidence limit 530-842 mg/kg) /Technical grade acid (> 99%)/; [R136] *LD50 Alectoris chukar (chukar) male and female 4 mo old oral 200-400 mg/kg /Technical grade acid (> 99%)/; [R136] *LD50 Anas platyrhynchos (mallard) male 4 mo old oral > 2000 mg/kg /Technical grade acid (> 99%)/; [R136] *LD50 COTURNIX JAPONICA (JAPANESE QUAIL) MALE 2 MO OLD ORAL 668 MG/KG (95% CONFIDENCE LIMIT 530-842 MG/KG) /TECHNICAL GRADE ACID (> 99%)/; [R136] *LD50 Coturnix japonica (Japanese quail) male and female 14 days old oral > 5000 ppm /Technical grade acid, 75%/; [R222] *The 2,4-D acid /100% granular was/ ... about half as toxic to fish /lake and cutthroat trouts/ at pH 8.5 as at pH 6.5. Static bioassay without aeration, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l; [R220, 1980.60] *Anabaenopsis raciborskii (blue green algae) at 10 mg/l: Stimulated growth and nitrogen fixation; At 100 mg/l, no significant inhibition of growth; At 1000 mg/l, complete inhibition of growth. /SRP: Formulation not specified/; [R72, 496] *Toxic dose Tubifex tubifex (worm) 80 mg/l /SRP: Unspecified salt or ester of 2,4-D/; [R72, 497] POPL: */Persons suffering from/ liver disease, kidney disease, cardiovascular disease, skin disease, convulsive disorders or neuropathy are at increased risk from 2,4-D exposure. [R70, 1981.1] ADE: *2,4-D ... was readily absorbed by humans after oral ingestion (5 mg/kg), and maximal plasma concns of 30 ug/ml were attained after 7-12 hr; 75% of the dose was excreted unchanged in the urine within 96 hr, and no metabolites were detected. [R223] *When (14)C-2,4-D was injected iv into volunteers, 100% was recovered in the urine. The rate of excretion ranged from about 3-5% of the dose/hr during the first 12 hr; it then declined gradually, but a trace was still detectable in urine collected 96-120 hr after injection. Following dermal application, only 5.8% appeared in the urine within 5 days. ... Six volunteers ... /ingested/ one dose of 2,4-D at the rate of 5 mg/kg. Absorption was rapid; the cmpd appeared in the blood within 1 hr, and reached its max level of 25-50 ppm in 7-12 hr in different men. 2,4-D appeared in urine within 2 hr. Ninety-six hr after ingestion, 76% of dose had been excreted unchanged in urine. [R91, 1322] *Distribution of 2,4-D occurs throughout the body, but there is no evidence that it is accumulated. Transformation in mammals appears to occur only to a slight extent and mainly involves the production of 2,4-D conjugates with sugars or amino acids. A single dose is excreted within a few days, mainly with the urine, and to a much lesser extent in the bile and feces. [R224] *Pretreatment of rats with 2,4-D (250 mg/kg, sc) so occupied binding sites on plasma proteins that the distribution of (14)C-2,4-D admin iv 3.5 to 4.5 hr later was changed relative to controls, the concn being less in the plasma and kidney and greater in the liver, brain, spinal fluid, testis, lung, heart, and muscle. [R118, 522] *... Human beings excrete 2,4-D mainly in the urine, and the blood plasma clearance times depend on the dose, individual characteristics, and the presence or absence of cmpds that may competitively inhibit 2,4-D excretion. For single oral doses of 2,4-D, the biological half-life in blood plasma is about one day, depending on the circumstances. However, forced alkaline diuresis may reduce this to as little as 3.7 hr. [R225] *FOUR MEN SPRAYING 2% EMULSION IN KEROSENE FROM TRACTORS WERE EXPOSED TO PHENOXY ACIDS. AIRBORNE CONCNS WITH STATIONARY SAMPLING POINT AND FROM THE INDIVIDUAL BREATHING ZONE SHOWED A MEAN 2,4-D AND 2,4,5-T CONCN OF 0.1-0.2 MG/CU M. PLASMA AND URINE LEVELS WERE FOLLOWED DURING THE WK OF EXPOSURE AND FOR 36 HR AFTER EXPOSURE. THE HIGHEST LEVELS OF PHENOXY ACIDS WERE FOUND IN URINE WITH A MEAN OF 8 (2,4-D) and 4.5 (2,4,5-T) UG/ML AND RANGING FROM 3-14 UG/ML FOR 2,4-D AND FROM 1-11 UG/ML FOR 2,4,5-T IN THE AFTERNOON AFTER A DAY OF EXPOSURE. THE MEAN 24 HR EXCRETION IN URINE WAS 9 MG OF 2,4-D AND APPROX 1 MG OF 2,4,5-T. [R226] *2,4-D was distributed evenly among various tissues in several species, after acute or chronic exposure. ... Plasma levels were usually slightly higher than other tissues, followed by renal levels, and then hepatic and pulmonary levels, although all were within the same order of magnitude. 2,4-D was further distributed to the plasma fraction of whole blood primarily, and to the cytosol subfraction in cells. 2,4-D showed high affinity binding to the albumin fraction of serum. 2,4-D was not accumulated in fat or muscle of sheep or cattle during a 28 day feeding experiment. [R227] *The rate of dermal absorption of 2,4-D has been measured in human volunteers; 100% of the dose was excreted in the urine during the subsequent 5 days. The biological half-life for excretion was 13 hr. (14)C-2,4-D was then applied to the forearm, and excretion of radioactivity was monitored over the subsequent 8 days. Using this method, 5.8% of the dose was absorbed and excreted. This rate was increased to 14.7% by occluding the application site with plastic film for 24 hr after dosing. [R228] *Plasma 2,4-D concn did not exceed 0.2 mg/l in workers exposed to 2,4-D ester at an atmospheric concn of 0.1 to 0.2 mg/l; no accumulation was noted during the work wk. ... Workers ... excreted 2,4-D urine concns of 3-14 mg/l after a day of exposure. [R229, 118] *AFTER SC INJECTION OF 2,4-D AND ITS BUTYL AND ISOOCTYL ESTERS INTO MICE @ 100 MG/KG, ESTERS WERE ELIM RAPIDLY, AND ONLY 5-10% OF THE 2,4-D REMAINED AFTER 1 DAY. ... 2,4-D WAS ELIM IN MILK OF COWS MAINTAINED IN PASTURES TREATED WITH 2,4-D OR ITS BUTYL OR ISOOCTYL ESTER. [R2, 494] *... ISOOCTYL ESTER OF 2,4-D DISAPPEARED FROM BODIES OF INJECTED MICE MORE RAPIDLY THAN 2,4-D ACID. [R230] */RELATIVE/ RATES OF DISAPPEARANCE FROM PLASMA OF 2,4-D OR ITS BUTYL AND ISOOCTYL ESTERS FOLLOWING SINGLE SC INJECTIONS OF 100 MG/KG BODY WT OF COMPOUNDS TO FEMALE C57BL/6 MICE WERE: BUTYL ESTER > ISOOCTYL ESTER > 2,4-D. [R231] *AFTER ORAL ADMIN OF 0.05 MG/KG BODY WT TO RATS, TRACES WERE DETECTED IN MILK OF LACTATING ANIMALS FOR 6 DAYS. WITHIN 24 HR AFTER ADMIN 2,4-D TO PREGNANT RATS, 16.8% OF DOSE WAS DETECTED IN UTERUS, PLACENTA, FETUS AND AMNIOTIC FLUID. 2,4-D ... PASSES THE PLACENTAL BARRIER IN PIGS. [R139] *The amounts of 2,4-D excreted by workers occupationally exposed to 2,4-D has been used to estimate total doses absorbed by these workers. Aerial applicators excreted an average 0.012 mg/kg body weight/day of 2,4-D after a 12 day exposure period; Ground applicators excreted a mean of 0.013 mg/kg of 2,4-D over a 6-day period after a 1 day exposure. [R232] *WHEN 2,4-D WITH LABELED CARBON WAS ADMIN ORALLY TO SHEEP, 96% OF DOSE WAS EXCRETED UNCHANGED IN URINE IN 72 HR, SLIGHTLY < 1.4% IN FECES. ... WHEN ADULT SHEEP AND CATTLE WERE FED 2,4-D IN DIET FOR 28 DAYS AT UP TO 2,000 PPM, KIDNEY CONTAINED HIGHEST AND LIVER SOMEWHAT LOWER CONCN OF 2,4-D AND ITS BREAKDOWN PRODUCT 2,4-DICHLOROPHENOL. WITHDRAWAL FROM TREATMENT FOR 7 DAYS RESULTED IN ALMOST COMPLETE ELIMINATION OF 2,4-D AND ITS MAJOR METABOLITE FROM TISSUES. IN RATS THAT RECEIVED 1-10 MG OF 2,4-D, THERE WAS ALMOST COMPLETE EXCRETION IN URINE AND FECES IN 48 HR; AT HIGHER DOSES SOME ACCUMULATION OCCURRED IN TISSUES. AFTER SC INJECTION OF 2,4-D INTO MICE AT 100 MG/KG ... ONLY 5-10% OF 2,4-D REMAINED AFTER 1 DAY. ... IN FEEDING STUDIES OF 2,4-D WITH DAIRY COWS AND STEERS, UNCHANGED 2,4-D WAS FOUND IN URINE. OTHER STUDIES DEMONSTRATED THAT 2,4-D WAS ELIMINATED IN MILK OF COWS MAINTAINED IN PASTURES TREATED WITH 2,4-D ... . [R2, 494] *In 1.4 minutes, 50% of intratracheally instilled doses of 2,4-D were absorbed by the /rat's/ lung, indicating that alveolar transport was probably by diffusion. [R232] *Levels of 2,4-D were measured in the rat brain and cerebrospinal fluid after a 100 mg/kg (slightly toxic) dose. In comparison, (250 mg/kg) produced myotonia and lethargy and resulted in 11- and 39-fold increases in 2,4-D concentration in the brain and cerebrospinal fluid respectively, while 500 mg/kg produced 18- and 67-fold increases, in 2,4-D concentrations, respectively. Increases in hepatic 2,4-D levels were also produced, although less dramatic. [R233] *... Female dogfish sharks (Squalus acanthias) were admin (14)C-2,4-D iv. Urine, bile, and blood were collected and analyzed for radioactivity, along with tissues. Urine contained 53% of the admin dose of 2,4-D in 4 hr, 68% in 1 day, and 90% in 6 days. 2% of the dose was excreted in bile in 6 days. From 94-98% of the radioactivity in urine and bile was conjugated to taurine, 2-4% was present as 2,4-D, acid and 4% as 2 unidentified metabolites. The half-life of plasma clearance of 2,4-D was 44 min. Tissue levels for the kidney and liver were 2-40 times that for the plasma, and were lower than plasma levels for muscle, brain, and cerebrospinal fluid. Plasma binding ... was about 57% for concns up to 50 ug/ml herbicide. ... [R234] *The chlorinated phenoxy acid herbicides appear to have similar pharmacokinetics. They are rapidly and almost completely absorbed from an oral dose. They distribute to other tisues and are highly protein-bound in the plasma. The chlorinated phenoxy acid herbicides are rapidly eliminated unchanged in the urine by an active process in the kidneys. Increasing doses apparently influence absorption, metab, distribution and elimination of the chlorinated phenoxy acid herbicides so that biological effects are increased. Combinations of chlorinated phenoxy acid herbicides are likely to result in additive or potentiated biological effects. Data suggest that chlorinated phenoxy acid herbicide toxicosis may be alleviated by treatment with fluids and bicarbonate to increase urinary pH and volume, thereby increasing excretion. [R235] *The distribution of 3 common (14)C-labelled chlorophenoxyacetic acid herbicides (2,4-dichlorophenoxyacetic acid or 2,4-D, 2-methyl-4-chlorophenoxyacetic acid or MCPA, 2,4,5-trichlorophenoxyacetic acid or 2,4,5-T) into the different brain areas was studied in rats pretreated with toxic doses of the herbicides (238-475 mg/kg). Also, their binding to proteins in rat plasma was determined in vitro by increasing the concns of chlorophenoxyacetic acids in the incubate from 0 to 1 mg/ml. Both 2,4-D AND 2-methyl-4-chlorophenoxyacetic acid pretreatments increased brain concns of (14)C-labelled herbicides more markedly than 2,4,5-T pretreatments. No essential differences were found in the distribution between the different brain areas. Protein-unbound fractions of 2,4-D AND 2-methyl-4-chlorophenoxyacetic acid in the plasma were higher than those of 2,4,5-T but the highest herbicide concn increased the protein-unbound fraction of 2,4,5-T more (7-13 fold) than of 2,4-D AND 2-methyl-4-chlorophenoxyacetic acid (5 fold). The greater incr in the penetration into the brain of 2,4,-D AND 2-methyl-4-chlorophenoxyacetic acid than of 2,4,5-T during their intoxication is due to factors other than the changes in their binding to plasma proteins and enhanced diffusion through the blood brain barrier. [R236] *This study was designed to measure potential dermal and respiratory exposure during the application of 2,4-dichlorophenoxy acetic acid, with 5 types of application equipment commonly used in the United Kingdom. For all 5 sprayers, potential respiratory exposure, where detectable at all, was negligible compared with potential dermal exposure. [R237] *The exposure of forestry ground crews applying 2,4-dichlorophenoxy acetic acid (2,4-D), dichloroprop, and picloram was determined as a function of varying application methods and safety measures. Backpack sprayers received very high exposures to herbicides due to absorption of the chemicals through their clothes and skin (0.04 to 0.24 mg/kg body weight for 2,4-D). ... [R238] *Renal slices were prepared from kidneys of male Sprague-Dawley rats and were preloaded by incubation with 7.65 ug of (14)Carbon 2,4-D in 3 ml buffer for 1 hr at 25 deg C. The slices were then transferred through a series of 18 sequential 1 min washes and the radioactivity transferred into each wash solution and the amount that remained in the tissue was counted. The rate constant for efflux was then calculated. Tissue extracts were analyzed by paper electrophoresis for radioactive metabolites of 2,4-D. The kinetics of efflux were comprised of a fast and a slow component. Compounds that significantly increased the slow phase when added to the efflux medium were probenecid, dinitrophenol, stilbene derivative, iodoacetamide, succinate; Succinate and lactate both increased the rate for the fast phase. The rate of 2,4-D efflux was temperature dependent, with faster rates for 15 deg C and 35 deg C than at 25 deg C. Efflux was significantly increased (slow phase only) in potassium free buffer, but was unaltered in calcium-free buffer. Uptake of 2,4-D was linear for 7 hr and transported 2 times more 2,4-D into the kidney than was transported out by the efflux mechanism. At 20 uM, 2,4-D produced a 50% inhibition of para-aminohippurate accumulation in renal cortical slices. ... /SRP: Formulation not specified/ [R239] *Absorption and urinary excretion of 2,4-dichlorophenoxyacetic acid sodium and 2,4-dichlorophenoxyacetic acid dimethylammonium salts were examined after single oral and mid-dorsal skin applications of the herbicides to male rats. Doses of 2.6 mg 2,4-D/kg body wt (2,4- dichlorophenoxyacetic acid sodium) and 1.9 mg 2,4-D/kg body wt (2,4- dichlorophenoxyacetic acid dimethylammonium) were applied. Quantitatively, with both salts, most of the orally administered herbicide (over 90%) was excreted in urine within 28 hr. However, 2,4-D urinary peak concentrations were measured 4.5 and 20.5 hr after dosing with 2,4-dichlorophenoxyacetic acid dimethylammonium and 2,4- dichlorophenoxyacetic acid sodium, respectively. Additionally, the volume of urine in the oral study was significantly increased with both salts when compared with the controls or the dermal exposure. After topical application, 2,4-D absorption was much lower than in the oral study. Urinary excretion only reached about 10 and 15% of the applied dose for 2,4-dichlorophenoxyacetic acid sodium and 2,4- dichlorophenoxyacetic acid dimethylammonium, respectively, by 5 days post-treatment. Further, it was found some elevations in hepatic cytochrome p450 activities. Ethylmorphine N-demethylase was only slightly induced by the herbicides while ethoxyresorufin O-deethylase activity was increased nearly 2 fold by 2,4-dichlorophenoxyacetic acid sodium. [R240] *2,4 D was rapidly absorbed, distributed, and excreted after oral administration to mice, rats, and goats. At least 86-94% of an oral dose was absorbed from the gastrointestinal tract in rats. 2,4 D was excreted rapidly and almost exclusively (85-94%) in urine by 48 hr after treatment, primarily as unchanged 2,4 D. [R44, p. V4 492] *Absorption of 2,4-D appears to be rapid and complete from the GI tracts of humans and experimental animals ... . Although ingestion is usually a relatively minor route of exposure, most toxicity testing of 2,4-D has been conducted by oral exposure. Because 2,4-D is absorbed more efficiently through the GI tract than through the skin, 2,4-D should be more toxic when ingested than when applied to the skin. [R44, p. V4 492] *Once absorbed, 2,4 D was widely distributed throughout the body, but did not accumulate because of its rapid clearance from the plasma and rapid urinary excretion ... . The excretion, tissue residues, and metab of 14C 2,4-D were investigated in a lactating goat given an oral dose of 483 ppm for 3 consecutive days in a capsule. About 90% of the dose was recovered in the urine and feces. Milk, liver, kidneys, composite fat, and composite muscle accounted for < 0.1% of the total dose received. The residues in the milk were 0.22-0.34 ppm at the morning milking and 0.04-0.06 ppm in the evening. Kidneys accounted for the highest residue concentration, 1.4 ppm; liver contained 0.22 ppm ... . [R44, p. V4 492] *Almost all of a 2,4-D oral dose in absorbed in humans within 24 hr. Peak plasma concns are reached between 4-24 hr ... . Six human volunteers received 5 mg/kg (370 mg/70 mg) of 2,4-D orally. The average peak plasma concn was 35 mg/L at 24 hr. The mean plasma half-life in this study was 33 hr. They are highly protein bound in plasma. Elimination is rapid. 2,4-D metabolites other than conjugates have not been detected in human urine. During the 4 days following the ingestion by the 6 subjects above, 77% of the dose was eliminated unchanged in the urine. All remained asymptomatic. In another study five male human volunteers ingested a single oral dose of 5 mg/kg 2,4-D. No detectable clinical effects were noted. The average plasma T1/2 was 11.6 hr with a mean urine T1/2 of 17.7 hr. 83% of the ingested oral dose was excreted as the parent cmpd, and 12.8% of the oral dose was excreted in the urine as an acid-labile conjugate. [R130, 1064] *...The physiologic distribution of ... 2,4-D in humans is not fully understood, but it appears that /it/ may distribute into only one or two compartments. This would be in contrast to other mammals, in which multiple compartments are found. It also appears that humans store 2,4-D in the liver and kidneys after high-level exposure, while the liver, kidney, lungs, spleen, and heart of other mammalian species have been found to have high 2,4-D levels. Urinary excretion is the primary route for elimination ... . It is important to note that it has been found that elimination is not first order; that is, the rate of excretion of ... 2,4-D depends on the initial concn. When the kinetics of a bioreaction are not first order, extrapolation of effects from high concns to low ones, or vice versa, usually is not possible unless the kinetics have been carefully studied and the rate constants calculated. [R241] *2,4-Dichlorophenoxyacetic acid (2,4-D), a widely used broadleaf herbicide, is under investigation in a study of peroxisome proliferators. To supplement that study, male and female rats, mice, and hamsters were dosed with 14C-2,4-D orally at 5 and 200 mg/kg and tissue distributions were determined. Blood, liver, kidney, muscle, skin, fat, brain, testes, and ovaries were examined. At early time points tissues from female rats consistently contained higher amounts of radioactivity than did corresponding tissues from males (up to 9 times). By 72 hr, tissue levels were equivalent and males and females had excreted equal amounts of radioactivity. This sex difference was absent in mice. In hamsters, males had higher tissue levels than females. Taurine, glycine, and glucuronide conjugates of 2,4-D were excreted along with parent. Metabolite profiles differed between species qualitatively and quantitatively; however, differences between sexes were minimal. Plasma elimination curves were generated in male and female rats after iv and oral administration. Kinetic analysis revealed significant differences in elimination and exposure parameters consistent with a greater ability to clear 2,4-D by male rats relative to females. [R242] *The role of biliary elimination in the metabolic disposition of 2,4-D was evaluated in male and female Sprague-Dawley rats, B6C3F1 mice, and Syrian hamsters. Following cannulation of the bile duct, an intragastric (ig) dose of 2,4-D (200 mg/kg) was administered and bile was collected at 30- or 60-min intervals for up to 6 h. Bile flow rates were constant in rats, increased in mice, and decreased in hamsters throughout the collection periods. Total recovery of radioactivity was greatest in male mice (about 7% of administered dose over 4 h). Female mice and rats of both sexes excreted about 3% over the same interval and male and female hamsters about 1%. About 71-88% of the activity in bile was parent compound. The glycine conjugate of 2,4-D was found in bile from mice, rats, and hamsters and the taurine conjugate in bile from mice. The only sex-dependent difference in the metabolite profile was in mice. Male mice excreted twice as much glycine conjugate as female mice. An additional minor metabolite (4-7%) was present in rat and mouse bile. This was tentatively identified as 2,4-D-glucuronide based on its hydrolysis by beta-glucuronidase. One more very minor metabolite (3%) was detected in rat bile but was not characterized due to its lability. [R243] *The distribution of 2,4-dichlorophenoxyacetic acid (2,4-D) was examined in maternal and fetal rabbits. Pregnant New Zealand rabbits (28-30 d gestational age) were anesthetized with ketamine/xylazine and the femoral vein and artery were catheterized for compound admin and sampling. Dams received iv [14C]2,4-D (12.5 microCi/kg) with unlabeled sodium 2,4-D (1, 10, or 40 mg/kg) in saline. Blood and tissue were collected up to 2 hr after dosing. Fetal to maternal plasma AUC ratios were 0.09, 0.07, and 0.16 after the 1, 10, or 40 mg/kg dose, respectively. Extraplasma AUCs were greatest in maternal kidney and uterus and lowest in maternal and fetal brain. A > fourfold elevation in fetal AUC was found when the dose was increased from 10 to 40 mg/kg, suggesting saturation of maternal plasma binding of 2,4-D. Although the in vitro fetal brain tissue to incubation media ratio was unity (1.03 + or - 0.1, mean + or - SD), fetal brain AUCs were 10% or less of the fetal plasma AUCs, indicating the brain barrier system to 2,4-D is functioning in the late-gestation fetal rabbit. [R244] *... Transport of the herbicide, 2,4-dichlorophenoxyacetic acid (2,4-D), was examined in rat renal cortical slices and basolateral membrane vesicles. In slices, uptake of 2,4-D increased steadily over time, approaching steady-state tissue/medium ratios of approximately 8 after 60 min. Probenecid, PAH and chlorophenol red inhibited steady-state uptake of 2,4-D. Accumulation of 10 microM 2,4-D was stimulated 2-fold by 60 microM glutarate; other dicarboxylic acids failed to stimulate uptake. In the presence of sodium, the addition of 5 mM LiCl or 2 mM ouabain to the bathing medium abolished glutarate stimulation. Removal of sodium from the bathing medium reversibly inhibited uptake as much as 75%. Furthermore, PAH inhibited 2,4-D uptake by slices in a dose-dependent manner, and increasing the external 2,4-D concentration decreased the inhibitory potency of PAH. In basolateral membrane vesicles, unlabeled 2,4-D inhibited sodium glutarate-coupled uptake of 3H-labeled PAH and 2,4-D in a concentration-dependent manner. Moreover, concentrative uptake of 2,4-D into vesicles could be driven by an outwardly directed gradient of glutarate or alpha KG that was generated by lithium-sensitive Na+/dicarboxylate cotransport or imposed experimentally. An outwardly directed gradient of unlabeled 2,4-D or PAH also stimulated uptake of 2,4-D. [R245] *... With control acetone vehicle, in vivo absorption of 2,4-D in the rhesus monkey was 8.6 +/- 2.1% of the dose, which compared closely to published human absorption of 6.0 +/- 2.4%. Percutaneous absorption from soil loads of 1 and 40 mg/cm2 were 9.8 +/- 4.0 and 15.9 +/- 4.7%, respectively, values similar to acetone vehicle. In vitro absorption in human skin calculated from skin contact accumulation over 24 hr was 1.8 +/- 1.7, 1.7 +/- 1.3, and 1.4 +/- 1.2% for soil loads of 5, 10, and 40 mg/cm2, respectively. Thus, soil load did not affect 24 hr percutaneous absorption. Current EPA recommended calculated reductions due to soil load are not supported by these results with 2,4-D. Percutaneous absorption of 2,4-D from acetone vehicle for 8 hr dosing period was 3.2 +/- 1.0%, one-third the value of 8.6 +/- 2.1% over 24 hr. With soil vehicle, absorption for 8 hr was only 0.03 +/- 0.02% for 40 mg/cm2 soil load and 0.05 +/- 0/.004% for 1 mg/cm2 soil load. Absorption for 16 hr was 2.2 +/- 1.2%. Absorption over time was linear for acetone vehicle, where total dose is deposited on skin, but not linear for soil vehicle, which had an 8 hr delay (lag time). This equates with a normal 8 hr work day where most of the contaminated soil can be washed off the skin. [R246] *The influx of 2,4-dichlorophenoxyacetic acid (2,4-D) into Chinese hamster ovary (CHO) cells was studied. The cells mainly took up but did not metabolize the undissociated form of the herbicide. The uptake of 2,4-D was carried out against a concentration gradient and was inhibited by sodium azide and dinitrophenol. The results presented here show that the herbicide influx was an active, energy dependent process. (Na+ + K+)ATPase does not seem to be involved because ouabain, an inhibitor of the enzyme, did not affect the 2,4-D uptake. [R247] *Percutaneous absorption of the 14C-ring-labeled phenoxy herbicide 2,4-D-amine (2,4-dichlorophenoxyacetic acid dimethylamine) was examined following topical applications of the herbicide to the palm and forearm of human volunteers. The effect of two vehicles (water and acetone) and the mosquito repellent DEET (N,N-diethyl-m-toluamide) on dermal absorption of 2,4-D-amine also was investigated. The total percent dermal absorption was calculated from the mean percent urinary recoveries and was not corrected for nonurinary excretion. The data revealed 14 +/- 4.5% (standard deviation) and 10 +/- 11.5% palmar absorption of 2,4-D-amine applied in water, with and without DEET, respectively, and 7 +/- 6.2% and 13 +/- 5.0% forearm absorption of the herbicide applied in water or acetone, respectively. Soap-and-water skin washes conducted at 24 h posttreatment removed up to 34% of the applied dose. Successive tape strips of skin taken at 24 h posttreatment demonstrated generally decreasing herbicide levels in the outer layers. The data bring into question the complete validity of the rhesus monkey model to predict human dermal absorption. [R248] *The percutaneous penetration of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4-D dimethylamine salt (DMA) was evaluated separately in five male volunteers who participated in both experiments. Urine samples collected for 144 h following dermal applications of 10 mg to the dorsum of the hand (9 cm2) were analyzed for 2,4-D. Following the acid application, an average of 4.46 +/- 0.849% was recovered in the urine and a significantly lower amount of 1.76 +/- 0.568% following the DMA application. Significantly higher amounts of 2,4-D DMA (7.68 +/- 0.493 mg) were washed off the hand 6 h following application as compared with 2,4-D acid (5.35 +/- 0.384 mg). These results indicate that, in addition to the differences in physical and chemical properties of the two compounds that will affect absorption, the amount of the chemical absorbed is related inversely to the amount of washed off. Urinary excretion of 2,4-D was not complete in all volunteers 144 h following either application, but in all cases it was approaching the limit of detection. An average of 84.8 +/- 2.55% and 76.8 +/- 8.05% of the total recovered in 144 h was recovered in the urine 96 h following 2,4-D acid and 2,4-D DMA application, respectively. Average, approximated half-lives for excretion were 39.5 +/- 8.1 h for the acid application and 58.5 +/- 13.2 h for the DMA application. [R249] METB: *STUDIES /IN PLANTS/ HAVE SHOWN COMPLEXES WITH PROTEIN OR AMINO ACIDS, OXIDN OF ACETATE MOIETY AND OF RING, HYDROLYSIS TO FREE PHENOL, AND COMBINATION WITH GLYCOSIDES. [R69, 132] *IN ... STUDIES WITH ENZYME PREPN FROM ARTHROBACTER SPECIE, 2,4-D WAS CONVERTED TO 2,4-D PHENOL AND GLYOXYLATE. CONDENSATION OF THE TWO GLYOXYLATE MOLECULES OCCURRED WITH LOSS OF CO2 FROM ONE CARBOXYL GROUP. A CMPD CHROMATOGRAPHICALLY IDENTICAL TO ALANINE WAS OBSERVED. WITH RING-LABELED 2,4-D, LABELED SUCCINATE WAS PRODUCED. [R250, 196] *BOTH PLANTS AND SOIL MICROORGANISMS HAVE CAPABILITY OF DEGRADING ACID SIDE CHAIN OF HIGHER HOMOLOGS /OF 2,4-D AND 2,4,5-T/ BY TWO CARBON SCISSION (OXIDATION). ... EVEN-NUMBERED SIDE CHAINS DEGRADE TO HERBICIDALLY ACTIVE ARYLOXYACETIC ACIDS. [R251] *2,4-D ESTERS ARE HYDROLYZED IN ANIMALS. THE PHENOXY ACIDS ARE EXCRETED PREDOMINANTLY AS SUCH IN THE URINE OF RATS AFTER THEIR ORAL ADMIN, ALTHOUGH MINOR PORTION IS CONJUGATED WITH AMINO ACIDS GLYCINE AND TAURINE AND WITH GLUCURONIC ACID. [R231] *BEAN, BLUEGRASS, AND CORN WERE EXPOSED TO 2,4-D. CHROMATOGRAPHIC ANALYSES INDICATED THAT ALL 3 PLANTS METABOLIZED 2,4-D. THE MAJOR METABOLITE APPEARED TO BE 4-HYDROXY-2,5-DICHLOROPHENOXYACETIC ACID ... AND MINOR METABOLITE ... 4-HYDROXY-2,3-DICHLOROPHENOXYACETIC ACID. ... ESSENTIALLY ALL 2,4-D ABSORBED BY BLUEGRASS OR CORN WAS RAPIDLY CONJUGATED. THIS REACTION WAS SLOWER IN BEANS. SOME SIDE CHAIN OXIDATION ALSO OCCURRED. ... 4-HYDROXY-2,3-DICHLOROPHENOXYACETATE ... /WAS/ DETECTED IN WILD BUCKWHEAT, WILD OAT, AND YELLOW FOXTAIL ONLY. 2-CHLORO-4-HYDROXYPHENOXYACETIC ACID WAS FOUND IN THE THREE FOREGOING SPECIES AND LEAFY SPURGE. /SRP: UNSPECIFIED SALT OR ESTER OF 2,4-D/ [R252] *AFTER FEEDING 2,4-D TO SHEEP AND CATTLE, ANALYSIS OF MUSCLE, FAT, LIVER AND KIDNEY SHOWED PRESENCE OF 2,4-DICHLOROPHENOL. /SRP: UNSPECIFIED SALT OR ESTER OF 2,4-D/ [R253] *SOYBEAN ROOT CALLUS CULTURES METABOLIZED 2,4-D. METABOLITES IDENTIFIED INCLUDED 2,4-D-GLUTAMIC ACID AND 2,4-D-ASPARTIC ACID CONJUGATES; OTHER NOT IDENTIFIED 2,4-D AMINO ACID CONJUGATES; 2,5-DICHLORO-4-HYDROXYPHENOXYACETIC ACID (4-OH-2,5-D); AND 5-OH-2,4-D ... IN A COMPARISON OF 2,4-D METABOLISM BY SOYBEAN CALLUS, SOYBEAN PLANT AND CORN PLANTS, NO QUALITATIVE DIFFERENCES WERE OBSERVED. HYDROXY CMPD, MAINLY AS GLUCOSIDES, WERE IDENTIFIED AS 5-OH-2,4-D, 4-OH-2,3-D, AND 4-OH-2,5-D. AMINO ACID CONJUGATES WERE IDENTIFIED AS 2,4-D CONJUGATES OF ASPARTIC ACID, GLUTAMIC ACID, ALANINE, VALINE, PHENYLALANINE, TRYPTOPHAN AND LEUCINE. THERE WERE SOME DATA THAT SUGGESTED THE PRESENCE OF AMINO ACID CONJUGATES OF RING HYDROXYLATED 2,4-D. /SRP: UNSPECIFIED SALT OR ESTER OF 2,4-D/ [R250, 193] *MALE VOLUNTEERS INGESTED SINGLE DOSE OF 5 MG/KG. EXCRETION OCCURRED MAINLY AS 2,4-D (82.3%) WITH SMALLER AMT AS 2,4-D CONJUGATE (12.8%). /SRP: UNSPECIFIED SALT OR ESTER OF 2,4-D/ [R254] *The conversion of 2,4-D to 2,4-dichlorophenol has been demonstrated in sunflowers, corn, barley, strawberries, and kidney beans. /SRP: Unspecified salt or ester of2,4-D/ [R255] *To determine whether the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) changes the way the liver metabolizes 2,4-dichlorophenoxyacetate (2,4-D), male Sprague-Dawley rats were injected with 2,3,7,8-tetrachlorodibenzo-p-dioxin (31.5 ug/kg body weight) or solvent carrier, 48 hr prior to removal of the liver for a liver perfusion system using (14)C-2,4-D (final concentration of 25 uM, 0.4 uCi/umol). ... Analysis of bile and perfusates from control liver showed primarily 2,4-D and a trace of 2,4-D-glycine. Liver from animals treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin produced results almost identical to the control. One exception was the presence of a new metabolite in amounts too small to identify. Analysis of the macromolecular components for covalently bound (14)C-2,4-D indicated that slightly more covalently bound 2,4-D was present in control liver than 2,3,7,8-tetrachlorodibenzo-p-dioxin treated liver. Analysis of whole liver homogenates for covalently bound 2,4-D showed no statistical difference between the control and 2,3,7,8-tetrachlorodibenzo-p-dioxin treated livers. [R256] *2,4-Dichlorophenoxyacetic acid (2,4-D) labeled with (14)C was found to be rapidly eliminated by laying hens and lactating goats dosed orally for 7 consecutive days at 18 mg/kg of food intake and for 3 consecutive days at 483 mg/kg of food intake, respectively. Excreta of hens and goats contained > 90% of the total dose within 24 hr after the final dose. Tissue residues were low and accounted for < 0.1% of the dose in these animals. For hens, the residues in muscle, liver, and eggs (0.006-0.030 ppm) were lower than those found in fat and kidney (0.028-0.714 ppm), 2,4-D equivalents. The tissue with highest residue in goat was the kidney at 1.44 ppm, 2,4-D equivalents. Milk, liver, composite fat, and composite muscle had significantly lower residue levels of 0.202, 0.224, 0.088, and 0.037 ppm, respectively. The most abundant tissue residue was 2,4-D and acid/base releasable residues of 2,4-D. A minor metabolite was identified as 2,4-dichlorophenol. [R257] BHL: *... The half-lives for urinary excretion were 3 hr in rats, 8 hr in calves, and hens, and about 12 hr in pigs. [R118, 522] *... In rats orally or intravenously admin, 2,4-D is excreted primarily in the urine with a half-life of approx 2 hr. [R258] *After six male volunteers each /orally/ ingested a subtoxic dose of 5 mg 2,4-D per kg, urine and blood samples were collected and monitored for 2,4-D levels. From pharmacokinetic analysis of the data, the half-life of plasma clearance was determined to be 33 hr. /SRP: Unspecified salt or ester of 2,4-D/ [R259] *AFTER INGESTION OF SINGLE 5 MG/KG ORAL DOSE ... /BY 5 MALE HUMAN VOLUNTEERS/, 2,4-D WAS ELIMINATED FROM PLASMA IN AN APPARENT 1ST ORDER PROCESS WITH AN AVG /SRP: BIOLOGICAL HALF-LIFE/ OF 11.7 HR. ALL SUBJECTS EXCRETED 2,4-D IN URINE WITH AVG /SRP: BIOLOGICAL HALF-LIFE/ OF 17.7 HR, MAINLY AS FREE 2,4-D (83.3%), WITH SMALLER AMT EXCRETED AS 2,4-D CONJUGATES (12.8%). /SRP: UNSPECIFIED SALT OR ESTER OF 2,4-D/ [R2, 494] ACTN: *SRP: 2,4-D mimics natural auxin (indole acetic acid) in its auxin-type /mode/ of action/. At herbicidal concns, growth but not cell division is disrupted and becomes uncontrolled. The plants are killed as a result. *... /CHLOROPHENOXY CMPD INCL 2,4-D ESTERS/ EXERT THEIR HERBICIDAL ACTION BY ACTING AS GROWTH HORMONES IN PLANTS. /CHLOROPHENOXY COMPOUNDS/ [R117] *Male Wistar rats were treated daily by gavage with ... 2,4-D (100-200 mg/kg body wt) ... induced proliferation of hepatic peroxisomes, decr serum lipid levels, incr hepatic carnitine acetyltransferase, and catalase. ... Data suggest ... compounds cause hypolipidemia, ... by preferentially incr lipid utilization in the liver. ... /SRP: Unspecified salt or ester of 2,4-D/ [R260] *2,4-dichlorophenoxyacetic acid (2,4-D) is a hormonal herbicide widely used in the world because of its efficacy in the control of broadleaf and woody plants. In this study we have demonstrated in vivo covalent binding of the phenoxyherbicide 2,4-D to a single protein of 52 kD (from rat liver mitochondrial preparation) detected through immunoblotting studies with the specific antiserum for 2,4-D. The direct involvement of 2,4-D in the formation of the adduct has also been demonstrated in vitro, using liver mitochondrial preparations exposed to 14C-UL-2,4-D. Radiolabeled protein separated by SDS-PAGE and afterwards electroeluted showed a single labeled protein of 52 kD. When mitochondria exposed to radiolabeled xenobiotic were devoid of their outer membrane, the specific activity observed suggest that protein involved in covalent interaction belongs to the inner mitochondrial membrane. We propose that covalent binding of the phenoxyherbicide 2,4-D to a very specific single protein of 52 kD observed in vitro and in vivo may be related to known alterations of the mitochondrial function. [R261] INTC: *The effects of prenatal exposure to a 2,4-dichlorophenoxyacetic acid (24-D)/2,4,5-trichlorophenoxyacetic acid mixture on brain glutamate, gamma-aminobutyric acid (GABA), protein, DNA, and RNA were studied in rats. Pregnant Sprague Daley rats were orally administered 0, 50, or 125 mg/kg per day of a 1:1 mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid on gestational days six to 15. The mixture was known to contain 0.0125 ppm of 2,3,7,8-tetrachlorodienzo-p-dioxin. On postnatal days one, 15, or 22, brains of neonates were separated into cerebrum, cerebellum, neocortex and thalamus/hypothalamus, and assayed for glutamate, DNA, RNA, protein and gamma-aminobutyric acid. Regional brain concentrations of protein, DNA, and RNA were not affected by prenatal exposure to the mixture, except for a decrease in the protein/DNA ratio in the hypothlamus induced by the 50 and 125 mg/kg doses on postnatal day 22. Glutamate was significantly reduced in the cerebrum and cerebellum in 1 day old neonates exposed prenatally to 50 and 125 mg/kg 2,4-dichlorophenoxyacetic acid/2,4,5-trichlorophenoxyacetic acid, while levels were not significantly altered in offspring examined at 15 and 22 postnatal days. gamma-Aminobutyric acid was not significantly affected in any brain region at any time. [R262] *Myotonia is characterized by prolonged contraction (delay in onset of relaxation) of skeletal muscle fibers with characteristic electromyographic findings. Calcium channel blocking drugs may be expected to reduce myotonia, should they promote the onset of relaxation in a contracted skeletal muscle. This study was aimed at evaluating the effect of diltiazem, a calcium channel blocking agent, on myotonia induced by 2,4-dichlorophenoxyacetic acid (2,4-D). In rat diaphragm, exposed to 2.5 mM 2,4-D in a tissue bath, myotonia was quantified by documenting the contraction time in response to direct stimulation with supramaximal electric stimuli. At a peak of myotonia, diltiazem was added to the tissue bath and the effect on evoked contraction studied over a period of 6 minutes. A concentration of 5 x 10(-5) M was found to be the most effective, causing a decrease in contraction time of more than 90% in 3 minutes. [R263] *The effects of Tordon-202c were examined on tumor production induced by urethan in female CD-1 mice. Tordon-202c contained picloram and 2,4-dichlorophenoxyacetic acid as its active ingredients. Mice were exposed to the Tordon-202c in the drinking water for 15 wk at levels up to 0.3%. Urethan was administered after the third week at 15 mg/g, ip. While no influence was noted on the size of the pulmonary adenoma tumors, there was an increase in the number of tumors produced. The increase in numbers was dependent on an increase in dose levels. The spontaneous tumor incidence in mice treated with saline rather than urethan was less than 3 tumors/mouse in all groups as compared to 12 tumors per mouse or greater in all urethan treated mice. The size of the spontaneous tumors appeared to be less than the corresponding urethan induced tumors but the low rate of spontaneous tumor formation precluded reliable statistical comparisons. [R264] *Probenecid increased the acute toxicity of chlorophenoxyacetic acids (2,4-D, 2,4,5-T and MCPA) in rats. Probenecid increased the brain to plasma ratios of all the three (14)C-labelled chlorophenoxyacetic acids. The increase was due only partly to the displacement of chlorophenoxyacids from their binding sites in rat plasma proteins by probenecid. 3. Probenecid did not change significantly the intracerebral distribution pattern of (14)C-labelled chlorophenoxyacetic acids. [R265] *Glyphosate was applied to johnsongrass at 0.28, 0.56, 0.84, and 1.12 kg/ha alone and in combination with 2,4-D or dicamba at 0.14, 0.28, 0.14, or 0.56 kg/ha. Johnsongrass shoot and root fresh weights measured 4 weeks after treatment were higher when glyphosate was applied with 2,4-D (0.28 kg/ha glyphosate) or dicamba (0.28 kg/ha or 0.56 kg/ha glyphosate) compared to glyphosate applied alone at these rates. The antagonism of johnsongrass control was not observed with combinations of some of the higher glyphosate rates with 2,4-D (0.56 or 0.84 kg/ha glyphosate) or dicamba (0.84 or 1.12 kg/ha glyphosate). The reduction of glyphosate activity on johnsongrass occurred when any of four forms of 2,4-D or two forms of dicamba were added to the glyphosate spray mixture. Glyphosate uptake intake into johnsongrass leaves and subsequent translocation to the roots was reduced by the presence of 2,4-D or dicamba. [R266] *Five female forestry workers who applied a mixture of 2,4-D and 2,4,5-T with paint brushes developed severe toxic contact eczema on the exposed parts of the skin. [R91, 1323] *Rats exposed in utero on gestational days 6-15, to nonfetotoxic and grossly nonteratogenic mixtures (50 or 100 mg/kg) of 2,4-D/2,4,5-T ... without significant contamination with 2,3,7,8-tetrachloro-p-dioxin manifested subtle developmental neurotoxicity. This dose did not affect maternal weight gain during pregnancy, length of gestation, total number of live pups, or male to female ratio of the litters. Maturation of swimming behavior was significantly delayed on postnatal day 7 in both treatment group. The concentration of norepinephrine in whole brain was significantly increased on postnatal day 15 in both treament groups, whereas the concentration of dopamine was increased on postnatal day 15 at 100 mg/kg. The turnover and efflux rate constant of dopamine in whole brain were significantly reduced whereas the turnover time increased on postnatal day 3. The efflux rate constant for norepinephrine decreased and the turnover time increased significantly on postnatal day 15 at 100 mg/kg. [R267] *Six beagle dogs were orally intubated with mixtures of a urea-based fertilizer, 2,4-D, mecoprop, dicamba and bensulide or chlorpyrifos. The mixtures were formulated as they were used in liquid application to lawns. The dogs were given volumes of 10 ml/kg body weight, delivering the following quantities of each ingredient: Urea, 623 mg/kg; P2O5, 24 mg/kg; K2O, 66 mg/kg; 2,4-D, 6.5 mg/kg; mecoprop , 3.26 mg/kg; Dicamba, 0.55 mg/kg; and bensulide, 60.93 mg/kg; or chlorpyrifos, 6.77 mg/kg. The dogs were given 3 consecutive daily doses of the mixture containing bensulide (round 1) or the mixture containing chlorpyrifos (round 2). The dogs did not exhibit any clinical signs of illness associated with the treatments. Effects on hematologic values or routine clinical chemical analyses did not occur with the round 2 mixture. Serum lactic dehydrogenase activity decreased by 50% after a single dose of the round 1 mixture was given. Plasma cholinesterase decreased to 50% of control values following the round 1 or 2 mixture; this decrease was not accompanied by cholinergic signs of intoxication. [R268] *Male CD-1 mice were exposed to Tordon 202c a picloram and 2,4-D combination herbicide in the drinking water at concentrations of 0.21, 0.42, and 0.84% solutions for 60 days prior to mating with untreated females. Subsequently there was no exposure to Tordon 202c during gestation. Fetal weight and crown-rump length were reduced in the highest dosage group. The incidence of malformed fetuses (eg, ablepharon, cleft palate, and unilateral agenesis of the testes) was increased in the middle dosage group while the incidence of fetuses with variants was increased in the lowest (eg, an extra pair of ribs) and the highest dosage groups (eg, incomplete ossification of the skeleton). The frequency of pregnancy failure was increased in the middle dosage group. Indices of paternal toxicity included increased lethality and decreased water consumption in the highest dosage group and increased relative spleen weights in the lowest and middle dosage groups. The results suggest paternally mediated reproductive toxicity. [R269] *The teratogenic effects of Tordon 202c, a picloram and 2,4-D combination formulation, are unknown. Pregnant CD-1 mice were exposed to Tordon 202c in the drinking water at concentrations of 0.10, 0.21, and 0.42% from day 6 to 15 of gestation. Fetal growth parameters including body weight and crown-rump length, were reduced in a dose dependent manner, as was placental weight. The incidence of dead fetuses/resorptions and malformed fetuses (especially cleft palate) was increased in the highest dosage group. A subtle indication of maternal toxicity was noted in the higest dosage group as evidenced by decreased water consumption and increased relative liver weight. Tordon 202c is embryotoxic and teratogenic in CD-1 mice when administered during organogenesis. [R270] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,4-D's production may result in its release to the environment through various waste streams; it's use as a systemic herbicide will result in its direct release to the environment. Environmental presence by 2,4-D may also occur as a result of the production and disposal of 2,4-D, and discharge of treated/untreated industrial effluents/wastes. If released to air, a vapor pressure of 8.25X10-8 mm Hg at 20 deg C indicates 2,4-D will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase 2,4-D will be removed from the atmosphere by wet and dry deposition. 2,4-D absorbs light in the environmental UV spectrum, and has the potential to undergo direct photolysis. If released to soil, 2,4-D is expected to have high to very high mobility based upon Kocs values ranging from 20 to 136. The pKa of 2.73 for 2,4-D indicates that this compound will primarily exist in anion form in the environment and anions generally do not adsorb to organic carbon and clay more strongly than the non-ionized form. Volatilization from moist soil surfaces is not expected to be an important fate process because anions will not volatilize. Biodegradation is by far the most important loss process for 2,4-D in most soils, leading to various hydroxylic aromatic products. The rate of degradation is affected by the concn of 2,4-D, temperature, organic matter content of soil, and whether there has been preexposure of the soil to 2,4-D, its salts, or esters. Typical half-lives are short, ranging from < 1 day to several weeks. If released into water, 2,4-D is not expected to adsorb to suspended solids and sediment based upon the range of Koc values. In water, 2,4-D will biodegrade with the rate dependent upon level of nutrients present, temperature, availability of oxygen, and whether there has been preexposure of the water to 2,4-D contamination. Typical half-lives of 10 to > 50 days have been reported with longer half-lives expected in oligotrophic waters and where a high concn of 2,4-D is present. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's pKa which indicates 2,4-D will exist almost entirely in the ionized form at pH values of 5 to 9. A BCF of 1 for bluegill sunfish suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Half-lives of 2-4 days were reported for 2,4-D photolysis in water solution irradiated at 356 nm. Occupational exposure to 2,4-D may occur through inhalation of dust and dermal contact with this compound at workplaces where 2,4-D is produced or used. Agricultural and commercial lawn care workers may be exposed to 2,4-D compounds during spraying operations using herbicides containing this chemical. Monitoring data indicate that the general population may be exposed to 2,4-D via ingestion of food and drinking water and dermal contact with herbicide products containing 2,4-D. (SRC) NATS: *2,4-D is not known to occur naturally(1). [R271] ARTS: *22,4-D's production may result in its release to the environment through various waste streams; it's use as a systemic herbicide(1) will result in its direct release to the environment(SRC). In 1992, the estimated annual agricultural use in the US was 36,800,000 pounds (17,000 metric tons)(2). Environmental pollution with 2,4-D may also occur as a result of the production and disposal of 2,4-D, or of its byproducts, and discharge of treated/untreated industrial effluents/wastes(3). Such pollution will be generally localized to the production site and to areas of waste dumping(3). Disposal of unused 2,4-D and washing of equipment may result in localized land/water pollution(3). [R272] FATE: *AQUATIC FATE: Persistence in aquatic systems depends on the water type, organic particulate matter, rain, sunlight, temperature, microbial degradation, volatilization, and oxygen content of the water. Accumulation in bottom sediments may also be a factor, but in general, not for the phenoxys. Microbial activity is the major means for detoxification of the phenoxys in soils, but is relatively unimportant in natural waters, but dominates in bottom mud sediments and in sludge. [R273] *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values ranging from 20 to 136(2-4), indicates that 2,4-D is expected to have high to very high mobility in soil(SRC). The pKa of 2,4-D is 2.73(5), indicating that this compound will primarily exist in the anion form in the environment and anions generally do not adsorb to soil more strongly than their neutral counterparts(6). Volatilization from moist soil surfaces is not expected to be an important fate process based upon this compound's pKa which indicates 2,4-D will exist almost entirely as an anion(SRC). 2,4-D is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure of 8.3X10-8 mm Hg at 20 deg C(5). Half-lives for 2,4-D volatilization from soil of 660 days (from 1 cm) and 7.1 yr (from 10 cm) were calculated by assuming a zero degradation rate(7). Biodegradation is by far the most important loss process for 2,4-D in most soils, leading to various hydroxylic aromatic products(8-10). The rate of degradation is affected by the conditions, especially the concns of 2,4-D and water content temperature and the organic content of soil and the status of preexposure of the soil to 2,4-D or its salts or its esters(11-12). Typical half-lives are short, ranging from < 1 day to several weeks(2,13-16). Longer half-lives in dry or sandy soils with low organic content are possible(16). Adsorption to soil will probably not be important but will depend on type of soil and organic content(2,3,17). In other soils rapid biodegradation is expected to prevent consequential leaching(2,13). Evaporation and hydrolysis will be negligible(7,18). [R274] *TERRESTRIAL FATE: Laboratory studies were conducted to determine the adsorption, desorption, hydrolysis, and breakdown of commercially formulated isooctyl ester and dimethylamine salt of 2,4-D in a Naff silt loam soil(1). More 2,4-D was adsorbed to the surface soil than to soil at lower depths, and the percentage of 2,4-D adsorbed decreased as the total amount of 2,4-D present increased(1). Adsorbed 2,4-D was gradually desorbed from soil by successively exchanging the solution in equilibrium with soil with distilled water(1). Formulated 2,4-D isooctyl ester applied to moist soil underwent hydrolysis to the anionic form at a rapid rate, with 80% of the ester hydrolyzed in 72 hr(1). High amounts of 2,4-D in runoff (sediment and water) retarded the active degradation of carboxyl 14C 2,4-D when 2,4-D was incubated in runoff from a wheat field treated with various formulations and rates of 2,4-D(1). At the end of the 10 wk of incubation in runoff or in soil, only 1% of the 14C 2,4-D originally applied to the soil could be identified as 2,4-D(1). In another study, the degradation kinetics of 14C-labeled 2,4-D were studied in a number of soils(2). Degradation rates in soils were not simple first order but generally increased until approx 20% of chemical remained, after which they declined(2). Average 50% decomposition time of 4.0 days was observed for 2,4-D(2). [R275] *AQUATIC FATE: Based on a classification scheme(1), Koc values ranging from 20 to 136(2-4), indicates that 2,4-D is not expected to adsorb to suspended solids and sediment(SRC). The pKa of 2,4-D is 2.73(5), indicating that this compound will primarily exist in the anionic form in the environment and anions generally do not adsorb to organic carbon and clay more strongly than their neutral counterparts(6). Volatilization from water surfaces is not expected to be an important fate process based upon this compound's pKa which indicates 2,4-D will exist almost entirely in the ionized form at pH values of 5 to 9(SRC). According to a classification scheme(7), a BCF of 1 for bluegill sunfish(8), suggests that bioconcentration in aquatic organisms is low(SRC). When 2,4-D is released to water, it will tend to biodegrade with the rate especially dependent upon level of nutrients present, temperature, availability of oxygen, and whether or not the water has a prior history of contamination by 2,4-D or other phenoxyacetic acids(9). Typical half-lives of 10 to > 50 days have been reported with longer half-lives expected in oligotrophic waters and where a high concn of 2,4-D is present(9,10). Degradation in sediments and lake muds is expected to be rapid with half-lives of < 1 day reported(11,12). Products of biodegradation include 2,4-dichlorophenol, other hydroxylic aromatics and polymeric acids(9). Half-lives of 2-4 days were reported for 2,4-D photolysis in water solution irradiated at 356 nm(13). A half-life of 50 min was reported for 2,4-D in water irradiated at 254 nm with products listed as 2,4-dichlorophenol, 4-chlorocatechol, 2-hydroxy-4-chlorophenoxyacetic acid, 1,2,4-benzenetriol, and polymeric humic acids(14). The quantitative effects using sunlight were essentially identical to the use of artificial light(14). Micellar solubilization and photosensitization by certain adjuvants may enhance the rate of photolysis of 2,4-D in aqueous solution(15). [R276] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,4-D, which has a vapor pressure of 8.25X10-8 mm Hg at 20 deg C is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase 2,4-D may be removed from the air by wet and dry deposition(SRC). The primary source of 2,4-D in air is spray applications of the herbicide or its mixture(2-5). Spray drift is capable of carrying it up to a few km(6). No data were found concerning direct photolysis of 2,4-D in the atmosphere, although 2,4-D exhibits an absorption maximum at 288 nm which extends to wavelengths > 290 nm suggesting that 2,4-D may be susceptible to direct photolysis(7). [R277] *Soil persistence and lateral movement of 2,4-D (2,4-dichlorophenoxy acetic acid) and picloram (4-amino-3,5,6-trichloropicolinic acid) were examined following their application as a stem-foliage spray for brush control on two power line rights-of-way. Ditches to collect runoff water were located 3, 10, 20, and 30 m downslope from the treated areas. Runoff water and soil samples were collected after 0.14, 0.43, 0.57, 1, 2, 4, 7, 8, 11, 15, 16, and 48 weeks and were analyzed for picloram and 2,4-D residues. Only 3 of 85 soil samples downslope from the target areas contained residues of 2,4-D, and only 1 of 85 down slope samples contained a detectable residue of picloram. Of 56 runoff water samples, only 11 contained 2,4-D residues and only 1 contained residues of picloram. The greatest distances down-slope at which residues were detected in runoff water were 20 and 10 m for 2,4-D and picloram, respectively. No residues of either herbicide were recovered in soil or water at 15 weeks or 48 weeks after spraying. Despite normal rainfall frequency and amounts in the first several weeks after spraying in mid-June, significant runoff of either herbicide was not evident at either study site. [R278] BIOD: *In long-term degradation studies of massive quantities of 2,4-D and 2,4,5-T in test grids, field plots and herbicide storage areas were carried out. The method of herbicide application had significant impact on the amount applied per unit area and hence on residue persistence: spills > or = soil incorporation > aerial application. 2,4,5-T was more persistent in the soil than 2,4-D. The formulation of the herbicide also had significant impact on its persistence: isooctyl ester > butyl ester > acid. The addition of coconut charcoal increases persistence of the phenoxy herbicide residues, especially residues of 2,4,5-T. The appearance of dichlorophenol and trichlorophenol in soils treated with 2,4-D and 2,4,5-T suggests that they are degradation products of the herbicides. A massive concn of herbicides does not sterilize the soils. Apparently, microbial populations respond both quantitatively and qualitatively to the presence of high concentrations of herbicides and may play an important role in their degradation. [R279] *AEROBIC: 2,4-D is readily and rapidly degraded in soil(1). The kinetics of 2,4-D disappearance suggest that microorganisms are responsible(1). The rate will depend on a number of factors including presence of acclimated organisms, nutrient levels, moisture level, temperature, and concn of 2,4-D(1-3). Typical half-lives range from less than 1 day to more than several weeks under the conditions used(4-8). Degradation with a mixture of microorganisms from activated sludge, soil and sediments lead to half-lives of 1.8-3.1 days under aerobic conditions(4,9). Particular species of microorganisms, of various types, have been isolated and shown to degrade phenoxyacetic acid herbicides in pure culture(1). Degradation of the phenoxyacetic acids proceeds by two main pathways(1). These are via a hydroxyphenoxy acetic acid intermediate or via the corresponding phenol(1). Warm, moist conditions and addition of organic matter stimulate degradation of 2,4-D(7). The breakdown of 2,4-D in two types of soil was investigated under dry and moist conditions and at two different temperatures(7). Generally, 2,4-D disappeared more rapidly from moist soil; after 14 days of a slow rate of disappearance, however, the removal rate from dry, sandy soil increased(7). Numbers of organisms degrading 2,4-D were initially much lower in sandy than in clay loams(7). However, numbers increased rapidly in sandy soils after the addition of the herbicide and, as a result, 2,4-D was eventually degraded more rapidly in sandy than in clay loams(7). In moist conditions, at 25 deg C, the half-life of 2,4-D was 7 days or less, whereas in dry conditions, at 35 deg C, it could be as long as 250 days(7). These latter conditions are unlikely to apply in most natural conditions where 2,4-D is likely to be used(7). First-order kinetics were observed for the degradation of 2,4-D in sandy loam and muck soils from Malaysia(10). Short half-lives were observed for 2,4-D in aerobic (3.4 days) muck soils(10). [R280] *AEROBIC: Using sewage-sludge bacteria incubated with 2,4-D, it was found that nearly all of the herbicide had disappeared after 7 days(1). Subsequent additions of 2,4-D led to destruction of the compound without a lag period; this suggests selection for organisms capable of degrading the compound(1). Similar results were obtained using bacteria from soil(1). The time needed for the disappearance of 90% of the added 2,4-D was 14 days with soil inocula(1). 2,4-D added subsequently was reduced by 70% within 3 to 4 days(1). Various tropical soils were used in the experiment and all showed a high capacity for degrading 2,4-D(1). The persistence of 2,4-D applied at recommended rates in agricultural soils in Canada was determined(2). In all but one soil, a sandy loam, the concn had declined by 50% within 7 days(2). In another study, degradation of 2,4-D was slower in acid soils(3). It took 6 weeks for 50% of the 2,4-D to disappear from the soil and 7% was still left after 24 weeks(3). In water-logged soil, there was reduced degradation of the herbicide(3). 2,4-D applied at about 1.5 mg/kg was readily degraded in soil(4). Adding extra carbon in the form of dried, digested sewage sludge had a short-term effect in enhancing degradation of the compound(4). The half-life of 2,4-D degradation in cultures of soil microorganisms at different pH was measured(5). In the pH range of 8.5 to 5.0, the half-life changed little, ranging from 5 to 8 days(5). At pH 4.5, the half-life increased to 21 days and, at pH 4.0, increased further to 41 days(5). 2,4-D treatment increased the numbers of soil microorganisms capable of metabolizing 2,4-D as the sole carbon source and those capable of co-metabolizing the herbicide(6); this increase was dependent on the concn of 2,4-D used(6). At 2,4-D concns between 5 and 50 mg/l, there was a significant increase in the numbers of organisms metabolizing 2,4-D, and at 5 mg/l there was a very pronounced increase in organisms co-metabolizing the compound(6). At much higher (500 mg/l) or much lower (1.2 ug/l) 2,4-D concns, there was no increase in the numbers of either metabolizing or co-metabolizing organisms(6). [R281] *AEROBIC: The degradation of 2,4-D in forest leaf litter was investigated(1). Litter from either alder, ceanothus, vine maple, bigleaf maple or Douglas fir showed comparable ability to degrade 2,4-D, the recovery of 2,4-D being between 60% and 70% after 15 days of incubation(1). In a second series of experiments, different formulations of 2,4-D were added to alder litter(1). About 50% of the free acid of 2,4-D was degraded within 15 days(1). 2,4-D was added to inocula of municipal sewage and the biological oxygen depletion (BOD) was monitored as a measure of degradation(2). The herbicide was added to carbon-depleted inocula such that the 2,4-D represented the sole carbon source(2). Less than 5% of the available oxygen was depleted, indicating poor biodegradation of 2,4-D because of low numbers of organisms capable of degrading the herbicide as their sole carbon source(2). A separate study showed that 2,4-D was not toxic to microorganisms in sewage(2). [R282] *AEROBIC: The degradation rate of 2,4-D in river water is related to the nutrient levels, sediment load, and dissolved organic carbon content of the water(1). Half-lives in river water of 18 to over 50 days (clear water) and 10 to 25 days (muddy water) with lag times of 6 to 12 days have been reported(1). The lag phase has been explained as the time for the small population of degrader organisms to become sufficiently numerous to cause detectable degradation of the chemical(2). The extent of mineralization in lake water was 72% in 60 days and was affected by levels of both inorganics and organics(3). Degradation is poor in oligotrophic water and where high 2,4-D concns are present(4) and 2,4-D was not mineralized in water from 2 of 3 lakes tested(5). A pilot study of seasonal changes in the capacity of river water in Western Australia to degrade 2,4-D indicated clear seasonal differences in both river water concns of the herbicide and the degrading capacity of river water(6). Rivers receiving agricultural run-off degraded 2,4-D better than those receiving run-off principally from forests(6). This was presumed to be the result of the preconditioning of organisms to the herbicide(6). The degrading ability of microbial communities taken from sediment cores from freshwater, estuarine, and marine sites was investigated(7). Some cores were pre-exposed to 2,4-D(7). Cores from freshwater sites showed increased degradation of 2,4-D after pre-exposure to the compound, whereas estuarine and marine cores did not show this effect(7). The adaptation of freshwater cores was maximal after 2 weeks and no longer detectable 6 weeks after pre-exposure(7). Oxidation of 81-85% 2,4-D in 24 hr (based on BOD) was observed in lake bottom muds(8). [R283] *ANAEROBIC: Degradation with a mixture of microorganisms from activated sludge, soil and sediments lead to half-lives of 69-135 days under anaerobic conditions(1). The formation of 2,4-dichlorophenol from 2,4-D in anaerobic sediment has been reported(2). Using a model ecosystem that reproduced the conditions of an anaerobic aquifer, 2,4-D was determined to be persistent(3). [R284] ABIO: *Photodegradation occurs at ortho chlorine with reductive dechlorination at 300 nm. /2,4-D/ [R285] *The rate constant for the vapor-phase reaction of 2,4-D with photochemically-produced hydroxyl radicals has been estimated as 6.6X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2.4 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). 2,4-D is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). No data were found concerning direct photolysis of 2,4-D in the atmosphere, although 2,4-D exhibits an absorption maximum at 288 nm which extends to wavelengths > 290 nm suggesting that 2,4-D may be susceptible to direct photolysis(3). Half-lives of 2-4 days were reported for 2,4-D photolysis in water solution irradiated at 356 nm(4). A half-life of 50 min was reported for 2,4-D in water irradiated at 254 nm with products listed as 2,4-dichlorophenol, 4-chlorocatechol, 2-hydroxy-4-chlorophenoxyacetic acid, 1,2,4-benzenetriol and polymeric humic acids(5). The quantitative effects using sunlight were essentially identical to the use of artificial light(5). Micellar solubilization and photosensitization by certain adjuvants may enhance the rate of photolysis in aqueous solution(6). [R286] BIOC: *A bioconcentration factor (BCF) of 1 was determined for bluegill sunfish exposed to 3 mg 2,4-D/l of water for 8 days(1). According to a classification scheme(2), a BCF of 1 for bluegill sunfish(2), suggests that bioconcentration in aquatic organisms is low(SRC). The BCF for channel catfish is 1X10-5(3) and for frog tadpoles is 2X10-3 (pH not stated, added as acid)(4). The BCF for three seaweeds ranged from 0.001-0.003 (pH 7.8, C14 ring-labeled 2,4-D)(5) and 6 for algae Chlorella fusca (pH not stated, C14 ring-labeled 2,4-D(6). There is no evidence that bioconcentration of 2,4-D occurs through the food chain(7). This has been demonstrated by large-scale monitoring for 2,4-D residues in soils, foods, feedstuffs, wildlife, human beings, and from examinations of the many routes of metabolism and degradation that exist in ecosystems(7). [R287] KOC: *Reported experimental 2,4-D (free acid) Koc values are 19.6 (average of 9 soils)(1) to 109.1 (average of 3 soils and range of 72.2-135.7)(2), and 20 to 79(3). According to a classification scheme(4), these Koc values suggest that 2,4-D is expected to have high to very high mobility in soil(SRC). The pKa of 2,4-D is 2.73(5), indicating that this compound will primarily exist in anionic form in the environment and anions generally do not adsorb to organic carbon and clay more strongly than their neutral counterparts(6). Adsorption appears to increase with increasing organic content and decreasing pH of soil(7). Average mobility for 14 soils: 0.72 (Rf units); range of 0.41 for silty loam to 1.0 for sandy loam(7). In general little runoff occurs with 2,4-D or its amine salts and runoff behavior is the inverse of adsorption behavior(8). Thus, 2,4-D can be desorbed from mineral soils, but not from those containing much organic matter(8). Percolating water appears to be the principal means of movement and diffusion is important only for transport over very small distance(8). Geometric mean concns of leached 2,4-D ranged from 0.55-0.87 ug/l at a depth of 0.2 m following applications (rate 1.1-3.3 kg/ha-yr) of the herbicide and irrigation of home garden lawns(9). Upward movement of 2,4-D occurs when the soil surface dries or if rapid evaporation occurs(9). Thus, 2,4-D can be concentrated at the soil surface, where it can be photolyzed, transported by wind either on dust or in vapor form, or leached downwards again(9). [R288] *The mean adsorption coefficient (Kd) of 2,4-D on four soils from rice-producing areas of Arkansas at pH 5 and 7 ranged from 0.06 to 0.59 L/kg(1). [R289] VWS: *The Henry's Law constant for 2,4-D is 8.6X10-6 atm-cu m/mole(1). This Henry's Law constant indicates that 2,4-D is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 4.3 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 52 days(SRC). However, the pKa of 2.73 is 2,4-D(3), indicating that this compound will primarily exist in anion form in the environment(SRC). Thus, volatilization from moist soil and water surfaces is not expected to be an important fate process because anions are not expected to volatilize(SRC). 2,4-D is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure of 8.3X10-8 mm Hg at 20 deg C(3). [R290] WATC: *DRINKING WATER: 237 wells in Ontario Canada were sampled over a 10 yr period and 2,4-D occurred in 23 wells as the single contaminant, 50 wells with 4 other contaminants, concns ranging from 0.01-14,600 ppb(1). In a National survey of pesticides in groundwater, it was detected in groundwater from 5 of 50 states at a maximum and mean concn of 49.5 ppb and 1.2 ppb, respectively(2). 60 of 415 Public Water Systems derived from surface water in the National Contaminant Occurrence Database (NCOD) contained dissolved 2,4-D; the mean dissolved 2,4-D concn at these 60 stations was 1.18 ug/l (range, 0.1-58 ug/l)(3). 52 of 3,029 Public Water Systems derived from groundwater in the National Contaminant Occurrence Database contained dissolved 2,4-D; the mean dissolved 2,4-D concn at these 52 stations was 0.87 ug/l (range, 0.08-8 ug/l)(3). Some of the samples from the NCOD could have been taken from source water samples(3). [R291] *SURFACE WATER: Reported as 2,4-D equivalents. The max concn of 2,4-D in Georgia and Florida pond waters was 0.345 ppm and 0.692 ppm, respectively(1); the concn of 2,4-D declined after 28 days to less than 0.005 ppm(1). In Missouri pond water, the max concn of 2,4-D was 0.630 ppm and after 56 days declined to less than 0.005 ppm(1). 2,4-D was detected in 1-10% of samples collected from streams in a survey of 11 Ontario agricultural watersheds monitored for 81 pesticides(2); 66 of 949 initial stream waters were positive(3). 2,4-D was tested for but not detected in Lake Erie (Monroe Water Treatment Plant), Lake Huron near shore water and tributaries, or Detroit River, Lake St. Clair and St. Clair River (detection limit= 0.05-5 parts per trillion)(4). The concn of 2,4-D in the Scioto River in Highby, OH was 0.12 ppb(5). [R292] *SURFACE WATER: Available data indicate that residues of 2,4-D rarely exceed several ug/liter in water(1). Exceptions may occur in the vicinity of 2,4-D herbicide spills or when the herbicide is used in quantities far in excess of the rates applied in normal agricultural or forestry practice(1). At the Hillsboro Canal, Laxahatchee National Wildlife Refuge, FL, the concn of 2,4-D was 0.037 ppm on day following application of 4.48 kg/ha acid equivalent and decreased to 0.001-0.004 ppm 56 days later(2). Levels in Guntersville Reservoir (Tennessee Valley Authority (TVA)), the concn of 2,4-D at 6 months after application of 20-40 pounds acid equivalent/acre was less than 0.001 ppm(3). 2,4-D was detected in 18 of 20 midwest streams sampled over a four year period at concn range 0.02-0.99 ppb(4). Fourteen of 20 streams were positive in an earlier 2 year study with 36 occurrences and concns ranging from 0.01 to 0.24 ppb(5); 2,4-D was not detected in 11 of 11 streams in the original 1967 study(6). The concn of 2,4-D was 0.245 ppb measured in South Skunk River water, Iowa in 1975(7). Less than 0.01 ppb of 2,4-D was measured in Rhine River water at km 865(8). The max concn of 2,4-D in surface waters from canals in South Florida was 14 ug/l (N=3)(9). [R293] *SURFACE WATER: Reported as 2,4-D equivalents. Following spraying in Cairn Edward Forest, Kircudbrightshire, Great Britain (4.5 kg in 135 liter water/ha), at 1,2,4,7 and 28 days later after application, the concns of 2,4-D of 1.5, 1.6, 2.0, 1.6 ppm and not detected were measured, (detection limit= 0.005 ppm), in drainage furrows(1). 2,4-D was detected in 17% of agricultural watersheds in Ontario, Canada monitored during 1981-85. In the Thames River, the mean concns in 1981, 1982, 1983, 1984 and 1985 were 0.7 ppb, 0.6 ppb, 0.3 ppb, 0.5 ppb and 0.5 ppb, respectively(2). In a U.S. National Surface Water Monitoring Program conducted during 1976-80, 2,4-D was detected in 1.6% of surface waters at a maximum concn of 1.9 ppb(3). 27 of 71 stations in the National Contaminant Occurrence Database (NCOD) contained dissolved 2,4-D in lake/reservoir; the mean dissolved 2,4-D concn at these 27 stations was 0.33 ug/l (range, 0.01-10 ug/l)(4). 73 of 256 stations in the National Contaminant Occurrence Database contained dissolved 2,4-D in other surface waters; the mean dissolved 2,4-D concn at these 73 stations was 0.36 ug/l (range, 0.01-15 ug/l)(4). [R294] *GROUNDWATER: 5 of 465 stations in the National Contaminant Occurrence Database (NCOD) contained dissolved 2,4-D in groundwater; the mean dissolved 2,4-D concn at these 5 stations was 4.0 +/- 9.8 ug/l (range, 0.01-24 ug/l)(1). The max concn of 2,4-D in groundwater from the US between 1992-96 was 0.54 ug/l (% detect = 0.43; N = 2,306)(2). In 1991, 2,4-D was detected in 4 of 57 prairie wells in Canada at concns ranging from 0.48 to 1.0 ng/l(3). [R295] *RAIN/SNOW: The median concn of 2,4-D in rainwater between February and October, 1996 at Gruze, Switzerland was 16 ng/l(1); the max concn was 23 ng/l(1). [R296] SEDS: *SEDIMENT: 2,4-D was detected but not quantified in sediments of the Detroit River and Lake Huron(1). Samples from seven TVA (Tennessee Valley Authority) reservoirs were all positive; the concn was 0.95-56 ppm measured 96 hr after application and 0.24-58 ppm measured 10 months after application of the butoxyethanol ester in the Watts Bar Reservoir; the concn of the control was 0.14 ppm (control), 0.14-33.6 ppm (42 days later), 0.3-0.49 (9 months later) - Guntersville Reservoir(2). The concn of 2,4-D residues in sediments of Florida and Georgia ponds were 0.6 ppm one day after treatment and ranged from trace to non-detectable 56 days after treatment(3). At the Loxahatchee National Wildlife Refuge, FL, the peak level of 2,4-D was 0.005 ppm which occurred 3-15 days after surface water application of 4.48 kg/ha acid equivalent(4). Concns of 2,4-D in Guntersville Reservoir (TVA) at 1, 14, 28, 60, 120 and 180 days after application of 20-40 lb/acre acid equivalent were 0.11, 0.25, 0.11, 0.30, 0.25 and less than 0.1 mg/kg respectively(5). [R297] *SOIL: Available data indicate that residues of 2,4-D rarely exceed 1 mg/kg in soil(1). Exceptions may occur in the vicinity of 2,4-D herbicide spills, or when the herbicide is used in quantities far in excess of the rates applied in normal agricultural or forestry practice(1). The concn of 2,4-D in Canadian agricultural soils ranged from not detected to 38 ug/kg dry weight(2). [R298] ATMC: *2,4-D was detected in 1 (urban) of 9 (4 urban, 5 rural) US sites at a concn of 4 ng/cu m(1). In south-central Washington in the year 1973, 7 stations averaged 0.31 ug/cu m 2,4-D; in 1974, 8 station average 0.22 ug/cu m(2). The source of 2,4-D being spray drift from croplands(2). 2 of 7 US sites were positive of 2,4-D(3). In Rome, NY (urban), the concn was 1.535 ng/cu m (1 of 19 samples positive)(3). In Jordan, NY (rural), the concn was 1.151 ng/cu m (1 of 26 samples positive)(3). In Saskatoon, Saskatchewan, Canada in 1972, the 33 day mean daily level in air was 600 ng/cu m of 2,4-D(4). Peak was 455 ug/cu m/day(4). [R299] FOOD: *One in 360 potato samples were positive for 2,4-D in a 1973 monitoring study(1). Average incident rate of detection of 2,4-D in food from 1964-69 ranged between 0.3-4.6% with the earlier years (1964-1966) being at the higher percentage(2-4); from 1969-1973 the average incident rate was 0.3-0.8%, again the higher value occurring earlier with concns ranging from trace to 0.02 ppm(5-8). 2,4-D was detected in 7 of 7,893 large fruit samples in 1970-1971; and 3 of 1,560 processed vegetable products in 1976(9). One out of over 100 toddler food composites contained 0.025 ppm of 2,4-D(10). [R300] *Available data indicate that residues of 2,4-D rarely exceed a few tens of ug/kg in food sources(1). Exceptions may occur in the vicinity of 2,4-D herbicide spills, in berries and mushrooms grown in treated right-of-way areas, or when the herbicide is used in quantities far in excess of the rates applied in normal agricultural or forestry practice(1). [R301] *2,4-D was detected at concns 0.02 ppm in one of 14 Ontario-grown cauliflower and tomato composite samples collected between 1980-85(1). 2,4-D was detected in Ontario-grown sweet cherries and strawberries collected in 1980-82 at concns 0.01 ppm (in 1 of 26 composites) and 0.02 ppm (in 3 of 60 composites), respectively(2). As part of the FDA Total Diet study between 1991-99, the mean concn of 2,4-D was determined in white bread (0.0051 ppm), raisin bran cereal (0.0042 ppm), oat ring cereal (0.002 ppm), and cracked wheat bread (0.006 ppm)(3). As part of a FDA Market Basket study, the ten-year avg concn of 2,4-D found in 234 ready-to-eat foods tested 37 times a year between 1982-1991 was 0.006 ug/g(4); 2,4-D was only found 1 time in 1 food item during this study(4). [R302] PFAC: PLANT CONCENTRATIONS: *Levels of 2,4-D in plankton (two samples from Guntersville Reservoir, Tennessee Valley Authority) 1, 8, and 24 hours and 14, 28, 30, 120, and 160 days after application of 20-40 lbs/acre acid equivalent of 2,4-D were 0.06, 0.88, 1.8, 2.6, 3.6, 2.2, 1.1, and 3.7 ppm of 2,4-D equivalents, respectively(1). Plankton filtrates at 1, 8, and 24 hours and 28, 60, and 180 days had 0.22, 0.20, 0.23, < 0.001, 0.013, and < 0.001 ppm of 2,4-D equivalents, respectively(1). [R303] FISH/SEAFOOD CONCENTRATIONS: *Levels of 2,4-D acid equivalents in 8 species of freshwater fish from the Guntersville Reservoir (Tennessee Valley Authority) after application of 20-40 lb/acre acid equivalent did not rise above the pretreatment level of < 0.10 mg/kg except for gizzard shad (0.34 mg/kg at 28 days, < 0.10 mg/kg (60 days), 0.22 mg/kg (120 days), < 0.10 mg/kg (180 days)(1,2). Authorized use of 2,4-D by cottage owners in Buckhorn Lake, Ontario, Canada for the years 1977 to 1980 ranged from 124 to 280 kg of active ingredient, annually. This would give predicted avg water concns of 2 to 4 ug/l during the June-July period. Twelve percent of fish caught during the pre-treatment period (i.e., May) had detectable residues of 2,4-D (< 5 to 30 ug/kg). In the early, post-treatment period (i.e., July), 69% of fish caught had mean residues ranging from < 5 to 136 ug/kg. In the late post-treatment period (i.e., October), 19% of fish caught had detectable residues of 2,4-D (< 5 to 60 ug/kg)(2). Following application of 4.48 kg/ha acid equivalent to the Hillsboro Canal, Loxahatchee National Wildlife Refuge, FL, 60 samples of fish were analyzed; 3 had levels > 0.10 mg/kg, 16 species had levels < 0.10 mg/kg, 41 had levels of not detected during a 5 month sampling period(3). [R304] ANIMAL CONCENTRATIONS: *The concn of 2,4-D in Florida gallinules from the Loxahatchee National Wildlife Refuge, FL following the application of 4.48 kg acid equivalent/ha were as follows: liver - 0.3 mg/kg, breast - 0.675 mg/kg/day; residues not detected 4 days later(1). [R305] MILK: *... No 2,4-D was detected in milk of a cow fed with more than 1 lb 2,4-D over a 6-wk period. [R55] *One pasture was sprayed with 2 lb per acre of 2,4-D isopropyl ester. ... Milk collected from the exposed cows and forage samples from the fields were analyzed for 2,4-D by gas chromatography. The highest levels of 2,4-D were 0.05-0.06 ppm. ... No 2,4-D was detected on the third day after exposure to the isopropyl ester. [R306] *2,4-D WAS ELIM IN MILK OF COWS MAINTAINED IN PASTURES TREATED WITH 2,4-D OR ITS BUTYL OR ISOOCTYL ESTER. [R2, 494] *2,4-D was detected in 7 of 4,638 samples of milk (fluid) in 1971(1). [R307] *We studied offspring of dams which had received 50, 70 or 700 mg/kg of 2,4-Dichlorophenoxyacetic acid (2,4-D) during nursing. Neonatal tissues and the stomach content (milk) were examined up to 16 post natal days to detect body and organs weight alterations and 2,4-D residues after 2,4-D maternal dosing every-other-day, from post natal day 1. We detected 2,4-D residues in stomach content, blood, brain and kidney of 4-day-old neonates breast-fed by 2,4-D exposed mothers and onward. 2,4-D residues were dose- and exposure-time-dependent. The highest dose impaired body growth, as well as low tissue weights and diminished stomach contents. Levels of 2,4-D residues in stomach content, blood, kidney and brain of post natal rats (age PD 4-PD 16) fed through lactation from dams treated with 2,4-D demonstrated that 2,4-D was transferred to the neonates and the diminished body and tissues weight during this developmental period could be due to a diminished milk intake or/and to the direct 2,4-D toxic effect. Besides, when the herbicide treatment (100 mg 2,4-D/kg) was withdrawn from the dams, 2,4-D residues remained in the stomach content of neonates for at least one week. [R190] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 471 workers are potentially exposed to 2,4-D in the US(1). The NOES Survey does not include farm workers(SRC). Occupational exposure to 2,4-D may occur through inhalation of dust and dermal contact with this compound at workplaces where 2,4-D is produced or used(SRC). Agricultural and commercial lawn care workers may be exposed to 2,4-D compounds during spraying operations using herbicides containing this chemical(2). Monitoring data indicate that the general population may be exposed to 2,4-D via ingestion of food and drinking water(SRC) and dermal contact with herbicide products containing 2,4-D(SRC). The general population in 2,4-D use areas would be exposed mainly through food containing 2,4-D residues and through 2,4-D residues in water(2). The contribution from air is negligible(2) except in high use areas where 2,4-D may be present in dust(3). [R308] *A number of studies summarized have demonstrated human exposure to 2,4-D(1). The primary mechanism for human exposure is through direct contact during use of the product(1). Forestry workers using backpack sprayers have estimated average exposures of 98 ug/kg/day, which is substantially lower in commercial pesticide applicators (2.75 ug/kg/day) and farm workers (5.78 ug/kg/day(1). However, these exposure estimates were obtained in workers not complying with current product label requirements for personal protective equipment (eye protection, chemical resistant gloves, long-sleeved shirt and pants, socks, and shoes)(1). The impact of the use of appropriate personal protective equipment on systemic 2,4-D exposure has been demonstrated from an investigation of workers employed as commercial lawn care specialists(1). Analysis of total 24-h urine samples collected from 45 applicators who applied 2,4-D everyday for 3 weeks prior to sampling revealed calculated human exposure doses of 0.0032, 0.0063, 0.00035, and 0.00138 mg/kg at four different work locations(1). Workers wore rubber gloves, protective aprons/coveralls, goggles or faceshield, and rubber boots during handling of concentrated pesticides(1). Glove and eye protection was optional during application of the diluted mixtures, and clothing consisted of rubber boats and a clean uniform of long pants and short-sleeve shirt(1). [R309] *Analyses of air in the breathing zone of workers, exposured during forest spray operations with tractor driven equipment 0 days after spraying of 2,4-D as a 2% emulsion in kerosene, resulted in a mean concentration in air of 0.1-0.2 mg/cu m(1). [R310] AVDI: *The total contribution from air, food, and water is estimated to be 0.3-2 ug/kg body weight per day(1). As part of an FDA Total Diet Study, the mean daily intake per unit body weight of 2,4-D between 1986-1991 was determined to be < 0.0001 ug/kg body wt/day for ages 6 mo to 65 yrs(2). [R311] BODY: *Urinalysis of six volunteer workers (wearing a full line of protective clothing) involved in mixing and loading 2,4-D ester solutions into aircraft and in guiding the spray aircraft in two conifer release program showed a maximum excretion level of 22.2 ug/kg body weight/day(1). The urinary excretion rate of 2,4-D in 45 commercial lawn care specialists who had been spraying the herbicide for a period of at least 3 weeks ranged from 0.4-6.3 ug/kg body weight/day(2). Thirty nine of 197 children living near and away from possible source of contamination had detectable levels of 2,4-D (detection limit 1 ppb) in their urine at a maximum concentration of 9 ppb(3). [R312] *A male suicide victim weighing 55 kg ingested an unknown quantity of pure 2,4-D acid in kerosene. ... 2,4-D concentration in tissues was 57.6-407.9 mg/kg. [R93] *A male suicide victim ingested 125 ml of 2,4-D (400 mg active ingredient/l) ... 2,4-D concentration in tissues < 400 mg/kg. [R97] *A female suicide victim (age not specified or body weight) ingested an unknown quantity of 2,4-D. ... 2,4-D concentration in tissues was 20-116 mg/kg. [R101] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *100 mg/cu m [R48] ADI: *OPP RfD= 0.003 mg/kg; EPA RfD= 0.01 mg/kg; WHO RfD= 0.3 mg/kg [R313] *NOEL: 500 ppm [R314] *NAS/NRC has calculated a no adverse effect level in water of 0.09 mg/l. The acceptable daily intake of 2,4-D has been set at 0.03 mg/kg by FAO/WHO. A level of 100 ug/l for domestic water supplies has been set by EPA on a health basis. [R315] ATOL: *Tolerances are established for residues of the herbicide, plant regulator, and fungicide 2,4-D (2,4-dichlorophenoxyacetic acid) in or on raw agricultural commodities as follows: apples: 5 ppm; apricots: 5 ppm; citrus fruits: 5 ppm; pears: 5 ppm; potatoes: 0.2 ppm; and quinces: 5 ppm. [R316] *The tolerance on apricots /5 ppm/ also includes residues of 2,4-D (2,4-dichlorophenoxyacetic acid) from the preharvest application of 2,4-D dimethylamine salt to apricots. [R317] *The tolerances on citrus fruits /5 ppm/ also includes residues of 2,4-D from the preharvest application of 2,4-D isopropyl ester and 2,4-D butoxyethyl ester and from the postharvest application of 2,4-D alkanolamine salts and 2,4-D isopropyl ester to citrus fruits. [R318] *Tolerances are established for residues of 2,4-D at: barley, grain: 0.5 ppm; blueberries: 0.1 ppm; corn, fodder: 20 ppm; corn, forage: 20 ppm; corn, fresh, sweet (kernel plus cob with husk removed): 0.5 ppm; corn, grain: 0.5 ppm; cranberries: 0.5 ppm; grapes: 0.5 ppm; grass hay: 300 ppm; grasses, pasture: 1,000 ppm; grasses, rangeland: 1,000 ppm; millet, forage: 20 ppm; millet, grain: 0.5 ppm; millet, straw: 20 ppm; nuts: 0.2 ppm; oats, forage: 20 ppm; oats, grain: 0.5 ppm; pistachios: 0.2 ppm; rice: 0.1 ppm; rice, straw: 20 ppm; rye, forage: 20 ppm; rye, grain: 0.5 ppm: sorghum, fodder: 20 ppm; sorghum, forage: 20 ppm; sorghum, grain: 0.5 ppm; stone fruits: 0.2 ppm; sugarcane: 2 ppm; sugarcane, forage: 20 ppm; wheat, forage: 20 ppm; and wheat, grain: 0.5 ppm. [R319] *Residues on /the commodities listed at 40 CFR 180.142(a)(2)/ ... may result from application of 2,4-D in acid form, or in the form of one or more of the following salts: (A) the inorganic salts: ammonium, lithium, potassium, and sodium; (B) the amine salt: alkanolamines of the ethanol and isopropanol series (C-12), alkyl (C-13), alkyl (C-14), alkylamines derived from tall oil, amylamine, diethanolamine, diethylamine, diisopropanolamine, dimethylamine, N,N-dimethyllinoleylamine, N,N-dimethyloleyamine, ethanolamine, ethylamine, heptylamine, isopropanolamine, isopropylamine, linoleylamine, methylamine, morpholine, octylamine, oleylamine, N-oleyl-1,3-propylenediamine, propylamine, triethanolamine, triethylamine triisopropanolamine, and trimethylamine. [R320] *Residues on /the commodities listed at 40 CFR 180.142(a)(2)/ ... may result from application of 2,4-D in acid form, or in the form of one or more of the following esters: amyl(pentyl), butoxyethoxypropyl, butoxyethyl, butoxypolyethylene glycol butyl ether, butoxypropyl, butyl, dipropylene glycol isobutyl ether, ethoxyethoxyethyl, ethoxyethoxypropyl, ethyl, ethoxypropyl, isobutyl, isooctyl (including, but not limited to, 2-ethylhexyl, 2-ethyl-4-methylpentyl, and 2-octyl), isopropyl, methyl, polyethylene glycol 200, polypropoxybutyl, polypropylene glycol, propylene glycol, propylene glycol butyl ether, propylene glycol isobutyl ether, tetrahydrofurfuryl, and tripropylene glycol isobutyl ether. [R321] *Tolerances are established for negligible residues of 2,4-D from application of its dimethylamine salt to irrigation ditch banks in the Western United States in programs of the Bureau of Reclamation, U.S. Department of Interior; cooperating water user organizations; the Bureau of Sport Fisheries, U.S. Department of Interior; Agricultural Research Services, U.S. Department of Agriculture; and the Corps of Engineers, U.S. Department of Defense. Where tolerances are established at higher levels from other uses of 2,4-D on the following crops, the higher tolerance applies also to residues from the irrigation ditch bank use cited in this paragraph. The established tolerances follow: avocados, 0.1(N); citrus fruits, 0.1(N); cottonseed, 0.1(N); cucurbits, 0.1(N); forage grasses, 0.1(N); forage legumes, 0.1(N); fruiting vegetables, 0.1(N); grain crops, 0.1(N); hops, 0.1(N); leafy vegetables, 0.1(N); nuts, 0.1(N); pome fruits, 0.1(N); root crop vegetables, 0.1(N); seed and pod vegetables, 0.1(N); small fruits, 0.1(N); and stone fruits, 0.1(N). [R322] *A tolerances is established for residues of 2,4-D sodium salt and alkanolamine salts (of the ethanol and isopropanol series), calculated as 2,4-D (2,4-dichlorophenoxyacetic acid) as follows: asparagus, 5 ppm. [R323] *A tolerances is established for residues of 2,4-D from application of its alkanolamine salts (of the ethanol and isopropanol series) as follows: strawberries, 0.5 ppm. [R324] *A tolerance is established for residues for 2,4-D from application of its dimethylamine salt for water hyacinth control in ponds, lakes, reservoirs, marshes, bayous, drainage ditches, canals, rivers, and streams that are quiescent or slow moving in programs conducted by the Corps of Engineers or other Federal, State, or local public agencies. Where tolerances are established at higher levels from other uses of the dimethylamine salt of 2,4-D on crops included within these commodity groups, the higher tolerances also apply to residues from the aquatic uses cited in this paragraph. The established tolerances follow: crops in paragraph (c) of this section, 1.0 ppm; crop groupings in paragraph (c) of this section, 1.0 ppm; fish, 1.0 ppm; and shellfish, 1.0 ppm. [R325] *Tolerances are established for residues of 2,4-dichlorophenoxyacetic acid (2,4-D) and/or its metabolite, 2,4-dichlorophenol (2,4-DCP) in food products of animal origin as follows: cattle, fat: 0.2 ppm; cattle, kidney: 2 ppm; cattle, meat: 0.2 ppm; cattle, meat byproducts (except kidney): 0.2 ppm; eggs: 0.05 ppm; goats, fat: 0.2 ppm; goats, kidney: 2 ppm; goats, meat: 0.2 ppm; goats, meat byproducts (except kidney): 0.2 ppm; hogs, fat: 0.2 ppm; hogs, kidney: 2 ppm; hogs, meat: 0.2 ppm; hogs, meat byproducts (except kidney): 0.2 ppm; horses, fat: 0.2 ppm; horses, kidney: 2 ppm; horses, meat: 0.2 ppm; horses, meat byproducts (except kidney): 0.2 ppm; milk: 0.1 ppm; poultry: 0.05 ppm; sheep, fat: 0.2 ppm; sheep, kidney: 2 ppm; sheep, meat: 0.2 ppm; and sheep, meat byproducts (except kidney): 0.2 ppm. [R326] *A tolerance is established for residues of 2,4-D from application of its dimethylamine salt or its butoxyethanol ester for Eurasian Watermilfoil control in programs conducted by the Tennessee Valley Authority in dams and reservoirs of the TVA system as follows: fish, 1.0 ppm. [R327] *A tolerance with regional registration as defined in section 180.1(n) is established for the residues of 2,4-D (2,4-dichlorophenoxyacetic acid). The tolerance includes residues from the application of 2,4-D and its N-oleyl-1,3-propylenediamine salt on the following raw agricultural commodity: raspberries, 1.0 ppm. [R328] *A tolerance that expires on December 31, 2001, is established for residues of the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) resulting from the preplant use of 2,4-D ester or amine in or on the food commodity as follows: soybean, seed 0.2 ppm. [R329] *The following tolerances are established for residues of 2,4-D (2,4-dichloro-phenoxyacetic acid) in the following processed feeds. Such residues may be present therein only as a result of application to the growing crop of the herbicides identified in this section: (i) 5 ppm in sugarcane bagasse and sugarcane molasses. (ii) 2 ppm in the milled fractions derived from barley, oats, rye and wheat to be ingested as animal feed or converted into animal feed. [R330] *Tolerances are established for residues of the herbicide 2,4-D (2,4-dichloro-phenoxyacetic acid) as follows: 5 ppm in sugarcane molasses, resulting from application of the herbicide to sugarcane fields. [R331] *Tolerances are established for residues of the herbicide 2,4-D (2,4-dichloro-phenoxyacetic acid) as follows: 2 ppm in the milled fractions (except flour) derived from barley, oats, rye, and wheat to be ingested as food or to be converted to food. Such residues may be present therein only as a result of application to the growing crop of the herbicides identified in 40 CFR 180.142. [R332] *Tolerances are established for residues of the herbicide 2,4-D (2,4-dichloro-phenoxyacetic acid) as follows: 0.1 ppm (negligible residue) in potable water. Such residues may be present therein only: (A) As a result of the application of the dimethylamine salt of 2,4-D to irrigation ditch banks in the Western United States to programs of the Bureau of Reclamation; cooperating water user organizations; the Bureau of Sport Fisheries, U.S. Department of the Interior; Agricultural Research Services, U.S. Department of Agriculture; and the Corps of Engineers, U.S. Department of Defense. (B) As a result of the application of the dimethylamine salt of 2,4-D for water hyacinth control in ponds, lakes, reservoirs, marshes, bayous, drainage ditches, canals, rivers and streams that are quiescent or slow moving in programs of the Corps of Engineers or other Federal, State, or local public agencies. (C) As a result of application of its dimethylamine salt or is butoxyethanol ester for Eurasian watermilfoil control in programs conducted by the Tennessee Valley Authority in dams and reservoirs of the TVA system. [R333] *A time-limited tolerance is established for 2,4-dichlorophenoxyacetic acid (2,4-D) in or on wild rice in connection with use of the pesticide under a section 18 emergency exemption granted by EPA. The tolerance will expire on the date specified ... wild rice, 0.1 ppm, 12/31/02. [R334] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 10 mg/cu m. [R335] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 mg/cu m. [R48] TLV: *8 Hr Time-Weighted Avg (TWA): 10 mg/cu m. [R84, 2002.25] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R84, 2002.6] *A4; Not classifiable as a human carcinogen. [R84, 2002.25] OOPL: *Max Allowable Concn (MAC) USSR 1 mg/cu m [R75, 1036] *Occupational exposure limits: Australia (1978) Time Weighted Avg (TWA) 10 mg/cu m; Belgium (1978) TWA 10 mg/cu m; Finland (1981) TWA 10 mg/cu m, Short Term Exposure Limit (STEL) 20 mg/cu m; Germany, Federal Republic of (1985) TWA 10 mg/cu m; Hungary (1974) TWA 10 mg/cu m; Japan (1978) TWA 10 mg/cu m; The Netherlands (1978) TWA 10 mg/cu m; Norway (1981) TWA 5 mg/cu m; Romania (1975) TWA 5 mg/cu m, Ceiling limit 10 mg/cu m; Switzerland (1978) TWA 10 mg/cu m; UK (1985) TWA 10 mg/cu m, STEL 20 mg/cu m; USSR (1977) Ceiling limit 1 mg/cu m; Yugoslavia (1971) Ceiling limit 10 mg/cu m. [R336] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 2,4-D is included on this list. [R337] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 70 ug/l [R338] FEDERAL DRINKING WATER GUIDELINES: +EPA 70 ug/l [R338] STATE DRINKING WATER STANDARDS: +(IL) ILLINOIS 10 ug/l [R338] +(NY) NEW YORK 50 ug/l [R338] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 70 ug/l [R338] +(ME) MAINE 70 ug/l [R338] +(MN) MINNESOTA 70 ug/l [R338] CWA: +2,4-D acid is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R339] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R340] RCRA: *D016; A solid waste containing 2,4-D may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R341] *U240; As stipulated in 40 CFR 261.33, when 2,4-D acid, salts and esters as commercial chemical products or manufacturing chemical intermediates or off-specification commercial chemical products or manufacturing chemical intermediates, become wastes, they must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R342] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. 2,4-Dichlorophenoxyacetic acid is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0073; Pesticide type: Fungicide, Herbicide (Growth Regulator); Registration Standard Date: 09/01/88; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): 2,4-Dichlorophenoxyacetic acid; Data Call-in (DCI) Date(s): 03/25/92, 03/03/95, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R343] *Tolerances are established for residues of the herbicide, plant regulator, and fungicide 2,4-D (2,4-dichlorophenoxyacetic acid) in or on raw agricultural commodities as follows: apples; apricots; citrus fruits; pears; potatoes; and quinces. [R316] *The tolerance on apricots also includes residues of 2,4-D (2,4-dichlorophenoxyacetic acid) from the preharvest application of 2,4-D dimethylamine salt to apricots. [R317] *The tolerances on citrus fruits also includes residues of 2,4-D from the preharvest application of 2,4-D isopropyl ester and 2,4-D butoxyethyl ester and from the postharvest application of 2,4-D alkanolamine salts and 2,4-D isopropyl ester to citrus fruits. [R318] *Tolerances are established for residues of 2,4-D at: barley, grain; blueberries; corn, fodder; corn, forage; corn, fresh, sweet (kernel plus cob with husk removed); corn, grain; cranberries; grapes; grass hay; grasses, pasture; grasses, rangeland; millet, forage; millet, grain; millet, straw; nuts; oats, forage; oats, grain; pistachios; rice; rice, straw; rye, forage; rye, grain: sorghum, fodder; sorghum, forage; sorghum, grain; stone fruits; sugarcane; sugarcane, forage; wheat, forage; and wheat, grain. [R319] *Residues on /the commodities listed at 40 CFR 180.142(a)(2)/ ... may result from application of 2,4-D in acid form, or in the form of one or more of the following salts: (A) the inorganic salts: ammonium, lithium, potassium, and sodium; (B) the amine salt: alkanolamines of the ethanol and isopropanol series (C-12), alkyl (C-13), alkyl (C-14), alkylamines derived from tall oil, amylamine, diethanolamine, diethylamine, diisopropanolamine, dimethylamine, N,N-dimethyllinoleylamine, N,N-dimethyloleyamine, ethanolamine, ethylamine, heptylamine, isopropanolamine, isopropylamine, linoleylamine, methylamine, morpholine, octylamine, oleylamine, N-oleyl-1,3-propylenediamine, propylamine, triethanolamine, triethylamine triisopropanolamine, and trimethylamine. [R320] *Residues on /the commodities listed at 40 CFR 180.142(a)(2)/ ... may result from application of 2,4-D in acid form, or in the form of one or more of the following esters: amyl(pentyl), butoxyethoxypropyl, butoxyethyl, butoxypolyethylene glycol butyl ether, butoxypropyl, butyl, dipropylene glycol isobutyl ether, ethoxyethoxyethyl, ethoxyethoxypropyl, ethyl, ethoxypropyl, isobutyl, isooctyl (including, but not limited to, 2-ethylhexyl, 2-ethyl-4-methylpentyl, and 2-octyl), isopropyl, methyl, polyethylene glycol 200, polypropoxybutyl, polypropylene glycol, propylene glycol, propylene glycol butyl ether, propylene glycol isobutyl ether, tetrahydrofurfuryl, and tripropylene glycol isobutyl ether. [R321] *Tolerances are established for negligible residues of 2,4-D from application of its dimethylamine salt to irrigation ditch banks in the Western United States in programs of the Bureau of Reclamation, U.S. Department of Interior; cooperating water user organizations; the Bureau of Sport Fisheries, U.S. Department of Interior; Agricultural Research Services, U.S. Department of Agriculture; and the Corps of Engineers, U.S. Department of Defense. Where tolerances are established at higher levels from other uses of 2,4-D on the following crops, the higher tolerance applies also to residues from the irrigation ditch bank use cited in this paragraph. The established tolerances follow: avocados; citrus fruits; cottonseed; cucurbits; forage grasses; forage legumes; fruiting vegetables; grain crops; hops; leafy vegetables; nuts; pome fruits; root crop vegetables; seed and pod vegetables; small fruits; and stone fruits. [R322] *A tolerances is established for residues of 2,4-D sodium salt and alkanolamine salts (of the ethanol and isopropanol series), calculated as 2,4-D (2,4-dichlorophenoxyacetic acid) as follows: asparagus. [R323] *A tolerances is established for residues of 2,4-D from application of its alkanolamine salts (of the ethanol and isopropanol series) as follows: strawberries. [R324] *A tolerance is established for residues for 2,4-D from application of its dimethylamine salt for water hyacinth control in ponds, lakes, reservoirs, marshes, bayous, drainage ditches, canals, rivers, and streams that are quiescent or slow moving in programs conducted by the Corps of Engineers or other Federal, State, or local public agencies. Where tolerances are established at higher levels from other uses of the dimethylamine salt of 2,4-D on crops included within these commodity groups, the higher tolerances also apply to residues from the aquatic uses cited in this paragraph. The established tolerances follow: crops in paragraph (c) of this section; crop groupings in paragraph (c) of this section; fish; and shellfish. [R325] *Tolerances are established for residues of 2,4-dichlorophenoxyacetic acid (2,4-D) and/or its metabolite, 2,4-dichlorophenol (2,4-DCP) in food products of animal origin as follows: cattle, fat; cattle, kidney; cattle, meat; cattle, meat byproducts (except kidney); eggs; goats, fat; goats, kidney; goats, meat; goats, meat byproducts (except kidney); hogs, fat; hogs, kidney; hogs, meat; hogs, meat byproducts (except kidney); horses, fat; horses, kidney; horses, meat; horses, meat byproducts (except kidney); milk; poultry; sheep, fat; sheep, kidney; sheep, meat; and sheep, meat byproducts (except kidney). [R326] *A tolerance is established for residues of 2,4-D from application of its dimethylamine salt or its butoxyethanol ester for Eurasian Watermilfoil control in programs conducted by the Tennessee Valley Authority in dams and reservoirs of the TVA system as follows: fish. [R327] *A tolerance with regional registration as defined in section 180.1(n) is established for the residues of 2,4-D (2,4-dichlorophenoxyacetic acid). The tolerance includes residues from the application of 2,4-D and its N-oleyl-1,3-propylenediamine salt on the following raw agricultural commodity: raspberries. [R328] *A tolerance that expires on December 31, 2001, is established for residues of the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) resulting from the preplant use of 2,4-D ester or amine in or on the food commodity as follows: soybean, seed. [R329] *The following tolerances are established for residues of 2,4-D (2,4-dichloro-phenoxyacetic acid) in the following processed feeds. Such residues may be present therein only as a result of application to the growing crop of the herbicides identified in this section: (i) in sugarcane bagasse and sugarcane molasses. (ii) in the milled fractions derived from barley, oats, rye and wheat to be ingested as animal feed or converted into animal feed. [R330] *Tolerances are established for residues of the herbicide 2,4-D (2,4-dichloro-phenoxyacetic acid) as follows: in sugarcane molasses, resulting from application of the herbicide to sugarcane fields. [R331] *Tolerances are established for residues of the herbicide 2,4-D (2,4-dichloro-phenoxyacetic acid) as follows: in the milled fractions (except flour) derived from barley, oats, rye, and wheat to be ingested as food or to be converted to food. Such residues may be present therein only as a result of application to the growing crop of the herbicides identified in 40 CFR 180.142. [R332] *Tolerances are established for residues of the herbicide 2,4-D (2,4-dichloro-phenoxyacetic acid) as follows: in potable water. Such residues may be present therein only: (A) As a result of the application of the dimethylamine salt of 2,4-D to irrigation ditch banks in the Western United States to programs of the Bureau of Reclamation; cooperating water user organizations; the Bureau of Sport Fisheries, U.S. Department of the Interior; Agricultural Research Services, U.S. Department of Agriculture; and the Corps of Engineers, U.S. Department of Defense. (B) As a result of the application of the dimethylamine salt of 2,4-D for water hyacinth control in ponds, lakes, reservoirs, marshes, bayous, drainage ditches, canals, rivers and streams that are quiescent or slow moving in programs of the Corps of Engineers or other Federal, State, or local public agencies. (C) As a result of application of its dimethylamine salt or is butoxyethanol ester for Eurasian watermilfoil control in programs conducted by the Tennessee Valley Authority in dams and reservoirs of the TVA system. [R333] *A time-limited tolerance is established for 2,4-dichlorophenoxyacetic acid (2,4-D) in or on wild rice in connection with use of the pesticide under a section 18 emergency exemption granted by EPA. The tolerance will expire on the date specified ... wild rice, 12/31/02. [R334] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Air Sampling Procedure: Commercial activated silica gel (60/70 mesh) was treated by Soxhlet extraction for two days using boiling methanol. The gel was then dried in an oven at 200 deg C for two days. Five grams of the gel was then packed into polyethylene air samplers ... and shielded from moisture. ... The samplers were placed on the vertical inlet of a vacuum line, 7 ft above ground level. The samplers were encased in a cage of mesh and the air flow was maintained at 10 l/min. The samplers were changed daily, wrapped to exclude moisture, and stored in a refrigerator until analysis. /SRP: Method is for the free acid and esters, not salts/ [R344] *NIOSH Method 5001. Analyte: 2,4-D and 2,4,5-T. Matrix: Air. Sampler: Filter (glass fiber, binder less). Flow Rate: 1 to 3 l/min. Sample Size: 100 liters. Shipment: Routine. Sample Stability: At least 1 week @ 25 deg C. /2,4-D and 2,4,5-T/ [R345] ALAB: *HIGH PERFORMANCE LIQ CHROMATOGRAPHY EVALUATED FOR DETERMINING HERBICIDE IN NON-FATTY FOODS. [R346] *... Green plant material ... /is/ extracted ... methylated ... and quantitated using a gas chromatograph equipped with an electron capture detector. ... Dried green wheat check samples ... yielded avg interlaboratory recoveries of 2,4-D of 83.3 and 88.2%. ... [R347] *Loss of 2,4-D by adsorption on Pyrex evaporating flasks and flint glass bottles was studied. 2,4-D may be quant recovered by direct methylation with diazomethane in Pyrex evaporating flasks; it may also desorbed with methylene chloride in the presence of strong sulfuric acid. This step must be taken when 2,4,-D is transferred from one glass vessel to another to ensure accuracy of data. [R348] *HIGH PERFORMANCE LIQUID CHROMATOGRAPHY DETN IN WATER. 2,4-D, SILVEX, AND 2,4-D DIMETHYLAMINE SALT WERE SEPARATED FROM ONE ANOTHER BY REVERSE-PHASE CHROMATOGRAPHY USING METHYL CYANIDE-WATER (75:25), ADJUSTED TO PH 3.6 WITH 1% ACETIC ACID, AS A MOBILE PHASE. THE COLUMN WAS MU BONDAPAK C18. [R349] *A procedure for detecting chlorophenoxy herbicides in water is described. The sample in water solution is acidified with hydrochloric acid to obtain a pH of 2 and extracted with successive 100, 50 and 50 ml portions of benzene. After evaporation of the benzene, the extract is methylated with diazomethane and reduced in volume to less than 0.1 ml to eliminate excess diazomethane. The extract is then diluted with acetone to a suitable volume for gas-liquid chromatography. The results indicate that the extraction method described would be applicable for determining possible water contamination by chlorophenoxy herbicides and their esters. Estimated minimum detectable amounts of the herbicides and esters studies, based on the relative instrument response, the sample size and the final volume (1 ml), were 0.01 to 0.05 ppb for dicamba, 2,4-D, 2,4,5-T, Silvex, isopropyl ester of 2,4-D and n-butyl ester of 2,4-D and 2 ppb for MCPA. The sensitivity of MCPA might be increased considerably by nitration or bromination before methylation. [R350] *Whole Plants: Macerate plant tissue with water. Add 0.6 M sodium hydroxide. Reflux or heat on a steam bath. Filter and wash the filter cake with water. Combine the filtrates. Suspend the filter cake in 2 M hydrochloric acid. Reflux or heat on a steam bath. Extract with equal volumes of ether (x3). Combine these with the filtrate. The above acid hydrolysis is done in case there are conjugates resistant to alkaline hydrolysis. The recovery of the above using only the alkaline hydrolysis was greater than 89 to 92% with (14)C-labeled material. ... Continue with a liquid/liquid cleanup, followed by electron capture/gas chromatography quantitiation ... using a pyrex column ... packed with 1:1 10% DC 200/15% QF-1 on 80/100 mesh Chromosorb W (AW-DMCS). The injector, column, and (63)nickel electron capture detector temperatures are 220, 195, and 220 deg C, respectively. The flow rate of nitrogen carrier is 80 ml/min. [R351] *Water: Filter out any particulate matter. Take a 1-liter or smaller volume sample. Saturate with sodium chloride. Adjust the pH to < 2 with hydrochloric acid. Extract with acetonitrile (5 x 500 ml). Adjust the saline solution to > pH 13 and extract with diethyl ether (3 x 500 ml). Reacidify to < pH 2 with hydrochloric acid and extract with acetonitrile (5 x 500 ml). Extraction is approximately 99% efficient. ... Continue with a liquid/liquid cleanup, followed by electron capture/gas chromatography quantitation ... using a pyrex column ... packed with 1:1 10% DC 200/15% QF-1 on 80/100 mesh Chromosorb W (AW-DMCS). The injector, column, and (63)nickel electron capture detector temperatures are 220, 195, and 220 deg C; respectively. The flow rate of nitrogen carrier is 80 ml/min. [R352] *Mass spectra: intense parent ion (P)= 162; intense P-glyoxal= 220. /SRP: Either can be used for specific ion monitoring/ [R353] *Product analysis of 2,4-D, salts, esters and mixed combination products are by acid-base titration or by gas liquid chromatography. Residues may be determined by gas liquid chromatography of derivatives. [R40, 325] *ELECTRON IMPACT MASS SPECTRA FOR CHLOROPHENOXY HERBICIDES WERE OBTAINED AND USED TO ESTABLISH SELECTIVE ION-MONITORING TECHNIQUES FOR AIRBORNE 2,4-D CMPD. TOTAL EFFLUENT GAS CHROMATOGRAPHY/MASS SPECTROMETRY EXTREMELY ADVANTAGEOUS FOR MAX SENSITIVITY AND REPRODUCIBILITY IN ENVIRONMENTAL ANALYSIS. [R354] *Sixteen samples of 2,4-D, as esters and the amine, both technical and formulated products were analyzed for the presence of different chlorinated dibenzo-p-dioxins. Determination was by gas chromatography/mass spectrometry using a packed column. The recovery was greater than 85% with the limit of detection being 1 ppb. [R355] *NIOSH Method 5001. Analyte: 2,4-D AND 2,4,5-T. Matrix: Air. Procedure: High performance liquid chromatography. For 2,4-D and 2,4,5-T this method has an estimated detection limit of 0.015 mg/filter/sample. The precision/RSD is 0.01 and the recovery is not given. Applicability: The working range is 1.5 to 20 mg/cu m of either compound for a 100 liter air sample. Interferences: High concentrations of ester of either compound do not interfere but require the use of a precolumn to prevent degradation of the HPLC column. /2,4-D and 2,4,5-T/ [R345] *EPA Method 1618. Gas chromatography with electron capture detector for the determination of phenoxy acid herbicides including 2,4-D by wide bone capillary column gas chromatography with selective detectors, as used by EPA Office of Waters Industrial Technology Division. [R356] *EPA Method O-3105. Gas chromatographic method with electron capture detector for the determination of organic substances in water and fluvial sediments. Under the prescribed conditions for 2,4-D, the estimated detection limit is 0.01 ug/l as defined by EPA. [R356] *An isocratic mobile phase of methanol containing phenoxyacetic acid-dilute acetic acid (70:30) achieved a good HPLC sepn of 2,4-D, 2,4,5-T and 2-(2,4,5-trichlorophenoxy)propionic acid (Silvex). The HPLC eluate was introduced into a mass spectrometer operated under methane enhanced electron capture neg ionization conditions through the particle beam interface. With the mass spectrometer operating in selected ion monitoring mode, detected limits in the low ug/l range were attained for all three acids. This is one of the first reports of LC coupled with MS through the particle beam interface for the detection of chlorophenoxy acid herbicides. Recoveries ranged from approx 89 to 134%. [R357] *In a simplified procedure for the detn of 2,4-D, soil samples were separated by supercritical fluid chromatography after extraction without derivatization and without the use of column chromatography for cleanup. A fused-silica capillary column coated with DB-1 stationary phase was used; CO2 was the mobile phase. Interferences in the chromatography separation were eliminated by using a tunably selective ion mobility detector. An atm pressure ion formed by the free acid was selectively monitored so the detector could monitor 2,4-D in the presence of other electron-capturing cmpd. For a randomly chosen soil sample, the level of 2,4-D detected was est at 500 ppb. [R358] *AREAL Method IP-8. Determination of Organochlorine Pesticides in Indoor Air. This method is applicable to the sampling and analysis of a variety of organochlorine pesticides in indoor air. Detection limit = 0.01 ug/cu m. [R359] *AREAL TO-10. Determination of Organochlorine Pesticides In Ambient Air Using Low Volume Polyurethane Foam (PUF) Sampling With Gas Chromatography/ Electron Capture Detector (GC/ECD). This method is applicable to ambient air samples containing variety of organochlorine pesticides. Detection limit unspecified. [R359] *AOAC Method 992.32. Chlorinated Acidic Pesticide Residues in Finished Drinking Water by Gas Chromatographic Method Using Electron Capture Detector. Applicable to quantitative determination of residues of 12 chlorinated acidic pesticides, in low ppb range, in finished drinking water. Detection limit unspecified. [R360] *APHA Method 6640-B. Chlorinated Phenoxy Acid Herbicides in Water by Liquid-Liquid Extraction and Gas Chromatography. Detection limit = 10 ng/l. [R361] *EPA Method 515.1. Determination of Chlorinated Acids in Water by Gas Chromatography with an Electron Capture Detector. This method is applicable to ground water and finished drinking water. Detection limit = 0.20 ug/l. [R359] *EPA Method 515.2. Determination of Chlorinated Acids in Water using Liquid-Solid Extraction and Gas Chromatography with an Electron Capture Detector. Detection limit = 0 .28 ug/l. [R359] *EPA Method 555. Determination of Chlorinated Acids in Water by High Performance Liquid Chromatography with a Photodiode Array Ultraviolet Detector. This method is applicable to the determination of certain chlorinated acids in ground water and finished drinking water. Detection limit = 1.30 ug/l. [R359] *EPA Method 615. The Determination of Chlorinated Herbicides in Industrial and Municipal Wastewater by Gas Chromatography using Electron Capture Detection. Detection limit = 1.20 ug/l. [R359] *EPA Method 8151-W. Determination of Chlorinated Herbicides by GC Using Methylation Or Pentafluorobenzylation Derivatization: Capillary Column Technique. This method is applicable to certain chlorinated acid herbicides in aqueous matrices. Detection limit = 0.2 ug/l. [R359] *EPA Method 8151-S. Determination of Chlorinated Herbicides by GC Using Methylation Or Pentafluorobenzylation Derivatization: Capillary Column Technique. This method is applicable to certain chlorinated acid herbicides in aqueous matrices. Detection limit = 0.11 ug/kg. [R359] CLAB: *A method is described for isolating acidic toxic substances from biological fluids by extraction followed by derivatization and chromatography to rectify the biomolecular matrix that is inevitably coextracted with water soluble materials. Toxic substance screening for contamination with polychlorinated organics was accomplished by using negative chemical ionization mass spectrometry. Recoveries exceeded 70% for 2,4-D. Quantitation was obtained with electron capture gas chromatography. [R362] *Fat Samples: Dissolve sample in hot ethanol; Reflux for 1 hr, and chill as in the above section. Add 2 ml 0.1 N sodium hydroxide. Extract with diethyl ether (3 x 3 ml). ... Continue with a liquid/liquid cleanup, followed by electron capture/gas chromatography quantitation ... using a pyrex column ... packed with 1:1 10% DC 200/15% QF-1 on 80/100 mesh Chromosorb W (AW-DMCS). The injector, column, and (63)nickel electron capture detector temperatures are 220, 195, and 220 deg C, respectively. The flow rate of nitrogen carrier is 80 ml/min. [R363] *Plasma: This is based on the method for the drug Clofibrate. Add enough hydrochloric acid to the sample for pH < 2. Extract with equal volumes of ether (x3). Continue as in the method in Section III.A.1. To measure the 2,4-D in complex form, add aqueous sodium hydroxide to the aqueous layer and ... continue with a liquid/liquid cleanup, followed by electron capture/gas chromatography quantitation ... using a pyrex column ... packed with 1:1 10% DC 200/15% QF-1 on 80/100 mesh Chromosorb W (AW-DMCS). The injector, column, and (63)nickel electron capture detector temperatures are 220, 195, and 220 deg C; respectively. The flow rate of nitrogen carrier is 80 ml/min. [R363] *Metabolites: This is a general method recommended by McLeod and Wales. Reflux 5 g of tissue for 1 hr with 19 ml of benzene and separate the supernatant from particulates by filtration through a medium-porosity fritted glass funnel via negative pressure. Re-extract the particulate matter again with fresh 10 ml (19:1) acetone/benzene. Combine the filtrates and concentrate to 25 ml. Use the low-temperature bath apparatus as laid out by McLeod and Wales. Further characterization of the actual metabolites has not been accomplished. There is much room for further separation technology. [R363] *In General: Renberg's method is simple, but not very quantitative (70 to 82% at 1 to 3 ppm) /for the determination of 2,4-D/. /The method involves/ a liquid/liquid cleanup, followed by electron capture/gas chromatography quantitation ... using a pyrex column ... packed with 1:1 10% DC 200/15% QF-1 on 80/100 mesh Chromosorb W (AW-DMCS). The injector, column, and (63)nickel electron capture detector temperatures are 220, 195, and 220 deg C; respectively. The flow rate of nitrogen carrier is 80 ml/min. 2) an ion exchange clean up in 0.1 M sodium hydroxide. [R363] *Muscle, Liver, and Kidney: ... a liquid/liquid cleanup, followed by electron capture/gas chromatography quantitation ... using a pyrex column ... packed with 1:1 10% DC 200/15% QF-1 on 80/100 mesh Chromosorb W (AW-DMCS). The injector, column, and (63)Ni electron capture detector temperatures are 220, 195, and 220 deg C; respectively. The flow rate of nitrogen carrier is 80 ml/min. An ion exchange cleanup can be utilized if 3 ml of 0.1 M sodium hydroxide is added with evaporation of the ether layer to 3 ml /for the determination of 2,4-D/. [R363] *From a 2,4-D applicator study, the measured quantity of urinary 2,4-D proved to be the best measure of the dose received. [R364] *2,4-D and the internal standard, 2,4,5-T, are extracted from acidified plasma or urine with ether. A back extraction is performed into a methylating reagent and the methyl esters are chromatographed on OV-17, with detection by flame ionization. 2,4-D retention time is 5 min. Sensitivity: 1 mg/l. Interferences: the specimen should be analyzed with and without the internal standard to ensure 2,4,5-T is not one of the constituents of the ingested herbicide. [R229, 119] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol (1980) EPA 440/5-80-042 Milby TH et al; Potential Health Effects Associated with the Use of Phenoxy Herbicides (1981) Norris LA; Residue Rev: The movement, persistence and fate of the phenoxy herbicides and TCDD in the forest. 77: 65-135 (1981) Nat'l Research Council Canada; Phenoxyherbicides (1978) NRCC No. 16075 WHO; Environ Health Criteria: 2,4-Dichlorophenoxyacetic Acid (2,4-D) (1984) Que Hee SS, Sutherland RG; The Phenoxyalkanoic Herbicides (1981) Veterans Administration; Review of Literature on Herbicides, Including Phenoxy Herbicides and Associated Dioxins Vol I (1981) VA Contract No. V101(93)P-823 Drinking Water Criteria Doc: 2,4-Dichlorophenoxyacetic acid (2,4-D) 1985 (Draft) ECAG-CIN 418 TEST: *The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on 2,4-dichlorophenoxyacetic acid is scheduled for peer review. Route: dosed feed; Species: peroxisome project, rats, mice, and hamster. NTP TR No 63. [R365] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 475 R2: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 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Springfield, VA: NTIS PB-214009, p. 219 (1972) (4) Que Hee SS et al; Environ Sci Technol 9: 62-69 (1975) R300: (1) IARC; Some Fumigants, the Herbicides 2,4-D and 2,4,5-T, Chlorinated Dibenzodioxins and Miscellaneous Industrial Chemicals. 15: 111-38 (1977) (2) Duggan RE et al; Science 151: 101-4 (1966) (3) Duggan RE et al; Pest Monit J 5: 73-212 (1971) (4) Duggan RE, Corneliussen PE; Pest Monit J 5: 331-41 (1972) (5) Manske DD, Johnson RD; Pest Monit J 9: 94-105 (1975) (6) Johnson RD, Manske DD; Pest Monit J 9: 157-69 (1976) (7) Manske DD, Corneliussen PE; Pest Monit J 8: 110-24 (1974) (8) Corneliussen PE; Pest Monit J 5: 313-30 (1972) (9) Duggan RE et al; Pesticide residue levels in foods in the United States from July 1, 1969 to June 30, 1976. Washington, DC: Food Drug Admin., Div Chem Technol. pp. 240 (1983) (10) Johnson RD et al; Pest Monit J 15: 39-50 (1981) R301: (1) WHO; Environ Health Criteria 29: 2,4-Dichlorophenoxyacetic Acid (2,4-D). Geneva, Switzerland: World Health Org. p.12 (1984) R302: (1) Frank R et al; J Assoc Off Anal Chem 70: 1081-86 (1987) (2) Frank R et al; Bull Environ Contam Toxicol 39: 272-9 (1987) (3) FDA; Total Diet Study- Summary of Residues Found Ordered By Pesticide Market Baskets 91-3-99-1. Available from Database Query page at http://www.cfsan.fda.gov/~acrobat/TDS1byps.pdf as of Nov 20, 2001. (4) Roger WM; J AOAC Int 78: 614-31 (1995) R303: (1) Wojtalik TA et al; Pest Monit J 4: 184-203 (1971) R304: (1) Wojtalik TA et al; Pest Monit J 4: 184-203 (1971) (2) Frank R et al; Environ Mon Assess 9: 71-82 (1987) (3) Schultz DP, Whitney EW; Pest Monit J 7: 146-52 (1974) R305: (1) Schultz DP, Whitney EW; Pest Monit J 7: 146-52 (1974) R306: Klingman DL et al; Weeds 14 (2): 164-7 (1966) as cited in Vet Admin Rev Lit on Herbicides Vol 2 p.187 (1981) VA Contract No. V101(93)p-823) R307: (1) Duggan RE et al; Pesticide residue levels in foods in the United States from July 1, 1969 to June 30, 1976. Food Drug Admin Div Chem Technol, pp. 240 (1983) R308: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) WHO; Environ Health Criteria 29: 2,4-Dichlorophenoxyacetic Acid (2,4-D). Geneva, Switzerland: World Health Org. p. 99 (1984) (3) Nishioka MG et al; Environ Sci Technol 33: 1359-65 (1999) R309: (1) Bingham E et al; Patty's Toxicology 5th ed. NY, NY: John Wiley and Sons 5: 674 (2001) R310: (1) Kolmodin-Hedman B, Erne K; Arch Toxicol Suppl 4: 318-21 (1980) R311: (1) WHO; Environ Health Criteria 29: 2,4-Dichlorophenoxyacetic Acid (2,4-D). Geneva, Switzerland: World Health Org. p. 99 (1984) (2) Gunderson EL; J AOAC Int 78: 1353-62 (1995) R312: (1) Frank R et al; Arch Environ Contam Toxicol 14: 427-35 (1985) (2) Yeary RA; Appl Ind Hyg 1: 119-21 (1986) (3) Hill RH et al; Arch Environ Contam Toxicol 18: 469-74 (1989) R313: USEPA/OPP; Health Effects Div RfD/ADI Tracking Report p.1 (8/26/91) R314: Federal Insecticide, Fungicide and Rodenticide Act Scientific Advisory Panel (1980) as cited in Milby TH et al; Potential Health Effects Associated with the Use of Phenoxy Herbicides p.10 (1981) R315: Sittig M; Handbook of Toxic and Hazardous Chemicals p.208 (1981) R316: 40 CFR 180.142(a)(1) (7/1/2001) R317: 40 CFR 180.142(a)(1)(i) (7/1/2001) R318: 40 CFR 180.142(a)(1)(ii) (7/1/2001) R319: 40 CFR 180.142(a)(2) (7/1/2001) R320: 40 CFR 180.142(a)(2)(i) (7/1/2001) R321: 40 CFR 180.142(a)(2)(ii) (7/1/2001) R322: 40 CFR 180.142(a)(3) (7/1/2001) R323: 40 CFR 180.142(a)(4) (7/1/2001) R324: 40 CFR 180.142(a)(5) (7/1/2001) R325: 40 CFR 180.142(a)(6) (7/1/2001) R326: 40 CFR 180.142(a)(8) (7/1/2001) R327: 40 CFR 180.142(a)(9) (7/1/2001) R328: 40 CFR 180.142(a)(10) (7/1/2001) R329: 40 CFR 180.142(a)(11) (7/1/2001) R330: 40 CFR 180.142(a)(12) (7/1/2001) R331: 40 CFR 180.142(a)(13)(i) (7/1/2001) R332: 40 CFR 180.142(a)(13)(ii) (7/1/2001) R333: 40 CFR 180.142(a)(13)(iii) (7/1/2001) R334: 40 CFR 180.142(b) (7/1/2001) R335: 29 CFR 1910.1000 (7/1/2001) R336: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 370 (1986) R337: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R338: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R339: 40 CFR 116.4 (7/1/2001) R340: 40 CFR 302.4 (7/1/2001) R341: 40 CFR 261.24 (7/1/2001) R342: 40 CFR 261.33 (7/1/2001) R343: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.70 (Spring, 1998) EPA 738-R-98-002 R344: Que Hee SS et al; Environ Sci Tech 9: 62 (1975) R345: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R346: BRAMLETT CL; EDRO SARAP RES TECH REP 1 (PAPER 52-74): 1-30 (1976) R347: Smith AE; J Assn off Anal Chem 67 (4): 794-8 (1984) R348: Kan GY P; J Assoc Off Anal Chem 65 Issue 3: 763-5 (1982) R349: EDWARDS RW ET AL; NBS SPEC PUBL (US) 519 (TRACE ORG ANAL: NEW FRONT ANAL CHEM) 87-94 (1979) R350: Devine JM, Zweig G; J Assoc Anal Chemists 52 (1): 187-9 (1969) R351: Que Hee SS, Sutherland RG; The Phenoxyalkanoic Herbicides p.196 (1981) R352: Que Hee SS, Sutherland RG; The Phenoxyalkanoic Herbicides p.204 (1981) R353: Que Hee SS, Sutherland RG; The Phenoxyalkanoic Herbicides p.80 (1981) R354: FARWELL SO ET AL, ANAL CHEM 48 (2): 420-6 (1976) R355: Cochrane WP et al; Pergamon Ser Environ Sci 5 (Chlorinated Dioxins Relat Cmpd): 209-13 (1982) R356: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.162 (1991) OST Pub 21W-4005 R357: Mattina MJ In; J Chromatogr 542 (2): 385-95 (1991) R358: Morrissey MA, Hill HH Jr; J Chromatogr Sci 27 (9): 529-33 (1989) R359: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R360: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. SUPP 166 R361: American Public Health Association, American Water Works Association, Warer Environment Federation. M.A.H. Franson (ed.); Standard Methods for the Examination of Water and Wastewater 20th ed., Washington, D.C. 1998.p. 6-105 R362: Tondeur Y, Dougherty RC; Environ Sci Technol 15 (2): 216-19 (1981) R363: Que Hee SS, Sutherland RG; The Phenoxyalkanoic Herbicides p.203 (1981) R364: FIFRA; Direct Testimony: Docket No. 415 p.31 (1980) R365: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 328 Record 45 of 1119 in HSDB (through 2003/06) AN: 210 UD: 200201 RD: Reviewed by SRP on 12/10/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: EUGENOL- SY: *ALLYLGUAIACOL-; *P-ALLYLGUAIACOL-; *4-ALLYLGUAIACOL-; *5-Allylguaiacol-; *4-ALLYL-1-HYDROXY-2-METHOXYBENZENE-; *4-ALLYL-2-METHOXYPHENOL-; *CARYOPHYLLIC-ACID-; *EUGENIC-ACID-; *P-EUGENOL-; *FEMA-NUMBER-2467-; *1-HYDROXY-2-METHOXY-4-ALLYLBENZENE-; *4-HYDROXY-3-METHOXYALLYLBENZENE-; *1-HYDROXY-2-METHOXY-4-PROP-2-ENYLBENZENE-; *2-METHOXY-4-ALLYLPHENOL-; *2-METHOXY-1-HYDROXY-4-ALLYLBENZENE-; *2-METHOXY-4-PROP-2-ENYLPHENOL-; *NCI-C50453-; *PHENOL,-4-ALLYL-2-METHOXY-; *PHENOL, 2-METHOXY-4-(2-PROPENYL)-; *SYNTHETIC-EUGENOL- RN: 97-53-0 MF: *C10-H12-O2 ASCH: Eugenol benzoate; 531-26-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OIL CONTAINING EUGENOL ... TREATED WITH 3% AQ SOLN OF NAOH; NONACID COMPONENTS ... EXTRACTED WITH ETHER. ALKALINE SOLN IS ACIDIFIED TO ISOLATE PHENOLS AND ... FRACTIONALLY DISTILLED UNDER REDUCED PRESSURE. TO AVOID FORMATION OF EMULSIONS, PRETREATMENT OF OIL WITH TARTARIC ACID ... PREFERRED. [R1] *OBTAINED FROM MANY NATURAL SOURCES; FROM OIL OF CLOVES. [R2, 612] *It can be extracted from clove oil with aqueous potassium hydroxide, followed by liberation with an acid, and distillation in a stream of CO2. It can be synthesized by the reaction of allyl chloride with guaiacol. [R3] FORM: *TECHNICAL PRODUCT CONTAINS 95-100% EUGENOL. [R1] *GRADES: TECHNICAL; UNITED STATES PHARMACOPEIA; "FOOD CHEMICAL CODEX" [R4, 501] MFS: *Firmenick Inc, Hq, PO Box 5880, Princeton, NJ 08543, (609) 452-1000; Firmenick Chemical Manufacturing Center, 928-964 Doremus Ave, Port Newark, NJ 07114; Production site: Port Newark, NJ 07114 [R5] *Givaudan Corp, Hq, 100 Delawanna Ave, Clifton, NJ 07014, (201) 365-8000; Chemicals Div; Fritzsche Dodge and Olcott Div, 76 Ninth Ave, New York, NY 10011; Production site: East Hanover, NJ 07936 [R5] *International Flavors and Fragrances Inc, Hq, 521 West 57th Street, New York, NY 10019, (212) 765-5500; Production site: Union Beach, NJ 07735 [R5] *Ungerer and Co, Hq, 4 Bridgewater Lane, Lincoln Park, NJ 07035, (201) 628-0600; Chemical Div, 110 N Commerce Way, Bethlehem, PA 18017; Production site: Bethlehem, PA 18017 [R5] OMIN: */INCOMPATIBLE WITH/ FERRIC CHLORIDE, POTASSIUM PERMANGANATE. [R2, 613] *EUGENOL HAS THE FLAVOR OF SPICE AND CLOVE WHEN USED AS A SYNTHETIC FLAVORING. IN THE FINISHED FLAVORING IT ACTS AS A FIXATIVE (REDUCES LOSS OF LIGHT VOLATILES), A TOP NOTE (GIVES IDENTITY ON FIRST IMPRESSION), AND A BODY (GIVES MAIN FLAVOR CHARACTERISTICS). /FROM TABLE/ [R6] *REPORTED USED IN NON-ALCOHOLIC BEVERAGES 1.4 PPM; ICE CREAM, ICES, ETC 3.1 PPM; CANDY 32 PPM; BAKED GOODS 33 PPM; GELATINS AND PUDDINGS 0.60 PPM; CHEWING GUM 500 PPM; CONDIMENTS 9.6-100 PPM; MEATS 40-2000 PPM. [R1] *[IARC MONOGRAPHS 1972-PRESENT V36 p.76] Heavy metal content must not exceed 0.004% max [R7] USE: *IN PERFUMERY INSTEAD OF OIL OF CLOVES; MFR OF VANILLIN [R2, 613] *RUBIFACIENT [R8] *CLOVE OIL SUBSTITUTE IN FOODS; GERMICIDE USED IN MEDICINE; FLAVOR CHEMICAL; INT FOR 4-ALLYLVERATROLE AND ISOEUGENOL (PERFUME) [R9] *Insect attractant. With phenylethyl butyrate as an adult Japanese beetle lure. [R10] *Denaturant for alcohol. [R11] *Eugenol can be used as an antioxidant in inks, and it has been reported to be useful as a fungicide in pharmaceuticals and cosmetics; no indication was found that eugenol is being used commercially for such purposes at present /1985/. Eugenol was formerly used internally in human medicine as an antiputrescent, but is no longer employed for this purpose. It has been used in the treatment of flatulent colic. [R11] *Eugenol is used principally as a fragrance and flavoring agent, as an analgesic in dental materials and nonprescription drug products, as an insect attractant, and as a chemical intermediate. [R3] *A DENTAL OBTUNDENT AND TOPICAL ANESTHETIC USED EXTENSIVELY TO REPLACE CLOVE OIL, PRINCIPALLY BY DENTISTS, WHO ALSO EMPLOY IT FOR ITS DISINFECTANT ACTION IN FILLING ROOT CANALS. [R12, 991] *IT IS USED AS A CHEMICAL INTERMEDIATE TO PRODUCE ISOEUGENOL ... . [R13, 1691] */ZINC-EUGENOL CEMENT USP IS USED/ IN GENERAL DENTAL PRACTICE ... AS A PULP CAPPING OR A TEMPORARY FILLING. [R12, 1268] +MEDICATION CPAT: *Eugenol is used primarily as a fragrance and flavoring agent, as an analgesic in dental materials and nonprescription drug products, as an insect attractant, and as a chemical intermediate. Several other applications have been reported, the commercial status of which is unknown. (1985) [R3] PRIE: U.S. PRODUCTION: *(1972) 2.15X10+8 g [R3] *(1975) 1.45X10+8 g [R3] *(1984) 1.63X10+8 g [R14] U.S. EXPORTS: *(1984) 1.51X10+9 g /Citronellal, Eugenol, Geraniol, Heliotropin, Hydroxycitronellal and Isoeugenol/ [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS OR PALE YELLOW LIQUID [R2, 612]; *CRYSTALS FROM HEXANE [R16] ODOR: *ODOR OF CLOVES [R2, 612] TAST: *SPICY, PUNGENT TASTE [R2, 612] BP: *253.2 DEG C @ 760 MM HG [R16] MP: *-9.2 TO -9.1 DEG C [R2, 612] MW: *164.20 [R2, 612] DEN: *1.0664 @ 20 DEG C/4 DEG C [R2, 612] DSC: +pka = 10.19 @ 25 deg C [R17] OWPC: +] Log Kow = 2.27 [R18] SOL: *PRACTICALLY INSOL IN WATER; SOL IN GLACIAL ACETIC ACID, 1 ML IN 2 ML 70% ALCOHOL, AQ FIXED ALKALI HYDROXIDE SOLUTIONS; MISCIBLE WITH ALCOHOL, CHLOROFORM, ETHER, OILS [R2, 613]; *Water: 0.0398 moles/l [R19]; +water solubility = 2.43X10+3 mg/l @ 25 deg C [R20] SPEC: *INDEX OF REFRACTION: 1.5416 @ 19.5 DEG C/D; 1.5380-1.5420 @ 20 DEG C/D; SPECIFIC OPTICAL ROTATION: -1 DEG 30 MIN [R1]; *INDEX OF REFRACTION: 1.5410 @ 20 DEG C/D [R2, 612]; *SADTLER REF NUMBER: 3880 (IR, PRISM) [R21]; *IR: 5146 (Coblentz Society Spectral Collection) [R22]; *UV: 3-254 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R22]; *NMR: 260 (Varian Associates NMR Spectra Catalogue) [R22]; *MASS: 1062 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R22] VAP: *1 MM HG @ 78.4 DEG C [R23, 2497] OCPP: *% IN SATURATED AIR: APPROX 0.004 AT 25 DEG C, 760 MM HG [R23, 2497] *DISTILLS BETWEEN 250 DEG C AND 255 DEG C [R12, 991] *OILY; BECOMES BROWN IN AIR; OPTICALLY INACTIVE [R4, 501] *Crystals; mp: 69-70 deg C; bp: 360 deg C; practically insol in water; freely sol in benzene, chloroform, ether, hot alcohol. /Eugenol benzoate/ [R2, 613] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FLPT: *ABOUT 104 DEG C [R1] EXPL: *Combustible [R4, 502] SSL: *LOW VOLATILITY [R13, 1691] *STABILITY IS RATED AS FAIR WHEN USED AS FOOD ADDITIVE [R6] *DARKENS AND THICKENS ON EXPOSURE TO AIR [R2, 612] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: No adequate data. 2) evidence in animals: Limited evidence. Overall summary evaluation of carcinogenic risk to humans is Group 3: The agent is not classifiable as to its carcinogenicity to humans. /From table/ [R24] HTOX: *NOT CORROSIVE LIKE PHENOL BUT INGESTION RESULTS IN GASTROENTERITIS. SYSTEMIC TOXICITY IS SIMILAR TO BUT LESS THAN THAT OF PHENOL PERHAPS BECAUSE OF ITS INSOLUBILITY IN WATER. AQUEOUS EMULSIONS BY MOUTH INDUCE VOMITING IN MAN ... PROMOTE/S/ GASTRIC SECRETION OF MUCIN. [R8] *EUGENOL SHOWED WEAK CYTOTOXIC ACTIVITY AGAINST HELA CELLS. [R25, 377] *Smoking of clove cigarettes /SRP: 60-65% tobacco, 30-35% clove buds/ has recently been associated with high altitude pulmonary edema. [R26] *Patch tests for eugenol in patients suffering from 'cosmetic dermatitis' were positive in 2.6% (4/155) of cases. [R27] *The cytotoxicity of eugenol to replicating cells, as mediated by the intracellular level of glutathione and by metabolic activation, was evaluated with the neutral red assay. The cytotoxicity of eugenol to human HFF fibroblasts and human HepG2 hepatoma cells was increased somewhat in the presence of a hepatic S9 microsoma fraction from Aroclor induced rats or hamsters. Exposure of human HepG2 hepatoma cells to eugenol depleted the level of intracellular glutathione. Cells treated with 1-chloro-2,4-dinitrobenzene or buthionine sulphoximine, agents that deplete intracellular glutathione, were hypersensitive to eugenol. A 1 hr pretreatment with 1- chloro-2,4-dinitrobenzene enhanced the cytotoxicity of eugenol, as did a 24 hr pretreatment with buthionine sulphoximine. Intracellular glutathione levels were, apparently significant in mediating the toxicity of eugenol. [R28] *84 patients with contact dermatitis (38 dentists, 18 dental nurses and 28 dental technicians) were studied. All were patch tested with standard patch test series of the Council for Mutual Economic Assistance countries and with some professional allergens. 31 (36.9%) of them had allergic occupational contact dermatitis and 39 (46.2%) had irritant contact dermatitis. The highest prevalence of irritant contact dermatitis was found among dental surgeons. The percentage of atopics in the group of patients with irritant contact dermatitis was twice greater compared to that in the group of patients with allergic contact dermatitis. The contact allergens most frequently encountered were acrylic compounds, disinfectants (eugenol, thymol, trioxymethylene) mercury compunds and anesthetics. [R29] NTOX: *POISONED RATS EXHIBITED PARESIS OF HIND LEGS AND JAW WITH ... PROSTRATION AND COMA. DEATH BELIEVED TO BE DUE TO PERIPHERAL VASCULAR COLLAPSE. [R8] *... ANIMALS THAT SURVIVED ACUTE EFFECTS REMAINED LETHARGIC, SHOWED KIDNEY INJURY AS MANIFESTED BY URINARY INCONTINENCE AND SOMETIMES HEMATURIA AND EXHIBITED MALFUNCTION OF HIND LEGS FOR SEVERAL DAYS. [R13, 1692] *... DOGS EXHIBITED VOMITING AFTER SINGLE DOSES OF 250 OR 500 MG/KG. DEATH OCCURRED AT HIGH LEVEL. PULMONARY EDEMA...NOTED IN SOME DOGS EXPOSED IV ... IV INJECTION ... DILUTED TO 1:20 TRANSIENTLY DECR SYSTEMIC ARTERIAL BLOOD PRESSURE AND MYOCARDIAL CONTRACTILE FORCE, IMPAIRED MOTOR ACTIVITY, AND INCR SALIVARY FLOW. [R23, 2534] *AQUEOUS EMULSIONS BY MOUTH INDUCE VOMITING IN ... DOGS AND PROMOTE GASTRIC SECRETION OF MUCIN. [R30] *THE STOMACHS OF RATS AND GUINEA PIGS GIVEN ORAL DOSES ... SHOWED DESQUAMATION OF THE EPITHELIUM, WITH PUNCTATE HEMORRHAGES IN PYLORIC AND GLANDULAR REGIONS OF THE STOMACH. ADDITIONAL EVALUATIONS TO MUCOUS MEMBRANES SHOWED THAT APPLICATION ... TO VENTRAL SURFACE OF THE TONGUE OF DOGS CAUSED ERYTHEMA AND OCCASIONALLY ULCERS. [R23, 2534] *... 20 MALE RATS GIVEN INITIAL ORAL DOSE OF 1.4 G ... /KG, WHICH WAS GRADUALLY INCR TO 4.0 G/KG ... 15 ... LIVED LONG ENOUGH TO RECEIVE MAX DOSE. ... ENLARGEMENT OF LIVER AND ADRENAL GLANDS ... OBSERVED AND HISTOLOGICAL EXAM OF FORESTOMACH ... REVEALED ... HYPERPLASIA AND HYPERKERATOSIS ... FOCAL ULCERATION. SMALL DEGREE OF OSTEOPOROSIS ... SEEN. [R23, 2534] *RATS GIVEN 4 DAILY DOSES OF APPROX 900 MG/KG SHOWED MINOR LIVER DAMAGE. NO LIVER DAMAGE ... IN RATS FED ... AT 1% IN DIET FOR ABOUT 4 MO. FEEDING OF ... 0.1 OR 1% IN DIET ... /TO/ RATS FOR 19 WK EXHIBITED NO EFFECT ON GROWTH, HEMATOLOGY, OR ORGAN WEIGHS AND HISTOLOGY. NO ADVERSE EFFECT ... IN ... RATS FED ... 79.3 MG/KG ... /DAY FOR 12 WK. [R23, 2534] *RESPIRATORY INHIBITION OF ISOLATED RAT LIVER MITOCHONDRIA BY EUGENOL WAS DOSE RELATED AND UNCOUPLED OXIDATIVE PHOSPHORYLATION FROM ELECTRON TRANSFER. [R31] *COMPARISON OF INFLAMMATORY RESPONSES PRODUCED BY COMMERCIAL EUGENOL AND PURIFIED EUGENOL. EACH MATERIAL WAS INJECTED SC BENEATH ABDOMINAL SKIN OF 40 WALTER REED RATS. STUDY SUGGEST THAT IMPURITIES IN COMMERCIAL EUGENOL DO CAUSE INCR IN INFLAMMATORY RESPONSE. [R32] *In rats, the intratracheal administration of eugenol produces interstitial hemorrhage and acute pulmonary edema. [R26] *Dogs given oral doses of 0.25 g/kg of eugenol demonstrated vomiting, weakness, lethargy, and ataxia. At 0.5 g/kg eugenol is capable of causing coma and death within 24 hr. The LD50 in eugenol in rats has been dtermined to be 1.8 ml/kg (1.93 g), with postmortem findings consistent with sudden cardiovascular collapse. [R33] *Iv administration of varying doses (0.05-0.15 ml of a 1:20 or 1:60 dilution) in dogs led to a transient fall in blood pressure and a reduction of myocardial contractile force. After single oral doses of 500 mg/kg body wt eugenol, 2/4 dogs with predominant symptoms of vomiting died; all animals receiving doses of 250 mg/kg body wt survived. Single and repeated oral administration of a 5% aqueous eugenol emulsion to dogs caused degeneration of the gastric mucosal cells. [R34] *Groups of 50 male and 50 female B6C3F1 mice, 6-7 wk old, were fed diets containing USP extra grade eugenol (purity > 99%, with up to 4 trace impurities) at levels of 0, 3000, or 6000 mg/kg of diet for 103 wk. Survival at 106 wk was 41/50, 35/50, and 35/50 among control, low dose, and high dose males, respectively; survival in females varied between 80-90%. ... The total numbers of male mice with hepatocellular tumors were 14/50 in control, 28/50 in low dose, and 18/49 in high dose animals; and those of females: 2/50 in control, 7/49 in low dose, and 9/49 in high dose animals. For hepatocellular tumors in female mice a trend test was significant (p= 0.02), as was a pair wise comparison test between the high dose and control groups (p= 0.02). For male mice, the trend test was not significant, but the pair wise comparison test between the low dose group and the control group was significant (p= 0.004). [R35] *Eugenol was not mutagenic to Escherichia coli WP2 uvrA when tested in the presence and absence of S9 derived from the livers of Aroclor induced rats. [R36] *Eugenol induced chromosomal aberrations in Chinese hamster ovary cells in the absence of an exogenous metabolic system. In a second study, chromosomal aberrations were induced by eugenol in Chinese hamster ovary cells only in the presence of S9 from Aroclor induced rats; a small increase in the incidence of sister chromatid exchange was also observed in the presence or absence of S9. [R27] *THE HYDROXYLATION OF DIMETHYLAMIDOPYRINE AND HEXOBARBITONE BY MOUSE LIVER MICROSOMES WAS WEAKLY INHIBITED BY EUGENOL IN VIVO. HEXOBARBITONE /CNS DEPRESSION/ AND ZOXAZOLAMINE PARALYSIS WERE SLIGHTLY PROLONGED IN MICE TREATED WITH EUGENOL. [R25, 377] *Bioassay directed fractionation of clove terpenes from the plant Eugenia caryophyllata has led to the isolation of the following five active known compounds: beta-caryophyllene, beta-caryophyllene oxide, alpha-humulene, alpha-humulene epoxide I, and eugenol. Their structures were determined on the basis of spectral analysis. These compounds showed significant activity as inducers of the detoxifying enzyme glutathione S-transferase in the mouse liver and small intestine. The ability of natural anticarcinogens to induce detoxifying enzymes has been found to correlate with their activity in the inhibition of chemical carcinogenesis. Thus, these sesquiterpenes show promise as potential anticarcinogenic agents. [R37] *The effect of betel leaf extract and some of its constituents, eugenol, hydroxychavicol, beta-carotene and alpha-tocopherol, on benzo(a)pyrene induced forestomach neoplasia in male Swiss mice was examined. Betel leaf and its constituents decreased the number of papillomas per animal with the maximum protection, considering molar dosage, exhibited by beta-carotene and alpha-tocopherol. Except for beta-carotene, eugenol, hydroxychavicol and alpha-tocopherol increased the levels of reduced glutathione in the liver while glutathione S-transferase activity was enhanced by all except eugenol. [R38] *Regulatory guidelines suggest testing chemicals up to cytotoxic doses in chromosomal aberration assays. To investigate the utility and limitations of various cytotoxicity indicators Chinese hamster ovary cells were used to test 8 chemicals with differing ratios of cytotoxicity to clastogenicity. Immediate or delayed cell killing and growth inhibition (adenosine triphosphate levels, cell counts, colony-forming efficiency) and cell-cycle perturbations (mitotic index; average generation time) were measured. Aberrations were scored 10 and 24 hr from the beginning of the 3 hr treatment. All 8 compounds induced aberrations at concentrations that reduced cell growth at 24 hr by 50% or less. Concentrations of each chemical which induced at least 15% cells with aberrations, gave little loss of colony-forming efficiency (0-20%) for mitomycin C, adriamycin, cadmium sulfate and 2,6-diaminotoluene in contrast to the marked loss of colony-forming efficiency (70-80%) for eugenol, 2-aminobiphenyl and 8-hydroxyquinoline. 2,4-Diaminotoluene was intermediate. Higher aberration yields were found at 24 hr than at 10 hr, even when minimal cell cycle delay was detected by average generation time estimates from BrdUrd labeled cells. Cells with multiple aberrations were seen at 24 but not at 10 hr, and often confirmed clastogenicity when there was only a weak increase in the percentage of cells with aberrations. Total adenosine triphosphate per culture did not always correlate with cell number, especially at later times after treatment. This is likely due to metabolic perturbations or altered cell biomass that are known to affect cell adenosine triphosphate content. Mitotic index suppression often did not correlate with average generation time, eg, only small increases in average generation time were seen for 8- hydroxyquinoline, 2,4-diaminotoluene and eugenol despite severe mitotic suppression at 10 hr. By 24 hr the mitotic index for all chemicals had recovered, sometimes exceeding control levels. Marked mitotic accumulation was seen at 10 hr for 2,4-diaminotoluene, indicating cell synchrony. Thus, the mitotic index has limited value for dose selection. In conclusion, even weakly active chemicals were detected at a single time without exceeding a 50% growth reduction at 24 hr. [R39] *Choice of harvest time is one of the most important variables in the assessment of whether a compound is clastogenic and in establishing a dose relation. The effects of sampling time on aberration yield was examined for 7 diverse chemicals in Chinese hamster ovary cells by harvesting at intervals from 9 to 30 hr after treatment for 3 hr with or without S9 metabolic activation. Both the percentage of aberrant cells and the total number of aberrations were observed. Data suggest that for most compounds a single harvest time approximately 17-21 hr after the beginning of a 3 hr treatment is optimal for aberration detection in Chinese hamster ovary cells. Maximal aberration yields were observed for eugenol from 15 to 21 hr. The use of 3 or more closely spaced concentrations, carefully selected to yield up to 50% toxicity, allowed detection of a positive response at a single harvest time for all 7 chemicals. [R40] *The effects of phenolic dental medicaments on lipoxygenase activities of rat dental pulp and human platelets were studied. The major product derived from (14)C arachidonic acid by the homogenate of rat dental pulp was 12-hydroxyeicosatetraenoic acid (15-hydroxyeicosatetraenoic acid). Eugenol and p-chlorophenol dose dependently inhibited hydroxyeicosatetraenoic acids formation. The IC50 values of eugenol and p-chlorophenol were 0.62 and 0.34 mM respectively. The concentrations of these compounds that inhibit lipoxygenase were similar to those required to inhibit cyclooxygenase. These compounds also inhibited 12-lipoxygenase of human platelets with a similar range of concentrations. The results show that phenolic dental medicaments inhibit pulpal and platelet lipoxygenase. Thus, inhibition of arachidonic acid metabolism by phenolic dental medicaments via the lipoxygenase pathway may be involved in the analgesic and anti-inflammatory effects of the medicaments in endodontic therapy. [R41] *Eugenol is widely used as a food flavoring agent and a dental analgesic. Mice treated with eugenol (400-600 mg/kg, orally) in combination with an inhibitor of glutathione synthesis, buthionine sulfoximine (1 hr before eugenol, 4 mmol/kg, ip) developed hepatotoxicity characterized by increases in relative liver weight and serum glutamic-pyruvic transaminase, hepatic congestion, and centrilobular necrosis of hepatocytes. Eugenol (up to 600 mg/kg) alone produced no hepatotoxicity. Drug metabolism inhibitors such as carbon disulfide, methoxsalen, and piperonyl butoxide prevented or significantly reduced the hepatotoxic effect of eugenol given in combination with buthionine sulfoximine. On the other hand, pretreatment with phenobarbital increased the hepatotoxicity. These results suggest that eugenol is activated by a cytochrome p450 dependent metabolic reaction and that the liver injury is caused by inadequate rates of detoxification of the resulting metabolite in mice depleted of hepatic glutathione by buthionine sulfoximine treatment. [R42] *The local lymph node assay is a novel predictive test for the identification of contact allergens. The collaborative study reported here was performed to evaluate the reliability of the method when performed in independent laboratories. Eight chemicals were examined in each of 4 participating laboratories and results compared with predictions of skin sensitizing activity made from concurrent Magnusson and Kligman guinea pig maximization tests performed in a single laboratory. The local lymph node assay has as its theoretical basis the fact that contact allergens induce T-lymphocyte proliferative responses. In practice, predictions of contact sensitizing potential are made following measurement of proliferation in lymph nodes draining the site of exposure to chemical, and derivation of a stimulation index using control values as the comparator. Although in the present study there was some variation between laboratories with respect to the absolute stimulation indices recorded, it was found that with all chemicals each laboratory made the same predictions of sensitizing activity. Six chemicals (2,4-dinitrochlorobenzene, formalin, eugenol, isoeugenol, p-phenylenediamine and potassium dichromate) yielded positive responses, and two (methyl salicylate and benzocaine) were negative, in each laboratory. Furthermore, with 7 of the 8 chemicals tested there was no significant difference between laboratories in terms of the characteristics of the dose-response relationships recorded. With the exception of one chemical (benzocaine), predictions made with the local lymph node assay were in accord with those derived from guinea pig maximization tests. These inter-laboratory comparisons demonstrate that the local lymph node assay is a robust and reliable method for the identification of at least moderate and strong contact allergens. [R43] *The naturally occurring alkenylbenzene, eugenol, was examined for its ability to form DNA adducts in the livers of mice that had been treated with up to 10 mg of the compound. No adducts were detected by (32)P postlabelling with a limit of detection of 1 adduct in 1X10+9 nucleotides. Under these conditions adducts were readily detected in liver DNA from the structurally related hepatocarcinogen safrole. [R44] *Eugenol, previously found to behave as a genotoxin in in vitro systems and as a noncarcinogen in rodents, was evaluated for its ability to induce genotoxic effects in vivo. Rats were given by gavage a single or two successive doses equal to one-half the corresponding LD50, killed at different times after treatment, and examined for the following end points: the frequency of both micronucleated polychromatic erythrocytes in the bone marrow and micronucleated hepatocytes (after partial hepatectomy), the in vivo-in vitro induction of DNA fragmentation, as measured by the alkaline elution technique, and of unscheduled DNA synthesis, as measured by autoradiography, in hepatocyte primary cultures. The two latter end points were also evaluated after in vitro exposure of hepatocytes to log-spaced subtoxic concentrations. Eugenol never produced effects indicative of genotoxic activity. [R45] *Eugenol produces hepatic injury in mice depleted of glutathione by pretreatment with buthionine sulfoximine. Several eugenol analogs were examined for their ability to cause hepatic injury after administration to mice in combination with buthionine sulfoximine. Hepatotoxicity was assessed by measuring relative liver weight, liver blood volume, and serum glutamic-pyruvic transaminase activity in mice. Comparison of the treated compounds showed that the structural requirements for toxic potency was a phenolic ring having an allyl substituent at the 4-position. These structural requirements can be explained by assuming that a vinylogous quinone methide formed by metabolic oxidation of eugenol plays a role in inducing hepatotoxicity in glutathione depleted mice. [R46] *Eugenol, an extract of cloves, has been associated with pulmonary edema when inhaled from commercially available clove cigarettes. The hypothesis that eugenol directly causes lung edema through oxidant mediated mechanisms was tested by infusing eugenol (0.1 and 1.0 mM) into isolated rabbit lungs perfused with a cell free albumin and physiologic salt solution. Lung edema (1.0 mM) was observed as demonstrated by increased lung weight gain and wet to dry lung weight ratios without alterations in mean pulmonary artery pressure. The oxygen metabolite scavengers catalase (1,000 unit/ml) and dimethylthiourea (30 mM) attenuated lung edema. Instillation of dimethylurea, superoxide dismutase, or heat-inactivated catalase did not prevent lung edema formation. It was concluded that eugenol causes lung edema in isolated lungs through oxidant mediated mechanisms in the absence of circulating formed blood elements. [R47] *The effects of treatment with naturally occurring antioxidants, selenium, beta-carotene, ferulic acid, esculin and eugenol during the promotional phase of tumor development were investigated in male F344 rats pretreated with 1,2-dimethylhydrazine and 1-methyl-1-nitrosourea. Animals were given 3 sc injections of 1,2- dimethylhydrazine at a dose of 40 mg/kg body weight within 1 wk and then were injected with 1-methyl-1-nitrosourea ip at a dose of 20 mg/kg body weight 2 times per wk for 2 wk. Thereafter, the were maintained on a diet containing either 0.2% beta-carotene, 2 ppm selenium, 1% ferulic acid, 1% esculin or 0.8% eugenol. At week 52 surviving rats were killed and complete histological examinations were performed. Administration of eugenol enhanced the development of both hyperplasia and papillomas in the forestomach. Eugenol decreased the incidence of kidney nephroblastomas. The results thus showed that eugenol exerts promoting activity for forestomach carcinogenesis while the other antioxidants might have weak organ specific inhibitory effects under these experimental conditions. [R48] *A number of alkenylbenzenes related to safrole and estragole are known to be hepatocarcinogenic in rats and/or mice, apparently by a genotoxic mechanism. However, they are not bacterial mutagens in the Ames test. The ability of a series of carcinogenic and non-carcinogenic congeners to induce unscheduled DNA synthesis was studied in freshly isolated rat hepatocytes in primary culture. The cytotoxicity of these compounds was assessed by lactate dehydrogenase leakage. Eugenol, for which evidence of carcinogenicity is equivocal or negative, did not induce unscheduled DNA synthesis. All compounds were markedly cytotoxic at concentrations between 1X10-3 and 1X10-2 M, irrespective of their structural features. [R49] *A study was conducted in male Fischer rats to assess the effect of dietary administration of eugenol on the activities of liver detoxifying enzymes, specifically, uridine diphosphate glucuronyltransferase, uridine diphosphate glucose dehydrogenase, and glutathione-S-transferase. Groups of rats were given diets containing 0, 1, 3, or 5% by weight eugenol for 22 days; in long term experiments lasting 23 wk, one group of rats received control diet and another group was alternatively fed the above named concentrations of eugenol. The activities of uridine diphosphate glucuronyltransferase in liver microsomes were tested of 1-naphthol, 4-nitrophenol, 4-hydroxybiphenyl, 4-methylumbelliferone, and bilirubin as substrates. The activities of uridine diphosphate glucose dehydrogenase and glutathione-S-transferase were tested using liver cytosol. The activities of liver microsomal uridine diphosphate glucuronyltransferase toward 1-naphthol, 4- nitrophenol, 4-hydroxybiphenyl, and 4-methylumbelliferone were enhanced by dietary administration of eugenol; activity on bilirubin was almost unchanged. Similar results for uridine diphosphate glucose dehydrogenase and glutathione-S-transferase activities in liver cytosol were obtained by dietary administration of eugenol. Glutathione-S-transferase activities toward 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene were increased markedly by dietary administration of eugenol. All enhancements of enzyme activities were related to the dietary level of eugenol. The content of cytochrome p450 in liver microsomes was not increased during the 13 wk period. No significant change in gamma-glutamyl transpeptidase, a marker for chemical carcinogenesis, was noted. It was concluded that eugenol may be a safe and nontoxic inhibitor of carcinogenesis. [R50] +... Under these experimental conditions, there was no evidence of carcinogenicity observed for male or female rats. For mice there was equivocal evidence of carcinogenicity since eugenol caused incr incidences of both carcinomas and adenomas of the liver in male mice at the 3,000 ppm dietary level and because eugenol was associated with an increase in the combined incidences of hepatocellular carcinomas or adenomas in female mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Equivocal; Female Mice: Equivocal. [R51] NTXV: *LD50 Rat oral 1930 mg/kg; [R34] *LD50 Mouse oral 3000 mg/kg; [R34] *LD50 Guinea pig oral 2130 mg/kg; [R34] NTP: +Carcinogenesis studies of eugenol (> 99% pure), ... were conducted by feeding diets containing 6,000 or 12,500 ppm of eugenol to groups of 50 female F344/N rats and by feeding diets containing 3,000 or 6,000 ppm to groups of 50 male F344/N rats and B6C3Fl mice of each sex for 103 weeks. Groups of 40 rats and 50 mice of each sex served as controls. ... Eugenol was given in the diets of female F344/N rats (0, 0.6, or 1.25%) and of male F344/N rats and male and female B6C3F1 mice (0, 0.3, or 0.6%) for 103 weeks. Under these experimental conditions, there was no evidence of carcinogenicity observed for male or female rats. For mice there was equivocal evidence of carcinogenicity since eugenol caused incr incidences of both carcinomas and adenomas of the liver in male mice at the 3,000 ppm dietary level and because eugenol was associated with an increase in the combined incidences of hepatocellular carcinomas or adenomas in female mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Equivocal; Female Mice: Equivocal. [R51] ADE: *NO ABSORPTION OF EUGENOL OCCURRED WITHIN 2 HR OF APPLICATION TO INTACT SHAVED SKIN OF MICE. ... OVER 70% OF AN ORAL DOSE OF EUGENOL WAS EXCRETED IN URINE OF RABBITS. [R25, 376] METB: *FOLLOWING IP INJECTION OF (14)C EUGENOL INTO RATS, RADIOACTIVITY WAS DISTRIBUTED IN VARIOUS ORGANS AND PRESENCE OF (14)CO2 IN EXPIRED AIR INDICATED THE DEMETHYLATION OF EUGENOL. [R25, 376] *Two metabolites of eugenol, 3-piperidyl-1-(3'-methoxy-4'-hydroxyphenyl)-1-propanone and 3-pyrrolidinyl-1-(3'-methoxy-4'-hydroxyphenyl)-1-propanone, have been isolated from rat urine. [R36] *The metabolism and toxic effects of eugenol were studied in isolated rat hepatocytes. Incubation of hepatocytes with eugenol resulted in the formation of conjugates with sulfate, glucuronic acid and glutathione. The major metabolite formed was the glucuronic acid conjugate. Covalent binding to cellular protein was observed using (3)H eugenol. Loss of intracellular glutathione and cell death were also observed in these incubations. Concentrations of 1 mM eugenol caused a loss of over 90% of intracellular glutathione and resulted in approximately 85% cell death over a 5 hr incubation period. The loss of the majority of glutathione occurred prior to the onset of cell death (2 hr). The effects of eugenol were concentration dependent. The addition of 1 mM N-acetylcysteine to incubations containing 1 mM eugenol was able to completely prevent glutathione loss and cell death as well as inhibit the covalent binding of eugenol metabolites to protein. Conversely, pretreatment of hepatocytes with diethylmaleate to deplete intracellular glutathione increased the cytotoxic effects of eugenol. These results demonstrate that eugenol is actively metabolized in hepatocytes and suggest that the cytotoxic effects of eugenol are due to the formation of a reactiv intermediate, possibly a quinone methide. [R52] ACTN: *THE INHIBITION BY EUGENOL OF GLUCURONIC ACID CONJUGATION IN STOMACH OF RATS AND GUINEA PIGS AND OF DOGS MAY HAVE SOME BEARING ON THE REPORTED MUCINOGENIC ACTIVITY OF EUGENOL AND ITS BENEFICIAL EFFECT ON GASTRIC ULCER FORMATION. [R25, 377] INTC: *VAN DUUREN BL, GOLDSCHMIDT BM; J NATL CANCER INST 5 (6): 1237 (1976). EUGENOL PARTIALLY INHIBITED BENZO[A]PYRENE CARCINOGENICITY. COMPD APPLIED TO MOUSE SKIN. *EUGENOL SHOWED WEAK TUMOR-PROMOTING ACTIVITY FOLLOWING ITS APPLICATION TO MOUSE SKIN SUBJECTED TO INITIATING TREATMENT WITH 7,12-DIMETHYLBENZ(A)ANTHRACENE. EUGENOL FAILED TO POTENTIATE GASTRIC TUMOR PRODUCTION BY 20-METHYLCHOLANTHRENE IN MICE. [R25, 377] *MUTAGENICITY OF EUGENOL IN AMES SALMONELLA TYPHIMURIUM ASSAY WAS INCREASED BY ADDITION OF 3'-PHOSPHOADENOSINE-5'-PHOSPHOSULFATE TO MICROSOMAL ASSAY. [R53] *Effects of topically applied betel leaf extract and its constituents, beta-carotene, alpha-tocopherol, eugenol and hydroxychavicol on 7,12-dimethylbenz(a)anthracene induced skin tumors were evaluated in two strains of mice. Eugenol showed minimal protection in both strains of mice. The mean latency period and survivors in betel leaf extract, beta-carotene, alpha-tocopherol and hydroxychavicol treated groups were remarkably high as compared to 7,12- dimethylbenz(a)anthracene alone treated group. Ip injection of betal leaf constituents showed a significant effect on both glutathione and glutathione S-transferase levels in the Swiss mouse skin. [R54] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *... HAS BEEN USED AS AN ANTIPYRETIC BUT IT IS RELATIVELY INEFFECTIVE. ... IT HAS... BEEN USED IN MEDICINE FOR THE STUDY OF MUCOUS SECRETION AND GASTRIC CYTOLOGY, WITHOUT GASTRIC RESECTION OR GASTROENTEROSTOMY. IT HAS BEEN SHOWN TO HAVE ANTHELMINTIC PROPERTIES. [R13, 1691] +Nonprescription medicines for toothache commonly contain eugenol, and some products for canker-sore may do so also. [R11] *Eugenol ... has been used as a topical dental anesthetic for many years. [R26] *Eugenol is used as a component of several dental materials (e.g., dental cements, impression pastes and surgical pastes). Such products are principally combinations of zinc oxide and eugenol in varying ratios. They are reported to be widely used in dentistry as temporary filing materials, cavity liners for pulp protection, capping materials, temporary cementation of fixed protheses, impression materials and major ingredients of endodontic sealers. In addition, eugenol has been used in dentistry for disinfecting root canals. [R3] *Analgesic (dental) [R2, 613] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *... PRESENT IN OIL OF CAMPHOR, JAVA CITRONELLA, CALIFORNIA LAUREL AND ACACIA FLOWERS. ... REMARKABLE AMT ... IN OCIMUM SANCTUM (70%) AND OCIMUM GRATISSIMUM (60%). EUGENOL IS ... FOUND IN OIL FROM VIOLET FLOWERS (21%). IN SOME PLANTS PROBABLY OCCURS AS GLUCOSIDE. [R1] *EUGENOL ... OCCURS IN CLOVE OIL (80-95%), PIMENTO OIL (80%), CINNAMON LEAF OIL (95%), AND BAY OIL (60%). [R13, 1690] *FOUND IN VOLATILE OILS FROM ... SASSAFRAS, MASSOY BARK, CANELLA, CULILAWAN, AND OTHER OILS. [R12, 991] *ESSENTIAL OIL FROM PIMENTA RACEMOSA (BAY OIL), AS WELL AS OILS FROM OTHER MEMBERS OF MYRTACEAS FAMILY EXHIBIT ANTIMICROBIAL EFFECT. MAIN CONSTITUENT OF THESE OILS WAS EUGENOL. [R55] *Eugenol is the major active ingredient in cloves. [R26] *The Flavor and Extract Manufacturers' Association of the United States (1978) has reported the occurrence of eugenol, without specific concentrations, in the following food sources: cocoa, Japanese ginger oil, loganberries, mace essential oil, sweet marjoram dried mushrooms, nutmeg, yellow passion fruit, black pepper, peppermint, pimento berry oil and tomatoes. Additional reported occurrences of eugenol are as follows: allspice tincture; Alpinia galanga oil; Apium graveolens seed essential oil; Artemisia glacialis (glacier wood worm) essential oil; Bupleurum chinense D.C. essential oil; Capsicum spp. (red pepper); Castanea creata Sieb et Zucc (chestnut) flower; Cinnamomum pauciflorum Nees leaf essential oil; corn silage; curcumalonga; Cytisus scoparius Link flower essential oil; fermented plum juice; Homalomena occulta oil; Jasminium odoratissimum oil; Juglans regia leaf oil; Laurus nobilis L. leaf; Ligustrum obtusifolium Sieb et Zucc flower essential oil; Ligustrum ovalifolium Hassk flower essential oil; Lonicera japonica flower essential oil; Magnolia salicifolia Maxim. bud; Mexalis accuminata bulb essential oil; Menyantes triforiata essential oils; Trachycarpus excelsa and T. fortune; and Vetiveria zizamioides G. root essential oil. [R56] FOOD: *REPORTED USED IN NON-ALCOHOLIC BEVERAGES 1.4 PPM; ICE CREAM, ICES, ETC 3.1 PPM; CANDY 32 PPM; BAKED GOODS 33 PPM; GELATINS AND PUDDINGS 0.60 PPM; CHEWING GUM 500 PPM; CONDIMENTS 9.6-100 PPM; MEATS 40-2000 PPM. [R1] *The Flavor and Extract Manufacturers' Association of the United States (1978) has reported the occurrence of eugenol, without specific concentrations, in the following food sources: cocoa, Japanese ginger oil, loganberries, mace essential oil, sweet marjoram dried mushrooms, nutmeg, yellow passion fruit, black pepper, peppermint, pimento berry oil and tomatoes. [R56] RTEX: *... LIKELY TO OCCUR BY DIRECT CONTACT OF SKIN AND EYES WITH OIL OR SOLUTIONS OF OIL. EXCESSIVE EXPOSURE TO VAPORS DOES NOT SEEM LIKELY IN VIEW OF LOW VOLATILITY AND PUNGENT ODOR ... IN HIGH CONCN. [R13, 1691] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *THE JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVE (1967) HAS PUBLISHED A MONOGRAPH AND SPECIFICATIONS FOR EUGENOL GIVING A CONDITIONAL ADI /ACCEPTABLE DAILY INTAKE/ OF 0-5 MG/KG. [R25, 376] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EUGENOL WAS DETERMINED BY HPLCON KONTRON RP-18 COLUMN OR ON NUCLEOSIL COLUMN. [R57] *... UV SPECTROPHOTOMETRY MAY BE USED TO YIELD RESULTS ACCURATE TO CONCN /IN AIR/ AS SMALL AS 0.005 MG/ML. [R23, 2533] *EUGENOL WAS DETERMINED IN OIL FROM CINNAMON LEAVES AND BARK BY GLC USING A NONPOLAR STATIONARY PHASE. [R58] *The analyte can be gas chromatographed as determined by Athen-ERL or S-Cubed. [R59] CLAB: *Sensitive HPLC assay used for the determination of eugenol in body fluids. Amt in the range 0.02-100 ug of eugenol/ml of body fluid were determined with intra-assay coefficients of variation < 4% (1.13-3.72%). [R60] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Eugenol in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 223 (1983) NIH Publication No. 84-1779 Maura A et al; Negative Evidence In-vivo of DNA-Damaging Mutagenic and Chromosomal Effects of Eugenol. Negative evidence in-vivo of DNA-damaging mutagenic and chromosamal effects of eugenol; Mutat Res 227 (2): 129-30 (1989). Rat granuloma pouch assay bone marrow micronucleus test. SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 198 R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 77 (1985) R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R5: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 648 R6: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 496 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V 36 76 (1985) R8: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-257 R9: SRI R10: Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-145 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 78 (1985) R12: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R13: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R14: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.119 R15: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-83 R16: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-244 R17: Kortum G et al; Pure and Applied Chemistry, Vol. 1, No 2-3 (1961) R18: Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) R19: Mueller M, Klein; Chemosphere 25: 769-82 (1992) R20: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R21: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-303 R22: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 629 R23: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 63 (1987) R25: Opdyke, D.L.J. (ed.). Monographs on Fragrance Raw Materials. New York: Pergamon Press, 1979. R26: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 920 R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 87 (1985) R28: Babich H et al; Toxicol In Vitro 7 (2): 105-9 (1993) R29: Berova N et al; Dermatol Monatsschr 176 (1): 15-8 (1990) R30: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-168 R31: COTMORE JM ET AL; ARCH ORAL BIOL 24 (8): 565 (1979) R32: WEBB JG ET AL; J DENT RES 60 (9): 1724 (1981) R33: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. 1471 R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 85 (1985) R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 83 (1985) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 86 (1985) R37: Zheng GQ et al; J Nat Prod 55 (7): 999-1003 (1992) R38: Bhide SV et al; J Ethnopharmacol 34 (2-3): 207-13 (1991) R39: Armstrong MJ et al; Mutat Res 265 (1): 45-60 (1992) R40: Bean CL et al; Mutat Res 265 (1): 31-44 (1992) R41: Dohi T et al; Dent Jpn (Tokyo) 27 (1): 45-9 (1990) R42: Mizutani T et al; Res Commun Chem Pathol Pharmacol 71 (2): 219-30 (1991) R43: Kimber I et al; Toxicol Lett 55 (2): 203-13 (1991) R44: Phillips DH; Mutat Res 245 (1): 23-6 (1990) R45: Allavena A et al; Teratog Carcinog Mutagen 12 (1): 31-41 (1992) R46: Mizutani T et al; Res Commun Chem Pathol Pharmacol 73 (1): 87-96 (1991) R47: McDonald JW, Heffner JE; Am Rev Respir Dis 143 (4 part 1): 806-9 (1991) R48: Imaida K et al; Cancer Lett 55 (1): 53-60 (1990) R49: Howes AJ et al; Food Chem Toxicol 28 (8): 537-42 (1990) R50: Yokota H et al; Biochemical Pharmacology 37 (5): 799-802 (1988) R51: Carcinogenesis Bioassay of Eugenol in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 223 (1983) NIH Publication No. 84-1779 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R52: Thompson DC et al; Chem Biol Interact 77 (2): 137-47 (1991) R53: TO LP ET ALL; BULL ENVIRON CONTAM TOXICOL 28 (6): 647 (1982) R54: Azuine MA et al; Indian J Exp Biol 29 (4): 346-51 (1991) R55: NADAL ET AL; COSMET PERFUM 88: 37 (1973) R56: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 80 (1985) R57: GRACZA L; DTSCH APOTH-ZTG 120 (40): 1859 (1980) R58: ANALYST (LONDON) 106 (1261): 456 (1981) R59: USEPA/SCC; Environmental Monitoring Methods Index p.264 (1992) R60: Fischer IU, Dengler HJ; J Chromatogr 525 (2): 369-77 (1990) RS: 47 Record 46 of 1119 in HSDB (through 2003/06) AN: 218 UD: 200303 RD: Reviewed by SRP on 5/20/1999 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYLDOPA- SY: *ALANINE, 3-(3,4-DIHYDROXYPHENYL)-2-METHYL-, L-(-)-; *ALDOMET-; *ALDOMETIL-; *ALDOMIN-; *AMD-; *L-2-AMINO-2-METHYL-3-(3,4-DIHYDROXYPHENYL)PROPIONIC ACID; *BAYER-1440-L-; *BAYPRESOL-; *L(-)-BETA-(3,4-DIHYDROXYPHENYL)-ALPHA-METHYLALANINE; *L-3-(3,4-DIHYDROXYPHENYL)-2-METHYLALANINE; *DOPAMET-; *DOPATEC-; *DOPEGYT-; *3-HYDROXY-ALPHA-METHYL-L-TYROSINE-; *HYPERPAX-; *L-(ALPHA-MD); *MEDOMET-; *ALPHA-MEDOPA-; *MEDOPREN-; *METHOPLAIN-; *ALPHA-METHYL-BETA-(3,4-DIHYDROXYPHENYL)-L-ALANINE; *ALPHA-METHYL-L-3,4-DIHYDROXYPHENYLALANINE-; *L-(-)-ALPHA-METHYL-BETA-(3,4-DIHYDROXYPHENYL)ALANINE; *L-ALPHA-METHYL-3,4-DIHYDROXYPHENYLALANINE-; *(-)-METHYLDOPA; *ALPHA-METHYL-DOPA-; *ALPHA-METHYLDOPA,-L-; *L-METHYLDOPA-; *L-ALPHA-METHYLDOPA-; *MK-351-; *MK-B51-; *NCI-C55721-; *NRC-2294-; *PRESINOL-; *PRESOLISIN-; *SEDOMETIL-; *SEMBRINA-; *L-TYROSINE,-3-HYDROXY-ALPHA-METHYL- RN: 555-30-6 MF: *C10-H13-N-O4 ASCH: Methyldopa sesquihydrate; 41372-08-1 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Pfister, Stein, US patent 2,868,818 (1959 to Merck and Co). Resolution: Jones et al, US patent 3,158,648 (1964 to Merck and Co); Compare Slates et al, J Org Chem 29, 1424 (1964). ... Synth from asymmetric intermediates: Reinhold et al, J Org Chem 33, 1209 (1968). [R1] *The product of the reaction of 3,4-dimethoxyphenylacetonitrile with sodium ethoxide is hydrolyzed with acid to give 3,4-dimethoxyphenylacetone. This is reacted with ammonium carbonate and potassium cyanide to form a substituted hydantoin intermediate which, on alkaline hydrolysis, yields racemic methyldopa. The acetylated form of this racemate is resolved using (-)-alpha-methylbenzylamine. The isolated acetylated (-)-methyldopate salt is deacetylated with base and treated with mineral acid to liberate (-)-methyldopa. US Pat 2,868,818 [R2] FORM: *METHYLDOPA, USP (ALDOMET), IS AVAILABLE FOR ORAL ADMIN IN TABLETS CONTAINING 125, 250, OR 500 MG. MORE SOL PREPN, METHYLDOPATE HYDROCHLORIDE, USP (ALDOMET ESTER HYDROCHLORIDE), IS AVAILABLE IN 5-ML VIALS (50 MG/ML) FOR PARENTERAL USE. [R3, 796] MFS: *MSD Quimica de Puerto Rico, Inc., P.O. Box 601, Barceloneta, PR 00617, 1(787)846-4100. Production site: Barceloneta, PR 00617 [R4] USE: +MEDICATION *ANTIHYPERTENSIVE AGENT [R5] CPAT: *100% AS AN ANTIHYPERTENSIVE AGENT (1976) [R5] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R5] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R5] U.S. IMPORTS: *(1975) 6.8X10+3 GRAMS (PRINCPL CUSTMS DISTS) [R5] +(1983) 3.15X10+5 g [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Minute, anhyd crystals from methanol [R1]; *WHITE TO YELLOWISH WHITE, FINE POWDER, WHICH MAY CONTAIN FRIABLE LUMPS [R7, 836] ODOR: *ODORLESS [R7, 836] TAST: *ALMOST TASTELESS [R7, 836] MW: *211.22 [R1] PH: *pH of saturated aq soln about 5.0 [R1] SOL: *In water @ 25 deg C: about 10 mg/ml; practically insol in common org solvents; sol in dil mineral acids [R1]; *Soluble in isopropanol, ethanol, and water. [R8, 1244] SPEC: *Max absorption: 281 nm (e= 2780); Specific optical rotation (1 in 0.1 N HCl): -4.0 +/- 0.5 deg @ 23 deg C/D [R1] OCPP: *Considerably hygroscopic; decomp @ approx 300 deg C; exists as sesquihydrate [R1] *Crystals from water /sesquihydrate/ [R1] *Sol in water @ 25 deg C: approx 10 mg/ml /D-form/ [R1] *Sol in water @ 25 deg C: approx 18 mg/ml /DL-form/ [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R8, 1245] SSL: *RELATIVELY STABLE IN BOTH LIGHT AND AIR [R7, 836] *Methyldopa is decomposed by oxidizing agents. [R9, 1510] STRG: *Methyldopa oral suspension should be stored in tight, light-resistant containers at a temperature less than 26 deg C and protected from freezing. Methyldopa tablets should be stored in well-closed containers at a temperature less than 40 deg C, preferably at 15-30 deg C. [R9, 1510] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *... AFTER DISCONTINUATION OF METHYLDOPA... HEMOLYTIC ANEMIA USUALLY RESOLVES WITHIN A MATTER OF WEEKS. SEVERE HEMOLYSIS MAY BE ATTENUATED BY TREATMENT WITH GLUCOCORTICOIDS. [R10, 788] HTOX: *...ADVERSE REACTIONS INCL DRUG FEVER AND, RARELY, GRANULOCYTOPENIA AND THROMBOCYTOPENIA. [R11, 709] *SALT AND WATER OFTEN ARE GRADUALLY RETAINED WITH PROLONGED USE OF METHYLDOPA ... [R10, 787] *... METHYLDOPA PRODUCES SEDATION THAT IS LARGELY TRANSIENT. [R10, 787] *A diminution in psychic energy may be a persistent effect in some patients, and depression occurs occasionally. ... Methyldopa may produce dryness of the mouth. Other side effects that are related to the pharmacological effects in the CNS include ... parkinsonian signs, and hyperprolactinemia that may become sufficiently pronounced to cause gynecomastia and galactorrhea. [R10, 787] *AT LEAST 20% OF PATIENTS WHO RECEIVE METHYLDOPA FOR A YEAR DEVELOP A POSITIVE COOMBS' TEST (ANTIGLOBULIN TEST) THAT IS DUE TO AUTOANTIBODIES DIRECTED AGAINST THE RH LOCUS ON THE PATIENTS' ERYTHROCYTES. THE DEVELOPMENT OF A POSITIVE COOMBS' TEST PER SE, HOWEVER, IS NOT AN INDICATION TO STOP TREATMENT WITH METHYLDOPA; 1-5% OF THESE PATIENTS WILL DEVELOP A HEMOLYTIC ANEMIA WHICH REQUIRES PROMPT DISCONTINUATION OF THE DRUG. ... ADVERSE EFFECTS THAT ARE EVEN MORE RARE INCLUDE LEUKOPENIA, THROMBOCYTOPENIA, RED CELL APLASIA, LUPUS ERYTHEMATOSUS-LIKE SYNDROME, LICHENOID AND GRANULOCMATOUS SKIN ERUPTIONS, MYOCARDITIS, RETROPERITONEAL FIBROSIS, PANCREATITIS, DIARRHEA, AND MALABSORPTION. [R10, 788] *SIDE EFFECTS CONSEQUENT TO ITS BLOCKADE OF SYMPATHETIC NERVES INCL...NAUSEA, WEAKNESS AND HEADACHE, BRADYCARDIA...DIARRHEA, AND IMPOTENCE. OTHER SIDE EFFECTS INCL...DECR LIBIDO IN MALES, BREAST ENLARGEMENT, AND PARESTHESIAS. ...IT MAY /RARELY/ CAUSE...PARKINSONISM, ARTHRALGIA, AND MYALGIA. ...OCCASIONALLY JAUNDICE MAY OCCUR. [R7, 837] *...CONTROLLED STUDY /WAS CONDUCTED/ IN WHICH 122 WOMEN WITH HYPERTENSION WERE TREATED WITH THIS DRUG. ONLY ONE /FETAL/ MALFORMATION OCCURRED (ABSENT KIDNEY WITH 2 UMBILICAL VESSELS). A BETTER PREGNANCY OUTCOME WAS ASSOCIATED WITH THE TREATMENT. [R12] *A 68-YR OLD MAN UNDERGOING ANTIHYPERTENSIVE TREATMENT WITH METHYLDOPA DEVELOPED DIARRHEA AND DIABETIC KETOACIDOSIS DURING HIS FIRST BRIEF TREATMENT; ABDOMINAL PAIN AND DIABETIC KETOACIDOSIS DURING THE SECOND; AND CHRONIC PANCREATITIS WITH EXOCRINE INSUFFICIENCY, ENDOCRINE INSUFFICIENCY AND HEAVY CALCIFICATION OVER 30 MO. THERE HAD BEEN NO SUGGESTION OF PANCREATIC OR BILIARY TRACT DISEASE BEFORE HE RECEIVED METHYLDOPA, AND BILIARY TRACT DISEASE WAS EXCLUDED BY SUBSEQUENT INVESTIGATIONS. METHYLDOPA-INDUCED PANCREATITIS HAS BEEN RECOGNIZED ONLY RECENTLY DESPITE WIDESPREAD USE OF THE DRUG. [R13] *IN 2 PATIENTS WITH RETROPERITONEAL FIBROSIS COMPUTERIZED TOMOGRAPHY WAS USED FOR DIAGNOSIS AND/OR POSTOPERATIVE FOLLOW-UP. METHYLDOPA IS POSTULATED AS THE CAUSATIVE AGENT IN ONE CASE. [R14] *IMMUNE HEMOLYTIC ANEMIA AND CHRONIC ACTIVE HEPATITIS DEVELOPED CONCURRENTLY IN 76-YR-OLD MAN AFTER PROLONGED THERAPY WITH METHYLDOPA. BOTH DISAPPEARED FOLLOWING CESSATION OF TREATMENT AND A SHORT COURSE OF A HIGH DOSE CORTICOSTEROID. INHIBITION OF T-SUPPRESSOR LYMPHOCYTE FUNCTION BY METHYLDOPA MAY BE INSTRUMENTAL IN THE EMERGENCE OF AUTOIMMUNE COMPLICATIONS FOLLOWING USAGE OF THE DRUG. [R15] *... one-third of ... patients were found to have sexual disturbances after methyldopa treatment ranging from a decrease in libido, inability to maintain an erection, and difficulty in ejaculation. [R16] *Fever occurs in 1-6% of patients taking methyldopa. /From table/ [R17, p. 6-9] *Methyldopa hepatitis occurs more commonly in patients > 35 yr and predominantly affects females. Acute hepatic injury has appeared within 4 wk of therapy in 50% of the patients reported and within 4-12 wk in 25$ of the cases. ... The fatality rate from acute hepatic injury is estimated to be 10%. /From table/ [R17, p. 26-10] NTOX: *METHYLDOPA...PRODUCES SEDATION IN LAB ANIMALS...AND HAS BEEN SHOWN TO HAVE NUMBER OF OTHER CNS EFFECTS. [R11, 708] *ERECTILE IMPOTENCE IS A COMMONLY REPORTED UNDESIRED SIDE EFFECT IN PT TREATED FOR HYPERTENSION WITH ALPHA-METHYLDOPA. HOWEVER, THE MECHANISM OF THAT DYSFUNCTION HAS NOT BEEN DETERMINED. IN 12 DAYS OF DAILY IP INJECTIONS, 300 MG/KG, OF ALPHA-METHYLDOPA ON ADULT MALE, LONG EVANS RATS AND THEIR AGE-MATCHED SALINE CONTROLS EFFECT OF THE DRUG UPON COPULATION, PENILE REFLEXES AND TISSUE CATECHOLAMINES WAS MEASURED. SIGNIFICANT DIFFERENCES BETWEEN CONTROL AND EXPERIMENTAL ANIMALS IN ALL PARAMETERS STUDIED. [R18] *IN ANESTHETIZED DOGS, ALPHA-METHYLDOPA DECR PLASMA VASOPRESSIN CONCN FROM A CONTROL VALUE OF 17 TO 7.4 PG/ML @ 120 MIN POSTINFUSION. PLASMA RENIN ACTIVITY DECR FROM 13.3-7 NG/ML/3 HR @ 120 MIN POSTINFUSION. BLOOD PRESSURE AND HEART RATE WERE NOT AFFECTED BY THE INFUSION. THE POSSIBILITY THAT VASOPRESSIN INHIBITION IS MEDIATED BY CENTRAL ALPHA-ADRENERGIC ACTIVATION BY ALPHA-METHYLNOREPINEPHRENE, A METABOLITE OF METHYLDOPA. [R19] +Pregnant CD rats were administered methyldopa (MD) suspended in corn oil by gavage at doses of 0, 50, 100, 250, or 500 mg/kg/day on gestation day 6 through 20. Clinical signs of toxicity (lethargy, rough coat, vaginal bleeding) were observed in the dams during treatment at 100, 250 and 500 mg/kg/day, with increased maternal mortality at both the 250 and 500 mg/kg/day levels. At gestational day 20, the dams were sacrificed and their fetuses were examined. MD significantly increased embryotoxicity at 500 mg/kg/day, as evidenced by an increase in the percentage of resorptions per litter. Average fetal body weight per litter decreased significantly as the dose of MD increased, in the 100, 250, and 500 mg/kg/day groups compared with controls. MD was not associated with any specific malformation or group of malformations at any of the dose levels in this study. [R20] +Alpha-methyldopa (MD) suspended in corn oil at 0, 100, 250, 500, or 750 mg/kg/day dose levels was administered by gavage to pregnant CD-1 mice (21-25 animals per dose group) on gestational days 6-17. MD caused maternal toxicity and embryolethality at 250 mg/kg/day. A significant increase in the number of resorptions was observed at the 500 and 750 mg/kg/day dose levels. At 500 and 750 mg/kg/day, clear evidence of prenatal mortality and intrauterine growth retardation as well as an incidence of malformed fetuses was observed. [R21] +... Conclusions: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for male or female F344/N rats fed diets containing 3,100 or 6,300 ppm. There was equivocal evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for male B6C3F1 mice, as shown by three dosed mice having uncommon tubular cell tumors of the kidney. There was no evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm. ... /alpha-Methyldopa sesquihydrate/ [R22] NTXV: *LD50 Rat oral 5000 mg/kg; [R8, 1244] *LD50 Rat ip 300 mg/kg; [R8, 1244] *LD50 Mouse ip 150 mg/kg; [R8, 1244] *LD50 Mouse iv 1700 mg/kg; [R8, 1244] *LD50 Rabbit oral 713 mg/kg; [R8, 1244] *LD50 Rabbit iv 713 mg/kg; [R8, 1244] NTP: +alpha-Methyldopa sesquihydrate (USP grade, greater than 99% pure) was selected for study because of widespread human exposure and the lack of carcinogenicity studies on this cmpd. ... Two yr studies were conducted in F344/N rats and B6C3F1 mice. The chemical was admin in feed because human exposure is primarily by the oral route. ... Dietary concn selected for male and female rats in the 2 yr studies were 0, 3,100, and 6,300 ppm. ... Dietary concn selected for male and female mice in the 2 yr studies were 0, 6,300, and 12,500 ppm. Diets containing the chemical at these concn were fed to groups of 50 male and 50 female rats and 50 male and 50 female mice for 103 wk. Conclusions: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for male or female F344/N rats fed diets containing 3,100 or 6,300 ppm. There was equivocal evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for male B6C3F1 mice, as shown by three dosed mice having uncommon tubular cell tumors of the kidney. There was no evidence of carcinogenic activity of alpha-methyldopa sesquihydrate for female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm. ... [R22] +Alpha-Methyldopa (MD) ... was evaluated for toxic and teratogenic effects in timed-pregnant CD rats exposed to alpha-Methyldopa on gestational days (gd) 6-20 and sacrificed on gestational day 20. Prior to the initiation of the teratology study, a preliminary study was conducted in order to establish appropriate doses for use in the teratology study. In the preliminary dose range-finding study, alpha-methyldopa, suspended in corn oil, was administered by gavage to timed-pregnant CD rats at doses of 0, 100, 250, 500, 750, and 1,000 mg/kg/day (6 animals/group) on gestational days 6-20. Animals were sacrificed and evaluated on gestational day 20. The results of the preliminary dose range-finding study indicated that the 1,000 mg/kg/day dose caused 33% mortality of confirmed-pregnant dams, and was therefore unsuitable for use in the teratology study. A probit plot analysis of the mortality data from the preliminary study suggested an LD10 of 581 mg/kg/day. Accordingly, doses of 0, 50, 100, 250, and 500 mg/kg/day alpha-methyldopa were chosen for admin in the teratology study. In the teratology study, alpha-methyldopa suspended in corn oil (0, 50, 100, 250 and 500 mg/kg/day) was administered by gavage to timed-pregnant CD rats on gestational days 6-20. The study was conducted using a two-replicate design, with 10-20 animals assigned to each dose group in each replicate. In each replicate, females were weighed and observed during daily treatment for clinical signs of toxicity. At sacrifice on gestational day 20, the gravid uterus of each dam was weighed. Following uterine dissection the number and status of uterine implantation sites was recorded. Each live fetus was weighed, sexed, and examined for external, visceral, and skeletal malformations. Fetal heart, whole head, and liver weight were recorded. A total of 19-22 dams (i.e., confirmed-pregnant females)/treatment group were evaluated in the study. During alpha-methyldopa treatment, dams in the teratology study exhibited observable signs of toxicity including lethargy, chromodacryorrhea, blue discoloration of the nose, diarrhea, rough coat, vaginal bleeding, and urogenital staining and wetness. Clinical signs of toxicity were observed most frequently at doses of 100 mg/kg/day or more. The maternal mortality was 0%, 0%, 0%, 8.7%, and 34.5% for animals in the vehicle through high dose group, respectively. The unexpected high mortality in the 500 mg/kg/day dose group was observed predominantly in the first replicate; exam of the study records did not provide an explanation for this occurrence. MD at doses of 100 mg/kg/day or more significantly reduced maternal body weight, maternal weight gain, gravid uterine weight and absolute maternal liver weight. Alpha-methyldopa significantly increased embryotoxicity at the 500 mg/kg/day dose level, as evidenced by a significant incr in the % resorptions/litter, the % nonlive implants/litter (resorptions and dead fetuses) and the % adversely affected implants/litter (nonlive implants plus malformed live fetuses). A trend toward an incr in the % dead fetuses/litter, % litters with dead fetuses, % litters with nonlive implants, and % litters with adversely affected implants was observed. However, this trend was not strictly dose-related and was determined primarily by an incr in these parameters at the high dose. For litters with live fetuses, the number of live fetuses/litter exhibited a trend toward a decr that did not appear to be biologically significant. However, avg fetal body weight/litter (male, female, or sexes combined) decreased as the dose of MD increased, with the 100, 250, and 500 mg/kg/day dose groups significantly below controls. The % fetuses malformed/litter and % male fetuses malformed/litter exhibited a trend toward an incr that was determined primarily by marginal increases occurring in the 250 and 500 mg/kg/day dose groups. This trend was not observed for the % female fetuses malformed/litter. Alpha-methyldopa was not associated with any specific malformation or group of malformations. For gestational day 20 rat fetuses, relative female fetal heart weight/litter was significantly greater than controls in the 500 mg/kg/day dose group, and mean absolute fetal head weight/litter for both sexes combined and for male fetuses was significantly reduced in the 250 and 500 mg/kg/day dose groups. No clearcut effects of treatment on mean absolute fetal heart weight/litter for males, females or for the sexes combined, relative fetal heart weight/litter for males or for the sexes combined, mean absolute female fetal head weight/litter or relative fetal head weight (males, females, or sexes combined)/litter were observed. In conclusion, in the teratology study, exposure of timed-pregnant CD rats to MO suspended in corn oil (0, 50, 100, 250, and 500 mg/kg/day) by gavage on gestational day 6-20, produced the following results: 1.A no effect level for maternal toxicity at 50 mg/kg/day, but significant maternal toxicity at 100, 250, and 500 mg/kg/day, with maternal mortality at both the 250 and 500 mg/kg/day dose levels. 2.A no effect level for embryo and fetal toxicity at 50 and 100 mg/kg/day, significant embryo toxicity at 500 mg/kg/day, and significant fetotoxicity at 250 and 500 mg/kg/day. 3.No clearcut teratogenic effect at any dose level, but a trend toward an incr in the incidence of malformations as a result of a marginal incr in the % malformed fetuses/litter, observed at the 250 and 500 mg/kg/day dose levels. In addition to the teratology study, a preliminary evaluation of perinatal survival and postnatal growth to postnatal day 22 of rat pups exposed in utero to alpha-methyldopa on gestational days 6-20 and fostered to untreated mothers was also conducted. For this preliminary perinatal and postnatal evaluation, alpha-methyldopa was administered in corn oil by gavage at doses of 0, 100, 250, 500 or 750 mg/kg/day to timed-mated females (6-7/group) on gestational days 6-20. During treatment, dams exposed to alpha-methyldopa exhibited observable signs of toxicity, predominantly at doses of 250 mg/kg/day and greater; no treatment-related deaths occurred. Exposure to alpha-methyldopa significantly reduced maternal body weight and absolute liver weight at doses of 250 mg/kg/day and above, and reduced maternal weight gain at doses of 500 mg/kg/day and above, but had no effect on relative maternal liver weight. Interestingly, alpha-methyldopa treatment significantly increased the length of the gestational period in the 500 and 750 mg/kg/day dose groups. On postnatal day 1, pups from vehicle or alpha-methyldopa-treated litters were examined for external malformations, weighed, sexed, and observed for clinical signs of toxicity and immediately reassigned by litter to untreated foster dams. Alpha-methyldopa had no significant effect on live litter size on /postnatal day/ 1, but by /postnatal day/ 4 perinatal survival exhibited a decreasing trend. In addition, when prenatal and perinatal mortality were considered together, the % cumulative mortality for both /postnatal day/ 1 and 4 exhibited an increasing trend. Alpha-methyldopa caused no evidence of malformation in /postnatal day/ 1 pups. However, avg pup body weight/litter exhibited a trend toward a decr on /postnatal day/ 1 that was evident but no longer significant after /postnatal day/ 4. Alpha-methyldopa treatment had no significant effect on absolute liver, brain or heart weight or on relative liver, brain, or heart weight of /postnatal day/ 22 pups. No overt differences in demeanor were observed in alpha-methyldopa-treated pups. /Alpha-Methyldopa/ [R23] +Alpha-Methyldopa (MD) ... was evaluated for toxic and teratogenic effects in timed-pregnant CD-1 mice exposed to alpha-Methyldopa on gestational days (gd) 6-17 and sacrificed on gestational days 17. Prior to the initiation of the teratology study, a preliminary study was conducted in order to establish appropriate doses for use in the teratology study. Alpha-Methyldopa suspended in corn oil (0, 100, 250, 500, 750 mg/kg/day) was administered by gavage to timed-pregnant CD-1 mice on gestational days 6-17. Females were weighed and observed during daily treatment for clinical signs of toxicity. At sacrifice on gestational days 17, the gravid uterus of each dam was weighed. Following uterine dissection, the number and status of uterine implantation sites was recorded. ... A total of 21-25 dams (i.e., confirmed-pregnant females)/treatment group were evaluated in the study. During alpha-Methyldopa treatment, dams at all dose levels exhibited observable signs of clinical toxicity including rough coat, weight loss, lethargy, vaginal bleeding, and alopecia at various sites on the body. Maternal mortality was 0%, 0%, 0%, 4.3%, and 16% of confirmed-pregnant females in the vehicle through high dose groups. Alpha-Methyldopa at doses of 250 mg/kg/day or more caused significant depression of maternal body weight, weight gain, gravid uterine weight, and absolute maternal liver weight, with 100 mg/kg/day representing a no effect level for these parameters. Alpha-Methyldopa significantly increased embryotoxicity at doses of 500 mg/kg/day and above, as evidenced by a significant incr in the % resorptions/litter and other indices. Live litter size was significantly reduced at 750 mg/kg/day, and live fetal body weight was depressed in female fetuses at doses of 500 and 730 mg/kg/day Alpha-Methyldopa and in male fetuses at doses of 250 mg/kg/day alpha-Methyldopa and above. Alpha-Methyldopa significantly increased the % fetuses malformed/litter and the % female fetuses malformed/litter at both 500 and 750 mg/kg/day. The % male fetuses malformed/litter was not significantly affected by treatment. Alpha-Methyldopa caused a trend toward an incr in the incidence of skeletal malformations, but this effect was marginal and not dose-related. Alpha-Methyldopa had no effect on the incidence of external or visceral malformations. Relative fetal heart and whole head weight were not adversely affected by treatment. In conclusion, exposure of timed-pregnant CD-1 mice to alpha-methyldopa (0, 100, 250, 500, or 750 mg/kg/day) by gavage on gestational days 6-17, produced the following results: 1) Alpha-Methyldopa at the 100 mg/kg/day dose level caused mild clinical signs of maternal toxicity in a small number of animals but was a no effect level for other indices of maternal, embryo, and fetal toxicity. 2) At 250 mg/kg/day, alpha-methyldopa caused significant maternal toxicity, a noticeable but statistically insignificant incr in measures of embryotoxicity, and evidence of marginal fetotoxicity. 3) At 500 and 750 mg/kg/day, clear evidence of prenatal mortality and intrauterine growth retardation was observed in the presence of significant maternal toxicity and/or mortality. 4) MO caused a small but significant incr in the incidence of malformed fetuses/litter at both 500 and 750 mg/kg/day which appeared to primarily involve female fetuses. The % fetuses malformed and the number of litters with fetuses with skeletal malformations also exhibited a trend toward an incr. These effects were noted only in the presence of significant maternal, embryo, and fetal toxicity, and therefore may be secondary to generalized effects of alpha-methyldopa. 5) Evaluation of fetal whole head weight and heart weight indicated that whereas head weight was proportional to body weight for all dose groups, heart weight was not as affected by intrauterine growth retardation. In addition to the teratology study, a preliminary evaluation of perinatal survival and postnatal growth to postnatal day 21 of mouse pups exposed in utero to alpha-methyldopa on gestational days 6-17 and fostered to untreated mothers was also conducted. In this preliminary perinatal and postnatal evaluation, MD was administered in corn oil by gavage at doses of 0, 100, 250, 500, or 750 mg/kg/day to timed-mated females (6-7/group) on gestational days (gd) 6-17. During treatment, dams exposed to alpha-methyldopa exhibited observable signs of toxicity that consisted of weight loss and lethargy, primarily at doses of 250 mg/kg/day or greater; there were no treatment-related maternal deaths. Alpha-Methyldopa had no effect on maternal body weight but caused a trend toward a decr in maternal weight gain, with 100 mg/kg/day being a no effect level. Alpha-Methyldopa had no significant adverse effect on live litter size, survival and growth of live pups to /postnatal day/ 4, or pup survival and growth to /postnatal day/ 21. Evaluation of pup relative liver, heart, and brain weight on /postnatal day/ 21 indicated that liver and heart weight were unaffected, but suggested that in utero exposure to alpha-methyldopa at doses of 250 mg/kg/day and above may result, in the postnatal period, in depressed brain growth relative to body growth. [R24] POPL: *Patients with renal failure are more sensitive to the antihypertensive effect of methyldopa ... [R10, 787] *In individuals who have sinoatrial node dysfunction, methyldopa may precipitate severe bradycardia and sinus arrest, including that which occurs with carotid sinus hypersensitivity. [R10, 787] *... may cause asthma to pharmaceutical workers. /From table/ [R25] ADE: *(14)C-METHYLDOPA ADMIN ORALLY TO HYPERTENSIVE PT IS RECOVERED EQUALLY FROM URINE AND FECES; PRODUCT IN FECES IS UNCHANGED METHYLDOPA, AND IN URINE METHYLDOPA AND ITS ETHEREAL SULFATE, TOGETHER WITH SMALL AMT OF 3-O-METHYL-METHYLDOPA AND METHYLDOPAMINE. [R26] *METHYLDOPA CROSSES THE PLACENTA... [R27, 571] *Methyldopa is partially absorbed from the GI tract. The degree of absorption varies among individuals and in the same patient from day to day, but generally about 50% of an oral dose is absorbed. [R9, 1510] METB: *METHYLDOPA YIELDS 3,4-DIHYDROXY-ALPHA-METHYLPHENETHYLAMINE, 3,4-DIHYDROXY-ALPHA-METHYL-L-PHENYLALANINE-O-SULFATE, and 4-HYDROXY-3-METHOXY-ALPHA-METHYL-L-PHENYLALANINE IN MAN. /FROM TABLE/ [R28] *METHYLDOPA...UNDERGOES DECARBOXYLATION AND BETA-HYDROXYLATION IN MOUSE AND RABBIT BRAIN TO YIELD ALPHA-METHYLNORADRENALINE. [R26] *...ADMIN IP TO RATS (14)C-METHYLDOPA IS EXCRETED IN URINE AS...3-O-METHYL-METHYLDOPA (14%), METHYLDOPAMINE AND ITS CONJUGATES (2%), 3-O-METHYL-METHYLDOPAMINE AND ITS CONJUGATES (6%), 3-METHOXY-4-HYDROXYPHENYLACETONE (6%), and 3,4-DIHYDROXYPHENYLACETONE (10%). [R26] *A REVIEW ON THE METAB OF ALPHA-METHYLDOPA. [R29] BHL: *The drug is ... eliminated with a half-life of about 2 hr. ... The half-life of methyldopa is prolonged to 4-6 hr in patients with renal failure. [R10, 787] *DISAPPEARANCE OF THE DRUG FROM PLASMA AFTER IV ADMIN IS BIPHASIC, AND THE TERMINAL HALF-TIME OF ELIMINATION FROM PLASMA IS ABOUT 2 HOURS. RENAL EXCRETION ACCOUNTS FOR ABOUT TWO THIRDS OF THE CLEARANCE OF DRUG FROM PLASMA. [R3, 795] *IN PT WITH SEVERELY IMPAIRED RENAL FUNCTION, ONLY ABOUT 50% OF DRUG IS EXCRETED DURING EARLY PHASE (T/2= 3 1/2 HR), AND SOME ACCUMULATION CAN OCCUR DURING CHRONIC ADMIN... BOTH TOTAL QUANTITY ABSORBED AND DISTRIBUTION OF METABOLITES IN URINE CAN VARY CONSIDERABLY IN DIFFERENT INDIVIDUALS AND IN SAME PT FROM DAY TO DAY. [R11, 709] ACTN: *METHYLDOPA...HAS HYPOTENSIVE ACTION INDEPENDENT OF ITS ANTIADRENERGIC ACTIONS; THIS IS PROBABLY PARTLY CENTRAL DEPRESSANT ACTION @ VASOMOTOR CENTER AND PARTLY PERIPHERAL ACTION OF UNKNOWN MECHANISM. [R7, 836] *... Alpha-methylnorepinephrine acts in the brain to inhibit adrenergic neuronal outflow from the brainstem, and this central effect is principally responsible for its antihypertensive action. [R10, 786] *IN CONSCIOUS RENAL HYPERTENSIVE RATS ALPHA-METHYLDOPA PRODUCED A LONG-LASTING FALL IN BLOOD PRESSURE WHICH WAS PARTIALLY ATTENUATED BY PRETREATMENT WITH NALTREXONE (5 MG/KG SC). PRETREATMENT WITH ANTISERUM TO BETA-ENDORPHIN APPLIED LOCALLY, ALSO BLOCKED THE DEPRESSOR RESPONSE. THESE RESULTS SUGGEST THAT THE FALL IN BLOOD PRESSURE OBSERVED AFTER ALPHA-METHYLDOPA AND ITS ACTIVE METABOLITE ALPHA-METHYLNORADRENALINE INVOLVES A BETA-ENDORPHIN LIKE PEPTIDE; A POSSIBLE SITE OF ACTION IS THE NUCLEUS TRACTUS SOLITARII. [R30] *A REVIEW ON THE MECHANISM OF ACTION. [R31] INTC: *LEVODOPA...REPORTED TO AUGMENT ANTIHYPERTENSIVE EFFECT OF METHYLDOPA IN MAN. [R11, 708] *ACUTE HYPOTENSIVE EFFECT OF METHYLDOPA HAS BEEN REPORTED TO BE ABOLISHED BY PRETREATMENT WITH RESERPINE, IMIPRAMINE, AND INTRAVENTRICULAR 6-HYDROXYDOPAMINE, AND TO BE ENHANCED BY MONOAMINE OXIDASE INHIBITOR TRANYLCYPROMINE. HYPOTENSION...BLOCKED BY INTRAVENTRICULAR ADMIN OF SMALL DOSE OF PHENTOLAMINE... [R11, 707] *METHYLDOPA...REPORTED TO AUGMENT AMPHETAMINE-INDUCED HYPERACTIVITY IN MICE... [R11, 708] *PHENOBARBITAL REPORTEDLY MAY INDUCE METABOLISM OF METHYLDOPA WHEN THESE AGENTS ARE ADMIN CONCURRENTLY. ... RELATED DRUGS--OTHER BARBITURATES WOULD BE EXPECTED TO ACT SIMILARLY TO PHENOBARBITAL. [R32] *Increases mean tolbutamide half-life by 24% in 1 study. /From table/ [R17, p. 48-39] *Concurrent use /with alcohol or central nervous system depression-producing medications/ may enhance the CNS depressant effects of either these medications or methyldopa. [R33, 2001] *Concurrent use /of coumarin- or indandione-derivative anticoagulants/ with methyldopa may increase the anticoagulant effect of these medications; adjustment of anticoagulant dosage based on prothrombin-time determinations is recommended. [R33, 2001] */Concurrent use with tricyclic antidepressants/ may reduce antihypertensive effects of methyldopa; the patient should be carefully monitored to confirm that the desired effect is being obtained. [R33, 2001] *Antihypertensive effects of methyldopa may be reduced when it is used concurrently with these medications; indomethacin, and possibly other nonsteroidal anti-inflammatory drugs (NSAIDs), may antagonize the antihypertensive effect by inhibiting renal prostaglandin synthesis and/or by causing sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained. [R33, 2001] *Concurrent use /with appetite suppressants, with the exception of fenfluramine/ may decrease the hypotensive effects of methyldopa. [R33, 2001] */When taken concurrently with estrogens/ estrogen-induced fluid retention tends to increase blood pressure. [R33, 2001] *Concurrent use /with fenfluramine/ may increase the hypotensive effects of methyldopa. [R33, 2001] *Concurrent use of haloperidol with methyldopa may cause unwanted mental effects such as disorientation and slowed or difficult thought process. [R33, 2001] *Hypotensive effects may be potentiated when these medications /other hypotension-producing medications/ are used concurrently with methyldopa; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use. [R33, 2001] *Concurrent use /of levodopa/ with methyldopa may alter the antiparkinsonian effects of levodopa and may also produce additive toxic CNS effects such as psychosis. [R33, 2001] *Concurrent use /of lithium/ with methyldopa may increase the risk of lithium toxicity, even though serum lithium concentrations remain within the recommended therapeutic range. [R33, 2001] *Methyldopa may cause hyperexcitability in patients receiving monoamine oxidase (MAO) inhibitors /including furazolidone, procarbazine, and selegiline/; headache, severe hypertension, and hallucinations have been reported. [R33, 2001] *Concurrent use with sympathomimetic pressor amines may decrease the hypotensive effect of methyldopa and potentiate the pressor effect of these medications; if concurrent use of cocaine, norepinephrine, or phenylephrine is indicated, caution is required, and only very small initial doses should be administered. [R33, 2001] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Adrenergic alpha-Agonists; Antihypertensive Agents; Sympatholytics [R34] *Methyldopa is indicated in the treatment of moderate to severe hypertension, including that complicated by renal disease. /Included in US product labeling/ [R33, 2000] *Methyldopa is an effective antihypertensive agent when given in conjunction with a diuretic. [R10, 788] *THE USUAL INITIAL DOSE OF METHYLDOPA IS 250 MG TWICE DAILY, AND THERE APPEARS TO BE LITTLE ADDNL EFFECT WITH DOSES OVER 2 G. [R10, 788] +MECHANISM AND ACTIONS OF ALPHA METHYLDOPA AND ANTIHYPERTENSIVE TREATMENT ARE DISCUSSED. [R35] +IN THE TREATMENT OF CARCINOID TUMOR /PRC: FORMER USE/ [R7, 837] WARN: *Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction and is not recommended for use in patients with pheochromocytoma. Methyldopa is contraindicated in patients with active hepatic disease, such as acute hepatitis and active cirrhosis, and in patients in whom previous methyldopa therapy was associated with liver abnormalities or direct Coombs' positive hemolytic anemia. Methyldopa is contraindicated in patients receiving monoamine oxidase (MAO) inhibitors. [R9, 1512] *Patients who are receiving methyldopa and who undergo dialysis may occasionally become hypertensive after the dialysis, since the drug is dialyzable. [R9, 1512] *Positive direct antiglobulin (Coombs') test results have been reported in about 10-20% of patients receiving methyldopa, usually after 6-12 months of therapy. This phenomenon is dose related, with the lowest incidence in patients receiving 1 g or less of methyldopa daily. In most patients, a postive Coombs' test associated with mehtyldopa therapy is not clinically important. Reversal of the positive Coombs' test occurs within weeks to months after discontinuance of the drug and usually becomes negative within 6 months. Hemolytic anemia has only rarely occurred, although 2 deaths have been reported in patients with methyldopa-induced hemolytic anemia. If anemia or a positive Coombs' test occurs, appropriate laboratory studies should be performed to determine if hemolysis is present; if there is evidence of hemolytic anemia, the drug should be discontinued. Discontinuance of the drug alone or initiation of corticosteroid therapy has produced remission of methyldopa-induced hemolytic anemia. [R9, 1511] *Nasal congestion occurs commonly in patients receiving methyldopa. Decreased libido and impotence frequently occur in males during therapy with the drug. [R9, 1511] *Adverse GI effects including nausea, vomiting, diarrhea, dry mouth, distention, constipation, flatus, and sore or "black" tongue have been reported during methyldopa therapy. Pancreatitis has also occurred. [R9, 1511] *Although appropriate studies on the relationship of age to the effects of methyldopa have not been performed in the geriatric population, the elderly my be more sensitive to the hypotensive and sedative effects. In addition, elderly patients are more likely to have age-related renal function impairment, which may require lower doses in patients receiving methyldopa. [R33, 2001] *Orthostatic hypotension with attendant dizziness, lightheadedness, and symptoms of cerebrovascular insufficiency may occur during methyldopa therapy and is an indication for dosage reduction. Orthostatic hypotension may be less pronounced with methyldopa than with guanethidine or ganglionic blocking agents but may be more severe than with reserpine, clonidine, hydralazine, propranolol, or thiazides. Syncope in older patients may be related to an increased sensitivity to methyldopa and advanced arteriosclerotic vascular disease and may be avoided by using lower dosages. [R9, 1511] *The most common adverse effect of methyldopa is drowsiness which occurs within the first 48-72 hours of therapy and may disappear with continued administration of the drug. Sedation commonly recurs when dosage is increased. A persistent decrease in mental acuity, including impaired ability to concentrate, lapses of memory, and difficulty in performing simple calculations, may occur and usually necessitates withdrawal of the drug. Other adverse nervous system effects which occur early in therapy include vertigo, headache, asthenia, and weakness. [R9, 1511] *ITS ACTION IS ERRATIC AND THIRD OF TREATED PT MAY NOT RESPOND TO THE DRUG. ... METHYLDOPA IS CONTRAINDICATED IN PRESENCE OF ACTIVE LIVER DISEASE AND IN PERSONS KNOWN TO BE SENSITIVE TO DRUG. [R36] *DISADVANTAGE OF METHYLDOPA IS WIDE RANGE OF EFFECTIVE DOSAGE (REQUIRING DOSE TITRATION) AND HIGH COST. [R37] *METHYLDOPATE HYDROCHLORIDE IS USED ONLY RARELY TO TREAT HYPERTENSIVE CRISES BECAUSE OF ITS ERRATIC ONSET OF ACTION. IN ADDITION, THE SEDATIVE EFFECT MAY INTERFERE WITH EVALUATION OF MENTAL STATUS. /METHYLDOPATE HYDROCHLORIDE/ [R27, 570] *IN PRESENCE OF RENAL INSUFFICIENCY, DELAYED EXCRETION MAY RESULT IN DRUG ACCUMULATION. ... METHYLDOPA OCCASIONALLY PRODUCES SYMPTOMATIC ORTHOSTATIC HYPOTENSION, AND PATIENT SHOULD BE INFORMED OF THIS POSSIBILITY. ... HEPATITIS IS USUALLY MILD AND IS GENERALLY REVERSIBLE FOLLOWING DISCONTINUATION OF METHYLDOPA BUT, IN FEW INSTANCES, RE-EXPOSURE TO DRUG CAUSED FATAL HEPATIC NECROSIS. [R27, 570] *METHYLDOPA AND ITS METABOLITES...IN BLOOD AND URINE CAN CAUSE FALSE-POSITIVE TESTS FOR PHEOCHROMOCYTOMA. [R11, 709] *PRELIMINARY RESULTS ARE PRESENTED THAT TREATMENT OF MOTHERS WITH METHYLDOPA DURING LATE PREGNANCY MAY SEVERELY INTERFERE WITH FETAL CEREBRAL MONOAMINE METABOLISM. [R38] *THE REPORTED INCIDENCES OF METHYLDOPA-INDUCED HEPATITIS AND HEMOLYTIC ANEMIA IS NOTABLY SMALL; HOWEVER, PRACTITIONERS SHOULD BE AWARE OF ITS ASSOCIATION WITH THESE DISORDERS. [R39] *Maternal Medication usually Compatible with Breast-Feeding: Methyldopa: Reported Sign or Symptom in Infant or Effect on Lactation: None. /From Table 6/ [R40] TOLR: *TOLERANCE SOMETIMES DEVELOPS IN UP TO THIRD OF INITIALLY RESPONSIVE PATIENTS. [R7, 836] *DRUG RESISTANCE MAY DEVELOP WHEN METHYLDOPA IS USED ALONE BUT IS NOT USUALLY PROBLEM WHEN DIURETIC IS GIVEN CONCOMITANTLY. [R37] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ MILK: *Methyldopa is distributed into milk; peak milk concentrations of free methyldopa are approximately 20-35% of those in maternal plasma following an individual dose during continuous therapy. The extent of distribution of methyldopa into milk has not been clearly determined, but it is estimated that about 0.02% of a daily maternal dose of 1 g would be ingested by a nursing infant and that this amount is probably not clincially important. [R9, 1510] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R41] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *METHYLDOPA WAS CHROMATOGRAPHED ON THIN-LAYER PLATES USING DIPHENYLAMINE AS A DETECTOR. SAMPLE WAS PLACED ON SILICA GEL 60F 254 THIN-LAYER PLATES AND CHROMATOGRAPHED, IF POSSIBLE WITH AN ACIDIC MOBILE PHASE. [R42] *SPECTROPHOTOMETRIC METHOD FOR DETERMINATION OF METHYLDOPA IS DESCRIBED IN WHICH IT FORMS COLORED COMPLEX WITH CHLORANIL @ PH 9 WITH MAX ABSORPTION @ 358 NM. [R43] CLAB: *A METHOD IS DESCRIBED USING REVERSE PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY AND ELECTROCHEMICAL DETECTION FOR DETERMINATION OF MULTIPLE CATECHOLAMINES AND THEIR CATECHOL METABOLITES IN PLASMA OR BRAIN TISSUE. ION-PAIRING CHROMATOGRAPHY WITH HNO3 OR TCA AS THE MOBILE PHASE PERMITTED SEPARATION AND QUANTITATION OF ALPHA-METHYLDOPA. [R44] *A GAS CHROMATOGRAPHIC-MASS SPECTROMETRIC METHOD FOR DETERMINATION OF ALPHA-METHYLDOPA IN BLOOD AND URINE INVOLVES STABLE ISOTOPE DILUTION USING ALPHA-TRIDEUTERIO-METHYLDOPA AS INTERNAL STD. REVERSE PHASE CHROMATOGRAPHY ON SMALL COLUMNS OF LIPIDEX 5000 IS USED TO REMOVE LIPIDS FROM PLASMA EXTRACTS AND FOR PURIFICATION OF URINE SAMPLES PRIOR TO THEIR DERIVATIZATION. [R45] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of alpha-Methyldopa Sesquihydrate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 348 (1989) NIH Publication No. 89-2803 /alpha-Methyldopa sesquihydrate/ MCLEOD PJ; ALPHA-METHYLDOPA INT SYMP 29 (1981) A REVIEW ON THE PHARMACOKINETICS OF ALPHA-METHYLDOPA. KERSTING F ET AL; CLIN EXP PHARMACOL PHYSIOL, SUPPL, 4(ISS MECH ACTIONS ALPHA-METHYLDOPA ANTIHYPERTENS TREAT) 11 (1978) REVIEW ON SITE OF ACTION OF ALPHA-METHYLDOPA IN LOWERING BLOOD PRESSURE. BOUDIER HA J ET AL; ALPHA-METHYLDOPA INT SYMP 35 (1981) A REVIEW WITH 37 REF ON THE HEMODYNAMIC EFFECT OF ALPHA-METHYLDOPA IN HYPERTENSION AND THE ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE MECHANISM OF ACTION. A REVIEW ON METHYLDOPA IN THE TREATMENT OF HYPERTENSION. [R46] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 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Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. 424 R26: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 180 R27: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. R28: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-55 R29: MUSCHOLL E; ALPHA METHYLDOPA INT SYMP 20 (1981) R30: PETTY MA, DE JONG W; CLIN SCI SUPPL 63 (8): 293 (1982) R31: KRONEBERG G; ALPHA-METHYLDOPA INT SYMP 6 (1981) R32: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. 557 R33: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R34: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R35: ZANCHETTI A (ED); IN: CLIN EXP PHARMACOL PHYSIOL, SUPPL (4) (1978) R36: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 786 R37: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 54 R38: BODIS J ET AL; LANCET 2: 498 (1982) R39: BRELAND BD, HICKS GS JR; DRUG INTELL CLIN PHARM 16 (6): 489 (1982) R40: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 141 (1994) R41: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R42: EGLI R, TANNER S; DIPHENYLAMINE IN THE MOBILE PHASE AS A UNIVERSAL DETECTION REAGENT IN THIN-LAYER CHROMATOGRAPHY; FRESENIUS Z ANAL CHEM 296(1) 45 (1979) R43: KORANY MA, WAHBI AA M; SPECTROPHOTOMETRIC DETERMINATION OF ISOPRENALINE SULFATE AND METHYLDOPA USING CHLORANIL; ANALYST (LONDON) 104(1235) 146 (1979) R44: FREED CR, ASMUS PA; BRAIN TISSUE AND PLASMA ASSAY OF L-DOPA AND ALPHA-METHYLDOPA METABOLITES BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION; J NEUROCHEM 32(1) 163 (1979) R45: SETCHELL KE ET AL; THE MEASUREMENT OF ALPHA-METHYLDOPA IN URINE AND PLASMA AS ITS N-BUTYL ESTER-PENTAFLUOROPROPIONATE DERIVATIVE USING STABLE ISOTOPE DILUTION GAS CHROMATOGRAPHY-MASS SPECTROMETRY; QUANT MASS SPECTROM LIFE SCI 2: 263 (1978) R46: SJOERDSMA A; METHYLDOPA; BR J CLIN PHARMACOL 13(1) 45 (1982) RS: 48 Record 47 of 1119 in HSDB (through 2003/06) AN: 222 UD: 200303 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORAL-HYDRATE- SY: *AQUACHLORAL-; *BI-3411-; *Chloraldural- (Swiss); *CHLORALDURAT- (GERMAN); *Chloralex-; *Chlorali-Hydras-; *CHLORAL,-MONOHYDRATE-; *Chloralvan-; *DORMAL-; *ESCRE-; *FELSULES-; *HS-; *HYDRAL-; *KESSODRATE-; *Kloralhydrat-; *Knockout-drops-; *LORINAL-; *NOCTEC-; *Novochlorhydrate-; *NYCOTON-; *NYCTON-; *PHALDRONE-; *RECTULES-; *SOMNOS-; *SONTEC-; *TOSYL-; *TRAWOTOX-; *TRICHLORACETALDEHYD-HYDRAT- (GERMAN); *TRICHLOROACETALDEHYDE-HYDRATE-; *TRICHLOROACETALDEHYDE,-HYDRATED-; *TRICHLOROACETALDEHYDE-MONOHYDRATE-; *1,1,1-TRICHLORO-2,2-DIHYDROXYETHANE-; *2,2,2-Trichloroethane-1,1-diol-; *TRICHLOROETHYLIDENE-GLYCOL- RN: 302-17-0 RELT: 2557 [CHLORAL] (ANALOG); 6894 [DICHLOROACETIC ACID] (Metabolite); 1779 [TRICHLOROACETIC ACID] (Metabolite); 157 [1,1,1-TRICHLOROETHANE] (METABOLITE) MF: *C2-H3-Cl3-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Made by adding required amt of water to trichloroacetaldehyde. [R1] *Insoluble chloral hydrate forms from the reaction of chloral with water. [R2] *Formed by adding one molecule of water to the carbonyl group of chloral (2,2,2-trichloroacetaldehyde). [R3] FORM: *Dosage Forms-Capsules: 250 and 500 mg, and 1 g; Elixir: 500 mg/5 ml; Suppositories: 325, 500, and 650 mg. Syrup: 250 and 500 mg/5 ml. [R4] *Noctec capsules contain 500 mg chloral hydrate per capsule, Noctec syrup contains 500 mg chloral hydrate per 5 ml [R5, 2098] *Grade: Technical, USP [R6] *Chloropent injection; Intravenous anesthetic; Each ml contains: chloral hydrate 42.5 mg; magnesium sulfate 21.2 mg; pentobarbital 8.86 mg; ethyl alcohol 14.25%; propylene glycol 33.8%; purified water, qs (for cattle and horses) [R7, p. 16/109] *Chloral hydrate capsules contain not less than 95.0 % and not more than 110.0 % of the labeled amount of chloral hydrate. [R8] *Chloral hydrate syrup contains not less than 95.0 % and not more than 110.0 % of the labeled amount of chloral hydrate. [R8] *Chloral hydrate and ethanol in combination are referred to as ... Mickey Finn. [R9] OMIN: *Street names for chloral hydrate principally reflect its mixture with alcohol, which enhances its action, so we have such well known terms as "knock-out drops" and "Mickey Finn." [R10, 836] *May be habit forming. This is a controlled substance (depressant) listed in the U.S. Code of Federal Regulations, Title 21 Parts 329.1 and 1308.14 (1995). [R1] *In industrial exposures ... The small quantities which can be tolerated by inhalation are usually metabolized so rapidly that no anesthetic symptons occur. [R11, p. V1 935] USE: *Therap cat: Sedative, hypnotic [R1] *Therap cat (vet): Anesthetic, sedative, hypnotic [R1] *Used as a rubifacient in topical preparations [R12, 1361] *MEDICATION (VET) [R7, p. 16/109] *As glue peptizing agent [R13] *Manufacture of DDT. [R1] *Medicine (sedative), manufacture of DDT, linaments. [R6] *Hypnotic ... possesses anticonvulsant and muscle relaxant activites. [R11, p. V13 1083] *Manufacture of dichloroacetic acid in the laboratory. [R11, p. V1 169] *Employed for the production of sedation in children undergoing diagnostic, dental, or other potentially uncomfortable procedures. [R3] *Manufacture of DDT; organic synthesis [R14] PRIE: U.S. PRODUCTION: *(1972) 1.14X10+10 G (ANHYDROUS CHLORAL) [R15] *(1975) 5.9X10+8 G (EST) [R15] U.S. IMPORTS: *(1972) 2.83X10+7 G [R15] *(1975) 4.8X10+7 G [R15] *(1984) 5.41X10+6 g [R16] *(1986) 1.03X10+5 lb [R17] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Large monoclinic plates [R1]; *COLORLESS OR WHITE CRYSTALS [R18]; *Transparent, colorless crystals [R6]; *Colorless liquid [R14] ODOR: *Aromatic, penetrating and slightly acrid odor [R1]; *Pungent but not acrid odor [R18] TAST: *Slightly bitter, caustic taste [R1] BP: *96 deg C (decomposes) [R19] MP: *57 deg C [R19] MW: *165.40 [R1] CORR: *... Corrosive to the skin and mucous membrane unless well diluted [R18] DEN: *1.9081 g/cu m @ 20 deg C/4 deg C [R19] OWPC: *log Kow= 0.99 [R20] PH: *3.5-4.4 (10% soln in water) [R5, 2097] SOL: *One gram of chloral hydrate dissolves in 1.3 ml alcohol, in 2 ml chloroform, in 1.5 ml ether, in 1.4 ml olive oil, in 0.5 glycerol, in 68 g carbon disulfide. [R1]; *Freely sol in acetone, methyl ethyl ketone. Moderately or sparingly sol in turpentine, petr ether, carbon tetrachloride, benzene, toluene. [R1]; *Very soluble in water, benzene, ethyl ether, and ethanol. [R19]; *water solubility = 9.31X10+6 mg/l @ 25 deg C [R21] SPEC: *IR: 5423 (Coblentz Society Spectral Collection) [R22]; *NMR: 10362 (Sadtler Research Laboratories Spectral Collection) [R22]; *MASS: 1054 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R22]; *Intense mass spectral peaks: 82 m/z, 111 m/z, 146 m/z [R23] VAPD: *5.1 (Air= 1) [R14] VAP: *15 mm Hg @ 25 deg C [R24] OCPP: *Decomposed by sodium hydroxide into chloroform; reduces ammoniacal silver nitrate [R1] *Incompatible with alkaline substances [R5, 2097] *Incompatible with soluble barbiturates, tannin, oxidizing agents, and alcohol (chloral alcoholate may crystallize out), phenazone, phenol, thymol, and quinine salts [R18] *PHARMACEUTICAL INCOMPATIBILITIES: IODIDE, CYANIDE, PERMANGANATE, BORAX, ALKALI HYDROXIDES AND CARBONATES, LEAD ACETATE, MONOBROMATED CAMPHOR, DIURETIN, ACETOPHENETIDIN, QUININE SULFATE, SALOL, THEOBROMINE SODIOSALICYLATE, SODIUM PHOSPHATE, UREA, URETHANE. [R25] *Miscible hygroscopic [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat or flame. [R26] DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen chloride/. [R26] OHAZ: *Slowly volatilizes when exposed to air. [R27] SERI: *Irritating to skin and mucous membranes ... [R12, 1361] *... Dangerous to eyes. [R27] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *SLOWLY VOLATILIZES ON EXPOSURE TO AIR. [R1] *Aqueous solutions of chloral hydrate decomposed rapidly when exposed to ultraviolet light, with the formation of hydrochloric acid, trichloroacetic acid, and formic acid. ... A 1% solution lost about 5% of its strength after storage at room temperature for 20 weeks. [R18] *Aqueous solutions are likely to develop mold growth. [R18] STRG: *CHLORAL HYDRATE ORAL SOLN SHOULD BE STORED IN LIGHT-RESISTANT CONTAINERS. ... CAPSULES SHOULD BE STORED @ 15-30 DEG C. [R5, 2097] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Chloral hydrate is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Preferably after mixing with another combustible fuel, care must be exercised to assure complete combustion to prevent the formation of phosgene; an acid scrubber is necessary to remove the halo acids produced. [R28] *The following wastewater treatment technology has been investigated for chloral hydrate: Concentration process: Solvent extraction. [R29] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *IDENTIFICATION: Chloral hydrate is used in human and veterinary medicine as a sedative and hypnotic drug. HUMAN EXPOSURE: The major route of exposure of the general public is from drinking water, as chloral hydrate is formed when drinking water is disinfected with chlorine. Since chloral hydrate is a metabolite of trichloroethylene and tetrachloroethylene, people will be exposed to chloral hydrate if they are exposed to these chemicals. The public will be exposed to the metabolites of chloral hydrate, trichloroacetic acid and dichloroacetic acid, as these chemicals are also formed when drinking water is disinfected with chlorine. In its use as a sedative for people, the metabolite trichloroethanol is responsible for the pharmacologic effect. No quantitative information is available from occupational exposure. Chloral hydrate is irritating to the skin and mucous membranes and often causes gastric distress, nausea and vomiting at the recommended clinical dose. An overdose of this drug produces (in order of progression) ataxia, lethargy, deep coma, respiratory depression, hypotension and cardiac arrhythmia. There is some evidence of hepatic injury in people surviving near lethal acute overdoses. Despite its long use in human medicine there is no published information on toxicity in controlled studies in humans following extended exposure. Chloral hydrate is completely absorbed and rapidly metabolized following oral admin. In humans the half-life of trichloroethanol and its glucuronide is about 8 hr; the half-life of trichloroacetic acid is about 4 days. Some data suggest that half-life of trichloroethanol is incr several fold in pre-term and full term infants compared with toddlers and adults. The major routes of excretion of the metabolites of chloral hydrate is elimination in the urine.Chloral hydrate and its metabolites have been found in milk from women treated with this drug. There no carcinogenicity data from humans. ANIMAL STUDIES: Acute administration of chloral hydrate to mice causes loss of coordination (ataxia). A 90 day study in mice shows no evidence of behavioral changes or other neurotoxicity. Chronic studies in rats and mice show no evidence of behavioral changes and no evidence of histopathological changes in the nervous tissue. A slight detriment in humoral immunity was observed following exposure of mice for 90 days. This drug has been tested for developmental effects in rats and mice. No structural abnormalities were observed. In a neurodevelopmental study in mice, there was a slight effect in passive avoidance learning. Two bioassays in rats show no incr in tumors at any site. Three separate bioassays in male mice showed an incr incidence of liver tumors. The most definitive of these studies shows an incr incidence and multiplicity of liver tumors at each of three exposures. These data show suggestive evidence of carcinogenicity in male mice but are not considered appropriate for conducting a human health risk assessment with a linear response at low exposure. A variety of results show that chloral hydrate is a weak gene mutagen and clastogen. Chloral hydrate induces aneuploidy in a wide variety of cell types. [R30] CARC: +WEIGHT-OF-EVIDENCE CHARACTERIZATION: Under the 1986 cancer guidelines (EPA), chloral hydrate is assigned to Group C, possible human carcinogen. Under the 1996 proposed guidelines (EPA) for carcinogen risk assessment, chloral hydrate shows suggestive evidence of human carcinogenicity by the oral route of exposure. There are no carcinogenicity data from humans. Two bioassays in rats in which chloral hydrate was administered by drinking water show no increase in tumors at any site. Because only minimal toxicity was observed in the livers of the rats in these bioassays, the tests were not conducted at the maximum tolerated dose. A chronic bioassay in female mice showed a slight increase in the severity grade of hyperplasia and a slight increase in the incidence of adenoma in the pituatary gland pars distalis at the highest exposure tested. There is some evidence that chloral hydrate causes hepatocellular tumors in male mice. An earlier study showing an increase of hepatocellular adenomas or trabecular carcinomas following a single bolus exposure could not be confirmed in a study using more animals and higher exposures. Three separate 2-year bioassays in male mice show an increased incidence of hepatocellular adenoma or carcinoma. There are no data identifying a lesion that is a precursor to the hepatocellular tumors. The strain of mice used has a very high spontaneous incidence of hepatocellular tumors. Two of the matabolites of chloral hydrate, trichloroacetic acid and dichloroacetic acid, have been shown to cause hepatocellular tumors in rodents. Trichloroacetic acid causes hepatocellular tumors only in mice. Dichloroacetic acid causes hepatocellular tumors in both rats and mice. There is an extensive database on genetic toxicity. A variety of results show that chloral hydrate is a weak gene mutagen and clastogen. Chloral hydrate induces aneuploidy in a wide variety of cell types. These latter effects are thought to arise by disruption of the spindle apparatus. A high concentration of chloral hydrate is required to cause observable effects. Although these data suggest that genotoxicity may play a role in the toxicity of chloral hydrate, the data indicate that these effects require concentrations that are unlikely to occur under physiological conditions at the exposures typically encountered from the environment. Collectively, these data provide suggestive evidence of carcinogenicity, but the weight of evidence is not sufficient to conduct a risk assessment assuming a linear response at low exposure. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R31] *Evaluation: There is inadequate evidence in humans for the carcinogenicity of chloral and chloral hydrate. There is inadequate evidence in experimental animals for the carcinogenicity of chloral. There is limited evidence in experimental animals for the carcinogenicity of chloral hydrate. Overall evaluation: Chloral and chloral hydrate are not classifiable as to their carcinogenicity to humans (Group 3). [R32] ANTR: *Since chloral hydrate causes serious arrhythmias as well as respiratory depression, all significant ingestions should have careful evaluation of respiratory status, an intravenous line, oxygen, and a cardiac monitor. [R33, 588] *All patients who have ingested amounts greater than the therapeutic dose ... in adults within 2 hours of ingestion should receive gut decontamination (ipecac/lavage, charcoal, cathartics). Rapid onset of action makes the use of syrup of ipecac hazardous in the lethargic patient. In such a setting, the immediate administration of activated charcoal is preferable to syrup of ipecac administration. Because of the corrosive properties of liquid chloral hydrate preparation, lavage tubes must be inserted carefully. The effectiveness of decontamination measures can be assessed with a /radiograph/ of the abdomen. Charcoal and cathartics should be given to all patients who present within 2 hours postingestion and to all patients with central nervous system depression. [R33, 588] *Hemodialysis effectively removes the active metabolite trichloroethanol at a rate of 120 to 162 ml/min. The plasma half-life decreased from 35 to 6 hours after hemodialysis of a patient who ingested 38 g chloral hydrate. The major indications are the failure of the patient to respond to supportive care or the presence of lethal drug levels. Resin hemoperfusion also effectively removes trichloroethanol at a rate similar to that of hemodialysis. Forced diuresis is ineffective. Exchange transfusion in an infant was not useful in removing substantial amounts of trichloroethanol. [R33, 588] *Hypotension should be treated with fluid challenges and alpha-adrenergic vasopressors (eg, levarterenol). Ventricular arrhythmias should be treated with lidocaine and then a beta-blocker drug (eg, propranolol). Watch for development of gastrointestinal hemorrhage, hepatic and renal dysfunction, and aspiration pneumonia as well as withdrawal symptoms. [R33, 588] HTOX: *PARADOXICAL EXCITEMENT IS OBSERVED RARELY. THE CONTINUED USE OF LARGE DOSES CAUSES PERIPHERAL VASODILATION, HYPOTENSION, VENTILATORY DEPRESSION, ARRHYTHMIAS, AND MYOCARDIAL DEPRESSION. [R34] *... IN DANGEROUS OVERDOSAGE THERE MAY BE MYDRIASIS. MODERATE DOSES ... AFFECT EYE MOVEMENTS, PARTICULARLY INTERFERING WITH CONVERGENCE, AND SOMETIMES CAUSING PTOSIS. ... CHLORAL HYDRATE ... MAY CAUSE SWELLING OF LIDS, HYPEREMIA AND EDEMA OF THE CONJUNCTIVAE, PLUS A SENSATION OF IRRITATION AND TEARING. [R35] *Ingestion /of 18 g chloral hydrate/ resulted in gastrointestinal hemorrhage followed by the development of esophageal strictures. [R33, 587] *Three patients are presented in whom life-threatening cardiac arrhythmias dominated the clinical presentation. These arrhythmias were resistant to standard antiarrhythmic therapy. [R36] *In a severe case of chloral hydrate intoxication treated with combined hemodialysis and hemoperfusion, the pharmacokinetics of the metabolites trichloroethanol, trichloroethanol glucuronide and trichloroacetic acid were studied. Indications of delayed absorption and some slowing of metabolism were found. At a blood flow rate of 200 ml/min, clearances by hemodialysis and hemoperfusion, respectively, in ml/min were estimated to be 188 and 156 for trichloroethanol, 184 and 181 for trichloroethanol glucuronide, 142 and 91 for trichloroacetic acid. Clearance by hemoperfusion declined with time. The half-lives of trichloroethanol and trichloroacetic acid were 3.2 and 4.3 hr during combined hemodialysis and hemoperfusion. After termination of treatment the half-life of trichloroethanol was 12.8 hr, whereas trichloroacetic acid was metabolized so slowly, that no reliable calculation could be performed. /Results suggest/ that hemodialysis andhemoperfusion are equally and highly efficient in the treatment of chloral hydrate poisoning, but hemoperfusion may increase the risk of gastric bleeding more than hemodialysis. Hemodialysis may therefore be preferable and should be tried in spite of low blood pressure. [R37] *Three patients are presented in whom life threatening cardiac arrhythmias dominated the clinical presentation. These arrhythmias were resistant to standard antiarrhythmic therapy. Also, selected features in eight patients who took overdoses of chloral hydrate who were admitted to an intensive care unit between 1981 and 1988 were reviewed. The pharmacology and toxicology of chloral hydrate are discussed with particular reference to the cardiac arrhythmias that are seen with overdosage. A proposed management scheme is detailed, including iv administered propranolol as the preferred first line antiarrhythmic agent. A case may be made for the discontinuation of the usage of chloral hydrate. [R36] *Oral chloral hydrate sedation in children is safely used prior to cross-sectional imaging. Two children with Leigh's disease who developed acute respiratory insufficiency following high dose oral chloral hydrate sedation was reported. [R38] *Chloral hydrate is commonly used to sedate children before computed tomography. However, no prospective study has been published of the safety and efficacy of chloral hydrate at high dose levels for children undergoing computed tomography. We define high dose levels of oral chloral hydrate to be 80-100 mg/kg, with a maximum total dose of 2 g. High dose chloral hydrate sedation was administered orally to 295 children for 326 computed tomographic examinations. Adverse reactions occurred in 7% of the children, with vomiting being the most common (4.3% of children). Hyperactivity and respiratory symptoms each occurred in less than 2% of children. Prolonged sedation ( > 2 hr) was not encountered in this series. Sedation was successful in producing motion free computed tomographic examinations, so that in 303 (93%) of the cases, no repeat computed tomography scans were needed. High dose oral chloral hydrate provides safe and effective sedation for children undergoing computed tomography. [R39] *To test the hypothesis that chloral hydrate can cause direct hyperbilirubinemia in the newborn, two retrospective analyses of the medical records of patients admitted to a neonatal intensive care unit during an 18 month period were conducted. In one analysis of 14 newborns who had nonhemolytic direct hyperbilirubinemia, 10 did not have an identified cause of direct hyperbilirubinemia, and all 10 had received chloral hydrate. In the second retrospective study, all newborns who received chloral hydrate were divided into groups according to whether or not direct hyperbilirubinemia had developed. The newborns with direct hyperbilirubinemia, compared with those without direct hyperbilirubinemia, had received a higher total accumulative dose of chloral hydrate (1035 + or - 286 vs 183 + or - 33 mg/kg + or - 1 SEM, respectively). In the patients with direct hyperbilirubinemia, the direct serum bilirubin levels increased 6.8 + or - 0.8 days after the chloral hydrate administration began and resolved after the chloral hydrate was discontinued or markedly decreased. These data support the hypothesis that prolonged use of chloral hydrate in newborns can be associated with direct hyperbilirubinemia. [R40] *A female patient with drug eruption due to Sirupus Chlorali hydrati SR is reported. The causal allergen was chloral hydrate itself. This could be identified even by patch test and oral provocation test. [R41] *Signs and symptoms of severe overdose are similar to those of barbiturate overdose, with respiratory depression and cardiovascular instability presenting the main threats to life. Symptoms begin with ataxia and lethargy and progress to deep coma often within 1 to 2 hours of ingestion. Pupils usually are miotic but dilate in the deeper stages of coma. The peculiar pearlike odor of chloral hydrate may help distinguish it from other sedative-hypnotics. [R33, 587] *Ten compounds /including chloral hydrate/ selected for use within a coordinated Commission of the European Communities program on aneuploidy induction were tested for their ability to induce CREST-positive micronuclei in cultured human diploid fibroblasts. Significant increases in CREST-positive micronuclei were produced by chloral hydrate. [R42] *... A patient developed a reversible symptomatic myocardial ischemia of 4 hr duration after chloral hydrate overdose. ... The evolution was favorable. Exposure to chlorinated hydrocarbons can be associated with myocardial ischemia particularly if the coronary circulation is compromised. [R43] NTOX: *THE ORAL LETHAL DOSE IN THE HORSE IS ... 100-150 G. ... HARMFUL EFFECTS ARE NOT SEEN WHEN THE DRUG IS GIVEN IV UNTIL AN AMT EQUIVALENT TO 370 MG/KG HAS BEEN ADMINISTERED. THE CLINICAL SIGNS OBSERVED IN HORSES RECEIVING TOXIC DOSES OF CHLORAL HYDRATE INCLUDE RELAXATION OF THE VOLUNTARY MUSCLES, STAGGERING, DILATATION OF THE PUPILS, LOWERING OF THE BODY TEMPERATURE, AND FINALLY A CONDITION OF DEEP STUPOR. DEATH RESULTS FROM RESPIRATORY FAILURE. [R44] *... CHLORAL HYDRATE, INHIBITS PROTEIN SYNTHESIS IN VIVO AND HAS BEEN SHOWN TO BLOCK METAPHASE IN SEGMENTING EGGS, WITH SOME ALTERATION IN CHROMOSOMAL STRUCTURE. [R45] *Despite precaution, perivascular injection of chloral hydrate solution sometimes occurs, and it is quite irritating to the tissues, especially in the horse. Severe pain, swelling, and necrosis of tissues result, including sloughing and destruction of the external jugular vein. ... When higher concentration are injected at the usual rate until the desired effect is observed clinically, the animal will exhibit further depression within 10-15 minutes after injection is stopped. [R46, 231] *Intracarotid injection may result in cerebrovascular endothelial injury with consequent edema and ischemic necrosis in the brain, especially in the horse. [R7, p. 16/110] *The ability of trichloroethylene and selected metabolites to induce single-strand breaks in hepatic DNA of male B6C3F1 mice and Sprague Dawley rats in vivo was evaluated using an alkaline unwinding assay. ... Chloral hydrate induced strand breaks in hepatic DNA in a dose-dependent manner in both species. Strand breaks in DNA were observed at doses that produced no observable hepatotoxic effects as measured by serum aspartate aminotransferase and alanine aminotransferase levels. The slopes of the dose-response curves and the order of potency of these metabolites differed significantly between rats and mice, suggesting that different mechanisms of single-strand break induction may be involved in the two species. [R47] *... The carcinogenic effect of chloral hydrate /was evaluated/. ... Fifteen day old C57BL x C3HF1 male mice were given a single dose of chloral hydrate in distilled water at two dose levels: group 1, 5 ug/g; group 2, 10 ug/g (20-25 mice per group). Thirty five mice given distilled water only served as controls. Animals were sacrificed at 24 hr and thereafter at various intervals to 92 weeks. The entire liver was fixed and examined histologically. Mice sacrificed between 48 and 92 weeks showed hepatic lesions ranging from hyperplastic to trabecular carcinomas. The tumor incidence in mice given 10 ug/g chloral hydrate (six of eight) was significantly higher (p < 0.05) than the incidence in the controls (two of 19). [R48] *The effect of two different mutations, one involving an alpha-tubulin and the other a beta-tubulin gene, on somatic segregation has been investigated in diploid strains of Aspergillus nidulans. Both mutations, particularly beta-tubulin, increase the level of spontaneous chromosomal mis-distribution phenomena, without affecting the frequency of crossing-over. The employment of homozygous strains for each of the two mutations in sensitivity tests toward various chemicals, allowed to clear identification of those interfering with microtubule assembly-disassembly processes (eg; chloral hydrate). [R49] *The immunofluorescent staining of kinetochores in micronuclei with antikinetochore antibodies was used to develop an in vitro assay for aneuploidy-inducing agents. The results show that about 80% of micronuclei induced by ... chloral hydrate contained kinetochores; only 9% of X-ray-induced micronuclei reacted positively to the antibody. These findings indicate that the in vitro micronucleus assay coupled with immunofluorescent staining of kinetochores can be a useful method for assessing ability of chemicals to induce aneuploidy and/or chromosome aberrations. [R50] *Chloral hydrate caused metaphase II hyperploidy when injected into mice ... . [R51] *Chloral hydrate was tested in V79 Chinese hamster cells, where it induced CREST-positive micronuclei. [R42] *Ten known or suspected spindle poisons /including chloral hydrate/ of the coordinated EEC program for induction of aneuploidy /were tested/ with the in vitro porcine brain tubulin assembly assay. The influence of the compounds on different parameters (lag-phase, polymerization velocity, endabsorption (steady-state level), reversibility, influence on disassembly at 4 degrees C) was evaluated. Chloral hydrate (IC30: 60 mM) led to an inhibition of tubulin assembly in vitro. The influence on the disassembly process was studied at 4 degrees C. Chloral hydrate reduced the disassembly rate but the end absorption of the control was not reached, the 30% reduction concn being 0.25 mM. [R52] *The induction of aneuploidy in cultured Chinese hamster cells by chloral hydrate has been studied. Chinese hamster embryonic diploid cells were grown as a monolayer in cover glasses. Treatments were performed with doses of 1X10-3, 2X10-3 and 3X10-3% of chloral hydrate for 1.5 hr. Treatments with 2X10-3% of acetaldehyde were used as positive controls. Untreated cultures were used as negative controls. Chloral hydrate induced chromosomal damage only with the two higher doses. No correlation was found between the amount of chromosoma damage induced and the dose of chloral hydrate employed. Chloral hydrate increased the frequency of aneuploid cells in relation to untreated controls e control, but did not significantly increased the frequencies of polyploid cells. These results indicate that aldehydes and chlorine-replaced aldehydes are strong inducers of aneuploidy despite some differences between chloral hydrate and acetaldehyde regarding cytotoxicity and polyploidy induction. [R53] *The metabolism of chloral hydrate was studied in rats with liver damage induced by carbon tetrachloride. Male Wistar rats were injected with carbon tetrachloride twice per week for 15 wk, and sacrificed 1 week after the final injection. Their livers were then perfused with addition of chloral hydrate to the perfusion system. The concn of chloral hydrate, trichloroethanol, and trichloroacetic acid in the perfusate were measured by GC. Perfusion rates were significantly lower in damaged livers than in controls. In both groups, 50 to 70% of the added chloral hydrate was excreted into the perfusate as trichloroethanol and trichloroacetic acid within 120 min. The trichloroethanol/trichloroacetic acid ratio was 1:1.3 in the control group and 2:1 in the group with induced liver damage. It is speculate that a high ratio of reduced NADP to oxidized NADP, and low chloral hydrate dehydrogenase activity in the damaged livers, promote the reduction of chloral hydrate to trichloroethanol and inhibit the oxidation of chloral hydrate to trichloroacetic acid. It was concluded that the metabolism of chloral hydrate is considerably different in damaged livers than in normal livers. [R54] *Induction of gastric mucosal injury by chloral hydrate was studied in rats. Adult male rats, strain not specified, were injected ip with 0, 200, 300, 400, or 500 mg/kg chloral hydrate or sc with 0, 400, 500, 600, or 700 mg/kg chloral hydrate. Selected rats were killed 0, 3, 6, 12, or 24 hr after injection and the stomachs were removed. Strips of the gastric wall were cut from the forestomach to the pylorus through the entire glandular mucosa and examined for mucosal ulcers. Ulcer indices, the total length of all mucosal ulcers per rat, were computed. Ulcers were first detected 6 hr after dosing. The maximum values of the ulcer index, 12.6 mm for ip injection and 6.8 mm after sc injection, occurred at 12 hr. The minimum effective dose for inducing ulcers was 400 mg/kg for ip injection and 600 mg/kg for sc injection. In ip doses of 500 mg/kg or greater and sc doses of 700 mg/kg or greater caused mortality within 12 hr. The authors conclude that chloral hydrate induces gastric ulcers in rats when injected ip or sc. The mechanism of ulcer induction is unknown. [R55] *Administration of chloral hydrate to mice by gavage at daily doses of 14.4 and 144 mg/kg bw for 14 consecutive days resulted in an increase in relative liver weight and a decrease in spleen size. [R56] *The release of striatal dopamine (DA) and its metabolites in response to locally incuded K+ depolarization was investigated in vivo in chloral hydrate anesthetized and freely moving rats. /Potassium chloride/ at concn of 30, 50 and 100 mM induced significant dose dependent incr in extracellular DA overflow in both chloral hydrate anesthetized and freely moving rats (P < 0.05). Extracellular levels of dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) were decr. The DA overflow in response to 30 mM potassium chloride stimulation in anesthetized rats was significantly greater than that in freely moving rats (P < 0.05). ... Chloral hydrate anesthesia resulted in significant decr in extracellular levels of DOPAC and significant incr in extracellular levels of HVA and 5-HIAA in comparison with freely moving rats (P < 0.05). ... The basal level of extracellular HVA in chloral hydrate anesthetized rats was significantly higher than that in moving rats. ... [R57] *Mice were exposed by inhalation to trichloroethylene or by ip injection of ... chloral hydrate. Early spermatids were analyzed for micronucleus (MN) frequency and the presence or absence of kinetochores using fluorochrome labeled anti-kinetochore antibodies. It was determined that 5 consecutive days of exposure to 5, 50 or 500 ppm TCE during preleptotene through early pachytene stages of meiotic cell development do not result in incr frequencies of spermatid MN. Chloral hydrate at 41, 83 or 165 mg/kg was positive for spermatid MN induction when treatments corresponsed to spermatogonial stem cell or preleptotene spermatocyte stages of development; negative results were /observed/ after treatments of leptoene zygotene or diakinesis metaphase stages. The significantly incr levels of MN observed were invariably of the kinetochore negative type. [R58] *... During culture in 125 ug/ml chloral hydrate germinal vesicle breakdown is delayed and most /mouse/ oocytes become arrested in meiosis I with bivalent chromosomes. Their spindles are asymmetric or attain fusiform poles. Oocytes which progress to metaphase II also possess astral instead of barrel shaped, anastral spindles characteristic for the controls. Resolution of the chiasmata without polar body extrusion during exposure to 50 and 125 ug/ml chloral hydrate results in significant rises in diploid metaphase II oocytes. Hyperploidy rates do not incr significantly at any concn of chloral hydrate, but hypoploidy levels are elevated at 125 ug/ml chloral hydrate. Chloral hydrate induces lagging of chromosomes during telophase I, inhibits spindle elongation in anaphase B and causes chromosome displacement from the spindle equator in metaphase I and II. Oocytes also become irreversibly arrested in maturation when exposed /to this cmpd/ prior to resumption of maturation, or when chloral hydrate is present during the first or second 8 hr of maturation. ... These data show unequivocally that chloral hydrate is a potent aneugen in female germ cells. ... [R59] *Chloral hydrate of greater than 99% purity was investigated on its mutagenic potential in a series of test systems according to the current EC guidelines. There were no indications for /the mutagenicity/ of chloral hydrate. [R60] *Metabolism of chloral hydrate by male B6C3F1 mouse liver microsomes generates free radical intermediates as evidenced by electron spin resonance spectroscopic analysis. The subsequent induction of endogenous lipid peroxidation was shown by analysis of the resulting products with high pressure liquid chromatography. Chloral hydrate was found mutagenic in Salmonella typhimurium strain TA104. Both lipid peroxidation and mutagenicity were efficiently inhibited by free radical scavengers alpha-tocopherol and menadione. [R61] +2-YEAR STUDY: Groups of female B6C3F1 mice (regimens A, B, C and D) and groups of male B6C3F1 mice (regimen E) recieved chloral hydrate in distilled water by gavage; control groups recieved distilled water only. In regimen A, groups of 48 female mice received 0, 25, 50 or 100 mg chloral hydrate/kg body weight 5 days/wk for 104 wk beginning when they were 28 days old. In regimen B, 24 female mice received 0 mg/kg and three groups of 48 female mice 100 mg/kg 5 days/wk when they were 28 days old.Eight mice from the 0 and 100 mg/kg groups were killed at 3, 6 or 12 months. The remaining mice were held without further dosing for the duration of the 2 yr study. In regimen C, groups of 48 female mice received a single dose of 0, 10, 25 or 50 mg/kg when they were 28 days old and were held for 104 wk. In regimens D and E groups of 48 female and 48 male mice, respectively, received a single dose of 0, 10, 25, 50 mg/kg when they were 15 days old and were held for 104 wk. ... CONCLUSIONS: Under the conditions of this 2 yr gavage study, there was equivocal evidence of carcinogenic activity of chloral hydrate in female B6C3F1 mice treated continuously for 2 yr based on the incr incidences of pituitary gland pars distalis adenomas. No incr incidences of neoplams were seen in female B6C3F1 mice that recieved a single dose of chloral hydrate at 15 or 28 days of age or in male B6C3F1 mice that received a single dose of chloral hydrate at 15 days of age. No hepatocarcinogenicity was seen under any dosing condition. [R62] HTXV: *Therapeutic blood level: 1.0 mg/100 ml; toxic blood level: 10 mg/100 ml; lethal blood level: 25 mg/100 ml. /From table/ [R63, 687] NTXV: *LD50 Rats oral 200-500 mg/kg; [R10, 837] *LD50 Horse oral 100-150 g; [R44] *LD50 Rat oral 479 mg/kg; [R26] *LD50 Rat skin 3030 mg/kg; [R26] *LD50 Rat ip 472 mg/kg; [R26] *LD50 Rat parenteral 710 mg/kg; [R26] *LD50 Mouse oral 1100 mg/kg; [R26] *LD50 Mouse ip 580 mg/kg; [R26] NTP: +2-YEAR STUDY: Groups of female B6C3F1 mice (regimens A, B, C and D) and groups of male B6C3F1 mice (regimen E) recieved chloral hydrate in distilled water by gavage; control groups recieved distilled water only. In regimen A, groups of 48 female mice received 0, 25, 50 or 100 mg chloral hydrate/kg body weight 5 days/wk for 104 wk beginning when they were 28 days old. In regimen B, 24 female mice received 0 mg/kg and three groups of 48 female mice 100 mg/kg 5 days/wk when they were 28 days old.Eight mice from the 0 and 100 mg/kg groups were killed at 3, 6 or 12 months. The remaining mice were held without further dosing for the duration of the 2 yr study. In regimen C, groups of 48 female mice received a single dose of 0, 10, 25 or 50 mg/kg when they were 28 days old and were held for 104 wk. In regimens D and E groups of 48 female and 48 male mice, respectively, received a single dose of 0, 10, 25, 50 mg/kg when they were 15 days old and were held for 104 wk. ... CONCLUSIONS: Under the conditions of this 2 yr gavage study, there was equivocal evidence of carcinogenic activity of chloral hydrate in female B6C3F1 mice treated continuously for 2 yr based on the incr incidences of pituitary gland pars distalis adenomas. No incr incidences of neoplams were seen in female B6C3F1 mice that recieved a single dose of chloral hydrate at 15 or 28 days of age or in male B6C3F1 mice that received a single dose of chloral hydrate at 15 days of age. No hepatocarcinogenicity was seen under any dosing condition. [R62] ADE: *Chloral hydrate has been detected in cerebrospinal fluid, milk, and fetal blood, and it may be found in unchanged form in the liver, stomach contents, and upper gastrointestinal tract shortly after drug overdose death. [R10, 836] *Chloral hydrate absorption is rapid and complete from the GI tract, with peak therapeutic levels developing within 1/2 to 1 hr. Chloral hydrate and its active metabolite trichloroethanol are highly lipid soluble and easily penetrate all membranes. The volume of distribution of chloral hydrate is 0.6 l/kg. [R33, 586] *CHLORAL HYDRATE IS RAPIDLY ABSORBED FROM GI TRACT FOLLOWING ORAL OR RECTAL ADMIN. ... FOLLOWING ADMIN OF SINGLE CHLORAL HYDRATE DOSE OF 15 MG/KG, PEAK PLASMA CONCN OF TRICHLOROETHANOL RANGED FROM 7-10 UG/ML IN ONE STUDY. [R5, 2097] *... Chloral hydrate and/or the active metabolite trichloroethanol have been detected in CSF, umbilical cord blood, fetal blood, and amniotic fluid. Following therapeutic doses of chloral hydrate, only small, clinically insignificant amt of the active metabolite are distributed into milk. [R5, 2097] *TRICHLOROETHANOL, THE ACTIVE METABOLITE OF CHLORAL HYDRATE, TRICHLOROETHANOL GLUCURONIDE, AND TRICHLOROACETIC ACID ARE SLOWLY EXCRETED IN URINE. SOME TRICHLOROETHANOL GLUCURONIDE MAY BE ... EXCRETED IN FECES. CHLORAL HYDRATE IS NOT EXCRETED IN URINE UNCHANGED. [R5, 2097] *Blood concentrations of trichloroethylene and trichloroethanol, a metabolite, reached average peak levels of 1 and 6 mg/l, respectively, in 5 subjects exposed to 100 ppm trichloroethylene for 6 hours ... same ... level /of trichloroethanol was/ seen 2 hours after the injection of a hypnotic dose (15 mg/kg) of chloral hydrate by 2 subjects. [R64] *... To examine the absorption of trichloroethylene and its metabolites from the urinary bladder of dogs, trichloroethylene and its metabolites, eg, chloral hydrate, free trichloroethanol, trichloroacetic acid and conjugated trichloroethanol, /were injected/ into the urinary bladder of anesthetized dogs, and the agents and their respective metabolites /were measured/ in the blood or serum, urine and bile. The percentage of water absorbed from the urinary bladder was 10-20% 2 hr after the administration of all substances. The percentage of agents absorbed was 60-70% for the trichloroethylene and trichloroacetic acid groups, and 50-60% for the chloral hydrate, free trichloroethanol and conjugated-trichloroethanol groups 2 hr after administration. The combined urinary and biliary excretion rates of the absorbed materials from the urinary bladder 2 hr after administration were 46% for free trichloroethanol, 30% for chloral hydrate, 6% for conjugated trichloroethanol and 0.5-1.0% for trchloroethylene and trichloroacetic acid. Urinary re-excretion rates of the total excreted amounts were 65-70% in trichloroethylene, chloral hydrate and free trichloroethanol groups, about 50% in trichloroacetic acid and 99% in conjugated trichloroethanol group. It is possible that all of the substances administered, particularly free trichloroethanol are metabolized to conjugated trichloroethanol in the urinary bladder. [R65] *Chloral hydrate and its metabolite, trichloroethanol reached 50-100% /in breast milk/ of maternal blood levels in most of 50 women given 1.3 g rectally. Drug and metabolites were detectable for up to 24 hr; the maximum dose that an infant could have received approximates a sedative dose. [R66, 174] *Chloral hydrate (CH) and its metabolites, trichloroacetate (TCA) and dichloroacetate (DCA) have been shown to induce liver tumors in male B6C3F1 mice. The pharmacokinetics of CH and its metabolites play an important role in its toxicity. /This experiment/ was designed to characterize the kinetics of CH metabolism, and the formation and elimination of TCA, DCA, trichloroethanol (TCOH) and trichloroethanol glucuronide (TCOG) in male B6C3F1 mice. Mice were dosed with 67.8, 678, 2034 umol/kg of CH through the tail vein. At selected time points, mice were /sacrificed/ and blood and liver samples were collected. Samples were assayed by GC for CH, TCOH, TCOG, TCA and DCA concn. After iv admin, CH rapidly disappeared from blood with a terminal half-life ranging from 5 to 24 min. Systemic clearance decr from 36.0 to 7.6 l/kg/hr with incr CH dose, demonstrating dose dependent pharmacokinetics. TCOH, TCOG TCA, and DCA were detected over the study period. Formation and metabolism of CH metabolites seemed to be dose dependent. The terminal half-lives of TCOH and TCOG were similar, ranging from 0.2 to 0.7 hr. TCA and DCA were formed rapidly from the metabolism of CH and cleared slowly from systemic circulation. The area under the blood concn time curve for DCA was 10-20% of that for TCA. Both TCA and DCA were slowly eliminated from systemic circulation. The concn time profile of DCA seemed to be driven by blood concn of TCA, suggesting the possibility of DCA from TCA metabolism. [R67] METB: *CHLORAL HYDRATE IS METABOLIZED BY LIVER AND ERYTHROCYTES TO FORM TRICHLOROETHANOL (ACTIVE METABOLITE). REDN OF CHLORAL HYDRATE ... TO TRICHLOROETHANOL ... IS CATALYZED BY ALCOHOL DEHYDROGENASE AND OTHER ENZYME. ... A SMALL BUT VARIABLE AMOUNT OF CHLORAL HYDRATE AND A LARGER PORTION OF TRICHLOROETHANOL ARE OXIDIZED TO TRICHLORACETIC ACID (AN INACTIVE METABOLITE), MAINLY IN THE LIVER AND KIDNEY. TRICHLOROETHANOL MAY ALSO BE CONJUGATED WITH GLUCURONIC ACID TO FORM TRICHLOROETHANOL GLUCURONIDE (UROCHLORALIC ACID), AN INACTIVE METABOLITE. [R5, 2097] *The metabolism of chloral hydrate was investigated in the isolated perfused rat liver system. The expriments were performed on rats that were administered carbon tetrachloride subcutaneously for 18 weeks to induce chronic liver damage and on untreated rats. Clearance of chloral hydrate from the perfusion system was lower in damaged liver than in control liver. In both groups, 50-70% of the added chloral hydrate was excreted into perfusate as trichloroethanol and trichloroacetic acid within 120 min. The trichloroethanol/trichloroacetic acid ratio was 1:1.3 in the control group compared to 2:1 in the damaged liver group. The findings suggest that chloral hydrate metabolism in the liver is affected by chronic damage. [R54] *The metabolism of chloral hydrate in the anoxic liver was studied in rats using liver perfusion methods. The changes in chloral hydrate metabolism induced by the alteration of the redox state of pyridine nucleotides under anoxia were also investigated. Adult male Wistar rats were used to establish a nonrecirculating, hemoglobin free liver perfusion system. In the anoxic liver the uptake of chloral hydrate decreased to about 80% of that in the oxygen supplied liver. An increase was noted in the reduction of chloral hydrate to trichloroethanol; the oxidation of chloral hydrate to trichloroacetic acid was decreased. An increase in the ratio of trichloroethanol/trichloroacetic acid was observed. There was, however, no significant change in the total trichloro compounds brought on by the anoxic conditions. About 14% of the chloral hydrate infused into the oxygen supplied liver was changed to substances other than CE or trichloroacetic acid. It was suggested that the decrease in chloral hydrate uptake was equivalent to the decrease of unknown metabolites. Pyruvate or lactate infusion both altered the trichloroethanol/trichloroacetic acid ratio under anoxic conditions. [R68] *NADH and NADPH dependent chloral hydrate reducing activities were investigated in various organs of male Wistar rats. Alcohol dehydrogenase and aldehyde reductase reduce chloral hydrate, a trichloroethylene metabolite, to trichloroethanol; NADH is required by alcohol dehydrogenase, and NADPH is required by aldehyde reductase. Rats were killed after a 24 hr fast, and organs were removed, homogenized, and centrifuged; supernatant was used for tests of chloral hydrate reducing activity. Liver, kidney and adrenals had higher chloral hydrate reducing activity than the other organs. However, from the viewpoint of chloral hydrate metabolizing capacity, chloral hydrate may be mainly metabolized in liver and kidney as adrenals have the lowest weight of all the organs tested. Liver had greater activity with NAD as a cofactor than NADPH. Organs other than the liver had high chloral hydrate reducing activity with NADPH. It was noted that adrenals had high NADPH linked chloral hydrate reduction activity in spite of having no NADH linked chloral hydrate reduction. The reason for this high chloral hydrate reducing activity is not known. [R69] *Chloral hydrate was administered to dogs at 25 mg/kg dose levels injected into the left femoral vein both in nonbypass and bypass dogs. Arterial blood samples were taken from the left femoral artery once before administration and at 30, 60, 90, and 120 min following administration. When measurements were taken of conjugated trichloroethylene, free trichloroethylene and trichloroacetic acid as metabolites of administered chloral hydrate, the levels of conjugated trichloroethylene and trichloroacetic acid in nonbypass dogs were higher than in bypass dogs, and levels of free trichloroethylene in nonbypass dogs were lower in both serum and urine than in bypass dogs. Reduction volumes of chloral hydrate to free trichloroethylene were larger than the conjugation volumes of free trichloroethylene in the bypass dogs compared to nonbypass dogs, indicating that alcohol dehydrogenase was comparatively abundant, while glucuronyl transferase was present in small amounts in extrahepatic organs as compared to the liver. These findings demonstrate the significance of extrahepatic mechanisms in the metabolism of chloral hydrate. [R70] *Chloral hydrate (CH) and its metabolites, trichloroacetate (TCA) and dichloroacetate (DCA) have been shown to induce liver tumors in male B6C3F1 mice. The pharmacokinetics of CH and its metabolites play an important role in its toxicity. /This experiment/ was designed to characterize the kinetics of CH metabolism, and the formation and elimination of TCA, DCA, trichloroethanol (TCOH) and trichloroethanol glucuronide (TCOG) in male B6C3F1 mice. Mice were dosed with 67.8, 678, 2034 umol/kg of CH through the tail vein. At selected time points, mice were /sacrificed/ and blood and liver samples were collected. Samples were assayed by GC for CH, TCOH, TCOG, TCA and DCA concn. After iv admin, CH rapidly disappeared from blood with a terminal half-life ranging from 5 to 24 min. Systemic clearance decr from 36.0 to 7.6 l/kg/hr with incr CH dose, demonstrating dose dependent pharmacokinetics. TCOH, TCOG TCA, and DCA were detected over the study period. Formation and metabolism of CH metabolites seemed to be dose dependent. The terminal half-lives of TCOH and TCOG were similar, ranging from 0.2 to 0.7 hr. TCA and DCA were formed rapidly from the metabolism of CH and cleared slowly from systemic circulation. The area under the blood concn time curve for DCA was 10-20% of that for TCA. Both TCA and DCA were slowly eliminated from systemic circulation. The concn time profile of DCA seemed to be driven by blood concn of TCA, suggesting the possibility of DCA from TCA metabolism. [R67] BHL: *The plasma half-life for therapeutic doses of chloral hydrate is 4 to 5 min, whereas for trichloroethanol /a metabolite/ is 8 to 12 hr and for trichloroacetic acid /a metabolite/, 67 hr. [R33, 586] *Chloral hydrate (CH) and its metabolites, trichloroacetate (TCA) and dichloroacetate (DCA) have been shown to induce liver tumors in male B6C3F1 mice. The pharmacokinetics of CH and its metabolites play an important role in its toxicity. /This experiment/ was designed to characterize the kinetics of CH metabolism, and the formation and elimination of TCA, DCA, trichloroethanol (TCOH) and trichloroethanol glucuronide (TCOG) in male B6C3F1 mice. Mice were dosed with 67.8, 678, 2034 umol/kg of CH through the tail vein. At selected time points, mice were /sacrificed/ and blood and liver samples were collected. Samples were assayed by GC for CH, TCOH, TCOG, TCA and DCA concn. After iv admin, CH rapidly disappeared from blood with a terminal half-life ranging from 5 to 24 min. Systemic clearance decr from 36.0 to 7.6 l/kg/hr with incr CH dose, demonstrating dose dependent pharmacokinetics. TCOH, TCOG TCA, and DCA were detected over the study period. Formation and metabolism of CH metabolites seemed to be dose dependent. The terminal half-lives of TCOH and TCOG were similar, ranging from 0.2 to 0.7 hr. ... [R67] ACTN: *CHLORAL HYDRATE HAS CNS DEPRESSANT EFFECTS ... MECHANISM OF ACTION OF DRUG IS NOT COMPLETELY KNOWN. CNS DEPRESSANT EFFECT ... IS BELIEVED TO RESULT MAINLY FROM ITS METABOLITE, TRICHLOROETHANOL, ALTHOUGH SOME ANIMAL STUDIES HAVE INDICATED THAT THE RAPID ONSET OF SEDATION AND HYPNOSIS THAT CHLORAL HYDRATE PRODUCES MAY BE DUE TO CHLORAL HYDRATE ITSELF AND THAT THE PROLONGED DURATION OF ACTION MAY BE DUE TO TRICHLOROETHANOL. [R5, 2097] INTC: *THE CONCURRENT INGESTION OF CHLORAL HYDRATE AND ALCOHOL CAUSES TWO CLINICALLY IMPORTANT INTERACTIONS. ONE IS AN ALLEGED ENHANCEMENT OF THE CNS DEPRESSANT EFFECTS OF CHLORAL HYDRATE AND ALCOHOL; THE OTHER IS A PROFOUND VASODILATION. [R71] *CHLORAL HYDRATE APPEARS TO BOTH INHIBIT AND ENHANCE METABOLISM OF SOME DRUGS IN MAN. IT MAY ... POTENTIATE OR ANTAGONIZE ORAL ANTICOAGULANTS ... CHLORAL HYDRATE ACCELERATES BIOTRANSFORMATION OF AMITRIPTYLINE. [R72, 362] *... COMBINATION OF CHLORAL HYDRATE AND FUROSEMIDE IN SOME PERSONS MAY CAUSE VASODILATATION AND FLUSHING, TACHYCARDIA, HYPOTENSION OR HYPERTENSION, AND SWEATING, WHICH THEY ATTRIBUTE TO DISPLACEMENT OF THYROXINE FROM BINDING PROTEINS. [R72, 362] *SYNERGISTIC EFFECT OF CHLORAL HYDRATE AND ETHANOL MAY BE DUE TO THEIR COUPLED REDOX REACTION IN THE ALCOHOLIC DEHYDROGENASE MEDIATED ENZYMATIC PROCESS. [R73] *Concurrent administration of chloral hydrate and warfarin has an unpredictable effect on the activity of coumarin and may result in excessive hypoprothrombinemia. [R33, 587] *There is a popular belief that chloral hydrate and ethanol in combination (the 'Mickey Finn') are supra-additive: experimental studies in several species have confirmed the existence of an interaction between these drugs. Its basis is ... inhibition of the metabolism of ethanol by chloral and enhancement of the generation of trichloroethanol by ethanol, in addition to the combined depressant effect of the two drugs. [R74, 365] *The liver alcohol dehydrogenase inhibitors, pyrazole and 4-methylpyrazole, have been tested for their ability to prolong drug-induced sleep times in mice. Both drugs (at 1 mmol/kg ip) prolonged the duration of loss of righting reflex following chloral hydrate. [R75] *In female mice, a synergistic relationship is illustrated with the loss of righting reflex after combinations of ethanol and chloral hydrate. [R76] *The first known pediatric case describing the interaction between intravenous iv furosemide and chloral hydrate in an 8 yr old boy with a history of Hodgkin's lymphoma who received 5 doses of 10 or 20 mg of iv furosemide between 5.25 and 22.25 hr after being given 3 different doses of oral chloral hydrate is presented. The patient was being treated for respiratory distress syndrome and had been receiving one g chloral hydrate for more than a month for night sedation. When he developed acute pulmonary edema, therapy with iv furosemide was initiated. Within 5 min of receiving each dose of furosemide, the patient experienced diaphoresis, facial flushing, moderate to severe agitation, tachycardia, and generalized feelings of warmth. The reactions abated after 15-20 min. When the drug interaction was recognized, the chloral hydrate was discontinued. An iv dose of furosemide given 50 hr after the final dose of chloral hydrate did not result in any reaction. [R77] *Maintaining rats under chloral hydrate anesthesia for the first 3 hr following the administration of 3,4-methylenedioxymethamphetamine blocks the decrease in forebrain concn of 5-hydroxytryptamine measured 1 week later. In contrast, the acute effect of 3,4-methylenedioxymethamphetamine (3 hr) on forebrai 5-hydroxytryptamine was not altered by the anesthetic. This protective effect of chloral hydrate was not due to an anesthetic-induced hypothermia but may be related to the hypothesized role of dopamine in the neurotoxic effects of 3,4-methylenedioxymethamphetamine. [R78] *The liver alcohol dehydrogenase inhibitors, pyrazole and 4-methylpyrazole, have been tested for their ability to prolong drug induced sleep times in mice. Both drugs (at 1 mmol/kg ip) prolonged the duration of loss of righting reflex following chloral hydrate, pentobarbitone, barbitone, temazepam and halothane, but not diethyl ether. This suggests that the effects of these pyrazoles are not specific to the inhibition of liver alcohol dehydrogenase. [R75] *... /Researchers/ reported a fatal hemorrhage in a patient who had received chloral hydrate and bishydroxycoumarin in combination without ill effect. ... It was later shown that chloral hydrate stimulates the metabolism of this anticoagulant. [R79] *Prolonged concurrent use /with other addictive medications especially CNS depressants with habituating potential/ may increase the risk of habituation; caution is recommended. [R80, 835] *Concurrent use /with alcohol or other CNS depression-producing medications/ may increase the CNS depressant effect of either these medications or chloral hydrate; caution is recommended and dosage of one or both agents should be reduced. [R80, 835] *Hypoprothrombinemic effects may be increased when these medications /coumarin- or indandione-derivative anticoagulants/ are used concurrently with chloral hydrate, particularly during the first 2 weeks of concurrent therapy, because of displacement of the anticoagulant from its plasma protein binding sites; with continued concurrent use, anticoagulant activity may return to baseline level or be decreased; frequent prothrombin-time determinations may be required, especially during initiation of chloral hydrate therapy, to determine if dosage adjustment of the anticoagulant is necessary. [R80, 835] *Administration of chloral hydrate followed by intravenous furosemide within 24 hours may result in diaphoresis, hot flashes, and variable blood pressure, including hypertension, due to a hypermetabolic state caused by displacement of thyroxine from its bound state. [R80, 835] *Several studies indicated that chloral hydrate can prolong the disappearance time of ethanol from the blood in mice. ... /It may result/ from inhibition of the enzyme alcohol dehydrogenase by chloral hydrate and trichloroethanol, its main metabolite. ... The effects of these two cmpd ... on the disappearance time of methanol in mice /was examined/. Also, the effect of a combination of ethanol and chloral hydrate on the disappearance time of methanol was /determined/. Several groups of six mice each received methanol (1 g/kg ip) followed immediately by one of the following treatments: saline (10 ml/kg); chloral hydrate (0.4 g/kg); trichloroethanol (0.36 g/kg); ethanol (4 g/kg); or a combination of chloral hydrate (0.2 g/kg) and ethanol (4 g/kg). The concn of methanol in blood were measured at 1,2, 4 and 8 hr after its admin. ... Results show that all the above treatments do prolong the disappearance time of methanol in the blood of mice to varying extents. The ethanol chloral hydrate combination produced the nost pronounced effect. [R81] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The lethal oral dose of chloral hydrate in adults is about 10 g; however, ingestion of 4 g has caused death, and some patients have survived ingestion of as much as 30 g. [R12, 1362] *Lethal doses /of chloral hydrate/ are between 5 and 10 g. [R9] THER: *Sedatives, Nonbarbiturate; Anesthetics, Intravenous [R82] *Chloral hydrate also has been used as an adjunct to opiates and analgesics in postoperative care and control of pain. However, it generally has been replaced by agents with better pharmacokinetic and pharmacodynamic profiles. /Included in US product labeling/ [R80, 834] *Chloral hydrate has been used as a routine sedative. However, it generally has been replaced by safer and more effective agents. /Included in US product labeling/ [R80, 834] *Chloral hydrate has been used for the treatment of insomnia. However, this medication is effective as a hypnotic only for short-term use; it has been shown to lose its effectiveness for both inducing and maintaining sleep after 2 weeks of administration. In addition, chloral hydrate generally has been replaced by agents with better pharmacokinetic and pharmacodynamic profiles. /Included in US product labeling/ [R80, 834] *Chloral hydrate is used to produce sedation in pediatric patients for certain dental and medical procedures. /NOT included in US product labeling/ [R80, 834] *Chloral hydrate is indicated preoperatively to relieve anxiety and produce sedation and/or sleep. /Included in US product labeling/ [R80, 834] *... MAY BE ESP USEFUL IN ELDERLY PATIENTS WHO TEND TO BECOME AGITATED WITH BARBITURATES AND AS A HYPNOTIC FOR INFANTS AND CHILDREN. [R83] *... /USED/ FOR NOCTURNAL AND PREOPERATIVE SEDATION. [R84] *CHLORAL HYDRATE IS A RELATIVELY SAFE, RAPIDLY EFFECTIVE, RELIABLE SEDATIVE AND HYPNOTIC AGENT FOR SHORT-TERM USE. ... THE UNPLEASANT TASTE AND ODOR OF CHLORAL HYDRATE CAN BE MINIMIZED BY THE USE OF CHILLED VEHICLES, CAPSULE FORM OR RECTAL ADMINISTRATION. [R34] *CHLORAL HYDRATE HAS LITTLE ANALGESIC ACTIVITY, AND EXCITEMENT OR DELIRIUM MAY OCCUR IN THE PRESENCE OF PAIN. IT IS EFFECTIVE AGAINST EXPERIMENTALLY INDUCED CONVULSIONS PRODUCED BY STRYCHNINE, PENTYLENETETRAZOL, AND ELECTROSHOCK AND HAS BEEN USED IN THE TREATMENT OF ECLAMPSIA AND TETANUS ... [R72, 361] *MEDICATION (VET): HYPNOTIC, ANESTHETIC, SEDATIVE, ANTIKETOTIC. ... AS LIGHT SEDATIVE, FOR ITS CEREBRAL EFFECTS IN EASING PAIN IN EQUINE COLICS, OR TO EASE HANDLING OF NERVOUS CATTLE, AND AFTER PROLAPSE OF VAGINA OR UTERUS, OR AS BASAL ... /CNS DEPRESSANT/ PRIOR TO ANESTHESIA FOR CATTLE AND HORSES ... AND IN ACETONEMIAS /KETONEMIA/ ... OF CATTLE. [R85] *MEDICATION (VET): ... TOPICALLY FOR ITS COMBINED ANESTHETIC, ANTISEPTIC, AND IRRITANT EFFECTS ... . [R85] *Vet: In the dog a 30% solution of chloral hydrate given iv in a dose of 300 mg/kg produces anesthesia for 60-85 minutes ... . [R46, 233] *Although chloral hydrate sedation has been proposed as an alternative to evaluation under anesthesia for pediatric patients who are unable to cooperate with routine test procedures, a careful study of the drug's safety and effectiveness is lacking. This study reports the effectiveness and safety of high-dose chloral hydrate forophthalmic examination in 302 patients between the ages of 1 month and 5 yr. The patients had nothing to eat or drink for 4 hr prior to drug administration. The patients were monitored during sedation and until fully awake. 88% of the patients (266/302) were successfully sedated without a supplemental dose. There were no reports of any complications including emesis, respiratory distress or depression, behavioral problems, changes in vital signs, patient injury, or hospital admission. The high-dose chloral hydrate protocol described, results in safe and generally successful sedation of pediatric patients for ophthalmic examination. [R86] *Chloral hydrate is frequently used to sedate infants for lung function testing. While no effect on respiratory function has been demonstrated, a recent study has reported a fall in oxygen saturation following sedation in wheezy infants. This study was designed to assess the effects of the closely related but less gastrically irritant drug triclofos sodium on respiratory rate, heart rate, and oxygen saturation in infants without cardiopulmonary disease. Paired measurements using respiratory inductance plethysmography and pulse oximetry were obtained in 10 infants (4-19 mo of age) during natural and sedated sleep. Following sedation with triclofos, mean respiratory rate rose by 1.9 breaths/mi (95% confidence intervals of the mean difference: 0.13-3.7/min). Mean heart rate rose by 5.5 beats/min (95% confidence interval: -0.9-11.9/min). Mean oxygen saturation fell by 0.68% (95% confidence interval -1.8-0.45%). None of these changes are considered to be of clinical importance, and only the change in respiratory rate reached statistical significance at the 5% level. [R87] *Five adult patients were admitted to the neurological department in a state of status epilepticus. All were treated unsuccessfully with iv diazepam and diphenylhydantoin. Administration of sodium valporate or phenobarbital also was ineffective. However, after treatment with intrarectal chloral hydrate, all seizures ceased. The excellent effect of this drug was proved both clinically and electrodiagnostically. Discussed is the possibility of using chloral hydrate to treat patients with status epilepticus in whom conventional treatment has failed. [R88] WARN: *THE MARGIN OF SAFETY IS TOO NARROW TO PERMIT THE DRUG TO BE USED AS A GENERAL ANESTHETIC AGENT. ... IN THERAPEUTIC DOSES, CHLORAL HYDRATE HAS LITTLE EFFECT ON RESPIRATION AND BLOOD PRESSURE. TOXIC DOSES PRODUCE SEVERE RESP DEPRESSION AND HYPOTENSION. ... CHLORAL HYDRATE IS CONTRAINDICATED IN PATIENTS WITH MARKED HEPATIC OR RENAL IMPAIRMENT, AND IT SHOULD PERHAPS BE AVOIDED IN PATIENTS WITH SEVERE CARDIAC DISEASE. IF GASTRITIS IS PRESENT, THE DRUG SHOULD NOT BE GIVEN ORALLY BUT MAY BE ADMIN IN OLIVE OIL AS A RETENTION ENEMA. [R74, 364] *CHLORAL DERIVATIVES PROBABLY SHOULD BE AVOIDED IN PATIENTS WITH INTERMITTENT PORPHYRIA. /CHLORAL DERIVATIVES/ [R72, 362] *PATIENT SHOULD BE WARNED THAT CHLORAL HYDRATE MAY IMPAIR ABILITY TO PERFORM HAZARDOUS ACTIVITIES REQUIRING MENTAL ALERTNESS OR PHYSICAL COORDINATION ... CHLORAL HYDRATE SHOULD BE USED CAUTIOUSLY IN PATIENTS WHO ARE MENTALLY DEPRESSED, HAVE SUICIDAL TENDENCIES OR HISTORY OF DRUG ABUSE. ... THE DRUG IS CONTRAINDICATED IN PATIENTS WITH MARKED HEPATIC OR RENAL IMPAIRMENT AND IN PATIENTS WHO HAVE PREVIOUSLY DEMONSTRATED HYPERSENSITIVITY OR AN IDIOSYNCRATIC REACTION TO DRUG. ORAL ADMIN OF CHLORAL HYDRATE SHOULD BE AVOIDED IN PATIENTS WITH ESOPHAGITIS, GASTRITIS, OR GASTRIC OR DUODENAL ULCERS. [R12, 1362] *Chloral hydrate should be admin during pregnancy only when clearly needed, since the drug crosses the placenta and the effects of the drug on the fetus are unknown. [R12, 1362] *Prolonged use of chloral hydrate may produce tolerance and physical and/or psychologic dependence. ... Fatalities resulting from overdosage have occurred in patients physically dependent on chloral hydrate. ... Sudden withdrawal of the drug from physically dependent persons may cause delirium tremens (sometimes fatal) and hallucinations, and for this reason, patients should be hospitalized and the drug withdrawn slowly. [R12, 1362] */Chloral hydrate/ can displace protein bound drugs often used by geriatric patients. *Maternal Medication usually Compatible with Breast-Feeding: Chloral Hydrate: Reported Sign or Symptom in Infant or Effect on Lactation: Sleepiness. /from Table 6/ [R89] *Chloral hydrate is not recommended for use in infants and children when repetitive dosing would be necessary. With repeated dosing, accumulation of the trichloroethanol and trichloroacetic acid metabolites may increase the potential for excessive CNS depression, predispose neonates to conjugated and nonconjugated hyperbilirubinemia, decrease albumin binding of bilirubin, and contribute to metabolic acidosis. [R80, 834] *Prolonged use of larger than usual therapeutic doses may result in psychic or physical dependence. [R80, 836] *Gastric irritation manifested by nausea, vomiting, and diarrhea is the most frequent adverse effect of oral chloral hydrate administration. Gastric irritation may be minimized by diluting the oral solution with water or other liquid or administering other oral dosage forms with liquids. Flatulence and unpleasant taste may also occur. [R5, 2097] *Residual sedation or hangover occurs infrequently following usual hypnotic doses of chloral hydrate. Occasionally, patients may become somnambulistic and may be disoriented and incoherent and exhibit paranoid behavior. Rarely, excitement, delirium, drowsiness, staggering gait, ataxia, lightheadedness, vertigo, dizziness, headache, nightmares, mental confusion, hallucinations, and malaise have occurred. [R5, 2097] *Cutaneous reactions to chloral hydrate are not common but have included scarlatiniform or erythematous rash, urticaria, angioedema, prupura, eczema, bullous lesions, and erythema multiforme. Sometimes cutaneous reactions have been accompanied by fever. [R80, 2097] *... IRRITANT ACTIONS /OF CHLORAL HYDRATE/ GIVE RISE TO AN UNPLEASANT TASTE, EPIGASTRIC DISTRESS, NAUSEA, AND OCCASIONAL VOMITING ... UNDESIRABLE CNS EFFECTS INCLUDE LIGHTHEADEDNESS, MALAISE, ATAXIA, AND NIGHTMARES. "HANGOVER" ALSO MAY OCCUR ... [R3] *SUDDEN WITHDRAWAL FROM THE HABITUAL USE OF CHLORAL HYDRATE MAY RESULT IN DELIRIUM AND SEIZURES, WITH A HIGH FREQUENCY OF DEATH WHEN UNTREATED. [R3] *Symptoms of chloral hydrate dependence are similar to those of chronic alcoholism and include drowsiness, lethargy, hangover, slurring of speech, incoordination, tremulousness, and nystagmus. [R5, 2098] *Chloral hydrate is commonly used for neonatal sedation, but blood levels are infrequently monitored, reflecting an under emphasis of acute toxic effects. This report describes a case of chloral hydrate toxicity in a term infant with cardiac, renal, neurologic, bladder and gastrointestinal dysfunction. The effects of exchange transfusion are described as well as pharmacokinetics. [R90] *Most sedative-hypnotic drugs (including ... chloral hydrate) produce physical and psychological dependence when taken in 3-10 times the sedative dose for 1-2 months. [R63, 685] *Chloral hydrate produces 1 to 2 hours of light anesthesia, with minimal effects on the cardiovascular system and on baroreceptor reflexes. It produces poor analgesia, and the higher doses required for surgery produce severe respiratory depression. [R91] */Chloral hydrate/ can displace protein bound drugs often used by geriatric patients. [R66, 225] *Chloral hydrate is commonly used to sedate children for diagnostic or therapeutic procedures. This drug has been /widely/ used for many years and there are remarkably few data on its long term health effects. ... Recent studies have shown that chloral hydrate is genotoxic, causing chromosome changes and other effects in vivo and in vitro. ... Chloral hydrate is a reactive metabolite of trichloroethylene, a known carcinogen. Two carcinogenicity studies using the oral route of admin in mice indicate the drug is potentially carcinogenic and in one /study/ after a single dose lower than the typical dose used for sedation. Practitioners should be aware of chloral hydrate's genotoxicity and potential carcinogenicity. ... [R92] IDIO: *RARELY, PATIENTS EXHIBIT IDIOSYNCRATIC REACTIONS TO CHLORAL HYDRATE AND MAY BE DISORIENTED AND INCOHERENT AND SHOW PARANOID BEHAVIOR. [R3] TOLR: *Tolerance may develop by the second wk of continual therapy. [R80, 836] *High-dose long-term use results in tolerance and physical dependence. Sudden withdrawal results in a serious abstinence syndrome similar to delirium tremens (seizures and psychosis) and responds to barbiturates or other sedative-hypnotic drugs. [R63, 695] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ MILK: *Chloral hydrate has been detected in /human/ ... milk ... . [R10, 836] *Chloral hydrate and its metabolite, trichloroethanol reached 50-100% /in breast milk/ of maternal blood levels in most of 50 women given 1.3 g rectally. Drug and metabolites were detectable for up to 24 hr; the maximum dose that an infant could have received approximates a sedative dose. In another study, drowsiness was noted in 1 infant the morning after a bedtime hypnotic dose of a chloral hydrate derivative in the mother. [R66, 174] *Following therapeutic doses of chloral hydrate, only small, clinically insignificant amt of the active metabolite are distributed into milk. [R12, 1361] BODY: *Chloral hydrate has been detected in /human/ ... milk ... . [R10, 836] *Chloral hydrate and its metabolite, trichloroethanol reached 50-100% /in breast milk/ of maternal blood levels in most of 50 women given 1.3 g rectally. [R66, 174] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 60 ug/l [R93] FDA: *Trichloroacetaldehyde hydrate is a chemical derivative of chloral, named in section 502(d) of the Federal Food, Drug, and Cosmetic Act and is hereby designated as habit forming. [R94] *Warning and caution statements for chloral hydrate are specifically required by law. PREPARATIONS CONTAINING HABIT-FORMING DERIVATIVES OF SUBSTANCES NAMED IN SECTION 502(d) OF THE FEDERAL FOOD, DRUG, AND COSMETIC ACT ... The statement "Warning-May be habit forming" is required to appear on the labels of all drugs containing derivatives designated in 21 CFR 329.1 ... as habit forming. [R95] *Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule IV(c) includes the depressant chloral hydrate, its salts, isomers and salts of isomers. DEA Code #2465. [R96] *Chloral hydrate is an indirect food additive for use only as a component of adhesives. [R97] *Animal drug specifications: Chloral hydrate, pentobarbital, and magnesium sulfate sterile aq soln contains 42.5 mg of chloral hydrate, 8.86 mg of pentobarbital and 21.2 mg of magnesium sulfate in each ml of sterile aq soln containing water, 33.8% propylene glycol, and 14.25% ethyl alcohol ... Conditions of use: ... For general anesthesia and as a sedative-relaxant in cattle and horses ... For intravenous use only: The drug is administered at a dosage level of 20 to 50 ml per 100 lb of body wt for general anesthesia until the desired effect is produced. Cattle usually require a lower dosage on the basis of body wt. When used as a sedative-relaxant, it is administered at a level of one-fourth to one-half of the anesthetic dosage level. Federal law restricts this drug to use by or on the order of a licensed veterinarian. [R98] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R99] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Chloral hydrate in drugs: Spectrophotometric method. Quinaldine ethyl iodide reacts with chloral hydrate to produce stable blue cyanine dye with A max at about 605 nm. Other polychlorinated compounds do not interfere. [R100] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R101] *OSW Method 8240B-S. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R101] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R101] *OSW Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R101] *EPA Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. Detection limit= 0.050 mg/kg. [R102] CLAB: *SPECTROPHOTOMETRIC METHOD FOR ANALYSIS OF BLOOD AND URINE HAS BEEN USED TO QUANTIFY TRICHLOROETHANOL IN FATAL CHLORAL HYDRATE POISONINGS. A 4 ML BLOOD SAMPLE IS EXTRACTED AT THE PH OF THE BLOOD WITH ETHER. A REACTION PRODUCT IS FORMED DURING HEATING OF THE ETHER PHASE WITH PYRIDINE AND SODIUM HYDROXIDE. A SPECTRUM OF THE REACTION PRODUCT HAS MAXIMA AT 368 AND 530 NM. 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V63 252 (1995) R57: Chen HT, Kandasamy SB; Neurochem Res 21 (6): 695-700 (1996) R58: Allen JW, et al; Mutat Res 323 (1-2): 81-8 (1994) R59: Eichenlaub-Ritter U, Betzendahl I; Mutagenesis 10 (6): 477-86 (1995) R60: Leuschner J, Leuschner F; Arznemittelforschung 41 (10): 1101-3 (1991) R61: Ni YC, et al; Biochem Biophys Res Commun 204 (2): 937-43 (1994) R62: Toxicology and Carcinogenesis Studies of Chloral hydrate in B6C3F1 Mice p.8-9 Technical Report Series No. 502 (2002) NIH Publication No. 02-4436 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R63: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R64: Baselt, R.C. Biological Monitoring Methods for Industrial Chemicals. 2nd ed. Littleton, MA: PSG Publishing Co., Inc. 1988. 290 R65: Hobara T et al; Toxicology 48 (2): 141-53 (1988) R66: Knoben, J.E. and P.O. Anderson (eds.) Handbook of Clinical Drug Data. 6th ed. Bethesda, MD: Drug Intelligence Publications, Inc. 1988. R67: Abbas RR, et al; Drug Metab Dispos 24 (12): 1340-6 (1996) R68: Kawamoto T et al; Toxicol Lett 40 (3): 225-31 (1988) R69: Ogino K et al; Bull Environ Contam Toxicol 44 (3): 377-9 (1990) R70: Hobara T et al; Pharmacol Toxicol 61 (1): 58-62 (1987) R71: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. 21 R72: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. R73: WONG LK, BIEMANN K; BIOCHEM PHARMACOL 27 (7): 1019-22 (1978) R74: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R75: Taberner PV, Unwin JW; J Pharm Pharmacol 39 (8): 658-9 (1987) R76: Gennings C et al; J Pharmacol Exp Ther 252 (1): 208-17 (1990) R77: Dean RP et al; Clin Pharm 10 (May): 385-7 (1991) R78: Schmidt CJ et al; Eur J Pharmacol 191 (2): 213-6 (1990) R79: Hayes, W.J., Jr., E.R. Laws Jr., (eds.). Handbook of Pesticide Toxicology Volume 1. General Principles. New York, NY: Academic Press, Inc., 1991. 71 R80: USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc. R81: Faci A, et al; Toxicol 131 (1): 1-7 (1998) R82: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R83: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 404 R84: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1004 R85: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 93 R86: Fox BE et al; J Pediatr Ophthalmol Strabismus 27 (5): 242-4 (1990) R87: Jackson EA et al; Pediatr Pulmonol 10 (1): 40-5 (1991) R88: Lampl Y et al; Ann Emerg Med 19 (6): 674-6 (1990) R89: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 140 (1994) R90: Anyebuno MA, Rosenfeld CR; Dev Pharmacol Ther 17 (1-2): 116-20 (1991) R91: Rice, S.A., K.J. Fish. Anesthetic Toxicity. New York, NY: Raven Press, Ltd., 1994. 25 R92: Salmon AG, et al; J Toxicol Clin Toxicol 33 (2): 115-21 (1995) R93: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R94: 21 CFR 329.1 (4/1/98) R95: 21 CFR 369.22 (4/1/98) R96: 21 CFR 1308.14 (4/1/98) R97: 21 CFR 175.105 (4/1/98) R98: 21 CFR 522.380 (4/1/98) R99: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R100: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. VI 562 R101: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R102: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R103: MCBAY AJ ET AL; J ANAL TOXICOL 4 (2): 99-101 (1980) R104: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 87 Record 48 of 1119 in HSDB (through 2003/06) AN: 230 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACETALDEHYDE- SY: *ACETIC-ALDEHYDE-; *Pesticide-Code:-202300-; *ETHANAL-; *ETHYL-ALDEHYDE- RN: 75-07-0 RELT: 40 [ACETIC ACID] (Metabolite); 190 [VINYL ACETATE] (Metabolic Precursor); 82 [ETHANOL] (Metabolic Precursor) MF: *C2-H4-O SHPN: UN 1089; Acetaldehyde IMO 3.1; Acetaldehyde STCC: 49 072 10; Acetaldehyde HAZN: U001; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The economics of various processes for mfr of acetaldehyde are strongly dependent on the price of the feedstock used. Since 1960, the liquid-phase oxidation of ethylene has been the process of choice. ... There is still commercial production by the partial oxidation of ethyl alcohol and hydration of acetylene. Acetaldehyde is also formed as a coproduct in the high temp oxidation of butane. A recently developed rhodium catalyzed process produces acetaldehyde from synthesis gas as a coproduct with ethyl alcohol and acetic acid. [R1, 100] *... The catalyst is an aqueous solution of lead chloride (PbCl2) and copper chloride (CuCl2). ... There are two variations for the production of acetaldehyde by the oxidation of ethylene; the two-stage process developed by Wacker-Chemie and the one-stage process developed by Farbwerke Hoechst. ... [R1, 101] *(1) Oxidation of ethylene, (2) vapor-phase oxidation of ethanol, (3) vapor-phase oxidation of propane and butane, (4) catalytic reaction of acetylene and water (chiefly in Germany) [R2] *(1) ethylene (Wacker oxidation process); (2) ethanol (catalytic dehydrogenation); (3) ethanol + oxygen (oxidation); (4) acetylene + water (vinylation); (5) oxygenates, Fischer-Tropsch, mixed (fractionation; coproduced with methanol/ethanol/isopropanol/n-butanol/isobutanol/amyl alcohol, primary/acetone/methyl ethyl ketone) [R3] FORM: *GRADES: COMMERCIALLY AVAIL AS 50% AQ SOLN OR 99% CP IN SMALL STEEL CYLINDERS. [R4] *Acetaldehyde is avail in USA with following typical specifications: purity, 99.5% min; acidity (as acetic acid), 0.1% max ... to meet the requirements of the Food Chemical Codex, acetaldehyde must pass an infrared identification test and meet the following specifications: purity, 99.0% min; acidity (as acetic acid) 0.1% max; non-volatile residue, 0.006% max ... . [R5] *99.5% grade [R6] MFS: *Eastman Chemical Co., P.O. Box 511, Kingsport, TN 37662, (423) 229-2196; Production site: Longview, TX 75607 [R7, 435] *Aldrich Chemical Co., Inc., 1001 West St. Paul Ave., Milwaukee, WI 53233, (800) 558-9160; Production site: not specified /Natural/ [R7, 613] *Penta Manufacturing Co., 50 Okner Parkway, Livingston, NJ 07039-1604, (973) 740-2300; Production site: Fairfield, NJ 07006 /Natural/ [R7, 613] OMIN: *FORMED DURING NATURAL ALCOHOLIC FERMENTATION PROCESS. RECOVERY IS EFFECTED BY SUITABLE FRACTIONATION, SUBSEQUENT PREPN OF ACETALDEHYDE AMMONIA, AND FINAL TREATMENT OF ADDITION CMPD WITH DIL SULFURIC ACID. [R4] *Acetaldehyde is produced by 3 companies in Germany, 2 companies in Spain and 1 company each in France, Italy, AND Switzerland. Total acetaldehyde production in western Europe on January 1, 1983 was more than 0.5 million tons, and production capacity is estimated to have been nearly 1 million tons. Most of this was based on the catalytic oxidation of ethylene; less than 10% was based on partial oxidation of ethanol, and a very small percentage was based on the hydration of acetylene. ... /It/ is produced (by oxidation of ethylene) by 7 companies in Japan. Their combined production is est to have been 278,000 tons in 1982, down from an est 323,000 tons in 1981. Japanese imports and exports of acetaldehyde are negligible. [R8] *Ethylene is the raw material for all acetaldehyde produced in the U.S. [R9] *In 1989, it was estimated that ... 98% of the worlds ... plant capacity used the Wacker-Hoechst process for the direct oxidation of ethylene. [R1, 94] USE: *For Acetaldehyde (USEPA/OPP Pesticide Code: 202300) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R10] *SYNTHETIC FLAVOR AND ADJUVANT [R11] *MFR SYNTHETIC RESINS, DYES [R12, 686] *Mfr paraldehyde, acetic acid, butanol, perfumes, aniline dyes, plastics, synthetic rubber, silvering mirrors, hardening gelatin fibers. [R13] *SYNTHETIC FLAVOR INGREDIENT USEFUL IN ALL FRUITS FOR LIFT; ESPECIALLY ORANGE, APPLE, AND BUTTER. [R14] *CHEM INT FOR PYRIDINE AND PYRIDINE BASES [R15] *CHEM INT FOR PENTAERYTHRITOL AND 1,3-BUTYLENE GLYCOL [R15] *CHEM INT FOR CHLORAL AND GLYOXAL [R15] *MONOMER FOR POLYACETALDEHYDE AND COMONOMER FOR COPOLYMERS [R15] *ALCOHOL DENATURANT [R15] *OXIDN PROMOTER IN MFR OF TEREPHTHALIC ACID [R15] *Intermediate for pesticides and photographic formulations. [R16] *Chemical intermediate for ester production, particularly ethyl acetate and isobutyl acetate. Other significant derivatives of acetaldehyde include ... lactic acid. [R17] *Manufacture of acetic acid and acetic anhydride, n-butanol, 2-ethylhexanol, peracetic acid, aldol, pentaaerythritol, pyridines, chloral, 1,3-butylene glycol, and trimethylolpropane; synthetic flavors. [R2] *Currently an important intermediate in the production of acetic acid, acetic anhydride, ethyl acetate, peracetic acid, pentaerythritol, chloral, glyococal, alkylamines, and pyridines. [R1, 94] *Used as an intermediate in the production of cellulose acetate, vinyl acetate resins, acetate esters, synthetic pyridine derivatives, and terephthalic acid. Other uses include: in the silvering of mirrors; in leather tanning, as a denaturant for alcohol; in fuel mixtures; as a hardener for gelatin fibers; in glue and casein products; as a preservative for fish and fruit; in the paper industry; as a synthetic flavoring agent; and in the manufacture of cosmetics. [R18] CPAT: *CHEM INT FOR ACETIC ACID, 61%; CHEM INT FOR PYRIDINE AND PYRIDINE BASES, 9%; CHEM INT FOR PERACETIC ACID, 8%; CHEM INT FOR PENTAERYTHRITOL, 7%; CHEM INT FOR 1,3-BUTYLENE GLYCOL, 2%; CHEM INT FOR CHLORAL, 1%; OTHER USES (INCL EXPORTS), 12% (1982) [R15] *USA acetaldehyde demand in 1978 was 1.30 billion lb; 1979, 1.35 billion lb; 1983, 1.58 billion lb. [R19] *Acetic acid, 50%; exports, 14%; miscellaneous including lactic acid and croton aldehyde, 13%; pyridine and pyridine bases, 8%; pentaerythritol, 7%; peracetic acid, 6%; 1,3-butyleneglycol, 2% (1986). [R20] *A survey of USA industry on the use of food additives reported that 8.6 thousand kg of acetaldehyde were used in 1976 as an important component of many flavors added to foods, such as milk products, baked goods, fruit juices, candies, desserts and soft drinks, at usual levels ... up to 0.047% (1976). [R8] *Acetaldehyde is one of the denaturants approved for use (at a level of 10 lb/100 gal (12 g/l) of alcohol) in the USA in specially denatured alcohol Formula No 29. Although the volume of this formula used in the USA each year is published, no information is available on the amount made with acetaldehyde. [R21] *Synthetic pyridine derivatives, peracetic acid, acetate esters by the Tischenko route, and pentaerythritol account for 40% of acetaldehyde demand. All of these materials may be prepared from alternative processes. [R1, 105] PRIE: U.S. PRODUCTION: *(1969) 748 kilotons; (1970) 726 kilotons; (1971) 680 kilotons; (1972) 644 kilotons; (1973) 635 kilotons; (1974) 649 kilotons; (1975) 499 kilotons; (1976) 612 kilotons; (1987) ca. 330 kilotons /Table/ [R1, 105] *(1985) 2.86X10+12 g [R17] *Annual production capacity as of Jan. 1, 1994: Eastman Chemical Company 250 miilion pounds, Hoechst Celanese Corp. 250 million pounds, Total 500 million pounds. [R9] U.S. IMPORTS: *(1985) 6.14X10+5 g [R22] U.S. EXPORTS: *(1985) 5.45X10+11 g [R17] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid or gas (above 69 degrees F) [R23, 2] ODOR: *Pungent, fruity odor [R2] TAST: *LEAFY GREEN TASTE [R14] BP: *21 deg C [R13] MP: *-123.5 deg C [R13] MW: *44.05 [R13] CTP: *Critical temperature: 188 deg C; critical pressure: 63.2 atm [R24] DEN: *0.788 @ 16 deg C/4 deg C [R13] DSC: *Ka = 0.7X10-14 @ 0 deg C [R25]; *pKa = 13.57 @ 25 deg C [R26] HTC: *-1166.37 kJ/mol @ 25 deg C (liquid) [R24] HTV: *26.11 kJ/mol @ 25 deg C [R24] SOL: *Miscible with ether, benzene [R27]; *Miscible with gasoline, solvent naphtha, toluene, xylene, turpentine, and acetone [R24]; *In water, 1X10+6 mg/l @ 25 deg C [R28] SPEC: *Index of refraction = 1.3316 @ 20 deg C [R27]; *MAX ABSORPTION (GAS): 178 NM (LOG E= 3.48); 181 NM (LOG E= 3.60); 181.5 NM (LOG E= 4.05) [R29]; *MAX ABSORPTION (CYCLOHEXANE): 290 NM (LOG E= 1.23) [R29]; *SADTLER REFERENCE NUMBER: 5824 (IR, PRISM) [R29]; *IR: 5645 (Coblentz Society Spectral Collection) [R30]; *UV: 5-4 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R30]; *NMR: 6 (Varian Associates NMR Spectra Catalogue) [R30]; *MASS: NIST 62124 (NIST/EPA/MCDC Mass Spectral Database 1990 Version); WILEY 97 (Atlas of Mass Spectral Data, John Wiley and Sons, NY) [R30] SURF: *21.2 mN/m at 20 deg C (1.0 mN/m = 1.0 dyn/cm) [R1, 95] VAPD: *1.52 (Air= 1) [R25] VAP: *902 mm Hg @ 25 deg C [R31] VISC: *0.2456 mPa.s at 15 deg C (1.0 mPa.s= 1.0 cP) [R24] OCPP: *Coefficient of expansion, 0.00169/deg C (0 to 30 deg C); latent heat of fusion, 3.24 kJ/mol; heat of solution in water, -6.82 kJ/mol at 25 deg C; dipole moment, 8.97X10-3 deg C.m [R1, 95] *One of the main products of the photooxidation of acetaldehyde /in polluted air/ is peroxyacetyl nitrate. [R32] *Heat capacity of liquid: 1.38 J/g-deg K at 20 degC; heat capacity of vapor: 1.24 J/g-deg K at 25 deg C, 101.3 kPa [R25] *Hydroxyl radical reaction rate constant = 1.58X10-11 cu cm/molc sec @ 25 deg C [R33] *Henry's Law constant = 6.67X10-5 atm cu m/mol @ 25 deg C [R34] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R35] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R35] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R35] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R35] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R35] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R35] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R35] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R35] FPOT: *Highly flammable liquid. [R36] *ACETALDEHYDE VAPOR LEAKING INTO A BUILDING EQUIPPED ONLY WITH FLAMEPROOF ELECTRICAL EQUIPMENT ... IGNITED, POSSIBLY ON CONTACT WITH RUSTED STEEL, CORRODED ALUMINUM OR HOT STEAM LINES. [R37, 270] *MIXTURES OF 30-60% OF ACETALDEHYDE VAPOR WITH AIR OR 60-80% WITH OXYGEN MAY IGNITE ON SURFACES AT 176 and 105 DEG C, RESPECTIVELY, OWING TO FORMATION AND SUBSEQUENT VIOLENT DECOMP OF PEROXYACETIC ACID. [R37, 270] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R38, p. 325-10] *Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R38, p. 325-10] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R38, p. 325-10] FLMT: *Lower flammable limit: 4.0% by volume; Upper flammable limit: 60% by volume [R38, p. 49-10] FLPT: *-38.89 deg C (Closed cup); -40 deg C (Open cup) [R39, 1991.1] AUTO: *347 deg F [R38, p. 49-10] FIRP: *Fight fire from protected location or maximum possible distance. use dry chemical, "alcohol resistant" foam, or carbon dioxide. water may be ineffective. Use water spray to keep fire exposed containers cool. [R38, p. 49-8] *If material is on fire or involved in a fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R40, 1] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame-consider evacuation of one-half (1/2) mile radius. [R40, 2] *In advanced, or massive fires, fire fighting should be done from a safe distance, or from a protected location. Use dry chemical, "alcohol" foam, or carbon dioxide. Water may be ineffective but water should be used to keep fire exposed containers cool. If leak or spill has not ignited, use water spray to disperse vapors. If it is necessary to stop a leak, use water spray to protect men attempting to do so. Water spray may be used to flush spills away from exposures and dilute to nonflammable mixtures. [R41] TOXC: *Toxic gases and vapors (such as carbon monoxide) may be released in a fire involving acetaldehyde. [R42, 1981.1] OFHZ: *Vapors are heavier than air and may travel a considerable distance to a source of ignition and flash back. [R43] EXPL: *LOWER, 4.1%; UPPER 55% BY VOLUME. [R44, 285] *ACETALDEHYDE SHOULD NOT BE ALLOWED TO ENTER A CONFINED SPACE SUCH AS A SEWER, BECAUSE OF THE POSSIBILITY OF AN EXPLOSION. [R42, 1981.4] *OXIDIZES READILY IN AIR TO FORM UNSTABLE PEROXIDES THAT MAY EXPLODE SPONTANEOUSLY. [R38, p. 49-7] REAC: *Reacts with oxidizing materials, halogens, amines, strong alkalies, and acids. [R38, p. 49-7] *OXYGENATION OF ACETALDEHYDE IN PRESENCE OF COBALT ACETATE AT -20 DEG C CAUSED PRECIPITATION OF 1-HYDROXYETHYL PEROXYACETATE (ACETALDHEYDE HEMI-PERACETATE), WHICH EXPLODED VIOLENTLY ON STIRRING. OZONE OR UV LIGHT ALSO CATALYZES THE AUTOXIDATION. [R37, 271] *Strong oxidizers, acids, bases, alcohols, ammonia and amines, phenols, ketones, HCN, H2S [Note: Prolonged contact with air may cause formation of peroxides that may explode and burst containers; easily undergoes polymerization]. [R23, 2] *Interaction /of hydrogen peroxide with acetaldehyde or desiccants/ gives the extremely explosive poly(ethylidene) peroxide, also formed on warming peroxidized diethyl ether. [R37, 1200] *Direct combination /of dinitrogen pentaoxide and acetaldehyde/ to produce ethylidene dinitrate at -196 deg C is violently explosive, but uneventful when the acetaldehyde is diluted with nitrogen. [R37, 1356] *SOME OF THE PRODUCTS OF INTERACTION OF ACETALDEHYDE AND MERCURY(II) SALTS (CHLORATE OR PERCHLORATE) ARE HIGHLY EXPLOSIVE AND EXTREMELY SHOCK-SENSITIVE. [R37, 271] *A drum contaminated with acetic acid was filled with acetaldehyde. The ensuing exothermic polymerization reaction caused a mild eruption lasting several hours. [R37, 271] *OXYGEN LEAKED INTO A FREE SPACE IN AN ACETALDEHYDE STORAGE TANK NORMALLY PURGED WITH NITROGEN. ACCELERATING EXOTHERMIC OXIDATION LED TO DETONATION. [R37, 272] DCMP: *Decomposes above 400 deg C to form ... methane and carbon monoxide. [R5] *When heated to decomposition it emits acrid smoke and fumes. [R36] POLY: *POLYMERIZATION MAY OCCUR IN PRESENCE OF ACID TRACES CAUSING EXOTHERMIC REACTION, INCREASED VESSEL PRESSURE, FIRE, AND EXPLOSION. [R45] *IMPURE MATERIAL WILL POLYMERIZE READILY IN PRESENCE OF TRACE METALS (IRON) OR ACIDS. ... ACETALDEHYDE IS POLYMERIZED VIOLENTLY BY CONC SULFURIC ACID. [R37, 271] *HAZARDOUS POLYMERIZATION MAY OCCUR. [R38, p. 49-8] ODRT: *Recognition in air= 2.1x10-1 ppm (chemically pure) [R46] *Odor low: 0.0002 mg/cu m; Odor high: 4.14 mg/cu m [R47] SERI: *Eye irritation sensitive persons: 25 ppm 15 min; eye irritation: 50 ppm 15 min; irritation of respiratory tract: 134 ppm 30 min; irritation of nose and throat: 200 ppm 15 min. [R48] EQUP: *Protective clothing should be freely available and operators instructed in its use. Chemical eye and face protection of an approved design should be mandatory in plant area, and, for maintenance work, plastic face shields should also be worn [R41] *Employees should be provided with and required to use splash-proof safety goggles where there is any possibility of this compound coming in contact with the eyes. [R42, 1981.3] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R49, 1979.8] *Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. [R42, 1981.2] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with liquid acetaldehyde. [R42, 1981.3] *Wear appropriate personal protective clothing to prevent skin contact. [R23, 3] *Wear appropriate eye protection to prevent eye contact. [R23, 3] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R23, 3] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R23, 3] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R23, 3] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R23, 3] OPRM: *Persons not wearing protective equipment and clothing should be restricted from areas of spills or leaks until cleanup has been completed. [R41] *SUITABLE PROTECTIVE CLOTHING, APRONS, HAND PROTECTION AND IMPERVIOUS FOOT PROTECTION SHOULD BE PROVIDED. WATER SHOWERS AND EYE IRRIGATION SYSTEMS SHOULD BE AVAIL ON PLANT AREA AND OPERATORS INFORMED OF THEIR LOCATION. [R50] *Contact lenses should not be worn when working with this chemical. [R23, 3] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R49, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R49, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R49, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R49, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of admin volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R49, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R49, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres for chem such as nitrosamines. Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R49, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by trained lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. ... contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R49, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R49, 1979.11] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R40, 2] *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. [R42, 1981.2] *Clothing wet with liquid acetaldehyde should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of acetaldehyde from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the acetaldehyde, the person performing the operation should be informed of acetaldehyde's hazardous properties. Any clothing which becomes wet with liquid acetaldehyde should be removed immediately and not reworn until the acetaldehyde is removed from the clothing. [R42, 1981.3] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Where there is any possibility that employee's eyes may be exposed to liquid acetaldehyde an eye-wash facility should be provided within the immediate work area for emergency use. [R42, 1981.3] *Skin that becomes wet with liquid acetaldehyde should be promptly washed or showered to remove any acetaldehyde. [R42, 1981.3] *In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R42, 1981.3] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R40, 1] *If material is not on fire or involved in a fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R40, 1] *The worker should immediately wash the skin when it becomes contaminated. [R23, 3] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R23, 3] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R51] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R52] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R53] STRG: *Store in a cool, dry, well-ventilated location. Inside storage should be in a standard liquids storage warehouse, room, or cabinet. Separate from oxidizing material and other reactive hazards. Store bulk quantities in detached tanks provided with refrigeration and inert gas cover. [R38, p. 49-8] *IT IS RECOMMENDED THAT STEEL STORAGE TANKS OF SUITABLE STD BE USED ... STORAGE VESSELS SHOULD BE FITTED WITH TEMP GAUGES AND AUTOMATIC WATER SPRAYS. ... ALL TANKS AND EQUIPMENT MUST BE EARTHED. TRANSFER OF MATERIAL BY PIPELINE MUST BE BY PRESSURE OF NITROGEN. ... DRUMS CONTAINING ACETALDEHYDE SHOULD NEVER BE STORED IN DIRECT SUNLIGHT OR OTHER WARM AREAS. [R50] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R49, 1979.13] *In transporting or storing acetaldehyde, precaution must be taken to prevent leaks and to ensure safe conditions, because this aldehyde boils at room temp. [R54] CLUP: *(1) Remove all ignition sources (2) Ventilate area to disperse gas (3) If in gaseous form, stop flow of gas (4) If in liquid form, for small quantities absorb on paper towels. Evaporate in safe place (fume hood). allow sufficient time for vapors to completely clear hood ductwork, then burn the paper in a location away from combustible materials. Large quantities can be reclaimed or collected and atomized in a suitable combustion chamber. Acetaldehyde should not be allowed to enter a confined space such as a sewer, because of possibility of an explosion. Sewers designed to preclude the formation of explosive concentration of acetaldehyde vapors are permitted. [R41] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R49, 1979.15] *Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Neutralize with sodium bisulfate (NaHSO4). [R40, 2] *Water spill: Add sodium bisulfate (NaHSO4). If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R40, 2] *Air spill: Apply water spray or mist to knock down vapors. [R40, 2] *Eliminate all ignition sources. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors, protect personnel, and dilute spills to form nonflammable mixtures. Control runoff and isolate discharged material for proper disposal. [R38, p. 49-7] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U001, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R55] *Acetaldehyde is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R56] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R57] *The following wastewater treatment technologies have been investigated for Acetaldehyde: Biological Treatment. [R58] *The following wastewater treatment technologies have been investigated for Acetaldehyde: Activated carbon. [R59] */IN LIQUID FORM/ LARGE QUANTITIES CAN BE RECLAIMED OR COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER. ... SEWERS DESIGNED TO PRECLUDE THE FORMATION OF EXPLOSIVE CONCN OF ACETALDEHYDE VAPORS ARE PERMITTED. [R42, 1981.] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R49, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": Total destruction ... by incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable ... Most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R49, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R49, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R49, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R49, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of acetaldehyde. There is sufficient evidence in experimental animals for the carcinogenicity of acetaldehyde. Overall evaluation: Acetaldehyde is possibly carcinogenic to humans (Group 2B). [R60] *A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R61] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on increased incidence of nasal tumors in male and female rats and laryngeal tumors in male and female hamsters after inhalation exposure. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R62] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Aggressive airway management may be necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aldehydes and related compounds/ [R63, p. 234-35] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Intubation should be considered at the first sign of upper airway obstruction caused by edema. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Treat seizures with diazepam ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aldehydes and related compounds/ [R63, 235] MEDS: *New employees who may be exposed to acetaldehyde should be examined prior to and periodically after beginning work with careful attention to the eyes, skin, and respiratory system. ... Chest radiographs and screening pulmonary function studies can provide useful baseline information. [R54] *The following medical procedures should be made available to each employee who is exposed to acetaldehyde at potentially hazardous levels: initial medical screening for history of certain medical conditions, ie, chronic respiratory, liver, kidney, or skin diseases which might place the employee at increased risk from acetaldehyde exposure. Periodic medical examination: any employee developing the above-listed conditions should be referred for further medical examinations. [R42, 1981.1] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R49, 1979.23] HTOX: *... /SOME/ EFFECTS /OF EXPOSURE/ ARE IRRITATION ... AND LUNG EDEMA. ... INHALATION DOES NOT CAUSE CHRONIC POISONING, AND DEATH IS DUE TO ANESTHESIA WHEN PROMPT, OR TO LUNG EDEMA WHEN DELAYED. [R64] *LARGE DOSES MAY CAUSE DEATH BY RESPIRATORY PARALYSIS. SYMPTOMS OF CHRONIC INTOXICATION RESEMBLE THOSE OF CHRONIC ALCOHOLISM. [R65] *HUMAN SUBJECTS WERE GIVEN INTRAVENOUS INFUSIONS TO RAISE BLOOD LEVEL TO 0.2 TO 0.7 MG % (ABOUT 10 TIMES NORMAL). AT THESE LEVELS AN INCREASE IN HEART RATE AND RESPIRATORY VENTILATION OCCURS, AND A SENSATION IS NOTED. [R66] *Intravenous infusion of 5% acetaldehyde (purity unspecified) at a rate of 20.6 to 82.4 mg/min for up to 36 min into normal human subjects caused an incr in heart rate, ventilation and dead space, and a decr in alveolar carbon dioxide levels. These symptoms are qualitatively and quantitatively similiar to those seen after ethanol intake in subjects previously treated with disulfiram (Antabuse), a known inhibitor of aldehyde dehydrogenase. [R67] *WHEN INFUSED INTRAVENOUSLY (AND PERHAPS WHEN INGESTED), ACETALDEHYDE IS SYMPATHOMIMETIC, AS EVIDENCED BY TACHYCARDIA AND HYPERTENSION. THIS REACTION IS DUE TO NOREPINEPHRINE RELEASE FROM ADRENERGIC NERVE ENDINGS. [R68] *ACETALDEHYDE ABSORBED OR GENERATED SYSTEMICALLY HAS NOT BEEN KNOWN TO BE TOXIC TO THE EYE, BUT EXPTL OBSERVATIONS ON HUMAN ... REPORTED FROM CZECHOSLOVAKIA INDICATE THAT AT CONCN OF 0.012 MG/CU M OF AIR, "CHANGES IN LIGHT SENSITIVITY OF THE EYE" WERE FOUND, AND CHANGES IN AUDITORY SENSITIVITY WERE FOUND AT 0.050 MG/CU M. [R69] *REPEATED EXPOSURE TO VAPORS CAUSES DERMATITIS AND CONJUNCTIVITIS. [R70] *Human lymphocytes (from known alcoholics) were exposed to acetaldehyde concn of 0.02 mg/ml and 0.04 mg/ml. Results indicate that chromosomal aberrations occurred at both concn. [R71] *Hepatocytes from livers of humans with alcoholic hepatitis were more susceptible to cytotoxicity of acetaldehyde than hepatocytes from normal liver of humans that were non-symptomatic or with viral hepatitis, alcoholic fatty liver, or stable alcoholic cirrhosis. [R72] *A 48 hr treatment with vinyl acetate (0.05-1 mM) induced a drastic increase in sister chromatid exchanges and (in first division cells) structural chromosome aberrations in cultured human lymphocytes. The effects were more pronounced in cultures of isolated lymphocytes than in whole-blood cultures. Gas chromatographic analysis of human whole-blood lymphocyte cultures treated for 10 sec to 20 min with vinyl acetate (5.4 mM) revealed a rapid degradation of vinyl acetate and formation of acetaldehyde. During the 20 min observation period, no degradation of vinyl acetate or formation of acetaldehyde were observed in complete culture medium without blood, which suggested that the reaction was enzymatic. Acetaldehyde induced sister chromatid exchanges in human whole-blood lymphocyte cultures at concentrations (0.125-2 mM) comparable to those used for vinyl acetate. The results indicate that vinyl acetate induces chromosome damage in cell cultures through enzyme-mediated hydrolysis to acetaldehyde. [R73] *Human leukocytes were incubated in the presence of vinyl acetate or acetaldehyde (10-20 mM) for 4 hr at 37 deg C in vitro. DNA damage was analysed by alkaline elution. None of the compounds induced a detectable increase in the frequency of DNA strand breaks. Cells exposed to 5 Gy of X-ray immediately after treatment and before alkaline elution showed a clear, dose-dependent retardation of the elution rate in comparison with X-irradiated control cells. These results demonstrate that both vinyl acetate and acetaldehyde induce DNA cross-links in human cells. [R74] *The effects of several aldehydes and peroxides on growth and differentiation of normal human bronchial epithelial cells were studied. Cells were exposed to formaldehyde and acetaldehyde. The effect of each agent on the following parameters was measured: (a) clonal growth rate; (b) squamous differentiation; (c) DNA damage; (d) ornithine decarboxylase activity; (e) nucleic acid synthesis; (f) aryl hydrocarbon hydroxylase activity; and (g) arachidonic acid and choline release. None of the agents were mitogenic, and their effects were assessed at concentrations which reduced growth rate (population doublings per day) to 50% of control. The 50% of control concentrations for the 6 hr exposure were found to be 0.21 mM formaldehyde and 30 mM acetaldehyde. Cells in controls (median cell planar area, 1150 sq mu), acetaldehyde-exposed cells were larger than controls (median cells planar area, 3200 sq mu). All agents increased the formation of cross-linked envelopes and depressed RNA synthesis more than DNA synthesis. Formaldehyde caused detectable amounts of both single-strand breaks and DNA-protein cross-links. [R75] *INVESTIGATIONS OF CILIOSTATIC EFFECT OF ALDEHYDES ARE OF SPECIAL INTEREST SINCE MANY HAVE IRRITATING EFFECT ON TRACHEAL MUCOSA. COMPARISON OF CILIOSTATIC EFFECT SHOWED FORMALDEHYDE TO BE MOST TOXIC FOLLOWED BY ACETALDEHYDE AND ACROLEIN. CROTONALDEHYDE AND METHACROLEIN SHOWED WEAKEST EFFECT. TECHNIQUE USED FOR OBSERVING TRACHEAL CILIARY ACTIVITY WAS THE IN VITRO TECHNIQUE. [R76] *LESS IRRITATING BUT STRONGER CENTRAL NERVOUS DEPRESSANT THAN FORMALDEHYDE. [R68] *Healthy volunteers (3 males and 3 females) were given 150 ml of tomato juice, containing 0 or 100 mg/kg L-methionine in the evening, and at 8:00 am the next day the subjects received L-methionine (0 or 100 kg) in tomato juice containing fructose (350 mg/kg). One hr after the morning dose of methionine or placebo, the subjects were given 0.5 g of ethanol/kg body wt. Breath samples were collected at 20, 30, 45, 60, 75, 90, 120, 150, and 180 min after the end of ethanol ingestion. Humans ingesting methionine exhibited on the avg a 22% decline in breath acetaldehyde levels over the time of measurements. Differences in acetaldehyde concn of placebo and methionine treated subjects were statistically significant (p < 0.03) Differences in breath ethanol concn were also statistically significant (p < 0.05). Peak calculated blood ethanol for those concn treated with placebo was 14.8 + or - 3.3 mM and concn for methionine treated subjects was 13.3 + or - 2.6 mM. Peak calculated blood acetaldehyde concn were 20.1 + or - 6.4 uM (placebo) and 14.3 + or - 7.9 uM (methionine). [R77] *Aldehydes increase airflow at concentrations below those that decrease respiratory frequency. /Aldehydes/ [R78] *A strong and highly significant correlation was observed between serum aspartate transaminase activity and an index of the cytotoxic activity associated with serum proteins modified by acetaldehyde in a group of 24 heavy drinkers. A weaker but significant correlation (R= 0.564, p= 0.008) was found between total serum creatine kinase activity and this index of serum cytotoxicity. As it is likely that the concentration of circulating modified protein was largely determined by the quantity of free acetaldehyde generated in the liver and that the aspartate transaminase activity was mainly derived from damaged hepatocytes, the data indicate a correlation between hepatic acetaldehyde generation and hepatocyte damage. This correlation may indicate either that increased quantities of acetaldehyde are released by damaged hepatocytes or that acetaldehyde is hepatotoxic in vivo. As only the creatine kinase isoenzyme present in skeletal muscle (CK-MM) was demonstrable in the serum in all but one of the patients, the circulating modified serum proteins may be toxic towards skeletal muscle cells. [R79] *Acetaldehyde induces chromosomal aberration and sister chromatid exchange in a variety of test systems. The mutagenic effect of acetaldehyde was studied at the hypoxanthine-guanine phosphoribosyl transferase locus in human lympocytes in vitro by selection of mutant cell clones in medium containing thioguanine. Cells treated with 1.2-2.4 mM acetaldehyde for 24 hr or 0.2-0.6 mM acetaldehyde for 48 hr showed a dose-dependent decrease of cell survival and a 3- to 16-fold increase of the mutant frequency. The inverse relationship between cell survival and mutant frequency was linear down to a relative survival of 15%. Forty-one mutant T-cell clones derived from cultures treated with 1.2 or 2.4 mM acetaldehyde and 15 from untreated controls were studied for deletion mutation. In the culture with a 16-fold increase of mutant frequency, 4 of 10 independent mutants (40%) showed partial deletions extending beyond the 3' coding sequences of the hypoxanthine-guanine phosphoribosyl transferase gene. Acetaldehyde is capable of inducing gene mutation at the hypoxanthine-guanine phosphoribosyl transferase locus in human cells, and deletion mutation affecting the 3'-end of the gene may be a major type of acetaldehyde induced mutation of this locus. [R80] *The conditions under which acetaldehyde induces sister chromatid exchange and DNA damage in human lymphocytes in vitro were investigated. Lymphocytes were collected from the blood of healthy donors, and cultured. Acetaldehyde exposure gave rise to DNA crosslinks, which were likely reponsible for at least part of its sister chromatid exchange inducing effect; the induction of sister chromatid exchange by acetaldehyde was largely dependent on the continuous presence of acetaldehyde in the culture medium; cells were more sensitive to the sister chromatid exchange inducing effect of acetaldehyde in late G1 than in early G1; and the sister chromatid exchange inducing activity of acetaldehyde in cells in culture medium remained almost constant for about 96 hours, suggesting that the capacity of human lymphocytes to metabolize acetaldehyde was very low if present at all. The apparent inability of human lymphocytes to detoxify acetaldehyde and its potent sister chromatid exchange inducing effect when continuously present in the culture medium suggests that repeated or continuous exposure resulting in concentrations of 10 to 100 uM/liter of acetaldehyde in the blood will have a small but detectable sister chromatid exchange inducing effect. [R81] *Acetaldehyde vapor irritation of the human eye is detectable at 50 ppm in air and becomes excessive for chronic industrial exposure above 200 ppm. Higher concn and extended exposure may injure the corneal epithelium, causing persistent lacrimation, photophobia and foreign body sensation. A splash of liquid acetaldehyde can be expected to cause painful but superficial injury of the cornea, with rapid healing; the liquid evaporates so rapidly at body temperature that contact is brief and self limited. [R82] *Inhalation at higher concn (greater than 100-200 ppm) can cause irritation to the mucous membranes and ciliastatic effects on the upper respiratory tract. Acetaldehyde may facilitate the uptake in the human body of other atmospheric contaminants by the bronchial epithelium because of its ciliotoxic and mucus coagulating effect. [R39, 1991.3] *A majority of ... unacclimated subjects ... experienced eye irritation at 50 ppm after 15 minutes; however, eye irritation in sensitive persons occurred after exposure at concn as low a 25 ppm for 15 minutes. This study also reported that at 200 ppm all subjects had red eyes and transient conjunctivitis, and a majority of the subjects suffered from nose and throat irritation at 200 ppm. The majority were willing to work an 8 hour day in 200 ppm of acetaldehyde. [R39, 1991.3] *The saturated aldehydes by inhalation show decreasing toxicity with increasing chain length in the order acetaldehyde, propionaldehyde, isobutyraldehyde, n-butyraldehyde, n-valeraldehyde and isovaleraldehye. [R68] *ACETALDEHYDE (2-20 MMOL) SIGNIFICANTLY INHIBITED UPTAKE OF ALPHA-AMINOISOBUTYRIC ACID IN HUMAN PLACENTAL VILLUS TISSUE IN VITRO. INHIBITION BY 10 MMOL WAS PARTIALLY REVERSIBLE. THUS, HUMAN PLACENTA IS RESISTANT TO ACUTE ETHANOL-ASSOCIATED EFFECTS UPON AMINO ACID TRANSPORT IN VITRO. [R83] *Acetaldehyde-DNA adducts have been observed in granulocytes and lymphocytes of human alcohol abusers. [R84] NTOX: *... CATS INHALING 380 PPM SHOW NO NOTICEABLE EFFECT, EVEN AFTER SEVEN HR; IF DOSE IS INCREASED FOURFOLD, TEMPORARY IRRITATION OF AIR PASSAGES IS OBSERVED. [R64] */ACETALDEHYDE INHALATION IN DOGS/ SHOWED THAT EXPOSURE AT 134 PPM FOR 30 MIN RESULTED IN MILD UPPER RESPIRATORY TRACT IRRITATION. HIGHER CONCN DECR RESPIRATORY RATE BY INHIBITION OF CNS. EXPOSURE AT 50 PPM PRODUCED EYE IRRITATION; 200 PPM ... /CAUSED/ CONJUNCTIVITIS ... . [R12, 686] *EFFECTS OF CHRONIC ACETALDEHYDE INHALATION HAVE ALSO BEEN EXAMINED IN HAMSTERS. INHALATION OF ACETALDEHYDE HAS BEEN SHOWN TO AFFECT BOTH BLOOD PRESSURE AND HEART RATE. IT HAS BEEN SUGGESTED THAT THESE EFFECTS ARE MEDIATED THROUGH RELEASE OF CATECHOLAMINES. [R12, 687] *OVARY CELLS (CHINESE HAMSTER OVARY) TREATED 7 OR 8 DAYS WITH ALCOHOLS AND WITH ACETALDEHYDE. CELLS WERE ALLOWED TO INCORPORATE BROMODEOXYURIDINE. ACETALDEHYDE INDUCED CHROMOSOMAL DAMAGE. [R85] *CHINESE HAMSTERS RECEIVED ACETALDEHYDE AT 0.01, 0.1 and 0.5 MG/KG BY IP INJECTION, AND BONE-MARROW METAPHASES WERE ANALYZED WITH RESPECT TO SISTER-CHROMATID EXCHANGES. THE SISTER CHROMATID EXCHANGE FREQUENCIES WERE ELEVATED BY ACETALDEHYDE AT 0.5 MG/KG, BUT NOT BY THE LOWER DOSES. [R86] *IV ADMIN OF ACETALDEHYDE IN GUINEA PIGS PRODUCED AN IMMEDIATE AND SIGNIFICANT INCREASE IN MEAN ARTERIAL PRESSURE FOLLOWED BY ITS PROGRESSIVE DECREASE RESULTING IN HYPOTENSION. HEART RATE INCREASED SIGNIFICANTLY. [R87] *FEMALE MICE WERE INJECTED IV WITH ACETALDEHYDE ON SINGLE OR MULTIPLE DAYS, AND EXAM ON 10 OR 12TH DAY OF GESTATION. MULTIPLE DAY EXPOSURES RESULTED IN HIGH INCIDENCE OF EMBRYONIC RESORPTIONS; HOWEVER, NEURAL TUBE DEFECTS WERE ENCOUNTERED IN SURVIVING EMBRYOS FROM SINGLE DAY INJECTIONS. [R88] *TOXICITY OF ACETALDEHYDE TO CEREBRAL CORTEX OF RATS WAS TESTED BY SUPERFUSION OF INTACT DURA FOR 1 HR. TISSUE CONCN OF 30 MMOL CAUSED AXONAL AND TERMINAL DEGENERATION, WHEREAS 11 MMOL WAS NOT TOXIC. IN TERMS OF TISSUE CONCN, IT WAS 27 TIMES MORE TOXIC THAN ETHANOL. [R89] *... In a 4 week study, groups of 10 male and 10 female rats were exposed to 0, 400, 1000, 2200, or 5000 ppm acetaldehyde for 6 hr/day, 5 days/wk. Treatment related changes observed at the 5000 ppm level included dyspnea and excitation during the first 30 min of each exposure, yellow-brown fur, severe growth retardation, increased numbers of neutrophils in the blood, reduced production of urine which resulted in a high urine specific gravity, increased lung weight, and severe degenerative hyperplastic and metaplastic changes of the nasal, laryngeal, and tracheal epithelium. [R90] *Day 10 rat embryos grown in presence of acetaldehyde in vitro /exhibited/ significant retardation in growth and development. A concentration response range for acetaldehyde induced embryotoxicity was defined, from no effect at 5 mM to lethality of all embryos at 100 mM ... . Direct embryotoxicity effects of acetaldehyde, the primary metabolite of ethanol, /occurred/ at concentrations as low as 25 mM. [R91] *The embryotoxicity of two ethanol metabolites, acetaldehyde and 2,3-butanediol, have been examined in cultured 10 day albino Wistar rat embryos over a 2 day period. At acetaldehyde concentrations of 100 and 260 uM, no significant effects were observed on embryonic protein, DNA, somite development, gross morphology, or viability. 800 uM was ... toxic causing rapid death and necrosis. 2,3-Butanediol at a culture medium concentration of 25 mM had no effect on any of the above parameters. ... [R92] *Acetaldehyde, the metabolite of ethanol was administered to pregnant CF rats ip (50 mg/kg) from day 8 through 15 of gestation and fetuses from different mothers were collected from day 16 through 21 of gestation. Fetuses were processed for alizarin skeletal staining. There was significant delay in ossification besides certain skeletal malformations such as wavy ribs. The delay in ossification may be one of the reasons for reduced birth weight and increased postnatal mortality and growth. [R93] *The effect of treatment of rats with acetaldehyde on the subcellular nicotinamide adenine dinucleotide(+) aldehyde dehydrogenase activities and acetaldehyde oxidation by isolated intact mitochondria of the liver and the brain was studied. Inhalation of acetaldehyde caused a significant decrease in the liver mitochondrial low Km aldehyde dehydrogenase activity, while brain mitochondrial aldehyde dehydrogenase activity remained unchanged. Acetaldehyde oxidation by isolated intact liver mitochrondria decreased significantly but that by brain mitochrondria remained unchanged after acetaldehyde inhalation. These findings /indicate/ the possibility that the brain enzyme may be exposed to lower concentration of acetaldehyde than the liver enzyme. [R94] *Groups of 35 male Syrian golden hamsters were exposed to 0 or 1500 ppm (2700 mg/cu m) acetaldehyde vapor for 7 hr/day on 5 days/week for 52 wk, and to weekly intratracheal instillations of 0, 0.0625, 0.125, 0.25, 0.5 or 1.0 mg benzo(a)pyrene suspended in saline for same time period. Groups of 5 animals were killed at 52 wk and remainder allowed to survive untreated for an additional 26 wk. There was no significant difference in mortality between animals exposed to acetaldehyde and those exposed to air, except for the subgroup treated with the highest dose of benzo(a)pyrene for which the mortality in the acetaldehyde-exposed animals was incr more rapidly than the mortality in the corresponding benzo(a)pyrene group exposed to air (p < 0.001 in both groups). No tumor was found in hamsters exposed to acetaldehyde only; but 3/30, 4/30, 9/30, 25/39 and 26/28 hamsters exposed to benzo(a)pyrene alone developed resp tract tumors and 1/28, 5/29, 8/29, 16/29 and 29/30 hamsters exposed to benzo(a)pyrene and acetaldehyde vapor developed the same type of tumor. [R95] *Groups of 36 male and 36 female Syrian golden hamsters, 6 wk of age, were exposed for 7 hr/day for 5 days/wk to room air (chamber controls) or to decr concn of acetaldehyde (distilled and analyzed by gas chromatography) (initial concn, 2500 ppm (4500 mg/cu m); final concn, 1650 ppm (2970 mg/cu m)) for 52 wk. Six animals killed and exam from each group had no tumor. The remaining animals were observed until 81 wk and killed. The incidences of respiratory tract tumors were 0/30, 8/29, 0/28 and 5/29 in control males, exposed males, control females and exposed females, respectively (p < 0.05). The acetaldehyde induced tumors were predominantly laryngeal carcinomas with a few laryngeal polyps, and nasal polyps and carcinomas. [R96] *Seven groups of 35 male and 35 female Syrian golden hamsters, 11 wk old, were given the following treatments weekly or biweekly for 52 wk: intratracheal instillations of saline (0.2 ml weekly; vehicle controls); acetaldehyde alone (two groups: one receiving 0.2 ml 2% acetaldehyde weekly, and one receiving 0.2 ml 4% acetaldehyde weekly); acetaldehyde plus benzo(a)pyrene or N-nitrosodiethylamine; or benzo(a)pyrene or N-nitrosodiethylamine (positive controls). After 13, 26 and 52 weeks, three animals/sex and per group were killed and autopsied. Expt was terminated at wk 104, when survivors were killed. At that time, overall mortality was 83% in males and 97% in females. Intratracheal instillations of acetaldehyde alone produced extensive "peribronchiolar adenomatoid lesions" in the lung, but no tumor. ... Benzo(a)pyrene and N-nitrosodiethylamine induced a variety of tumors in several segments of the resp tract. This tumor response was not influenced by simultaneous treatment with acetaldehyde. [R95] */In rats/ acetaldehyde could mediate a number of the toxic effects of alcohol both in ... /female rats/ and their offspring. Thus, /an assessment of/ the blood acetaldehyde response to ethanol (3 g/kg) at various stages of the female reproductive cycle /was accomplished/. Blood levels were low throughout the various phases of the estrous cycle and during most of pregnancy. By contrast, a 4-fold rise in maternal blood acetaldehyde occurred at the end of pregnancy (day 20), continued to increase during lactation (17-fold at day 14) and returned to non-pregnant values after weaning or after pup removal at birth. Both enhanced rate of ethanol oxidation and decreased activity of the low Km aldehyde dehydrogenase in liver mitochondria contributed to the increased acetaldehyde levels. Acetaldehyde was detectable in fetal blood, but only a small fraction of the high maternal values in pregnancy reached the fetus through the umbilical vein. Chronic alcohol administration resulted in decreased fetal size and striking enlargement of the placenta with possible implication of abnormal fetal development. Thus, the high maternal acetaldehyde levels at the end of pregnancy may exert deleterious effects on many maternal organs, including those (such as placenta) which are required for normal fetal development. [R97] *Two groups of 12 male Wistar rats received either 243 ppm of acetaldehyde or 5.7 ppm of formaldehyde for 8 hr a day, 5 days a week during 5 weeks. These levels represent three times the threshold limit values for these substances in Brazilian legislation. The animals were evaluated by pulmonary function tests before and after exposure to the pollutants. The data obtained from these rats were compared with those of 12 controls, housed in identical conditions for the same length of time but breathing normal air. The results showed an increase of the functional residual capacity, residual volume, total lung capacity and respiratory frequency in the rats exposed to acetaldehyde atmosphere. The animals exposed to formaldehyde did not present pulmonary function alterations when compared with the controls. Damage was caused by acetaldehyde to the peripheral regions of the lung parenchyma, affecting small airways or altering pulmonary elastic properties. [R98] *Alkaline elution was employed to study DNA damage in Chinese hamster ovary-Kl cells treated with a series of biotic and xenobiotic aldehydes. DNA cross-linking was measured in terms of the reduction in the effect of methyl methanesulphonate on the kinetics of DNA elution and was observed in cells treated with formaldehyde, acetaldehyde, methylglyoxal and malonaldehyde. Propionaldehyde, valeraldehyde, hexanal, and 4-hydroxynonenal produced DNA single strand breaks, or lesions which were converted to breaks in alkali. Both types of DNA damage occurred in cells exposed to malonaldehyde. These findings support the hypothesis of a carcinogenic effect of the aldehydic products (malonaldehyde, methylglyoxal, propionaldehyde, hexanal, 4-hydroxynonenal) released in biomembranes during lipid peroxidation. Acetaldehyde did not cause DNA breaks. [R99] *Acetaldehyde was ... tested for mutagenicity using the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program (NTP). Acetaldehyde was tested at doses of 0.033, 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. /Acetaldehyde was negative in these tests and/ the highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. Total clearing of the background bacterial lawn was exhibited in some cultures using strains TA100, TA1535, and TA1537 at the high dose without activation. [R100] *Acetaldehyde was ... /tested/ for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster using a standard protocol approved by the National Toxicology Program. ... Canton-S wild-type males were treated with concentrations of the test chemical that result in approximately 30% mortality. ... Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods. Acetaldehyde at a dose of 22,500 ppm, when administered to males by injection, was positive in this assay. [R101] *In an in vitro study, a suppressive effect on rat testicular steroidogenesis was reported at concn as low as 50 uM (2.2 ug/ml) acetaldehyde. [R102] *Incubation of acetaldehyde (100 mg %) with isolated hepatocytes for 60 min significantly increased lipid peroxide formation, which was inhibited by prior addn of antioxidants such as vitamin E or glutathione. [R102] *Acetaldehyde caused a dose-dependent induction of chromosomal aberrations in Vicia faba root-tip meristems. [R103] *NO EXTRAVASATION OF SODIUM FLUORESCEIN FROM CAPILLARIES OF THE CEREBRAL CORTEX AND RETINA COULD BE DEMONSTRATED IN RATS DURING SEVERE NONLETHAL ETHANOL AND/OR ACETALDEHYDE POISONING. THE RESULTS DO NOT EXCLUDE THE POSSIBILITY THAT REPEATED INTOXICATIONS MAY GRADUALLY OPEN THE BLOOD-BRAIN AND BLOOD-RETINAL BARRIERS, BUT DO INDICATE THE ABSENCE OF AN EFFECT DURING ACUTE INTOXICATION. [R104] *Male Wistar rats were used to study the capability of acetaldehyde (supplied exogenously or metabolically from ethanol) to initiate liver damage as indicated by enzyme leakage, hepatic fat accumulation, and histologic changes. Measurement of glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, and sorbitol dehydrogenase in serum was used to assess hepatotoxicity. Acetaldehyde given orally (17.9 or 35.8 mmol/kg) or ip (4.5 or 9.0 mmol/kg) did not affect glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, sorbitol dehydrogenase, enzyme activities, triglyceride levels or cause histologic changes when compared to controls. Pretreatment with disulfiram in tylose suspension (1 g/kg orally, 16 hr prior to acetaldehyde) caused no effects different from controls when acetaldehyde was exogenously administered. Treatment of rats with ethanol (6 g/kg orally as a 40% solution, n= 6) or with disulfiram (1 g/kg orally in 20 ml/kg tylose, n= 6) alone induced no measurable hepatotoxic response. Oral treatment with disulfiram 16 hr prior to treatment with ethanol (n= 19) caused significant increases (p < 0.05) in the level of GOT and serum triglycerides within 48 hr, and a slight fatty degeneration of the liver was observed. After combined treatment, the serum acetaldehyde concentration (n= 3) was 9.4 mg/l at 30 min and 8.7 mg/l at 180 min. Ip injection of ethanol (4 g/kg) after treatment with disulfiram produced an increase in glutamic-oxaloacetic transaminase (p < 0.05) but not serum triglycerides within 48 hr. Fatty degeneration and hepatic necrosis were observed in 2 of 6 animals. [R105] *Progression and/or regression of nasal mucosal damage was studied in four groups of 30 male and 30 female SPF-bred Wistar rats exposed to 0, 750, 1500, or 3000/1500 ppm of acetaldehyde for 6 hr/day, 5 days/wk, for 52 weeks with a recovery period of 26 or 52 weeks. Acetaldehyde concentration for the high exposure group was gradually decreased from 3000 ppm (day 0-141) to 1500 ppm (day 313 onwards) due to growth retardation and early mortality. From each exposure group, 10 male and 10 female rats were examined following a 26 wk recovery period, and 20 male and 20 female rats were examined following a 52 wk recovery period. At the end of 52 wk exposure to the highest acetaldehyde concentration, most animals exhibited labored respiration and mouth breathing. A dose-dependent increase in frequency of adenocarcinomas, nasal tumors, and squamous cell carcinomas was noted for male and female rats following 52 wk acetaldehyde exposure, and during a 26 wk post-exposure recovery period. Varying degrees of pathological alterations including degeneration of olfactory epithelium, hyper- and metaplastic changes in respiratory epithelium, and rhinitis were observed for animals following acetaldehyde exposure at all concentrations. Restorative activity of olfactory epithelium was observed for rats during the 26 and 52 wk recovery periods following exposure to low and mid acetaldehyde levels, but not for the group exposed to 3000/1500 ppm. [R106] *The Drosophila wing somatic mutation and recombination test was applied to a series of chemicals to determine its suitability in genotoxicity screening. Chronic feeding of acetaldehyde for 48 hr at a concentration of 0.18 mM gave weak but reproducible effects for all three categories of spots: small single, large single, and twin. [R107] *Rats were given a single dose of acetaldehyde (0.5 mg/kg) ip. The animals were killed 0.5, 1, 2, 4, 6, 9, 12, and 24 hr after treatment for determination of lipid peroxide levels in liver homogenate and its subcellular fractions. Malondialdehyde levels in liver homogenate were highest (630 + or - 60 pmol/mg) a half hour after the acute dose and declined to control levels of about 500 pmol/mg by 6 hr. Mitochondrial malondialdehyde levels were elevated at 2 and 4 hours after treatment (maximum 837 + or - 110 pmol/mg) being similar to the control (682 + or - 77 pmol/mg) before and after this period. [R108] *Preimplantation two cell stage mouse embryos, obtained from superovulated CF-1 mice, were exposed to acetaldehyde through the culture medium for 60 min followed by a 105 hr incubation period. Scoring was based on a system which recognized eight different stages of development, zero for dead cells of the two and four cell stage to 7 for hatching blastocyst. Embryos treated with 5 and 10 mg acetaldehyde per 100 ml were not different from controls. Treatments of 50 mg acetaldehyde/100 ml medium and higher were completely lethal. [R109] *The objectives of this study were to elucidate the ontogeny of the activity of alcohol dehydrogenase, low Km aldehyde dehydrogenase, and high Km aldehyde dehydrogenase in the liver and placenta of the guinea pig. There was low alcohol dehydrogenase activity in fetal liver and placenta throughtout gestation and in neonatal liver. The fetal liver low Km aldehyde dehydrogenase activity increased progressively and, at 60 days of gestation, was similar to adult liver activity, as was also the case for neonatal liver enzyme activity. Placental low Km aldehyde dehydrogenase activity was less than adult liver activity throughout gestation. Fetal hepatic high Km aldehyde dehydrogenase activity increased during gestation, but was less than adult liver activity, as was also the case for neonatal liver enzyme activity. Placental high Km aldehyde dehydrogenase activity was low throughout gestation. For oral administration of 0.5 g ethanol/kg maternal body weight to pregnant guinea pigs at mid-gestation (34 days), the maternal blood and fetal body ethanol concentration-time curves were similar. Acetaldehyde was measureable in maternal blood and fetal body at similar concentrations, which were 100- to 1000-fold less than the respective ethanol concentrations. The major differences in the diposition of ethanol and acetaldehyde at near-term pregnancy, compared with mid-gestation, was the lack of measurable acetaldehyde in fetal blood. The guinea pig fetus throughout gestation has virtually no capacity to oxidize ethanol, and its duration of exposure to ethanol is regulated by maternal hepatic alcohol dehydrogenase catalyzed biotransformation of ethanol. The fetus, however, appears to have increasing low Km aldehyde dehydrogenase-dependent capacity to oxidize ethanol-derived acetaldehyde during development, and would appear to be increasingly protected from exposure to acetaldehyde as gestation progresses. [R110] *The ethanol and acetaldehyde uptake by the lactating rat mammary gland as well as their effects on this gland at the ultrastructural level were studied. The extraction of acetaldehyde was greater than that of ethanol both after chronic and acute ethanol treatment. Chronic ethanol administration resulted in a loss of the mammary cell polarization, in a reduction of the Golgi dictyosomal elements and in several abnormalities at the level of casein maturation and secretion, whereas lipid synthesis and secretion did not seem to be affected. Normal spherical casein micelles took on a filament-like structure and casein vesicles appeared fused together forming macrovesicles. All these alterations were specific of ethanol and/or acetaldehyde action and were not due to the associated malnutrition, as deduced from the lack of effects in the nutritional control group. [R111] *The influence of ethanol and acetaldehyde on skeletogenesis was investigated in Sprague-Dawley rats. Pregnant animals were divided into three groups as follows: I, Controls (distilled water, intragastrically and ip), II. Ethanol (0.015 ml/g body weight, 25% v/v, intragastrically, III. Acetaldehyde (200 mg/kg body weight, 3% solution, ip). The animals were treated from gestational day 6 through 18, and on day 20, external anomalies were not detected in any of the fetuses. Fetal weight was significantly reduced in fetuses exposed to ethanol and acetaldehyde; and in the ethanol-treated group CR-length was also significantly less than the control value. Both axial and appendicular skeletal bones were affected in their development following in utero exposure to ethanol and acetaldehyde, with a higher frequency of defects in fetuses exposed to ethanol. Anomalies of the ribs and vertebrae were commonly seen in both treatment groups. The cranial bones, sternum, hyoid bone, and the metacarpal and metatarsal bones were retarded in their development with signs of delayed ossification and hypoplasia. [R112] *Pregnant rats were treated from day 9 through 12 of gestation with 12.5% ethanol, 25% ethanol, 1% acetaldehyde, cyanamide (an inhibitor of the enzyme aldehyde dehydrogenase), or a combination of cyanamide and ethanol. Embryos were recovered on gestational day 12 and were quantitatively assessed on the basis of 16 recognizable developmental endpoints (morphological scores). The head and the crown-rump lengths of the embryos were also measured. Total resorption occurred in two animals treated with cyanamide and two treated with cyanamide and ethanol. Acetaldehyde and ethanol (at both concentrations) were found to reduce the head length of the embryos but had no significant effects on morphological scores and crown-rump length. The combination of ethanol with cyanamide caused a greater reduction in head length and also significantly reduced crown-rump length, as well as the morphological scores. The deleterious effects of ethanol could be attributed to acetaldehyde, its primary metabolite, although other underlying factors cannot be ruled out. [R113] *Methylation of DNA at the 5' position of cytosine (5 MeC) is associated with control of gene expression. The effect of dietary ethanol and the ethanol metabolite acetaldehyde on DNA methylation was investigated as a potential contributing factor to the teratology seen in the fetal alcohol syndrome. Nine day pregnant mice were given ethanol (3 g/kg) orally twice a day for 3 days. Fetal nuclei and DNA were isolated 5 hours after the last ethanol treatment. Nuclear methylase activity, assayed by the incorporation of 3H-CH3 donated by S-adenosylmethionine, was significantly depressed in the alcohol-fed animals. The DNA of these fetuses also was shown to be hypomethylated related to controls by its ability to serve as a CH3 acceptor using HPaII methylase, which produces 5 MeC in the sequence GGCC. In vitro, acetaldehyde (40-100 uM) but not ethanol (100 mM) inhibited nuclear methylase activity. [R114] *Human and rat O6-methylguanine transferase are inhibited in vitro by ethanol at concentrations of 10 to 50 mM and by acetaldehyde, the first metabolite of ethanol, at concentrations as low as 0.01 uM. Several other enzymes, including glyceraldehyde-3-phosphate dehydrogenase and yeast alcohol dehydrogenase, which like O6-methylguanine transferase have cysteines in their active sites, were not inhibited by acetaldehyde at the levels that inhibited O6-methylguanine transferase. Disulfiram, an acetaldehyde dehydrogenase inhibitor, enhanced the inhibitory effect of ethanol in vivo. The inhibitory effect of ethanol on O6-methylguanine transferase activity is mediated primarily via its metabolite, acetaldehyde. [R115] NTOX: *In rats, ethanol intake as low as 4 g/kg per day induced mitochondrial alterations, detected by a decrease in mitochondrial O2 uptake supported by substrates entering at the three sites of coupled phosphorylation. Since acetaldehyde oxidation occurs mainly inside the mitochondria, linked to the respiration chain, the effect of daily previous administration of low doses of ethanol on the acetaldehyde oxidation rate by intact rat liver mitochondria was studied. Determination of acetaldehyde oxidation rate and O2 uptake accompanying acetaldehyde removal by liver mitochondria indicates that the mean value of these parameters studied in rats consuming low amount of ethanol (0.5-3.0 g/kg per day) was significantly higher than that of controls drinking only water (in state 3, and in state 4). This enhancing effect of ethanol cannot be ascribed to an uncoupling of oxidative phosphorylation and also not to a change in aldehyde dehydrogenase activity which was measured in disrupted mitochondria. On the other hand, high ethanol consumption (4-7 g/kg per day), which alters mitochondrial function, did not decrease mitochondrial acetaldehyde oxidation, as compared to rats drinking water only. This result differs from the decrease induced by higher levels of previous ethanol intake (12-14 g/kg per day). [R116] *The testicular genotoxic effects of vinylacetate and its hydrolysis product, acetaldehyde, were studied in mice by analyzing the induction of morphologically abnormal sperm and meiotic micronuclei. Vinylacetate significantly increased the frequency of sperm abnormalities at 500 mg/kg/day while lower doses were ineffective. Acetaldehyde did not induce abnormal sperm. Neither of the compounds influenced the frequency of meiotic micronuclei. Vinylacetate, but not acetaldehyde, caused a dose-dependent decrease in sperm production and a reduction of testicular weight at 500 and 125 mg/kg/day. [R117] *Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 vs, 120 nmoles/g colon), but was not affected by chronic ethanol feeding. Furthermore, germ-free rats had significantly lower acetaldehyde concentrations in the rectum and in the cecum compared with conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair fed liquid diets. By the metaphase-arrest technique, alcohol feeding induced rectal, but not cecal hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity. Chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. [R118] *A subacute oral toxicity study of acetaldehyde and formaldehyde was carried out in rats. Male and female 5 wk old rats received one of the aldehydes in the drinking water for a period of 4 wk, acetaldehyde being given at dose levels of 25, 125 and 675 mg/kg body weight/day and formaldehyde at dose levels of 5, 25, and 125 mg/kg body weight/day. Hyperkeratosis of the forestomach, observed only in the top dose rats, was the only adverse effect of acetaldehyde detected. Effects of formaldehyde, also observed only in the top dose group, were yellow discoloration of the fur, decreased protein and albumin levels in the blood plasma, thickening of the limiting ridge and hyperkeratosis in the forestomach, and focal gastritis in the glandular stomach. In this study the no observed adverse effect levels of acetaldehyde and formaldehyde were 125 and 25 mg/kg body weight/day, respectively. [R119] *Rats which received acetaldehyde by ip injection on a single occasion sustained neural degeneration in the cerebral cortex detectable with both light and electron microscopy. The degeneration was more intense and included the hippocampus when acetaldehyde exposure was given on 5 consecutive days in the form of ethanol vapor inhalation and disulfiram injections. Pretreatment of animals with a combination 2.5 g lysine/kg plus 50 mg pyridoxyl phosphate/kg did not alter the degree of degeneration response to either a single injection of acetaldehyde or 5 days acetaldehyde treatment. Penicillamine injections (1.2 g/kg) did offer some (but not complete) cytoprotective value against the neurotoxicity of acetaldehyde. This cytoprotective action was effective at concentrations of acetaldehyde which are not distant from clinically observed concentrations. [R120] *Primary cultures of adult mouse sensory neurons maintained for 8 days in vitro, in both the presence of non-neuronal cell outgrowth and in non-neuronal cell-reduced cultures, were exposed to ethanol, acetaldehyde. LD50's of 600 micro M acrolein and 100 mM propanola were obtained after 2 hr exposures and after 48 hr with 1mM acetaldehyde and 500 mM ethanol. Morphological effects were evident by scanning electron microscopy with sub-acute doses for each agent, using both lower concentrations and shorter exposures. Membrane pitting of the perikaryon and a reduction in the proportion of neurons bearing neurites were common signs of toxic insult. The neurites of treated cells were thicker and more irregular than those of untreated cells; this proved a good indicator of specific neurotoxicity rather than merely a cytotoxic response. [R121] *The cytogenetic activity of ethanol and its main metabolic derivative, acetaldehyde in cultured Chinese hamster cells. Acetaldehyde induced an increase of aneuploidy and chromosome breaks and exchanges. Ethanol only induced an increase of achromatic lesions (gaps). However, following treatment with acetaldehyde, the most notable effect was an increase of hypodiploid cells and a parallel increase of multinucleated in interphase cells, the frequency of hyperdiploid cells being considerably lower. A strong correlation has been found on comparing the frequency of hypodiploid cells to the frequency of hyperdiploid plus multinucleated interphase cells. There exists a higher chance of hypodiploid cells reaching the second mitosis after treatment and the main effect of acetaldehyde is the induction of hypodiploidy rather than hyperdiploidy and chromosome aberrations. [R122] *Tests of acetaldehyde for carcinogenic and mutagenic activity in higher animals have been negative, although acetaldehyde will produce chromosomal aberrations in plant and lower animal test systems. [R44, 305] *Acetaldehyde has been shown to induce mutagenic and cytogenic changes in many mutagenic assays. In mammalian in vitro assays, it has produced sister chromatid exchanges and chromosomal breaks in and aberrations ... in Chinese hamster ovary (CHO) cell cultures in a dose related manner. Acetaldehyde was not mutagenic in Escherichia coli systems and Drosophila melanogaster. Acetaldehyde was not mutagenic in several strains of Salmonella tryphimurium with and without liver microsomes and in one strain of Salmonella trphimurium without metabolic activation. In in vivo assays, acetaldehyde has produced chromosomal aberrations in rats and sister chromatid exchanges in mice and hamsters. [R39, 1991.2] *In a 4 week inhalation study, rats were exposed at 400-500 ppm acetaldehyde 6 hr/day, 5 day/week. At 1000 and 2200 ppm, the major changes included: growth retardation, an increase in the production of urine in males, and a slight to moderate degeneration with and without hyperplasia and metaplasia of the nasal epithelium. At 400 ppm, the only change seen was slight degeneration of the olfactory epithelium. [R39, 1991.2] *In starch irradiated with from 1 krad to 2 mrad, 40 mg acetaldehyde was formed per mrad of irradiation. Aldehydes may be responsible for the toxic effects of carbohydrates exposed to the high doses of ionizing radiation used in the sterilization of food. [R123] *Acetaldehyde, the hepatic metabolite product of ethanol oxidation has negative inotropic effects at blood concentrations that occur after a moderate ethanol intake. At higher concentrations, acetaldehyde releases catechlolamines; hence it produces sympathomimetic effects. Such an effect gradually decreases with aldehydes of increasing chain length. [R124, 442] */ACETALDEHYDE/ HAS BEEN SHOWN TO INTERFERE WITH MITOCHONDRIAL OXYGEN CONSUMPTION IN RAT LIVER AND ... ENERGY PRODUCTION. [R12, 686] *INCORPORATION OF (3)H-THYMIDINE INTO DNA WAS SIGNIFICANTLY DIMINISHED BY TREATMENT WITH ETHANOL AND ACETALDEHYDE IN REGENERATING RAT LIVER, RAT CELLS IN CULTURE, AND RAT FETAL TISSUES. [R125] *IN EXPERIMENTS CONDUCTED UNDER NEAR PHYSIOLOGICAL CONDITIONS OF TEMPERATURES, PH, AND IONIC STRENGTH, ACETALDEHYDE AT CONCN SIMILAR TO THOSE FOUND IN LIVER AFTER HIGH DOSES OF ETHANOL ACTED AS A REVERSIBLE INHIBITOR OF THE NICOTINAMIDE ADENINE DINUCLEOTIDE DEPENDENT ETHANOL OXIDATION. [R126] *The effects of several potential inhibitors of N-nitrosodimethylamine metabolism were studied in perfused rat livers. Acetaldehyde inhibited N-nitrosodimethylamine metabolism. [R127] *Acetaldehyde ... had no effect on /fetal mouse/ thymocyte subpopulation ratios or cell numbers at a physiologic concn (50 uM) /in organ culture/. [R128] *Acute ethanol administration (3 g/kg twice a day) to pregnant mice, from the 9th through the 11th day of gestation, resulted in hypomethylation of fetal deoxyribonucleic acid (DNA). Nuclei isolated from the fetuses of the ethanol-treated mice had lower levels of methylase activity relative to controls even in the presence of excess S-adenosylmethionine, which serves as the methyl donor for the enzyme DNA methyltransferase. Acetaldehyde, at concentrations as low as 3 to 10 uM, inhibited DNA methyltransferase activity in vitro. Since DNA methylation is thought to play an important role in the regulation of gene expression during embryogenesis, ethanol-associated alterations in fetal DNA methylation may contribute to the developmental abnormalities seen in the fetal alcohol syndrome. [R129] *Rat embryos were explanted on days 9.5 or 10 of gestation and cultured for 48 to 30 hr, respectively, In rat serum containing 0, 3, 6, 9 mg/ml of ethanol; 0, 10, 20 ug/ml of acetaldehyde; 3 mg/ml ethanol + 10 ug/ml acetaldehyde. At the end of the culture period the embryos were evaluated for vitality, and scored. Some of them were also examined histologically. Embryos exposed to ethanol from day 9.5 showed a dose-related growth retardation associated with a high frequency of malformations (open neural tube, heart defects, branchial arch hypoplasia). The exposure of 9.5 day embryos to 20 ug/ml acetaldehyde resulted in 100% embryolethality whereas 10 ug/ml induced growth retardation and teratogenic effects. When 10 day embryos were exposed to 3 mg/ml ethanol or 10 ul/ml acetaldehyde no effects were observed, but the highest levels of ethanol produced a moderate growth retardation and morphologic defects. Exposure to 20 ug/ml acetaldehyde induced hypoplasia of the first arch, but did not alter the score value. The histologic examination of these embryos revealed severe lesions at the level of the neuroepithelium and of the branchial mesenchyma. Similar effects were observed in embryos exposed simultaneously to 3 mg/ml ethanol and 10 ug/ml acetaldehyde. [R130] *Llv.52 has been shown to bring out a faster elimination of acetaldehyde from the body and thus prevent alcoholic liver damage. Other toxic effects of alcohol may also be due to acetaldehyde and may be prevented by Liv.52. In this study, rats were given 20 (v/v) ethanol in drinking water, during the gestation period, and the effect on maternal body weight and fetal outcome was noted. The protective effect of Liv.52 administration during the gestation period was studied. The results show that ethanol ingestion caused a decrease ln gestational weight gain, total fetal weight, and number of lave fetuses. There were increases in resorptions. Liv.52 administration reduced the deleterious effects of ethanol. The concentration of acetaldehyde in the amniotic fluid of ethanol-consuming animals was 0.727 ug/ml. Liv.52 administration lowered it to 0.244 ug/ml. The protective effect of Liv.52 could be due to the rapid elimination of acetaldehyde. [R131] *The effects of intake of acetaldehyde, the proximal metabolite of ethanol, were studied in two groups of Fischer strain rats. Virgin rats were mated at 3 months of age or at 8 months of age. The acetaldehyde intake group was given a 2% aqueous solution of acetaldehyde for the first time on the first day of pregnancy. The solution was then given once a day, oral net acetaldehyde 240 mg/kg bw through gestation, labor and lactation. The control group was not exposed to acetaldehyde. Comparative observations were made on both maternal rats and their offspring 1) Maternal body weight gain between the first and 20th day of pregnancy was significantly low in the acetaldehyde group compared with the control group (3 month old p less than 0.05. As for placental weight, 3 month old acetaldehyde mothers showed no significant differences from the controls, whereas 8 month old acetaldehyde mothers weighed significantly less than those in the control group (p less than 0.01. Histological /examination/ disclosed that the brain, liver, and kidney had slight changes in all acetaldehyde mothers, whereas the control group showed almost no changes. 2) The average number of fetuses at the 20th day of gestation, neonates per litter, did not significantly differ among the groups. 3) As for the body weight of the offspring of 3 month old mothers, the acetaldehyde neonates and 10 day old offspring weighed significantly less than those in the control group (p less than 0.01, p less than 0.01). In the case of 8 month old mothers, the acetaldehyde fetuses at the 20th day of gestation and neonates weighed significantly less than controls (p less than 0.01, p less than 0.01). 4) Histological /examination/ of the brain, lung, liver, kidney, and thymus in offspring revealed remarkable visceral immaturity and hemorrhage in the acetaldehyde group, as compared to controls. [R132] *... reported the activity of acetaldehyde against the fungi affecting stored apples and pears (Colletotrichum gloeosporioides, Cryptosporiopsis malicorticis, Phlyctaena vagabunda, Botrytis cinerea, and Alternaria tenuis). Acetaldehyde was rapidly lethal at low concn: after a 24-hr treatment period, the lethal conc of acetaldehyde ranged from 0.036 ug/m3 (A. tenuis) to 0.09 ug/m3 (C. gloeosporioides). Acetaldehyde remained lethal for five fungi, even when the treatment lasted only 20 min (0.90 ug/m3 for P. vagabunda C. malicorticis, and A. tenuis, and 0.36 ug/m3 for C. gloeosporioides and B. cinerea). [R133, p. 57 (1995)] *... studied acetaldehyde as a fumigant for control of the green peach aphid (Myzus persicae) on head lettuce (Lactuca sativa). When aphids were placed on the lettuce prior to fumigation, 0.36 ug acetaldehyde/m3 and a 3-4 hr exposure were required for 100% mortality. A similar treatment (0.27-0.36 ug/m3 for 4 hr) was found to cause 100% mortality of aphids on lettuce ... . [R133, p. 58 (1995)] *The fumigant effect of acetaldehyde was tested on the garden slug (Arion hortensis; weight range, 0.2-0.5 g) and the grey field slug (Argriolimax reticulatux; weight range, 0.3-0.6 g). It caused both species to close the pulmonary aperture and to secrete excess 'irritation' mucus. Medial lethal values of 7.69 ... mg/l/hr for A. reticulatus and of 8.91 ... mg/l/hr for A. hortensis were found ... . [R133, p. 58 (1995)] *The seed germination of the onion (Allium cepa L.), carrot (Daucus carota L.), Palmer Amaranth (Amaranthus palmeri S Wats.), and tomato (Lycopersicon esculentum Mill.) after exposure to acetaldehyde (up to 1.52 mg/l), was examined ... . After a 3-day exposure, acetaldehyde inhibited the seed germination of all four plants by more than 50%. Seeds inhibited by a 3-day exposure to acetaldehyde followed by a 4-day recovery period germinated to the same extent as the controls after 7 days, except for the Palmer Amaranth, which remained inhibited. [R133, p. 58 (1995)] *Ip injection of male albino rats with 200 mg acetaldehyde/kg bw, daily, for 10 days, with additional pyrazole treatment to inhibit the conversion of acetaldehyde to ethanol, caused fatty accumulation in the liver, as indicated by accumulation of total lipids, triacyl glycerols, and total cholesterol, incr glycogenolysis, and a shift in metabolism from the citric acid cycle towards the pentose phosphate pathway in the liver. Serum triacyl glycerol, total cholesterol, and free fatty acid levels were also incr. Changes were similar in rats not receiving pyrazole pretreatment ... . The same treatment altered thyroid function, as indicated by lower serum T4 and decr iodine uptake in male albino rats, though these effects may have been secondary to the observed hepatic changes ... and histopathological changes of the pancreas, with resulting changes in trypsinogen levels and amylase secretion and activity in female Sprague-Dawley rats ... . [R133, p. 61 (1995)] *Groups of 20 Syrian hamsters were exposed to acetaldehyde vapour at 0, 700, 2400, or 8200 mg/m3 (0, 390, 1340, or 4560 ppm) for 6 hr/day, 5 days/wk, for 13 wk. Incr relative lung and heart weights as well as grouth retardation were reported after exposure to 8200 mg/m3, though there were no incr in mortality in any of the exposed groups ... . At the highest concn, there were severe degenerative, hyperplastic, and metaplastic changes in the epithelium as well as subepithelial glands and turbinate bones. Rhimitis was observed, with abundant nasal discharge and salivation. The epithelium of the larynx, trachea, and lungs was damaged, with some focal hyperplasia and metaplasia, accompanied by tracheitis and focal bronchopneumonia. Changes in the tracheal epithelium were also oberved at 2400 mg/m3. ... (NOEL: 700 mg/m3; LOEL: 2400 mg/m3). [R133, p. 62 (1995)] *Acetaldehyde (0.1% or 1.0% for 2 hr) induced mutations in genes that affect the egg-laying system of Caenorhabditis elegans ... . [R133, p. 71 (1995)] *Acetaldehyde induced chromosome malsegregation and mitotic cross-over (yA2 marker) in Aspergillus nidulans diploid strain P1 during early conidial germination ... . [R133, p. 71 (1995)] *Wistar rats (55/sex per dose) were exposed for life (6 hr/day, 5 days/wk, for 28 mo) to acetaldehyde concn of 1350, 2700, or 1800-5400 mg/m3 (the last conc was gradualy reduced from 5400 mg/m3 in wk 20 to 1800 mg/m3 in wk 52). Satellite groups of 5-10 additional rats of each sex were killed at 13, 26, and 52 wk. Growth retardation occurred throughout the study at all dose levels. Mortality was greater than in controls in all dose groups and all of the animals in the high-dose group had died by wk 102. At wk 52, there were generative changes in the olfactory nasal epithelium at all dose levels incl slight to severe hyperplasia and keratinized stratified metaplasia of the larynx (high dose only) and generative changes of the upper respiratory epithelium (incl papillomatous hyperplasia at the top dose only). In the trachea, there was focal flattening and irregular arrangement of the epithelium in 3/10 top-dose males at 52 wk. In satellite groups of 30 rats per sex, for which there was a 26-2k recovery period after 52 wk of exposure, there was evidence of partial regeneration of the olfactory epithelium in the low- and mid-dose groups; there was also progression from hyperplasia and metaplasia to neoplasia in some animals. At 28 mo, carcinomas of the nose developed in all exposed groups ... . Although tumor incidence was dose-related, the latency period appeared to be independent of concn. First tumors in all groups appeared during the 12th mo of exposure. The incidence of tumors was not inc in the lungs, larynx, and trachea. [R133, p. 76 (1995)] NTXV: *LD50 Rat oral 1930 mg/kg; [R134] *LD50 Rat sc 640 mg/kg; [R134] *LD50 Mouse sc 560 mg/kg; [R134] *LD50 Rat oral 661 mg/kg; [R36] *LC50 Rat inhalation 37 g/cu m/30 min; [R36] *LC50 Mouse inhalation 1500 ppm/4 hr; [R36] *LD50 Mouse iv 212 mg/kg; [R36] *LD50 Rabbit skin 3540 mg/kg; [R36] *LC50 Hamster inhalation 17,000 ppm/4 hr; [R36] *LD50 Hamster intratracheal 96 mg/kg; [R36] *LD50 Mouse oral 1230 mg/kg; [R133, p. 59 (1995)] *LD50 Dog oral > 600 mg/kg; [R133, p. 59 (1995)] *LC50 Rat inhalation 24 g/m3/4 hr; [R133, p. 59 (1995)] *LC50 Syrian hamster inhalation 31 g/m3/4 hr; [R133, p. 59 (1995)] *LD50 Mouse ip 500 mg/kg; [R133, p. 59 (1995)] *LD50 Pregnant mouse iv 165 mg/kg; [R133, p. 59 (1995)] ETXV: *LC100 Aphid 0.25% acetaldehyde for 2 hr (fumigation flask); [R135] *LC100 Aphid 1.5-2.0% acetaldehyde for 2-3 hr (in air-tight jars); [R136] *TLm Pin perch 70 mg/l/24 hr /Conditions of bioassay not specified/; [R48] *TLm Sunfish 53 mg/l/96 hr /Conditions of bioassay not specified/; [R48] *EC50 Pimephales promelas (fathead minnow) 30.8 mg/l/96 hr (confidence limit 28.0-34.0 mg/l), flow-through bioassasy with measured concentrations, 23.9 deg C, dissolved oxygen 7.2 mg/l, hardness 53.0 mg/l calcium carbonate, alkalinity 43.2 mg/l calcium carbonate, and pH 7.63. Effect: loss of equilibrium. (Test 1); [R137] *LC50 Pimephales promelas (fathead minnow) 37.2 mg/l/96 hr (confidence limit 31.1- 44.4 mg/l), flow-through bioassay with measured concentrations, 21.6 deg C, dissolved oxygen 7.5 mg/l, hardness 46.6 mg/l calcium carbonate, alkalinity 40.5 mg/l calcium carbonate, and pH 7.1. (Test 2); [R138] *LC50 Poecilia reticulata (guppy) 35 mg/l, semi-static, 10 laboratory-reared and acclimated fish, 2-3 mo old /conditions of bioassay not further specified/; [R139, p. 57 (1995)] *LC50 Lepomis macrochirus (bluegill) 53 mg/l/96 hr, static conditions /conditions of bioassay not further specified/; [R133, p. 57 (1995)] *EC50 Daphnia magna (waterflea) 42 mg/l/48 hr, static conditions, immobilization /conditions of bioassay not further specified/; [R133, p. 57 (1995)] TCAT: ?Chronic toxicity and oncogenicity of acetaldehyde were evaluated in groups of male and female Wistar rats (105/sex/group) exposed via inhalation for 6 hrs/day, 5 days/week for a maximum of 27 months to 0, 750, 1500 ppm acetaldehyde or initially to 3000 ppm which was gradually decreased to a final concentration of 1000 ppm in week 52 and beyond. A significant difference between treated animals and controls was observed in the following: mortality (dose-related increase in all treated groups), body weights (dose-related decrease in all male groups and females of the mid- and high-dose groups), alkaline phosphatase activity in the blood plasma (increased in all high-dose animals), nose lesions (dose related increase in number and severity at all dose levels), squamous metaplasia accompanied by slight to severe hyperkeratosis of the respiratory epithelium (found in most of the mid- and high-dose groups, none of the low-dose groups or controls), squamous cell carcinomas (dose related increase, found mainly in mid- and high-dose groups), adenocarcinomas (increased in all treated groups), and larynx hyperplasia and keratinized squamous metaplasia of the epithelium in the vocal cord region (found in most animals in the mid- and high-dose groups). [R140] ?Subchronic inhalation toxicity was evaluated with male albino SPF Wistar rats (10/group) exposed to acetaldehyde (AA) for 6 hrs/day, 5 days/week for 4 weeks using different exposure profiles. Animals were exposed to nominal concentrations of 0, 150 or 500 ppm either continuously for 6 hrs or in two 3-hr periods with an interruption of 1.5 hrs. Also, animals were exposed to 500 ppm continuously for 6 hrs/day with 3-4 superimposed 5-minute peak exposures/period of 2500-3500 ppm or exposed to 110 ppm for two 3-hr periods with 4 superimposed 5-minute peak exposures/period of 660 ppm. Compared to controls, animals exposed to AA exhibited statistically significantly decrease in the number, viability and phagocytosing capacity of macrophages in lung lavages from the high-dose groups (no additional effects due to interruption or peak exposures). There were no significant differences between animals exposed or not exposed to AA in body weight, lung weights and biochemical parameters determined in lung lavages, or gross examination at autopsy. Histopathological changes were observed in the nose of animals exposed to 500 ppm AA characterized by loss of microvilli accompanied by thinning and disarrangement of the layer of olfactory epithelium (no additional effects due to interruption or peak exposures). No compound-related effects on the pulmonary macrophages or histopathology were noted in the groups exposed to at least 150 ppm with or without peak exposures. [R141] POPL: */Workers with/ chronic respiratory, liver, kidney, or skin diseases. [R42, 1981.2] *Hepatocytes from livers of humans with alcoholic hepatitis were more susceptible to cytotoxicity of acetaldehyde than hepatocytes from normal liver of humans that were non-symptomatic or with viral hepatitis, alcoholic fatty liver, or stable alcoholic cirrhosis. [R72] *On the basis of the content of acetaldehyde in cigarettes ... it is likely that cigarettes contribute significantly to the total intake of acetaldehyde by smokers. [R139, p. 46 (1995)] *An incr sensitivity to ethanol with respect to facial flushing was observed in certain human populations (esp of Oriental origin), which was ascribed to genetic differences in acetaldehyde elimination, due to aldehyde dehydrogenase polymorphism ... . [R133, p. 83 (1995)] *The fetal alcohol syndrome is a specific pattern of congenital abnormalities found in children of mothers who drink heavily. [R133, p. 84 (1995)] ADE: *PENETRATION OF ACETALDEHYDE INTO CEREBROSPINAL FLUID WAS STUDIED IN HUMAN VOLUNTEERS DURING CALCIUM CARBIMIDE-ETHANOL INTERACTION. RESULTS INDICATE THAT ACETALDEHYDE PENETRATES HUMAN BLOOD CEREBROSPINAL FLUID BARRIER. [R142] *Intravenous infusion of 0.5 to 5% solutions of acetaldehyde to rabbits resulted in rapid elimination of acetaldehyde, at rate of 7-10 mg/min. [R143, (1985)] *Hepatic and blood acetaldehyde concentrations during ethanol oxidation were determined in C57 and DBA mice. Liver acetaldehyde was determined with the perchloric acid-thiourea method (no artifactual acetaldehyde formation). Levels ranging from 5 to 118 nmole/g were observed. At ethanol concentrations below 50-60 umole/g, liver acetaldehyde concentrations were higher in DBA compared with C57 mice. A positive correlation was found between the ethanol and acetaldehyde concentration, when ethanol concentration was below 25 (DBA) or 70 umole/g (C57). At higher ethanol concentrations the correlations tended to become negative. Hemolysis causes artifactual formation of acetaldehyde when blood acetaldehyde is determined using thiourea or semicarbazide methods. The magnitude of the artifactually formed acetaldehyde was of such order that no conclusions regarding the existence of true in vivo blood acetaldehyde concentrations could be drawn. [R144] *The effect of ethanol on tissue distribution of acetaldehyde following exposure to acetaldehyde was studied in rats. Male Sprague-Dawley rats were exposed to 20 mM acetaldehyde vapor for 1 hr. They were also administered 0 or 3 g/kg ethanol intragastrically. Blood samples were taken at selected times after acetaldehyde exposure was discontinued and analyzed for acetaldehyde. Other animals were killed immediately after acetaldehyde exposure or 3 hr after ethanol and the liver, blood, kidney, spleen, heart muscle, and skeletal were taken for acetaldehyde analysis. Acetaldehyde disappeared rapidly from the blood with a halflife of 3.1 min. After acetaldehyde inhalation, peripheral blood had the highest acetaldehyde content; other tissue concn were similar except for the liver which had a much lower acetaldehyde content. Acetaldehyde concn after ethanol admin were higher in the liver and blood than in other tissues. ... Blood acetaldehyde is not taken up by hepatocytes to any appreciable extent or hepatic acetaldehyde metabolism is very rapid. ... Inhalation exposure is a viable model for studying acetaldehyde toxicity. [R145] *CD-1 mice were treated ip on day 10 of gestation with 4, 6, or 7 g/kg ethanol. Maternal and embryonic tissues were analysed for ethanol and acetaldehyde levels 5 min to 24 hr after treatment. ... Acetaldehyde was detectable in maternal blood following all treatments and in maternal liver and embryos following treatment with 7 g/kg ethanol. [R146] *The effect of short term maternal ethanol administration on the disposition of ethanol in the ovine maternal-fetal unit was determined. Near term pregnant ewes (between 125 and 134 days of gestation; term, 147 days) received 1 hr iv infusion of 1 g of ethanol/kg of maternal body weight once per day for six days (N= 6 ewes) or an equivalent volume of saline for six days (N= 6 ewes). On the seventh day, the ethanol and saline pretreated animals were administerd 1 g of ethanol/kg of maternal body weight once per day. Concentrations were determined in maternal blood, fetal blood, and amniotic fluid samples obtained at selected times during the 14 hr study. Short term maternal administration of once-daily moderate dose ethanol did not produce major changes in the disposition of ethanol and its proximate metabolite, acetaldehyde, in the maternal, fetal, and amniotic fluid compartments during near-term ovine pregnancy. [R147] *The disposition kinetics of ethanol and acetaldehyde were investigated in 10 healthy subjects who fasted overnight, took an oral dose of calcium carbimide 50 mg and, 2 hr later, ingested 0.25 g/kg ethanol. Pharmacokinetic parameters estimated for ethanol showed statistically significant, but clinically unremarkable, changes following calcium carbimide ingestion. Acetaldehyde disposition was markedly different, with peak blood concentrations of 40-242 umol/l compared with 1.7-6.5 umol/l after placebo and significant increases in apparent elimination half-life and area under the concentration-time curve. The interaction of ethanol and calcium carbimide caused intense facial flushing in all subjects tested beginning 20-30 min after drinking. Results do not support a significant role of acetaldehyde in regulating in vivo oxidation of ethanol in humans. [R148] *... It is not known however whether acetaldehyde reaches the human fetus either by placental production or transfer. Studies utilizing the perfused human placental cotyledon show that the human placenta oxidizes ethanol to acetaldehyde releasing it into the fetal perfusate. Moreover when acetaldehyde is present in the maternal perfusate it is transferred to the fetal side reaching approximately 50% of the maternal level. [R149] *Acetaldehyde is rapidly absorbed and completely metabolized in body tissue, mostly in mammalian liver tissue. ... < 5% escapes in expired air, and no excretion in the urine has been found. The principal route for excretion of acetaldehyde is metabolism. [R39, 1991.3] *In humans, at low levels of exposure (concns up to 100 ppm in air), acetaldehyde is rapidly absorbed and metabolized. Acetaldehyde is apparently metabolized to N-nitroso-2-methylthiazolidine 4-carboxylic acid. This chemical was detected in the urine of human subjects during both oral and nasal breathing. [R39, 1991.3] *Six dogs were each given a single 600 mg/kg body weight dose of acetaldehyde by stomach tube. In two dogs, the maximum plasma concentration was reached after 15 minutes, while in the others plasma acetaldehyde was either close to the limit of detection (2 ug/ul) or was not detectable. Urinary recovery of acetaldehyde was < 0.02% of the dose. [R150] *... the results of toxicity studies indicate that absorption via the lungs and GI tract does occur. The physical and chemical properties of acetaldehyde indicate that absorption via the skin is also possible. [R133, p. 48 (1995)] *... following a single intragastric admin of 4500 mg ethanol/kg bw to male and female Wistar rats, acetaldehyde was detected in the blood and in brain interstitial fluid collected from the caudate nucleus and the thalamus-hypothalamus region. Following admin of disulfiram ... 20 hr prior to exposure to ethanol, there was a 6-fold incr in the concn of acetaldehyde in the blood and brain. Although acetaldehyde was found in interstitial fluid, none was detected in whole brain ... . [R133, p. 49 (1995)] *... used the blood of 5 healthy individuals, 6 alcoholic patients, and 2 baboons to show that, after alcohol consumption, most of the blood acetaldehyde was found in the red blood cells. In vivo, the acetaldehyde concn in red cells was about 10 times higher than that in the plasma. No significant variations were seen between the 3 groups. [R139, p. 50 (1995)] METB: *... THE EFFECTS OF ETHYL ALCOHOL ARE INDICATIVE OF EFFECTS OF ACETALDEHYDE, BECAUSE IT IS THE MAJOR METABOLITE OF ETHYL ALCOHOL. /ACETALDEHYDE IS/ ... THE PRINCIPAL METABOLIC BUILDUP PRODUCT OF DISULFIRAM THERAPY. [R12, 687] */IN THE OXIDATION OF ALCOHOL IN LIVER/ THE PRIMARY STEP IS OXIDATION OF ALCOHOL TO ACETALDEHYDE BY ALCOHOL DEHYDROGENASE ... THE ACETALDEHYDE IS CONVERTED TO ACETYL COENZYME A, WHICH IS THEN OXIDIZED THROUGH THE CITRIC ACID CYCLE OR UTILIZED IN VARIOUS ANABOLIC REACTIONS INVOLVED IN SYNTHESIS OF CHOLESTEROL, FATTY ACIDS AND OTHER TISSUE CONSTITUENTS. [R151] *A culture model is described for the study of acetaldehyde metabolism by explanted postimplantation rat and mouse conceptuses. The ability of 12 day rat and 10 day mouse embryos to metabolize acetaldehyde was demonstrated. The elimination rate for the 12 day rat conceptus using an initial acetaldehyde concentration of 1 mM in the medium was found to be 1.8 nmol/mg per min. When the conceptus was divided into embryonic and extraembryonic tissue, the rates were 1.6 and 2.2 nmol/mg per min, respectively. When the acetaldehyde concn was reduced to 50 microM the rate was 0.095 nmol/mg per min. The results provide further evidence for a functional barrier that prevents acetaldehyde entry to the embryo. A comparative experiment using CBA/beige mouse conceptus showed that acetaldehyde elimination characteristics may be qualitatively similar to those in rat embryos, but that the estimated elimination rate of 0.8 nmol/mg per minute was less than half that of the rat. Thus the metabolic barrier may be less efficient in the mouse. This may be important in view of the greater sensitivity of the mouse to ethanol embryotoxicity. [R152] *Homogenates of respiratory and olfactory tissue from the rat nasal cavity were examined for their capacity to catalyze the NAD(+)-dependant oxidation of formaldehyde (in the presence and absence of glutathione) and of acetaldehyde. Both aldehydes were oxidized efficiently by nasal mucosal homogenates, and formaldehyde dehydrogenase and aldehyde dehydrogenase were tentatively identified in both tissue samples. At least two isoenzymes of aldehyde dehydrogenase differing either with respect to their apparent Km and max values with acetaldehyde as substrate, were found in the nasal mucosa, one of which may catalyze the oxidation of both formaldehyde and acetaldehyde. ... Repeated exposures of rats to formaldehyde (15 ppm, 6 hr/day, 10 days) or to acetaldehyde (1500 ppm, 6 hr/day, 5 days) did not substantially affect the specific activities of formaldehyde dehydrogenase and aldehyde dehydrogenase in nasal mucosal homogenates. Glutathione is a cofactor for formaldehyde dehydrogenase; the concentration of nonprotein sulfhydryls in respiratory mucosal homogenates was approximately 2.8 umoles/g and was not changed significantly by repeated exposures to formaldehyde (15 ppm, 6 hr/day, 9 days). These data indicate that the rat nasal mucosa, which is the major target site for both aldehydes in inhalation toxicity studies, can metabolize both formaldehyde and acetaldehyde, and that the specific activities of formaldehyde and aldehyde dehydrogenase in homogenates of the nasal mucosa are essentially unchanged following repeated exposures to toxic concentrations of either compound. [R153] *Acetaldehyde is a toxic metabolite formed in the mammalian liver during the oxidation of ethanol. [R143, (1984)] *Concurrent admin of acetaldehyde, L-cysteine and nitrite to rats yielded n-nitroso-2-methylthiazolidine-4-carboxylic acid (cis- and trans-isomers), > 90% of which was excreted in the urine. [R143, (1985)] *The metabolism curves for both ethanol and acetaldehyde after an acute intragastric or iv administration to the mother, have been studied. Metabolism of ethanol followed a very similar pattern in both the pregnant and their control virgin rats, whereas the levels of acetaldehyde derived from the metabolism of the administered ethanol were significantly higher in the pregnant animals, this fact implying that, in late gestation, there is a decrease in the mother's capacity for acetaldehyde metabolism. At the fetal side of the placenta, 150 min after the administration, the concentration of ethanol was similar to that found in the mother's circulation, thus proving a fluid transit of this metabolite through the placenta. The concentration of acetaldehyde in the fetus was relatively high, after the intragastric administration of the ethanol dose. At certain ethanol concentrations, acetaldehyde can cross the rat placenta. [R154] *The activity of alcohol dehydrogenase was determined in the near-term pregnant ewe. There was little alcohol dehydrogenase activity in fetal liver (4.4%) and placenta (0.2%) compared with maternal liver. Low Km (uM acetaldehyde) acetaldehyde activity was similar in the three tissues. High Km (mM acetaldehyde) aldehyde dehydrogenase activity was less in fetal liver (57%) and placenta (16%) compared with maternal liver. These data and the pharmacokinetics of ethanol and its proximate metabolite, acetaldehyde, in the near-term pregnant ewe indicate that ethanol elimination from the maternal-fetal unit is regulated primarily by maternal hepatic alcohol dehydrogenase-catalyzed biotransformation of ethanol, and low Km aldehyde dehydrogenase activity in the fetal liver and placenta protects the fetus from exposure to ethanol-derived acetaldehyde, which is produced primarily in the maternal compartment. [R155] *Blood concentrations of ethanol and acetaldehyde were determined in suckling rats after a single oral ethanol gavage. After intragastric administration of 3 g/kg body weight of ethanol, ethanol concentrations were much higher in suckling rats than in adult animals, expecially at 90, 120, and 180 min after its administration. In addition, acetaldehyde concentrations were undetectable in suckling rats as opposed to adult rats, in whom micromolar concentrations were detected. Thus 5 to 30 day old rats seem to have a limited capacity for in vivo ethanol metabolism. The analysis of hepatic alcohol dehydrogenase activity revealed that it was very low at birth and it increased progressively with time attaining adult levels after 20 days of life. The alcohol dehydrogenase activity present in the liver of suckling rats presented similar Km values and sensitivity to pyrazole as adult rat liver. Thus, the pattern of in vivo ethanol elimination during the suckling period is not explained by hepatic alcohol dehydrogenase activity. At birth, hepatic aldehyde dehydrogenase activity was low and it increased reaching adult levels during the suckling period. Adult levels for the component of low Km were attained earlier than for the component of high Km. The low affinity hepatic aldehyde dehydrogenase component in the newborn was different from that in the adult as assessed by kinetic studies and by its sensitivity to disulfiram. [R156] *Acetaldehyde, the primary hepatic oxidative metabolite of ethanol, may contribute to fetal injury associated with maternal ethanol ingestion. Studies utilizing the perfused human placental cotyledon show that the human placenta oxidized ethanol to acetaldehyde, releasing it into the fetal perfusate. Moreover, when acetaldehyde is present in the maternal perfusate, it is transferred to the fetal side, reaching approximately 50 percent of the maternal level. [R149] *The activities of aldehyde dehydrogenase and alcohol dehydrogenase were measured in term placentas of 13 alcoholic women and 16 matched controls. With acetaldehyde 8 mmol/1 as substrate, the aldehyde dehydrogenase activity was 29.1 + or - 12.2 and 34.4 + or - 15.3 u/g of wet weight (mean + or - SD; p > 0.4) for alcoholics and controls, respectively. With 50 umol of acetaldehyde, aldehyde dehydrogenase activity was undetectable in both groups. No alcohol dehydrogenase activity could be detected in the placentas. The weights of placentas and newborns were significantly lower in the alcoholic group (placentas: 526 + or - 116 vs 653 + or - 77 g, p < 0.005; newborns 2,878 + or - 417 vs 3,595 + or - 346 g, p < 0.001. In chronic alcohol abuse, the placenta plays a negligible role in the metabolism of ethanol and acetaldehyde. [R157] *Aldehyde dehydrogenase V-A isozymes in saliva were detected in 96 patients with or without liver disease in order to clarify the relationships of the presence or absence of aldehyde dehydrogenase V-A isozymes to the metabolism of acetaldehyde and alcoholic liver disease. The incidence of aldehyde dehydrogenase V-A deficiency was not different between the patients with alcoholic liver disease and those with non-alcoholic liver disease, nor between the patients with liver and disease and without liver disease in no relation to alcohol misuse. Acetaldehyde metabolism was not different between aldehyde dehydrogenase V-A deficient and non-deficient patients even in the aldehyde dehydrogenase I-deficient patients. Aldehyde dehydrogenase V-A isozymes play virtually no role in the metabolism of acetaldehyde and its deficiency is not related to the development of alcoholic liver disease. [R158] *... Enzyme capable of converting ethanol to acetaldehyde is catalase, which by virtue of its peroxidative activity uses hydrogen peroxide to perform the oxidation. However, normally there is very little peroxide available to support the reaction in hepatocytes, and its unlikely that catalase can account for more than 10% of ethanol metabolism. This level could change if peroxide levels in hepatocytes were elevated. ... Clofibrate, which stimulates peroxisomal fatty acid oxidation, increases peroxide levels and thereby enchances ethanol oxidation by catalase. [R124, 698] *Gas chromatographic analysis of human whole-blood lymphocyte cultures treated for 10 sec to 20 min with vinyl acetate (5.4 mM) revealed a rapid degradation of vinyl acetate and formation of acetaldehyde. During the 20 min observation period, no degradation of vinyl acetate or formation of acetaldehyde were observed in complete culture medium without blood, which suggested that the reaction was enzymatic. Acetaldehyde induced sister chromatid exchanges in human whole-blood lymphocyte cultures at concentrations (0.125-2 mM) comparable to those used for vinyl acetate. The results indicate that vinyl acetate induces chromosome damage in cell cultures through enzyme-mediated hydrolysis to acetaldehyde. [R73] *In humans, at low levels of exposure (concns up to 100 ppm in air), acetaldehyde is rapidly absorbed and metabolized. Acetaldehyde is apparently metabolized to N-nitroso-2-methylthiazolidine 4-carboxylic acid. This chemical was detected in the urine of human subjects during both oral and nasal breathing. A fraction of this may be formed as a two-step synthesis in vivo from acetaldehyde and L-cysteine to yield 2-methylthiazolidine 4-carboxylic acid, which is easily nitrosated. [R39, 1991.3] *Although catalase and other oxidases may contribute to metabolism .. because of its high affinity, at least 90% of acetaldehyde is oxidized by mitochondrial ALDH ... reducing NAD+ to NADH in the process. This step can be blocked by disulfiram. [R133, p. 51 (1995)] *ALDH localization in the respiratory tract of Fischer-344 rats was studied ... . Histochemical studies indicated activity principally in the nasal respiratory epithelium, esp in the supranuclear cytoplasm of ciliated epithelial cells. Activity was also high in the Clara cells of the lower bronchioles. The tracheal epithelia possessed only low levels of ALDH. The olfactory epithelium was almost devoid of ALDH activity. [R133, p. 51 (1995)] *In an in vitro study ... studied the metabolism of acetaldehyde in isolated dog, rat, guinea-pig, and baboon kidney-cortex tubules. Acetaldehyde was found to be metabolized by the tubules at high rates and in a dose-dependent manner in all four species. It was noted that, at all acetaldehyde concn, most of the acetaldehyde removed was recovered as acetate in dog, guinea-pig, and baboon, but not in rat kidney tubules. [R133, p. 52 (1995)] *Human liver ALDH consists of at least 4 main isoenzymes, which are also present in many other tissues ... . Mitochondrial ALDH is inactive in at least 40% of the Oriental population. The frequently observed intolerance to alcohol (the "flushing" reaction) is linked to this deficiency, which is produced by an inherited positive mutation in the corresponding gene ... . Subjects with phenotypic deficiency have always shown the presence of at least one mutant gene (heterozygous or homozygous) ... . [R133, p. 53 (1995)] *In vitro, acetaldehyde (0.04-0.88 g/l) was metabolized at high rates and in a dose-dependent manner in isolated human kidney-cortex tubules ... . [R133, p. 53 (1995)] BHL: *< 15 min in the circulation [R39, 1991.3] INTC: *The possibility that acetaldehyde accumulation potentiates the acute toxicity of ethanol was studied by pretreating rats with cyanamide, an aldehyde dehydrogenase inhibitor. At death, the concn of acetaldehyde in heart, blood, and cerebrospinal fluid was 7 to 9 times higher than in rats given ethanol only. [R159] *Calcium pantothenate, calcium 4'-phosphopantothenate ... pantethine ... substantially decreased the toxicity of ip administered acetaldehyde in mice. The pantothenates were administered 20-30 minutes prior to ... acetaldehyde /administration/. [R160] *... Combinations of acetaldehyde plus nicotine, acetaldehyde plus caffeine, and acetaldehyde plus dopamine ... exhibited lethal synergy /in rats/. Protection against the lethal synergy of these combinations could be demonstrated by oral pretreatment with l-ascorbic acid, l-cysteine, or phenoxybenzamine (alpha-adrenergic blocker), but not propranolol (beta-adrenergic blocker). [R161] *Administration of acetaldehyde by inhalation or ip (in repeated doses) /to rats/ provokes ... micronecrosis in the myocardium. Administration of acetaldehyde ... potentiates the cardionecrotic action of adrenalin. Pretreatment with L-DOPA potentiates while that of L-alpha-methyl-DOPA or alpha-methyltyrosine averts the necrotic action of acetaldehyde. [R162] *Chinese hamster ovary cells exposed to ultraviolet light, methyl methanesulfonate, mitomycin C or bleomycin and then post treated with acetaldehyde (0.01 or 0.02%) contained more chromosomal aberrations than cells exposed to the mutagenic agents alone. Chromatid exchanges were predominantly increased in cultures treated first with the ultraviolet light, methyl methanesulfonate, or mitomycin C and then with acetaldehyde, whereas chromosome breaks and chromatid exchange were the major types of aberrations increased in the cultures treated with bleomycin and acetaldehyde. [R163] *Disulfiram inhibits enzymatic oxidation of acetaldehyde to acetate which occurs in the liver during normal alcohol catabolism. Disulfiram competes with nicotinamide adenine dinucleotide for aldehyde dehydrogenase. When small amounts of alcohol are ingested after disulfiram administration, the acetaldehyde concentration in blood may increase to 5 to 10 times the concentration observed after the metabolism of the same amount of alcohol used alone. High blood concentrations of acetaldehyde may produce the unpleasant symptoms of the disulfiram-alcohol reaction (the acetaldehyde syndrome). Others feel that the carbon disulfide metabolite of disulfiram produces many of the disagreeble symptoms. [R164] *The dicarbonyl compound methylglyoxal potentiated the cell inactivating effect of cis-dichlorodiammine-platinum (II) when cultured human NHIK 3025 cells were treated with both drugs in simultaneous combination. Glyoxal, another dicarbonyl compound, did not affect cis-dichlorodiammine-platinum (II)-induced cytotoxicity in any manner, nor did the acetaldehyde and propionaldehyde. [R165] *The effects of ethanol and acetaldehyde on the clastogenicity of ultraviolet light (UV), methyl- methanesulfonate, mitomycin-C, and bleomycin were investigated in Chinese hamster ovary cells. Both ethanol and acetaldehyde synergistically potentiated the clastogenicity of the tested clastogens. While ethanol itself did not induce apparent chromosome aberrations induced by the various clastogens. Chromatid exchanges were predominantly increased in cultures treated with UV, methyl methanesulfonate, or mitomycin-C followed by ethanol, whereas chromosome breaks and chromatid exchanges were the major types of aberrations potentiated in cultures treated with bleomycin and ethanol. Post treatment with acetaldehyde also potentiated the chromosome aberrations induced by UV, methyl-metehanesulfonate, mitomycin-C, and bleomycin; the main types of aberrations which were increased were similar to those increased by post treatment with ethanol. [R166] *Ethanol, in vivo, inhibits the metabolism of ethyl carbamate in mice. To characterize the enzyme system responsible, the metabolic products of ethanol metabolism were studied to determine whether ethanol or its metabolites is inhibitory. Acetaldehyde (400 mg/kg) is a potent inhibitor of ethyl carbamate metabolism for about 2 hr in vitro, but sodium acetate is not. Disulfiram (200 mg/kg) has a prolonged inhibitory effect; this effect is enhanced and extended when the disulfiram is combined with acetaldehyde (400 mg/kg). Acetaldehyde is an inhibitor of the metabolism of ethyl carbamate. [R167] *In preliminary studies with mice, blood was obtained from the tails of mice (C57B1/6) which had been given ethanol, 4.8 g/kg, 90 min earlier. Acetaldehyde levels in blood remained relatively constant over a 6 hr period after ethanol admin, while blood ethanol levels declined between the 90 min and 480 min assay times. Pretreatment of mice with methionine or fructose (350 mg/kg) had little effect on the concn of ethanol found in blood of C57BL/6 or DBA/2 mice at 90, 180, 360, or 480 min after ethanol. Methionine significantly reduced circulating acetaldehyde levels without altering circulating levels of ethanol. Hepatic levels of acetaldehyde were also lowered by methionine. Groups of DBA/2 mice (n= 6) were given 4.8 g/kg ethanol by mouth, along with one of the following treatments: 1) 0.9% saline by mouth 0.15 ml/10 g body wt, 1 hr before receiving ethanol; 2) 970 mg/kg methionine, by mouth, 1 hr before ethanol; 3) 970 mg/kg methionine ip, 1 hr before ethanol; or 4) 970 mg/kg methionine ip, 1 hr after ethanol. At 90 min after ethanol admin, blood acetaldehyde levels of groups 2 and 3 differed significantly from the other 2 groups (p < 0.05) and at 210 min group 4 was significantly different from group 1 (p < 0.05). [R77] *Male AA and ANA rats were admin solutions containing D,L-methionine (900 mg/kg, per os), potassium citrate (250 mg/kg) and pyridoxal phosphate (2 mg/kg). The methionine soln or vehicle was admin 1 hr before the rats received ethanol (1.5 g/k ip), and tail blood (0.2 ml) was obtained at 60, 120, and 180 min after ethanol admin. Methionine significantly reduced circulating acetaldehyde levels without altering circulating levels of ethanol. ANA rats exhibited higher circulating levels of acetaldehyde compared to AA rats. In certain rats, liver acetaldehyde levels were determined, 195 min after receiving ethanol. Hepatic levels of acetaldehyde were also lowered by methionine. Acetaldehyde levels in liver of AA rats were lowered from 6 uM to 1 uM, and for ANA rats from 19 uM to 8 uM. [R77] *Ethanol and acetaldehyde potentiate MPTP toxicity in mice, selectively enhancing dopamine depletion in the striatum and markedly increasing loss of DA neurons in the substantia nigra. Several months after these combined treatments there is no evidence of any recovery. In vivo experiments indicated that relatively low doses of ethanol or acetaldehyde potentiate directly MPP+ toxicity, apparently without interfering with its pharmacokinetics. However when higher doses of these drugs were administered, they also decreased MPP+ clearance from the striatum. Acetaldehyde also increased initial MPTP accumulation in the whole brain but failed to enhance MPP+ levels, thus indicating the acetaldehyde effect is not related to MPTP metabolism. In vitro studies confirmed that acetaldehyde does not modify MPTP metabolism in striatal or mesencephalic astrocytes in culture. In mesencephalic neuronal cultures acetaldehyde does not change the levels of MPP+ uptake (MPP+ is accumulated in putative dopamine neurons in vitro with a mechanism similar to that of the dopamine high affinity uptake) nor its spontaneous release. The slower MPP+ clearance from the stratum after acetaldehyde is not related to a direct effect of acetaldehyde on dopamine neurons or astrocytes. [R168] *Llv.52 has been shown to bring out a faster elimination of acetaldehyde from the body and thus prevent alcoholic liver damage. Other toxic effects of alcohol may also be due to acetaldehyde and may be prevented by Liv.52. In this study, rats were given 20 (v/v) ethanol in drinking water, during the gestation period, and the effect on maternal body weight and fetal outcome was noted. The protective effect of Liv.52 administration during the gestation period was studied. The results show that ethanol ingestion caused a decrease ln gestational weight gain, total fetal weight, and number of lave fetuses. There were increases in resorptions. Liv.52 administration reduced the deleterious effects of ethanol. The concentration of acetaldehyde in the amniotic fluid of ethanol-consuming animals was 0.727 ug/ml. Liv.52 administration lowered it to 0.244 ug/ml. The protective effect of Liv.52 could be due to the rapid elimination of acetaldehyde. [R131] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Acetaldehyde's production and use in the manufacture of acetic acid, synthetic flavors, and other chemicals may result in its release to the environment through various waste streams. Acetaldehyde is found in auto exhaust, tobacco smoke, and emissions from power plants using fossil fuels, wood, or trash. Acetaldehyde is a natural product of combustion and photo-oxidation of hydrocarbons commonly found in the atmosphere; it also is an intermediate product in the metabolism of ethanol and sugars. If released to air, acetaldehyde is a gas and will exist in the gas phase. Gas-phase acetaldehyde will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 24 hrs. Acetaldehyde absorbs solar radiation and dissociates to form free radicals; the photolysis half-lives range from 8.4 to 16 hrs. If released to soil, acetaldehyde is expected to have very high mobility based upon an estimated Koc of 1. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 6.7X10-5 atm-cu m/mole. Acetaldehyde will volatilize from dry soil surfaces because it is a gas. If released into water, acetaldehyde is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Acetaldehyde is expected to biodegrade rapidly in the environment under aerobic and anaerobic conditions. Acetaldehyde, present at 100 mg/l, reached 80% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 6.5 hrs and 5.3 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Acetaldehyde is not expected to chemically hydrolyze in the environment due to the lack of hydrolyzable functional groups. Occupational exposure to acetaldehyde may occur through inhalation of this compound at workplaces where acetaldehyde is produced or used. Monitoring data indicate that the general population may be exposed to acetaldehyde via inhalation of ambient air and tobacco smoke, and ingestion of food containing acetaldehyde. (SRC) NATS: *Acetaldehyde is a natural product of combustion and photo-oxidation of hydrocarbons commonly found in the atmosphere(1). Acetaldehyde is an intermediate product in the metabolism of ethanol and sugars(1); therefore occurs in trace quantities in human blood(1). It is present in small amounts in all alcoholic beverages, e.g., beer, wine, and spirits and in plant juices and essential oils, roasted coffee and tobacco smoke(1). Plant volatiles, forest fires, volcanos, animals wastes, and insects are sources of acetaldehyde(2). [R169] ARTS: *Acetaldehyde's production and use in the manufacture of acetic acid and acetic anhydride, n-butanol, 2-ethylhexanol, peracetic acid, aldol, pentaaerythritol, pyridines, chloral, 1,3-butylene glycol, and trimethylolpropane, and synthetic flavors(1) may result in its release to the environment through various waste streams(SRC). Acetaldehyde is found in pulp mill effluent(2), auto exhaust, and tobacco smoke(3-5). Emissions of acetaldehyde occurs from power plants using fossil fuels, wood or trash(4,6). Aldehyde emissions (e.g., acetaldehyde) occur from residential wood burning; it is estimated to be between 14 and 54 giga grams/yr which is comparable to power plant emissions and between 22 and 84% of all automobile emissions(6); it is likely that residential wood burning is the major source of primary aldehydes in some areas during winter months(6). Chlorination can result in the production of acetaldehyde in water(7). [R170] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that acetaldehyde is expected to have very high mobility in soil(SRC). Volatilization of acetaldehyde from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 6.7X10-5 atm-cu m/mole(3). The potential for volatilization of acetaldehyde from dry soil surfaces may exist(SRC) based upon a vapor pressure of 902 mm Hg(4). Acetaldehyde is expected to biodegrade rapidly in the environment under aerobic and anaerobic conditions(5-7). Acetaldehyde, present at 100 mg/l, reached 80% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(5). Acetaldhyde was oxidized in a silty clay loam but no rates were given(8). [R171] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that acetaldehyde is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 6.7X10-5 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 6.5 hrs and 5.3 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 3(SRC), from its estimated log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Acetaldehyde is expected to biodegrade rapidly in the environment under aerobic and anaerobic conditions(7-9). Acetaldehyde, present at 100 mg/l, reached 80% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(7). In a die-away test in seawater, acetaldehyde concns declined to approximately 25% of initial values in 1 hr, whereas no decline in concn was observed in sterile controls(8). [R172] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), acetaldehyde is a gas under ambient conditions(2). Gas-phase acetaldehyde is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 24 hrs(SRC), calculated from its rate constant of 16X10-12 cu cm/molecule-sec at 25 deg C(3). Acetaldehyde absorbs solar radiation (> 290 nm)(4) and dissociates to form free radicals(5). The half-life in the atmosphere resulting from photolysis is reported as 8.4 hr(5) and 16 hr (6). [R173] BIOD: *AEROBIC: Acetaldehyde is expected to biodegrade rapidly in the environment under aerobic conditions(SRC). Acetaldehyde, present at 100 mg/l, reached 80% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). Acetaldehyde was also easily biodegraded by biological sewage treatment(2). Laboratory tests confirm the degradability of acetaldehyde by acclimated sludge and sewage(3-7) with theoretical BODs of 28% in 24 hr(3), 100% in 5 hr(4), 40.5% in 5 days(8), and 70% in 5 days(5). Unless special care was taken, some of the losses reported could be due to volatilization(SRC). Acetaldehyde was oxidized in a silty clay loam but no rates were given(9). In a die-away test in seawater, acetaldehyde concns declined to approximately 25% of initial values in 1 hr, whereas no decline in concn was observed in sterile controls(10). [R174] *ANAEROBIC: Acetaldehdye degrades by anaerobic biological treatment(1-4) with 97% utilization being reported in a system with a 20 day hydraulic retention time(2) and 67% being removed in an anaerobic lagoon(4). [R175] ABIO: *The rate constant for the vapor-phase reaction of acetaldehyde with photochemically-produced hydroxyl radicals is 16X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 24 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(SRC). Acetaldehyde absorbs solar radiation (> 290 nm)(2) and dissociates to form free radicals(3). The half-life in the atmosphere resulting from this photolysis is reported as 8.4 hr(3) and 16 hr (4). Another investigator calculates a photolysis half-life at 55 deg N latitude as 34 hr in summer and 296 hr in winter(5). Acetaldehyde also reacts with several atmospheric species, such as nitrogen dioxide and the nitrate radical(3,6-8). The reaction with nitrate radicals has been recognized as an important nighttime sink for some chemicals. The half-life for the reaction of acetaldehyde with nitrate radicals is 72 hr(8). The reactivity of acetaldehyde in photochemical smog where a complex mixture of radicals and reactive organic chemicals exist is complex. Acetaldehdye is both produced and consumed under such conditions and the half-life will be a maximum of a few hours(9,10). Acetaldehyde is photochemically produced in unsterilized and sterilized seawater, presumably from natural dissolved organic matter, upon irradiation with midday sunlight for 4-8 hr(11). Aldehyde concns in seawater placed outside showed clear diurnal variations; concns reached a maximum during the late afternoon and quickly decreased to predawn levels after sunset(11). Acetaldehyde is not expected to chemically hydrolyze in the environment due to the lack of hydrolyzable functional groups(12). [R176] BIOC: *An estimated BCF of 3 was calculated for acetaldehyde(SRC), using an estimated log Kow of -0.17(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R177] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for acetaldehyde can be estimated to be 1(SRC). According to a classification scheme(2), this estimated Koc value suggests that acetaldehyde is expected to have very high mobility in soil(SRC). [R178] VWS: *The Henry's Law constant for acetaldehyde is 6.7X10-5 atm-cu m/mole(1). This Henry's Law constant indicates that acetaldehyde is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 6.5 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5.3 days(SRC). Acetaldehyde's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of acetaldehyde from dry soil surfaces may exist(SRC) based upon a vapor pressure of 902 mm Hg(3). [R179] WATC: *DRINKING WATER: In a 10 city survey representing different sources and types of contamination of raw water supply, acetaldehyde was detected in 4 of 10 supplies(1,2); the concn of acetaldehyde in the water supplies of Philadelphia and Seattle were 0.1 ppb(1,2). Acetaldehyde was detected but not quantified in the drinking water of New Orleans(3), Cincinnati, Miami, Ottuma (IA)(4), and Durham(NC)(2). Median concns of acetaldehyde in drinking water from 35 US treatment plants were 2.7, 2.6, and 1.8 ppb in Summer 1988, Fall 1988, and Winter 1989, respectively(5). [R180] *SURFACE WATER: Acetaldehyde was detected but not quantified in the Mississippi River at New Orleans(1). The concn of acetaldehyde in surface seawater off the southwest coast of Florida was 19 nM at mid afternoon (max concn) and 2 nM at 6 AM(2). [R181] *RAIN/FOG: Analysis of rain, mist and dew samples, collected in Petten (The Netherlands) during 1987 and 1988, showed acetaldehyde levels of 5 to 185 ug/l for rain (N= 8), 15 and 200 ug/l for dew and 30 ug/l for mist(1). The range of concns of acetaldehyde in ice fog (Fairbanks, AK), rain (5 sites-California), clouds (California), mist (2 sites-California), and fog (4 sites-California) were 0.007-0.13 ppm, 0-0.11 ppm (2 of 6 sites positive), 0-0.59 ppm, 0.10-0.11 ppm, and 0-0.17 ppm, respectively(2). Cloud and rain water samples were collected in the Spring of 1991 in the Vosges mountains (France) and analyzed for acetaldehyde; the mean concn of acetaldehyde was 17 ug/l (range, not detected (detection limit unspecified) to 58 ug/l) and 12 ug/l (range, 8 to 17 ug/l) for cloud and rain water samples, respectively(3). The mean and range of concns of acetaldehyde in precipitation over Hanover, Germany were 12.0 and 1.5-20.5 ppb, respectively(4). [R182] EFFL: *The concn of acetaldehye from gasoline engine exhaust ranged from 0.8 to 4.9 ppm(1); the concn in diesel exhaust was 3.2 ppm(1). Acetaldhyde was detected in the effluent from chemical plants into Mobile River (Alabama) and Pacolet and Enoree River (South Carolina)(2). Effluent from sewage treatment plants contained acetaldehye(2), although it has not been determined whether the acetaldehyde was in the influent or formed as a product of microbial degradation(3). Acetaldhyde was detected in coffee-roasting operations (range, 14-22 mg/cu m), from a lithographic plate coater (range, 0.5-4.1 mg/cu m), from an automobile-spray booth (range, 2.5-3.4 mg/cu m), from plants manufacturing acrylic acid (concns unspecified), and from a fat-rendering plant (range, 3.4-6.8 mg/cu m)(4). The emission of acetaldehyde from a new carpet was measured in a large-scale environmental chamber; the specific mass emission of acetaldehyde from a textured loop, 100% nylon-6, solution dyed carpet over a 168 h period was 2.52 mg/sq m(5). The emission rate of acetaldehyde during the operation of dry-process photocopiers ranged from below the detection limit to 1,600 ug/hr per copier(6). [R183] ATMC: *RURAL/REMOTE: The avg concn of acetaldehyde over a 24 hr period at Pt Barrows, Alaska was 0.24 ppb (range, 0-0.3 ppb; 7 of 25 samples positive)(1). At 2 rural sites near Tuscon, AZ (18 measurements), the mean concn was 6.9 ppb (standard deviation = 6.9 ppb)(2). [R184] *URBAN/SUBURBAN: The annual avg concn of acetaldehyde between July 1982-May 1983 at Brookhaven National Laboratory, (Upton, NY) was 2.9 ppb (vol/vol)(1); seasonal mean levels of acetaldehyde are 1, 8.4, 3.5, and 3.2 ppb in Winter, Spring, Summer, and Fall, respectively(1). At the University of Southern California (Los Angeles, CA), the concn of acetaldehyde was between 2-39 ppb (vol/vol)(2). At the UCLA campus (Los Angeles, CA) during light to moderate smog, the concn of acetaldehyde ranged between 0-32 ppb(3). At Claremont, CA during severe smog, the concn of acetaldehyde (day or night time) ranged from 3-35 ppb; the concn in air particulate matter ranged from 2-406 ng/cu m(3). In a 1985 study in Claremont, CA for over five days in September, acetaldehyde concns ranged from 1.0 to 9.0 ppb with a median concn of 4.0 ppb(4); highest values were observed in the afternoons(4). A one year study at six locations in southern California found 24-hr ambient levels reaching 13 ppb and location average values ranging from 2.9 to 4.8 ppb(5). At Tuscon, AZ, the mean concn of acetaldehyde was 23 ppb (std dev, 12 ppb; N = 17)(6). [R185] *URBAN/SUBURBAN: The mean concn of acetaldehyde at five US cities were as follows: Pittsburgh, 1.4 ppb; Chicago, 2.1 ppb; Downey, CA, 8.5 ppb; Houston, 2.2 ppb; Denver, 1.0 ppb(1). Acetaldehyde was detected in air from San Paulo, Brazil (range, 2.3-7 ppb; July 1988)(2) and Grenoble, France (range, 1-10 ppb; May 1995)(3). The concn of acetaldehyde in air from Rome, Italy ranged from 3.1-17.4 ppb between Jun-Jul 1994 and from 2.9-6.6 ppb between Jan-Mar 1995(4). The concn of acetaldehyde at the Univ of Mexico campus between Mar-May 1993 ranged from 2.0 to 66.7 ppb(5). Ambient levels of acetaldehyde from 24 samples were collected every day at 6 Southern California locations between 9/2/88 and 9/25/89; avg concns in Anaheim, Azusa, Burbank, Hawthorne, Upland, and W. Los Angeles were 3.5 ppb (max, 7.8 ppb), 3.1 ppb (max, 7.7 ppb), 4.8 ppb (max, 10.0 ppb), 2.9 ppb (max, 9.4 ppb), 3.9 ppb (max, 13.2 ppb), and 3.8 ppb (max, 9.3 ppb), respectively(6). The mean concn of acetaldehyde in outdoor suburban air from central New Jersey (sampling period; Jun 21 to Aug 5, 1992) was 2.64 ppb (range, 0.99-12.66 ppb)(7). [R186] *SOURCE DOMINATED: In the US, the range and median concns of acetaldehyde at source dominated locations were 2.0 to 69 ppb, and 7.8 ppb (36 samples), respectively(1). [R187] *INDOOR AIR: The concn of acetaldehyde in 14 homes and a small office building in northern Italy ranged from 1 to 48 ug/cu m with a mean value of 17 ug/cu m(1). The ratio of the minimum, maximum, mean, and median concn in indoor versus outdoor air was 0.5, 24, 6.0, and 3.6, respectively. The concn of acetaldehyde measured in EPA headquarters building in Washington, DC ranged from 3.8 to 11.1 ug/cu m with a median value of 5.2 ug/cu m(2). [R188] FOOD: *The acetaldehyde concn in 18 European beers was reported to range from 2.6-13.5 mg/l. ... /It was detected/ in commercial wine samples in Japan at levels of 0.2-1.2 mg/l. It has also been identified in Cuba in the aqueous condensate obtained from the concentration of sweet orange juice. Acetaldehyde has been detected in cheese, heated skim milk, cooked beef, cooked chicken, and rum. Trace quantities ... are present in a flavoring used to impart a butter-like flavor to processed foods, especially margarine. [R189] *Acetaldehyde was detected but not quantified in pineapples, apples, grapefruit, bananas, peaches, pears, blackcurrants, strawberries, oranges, grapes and raspberries(1). Acetaldehyde was detected in coffee(2), kiwi fruit(3), chicken breast(4), and roasted filberts(5). The acetaldehyde concn in 18 European beers was reported to range from 2.6-13.5 mg/l(6). It was detected in commercial wine samples in Japan at levels of 0.2-1.2 mg/l(6). It has also been identified in Cuba in the aqueous condensate obtained from the concn of sweet orange juice(6). Acetaldehyde has been detected in cheese, heated skim milk, cooked beef, cooked chicken, and rum(6). Trace quantities are present in a flavoring used to impart a butter-like flavor to processed foods, especially margarine(6). The concns of acetaldehyde in cooked sweet corn products, such as canned cream, canned kernel, frozen kernel, and fresh kernel, were 1.4, 1.0, 1.2, and 1.7 ppm, respectively(7). The concn of acetaldehyde in popcorn was 4.6 mg/kg(8). In Japan, acetaldehyde was detected in sake (range, 14.8 to 60.2 ppm), wine (range, 32.8 to 65.9 ppm), beer (range, 5.23 to 11.7 ppm), whiskey (range, 25.0 to 102.0 ppm), apple juice (11.8 ppm), nonfat milk (0.82 ppm), whole milk (1.65 ppm), cola (0.461 ppm), root beer (0.579 ppm), orange juice (9.82 ppm), nonfat yogurt (5.28 ppm), soy sauce (4.33 ppm), instant coffee (1.09 ppm), roasted coffee beans (1.08 ppm), instant tea (0.585 ppm) cocoa (0.616 ppm), and green tea (0.472 ppm)(9). [R190] PFAC: PLANT CONCENTRATIONS: *Acetaldehyde is found in plants since it is an intermediate product of respiration in higher plants. It is found in all ripe fruits that have tart tastes before ripening(1). [R191] ANIMAL CONCENTRATIONS: *Acetaldehye is produced at an intermediate level of sugar metabolism, although no specific data on levels in animals could be found in the literature(1). [R192] MILK: *Four of eight samples of mother's milk were positive for acetaldehyde(1). [R193] OEVC: *Acetaldehyde is detected in cigarette smoke at concns ranging from 0.18 to 1.44 mg/cigarette(1). Environmental tobacco smoke was analyzed after smoking of research cigarettes by a machine in an experimental chamber 13.6 cu m in volume(2). Acetaldehyde concns (ug/cu m) were 16 and 12 with no smoking, 87 and 94 with one cigarette every 30 min, and 205 and 233 with one cigarette every 15 min(2). Concns of acetaldehyde using commercial brands of cigarettes in the chamber and in a tavern setting were similar to those produced by the research cigarettes(2). Acetaldehyde has been detected in marijuana cigarettes at a concn of 1,200 ug/cigarette(3). [R194] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 216,533 workers (97,770 of these are female) are potentially exposed to acetaldehyde in the US(1). Occupational exposure to acetaldehyde may occur through inhalation of this compound at workplaces where acetaldehyde is produced or used(SRC). Acetaldehye was reported at levels of 1-7 mg/cu m in the workroom air of an aldehyde factory in Germany after equipment leakages(2). Monitoring data indicate that the general population may be exposed to acetaldehyde via inhalation of ambient air and tobacco smoke, and ingestion of food containing acetaldehyde(SRC). [R195] AVDI: *In Sweden between Dec 1986 to Aug 1987, the mean yearly exposure to acetaldehyde from air pollution was 1.0 ug/cu m(1). [R196] BODY: *Four of eight samples of Mother's milk were positive for acetaldehyde(1). The concn of acetaldehyde in exhaled human breath ranged from 3 to 7 ppb for 3 subjects breathing medical air 5 min prior to measurement(2); the concn of acetaldehyde in exhaled human breath ranged from not detected to 89.5 ppb for 8 subjects breathing purified air(2). In another study, the concn of acetaldehyde in expired air from human subjects ranged from 8.5 to 79.0 ug/hr(3). Acetaldehye is produced at an intermediate level of sugar metabolism in the body and therefore occurs in trace quantities in blood(4). [R197] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *2000 ppm; NIOSH considers acetaldehyde to be a potential occupational carcinogen. [R23, 2] ADI: *The FAO/WHO acceptable daily intake is 0.0-2.5 mg/kg body weight. The level of use as a food additive (flavorings) is 1-300 ppm. [R198] ATOL: *The fungicide acetaldehyde, when used postharvest as a storage fumigant is exempt from the requirement of a tolerance for residues in or on apples and strawberries. [R199] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 200 ppm (360 mg/cu m). [R200] *Vacated 1989 OSHA PEL TWA 100 ppm (180 mg/cu m); STEL 150 ppm (270 mg/cu m) is still enforced in some states. [R23, 359] NREC: *NIOSH considers acetaldehyde to be a potential occupational carcinogen. [R23, 2] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R23, 2] TLV: *Ceiling limit 25 ppm [R201] *A3: Confirmed animal carcinogen with unknown relevance to humans. [R201] OOPL: *GUIDELINE: Australia TWA 180 mg/cu m, 100 ppm (1978); Finland TWA 90 mg/cu m, 50 ppm, AND STEL 135 mg/cu m, 75 ppm (1981); Federal Republic of Germany TWA 90 mg/cu m, 50 ppm (1984); Italy TWA 100 mg/cu m, 55 ppm (1978); Netherlands TWA 180 mg/cu m, 100 ppm (1978); Romania TWA 100 mg/cu m, 200 mg/cu m (maxium) (1975); Sweden TWA 45 mg/cu m, 25 ppm, AND STEL 90 mg/cu m, 50 ppm (1981). [R202] *REGULATION: Belgum TWA 180 mg/cu m, 100 ppm (1978); Czechoslovakia TWA 200 mg/cu m, 400 mg/cu m (ceiling/10 min) (1976); German Democratic Republic TWA 100 mg/cu m, 100 mg/cu m (maximum/30 min) (1977); Poland Ceiling 100 mg/cu m (1976); Switzerland TWA 180 mg/cu m, 100 ppm (1978); USSR 5 mg/cu m (Maximum) (1977); Yugoslavia 360 mg/cu m, 200 ppm (Ceiling) (1971). [R202] *Emergency Response Planning Guidelines (ERPG): ERPG(1) 10 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 200 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 1000 ppm (not life threatening) up to 1 hr exposure. [R203] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Acetaldehyde is produced, as an intermediate or a final product, by process units covered under this subpart. [R204] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Acetaldehyde is included on this list. [R205] CWA: +Acetaldehyde is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R206] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R207] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R208] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Acetaldehyde is included on this list. [R209] RCRA: *U001; As stipulated in 40 CFR 261.33, when acetaldehyde, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R210] FDA: *Synthetic flavoring substances and adjuvants /for human consumption/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Acetaldehyde is included on this list. [R211] *Acetaldehyde used as a synthetic flavoring substance and adjuvant in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R212] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2539. Analyte: Acetaldehyde. Sampler: Solid sorbent tube (10% 2-(hydroxymethyl) piperidine on XAN 120 mg/60 mg). Flow Rate: 0.01 to 0.05 l/min: Shipment: @ 25 deg C or lower. Sample Stability: Stable greater or equal to 1 week @ 25 deg C. [R213] *NIOSH Method 2538. Analyte: Acetaldehyde. Matrix: Air. Sampler: Solid sorbent tube (2-(hydroxymethyl) peperidine (2-HMP) on XAD-2, 450 mg/225 mg). Flow Rate: 0.01 to 0.05 l/min: Sample Size: 3 liters. Shipment: Routine. Sample Stability: 100% recovery after 21 days @ 0 deg C. [R213] *NIOSH Method 3507. Analyte: Acetaldehyde. Matrix: Air. Sampler: Liquid in bubbler (midget bubbler containing 15 ml air and T solution @ pH 4.5). Flow Rate: 0.1 to 0.5 l/min: Sample Size: 60 liters. Shipment: Seal bubblers to prevent leakage before shipping; protect from light. Sample Stability: 100% recovered after 1 week @ 25 deg C in dark. [R213] *EPA OSW Method 0100. Sampling for Formaldehyde and Other Carbonyl Compounds in Indoor Air. This method provides procedures for the sampling of various carbonyl compounds in indoor air by derivatization with 2,4-dinitrophenylhydrazine (DNPH) in a silica gel cartridge. [R214] ALAB: *Acetaldehyde is detected in indoor and outdoor air by gas chromatography/mass spectrometry with a limit of detection of 0.9 ug/cu m for 2 liter samples. in industrial emissions (air) by gas chromatography equipped with flame ionization detector and has limit of detection of 1.2 mg/cu m for 200 liter samples. [R215] *Acetaldehyde is detected in automobile exhaust by high performance liquid chromatography equipped with ultraviolet detection and has limit of detection of 18 ug/cu m for 20 liter samples; in flue gases from wood furnaces and stoves by gas chromatography with flame ionization detector (limit of detection is not given) [R215] *Acetaldehyde is detected in volatile emissions from wastewater by gas chromatography with flame ionization detection (limit of detection is not given) in aqueous solutions/industrial effluents by gas chromatography/mass spectrometry with limit of detection of 200 ug/l in plants (cotton) by gas chromatography/mass spectrometry (limit of detection is not given). [R215] *Acetaldehyde is detected in wine and beer by HPLC. Limit of detection in wine is 0.01 ug; limit of detection in beer is not given. [R215] *A high performance liquid chromatographic method for the simultaneous determination of C1 to C2 aldehydes and organic acids in aqueous samples has been developed. Aldehydes and organic acids are separated after derivatization of the aldehydes by 2,4-dinitrophenylhydrazine and by gradient elution on reversed-phase material (Spherisorb, RP-18). Measurement is by UV and conductivity, respectively. Derivatization of aldehydes stabilizes samples for up to 5 days in the field. The detection limit is 10 ug/l for acetaldehyde. [R216] *EPA Method 554. Determination of Carbonyl Compounds in Drinking Water by Dinitrophenylhydrazine Derivatization and High Performance Liquid Chromatography. This method is used for the determination of selected carbonyl compounds in finished drinking water or raw source water. Detection limit = 69 ug/l. [R214] *OSW Method 8315. Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC). This method is applicable to various matrices by derivatization with 2,4-dinitrophenylhydrazine (DNPH). Detection limit = 44 ug/l. [R214] *OSW Method 8315A-LLE. Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC) Using Liquid-Liquid Extraction. This method is applicable to the determination of free carbonyl compounds in various matrices by derivatization with 2,4-dinitrophenylhydrazine (DNPH). Detection limit = 110 ug/l. [R214] *OSW Method 8315A-LSE. Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC) using Liquid-Solid Extraction. This method is applicable to the determination of free carbonyl compounds in various matrices by derivatization with 2,4-dinitrophenylhydrazine (DNPH). Detection limit = 44 ug/l. [R214] *NIOSH Method 2539. Screening of Aldehydes by Gas Chromatography. This method is applicable to air samples. Detection limit = 0.4 mg/cu m. [R213] *NIOSH Method 2538. Determination of Acetaldehyde by Gas Chromatography. This method is applicable to air samples. Detection limit = 0.2 mg/cu m. [R213] *NIOSH Method 3507. Determination of Acetaldehyde by High Performance Liquid Chromatography. Detection limit = 2 mg/cu m. [R213] *AREAL Method IP-6A. Determination of Formaldehyde and Other Aldehydes in Indoor Air Using a Solid Adsorbent Cartridge. This method is applicable for the determination of formaldehyde, but with modification, and fourteen other aldehydes that can be detected in indoor air. Detection limit = 0.01 ppb. [R214] *AREAL Method IP-6B. Determination of Formaldehyde and Other Aldehydes in Indoor Air Using a Continuous Colorimetric Analyzer. This method is applicable to the sampling and analysis of formaldehyde in indoor air using the automated wet-chemical colorimetric analyzer with a continuous signal output. Detection limit = 0.03 ppb. [R214] *AREAL Method IP-6C. Determination of Formaldehyde and Other Aldehydes in Indoor Air Using Passive Sampling Device. This method is applicable passive sampling of formaldehyde (CH2O) and other aldehydes in indoor air. Detection limit unspecified. [R214] *AREAL Method TO-11. Determination of Formaldehyde in Ambient Air using Adsorbent Cartridge Followed by High Performance Liquid Chromatography (HPLC). This method is applicable for determination of formaldehyde in ambient air. Detection limit = 0.01 ppb. [R214] CLAB: *GAS-LIQUID CHROMATOGRAPHIC DETERMINATION OF ETHANOL AND ACETALDEHYDE IN BLOOD. [R217] *ACETALDEHYDE CONCN IN BLOOD FROM 15 NORMAL PT WAS APPROX 60 UMOL/L AS DETERMINED BY HIGH-PRESSURE LIQUID CHROMATOGRAPHY. ACETALDEHYDE WAS PROBABLY BOUND TO NONDIALYZABLE BLOOD ELEMENTS. [R218] *A NEW TECHNIQUE IS DESCRIBED FOR MEASURING ACETALDEHYDE IN THE BREATH, BY FREEZING OUT THE VOLATILE COMPONENTS OF BREATH IN LIQ NITROGEN, THEN ASSAYING THIS CONCENTRATED SPECIMEN BY GAS CHROMATOGRAPHY. [R219] *ACETALDEHYDE IN HUMAN BLOOD IS DETERMINED BY GAS CHROMATOGRAPHY. METHOD UTILIZES SODIUM NITRITE-SULFOSALICYLIC ACID AS AN INHIBITOR OF ETHANOL OXIDIZING SYSTEMS BY MEANS OF WHICH INTERFERENCE OF ETHANOL IS REDUCED. [R220] *Acetaldehyde is detected in biological fluids by gas chromatography equipped with flame ionization detector and has limit of detection of 0.5 to 32 mg/l (range of detection) in mother's milk by gas chromatography/mass spectrometry (limit of detection is not given). [R215] *Hepatic and blood acetaldehyde concentrations during ethanol oxidation were determined in C57 and DBA mice. Liver acetaldehyde was determined with the perchloric acid-thiourea method (no artifactual acetaldehyde formation). Levels ranging from 5 to 118 nmole/g were observed. At ethanol concentrations below 50-60 umole/g, liver acetaldehyde concentrations were higher in DBA compared with C57 mice. A positive correlation was found between the ethanol and acetaldehyde concentration, when ethanol concentration was below 25 (DBA) or 70 umole/g (C57). At higher ethanol concentrations the correlations tended to become negative. Hemolysis causes artifactual formation of acetaldehyde when blood acetaldehyde is determined using thiourea or semicarbazide methods. The magnitude of the artifactually formed acetaldehyde was of such order that no conclusions regarding the existence of true in vivo blood acetaldehyde concentrations could be drawn. [R144] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Services, Research Triangle Park, NC. (2000) SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V1 (1991) R2: Lewis, R.J., Sr (Ed.). 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V36 110 (1985) R216: Keuken MP, Schoonebeek CAM; Int J Environ Anal Chem 35 (4): 227-39 (1989) R217: BRIEN ET AL; CLIN CHIM ACTA 87 (1): 175 (1978) R218: THOMAS M ET AL; LANCET 2 (8245): 530-1 (1981) R219: DANNECKER JR ET AL; ANAL BIOCHEM 114 (1): 1-7 (1981) R220: CHRISTENSEN JM ET AL; CLIN CHEM ACTA 116 (3): 389-95 (1981) RS: 205 Record 49 of 1119 in HSDB (through 2003/06) AN: 240 UD: 200211 RD: Reviewed by SRP on 8/23/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: COBALTOUS-SULFATE- SY: *Cobalt-Brown-; *COBALT- (II)-SULFATE; *COBALT- (II)-SULFATE- (1:1); *COBALTOUS-SULFATE-SALT- (1:1); *COBALT-SULFATE- (1:1); *COBALT- (2+)-SULFATE; *COBALT-SULFATE- (COSO4); *SULFURIC-ACID,-COBALT- (2+)-SALT- (1:1) RN: 10124-43-3 RELT: 519 [COBALT] MF: *Co-O4-S ASCH: Cobalt(II) sulfate heptahydrate; 10026-24-1 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Action of sulfuric acid on cobaltous oxide. [R1] *Cobaltous ... sulfate ... /is/ formed by the interaction of the metal ... hydroxide, or carbonate with /sulfuric/ ... acid. [R2, 1606] FORM: *Cobalt Brown: a pigment prepared by calcining a mixture of ammonium sulfate, cobalt sulfate, and ferrous sulfate. [R3] *Cobalt Vitriol: Cobaltous sulfate, CoSO4.7H2O /Heptahydrate/ [R3] *Liquid, crystal grades; crystals and soln form, feed, technical and reagent grades [R4] *Powder grades; crystal, feed grades /Monohydrate/ [R4] MFS: *Chemtech Industries, Inc, Harston Division, Hq, 1655 Des Peres Road, PO Box 31000, St. Louis, MO 63131, (314) 966-9900; Production site: Brooklyn, NY 11218 [R5] *Kaiser Tech Limited, Harshaw/Filtrol Partnership, Hq, 30100 Chagrin Boulevard, Cleveland, OH 44124, (216) 292-9200; Production site: 1000 Harvard Avenue, Cleveland, OH 44109 [R5] *Mooney Chemicals, Inc, Hq, 2301 Scranton Road, Cleveland, OH 44113, (216) 781-8383; Production site: Two-Mile Run, Franklin, PA 16323 [R5] *The Shepherd Chemical Company, Hq, 4900 Beech Street, Cincinnati, OH 45212, (513) 731-1110; Production site: Cincinnati, OH 45212 [R5] *The Hall Chemical Company, Hq, PO Box 200, 28960 Lakeland Boulevard, Wickliffe, OH 44092-0200, (216) 944-8500; Production sites: Route 69, Arab, AL 35016; Wickliffe, OH 44092 [R5] *Phillipp Brothers Chemicals, Inc, Hq, One Parker Plaza, Fort Lee, NJ 07024, (215) 587-7000; Subsidiary: CP Chemicals, Inc, One Parker Plaza, Fort Lee, NJ 07024, (201) 944-6020; The Prince Manufacturing Company, One Parker Plaza, Fort Lee, NJ 07024; Production site: Sewaren, NJ 07077; Bowmanstown, PA 18030; Radio Road, Quincy, IL 62306 [R5] *The Procter and Gamble Company, Hq, 301 East Sixth St, PO Box 599, Cincinnati, OH 45201, (513) 983-2641; Subsidiary: Richardson-Vicks, Inc, 10 Westport Rd, Wilton, CT 06897, (203) 762-2222; Subsidiary: JT Baker Inc, (210) 859-2151; Production site: 222 Red School Ln, Phillipsburg, NJ 08865 [R5] OMIN: *CONTAINS APPROX 38% COBALT. [R6, 125] *PREPN: CLARK ET AL, J AM CHEM SOC 42, 2483 (1920); HAMMEL, ANN CHIM 11, 247 (1939); GMELIN'S COBALT (8TH ED) 58, (PART A) 324-336 (1932) AND SUPPLEMENT, 628-647 (1961). REVIEW: DE BIE, DOYEN, COBALT 15, 3-13; 16, 3-15 (1962). [R7] USE: *USED IN STORAGE BATTERIES; IN COBALT-ELECTROPLATING BATHS; AS DRIER FOR LITHOGRAPHIC INKS, VARNISHES; IN CERAMICS, ENAMELS, GLAZES TO PREVENT DISCOLORING; IN CO PIGMENTS FOR DECORATING PORCELAIN [R7] *Used in animal feeds and sometimes added in small quantities in mixed fertilizers for use on pastures where the forage is deficient in cobalt. /Heptahydrate/ [R8] *Added to nickel plating baths to improve smoothness, brightness, hardness, and ductility of deposits. [R2, 1607] +MEDICATION *USUAL SOURCE OF WATER-SOLUBLE COBALT SINCE IT IS MOST ECONOMICAL AND IT SHOWS LESS TENDENCY TO DELIQUESCE OR DEHYDRATE THAN CHLORIDE OR NITRATE. [R7] *IN ENDEMIC AREAS TOP DRESSING OF THE SOIL WITH 100-150 G OF COBALT SULFATE/ACRE IS GENERALLY SUFFICIENT TO PREVENT DEFICIENCY. [R9, 646] +MEDICATION (VET): PRIE: U.S. IMPORTS: *(1986) 7.97X10+4 lb [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *RED TO LAVENDER DIMORPHIC, ORTHORHOMBIC CRYSTALS [R7]; *DARK BLUISH CUBIC CRYSTALS [R11, p. B-87]; *RED POWDER [R1] MP: *735 DEG C [R1] MW: *155.00 [R7] DEN: *3.71 @ 25 DEG C/4 DEG C [R7] SOL: *36.2 G/100 ML WATER @ 20 DEG C [R11, p. B-87]; *84 G/100 ML WATER @ 100 DEG C [R11, p. B-87]; *1.04 G/100 ML METHANOL @ 18 DEG C [R11, p. B-87]; *INSOL IN AMMONIA [R11, p. B-87] OCPP: *STABLE TO 708 DEG C [R7] *Mol wt: 281.10; red-pink, monoclinic crystals; index of refraction: 1.477, 1.483, 1.489; density: 1.948 at 25 deg C/25 deg C; MP: 96.8 deg C; BP: 420 deg C (loses 7H2O); solubility: 60.4 g/100 cc water at 3 deg C, 67 g/100 cc water at 70 deg C, 2.5 g/100 cc alcohol at 3 deg C, 54.5 g/100 cc methanol at 18 deg C /Heptahydrate/ [R11, p. B-878] *Mol wt: 263.08; red monoclinic crystals; index of refraction: 1.531, 1.549, 1.552; density: 2.019 at 15 deg C/15 deg C; MP: 95 deg C (loses 2H2O) /Hexahydrate/ [R11, p. B-87] *Mol wt: 173.01; red crystals; index of refraction: 1.603, 1.639, 1.683; density: 3.075 at 25 deg C; sol in water /Monohydrate/ [R11, p. B-87] *Structure reported to be cobaltous sulfate heptahydrate; on heating dehydrates to the hexahydrate at 41.5 deg C, and to the monohydrate at 71 deg C /Heptahydrate/ [R7] *Structure reported to be Co(H2SO5) /Monohydrate/ [R7] *Odorless; heat of solution: 23 BTU/lb= 13 cal/g= 0.54X10+5 J/kg; solubility: 35.040 lb/100 lb water at 70 deg F /Heptahydrate/ [R12] *In its cmpd cobalt occurs normally in the oxidation states +2 and +3 more seldom in the oxidation states 0, +1, and +4. In normal salts the bivalent form is more stable than the trivalent one, the reverse is true for cobalt complexes. /Cobalt cmpd/ [R13, 252] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- TOXC: *Toxic cobalt oxide fumes may form in fire. /Heptahydrate/ [R12] REAC: *Tert-butyl hydroperoxide is very dangerous when exposed to heat or flame or by spontaneous chemical reaction. Slow first order decomp can be accelerated by the presence of 1 mole percent of ... cobalt ... salts. /Cobalt salts/ [R14] *Contact of dust with strong oxidizers may cause fire and explosions. /Cobalt metal fume and dust/ [R15, 1981.2] DCMP: *WHEN HEATED TO DECOMPOSITION ... EMITS TOXIC FUMES OF /SULFUR OXIDES/. [R16] SERI: *Dust: Irritating to eyes, nose, and throat. ... Solid: Irritating to skin and eyes. /Heptahydrate/ [R12] EQUP: *Bureau of mines approved respirator; goggles; protective gloves /Heptahydrate/ [R12] *FOR TEMPORARY OPERATIONS /WHICH PRODUCE DUST OR FUME/ OR WHEN VENTILATION IS NOT PRACTICABLE, AN AIR-LINE RESPIRATOR SHOULD BE WORN. IF VENTILATION ... NOT SATISFACTORY, DUST AND/OR FUME RESPIRATOR CAN BE USED. /COBALT, ALLOYS AND CMPD/ [R17, 495] *... The maintenance worker should wear protective clothing, personal protection equipment, incl eye protection, and suitable respiratory protective equipment. When the catalyst takes the form of a harmful gas or vapor, exhaust ventilation, breathing apparatus and protective clothing should be provided. /Catalysts, cobalt cmpd/ [R17, 426] *Respirator selection: Upper limit devices recommended by NIOSH: 0.5 mg/cu m: any dust and mist respirator except single-use respirators; 1 mg/cu m: any dust and mist respirator except single-use and quarter-mask respirators or any dust, mist, and fume respirator with a full facepiece or any supplied air respirator or any self-contained breathing apparatus; 2.5 mg/cu m: any powdered air-purifying respirator with a dust and mist filter or any supplied-air respirator operated in a continuous flow mode or any powered air-purifying respirator with a dust, mist, and fume filter; 5 mg/cu m: any air-purifying full facepiece respirator with a high-efficiency particulate filter or any self-contained breathing apparatus with a full facepiece or any supplied-air respirator with a full facepiece; 20 mg/cu m: any supplied-air respirator with a full facepiece and operated in a pressure-demand or other positive pressure mode; Emergency or planned entry in unknown concn or IDLH conditions: any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode or any supplied-air respirator with a full facepiece and operated in a pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode; Escape: any air-purifying full facepiece respirator with a high-efficiency particulate filter or any appropriate escape-type self-contained breathing apparatus /Cobalt metal, fume, and dust (as Co)/ [R18] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with cobalt dust. /Cobalt metal fume and dust/ [R15, 1981.2] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PROCESSES WHICH PRODUCE COBALT DUST OR FUME ... SHOULD BE PROVIDED WITH AN EFFECTIVE LOCAL EXHAUST VENTILATION. /COBALT, ALLOYS AND CMPD/ [R17, 495] *Avoiding skin contact may be difficult but ... barrier creams can be tried. ... Severely affected patient must be removed to ... occupations /not involving cobalt exposure/. /Cobalt, alloys and cmpd/ [R17, 495] *Contact lenses should not be worn when working with these chemicals. /Cobalt metal, fumes and dust/ [R15, 1981.3] *Employees should wash promptly when skin becomes contaminated; work clothing should be changed daily if it is reasonably probable that the clothing is contaminated; promptly remove non-impervious clothing that becomes contaminated /Cobalt metal, fume, and dust (as Co)/ [R18] *If employees' clothing ... have become contaminated with cobalt dust, employees should change into uncontaminated clothing before leaving the work premises. Clothing contaminated with cobalt dust should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of cobalt dust from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the cobalt dust, the person performing the operation should be informed of cobalt dust's hazardous properties. Non-impervious clothing which becomes contaminated with cobalt dust should be removed promptly and not reworn until the cobalt dust is removed from the clothing. /Cobalt dust/ [R15, 1981.3] *Skin that becomes contaminated with cobalt dust should be promptly washed or showered with soap or mild detergent and water to remove any cobalt dust. Eating and smoking should not be permitted in areas where cobalt metal fume or dust are generated, handled, processed, or stored. Employees who handle cobalt metal fume or dust should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. /Cobalt metal fume and dust/ [R15, 1981.3] *Employers should institute programs that emphasize good personal hygiene to prevent skin and respiratory irritation caused by cobalt containing dusts. After working with cobalt products, workers should thoroughly wash their hands and face before drinking, eating, or smoking. If skin contact with cobalt solutions occurs, the worker should wash the affected skin promptly. The employer should provide showers if workers have substantial contact with cobalt. These workers should be encouraged to wash or shower after each workshift. Employers should prohibit smoking or carrying of tobacco products, and should prohibit eating, food handling, or food storage within the work area. /Cobalt and cobalt salts/ [R19] *General plant maintenance must be conducted regularly to prevent cobalt containing dusts from accumulating in work areas. Cleaning should be performed with vacuum pickup or wet mopping to minimize the amount of dust dispersed into the air. A decontamination room should be available for cleaning equipment that is to receive major overhaul or maintenance. Spills of cobalt-containing material should be promptly cleaned up to minimize inhalation or dermal contact. /Cobalt and cobalt salts/ [R20] *Special precautions are necessary when workers must enter tanks or vessels, such as reaction vessels containing cobalt catalysts or vessels used to prepare cobalt salts. Before any worker enters a vessel, all sources for transferring cobalt and other materials into or out of the vessel must be blanked to prevent their entry. The vessel interior must then be washed with water and purged with air. After purging the vessel's atmosphere with suitable instruments to ensure that no hazards from fire, explosion, oxygen deficiency, or dust inhalation exist. No one should enter a tank or vessel without first being equipped with an appropriate respirator and a secured lifeline or harness. Mechanical ventilation should be provided continuously when workers are inside the tank. At least one other worker similarly equipped with respiratory protection, lifeline, and harness should watch at all times from outside the vessel. Workers inside the tank must be able to communicate with those persons outside. Other workers must be available to assist in an emergency. Flame- or spark-generating operations, such as welding or cutting, should be performed only when an authorized representative of the employer has signed a permit based on a finding that all necessary safety precautions have been taken. /Cobalt and cobalt salts/ [R21] SSL: *SOLN CONTAINING COBALTOUS ION CO(2+) ARE RELATIVELY STABLE ... /COBALTOUS ION CO(2+)/ [R22, 246] CLUP: *Liquid material spills can be copiously flushed with water and channeled to a treatment system or holding tank for reclamation or proper disposal. Spills of dry material can be removed by vacuuming or wet mopping. Some spills can be removed by hosing, first with a mist of water to dampen the spilled material and then with a more forceful stream that flushes it into a holding tank or other facility for handling contaminated water. Work surfaces or contaminated clothing should never be cleaned by dry sweeping or blowing with pressurized hoses. Recovery systems used to reclaim waste metals should comply with federal, state, and local regulations. All waste materials generated in the handling of cobalt-containing substances should be disposed of in compliance with federal, state, and local regulations. /Cobalt and cobalt salts/ [R20] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *... Proper mixing of the cobalt waste and the soil is essential to preventing excessive plant accumulation of cobalt. /Cobalt/ [R23, 256] *Cobalt metal may be recovered from scrap ... as alternatives to disposal. [R24, 255] *... Cobalt cmpd /may be recovered/ from spent catalysts as alternatives to disposal. [R24, 255] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A3; Confirmed animal carcinogen with unknown relevance to humans. /Cobalt, elemental, and inorganic cmpd, as Co/ [R25, 2002.24] MEDS: *The following medical procedures should be made available to each employee who is exposed to cobalt metal fumes and dust at potentially hazardous levels. Initial medical examination: A complete history and physical examination: The purpose is to detect conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the respiratory system should be stressed. The skin should be examined for evidence of chronic disorders. 14x17 inch chest roentgenogram: Cobalt may cause human lung damage. Surveillance of the lungs is indicated. Forced Vital Capacity and Forced Expiratory Volume (1 sec): Cobalt is reported to decrease pulmonary function. Periodic surveillance is indicated. Periodic medical examination: The aforementioned medical examinations should be repeated on an annual basis. /Cobalt metal fume and dust/ [R15, 1981.1] *In preemployment exam, special attention should be given to a histroy of skin diseases, allergic dermatitis, baseline allergic resp diseases, and smoking history. ... Periodic exam should be directed toward skin and resp symptoms and lung function. /Cobalt and cmpd/ [R24, 254] HTOX: *NIOSH considers the information available sufficient to conclude that cobalt metal and salts, and probably cobalt oxides and a number of organo-cobalt complexes, can damage the kidneys. These effects are thought to occur only at levels that also produce other toxic effects. /Cobalt salts/ [R26] *... SEVERE CARDIAC FAILURE AND SOME DEATHS IN MAN RESULTED FROM CONSUMPTION OF LARGE AMT OF BEER CONTAINING 1.2-1.5 PPM COBALT. THE ELEMENT WAS ADDED TO BEER TO PROMOTE OPTIMAL FOAM STABILIZATION. /COBALT SALTS/ [R27] *... Some of these beer drinking patients /were studied/ and reported typical signs of heart failure with shortness of breath, ankle edema, and in some cases, cyanosis and ECG changes /were observed/. ... In a retrospective study, hearts of victims were shown to have about 10 times the cobalt concn of controls, 0.5 mg/kg wet wt and 0.04 mg/kg wet, respectively. /Cobalt/ [R28, p. V2 225] *COBALT AND ITS SALTS WOULD APPEAR TO HAVE CUMULATIVE TOXIC ACTION UNDER CONDITIONS IN WHICH ELIMINATION CANNOT KEEP PACE WITH ABSORPTION. /COBALT AND SALTS/ [R2, 1611] *Industrial experience has indicated that cobalt dust and fumes may cause dermatitis and pneumoconiosis. /Cobalt dust and fume/ [R17, 423] *IN TOXIC DOSES SOL SALTS ACT LOCALLY ON GI TRACT ... /PRODUCING/ PAIN, VOMITING, ETC. SYSTEMIC EFFECTS IN MAN INCL PECULIAR VASODILATATION (FLUSHING) OF FACE AND EARS, MILD HYPOTENSION, RASH, TINNITUS AND NERVE DEAFNESS. /COBALT SALTS/ [R29] *POLYCYTHEMIA IS CHARACTERISTIC RESPONSE OF ... HUMANS, TO INGESTION OF EXCESSIVE AMT OF COBALT. ... EPIDEMIOLOGIC STUDIES SUGGEST THAT INCIDENCE OF GOITER IS HIGHER IN REGIONS CONTAINING INCREASED LEVELS OF COBALT IN WATER AND SOIL. /COBALT/ [R30, 611] *Occupational inhalation of cobalt salts in the cemented carbide industry may cause respiratory symptoms probably as a result of irritation of the pulmonary tract. /Cobalt salts/ [R30, 612] *... OCCASIONALLY FATAL RESPONSES OCCURRED FROM EXPOSURES OF ORDER OF 1 TO 2 MG OR LESS COBALT/CU M. ... A DERMATITIS OF ALLERGIC TYPE HAS BEEN DESCRIBED ... FROM CONTACT WITH COBALT AND ITS CMPD; A CARBOLOY ITCH HAS ALSO BEEN DESCRIBED. /COBALT AND COBALT CMPD/ [R31] *It has been reported that cobalt salts impair the aggregation of platelets, thus inhibiting blood coagulation. Compared with normal persons the erythropoeitin level in blood of 21 workers had been 0.43 and 1.6 mg/cu m. Thirty five cobalt exposed workers showed elevated levels of immuno and other plasma proteins in blood. /Cobalt salts/ [R13, 256] *Potential symptoms as a result of exposure /to cobalt metal, fume, and dust (as Co)/: cough, dyspnea, decr pulmonary function; weight loss ... diffuse nodular fibrosis; respiratory hypersensitivity. /Cobalt metal, fume, and dust (as Co)/ [R18] *... The effects of cobalt on the heart have been studied because of an outbreak of acute cardiomyopathy in beer drinkers. The amount of cobalt consumed by these beer drinkers was substantially more than that inhaled by workers exposed at the current federal limit. The effects of cobalt on the heart probably are less of a hazard than pulmonary fibrosis, although studies are needed to determine whether or not adverse effects on the heart become demonstrable following long-term exposures. ... Polycythemia and subsequent development of thyroid hyperplasia have also occurred following ingestion of cobalt salts. ... Polycythemia does not appear to be a particularly toxic response, especially in workers exposed to cobalt at 0.1 mg/cu m or less. Experiments in animals suggest that some persons might develop changes in the thyroid even at these low concn, especially when individual susceptibility is considered. /Cobalt salts/ [R32] *Some cobaltous salts have been implicated as a causative agent in certain forms of cardiac disease. Cobalt ... was used as a foam stabilizer in beer during the mid 1960's in various countries, including the United States. Between 1964 and 1966, american breweries reportedly added 1-1.5 ppm of cobaltous chloride to 20-25% of all beer sold in the United States. At the same time, several epidemics of a peculiar form of cardiomyopathy occurred among heavy beer drinkers in Quebec, Belgium, Omaha, Minneapolis, and New York. All patients were heavy beer drinkers. For example, the Quebec group consumed daily from 2 to more than 6 l of beer containing 0.8 to more than 1.6 ppm cobalt/l. The signs and symptoms of illness in beer drinking patients included gastrointestinal problems labored breathing, abdominal pain, cyanosis, lowered blood pressure, heart enlargement, pericardial effusion, rapid heart rate, and electrocardiographic (ECG) abnormalities. In one group, azotemia or oliguria, or both, were frequently noted, especially in fatal cases. /Cobalt salts/ [R33] *Inhalation causes shortness of breath, lung densities, dermatitis with hyperemia and vesiculation. Ingestion causes hypotension, pericardial effusion, polycythemia, congestive failure, pain, vomiting, nerve deafness, convulsions, enlargement of the thyroid. /Cobalt dust and fumes/ [R34] *... THREE CASES OF PNEUMOCONIOSIS IN TUNGSTEN CARBIDE TOOL INDUSTRY WHERE EXPOSURE TO COBALT POWDER, OXIDE OR SALT, HAD VARIED BETWEEN 0.1 and 0.2 MG CO/CU M FOR 2.5-7 YR /ARE REPORTED/. IT WAS STATED THAT THESE 3 MEN WERE ONLY WORKERS WITH PNEUMOCONIOSIS OUT OF 1500 MEN WITH SIMILAR EXPOSURE CONDITIONS. /COBALT POWDER, OXIDE OR SALT/ [R28, p. V2 221] *Cobalt accumulates in the serum of uremic patients and is believed to contribute to the myocardial failure often observed. /Cobalt/ [R35] NTOX: *Peroral admin of cobalt (as cobaltous sulfate and cobaltous chloride) to rats and rabbits in doses ranging from 10 to 100 mg/kg body wt, for periods exceeding two wk, produces the same cardiotoxic effects as those observed following parenteral dosing. [R28, p. V2 224] *Sheep given a single dose of hydrated cobalt sulfate were killed by quantities between 15 and 55 g, the avg lethal dose being 330 mg/kg. /Hydrated cobalt sulfate/ [R36] *In 20 male guinea pigs fed cobaltous sulfate for 5 weeks at high levels (stated to be 20 mg cobalt/kg daily), heart weights and ratios of heart weight to body weight were increased, and pericardial effusion was observed in 9 (45%) animals; myocardial degenerative changes were present in 15 (75%). [R37] *... SOLUBLE SALTS BY INTRATRACHEAL INJECTION, ACT AS ACUTE LUNG IRRITANTS, PRODUCING EDEMA AND HEMORRHAGE WITH A CONSIDERABLE OUTPOURING OF FLUID FROM CAPILLARIES IN THE PERITONEAL CAVITY; THIS WAS BELIEVED TO BE CAUSE OF DEATH IN SOME ANIMALS FROM SHOCK DUE TO FLUID LOSS. /SOL COBALT SALTS/ [R38, 136] *... INTRATRACHEAL INJECTION OF COBALT SALTS /IN RATS/ CAUSES ... HYPERPLASIA OF BONE MARROW ... /COBALT SALTS/ [R39, 285] *MILD COBALT TOXICITY CAUSES HYPERGLYCEMIA IN DOGS BECAUSE OF TRANSIENT AND REVERSIBLE DAMAGE TO ALPHA CELLS OF PANCREAS. ... IN RABBITS, COBALT SALTS CAUSE CARDIOTOXICITY. ... CARDIOTOXICITY OF COBALT IS CONFIRMED BY STRUCTURAL CHANGES IN RAT HEART MYOFIBRILS AND MITOCHONDRIA PRODUCED BY IP INJECTIONS OF 5 MG CO/KG (IN SALT FORM) DAILY FOR 11 DAYS. /COBALT SALTS/ [R39, 288] *... ACUTE COBALT TOXICITY IN SOME ANIMALS HAS BEEN DEMONSTRATED ONLY @ VERY HIGH DOSES ... CHICKENS @ 50 MG/KG OF DIET/DAY AND ... SHEEP @ 6 MG/KG OF BODY WT/DAY. AT DOSES UNDER 5 MG/KG OF DIET (OR UNDER 2 MG/KG OF BODY WT) NO ADVERSE EFFECTS WERE NOTED. AT HIGHER DOSAGES, A LOSS OF APPETITE, LOSS OF WT, AND DEBILITATION WERE OBSERVED. /COBALT/ [R22, 248] *SIGNS OF ACUTE POISONING IN ANIMALS FED COBALT SALTS CONSIST OF DIARRHEA, LOSS OF APPETITE, PARALYSIS OF HIND LEGS AND LOWERING OF BODY TEMP PRIOR TO DEATH. WITH HIGH DOSES, ANURIA OCCURRED, AND WITH SMALLER DOSES, ALBUMINURIA /OBSERVED IN ANIMALS FED COBALT SALTS/. ONE OF IMMEDIATE SIGNS IS CUTANEOUS VASODILATION, ESP OF NOSE AND EAR, WITHIN 3 MIN AFTER ADMIN AND PERSISTING FOR ABOUT 1 HR. BLOOD PRESSURE MAY FALL. MICROSCOPICALLY, ALL ORGANS ARE CONGESTED, WITH SMALL FOCAL HEMORRHAGES ON SEROSAL SURFACES AND LARGE HEMORRHAGES IN LIVER AND ADRENALS; BONES SHOW HYPERPLASTIC MARROW. LUNG SHOW ALVEOLAR THICKENING; KIDNEYS, TUBULAR DEGENERATIVE CHANGES. FIBERS OF MYOCARDIUM ARE PALE AND SHRUNKEN AND PANCREAS SHOW DEGENERATIVE CHANGES. /COBALT SALTS/ [R2, 1610] *... DIETARY COMPONENTS CAN GREATLY MODIFY THE TOXICITY OF INGESTED COBALT ... WEANLING RATS DIED ON DAILY DOSES 1 and 0.5 MG OF COBALT FOR 3.5 MO WHEN FED A MILK DIET. RATS, HOWEVER WERE REPORTED TO TOLERATE DAILY DOSE OF 1 MG OF COBALT IN THEIR WATER FOR 14 WK WHEN FED USUAL LAB FOOD. /COBALT/ [R2, 1611] *A POLYCYTHEMIC LEVEL OF SOL COBALT CMPD FOR RATS IS CONSIDERED TO BE 40 MG/KG ORALLY, 2.5 MG/KG BY INJECTION. /COBALT CMPD/ [R2, 1611] *ANIMALS ... DEMONSTRATE AN INCREASE IN RESPIRATION, AS WELL AS TREMORS AND CONVULSIONS. ... TOXIC NEPHRITIS MAY RESULT /AFTER CHRONIC ADMIN/. /COBALT SALTS/ [R29] *Cobalt and cobalt cmpd have been found to induce a variety of toxic effects in the eyes of experimental animals ... . /Cobalt and cmpd/ [R40] *Phytotoxicity from soil cobalt results in plants containing 50-100 ppm when foliar symptoms are apparent. ... Phytotoxicity inhibited pumping sugars from mesophyll cells into the phloem and veins, severely altering energy transport to rapidly growing tissues. /Cobalt/ [R41] *Divalent inorganic cmpd have a higher acute toxicity compared to trivalent ones. /Divalent and trivalent cobalt inorganic cmpd/ [R28, p. V2 223] *The first evidence that cobalt may induce malignant tumors in animals was presented ... in 1942. ... Two neoplasias (one adenocarcinoma of the lung and one osteosarcoma of the bone) /were produced/ in six rabbits given about 0.1 g of sol cobalt injected directly into the bone. /Sol cobalt cmpd/ [R28, p. V2 227] *Single and repeated subcutaneous or intramuscular injection of cobalt powder and salts in doses of 10-30 mg to rats may cause sarcomata at the site of injection. /Cobalt powder and salts/ [R28, p. V2 227] *... /Cobalt is/ reported to affect male reproductive capacity. /From table/ [R30, 453] *Dietary cobalt cmpd are not involved in carcinogenesis in mammals, but parenteral injection of cobalt metal powder, oxides, sulfides, and other cmpd produces malignant tumors in experimental animals at the site of injection, in the thyroid gland and in other organs. /Cobalt sulfide/. [R42] +... Conclusions: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on incr incidences of alveolar/bronchiolar neoplasms. Marginal incr of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of the carcinogenic activity in female F344/N rats based on incr incidences of alveolar/bronchiolar neoplasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in male and female B6C3F1 mice based on incr incidences of alveolar/bronchiolar neoplasms. /Cobalt sulfate heptahydrate/ [R43] NTXV: *LD100 Dog intravenous 16.2 mg/kg /Heptahydrate/; [R39, 286] NTP: +... Male and female F344/N rats and B6C3F1 mice were exposed to cobalt sulfate heptahydrate (approximately 99% pure) by inhalation for 2 yr. ... Groups of 50 male and 50 female F344/N rats were exposed to aerosols containing 0, 0.3, 1.0 or 3.0 mg/cu m cobalt sulfate heptahydrate 6 hr/day, 5 days/wk for 105 wk. ... Groups of 50 male and 50 female B6C3F1 mice were exposed to aerosols containing 0, 0.3, 1.0 or 3.0 mg/cu m cobalt sulfate heptahydrate 6 hr/day, 5 days/wk for 105 wk. Conclusions: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on incr incidences of alveolar/bronchiolar neoplasms. Marginal incr of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of the carcinogenic activity in female F344/N rats based on incr incidences of alveolar/bronchiolar neoplasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in male and female B6C3F1 mice based on incr incidences of alveolar/bronchiolar neoplasms. /Cobalt sulfate heptahydrate/ [R43] POPL: *Workers with history of skin diseases ... /performing/ jobs where skin contact occurs. /Cobalt, alloys, and cmpd/ [R17, 495] ADE: *Sheep given a single dose of hydrated cobalt sulfate were killed. ... The livers contained 400-1200 ppm of cobalt. In cattle dying after a massive overdose of hydrated cobalt sulfate livers contained 5-300 ppm, kidneys 30-200 ppm. /Hydrated cobalt sulfate/ [R36] *COBALT ACCUMULATED IN HAIR. /COBALT/ [R44] *THE FACT THAT VERY LITTLE OF THE RADIOACTIVE COBALT ADMIN ORALLY, OR ... IV, REMAINS IN TISSUES AFTER 10 DAYS SUGGESTS THAT ABSORPTION AND RETENTION ARE POOR. WITH INJECTION ... ONLY 5% WAS RETAINED; OF THIS 1% WAS IN LIVER, BUT THERE WAS MARKED ACCUM IN ADRENALS. WITH ORAL ADMIN ONLY LIVER RETAINED SIGNIFICANT AMT. EXCRETION IS CHIEFLY BY FECES, ABOUT 80% APPEARING WITHIN 5 DAYS, MOST OF IT WITHIN 48 HR. REMAINING AMT IS RAPIDLY ELIMINATED BY KIDNEYS. /COBALT/ [R38, 134] *COBALT IS POORLY ABSORBED FROM DIGESTIVE TRACT /IN RUMINANT/. [R45] *COBALT IS NOT SEQUESTERED; IT IS STORED IN INTESTINAL MUCOSA AND SUBSEQUENTLY LOST THROUGH NORMAL DESQUAMATION OF EPITHELIUM. SINCE COBALT FORMS NO INSOL COMPLEXES IN NEUTRAL AND ALKALINE MEDIA, ABSORPTION OCCURS ... IN PROXIMAL AND DISTAL REGIONS OF INTESTINE. /COBALT SALTS/ [R39, 284] *SMALL DOSES OF PARENTERALLY INJECTED COBALT SALTS ARE ABSORBED SLOWLY FROM INJECTION SITES, WHILE IV INJECTED SOL SALTS ARE BOUND TO ALPHA-GLOBULINS AND ARE DISTRIBUTED TO TISSUES QUICKLY. /COBALT SALTS/ [R39, 285] *COBALT CONTENT OF FRESH TISSUES OF NORMAL, UNEXPOSED DOGS, RABBITS, AND RATS RANGED FROM FEW UG (BONE) TO FEW TENTHS UG (THYROID AND ADRENALS) ... PANCREAS, KIDNEY, AND LUNG SHOWED INTERMEDIATE AMT. SPLEENS OF RABBITS AND RATS CONTAINED FAR HIGHER AMT THAN DID THIS ORGAN IN DOGS ... . /COBALT/ [R2, 1613] *THE DEGREE OF GI ABSORPTION OF COBALT AND ITS SALTS DEPENDS ON DOSE; VERY SMALL DOSES OF THE ORDER OF FEW UG/KG ARE ABSORBED ALMOST COMPLETELY; LARGER DOSES ARE LESS WELL ABSORBED. ... 10 UG OF (60)COBALT /WAS ADMIN/ TO RATS, MORE THAN 30% EXCRETED IN URINE WHEN GIVEN ORALLY, AND MORE THAN 90% WHEN INJECTED. ... GLANDULAR ORGANS, PARTICULARLY PANCREAS, ACCUMULATED LARGEST AMT, AS DID THE LIVER, SPLEEN, AND KIDNEYS. ... COBALT IN PANCREAS IS BOUND TO CELLULAR COMPONENTS WITH LESSER AMT IN PANCREATIC JUICES. /COBALT/ [R2, 1613] *COBALT SALTS ARE GENERALLY WELL ABSORBED AFTER ORAL INGESTION PROBABLY IN JEJUNUM. DESPITE THIS FACT, INCR LEVELS TEND NOT TO CAUSE SIGNIFICANT ACCUM. ABOUT 80% ... INGESTED COBALT IS EXCRETED IN URINE. OF REMAINING, ABOUT 15% IS EXCRETED IN FECES BY ENTEROHEPATIC PATHWAY ... MILK AND SWEAT ARE ... SECONDARY ROUTES /OF EXCRETION/ ... /COBALT SALTS/ [R30, 611] *GI ABSORPTION OF COBALT IS DEPENDENT ON THE TYPE OF COMPOUND GIVEN, DOSE AND NUTRITIONAL STATUS OF THE ANIMAL. /COBALT/ [R28, p. V2 215] *GI ABSORPTION IS REPORTED TO VARY FROM 5-45%. [R46] *Cobalt taken up orally is ... eliminated with the feces /between 60 and 95%/. Of the cobalt given iv ... only 11% could be detected in feces. /Cobalt/ [R13, 254] *In blood: Conventional reference range: 0.20-0.28 ug/dl; international recommended reference range: 33.9-47.5 nmol/l /Cobalt/ [R47] *In serum: Conventional reference range: 0.12-0.20 ug/dl; international recommended reference range: 20.4-33.9 nmol/l /Cobalt/ [R47] *In serum: Conventional reference range: 0.011 ug/dl; international recommended reference range: 1.87 nmol/l /Cobalt/ [R47] *In urine: conventional reference range: 1-7 ug/l; international recommended reference range: 17.0-118.8 nmol/l /Cobalt/ [R47] *Of the cobalt which is ingested in the daily diet, about 86% is excreted in the urine and 14% in the feces. /Cobalt/ [R48] *In normal subjects an average of 18% of an oral dose of radioactive cobalt was eliminated in the 24 hours urine. [R49] *Nonradioactive and radioactive metal salts were administered intravenously to Sprague Dawley rats. The highest amount of each metal approached the maximum tolerated dose. Cobalt, silver , and manganese were eliminated rapidly. The elimination of 20 to 50 percent of the dosage was observed for copper, thalium, bismuth, lead, cesium, gold, zinc, mercury, selenium, and chromium. The slowest excretion rate was measured for arsenic, cadmium, iron, methyl-mecury, and tin. No substantial elimination rate decline was observed for methyl-mercury and iron and the decline was small for thalium, cesium, mercury, tin, cobalt, silver, zinc, chromium, and arsenic. Elimination of silver and manganese via feces was fast, with more than 70 percent eliminated on the first day. Copper, thalium, lead, and zinc were excreted at a slower rate, with 30.6 to 38.3 percent excreted on the first day. The rest of the metals were eliminated slowly by the intestinal route. Cobalt was removed rapidly via urine, while lead, tin, zinc, methyl-mercury, silver, iron, manganese , and cadmium were eliminated slowly. The biliary excretion of silver, arsenic, and manganese was fast, with 25.5, 30.2 and 16.2 percent eliminated in two hours. Copper, selenium, cadmium, lead, bismuth and cobalt were eliminated at an intermediate rate via the biliary route. Silver, arsenic, manganese, copper, selenium, cadmium, lead, bismuth, and methyl-mercury were highly concentrated in bile relative to plasma. Liver and kidney contained the highest concentrations of most metals. The intestinal route was the major path of elimination for silver, manganese, copper, thallium, lead, zinc, cadmium, iron and methyl-mercury. Cobalt, cesium, gold, selenium, chromium, were removed predominantly by urine. For bismuth, mercury, arsenic, and tin the two routes were similar. [R50] BHL: *It appears that independent of exposure route (inhalation, injection or ingestion), most of the cobalt will be eliminated rapidly /in humans/. A small proportion is, however, eliminated slowly, having a biological half-time in the order of yr. /Cobalt/ [R28, p. V2 218] *BEHAVIOR OF (60)COBALT IN MAN FOR UP TO 11 YR AFTER ACCIDENTAL INHALATION WAS OBSERVED ... AFTER FAST CLEARANCE OF MAIN PART OF ABSORBED COBALT, THE REST (ABOUT 10%), HAD A BIOLOGICAL HALF-TIME IN CHEST AS WELL AS IN WHOLE BODY OF 5-15 YR. /COBALT/ [R28, p. V2 219] *Accidentally swallowed (60)Cobalt is eliminated with half-lives of 0.5, 2.7, and 59 days. Over 90% of cobalt taken up parenterally is eliminated within a few days. Only 10% of the dose shows a half-life of 2 yr. Following pulmonary uptake of (60)Cobalt, a further very long half-life of 5-10 yr has been observed. /Cobalt/ [R13, 254] ACTN: *Cobalt stimulates the production of erythropoietin. It is thought that cobalt acts by inhibition of enzymes involved in oxidative metabolism and that the response is the result of tissue hypoxia. More specifically, cobalt blocks the conversion of pyruvate to acetyl coenzyme A and of alpha-ketoglutarate to succinate. /Cobalt/ [R51] *AT ... (1 TO 5 MG OF COBALT/KG AS SOLUBLE SALT BY MOUTH), POLYCYTHEMIA DEVELOPS BY MECHANISM BELIEVED TO BE DIRECT STIMULATING ACTION ON RED BONE MARROW AND POSSIBLE EXTRAMEDULLARY HEMOPOIETIC TISSUE IN OTHER ORGANS. ... IT ... APPEARS ... THAT COBALT-STIMULATED ERYTHROPOIETIC FACTOR IS PART OF MECHANISM ... /COBALT SALTS/ [R2, 1614] *COBALT IONS DEPRESS OXYGEN UPTAKE IN HEART MITOCHONDRIA BY INHIBITING THE ENZYMES ALPHA-KETOGLUTARATE DEHYDROGENASE AND PYRUVATE DEHYDROGENASE. /COBALT IONS/ [R39, 288] *THE ORAL ACTION OF COBALT IN TISSUE IS ATTRIBUTED TO THE INACTIVATION OF THIOL GROUPS. ... THE COBALT INHIBITION OF ALPHA-KETOGLUTARATE DEHYDROGENASE IS CAUSED BY A COMPLEXING OF COBALT WITH THIOL GROUPS OF ALPHA-LIPOIC ACID, A COFACTOR IN THESE ENZYME SYSTEMS. ORAL ADMIN OF SULFUR CONTAINING AMINO ACIDS AND HISTIDINE REDUCES COBALT TOXICITY BY FORMING NONIONIZED, SOL CHELATES WHICH PROTECT THIOL GROUP CONTAINING COFACTORS AND ENZYMES. /COBALT SALTS/ [R39, 289] *Cobalt speeds up ATP turnover, activates arginase, and inhibits delta-aminolevulinic acid synthase. Cobalt exerts effects on mixed function oxidases of the liver and enhances acylamino acid hydrolase and yeast enolase. /Cobalt/ [R13, 255] INTC: *COBALT ACTS WITH ALCOHOL TO PRODUCE SEVERE CARDIAC EFFECTS @ CONCN AS LOW AS ABOUT 1.2-1.5 MG/L OF BEER. /COBALT/ [R22, 249] *... GROWTH RETARDATION AND REDUCTION IN HEART WT /WERE OBSERVED/ FOLLOWING A 35-DAY INGESTION OF WATER WHICH CONTAINED 1 ML ETHANOL AND 1 MG COBALT/10 ML WATER. GUINEA PIGS ALSO SHOW THIS COBALT-ETHANOL SYNERGISM BY GROWTH RETARDATION AND MYOCARDIAL FATTY DEGENERATION. /COBALT SALTS/ [R39, 288] *COBALT IS REPORTED TO ACT SYNERGISTICALLY WITH ANTIBIOTICS ... IN VITRO AND IN VIVO (MICE). IF ANTIBIOTICS ALSO SYNERGIZE ACTION OF COBALT, IT COULD POSSIBLY EXPLAIN ENHANCED SENSITIVITY TO COBALT SEEN IN SOME EXPOSED INDIVIDUALS. /COBALT SALTS/ [R2, 1615] *INJECTION OF METHIONINE PREVIOUS TO COBALT INJECTION IS SAID TO PREVENT OR GREATLY REDUCE SEVERITY OF TOXIC SYMPTOMS. /COBALT SALTS/ [R36] *Cardiomyopathy has been caused by excessive intake of cobalt, particularly from drinking of beer to which 1 ppm cobalt was added to enhance its foaming qualities. ... Alcohol may have served to potentiate the effect of the cobalt. /Cobalt/ [R30, 611] *... Simultaneous admin of iron and cobalt reduces absorption of cobalt. /Cobalt/ [R28, p. V2 216] *... Co(2+) ions are inhibiting to the uptake of iodine into the thyroid gland. /Cobalt ions/ [R13, 255] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ BION: *COBALT IS AN ESSENTIAL MICRONUTRIENT FOR MAMMALS, BUT EXCEPT FOR ITS ROLE IN VIT B12, THE FUNCTION OF COBALT IS UNKNOWN. HOWEVER, GLYCYLGLYCINE DIPEPTIDASE CONTAINS COBALT IN A BOUND FORM. UNLIKE OTHER TRANSITION METALS, COBALT IS NOT REQUIRED FOR MAMMALS EITHER AS IONS OR IN LOOSELY BOUND ORG FORMS. COBALT DEFICIENCY LEADS TO STUNTED GROWTH, ANEMIA, AND DEATH. DEFICIENCY DISEASES OF CATTLE AND SHEEP IN CO-DEFICIENT AREAS ... ARE WELL DOCUMENTED, BUT IT IS VERY DIFFICULT TO DEVELOP ... IN LAB ANIMALS SINCE COBALT IS READILY STORED, IS UBIQUITOUS IN NATURE, AND IS REQUIRED IN SUCH SMALL QUANTITIES ... A DAILY INTAKE OF ABOUT 50 UG COBALT (OF WHICH 40 UG IS IN THE FORM OF VIT B12) MAINTAINS COBALT EQUILIBRIUM IN THE HUMAN. RUMINANTS UTILIZE COBALT DIRECTLY, SINCE RUMINANT BACTERIA USE COBALT TO SYNTHESIZE VIT B12. /COBALT/ [R39, 284] *STATE OF DEFICIENCY (VET): ... /DEFICIENCY SYMPTOMS IN SHEEP AND CATTLE ARE/ MARASMUS, POOR HAIR COAT ... ANEMIA, WEAK OFFSPRING, DECR MILK PRODUCTION, ANOREXIA, SCALY SKIN, MUSCULAR INCOORDINATION, AND OCCASIONALLY CONSTIPATION OR DIARRHEA ARE SOME OF THE MANY SYMPTOMS. /COBALT/ [R6, 124] *STATE OF DEFICIENCY (VET): ... COBALT AS COMPONENT OF VITAMIN B12 IS NECESSARY FOR ERYTHROPOIESIS IN RUMINANTS ... IN ABSENCE OF COBALT, VITAMIN B12 IS DEFICIENT AND PROPIONIC ACID /MAJOR RUMEN FERMENTATION METABOLITE/ CANNOT BE UTILIZED. /COBALT/ [R9, 646] THER: +MEDICATION (VET): Cobalt sulfate has been used in veterinary medicine in the prevention and treatment of cobalt-deficiency diseases in ruminants. [R52] *IN MAN, SUBSTANCE MAY IMPROVE HEMATOCRIT, HEMOGLOBIN, AND ERYTHROCYTE VALUES IN SOME PT WITH REFRACTORY ANEMIA OF VARIOUS TYPES (SICKLE CELL DISEASE, THALASSEMIA, CHRONIC INFECTION OR RENAL DISEASE, ANEMIA ASSOCIATED WITH NEOPLASTIC DISEASE, VARIOUS OTHER REFRACTORY ANEMIAS OF UNKNOWN CAUSE) ... /COBALT/ [R53] *THE ONLY DISEASES IN WHICH THE CLINICAL USE OF COBALT IS STILL ADVOCATED BY SOME IS THE NORMOCHROMIC, NORMOCYTIC ANEMIA ASSOC WITH SEVERE RENAL FAILURE. /COBALT/ [R51] WARN: *USE OF THIS POTENTIALLY TOXIC METAL IS BEST LEFT TO EXPERT IN CLINICAL HEMATOLOGY; ITS USE AS ADJUNCT TO IRON THERAPY FOR IRON DEFICIENCY IS WORTHY OF CONTEMPT GENERATED BY ANY "SHOTGUN" THERAPEUTIC PREPN. /COBALT/ [R53] *Goiter is a well known side effect of cobalt therapy in the medical treatment of certain anemias. ... Usually these adverse effects are regarded as reversible. /Cobalt/ [R28, p. V2 226] *VET: COBALT IS NOT EFFECTIVE PARENTERALLY /IN CATTLE AS A SUBSTRATE FOR VITAMIN B12/ SINCE ITS ACTIVE ORG FORM MUST BE SYNTHESIZED IN RUMEN. /COBALT SALTS/ [R9, 647] *... PRODUCED PRONOUNCED ACTIVATION OF ACNE (FOLLICULITIS) IN PT TAKING VITAMIN-FE-MINERAL SUPPLEMENTS CONTAINING COBALT ... DERMAL MANIFESTATIONS DISAPPEARED WHEN COBALT DISCONTINUED. /COBALT/ [R54] *... Daily doses of 3 mg/kg body wt ... had been tolerated by pt suffering from anemia. ... This therapy, however, led to hypothyroidism and thyroid hyperplasia. /Cobalt salts/ [R13, 255] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *... Occurs in nature as the mineral bieberite. /Hexahydrate/ [R7] *MAJOR SOURCE OF COBALT IS FOOD; CONCN IN GREEN, LEAFY VEGETABLES MAY BE AS GREAT AS 0.5 MG/KG DRY WT. /TOTAL COBALT/ [R22, 308] FATE: *TERRESTRIAL FATE: IN PROCESS OF WEATHERING, COBALT MAY BE TAKEN INTO SOLN MORE READILY THAN NICKEL ... IT IS ADSORBED TO GREAT EXTENT BY HYDROLYSATE OR OXIDATE SEDIMENTS. COBALT MAY BE TAKEN INTO SOLN IN SMALL AMT THROUGH BACTERIOLOGICAL ACTIVITY SIMILAR TO THAT CAUSING SOLN OF MANGANESE. [R22, 247] *Terrestrial Fate: The availability of cobalt is primarily regulated by pH and is usually found in soils as divalent cobalt. At low pH it is oxidized to trivalent cobalt and often found associated with iron. Adsorption of divalent cobalt on soil colloids is high between pH 6 and 7, whereas leaching and plant uptake of cobalt are enhanced by a lower pH. /Cobalt salts/ [R23, 255] BIOC: *Food Chain Concn Potential: Bioconcentration of 200-1000 fold only under constant exposure. Not significant in spill conditions. /Heptahydrate/ [R12] *Only a few plant species accumulate cobalt above the 100 ppm which causes severe phytotoxicity. Hyperaccumulators of cobalt have been found which contain over 1% cobalt in dry leaves. /Cobalt salts/ [R41] KOC: *Soil pH is very important in cobalt uptake and phyto-toxicity. More acidic soils sorb cobalt less strongly ... /Cobalt salts/ [R41] WATC: *Drinking water: Drinking water exhibits low concn of cobalt, usually between 0.1-5 ug/l. In fresh water, about equal concn are found. /Total cobalt/ [R28, p. V2 214] *Seawater: Seawater has been shown to contain less cobalt than freshwater /usually between 0.1-5 ug/l/. /Total cobalt/ [R28, p. V2 214] *COBALT ... OBSERVED IN NATURAL WATERS ONLY IN TRACE AMT. MOST WATERS HAVE NO DETECTABLE COBALT AND VALUES GREATER THAN 10 UG/L ARE RARE. MAX RECORDED VALUE IN ANY OF SEVERAL BROAD STUDIES WAS 99 UG/L. /TOTAL COBALT/ [R22, 308] SEDS: *The concn of cobalt in soils ranges from 1 to 40 mg/kg with an avg of 8 ppm. /Total cobalt/ [R23, 255] ATMC: *Cobalt concn in ambient air during manufacturing of cobalt salts: medium: 0.2 mg/cu m; range: 0.1-3.0 mg/cu m; personal sampling /From table; cobalt salts/ [R13, 258] *Cobalt concn in ambient air during production of cobalt salts: mean values between 49 and 1046 ug/cu m; stationary sampling /From table; cobalt salts/ [R13, 258] *Cobalt concn in ambient air during painting pottery with sol cobalt salts: range: 0.07-8.61 mg/cu m /From table; sol cobalt salts/ [R13, 259] *Reported concn in ambient air of several places in North and South America and in the United Kingdom range between 0.07 and 5 ng/cu m. ... air samples collected near a Belgian cobalt manufacturing plant showed levels 0.4-7.3 ng/cu m. /Total cobalt/ [R13, 260] *The atmospheric concn of cobalt in remote areas is very low, less than 1 ng/cu m in the antarctic. ... In other areas the ambient air concn is usually higher, in the order of 1 ng/cu m. Levels exceeding 10 ng/cu m have occasionally been reported in heavily industrialized cities. /Total cobalt/ [R28, p. V2 214] FOOD: *... 30 to 50 ug/kg dry wt ... /was/ found in vegetables ... /Total cobalt/ [R28, p. V2 213] PFAC: PLANT CONCENTRATIONS: *Common plants such as lettuce, beets, cabbage, spinach, and sweet potatoes act as sources of dietary cobalt containing from a few hundredths ppm (sweet potatoes) to 0.7 ppm (spinach) on a moisture-free basis. /Total cobalt/ [R2, 1612] FISH/SEAFOOD CONCENTRATIONS: *... 30 to 50 ug/kg dry wt ... /was/ found in fish ... /Total cobalt/ [R28, p. V2 213] OEVC: *The tobacco contained about 0.3 to 0.5 mg cobalt/kg dry wt. When the cigarettes were smoked in a standard smoking-machine, 0.5% was found in the mainstream. /Total cobalt/ [R28, p. V2 214] RTEX: *The toxicologically important routes of entry for cobalt metal, fume, and dust (as Co) are inhalation, ingestion, and skin and/or eye contact. /Cobalt metal, fume, and dust (as Co)/ [R18] */IT HAS BEEN/ ... POINTED OUT THAT COBALT WAS INVARIABLY PRESENT IN ATMOSPHERE EVEN IN PLACES WHERE NO MANUFACTURING OPERATIONS WERE IN QUESTION, AND THAT ALL INDIVIDUALS EMPLOYED IN PLANTS BREATHED IN SOME COBALT EVEN IF IN MINUTE AMT. /TOTAL COBALT/ [R38, 138] *... COBALT ALLERGY IS SEEN IN MANY OCCUPATIONS INCL BUILDING AND CIVIL ENGINEERING METALWORK, PRINTING, AND POTTERY, LEATHER AND TEXTILE INDUSTRIES; COBALT MAY SOMETIMES BE THE CAUSATIVE AGENT IN CEMENT ECZEMA. /COBALT, ALLOYS AND CMPD/ [R17, 495] *Occupations with potential exposure to cobalt: acetic acid makers; alloy makers; alnico magnet makers; ammonia mask makers; barometer makers; bright platers; catalyst workers; cement makers; cemented carbide workers; ceramic workers; cement makers; cobalt soap makers; cosmetic makers; dye workers; drug makers; electroplaters; enamelers; ethyl acrylate makers; fertilizer workers; frit workers; gas mask makers; gasoline blenders; glass colorers; glaze workers; high-speed tool steel workers; hygrometer makers; ink makers; iron-cobalt platers; lamp filament makers; magnet steel workers; metal smelterers; nickel by-product workers; paint drier makers; painters; porcelain workers; protective-coating makers; refractory brick makers; rubber makers; silicate paint makers; stone preserver makers; weatherproof cement makers; welders. /From table/ /Cobalt and cmpd/ [R55] *More than a million workers in the USA are potentially exposed to cobalt or its cmpd, many of them, however, to a limited degree, eg, when using cobalt-containing paint driers. Heavier exposure may result from mining processes, in the production of cobalt powder and alloys and in the cemented tungsten carbide industry. /Cobalt and cmpd/ [R13, 253] *Liberation during grinding and sharpening of cemented carbide and steel tools; during synthesis of cobalt cmpd for use as catalysts and driers; during refining and concn of ores. /Cobalt metal, fumes and dust/ [R15, 1981.3] AVDI: *The average daily intake of cobalt from food for adults in the United States has been estimated to be about 300 ug, with an additional 6 ug obtained from water and less than 0.1 ug from community air. /Total cobalt/ [R56] *... The human daily dietary intake was estimated to be about 40-50 ug. /Total cobalt/ [R13, 254] *... The avg daily intake of cobalt from food is 5-45 ug. ... the normal intake of cobalt in Finland ... /has been observed to be/ at an overall avg of 13 ug/day. /Total cobalt/ [R28, p. V2 213] BODY: */The body of/ an adult person contains only up to 1 mg of cobalt ... concn in blood and urine ... below 1 ug/l ... . /Total cobalt/ [R13, 254] *Type of exposure: manufacturing cobalt salts; cobalt concn in urine: mean: 0.34 mg/l; range: 0.1-0.9 mg/l /From table; cobalt salts/ [R13, 258] *Type of exposure: producing cobalt salts; cobalt concn in blood: mean values of 5-48 ug/l; in urine: mean values of 19-438 ug/l; sampling post shift /From table; cobalt salts/ [R13, 258] *Type of exposure: painting pottery with sol cobalt salts; cobalt concn in blood: mean: 2.16 ug/l; in urine: mean: 8.35 ug/mmol creatinine /From table/ /Total cobalt/ [R13, 259] *In autopsy studies, liver has been shown to contain the highest concn of cobalt, individual values ranging from 0.01 to 0.07 mg Co/kg wet wt. With regard to vitamin B12, the total liver content is estimated to be 1.7 mg, which corresponds to a cobalt concn in 1.7 kg liver of 0.04 mg/kg wet wt. ... In worker exposed to cobalt, the lung and lymph node concn of cobalt were about 0.1-1 mg/kg compared to 0.005 mg/kg wet wt in two controls. Plasma or serum concn are usually reported to be in the range of 0.1-0.5 ug/l. ... Using neutron activation ... a normal range of 0.9-3.9 ug/l in whole blood /was found/. ... Using AAS arrived at a somewhat lower avg (0.5 ug/l). In urine samples ... from normal adult persons, the cobalt concn were reported to be around 0.1-2 ug/l. ... In blood an avg of 0.5 ug Co/l in controls and 10.5 ug Co/l in workers exposed to 0.09 mg Co/cu m /were found/. /Total cobalt/ [R28, p. V2 219] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +20 mg/cu m /Cobalt metal, dust, and fume (as Co)/ [R57] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.1 mg/cu m. /Cobalt metal, dust, and fume (as Co)/ [R58] +Vacated 1989 OSHA PEL TWA 0.5 mg/cu m is still enforced in some states. /Cobalt metal, dust and fume, as Co/ [R59] TLV: +8 hr Time Weighted Avg (TWA): 0.02 mg/cu m. /Cobalt, elemental, and inorganic cmpd, as Co/ [R25, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Cobalt, elemental, and inorganic cmpd, as Co/ [R25, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. /Cobalt, elemental, and inorganic cmpd, as Co/ [R25, 2002.24] +Biological Exposure Index (BEI): Determinant: cobalt in urine; Sampling Time: end of shift at end of workweek; BEI: 15 ug/l. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. /Cobalt/ [R25, 2002.89] +Biological Exposure Index (BEI): Determinant: cobalt in blood; Sampling Time: end of shift at end of workweek; BEI: 1 ug/l. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Cobalt/ [R25, 2002.89] OOPL: *In the Federal Republic of Germany, industrial cobalt emission has been limited to 1 mg/cu m for metallic cobalt and its slightly sol cmpd and 50 mg/cu m for other cmpd ... /Cobalt and cmpd/ [R13, 260] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Cobaltous sulfate is included on this list. [R60] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.70 ug/l /Cobalt/ [R61] +(WI) WISCONSIN 40 ug/l /Cobalt/ [R61] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R62] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 7027: Analyte: cobalt; Matrix: air; Sampler: filter (0.8-um cellulose ester membrane); Flow rate: 1-3 l/min; Vol: min: 30 l @ 0.1 mg/cu m, max: 1500 l; Stability: stable /Total cobalt/ [R63, p. V1 7027-1] *NIOSH 7300: Analyte: cobalt; Matrix: air; Sampler: filter (0.8-um cellulose ester membrane); Flow rate: 1-4 l/min; Vol: min: 25 l, max: 2000 l; Stability: stable /Total cobalt/ [R63, p. V1 7300-1] *NIOSH 8005: Analyte: cobalt; Specimen: blood or tissue; Vol: 10 ml blood or 1 g tissue; Preservative: heparin for blood, none for tissue; Controls: collect 3 blood specimens from unexposed workers; Stability: not established /Cobalt and cmpd/ [R63, p. V1 8005-1] ALAB: *EPA Method 9035: Sulfate (Colorimetric, Automated, Chloranilate) Method 9035 is applicable to ground water, drinking and surface waters, and domestic and industrial wastes containing 10 to 400 mg Sulfate ion/l. When solid barium chloranilate is added to a solution containing sulfate, barium sulfate is precipitated, releasing the highly colored acid chloranilate. The color intensity in the resulting chloraniline acid solution is proportional to the amount of sulfate present. Ions causing interference (calcium, aluminum, and iron) can be removed by passage through an ion exchange column. In a single laboratory (EMSL), using surface water samples at concentrations of 39, 111, 188, and 294 mg Sulfate/l, the standard deviations were + or - 0.6, + or - 1.0, + or - 2.2, and + or - 0.8 respectively. In a single laboratory (EMSL), using surface water samples at concentrations of 82 and 295 mg Sulfate/l, recoveries were 99% and 102% respectively. /Sulfate/ [R64] *EPA Method 9036: Sulfate (Colorimetric, Automated, Methylthymol Blue, AAII) Method 9036 is applicable to ground water, drinking and surface waters, and domestic and industrial wastes. Samples in the range of 0.5 to 300 mg Sulfate ion/l can be analyzed. the sample if first passed through a soduim-form cation-exchange column to remove multivalent metal ions. The sample containing sulfate is then reacted with and alcohol solution of barium chloride and methylthymol blue at a pH of 2.5-3.0 to form barium sulfate. The combined solution is raised to a pH of 12.5-13.0 so that excess barium reacts with methylthymol blue The uncomplexed methylthymol blue color is gray; if it is all chelated with barium, the color is blue. Initially, the barium and methylthymol blue are equimolor and equivalent to 30 mg Sulfate ion/liter; thus the amount of uncomplexed methylthymol blue is equal to the sulfate present. In a single laboratory the estimated standard deviation, calculated from duplicate analyses of 26 surface and waste waters at a mean concentration of 110 mg/l was + or - 1.6 mg/l. The mean recovery from 24 surface and waste waters was 102%. /Sulfate/ [R64] *EPA Method 9038: Sulfate (Turbidimetric) Method 9038 is applicable to ground water, drinking and surface waters, and domestic and industrial wastes. This method is suitable for all concentration ranges of sulfate (Sulfate ion); however, in order to obtain reliable readings, use a sample aliquot containing not more than 40 mg/l of Sulfate ion. The minimum detectable limit is approximately 1 mg/l of Sulfate ion . Sulfate ion is converted to a barium sulfate suspension under controlled condition. The resulting turbidity is determined by a nephelometer, filter photometer, or spectrophotometer and compared with a curve prepared from standard sulfate solution. /Sulfate/ [R64] *Method 426A: Gravimetric Method with Ignition of Residue. Sulfate is precipitation in a hydrochloric acid solution as barium sulfate by the addition of barium chloride. The precipitation is carried out near the boiling temperature, and after a period of digestion the precipitate is filtered, washed with water until free of Chloride ion ignited or dried, and weighed as Barium sulfate. This method is suitable for Sulfate ion concentrations above 10 mg/l. /Sulfate/ [R65] *EPA Method 375.1 is an automated, colorimetric method applicable to the determination of sulfate in drinking and surface waters and domestic and industrial waste, in the range of 10 to 400 mg SO4/l. When solid barium chloranilate is added to a solution containing sulfate, barium sulfate is precipitated, releasing the highly colored acid chloranilate ion. The color intensity in the resulting chloranilic acid is proportional to the amount of sulfate present. In a single laboratory (EMSL), using surface water samples at concentrations of 39, 111, 188, and 294 mg SO4/l, the standard deviations were + or - 0.6, + or - 1.0, + or - 2.2, + or - 0.8, respectively. In a single laboratory (EMSL), using surface water samples at concentrations of 82 and 295 mg SO4/l, recoveries were 99% and 102%, respectively. /Sulfate/ [R66] *EPA Method 375.2 is a an automated, colorimetric method for the determination of sulfate in drinking and surface waters and domestic and industrial wastes. Samples in the range of 3 to 300 mg SO4/l can be analyzed. The sensitivity of the method can be increased by a minor modification to analyze samples in the range of 0.5 to 30 mg SO4/l. A sample containing sulfate is reacted with barium chloride and methyl thymol blue (MTB) to form barium sulfate. Excess barium reacts with MTB; the amount of uncomplexed MTB is equal to the sulfate present. In a single laboratory the estimated standard deviation, calculated from duplicate analysis of 26 surface and wastewaters at a mean concentration of 110 mg/l was + or - 1.6 mg/l. The mean recovery from 24 surface and wastewaters was 102%. /Sulfate/ [R67] *A gravimetric method applicable to the determination of sulfate in drinking, surface, and saline water and domestic and industrial wastes. This method is the most accurate method for sulfate concentrations above 10 mg/l. Therefore, it should be used whenever results of the greatest accuracy are required. Sulfate is precipitated as barium sulfate in a hydrochloric acid medium by the addition of barium chloride. After a period of digestion, the precipitate is filtered, washed with hot water until free of chloride, ignited, and weighed as BaSO4. A synthetic unknown sample containing 259 mg/l, was analyzed in 32 laboratories by the gravimetric method, with a relative standard deviation of 4.7% and a relative error of 1.9%. /Sulfate/ [R68] *EPA Method 375.4 is a turbidimetric method applicable to the determination of sulfate in drinking and surface waters and domestic and industrial wastes. The method is suitable for all concentration ranges of sulfate; however, in order to obtain reliable readings, use a sample aliquot containing not more than 40 mg SO4/l. The minimum detectable limit is approximately 1 mg/l sulfate. Sulfate ion is converted to a barium sulfate suspension under controlled conditons. The resulting turbidity is determined by a nephelometer, filter photometer or spectrophotometer and compared to a curve prepared from standard sulfate solutions. A synthetic unknown sample containing 259 mg/l sulfate, was analyzed in 19 laboratories by the turbidimetric method, with a relative standard deviation of 9.1% and a relative error of 1.2%. /Sulfate/ [R69] *DETERMINATION OF COBALT IN ANIMAL FEED. COMPARE COLOR WITH STD COBALT SOLN IN PHOTOELECTRIC COLORIMETER, USING GREEN OR NUMBER 54 FILTER, OR IN SPECTROPHOTOMETER @ 540 NM. /TOTAL COBALT/ [R70, p. 13/137 7.104] *COBALT IN FERTILIZERS DETERMINED BY SPECTROPHOTOMETER AT 530 NM. /TOTAL COBALT/ [R70, p. 13/22 2.124] *WITH DETECTION LIMITS AT 10 UG/L, COBALT IN FRESH WATER IS NOT NORMALLY DETECTABLE BY DIRECT FLAME ATOMIZATION; A CONCN STEP IS USUALLY REQUIRED FOR COBALT DETERMINATION IN WATER. THE US GEOLOGICAL SURVEY USES APDC SOLVENT EXTRACTION PROCEDURE IN WHICH THE COBALT-APDC COMPLEX IS EXTRACTED AT PH OF 2.8 WITH METHYLISOBUTYLKETONE. EXTRACTION WITH DIETHYLDITHIOCARBAMATE AND DITHIZONE HAVE ALSO BEEN DESCRIBED. ... THE GRAPHITE FURNACE TO ENHANCE ATOMIZATION OF THE COBALT IN FRESH WATER /WAS USED/; THE DETECTION LIMIT IS 0.4 UG/L. /TOTAL COBALT/ [R22, 249] *NIOSH 7900: Analyte: cobalt; Matrix: air; Sampler: filter (0.8-um cellulose ester membrane); Flow rate: 1-3 l/min; Vol: min: 30 l @ 0.1 mg/cu m, max: 1500 l; Stability: stable; Technique: atomic absorption, flame; Wavelength: 240.7 nm; Range: 3 to 90 ug/sample; Est LOD: 0.6 ug/sample; Precision (Sr): 0.03; Interferences: the use of D2 or H2 continuum background correction is required to control molecular or flame absorption /Total cobalt/ [R63, p. V1 7027-1] *NIOSH 7300: Analyte: cobalt; Matrix: air; Sampler: filter (0.8-um cellulose ester membrane); Flow rate: 1-4 l/min; Vol: min: 25 l, max: 2000 l; Stability: stable; Technique: inductively coupled argon plasma, atomic emission spectroscopy; Wavelength: 231.2 nm; Range: 2.5-1000 ug/sample; Precision (Sr): 0.040 @ 2.5 ug/filter, 0.005 @ 1000 ug/filter; Interferences: spectral, minimized by wavelength selection, interelement and background correction /Total cobalt/ [R63, p. V1 7300-1] *USING X-RAY FLUORESCENCE SPECTROMETRY ANALYSIS OF AIRBORNE PARTICULATE MATTER FOR COMMON METALS PERFORMED RAPIDLY ON CORRECTION FILTERS WITHOUT CHEM PROCESSING. /TOTAL COBALT/ [R71] *CONCN OF TRACE METALS IN SAMPLES PREPD BY DIRECT WET ASHING OR WET DIGESTION DETERMINED BY FLAME OR FLAMELESS ATOMIC ABSORPTION SPECTROPHOTOMETRY UP TO DETECTION LEVEL AS LOW AS 0.01 PPM DEPENDING ON THE METAL. /TOTAL COBALT/ [R72] *WASTEWATER, WATERS, SLUDGES, MILK SUBSTITUTES, PEACH, AND APPLE LEAVES WERE ANALYZED BY THE INDUCTIVELY COUPLED ARGON PLASMA OPTICAL EMISSION SPECTROSCOPY METHOD FOR TRACE METALS (INCL COBALT). /TOTAL COBALT/ [R73] *Neutron activation analysis (NAA) ... and voltammetry are the analytical methods mainly used for the determination of cobalt in environmental matrices. With NAA ng/kg concn of cobalt can be determined. This method offers the advantage that it works without destruction of the sample. /Total cobalt/ [R13, 260] *EPA Method 219.1 is applicable for the determination of cobalt in drinking, surface, and saline waters, and domestic and industrial wastes by (direct aspiration/furnace) atomic absorption. At a wavelength of 240.7 nm, cobalt has a detection limit of 0.05 mg/l, a sensitivity of 0.2 mg/l and an optimum concentration range of 5.0 mg/l. /Total cobalt/ [R74] CLAB: *ATOMIC ABSORPTION SPECTROSCOPY ... FOR DETERMINATION OF COBALT IN BLOOD AND URINE ... SLAVIN W ET AL, "THE DETERMINATION OF TRACE METALS BY ATOMIC ABSORPTION SPECTROPHOTOMETRY", ATOMIC ABSORP NEWS LETTER NO 17, PERKINELMER CORP, NORWALK, CT, P 7. /COBALT SALTS/ [R2, 1609] *... a chemical method for the determination of cobalt in biologic material by extracting very small amt (often less than 1 ug) with sodium diethyldithiocarbamate and reading the complex at 550 mu, after destroying interfering colors with nitric acid /was described/. The method has a sensitivity of 0.1 ug and a range of 0 to 5 ug/10 ml soln. /Total cobalt/ [R2, 1609] *A spectrochemical method for determining nanogram amt in biologic fluids ... is performed using an ion exchange concn method to separate nanogram amt of cobalt ions from extraneous elements, followed by a copper spark procedure which improves the limit of detection. /Cobalt/ [R2, 1609] *NIOSH 8005: Analyte: cobalt; Specimen: blood or tissue; Vol: 10 ml blood or 1 g tissue; Preservative: heparin for blood; none for tissue; Stability: not established; Technique: inductively-coupled argon plasma-atomic emission spectroscopy; Wavelength: 231.2 nm; Range: 10-10,000 ug/100 g blood, 2-2000 ug/g tissue; Est LOD: 1 ug/100 g blood, 0.2 ug/g tissue; Precision (%Sr): 21; Interferences: spectral, minimized by wavelength selection and interelement correction factors. /Total cobalt/ [R63, p. V1 8005-1] *HAIR AND LIVER SAMPLES WERE ANALYZED BY THE INDUCTIVELY COUPLED ARGON PLASMA OPTICAL EMISSION SPECTROSCOPY METHOD FOR TRACE METALS (INCL COBALT). /TOTAL COBALT/ [R73] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Report on the Toxicity Studies of Cobalt Sulfate Heptahydrate in F344/N Rats and B6C3F1 Mice (Inhalation Studies) NTP TOX 5 (1991) NIH Pub No. 91-3124 DHHS/ATSDR; Toxicological Profile for Cobalt (1992) ATSDR/TP-91/10 SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 295 R2: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R3: Pearce, J. (ed.). Gardner's Chemical Synonyms and Trade Names. 9th ed. Aldershot, Hants, England: Gower Publsihing Company, 1987. 185 R4: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 181 R5: SRI. 1988 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1988.. 537 R6: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. R7: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 347 R8: Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989.,p. B-18 R9: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. R10: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-514 R11: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R12: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R13: Seiler, H.G., H. Sigel and A. Sigel (eds.). Handbook on the Toxicity of Inorganic Compounds. New York, NY: Marcel Dekker, Inc. 1988. R14: National Research Council. Prudent Practices for Handling Hazardous Chemicals in Laboratories. Washington, DC: National Academy Press, 1981. 149 R15: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R16: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 568 R17: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R18: NIOSH. Pocket Guide to Chemical Hazards. 2nd Printing. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, February 1987.85 R19: NIOSH; Criteria Document: Cobalt p.36 (1981) DHEW Pub. NIOSH 82-107 R20: NIOSH; Criteria Document: Cobalt p.37 (1981) DHEW Pub. NIOSH 82-107 R21: NIOSH; Criteria Document: Cobalt p.38 (1981) DHEW Pub. NIOSH 82-107 R22: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R23: Brown, K.W., G. B. Evans, Jr., B.D. Frentrup (eds.). Hazardous Waste Land Treatment. Boston, MA: Butterworth Publishers, 1983. R24: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R25: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R26: NIOSH; Criteria Document: Cobalt p.23 (1981) DHEW Pub. NIOSH 82-107 R27: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 967 R28: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986. R29: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-143 R30: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. R31: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.144 R32: NIOSH; Criteria Document: Cobalt p.2 (1981) DHEW Pub. NIOSH 82-107 R33: NIOSH; Criteria Document: Cobalt p.14 (1981) DHEW Pub. NIOSH 82-107 R34: Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987. 244 R35: Lins LE, Pehrsson K; Lancet 1: 119-92 (1976) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 84 (1980) R36: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 44 R37: Mohiuddin SM et al; Am Heart J 80: 532-43 (1970) as cited in NIOSH; Criteria Document: Cobalt p.15 (1981) DHEW Pub. NIOSH 82-107 R38: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. R39: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. R40: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 247 R41: Parr, J.F., P.B. Marsh, and J.M. Kla (eds.). Land Treatment of Hazardous Wastes. Park Ridge, New Jersey: Noyes Data Corporation, 1983. 176 R42: Luckey, T.D. and B. Venugopal. Metal Toxicity in Mammals, 1. New York: Plenum Press, 1977. 186 R43: Toxicology and Carcinogenesis Studies of Cobalt Sulfate Heptahydrate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 471 (1998) NIH Publication No. 98-3961 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R44: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 203 R45: Jones, L.M., et al. Veterinary Pharmacology and Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. 800 R46: Friberg, L., G.R. Nordberg, and V.B. Vouk. Handbook on the Toxicology of Metals. New York: Elsevier North Holland, 1979. 402 R47: Tietz, N.W. (ed.). Clinical Guide to Laboratory Tests. Philadelphia, PA: W.B. Saunders Co., 1983. 128 R48: Schroeder HA et al; J Chron Dis 20: 869-90 (1967) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 84 (1980) R49: Sorbie J et al; Can Med Assoc J 104: 777-82 (1971) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 84 (1980) R50: Gregus Z, Klaassen CD; Toxicol Appl Pharm 85 (1): 24-38 (1986) R51: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. 1319 R52: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 1697 R53: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1320 R54: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1032 R55: NIOSH; Criteria Document: Cobalt p.28 (1981) DHEW Pub. NIOSH 82-107 R56: NIOSH; Criteria Document: Cobalt p.5 (1981) DHEW Pub. NIOSH 82-107 R57: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS(NIOSH) Publication No. 90-117. Washington, DC: U.S. Government Printing Office, June 1990 72 R58: 29 CFR 1910.1000 (7/1/98) R59: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 362 R60: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R61: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R62: 40 CFR 712.30 (7/1/88) R63: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R64: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R65: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.464-66 (1985) R66: USEPA; Methods for Chemical Analysis of Water and Wastes p.375.1 (1983) R67: USEPA; Methods for Chemical Analysis of Water and Wastes p.375.2(1983) R68: USEPA; Methods for Chemical Analysis of Water and Wastes p.375.3 (1983) R69: USEPA; Methods for Chemical Analysis of Water and Wastes p.375.4 (1983) R70: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982. R71: LUKE CL ET AL; ENVIRON SCI TECHNOL 6 (13): 1105-9 (1972) R72: HUNG GW; JT CONF SENS ENVIRON POLLUT (CONF PROC), 4TH; 765-70 (1978) R73: WARD AF ET AL; ENVIRON ANAL (PAP ANNU MEET FED ANAL CHEM SPECTROSC SOC) 3RD: 245-52 (1977) R74: USEPA; Methods for Chemical Analysis of Water and Wastes p.219.1 (1983) RS: 75 Record 50 of 1119 in HSDB (through 2003/06) AN: 250 UD: 200303 RD: Reviewed by SRP on 12/1/1988 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CRESOL- SY: *ACIDE-CRESYLIQUE- (FRENCH); *AR-TOLUENOL-; *BACILLOL-; +o-CRESOL-; *CRESOLI- (ITALIAN); *Cresolum-crudum-; *CRESYLIC-ACID-; +Pesticide-Code:-022101-; *HYDROXYMETHYLBENZENE-; *HYDROXYTOLUOLE- (GERMAN); *KRESOLE- (GERMAN); *KRESOLEN- (DUTCH); *Kresolum-venale-; *KREZOL- (POLISH); *METHYL-PHENOL-; *PHENOL,-METHYL-; *TEKRESOL-; *Tricresol-; *Tricresolum-; *Trikresolum- RN: 1319-77-3 RELT: 1815 [m-CRESOL]; 1814 [P-CRESOL]; 1813 [O-CRESOL] MF: *C7-H8-O SHPN: UN 2076; Cresol (o-, m-, and p-) IMO 6.1; Cresol (o-, m-, and p-) STCC: 49 314 17; Cresol (o-, m-, and p-) HAZN: U052; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. F004; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OBTAINED FROM COAL TAR: PAULSEN, USA PATENT 2,998,457 (1962 TO ASHLAND OIL AND REF). ... PREPN BY SULFONATION OF TOLUENE: ENGLUND ET AL, IND ENG CHEM 45, 189 (1953); BY OXIDATION OF TOLUENE, BRAUNWARTH, WINSTED, USA PATENT 2,994,722 (1961 TO PURE OIL CO). [R1] FORM: *GRADES: VARIOUS, DEPENDING ON PHENOL CONTENT, OR OTHER PROPERTIES. NF GRADE CONTAINS NOT MORE THAN 5% PHENOL. [R2] *... IT IS FORMULATED AS SAPONATED CRESOL SOLN (50% CRESOL) IN ORDER TO BE MISCIBLE WITH WATER. [R3] *PURE CRESOL IS A MIXTURE OF ORTHO-, META- AND PARA-ISOMERS. CRUDE CRESOL (COMMERCIAL CRESOL) IS A MIXTURE OF AROMATIC CMPD CONTAINING ABOUT 20% OF O-CRESOL, 40% OF M-CRESOL, and 30% OF P-CRESOL WITH SMALL AMT OF PHENOL AND XYLENOLS. [R4, 2597] MFS: *Merichem Co, 4800 Texas Commerce Tower, Houston, TX 77002-3068, (713) 224-3030 [R5] OMIN: *CRESYLIC ACIDS: COMMERCIAL MIXTURES OF PHENOLIC MATERIALS BOILING ABOVE CRESOL RANGE. AN ARBITRARY STANDARD IN USE FOR CRESYLIC ACIDS IS THAT 50% MUST BOIL ABOVE 204 DEG C. IF BOILING POINT IS BELOW 204 DEG C, MATERIAL IS CALLED CRESOL ... CRESYLIC ACID VARIES WIDELY ACCORDING TO ITS SOURCE AND BOILING RANGE. [R2] USE: +For Cresol (USEPA/OPP Pesticide Code: 022101) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R6] *FOR MAKING SYNTHETIC RESINS [R1] *IN MANUFACTURE OF TRICRESYL PHOSPHATE; ORE FLOTATION; TEXTILE SCOURING AGENT; ORGANIC INTERMEDIATE, MFR OF SALICYLALDEHYDE, COUMARIN, HERBICIDES AND SURFACTANT [R2] *WIDE USE IN DEGREASING CMPD, PAINTBRUSH CLEANERS, AND ADDITIVES TO LUBRICATING OILS [R7] *FUMIGANT; IN PHOTOGRAPHIC DEVELOPERS AND EXPLOSIVES [R8] *Many household disinfecting solutions contain it as sanitizing agent. [R9] +MEDICATION (VET): */Cresols/ have wide applications in synthetic resin, explosive, petroleum, photographic, paint and agricultural industries [R4, 2597] CPAT: +Phenolic resins, 20%; wire enamel solvents 20%; agricultural chemicals, 10%; phosphate esters, 5%; disinfectants and cleaning compounds, 5%; ore flotation, 5%; miscellaneous and exports, 25% (1979) [R10] PRIE: U.S. PRODUCTION: *(1984) 5.33X10+10 g [R11] *60,413x10+3 lb /includes (o,m,p)- cresol from coal tar, m-cresol, p-cresol, cresylic acid refined from petroleum and coal tar and (m,p)-cresol from petroleum. Does not include data from coke oven and gas-retort ovens. [R12] *(1972) 4.81X10+10 GRAMS (O,M AND P-CRESOL) [R13] *(1975) 3.30X10+10 GRAMS (ALL ISOMERS) [R13] *(1982) 1.07X10+10 G (INCL P-CRESOL) [R13] *(1984) 3.49X10+10 g /includes (o,m,p)- cresol from coal tar, m-cresol, p-cresol, cresylic acid refined from petroleum and coal tar, and (m,p)- cresol from petroleum/ [R11] *(1985) 36,399x10+3 lb /includes (o,m,p)- cresol from coal tar, m-cresol, p-cresol, cresylic acid refined from petroleum and coal tar, and (m,p)- cresol from petroleum/ [R12] *(1972) 4.81X10+10 GRAMS (O,M AND P-CRESOL) [R13] *(1975) 3.30X10+10 GRAMS (ALL ISOMERS) [R13] U.S. IMPORTS: *(1984) 5.29x10+9 g [R14] *(1986) 13,662,118 lb [R15] *(1981) 1.26X10+9 G 0- AND M-, PRINCPL CUSTM DIST [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS, YELLOWISH, BROWNISH-YELLOW, OR PINKISH LIQUID [R1] ODOR: *Phenol-like, sometimes empyreumatic odor [R16]; *Sweet, tarry [R17] TAST: *Pungent [R18] BP: *191-203 DEG C [R2] MW: *108.13 [R1] DEN: *1.030-1.038 @ 25 DEG C/25 DEG C [R1] DSC: +pKa = 10.22 @ 25 deg C [R19] HTC: *-14,720 to -14,740 Btu/lb= -8180 to -8190 cal/g= -342.5 to -342.9x10+5 J/kg [R20] HTV: *200 Btu/lb= 110 cal/g= 4.6x10+5 J/kg (est) [R20] OWPC: +The log octanol-water partition coefficients of the cresol isomers range from 1.94-1.96. [R21] PH: *SATURATED SOLN ARE NEUTRAL OR SLIGHTLY ACID TO LITMUS [R16] SOL: *SOL IN ABOUT 50 PARTS WATER [R1]; *MISCIBLE WITH ALCOHOL, BENZENE, ETHER, GLYCEROL, PETROLEUM ETHER; SOL IN SOLUTIONS OF FIXED ALKALI HYDROXIDES [R1]; *SOL IN VEGETABLE OILS [R4, 2598]; *SOL IN GLYCOL [R2] SPEC: *... In the direct-reading infrared analyzers, cresol reportedly absorbs at the 8.6 um wavelength, with a sensitivity of 0.3 ppm. [R22]; *INDEX OF REFRACTION: 1.5353 @ 24 DEG C /SRP: COMMERCIAL PRODUCT/ [R4, 2598] VAPD: *3.72 (AIR= 1) [R4, 2598] VAP: +vapor pressure = 0.17 mm Hg @ 25 deg C [R23] VISC: *Varies from 4.49 to 7.0 cp at 40 deg C depending on isomer. [R24] OCPP: *A SOLN IN WATER IS NEUTRAL TO BROMOCRESOL PURPLE; NOT LESS THAN 90% BY VOL [R1] *WT/GAL 8.66-8.68 LB [R2] *Henry's Law constant ranging from 8.7X10-7 to 1.6X10-6 atm cu m/mole (calculated values) [R25] +1 MM HG @ 38-53 DEG C [R26, 814] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of cresol stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, dermal absorption), exposure to this colorless, yellowish, brownish-yellow, or pinkish, sweet-smelling liquid may occur from its use as a solvent, fumigant, or disinfectant, or its use in the synthesis of phenolic resins. Effects from exposure may include serious burns to the skin and eyes (sometimes causing blindness), weakness, headache, dizziness, unconsciousness, and deah from cardiac or pulmonary failure, or damage to the kidney or liver. Both the OSHA PEL and the ACGIH TLV for cresol have been set at 5 ppm. Airborne levels of cresol should be controlled through the use of local exhaust ventilation. In emergency situations, a self-contained breathing apparatus should be worn. Skin exposure presents the most common hazard, and should be protected against by wearing a face shield, rubber gloves and boots, and chemical protective clothing which is specifically recommended by the shipper or producer. If contact does occur, immediately flush affected skin or eyes with running water for at least 15 minutes, and remove and isolate contaminated clothing at the site. While cresol does not ignite easily, it can burn, emitting highly toxic fumes. Also, containers may explode in the heat of a fire. For small fires involving cresol, extinguish with dry chemical, CO2, Halon, water spray, or standard foam, and for large fires, use water spray, fog, or standard foam. Runoff from fire control water may give off poisonous gases or cause pollution, and should be controlled by diking, as necessary. Cresol should be stored in iron or steel containers, in cool, dry, dark, well-ventilated areas, away from oxidizing materials, sources of physical damage, and sources of ignition, such as sparks or flames. Cresol may be shipped via air, rail, road, or water in containers bearing the label, "Poison". Small spills of cresol may be taken up with sand or other noncombustible absorbent and placed into containers for later disposal. Large spills should first be diked to prevent cresol from entering water sources or sewers, then contained in excavated pits or other holding areas that are sealed with an impermeable flexible membrane liner. Bulk liquid can be neutralized with crushed limestone or soda ash, and absorbed with fly ash, cement powder, or sawdust. Spills of cresol in water may need to be trapped at the bottom with sand bag barriers, activated charcoal applied, and trapped material removed with mechanical dredges or lifts. Prior to implementing permanent land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance. Also, cresol is a potential candidate for rotary kiln, and fluidized bed forms of incineration. DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Cresols/ [R27] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Cresols/ [R27] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Cresols/ [R27] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Cresols/ [R27] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Cresols/ [R27] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Cresols/ [R27] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Cresols/ [R27] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Cresols/ [R27] FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME. [R26, 814] NFPA: +Health: 3. 3= Materials extremely hazardous to health but areas may be entered with extreme care. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms, and waist should be provided. No skin surface should be exposed. [R28, p. 325-28] +Flammability: 2. 2= Material which must be moderately heated before ignition will occur. Water spray may be used to extinguish the fire because the material can be cooled below its flash point. [R28, p. 325-28] +Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R28, p. 325-28] FLMT: +lower: 1.4% at 300 deg F (150 deg C) [R28, p. 325-28] FLPT: +178 deg F (81 deg C) closed cup [R28, p. 325-28] AUTO: +1110 deg F (599 deg C) [R28, p. 325-28] FIRP: +USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. [R28, p. 49-43] +Water may be used to blanket fire. [R28, p. 325-28] TOXC: *Flammable toxic vapors are given off in a fire. [R20] OFHZ: *Sealed closed containers can build up pressure if exposed to heat (fire). [R20] EXPL: *SLIGHT, IN FORM OF VAPOR WHEN EXPOSED TO HEAT OR FLAME ... [R26, 814] *EXPLOSIVE RANGE: < or = 1.35% AT 300 DEG F. [R26, 814] REAC: *DANGEROUS ... IT CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R26, 814] +Strong oxidizers, acids. /ortho, meta, and para-Cresol/ [R29] DCMP: *DANGEROUS; WHEN HEATED TO DECOMP, IT EMITS HIGHLY TOXIC FUMES ... [R26, 814] ODRT: *Low threshold= 0.012 mg/cu m; High threshold= 22.000 mg/cu m. [R30] SERI: *Vapors cause irritation of eyes, nose, and throat. [R20] *Cresol is a strong dermal irritant [R8] EQUP: *EYE PROTECTION SHOULD ... BE PROVIDED AGAINST DROPLETS OR SPRAY. /CRESOLS, CRESOTES AND DERIVATIVES/ [R9] *Organic vapor canister unit (USBM type B) approved by US Bureau of Mines; rubber gloves, face shield, coveralls and/or rubber apron, rubber shoes, or boots. [R20] *The use of respirators to achieve compliance with the recommended exposure limits is permitted only: (a) during the time necessary to install or test the required engineering controls, and (b) during emergencies or during nonroutine operations, such as maintenance or repair activities, when the concentration of airborne cresol may exceed the permissible environmental limit. [R31] *IN THE FACTORY IT IS NECESSARY TO TAKE ... PRECAUTIONS IN HANDLING CRESOL. RUBBER CLOTHES AND ARTICLES ... CAN ... GIVE EFFECTIVE PROTECTION. [R32] *... TO PREVENT ABSORPTION THROUGH SKIN ... WEAR RUBBER HAND PROTECTION AND APRONS. /CRESOLS, CRESOTE AND DERIVATIVES/ [R9] +Wear appropriate personal protective clothing to prevent skin contact. /ortho, meta, and para-Cresol/ [R29] +Wear appropriate eye protection to prevent eye contact. /ortho, meta, para-Cresol/ [R29] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. /ortho, meta, para-Cresol/ [R29] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.) /ortho, meta, para-Cresol/ [R29] +Recommendations for respirator selection: Max. concn for use:23 ppm. Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Any supplied-air respirator. /ortho, meta, para-Cresol/ [R29] +Recommendations for respirator selection: Max. concn for use:57.5 ppm. Any supplied-air respirator operated in a continuous-flow mode. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. /ortho, meta, para-Cresol/ [R29] +Recommendations for respirator selection: Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. Max. concn for use:115 ppm. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. /ortho, meta, para-Cresol/ [R29] +Recommendations for respirator selection: Max. concn for use:250 ppm. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. /ortho, meta, para-cresol/ [R29] +Recommendations for respirator selection: Emergency or planned entry into unknown concn or idlh conditions. Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /ortho, meta, para-cresol/ [R29] +Respirators for escape purposes only: Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /ortho, meta, para-cresol/ [R29] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emmissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. +Contact lenses should not be worn when working with this chemical. /ortho, meta, and para-Cresol/ [R29] +The worker should immediately wash the skin when it becomes contaminated. /ortho, meta, and para-Cresol/ [R29] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /ortho, meta, and para-Cresol/ [R29] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /ortho, meta, and para-Cresol/ [R29] *Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. [R33] *Air spill: Apply water spray or mist to knock down vapors. Vapor knockdown water is corrosive or toxic and should be diked for containment. [R33] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *Crystals or liquid darken with exposure to air and light. [R26, 815] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R34] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R35] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R36] STRG: *PROTECT FROM LIGHT. [R1] +STORE IN A COOL, DRY, WELL VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS. [R28, p. 49-43] *All bulk containers that hold cresol shall carry, in a readily visible location, a label that bears the trade name of the product, if appropriate, and information on the effects of exposure to the compound on human health. [R37] *Cresol should be stored in iron or steel containers, properly labelled. /Cresols, cresotes and derivatives/ [R9] CLUP: *Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, apply activated carbon at ten times the spilled amount in region of 10 ppm or greater concentration. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R33] *Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, sawdust, or commercial sorbents. [R33] *Neutralize spilled material with crushed limestone, soda ash, or lime. [R33] *Air spill: Apply water spray or mist to knock down vapors. Vapor knockdown water is corrosive or toxic and should be diked for containment. [R33] *Optimum conditions for removing cresol from wastewater with Lewatit MP 500 (a strong-base, large-pore, polystyrene-based anion exchange resin) were pH 6, 30 deg C, and a flow rate of 1 l/hr, and when removing cresol from 10 mg/l solutions, the capacity of the exchanger was 0.46 equiv/l. [R38] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Cresols: Potential candidate for rotary kiln incineration, with a temp range of 820 to 1,600 deg C (1,500 to 2,900 deg F) and a residence time of seconds. Also a potential candidate for fluidized bed incineration, with a temp range of 450 to 980 deg C (840 to 1,800 deg F) and a residence time of seconds. [R39] *Chemical Treatability of Cresol; Concentration Process: Activated Carbon; Chemical Classification: Phenols; Scale of Study: continuous flow, pilot scale; Type of Wastewater Used: Hazardous material spill; Results of Study: 96.5% reduction with 8.5 min contact time (250,000 gal spill treated by EPA mobile treatment trailer). [R40] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R41] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R41] +Waste waters with medium cresol contents (5-50 mg/l) may be subjected to a biological treatment (oxidation ponds, trickling filters, activated sludge basins). In this way it is possible to reduce the cresol content to 1 to 0.5 mg/l. In order to lower the content still further, chemical or physicochemical treatment methods are required (treatment with activated charcoal, ozone). With ozone the content of biologically pretreated refinery effluents can be reduced from 0.35 to 0.16 mg/l to 0.003 mg/l. Cresol wastes of high concn are destroyed in special waste incinerators. Recommendable methods: Incineration, discharge to sewer, and chemical treatment. Peer-review: Concentrated aqueous cresol soln should be adsorbed on an organic solid and incinerated. More dilute cresol soln can be purified by passing through activated carbon columns. The eluate can be discharged to sewer, and carbon incinerated. Only dilute cresol soln can be discharged to sewer. Oxidation with ozone, chlorine dioxide destroys cresol. The resulting soln can be discharged. This is only applicable to dilute cresol soln. Chlorine dioxide is also a hazardous material. Do not use chlorine to oxidize cresols. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R42] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +The general population can be exposed to cresols from air inhalation, drinking water, food and beverage ingestion and dermal contact. ... Cresols are absorbed across the respiratory and GI tracts and through the skin. ... Gastrointestinal and dermal absorption are rapid and extensive. Cresols are distributed to all the major organs. The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. Minor metabolic pathways for cresols include hydroxylation of the benzene ring and side-chain oxidation. The major route for elimination of cresols from the body is renal excretion in the form of conjugates. Acute poisoning with cresol vapors is unlikely due to the low vapor pressure of these compounds. ... Cresols are highly irritating to the skin and eyes of rabbits, rats and mice. Short term exposure to inhaled mixtures of o-cresol aerosol and vapor resulted in irritation of the respiratory tract, small hemorrhages in the lung, body weight reduction and degeneration of heart muscle, liver, kidney and nerve cells. Short term ... oral exposure ... resulted in reduced body weights, organ weight changes and histopathological changes in the respiratory and GI tracts of rats. In mice ... more severe effects were reported, and at the highest concns death resulted from exposure to o-, m- and p-cresols but not from exposures to mixtures of isomers. Longer term exposure to vapors of o-, m-, and p-cresol ... resulted in weight loss, reduced locomotor activity, inflammation of nasal membranes and skin and changes in the liver. Oral exposures for up to 13 weeks of mice, rats, and hamsters, resulted in mortality, tremor, reduced body weights, hematological effects, incr in organ weight, and hyperplasia of nasal and forestomach epithelium. Oral and inhalation exposure to cresol isomers result in lengthened estrus cycle and histopathological changes in the uterus and ovaries of rats and mice. No adverse effects on spermatogenesis were observed ... Mild fetotoxic effects have been reported ... but only minor treatment-related developmental effects ... Some evidence of genotoxicity has been reported to result in vitro ... No positive results were obtained in in vivo studies. ... /In humans/ ingestion of cresols results in burning of the mouth and throat, abdominal pain and vomiting. The target tissues/organs of ingested cresols in humans are the blood and kidneys, and effects on the lungs, liver, heart and CNS have also been reported. In severe cases, coma and death may result. Dermal exposure has been reported to cause severe skin burns, scarring, systemic toxicity and death. Occupational exposure to cresols usually results from dermal contact. Acute exposures can result in severe burns, anuria, coma and death. Very few data are available regarding reproductive effects and there are no data on carcinogenicity in humans. ... At concns normally found in the environment, cresols do not pose any significant risk for the general population. However, the potential for adverse health effects exists in the case of people with renal insufficiency or specific enzyme deficiency and under conditions of high exposure. [R43] CARC: +CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. /2-Methylphenol, 3-Methylphenol, and 4-Methylphenol/ [R44] MEDS: */It is recommended that a/ preplacement medical examinations should include at least: ... a urinalysis that includes a microscopic examination. Additional tests, such as complete blood counts and liver and kidney function tests, should be considered by the responsible physican. ... An evaluation of the worker's ability to use positive and negative pressure respirators. ... Periodic examinations shall be made available on at least an annual basis. These examinations should include ... interim medical and work histories. ... Employees complaining of skin abnormalities, such as scaling, crusting, or irritation, that may be attributed to exposure to cresol shall be medically evaluated. ... Pertinent medical records shall be maintained by the employer for all employees occupationally exposed to cresol. Such records shall be retained for at least 30 years after termination of employment. Records of environmental exposures applicable to an employee shall be included in the employee's medical records. These records shall be made available to the designated medical representatives of the /Secretary of Health and Human Services/, the Secretary of Labor, and the employer, employee, or former employee. [R45] *... In cases of splashes, spills, or leaks where significant skin or eye contact with, or inhalation of the material occurs, appropriate medical personnel shall be notified. Medical attendants shall be informed of the possibility of delayed systemic effects, and the persons so exposed shall be observed for a minimum of 72 hours. Medical examinations ... shall be made available as warranted by the results of the 72 hour observation period. [R46] HTOX: *SYMPTOMATOLOGY: 1. Burning pain in mouth and throat. White necrotic lesions in mouth, esophagus and stomach. Abdominal pain, vomiting ... and bloody diarrhea. 2. Pallor, sweating, weakness, headache, dizziness, tinnitus. 3. Shock: Weak irregular pulse, hypotension, shallow respirations, cyanosis, pallor, and a profound fall in body temperature. 4. Possibly fleeting excitement and confusion, followed by unconsciousness ... 5. Stertorous breathing, mucous rales, rhonchi, frothing at nose and mouth and other signs of pulmonary edema are sometimes seen. Characteristic odor of phenol on the breath. 6. Scanty, dark-colored ... urine ... moderately severe renal insufficiency may appear. 7. Methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia have been reported ... 8. Death from respiratory, circulatory or cardiac failure. 9. If spilled on skin, pain is followed promptly by numbness. The skin becomes blanched, and a dry opaque eschar forms over the burn. When the eschar sloughs off, a brown stain remains. /Phenol/ [R47, p. II-346] *IN MAN ... LUNG SHOWED HYPEREMIA, EMPHYSEMA, EDEMA, BRONCHOPNEUMONIA WITH PETECHIAL HEMORRHAGES IN PLEURA. LIVER SHOWED TURBIDITY, INFLAMMATORY REACTIONS, FATTY DEGENERATION; KIDNEY SHOWED PARENCHYMATOUS, HEMORRHAGIC NEPHRITIS; MYOCARDIUM ... DEGENERATED ... HEMORRHAGES IN EPICARDIUM AND ENDOCARDIUM. [R4, 2599] *A CASE OF METHEMOGLOBINEMIA WITH MASSIVE HEMOLYSIS AND HEINZ BODIES COMPLICATED BY ANURIA AND IRREVERSIBLE SHOCK IS DESCRIBED. ... LEADS TO SUSPECT ACUTE CRESYL POISONING. COMPARABLE CASES REPORTED IN LITERATURE AND IN VITRO TESTS DEMONSTRATE THE TOXIC ACTION OF CRESOLS ON RED BLOOD CELLS. [R48] *CRESOL IN CONTACT WITH SKIN CAN CAUSE SERIOUS BURNS. THE SKIN, AT FIRST RED, BECOMES WHITE AND BLISTERS FORM, AND ACCORDING TO THE CONCENTRATION AND LENGTH OF CONTACT, THERE IS ECZEMA OR ULCERATION. THE WHITE PATCHES CAN TURN BROWN OR BLACK (SIGNS OF GANGRENE). [R32] *... A 49 year old woman ingested 250 ml of 40% ethyl alcohol and 250 ml of Lysol, which was reported to contain 50% cresol in potassium soap. She was unconscious when admitted to the hospital and suffered from respiratory disturbance. A medical examination revealed high blood pressure, rapid pulse rate, low hemoglobin concentration, and a low red cell count. Kidney problems, which worsened during the next 3 days, were indicated by the presence of blood in the urine, oliguria with accompanying metabolic acidosis, accumulation of nitrogen metabolites in the blood, and blood electrolyte imbalance. Dialysis was performed, but the patient's condition remained serious. There were also indications ... that either the stomach or intestinal wall had been perforated, but surgery revealed acute inflammation of the pancreas with peritoneal involvement. The woman was treated with diuretics, which gradually relieved the excess nitrogen metabolites, electrolyte imbalance, oliguria, and acidosis. ... Kidney malfunction /was attributed/ to the direct action of cresol and the pancreatitis to the irritant action of both the cresol and alcohol, including the alcohol that had been consumed prior to the incident. /It was observed/ ... that these compounds, by directly irritating the mucous lining of the duodenum, constricted the sphincter of the pancreatic and bile ducts and thereby disrupted drainage of pancreatic fluid. ...The woman's survival, despite pancreatic complications, /was attributed/ to the early dialysis, which they thought had quickly reduced the amount of circulating cresol. [R49] *Nonoccupational dermal exposure to cresol has resulted in injury and death. In 1975, ... a male infant had about 20 ml of a 90% cresol solution in water accidentally poured over his head. Within 5 minutes, the baby was unconscious and cyanotic. He died 4 hours later. Chemical burns were evident on about 7% of his skin. Examination of the internal organs revealed edema, hemorrhagic effusions from the peritoneum, pleura, and pericardium, and congestion in the brain and kidneys. The blood contained 12 mg of cresol/100 ml. Microscopic examination of the tissues revealed destruction of the epidermis with loss of the stratum corneum, extensive centrilobular and midzonal necrosis of the liver, edema of the brain, and signs of early acute tubular necrosis of the kidneys. [R50] *Prolonged or repeated absorption of low concentrations of cresol through the skin, mucous membranes, or respiratory tract may cause chronic systemic poisoning. Symptoms and signs of chronic poisoning include vomiting, difficulty in swallowing, salivation, diarrhea, loss of appetite, headache, fainting, dizziness, mental disturbances, and skin rash. Death may result if there has been severe damage to the liver and kidneys. [R51, 192] *Lethal concn in blood is 12 mg% (120 ug/ml). [R52] *... Two cases of transitional cell sarcoma of the bladder and a case of squamous cell carcinoma of the vocal cords have been found in workers occupationally exposed to cresols and other chemicals. [R53] *When cresol is absorbed into the body either through the lung, through the skin, mucous membranes, or by swallowing, it may cause systemic poisoning. The signs and symptoms of systemic poisoning may develop in 20 or 30 minutes. These toxic effects include weakness of the muscles, headache, dizziness, dimness of vision, ringing of the ears, rapid breathing, mental confusion, loss of consciousness, and sometimes death. [R51, 192] *When cresol contacts the skin, it may not produce any sensation immediately. After a few moments, prickling and intensive burning occur. This is followed by loss of sensory feeling. The affected skin shows wrinkling, white discoloration, and softening. Later gangrene may occur. If cresol contacts the eyes, it may cause extensive damage and blindness. A skin rash may result from repeated or prolonged exposure of the skin to low concentrations of cresol; discoloration of the skin may also occur. [R51, 192] *ONE-THIRD G OF ... CRESOL ... MAY CAUSE DANGEROUS SYMPTOMS. 3 G ... MAY BE FATAL, ... [R54, 165] *... CRESOL ... IS A STRONG DERMAL IRRITANT AND CAUSES FREQUENT DERMATITIS ... SERIOUS OR EVEN FATAL POISONING MAY RESULT IF LARGE AREAS OF SKIN ARE WET WITH CRESOL AND NOT REMOVED IMMEDIATELY. [R8] *CRESOL IS SLIGHTLY MORE CORROSIVE /TO THE SKIN OR EYES/ THAN PHENOL, BUT SYSTEMIC EFFECTS MAY BE A LITTLE MILDER BECAUSE OF SLOWER ABSORPTION. [R47, p. II-192] *AQ SOLN STRONGER THAN 2% ... SHOULD NOT BE APPLIED TO SURFACE OF BODY. /PHENOL, CRESOLS/ [R55] *... CRESOL IS NOT SUFFICIENTLY VOLATILE TO CONSTITUTE A RESPIRATORY HAZARD /AS A VAPOR/ UNDER NORMAL CONDITIONS. [R8] *MAIN HAZARD ACCOMPANYING ITS USE IN INDUSTRY LIES IN ITS ACTION ON SKIN AND MUCOUS MEMBRANES, WITH PRODUCTION OF SEVERE CHEMICAL BURNS AND DERMATITIS ... [R26, 814] *It is a general protoplasmic poison and is toxic to all cells. [R9] *A patient with massive intravascular Heinz-body hemolytic anemia associated with the presence of bizarre looking erythrocytes following the oral ingestion of approx 100 ml of penetrating oil, a petroleum distillate /product/ containing 85% kerosene, 12% cresol and 2% surfactant, is described. /The patient/ was treated successfuly with immediate erythrocytapheresis and forced diuresis. [R56] NTOX: *CONCN SOLN OF ... CRESOL HAVE VIOLENT CORROSIVE EFFECT AND PROSTRATION FROM SHOCK MAY FOLLOW INGESTION OF LARGE AMT. [R57] *PURE CRESOLS ... HAVE CAUSED PERMANENT OPACIFICATION AND VASCULARIZATION WHEN APPLIED FULL STRENGTH TO RABBIT EYES. ... A DROP OF 33% SOLN APPLIED TO RABBIT EYES AND REMOVED BY IRRIGATION WITHIN 60 SECONDS CAUSED ONLY MODERATE INJURY, FROM WHICH THE CORNEAS RECOVERED. [R7] *In rats, dermal exposure with 1.0-1.7 ml/kg for 1-2 hr caused skin discoloration, death. [R58] *... Three groups of six rats each (sex and age unspecified) were exposed to tricresol vapor at concentrations of 2.4, 0.1, and 0.01 mg/cu m for 24 hr. Three other groups of six rats served as controls. No description was given of the exposure method or of the system used to generate the vapor. After the rats had been exposed for 24 hr, the amount of neutral red dye absorbed by the lung tissue was measured. ... The ... dye absorption /was considered/ as an indication of protein denaturation, which ... was one of the toxic actions of tricresol. An increase in the absorption of dye or decrease in the excretion of dye would indicate a denaturation of protein. The absorption of the dye, expressed in extinction units, was measured spectrophotometrically. In rats exposed to tricresol at a concentration of 2.4 mg/cu m, absorption was significantly higher than it was in the controls (p < 0.001). This was also the case at 0.1 mg/cu m (p < 0.05), but, at 0.01 mg/cu m, the effect was not significant (p > 0.05). Dye absorption at the 0.01 mg/cu m level was greater than that seen at 0.1 mg/cu m, indicating that there was no direct dose-response relationship. The value for the control animals used in the group ... exposed at 2.4 mg/cu m was markedly different from control values for the 0.1 and 0.01 mg/cu m groups. [R59] *A group of NR rats were exposed to 0.05 mg/cu m or 0.0052 mg/cu m tricresol (proportions of isomers not specified) by inhalation for 3 months. The high-dose group exhibited less weight gain, increased CNS excitability, increased oxygen consumption, histologic changes in lung and liver and ... decreased gamma-globulin content of the serum. ... No significant changes were observed in the low-dose group, which /indicated that/ this concentration (0.0052 mg/cu m) as the mean daily maximum permissible concentration for the cresol mixture in atmospheric air. [R60] *In a reverse mutation assay, a mixture of 3 cresol isomers at 0.005-50 ul/plate with or without S9 from Aroclor induced rats (activating system) was negative in Salmonella typhimurium strains TA1535, TA1538, TA1537, TA98, and TA100 at all doses. /From Table/ [R61] *... Sublethal concentrations of cresols were capable of producing abnormal metaphases and anaphases in onion root tip cells, Allium cepa, undergoing mitosis. [R62] *In a forward mutation assay, a mixture of 3 cresol isomers at 0.488-750 nl/ml, with or without S9 from Aroclor induced rats (activating system) produced dose related increases in mutation frequency with activation in mouse lymphoma cell culture; without activation, equivocal results suggestive of weak mutagenic activity were seen. /From Table/ [R63] *In an unscheduled DNA synthesis assay, a mixture of 3 cresol isomers at 0.5-100 nl/ml was weakly active in rat hepatocytes in cell culture. /From Table/ [R64] *In a sister chromatid exchange (SCE) assay, a mixture of 3 cresol isomers at 15.6-200 nl/ml and 0.5-100 nl/ml, with or without S9 (activating system), induced SCE in Chinese hamster ovary cells in cell culture. Addition of the activating system reduced the number of observed SCE. /From Table/ [R63] *TUMOR PROMOTER IDENTIFIED IN PARTICULATE PHASE OF TOBACCO SMOKE: 7,200 UG/100 CIGARETTES (QUANTITATIVE VALUE). /FROM TABLE/ [R65] NTXV: *LD50 Rabbit single skin penetration 2,000 (700-5,900) mg/kg with skin corrosion; [R66] ETXV: *TLm Bluegill 24 mg/l/96 hr (fresh water) /Conditions of bioassay not specified/; [R20] *TLm Shrimp 10-100 ppm/48 hr (salt water) /Conditions of bioassay not specified/; [R20] *LC50 Gammarus fasciatus 7.0 mg/l/48 hr (Immature stage); [R67] *LC50 Asellus militaris 21.6 mg/l/48 hr (Immature stage); [R67] *LC50 Ophryotrocha diadema 33-100 mg/l/48 hr; [R68] *LC50 Gammarus fasciatus 24.9 mg cresol/l/48 hr (adult male); 34.3 mg cresol/l/48 hr (adult females); 33.9 mg cresol/l/48 hr (oviparous females); [R67] *LC50 Asellus militaris 65.4 mg cresol/l/48 hr (adult male); 68.0 mg cresol/l/48 hr (adult females); 61.9 mg cresol/l/48 hr (oviparous females); [R67] NTP: +A mixture of Meta-/Para-cresol (MPCRE; 58.7%/41.3%, respectively) was evaluated for reproductive toxicity in CD-1 (Swiss) mice using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. Exposure to MPCRE, at levels ranging from a mean of 362 mg/kg/day in the low-dose group (0.25% in feed) to a mean of 1682 mg/kg/day in the high-dose group (1.5% in feed), for 14 wks of cohabitation, did not significantly affect most measures of reproductive competence, including initial fertility, the proportion of pups born alive, or the sex of pups born alive. However, adjusted the pup weight and the number of live pups/litter (both sexes) were decreased by 5 and 20%, respectively, and cumulative days to the fifth litter were increased by almost 3 days in the high-dose group compared to controls. F0 body weight and feed consumption, after 16 wks of MPCRE exposure, were decreased at the 1.0 and 1.5% dose levels, especially in delivering and lactating dams. MPCRE at the 1.5% level decreased body weight and increased kidney and liver weights of F0 animals. Toxicity to reproductive organs at the 1.5% dose level was observed in the form of decreased epididymal and seminal vesicle weights by 10 and 21%, respectively, with no change in testis weight, sperm parameters, or testicular and epididymal histopathology. Crossover mating did not clearly reveal the affected sex as the only parameter affected (adjusted live pup weight) was decreased if either sex was dosed at the 1.5% level. Although birth weights of F1 animals were minimally decreased (5.0%) in the high-dose group, MPCRE decreased preweaning growth by 26% and postweaning survival by 39% in the F1 generation. Calculated MPCRE exposure in high-dose F1 animals averaged 2490 mg/kg/day for males and 2939 mg/kg/day for females. Treatment-related clinical signs were reduced size, dehydration, lethargy, and rough coat in the high-dose group. MPCRE at 1.5% in feed had no effect on the reproductive competence of the F1 generation. At both the 1.0 and 1.5% dose level, male body and reproductive organ weights (prostate, seminal vesicles, testes) were decreased and relative liver and kidney weights were increased, but there were no effects on sperm parameters or histopathology. Female terminal body weights were reduced at the two highest dose levels, as was ovarian weight in all three dosed groups, while kidney and liver weights were increased in all dosed groups. There was no effect of treatment on estrous cyclicity or ovarian, liver, or kidney histopathology. An MTD for systemic and reproductive toxicity of MPCRE for F0 animals was established at the 1.5% dose level, based on decreased body weight at necropsy, increased relative liver weight, and decreased absolute and relative seminal vesicle weight. An MTD of 1.0% MPCRE for systemic and reproductive toxicity was established for F1 animals, based on decreased body weight, increased relative liver weight, and decreased relative prostate and seminal vesicle weight. In summary, minimal reproductive toxicity was apparent, but only in the presence of significant systemic toxicity. [R69] POPL: +... the potential for adverse health effects exists in the case of people with renal insufficiency or specific enzyme deficiency and under conditions of high exposure. [R70] ADE: *CRESOL IS ABSORBED THROUGH SKIN, OPEN WOUNDS, AND MUCOUS MEMBRANES OF GASTROENTERIC AND RESP TRACTS. RATE OF ABSORPTION THROUGH SKIN DEPENDS MORE UPON SIZE OF AREA EXPOSED THAN ON CONCENTRATION OF MATERIAL APPLIED. MAJOR ROUTE OF EXCRETION ... IS URINE, BUT CONSIDERABLE AMOUNTS MAY BE EXCRETED IN BILE AND TRACES IN EXHALED AIR. [R4, 2599] *All 6 hydrocarbons tested were excreted from the gills of Dolly Varden (Salvelinus malma), although less of the largest and least polar cmpd was excreted. Approx equal amounts of the administered (14)C-labeled cresol (28.9%) was excreted from the gills. A large amt of administered (14)C-labeled cresol (38%) was recovered from the cloacal chamber. [R71] *THE PHENOLS /INCLUDING CRESOLS/ ... ARE PARTLY DETOXICATED BY LIVER, EXCRETED BY KIDNEY AS ETHEREAL SULFATES AND GLYCURONATES AND AS UNCHANGED CMPD. A TRACE IS EXCRETED BY LUNG. [R54, 166] METB: *IN THE BODY, SOME OF IT IS OXIDIZED TO HYDROQUINONE AND PYROCATECHIN, AND REMAINDER AND LARGEST PROPORTION IS EXCRETED UNCHANGED OR CONJUGATED WITH GLYCURONIC AND SULFURIC ACIDS. [R9] *... CRESOLS ARE EXCRETED BY RABBIT PRIMARILY AS OXYGEN CONJUGATES; 60-72% AS ETHER GLUCURONIDES, 10-15% AS ETHEREAL SULFATES ... [R4, 2599] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +MEDICATION (VET): LOCAL ANTISEPTIC, PARASITICIDE, DISINFECTANT; HAS BEEN USED AS INTESTINAL ANTISEPTIC [R1] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Cresols are released to the atmosphere in auto and diesel exhaust, during coal tar and petroleum refining, wood pulping, and during its use in manufacturing, metal refining, etc. Wastewater from these industries as well as municipal wastewater treatment plants contain cresols. When released to the atmosphere, cresols will degrade by reacting with photochemically produced hydroxyl radicals during the day (half-life 8-10 hr). However, at nighttime reaction with nitrate radicals predominate (half-life 2-5 min). In addition, cresols are soluble compounds and will be scavenged by rain. When released into natural waters, degradation generally occurs within 8 hours after an acclimation period of up to several days. However, in oligotrophic lakes, estuarine, and marine waters the degradation process would be expected to take longer. Volatilization, adsorption, and bioconcentration are not important. Cresols are mobile in soil but biodegradation is probable although data are scant. Human exposure will be primarily by inhalation in the workplace or in source areas. (SRC) NATS: *Coal, petroleum, constituent in wood, constituent in natural runoff. [R72] ARTS: *Cresol is released into the environment in emissions and effluents from its production and use as a disinfectant, chemical intermediate, textile scouring agent, surfactant, and ore flotation agent(1); It may be released during coal tar and petroleum refining as well as organic chemicals, plastics, and resins manufacture(2). It is found in auto/diesel exhaust, emissions from wood pulping, tobacco smoke, and sewage(2-4). [R73] FATE: *Atmospheric Fate: Cresols are not expected to persist in the atmosphere because: 1) cresols have low estimated half-lives (less than 1 day); 2) they are sensitive to photolysis; and 3) the water solubility of cresols may ... cause transport of cresols from the atmosphere to the soil or aqueous environment. [R74, (7/11/83] *Terrestrial Fate: ... While there is substantial release of cresols to the soil, this route of environmental exposure is not expected to be a problem. Cresols are readily biodegraded by soil microflora and are mobile in soils. Therefore, cresols will not persist in soils and will probably be leached, due to their water solubility, into the aquatic environment where they will be degraded by microorganisms. [R74, (7/11/83)] *Terrestrial Fate: The degradation rates of cresols in soil may decrease at lower temperatures (-2 to 5 deg C). [R75] *Aquatic Fate: Cresols do not contain any functional groups that are hydrolyzable. Therefore, hydrolysis of these compounds in aquatic media is unlikely. [R76] *TERRESTRIAL FATE: Cresols exhibit low soil adsorption and would therefore be mobil in soil. They biodegrade fairly rapidly in water and there is evidence that they biodegrade in soil. One estimate of the biodegradation half-life in subsoil from concentration decreases at sampling points under a solid waste tip (dump) is 3.7 days. However, this type of estimation is subject to error. (SRC) *AQUATIC FATE: Cresol will degrade primarily due to biodegradation in eutrophic waters although photolysis may make a contribution in oligotrophic lakes based on modeling studies. Biodegradation generally occurs within 8 hours after several days of acclimation, except in oligotrophic lakes, estuarine, and marine waters where degradation takes several days. Degradation is much slower under anaerobic conditions especially for the ortho isomer. (SRC) *ATMOSPHERIC FATE: The photodegradation half-life of cresol isomers during the daytime is 8-10 hr while at night it is only 2-4 min. The dominant reactions are with hydroxyl radicals during the day and with nitrate radicals at night. Daytime half-lives would be reduced under smog conditions. Cresols are highly soluble compounds and gas scavenging will be an efficient removal process as is reflected by high concentrations in rain(1,SRC). [R77] BIOD: *... A certain period of adaptation is required by the microorganisms before degradation can proceed. It has been shown that pure cultures including strains of Pseudomonas putida, Trichosporon cutaneum, Pseudomonas alcaligens, Pseudomonas aeruginosa, Alcaligenes eutrophus, and Bacillus stearothermophilis, can biodegrade cresols. Similarly, cresols were found to biodegrade in aquatic media with mixed microorganisms (such as activated sludge or mixed soil microorganisms). [R78] *... Biodegradation is likely to be the fate determining process for cresols in most aquatic systems. In ponds, rivers, and eutrophic lakes the half-life of biodegradation of cresols may vary from 5-12 hours. In oligotrophic lake water, the biotransformation rate for cresols may be too slow and photolysis may determine its fate in such bodies of water. [R79] *Cresol isomers are reported to biodegrade rapidly in screening tests(1-5). Biodegradation in natural waters has been studied extensively for p-cresol and biodegradation generally occurred within 8 hours after several days of acclimation except for oligotrophic lakes and marine waters where degradation took several days(6,7). m-Cresol has a reported half-life of 1-6 days in estuarine water throughout the year(8). The degradation is faster in fresh water and slower in marine water(8). One older study has compared the time for complete removal of all three cresol isomers in river water at 20 and 4 deg C (9). The removal time for the o- and m- isomers was 2 and 7 days at 20 and 4 deg C, respectively, while for the p- isomer it was 6 and 19 days(9). When incubated under anaerobic conditions using a digester sludge inocula mineralization occurred in < 8 weeks for the m- and p- isomers but no mineralization occurred in the o- isomer in that time period(10). None of the three isomers were mineralized in 29 weeks when incubated with anaerobic lake sediment(10). The half-life of cresol in subsurface soil was estimated to be 3.7 days from measurements of concentrations at sampling points below a solid waste tip in the Netherlands (11). Cresol isomers are reported to biodegrade in soil but no rates were reported(12). [R80] *Two factors that may influence the biodegradation rate of cresols in natural aquatic media are the temperature and the quality of the water. In general, freshwater media have the maximum biotransformation rate for cresols, followed by somewhat lower rates for estuarine waters. Rates for marine waters are much lower than for other kinds of water. ... A decrease in temperature from 24 to 11 deg C increased the biotransformation half-life by a factor of > 20; however, the rate of biodegradation of cresols in marine water was so low that the lowering of water temperature would not change the biodegradation rate appreciably. [R81] ABIO: *During the daytime cresols react in the atmosphere principally with photochemically generated hydroxyl radicals with a half-life of 8-10 hr(1,2). However, at night, especially in moderately polluted atmospheres where concentrations of ozone and nitrate are high, the reaction with nitrate radicals is a major sink (half-life 2-5 min) with the formation of nitrocresols(3). During the daytime, photochemical smog conditions will accelerate photooxidation with half-lives of 1-5 hr being reported(4,5). Nitrocresols are also formed under these conditions(6). Cresols absorb light longer than 290 nm. The photolysis half-life of p-cresol in pure water by sunlight is 35 days and only 3 days when humic acids are present(7). These half-lives will presumably be similar for the other isomers. In the presence of the photosensitizing dye, methylene blue, cresol has a half-life of 19 and 53 minutes under aerobic and anaerobic conditions, respectively(8). Since cresols do not have any hydrolyzable groups, hydrolysis in aqueous media will not be significant(SRC). [R82] BIOC: *The log octanol-water partition coefficients of the cresol isomers range from 1.94-1.96(1) from which one estimates a bioconcentration factor of 18(2,SRC). Therefore cresol would not be expected to bioconcentrate significantly in fish (SRC). [R83] KOC: *The values for Koc in Brookstone clay loam soil are 22, 35, and 49 for the o-, m-, and p- isomers, respectively, whereas the corresponding values calculated from the water solubilities range from 18-19 g/100g(1). The soil/water distribution constant for 5 fine textured B horizon clay soils range from 2.8-500 and 5-50 for o- and p-cresol, respectively(2). Adsorption capacity tended to be higher when iron oxide levels and pH were high(2). The low adsorptivity of the m- isomer to subsurface soils is evidenced by its elution in one pore volume in a soil column transport experiment using a 20 cm column filled with aquifer sediment collected at a 30 m depth(3). [R84] VWS: *Cresols have low volatilities from water with calculated Henry's Law constant ranging from 8.7X10-7 to 1.6X10-6 atm cu m/mole (1,SRC). As such they will partition into the aqueous phase and evaporation from water will not be an important loss process(2). [R85] WATC: *DRINKING WATER: The o- isomer has been detected but not quantified in drinking water in the USA(1,2). [R86] *SURFACE WATER: Detected in the Kanawha River, WV at Winfield and Huntington(1). Industrial location on unspecified river in USA, Nov. 1975-Sept. 1976, 1-10 ppb detected in water but not detected in sediment(2). Delaware R, upstream from Philadelphia - not detected in Aug 1976(3) or Aug 1977(4) but 2 ppb detected in 1 out of 5 samples in March 1977(3). [R87] *GROUNDWATER: Highest concn detected in contaminated groundwater in the Netherlands 10 ppb(1). Leachates from Maxey Flats and West Valley radioactive waste disposal sites 2.0-4.2 ppm(2). Two landfill leachate plumes in Ontario 63 and 610 ppb whereas cresols were not detected in background wells(3). Groundwater in a sand aquifer at a wood preserving facility in Pensacola, FL (5 sites, 5 depths 0-13.7 ppm) maximum range measured for an individual isomer(4). Hoe valley underground coal gasification site, WY - 2 aquifers (15 mo after gasification complete) 63-6600 and 10-16000 ppb for the o- and p- isomers, respectively(5). [R88] *RAIN/SNOW: Portland, OR - seven rain events (o-isomer) range 240-2800 parts/trillion; (m,p-isomer) range 380-2000 parts/trillion; dissolved in rain/water(1). [R89] EFFL: *Sewage treatment plant effluent treating industrial wastes on Delaware River at Philadelphia 20 ppb(1). Wastewater from an unspecified chemical plant 70-150 ppb (2). Identified in finished water from advanced waste treatment plants(3). [R90] ATMC: *SOURCE AREAS: Oil shale wastewater facility 1.3 ppb(2). The o- isomer was found in 6 source areas of USA (54 samples) 1.6 ppb median(1). RURAL: not detected(1,2). URBAN: not detected(1,2). Portland, OR - during seven rain events 19-51 parts per trillion, 28.6 parts per trillion, mean (m- and p- ismomer) and 10-29 parts per trillion, 15.6 parts per trillion mean (o- isomer) in gas phase(3). Particulate matter associated cresol was generally < 1% gas-phase cresol(3). [R91] RTEX: *Estimates indicate that between 600,000 and 1.2 million people are exposed to cresols each year via manufacturing, processing, and/or use activities. [R92] *Maintenance and repair workers, especially those working on ventilation systems or in enclosed environments, have a high risk of exposure because of the nature of their work. To minimize or prevent exposure, they must be familiar with the hazards of the materials that may be encountered and with proper work practices, as well as have adequate supervisory control. [R93] *A partial list of occupations in which exposure may occur includes: Antioxidant makers, chemical disinfectant workers, dye makers, flotation agent makers, foundry workers, insulation enamel workers, paint remover workers, pitch workers, plastic makers, resin makers, stain workers and wool scourers. [R51, 151] AVDI: *AIR INTAKE: (assume typical concn 44.2 parts per trillion) 4.0 ug; WATER INTAKE: insufficient data; FOOD INTAKE: insufficient data. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +250 ppm /ortho, meta, and para-Cresol/ [R29] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (22 mg/cu m). Skin Designation. [R94] NREC: +Recommended Exposure Limit: 2.3 ppm (10 mg/cu m) 10 hr TWA /ortho, meta, and para-Cresol/ [R29] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm, skin. /Cresol, all isomers/ [R95, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Cresol, all isomers/ [R95, 2002.6] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Cresol is produced, as an intermediate or final product, by process units covered under this subpart. [R96] WSTD: STATE DRINKING WATER GUIDELINES: +(MN) MINNESOTA 30 ug/l [R97] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R98] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA. [R99] RCRA: *As stipulated in 40 CFR 261.33, when cresol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (see 40 CFR 261.5). [R100] *When cresol is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F004), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. [R101] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A known volume of air is drawn through a silica gel tube consisting of 2, 20/40 mesh silica gel sections, 150 and 75 mg, separated by a 2 mm portion of urethane foam. The collected sample is desorbed with acetone and analyzed by gas chromatography. (This method for sampling and analysis is adapted from NIOSH Method No S167) [R102] ALAB: *COLORIMETRIC DETERMINATION OF PREPARATIONS CONTAINING PHENOL, APPLICABLE TO CRESOLS. [R103] *CRESOL WAS DETERMINED IN A 50% SOAP SOLUTION BY DETERMINING ITS UV ABSORPTION AT 239 NM. THE UV METHOD GAVE RELIABLE RESULTS IN LESS TIME THAN THE CONVENTIONAL INDIAN PHARMACOPEIA (IP) METHOD. [R104] *Infrared spectrophotometry was shown to be effective in identifying cresol from other structurally related substances. Identification and quantitative analyses of the cresol isomers, phenol, and xylenols were possible when either cyclohexane or carbon disulfide was used as the solvent. In the direct-reading infrared analyzers, cresol reportedly absorbs at the 8.6 um wavelength, with a sensitivity of 0.3 ppm. [R22] *Ultraviolet spectrophotometry has been used to determine cresol in air samples. Cresol was measured by detecting particular absorption bands, but interference from other air contaminants with absorption bands in the same range reduced the sensitivity and precision of the ultraviolet spectrophotometric method ... Paper and thin-layer chromatography have been suggested as methods for the separation and analysis of cresol and structurally similar compounds. [R105] *Acetone desorbed samples are analyzed using gas chromatography equipped with a flame ionization detector. The column is packed with 10% free fatty acid polymer in 80/100 mesh, acid washed DMCS Chromosorb W. The useful range of this method is 5-60 mg/cu m. (This method for sampling and analysis is adapted from NIOSH Method No S167). [R102] *Analyte: cresol isomers; Matrix: air; Range: 0.1-1.2 mg/sample; Procedure: absorption on silica gel, desorption with acetone, gas chromatography. [R106] CLAB: *The concentrations of phenol and cresol in alkaline solutions were determined quantitatively using a colorimetric procedure. When reacted with Folin-Denis reagent, the compounds yielded distinct colors whose intensities could be measured. The concentration of the cresol isomers was determined as total cresol. This method has been applied to analysis of cresol and phenol in biologic fluids, such as blood and urine. /Cresols/ [R107] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: GORDON P; AIR POLLUTION ASSESSMENT OF CRESOLS; 1-76 PP (1976) PB-256737. THE TOXIC EFFECTS AND REMOVAL OF CRESOL FROM WASTE GASES ARE DISCUSSED. NIOSH; Criteria Document: Cresol (1978) DHEW Pub. NIOSH 78-133 USEPA/ECAO; Health and Environmental Effects Profile: Cresols (1985) ECAO-CIN-P138 Santodonato J; Monograph on Human Exposure to Chemicals in the Workplace: Cresols Govt Rpts Announcements and Index 7: (1986). This report presents a summary and evaluation of information relevant to an occupational hazard assessment of cresols. USEPA; Chemical Profiles: Cresylic Acid 4pp (1985). Aspects covered in this data sheet /include the following/: Chemical identity, exposure limits, physiochemical properties, fire and explosion hazards, reactivity, health hazards, uses, and handling of spills or releases. DHHS/NTP; NTP Report on the Toxicity Studies of Cresols in F344/N Rats and B6C3F1 Mice (Feed Studies) NTP TOX 9 (1991) DHHS/ATSDR; Toxicological Profile for Cresols: o-Cresol, p-Cresol, m-Cresol (1992) ATSDR/TP-91/11 SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 369 R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 320 R3: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. 971 R4: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R5: SRI. DIRECTORY OF CHEMICAL PRODUCERS-USA 1987, p.550 R6: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Cresol (1319-77-3). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of October 24, 2002. R7: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 283 R8: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.148 R9: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 569 R10: CHEMICAL PRODUCTS SYNOPSIS: Cresols and Cresylic Acids, 1980 R11: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.25 R12: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.29 R13: SRI R14: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-328 R15: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-493 R16: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1109 R17: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 49-32 R18: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 559 R19: Kortum G et al; Pure and Applied Chemistry, Vol. 1, No 2-3 (1961) R20: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R21: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 32 R22: NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 R23: Popendorf W; J Am Ind Hyg Assoc 45:719-26 (1984) R24: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 67th ed. Boca Raton, FL: CRC Press, Inc., 1986-87.,p. F-39 R25: Leuenberger C et al; Water Res 19: 885-94 (1985); Lyman WJ et al; Handbook of Chem Property Estimation Methods Environ Behavior of Org Chem McGraw-Hill pp 15.1-15.33 (1982) R26: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R27: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R28: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R29: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 78 R30: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R31: NIOSH; Criteria Document: Cresol p.8 (1978) DHEW Pub. NIOSH 78-133 R32: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 123 R33: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.203 R34: 49 CFR 171.2 (7/1/96) R35: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 130 R36: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6108 (1988) R37: NIOSH; Criteria Document: Cresol p.6 (1978) DHEW Pub. NIOSH 78-133 R38: Ozcan E, Benlioglu G; Chim Acta Turc 9 (1): 291-6 (1981) R39: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-2, 3-12 (1981) EPA 68-03-3025 R40: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-174 (1982) R41: 40 CFR 165 (7/1/88) R42: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 146 R43: Environmental Health Criteria 168: Cresols pp. 17-21 (1995) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. R44: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 2-Methylphenol (95-48-7), 3-Methylphenol,(108-39-4), 4-Methylphenol (106-44-5) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R45: NIOSH; Criteria Document: Cresol p.4-5 (1978) DHEW Pub. NIOSH 78-133 R46: NIOSH; Criteria Document: Cresol p.5 (1978) DHEW Pub. NIOSH 78-133 R47: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R48: LARCAN A ET AL; EUR J TOXICOL ENVIRON HYG 7 (1): 5-8 (1974) R49: Klimkiewicz et al; Wiad Lek 27: 1211-14 (1974) as cited in NIOSH; Criteria Document: Cresol p.32-33 (1978) DHEW Pub. NIOSH 78-133 R50: Green MA; Med Sci Law 15: 65-6 (1975) as cited in NIOSH; Criteria Document: Cresol p.28 (1978) DHEW Pub. NIOSH 78-133 R51: Sittig, M. Handbook of Toxic And Hazardous Chemicals. Park Ridge, NJ: Noyes Data Corporation, 1981. R52: Winek, C.L. Drug and Chemical Blood-Level Data 1985. Pittsburgh, PA: Allied Fischer Scientific, 1985. R53: USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.38 (1985) ECAO-CIN-P138 R54: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. R55: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 967 R56: Cote MA et al; Can Med Assoc J 130 (10): 1319-22 (1984) R57: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 104 R58: Campbell J; Soap Sanit Chem 17: 103-11, 121 (1941) as cited in NIOSH; Criteria Document: Cresol p.59 (1978) DHEW Pub. NIOSH 78-133 R59: Kurlyandski BA et al; Gig Sanit 5: 85-87 (1975) as cited in NIOSH; Criteria Document: Cresol p.45-46 (1978) DHEW Pub. 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Washington, DC: American Chemical Society, 1976. 356 R66: Vernot EH et al; Toxicol and Appl Pharm 42: 417-23 (1977) R67: Emery RM; Water Res 4 (7): 485-91 (1970) as cited in USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.35 (1985) ECAO-CIN-P138 R68: Parker JG; Water Res 18 (7): 865-68 (1984) as cited in USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.35 (1985) ECAO-CIN-P138 R69: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Meta-/Para-Cresol (MPCRE) (CAS No. 1319-77-3) in CD-1 Swiss Mice, NTP Study No. RACB90003 (May 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R70: Environmental Health Criteria 168: Cresols pp. 20 (1995) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. R71: Thomas RE, Rice SD; Physiol Mech Mar Pollut Toxic, (Proc Symp Pollut Mar Org) p.161-76 (1982) R72: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 403 R73: (1) Hawley GG; Condensed Chem Dictionary 10th ed Von Nostrand Reinhold NY p 285 (1981) (2) Verschueren K; Handbook of Environ Data on Org Chem 2nd ed Von Nostrand Reinhold NY pp 403-10 (1983) (3) Graedel TE; Chem Compound in the Atmosphere Academic Press NY pp 256-7 (1978) (4) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) R74: 48 FR 31814 R75: Medvedev VA, Darydov VD; Pochvovedenie (11): 22-28 (1972) as cited in USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.13 (1985) ECAO-CIN-P138 R76: USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.7 (1985) ECAO-CIN-P138 R77: (1) Leuenberger C et al; Environ Sci Tech 19: 1053-8 (1985) R78: USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.8 (1985) ECAO-CIN-P138 R79: Smith JH et al; Environmental Pathways of Selected Chemicals in Freshwater Systems, Part II (1978) EPA 600/7-78-074 as cited in USEPA/ECAO; Health and Environmental Effect Profile: Cresols p.11 (1985) ECAO-CIN-P138 R80: (1) Sasaki S; pp 283-98 in Aquatic Pollut Transf Biol Effects Hutzinger O et al; eds Oxford Pergamon (1978) (2) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (3) Baird RB et al; Arch Environ Contam Toxicol 2: 165-78 (1974) (4) Pitter P; Water Res 10: 231-5 (1976) (5) Singer PC et al; Treatability and Assess of Coal Conversion Wastewaters Phase 1 p 178 USEPA-600/7-79-248 (1979) (6) Smith JH et al; Environ Pathways of Selected Chem in Fresh Water Systems Part II Laboratory Studies USEPA-600/7-78-074 (1978) (7) Rogers JE et al; Microbiol Transformation of Xenobiotics in Aquatic Environ p 105 USEPA-600/3-84-043 (1984) (8) Pfaender FK, Bartholomew GW; Appl Environ Microbiol 44: 159-64 (1982) (9) Ludzack F, Ettinger MB; J Water Pollut Control Fed 32: 1173-1200 (1960) (10) Horowitz A et al; Dev Ind Microbiol 23: 435-44 (1982) (11) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) (12) Medvedev VA, Davydov VD; Pochvovedenie p 22-8 (1972) R81: USEPA/ECAO; Health and Environmental Effects Profile: Cresols p.9-10 (1985) ECAO-CIN-P138 R82: (1) Atkinson R; Chem Rev 85: 69-201 (1985) (2) Atkinson R et al; Adv Photochem 11: 375-488 (1979) (3) Atkinson R et al; Int J Chem Kinetics 16: 887-98 (1984) (4) Atkinson R et al; Int J Chem Kinetics 12: 779-836 (1980) (5) Grosjean D; Environ Sci Tech 19: 968-74 (1985) (6) Nojima K, Kanno S; Chemosphere 6: 371-6 (1977) (7) Smith JH et al; Environ Pathways of Selected Chem in Freshwater Systems Part II Lab Studies USEPA-600/7-78-074 (1978) (8) Sargent JW, Sanks Rl; J Water Pollut Control Fed 46: 2547-54 (1974) R83: (1) Hansch C, Leo AJ; Medchem Project Issue No. 19, Claremont, CA Pomona College (1981) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Environ Behavior of Org Compounds McGraw-Hill pp 5.1-5.27 (1982) R84: (1) Boyd SA; Soil Sci 134: 337-43 (1982) (2) Artiola-Fortuny J, Fuller WH; Soil Sci 133: 18-26 (1982) (3) Goerlitz DF et al; Environ Sci Technol 19: 955-61 (1985) R85: (1) Leuenberger C et al; Water Res 19: 885-94 (1985) (2) Lyman WJ et al; Handbook of Chem Property Estimation Methods Environ Behavior of Org Chem McGraw-Hill pp 15.1-15.33 (1982) R86: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol.II p 397 USEPA-600/1-84-020B (1984) (2) Kopfler FC et al; Adv Environ Sci Technol 8(Fate Pollut Air Water Environ): 419-33 (1977) R87: (1) Kawahara FK; Environ Sci Technol 5: 235-9 (1971) (2) Jungclaus GA et al; Environ Sci Technol 12: 88-96 (1978) (3) Sheldon LS, Hites RA; Environ Sci Technol 12: 1188-94 (1978) (4) Sheldon LS, Hites RA; Environ Sci Technol 13: 574-9 (1979) R88: (1) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) (2) Francis AJ et al; Nuclear Tech 50: 158-63 (1980A) (3) Reinhard M et al; Environ Sci Technol 18: 953-61 (1984) (4) Goerlitz DF et al; Environ Sci Technol 19: 955-61 (1985) (5) Stuermer DH et al; Environ Sci Technol 16: 582-7 (1982) R89: (1) Leuenberger C et al; Environ Sci Technol 19: 1053-8 (1985A) R90: (1) Hites RA; p 107-19 in Proc Natl Conf Munic Sludge Manag 8th (1979) (2) Jungclaus GA et al; Environ Sci Technol 12: 88-96 (1978) (3) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol 2 Computer-Printed Tabulations of Compound Identification Results for Large Volume Concentrates p 397 USEPA-600/1-84-020B (1984) R91: (1) Brodzinsky R, Singh HB; Volatile Org Chem in the Atmos An Assess of Available Data p 198 SRI 68-02-3452 (1982) (2) Hawthorne SB, Sievers RE; Environ Sci Technol 18: 483-90 (1984) (3) Leuenberger C et al; Environ Sci Technol 19: 1053-8 (1985) R92: 48 FR 31813 (7/11/83) R93: NIOSH; Criteria Document: Cresol p.71 (1978) DHEW Pub. NIOSH 78-133 R94: 29 CFR 1910.1000 (7/1/98) R95: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R96: 40 CFR 60.489 (7/1/87) R97: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R98: 40 CFR 116.4 (7/1/88) R99: 40 CFR 712.30 (7/1/88) R100: 40 CFR 261.33 (7/1/88) R101: 40 CFR 261.31 (7/1/88) R102: NIOSH; Criteria Document: Cresol p.92-103 (1978) DHEW Pub. NIOSH 78-133 R103: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/71 5.014 R104: TALWAR AB ET AL; INDIAN J PHARM SCI 40 (4): 135-6 (1978) R105: NIOSH; Criteria Document: Cresol p.63 (1978) DHEW Pub. NIOSH 78-133 R106: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V1 2001-1 R107: Chapin RM; J Biol Chem 47: 309-14 (1921) as cited in NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 RS: 82 Record 51 of 1119 in HSDB (through 2003/06) AN: 254 UD: 200210 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CUMENE-HYDROPEROXIDE- SY: *CHP-; *CUMEENHYDROPEROXYDE- (DUTCH); *ALPHA-CUMENE-HYDROPEROXIDE-; *CUMENT-HYDROPEROXIDE-; *CUMENYL-HYDROPEROXIDE-; *CUMOLHYDROPEROXID- (GERMAN); *CUMYL-HYDROPEROXIDE-; *ALPHA-CUMYL-HYDROPEROXIDE-; *7-CUMYL-HYDROPEROXIDE-; *ALPHA,ALPHA-DIMETHYLBENZYL-HYDROPEROXIDE-; *Hydroperoxide-de-cumene-; *HYDROPEROXIDE,-ALPHA,ALPHA-DIMETHYLBENZYL-; *HYDROPEROXIDE,-1-METHYL-1-PHENYLETHYL-; *HYDROPEROXYDE-DE-CUMYLE- (FRENCH); *IDROPEROSSIDO-DI-CUMENE- (ITALIAN); *IDROPEROSSIDO-DI-CUMOLO- (ITALIAN); *ISOPROPYLBENZENE-HYDROPEROXIDE- RN: 80-15-9 MF: *C9-H12-O2 SHPN: UN 3107; Organic peroxide type E, liquid UN 3108; Organic peroxide type E, solid UN 3109; Organic peroxide type F, liquid UN 3110; Organic peroxide type F, solid UN 3117; Organic peroxide type E, liquid, temperature controlled UN 3118; Organic peroxide type E, solid, temperature controlled UN 3119; Organic peroxide type F, liquid, temperature controlled UN 3120; Organic peroxide type F, solid, temperature controlled IMO 5.2; Organic peroxide type E, solid or liquid; Organic peroxide type F, solid or liquid; Organic peroxide type F, liquid or solid, temperature controlled; Organic peroxide type E, liquid or solid, temperature controlled STCC: 49 195 25; Cumene hydroperoxide HAZN: U096; Cumene hydroperoxide MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OXIDATION OF CUMENE WITH AIR AT ELEVATED TEMP AND PRESSURE USING AQUEOUS SODIUM CARBONATE CATALYST [R1] *Cumene + oxygen (oxidation) [R2] IMP: *Impurities found in 80-95% cumene hydroperoxide include: cumene, dimethyl phenylcarbinol, and acetophenone. [R3, (1986)] FORM: *77-85%, the balance being cumene hydrocarbon. [R4] *Cumene hydroperoxide, 80-95%; cumene, 9.6-16.8%; dimethyl phenyl carbinol, 2.9-4.6%; and acetophenone, 0.3-0.8%. [R3, (1984)] *Hyperiz *Percumyl H *Trigonox K 80 *An aqueous solution containing 78-84% peroxide [R2] MFS: *Aristech Chemical Corp, Hq, 600 Grant St, Pittsburgh, PA 15219, (412) 433-2747; Production site: Ironton, OH 45638 [R5] *Aztec Peroxides, Inc., One Northwind Plaza, 7600 West Tidwell, Suite 500, Houston, TX 77040, (713) 895-2000; Production site: Elyria, OH 44035 [R5] *Elf Atochem North America, Inc., 2000 Market Street, 21st Floor, Philadelphia, PA 19103-3222, 215-419-7000; Production site: Geneseo, NY 14454 [R5] *Hercules Incorporated, 1313 North Market Street, Wilmington, DE 19894-0001, (302) 594-5000, Production site: Gibbstown, NJ 08027 [R5] OMIN: *It should be mentioned that hydroperoxides are so sensitive to decomposition by multivalent metal ions that traces of these metals must be kept away from these chemicals. [R6] *Two iodometric methods for the concn and analysis of water samples containing organic oxidants were applied to rivers and wastewaters in Illinois, Delaware, Pennsylvania. Oxidant concentrations detected were as high as 2.5 as little as 10-8 M. Compounds possibly responsible for the oxidizing activity included N-chloro compounds, organic peroxides, or quinones. [R7] USE: *Production of acetone and phenol; polymerization catalyst, particularly in the redox systems, used for rapid polymerization. [R8, 243] *Unsaturated polyester resin crosslinking agent; polymerization initiator [R2] *Production of acetone, phenol, and alpha-methylsytrene [R9] *CURING AGENT FOR UNSATURATED POLYESTER RESINS [R1] *INITIATOR FOR POLYMERIZATION OF STYRENE AND ACRYLIC MONOMER [R1] *CHEM INT FOR DICUMYL PEROXIDE, A CROSS-LINKING AGENT [R1] PRIE: U.S. PRODUCTION: *(1978) 2.14X10+12 G (CAPTIVE CONSUMPTION-EST) [R1] *(1982) 1.68X10+12 G (CAPTIVE CONSUMPTION-EST) [R1] *(1985) 5.14X10+8 g [R10] *(1992) 380,000 Kg [R11] *(1993) 350,000 Kg CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to pale-yellow liq [R8, 315]; *Colorless liquid [R2] BP: *53 deg C @ 0.013 kPa [R12] MW: *152.19 [R13] CORR: *Reactive with metal containing materials. CTP: *Critical temperature: 605 K; critical pressure: 3.34X10+6 Pa [R14] DEN: *1.0619 @ 20 deg C [R12] HTC: *-7,400 cal/g= -310X10+5 J/kg [R4] HTV: *6.99X10+7 J/kmol @ 298.15 K [R14] SOL: *Readily soluble in alcohol, acetone, esters, hydrocarbons, and chlorinated hydrocarbons. [R8, 315]; *Soluble in ether. [R15, 140]; *In water, 1.39X10+4 mg/l @ 25 deg C [R16] SPEC: *Index of refraction: 1.5242 @ 20 deg C [R12] SURF: *2.8X10-2 N/m @ 264 deg K [R14] VAP: *3.27X10-3 mm Hg @ 25 deg C [R14] OCPP: *BP: > 200 deg C [R9] *First order half-life of disappearance is > 500 hours at 120 deg C [R9] *Active oxygen content 10.5%; Cumene is oxidized w/atmospheric oxygen at 120 deg C. The selectivity is 95% at a conversion of 15%. [R12] *The product has a 10 hour half-life at 158 deg C [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: May explode from heat or contamination. May ignite combustibles (wood, paper, oil, clothing, etc.). May be ignited by heat, sparks or flames. May burn rapidly with flare-burning effect. Containers may explode when heated. Runoff may create fire or explosion hazard. [R17] +Health: TOXIC; inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns, or death. Contact of vapor or substance with eyes may cause blindness within minutes. Fire may produce irritating, corrosive and/or toxic gases. Toxic fumes or dust may accumulate in confined areas (basement, tanks, hopper/tank cars, etc.). Runoff from fire control or dilution water may cause pollution. [R17] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R17] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R17] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R17] +Fire: Small fires: Water spray or fog is preferred; if water not available use dry chemical, CO2, or regular foam. Large fires: Flood fire area with water from a distance. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Do not move cargo or vehicle if cargo has been exposed to heat. Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R17] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Keep substance wet using water spray. Stop leak if you can do it without risk. Small spills: Take up with inert, damp, noncombustible material using clean non-sparking tools and place into loosely covered plastic containers for later disposal. Large spills: Wet down with water and dike for later disposal. Prevent entry into waterways, sewers, basements or confined areas. DO NOT CLEAN-UP OR DISPOSE OF, EXCEPT UNDER SUPERVISION OF A SPECIALIST. [R17] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. Remove material from skin immediately. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R17] FPOT: *ALL ORGANIC PEROXIDES ARE HIGHLY FLAMMABLE, AND FIRES INVOLVING BULK QUANTITIES OF PEROXIDES SHOULD BE APPROACHED WITH EXTREME CAUTION. /ORGANIC PEROXIDES/ [R18, 63] NFPA: *Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R19, p. 325-29] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R19, p. 325-29] *Reactivity: 4. 4= This degree includes those materials that, in themselves, are readily capable of detonation, explosive decomposition, or explosive reaction at normal temperatures and pressures. This includes materials that are sensitive to localized mechanical or thermal shock. If a material having this Reactivity Hazard Rating is involved in an advanced or massive fire, the area should be immediately evacuated. [R19, p. 325-29] FLMT: *0.9-6.5% [R20] FLPT: *175 deg F (79 deg C) (Closed cup) [R19, p. 325-29] FIRP: *FIGHT FIRES FROM EXPLOSION-RESISTANT LOCATION. IN ADVANCED OR MASSIVE FIRES, AREA SHOULD BE EVACUATED. IF FIRE OCCURS IN VICINITY OF ... MATERIAL, WATER SHOULD BE USED TO KEEP CONTAINERS COOL. CLEAN-UP AND SALVAGE ... SHOULD NOT BE ATTEMPTED UNTIL ALL OF PEROXIDE HAS COOLED COMPLETELY. [R21] *In case of fire, water should be applied by the sprinkler system or by hose from a safe distance, preferably with a fog nozzle. Foam may be necessary instead if the peroxide is diluted in a low density flammable solvent. Portable extinguishers should not be used except for very small fires. Peroxides threatened by fire should be wetted from a safe distance for cooling. /Peroxides, Organic and Inorganic/ [R22, p. 104.350] TOXC: *Toxic phenol vapors may form from hot material. [R4] EXPL: *May explode on heating at about 150 deg C /From table/ [R22, p. 104.353] REAC: *A mixture of dimeric and trimeric dibromo compounds with the hydroperoxide in benzene may react vigorously or explode if the solution is heated to concentrate it. [R23] *The substance is a strong oxidant and reacts violently with combustible and reducing materials, causing fire and explosion hazard. Contact with copper or lead alloys and mineral acids may lead to violent decomposition. /From table/ [R22, p. 104.353] +Cumene hydroperoxide catalytically decomposes with addition of small quantities of sodium iodide. [R19, p. 491-181] DCMP: +At concn of 91 and 95%, cumene hydroperoxide decomposed violently at about 150 deg C. [R19, p. 491-66] *Above 125 deg C principal hazard is phenol formation. Other compounds which have been reported to be formed are 2-phenyl, 2-hydroxypropane acetophenone. [R24] *When heated to decomp ... emits acrid smoke and fumes. [R25] +Contaminants may catalyze decomposition at lower temperatures. [R19, p. 491-66] EQUP: *... STRONGLY RECOMMENDED THAT WORKMEN WEAR SAFETY GOGGLES, AN APRON, AND RUBBER BOOTS. /ORG PEROXIDES/ [R26] *Persons handling peroxides should use safety glasses with side shields, goggles or face shield for eye protection. Emergency eyewash facilities should be provided. Gloves, aprons and other protective clothing as necessary should be used to prevent skin contact. Clothing and equipment that generate static electricity should be avoided. Smoking should be prohibited. /Peroxides, Organic and Inorganic/ [R22, p. 104.350] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. SSL: *Stable if kept below 125 deg F and out of direct sunlight. [R4] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] CLUP: *... SPILLED MATERIAL SHOULD BE ABSORBED (AFTER EXTINGUISHMENT IN CASE OF FIRE) WITH NONCOMBUSTIBLE ABSORBENT, SUCH AS VERMICULITE, SWEEP UP AND PLACE IN PLASTIC CONTAINER FOR IMMEDIATE DISPOSAL. DO NOT USE SPARK-GENERATING METALS OR CELLULOSIC MATERIALS ... FOR ... HANDLING SPILLED MATERIALS. [R30] *Spills on water body: if the spill occurs on a large flowing water body, collect the chemical by booming, skimming, and dredging. [R3, (1984)] *Absorb spill with sand. [R15, 139] *Spills should be cleaned up promptly using non-sparking tools and an inert, moist diluent such as vermiculite or sand. Sweepings may be placed in open containers or polyethylene bags and the area washed with water and detergent. Spilled, contaminated, waste or questionable peroxides should be destroyed. /Peroxides, Organic and Inorganic/ [R22, p. 104.350] *Most peroxides can be hydrolyzed by adding them slowly with stirring to about ten times their weight of cold 10% sodium hydroxide solution. The reaction may require several hours. /Peroxides, Organic and Inorganic/ [R22, p. 104.350] *Dilute and drain into the sewer with abundant water. /Hydrogen peroxide/ [R31] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U096, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R32] *Cumene hydroperoxide is a good candidate for incineration by liquid injection incineration with a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. It is also a good candidate for rotary kiln incineration, with a temperature range of 820 to 1600 deg C and a residence time of seconds, and fluidized bed incineration, with a temperature range of 450 to 980 deg C and a residence time of seconds. [R33] *Organic peroxides should never be flushed down the drain. /Organic peroxides/ [R18, 65] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool .... . Do not attempt to neutralize because of exothermic reaction. Cover skin burns with dry, sterile dressings after decontamination ... . /Organic peroxides/ [R34] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Early intubation, at the first sign of upper airway obstruction, may be necessary. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Organic peroxides/ [R34] *Peroxides should be washed promptly from the skin to prevent irritation. In the case of eye contact, the eyes should be flushed immediately with large amounts of water, and medical attention should be obtained. ... Medical attention should also be obtained in case of accidental ingestion. ... /Peroxides, Organic and Inorganic/ [R22, p. 104.350] MEDS: *Initial Medical Screening: Employees should be screened for history of certain medical conditions which might place the employee at an increased risk. ... /Screen for/ eye, skin, and chronic respiratory diseases. /Hydrogen peroxide/ [R35] HTOX: *KNOWN SKIN SENSITIZER. TOXIC BY INHALATION, SKIN ABSORPTION, AND INGESTION. [R30] *Some organic peroxide vapors are irritating and may also cause headaches. Intoxication is similar to alcohol, and lung edema /may result/ if inhaled at high concentrations. /Organic peroxides/ [R36] *ORG PEROXIDES IN CONTACT WITH SKIN CAN CAUSE IRRITATION AND EVEN BURNS. /ORG PEROXIDES/ [R26] *... This peroxide is moderately toxic when ingested or inhaled. Prolonged inhalation of vapors of CHP causes headache and throat irritation. ... [R37] *This peroxide causes burning and throbbing when in contact with the skin. [R37] *Health Hazards: Inhalation - burning sensation, cough, labored breathing; Skin - redness, skin burns, pain; Eyes - redness, pain severe deep burns; Ingestion - abdominal pain, burning sensation. /From table/ [R22, p. 104.352] *The main toxic effect of most peroxides is irritation of skin, mucous membranes and eyes. Prolonged or intense skin contact or splashes in the eyes may cause severe injury. ... /Peroxides, Organic and Inorganic/ [R22, p. 104.349] NTOX: *... A DROP OF 10% SOLN IN PROPYLENE GLYCOL TO RABBIT EYES ... WAS FOUND TO CAUSE REACTION GRADED BETWEEN 46 and 79 ON SCALE OF 1 TO 100, PERSISTING AT LEAST A WK ... MAX CONCN IN SOLN IN DIMETHYL PHTHALATE OR PROPYLENE GLYCOL ... NOT ... IRRITATING TO EYES WAS 1%. WASHING ... WITH WATER WITHIN 4 SEC PREVENTED INJURY IN ALL CONCN. [R38] *CUMENE HYDROPEROXIDE AT SUBLETHAL CONCN INITIALLY PREVENTS GROWTH OF MICELIA OF WILD-TYPE NEUROSPORA CRASSA, BUT AFTER A TIME CELLS GROW AT A SUBNORMAL STEADY-STATE RATE. [R39] *RATS WERE TREATED FOR 4 WK WITH CHLORPHENTERMINE-HCL (30 MG/KG, IP, 5 DAYS/WK), CAUSING PROFOUND PHOSPHOLIPIDOSIS IN THE ALVEOLAR MACROPHAGES. THE SUSCEPTIBILITY OF THE PHOSPHOLIPIDOTIC ALVEOLAR MACROPHAGES TO LIPID PEROXIDATION WAS EXAMINED AND COMPARED TO ALVEOLAR MACROPHAGES FROM UNTREATED RATS. THE LIPID PEROXIDATION WAS INDUCED BY INCUBATION OF CELLS WITH CUMENE HYDROPEROXIDE. A DOSE-DEPENDENT INCR OF MALONYL DIALDEHYDE FORMATION WAS OBSERVED IN LIPIDOTIC AND CONTROL ALVEOLAR MACROPHAGES. TWO-3 TIMES MORE MALONYL DIALDEHYDE WAS FOUND IN LIPIDOTIC ALVEOLAR MACROPHAGES THAN IN CONTROLS AT THE HIGHER DOSE OF CUMENE HYDROPEROXIDE. [R40] *THE HYDROPEROXIDES OF METHYL LINOLEATE AND METHYL LINOLENATE WERE MUTAGENIC TO SALMONELLA TYPHIMURIUM IN THE AMES TEST. OF THE VARIOUS HYDROCARBON PEROXIDES, ONLY THE HYDROPEROXIDE TYPE R-OOH, TERT-BUTYL HYDROPEROXIDE AND CUMENE HYDROPEROXIDE SHOWED MUTAGENICITY, WHEREAS DIALKYL AND DIACYL PEROXIDES SHOWED NO ACTIVITY. [R41] *PERFUSION OF RAT HEARTS WITH CUMENE HYDROPEROXIDE LED TO RELEASE OF MALONDIALDEHYDE AND PROTEIN, BUT NOT OF FLUORESCENT MATERIAL, INTO THE CORONARY PERFUSATE. [R42] *Application of 1-2 drops of cumene hydroperoxide (73%) to rabbit skin (circular area. 2 cm diameter) produced erythema, edema, and vesiculation within 2-3 days. 1 mg applied to the eye of rabbits caused redness of palpebral conjunctiva and chemosis. [R43] *8.8X10-7 to 9.3X10-7 ppm of cumene hydroperoxide inhaled by mice for 2 hours, the animals exhibited reduced leukocyte counts. [R44] *Dermal application of cumene hydroperoxide (0.5 mg/specimen/day) to guinea pigs caused skin necrosis after 7-10 days of application. [R44] *Mutagenic activity of cumene hydroperoxide was observed in the C1B/w Drosophila melanogaster test. [R45] *... A 77-week test in which 20 rats /SRP: (female, Spraque-Dawley)/ each were administered 100 mg /SRP: (once per week)/ of cumene hydroperoxide by sc injection failed to produce any tumors. [R46] *Cumene hydroperoxide was found to be nonmutagenic in the dominant lethal assay in mice. [R47] *Cumene hydroperoxide was found to be mutagenic in Escherichia coli 15T-9-13. [R48] *Cumene hydroperoxide was mutagenic toward Neurospora. [R47] *Toxicity threshold for cumene hydroperoxide was determined to be 1.2 mg/l for Microcystis aeruginosa (blue green algae) and 7.4 mg/l for Scenedesmus quadricauda (green algae). [R49] *Rats (n=2) exposed to 50 ppm of cumene hydroperoxide for three 4-hr periods experienced incoordination, tremor, and /SRP: CNS depression/. One died. Autopsy (histological) indicated congested lung and kidneys. Rats (n=6) exposed to 31.5 ppm of cumene hydroperoxide for seven 5-hr periods exhibited salivation, respiratory difficulty, tremors, and hyperemia of ears and tail. Histological examination indicated emphysema and thickening of alveolar walls. Rats (n=6) exposed to 16 ppm of cumene hydroperoxide for twelve 4.5-hr periods experienced salivation, and nose irritation while autopsy indicated organs to be normal. [R50] *Rats given 95 mg/kg of cumene hydroperoxide by ip injection /showed/ signs of weakness, loss of equilibrium, prostration, and porphyrin deposition in the nostrils. [R44] *Isolated rat hepatocytes were treated with cumene hydroperoxide at concentrations not inducing irreversible cell damage. An enhanced lipid peroxidation, a decrease of glucose 6-phosphatase activity and cytochrome p450 content, and a /SRP: increase in aminopyrine demethylase. Cumene hydroperoxide decreased lipoprotein secretion and slightly decreased valine incorporation into protein./ [R51] */SRP: POTENTIAL TOXIC ACTION OF WATER POLLUTANTS WAS TESTED BY MEASURING THE IMMOBILIZATION OF DAPHNIA MAGNA, STRAIN IRCHA. THE MEAN EFFECTIVE CONCENTRATION (EC 50) FOR CUMENE HYDROPEROXIDE WAS LESS THAN 10 MG/L/. [R52] *THE TOXICITY THRESHOLD FOR URONEMA PARDUCZI WAS LESS THAN 1 MG/L FOR CUMENE HYDROPEROXIDE. [R53] *The response of isolated hepatocytes from vitamin-E deficient and selenium deficient rats to cumene hydroperoxide ... was investigated. Hepatocytes of male Sprague-Dawley rats fed deficient diets were incubated with 0.5 mmol of cumene hydroperoxide, ... . Cell viability, glutathione (GSH) concn, and lipid peroxidation by measurement of thiobarbituric acid (TBA) reactive substances was determined during a 4 hr incubation. Exposure to cumene hydroperoxide resulted in total loss of cell viability in hepatocytes within 4 hr of treatment. Hepatocytes of rats on the vitamin-E deficient diet lost complete viability after 2 hr. The concn of TBA reactive substances was increased 3 fold. [R54] *Cumene hydroperoxide was evaluated for mutagenicity in the Salmonella/ microsome preincubation assay using the standard protocol approved by the National Toxicology Program (NTP). Cumene hydroperoxide was tested at doses of 0.03, 0.10, 0.30, 1.0, 3.3, 10, 16, 33, 67, 100, and 167 ug/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Cumene hydroperoxide was positive in these tests and the lowest positive dose tested in any S. typhimurium strain was 33 ug/plate. Total clearing of the background bacterial lawn occurred at 167 ug/plate. [R55] *Inhalation experiments conducted in six female rats exposed to 16 ppm 12 times, each exposure lasting 4 to 5 hr, produced salivation and nose irritation. All organs were normal at necropsy. When the concentration was increased to 31.5 ppm for six rats for seven exposures, 5 hr each, respiratory difficulty was noted along with salivation, tremor, weight loss, and hyperemia of eyes and tail. The lungs were the target organ showing emphysema and thickening of the alveolar walls. Two rats were exposed to 50 ppm; one died of congested lungs and kidneys. [R37] *Necropsy of rats used in the inhalation LC50 test showed severe inflammation of the trachea and lungs. [R37] *... Edema, erythema, and vesiculation may take 2 to 3 days to appear. The maximal concentration that produced no irritation to rabbit skin was 7 percent. High concentrations of CHP applied directly to the eyes of rabbits affected the cornea, iris, and conjunctiva extensively. Washing the eyes with water for 4 sec after application prevented any adverse reactions. The maximal nonirritating concentration to rabbits' eyes was 1 percent. [R37] NTXV: *LDLo Mouse oral 5,000 mg/kg; [R44] *LC50 Mouse inhalation 200 ppm/4 hr; [R44] *LD50 Mouse subcutaneous 400 mg/kg; [R46] *LD50 Rat dermal (occluded) 0.5-1.0 ml/kg; [R44] *LD50 Rat dermal (non-occluded) 1.13-1.43 ml/kg; [R44] *TDLo Mouse inhalation 304 mg/kg; toxic and neoplastic effects; [R15, 139] *TDLo Mouse subcutaneous 10 g/kg/76 wk (total dose); toxic and neoplastic effects; [R15, 140] TCAT: ?Subchronic toxicity was evaluated in groups of 20 Fischer 344 rats (10 male and 10 female) exposed daily for 6 hours to 1, 6, 31, or 124 mg/m3 cumene hydroperoxide, 5 days a week for 3 months. Exposure at 124 mg/m3 was terminated after 5 days due to excessive toxicity; mortality was observed in 6/10 male, and 3/10 female rats at 12 days at which time the surviving animals were sacrificed. Clinical observations of animals in the 124 mg/m3 dose group at 12 days included eye and nose irritation, breathing difficulties, and decreased body weights. Pathological observations attributed to the effect of the test article in animals that died or were sacrificed in the 124 mg/m3 dose group included ulceration and inflammation of the cornea, nasal turbinates and lining of the stomach; while observations of thymic atrophy, depletion of lymphoid tissue in the germinal centers of some lymph nodes and the spleen, decreased lipid content of the liver, and decreased circulating white blood cells, were attributed to stress. Hematological observations in the 124 mg/m3 dose group included a generalized decrease in PCV, RBC and WBC count and a decrease in hemoglobin levels. Cumene hydroperoxide did not induce biologically significant changes in clinical, pathological, hematological, and biochemical parameters, or in urinalysis values, when administered at concentrations of 1, 6, or 31 mg/m3 in the animals maintained on exposure for the full 90 days. [R56] POPL: *Individuals with eye, skin, and chronic respiratory diseases /may be/ at an increased risk. /Hydrogen peroxide/ [R35] ADE: *LIQUID PEROXIDES CAN BE ABSORBED THROUGH THE SKIN. /ORG PEROXIDES/ [R26] METB: *Cumene hydroperoxide penetrates human red blood cells ... reduced by glutathione in the reaction catalyzed by glutathione peroxidase. Cumenol, water, and oxidized gluthathione were products. [R57] *Enzymatic reduction of cumene hydroperoxide leads to the formation of cumenol (2-phenylpropan-2-ol) in vitro. [R58] ACTN: *THE CUMENE HYDROPEROXIDE-HEMATIN SYSTEM REACTS WITH 5,5-DIMETHYL-1-PYRROLINE-1-OXIDE TO FORM THE NITROXIDE 5,5-DIMETHYL-PYRROLIDONE-(2)-OXYL-(1) (DMPOX). DMPOX IS FORMED VIA SPIN TRAPPING OF A CUMENE HYDROPEROXYL RADICAL FOLLOWED BY AN INTRAMOLECULAR CARBANION DISPLACEMENT. ACTIVATION OF CARCINOGEN N-HYDROXY-2-ACETYL AMINOFLUORENE BY CUMENE HYDROPEROXIDE-HEMATIN SYSTEM IS MOST LIKELY MEDIATED BY CUMENE HYDROPEROXYL RADICAL. [R59] *Cumene hydroperoxide oxidized cholesterol to the carcinogen 5,6-epoxide (5,6-alpha-epoxy-5-alpha-cholestan-3-beta-ol). [R60] INTC: *THE RATE OF OXIDATION OF BENZO(A)PYRENE IN 3-METHYLCHOLANTHRENE (3-MC)-INDUCED RATS WAS 20-FOLD HIGHER THAN THAT IN THE INTACT MICROSOMAL SYSTEM. IN THE CASE OF 3-MC-INDUCED MICROSOMES CONTAINING NADPH, THE YIELD AND DISTRIBUTION OF BENZO(A)PYRENE DIOLS, ESPECIALLY BENZO(A)PYRENE-9,10-DIHYDRODIOL WAS APPROX 50% HIGHER COMPARED TO THE TOTAL DIOLS. THE SPECTRUM OF BENZO(A)PYRENE DIOL WAS SHARPLY ALTERED IN ENZYME SYSTEMS CONTAINING CUMENE HYDROPEROXIDE INSTEAD OF NADPH. [R61] *... SHOWN THAT THE NADPH AND CUMENE HYDROPEROXIDE SUPPORTED DEALKYLATION REACTIONS ARE INHIBITED BY A TYROSINE-COPPER (II) COMPLEX AND SUCH COMPLEXES ARE KNOWN TO HAVE SUPEROXIDE DISMUTASE ACTIVITY. [R62, p. S94] *Cumene hydroperoxide with ox blood hematin converted the carcinogen n-hydroxy-2- acetoaminofluorene to a nitroxyl-free radical. The free radicals were converted to n-acetoxy-2-acetylamino-fluorene and 2-nitrosofluorene. [R63] *... SEVERAL HYDROXYLATING AGENTS ... TESTED WITH BENZPHETAMINE AS SUBSTRATE ... CUMENE HYDROPEROXIDE /WAS MOST EFFECTIVE/. [R62, 113] *ORGANIC HYDROPEROXIDES ... MAY SUPPORT THE CYTOCHROME P450 MEDIATED HYDROXYLATION OF VARIETY OF SUBSTRATES. ... INVESTIGATED REACTIONS USING HIGHLY PURIFIED P450, LIPID WAS REQUIRED FOR OPTIMAL ACTIVITY. ... SEVERAL HYDROXYLATING AGENTS ... TESTED WITH BENZPHETAMINE AS SUBSTRATE ... CUMENE HYDROPEROXIDE /WAS MOST EFFECTIVE/. [R62, 113] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Cumene hydroperoxide's production and use in the production of acetone, phenol, and alpha-methylsytrene, and as a polymerization catalyst may result in its release to the environment through various waste streams. Small quantities might be formed in the atmosphere and natural waters from cumene. If released to air, a vapor pressure of 3.27X10-3 mm Hg at 25 deg C indicates cumene hydroperoxide will exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase cumene hydroperoxide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 45 hours. If released to soil, cumene hydroperoxide is expected to have slight mobility based upon an estimated Koc of 2300. However, hydroperoxides react with a variety of compounds and are reduced readily to the corresponding alcohols. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 4.7X10-8 atm-cu m/mole. If released into water, cumene hydroperoxide is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 9 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to cumene hydroperoxide may occur through inhalation and dermal contact with this compound at workplaces where cumene hydroperoxide is produced or used. (SRC) NATS: *Small quantities of cumene hydroperoxide might be formed in the atmosphere from cumene by light catalyzed auto-oxidation(1) and by reaction of cumene with alkylperoxy radicals and oxygen in natural waters(2). [R64] ARTS: *Cumene hydroperoxide's production and use in the production of acetone, phenol, and alpha-methylsytrene(1), as a polymerization catalyst(2), and as a polyester resin crosslinking agent(3), may result in its release to the environment through various waste streams(SRC). The source of cumene hydroperoxide in the extrusion area of an electrical cable insulation plant was from the degradation of dicumyl peroxide(4). [R65] FATE: *TERRESTRIAL Based on a classification scheme(1), an estimated Koc value of 2300(SRC), determined from a structure estimation method(2), indicates that cumene hydroperoxide is expected to have slight mobility in soil(SRC). However, hydroperoxides react with a variety of compounds and are reduced readily to the corresponding alcohols(5). They are decomposed readily by multivalent metal ions, are photo- and thermally sensitive and undergo initial oxygen-oxygen bond homolysis, and they are readily attacked by free radicals, undergoing induced and self-induced decomposition(5). Chemical degradation is expected to be the dominant fate process in soil. Volatilization of cumene hydroperoxide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.7X10-8 atm-cu m/mole(SRC) derived from its vapor pressure, 3.27X10-3 mm Hg(3), and water solubility, 1.39X10+4 mg/l(4). Cumene hydroperoxide is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 3.27X10-3 mm Hg(3). [R66] *AQUATIC FATE: Cumene hydroperoxide is expected to rapidly react with organic matter in soil and water and be rapidly decomposed by metal ions in water. Based on a classification scheme(1), an estimated Koc value of 2300(SRC), determined from an estimation method(2), indicates that cumene hydroperoxide is expected to adsorb to suspended solids and sediment(SRC). However, hydroperoxides react with a variety of compounds and are reduced readily to the corresponding alcohols(9). They are decomposed readily by multivalent metal ions, are photo- and thermally sensitive and undergo initial oxygen-oxygen bond homolysis, and they are readily attacked by free radicals, undergoing induced and self-induced decomposition(9). Chemical degradation is expected to be the dominant fate process in water. Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.7X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 3.27X10-3 mm Hg(4), and water solubility, 1.39X10+4 mg/l(5). According to a classification scheme(6), an estimated BCF of 9(SRC), from an estimated log Kow of 2.2(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low. [R67] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cumene hydroperoxide, which has a vapor pressure of 3.27X10-3 mm Hg at 25 deg C(2), is expected to exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase cumene hydroperoxide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 45 hours(SRC), calculated from its rate constant of 8.6X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Cumene hydroperoxide absorbs light in the environmental spectrum and has the potential for direct photolysis(4). [R68] ABIO: *The rate constant for the vapor-phase reaction of cumene hydroperoxide with photochemically-produced hydroxyl radicals has been estimated as 8.6X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of approximately 45 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Hydroperoxides are decomposed by redox reactions with multivalent metal ions (any oxidation state), acid catalyzed hydrolysis, attack by free radicals and photodissociation(2-4). The latter process readily occurs for cumene hydroperoxide when irradiated with light at 313 nm in organic solvents but no information could be found in the literature on its photodissociation under environmental conditions(2). No specific data could be found on the degradation rates of cumene hydroperoxides by the other degradation mechanisms. It should be mentioned that hydroperoxides are so sensitive to decomposition by multivalent metal ions that traces of these metals must be kept away from these chemicals(3). Reactions with free radicals are also rapid and would be expected to result in decomposition in natural waters and urban atmospheres(3-5). [R69] BIOC: *An estimated BCF of 9 was calculated for cumene hydroperoxide(SRC), using an estimated log Kow of 2.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. Chemical degradation is expected to be the dominant fate process in water because of reaction with organic matter and therefore, would attenuate the amount of cumene hydroperoxide that is biologically available(SRC). [R70] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for cumene hydroperoxide can be estimated to be 2300(SRC). According to a classification scheme(2), this estimated Koc value suggests that cumene hydroperoxide is expected to have slight mobility in soil. Hydroperoxides react with multivalent metal ions and other species ubiquitous in soil and are readily reduced to the corresponding alcohols(3). Therefore, it is expected to chemically degrade rapidly in soil and is not expected to travel long distances in soil or migrate to groundwater(SRC). [R71] VWS: *The Henry's Law constant for cumene hydroperoxide is estimated as 4.7X10-8 atm-cu m/mole(SRC) derived from its vapor pressure, 3.27X10-3 mm Hg(1), and water solubility, 1.39X10+4 mg/l(2). This Henry's Law constant indicates that cumene hydroperoxide is expected to be essentially nonvolatile(3). Cumene hydroperoxide is not expected to volatilize from dry soil surfaces based upon a vapor pressure of 3.27X10-3 mm Hg(1). It is expected to rapidly decompose in soil and water(4) and consequently attenuate volatilization to the atmosphere(SRC). [R72] EFFL: *Cumene hydroperoxide may be emitted as an air pollutant from industrial sources that produce cyclic crudes and intermediates, and industrial organic chemicals(1). [R73] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 234,305 workers (69,933 of these are female) are potentially exposed to cumene hydroperoxide in the US(1). Occupational exposure to cumene hydroperoxide may occur through inhalation and dermal contact with this compound at workplaces where cumene hydroperoxide is produced or used(SRC). Cumene hydroperoxide (0 to 60 ug per cu meter air) was measured at a electrical cable insulation plant in the extrusion area(2). [R74] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: *Soviet recommended maximal allowable concentration of cumene hydroperoxide is 0.001 ppm. [R75] *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 1 ppm, skin. [R76] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Cumene hydroperoxide is produced, as an intermediate or a final product, by process units covered under this subpart. [R77] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R78] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1-Methyl-1-phenylethyl hydroperoxide is included on this list. [R79] RCRA: *U096; As stipulated in 40 CFR 261.33, when alpha,alpha-dimethybenzylhydroperoxide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R80] FDA: *Cumene hydroperoxide is an indirect food additive for use only as a component of adhesives. [R81] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *... Volatile organics ... were collected on activated charcoal, desorbed with trichlorofluoromethane and analyzed by GC/MS (gas chromatography/mass spectrometry). Compounds were identified and quantitated; their cumulative concentrations ranged from 25-27,000 mug/cu m. [R82] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: ITC/USEPA; Information Review #131 Cumene Hydroperoxide (1980) Aringer L; Criteria Document for Exposure Limits-Benzoyl Peroxide, Cyclohexanone Peroxide, Dicumyl Peroxide, Methyl Ethyl Ketone Peroxide. Arbetarskyddsstyrelsen, Publikationsservice, 171 84 Solna, Sweden 64pp. (1985) SO: R1: SRI R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 243 R3: NIH/EPA; OHM/TADS R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 536 R6: Sheppard CS, Kamath V; Kirk-Othmer Encycl Chem Technol. 3rd ed. NY, NY: John Wiley and Sons 13: 363-4 (1981) R7: Larson RA et al; Chemosphere 10 (11/12): 1335-38 (1981) R8: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. R9: Perimutter H et al; Environ Sci Tech 27: 126-133 (1993) R10: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.263 R11: United States International Trade Commission. Synthetic Organic Chemicals--United States Production and Sales, 1992. USITC. Publication 2720, February 1992. 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Prudent Practices for Handling Hazardous Chemicals in Laboratories. Washington, DC: National Academy Press, 1981. R19: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R20: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R21: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 49-105 R22: International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998. R23: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 786 R24: ITC/USEPA; Information Review #131 Cumene Hydroperoxide p.1 (1980) R25: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1981 R26: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 166 R27: 49 CFR 171.2 (7/1/96) R28: IATA. Dangerous Goods Regulations. 41st Ed.Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2000.,p. 196-7 R29: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.5227,5237,5228,5238,5229,5239,5230,5240 (1988) R30: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 49-33 R31: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 278 R32: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R33: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (June 1981) EPA 68-03-3025 R34: Bronstein, A.C., P.L. 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NY, NY: John Wiley and Sons 13: 363-4 (1981) (4) Norrish RGW, Searby MH; Proc Roy Soc London Ser A 237: 464-75 (1976) (5) Graedel TE; Chemical Compounds in the Atmosphere, Orlando, FL: Academic Press p.241 (1979) R70: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R71: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Sanchez J et al; Kirk-Othmer Encycl Chem Technol. 4th. NY, NY: Wiley 18: 230-310 (1996) R72: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data. Amer Inst Chem Eng. NY, NY: Hemisphere Pub Corp 5 Vol (1989) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ AZ, of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) Sanchez J et al; Kirk-Othmer Encycl Chem Technol. 4th. NY, NY: Wiley 18: 230-310 (1996) R73: (1) PES, Inc; Toxic Air Pollutant/Source Crosswalk A Screening. Research Triangle Park, NC: USEPA-450/4-87-023A, NTIS PB88-161146 pp. 2-140 (1987) R74: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Cocheo et al; Am Ind Hyg Assoc J 44: 521-7 (1983) R75: Gage JC; Brit J Ind Med 27: 1-18 (1970) as cited in ITC/USEPA; Information Review #130 (Draft) Cumene Hydroperoxide p.8 (1980) R76: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R77: 40 CFR 60.489 (7/1/99) R78: 40 CFR 302.4 (7/1/99) R79: 40 CFR 716.120 (7/1/99) R80: 40 CFR 261.33 (7/1/99) R81: 21 CFR 175.105 (4/1/99) R82: Cocheo V, et al; Am Ind Hyg Assoc J 44 (7): 521-7 (1983) RS: 53 Record 52 of 1119 in HSDB (through 2003/06) AN: 287 UD: 200211 RD: Reviewed by SRP on 12/01/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DECAHYDRONAPHTHALENE- SY: *BICYCLO- (4.4.0)DECANE; *DEC-; *DECALIN-; *DEKALIN-; *DEKALINA- (POLISH); *Naphthalane-; *NAPHTHALENE,-DECAHYDRO-; *NAPHTHAN-; *NAPHTHANE-; *PERHYDRONAPHTHALENE- RN: 91-17-8 MF: *C10-H18 SHPN: UN 1147; Decahydronaphthalene IMO 3.3; Decahydronaphthalene STCC: 49 131 67; Decahydronaphthalene ASCH: Cis-Decahydronaphthalene; 493-01-6; Trans-Decahydronaphthalene; 493-02-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HYDROGENATION OF NAPHTHALENE IN GLACIAL ACETIC ACID IN PRESENCE OF PLATINUM CATALYST @ 25 DEG C AND 130 ATM YIELDS MIXT OF 77% CIS-DECALIN AND 23% TRANS-DECALIN. HYDROGENATION OF TETRALIN UNDER SAME CONDITIONS YIELDS ALMOST ONLY CIS-DECALIN. ... HYDROGENATION OF DELTA-4A(8A)-OCTALIN IN ETHANOL IN PRESENCE OF PLATINUM YIELDS TRANS-DECALIN AS MAIN COMPONENT. [R1] *BY TREATMENT OF NAPHTHALENE IN FUSED STATE (ABOVE 100 DEG C) WITH HYDROGEN IN PRESENCE OF COPPER OR NICKEL CATALYST. [R2] IMP: *... The major impurity ... 1,2,3,4-tetrahydronaphthalene. /Commercial product/ [R3, p. 15(81) 704] FORM: *GRADE: TECHNICAL. [R2] *The commercial product may be practically all trans-Decalin, or a mixture containing up to 60% cis-Decalin. [R1] *Grades or purity: ... mixture of cis-(35%) and trans-(65%) isomers. ... Spectro grade. [R4] *The commercial product typically has a decahydronaphthalene content > or equal to 97% wt% ... /Commercial product/ [R3, p. 15(81) 704] MFS: +E I DuPont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Deepwater, NJ 08023 [R5] USE: *SOLVENT FOR NAPHTHALENE, FATS, RESINS, OILS, WAXES; INSTEAD OF TURPENTINE IN LACQUERS, SHOE POLISHES, FLOOR WAXES; IN MOTOR FUEL AND LUBRICANTS; PATENT FUEL IN STOVES [R1] *IN RESEARCH AS PHARMACOLOGICAL, NONCARCINOGENIC VEHICLE IN LONG-TERM SKIN PAINTING AND SOMATIC MUTATION STUDIES [R6, 3240] *IN CLEANING MACHINERY; STAIN REMOVER; CLEANING FLUIDS [R2] CPAT: *... Phthalic anhydride was used in the manufacture of alkyd and polyester resins, dyes, pigments, pharmaceuticals, and insecticides. In the manufacture of insecticides, 12.2% was used to make insecticides such as 1-naphthyl-N-methylcarbamate (carbaryl). 11% percent was used as an intermediate in the manufacturing of dyestuffs, pigments, and pharmaceuticals. The remainder was used in the manufacture of alkyl-naphthalenesulfonates (used in the manufacture of detergents and textile wetting agents), alkylnaphthalenes (used in making textile spinning lubricants), chlorinated naphthalenes and tetra- and decahydronaphthalenes (used in solvent mixtures). /Alkylnaphthalenes/ [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear colorless liquid [R8] ODOR: *SLIGHT ODOR RESEMBLING MENTHOL; PURE DECALIN DOES NOT SMELL OF NAPHTHALENE [R1] MW: *138.24 [R1] DEN: *55.500 lb/cu ft at 70 deg F [R4] HTC: *-19,200 BTU/lb= -10,700 cal/g= -447x10+5 J/kg [R4] HTV: *130 BTU/lb= 71 cal/g= 3.0x10+5 J/kg [R4] SOL: *VERY SOL IN CHLOROFORM, METHANOL, ETHER, ALCOHOL; MISCIBLE WITH MOST KETONES, ESTERS; MISCIBLE WITH PROPYL AND ISOPROPYL ALCOHOLS. [R1]; +Water solubility of 0.9 ppm @ 25 deg C [R9] SPEC: +Intense mass spectral peaks: 67 m/z (100%), 138 m/z (99%), 96 m/z (96%), 82 m/z (80%) [R10] SURF: *30 dynes/cm= 0.030 N/m at 20 deg C [R4] VAPD: *4.8 (AIR= 1) [R11] VAP: +vapor pressure = 2.3 mm Hg @ 25 deg C [R12] VISC: *1.788 CP at 70 deg F [R4] OCPP: *MAX ABSORPTION: LESS THAN 210 NM /CIS- AND TRANS-ISOMERS/ [R13] *CONVERSION FACTORS: 1 PPM= 5.65 MG/CU M /CIS- AND TRANS-ISOMERS/ [R6, 3231] *MP: -30.4 DEG C; BP: 187.25 DEG C ; DENSITY: 0.8700 @ 20 DEG C/4 DEG C /TRANS-ISOMER/ [R1] *MP: -43.26 DEG C; BP: 195.7 DEG C; DENSITY: 0.8963 @ 20 DEG C/4 DEG C /CIS-ISOMER/ [R1] *Solubility: > 10% in acetone, benzene, ether and ethanol /Cis- and trans-isomers/ [R14] *SOL IN CHLOROFORM /CIS- AND TRANS ISOMERS/ [R15, p. C-238] *SLIGHTLY SOL IN METHANOL /TRANS-ISOMER/ [R15, p. C-238] *INDEX OF REFRACTION: 1.4810 @ 20 DEG C/D /CIS-ISOMER/; 1.4695 @ 20 DEG C/D /TRANS-ISOMER/ [R15, p. C-238] *Volatile with steam [R1] *Heat of vaporization: 10,515.4 g cal/g mole /Cis-isomer/ [R15, p. C-678] *Heat of vaporization: 8,749.1 g cal/g mole /Trans-isomer/ [R15, p. C-678] *Vapor density: 4.77 (air= 1) /Trans-isomer/ [R11] +IR: 6300 (Coblentz Society Spectral Collection) /Cis-isomer/; 6301 (Coblentz Society Spectral Collection) /Trans-isomer/ [R14] +NMR: 8008 (Sadtler Research Laboratories Spectral Collection) /Cis-isomer/; 401 (Johnson and Jankowski, Carbon-13 NMR Spectra, John Wiley and Sons, New York) /Trans-isomer/ [R14] +MASS: 727 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Cis-isomer/; 725 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Trans-isomer/ [R14] *Enthalpies of formation: -52.45 kcal/mol /Cis-isomer/; -55.14 kcal/mol /Trans-isomer/ [R16] *Gibbs energies of formation: 16.47 kcal/mol /Cis-isomer/; 13.79 kcal/mol /Trans-isomer/ [R16] *Entropies: 63.34 kcal/mol /Cis-isomer/; 63.32 kcal/mol /Trans-isomer/ [R16] *Heat capacities: 55.45 kcal/mol /Cis-isomer/; 54.61 kcal/mol /Trans-isomer/ [R16] *Liquid water interfacial tension: 51.5 dynes/cm= 0.0515 N/m at 20 deg C [R4] *Liquid heat capacity= 0.391 BTU/lb-deg F @ 70 deg F [R4] *Liquid thermal conductivity= 0.735 BTU-in/hr-sq ft-deg F at 135 deg C [R4] *Saturated vapor density= 0.00269 lb/cu ft @ 130 deg F [R4] *Viscosity: 2.99 CP at 25 deg C /Cis-isomer/; 1.936 CP at 25 deg C /Trans-isomer/ [R3, p. 15(81) 703] +0.123 lb/sq inch at 130 deg F /SRP: 2.3 mm Hg at 25 degrees C/ [R4] +hydroxyl radical rate constant = 2.02X10-11 cu cm/molc sec @ 25 deg C [R17] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of decahydronaphthalene stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this clear, colorless, slightly menthol-smelling liquid may occur from its use as a chemical intermediate, in the manufacture of paints, lacquers, varnishes, shoe creams, and floor waxes, rubber, asphalt, and printing inks. Effects from exposure may include contact burns to the skin and eyes, irritation of the mucous membranes, defatting dermatitis and eczema (from prolonged or repeated contact), numbness, headache, CNS depression (dizziness), vomiting, and fatal chemical pneumonitis (if the liquid is aspirated). In activities and situations where over-exposure may occur, wear a self-contained breathing apparatus and chemical protective clothing. If contact should occur, immediately flush affected eyes and skin with running water for at least 15 minutes. Remove contaminated clothing and shoes at the site. This material may be ignited by heat, sparks, or flames. Further, its heavier than air vapor may travel to a source of ignition and flash back. Containers may explode in the heat of a fire. For fires involving decahydronaphthalene, extinguish with dry chemical, CO2, Halon, water spray, fog, or standard foam. Isolate for 1/2 mile in all directions if a tank car or truck is involved in the fire. Decahydronaphthalene may be shipped domestically via air, rail, road, or water. Storage should be away from sources of ignition and oxidizing materials. Also, avoid prolonged exposure of this substance to air because of the possible formation of dangerous peroxides. Take up small spills of decahydronaphthalene with sand or other noncombustible absorbent and place into containers for later disposal. Dike far ahead of large spills to prevent decahydronaphthalene from entering confined spaces such as sewers where its vapor may create an explosion hazard. Before implementing land disposal of waste decahydronaphthalene, consult with environmental regulatory agencies for guidance. DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R18] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R18] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R18] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R18] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R18] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R18] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R18] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R18] FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME ... [R19] NFPA: +Health: 2. 2= Materials hazardous to health, but areas may be entered freely with full face mask self contained breathing apparatus which provides eye protection. [R20, p. 325-30] +Flammability: 2. 2= Material which must be moderately heated before ignition will occur. Water spray may be used to extinguish the fire because the material can be cooled below its flash point. [R20, p. 325-30] +Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R20, p. 325-30] +Health: 0. 0= Materials which on exposure under fire conditions would offer no hazard beyond that of ordinary combustible material. /Trans-isomer/ [R20, p. 325-31] +Flammability: 2. 2= Material which must be moderately heated before ignition will occur. Water spray may be used to extinguish the fire because the material can be cooled below its flash point. /Trans-isomer/ [R20, p. 325-31] +Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. /Trans-isomer/ [R20, p. 325-31] FLMT: +LOWER 0.7% @ 100 DEG C; UPPER 4.9% @ 100 DEG C [R20, p. 325-30] +LOWER 0.7%; UPPER 5.4% /TRANS-ISOMER/ [R20, p. 325-31] FLPT: +58 DEG C (CLOSED CUP) [R20, p. 325-30] AUTO: +250 DEG C; 255 DEG C /TRANS-ISOMER/ [R20, p. 325-30] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEMICAL. [R19] *Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. [R8] EXPL: *0.7-4.9% [R21] REAC: *... Can react with oxidizing materials. [R19] SERI: *Decalin is irritating to the eyes, skin, and mucous membranes ... [R6, 3240] EQUP: *Wear appropriate chemical protective gloves, boots and goggles. [R8] */NIOSH approved respirators/ ... or self contained breathing apparatus if in enclosed tank; ... protective cream ... face shield. [R4] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock down vapors. [R8] *Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R8] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. [R22] SSL: *ON LONG EXPOSURE TO AIR FORMS DANGEROUS CONCN OF PEROXIDE [R23] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R24] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R25] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R26] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *DERMATITIS AND CONJUNCTIVAL IRRITATION. SYSTEMIC TOXICITY IS NOT WELL DEFINED BUT NO SERIOUS INDUSTRIAL POISONINGS ARE KNOWN. [R27] *LIQ ALICYCLIC HYDROCARBONS WILL DEHYDRATE AND DELIPIDIZE THE SKIN ON ... CONTACT AND CAUSE DERMATITIS. DIRECT CONTACT ... WITH LUNG TISSUE (ASPIRATION) WILL CAUSE PULMONARY EDEMA, PNEUMONITIS, AND HEMORRHAGE. THE VAPORS IN SUFFICIENT CONCN WILL CAUSE IRRITATION OF MUCOUS MEMBRANES. /ALICYCLIC HYDROCARBONS/ [R28, 1208] *... BROWNISH GREEN URINE ... REPORTED IN WORKERS EXPOSED TO A MIXTURE OF DECALIN AND TETRALIN. [R6, 3241] *IN ... MAN ... EMPLOYED IN CLEANING PAVING STONES WITH DECALIN ... VESICULAR ECZEMA WAS PRESENT ON AREAS IN CLOSEST CONTACT WITH DECALIN-THE FOREARMS AND SACRAL REGION. IT WAS ACCOMPANIED BY INTENSIVE PRURITUS, AND SKIN TESTS SHOWED SENSITIVITY TO DECALIN ... THE URINE CONTAINED TRACES OF ALBUMIN AND UROBILIN, AND A FEW LEUKOCYTES IN SEDIMENT SUGGESTING INVOLVEMENT OF KIDNEYS. [R29] *Excessive exposure to high concn causes numbness, nausea, headache, and vomiting. [R3, p. 15(81) 704] NTOX: *VAPOR EXPOSURES IN GUINEA PIGS CAUSE CATARACTS ... [R27] *IN ... EXPERIMENTS WITH GUINEA PIGS, BY ORAL ADMIN, CUTANEOUS APPLICATION AND INHALATION, EFFECTS OF DECALIN WERE FUNDAMENTALLY THE SAME AS THOSE OF TETRALIN, ESP WITH REGARD TO LIVER (ATROPHY) AND KIDNEYS (NEPHROSIS); IN ONE ANIMAL THERE WAS UNEXPLAINABLE CALCIFICATION OF KIDNEY. [R29] *OF 3 GUINEA PIGS EXPOSED TO VAPOR CONCENTRATION OF 319 PPM (1.8 MG/L) FOR 8 HR/DAY, ONE DIED ON DAY 1, SECOND ON DAY 21, AND THE THIRD ON DAY 23. GROSS AND MICROSCOPIC EXAM REVEALED LUNG CONGESTION, KIDNEY AND LIVER INJURY. DECALIN APPLIED TO 6 SQ CM OF GUINEA PIG SKIN ON TWO SUCCESSIVE DAYS RESULTED IN DEATHS 10 DAYS POST-EXPOSURE. THE SYSTEMIC TISSUE INJURY WAS THE SAME AS FROM ITS INHALATION. ... GUINEA PIGS DOSED ORALLY, BUT NOT BY INHALATION OR PERCUTANEOUS ADMIN, WITH DECALIN HAVE SHOWN BROWNISH GREEN URINE ... [R6, 3241] *Following short term (24-90 days) exposure of male F344 rats by inhalation, nephrotoxic lesions, especially hyaline droplets and necrosis were found. Of the several strains examined, only male rats exhibited kidney sensitivity. A major component of the hyaline droplets was alpha-2mu-globulin, the main urinary protein of male rats. [R30] *Decalin was evaluated for developmental toxicity in a proposed new short term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid pregnancy and allowed to go to term. Observations were then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Forty-eight pregnant CD-1 mice were given 2700 mg/kg/day decalin in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. Decalin caused 14% maternal mortality associated with a significant increase in maternal weight gain. Decalin had no effect in the offspring of treated mice for the parameters assayed. [R31] *Decahydronaphthalene ... tested by dropping on rabbit eyes, caused no injury. Admin systematically to rabbits ... it caused cataracts even more readily than naphthalene. [R32] *Male and female Fischer 344 rats were given decalin by oral gavage for 5 or 12 consecutive days in order to determine whether oral dosing would result in light microscopically evident renal effects that were comparable to those that have been observed after inhalation exposure. Decalin (in corn oil vehicle) was administered at doses of 0, 0.1, 0.5, 1.0 or 2.0 g/kg body weight to male rats, and 0, 1.0, 1.5, 1.75 or 2.0 g/kg to female rats. Biopsies of the kidneys of selected control and high dose male rats were taken for examination by electron microscopy. Sections of kidneys from all control and treated rats were examined by light microscopy. The kidneys of all male control rats contained minimal levels of hyaline droplets within the cytoplasm of proximal convoluted tubule epithelial cells. Decalin induced alterations in the kidneys of male rats included an exacerbation of the hyaline droplet/globule levels found in controls and the formation of granular casts in the outer zone of the renal medulla. The exacerbated formation of hyaline droplets was characterized light microscopically by a marked dose related increase in the number and size of individual droplets/globules and ultrastructurally by a marked increase in the size range of, and the presence crystalline inclusions in, the proximal convoluted tubule epithelial cell phagolysosomal populations. No other ultrastructural alterations occurred that differentiated treated male rats from control males. The formation of granular casts was dose and time related, occurring in 60% of male rats given 0.5 g decalin/kg for 12 days and in 100% of those given 1.0 g decalin/kg for 12 days. Light microscopy revealed no differences between the kidneys of control and decalin treated female rats, and no hyaline droplets or granular casts were observed in the kidneys of any female rat killed after 5 or 12 days. [R33] NTXV: *LD50 Rat oral 4.2 g/kg; [R1] ADE: *DECALIN IS METABOLIZED AND EXCRETED IN THE URINE CONJUGATED WITH GLUCURONIC ACID. [R28, 1215] METB: *CIS- AND TRANS-DECALIN GAVE RISE TO RACEMIC DECANOLS WHEN METABOLIZED IN THE RABBIT, AND WERE GENERALLY EXCRETED IN THE URINE, CONJUGATED WITH GLUCURONIC ACID. /CIS- AND TRANS-ISOMERS/ [R6, 3241] *The metabolism of naphthalene in mammals has been extensively studied. Naphthalene is first metabolized by hepatic mixed function oxidases to the epoxide, naphthalene-1,2-oxide. This epoxide has the distinction of being the first arene oxide metabolite to have been isolated. Epoxide formation is an obligatory step. The epoxide can be enzymatically converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydronaphthalene or conjugated with glutathione. The dihydrodiol can then be conjugated to form a polar compound with glucuronic acid or sulfate or be further dehydrogenated to form the highly reactive 1,2-dihydroxynaphthalene. This too can be enzymatically conjugated with sulfate or glucuronic acid or spontaneously oxidized to form another highly reactive compound, 1,2-naphthoquinone. /Naphthalene/ [R34] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Decahydronaphthalene a component of crude oil and a product of combustion, is produced and released to the environment during natural fires. Emissions from petroleum refining, coal tar distillation, and gasoline and diesel fueled engines are major contributors of decahydronaphthalene to the environment. Decahydronaphthalene is also used as a chemical intermediate and a general solvent. Consequently, decahydronaphthalene is released to the environment via manufacturing effluents were decahydronaphthalene is produced and used. Because of the widespread use of decahydronaphthalene in a variety of products, decahydronaphthalene is also released to the environment through the disposal of these products and municipal waste water treatment facilities. Decahydronaphthalene should biodegrade in acclimated environments under the proper conditions. Decahydronaphthalene is not expected to undergo hydrolysis or photolysis in the environment. A calculated Koc range of 4700 to 9600 indicates that decahydronaphthalene will be slightly mobile to immobile in soil. In aquatic systems, decahydronaphthalene may partition from the water column to organic matter contained in sediments and suspended solids. Decahydronaphthalene has the potential to bioconcentrate in aquatic systems. A Henry's Law constant of 4.70X10-1 atm-cu m/mole at 25 deg C suggests volatilization of decahydronaphthalene from environmental waters should be rapid. The volatilization half-lives from a model river and model pond, the latter considers the effect of adsorption, have been estimated to be 3.4 hr and 28.1 days, respectively. Decahydronapthalene is expected to exist entirely in the vapor phase in ambient air. Reaction with photochemically produced hydroxyl radicals (half-life of 20.3 hr) is likely to be an important fate process in the atmosphere. The most probable human exposure would be occupational exposure, which may occur through dermal contact or inhalation at places where decahydronapthalene is produced or used. Non occupational exposures would most likely occur via urban atmospheres, contaminated drinking water supplies and recreational activities at contaminated waterways. (SRC) NATS: *DECALIN OCCURS NATURALLY IN CRUDE OIL. [R6, 3240] *Decahydronaphthalene is a natural component of crude oil(1). Decahydronaphthalene is also a product of combustion and can be released to the environment via natural fires associated with lightening, volcanic activity, and spontaneous combustion(SRC). [R35] ARTS: *The possible contamination of drinking water from water pipe materials was investigated. Polyurethane pipes leached chlorobenzene and aromatic compounds. Homogenous polyvinylchloride pipe leached low concentrations of 3 contaminants. /Polyvinylchloride, dibenzofuran diphenyl, and decahydronaphthalene/ [R36] *Decahydronaphthalene is emitted to the environment by effluents from petroleum refining and coal tar distillation(1). The combustion of gasoline and diesel fuels releases decahydronaphthalene to the atmosphere(2). Decahydronaphthalene is used as a chemical intermediate and in the manufacture of paints, lacquers, varnishes, shoe creams and floor waxes; and as a powerful solvent for oils, resins, waxes, rubber, asphalt, aromatic hydrocarbons and printing ink(1). Consequently, decahydronaphthalene is released to the environment via manufacturing effluents where it is produced or used. Because of the widespread use of decahydronaphthalene in a variety products(1), decahydronaphthalene is also released to the environment through the disposal of these products and municipal waste water treatment facilities(3). [R37] FATE: *TERRESTRIAL FATE: Data regarding the biodegradation of decahydronaphthalene in soil were not available. However, limited marine water and sediment grab sample data suggest that decahydronaphthalene will biodegrade in acclimated soils under the proper conditions. Decahydronaphthalene is not expected to undergo hydrolysis or photolysis in soil. A calculated Koc range of 4700 to 9600(1) indicates decahydronaphthalene will be slightly mobile to immobile in soil(2). A Henry's Law constant of 4.70x10-1 atm-cu m/mole at 25 deg C(SRC) suggests volatilization of decahydronaphthalene from moist soils with a low organic matter content may be rapid(SRC). [R38] *AQUATIC FATE: Limited data suggest that decahydronaphthalene will biodegrade in acclimated aquatic systems under the proper conditions. Decahydronaphthalene is not expected to undergo hydrolysis or photolysis in environmental waters. Decahydronaphthalene has the potential to bioconcentrate in aquatic systems. Decahydronaphthalene may also partition from the water column to organic matter contained in sediments and suspended solids(1). A calculated Henry's Law constant of 4.70X10-1 atm-cu m/mole at 25 deg C(SRC) suggests volatilization of decahydronaphthalene from environmental waters should be rapid(2). Based on this Henry's Law Constant, the volatilization half-life from a model river has been estimated to be 3.4 hr(2,SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be about 28.1 days(3,SRC). [R39] *ATMOSPHERIC FATE: Based upon a vapor pressure of 2.3 mm Hg at 25 deg C(1), decahydronaphthalene is expected to exist entirely in the vapor phase in ambient air(2). In the atmosphere, direct photolysis or hydrolysis of decahydronaphthalene is unlikely to occur. Reactions of decahydronaphthalene with photochemically produced hydroxyl radicals is likely to be an important fate processes in ambient air. An estimated rate constant at 25 deg C of 1.90X10-11 cu cm/molecule-sec for the vapor phase reaction with hydroxyl radicals corresponds to a half-life of 20.3 hours at atmospheric concn of 5X10+5 hydroxyl radicals(3). [R40] BIOD: *... Degradation in seawater by oil oxidizing micro-organisms: 13.6% breakdown after 21 days at 22 deg C in stoppered bottles containing a 1000 ppm mixture of alkanes, cycloalkanes, and aromatics [R41] *Both marine water and sediment grab samples from an oiled and pristine beach areas and mud from an intertidal zone were unable to degrade decahydronaphthalene(1). However, decahydronaphthalene was degraded in water from a stagnant pond that had been acclimated to oil(1). Acclimated mixed cultures in mineral salt media were able to degrade 50% of a crude oil containing decahydronaphthalene within 48 hr(2). [R42] ABIO: *Alkanes are generally resistant to hydrolysis(1) and cyclic alkanes do not absorb UV at wavelengths greater than 290 nm(2). Therefore, decahydronaphthalene probably will not undergo hydrolysis or photolysis in the environment. The rate constant for the vapor-phase reaction of decahydronaphthalene with photochemically produced hydroxyl radicals was estimated to be 1.90X10-11 cu cm/molecule-sec at 25 deg C; which corresponds to an atmospheric half-life of about 20.3 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(3). [R43] BIOC: *Based on a water solubility of 0.9 mg/L(1) and an estimated log Kow of 4.79(2), the log BCF of decahydronaphthalene has been calculated to range from 2.82 to 3.27 from various regression-derived equations(3,SRC). These log BCF values suggest decahydronaphthalene has the potential to bioconcentrate in aquatic systems(SRC). [R44] KOC: *Based on a water solubility of 0.9 ppm(1) and an estimated log Kow of 4.79(2), the Koc of decahydronaphthalene has been calculated to range from 4700 to 9600 from various regression-derived equations(3,SRC). These Koc values indicate decahydronaphthalene will be slightly mobile to immobile in soil(4). [R45] VWS: *Based upon a water solubility of 0.9 ppm(1) and a vapor pressure of 2.3 mm Hg at 25 deg C(2), a Henry's Law Constant of 4.70X10-1 atm-cu m/mole has been calculated(SRC). This value indicates volatilization of decahydronaphthalene from environmental waters should be rapid(3). The volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 3.4 hr(3,SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be 28.1 days(4,SRC). [R46] WATC: *DRINKING WATER: Decahydronaphthalene was listed as a contaminant found in drinking water at Tuscaloosa, Al(1). [R47] *SURFACE WATER: Decahydronaphthalene is also listed as a contaminant of coastal waters off Narragansett Bay, RI(1) and Los Angeles River stormwaters(2). [R48] *GROUND WATER: Decahydronaphthalene was identified in ground water contaminated by sewage treatment facility at Falmouth, MA(1). [R49] EFFL: *Data from Sept 2 1979 identified decahydronaphthalene as a gaseous emission of the vehicle traffic through the Allegheny Mountain Tunnel of the Pennsylvania Turnpike(1). Decahydronaphthalene was detected in the municipal wastewaters from sewage treatment plants in Falmouth, MA(2). [R50] ATMC: *Data from Sept 2 1979 identified decahydronaphthalene as air pollution contaminant in the Allegheny Mountain Tunnel of the Pennsylvania Turnpike(1). Decahydronaphthalene was detected in the ambient air of Paris, France in 1972(2). [R51] RTEX: *IN ... MAN ... EMPLOYED IN CLEANING PAVING STONES WITH DECALIN ... [R29] *NIOSH (NOHS Survey 1972- 1974) has statistically estimated that 935 workers are potentially exposed to decahydronaphthalene in the USA(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 28 workers are potentially exposed to decahydronaphthalene in the USA(2). The most probable human exposure would be occupational exposure, which may occur through dermal contact or inhalation at places where decahydronaphthalene is produced or used. Non-occupational exposures would most likely occur via urban atmospheres, contaminated drinking water supplies and recreational activities at contaminated waterways(SRC). [R52] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A METHOD FOR HIGH-VOL SAMPLING OF AIRBORNE POLYCYCLIC AROMATIC HYDROCARBONS USING GLASS FIBER FILTERS AND POLYURETHANE FOAM IS DISCUSSED. ANALYSIS WAS BY HIGH RESOLUTION GAS CHROMATOGRAPHY. [R53] *Air samples of polycyclic aromatic hydrocarbons (PAH) were collected on standard glass fiber filter with a back up section of Amberlite XAD-2. Filter and XAD were solvent-desorbed and solutions were submitted to high performance liq chromatographic analysis using fluorimetric detection. Recovery of polycyclic aromatic hydrocarbons from XAD-2 was 80-100%. The method was rapid and sensitive for the determination of the most important workplace polycyclic aromatic hydrocarbons. [R54] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Burks SL; Environ Int 7 (4): 271-84 (1982). Pollutants in petroleum refinery waste waters and their effects upon aquatic organisms are reviewed. Hauser TR, Bromberg SM; Environ Monitor Assess 2 (3): 249-72 (1982). The monitoring by EPA of the air, water, soil, sediments and biota at Love Canal for selected contaminants is discussed. Type and quantity of waste products reportedly buried are listed. SCHMELTZ I ET AL; VOL 3, POLYNUCLEAR AROMATIC HYDROCARBONS. SECOND INTERNATIONAL SYMPOSIUM ON ANALYSIS, CHEMISTRY, AND BIOLOGY. SEPT 1977, ISBN 0-89004-241-1: 47-60 (1978). BIOASSAYS OF NAPHTHALENE FOR COCARCINOGENIC ACTIVITY RELATION TO TOBACCO CARCINOGENESIS WAS DISCUSSED. /NAPHTHALENE AND ALKYL NAPHTHALENES/ WHO; Environmental Health Criteria 119: Principles and Methods for the Assessment of Nephrotoxicity Associated with Exposure to Chemicals (1991) Malins DC, Hodgins HO; Environ Sci Technol 15 (11): 1273-80 (1981). An overview of the current state of knowledge on the uptake, disposition, and effects of petroleum compounds in marine fishes is presented. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that a pathology working group is reviewing data from a two year study on decalin. Route: inhalation; Species: rats, mice, and rats. [R55] SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 411 R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 347 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 549 R6: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R7: Thiessen G. Kirk-Othmer, Encyclopedia of Chemical Technology 2nd Ed. Vol 13 (1967) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene p.34 (1980) EPA 440/5-80-059 R8: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.215 R9: Yalkowsky SH et al; Arizona Data Base of Water Solubility (1987) R10: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 34 R11: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 325M-30 R12: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. R13: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-270 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 536 R15: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R16: Dean, J.A. Handbook of Organic Chemistry. New York, NY: McGraw-Hill Book Co., 1987.,p. 5-12 R17: Atkinson R; Journal of Physical And Chemical Reference Data. Monograph No 1 (1989) R18: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-130 R19: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 857 R20: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R21: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 693 R22: NIOSH. Pocket Guide to Chemical Hazards. 2nd Printing. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, February 1987.170 R23: National Research Council. Prudent Practices for Handling Hazardous Chemicals in Laboratories. Washington, DC: National Academy Press, 1981. 64 R24: 49 CFR 171.2 (7/1/96) R25: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 133 R26: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3127 (1988) R27: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-153 R28: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R29: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 139 R30: Bruner RH, Pitts LL; Nephrotoxicity of Hydrocarbon Propellants to Male, Fischer 344 Rats; Air Force Aerosp Med Res Lab, (Tech Rep) AFAMRL-TR (US); Iss AFAMRL-TR-82-101, Proc Conf Environ Toxicol 13th: 337-49 (1983) R31: Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987) R32: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 306 R33: Stone LC et al; Food Chem Toxicol 25 (1): 43-52 (1987) R34: Jerina et al; Biochem J 9: 147 (1970) as cited in USEPA; Ambient Water Quality Criteria Doc: Naphthalene p.30 (1980) EPA 440/5-80-059 R35: (1) Gaydos RM; Kirk-Othmer Encycl Chem Tech 3rd NY, NY: Wiley 15: 698-719 (1981) R36: Eklund G et al; Vatten 34 (3): 207-9 (1978) R37: (1) Gaydos RM; Kirk-Othmer Encycl Chem Tech 3rd NY, NY: Wiley 15: 698-719 (1981) (2) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (3) Barber LB et al; Environ Sci Technol 22: 205-11 (1988) R38: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (2) Swann RL et al; Res Rev 85: 16-28 (1983) R39: (1) Swann RL et al; Res Rev 85: 16-28 (1983) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-15 to 15-29 (1982) (3) USEPA; EXAMS II Computer Simulation (1987) R40: (1) Boublik T et al; Vapor Pressures of Pure Substances. Elsevier NY p. 607 (1984) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; Intern J Chem Kin 19: 799-828 (1987) R41: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 446 R42: (1) Mulkins-Phillips GJ, Stewart JE; Appl Microbiol 28: 915-922 (1974) (2) Soli G, Bens EM; Biotech Bioeng 24: 319-30 (1972) R43: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 7-4 (1982) (2) Silverstein RM, Bassler GC; Spectrometric Id of Org Cmpd, J Wiley and Sons Inc p. 148-169 (1963) (3) Atkinson R; Intern J Chem Kin 19: 799-828 (1987) R44: (1) Yalkowsky SH et al; Arizona Data Base of Water Solubility (1987) (2) CLOGP; PCGEMS Graphical Exposure Modeling System USEPA (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-4, 5-10 (1982) R45: (1) Yalkowsky SH et al; Arizona Data Base of Water Solubility (1987) (2) CLOGP; PCGEMS Graphical Exposure Modeling System USEPA (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (4) Swann RL et al; Res Rev 85: 16-28 (1983) R46: (1) Yalkowsky SH et al; Arizona Data Base of Water Solubility (1987) (2) Boublik T et al; Vapor Pressures of Pure Substances. Elsevier NY p. 607 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-15 to 15-29 (1982) (4) USEPA; EXAMS II Computr Simulation (1987) R47: (1) Bertsch W et al; J Chromat 112: 701-18 (1975) R48: (1) Wakeham SG et al; Can J Fish Aquat Sci 40: 304-21 (1983A) (2) Eaganhouse RP et al; Environ Sci Technol 15: 315-26 (1981) R49: (1) Barber LB et al; Environ Sci Technol 22: 205-11 (1988) R50: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (2) Barber LB et al; Environ Sci Technol 22: 205-11 (1988) R51: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (2) Raymond A, Guiochon G; Environ Sci Technol 8: 143-8 (1974) R52: (1) NIOSH; National Occupational Hazard Survey (NOHS) (1974) (2) NIOSH; National Occupational Exposure Survey (NOES) (1983) R53: THRANE KE, MIKALSEN A; ATMOS ENVIRON 15 (6): 909-18 (1981) R54: Andersson K et al; Chemosphere 12 (2): 197-208 (1983) R55: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 43 Record 53 of 1119 in HSDB (through 2003/06) AN: 338 UD: 200210 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIISOPROPANOLAMINE- SY: *BIS(2-HYDROXYPROPYL)AMINE; *BIS(2-PROPANOL)AMINE; *DIPA-; *DIPROPYL-2,2'-DIHYDROXY-AMINE-; *1,1'-IMINOBIS(2-PROPANOL); *1,1'-IMINODI-2-PROPANOL-; *2-PROPANOL,-1,1'-IMINOBIS-; *2-PROPANOL,-1,1'-IMINODI- RN: 110-97-4 MF: *C6-H15-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF PROPYLENE OXIDE WITH AMMONIA AND SEPARATION FROM MONO- AND TRIS(2-HYDROXYPROPYL)AMINE [R1] FORM: +DIISOPROPANOLAMINE IS 40-45 wt% OF SULFINOL SOLVENT [R2] MFS: *DOW CHEMICAL USA, MIDLAND, MICH 48640 [R1] *UNION CARBIDE CORP, CHEMS AND PLASTICS, DIV, INSTITUTE AND SOUTH CHARLESTON, W VA 25303 [R1] +ASHLAND CHEMICAL CO. INDUSTRIAL CHEMICALS AND SOLVENTS DIV., P.O. BOX 2219, COLUMBUS, OH 43216, (614)889-3333 [R3] +UNIVERSAL PRESERVACHEM, INC., 284 N. SIXTH ST., BROOKLYN, NY 11211, (718)782-7429 [R3] +BASF WYANDOTTE CORP, 100 CHERRY HILL RD., PARSIPPANY, NJ 07054, (201)263-3400 [R4] USE: *CHEMICAL INTERMEDIATE; AGENT FOR REMOVAL OF HYDROGEN SULFIDE FROM NATURAL GAS [R1] *EMULSIFYING AGENTS FOR POLISHES, TEXTILE SPECIALTIES, LEATHER COMPD, INSECTICIDES, CUTTING OILS AND WATER PAINTS [R5, 299] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] +(1986) ND U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] +(1986) ND U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS [R6] BP: *249-250 DEG C AT 745 MM HG [R6] MP: *44.5-45.5 DEG C [R6] MW: *133.19 [R6] DEN: *0.989 @ 20 DEG C/4 DEG C [R6] OWPC: +log Kow= -0.82 [R7] SOL: *SOL IN WATER, ETHANOL; SLIGHTLY SOL IN ETHER [R6]; +water solubility = 8.6X10+5 mg/l @ 25 deg C [R8] VAP: *0.02 MM HG @ 42 DEG C [R5, 299] VISC: *1.98 POISE @ 45 DEG C [R5, 299] OCPP: *CAN REACT WITH OZIDIZING MATERIALS [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R10] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R10] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R10] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. [R10] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R10] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R10] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R10] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R10] FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME. [R9] FLPT: *260 DEG F [R5, 102] FIRP: *ALCOHOL FOAM, CARBON DIOXIDE, DRY CHEMICALS. [R9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *INSTILLATION OF 50 MG OF DIPA INTO RABBIT EYES CAUSED A BURN OF EYELID, EYEBALL, AND CORNEAL MUCOSA. SPONTANEOUS RECOVERY WITHIN 22 DAYS. A CATARACT SURROUNDED BY OPAQUE CORNEA REMAINED AFTER THE BURN. [R11] +Diisopropanolamine was found to be negative when tested for mutagenicity using the Salmonella/ microsome preincubation assay, chemicals, using the standard protocol approved by the National Toxicology Program (NTP). Diisopropanolamine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 10.000 mg/plate. This dose exhibited slight to total clearing of the background bacterial lawn in all strains tested both with and without metabolic activation. [R12] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETECTION BY GAS CHROMATOGRAPHY WITH FLAME IONIZATION. [R13] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V22 p.270 R3: OPD CHEMICAL BUYERS DIRECTORY 1985 p.294 R4: CHEMICALWEEK BUYERS' GUIDE '86 p.305 R5: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. R6: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-109 R7: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 25 R8: Kuhne R et al; Chemosphere 30:2061-77 (1995) R9: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 591 R10: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-132 R11: TOROPKOV VV; CLINICAL-MORPHOLOGICAL STUDY ON THE EFFECT OF ISOPROPANOLAMINES ON THE EYE; GIG TR PROF ZABOL 2: 48 (1980) R12: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R13: LANGVARDT PW, MELCHER RG; DETERMINATION OF ETHANOL- AND ISOPROPANOLAMINES IN AIR AT PARTS-PER-BILLION LEVELS; ANAL CHEM 52(4) 669 (1980) RS: 9 Record 54 of 1119 in HSDB (through 2003/06) AN: 339 UD: 200303 RD: Reviewed by SRP on 1/31/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BIS(2-ETHYLHEXYL)PHTHALATE SY: *AI3-04273-; *BEHP-; *1,2-BENZENEDICARBOXYLIC ACID, BIS(ETHYLHEXYL) ESTER; *1,2-BENZENEDICARBOXYLIC ACID, BIS(2-ETHYLHEXYL) ESTER; *BIS(2-ETHYLHEXYL)-1,2-BENZENEDICARBOXYLATE; *BISOFLEX-81-; *BISOFLEX-DOP-; *COMPOUND-889-; *DAF-68-; *DEHP-; *DI(2-ETHYLHEXYL)ORTHOPHTHALATE; *DI- (ETHYLHEXYL)-PHTHALATE; *DI-2-ETHYLHEXYLPHTHALATE-; *Dioctyl-phthalate-; *Di-sec-octyl-phthalate-; *DOF- (RUSSIANPLASTICIZER); *DOP-; +DIETHYLHEXYL-PHTHALATE-; +Pesticide-Code-295200-; *ERGOPLAST-FDO-; *ERGOPLAST-FDO-S-; *ETHYLHEXYL-PHTHALATE-; *2-ETHYLHEXYL-PHTHALATE-; *EVIPLAST-80-; *EVIPLAST-81-; *FLEXIMEL-; *FLEXOL-DOP-; *FLEXOL-PLASTICIZER-DOP-; *GOOD-RITE-GP-264-; *HATCOL-DOP-; *HERCOFLEX-260-; *KODAFLEX-DOP-; *MOLLAN-O-; *NCI-C52733-; *NUOPLAZ-DOP-; *Octoil-; *Octyl-phthalate-; *PALATINOL-AH-; *PHTHALIC ACID, BIS(2-ETHYLHEXYL) ESTER; *PHTHALIC-ACID-DIOCTYL-ESTER-; *PITTSBURGH-PX-138-; *PLATINOL-AH-; *PLATINOL-DOP-; *RC-PLASTICIZER-DOP-; *REOMOL-D-79P-; *REOMOL-DOP-; *SICOL-150-; *STAFLEX-DOP-; *TRUFLEX-DOP-; *VESTINOL-AH-; *VINICIZER-80-; *WITCIZER-312- RN: 117-81-7 RELT: 1345 [DI-N-OCTYL PHTHALATE] MF: *C24-H38-O4 HAZN: U028; Bis(2-ethylhexyl)phthalate ASCH: Mono-(2-ethylhexyl)phthalate; 4376-20-9 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN: GARNER, WATSON, US PATENT 2,508,911 (1950 TO SHELL); BRITISH PATENT 747,260 (1956 TO CHEMISCHE WERKE HULS). [R1] *2-Ethylhexanol + phthalic anhydride (esterification) [R2] FORM: +USEPA/OPP Pesticide Code 295200; Trade Names: Bisoflex dop, Celluflex dop, Compound 889, Eviplast 80, Fleximel, Flexol dop, Hercoflex 260, Kodaflex dop, NCI-C52733, Octoil, Palatinol AH, Pittsburgh PX-138, Polycizer 162, PX-138, RC Plasticizer DOP, Sicol 150, Staflex DOP, Truflex DOP, Union Carbide flexol 380, Vestinol AH, Vinicizer 80, Witcizer 312. [R3] MFS: *Aristech Chemical Corporation, Hq, 600 Grant Street, Pittsburgh, PA 15219-2704, (412) 433-2747; Chemicals Division; Production site: 200 Neville Road, Neville Island, PA 15225. [R4] *Eastman Chemical Company, Hq, PO Box 511, Kingsport, TN 37662, (423) 229-2000; Tennessee Eastman Division; Production site: Kingsport, TN 37662. [R4] *Velsicol Chemical Corporation, Hq, 10400 W Higgins Road, Suite 600, Rosemont, IL 60018-5119, (847) 298-9000; Production site: Route 297, Chestertown, MD 21620. [R4] OMIN: *...'DIOCTYL PHTHALATE' (DOP) ... IS THE ... MOST WIDELY USED /PHTHALATE ESTER/ ... THE TRIVIAL NAME IS RATHER MISLEADING FOR DOP IS NOT DI-N-OCTYL PHTHALATE BUT THE BRANCHED-CHAIN ISOMER DI-(2-ETHYLHEXYL) PHTHALATE. [R5] USE: +For Bis(2-ethylhexylphthalate) (USEPA/OPP Pesticide Code: 295200) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R3] +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R6] *... IN PLASTICIZING A VARIETY OF POLYMERIC MATERIALS: NATURAL RUBBER, SYNTHETIC RUBBER ... CELLULOSE ACETATE BUTYRATE, ETHYL CELLULOSE, NITROCELLULOSE, POLYMETHYL METHACRYLATE, POLYVINYL BUTYRAL, POLYSTYRENE, AND POLYVINYLIDINE CHLORIDE. [R7] *Plasticizer manufacture; plastics manufacture and recycling, processing; organic pump fluid [R8, 867] *PLASTICIZER FOR POLYVINYL CHLORIDE RESINS [R9] *PLASTICIZER FOR VINYL CHLORIDE COPOLYMER RESINS [R9] *PLASTICIZER FOR OTHER RESINS AND SYNTHETIC RUBBERS [R9] *COMPONENT OF DIELECTRIC FLUIDS IN ELECTRICAL CAPACITATORS [R9] *SOLVENT-EG, FOR ERASABLE INK [R9] *ACARICIDE FOR USE IN ORCHARDS [R9] *INERT INGREDIENT IN PESTICIDE FORMULATIONS [R9] *VACUUM PUMP OIL [R9] *TESTING AGENT FOR AIR FILTRATION SYSTEMS [R9] *Plasticizer for ... chlorinated rubber [R10, 1987] *Used widely in insect repellant formulations, cosmetics, rubbing alcohol, liquid soap, detergents, decorative inks, lacquers, munitions, industrial and lubricating oils, defoaming agents during paper and paperboard manufactures, and as pesticide carriers. /Phthalic Esters/ [R11] *Photographic film, wire and cable, adhesives [R12] *As plasticizer in flexible vinyl products. As a replacement for PCBs in dielectric fluids for elctric capacitors. [R1] *Plasticizer (polyvinyl chloride, rubber, adhesives, PVA emulsion paints, lacquers); non-reactive epoxy resin diluent. [R2] *Plasticizer; also used as an insulating fluid in electrical transformers and pressure-sensitive printing. [R13] CPAT: *PLASTICIZER FOR POLYVINYL CHLORIDE, 87%; PLASTICIZER FOR OTHER VINYL RESINS, 7%; OTHER PLASTICIZER USE, 3%; OTHER NON-PLASTICIZER USE, 3% (1979 EST) [R9] *Polyvinyl chloride, 95%; other, 5% (1986) /estimated/ [R10, (1987)] PRIE: U.S. PRODUCTION: *(1982) 251,067,000 lbs [R14] *(1977) 1.77X10+11 G [R9] *(1982) 1.14X10+11 G [R9] *(1986) 1.30X10+11 g [R10, (1987)] *(1988) No data published [R15] U.S. IMPORTS: *(1986) 2.70X10+9 g [R10, (1987)] U.S. EXPORTS: *(1986) 5.40X10+9 g [R10, 1987] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, oily liquid. [R16] ODOR: *SLIGHT ODOR [R17]; *Slight odor. [R16]; *Odorless [R18] BP: *230 DEG C @ 5 MM HG [R19, 2344] MP: *-55 deg C [R20] MW: *390.56 [R1] DEN: *0.9861 @ 20 DEG C/20 DEG C [R21, (1982)] HTC: *-15,130 BTU/LB= -8410 CAL/G= -352X10+5 JOULES/KG [R17] OWPC: +log Kow= 7.60 [R22] SOL: *LESS THAN 0.01% IN WATER @ 25 DEG C [R23]; *Soluble in blood and fluids containing lipoproteins [R24]; *MISCIBLE WITH MINERAL OIL AND HEXANE [R25]; *In water, 0.285 mg/l at 24 deg C. [R26]; *Slightly soluble in carbon tetrachloride. [R20] SPEC: *INDEX OF REFRACTION: 1.4836 @ 20 DEG C/D [R21, (1972)]; *Intense mass spectral peaks: 149 m/z (100%), 57 m/z (32%), 167 m/z (29%), 71 m/z (21%) [R27]; *IR: 2526 (Coblentz Society Spectral Collection) [R28]; *NMR: 9392 (Sadtler Research Laboratories Spectral Collection) [R28]; *MASS: 2-708 (Archives of Mass Spectral Data, John Wiley and Sons, New York) [R28] SURF: *LIQUID SURFACE TENSION: EST 15 DYNES/CM= 0.015 N/M @ 20 DEG C LIQUID-WATER INTERFACIAL TENSION: EST 30 DYNES/CM= 0.03 N/M @ 20 DEG C. [R17] VAPD: *16.0 (air=1) [R19, 2345] VAP: *7.23X10-8 mm Hg at 25 deg C /from experimentally-derived coefficients/ [R29] VISC: *81.4 CENTIPOISES @ 20 DEG C [R21, (1982)] OCPP: *POUR POINT: -46 DEG C; 8.20 LB/GAL @ 20 DEG C [R30] *1 PPM= APPROX 15.94 MG/CU M [R19, 2345] *4.3 Relative dielectric constant (@ 60 Hz, 100 deg C); 0.5% Dissipation factor (@ 60 Hz, 100 deg C); 42 kV dielectric strength (ASTM D 877); 25 ul/min Gas absorption coefficient (ASTM D 2300) [R31] *Vapor pressure = 9.75X10-6 mm Hg @ 25 deg C [R32] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 0. 0= Materials that on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R33] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R33] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R33] FLMT: +0.3% BY VOL @ 474 DEG F (245 DEG C) [R33] FLPT: +420 DEG F (215 DEG C) OPEN CUP [R33] AUTO: +735 DEG F (390 DEG C) [R33] FIRP: *DRY POWDER, CARBON DIOXIDE, FOAM. WATER OR FOAM MAY CAUSE FROTHING. [R17] REAC: +Nitrates; strong oxidizers, acids and alkalis. [R34, 118] DCMP: *When heated to decomp it emits acrid smoke. [R35] SERI: *... MAY GIVE OFF IRRITATING VAPOR @ HIGH TEMPERATURE. [R17] *Caution: Potential symptoms of overexposure are irritation of eyes and mucous membranes. [R1] *DEHP has been shown to be a weak irritant to mammalian skin when admin topically or intradermally (0.2 mL of an emulsion of 100 g/L). [R36] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R37, 1979.8] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R34, 118] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R34, 118] OPRM: +Contact lenses should not be worn when working with this chemical. [R34, 118] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SYNTH OF PHTHALATES REQUIRE GOOD VENTILATION IN ORDER TO PREVENT CONTAMINATION OF AIR WITH PHTHALIC ANHYDRIDE OR ALCOHOLS. THERE MAY BE ALSO SOME NEED FOR SKIN PROTECTION. HANDLING MINERAL ACIDS USED AS CATALYSTS REQUIRES ORDINARY PRECAUTIONS. /PHTHALATES/ [R38] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R37, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R37, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R37, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R37, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R37, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R37, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R37, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R37, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R37, 1979.11] SSL: *STABLE [R39] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R37, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R37, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R37, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R37, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U028, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R40] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R37, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R37, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R37, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R37, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R37, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +/Di(2-ethylhexyl)phthalate (DEHP)/ has been found in various types of food, such as fish, shellfish, eggs and cheese. ... Blood transfusions and other medical treatment using plastic devices may lead to involuntary human exposure to DEHP. ... Available data on oral administration indicate that DEHP is hydrolyzed in the gut by pancreatic lipase. The metabolites formed, i.e., mono(2-ethylhexyl)phthalate and 2-ethyl hexanol, are rapidly absorbed. ... When administered orally, DEHP is extensively hydrolyzed in the gut in certain animals, e.g., rats, and is mainly distributed as monoethylhexyl phthalate. However, hydrolysis occurs to a much lesser extent in primates and humans. ... Several further metabolites have been identified, omega- and omega-1-oxidation being the major metabolic pathways. ... DEHP metabolism shows considerable species differences, e.g., the omega-oxidation pathway is less extensive in humans than in rats. ... Bile and urine are the major excretory pathways. ... Hepatomegaly and increased relative kidney weights have been observed in treated animals in long term studies ... also hypertrophic cells in the anterior pituitary. Several studies have shown testicular atrophy ... Younger rats seem to be more susceptible than older ones, and rats and mice seem to be more sensitive than marmosets and hamsters. Reversibility of the atrophy has been observed. ... DEHP, as well as monoethylhexyl phthalate, shows teratogenic properties. ... Tests for mutagenicity and related end points have been negative in most studies. DEHP may induce cellular transformation, and it has been shown to be carcinogenic ... in rats and ... in mice. There was a dose-related increase in hepatocellular tumors in both sexes of both species. The induction of hepatic peroxisome proliferation and cell replication is strongly associated with the liver carcinogenic effects of certain non-genotoxic carcinogens including DEHP. However, marked differences have been observed among animal species with respect to DEHP-induced peroxisome proliferation. ... DEHP metabolites do not produce peroxisome proliferation in cultured human hepatocytes. ... Only very limited information is available on the effects of DEHP on humans. Mild gastric disturbances, but no other deleterious effects, were reported for two subjects ... Although few relevant studies have been reported, the acute toxicity of DEHP to algae, plants, ... and birds appears to be low. studies have been reported, the acute toxicity of DEHP to algae, plants, ... and birds appears to be low. [R41] CARC: *Classification of carcinogenicity: 1) evidence in humans: no data; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/ [R42] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Orally administered DEHP produced significant dose-related increases in liver tumor responses in rats and mice of both sexes. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R43] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R44, 2002.28] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Esters and related compounds/ [R45] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 l/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R45] MEDS: *Consider the points of attack (eyes, upper respiratory system, skin, central nervous system) in preplacement and periodic physical examinations. [R46] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R37, 1979.23] HTOX: */Dialysis patients were examined for liver changes/ ... These patients were receiving approx 150 mg of DEHP per wk intravenously during their treatment. At 1 month, no morphological liver changes were observed by liver biopsy. At 1 yr, peroxisomes were described as being "significantly higher in number". No other observations were made. ... livers in dialysis patients compared with those of healthy individuals would be exposed to a greater number of blood contaminants at higher levels because of their impaired clearance abilities. There were no other data describing the effects of DEHP in humans other than those proposed as possible effects in persons receiving intravenous solutions. [R47] *... HUMAN DERMAL PATCH TESTING SHOWED NO IRRITATION OR SENSITIZATION. [R48, 3053] *IN TWO HUMAN VOLUNTEERS WHO INGESTED 5 and 10 G ... NO SYMPTOMS OCCURRED FROM 5-G DOSE AND ONLY MILD GASTRIC DISTURBANCES AND LOOSE STOOLS FROM LARGER DOSE. [R48, 3054] *OCCUPATIONAL EXPOSURE TO ATMOSPHERIC LEVELS OF 0.0006-0.01 PPM (0.001-0.016 MG/CU M) ... FOR 10-34 YR DID NOT INCREASE FREQUENCY OF CHROMOSOMAL ABERRATIONS IN BLOOD LEUKOCYTES. [R49] *DEHP showed no increases in chromosomal aberrations in human fetal lung cells or human leukocytes. ... [R50] *HUMAN BLOOD STORED UNDER STANDARD BLOOD BANK CONDITIONS (POLYVINYL-CHLORIDE PACKS) FOR 21 DAYS CONTAINED 0.15 UMOL (59 UG/ML) ... CONCN OF 0.10 UMOL (39 UG/ML) INHIBITED GROWTH OF CULTURED HUMAN DIPLOID FIBROBLASTS. [R51] *DEHP was identified in neonatal tissues after the insertion of umbilical catheters. Three infants who died of necrotizing enterocolitis had significantly higher DEHP values in the gut than infants not having this disorder. There was generally an increase in DEHP content of the tissue if the specific patient had received blood products. Residue levels were measured in both heart and gastrointestinal tissues. The average level of DEHP in heart tissue was 1.27 ug/g. In the gut of the three patients having died of gastrointestinal disorders, the levels ranged from 0.016 to 0.63 ug/g. [R52] *... A central nervous depressant if absorbed. /Phthalate acid esters/ [R24] *... The phthalates represent one of the lowest toxicity classes used in industry. /Phthalates/ [R48, 3047] *Two adults who swallowed 5 or 10 g DEHP experienced no untoward effects apart from mild gastric disturbances and moderate diarrhea with 10 g DEHP ... Three cases of nonspecific hepatitis were described among 27 hemodialysis patients with terminal renal failure. The PVC blood tubing used released DEHP at a concn of 10-20 mg/L of perfusate. The symptoms and signs of hepatitis disappeared rapidly when the use of tubing that did not contain DEHP was resumed ... . [R53] *In three pre-term infants artificially ventilated with PVC respiratory tubes, unusual lung disorders (opacification of the lung) were observed during the fourth week of life. It was assumed by the authors that these lung disorders were casually related to the exposure to DEHP released from the respiratory tubes ... . [R53] *In a study involving a Swedish PVC-processing factory, peripheral nervous system symptoms and signs were investigated among 54 male workers exposed mainly to DEHP, diisodecylphthalate, and some butylbenzylphthalate. The workers were divided into three groups of approx equal size and with mean phthalate exposure of 0.1, 0.2, and 0.7 mg/cu m. Some workers displayed various peripheral nervous system symptoms and signs, but these were not related to the level of exposure. None of the workers reported symptoms indicated work-related obstructive lung disease. Conventional lung function tests also showed no assoc with exposure ... However, several biochemical parameters showed significant assoc with exposure. There was a slight decr in the hemoglobin level with longevity of employment as well as with exposure in the last year. The serum alpha-1-antitrypsin level increased slightly with length of employment and the serum immunoglobulin A level rose with rising exposure during the last year ... . [R53] *IN A PRELIMINARY STUDY OF 150-250 WORKERS EXPOSED TO VAPORS IN AIR MIXTURES OF DIBUTYL PHTHALATE, DIETHYL PHTHALATE, AND DI-2-ETHYL HEXYL PHTHALATE, 19 PERSONAL AIR SAMPLES (COLLECTED IN THE BREATHING ZONE OF EMPLOYEES), 4 HR DURATION EACH, WERE TAKEN OVER 8 DIFFERENT DAYS AT A NUMBER OF LOCATIONS IN THE VICINITY OF THE OPERATIONS. THE RESULTS OF THE AIR ANALYSIS RANGED FROM 1-6 PPM, (8-15 MG/CU M). IN A DIAGNOSTIC, MULTIPHASIC TESTING OPERATION, NO PHTHALATES IN BLOOD WERE FOUND BEFORE AND AFTER THE PHTHALATE EXPOSURE, AND NO PERIPHERAL POLYNEURITIS WAS OBSERVED IN THE POPULATION. [R54] *COMPARATIVE TOXICITY OF PHTHALATE ESTERS TO HELA-S3 CELLS WAS STUDIED BY DETERMINING THEIR EFFECT ON DOUBLING TIME OF THE CELLS. THE TOXICITY OF THE ESTERS DECREASING IN ORDER: DIETHYL PHTHALATE, BUTYL PHTHALYL BUTYL GLYCOLATE, DI-ISO-BUTYL PHTHALATE, ETHYL PHTHALYL ETHYL GLYCOLATE, BIS(2-ETHYLHEXYL) PHTHALATE, DIMETHYL ISOPHTHALATE, DIBUTYL PHTHALATE, METHYL PHTHALYL ETHYL GLYCOLATE, DIMETHYL PHTHALATE, AND DIOCTYL PHTHALATE. [R55] NTOX: *IN 1-YR DOG FEEDING STUDY ... ADMIN ONCE A DAY IN CAPSULE FORM, @ 0.06 and 0.09 ML/KG/DAY. ... LOW GENERAL TOXICITY, WITH NO ORGAN WEIGHT DEVIATIONS /NOTED/. ONE EXCEPTION CONSISTED OF FATTY VACUOLIZATION AND CONGESTED AREAS IN LIVER AND CLOUDY SWELLING OF KIDNEY @ 0.09 LEVEL. LIVER FUNCTION TESTS WERE NEGATIVE. THUS A 0.06 ML/KG/DAY NO-EFFECT LEVEL WAS ESTABLISHED. [R48, 3054] *NEITHER DEHP NOR MONO(2-ETHYLHEXYL) PHTHALATE ADMIN IP FOR 5 DAYS AT 50 OR 100 MG/KG/DAY ALTERED ZN LEVELS OR DNA/RNA RATIOS IN MOUSE TESTES. EXTENDING THE TREATMENT (EVERY OTHER DAY FOR 20 DAYS) CAUSED SOME CHANGES IN ZN LEVELS IN ANTERIOR PROSTATES AND TESTES OF RATS. [R56] *IN FETUSES FROM RATS RECEIVING 0.5% OR 1.0% IN STOCK DIET, INCORPORATION OF (14)C-LABELED ACETATE AND MEVALONATE INTO C27 STEROLS, C30 STEROLS, AND SQUALENE FRACTIONS OF BRAIN TISSUE INCUBATED IN VITRO WAS REDUCED. INHIBITORY EFFECT ON LIPID METABOLISM IS TRANSMITTED ACROSS PLACENTAL BARRIER TO DEVELOPING FETUS AND ABNORMAL PATTERN OF LIPID METABOLISM IN RATS DELIVERED FROM BIS(2-ETHYLHEXYL) PHTHALATE-FED FEMALES IS ONLY PARTIALLY RESTORED TO NORMAL DURING SUCKLING PERIODS. [R57] *FEEDING NORMAL OR LOW PROTEIN DIETS CONTAINING DI-2-ETHYLHEXYL PHTHALATE (DEHP) @ 0.5% LEVEL TO YOUNG RATS FOR 10 DAYS RESULTED IN AN ENLARGEMENT OF LIVER AND SIGNIFICANT INCREASE IN HEPATIC PHOSPHOLIPIDS COMPARED WITH THOSE OF CONTROL RATS. THE PERCENTAGE OF PHOSPHATIDYLETHANOLAMINE IN RATS FED DEHP WAS INCREASED SIGNIFICANTLY, WHEREAS THAT OF PHOSPHATIDYLCHOLINE WAS DECREASED. [R58] *DEHP WAS FED TO RATS AND RABBITS FOR 4 WK @ 0.5% and 1.0%, RESPECTIVELY. IN RATS, BUT NOT RABBITS, DEHP FEEDING SIGNIFICANTLY REDUCED INCORPORATION OF LABELED MEVALONIC ACID INTO TOTAL STEROLS, DIGITONIN-PRECIPITABLE STEROLS AND SQUALENE. INHIBITION OF HEPATIC STEROLOGENESIS PREVIOUSLY OBSERVED WITH DEHP FEEDING IN RATS WAS ALSO OBSERVED IN RABBITS. DEHP FEEDING SIGNIFICANTLY REDUCED SERUM CHOLESTEROL IN RATS BUT NOT IN RABBITS. [R59] *DI(2-ETHYLHEXYL)PHTHALATE INCR THE AMT OF HEPATIC CYTOCHROME P-450, AND ACTIVITIES OF EPOXIDE HYDRATASE AND GLUTATHIONE S-TRANSFERASE, WHEN ADMIN INTRAGASTRICALLY TO RATS. [R60] *EMBRYOLETHAL AND TERATOGENIC EFFECTS IN SPRAGUE-DAWLEY RATS WERE ... DEMONSTRATED ... WITH IP INJECTIONS OF 5 OR 10 G/KG BODY WT ON DAYS 5, 10 and 15 OF GESTATION. SOME OR ALL OF THE FOLLOWING EFFECTS ... OBSERVED: RESORPTIONS, GROSS ABNORMALITIES, FETAL DEATH OR DECR FETAL SIZE. [R61] *... 6-WK-OLD B6C3F1 MICE WERE GIVEN DIETS CONTAINING 0 (CONTROL), 3000 OR 6000 MG/KG ... (GREATER THAN 99.5% PURE, WITH 2 IMPURITIES FOUND BY GLC) FOR 103 WK. /AFTER 105 WK/ ... LIVER-CELL TUMORS ... OBSERVED IN TREATED COMPARED WITH CONTROL ANIMALS. INCIDENCES OF HEPATOCELLULAR ADENOMAS IN CONTROL, LOW- AND HIGH-DOSE GROUPS WERE AS FOLLOWS: MALES- 6/50, 11/48 and 10/50; FEMALES- 1/50, 5/50 and 1/50, RESPECTIVELY. INCIDENCES OF HEPATOCELLULAR CARCINOMAS IN CONTROL, LOW- AND HIGH-DOSE GROUPS ... MALES- 9/50, 14/48 and 19/50; FEMALES- 0/50, 7/50 and 17/50, RESPECTIVELY. METASTASES OF HEPATOCELLULAR CARCINOMAS ... FOUND IN LUNGS OF 7 LOW-DOSE AND 5 HIGH-DOSE MALES AND OF 1 LOW-DOSE AND 7 HIGH-DOSE FEMALES. NO METASTATIC HEPATOCELLULAR CARCINOMAS OCCURRED IN LUNGS OF CONTROL MICE OF EITHER SEX. NO OTHER NEOPLASTIC LESION ... FOUND TO BE ASSOCIATED WITH TREATMENT. [R62] *... 5-6 WK OLD FISCHER 344 RATS. ... MAINTAINED ON DIET CONTAINING 6000-12,000 MG/K (PPM) ... FOR 103 WK. ... ANIMALS WERE KILLED @ 104-105 WK; NO DIFFERENCE IN SURVIVAL. ... OBSERVED BETWEEN TREATED AND CONTROL RATS. CHRONIC EXPOSURE...WAS ASSOCIATED WITH APPEARANCE OF LIVER-CELL TUMORS. INCIDENCES OF NEOPLASTIC NODULES IN CONTROLS, LOW- AND HIGH-DOSE GROUPS WERE ... MALES- 2/50, 5/49 and 7/49; FEMALES- 0/50, 4/49 and 5/50, RESPECTIVELY. INCIDENCES OF HEPATOCELLULAR CARCINOMAS IN CONTROLS, LOW- AND HIGH-DOSE GROUPS WERE ... MALES- 1/50, 1/49 and 5/49 FEMALES- 0/50, 2/49 and 8/50, RESPECTIVELY. NO OTHER NEOPLASTIC LESION OR TUMOR WAS FOUND TO BE POSITIVELY ASSOCIATED WITH TREATMENT. [R63] *... NO DEATHS IN MALE, ALBINO RATS GIVEN 30,000 MG/KG (APPROX 1.9 G/KG BODY WEIGHT/DAY) IN DIET FOR 90 DAYS, ALTHOUGH BODY WEIGHT GAIN WAS REDUCED ... AS WELL AS WITH 15,000 MG/KG; NO EFFECTS ... OBSERVED WITH 7500 MG/KG. THE ONLY PATHOLOGICAL LESION WAS TESTICULAR DEGENERATION. [R64] *THE MUTAGENIC/CARCINOGENIC ACTIVITY OF DEHP WERE STUDIED IN BACTERIA AND MAMMALIAN CELLS. DEHP DID NOT EXERT A DOSE-DEPENDENT DNA DAMAGING EFFECT TO BACILLUS SUBTILIS IN REC-ASSAY; HOWEVER, IT SHOWED MUTAGENIC ACTIVITY TO SALMONELLA TYPHIMURIUM TA-100 WITH AND WITHOUT S-9 MIXTURE /SRP: NOT CONFIRMED IN A NUMBER OF LABORATORIES/. TRANSPLACENTAL ADMIN OF DEHP TO SYRIAN GOLDEN HAMSTER EMBRYOS WAS CARRIED OUT BY ADMIN DEHP TO GRAVID ANIMALS ON DAY 11 OF GESTATION, FOLLOWED BY CULTIVATION OF EMBRYONIC CELLS FOR 15-20 DAYS. DEHP INDUCED 8AG/6TG-RESISTANT MUTATION, CHROMOSOMAL ABERRATIONS AND MORPHOLOGICAL TRANSFORMATION IN THE EMBRYONIC CELLS. [R65] *DEHP WAS MIXED WITH A DIET AT GRADED LEVELS OF 0.05, 0.1, 0.2, 0.4, and 1.0 WT% AND GIVEN TO PREGNANT MICE THROUGHOUT GESTATION. MATERNAL WT GAIN WAS SUPRESSED AND FETAL RESORPTIONS INCREASED AT 0.2, 0.4, and 1.0% DEHP. THE MAJOR MALFORMATIONS WERE NEURAL TUBE DEFECTS (EXENCEPHALY AND MYELOSCHISIS) WITH INTRAUTERINE GROWTH RETARDATION AND DELAYED OSSIFICATION. [R66] *DEHP showed no increases in chromosomal aberrations in Chinese hamster cells exposed in culture. [R67] *High doses of DEHP produces dominant and lethal antifertility effects in mice after a single intraperitoneal injection (12.8 ml/kg DEHP). [R67] *Pregnant rats were administered 4 ml/kg DEHP ip on days 3, 6 and 9 of gestation. At this dose level implantation was prevented in 4/5 rats. When the dose was reduced to 2 ml/kg, a similar response was observed in 4/5 rats. Adverse effects on parturition were produced in dams treated with DEHP, such as excessive bleeding, incomplete expulsion of fetuses and maternal deaths. [R68] *A concn of 4 ug/ml of DEHP in tissue culture media produced complete cessation of beating chick embryo heart cells. Up to 98-99% of the cells were dead within a 24 hr period. [R69] *DEHP solubilized with a surfactant and injected iv in rats produced lung involvement and death. [R70] *In chronic toxicity tests on rainbow trout, brook trout, fathead minnows, and channel catfish, the amount of vertebral collagen synthesis was found to decrease in the presence of bis(2-ethyl hexyl)phthalate. [R71] *Depressed reproduction occurred in the waterflea, Daphnia magna, at concn of 3, 10, and 30 ug/l of bis(2-ethylhexyl)phthalate. [R72] *In the Atlantic cod (Gadus morhua), the synthesis of steroid hormones such as testosterone and 11-ketotestosterone was affected by exposures as low as 1 mg/l. [R72] *Groups of male and female Fischer 344 rats and male and female B6C3F1 mice were fed diets contg. 6000 or 12000 (rats) or 3000 or 6000 (mice) mg DEHP/kg feed for 103 consecutive wk. ... Seminiferous tubular degeneration and hypertrophy of cells in the anterior pituitary were observed in male mice at 6000 mg/kg. ... Treatment with DEHP caused liver tumors in both sexes of mice and rats ... 20/57 hepatocellular carcinomas diagnosed in DEHP-treated mice (sexes and doses combined) had metastasized to the lung. Pulmonary metastases were not observed in the control mice or in any of the rats. [R73] *TWELVE PHTHALIC ACID ESTERS TESTED: MOST WERE 2-4 TIMES MORE TOXIC CHRONICALLY THAN ACUTELY IN MICE AFTER IP ADMIN. /PHTHALATE ACID ESTERS/ [R74] *Male F344 rats and female B6C3F1 mice were treated for 14 days with di(2-ethylhexyl)phthalate. Activities of enzymes responsible for the production (peroxisomal CoA oxidase (GSHPX)) of hydrogen peroxide were assayed in liver homogenates prepared from treated animals. The activities of the peroxisomal enzymes PCO (peroxisomal palmitoyl CoA oxidase) and Cat were enhanced 5 to 25 fold and 1.5 to 3 fold respectively by treatment with the peroxisome proliferator. The activity of GSHPX, a cytoplasmic enzyme, was decreased 40-60% in liver homogenates prepared from treated animals compared to control animals. A kinetic treatment of the rates of formation hydrogen peroxide by catalase was used to estimate steady-state hydrogen peroxide concentrations during peroxisomal oxidation of palmitoyl CoA. Increases in peroxisomal steady-state hydrogen peroxide for the F344 rat liver homogenates correlated well with the carcinogenic potential of di(2-ethylhexyl)phthalate. Increases in the steady-state hydrogen peroxide were also calculated for liver homogenates prepared from mice treated with these compounds. Decreases in liver lipid peroxidation were observed after treatment with di(2-ethylhexyl)phthalate in both species. [R75] *Di(2-ethylhexyl)phthalate (DEHP) is a peroxisome proliferator that was hepatocarcinogenic in female rats in a National Toxicology Program two year bioassay. However, DEHP was negative for promotional activity when tested using the same sex and strain of rat and dosing regimen that resulted in hepatocarcinogenicity. The carcinogenic response of peroxisome proliferators may be related to excess production of reactive oxygen species in the cell. No initiating activity was found when DEHP was administered in a single, oral dose (10 g/kg) or after 12 weeks of feeding at a dietary concentration of 1.2% when each was followed by a promotion regimen. There was no increased in number or mean volume of foci when liver sections were examined using multiple histologic markers and no tumors were identified. [R76] *In the present study, the effects of di(2-ethylhexyl) phthalate on choline-deficient diet-induced liver membrane lipid peroxidation were investigated in rats by determining the extents of conjugated diene formation. No evidence of lipid peroxidation was detected in the microsomal lipids of the liver after administration of DEHP at concn of 0.16% and 1%, respectively, for 1, 2, and 4 wk. When added to a CD diet, DEHP effectively protected against the diet-induced lipid peroxidation. There was an increase in cellular glutathione levels after 4 wk and an increase in catalase activity after 2 wk in the liver of rats fed DEHP. The levels of activity of the glutathione peroxidase and glutathione S-transferase were significantly reduced. [R77] */A study was conducted to determine/ subtle alterations in the cell morphology ... by means of image processing to evaluate the nuclei of hamster hepatocytes after treatment with di(2-ethylhexyl)phthalate given in single ip doses of 30, 300, and 3000 mg/kg. The results indicate that by using specially developed methods for analysis of images of cell nuclei and chromatin structure, it is possible to recognize changes eluding detection with usual light microscopy. [R78] *Chronic toxicity and carcinogenicity studies of cmpd containing a 2-ethylhexyl moiety, including DEHP were conducted in Fischer 344 rats and B6C3F1 (hybrid) mice. All of the 2-ethylhexyl-containing compounds studied possessed some hepatocarcinogenic activity, indicating that this moiety may have a propensity for causing hepatocarcinogenesis in mice, particularly those of the female sex. The 2-ethylhexyl compound that caused the greatest hepatocarcinogenic response in mice, DEHP was also hepatocarcinogenic in rats. Similarly, those with a relatively greater effect in female mice were also active in male mice. Thus, sex and species differences in 2-ethylhexyl- induced hepatocarcinogenesis in rodents are probably quantitative rather that qualitative in nature. [R79] *The mutagenic potential of di-2-ethylhexyl phthalate (DEHP) was tested in Salmonella typhimurium cultures using the Ames test procedure. The strains tested were TA98, TA100, TA1535, TA1537, TA1538, and TA2637, for base-pair substitution or frameshift type mutations. DEHP exhibited no mutagenicity in any of the strains of tested, with or without S9 metabolic activation. [R80] *Mono(2-ethylhexyl) phthalate (MEHP) one of the main metabolites of di(2-ethylhexyl) phthalate (DEHP) exerted embryo/fetotoxic effects similar to those of DEHP at lower doses. Oral administration of MEHP (1 ml/kg) to the mice on day 7, 8, or 9 of gestation resulted in < 32% of live fetuses, all of which were deformed. When DEHP (10 ml/kg) was given to the pregnant mice on day 8 of gestation, approximately 0.03% and 0.003% of the administered dose was found in fetuses as DEHP and MEHP, respectively, after 12 hr. The presence of the MEHP in fetuses is probable due to the transplacental crossing of the MEHP formed in the maternal body, since the fetuses of mice up to day 9 of pregnancy showed no hydrolysis of DEHP to MEHP. Crossing of MEHP through the placenta was proven by an experiment in which MEHP was administered in pregnant mice. A single injection of MEHP (25 or 50 mg/kg), but not DEHP (500 mg/kg) into pregnant mice, induced high incidence of somatic mutations in the coat hair of offsprings; thus MEHP could be responsible for the embryotoxic fetotoxic effects observed with DEHP. [R81] *The carcinogenic effects of di(2-ethylhexyl)phthalate, including its potential as an initiator and as a promoter of carcinogenesis, were studied in mouse liver and skin and in rat liver in vivo, and in mouse epidermis-derived JB6 cells in vitro. A mouse model for liver initiation and promotion involved initiation by injection of N-nitrosodiethylamine (DEN) ip into male B6C3F1 mice at 4 wk of age, followed by exposure to either di(2-ethylhexyl)phthalate in the diet (3000, 6000, or 12,000 ppm) or phenobarbital in the drinking water (500 ppm), beginning 1-2 wk later and continuing for periods of from 1 day to 18 months. Female F344/NCr rats were subjected to a similar protocol in which promotion continued for 14 wk. Di(2-ethylhexyl)phthalate promoted focal hepatocellular proliferative lesions, including hyperplastic foci and neoplasms initiated by DEN in mice but not in rats. Skin-painting studies in female CD-1 or Sencar mice involved initiation by a single topical exposure to DMBA applied to the dorsal skin, followed by repeated percutaneous exposure to a tumor promoter, either di(2-ethylhexyl)phthalate or TPA. To test for two stage skin tumor promotion, Sencar mice were initiated with DMBA and then TPA was administered for only 2 wk, after which di(2-ethylhexyl)phthalate was subsequently administered for 26 wk. Di(2-ethylhexyl)phthalate displayed very weak complete promoting activity and definite second stage promoting activity in Sencar mouse skin, but was inactive on CD-1 mouse skin. [R82] *Di(2-ethylhexyl)phthalate (DEHP) depressed serum cholesterol (40%) and proliferated hepatic mitochondria (100%) when administered in the diet (2%, w/w) to the rat. Microsomes isolated from the livers of animals administered DEHP showed lowered specific activity of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (50%). The incorporation of acetate but not of mevalonate into hepatic cholesterol was decreased (52%) in these animals. The release of bile acids was greatly enhanced (100%), and the activity of cholesterol 7-alpha-hydroxylase, the regulatory enzyme in the pathway of bile acid formation, was stimulated (70%) on DEHP administration. [R83] *The oral and ip administration of di(2-ethylhexyl) phthalate (DEHP) to the marmoset monkey at doses up to 5 mmole DEHP/kg body weight/day for 14 days did not induce morphological or biochemical changes in the liver or testis comparable with those obtained in rats given the same amount of DEHP. [R84] *Rats were orally administered (14)C di(2-ethylhexyl) phthalate (DEPH) or (14)C mono(2-ethylhexyl) phthalate (MEHP) at doses of 50 and 500 mg/kg for 3 consecutive days. Urine was collected at 24 hr intervals, and metabolite profiles were determined. After a single dose of either compound, urinary metabolite profiles were similar to thise previously reported. However, after multiple administration of both DEHP and MEHP at 500 mg/kg, increases in omega-/beta-oxidation products, mono(3-carboxy-2-ethylpropyl) phthalate, and mono(5-carboxy-2-ethylpentyl) phthalate, and decreases in omega-1-oxidation products, mono(2-ethyl-5-oxohexyl) phthalate, were seen. [R85] *Male rats were fed diets containing either 0.5% clofibric acid or 2% DEHP for 2 yr. Both compounds produced liver enlargement which was accompanied by the formation of liver nodules. Hepatic peroxisomal and microsomal fatty acid oxidizing enzyme activities were induced in both large nodules and host tissue (ie tissue remaining after removal of large nodules) preparations from clofibric acid and DEHP-treated rats. Increased lipid peroxidation was observed by measurement of conjugated dienes in host tissue homogenates from clofibric acid and DEHP-treated rats. Microsomal NADPH-dependent lipid peroxidation was also stimulated. Histological examination revealed extensive lipofuscin deposition in nonnodular, but not in nodular, tissue sections from treated rats. [R86] *The subcutaneous administration of 1-10 mg of undiluted di(2-ethylhexyl)phthalate (DEHP) to adult male ICR mice on day 1, 5, and 10 was followed by mating, one to one, with untreated adult virgin females. A single mating at day 21 resulted in a reduction in the incidence of pregnancies in the DEHP-treated groups. On the other hand, repeated matings with fresh females starting on day 2, 6, 11, 16, and 21, and at weekly intervals through 8 wk, revealed no perceptible effect of DEHP on the incidence of pregnancy. Examination of surgically exposed uteri and ovaries of pregnant females on day 13 of gestation revealed an increase in the incidence of preimplantation losses and early fetal deaths in the DEHP-treated groups; consequently, there were fewer viable fetuses per pregnancy. [R87] *The effects of DEHP on sperm morphology and peripheral blood mironuclei were studied for 12 wk following 5 subacute ip injections of DEHP at 1/6, 1/12, and 1/60 of the LD50 day. Sperm morphology was examinied in adult mice and rats, whereas peripheral blood micronuclei were scored in mice up to 4 wk after treatment. In mice, DEHP at 1/6 LD50 significantly depressed body weight gain for up to 12 wk after treatment, and reduced epididymal sperm number by 4 wk. Numbers of morphology abnormal sperm did not differ from controls in the 12 wk following treatment. In addition, DEHP did not increase the numbers of peripheral blood micronuclei. Studies in the rat indicated that exposure to doses of 1/6 and 1/12 of the LD50/day of DEHP resulted in a reduced gain in body weight compared to controls. Testis weight, sperm number, and numbers of morphology abnormal sperm were unaffected by DEHP following treatment. [R88] *A 3-day-old neonatal rat model was used to assess the toxicity of DEHP following subchronic administration by iv route. The administration of DEHP (164.8 mg/kg for 18 days) resulted in a small but significant increase in liver weight and serum aspartate aminotransferase activity. However, no conclusive histopathological alternations could be discerned between livers from DEHP and normal saline (control) animals. [R89] *The plasticizer bis(2-ethylhexyl) phthalate (BEHP) was administered to male rats at doses of 2, 0.2, and 0.02% in the diet for two years (number and strain of rats not given) and effects on the liver were studied. Electron micrographs of the liver showed an alteration in size and structure of the peroxisomes and induction of mitochondria. The rate of protein synthesis in mitochondria and microsomes, as monitored by radiolabeled leucine, was found to increase; the average half-life of mitochondrial proteins increased from about 6 days to about 25 days. The enzymes, cyanide-insensitive palmitoyl-CoA dehydrogenase and carnitine acetyltransferase, were induced in the liver and increased continuously over the treatment period. At the highest dose level, microsomal cytochrome P-450 initially increased and then decreased to the initial level during prolonged treatment. The lipid, dolichol, increased in mitochondrial-lysosomal fractions, and the phosphorylated form, dolichol-P, decreased substantially. Glycosyltransferase activities in liver microsomes were diminished. Of several metabolites of BEHP, only mono(2-ethylhexyl)phthalate effectively induced peroxisomal beta-oxidation. [R90] *At high dose levels, di-2-ethylhexylphthalate impairs fertility in the male rat and mouse by causing degeneration of the seminiferous tubules in the rat and by depleting gonadal zinc in both mouse and rat. ... Mono-2-ethylhexylphthalate ... a major metabolite of di-2-ethylhexylphthalate, alters the uptake of zinc by rodent gonads and accessory sex organs. In culture, mono-2-ethylhexylphthalate also causes the separation of the germ cells from Sertoli cells. The decreases in zinc levels lead to the speculation that this is the causative factor for the changes observed in the male reproductive tract after phthalate treatment. However, the coadministration of zinc with di-2-ethylhexylphthalate does not prevent testicular atrophy in young male rats. Coadministration only increases the zinc levels in the liver and serum but not in the testes. [R91, 290] *Doses of 3.4 g/kg bw/day give by gavage (in olive oil) for periods of up to 90 days caused the death of 15/20 rats ... However, no deaths were reported among rats fed 3% DEHP in the diet (1.9 g/kg bw) for 90 days ... or in a rat study ... after dietary dosing (< or = 50 g/kg) for 14 days ... . [R92] *Oral admin of DEHP at a rate of > or = 0.4 g/kg body weight/day resulted in a weight gain decr in rats within a few days ... In a 17-wk feeding study where rats were given 2, 10 or 20 g DEHP/kg diet, a decreased bw was observed ... Reduction in bw was also observed in rats given dietary levels of 12.5 or 25 g/kg for 13 weeks. Dosages of 1.6-6.3 g/kg resulted in either slight elevations of body weight or no effect ... Reductions in hemoglobin, packed cell volume and erythrocyte numbers were observed in rats given 10 or 20 g DEHP/kg diet for 17 wk, but not when they were given 2 g/kg for the same period ... Cystic kidneys and centrilobular necrosis were noted in one strain of mice (ddY) fed 2.5 or 25 g DEHP/kg for 2 weeks, but not in another strain (B6C3F1), even with a higher exposure level and a longer exposure period ... . [R92] *DEHP administered iv at a rate of 25-500 mg/kg/day for 2-4 weeks to beagle dogs resulted in pulmonary hemorrhage and inflammatory response similar in appearance to the "shock-lung" effect ... . [R92] *In an inhalation study, Wistar rats were exposed in a head-nose inhalation system to DEHP aerosols of respirable particle size. Exposure duration was 6 hr/day, 5 days/wk for 4 wk at target concn of 0, 0.01, 0.05, and 1.0 mg/L. A statistically significant incr in relative lung weights was found in the males given the highest dosage, and this was accompanied by foam cell proliferation and thickening of the alveolar septa ... . [R92] *Liver mitochondrial enzymes and mitochondrial morphology have been reported to be influenced by DEHP admin ... Recent results suggest that the in vitro effects of DEHP (> or = to 20 umol/L) on mitochondrial functions are mainly related to the action on membrane lipids surrounding the adenine nucleotide translocator, which reduces the rate of adenine nucleotide exchange across the mitochondrial membrane ... . [R93] *... the renal effects of DEHP given by gavage to young male rats at a dosage of 2.14 mg/kg bw three times/wk for up to 12 mo. A 50% reduction in creatinine clearance and an incr in the severity of renal cyst formation was observed. This lesion was consistent with spontaneous nephropathy commonly observed in old rats; exposure may cause an onset in younger rats. Furthermore, DEHp fed at 6 and 12 g/kg diet for 2 yr did not produce renal lesions in male and female F-344 rats ... . [R94] *Seminiferous tubular atrophy, comprising a loss of spermatids and spermatocytes, occurred when 4-wk-old Wistar rats were given 2800 mg DEHP/kg by oral intubation for 10 days ... In similarly treated 10-wk-old rats, about 50% of the tubules were atrophic and the remainder unaffected. However, no testicular damage was detected in treated 15-wk-old rats. When 20 g DEHP/kg was given in the diet (approx 1200 mg DEHP/kg/day) to 4-wk-old rats, the lesions produced were reversible whether treatment stopped before or continued until after the control rats had reached sexual maturity. [R95] NTOX: *In rats given 10 or 20 g DEHP/kg diet, the testis atrophy was dose dependent after approx 2 weeks of feeding. This atrophy was accompanied by pituitary changes, i.e., enlargement and vacuolization of the basophils of the pars distalis, corresponding to the formation of the so-called castration cells seen after gonadectomy ... In a subsequent study, there was a reduction in testicular and prostatic zinc levels concomitant with incr urinary excretion of zinc ... . [R95] *In a rat study ... the serum testosterone levels in rats fed 20 g DEHP/kg diet were reduced by approx 50%. The total amount per testis decr, but the concn rose to 150% of the original value because of the testicular atrophy. Simultaneous admin of testosterone of zinc had no protective effect on the atrophy but did prevent the weight reduction of the sex organs such as the epididymis ... In a further study, it was found that a low-zinc diet aggravated the DEHP-induced testicular atrophy ... . [R95] *In a study ... on female Wistar rats given 0.34 or 1.7 g DEHP/kg by gavage during the first 21 days of gestation, the only untoward effect was a reduction in fetal body weight. When DEHP (0, 5, 10, 15 or 20 g/kg) was admin orally to Fischer-344 rats on gestational days 0 to 20, maternal toxicity and reduced fetal body weight per litter were observed at the three highest dose levels. The number of fetuses/litter was unaffected by the treatment ... . [R96] *Ip injections of 4.93 or 9.86 g DEHP/kg on days 5, 10, and 15 of gestation resulted in an incr in the number of resorptions and reduced fetal weight in Sprague-Dawley rats ... In the highest-dose group, gross abnormalities, such as twisted hind legs and anophthalmia, were noted but no skeletal defects were observed. [R97] *Many studies have been performed using a variety of strains of Salmonella typhimurium and DEHP doses of up to 10 mg/plate. Incubations both with and without exogenous activation systems have been performed. S9 mix from rats induced by Aroclor 1254 has frequently been used, but other species and other inducers have also been used to produce metabolic activation systems. With one exception ... these test results have all been negative ... and in a IPCS collaborative study ... all five laboratories reported negative results. Bacteria other than S. typhimurium have also been used; negative results were obtained with E. coli WP2 at doses of up to 2 mg/plate ... . [R98] *Negative results were obtained when pooled urine from rats, treated with 2000 mg DEHP/kg/day for 15 days, was tested for genotoxic activity. A direct plating procedure was used with S. typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, both with and without S9 and beta-glucuronidase/aryl sulfatase as the activation system. When 2-ethylhexanol was tested according to the same protocol, the result was also negative ... . [R99] *The induction of mutations by DEHP has been studied in various fungal species. In the IPCS collaborative study on in vitro assay systems ... DEHP was considered to be negative in 6/7 assays. Positive results were obtained with Saccharomyces cerevisiae, both with and without S9 activation, at lowest effective concn of 1541 mg/L and 3081 mg/L, respectively. However, other laboratories using different strains of S. cerevisiae or Schizosaccharomyces pombe reported negative results at a max tested concn of 5000 mg/L. [R99] *Mouse lymphoma cells (L5178Y), Chinese hamster V79 cells, and human lymphoblasts have been used to study the mutagenic effect of DEHP in cultured mammalian cells. ... Mouse lymphoma cells were exposed to DEHP without S9, and two concn (7.5 and 20 mg/L) gave positive results. In a separate study ... where MEHP, 2-ethylhexanol, and DEHP were tested in the mouse lymphoma cell assay, all three substances were found to be non-mutagenic. The concn used were 0.016-1.0 mL/L (without S9) and 0.067-5.0 mL/L (with S9) for DEHP, and 0.013-1.0 mL/L for MEHP and 2-ethylhexanol. [R100] *DEHP has also been tested for mutagenicity in Drosophila melanogaster using the sex-linked recessive lethal (SLRL) test and various somatic recombination and mutation assays. SLRLs were not induced by DEHP (20 ug/g) administered by injection ... Negative results for DEHP were also reported in the SLRL mutation assay on Drosophila melanogaster larvae ... DEHP gave a positive response in the unstable eye mosaic test at a dose of 6.1 g/L, in two separate experiments, but neither lower nor higher concn produced any response. No activity was seen in the wing spot test with a single dose of 6.1 g/L. It was concluded that DEHP exhibits marginally positive mutagenicity ... . [R100] *Various end-points, such as unscheduled DNA synthesis (UDS) and single strand breaks, have been used to detect DNA damage induced by DEHP in a variety of mammalian test systems. ... negative results were obtained when single strand breaks were measured, either by alkaline elution in hepatocytes (up to 3.907 g/L) or alkaline sucrose sedimentation in CHO cells (up to 39 g/L). UDS in either isolated hepatocytes or cultured HeLa cells was investigated by four different laboratories. One investigator detected a positive response using isolated hepatocytes, but, since this result was only statistically significant at one dose and not dose related, the consensus was that DEHP does not cause UDS. [R100] *The carcinogenicity of DEHP in rats has been confirmed in two further studies ... /one of which/ found a 78.5% incidence in a group of 14 male Fischer-344 rats fed a diet containing 20 g DEHP/kg for up to 108 wk, whereas the incidence in the 10 controls was 10%. .../another study/ found either hepatocellular carcinomas or neoplastic nodules in 6/20 animals after female Fischer-344 rats were exposed for 2 yr to a diet containing 12 g/kg. [R101] *DEHP has been investigated in two life-time studies on Syrian hamsters ... In one study, groups of 25 male and 25 female 6-wk-old hamsters were assigned to each of six groups: untreated control; 3 g DEHP/kg bw given ip once/wk for 18 weeks; the same dose once every 2 wk for 18 wk; the same dose once every 4 wk for 32 wk; the same dose once every 4 wk for 32 wk plus N-dimethyl nitrosamine (NDMA) at 1.67 mg/kg bw given orally once/wk; and the same dose of NDMA without DEHP treatment. NDMA incr the tumor rate for malignant liver tumors, mainly hemangioendotheliomas. Co-administration of DEHP with NDMA neither incr nor decr the tumor rates. No significant differences of tumor rates were observed in groups treated with DEHP alone compared with controls. [R102] *... also investigated the life-time, whole-body exposure of Syrian hamsters to DEHP vapor alone in air or in combo with orally administered NDMA. The low doses of DEHP (15 ug/cu m, resulting in a total exposure of about 7.5 ug/kg bw) in this study render it inadequate for the assessment of the long-term effects of DEHP alone. In combo with NDMA, this low level of DEHP was assoc with highly significant (P < 0.001) decr in hepatic hemangioendothelioma and fibrosarcomas combined in males and females combined. This unexpected result should be further investigated to evaluate its significance. [R103] *DEHP has been shown to be a weak irritant to mammalian skin when admin topically or intradermally (0.2 mL of an emulsion of 100 g/L) ... no irritation occurred when undiluted DEHP was instilled into the eye of rabbits. [R36] *... Weanling male B6C3F1 mice ... received a single ip injection (80 mg/kg) of diethylnitrosamine (DEN) at 4 weeks of age, followed by oral administration of phenobarbital or DEHP ... for up to 6 months. Phenobarbital was administered in drinking water at 500 ppm and DEHP in the feed at 3,000, 6,000 or 12,000 ppm. ... Few foci were seen at 2,4 or 6 months in mice exposed to DEN, phenobarbital or DEHP alone, while numerous foci and neoplasms were seen in mice given DEHP or phenobarbital after DEN. ... Foci and tumors appeared earlier in mice given higher dietary levels of DEHP than in those given lower doses ... in DEHP-exposed mice, basophilic foci and neoplasms predominated; ... more malignant in appearance than neoplasms in phenobarbital-exposed mice. [R104] *The plasticizer bis(2-ethylhexyl) phthalate (BEHP) was administered to male rats at doses of 2, 0.2, and 0.02% in the diet for two years (number and strain of rats not given) and effects on the liver were studied. Electron micrographs of the liver showed an alteration in size and structure of the peroxisomes and induction of mitochondria. The rate of protein synthesis in mitochondria and microsomes, as monitored by radiolabeled leucine, was found to increase; the average half-life of mitochondrial proteins increased from about 6 days to about 25 days. The enzymes, cyanide-insensitive palmitoyl-CoA dehydrogenase and carnitine acetyltransferase, were induced in the liver and increased continuously over the treatment period. At the highest dose level, microsomal cytochrome P-450 initially increased and then decreased to the initial level during prolonged treatment. The lipid, dolichol, increased in mitochondrial-lysosomal fractions, and the phosphorylated form, dolichol-P, decreased substantially. Glycosyltransferase activities in liver microsomes were diminished. Of several metabolites of BEHP, only mono(2-ethylhexyl)phthalate effectively induced peroxisomal beta-oxidation. [R90] *A continuous breeding protocol was utilized to examine the reproductive toxicity of three phthalate esters. CD-1 mice were given diets with either di-n-propyl phthalate (DPrP: 0.0, 1.25, 2.5, or 5.0%), di-n-pentyl phthalate (DPP: 0.0, 0.5, 1.25, or 2.5%), or di-n-octyl phthalate (DOP: 0.0 1.25, 2.5, or 5.0%). Both male and female mice (20 pairs per treatment group, 40 pairs of control animals) were dosed for 7 days prior to and during a 98-day cohabitation period. Reproductive function was evaluated during the cohabitation period by measuring number of litters per pair, live pups per litter, and pup weight. There was no apparent effect on reproductive function in the animals exposed to di-n-octyl phthalate at dose levels sufficient to cause a significant increase in liver weight. Both di-n-propyl phthalate and di-n-pentyl phthalate were toxic to the reproductive system as evidenced by a complete inhibition of fertility at 1.25 and 2.5% di-n-pentyl phthalate or 5.0% di-n-propyl phthalate, and reduced fertility (litters/pair and live pups/litter, 0.5% di-n-pentyl phthalate; live pups/liter, 2.5% di-n-propyl phthalate). Toxicity of di-n-pentyl phthalate had a strong male component and female component, whereas di-n-propyl phthalate was more toxic to the female than the male reproductive system. Di-n-pentyl phthalate and di-n-propyl phthalate treatment was associated with decreased body weight, increased liver weight, decreased testis and epididymis weights, decreased epididymal sperm concentration, and elevated seminiferous tubule atrophy. A comparison of seven phthalate esters tested using this continuous breeding protocol indicates the relative order of reproductive toxicity as diethylhexyl, dihexyl, dipentyl, dibutyl, dipropyl; diethyl and dioctyl are nontoxic. [R105] *The short term effects of di(2-ethylhexyl)-phthalate (DEHP), di-(n-hexyl)-phthalate (DnHP) and di-(n-octyl)-phthalate (DnOP) were studied in rats. Male Wistar albino rats were used in the experiments. Groups of animals were fed diets containing 20 g/kg of diet of either di(2-ethylhexyl)-phthalate, di-(n-hexyl)- phthalate, or di-(n-octyl)-phthalate for a period of 3 weeks. Animals were inspected daily, and were sacrificed 3, 10, and 21 days after the beginning of treatment. The liver and genital apparatus were removed and weighed. Portions of the liver and kidney were prepared for electron microscopy. Another portion of the liver was used for biochemical studies. This portion was homogenized and centrifuged to isolate the microsomal pellet which was resuspended and used for enzymic and chemical estimations of glucose-6-phosphatase, 5'-nucleotidase, succinate-dehydrogenase catalase, cytochrome p450, and cyanide insensitive palmitolyl CoA oxidation. Animals treated with di(2-ethylhexyl)-phthalate gained slightly less weight and showed markedly enlarged livers compared to the animals in the other groups. Treatment with both di-(n-octyl)-phthalate and di-(n-hexyl)-phthalate resulted in slight, but statistically significant, liver enlargement. No gross changes were noted in the kidneys or pancreas of the treated animals. Animals treated with di(2-ethylhexyl)-phthalate showed both a reduction in weight and an atrophy of the testes. Electron microscopy of livers from rats treated for 3 days with di(2-ethylhexyl)-phthalate showed marked changes, especially in the peroxisomes and in the mitochondria. Different changes were noted in livers of animals treated with di(n-hexyl)-phthalate and di-(n-octyl)-phthalate. Many of the enzyme activities were markedly changed by the treatments. The authors conclude that the short term effects of rat liver of di(2-ethylhexyl)-phthalate administration differ markedly from the effects of its straight chain analogs di-(n-hexyl)-phthalate and di-(n-ocytl)-phthalate. [R106] *In a continuous breeding protocol COBS-Crl:CD-outbred-albino-mice were fed diets containing diethyl phthalate (DEP), di-n-butyl-phthalate (DBP), di-n-hexyl-phthalate (DHP), or di(2-ethylhexyl)phthalate (DEHP) to determine the reproductive effects of these compounds. The following levels of the phthalic acid esters were used: diethyl phthalate, 0.25, 1.25, or 2.5%; di-n-butyl-phthalate, 0.03, 0.3, or 1.0%; di-n-hexyl-phthalate, 0.3, 0.6, or 1.2%; di(2-ethylhexyl)phthalate , 0.01, 0.1, 0.3%. The number of fertile matings was adversely affected by the highest dose levels of di-n-butyl-phthalate, di-n-hexyl-phthalate and di(2-ethylhexyl)phthalate. Some decrease in body weight gain was noted for the top dose levels of di-n-butyl-phthalate and di-n-hexyl phthalate, but not di(2-ethylhexyl)phthalate. At dose levels where fertile matings occurred, a decrease was noted either in the number of live pups per litter or in the proportion of pups born alive. Diethyl phthalate caused decreased body weight gain, but did not affect reproduction. While diethyl phthalate did not affect fertility in the first generation, it was associated with decreased litter size in the second generation. Di-n-hexyl-phthalate and di(2-ethylhexyl)phthalate decreased epididymal sperm concentration, increased the percentage of abnormal sperm, and decreased percentages of motile sperm. The failure of di-n-butyl-phthalate to produce significant adverse effects in male mice fertility seems to be a species/specific response. [R107] *... Oral administration of di(2-ethylhexyl)-phthalate led to decreased testicular weight and associated histological changes within the seminiferous tubules, and depletion of germinal epithelium to only Sertoli cells, spermatogonia and a small number of spermatocytes. ... Similar pathobiologic effects were associated with administration of d-n-pentyl-phthalate, di-n-hexyl-phthalate, and particularly di-n-butyl-phthalate. These phthalates were found to be metabolized in vivo to their corresponding monoesters by nonspecific esterases in the intestinal mucosa and other tissues. Such monoesters also were effective in producing testicular damage in exposed rats. Phthalates induced increased urinary zinc excertion and a reduced level of this element within testicular tissue. ... [R108] *The effects of phthalic acid esters on concentrations of testosterone and zinc in testicular tissues were studied. Young male Wistar rats were fed diets containing 2% dimethyl, diethyl, di-n-butyl, di-iso-butyl (DIBP), di-n-octyl (DOP), di-2-ethylhexyl phthalate, or o-phthalic acid for one week. The animals were then killed, samples of blood were collected, and the fresh weights of the testes, liver, and kidneys were obtained. ... Testicular weights were decreased in rats fed di-n-butyl, di-iso-butyl and di-2-ethylhexyl phthalates. Rats treated with di-n-butyl, di-iso-butyl or di-2-ethylhexyl phthalate had decreased zinc concentrations in the testes and liver, while di-n-octyl-treated rats had decreased zinc concentrations ... were found in the serum and tested of dimethyl, and diethyl, treated rats, while testosterone levels were significantly increased in the testes of rats fed di-n-butyl, di-iso-butyl and di-2-ethlyhexyl phthalate. [R109] *Eight phthalic acid esters were studied in a rat teratogenicity study. The esters included dimethyl, dimethoxyethyl, diethyl, dibutyl, diisobutyl, butyl carbobutoxymethyl, dioctyl and di-(2-ethylhexyl) phthalates. For all the esters, except two, the dose administered intraperitoneally to pregnant female rats was 1/10, 1/5, or 1/3 the acute LD50. For these esters, the doses /administered undiluted/ ranged from a low of 0.305 ml/kg for dibutyl phthalate to a high of 2.296 ml/kg for butyl carbobutoxymethyl phthalate. Di-(2-ethylhexyl) phthalate and dioctyl phthalate were given at doses of 5 and 10 ml/kg because of their very low acute toxicity. Control groups included: untreated rats, treated with 10 mg/kg of distilled water, rats treated with 10 ml/kg of normal saline and rats treated with 10 ml/kg and 5 ml/kg of cottonseed oil. All treatments took place on days 5, 10, and 15 of gestation. On the 20th day, all rats were sacrificed and the uterine horns and ovaries were surgically exposed to permit counting and recording of the number of corpora lutea, resorption sites, and viable and dead fetuses. Additionally, both viable and nonviable fetuses were excised, weighed, and examined for gross malformation. Thirty to fifty percent of the fetuses (using those which showed no gross malformation when possible) were prepared as transparent specimens to permit visualization of skeletal deformities. All of the esters produced gross or skeletal abnormalities which were dose related. The most common gross abnormalities in the treated animals were absence of tail, anophthalmia, twisted hands and legs, and hematomas. Skeletal abnormalities included elongated and fused ribs (bilateral and unilateral), absence of tail bones, abnormal or incomplete skull bones, and incomplete or missing leg bones. Dead fetuses were found in the groups treated with dimethyl, dimethoxyethyl, and diisobutyl phthalates. The most embryotoxic agent in the series was dimethoxyethyl phthalate. Each of the esters also reduced the weight of the fetuses when compared to the controls. Even at the high dose levels (5 and 10 ml/kg), di-2-ethylhexyl and dioctyl phthalates had the least adverse effects on embryo/fetus development. [R110] *Seven phthalate esters of different chain lengths and degrees of branching were evaluated for their ability to induce peroxisomes in the livers of Fischer-344 rats. The esters included di(2-ethylhexyl)phthalate, butyl(benzyl)phthalate di(n-butyl)phthalate, di(isodecyl)phthalate, di(isononyl)phthalate, di(undecyl)phthalate, di(n-hexyl,n-octyl,undecyl) phthalate, and di(heptyl,nonyl,undecyl)phthalate. Each of the compounds was fed to groups of five male and five female rats in the diet at concentrations of 2.5, 1.2, and either 0.6 or 0.3 percent for a period of 21 days. Cyanide insensitive palmitoyl-CoA oxidation, lauric-acid-11-hydroxylase, and lauric-acid-12-hydroxylase were assayed in the liver microsomes. Cholesterol and triglyceride concentrations were measured in the serum. The results indicated that none of the esters was more potent than di(2-ethylhexyl) phthalate. The most sensitive parameters were relative liver weight and cyanide insensitive palmitoyl-CoA oxidation. The latter parameter was assumed to be an indicator of peroxisome proliferation and thereby predictive of liver tumorigenesis. [R111] *In cultured hepatocytes, as in vivo, mono-2-ethylhexyl phthalate (MEHP) and its straight chain analogues mono-n-hexyl phthalate (MnHP) and mono-n-octyl phthalate (MnOP) each cause accumulation of lipid but only mono-2-ethylhexyl phthalate produces significant induction of peroxisomal fatty acid oxidizing enzymes. To elucidate the mechanisms underlying this lipid accumulation ... the effects of these phthalates and the drug clofibric acid on fatty acid metabolism in suspensions of isolated hepatocytes /was investigated/. The effects were found to be markedly dependent on the nutritional state of the animals from which the hepatocytes were isolated. In hepatocytes isolated from animals fasted overnight, or animals fed ad libitum but killed at approximately 2:30 PM, mono-2-ethylhexyl phthalate, mono-n-hexyl phthalate, mono-n-octyl phthalate and clofibric acid each caused a marked rapid stimulation of fatty acid oxidation and the synthesis of triglycerides in hepatocytes when incubated in Hanks saline. Export of very low density lipoprotein (VLDL) from the cells was either unchanged or somewhat reduced. In contrast, in hepatocytes isolated from rats fed ad libitum but killed at approximately 9:30 AM mono-2-ethylhexyl phthalate and clofibric acid did not alter fatty acid oxidation or triglyceride synthesis, while mono-n-octyl phthalate and mono-n-hexyl phthalate increased triglyceride synthesis but decreased fatty acid oxidation. The effects of fasting were largely abolished by incubations of the cells in a complete tissue culture medium (Liebowitz L-15). The results suggest that mono-2-ethylhexyl phthalate and its straight chain analogs can, either as the free acid or the CoA ester, mimic the action of fatty acids in the allosteric regulation of fatty acid metabolism. [R112] *Male Sprague-Dawley rats were subjected to two-thirds partial hepatectomy which was followed 18 hr later by an intraperitoneal injection of diethylnitrosamine (DEN) at a dose of 30 mg/kg. Di(2-ethylhexyl)phthalate (DEHP) was added to the diet at 0.5%. Mono(2-ethylhexyl)phthalate (MEHP) and 2-ethylhexanol (2-EH) were added at equimolar levels with di(2-ethylhexyl)phthalate. Di-n-octyl-phthalate (DOP) was added to 1%. The development of gamma-glutamyl-transpeptidase positive (GGT+) foci was strongly induced by di-n-octyl-phthalate in the livers of rats that had received a subcarcinogenic dose of diethylnitrosamine. None of the other compounds showed any tumor promoting activity. The development of gamma-glutamyl-transpeptidase positive preneoplastic foci in livers of rats was neither enhanced nor suppressed when rats were fed a dose equimolar to 0.5% di(2-ethylhexyl)phthalate. An elevated carnitine acetyltransferase (CAT) level was found following treatment with mono(2-ethylhexyl)phthalate or di(2-ethylhexyl)phthalate. Mono(2-ethylhexyl)phthalate significantly decreased liver gamma-glutamyl-transpeptiase activity. In addition mono(2-ethylhexyl) phthalate lowered the mean number of foci/square centimeter below that of the 2-ethylhexanol treated group. /It was found/ that di-n-octyl-phthalate can act as a tumor promoter, and this activity seems to be unrelated to liver peroxisome proliferation (as measure by carnitine acetyltransferase). [R113] *Di(2-ethylhexyl) phthalate tested negative to sex-linked recessive lethal for heritable genetic effects in Drosophila in FY1985. [R114] *Di(2-ethylhexyl) phthalate tested negative to sister chromatid exchanges for cytogenetic effects in chinese hamster ovary cells in FY1985. [R115] *A bioassay of di(2-ethylhexyl)phthalate ... for possible carcinogenicity was conduced by feeding diets containing 6,000 or 12,000 ppm of the test chemical to groups of 50 male and 50 female F344 rats and 3,000 or 6,000 ppm to groups of 50 male and 50 female B6C3F1 mice for 103 wk. Controls consisted of 50 untreated rats and 50 untreated mice of either sex. ... Under the conditions of this bioassay, di(2-ethylhexyl)phthalate was carcinogenic for F344 rats and B6C3F1 mice, causing incr incidences of female rats and male and female mice with hepatocellular carcinomas, and inducing an incr incidence of male rats with either hepatocellular carcinomas or neoplastic nodules. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R116] NTXV: *LD50 Rat oral > 25 g/kg; [R117] *LD50 Mouse oral > 30 g/kg; [R117] *LD50 Rabbit oral 33.9 g/kg; [R117] *LD50 Guinea pig oral 26.3 g/kg; [R117] *LD50 Guinea pig dermal 10 g/kg; [R117] *LD50 Rabbit dermal 25 g/kg; [R117] *LD50 Rat ip 30.7 g/kg; [R117] *LD50 Mouse ip 14-75 g/kg; [R117] ETXV: *LC50 Daphnia magna 11,000 ug/l duration not specified. /Static, unmeasured bioassay/; [R118] *LC50 Lepomis macrochirus > 770,000 ug/l/96 hr. /Conditions of bioassay not specified/; [R119] *EC50 Gymnodinium breve growth rate 3.1% vol/vol/96 hr /Conditions of bioassay not specified/; [R120] *LC50 GAMMARUS PSEUDOLIMNAEUS MORE THAN 32 MG/L/96 HR AT 21 DEG C; JUVENILE /STATIC BIOASSAY/; [R121] *LC50 ONCORHYNCHUS KISUTCH (COHO SALMON) MORE THAN 100 MG/L/96 HR AT 16 DEG C; WT 1.5 G /STATIC BIOASSAY/; [R121] *LC50 SALMO GAIRDNERI (RAINBOW TROUT) MORE THAN 100 MG/L/96 HR AT 12 DEG C; WT 1.5 G /STATIC BIOASSAY/; [R121] *LC50 ICTALURUS PUNCTATUS (CHANNEL CATFISH) MORE THAN 100 MG/L/96 HR AT 20 DEG C; WT 1.5 G /STATIC BIOASSAY/; [R121] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) MORE THAN 100 MG/L/96 HR AT 17 DEG C; WT 0.6 G /STATIC BIOASSAY/; [R121] *LC50 Bluegill > 770,000 ug/l/96 hr /Conditions of bioassay not specified/; [R119] *LC50 Daphnia magna: 1,000-5,000 ug/l/48 hr /Conditions of bioassay not specified/; [R122] *LC50 Chironomus plumosus (Midge): > 18,000 ug/l/48 hr /Conditions of bioassay not specified/; [R123] *LC50 Red-tide dinoflagellate (Gymnodinium breve) > 10% w:v/96 hr /Conditions of bioassay not specified/; [R8, 873] *LC50 Brine shrimp (palaemonetes pugio) > 1 mg/L/28 d /Conditions of bioassay not specified/; [R8, 873] *LC50 Scud (Gammarus pseudolimnaeus) > 32 mg/L/96 hr /Conditions of bioassay not specified/; [R8, 873] *LC50 Daphnia magna 9.4; 11 mg/L/48 hr /Conditions of bioassay(s) not specified/; [R8, 873] *LC50 Lepomis macrochirus > 770 mg/L/96 hr /Conditions of bioassay not specified/; [R8, 873] *LC50 Sheepshead minnow > 550 mg/L/96 hr /Conditions of bioassay not specified/; [R8, 873] NTP: *A bioassay of di(2-ethylhexyl)phthalate ... for possible carcinogenicity was conduced by feeding diets containing 6,000 or 12,000 ppm of the test chemical to groups of 50 male and 50 female F344 rats and 3,000 or 6,000 ppm to groups of 50 male and 50 female B6C3F1 mice for 103 wk. Controls consisted of 50 untreated rats and 50 untreated mice of either sex. ... Under the conditions of this bioassay, di(2-ethylhexyl)phthalate was carcinogenic for F344 rats and B6C3F1 mice, causing incr incidences of female rats and male and female mice with hepatocellular carcinomas, and inducing an incr incidence of male rats with either hepatocellular carcinomas or neoplastic nodules. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R116] +Diethylhexyl phthalate (DEHP) ... was administered to timed-mated Swiss CD-l mice (F0 generation) on gestational days (gd) 0-17. Dietary concns of 0%, 0.01%, 0.025%, or 0.05% DEHP resulted in average doses of 0, 19, 48, and 95 mg/kg/day, respectively. DEHP was not added to the diet of P0 animals after /gestational day/ 17, or to the diet of F1 animals. P0 dams were evaluated for DEHP toxicity (Task 1), and their offspring were evaluated for viability, growth and development (Task 2). At 52-57 days of age, F1 males and females were mated within treatment groups, and the F2a offspring were evaluated for viability and growth through postnatal day (pnd) 4 (Task 3). Suggestive evidence of an adverse reproductive effect was observed during Task 3 in the first replicate of this investigation. Therefore, F1 animals were rebred across the high-dose and control groups in order to distinguish between potential effects upon each sex (Task 4). The resultant F2b litters were evaluated for viability and growth through /postnatal day/ 4. F0 maternal food consumption (g/kg/day) and weight gain during treatment were not influenced by DEHP. Maternal body weight exhibited a dose-related decreasing trend on /postnatal day/ 4 and 7, but pairwise comparisons of DEHP-exposed groups to the control group were not significant. No other evidence of DEHP toxicity was noted in F0 dams through scheduled sacrifice. DEHP treatment did not affect the number of implantation sites/dam, the % fertile matings, the % pregnancies with live litters on /postnatal day/ 1, or the % viable litters through /postnatal day/ 4. For F1 litters, the % prenatal mortality was significantly increased at the high dose (9.0, 6.0, 1.4 and 26.4%/litter for the control through high-dose groups, respectively), and a concomitant decr in live litter size on /postnatal day/ 1 was also observed (10.9, 11.5, 10.8 and 8.5 live pups/litter, respectively). During the neonatal period (/postnatal day/ 1-4), the % of viable pups was significantly decreased at 0.05% DEHP. During the postnatal period (/postnatal day/ 4-169), minor reductions in F1 female body weight were observed during Task 3. No other effects of DEHP were observed upon growth, viability, age at acquisition of developmental landmarks (i.e., incisor eruption, wire grasping, eye opening, testes descent or vaginal opening), or spontaneous locomotor activity on /postnatal day/ 14, 21 or 50. No adverse effects were observed upon the reproductive performance of the F1 generation, except for a reduction of F2a live litter size at 0.05% DEHP in the first study replicate. The growth and viability of the F2a and F2b litters through /postnatal day/ 4 were unaffected by treatment. Reproductive organs of F1 males and females did not differ in weight between the high-dose and control groups, nor were any treatment-related histopathologic findings revealed. In summary, F0 females were exposed to DEHP (0%, 0.01%, 0.025% and 0.050%) in the diet on /gestational day/ 0-17. No adverse effects were observed at 0.01% DEHP (19 mg/kg/day) or at 0.025S DEHP (48 mg/kg/day) except for minor, transient decreases in F1 female weight during Task 3. At 0.05% (95 mg/kg/day), indications of F0 maternal toxicity were minimal. Pre- and early postnatal (/postnatal day/ 1-4) mortality of the F1 offspring were significantly increased at the high dose, and a transient reduction of F1 female body weight was observed during Task 3. Despite the presence of this developmental toxicity at 0.05%, no further residual or delayed effects were observed upon the growth, viability, development or reproductive performance of the F1 generation between /postnatal day/ 4-169. [R124] +Diethylhexyl phthalate (DEHP) ... was administered to timed-mated Fischer 344 rats (F0 generation) on gestational days (gd) 0-20. Treatment groups received either O%, 0.25%, 0 50%, or 1.00% DEHP in the diet, with resultant average doses of 0, 164, 313 or 573 mg DEHP/kg/day, respectively. Maternal food consumption (g/kg/day) and weight gain during treatment were reduced in a dose-related manner; food consumption was significantly lower than controls in the mid- and high-dose groups, but maternal weight gain was significantly reduced only at the high dose. Postpartum maternal body weight was reduced at the high dose on postnatal day (pnd) 1, but no further maternal effects were observed through scheduled sacrifice of F0 dams on /postnatal day/ 28. The number of implantation sites/dam did not differ across groups, nor were treatment-related effects observed for the % fertile matings, % live litters (/postnatal day/ 1), or % viable litters (/postnatal day/ 1-4). Postimplantation mortality was increased in the mid- and high-dose groups (7.80%, 8.57%, 21.40% and 19.52% per litter for the control through high- dose groups, respectively), but this effect was statistically significant only at the mid dose. On /postnatal day/ 1, average litter size and average pup body weight/litter were decreased in a dose-related manner (9.47, 9.3, 8.18, and 8.0 live pups/litter, and 4.91, 4.86, 4.75 and 4.52 g, respectively, in the control through high-dose groups); the effect upon pup body weight was statistically significant only for the high-dose group. During the postnatal period (/postnatal day/ 4 through sacrifice), F1 litters from DEHP-treated dams were comparable to controls for postnatal growth and viability, age of acquisition for developmental landmarks (i.e., incisor eruption, wire grasping, eye opening, testes descent or vaginal opening), and levels of spontaneous locomotor activity on /postnatal day/ 21, 35, 38 and 55. Exposure of F0 dams to DEHP failed to result in any adverse effect upon reproductive performance in the F1 generation, or upon growth and viability of F2A litters through /postnatal day/ 4. Appropriate statistical analysis of F1 reproductive organ weights could not be performed since potential confounding factors, especially age of F1 animals at sacrifice and relative timing of prior reproductive events, were not systematically controlled in this study. However, microscopic evaluation of reproductive organs from F1 males and females revealed no treatment-related histopathologic effects. In summary, F0 females were exposed to DEHP (0%, 0.25%, 0.50%, or 1.00%) in the diet on /gestational day/ O-20. No adverse effects were observed in the 0 25% DEHP group (average intake=164 ng DEHP/kg/day). Moderate maternal toxicity (decreased food intake; decreased maternal weight gain), as well as reduced pre- and perinatal growth and viability of the F1 generation were observed in the 0.50% and /or 1.00% DEHP groups (average intake =313 and 573 ug DEHP/kg/day, respectively). Despite the presence of significant maternal and developmental toxicity at 0.5% and 1.00% during treatment and during the perinatal period, no residual or delayed effects were observed upon the growth, viability, development or reproductive performance of the F1 generation between /postnatal day/ 4-128. [R125] +... Timed pregnant Fischer 344 rats were exposed to diethylhexyl Phthalate in the feed on gestational days 0 through 20 at levels of 2.0% (20,000 ppm), 1.5% (15,000 ppm), 1.0% (10,000 ppm), 0.5% (5000 ppm) or 0.0% (0 ppm). These dose groups are referred to as diethylhexyl Phthalate-2.0, diethylhexyl Phthalate-1.5, diethylhexyl Phthalate-1.0, diethylhexyl Phthalate-0.5 or diethylhexyl Phthalate-0.0, respectively. Dams were weighed on gestational days 0, 4, 8, 12, 16 and 20 (immediately following sacrifice), and were observed for clinical signs of toxicity. Food and water were also measured on these days. At sacrifice on gestational day 20, maternal blood was taken for subsequent plasma zinc analysis, and dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses). Live fetuses were dissected from the uterus, fetal blood was collected for subsequent plasma zinc analysis, and fetuses were evaluated for live litter size, body weights, sex ratios and gross morphological abnormalities. All live fetuses were examined for visceral malformations employing the Staples' fresh tissue dissection method (Staples, 1974). Half of the fetuses were decapitated prior to dissection and the heads were fixed in Bouin's solution for free-hand sectioning and examination (Wilson's Technique). All fetal carcasses were cleared and stained with Alizarin Red S and examined for skeletal malformations. There was no maternal mortality in any dose group in this study. There was a significant dose-response trend toward reduced maternal body weight on gestational days 4, 8, 12 and 16, but not gestational day 0 (prior to onset of exposure), with the values from diethylhexyl Phthalate-1.5 and diethylhexyl Phthalate-2.0 dose groups significantly lower than in controls for all interim weights. In addition, the value for diethylhexyl Phthalate-1.0 was significantly lower than controls for gestational days 4, 8 and 12. Maternal weight at sacrifice, maternal weight gain during gestation or treatment, and absolute weight gain were all significant for trend with the values from the diethylhexyl Phthalate-1.0, diethylhexyl Phthalate-1.5, and diethylhexyl Phthalate-2.0 dose groups lower than in controls for all these parameters. Gravid uterine weight exhibited a dose-related decrease,with the value from the diethylhexyl Phthalate-2.0 dose group significantly lower than in controls. Maternal liver weight and relative liver weight exhibited a dose-related increase with values for all diethylhexyl Phthalate dose groups higher than for controls. Clinical signs of toxicity, which included piloerection, rough coat, and reduced food intake, were seen in all diethylhexyl Phthalate dose groups in a dose-related manner. There were no dose-related differences observed in the number of corpora lutea or implantation sites per dam, nor in the percent preimplantation loss. The number and percent of resorptions, non-live (dead plus resorbed), and affected (non-live plus malformed) per litter were all increased in a dose-dependent manner with the values for the diethylhexyl Phthalate-2.0 group significantly higher than for controls for all of these parameters. Number of live fetuses per litter exhibited a dose-related decrease with the value for diethylhexyl Phthalate-2.0 significantly lower than in controls. The number and percent of fetal deaths per litter were unaffected by treatment. Among live litters, there were no effects of treatment on number of males or females per litter. There were dose-related decreases in body weight for male and female fetuses combined and separately per litter; values for these three parameters were significantly elevated in the diethylhexyl Phthalate-0.5 dose group relative to controls, and significantly reduced in all higher dose groups (diethylhexyl Phthalate 1.0, diethylhexyl Phthalate-1.5 and diethylhexyl Phthalate-2.0) relative to control values. There was a significant dose-related upward trend in the percent fetuses malformed per litter, but no significant pairwise comparisons. There were no dose-related differences in the number of fetuses malformed per litter, or in the number or percentage of male or female fetuses malformed per litter. Plasma zinc analysis indicated no apparent differences between diethylhexyl Phthalate-exposure dams and fetuses and controls. In conclusion, diethylhexyl phthalate in the feed produced an increased trend in the percent fetuses malformed but no significant pairwise comparisons in F-344 rats exposed during the entire gestation period (gestational days 0 through 20), at dose levels which produced significant maternal and fetal toxicity, i.e., 1.0%, 1.5%, and 2%. [R126] +... Timed-pregnant CD-1 mice were exposed to diethylhexyl phthalate in the feed on gestational days 0 through 17 at levels of 0.15% (1500 ppm), 0.10% (1000 ppm), 0.05% (500 ppm), 0.025% (250 ppm) or 0.0% (0 ppm). These dose groups are referred to as diethylhexyl Phthalate-0.15, diethylhexyl phthalate-0.10, diethylhexyl phthalate-0.05, diethylhexyl phthalate-0.025 or diethylhexyl phthalate-0.0, respectively. Dams were weighed on gestational days 0, 4, 8, 12, 16 and 17 (immediately following sacrifice), and were observed for clinical signs of toxicity. Food and water were also measured on these days. At sacrifice on gestational day 17, maternal blood was taken for subsequent plasma zinc analysis, and dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e., resorptions, dead fetuses, live fetuses). Live fetuses were dissected from the uterus, fetal blood was collected for subsequent plasma zinc analysis and fetuses were evaluated for live litter size, body weights, sex ratios and gross morphological abnormalities. All live fetuses were examined for visceral malformations employing the Staples' fresh tissue dissection method ... . Half of the fetuses were decapitated prior to dissection and the heads were fixed in Bouin's solution for freehand sectioning and examination (Wilson's Technique). All fetal carcasses were cleared and stained with Alizarin Red S and examined for skeletal malformations. There was no maternal mortality in any dose group in this study. There was a significant dose-response trend toward reduced maternal body weight on gestational days 12, 16, and 17 but not gestational days 0 (prior to onset of exposure), 4 or 8, with the values from diethylhexyl Phthalate-0.10 and diethylhexyl phthalate-0.15 dose groups significantly lower than in controls for gd 12, 16 and 17 weights. Maternal weight gain during gestation or treatment, was significant for trend with the values from the diethylhexyl Phthalate-0.10, and diethylhexyl Phthalate-0.15 dose groups lower than in controls. Gravid uterine weight exhibited a dose-related decrease with the values from diethylhexyl Phthalate-0.10 and diethylhexyl phthalate-0.15 dose groups significantly lower than in controls. Maternal relative liver weight exhibited a dose-related increase with values for the diethylhexyl phthalate-0.10 and diethylhexyl phthalate-0.15 dose groups higher than for controls. Clinical signs of toxicity, which included piloerection, lethargy, and rough coat were seen in all diethylhexyl Phthalate dose groups in a dose-related manner. There were no dose-related differences observed in the number of corpora lutea or implantation sites per dam, nor in the percent preimplantation loss. The number and percent of resorptions, dead, nonlive (dead plus resorbed), and affected (nonlive plus malformed) per litter were all increased in a dose-dependent manner with the values for the diethylhexyl phthalate-0.10 and diethylhexyl phthalate-0.15 dose groups significantly higher than for controls for all of these parameters. Number of live fetuses and number of males or females per litter exhibited a dose-related decrease with the value for diethylhexyl phthalate-0.10 and diethylhexyl phthalate-0.15 groups significantly lower than in controls for total fetuses and females. For males per litter, only the diethylhexyl phthalate-0.15 dose group value was reduced relative to controls. There were dose- related decreases in body weight for male and female fetuses combined and separately per litter; values for these three parameters were significantly reduced in the diethylhexyl phthalate-0.15 dose group relative to controls. Female fetal body weight per litter was also reduced in the diethylhexyl phthalate-0.10 group relative to controls. There were significant dose-related increases in the number and percentage of fetuses malformed per litter, and in the number or percentage of male or female fetuses malformed per litter. Plasma zinc analysis indicated no apparent differences between diethylhexyl phthalate-exposed dams and fetuses and controls. In conclusion, diethylhexyl phthalate in the feed was teratogenic to CD-1(R) mice exposed during the entire gestation period (gestational days 0 through 17), at dose levels which produced significant maternal and other fetal toxicity, i.e., 0.10% and 0.15%, and at a dose level which produced no significant maternal or other fetal toxicity (0.05% diethylhexyl phthalate). Major malformations observed included external, visceral and skeletal defects. The "no observable effect level" (NOEL) for diethylhexyl phthalate in this study was 0.025%, where there was no significant maternal or fetal toxicity, including teratogenicity. [R127] TCAT: Bis(2-ethyl hexyl)phthalate (DEHP) was examined for its effect on cell transformation using the BALB/3T3 transformation assay, at nominal concentrations of 21.0, 14.0, 7.0, 3.5 and 0.875 nl/ml (corresponding to relative survivals of approximately 10, 20, 35, 58 and 82%). DEHP did not induce a significant number of transformed foci over the concentration range of 21.0 to 0.875 nl/ml. This concentration range corresponded to approximately 10% to 90% survival in the preliminary cytotoxicity test and 6% to 109% survival in the concomitant cytotoxicity test. [R128] Bis(2-ethylhexyl) phthalate (DEHP) was examined for its effect on cell transformation using the BALB/3T3 transformation assay, performed in closed flasks in the presence of metabolic activation by primary rat hepatocytes, at nominal concentrations ranging from 100.0 ul/ml (10% v/v) to 6.25 ul/ml (0.625% v/v). The average number of foci/flask ranged from 0.019 at 12.5 ul/ml to zero for the 25.0 and 100.0 ul/ml treatments. DEHP did not induce the appearance of significant number of transformed foci at any concentration tested. This concentration range corresponded to approximately 43% to nearly 84% survival in the concomitant cytotoxicity test. [R128] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexyl phthalate was tested at 1.0, 0.3, 0.1 and 0.003 ul/ml, with cell survival ranging from 96.3-26.8% relative to the solvent control (acetone). The highest concentration of test material induced the appearance of a significant number of transformed foci (p < 0.01, Poisson distribution). [R129] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexyl phthalate was tested at 1.0, 0.3, 0.1 and 0.003 ul/ml, with cell survival ranging from 96.1-49.6% relative to the solvent control (acetone). The data suggest that the test material did not induce the appearance of a significant number of transformed foci (p < 0.05, Poisson distribution). [R130] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexyl phthalate was tested at 1.0, 0.3, 0.1 and 0.003 ul/ml, with cell survival ranging from 94.9-18.9% relative to the solvent control (acetone). Test material did not induce the appearance of a significant number of transformed foci. [R131] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the presence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexyl phthalate was tested at 1.0, 0.3 and 0.1 ul/ml, with cell survival ranging from 96.7-78.7% relative to the solvent control (acetone). Test material did not induce the appearance of a significant number of transformed foci (p > 0.05, Poisson distribution). [R132] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexyl phthalate was tested at 1.0, 0.1 and 0.01 ul/ml, with cell survival ranging from 87.3-10.4% relative to the solvent control (acetone). Test material induced the appearance of a significant number of transformed foci (p less than or equal to 0.02, Poisson distribution). [R133] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=3 days), di-2-ethylhexyl phthalate was tested at 32.8, 16.4, 8.2, 4.1 and 1.64 ug/ml, with cell survival ranging from approximately 25-100% relative to the solvent control (DMSO). Test material did not induce the appearance of a significant number of transformed foci (p less than or equal to 0.05, Kastenbaum-Bowman test). [R134] The effects of oral exposure to di-(2-ethylhexyl) phthalate (DEHP) on selected tissues of male Fischer 344 rats (8/group), especially effects on the testes, were evaluated. The rats were exposed to DEHP in the diet at dose levels of 0 or 2% (w/w) (2 treated groups), for one week. No significant differences were observed between treated and control animals in any of the tissues examined which could be related to the exposure to EHP, including the testes, epididymides, liver, kidneys, and any unusual lesions. No significant differences were observed between treated and control animals in any histopathology examinations including the testes (number of multinucleated spermatids, degree of spermatogenesis) and the epididymis (numbers of spermatozoa and spermatids). [R135] The ability of bis(2-ethyl hexyl)phthalate to induce specific locus mutations at the TK locus in cultured l5178Y mouse lymphoma cells (mouse lymphoma mutagenesis assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Concentrations of 7.81 ul/ml to 250 ul/ml in the absence of rat liver S9 fraction induced mutant frequencies that ranged from 10.7 x 10-6 to 206.7 x 10-6 (mutant frequency of 206.7 x 10-6 was due to toxicity and was not considered in the evaluation). Thus, no significant mutagenic activity was exhibited at any of the concentration levels. In the presence of metabolic activation by rat liver S9 fraction, no mutagenic activity was demonstrated with concentrations of bis(2-ethyl hexyl)phthalate up to 450 ul/ml. A wide range of toxicities were induced without inducing significant, reliable increases in the mutant frequencies. [R128] The ability of di-(2-ethylhexyl)phthalate to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity determinations 10 nonactivated cultures treated with 0.21, 0.16, 0.12, 0.089, 0.067, 0.05, 0.038, 0.028, 0.021 and 0.016ul/ml were cloned, producing a range of 12 - 93% total growth. Ten activated cultures treated with 1.2, 0.88, 0.67, 0.50, 0.38, 0.28, 0.21, 0.16, 0.12 and 0.089ul/ml were cloned, producing a range of 41 - 109% total growth. None of the cultures produced mutant frequencies significantly greater than the solvent control (EtOH). [R136] The ability of di(2-ethylhexyl)phthalate (DEHP) to induce mutations at the HGPRT gene locus in Chinese hamster ovary (CHO) cells in vitro, was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. DEHP was tested at 5 concentrations over the range of 5.0 nl/ml to 80.0 nl/ml, with and without metabolic activation. No toxicity was observed up to the limit of solubility (20 nl/ml) or higher, and no dose-related increases in mutant frequency were observed. A statistically significant increase in mutant frequency was observed for one insoluble treatment (80 nl/ml), but not for the duplicate test. [R137] Bis(2-ethyl hexyl)phthalate was examined for mutagenic activity in Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537 and TA1538, both with and without addition of rat liver S9 fraction to provide metabolic activation. Using the plate incorporation technique at a dose range of 0.15-150 ul/plate, all assays were negative both with and without metabolic activation. [R128] The mutagenicity of urine from Sprague-Dawley rats dosed daily by gavage for 15 days with 2,000mg/kg of di-(2-ethylhexyl)phthalate was evaluated in Salmonella tester strains TA 98, TA100, TA1535, TA1537 and TA1538 (Modified Ames Test), both in the presence and absence of Aroclor-induced rat liver S9 metabolic activation and beta-glucuronidase/aryl sulfatase. Cultures were dosed with up to 2ml of urine using direct plating procedures. The urine of rats treated with di-(2-ethylhexyl)phthalate did not cause a positive response under any of the test conditions. [R138] Bis(2-ethyl hexyl)phthalate (DEHP) was evaluated for the ability to increase the incidence of micronucleated polychromatic erythrocytes in bone marrow of male and female B6C3F1 mice treated by single and multiple intraperitoneal injections (micronucleus test). Groups of 12 mice (6 male, 6 female) were injected with DEHP in corn oil at a dose of 5 g/kg (calculated LD50/7 dose greater than 5 g/kg). Polychromatic erythrocytes (PCE's) were harvested once at 30 hrs after treatment for single dosed rats, and at 48 hrs after treatment for multiple dosed treatment groups. There was no significant difference in percent micronucleated PCEs between single and multiple dosed groups, or between male and female mice. [R128] The effect of bis(2-ethyl hexyl)phthalate (DEHP) was examined in the rat hepatocyte primary culture/DNA repair assay. At concentrations of 5.0 - 100 nl/ml the test material did not induce significant changes over the solvent control in the nuclear labeling of primary rat hepatocytes. Eight treatments resulting in a survival range of 74.8% to 97.8% were analyzed for the induction of DNA repair synthesis. No dose-related response was observed. [R128] C14-Di(2-ethylhexyl)phthalate was administered to three groups (12 rats/group) of male Fischer-344 rats at nominal concentrations of 1000, 6000 or 12000 ppm in the diet for 24 hrs, after 0, 6 or 20 days prior exposure to equal concentrations of unlabeled DEHP in the diet. The percentage of the dose excreted in urine increased with dose, from 53% at 1000 ppm to 62-69% at 6000 and 12000 ppm, with the initial ca. 10-15% being excreted during the first 24 hrs. At all dose levels and exposure times, 24-38% of the dose consumed was excreted via the fecal route. Fecal excretion occurred primarily during the second 24 hrs, (11-19% of the dose). The percentage of the dose excreted in feces increased with increased dose from 35-38% at 1000 ppm, to 24-30% at 6000 ppm. As with urinary excretion, prior exposure to DEHP did not affect the extent or rate of fecal excretion. DEHP equivalents were detectable at low concentrations in the liver, 112 hrs after the start of administration. Total recoveries of the 14C-DEHP radioactivity consumed were less than 100% for all animals. Total recoveries of radioactivity were not affected by dose or by prior exposure to DEHP. [R139] C14-Di(2-ethylhexyl)phthalate (C14-DEHP) was administered by gavage to three male Cynomolgus monkeys, five male Fischer-344 rats and five groups of male B6C3F1 mice (5/group) at a nominal dose of 100 mg/kg. All species excreted approximately 30-40% of the dose via the urinary route, primarily during the first 12 hrs for rats and mice, and during the first 24 hrs for monkeys. Only minimal excretion (ca. 5% or less of the dose) occurred after 24 hrs in all species. All species excreted approximately 50% of the dose via the fecal route, primarily during the first 24 hrs for rats and mice, and during the first 24 hrs for monkeys. DEHP equivalents were detectable in some tissues in all species. The mean concentrations detected, with the exception of monkey liver and rat intestinal contents, were less than 1 ug/g. The highest concentrations were detected in the liver, intestinal contents and fat for monkeys, rats and mice respectively. Total recoveries of the 14C-DEHP radioactivity administered were 79%, 87% and 90% for monkeys, rats and mice respectively. DEHP was less than 100% absorbed by all three species after oral administration at 100 mg/kg. [R140] The absorption, distribution and elimination of [2-hexyl 14C] di(2-ethylhexyl)phthalate (14C-DEHP) was studied in four male Sprague-Dawley rats administered 14C-DEHP by gavage at a nominal dose of 100 mg/kg of body weight. 61.5% of the radioactivity was recovered in the feces, of which 34% and 4% were unchanged DEHP and MEHP respectively. The remainder (29.9%) was eliminated in the urine in the form of metabolites and expired air as 14CO2 (3.7%). The excretion of expired 14CO2 was biphasic with an alpha-phase half-life of 3.1 hrs and a beta-phase half-life of 41.1 hrs. [R141] The ability of di-2-ethylhexyl phthalate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexyl phthalate was tested at 49.8, 24.9, 12.5, 4.98 and 0.498 ul/ml, with cell survival ranging from approximately 21-90% relative to the solvent control (acetone). Test material did not induce the appearance of a significant number of transformed foci (Kastenbaum-Bowman test). [R142] Toxicity was evaluated in three groups of male and female Fischer 344 rats ingesting dietary levels of 0.1, 0.6 or 1.2% di-ethylhexyl phthalate (DEHP) for 3 weeks. Male rats fed 0.1% DEHP had higher liver weights. Males receiving 0.6% and 1.2% DEHP showed: increased kidney weights; reduced serum cholesterol levels; increased hepatic levels of catalase; and heptocellular hypertrophy. Males receiving 1.2% DEHP showed: increased liver weights; increased catalase activity; and heptocellular hypertrophy. Female rats receiving 0.6% and 1.2% DEHP showed: increased kidney weights; reduced serum cholesterol levels; and increased hepatic levels of catalase. Increased liver weight and catalase activity were observed in females receiving 1.2% DEHP. Serum triglyceride levels in rats receiving all dietary levels were significantly reduced. An increase in the number of peroxisomes and cytoplasmic vacuolation was observed in hepatocytes from some high dose control groups. Following a 2-week recovery period, liver weights decreased, but remained significantly higher than controls; triglyceride levels, cholesterol levels, and catalase activities all returned to control levels. Catalase levels in both male and female rats declined but remained significantly higher than control levels; and heptocellular hypertrophy was present in only one male from the 1.2% dose group. [R143] ?The mutagenicity of di-(2-ethylhexyl)phthalate was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests, bis(2-ethylhexyl)phthalate, diluted in DMSO, was tested at concentrations up to 10ul/plate using the plate incorporation technique. Bis(2-ethylhexyl)phthalate did not cause a positive response in any tester strain with or without metabolic activation. [R144] ?The mutagenicity of bis(2-ethylhexyl) phthalate was evaluated in a dominant lethal assay using 4 groups of 25 male ICR/SIM mice orally exposed by gavage to dose levels of 0, 2465, 4930 or 9860 mg/kg/day (in corn oil vehicle) for 5 consecutive days. Following exposure, 20 males were selected from each treatment group and each male was mated for 7 days/week with 2 untreated females/week for 8 consecutive weeks. Females were sacrificed 14-17 days from the first day of cohabitation. There were statistically significant increases over control values in average dead implants (low- and high-dose level, mating week 1) ratio of dead to total implants (low-dose, mating week 1), and death indices (low-dose level, mating week 1). There were statistically significant decreases relative to control values in average dead implants (mid-dose level, mating weeks 3 and 4) and ratio of dead to total implants (mid-dose level, mating week 3). These results were reported to be within the normal range for these animals and were not considered to be biologically significant. No dose-response relationships were observed. [R145] ?The ability of bis(2-ethylhexyl) phthalate to cause chromosome aberrations was evaluated in the bone marrow cells of male Fischer 344 rats (5/group) exposed orally be gavage at dose levels of 0, 0.5, 1.7 or 5.0 ml/kg/day for 5 consecutive days. Fifty cells/animal were scored for chromosome aberrations. There were no significant differences observed between treated and control animals with respect to percentage of cells with aberrations and total number of aberrations/cell. [R146] ?The effect of Di-(2-ethylhexyl)phthalate was examined in the rat hepatocyte primary culture/DNA repair assay. The test article did not induce an increase in the number of grains/nuclei, % nuclei with = > 6 grains, or the % nuclei with = > 20 grains, when administered to freshly isolated Fischer 344 rat liver hepatocytes at concentrations ranging from 0.078 to 10.0 ul/ml. Cytotoxicity was not observed during the assay, and the test article was observed to be insoluble under the conditions of the test. [R147] POPL: *Time-averaged concn of DEHP, MEHP, and phthalic acid in the blood of patients undergoing maintenance hemodialysis were 1.9, 1.3, and 5.2 mg/L, respectively ... Such patients are considered to be at risk of potential DEHP toxicity through prolonged contact with medical plastic products that contain DEHP. The relatively high circulating level of phthalic acid may indicate an altered metabolism of DEHP in uremic patients ... . [R148] ADE: *When administered either IV or orally ... it is mainly excreted in urine and bile. [R24] *IT APPEARED TO BE RAPIDLY CLEARED FROM BLOOD, MOST BEING REMOVED WITHIN 5-7 HR OF COMPLETION OF DIALYSIS. [R149] *IN ONE STUDY OF SUBJECTS WHO RECEIVED HEMODIALYSIS, BLOOD TRANSFUSIONS OR BLOOD THAT HAD PREVIOUSLY BEEN IN CONTACT WITH POLYVINYL CHLORIDE MEDICAL PRODUCTS, DI(2-ETHYLHEXYL) PHTHALATE WAS FOUND AT THE FOLLOWING LEVELS (UG/G WET TISSUE): BRAIN (1.9), HEART (0.5), KIDNEY (1.2-2.2), LIVER (1.5-4.6), LUNG (1.4-2.2) AND SPLEEN (2.2-4.7). [R62] *THE LEVELS OF DI(2-ETHYLHEXYL) PHTHALATE IN NEONATAL HEART TISSUE FROM INFANTS WHO HAD UNDERGONE UMBILICAL CATHETERIZATION, EITHER ALONE OR WITH ADMIN OF BLOOD PRODUCTS, WERE REPORTED TO BE HIGHER THAN THOSE IN SIMILAR TISSUE FROM UNTREATED INFANTS. [R62] *IV ADMIN DI(2-ETHYLHEXYL) PHTHALATE IS CLEARED RAPIDLY FROM SERUM; THE MAJORITY IS EXCRETED IN URINE WITHIN 24 HR POST-TRANSFUSION. ... SMALL AMOUNT OF DI(2-ETHYLHEXYL) PHTHALATE (OR ITS METABOLITES) HAVE BEEN ISOLATED FROM HUMAN BIOPSIES OR AUTOPSIED MATERIALS; THE PRESENCE OF PLASTICIZER COULD NOT ALWAYS BE CORRELATED WITH A HISTORY OF BLOOD TRANSFUSIONS ... LEVELS OF 0.06 +/- 0.02 MG/KG FRESH WEIGHT HAVE BEEN REPORTED IN PLACENTAS OF 10 NORMAL BIRTHS ... [R49] *THERE IS LITTLE OR NO TISSUE ACCUMULATION OF RADIOACTIVITY IN RATS FOLLOWING REPEATED DIETARY TREATMENT WITH (14)C-DI(2-ETHYLHEXYL) PHTHALATE. HIGHEST CONCN WERE FOUND IN LIVER (110-165 MG/KG) AND FAT (60-80 MG/KG) AFTER SUBCHRONIC EXPOSURE OF RATS TO 5000 MG/KG (PPM) IN DIET. ESTIMATED TISSUE HALF-LIVES FOR THIS CMPD (AND ITS METABOLITES) IN RATS ARE 3-5 DAYS FOR FAT AND 1-2 DAYS FOR OTHER TISSUES. [R61] *OF FISH (GAMBUSIA), SNAIL (PHYSA), DAPHNIA MAGNA, MOSQUITO LARVAE (CULEX PIPENS QUINQUEFASCIATUS), AND ELODEA EXPOSED TO 10 PPM (14)C-LABELED BIS(2-ETHYLHEXYL) PHTHALATE FOR 1-48 HR, MINIMUM AND MAXIMUM PHTHALATE CONCN OCCURRED IN ELODEA AT 37 PPM, AND CULEX LARVAE AT 11,873 PPM, RESPECTIVELY. OF THESE ORGANISMS EXPOSED TO 0.1 PPM FOR 1-48 HR, MINIMUM AND MAXIMUM PHTHALATE CONCNS WERE NOTED IN GAMBUSIA AT 0.85 PPM, AND PHYSA A 85.75 PPM, RESPECTIVELY. [R150] *PLASTIC STRIPS CONTAINING (14)C CARBONYL-LABELED DI-2-ETHYLHEXYL PHTHALATE (DEPH) WERE IMMERSED IN STERILE MOUSE PLASMA FOR 78 DAYS AT 22 DEG C, NO OTHER SOLUBILIZING SUBSTANCES WERE ADDED. THE PLASTIC STRIPS WERE THE POLYVINYL CHLORIDE FORMULATION USED FOR BLOOD BAGS. ONE MILLILITER OF THE PLASMA, CONTAINING 2.293 MUG OF (14)C DEPH WAS INJECTED IV WITHOUT ANY FUTHER PREPARATION INTO ADULT MALE MICE OF THE CD-1 STRAIN. MICE WERE FROZEN BY IMMERSION IN DRY ICE-HEXANE AFTER LIGHT ETHER ANESTHESIA. AUTORADIOGRAPHY OF WHOLE-BODY SAGITTAL SECTIONS TAKEN AT LEAST EVERY 200 MUM THROUGH THE LEFT HALF OF EACH ANIMAL REVEALED A RAPID ACCUMULATION OF RADIOACTIVITY IN THE KIDNEY AND LIVER, WITH RAPID EXCRETION INTO URINE, BILE AND INTESTINE. THE COMPOUND WAS RAPIDLY ELIMINATED BY THE KIDNEY AND LIVER; THERE WAS NO EVIDENCE OF RETENTION IN ANY TISSUES IN THE BODY. THERE WAS NO ACCUMULATION IN SPLEEN OR LUNG. [R151] *Following iv admin of (14)C-labelled DEHP, to rats, blood levels of radioactivity were monitored. A bi-phasic curve was noted when the data was plotted as log DEHP vs time. The initial slope lead to a half-life of 9 min while the second slope gave a half-life of 22 min. Within 1 hr, 8% of the total injected DEHP was found in water-soluble metabolites, primarily in the liver, intestinal contents and urine. 24 hr after injection, 54.6% of the initial dose was recovered as water-soluble metabolites primarily in the intestinal tract, excreted feces and urine. Only 20.5% was recovered in organic extractable form. [R152] *Rhesus monkeys repeatedly infused iv with small amounts of DEHP (total dose 21 to 69 mg/kg) showed some retention of this compound in their livers several months after the infusion was halted. [R153] *THE LEVELS OF DI(2-ETHYLHEXYL) PHTHALATE IN NEONATAL HEART TISSUE FROM INFANTS WHO HAD UNDERGONE UMBILICAL CATHETERIZATION, EITHER ALONE OR WITH ADMIN OF BLOOD PRODUCTS, WERE REPORTED TO BE HIGHER THAN THOSE IN SIMILAR TISSUE FROM UNTREATED INFANTS. [R62] *After a single application of 14C-labelled DEHP (61.5 mg/kg) to the back of F-344 rats, clipped 1 hr before treatment, urine and feces were collected every 24 hr for 7 days. The amount of 14C excreted was taken as an index of the percutaneous absorption, and about 5% of the dose given was excreted ... . [R154] *Studies with 14C-labelled DEHP indicated that at least 50% of the radioactivity of a single dose (2.9 mg/kg) was absorbed in the rat intestine since 42% and 14% were excreted in urine and bile, respectively, after 7 days ... . [R154] *At an oral dose level of 2 g/kg, the bioavailability of DEHP in rats, as measured in blood by HPLC, was 14%, whereas at an ip dose level of 4 g/kg only 5% was recovered, again indicating a role for hydrolysis of DEHP in the gut ... . [R154] *The systemic availability of DEHP was only 5% when a dose of 4 g/kg was given ip to rats. Relatively small amounts of MEHP were recovered in the blood in this study ... . [R155] *Orally admin DEHP is mainly distributed as MEHP in rats ... Unmetabolized DEHP was recovered in the liver only after large oral doses (> 0.5 g/kg) were given, indicating a threshold phenomenon in the absorption and distribution ... peak concn of MEHP in blood was reached 15 min after oral or ip admin of MEHP. The half-time of MEHP in blood or plasma in the rat is shorter than that of DeHP ... The in vitro plasma protein binding of MEHP in the rat reaches approx 98% ... . [R155] *A phenomenon known as "shock-lung" has been reported to occur following iv admin of DEHP to rats and other species. Two hr after an emulsion of DEHP was given, between 13% and 48.6% of DEHP-radiolabelled material was found in the lungs of rats, as compared to 26.3-38.2% in the liver ... This phenomenon may be relevant to human exposure via iv admin from bags and tubing containing DEHP. [R156] *The DEHP plasma level in newborn infants given exchange transfusions may reach about 10 mg/L ... This level is about twice as high as those found in leukemia patients receiving platelet concn and about five times as high as levels found in hemodialyzed patients. After treatment, this level falls rapidly to about 3 mg/L within 2 hr, and then there is a further drop with a half-time of about 10-12 hr ... . [R156] *After the oral admin of non-radioactive DEHP (0.45 mg/kg) to human volunteers, it was found that 15-25% was excreted in urine as MEHP or oxidized metabolites within 2-3 days ... . [R157] *Healthy subjects were exposed to the inhalation of 0.5 or 2.0 mg/cu m of bis (2-ethylhexyl) phthalate 8 hours a day for five (5) days, group A and B, respectively. In group A, concn in blood incr after first exposure to 165 mug/l and after 2-5th exposure stabilized at 72-114 ug/l; concn in urine after first exposure incr to 88.5 ug/l, moderated after second and third exposure, and after fifth exposure incr to 45.2 ug/l. In group B, after first exposure concn in blood and urine incr to 505 and 250 ug/l, respectively, and continuously incr during the following exposures to 803 and 576 ug/l, respectively, on day 5. Apparently, in both groups di(2-ethylhexyl) phthalate is accumulated faster that it can be metabolized or excreted. [R158] *In the marmoset, the excretion profile of (14)C-DEHP following oral, ip, and iv administration and the lower tissue levels of radioactivity demostrated a considerably reduced absorption in this species compared to the rat. [R84] *This study examined the extent of dermal absorption of a series of phthalate diesters in the rat. Those tested were dimethyl, diethyl, dibutyl, diisobutyl, dihexyl, di(2-ethylhexyl), diisodecyl, and benzyl butyl phthalate. Hair from a skin area (1.3 cm in diameter) on the back of male F344 rats was clipped, the 14(C)phthalate diester was applied in a dose of 157 mumol/kg, and the area of application was covered with a perforated cap. The rat was restrained and housed for 7 days in a metabolic cage that allowed separate collection of urine and feces. Urine and feces were collected every 24 hr, and the amount of (14)C excreted was taken as an index of the percutaneous absorption. At 24 hr, diethyl phthalate showed the greatest excretion (26%). As the length of the alkyl side chain increased, the amount of (14)C excreted in the first 24 hr decreased signficantly. The cumulative percentage dose excreted in 7 days was greatest for diethyl, dibutyl, and diisobutyl phthalate, about 50-60% of the applied (14)C; and intermediate (20-40%) for dimethyl, benzyl butyl, and dihexyl phthalate. Urine was the major route of excretion of all phthalate diesters except for diisodecyl phthalate. This compound was poorly absorbed and showed almost no urinary excretion. After 7 days, the percentage dose for each phthalate that remained in the body was minimal showed no specific tissue distribution. Most of the unexcreted dose remained in the area of application. These data show that the structure of the phthalate diester determines the degree of dermal absorption. Absorption maximized with diethyl phthalate and then decreased significantly as the alkyl side chain length increased. [R159] *The dispositions of the plasticizer di-(2-ethylhexyl) phthalate (DEHP) and its primary metabolite mono-(ethylhexyl) phthalate (MEHP) were studied in newborn infants subject to exchange transfusions. During a single exchange transfusion the amounts of di-(2-ethylhexyl) phthalate and mono-(ethylhexyl) phthalate infused ranged from 0.8-3.3 and 0.05-0.20 mg/kg body weight, respectively. There were indications that about 30% of the infused di-(2-ethylhexyl) phthalate originated from parts of the transfusion set other than the blood bag. Approximately 30% of the infused amount of di(2-ethylhexyl) phthalate was withdrawn during the course of each transfusion. Immediately after the transfusions the plasma levels of di-(2-ethylhexyl) phthalate ranged between 5.8 and 19.6 mug ml, and subsequently they declined rapidly. This decline, probably reflecting distribution of di(2-ethylhexyl) phthalate within the body, was followed by a slower elimination phase. The half-life of this phase was approximately 10 hr. [R160] METB: *When admin either iv or orally, it is rapidly metabolized to derivatives of mono-(2-ethylhexyl)-phthalate. ... [R24] *RATS HAVE BEEN REPORTED TO METABOLIZE DI(2-ETHYLHEXYL) PHTHALATE TO 5-KETO-2-ETHYLHEXYL PHTHALATE, 5-CARBOXYL-2-ETHYLPENTYL PHTHALATE, 5-HYDROXY-2-ETHYLHEXYL PHTHALATE AND 2-CARBOXYMETHYLBUTYL PHTHALATE AFTER INITIAL HYDROLYSIS TO MONO(2-ETHYLHEXYL) PHTHALATE. [R161] *AFRICAN GREEN MONKEYS AND FERRETS, IN CONTRAST TO RATS, EXCRETE DI(2-ETHYLHEXYL) PHTHALATE METABOLITES IN URINE AS GLUCURONIDE DERIVATIVES OF MONO(2-ETHYLHEXYL) PHTHALATE. GLUCURONIDATION APPEARS TO OCCUR AT THE FREE CARBOXYL GROUP, WHILE 2-ETHYLHEXYL SUBSTITUENT IS OXIDIZED TO AN ALCOHOL. [R161] *TROUT (SALMO GAIRDNERI) LIVER HOMOGENATES METABOLIZED DI-2-ETHYLHEXYL PHTHALATE (DEHP) TO MONOETHYLHEXYL PHTHALATE (MEHP) WITHOUT ADDED NADPH AND TO MEHP AND MORE POLAR METABOLITES WITH ADDED NADPH. [R162] *Liver, kidney and lung homogenates from 45 and 630-d-old rats were incubated with 0.5 muCi of (14)C-labeled DEHP for 40 min at 37 deg C. Radiochromatogram scans ... showed monoethylhexyl phthalate (MEHP) and DEHP. ... A dramatic reduction in the formation of MEHP was observed only with homogenates of livers from the old animals. [R163] *Fathead minnows, exposed to DEHP, converted this material to mono-2-ethylhexyl phthalate (MEHP) and a glucose conjugate. The same metabolites were observed in rainbow trout. Liver microsomes converted DEHP and DBP to the mono esters and 2 polar metabolites. In sediment, after hydrolysis to MEHP, decarboxylation and ring cleavage occurred. [R164] *Studies with Pseudomonas testoseroni NH 1000 indicated that this organism metabolized phthalate through 4-hydroxyphthalate, m-hydroxybenzoate, protocatecuate and alpha-hydroxy-gamma-carboxymuconic semi-aldehyde. [R164] *There appears to be a general similarity of catabolism and excretion of phthalate esters among a wide range of biological systems. Four basic reaction sequences have been identified: (1) hydrolysis of the ester; ... (3) oxidation of the liberated alcohol; and (4) oxidation of the alkyl side-chain while bound to the phthalate ester. /Phthalate esters/ [R165] *Metabolic studies of di-(2-ethylhexyl)phthalate in the rat showed that following ingestion, the diester is partially hydrolyzed to the monoester by GI nonspecific esterases prior to absorption. The subsequent metabolism of the monoester mono-(2-ethylhexyl)phthalate proceeds by oxidation and conjugation of the alkyl side chain by the liver. [R91, 125] *DEHP is hydrolyzed in vitro by pancreatic lipase to MEHP ... indicating that this metabolism would occur mainly in the gut lumen. In rats about 80% of an oral dose of DEHP undergoes mono-deesterification ... while intra-arterially admin DEHP is only slowly converted to MEHP ... Studies on the hydrolysis of DEHP in homogenates from different organs ... indicate a very high activity in pancreatic juice and a comparatively low activity in liver ... . [R156] *There are marked species differences in the metabolism of DEHP. Thus w-oxidation seems to play a dominant role in the rat and guinea pig ... but to be a minor pathway in the mouse, hamster, green monkey, cynomolgus monkey, and marmoset ... . In guinea pigs there are few w-1 metabolites of MEHP ... . This may have toxicological significance because certain w-1-oxidation metabolites have been identified as active agents in peroxisomal proliferation in rat hepatocytes ... . [R166] *No conjugated metabolites were detected in the urine of DEHP-treated rats, but a minor portion was conjugated in the urine of hamsters ... A major portion of glucuronide conjugates was found in the urine of the marmoset, mouse, guinea-pig, and green monkey, and in human urine ... glucuronidation of DEHP metabolites was insignificant in rats. Studies in primates, including the African green monkey ... marmoset ... cynomolgus monkey ... and man ... demonstrated that conjugation of DEHP can occur at the carboxylic acid moiety following a single ester hydrolysis. [R166] *Repeated oral admin of DEHP or MEHP at high doses (500 mg/kg) to rats leads to a change in the metabolic profile; there is an incr in w-oxidized metabolites and a decr in w-1-oxidized metabolites ... In rats give 2% DEHP in the diet for 1 wk, a 4-fold incr in peroxisomal beta-oxidation was found. beta-Oxidation of fatty acids induced by DEHP appears to occur via mitochondrial and peroxisomal pathways that are similar to normal pathways ... Drug-metabolizing enzyme activities have been studied after DEHP admin, and in some cases changes were observed ... . [R166] *The same metabolites as those found in rat urine can be detected in human urine. One study on iv injected DEHP ... and one on orally admin DEHP ... indicated that humans metabolize DEHP by w- and w-1-oxidation as well as by oxidation of the ethyl side chain. However, the w-oxidation-pathway seems to be a minor pathway in man ... More than half of the metabolites recovered in human urine are conjugated metabolites ... . [R166] *The disposition of DEHP and 4 of its major metabolites was studied in male rats given single infusions of a DEHP emulsion in doses of 5, 50, or 500 mg DEHP/kg. Plasma concns. of DEHP and metabolites were followed for 24 hr after the start of the infusion. The kinetics of the primary metabolite mono(2-ethylhexyl)phthalate (MEHP) was studied separately. The concentrations of DEHP in plasma were at all times considerably higher than MEHP, and the concentrations of MEHP were much higher than the other investigated metabolites. In animals given 500 mg DEHP/kg, the areas under the plasma concentration-time curves (AUCs) of the other investigated metabolites were approximately 15% of MEHP. Parallel decreases in the plasma concentrations of DEHP, MEHP, and the omega- and (omega-1) oxidized metabolites indicated that the elimination of DEHP was the rate-limiting step in the disposition of the metabolites. Thus, the clearance of MEHP was higher than DEHP. Nonlinear increases in the AUCs of DEHP and MEHP indicated saturation in the formation as well as the elimination of the potentially toxic metabolite MEHP. [R167] *Strains of Mycobacterium and Nocardia isolated because of their ability to use di(2-ethylhexyl) phthalate (DEHP) as sole carbon source also grew on diethyl, diisooctyl, and butyl benzyl phthalates. As the two bacteria grew on di(2-ethylhexyl) phthalate, they excreted products that increased the solubility of di(2-ethylhexyl) phthalate and diisooctyl, dihexyl, and diisodecyl but not butyl benzyl or di-n-butyl phthalates. The solubilizer was produced by Mycobacterium sp. even when grown on a water-soluble substrate such as acetate. Addition of the solubilizer to culture media enhanced the degradation of di(2-ethylhexyl) phthalate and diisooctyl phthalate by Mycobacterium sp. and Nocardia sp. but not butyl benzyl phthalate. The extent of di(2-ethylhexyl) phthalate degradation by Mycobacterium sp. in media amended with the solubilizer was reduced and the initiation of degradation was delayed if the slubilizer was first treated with protease. The effect of protease was not a result of its toxicity to Mycobacterium or use of the enzyme preparation for growth of the organism. The results thus show that microbial products increase the solubility of certain phthalates and enhance their degradation. [R168] BHL: *In fish, the half life may be as short as 1.5 hr, yielding 99% clearance in 24 hr. /Phthalate esters/ [R165] *The levels of DEHP and MEHP in plasma have been studied in newborn infants given blood exchange transfusions. In one case the MEHP half-life was the same as for DEHP (about 12 hr), indicating that the hydrolysis of DEHP was the rate-limiting metabolic step. However, in other children the half-time of MEHP was longer than that of DEHP ... . [R148] *After the iv admin of radiolabelled DEHP, at least two elimination phases of radioactivity, with short half-lives (4.5-9 and 22 min, respectively), were observed in rat blood ... After 7 wk of oral admin, the elimination phase in the liver was considerably slower, the half-life being 3-5 days ... No accumulation of DEHP or MEHP was observed when the dosage was 2.8 g/kg/day for 7 days ... nor was there any in a long-term (5-7 weeks) feeding study at a dose level of 1 or 5 g/kg diet (corresponding to a daily dose of about 50 and 250 mg/kg bw) ... . [R157] *IN MAN ... ESTIMATED THAT THE HALF-LIFE OF DEHP ADMIN IV IN A SOLUBILIZED STATE IS APPROX 28 MINUTES. [R169] ACTN: *Covalent binding of DEHP to rat liver DNA as a mechanism of action contributing to the observed induction of liver tumors after a lifetime fedding of rodents with high doses of DEHP was studied. DEHP radiolabeled in different positions was administered orally to female F344 rats with or without pretreatment for 4 wk with 1% unlabeled DEHP in the diet. Liver DNA was isolated after 16 hr and analyzed for radioactivity. HPLC analysis of enzyme-degrased DNA revealed that the normal nucleosides had incorporated radiolabel whereas no radioactivity was detectable in those fractions where the carcinogen-modified nucleoside adducts are expected. A quantitative evaluation of the negitive data in terms of limit of detection for a covalent binding index indicates that covalent interaction with DNA is highly unlikely to be the mode of tumorigenic action of DEHP in rodents. [R170] *In an attempt to establish which compound or compounds are responsible for the testicular damage observed after administration of di-(2-ethylhexyl)phthalate (DEHP) in rats, the effects of the parent compound and five of its major metabolites (mono-(2-ethylhextyl), mono-(2-ethyl-5-oxohexyl)phalate and mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHP), 2-ethylhexanol (2-EH), mono-(5-carboxy-2-ethylpenyl)phthalate) were investigated in vivo and in vitro. The plasma concentrations and areas under the plasma concentration-time curves (AUC's) of each of the MEHP-derived metabolites were considerably lower than those of MEHP both after single and after repeated administration of 2.7 mmol of DEHP/kg body weight. The mean elimination half-life of MEHP was significantly shorter in animals given repetitive doses than in those given a single dose, but there was no statistically significant difference between the mean AUC values. No testicular damage was observed in young rats given oral doses of 2.7 mmol of DEHP or 2-EH/kg body weight daily for five days. In animals which received corresponding doses of MEHP the number of degenerated spermatocytes and spermatids was increased, whereas no such effects were found in animals give the MEHP-derived metabolites. MEHP was also the only compound that enhanced germ cell detachment from mixed primary cultures of Sertoli and germ cells. [R171] *It is hypothesized that the teratogen di(2-ethylhexyl) phthalate (DEHP) acts by in vivo hydrolysis to 2-ethylhexanol (2-EXHO), which in turn is metabolized to 2-ethylhexanoic acid (2-EXHA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with administration of these agents on day 12 of geatation. On an equimolar basis DEHP was least potent, 2-ethylhexanol was intermediate, and 2-ethylhexanoic acid was the most potent of the three agents, which is consistent with the hypothesis. Similarity in the types of defects found with these agents also suggests a common mechanism, with 2-ethylhexanoic acid as the proximate teratogen. [R172] INTC: *HEXOBARBITAL AND PENTOBARBITAL SLEEPING TIMES IN MICE WERE PROLONGED BY PRETREATMENT WITH DI(2-ETHYLHEXYL) PHTHALATE, BUT AMINOPYRINE SERUM HALF-LIFE WAS UNAFFECTED. [R64] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Bis(2-ethylhexyl)phthalate has been reported to be a possible natural product in animals and plants. Bis(2-ethylhexyl)phthalate has been found in floor tiles, various types of furnishings for households and transportation vehicles, food packaging systems, industrial tubing and conduits, medical tubing, catheters and blood containers, certain types of dental material, coatings for drugs, and numerous other products. Bis(2-ethylhexyl)phthalate's production and use as a plasticizer and as an insulating fluid in electrical transformers may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 7.23X10-8 mm Hg suggests this compound will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase bis(2-ethylhexyl)phthalate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 18 hours. Particulate-phase bis(2-ethylhexyl)phthalate will be physically removed from the atmosphere by wet and dry deposition. Half-lives for the reaction of gas-phase hydroxyl radicals with bis(2-ethylhexyl)phthalate adsorbed onto various aerosols were as follows, days: 1.1 on silicon dioxide; 1.2 on aluminum oxide; 1.3 on iron(III) oxide; and 2.0 on coal fly ash. After 14 hours irradiation with a 300 W xenon lamp, evolved carbon dioxide reached 0.5 to 0.7 mg/g bis(2-ethylhexyl)phthalate; 2-ethyl-1-hexene, 2-ethylhexanol, and phthalic acid were identified in the irradiated residue. If released to soil, measured Koc values ranging from 87,420 to 510,000 indicate bis(2-ethylhexyl)phthalate will be immobile. Volatilization is not expected to be an important process from wet or dry soil surfaces based upon an estimated Henry's Law constant of 1.3X10-7 atm-cu m/mole and this compound's measured vapor pressure, respectively. Biodegradation is expected to be an important process in both water and soil under aerobic conditions. Mineralization rates ranged from 50% after 20 days in Erie silt loam to 22 to 32% in three soils after 60 days. River die-away tests have reported half-lives of 2 to 3 weeks. It was biodegraded with a half-life of 60 to 70 hours in groundwater impacted by bis(2-ethylhexyl)phthalate, ethylbenzene, and xylenes. If released into water, measured soil/sediment Koc values ranging from 87,420 to 510,000 and suspended solid Koc values ranging from 22,000 to 1X10+6 indicate bis(2-ethylhexyl)phthalate will adsorb to suspended solids and sediment in the water column. Volatilization from water surfaces is not expected to occur based upon the estimated Henry's Law constant. Hydrolysis is not expected to be an important process based upon a half-life of 2000 years at pH 7. Measured BCFs of 115 and 851 in bluegill sunfish and fathead minnows indicate bioconcentration in aquatic organisms will be high. However, experiments with rainbow trout showed that the majority of (14)C-bis(2-ethylhexyl)phthalate did not reach the systemic circulation of the fish, but was present in the exposure water as metabolites as a result of presystemic branchial metabolism of this compound. Occupational exposure to bis(2-ethylhexyl)phthalate may occur through inhalation of aerosols and dermal contact with this compound at workplaces where bis(2-ethylhexyl)phthalate is produced or used. The general population may be exposed to bis(2-ethylhexyl)phthalate via inhalation of ambient air, ingestion of contaminated food and drinking water, and dermal contact with products containing this compound. (SRC) NATS: *Bis(2-ethylhexyl)phthalate has been reported to be a possible natural product in animals and plants(1). [R173] ARTS: *Bis(2-ethylhexyl)phthalate's production and use as a plasticizer and as an insulating fluid in electrical transformers(1) may result in its release to the environment through various waste streams(SRC). Bis(2-ethylhexyl)phthalate is found in floor tiles, various types of furnishings for households and transportation vehicles, food packaging systems, industrial tubing and conduits, medical tubing, catheters and blood containers, certain types of dental material, coatings for drugs, and numerous other products(2). The phthalate esters are also used as defoaming agents in manufacturing paper, as a vehicle for perfumes in cosmetic products and in lubricating oils(2). [R174] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), measured soil/sediment Koc values ranging from 87,420 to 510,000(2) indicate that bis(2-ethylhexyl)phthalate is expected to be immobile in soil(SRC). Volatilization of bis(2-ethylhexyl)phthalate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 7.23X10-8 mm Hg(4) and water solubility, 0.285 mg/l(5). Bis(2-ethylhexyl)phthalate is not expected to volatilize from dry soil surfaces based on its vapor pressure(4). Bis(2-ethylhexyl)phthalate was decomposed in soil with amounts of 15 to 50% remaining after 80 days(6). Mineralization ranged from 22 to 32% (14)CO2 in three soils after 60 days incubation(7). 50% mineralization was observed after 20 days in Erie silt loam(8). [R175] *AQUATIC FATE: Based on a classification scheme(1), measured soil/sediment Koc values ranging from 87,420 to 510,000(2) and suspended solid Koc values ranging from 22,000 to 1X10+6(2) indicate that bis(2-ethylhexyl)phthalate is expected to adsorb to suspended solids and sediment in water(SRC). Bis(2-ethylhexyl)phthalate is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 1.3X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 7.23X10-8 mm Hg(4) and water solubility, 0.285 mg/l(5). According to a classification scheme(6), BCFs of 851 and 115 measured in fathead minnows (Pimephales promelas)(7) and bluegill sunfish (Lepomis macrochirus)(8), respectively, suggest that bioconcentration in aquatic organisms is high(SRC). However, experiments with rainbow trout (Salmo gairdneri) showed that the majority of (14)C-bis(2-ethylhexyl)phthalate did not reach the systemic circulation of the fish, but was present in the exposure water as metabolites(9). A hydrolysis half-life of 2000 years at pH 7(2) suggests hydrolysis will not be an important environmental process(SRC). Biodegradation in aquatic systems is expected to be an important process under aerobic conditions(SRC). Acclimation is very important; in unacclimated systems no biodegradation was observed(10). River die-away tests have reported half-lives of 2 to 3 weeks(11-13). It was biodegraded with a half-life of 60 to 70 hours in groundwater impacted by bis(2-ethylhexyl)phthalate, ethylbenzene, and xylenes(14). Under anaerobic conditions in water/sediment mixtures, no biodegradation of bis(2-ethylhexyl)phthalate occurs(15,16). [R176] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bis(2-ethylhexyl)phthalate, which has a measured vapor pressure of 7.23X10-8 mm Hg at 25 deg C(2,SRC), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase bis(2-ethylhexyl)phthalate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 18 hours(3,SRC). Particulate-phase bis(2-ethylhexyl)phthalate may be physically removed from the air by wet and dry deposition(SRC). Bis(2-ethylhexyl)phthalate absorbs light in the environmental spectrum(4) indicating a potential for direct photolysis(SRC). Half-lives for the reaction of gas-phase hydroxyl radicals with bis(2-ethylhexyl)phthalate adsorbed onto various aerosols were as follows, days: 1.1 on silicon dioxide; 1.2 on aluminum oxide; 1.3 on iron(III) oxide; and 2.0 on coal fly ash(5,SRC). [R177] BIOD: *AEROBIC: Bis(2-ethylhexyl) phthalate biodegrades rapidly under aerobic conditions following acclimation in biodegradation screening tests(1,2,5,7) in river or lake water(4,5,8), in water/sediment systems(3,6) and in activated sludge(5). Bis(2-ethylhexyl) phthalate was degraded with gradual adaptation; 0, 43, 80, and 95% biodegradation were observed in the original culture, first, second, and third weekly subcultures, respectively, in static flask screening tests using a settled domestic wastewater inoculum(2). River die-away tests have reported half-lives of 2 to 3 weeks(3,4,5). Half-lives of 0.8 days have been reported for bis(2-ethylhexyl) phthalate in activated sludge(5). In oligotrophic lake samples, no degradation occurs(8). Limited data suggest some biodegradation in soil(9,10). Bis(2-ethylhexyl) phthalate subjected to static culture flask biodegradability tests was almost completely bio-oxidized at the end of 3 weeks(11). > 64% removal of bis(2-ethylhexyl) phthalate was observed in a low-loaded activated sludge reactor (hydraulic residence time, 7 hrs; solids retention time, 15 days; BOD loading, 0.21 kg/cu m-day; average volatile suspended solids (VSS) per L of reactor volume, 962; food to microorganisms ratios, 0.20 mg BOD5/mg VSS-day; air-to-liquid volumetric ratio, 13.4) and a biological aerated filter (hydraulic residence time, 0.47 hrs; solids retention time, 5.1 days; BOD loading, 1.17 kg/cu m-day; average volatile suspended solids (VSS) per L of reactor volume, 4230; food to microorganisms ratios, 0.28 mg BOD5/mg VSS-day; air-to-liquid volumetric ratio, 2.0)(12). Observed biological half-lives for bis(2-ethylhexyl) phthalate under aerobic conditions are as follows: pure culture (Penicillium lilacum), 30 days; river water, 4.5 weeks; hydrosoil, 14 days; activated sludge, 17 days; and soil, 31 to 98 days(13). In pure cultures, accumulation of either the monoester or 2-ethylhexanol has been observed(13). In a biodegradability screening test using an activated sludge inoculum based on carbon dioxide evolution, bis(2-ethylhexyl) phthalate reached 4 to 5% ThCO2 (theoretical amount of CO2 of this compound) after 28 days at an initial carbon content of 34.1 to 38.7 mg/l(14). 76 and 71% removal of bis(2-ethylhexyl) phthalate was observed in a trickling filter system and an activated sludge system, respectively(15). Bis(2-ethylhexyl) phthalate was biodegraded with a half-life of 60 to 70 hours in groundwater impacted by this compound, ethylbenzene, and xylenes(16). 81.5% (mean) biodegradation of bis(2-ethylhexyl) phthalate was observed after 24 hours in semicontinuous activated sludge tests; 4 days were required to reach > 90% biodegradation in the activated sludge die-away portion of this test(17). [R178] *AEROBIC: Half-lives of bis(2-ethylhexyl) phthalate in outdoor lysimeter experiments from fallow fields were 54 and 21 days in silty sand and silty loam, respectively; in fields grown with barley, half-lives of bis(2-ethylhexyl) phthalate were 200 and 14 days in silty sand grown and in silty loam, respectively(1). In three soils, (14)C-bis(2-ethylhexyl) phthalate, 10 mg/kg, mineralization ranged from 22 to 32% (14)CO2 after 60 days incubation(2). When present in soil in some nonaqueous-phase liquids, bis(2-ethylhexyl) phthalate was not appreciably mineralized; < 5% mineralization was observed after 15 days in Erie silt loam when dissolved in 2,2,4,4,6,8,8-heptamethylnonane, 50% mineralization was observed after 20 days in Erie silt loam with no added nonaqueous-phase liquids(3). Bis(2-ethylhexyl) phthalate was decomposed slowly in soil with amounts of 15 to 50% remaining after 80 days(4). The low rate and extent of mineralization of bis(2-ethylhexyl) phthalate in heptamethylnonane present in slurries of aquifer solids was increased by inoculation of acclimated microbial cultures(5). [R179] *ANAEROBIC: Under anaerobic conditions in water/sediment mixtures, no biodegradation of bis(2-ethylhexyl)phthalate occurs(1,2). During anaerobic digestion of municipal sludge an overall removal of 83.3% was observed; 61% was removed in primary digestion, 58.5% of the bis(2-ethylhexyl)phthalate entering secondary digestion was degraded(3). In two anaerobic bioassays bis(2-ethylhexyl)phthalate was partially metabolized, but little mineralization was observed(4). Bis(2-ethylhexyl)phthalate was not degraded by any of the anaerobic microbial consortia collected from four distinct ecosystems including freshwater lake sediment, salt marsh sediment, anaerobic digester sludge, and anaerobic leachate from a lab-scale simulated landfill digester(5). Bis(2-ethylhexyl)phthalate at concentrations of 25, 50, 100, and 200 mg C/l reached 48, 26, 19, and 6% of its theoretical gas production, respectively, following lag periods of 24, 25, 28, and > 60 days, respectively, in Reading sludge after 60 days incubation under anaerobic conditions(6). 26% degradation was observed during anaerobic digestion of sludge with a 30 day solids retention time(7). Bis(2-ethylhexyl)phthalate was persistent in experiments with batch anaerobic digestion of spiked sewage sludge at chemical concentration ranges of 0.5 to 10 mg/l(8). [R180] ABIO: *The rate constant for the vapor-phase reaction of bis(2-ethylhexyl)phthalate with photochemically-produced hydroxyl radicals has been estimated as 2.2X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 18 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). An aqueous hydrolysis half-life of 2000 years was determined at pH 7(2). Rate constants for the reaction of gas-phase hydroxyl radicals with bis(2-ethylhexyl)phthalate adsorbed onto various aerosols were as follows, cu cm/s: 1.36X10-11 on silicon dioxide; 1.4X10-11 on aluminum oxide; 1.28X10-11 on iron(III) oxide; and 0.8X10-11 on coal fly ash(3). Corresponding half-lives at a hydroxyl radical concentration of 5X10+5 cu cm are 1.1, 1.2, 1.3, and 2.0 days, respectively(3,SRC). Bis(2-ethylhexyl)phthalate absorbs light in the environmental spectrum indicating a potential for direct photolysis(4). Irradiation of bis(2-ethylhexyl)phthalate with a 300 W xenon lamp resulted in the decomposition of this compound with gaseous carbon dioxide being one of the main products; after 14 hours irradiation, evolved carbon dioxide reached 0.5 to 0.7 mg/g bis(2-ethylhexyl)phthalate(4). 2-Ethyl-1-hexene, 2-ethylhexanol, and phthalic acid were found in the residue of the irradiated bis(2-ethylhexyl)phthalate(4). [R181] BIOC: *Bioconcentration factor for Rainbow Trout: 42-113; Duration, 36 days, whole body. [R182] *Bioconcentration factor for Fathead minnow 155-886; Duration, 56 days, whole body. [R182] *Bioconcentration factor for Gammarus pseudolimnaeus (scud): 54-2,680 (from dry to wet weight); Duration, 14-21 days, whole body. [R182] *Bioconcentration factor for Aselius brevicaudus (sowbug): 14-50 (from dry to wet weight); Duration, 21 days, whole body. [R182] *Experimental BCF values range from a log 2 to 4 in fish and invertebrates(1-7). Log BCFs of 2.93 and 2.06 were measured in fathead minnows (Pimephales promelas)(2) and bluegill sunfish (Lepomis macrochirus), respectively(3). According to a classification scheme(8), these BCFs suggest that bioconcentration in aquatic organisms is high(SRC). However, experiments with rainbow trout (Salmo gairdneri) showed that the majority of (14)C-bis(2-ethylhexyl)phthalate did not reach the systemic circulation of the fish, but was present in the exposure water as metabolites as a result of presystemic branchial metabolism of this compound during uptake from the water to the blood(9). [R183] KOC: *Bis(2-ethylhexyl) phthalate has a strong tendency to adsorb to soil and sediments(SRC). Calculated log Koc values of 4 to 5 have been reported(1,2). Experimental evidence demonstrates strong partitioning to clays and sediments (log K = 4 to 5)(3). A Koc of 87,420 was measured for a Broome County, NY, soil(4). Soil/sediment Koc values range from 87,420 to 510,000(5). Suspended solid Koc values range from 22,000 to 1X10+6(5). Sediment/water partition coefficient of 4.82X10+5 +or- 3.52X10+5 were determined in three standard US EPA sediments (supplied and characterized by the EPA)(6). According to a recommended classification scheme(7), these measured Koc values suggest that bis(2-ethylhexyl)phthalate is expected to be immobile in soil(SRC). Elution of bis(2-ethylhexyl)phosphate from a contaminated sediment with flowing water was unsuccessful due to irreversible adsorption(8). Breakthrough of bis(2-ethylhexyl) phthalate was not detected from two undisturbed soil columns following percolation of about 30 pore volumes(8). Sorption removal accounted for 1.8% and 1.9% of the bis(2-ethylhexyl) phthalate present in the influent of a high-loaded laboratory scale activated sludge reactor (hydraulic residence time, 2.2 hrs; solids retention time, 5 days; BOD loading, 0.66 kg/cu m-day; average volatile suspended solids (VSS) per L of reactor volume, 1160; food to microorganisms ratios, 0.55 mg BOD5/mg VSS-day; air-to-liquid volumetric ratio, 12.6) and a biological aerated filter reactor (hydraulic residence time, 0.23 hrs; solids retention time, 4.3 days; BOD loading, 2.34 kg/cu m-day; average volatile suspended solids (VSS) per L of reactor volume, 4430; food to microorganisms ratios, 0.53 mg BOD5/mg VSS-day; air-to-liquid volumetric ratio, 2.0), respectively(9). Adsorption of bis(2-ethylhexyl) phthalate onto suspended particulates in sea water reached equilibrium in about 2 to 3 hours(10). Reportedly between one-half and two-thirds of the bis(2-ethylhexyl) phthalate in Mississippi river water is associated with particulate matter(11). Sorption of bis(2-ethylhexyl) phthalate onto digester solids accounted for 69% of its removal during anaerobic digestion of sludge(12). [R184] VWS: *The Henry's Law constant for bis(2-ethylhexyl)phthalate is estimated as 1.3X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 7.23X10-8 mm Hg(1), and water solubility, 0.285 mg/l(2). This value indicates that bis(2-ethylhexyl)phthalate is expected to be essentially nonvolatile from water surfaces(3,SRC). Bis(2-ethylhexyl)phthalate's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Bis(2-ethylhexyl)phthalate is not expected to volatilize from dry soil surfaces(SRC) based on a vapor pressure of 7.23X10-8 mm Hg(1). Evaporation rates from the leaves of Sinapis alba in a closed terrestrial simulation chamber of < 0.8 and < 0.5 ng/sq cm-hr (below detection limits) during time intervals of 0-1 and 8-15 days after application of 2.78 ug/sq cm onto the leaves, respectively(4). [R185] WATC: *A level of approximately 0.6 ppm DEHP was percent at the mouth of the Mississippi River. [R186] *DRINKING WATER: US Cities - 0.04 to 30 ppb, 4 pos out of 10(1); 170 parts/trillion groundwater well in NY(2). Bis(2-ethylhexyl)phthalate was detected in 9 of 1,955 drinking water samples from California at concentrations ranging from 3.3 to 93.0 ug/l, mean 19.57 ug/l(3). [R187] *GROUNDWATER: Bis(2-ethylhexyl)phthalate was detected at a concentration of 2.4 ppb in landfill groundwater(1); groundwater receiving wastewater applications to land 0.11 to 1.40 ppb(2). Groundwater samples from a monitoring well at the Lang Property site in Pemberton Township, NJ, where unauthorized disposal of hazardous waste occurred, contained bis(2-ethylhexyl)phthalate at a maximum concentration of 8 ug/l, average 4 ug/l(3). 32% of the groundwater samples from wood treatment facilities across the US contained bis(2-ethylhexyl)phthalate at an average concentration of 14 ug/l(4). [R188] *SURFACE WATER: US Industrialized river basins 132 of 203 samples pos(1) 1 to 80 ppb(1-3). Concn of bis(2-ethylhexyl) phthalate (parts per trillion) in Mississippi River were: Lake Itasca, MN (river source), 190; Cario, IL, 84; 20 miles south of Memphis, TN, 350; and Carrolton St. water intake in New Orleans, LA, 64(4). Average surface water concentrations of bis(2-ethylhexyl) phthalate in samples from the Lang Property site in Pemberton Township, NJ were 10 ug/l(5). Bis(2-ethylhexyl) phthalate was detected in water and suspended sediments collected from the Niagara River at Fort Erie and Niagara-on-the-Lake between Dec 1984 and March 1986(6). A sample of river water from the Fenholloway River, FL collected downstream of the outfall from a kraft mill contained 26 ug/l bis(2-ethylhexyl) phthalate(7). Bis(2-ethylhexyl) phthalate residues were detected in Klang river water, Malaysia between Jan 1992 and Feb 1993 at concentrations ranging from 3.1 to 64.3 ug/l(8). Bis(2-ethylhexyl) phthalate was isolated from Putah Creek water, Sacramento River water, and Clear Lake water, CA in Dec 1993(9). Bis(2-ethylhexyl) phthalate was detected in the dissolved and particulate phase in water samples from the River Mersey Estuary, UK, at concentrations ranging from 0.125 to 0.693 ug/l and 279.78 to 637.96 ng/g, respectively(10). Bis(2-ethylhexyl) phthalate was detected in water samples collected near the Humber, Mersey, Tamar, Tees, and Tyne estuaries in May to June 1988 and Nov to Dec 1989 at concentrations ranging from < 50 to 8400 ng/cu dm(11). Bis(2-ethylhexyl) phthalate was detected in surface Antarctic snow at median concentrations of below detection limit to 88 ng/l in 1987 to 1988, 66 to 147 ng/l in 1988 to 1989, and 173 to 289 ng/l in 1990 to 1991(12). [R189] *SEAWATER: Bis(2-ethylhexyl) phthalate was detected in the Gulf of Mexico at an avg concentration of 112 parts per trillion(1) and in Galveston Bay, TX at an avg concentration of 600 parts per trillion, range 54 to 3000 parts per trillion(2). Bis(2-ethylhexyl) phthalate was detected in the dissolved fraction of water samples from 16 sites in the Mersey Estuary, UK, at concentrations ranging from 83 to 335 ng/l; it was detected in the particulate fraction of water samples from 17 sites at concentrations ranging from 182 to 1,700 ng/g(3). [R190] *RAIN/SNOW: Bis(2-ethylhexyl)phthalate was detected in the North Pacific avg 55 parts per trillion, 5 to 213 parts per trillion(1); Urban College Station, TX, Feb-May, 1979, unfiltered rain, 2.6 parts per trillion avg concn(2). [R191] EFFL: *Industries with mean bis(2-ethylhexyl) phthalate concns exceeding 200 ppb in treated wastewater were: auto and other laundries, 440 ppb; coal mining, 940 ppb; aluminum forming, < 13,000 parts per trillion; foundries, 1,100 ppb(1). Mean concns of bis(2-ethylhexyl) phthalate in wastewater from water-based paint plants and ink manufacturing plants 400 ppb and 12,500 ppb, respectively(2). Bis(2-ethylhexyl) phthalate has been detected in diesel exhaust(2). Groundwater from four USA rapid-infiltration sites for municipal primary and secondary effluents contained bis(2-ethylhexyl) phthalate at concns ranging from 0.11 to 1.40 ug/l, 0.55 ppb avg of 3 sites; it was detected and verified, but not quantitated at 1 site(3). Emission rates of bis(2-ethylhexyl) phthalate from four municipal wastewater sludge incinerators sampled from April to Oct 1987 ranged from not detected to 1.1 g/hr(4). Analysis of NYC municipal wastewaters from 1989 to 1993 revealed bis(2-ethylhexyl) phthalate at concns ranging from 10 to 180 ug/l in the influent and 5 to 50 ug/l in the effluent(5). The bis(2-ethylhexyl) phthalate concn in effluent from an advanced wastewater treatment plant in Orange County, CA ranged from < 4 to 15 ug/l(6). Effluent samples from three New Jersey publicly owned treatment works contained bis(2-ethylhexyl) phthalate at estimated concns ranging from 50 to 103 ppb(7). Industrial landfill leachate and municipal landfill leachate contained < 0.01 to 53 mg/l and 34 to 150 mg/l bis(2-ethylhexyl) phthalate, respectively(8). Bis(2-ethylhexyl) phthalate was detected in fly ash and fly ash-bottom ash mixtures from municipal solid waste incineration at a concns of 7 to 95 ug/kg fly ash and 1,500 to 7,400 ug/kg fly ash-bottom ash(9). Bis(2-ethylhexyl) phthalate was detected at a maximum concn of 3.0X10+6 ug/kg at the Bayou Bonfouca hazardous waste site located in Slidell, Louisiana(10). It was detected in leachate and associated sediment from the Ludlow Sand and Gravel site, Paris, NY(11). Bis(2-ethylhexyl) phthalate was identified in Prestwich (Manchester, UK) sewage treatment effluent at a concn of 1.9 ug/l(12). [R192] SEDS: *SEDIMENT: Bis(2-ethylhexyl) phthalate was detected in surface sediment samples from: the Rhine and Ijessel Rivers at concentrations ranging from 1 to 70 ppm, the Mississippi R delta at a mean concentration of 0.069 ppm, the Gulf of Mexico, nearshore (offshore), at a mean concentration of 0.007 (0.002) ppm, and in Lake Superior sediments at a concentration of 200 ppm(1). It was detected in sediments from Galveston Bay, TX at an avg concn of 0.022 ppm(2). Sediments from the Chesapeake Bay contained bis(2-ethylhexyl) phthalate at concn ranging from 0.022 to 0.18 ppm(3). Sediments collected from 8 coastal sites in Portland, ME, contained bis(2-ethylhexyl) phthalate at concn ranging from 60 to 7800 ng/g, average 1500 ng/g(4). Bis(2-ethylhexyl) phthalate was detected in 16% of 31 sediment samples collected from the Detroit River in 1982 at mean concentrations ranging from 0.12 to 1.18 mg/kg(5). Bis(2-ethylhexyl) phthalate residues were detected in sediment samples of Klang River water, Malaysia, at concentrations ranging from 493 to 15,015 ng/g dry weight(6). It was detected in surface sediments from the River Mersey Estuary at Speke and Runcorn, UK at concentrations of 1.220 and 1.199 ug/g dry weight(7). [R193] *SOIL: Bis(2-ethylhexyl)phthalate was detected in soil and sediment samples from the Havertown PCP site in Havertown, PA at a maximum concentration of 34,000 and 2100 ug/kg, respectively(1). Soil samples collected from the Fountain Avenue Landfill, NJ contained bis(2-ethylhexyl)phthalate at concentrations ranging from not detected to 16,239.5 ug/kg dry soil(2). Bis(2-ethylhexyl)phthalate was detected in subsurface soil from Carolawn an abandoned waste storage and disposal facility in Fort Lawn, SC at concentration ranging from not detected to 0.33 mg/kg at a depth of 3.0 to 6.3 feet(3). It was also detected in shallow soil at this site at concentrations ranging from not detected to 55 mg/kg(3). [R194] ATMC: *URBAN: Bis(2-ethylhexyl) phthalate was detected in ambient air from three urban sites in New York City (Queens, Brooklyn, and Staten Island) in 1975 at concn of 10.2, 16.8, and 14.2 ng/cu m, respectively(1). It was detected at concentrations ranging from 26 to 132 ug/1000 cu m in air samples collected near Antwerp, Belgium; airborne particulate matter collected near the Csomic Ray Laboratory of Chacaltaya, Bolivia contained 17 and 20 ug/1000 cu m bis(2-ethylhexyl) phthalate(2). It was detected in urban air samples from Belgium at avg bis(2-ethylhexyl) phthalate concn of 54.1 ug/1000 cu m in particulates and 127 ug/1000 cu m in the gas phase(3). The median atmospheric concentration of bis(2-ethylhexyl) phthalate in Sweden was 2.0 ng/cu m; median precipitation concentration from both wet and dry deposition was 48 ng/l(4). Mean atmospheric concentrations in the Great Lakes, Portland, OR, and Enewetak Atoll in the North Pacific Ocean were 2.0, 0.39, and 1.4 ng/cu m, respectively; mean precipitation concentrations for these areas were 6, 2.6, and 55 ng/l, respectively(4). RURAL/REMOTE: It was detected in rural air in College Station, TX, 1979 to 1980, 0.77 to 3.60 ng/cu m(5). It was detected in the air of Pigeon Key, FL, the Gulf of Mexico, and the North Atlantic at concentrations of 16.6, 1.2, and 2.9 ng/cu m, respectively(6). [R195] *SOURCE DOMINATED: The maximum air concentration of bis(2-ethylhexyl)phthalate at the Havertown PCP site, PA was 400 ng/cu m(1). [R196] FOOD: *Migration of DEHP from paper, aluminum foil, and plastic to instant cream soup (14 months after manufacture): total ppm of phthalate esters in packaging materials was 24.52 ppm, of which 1.35 ppm was DEHP, and total ppm of phthalate esters in foodstuff was 1.77 ppm, of which 0.04 ppm was DEHP. /From table/ [R197] *Migration of DEHP from paper and plastic to fried potato cakes (1 month after manufacture): total ppm of phthalate esters in packaging materials were 396.91 ppm, of which 385.85 ppm were DEHP, and total ppm of phthalate esters in food stuff were 1.16 ppm, of which 0.05 ppm were DEHP. In another potato cake sample the figures were 34.78 ppm, 11.80 ppm, and 10.27 ppm, 9.06 ppm respectively, but the time after manufacture was not specified. /From table/ [R197] *Migration of DEHP from plastic and laminated film to Tempura (frying) powder (3 months after manufacture): total ppm of phthalate esters in packaging materials were 3,745.28 ppm, of which 3,675.0 ppm were DEHP, and total ppm of phthalate esters in foodstuff were 82.78 ppm, of which 68.08 ppm were DEHP. /From table/ [R197] *Migration of DEHP from plastic and laminated film to tempura (frying) powder (4 months after manufacture): total ppm of phthalate esters in packaging materials were 8.59 ppm, of which 2.30 ppm were DEHP, and total ppm of phthalate esters in foodstuff were 0.50 ppm, of which 0.11 ppm were DEHP. /From table/ [R197] *Because bis(2-ethylhexyl) phthalate is used as a plasticizer in polyvinyl chloride (plastic wrap) which may contact food, some bis(2-ethylhexyl) phthalate in foods may be due to migration from packaging materials(1). In Japan, concentrations in foodstuffs that were in contact with packaging material varied from 0 to 68 ppm(1). [R198] *Bis(2-ethylhexyl)phthalate was detected in 16 of 16 samples of 80 proof vodka at concentration of 62 to 212 ppb and 8 of 8 samples of 100 proof vodka at 144 to 326 ppb(1). It was also detected in 23 of 26 samples of flavored vodka at 128 and 492 ppb(1). Bis(2-ethylhexyl)phthalate was detected in the following foods packaged in glass containers capped with twist-off caps, mg/kg: wild cherry jam, 0.13; pickled chillies, 0.65; ketchup, 0.12; hot ketchup, 0.05; tomato juice, 0.05; and orange juice, 0.02(2). Concentrations of bis(2-ethylhexyl)phthalate in egg whites of chicken eggs collected from retail stores in Japan in 1977 ranged from 0.05 to 0.4 ppm(1). [R199] PFAC: FISH/SEAFOOD CONCENTRATIONS: *DEHP was found in fish available to Canadian consumers at concentrations of 0-160 ug/kg. [R200] *DEHP found in hatchery-reared juvenile Atlantic salmon at concentrations of 13,000- 16,000 ug/kg (lipid). [R200] *DEHP found in channel catfish located in Mississippi and Arkansas at concentration of 3,200 ug/kg. Also found in channel catfish at Fairpoint National Fish Hatchery, Iowa, at a concentration of 400 ug/kg. [R200] *Marine fish and shellfish - 10-100 ppb(1,2); Processed canned tuna and salmon in Canada - 40-160 ppb(3); fish, Lake Superior - 0.3-0.7 ppb(4). Bis(2-ethylhexyl)phthalate was detected in fish from the following rivers in WI, mg/kg: Menominee, < 0.80 to 32.10; Kinnickinnic, 4.30; Wolf, 0.30 to 1.80; Fox above DePere, 0.05 to 0.60; Fox below Depere, 1.5 to 3.4; Chequamegon Bay, < 0.20 to 0.12; Milwaukee, < 1.0; Sheboygan, < 0.04 to 2.0; and the Black and Ashtabula Rivers in OH, < 0.04 to 0.76(5). It was detected in the following fish from Lake Michigan tributaries, mg/kg wet weight: common carp in the St. Joseph River, 0.62; northern pike from the Escanaba River, 0.94; and rock bass from the Ford River, 0.49(6). Bis(2-ethylhexyl)phthalate residues were detected in the following organisms from the Blanco River, Veracruz, Mexico, ug/g, extractable lipid basis: Machrobranchium sp., 791.2; C. paralellus, 452.0; O. imiceps, 9876.1; C. arenarius, 432.6; O. niloticus, 167.6 to 8061.5; and Penaeus sp., 1410.6(7). [R201] ANIMAL CONCENTRATIONS: *DEHP was found in common seal pup blubber at concentrations of 13,000-16,000 ug/kg. [R202] *Bis(2-ethylhexyl)phthalate has been detected in animal tissues at the following concentrations, ug/kg: cow heart, 135; rat heart, 1.29; rabbit heart, 1.18; dog heart, 0.36; and soil arthropods, 2.8(1). [R203] MILK: *Bis(2-ethylhexyl)phthalate was detected in 80 mg/l of milk (whole milk basis, one sample), not detected in later samples from the same farm(1). [R204] OEVC: *Bis(2-ethylhexyl)phthalate has been detected in commercial organic solvents(1). Bis(2-ethylhexyl)phthalate was tentatively identified in bulk coal tar and 1-year aged coal tar film at concentrations of 930 and 540 mg/kg, respectively(2). Bis(2-ethylhexyl)phthalate content of some common laboratory items, ppm: Tygon tubing, 20,000; neoprene stopper, 1,600; black rubber tubing, 250; black rubber stopper, 30; cork, 6; amber latex tubing, 4; glass wool, 1; Teflon sheet, 0.8; polyethylene tubing, 0.8; aluminum foil, 0.3; tap water, 0.0015; sodium chloride, 0.0015; sodium sulfate, 0.002; Florisil, 0.00005; and distilled water, < 0.00005(3). Bis(2-ethylhexyl)phthalate was detected in sludge samples at the following average concentrations, ug/kg: Southerly raw sludge, 2,313; Jackson Pike combined domestic sludge, 9,767; and Jackson Pike oxidized sludge, 36,670(4). In a nationwide survey of raw sludge, bis(2-ethylhexyl)phthalate was detected in 95% of the samples at concentrations ranging from 20 to 35,000 mg/kg(4). Qualitative analysis of extracts from a carpet sample confirmed the presence of bis(2-ethylhexyl)phthalate(5). It was identified in weathering crusts from cathedrals in Sevilla, Spain and Mechelen, Belgium(6). [R205] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 261,829 workers (84,056 of these are female) are potentially exposed to bis(2-ethylhexyl)phthalate in the US(1). Occupational exposure to bis(2-ethylhexyl)phthalate may occur through inhalation of aerosols and dermal contact with this compound at workplaces where bis(2-ethylhexyl)phthalate is produced or used(SRC). The general population may be exposed to bis(2-ethylhexyl)phthalate via inhalation of ambient air, ingestion of contaminated food and drinking water, and dermal contact with products containing this compound(SRC). [R206] *Humans are primarily exposed to bis(2-ethylhexyl) phthalate through drinking water, ambient air, fish and seafood, and foods which have been in contact with packaging materials that use bis(2-ethylhexyl) phthalate as a plasticizer(SRC). Humans also receive significant exposures to bis(2-ethylhexyl) phthalate during blood transfusions due to migration of bis(2-ethylhexyl) phthalate into the blood from the blood bag(1). [R207] *DI(2-ETHYLHEXYL) PHTHALATE WAS DETECTED IN WHOLE BLOOD THAT HAD BEEN STORED IN POLYVINYL CHLORIDE BLOOD BAGS @ LEVELS RANGING FROM 75-109 MG/L ... AND IN PLASMA STORED IN SUCH BAGS @ LEVELS UP TO 250 MG/L. ANOTHER STUDY SHOWED CONCN OF 66 MG/L IN BLOOD STORED IN THESE BAGS ... BLOOD STORED @ 4 DEG C IN SUCH BAGS LEACHED DI(2-ETHYLHEXYL) PHTHALATE FROM THE PLASTIC AT A LINEAR RATE OF APPROX 2.5 + OR - 0.3 MG/L PER DAY ... [R208] AVDI: *AIR INTAKE (assume 0.39 to 14 ng/cu m)(1,2) - 7.8 to 280 ng; WATER INTAKE (assume 0.04 to 30 ppb)(3,4)- 0.08 to 60 ug. (SRC) [R209] BODY: *Bis(2-ethylhexyl) phthalate was detected in human adipose tissue at concns of 0.30 to 1.15 ppm(1,2). [R210] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers bis-(2-ethylhexyl)-phthalate to be a potential occupational carcinogen. [R34, 118] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 5 mg/cu m. [R211] +Vacated 1989 OSHA PEL TWA 5 mg/cu m; STEL 10 mg/cu m is still enforced in some states. [R34, 363] NREC: +NIOSH recommends that di-sec octyl phthalate be regulated as a potential human carcinogen. [R34, 118] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R34, 118] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 mg/cu m. [R34, 118] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 10 mg/cu m. [R34, 118] TLV: +8 hr Time Weighted Avg (TWA): 5 mg/cu m. [R44, 2002.28] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R44, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R44, 2002.28] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Bis(2-ethylhexyl)phthalate is included on this list. [R212] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 6 ug/l [R213] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 4 ug/l [R213] STATE DRINKING WATER GUIDELINES: +(ME) MAINE 25 ug/l [R213] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Phthalate esters/ [R214] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester is included on this list. [R215] *A testing consent order is in effect for di-2-ethylhexyl phthalate for chemical fate testing. FR citation: 1/9/89. [R216] RCRA: *U028; As stipulated in 40 CFR 261.33, when 1,2-benzenedicarboxylic acid, bis(2-ethylhexyl) ester, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R217] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Bis(2-ethylhexyl) phthalate is found on List C. Case No: 3112; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Bis(2-ethylhexyl) phthalate; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R6] FDA: *Dioctylphthalate an indirect food additive for use only as a component of adhesives. [R218] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 5020. Analyte: Bis(2-ethylhexyl) phthalate. Matrix: Air. Sampler: Filter (0.8-um celluiose ester membrane). Flow Rate: 1 to 3 l/min: Sample Size: 50-liters. SHIPMENT: Routine. Sample Stability: Bis(2-ethylhexyl)phthalate is greater or equal to 6 days @ 25 deg C; Dor not known. [R219] *Precleaned mason glass jars, with capliners of clean aluminum foil, /were used/ for collection and storage of water, sediment and biota samples. Whole fish samples were wrapped in aluminum foil and stored at or below 0 deg C. The skin or shells of biota samples were removed when possible and discarded before sample analysis. /Phthalate esters/ [R220] *The concentration of phthalate esters from aqueous samples has been investigated ... using XAD resin and polyurethane foam. These on-site concentration techniques may help to simplify phthalate ester analysis if enough water can be sampled to give quantities of phthalate esters well above background levels. /Phthalate esters/ [R221] ALAB: *Gas chromatography is the most common method of analysis particularly for trace levels. Detection can be done with electron capture or flame ionization detectors. [R222] *METHOD FOR DETERMINING PHTHALATE ESTERS IN ENVIRONMENTAL SAMPLES USING A SINGLE EXTRACT BY DUAL COLUMN LIQUID CHROMATOGRAPHY FRACTIONATION AND GC/ELECTRON CAPTURE DETECTION. /PHTHALATE ESTERS/ [R223] *NIOSH Method 5020. Analyte: Bis(2-ethylhexyl)phthalate. MATRIX: Air. Procedure: Gas chromatography, flame ionization detector. For bis(2-ethylhexyl)phthalate this method has an estimated detection limit of 0.01 mg/sample. The overall precision/RSD is 0.05 @ 0.07 to 0.3 mg/sample. Applicability: The working range is 1 to 20 mg/cu m for a 50-liter air sample. Interferences: None identified. [R219] *EPA Method 8060. Gas Chromatography using solvent flush technique and a electron capture detector or a flame ionization detector for the detection of ppb levels of phthalate esters in solid waste. Ground water samples should be determined by electron capture detector. For bis(2-ethylhexyl)phthalate the method detection limit for electron capture detector is 2.0 ug/l and for flame ionization detector is 20 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R224] *EPA Method 8250. Packed Column Gas Chromatography/Mass Spectrometry Technique for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soil, and groundwater. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride and capable of being eluted wtih derivatization as sharp peaks from a gas chromatographic packed column. Under the prescribed conditions, bis(2-ethylhexyl)phthalate has a detection limit of 2.5 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R224] *EPA Method 606. Gas Chromatography with electron capture detection for the anlaysis of phthalate esters including bis(2-ethylhexyl) phthalate in municipal and industrial discharges. Under the prescribed conditions, for bis(2-ethylhexyl)phthalate the method has a detection limit of 2.0 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R225] *EPA Method 1625. Isotope Dilution Capillary Column Gas Chromatography/Mass Spectrometry method for the determination of semivolatile organic compounds in municipal and the industrial discharges. By adding a known amount of a labeled compound to every sample prior to purging, a correction for recovery of the pollutant can be made. If labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, for the labeled, unlabeled is(2-ethylhexyl)phthalate the method has a minimum detection level of 10 ug/l, and 10 ug/l, respectively. The initial precision is .29 ug/l, the accuracy is 32 to 205 ug/l, and the labeled compound recovery is 18 to 364%. [R225] *EPA Method 625. Gas Chromatography/Mass Spectrometry Method for the analysis of acid/base/neutral extractables including bi(2-ethylhexyl)phthalate in municipal and industrial discharges. Under the prescribed conditions for bis(2-ethylhexyl)phthalate the method has a detection limit of 2.5 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R225] *EMSLC Method 506. Determination of Phthalate and Adipate Esters in Drinking Water by Liquid-liquid Extraction or Liquid-solid Extraction and Gas Chromatography with Photoionization Detection, CGCPID, drinking water, method detection limit 2.3 ug/l. [R226] *OSW Method 8061. Determination of Phthalate Esters by Gas Chromatography using a Capillary Column and Electron Capture Detector (GC/ECD), CGCECD, various, method detection limit 270 ng/l. [R227] *OSW Method 8410. Determination of Semivolatile Organics by using the Gas Chromatography/ Fourier Transform Infrared (GC/FTIR) with a Capillary Column - Base/Neutral Extractables, GCFTIR, various, identification limit 13 ug/l. [R227] *OSW Method 8270B. Determination of Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique, CGCMS, soil/waste, estimated quantitation limit 660 ug/kg. [R227] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: KAUL AF ET AL; CLIN PHARM 16 (9): 689 (1982). A REVIEW OF POSSIBLE TOXICITY OF DI-2-ETHYLHEXYLPHTHALATE (DEHP) IN PLASTIC INTRAVENOUS CONTAINERS: EFFECTS ON REPRODUCTION. NORTHRUP S ET AL; J TOXICOL ENVIRON HEALTH 10 (3): 493 (1982). A REVIEW WITH MANY REFERENCES ON THE CARCINOGENICITY OF BIS(2-ETHYLHEXYL) PHTHALATE. AUTIAN J; ENVIRON HEALTH PERSPECT 45: 115 (1982). IN ADDITION TO REVIEWING THE TERATOGENIC, MUTAGENIC, AND ANTIFERTILITY ACTIVITY OF PHTHALATES, NEW DATA SHOWED THAT DEHP HAD ANTIFERTILITY ACTIVITY IN MALE MICE. USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters (1980) EPA 440/5-80-067. Nat'l Research Council Canada; Phthalate Esters in the Aquatic Environment (1980) NRCC No. 17583. DHHS/ATSDR; Toxicological Profile for Di(2-ethylhexyl)phthalate TP-92/05 (1993) Rock G et al; Environ Health Perspect 65: 309-16 (1986). A review with 25 references on the leaching of DEHP into blood and blood products stored in plastic containers, toxic metabolites of DEHP, its interaction with blood elements and more are discussed. Albro PW; Environ Health Perspect 65: 293-8 (1986). A review with 33 references on the metabolism of DEHP and the toxicity of DEHP and its metabolites. WHO; Environmental Health Criteria 131: Diethylhexyl Phthalate (1992) DHHS/NTP; Carcinogenesis Bioassay of Di(2-ethylhexyl)phthalate in F344 Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 217 (1982) NIH Publication No 82-1773 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 210 R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 304 R3: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Bis(2-ethylhexylphthalate) (117-81-7). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of October 24, 2002. R4: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 824 R5: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. 238 R6: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.270 (Spring, 1998) EPA 738-R-98-002 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 271 (1982) R8: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. R9: SRI R10: CHEMICAL PRODUCTS SYNOPSIS: Dioctylphthalate R11: Nat'l Research Council Canada; Phthalate Esters in the Aquatic Environment p.27 (1980) NRCC No 17583 R12: Nat'l Research Council Canada; Phthalate Esters in the Aquatic Environment p.49 (1980) NRCC No 17583 R13: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994.p. V9 803 R14: United States International Trade Commission. Synthetic Organic Chemicals-- United States Production and Sales, 1981. USITC Publications 1291 Washington, DC: United States International Trade Commission, 1981.173 R15: United States International Trade Commission. 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Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 270 R22: Debruijin J et al; J Environ Toxicol Chem 8: 499-512 (1989) R23: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 265 R24: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-204 R25: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.223 R26: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Version (1992) R27: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 25 R28: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. 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Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp, Vol 5 (1996) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Version (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) Loekke H, Bro-Rasumussen F; Chemosphere 10: 1223-35 (1981) R186: USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters p.C-2 (1980) EPA 440/5-80-067 R187: (1) Keith LH et al; Ident and Anal of Organ Pollut in Water. Ann Arbor,MI: Ann Arbor Press p 329-73 (1976) (2) Burmaster DE; Environ 24: 6-13 (1982) (3) Storm DL; pp. 67-124 in Water Contamination and Health, Wang RGM ed, NY,NY: Marcel Dekker, Inc (1994) R188: (1) Dunlap WJ et al; Organic Pollutants Contributed to Groundwater by a Landfill. USEPA-600/9-76-004 p. 96-110 (1976) (2) Hutchins SR et al; Environ Toxicol Chem 2: 195-216 (1983) (3) USEPA; Superfund Record of Decision (EPA Region 2): Lang Property, Pemberton Township, NJ USEPA/ROD/RO2-86/031. NTIS PB87-188470, Washington, DC (1987) (4) Rosenfeld JK, Plumb RH Jr; Ground Water Monit Rev 11: 133-40 (1991) R189: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters. USEPA-568/6-77-015 and 015a p. 75 (1977) (2) Sheldon LS, Hites RA; Environ Sci Tech 12: 1188-94 (1978) (3) Sheldon LS, Hites RA; Environ Sci Tech 13: 574-9 (1979) (4) DeLeon IR et al; Chemosphere 15: 795-805 (1986) (5) US EPA; Superfund Record of Decision (EPA Region 2): Lang Property, Pemberton Township, NJ EPA/ROD/RO2-86/031. PB87-188470, Washington, DC (1987) (6) Great Lake Water Quality Board; Report to the International Joint Commission, Vol II (1989) (7) Watts GB, Locke BR; Environ Sci Technol 27: 2311-7 (1993) (8) Tan GH; Bull Environ Contam Toxicol 54: 171-6 (1995) (9) Umano K et al; Bull Environ Contam Toxicol 56: 558-65 (1996) (10) Preston MR, Al-Omran LA; Environ Pollut 62: 183-93 (1989) (11) Law RJ et al; Wat Sci Tech 24: 127-34 (1991) (12) Desideri PG et al; J Environ Anal Chem 55: 33-46 (1994) R190: (1) Giam CS et al; Mar Pollut Transfer p 375-86 (1976) (2) Murray HE et al; Bull Environ Contam Toxicol 26: 769-74 (1981) (3) Preston MR, Al-Omran LA; Mar Pollut Bull 17: 548-53 (1986) R191: (1) Atlas E, Giam CS; Science 211: 163-5 (1981) (2) Mazurek MA; Simoneit BRT; Crit Rev Environ Control 16: 69 (1986) R192: (1) USEPA; Treatability Manual page I.65-3 USEPA-600/2-82-001a (1982) (2) IARC; Monograph. Some Industrial Chemicals and Dyestuffs 29: 274 (1982) (3) Hutchins SR, Ward CH; J Hydrol 67: 223-22 (1984) (4) Vancil MA et al; Emissions of Metals and Organics from Municipal Wastewater Sludge Incinerators, Project Summary. USEPA Risk Reduction Eng Lab, Cincinnati, OH USEPA/600/S2-91/007 (1991) (5) Srubin AI et al; Water Environ Res 68: 1037-44 (1996) (6) McCarty PL, Reinhard M; J Water, Pollut Control Fed 52: 1907-22 (1980) (7) Clark LB et al; Res J WPCF 63: 104-13 (1991) (8) Brown KW, Donnelly KC; Haz Wast Haz Mater 5: 1-30 (1988) (9) Shane BS et al; Arch Environ Contam Toxicol 19: 665-73 (1990) (10) Acharya AP, Ives P; J Air Waste Manage Assoc 44: 1195-1203 (1994) (11) USEPA; Superfund Record of Decision (EPA Region 2): Ludlow Sand and Gravel Site, Town of Paris, Oneida County, NY (First Remedial Action) U.S. EPA (Off Emerg Rem Response, Washington, DC) USEPA/ROD/RO2-88/067; PB89-182521 (1988) (12) Fatoki OS, Vernon F; Sci Total Environ 95: 227-32 (1990) R193: (1) Giam CS, Atlas EL; Die Naturwissenschaften 67:508 (1980) (2) Murray HE et al; Bull Environ Contam Toxicol 26: 769-74 (1981) (3) Peterson JC, Freeman DH; Environ Sci Technol 16: 464-9 (1982) (4) Ray LE et al; Chemosphere 12: 1031-8 (1983) (5) Great Lake Water Quality Board; Report to the International Joint Commission, Vol II (1989) (6) Tan GH; Bull Environ Contam Toxicol 54: 171-6 (1995) (7) Preston MR, Al-Omran LA; Environ Pollut 62: 183-93 (1989) R194: (1) USEPA; Superfund Record of Decision (EPA Region 3): Havertown PCP site, Haverford Township, Delaware County, PA (First Remedial Action) USEPA (Off Emerg Remed Response, Washington, DC USA) Report 1989, USEPA/ROD/RO3-89/076; NTIS PB90-178112 (1989) (2) Rugge CD, Ahlert RC; Water Res 26: 519-26 (1992) (3) ATSDR; Public Health Assessment for Carolawn, Fort Lawn, Chester County, SC, Region 4, CERCLIS No SCD980558316 Addendum. NTIS PB93-146249 (1993) R195: (1) Bove JL et al; Int J Environ Anal Chem 5: 189 (1978) (2) Cautreels W et al; Sci Total Environ 8: 79 (1977) (3) Cautreels W, Van Cauwenberghe K; Atmos Environ 12: 1133-41 (1978) (4) Thuren A, Larsson P; Environ Sci Technol 24: 554-9 (1990) (5) Duce RA et al; Rev Geophysics Space Physics 21: 921-52 (1983) (6) Atlas E, Giam CS; Science 211: 163-5 (1981) R196: (1) USEPA; Superfund Record of Decision (EPA Region 3): Havertown PCP site, Haverford Township, Delaware County, PA (First Remedial Action) U.S. EPA (Off Emerg Remed Response, Washington, DC USA) Report 1989, USEPA/ROD/RO3-89/076, NTIS PB90-178112 (1989) R197: USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters p.C-5 (1980) EPA 440/5-80-067 R198: (1) USEPA; Ambient Water Quality Criteria for Phthalate Esters USEPA-440/5-80-067 p. C-4 (1980) R199: (1) Leibowitz JN et al; J AOAC Inter 78: 730-5 (1995) (2) Gramiccioni L et al; Rass Chim 42: 3-7 (1990) (3) Ishida M et al; J Agr Food Chem 29: 72 (1981) R200: Nat'l Research Council Canada; Phthalate Esters in the Aquatic Environment p.61 (1980) NRCC No. 17583 R201: (1) Giam CS et al; Anal Chem 47: 2225-9 (1975) (2) Giam CS et al; Mar Pollut Transfer p 375-86 (1976) (3) Williams DT; J Agr Food Chem 21: 1128-9 (1973) (4) Swain WR; J Great Lakes Res 4:398-407 (1978) (5) DeVault DS; Arch Environ Contam Toxicol 14: 587-94 (1985) (6) Camanzo J et al; J Great Lakes Res 13: 296-309 (1987) (7) Albert LA; Adv Environ Sci Technol 23: 541-77 (1990) R202: Nat'l Research Council Canada; Phthalate Esters in the Aquatic Environment p.61(1980) NRCC No. 17583 R203: (1) Wams TJ; Sci Total Environ 66: 1-16 (1987) R204: (1) Cerbulis J, Ard JS; J Assoc Off Anal Chem 501: 646-50 (1967) R205: (1) IARC; Some Industrial Chemicals and Dyestuffs 29: 269 (1980) (2) Nelson EG et al; Environ Sci Technol 30: 1014-22 (1996) (3) Giam CS et al; The Handbook of Environmental Chemistry of Anthropogenic Compounds, 67-141 (1984) (4) Stonerook H; J Water Pollut Control Fed 56: 1093-8 (1984) (5) Pleil JD, Whiton RS; Appl Occup Environ Hyg 5: 693-9 (1990) (6) Fobe BO et al; Environ Sci Technol 29: 1691-1701 (1995) R206: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R207: (1) IARC; Some Industrial Chemicals and Dyestuffs 29: 269 (1980) R208: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 275 (1982) R209: (1) Bove JL et al; Int J Environ Anal Chem 5: 189 (1978) (2) Thuren A, Larsson P; Environ Sci Technol 24: 554-9 (1990) (3) Storm DL; pp. 67-124 in Water Contamination and Health, Wang RGM ed, NY,NY: Marcel Dekker, Inc (1994) (4) Keith LH et al; Ident and Anal of Organ Pollut in Water. Ann Arbor MI: Ann Arbor Press p 329-73 (1976) R210: (1) Mes J, Campbell DS; Bull Environ Contam Toxicol 16: 53-60 (1976) (2) Campbell DS et al; Bull Environ Contam Toxicol 12: 721-5 (1974) R211: 29 CFR 1910.1000 (7/1/98) R212: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R213: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R214: 40 CFR 401.15 (7/1/87) R215: 40 CFR 716.120 (7/1/96) R216: 40 CFR 799.5000 (7/1/96) R217: 40 CFR 261.33 (7/1/96) R218: 21 CFR 175.105 (4/1/96) R219: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5020-1 R220: Nat'l Research Council Canada; Phthalate Esters p.39 (1980) NRCC No. 17583 R221: Nat'l Research Council Canada; Phthalate Esters p.40 (1980) NRCC No. 17583 R222: Van Rossum; J Chromatography 150: 381 (1978) R223: RUSSELL DJ, MCDUFFIE B; INT J ENVIRON ANAL CHEM 15 (3): 165-84 (1983) R224: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R225: 40 CFR 136 (7/1/90) R226: USEPA; EMMI. Environmental Monitoring Methods Index. Version 2.0 NTIS PB-95-502415 (1995) R227: USEPA; Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September 1994 (1994) RS: 226 Record 55 of 1119 in HSDB (through 2003/06) AN: 343 UD: 200302 RD: Reviewed by SRP on 5/6/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BIS(2-ETHYLHEXYL) ADIPATE SY: *ADIPIC ACID, BIS(2-ETHYLHEXYL) ESTER; *ADIPOL-2EH-; *AI3-28579-; *BEHA-; *BIS-(2-ETHYLHEXYL)ESTER KYSELINY ADIPOVE (Czech); *Bis(2-Ethylhexyl)Hexanedioate; *BISOFLEX-DOA-; *DEHA-; *Di-2-ethylhexyl-adipate-; *DIOCTYL-ADIPATE-; *DOA-; *EFFOMOLL-DOA-; *ERGOPLAST-AdDO-; *FLEXOL-A-26-; *FLEXOL-PLASTICIZER-10-A-; *FLEXOL-PLASTICIZER-A-26-; *HEXANEDIOIC ACID, BIS(2-ETHYLHEXYL) ESTER; *HEXANEDIOIC ACID, DI(2-ETHYLHEXYL) ESTER; *HEXANEDIOIC-ACID,-DIOCTYL-ESTER-; *Kemester-5652-; *KODAFLEX-DOA-; *MONOPLEX-DOA-; *NCI-C54386-; *NSC-56775-; *OCTYL-ADIPATE-; *PLASTOMOLL-DOA-; *PX-238-; *REOMOL-DOA-; *RUCOFLEX-PLASTICIZER-DOA-; *SICOL-250-; *STAFLEX-DOA-; *TRUFLEX-DOA-; *VESTINOL-OA-; *WICKENOL-158-; *WITAMOL-320- RN: 103-23-1 MF: *C22-H42-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ADIPIC ACID AND 2-ETHYLHEXANOL IN THE PRESENCE OF AN ESTERIFICATION CATALYST SUCH AS SULFURIC ACID OR P-TOLUENESULFONIC ACID [R1] *Reaction of adipic acid and 2-ethylhexanol [R2, 304] IMP: *0.01-0.02 maximal acidity (as adipic acid), 0.05-0.1% maximal moisture [R3] FORM: *Trade Names: Adipol 2EH; Bisoflex DOA; Effomoll DOA; Ergoplast AdDO; Flexol A26; Kodaflex DOA; Mollan S; Monoplex DOA; Plastomoll DDA; PX-238; Reomol DOA; Rucoflex Plasticizer DOA; Sicol 250; Staflex DOA; Truflex DOA; Uniflex DOA; Estinol DOA; Wickenol 158; Witamol 320 [R4] *Palatinol DOA (Badische), Plasthall DOA (CP Hall), Nuoplax (Nuodex) [R5] *Grade: 99% min [R6, 378] MFS: *Aristech Chemical Corp., 600 Grant St., Pittsburgh, PA 15219-2704, (412)433-2747; Production site: Chemicals Division, Neville Island, PA 15219-2704 [R7] *Arizona Chemical, 1001 E. Business Hwy. 98, Panama City, FL 32401, (850)785-6700; Production site: Dover, OH, 44622 [R7] *Eastman Kodak Co., P.O. Box 511, Kingsport TN 37662, (432)229-2196, Tennessee Eastman Division; Production site: Kinsport, TN 37662 [R7] *The C.P. Hall Co., 311 South Wacker Dr., Suite 4700, Chicago, IL 60606, (312)554-7400; Production site: Chicago, IL 60606 [R7] *Inolex Chemical Co., Jackson and Swanson Sts., Philadelphia, PA 19148, (215)271-0800; Production site: Philadelphia, PA 19148 [R7] *Staflex Products, Inc., 50 Middlesex Ave., Carteret, NJ 07008, (732)541-4201; Production site: Carteret, NJ 07008 [R7] *Unitex Chemical Corp., 520 Broome Rd., Greensboro, NC 27406, (336)378-0965; Production site: Greensboro, NC 27406 [R7] *Velsicol Chemical Corp., 10400 W. Higgins Rd., Suite 600, Rosemont, IL 60018-3713, (800)843-7759; Production site: Chestertown, MD 21620 [R7] OMIN: *IN FRANCE AND ITALY DIOCTYL ADIPATE IS PERMITTED CONSTITUENT OF PLASTICS INTENDED FOR CONTACT WITH FOODSTUFFS. [R8, 359] USE: *Plasticizer, commonly blended with general purpose plasticizers, such as /di-n-octyl phthalate/ and /diisooctyl phthalate/ in processing polyvinyl and other polymers; solvent; aircraft lubes [R6, 378] *Functional (hydraulic) fluid [R9] *Plasticizer or solvent in the following cosmetics: bath oils, eye shadow, cologne, foundations, rouge, blusher, nail-polish remover, moisturizers and indoor tanning preparations [R9] *... PVC film now used in meat wrapping operations contains bis(2-ethyl hexyl) adipate (DOA) as its major plasticizer. [R10] CPAT: *100% AS A VINYL PLASTICIZER (EST)(1976) [R1] PRIE: U.S. PRODUCTION: *(1972) 2.04X10+10 GRAMS [R1] *(1975) 1.38X10+11 GRAMS [R1] *(1984) 1.25X10+10 g [R11] *(1991) 24,343 kg [R12] U.S. IMPORTS: *(1972) NEGLIGIBLE [R1] *(1974) 1.9X10+9 GRAMS (PRINCPL CUSTMS DISTS) [R1] U.S. EXPORTS: *(1972) 2.77X10+9 GRAMS (EST) [R1] *(1984) 7.54X10+8 g /Adipic Acid Esters of Monohydric Alcohols/ [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS OR VERY PALE AMBER LIQ [R8, 358]; *Light colored, oily liquid. [R6, 377] ODOR: *SLIGHT AROMATIC SMELL [R8, 358]; *Odorless [R14]; *Mild [R15] BP: *214 deg C @ 5 mm Hg [R16, p. 3-187] MP: *-67.8 deg C [R16, p. 3-187] MW: *370.57 [R16, p. 3-187] CTP: *Critical temperature: 571.84 deg C (845 K); Critical pressure: 1.1200X10+6 Pa [R17] DEN: *0.922 @ 25 deg C/4 deg C [R16, 30187] HTC: *-15,430 Btu/lb= -8,580 cal/g= -359X10+5 Joules/kg [R14] HTV: *1.2542X10+8 J/kmol at -111.66 deg C [R17] PH: *Acidity: 0.25 (meg/100 gm. max) [R15] SOL: *SOL IN MOST ORG SOLVENTS; INSOL OR VERY SLIGHTLY SOL IN GLYCERINE AND GLYCOLS [R8, 358]; *Soluble in ethanol, ethyl ether, acetone, and acetic acid [R16, p. 3-187]; *In water, 0.78 mg/l @ 22 deg C [R18] SPEC: *Index of refraction: 1.4474 @ 20 deg C/D [R16, p. 3-187]; *Intense mass spectral peaks: 41 m/z (100%), 57 m/z (90%), 55 m/z (73%), 43 m/z (62%) [R19]; *IR:8003 (Sadtler Researd Laboratories IR Grating collection) [R20]; *Mass: 2-710 (Archives of Mass Spectral Data, John Wiley and Sons, New York) [R20] VAPD: *12.8 (Air= 1) [R2, 3035] VAP: *8.5X10-7 mm Hg at 20 deg C [R18] VISC: *13.7 cP @ 20 deg C [R6, 378] OCPP: *Pour point: -75 deg C [R6, 378] *VAPOR PRESSURE: 2.4 MM HG @ 200 DEG C [R21, 1881] *Henry's Law constant= 4.34X10-7 atm-cu m/mole @ 20 deg C [R18] *Wt/gal: 7.71 lb (20 deg C) SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME; CAN REACT WITH OXIDIZING MATERIALS. [R22] *Combustible [R23] NFPA: *Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R24] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R24] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R24] FLMT: *LOWER FLAMMABLE LIMIT: 0.4% BY VOLUME @ 242 DEG C [R24] FLPT: *402 DEG F (206 DEG C) (OPEN CUP) [R24] AUTO: *710 DEG F (377 DEG C) [R24] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEM ... . [R22] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R25] SERI: *Liquid irritating to the eyes. [R26] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. STRG: *IN GENERAL, MATERIALS ... TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS ... SHOULD BE STORED IN COOL ... VENTILATED PLACE, OUT OF ... SUN, AWAY FROM ... FIRE HAZARD ... BE PERIODICALLY INSPECTED AND MONITORED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED. [R22] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R27] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an absence of human data and increased incidence of liver tumors in female mice. Except for a positive dominant lethal assay, there was no evidence of genotoxicity; this compound does, however, exhibit structural relationships to other nongenotoxic compounds classified as probable and possible human carcinogens. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R28] HTOX: *Moderately toxic by intravenous route. Mildly toxic by ingestion. Experimental reproductive effects. Mutation data reported. ... Questionable carcinogen with experimental carcinogenic data. [R25] NTOX: *No acute effect has been observed some hours after oral administration to guinea pigs of doses of dioctyl adipate equal to or less than 14 ml/kg body weight. Yet in the succeeding days (3-21 days) half of the animals died. [R8, 358] *DOG WAS FED 2 G/KG IN DIET FOR ... 2 MO WITH ONLY TRANSIENT LOSS OF APPETITE AND WITH NO CHANGES IN BLOOD, URINE, OR HISTOPATHOLOGY ... /IT/ WAS GIVEN TO RATS IN FOOD IN DOSES OF 0.16 TO 4.74 G/KG/DAY. DEATHS WERE PRODUCED @ 4.74 G/KG ... NO EFFECTS ON GROWTH, APPETITE, LIVER AND KIDNEY WT, OR HISTOPATHOLOGY ... @ 0.16 G/KG. [R21, 1891] *DI-2-ETHYLHEXYL ADIPATE HAS BEEN FED TO RATS @ LEVELS OF 0.5, 2, and 5% IN DIET FOR ... A MO WITH ... DEFINITE GROWTH EFFECT @ 5%, BUT NOT @ LOWER LEVELS. NO EFFECTS WERE FOUND @ ANY LEVELS IN BLOOD OR URINE, NOR IN HISTOPATHOLOGY. [R21, 1891] *DI(2-ETHYLHEXYL)ADIPATE RATED 1 ON RABBIT EYES. /RATED NUMERICALLY ON SCALE OF 1 TO 10 ACCORDING TO DEGREE OF INJURY OBSERVED AFTER 24 HR, PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA. MOST SEVERE INJURIES HAVE BEEN RATED 10./ [R29] *Male ICR mice given a single i.p. dose of 0.5-10 ml (0.45-9.2 g)/kg bw and mated for eight successive weeks showed evidence of reduced fertility when given the highest dose. [R30] *Groups of 5 Sprague Dawley rats were given i.p. injections of 1, 5 or 10 ml (0.9, 4.5 or 9.2 g)/kg bw di(2-ethylhexyl) adipate on days 5, 10 and 15 of pregnancy. No embryolethality occurred, but reduced fetal weight was seen with the two highest doses. [R30] *MALE RATS WERE FED BIS(2-ETHYLHEXYL) ADIPATE @ DIETARY CONCN OF 2% FOR 3 WK. HEPATIC PEROXISOME PROLIFERATION IN ASSOC WITH INCR IN LIVER SIZE AND HEPATIC ACTIVITIES OF PEROXISOME-ASSOC ENZYME CATALASE AND CARNITINE ACETYLTRANSFERASE AND HYPOLIPIDEMIA. [R31] *Di(2-ethylhexyl)adipate was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of Di(2-ethylhexyl)adipate that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of Di(2-ethylhexyl)adipate tested by injection (5000 ppm) or feeding (20,000 ppm) were negative in this assay. [R32] *When rats were fed diets containing di(2-ethylhexyl)adipate at doses equivalent to 0.16 g/kg/day for 90 days, no effects on growth or on liver or kidney weights or histopathologic effects were observed. However, reduced growth and altered liver or kidney weights were observed in the rats receiving 2.9-4.7 g/kg/day for 90 days. [R33] *Di(2-ethylhexyl)adipate was not mutagenic for Salmonella typhimurium TA 1535, TA 1537, TA 1538, TA 98, and TA 100, with and without activation, or for Saccharomyces cerevisiae. [R33] *The ability of different tumor promoters to stimulate DNA synthesis in the liver of rats and mice was determined. Iva:SIV-50 SD rats, Osborne Mendel rats, Crl:CD(SD)BR rats, CDF(F-344)CrlBR rats, or B6C3F1/CrlBR mice were given a single dose of one of 13 test compounds by gavage. The incorporation of orally administered radiolabelled thymidine into liver DNA was measured in the peak phase of the diurnal cycle, 24 hr after administration of the test compounds. The only result which was not consistent with bioassay data on carcinogenicity was for the plasticizers di(2-ethylhexyl)adipate and di(2-ethylhexyl)phthalate which were both positive in this test, although bioassay tests with di(2-ethylhexyl)adipate have been negative in rats. [R34] *A study was conducted of the proximate peroxisome proliferators derived from the plasticizer DEHA and possible species differences in response to these agents. Primary hepatocyte cultures were prepared using male Alderley Park mice, male Alderley Park rats, male Alderley Park guinea pigs and male marmosets. Marked differences in potency for the stimulation of peroxisomal beta oxidation were observed following the exposure of mouse hepatocytes to metabolites of DEHA. The primary metabolites of DEHA, mono(2-ethylhexyl)adipate and 2-ethylhexanol, were approximately equipotent in inducing peroxisomal beta oxidation. The secondary metabolite 2-ethylhexanoic acid was the most potent peroxisome proliferator examined, stimulating peroxisomal beta oxidation by 25 fold at a concn of 1 mM. The hydroxylated metabolite of 2-ethylhexanoic acid, 2-ethyl-5-hydroxyhexan-1-oic acid was considerably less potent than 2-ethylhexanoic acid. The other tertiary metabolites of DEHA, 2-ethyl-5-oxohexan-oic acid and 2-ethylhexan-1,6-dioic acid had little effect on peroxisomal beta oxidation causing only a two to three fold induction at a concn of 2 mM. 2-Ethylhexanoic acid, 2-ethylhexanol and mono(2-ethylhexyl)adipate at concn above 1 mM resulted in cytotoxicity which was characterized by blebbing, or rounding of the cells and detachment from the cultured flasks. DEHA had no effect on peroxisomal beta-oxidation in rat hepatocyte cultures, even at concn of up to 5 mM. None of the chemicals stimulated peroxisomal beta oxidation in guinea pig or marmoset hepatocytes up to concn of 2 mM. [R35] *Four metabolites of the rat liver carcinogen di(2-ethylhexyl)phthalate (mono-(2-ethylhexyl)phthalate, mono-(2-ethyl-5-hydroxyhexyl)phthalate, mono-(2-ethyl-5-oxohexyl)phthalate, and mono-(5-carboxy-2-ethylpentyl)phthalate) and 3 structurally related derivatives di(2-ethylhexyl)adipate (mono-(2-ethylhexyl)adipate, mono-(2-ethyl-5-hydroxyhexyl)adipate, and mono-(2-ethyl-5-oxohexyl)adipate) were tested for mutagenicity in the Ames assay using Salmonella typhimurium strains TA97, TA98, TA100, and TA102, with and without a metabolic activation preparation. Aroclor 1254 induced rat liver S9 and di(2-ethylhexyl)phthalate induced rat liver S9 were used. Concn of these compounds up to 1000 ug/plate were negative with all tester strains in the presence or absence of metabolic activation. [R36] *To investigate a proposed relationship between induction of hepatic microsomal lauric acid hydroxylase activity and peroxisome proliferation in the liver, male Wistar rats were treated with peroxisome proliferating compounds, and the lauric acid hydroxylase activity, the immunochemical detectable levels of cytochrome p450 4A1 and the activities of peroxisomal enzymes were determined. After treatment with aroclor 1254, phenobarbital or 3-methylcholanthrene total cytochrome p450 was 1.7-2.7 times induced. However, no induction of lauric acid omega-hydroxylase activities or p450 4A1 levels were found. After treatment of rats with di(2-ethylhexyl)phthalate a dose-dependent induction of lauric acid omega-hydroxylase activities, levels of cytochrome p450 4A1 and peroxisomal fatty acid beta-oxidation was found. The plasticizer, di(2-ethylhexyl)adipate, did not induce levels of p450 4A1, lauric acid omega-hydroxylase activities or palmitoyl-CoA oxidase activities. With the compounds tested a close association between the induction of lauric acid omega-hydroxylase activities and peroxisomal palmitoyl-CoA oxidase activity was found. These data support the theory that peroxisome proliferating compounds do induce lauric acid omega-hydroxylase activities. [R37] *The dose response relationships for peroxisome proliferation due to DEHA, 2-ethylhexanol, 2-ethylhexanoic acid have been investigated in rats and mice. Linear dose response relationships were observed for induction of cyanide insensitive palmitoyl CoA oxidation, used as a enzyme marker of peroxisome proliferation, by DEHA, 2-ethylhexanol and 2-ethylhexanoic acid in both species. Relative liver weights were also increased in a dose related manner. On a molar basis, DEHA was twice as potent at 2-ethylhexanol or 2-ethylhexanoic acid which were equipotent and palmitoyl CoA oxidation was stimulated to a greater extent in male mice than in rats or female mice. At doses above 8 mmol/kg/day, 2-ethylhexanol was toxic to rats (both sexes) and similarly 2-ethylhexanoic acid at 13.5 mmol/kg/day lead to the death of female rats. In attempt to explain the species difference in carcinogenicity of DEHA previously reported, Fischer 344 rats and B6C3F1 mice were used. DEHA administration (2.5 g/kg/day) to Fischer 344 rats and B6C3F1 mice lead to toxicity. Liver weights were increased in a dose related fashion by DEHA administration to both rats and mice, palmitoyl CoA oxidation but not catalase was markedly increased (up to 15 fold in male rats). Light microscopy examination indicated some glycogen loss, a dose related hypertrophy and increased eosinophilia in both rats and mice. Electron microscopy confirmed peroxisome proliferation accompanied by a marked reduction of lipid in the centrilobular hepatocytes. The data suggest 2-ethylhexanoic acid to be the proximate peroxisome proliferator derived from DEHA. These data indicate a higher sensitivity for Fischer 344 rats than B6C3F1 mice to hepatic peroxisome proliferation due to DEHA. The carcinogenicity bioassays previously reported showed an incidence of hepatic tumors only in B6C3F1 mice. [R38] *Weanling inbred Fischer-344 rats and weanling hybrid B6C3F1 mice were used to study the carcinogenic properties of di(2-ethylhexyl) phthalate, DEHA, tris(2-ethylhexyl) phosphate and 2-ethylhexyl sulfate. Animals were chronically exposed for 2 yr. Each compound, which contained a 2-ethylhexyl moiety, di(2-ethylhexyl) phthalate, DEHA, tris(2-ethylhexyl) phosphate, and 2-ethylhexyl sulfate, caused hepatocarcinogenesis, particularly in female mice. The strongest hepatocarcinogenic activity was demonstrated by di(ethylhexyl) phthalate which displayed the same effect in rats. [R39] *Peroxisome proliferation is inducible in hepatocytes of rodent and nonrodent species by structurally dissimilar hypolipidemic drugs and certain phthalate ester plasticizers. The induction of peroxisome proliferation appears to be a tissue specific response limited largely to the hepatocyte. Peroxisome proliferation is associated with increases in the activity of the H2O2-generating peroxisomal fatty acid beta-oxidation system and in the amount of peroxisome proliferation associated 80,000 MW polypeptide. Chronic administration of these non-DNA damaging and nonmutagenic peroxisome proliferators to rats and mice results in the development of hepatocellular carcinomas. Comparative morphometric and biochemical data from rats treated with varying dose levels of ciprofibrate, a hypolipidemic drug, and di(2-ethylhexyl phthalate, and di(2-ethylhexyl) adipate, the widely used plasticizers, indicate that the hepatocarcinogenic potency of these agents is correlatable with their ability to induce peroxisome proliferation, peroxisomal beta-oxidation and 80,000 MW polypeptide. Available evidence strongly favors the role of peroxisome proliferation associated oxidative stress in the induction of liver tumors by peroxisome proliferators. [R40] *8-Hydroxydeoxyguanosine levels were examined in liver and kidney DNA after di(2-ethylhexyl)phthalate, DEHA and phthalic anhydride administration to male 6 wk old F-344 rats in the diet at concn of 1.2, 2.5 and 1.5%, respectively. Significant increases in 8-Hydroxydeoxyguanosine levels were observed only in the liver (target organ of di(2-ethylhexyl)phthalate and DEHA carcinogenesis) DNA after 1 and 2 wk of treatment with di(2-ethylhexyl)phthalate and DEHA, respectively. The results suggest the involvement of oxidative DNA damage in hepatocarcinogenesis by peroxisome proliferators. [R41] *Steady state concn of hydrogen peroxide resulting from peroxisomal beta-oxidation were evaluated in liver homogenates of rats and mice treated with the peroxisome proliferators di(2-ethylhexyl)phthalate, di(2-ethylhexyl)adipate (DEHA), or nafenopin to compare these changes with the carcinogenic potential of these chemicals. Male F344 rats and female B6C3F1 mice were treated daily for 14 days with 2 g/kg di(2-ethylhexyl)phthalate or DEHA or 0.25 g/kg nafenopin. Treatment with each of the peroxisome proliferators caused significant increases in peroxisomal-acyl-coenzyme-A and catalase, and a decrease in glutathione peroxidase in both rats and mice. Treatment of rats with the peroxisome proliferators caused increases in steady state hydrogen peroxide concn in liver homogenates, with the greatest increase, approximately 13 fold caused by nafenopin, followed by DEHA, and by di(2-ethylhexyl)phthalate which caused only a two fold increase. In the mouse, control values for steady state hydrogen peroxide were approximately three fold higher than those for the rat In mouse liver homogenates, di(2-ethylhexyl)phthalate caused a ten fold increase in steady state hydrogen peroxide concn, nafenopin produced a five fold increase, and DEHA caused a two fold increase. [R42] NTXV: *LD50 Rat iv 0.90 ml/kg; [R33] *LD50 Rat oral 5.6 g/kg; [R33] *LD50 Rat ip 47 ml/kg; [R33] *LD50 Rat (male, F344) oral, gavage 45 g/kg; [R33] *LD50 Rat (female, F344) oral, gavage 25 g/kg; [R33] *LD50 Mouse (Harlan/ICR Swiss) male/female ip 47 ml/kg; [R33] *LD50 Mouse (male, B6C3F1) oral, gavage 15 g/kg; [R33] *LD50 Mouse (female, B6C3F1) oral, gavage 25 g/kg; [R33] *LD50 Rat oral 9110 mg/kg; [R25] *LD50 Rabbit iv 540 mg/kg; [R25] NTP: *A carcinogenesis bioassay was conducted by feeding diets containing 12,000 or 25,000 ppm of di(2-ethylhexyl)adipate to groups of 50 male and 50 female F344 rats and 50 male and 50 female B6C3F1 mice for 103 weeks. Groups of 50 undosed rats and mice of each sex served as controls. All surviving animals were killed at 104 to 107 weeks. Mean body weights of high-dose rats and mice of either sex were lower than those of the controls throughout the study. Compound administration was not associated with tumor formation in F344 rats of either sex. Hepatocellular carcinomas or adenomas occurred in mice of both sexes in a dose-related fashion at incidences that were significantly higher for high-dose males and for low- and high-dose females than those in controls. When compared with the incidence in historical laboratory control mice, however, the liver tumors in male mice could not be clearly related to compound administration. Under the conditions of this bioassay, di(2-ethylhexyl)adipate was not carcinogenic for F344 rats. Di(2-ethylhexyl)adipate was carcinogenic for female B6C3F1 mice, causing increased incidences of hepatocellular carcinomas, and was probably carcinogenic for male B6C3F1 mice, causing hepatocellular adenomas. [R43] TCAT: ?The ability of di-2-ethylhexyl adipate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary clonal toxicity determinations (exposure time=72 hrs), di-2-ethylhexyl adipate, in 0.5% acetone, was tested at 3.38, 6.75, 13.5, and 27.0 nl/ml, with cell survival ranging from 89.0-31.7% relative to the solvent control. The material did not induce the appearance of a significant number of transformed foci (Bailey's modification of Student's t-test). [R44] ?Effects on the liver and liver lipids were evaluated in groups of male and female Fischer 344 rats (5/sex/dose) fed nominal concentrations of 0, 0.1, 0.6, 1.2, or 2.5% di-2-ethylhexyl adipate in the diet for 21 days. Toxicity was evident by statistical differences between dosed groups and control groups for: mean body weights (2.5% group, males and females), absolute and relative liver weights (0.6, 1.2 and 2.5% group females, 1.2 and 2.5% group males), relative kidney weights (1.2 and 2.5% groups male and female). There were no statistically significant differences in absolute and relative testes weights or levels of serum triglycerides and cholesterol between dosed and control groups. Liver biochemistry revealed statistically significant differences between treated and controls as indicated by an increase in cyanide-insensitive palmitoyl-CoA oxidation (1.2 and 2.5% group males, 2.5% group females), an increase in the lauric acid 12-hydroxylase activity (0.6-2.5% groups male and female), increase in lauric acid 11-hydroxylase activity (0.6 and 1.2% group males, although no clear dose response was observed), and hepatic protein levels (increased in the 2.5% group males and decreased in the 2.5% group females). There was a dose related increase in peroxisome proliferation at doses above 0.1% although the 0.6 and 1.2% group females were given equal scores. [R45] ?The rate of hydrolysis of di-2-ethylhexyl adipate was determined in intestinal homogenates prepared from male Sprague-Dawley rats at 37 degC in a water bath shaker. Hydrolysis was rapid with an estimated half-life of 6.0 min. [R46] ?The ability of di-2-ethylhexyl adipate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the presence of added metabolic activation by Aroclor-induced rat liver S9 fraction was evaluated. Based on preliminary clonal toxicity determinations (exposure time=48 hrs), di-2-ethylhexyl adipate, in 0.5% acetone, was tested at 42, 28, 7, 0.7 and 0.07 ul/ml, with cell survival ranging from 52.3% to 11.5% relative to the solvent control. The test material did not induce the appearance of a significant number of transformed foci (Bailey's modification of Student's t-test). [R47] ?The ability of di-2-ethylhexyl adipate to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the absence of added metabolic activation was evaluated. Based on preliminary clonal toxicity determinations (exposure time=20-24 hrs), di-2-ethylhexyl adipate was tested at 0.3, 0.1, 0.003 and 0.01 ul/ml, with cell survival ranging from 99.7-43.5% relative to the solvent control (acetone). The test material did not induce the appearance of a significant number of transformed foci. [R48] ?The mutagenic effect of di-2-ethylhexyl adipate was evaluated in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was administered at levels from 0.025 to 10.0 mg/plate in the plate incorporation assay and was not found to be mutagenic in the presence or absence of activation. In a preliminary range finding study, di-2-ethylhexyl adipate levels up to 10 mg/plate were non-toxic to cells [R49] ?The mutagenicity of urine from Sprague-Dawley rats dosed daily by gavage for 15 days with 2,000 mg/kg of di(2-ethylhexyl)adipate was evaluated in Salmonella tester strains TA 98, TA100, TA1535, TA1537 and TA1538 (Modified Ames Test), both in the presence and absence of Aroclor-induced rat liver S9 metabolic activation and beta-glucuronidase/aryl sulfatase. Cultures were dosed with up to 2 ml of urine using direct plating procedures. The urine of rats treated with bis(2-ethylhexyl)phthalate did not cause a positive response under any of the test conditions. [R50] ?Di-2-ethylhexyl adipate was examined for mutagenic activity in Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537 and TA1538 with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was not mutagenic in the plate incorporation assay when administered at concentrations ranging from 0.15 to 150 ul/plate in the presence or absence of activation. In a preliminary range finding study, di-2-ethylhexyl adipate was demonstrated to be non-toxic to cells at concentrations up to 150 ul (0.15 ml) /plate. [R51] ?The frequency of forward mutation at the TK locus was determined in L5178Y mouse lymphoma cells exposed in vitro to di-2-ethylhexyl adipate, with or without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was not mutagenic at concentrations up to 1000 nl/ml in the absence of activation, or at concentrations ranging from 15.6 to 250 nl/ml in the presence of activation. Toxicity to cells, as indicated by the percent relative growth parameter, was 21.4% at the high dose level in the absence of activation, and ranged from 69.6 to 19.7% at the levels tested in the presence of activation. [R52] ?The ability of di-2-ethylhexyl phthalate to increase the incidence of micronucleated polychromatic erythrocytes was evaluated in bone marrow cells of male and female B6C3F1 mice receiving a single or multiple intraperitoneal injection (Micronucleus Test). Based on preliminary toxicity determinations, two groups of mice (6/sex) were administered the test material at 5g/kg/day for either one (single) or two (multiple) days. Four animals per sex were selected per dose group at random for scoring 1000 polychromatic erythrocytes per animal. There was no significant difference (students t-test) in the percent of micronucleated polychromatic erythrocytes between treated animals and vehicle control (corn oil) animals. [R53] ?The effect of Di-(2-ethylhexyl) adipate was examined in the rat hepatocyte primary culture/DNA repair assay. Fischer F344 rat liver hepatocytes were exposed to concentrations of test article ranging from 5 to 1000 nl/ml for 20 to 24 hours in closed culture vessels; induction of significant changes in the extent of nuclear labeling were not observed at any concentration. The relative survival was reported to be slightly decreased at the 1000 nl/ml dose level (84%). [R54] ADE: *The absorption, distribution, and elimination of DEHA were studied in mice and rats. Male Sprague Dawley rats, male NMRI mice, and pregnant female NMRI mice on day 17 of gestation were administered (14)C labeled DEHA dissolved in dimethyl sulfoxide or corn oil iv or intragastrically. The DEHA was labeled on the carbonyl or alcohol moiety. Animals were killed 5 min to 4 days after dosing, and the tissue distribution of (14)C activity was determined by whole body autoradiography. The tissue distribution of (14)C activity from carbonyl labeled DEHA was similar in all animals. Highest levels of radioactivity were observed in the body fat, liver, and kidney after intragastrically or iv administration. (14)C activity from alcohol labeled DEHA was found in the bronchi of male mice. In pregnant mice, (14)C activity was observed in the fetal liver, intestine, and bone marrow during the first 24 hr after carbonyl labeled DEHA was given. Very little radiolabel was found in fetuses of mice given alcohol labeled DEHA. No DEHA derived radioactivity was found in mice 4 days after dosing. Blood DEHA concn in rats increased faster and were two or three times higher when the dose was given in DMSO rather than corn oil. Significant amounts of DEHA were excreted in the bile of rats treated with DEHA in DMSO. Very little biliary elimination of radiolabel occurred in animals given carbonyl labeled DEHA. DEHA was excreted in the urine, the amounts being smaller in animals used in the bile collection experiments. The vehicle had very little effect on the amount excreted. DEHA is poorly absorbed from an oil solution. [R55] METB: *In vivo and in vitro metabolism of the plasticizer DEHA was examined in the rat to determine the different steps involved in the hepatic concn of peroxisomal proliferators. In the in vivo studies, different doses of DEHA and mono-(2-ethylhexyl)-adipate were administered by gavage to Wistar rats for 5 days. In the in vitro studies, hepatocytes were isolated by in situ perfusion. No DEHA was recovered in rat urine 24 hr after administration; adipic acid was the main metabolite. Only the 2-ethylhexanol pathway showed further metabolites, mainly 2-ethylhexanoic acid which was either conjugated or submitted to other pathways. While 2-ethylhexanoic acid glucuronidation appeared to be dose and time dependent, 2-ethylhexanol glucuronidation was more stable. In vitro, the first hydrolysis of DEHA appeared to be a rate limiting step. When mono-(2-ethylhexyl) adipate was added directly to the culture medium, all the metabolites identified in the in vivo study were found. Glucuronidation of both 2-ethylhexanol and 2-ethylhexanoic acid was dose and time dependent. [R56] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Bis(2-ethylhexyl) adipate may be released into the environment during its manufacture and distribution, during PVC blending operations and from commercial and consumer use of finished products. It can also be released in emissions from waste incineration and from leaching from plastics where it is used as a plasticizer. If released to air, a vapor pressure of 8.5X10-7 mm Hg at 20 deg C indicates bis(2-ethylhexyl) adipate will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase bis(2-ethylhexyl) adipate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 0.63 days. Particulate-phase bis(2-ethylhexyl) adipate may be removed from the air by wet and dry deposition. Bis(2-ethylhexyl) adipate may undergo direct photolysis in the environment, since this compound contains a functional group that can absorb light > 290 nm. If released to soil, bis(2-ethylhexyl) adipate is expected to be immobile based upon an estimated Koc of 49,000. If released to soil, bis(2-ethylhexyl) adipate is expected to biodegrade readily, as indicated by screening tests. Volatilization from moist soil surfaces is not expected to be an important fate process based upon a Henry's Law constant of 4.34X10-7 atm-cum/mole. If released into water, bis(2-ethylhexyl) adipate is expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. If released to water, bis(2-ethylhexyl) adipate is expected to biodegrade readily, as indicated by screening tests. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's Henry's Law constant. Bis(2-ethylhexyl) adipate is expected to undergo hydrolysis due to the presence of hydrolyzable functional groups. Estimated hydrolysis half-lives are 3 years and 120 days at pH values of 7 and 8, respectively. A BCF of 27 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to bis(2-ethylhexyl) adipate may occur through inhalation and dermal contact with this compound at workplaces where bis(2-ethylhexyl) adipate is produced or used. The general population can be exposed through consumption of foods stored in plastic films or tubing. (SRC) NATS: *Di(2-ethylhexyl) adipate is not known to occur as such in nature(1). [R57] ARTS: *Bis(2-ethylhexyl) adipate's production and use as a plasticizer and solvent(1) may result in its release to the environment through various waste streams(SRC). Bis(2-ethylhexyl) adipate has been detected in fly ash from municipal waste incineration(2). Bis(2-ethylhexyl) adipate has been detected in wastewater effluents from publicly-owned treatment works (POTW) and chemical manufacturing plants(3-5). Bis(2-ethylhexyl) adipate can leach from PVC plastics where it is used as a plasticizer(6,7). Bis(2-ethylhexyl) adipate may be released into the environment during its manufacture and distribution, during PVC blending operations and from commercial and consumer use of finished products(8). [R58] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 49,000(SRC), determined from a structure estimation method(2), indicates that bis(2-ethylhexyl) adipate is expected to be immobile in soil(SRC). The dominant degradation process in the soil environment is expected to be microbial degradation. Biodegradation test results indicate that bis(2-ethylhexyl) adipate is readily biodegradable(3,4). Therefore, the dominant degradation process in the soil environment is expected to be microbial degradation(SRC). Volatilization of bis(2-ethylhexyl) adipate from moist soil surfaces is not expected to be an important fate process(SRC) given a Henry's Law constant of 4.34X10-7atm-cu m/mole(3). Bis(2-ethylhexyl) adipate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 8.5X10-7mm Hg(3). [R59] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 49,000(SRC), determined from an estimation method(2), indicates that bis(2-ethylhexyl) adipate is expected to adsorb to suspended solids and sediment in water(SRC). Biodegradation test results indicate that bis(2-ethylhexyl) adipate is readily biodegradable(4). Therefore, the dominant degradation process in the aquatic environment is expected to be microbial degradation(4). Volatilization from water surfaces is not expected(3) based upon a Henry's Law constant of 4.34X10-7 atm-cu m/mole(4). According to a classification scheme(5), a BCF of 27(4), suggests the potential for bioconcentration in aquatic organisms is low. Bis(2-ethylhexyl) adipate is expected to hydrolyze producing 2-ethylhexanol and hexanoic acid(SRC). Estimated hydrolysis half-lives are 3 years and 120 days at pH values of 7 and 8, respectively(6). [R60] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bis(2-ethylhexyl) adipate, which has a vapor pressure of 8.5X10-7 mm Hg at 20 deg C(3), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase bis(2-ethylhexyl) adipate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 0.63 days(SRC), calculated from its rate constant of 2.5X10-11 cu cm/molecule-sec at 25 deg C(4) determined using a structure estimation method(2). Particulate-phase bis(2-ethylhexyl) adipate may be removed from the air by wet and dry deposition(SRC). Bis(2-ethylhexyl) adipate may undergo direct photolysis in the environment, since this compound contains a functional group that can absorb light > 290 nm(5). [R61] BIOD: *AEROBIC: In a semi-continuous activated sludge method used to simulate sewage treatment plant biodegradation, bis(2-ethylhexyl) adipate was observed to undergo primary degradation of 65-96% (at concns of 5 and 20 mg added/24 hr)(1); in a CO2 evolution study, bis(2-ethylhexyl) adipate was observed to undergo an ultimate degradation of 94% over a 35-day incubation period which corresponds to a first-order half-life of 2.7 days(1). Bis(2-ethylhexyl) adipate, present at 100 mg/l, reached 67-74% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(2). [R62] ABIO: *The rate constant for the vapor-phase reaction of bis(2-ethylhexyl) adipate with photochemically-produced hydroxyl radicals has been estimated as 2.5X10-11 cu cm/molecule-sec at 25 deg C(4). This corresponds to an atmospheric half-life of about 0.63 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Bis(2-ethylhexyl) adipate is expected to hydrolyze producing 2-ethylhexanol and hexandioic acid(SRC). A base-catalyzed second-order hydrolysis rate constant of 0.07 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 3 years and 120 days at pH values of 7 and 8, respectively(2). Bis(2-ethylhexyl) adipate may undergo direct photolysis in the environment, since this compound contains a functional group that can absorb light > 290 nm(3). [R63] BIOC: *A whole-fish BCF of 27 was observed for blue-gill fish exposed to bis(2-ethylhexyl) adipate levels of 250 ug/l for a 28-day period(1). According to a classification scheme(2), this measured BCF value suggests the potential for bioconcentration in aquatic organisms is low. [R64] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for bis(2-ethylhexyl) adipate can be estimated to be 49,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that bis(2-ethylhexyl) adipate is expected to be immobile in soil. [R65] VWS: *The Henry's Law constant for bis(2-ethylhexyl) adipate is 4.34X10-7 atm-cu m/mole(1). This Henry's Law constant indicates that bis(2-ethylhexyl) adipate is not expected to volatilize from water surfaces(2). Bis(2-ethylhexyl) adipate's Henry's Law constant(4) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Bis(2-ethylhexyl) adipate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 8.5X10-7 mm Hg(1). [R66] WATC: *IT IS AMONG ORG CONTAMINANTS FOUND IN DRINKING WATER WITH HIGHEST CONCN IN FINISHED WATER BEING 20.0 UG/L. /FROM TABLE/ [R67] *DRINKING WATER: A tap water sample taken from Tobata-ku, Kitakyushu, Japan (sampling date not reported) contained a bis(2-ethylhexyl) adipate concn of 77 ppb(1). A finished drinking water sample collected from a Philadelphia treatment plant in Aug 1977 contained a bis(2-ethylhexyl) adipate concn of 0.002 ppb(2). A bis(2-ethylhexyl) adipate concn of 0.1 ug/l was detected in finished drinking water sample taken from a New Orleans treatment plant in July 1974(3). Bis(2-ethylhexyl) adipate was qualitatively detected in drinking water samples collected from treatment facilities in Cincinnati, OH (Oct 1978), Miami, FL (Feb 1976), New Orleans, LA (Jan 1976), and Ottumwa, IA (Sep 1976)(4). [R68] *SURFACE WATER: Bis(2-ethylhexyl) adipate was detected in the Delaware River at levels of 0.08-0.3 ppb during the winter of 1977 and 0.02-0.3 ppb during the summer of 1976(1). Bis(2-ethylhexyl) adipate was detected at levels between 1 and 30 ppb in surface water samples taken from the Monatiquot River in MA during Mar 1973(2). Concns of 130 ng/l and 35 ng/l were detected in Mississippi River water collected from Lake Itasca, Minnesota (source of the Mississippi River) and from New Orleans, LA, respectively, in the summer of 1984(3). Bis(2-ethylhexyl) adipate was detected (detection limit of 0.2 ug/l) in water samples collected in Aug 1982 from 5 of 23 US sites at levels of 0.2-1.0 ug/l(4); samples with positive detections were from the Ohio River (PA), Lake Ontario, Mississippi River (below St Louis), Mississippi River (Memphis, TN) and San Francisco Bay(4). Bis(2-ethylhexyl) adipate was detected, not quantified in samples collected from the River Tuchibuchi (Japan)(5). [R69] EFFL: *Bis(2-ethylhexyl) adipate concns of 2-70 ppb were detected in effluent waters collected from three NJ POTW (publicly owned treatment works) that were sampled three times during a 1-yr period(1); two of the plants were in industrial areas while the third was in a rural area with no known industrial input(1); however, the rural POTW had the highest detected concn(1). Bis(2-ethylhexyl) adipate was detected in 9 of 28 wastewater samples (detection limit 1 ppb) taken from waste treatment plants, industrial effluents and polluted fiords in Norway(2). A wastewater effluent collected from a chemical plant on the Delaware River in Aug 1977 contained a bis(2-ethylhexyl) adipate concn of 2000 ppb(3). Bis(2-ethylhexyl) adipate was qualitatively detected in water samples collected from advanced waste treatment facilities in Lake Tahoe, CA (Oct 1974), Pomona, CA (Sep 1974), Orange County, CA (Jan 1976), and Washington, DC (Sep 1974)(4). Bis(2-ethylhexyl) adipate was detected in 1 of 4 air samples collected from the 700 MW power station of Flensburg, Germany at a concentration of 73,000 ng/cu nm(5). Bis(2-ethylhexyl) adipate was detected in incoming leachate samples collected from a municipal landfill in Hyllstofta, Sweden with an average concentration of 3250 ng/l; after nitrification an average concentration of 6185 ng/l was detected and after denitrification, an avg concn of 8000 ng/l was detected(6). [R70] SEDS: *SEDIMENT: Bis(2-ethylhexyl) adipate was detected, not quantified in sediment samples collected from Lake Jusan and bottom material samples collected from Mutsu Bay (Japan)(1). [R71] ATMC: *INDOOR: Based upon indoor air monitoring of an office building, the representative indoor air concn of bis(2-ethylhexyl) adipate was determined to be 2.0 ng/cu m(1); the source of the bis(2-ethylhexyl) adipate was thought to be from plasticizer uses in plastics(1). [R72] FOOD: *Bis(2-ethylhexyl) adipate was qualitatively detected in the aroma isolate of mango fruit(1); the source of the bis(2-ethylhexyl) adipate was migration from the PVC film in which the fruit was wrapped during storage(1). The following concns of bis(2-ethylhexyl) adipate (in mg/kg) were detected in retail foodstuffs packaged in cling-film plastic wrap(2): fresh fruits and vegetables: 0.2-6.4; sandwiches: 30-212; cheese: 28-135; fresh pork: 1.8-64; fresh lamb: 2.9-11; fresh beef: 1.0-8.0; fresh chicken: 8.5-53(2); draught beer had levels of 0.01-0.07 mg/kg which presumably came from plasticizer migration from plastic tubing(2); bottled beverages had levels of 0.01-0.1 mg/kg which presumably came from plastic closure seals(2). Bis(2-ethylhexyl) adipate migrations from PVC food wrap films of 41-362 mg/kg were measured for various exposures of food (sandwich, cheese, cake, chicken, biscuits) to the food wrap(3). Bis(2-ethylhexyl) adipate was detected, not quantified, in 200 g of roasted Chinese chestnuts collected from a commercial grower in Western Pennsylvania(4). [R73] RTEX: *Occupational exposure to bis(2-ethylhexyl) adipate occurs during its production, its use as a plasticizer and its use as a lubricant and functional fluid(1); exposure can occur through dermal contact and inhalation(1,SRC). Since bis(2-ethylhexyl) adipate plasticizer will migrate from plastic food wrap films used to store food(2-5), the general population will be exposed to bis(2-ethylhexyl) adipate through consumption of food(1,SRC). Inhalation of indoor air in office buildings using bis(2-ethylhexyl) adipate plastics is another route of human exposure(6). [R74] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 15,636 workers (3,628 of these are female) are potentially exposed to bis(2-ethylhexyl) adipate in the USA(1). The avg concn of bis(2-ethylhexyl) adipate in the air of a meat-wrapping department of a supermarket, as a result of heating polyvinyl chloride film during meat packaging operations, was estimated to be 0.014 ppm (0.2 mg/cu m)(2). Based upon indoor air monitoring of an office building, the representative indoor air concn of bis(2-ethylhexyl) adipate was determined to be 2.0 ng/cu m(4); the source of the bis(2-ethylhexyl) adipate was thought to be from plasticizer uses in plastics(4). Occupational exposure to bis(2-ethylhexyl) adipate may occur through inhalation and dermal contact with this compound at workplaces where bis(2-ethylhexyl) adipate is produced or used. The general population can be exposed through consumption of foods stored in plastic films; bis(2-ethylhexyl) adipate is used as plasticizer in various food storage wraps and it has been shown to migrate into stored foods(SRC). [R75] BODY: *Bis(2-ethylhexyl) adipate was detected, not quantified, in 1 of 8 tissue samples collected from persons between the ages of 0-14 years, 4 of 8 tissue samples collected from persons between the ages of 15-44 years, and 3 of 8 tissue samples collected from persons above 45 years of age(1). Bis(2-ethylhexyl) adipate was detected in 7 of 46 tissue samples collected from people between April and June, 1984 at concentrations ranging from 0.002 to 0.165 ug/g(1). [R76] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 400 ug/l [R77] FEDERAL DRINKING WATER GUIDELINES: +EPA 400 ug/l [R77] STATE DRINKING WATER GUIDELINES: +(ME) MAINE 400 ug/l [R77] FDA: *Di(2-ethylhexyl) adipate is an indirect food additive for use only as a component of adhesives. [R78] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HIGH PRESSURE LIQ CHROMATOGRAPHY (HPLC) FOR SAMPLE CLEANUP OF DRINKING WATER EXTRACTS FOR LATER ANALYSIS BY GC/MS (GAS CHROMATOGRAPHY/MASS SPECTROMETRY) IS DESCRIBED. [R79] *Gas chromatography/flame ionization detection analysis of di(2-ethylhexyl) adipate in meat and meat/fat mixtures detection limit is not given. [R80] *EMSLC Method 506. Determination of Phthalate and Adipate Esters in Drinking Water by Liquid-Liquid Extraction or Liquid-Solid Extraction and Gas Chromatography with Photoionization Detection. Detection limit= 12.000 ug/l. [R81] *EMSLC Method 525.1. Determination of Organic Compounds in Drinking Water by Liquid-Solid Extraction and Capillary Column Gas Chromatography and Mass Spectrometry. Revision 2.2. Detection limit= 0.60 ug/l. [R82] *EMSLC Method 525.2. Determination of Organic Compounds in Drinking Water by Liquid-Solid Extraction and Capillary Column Gas Chromatography and Mass Spectrometry. Revision 1.0. [R82] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Di(2-ethylhexyl)adipate in F344 Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 212 (1982) NIH Publication No 81-1768 USEPA/ODW: Dinking Water Criteria Document for Di(2-Ethylhexyl) Adipate (1990) Final Report on the Safety Assessment of Dioctyl Adipate and Diisopropyl Adipate; J Am Coll Toxicol 3 (3): 101-30 (1984) Ashby J et al; Mechanistically Based Human Hazard Assessment of Peroxisome Proliferator Induced Hepatocarcinogenesis; Human and Experimental Toxicology 13 (Suppl 2): S1-S117 (1994) SO: R1: SRI R2: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 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USEPA-600/1-84-020A (NTIS PB85-128221) p. 45-6, 141, 163 (1984) R69: (1) Sheldon LS, Hites RA; Environ Sci Technol 12: 1188-94 (1978) (2) Hites RA; J Chromatogr Sci 11: 570-4 (1973) (3) DeLeon IR et al; Chemosphere 15: 795-805 (1986) (4) Felder JD et al; Environ Toxicol Chem 5: 777-84 (1986) (5) Ishizuka S; Amori-Ken Kankyo Hoken Senta Kenkyu Hokoky 5: 26-35 (1995) R70: (1) Clark LB et al; Res J WPCF 63: 104-13 (1991) (2) Sporstoel S et al; Int J Environ Anal Chem 21: 129-38 (1985) (3) Sheldon LS, Hites RA; Environ Sci Technol 13: 574-9 (1979) (4) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1, USEPA-600/1-84-020A (NTIS PB85-128221) pp. 45-6, 141, 163 (1984) (5) Wienecke J et al; Chemosphere 25: 1889-95 (1992) (6) Welander U, Henrysson T; Water Environ Res 70: 1236-41 (1998) R71: (1) Ishizuka S; Amori-Ken Kankyo Hoken Senta Kenkyu Hokoky 5: 26-35 (1995) R72: (1) Weschler CJ, Shields HC; in Proc - APCA 79th Annual Meeting Vol 4: 86-52.2 (1986) R73: (1) MacLeod AJ, Synder CH; J Agric Food Chem 36: 137-9 (1988) (2) Harrison N; Food Addit Contam 5: 493-9 (1988) (3) Gilbert J et al; Food Addit Contam 5: 513-23 (1988) (4) Morini G, Maga JA; Lebensm -Wiss U -Technol 28: 638-40 (1995) R74: (1) IARC; IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 29: 257-64 (1982) (2) MacLeod AJ, Synder CH; J Agric Food Chem 36: 137-9 (1988) (3) Harrison N; Food Addit Contam 5: 493-9 (1988) (4) Gilbert J et al; Food Addit Contam 5: 513-23 (1988) (5) Schwope AD, Reid RC; Food Addit Contam 5: 445-54 (1988) (6) Weschler CJ, Shields HC; in Proc - APCA 79th Annual Meeting Vol 4: 86-52.2 (1986) R75: (1) US Dept Health Human Serv; Public Health Service, Cntr Disease Control, Natl Instit Occu Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). In National Library of Medicine's current MEDLARS, as of Jan., 2000 (2) IARC; IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 29: 257-64 (1982) (4) Weschler CJ, Shields HC; in Proc - APCA 79th Annual Meeting Vol 4: 86-52.2 (1986) R76: (1) Onstot JD, Stanley JS; Water Environ Res 70: 1236-41 (1989) R77: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R78: 21 CFR 175.105 (4/1/99) R79: THRUSTON AD JR; J CHROMATOGR SCI 16 (6): 254-9 (1978) R80: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 261 (1982) R81: USEPA; Methods for the Determination of Organic Compounds in Drinking Water, Supplement I, USEPA/600/4-90/020, July 1990 R82: USEPA; Methods for the Determination of Organic Compounds in Drinking Water, USEPA/600/4-88/039, December 1988, Revised July 1991 RS: 64 Record 56 of 1119 in HSDB (through 2003/06) AN: 384 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZOIN- SY: *BENZOYLPHENYLCARBINOL-; *BITTER-ALMOND-OIL-CAMPHOR-; *ETHANONE,-2-HYDROXY-1,2-DIPHENYL-; *ALPHA-HYDROXYBENZYL-PHENYL-KETONE-; *ALPHA-HYDROXY-ALPHA-PHENYLACETOPHENONE-; *2-HYDROXY-2-PHENYLACETOPHENONE-; *NCI-C50011-; *PHENYLBENZOYL-CARBINOL- RN: 119-53-9 MF: *C14-H12-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF POTASSIUM CYANIDE AND BENZALDEHYDE (BENZOIN CONDENSATION) [R1] *PREPD BY TREATING AN ALCOHOLIC SOLN OF BENZALDEHYDE WITH AN ALKALI CYANIDE: ADAMS, MARVEL, ORG SYN VOL 1, PAGE 33 (1921); COLL VOL I, 88; ARNOLD, FUSON, J AM CHEM SOC 58, 1295 (1936); LF FIESER, ORGANIC EXPERIMENTS (DC HEALTH AND CO, BOSTON, 1964), PAGES 211-214. [R2] MFS: +Akzo America, Inc, Akzo Chemicals Inc, Hq, 111 W 40th St, New York, NY 10018, (212) 382-5500; Akzo Chemical Division, 300 S Riverside Plaza, Chicago, IL 60606; Production site: Edison, New Jersey 08817 [R3] +Chemical Dynamics Corp, Hq, 3001 Hadley Rd, South Plainfield, NJ 07080, (201) 753-5000 [R3] +Greenwood Chemical Co, Hq, State Highway 690, Greenwood, VA 22943, (703) 456-6832 [R3] +Nickstadt-Moeller, Inc, Hq, 1312 Fifth Street, PO Box 6, North Bergen, NJ 07047, (201) 943-9300; Production site: 1169 Edgewater Avenue, Ridgefield, NJ 07657 [R3] +Penco of Lyndhurst Inc, Hq, 540 New York Ave, Lyndhurst, NJ 07071, (201) 935-6600 [R3] OMIN: *REPORTED USES: NON-ALCOHOLIC BEVERAGES: 4.5 PPM; ICE CREAM, ICES, ETC: 0.54 PPM; CANDY 2.0 PPM; BAKED GOODS 1.4 PPM, GELATINS AND PUDDINGS: 0.10 PPM. [R4] *SWEET FLAVORS, VANILLA, BUTTERSCOTCH. /FROM TABLE/ [R5] *FEMA NUMBER: 2132 [R6] USE: *IN ORGANIC SYNTHESES [R2] *PRINCIPLY AS A FLAVOR INGREDIENT; ANTISEPTIC; PHOTOPOLYMERIZATION CATALYST; INT FOR ALPHA-BENZOIN OXIME (ANALYT REAGENT FOR METALS), WETTING AGENTS, EMULSIFYING AGENTS, STILBESTROL PRODUCTS [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.5X10+5 GRAMS [R1] U.S. IMPORTS: *(1975) ND [R1] U.S. EXPORTS: *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW CRYSTALS [R7]; *WHITE CRYSTALS [R8] ODOR: *SWEET NON-DESCRIPT ODOR [R5] TAST: *SWEET NON-DESCRIPT TASTE [R5] MW: *212.22 VAP: *1 MM HG @ 135.6 DEG C [R7] OCPP: *REDUCES FEHLING'S SOLN /DL-FORM/ [R2] *NEEDLES FROM METHANOL /L-FORM/; NEEDLES /D-FORM/ [R9] *SIX-SIDED MONOCLINIC PRISMS FROM ALCOHOL /DL-FORM/ [R2] *BP:344 DEG C @ 768 MM HG; MP:137 DEG C; DENSITY: 1.310 @ 20 DEG C/4 DEG C /DL-FORM/ [R9] *SOL IN 3335 PARTS WATER, MORE SOL IN HOT WATER; SOL IN 5 PARTS PYRIDINE; ACETONE; SOL IN BOILING ALC; SLIGHTLY SOL IN ETHER /DL-FORM/ [R2] *SOL IN HOT METHANOL; SOL IN HOT ALCOHOL; ACETONE /D AND L-FORMS/ [R9] *SOL IN PYRIDINE /D-FORM/ [R9] *SPECIFIC OPTICAL ROTATION: -117.5 DEG @ 12 DEG C/D (ACETONE, 1.25%) /L-FORM/ [R9] *SPECIFIC OPTICAL ROTATION: +92.8 DEG @ 15 DEG C/D (PYRIDINE, 1%) /D-FORM/ [R9] *MAX ABSORPTION (ETHANOL): 247 NM (E= 14,500); MAX ABSORPTION (CHLOROFORM): 2.88, 5.93, 6.21, 6.28, 6.85 NM (IR) /DL-FORM/ [R2] *MAX ABSORPTION (ALCOHOL): 248 NM (LOG E= 4.1); SADTLER REFERENCE NUMBER: 2722 (IR, PRISM); 736 (UV); SOL IN HOT ACETIC ACID; CHLOROFORM /DL-FORM/ [R9] *MP:133-4 DEG C /D AND L FORMS/ [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN HEATED... [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: +Benzoin was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Benzoin was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.0333, 0.100, 0.333, 0.3333, 0.667, 1.000, and 3.3333 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 3.3333 mg/plate. Precipitate was observed in most cultures at the high dose and also some clearing of the background bacterial lawn was also seen. [R10] +... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R11] NTP: +A bioassay of benzoin for possible carcinogenicity was conducted by incorporating the test chemical in diets of F344 rats and B6C3F1 mice. ... Groups of 50 male rats were fed diets containing 125 or 250 ppm benzoin for 104 wk, and similar groups of female rats received feed containing 250 or 500 ppm. Groups of 50 mice if each sex were fed diets containing 2,500 or 5,000 ppm benzoin for 104 wk. Groups of 50 untreated rats and mice of each sex were used as matched controls. ... Under the conditions of this bioassay, benzoin was not carcinogenic in F344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R11] METB: *BENZOIN YIELDS HYDROBENZOIN AND MESO-HYDROBENZOIN IN CURVULARIA. ACKLIN, W ET AL, CROAT CHEM ACTA, 37, 11 (1965). /FROM TABLE/ [R12] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3. 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5.0 G/KG, BETWEEN 1 OUNCE AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB). [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *NOT REPORTED FOUND IN NATURE. [R4] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *121.1164, LIMITATIONS: SYNTHETIC FLAVOR; 8.390, LIMITATIONS: DILUENT IN INKS FOR MARKING FRUITS AND VEGETABLES. PRODUCT SPECIFICATIONS APPLY. [R6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of Benzoin for Possible Carcinogenicity (1980) Technical Rpt Series No. 204 DHEW Pub No. (NIH) 80-1760 SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 143 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 479 R4: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 43 R5: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 259 R6: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 799 R7: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 443 R8: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 99 R9: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-200 R10: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R11: Bioassay of Benzoin for Possible Carcinogenicity (1980) Technical Rpt Series No. 204 DHEW Pub No. (NIH) 80-1760, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R12: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. B-9 R13: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-156 RS: 8 Record 57 of 1119 in HSDB (through 2003/06) AN: 388 UD: 200210 RD: Reviewed by SRP on 9/9/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZALDEHYDE- SY: *ALMOND-ARTIFICIAL-ESSENTIAL-OIL-; *ARTIFICIAL-ALMOND-OIL-; *Artificial-essential-oil-of-almond-; *Benzaldehyde-FFC-; *Benzene-carbaldehyde-; *BENZENECARBONAL-; *BENZENECARBOXALDEHYDE-; *BENZENEMETHYLAL-; *BENZOIC-ALDEHYDE-; *NCI-C56133-; *Oil-of-bitter-almond-; *PHENYLMETHANAL-; *Synthetic-oil-of-bitter-almond- RN: 100-52-7 MF: *C7-H6-O SHPN: NA 1989; Benzaldehyde IMO 9.0; Benzaldehyde STCC: 49 131 11; Benzaldehyde MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ALKALINE HYDROLYSIS OF BENZAL CHLORIDE [R1] *... BY OXIDN OF TOLUENE. [R2] *From benzal chloride and lime [R3, 164] *Air oxidation of toluene with uranium or molybdenum oxides as catalysts; extraction from oil of bitter almonds. [R3, 127] IMP: *Usually chlorides. Method of purification: Rectification. [R4] *SPECIFICATIONS, ESP REGARDING IMPURITIES, VARY CONSIDERABLY FOR GRADES USED FOR DYE MFR FROM THOSE USED IN PERFUMERY. [R4] *Benzal chloride, nitrobenzene, and benzoic acid were detected as impurities in benzaldehyde. [R5] *IMP. IN USP GRADE: ARSENIC, 3 ppm MAX; HEAVY METALS, 40 ppm MAX; LEAD, 10 ppm MAX [R6] FORM: *CMPD BENZALDEHYDE ELIXIR NF. DISSOLVE BENZALDEHYDE (0.5 ML) AND VANILLIN (1 G) IN ALC ... SYRUP ... ORANGE FLOWER WATER ... and ... PURIFIED WATER ... . [R7] *BENZALDEHYDE FFC GRADE OF BENZALDEHYDE FREE FROM CHLORINE. [R3, 165] *Grades or purity: Technical grade - 98.0%; NF (FCC) grade - 98.0% [R8] MFS: *Kalama Chemical Inc, Hq, The Bank of California Center, Suite 1110, Seattle, WA 98164, (206) 682-7890; Production site: Kalama, WA 98625 /Technical/ [R9] OMIN: *POSSIBLE PROBLEMS...MAY OCCUR WHEN POLYSTYRENE SYRINGES ARE USED WITH CERTAIN TYPES OF DRUG PRODUCTS THAT CONTAIN...BENZALDEHYDE...SINCE.../IT/ CAN EXTRACT AND DISSOLVE THE PLASTIC. [R10] *PRODUCT DISCONTINUED BY TENNECO CHEMICAL INC [R11, p. :C-46] *REPORTED USES: NON-ALCOHOLIC BEVERAGES 36 PPM; ALCOHOLIC BEVERAGES 50-60 PPM; ICE CREAM 42 PPM; CANDY 120 PPM; BAKED GOODS 110 PPM; GELATINS, PUDDINGS 160 PPM; CHEWING GUM 840 PPM. [R2] *CARCINOSTATIC BENZALDEHYDE IS TREATED WITH CYCLODEXTRIN TO FORM BENZALDEHYDE-CYCLODEXTRIN INCLUSION COMPOUNDS, WHICH ARE THEN COATED WITH INTESTINAL SOLUTION COATING MATERIAL. TREATMENT WITH CYCLODEXTRIN PREVENTS THE OXIDATION OF BENZALDEHYDE. APPROX 50% OF BENZALDEHYDE WAS RELEASED INTO ARTIFICIAL GASTRIC JUICE WITHIN 3 HR. [R12] *FEMA NUMBER 2127 [R13] *Because of its activity as an enzyme inhibitor ... /it/ has been used in studiesof enzyme kinetics ... and in thermodynamic studies of chymotrypsin. [R14, 117] */Benzaldehyde Elixir NF is/ a useful vehicle for administering bromides and other salts, especially when a low salt content is desired. [R7] *Benzaldehyde has been identified in the defensive excretions of harvester ants and millipedes, and as a major male pheromone of several noctuid Lepidoptera. It is present in the alarm pheromone of Trigonoma stingless bees. [R14, 116] *It has been shown that 2-hydroxyamino-1-phenylpropan-1-ol ... undergoes rapid oxidative decomposition in the presence of small quantities of Cu+ ions to give benzaldehyde and acetaldoxime. [R15] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R16] *BEE REPELLENT /FORMER PESTICIDE/ [R11, p. C-46] *REACTED WITH VINYL FIBERS TO IMPART ELASTIC RECOVERY; INT FOR NUMEROUS DERIV, INCL DYES; ODORANT IN PERFUMES; FLAVORING INGREDIENT [R1] +CHEM INTERMEDIATE FOR AROMATIC ALC; SOLVENT FOR OILS, RESINS, SOME CELLULOSE ETHERS, CELLULOSE ACETATE AND NITRATE; MFR BENZOIC ACID; PHOTOGRAPHIC CHEM [R4] *MANUFACTURE OF ... CINNAMIC AND MANDELIC ACIDS [R3, 165] *TECHNICAL GRADE BENZALDEHYDE IS LARGELY USED AS AN INTERMEDIATE ... FOR THE MANUFACTURE OF ODORANTS AND FLAVORING CHEMICALS, MAINLY CINNAMALDEHYDE, AMYL CINNAMALDEHYDE, HEXYL CINNAMALDEHYDE AND CINNAMYL ALCOHOL. NF BENZALDEHYDE IS USED DIRECTLY AS A FLAVORING AGENT, PARTICULARLY FOR ARTIFICIAL CHERRY AND ALMOND FLAVORS [R17] *STARTING MATERIAL FOR PHARMACEUTICALS (AMPICILLIN) AND PESTICIDES (DIBENZOQUAT) [R17] CPAT: *45% IS USED AS AN ODORANT AND FLAVORING CHEM; 30% AS AN INT FOR DYES; AND 25% FOR THE MFR OF OTHER CHEMS (1965) [R1] */PRIMARILY/ USED AS AN INTERMEDIATE ... FOR THE MANUFACTURE OF ODORANTS AND FLAVORING CHEMICALS (1978 DATA) [R17] PRIE: U.S. PRODUCTION: *(1972) 2.09X10+9 GRAMS [R1] *(1975) 4.31X10+9 GRAMS [R1] U.S. IMPORTS: *(1983) 6.16X10+7 g [R18] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R2] ODOR: *Odor of volatile oil of almond [R3, p. 165]; *Bitter almonds [R19] TAST: *BURNING AROMATIC TASTE [R3, 165]; *Similar to bitter almond [R2] BP: *179 DEG C [R3, 165] MP: *-26 DEG C; FP: -56 DEG C [R20, p. 3-680] MW: *106.12 [R3, 165] CTP: *666 deg F= 352 deg C= 625 deg K; 316 psia= 21.5 atm= 2.18 MN/square m [R8] DEN: *1.050 @ 15 DEG C/4 DEG C [R3, 165] HTC: *843.2 kg cal at 25 deg C [R21, p. D-283] HTV: *11,657.8 g cal/g mol [R21, p. C-729] OWPC: +log Kow = 1.48 [R22] SOL: +water solubility = 3000 mg/l @ 25 deg C [R23]; *VERY SOL IN ETHER, ACETONE, BENZENE, PETROLEUM ETHER [R20, p. 3-68]; *SOL 1:1-1:1.5 IN 70% ALCOHOL; 1:2.5 IN 60% ALCOHOL; 1:8 IN 50% ALCOHOL [R2]; *MISCIBLE WITH FIXED AND VOLATILE OILS [R24]; *SOL IN LIQ AMMONIA [R21, p. C-140]; *Solubility of water in benzaldehyde @ 20 deg C, wt%: 1.5 [R19] SPEC: *INDEX OF REFRACTION: 1.5456 @ 20 DEG C/D [R25]; *MAX ABSORPTION (CYCLOHEXANE): 241 NM (LOG E= 4.15); 247 NM SHOULDER (LOG E= 4.06); 277.5 NM (LOG E= 3.08); 287 NM SHOULDER (LOG E= 3.00); SADTLER REFERENCE NUMBER: 3010 (IR, PRISM); 868 (UV) [R21, p. C-140]; *IR: 364 (Sadtler Research Laboratories IR Grating Collection) [R26]; *UV: 6-106 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R26]; *NMR: 151 (Varian Associates NMR Spectra Catalogue) [R26]; *MASS: 315 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R26] SURF: *40.0 dynes/cm= 0.040 N/m at 20 deg C [R8] VAPD: *3.66 (AIR= 1) [R27] VAP: +0.127 mm Hg @ 25 deg C [R28] VISC: *1.39 cp at 25 deg C [R21, p. F-52] OCPP: *IT REDUCES AMMONIACAL SILVER NITRATE, BUT NOT FEHLING'S SOLN [R3, 165] *Oxidizes in air to benzoic acid; volatile with steam. [R3, 164] *Enthalpy of combustion: 3525.1 kJ/mol (liquid), 3575.4 kJ/mol (gas) [R20, p. 5-87] *Heat of combustion: -7630 cal/g = -319.5 X 10+5 J/kg = -13730 Btu/lb [R29] *Henry's Law constant = 2.6X10-5 atm cu m/mole at 25 deg C [R30] +hydroxyl radical rate constant = 1.29X10-11 cu-cm/molc sec @ 25 deg C [R31] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R32] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R32] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R32] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R32] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R32] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R32] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R32] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R32] FPOT: *MODERATE WHEN EXPOSED TO HEAT OR FLAME... [R33] +Combustible liquid. [R34, p. 49-24] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R34, p. 325-16] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R34, p. 325-16] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R34, p. 325-16] FLPT: +145 deg F, 63 deg C (Closed cup) [R34, p. 325-16] *73.9 deg C (Open cup) [R35] AUTO: +377 DEG F, 192 DEG C [R34, p. 325-16] FIRP: +Use water spray, dry chemical, foam, or carbon dioxide. Use water to keep fire-exposed containers cool. [R34, p. 49-24] TOXC: *Benzoic acid [R29] EXPL: *Combustible [R4] REAC: *Benzaldehyde ... /will/ react violently with 90% performic acid. [R36] ODRT: *0.042 ppm [R29] SERI: *Inhalation of concentrated vapor may irritate eyes, nose and throat. Liquid is irritating to eyes. Prolonged contact with the skin may cause irritation. [R8] *HIGHLY IRRITANT ACTION ON ... MUCOUS MEMBRANES OF THE RESPIRATORY TRACT. /ALDEHYDES/ [R33] EQUP: +Wear full protective clothing and positive pressure self contained breathing apparatus. [R34, p. 49-24] OPRM: */In emergency/: stop discharge if possible. Keep people away. Avoid contact with liquid. Call fire department. Isolate and remove material. Notify local health and pollution control agencies. [R29] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *BECOMES YELLOWISH ON KEEPING [R3, 165] *OXIDIZES IN AIR TO BENZOIC ACID [R3, 165] STRG: +STORE IN COOL, DRY, WELL VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS,REDUCING AGENTS, ALKALIES. [R34, p. 49-25] *KEEP TIGHTLY CLOSED AND PROTECTED FROM LIGHT. [R3, 165] *Tank cars, stainless steel drums, glass carboys, tins, bottles. [R29] CLUP: +Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors and protect personnel. Absorb in combustible material for proper disposal. [R34, p. 49-25] DISP: *Incineration: Dissolve in a combustible solvent, then spray the soln into the furnace with afterburner. [R37] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *MAY CAUSE CONTACT DERMATITIS. [R3, 165] *ACTS AS A FEEBLE LOCAL ANESTHETIC. CAUSES CNS DEPRESSION IN SMALL DOSES AND CONVULSIONS IN LARGER DOSES. [R33] *PRODUCES ... RESPIRATORY FAILURE. [R38] *VAPORS CAUSE SLIGHT IRRITATION OF EYES [R39] *In patch tests using 5% benzaldehyde in vaseline, positive reactions were observed in ten of 100 patients. Positive reactions occurred in patients with sensitivity to benzoic acid or vanillin. [R14, 116] *The effect of the carcinostatic drug benzaldehyde on hyperthermia-induced cytotoxicity was studied in various types of cultured mammalian cell lines by colony formation assay. The treatment of HeLa cells with nontoxic concn (1X10-4 mM) at 42 and 43 deg C for up to 3 hr induced enhancement of cell killing. The enhancement of cell killing incr as the time and concn of BA treatment were increased at elevated temp. [R40] *Benzaldehyde caused a dose-dependent reduction of proliferation of HeLa cells in vitro. This effect might be caused by a reversible and mild growth modulation, since no serious morphological damage was observed. Delay of the S AND G2 periods in the cell cycle upon addition of benzaldehyde was observed by the pulse labeling technique using (3)H thymidine. [R41] *... ORAL FATAL DOSE IN MAN IS ESTIMATED TO BE ABOUT 2 OUNCES. [R38] *ALL THE ALDEHYDES POSSESS ANESTHETIC PROPERTIES, BUT THIS IS OBSCURED BY THEIR HIGHLY IRRITANT ACTION ON THE EYES AND MUCOUS MEMBRANES OF THE RESPIRATORY TRACT. /ALDEHYDES/ [R33] +May be harmful if absorbed through skin or inhaled. /CNS depressant/ in high concentrations. Acts as local anesthetic. Irritating to skin, eyes, and respiratory system. [R34, p. 49-25] *Effect of benzaldehyde on growth of malignant human cells (HL60 promyelocytic leukemia cells, KG-1 myeloid leukemia cells, chronic lymphocytic leukemia cells and human tumor colony forming cells from 30 patients with solid tumors), and its effects in vivo against 2 human tumor xenografts (T222 epidermoid carcinoma and T380 ovarian carcinoma) established from primary specimens were studied. Benzaldehyde was found to lack significant activity against most human tumors tested in these exptl systems. [R42] NTOX: *EPILEPTIFORM CONVULSIONS OBSERVED IN RABBITS. [R38] *Benzaldehyde (1%) fed to rats for 14 days decreased body and liver weight gains.... oral administration of 435 mg/kg (approximately one third of the LD50) to rats daily for 4 days caused the death of one out of six rats. ...applied full strength to intact or abraded rabbit skin for 24 hr under occlusion was moderately irritating. [R14, 115] *Injected into rabbits it produced a marked relaxation of the intestines and urinary bladder and marked vasodilation of the splanchnic vessel. Injection of 4 ml of a 5% solution iv into a cat caused a fall in blood pressure and slowing of respiration. [R14, 116] *Rats and mice were treated daily (5 days/wk) by gavage either in 12 doses of 0 (vehicle control), 100 (rats only), 200, 400, 800, 1600 or (for mice only) 3200 mg/kg/day (followed by 2 days' observation without treatment), or for 90 days in doses of 0, 50, 100, 200, 400 or 800 mg/kg/day (rats) or 0, 75, 150, 300, 600 or 1200 mg/kg/day (mice). In acute studies, benzaldehyde induced deaths and decr body wt gain in both sexes of rats given 800 or 1600 mg/kg/day and caused deaths in both sexes of mice given 1600 or 3200 mg/kg/day. In 90 day studies, deaths occurred in boths sexes of rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Body-wt gain was depressed in male rats on 800 mg/kg/day, in male mice on 600 mg/kg/day, and in female mice on 1200 mg/kg/day. Necrotic and degenerative lesions were seen in cerebellar and hippocampal regions of brain in both sexes of rats given 800 mg/kg/day, but not in mice. Renal tubular necrosis occurred in male and female rats on 800 mg/kg/day and in male mice on 1200 mg/kg/day. Mild epithelial hyperplasia or hyperke ratosis of forestomach was seen in male and female rats on 800 mg/kg/day. The no-observed toxic effect doses admin by gavage were 400 mg/kg/day in male and female rats, 300 mg/kg/day in male mice and 600-1200 mg/kg/day in female mice. [R43] *The sensory irritating potential of a series of saturated and unsaturated aliphatic and cyclic aldehydes was investigated in B6C3F1 AND Swiss Webster mice. Cyclic aldehydes produced RD50 values (concn which elicits a 50% decr in respiratory rate) between 60 and 400 ppm. Tentative threshold limit values (TLVs), based upon prevention of sensory irritation, were extrapolated from the RD50 values of Swiss Webster mice. Good agreement was found with currently published TLVs. [R44] *In dilutions of 1:100 in cottonseed oil was germicidal to Bacillus coli. Inhibited in vitro growth of Saprolegnia parasitica at 2000 ppm but not at 200 ppm. [R14, 117] *Benzaldehyde had an inhibitory effect on the proliferation of chemically transformed rat liver epithelial cells, Culb TC/R/TC. Such cells treated with bezaldehyde (2X10-3 M) ceased proliferation by 4th or 6th day of cultivation, whereas control cells continued to proliferate through the period (14 days). Benzaldehyde also inhibited the accum of cells with no marked morphological change. These effects were temporary and reversible. Data suggested the restoration of cell-cell contact inhibition to Culb TC/T/TC cells by benzaldehyde treatment. [R45] *Benzaldehyde inhibited the growth of SV40 transformed rat embryo fibroblasts only in the presence of glucose or mannose containing medium. It did not affect the growth of normal rat embryo fibroblasts. [R46] *The effect of the carcinostatic drug benzaldehyde on hyperthermia induced cytotoxicity was studied in various types of cultured mammalian cell lines by colony formation assay. Enhancement of hyperthermic cell killing was much greater in SV40-transformed rat fibroblasts than in the untransformed cell line. The enhancement of cell killing incr as the time and concn of BA treatment were increased at elevated temp. [R40] *In in vitro tests benzaldehyde (1:1000 in a 0.9% saline solution) was lethal to male pork ascarids within 4 hr. [R14, 117] *Benzaldehyde was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton S wild type males were treated with concentrations of BA that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of benzaldehyde tested by injection (2500 ppm) and feeding (1150 ppm) were negative in this assay. [R47] *Benzaldehyde was not mutagenic in six strains of Salmonella typhimurium and did not induce chromosomal aberrations in CHO cells, with or without exogenous metabolic activation. Benzaldehyde induced increases in trifluorothymidine resistant mouse lymphoma cells in the absence of exogenous metabolic activation and increased sister chromatid exchanges in CHO cells in both the presence and absence of metabolic activation. Sex linked recessive lethal mutations were not induced in the germ cells of adult male D. melanogaster administered benzaldehyde by feeding or by injection. [R48] NTXV: *LD50 Rabbit dermal 1250 mg/kg; [R49] *LD50 Guinea pig oral 1000 mg/kg; [R49] *LD50 Rat oral 1300 mg/kg; [R49] *LD50 Mouse ip 1000 mg/kg; [R49] *LD50 Rabbit sc 5.0 g/kg; [R50] NTP: *2-Year studies were conducted by administering 0, 200, or 400 mg/kg benzaldehyde in corn oil by gavage, 5 days per week for 103 weeks to groups of 50 male B6C3F1 mice. Groups of 50 female B6C3F1 mice were administered 0, 300, or 600 mg/kg benzaldehyde for 103 weeks. Mean body weights of dosed ... mice were similer to their respective vehicle controls throughout the studies. No ... significant differences /in survival/ were observed between any groups ... of mice (survival--vehicle control male mice: 32/50; low dose 33/50; high dose 31/50; female mice: 30/50; 27/50; 35/50). The only effects of benzaldehyde were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). the increased incidences of papillomas were accompanied by dose related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female 12/50; 23/50; 39/50). ... Under the conditions of these 2 year gavage studies, ... there was some evidence of carcinogenic activity of benzaldehyde for male or female B6C3F1 mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach. Male and female mice might have been able to tolerate higher doses. [R51] *2 Year studies were conducted by administering 0, 200, or 400 mg/kg benzaldehyde in corn oil by gavage, 5 days per week for 103 weeks to groups of 50 male and 50 female /F344/N/ rats. ... Mean body weights of dosed rats were similar to their respective vehicle controls throughout the studies. The survival of the high dose group of male rats was lower than that of the vehicle controls after 1 year, no other significant differences were oberved between any groups of rats (survival--male rats: vehicle control, 37/50; low dose, 29/50; high dose, 21/50; female rats: 33/50; 33/50; 29/50). ... Under the conditions of these 2 year gavage studies, there was no evidence of carcinogenic activity of benzaldehyde for male or female F344/N rats receiving 200 or 400 mg/kg per day. Female rats might have been able to tolerate higher doses. [R51] ADE: *THIS PROBABLY ... /ABSORBED/ @ A RELATIVELY SLOW RATE IN LIVER, BUT IT IS USUALLY COMPLETE EXCEPT WHERE SUBSTITUENTS SUCH AS HYDROXY GROUPS MAKE IT CAPABLE OF BEING EXCRETED BY ALTERNATE METABOLIC PATHWAYS SUCH AS SULFATE OR GLUCURONIC-ACID CONJUGATIONS ON THE HYDROXY GROUP. THE AROMATIC ALDEHYDES, SUCH AS BENZALDEHYDE, ARE OXIDIZED TO THE CORRESPONDING ACIDS. [R52] *After ip administration to rats, 29.3% (21-37%) was excreted in the urine as hippuric acid. [R14, 116] METB: *BENZALDEHYDE YIELDS BENZYL ALC IN RABBIT: ROBERTSON, JS AND PJ DUNSTAN, BIOCHEM J 127 (119) 1972; YIELDS ERYTHRO-PHENYLSERINE AND L-THREO-PHENYLSERINE IN MAN: BRUNS, FH AND L FIEDLER, NATURE (LONDON) 181, 1533 (1958). /FROM TABLE/ [R53] *HEPATIC SOL FRACTION CONTAINS A NUMBER OF ALDEHYDE OXIDASES TRANSFORMING ALDEHYDES TO THE CORRESPONDING CARBOXYLIC ACIDS. FOR EXAMPLE, MOLYBDOFLAVOPROTEINS ALDEHYDE OXIDASE AND XANTHINE OXIDASE CATALYZE METAB OF SALICYLALDEHYDE AND BENZALDEHYDE. [R54] *... Benzaldehyde, a cleavage product of amphetaminil, was rapidly converted to hippuric acid in the blood, brain, and adipose tissue of rats and then excreted in the urine ... . [R14, p. 116] *Infusion of benzaldehyde to perfused rat liver increased hepatic ethane production. Results obtained with inhibitors of hepatic aldehyde metabolism suggest that the metabolism of benzaldehyde is required for ethane production. Radical scavenging by addition of cyanidanol or by pretreatment with vitamin E abolished ethane release, in agreement with lipid peroxidation as a source of alkane production during aldehyde metabolism. [R55] ACTN: *Large injected doses of benzaldehyde exert their most important toxic effects on the medulla, with slowing or paralysis of respiration. [R14, 116] *The mechanism by which benzaldehyde inhibits cell growth was investigated using human NHIK 3025 cells. The hypothesis proposed is that the drug might inhibit a process in the cells which activates enzymes. Such an effect might possibly entail a reduced protein synthesis as well as a prolonged mitosis. In addn, it might also count for the reported detransforming activity on malignant cells. [R56] INTC: *Binary mixtures of crotonaldehyde, furfural, acrolein, acetaldehyde, benzaldehyde, butyraldehyde, formalin, and salicylaldehyde were tested for toxicity to Chilomonas paramecium. Significant increases (8 fold) in toxicity were found with combination of crotonaldehyde with furfural, benzaldehyde, and acrolein and for acetaldehyde with furfural and acrolein. Lesser potentiation of toxicity (4-fold) was found with crotonaldehyde and butyraldehyde or formalin, furfural and benzaldehyde, and acrolein and butyraldehyde. [R57] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Exptl Use: Benzaldehyde significantly inhibited peptic activity in artificial gastric juice in vitro (20-45% inhibition) and in vivo to the extent of 87% in normal healthy persons and ulcer patients. [R14, 116] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Benzaldehyde is released to the environment in emissions from combustion processes such as gasoline and diesel engines, incinerators and wood burning. It is formed in the atmosphere through photochemical oxidation of toluene and otheraromatic hydrocarbons. It occurs naturally in various plants. If released to the atmosphere, benzaldehyde will degrade by reaction with photochemically produced hydroxyl radicals (half-life of 29.8 hr); direct photolysis may contribute to its atmospheric degradation. Physical removal from air by wet deposition can occur. If released to soil or water, the major degradation pathway is expected to be biodegradation. Physical transport from water can occur through volatilization. Estimated Koc values (9-71) suggest that benzaldehyde will leach in soil. Occupational exposure to benzaldehyde occurs through inhalation of vapor and dermal contact. The general population is exposed to benzaldehyde through consumption of food (where it occurs either naturally or as an intentional food additive) and inhalation of contaminated air. (SRC) NATS: *PRESENT AS CYANURIC GLUCOSIDE (AMYGDALIN) IN BITTER ALMOND, PEACH, APRICOT KERNEL, AND OTHER PRUNUS SPECIES. AMYGDALIN IS ALSO PRESENT IN VARIOUS PARTS OF THE FOLLOWING PLANTS: SAMBUCUS NIGRA, CHRYSOPHYLLUM ARTEN, ANACYCLUS OFFICINARUM, ANACYCLUS PEDUNCULATUS, DAVALLIA BRASILIENSIS, LACUMA DELICIOSA, LACUMA MULTIFLORA AND OTHERS. FREE BENZALDEHYDE HAS BEEN REPORTED FOUND IN SEVERAL ESSENTIAL OILS: HYACYNTH, CITRONELLA, ORRIS, CINNAMON, SASSAFRAS, LABDANUM, AND PATSCHOULLI. [R2] *Benzaldehyde occurs naturally as a volatile plant product(1,2); for example, benzaldehyde is a major constituent of cranberry aroma(2). Benzaldehyde is formed in the atmosphere as a product of the photochemical degradation of toluene(3-5); as much as 15% of the products resulting from the reaction of toluene with OH radicals will be benzaldehyde(5). Photochemical reactions of aromatic precursors other than toluene (such as styrene and methylstyrene) can also form benzaldehyde in the atmosphere(6). Benzaldehyde has been found to occur naturally in various fruits such as peaches, black currants, strawberries, grapes, and raspberries(7). [R58] ARTS: */PRESENT IN/ HICKORY SMOKE [R19] *DETECTED IN GASOLINE EXHAUST < 0.1-13.5 ppm, IN DIESEL EXHAUST 0.3 ppm [R59] *Benzaldehyde has been detected in atmospheric emissions from fireplaces and wood burning(1,2). Benzaldehyde has been identified in volatile emissions from sanitary landfills(3). Exhaust emissions from gasoline and hydrocarbon engines have been found to contain benzaldehyde(4-7). Benzaldehyde has been detected in flue gas emissions from waste incineration(8,9). Aqueous effluents from coal conversion facilities can contain benzaldehyde(10,11). Benzaldehyde has been identified in aqueous effluents from sewage treatment plants, chemical plants, and textile plants(12). [R60] FATE: *TERRESTRIAL FATE: The primary degradation process in soil is expected to be biodegradation. A number of biological screening studies have demonstrated that benzaldehyde is readily biodegradable. Estimated Koc values of 34 and 150 suggest that benzaldehyde will leach readily(1,SRC). [R61] *AQUATIC FATE: The major environmental degradation process for benzaldehyde in water is probably biodegradation. A number of biological screening studies have demonstrated that benzaldehyde is readily biodegradable. Volatilization may have some importance; volatilization half-lives of 37 hr and 17 days have been estimated for a model river (one meter deep) and an environmental pond, respectively(2,3). Direct photolysis may occur in brightly sunlit waters; however, reliable photolysis rates are not available. Aquatic hydrolysis, adsorption to sediment, and bioconcentration are not expected to be important fate processes(SRC). [R62] *ATMOSPHERIC FATE: Based upon a vapor pressure of 1.27 mm Hg at 25 deg C(1), benzaldehyde is expected to exist primarily in the vapor-phase in the ambient atmosphere(2,SRC). Vapor-phase benzaldehyde will degrade in an average ambient atmosphere by reaction with photochemically produced hydroxyl radicals (estimated half-life of 29.8 hr)(3,SRC). Direct photolysis and reaction with nitrate radicals (during night-time hrs) will also contribute to its atmospheric degradation. Small quantities of benzaldehyde have been detected in atmospheric aerosol particulates(4,5); particulate material can be physically removed from air via dry and wet deposition. Benzaldehyde's detection in rain, snow, fog, and cloud water(6,7) indicates that wet deposition has some environmental importance(SRC). [R63] BIOD: *BOD: 50%, 10 days; 150%, 5 days [R8] *Benzaldehyde had a 5 day theoretical BOD of 36% using the AFNOR T test and inoculum from 3 polluted surface waters(1). Using a sewage inocula and standard dilution water, benzaldehyde had a 10-day theoretical BOD of 62%(2). Theoretical BODs of 41-70% were observed (at 500 ppm conc) in Warburg respirometers using 3 different activated sludge seeds and 6 days of inubation(3). Theoretical BOD of 13% was observed (at 500 ppm conc) in a Warburg respirometer using a digester sludge seed acclimated to benzene and 6 hr incubation(4). Theoretical BODs of 30-38% were observed (at 250 ppm conc) in Warburg respirometers using activated sludge seeds acclimated to phenol, benzyl alcohol or anthranilic acid and 12 hr incubation(5). About 99% of initial benzaldehyde was removed (based upon COD) in 5 days of incubation using an activated sludge inocula that had been acclimated to benzaldehyde for 20 days(6). Five-day theoretical BODs of 77.2% and 63.5% were measured using the standard dilution method and seawater dilution method, respectively(7). [R64] *The biodegradability of benzaldehyde in aqueous environments was measured using five different screening methods (BOD dilution, Shake Flask, CO2 Evolution, Gledhill, and activated sludge)(1); quantitative biodegradation was observed to begin immediately and occurred in most cases within the first 3 days of incubation(1); benzaldehyde was metabolized rapidly in all methods(1); degradation was slowest in the CO2 evolution test where 60% was mineralized in 7 days and nearly 100% mineralized in 28 days(1). Using an electrolytic respirometer and an activated sludge inocula, theoretical BODs of 77-85% were observed after 100-130 hr of incubation(2). A 7 day CO2 evolution of 73% was measured in a system using a sludge inoculum(3); very little CO2 was evolved in a sterile control system(3). [R65] ABIO: *The rate constant for the vapor-phase reaction of benzaldehyde with photochemically produced hydroxyl radicals has been experimentally determined to be 1.29X10-11 cu cm/molecule-sec at room temperature which corresponds to an atmospheric half-life life of about 29.8 hr at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Aldehydes are generally resistant to aqueous environmental hydrolysis(2), therefore, benzaldehyde is not expected to chemically hydrolyze in the environment(SRC). The rate constant for the reaction between photochemically produced hydroxyl radicals in water and benzaldehyde is 4.4X10+9 l/mole-sec(3); assuming that the conc of hydroxyl radicals in brightly sunlit natural water is 1X10-17 M(4), the half-life would be about 182 days(SRC). The rate constant for the vapor-phase reaction of benzaldehyde with atmospheric nitrate radicals has been experimentally determined to be 2.0X10-15 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 16.7 days at an atmospheric concn of 2.4X10+8 nitrate radicals per cu cm(5,SRC). The atmospheric reaction between benzaldehyde and ozone is too slow to be important environmentally(6). [R66] *Benzaldehyde absorbs UV irradiation weakly (extinction coefficient of 0-30/M-cu cm) in the spectra between 300 and 380 nm in both the solution-phase (hexane solvent) and gas-phase(1,2); although the absorption is relatively weak, the quantum yield (which is approximately 0.34- 0.41) is quite high(1) and it suggests that benzaldehyde may directly photolyze in the environment(SRC); reliable environmental photolysis rates are not available(SRC). [R67] BIOC: *Based upon a measured log Kow of 1.48(1) and a water solubility of 6950 mg/l at 25 deg C(2), the BCF for benzaldehyde can be estimated to be 7.8 and 4.2, respectively, from recommended regression-derived equations(3,SRC). These BCF values suggest that bioconcentration in aquatic organisms is not important(SRC). [R68] KOC: *Based upon a measured log Kow of 1.48(1) and a water solubility of 6950 mg/l at 25 deg C(2), the Koc for benzaldehyde can be estimated to be about 150 and 34, respectively, from recommended regression-derived equations(3,SRC). These Koc estimations indicate high to very high soil mobility(4). [R69] VWS: *Benzaldehyde has an experimentally measured Henry's Law constant of 2.67X10-5 atm cu m/mole at 25 deg C(1); a Henry's Law constant of this magnitude indicates that volatilization from environmental waters is possibly significant, but may not be rapid(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 37 hours(2,SRC). Volatilization half-life from an model environmental pond (2 meters deep) can be estimated to be about 17 days(3,SRC). [R70] WATC: *DRINKING WATER: A benzaldehyde conc of 0.03 ug/L was detected in the drinking water taken from the Carrollton Water Treatment Plant in New Orleans, LA in Aug 1974(1). Benzaldehyde was qualitatively detected in various drinking water samples collected in Philadelphia, PA between Feb 1975 and Jan 1977(2). Benzaldehyde has been detected (no concn available) for drinking water samples from Poplarville, MS (Mar 2, 1979), Cincinnati, OH (Oct 17, 1979, Jan 14, 1980), Miami, FL (Feb 3, 1976), New Orleans. LA (Jan 14, 1976), Philadelphia, PA (Feb 10, 1976), and Ottumwa, IO (Sep 10, 1976)(3). [R71] *SURFACE WATERS: Benzaldehyde was detected in only one of 204 water samples (concn > 1 ppb) collected from 14 heavily industrialized river basins in the US(1). Benzaldehyde was qualitatively detected in water samples taken from Lake Ontario(2). A benzaldehyde concn of 0.03 ug/L was detected in samples of lake water collected from Lake Pontchartrain (New Orleans, LA) in Jan 1980(3). [R72] *GROUND WATER: Benzaldehyde was detected (no concn reported) in 1 of 2963 ground water wells that were monitored in 28 of California's 58 counties as of Apr 1984(1). The maximum conc of benzaldehyde detected in CA ground water is reported to be 2.0 ug/l(2). [R73] *SEAWATER: Grab samples collected from coastal and open surface waters contained benzaldehyde levels of 0-15 ng/kg(1). [R74] *RAIN/SNOW: Benzaldehyde levels of 0-0.57 ug/ml (mean conc 0.05 ug/ml) have been detected in cloud water collected from Henninger Flats, CA(1); levels of 0.08-0.19 ug/ml have been detected in ice fog water collected from Fairbanks, Alaska(1); rain water collected in Carson, CA contained a benzaldehyde concn of 0.09 ug/ml(1). [R75] EFFL: *Benzaldehyde levels of 12-15 ppb were detected in wood smoke(1). Benzaldehyde levels of 0.002-0.102 g/kg wood have been detected in emissions from fireplaces burning pine, cedar, oak and ash wood(2). Emissions from gasoline powered automobiles were found to contain benzaldehyde concns of 0.7 to 19 mg/km traveled(3,4). Benzaldehyde concn in exhausts from engines burning simple hydrocarbons was < 0.1-13.5 ppm(5). Flue gas emissions from a waste incinerator on a high-rise building in Norway had a benzaldehyde concn of 6 ug/cu m(6). [R76] SEDS: *Benzaldehyde was qualitatively detected in sediments taken from Tobin Lake in Saskatchewan, Canada(1) and in sediments collected near hazardous waste sites along the Niagara River(2). Soil samples collected along the Buffalo River in Buffalo, NY contained a benzaldehyde concn of 4 ppm, but river sediments had no detectable levels(3). [R77] ATMC: *SOURCE DOMINATED: A field monitoring study along a highway in Raleigh, NC in May 1983 detected benzaldehyde levels of 8.91- 15.26 ppb(1); the primary source of the benzaldehyde was considered to be exhaust from cars and trucks(1). Benzaldehyde was detected in 10 of 12 ambient air samples collected near an American Cyanamide production facility in Linden, NJ between 1976 and 1978 at levels of 36-557 ng/cu m(2). [R78] *URBAN/SUBURBAN: The gas-phase concn of benzaldehyde in ambient Los Angeles, CA air during photochemical pollution episodes (July-Oct 1980) ranged from 0 to 2 ppb with a median concn of about 0.5 ppb(1). Air sample collected from Claremont, CA in Sept 1985 contained benzaldehyde levels of < 0.1 to 0.8 ppb(2); sampling was not conducted during any smog/pollution episodes(2). Benzaldehyde levels in Los Angeles, CA air in the fall of 1981 was 0-2 ppb(3). Monitoring of indoor air in 40 homes in the Oak Ridge-Knoxville, TN area between Apr 1982 and Feb 1983 detected a mean benzaldehyde concn of 51.8 ug/cu m (max conc of 264.5 ug/cu m)(4). [R79] FOOD: *Benzaldehyde has been qualitatively detected as a volatile constituent of baked potatoes(1), cassava products(2), mountain cheese(3), nectarines(4), fried bacon(5), roasted filbert nuts(6), dried legumes(7), peaches(8), clove oil(9), chickpeas(10), cooked beef(11), and fried chicken(12). Benzaldehyde is used directly as a flavoring agent in foods (especially for artificial cherry and almond flavors) in quantities that approach 0.5 million lb/yr(13). [R80] MILK: *Benzaldehyde was qualitatively detected in 8 of 12 samples of human milk collected from volunteers in Bayonne, NJ, Jersey City, NJ, Bridgeville, PA, and Baton Rouge, LA(1). [R81] OEVC: *Benzaldehyde has been identified in tobacco smoke(1). [R82] RTEX: *Occupational exposure to benzaldehyde can occur through dermal contact and inhalation of vapors. Benzaldehyde's use as a flavoring agent and its natural occurrence in many foods will expose the general population through oral consumption(1,2). The general population is also exposed to benzaldehyde through its occurrence in ambient air(SRC). [R83] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 30,517 workers are potentially exposed to benzaldehyde in the USA(1). NIOSH (NOHS Survey 1972-1974) has statistically estimated that 15,985 workers are potentially exposed to benzaldehyde in the USA(2). [R84] BODY: *Benzaldehyde was qualitatively detected in 8 of 12 samples of human milk collected from volunteers in Bayonne, NJ, Jersey City, NJ, Bridgeville, PA, and Baton Rouge, LA(1). [R81] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: +Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 2 ppm; Short-term Exposure Limit (STEL) 4 ppm, 15 min. [R85] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 700 ug/l [R86] TSCA: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Benzaldehyde is produced, as an intermediate or a final product, by process units covered under this subpart. [R87] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Benzaldehyde is found on List C. Case No: 3025; Pesticide type: Insecticide; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Benzaldehyde; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R16] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *BENZALDEHYDE AND ITS IMPURITIES WERE SEPARATED BY HPLC. DETECTION LIMITS OF NITROBENZENE WERE 6 UG, BENZAL CHLORIDE 0.788 UG, BENZOIC ACID 0.1 UG (ALL IN 1 UL BENZALDEHYDE). [R88] *Benzylamine and its metabolites were detected in in vitro experiments by HPLC. [R89] *Aldehydes (including benzaldehyde) were detected in exhaust gas by HPLC equipped with fluorescence detector. [R90] *Proton magnetic resonance spectroscopy was used for the quantitative detection of benzaldehyde in bitter almond oil. Nitrotoluene was the internal standard. Standard deviation was 0.76%. The method is simple and accurate, requires less oil than the hydroxylamine method and does not require expensive reagents or solvents and permits the detection of adulterants. [R91] *Benzaldehyde in almond extract is determined by gravimetric method, alternative gravimetric method, and UV spectrophotometric method. [R92] *A ... purge and trap GC analysis of volatile organic carbon compounds in water was designed. ... The method separated over 200 organic compounds within 40 min using flame ionization and ion trap detection and is capable of quantitation down to 5 ng/l per component. ... Percentage recoveries of benzaldehyde with the two series of tubes (all Tenax-TA or 3 different kinds) were 75.3, 20.1, and 4.6%, and 75.2, 24.8, and 0.2% for tubes 1, 2, and 3, respectively. The recoveries of benzaldehyde from water at 30 and 60 C were 70 and 91%, respectively. [R93] *EPA Method IP-1B.Combined GC/MS method for the determination of volatile organic compounds in indoor air using solid absorbent tubes. Under the prescribed conditions, benzaldehyde has a detection limit of 5.90 ng/l as defined by EPA. [R94] *EPA Method IP-6A.Determination of formaldehyde and other aldehydes in indoor air using HPLC coupled with UV absorption detector at 360 nm. Sampling rate and time are dependent upon carbonyl concentration in the test atmosphere. Under the prescribed conditions, benzaldehyde has a sensitivity of 0.01 ppb as defined by EPA. [R94] *EPA Method IP-6C.Determination of formaldehyde and other aldehydes including benzaldehyde in indoor air using HPLC coupled with UV detector. Formaldehyde and other aldehydes diffuse into the passive sampling device and react with 2,4-dinitrophenylhydrazine in the presence of an acid to form a stable DNPH-derivative as defined by EPA. [R94] *EPA Method MTO-11. Determination of formaldehyde in ambient air using adsorbent cartridge followed by HPLC with an UV absorption detector at 360 nm. The sensitivity for benzaldehyde is 0.01 ppb as defined by EPA. [R94] *EPA Method IP-6B.Determination of formaldehyde and other aldehydes in indoor air using a continuous colorimetric analyzer. The air flow rate must be kept constant at 0.5 l/min and should be periodically checked using a flowmeter. No detection limit is given for benzaldehyde. [R94] CLAB: *The total concn of orally admin benzaldehyde present in human blood in free and bound forms was detected by liq chromatography. The highest level detected was 1.3-1.5 ug/ml. [R95] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: The Food Chemicals Codex (1972) has a monograph on benzaldehyde and the Joint FAO/WHO Expert Committee has published a monograph and specifications. DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzaldehyde in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 378 (1990) NIH Publication No. 90-2833 SO: R1: SRI R2: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 40 R3: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 127 R5: Block JH, Levine HL; J Chromatogr 166 (1): 313-5 (1978) R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 739 (1978) R7: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1232 R8: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R9: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 478 R10: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 545 R11: Farm Chemicals Handbook 1992. Willoughby, OH: Meister Publishing Co., 1992. R12: TAKEUCHI S ET AL; JPN KOKAI TOKKYO KOHO PATENT 78142516 12/12/78 (INSTITUTE OF PHYS AND CHEM RESEARCH) R13: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 799 R14: Opdyke, D.L.J. (ed.). Monographs on Fragrance Raw Materials. New York: Pergamon Press, 1979. R15: The Royal Society of Chemistry. Foreign Compound Metabolism in Mammals. Volume 6: A Review of the Literature Published during 1978 and 1979. London: The Royal Society of Chemistry, 1981. 248 R16: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.237 (Spring, 1998) EPA 738-R-98-002 R17: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 740 (1978) R18: USITC. IMPORTS OF BENZENOID CHEM AND PROD p.10 (1983) R19: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 736 (1978) R20: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993. R21: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979. R22: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 28 R23: Sherman PD; Aldehydes; In: Kirk-Othmer Encycl Chem Tech 3rd Ed 1: 790-8 (1978) R24: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1229 R25: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 150 R26: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 134 R27: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2663 R28: Ambrose D et al; J Chem Therm 7: 1143-57 (1975A) R29: Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. 9:6/1989 R30: Betterton EA, Hoffmann MR; Environ Sci Technol 22: 1415-8 (1988) R31: Atkinson R; Journal of Physical And Chemical Reference Data. Monograph No 1 (1989) R32: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-129 R33: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 354 R34: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R35: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 737 (1978) R36: Bretherick, L. Handbook of Reactive Chemical Hazards. 3rd ed. Boston, MA: Butterworths, 1985. 669 R37: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 99 R38: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-167 R39: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 178 R40: Ishida A et al; Cancer Res 43 (9): 4216-20 (1983) R41: Nambata T et al; Gann 72 (2): 289-92 (1981) R42: Taetle R, Howell SB; Cancer Treat Rep 67 (6): 561-6 (1982) R43: Kluwe WM et al; Food Chem Toxicol 21 (3): 245-50 (1983) R44: Steinhagen WH, Barrow CS; Toxicol Appl Pharmacol 72 (3): 495-503 (1984) R45: Nambata T et al; Agric Biol Chem 45 (12): 2815-21 (1981) R46: Watanuki M, Sakaguchi K; Agric Biol Chem 45 (1): 319-21 (1981) R47: Woodruff RC et al; Environ Mutagen 7:677-702 (1985) R48: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzaldehyde in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.4 (1988) Technical Rpt Series No. 332 NIH Pub No. 88-2588 R49: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzaldehyde in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.15 (1988) Technical Rpt Series No. 332 NIH Pub No. 88-2588 R50: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 236 R51: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzaldehyde in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.3 (1988) Technical Rpt Series No. 378 NIH Pub No. 88-2588 R52: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1965 R53: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. B-1 R54: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 311 R55: Mueller A, Sies H; Eur J Biochem 134 (3): 599-602 (1983) R56: Pettersen EO et al; Eur J Cancer Clin Oncol 19 (7): 935-40 (1983) R57: Bringmann G et al; Z Wasser Abwasser Forsch 15 (5): 239-42 (1982) R58: (1) Graedel TE; Chemical Compounds in the Atmosphere. NY: Academic Press p. 177 (1976) (2) Nicholas HJ; Phytochemistry Vol II NY,NY: Van Nostrand Reinhold Co p. 396 (1971) (3) Leone JA, Seinfeld JH; Int J Chem Kinet 16: 159-93 (1984) (4) Atkinson R et al; Int J Chem Kinet 12: 779-836 (1980) (5) Hendry DG et al; Reactions of Oxy Radicals in the Atmosphere USEPA-600/3-79-010 (1979) (6) Grosjean D; Sci Total Environ 46: 41-59 (1985) (7) National Research Council; Formaldehyde and Other Aldehydes USEPA-600/6-82-002 (NTIS PB82-180498) (1982) R59: VERSCHUEREN. HDBK ENVIRON DATA ORG CHEM 1983 p.235 R60: (1) Kleindienst TE et al; Environ Sci Technol 20: 493-501 (1986) (2) Lipari F et al; Environ Sci Technol 18: 326-30 (1984) (3) LaRegina J et al; Environ Prog 5: 18-27 (1986) (4) Westerholm RN et al; Environ Sci Technol 22: 925-30 (1988) (5) Victorin K et al; Chemosphere 17: 1767-80 (1988) (6) Seizinger DE, Dimitriades B; J Air Pollut Control Assoc 22: 47-51 (1972) (7) Smith LR; Characterization of Emissions from Motor Vehicles Designed for Low Nitrogen Oxide (NOX) Emissions USEPA-600/2-80-176 (NTIS PB81- 155327) (1980) (8) James RH et al; J Air Pollut Control Assoc 35: 959-69 (1985) (9) Benestad C et al; Chemosphere 16: 813-20 (1987) (10) Giabbai MF et al; Intern J Environ Anal Chem 20: 113-29 (1985) (11) Singer PC et al; Assessment of Coal Conversion Wastewaters: Characterization and Preliminary Biotreatability USEPA-600/7-78-181 (NTIS PB-294338) (1978) (12) Shackelford WM, Keith LM; Frequency of Organic Compounds Identified in Water. USEPA-600/4-76-062 p. 63 (1976) R61: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 4-9 (1990) R62: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 4-9 (1990) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 15-15 to 15-29 (1990) (3) US EPA; EXAMS II Computer Simulation (1987) R63: (1) Ambrose D et al; J Chem Therm 7: 1143-57 (1975) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; J Phys Chem Ref Data, Monograph 1, p. 145 (1989) (4) Cautreels W, Vancauwenberghe K; Atmos Environ 12: 1133-41 (1978) (5) Yokouchi Y et al; Chemosphere 16: 47-53 (1987) (6) Grosjean D, Wright B; Atmos Environ 17: 2093-6 (1983) (7) Lunde G et al; Organic Micropollutants in Precipitation in Norway. SNSF Project, FR-9-76 (1976) R64: (1) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (2) Heukelekian H, Rand MC; J Water Pollut Control Assoc 27: 1040-53 (1955) (3) Lutin PA et al; Purdue Univ Eng Bull, Ext Series 118: 131-45 (1965) (4) Malaney GW, McKinney RE; Water Sewage Works 113: 302-9 (1966) (5) McKinney RE et al; Sew Indust Wastes 28: 547-57 (1956) (6) Pitter P; Water Res 10: 231-5 (1976) (7) Takemoto S et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) R65: (1) Means JL, Anderson SJ; Water Air Soil Pollut 16: 310-15 (1981) (2) Urano K,Kato Z; J Hazardous Mater 13: 135-45 (1986) (3) Boatman RJ et al; Environ Toxicol Chem 5: 233-43 (1986) R66: (1) Atkinson R; J Phys Chem Ref Data Monograph No. 1, p. 154 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 7-4 (1990) (3) Buxton GV et al; J Phys Chem Ref Data 17: 706 (1988) (4) Mill T et al; Sci 207: 886-7 (1980) (5) Atkinson R et al; Environ Sci Technol 21: 1123-26 (1987) (6) Grosjean D; Sci Total Environ 46: 41-59 (1985) R67: (1) Berger M et al; J Amer Chem Soc 95: 1717-25 (1973) (2) Majer JR et al; Trans Faraday Soc 65: 1846 (1969) R68: (1) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College(1985) (2) Yalkowsky SH; Arizona Database of Aqueous Solubilities. College of Pharmacy, Univ AZ (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 5-4, 5-10 (1990) R69: (1) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College(1985) (2) Yalkowsky SH; Arizona Database of Aqueous Solubilities. College of Pharmacy, Univ AZ (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 4-9 (1990) (4) Swann RL et al; Res Rev 85: 23 (1983) R70: (1) Betterton EA, Hoffmann MR; Environ Sci Technol 22: 1415-8 (1988) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc pp. 15-15 to 15- 29 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation, NY: Hemisphere Pub Corp (1989) R71: (1) Keith LH et al; pp. 329-73 in Ident Anal Organic Pollut Water. Ann Arbor, MI: Ann Arbor Press (1976) (2) Suffet IH et al; Water Res 14: 853-67 (1980) (3) Lucas, SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1 USEPA-600/1-84-020A. p. 135 (1984) R72: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters USEPA-560/6-77-015a p. 72 (1977) (2) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem, Volume 1 - Summary. Report to the Great Lakes Water Quality Board. Windsor Ontario, Canada p. 55 (1983) (3) McFall JA et al; Chemosphere 14: 1253-65 (1985) R73: (1) Cohen DB; ACS Symp Ser 315(Eval Pestic Ground Water): 499- 529 (1986) (2) Hallberg GR; Agr Ecosyst Environ 26: 299-367 (1989) R74: (1) Sauer TC Jr; Org Geochem 3: 91-101 (1981) R75: (1) Grosjean D, Wright B; Atmos Environ 17: 2093-6 (1983) R76: (1) Kleindienst TE et al; Environ Sci Technol 20: 493-501 (1986) (2) Lipari F et al; Environ Sci Technol 18: 326-30 (1984) (3) Westerholm RN et al; Environ Sci Technol 22: 925-30 (1988) (4) Victorin K et al; Chemosphere 17: 1767-80 (1988) (5) Seizinger DE, Dimitriades B; J Air Pollut Control Assoc 22: 47-51 (1972) (6) Benestad C et al; Chemosphere 16: 813-20 (1987) R77: (1) Samolloff MR et al; Environ Sci Technol 17: 329-34 (1983) (2) Elder VA et al; Environ Sci Technol 15: 1237-43 (1981) (3) Nelson CR, Hites RA; Environ Sci Technol 14: 1147-9 (1981) R78: (1) Zweidinger RB et al; Environ Sci Technol 22: 956-62 (1988) (2) Pellizzari ED; Quantification of Chlorinated Hydrocarbons in Previously Collected Air Samples USEPA-450/3-78-112 (1978) R79: (1) Grosjean D; Environ Sci Technol 16: 254-62 (1982) (2) Grosjean D; Atmos Environ 22: 1637-48 (1988) (3) Grosjean D, Fung K; J Air Pollut Control Assoc 34: 537-43 (1984) (4) Hawthorne AR et al; pp 514-26 in Spec Conf Meas Monit Non-Criter (Toxic) Contam Air, Frederick, ER ed Pittsburgh, PA: APCA (1981) R80: (1) Coleman EC et al; J Agric Food Chem 29: 42-9 (1981) (2) Dougan J et al; J Sci Food Agric 34: 874-84 (1983) (3) Dumont JP, Adda J; J Agric Food Chem 26: 364-7 (1878) (4) Engel KH et al; J Agric Food Chem 36: 549-53 (1988) (5) Ho CT et al; J Agric Food Chem 31: 336-42 (1983) (6) Kinlin TE et al; J Agric Food Chem 20: 1021 (1972) (7) Lovegren NV et al; J Agric Food Chem 27: 851-3 (1979) (8) Meredith FI et al; J Agric Food Chem 37: 1210-4 (1989) (9) Muchalal M, Crouzet J; Agric Biol Chem 49: 1583-9 (1985) (10) Rembold H et al; J Agric Food Chem 37: 659-62 (1989) (11) Shibamoto T et al; J Agric Food Chem 29: 57-63 (1981) (12) Tang J et al; J Agric Food Chem 31: 1287-92 (1983) (13) Williams AE; Kirk-Othmer Encycl Chem Technol 3rd ed. NY,NY: John Wiley and Sons 3: 736-43 (1978) R81: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R82: (1) Graedel TE; Chemical Compounds in the Atmosphere. NY: Academic Press p. 177 (1976) R83: (1) Williams AE; Kirk-Othmer Encycl Chem Technol 3rd ed. NY,NY: John Wiley and Sons 3: 736-43 (1978) (2) National Research Council; Formaldehyde and Other Aldehydes. USEPA-600/6-82-002 (NTIS PB82-180498) (1982) R84: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1974) R85: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R86: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R87: 40 CFR 60.489 (7/1/91) R88: BLOCK JH, LEVINE HL; J CHROMATOGR 166 (1): 313 (1978) R89: Jones DP; J Chromatogr 305 (1): 256-60 (1984) R90: Swarin SJ, Lipari F; J Liq Chromatogr 6 (3): 425-44 (1983) R91: Aboutabl EA et al; Pharmazie 37 (3): 213-4 (1982) R92: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. V2 904 R93: Bianchi A et al; J Chromatogr 467 (1): 111-28 (1989) R94: USEPA/SCC; Environmental Monitoring Methods Index p.5 (1992) R95: Takeuchi S et al; Rikagaku Kenkyusho Hokoku 59 (4): 134-7 (1983) RS: 63 Record 58 of 1119 in HSDB (through 2003/06) AN: 426 UD: 200303 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-CHLOROETHANOL- SY: *AETHYLENECHLORHYDRIN-; *2-CHLOORETHANOL- (DUTCH); *2-CHLORAETHANOL- (GERMAN); *CHLOROETHANOL-; *BETA-CHLOROETHANOL-; *DELTA-CHLOROETHANOL-; *2-CHLORO-1-ETHANOL-; *BETA-CHLOROETHYL-ALCOHOL-; *2-CHLOROETHYL-ALCOHOL-; *CHLOROETHYLOWY-ALKOHOL-; *2-CLOROETANOLO-; +Pesticide-Code:-600502-; *ETHANOL,-2-CHLORO-; *ETHENE,-CHLOROHYDRIN-; *ETHYLCHLOROHYDRIN-; *ETHYLEEN-CHLOORHYDRINE-; *ETHYLENE-CHLORHYDRIN-; *ETHYLENE-GLYCOL,-CHLOROHYDRIN-; *GLICOL-MONOCLORIDRINA-; *GLYCOL-CHLOROHYDRIN-; *GLYCOLMONOCHLOORHYDRINE-; *GLYCOL-MONOCHLOROHYDRIN-; *GLYCOMONOCHLORHYDRIN-; *BETA-HYDROXYETHYL-CHLORIDE-; *2-HYDROXYETHYL-CHLORIDE-; *MONOCHLORHYDRINE-DU-GLYCOL-; *2-MONOCHLOROETHANOL-; *NCI-C50135- RN: 107-07-3 RELT: 939 [CHLOROACETIC ACID] (Analog) MF: *C2-H5-Cl-O SHPN: UN 1135; ETHYLENE CHLOROHYDRIN IMO 6.1; Ethylene chlorohydrin MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ETHYLENE OXIDE AND AQUEOUS METALLIC CHLORIDES [R1] *MADE FROM ETHYLENE BY THE ACTION OF A HYPOCHLORITE. [R2] *2-Chloroethanol can be synthesized by reaction of hypochlorous acid with ethylene. [R3] IMP: *THE COMMERCIAL PRODUCT CONTAINS AS ITS CHIEF IMPURITIES ETHYLENE DICHLORIDE AND DICHLOROETHYL ETHER. [R4, 397] FORM: *GRADES: ANHYDROUS; 38%. [R5] *Grades or Purity: 99+% [R6] MFS: *UNION CARBIDE CORP, CHEMS AND PLASTICS DIV, INSTITUTE AND SOUTH CHARLESTON, WV [R1] *Eastman Kodak Co, Eastman Organic Chemicals, Rochester, NY 14650 [R6] OMIN: *For many years 2-chloroethanol was manufactured on a large scale as a precursor to ethylene oxide, but this process has been almost completely displaced by the direct oxidation of ethylene to ethylene oxide. [R7] USE: +For 2-Chloroethanol (USEPA/OPP Pesticide Code: 600502) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R8] *MFR OF INSECTICIDES; TREATING SWEET POTATOES BEFORE PLANTING [R2] *Introduction of hydroxyethyl group in organic synth; solvent for cellulose acetate, ethylcellulose; activate sprouting of dormant potatoes; mfg of ethylene oxide and ethylene glycol, insecticides. [R5] *USED TO PRODUCE ETHYLENE GLYCOL AND ETHYLENE OXIDE; EMPLOYED FOR SEPN OF BUTADIENE FROM HYDROCARBON MIXT; IN DEWAXING AND REMOVING NAPHTHENES FROM MINERAL OIL, IN REFINING OF ROSIN; IN EXTRACTION OF PINE LIGNIN; SOLVENT FOR CELLULOSE ETHERS [R9, 4675] *INTERMED FOR INDIGO, NUMEROUS OTHER CHEMICALS; INTERMED FOR THIODIETHYLENE GLYCOL (TEXTILE PRINTING SOLVENT); INTERMED FOR DICHLOROETHYL FORMAL FOR MFR OF POLYSULFIDES [R1] *2-Chloroethanol may be used in the manufacture of dye intermediates, pharmaceuticals, plant-protecting agents, pesticides and plasticizers. [R10] *FOR REMOVAL OF TAR SPOTS; CLEANING AGENT FOR MACHINES [R4, 397] PRIE: U.S. PRODUCTION: *(1972) NOT MORE THAN 1.6X10+10 GRAMS [R1] *(1975) AT LEAST 2.0X10+10 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS GLYCERINE-LIKE LIQ [R4, 397]; +Colorless liquid. [R11] ODOR: *FAINT ETHEREAL ODOR [R12]; *SWEET, PLEASANT [R6]; +Faint ether-like odor. [R11] BP: *128-130 DEG C @ 760 MM HG [R2] MP: *-67.5 DEG C [R13, p. C-296] MW: *80.51 [R14] DEN: *1.197 @ 20 DEG C/4 DEG C [R2] DSC: *pKa = 14.31 @ 25 Deg C [R15] HTC: *-6487 Btu/lb= -3604 cal/g= -150.8X10+5 J/kg [R6] HTV: *10740.6 G CAL/G MOLE [R13, p. C-727] OWPC: +log Kow = -0.06 [R16] SOL: *SOL IN ALL PROPORTIONS IN WATER, ALC, ORG SOLVENTS; SLIGHTLY SOL IN ETHER [R13, p. C-296]; *SOL IN VARIOUS RESINS [R4, 397]; +Infinitely soluble in aqueous solution (1X10+6 mg/l @ 25 deg C) [R15] SPEC: *INDEX OF REFRACTION: 1.4419 @ 20 DEG C/D [R2]; *IR: 73 (Sadtler Research Laboratories Prism Collection) [R17]; *NMR: 12 (Varian Associates NMR Spectra Catalogue) [R17]; *MASS: 105 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R17] VAPD: *2.78 (AIR= 1) [R18] VAP: *4.9 MM HG @ 20 DEG C [R9, 4676] VISC: *0.0343 POISE @ 20 DEG C [R5] OCPP: *Coefficient of expansion 0.00089 @ 20 Deg C; Wt/Gal= 10.0 Lb @ 20 Deg C; autoignition temperature 425 Deg C [R5] *CONVERSION FACTORS: 1 MG/L IS EQUIV TO 303.8 PPM AND 1 PPM IS EQUIV TO 3.29 MG/CU M @ 25 DEG C, 760 MM HG [R9, 4677] *WHEN HEATED WITH WATER TO 100 DEG C IT DECOMPOSES INTO GLYCOL AND ALDEHYDE; WHEN HEATED TO 184 DEG C, IT DECOMPOSES INTO ETHYLENE CHLORIDE AND ACETALDEHYDE; DENSITY OF SATURATED AIR: 1.011 @ 20 DEG C; 1.022 @ 30.3 DEG C; PERCENT IN SATURATED AIR: 0.644 @ 20 DEG C; 1.32 @ 30.3 DEG C [R9, 4676] *Vapor pressure = 7.18 mm Hg @ 25 Deg C [R19] *Standard Heat of Fusion = -70.6 kcal/mol @ 25 Deg C [R15] +Henry's Law constant = 7.61X10-7 atm-cu m/mole (est from vp/wsol). [R20] +hydroxyl radical rate constant = 1.40X10-12 cu-cm/molc sec @ 25 deg C [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R22, p. G-131] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R22, p. G-131] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R22, p. G-131] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R22, p. G-131] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R22, p. G-131] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R22, p. G-131] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R22, p. G-131] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R22, p. G-131] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.3 kilometers (0.2 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 60 meters (200 feet); then, PROTECT persons Downwind during DAY 0.6 kilometers (0.4 miles) and NIGHT 1.3 kilometers (0.8 miles). [R22, p. TABLE] FPOT: *MODERATE, WHEN EXPOSED TO HEAT, FLAME OR OXIDIZERS. [R23] NFPA: +Health: 4. 4= Materials that, on very short exposure, could cause death or major residual injury, including those that are too dangerous to be approached without specialized protective equipment. A few whiffs of the vapor or gas can cause death, or contact with the vapor or liquid may be fatal, if it penetrates the fire fighter's normal protective gear. The normal full protective clothing and breathing apparatus available to the typical fire fighter will not provide adequate protection against inhalation or skin contact with these materials. [R24, p. 325-8] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R24, p. 325-26] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not reactive with water. Normal fire fighting procedures may be used. [R24, p. 325-26] FLMT: +Lower flammable limit: 4.9% by volume; Upper flammable limit: 15.9% by volume [R24, p. 325-26] FLPT: *105 deg F (40 deg C) (open cup) [R2] AUTO: +797 DEG F; 425 DEG C [R24, p. 325-26] FIRP: *Water, alcohol foam, dry chemical, or carbon dioxide. [R25] TOXC: *Toxic hydrogen chloride and phosgene fumes may be formed /during combustion/. [R25] *... Carbon monoxide may be released in a fire involving ethylene chlorohydrin. [R26] OFHZ: *Vapors are heavier than air and may flash back to a source of ignition. [R25] EXPL: +UPPER 15.9%; LOWER 4.9% [R27, 134] REAC: *... WILL REACT WITH WATER OR STEAM TO PRODUCE TOXIC AND CORROSIVE FUMES ... . [R23] *Contact with strong oxidizers may cause fires and explosions. Contact with strong caustics may cause formation of flammable ethylene gas. [R26] +Strong oxidizers, strong caustics, water or steam. [R27, 134] +Mixing ethylene chlorohydrin and chlorosulfonic acid in a closed container caused the temperature and pressure to increase. [R24, p. 491-58] +Mixing ethylene chlorohydrin and ethylene diamine in a closed container caused the temperature and pressure to increase. [R24, p. 491-58] +Mixing sodium hydroxide and chlorohydrin in a closed container caused the temperature and pressure to increase. [R24, p. 491-179] DCMP: *... WHEN HEATED TO DECOMPOSITION, IT EMITS HIGHLY TOXIC FUMES OF PHOSGENE ... . [R23] SERI: *The vapor is not sufficiently irritating to eyes and respiratory mucous membranes to prevent serious systemic poisoning. [R28] EQUP: *Organic canister mask or self-contained breathing apparatus; goggles or face shield ... . [R25] *... Rubber gloves offer little protection, since dangerous amt of beta-chloroethyl alcohol or its aqueous soln rapidly penetrate through rubber. [R9, 4676] +Wear appropriate personal protective clothing to prevent skin contact. [R27, 134] +Wear appropriate eye protection to prevent eye contact. [R27, 134] +Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R27, 134] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R27, 134] +Recommendations for respirator selection. Max concn for use: 7 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R27, 134] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full face piece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R27, 134] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R27, 134] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Clothing contaminated with liquid ethylene chlorohydrin should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of ethylene chlorohydrin from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the ethylene chlorohydrin, the person performing the operation should be informed of ethylene chlorohydrin's hazardous properties. [R26] +Contact lenses should not be worn when working with this chemical. [R27, 134] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. [R27, 134] +Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R27, 134] SSL: *IT EVAPORATES READILY AT ROOM TEMPERATURE [R29] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R30] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R31] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R32] CLUP: *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be collected and atomized in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. Ethylene chlorohydrin should not be allowed to enter a confined space, such as a sewer, because of the possibility of an explosion. [R26] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *1. By absorbing it in vermiculite, dry sand, earth or a similar material and disposing in a secured sanitary landfill. 2. By atomizing in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R33] MEDS: *The following medical procedures should be made available to each employee who is exposed to ethylene chlorohydrin at potentially hazardous levels: ... A complete history and physical examination. ... Examination of the respiratory system, liver, kidneys, and central nervous system should be stressed. The skin should be examined for evidence of chronic disorders. ... A profile of liver function should be obtained by using a medically acceptable array of biochemical tests. ... Since kidney damage has been observed from exposure, a urinalysis should be obtained to include at a minimum specific gravity, albumin, glucose, and microscopic /examination/ of centrifuged sediment. ... The aforementioned medical examinations should be repeated on a semi-annual basis for the first two years and annually thereafter. [R26] HTOX: *... A fatal case of ethylene chlorohydrin poisoning in a man resulting from a 2 hr exposure at a est conc of 300 ppm /was reported/. /Investigators/ described one fatal and several non-fatal cases of ethylene chlorohydrin poisoning in industrial workers. The autopsy showed severe damage to the liver and brain and changes in many other organs. The survivors had nausea, vomiting, and irritation of the eyes, nose, and lungs. The exposure conc (for unspecified periods) were est at between 300 and 500 ppm. [R34, 1991.601] *It can induce ... dizziness, visual disturbances, weakness ... dyspnea, shock, cyanosis and coma. Several fatal cases with brain edema and lung edema have been reported from indust exposure to this cmpd by inhalation or by the dermal route. [R35] *A 23 MO OLD BOY DRANK 1-2 ML OF ETHYLENE CHLOROHYDRIN AND DIED. CLINICAL COURSE OF HIS ILLNESS AND NECROPSY FINDINGS ARE DESCRIBED. [R36] *The acute poisoning, by ingestion of film cement, in two children was discussed. [R37] *The corneal endothelial toxicity of ethylene chlorohydrin was studied. Isolated human corneas were mounted in a specular microscope and the endothelia perfused with a balanced salt soln containing varying concentrations of ethylene chlorohydrin (0-2500 ppm). Some corneas were also perfused with a solution of mannitol or urea in a balanced salt solution as osmotic controls. Despite marked changes in corneal thickness, cellular ultrastructure remained intact except in corneas perfused with 2500 ppm ethylene chlorohydrin. The maximum nondamaging concn for the corneal endothelium was 1250 ppm ethylene chlorohydrin. [R38] *VAPOR /IS/ MORE TOXIC THAN ETHYLENE DICHLORIDE. [R39, p. 11-119] *It is highly toxic via all routes. [R35] *There is little margin of safety between early reversible symptoms and fatal intoxication. Absorption by any route, including the skin, may lead to severe illness or death. Contact with vapor causes irritation of mucous membranes, nausea, vomiting, vertigo, incoordination, numbness, and visual disturbance. With higher concentrations, headache, severe thirst, delirium, low blood pressure, collapse, shock, and coma may result. ... Death results from pulmonary edema or from congestion and edema of the brain. [R26] *... In human eyes corneal burns have been observed to recover within 48 hr. Skin contact is particularly hazardous, because there are no signs of immediate irritation to warn the victim of exposure. [R26] *Inhalation causes irritation of upper respiratory system, nausea, headache, delirium, coma, collapse. Liquid causes irritation of eyes and skin; prolonged contact with skin may allow penetration into body and cause same symptoms as following ingestion or inhalation. Ingestion causes nausea, headache, delirium, coma, and collapse. [R25] *Men surviving exposure to toxic conc have had burning sensation in the eyes and nose, and numbness of the hands and fingers. Serious and sometimes fatal poisoning involves the nervous, hepatic, renal, and vascular systems, but no permanent ocular disturbances have been reported in survivors. [R28] *In fatalities among humans exposed to 2-chloroethanol the following signs of intoxication were reported: nausea, vomiting, incoordination of the legs, vertigo, weakness, weak irregular pulse, and respiratory failure. Vomiting of bile, profuse perspiration, headache, visual disturbance, decreased blood pressure, hematuria, and spastic contracture of the hands were reported ... . Fatty degeneration of the liver and edema, collapse, and extravasation of the lungs were insufficient to account for death. [R9, 4683] *A case of acute poisoning is reported in which a 24 yr old subject suffered CNS, respiratory, and cardiovascular disturbances, resulting in hypoxia and dysfunction of organs and collapse. Dystrophic and necrobiotic changes in the heart, and liver and kidney damage were reported. [R9, 4684] *Death occurred in less than 12 hr following ingestion of approx 2 ml of 2-chloroethanol by a 2 yr old child. Vomiting, cyanosis, and respiratory difficulty occurred rapidly after ingestion. [R9, 4684] *Human corneal burns from a splash have been known to recover promptly, usually in forty-eight hr. [R28] NTOX: *... EXPOSURES OF 15 MIN A DAY AT CONCENTRATIONS OF 900 TO 1000 PPM ETHYLENE CHLOROHYDRIN WERE FATAL TO RATS WITHIN A FEW DAYS. [R34, 1991.600] *... IV INJECTION (BUT NOT INHALATION) OF 2-CHLOROETHANOL INDUCED A DECREASE IN BLOOD PRESSURE AND INHIBITION OF RESPIRATION IN CATS, BUT ... VAGAL ACTION AND CARDIOVASCULAR REFLEXES WERE NOT ALTERED. [R9, 4683] *RATS MAINTAINED ON DIETS CONTAINING ... CONCN RANGING FROM 0.01 TO 0.08% FOR AT LEAST 220 DAYS GREW NORMALLY, BUT THOSE FED ON DIETS FROM 0.12 TO 0.24% HAD RETARDED GROWTH. THE TISSUES OF THE RATS AT ALL LEVELS WERE WITHOUT HISTOPATHOLOGICAL ALTERATION. [R9, 4681] *... MICROSCOPIC EXAMINATION OF THE LIVER, KIDNEYS, AND LUNGS OF A MOUSE THAT DIED FOLLOWING INHALATION OF 2-CHLOROETHANOL ... /REVEALED/ EDEMA, CAPILLARY ENGORGEMENT, AND INTERSTITIAL HEMORRHAGES OF ALL THESE ORGANS. ... THE KIDNEYS WERE THE EARLIEST FOCUS OF STRESS, SINCE FOLLOWING EXPOSURE TO THE VAPOR THERE WERE LARGE NUMBERS OF HEMORRHAGES ... AND ... COMPLETE DISINTEGRATION OF THE CEL OF THE CONVOLUTED TUBULES. CONGESTION, FORMATION OF PIGMENT, AND FATTY DEGENERATION WERE OBSERVED IN THE LIVER. [R9, 4680] *GUINEA PIGS SURVIVED A DOSE OF 5.0 MG/L BY INHALATION FOR A PERIOD OF 0.9 HR. MICE WERE KILLED WHEN EXPOSED TO A DOSE OF 4.5 MG/L BY INHALATION FOR 0.5 HR. CATS DIED AFTER EXPOSURE BY INHALATION TO A DOSE OF 2.5 MG/L FOR 4 HR (THREE TIMES). /FROM TABLE/ [R9, 4680] *IN CATS, POISONING IS ATTENDED BY TEMPORARY SLUGGISH REACTION OF THE PUPIL TO LIGHT, AND BY NYSTAGMUS. [R28] *Aq soln injected into the anterior chamber of rabbit eyes daily for 5 days at conc from 1% to 20% produced iritis, and corneal opacification at the high conc. At 10% and 20% conc there was also cataract and rupture of the lens. [R28] *PURE, UNDILUTED 2-CHLOROETHANOL APPLIED TO INTACT OR ABRADED RABBIT SKIN FOR 2 HR PRODUCED ONLY BARELY PERCEPTIBLE ERYTHEMA, BUT PENILE MUCOSAL, OCULAR, SC, AND MUSCULAR TISSUE WERE MORE SENSITIVE AND THE PURE SUBSTANCE PRODUCED MODERATE TO SEVERE IRRITATION. 2-CHLOROETHANOL WAS TOXIC TO MOUSE FIBROBLAST AND 10-DAY-OLD CHICK EMBRYO CULTURES @ DIL UP TO 1:10. [R40] *ADMIN OF 6.4 MG/KG/DAY 2-CHLOROETHANOL IP FOR 1 MO OR 12.8 MG/KG GIVEN 3 TIMES/WK FOR 3 MO HAD NO EFFECT IN RATS. CARDIOVASCULAR, RESP AND NEUROMUSCULAR FUNCTIONS IN RABBITS @ HIGH IV DOSES (606.5 MG/KG) CAUSED DECR IN SYSTOLIC AND DIASTOLIC PRESSURE CAUSING DEATH DUE TO FAILURE OF THE RESP CENTER OF THE MEDULLA. [R41] *2-CHLOROETHANOL WAS CYTOTOXIC IN CELL CULTURE AND HAD AN INHIBITORY EFFECT UPON CELL GROWTH IN CULTURES. [R42] *INTRACUTANEOUS INJECTIONS OF SEVERAL CONCN TO SHAVED BACK OF ALBINO RABBITS PRODUCED INFLAMMATORY REACTION. IN HIGHER CONCN COAGULATIVE NECROSIS OF COLLAGEN AND DERMAL CELLULAR STRUCTURES WAS PRESENT. LOWER CONCN CAUSED POLYMORPHONUCLEAR LEUKOCYTES AND EDEMA. [R43] *ALBINO WISTAR RATS WERE ADMIN 2-CHLOROETHANOL SC AT 0-20 MG/KG DAILY FOR 7 DAYS. IT CAUSED IMPAIRMENT OF DRUG METABOLIZING ENZYMES AND PHOSPHATASES IN THE LIVER. [R44] *The corneal endothelial toxicity of ethylene chlorohydrin was studied. Isolated rabbit corneas were mounted in a specular microscope and the endothelia perfused with a balanced salt soln containing varying concentrations of ethylene chlorohydrin (0-2500 ppm). Some corneas were also perfused with a solution of mannitol or urea in a balanced salt solution as osmotic controls. Despite marked changes in corneal thickness, cellular ultrastructure remained intact except in corneas perfused with 2500 ppm ethylene chlorohydrin. The maximum nondamaging concn for the corneal endothelium was 1250 ppm ethylene chlorohydrin. [R38] *In rats, the administration of chloroethanol (50 mg/kg) caused 63 and 59% decreases in the glutathione levels in the liver and kidney, respectively. In the kidney, the levels of glucose, glucose 6-phosphate, fructose 1,6-diphosphate, and triose phosphates were decreased while pyruvate was increased. [R45] *Ethylene chlorohydrin administered intragastrically to pregnant CD-1 mice from the 6th to the 16th day of gestation at a dose of 100 mg/kg produced a significant reduction in maternal wt gain and a decrease in fetal body wt and liver wt. A dose of 150 mg/kg was maternally lethal. [R46] *Ethylene chlorohydrin (given ip for 5 days at 90 mg/kg) was lethal to 5 of 12 male mice within 1 wk. When chlorohydrin at 30 and 60 mg/kg (5 days/wk for 5 wk) was injected ip into male mice, mating ability and fertility were not affected and cytogenetic analysis of 1051 male progeny indicated no increase over control levels of heritable translocation heterozygotes. [R47] *The effects of 2-chloroethanol (2-CE) on rat tissue following in vitro and in vivo exposure were studied. At concn about 2.5 mg/mL, protein synthesis in liver slices was inhibited; at concn of about 25 mg/mL, RNA synthesis and respiration were also impaired. Single oral doses to young adult rats at levels of 15-40 mg/kg depressed liver nonprotein sulfhydryl GSH concn and liver protein but not RNA synthesis. Liver lipid was increased by 7 hr after a single oral dose of 30 mg/kg. Female rats were more sensitive than male rats. Protein synthesis was also depressed in kidneys of 2-CE-treated male rats but at higher doses than those needed for this effect to occur in the livers. Liver polysome disaggregation also occurred after oral 2-CE doses of 20 mg/kg and greater. The effects of 2-CE on ribosome profiles and protein synthesis were at least partially reversed by concurrent ip administration of cysteine. [R48] *Chicks received an acute dose or 8 doses intragastrically of 60 or 40 mg/kg ethylene chlorohydrin (ECH), respectively, and were sacrificed 18 hr after the last dose. Mitochondrial elongation of fatty acids decreased. Cytochrome c oxidase activity in fresh whole liver homogenate was higher suggesting that the mitochondrial membrane integrity is compromised by the ECH treatment. Plasma and liver triglyceride levels were elevated in both the single and multiple ECH dose groups. Liver to body wt ratios were higher in both treatment groups when compared to their controls. Histological examination of the liver of ECH-treated chicks showed cytoplasmic clearing of the cells but no vacuolization or centrilobular necrosis. Serum isocitrate dehydrogenase levels were higher in the multiple treatment ECH group. [R49] *The carcinogenicity of 2-chloroethanol was investigated in NMRI mice and rats. 2-Chloroethanol was administered sc once weekly to groups of 100 female NMRI mice (3.0 mg/kg, 1.0 mg/kg and 0.3 mg/kg, respectively). Tricaprylin was the solvent. The mean total dose/mouse was 175.9 mg/kg, 76.3 mg/kg and 23.0 mg/kg, respectively. Rats were admin 10.0 and 2.5 mg/kg body wt (in single dosage) intragastrically. Solvent was salad oil. No carcinogenic effect observed. [R50] *INHALATION OF 2-CHLOROETHANOL BY ANIMALS /MICE, RATS, GUINEA PIGS/ RESULTED IN NASAL IRRITATION, INCOORDINATION, CONVULSIONS, PROSTRATION, AND RESPIRATORY FAILURE. [R9, 4680] */Investigators/ observed increased chromosome aberrations in bone marrow of rats exposed at 0.22 ppm of ethylene chlorohydrin. Cytogenic analysis of the bone marrow from rats exposed to ethylene chlorohydrin at conc below 0.22 ppm had negative results. [R34, 1991.601] *In 2-yr dermal study with ethylene chlorohydrin, there was no evidence of carcinogenicity in rats given 50 or 100 mg/kg/day or in mice given 7.5 or 15 mg/animal/day. [R34, 1991.601] *... Rats /were exposed/ to air that was bubbled through aqueous solutions of beta-chloroethyl alcohol maintained at 40 deg C. Rats exposed for 1 hr to air passed through 12.5, 25, or 50 percent aqueous beta-chloroethyl alcohol died 1 or 2 hr after the exposure. Rats that were exposed, during three periods each of 1 hr duration over a total period of less that 2 days, to air bubbled through a 6.25 percent aqueous solution of this alcohol died ... /following/ the third exposure. A total of four exposure periods to air bubbled through a 3.13 percent solution, each of 2 hr duration on two consecutive days, resulted in morbidity, depression, paralysis, and mortality among rats. [R9, 4679] *Rats were injected three times weekly for 3 months with doses of 32, 12.8, or 6.4 mg/kg with no effect except increased mortality at 32 mg/kg. Rats that were injected for 30 days with a dose of 12.8 mg/kg showed increased mortality and marked decrease in body weight, but no histopathologic changes in the major organs examined. No effects were obseved at the 6.4 mg/kg dose level. [R9, 4681] *Ethylene chlorhydrin or 2-chloroethanol, a reaction product of ethylene oxide and sodium chloride, /was administered/ to dogs, rats, and monkeys for 90 days without evidence of neurotoxicity. [R51] *The genotoxic effects of 2-chloroethanol, 8-hydroxyquinoline, 2,6-toluenediamine, and eugenol were studied in Sprague-Dawley-rats. Animals were treated with half of the 50%; lethal dose of each substance by gavage. One group was treated 20 hours after partial hepatectomy, and liver and bone marrow cells examined after 48 hours; another group was treated 30 and 6 hours prior to sacrifice and bone marrow cells examined and primary cultures prepared from the liver; and a third group was sacrificed 2 hours after treatment and hepatocyte primary cultures prepared. No increases in the appearance of micronucleated hepatocytes were seen in any treated animals after partial hepatectomy. No increases in the numbers of micronucleated polychromatic erythrocytes or changes in the frequencies of polychromatic erythrocytes were seen in the bone marrow of animals in either of the first two experimental groups. No significant increases in unscheduled DNA synthesis were seen in the third group of animals upon autoradiographic evaluation of hepatocyte primary cultures and no evidence of DNA fragmentation was found. Treatment of rat primary hepatocyte cultures with the four test compounds for 20 hours did not result in DNA fragmentation or unscheduled DNA synthesis. /It was/ concluded that contrary to their actions in in-vitro carcinogenicity tests the tested compounds do not produce significant in-vivo genotoxic effects. [R52] *The effect of 2-chloroethanol (CE), 2,2-dichloroethanol (DCE) and 2,2,2-trichloroethanol (TCE) on rat liver mitochondrial respiration was studied. Rat liver mitochondria were isolated in a medium consisting of 250 mM sucrose, 10 mM Tris-HCl and 1 mM EDTA (pH 7.4). Mitochondrial respiration was determined with an oxygen electrode at 30 deg C and the polarographic buffer consisted of 250 mM mannitol, 10 mM potassium chloride, 10 mM potassium phosphate, 5 mM magnesium chloride, 0.2 mM EDTA and 10 mM Tris-hydrochloric acid (pH 7.4). With succinate as the respiratory substrate and using chloroethanols (150 mM), 2-chloroethanol stimulated respiration by 28.2 + or - 6 5% and 2,2-dichloroethanol by 202.7 + or - 8.2% while 2,2,2-trichloroethanol inhibited mitochondrial respiration (> 95%). The effect of change in the concentration of chloroethanols on mitochondrial respiration was also studied. Chloroethanol showed maximum stimulation at 600 mM (97.6%), 2,2-dichloroethanol at 150 mM (202.6%) and 2,2,2-trichloroethanol at 30 mM (313.6%). Respiratory stimulation was independent of mitochondrial protein concentration. Chloroethanols (optimal concentrations for respiratory stimulation with succinate) inhibited mitochondrial respiration when glutamate-malate was used as the respiratory substrate. Estimation of adenosine triphosphate (ATP) showed that chloroethanols inhibited the synthesis of adenosine triphosphate. These results indicate that chloroethanols stimulate mitochondrial respiration by uncoupling oxidative phosphorylation and that the uncoupling potency is proportional to the extent of chlorination at the beta-position of haloethanol. [R53] +... Under the conditions of these 2 yr dermal studies, there was no evidence of carcinogenicity of 2-chloroethanol for male and female F344/N rats given 50 or 100 mg/kg per day or for male and female Swiss CD-1 mice given 7.5 or 15 mg/kg day. [R54] NTXV: *LD50 Rat oral 58 mg/kg; [R55] *LD50 Rat sc 72 mg/kg; [R9, 4679] *LD50 Rabbit dermal 67.8 mg/kg; [R9, 4679] *LD50 Rat dermal 84 mg/kg; [R9, 4679] ETXV: *LC50 Pimephales promelas (fathead minnow) 83.7 mg/l/96 hr (95% confidence limit 75.0-93.4 mg/l), flow-through bioassay with measured concentrations, 24.0 deg C, dissolved oxygen 7.1 mg/l, hardness 52.3 mg/l calcium carbonate, alkalinity 44.2 mg/l calcium carbonate, and pH 7.22; [R56] NTP: +Toxicology and carcinogenesis studies of 2-chloroethanol (99% pure) ... were conducted by dermal application of 2-chloroethanol dissolved in 70% ethanol 30% water (w/v) solutions to 50 F344/N rats of each sex at doses of 0, 50 or 100 mg/kg for 103 wk or to groups of 50 Swiss CD-1 mice of each sex at doses of 0, 7.5 or 15 mg per animal for 104 wk ( 0, 253 or 630 mg/kg at wk 1, 0, 180, 411 mg/kg at wk 100). The control group received skin applications of the vehicle, the mouse studies also included untreated control groups of 50 male and 50 females. ... Under the conditions of these 2 yr dermal studies, there was no evidence of carcinogenicity of 2-chloroethanol for male and female F344/N rats given 50 or 100 mg/kg per day or for male and female Swiss CD-1 mice given 7.5 or 15 mg/kg day. [R54] +... Ethylene chlorohydrin (0, 60 or 120 mg/kg/day, intravenous) in 5% dextrose was administered daily in a volume of 1 mL/kg of body weight on gestational days (gd) 4-6, 6-8, 8-10 or 10-12. Plug-positive females were matched by body weight across treatment groups prior to the initiation of dosing and weighed daily during treatment. At sacrifice on gd 17 a total of 34-54 dams (i.e., confirmed-pregnant females) per treatment group from each exposure period were evaluated. The gravid uterus of each dam was weighed and the number of implantation sites and live, dead or resorbed fetuses were recorded. All live fetuses were weighed, sexed and examined for external, visceral and skeletal malformations. Administration of the low dose of ethylene chlorohydrin (60 mg/kg/day) did not result in any statistically significant expression of maternal toxicity, regardless of the period of administration. Evidence of embryotoxicity in the low-dose group was observed only following exposure to ethylene chlorohydrin on gd 8-10, a treatment which significantly decreased the average fetal body weight per litter. No statistically significant change in the incidence of malformed fetuses per litter was observed for any exposure period at the low dose. Administration of the high dose of ethylene chlorohydrin (120 mg/kg/day) resulted in mortality rates of 0%, 8%, 12.3% and 15.6% among plug-positive females treated on estational days 4-6, 6-8, 8-10 and 10-12, respectively. The high-dose group also exhibited a significant dose-related reduction in maternal weight gain during treatment for each of the exposure periods. In addition, dams treated on estational days 8-10 or 10-12 showed decreased gestational weight gain, as well as decreased gravid uterine weight, but no decrease in absolute maternal weight gain. Ethylene chlorohydrin (120 mg/kg/day) produced dose-related signs of embryotoxicity including a significant reduction in average fetal body weight per litter for each exposure period. Litters from females exposed to the high dose on estational days 4-6, 8-10 or 10-12 also exhibited a significant increase in the percentage per litter of resorbed, nonlive and affected fetuses. A significant increase in the percentage of malformed fetuses per litter was observed in only one exposure group (i.e., ethylene chlorohydrin, 120 mg/kg/day on estational days 8-10) which exhibited 2.3% malformed fetuses per litter as compared to 0.2% malformed fetuses per litter for the vehicle control group. Further examination of the data indicated that this effect was statistically significant only for one of four study replicates, in which the mortality rate for treated females was 46.7%. In conclusion, ethylene chlorohydrin (0, 60 or 120 mg/kg/day) administered to timed pregnant CD-l mice on estational days 4-6, 6-8, 8-10 or 10-12 was associated in a dose-related manner with maternal and fetal toxicity (reduced body weight). An increase in the incidence of malformed fetuses was seen only at one exposure period (gd 8-10) and at a dose of ethylene chlorohydrin (120 mg/kg/day) which was associated with increased maternal mortality. [R57] +Ethylene Chlorohydrin (ECH) (2-chloroethanol) ... was evaluated for toxic and teratogenic effects in artificially inseminated New Zealand white (NZW) rabbits which were matched for body weight across treatment groups on gestational day (gd) 0. Ethylene Chlorohydrin in 5% dextrose was administered daily in a volume of 0.3 ml/kg of body weight on gd 6 through 14 at dosages of 0, 9, 18 or 36 mg/kg/day, intravenous. An untreated control group was also included in the study. Females were weighed and observed daily during treatment for clinical signs of toxicity. At sacrifice on gestational day 30, a total of 15 to 21 dams (i.e., confirmed-pregnant females) per treatment group were evaluated. ... Administration of ethylene Chlorohydrin (0, 9, 18 or 36 mg/kg/day, intravenous) on gestational day 6- 14 resulted in mortality rates of 4.3% (1/23), 5.2% (1/19), 13.6% (3/22) and 15.0% (3/20) for the vehicle control through high-dose groups, respectively. No unscheduled deaths occurred among 17 untreated females. Clinical signs observed in the ethylene Chlorohydrin (0, 9, 18 or 36 mg/kg/day) groups included hyperactivity, lacrimation and diarrhea, but no apparent relation to dose was observed. Measures of maternal body weight (gestational day 0, 6, 10, 14 and 30), maternal weight gain (i.e., weight gain during gestation, weight gain during treatment and absolute weight gain), gravid uterine weight and maternal liver weight were not found to differ statistically among treatment groups. Examination of uterine contents on gd 30 revealed no differences among groups in the percentage of resorbed, dead, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive plus malformed) fetuses per litter. Nor were average live litter size, percentage of males per litter or average fetal body weight per litter altered by ethylene Chlorohydrin treatment. No evidence of a treatment-related teratogenic effect was observed, even at the highest dose. In conclusion, no evidence was observed for a fetotoxic or teratogenic effect of ethylene Chlorohydrin (0, 9, 18 or 36 mg/kg/day, intravenous) administered to NZW rabbits on gd 6-14. [R58] ADE: *... MAY BE ABSORBED THROUGH THE SKIN. [R23] *... MAY BE ABSORBED THROUGH ... GI TRACT, OR BY INHALATION. [R59] *The excretion and tissue distribution of (14)C-labeled chloroethanol were studied in rats following single oral admin of 5 and 50 mg/kg. At both dose levels, the radioactivity was rapidly eliminated, mainly in the urine. On the first day 77.2% of the dose was found in the urine, 1.7% in the feces, and 1.0% as CO2 in the expired air. Only 2.8% was excreted by these routes during the following 3 days. The residual radioactivity after 4 days was almost equally distributed. Approx 0.4% of the dose was in the liver and 3% in the whole organism. [R60] METB: *IN VIVO, IT IS OXIDIZED TO CHLOROACETIC ACID ... . [R4, 398] *2-CHLOROETHANOL WAS GIVEN ORALLY TO RATS. LIVER GLUTATHIONE WAS RAPIDLY DEPLETED AND S-CARBOXYMETHYLGLUTATHIONE WAS FORMED. TOXICITY OF 2-CHLOROETHANOL IS PROBABLY DUE TO ITS CONVERSION TO CHLOROACETALDEHYDE IN VIVO. [R61] *2-chloroethanol was detected in the blood and liver of rats during the first 24 days after oral dosing of CH2ClCH2Cl /ethylene dichloride/ at 750 mg/kg. [R62] *Disposition and metabolism of 1-(2-chloroethyl)-3-(2',3',4'-tri-O-acetylribopyranosyl)-1-nitrosourea (RPCNU) were studied in rats after labeling RPCNU with (14)C- in 3 different positions. Within the first min after injection, most of the radioactivity derived from ethyl-(14)C groups was recovered as volatile products. Among these, 2-chlorothanol was identified as a main component. [R63] *Excretion and tissue distribution of (14)C-labeled chloroethanol were studied in rats following single oral administration of 5 and 50 mg/kg. Examination of the urine on DEAE-Sephadex revealed 2 metabolites which were identified by gas chromatography/mass spectroscopy analysis as thiodiacetic acid and thionyldiacetic acid. Unchanged chloroethanol, chloroacetic acid, S-carboxymethylcysteine, and sulfonyldiacetic acid were not found in the urine. [R60] *... /2-Chloroethanol/ is converted to S-carboxymethylglutathione by rat liver in vivo and in vitro. [R9, 4683] BHL: *The elimination half-life and clearance value for 2-chloroethanol was 40.8 min following iv admin to beagle dogs. [R64] INTC: *Simultaneous administration of ethyl alcohol increased the LD50 of ethylene chlorohydrin regardless of the route of administration (peroral or percutaneous). Necrotic lesions produced in the liver and kidney by ethylene chlorohydrin were also reduced in number and extent by ethanol. Blood concn of the chlorohydrin were raised by ethanol administration, which suggests that the protective effect is due to competitive inhibition of chlorohydrin metabolism to chloroacetaldehyde. [R65] *2-Chloroethanol is thought to interfere with the detoxification mechanisms of the alkaloids. Chickens were administered monocrotaline after separate groups were pretreated with BHA and 2-chloroethanol. There was an apparent deleterious effect of monocrotaline in 2-chloroethanol-pretreated chickens, similar to that in non-pretreated birds, with respect to growth rates, morbility, mortality, and hepatic histopatholoqy. Monocrotaline pyrrole formation was measured in chickens pretread with BHA and 2-chloroethanol by means of the Erlich reagent reaction spectrophotometric assay. There was a significant difference in pyrrole production between the treatment groups. The 2-chloroethanol plus-monocrotaline (40 mg/kg), BHA (500 mg/kg) plus monocrotaline, nonocrotaline, BHA (100 mg/kg) plus monocrotaline (20 mg/kg), and BHA (500 mg/kg) plus 2-chloroethanol and monocrotaline groups had decreasing amounts of pyrrole metabolite formation respectively. [R66] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *4= VERY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG, BETWEEN 1 TEASPOON AND 1 OUNCE FOR 70 KG PERSON (150 LB). [R39, p. II-119] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Chloroethanol may be released to the environment during its production, transport, storage, disposal and use. Formerly 2-chloroethanol was a major industrial precursor for ethylene oxide. However, this process for manufacturing ethylene oxide has been almost entirely supplanted. It is also formed during the fumigation of foodstuffs with ethylene oxide. If released on soil, 2-chloroethanol would be expected to leach because of its estimated very low adsorptivity to soil and may biodegrade. It should not volatilize from moist soil, but may evaporate from dry soil and other surfaces. 2- Chloroethanol's fate in the aquatic environment is not clear. Based on data from screening tests, it may biodegrade. It would not be expected to volatilize from surface waters, adsorb to sediment or bioconcentrate in aquatic organisms. 2-Chloroethanol reacts with photochemically-produced hydroxyl radicals in the atmosphere, as a result of which its half-life in the atmosphere will be approximately 11.5 days. 2-Chloroethanol is soluble in water and would be washed out of the air by rain. Occupational exposure to 2- chloroethanol would be via inhalation and dermal contact. The general population may be exposed via ingestion of food containing residues of 2- chloroethanol. (SRC) ARTS: *2-Chloroethanol may be released to the environment during its production, transport, storage, disposal and use. In past years it was produced in a large scale as an intermediate in the manufacture of ethylene oxide(1) which may have resulted in considerable releases. However, this process has been almost completely supplanted(1). 2-Chloroethanol is produced when polyvinylchloride (PVC) plastics are sterilized with ethylene oxide(1). It is also formed during the fumigation of foodstuffs with ethylene oxide(2). [R67] FATE: *TERRESTRIAL FATE: If released on soil 2-chloroethanol would be expected to leach because of its estimated very low adsorptivity to soil. In view of its low estimated Henry's Law constant, 1.04X10-7 atm-cu m/mole(1), and low estimated adsortivity to soil, 2-chloroethanol would not be expected to volatilize from moist soil. However, it would be expected to volatilize from dry soil and other surfaces because it's vapor pressure is appreciable, 7.18 mm Hg at 25 deg C(2). 2-Chloroethanol was readily biodegradable in screening tests and biological treatment simulations tests which suggest that it may biodegrade in soil(SRC). [R68] *AQUATIC FATE: If released in water, the fate of 2-chloroethanol is not clear. In view of its low estimated Henry's Law constant, 1.04X10-7 atm-cu m/mole(1), 2-chloroethanol would not be expected to volatilize from surface waters. It would not be expected to adsorb to sediment, bioconcentrate in fish, photolyze or hydrolyze. However, based on data from screening tests, it may biodegrade(SRC). [R69] *ATMOSPHERIC FATE: 2-Chloroethanol reacts with photochemically-produced hydroxyl radicals in the atmosphere and has a rate constant of 1.40X10-12 cu cm/molec-sec(1) for this reaction. Assuming a hydroxyl radical concn of 5X10+5 per cu cm, the half-life of 2-chloroethanol in the atmosphere will be 11.5 days(SRC). 2-Chloroethanol is soluble in water(2) and would be subject to washout by rain. [R70] BIOD: *2-Chloroethanol is readily biodegradable in screening tests and biological treatment simulations using sewage and activated sludge inocula(1-6). Various investigators have obtained the following results in percent of theoretical BOD in screening tests using sewage inocula: 57% in 20 days(1); 50% in 10 days(2); and 87% in 10 days(3). The results of these screening tests indicate that acclimation is important in the biodegradation process. [R71] *In two simulated biological treatment plants using activated sludge, 45% removal of 2-chloroethanol in 24 hr was obtained with about 5% due to evaporation(1) and 45% of theoretical BOD was removed in 10 days(2). Results obtained in a biodegradability test performed using process wastewater and activated sludge found a 20% COD removal in conflict to a 1% total organic carbon (TOC) removal in 24 hours(4). 2-Chloroethanol's degradation pathway is via 2-chloroacetaldehyde and monochloroacetate to glycolic acid(3). [R72] ABIO: *2-Chloroethanol reacts with photochemically-produced hydroxyl radicals in the atmosphere with a rate constant of 1.40X10-12 cu cm/molec-sec(1). Assuming a hydroxyl radical concentration of 5X10+5 per cu cm, the half-life of 2-chloroethanol in the atmosphere will be 11.5 days(SRC). 2-Chloroethanol undergoes neutral and acid catalyzed hydrolysis with respective rate constants of 4.5X10-6 1/hr and 36 L/mol-hr at 25 deg C(3). The resulting hydrolysis half-life at pH 7 is calculated to be 9.8 yr(3). Haloalcohols do not absorb UV light > 290 nm(4) and therefore would not undergo direct photolysis. [R73] BIOC: *Using the log octanol/water partition coefficient for 2-chloroethanol, 0.03(1), one can estimate a BCF of 0.62 using a recommended regression equation(2,SRC). Therefore, 2-chloroethanol would not be expected to bioconcentrate in aquatic organisms. [R74] KOC: *The Koc for 2-chloroethanol estimated from molecular structure is 1.33(1). According to a suggested classification scheme, a Koc of this magnitude indicates that 2-chloroethanol will exhibit very high mobility in soil(2). [R75] VWS: *The Henry's Law constant for 2-chloroethanol is estimated to be 1.04X10-7 atm-cu m/mole(1). Such a low Henry's Law constant indicates that volatilization from rivers and lakes will not be an important fate process for 2-chloroethanol(2). In view of its low Henry's Law constant and low estimated adsorptivity to soil, volatilization from moist soil should be negligible(2). 2-Chloroethanol's vapor pressure is 7.18 mm Hg at 25 deg C(3) and therefore it should readily volatilize from dry soil and other surfaces. [R76] FOOD: *2-Chloroethanol and 2-chloroethanol fatty acid esters are byproducts of the ethylene oxide fumigation of foods(1). Furthermore, 2-chloroethanol fatty acid esters are hydrolyzed to 2-chloroethanol in model digestive systems(1). The level of 2-chloroethanol found in samples of black walnuts and a variety of spices (item, concn in ppm) was: allspice, 810-880; black pepper, 0.2-45; black walnuts, 1.9-4.8; chili powder, 0.8-45; cocoa, not detected; mint flakes, 0.6; mushrooms, not detected - 0.4; Nacho cheese mix, not detected - 14; nutmeg, 16-37; onion powder, not detected; paprika, not detected - 513; parsley flakes, 0.4; red pepper, 3.6-490; seafood seasoning, 33; taco seasoning, 115-117; vegetable flakes, 0.35-0.6; and white pepper, 0.78(1). [R77] RTEX: *Occupational exposure to 2-chloroethanol would be via inhalation and dermal contact. The general population would be exposed via ingestion of food containing residues of 2-chloroethanol(1,SRC). [R78] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 476 workers, including 68 females, are exposed to 2-chloroethanol in the USA(1). [R79] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +7 ppm [R27, 134] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (16 mg/cu m). Skin Designation. [R80] +Vacated 1989 OSHA PEL Ceiling limit 1 ppm (3 mg/cu m), skin designation, is still enforced in some states. [R27, 364] NREC: +Recommended Exposure Limit: Ceiling value: 1 ppm (3 mg/cu m), skin. [R27, 134] TLV: +Ceiling Limit: 1 ppm, skin. [R33] +A4; Not classifiable as a human carcinogen. [R33] OOPL: *Australia: peak limitation, 1 ppm, skin (1990); Federal Republic of Germany: 1 ppm, short-term level 5 ppm, 30 min, twice per shift, skin, Pregnancy group C, no reason to fear a risk of damage to the developing embryo or fetus when MAK and BAT values are adhered to (1990); Sweden: ceiling value 1 ppm, skin (1989); United Kingdom: 10-minute STEL 1 ppm, skin (1991). [R34, 1991.601] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. ETHYLENE CHLOROHYDRIN is produced, as an intermediate or a final product, by process units covered under this subpart. [R81] CERC: +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Chloroethanol is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R82] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Analyte: Ethylene chlorohydrin. Matrix: Air. Procedure: Adsorption on charcoal, desorption with eluent, gas chromatography. Range: 7-30 mg/cu m. [R83] *A simple quantitative method for the determination of residual ethylene chlorohydrin in fumigated foodstuffs was described. The method was based on a solvent extraction and quantitative determination of ethylene chlorohydrin by capillary gas chromatography using dibutyl ketone as internal standard. The detection limit was 2 ng. Recoveries from foodstuffs were between 85 and 99% in the concn range of up to 100 ppm. [R84] *A gas chromatographic method was developed for the determination of ethylene chlorohydrin in aqueous ophthalmic solutions. [R85] *ASTM D3695. Standard Test Method for Volatile Alcohols in Water by Direct Aqueous-Injection Gas Chromatorgraphy. GCFID, detection limit 1.0 mg/L [R86] *USEPA Volatile Organics by Gas Chromatography/Mass Spectrometry (GC/MS): Packed Column Technique OSW 8240A-S, -W. GCMS, no detection limit reported [R87] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroethanol in F344/N Rats and B6C3F1 Mice Technical Report Series No. 275 (1985) NIH Publication No. 86-2531 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 598 R3: Kirk-Othmer Encycl Chem Technol, 4th ed 6: 142 (1993) R4: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 485 R6: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R7: Kirk-Othmer Encycl Chem Technol, 4th ed 6: 147 (1993) R8: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on 2-Chloroethanol (107-07-3). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of October 24, 2002. R9: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R10: Kirk-Othmer Encycl Chem Technol, 4th ed 6: 153 (1993) R11: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 134 R12: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 657 R13: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979. R14: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 71st ed. Boca Raton, FL: CRC Press Inc., 1990-1991.,p. 3-237 R15: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 701 R16: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 4 R17: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 621 R18: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1493 R19: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R20: Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) R21: Atkinson R; Journal of Physical And Chemical Reference Data. Monograph No 1 (1989) R22: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000 R23: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 712 R24: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R25: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R26: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R27: NIOSH. 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Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R35: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 112 R36: MILLER V ET AL; ARCH DIS CHILDHOOD 45 (242): 589-90 (1970) R37: Kvistad PH et al; Hum Toxicol 2 (2): 311-3 (1983) R38: Edelhauser HF et al; J Toxicol, Cutaneous Ocul Toxicol 2 (1): 7-39 (1983) R39: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976. 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Boca Raton, FL: CRC Press, Inc., 1985. 87 R52: Allavena A et al; Teratogenesis, Carcinogenesis, and Mutagenesis, 12 (1): 31-41 (1992) R53: Bhat HK et al; Toxicol Lett (AMST) 59 (1-3)203-12 (1993) R54: Toxicology and Carcinogenesis Studies of 2-Chloroethanol (Ethylene Chlorohydrin in F344/N Rats and Swiss CD-1 Mice. Technical Report Series No. 275 (1985) NTIS Publication No. PB86-145513/AS U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R55: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-178 R56: Geiger D.L., Poirier S.H., Brooke L.T., Call D.J., eds. Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Vol. III. Superior, Wisconsin: University of Wisconsin-Superior, 1986.36 R57: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Ethylene Chlorohydrin (CAS No. 107-07-3) in CD-1 Mice, NTP Study No. TER84070A TER84070B TER84070C TER84070D (August 31, 1983) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R58: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Ethylene Chlorohydrin (CAS No. 107-07-3) in New Zealand White Rabbits, NTP Study No. TER84071 (August 31, 1983) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R59: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 266 R60: Grunow W, Altmann HJ; Arch Toxicol 49 (3-4): 275-84 (1982) R61: JOHNSON MK; BIOCHEM PHARMACOL 16 (1): 185-99 (1967) R62: The Royal Society of Chemistry. Foreign Compound Metabolism in Mammals. Volume 6: A Review of the Literature Published during 1978 and 1979. London: The Royal Society of Chemistry, 1981. 335 R63: Godeneche D et al; Cancer Res 42 (2): 525-9 (1982) R64: Martis L et al; J Toxicol Environ Health 10 (4-5): 847-56 (1982) R65: Bonitenko J et al; Gigiena Trudai Professional'nye Zabolevanija 9: 44-5 (1981) R66: Dickinson JO, Braun RC; Vet Hum Toxicol 29 (1): 11-5 (1987) R67: (1) Gordon YT et al; Chlorohydrins. Ullmann's Encycl of Indust Chem A6: 565- 76 NY: VCH Publishers (1986) (2) Yurawecz MP; J Assoc Off Aanl Chem 70: 10113 (1987) R68: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds. 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ASTM, 1916 Race Street, Philadelphia, PA R87: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) RS: 68 Record 59 of 1119 in HSDB (through 2003/06) AN: 503 UD: 200302 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BIS(2-CHLORO-1-METHYLETHYL) ETHER SY: *BCIE-; *BCMEE-; *BIS(BETA-CHLOROISOPROPYL) ETHER; *(2-CHLORO-1-METHYLETHYL) ETHER; *DCIP- (NEMATOCIDE); *DICHLORODIISOPROPYL-ETHER-; *BETA,BETA'-DICHLORODIISOPROPYL-ETHER-; *2,2'-DICHLORODIISOPROPYL-ETHER-; *DICHLOROISOPROPYL-ETHER-; *2,2-DICHLOROISOPROPYL-ETHER-; *ETHER, BIS(2-CHLORO-1-METHYLETHYL); *NCI-C50044-; *PROPANE, 2,2'-OXYBIS(1-CHLORO- RN: 108-60-1 MF: *C6-H12-Cl2-O SHPN: UN 2490; Dichloroisopropyl ether IMO 6.1; Dichloroisopropyl ether STCC: 49 363 15; Dichloroisopropyl ether HAZN: U027; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FORMED AS A BY-PRODUCT IN THE CHLOROHYDRINATION PROCESS FOR CONVERTING PROPYLENE TO PROPYLENE OXIDE [R1] IMP: *Available in research quantities as a mixture containing approximately 30% of the isomeric 2-chloro-1-methylethyl(2-chloro-n-propyl)ether and smaller amounts of other isomers as impurities. [R2] MFS: *Dow Chemical U.S.A. Hq: 2020 Dow Center Midland, MI 48674 (517)636-1000; Production site: 2301 N. Brazosport Blvd Freeport, TX 77541 [R3] OMIN: *DICHLORODIISOPROPYL ETHER WAS EFFECTIVE FOR PROMOTION OF ADVENTITIOUS ROOT GROWTH IN TOMATOES. [R4] USE: *HAS BEEN USED AS AN INTERMEDIATE IN MFR OF DYES, RESINS, AND PHARMACEUTICALS; USED IN TEXTILE PROCESSES [R5] *Bis(2-chloro-1-methylethyl)ether is apparently used as a nematocide in Japan, ... but there is no evidence that the compound is used commercially in the USA. Other uses ... include: as a combatant in liver fluke infections, in the preparation of glycol esters, in fungicidal preparations, and as an insecticidal wood preservative. ... Bis(2-chloro-1-methylethyl)ether is not registered in the USA for use as a pesticide. [R6] *Solvent for fats, greases, extractant, paint and varnish removers, spotting agents and cleaning solutions. [R7, 379] PRIE: U.S. PRODUCTION: *(1972) 1.35X10+10 G (EST) [R1] *(1975) GREATER THAN 4.54X10+5 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R8, 435] BP: *187 DEG C @ 760 MM HG [R9] MP: *-96.8 TO -101.8 DEG C [R10] MW: *171.07 [R9] DEN: *1.103 @ 20 DEG C/4 DEG C [R9] OWPC: +log Kow= 2.48 [R11] SOL: *MISCIBLE IN ORGANIC SOLVENTS [R12, 449]; *MISCIBLE IN ETHYL ALCOHOL, ETHYL ETHER, ACETONE [R9]; *Water solubility of 1700 ppm at 20 deg C. [R13] SPEC: *INDEX OF REFRACTION: 1.4505 @ 20 DEG C/D [R9]; +IR: 10994 (Sadtler Research Laboratories IR Grating Collection) [R14]; +MASS: 1124 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R14] VAPD: *5.9 (AIR= 1) [R12, 449] VAP: *0.56 mm Hg @ 20 deg C [R13] VISC: *0.0230 POISE @ 20 DEG C [R7, 379] OCPP: *WT/GAL 9.3 LB @ 20 DEG C; COEFFICIENT OF EXPANSION 0.00096 @ 20 DEG C [R7, 399] *PER CENT IN SATURATED AIR: 0.12 @ 25 DEG C, 760 MM HG; DENSITY OF SATURATED AIR: 1.05 @ 25 DEG C, 760 MM HG (AIR= 1) [R12, 449] *Henry's Law constant: 0.00626 [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R16] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R16] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R16] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R16] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R16] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R16] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R16] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R16] FPOT: *MODERATE, WHEN EXPOSED TO HEAT, FLAME OR POWERFUL OXIDIZERS. [R8, 435] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R17] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R17] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R17] FLPT: +185 deg F (Open cup) [R17] FIRP: *WATER TO BLANKET FIRE, FOAM, CARBON DIOXIDE, DRY CHEMICAL. [R8, 435] *If material is on fire or involved in fire: Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water and apply water from as far a distance as possible. Solid streams of water may be ineffective. Use foam, dry chemical, or carbon dioxide. Use water spray to knockdown vapors. [R18] *Personnel protection: Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R18] EXPL: *DANGEROUS: WHEN HEATED OR EXPOSED TO FLAME OR SPARKS. IN ADDITION TO RISK OF EXPLOSION FROM AIR MIXT OF ETHER VAPORS, ETHERS TEND TO FORM PEROXIDES UPON STANDING. WHEN ETHERS CONTAINING PEROXIDES ARE HEATED THEY CAN DETONATE. /ETHERS/ [R8, 715] REAC: *INCOMPATIBLE WITH OXIDIZING MATERIALS [R8, 435] *With atmospheric oxygen, ethers can react to form unstable peroxides which can explode. Strong acids act to convert ethers to unstable oxonium salts. /Ethers/ [R15] DCMP: *WHEN HEATED TO DECOMP, EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. [R8, 435] ODRT: *Odor detection in water= 3.2x10(-1) ppm, chemically pure. [R19] SERI: *Moderately toxic by skin contact and inhalation. An eye irritant. [R8, 435] EQUP: *Personnel protection: Wear appropriate chemical protective boots, protective gloves, and goggles. [R18] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock-down vapors. [R18] *Personnel protection: Avoid breathing vapors. Keep upwind. Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R18] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R20] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R21] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R22] STRG: *Ethers should not be stored near powerful oxidizers or in areas of high fire hazard. They should be kept cool and the containers electrically grounded to avoid sparks. /Ethers/ [R8, 715] CLUP: *Waste water treatment: Activated carbon: absorbability: 0.20 g/g C; 100% redn, at 1,800 mg/l influent; conventional municipal; treatment: influent 0.024 mg/l; conventional plus activated carbon: influent 0.048 mg/l. [R23] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U027, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R24] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. Also, a potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. Also, a potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R25] *Dichlorodiisopropyl ether wastes are destroyed in special waste incinerators. Due to the high hydrogen chloride content of the flue gases incineration takes place predominantly at sea. Recommendable method: Incineration. Not recommendable method: Evaporation. [R26] *This compound should be susceptible to removal from waste water by air stripping. /Bis(2-chloroethyl)ether/ [R27] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of bis(2-chloro-1-methylethyl)ether were available. There is limited evidence in experimental animals for the carcinogenicity of bis(2-chloro-1-methylethyl)ether. Overall evaluation: Bis(2-chloro-1-methylethyl)ether is not classifiable as to its carcinogenicity to humans (Group 3). [R28] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Provide a low-stimulus environment. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Treat frostbite by rapid rewarming ... . /Ethers and related compounds/ [R29, 224] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: To keep open, "minimal flow rate"/. Use lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Ethers and related compounds/ [R29, 225] MEDS: *A complete history and physical examination: The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the respiratory tract, liver, and the central nervous system should be stressed. 14 inch x 17 inch chest roentgenogram and FVC and FEV (1 sec) /should also be performed/. The above medical examinations are to be repeated on an annual basis, except that an x-ray is necessary only when indicated by the results of pulmonary function testing, or signs and symptoms of respiratory disease. /Bis(2-chloroethyl ether)/ [R30] HTOX: *The toxicity of /bis(2-chloro-1-methylethyl) ether/ is somewhat less than that of the dichloroethyl ether but damage occurs in the liver and kidneys rather than in the lungs. /Bis(2-chloro-1-methylethyl) ether/ causes no primary irritation of the skin but may penetrate the skin sufficiently to cause death. ... No cases of injury to health of humans have been reported. [R31, 786] *With the notable exception of the chloromethyl ethers and the glycidyl ethers, the ethers as a group have little general toxicological action in industrial use. Their /CNS depressant/ action causes them to produce loss of consciousness on appreciable exposure and, as good fat solvents, they cause dermatitis on repeated or prolonged skin contact. Enclosure and ventilation are to be employed to avoid excessive exposure. Barrier creams and impervious gloves assist in preventing skin irritation. In the event of loss of consciousness, the person should be removed from the contaminated atmosphere and given artificial respiration and oxygen. /Chloromethyl ethers/ [R31, 785] NTOX: *RATS WERE FED 22 DOSES ... IN OLIVE OIL BY STOMACH TUBE DURING A PERIOD OF 31 DAYS. EVEN THE LOWEST DOSE ... 0.01 G/KG CAUSED A DECREASE IN GROWTH RATE ... AT ... HIGHEST DOSAGE LEVEL, 0.20 G/KG, BOTH LIVER AND KIDNEY WT (PER UNIT OF BODY WT) ... INCREASED. SPLEEN WT ALSO INCREASED ... [R12, p. 475-6] *NO PRIMARY IRRITATION OF THE SKIN AFTER 20 APPLICATIONS TO THE EAR OF RABBITS WAS NOTED ... AND ONLY SCALINESS AFTER SAME NUMBER OF APPLICATIONS BY POULTICE METHOD TO SKIN OF ABDOMEN ... [R32, 519] *ALL 10 RATS SURVIVED A 6 HR EXPOSURE TO 350 PPM, BUT 2 OF 5 DIED AFTER AN 8 HR EXPOSURE. THESE ANIMALS EXHIBITED MODERATE LUNG CONGESTION AND SOME LIVER NECROSIS. ONE OF 4 ANIMALS DIED AFTER AN 8 HR EXPOSURE TO 175 PPM. WHEN RATS WERE EXPOSED TO 700 PPM, DEATHS OCCURRED AFTER 6 HR OF EXPOSURE. AUTOPSY REVEALED SLIGHT LUNG IRRITATION AND MODERATE TO SEVERE LIVER DAMAGE. [R12, 476] *RATS EXPOSED TO AN ATMOSPHERE BELIEVED TO BE ESSENTIALLY SATURATED ... EXHIBITED SIGNS OF IMMEDIATE EYE IRRITATION AND SOME INCOORDINATION; THE MAX EXPOSURE TIME CAUSING NO DEATH WAS 1 HR. [R12, 476] *10000 PPM IN DIET CAUSED DECR BODY WT GAIN AND FOOD CONSUMPTION. MILD ANEMIA, HEMOSIDERIN DEPOSITION, AND INCR EXTRAMEDULLARY HEMATOPOIESIS OF SPLEEN WERE ALSO OBSERVED. AT 2000 PPM IT INHIBITED BODY WT GAIN AND CAUSED ANEMIC TENDENCY IN FEMALE MICE. NO INCR IN FREQUENCY OF AGE-RELATED LESIONS AND TUMORS WAS OBSERVED. THE MAX NO-EFFECT LEVELS TOWARD MALE AND FEMALE MICE WERE 2000 and 400 PPM, RESPECTIVELY. [R33] *ADULT MALE MICE WERE TREATED BY GAVAGE DAILY FOR 8 WK AT 3 DOSE LEVELS. THE MALES WERE MATED TO VIRGIN FEMALES. F1 MALES WERE EXAMINED CYTOGENETICALLY AFTER 2 BREEDINGS. ALL BREEDING DATA WERE EVALUATED AND CORRELATED WITH CYTOGENETIC EXAMINATIONS. NO POSITIVE RECIPROCAL TRANSLOCATIONS WERE OBSERVED IN THE CONTROL OR BIS(2-CHLOROETHYL) ETHER-TREATED GROUPS. [R34] *228 PESTICIDES WERE TESTED FOR MUTAGENICITY USING 5 STRAINS OF SALMONELLA TYPHIMURIUM (TA100, TA98, TA1535, TA1537, AND TA1538) AND 1 STRAIN (WP2 HCR) OF ESCHERICHIA COLI. PESTICIDES WERE TESTED UP TO A DOSE OF 5000 UG/PLATE, UNLESS THEY PROVED TOXIC TO BACTERIA AT THAT POINT. BIS(2-CHLORO-1-METHYLETHYL)ETHER WAS NEGATIVE. [R35] *PRELIMINARY EVALUATION SUGGESTS THAT HERITABLE TRANSLOCATIONS DID NOT OCCUR IN MICE AFTER ADMIN OF BIS(2-CHLOROISOPROPYL) ETHERS. [R36] *Bis(2-chloro-1-methylethyl)ether was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Bis(2-chloro-1-methylethyl) ether was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.0033, 0.010, 0.033, 0.100, 0.333, 0.666, 1.000, 1.666, and 3.333 mg/plate. The lowest positive dose tested in any S typhimurium strain was 0.100 mg/plate in strain TA1535 with hamster liver S-9. The compound was also positive in strain TA100 at a dose of 0.333 mg/plate with hamster S-9. No effect was seen using rat liver S-9 in either of these strains at any dose. When tested in strains TA97, TA98, and TA1537, no effects were seen under any test conditions (with or without activation) at any dose tested. [R37] *ICR mice of both sexes fed diets containing bis(2-chloro-1-methylethyl)ether (98.5% pure) at 0, 80, 400, 2000, or 10,000 ppm for 104 wk did not develop an increased incidence of tumors. [R38] *Effects on 2 male and 2 female rats which were exposed to vapor concn of 700 ppm bis(2-chloro-1-methylethyl)ether for 5 hr were irritation of nose and eyes, respiratory difficulty, death of 2 animals. At autopsy: congested liver and kidney. Effects on 4 male and 4 female rats exposed to a vapor concn of 350 ppm 8 times for 5 hr were lethargy, respiratory difficulty, and retarded weight gain. At autopsy: congested liver and kidney. Effects on 4 male and 4 female rats exposed to vapor concn of 70 ppm 20 times for 6 hr were lethargy, and retarded weight gain. At autopsy: organs normal. 4 male and 4 female rats exposed to vapor concn of 2 ppm 20 times for 6 hr showed no symptoms of toxicity. At autopsy: organs normal. /From table/ [R39] *The lowest vapor concentrations to which animals have been exposed is 175 ppm. One of four rats died after an exposure of 3 hr. [R31, 786] +... Under the conditions of this bioassay, the technical grade material, bis(2-chloro-1-methylethyl)ether, was not carcinogenic in F344 rats of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative. [R40] +... Under the conditions of this bioassay, bis (2-chloro-1-methylethyl)ether, containing 2-chloro-1-methylethyl (2-chloropropyl)ether, was carcinogenic for B6C3Fl mice, causing increased incidences of alveolar/bronchiolar adenomas in male and females and hepatocellular carcinomas in males. In addition, the occurrence of a low incidence of squamous cell papillomas or carcinomas in the stomach or forestomach of females (a rare tumor in B6C3Fl mice) was probably associated with the admin of bis(2-chloro-1-methylethyl)ether. Levels of Evidence of Carcinogenicity: Male Mice: Positive; Female Mice: Positive. [R41] NTXV: *LC50 Rat inhalation 350 ppm/8 hr; [R23] *LD50 Rat single oral 0.24 (0.22-0.27 g/kg in a suitable vehicle). /From table/; [R12, 456] *LD50 Rabbit single percutaneous 3.00 (1.78-5.04) ml/kg. /From table/; [R12, 456] *Inhalation of metered vapor concn by rats: Concn: 1.000 ppm Time: 4 hr Mortality: 1/6. /From table/; [R12, 456] *LD50 Rat male acute oral 503 mg/kg; [R42] *LD50 Mouse male acute oral 296 mg/kg; [R42] *LD50 Mouse female acute oral 536 mg/kg; [R42] *LD50 Rat acute percutaneous > 2000 mg/kg; [R42] *LC50 Mouse and rat inhalation 12.8 mg/l air (4hr); [R42] NTP: +A bioassay of technical grade bis(2-chloro-1-methylethyl) ether for possible carcinogenicity was conducted by admin the test chemical by gavage to F344 rats. Groups of 50 rats of each sex were admin a solution of bis(2-chloro-1-methylethyl) ether in corn oil 5 days/wk at either 100 or 200 mg/kg/day for 103 wk. Vehicle controls consisted of groups of 50 rats of each sex that were admin corn oil alone. Untreated control groups of the same size were also used. All surviving rats were killed at wk 104 or 105. ... Under the conditions of this bioassay, the technical grade material, bis(2-chloro-1-methylethyl)ether, was not carcinogenic in F344 rats of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative. [R40] +A carcinogenesis bioassay of bis (2-chloro-1-methylethyl)ether (~70%), containing ~30% 2-chloro-1-methylethyl (2-chloropropyl) ether, was conducted by admin 100 or 200 mg/kg bis(2-chloro-1-methylethyl)ether in corn oil by gavage 5 times per week for 103 weeks to groups of 50 B6C3Fl mice of each sex. Fifty mice of each sex received corn oil alone and served as vehicle controls. ... Under the conditions of this bioassay, bis (2-chloro-1-methylethyl)ether, containing 2-chloro-1-methylethyl (2-chloropropyl)ether, was carcinogenic for B6C3Fl mice, causing increased incidences of alveolar/bronchiolar adenomas in male and females and hepatocellular carcinomas in males. In addition, the occurrence of a low incidence of squamous cell papillomas or carcinomas in the stomach or forestomach of females (a rare tumor in B6C3Fl mice) was probably associated with the admin of bis(2-chloro-1-methylethyl)ether. Levels of Evidence of Carcinogenicity: Male Mice: Positive; Female Mice: Positive. [R41] ADE: *... IT IS RAPIDLY ABSORBED FROM SKIN ... [R32, 518] *After single oral doses, bis(2-chloroisopropyl) ether (BCIE) appeared to be readily absorbed by both /female rats and monkeys/. In the monkey, the blood radioactivity level reached a high peak within two hr and then declined in a biphasic manner, with a half-life of about five hr and greater than two days for the first and second phases, respectively. In the rat, the blood radioactivity level reached a maximum between 2 and 4 hr after dosing and then slowly declined with a half-life of two days. There was a substantial difference in the tissue distribution and excretion pattern seven days after a single parenteral dose of 30 mg/kg of (14)C-BCIE. The monkey retained substantially higher amounts of radioactivity in the liver (equivalent to 28.8 ug/g BCIE) than did the rat (3.2 ug/g). Higher quantities were also found in the muscle; brain of the monkey. ... With respect to the percentage of admin dose recovered in the tissues and excreta, higher amounts of radioactivity were found in the fat (1.98%), urine (63.36%), feces (5.87%), and expired air (15.96%) of the rat. The corresponding figures in the monkey were 0.78%, 28.61%, 1.19%, and 0%. [R43] METB: *Metabolites of bis(2-chloroisopropyl)ether in the rat included 1-chloro-2-propanol, propylene oxide, 2-(1-methyl-2-chloroethoxy)-propionic acid, and carbon dioxide. [R44] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Bis(2-chloro-1-methylethyl) ether's production and use in the textile industry and as a solvent for natural and synthetic resins may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.56 mm Hg at 25 deg C indicates bis(2-chloro-1-methylethyl) ether will exist solely as a vapor in the ambient atmosphere. Vapor-phase bis(2-chloro-1-methylethyl) ether will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 28 hours (1.2 days). If released to soil, bis(2-chloro-1-methylethyl) ether is expected to have very high mobility based upon a Koc of 47. It may be resistant to biodegradation in environmental media based upon screening test data from studies using activated sludge or sewage inocula. Many ethers are known to be resistant to biodegradation. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 7.4X10-5 atm-cu m/mole. If released into water, bis(2-chloro-1-methylethyl) ether is not expected to adsorb to suspended solids and sediment in water based on the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based on its estimated Henry's Law constant. The volatilization half-life from a model river and a model lake is estimated as approximately 19 hours and 10 days, respectively. A BCF of 5.2 to 12 suggests that bioconcentration in aquatic organisms is low. Bis(2-chloro-1-methylethyl) ether is not expected to hydrolyze in the environment due to lack of hydrolyzable functional groups. The most probable routes of general population exposure to bis(2-chloro-1-methylethyl) ether are via inhalation of contaminated air and ingestion of contaminated drinking water. Inhalation and dermal exposure will be expected to be highest in workplaces where bis(2-chloro-1-methylethyl) ether is made and used. (SRC) ARTS: *Bis(2-chloro-1-methylethyl) ether's production and use in the textile industry and as a solvent for natural and synthetic resins(1) may result in its release to the environment through various waste streams(SRC). [R45] FATE: *AQUATIC FATE: Assuming a first order reduction of concentration ... the following half-lives were derived: 3-30 days in river water and 30-300 days in lake and groundwater. [R46] *ATMOSPHERIC FATE: The vapor pressure of bis(2-chloroisopropyl) ether suggests that it might be sufficiently volatile to be transported into the atmosphere. [R47, p. 66-3] *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc of 47(2) indicates that bis(2-chloro-1-methylethyl) ether is expected to have very high mobility in soil(SRC). Volatilization of bis(2-chloro-1-methylethyl) ether from moist soil surfaces is expected to be important(3,SRC) given an estimated Henry's Law constant of 7.4X10-5 atm-cu m/mole(SRC), calculated from its water solubility(4) and vapor pressure(4). Aqueous screening test data from studies using activated sludge(5,6) suggest that bis(2-chloro-1-methylethyl) ether may be resistant to biodegradation in environmental media(SRC). In one study, bis(2-chloro-1-methylethyl) ether showed no biodegradation after 5 days when incubated with Ohio River water(7). In general, many ethers are known to be resistant to biodegradation(8). By analogy to bis(2-chloroethyl) ether, which has a hydrolytic half-life of about 20 years(9), hydrolysis of bis(2-chloro-1-methylethyl) ether is not expected to be an important fate process(SRC). [R48] *AQUATIC FATE: Based on a classification scheme(1), a Koc of 47(2) indicates that bis(2-chloro-1-methylethyl) ether is not expected to adsorb to suspended solids and sediment in water(SRC). Bis(2-chloro-1-methylethyl) ether is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 7.4X10-5 atm-cu m/mole(SRC), calculated from its water solubility(4) and vapor pressure(4). Estimated volatilization half-lives for a model river and model lake are 19 hours and 10 days, respectively(3,SRC). According to a classification scheme(5), a BCF of 5.2 to 12(6) suggests the potential for bioconcentration in aquatic organisms is low(SRC). Bis(2-chloro-1-methylethyl) ether may be resistant to biodegradation under both aerobic and anaerobic conditions in environmental media based upon screening test data from studies using activated sludge(6,7SRC). In one study, bis(2-chloro-1-methylethyl) ether showed no biodegradation after 5 days when incubated with Ohio River water(8). In general, many ethers are known to be resistant to biodegradation(9). By analogy to bis(2-chloroethyl)ether, which has a hydrolytic half-life of about 20 years(10), hydrolysis of bis(2-chloro-1-methylethyl) ether is not expected to be an important fate process(SRC). [R49] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bis(2-chloro-1-methylethyl) ether, which has a vapor pressure of 0.56 mm Hg at 20 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase bis(2-chloro-1-methylethyl) ether is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 28 hours(3,SRC). [R50] BIOD: *AEROBIC GRAB SAMPLES: Bis(2-chloro-1-methylethyl) ether showed no biodegradation after 5 days at 20 deg C when incubated with Ohio River water at an initial concentration of 33 mg/l(1). Three bank infiltration studies from the Rhine river in The Hague showed a concentration of approximately 0.5 ug/l, which was not reduced at all after infiltration(2). In the Netherlands, 33% removal in < 1 yr and 90% removal in < 3 months was observed after bank and dune infiltration of Rhine water, respectively(3). A degradation half-life has been estimated to be 59 days and 3.1 days for bis(2-chloro-1-methylethyl) ether in a lake in the Rhine basin and in the Rhine river, respectively, based upon field monitoring data (includes dilution and evaporation)(3). AEROBIC SCREENING STUDIES: Bis(2-chloro-1-methylethyl) ether, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum(4). Bis(2-chloro-1-methylethyl) ether did not degrade after an experimental period of 40 days under aerobic conditions(5). In a static-culture-flask biodegradation screening procedure, utilizing biochemical oxygen demand and dilution water containing 5 mg of yeast extract per liter as the synthetic medium, bis(2-chloro-1-methylethyl) ether was found to be significantly biodegradable with rapid adaptation. At a test concentration of 5 mg/l, the original culture achieved 85% biodegradation in 7 days and subcultures 100% in 7 days; when the test concentration was 10 mg/l, 63% biodegradation of the original culture was observed in 7 days and 100% in subcultures(6). [R51] *ANAEROBIC: Bis(2-chloro-1-methylethyl) ether did not degrade after an experimental period of 40 days under anaerobic conditions(1). The calculated half-life for the chemical reductive dehalogenation of bis(2-chloro-1-methylethyl) ether was determined to be 903 days(2). [R52] ABIO: *Direct photolysis would not be expected to occur in surface waters in the troposphere since bis(2-chloroisopropyl) ether does not possess any chromophores that absorb radiation in the visible or near UV regions. [R47, p. 66-2] *The rate constant for the vapor phase reactions of bis(2-chloro-1-methylethyl) ether with photochemically produced hydroxyl radicals has been determined to be 1.39X10-11 cu cm/molecule-sec at 25 deg C(1), which corresponds to a half-life of 28 hours (1.2 days) at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm (SRC). By analogy to bis(2-chloroethyl)ether, which has an estimated hydrolysis half-life about 20 yrs at 25 deg C(2), hydrolysis of bis(2-chloro-1-methylethyl) ether should be slow and independent of pH(SRC). [R53] BIOC: *... The weighted average bioconcentration factor for ... bis(2-chloroisopropyl) ether /in/ the edible portion of all freshwater and estuarine aquatic organisms consumed by Americans is calculated to be ... 2.47. [R54] *An BCF of 5.2 to 12 in carp was determined for bis(2-chloro-1-methylethyl) ether(1). According to a classification scheme(2), this BCF suggests that bioconcentration in aquatic organisms is low. [R55] KOC: *Because of its water solubility, some migration through the soil may occur. [R47, p. 66-3] *The value of the log octanol/water partition coefficient ... 2.58, does indicate, ... some potential for adsorption on suspended organic matter. [R47, p. 66-4] *The Koc of bis(2-chloro-1-methylethyl) ether in various soils was determined to be 47(1). According to a classification scheme(2), this estimated Koc value suggests that bis(2-chloro-1-methylethyl) ether is expected to have very high mobility in soil(SRC). [R56] VWS: *... The half-life with respect to volatilization for bis(2-chloroisopropyl) ether from a body of water /is calculated/ to be 1.37 days. [R47, p. 66-3] *The Henry's Law constant for bis(2-chloro-1-methylethyl) ether is estimated as 7.4X10-5 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.56 mm Hg(1), and water solubility, 1,700 mg/l(1). This Henry's Law constant indicates that bis(2-chloro-1-methylethyl) ether is expected to volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is approximately 19 hours(2,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is approximately 10 days(2,SRC). Bis(2-chloro-1-methylethyl) ether's Henry's Law constant(1,2,SRC) indicates that rapid volatilization from moist soil surfaces may occur(SRC). [R57] WATC: *Bis(2-chloroisopropyl) ether has been detected but not quantified in the Mississippi River, ... rivers, lakes, and groundwater in the Netherlands ... and finished drinking water at an unidentified site in NC. [R58] *Concn in New Orleans drinking water averaged 0.10 ng/cu m. [R59] *Levels in the drinking water of 9 unnamed cities ranged from 0.02-1.58 ug/l. [R60] *At the Carrollton station and two sites in Jefferson Parish, LA the finished drinking water ... /contained/ 0.018, 0.08, and 0.03 ug/l respectively. [R61] *A National Organics Monitoring Survey of USA drinking water, ... bis(2-chloroisopropyl) ether was found in 8 of 113 cities (7-1%) with a mean concn of positives equal to 0.17 ug/l. /From table/ [R62] *Industrial outfall on the Ohio River ranged from 0.5-35 mg/l. Raw intake of an Evansville, IN water treatment facility had levels of 2.0 ug/l and tap water of 0.8 ug/l [R63] *Present in finished drinking water of Cincinnati, Ohio and Cleveland, Ohio [R63] *GROUNDWATER: At the Zwolle water utility in the Netherlands, bis(2-chloro-1-methylethyl) ether was detected in 7 observations made in 1978 at a maximum concn of 3 ug/l following bank infiltration of Rhine river water(1). Three influent water tests from the Rhine river in The Hague showed a concn of approximately 0.5 ug/l, which was not reduced at all after infiltration(1). Bis(2-chloro-1-methylethyl) ether was detected in groundwater in the surroundings of an industrial gypsum waste deposit, situated between the channel Ghent-Terneuzen and the Scheldt estuary, Netherlands; concns ranged from approximately 300 to 1,100 ug/l(2). Bis(2-chloro-1-methylethyl) ether was detected in groundwater collected from wellfields across the Netherlands, concn unknown(3). [R64] *DRINKING WATER: Bis(2-chloro-1-methylethyl) ether has been identified in tap water from bank filtered Rhine water in the Netherlands at a maximum concn of 3,000 ng/l(1). Bis(2-chloro-1-methylethyl) ether has been detected in 8 of 113 samples at an average concn of 0.17 ug/l in drinking water from 113 community water supplies from May-June 1976(2). Bis(2-chloro-1-methylethyl) ether has been detected in 7 of 110 samples at an average concn of 0.11 ug/l in drinking water from 110 community water supplies from November 1976-January 1977(2). It has been identified in municipal drinking water at a concn of 0.8 ug/l in Evansville,IN on August 25, 1971(5). Bis(2-chloro-1-methylethyl) ether has been detected in the water supply of Cleveland,OH(3). Bis(2-chloro-1-methylethyl) ether has been detected at a concn of 0.18 ug/l in finished water from the Carrollton water plant in the New Orleans,LA area(4). [R65] *SURFACE WATER: Bis(2-chloro-1-methylethyl) ether has been detected in water at mean concns of 0.10 and 19 ug/l from the New Orleans/Baton Rouge, LA and Houston, TX areas, respectively(1). Bis(2-chloro-1-methylethyl) ether has been detected in water from the Rhine river in the Netherlands at an average concn of 4 ug/l with a maxima of 15 ug/l during 1978-1979; samples were taken every two weeks(2). According to the STORET database, bis(2-chloro-1-methylethyl) ether has been detected in ambient water from the U.S.A. at a median concn of < 10.000 ug/l(3). The concn of stormwater detected in roof areas, parking areas, vehicle service areas, landscaped areas, and urban creeks of Birmingham, Al averaged 99, 130, 120, 85, and 59 ug/l, respectively(4). [R66] EFFL: *Release of bis(2-chloro-1-methylethyl)ether ... in wastewater from industrial processes, particularly in proplylene glycol manufacturing is estimated to be one million lb per yr. /Separate figures not given; 1979/ [R67] *Bis(2-chloro-1-methylethyl) ether has been detected in U.S. rivers as a result of industrial outfall from propylene glycol production(1,2) at concns ranging from 0.2-5 ug/l (Ohio River) from August-September 1971(2). Bis(2-chloro-1-methylethyl) ether has been detected in water samples from a specially constructed leachate treatment plant located at Love Canal (Niagara Falls, NY)(3). According to the STORET database, bis(2-chloro-1-methylethyl) ether has been detected in effluents in the U.S.A. with a median concn of < 10.000 ug/l(4). In a study conducted from 1989-1993, bis(2-chloro-1-methylethyl) ether was detected in New York City Municipal wastewaters at a concn of 8 ug/l(5). [R68] SEDS: *According to the STORET database, bis(2-chloro-1-methylethyl) ether has been detected in sediment from the USA at a median concn of < 500.0 ug/kg (dry)(1). [R69] PFAC: PLANT CONCENTRATIONS: *Single or duplicate injection of 2667 ppm or 4000 ppm bis(2-chloro-1-methylethyl)ether emulsion, at 3 and 2 l/sq m, respectively, gave good control of root knot nematodes in soil, without leaving residues in figs. [R70] FISH/SEAFOOD CONCENTRATIONS: *Bis(2-chloro-methylethyl) ether has been identified in fish collected from Lake Michigan and tributary streams in 1983(1). [R71] OEVC: *According to the STORET database, bis(2-chloro-1-methylethyl) ether has been detected in biota in the USA at a median concn of < 2.2 mg/kg(1). [R69] RTEX: *Bis(2-chloro-1-methylethyl) ether has been detected in drinking water(1-5); therefore, exposure to the general population is expected to occur through consumption of contaminated drinking water(SRC). In occupational settings, exposure to bis(2-chloro-1-methylethyl) ether may occur through inhalation of vapors and through eye and skin contact(SRC). [R72] *Workers in areas where bis(2-chloro-1-methylethyl)ether is produced as a byproduct of the chlorohydrin process have the potential for exposure. [R73] *The use of bis(2-chloro-1-methylethyl)ether (BCMEE) in paint and varnish removers, in spotting and cleaning solutions, and the potential for its use as a nematocide, fungicide, or insecticide ... suggest the possibility of consumer exposure. However, ... there is no evidence that BCMEE is used for these purposes in the USA. The presence of BCMEE in finished drinking water /1983/ suggests a more likely means of consumer exposure. [R63] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 300 ug/l [R74] STATE DRINKING WATER GUIDELINES: +(NH) NEW HAMPSHIRE 300 ug/l [R74] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Cloroalkyl ethers/ [R75] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R76] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Bis(2-Chloro-1-methylethyl)ether is included on this list. [R77] RCRA: *U027; As stipulated in 40 CFR 261.33, when bis(2-chloro-1-methylethyl)ether, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R78] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *EPA Method 625: Grab samples of water in municipal and industrial discharges must be collected in glass containers, amber, 1 l or 1 qt, fitted with a screw cap lined with Teflon, except that the bottles must not be prerinsed with sample before collection. Fill the sample bottles, and if residual chlorine is present, add 80 mg of sodium thiosulfate per liter of sample and mix well. All samples must be iced or refrigerated from the time of collection until analysis. All samples must be extracted within 7 days of collection and completely analyzed within 40 days of extraction. Extraction is performed by adding 60 ml of methylene chloride to the sample in a separatory funnel and shaking. The combined extract is then concentrated using a Kuderna-Danish apparatus. [R79] *EPA Method 1625: Collect water samples in municipal and industrial discharges in glass containers, amber, 1.1 l minimum with threaded caps lined with Teflon. Maintain samples at 0-4 deg C from the time of collection until extraction. If residual chlorine is present, add 80 mg sodium thiosulfate per liter of water. Extraction is performed by adding methylene chloride to the samples in a continuous liquid-liquid extractor and concentrated with a Kuderna-Danish apparatus. Begin sample extraction within seven days of collection, and analyze all extracts within 40 days of extraction. [R79] ALAB: *EPA Method 611: A gas chromatography method for the analysis of semivolatile organic compounds in municipal and industrial discharges, consists of a glass column, 1.8 m x 2 mm ID, packed with Supelcoport (100/120 mesh) coated with 3% SP-1000, with a halide specific detector (electrolytic conductivity or microcoulometric), and helium as the carrier gas at a flow rate of 40 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 60 deg C for two min after injection then programmed at 8 deg C/min to 230 deg C and held for four min. For bis(2-chloroisopropyl) ether, this method has a detection limit of 0.8 ug/l and an overall precision of 0.36 times the average recovery + 0.79, over a working range of 1.0 to 626 ug/l. [R79] *EPA Method 625: A gas chromatography/mass spectrometry method for the analysis of semivolatile organic compounds in municipal and industrial discharges, consists of a glass column, 1.8 m x 2 mm ID, packed with Supelcoport (100/120 mesh) coated with 3% SP-2250, with the detection performed by the mass spectrometer, and helium as the carrier gas at a flow rate of 30 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 50 deg C for 4 minutes and then programmed immediately at 8 deg/min to a final temperature of 270 deg C. For bis(2-chloroisopropyl) ether, this method has a detection limit of 5.7 ug/l and an overall precision of 0.36 times the average recovery + 0.67, over a working range of 5 to 1300 ug/l. [R79] *EPA Method 1625: Semivolatile Organic Compounds. An isotope dilution gas chromatography/mass spectrometry method for the determination of semivolatile organic compounds in municipal and industrial discharges. This method is designed to meet the survey requirements of Effluent Guidelines Division (EGD) and the National Pollution Discharge Elimination System (NPDES).Extraction is performed by adding methylene chloride to the samples in a continuous liquid-liquid extractor and concentrated with a Kuderna-Danish apparatus. Under the prescribed conditions, unlabeled bis(2-chloro-1- methylether) ether has a detection limit of 10 ug/l and a mean retention time of 799 sec. This method has an initial precision of 17 ug/l and an accuracy of 81-138 ug/l for the unlabeled compound. [R79] *EPA Method 8010: Halogenated Volatile Organics: Samples can be analyzed by direct injection or purge-and-trap using GC with flame ionization detector. Under the prescribed conditions, bis(2-dichloroisopropyl) ether can be analyzed using this method. No statistical analysis was determined. [R80] *EPA Method 8250: GC/MS for Semivolatile Organics: Packed Column Technique: Extracted samples are analyzed using GC coupled with mass spectrometry. Under the prescribed conditions, bis(2-dichloroisopropyl) ether has a detection limit of 5.7 ug/l, a retention time of 9.3 min, and an overall precision of 0.25 times the average recovery + 1.04 ug/l, over a working range of 5-1300 ug/l. [R80] *EPA Method 8270: GC/MS for Semivolatile Organics: Capillary Column Technique: Extracted samples are analyzed using GC coupled with mass spectrometry. Under the prescribed conditions, bis(2-dichloroisopropyl) ether has a retention time of 7.22 min and an overall precision of 0.25 times the average recovery + 1.04 ug/l, over a working range of 5-1300 ug/l. [R80] *EPA Method 3510: Separatory Funnel Liquid-Liquid Extraction: A measured volume of sample is serially extracted with methylene chloride. The sample is then dried and concentrated using a Kuderna-Danish apparatus. This method is applicable to the extraction and concentration of water-insoluble and slightly water-soluble organics from aqueous samples. [R80] *EPA Method 3520: Continuous Liquid-Liquid Extraction: A measured volume of sample is extracted with methylene chloride. After distillation, the sample is then dried and concentrated using a Kuderna-Danish apparatus. This method is applicable to the extraction and concentration of water-insoluble and slightly water-soluble organics from aqueous samples. [R80] *EPA Method 3540: Soxhlet Extraction: A solid sample is mixed with anhydrous sodium sulfate and extracted using an appropriate solvent in a Soxhlet extractor. The sample is then dried and concentrated using a Kuderna-Danish apparatus. This is a procedure for extracting nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. [R80] *EPA Method 3550: Sonication Extraction: A solid sample is mixed with anhydrous sodium sulfate to form a free-flowing powder. This is solvent extracted three times using a horn-type sonicator. The sample is then dried and concentrated using a Kuderna-Danish apparatus. This method is applicable to the extraction of nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. [R80] *EPA Method 3580: Waste Dilution: One gram of sample is weighed into a capped tube and the sample is diluted with an appropriate solvent. This method is designed for wastes that may contain organic chemicals at a level greater than 20,000 mg/kg. It is recommended that an aliquot of the diluted sample be cleaned up with an applicable technique. [R80] *EPA Method 5030: Purge and Trap: An inert gas is bubbled through the solution at ambient temperature, and the volatile components are efficiently transferred from the aqueous phase to the vapor phase. After purging is complete, th sorbent column is heated and backflushed with inert gas to derorb the components onto a GC column. Water samples can be analyzed directly, while preparation is necessary for water-miscible liquids, solids, and wastes and soil/sediments. [R80] *EMSLC Method 625: Base/Neutral and Acid Organics in Wastewater: Protocol for the Analysis of Base/Neutral and Acid Extractable (BNA) Organic Priority Pollutants in Industrial and Municipal Wastewater; capillary gas chromatography with low resolution mass spectrometry, wastewater, detection limit of 5.7 ug/l. [R81] *EMSLC Method 625-S: Organics in Sludge - Base/Neutral and Acid: Analysis of Extractable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge; Gas chromatography with low resolution mass spectrometry, sludge, detection limit of 5.7 ug/l. [R81] *EAD Method 1625: Semivolatiles - Soil, GC/MS: Semivolatile Organic Compounds by Isotope Dilution GCMS; Capillary gas chromatography with low resolution mass spectrometry, soil, detection limit of 39.05 ug/kg. [R81] *SFSAS Method SFSAS_29: Organics in Biological Tissue: Extraction and Analysis of Organics in Biological Tissue; capillary gas chromatography with low resolution mass spectrometry, biological tissue, detection limit of 0.050 mg/kg. [R81] CLAB: *A HIGHLY SPECIFIC MASS FRAGMENTOGRAPHIC METHOD FOR QUANTITATIVE DETERMINATION OF DCIP IN RAT TISSUES WAS DEVELOPED. DCIP IN THE WHITE ADIPOSE TISSUE, LIVER, KIDNEY AND BLOOD OF RAT WAS STEAM DISTILLED AND TRAPPED IN TOLUENE. THE TOLUENE SOLUTION WAS DRIED OVER ANHYDROUS SODIUM SULFATE AND INJECTED DIRECTLY INTO A GAS CHROMATOGRAPH-MASS SPECTROMETER (GC-MS), EQUIPPED WITH A MULTIPLE ION DETECTOR. DCIP WAS DETERMINED BY COMPARING THE PEAK HEIGHTS OF 2 ION FRAGMENTS (M/E MASS-CHARGE RATIO) 121 AND 123) WITH THE CORRESPONDING PEAK HEIGHTS OF KNOWN AMOUNTS OF STANDARDS. /NO/ INTERFERENCE ON THE MASS FRAGMENTOGRAMS WAS ... OBSERVED IN THE ANALYSIS OF THE RAT TISSUES. USING 10 G OF THE SAMPLE, THE METHOD WAS SENSITIVE TO 0.05 PPM AND THE RECOVERIES OF DCIP AVERAGED 87 + OR - 16%. [R82] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Chloroalkyl Ethers (1980) EPA 440/5-80-030 USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) (1983) Clarke RM et al; Sci Total Environ 53 (3): 153-172 (1986). Drinking water and cancer mortality. DHEW/NCI; Bioassay of Technical Grade Bis(2-chloro-1-methylethyl)ether for Possible Carcinogenicity (1979) Technical Rpt Series No. 191 DHEW Pub No. (NIH) 79-1747 DHHS/NTP; Carcinogenesis Bioassay of Bis(2-chloro-1-methylethyl) ether (~70%) Containing 2-Chloro-1-methylethyl-(2-chloropropyl) ether (~30%) in B6C3F1 Mice Technical Report Series No. 239 (1982) NIH Publication No. 83-1795 Kawamoto K, Urano K; Parameters for predicting fate of organochlorine pesticides in the environment: III. Biodegradation rate constants; Chemosphere 21 (10-11): 1141-52 (1990). Aerobic and anaerobic biodegradation rate constants of 10 principal organochlorine pesticides were investigated to predict their fate in the environment. SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. Suppl 7 150 R3: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 473 R4: MATSUMOTO M ET AL; JAPAN PATENT NO 74 09195 03/02/74 (SHOWA DENKO KK) R5: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1677 R6: USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.4 (1983) R7: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R8: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-277 R10: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2496 R11: Kawamoto K, Urano K; Chemosphere 18:1987-96 (1989) R12: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R13: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 339 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 423 R15: USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.2 (1983) R16: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-35 R18: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 355 R19: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 49 R20: 49 CFR 171.2 (7/1/96) R21: IATA. Dangerous Goods Regulations. 39th Ed. Montreal, Canada and Geneva, Switzerland : International Air Transport Association, Dangerous Goods Regulations, 1998. 128 R22: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6118 (1988) R23: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 490 R24: 40 CFR 240-280, 300-306, 702-799 (7/1/97) R25: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-11 (1981) EPA 68-03-3025 R26: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 177 R27: USEPA/ORD; Innovative and Alternative Technology Assessment Manual pp.3-5, 3-11,12 (1980) EPA 430/9-78-009 R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 71 1277 (1999) R29: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R30: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.1 R31: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R32: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R33: MITSUMORI K ET AL; NIPPON NOYAKU GAKKAISHI 4 (3): 323 (1979) R34: JORGENSON TA ET AL; MUTAT RES 53 (1): 124 (1978) R35: MORIYA M ET AL; MUTAT RES 116: 185 (1983) R36: JORGENSON TA ET AL; MUTAT RES 53: 124 (1978) R37: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R38: Mitsumori K et al; Nippon Noyaka Gakkaishi 4 (3): 323-35 (1979) R39: USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.10 (1983) R40: Bioassay of Technical Grade Bis(2-chloro-1-methylethyl)ether for Possible Carcinogenicity (1979) Technical Rpt Series 191 DHEW Pub No. (NIH) 79-1747, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R41: Carcinogenesis Bioassay of Bis(2-chloro-1-methylethyl)ether (~ 70%) Containing 2-Chloro-1-methylethyl(2-chhloropropyl)ether (~30%) in B6C3F1 Mice (Gavage Study) Technical Report Series No. 239 (1982) NIH Publication No. 83-1795 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R42: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994. 283 R43: USEPA; Ambient Water Quality Criteria Doc: Chloroalkyl Ethers p.C-20-1 (1980) EPA 440/5-80-030 R44: USEPA; Ambient Water Quality Criteria Doc: Chloroalkyl Ethers p.C-21 (1980) EPA 440/5-80-030 R45: (1) Heitmann W et al; Ullmann's Encycl Indust Chem, 5th ed. Deerfield Beach,FL: VCH Publ A10: 23-43 (1987) R46: USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.6 (1983) R47: Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979. R48: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Kawamoto K, Urano K; Chemosphere 19: 1223-231 (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Tomlin CDS; The Pesticide Manual. 11th Ed. Crop Protection Pub: British Crop Protection Council 49 Downing St, Farnham United Kingdom (1997) (5) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Kawamoto K, Urano K; Chemosphere 21: 1141-152 (1990) (7) Kleopfer RD, Fairless BJ; Environ Sci Technol 6: 1036-37 (1972) (8) Alexander M; Biotechnol Bioeng 15: 611-47 (1973) (9) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants USEPA-440/4-81-014 Washington,DC USEPA (1981) R49: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Kawamoto K, Urano K; Chemosphere 19: 1223-231 (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Tomlin CDS; The Pesticide Manual. 11th Ed. Crop Protection Pub: British Crop Protection Council 49 Downing St, Farnham United Kingdom (1997) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (7) Kawamoto K, Urano K; Chemosphere 21: 1141-152 (1990) (8) Kleopfer RD, Fairless BJ; Environ Sci Technol 6: 1036-37 (1972) (9) Alexander M; Biotechnol Bioeng 15: 611-47 (1973) (10) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants USEPA-440/4-81-014 Washington,DC USEPA (1981) R50: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Tomlin CDS; The Pesticide Manual. 11th Ed. Crop Protection Pub: British Crop Protection Council 49 Downing St, Farnham United Kingdom (1997) (3) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) R51: (1) Kleopfer RD, Fairless BJ; Environ Sci Technol 6: 1036-37 (1972) (2) Piet GJ, Zoeteman BCJ; J Amer Water Works Assoc 72: 400-4 (1980) (3) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) (4) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (5) Kawamoto K, Urano K; Chemosphere 21: 1141-152 (1990) (6) Tabak HH et al; JWPCF 53: 1503-17 (1981) R52: (1) Kawamoto K, Urano K; Chemosphere 21: 1141-152 (1990) (2) Van Beelen P; Stygologia 5: 199-212 (1990) R53: (1) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) (2) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants USEPA-440/4-81-014 Washington, DC USEPA (1981) R54: USEPA; Ambient Water Quality Criteria Doc: Chloroalkyl Ethers p.C-16 (1980) EPA 440/5-80-030 R55: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R56: (1) Kawamoto K, Urano K; Chemosphere 19: 1223-231 (1989) (2) Swann RL et al; Res Rev 85: 23 (1983) R57: (1) Tomlin CDS; The Pesticide Manual. 11th Ed. Crop Protection Publ: British Crop Protection Council 49 Downing St, Farnham United Kingdom (1997) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R58: USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.7 (1983) R59: Pellizzari ED et al; RTP, NC EPA/560/13-79-006 (1979) as cited in USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.7 (1983) R60: Dressman RC et al; Environ Sci Technol 11 (7): 719-21 (1977) as cited in USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.7 (1983) R61: USEPA; Ambient Water Quality Criteria Doc: Chloroalkyl Ethers p.C-10 (1980) EPA 440/5-80-030 R62: USEPA; Ambient Water Quality Criteria Doc: Chloroalkyl Ethers p.C-12 (1980) EPA 440/5-80-030 R63: USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.5 (1983) R64: (1) Piet GJ, Zoeteman BCJ; J Amer Water Works Assoc 72: 400-4 (1980) (2) Quaghebeur D et al; Comm Eur Communities, Eur 10388. Org Micropollut Aquat Environ. pp 142-46 (1986) (3) Van Beek et al; Proc Inf Comm Hydrol Res; CHO-TON. 38: 193-205 (1987) R65: (1) Piet GJ, Morra CF; pp. 31-42 in Artificial Groundwater Recharge (Water Resources Engineering Series) Huisman L, Olsthorn TN Eds, Pitman Pub (1979) (2) Mello W; Investigations of Selected Environ Pollutants USEPA-560/2-78-006 (1978) (3) Sanjivamurthy VA; Water Res 12: 31-3 (1978) (4) Keith LH et al; pp. 329-73 in Ident Anal Organic Pollut Water Keith,LH ED Ann Arbor,MI Ann Arbor Press (1976) (5) Kleopfer RD, Fairless BJ; Environ Sci Technol 6: 1036-7 (1972) R66: (1) Pellizzari ED et al; Formulation of Preliminary Assessment of Halogenated Organic Compounds in Man and Environmental Media USEPA/560/13-79-006 Research Triangle Park, NC: USEPA (1979) (2) Piet GJ, Zoeteman BCJ; J Amer Water Works Assoc 72: 400-4 (1980) (3) Staples CA et al; Environ Toxicol Chem 4131-42 (1985) (4) Pitt R et al; Water Environ Research 67: 260-75 (1995) R67: Fishbein L; Sci Total Environ 11: 223-57 (1979) as cited in USEPA; Chemical Hazard Information Profile: Bis(2-chloro-1-methylethyl)ether (Draft) p.5 (1983) R68: (1) Fishbein L; Sci Total Environ 11: 223-57 (1979) (2) Kleopfer RD, Fairless BJ; Environ Sci Technol 6: 1036-7 (1972) (3) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) (4) Staples CA et al; Environ Toxicol Chem 41: 31-42 (1985) (5) Stubin AI et al; Water Environ Research 68: 1037-44 (1995) R69: (1) Staples CA et al; Environ Toxicol Chem 4131-42 (1985) R70: Seko S et al; Kinki Chugoku Nogyo Kenkyu 67: 38-41 (1984) R71: (1) Camanzo J et al; J Great Lakes Res 13: 296-309 (1987) R72: (1) Piet GJ, Morra CF; pp 31-42 in Artificial Groundwater Recharge (Water Resources Engineering Series) Huisman L, Olsthorn TN Eds, Pitman Pub (1979) (2) Mello W; Investigations of Selected Environ Pollutants USEPA-560/2-78-006 (1978) (3) Sanjivamurthy VA; Water Res 12: 31-3 (1978) (4) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982) (5) Keith LH et al; pp 329-73 in Ident Anal Organic Pollut Water Keith,LH ED Ann Arbor,MI Ann Arbor Press (1976) R73: USEPA; Chemical Hazard Information Profile Bis(2-chloro-1-methylethyl)ether (Draft) p.5 (1983) R74: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R75: 40 CFR 401.15 (7/1/88) R76: 40 CFR 302.4 (7/1/97) R77: 40 CFR 716.120 (7/1/97) R78: 40 CFR 261.33 (7/1/97) R79: 40 CFR 136 (7/1/88) R80: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R81: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R82: SATO K ET AL; J PESTIC SCI (NIHON NOYAKUGAKU KAISHI) 2 (2): 173-6 (1977) RS: 67 Record 60 of 1119 in HSDB (through 2003/06) AN: 505 UD: 200211 RD: Reviewed by SRP on 08/07/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALLYL-GLYCIDYL-ETHER- SY: *AGE-; *ALLIL-GLICIDIL-ETERE- (ITALIAN); *1-ALLILOSSI-2,3-EPOSSIPROPANO- (ITALIAN); *ALLYL-2,3-EPOXYPROPYL-ETHER-; *ALLYLGLYCIDAETHER- (GERMAN); *1-ALLYLOXY-2,3-EPOXY-PROPAAN- (DUTCH); *1-ALLYLOXY-2,3-EPOXYPROPANE-; *1-ALLYLOXY-2,3-EPOXYPROPAN- (GERMAN); *1,2-EPOXY-3-ALLYLOXYPROPANE-; *ETHER,-ALLYL-2,3-EPOXYPROPYL-; *GLYCIDYL-ALLYL-ETHER-; *NCI-C56666-; *OXIRANE, ((2-PROPENYLOXY)METHYL)-; *OXYDE-D'ALLYLE-ET-DE-GLYCIDYLE- (FRENCH); *PROPANE, 1-(ALLYLOXY)-2,3-EPOXY- RN: 106-92-3 MF: *C6-H10-O2 SHPN: UN 2219; Allyl glycidyl ether IMO 3.3; Allyl glycidyl ether MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... MANUFACTURED THROUGH THE CONDENSATION OF ALLYL ALCOHOL AND EPICHLOROHYDRIN WITH SUBSEQUENT DEHYDROCHLORINATION WITH CAUSTIC TO FORM THE EPOXY RING. [R1, 2197] MFS: +CPS Chemical Company, Inc, Hq, Old Waterworks Rd, Old Bridge, NJ 08857-9990, (201) 727-3100; Production site: West Memphis, AR 72301 [R2] OMIN: *IT IS NOT CLASSIFIED AS DANGEROUS ARTICLE AND IS NOT REGULATED BY THE BUREAU OF EXPLOSIVES. [R1, 2197] USE: *STABILIZER OF CHLORINATED COMPOUNDS, VINYL RESINS, RUBBER; RESIN INTERMEDIATE [R1, 2197] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R1, 2199]; +Colorless liquid ... [R3, 10] ODOR: *CHARACTERISTIC, NOT UNPLEASANT ODOR [R1, 2199]; +... Pleasant odor. [R3, 10] BP: *153.9 DEG C AT 760 MM HG [R1, 2199] MP: *FREEZING POINT: FORMS GLASS @ -100 DEG C [R1, 2199] MW: *114.06 DEN: *SP GR: 0.9698 AT 20 DEG C/40 DEG C [R1, 2199] SOL: *14.1% IN WATER; MISCIBLE WITH ACETONE, TOLUENE, AND OCTANE [R1, 2199] SPEC: *INDEX OF REFRACTION: 1.4348 @ 20 DEG C [R1, 2199]; *IR: 2:125C (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R4] VAPD: *3.32 @ 25 DEG C (AIR= 1) [R1, 2199] VAP: *4.7 MM HG AT 25 DEG C [R1, 2199] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R5] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R5] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R5] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R5] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R5] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R5] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R5] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R5] FLPT: *135 DEG F (OPEN CUP) [R1, 2199] REAC: +Strong oxidizers. [R3, 10] ODRT: *44 mg/cu m odor low; 44 mg/cu m odor high. [R6] SERI: *Skin and eye irritant. [R7] */Glycidyl ethers/ are primary skin and eye irritants. ... /Glycidyl ethers/ [R8] *Dermal contact is the usual mode of exposure, but droplets in mist can also attack the eyes and respiratory tract. Glycidyl and diglycidyl ethers tend to be irritants and sensitizing agents. /Glycidyl and diglycidyl ethers/ [R9] EQUP: *Workers should be provided with and required to use chemical protective clothing, gloves, face shields (8 inch minimum), and other appropriate protective clothing necessary to prevent skin contact with allyl glycidyl ether. ... Use splash-proof safety goggles where allyl glycidyl ether may come in contact with the eyes. [R10, 1981.3] +Wear appropriate personal protective clothing to prevent skin contact. [R3, 11] +Wear appropriate eye protection to prevent eye contact. [R3, 11] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R3, 11] +Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). Any powered, air-purifying respirator with organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any supplied-air respirator. Any self-contained breathing apparatus with a full facepiece. [R3, 11] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R3, 11] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R3, 11] OPRM: +Contact lenses should not be worn when working with this chemical. [R3, 11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Clothing which becomes contaminated with allyl glycidyl ether should removed immediately and placed in closed containers for storage until it can be discarded or until provision is made for removal of alllyl glycidyl ether from clothing. If the clothing is to be laundered or cleaned, the person performing the operation should be informed of allyl glycidyl ether's hazardous properties. [R10, 1981.] *Where there is any possibility of a worker's eyes being exposed to AGE, an eye-wash fountain should be provided within the immediate work area for emergency use. ... [R10, 1981.] *Where there is any possibility of a worker's body being exposed to AGE, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. ... [R10, 1981.] +The worker should immediately wash the skin when it becomes contaminated. [R3, 11] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R3, 11] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R11] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R12] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R13] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R14, 2002.14] HTOX: *SEVERAL CASES OF DERMATITIS AND 1 CASE OF EYE IRRITATION CONSTITUTE THE HUMAN DATA. [R15] *Allyl glycidyl ether is a CNS depressant and also causes acute pulmonary edema. It is classified as slightly toxic after oral administration and percutaneous application, appreciably irritating and injurious to the eyes and skin, capable of causing skin sensitization in human subjects ... . [R1, 2199] *Short-term (acute): Exposure to AGE can cause moderate irritation of the skin and severe irritation of the eyes and respiratory tract. Long-term (chronic): Exposure to AGE can cause dermatitis with itching, swelling, and blisters. Skin sensitization to AGE and cross sensitization with other epoxy agents can also occur. [R10, 1981.] *Dermal contact is the usual mode of exposure, but droplets in mist can also attack the eyes and respiratory tract. Glycidyl and diglycidyl ethers tend to be irritants and sensitizing agents. /Glycidyl and diglycidyl ethers/ [R9] NTOX: *... CLASSIFIED AS A MODERATE PRIMARY SKIN IRRITANT AND SEVERE EYE IRRITANT. ... SYSTEMIC TOXICITY TO RATS WAS OBSERVED AFTER 50 DAILY, 7 HOUR EXPOSURES AT 260, 400 AND 900 PPM, MANIFESTED BY INCREASED WEIGHT GAIN AT 260 PPM, AND HIGH MORTALITY AT 600 AND 900 PPM. [R15] *KIDNEYS OF ... /RATS/ EXPOSED TO 400 PPM /50 DAYS/ ... EXCESSIVE KIDNEY-BODY WT RATIOS. 260 PPM ... VERY SLIGHT IRRITATION OF EYES AND SLIGHT RESPIRATORY DISTRESS. AT HIGHER LEVELS CORNEAL OPACITIES ... AND SEVERE RESPIRATORY DIFFICULTIES. ... AUTOPSY SHOWED BRONCHOPNEUMONIA, EMPHYSEMA, BRONCHIECTASIS, PNEUMONITIS AND HEMORRHAGE. [R15] */AT LEVELS HIGHER THAN 260 PPM AUTOPSY OF RATS EXPOSED 50 DAYS REVEALED/ ... MOTTLED DISCOLORATION OF THE LIVER AND ENLARGED ADRENAL GLANDS. 2 ANIMALS EXPOSED TO 900 PPM HAD NECROTIC SPLEENS. ... PREDOMINANT TOXICOLOGIC ACTIVITY WAS DEPRESSION OF CNS AFTER INTRAGASTRIC ADMINISTRATION. [R15] *ADMIN TO MICE AND RATS ORALLY PRODUCED MODERATE DEPRESSION AND DYSPNEA WITHIN 15-19 MIN. DEATH OCCURRED IN 4 HR TO 5 DAYS. ... @ AUTOPSY HYPOTONICITY OF ENTERIC TRACT AND EXTENSIVE ADHESIONS OF STOMACH WALLS TO ADJACENT TISSUES WERE NOTED. NO CHARACTERISTIC MICROSCOPIC PATHOLOGY OCCURRED ... . [R1, 2199] */ADMIN TO RATS AND MICE ORALLY, DEATH IN 4 HR-5 DAYS/ ... AT AUTOPSY ... OCCASIONALLY THE LIVER SHOWED FOCAL AREAS OF NECROSIS. [R1, 2199] *PERCUTANEOUS ABSORPTION. DEPRESSION OCCURRED PROGRESSIVELY DURING THE 7 HR OF CONTACT. ... NECROPSY SHOWED CONSTRICTED KIDNEYS AND SPLEENS. [R1, 2199] *VAPOR EXPOSURES. ... MICE AND RATS SHOWED SEVERE IRRITATION OF THE EYES AND RESPIRATORY TRACT ACCOMPANIED BY LACRIMATION AND SALIVATION, DYSPNEA AND SEVERE GASPING AND GASEOUS DISTENTION OF THE ABDOMEN. ... CORNEAL OPACITIES OCCURRED IN RATS. [R1, 2199] *TESTICULAR ATROPHY AND HEMOPOIETIC ABNORMALITIES WERE OBSERVED IN LAB ANIMALS (RAT, RABBIT, DOG) AFTER EXPOSURE TO ALLYL GLYCIDYL ETHER. [R16] *MUTAGENICITY WAS EVALUATED BOTH WITH AND WITHOUT ADDITION OF RAT LIVER MICROSOMAL EXTRACT. ALLYL GLYCIDYL ETHER WAS MUTAGENIC IN TA100 STRAIN, CAUSING REVERSION OF BACTERIA TO HISTIDINE INDEPENDENCE. [R17] *Rat: 400 mg/kg im injections on days 1, 2, 8, and 9; animals sacrificed on day 12; focal necrosis of the testes in 1 of 2 of the 3 surviving rats, atrophy or loss of lymphoid tissue in 2 of 3 rats, decreased leukocyte count. [R18, 180] *Allyl glycidyl ether causes severe but reversible corneal damage when dropped on a rabbits eye. High vapor concentration produces corneal opacities in rats. [R19] *In mice and rats, acute inhalation or oral administration of AGE caused tearing, nasal discharge, dyspnea (breathing difficulty), ... and death (due to pulmonary edema and central nervous system depression); acute intramuscular injection in rats produced testicular degeneration and toxic effects on the hematopoietic (blood-cell-forming) systems, including decreased leukocyte counts and atrophy of lymphoid tissue. Subchronic inhalation AGE by rats caused central nervous system depression, reduction in weight gain, corneal opacity, pneumonia, emphysema, and enlarged adrenal glands. AGE was mutagenic in bacterial test systems ... [R10, 1981.] NTXV: *LD50 Rabbit percutaneous 2.55 g/kg; [R1, 2199] *LC50 Mouse inhalation 270 ppm/4 hours; [R15] *LC50 Rat inhalation 670 ppm/8 hr; [R15] *LD50 Mouse intragastric 0.39 g/kg; [R15] *LD50 Rat intragastric 1.60 g/kg; [R15] ETXV: *LD50 Goldfish 78 mg/l/24 hr /Conditions of bioassay not specified/; [R18, 179] *LD50 Goldfish 30 mg/l/96 hr /Conditions of bioassay not specified/; [R18, 179] NTP: +Toxicology and carcinogenesis studies were conducted by exposing groups of 50 Osborne-Mendel rats and B6C3F1 mice of each sex to allyl glycidyl ether (greater than 97% pure) by inhalation for 6 hr/day, 5 days/wk for ... 2 yr. ... Under the conditions of these 2 yr inhalation studies, there was equivocal evidence of carcinogenic activity of allyl glycidyl ether for male Osborne-Mendel rats, based on the presence of one papillary adenoma of respiratory epithelial origin, one squamous cell carcinoma of the respiratory epithelial origin, and one poorly differentiated adenocarcinoma of olfactory epithelial origin, all occurring in the nasal passage of males exposed to 10 ppb. There was no evidence of carcinogenic activity of allyl glycidyl ether for female rats. One papillary adenoma of the respiratory epithelium was present in a female rat exposed to 5 ppm. There was some evidence of carcinogenic activity of allyl glycidyl ether for male B6C3F1 mice based on the presence of three adenomas of the respiratory epithelium, dysplasia in four males, and focal basal cell hyperplasia of the respiratory epithelium in seven males in the nasal passage of mice exposed to 10 ppm. There was equivocal evidence of carcinogenic activity of allyl glycidyl ether for female mice, based on the presence of one adenoma of the respiratory epithelium and focal basal cell hyperplasia of the respiratory epithelium in seven females exposed to 10 ppm. The sensitivity of the assay to detect potential carcinogenicity may have been reduced in male rats because of poor survival in all groups. [R20] TCAT: ?The mutagenicity of allyl glycidyl ether (AGE) was evaluated in Salmonella tester strains TA98 and TA1535, both in the presence and absence of added metabolic activation by either Aroclor-induced or phenobarbitol-induced rat liver S9 fraction. AGE was tested for mutagenicity at concentrations of 0.5, 1.0 and 2.0 micromoles/plate using the plate incorporation method. AGE caused a positive response in tester strain 1535 at 2.0 micromoles/plate in the presence of metabolic activation by Aroclor-induced rat liver S9 fraction. [R21] ?The effect of allyl glycidyl ether was examined in the DNA repair assay. Human mononucleated white cells in G-0 phase were exposed to 1, 10, 100 or 500 ppm test article (dissolved in DMSO) for 5 hours. Exposure at any concentration did not statistically significantly (Duncan's LSD test, p > 0.05) increase the number of grains per nucleus counted on autoradiographs, or increase the intracellular incorporation of tritiated thymidine measured by liquid scintillation counting. In a preliminary range finding test, toxicity was reported at the upper dose levels used in the definitive test. [R22] ?The mutagenicity of allyl glycidyl ether (AGE) was evaluated in male B6D2F1 mice (at least 10) dermally exposed to GBE at a dose level of 1.5 g/kg three times/week for a minimum of 8 weeks. Following the treatment period, the male mice were mated with 3 untreated, virgin female B6D2F1f mice for one week and mated with 3 fresh females for a second week. Significant differences were observed between treated and control mice in the following: proportion of deaths/pregnancy (decreased throughout the study). Significant differences were observed between treated mice over time in the following: number of implants/pregnancy (decreased versus controls in 1st week post-treatment, decreased versus controls in 2nd week post-treatment). There were no differences between treated and control mice or in treated mice over time with respect to percent pregnancy. [R21] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +50 ppm [R3, 10] OSHA: +Permissible Exposure Limit: Table Z-1 Ceiling value: 10 ppm (45 mg/cu m). [R23] +Vacated 1989 OSHA PEL TWA 5 ppm (22 mg/cu m); STEL 10 ppm (44 mg/cu m) is still enforced in some states. [R3, 359] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 ppm (22 mg/cu m). [R3, 10] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 10 ppm (44 mg/cu m). Skin. [R3, 10] TLV: +8 hr Time Weighted Avg (TWA): 1 ppm. [R14, 2002.14] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R14, 2002.6] +A4; Not classifiable as a human carcinogen. [R14, 2002.14] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Oxirane, ((2-propenyloxy)methyl)- is included on this list. [R24] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R25] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method S346. Analyte: Allyl glycidyl ether. Matrix: Air. Procedure: Adsorption on Tenax-GC. Flow Rate: 0.2 l/min. Sample Size: 3 liters. [R26] ALAB: *SAMPLING AND ANALYTICAL METHODS WERE DEVELOPED FOR 130 SUBSTANCES INCLUDING ALLYL GLYCIDYL ETHER. [R27] *THE HYDROCHLORIC ACID-DIOXANE METHOD FOR EPOXY GROUPS OR GLC IS SUGGESTED FOR DETERMINATION IN ATMOSPHERE. [R1, 2199] *PHOTOMETRIC DETERMINATION OF ALLYL GLYCIDYL ETHER IN AIR. SENSITIVITY IS 1-5 MG/5 ML OF AIR. [R28] *NIOSH Method S346. Analyte: Allyl glycidyl ether. Matrix: Air. Procedure: Gas chromatography flame ionization detection. Method Evaluation: Method was validated over the range of 19 to 87 mg/cu m using a 3 liter sample. Precision (CVt): 0.057. [R26] *Solid sorbent sampling and chromatographic determination of glycidyl ethers in air. [R29] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Allyl glycidyl ether in Osborne-Mendel Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 376 (1990) NIH Publication No. 90-2831 SO: R1: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 448 R3: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R4: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 56 R5: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-129 R6: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R7: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 40 R8: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 787 R9: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-411 R10: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R11: 49 CFR 171.2 (7/1/96) R12: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 94 R13: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3116-2 (1988) R14: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R15: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.20 R16: LANE JM; VET HUM TOXICOL 22 (2): 99 (1980) R17: WADE MJ ET AL; MUTAT RES 66 (4): 367 (1979) R18: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R19: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 70 R20: DHHS/NTP; Toxicology and Carcinogenesis Studies of Allyl Glycidyl Ether in F344/N Rats and B6C3F1 Mice Technical Report Series No. 376 (1990) NIH Publication No. 90-2831 R21: University of Texas Medical Branch; Final Report on the Epoxides Evaluated for Mutagenicity. (1977), EPA Document No. 878211534, Fiche No. OTS0206138 R22: University of Texas Medical Branch at Galveston; Report to the Dow Chemical Company Integrated Mutagenicity Testing Program (1977), EPA Document No. 878211534, Fiche No. OTS0206138 R23: 29 CFR 1910.1000 (7/1/98) R24: 40 CFR 716.120 (7/1/90) R25: 40 CFR 712.30 (7/1/90) R26: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V4 S346 R27: TEN NIOSH ANALYTICAL METHODS, SET 2. US NTIS, PB REPL ISS PB-271464 316 (1977) R28: EREMYAN EV, DAVTYAN KA; ARM KHIM ZH 30 (1): 50 (1977) R29: Levin JO et al; J Chromatogr 454: 121-8 (1988) RS: 26 Record 61 of 1119 in HSDB (through 2003/06) AN: 511 UD: 200302 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ASBESTOS- SY: +ASBESTOS-DUST-; +ASBESTOSE- (GERMAN); +ASBESTOS-FIBER-; +ASBESTOS-FIBRE-; +ASCARITE- RN: 1332-21-4 RELT: 2957 [AMOSITE] (Mixture Component); 2966 [CHRYSOTILE ASBESTOS] (Mixture Component); 4212 [TREMOLITE ASBESTOS] (Mixture Component) MF: +UVCB ASCH: Anthophyllite; 17068-78-9; Actinolite; 13768-00-8; Crocidolite; 12001-28-4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +The mineral is mined or quarried with its parent rock. [R1, 186] +Imbedded asbestos fibers are removed from the ore by a repeated series of crushing, fiberizing, screening, aspirating, and grading operations (milling). ... The ore is crushed, dried, and fiberized in a variety of impact mills. The short fiber and granular material is removed by screening the fiberized mass. The oversized fractions are stratified on a screen where the spherical, granular material of high density seeks the screen's surface and the fluffy, low-density fiber rises to the top of the bed. At the end of the screen, the fiber is separated from the rock by an aspirating hood. ... Fibers recovered from these primary screening operations are rescreened to removed entrapped granular material and classified into grades by fiber length. ... Conventional asbestos milling uses large quantities of air both for separating the fibers as they are freed from the ore and for dust control. Approx 130 cu m/sec (275,000 cfm) are used to process one metric ton of ore. Preconcentration of ore includes selective grinding, screening, and magnetic techniques. [R2, p. 3(78) 279] +Treatment of asbestos: Wet processing /is where/ asbestos is separated from heavier rock through a series of flotation devices. It is then collected between pillow filters, extruded and dried in pellet form, or it is fluff-dried and packaged as loose fibrous material. [R3] IMP: +... During preparation of the fiber by the separation of the bundles, contamination by oils and other substances can readily occur. Virgin asbestos may also contain small amounts of oils and waxes. Trace amounts of a number of metals, including nickel, chromium, cobalt and manganese are present in many samples. [R1, 186] +Samples of commercially used asbestos, especially chrysotile, are frequently contaminated by small amounts of other fibrous minerals. Among these are tremolite and brucite. [R4] +Trace metals (beryllium, cadmium, chromium, cobalt, copper, ... manganese, nickel, and thallium) may be present as natural impurities in asbestos. [R5] FORM: +Typical chemical compositions of amphibole asbestos: silicon dioxide, 49-53%; magnesium oxide, 0-3%; ferrous oxide, 13-20%; ferric oxide, 17-20%; aluminum oxide, 0 to 0.2%; calcium oxide, 0.3-2.7%; potassium oxide, 0 to 0.4%; sodium oxide, 4 to 8.5%; and water, 2.5-4.5%. /Crocidolite/ [R2, p. 3(78) 277] +Typical chemical compositions of amphibole asbestos: silicon oxide, 56-58%; magnesium oxide, 28-34%; ferrous oxide, 3-12%; aluminum oxide, 0.5-1.5%; and water, 1-6%. /Anthophyllite/ [R2, p. 3(78) 277] +Typical chemical compositions of amphibole asbestos: silicon oxide, 51-52%; magnesium oxide, 15-20%; ferrous oxide, 5-15%; ferric oxide, 0-3%; aluminum oxide, 1.5 to 3%; calcium oxide, 10-12%; potassium oxide, 0 to 0.5%; sodium oxide, 0.5-1.5%; and water, 1.5-2.5%. /Actinolite/ [R2, p. 3(78) 277] MFS: +International Commodities Export Corp, 707 Westchester Ave, White Plains, NY 10604, (914) 683-8300 [R6] OMIN: +Asbestos is a generic term describing a variety of naturally formed hydrated silicates that, upon mechanical processing, separate into mineral fibers. There are two fundamental varieties of asbestos: serpentine and the amphiboles. Serpentine asbestos is known as chrysotile and the amphiboles include five species identified as anthophyllite, amosite, crocidolite, actinolite, and tremolite. Each of these varieties of asbestos differ from each other chemically. [R2, p. 3(78) 267] +Asbestos fibers are unique minerals combining unusual physical and chemical properties which make them useful in the manufacture of a wide variety of residential and industrial products. Historical records show that asbestos has been known for more than 2000 years. ... The asbestos industry per se had its inception in the 18th century in the Russian Ural mountains and by the mid 19th century ... asbestos was discovered and mined on a commercial scale at Thetford Asbestos in Quebec, Canada. ... The amphibole asbestos industry is of more recent origin. [R2, p. 3(78) 267] +Blue asbestos (crocidolite) was discovered in South Africa about 1803 to 1806, but not until 1893 ... was this variety commercially exploited. /Crocidolite/ [R2, p. 3(78) 267] +Chrysotile, amosite, and crocidolite are the asbestos species of major commercial significance. [R2, p. 3(78) 267] +Tremolite and actinolite are of little commercial value, but may be mixed with true talc (an amorphous magnesium silicate) to make commercial talc. Cosmetic talcs are in general free of fibrous silicates. /Actinolite/ [R1, 185] +What visually appears to be a single fiber in commercial grades of asbestos is in actually a bundle of a larger number of individual fibrils. These bundles can be subdivided into a multitude of finer bundles, but only with special processing can a large portion of fiber mass be divided to its ultimate fibril diameter. The surface areas of commercial asbestos fibers vary with the extent of mechanical defibrillation. [R2, p. 3(78) 273] +The term harshness in the asbestos industry refers to the fiber's brittleness, flexibility, form, and modulus of elasticity. ... These differing physical characteristics account for the different operating characteristics exhibited in the manufacture of various asbestos containing products. [R2, p. 3(78) 273] +Crocidolite ... /is/ produced in significant quantities only in South Africa. Main producing areas are at Bosrand, Cornheim, Ouplaas, Owendale, the Kuruman area in the Cape Province, and the Lyndenburg District in the Transvaal. Prodn statistics vary widely with the source of information. In 1976, 178 metric tons were produced in South Africa. /Crocidolite/ [R2, p. 3(78) 280] +The main prodn of /anthophyllite/ was in the Paakkila area of north East Finland where it has been mined since 1918. Mining has now ceased. /Anthophyllite/ [R1, 186] +The major properties of concern are length, granular content, degree of openness or effective surface area, drainage or filtration rate, color, absorption, electrical resistivity, bulk density, and strength giving properties. [R2, p. 3(78) 280] +Materials which may serve as asbestos substitutes are: 1) polypropylene: reinforcement of cement; 2) glass: reinforcement of cement, friction materials; 3) carbon: friction materials; 4) steel: friction materials; 5) mineral wool: insulation board; 6) vermiculite: fire protection, friction materials; 7) silicon nitride: friction materials; 8) ceramic paper: dental castings; 9) alumina and zirconia: high temperature insulation, filtration. /Data derived from table/ [R7] +Asbestos is a generic term which is divided into serpentine asbestos (chrysotile, white asbestos) and amphilboles: actinolite, amosite (brown), anthophyllite, crocidolite (blue), and tremolite. [R8] +THE US NAVY TESTED SHIPBOARD TRANSFORMERS, ONE WITH ASBESTOS AND ONE WITHOUT. AMONG THE TESTS CONDUCTED, THE TRANSFORMER CONTAINING ASBESTOS SURPASSED ALL OTHERS BY 300 DEG F IN THE DETERMINATION OF FAILURE TEMPERATURE ON VARIOUS OVERLOADS. ALSO, AIR EMISSION TESTS DEMONSTRATED THAT LITTLE, IF ANY, ASBESTOS FIBER WAS EMITTED DURING ACTUAL OPERATING CONDITIONS [R9] +A NEOPRENE SPRAY PROCESS WAS DEVELOPED FOR COATING ASBESTOS FIBERS TO PREVENT THEIR ESCAPE FROM CONSTRUCTION COMPONENTS USED IN BUILDING INTERIORS [R9] +A promising substitute for asbestos for cement reinforcement is glass fiber made from slate and limestone. [R10] +Asbestos is commercially mined and milled in ... states of California, Arizona, and Vermont. [R11] +The Consumer Product Safety Commission has banned general use garments containing asbestos. The use of asbestos in special garments such as fire fighting suits is permitted, ... only if they are constructed so that asbestos fibers will not become airborne under normal conditions of use. [R12] +In Beshada vs Johns-Manville Products Corp, the Supreme Court of New Jersey held that a state of art defense is unavailable in cases brought under a theory of strict liability for failure to warn. The court indicated that asbestos producers may be held liable for their products' harm even if the health hazards of asbestos were unknown and not discoverable when the products were /sold/. [R13] +The material from the separating mill was largely unopened bundles of fibers. For many purposes it was necessary to open the fiber by separating the bundles into their constituent fibers, which greatly increases the bulk of the material. [R1, 186] +Magnesium ... which occurs naturally in asbestos ... contributes to the surface charge of the asbestos fibers. [R5] +... Parenteral drugs may be contaminated during their manufacture if asbestos is used as a filtration medium. [R14] +ASBESTOS CONTENT OF PRODUCT IS NOT NECESSARILY INDICATION OF ITS RELATIVE HEALTH RISK, FOR IN MANY PRODUCTS FIBERS ARE TIGHTLY BOUND TO MATRIX OR ENCAPSULATED. POTENTIAL HEALTH RISK ARISES WHEN ASBESTOS FIBERS ARE SET FREE, EG, DURING DRILLING OR SAWING OF ASBESTOS CEMENT SHEETS. /ASBESTOS PRODUCTS/ [R15] USE: +The largest use of asbestos is in asbestos cement for products such as pipes, ducts, and flat and corrugated sheets. Pipe products find use in water supply, sewage disposal, and irrigation systems. Asbestos cement sheets are used in a wide variety of construction applications. Other uses of asbestos include fire resistant textiles, friction materials (ie, brake linings), underlayment and roofing papers, and floor tiles. [R2, p. 3(78) 280] +Crocidolite can be spun and woven using modified cotton industry machinery; the asbestos cloth is used for fireproof clothing and curtains. [R1, 187] +INERT FILLER MEDIUM (LAB AND COMMERCIAL) [R16] +REINFORCING MATERIAL IN VINYL AND ASPHALT FLOORING PRODUCTS /FORMER USE/ [R17] +REINFORCING PIGMENT IN SURFACE COATINGS AND SEALANTS [R17] +REINFORCING FILLER IN ELASTOMERS FOR PACKING AND GASKETS [R17] +FIRE AND ROT RESISTING MATERIAL IN FELTS (EG, FOR ROOFING) [R17] +RAW MATERIAL FOR ASBESTOS BASED PAPER [R17] +COMPONENT OF TEXTILES (EG, FOR USE IN FIREPROOF CLOTHING) [R17] +THERMAL AND ELECTRICAL INSULATION MEDIUM [R17] +COMPONENT OF INDUSTRIAL TALCS [R17] +FILLER IN INDUSTRIAL GREASES [R17] +COMPONENT OF TAPING CMPD [R17] +HEAT RESISTING ADDITIVE TO METALS (EG, FOR SPACECRAFT) [R17] +Selected asbestos products and their end uses: Valve, flange, and pump components; clutch/transmission components; industrial friction components; automotive/truck body coatings; electronic motor components; chemical process piping; water supply piping; conduits for electric wire; commercial/industrial dryer felts; theater curtains and fireproof draperies; gas vapor ducts for corrosive compounds; table pads and heat protective mats; molten glass handling equipment; underlayment for sheet flooring; hoods, vents for corrosive chemicals; chemical tanks and vessel manufacturing; portable construction buildings; electrical switchboards and components; laboratory furniture; and cooling tower components. /Data derived from table/ [R18] +About 98% of the crocidolite is used in the production of asbestos cement pipe, because of its hardness, brittleness, and high tensile strength, which add to the ridigity of the end product, and its superior filtration qualities, which enhance the drainage of water, permitting cement to dry more rapidly. ... A very large proportion of total asbestos use is accounted for by shorter length fibers. ... /Crocidolite/ [R19] +Former use: Spraying of asbestos fibre mixed with cement and other binders started in about 1935 and was 1st used for insulation of railway carriages. Later it was used in greatly increased amounts for fire protection and insulation in naval ships and in storage buildings. After the Second World War its use was ... expanded for encasing structural steel in buildings to prevent rapid bending in the event of fire. ... in the late 1960s when the extent of hazards from this use of asbestos became apparent spraying decreased and is now banned in many countries. [R1, 187] CPAT: +COMPONENT OF FRICTION MATERIALS, 21%; REINFORCING MATERIAL IN FLOORING PRODUCTS, 20%; REINFORCING MATERIAL IN CEMENT FOR PIPES, 15%; FOR SHEETS, 4%; REINFORCING PIGMENT IN SURFACE COATINGS AND SEALANTS, 10%; REINFORCING FILLER IN ELASTOMERS FOR PACKING AND GASKETS, 6%; FIRE AND ROT RESISTING MATERIAL IN FELTS, 3%; RAW MATERIAL FOR ASBESTOS-BASED PAPER, 1%; OTHER USES, 20% (1983) [R17] +(1973): Construction materials: 30%; floor tiles: 21%; friction products: 8%; paper: 10% asphalt felts: 5%; packing and gaskets: 3%; insulation: 1.5%; textiles: 1.5%; others: 20%. [R20] +(1975) 550,900 metric tons [R21] +Between 1974 and 1975 asbestos consumption declined 27% from 856,000 to 629,000 tons. [R22] +Replacement of asbestos by other materials believed to be safer has been widespread since the mid 1970s. Man-made mineral fibers and other insulating materials are rapidly replacing asbestos for heat insulation. But for other uses ... /such as/ asbestos cement, friction materials and some felts and gaskets, substitution is not ... /yet/ practicable. [R1, 190] +Friction products, 22%; asbestos cement pipe, 18%; coatings and compounds, 15%; packing and gaskets, 9%; asbestos cement sheet, 8%; and other, 28% (1986) [R23] +FRICTION PRODUCTS, 22%; FLOORING PRODUCTS, 21%; ASBESTOS CEMENT PIPE, 16%; COATINGS AND COMPOUNDS, 10%; PACKING AND GASKETS, 6%; ASBESTOS CEMENT SHEET, 5%; ROOFING PRODUCTS, 3%; PAPER AND TEXTILES, 1%; AND OTHER, 16% (1985) /FOR ASBESTOS/ [R24] +(1988) Asbestos was consumed in roofing products, 28%; friction products, 26%; asbestos cement pipe, 14%; packing and gaskets, 13%; paper, 6%; and other 13%. [R25] PRIE: U.S. PRODUCTION: +(1977) 9.26X10+10 G [R17] +(1982) 6.36X10+10 G [R17] +(1985) 5.7X10+4 metric tons [R25] +(1986) 5.1X10+4 metric tons [R25] +(1987) 5.1X10+4 metric tons [R25] U.S. IMPORTS: +(1977) 5.51X10+11 G [R17] +(1982) 2.42X10+11 G [R17] +In 1974, 96.5% of the asbestos imported ... was from Canada. [R26] +(1985) 1.42X10+5 metric tons [R25] +(1986) 1.08X10+5 metric tons [R25] +(1987) 9.4X10+4 metric tons [R25] U.S. EXPORTS: +(1977) 3.45X10+10 G [R17] +(1982) 5.90X10+10 G [R17] +(1985) 4.6X10+4 metric tons [R25] +(1986) 4.7X10+4 metric tons [R25] +(1987) 6.0X10+4 metric tons [R25] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +FINE, SLENDER, FLAXY FIBERS [R27]; +White or greenish (chrysotile), blue (crocidolite), or gray-green (amosite) fibrous ... solids. [R28, 22] ODOR: +... Odorless ... [R28, 22] OCPP: +Of mineral origin, asbestos does not burn, does not rot, and , dependent on the variety, possesses extremely high tensile strength as well as resistance to acids, bases, and heat. Similarly, when processed into long, thin fibers, asbestos is sufficiently soft and flexible to be woven into fire resistant fabrics. [R2, p. 3(78) 267] +Chemical composition, 7MgO.8SiO2.H2O /Anthophyllite/ [R2, p. 3(78) 267] +Chemical composition, 2CaO.4MgO.FeO.8SiO2.H2O /Actinolite/ [R2, p. 3(78) 267] +Chemical composition, Na2O.Fe2O3.3FeO.8SiO2.H2O /Crocidolite/ [R2, p. 3(78) 267] +Tensile strength of the asbestos fiber is an important and highly significant physical property. The tensile strength values for the different asbestos varieties should be considered as relative for the different variety rather than specific, since all these measured values are far less than the theoretical value of over 10,000 MPa (1.45X10+6 psi) attributable to silicate chain structures. Physical strengths of asbestos are adversely affected by elevated temperatures. [R2, p. 3(78) 273] +The typical tensile strengths of asbestos fibers have the order: crocidolite > chrysotile > amosite > anthophyllite > tremolite > actinolite [R2, p. 3(78) 278] +Commercial amphiboles are harsh fibers. They are relatively stiff, brittle, and coarser in diameter than crysotile, and rodlike in appearance under the microscope. /Amphiboles/ [R2, p. 3(78) 276] +The structure of all the amphiboles consists of two chains or ribbons based on SiO4O11 units separated by a band of cations. Seven cations form the basal unit. Two hydroxyl groups are attached to the central cation in each unit cell. These hydroxyls ... are contained entirely within the amphibole structure. The final structure is composed of stacks of these sandwich ribbons. The bonding between these ribbons is rather weak and the crystals are easily cleaved parallel to the ribbons ... If the cleavage is very facile, the result is an asbestiform mineral. /Amphiboles/ [R2, p. 3(78) 276] +... The amphibole asbestos fibers dehydroxylate and decompose at elevated temperatures. The presence of large quantities of iron (particularly ferrous iron) makes the decomposition or thermal analysis determinations particularly complex and very dependent on the composition of the atmosphere. ... Compared to crysotile, the amphibole fibers are relatively acid resistant. However, under boiling conditions and high acid concn the amphiboles can exhibit wt losses of approx 2-20%. ... Amphiboles fibers have a negative charge ... The magnitude of the charge exhibited by the amphiboles is substantially lower than chrysotile's. /Amphiboles/ [R2, p. 3(78) 277] +Relative order of acid resistance is: tremolite > anthophyllite > crocidolite > actinolite > amosite > chrysotile. [R2, p. 3(78) 278] +Amphibole fibers do not divide into fibrils as fine in diameter or as symmetrical as the chrysotile variety. Ultimate diameter of amphiboles have been reported to be about 0.1 um and the surface areas of amphibole asbestos are considerably smaller than chrysotile. /Amphiboles/ [R2, p. 3(78) 278] +Fully fiberized commercial grades of crocidolite have surface areas by gas adsorption of 3-15 sq m/g. /Crocidolite/ [R2, p. 3(78) 278] +Structure: lamellar, fibrous asbestiform; mineral association: in crystalline schists and gneisses; origin: metamorphic, usually from olivine; veining: slip, mass fiber unoriented and interlacing; essential composition: magnesium silicate with iron; crystal structure: prismatic, lamellar to fibrous; crystal system: orthorhombic; color: gray white, brown, gray, or green; luster: viterous to pearly; Mohs hardness: 5.5-6.0; specific gravity: 2.85-3.1; cleavage: 110%; optical properties: biaxial positive extinction parallel; index of refraction: about 1.61; Seger cones fusibility: infusible or difficult to fuse; flexibility: very brittle, nonflexible; length: short; texture: harsh; acid resistance: fairly resistant to acids; spinnability: poor; specific heat: 879 J/kg deg K or 0.210 Btu/lb deg F. /Anthophyllite/ [R2, p. 3(78) 274] +Structure: fibrous in iron stones; mineral association: in iron rich silicious argillite in quartzose schists; origin: regional metamorphism; veining: cross fiber; essential composition: silicate of sodium and iron water; crystal structure: fibrous; crystal system: monoclinic; color: lavender, blue; luster: silky to dull; Mohs hardness: 4; specific gravity: 3.2-3.3; cleavage: 110%; optical properties: biaxial extinction inclined; index of refraction: 1.7 pleochroic; Seger cones fusibility: fusible at 3, 1145-1170 deg C; flexibility: fair to good; length: short to long; texture: soft to harsh; acid resistance: fairly resistant to acids; spinnability: fair; specific heat: 841 J/kg deg K or 0.201 Btu/lb deg F. /Crocidolite/ [R2, p. 3(78) 274] +Structure: reticulated long prismatic crystals and fibers; mineral association: in limestone and in crystalline schists; origin: results of contact metamorphism; veining: slip or mass fiber; essential composition: calcium, magnesium, and iron silicates, water up to 5%; crystal structure: long and thin columnar to fibrous; crystal system: monoclinic; color: green; luster: silky; Mohs hardness: about 6; specific gravity: 3.0-3.2; cleavage: 110%; optical properties: biaxial negative extinction inclined; index of refraction: 1.63 weakly pleochroic; Seger cones fusibility: fusible at 4, 1165-1190 deg C; flexibility: brittle and nonflexible; length: short to long; texture: harsh; acid resistance: relatively insol in hydrochloric acid; spinnability: poor; specific heat: 908 J/kg deg K or 0.217 Btu/lb deg F. /Actinolite/ [R2, p. 3(78) 274] +Asbestos minerals, despite a relatively high fusion temperature, are completely decomposed at temperatures of 1000 deg C. Both the dehydroxylation temperature and decompostion temperature increase with increased magnesium oxide content among the various amphibole species. ... Most materials have a negative surface charge in aqueous systems. However, since chrysotile has a positive charge, it will attract, or be attracted to, most dispersed materials. The highly reactive surface of asbestos causes many surface reactions which are intermediate between simple absorption and a true chemical reaction. The absorption of various materials on the surface of chrysotile has a greater affinity for polar molecules (eg water, ammonia) than for non-polar molecules. [R29] +Amphiboles can ... occur in nonfibrous forms which may result because of structural disorder. The dominant cations are magnesium, ferrous, ferric, sodium, and calcium. Minor isomorphic substitutions of aluminum, titanium, potassium, and lithium also occur. Because of the wide compositional range, the amphiboles are often assigned to three generic series; ie, the anthophyllite cummingtonite series, the calcic amphiboles and the soda amphiboles. /Amphiboles/ [R2, p. 3(78) 276] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Some may burn but none ignite readily. Those substance designated with a "P" may polymerize explosively when heated or involved in a fire. Containers may explode when heated. Some may be transported hot. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +Health: Inhalation of material may be harmful. Contact may cause burns to skin and eyes. Inhalation of asbestos dust may have a damaging effect on the lungs. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control may cause pollution. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +Evacuation: Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +Fire: Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Do not scatter spilled material with high pressure water streams. Dike fire-control water for later disposal. Fire involving tanks: Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from engulfed in fire tanks. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +Spill or leak: Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent dust cloud. Avoid inhalation of asbestos dust. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Small spills: Take up with sand or other noncombustible absorbent material and place into containers for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Cover powder spill with plastic sheet or tarp to minimize spreading. Prevent entry into waterways, sewers, basements or confined areas. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Asbestos; Asbestos, blue; Asbestos, brown; Asbestos, white/ [R30] FIRP: +If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire (material itself does not burn or burns with difficulty). /Asbestos articles, not elsewhere classified; asbestos crude; asbestos scrap/ [R31] DCMP: +Asbestos minerals, despite a relatively high fusion temperature, are completely decomposed at temperatures of 1,000 deg C. [R32] +The resistance of the asbestos fibers to attack by reagents other than acid as excellent up to temperatures of approximately 100 deg C with rapid deterioration observed at higher temperatures. [R33] EQUP: +Basic protection ... coveralls ... made of cotton polyester material. Cotton alone cannot be used because static build-up causes fibers to adhere to cloth. ... Provide head covering /such as/ surgical caps. [R34] +Foot coverings, /such as/ canvas booties, rubber galoshes, or safety shoes /should be used/. [R34] +Respirators may always be necessary during the cleaning or repair of exhaust ductwork or during manual shakedown of collection bags in baghouses. ... This form of protection may be the only feasible method of controlling asbestos exposure during the removal of thermal insulation or the application of some asbestos products. ... The type of respirator needed ... powered versus man powered will be indicated by the concn of airborne asbestos fiber. ... Respirators require proper fitting, maintenance, and cleaning to be effective. [R35] +PRECAUTIONS FOR "CARCINOGENS": ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R36, 1979.8] +For airborne concentration of asbestos, tremolite, anthophyllite, actinolite, or a combination of these minerals not in excess of 2 fibers/cc, a half-mask air-purifying respirator, other than a disposable respirator, equipped with high efficiency filters is required. [R37] +For airborne concentration of asbestos, tremolite, anthophyllite, actinolite, or a combination of these minerals not in excess of 10 fibers/cc, a full facepiece air-purifying respirator equipped with high efficiency filters is required. [R37] +For airborne concentration of asbestos, tremolite, anthophyllite, actinolite, or a combination of these minerals not in excess of 20 fibers/cc, any powered air-purifying respirator equipped with high efficiency filters and any supplied air respirator operated in continuous flow mode is required. [R37] +For airborne concentration of asbestos, tremolite, anthophyllite, actinolite, or a combination of these minerals not in excess of 200 fibers/cc, full facepiece supplied air respirator operated in pressure demand mode is required. [R38] +For airborne concentration of asbestos, tremolite, anthophyllite, actinolite, or a combination of these minerals greater than 200 fibers/cc, full facepiece supplied air respirator operated in pressure demand mode equipped with an auxiliary positive pressure self-contained breathing apparatus. [R38] +If an employee is exposed to asbestos, tremolite, anthophyllite, actinolite, or a combination of these materials above the permissible exposure limit, or where the possibility of eye irritation exists, ... /the employee shall use:/ coveralls or similar full body work clothing; gloves, head coverings, and foot coverings; and face shields, vented goggles, or other appropriate protective equipment. [R38] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R28, 23] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R28, 23] +Wear appropriate personal protective clothing to prevent skin contact. [R28, 23] +Wear appropriate eye protection to prevent eye contact. [R28, 23] OPRM: +Reduction of asbestos dust exposure is at present the only known method of preventing disease among asbestos industry workmen. [R2, p. 3(78) 281] +Prevention of dust prodn and its effective control at the site of prodn is the basis of technical control. Once the dust is airborne in the general atmosphere, its elimination and control become expensive and relatively ineffective. Thus, successful technical control starts with enclosing machines and applying local exhaust ventilation at points where the equipment has to be opened, for example where bags of fiber are fed into mixers or the fiber comes out of the machine at the bagging end of the mills. Damping of the fiber before mixing with other products and during spinning and weaving can greatly assist the elimination of dust prodn. ... Exhaust ventilation is required where asbestos-containing products are ground, sawn, drilled, or turned, and the cleaning up should be done by vacuum cleaners rather than brushes. [R1, 187] +In many circumstances, such as removing old insulation and spraying new material personal protection is essential. A well fitting dust mask may be adequate for some jobs where esposure is intermittent; where longer exposures occur in conditions where dust control is inadequate, such as the removal of old insulation in large amounts, full respiratory protective equipment should be used. It is now common practice to require complete isolation of the area where old insulation is being removed to protect those in the vicinity. [R1, 187] +... Asbestos dust in clothing has been shown to be a possible hazard, a change of clothing at the job should be provided and its use made obligatory. Laundering of the clothing will be needed. [R1, 187] +Pollution control technology in Canadian asbestos mines and mills ... the industry has taken several steps to improve worker safety ... the amount of airborne dust in the workplace has been reduced by: 1) wet processing of fibers during textile manufacture, and 2) encapsulation of the yarn by chemical dispersing agents which inhibited small asbestos fibrils from breaking away. [R39] +Sealants /are now available/ which help prevent the release of asbestos from surfaces which are flaking. [R40] +Adequate exhaust ventilation, with negative pressure ... should be provided to remove airborne fibers. [R41] +... A strong corporate /policy/ should be established against the practice of eating, drinking, or smoking on the job. These activities should be restricted to a designated, clean location visited only after established decontamination procedures have been followed. [R42] +Do not wear work clothing outside the work area ... this will curtail exposure of other individuals. Use a vacuum to remove asbestos fibers from work clothing. [R34] +A survey of control technology for reducing asbestos exposure during bag opening, emptying, and disposal operations at General Motors Corporation, Inland Division, Vandalia, Ohio was conducted in November and December, 1983. Engineering controls consisted of using an automatic bag opening machine, isolation of the operation, and local exhaust ventilation to control emissions from the inlet and bottom of the machine, where asbestos was discharged into trash hoppers. Vacuuming was used to prevent the floors from becoming asbestos emission sources. Respirators were worn during all jobs that had a potential for asbestos exposure. The author notes that when bag opening, emptying, and disposal operations are proceeding normally, worker exposure is below 0.1 fibers/cc. Additional efforts may be required to reduce worker exposure while loading the conveyor. [R43] +Keep material out of water sources and sewers. /Asbestos articles, not elsewhere classfied; asbestos crude; asbestos scrap/ [R31] +PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R36, 1979.8] +PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R36, 1979.9] +PRECAUTIONS FOR "CARCINOGENS": Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R36, 1979.9] +PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R36, 1979.10] +PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R36, 1979.10] +PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R36, 1979.10] +PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R36, 1979.11] +Do not handle broken packages unless wearing appropriate personal protective equipment. /Asbestos articles, not elsewhere classified; Asbestos crude; asbestos scrap/ [R31] +Asbestos mortar, cement, or plaster mixed in dosed bags of other containers; that asbestos scrap waste be collected and disposed of in sealed bags; that clean up of asbestos dust be done by vacuum cleaners; that local exhaust and ventilation of power tools be provided; and that workers be given access to protective clothing and acceptable respirators. [R44] +Local exhaust ventilation and dust collection systems shall be designed, constructed, installed, and maintained in accordance with good practices such as those found in the American National Standard Fundamentals Governing Systems, ANSI 29.2-1979. [R37] +Employees who work in areas where their airborne exposure is above the permissible exposure limit /should/ shower at the end of the work shift. [R37] +Employees who work in areas where airborne exposure is above the permissible exposure limit /shall/ wash their hands and faces prior to eating, drinking, or smoking. [R37] +Employees /shall/ not enter lunchroom facilities with protective work clothing or equipment unless surface asbestos, tremolite, anthophyllite, and actinolite fibers have been removed from the clothing or equipment by vacuuming or other method that removes dust without causing the asbestos, tremolite, anthophyllite, or actinolite to become airborne. [R37] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +Contact lenses should not be worn when working with this chemical. [R28, 23] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should wash daily at the end of each work shift. [R28, 23] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R28, 23] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R45] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R46] STRG: +PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R36, 1979.13] CLUP: +TECHNIQUES ARE AVAILABLE TO MINIMIZE THE CONCN OF ASBESTOS FIBERS IN DRINKING WATER. FILTRATION RESEARCH CONDUCTED AT LOCATIONS ON LAKE SUPERIOR AND IN THE CASCADE MOUNTAINS IN WASHINGTON HAS SHOWN THAT AMPHIBOLE AND CHRYSOTILE FIBERS CAN BE REMOVED BY GRANULAR MEDIA FILTRATION. PILOT SCALE AND DISTRIBUTION SYSTEM RESEARCH PROJECTS HAVE SHOWN THAT ASBESTOS CEMENT (AC) PIPES CAN BE PROTECTED FROM DISSOLUTION AND LEACHING EFFECTS THAT CAN RESULT IN RELEASE OF ASBESTOS FIBERS INTO DRINKING WATER. SUGGESTED TECHNIQUES INCL MODIFYING LOW PH, LOW ALKALINITY WATER SO THEY ARE NOT AGGRESSIVE; COATING THE PIPE WALL WITH A CHEMICAL PRECIPITATE; AND APPLYING A CEMENT MORTAR LINING TO THE PIPE WALL. [R47] +PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R36, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. +Asbestos-containing wastes are disposed of by depositing them in dumps. To prevent the formation of dust, the waste should be moistened during loading and, on dry days, covered immediately after dumping. Recommendable method: Landfill. Peer-review: No one should handle fibrous or dusty asbestos waste without a suitable ... /NIOSH approved respirator/. Asbestos waste should be put into good quality plastic bags and sealed as it is produced. These bags should then be buried at the landfill without opening, and immediately covered with 1.5-2 m of non-asbestos waste. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R48] +Asbestos is a poor candidate for incineration. [R49] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. [R50] +CLASSIFICATION: A; human carcinogen. BASIS FOR CLASSIFICATION: Observation of increased mortality and incidence of lung cancer, mesotheliomas and gastrointestinal cancer in occupationally exposed workers are consistent across investigators and study populations. Animal studies by inhalation in two strains of rats showed similar findings for lung cancer and mesotheliomas. Animal evidence for carcinogenicity via ingestion is limited (male rats fed intermediate-range chrysotile fibers; i.e., greater than (> ) 10 um length, developed benign polyps), and epidemiologic data in this regard are inadequate. HUMAN CARCINOGENICITY DATA: Sufficient. ANIMAL CARCINOGENICITY DATA: Sufficient. [R51] +A1; Confirmed human carcinogen. /Asbestos, all forms/ [R52, 2002.16] MEDS: +Asbestos workers with clinical symptoms of hoarseness, or pain, or soreness of the throat should be referred to an ear, nose, and throat specialist for a detailed otolaryngologic examination of the upper respiratory tract /for detection of laryngeal cancer/. [R53] +Follow up medical examinations for asbestos exposed workers is /based on the following parameters/: Nonsmokers, ex-smokers and smokers who do not inhale: A) No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray, and sputum cytology; B) more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; C) 40 years old and older, at least 20 years from onset of asbestos exposure: Add fecal occult blood testing and an examination of the oral cavity every 6 months. Smokers who inhale: 1) Less than 15 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray and sputum cytology every 4 months. 2) 15-20 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 6 months; more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months. 3) More than 20 years from onset of asbestos exposure: Less than 40 years old a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; 40 years old and older: add fecal occult blood testing and an examination of the oral cavity every 6 months. [R54] +PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R36, 1979.23] HTOX: +The specific diseases associated with asbestos are: asbestosis (a form of fibrosis of the lung); cancers of the bronchi, pleura and peritoneum and probably other organs; and asbestos corns of the skin. All these, with the exception of corns, are due to the inhalation of asbestos fibers and consequently any process which gives rise to large amounts of asbestos dust may constitute a health hazard. [R1, 187] +SPICULES OF ASBESTOS EASILY PENETRATE THE SKIN, ESP THE FINGERS IN THOSE BAGGING THE FIBER. CHRONIC IRRITATION OF THE DERMIS OCCURS WITH THE FORMATION OF CORNS ... CANCERS OF THE SKIN ARE NOT PRODUCED. [R55, 122] +Asbestos corns on the fingers (areas of thickened skin surrounding implanted fibers) are now much less common because much of the asbestos fiber is packed mechanically and gloves are worn. Corns do not lead to skin tumors and disappear on removal of the fibers. [R1, 189] +Asbestosis is defined as a diffuse interstitial fibrosis of the lung, the result of exposure to asbestos dust. Neither the clinical features nor the pathology are sufficiently different from other causes of interstitial fibrosis to allow confident diagnosis without evidence of significant exposure to asbestos dust in the past, or the detection of asbestos fibers or bodies in the lung tissue greatly in excess of that commonly seen in the general population. ... Asbestosis is usually used to describe the parenchymal fibrosis but not that occurring in the parietal pleura. [R1, 188] +/Pathology of asbestosis/: The retained fibers in the alveolar region are 3 um or less in diameter but may be up to 200 um long. ... A portion of the longer fibers, esp amphiboles, become coated with an iron protein complex producing the drumstick appearance of asbestos bodies. All types of asbestos cause similar fibrosis. The fibrosis starts in the resp bronchioles with collections of macrophages containing fibers, and others lying free. These deposits organize, collagen replacing the initial reticulum web. Initially only a few resp bronchioles are affected, but the fibrosis spreads centrally to the terminal bronchioles and peripherally to the acinus. The areas increase in size and coalesce causing diffuse interstitial fibrosis with shrinkage. The process starts in the bases spreading upwards as the disease progresses; in advanced disease the whole lung structure is distorted and replaced by dense fibrosis, cysts, and some areas of emphysema. The pleura, both visceral and parietal surfaces, are affected by the fibrosis. ... The visceral surface may be sclerosed up to 1 cm thick. In the parietal pleura thickening starts as a basket-weave pattern of fibroblasts, the sheets of fibrosis lying along the line of the ribs esp in the lower thorax and posteriorly. The edges become rolled and crenated and, after many years, calcified. The parietal thickening may be extensive and thick with little or no parenchymal fibrosis. [R1, 188] +The signs and symptoms of asbestosis are similar to those caused by other diffuse interstitial fibroses of the lung. Increased breathlessness on exertion is usually the first symptom, sometimes assoc with aching or transiet sharp pains in the chest. A cough is not usually present except in the late stages when distressing paroxysms occur. Increased sputum is not present unless there is bronchitis, the result of smoking. The onset of symptoms (except following very heavy exposure) is usually slow and the subject may have forgotten having any contact with asbestos. Persistent dull chest pain and hemoptysis indicate the need to investigate further the diagnosis of bronchial or mesothelial cancer. The most important physical sign is the presence of high-pitched fine crepitations (crackles) at full inspiration and persisting after coughing. They occur initially in the lower axillae and extend more widely later. ... Clubbing of the fingers and toes was formerly regarded as an important physical sign. ... Its severity does not relate well to other aspects of the diagnosis. ... It is possible that its presence relates to the rapidity of progression of the disease. [R1, 188] +ALL TYPES OF ASBESTOS ARE KNOWN TO CAUSE INFLAMMATORY CHANGES IN LUNG AND PLEURAE ... AND LUNG CANCER. HOWEVER, THERE IS EXPTL AND EPIDEMIOLOGIC EVIDENCE THAT THERE MAY BE DIFFERENCES IN THE POTENTIAL OF DIFFERENT ASBESTOS TYPES TO PRODUCE DISEASE. ... IT HAS BEEN SUGGESTED THAT CROCIDOLITE HAS GREATEST POTENTIAL TO PRODUCE DISEASE; CHRYSOTILE, THE SMALLEST; WITH AMOSITE OCCUPYING AN INTERMEDIATE POSITION. [R56] +Numerous reports from several countries have described cases or series of pleural and peritoneal mesotheliomas in relation to occupational exposure to various types and mixtures of asbestos (including talc containing asbestos), although occupational exposures have not been identified in all cases. Mesotheliomas of the tunica vaginalis testis and of the pericardium have been reported in persons occupationally exposed to asbestos. ... In some of these case reports and in other studies, asbestos fibers were identified in the lung. Amphibole fibers usually predominated, but in a few cases mainly or only chrysotile fibers were found. The long latency required for mesotheliomas to develop after asbestos exposure has been documented in a number of publications. An increasing proportion of cases has been seen with increasing duration of exposure. [R50] +Environmental exposure either in the houses of asbestos workers or in the neighborhood of asbestos mines or factories has been noted in some of the cases. It has been est that a third of the mesotheliomas occurring in the USA may be due to nonoccupational exposure. In a study from Israel, the incidence of mesothelioma was found to be higher among those born in the USA or in Europe relative to those born in Israel. [R50] +A number of epidemiological studies of resp cancer and mesothelioma have been reported in relation to exposure to unspecified or complex mixtures of asbestos in shipyard work. The risk ratio for lung cancer has usually been moderately increased ... in these studies and in studies on various other occupational groups with similarly job-related but unspecified or complex asbestos exposures. Risk ratios of about 2-5 have been reported in some studies, but the ratio was considerably higher in one rather small study and did not exceed unity in another. In one study, individuals suffering from asbestosis had a considerably greater risk for lung cancer, with a risk ratio of 9.0. In some of the studies referred to, a number of mesotheliomas were also observed. Abdominal mesotheliomas have been mistaken for pancreatic cancer. Mesothelioma cases have been observed to have a relatively lower fiber content in the lung than lung cancer cases. [R50] +Laryngeal cancer has been considered in 2 case control studies, resulting in risk ratios of 2.4 and 2.3 that relate to shipyard work and unspecified exposure, respectively. A cohort study of insulation workers showed a relative risk of 1.9, based on 9 cases. A case series indicated a high frequency of exposure to asbestos, esp in low-grade smokers. ... Two correlation studies have also indicated a relationship between laryngeal cancer and exposure to asbestos. [R57, (1997)] +With regard to mesotheliomas, 1 study suggested a particularly high risk of combined exposure to chrysotile and amphiboles (risk ratio, 61), thus almost multiplying the risk ratios (6 and 12, respectively) of exposures to chrysotile and to amphibole alone. /Chrysotile and amphiboles/ [R57, (1987)] +Cancers other than the lung or mesothelioma have been observed in many studies. Some indicated an approx 2 fold risk with regard to GI cancer in connection with shipyard work, and some increased risk was also seen in assoc with exposure to both chrysotile and crocidolite, to crocidolite or to chrysotile. ... Bile-duct cancer appeared in excess in 1 study based on record-linking, and large-cell lymphomas of the GI tract and oral cavity appeared to be strongly related to asbestos exposure in 1 small study covering 28 cases and 28 controls, giving a risk ratio of 8; however, 10 cases and 1 control also had a history of malaria. An excess of lymphopoietic and hematopoietic malignancies has been reported in plumbers, pipe-fitters, sheet-metal workers and others with asbestos exposure. /Chrysotile and crocidolite/ [R58] +No clear excess of cancer has been associated with the presence of asbestos fibers in drinking water. [R58] +AT PRESENT, IT IS NOT POSSIBLE TO ASSESS WHETHER THERE IS A LEVEL OF EXPOSURE IN HUMANS BELOW WHICH AN INCREASED RISK OF CANCER WOULD NOT OCCUR. [R59] +FIVE TYPES OF ASBESTOS PLUS SILICA AND GLASS WOOL FIBERS WERE TESTED FOR THEIR ABILITY TO ACTIVATE ALTERNATIVE COMPLEMENT PATHWAY AND GENERATE CHEMOTACTIC FACTOR ACTIVITY FROM FRESH NORMAL HUMAN SERUM. ALL 5 OF THE ASBESTOS FIBERS TESTED (INCLUDING ANTHOPHYLLITE AND CROCIDOLITE) ACTIVATED THE ALTERNATIVE PATHWAY. IN ADDN IT WAS DEMONSTRATED THAT CHEMOTACTIC FACTOR ACTIVITY WAS GENERATED WHEN ASBESTOS FIBERS WERE INCUBATED WITH FRESH NORMAL HUMAN SERUM. THESE OBSERVATIONS SUGGEST THAT THE COMPLEMENT SYSTEM MAY MEDIATE THE INITIAL INFLAMMATORY RESPONSE OBSERVED UPON EXPOSURE TO CERTAIN TYPES OF ASBESTOS FIBERS. [R60] +METASTASES IN MULTIPLE DISTANT SITES, INCL THE SKIN, DEVELOPED IN A 54 YR OLD MAN WITH DIFFUSE MALIGNANT ABDOMINAL MESOTHELIOMA. THIS MIGHT REPRESENT THE FIRST REPORTED CASE OF CUTANEOUS METASTASIS ARISING FROM MALIGNANT MESOTHELIOMA. RECENT ADVANCES IN DIAGNOSTIC TECHNIQUES, SUCH AS ELECTRON MICROSCOPY, MAY BE HELPFUL IN DIFFERENTIATING THIS CONDITION FROM METASTATIC ADENOCARCINOMA. [R61] +ASBESTOS DUSTS (CHRYSOTILE AND CROCIDOLITE) CAUSED NO DOSE-RELATED INCR IN THE FREQUENCY OF SISTER CHROMATID EXCHANGE IN ANY CELL TYPES (HUMAN FIBROBLASTS AND LYMPHOBLASTOID CELLS). MITOTIC DELAY WAS INDUCED IN HUMAN FIBROBLASTS. /CHRYSOTILE AND CROCIDOLITE/ [R62] +A SERIES OF 144 CASES OF MESOTHELIOMA AMONG ASBESTOS WORKERS INDICATED IMPORTANT DIVERGENCES FROM EPIDEMIOLOGICAL PATTERN SHOWN TO EXIST FOR ASBESTOS RELATED LUNG CANCER. [R63] +Changes in pulmonary function considered most characteristic of asbestos are: 1) General reduction of lung volume, especially vital capacity (VC); 2) Decrease of pulmonary flow rates as indicated by forced expiratory volume in one second FEV (1.0); 3) Imparied alveolar-capillary diffusing capacity, reflected by reduced oxygenation of the arterial blood and increased alveolar-arterial partial pressure oxygen gradient (alveolar-capillary block syndrome). [R64] +Diseases considered to be associated with asbestos exposure /eg, in insulation workers/ include ... bronchogenic carcinoma, and cancers of the /gastrointestinal tract/ including esophageal, stomach, colon, and rectum. [R65] +A group of health scientists tested the association between the use of asbestos-cement piping for drinking water supplies and the incidence of kidney and gastrointestinal cancers in Utah. The study found no consistent cancer incidence difference in communities with asbestos pipes compared to communities without the pipes. Leaching from the pipes was minimal. [R66] +The prevalence of atypical cytology has been determined in relation to age, smoking and asbestos exposure for male workers employed in 3 mines in the Province of Quebec. Overall participation was 71%. Out of 867 participating workers, 626 (72%) presented a deep cough specimen within normal limits, 74 (8.5%) presented a specimen with mild atypical metaplasia and 10 (1.2%) presented a specimen with moderate atypical metaplasia. Four lung carcinomas were identified. 5% of the workers initially interviewed did not return their specimen and 12.7% had unsatisfactory test results. Proportions of cellular atypia increased with age and asbestos exposure. Using logistic regression analysis, estimated probabilities of abnormal cytology for workers aged 25 years when they started mining increased with both years of asbestos exposure and exposure index measured in fibers per cu m. [R67] +A retrospective study of 197 workers was carried out to analyze deaths from asbestosis or asbestos-related disease. The number of deaths from mesothelioma (101) was almost double that from bronchogenic carcinoma (67), and more than 3 times that from asbestosis (29). [R68] +The cause-specific mortality experience of 31,150 male asbestos workers in England and Wales (1971-1981) was evaluated in a retrospective cohort study. The study population was divided into workers with occupational exposure before the inception of asbestos regulations in 1969 and those who worked with asbestos only after 1969. Duration of exposure ranges from < 10 to > 20 yr. Information on exposure concentration was not provided. Overall mortality was lower than expected but there was a statistically significant excess of lung cancer deaths in workers exposed prior to 1969 (SMR= 136, p < 0.01). There was a small nonsignificant increase in lung cancer in workers exposed after 1969; however, the time from first exposure for this group is too short to exclude an excess of asbestos related disease. Insulation workers had the greatest excess of lung cancer deaths (SMR= 256). There was no excess in alimentary tract cancer and the population showed a signifcant deficit in bowel cancer mortality (SMR= 54). [R69] +The role of asbestos exposure was studied in a case-control study of 175 lung cancer cases and 176 controls during a 5 yr period from two county hospitals in Norway. Information on asbestos exposure was obtained from personal interviews, and allocated to four exposure categories according to intensity and duration of exposure. A statistically significant (p < 0.007) trend in risk ratio related to degree of exposure was observed, with a more than fourfold risk among the heavily exposed. The strongest association was found between asbestos exposure and small cell carcinoma (RR= 3), and the weakest association between asbestos exposure and adenocarcinoma (RR= 2.2). Very high risk ratios were observed among asbestos-exposed subjects who were heavy smokers, and the interaction conformed more closely to a multiplicative model than to an additive one. [R70] +In a cross sectional study, the frequencies of baseline and benzo(a)pyrene induced sister chromatid exchanges were measured in peripheral blood lymphocytes from 22 male asbestos exposed workers and 10 nonexposed workers of comparable age. Four groups were defined for study based on asbestos exposure and cigarette smoking. Mean duration of asbestos exposure was 31.3 yr in smokers and 29.3 yr in nonsmokers. The mean pack yr history of smoking for the asbestos exposed population was 45.7 pack yr and 75 pack yr in controls. Among asbestos exposed workers, lymphocytes from those who smoked were significantly more susceptible to the induction of SCE by in vitro exposure to benzo(a)pyrene (p= 0.01) than were the lymphocytes from nonsmokers. Active smoking elevated the baseline SCE frequency in both asbestos-exposed and nonexposed workers (p= 0.001). Asbestos exposure alone was not associated with an enhanced susceptibility to the induction of SCE by benzo(a)pyrene or with an elevation in baseline SCE. [R71] +IN 1973, AMPHIBOLE ASBESTOS FIBERS WERE DISCOVERED IN THE MUNICIPAL WATER SUPPLY OF DULUTH, MINNESOTA. THE ENTIRE CITY POPULATION OF APPROX 100,000 WAS EXPOSED FROM THE LATE 1950S THROUGH 1976 AT LEVELS OF 1-65 MILLION FIBERS/L OF WATER. SURVEILLANCE OF CANCER INCIDENCE IN RESIDENTS WAS INITIATED TO DETERMINE THE HEALTH EFFECT FROM INGESTION OF ASBESTOS. LUNG CANCER IN FEMALES WAS CONSIDERED OF BIOLOGICAL SIGNIFICANCE. THE MESOTHELIOMA INCIDENCE RATE WAS NO MORE THAN EXPECTED. /AMPHIBOLE ASBESTOS/ [R72] +In a study involving 17,800 insulation workers, the death rate for non-smokers was 5.17 times that of a non-smoking control population. The death rate was 53.24 times that of the non-smoking control population or 4.90 times the death rate for a comparable group of non-exposed smokers. Cancers of the larynx, pharynx, and buccal cavity in insulators were also found to be associated with cigarette smoking, together with some non-malignant asbestos effects such as fibrosis and deaths due to asbestosis. [R73] +Asbestos can cross the mammalian placental barrier. Furthermore, asbestos is a common contaminant of the talc used as a dusting powder for contraceptives from which it may enter the uterus. Research is needed to determine the level of in utero asbestos exposure and possible effects to the fetus because of inhalation or ingestion of asbestos or the use of talc-bearing contraceptives. [R74] +Cancer mortality for the populations was studied in 40 census tracts of Escambia County, FL that have been receiving drinking water through asbestos cement pipes for up to 40 years. Cancer mortality data from these 40 census tracts were compared with data from other tracts were asbestos cement pipe was not in use. No statistical association was observed between cancer deaths and the use of asbestos cement. [R75] +The /prospective/ study of /17,800/ USA and Canadian insulators /exposed primarily to chrysotile ... and amosite showed that/ lung tumors ... accounted for ... 21% of /2271/ deaths. 8% were from mesothelioma of the pleura or peritoneum, and 7% ... from asbestos ... 675 excess malignacies occurred, constituting 30% of all deaths. In addition ... the incidences of cancers of the larynx, pharynx and buccal cavity, and kidney were significantly elevated. Other tumors ... as a group ... were significantly in excess. [R76] +Exposure-response relationship for mesothelioma /was compared/ from 3 studies /and showed that/ no deaths were seen for exposure periods less than 3 months. At > 3 to 15.4 months exposure, the deaths/1000 person years ranged from 0.5 to 1.7 and at 57 months exposure, 1.7 deaths/1000 person years. [R77] +Retirees of the largest USA asbestos manufacturer showed lung cancer risks ranging from 1.7 times that expected in the lowest exposure category to 5.6 times that exposed in the highest. [R78] +among some exposed groups, 50 to 80% of individuals employed for 20 or more years were found to have abnormal x-rays characteristic of asbestos exposure. ... The progression of asbestosis depends on both cumulative exposure and time from exposure. [R79] +Among female workers, ovarian cancer has been found in excess. [R80] +Death from bronchogenic carcinoma among asbestos workers was more frequent than expected in the general population, and was the leading cause of death among insulation workers (3 times more common than mesothelioma). Three cohorts were followed. Among New York-New Jersey insulation workers in the construction industry with 20 or more years of exposure to asbestos, the incidence of lung cancer was approximately 8/1000 man-years, an eightfold increase over the general USA population. [R81] +Cancers of the digestive tract (stomach, colon, rectum) were also linked to asbestos exposure. In a study of 623 asbestos workers, these cancers accounted for 41 deaths while only 13 were expected from experience with the general population. During processing of rice, the Japanese add talc which usually has asbestos as an impurity. There was a positive correlation between the incidence of stomach cancer and rice consumption in the Japanese. Futhermore, chrysotile and amphibole asbestos fibers were found in the gastric tumors. [R82] +Asbestos fibers are toxic to macrophages, cells responsible for cleaning infectious agents and foreign material from the respiratory tract. [R82] +Respiratory exposure to high levels of asbestos in the workplace has been associated with pain in the chest, pleural frictional rubbing, rales (wheezing sound in the lower pulmonary region), cyanosis (low oxygen content of blood), loss of weight, clubbing of the fingers and formation of asbestos warts on the hands. [R83] +A study of the largest factory of the company but not limited to retirees, shows a considerably different mortality pattern. All 689 maintenance and production employees on January 1, 1959, who were first employed at least 20 years earlier were followed through 1976. In this group, 274 deaths occurred, whereas 188.19 were expected. Fourteen pleural and 12 peritoneal mesotheliomas accounted for nearly 10% of the deaths, most recurring before age 65. A strong correlation with estimated dust exposure was seen in deaths form asbestosis, but not with the asbestos related malignancies. Gastrointestinal cancer was especially high in the lowest of four dust categories (11 observed versus 3.15 expected) and only elevated slightly in the higher exposure categories. In the highest dust category, the overall cancer was not dramatically increased, but 40% of the deaths were from asbestosis. Individuals in this department tended to die of nonmalignant disease before reaching the age of greatest risk for cancer. [R84] +The mortality of a large workforce employed to manufacture friction products was analyzed. All individuals employed after 1940 were included in the study and the mortality experience through 1979 was determined. Exposure estimates were made by reconstructing work and ventilation conditions of earlier years. Fiber measurements from these reconstructed conditions suggested that exposures before 1931 exceeded 20 fibers/ml but those afterwards seldom exceeded 5 fibers/ml. From 1970, exposures were less than 1 fiber/ml. These relatively low intensities of exposure kept the average cumulative exposure for the group to less than 50 fibers- yr/ml. The overall mortality of all study participants, 10 years and more after the onset of exposure, was no greater than expected for all causes. The number of deaths from cancer of the lung and pleura was slightly elevated in men (151 observed vs 139.5 expected) but the excess was largely accounted for by eight mesothelioma deaths. No unusual mortality was found in study participants employed 10 or more years. Using a case control analysis according to cumulative exposure, estimated that the lung cancer increased risk was 0.06% per fiber yr/ml (Kl = 0.0006) with an upper 90% confidence limit of 0.8% per fiber yr/ml. [R85] NTOX: +... GROUPS OF CD WISTAR RATS /WERE EXPOSED/ TO 5 UNION INTERNATIONALE CONTRE LE CANCER ASBESTOS SAMPLES (AMOSITE, ANTHOPHYLLITE, CROCIDOLITE AND RHODESIAN AND CANADIAN CHRYSOTILES) AT CONCN OF ABOUT 12 MG/CU M RESPIRABLE DUST FOR 7 HR/DAY ON 5 DAYS/WK, FOR SEVERAL LENGTHS OF EXPOSURE: 1 DAY (7 HR), 3 MO, 6 MO, 12 MO OR 24 MO. AT THE END OF EXPOSURES, THE AMT OF DUST IN THE LUNGS OF ANIMALS EXPOSED TO THE 2 CHRYSOTILE SAMPLES WAS MUCH LESS THAN THAT IN ANIMALS EXPOSED TO THE 3 AMPHIBOLE SAMPLES. HOWEVER, ALL TYPES OF FIBER PRODUCED ASBESTOSIS, WHICH WAS PROGRESSIVE AFTER REMOVAL FROM THE DUST. FUTHERMORE, WHEREAS NO CARCINOMAS OF THE LUNG WERE FOUND IN THE CONTROL GROUP, CARCINOMAS OF THE LUNG AND MESOTHELIOMAS WERE DEMONSTRATED IN THE GROUPS EXPOSED TO CANADIAN CHRYSOTILE AND TO THE AMPHIBOLES. ONLY CARCINOMAS OF THE LUNG WERE SEEN WITH RHODESIAN CHRYSOTILE ... AN INCREASING INCIDENCE OF NEOPLASMS WAS OBSERVED WITH INCREASING EXPOSURES TO EACH FORM OF ASBESTOS. EVEN AS LITTLE AS 1 DAY OF EXPOSURE (PROVIDING THE ANIMALS WERE ALLOWED TO SURVIVE AND WERE OBSERVED) PRODUCED NEOPLASIA. [R86] +/INTRAPLEURAL ADMIN TO CD WISTAR AND OSBORNE-MENDEL RATS/ ALL COMMERCIAL TYPES OF ASBESTOS HAVE PRODUCED MESOTHELIOMAS IN C/D WISTAR RATS. A DOSE OF 20 MG OF THE FIVE UICC STANDARD REFERENCE SAMPLES (SEE SECTION 1.3B) PRODUCED MESOTHELIOMAS IN VARYING NUMBERS - CROCIDOLITE 61%, AMOSITE 36%, ANTHOPHYLLITE 34%, CANADIAN CHRYSOTILE 30% AND RHODESIAN CHRYSOTILE 19%. WITH A DOSE OF 40 MG OF ASBESTOS DUST ON GELATIN-COATED FIBRE-GLASS PLEDGETS, /IT WAS/ FOUND THAT THREE OF THE UICC SAMPLES, CROCIDOLITE, AMOSITE AND RHODESIAN CHRYSOTILE, ALL PRODUCED MESOTHELIOMAS IN ABOUT 60% OF THEIR OSBORNE-MENDEL RATS. INDUCED MESOTHELIOMAS WITH 60 MG OF RUSSIAN CHRYSOTILE. IN ALL THESE STUDIES THERE WAS A LONG LATENT PERIOD BETWEEN INOCULATION AND APPEARANCE OF THE TUMOURS. EVIDENCE THAT THE RESPONSE WAS DOSE RELATED. MESOTHELIOMAS HAVE ALSO BEEN PRODUCED BY OTHER WORKERS: IN RATS, IN HAMSTERS AND IN RABBITS. [R87] +IN EARLY EXPERIMENTS, IT WAS DEMONSTRATED THAT GUINEA PIGS AND MONKEYS EXPOSED BY /INHALATION/ TO 4 COMMERCIAL TYPES OF ASBESTOS DEVELOPED FIBROTIC LESIONS OF LUNG AND PLEURA ... . IN MORE RECENT EXPERIMENTS, THIS FINDING HAS BEEN CONFIRMED IN RATS AND HAMSTERS. [R88] +ALL COMMERCIAL FORMS OF ASBESTOS TESTED ARE CARCINOGENIC IN MICE, RATS, HAMSTERS AND RABBITS. ... THE SIZE AND SHAPE OF FIBERS INFLUENCE THE INCIDENCE OF TUMORS; FIBERS LESS THAN 0.5 UM IN DIAMETER ARE MORE ACTIVE IN PRODUCING TUMORS. [R89, (1977)] +BENIGN ASBESTOS PLEURISY IS A MANIFESTATION OF ASBESTOS-INDUCED DISEASE THAT IS NOT UNCOMMON BUT OFTEN IS IGNORED. CROCIDOLITE ASBESTOS INJECTED INTO THE RABBIT PLEURAL SPACE CAUSED THE APPEARANCE OF CHEMOTACTIC ACTIVITY IN AN EXUDATIVE EFFUSION, CHARACTERIZED BY A POLYMORPHONUCLEAR LEUKOCYTE RESPONSE THAT PEAKED 4 HR AFTER INJECTION. /CROCIDOLITE ASBESTOS/ [R90] +THE HEMOLYTIC ACTIVITY OF SHORT ASBESTOS FIBERS WAS STUDIED USING RAT AND SHEEP RED BLOOD CELLS. THE INITIAL VELOCITY OF HEMOLYSIS IS PROPORTIONAL TO THE CONCN OF FIBERS. [R91] +THE EFFECTS OF 3 MO INTERMITTENT INHALATIONAL EXPOSURES OF AMPHIBOLE AND SERPENTINE ASBESTOS ON THE CONSTITUENTS OF THE LOWER RESP TRACT WAS STUDIED. BRONCHOALVEOLAR LAVAGE (BAL) ANALYSES WERE PERFORMED ON 3 GROUPS OF RATS: 1 GROUP WAS EXPOSED TO CHRYSOTILE (SERPENTINE) ASBESTOS, SECOND GROUP WAS EXPOSED TO CROCIDOLITE AMPHIBOLE ASBESTOS, WHILE THE THIRD GROUP WAS SHAM-EXPOSED. THE TOTAL BAL CELL YIELDS AND MACROPHAGE CONTENT OF BAL CELLS WERE SIGNIFICANTLY LOWER AFTER ASBESTOS EXPOSURE, ESPECIALLY IN THE CHRYSOTILE-EXPOSED GROUP. THESE EFFECTS PERSISTED FOR AS LONG AS 1 YR AFTER CESSATION OF EXPOSURE. MULTINUCLEATED MACROPHAGES WERE SEEN IN BAL CELLS FROM BOTH ASBESTOS-EXPOSED GROUPS. STRIKING ULTRASTRUCTURAL ALTERATIONS OF MACROPHAGE MORPHOLOGY WERE NOTED IN BAL CELLS FROM BOTH GROUPS OF ASBESTOS EXPOSED RATS. CHRYSOTILE FIBERS WERE NOT SEEN IN ANY BAL CELLS FROM CHRYSOTILE-EXPOSED ANIMALS. HOWEVER, 15 MO AFTER TERMINATING THE EXPOSURE REGIMEN, A SIZEABLE PROPORTION OF BAL MACROPHAGES FROM CROCIDOLITE-EXPOSED RATS CONTAINED PHAGOCYTOSED ASBESTOS FIBERS. /AMPHIBOLE AND SERPENTINE/ /CHRYSOTILE AND CROCIDOLITE/ [R92] +THE EFFECTS OF UNION INTERNATIONALE CONTRE LE CANCER CROCIDOLITE AND CHRYSOLITE A, EITHER OXALIC ACID-LEACHED OR UNLEACHED, ON THE VIABILITY, MORPHOLOGY AND GROWTH CHARACTERISTICS OF RAT PLEURAL MESOTHELIAL CELLS (PMC) WERE EXAMINED. ADDN OF 5 OR 10 UG/ML OF CROCIDOLITE, EITHER LEACHED OR UNLEACHED, DID NOT SIGNIFICANTLY CHANGE THE GROWTH RATE. A SLIGHT VACUOLATION OF THE CELLS OCCURRED. LEACHED CHRYSOTILE INHIBITED GROWTH AT A CONCN OF 50 UG/ML; WITH 5 OR 10 UG/ML, NO SPREADING OCCURRED, BUT A SHRINKAGE OF SOME CELLS WAS OBSERVED. RESULTS CONFIRM THE DIFFERENT IN VITRO REACTIVITIES OF THE 2 KINDS OF UNLEACHED ASBESTOS FIBERS. LEACHING OF CHRYSOTILE FIBERS DECR THEIR REACTIVITY; ALTERNATIVELY, LEACHING OF CROCIDOLITE INCREASED THE EFFECTS ON PMC. /CHRYSOTILE AND CROCIDOLITE/ [R93] +The ability of particulate air pollutants (and possible constituents) to alter pulmonary host defenses was examined using an in vitro alveolar macrophage cytotoxicity assay and an in vivo bacterial infectivity screening test which employed intratracheal injection of the particles. A wide range of response between particles was seen at the 1.0 mg/ml level in vitro and the 0.1 mg/mouse level in vivo. A sample of fluidized-bed coal fly ash, bentonite, asbestos, some ambient air particles and heavy metal oxides greatly increased susceptibility to pulmonary bacterial infection. Most coal fly ash samples and some air particles caused moderate increases in infectivity, while diesel particulates, volcanic ash, and crystalline silica caused only small increases. Cytotoxic effects on macrophages in vitro were observed with most of the particles. The in vivo and in vitro assays produced a similar ranking of toxicity, however, not all particles that were highly cytotoxic were potent in increasing bacterial infectivity. Increased toxicity measurable by either assay often appeared to be associated with small size or with the presence of metal in the particles. [R94] +Experimental coniosis was induced by intratracheal administration to rats of 25 mg or 50 mg of Portland cement, asbestos-cement, as well as chrysotile and crocidolite asbestos. The rats were sacrificed 90, 165 and 180 days after dust administration. The weight of wet lungs and hydroxyproline content in lungs were determined. Statistically significant lower values of fibrogenic effects indices following cement dust administration, as compared to those indices for the other dusts, were found. On the other hand, no significant differences were found between fibrogenic effects indices for asbestos-cement containing approx 13% of asbestos and pure asbestos dusts (chrysotile or crocidolite). Furthermore, it seems that the duration of dust action is more important than the dust dose in the development of fibrogenic asbestosis. /Chrysotile and crocidolite/ [R95] +The ability of asbestos-elicited murine peritoneal macrophages to release superoxide anion and hydrogen peroxide, following in vitro triggering has been investigated. The asbestos-elicited macrophages produced increased levels of superoxide and hydrogen peroxide compared to control macrophages and similar levels to those produced by Corynebacterium parvum elicited macrophages. The supernatants from asbestos-elicited macrophages which had been triggered in vitro were capable of impairing the ability of alpha-1-protease inhibitor to inhibit elastase function. The catalase sensitivity of this effect showed it to be due to hydrogen peroxide. [R96] +Enzymatic studies on asbestotic rat lungs revealed increased levels of fumarase and cytochrome C oxidase, and decreased levels of aconitase. [R97] +Rats which received asbestos intratracheally had ... decreased number of lung mitochondria, decreased activities of magnesium(2+) and calcium(2+)-activated ATPase and increased activities of cytochrome C oxidase and diaphorase. [R98] +Treatment of calf thymus DNA with various types of asbestos fibers in the presence of hydrogen peroxide under physiological conditions (pH 7.4, 37 deg C) resulted in the hydroxylation of the C-8 position of guanine residues. DNA strand scission was also detected after these treatments. [R99] +In these studies the samples from Oregon and Turkey produced a very high incidence of tumors. All the rats inoculated intrapleurally with Oregon erionite and almost all those inoculated with the Turkish fiber died with a mesothelioma. Inhalation of the Oregon erionite induced a similar effect. No other dusts ... investigated have produced this high incidence of tumors particularly following inhalation. [R100] +[MUTATION RESEARCH 76: 169 (1980)] ESCHERICHIA COLI WP2,UVRA - REVERSE MUTATION STUDIES WITH METABOLIC ACTIVATION: NEGATIVE. [R101] +In Chinese hamster cells, chrysotile and crocidolite have produced genetic damage and morphologic transformation. /Chrysotile and crocidolite/ [R102] +Chrysotile, amosite, and anthophyllite showed no mutagenic activity toward tester strains of Escherichia coli or Salmonella typhimurium. /Chrysotile, amosite, and anthophyllite/ [R103] +6 week old male F344 rats were fed 10 mg of asbestos 3 times/week for 10 weeks. The animal tissues were examined at 34 weeks or after their natural death. Intestinal cancer (not significant) was observed; however, no toxic effects were reported. [R104] +Pregnant CD-1 mice /were given/ (10-12/dose) 4, 40 or 400 mg asbestos/kg body weight (1.43, 14.3 or 143 mg asbestos/ml) in their drinking water during days 1-15 of gestation. Water consumption did not vary between the different dosage groups. There was also no difference in embryo survival between the treatment groups and the controls, which received only tap water. There were no signs of maternal toxicity. [R105] +Early lesions /similar to those reported earlier: multinucleated giant cells, lymphocytes, and fibroblasts/ were found in rats /following inhalation of asbestos fibers/ and consisted of a proliferation of macrophages and cell debris in the terminal bronchioles and alveolae. [R106] +The effects of ingested asbestos on the colon of weanling F344 rats was studied. Based on results of preliminary experimentation, the dosage was established at 10% by weight of a standard laboratory diet. Two hundred forty animals comprised the test group; there were also 242 control rats fed 10% nonnutritive cellulose and a group of 121 controls was fed normal laboratory chow. The study was terminated at 32 months. Epithelial tumors of the colon (8 adenocarcinomas and 1 adenoma) were found in nine of the rats. Four tumors were in asbestos fed rats, two tumors in the nonutritive cellulose fed group, and three tumors were found in the standard laboratory diet controls. Also, one malignant mesothelioma was found in the asbestos fed group. Although the differences in the numbers of tumors between asbestos fed animals and controls were not significant, the authors believe their experimentation suggests that ingested asbestos is not inert in the colon. Included in their result is the discovery that cyclic-AMP levels in the colon were significantly lower in asbestos fed animals vs controls. [R107] +Asbestos has ... been observed to increase the levels or activities of the following enzymes: ... lactic dehydrogenase, acid phosphatase, glutamic pyruvate transaminase, lipase, cathepsin D, acid RNAase, B-glucuronidase, B-N-acetyl glucos-aminidase, sucrase, alkaline phosphatase, ATPase, and p-nitrophenyl acetate hydrolase. [R108] +PET DOGS WITH SPONTANEOUS MESOTHELIOMA WERE USED TO IDENTIFY ENVIRONMENTAL EXPOSURES THAT MIGHT INCR THEIR OWNER'S RISK OF ASBESTOS-RELATED DISEASE. EIGHTEEN HISTOLOGICALLY CONFIRMED CANINE MESOTHELIOMAS WERE DIAGNOSED AT THE VETERINARY HOSPITAL OF THE UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, FROM APRIL 1977 TO DECEMBER 1981. SIXTEEN OWNERS OF CASES AND 32 OWNERS OF AGE, BREED, AND SEX-MATCHED CONTROLS WERE INTERVIEWED TO DETERMINE THEIR OCCUPATION AND MEDICAL HISTORY AND THEIR DOG'S MEDICAL HISTORY, LIFE STYLE, DIET, AND EXPOSURE TO ASBESTOS. AN ASBESTOS-RELATED OCCUPATION OR HOBBY OF A HOUSEHOLD MEMBER AND USE OF FLEA REPELLANTS ON THE DOG WERE SIGNIFICANTLY ASSOCIATED WITH MESOTHELIOMA. IN ADDITION, THERE WAS A TREND INDICATING AN INCREASED RISK OF MESOTHELIOMA WITH AN URBAN RESIDENCE. LUNG TISSUE FROM THREE DOGS WITH MESOTHELIOMA AND ONE DOG WITH SQUAMOUS CELL CARCINOMA OF THE LUNG HAD HIGHER LEVELS OF CHRYSOTILE ASBESTOS FIBERS THAN LUNG TISSUE FROM CONTROL DOGS. [R109] +Conclusions: Under the conditions of these feed studies, crocidolite asbestos was not overtly toxic and did not cause a carcinogenic response in F344/N rats for their lifetime. [R110] NTP: +Carcinogenesis studies of crocidolite asbestos were conducted with male and female F344/N rats. This form of asbestos was administered at a concentration of 1% in pelleted diet for the lifetime of the rats starting with the dams of the study animals The studies were started in January 1978 and ended in December 1980. Group sizes were 118 for male and female controls and 250 for male and female crocidolite asbestos exposed rats. Conclusions: Under the conditions of these feed studies, crocidolite asbestos was not overtly toxic and did not cause a carcinogenic response in F344/N rats for their lifetime. [R110] TCAT: ?Chronic toxicity was evaluated in 50 male Sprague-Dawley rats, and 15 male Syrian hamsters exposed to asbestos via inhalation at a nominal concentration of 85 mg/m3 for 7 months, followed by a lifetime observation period. In the exposed rat group, the pulmonary responses included alveolar adenomatous proliferation, non-progressive fibrosis, squamous metaplasia and a substantial incidence of pulmonary carcinoma formation (6/34). Mean body weight of exposed rats was significantly lower after 1 month of exposure, it remained low until 14 months post exposure. Mortality data for the rat group indicated no significant difference between exposed and control rats. Mortality in the exposed hamster group was significantly increased during the 7 month exposure period. No pulmonary neoplasms were noted in the surviving hamsters, (the ability to evaluate long-term pulmonary effects was severely limited due to early mortality of 8/15 hamsters). The mean body weight for hamsters was statistically decreased during the first month of exposure, but statistically increased and remained so for the remainder of the study. Histopathologic studies of other, non-pulmonary tissues were not significantly different from the control group for rats or hamsters. [R111] POPL: +Special groups at risk may include neonates and children; however, no data exist on the relative sensitivity to asbestos of infants and children undergoing rapid growth. Concern exists because fibers deposited in the tissues of young may have an extremely long residence time during which malignant changes could occur. In addition, risk could be influenced by differential absorption rates which have not been fully studied at this time. Individuals on kidney dialysis machines may also be at greater risk as fluids, potentially contaminated with asbestos fibers can enter the blood stream directly or, in selected instances, the peritoneal cavity (peritoneal dialysis). An increased risk is also associated with increased exposure to asbestos in water in municipalities such as San Francisco or Seattle where asbestos occurs naturally in water, in cities where there is a interaction between aggressive water and asbestos-cement pipe, or in cities whose water may be contaminated as a result of asbestos operations. [R112] +Hypersusceptible individuals have not been defined for ingested exposures to mineral fibers. It is well known that smokers exposed to asbestos dusts from inhalation are at a higer risk of developing lung cancer than are nonsmokers with similar exposures. [R113] ADE: +Inhaled fibers deposit by sedimentation, diffusion, impaction, and interception in airways of the respiratory system. The mathematical model developed ... for the resp deposition of ordered cylindrical rods showing periodic motion has been adapted to 3 rod configurations in random orientation. Their results suggest that for aerosols having distributions such as Union Internationale Contre le Cancer asbestos samples dispersed by the dispenser ... straight uniform fibers may deposit in pulmonary spaces in about twice the number of irregularly shaped fibers which may be judged to be in random orientation. [R114, 603] +Actin, the contractile protein within cells, may be responsible for movement of asbestos particles through the epithelium to the lung interstitium where the fibers react with macrophages and fibroblasts. [R114, 604] +Two human studies gave evidence for the penetration and migration of asbestos. ... Amphibole asbestos /has been detected/ in the urine of Minnesota residents who ingested drinking water contaminated with 5X10+7 fibers/l. ... amphibole asbestos in lung > liver > jejunum of persons exposed to high oral intake of the mineral /has been observed/. /Amphibole asbestos/ [R114, 604] +AFTER INTRAPLEURAL OR SUBCUTANEOUS INOCULATION, THE ONLY TRANSLOCATION THAT OCCURRED WAS OF A MINUTE FRACTION OF THE FINER FIBERS. ... OCCASIONAL ASBESTOS FIBERS OR BODIES HAVE BEEN REPORTED IN OTHER TISSUES, INCLUDING PANCREAS, SPLEEN AND THYROID. THERE IS NO INFORMATION ON HOW FIBERS ... REACH THESE SITES. [R115] +FOLLOWING INHALATION ... FIBERS FOUND IN ... LUNG TISSUE ARE USUALLY LESS THAN 3 UM IN DIAMETER AND LESS THAN 100 UM IN LENGTH. THICKER OR LONGER FIBERS ARE EITHER NOT INHALED OR ARE RAPIDLY CLEARED FROM RESP TRACT. ON WEIGHT BASIS, ONLY VERY SMALL PROPORTION OF INHALED FIBER IS RETAINED. [R115] +... ASBESTOS WAS INOCULATED INTRAPLEURALLY, THE MAJORITY OF FIBER WAS CLEARED DURING THE FIRST 10 DAYS; BUT SUBSEQUENTLY THERE WAS A VERY SLOW ELIMINATION THROUGH THE GUT. IN FEEDING EXPERIMENTS ALMOST ALL THE FIBER WAS ELIMINATED. [R115] +IN PERSONS OCCUPATIONALLY EXPOSED TO ASBESTOS, SMALLER NUMBERS OF ASBESTOS BODIES OR FIBERS THAN ARE SEEN IN LUNG TISSUE HAVE BEEN FOUND IN EXTRA-PULMONARY TISSUE, INCL TONSILS, THORACIC AND ABDOMINAL LYMPH NODES, PLEURA, PERITONEUM, LIVER, SPLEEN, KIDNEY AND SMALL INTESTINE. [R116] +THE PHYSICAL CHARACTERISTICS OF ASBESTOS FIBERS THAT PENETRATE TO LUNG PARENCHYMA ... /DEMONSTRATE/ FIBER RESPIRABILITY WAS LARGELY A FUNCTION OF FIBER DIAMETER. ... 5000 ASBESTOS FIBERS FROM LUNGS OF 10 DECEASED PERSONS WHO HAD BEEN OCCUPATIONALLY EXPOSED ... SHOWED THAT ... ALL /WERE/ LESS THAN 0.5 UM IN DIAMETER. [R117] +Studies with animals demonstrated that ingested asbestos can cross the gastrointestinal mucosa and from there can be transported to other sites in the body. Humans who consumed water containing asbestos were found to have asbestos fibers in their urine. [R118] +Shorter fibers are preferentially removed /from the lungs of rats/ after one week following inhalation ... longer fibers reaching the alveolar spaces are trapped. [R119] +The observation in humans of peritoneal mesothelioma, excess cancer of the stomach, colon, and rectum, and ... cancers at other non-respiratory sites ... could result from the migration of ... fibers to and across the gastrointestinal mucosa. ... Fibers may reach organs in the peritoneal cavity by transdiaphragmatic migration or lymphatic-hematogenous transport. [R120] +Evidence for the human intestinal uptake ("persorption") of particles as large as 75 um is provided by the observation of starch granules in blood only minutes after ingestion. [R121] +Most inhaled or directly ingested asbestos particles which pass through the gastrointestinal tract are excreted in feces. As mentioned previously, some fibers are absorbed by the gastrointestinal tract and are eventually eliminated through the urinary tract. [R122] +RATS WERE FED A DIET SUPPLEMENTED WITH AN ASBESTOS/MARGARINE FORMULATION FOR PERIODS UP TO 1 YR. UICC STD REF SAMPLES OF AMOSITE WERE USED. THERE WAS NO EVIDENCE OF ASBESTOS RETENTION WITHIN GUT LUMEN, AND NO SIGN OF CELL PENETRATION OR DAMAGE TO INTESTINAL MUCOSA WERE OBSERVED. [R123] +Dosages of 1-3 mg (1 mg/ml of water) were injected into the femoral vein of female Wistar rats at 2 day intervals from days 10-14 of gestation. Total dose varied from 4-12 mg of asbestos. The fetuses were removed by Caesarean section the day before parturition in a manner that prevented cross-contamination from the mother; the livers and lungs were than analyzed by electron microscopy. Asbestos fibers were found to cross the placenta but the extent of this occurrence was higly variable. The livers and lungs analyzed were selected at random and thus could have come from different fetuses in the same uterus. In the first experiment, the highest number of fibers found in fetal liver and lungs came from a dam administered four 3 mg injections (total dose= 12 mg). Numbers of fibers found in liver and lungs were 27.03X10+6 fibers/g and 139.97X10+6 fibers/g, respectively. In a second experiment, the higest number of fibers found in fetal liver and lung came from a dam administered five 2 mg injections (total dose= 10 mg). Numbers of fibers found in the liver and lung were 100.12X10+6 fibers/g and 2.90X10+6 fibers/g, respectively. [R124] +The deposition and clearance of fibers from the lung suggest that most inhaled fibers (approximately 99%) are eventually cleared from the lung by ciliary or phagocytic action. [R125] +Fibers were detected in beverages (beer, wine and soft drinks) and were studied to see if such fibers consumed orally can pass through the intestinal wall and enter the bloodstream. A stock solution was made to contain fibers the same length as those found in beverages (0.5-2) and determined to contain 9.4x10+6 fibers/l. An aliquot (assumed to be 350 ml) was then administered intragastrically to rats (number, species and sex not known). Asbestos fibers were found to accumulate in the omentum surrounding the small intestine, brain and lung. ... counts could not be made on the liver and kidneys. [R126] BHL: +There is no evidence that inhaled or ingested asbestos is completely cleared from the body. It is likely that some fraction of the asbestos in the body is retained for long periods, if not for life. [R127] ACTN: +In an effort to understand the properties of asbestos fibers that might contribute to their toxicity, ... three different varieties of asbestos /were incubated/ with phospholipid emulsions and ... evidence of lipid peroxidation /were looked for/. Although all three types of asbestos were able to catalyze lipid peroxidation in the native state, this catalytic activity was inhibited by pre-washing of the asbestos with the iron chelator desferroxamine. This suggests that: lipid peroxidation may be one of the mechanisms by which asbestos produces tissue injury, and treatment with iron chelators might diminish the potential to produce this injury. [R128] +Animal experimentation ... indicated that the important factor in the carcinogenicity was the dimensionality of the fibers rather than their chemical properties. ... Greatest carcinogenicity was related to fibers that were less than 2.5 cu m in diameter and longer than 10 cu m. [R129] +In terms of carcinogen mechanisms, asbestos appears to act like a lung cancer promoting agent ... Promotional effect does not diminish with time after cessation of exposure ... Inhalation of the fibers can precede initiating events because the fibers remain continously available in the lung to act after other necessary carcinogenic processes occur. [R130] INTC: +THE CELL TRANSFORMING ABILITY OF ASBESTOS DUSTS (AMOSITE AND CROCIDOLITE ASBESTOS) WAS INVESTIGATED USING C3H10T1/2 MURINE FIBROBLAST CULTURES. THE DUSTS WERE CAPABLE OF AUGMENTING THE ONCOGENIC EFFECT OF BENZO(A)PYRENE. THIS SYNERGISTIC EFFECT WAS EVIDENT WHEN FIBERS AND CHEMICALS WERE ADDED TO CULTURES AS SIMPLE MIXTURES AND WHEN BENZO(A)PYRENE WAS ADSORBED TO THE SURFACE OF FIBERS. /Amosite and crocidolite/ [R131] +After inhalation of (222)Ra at equilibrium with radon daughters, male Sprague-Dawley rats were inoculated intrapleurally with 2 mg of unleached or acid-leached asbestos fibers. ... The additive co-carcinogenic effects of this type of malignant insult were demonstrated by increased incidence of malignant thoracic tumors. In rats given mineral materials, bronchopulmonary carcinomas and mixed carcinomas were observed, as well as typical mesotheliomas and combined pulmonary pleural tumors, whereas in control rats inhaling radon alone, only bronchopulmonary carcinomas occurred. [R132] +Asbestosis mortality for workers who smoked 20 or more cigaretes a day was 2.8 times higher than that for workers who never smoked regularly. ... Interactive effects between cigarette smoking and the prevalence of x-ray abnormalities have been reported. ... No relationship between cigarette smoking and the risk of death from mesothelioma or gastrointestinal cancer was found. [R133] +Trace metals (beryllium, cadmium, chromium, cobalt, copper, iron, manganese, nickel, thallium) may be present as natural impurities in asbestos or may be added inadvertently during milling and handling. The release of these contaminating metals in a biologically active form when the asbestos fibers are deposited in soft tissue may be involved in the etiology of some asbestos-related diseases. [R134] +The relationship between asbestos exposure and smoking indicates a synergistic effect of smoking with regard to lung cancer. Further evaluations indicate that this synergistic effect is close to a multiplicative model. ... The risk of mesothelioma appears to be independent of smoking, and a significantly decreasing trend in risk was observed with the amount smoked in 1 study. [R58] +The in vitro cytotoxicity and oncogenicity of both native and acid-leached asbestos fibers were studied using the C3H10T1/2 cell model. Both native and leached fibers induced a dose-dependent toxicity. At high fiber concentrations, acid leached fibers were less toxic than their untreated counterparts. Whereas asbestos fibers alone do not induce oncogenic transformation at the concn examined, both leached and native fibers synergistically enhanced the oncogenicity of gamma irradiation. Although no significant chromosomal aberrations or sister chromatid exchanges were found in asbestos-treated cultures, a higher number of sister chromatid exchanges was observed in cells treated with both asbestos and radiation compared to cells receiving radiation alone. The enhancement in radiation induced oncogenicity by asbestos fibers may be attributed to the mere physical presence of the fibers rather than any chemical contaminants the fibers may contain. Furthermore, the carcinogenicity of asbestos may be unrelated to genotoxicity. [R135] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: +ASBESTOS IS GENERIC TERM THAT APPLIES TO GROUP OF NATURALLY OCCURRING, HYDRATED MINERAL SILICATES THAT ARE SEPARABLE INTO ASBESTOS FIBERS. [R136] +Asbestos occurs naturally in the air because of wind erosion of asbestos bearing rocks and soil. [R137] +Asbestos is a natural contaminant of talc. ... Asbestos represents less than 1% of the samples of cosmetic talcs tested. [R138] ARTS: +Asbestos fibers have been released into water by the dumping of ... mining tailings into lakes, by the runoff of process and air scrubber water into lakes and streams, and by the use of asbestos cement pipes in water supply systems. [R139] +During 1970, an estimated 15,000 metric tons of asbestos were released into Canadian air from mining, manufacturing, construction, and automobile break linings. [R139] +A ... study /1976/ of street dust in Washington, DC, showed approximately 50,000 fibers per gram /asbestos/, much of which appeared to come from brake linings. Autopsies of New York City residents with no known occupational exposure showed 24 to 28 lung samples to contain asbestos fibers, perhaps resulting from asbestos from brake linings and the flaking of sprayed asbestos insulation material. [R140] +MINUTE QUANTITIES OF FIBERS ARE PRESENT IN WATER, BEVERAGES AND PHARMACEUTICAL PREPARATIONS WHEN ASBESTOS FILTERS HAVE BEEN USED [R141] +ASBESTOS FIBERS MAY BE LIBERATED INTO AIR IN DANGEROUS AMT @ ALL STAGES IN USE OF ASBESTOS IN MINING. MILLING, PROCESSING, FORMING ASBESTOS CONTAINING PRODUCTS, AND IN DUMPING WASTE. RISKS ARE HIGHEST WHERE DUST CONTAINS LARGEST NUMBER OF FINE FIBERS. [R55, 123] +... Air concentrations measured by optical microscopy have been observed in circumstances where asbestos materials in schools and other buildings are disturbed by routine or abnormal activity. ... Maintainance and renovation work can lead to substantially elevated asbestos levels. [R142] +Over one million tons of asbestos is contained in friable materials in ships, buildings, power plants, chemical plants, refineries, and other locations of high temperature equipment. The maintenance, repair, and removal of this material will account for the principal exposures to workers and emmisions into the environment (both in and out of buildings) in the future. [R143] FATE: +ATMOSPHERIC FATE: Asbestos, as a mineral, is not affected by photolytic processes. [R144, p. 7-9] +ATMOSPHERIC FATE: The importance of the transport of asbestos from the surface of aquatic environments by wind-activated aerosol formation is presently indeterminate. The mobilization of asbestos from the surface of highways and soils into the atmosphere by the action of wind has been observed in urban air. [R144, p. 7-9] +Dumping of asbestos-bearing mine wastes onto soil resulted in areas largely devoid of vegetation probably due to the alkaline nature of the serpentine host rock. This situation was temporarily remedied by the addition of nitrogen-phosphorus-potassium fertilizer and manure. [R145] BIOD: +Asbestos is considered to be non-biodegradable by aquatic organisms. [R144, p. 7-13] BIOC: +No evidence was found regarding the bioaccumulation of asbestos in aquatic organisms. [R144, p. 7-13] KOC: +It appears that asbestos does not have an adsorptive affinity for the solids normally found in natural water systems; however, some materials, notably trace metals and organic cmpd, have an affinity for asbestos minerals. [R144, p. 7-10] WATC: +DRINKING WATER: IN 1973, AMPHIBOLE ASBESTOS FIBERS WERE DISCOVERED IN THE MUNICIPAL WATER SUPPLY OF DULUTH, MINNESOTA. THE ENTIRE CITY POPULATION OF APPROX 100,000 WAS EXPOSED FROM THE LATE 1950S THROUGH 1976 AT LEVELS OF 1-65 MILLION FIBERS/L OF WATER. [R146] +DRINKING WATER: Asbestos (millions of fibers/l) in Canadian drinking water: Belleville: Bay of Quinte: 0.533; Brantford: Grand River: 0.570; Brockville: St. Lawrence River: 0.446 (no filtration plant) Chatham: Thames River: 0.595; Cornwall: St. Lawrence River: 2.11; Hamilton: Lake Ontario: 0.456; Niagara Falls: Niagara River: 2.58; North Bay: Trout Lake: 0.384 (no filtration plant); Oshawa: Lake Ontario: 0.557; Ottawa: Ottawa River: 0.136; Pembroke: Ottawa River: 2.85; Peterborough: Otonabee River: 1.86; Port Colborne: Welland Ship Canal: 0.608; Sarnia: Lake Huron: 3.87 (no filtration plant); Sault St. Marie: St. Marys River: 0.248; St. Catharines: Welland Ship Canal: 1.03; St. Thomas: Lake Erie: 1.60; Sudbury: Ramsey Lake: 0.297 (no filtration plant); Toronto: Lake Ontario: 1.90; Welland: Welland Ship Canal: 0.820. /Data derived from table/ [R147] +DRINKING WATER: Asbestos content from Canadian rivers and lakes, and in drinking water /is as follows/: Ottawa, Ottawa River, tap water: 2.0x10+6 fibers/l; Toronto, Lake Ontario, tap water: 4.4x10+6 fibers/l; Montreal, St. Lawrence River, tap water: 2.4x10+6 fibers/l; Hull, Ottawa River, tap water: 9.5x10+6 fibers/l (water supply unfiltered); Beauport, St. Lawrence River, tap water: 8.1x10+6 fibers/l (water supply unfiltered); Drummondville, St. Francais River, tap water: 2.9x10+6 fibers/l; Thetford Mines, Lac a la Truite, tap water, 172.7x10+6 fibers/l (water supply unfiltered); Ottawa top 30 cm melted snow, 33.5x10+6 fibers/l; Ottawa, Ottawa River, river water, 9.5x10+6 fibers/l. /Data derived from table/ [R148] +DRINKING WATER: Drinking waters from Thetford mines, Quebec, site of a major asbestos deposit and mine, contained up to 170x10+6 fibers of asbestos per l. [R149] +DRINKING WATER: Water concentrations of asbestos are usually less than 1x10+6 fibers of all sizes per liter although significantly higher values (1x10+8 fibers/l) have been found in circumstances where water systems have been in contact with asbestiform minerals or where contamination of water supply exists. Fiber mass concentrations corresponding to fiber concentrations are usually less than 0.01 ug/l. Thus, direct water ingestion usually leads to exposure of less than 0.02 ug/day. [R150] +DRINKING WATER: ... Data suggests that 1x10+6 fibers corresponds to from 2x10-4 to 2x10-3 ug in water systems. Data on asbestos concentrations from erosion of fibers from asbestos/cement cooling tower panels indicate that the mass of 1x10+6 fibers is from 0.01 to 0.2 ug. [R151] +Samples from 365 cities have been collected and analyzed by electron microscopy by the USEPA. Of these, 45% had detectable levels of asbestos, usually of the chrysotile variety. [R152] ATMC: +Mean airborne concentrations of asbestos in US cities are 2.1-4.3 ng/cu m. [R153] +During 1973, the dust levels from Canadian asbestos mines and mills were as high as 83 fibers/cu m. [R139] +MEAN AIR CONCN OF AMPHIBOLE FIBERS IN COMMUNITIES SURROUNDING MILLING OPERATIONS HAVE BEEN REPORTED TO RANGE FROM 2.6-8.9X1X10+3 FIBERS/CU M. ... CONCN OF AS HIGH AS 11X1X10+6 AMPHIBOLE FIBERS/CU M OF AIR WERE REPORTED NEAR SPECIFIC POINT EMISSION SOURCES. /AMPHIBOLE FIBERS/ [R154, p. V14 71] +The ambient air concentrations near the Union Carbide mill and waste pile in King City, CA and near the Johns-Manville mill and water dump in Coalinga, CA were 1.03 million fibers/cu m and 593 million fibers/cu m, respectively. [R155] +Air concentrations over 24 hours in metropolitan areas usually are less than 5 ng/cu m but can range up to 20 ng/cu m. Values up to 50 ng/cu m are found during daytime hours in locations were construction activities and traffic can be contributing sources. A significant fraction of the fibers inhaled can be brought up from the respiratory tract and swallowed. This leads to an ingestion exposure from air sources of up to 0.1 ug/day, although most of the population exposure is from 0.01 to 0.05 ug/day. [R156] +3 different /USA/ laboratories ... found that the average fiber concn of asbestos dust in insulation work between 1968 and 1971 ranged from about 3 to 6 fibers/ml. ... In the Devonport Naval Dockyard in Great Britain ... 8.9 fibers/ml /was obtained/ for the average of long-term samples of asbestos concn. ... Peak exposures could ... exceed 100 fibers/ml /for 2 to 5 minute concn of asbestos/ during the mixing of cement. [R157] FOOD: +Asbestos content is specified for the following: Canadian beer: 4.3-6.6x10+6 fibers/l; USA beer: 1.1-2.0x10+6 fibers/l; Spanish sherry: 2.0x10+6 fibers/l; Canadian sherry: 4.0x10+6 fibers/l; South African sherry: 2.6x10+6 fibers/l; Canadian port: 2.1x10+6 fibers/l; French vermouth: 1.8x10+6 fibers/l; Italian vermouth: 11.7x10+6 fibers/l; French wine: 64.0x10+6 fibers/l; Ginger ale: 12.2x10+6 fibers/l; Tonic water: 1.7x10+6 fibers/l; Orange (softdrink): 2.5x10+6 fibers/l. /Data derived from table/ [R158] PFAC: FISH/SEAFOOD CONCENTRATIONS: +Asbestos mine tailings from a mill in Germany were dumped in a region containing large numbers of mussel beds. Mussels were examined after exposure to water containing asbestos in concentrations up to 100 mg/l. Fibers penetrated the epithelial tissue of the stomach and the intestinal tract and were present even when the mussels were kept for several weeks in unpolluted water. [R159] OEVC: +THERE ARE OVER 2000 RECORDED USES OF ASBESTOS MINERALS IN UNITED STATES. FROM THIS ONE CAN CONCLUDE THAT THERE WILL BE CORRELATION BETWEEN POPULATION AND INDUST ACTIVITY AND CONCN OF ASBESTOS IN ENVIRONMENT. [R160] +Measurements using electron microscopic techniques have established the presence of asbestos in the urban ambient air, usually at concentrations less than 10 ng/cu m. Concentrations of 100 ng/cu m to 1000 ng/cu m have been measured near specific asbestos emission sources, in schools where asbestos containing materials are used for sound control, and in office buildings where similar materials are used for fire control. [R161] +Measurements using electron microscopic techniques have established the presence of asbestos in the urban ambient air, usually at concentrations less than 10 ng/cu m. Concentrations of 100 ng/cu m to 1000 ng/cu m have been measured near specific asbestos emission sources, in schools where asbestos containing materials are used for sound control, and in office buildings where similar materials are used for fire control. [R161] RTEX: +Asbestos /enters the human body/ from gastrointestinal and respiratory tract exposure. [R149] +Asbestos is usually taken into the body by inhalation or ingestion and it is then distributed to most organs via the blood or lymphatic systems. [R162] +Assuming that asbestos is present at the highest accurate concentration, ie, > 9999.99 million fibers/liter the daily intake for a 70 kg adult male consuming 2 liters of drinking water/day would be > 20 billion fibers/day. [R163] +ASBESTOS FIBERS MAY BE LIBERATED INTO AIR IN DANGEROUS AMT ... IN MINING, MILLING, PROCESSING, OF ASBESTOS CONTAINING PRODUCTS AND DUMPING WASTE. ... FIBERS LESS THAN 3 UM IN DIAM AND FROM 10-200 UM IN LENGTH ARE MOST IMPORTANT CAUSE OF ASBESTOSIS. [R55, 123] +CONTENTS AND TYPES OF ASBESTOS IN FIREPROOFING INSULATION MATERIALS SPRAYED ON CEILINGS OF 127 BUILDINGS THROUGHOUT THE USA WERE STUDIED. DURING REMOVAL OF SPRAYED MATERIALS, WORKERS WERE EXPOSED TO EXTREMELY HIGH CONCENTRATIONS (AVG 16.4 FIBERS/CC) WHEN DRY METHODS WERE USED. WHEN WET METHODS WERE USED DURING REMOVAL, THE AIRBORNE FIBER CONCENTRATIONS WERE REDUCED TO LESS THAN 2 FIBERS/CC. [R164] +... EXPOSURES OCCUR DURING END-PRODUCT USE, AMONG ASBESTOS INSULATION WORKERS, AMONG BRAKE REPAIR AND BRAKE MAINTENANCE WORKERS, AND AS RESULT OF INDIRECT OCCUPATIONAL EXPOSURES, PARTICULARLY IN SHIP BUILDING AND SHIP REPAIR, AND IN CONSTRUCTION INDUSTRY. OTHER EXPOSURES OCCUR IN RELATION TO INSPECTION AND MAINTENANCE WORK ON ASBESTOS CONTAINING STRUCTURES AND EQUIPMENT, IN REFINERIES AND CHEMICAL PLANTS, BUILDINGS, RAILWAY LOCOMOTIVES AND WAGONS, SHIPYARDS AND POWER PLANTS. ... BUILDING DEMOLITION AND WASTE DISPOSAL. ... EXPOSURE MAY OCCUR DURING WEARING OF ASBESTOS SAFETY GARMENTS. [R165] +Talc /which is often contaminated with asbestos/ is used in the following products: cosmetics, spray and dusting powder, insecticides, white shoe polishes, as a filler for soap, dusting powders for toy balloons, condoms, and contraceptive diaphragms. [R166] +Occupations for potential exposure to asbestos include: asbestos textile production, asbestos paper production, asbestos cement pipe and sheet production, automotive brake and clutch repair, construction, and insulation production. [R167] +Insulation workers using asbestos materials and automotive brake repairmen have been exposed to airborne asbestos levels up to 133 and 72 fibers/cu m, respectively. [R139] +Exposure to airborne asbestos in the home may /result from use of/ spackling compounds, certain types of insulation, and some workers may bring home some material ... on their work clothing. [R139] +Exposure profiles for respirable silica dust in 15 mining industry groups that were prepared from the 1977-1981 Mine Safety and Health Administration (MSHA) MIDAS files are presented as probability distribution graphs. The dust exposure data have been organized into data sets according to industry group, operation category, and location (surface and underground) as discussed in this report. There are 15 industry groups: copper, gold and silver, iron, lead and zinc, molybdenum, uranium, other metals, limestone, other stone, clay and shale, asbestos, talc, oil shale, sand and gravel, and other nonmetals. Operation and location are classified into 14 categories: surface drilling; underground drilling, blasting, cutting and boring; surface production; surface mobile transport; surface haulageway maintenance; underground production; underground haulageway maintenance; crushing or grinding, and sizing; concentrating and finishing; non specific surface; and non specific underground. [R168] +...MAY OCCUR DURING MINING OF FIBROUS MINERALS... [R89] +IN MOST INDUSTRIAL ENTERPRISES DIFFERENT TYPES OF FIBER ARE USED, SO EXPOSURE TO A SINGLE ASBESTOS TYPE ARE UNUSUAL. [R154, p. V14 62] +Occupational settings in which individuals who may be at risk from indirect exposure to asbestos include: gold mining, cigarette filter manufacture, automobile transmission parts manufacture, dentistry, and agriculture. [R169] +Asbestos is present in the soil, water and air, and may be added to these media from mining, wearing of automobile brake linings, asbestos textile manufacturing, asbestos spraying for fireproofing, and the use of asbestos in construction materials. The multitude of uses for this non-combustible insulating material means that exposure may be both occupational and non-occupational (environmental); for most people, exposure to at least a low level of asbestos ocurs on a daily basis. [R162] +... Dietary materials that have been reported to contain, or are likely to contain, asbestos include foods such as vegetable oil, lard, mayonnaise, ketchup and meats ... and beverages such as beers, sherries, ports, vermouth and soft drinks. [R170] +Other sources of exposure in the home are: dustfall from mines and industry; roofing; vinyl-asbestos flooring; furnace pipe insulation; electric irons; stoves; millboard; paint; caulks; ironing board covers; toasters and hairdryers. [R171] +Currently, all major commercial asbestos varieties, chrysotile, amosite, and crocidolite, have been found to produce a significant incidence of asbestos-related disease among workers ocupationally exposed in mining and milling, in manufacturing, and in the use of materials containing the fiber. The predominant route of exposure has been inhalation, although some asbestos may be swallowed directly or after being brought up from the rspiratory tract. Not only has asbestos disease been found among individuals exposed to the fiber directly as a result of excessive work exposures in decades past, but asbestos-associated cancer has also been identified, albeit less frequently, among those with inhalation exposures of lesser intensity, including those who had worked near the application or removal of asbestos material, those with history or residing in the vicinity of asbestos plants, and those who had lived in the household of an asbestos worker. [R172] +The committee considered the health risks posed by non-occupational airborne exposures to asbestos and other natural or synthetic asbestiform fibers. This issue is important because many people may be exposed to these materials, although at relatively low levels. ... Non-occupational exposure to asbestiform fibers in air present a risk to human health. [R173] +DOMESTIC EXPOSURE OF HOUSEHOLD CONTACTS TO ASBESTOS MAY OCCUR FROM DUSTS BROUGHT HOME ON WORKERS' CLOTHES, SHOES, HAIR, EQUIPMENT, ETC. ... ASBESTOS LEVELS /WERE FOUND/ RANGING FROM 100-500 NG/CU M IN THE HOUSES OF WORKMEN. [R174] +Certain beverages are either made from water already containing asbestos fibers or are clarified (beer, wine) by filtration through asbestos filter pads from which fibers may be released. The asbestos fiber levels in other foods are largely unknown. [R118] +The hazard from environmental asbestos exposure showed that mesothelioma could occur among individuals whose potential asbestos exposure consisted of having resided near an asbestos factory or in the household of an asbestos worker. Twenty of 76 cases from the files of the London hospital were the result of such exposures. [R175] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers asbestos to be a potential occupational carcinogen. [R28, 22] OSHA: +The employer shall ensure that no employee is exposed to an airborne concentration of asbestos in excess of 0.1 fiber/cu cm of air as an 8-hr TWA as determined by the method prescribed in Appendix A to this section, or by an equivalent method. [R176] +The employer shall ensure that no employee is exposed to an airborne concentration of asbestos in excess of 1.0 fiber/cu cm of air as averaged over a sampling period of 30 min as determined by the method prescribed in Appendix A to this section, or by an equivalent method. [R176] NREC: +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R28, 22] +NIOSH considers asbestos to be a potential occupational carcinogen. [R28, 22] +For asbestos fibers > 5 micrometers in length, NIOSH recommends a REL of 100,000 fibers per cubic meter of air (100,000 fibers/cu m), which is equal to 0.1 fiber per cubic centimeter of air (0.1 fiber/cu cm). [R28, 22] TLV: +8 hr Time Weighted Avg (TWA): 0.1 fibers/cc; respirable fibers: length greater than 5 um; aspect ratio greater than or equal to 3:1. /Asbestos, all forms/ [R52, 2002.16] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Asbestos, all forms/ [R52, 2002.6] +A1; Confirmed human carcinogen. /Asbestos, all forms/ [R52, 2002.16] OOPL: +Regulations regarding asbestos levels in air in the workplace, ... United Kingdom: 2 fibers/cu m average over 4 hr for chrysotile, amosite, and anthophyllite also 12 fibers/cu m average over 10 min (for above mentioned fibers), crocidolite 0.2 fibers/cu m average over 10 minutes; Federal Republic of Germany: Chrysotile: 0.15 mg/cu m; Italy: 5 fibers/cu m; Denmark: 2 fibers/cu m, (ban asbestos for insulation work; special permission required to use crocidolite); USSR: 2 mg/cu m (if asbestos content > 10% of total dust; German Democratic Republic: 100 particles/cu m if asbestos content > 40%; South Africa: 2 fibers/cu m; Finland: 5 fibers/cu m (to be lowered to 2 fibers/cu m (ban crocidolite and ban spraying); Norway: 5 fibers/cu m (to be lowered to 2 fibers/cu m); Sweden: 2 fibers/cu m (special permission required to use crocidolite). /Data derived from table/ [R177] +Bureau of Mines (Department of Interior): regulation applies to surface work areas of underground and surface coal mines: longer than 5 um length/width ratio at least 3:1 in 20 randomly selected fields using phase contrast microscopy at 400-450X magnification is 2 fibers/ml 8 hr time-weighted average. [R178] ASTD: +Asbestos has been designated as a hazardous air pollutant under section 112 of the Clean Air Act. [R179] +A national air emission standard ... requires either the institution of specified air-cleaning methods or else no viable emissions (except water) to the outside air. This standard applies to the milling of asbestos (but not to adjacent storage depots); manufacturing or processing of specified products; renovating or demolishing certain buildings (but not ships) containing more than a specified amount of friable asbestos insulation; and to wastes containing commercial asbestos or products of asbestos mining and milling. Friable or spray-on insulating materials, except when applied to equipment or machinery, must contain no commercial asbestos; however, spray-on-paints, decorative materials, and weather-proofing are not regulated. [R180] +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Asbestos is included on this list. [R181] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 7 mf/l (million fibers/l) [R182] CWA: +Based on a consumption of 2 liters of drinking water and considering the risk levels of 1x10-7, 1x10-6, and 1x10-5, the corresponding interim criteria are 3,000 fibers/l, 30,000 fibers/l, and 300,000 fibers/l, respectively. [R183] CERC: +Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). /Friable asbestos/ [R184] TSCA: +After review of the law and legislative history, GAO determined EPA does have the authority to negotiate voluntary agreements with the chemical industry for needed health and environmental effects tests for chemical substances in lieu of issuing administrative rules formally requiring such testing. Although the voluntary approach is in the early stages, EPA believes that this information could be available 12 to 18 months earlier than otherwise. This report also provides information on (1) EPA's criteria for assessing chemcial risks, (2) the regulation of asbestos by EPA and other Federal Agencies, (3) EPA's proposed exemption of small chemical manufacturers from certain reporting and record keeping requirements, and (4) EPA's requirement for information on 250 chemicals. [R185] +The Asbestos-in-Schools Identification and Notification Rule effective June 28, 1982, required all public and private local education agencies (LEAs) to (1) inspect for friable materials; (2) sample and analyze these materials when found; (3) post notice of inspection results and notify employees and parents in schools with asbestos containing friable materials (ACFM); and (4) maintain records of the findings at the local education agencies and schools. A stratified systematic sample of 1,800 public and 800 private local education agencies was randomly selected proportionate to the square root of enrollment. A telephone survey found that 83% of the local education agencies have begun or completed inspections and 94% of all schools have been inspected. Of the schools inspected, 35% found asbestos containing friable materials. Almost all local education agencies asbestos containing friable materials have abatement programs (93%), about 1/3 of which (31%) are operations/maintenance only. Only 9% of the local education agencies were in compliance with the rule by June 28, 1983, the rule's compliance date; and 11% were by January 1984, the date of the survey. Record-keeping and notification were the major problem areas of noncompliance. QA site visits were made to 38 local education agencies and 94 schools within these local education agencies were inspected. The local education agencies data collected during the site visits agreed substantially with the telephone survey data. [R186] +Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. As cited in the preamble of 51 FR 41329. Asbestos is included on this list. [R187] FDA: +Asbestos is an indirect food additive for use only as a component of adhesives. For use only as polymerization control agent. [R188] +Asbestos is used as a reinforcement to facilitate the production of cross linked polyester resins or added there to import desired technical and physical properties. [R189] +Asbestos fibers are employed in the production of phenolic resins which will be used as the contact surface of molded articles intended for repeated use in contact with monoacid food (pH above 5.0). [R190] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: +SAMPLE IS COLLECTED WITH A HIGH VOLUME SAMPLER ON MICROSORBAN PAPER. THE PAPER IS DISSOLVED IN BENZENE. [R191] +NIOSH 7402: Analyte: asbestos fibers; Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25 mm diameter; conductive cassette); Flow rate: 0.5-16 l/min; Vol: min: 400 l at 0.1 fiber/ml; max: 10,000 l; Sample stability: stable. Shipment is routine (securely packed to reduce shock). [R192, p. V1 7402-1] +NIOSH 7400: Analyte: Fibers (including asbestos fibers); Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25 mm diameter; conductive cowl on cassette); Flow rate: 0.5 to 16 l/min; Minimum vol: 400 l at 0.1 fiber/ml; Maximum vol: 10,000 l; Stability: stable. Shipment is routine (securely packed to reduce shock). [R192, p. V1 7400-1] ALAB: +JEFFREY MINE AND COALING MINE CHRYSOTILE, 2 ASBESTOS SAMPLES PREPARED FOR EXPERIMENTAL HEALTH SCIENCES, AND THE UNION INTERNATIONALE CONTRE LE CANCER B CHRYSOTILE REFERENCE SAMPLE HAVE BEEN CHARACTERIZED IN THE AEROSOLIZED STATE USING GRAVIMETRIC MEASUREMENTS, LIGHT MICROSCOPY, AND X-RAY ENERGY SPECTROMETRY. [R193] +Light microscopy, with phase contrast at 400X: feature examined: morphology, limit of resolution about 0.5 um; dispersion staining: feature examined: refractive index and morphology, skilled operators can distinguish asbestos fibers. Limit of resolution about 0.5 um sq m; X-ray difraction: crystal structure; infrared spectroscopy: characteristic absorption bands; atomic absorption: elemental composition; neutron activation: elemental composition; emission spectroscopy: elemental composition; thermal analysis (TGA AND DTA): weight loss on heating due to dehydroxylation; scanning electron microscopy with microprobe: surface topology of the fiber and elemental analysis, most scanning electron microscopes have a theoretical resolution limit of about 10.0-20.0 nm. Background can give interference; transmission electron microscopy with microprobes, feature examined: shape outline, electron diffraction and elemental analysis, resolution limit down to 0.40 nm. Transfer to grid can lead to statistical errors in counting. [R194] +A method for cryogenically grinding and separating (by size) fibrogenic minerals in the 1 micron size range is described and verified for chrysotile asbestos, quartz, forsterite (an olivine), and tantalum with a battery of analytical tests. Through use of energy dispersive X-ray photoelectron spectroscopy, and X-ray diffraction analysis it is shown that the grinding and separation procedure described does not alter the mineral composition, preserves the trace element composition, maintains the surface composition, and preserves the crystalline structure. Further, investigation of electrokinetic properties of these dusts by electrophoretic quasi-elastic light scattering is described. The small size dispersity of these samples facilitates use of this technique for the determination of the apparent electrokinetic charge and estimations of surface charge density at ionic strengths below physiological. It is suggested that analyses of the type described here be an integral part of studies of the fibrogenic, immunologic, or toxicologic properties of such minerals. /Chrysotile asbestos/ [R195] +A field study was conducted to measure asbestos fiber concentrations during brake repair for mechanics in the Federal Republic of Germany. In addition to asbestos air sampling, 210 occupational histories describing working conditions under which brake maintenance is carried out were evaluated. Ninety dust concentration measurements in 76 service stations with static and personal samplers during brake maintenance operations. Sampling times varied from less than 3 min to more than 1 hr depending on the duration of the work operation. Samples were analyzed by phase contrast microscopy and scanning transmission electron microscopy. Fiber concentrations during brake service operations were 0.1X10+6/cu m (0.1 fiber per cc) on average. Average fiber dosages (fiber concentration X sampling time) ranged from 4X10+6 fiber/cu m/min for dry brushing and grinding to 10X10+6 fibers/cu m/min for machine grinding. Electron microscopy of brake drum dust indicated very high concentrations of short fibers; fibers with lengths > 5 um constituted less than 1% of all the chrysotile fibers counted. [R196] +BOTH TRANSMISSION AND SCANNING ELECTRON MICROSCOPY ... USED TO IDENTIFY AND QUANTIFY ... FIBERS. ... MICROCHEMICAL ANALYSIS (ELECTRON MICROPROBE ANALYSIS) ... . /ASBESTOS FIBERS/ [R197] +METHODS OF CONFIRMING ASBESTOS CAN INCLUDE OPTICAL TESTING USING POLARIZED LIGHT, FIRST ORDER RED OR OTHER RETARDATION PLATES, ANGLES OF EXTINCTION, DISPERSION STAINING. BULK SAMPLES MAY BE ANALYZED BY X-RAY DIFFRACTION OR IR ABSORPTION OF DIFFERENTIAL THERMAL ANALYSIS. [R198] +TRANSMISSION ELECTRON MICROSCOPY ... PARTICAL MORPHOLOGY CAN BE ACCURATELY OBSERVED AND ELECTRON DIFFRACTION PATTERNS ARE DISPLAYED. NIOSH (NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH), "RE-EXAMINATION AND UPDATE OF INFORMATION ON THE HEALTH EFFECTS OF OCCUPATIONAL EXPOSURE TO ASBESTOS," WASHINGTON DC (1977). [R197] +NIOSH 7402: Analyte: asbestos fibers; Matrix: air: Technique: Transmission electron microscopy; Range: 100-1300 fibers/sq mm filter area; Precision: 0.28 when 65% of fibers are asbestos; 0.20 when adjusted fiber count is applied to PCM count; Est limit of detection: 1 confirmed asbestos fiber above 95% of expected mean blank value; Interferences: Non-asbestiform amphiboles may interfere in the transmission electron microscopy analysis if the individual particles have aspect ratios greater than 3:1. These interferences can only be eliminated by quantitative zone axis electron diffraction analysis. NIOSH method 7400 (phase-contrast microscopy) is designed for use with this method. [R192, p. V1 7402-1] +NIOSH 7400: Analyte: asbestos fibers; Matrix: air: Technique: Light microscopy, phase contrast; Range: 100-1300 fibers/sq mm filter area; Precision: 0.10 to 0.12 (based on OSHA regulations for rule A); Est limit of detection: 7 fibers/sq mm filter area. This method gives an index of airborne fibers in workplace atmospheres. Phase contrast microscopy will not differentiate between asbestos and other fibers; use this method in conjunction with electron microscopy (eg, Method 7402) for positive identification. Fibers < about 0.25 um diameter will not be detected by this method. Any other airborne fiber may interfere. Chain-like particles may appear fibrous. High levels of non fibrous dust particles may obscure fibers in the field of view and increase the detection limit. [R192, p. V1 7400-1] CLAB: +... /An X-ray procedure has been used to determine/ how much of each type of /asbestos/ fiber ... /was/ present in small samples ... /of/ lung residues. ... By using an electron microscope with an energy dispersion X-ray analysis attachment the morphology of even the smallest fibers can be recorded. ... X-ray dispersion equipment provides quantitative elemental assessment even at several points on a single fibre only 0.2 um in diameter and a few um long. X-ray diffraction is useful and quicker, but cannot separate chrysotile fibers from particles of the parent serpentine rock, nor always separate the types of amphiboles. [R1, 186] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: MARSH GM; ENVIRON HEALTH PERSPECT 53: 49-56 (1983). REVIEW: THIRTEEN EPIDEMIOLOGIC STUDIES OF INGESTED ASBESTOS CONDUCTED IN 5 AREAS OF THE USA AND CANADA WERE REVIEWED AND EVALUATED FOR THE DEFINITIVENESS AND APPLICABILITY REGARDING THE DEVELOPMENT OF AMBIENT WATER QUALITY STANDARDS. USDHEW/NIOSH; Revised Recommended Asbestos Standard (1976) DHEW (NIOSH) Pub No. 77-169 USDHEW/NIOSH; Occupational Exposure to Talc Containing Asbestos (1980) DHEW (NIOSH) Pub No. 80-115 USEPA; Ambient Water Quality Criteria Doc: Asbestos (1980) EPA 440/5-80-022 Nat'l Research Council Canada; Effect of Chromium, Alkali Halides, Arsenic, Asbestos, Mercury in the Canadian Environment (1980) NRCC No. 17585 Nat'l Research Council Canada; Asbestos (1979) NRCC No. 16452 Toxicity of Fibers. 1970-July 1983. Govt Rpts Announcements and Index 20: (1983). This bibliography contains citations concerning the toxicity of occupational exposures to fibers and composite materials. Topics include respiratory illnesses due to chronic exposure to asbestos and glass fibers, and methods and equipment for control of airborne fibers. NTIS; Asbestos and Silicate Pollution December 1979-March 1982. Govt Rpts Announcements and Index 21: (1983). This bibliography cites federally funded research reports on air and water pollution by silica, asbestos, silicates, and silicon dioxide. The citations cover sources, control, detection, and effects on plants, animals, and humans (silicosis, asbestosis, and toxicity). UNTIS; Industrial Health Hazards Due to Atmospheric Factors, April 1982-May 1983 Govt Rpts Announcements and Index 19: (1983). This bibliography contains abstracts of research reports covering such topics as industrial medicine, occupational diseases, health of miners, and the toxicological factors of various pollutants ... including asbestos. Condie LW; Environ Health Perspect 53: 3-9 (1983). There has been great public concern about the adverse health effects resulting from the presence of asbestos fibers in municipal drinking water supplies. This article reviews and summarizes the carcinogenic potential of asbestos following its ingestion. The long-term, high-level of ingestion of various types of asbestos fibers in more than one animal species failed to produce any definite, reproducible, organ-specific carcinogenic effect. USEPA/ECAO; Asbestos Health Update (1984) EPA 600/8-84-003A Becklake MR; Amer Rev Resp Dis 126 (2): 187-94 (1982). Asbestos-related diseases of the lungs and pleura /are reviewed along with/ current clinical issues. Canadian Center for Occupational Health and Safety; A Review of Four Major Reports on the Health Hazards of Asbestos 93 pp. (1981) Council of Europe/Committee of Ministers; Resolution on Technical and Personal Protective Measures for the Prevention of Exposure of Workers to Asbestos Dust; 4 pp (1980) Acheson ED, Gardner MJ; Asbestos - The Control Limit for Asbestos; HM Stationery Office 26 pp. (1983) Bishop K et al; Bull Environ Contam Toxicol 34 (3): 301-8 (1985). Identification of asbestos and glass fibers in municipal sewage sludges. WHO; Environ Health Criteria: Asbestos and Other Natural Mineral Fibers (1986) USEPA; Health and Environmental Effects Profile for Asbestos (1979) U.S. Dept Health and Human Services/Agency for Toxic Substances Disease Registry; Toxicological Profile for Asbestos (Update) (1995) NTIS # PB/95-264305 DHHS/NTP; Toxicology and Carcinogenesis Studies of Crocidolite Asbestos in F344/N Rats (Feed Studies) Technical Report Series No. 280 (1988) NIH Publication No. 89-2536 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: USDHEW/NCI; Asbestos: An Information Resource p.72 DHEW Pub No. NIH 79-1681 (1978) R4: Davis JM et al; Carcinogenesis 6 (5): 667-74 (1985) R5: Nat'l Research Council Canada; Asbestos p.21 (1979) NRCC No. 16452 R6: Van, H. (ed.). OPD Chyemical Buyer's Directory 1989. 76th ed, New York, NY: Schnell Publishing Co., Inc. 1989. 102 R7: Nat'l Research Council Canada; Asbestos p.55 (1979) NRCC No. 16452 R8: Nat'l Research Council Canada; Asbestos p.34 (1979) NRCC No. 16452 R9: BUREAU OF MINES. MINERALS YEARBOOK 1983 V1 p.118 R10: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 101 R11: USDHEW/NCI; Asbestos: An Information Resource p.5 (1978) DHEW Pub No. NIH 79-1681 R12: USDHEW/NCI; Asbestos: An Information Resource p.7 (1978) DHEW Pub No. NIH 79-1681 R13: Berman J; Am J Law Med 10 (1): 93-114 (1984) R14: Nicholson WJ et al; Science 177: 171-3 (1972) as cited in Nat'l Research Council Canada; Asbestos p.51 (1979) NRCC No. 16452 R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 30 (1978) R16: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 117 R17: SRI R18: USDHEW/NCI; Asbestos: An Information Resource p.14 (1978) DHEW Pub No. NIH 79-1681 R19: USDHEW/NCI; Asbestos: An Information Resource p.15 (1978) DHEW Pub No. NIH 79-1681 R20: Vagt GO; Asbestos 1973 Canadian Minerals Yearbook p.41-49 (1974) as cited in Nat'l Research Council Canada; Asbestos p.30 (1979) NRCC No. 16452 R21: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-1 (1980) EPA 440/5-80-022 R22: USDHEW/NCI; Asbestos: An Information Resource p.9 (1978) DHEW Pub No. NIH 79-1681 R23: BUREAU OF MINES. MINERAL COMMODITY SUMMARIES 1987 p.14 R24: BUREAU OF MINES. MINERAL COMMODITY SUMMARIES 1986 p.14 R25: BUREAU OF MINES. MINERAL COMMODITY SUMMARIES 1989 P.18 R26: USDHEW/NCI; Asbestos: An Information Resource p.9 DHEW Pub No. NIH 79-1681 (1978) R27: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 110 R28: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R29: Speil S, Leineweber JP; Environ Res 2: 166 (1969) as cited in USEPA; Health and Environmental Effects Profile for Asbestos p.12-6 (1969) R30: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-171 R31: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.68 R32: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-3 (1980) EPA 440/5-80-022 R33: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-5 (1980) EPA 440/5-80-022 R34: USDHEW/NCI; Asbestos: An Information Resource p.79 (1978) DHEW Pub No. NIH 79-1681 R35: USDHEW/NCI; Asbestos: An Information Resource p.78 (1978) DHEW Pub No. NIH 79-1681 R36: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R37: 29 CFR 1910.1001 (7/1/88) R38: 20 CFR 1910.1001 (7/1/88) R39: Curtis RA, Bierbaum PJ; Am Ind Hyg Assoc J 36 (2): 115-25 (1975) as cited in Nat'l Research Council Canada; Asbestos p.52 (1979) NRCC No. 16452 R40: Nat'l Research Council Canada; Asbestos p.53 (1979) NRCC No. 16452 R41: USDHEW/NCI; Asbestos: An Information Resource p.68 (1978) DHEW Pub No. NIH 79-1681 R42: USDHEW/NCI; Asbestos: An Information Resource p.76 (1978) DHEW Pub No. NIH 79-1681 R43: Heitbrink WA; In-Depth Survey Report: Control Technology for Solids Material Handling at General Motors Corporation, Inland Division, Vandalia, Ohio 34 pp. (1985) NIOSH Report No. CT-144-14B R44: Origins of Human Cancer; Hiatt HH (eds) Book C: Human Risk Assesment Vol #4 p.1786 (1977) R45: 49 CFR 171.2 (7/1/96) R46: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.9014 (1988) R47: LOGSDON GS; ENVIRON HEALTH PERSPECT 53: 169-76 (1983) R48: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 96 R49: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-11 (1981) EPA 68-03-3025 R50: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 106 (1987) R51: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Asbestos (1332-21-4) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R52: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R53: USDHEW/NCI; Asbestos: An Information Resource p.96 (1978) DHEW Pub No. NIH 79-1681 R54: USDHEW/NCI; Asbestos: An Information Resource P.93 (1978) DHEW Pub No. NIH 79-1681 R55: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R56: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.40 R57: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 107 R58: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 108 (1987) R59: IARC. 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V14 81 (1977) R60: WILSON MR ET AL; J ALLERGY CLIN IMMUNOL 60 (4): 218-22 (1977) R61: ORDONEZ NG, SMITH JL JR; ARCH DERMATOL 119 (10): 827-30 (1983) R62: CASEY G; MUTAT RES 116 (3-4): 369-77 (1983) R63: BROWNE K; ARCH ENVIRON HEALTH 38 (5): 261-66 (1983) R64: USDHEW/NCI; Asbestos: An Information Resource p.36 (1978) DHEW Pub No. NIH 79-1681 R65: USEPA/OHEA; Asbestos Health Assessment Update (Draft) p.5 (1984) EPA 600/8-84-0034A R66: Sadler TD et al; J Commun Hlth 9 (4): 285-93 (1984) R67: Kobusch AB et al; J Chron Dis 37 (8): 599-607 (1984) R68: Barnes R; Med J Aust 2: 221-24 (1983) R69: Hodgson JT, Jones RD; Br J Ind Med 43: 158-64 (1986) R70: Kjuus H et al; Scand J Work Environ Health 12: 203-9 (1986) R71: Kelsey KT et al; JNCI 77 (2): 321-27 (1986) R72: SIGURDSON EE; ENVIRON HEALTH PERSPECT 53: 61-67 (1983) R73: Hammond EC et al; Arch Environ Health 29: 341 (1979) as cited in USEPA; Health and Environmental Effects Profile for Asbestos; p.12-11 (1979) EPA No 12 R74: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.138 (1979) NRCC No. 16452 R75: Millette JR et al; Environ Health Perspect 53: 91-98 (1983) as cited in USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.VI-13 (1985) R76: Selikoff IJ et al; Ann NY Acad Sci 330: 91-116 as cited in USEPA; Asbestos Health Assessment Update (Draft) p.11-13 (1984) EPA-600/8-84-003A R77: USEPA; Asbestos Health Assessment Update (Draft) p.14-16 (1984) EPA-600/8-84-003A R78: Enterline PE, Henderson V; Arch Environ Health 27: 312-17 (1973) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.5 (1984) EPA-600/8-84-003A R79: Lewinsohn HC; R Soc Health J 92: 69-77 (1972) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.5 (1984) EPA-600/8-84-003A R80: Newhouse ML et al; Br J Ind Med 29: 134-41 (1972) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.57 (1984) EPA-600/8-84-003A R81: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.113 (1979) NRCC No. 16452 R82: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.19 (1979) NRCC No. 16452 R83: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.17 (1979) NRCC No. 16452 R84: Enterline PE et al; J Occup Med 14: 897 (1972) as cited in USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-76-77 (1980) EPA 440/5-80-022 R85: Newhouse ML, Berry G; Br J Ind Med 36: 98-112 (1983) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.47 (1984) EPA-600/8-84-003A R86: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 44 (1977) R87: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V2 27 (1973) R88: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 60 (1977) R89: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 80 R90: SHORE BL ET AL; AM REV RESPIR DIS 128 (3): 481-85 (1983) R91: PELE JP, CALVERT R; ENVIRON RES 31 (1): 164-75 (1983) R92: KAGAN E ET AL; ENVIRON RES 32 (2): 382-97 (1983) R93: JAURAND MC ET AL; ENVIRON HEALTH PERSPECT 51: 153-58 (1983) R94: USEPA/HERL; Inhalable Particles and Pulmonary Host Defense: In Vivo and In Vitro Effects of Ambient Air and Combustion Particles 15 pp. (1985) EPA 600/J-85-026 R95: Wozniak H, Wiecek E; Med Pr 35 (4): 269-72 (1984) R96: Donaldson K et al; Inflammation 9 (2): 139-47 (1985) R97: Rahman Q et al; Environ Res 14: 487-98 (1977) as cited in Nat'l Research Council Canada; Asbestos p.80 (1979) NRCC No. 16452 R98: Beg MU et al; Environ Physiol Biochem 3: 185-91 (1973) as cited in Nat'l Research Council Canada; Asbestos p.80 (1979) NRCC No. 16452 R99: Kasai H, Nishimura S; Gann 75 (10): 841-44 (1984) R100: Wagner JC et al; Br J Cancer 51 (5): 727-30 (1985) R101: GENE-TOX Program: Current Status of Bioassay in Genetic Toxicology. U.S. Environmental Protection Agency, Washington, DC. Office of Toxic Substances and Pesticides. (For program information, contact Environmental Mutagen Information Center, Oak Ridge National Laboratory, Post Office Box Y, Oak Ridge, Tennessee 37830. Telephone (615) 574-7871) R102: Sincock AM; Nature 257: 58 (1977) as cited in USEPA; Health and Environmental Effects Profile for Asbestos p.12-11 (1979) R103: Chamberlain M, Tarmy EM; Mutat Res 43: 159 (1977) as cited in USEPA; Health and Environmental Effects Profile for Asbestos p.12-11 (1979) R104: Ward JM et al; J Environ Pathol Toxicol 3: 301-12 (1980) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.V-5 (1985) R105: Schneider U, Maurer RR; Teratology 15: 273-80 (1977) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.V-22 (1985) R106: Davis JMG et al; Br J Cancer 37: 673-88 (1978) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.76 (1984) EPA-600/8-84-003A R107: Donham KJ et al; Cancer (March Suppl) 45: 1073-84 (1980) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.VII-2 (1985) R108: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.80 (1979) NRCC No. 16452 R109: GLICKMAN LT ET AL; ENVIRON RES 32 (2): 305-13 (1983) R110: Toxicology and Carcinogenesis Studies of Crocidolite Asbestos in F344/N Rats (Feed Studies). Technical Report Series No. 280 (1988) NIH Publication No. 89-2536 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R111: Dow Chemical Co.; Effects From Chronic Inhalation of Asbestos Pipe-Covering Dust in Rats and Hamsters. (1976), EPA Document No. 878211593, Fiche No. OTS0206137 R112: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (1980) EPA 440/5-80-022 R113: Hammond EC et al; Health Hazards of Asbestos Exposure 473-90 (1979) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.VI-21 (1985) R114: Seiler, H.G., H. Sigel and A. Sigel (eds.). Handbook on the Toxicity of Inorganic Compounds. New York, NY: Marcel Dekker, Inc. 1988. R115: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 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V14 72 (1977) R118: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.14 (1979) NRCC No. 16452 R119: Morgan A et al; Br J Ind Med 35: 146-53 (1978) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.74 (1984) EPA-600/8-84-003A R120: USEPA; Asbestos Health Assessment Update (Draft) p.74-76 (1984) EPA-600/8-84-003A R121: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-29 (1980) EPA 440/5-80-022 R122: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-32 (1980) EPA 440/5-80-022 R123: BOLTON RE, DAVIS J MG; ANN OCCUP HYG 19 (2): 121-8 (1976) R124: Cunningham HM, Moodie CA; Arch Environ Contam Toxicol 6: 507-13 (1977) as cited in USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.III-10 (1985) R125: USEPA; Asbestos Health Assessment Update (Draft) p.92 (1984) EPA-600/8-84-003A R126: Cunningham HM, Pontefract RD; J Assoc Off Anal Chem 56: 976 (1973) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.III-8 (1985) R127: Nat'l Research Council Canada; Executive Reports Effects of Chromium, Alkali Halides, Arsenic, Asbestos, Mercury, Cadmium p.54 (1980) NRCC No. 17585 R128: Weitzman SA, Weitberg AB; Biochem J 225 (1): 259-62 (1985) R129: USEPA; Asbestos Health Assessment Update (Draft) p.9 (1984) EPA-600/8-84-003A R130: USEPA; Asbestos Health Assessment Update (Draft) p.23 (1984) EPA-600/8-84-003A R131: POOLE A ET AL; ENVIRON HEALTH PERSPECT 51: 319-24 (1983) R132: Bignon J et al; Carcinogenesis 4 (5): 621-28 (1983) R133: Hammond EC et al; Ann NY Acad Aci 330: 473-90 (1979) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.27 (1984) EPA-600/8-84-003A R134: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.21 (1979) NRCC No. 16452 R135: Hei TK et al; Br J Cancer 52 (4): 591-97 (1985) R136: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3021 R137: Nat'l Research Council Canada; Asbestos p.42 (1979) NRCC No. 16452 R138: Luckewitz W; J Soc Cosmet Chem 26: 431-37 (1975) as cited in Nat'l Research Council Canada; Asbestos p.51 (1979) NRCC No. 16452 R139: Nat'l Research Council Canada; Asbestos p.13 (1979) NRCC No. 16452 R140: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 93 R141: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V2 25 (1973) R142: Sawyer RN; Ann NY; Acad Sci 330: 579-86 (1979) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.102 (1984) EPA-600/8-84-003A R143: Nicholson WJ; Ann NY Acad Sci 271: 152-69 (1976) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.62 (1984) EPA-600/8-84-003A R144: Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979. R145: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.15 (1979) NRCC No. 16452 R146: SIGURDSON EE; ENVIRON HEALTH PERSPECT 53: 61-7 (1983) R147: Kay GH; J Am Water Works Assoc 65: 513-14 (1974) as cited in Nat'l Research Council Canada; Asbestos p.41 (1979) NRCC No. 16452 R148: Cunningham HM, Pontefract RD; Nature 232: 332-3 (1971) as cited in Nat'l Research Council Canada; Asbestos p.40 (1979) NRCC No. 16452 R149: Nat'l Research Council Canada; Asbestos p.14 (1979) NRCC No. 16452 R150: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.98-99 (1980) EPA 440/5-80-022 R151: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-19 (1980) EPA 440/5-80-022 R152: Millette JR; Environmental Health Effects Reseach Report (1979) EPA 600/1-79- 150 as cited in USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-13 (1980) EPA 440/5-80-022 R153: Carter LJ; Science 197: 237-40 (1977) as cited in Nat'l Research Council Canada; Asbestos p.42 (1979) NRCC No. 16452 R154: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R155: USEPA; Office of Toxic Substances Summary Report of Asbestos Monitoring Data (1982) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.IV-12 (1985) R156: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-98 (1980) EPA 440/5-80-022 R157: USEPA; Asbestos Health Assessment Update (Draft) p.36-37 (1984) EPA-600/8-84-003A R158: Nat'l Research Council Canada; Asbestos p.38 (1979) NRCC No. 16452 R159: Halsband E; The Effects of Asbestos Waste Products on Mussels (Myilus edulis). Int Council Exploration of the Seas, Fisheries Improvement Comm (1974) as cited in Nat'l Research Council Canada; Asbestos p.67 (1979) NRCC No. 16452 R160: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 152 R161: USEPA; Asbestos Health Assessment Update (Draft) p.109 (1984) EPA-600/8-84-003A R162: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.23 (1979) NRCC No. 16452 R163: Millette JR et al; Environ Health Perspect 53: 91-98 (1983) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.IV-8 (1985) R164: PAIK NW ET AL; AM IND HYG ASSOC J 44 (6): 428-32 (1983) R165: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 37 (1977) R166: Nat'l Research Council Canada; Asbestos p.51 (1979) NRCC No. 16452 R167: USDHEW/NCI; Asbestos: An Information Resource p.80-2 DHEW Pub No. NIH 79-1681 (1978) R168: Chen CK et al; Technological Feasibility of Controlling Asbestos and Silica at Mines and Mills. 248 pp (1983) NIOSH Contract No. PHS-NIOSH-210-81-4101 R169: Nat'l Research Council Canada; Asbestos p.46 (1979) NRCC No. 16452 R170: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.IV-8 (1985) R171: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.52 (1979) NRCC No. 16452 R172: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.63 (1980) EPA 440/5-80-022 R173: NRC; Asbestiform Fibers: Nonoccupational Health Risks 345-pp. (1985) EPA Contract No. 68-01-4655 R174: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 38 (1977) R175: Newhouse ML, Thompson H; Br J Ind Med 22: 261 (1965) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.114 (1984) EPA-600/8-84-003A R176: 29 CFR 1910.1001(c) (7/1/98) R177: Zielhuis RL; Public Health Risks of Exposure to Asbestos. Comm Eur Commun Report No. LCC 76-5 1964 149 pp. (1977) as cited in Nat'l Research Council Canada; Asbestos p.56 (1979) NRCC No. 16452 R178: USDHEW/NCI; Asbestos: An Information Resource p.B-1 DHEW Pub No. NIH 79-1681 (1978) R179: 40 CFR 61.01 (7/1/88) R180: USDHEW/NCI; Asbestos: An Information Resource p.6 DHEW Pub No. NIH 79-1681 (1978) R181: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R182: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R183: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-113 (1980) EPA 440/5-80-022 R184: 54 FR 33419 (8/14/89) R185: GAO/Resources Community Economic Div; EPA Implementation of Selected Aspects of the Toxic Substances Control Act 30 pp (1983) GAO/RCED-83-62, B-209343 R186: Greenblatt J; Evaluation of the Asbestos-in-Schools Identification and Notification Rule 245 pp (1985) EPA Contract No. 68-01-6721 R187: 40 CFR 712.30 (7/1/88) R188: 21 CFR 175.105 (4/1/88) R189: 21 CFR 177.2420 (4/1/88) R190: 21 CFR 177.2410 (4/1/88) R191: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 702 R192: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R193: PINKERTON KE ET AL; ENVIRON RES 31 (1): 32-53 (1983) R194: Harwood CF, Yamate G; Resumes Commun Conf Int Phys Chim Miner Amiante Section 7.30 21 pp. (1975) as cited in Nat'l Research Council Canada; Asbestos p.59 (1979) NRCC No. 16452 R195: Thorne PS et al; Environ Res 36 (1): 89-110 (1985) R196: Rodelsperger K et al; Am J Ind Med 10: 63-72 (1986) R197: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 41 (1977) R198: DIXON W; MICROSCOPE 26 (4TH QUARTER): 183 (1978) RS: 158 Record 62 of 1119 in HSDB (through 2003/06) AN: 513 UD: 200303 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4,4'-BISPHENOL-A- SY: *BISFEROL-A- (CZECH); *2,2-BIS-4'-HYDROXYFENYLPROPAN- (CZECH); *BIS(4-HYDROXYPHENYL) DIMETHYLMETHANE; *BETA,BETA'-BIS(P-HYDROXYPHENYL)PROPANE; *2,2-BIS(P-HYDROXYPHENYL)PROPANE; *2,2-BIS(4-HYDROXYPHENYL)PROPANE; *BIS(4-HYDROXYPHENYL)PROPANE; *BISPHENOL-; *BISPHENOL-A-; *P,P'-BISPHENOL-A-; *DIAN-; *DIANO-; *P,P'-DIHYDROXYDIPHENYLDIMETHYLMETHANE-; *4,4'-DIHYDROXYDIPHENYLDIMETHYLMETHANE-; *P,P'-DIHYDROXYDIPHENYLPROPANE-; *2,2-(4,4'-DIHYDROXYDIPHENYL)PROPANE; *4,4'-DIHYDROXYDIPHENYLPROPANE-; *4,4'-DIHYDROXYDIPHENYL-2,2-PROPANE-; *BETA-DI-P-HYDROXYPHENYLPROPANE-; *2,2-DI(4-HYDROXYPHENYL)PROPANE; *DIMETHYL BIS(P-HYDROXYPHENYL)METHANE; *DIMETHYLMETHYLENE-P,P'-DIPHENOL-; *DIPHENYLOLPROPANE-; *2,2-DI(4-PHENYLOL)PROPANE; *IPOGNOX-88-; *ISOPROPYLIDENEBIS(4-HYDROXYBENZENE); *P,P'-ISOPROPYLIDENEBISPHENOL-; *4,4'-ISOPROPYLIDENEBISPHENOL-; *P,P'-ISOPROPYLIDENEDIPHENOL-; *4,4'-ISOPROPYLIDENEDIPHENOL-; *4,4'-(1-METHYLETHYLIDENE)BISPHENOL; *NCI-C50635-; *PARABIS-A-; *PHENOL,-4,4'-DIMETHYLMETHYLENEDI-; *PHENOL,-4,4'-ISOPROPYLIDENEDI-; *PHENOL, 4,4'-(1-METHYLETHYLIDENE)BIS-; *PLURACOL-245-; *PROPANE, 2,2-BIS(P-HYDROXYPHENYL)-; *Rikabanol-; *Ucar-bisphenol-HP- RN: 80-05-7 MF: *C15-H16-O2 ASCH: BISPHENOL B; 77-40-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Produced by the condensation of two moles of phenol with one mole of acetone while bubbling hydrogen chloride through the mixture. [R1] IMP: *Impurities of the phenol-acetone condensation reaction are the tri- or mono-hydroxy by-products [R1] FORM: *... 4,4'-DIHYDROXYDIPHENYLDIMETHYLMETHANE IS GENERALLY AVAIL AS THIN PLATES AND HAS FOLLOWING PROPERTIES: BISPHENOL CONTENT GREATER THAN 99%; PHENOL CONTENT LESS THAN 0.1%; WATER CONTENT LESS THAN 1%; ASH LESS THAN 0.02%; AND IRON LESS THAN 0.001%. [R2, 330] *Available as flake, crystalline or prilled material [R1] MFS: *DOW CHEM USA, FREEPORT, TX [R3] *GENERAL ELECTRIC CO, PLASTICS BUSINESS DIV, ENGINEERING PLASTICS PRODUCT DEPT, MT VERNON, IN [R3] *SHELL CHEM CO, POLYMERS AND DETERGENT PRODUCTS, DEER PARK, TX [R3] *UNION CARBIDE CORP, CHEMS AND PLASTICS DIV, MARIETTA, OH, UNION CARBIDE CARIBE, INC, SUBSID, PENUELAS, PR [R3] *ACC Holdings Corp, Hq, Aristech Chemical Corp, 600 Grant Street, Pittsburgh, PA 15214-2704, (412) 433-2747; Production site: Haverhill, OH 45636 [R4] OMIN: *Impurities of phenol-acetone condensation can be removed by distillation and extractive crystalliation under pressure. [R1] USE: *AS FUNGICIDE [R5] *CHEM INT FOR EPOXY, PHENOXY AND POLYSULFONE RESINS [R3] *FLAME RETARDANTS; RUBBER CHEMICALS; CHEM INT FOR CERTAIN POLYESTER RESINS. [R6] *Chem int for polycarbonate [R7] *Chem int for hydroquinone production [R8] CPAT: *53% AS A CHEM INT FOR EPOXY RESINS; 31% AS A CHEM INT FOR POLYCARBONATE RESINS; 16% IN MISC APPLICATIONS INCL AS A CHEM INT FOR PHENOXY AND POLYSULFONE RESINS (1973) [R3] *Polycarbonate Resins, 52%; Epoxy Resins, 41%; Tetrabromobisphenol A, 2%; Miscellaneous, 5% (1984) [R1] *Chemical Profile: Bisphenol-A. Polycarbonate resins, 50%; epoxy resins, 32%; miscellaneous, including unsaturated polyester resins, polysulfone resins, polyarylate resins and flame retardants, 6%; exports, 12%. [R9] *Chemical Profile: Bisphenol-A. Demand: 1986: 823 million lb; 1987: 880 million lb; 1991 /projected/: 1.050 million lb. (Includes exports). [R9] PRIE: U.S. PRODUCTION: *(1972) 1.16X10+11 G [R3] *(1975) 1.33X10+11 G [R3] *(1984) 3.46X10+11 g [R10] *(1991) 1.37X10+9 lbs [R4] U.S. IMPORTS: *(1972) NEGLIGIBLE [R3] *(1975) 6.07X10+7 G (PRINCPL CUSTMS DISTS) [R3] U.S. EXPORTS: *(1972) AT LEAST 7.26X10+9 G [R3] *(1973) 1.1X10+10 G (EST) [R3] *(1984) 1.92X10+10 g [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALLIZES AS PRISMS FROM DIL ACETIC ACID AND AS NEEDLES FROM WATER [R12]; *WHITE FLAKES [R6]; *white to cream [R13] ODOR: *MILD PHENOLIC ODOR [R5] BP: *220 DEG C AT 4 MM HG [R5] MP: *150-155 DEG C [R5] MW: *228.28 [R5] DEN: *1.195 AT 25 DEG C/25 DEG C [R6] OWPC: *log Kow= 3.32. [R14] SOL: *Sol in ether, benzene [R12]; *Sol in aq alkaline soln, alc, acetone; slightly sol in carbon tetrachloride. [R5]; *Water solubility: 120 mg/l at 25 deg C. [R15] SPEC: *MAX ABSORPTION (ALC): 227 NM (LOG E= 4.4); 275 NM (LOG E= 3.8); SADTLER REF NUMBER: 1070 (IR, PRISM); 216 (IR, GRATING); 325 (UV) [R16]; *Intense mass spectral peaks: 213 m/z (100%), 228 m/z (26%), 119 m/z (25%), 214 m/z (14%) [R17]; *IR: 2:599F (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R18, p. V1 304]; *NMR: 4:151B (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R18, p. V1 304]; *MASS: 1534 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R18, p. V1 304]; *IR: 2233 (Coblentz Society Spectral Collection) [R18, p. V2 140]; *UV: 325 (Sadtler Research Laboratories Spectral Collection) [R18, p. V2 140]; *NMR: 18699 (Sadtler Research Laboratories Spectral Collection) [R18, p. V2 140]; *MASS: 1625 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R18, p. V2 140] VAP: *4X10-8 mm Hg at 25 deg C (est) [R19] OCPP: *DECOMPOSES ABOVE 8 MM PRESSURE WHEN HEATED ABOVE 220 DEG C [R5] *IR: 2:599G (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) /Bisphenol B/ [R18, p. V1 305] *NMR: 4:151G (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) /Bisphenol B/ [R18, p. V1 305] *Henry's Law Constant= 1X10-10 atm-cu m/mole at 25 deg C (est). [R20] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible [R6] FLPT: *175 DEG F (79.4 DEG C) [R6] *415 deg F (Open cup) [R13] FIRP: *Foam, dry chemical, carbon dioxide. [R13] SERI: *Solid irritating to skin and eyes. ... Dusts irritating to upper respiratory passages ... . [R13] EQUP: *Approved dust mask and clean, body covering clothing sufficient to prevent excessive or repeated exposure to dust, fumes, or soln. Safety glasses with side shields. [R13] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *A single clinical report describes photoallergic contact dermatitis to bisphenol A, with subsequent persistent light reactivity, in a group of eight outdoor workers. [R21] NTOX: *BISPHENOL A ... HAS BEEN REPORTED WHEN TESTED AS 5% SOLN IN DIMETHYLSULFOXIDE OR PROPYLENE GLYCOL TO CAUSE "SEVERE INJURY" TO EYE. [R22] *ACUTE TOXICITY OF BISPHENOL IS RELATIVELY LOW. ... AT 1-3 HR AFTER INGESTION, ANIMALS EXHIBITED A CERTAIN ATONY WHICH CAN GO AS FAR AS DEEP SLEEP. PROFUSE DIARRHEA OCCURS WITH MOST RATS. LIKE E-CAPROLACTAM, BISPHENOL HAS DIURETIC ACTION. IT IS ALMOST 5 TIMES THAT OF UREA. ... /IT ALSO/ HAS MARKED ESTROGENIC ACTION. [R2, 331] */IN SUBACUTE TOXICITY STUDIES/ LAB EXAM DID NOT REVEAL ANY ABNORMAL SYMPTOMS ... /BUT/ MARKED REDN IN RATE OF INCR IN BODY WT IN TREATED ANIMALS, WHETHER MALE OR FEMALE /WAS OBSERVED/. ... 1% IN FOOD FOR 8 WK CAUSES MARKED DROP IN GROWTH. [R2, 331] *Reproduction and fertility assessment in CD-1 mice admin Biphenol A. Continuous exposure to Bisphenol A for 2 wk via sc Silastic implants containing 0-100 mg Bisphenol A during dose range finding study caused no overt toxicity, but did seem to incr the wt of the reproductive tract in high dose females. [R23] *Bisphenol A was evaluated for developmental toxicity in CD rats (0, 160, 320, or 640 mg/kg/day) and CD-1 mice (0, 500, 750, 1000, or 1250 mg/kg/day) dosed daily by gastric intubation on gestational days 6 through 15. Timed-pregnant dams were sacrificed 1 day prior to parturition, the uterine contents were examined, and all fetuses were examined for external, visceral, and skeletal malformations. In rats, maternal weight gain during gestation, weight gain corrected for gravid uterine weight, and weight gain during treatment were significantly reduced at all bisphenol A doses. Gravid uterine weight and average fetal body weight per litter were not affected by bisphenol A. No increase in percentage resorptions per litter or percentage fetuses malformed per litter was detected. In mice, maternal mortality occurred at all bisphenol A doses, reaching 18% at the high dose, which also produced a significant decrease in maternal body weight gain during gestation and treatment. Weight gain corrected for gravid uterine weight was not affected by bisphenol A. Reductions in gravid uterine weight and average fetal body weight were observed with the 1250 mg/kg dose of bisphenol A. Relative maternal liver weight was increased at all doses of bisphenol A. There was a significant increase in the percentage of resorptions per litter with 1250 mg bisphenol A/kg/day. Bisphenol A treatment at maternally toxic dose levels during organogenesis produced fetal toxicity in mice but not in rats and did not alter fetal morphologic development in either species. [R24] +A carcinogenesis bioassay of bisphenol A ... was conducted by feeding diets containing 1,000 or 2,000 ppm of test chemical to groups of 50 F344 rats of either sex, 1,000 or 5,000 ppm to groups of 50 male B6C3F1 mice, 5,000 or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 wk. Groups of 50 rats and 50 mice of either sex served as controls. ... Under the conditions of this bioassay, there was no ... evidence that bisphenol A was carcinogenic for F344 rats or B6C3F1 mice of either sex. [R25] NTXV: *LD50 Rat male oral 4.1 g/kg; [R26] *LD50 Rat female oral 3.3 g/kg; [R26] *LD50 Mouse male oral 5.28 g/kg; [R26] *LD50 Mouse female oral 4.1 g/kg; [R26] *LD50 Mouse oral 2.5 g/kg; [R27] ETXV: *LC50 Pimephales promelas (fathead minnow) 4.7 (4.0 to 5.5) mg/l/96 hr, static test; [R28] *LC50 Pimephales promelas (fathead minnow) 4.6 (3.6 to 5.4) mg/l/96 hr, flow-through test; [R28] *LC50 Menidia menidia (Atlantic silverside) 9.4 (8.3 to 11) mg/l/96 hr /Conditions of bioassay not specified/; [R28] NTP: +A carcinogenesis bioassay of bisphenol A ... was conducted by feeding diets containing 1,000 or 2,000 ppm of test chemical to groups of 50 F344 rats of either sex, 1,000 or 5,000 ppm to groups of 50 male B6C3F1 mice, 5,000 or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 wk. Groups of 50 rats and 50 mice of either sex served as controls. ... Under the conditions of this bioassay, there was no ... evidence that bisphenol A was carcinogenic for F344 rats or B6C3F1 mice of either sex. [R25] +Bisphenol A (BPA) was examined in the Reproductive Assessment by Continuous Breeding protocol using Swiss mice. Continuous exposure to BPA for 2 wks via sc Silastic(R) implants containing 0, 6.25, 12.5, 25, 50 or 100 mg BPA during Task 1 (dose range-finding study) caused no overt toxicity, but did seem to incr the weight of the reproductive tract in high dose females. Although this incr in reproductive tract weight was not statistically significant, it suggested possible estrogenic activity of the test chemical. Therefore, dose levels of 0, 25, 50 and 100 mg of BPA, given via sc Silastic(R) implants, were selected for Task 2 (continuous breeding). During Task 2 several animals in each treatment group expelled their implants through cutaneous lesions that developed directly over the implants or at the site of the initial incision. When this occurred, animals were reimplanted with Silastic(R) tubing containing the original amount of BPA; several animals received new implants on three different occasions during Task 2. Although some of the reproductive parameters measured during Task 2 differed significantly among treatment groups, these differences appeared to be due to chance alone. Because the Silastic(R) implants tended to be expelled and since they appeared to release too little BPA to cause generalized or reproductive toxicity, the present study was terminated at the conclusion of Task 2. Under the conditions of this study, no effects of BPA on fertility and reproduction in male and female CD-l mice were observed. Further studies at higher doses and by other means of admin are required to investigate the reproductive toxicity of BPA. [R29] +Bisphenol A (BPA) ... was tested for its effects on reproduction and fertility in CD-1 mice, following the standard NTP protocol. Data on body weights, clinical signs, and food and water consumptions were collected during the dose-range-finding phase (Task 1), and used to set exposure concns for Task 2 at 0.0, 0.25, 0.5, and 1.0% in feed. For females, feed consumption dropped by 19% for the medium dose group and by 23% for the high dose group. These concns produced estimated daily intakes of nearly equal to 437, 875, and 1750 mg/kg/day. For the continuous cohabitation phase (Task 2), the mean number of litters/pair dropped by 5% (at 0.5% BPA) and by 9% (at 1.0% BPA), while the number of live pups/litter dropped by 20% at the medium dose and by 48% at the high dose. Pup weight adjusted for litter size was unchanged. Postpartum dam weights were reduced only at the high dose, by nearly equal to 8-9%. Interestingly, cumulative days to litter increased by up to 10% for the high dose group. Mice from the last litter in all three dose groups and controls were reared by their dams until weaning, when they were fed BPA at the same concn received by their parents. The reductions in litter size spurred the conduct of a Task 3 crossover mating trial of the F0 mice to determine the affected sex. In the treated male X control female group, there were 25% fewer pups (compared to the control X control group). The number of live pups in the treated female X control male group was reduced by 51%. Pup weight and viability were not affected. After the Task 3 litters were delivered and evaluated, the F0 mice from the control and 1% BPA groups were killed and necropsied. Male body weight was unchanged, while liver and kidney weights increased by 29% and 16%. Seminal vesicle weight was reduced by 19%, while sperm motility dropped by 39% in the high dose animals. Female body weights in the 1% BPA group were reduced by 4%, while adjusted liver and kidney weights were reduced by 27% and 10%, respectively. For the second generation animals, weaning weights were equivalent across groups, but pup mortality before weaning was significantly increased at 1% BPA. Adult body weight at the time of mating was unaffected at any dose in either sex. F1 mice were mated within treatment levels. There was no effect on mating or fertility indices, or on the number of live pups/litter, the proportion born alive, or the adjusted live pup weight. After the F2 pups had been evaluated and discarded, the F1 adults were killed and necropsied. Male body weight was not affected, while adjusted liver weights were increased by 7%, 7%, and 29% (low to high doses, respectively). Male kidney weights adjusted for body weight were increased by 16%, 20%, and 20%. Right epididymal weight was reduced by 7%, 16%, and 18%. Seminal vesicles weight was reduced by 11% and 28% at the low and high dose levels, respectively. The 10% reduction at the middle dose level did not reach statistical significance. For females, body weight was not affected, while body-weight-adjusted liver weights were increased by 6%, 13%, and 20%, and kidney weights were increased by 13%, 15%, and 13%. None of the sperm endpoints measured were significantly affected in a dose-dependent manner. Although sperm count was reduced dose-dependently, to a max of 18% less than controls, this reduction did not reach statistical significance. In summary, exposure of the first generation mice to 0.5% or 1.0% resulted in a reduction in number of litters/pair, live pups/litter, and live pup weight. At the high dose, this occurred in the presence of increases in liver and kidney weights. The second generation did not appear more sensitive than the first to the reproductive toxicity of Bisphenol A. [R30] +Bisphenol A (BPA), ... was evaluated for toxic and teratogenic effects in timed-pregnant Sprague Dawley CD rats (n=27-29). Bisphenol A (0, 160, 320, 640 and 1280 mg/kg/day) suspended in corn oil was given by gavage (5.0 ml/kg body weight) daily on gestational days (gd) 6 through 15. Females were weighed and observed daily. At sacrifice a total of 18-29 confirmed-pregnant females per treatment group were evaluated. The gravid uterus of each dam was weighed, and the number of implantation sites and live, dead, or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral, and skeletal malformations. ... Maternal mortality was 0% for all but the 1280 mg/kg/day dose group, which was 26%. Due to this high mortality, data from the 1280 mg/kg/day group will not be further considered in this summary. Maternal body weight on gestational day 0 and gestational day 6 did not differ among the remaining dose groups. But at gestational day 11 and 15, maternal body weight was lowered for all Bisphenol A treatment groups. Gravid uterine weight, absolute maternal liver weight, and relative maternal liver weight were unaffected by treatment. Bisphenol A produced NO significant fetal effects at doses 3/4 640 mg/kg. In conclusion, Bisphenol A in rats was not a developmental toxicant at doses that were maternally toxic. The developmental NOAEL was 640 mg/kg. A maternal NOAEL was not established, based on effects on maternal body weight; the LOAEL for maternal body weight effect in this study was 160 mg/kg. [R31] +Bisphenol A (BPA), ... was evaluated for toxic and teratogenic effects on timed-pregnant Swiss ICR CD-l mice. Bisphenol A (O, 500, 750, 1000, and 1250 mg/kg/day) suspended in corn oil was given by gavage (10.0 ml/kg body weight) daily on gestational days (gd) 6 through 15. Timed-pregnant dams (n= 29-33/group) were sacrificed 1 day prior to parturition, the uterine contents were examined, and all fetuses were examined for external, visceral, and skeletal malformations. ... Maternal mortality occurred at all bisphenol A doses: 7.1%, 3.6%, 6.3%, and 18.2% for the low through high dose groups, respectively. Maternal body weight on gestational day 0, gestational day 6, and gestational day 11 did not differ among dosed groups. Maternal body weight was decreased in the 1250 mg/kg/day dose group on gestational days 15 (by 10%) and 17 (by 16%). Gravid uterine weight was depressed in the 1250 mg/kg/day dose group by 32%. Weight gain corrected for gravid uterine weight was not affected by bisphenol A . Relative maternal liver weight (i.e., corrected for body weight) was increased at all doses (by 9%, 13%, 17%, and 25% respectively). There was a significant increase in the percentage of resorptions per litter at the high dose from a control value of 14%, to 40%. Malformation incidence was not altered by bisphenol A . There was a 13-15% decrease in individual fetal weight, seen only at the high dose. Bisphenol A treatment at maternally toxic dose levels produced fetal toxicity but did not alter fetal morphologic development. Based on mortality at all doses, no NOAEL was established for dams. The NOAEL for fetal malformations is 1250 mg/kg/day. [R32] TCAT: ?Subchronic toxicity was evaluated in groups of male and female beagle dogs (4/sex/concn level) ingesting bisphenol-A via the diet for 90 days at nominal concentrations of 1000, 3000 and 9000 ppm. Parameters such as general behavior and appearance, ophthalmoscopy, body weights, food consumption, hematological and biochemical studies or urinalysis, were not consistently affected by the treatment. No compound related gross pathologic lesions were observed in any of the dogs in the treated groups. A group mean relative liver weight increase at the 9000 ppm concentration level was regarded as compound related. [R33] ?Subchronic inhalation toxicity was evaluated in groups of male and female Charles River CD rats (10/sex/concn level) ingesting bisphenol-A via the diet for 90 days at nominal concentrations of 100, 250, 500, 750 and 1000 ppm. In the male group given 1000 ppm there was a slight decrease in body weight when compared to the control group. Food consumption values were slightly higher for treated female rats than for female control rats. Other parameters of general behavior, appearance and survival of the treated F0 parents were not consistently affected by the treatment. At 100 days of age F0 parents were mated to produce F1 offspring. 15 Male and 15 female F1 rats were treated via the diet with bisphenol-A for 90 days. Body weight gains of the F1 male rats were slightly lower at the 750 ppm concn level. Other parameters such as appearance, survival, male and female fertility indices, female estrous cycles, length of gestation period, number of pups/litter, and pup body weights were not consistently affected by the treatment. [R34] ?Subchronic toxicity was evaluated in weanling rats (f1) obtained from the mating of Charles River CD rats fed biphenol-A in the diet during their growth and reproductive period. Groups of male and female rats (10/sex/concn level) ingested bisphenol-A via the diet for 90-days at nominal concentrations of 1000, 3000 and 9000 ppm. In the F0 generation, body weight gain was slightly decreased at the 3000 ppm concn level, and moderately decreased at the 9000 ppm level. Other parameters such as, general behavior, food consumption, appearance, ophthalmoscopy or hematological, biochemical, urinalysis studies, fertility indices, number of pups/litter and pup survival were not consistently affected by the treatment. At the age of 100 days, the F0 rats were mated 1 to 1, and subsequently the offspring (F1) rats were initiated on the 90-day feeding study of bisphenol-A. Reproductive effects were evaluated using 15 male and 15 female rats per concn level (1000,3000 or 9000 ppm). in the F1 generation, slight reductions in body weight (at 21 days of age) were noted for pups at the 3000 and 9000 ppm levels. Body weight gain was moderately decreased for female rats at 1000 ppm, and for male and female rats at the 3000 and 9000 ppm levels. food consumption also decreased for male rats at the 9000 ppm level and for all treated females. Other parameters as mentioned above were not consistently affected by the treatment. [R35] ?Bisphenol A was examined for mutagenic activity in agar overlay cultures and liquid suspension cultures of Salmonella typhimurium, strain TA-1538, Escherichia coli, strain WP2 and WP2 uvrA, and in liquid cultures of Saccharomyces cerevisiae, strain JD1. Assays were performed in the presence and absence of added metabolic activation by Aroclor-induced rat liver S-9 fraction. None of the bacterial cultures tested from 0.1 - 1.0mg/ml in liquid cultures and from 0.2 - 500ug/plate in agar cultures produced an increase in the reversion frequency relative to the controls. Yeast cultures tested at concentrations of 0.01, 0.1 and 0.5mg/ml did not cause an increase in the frequency of mitotic gene conversion relative to the controls. [R36] ?The ability of Bisphenol A to cause chromosome aberrations was evaluated in a cultured epithelial cell line (RL1) of the Carworth Farm E rat. Based on preliminary toxicity determinations, monolayer cultures were treated with 0, 10, 20, 25 and 30ug/ml and incubated for 21 hours prior to the addition of colcemid. Chromosome changes were analyzed in 100 cells from each culture. The incidence of chromosome damage in the treated cultures did not differ from the negative control (DMSO). [R37] ?The fate of bisphenol A was evaluated in male Carworth Farms-Elias rats ingesting 14C-bisphenol A via gavage in a single dose of 800mg/kg. The 14C-metabolites were evaluated daily in the pooled urine and feces of 4 treated rats per study for 8 days. Two studies were preformed, in which the majority of the administered dose was excreted in 24 hours while in the third study, almost equal amounts of the administered dose was excreted at 24 and 48 hours post treatment. An average of 28% of the administered dose was excreted in the urine and 56% in the feces. Total recoveries of the labeled averaged 88%. Evaluation of the 14C-content in carbon dioxide collected from six treated animals placed in a metabolic chamber over a four hours period, disclosed no evidence of radioactivity. [R38] ?Subchronic toxicity was evaluated in one group of 10 Sherman rats (5 male and 5 female) ingesting diphenylol propane in the diet at levels of 0.002, 0.008, 0.03, 0.15 and 0.52 gm/kg body weight/day for 90 days. The test article did not induce statistically significant (test type not reported) changes in mortality, appetite, weight gain, body length, fatness, liver and kidney weights, and micropathology of the small intestine, kidney, liver, spleen, and testes at any dose level. [R39] ?Subchronic toxicity was evaluated in four groups of 2 beagle dogs (1 male and 1 female) ingesting bisphenol A via the diet at levels of 2000, 4000, 8000 or 12000 ppm for 14 days. Mortality was not observed during the study and all animals were sacrificed after 14 days. The test article did not induce changes in general appearance and behavior, body weight, or food consumption. Slight focal mucosal congestion and hemorrhage of the gastrointestinal tract was reported in treated animals, however, these effects were also occasionally observed in controls. [R40] ?Subchronic toxicity was evaluated in groups of 8 beagle dogs (4 male and 4 female) ingesting bisphenol-A via the diet at levels of 1000, 3000, or 9000 ppm for 90 days. Mortality was not observed at any dose level and animals were sacrificed after 90 days. The test article did not induce changes in general behavior and appearance, ophthalmological parameters, body weight, food consumption, hematological and biochemical parameters, or urinalysis values at any dose level. Bisphenol-A did not induce compound related gross pathologic lesions at any dose level, and lesions were not observed on microscopic analysis of the following tissues from high dose group animals: adrenals, aorta, brain, esophagus, eye (+ optic nerve), gallbladder, duodenum, jejunum, ileum, cecum, colon, rectum, urinary bladder, kidneys, liver, lungs, mesenteric lymph node, skin, nerve, skeletal muscle, spleen, pancreas, pituitary, prostrate/uterus, bone marrow, salivary gland, spinal cord, stomach, testis/ovary, thymus, thyroid/parathyroid, and tongue. A group mean relative liver weight increase observed at the 9000 ppm dose level was considered to be compound related. Statistical analyses were not reported. [R41] ?Subchronic toxicity was evaluated in groups of 10 Charles River CD rats (5 male and 5 female) ingesting bisphenol-A via the diet at dosage levels of 2000, 4000, 8000, or 12000 ppm for 14 days. Mortality was not observed at any dose level and rats were sacrificed after 14 days. Slight to moderate dose related decreases in body weight gain were observed in male rats at the 4000, 8000 and 12000 ppm dosage levels; very slight decreases were observed in females at the 8000 and 12000 ppm levels. Food consumption was slightly lower in males in the 8000 and 12000 ppm groups as compared to males in the 2000 and 4000 ppm groups. The test article did not induce changes in general behavior and appearance at any dose level, while compound related gross pathologic lesions were not observed on necropsy of animals in any dose group. Statistical analysis was not reported. [R42] ?Subchronic inhalation toxicity was evaluated in groups of 40 Fischer 344 rats (20 male, 20 female) receiving nine 6 hour whole body exposures to bisphenol-A at nominal concentrations of 0, 10, 50 or 150 mg/m3 over a period of 2 weeks. Mortality was not observed at any concentration level. Following sample collection, half of the male and female rats were sacrificed immediately, and half after a 29 day recovery period. Clinical observations during the exposure period included porphyrin like material around the nose in males exposed to 50 or 150 mg/m3, and perineal soiling in females exposed to 150 mg/m3. Body weights of males exposed to 150 mg/m3 were statistically significantly (Bartletts test, p < 0.01) decreased during the exposure period, but were within normal limits one week following exposure. The test article did not induce changes in hematology parameters, clinical blood chemistry, or urinalysis data at any dose level. Histological examination of rats sacrificed immediately after treatment revealed minor inflammation of the epithelial lining of the nasal cavity in males exposed to 150 mg/m3, and in females exposed to 50 or 150 mg/m3. Very slight to slight hyperplasia of squamous epithelium in the nasal cavity was observed in males and females exposed to 50 or 150 mg/m3. All treatment related changes were reversible within the 29-day recovery period. [R43] ADE: *When administered as a single dose by gavage to male CFE rats, 28% of the (14)C-labeled bisphenol A was excreted in the urine (primarily as the glucosamide) and 56% in the feces (20% as free bisphenol A, 20% as a hydroxylated bisphenol A, and the rest as an unidentified conjugate). No carbon-labeled residues were detected in animals killed after 8 days. [R44] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *The primary sources of environmental release of bisphenol A are expected to be effluents and emissions from its manufacturing facilities and facilities which manufacture epoxy, polycarbonate, and polysulfone resins. If released to soil bisphenol A is expected to have moderate to low mobility. This compound may biodegrade under aerobic conditions following acclimation. If released to acclimated water, biodegradation would be the dominant fate process (half-life less than or equal to 4 days). In nonacclimated water, bisphenol A may biodegrade after a sufficient adaptation period, it may adsorb extensively to suspended solids and sediments or it may photolyze. If released to the atmosphere, bisphenol A is expected to exist almost entirely in the particulate phase. Bisphenol A in particulate form may be removed from the atmosphere by dry deposition or photolysis. The small fraction of bisphenol A which would exist in the vapor phase may react with photochemically generated hydroxyl radicals (half-life 4 hours) or it may photolyze. Photodegradation products of bisphenol A vapor are phenol, 4-isopropylphenol, and a semiquinone derivative of bisphenol A. The most probable routes of human exposure to bisphenol A are inhalation and dermal contact of workers involved in the manufacture, use, transport or packaging of this compound or use of epoxy powder paints. (SRC) ARTS: *The primary sources of environmental release of bisphenol A are expected to be effluents and emissions from manufacturing and use facilities where it is used in the manufacture of epoxy, polycarbonate, and polysulfone resins(1-3). Bisphenol A is a thermal degradation product of epoxy resin and powder paint used to paint metal objects(4-5). [R45] FATE: *TERRESTRIAL FATE: If released to soil, bisphenol A is expected to have moderate to low mobility because of its water solubility(1). Based upon aqueous biodegradation tests(1-2), bisphenol A may biodegrade under aerobic conditions following acclimation. This compound is not expected to undergo chemical hydrolysis or volatilize significantly from soil surfaces(SRC). [R46] *AQUATIC FATE: If released to acclimated water, biodegradation would be the dominant fate process (half-life less than or equal to 4 days)(1). In nonacclimated waters, bisphenol A biodegrades(1), it may adsorb extensively to suspended solids and sediments, or it may photolyze. This compound is not expected to bioaccumulate significantly in aquatic organisms, volatilize, or undergo chemical hydrolysis(SRC). [R47] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of 4X10-8 mm Hg at 25 deg C(1,SRC), bisphenol A is expected to exist almost entirely in the particulate phase in the atmosphere(2). Bisphenol A particles may be removed from the atmosphere by dry deposition or photolysis. The small fraction of bisphenol A which would exist in the vapor phase may react with photochemically generated hydroxyl radicals (half-life 4 hours) or it may photolyze. Photodegradation products of bisphenol A vapor are phenol, 4-isopropylphenol, and a semiquinone derivative of bisphenol A(SRC). [R48] BIOD: *Half-life of 3 mg/L bisphenol A in natural receiving waters: bisphenol A plant discharge, 3 days; Patricks Bayou water (obtained 200 yards downstream from a Bisphenol A plant discharge), 2.5 days; and Houston Ship Channel water, 4 days(1). Loss was attributed to biodegradation since 3 mg/L bisphenol A in a control sample (deionized water) underwent no observable change in concentration over an 8 day test period. 105 mg/L bisphenol A, acclimated activated sludge inocula from an industrial wastewater treatment plant, 72% COD removal in 24 hours(2). OECD biodegradation screening test, domestic sewage as seed, < 1% degradation in 28 days(1). Bisphenol A was not oxidized in either the Closed Bottle Test or the Modified Sturm Test(1). Japanese MITI Test: 100 mg/L substrate, 30 mg/L activated sludge, < 30% degradation in 2 weeks(2-3). [R49] ABIO: *Bisphenol A is not expected to undergo chemical hydrolysis under environmental conditions since it contains no hydrolyzable functional groups(1). In neutral and acidic methanol solutions, bisphenol A exhibits slight absorption of UV light wavelengths > 290 nm, while in basic methanol solution bisphenol A exhibits significant absorption of UV > 290 nm(2). These data indicate that bisphenol A has the potential to photolyze in water, and that this potential is somewhat greater under basic conditions(SRC). These data also indicate that bisphenol A has potential to undergo photolysis in the atmosphere(SRC). Photodecomposition products of bisphenol A vapor are phenol, 4-isopropylphenol, and a semiquinone derivative of bisphenol A(3). The half-life for bisphenol A vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 4 hours based on a reaction rate constant of 6.0X10-11 cu cm/molecule-sec at 25 deg C and an average hydroxyl radical concentration of 8.0X10+5 molecules/cu cm(4). However, bisphenol A is expected to exist almost entirely in the particulate phase in the atmosphere, and reaction with hydroxyl radicals is expected to be much slower in particulate form than in vapor form(SRC). [R50] BIOC: *A bioconcentration factor (BCF) of < 100 was measured for bisphenol A in carp(1). BCF of 42 and 196 were estimated for bisphenol A based on a water solubility of 120 mg/L at 25 deg C and a log Kow of 3.32, respectively(2-4,SRC). These BCF value indicate that bisphenol A should not bioaccumulate significantly in aquatic organisms(SRC). [R51] KOC: *Soil adsorption coefficients (Koc) of 314 and 1524 have been estimated for bisphenol A based on a water solubility of 120 mg/L at 25 deg C and a log Kow of 3.32, respectively(1-3,SRC). These Koc values suggest that mobility of bisphenol A in soil would be moderate to low and that adsorption to suspended solids would be moderate to extensive(4,SRC). [R52] VWS: *Henry's Law constant for bisphenol A can be estimated to be on the order of 1X10-10 atm-cu m/mole at 25 deg C using an estimated vapor pressure of 4X10-8 mm Hg at 25 deg C and a water solubility of 120 mg/L at 25 deg C(1-2,SRC). This value of Henry's Law constant suggests that volatilization would be insignificant from all bodies of water(3). Due to its relatively low vapor pressure and its tendency to adsorb to soil, bisphenol A is not expected to volatilize significantly from wet or dry soil surfaces. [R53] WATC: *SURFACE WATER: Water samples collected from rivers in the Tokyo, Japan area, 1974-1978, concn range of pos. samples 0.06-1.9 ug/L(1). [R54] EFFL: *Dec. 1974, qualitatively identified in the effluent from a chemical industry in Mt. Vernon, IN(1). [R55] SEDS: *Not detected in soil samples taken from residential area of Tokyo, Japan where bisphenol A had been detected in atmospheric fallout(1). [R56] ATMC: *Atmospheric fallout collected from a residential area of Tokyo, Japan between Feb. 1976 and Jan. 1978, 8 samples, 63% pos., deposition rate of bisphenol A in pos. samples 0.04-0.2 ug/sq m/day(1). [R56] RTEX: *The most probable routes of human exposure to bisphenol A are inhalation and dermal contact of workers involved in the manufacture, use, transport or packaging of this compound or use of epoxy powder paint(1,SRC). [R57] *9,446 workers are potentially exposed to bisphenol A based on statistical estimates derived from the NIOSH survey conducted 1981-83 in the USA(1). However, this estimate does not include exposure to tradename compounds which contain bisphenol A. 281,011 workers are potentially exposed to bisphenol A based on statistical estimates derived from the NIOSH survey conducted 1972-74 in the USA(2). [R58] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Bisphenol A is produced, as an intermediate or a final product, by process units covered under this subpart. [R59] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 350 ug/l [R60] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Bisphenol A is included on this list. [R61] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R62] *Manufacturers and processors of bisphenol A are required to conduct inhalation toxicity testing under TSCA section 4. [R63] FDA: *4,4'-Isopropylidinediphenol is an indirect food additive for use only as a component of adhesives. [R64] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 333. Analyte: Bisphenol A. Matrix: Air. Procedure: Filter collection, acetonitrile extraction. Flow Rate: 1.6 l/min. Sample Size: 288 liters. [R65, p. V6 333-1] ALAB: *Air samples are concn on silica by the tube pump, desorbed and analyzed by high-pressure liquid chromatography. Using a 10 liter air sample, a concn range of 0.5-50 mg/cu m can be detected. [R66] *NIOSH Method 333. Analyte: Bisphenol A. Matrix: Air. Procedure: High performance liquid chromatography. Method Evaluation: Method was validated over the range of 0.551 to 1.77 mg/cu m using a 288 liter sample. Method detection limit: 0.2. Precision (CVt): 0.018. Applicability: Under the conditions of sample size (288 liters) the useful range is 0.4 to 511 mg/cu m. Interferences: No specific interferences. [R65, p. 333-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Bisphenol A in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 215 (1982) NIH Publication No. 82-1771 SO: R1: Chemical Products Synopsis: Bisphenol A, 1984 R2: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R3: SRI R4: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 490 R5: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 199 R6: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 154 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 658 (1984) R8: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V13 53 (1981) R9: Kavaler AR; Chemical Marketing Reporter 232 (4): 46 (1987) R10: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.25 R11: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-72 R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 64th ed. Boca Raton, Florida: CRC Press Inc., 1983-84.,p. C-464 R13: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R14: SRC; Dorn PB et al; Chemosphere 16: 1501-7 (1987) R15: SRC; Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) R16: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-446 R17: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 115 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R19: SRC; Neely WB, Blau GE; p. 30-2 in Environmental Exposure from Chemicals Vol. 1 Boca Raton, FL: CRC Press (1985) R20: SRC; Neely WB, Blau GE; p. 30-2 in Environmental Exposure from Chemicals Vol 1 Boca Raton, FL: CRC Press (1985) R21: Maguire HC Jr; Acta Derm Venereol (Stockh) 68 (5): 408-12 (1988) R22: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 148 R23: Bisphenol A: Reproduction and Fertility Assessment in CD-1 Mice When Administered Via Subcutaneous Silastic Implants. Report: 192 pp. (1984) ISS NTP-84-015;NTIS Order No PB84-155308 R24: Morrissey RE et al; Fund Appl Toxicol 8 (4): 571-82 (1987) R25: DHHS/NTP; Carcinogenesis Bioassay of Bisphenol A in F344 Rats and B6C3F1 Mice (Feed Study) p.vii (1982) Technical Rpt Series No. 215 NIH Pub No. 82-1771 R26: DHHS/NTP; Carcinogenesis Bioassay of Bisphenol A in F344 Rats and B6C3F1 Mice (Feed Study) p.4 (1982) Technical Rpt Series No. 215 NIH Pub No. 82-1771 R27: DHHS/NTP; Carcinogenesis Bioassay of Bisphenol A in F344 Rats and B6C3F1 Mice (Feed Study) p.1 (1982) Technical Rpt Series No. 215 NIH Pub No. 82-1771 R28: Alexander HC et al; Environ Toxicol 7 (1): 19-26 (1988) R29: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Bisphenol A: (CAS No. 80-05-7) Reproduction and Fertility Assessment in CD-1 Mice When Administered Via Subcutaneous Silastic(R) Implants, NTP Study No. RACB82081 (January 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R30: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Bisphenol A: (CAS No. 80-05-7) Reproduction and Fertility Assessment in CD-1 Mice When Administered in the Feed, NTP Study No. RACB84080 (May 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R31: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Bisphenol A: (CAS No. 80-05-7) Administered to CD Rats on Gestational Days 6 Through 15, NTP Study No. TER85051 (February 15, 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R32: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Bisphenol A (CAS No. 80-05-7) Administered to CD-1 Mice on Gestational Days 6 Through 15, NTP Study No. TER85052 (February 15, 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R33: International Research and Development Corporation; 90 Day Oral Toxicity Study in Dogs, (1976), EPA Document No. 40-8486013, Fiche No. OTS0509954 R34: International Research and Development Corporation; Reproduction and Ninety Day Feeding Study in Rats, (1978), EPA Document No. 40-8486013, Fiche No. OTS0509954 R35: International Research and Development Corporation; Reproduction and Ninety Day Oral Toxicity Study in Rats, (1976), EPA Document No. 40-8486013, Fiche No. OTS0509954 R36: Shell Toxicology Laboratory (Tunstall); Toxicity Tests with Diphenylol Propane (DDP): In Vitro Mutation Studies, (1978), EPA Document No. 878214488, Fiche No. OTS0206596 R37: Shell Toxicology Laboratory (Tunstall); Toxicity Tests with Bisphenol A: In Vitro Mutation Studies, (1978), EPA Document No. 878214488, Fiche No. OTS0206596 R38: Mellon Institute of Industrial Research; The metabolism of Bisphenol A in the Rat, (1962), EPA Document No. 8778214659, Fiche No. OTS0206612 R39: Mellon Institute of Industrial Research; The Acute and Subacute Toxicity of Diphenylol Propane (1948), EPA Document No. 878214657, Fiche No. OTS0206612 R40: International Research and Development Corporation; Fourteen Day Range Finding Study in Dogs (1976), EPA Document No. 878214680, Fiche No. OTS0206618 R41: International Research and Development Corporation; Ninety Day Oral Toxicity Study in Dogs (1976), EPA Document No. 878214682, Fiche No. OTS0206618 R42: International Research and Development Corporation; Fourteen Day Range Finding Study in Rats (1976), EPA Document No. 878214679, Fiche No. OTS0206618 R43: Dow Chemical Company; Bisphenol A: 2-Week Aerosol Toxicity Study With Fischer 344 Rats, (1985), EPA Document No. 40-8586071, Fiche No. OTS0510007 R44: DHHS/NTP; Carcinogenesis Bioassay of Bisphenol A in F344 Rats and B6C3F1 Mice (Feed Study) p. 1 (1982) Technical Rpt Series No. 215 NIH Pub No. 82-1771 R45: (1) Reed HWB; Kirk-Othmer Encycl Chem Tech 3rd ed. NY: Wiley 2: 90 (1978) (2) Chemical Marketing Reporter; Chemical Profile: Bisphenol A NY: Schnell Publishing July 16 (1984) (3) Dorn PB et al; Chemosphere 16: 1501-7 (1987) (4) Peltonen K et al; Am Ind Hyg Assoc J 47: 399-403 (1986) (5) Peltonen K; J Anal Appl Pyrolysis 10: 51-7 (1986) R46: (1) Dorn PB et al; Chemosphere 16: 1501-7 (1987) (2) Matsui S et al; Prog Water Technol 7: 645-59 (1975) R47: (1) Dorn PB et al; Chemosphere 16: 1501-7 (1987) R48: (1) Neely WB, Blau GE; p. 30-2 in Environmental Exposure from Chemicals Vol. 1 Boca Raton, FL: CRC Press (1985) (2) Eisenriech SJ et al; Environ Sci Tech 15: 30-8 (1981) R49: (1) Dorn PB et al; Chemosphere 16: 1501-7 (1987) (2) Matsui S et al; Prog Water Technol 7: 645-59 (1975) (3) Kawasaki M; Ecotoxic Environ Safety 4: 444-54 (1980) (4) Sasaki S; pp. 283-98 in Aquatic Pollutants: Transformation and Biological Effects Hutzinger O et al eds Oxford: Pergamon Press (1978) R50: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill p. 7-4 (1982) (2) Sadtler; Standard UV Spectra No. 325 Philadelphia, PA: Sadtler Research Lab (1966) (3) Peltonen K et al; Photochem and Photobio 43: 481-4 (1986) (4) GEMS; Graphical Exposure Modelling System. FAP. Fate of Atmos Pollut (1987) R51: (1) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (2) Dorn PB et al; Chemosphere 16: 1501-7 (1987) (3) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill p. 5-5 (1982) R52: (1) Dorn PB et al; Chemosphere 16: 1501-7 (1987) (2) Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill p. 4-9 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R53: (1) Neely WB, Blau GE; p. 30-2 in Environmental Exposure from Chemicals Vol 1 Boca Raton, FL: CRC Press (1985) (2) Dorn PB et al; Chemosphere 16: 1501-7 (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill p. 15-16 (1982) R54: (1) Matsumoto G; Water Res 16: 551-7 (1982) R55: (1) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Water p.88 USEPA-600/4-76-062 (1976) R56: (1) Matsumoto G, Hanya T; Atmos Environ 14: 1409-19 (1980) R57: (1) Peltonen K et al; Am Ind Hyg Assoc J 47: 399-403 (1986) R58: (1) NIOSH; National Occupational Exposure Survey (NOES) (1985) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1974) R59: 40 CFR 60.489 (7/1/91) R60: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R61: 40 CFR 716.120 (7/1/91) R62: 40 CFR 712.30 (7/1/91) R63: 40 CFR 799.940 (7/1/91) R64: 21 CFR 175.105 (4/1/91) R65: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R66: Oomens AC, Schuurhuis FG; International Archives of Occupational and Environmental Health 52 (1): 43-8 (1983) RS: 49 Record 63 of 1119 in HSDB (through 2003/06) AN: 521 UD: 200302 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-DICHLOROBENZENE- SY: *AI3-00053-; *BENZENE,-O-DICHLORO-; *BENZENE,-1,2-DICHLORO-; *CHLOROBEN-; *CLOROBEN-; *O-DICHLOR-BENZOL-; *O-DICHLOROBENZENE-; *DICHLOROBENZENE,-ORTHO,-LIQUID-; *O-DICHLOROBENZOL-; *Dilatin-DB-; *Dowtherm-E-; *NCI-C54944-; *Caswell-No-301-; *ORTHODICHLOROBENZENE-; *ORTHODICHLOROBENZOL-; *EPA-Pesticide-Chemical-Code-059401- RN: 95-50-1 RELT: 6372 [DICHLOROBENZENE] (Mixture) MF: *C6-H4-Cl2 SHPN: UN 1591; Dichlorobenzene, ortho IMO 6.1; Dichlorobenzene, ortho STCC: 49 411 27; Dichlorobenzene, ortho, liquid HAZN: U070; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. F002; A hazardous waste from nonspecific sources when a spent solvent. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CHLORINATION OF BENZENE OR MONOCHLOROBENZENE IN THE PRESENCE OF A CATALYST [R1] *... BY SANDMEYER PROCEDURE FROM APPROPRIATE CHLOROANILINE, AND ALONG WITH O- AND P-DICHLOROBENZENES, BY CHLORINATION OF CHLOROBENZENE. [R2] IMP: *High purity grade: less than 0.2% 1,2,4-trichlorobenzene and less than 0.005% monochlorobenzene. Technical grade: less than 19.0% other dichlorobenzenes isomers, less than 1.0% trichlorobenzenes and less than 0.05% monochlorobenzene. [R3] FORM: *... AVAIL IN USA AS TECHNICAL GRADE TYPICALLY CONTAINING 98.7% BY WT OF ORTHO-ISOMER AND 1.3% OF META- AND PARA-ISOMERS COMBINED. IT HAS ... MOISTURE CONTENT OF 80 PPM. ... ALSO AVAIL IN USA IN GRADE WHICH ... CONTAINS 83% OF ORTHO-ISOMER, 17% OF META- AND PARA-ISOMERS ... AN EMULSIFIABLE FORM OF ... LATTER PRODUCT CAN ... /BE OBTAINED/. [R4] *High purity grade: 98.0% minimum active ingredient; technical grade: 80-90% active ingredient [R3] MFS: *Monsanto Co, Hq, 800 N Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Monsanto Chemical Co, Production site: Sauget, IL 62201 [R5] *PPG Industries, Inc, Hq One PPG Place, Pittsburgh, PA 15272, (412) 434-3131; Chemicals Group; Production site: New Martinsville, Natrium, WV 26155 [R5] *Standard Chlorine Chemical Co, Inc, Hq, 1035 Belleville Turnpike, Kearny, NJ 07032, (201) 997-1700; Production site: Governor Lea Road, Delaware City, DE 19706 [R5] OMIN: *SEPARATION OF MIXT CONTAINING M-, O-, AND P-DICHLOROBENZENES BY DISTILLATION AND CRYSTALLIZATION: MUELLER, WOLZ, FRENCH PATENT 1,374,863 (1964 TO BAYER), CA 62, 493E (1965), CORRESPONDING TO BRITISH PATENT 999,845. [R2] *Product discontinued by The Dow Chemical Company [R6] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R7] *SOLVENT FOR WAXES, GUMS, RESINS, TARS, RUBBERS, OILS, ASPHALTS, INSECTICIDE FOR TERMITES AND LOCUST BORERS [R2] *REMOVING SULFUR FROM ILLUMINATING GAS; AS INTERMED IN MFR OF DYES; AS HEAT TRANSFER MEDIUM [R2] *AS DEGREASING AGENT FOR METALS, LEATHER, WOOL; AS INGREDIENT OF METAL POLISHES [R2] *INDUST ODOR CONTROL [R8] *Herbicide, insecticide, and soil fumigant [R9] *AS SOLVENT MIXT USED TO REMOVE LEAD AND CARBONACEOUS DEPOSITS FROM ENGINE PARTS; AS COMPONENT OF RUST-PROOFING MIXT [R10] *AS A MAGNETIC COIL COOLANT; IN WOOD-PRESERVING CMPD [R10] *CHEM INTERMED FOR MAKING AGRIC CHEM; EMULSIFIABLE FORM RECOMMENDED FOR DEODORIZING GARBAGE AND SEWAGE [R11] *ORG SYNTH ESP OF PESTICIDES AND SOLVENT IN CHEM PROCESSES [R1] *Used as a process solvent in the manufacture of toluene diisocyanate. [R12, 22] *Ortho-dichlorobenzene is used as a solvent in the following applications: motor-oil additive formulations; paints; formulations for removing paints; firearm cleaners; dissolution of pitch on papermaking felts; a carrier for wood preservatives and repellents; and upper cylinder lubricants [R13] *Hydrolysis of 1,2-dichlorobenzene with KOH and NaOH gives ortho-chlorophenol /an intermediate for dyestuffs and initiator for higher chlorinated phenols/ [R14] *Manufacture of 3,4-dichloroaniline. [R8] CPAT: *53% FOR ORGANIC SYNTHESIS (CHIEFLY FOR PESTICIDES); 20% FOR SOLVENT IN TOLUENE DI-ISOCYANATE PROCESS; 15% FOR MISC SOLVENT USES; 8% FOR DYESTUFFS MFR, 4% FOR MISC USES (1973) [R1] *Organic synthesis (mainly for production of 3,4-dichloroaniline), 70%; solvents for toluene diisocyanate production, 15%; miscellaneous solvent usage, 8%; dye manufacture 4%; and other application, 3% (1978) [R15] *CHEMICAL PROFILE: o-Dichlorobenzene. Demand: 1995: 35 million lb; 1996: 35 million lb; 2000 /projected/: 36 million lb. [R16] PRIE: U.S. PRODUCTION: *(1972) 2.83X10+10 GRAMS [R1] *(1975) 2.48X10+10 GRAMS [R1] *6.4 to 40.9X10+9 g [R17, (1977)] *2.2X10+9 g [R17, (1981)] *(1979) 2.60X10+10 g [R18] U.S. IMPORTS: *(1972) 6.30X10+06 GRAMS [R1] *(1975) 1.23X10+9 GRAMS (PRINCPL CUSTMS DISTS) [R1] U.S. EXPORTS: *(1972) ESTIMATED TO BE NEGLIGIBLE [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R8]; +Colorless to pale-yellow liquid ... [R19, 96] ODOR: *PLEASANT ODOR [R8]; +... Pleasant, aromatic odor. [R19, 96] BP: *180.1 DEG C @ 760 MM HG [R20, p. 3-39] MP: *-16.7 DEG C [R20, p. 3-39] MW: *147.00 [R20, p. 3-39] CTP: *Critical temperature: 417.2 deg C; Critical pressure: 4031 kPa [R21] DEN: *1.3059 g/ml @ 20 DEG C/4 DEG C [R20, p. 3-39] HTC: *-7969 Btu/lb= -4427 cal/g= -185.4X10+5 J/kg [R22] HTV: *311 J/g [R21] OWPC: *log Kow= 3.43 [R23] SOL: *Miscible with alcohol, ether, benzene. [R2]; *Soluble in ethanol, ether, and benzene; very soluble in acetone. [R20, p. 3-39]; *In water, 156 mg/l at 25 deg C [R24] SPEC: *Intense mass spectral peaks: 146 m/z (100%), 148 m/z (64%), 111 m/z (38%), 75 m/z (23%) [R25]; *IR: 4275 (Coblentz Society Spectral Collection) [R26]; *UV: 303 (Sadtler Research Laboratories Spectral Collection) [R26]; *NMR: 746 (Sadtler Research Laboratories Spectral Collection) [R26]; *MASS: 817 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R26] SURF: *36.61 dyn/cm [R21] VAPD: *5.05 [R27] VAP: *1.36 mm Hg @ 25 deg C /from experimentally derived coefficients/ [R28] VISC: *1.324 mPa.s at 25 deg C [R20, p. 6-247] OCPP: *PERCENT IN SATURATED AIR: 0.2 (25 DEG C) [R29] *EQUIVALENCIES: 1 MG/L= 166.3 PPM AND 1 PPM= 6.01 MG/CU M @ 25 DEG C AND 760 MM HG [R29] *Partition coefficients at 37 deg C for 1,2-dichlorobenzene into blood= 423; into oil= 39,900. [R30] *Heat of fusion 21.01 cal/g [R22] *Saturated liquid density 81.45 lb/cu ft @ 70 deg F [R22] *Liquid heat capacity: 1.159 J/g [R21] *Liquid thermal conductivity= 0.121 W/w.k [R21] *Saturated vapor pressure= 0.025 lb/sq in @ 70 deg F [R22] *Saturated vapor density= 0.00065 lb/cu ft @ 70 deg F [R22] *Ideal gas heat capacity= 0.184 Btu/lb ft @ 75 deg F [R22] *Dielectric constant= 12.12 at 293.2 K [R20, p. 6-169] *Dipole moment: 2.50 D (D= debye) [R20, p. 9-50] *Henry's Law constant = 0.0015 atm-cu m/mol at 20 deg C [R31] *Hydroxyl radical rate constant = 4.2X10-13 cu-cm/molc sec @ 25 deg C [R32] *Heat of Fusion = 86.11 J/g [R21] *Heat of Formation of Liquid = -125.23 J/g [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R33] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R33] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R33] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R33] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R33] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R33] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R33] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R33] FPOT: +Combustible liquid. [R34, p. 49-49] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R34, p. 325-34] +Flammability 2, 2= Liquids which must be moderately heated before ignition will occur and solids that readily give off flammable vapors. Water spray may be used to extinguish the fire because the material can be cooled to below its flash point. [R34, p. 325-34] +Reactivity 0, 0= Materials which are normally stable even under fire exposure conditions, and which are not reactive with water. Normal fire fighting procedures may be used. [R34, p. 325-34] FLMT: *2 TO 9% BY VOL IN AIR [R35, 1455] FLPT: *155 deg F (Open Cup); 151 deg F (Closed Cup) [R35, 1455] AUTO: *1198 DEG F [R36] FIRP: +USE WATER SPRAY, DRY CHEM, FOAM, OR CARBON DIOXIDE. USE WATER TO KEEP FIRE-EXPOSED CONTAINERS COOL. EXTINGUISH FIRE USING AGENT SUITABLE FOR SURROUNDING FIRE. [R34, p. 49-50] +WEAR FULL PROTECTIVE CLOTHING AND POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. [R34, p. 49-49] +APPROACH FIRE FROM UPWIND TO AVOID HAZARDOUS VAPORS AND TOXIC DECOMP PRODUCTS. [R34, p. 49-50] OFHZ: *Poisonous gases are produced in fire [R22] EXPL: *EXPLOSIVE LIMITS OF O-DICHLOROBENZENE ARE 2 TO 9% BY VOL IN AIR. [R35, 1455] REAC: +Strong oxidizers, aluminum, chlorides, acids, acid fumes. [R19, 96] *Slow reaction with aluminum may lead to explosion during storage in a sealed aluminum container. [R37] *DANGEROUS: ON CONTACT WITH ACIDS OR ACID FUMES THEY EVOLVE HIGHLY TOXIC /HYDROGEN CHLORIDE/ FUMES. [R37] DCMP: *DANGEROUS: WHEN HEATED TO DECOMPOSITION ... THEY EVOLVE HIGHLY TOXIC /HYDROGEN CHLORIDE/ FUMES. [R37] ODRT: *ODOR OF O-DICHLOROBENZENE IS DETECTABLE BY AVG PERSON AT 50 PPM IN AIR. ODOR BECOMES STRONG AND IRRITATION NOTICEABLE AT ... CONCN AROUND 100 PPM. IT HAS FAIR WARNING PROPERTIES AT THIS LEVEL BUT POSSIBILITY OF ADAPTATION SHOULD BE RECOGNIZED. [R35, 1458] *Odor threshold low= 12.0 mg/cu-m, Odor threshold high= 300.0 mg/cu-m, Irritating concentration= 150.0 mg/cu-m (From table). [R38] SERI: *VAPORS AND SPRAYS ARE IRRITATING TO EYES, NOSE AND THROAT [R39] EQUP: *USUAL PRECAUTIONS MUST BE TAKEN IN FACTORY; AVOIDANCE OF CONTACT WITH SKIN AND EYES, USE OF GOGGLES AND RUBBER GLOVES WHILE HANDLING PRODUCT. [R40] */When handling this substance wear/ rubber footwear, and an apron. [R22] *The American Society for Testing and Materials cell was utilized to study permeation of chlorobenzene, o-dichlorobenzene, and m-dichlorobenzene, and o- and p-chlorotoluenes through Viton (unsupported) and nitrile (supported and unsupported) glove materials using isopropanol as collecting solvent, and FID (flame ionization detector)/gas chromatography for quantitation. Adequate mixing in the collection chamber was accomplished by externally agitating the ASTM cell at the required speed in a moving-tray water bath at 25 deg C. The Viton glove did not show permeation even after 4 hr. The nitrile gloves showed breakthrough times of < 1 hr. The steady state molar flux rates for unsupported or supported nitrile gloves, or for the different challenge solvents were not statistically different. Breakthrough times were better indicators of permeation than steady state molar flux rates. A mixed permeation mechanism was proposed, depending on swelling of the glove material. [R41] +Wear appropriate personal protective clothing to prevent skin contact. [R19, 97] +Wear appropriate eye protection to prevent eye contact. [R19, 97] +Recommendations for respirator selection. Max concn for use: 200 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R19, 97] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R19, 97] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R19, 97] OPRM: +Contact lenses should not be worn when working with this chemical. [R19, 97] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *A complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R42, 1981.3] *Employees who handle liquid o-dichlorobenzene should wash their hands thoroughly with soap, or mild detergent and water before eating, smoking, or using toilet facilities. [R42, 1981.3] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. +The worker should immediately wash the skin when it becomes contaminated. [R19, 97] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R19, 97] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R43] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R44] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R45] STRG: +STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS. [R34, p. 49-50] CLUP: *Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or concrete. Absorb bulk liquid with fly ash, or cement power. Apply "universal" gelling agent to immobilize spill. [R46] *Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved in region of 10 ppm or greater concn apply activated carbon at 10 times the spilled amount. Remove trapped material with suction hoses. Use mechanical drifts or lifts to remove immobilized masses of pollutants and precipitates. [R46] *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be reclaimed or collected and atomized in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. [R42, 1981.3] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers U070, F002, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R47] *... Halogenated compounds may be disposed of by incineration provided they are blended with other compatible wastes or fuels so that the composite contains less than 30% halogens and the heating value is from 7000 to 9000 BTU/1b. Liquid injection, rotary kiln, and fluidized bed incinerators are typically used to destroy liquid halogenated wastes. ... Temperatures of at least 2000 - 2200 deg F and residence times /of more than 2 sec/ ... are required for the destruction of halogenated aromatic hydrocarbons. [R48] *Potential candidate for rotary kiln incineration, with a temperature range of 820 to 1,600 deg C, and a residence time of seconds. Also a potential candidate for liquid injection incineration, with a temperature range of 650 to 1,600 deg C, and a residence time of 0.1 to 2 seconds. [R49] *Chemical Treatability of 1,2-Dichlorobenzene; Concentration Process: Stripping; Chemical Classification: Aromatic; Scale of Study: Full Scale, Continuous Flow; Type of Wastewater Used: Domestic Wastewater; Results of Study: 70% reduction by air stripping. [R50] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of dichlorobenzenes. There is evidence suggesting a lack of carcinogenicity in experimental animals of ortho-dichlorobenzene. ... Overall evaluation: ortho-Dichlorobenzene is not classifiable as to its carcinogenicity to humans (Group 3). /Dichlorobenzenes/ [R51] *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Based on no human data and evidence of both negative and positive trends for carcinogenic responses in rats and mice. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate. [R52] +A4. Not classifiable as a human carcinogen. [R53] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Lindane and related compounds/ [R54, p. 284-5] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Lindane and related compounds/ [R54, 285] MEDS: *Employees should be screened for history of liver, kidney, or skin disease, which might place the employee at increased risk from o-dichlorobenzene exposure. [R42, 1981.1] HTOX: *TOXICOLOGICAL EFFECT OF O-DICHLOROBENZENE IS PRIMARILY INJURY TO LIVER AND SECONDARILY TO KIDNEYS. SHORT EXPOSURES AT HIGH CONCN MAY RESULT IN DEPRESSION OF CNS ALTHOUGH THIS MATERIAL IS BUT WEAKLY ANESTHETIC. [R35, 1455] *Karyotype analysis of leukocytes in laboratory workers exposed to 1,2-dichlorobenzene during pest control revealed that a significant number of altered cells, identified as having clastogenic chromosomal alterations, were present. [R55] *NO EVIDENCE IN WORKERS OF ORG INJURY OR OF UNTOWARD HEMATOLOGICAL EFFECTS HAS BEEN FOUND ATTRIBUTABLE TO EXPOSURE TO AIR CONTAINING ORTHO-DICHLOROBENZENE AT CONCN RANGING FROM 1-44 PPM (AVG, 15 PPM) FOR MANY YEARS. [R56] *Seventeen chemicals (solvents, insecticides and intermediates used in the production of textiles and resins) were tested in a short-term in vitro system with human lymphocytes to determine their action. The parameters studied were tritiated thymidine uptake and cell viability in cultures grown with or without a rat liver metabolizing system (S-9 mix). 1,3-Dichlorobenzene, 1,2-dichlorobenzene, hexane, 1,2-diiodoethane, 1,4-dichlorobenzene, tetrachloroethylene, 2,3-dibromopropanol, chloromethyl methyl ether, 1,2- and 1,3-dibromopropane, in order, exerted the more toxic effects. ... The chemicals were non-toxic in the presence of the metabolizing system with the exception of 1,2- and 1,3-dichlorobenzene which maintained to ... some degree, their toxicity even in the presence of the S-9 mix. [R57] *IN 2 SUBJECTS WITH CHRONIC LYMPHOID LEUKEMIA, 1 HAD BEEN EXPOSED TO GLUE CONTAINING 2% ORTHO-DICHLOROBENZENE FROM 1945-1961, AND OTHER HAD BEEN EXPOSED FROM 1940-1950 TO SOLVENT CONTAINING ORTHO- (80%), META- (2%) AND PARA- (15%) DICHLOROBENZENE ... /SRP: ACTUAL CARCINOGENIC AGENT IN THESE EXPOSURES HAS NOT BEEN IDENTIFIED/ [R58] *Ribonucleic acid (RNA) and protein synthesis was found to be strongly inhibited in HeLa cells exposed for 30 minutes to 350 ug/ml concn of o-dichlorobenzene. A possible mechanism leading to such inhibition is the uncoupling of oxidative phosphorylation. [R12, 24] *Inhalation of dichlorobenzene vapors was primarily responsible for most ... of a series of clinical cases of poisoning. ... 1,2-Dichlorobenzene was the principal or a significant ingredient in ... these case reports. [R59] *Analyses of workroom air associated with 1,2-dichlorobenzene manufacture and handling operations at the Dow Chemical Company ... revealed no evidence of organic injury or adverse hematologic effects attributable to 1,2-dichlorobenzene exposure [R60] *VAPORS AND SPRAYS ARE IRRITATING TO EYES, NOSE AND THROAT BUT EFFECT SEEMS TO DISAPPEAR QUICKLY. WHEN SWALLOWED ... /THEY/ CAUSE BURNING PAIN IN STOMACH, NAUSEA, VOMITING AND DIARRHEA. HEMOGLOBIN MAY CHANGE TO METHEMOGLOBIN WITH RESULTING DUSTY COLOR OF SKIN; LIVER AND KIDNEY MAY BE DAMAGED. /DICHLOROBENZENES/ [R39] *Intense erythema and edema appeared promptly when the cmpd is applied locally. [R35, 1458] +May be harmful if absorbed through skin or inhaled. Irritating to skin, eyes, and respiratory system. [R34, p. 49-50] NTOX: *... /RATS WERE/ FED O-DICHLOROBENZENE BY STOMACH TUBE, 5 DAYS/WK FOR ... 138 DOSES IN 192 DAYS. ... AT DOSE OF 376 MG/KG OF BODY WT/DAY ... MODERATE INCR IN AVG LIVER WT AND SLIGHT INCR IN AVG KIDNEY WT. THERE WERE SLIGHT HISTOPATHOLOGICAL CHANGES IN LIVER. AT ... 188 MG/KG/DAY ... SLIGHT INCR IN LIVER AND KIDNEY WT ... [R35, 1456] *RATS SURVIVED A SINGLE 7 HR-EXPOSURE TO 539 PPM. THESE ANIMALS SHOWED DROWSINESS, UNSTEADINESS, AND EYE IRRITATION. ... THERE WAS AN INCREASE IN WT OF LIVER AND KIDNEYS. MICROSCOPIC EXAMINATION SHOWED CENTRAL LOBULAR NECROSIS IN LIVER AND CLOUDY SWELLING OF TUBULAR EPITHELIUM OF KIDNEYS. [R35, 1456] *... ANIMALS /WERE EXPOSED/ 7 HOURS/DAY, 5 DAYS/WEEK TO VAPORS OF O-DCB. AT A CONCN OF 93 PPM IN AIR, RATS, GUINEA PIGS, AND RABBITS SURVIVED FOR PERIODS OF 6 TO 7 MO. THE EXPOSED ANIMALS SHOWED NO DELETERIOUS EFFECTS ON GROWTH, MORTALITY, ORGAN WEIGHT, HEMATOLOGY, OR HISTOPATHOLOGY. [R35, 1457] *THE MAXIMUM TOLERATED DOSE FOR RATS OF ORTHO-DICHLOROBENZENE ADMINISTERED BY GAVAGE ON 5 DAYS A WEEK FOR ABOUT 28 WEEKS LIES BETWEEN 19-190 MG/KG BODY WT/DAY. [R56] *... GUINEA PIGS /WERE FED/ O-DICHLOROBENZENE IN SOLN IN OLIVE OIL. ALL GUINEA PIGS SURVIVED 0.8 G/KG OF BODY WT BUT THEY ALL SUCCUMBED TO 2.0 G/KG OF BODY WT. [R35, 1455] *... RATS SURVIVED /ACUTE VAPOR EXPOSURE/ 2 HOURS AT A CONCN OF 977 PPM IN AIR AND SUCCUMBED TO AN EXPOSURE OF 7 HOURS AT THE SAME CONCN. [R35, 1456] *... 1000 PPM OF O-DICHLOROBENZENE WAS FATAL TO GUINEA PIGS AFTER 20 HR. [R61] *1,2-DICHLOROBENZENE AT DOSE OF 5.0 MMOL/KG, IP TO RATS, INCR BILE DUCT-PANCREATIC FLUID (BDPF) FLOW AND DECR ITS PROTEIN CONCN 24 HR AFTER TREATMENT. [R62] *O-DICHLOROBENZENE AS IDENTIFIED BY 96 HR LC50 OF 500 MG/L WAS HAZARDOUS TO FRESHWATER MINNOWS AND TO SALTWATER SHRIMP. [R63] *o-Dichlorobenzene (o-DCB), and p-dichlorobenzene (p-DCB), were evaluated for teratogenic potential in rats (o-DCB only) and rabbits. Groups of bred rats and inseminated rabbits were exposed to 0, 100, 200, or 400 ppm of o-dichlorobenzene /while/ groups of inseminated rabbits were exposed to 0, 100, 300, or 800 ppm p-dichlorobenzene. Animals were exposed for 6 hr/day on days 6 through 15 (rats) or days 6 through 18 (rabbits) of gestation. Maternal toxicity, as evidenced by a significant decrease in body weight gain, was observed in all groups of o-dichlorobenzene exposed rats and liver weight was significantly increased in the 400 ppm o-dichlorobenzene exposed group. Slight maternal toxicity was observed in groups of rabbits exposed to 400 ppm o-dichlorobenzene or 800 ppm p-dichlorobenzene as indicated by significantly decreased body weight gain during the first three days of exposure. Inhalation of up to 400 ppm of o-dichlorobenzene was /neither/ teratogenic nor fetotoxic in rats and neither o-dichlorobenzene or p-dichlorobenzene was teratogenic nor fetotoxic in rabbits at exposure levels up to 400 or 800 ppm, respectively. [R64] *Acute toxicity tests with six chlorobenzenes (monochlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, and hexachlorobenzene) were performed on several aquatic organisms at different trophic levels. Fertility impairment on Daphnia and photosynthesis inhibition on Selenastrum were also studied. Results were discussed together with physicochemical properties of the molecules to identify structure-activity relationships, and to predict environmental distribution. [R65] *o-Dichlorobenzene injected ip into male Sprague-Dawley rats produced centrilobular necrosis that was enhanced by prior administration of phenobarbital, which was also found to enhance the excretion of metabolites of o-dichlorobenzene. [R12, 23] *Female Wistar rats dosed orally with o-dichlorobenzene at a level of 250 mg/kg for 3 days had an incr in liver weights, microsomal protein content, and enhanced 5-aminopyrine demethylase activity in the liver. [R12, 23] *o-Dichlorobenzene was tested for carcinogenicity in both sexes of the B6C3F1 mice and the Fischer 344 rats. Dosages of 60 or 120 mg/kg were administered by gavage to both sexes of the mice, and the rat. o-Dichlorobenzene was administered in corn oil to groups of 50 rats and 50 mice of each sex 5 days/wk for 2 yr. There were corresponding vehicle and untreated control groups of 50 rats and 50 mice of each sex. No compound-related carcinogenic effect was detected in either sex of the mice or rats; however, the maximum tolerated dose was probably not used in this study. No other effects were reported. [R12, 24] *Mutagenicity was assayed with Salmonella typhimurium strains TA100, TA98, UTH8414, and UTH8413. None of the three dichlorobenzenes (1,2-, 1,3- and 1,4-) was mutagenic in any strain with or without S9 /SRP: rat liver metabolizing system/ from Aroclor treated rats. [R66] *Liver damage in the rat was investigated by measurements of serum enzyme activities at 24 hr after single or repeated inhalation exposure to one of 6 toxicants including o-dichlorobenzene. o-Dichlorobenzene at 305 ppm (but not at 204 ppm) for 4 hr markedly increased (greater than 3-fold) serum glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SODH) activities. Repeated exposure (6 hr/day, 2 or 4 days) to o-dichlorobenzene at 309 ppm caused lesser increases in the enzyme activities at 24 hr after last treatment. Serum glutamate dehydrogenase and sorbitol dehydrogenase are more sensitive indicators of toxicity than glutamic oxaloacetic transaminase or glutamic pyruvic transaminase. [R67] *o-Dichlorobenzene given orally to rats for 60 to 120 days increased liver weights and triglyceride levels of rats more than the controls. The level of hepatic ATP was lower than that in the liver of control rats. o-Dichlorobenzene decreased state 3 respiration, while increasing state 4 respiration. [R68] *A test was developed using Tetrahymena pyriformis in order to determine the toxicity of various chemicals. Precultured Tetrahymena pyriformis was exposed for 24 hr at 30 deg C to various concentrations of chemicals. The concentration of the chemical, at which the proliferation of Tetrahymena pyriformis was restricted to one-half of the blank test (EC50), was determined. The method, applied to 57 chemicals, demonstrated that it could be used to detect the chemicals at low concentrations rapidly and with ease. The EC50 values showed a good relationship with 48 hr LC50 values for Himedaka (Oryzias latipes), and could be explained on the basis of the partition coefficient between water and n-octanol. EC50 for o-dichlorobenzene was 51 mg/l (350 umol/l). [R69] *... Acute and chronic toxicity to fresh water aquatic life occur at concentrations as low as 1,120 and 763 ug/l, respectively. ... ... Acute toxicity to saltwater aquatic life occurs at concentrations as low as 1,970 ug/l ... [R70] *RATS WERE TREATED WITH EACH ISOMER OF DICHLOROBENZENE (DCB) IN AN ORAL DOSE OF 250 MG/KG ONCE DAILY FOR 3 DAYS. ACTIVITIES OF AMINOPYRINE DEMETHYLASE AND ANILINE HYDROXYLASE WERE ENHANCED MARKEDLY BY TREATMENT WITH M-DICHLOROBENZENE, WHEREAS CYTOCHROME CONTENT WAS NOT ALTERED SIGNIFICANTLY BY TREATMENT WITH ANY ISOMERS OF DICHLOROBENZENE. DELTA-AMINO LEVULINIC ACID SYNTHETASE ACTIVITY WAS ENHANCED 63, 32 AND 42% BY TREATMENT WITH O-, M-, P-DCB RESPECTIVELY, BUT THESE ENHANCEMENTS WERE NOT PARALLELED BY CYTOCHROME P450 CHANGE. [R71] *Eight halogenated benzenes, including bromobenzene (BB), chlorobenzene (CB), three isomers of dichlorobenzene (DCB) and three isomers of trichlorobenzene (TCB) were tested for acute toxicity (LD50) and clastogenicity in 8 week old NMRI mice by ip administration. Four doses of each chemical (up to 70% of LD50) were tested for clastogenic activity. Each compound was administered in two equal doses, 24 hr apart. Increased formation of micronucleated polychromatic erythrocytes, observed in femoral bone marrow, 30 hr after the first injection, was considered to be due to the clastogenic activity of the test compound. All the halogenated benzenes tested were found to be clastogenic. The highest clastogenic activities were induced by m-DCB and BB. Among three isomers of DCB, m-DCB significantly induced more micronuclei than o-DCB or p-DCB. No significant differences were found between the clastogenic activities of TCB isomers. [R72] *A dynamic liver culture system, using short term viable tissue culture of rat liver slices, is described. Following initial recovery periods of 2 to 6 hr; potassium ion and adenosine triphosphate (ATP) content were maintained for 16 to 20 hr, and protein synthesis increased linearly for 16 hr. The order of decreasing toxicity of dichlorobenzenes, measured by potassium ion content, protein synthesis, and release of lactic dehydrogenase, was 1,2-dichlorobenzene, 1,3-dichlorobenzene, and 1,4-dichlorobenzene, in agreement with a similar order obtained in vivo. The dichlorobenzenes were less toxic in slices from Sprague-Dawley rats than in Fischer rats. This finding was confirmed by studies in vivo. [R73] *Linear free energy-related (LFER) and de novo models are applied to the study of quantitative relations between structure and acute toxicity of chlorinated organic compounds. The chemicals studied include chlorophenols, chlorobenzenes, and acyclic chlorocarbons and the properties regressed are median lethal concn for guppy (Poecilia reticulata) and inhibition of phenol degradtion. The correlations reveal that toxicity tends to incr as the contaminants have more chloro substituents. Chlorophenols are less toxic than chlorobenzenes. [R74] *The acute toxicities of chlorophenols, chlorobenzenes, and p-substituted phenols to rainbow trout (Salmo gairdneri) as ip injection lethality, serum sorbitol dehydrogenase activity, and 96 hr lethal concn were investigated in terms of quantitative structure-activity correlations (QSARs). The effects of chlorophenols and chlorobenzenes were primarily related to their octanol/water partition coefficients (log P). The slopes of the QSARs of chlorophenols for rainbow trout were nearly parallel to those of acute and semichronic chlorophenols toxicities to bluegill (Lepomis macrochirus), guppy (Poecilia reticulata), waterflea (Daphnia magna), and the marine organism Photobacterium phosphoreum, indicating similar mechanisms of toxic effect. [R75] *For chlorobenzenes (n= 0-5) experimental 48 hr median effective concn (EC50) data are reported for Daphnia magna in a closed system and relations established between EC50, solubility, and otanol/water partition coefficient. ... [R76] *Toxicities of 68 chloro derivatives of phenol, aniline, nitrobenzene, pyridine, and benzene varied substantially with their log P values (octanol/water partition coefficients). The Microtox toxicity values (with bioluminescent Photobacterium phosphoreum) correlated with the log P values. The toxicity of these compounds is positive dependent on the number of Cl atoms and the nature of functional group. [R77] *Liver damage resulting from 4 hr exposure to bromobenzene (146-957 ppm) and 1,2-dichlorobenzene (245-739 ppm) as model toxicants was evaluated in rats. The modifications considered were the increases in serum glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities and the decreases in centrolobular liver cell glucose-6-phosphatase staining intensity. A linear inverse relationship was established between the logarithmic values of blood enzyme activities and liver glucose-6-phosphatase staining intensity. In addition, the levels of exposure to each test chemical were found to be linearly related to liver glucose-6-phosphatase staining intensity and to the logarithmic values of blood enzyme activities. [R78] *Developmental, genetic, and reproductive toxicities of benzene, chlorobenzene, and o-, m-, and p-dichlorobenzenes were investigated in sea urchin, Paracentrotus lividus. Toxicity order depended on whether the target organ was embryo or sperm. Benzene was active in sea urchin sperm causing developmental and mitotic abnormalities in offspring. Benzene also showed a significant increase in developmental defects following embryo exposure. For chlorobenzene, developmental defects were seen when the concn was increased to 10(-4) M. m-Dichlorobenzene caused a strong increase in developmental defects and also in mitotic abnormalities. [R79] *... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of 1,2-dichlorobenzene for male or female F344/N rats or B6C3F1 mice receiving 60 or 120 mg/kg/day. ?evels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R80] *Rats survived inhalation exposure for 2 hr at a concentration of 977 ppm but died after a 7-hr exposure. Rats that survived a 7-hr exposure at 539 ppm o-DCB showed liver necrosis and kidney tubule damage. Liver damage in rats was produced in another study at concentrations of from 50 to 800 ppm and exposures lasting between 0.5 and 1 hr at 390 ppm produced liver necrosis in three of six rats. Mice exposed for 1 hr to saturated o-DCB vapor (calculated between 2000 and 3000 ppm) showed prompt narcosis followed by central depression and cyanosis (and death in 24 hr). [R81, 1991.406] *In rats and guinea pigs exposed at 93 ppm, 7 hr/day for 6 to 7 months, the male guinea pigs had a decrease in spleen weight without any histopathologic changes. [R81, 1991.406] *In separate 13-week studies in mice and rats, oral doses of 500 mg o-DCB/kg caused decreased survival (except in male rats). This dose produced necrosis and hepatocellular degeneration and depletion of lymphocytes in both the spleen and thymus and renal tubular degeneration in male rats. Multifocal mineralization of the myocardial fibers of the heart and skeletal muscle were seen in mice. At a dose of 250 mg/kg, necrosis of individual hepatocytes was evident except in the female mice. At a dose of 125 mg/kg, minimal hepatocellular necrosis was observed in a few rats. [R81, 1991.407] *Rats and rabbits were exposed by inhalation at either 100, 200, or 400 ppm o-DCB, 6 hr/day, from gestation days 6 through 15 (rats) and days 6 through 18 (rabbits). Maternal toxicity was reflected by a reduced rate of bodyweight gain in all groups of the treated rats. Liver weights were increased at 400 ppm. No evidence of a fetal response was seen at any concentration. Female rabbits exposed at 400 ppm showed a decreased rate of weight gain over the first 3 exposure days without signs of a fetal response. [R81, 1991.407] *Male rats given single intraperitoneal injections of either 50, 100, 250, 300, or 800 mg o-DCB/kg showed dose-related, morphologic alterations in sperm consisting of misshapen head, acrosomal defects, and tail abnormalities. [R81, 1991.407] *Fischer 344 (F344) rats are reportedly 75-fold more sensitive than Sprague Dawley (S-D) rats to 1,2-dichlorobenzene (o-DCB) hepatotoxicity. Lethality studies were conducted since no information was available regarding the ultimate consequence of this sensitivity in terms of animal survival in the two strains. LD50S for o-DCB (1.66 ml/kg and 1.76 ml/kg in male F344 and S-D rats, respectively) did not differ. Several studies have shown the importance of tissue repair on animal survival following exposure to toxic chemicals. The objective of this study was to investigate if differential rates of cell division and tissue repair might explain the lack of difference in LD50 dose between the two strains despite higher hepatotoxic injury in F344 rats. Age-matched male S-D and F344 rats were administered o-DCB (0.2, 0.6, 1.2 ml/kg, i.p.); injury and tissue repair occurring as two dynamic but opposing events were measured over time. Liver injury was assessed by measuring plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities and by liver histopathology. Higher plasma ALT elevations were observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. Using SDH as a marker of liver injury, the strain difference was evident only at 0.2 ml o-DCB/kg. Liver regeneration was estimated by 3H-thymidine incorporation into hepatonuclear DNA and via proliferating cell nuclear antigen (PCNA) assay. Prompt and significantly higher hepatocellular regeneration beginning at 36 h was evident in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. The significantly higher depletion of hepatic glycogen observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg occurred without significant changes in plasma glucose and is consistent with highly stimulated tissue repair seen in these rats at the corresponding doses. However, increasing the dose further to 1.2 ml o-DCB/kg results in a delayed (S-phase synthesis begins at 48 h) and diminished response to o-DCB. These findings suggest that a significantly higher rate of tissue repair in F344 rats helps them overcome higher liver injury inflicted by o-DCB. This differential in tissue repair in the two strains may play a vital role in equalizing the ultimate outcome of toxicity in the two strains. [R82] NTXV: *LD50 Guinea pig oral 0.8-2.0 ug/kg; [R12, 23] *LC50 Mouse inhalation 6,825 mg/cu m/6 hr; [R12, 23] NTP: *... Two yr toxicology and carcinogenesis studies of 1,2-dichlorobenzene (> 99% pure) were conducted by administering the test cmpd in corn oil by gavage 5 days/wk for 103 wk to groups of 50 male and 50 female F344/N rats and B6C3F1 mice at doses of 60 and 120 mg/kg. Groups of 50 rats and 5 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of 1,2-dichlorobenzene for male or female F344/N rats or B6C3F1 mice receiving 60 or 120 mg/kg/day. ?evels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R80] TCAT: ?The effects of o-dichlorobenzene were examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity determinations, o-dichlorobenzene was tested at concentrations of 0%, and 5 different concentrations ranging from 1x10(-7)% to 1x10(-3)% (v/v). None of the concentrations tested caused a significant increase in the unscheduled DNA synthesis over the solvent control (DMSO), and these concentrations were not genotoxic to the hepatocytes. [R83] ?An inhalation teratology study was conducted with pregnant Fischer 344 rats and inseminated New Zealand white rabbits receiving whole body exposure to ortho-dichlorobenzene at nominal concentrations of 0, 100, 200 or 400ppm. At each concentration, 30 or 32 bred rats and 28 or 30 inseminated rabbits were exposed for 6hrs/day on days 6-15 of gestation (rats) and on days 6-18 of gestation (rabbits). Maternal toxicity was evident by depressed body weight gain in both test species and significantly elevated liver weights in 400ppm treated rats. The incidence of major malformations among the fetuses of either test species was not significantly increased over the controls. [R84] ?The mutagenicity of ortho-dichlorobenzene was evaluated in Salmonella tester strain TA100 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Ortho-dichlorobenzene, diluted with DMSO, was tested at concentrations up to 5.0ul/plate using the plate incorporation technique. Ortho-dichlorobenzene did not cause a positive response in tester strain TA100 with or without metabolic activation. [R85] ?The mutagenicity of ortho-dichlorobenzene was evaluated in Salmonella tester strains TA1535, TA1537, TA1538, TA98 and TA100 (Ames Test) and in Saccharomyces cerevisiae strain D4, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, ortho-dichlorobenzene, diluted in culture medium, was tested at concentrations up 100ul/plate using the plate incorporation technique. Ortho-dichlorobenzene caused a positive response the tester strain TA100 with metabolic activation, but a dose response was not observed. All other tester strains did not produce a positive result with or without metabolic activation. [R86] ?The mutagenic potential of ortho-dichlorobenzene was evaluated in the germ cells (Sex-Linked Recessive Lethal Mutations) of Drosophila males exposed by inhalation. Based on preliminary toxicity determinations, groups of males files received nominal concentrations of 11,000, 14,000, 16,000 or 17,000ppm in sealed hypovials, resulting in a range of 34 - 0% mortality during exposure and pre-mating. None of the treatments produced mutant frequencies significantly greater than the negative control (air only). [R87] ?The ability of ortho-dichlorobenzene to cause chromosome aberration was evaluated in bone marrow cells of male Charles River rats (30/group) receiving subcutaneous doses of 0.04, 0.2 and 1g/kg/day for 16 days. Six animals per dose were sacrificed after 1, 2, 4, 8 and 16 days of treatment. Toxicity was indicated in the high dose animals by increased mortality and decreased body weight gain compared with control animals. No differences were observed between treatment groups and controls for mean red blood cell counts, mean hemoglobin concentrations and mean hematocrit values. Ortho-dichlorobenzene did not induce an statistically significant (t-test) increase in the number of chromosome aberrations observed relative to the control at any dose level regardless of sacrifice time. [R88] ?The ability of ortho-dichlorobenzene to cause chromosome aberrations was evaluated in bone marrow cells of Sprague-Dawley rats (3/sex/treatment) sacrificed at 6, 12 and 24 hours following a single intraperitoneal injection at 150, 300 or 600mg/kg. Due to an error in calculating the stock solution, the 12 and 24 hour assays were preformed at concentrations of 135, 270 and 540mg/kg. 100 metaphases per animal were analyzed. Ortho-dichlorobenzene did not cause a statistically significant increase in the frequency of chromosomal breaks or aberrations at any of the dose levels regardless of sacrifice time relative to the controls (DMSO). [R89] ?The ability of ortho-dichlorobenzene to induce chromosome aberrations in cultured Chinese Hamster ovary (CHO) cells was evaluated in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. The maximum dose selected for both nonactivated and activated cultures was the solubility of ortho-dichlorobenzene in water, 140ug/ml (literature value). Although isolated test points with ortho-dichlorobenzene cause a statistically significant (Chi-Square Test) increase in the frequency of the chromosomal aberrations with and without metabolic activation compared to the negative control (DMSO), the assays were considered negative due to lower than average frequency of chromosomal breaks in the negative control. [R90] ?The effect of ortho-dichlorobenzene (DCB) was examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, DCB, diluted with DMSO, was tested at 8 concentrations ranging from 1.0 to 1x10(-7)% (v/v). Cultures were exposed to DCB for 18 hrs and 20 nuclei were randomly counted due to no obviously positive cells being observed upon scanning of the slides. Concentration of 0.01% and above were cytotoxic. None of the non-cytotoxic concentrations tested caused a significant increase in unscheduled DNA synthesis over the solvent control. [R91] POPL: *Persons with existing pathology (hepatic, renal, central nervous system, blood), or metabolic disorders, who are taking certain drugs (hormones, or otherwise metabolically active) or who are otherwise exposed to dichlorobenzenes or to related (chemically or biologically) chemicals, by such means as occupation or domestic use or abuse ... might well be considered at increased risk from exposure to dichlorobenzenes. /Dichlorobenzenes/ [R92] */Individuals who suffer from/ skin, liver, kidney, or chronic respiratory disease, will be at an increased risk if they are exposed to chlorobenzenes. /Chlorobenzenes/ [R42, 1981.1] ADE: *THE MORE PRONOUNCED TOXICITY TO THE LIVER OF THE ORTHO-ISOMER HAS BEEN ASSOCIATED WITH A MORE PRONOUNCED BINDING OF THE CMPD OR ITS INTERMEDIATE METABOLITES TO LIVER PROTEINS ... [R56] *The dichlorobenzenes may be absorbed through the lung, gastrointestinal tract, and intact skin. Relatively low water solubility and high lipid solubility favor their penetration of most membranes by diffusion, including pulmonary and GI epithelia, the brain, hepatic parenchyma, renal tubules, and the placenta. /Dichlorobenzenes/ [R93] METB: *AFTER INGESTION OF O-DICHLOROBENZENE, URINE OF RABBITS WAS FOUND TO CONTAIN 2,3- AND 3,4-DICHLOROPHENOL FREE AND O-GLUCURONIC AND SULFURIC ACID CONJUGATES, 3,4- AND 4,5-DICHLOROCATECHOL FREE AND AS THE O-GLUCURONIDE AND SULFATE, AND 3,4-DICHLOROPHENYLMERCAPTURIC ACID. [R94] *THE EFFECT OF INDUCERS AND INHIBITORS OF MICROSOMAL MIXED-FUNCTION OXIDASES ON THE FATE OF METABOLISM AND THE EXTENT OF BINDING OF ORTHO- AND PARA-DICHLOROBENZENE TO CELLULAR CONSTITUENTS SUGGESTS THAT ARENE OXIDES (EPOXIDE) MAY BE PRECURSORS OF THE EXCRETED METABOLITES ... [R56] *O-DICHLOROBENZENE YIELDED N-ACETYL-S-(3,4-DICHLOROPHENOXY)-L-CYSTEINE IN RABBITS. /FROM TABLE/ [R95] *Metabolism of ... 1,2-dichlorobenzene (1,2-DCB), was studied ... in chinchilla rabbits. Single doses of 500 mg compound/kg body weight were given by stomach tube ... . Results showed 1,2-DCB to be primarily metabolized by oxidation to 3,4-dichlorophenol, and excreted (primarily in urine) as conjugates of glucuronic and sulfuric acids. Peak excretion of these conjugates occurred on the first day after dosing. Minor metabolites also formed and excreted as conjugates included 2,3-dichlorophenol ... 4,5-dichlorocatechol, 3,4-dichlorocatechol, and 3,4-dichlorophenylmercapturic acid. Metabolism and urinary excretion of 1,2-DCB was considered relatively slow, being essentially complete 5 to 6 days after dosing. [R96] *The excretion of o-dichlorobenzene by rabbits given a single oral dose of 500 mg/kg /was measured/. Virtually all of the cmpd was excreted in 6 days, predominately in urinary conjugates as glucuronide (48%), ethereal sulfate (21%), and mercapturic acid (5%). The remainder was excreted as mono-phenols. [R12, 23] *1,2,4-Trichlorobenzene (TCB) was reductively converted into monochlorobenzene (MCB) via dichlorobenzenes (DCBs) on incubation with intestinal contents of rats. When the amounts of MCB produced from o-DCB, m-DCB, or p-DCB as substrates were compared, the amount was the least in the case of o-DCB. This was consistent with the finding that o-DCB tended to accumulate more than the other isomers. The mechanism of the reductive dechlorination of aromatic compounds is not well understood. [R97] *A Pseudomonas species that was capable of growth on 1,2-dichlorobenzene (o-DCB) or chlorobenzene as a sole source of carbon and energy was isolated by selective enrichment from activated sludge. Extracts of o-DCB-grown cells converted radiolabeled o-DCB to 3,4-dichloro-cis-1,2-dihydroxycyclohexa-3,5-diene (o-DCB dihydrodiol). 3,4-Dichlorocatechol and o-DCB dihydrodiol accumulated in culture fluids of cells exposed to o-DCB. The results suggest that o-DCB is initially converted by a dioxygenase to a dihydrodiol, which is converted to 3,4-dichlorocatechol by an NAD+ dependent dehydrognase. Ring cleavage of 3,4-dichlorocatechol is by a catechol 1,2-oxygenase to form 2,3-dichloro-cis,cis-muconate. Preliminary results indicate that chloride is eliminated during subsequent lactonization of the 2,3-dichloro-cis,cis-muconate, followed by hydrolysis to form 5-chloromaleylacetic acid. [R98] *1,2,4-Trichlorobenzene (TCB) labeled with (14)C was given orally to rats at a dosage of 50 mg/kg. ... Trapped radioactivity in the expired air amounted to 2.1% of the dose, but production of labeled CO2 was negligible. Dichlorobenzenes and unchanged TCB were confirmed in the expired air. Reductive dechlorination seems to be catalyzed by intestinal microflora enzymes. [R99] ACTN: *THE MORE PRONOUNCED TOXICITY TO THE LIVER OF THE ORTHO-ISOMER HAS BEEN ASSOCIATED WITH A MORE PRONOUNCED BINDING OF THE CMPD OR ITS INTERMEDIATE METABOLITES TO LIVER PROTEINS ... [R56] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Dichlorobenzene's production and use as a solvent, as a starting material in the manufacture of 3,4-dichloroaniline, and its application as a insecticide will result in its release to the environment through various waste streams. Based on a vapor pressure of 1.4 mm Hg at 25 deg C, 1,2-dichlorobenzene is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of 38 days. 1,2-Dichlorobenzene is expected to have moderate to low mobility in soils based upon log Koc values in the range of 2.5-4.3 measured in soils and sediment. Volatilization of 1,2-dichlorobenzene from dry soil surfaces is expected to be an important fate process based upon the vapor pressure of this compound and a volatilization half-life of about 4 days measured in silt loams. Volatilization from moist soil surfaces is expected based on the Henry's Law constant of 1.5X10-3 atm-cu m/mole at 20 deg C. A 0% theoretical BOD in sludge over a 4 week incubation period suggests that biodegradation is expected to be slow in soil and water. In water, 1,2-dichlorobenzene is expected to adsorb to sediment or particulate matter based on its measured Koc values. This compound is expected to volatilize from water surfaces given its Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4 and 120 hours, respectively. The potential for bioconcentration in aquatic organisms is considered moderate to high based on BCF values in the range of 90 to 560 measured in fish. Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where 1,2-dichlorobenzene is produced or used. The general population may be exposed to 1,2-dichlorobenzene via inhalation of ambient air, ingestion of food and drinking water. (SRC) NATS: *THE CHEMICAL IS NOT KNOWN TO OCCUR IN NATURE. [R100] ARTS: *Dichlorobenzenes have been detected or quantified in rivers, groundwater, municipal and industrial discharges, and drinking water. Dichlorobenzenes enter the water systems (raw and contaminated water) from the use of 1,2-DCB as a deodorant in industrial wastewater treatment. [R101] *1,2-Dichlorobenzene's production and use as a solvent, as a starting reagent in the manufacture of 3,4-dichloroaniline, and it's application as an insecticide will result in its release to the environment through various waste streams(1,2,SRC). [R102] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), and Koc values of 280(2) and 320(3) measured in soil, 1,2-dichlorobenzene is expected to have moderate mobility in soil(SRC). Volatilization of 1,2-dichlorobenzene is expected from moist soil surfaces given its Henry's Law constant of 1.5X10-3 atm-cu m/mole at 20 deg C(4). Volatilization of 1,2-dichlorobenzene from dry soil surfaces is expected based on a vapor pressure of 1.4 mm Hg at 25 deg C(5). The volatilization half-life of 1,2-dichlorobenzene from Captina and McLaurin sandy loam soils was measured as about 4 days(6). A 0% theoretical BOD in sludge over a 4 week incubation period(7) suggests that biodegradation is expected to be slow in soil(SRC). 1,2-Dichlorobenzene is resistant to biodegradation in soils, with half-lives expected to be greater than 9 months(8). [R103] *AQUATIC FATE: Based on a recommended classification scheme(1), and log Koc values of 3.7(2) and 4.3(3) measured in sediment, 1,2-dichlorobenzene is expected to adsorb to suspended solids and sediment in water(SRC). 1,2-Dichlorobenzene is expected to volatilize from water surfaces(4,SRC) given its Henry's Law constant of 1.5X10-3 atm-cu m/mole at 20 deg C(5). Estimated volatilization half-lives for a model river and model lake are 4 and 120 hours, respectively(4,SRC). According to a classification scheme(6), BCF values in the range of 90 to 560, measured in carp(7) and trout(8), suggest that bioconcentration in aquatic organisms is moderate to high. A 0% theoretical BOD in sludge over a 4 week incubation period(7) suggests that biodegradation is expected to be slow in water(SRC). [R104] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-dichlorobenzene, which has a vapor pressure of 1.4 mm Hg at 25 deg C(2), is expected to exist in the vapor phase in the ambient atmosphere. Vapor-phase 1,2-dichlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 38 days(3,SRC). [R105] BIOD: *A 0% theoretical BOD in sludge over a 4 week incubation period(1) suggests that biodegradation is expected to be slow in soil and water(SRC). 1,2-Dichlorobenzene is resistant to biodegradation using the Japanese MITI test(2). Dichlorobenzene isomers were slowly biodegraded (6.3% of theoretical CO2 evolution in 10 weeks) in an alkaline soil sample(3). 1,2-Dichlorobenzene was biodegraded by an acclimated anaerobic sediment slurry obtained from the Tsurumi River, Japan(4). The first-order biodegradation rate constant was 0.0188 days-1, corresponding to a half-life of about 37 days(4). The first-order biodegradation rate constant of 1,2-dichlorobenzene in pure culture laboratory batch microcosms was 0.06 days-1, corresponding to a half-life of about 12 days following a 13 day lag period(5). The rate constant for 1,2-dichlorobenzene in a heterogeneous aquifer at the Columbus Air Force Base, Mississippi was 0.0059 days-1, corresponding to a biodegradation half-life of about 117 days(6). 1,2-Dichlorobenzene is resistant to biodegradation in soils, with half-lives expected to be greater than 9 months(7). [R106] ABIO: *The rate constant for the vapor-phase reaction of 1,2-dichlorobenzene with photochemically-produced hydroxyl radicals has been measured as 4.2X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 38 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 1,2-Dichlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of functional groups to hydrolyze(SRC). [R107] BIOC: *The sorption of 8 organic compounds by a representative green alga, Selenastrum capricornutum, was determined by GLC by a series of linear model experiments. The log10 bioconcentration factors (BCF), defined as the ratio of the concentration on/in the algae to the concentration in the aqueous medium, were as follows: benzene 3.32, toluene 3.18, chlorobenzene 3.69, 1,2-dichlorobenzene 4.17. The relation of log10 BCF correlation with log10 octanol-water partition coefficient (P) was determined to be log10 BCF= 0.46 log10 P + 2.36. [R108] *BCF values of 150 to 230 were measured in carp exposed to 0.1 mg/l of 1,2-dichlorobenzene during an 8 week incubation period and BCF values of 90 to 260 were measured in carp exposed to 0.01 mg/l of 1,2-dichlorobenzene during an 8 week incubation period(1). 1,2-Dichlorobenzene BCF values of 270 to 560 were experimentally determined for rainbow trout exposed up to 119 days in laboratory aquariums(2). A whole body BCF of 66 was determined for bluegill sunfish exposed to 1,2-dichlorobenzene over a 28-day period in a continuous flow system(3). According to a classification scheme(4), these BCF values suggest that bioconcentration in aquatic organisms is moderate to high. [R109] KOC: *Experimental Koc values of 280(1) and 320(2) were determined for 1,2-dichlorobenzene in silt loam soils. A log Koc value of 3.7 was reported for 1,2-dichlorobenzene in sediment obtained from the Ise Bay, Japan(3) and a log Koc value of 4.3 was measured from sediment of Lake Ketelmeer, Netherlands(4). According to a recommended classification scheme(5), these Koc values suggest that 1,2-dichlorobenzene has moderate to low mobility in soil. [R110] VWS: *The Henry's Law constant for 1,2-dichlorobenzene is 1.5X10-3 atm-cu m/mole at 20 deg C(1). This value indicates that 1,2-dichlorobenzene will volatilize from water(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 4 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 120 hours(2,SRC). 1,2-Dichlorobenzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is expected. 1,2-Dichlorobenzene is expected to volatilize from dry soil surfaces based on a vapor pressure of 1.4 mm Hg at 25 deg C(3). The volatilization half-life of 1,2-dichlorobenzene from Captina and McLaurin sandy loam soils was measured as about 4 days(4). [R111] WATC: *DRINKING WATER: A mean 1,2-dichlorobenzene concn of 0.003 ppb was detected in drinking water samples from 3 cities near Lake Ontario in 1980(1). A concn of 1 ppb was detected in Miami, FL drinking water and qualitative detections were reported for Philadelphia, PA and Cincinnati, OH(2). 1,2-Dichlorobenzene was found in 2 of 945 finished water supplies throughout the US that use groundwater sources at concns of 2.2 and 2.7 ppb(3). 1,2-Dichlorobenzene was identified, not quantified in Cleveland, OH tap water(4) and two drinking water supply sources in the United Kingdom(5). 1,2-Dichlorobenzene was identified, not quantified, in the drinking water of Alexandria, Egypt(6). [R112] *GROUNDWATER: 1,2-Dichlorobenzene was positively detected in 20 of 685 groundwaters analyzed in NJ during 1977-1979 with 6,800 ppb the highest concn found(1). 1,2-Dichlorobenzene was detected at concns of less than 4 ng/l in groundwater from the Edwards Aquifer, TX(2). 1,2-Dichlorobenzene was detected at max concns of 2.7 and 13 ug/l in groundwater near landfills at unspecified locations in Finland/Sweden and Germany/USA/Canada(3). [R113] *SURFACE WATERS: 1,2-Dichlorobenzene was detected in 15 of 463 surface waters analyzed in NJ during 1977-1979 with 8.2 ppb the highest concn found(1). Mean concs of 5 and 6 parts per trillion were detected in Lake Ontario and Grand River water, respectively, during 1980 near Niagara Falls; concns of 0-56 parts per trillion were found in the Niagara River(2). 1,2-Dichlorobenzene was detected at concns of 4-240 parts per trillion (mean concn of 23 parts per trillion) in the Niagara River at Niagara-On-The-Lake between 1981 and 1983(3) and concns of 5.6-190 parts per trillion (mean concn of 18 parts per trillion) were detected in the Niagara River between 1981 and 1983(4). An avg concn of 20 parts per trillion was found in the Niagara River near Niagara-On-The-Lake between Sept and Oct 1982(5). Positive detection of 1,2-dichlorobenzene was reported by 0.6% of 1077 USEPA STORET stations(6). 1,2-Dichlorobenzene was identified, not quantified, in the Delaware and Raritan Canal in NJ(7). 1,2-Dichlorobenzene was detected at concns below 0.5 ppb in the Rhine River between 1978-1982(8). An avg 1,2-dichlorobenzene concn of 0.32 ppb was found in the Rhine River near Dusseldorf in 1984(9). 1,2-Dichlorobenzene was detected at mean concns of 0.34 ng/l (Edwards Point) and 0.34 ng/l (Port Lambton) in Ontario, Canada(10). 1,2-Dichlorobenzene was detected at an avg concn of 0.21 ug/l in 48 of 136 samples of river water in Osaka, Japan(11). 1,2-Dichlorobenzene was detected at concns of 0-0.7 ug/l in Lake Ketelmeer, Netherlands(12) and at concns of 0-146 ng/l in Ise Bay, Japan(13). 1,2-Dichlorobenzene was detected in the Elbe River, Germany at concns of 2.2-74 ng/l(14). [R114] *RAIN/SNOW: A mean 1,2-dichlorobenzene concn of 0.49 parts per trillion was detected in Portland, OR rainwater during March-April 1982(1); Concn of not detected to 0.62 parts per trillion found in Portland, OR rainwater during 1984(2). [R115] EFFL: *1,2-Dichlorobenzene was detected in the leachate of municipal landfills in the US at concns of 3-32 g/l(1) and 21-33 ug/kg in the ash of municipal waste incinerators in the US(2). 1,2-Dichlorobenzene was detected at a concn of 0.02 ug/cu m in the effluent of a hazardous waste incinerator in Germany(3). The annual US emission of 1,2-dichlorobenzene was 160 tons in 1990(4). 1,2-Dichlorobenzene was detected at mean concns of 0.03 to 0.20 mg/cu m in the air of municipal landfills in Finland(5). 1,2-Dichlorobenzene was detected at concns of 4-5 ug/l in the effluent of New York City municipal wastewater(6). 1,2-Dichlorobenzene was detected in landfill leachate in Sweden at concns of less than 1 to 1.3 ug/l(7). [R116] SEDS: *1,2-Dichlorobenzene was detected in the sediment of Lake Ketelmeer, Netherlands at concns of 350 and 220 ng/kg(1). 1,2-Dichlorobenzene was detected in sediment off the coast of Taiwan at concns of 2-5 ng/kg(2). Mean 1,2-dichlorobenzene concs of 1,8,2 and 11 ppb were detected in the superficial sediments from Lakes Superior, Huron, Erie, and Ontario, respectively(3). 1,2-Dichlorobenzene was detected at concns of 0-516 ng/g in sediment from Ise Bay, Japan(4). 1,2-Dichlorobenzene was detected in the sediment of 7 rivers and 1 port in Niigata, Japan at concns of less than 0.03 to 1.4 ng/g(5). [R117] ATMC: *1,2-Dichlorobenzene ... measured in aerial fallout and high volume samples taken at various locations in the Los Angeles area yielded the following concentrations; Catalina Island < 8 ng/sq m; San Clemente < 27 ng/sq m; Santa Barbara < 53 ng/sq m. [R118] *Concentrations (mean) of o-dichlorobenzene were: 0.03 ppb (detected in 29 of 38 samples) in Newark NJ; 0.02 ppb (24 of 37 samples) in Elizabeth NJ; and 0.01 ppb (27 of 35 samples) in Camden NJ during July-August 1981. [R119] *URBAN/SUBURBAN: The mean 1,2-dichlorobenzene concentrations from 226 source-dominant points and 674 urban/suburban points in the US have been reported to be 200 and 56 parts per trillion, respectively(1). An avg concn of 0.61 ppb was reported for 1,2-dichlorobenzene near industrial areas in NJ(2). Mean concns of 12.5, 22.6 and 4.0 parts per trillion were detected for 1,2-dichlorobenzene in the ambient air of Los Angeles, CA, Phoenix, AZ and Oakland, CA, respectively, during Apr-May 1979(3). Mean concns of 0.01-0.03 ppb were detected in the ambient air of three NJ cities during July-Aug 1981(4). A mean concn of 5.8 ng/cu m was reported for 1,2-dichlorobenzene in the ambient air of Portland, OR during 1984(5). 1,2-Dichlorobenzene was detected at mean concns of 130 ppb (Los Angeles, CA), 40 ppb(Oakland, CA), 10 ppb(Riverside, CA), 1 ppb(Portland, OR) and 56 ppb(unspecified urban locations in the US)(6). [R120] *RURAL/REMOTE: The mean 1,2-dichlorobenzene concentrations from 9 rural sources in the US was 1.8 parts per trillion(1). 1,2-Dichlorobenzene was detected at an avg concn of 0.06 ppb in rural residential areas of NJ(2). [R121] *INDOOR AIR: 1,2-Dichlorobenzene was detected at median concns of 0.1-2.2 ug/cu m in US homes(1). The mean 3-day concn of dichlorobenzene isomers was 0-7 ug/cu m in 7 buildings in the US(2). The combined isomers of dichlorobenzene were identified, not quantified, in 10 of 14 indoor air samples from 4 buildings in the US(2). 1,2-Dichlorobenzene was identified, not quantified, in the indoor air from 24 of 26 buildings in Finland(3). The mean concn of 1,2-dichlorobenzene measured in houses in Kuwait from Dec 1994 to Jan 1995 was 1,679 ug/cu m(4). [R122] FOOD: *1,2-Dichlorobenzene was detected at a concn of 1.0 ng/g in market meat samples in Yugoslavia(1) and in 45 of 234 table ready foods in the US at an avg concn of 9.47 ppb(2). 1,2-Dichlorobenzene was detected in high-fat foods at concns of 49-113 ng/g and in low-fat foods at 11-78 ng/g(3). 1,2-Dichlorobenzene was detected in potatoes at a concn of 0.328 mg/kg and peas at a concn of 0.112 mg/kg(4). [R123] PFAC: PLANT CONCENTRATIONS: *1,2-Dichlorobenzene has been detected at unspecified concns in the roots of wheat plants grown from lindane-treated seeds(1). 1,2-Dichlorobenzene was identified, not quantified, in plant material grown in an Illinois coal refuse reclamation site(2). [R124] FISH/SEAFOOD CONCENTRATIONS: *1,2-Dichlorobenzene was detected at concns of 0.3, 1, 1 and 1 ppb in trout taken from Lake Superior, Lake Huron, Lake Erie and Lake Ontario, respectively, during 1980(1). Concns of 0-4.0 ug/kg were found in Flatfish off the California coast near Los Angeles(2) and a mean concn of less than 0.031 mg/kg was found in the muscle tissue of 8 seafood species caught off the California coast(2). Fish and mussels taken from rivers in Slovenia and the Gulf of Trieste (Yugoslavia) were found to contain trace levels to 1.2 ug/g of 1,2-dichlorobenzene (on a fat basis)(3). [R125] MILK: *Mean 1,2-dichlorobenzene of 13 ug/kg (fat basis) detected in Yugoslavian human adipose tissue and 9 ug/kg (as is basis) or 230 ug/kg (fat basis) in human milk. [R126] *A survey of human milk from the general population of Canada found 1,2-dichlorobenzene residues in 17 percent of the samples at an avg concn of 2 ppb(1). 1,2-Dichlorobenzene was detected in human milk at 9 ug/kg(2). [R127] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 76,818 workers (12,654 of these are female) are potentially exposed to 1,2-dichlorobenzene in the US(1). Occupational exposure to 1,2-dichlorobenzene may be through inhalation and dermal contact with this compound at workplaces where 1,2-dichlorobenzene is produced or used(SRC). 1,2-Dichlorobenzene levels up to 8.5 ppm (51 mg/cu m) were detected in the breathing zones of a chlorobenzene factory(2). The general population may be exposed to 1,2-dichlorobenzene via inhalation of ambient air, ingestion of food and drinking water(SRC). [R128] AVDI: *Based on monitoring data at three USA urban sites (Los Angeles, Phoenix, Oakland), the AVDI for 1,2-dichlorobenzene has been estimated to be 0.5-2.8 ng/day(1). The AVDI of 1,2-, 1,3- and 1,4-dichlorobenzene isomers in the Netherlands is 7.0 ug/day(2). [R129] BODY: *Dichlorobenzene was detected in whole blood (3.12 ng/g) and adipose tissue (2.28 ng/g) from the general population of Canada(1). 1,2-Dichlorobenzene was detected in the personal air of Los Angeles, CA residents at concns of 0.3-0.4 ug/cu m and residents of Contra Costa, CA at concns of 0.6 ug/cu m(2). 1,2-Dichlorobenzene was detected in the breath of Los Angeles, CA residents at concns of 0.04-0.1 ug/cu m and residents of Contra Costa, CA at concns of 0.08 ug/cu m(2). [R130] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +200 ppm [R19, 96] OSHA: +Permissible Exposure Limit: Table Z-1 Ceiling value: 50 ppm (300 mg/cu m). [R131] NREC: +Recommended Exposure Limit: 15-Min Ceiling Value: 50 ppm (300 mg/cu m). [R19, 96] TLV: +8 hr Time Weighted Avg (TWA) 25 ppm; 15 min Short Term Exposure Limit (STEL) 50 ppm [R53] +A4. A4= Not classifiable as a human carcinogen. [R53] OOPL: *THE MAXIMUM ALLOWABLE CONCN IN THE USSR IS 20 MG/CU M. [R132] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. o-Dichlorobenzene is produced, as an intermediate or a final product, by process units covered under this subpart. [R133] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 600 ug/l [R134] STATE DRINKING WATER STANDARDS: +(NJ) NEW JERSEY 600 ug/l [R134] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 620 ug/l [R134] +(CA) CALIFORNIA 130 ug/l [R134] +(ME) MAINE 85 ug/l [R134] +(MN) MINNESOTA 600 ug/l [R134] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R135] +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. [R136] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.5 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R137] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulagated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2-Dichlorobenzene is included on this list. [R138] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA. [R139] RCRA: *F002; When 1,2-dichlorobenzene is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F002), as stated in 40 CFR 261.31, and must be managed according to state and/or federal hazardous waste regulations. [R140] *U070; As stipulated in 40 CFR 261.33, when 1,2-dichlorobenzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R141] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. 1,2-Dichlorobenzene is found on List C. Case No: 3057; Pesticide type: Antimicrobial; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): 1,2-Dichlorobenzene; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R7] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Analyte: 1,2-Dichlorobenzene; Matrix: Air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01-0.2 l/min; Vol: min: 1 @ 50 ppm, max: 60; Stability: Not determined [R142] *Air Sample: ... Ambient air was drawn through a 1.5X6.0 cm bed of Tenax-GC ... so that vapors were collected completely on the resin. ... [R143] *Air Samples: ... An air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. /Chlorobenzenes/ [R144] ALAB: *NIOSH 1003-2. Analyte: 1,2-Dichlorobenzene; Matrix: Air; Sampler: Solid sorbent tube (coconut shell charcoal); Procedure: Desorption: 1 ml CS2, stand 30 min; Gas chromatography, flame ionization detector; Range: 27 to 330 ppm; Precision: 0.068; Est LOD: 0.01 mg/samp; Interferences: None /Hydrocarbons, halogenated/ [R145] *Air Sample: ... Ambient air is drawn through a 1.5X6.0 cm bed of Tenax-GC ... so that vapors were collected completely on the resin. The sample was then thermally desorbed and the vapors passed through a cryogenically cooled trap and subsequently introduced into a gas chromatograph-mass spectrometer (GC-MS). Estimated detection limits for monochlorobenzene is 2.1 ng/cu m; 1,2-dichlorobenzene 1.0 ng/cu m; and 1,3-dichlorobenzene 0.7 ng/cu m. [R146] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. [R147] *OSW Method 8020A. Determination of Aromatic Volatile Organics by Gas Chromatography. [R147] *OSW Method 8120A. Determination of Chlorinated Hydrocarbons by Gas Chromatography. [R147] *OSW Method 8240B. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R147] *OSW Method 8250A. Determination of Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry. [R147] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R147] *OSW Method 8270B. Determination of semivolatile organic compounds by gas chromatography/mass spectrometry (GC:MS). Capillary column technique. [R147] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. [R148] *EPA Method 602. Purgeable Aromatics in Wastewater by Gas Chromatography with Photoionization Detection. [R148] *EPA Method 612. Chlorinated Hydrocarbons in Wastewater by Gas Chromatography with Electron Capture Detection. [R148] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. [R148] *EPA Method 625. Protocol for the Analysis of Base/Neutral and Acid Extractable (BNA) Organic Priority Pollutants in Industrial and Municipal Wastewater. [R148] *EPA Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. [R148] *Chlorinated benzenes have been found as contaminants in foods and water. Because of differences in the electron capture response of the isomers at each chlorination level, residue quantitation requires the separation of all 12 chlorobenzenes. Resolution studies were made on packed and capillary columns coated with Kovats' Ca87H176 hydrocarbon, OV-101, OV-210, OV-17 and Carbowax 20M. Satisfactory resolution of all 12 chlorobenzenes was obtained with a Carbowax 20M-coated column operated isothermally at 120 deg C. /Chlorinated benzenes/ [R149] *Air Samples: ... An air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. The adsorbent is desorbed with carbon tetrachloride and analyzed by GC using a photoionization detector. When using this method the minimum detection limits for mono-, di-, tri-, tetra-, and pentachlorobenzenes are 15, 20, 30, 35, and 45 ppb (v/v), respectively. /Chlorobenzenes/ [R150] *An intergrated analytical procedure for determining chlorinated benzene contaminants that enables quantitation of individual isomers as low as 0.4 ug/kg in sediment samples was developed. Preparation of the sample can be performed by using 1 of 3 techniques, namely, Soxhlet extraction, ultrasonic extraction, or steam distillation. Although all 3 methods are quantitative, the steam distillation method was found to be the most efficient for the determination, insofar as time and simplicity are concerned. Chlorinated benzenes were then characterized and quantified by open tubular column gas chromatography with electron capture detection. Detection limits of this method were 0.4-1.0 ug/kg of individual chlorobenzene isomers. Chlorobenzene recovery from bottom sediment samples at concentration levels between 1 and 100 ug/kg was 86 +/- 14 %. /Chlorinated benzenes/ [R151] CLAB: *DETERMINATION OF CHLOROBENZENES (INDUSTRIAL PRODUCTS) MONOCHLOROBENZENE THROUGH HEXACHLOROBENZENE @ PPB LEVELS IN HUMAN URINE AND BLOOD SAMPLES BY GAS CHROMATOGRAPHY WITH PHOTOIONIZATION DETECTION. [R152] *A method was developed to analyze rat tissue, fat and blood for some chlorinated compounds found in an extract of soil from an industrial waste site. Extraction with hexane and ethyl ether-hexane (1 + 1) was followed by concentration over steam, and gas chromatographic analysis with an electron capture detector. Volatile compounds were analyzed in a glass column coated with 6% SP-2100 plus 4% OV-11 on Chromosorb W Semivolatile compounds, chlorinated compounds and pesticides were analyzed in a 70 m glass capillary column coated with 5% OV-101. Phenols were analyzed in a glass column packed with 1% SP-1240 DA on Supelcoport. The most efficient means of separation was to use the same glass column for volatile compounds, a DB-5 fused silica capillary column for semivolatile compounds, pesticides and phenols, and the same 1% SP-1240 DA glass column for separation of beta-BHC and pentachlorophenol. Recoveries ranged from 86.3 + or - 9.1% (mean + or - SD) to 105 + or - 10.4%. Sensitivities for semivolatile chlorinated compounds, pesticides and phenols were 4 ng/g for fat, 1 ng/g for tissue, and 0.2 ng/ml for blood. Sensitivities for volatile compounds were 4 fold higher (16, 4, 0.8, respectively). Sensitivities for dichlorobenzenes and dichlorotoluenes were 8 ng/g for fat, 2 ng/g for tissue and 0.4 ng/ml for blood. /Chlorinated cmpd/ [R153] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes (1980) EPA 440/5-80-039 USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes (1980) EPA 440/5-80-028 USEPA; Health Assessment Document: Chlorinated Benzenes (1985) EPA-600/8-84-015F USEPA/OWRS: Quality Criteria for Water 1986 1,2-Dichlorobenzene (1986) EPA 440/5-83-001 Canton JH et al; Resol Toxicol Pharmacol 5 (2): 123-31 (1985). Sixteen chlorine/nitrogen containing compounds were classified into black (ie substances which should be terminated as water pollutants) or gray (ie substances which should be decreased as water pollutants) list substances on the basis of acute toxicity, biodegradability, and accumulation. Dellinger B et al; Hazard Waste 1 (2): 137-57 (1984). Dichlorobenzenes, Dangerous Prop Ind Mater Rpt 6 (2): 50-7 (1986). Review of dichlorobenzene toxicology, health hazards and Safety measures. Brusick DJ; IARC Sci Pub 77: 393-7 (1986). Genotoxicity of hexachlorobenzene and other chlorinated benzenes. DHHS/NTP; Toxicology and Carcinogenesis Studies of 1,2-Dichlorobenzene in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 255 (1985) NIH Publication No. 86-2511 USEPA; Drinking Water Criteria Doc: ortho-Dichlorobenzene, meta-Dichlorobenzene, para-Dichlorobenzene (Draft) 174p (1986) SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 517 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 214 (1982) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 233 (1974) R5: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 541 R6: Farm Chemicals Handbook 87. Willoughby, Ohio: Meister Publishing Co., 1987.,p. C 188 R7: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.249 (Spring, 1998) EPA 738-R-98-002 R8: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 377 R9: Farm Chemicals Handbook 1998. Willoughby, OH: Meister Publishing Co., 1998.,p. C-289 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 234 (1974) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 235 (1974) R12: National Research Council. Drinking Water and Health. Volume 5. Washington, D.C.: National Academy Press, 1983. R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 218 (1982) R14: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 5(79) 865 R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 217 (1982) R16: Kavaler AR; Chemical Marketing Reporter Sept 9 (1996) R17: USITC R18: IARC MONOGRAPHS 1972-PRESENT V29 p.217 R19: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R20: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996. R21: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 89 R22: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R23: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 17 R24: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R25: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 69 R26: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 168 R27: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 932 R28: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R29: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3612 R30: Sato A, Nakajima T; Scand J Work Environ Health 13: 81-93 (1987) R31: Staudinger J, Roberts PV; Crit Rev Environ Sci Technol 26: 205-297 (1996) R32: Atkinson R; Journal of Physical And Chemical Reference Data. Monograph No 1 (1989) R33: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-152 R34: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R35: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R36: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 376 R37: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1090 R38: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R39: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 176 R40: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 149 R41: Mikatavage M et al; Am Ind Hyg Assoc J 45 (9): 617-621 (1984) R42: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R43: 49 CFR 171.2 (7/1/96) R44: IATA. Dangerous Goods Regulations. 39th Ed. Montreal, Canada and Geneva, Switzerland : International Air Transport Association, Dangerous Goods Regulations, 1998. 127 R45: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6116 (1988) R46: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 347 R47: 40 CFR 240-280, 300-306, 702-799 (7/1/97) R48: 40 CFR 260.340 - 260.351 (1985) R49: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-12 (1981) EPA 68-03-3025 R50: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-96 (1982) R51: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 73 265 (1999) R52: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 1,2-Dichlorobenzene (95-50-1) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R53: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 30 R54: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R55: Zapata-Gayon C et al; Arch Environ Health 37: 231 (1982) R56: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 239 (1974) R57: Perocco P et al; Toxicol Lett 16 (1-2): 69-75 (1983) R58: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 240 (1974) R59: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes p.C-12 (1980) EPA 440/5-80-039 R60: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes p.C-27 (1980) EPA 440/5-80-039 R61: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values, 4th ed., 1980. Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.126 R62: YANG KH ET AL, TOXICOL APPL PHARMACOL 47: 505 (1979) R63: CURTIS MW ET AL; WATER RES 13: 137 (1979) R64: Hayes WC et al; Fundam Appl Toxicol 1: 190-202 (1985) R65: Calamari D et al; Chemosphere 12 (2): 253-62 (1983) R66: Connor TH et al; Toxicol Lett 25: 33-40 (1985) R67: Brondeau MT et al; Toxicol Lett 19: 139-46 (1983) R68: Mori T; Okayama Igakkai Zasshi 94 (11/12): 967-72 (1983) R69: Yoshioka Y et al; Sci Total Environ 43 (1,2): 149-58 (1985) R70: USEPA/OWRS; Quality Criteria for Water 1986 1,2-Dichlorobenzene (1986) EPA 440/5-86-001 R71: ARIYOSHI ET AL, CHEM PHARM BULL 23 (4): 824-830 (1975) R72: Mohtashamipur E et al; Mutagenesis 2 (2): 111-14 (1987) R73: Sipes IG et al; Arch Toxicol (Suppl 11): 20-33 (1987) R74: Gombar VK; QSAR Environ Toxicol Proc Int Workshop 2nd 125-33 (1987) R75: Kaiser KLE et al; QSAR Environ Toxicol Proc Workshop Quant Struct Act Relat (QSAR) Environ Toxicol 189-206 (1984) R76: Bobra a et al; Environ Toxicol Chem 4 (3): 297-305 (1985) R77: Kaiser KLE, Ribo JM; Pharmacochem Libr 8 (ISS QSAR Toxicol Xenobiochem): 27-38 (1985) R78: Brondeau MT et al; Toxicol Lett 31 (2): 159-66 (1986) R79: Pagano G et al; Bull Environ Contam Toxicol 40 (4): 481-8 (1988) R80: Toxicology and Carcinogenesis Studies of 1,2-Dichlorobenzene (o-Dichlorobenzene) in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 255 (1985) NIH Publication No. 86-2511 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R81: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R82: Kulkarni SG et al; Archives of Toxicology 70 (11): 714-23 (1996) R83: Naylor Dana Institute for Disease Prevention; Study of the Cultured Liver Cells of Three Chlorinated Benzenes, Final Report. (1983), EPA Document No. FYI-AX-0284-0291, Fiche No. 0291-0 R84: Dow Chemical U.S.A.; Orthodichlorobenzene -- Inhalation Teratology Study in Rats and Rabbits, (1982), EPA Document No. FYI-AX-0782-0198, Fiche No. OTS0000198-0 R85: Rohm and Haas Toxicology Department; Genetic Toxicology Report, (1979), EPA Document No. 878212181, Fiche No. OTS0205181 R86: Litton Bionetics Inc.; Mutagenicity Evaluation of Ortho-Dichlorobenzene, Final Report, (1976), EPA Document No. 878212180, Fiche No. OTS0205976 R87: Zoology Department of the University of Wisconsin; Drosophila Sex Linked Recessive Lethal Test on Ortho-Dichlorobenzene, Draft Report, EPA Document No. 40-8320545, Fiche No. OTS0511274 R88: Rohm and Haas Toxicology Department; Ortho-Dichlorobenzene: Myelotoxicity and Cytogenetic Study in Rats, (1979), EPA Document No. 878212182, Fiche No. OTS0205976 R89: Bioassay Systems Corporation; Effects of Ortho-Dichlorobenzene on the In-Vivo Induction of Chromosomal Aberrations in Rat Bone Marrow Cells, Draft Report, (1983), EPA Document No. 40-8320545, Fiche No. OTS0511274 R90: Bioassay Systems Corporation; Effects of Ortho-Dichlorobenzene on the Induction of Chromosomal Aberrations in Chinese Hamster Ovary Cells, Draft Report, (1982), EPA Document No. 40-8320545, Fiche No. OTS0511274 R91: Naylor Dana Institute; Study of the Effects on Cultured Liver Cells of Three Chlorinated Benzenes, Final Report. (1983), EPA Document No. 40-8420666, Fiche No. OTS0511367 R92: Sittig, M. Handbook of Toxic And Hazardous Chemicals. Park Ridge, NJ: Noyes Data Corporation, 1981. 228 R93: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes p.C-14 (1980) EPA 440/5-80-039 R94: Menzie, C.M. Metabolism of Pesticides. U.S. Department of the Interior, Bureau of Sport Fisheries and Wildlife, Publication 127. Washington, DC: U.S. Government Printing Office, 1969. 155 R95: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-15 R96: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes p.C-15-16 (1980) EPA 440/5-80-039 R97: Tsuchiya T, Yamaha T; Agric Biol Chem 47 (5): 1163-5 (1983) R98: Haigler BE et al; Appl Environ Microbiol 54 (2): 294-301 (1988) R99: Tanaka A et al; Arch Toxicol 59 (2): 82-8 (1986) R100: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 237 (1974) R101: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes p.C-1 (1980) EPA 440/5-80-039 R102: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Reinhold Co., p. 377 (1993) (2) Budvari S; Merck Index, 12th ed, Whitehouse Station, NJ Merck and Co. p 517 (1996) R103: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Chiou CT et al; Sci 206: 831-32 (1979) (3) Chiou CT et al; Environ Sci Technol 17: 227-31 (1983) (4) Staudinger J, Roberts PV; Crit Rev Environ Sci Technol 26: 205-97 (1996) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington,DC: Taylor and Francis, (1989) (6) Anderson TA et al; J Environ Qual 20: 420-24 (1991) (7) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (8) Roy WR; pp. 411-46 in Contam Groundwaters. Adrian,DC et al., eds. Northwood,UK: Sci Rev (1994) R104: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Masunga S et al; J Environ Sci Health A31: 887-903 (1996) (3) Tenhulscher TEM et al; Chemosphere 35: 2331-44 (1997) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (5) Staudinger J, Roberts PV; Crit Rev Environ Sci Technol 26: 205-97 (1996) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (8) Oliver BG, Niimi AJ; Environ Sci Technol 17:287-91 (1983) R105: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington,DC: Taylor and Francis (1989) (3) Atkinson R; J Phys Chem Ref Data Monograph No 1 (1989) R106: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Kitano M; Biodegradation and Bioaccumulation Test on Chem Sub OECD Tokyo Meeting Reference Book TSU-No.3 (1978)(3) Haider K et al; Arch Microbiol 9 : 183 (1974) (4) Masunga S et al; Wat Sci Technol 33: 173-80 (1996) (5) Nielsen PH et al; Environ Sci Technol 30: 31-37 (1996) (6) Stauffer TB et al; A Natural Gradient Tracer Experiment in a Heterogeneous Aquifer With Measured I Situ biodegradation Rates: A Case For Natural Attenuation EPA/540/R-94 515 (1994) (7) Roy WR; pp. 411-46 in Contam Groundwaters. Adriano DC et al; Eds. Northwood,UK: Sci Rev (1994) R107: (1) Atkinson R; J Phys Chem Ref Data Monograph No 1 (1989) R108: Casserly DM et al; Water Res 17 (11): 1591-4 (1983) R109: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Oliver BG, Niimi AJ; Environ Sci Technol 17: 287-91 (1983) (3) Barrows ME et al; pp. 379-92 in Dyn Exposure Hazard Assess Toxic Chem Ann Arbor,MI: Ann Arbor Sci (1980)(4) Franke C et al; Chemosphere 29: 1501-14 (1994) R110: (1) Chiou CT et al; Sci 206: 831-32 (1979) (2) Chiou CT et al; Environ Sci Technol 17: 227-31 (1983) (3) Masunga S et al; J Environ Sci Health A31: 887-903 (1996) (4) Tenhulscher TEM et al; Chemosphere 35: 2331-44 (1997) (5) Swann RL et al; Res Rev 85: 23 (1983) R111: (1) Staudinger J, Roberts PV; Crit Rev Environ Sci Technol 26: 205-97 (1996) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3)Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington,DC: Taylor and Francis (1989) (4) Anderson TA et al; J Environ Qual 20: 420-24 (1991) R112: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532 (1982) (2) USEPA; Preliminary Assessment of Suspected Carcinogens in Drinking Water An Interim Report to Congress (1975) (3) Westrick JJ et al; J Amer Water Works Assoc 76: 52 (1984) (4) Sanjivamurthy VA; Water Res 12: 31 (1978) (5) Fielding M et al; Organic Micropollut in Drinking Water Medmenham, Eng Water Res Cent TR-159 (1981) (6) Hassan AAM et al; Bull Environ Contam Toxicol 56: 397-404 (1996) R113: (1) Page GW; Environ Sci Technol 15: 1475 (1981) (2) Buszka PM et al; Anal Chem 67: 3659-67 (1995) (3) Assmuth TW, Strandberg T; Wat Air Soil Pollut 69: 179-99 (1993) R114: (1) Page GW; Environ Sci Technol 15: 1475-81 (1981) (2) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-36 (1982) (3) Oliver BG, Nicol KD; Sci Tot Env 39: 57-70 (1984) (4) Oliver BG; Symp Amer Chem Soc, Div Environ Chem 186th Natl Mtg 23: 421 (1983) (5) Oliver BG, Charlton MN; Environ Sci Technol 18: 903-08 (1984) (6) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (7) Granstrom ML et al; Water Sci Technol 16: 375-80 (1984) (8) Malle KG; Z Wasser-Abwasser Forsch 17: 75 (1984) (9) Sontheimer H et al; Sci Tot Env 47: 27-44 (1985) (10) Chan CH; Wat Pollut Res J Canada 28: 451-71 (1993) (11) Yamamoto K et al; Environ Pollut 95: 135-43 (1997) (12) Tenhulscher TEM et al; Chemosphere 35: 2331-44 (1997) (13) Masunga S et al; Wat Res 25: 289-97 (1991) (14) Gotz R et al; Chemosphere 36: 2085-2101 (1998) R115: (1) Pankow JF et al; Environ Sci Technol 18: 310-17 (1984) (2) Ligocki MP et al; Atmos Environ 19: 1609 (1985) R116: (1) Roy WR; pp. 411-46 in Contam Groundwaters. Adriano DC et al; Eds., Northwood,UK: Sci Rev (1994) (2) Shane BS et al; Arch Environ Contam Toxicol 19: 665-73 (1990) (3) Jay K, Stieglitz L; Chemosphere 30:1249-60 (1995) (4) Dempsey CR J Air Waste Manage Assoc 43: 1374-79 (1993) (5) Assmuth T, Kalevi K; Chemosphere 24: 1207-16 (1992) (6) Stubin AI et al; Wat Environ Res 68: 1037-44 (1996) (7) Oman C, Hynning P; Environ Pollut 80: 265-71 (1993) R117: (1) Beurskens JEM et al; Water Sci Technol 29: 77-85 (1994) (2) Lee CL, Fang MD; Chemosphere 35: 2039-50 (1997) (3) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-36 (1982) (4) Masunga S et al; Wat Res 25: 289-97 (1991) (5) Kawata K et al; Bull Environ Contam Toxicol 58: 893-900 (1997) R118: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes p.C-5 (1980) EPA 440/5-80-039 R119: Harkov R et al; J Air Pollut Control Assocn 33: 1177-83 (1983) R120: (1) Brodzinsky R, Singh HB; Volatile Org Chem in the Atmosphere: An Assess of Available Data Menlo Park, CA Atmospheric Sci Cntr, SRI Internatl pp. 198 (1982) (2) Bozzilli JW, Kebbekus BB; J Environ Sci Health 17: 693 (1982) (3) Singh HB et al; Atmos Environ 15: 601-12 (1981) (4) Harkov R et al; J Air Pollut Control Assoc 33: 1177 (1983) (5) Ligocki MP et al; Atmos Environ 19: 1609 (1985) (6) Grosjean D; Sci Total Environ 100: 367-414 (1991) R121: (1) Brodzinsky R, Singh HB; Volatile Org Chem in the Atmosphere: An Assess of Available Data Menlo Park, CA Atmospheric Sci Cntr, SRI Internatl pp. 198 (1982) (2) Bozzilli JW, Kebbekus BB; J Environ Sci Health 17: 693 (1982) R122: (1) Wallace LA et al; Environ Res 50: 37-55 (1989) (2) Wallace LA et al; Volatile Organic Chemicals in 10 Public Access Buildings. USEPA/600/D-87/152 (1987) (3) Kostiainen K; Atmos Environ 29: 693-702 (1995) (4) Bouhamra WS et al; Environ Intl 23: 197-204 (1997) R123: (1) Jan J; Mitt Geb Lebensmittelunters Hyg 74: 420-6 (1983) (2) Heikes DL et al; J Agric Food Chem 43: 2869-75 (1995) (3) Daft JL; J Agric Food Chem 37: 560-64 (1989) (4) Wang MJ, Jones KC;J Agric food Chem42: 2322-28 (1994) R124: (1) IARC; Some Industrial Chemicals and Dyestuffs 29: 213 (1982) (2) Webber MD et al; J Environ Qual 23: 1019-26 (1994) R125: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-6 (1982) (2) Young DR et al; Water Chlorination Environ Impact Health Eff 3: 471-86 (1980) (3) Jan J, Malnersic S; Bull Environ Contam Toxicol 24: 824 (1980) R126: Jan J; Bull Environ Contam Toxicol 30: 595 (1983) R127: (1) Davies D, Mes J; Bull Environ Contam Toxicol 39: 743-50 (1987) (2) Jan J; Bull Environ Contam Toxicol 30: 595-99 (1983) R128: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) IARC; Some Industrial Chemicals and Dyestuffs 29: 214 (1982) R129: (1) Singh HB et al; Atmos Environ 15: 601 (1981) (2) Guichert R, Schulting; Sci Total Environ 43: 193-219 (1985) R130: (1) Mes J; Bull Environ Contam Toxicol 48: 815-20 (1992) (2) Wallace LA; The Total Exposure Assessment Methodology Study. USEPA/600/S6-87/002 (1987) R131: 29 CFR 1910.1000 (7/1/98) R132: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 238 (1974) R133: 40 CFR 60.489 (7/1/97) R134: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R135: 40 CFR 116.4 (7/1/87) R136: 40 CFR 401.15 (7/1/87) R137: 40 CFR 302.4 (7/1/97) R138: 40 CFR 716.120 (7/1/97) R139: 40 CFR 712.30 (7/1/97) R140: 40 CFR 261.31 (7/1/97) R141: 40 CFR 261.33 (7/1/96) R142: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 1003-1 R143: Krost KJ et al; Anal Chem 54 (4): 810-7 (1982) as cited in USEPA; Health Assessment Document: Chlorinated Benzenes p.3-16 (1985) EPA 600/8-84-015 R144: Langhorst ML, Nestrick TJ; Anal Chem 51 (12): 2018-25 as cited in USEPA; Health Assessment Document: Chlorinated Benzenes p.3-17 (1985) EPA-600/8-84-015 R145: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R146: Krost KJ et al; Anal Chem 54 (4): 810-7 (1985) as cited in USEPA; Health Assessment Document: Chlorinated Benezenes p.3-16 EPA 600/8-84-015F R147: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R148: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R149: Miller LJ et al; J Assoc Off Anal Chem 66 (3): 677-83 (1983) R150: Langhorst ML, Nestrick TJ; Anal Chem 51 (12): 2018-25 (1979) as cited in USEPA; Health Assessment Document: Chlorinated Benzenes p.3-17 (1985) EPA 600/8-84-015F R151: Onuska FI, Terry KA; Anal Chem 57 (4): 801-5 (1985) R152: LANGHORST ML ET AL; ANAL CHEM 51 (12): 2018 (1979) R153: Stein VB, Narang RS; J Assoc Off Anal Chem 67 (1): 111-16 (1984) RS: 110 Record 64 of 1119 in HSDB (through 2003/06) AN: 523 UD: 200303 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,4-DICHLOROBENZENE- SY: *A13-0050-; *BENZENE,-P-DICHLORO-; *BENZENE,-1,4-DICHLORO-; *P-CHLOROPHENYL-CHLORIDE-; *P-DICHLOORBENZEEN- (DUTCH); *1,4-DICHLOORBENZEEN- (DUTCH); *P-DICHLORBENZOL- (GERMAN); *1,4-DICHLOR-BENZOL- (GERMAN); *DI-CHLORICIDE-; *P-DICHLOROBENZENE-; *DICHLOROBENZENE,-PARA,-SOLID-; *P-DICHLOROBENZOL-; *P-DICLOROBENZENE- (ITALIAN); *1,4-DICLOROBENZENE- (ITALIAN); +Pesticide-Code:-061501.-; *EVOLA-; *NCI-C54955-; *Caswell-No-632-; *PARADI-; *PARADICHLOROBENZENE-; *Paradichlorobenzol-; *PARADOW-; *PARAMOTH-; *PARAZENE-; *PDB-; *PERSIA-PERAZOL-; *EPA-Pesticide-Chemical-Code-061501-; *SANTOCHLOR- RN: 106-46-7 RELT: 6372 [DICHLOROBENZENE] (Mixture) MF: *C6-H4-Cl2 SHPN: UN 1592; Dichlorobenzene, para, solid IMO 6.1; Dichlorobenzene, para STCC: 49 411 28; Dichlorobenzene, para, solid HAZN: U072; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. D027; A waste containing 1,4-dichlorobenzene may (or may not) be characterized a hazardous waste following testing for the toxicity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPARATION BY SANDMEYER PROCEDURE FROM THE APPROPRIATE CHLOROANILINE, AND, ALONG WITH ORTHO- AND PARA-DICHLOROBENZENES, BY CHLORINATION OF CHLOROBENZENE. [R1] *para-Dichlorobenzene is ... produced commercially by the direct chlorination of benzene in the liquid phase in the presence of Friedel-crafts catalyst (usually ferric oxide) and fractionation of the resulting mixture of chlorinated benzenes. [R2] IMP: *COMMERCIAL PARA-DICHLOROBENZENE IS AVAIL IN USA AS TECHNICAL GRADE LIQUID TYPICALLY CONTAINING 0.08% BY WT OF MIXT OF META AND ORTHO ISOMERS. [R3] *Typical composition for para-dichlorobenzene has been reported: ortho-dichlorobenzene, < 0.5% meta-dichlorobenzene, < 0.5% and monochlorobenzene and trichlorobenzenes, < 0.1% [R4] FORM: *COMMERCIAL PARA-DICHLOROBENZENE IS AVAIL IN USA AS TECHNICAL GRADE LIQUID [R3] *Crystalline material pressed into various forms; solutions in volatile solvents or in an oil suspension. [R5] *Technical grade with high purity: 100% in crystalline form and 99.92% in liquid form (on an anhydrous basis) [R6] *IT IS ALSO AVAIL AS CRYSTALS IN SEVERAL PARTICLE SIZES CONTAINING NO DETECTABLE IMPURITIES. [R3] MFS: *Monsanto Co, Hq 800 N Lindbergh Blvd, St. Louis, Mo 63167, (314) 694-1000; Production site: Monsanto Chemical Co, Sauget IL 62201 [R7] *PPG Industries, Inc, Hq One PPG Place, Pittsburgh, PA 15272, (412) 434-3131; Production site: Chemicals Group, PO Box 161, New Martinsville, WV, Natrium, WV 26155 [R7] *Standard Chlorine Chemical Co, Inc, Hq 1035 Belleville Turnpike, Kearny, NJ 07032, (201) 997-1700; Production site: Governor Lea Road, Delaware City, DE 19706 [R7] OMIN: *BY-PRODUCT IN THE MANUFACTURE OF MONOCHLOROBENZENE BY DIRECT CHLORINATION OF BENZENE [R8] *SEPARATION OF MIXT CONTAINING M-, O-, AND P-DICHLOROBENZENES BY DISTILLATION AND CRYSTALLIZATION: MUELLER, WOLZ, FRENCH PATENT 1,374,863 (1964 TO BAYER), CA 62, 493E (1965), CORRESPONDING TO BRITISH PATENT 999,845. [R1] USE: +For 1,4-Dichlorobenzene (USEPA/OPP Pesticide Code: 061501) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R9] *INSECTICIDAL FUMIGANT; POPULAR FOR DOMESTIC USE AGAINST CLOTHES MOTHS [R1] *Moth repellent, general insecticide, germicide, space odorant, manufacture of 2,5-dichloroaniline, dyes, intermediates, pharmacy, agricultural. [R10] *p-Dichlorobenzene is sometimes used as a deodorant for garbage and restrooms, as well as an insecticide for control of fruit borers and ants. [R11, 1981.3] *May be applied to tobacco seed beds for blue mold control; for the control of peach tree borer; and mildew and mold on leather and fabrics. [R12] *Gallery injections with 6 insecticides and 3 fumigants were tested for comparative effectiveness in controlling Prionoxystus robiniae (Peck), and Paranthrene simulans (Grote). The three fumigants (carbon disulfide, Serafume, and paradichlorobenzene) provided complete control. [R13] *It is used as an additive in resin-bonded abrasive wheels to provide a more open structure, and vaporizes during the curing operation leaving pores and wider grain spacing. [R14, p. 1(78) 43] *Hydrolysis of 1,4-dichlorobenzene with cupric salts and hydroxylamine gives the para-chlorophenols. [R14, p. 5(79) 865] *Intermediate for dyestuff [R15, p. V6 99] *The reaction of p-dichlorobenzene with sodium sulfide in a polar organic solvent to produce poly(phenylene sulfide) /An engineering plastic used for surface coatings and model resins/. [R15, p. V6 99] *Para-dichlorobenzene may have had minor use as an extreme-pressure lubricant. [R16] *... applications include use as an intermediate in organic synthesis and as on animal repellant. [R17] *Use in pig stalls as an odor control agent [R18] CPAT: *35-40% FOR MOTH CONTROL; 35-40% AS SPACE DEODORANT; 25% OR LESS FOR MISC APPLICATIONS INCLUDING USE AS A DYE INTERMEDIATE AND IN INSECTICIDE MANUFACTURE (1972) [R8] *Space deodorant, 55%; moth control, 35%; and other applications, 10% (1978) [R19, (1982)] *CHEMICAL PROFILE: p-Dichlorobenzene. Demand: 1995: 70 million lb; 1996: 75 million lb; 2000 /projected/: 82 million lb. [R20] *Synthetic fabrics, which do not require proofing, as well as decline in consumption due to availability of less costly /equally efficient products will produce growth rate of 2 to 3%/year through 1983. [R21] PRIE: U.S. PRODUCTION: *(1972) 3.5X10+10 GRAMS [R8] *(1975) 2.08X10+10 GRAMS [R8] *(1977) 16 to 116X10+6 lb [R22] *(1981) 15X10+6 lb [R22] U.S. IMPORTS: *(1978) 1.09X10+7 g [R19] U.S. EXPORTS: *(1972) 4.5X10+9 GRAMS [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystals [R10]; *MONOCLINIC PRISMS, LEAVES FROM ACETONE [R23]; *Available as pure crystals [R12]; +Colorless or white crystalline solid ... [R24, 96] ODOR: *DISTINCTIVE AROMATIC ODOR BECOMES VERY STRONG AT CONCN BETWEEN 30 and 60 PPM [R25, 3624]; *Penetrating odor [R10]; +... Mothball-like odor. [R24, 96] BP: *174 DEG C @ 760 MM HG [R26, p. 3-39] MP: *52.7 DEG C [R26, p. 3-39] MW: *147.0 [R26, p. 3-39] CORR: *NON-CORROSIVE [R1] CTP: *Crticial temperature: 407.5 deg C; Critical pressure: 4109 kPa [R15, p. V6 89] DEN: *1.2475 g/ml @ 20 DEG C/4 DEG C [R26, p. 3-39] HTV: *297.4 J/g [R15, p. V6 89] OWPC: *Log Kow= 3.44 [R27] SOL: *Sol in chloroform, carbon disulfide, benzene, ether, alcohol. [R1]; *Very soluble in ethanol and acetone; soluble in ether. [R26, p. 3-39]; *In water, 76 mg/l at 25 dec C. [R28] SPEC: *Intense mass spectral peaks: 146 m/z (100%), 148 m/z (64%), 111 m/z (35%), 75 m/z (22%) [R29]; *IR: 4279 (Coblentz Society Spectral Collection) [R30]; *UV: 55 (Sadtler Research Laboratories Spectral Collection) [R30]; *NMR: 715 (Sadtler Research Laboratories Spectral Collection) [R30]; *MASS: 818 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R30] SURF: *31.4 dynes/cm [R15, p. V6 90] VAPD: *5.08 [R31] VAP: *1.74 mm Hg at 25 deg C /from experimentally derived coefficients/ [R32] VISC: *0.839 mNXsXm-2 @ 55 deg C; 0.668 mNXsXm-2 @ 79 deg C [R33] OCPP: *NON-STAINING [R1] *Conversion factors: 1 mg/l = 166.3 ppm, 1 ppm = 6.01 mg/cu m at 25 dec C, 760 mm Hg [R25, 3612] *PERCENT IN SATURATED AIR: 0.2 (25 DEG C) [R25, 3612] *EQUIVALENCIES: 1 MG/L= 166.3 PPM AND 1 PPM= 6.01 MG/CU M @ 25 DEG C AND 760 MM HG [R25, 3612] *Heat of fusion = 123.8 J/g [R15, p. V6 89] *Liquid thermal conductivity= 0.105 W/m.K [R15, p. V6 89] *Dielectric constant= 2.3943 at 328.2 K [R26, p. 6-169] *Dipole moment: 0 [R33] *Henry's Law constant = 2.7X10-3 atm cu-m/mol @ 20 deg C [R34] *Hydroxyl radical rate constant = 3.2X10-13 cu cm/molc sec @ 25 deg C [R35] *Heat Capacity of Liquid= 1.188 J/g [R15, p. V6 89] *Heat of Formation of Liquid= -284.6 J/g [R15, p. V6 89] *Heat of Fusion= 123.8 J/g [R15, p. V6 89] *Crystals sublime at ordinary temperatures [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R36] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R36] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R36] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R36] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R36] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R36] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R36] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R36] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R37, p. 325-34] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R37, p. 325-34] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R37, p. 325-34] FLPT: *150 Deg F (closed cup) [R38] FIRP: +APPROACH FIRE FROM UPWIND TO AVOID HAZARDOUS VAPORS AND TOXIC DECOMP PRODUCTS. USE WATER SPRAY, DRY CHEM, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. EXTINGUISH FIRE USING AGENT SUITABLE FOR SURROUNDING FIRE. /O-DICHLOROBENZENE/ [R37, p. 49-50] +Water may be used to blanket fire. [R37, p. 325-34] TOXC: *Toxic gases and vapors (such as hydrogen chloride and carbon monoxide) may be released in a fire involving p-dichlorobenzene. [R11, 1981.2] REAC: *DANGEROUS: WHEN HEATED TO DECOMPOSITION OR ON CONTACT WITH ACIDS OR ACID FUMES THEY EVOLVE HIGHLY TOXIC /HYDROGEN CHLORIDE/ FUMES. CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R39] +Strong oxidizers (such as chlorine or permanganate). [R24, 96] DCMP: *DANGEROUS: WHEN HEATED TO DECOMPOSITION IT EMITS TOXIC /HYDROGEN/ CHLORIDE FUMES. [R39] SERI: *Exposure to p-dichlorobenzene may cause irritation of the eyes, nose, and throat. [R11, 1981.1] *VAPORS AND SPRAYS ARE IRRITATING TO EYES, NOSE AND THROAT. [R40] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R41, 1979.8] +Wear appropriate personal protective clothing to prevent skin contact. [R24, 97] +Wear appropriate eye protection to prevent eye contact. [R24, 97] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R24, 97] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R24, 97] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R24, 97] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R24, 97] OPRM: +Contact lenses should not be worn when working with this chemical. [R24, 97] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R41, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R41, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R41, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R41, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R41, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R41, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres for /chemical carcinogens/. Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R41, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R41, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R41, 1979.11] +The worker should immediately wash the skin when it becomes contaminated. [R24, 97] +The worker should wash daily at the end of each work shift. [R24, 97] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R24, 97] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R24, 97] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R42] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R43] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R41, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R41, 1979.13] STRG: *MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMPOSE INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL WELL VENTILATED PLACE, OUT OF THE DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED ... [R44] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R41, 1979.13] +STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS. /o-DICHLOROBENZENE/ [R37, p. 49-50] CLUP: *Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved in region of 10 ppm or greater concn, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. [R45] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R41, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U072, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R46] *p-Dichlorobenzene may be disposed of: 1) by making packages of p-dichlorobenzene in paper or other flammable material and burning in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. 2) By dissolving p-dichlorobenzene in a flammable solvent (such as alcohol) and atomizing in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. Recommendable method: Incineration. [R47] *... Halogenated compounds may be disposed of by incineration provided they are blended with other compatible wastes or fuels so that the composite contains less than 30% halogens and the heating value is from 7000 to 9000 BTU/lb. Liquid injection, rotary kiln, and fluidized bed incinerators are typically used to destroy liquid halogenated wastes. ... Temperatures of at least 2000 - 2200 deg F and residence times /of more than 2 sec/ ... are required for the destruction of halogenated aromatic hydrocarbons. [R48] *EPA A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. [R49] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R41, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": Total destruction ... by incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose.The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R41, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R41, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R41, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R41, 1979.17] *Chemical Treatability of 1,4-Dichlorobenzene; Concentration Process: Stripping; Chemical Classification: Aromatic; Scale of Study: Full Scale, Continuous Flow; Type of Wastewater Used: Domestic Wastewater; Results of Study: 90% reduction by air stripping. [R50] *Chemical Treatability of 1,4-Dichlorobenzene; Concentration Process: Activated Carbon; Chemical Classification: Aromatic; Scale of Study: Full scale, Continuous Flow; Type of Wastewater Used: Domestic Wastewater; Results of Study: 60% removal; (treatment of effluent from 0.66 cu m/sec biological system). [R51] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of dichlorobenzenes. ... There is sufficient evidence in experimental animals for the carcinogenicity of para-dichlorobenzene. Overall evaluation: In making the overall evaluation of the carcinogenicity of para-dichlorobenzene to humans, the Working Group concluded that para-dichlorobenzene produces renal tubular tumors in male rats by a non-DNA reactive mechanism, through an alpha-2-globulin associated response. Therefore, the mechanism by which para-dichlorobenzene incr the incidences of renal tubular tumors in male rats is not relevant to humans. para-Dichlorobenzene caused a high incidence of liver tumors in male and female mice. Supporting evidence that its mechanism of action of carcinogenesis may be relevant for humans includes evidence that it causes DNA damage in liver and spleen of mice and weakly binds to DNA in mouse liver. ... para-Dichlorobenzene is possibly carcinogenic to humans (Group 2B). /Dichlorobenzene/ [R52] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R53, 2002.26] ANTR: *Accidental mothball ingestion is very common in children. Mothballs consist either of naphthalene or para-dichlorobenzene, the toxicities of which are very different. This article focuses on the management of mothball ingestion with reference to these major ingredients. [R54] *In order to develop a rapid, simple test to differentiate toxic naphthalene from the less toxic mothball ingredient para-dichlorobenzene, both types of mothballs were dissolved in ... turpentine. ... Turpentine, dissolved para-dichlorobenzene at a much more rapid rate than napthalene. After 60 minutes, all of the para-dichlorobenzene mothballs had dissolved, while at least 25% of the naphthalene remained. Thus, when confronted with an ingestion of unlabeled mothballs, the physician could gain preliminary information regarding possible toxicity by dissolving a remaining mothball in turpentine for 60 minutes. [R55] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Lindane and related compounds/ [R56, p. 284-5] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. @@ Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Lindane and related compounds/ [R56, 285] MEDS: *... AMT OF 2,5-DICHLOROPHENOL PRESENT IN URINE CAN SERVE AS INDICATION OF EXPOSURE. [R57] *Recommended medical surveillance ... a complete history and physical examination: The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the liver, respiratory tract, eyes, and kidneys should be stressed. The skin should be examined for evidence of chronic disorders. [R11, 1981.1] *PRECAUTIONS FOR "CARCINOGENS": ... in relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may precede them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical Carcinogens/ [R41, 1979.23] HTOX: *SOLID PARTICLES, VAPOR, OR FUMES OF P-DICHLOROBENZENE ARE VERY PAINFUL TO THE EYES AND NOSE. ... /VAPOR/ IS PAINFUL TO MOST PEOPLE IN CONCN BETWEEN 50 AND 80 PPM AND THE DISCOMFORT BECOMES QUITE SEVERE AT 160 PPM. [R25, 3624] *SOLID P-DICHLOROBENZENE HAS VERY LITTLE EFFECT ON THE SKIN. IT DOES PRODUCE A BURNING SENSATION WHEN HELD IN CLOSE CONTACT FOR EXCESSIVE PERIODS OF TIME. [R25, 3624] *VAPORS MAY CAUSE IRRITATION TO SKIN, THROAT, AND EYES. PROLONGED EXPOSURE TO HIGH CONCN MAY CAUSE WEAKNESS, DIZZINESS, LOSS OF WEIGHT, LIVER INJURY MAY DEVELOP. [R58] *... reported the case of a patient who suffered swelling of the feet, ankles, and hands after mothproofing garments all day with p-dichlorobenzene. [R59] *ONE CASE OF PULMONARY GRANULOMATOSIS AND TWO CASES OF HEMOLYTIC ANEMIA ... /ARE/ REPORTED. A CASE OF ALLERGIC PURPURA AFTER EXPOSURE TO PARA-DICHLOROBENZENE HAS ALSO BEEN DESCRIBED. [R60] *According to report ... the lenses of a twenty-seven old woman became completely cataractous twelve to fourteen months after an attack of hepatic enlargement, jaundice, and loss of wt which was ascribed to excessive exposure to vapors of para-dichlorobenzene in her home; the exposure had been discontinued for one year before development of cataracts. ... a second woman, aged twenty-five, had monocular, immature, anterior peripheral cortical cataract with a history of jaundice and wt loss six months earlier; it was suspected that she had been poisoned by vapors from 2 cans of para-dichlorobenzene which were kept in a closet in which in the previous year the patient spent considerable time sewing. [R61] *... reported the case of female worker who suffered tingling of the hands and, after 18 months, vertigo and loss of weight from working with a mixture of 90 parts of p-dichlorobenzene and 10 parts of hexachloroethane. [R59] *... /58 MEN WORKING WITH P-DICHLOROBENZENE CONTINUOUSLY OR INTERMITTENTLY AT CONCN/ FROM 50-170 PPM WITH AVG OF 105 PPM ... /COMPLAINED/ OF EYE AND NOSE IRRITATION ... ; /AT/ 15-85 PPM WITH AVG OF 45 PPM ... THERE WERE NO COMPLAINTS. [R25, 3625] *Exposure to p-dichlorobenzene may cause headache, swelling around the eyes, and a runny nose. [R11, 1981.1] *IN 2 SUBJECTS WITH CHRONIC LYMPHOID LEUKEMIA, 1 HAD BEEN EXPOSED TO GLUE CONTAINING 2% ORTHO-DICHLOROBENZENE FROM 1945-1961, AND OTHER HAD BEEN EXPOSED FROM 1940-1950 TO SOLVENT CONTAINING ORTHO- (80%), META- (2%) AND PARA- (15%) DICHLOROBENZENE ... /PRC- ACTUAL CARCINOGENIC AGENT IN THESE EXPOSURES HAS NOT BEEN IDENTIFIED/ (GIRARD ET AL, 1969) [R57] *ABOVE 160 PPM ... /ODOR/ IS INTOLERABLE TO ANY PERSON WHO HAS NOT WORKED IN IT LONG ENOUGH TO HAVE HAD SOME ADAPTATION. THIS ODOR AND IRRITATING EFFECT ARE GOOD WARNINGS TO PREVENT OVEREXPOSURE TO P-DICHLOROBENZENE. IT SHOULD BE RECOGNIZED ... THAT A PERSON MAY BECOME SUFFICIENTLY ACCUSTOMED TO ODOR TO TOLERATE HIGH CONCN. [R25, 3625] *It may also cause headache, swelling around the eyes, and a runny nose. [R11, 1981.1] *VAPORS AND SPRAYS ARE IRRITATING TO EYES, NOSE AND THROAT BUT EFFECT SEEMS TO DISAPEAR QUICKLY. WHEN SWALLOWED ... /THEY/ CAUSE BURNING PAIN IN STOMACH, NAUSEA, VOMITING AND DIARRHEA. HEMOGLOBIN MAY CHANGE TO METHEMOGLOBIN WITH RESULTING DUSTY COLOR OF SKIN; LIVER AND KIDNEY MAY BE DAMAGED. /DICHLOROBENZENES/ [R40] *The dichlorobenzenes may be absorbed through the lung, gastrointestinal tract, and intact skin. Relatively low water solubility and high lipid solubility favor their penetration of most membranes by diffusion, including pulmonary and GI epithelia, the brain, hepatic parenchyma, renal tubules, and the placenta. /Dichlorobenzenes/ [R62] *Seventeen chemicals (solvents, insecticides and intermediates used in the production of textiles and resins) were tested in a short-term in vitro system with human lymphocytes to determine their action. The parameters studied were tritiated thymidine uptake and cell viability in cultures grown with and without a rat liver metabolizing system (S-9 mix). 1,3-Dichlorobenzene, 1,2-dichlorobenzene, hexane, 1,2-diiodoethane, 1,4-dichlorobenzene, tetrachloroethylene, 2,3-dibromopropanol, chloromethyl methyl ether, 1,2- and 1,3-dibromopropane, in order, exerted the more toxic effects ... . The chemicals were non-toxic in the presence of the metabolizing system with the exception of 1,2- and 1,3-dichlorobenzene which maintained to ... some degree, their toxicity even in the presence of the S-9 mix. [R63] *FUMES FROM SURFACE OF HOT P-DICHLOROBENZENE MAY IRRITATE SKIN SLIGHTLY WHEN CONTACT IS REPEATED OR PROLONGED. [R64] NTOX: *FOR RABBITS, 340 PPM DAILY FOR 8 HOURS FOR 2 MONTHS CAUSED DETECTABLE HISTOLOGICAL CHANGES IN LUNGS, and 800 PPM FOR SAME EXPOSURE CAUSED DEATH OF 10%. NO EFFECT WAS PRODUCED BY 150 PPM. [R40] *... RATS, GUINEA PIGS AND RABBITS EXPOSED /5 DAYS/WK, 7 HR/DAY FROM FEW TO 69 TIMES/ TO 798 PPM IN AIR ... SHOWED TREMORS, WEAKNESS, LOSS OF WT, EYE IRRITATION AND UNKEMPT APPEARANCE. SOME ... BECAME UNCONSCIOUS. ... LIVER SHOWED CLOUDY SWELLING AND CENTRAL NECROSIS. ... SLIGHT CLOUDY SWELLING OF TUBULAR EPITHELIUM OF KIDNEYS IN SOME ... [R25, 3619] *... RATS /WERE FED P-DICHLOROBENZENE/ AS 20% SOLN IN OLIVE OIL. ... THEY SURVIVED SINGLE DOSES OF 1 G/KG BODY WT, BUT ... SUCCUMBED TO A DOSE OF 4 G/KG BODY WT. GUINEA PIGS WERE FED 50% SOLN AND SURVIVED 1.6 G/KG OF BODY WT AS SINGLE DOSE AND SUCCUMBED TO A DOSE OF 2.8 G/KG OF BODY WT. [R25, 3618] *AT CONCN OF 158 PPM ... FROM 137 TO 219 DAYS ... THERE WAS SLIGHT GROWTH DEPRESSION OF GUINEA PIGS. LIVER WT WERE SLIGHTLY INCR IN MALE AND FEMALE RATS AND IN FEMALE GUINEA PIGS. [R25, 3619] *RATS WERE FED 5 DAYS/WK FOR TOTAL OF 138 DOSES IN 192 DAYS. AT ... 376 MG/KG INCR IN LIVER WT AND SLIGHT INCR IN KIDNEY WT ... OBSERVED. ... EXAM OF ... LIVER REVEALED SLIGHT CIRRHOSIS AND FOCAL NECROSIS. AT 188 MG/KG, SLIGHT INCR IN AVG WT OF LIVER AND KIDNEY OCCURRED. AT 18.8 MG/KG OF BODY WT/DOSE, NO EFFECTS COULD BE OBSERVED. [R25, 3620] *In no instance have cataracts been reported in animals ... after exposure to p-dichlorobenzene which was assuredly pure. ... With high exposures to high concentrations of vapor and feeding of the material dissolved in olive oil to rabbits (0.5 to 1g/kg per day for 260 days in a year) has failed in all instances to induce cataracts. ... Rabbits exposed repeatedly to 770-880 ppm in air for 8 hr/day developed transient edema of cornea, and as much as 3-5 diopters of edema of optic nerveheads, edema of neighboring retina, and congestion of retinal veins, but no hemorrhages or exudates; eyes returned to normal in 17 days after discontinuing exposure. [R61] *... FEEDING RABBITS 5 G P-DICHLOROBENZENE DAILY CAUSED OPACITY OF LENS IN 3 WK. REPEATED WORK FAILED TO PRODUCE OPACITY. ... /IT WAS/ BELIEVED THAT EFFECT WAS PRODUCED BY NAPHTHALENE WHICH MAY HAVE CONTAMINATED SAMPLE. [R59] *The effect of p-dichlorobenzene (p-DCB) was studied in the root tips of germinating lentil seeds. Several mitotic variations were noted when root tips of Lens esculenta var microsperma were treated with p-DCB beyond 6 hr. ... p-DCB also produced a marked effect on the germination of seeds. The germination and growth of /variants/ were inversely proportional to the /dosage/ of p-DCB. Low dose treatments, 25-100 mg p-DCB caused no visible effect /during/ the ... early stages of germination. Doses of 750 mg to 1 g caused greatly retarded growth, and some mortality. Chromosomes in the resting anaphase, or telophase stages were not significantly affected. Various types of anomalies were noted in the morphology of chromosomes at metaphase. Precocious separation of the chromatids was also noted, along with fragmentation of the chromosomes and chromatids. In certain cases, the cells in early telophase stage showed chromosome bridges, which may have been formed due to the sticky nature of the chromosomes. Usually these bridges separated, with the broken ends withdrawing into the resting nuclei. [R65] *1,4-Dichlorobenzene increased the frequency of reverse mutations in Aspergillus nidulans. [R66] *Acute toxicity tests with six chlorobenzenes, (monochlorobenzene, 1,2-dichlorobenzene, 1,4-dichlorobenzene, 1,2,3-trichlorobenzene, 1,2,4-trichlorobenzene, and hexachlorobenzene) were performed on several aquatic organisms at different trophic levels. Fertility impairment on Daphnia and photosynthesis inhibition on Selenastrum were also carried out. Results were discussed together with physicochemical properties of the molecules to identify structure-activity relationships and to predict environmental distribution. [R67] *Results from recent long term inhalation, mutagenicity, embryotoxicity and metabolism studies on p-dichlorobenzene (p-DCB) are reviewed. Groups of male and female rats and female mice were exposed for 5 hr/day on 5 days/week 75 or 500 ppm for a total period of 76 weeks (rats) or 57 weeks (female mice) followed by 36 weeks (rats) or 19 weeks (female mice) without p-DCB exposure. No overt signs of toxicity were apparent at any exposure level nor were there any treatment-related effects on the biochemical determinations, urine analysis, or hematological parameters. Slightly elevated urinary coproporphyrin excretion and increased liver and kidney weights were regarded as treatment related effects in the 500 ppm exposure group of rats. The non-tumor and tumor pathology did not indicate any treatment related effect in any group of either species. An embryotoxicity and teratology study on rats exposed to 0, 75, 200, or 500 ppm p-DCB vapor in air during the period of organogenesis did not demonstrate any signs of embryo- or fetotoxicity or teratogenicity at any exposure level. In a series of mutagenicity tests including Salmonella typhimurium, dominant lethal, and cytogenetic assays, p-DCB did not produce a mutagenetic response. [R68] *Ortho-dichlorobenzene and para-dichlorobenzene (p-DCB) were evaluated for teratogenic potential in rats (ortho-dichlorobenzene only) and rabbits. Groups of bred rats and inseminated rabbits were exposed to 0, 100, 200, or 400 ppm of ortho-dichlorobenzene /while/ groups of inseminated rabbits were exposed to 0, 100, 300, or 800 ppm p-DCB. Animals were exposed for 6 hr/day on days 6-15 (rats) or 6-18 (rabbits) of gestation. Maternal toxicity, as evidenced by a significant decr in body weight gain, was observed in all groups of ortho-dichlorobenzene exposed rats and liver weight was significantly increased in the 400 ppm ortho-dichlorobenzene exposed group. Slight maternal toxicity was observed in groups of rabbits exposed to 400 ppm ortho-dichlorobenzene or 800 ppm p-DCB as indicated by significantly decreased body weight gain during the first 3 days of exposure. Inhalation of up to 400 ppm of ortho-dichlorobenzene was /neither/ teratogenic or fetotoxic in rats and neither the ortho or the para isomer was teratogenic or fetotoxic in rabbits at exposure levels less than or equal to 400 or 800 ppm, respectively. [R69] *Mutagenicity was assayed with Salmonella typhimurium strains TA100, TA98, UTH8414, and UTH8413. None of the three dichlorobenzenes (1,2-, 1,3-, and 1,4-) was mutagenic in any strain with or without S9 /SRP: rat liver metabolizing system/ from Arochlor treated rats. [R70] *... Acute and chronic toxicity to freshwater aquatic life occur at concentrations as low as 1,120 and 763 ug/l ... acute toxicity to saltwater aquatic life occurs at concentrations as low as 1,970 ug/l. [R71] *RATS WERE TREATED WITH EACH ISOMER OF DICHLOROBENZENE (DCB) IN AN ORAL DOSE OF 250 MG/KG ONCE DAILY FOR 3 DAYS. ACTIVITIES OF AMINOPYRINE DEMETHYLASE AND ANILINE HYDROXYLASE WERE ENHANCED MARKEDLY BY TREATMENT WITH M-DICHLOROBENZENE, WHEREAS CYTOCHROME CONTENT WAS NOT ALTERED SIGNIFICANTLY BY TREATMENT WITH ANY ISOMERS OF DICHLOROBENZENE. DELTA-AMINO LEVULINIC ACID SYNTHETASE ACTIVITY WAS ENHANCED 63, 32 AND 42% BY TREATMENT WITH O-, M-, P-DCB RESPECTIVELY, BUT THESE ENHANCEMENTS WERE NOT PARALLELED BY CYTOCHROME P450 CHANGE. [R72] *The teratogenic effect of p-dichlorobenzene was evaluated in pregnant CD rats treated on day 6 through 15 with 0, 250, 500, 750 or 1000 mg/kg p-dichlorobenzene administered by gavage. Exposure to p-dichlorobenzene induced maternal weight retardation only at 500 mg/kg and higher; no differences were observed in liver weight of treated females as compared to controls. Mean fetal weight was significantly reduced only at the highest dose level. The occurrence of visceral and skeletal malformations recorded in fetuses of dams treated with p-dichlorobenzene was no different from that of controls; a significant increase in the number of skeletal variations was observed at 750 and 1000 mg/kg; a dose related increase in the frequency of extra ribs was recorded starting at 500 mg/kg. No differences were observed in comparison with control values in the degrees of ossification of selected areas. A reduction in fetal weight was observed at the 1000 mg/kg dose level. Since the embryotoxic effects were associated with a reduction in food consumption and weight gain of the exposed dams, the effects /may be/ a consequence of maternal suffering, rather than a direct effect of the chemical on the embryonic development. ... Oral exposure to p-dichlorobenzene is not teratogenic in the rat. [R73] *Sperm abnormalities and ultrastructural changes in rat testes were noted following acute exposure to para-dichlorobenzene. Light microscopic examination showed increased levels of abnormal sperm such as excessive curvature, banana and wedge shaped heads as well as twisting and curling tails. Ultrastructural changes included increased lysosomal-like structures in association with pleomorphic membranous bodies in the cytoplasm of early spermatids. Also, membranous remnants and vesicles were seen in the tubular lumen. ... para-dichlorobenzene interfered with spermiogenesis. [R74] *Administration of monochlorobenzene, p-dichlorobenzene, or 1,2,4-trichlorobenzene at single doses of 800 mg/kg produced an increase in the total porphyrin content of liver of day old chicks. Porphyrinogenic activity was higher in p-dichlorobenzene and 1,2,4-trichlorobenzene treated chicks than in monochlorobenzene treated chicks. Administration of any of these compounds to chick embryos (40 mg/egg) failed to produce an induction of liver porphyrins. 1,2,4-trichlorobenzene enhanced the excretion of porphyrin in bile in chicks but not of chick embryos. In day old chicks 1,2,4-trichlorobenzene increased hepatic cytochrome p450 levels and the activity of 7-ethoxyresorufin deethylase. 7-Ethoxycoumarin deethylase activity was decreased while cytosolic glutathione S-transferase activity was unchanged. These results point out the differential response of chick embryos and day old chicks to chlorobenzene-induced changes in porphyrin metabolism as well as the differential induction of microsomal monooxygenases in chicks by 1,2,4-trichlorobenzene. [R75] *... Eight halogenated benzenes, including bromobenzene (BB), chlorobenzene (CB), three isomers of dichlorobenzene (DCB) and three isomers of trichlorobenzene (TCB) were tested for acute toxicity (LD50) and clastogenicity in 8 week old NMRI mice by intraperitoneal administration. Four doses of each chemical (up to 70% of LD50) were tested for clastogenic activity. Each compound was administered in two equal doses, 24 hr apart. Increased formation of micronucleated polychromatic erythrocytes, observed in femoral bone marrow, 30 hr after the first injection, was considered to be due to the clastogenic activity of the test compound. All the halogenated benzenes tested were found to be clastogenic. The highest clastogenic activities were induced by m-dichlorobenzene and bromobenzene. Among three isomers of dichlorobenzene, m-dichlorobenzene significantly induced more micronuclei than o-DCB or p-dichlorobenzene. No significant differences were found between the clastogenic activities of trichlorobenzene isomers. [R76] *... A dynamic liver culture system, using short term viable tissue culture of rat liver slices, is described. Following initial recovery periods of 2 to 6 hr; potassium ion and adenosine triphosphate (ATP) content were maintained for 16 to 20 hr, and protein synthesis increased linearly for 16 hr. ... The order of decreasing toxicity of dichlorobenzenes, measured by potassium ion content, protein synthesis, and release of lactic dehydrognase, was 1,2-dichlorobenzene, 1,3-dichlorobenzene, and 1,4-dichlorobenzene, in agreement with a similar order obtained in vivo. The dichlorobenzenes were less toxic in slices from Sprague-Dawley rats than in Fischer rats. This finding was confirmed by studies in vivo. [R77] *Developmental, genetic, and reproductive toxicities of benzene, chlorobenzene, and o-, m-, and p-dichlorobenzenes were investigated in sea urchin, Paracentrotus lividus. Toxicity order depended on whether the target organ was embryo or sperm. Benzene was active in sea urchin sperm causing developmental and mitotic abnormalities in offspring. Benzene also showed a significant increase in developmental defects following embryo exposure. For chlorobenzene, developmental defects were seen when the concn was increased to 10(-4) M-Dichlorobenzene caused a strong increase in developmental defects and also in mitotic abnormalities. [R78] *Under the conditions of these 2 yr gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an incr incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by incr incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the admin of 1,4-dichlorobenzene. [R79] *When rats, guinea pigs, and rabbits were exposed for 30 min a day to an initial nominal concentration of 16,640 ppm (100,000 mg/m3), a few showed simple eye and nose irritation, but most showed intense irritation, muscle twitches, loss of righting reflex, horizontal and vertical nystagmus, and rapid labored breathing. Recovery after each exposure required only 30-120 min in most animals, but a few died. This treatment led to a granulocytopenia and some tendency to increased lymphocytes, so that there was little effect on total white count. [R80, 708] *When rats, guinea pigs, and rabbits were exposed for 8 hr/day, 5 days/wk, for as many as 69 exposure days to a measured average concentration of 798 ppm (4800 mg/m3), some of the animals died and all exhibited weakness, tremors, weight loss, eye irritation, and coma. Rabbits that survived 62 exposures apparently recovered completely within 17 days. When rats and guinea pigs were exposed 7 hr/day, 5 days/wk, for 6 months to an average concentration of 341 ppm (2050 mg/m3), the only positive findings included slight growth depression, slight increase in liver and kidney weights, and slight histological changes. Similar exposure of rats, guinea pigs, rabbits, and one monkey to an average concentration of 158 ppm (950 mg/m3) produced similar but less pronounced changes in rats and guinea pigs only. When the same five species were exposed to a measured concentration of 96 ppm (580 mg/m3) for 6 months or more, no adverse effect was detected in any of them, as judged by gross appearance, behavior, growth, organ weight, hematological studies, and clinical findings. [R80, 708] *...causes alpha 2u-globulin nephropathy or hyaline droplet nephropathy. This nephropathy occurs in male but not in female rats, is characterized by the accumulation of protein droplets in the S2 segment of the proximal tubule, and results in single-cell necrosis, the formation of granular casts at the junction of the proximal tubule and the thin loop of Henle, and cellular regeneration. [R81] *... rats were treated for 13 weeks with oral doses ranging from 37.5 to 1500 mg/kg. Mortality was produced at doses of 900 mg/kg or greater, and body weights were adversely affected by 600 mg/kg or greater. In the animals given 1200 or 1500 mg/kg, degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates and small intestinal mucosa were produced. At doses of 300 mg/kg or greater, male rats showed kidney damage characterized by degeneration or necrosis of the renal cortical tubular epithelial cells. These lesions appear specific to the male rat and were not seen in treated females at doses up to 1500 mg/kg. Clinical pathologic changes consistent with liver damage were seen at doses of 600 mg/kg or greater, and urinary coproporphyrins were elevated at 1200 mg/kg. [R82, 1991.410] *Rabbits exposed 8 hr/day for a total of 62 exposures in 83 days at 770-800 ppm p-DCB exhibited tremors, weakness, and death, along with edema of the cornea and opacity of the lens. No opacity of the lens was noted in rabbits exposed for 5 to 47 days to vapors of p-DCB; however, there was liver damage and mortality. [R82, 1991.411] *The effects of 1,4-dichlorobenzene (DCB) have been compared in male F344 rats given 0 (corn oil control), 25, 75, 150, and 300 mg/kg DCB and male B6C3F1 mice given 0 (corn oil control), 300, and 600 mg/kg DCB by daily oral gavage five days per week for 1, 4, and 13 weeks. The two highest rat and both mouse dose levels were the same as those employed in a NTP bioassay, where DCB produced kidney tumors in male rats and liver tumors in mice. DCB produced significant dose-related increases in relative liver weight in both the rat and the mouse which was associated with, respectively, mild and marked centrilobular hypertrophy. Administration of DCB also produced a sustained induction of microsomal cytochrome P450 content and 7-pentoxyresorufin O-depentylase activity in both species. Western immunoblotting studies demonstrated that DCB induced CYP2B isoenzyme(s) in both rat and mouse liver microsomes. Replicative DNA synthesis was studied by implanting osmotic pumps containing 5-bromo-2'-deoxyuridine in study Weeks 0-1, 3-4, and 12-13. In the rat hepatocyte labeling index values were only increased in animals given 300 mg/kg DCB for 1 week, whereas hepatocyte labeling index values were significantly increased in mice given 300 and 600 mg/kg DCB for 1 and 4 weeks. DCB treatment produced significant increases in rat renal P1/P2 proximal tubule cell labeling index values at all time points, whereas little effect was observed in mouse kidney. The observed species difference in DCB-induced liver tumor formation may reflect the greater sensitivity of the mouse to tumor promotion by a CYP2B inducer. For the kidney, the present data provides further evidence that while DCB-induced alpha2U-globulin nephropathy is associated with a sustained stimulation of cell replication in male rat renal proximal tubule cells, this effect is not observed in the male mouse. [R83] NTXV: *LD50 Rat (male, adult) po 3863 mg/kg (95% confidence interal 3561-4153 mg/kg) /From table/; [R84] *LD50 Rat (female, adult) po 3790 mg/kg (95% confidence interval 3425-4277 mg/kg) /From table/; [R84] *LD50 Rat (male, adult) dermal > 6000 mg/kg /From table/; [R84] *LD50 Rat (female, adult) dermal > 6000 mg/kg /From table/; [R84] *LD50 Rat oral 500 mg/kg; [R39] *LD50 Mouse oral 2950 mg/kg; [R39] *LD50 Mouse ip 2 g/kg; [R39] *LD50 Mouse sc 5145 mg/kg; [R39] *LD50 Rabbit oral 2830 mg/kg; [R39] ETXV: *LC50 Lepomis macrochirus (bluegill sunfish) 4.54 mg/l/24 hr; 4.3 mg/l/48 hr; 4.25 mg/l/96 hr /Static bioassay/; [R85] *LC50 Sheepshead minnow 7.5-10 mg/l/24 hr; 7.17 mg/l/48 hr; 7.4 mg/l/96 hr /Static bioassay/; [R86] *LC50 Poecilia reticulata (guppy) 4.0 ppm/14 days /Conditions of bioassay not specified/; [R87] *LC50 Pimephales promelas (fathead minnow) 35.4 mg/l /24 and 48 hr; 33.7 mg/l/96 hr /Conditions of bioassay not specified/; [R87] *LC50 Palaemonetes pugio (grass shrimp) 129 mg/l/48 hr; 69 mg/l/96 hr /Conditions of bioassay not specified/; [R87] NTP: *... Carcinogenesis studies were conducted by admin 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 yr (50 animals per group). Under the conditions of these 2 yr gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an incr incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by incr incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the admin of 1,4-dichlorobenzene. [R79] TCAT: ?The mutagenic potential of para-dichlorobenzene was evaluated in the germ cells (Sex-Linked Recessive Lethal Mutation Assay) of Drosophila males exposed by inhalation. Based on preliminary toxicity determinations, groups of flies received nominal concentrations of 6,000, or 15,600 ppm/hr, resulting in a range of 3.4 - 23% mortality during exposure and pre-mating. None of the treatments produced mutant frequencies significantly greater than the negative control (air only). [R88] ?The frequency of forward mutations was determined at the HGPRT locus in Chinese Hamster Ovary cells exposed in vitro to p-dichlorobenzene with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was not mutagenic at concentrations ranging from 25 to 250 ug/ml in the presence of activation (-serum), and without activation (+ and - serum). In preliminary cytotoxicity assays, the percent survivors parameter ranged from 0.03 to 2.1% at the high dose level under all conditions of exposure. [R89] ?The ability of para-dichlorobenzene to cause chromosome aberrations in cultured Chinese hamster ovary (CHO) cells was evaluated in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, both nonactivated and activated cultures were treated with duplicate 5, 10, 20, 30 and 50ug/ml of test material. Nonactivated cultures were incubated with the test material for 12 hours and activated cultures were incubated for 2 hours with test material and then incubated for addition 10 hours with replaced normal medium. Only cells at the highest three treatments were analyzed for chromosomal damage. Nonactivated cultures produced significantly (chi-square test) greater chromosome aberration frequencies relative to the negative control (DMSO), but this data was dismissed due to erratic negative control values. None of the negative control chromosome aberrations frequencies exceed the 95% confidence limit of the historical controls. Activated cultures did not produce a significantly greater (chi-square test) increase in the frequencies of chromosomal aberrations relative to the negative control (DMSO). [R90] ?The fate of 1,4-dichlorobenzene (DCB) was studied in male Wistar rats in a urine study (5/group) and in a blood and tissue study (25/group, 5/group sacrificed 1, 2, 4, 8, and 14 days after exposure). The rats in both studies were exposed by gavage to single doses of 100 or 1000 mg/kg. After 1 day, DCB (28 ug/ml) and 1,4-dichlorophenol (DCP) (26 ug/ml) were observed in the plasma of high-dose animals. These levels dropped rapidly during day 2; only DCP (0.35 ug/ml) was detected after 4 days. Low-dose animal plasma after day 1 contained DCB (0.3 ug/ml) and DCP (0.5 ug/ml). Most of the DCP (conjugated form) was eliminated in the urine within 1 (low-dose) or 2 days (high-dose). DCP is still detectable on days 3 (low-dose) and 7 (high-dose) in the urine. Sixty (low-dose) and 40% (high-dose) of the DCB is eliminated in the urine. DCB was found in the fatty tissue at 50 (low-dose) and 3,600 ug/g (high-dose) on day 1, although these level dropped rapidly to 2.3 and 100 ug/g on day 2 and to traces by day 4. In high-dose animals, DCB (67 ug/g) and DCP (2.5 ug/g) were found in the hepatic tissue after day 1 and these levels drop off rapidly, and DCB (40 ug/g) and DCP (12 ug/g) were found in the renal tissue after day 1 and the DCB level dropped off rapidly, whereas DCP still present at 0.5 ug/g after day 4. Only traces of DCB and DCP were found in the hepatic and renal tissue of low-dose animals. [R91] ?The distribution and metabolism of 1,4-dichlorobenzene (DCB) was studied in male and female rats (15/sex/group, strain not reported) exposed by inhalation to concentrations of 75 or 500 ppm DCB 5 hrs/day, 5 days/week for up to 18 months (mo). Animals (5/sex/group) were sacrificed 6, 18, and 24 mo after the commencement of exposure. The levels (ug/ml) of 2,5-dichlorophenol (DCP, metabolite) in the plasma of low/high-dose males were 1.4/10.4 at 6 mo and 0/2.0 at 18 mo, and of low/high-dose females were 1.8/8.6 at 6 mo and 0/3.7 at 8 mo. The levels (ug/g) of DCB in the fatty tissue of low/high-dose males were 29.0/831.3 at 6 mo, 1.9/120.7 at 18 mo, and 0/0 at 24 mo, and of low/high-dose females were 44.7/494.7 at 6 mo, 2.9/169.7 at 18 mo, and 0/0 at 24 mo. The levels (ug/ml) of DCP in the urine of low/high-dose males were 249.5/79.3 at 6 mo and 25.0/666.8 at 8 mo, and of low/high-dose females were 227.5/313.0 at 6 mo and 12.9/1160.3 at 8 mo. Neither DCB nor DCP were detected in the hepatic tissue of low-dose males or females at any time. The levels (ug/g) of DCB/DCP in hepatic tissue of high-dose males were 5.0/2.9 at 6 mo and 2.7/0.2 at 8 mo, and of high-dose females were 5.0/0.8 at 6 mo and 2.9/0.2 at 8 mo. Twenty-four mo urine samples were not available. [R92] ?The distribution of 1,4-dichlorobenzene (DCB) was studied in male Wistar rats (25/group) fed a diet containing DCB (in a 1:1 mixture with Wessalin S) at concentrations of 100 or 1000 ppm DCB for up to 28 days. Four animals/group were sacrificed at 3, 7, 14, 21, and 28 days and samples of blood, liver, kidney, and fatty tissue were analyzed for DCB and 2,5-dichlorophenol (DCP) content. DCP was not detected in the fatty tissue and neither DCB or DCP could be detected in the plasma, hepatic or renal tissues of low-dose animals. DCP was not detected in the fatty tissue of high-dose animals. In high-dose animals, the plasma levels of DCB and DCP decrease rapidly from days 3-7 and then steady state concentrations (approximately 0.5 and 1.0 ug/ml, respectively (resp)) are reached which slowly decrease through day 28. Levels of DCB (ug/g) in the fatty tissue of high- and low-dose animals were approximately 49 and 3 on day 3, 17 and 2 on day 7, and 19 and 2 on day 28, resp. Levels (ug/g) of DCB and DCP in the hepatic tissue of high-dose animals were 1.3 and 0.2 on day 3, 0.4 and 0.1 on day 7, and 0.5 and 0.2 on day 28, resp. Levels (ug/g) of DCB and DCP in the renal tissue of high-dose animals were 0.7 and 0.9 on day 3, 0.3 and 0.3 on day 7, and 0.3 and 0.5 on day 7, resp. Neither DCB nor DCP were detected in fatty, hepatic or renal tissue at 35 days. [R91] POPL: *Persons with existing pathology (hepatic, renal, central nervous system, blood), or metabolic disorders, who are taking certain drugs (hormones, or otherwise metabolically active) or who are otherwise exposed to dichlorobenzenes or to related (chemically or biologically) chemicals, by such means as occupation or domestic use or abuse ... might well be considered at increased risk from exposure to dichlorobenzenes. /Dichlorobenzenes/ [R93] */Individuals who suffer from/ skin, liver, kidney, or chronic respiratory disease, will be at an increased risk if they are exposed to chlorobenzenes. /Chlorobenzenes/ [R11, 1981.1] ADE: *THE MATERIAL IS APPARENTLY WELL ABSORBED BY THE GASTROINTESTINAL TRACT AND FROM LUNG BUT NOT APPRECIABLY THROUGH SKIN. [R25, 3625] *MOTH REPELLENT PARA-DICHLOROBENZENE WAS DETECTED IN HUMAN ADIPOSE TISSUE AND BLOOD AS POLLUTANT TOGETHER WITH POLYCHLORINATED BIPHENYLS. [R94] *Absorption of 1,4-dichlorobenzene through the gastrointestinal tract is rapid. Oral doses of 200 or 800 mg/kg to male Wistar rats appeared in the blood and adipose, kidney, liver, lung, heart, and brain tissue within 30 minutes. [R95] *The dichlorobenzenes may be absorbed through the lungs, gastrointestinal tract, and the intact skin. Relatively low water solubility and high lipid solubility favor their penetration of most membranes by diffusion, including pulmonary and GI epithelia, the brain, hepatic parenchyma, renal tubules, and the placenta. /Dichlorobenzenes/ [R96] *Studies were carried out to determine the concentration of p-dichlorobenzene in the urine of workers exposed to the compound in a chemical factory and to determine whether a correlation exists between the weighted levels of p-dichlorobenzene in the air and the urinary levels recorded. Urine samples /were/ obtained from four workers with various lengths of occupational exposure to p-dichlorobenzene at the beginning and at the end of the work shift. The average concn of p-dichlorobenzene in the breathing zone of the workers was 44.72 mg/cu m. The levels of p-dichlorobenzene determined in the urine of the workers ranged from 5.2 to 125 ug/l. The differences between the levels of p-dichlorobenzene in the urine at the beginning and at the end of the shift, and the levels of p-dichlorobenzene in the air of the workplace were statistically significant. Based on a daily level of exposure to p-dichlorobenzene equal to 450 mg/cu m, which is the weighted exposure level established by the American Conference of Government Industrial Hygienists in 1984, ... a biological exposure index of 250 ug/l as the difference between the levels of p-dichlorobenzene in the urine at the beginning and at the end of the shift has been proposed. [R97] *The dichlorobenzenes may be absorbed through the lung, gastrointestinal tract, and intact skin. Relatively low water solubility and high lipid solubility favor their penetration of most membranes by diffusion, including pulmonary and GI epithelia, the brain, hepatic parenchyma, renal tubules, and the placenta. /Dichlorobenzenes/ [R62] *... In a previous study of selected children in AR, /it was found/ that 96% of the children had detectable urinary concn of 2,5-dichlorophenol, the metabolite of p-dichlorobenzene. In the current study in a sample of 1,000 adults who lived throughout the USA, 98% had detectable levels of p-dichlorobenzene in their blood. Urinary 2,5-dichlorophenol concn ranged up to 8,700 ug/l (median and mean concn of 30 ug/l and 200 ug/l, respectively). p-Dichlorobenzene blood concn ranged up to 49 ug/l, with median and mean concn of 0.33 ug/l and 2.1 ug/l, respectively). The Pearson correlation coefficient for 2,5-dichlorophenol in urine and p-dichlorobenzene in blood was 0.82 (p < 0.0001), thus demonstrating a strong association between these exposure measurements. Neither age nor gender was related to urinary 2,5-dichlorophenol or blood p-dichlorobenzene concn (p > 0.40). ... [R98] *Following repeated daily exposures for 10 days to 1000 ppm p-dichlorobenzene vapor for 3 hr/day or administration of oral or subcutaneous doses of 250 mg/kg/day, tissue concentration of 14C activity did not increase after 6 days of exposure but tended to decrease. During a 5-day postexposure interval after the last dose, 91-97% of the excreted radioactivity was recovered in the urine, 1-6% in the feces, and 0.2-6.4% in the expired air. In rats with cannulated bile ducts, 46-63% of the dose was recovered in the bile and appeared to be reabsorbed in the intact animal ... and ultimately excreted in the urine. ... [R80, 709] METB: *AFTER INGESTION OF P-DICHLOROBENZENE, 2,5-DICHLOROPHENOL (30%) FREE AND AS THE GLUCURONIDE AND SULFATE AND 2,5-DICHLOROQUINOL (6%) WERE EXCRETED. IN HUMANS, 2,5-DICHLOROPHENOL WAS ALSO FOUND IN THE URINE. [R99] *AFTER ORAL ADMIN OF PARA-DICHLOROBENZENE TO RATS, 2 METAB DETECTED IN BLOOD. METABOLITES M-1 AND M-2 ARE 2,5-DICHLOROPHENYL METHYL SULFOXIDE AND 2,5-DICHLOROPHENYL METHYL SULFONE. CONCN OF M-1 IN BLOOD WAS HIGHER THAN M-2 FOR 12 HR AFTER DOSING, BUT BLOOD LEVEL OF M-2 WAS HIGHER THEREAFTER. AFTER ORAL ADMIN OF P-DCB TO RATS 2,5-DICHLOROPHENOL WAS MAJOR METABOLITE. [R94] *Rabbits were fed an oral dose of 0.5 g/kg of p-dichlorobenzene /which was then/ oxidized to 2,5-dichlorophenol (35%); conjugated to form glucuronide (36%) and ethereal sulfate (27%); or excreted as 2,5-dichloroquinol (6%). [R100] *The metabolism of p-dichlorobenzene was extensively studied in rats following repeated inhalation, oral, or subcutaneous doses. After these exposures, residues detected by (14)C content were observed in fat, kidneys, liver, and lungs, but they declined rapidly to levels below limits of detection within 5 days after exposure. From 91%-97% of the dose was excreted in the urine. [R101] *THE EFFECT OF INDUCERS AND INHIBITORS OF MICROSOMAL MIXED-FUNCTION OXIDASES ON THE FATE OF METABOLISM AND THE EXTENT OF BINDING OF ORTHO- AND PARA-DICHLOROBENZENE TO CELLULAR CONSTITUENTS SUGGESTS THAT ARENE OXIDES (EPOXIDE) MAY BE PRECURSORS OF THE EXCRETED METABOLITES ... [R60] *1,2,4-Trichlorobenzene (TCB) was reductively converted into monochlorobenzene (MCB) via dichlorobenzenes (DCBs) on incubation with intestinal contents of rats. When the amounts of MCB produced from o-DCB, m-DCB, or p-DCB as substrates were compared, the amount was the least in the case of o-DCB. This was consistent with the finding that o-DCB tended to accumulate more than the other isomers. The mechanism of the reductive dechlorination of aromatic compounds is not well understood. [R102] *The metabolism and kinetics of 1,4-dichlorobenzene (1,4-DCB) were examined in male Wistar-rats. Animals were gavaged with 10 to 250 mg/kg of radiolabeled 1,4-DCB. Rats were induced with 0.1% isoniazid for 10 days before dosing. Blood, urine, feces, exhaled air, and bile were collected repeatedly for up to 6 days after treatment. After 168 hours, the rats were sacrificed and examined. Blood, urine, feces, expired air, bile, and organs were analyzed for total radioactivity. Urinary metabolites were analyzed via high pressure liquid chromatography and mass spectrometry. Plasma concentrations of 1,4-DCB were measured using gas chromatography. Dose did not affect the clearance and half life of 1,4-DCB in the plasma. The area under the concentration time curves was smaller and the clearance of 1,4-DCB was greater in rats induced with isoniazid, compared to control rats. Among control rats, the maximum plasma 1,4-DCB concentration (Cmax) increased dose dependently from 6.75+/-0.04 micromoles per liter (micromol/l) after a 10 mg/kg dose to 104 +/- 27 umol/l after a 250mg/kg dose. Among induced rats, Cmax equaled 22.2 +/- 7.8 umol/l after a 50 mg/kg dose and 76.9 +/-23 umol/l after a 250 mg/kg dose. Less than 1% of the 1,4-DCB dose was excreted in air. Less than 0.05% of the radioactivity was recovered in body organs. In control rats, 80 and 4% of the 1,4-DCB dose were eliminated in the urine and feces, respectively. In induced rats, 92 to 97% and 5% of the 50 mg/kg 1,4-DCB dose and 80 to 85% and 4% of the 250 mg/kg 1,4-DCB dose were excreted in the urine and feces, respectively. Bile excretion of 1,4-DCB increased with increasing dose. Urinary metabolites included sulfates, glucuronides, mercapturic acids, and 2,5-dichlorophenol (2,5-DCP). Sulfates were the most abundant metabolites and 2,5-DCP was the least abundant metabolite. [R103] ACTN: *The formation of metabolic arene oxide intermediate has been associated with mutagenesis and carcinogenesis, and halobenzenes have been shown to form reactive intermediates ... Chromosomal and other nuclear derangements in roots of Allium ... exposed ... to 1,4-dichlorobenzene ... abnormal chromosome numbers were found in dividing nuclei ... . [R104] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,4-Dichlorobenzene's production and application as an insecticide, space deodorant and a chemical intermediate will result in its release to the environment through various waste streams. Based on a vapor pressure of 1.7 mm Hg at 25 deg C, 1,4-dichlorobenzene is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,4-dichlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of 50 days. 1,4-Dichlorobenzene is expected to have moderate to low mobility in soils based upon log Koc values in the range of 2.5-4.8 measured in sois and sediment. Volatilization of 1,4-dichlorobenzene from dry soil surfaces is expected to be an important fate process based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is expected based on the Henry's Law constant of 2.7X10-3 atm-cu m/mole at 20 deg C. 1,4-Dichlorobenzene is not expected to biodegrade in soils or water with reported biodegradation half-lives of about a year or longer. In water, 1,4-dichlorobenzene is expected to adsorb to sediment or particulate matter based on its measured Koc values. This compound is expected to volatilize from water surfaces given its Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4 and 120 hours, respectively. Bioconcentration in aquatic organisms is considered moderate to high based on BCF values in the range of 60 to 720 measured in fish. Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where 1,4-dichlorobenzene is produced or used. The general population may be exposed to 1,4-dichlorobenzene via inhalation of ambient air, ingestion of food and drinking water. (SRC) NATS: *Dichlorobenzenes are not known to occur as such in nature(1). [R105] ARTS: *1,4-Dichlorobenzene's production and application as an insecticide, space deodorant and a chemical intermediate will result in its release to the environment through various waste streams(1,2,SRC). [R106] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), and Koc values of 273 and 390(2,3) measured in soil, 1,4-dichlorobenzene is expected to have moderate mobility in soil(SRC). Volatilization of 1,4-dichlorobenzene is expected from moist soil surfaces given its Henry's Law constant of 2.7X10-3 atm-cu m/mole at 20 deg C(4). Volatilization of 1,4-dichlorobenzene from dry soil surfaces is expected based on a vapor pressure of 1.7 mm Hg at 25 deg C(5). 1,4-Dichlorobenzene is not expected to biodegrade in soils with biodegradation half-lives of about a year or longer(6,7). [R107] *AQUATIC FATE: Based on a recommended classification scheme(1), and a log Koc value of 4.8(2) measured sediment, 1,4-dichlorobenzene is expected to adsorb to suspended solids and sediment in water(SRC). 1,4-Dichlorobenzene is expected to volatilize from water surfaces(3,SRC) given its Henry's Law constant of 2.7X10-3 atm-cu m/mole at 20 deg C(4). Estimated volatilization half-lives for a model river and model lake are 4 and 120 hours, respectively(3,SRC). According to a classification scheme(5), BCF values in the range of 60 to 720, measured in fish(6-8), suggest that bioconcentration in aquatic organisms is moderate to high(SRC). 1,4-Dichlorobenzene is not expected to biodegrade in water or sediment with biodegradation half-lives of about a year or longer(9,10). [R108] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,4-dichlorobenzene, which has a vapor pressure of 1.7 mm Hg at 25 deg C(2), is expected to exist in the vapor phase in the ambient atmosphere. Vapor-phase 1,4-dichlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 50 days(3,SRC). [R109] BIOD: *Chlorobenzenes have been observed to degrade under aerobic but not anaerobic conditions. ... The chlorobenzenes, 1,4-dichlorobenzene, 1,2,4-trichlorobenzene, and 1,2,3-trichlorobenzene decomposed under aerobic conditions in the aquifer near the Glatt River and are suggested to have degraded to chlorinated phenols and catechols. ... The rate of degradation was slower than for the alkyl aromatics, perhaps because the breaking of the halogen bond slows the process. Chlorobenzenes in a Swiss study persisted for at least seven years under anaerobic conditions. The above chlorobenzenes also decomposed above but not below the water table in a shallow fluvial aquifer in Oklahoma. [R110] *An unspecified initial concn of 1,4-dichlorobenzene was biodegraded between 25 and 90 percent in soil column experiments using sediment from the Rhine River over a 300 day incubation period(1). Dichlorobenzene isomers were slowly biodegraded (6.3% of theoretical CO2 evolution in 10 weeks) in an alkaline soil sample(2). 1,4-Dichlorobenzene was slowly biodegraded by an acclimated anaerobic sediment slurry obtained from the Tsurumi River, Japan(3). The first-order biodegradation rate constant was 0.0018 days-1, corresponding to a half-life of about 385 days(3). No biotransformation of 1,4-dichlorobenzene was observed in an anaerobic Rhine River sediment column over a 12 month period(4). The first-order biodegradation rate of 1,4-dichlorobenzene in a biofilm system was 5.0-20.0X10-4 days-1, corresponding to half-lives on the order of a year or longer(5). 1,4-Dichlorobenzene was not biodegraded in aquifers from Vejen and Grindsted, Denmark during a 50 day incubation period(6). 1,4-Dichlorobenzene was found to be degradation-resistant using the Japanese MITI test(7). [R111] ABIO: *The rate constant for the vapor-phase reaction of 1,4-dichlorobenzene with photochemically-produced hydroxyl radicals has been measured as 3.2X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 50 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 1,4-Dichlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of functional groups to hydrolyze(SRC). [R112] BIOC: *BIOACCUMULATION INCR WITH LOG P OCT (PARTITION COEFFICIENT OF SUBSTANCE BETWEEN N-OCTANOL AND WATER), UNTIL REACHING AN OPTIMUM AT LOG POCT= 6.5. [R113] *A mean BCF value of 78 was measured in mosquito fish exposed to 57-233 ug/l of 1,4-dichlorobenzene during 1 to 4 day incubation periods(1). Mean BCF values of 370 to 720 were experimentally determined for rainbow trout exposed to unspecified concns of 1,4-dichlorobenzene up to 119 days in laboratory aquariums(2). A whole body BCF of 60 was determined for bluegill sunfish exposed to 1,4-dichlorobenzene over a 28-day period in a continuous flow system(3). According to a classification scheme(4), these BCF values suggest that bioconcentration in aquatic organisms is moderate to high. [R114] KOC: *An experimental Koc value of 273(1) was determined for 1,4-dichlorobenzene in silt loam soil and a value of 390 was reported in Lincoln fine sand(2). A log Koc value of 4.8 was measured for 1,4-dichlorobenzene from sediment of Lake Ketelmeer, Netherlands(3). According to a recommended classification scheme(4), these Koc values suggest that 1,4-dichlorobenzene has moderate to low mobility in soil(SRC). [R115] VWS: *The Henry's Law constant for 1,4-dichlorobenzene is 2.7X10-3 atm-cu m/mole at 20 deg C(1). This value indicates that 1,4-dichlorobenzene will volatilize from water(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 4 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 120 hours(2,SRC). 1,4-Dichlorobenzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is expected. 1,4-Dichlorobenzene is expected to volatilize from dry soil surfaces based on a vapor pressure of 1.7 mm Hg at 25 deg C(3). [R116] WATC: *DRINKING WATER: A mean 1,4-dichlorobenzene concn of 0.013 ppb was reported in drinking water samples from 3 cities near Lake Ontario in 1980(1). A concn of 0.5 ppb was detected in Miami, FL drinking water and qualitative detections were reported for Philadelphia, PA and Cincinnati, OH(2). 1,4-Dichlorobenzene was identified, not quantified in Cleveland, OH tap water(3) and 14 drinking water supply sources in the United Kingdom(4). 1,4-Dichlorobenzene was detected at an avg concn of below 1 ppb in 30 potable Canadian water sources(5). 1,4-Dichlorobenzene was detected at mean concns of 0.60-0.74 ppb in 9 of 945 finished water supplies in the US(6). 1,4-Dichlorobenzene was identified, not quantified, in chlorine treated drinking water in the US(7) and a municipal well in Eau Claire, WI(8). 1,4-Dichlorobenzene was detected in 11 percent of 11,659 samples of California drinking water at a mean concn of 1.15 ug/l(9). 1,4-Dichlorobenzene was identified, not quantified, in drinking water from Milan, Italy(10). [R117] *GROUNDWATER: 1,4-Dichlorobenzene was detected in 19 of 685 groundwaters analyzed in NJ during 1977-1979 with 995 ppb the highest concn found(1). 1,4-Dichlorobenzene was detected at concns of less than 4 ng/l to 7 ng/l in groundwater from the Edwards Aquifer, TX(2). 1,4-Dichlorobenzene was identified, not quantified, in groundwater from the Lower Llobregat aquifer in Spain(3). 1,4-Dichlorobenzene was detected in groundwater near Boulder, CO (0.5 ppb) and Phoenix, AZ (0.07 ppb)(4). 1,4-Dichlorobenzene was detected in groundwater collected in Texas at concns of 0-33 ppb(5). [R118] *SURFACE WATERS: 1,4-Dichlorobenzene was detected in 26 of 463 surface waters analyzed in NJ during 1977-1979 with 30.5 ppb the highest concn found(1). Mean 1,4-dichlorobenzene concns of 45, 4 and 10 parts per trillion were found in Lake Ontario, Lake Huron and the Grand River, respectively(2). 1,4-Dichlorobenzene was detected at concns of 9-310 parts per trillion (mean concn of 36 parts per trillion) in the Niagara River at Niagara-On-The-Lake between 1981 and 1983(3) and concns of 9-110 parts per trillion (mean concn of 24 parts per trillion) were detected elsewhere in the Niagara River between 1981 and 1983(4). An avg concn of 48 parts per trillion was found in the Niagara River near Niagara-On-The-Lake between Sept and Oct 1982(5). Positive detection of 1,4-dichlorobenzene was reported by 3 percent of 8,576 USEPA STORET stations(6). 1,4-Dichlorobenzene was identified, not quantified, in the Delaware and Raritan Canal in NJ(7). 1,4-Dichlorobenzene was detected at concns below 0.5 ppb in the Rhine River between 1978-1982(8). An avg 1,4-dichlorobenzene concn of 0.19 ppb was found in the Rhine River near Dusseldorf in 1984(9). 1,4-Dichlorobenzene was detected at mean concns of 2.82 ng/l (Edwards Point) and 1.56 ng/l(Port Lambton) in Ontario, Canada(10). 1,4-Dichlorobenzene was detected at concns of 0-0.3 ug/l in Lake Ketelmeer, Netherlands(11). 1,4-Dichlorobenzene was detected in rivers in Osaka, Japan at a mean concn of 0.20 ug/l(12). 1,4-Dichlorobenzene was detected at a median concn of 158 ng per cubic decimeter in the Scheldt estuary, Netherlands(13). 1,4-Dichlorobenzene was detected in the Elbe River, Germany at concns of 6.5-49 ng/l(14). [R119] *RAIN/SNOW: A mean 1,4-dichlorobenzene concn of 0.66 parts per trillion was detected in Portland, OR rainwater during March-April 1982 and a mean concn of 5.5 parts per trillion was detected between October-December(1). The avg concn of 1,4-dichlorobenzene in rainwater in Portland, OR was 4.1 parts per trillion in 1984(2). [R120] EFFL: *1,4-Dichlorobenzene was detected in the ash of municipal waste incinerators in the US at concns of 51, 11 and 26 ug/kg(1). 1,4-Dichlorobenzene was detected at a concn of 0.51 ug/cu m in the effluent of a hazardous waste incinerator in Germany(2). 1,4-Dichlorobenzene was detected at mean concns of less than 0.05 to 0.18 mg/cu m in the air of municipal landfills in Finland(3). The annual US emission of 1,4-dichlorobenzene was 409 tons in 1990(4). 1,4-Dichlorobenzene has been detected in the leachate of municipal landfills in the US at concns of 1-250 g/l(5). 1,4-Dichlorobenzene is one of the most frequently observed organic compounds in landfill leachate, occurring at concns of 0.1-16 ug/l(6). [R121] SEDS: *1,4-Dichlorobenzene was detected in the sediment of Lake Ketelmeer, Netherlands at concns of 550 and 210 ng/kg(1). Mean 1,4-dichlorobenzene concns of 5, 16, 9 and 94 ppb were detected in the superficial sediments from Lakes Superior, Huron, Erie, and Ontario, respectively(2). 1,4-Dichlorobenzene was detected at concns of less than 0.3 ng/g to 0.8 ng/g in the sediment of 7 rivers and ports in Niigata, Japan(3). 1,4-Dichlorobenzene was detected at concns of 110-150 ng/g in suspended sediment from Lake Ontario, at depths of 20-68 meters and an avg concn of 63 ng/g for the bottom sediment(4). 1,4-Dichlorobenzene was identified, not quantified, in sediment from Dokai Bay, Japan(5). 1,4-Dichlorobenzene was detected at median concns of 91, 68, 50 and 39 ng/g in sediment taken from the Scheldt estuary, Netherlands(6). 1,4-Dichlorobenzene was detected in sediment at concns of 200-550 ug/kg in Lake Ketelmeer, Netherlands(7). 1,4-Dichlorobenzene was detected in sediment off the coast of Taiwan at concns of 3-12 ng/kg(8). [R122] ATMC: *In workplace atmospheres associated with the manufacture of 1,4- dichlorobenzene, measurements were made that found 1,4-dichlorobenzene at air concentrations averaging 204 mg/cu m (Range: from 42-288 mg/cu m) near shoveling and centrifuging, and 150 mg/cu m (Range: from 108-204 mg/cu m) during pulverizing and packaging. No concentrations less than 48 mg/cu m were found. [R123] *1,4-Dichlorobenzenes were detected in a residential area and on a main street in Tokyo, alongside a major highway 30 km northwest of Tokyo, and on a farm 15 km northwest of Tokyo at concn of 4.2x10-3 mg/cu m, 2.9x10-3 mg/cu m, 2.4x10-3 mg/cu m and 2.1x10-3 mg/cu m, respectively. [R124] *Concentrations (mean) of para-dichlorobenzene were: 0.05 ppb (detected in 32 of 38 samples) in Newark, NJ; 0.07 ppb (30 of 37 samples) in Elizabeth NJ; and 0.04 ppb (34 of 35 samples) in Camden NJ during July-August 1981. [R125] *URBAN/SUBURBAN: The mean 1,4-dichlorobenzene concentrations from 36 source-dominant points and 392 urban/suburban points in the US have been reported to be 2.6 and 290 parts per trillion, respectively(1). 1,4-Dichlorobenzene was detected at mean concns of 20 ppb (Portland, OR) and 290 ppb (unspecified urban locations in the US)(2). Combined 1,3- and 1,4-dichlorobenzene was detected in the air of Bayonne, NJ at concns of 1.2-1.7 ug/cu m, in Los Angeles, CA at concns of 9.4 and 24 ug/cu m and Contra Costa, CA at 2.2 ug/cu m(3). Mean concns of 0.04-0.07 ppb of 1,4-dichlorobenzene were detected in the air of 3 NJ cities during July-August 1981(4). The urban air of Tokyo contained 1,4-dichlorobenzene at concns of 2.7-4.2 ug/cu m, while suburban Tokyo air contained 1,4-dichlorobenzene at concns of 1.5-2.4 ug/cu m(5). 1,4-Dichlorobenzene was detected at a mean concn of 0.15 ppb in Washington DC(6). 1,4-Dichlorobenzene was detected at a mean concn of 4.16 ug/cu m in 44 urban/suburban locations in the US from 1976-1986 and at a mean concn of 1.04 ug/cu m in 11 US cities in 1990(7). [R126] *RURAL/REMOTE: 1,4-Dichlorobenzene was identified, not quantified, in the Sierra Mountains, CA(1) and in a forest in Germany(2). [R127] *INDOOR AIR: The mean 3-day concn of dichlorobenzene isomers was 0-7 ug/cu m in 7 buildings in the US(1). The combined isomers of dichlorobenzene were identified, not quantified, in 10 of 14 indoor air samples from 4 buildings in the US(1). 1,4-Dichlorobenzene was identified, not quantified, in the indoor air from 26 of 26 buildings in Finland(2). The mean concn of 1,4-dichlorobenzene measured in houses in Kuwait from Dec 1994 to Jan 1995 was 742 ug/cu m(3). 1,4-Dichlorobenzene was detected in homes of non-smokers at a mean concn of 3.45 ug/cu m and homes of smokers at a mean concn of 10.22 ug/cu m(4). The median concn of 1,4-dichlorobenzene in homes in Italy, Germany, the Netherlands and the US was 5 ug/cu m(5). The max concn of 1,4-dichlorobenzene in 300 Dutch homes was 299 ug/cu m(6). [R128] FOOD: *1,2-Dichlorobenzene was identified, not quantified in 69 of 234 table ready foods in the US at an avg concn of 10.7 ppb(1). 1,4-Dichlorobenzene was detected in scrambled eggs at concns of 18 and 28 ng/g(2). 1,4-Dichlorobenzene was detected in butter (1.3-2.7 ug/kg), margarine (12.2-14.5 ug/kg), peanut butter(1.2-8.8 ug/kg), flour(7.3 ug/kg) and pastry mix (22 ug/kg)(3). 1,4-Dichlorobenzene was detected at a concn of 5 ng/g in market meat samples in Yugoslavia(4). 1,4-Dichlorobenzene was detected in carrots (0.198 and 0.416 mg/kg), potatoes (0.0224 mg/kg), cauliflower(0.214 and 0.529 mg/kg), lettuce (0.237 and 0.118 mg/kg), beans(0.717 and 0.117 mg/kg), peas(1.31 mg/kg) and tomatoes(0.619 mg/kg)(5). [R129] PFAC: PLANT CONCENTRATIONS: *1,4-Dichlorobenzene has been detected at unspecified concns in the roots of wheat plants grown from lindane-treated seeds(1). 1,4-Dichlorobenzene was identified, not quantified, in plant material grown in an Illinois coal refuse reclamation site(2). [R130] FISH/SEAFOOD CONCENTRATIONS: *... Detectable levels of 1,4-dichlorobenzene /were found/ in fish of the Japanese coastal waters. A species of mackerel ... contained 0.05 mg/kg (wet weight). [R131] *1,4-Dichlorobenzene was detected at concns of 1, 4 and 2-4 ppb in trout taken from Lake Erie, Lake Huron and Lake Ontario, respectively, during 1980(1). 1,4-Dichlorobenzene was identified, not quantified, in fish caught in the Great Lakes(2) and detected in fish and mussels from Slovenia at concns of trace amounts to 0.45 ug/g(3). Mackerel caught in Japanese coastal waters contained 1,4-dichlorobenzene at a concn of 0.05 mg/kg(4). [R132] ANIMAL CONCENTRATIONS: *Bovine tissue with an unusual smell was reported to contain 1,4-dichlorobenzene concn of 4.4-55.9 mg/kg in muscle, 165 mg/kg in perirenal fat, 11.3 mg/kg in pancreas, 1.9 mg/kg in lung, 3.4 mg/kg in liver and 2.8 mg/kg in spleen(1). Samples of adipose tissue from pigeons captured in central and suburban Tokyo contained mean concn of 1.35-2.43 mg/kg(1). [R105] MILK: *Concentrations of 5.3 ng/g 1,4-dichlorobenzene were found in market milk samples in Yugoslavia(1). [R133] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 32,449 workers (8,669 of these are female) are potentially exposed to 1,4-dichlorobenzene in the US(1). Occupational exposure to 1,4-dichlorobenzene may be through inhalation and dermal contact with this compound at workplaces where 1,4-dichlorobenzene is produced or used(SRC). The max observed concn of 1,4-dichlorobenzene in the breathing zones of 8 solid waste composting facilities in the US was 2 ug/cu m(2). 1,4-Dichlorobenzene was detected at concns of 32.5-52.1 mg/cu m in work place air of a monochlorobenzene manufacturing plant(3). The general population may be exposed to 1,4-dichlorobenzene via inhalation of ambient air, ingestion of food and drinking water(SRC). [R134] AVDI: *The AVDI of 1,2-, 1,3- and 1,4-dichlorobenzene isomers in the Netherlands is 7.0 ug/day(1). The AVDI of 1,4-dichlorobenzene in Japan was reported as 72.92 ug(2). [R135] BODY: *Dichlorobenzene isomers were detected in human blood samples taken from residents of Love Canal, NY at concns of 1-68 ng/l(1). Combined 1,3-, 1,4-dichlorobenzene was detected in the personal air of Los Angeles, CA residents at concns of 12 and 18 ug/cu m and residents of Contra Costa, CA at a concn of 5.5 ug/cu m(2). Combined 1,3-, 1,4-dichlorobenzene was detected in the breath of Los Angeles, CA residents at concns of 3.5 and 2.8 ug/cu m and residents of Contra Costa, CA at a concn of 2.5 ug/cu m(2). 1,4-Dichlorobenzene was identified, not quantified, in human adipose tissue in the US(3). 1,4-Dichlorobenzene was detected in human adipose tissue at a concn of 146 ug/kg(4). [R136] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers p-dichlorobenzene to be a potential occupational carcinogen. [R24, 96] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 75 ppm (450 mg/cu m). [R137] *Vacated 1989 OSHA PEL TWA 75 ppm (450 mg/cu m); STEL 110 ppm (675 mg/cu m) is still enforced in some states. [R24, 362] NREC: +NIOSH considers p-dichlorobenzene to be a potential occupational carcinogen. [R24, 96] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R24, 96] TLV: +8 hr Time Weighted Avg (TWA): 10 ppm. [R53, 2002.26] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R53, 2002.26] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R53, 2002.6] OOPL: *USSR MAC to skin is 20 mg/cu m of air [R138] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. p-Dichlorobenzene is produced, as an intermediate or a final product, by process units covered under this subpart. [R139] +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,4-Dichlorobenzene is included on this list. [R140] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 75 ug/l [R141] FEDERAL DRINKING WATER GUIDELINES: +EPA 75 ug/l [R141] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 5 ug/l [R141] +(MA) MASSACHUSETTS 5 ug/l [R141] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 75 ug/l [R141] +(CT) CONNECTICUT 75 ug/l [R141] +(ME) MAINE 27 ug/l [R141] +(MN) MINNESOTA 10 ug/l [R141] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R142] +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. [R143] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.5 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R144] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA. [R145] *Pursuant to section 8(d) of TSCA, EPA promulagated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,4-Dichlorobenzene is included on this list. [R146] RCRA: *U072; As stipulated in 40 CFR 261.33, when 1,4-dichlorobenzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R147] *D027; A solid waste containing 1,4-dichlorobenzene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R148] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. p-Dichlorobenzene is found on List C. Case No: 3058; Pesticide type: Insecticide, fungicide, rodenticide, antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): p-Dichlorobenzene; Data Call-in (DCI) Date(s): 10/02/92, 02/07/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R149] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Two methods for the collection of ambient organic vapors at the ng/cu m to ug/cu m level were utilized in field sampling at a residential site in Portland during the winter and spring of 1984. The methods were adsorption/solvent extraction with polyurethane foam plugs (ASE/PUFP) and adsorption/thermal desorption with Tenax-GC cartridges (ATD/Tenax-GC). ASE/PUFP was used with a single sample flow rate in a single channel of the sampler. ATD/Texax-GC was used with 2 different sample flow rates in 2 separate channels. Each method was well suited to the analysis of compounds in a specific range of volatility. Some intermediate-volatility compounds were determined with all 3 sampling channels. The coefficients of variation for the 3 channels pooled over 7 events were 9-36% for compounds in the range of volatility between acenaphthene and pyrene. The low sample volumes used with ATD/Tenax-GC for determination at the ng/cu m level make it and attractive method for many applications. /Ambient organic vapors/ [R150] *Analyte: 1,4-Dichlorobenzene; Matrix: Air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01-0.2 l/min; Vol: min: 1 l at 75 ppm, max: 10 l; Stability: not determined [R151] ALAB: *NIOSH 1003-2. Analyte: 1,4-Dichlorobenzene; Matrix: Air; Procedure: Gas chromatography, flame ionization detector; Desorption: 1 ml CS2, stand 30 min; Range: 0.2 to 4 mg/samp; Precision: 0.052; Est LOD: 0.01 mg/samp; Interferences: None /Hydrocarbons, halogenated/ [R152] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. [R153] *OSW Method 8020A. Determination of Aromatic Volatile Organics by Gas Chromatography. [R153] *OSW Method 8120A. Determination of Chlorinated Hydrocarbons by Gas Chromatography. [R153] *OSW Method 8240B. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R153] *OSW Method 8250A. Determination of Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry. [R153] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R153] *OSW Method 8270B. Determination of semivolatile organic compounds by gas chromatography/mass spectrometry (GC:MS). Capillary column technique. [R153] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. [R154] *EPA Method 602. Purgeable Aromatics in Wastewater by Gas Chromatography with Photoionization Detection. [R154] *EPA Method 612. Chlorinated Hydrocarbons in Wastewater by Gas Chromatography with Electron Capture Detection. [R154] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. [R154] *EPA Method 625. Protocol for the Analysis of Base/Neutral and Acid Extractable (BNA) Organic Priority Pollutants in Industrial and Municipal Wastewater. [R154] *EPA Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. [R154] *Three analytical procedure that can be used to distinguish nephthalene from the less toxic mothball component para-dichlorobenzene. An initial presumptive identification can be made by noting the characteristic aroma of the two substances. This can be followed by one of the three analytical tests, each of which is simple to perform, gives an answer in seconds to minutes, and is definitive enough to eliminate the need for costly additional testing at an analytical reference laboratory. These tests have as additional advantages that the endpoints are dramatic and the reagents are commonly available. [R155] *Chlorinated benzenes have been found as contaminants in foods and water. Because of differences in the electron capture response of the isomers at each chlorination level, residue quantitation requires the separation of all 12 chlorobenzenes. Resolution studies were made on packed and capillary columns coated with Kovats' Ca87H176 hydrocarbon, OV-101, OV-210, OV-17 and Carbowax 20M. Satisfactory resolution of all 12 chlorobenzenes was obtained with a Carbowax 20M-coated column operated isothermally at 120 deg C. /Chlorinated benzenes/ [R156] *Air Samples: ... An air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. The adsorbent is desorbed with carbon tetrachloride and analyzed by GC using a photoionization detector. When using this method the minimum detection limits for mono-, di-, tri-, tetra-, and pentachlorobenzenes are 15, 20, 30, 35, and 45 ppb (v/v), respectively. /Chlorobenzenes/ [R157] *An intergrated analytical procedure for determining chlorinated benzene contaminants that enables quantitation of individual isomers as low as 0.4 ug/kg in sediment samples was developed. Preparation of the sample can be performed by using 1 of 3 techniques, namely, Soxhlet extraction, ultrasonic extraction, or steam distillation. Although all 3 methods are quantitative, the steam distillation method was found to be the most efficient for the determination, insofar as time and simplicity are concerned. Chlorinated benzenes were then characterized and quantified by open tubular column gas chromatography with electron capture detection. Detection limits of this method were 0.4-1.0 ug/kg of individual chlorobenzene isomers. Chlorobenzene recovery from bottom sediment samples at concentration levels between 1 and 100 ug/kg was 86 +/- 14 %. /Chlorinated benzenes/ [R158] CLAB: *The measurement of 2,5-dichlorophenol concn in urine provides a useful index of exposure to p-dichlorobenzene. ... 2,5-Dichlorophenol has been determined in urine by colorimetry, but this method is subject to interference by other phenolic substances. A more specific procedure is presented which involves gas chromatography with electron-capture detection. [R159] *DETERMINATION OF CHLOROBENZENES (INDUSTRIAL PRODUCTS) MONOCHLOROBENZENE THROUGH HEXACHLOROBENZENE @ PPB LEVELS IN HUMAN URINE AND BLOOD SAMPLES BY GAS CHROMATOGRAPHY WITH PHOTOIONIZATION DETECTION. /CHLOROBENZENES/ [R160] *A method was developed to analyze rat tissue, fat and blood for some chlorinated compounds found in an extract of soil from an industrial waste site. Extraction with hexane and ethyl ether-hexane (1 + 1) was followed by concentration over steam, and gas chromatographic analysis with an electron capture detector. Volatile compounds were analyzed in a glass column coated with 6% SP-2100 plus 4% OV-11 on Chromosorb W Semivolatile compounds, chlorinated compounds and pesticides were analyzed in a 70 m glass capillary column coated with 5% OV-101. Phenols were analyzed in a glass column packed with 1% SP-1240 DA on Supelcoport. The most efficient means of separation was to use the same glass column for volatile compounds, a DB-5 fused silica capillary column for semivolatile compounds, pesticides and phenols, and the same 1% SP-1240 DA glass column for separation of beta-BHC and pentachlorophenol. Recoveries ranged from 86.3 + or - 9.1% (mean + or - SD) to 105 + or - 10.4%. Sensitivities for semivolatile chlorinated compounds, pesticides and phenols were 4 ng/g for fat, 1 ng/g for tissue, and 0.2 ng/ml for blood. Sensitivities for volatile compounds were 4 fold higher (16, 4, 0.8, respectively). Sensitivities for dichlorobenzenes and dichlorotoluenes were 8 ng/g for fat, 2 ng/g for tissue and 0.4 ng/ml for blood. [R161] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes (1980) EPA 440/5-80-039 HAWKINS DR ET AL, XENOBIOTICA; 10 (2): 81 (1980). DISCUSSES DISTRIBUTION, EXCRETION, AND BIOTRANSFORMATION OF P-DICHLORO-(14)C-BENZENE IN RATS. USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes (1980) EPA 440/5-80-028 USEPA; Health Assessment Document: Chlorinated Benzenes (1985) EPA-600/8-84-015F Commission of the European Communities, p-Dichlorobenzene 16 pp (1986) Pub No. EUR 10531EN. Review of p-dichlorobenzene which indicates various names, formula, occurence, physical and chemical properties and other significant data. Chemical Review: 1,4-Dichlorobenzene. Dangerous Prop Ind Mater Rep 7 (4): 7-24 (1987). Review of the health hazard, safety health and handling, and toxicology of 1,4-dichlorobenzene. Reeves Rr, Pendaris RO; J Am Osteopath Assoc 85 (12): 806-8 (1985). A new method for the differentiation of naphthalene and para-dichlorobenzene mothballs. Canton JH et al; Resol Toxicol Pharmacol 5 (2): 123-31 (1985). Sixteen chlorine/nitrogen containing compounds were classified into black (ie substances which should be terminated as water pollutants) or gray (ie substances which should be decreased as water pollutants) list substances on the basis of acute toxicity, biodegradability, and accumulation. Dichlorobenzenes, Dangerous Prop Ind Mater Rpt 6 (2): 50-7 (1986). Review of dichlorobenzene toxicology, health hazards and safety measures. Brusick DJ; IARC Sci Pub 77: 393-7 (1986). Genotoxicity of hexachlorobenzene and other chlorinated benzenes. 51 FR 24657-67 (1986). Chlorinated benzenes, final test rule. USEPA; Drinking Water Criteria Doc: ortho-Dichlorobenzene, meta-Dichlorobenzene, para-Dichlorobenzene (Draft) 174p (1986). USA Environmental Protection Agency Drinking Water Criteria Document on o-, m- and p-dichlorobenzene. This criteria document is an extensive review of the following topics: Physical and chemical properties of o-, m- and p-dichlorobenzene. Toxicokinetics and human exposure to o-, m- and p-dichlorobenzene. Health effects of o-, m- and p-dichlorobenzene in humans and animals. Mechanisms of toxicity of o-, m- and p-dichlorobenzene. Quantification of toxicological effects of o-, m- and p-dichlorobenzene. 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USEPA/600/D-87/152 (1987) (4) Harkov R et al; J Air Pollut Control Assoc 33: 1177-83 (1983) (5) Morita M, Ohi G; Environ Pollut 8: 269-74 (1975) (6) Hendler AH, Crow WL; Proc Annu Meet Air Waste Manage Assoc 8th 92/75.05 pp. 17 (1992) (7) Kelly TJ et al; Ambient Concentration Summaries For Clean Air Act Title III Hazardous Air Pollutants. USEPA/600/R-94/090 (1993) R127: (1) Helmig D, Arey J; Sci total Environ 112: 233-50 (1992) (2) Helmig D et al; Chemosphere 19: 1399-1412 (1989) R128: (1) Wallace LA et al; Volatile Organic Chemicals in 10 Public Access Buildings. USEPA/600/D-87/152 (1987) (2) Kostiainen K; Atmos Environ 29: 693-702 (1995) (3) Bouhamra WS et al; Environ Intl 23: 197-204 (1997) (4) Heavner DL et al; Environ Intern 21: 3-21 (1995) (5) Crump DR; Issues Environ Sci Technol 4: 109-24 (1995) (6) Otson R, Fellin P; pp. 335-421 in Gas Pollut Charact Cycl. Nriagu JO ed. 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Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R142: 40 CFR 116.4 (7/1/87) R143: 40 CFR 401.15 (7/1/87) R144: 40 CFR 302.4 (7/1/97) R145: 40 CFR 712.30 (7/1/97) R146: 40 CFR 716.120 (7/1/97) R147: 40 CFR 261.33 (7/1/96) R148: 40 CFR 261.24 (7/1/97) R149: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.250 (Spring, 1998) EPA 738-R-98-002 R150: Ligocki MP, Pankow JF; Anal Chem 57 (6): 1138-44 (1985) R151: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 1003-1 R152: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. 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Rockville, MD: Government Institutes (1997) R155: Ambre J et al; Ann Emerg Med 15 (6): 724-6 (1986) R156: Miller LJ et al; J Assoc Off Anal Chem 66 (3): 677-83 (1983) R157: Langhorst ML, Nestrick TJ; Anal Chem 51 (12): 2018-25 (1979) as cited in USEPA; Health Assessment Document: Chlorinated Benzenes p.3-17 (1985) EPA 600/8-84-015F R158: Onuska FI, Terry KA; Anal Chem 57 (4): 801-5 (1985) R159: Baselt RC, Biological Monitoring Methods for Industrial Chemicals p. 109 (1980) R160: LANGHORST ML ET AL; ANAL CHEM 51 (12): 2018 (1979) R161: Stein VB, Narang RS; J Assoc Off Anal Chem 67 (1): 111-16 (1984) RS: 142 Record 65 of 1119 in HSDB (through 2003/06) AN: 531 UD: 200211 RD: Reviewed by SRP on 11/07/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-AMINOETHANOL- SY: *AETHANOLAMIN- (GERMAN); *2-AMINOAETHANOL- (GERMAN); *2-AMINOETANOLO- (ITALIAN); *AMINOETHANOL-; *BETA-AMINOETHANOL-; *2-AMINO-1-ETHANOL-; *BETA-AMINOETHYL-ALCOHOL-; *1-AMINO-2-HYDROXYETHANE-; *COLAMINE-; *ETANOLAMINA- (ITALIAN); *Ethanolamine-; *BETA-ETHANOLAMINE-; *ETHANOL,-2-AMINO-; *ETHYLOLAMINE-; *GLYCINOL-; *2-HYDROXYETHANAMINE-; *BETA-HYDROXYETHYLAMINE-; *2-HYDROXYETHYLAMINE-; *MEA-; *MEA- (ALCOHOL); *MONOAETHANOLAMIN- (GERMAN); *MONOETHANOLAMINE-; *OLAMINE-; *THIOFACO-M-50-; *USAF-EK-1597- RN: 141-43-5 MF: *C2-H7-N-O SHPN: UN 2491; MONOETHANOLAMINE IMO 8.0; MONOETHANOLAMINE MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD ON LARGE SCALE BY AMMONOLYSIS OF ETHYLENE OXIDE; ALSO FROM NITROMETHANE AND FORMALDEHYDE. [R1] FORM: *GRADES: TECHNICAL; NF /NATIONAL FORMULARY/ [R2] *Grades or Purity: NF; 85% (15% water); commercial; 99+% [R3] MFS: *DOW CHEM USA, MIDLAND, MICH [R4] *GLYCO CHEMS INC, GREENWICH, CONN [R4] *JEFFERSON CHEM CO, INC, HOUSTON, TEX [R4] *KOCH INDUST, INC, KOCH CHEM CO, SUBSID, ORANGE, TEX [R4] *OLIN CORP, DESIGNED PRODUCTS DIV, BRANDENBURG, KY [R4] *UNION CARBIDE CORP, CHEMS AND PLASTICS DIV, SEADRIFT, TEX [R4] USE: *CO2 AND HYDROGEN SULFIDE EXTRACTION FROM NATURAL GAS AND OTHER GASES; PHARMACEUTIC AID; DISPERSING AGENT FOR AGRICULTURAL CHEMICALS; SOFTENING AGENT FOR HIDES; USED IN ACCELERATOR IN MFR OF ANTIBIOTICS; FOR PRODN OF EMULSIFIERS; IN POLISHES, IN HAIR WAVING SOLN; IN SYNTH OF SURFACE ACTIVE AGENTS [R1] *CORROSION INHIBITOR; RUBBER ACCELERATOR [R2] *GAS CONDITIONING (SCRUBBING) AGENT IN PRODN OF AMMONIA AND IN OTHER APPLICATIONS; CHEM INT FOR FATTY ETHANOLAMINES [R4] *USED IN THE PREPARATION OF DIMETHYLOL DERIVATIVES OF TETRAHYDRO-5-ALKYL-S-TRIAZONE [R5] */ALKANOLAMINES/ ARE USED TO NEUTRALIZE FATTY ACIDS TO FORM SPECIALTY SOAPS: COSMETIC PREPARATIONS, SOLUBLE CUTTING OILS, USED IN TEXTILE PROCESSING, FURNITURE, FLOOR, AND AUTOMOBILE POLISHES AND EMULSION PAINTS [R6] CPAT: *APPROXIMATELY 49% IS USED FOR GAS CONDITIONING (SCRUBBING); ESTIMATED CONSUMPTION PATTERN FOR MONO-, DI-, AND TRIETHANOLAMINES TOGETHER IS 37% FOR SYNTHESIS OF SOAPS AND DETERGENTS FOR TEXTILES, TOILET GOODS, METALS, AND OTHER SPECIALTY SURFACTANT USES; 22% FOR GAS CONDITIONING AND PETROLEUM USE; 20% EXPORTED; 5% FOR SYNTHESIS OF MORPHOLINES; 16% FOR MISC APPLICATIONS INCLUDING EMULSION POLISHES AND HERBICIDES (1973) [R4] PRIE: U.S. PRODUCTION: *(1972) 3.7X10+10 G [R4] *(1975) 3.75X10+10 GRAMS [R4] *(1984) 198,274X10+3 LB [R7] *(1988) 2.2X10+8 LB [R8] U.S. IMPORTS: *(1972) 1.8X10+10 G [R4] U.S. EXPORTS: *(1972) 7.4X10+9 G [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *VISCOUS, CLEAR, HYDROSCOPIC FLUID [R9, p. II-105]; *VISCOUS LIQUID [R1]; +Colorless, viscous liquid or solid (below 51 degrees F) ... [R10, 128] ODOR: *UNPLEASANT, FISHY, AMMONIACAL [R11]; +... Unpleasant, ammonia-like odor. [R10, 128] BP: *170.8 DEG C @ 760 MM HG [R1] MP: *10.3 DEG C [R1] MW: *61.08 [R1] CTP: *Critical temp: 646 deg F= 341 deg C= 614 deg K; Critical pressure: 647 psi= 44 atm= 4.45 MN/sq m [R3] DEN: +1.0180 @ 20 DEG C/4 DEG C [R12, p. C-296] DSC: +PKA: 9.50; KA: 3.16X10-10 @ 25 DEG C [R12, p. D-161] HTC: *-10710 Btu/lb= -5950 cal/g= -249X10+5 J/kg [R3] HTV: *360 Btu/lb= 200 cal/g= 8.37X10+5 J/kg [R3] OWPC: +log Kow = -1.31 [R13] PH: *25% AQ SOLN: 12.1; 0.1 N AQ SOLN: 12.05 [R1] SOL: *MISCIBLE WITH WATER, METHANOL, ACETONE; SOLUBILITY IN BENZENE, 25 DEG C: 1.4%, IN ETHER: 2.1%, IN CARBON TETRACHLORIDE: 0.2%, IN N-HEPTANE: LESS THAN 0.1% [R1]; *MISCIBLE WITH CHLOROFORM, GLYCERIN; IMMISCIBLE WITH FIXED OILS, SOLVENT HEXANE [R14]; *SLIGHTLY SOL IN PETROLEUM ETHER [R15]; +water solubility = 1X10+6 mg/l [R16] SPEC: *INDEX OF REFRACTION: 1.4539 @ 20 DEG C/D [R1]; *IR: 123 (Sadtler Research Laboratories Prism Collection) [R17]; *UV: 2260 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) [R17]; *NMR: 9143 (Sadtler Research Laboratories Spectral Collection) [R17]; *MASS: 41 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R17] VAPD: +2.1 (AIR= 1) [R18] VAP: +0.404 mm Hg at 25 deg C [R19] VISC: *AT 25 DEG C, 18.95 CENTIPOISES; AT 60 DEG C, 5.03 CENTIPOISES [R1] OCPP: *1 GAL WEIGHS 8.45 LB (USA); ABSORBS CARBON DIOXIDE; HYGROSCOPIC LIQUID; DIPOLE MOMENT: 2.27 [R1] *DISSOLVES MANY ESSENTIAL OILS [R14] *DELIQUESCENT CRYSTALS FROM ALC, MP: 75-77 DEG C /HYDROCHLORIDE/ [R1] *Heat of Soln: (est) -17 Btu/lb= -10 cal/g= -0.4X10+5 J/kg [R3] *VAPOR PRESSURE: 0.4 MM HG @ 20 DEG C [R20] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Ethanolamine; Ethanolamine, solution; Monoethanolamine/ [R21] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R22, p. 325-] +Flammability: 2. 2= Liquids which must be moderately heated before ignition will occur and solids that readily give off flammable vapors. Water spray may be used to extinguish the fire because the material can be cooled to below its flash point. [R22, p. 325-47] +Reactivity: 0. 0= Materials which are normally stable even under fire exposure conditions, and which are not reactive with water. Normal fire fighting procedures may be used. [R22, p. 325-47] FLMT: +lower: 3.0%; upper: 23.5% (by volume) @ 140 deg C [R22, p. 325-47] FLPT: +186 DEG F (86 DEG C) (CLOSED CUP) [R22, p. 325-47] AUTO: +770 DEG F (410 DEG C) [R22, p. 325-47] FIRP: +USE WATER SPRAY, DRY CHEMICAL "ALCOHOL RESISTANT" FOAM OR CARBON DIOXIDE. USE WATER TO KEEP FIRE-EXPOSED CONTAINERS COOL. [R22, p. 49-63] +/IN FIRE CONDITIONS/ WEAR SPECIAL PROTECTIVE CLOTHING AND POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. [R22, p. 49-63] EXPL: +INCR IN TEMP AND PRESSURE OCCURRED WHEN EACH OF THE FOLLOWING CHEM WAS MIXED WITH 2-AMINOETHANOL IN A CLOSED CONTAINER: ACETIC ACID, ACETIC ANHYDRIDE, ACROLEIN, ACRYLIC ACID, ACRYLONITRILE, CHLOROSULFONIC ACID, EPICHLOROHYDRIN, HYDROCHLORIC ACID, HYDROFLUORIC ACID, MESITYL OXIDE, NITRIC ACID, OLEUM, PROPIOLACTONE (BETA-). INCR IN TEMP AND PRESSURE OCCURRED WHEN EACH OF THE FOLLOWING CHEM WAS MIXED WITH 2-AMINOETHANOL IN A CLOSED CONTAINER: SULFURIC ACID, VINYL ACETATE. [R22, p. 491-17] *5.5-17% [R23] REAC: +Strong oxidizers, strong acids, iron [Note: May attack copper, brass, and rubber]. [R10, 128] ODRT: *Water odor threshold: 20000 mg/l @ pKa of 9.5. Air odor threshold: 2.6 ppm. Odor Safety Class: C. C= Odor safety factor from 1-26. Less than 50% of distracted persons perceive warning of TLV. [R24] SERI: +IRRITATING TO SKIN, EYES AND RESPIRATORY SYSTEM. [R22, p. 49-63] EQUP: *Full face shield; goggles; eye wash facility. [R3] +WEAR SPECIAL PROTECTIVE CLOTHING AND POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. [R22, p. 49-63] +Wear appropriate personal protective clothing to prevent skin contact. [R10, 129] +Wear appropriate eye protection to prevent eye contact. [R10, 129] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R10, 129] +Recommendations for respirator selection. Max concn for use: 30 ppm. Respirator Class(es): Any chemical cartridge respirator with cartridge(s) providing protection against the compound of concern. May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Any powered, air-purifying respirator with cartridge(s) providing protection against the compound of concern. May require eye protection. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R10, 129] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R10, 129] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Any appropriate escape-type, self-contained breathing apparatus. [R10, 129] OPRM: *Vapor hazard index (VHI) is defined as concn of saturated vapor divided by TLV multiplied by 1000. The dimension of the VHI is temp dependent and is an indication of vapor hazard potential. VHI number= 0.4 at 20 deg C. [R25] +Contact lenses should not be worn when working with this chemical. [R10, 129] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. +The worker should immediately wash the skin when it becomes contaminated. [R10, 129] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R10, 129] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R10, 129] SSL: *AFFECTED BY LIGHT [R14] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R26] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R27] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R28] STRG: +SEPARATE FROM OXIDIZING MATERIALS, ACIDS, AND HALOGENS. STORE IN A COOL, DRY, WELL-VENTILATED LOCATION. [R22, p. 49-63] CLUP: *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. If in liquid form, for small quantities, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be reclaimed or collected and atomized in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. 4. If in solid form, allow to melt and follow (3) above. [R29] DISP: *1. By absorbing it in vermiculite, dry sand, earth or a similar material and disposing in a secured sanitary landfill. 2. By atomizing in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. [R29] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *... WHEN UNDILUTED MONOETHANOLAMINE IS APPLIED TO HUMAN SKIN ON GAUZE FOR 1 1/2 HR, ONLY MARKED REDNESS AND INFILTRATION OF THE SKIN RESULT. [R30, 3168] +CAUSES SEVERE EYE AND SKIN BURNS. MAY BE HARMFUL IF ABSORBED THROUGH SKIN OR INHALED. IRRITATING TO SKIN, EYES, RESPIRATORY SYSTEM. [R22, p. 49-63] *USUALLY PRESENT AS A NEUTRAL SALT OF ANY ONE OF MANY ACIDS AND AS SUCH THE MONOETHANOLAMINE CATION IS BELIEVED NOT TO BE SIGNIFICANTLY TOXIC ... . [R9, p. II-106] *It is shown that monoethanolamine and triethanolamine are weak inducers of chromosome breaks in cultures of human lymphocytes. [R31] NTOX: *... FOUND THAT IV INJECTIONS ... IN DOGS RESULTED IN INCREASED BLOOD PRESSURE, DIURESIS, SALIVATION, AND PUPILLARY DILATION. ... LARGER DOSES PRODUCED SEDATION, COMA, AND DEATH FOLLOWING DEPRESSION OF BLOOD PRESSURE AND CARDIAC COLLAPSE. [R30, 3167] *RATS, RABBITS, AND MICE WERE LESS SUSCEPTIBLE THAN GUINEA PIGS BUT MORE SUSCEPTIBLE THAN CATS OR DOGS. 60 OF 61 ANIMALS SURVIVED EXPOSURE TO INHALATION OF CONCN OF 0.26 TO 0.27 MG/L FOR 7 HR ON EACH OF 5 CONSECUTIVE DAYS AND 25 OF 26 ANIMALS SURVIVED 25 7 HR EXPOSURES (... 5 WEEKS) TO CONCN OF 0.26 MG/L. ... REPORTS THAT DOGS, RATS, AND GUINEA PIGS SURVIVED INHALATION OF 12 TO 25 PPM FOR 90 DAYS, WHEREAS FRACTIONAL MORTALITY OCCURRED IN 24 TO 30 DAYS AT 100 PPM (DOGS) AND 66 TO 75 PPM (RODENTS). SKIN IRRITATION AND LETHARGY OCCURRED AT 5 AND 12 PPM. [R30, 3168] *... IN A 90 DAY SUBACUTE ORAL TOXICITY STUDY IN RATS: MAX DAILY DOSE WITH NO EFFECT, 0.32 G/KG ... DOSE AT WHICH ALTERED LIVER OR KIDNEY WT WAS SEEN, 0.64 G/KG; DOSE AT WHICH MICROSCOPIC PATHOLOGICAL CHANGES AND DEATHS APPEARED, 1.28 G/KG. [R30, 3168] *... IN ANESTHETIZED DOGS ... ETHANOLAMINE /FOUND/ TO BE A CENTRAL NERVOUS SYSTEM STIMULANT AT LOW DOSES AND A CENTRAL NERVOUS SYSTEM DEPRESSANT AT LETHAL DOSES. [R32] */ANIMALS/ ... EXPOSED ... CONTINUOUSLY TO VAPOR FOR 24 HR A DAY, 7 DAYS A WK, FOR FROM 24 TO 90 DAYS (EXCEPT ... 15 MIN EACH DAY) ... DOGS EXPOSED 30 DAYS AT 100 PPM WERE APATHETIC AND HAD POOR APPETITES. RATS AND GUINEA PIGS WERE SIMILARLY AFFECTED. ALL SPECIES EXPERIENCED DERMAL EFFECTS, VARYING FROM ULCERATION TO HAIR LOSS ... . [R32] *... EXPOSED LABORATORY ANIMALS TO ETHANOLAMINE VAPOR AND TO MIST. RATS, MICE, RABBITS, AND GUINEA PIGS EXPOSED @ HIGH CONCENTRATIONS DEVELOPED PULMONARY, HEPATIC, AND RENAL LESIONS. ... FOUND NO DIFFERENCE IN MORTALITY AS A RESULT OF PHYSICAL STATE OF THE AIR-BORNE CMPD, IE VAPOR OR MIST. [R32] *DROP OF ETHANOLAMINE APPLIED TO RABBIT EYES CAUSES INJURY SIMILAR TO THAT CAUSED BY AMMONIA, BUT SLIGHTLY LESS SEVERE, GRADED 9 ON A SCALE OF 10. [R11] *Monoethanolamine was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Monoethanolamine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.010, 0.033, 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. [R33] *The embryopathic effects of high doses of ethanolamine were evaluated in pregnant Long-Evans rats during oranogenesis. Ethanolamine was given by gavage at levels of 0, 500, 300, or 50 mg/kg/day (24%, 14.4%, or 2.4% of the LD50 value). Ethanolamine caused dose-dependent increases in intrauterine deaths, malformations, and intrauterine growth retardation. Embryolethality caused by 500 mg/kg of ethanolamine was not random: male pups contiguous to two male siblings (designated mMm) were almost quantitatively replaced by resorptions that were contiguous to two male pups (designated mRm) (mMm pups constituted 6.7% of control implants and decreased to only 0.9% of group II implants while mRm resorptions increased from 0.3% in controls to 5.6% in group II dams). Intrauterine growth retardation and increases in gross structural anomalies (considered indicative of depressed fetal growth) more severely affected male than female offspring at all dose levels. Pups of either sex who were contiguous to male siblings were more adversely affected than those offspring contiguous to one or more female siblings. [R34] *It is shown that monoethanolamine and triethanolamine are weak inducers of chromosome breaks in Crepis capillaris seeds, and induce low levels of gene mutations in the Ames systems. [R31] ADE: *... IN /LEAD/ INDUSTRY ... THE EXCRETION RATE IN MEN VARIES BETWEEN 4.8 AND 22.9 MG/DAY WITH A MEAN OF 0.162 MG/KG /BODY WEIGHT/. ELEVEN WOMEN WERE OBSERVED TO EXCRETE LARGER AMT, VARYING BETWEEN 7.7 and 34.9 MG/DAY ... MEAN EXCRETION RATE OF 0.492 MG/KG/DAY. THE EXCRETION RATES IN ANIMALS WERE, APPROX, FOR CATS, 0.47 MG/KG/DAY; RATS, 1.46 MG/KG/DAY; RABBITS, 1.0 MG/KG/DAY. FROM 6 TO 47 PERCENT OF MONOETHANOLAMINE ADMIN TO RATS MAY BE RECOVERED IN THE URINE. [R30, 3168] *PERSISTENCE OF LOW LEVELS OF RADIOACTIVITY IN DOG WHOLE BLOOD WAS OBTAINED AFTER ADMIN OF (14)C-LABELED ETHANOLAMINE. EXCRETION OF RADIOACTIVITY AS % OF DOSE IN DOG URINE WAS 11. AFTER 24 HR TOTAL BLOOD RADIOACTIVITY AS % OF DOSE WAS 1.69. [R35] METB: *ETHANOLAMINE IS NATURALLY FORMED IN MAMMALS FROM SERINE AND IS A NORMAL CONSTITUENT OF MAMMALIAN URINE. FORTY PERCENT OF (15)N-LABELED ETHANOLAMINE APPEARS AS UREA WITHIN 24 HR WHEN GIVEN TO RABBITS, SUGGESTING THAT IT IS DEAMINATED. IT IS ALSO METHYLATED TO CHOLINE AND CONVERTED TO SERINE AND GLYCINE. MONOMETHYLAMINOETHANOL AND DIMETHYLAMINOETHANOL ARE INTERMEDIATES IN THE CONVERSION TO CHOLINE. [R30, 3165] *ETHANOLAMINE (MONOETHANOLAMINE) IS A NORMAL INTERMEDIATE IN THE METABOLISM OF SOME ANIMAL SPECIES, HAVING A PART IN THE FORMATION OF PHOSPHOLIPIDS ... . [R32] *The distribution and metabolism of topical (14)C ethanolamine was studied in vivo, using athymic nude mice, human skin grafted onto athymic nude mice, and in vitro, using excised pig skin. Ethanolamine was the only radioactive phospholipid base detected in the human skin grafts, in the mouse skin, and in the pig skin. Ethanolamine that penetrated human skin grafts or mouse skin was extensively metabolized in the animal. The liver is a major site for metabolism of ethanolamine, containing over 24% of the applied radioactive dose. The kidneys, lungs, brain, and the heart contained 2.53, 0.55, 0.27, and 0.15% of the dose, respectively. Hepatic, human skin graft, and mouse skin proteins were also highly radioactive. Over 18% of the topical radioactive dose oxidized to (14)CO2 and 4.6% was excreted in the urine over 24 hr. Urea, glycine, serine, choline, and uric acid were the urinary metabolites of ethanolamine. [R36] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Aminoethanol (MEA) may be released to the environment in emissions or effluents from sites of its manufacture or use, in urine, from disposal of consumer products containing this compound (i.e. cleaning products), and use of agricultural chemicals in which this compound is used as a dispersing agent. In soil and water, MEA is expected to biodegrade fairly rapidly following acclimation (half-life on the order of days to weeks). In soil, residual MEA may leach into groundwater. In the atmosphere, MEA is expected to exist almost entirely in the vapor phase. The dominant removal mechanism is expected to be reaction with photochemically generated hydroxyl radicals (half-life 4 hours). This compound may also be removed from the atmosphere in precipitation. The most probable route of exposure to MEA is dermal contact with personal care products (i.e. soaps, hair waving solutions), detergents, and other surfactants containing this compound. (SRC) NATS: *Normal metabolic intermediate in some animals species, having a part in the formation of phospholipids and choline(1). Constituent of urine(1). [R37] ARTS: *2-Aminoethanol may be released to the environment in emissions or effluents from sites of its manufacture or industrial use, from disposal of consumer products which contain this compound, and from application of agricultural chemicals in which this compound is used as a dispersing agent(1,2,SRC). [R38] FATE: *TERRESTRIAL FATE: If released to soil, 2-aminoethanol (MEA) is expected to biodegrade fairly rapidly following acclimation (half-life on the order of days to weeks). MEA is expected to leach in soil. Volatilization from soil surfaces is not expected to be an important fate process. (SRC) *AQUATIC FATE: If released to water, 2-aminoethanol should undergo biodegradation. The half-life of this compound is expected to range from a few days to a few weeks depending, in large part, on the degree of acclimation of the system. Bioconcentration in aquatic organisms, adsorption to suspended solids and sediments, and volatilization are not expected to be important fate processes in water. (SRC) *ATMOSPHERIC FATE: Based on a vapor pressure of 0.26 mm Hg at 25 deg C(1), 2-aminoethanol (MEA) is expected to exist almost entirely in the vapor phase in the atmosphere(2,SRC). The dominant removal mechanism is expected to be reaction with photochemically generated hydroxyl radicals (half-life 4 hours). The complete solubility of MEA in water suggests that this compound may also be removed from the atmosphere in precipitation(SRC). [R39] BIOD: *Biological Oxygen Demand (BOD): 78%, 5 days; (theor) 0%, 5 days; 64%, 20 days [R3] *Monoethanolamine contained in wastewater from the ethylene manufacturing process is not toxic to aquatic microorganisms participating in biol wastewater treatment, and selfpurification of reservoirs when in concn of 200, 300, 50, and 20 mg/L for protozoans, saprophyte bacteria, first phase nitrification bacteria, and second phase nitrification bacteria, respectively. [R40] *BOD water - electrolytic respirometer, initial concn 100 ppm, 5 day 50% Theoretical Biochemical Oxygen Demand, sewage inoculum(1,2). BOD water, initial concn 10 ppm, 5 day - 34% Theoretical Biochemical Oxygen Demand, 20 day - 40% Theoretical Biochemical Oxygen Demand, sewage inoculum(3). BOD water, initial concn 2.5 ppm, 5 day 61-84% Theoretical Biochemical Oxygen Demand, sewage inoculum(4). BOD water, 10 day 65% Theoretical Biochemical Oxygen Demand, sewage inoculum(5). BOD water, initial concn 2.5 ppm, 5, 10, 20, and 50 days - 0, 58.4, 64.0, and 75.0% Theoretical Biochemical Oxygen Demand, respectively, sewage inoculum(6). BOD water, 5 day 71% Theoretical Biochemical Oxygen Demand, and 98% COD removal, sewage inoculum(7). Japanese Ministry of International Trade and Industry (MITI), initial concn 100 ppm, 14 days 49.2% Theoretical Biochemical Oxygen Demand (nitrogen dioxide endproduct) and 93.6% Theoretical Biochemical Oxygen Demand (ammonia endproduct), activated sludge inoculum(8). [R41] ABIO: *The half-life for 2- aminoethanol vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 11 hours based on an estimated reaction rate constant of 3.5X10-11 cu cm/molecules-sec at 25 deg C and an average ambient hydroxyl concentration of 5X10+5 molecules/cu cm(1,SRC). [R42] BIOC: *A bioconcentration factor (BCF) of < 1 was estimated for 2-aminoethanol (MEA) based on a log Kow of -1.31(1,2,SRC). This BCF value and complete solubility of MEA in water suggest that this compound does not bioconcentrate significantly in aquatic organisms(3 SRC). [R43] KOC: *A soil adsorption coefficient (Koc) of 5 was estimated for 2- aminoethanol (MEA) based on a log Kow of -1.31(1,2,SRC). This Koc value and the complete solubility of MEA in water suggests that this compound would be extremely mobile in soil and would not adsorb appreciably to suspended solids and sediments in water(3,4,SRC). [R44] VWS: *Henry's Law Constant= 4X10-8 atm-cu m/mol at 25 deg C (est) [R45] PFAC: PLANT CONCENTRATIONS: *Identified in marine and freshwater algae(1). [R46] RTEX: *The most probable route of exposure to 2-aminoethanol (MEA) is dermal contact with personal care products (i.e. soaps, hair waving solutions), detergents, and other surfactants in which this compound is an ingredient(1,2,SRC). [R47] *NIOSH (NOES Survey 1972- 1974) has statistically estimated that 1,754,175 workers are potentially exposed to 2-aminoethanol (MEA) in the USA(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 57,513 workers are potentially exposed to MEA in the USA(2). However, this figure does not include exposure to tradename products which contain MEA. [R48] BODY: *2-Aminoethanol (MEA) is a normal constituent of human urine. Average excretion rate: men - 0.162 mg/kg per day; women - 0.492 mg/kg per day; cats 0.47 mg/kg per day; rats - 01.46 mg/kg per day; and rabbits - 1.0 mg/kg per day(1). [R49] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +30 ppm [R10, 128] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 3 ppm (6 mg/cu m). [R50] +Vacated 1989 OSHA PEL TWA 3 ppm (8 mg/cu m); STEL 6 ppm (15 mg/cu m) is still enforced in some states. [R10, 364] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 3 ppm (8 mg/cu m). [R10, 128] +Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 6 ppm (15 mg/cu m). [R10, 128] TLV: +8 hr Time Weighted Avg (TWA): 3 ppm; 15 min Short Term Exposure Limit (STEL): 6 ppm. [R51] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethanolamines are produced, as an intermediate or a final product, by process units covered under this subpart. /Ethanolamines/ [R52] FIFR: *Active Ingredients with Recent Production Pending Cancellation of all Products for Non-payment of 1990 Registration Fees: Ethanolamine (CAS 141-43-5). Use: disinfectant/antimicrobial uses. Year last produced: 1989. Registration N. 058018-00001. Product Name: Pro Way Brand Realclean Spray Concentrate. /From Table 2/ [R53] FDA: *Ethanolamine is an indirect food additive for use only as a component of adhesives. [R54] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A PROCEDURE IS DESCRIBED FOR PERSONNEL OR AREA MONITORING OF ETHANOLAMINE IN AIR. ALKANOLAMINES ARE COLLECTED FROM AIR ON AL2O3 /ALUMINUM TRIOXIDE/ SAMPLING TUBES AND DESORBED WITH AQ 1-OCTANESULFONIC ACID. WATER IS REMOVED VIA LYOPHILIZATION AND THE RESULTING SALTS ARE DERIVATIZED WITH 1-(HEPTAFLUOROBUTYRYL)IMIDAZOLE. [R55] *NIOSH Method 3509. Analyte: 2-Aminoethanol. Matrix: Air. Sampler: Impinger (15 ml 2mM hexanesulfonic acid). Flow Rate: 0.5 to 1 l/min: Sample Size: 100 liter. Shipment: Routine. Sample Stability: Stable at least 3 weeks @ 20 deg C. [R56, p. 3509-1] *NIOSH Method 2007. Analyte: 2-Aminoethanol. Matrix: Air. Sampler: Solid sorbent tube (silica gel, 300 mg/150 mg). Flow Rate: 0.01 to 0.2 l/min: Sample Size: 20 liter. Shipment: Routine. Sample Stability: At least 4 weeks @ 25 deg C. [R56, p. 2007-1] ALAB: *NIOSH Method 2007. Analyte: 2-Aminoethanol. Matrix: Air. Procedure: Gas chromatography, flame ionization detector. For 2-aminoethanol this method has an estimated detection limit of 0.005 mg/sample. The precision/RSD is 0.026 @ 0.6 to 2.7 mg/sample and the recovery is not given. Applicability: The working range is 5 to 300 mg/cu m for each cmpd in a 20 liter air sample. Interferences: None identified. [R56, p. 2007-1] *NIOSH Method 3509. Analyte: 2-Aminoethanol. Matrix: Air. Procedure: Ion chromatography, ion pairing. For 2-aminoethanol this method has an estimated detection limit of 7 to 20 ug/sample. The precision/RSD is 0.028 and the recovery is not given. Applicability: The working range is 0.08 to 12 ppm (0.2 to 30 mg/cu m) for a 100 l sample. Interferences: Large amines do not interfere. [R56, p. 3509-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Beyer KH Jr et al; Final Report on the Safety Assessment of Triethanolamine, Diethanolamine, and Monoethanolamine; J Am Coll Toxicol 2 (7): 183-235 (1983). A review with 245 references of oral and dermal toxicity, skin irritation, mutagenicity, carcinogenicity, sensitization, phototoxicity and photosensitization data on monoethanolamine. DHHS/NIOSH; Screening of Priority Chemicals for Reproductive Hazards. Monoethanolamine (CAS No. 141-43-5) (1987), NTIS PB89-139067 SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 588 R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 474 R3: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R4: SRI R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 457 (1978) R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V21 179 (1983) R7: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.254 R8: United States International Trade Commission. Synthetic Organic Chemicals- United States Production and Sales, 1988. USITC Publication 1989. Washington, DC: United States International Trade Commission, 1989.p. 15-3 R9: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R11: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 410 R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979. R13: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 5 R14: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1256 R15: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. C-296 R16: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. R17: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 610 R18: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 2065 R19: SRC; Dow Chemical; The Alkanolamine Handbook Midland, MI: Dow Chemical (1980) R20: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 603 R21: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R22: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R23: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 141 R24: Amoore JE, Hautala E; J Appl Toxicol 3 (6): 272-90 (1983) R25: Pitt MJ; Chem Ind (London) (20): 804-6 (1982) R26: 49 CFR 171.2 (7/1/96) R27: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 146 R28: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.8161 (1988) R29: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R30: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R31: Arutiunian RM et al; Tsitol Genet 21 (6): 450-4 (1987) R32: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.235 R33: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R34: Mankes RF; Teratogenesis Carcinog Mutagen 6 (5): 403-17 (1986) R35: RHODES C, CASE DE; XENOBIOTICA 7 (1-2): 112 (1977) R36: Klain GJ et al; Fundam Appl Toxicol 5 (6 Pt 2): S127-33 (1985) R37: (1) Am Conf Ind Hyg; Appendix: Documentation of the Threshold Limit Values and Biological Exposure Indices 5th ed p. 235 Cincinnati, OH (1986) R38: (1) Liepins R et al; Industrial Process Profiles for Environmental Use. USEPA-600/2-77-023f NTIS PB-281 478 pp. 6-386-6-387 (1977) (2) Hawley GG; The Condensed Chemical Dictionary 10th ed NY: Van Nostrand Reinhold p. 420 (1981) R39: (1) Dow Chemical; The Alkanolamine Handbook Midland, MI: Dow Chemical (1980) (2) Eisenreich SJ et al; Environ Sci Tech 15: 30-8 (1981) R40: Lakhina KG et al; Neftepererab Neftekhim (Moscow) (7): 56-7 (1981) R41: (1) Urano K, Kato Z; J Hazard Mater 13: 135-45 (1986) (2) Urano K, Kato Z; J Hazard Mater 13: 147-59 (1986) (3) Young RHF et al; J Water Pollut Contr Fed 40: 354-68 (1968) (4) Heukulekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) (5) Mills EJ, Stack VT; Proc 8th Ind Waste Conf Eng Bull Purdue Univ: Ext Ser 83: 492-517 (1954) (6) Lamb CB, Jenkins GF; pp 326-39 in Proc 8th Ind Waste Conf Purdue Univ (1952) (7) Bridie AL et al; Water Res 13: 627- 30 (1979) (8) Kitano M; OECD Tokyo Meeting Reference Book Tsu-No. 3 (1978) R42: (1) Atkinson R; Inter J Chem Kinet 19: 799-828 (1987) R43: (1) Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; p. 5-5 in Handbook of Chemical Property Estimation Methods NY: McGraw-Hill (1982) (3) Dow Chemical; The Alkanolamines Handbook Midland, MI: Dow Chemical (1980) R44: (1) Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; p. 4-9 in Handbook of Chemical Property Estimation Methods NY: McGraw-Hill (1982) (3) Dow Chemical; The Alkanolamines Handbook Midland, MI: Dow Chemical (1980) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R45: SRC; Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) R46: (1) Kneifel H et al; J Phycol 13: 36 (1977) R47: (1) Hawley GG; The Condensed Chemical Dictionary 10th ed NY: Van Nostrand Reinhold p. 420 (1981) (2) Chemical Marketing Reporter; Chemical Profile: Ethanolamine NY: Schnell Publishing Nov 10 (1986) R48: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1974) R49: (1) Clayton GD, Clayton FE; p. 3168 in Patty's Industrial Hygiene and Toxicology 3rd ed Vol 2B NY: Wiley-Interscience (1981) R50: 29 CFR 1910.1000 (7/1/98) R51: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.31 R52: 40 CFR 60.489 (7/1/91) R53: 56 FR 4994 (2/7/91) R54: 21 CFR 175.105 (4/1/91) R55: LANGVARDT PW, MELCHER RG; ANAL CHEM 52 (4): 669-71 (1980) R56: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. RS: 41 Record 66 of 1119 in HSDB (through 2003/06) AN: 533 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYL-CHLORIDE- SY: *AETHYLCHLORIDE- (GERMAN); *AETHYLIS-CHLORIDUM-; *AI3-24474-; *ANODYNON-; *CHELEN-; *CHLOORETHAAN- (DUTCH); *CHLORENE-; *CHLORETHYL-; *CHLOROAETHAN- (GERMAN); *CHLOROETHANE-; *CHLORURE-D'ETHYLE- (FRENCH); *CHLORYL-; *CHLORYL-ANESTHETIC-; *CLORETILO-; *CLOROETANO- (ITALIAN); *CLORURO-DI-ETILE- (ITALIAN); *DUBLOFIX-; *ETHANE,-CHLORO-; *ETHER-CHLORATUS-; *ETHER-HYDROCHLORIC-; *ETHER-MURIATIC-; *ETYLU-CHLOREK- (POLISH); *KELENE-; *MONOCHLORETHANE-; *MONOCHLOROETHANE-; *MURIATIC-ETHER-; *NARCOTILE-; *NCI-CO6224- RN: 75-00-3 MF: *C2-H5-Cl SHPN: UN 1037; Ethyl chloride (Cylinders and ampoules in boxes) IMO 2.1; Ethyl Chloride STCC: 49 081 62; Ethyl Chloride MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by the action of chlorine on ethylene in the presence of hydrochloric acid and light; by action of chlorine on ethylene in presence of chlorides of copper, iron, antimony, and calcium; by heating alcohol, hydrochloric acid and zinc chloride. [R1] *THERMAL CHLORINATION OF ETHANE. [R2] *By-product of vinyl chloride production or direct reduction of vinyl chloride; hydrochlorination of ethylene. [R3] IMP: *If prepared from industrial methylated spirit it contains a small variable proportion of methyl chloride. [R4, 748] FORM: *Grades: Technical; USP [R5] *High purity (99.7%, liquid phase) grade. [R6] *Matheson Gas Products 99.7% minimum grade. [R6] *CP grade, minimum purity 99.7%. [R6] MFS: *Dow Chemical USA, Hq, 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 [R3] *PPG Industries, Inc, Hq, One PPG Place, Pittsburgh, PA 15272, (412) 434-3131; Chemicals Group; Production site: Lake Charles, LA 70602 [R3] OMIN: *ETHYL CHLORIDE IS COMMERCIALLY AVAILABLE IN METAL TUBES WITH VALVE CLOSURES OR IN GLASS BOTTLES WITH SPRING RELEASE CLOSURES. THESE CONTAINERS HAVE VARIOUS SIZE NOZZLE OPENINGS FOR REGULATION OF SPRAY. [R7] *DOW USES MATERIAL CAPTIVELY FOR ETHYL CELLULOSE PRODUCTION AND SELLS MATERIAL; HERCULES MAINTAINS A FACILITY FOR ETHYL CHLORIDE MANUFACTURE. [R2] *IN 1982: STAUFFER IDLED ITS LONG BEACH, CA PLANT; ETHYL CORP PLACED ITS BATON ROUGE, LA PLANT ON STANDBY. [R2] *THE EPA PHASEDOWN OF ALKYL LEAD COMPOUNDS IN GASOLINE CAUSED A STEADY DECLINE IN THE USE OF ETHYL CHLORIDE. [R2] USE: *CHEMICAL INTERMEDIATE [R8] *Refrigerant, solvent, alkylating agent, starting point in the mfr of tetraethyl lead, topical anesthetic [R1] *MEDICATION (VET) *MEDICATION *IN SYNTHESIS OF ETHYL COMPOUNDS [R9] *Manufacture of tetraethyl lead and ethylcellulose; organic synthesis; alkylating agent; refrigeration; analytical reagent; solvent for waxes; insecticides [R5] *Use in organic synthesis of perchloroethane, esters, and Grignard reagents. [R10, 1981.3] *Use in manufacture of dyes and drugs, use as a propellant in aerosols. [R10, 1981.3] *Use in manufacture of perfumes. [R10, 1981.3] CPAT: *90% FOR TETRAETHYL LEAD; 10% FOR MISC APPLICATIONS INCLUDING USE AS A SOLVENT, A REFRIGERANT, AND IN THE MANUFACTURE OF ETHYL CELLULOSE PLASTICS, DYES, AND PHARMACEUTICALS (1972) [R8] *(1984) 80% TETRAETHYL LEAD; 15% ETHYL CELLULOSE; 5% MISC (EST) [R2] PRIE: U.S. PRODUCTION: *(1972) 2.61X10+11 G [R8] *(1975) 2.61X10+11 GRAMS [R8] *(1984) 1.32X10+11 g [R11] *(1988) 1.51X10+8 lbs [R12] U.S. IMPORTS: *(1972) NEGLIGIBLE [R8] *(1975) 2.23X10+6 GRAMS [R8] U.S. EXPORTS: *(1972) NEGLIGIBLE [R8] *(1975) LESS THAN 5.22X10+10 GRAMS (EST) [R8] *(1984) 9.13X10+9 g [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R14]; *Colorless gas or liquid (below 54 degrees F) ... [Note: Shipped as a liquefied compressed gas]. [R15, 134] ODOR: *Ethereal odor [R1]; *Pungent [R14]; *... Pungent, ether-like odor ... [R15, 134] TAST: *Burning taste [R1] BP: *12.3 deg C @ 760 mm Hg [R1] MP: *-138.7 deg C [R1] MW: *64.51 [R1] CORR: *Reacts with water or steam to produce corrosive fumes. [R16] *Liquid ethyl chloride will attack some forms of plastics, rubber, and coatings. [R10, 1981.2] CTP: *Critical temperature: 187 deg C; critical pressure: 52 atm [R1] DEN: *0.9214 @ 0 deg C/4 deg C [R1] HTC: *-316.7 kg cal/g mol wt at 20 deg C (vapor) [R17, p. D-274] HTV: *6,310.6 g cal/g mole [R17, p. C-671] OWPC: *log Kow= 1.43 [R18] SOL: *0.574 g/100 ml in water @ 20 deg C [R1]; *48.3 g/100 ml in alc [R1]; *0.447 g/100 g water at 0 deg C [R19]; *Solubility: 0.07 g water/100 g ethyl chloride at 0 deg C; 103 g acetone/100 g ethyl chloride at 25 deg C; 110 g benzene/100 g ethyl chloride at 25 deg C; 87 g n-heptane/100 g ethyl chloride at 25 deg C; 48 g ethanol/100 g ethyl chloride at 21 deg C; 37 g methanol/100 g ethyl chloride at 25 deg C; 0.6 G water/100 g ethyl chloride at 20 deg C [R19]; *Miscible with ether [R1]; *Water solubility = 5.68X10+3 mg/l @ 20 deg C [R20] SPEC: *INDEX OF REFRACTION: 1.3676 @ 20 DEG C/D [R21]; *Index of refraction: 1.001 @ 25 deg C/D [R19]; *IR: 533 (Sadtler Research Laboratories Prism Collection) [R22]; *NMR: 11 (Varian Associates NMR Spectra Catalogue) [R22]; *MASS: 45 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R22] SURF: *19.5 dynes/cm at 20 deg C [R23] VAPD: *2.22 (Air= 1.00) [R1] VAP: *1010 mm Hg at 20 deg C [R24] EVAP: *Much higher than 1 (butyl acetate= 1). [R10, 1981.2] VISC: *0.279 cP at 10 deg C [R19] OCPP: *1 mg/l air= 379 ppm @ 25 deg C, 760 mm Hg; 1 ppm= 2.64 mg/cu m air @ 25 deg C, 760 mm Hg [R25, 4082] *Liquid water interfacial tension: (est) 40 dynes/cm at 0 deg C [R23] *Ratio of specific heats of vapor: 1.155 [R23] *Heat of fusion: 16.49 cal/g [R23] *Liquid heat capacity= 0.392 Btu/lb/degree F @ 50 deg C [R23] *Liquid thermal conductivity= 0.861 Btu-in/hr-sq ft/per degree F at 50 deg C [R23] *Saturated vapor pressure= 22.400 lb/sq in @ 75 deg C [R23] *Saturated vapor density= 0.25180 lb/cu ft @ 75 deg C [R23] *Ideal gas heat capacity= 0.231 Btu/lb ft @ 75 deg F [R23] *Burns with a smoky, greenish flame ... . [R1] *Henry's Law constant = 1.11X10-2 atm-cu m/mol @ 24 deg C [R26] *Hydroxyl radical rate constant= 4.11X10-13 cu cm/molecule-sec @ 25 deg C [R27] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: EXTREMELY FLAMMABLE. Will be easily ignited by heat, sparks or flames. Will form explosive mixtures with air. Vapors from liquefied gas are initially heavier than air and spread along ground. Vapors may travel to source of ignition and flash back. Containers may explode when heated. Ruptured cylinders may rocket. [R28] +Health: Vapors may cause dizziness or asphyxiation without warning. Some may be irritating if inhaled at high concentrations. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Fire may produce irritating and/or toxic gases. [R28] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. [R28] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. Always wear thermal protective clothing when handling refrigerated/cryogenic liquids. [R28] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for l600 meters (1 mile) in all directions; also, consider initial evacuation for 1600 meters (1 mile) in all directions. [R28] +Fire: DO NOT EXTINGUISH A LEAKING GAS FIRE UNLESS LEAK CAN BE STOPPED. Small fires: Dry chemical or CO2. Large fires: Water spray or fog. Move containers from fire area if you can do it without risk. Fire involving Tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R28] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. If possible, turn leaking containers so that gas escapes rather than liquid. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Do not direct water at spill or source of leak. Prevent spreading of vapors through sewers, ventilation systems and confined areas. Isolate area until gas has dispersed. CAUTION: When in contact with refrigerated/cryogenic liquids, many materials become brittle and are likely to break without warning. [R28] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. Clothing frozen to the skin should be thawed before being removed. In case of contact with liquefied gas, thaw frosted parts with lukewarm water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R28] FPOT: *FLAMMABLE GAS AT ORDINARY TEMP AND PRESSURE. [R29] *HIGHLY DANGEROUS, WHEN EXPOSED TO HEAT OR FLAME. [R30] NFPA: *Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R31] *Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R31] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R31] FLMT: *Lower limit 3.8% - Upper limit 15.4% [R31] FLPT: *-58 deg F (-50 deg C) (Closed cup) [R31] AUTO: *519 DEG C (966 DEG F) [R31] FIRP: *Water fog, carbon dioxide, dry chemical. For large fire it is best to allow material to burn while cooling surrounding equipment. Stop flow of ethyl chloride. [R23] *If material on fire or involved in fire: Do not extinguish fire unless flow can be confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical or carbon dioxide. [R32, 446] *If fire becomes uncontrollable or container is exposed to direct flame - consider evacuation of one-third (1/3) mile radius. [R32, 447] TOXC: *... FORMS PHOSGENE ON COMBUSTION ... . [R30] OFHZ: *Flashback along vapor trail may occur. [R23] EXPL: *(% BY VOL IN AIR): LOWER: 3.6%, UPPER 14.8% [R29] *Severe, when exposed to flame. [R30] *Vapor may explode if ignited in an enclosed area. [R23] REAC: *... CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R30] *... REACTS WITH WATER OR STEAM TO PRODUCE TOXIC AND CORROSIVE FUMES ... . [R30] *Incompatibilities: Contact with chemically active metals such as sodium, potassium, calcium, powdered aluminum, zinc, and magnesium may cause fires and explosions. [R10, 1981.2] *Chemically-active metals such as sodium, potassium, calcium, powdered aluminum, zinc and magnesium; oxidizers; water or steam [Note: Reacts with water to form hydrochloric acid]. [R15, 134] DCMP: *Thermally stable to 400 deg C; thermal splitting yields ethylene and hydrogen chloride. [R33] *Hazardous decomposition products: Toxic gases and vapors (such as hydrogen chloride, phosgene, and carbon monoxide) may be release in a fire involving ethyl chloride. [R10, 1981.2] ODRT: *10-12 mg/cu m (recognition in air) [R34] SERI: *Vapor may be irritating to mucous membranes. [R35] *Vapor: irritating to eyes, nose and throat. ... Liquid: irritating to skin and eyes. [R23] EQUP: *Wear safety glasses, rubber gloves, ... coveralls. [R36] *Respirator selection: 10,000 ppm: supplied-air respirator or self-contained breathing apparatus; 20,000 ppm: supplied-air respirator with full facepiece, helmet, or hood or self-contained breathing apparatus with full facepiece or type C supplied-air respirator with full facepiece operated in pressure-demand or other positive pressure mode or with full facepiece, helmet, or hood operated in continuous-flow mode; escape: gas mask with organic vapor canister (chin-style or front- or back-mounted canister) or self-contained breathing apparatus [R37, 418] *Wear appropriate chemical protective gloves, boots and goggles. Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R38] *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. [R10, 1981.2] *Wear appropriate personal protective clothing to prevent skin contact. /Liquid/ [R15, 135] *Wear appropriate eye protection to prevent eye contact. /Liquid/ [R15, 135] *Recommendations for respirator selection. Max concn for use: 3800 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R15, 135] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R15, 135] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R15, 135] OPRM: *... CARE OF A MASSIVE EVOLUTION OF VAPOR FOLLOWING A SERIOUS LEAK OR SPILLAGE FROM PLANT AND SAFEGUARDS MUST BE PROVIDED IN THE FORMS OF SILLS, KERBS, AND THE DESIGN OF FLOORS TO LIMIT THE SPREAD OF ESCAPING LIQUID. [R39] *Remove clothing immediately if wet or contaminated /with ethyl chloride/ to avoid flammability hazard. [R37, 418] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R32, 446] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R32, 447] *Evacuation: If material leaking (not on fire), downwind evacuation must be considered. Consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R32, 447] *Clothing wet with liquid ethyl chloride should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of ethyl chloride from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the ethyl chloride, the person performing the operation should be informed of ethyl chloride's hazardous properties. [R10, 1981.2] *Contact lenses should not be worn when working with this chemical. /Liquid/ [R15, 135] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R15, 135] SSL: *AT LOW TEMP OR UNDER INCREASED PRESSURE, ETHYL CHLORIDE IS A MOBILE, VERY VOLATILE LIQUID. [R29] *WHEN LIBERATED AT ORDINARY ROOM TEMP FROM ITS SEALED CONTAINER (USUALLY A TUBE WITH AUTOMATIC CLOSURE) IT VAPORIZES AT ONCE [R29] *Thermally stable to 400 deg C [R33] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R40] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R41] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R42] STRG: *MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMPOSE INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL WELL VENTILATED PLACE, OUT OF THE DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED ... [R43] *ETHYL CHLORIDE SHOULD BE ... STORED IN TIGHT CONTAINERS, PREFERABLY HERMETICALLY SEALED ... . [R7] *Protect containers against physical damage. Outdoor or detached storage is preferred. For indoor storage, store in a standard flammable liquid storage room. Keep away from ignitable materials or oxidizing agents. Remove any sources of ignition, spark or heat. [R36] *Storage temp: ambient [R23] CLUP: *Waste water treatment: evaporation from water at 25 deg C of 1 ppm solution (still air, avg depth 6.5 cm), 50% after 21 min, 90% after 79 min [R34] */SRP: For laboratory spills:/ Absorb the spills with paper towels or the like materials. Place in hood to evaporate. [R36] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Ethyl chloride is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Incineration of ethyl chloride, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R44] *Ethyl chloride boils @ 12 deg C, therefore it is commonly a gas at ambient temp, and will be in pressurized cylinders. Thermal destruction methods may be difficult to apply unless a gas feed to the incinerator can be arranged. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R45] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of chloroethane. There is limited evidence in experimental animals for the carcinogenicity of chloroethane. Overall evaluation: Chloroethane is not classifiable as to its carcinogenicity to humans (Group 3). [R46] +A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R47, 37] ANTR: *Irrigate eyes with water. Wash contaminated areas of body with soap and water. [R48] *Eye Exposure: If liquid ethyl chloride gets into the eyes, wash eyes immediately with large amounts of water, lifting the lower and upper lids occasionally. Get medical attention immediately. [R10, 1981.3] *Skin Exposure: If liquid ethyl chloride gets on the skin, promptly wash the contaminated skin with water if the ethyl chloride has not already evaporated. If liquid ethyl chloride soaks through the clothing, remove the clothing immediately and flush the skin with water. Do not use hot water for skin flushing. If irritation is present after washing, get medical attention. [R10, 1981.3] *Breathing: If a person breathes in large amounts of ethyl chloride, move the exposed person to fresh air at once. If breathing has stopped, perform artificial respiration. Keep the affected person warm and at rest. Get medical attention as soon as possible. [R10, 1981.3] *Rescue: Move the affected person from the hazardous exposure. If the exposed person has been overcome, notify someone else and put into effect the established emergency rescue procedures. Do not become a casualty. Understand the facility's emergency rescue procedures and know the locations of rescue equipment before the need arises. [R10, 1981.3] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and seat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin bums with sterile dressings after decontamination ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R49] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the unconscious patient. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of cardiac irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R49] MEDS: *Recommended medical surveillance: The following medical procedures should be made available to each employee who is exposed to ethyl chloride at potentially hazardous levels: Initial Medical Screening: Employees should be screened for history of certain medical conditions: which might place the employee at increased risk from ethyl chloride exposure. Liver Disease: Ethyl chloride is known as a liver toxin in animals and justifies consideration before exposing persons with impaired liver function. Kidney disease: Ethyl chloride is known as a kidney toxin in animals and justifies special consideration before exposing person with impaired renal function. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of ethyl chloride might cause exacerbation of symptoms due to its irritant properties. Cardiovascular disease: In persons with impaired cardiovascular function, especially those with a history of cardiac arrhythmias, the inhalation of ethyl chloride might cause exacerbation of disorders of the conduction mechanism due to its sensitizing effects on the myocardium. Periodic Medical Examination: Any employee developing /these/ ... conditions should be referred for further medical exmaination. [R10, 1981.1] HTOX: *... THE LIQUID SPILLED ON THE SKIN MAY CAUSE RAPID COOLING AND POSSIBLY FROST BITE. [R25, 4083] */CNS DEPRESSANT/ CONCN IN MAN: 105.6 MG/L (40,000 PPM) RESPONSE: AFTER 2 INHALATIONS, STUPOR, IRRITATION OF EYES, AND STOMACH CRAMPS; 88.7 MG/L (33,600 PPM) RESPONSE: AFTER 30 SECONDS, QUICKLY INCREASED TOXIC EFFECT; 66 MG/L (25,000 PPM) RESPONSE: LACK OF COORDINATION /FROM TABLE/ [R25, 4084] */CNS DEPRESSANT/ CONCN IN MAN: 52.8 MG/L (20,000 PPM) RESPONSE: AFTER 4 INHALATIONS, DIZZINESS AND SLIGHT ABDOMINAL CRAMPS; 50.4 MG/L (19,000 PPM) RESPONSE: WEAK ANALGESIA AFTER 12 MIN; 34.3 MG/L (13,000 PPM) RESPONSE: SLIGHT SYMPTOMS OF POISONING /FROM TABLE/ [R25, 4084] *MILDLY IRRITATING TO MUCOUS MEMBRANES. HIGH CONCN OF VAPORS CAUSES CNS DEPRESSION, UNCONSCIOUSNESS. [R29] *... Acute, high-level exposure ... the possibility of potentiation of adrenalin and resultant cardiac arrhythmias. [R50] *Ethyl chloride may cause liver and kidney damage. [R10, 1981.1] *THE PRINCIPAL /ACUTE/ PROBLEM IN INDUSTRIAL USE WILL BE THAT TYPICAL OF AN ANESTHETIC MATERIAL WHERE THE "DRUNKENNESS" AND INCOORDINATION MAY LEAD TO INEPT OPERATION AND, THEREFORE, THE POSSIBILITY OF AN INJURY. [R25, 4082] *Ethyl chloride is much less toxic than methyl chloride and many other lower chlorinated aliphatic hydrocarbons ... . [R51] *It is potentially damaging to the liver and is known to alter cardiac rhythmn. [R52] *Some workers occupationally exposed to monochloroethane exhibited some pathological changes in the sympathetic nervous system and decreased phagocyte activity of leukocytes. [R53] *Respiratory and circulatory failures occur rapidly following overdosage. [R54] NTOX: *RESPONSE OF GUINEA PIGS TO VAPOR IN AIR: CONCN 23-24% FOR 5-10 MIN UNCONSCIOUS, SOME DEATHS; CONCN 15.3% FOR 40 MIN SOME DEATHS IN 30 MIN; SOME SURVIVED 40 MIN; CONCN 9.1% FOR 30 MIN SURVIVED- HISTOPATHOLOGICAL CHANGES ... LUNG, LIVER; CONCN 5% FOR 40 MIN SURVIVED- LUNG CONGESTED /FROM TABLE/ [R25, 4084] *RESPONSE OF GUINEA PIGS TO VAPOR IN AIR: CONCN 4% FOR 122 MIN SURVIVED- RETURNED TO NORMAL; FOR 270 MIN SURVIVED- HISTOPATHOLOGICAL CHANGES IN THE LUNGS, LIVER, AND KIDNEYS; FOR 540 MIN SOME DEATHS; CONCN 1% FOR 510 MIN SURVIVED- HISTOLOGICAL CHANGES IN LIVER AND KIDNEYS. /FROM TABLE/ [R25, 4084] *Ethyl chloride liquefied under moderate pressure and sprayed on rabbit corneas has caused epithelial damage, not attributable to temp lowering, but to solvent or chemical action. [R55] *Guinea pigs died from a 9 hour exposure to 40,000 ppm but survived 4-1/2 hour exposure; histopathological changes in the lung, liver, and kidneys were observed in animals in the latter group. [R10, 1981.1] *Monochloroethane causes kidney damage; fatty changes in liver, kidney and heart in unspecified species. /From table/ [R56] *A two hr LC50 of 152 mg/l (57600 ppm) has been reported in rodents. Deaths were anesthetic in nature but hyperemia, edema, and hemorrhages were reported in the internal organs, brain, and lung. Repeated 2 hr exposures for 60 days to 14 mg/l (5300 ppm) caused a decr in the phagocytic activity of the leukocytes, lowered hippuric acid formation in the liver, and resulted in histological or pathological changes in the liver, brain, and lung. ... [R25, 4083] *Groups of 6 male and 6 female rats plus 2 male beagle dogs were exposed 6 hr/day, 5 days/wk for 2 wk to either 0, 1600, 4000, or 10,000 ppm ethyl chloride vapor. Except for possible CNS effects during exposure to 10,000 ppm, female rats and male dogs were unaffected as shown by histological and clinical chemical evaluation and organ and body wt measurements. Liver wt was slightly incr in male rats at 4000 and 10,000 ppm. This was the only change in this sex of the rats except for CNS depression. [R25, 4083] *In BALB/c-3T3 cell transformation assay, chloroethane induced a dose-dependent cytotoxicity but failed to elicit a consistent transformation response. [R57] *Groups of 30 pregnant CF-1 mice were exposed to chloroethane at concentrations of 0, 500, 1,500 ppm for 6 hours per day on days 6-15 of gestation. No significant effects on maternal body weight, body weight gain, liver weight, reproductive parameters, or fetal body weight were observed. No external, visceral, or skeletal malformations were observed in fetal mice. There was a small increase in the incidence of foramina of the skull bones in fetuses from the 5,000 ppm group. [R58] *When placed in the eye of a rabbit, monochloroethane produced corneal opacity which was attributed to chemically induced epithelial damage ... . When sprayed for 5 sec on the bared sclera in rabbit eyes, there was a transient elevation in intraocular pressure followed by transient hypotony. [R59] *Chloroethane, tested within the closed environment of a desiccator, was mutagenic with and without exogenous metabolic activation in Salmonella typhimurium strain TA1535; in strain TA100, a positive response was observed only with activation. No mutagenic activity was observed in Salmonella typhimurium strain TA98 with or without metabolic activation. [R60] HTXV: *Lethal (blood level): 40.0 mg %, (400.0 ug/ml) [R61] NTXV: *LC50 Rat inhalation 152 mg/l/2 hr; [R62] NTP: *Toxicology and carcinogenesis studies of chloroethane (99.5% pure), ... were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to chloroethane by whole-body inhalation once for 4 hours or for 6 hours per day, 5 days per week for ... 2 years. The survival of the exposed groups of both male (after day 330) and female (after day 574) mice was significantly lower than that of controls (final survival male: 28/50: 11/50: female: 32/50; 2/50). The majority of exposed female mice died as a result of uterine carcinomas. Male mice, and particularly exposed mice, died early as a result of an ascending urinary tract infection. ... There was equivocal evidence of carcinogenic activity of chloroethane for male F344/N rats, as indicated by benign and malignant epithelial neoplasms of the skin. For female F344/N rats, there was equivocal evidence of carcinogenic activity, as indicated by three uncommon malignant astrocytomas of the brain in the exposed group. The study in male B6C3F1 mice was considered to be an inadequate study of carcinogenicity because of reduced survival in the exposed group. However, there was an increased incidence of alveolar/bronchiolar neoplasms of the lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, as indicated by carcinomas of the uterus. A marginally increased incidence of hepatocellular neoplasms was observed in the exposed group. [R63] TCAT: ?The ability of chloroethane to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary clonal toxicity determinations, chloroethane was tested at concentrations of 0, 4, 20, 100 and 250 ug/ml, with cell survival ranging from 92% to 41% relative to the control. Chloroethane induced a clear dose-dependent positive transformation response in the tests. [R64] ?The effects of chloroethane were examined in the mouse hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, chloroethane was tested at concentrations of 0, 2.5, 5.0, 10, 15 and 20%. The highest 3 concentrations were toxic but none of the concentrations tested caused a significant increase in unscheduled DNA synthesis over solvent controls (DMSO). [R65] ?The mutagenicity of chloroethane was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, a known volume of chloroethane was tested as a gas in a 9 liter desiccator. Chloroethane was mutagenic to strains TA1535 and TA100, both with and without activation, but not mutagenic to the other two strains in any of the tests. [R66] POPL: *Those individuals who are exposed to known hepatoxins or have liver disease may constitute a group at risk. [R67] *ALCOHOLICS AND WORKERS WITH LIVER DYSFUNCTION SHOULD /BE PROTECTED/ WHERE THERE IS SIGNIFICANT EXPOSURE TO CHLORINATED HYDROCARBONS WHICH MAY CAUSE INJURY. /CHLORINATED HYDROCARBONS/ [R39] ADE: *IT IS EASILY ABSORBED THROUGH MUCOUS MEMBRANES AND THE LUNG AND THROUGH THE SKIN. ETHYL CHLORIDE IS QUICKLY ELIMINATED FROM THE BODY; MOST OF THIS ELIMINATION OCCURS THROUGH THE LUNG. [R68] *The major portion of an inhaled dose is eliminated unchanged in exhaled breath, but minute traces may remain in the blood for some time ... . Some of the compound is also excreted in the urine, feces, and sweat. [R69] METB: *... Ethyl chloride is not metabolized to a significant degree. [R70] *... Dechlorination of a number of chloroethanes ... /was evaluated/ using hepatic microsome preparations from rats. ... For monochloroethane, enzymatic losses of chlorine amounted to less than 0.5 percent of the initial amount of radiolabel used. However, ... some dechlorination (not quantified) occurred in the absence of NADP, suggesting an alternate pathway of metabolism or a nonenzymatic breakdown of the compound. [R71] INTC: *IN THE PRESENCE OF ... /HALOGENATED HYDROCARBON ANESTHETICS, INCL ETHYL CHLORIDE/, ADMIN OF EPINEPHRINE, ISOPROTERENOL, OR LEVARTERENOL MARKEDLY INCR INCIDENCE OF CARDIAC ARRHYTHMIAS. [R72] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Anesthetics, Local [R73] *Ethyl chloride is applied topically as a spray. [R74] *For use in local anesthesia ... /and/ used as a counterirritant ... . [R74] *MEDICATION (VET): Use of ethyl chloride ... restricted to the cat. ... May also be used to anesthetize birds. ... /Also/ for parakeets and canaries ... . [R54] *Ethyl chloride is still available in emergency rooms for use as a local anesthetic. [R75, 769] *Spraying of prolapsed hemorrhoids with ethyl chloride facilitated the reduction of strangulation. [R4, 749] *VET: TOPICAL ANESTHETIC [R29] WARN: *Because ethyl chloride is highly flammable, it should not be used in areas where ignition may occur. ... The drug should not be applied to broken skin or mucous membranes. During application of ethyl chloride, the skin adjacent to the area being treated should be covered with petrolatum to protect against tissue sloughing. ... Caution must be observed to avoid spilling the liquid on the skin. ... Deep general anesthesia followed by death has been reported. ... The patient should be observed for delayed nephrotoxicity or hepatotoxicity. [R74] *... The drug incr cardiac irritability and causes spontaneous arrhythmias. Asystole may occur before medullary paralysis. For this reason, the use of the drug by inhalation has been abandoned. [R75, 768] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethyl chloride's production and use as a refrigerant, solvent, anesthetic and in organic synthesis may result in its release to the environment through various waste streams. If released to air, ethyl chloride will exist in the gas phase in the ambient atmosphere based upon a vapor pressure of 1.01X10+3 mm Hg at 20 deg C. Gas-phase ethyl chloride will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 39 days. If released to soil, ethyl chloride is expected to have very high mobility based upon an estimated Koc of 24. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 1.11X10-2 atm-cu m/mole. Ethyl chloride will volatilize from dry soil surfaces based upon its vapor pressure. If released into water, ethyl chloride is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 0.9 hours and 3.2 days, respectively. An estimated BCF of 2.5 suggests bioconcentration in aquatic organisms is low. Hydrolysis of ethyl chloride is not expected to be an important environmental fate process due to the slow estimated hydrolysis rate. Occupational exposure to ethyl chloride may occur through inhalation and dermal contact with this compound at workplaces where ethyl chloride is produced or used. General population exposure to ethyl chloride may occur through inhalation of contaminated ambient air. (SRC) NATS: *Ethyl chloride does not occur as a natural product(1). [R76] ARTS: *Ethyl chloride can be released to the environment through process and fugitive emissions involved with its production and primary use as a chemical intermediate, through evaporation from solvent, aerosol, and anesthetic uses, and through stack emissions from plastics and refuse combustion(1,SRC). Ethyl chloride has been shown to be formed as a metabolite of the microbial degradation of various chlorinated solvents in soil systems(2,3), and anoxic groundwater microcosms(5). Standard chlorination treatment of landfill leachate can inadvertently yield small amounts of ethyl chloride(4). Wastewater effluents from treatment facilities and direct leaching from landfills can also release ethyl chloride to the environment(SRC). [R77] *Ethyl chloride's production and use as a refrigerant, solvent and in organic synthesis(1,2) may result in its release to the environment through various waste streams. Ethyl chloride can be released to the environment through stack emissions from plastics and refuse combustion(3). Ethyl chloride has been shown to be formed as a metabolite of the microbial degradation of various chlorinated solvents in soil systems(4,5), and anoxic groundwater microcosms(4). Standard chlorination treatment of landfill leachate can inadvertently yield small amounts of ethyl chloride(6). [R78] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 24(SRC), determined from a structure estimation method(2), indicates that ethyl chloride is expected to have very high mobility in soil(SRC). Volatilization of ethyl chloride from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 1.11X10-2 atm-cu m/mole(3). Volatilization of ethyl chloride from dry soil surfaces is expected(SRC) based upon a vapor pressure of 1.01X10+3 mm Hg(4). [R79] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 24(SRC), determined from an estimation method(2), indicates that ethyl chloride is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1.1X10-2 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 0.9 hours and 3.2 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 2.5(SRC), from its log Kow of 1.43(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. [R80] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethyl chloride, which has a vapor pressure of 1.01X10+3 mm Hg at 20 deg C(2), is expected to exist solely as a gas in the ambient atmosphere. Gas-phase ethyl chloride is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 39 days(SRC), calculated from its rate constant of 4.11X10-13 cu cm/molecule-sec at 25 deg C(3). [R81] BIOD: *AEROBIC: Ethyl chloride, present at 1.84 and 4.19 mg/l, reached 1% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 2 mg/l and the closed bottle test(1). [R82] *ANAEROBIC: Chlorinated ethanes and methanes were found to release 50-70% of the organically bound chlorine when incubated under anaerobic laboratory conditions(1). [R83] ABIO: *The rate constant for the vapor-phase reaction of ethyl chloride with photochemically-produced hydroxyl radicals is 4.11X10-13 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 39 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2). Ethyl chloride does not absorb UV light above 290 nm indicating that direct photolysis will not occur in the troposphere(3,4). Oxidation of ethyl chloride in water via singlet oxygen or peroxy radicals is too slow to be environmentally important(4). Hydrolysis of ethyl chloride is not expected to be an important environmental fate process based upon an estimated hydrolysis half-life of 38 days(5). Ethyl chloride is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R84] BIOC: *Food chain concn potential: none [R23] *An estimated BCF of 2.5 was calculated for ethyl chloride(SRC), using a log Kow of 1.43(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R85] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for ethyl chloride can be estimated to be 24(SRC). According to a classification scheme(2), this estimated Koc value suggests that ethyl chloride is expected to have very high mobility in soil. [R86] VWS: *The Henry's Law constant for ethyl chloride is 1.11X10-02 atm-cu m/mole(1). This Henry's Law constant indicates that ethyl chloride is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 0.9 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 3.2 days(SRC). Ethyl chloride's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of ethyl chloride from dry soil surfaces may exist(SRC) based upon a vapor pressure of 1.01X10+03 mm Hg(3). [R87] WATC: *DRINKING WATER: Ethyl chloride was qualitatively identified in drinking water from Miami, FL, Philadelphia, PA and Cincinnati, OH(1). [R88] *GROUNDWATER: Ethyl chloride was detected in less than 10% of 30 samples collected from the shallow groundwater zone of the Denver metropolitan area in 1993; the maximum concentration detected was 2.3 ug/l(1). Ethyl chloride was detected in groundwater in Wisconsin at a level of 90 ug/l 80 m downgradient from a contamination source of chlorinated solvents; the presence of the ethyl chloride was attributed to breakdown of other chlorinated compounds(2). Ethyl chloride levels of 4.3-136 ppb were identified in groundwater beneath the Miami Drum waste site in FL(3). [R89] *SURFACE WATER: An analysis of the USEPA STORET Data Base has reported positive detection of ethyl chloride in 6.0% of 994 ambient water observation stations at a median concn below 10 ppb(1). [R90] EFFL: *An ethyl chloride concn of 1.5 ppb was detected in the final wastewater effluent from a Los Angeles County treatment facility in 1981(1). An analysis of the USEPA STORET Data Base has reported positive detection of ethyl chloride in 2.6% of 1323 effluent observation stations at a median concn below 10 ppb(2). Raw wastewaters from 9 organic chemical manufacturing facilities contained a mean ethyl chloride concn of 240 ppb(3). Ethyl chloride was qualitatively detected in leachates and associated groundwaters from various municipal landfills in Minnesota(4). Ethyl chloride has been identified as a gas emitted from landfill simulators(5). [R91] SEDS: *Ethyl chloride was qualitatively identified in the soil/sediment/water matrix of the Love Canal near Niagara Falls, NY in 1980(1). An analysis of the USEPA STORET Data Base has reported positive detection of ethyl chloride in 0.3% of 354 sediment observation stations(2). Mean ethyl chloride levels of 0.2 ppb (wet wt) were detected in sediment taken from one location of Lake Pontchartrain in LA in 1980(3). [R92] ATMC: *Atmospheric levels of ethyl chloride in the rural air of Pullman, WA were below 5 parts per trillion during monitoring between Dec 1974 and Feb 1975(1). Mean ambient air concentrations of 227, 46, 41, and 87 parts per trillion ethyl chloride were detected in Houston,TX, St. Louis,MO, Denver,CO and Riverside,CA respectively, in 1980(2). [R93] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Mean ethyl chloride levels of 7.6 ppb (wet wt) were detected in oysters taken from one location of Lake Pontchartrain in LA in 1980(1). [R94] MILK: *Monochloroethane was ... found in samples of human milk collected from women residing in several United States urban areas. [R95] RTEX: *Inhalation of gas, slight percutaneous absorption, ingestion, eye and skin contact. [R37, 417] *Data concerning workplace exposure to chloroethane are limited; however, an Occupational Safety and Health Administration (OSHA) survey of one tetraethyl lead manufacturer determined that, on the average, workers were exposed to 0.425 mg/cu m with a maximum of 1.143 mg/cu m. [R96] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 49,210 workers (35,368 of these are female) are potentially exposed to ethyl chloride in the US(1). Occupational exposure to ethyl chloride may occur through inhalation and dermal contact with this compound at workplaces where ethyl chloride is produced or used. General population exposure to ethyl chloride can occur through inhalation of contaminated ambient air(SRC). [R97] AVDI: *AIR INTAKE: 2.4-13.5 ug/day (average) based on monitoring of four US cities in 1980(1). WATER INTAKE: insufficient data. FOOD INTAKE: insufficient data. [R98] BODY: *Ethyl chloride was qualitatively identified in 2 of 12 human milk samples collected from women at four USA locations(1). [R99] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *3800 ppm [Based on 10% of the lower explosive limit for safety considerations even though the relevant toxicological data indicated that irreversible health effects or impairment of escape existed only at higher concentrations.] [R15, 134] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1000 ppm (2600 mg/cu m), skin. [R100] NREC: *Handle with caution in the work place. [R15, 134] *NIOSH considers ethylene dichloride; hexachloroethane; 1,1,2,2-tetrachloroethane; and 1,1,2-trichloroethane; to be potential occupational carcinogens. Additionally, NIOSH recommends that the other five chloroethane compounds: 1,1-dichloroethane; ethyl chloride; methyl chloroform; pentachloroethane; and 1,1,1,2-tetrachloroethane be treated in the workplace with caution because of their structural similarity to the four chloroethanes shown to be carcinogenic in animals. [R15, 134] TLV: +8 hr Time Weighted Avg (TWA) 100 ppm, skin [R47, 37] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R47, 6] +A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R47, 37] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethyl chloride is produced, as an intermediate or a final product, by process units covered under this subpart. [R101] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Ethyl chloride is included on this list. [R102] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 140 ug/l [R103] +(WI) WISCONSIN 400 ug/l [R103] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R104] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R105] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Ethane, chloro- is included on this list. [R106] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2519. Analyte: Ethyl chloride. Matrix: Air. Sampler: Solid sorbent tubes (2 coconut shell charcoal tubes, 400 mg and 200 mg). Flow Rate: 0.01 to 0.05 l/min. Sample Size: 3-liters. Shipment: Separate front and back butes. Sample Stability: Greater or Equal to 7 days @ 25 deg C. [R107] ALAB: *NIOSH Method 2519. Analyte: Ethyl chloride. Matrix: Air. Procedure: Gas chromatography, flame ionization detector. For ethyl chloride this method has an estimated detection limit of 0.01 mg/sample. The overall precision/RSD is 0.024 @ 3.4 to 15 mg/sample. Applicability: The working range is 330 to 6700 mg/cu m (130 to 2500 ppm) for a 3-liter air sample. Interferences: None known. [R107] *EPA Method 502.1. Purge-and-Trap Gas Chromatography with halogen-specific detector for the determination of halogenated volatile compounds including chloroethane in finished drinking water, raw source water, or drinking water in any treatment stage. Under the prescribed conditions, for chloroethane the method detection limit is 0.008 ug/l. [R108] *EPA Method 502.2: Purge-and-Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. The method is applicable for the determination of volatile organic compounds in finished drinking water, raw source water, or drinking water in any treatment stage. For chloroethane, no results were given for the photoionization detector. The method has a detection limit of 0.1 ug/l, a percent recovery of 96%, and a standard deviation of recovery of 3.8 using the electrolytic conductivity detector. [R108] *EPA Method 524.1. Purge-and-Trap Gas Chromatography/Mass Spectrometry. The method is applicable for the determination of volatile organic compounds in water, finished drinking water, raw source water, or drinking water in any treatment stage. For chloroethane the method has no detection limit and no standard deviation. [R108] *EPA Method 601. Purge-and-Trap Gas Chromatography with electrolytic conductivity detection for the analysis of purgeable halocarbons including chloroethane in municipal and industrial discharges. Under the prescribed conditions, the method detection limit for chloroethane is 0.52 ug/l. The method is recommended for use in the concentration range from the method detection limit to 1000 times that limit. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R109] *EPA Method 624. Purge-and-Trap Gas Chromatography/Mass Spectrometry for the analysis of purgeable organics including chloroethane in the municipal and industrial discharges. Under the prescribed conditions, for chloroethane the method has no given detection limit. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R109] *EPA Method 1624-S. Volatile Organic Compounds by Isotope Dilution GCMS. This method is applicable to the analysis of soils and sludges for VOCs. The method detection limit is reported as 24 ppm. [R110] *EPA Method 1624-W. Volatile Organic Compounds by Isotope Dilution GCMS. This method is applicable to the analysis of water for VOCs. The method detection limit is reported as 50 ug/l. [R110] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: TSCA CHIPs present a preliminary assessment of ethyl chloride's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404. USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes (1980) EPA 440/5-80-0269. DHHS/ATSDR; Toxicological Profile for Chloroethane (1989) ATSDR/TP-89/07 USEPA; Summary Review of Health Effects Associated with Monochloroethane Health Issue Assessment. (1988) NTIS PB 88-236047 DHHS/NTP; Toxicology and Carcinogenesis Studies of Chloroethane in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 346 (1989) NIH Publication No. 90-2801 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 645 R2: CHEMICAL PRODUCTS SYNOPSIS: ETHYL CHLORIDE, 1984 R3: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 592 R4: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 464 R6: Kuney, J.H. (ed.). CHEMCYCLOPEDIA 90. Washington, DC: American Chemical Society, 1990. 236 R7: ASHP. American Hospital Formulary Service -Drug Information 87. Bethesda, MD: American Society of Hospital Pharmacists, 1987. (Plus Supplements, 1987)) 1910 R8: SRI R9: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 284 R10: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R11: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.258 R12: United States International Trade Commission. Synthetic Organic Chemicals- United States Production and Sales, 1988. USITC Publication 1989. Washington, DC: United States International Trade Commission, 1989.p. 15-7 R13: BUREAU OF THE CENSUS. U.S. EXPORTS 1984 p.2-74 R14: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 49-48 R15: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R16: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 1607 R17: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 67th ed. Boca Raton, FL: CRC Press, Inc., 1986-87. R18: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 4 R19: Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991. 147 R20: Horvath AL; Halogenated hydrocarbons: solubility-miscibility with water. New York, NY: Marcel Dekker, Inc pp. 889 (1982) R21: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-239 R22: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 615 R23: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R24: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R25: Clayton, G.D., F.E. Clayton (eds.) 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Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Gossett JM; Env Sci Technol 21: 202-6 (1987) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R81: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Part 2 American Institute of Chemical Engineers Taylor and Francis Washington DC (1995) (3) Atkinson R; J Phys Chem Ref Data Monograph No. 2 p. 89 (1994) R82: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R83: (1) Haider K; pp. 200-4 in Comm Eur Communities, EUR 1980 EUR 6388, Environ Res Programme (1980) R84: (1) Atkinson R; J Phys Chem Ref Data Monograph No. 2 p. 89 (1994) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Hubrich C, Stuhl F; J Photochem 12: 93-107 (1980) (4) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants USEPA-440/4-81-014 p. 141-2 (1981) (5) Howard PH et al; Handbook of Environmental Degradation Rates. Chelsea, MI: Lewis Pub p. 136-7 (1991) R85: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R86: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R87: (1) Gossett JM; Env Sci Technol 21: 202-6 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Part 2 American Institute of Chemical Engineers Taylor and Francis Washington DC (1995) R88: (1) USEPA; Preliminary Assessment of Suspected Carcinogens in Drinking Water. Interim Report to Congress, June, 1975. Washington, DC p. 9 (1975) R89: (1) Bruce BW, McMahon PB; J Hydrol 186: 129-51 (1996) (2) Cline PV, Viste DR; Waste Manage Res 3: 351-60 (1985) (3) Myers VB; Natl Conf Manage Uncontrolled Hazard Waste Sites p. 354-7 (1983) R90: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R91: (1) Young DR et al; pp. 871-84 in Water Chlorination: Environ Impact Health Eff 4(Book2) (1983) (2) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (3) USEPA; Treatability Manual. USEPA-660/2-82-001a p. I.12.5-2 (1981) (4) Sabel GV, Clark TP; Waste Manage Res 2: 119-30 (1984) (5) Vogt WG, Walsh JJ; p. 9 in Proc APCA Annual Meet 78th (Vol 6) (1983) R92: (1) Hauser TR, Bromberg SM; Environ Monitor Assess 2: 249-72 (1982) (2) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (3) Ferrario JB et al; Bull Environ Contamin Toxicol 34: 246-55 (1985) R93: (1) Grimsrud EP, Rasmussen RA; Atmos Environ 9: 1014-17 (1975) (2) Singh HB et al; Atmospheric Measurements of Selected Hazardous Organic Chemicals EPA- 600/S3-81-032 p.4-5 (1981) R94: (1) Ferrario JB et al; Bull Environ Contamin Toxicol 34: 246-55 (1985) R95: USEPA; Summary Review of Health Effects Associated with Monochloroethane Health Issue Assessment. p.16 (1988) NTIS PB 88-236047 R96: NTP; Toxicology and Carcinogenesis Studies of Chloroethane in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.13 Report # 346 (1989) NIH Pub # 90-2801 R97: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R98: (1) Singh HB et al; Atmospheric Measurements of Selected Hazardous Organic Chemicals. USEPA-600/S3-81-032 p. 4-5 (1981) R99: (1) Pellizzari ED et al; Bull Environ Contamin Toxicol 28: 322-8 (1982) R100: 29 CFR 1910.1000 (7/1/99) R101: 40 CFR 60.489 (7/1/99) R102: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R103: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R104: 40 CFR 116.4 (7/1/99) R105: 40 CFR 302.4 (7/1/99) R106: 40 CFR 716.120 (7/1/99) R107: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2519-1 R108: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R109: 40 CFR 136 (7/1/91) R110: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 72 Record 67 of 1119 in HSDB (through 2003/06) AN: 538 UD: 200211 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLENE-GLYCOL-MONO-N-BUTYL-ETHER- SY: *A13-0993-; *BUCS-; *BUTOKSYETYLOWY-ALKOHOL- (POLISH); *2-BUTOSSI-ETANOLO- (ITALIAN); *2-BUTOXY-AETHANOL- (GERMAN); *Butoxyethanol-; *BETA-BUTOXYETHANOL-; *N-BUTOXYETHANOL-; *2-BUTOXYETHANOL-; *2-BUTOXY-1-ETHANOL-; *BUTYL-CELLOSOLVE-; *BUTYL-CELLU-SOL-; *Butylcelosolv- (Czech); *O-BUTYL-ETHYLENE-GLYCOL-; *BUTYL-GLYCOL-; *BUTYLGLYCOL- (FRENCH,GERMAN); *BUTYL-OXITOL-; *Caswell-No-121-; *CHIMEC-NR-; *DOWANOL-EB-; *Ektasolve-EB-; *EPA-Pesticide-Chemical-Code-011501-; *Eter-monobutilico-del-etilenglicol- (Spanish); *ETHANOL,-2-BUTOXY-; *Ether-monobutylique-de-L'ethyleneglycol- (French); *ETHYLENE-GLYCOL-BUTYL-ETHER-; *ETHYLENE-GLYCOL-N-BUTYL-ETHER-; *Ethylene-glycol-monobutyl-ether-; *GAFCOL-EB-; *GLYCOL-BUTYL-ETHER-; *GLYCOL-MONOBUTYL-ETHER-; *MONOBUTYL-ETHER-OF-ETHYLENE-GLYCOL-; *Monobutyl-ethylene-glycol-ether-; *MONOBUTYL-GLYCOL-ETHER-; *3-Oxa-1-heptanol-; *POLY-SOLV-EB- RN: 111-76-2 MF: *C6-H14-O2 SHPN: UN 2369; Ethylene glycol monobutyl ether IMO 6.1; Ethylene glycol monobutyl ether MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *(1) BY REACTION OF ETHYLENE OXIDE WITH SUITABLE ALCOHOL, WITH VARIOUS CATALYSTS. (2) BY REACTING ETHYLENE CHLOROHYDRIN OR ETHYLENE GLYCOL WITH SODIUM HYDROXIDE AND DIALKYL SULFIDE. [R1, 609] FORM: *GRADE: TECHNICAL [R2] MFS: *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Main St, Midland, MI 48667 [R3] *Eastman Chemical Co, Hq, PO Box 511, Kingsport, TN 37662; Texas Eastman Division; Production site: Longview, TX 75607 [R3] *Occidental Petroleum Corporation, Hq, 10889 Wilshire Blvd, Suite 1500, Los Angeles, CA 90024, (213) 879-1700; Petrochemicals, Occidental Tower, 5005 LBJ Freeway, PO Box 809050 (75380), Dallas, TX 75244 (214) 404-3800. Ethylene oxide and Derivatives Division; Production site: Bayport, TX 77000 [R3] *Shell Chemical Co, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production site: Geismar, LA 70734 [R3] *Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817, (203) 794-2000; Solvents and Intermediates; Production site: Seadrift, TX 77983 [R3] OMIN: *OTHER EFFECTIVE FOG REDUCING MIXT TESTED INCL HEXADECANOL WITH OCTADECANOL AND ETHYLENE MONOBUTYL ETHER. [R4] *Ethylene Glycol Monobutyl Ether is now /1983/ the largest volume glycol ether produced. [R5] USE: *IN HYDRAULIC FLUIDS [R1, 609] *The preferred coupling agent for many water-based coatings. [R5] *Used to make acetate esters as well as phthalate and stearate plasticizers. [R5] *A coupling agent to stabilize immiscible ingredients in metal cleaners, textile lubricants, cutting oils and liquid household products. [R5] *Solvent for nitrocellulose resins, spray lacquers, quick-drying lacquers varnishes, enamels, drycleaning cmpd, varnish removers, textile (preventing spotting in printing or dyeing), mutual solvent for "soluble" mineral oils to hold soap in solution and to improve the emulsifying properties. [R2] *Crude oil/water coupling solvent (oil-well work-overs); solvent (surface coatings, adhesives, organosol production). [R6] *In vinyl and acrylic paints as well as lacquers and varnishes. Also in aqueous cleaners to solubilize organic surfactants. [R7, p. V4 696] *As a solvent in cosmetics. [R7, p. V7 585] CPAT: *41% AS SOLVENT FOR PROTECTIVE COATINGS; 18% AS SOLVENT FOR METAL CLEANERS AND LIQUID HOUSEHOLD CLEANERS; 9% FOR SYNTHESIS OF 2-BUTOXYETHYL ACETATE; 1% FOR SYNTHESIS OF DI(2-BUTOXYETHYL) PHTHALATE; 31% FOR OTHER SOLVENT USES (1972) [R8] *Intermediates, 20%; Coatings solvent, 65%; Miscellaneous solvents, 15% (1983) [R5] PRIE: U.S. PRODUCTION: *(1972) 6.05X10+10 GRAMS [R8] *(1975) 5.93X10+10 GRAMS [R8] *(1984) 1.23X10+11 g [R9] U.S. IMPORTS: *(1972) NEGLIGIBLE [R8] *(1984) 4.02x10+7 g [R10] U.S. EXPORTS: *(1972) 4.01X10+9 GRAMS [R8] *(1975) 5.45X10+9 GRAMS [R8] *(1984) 3.24X10+10 g [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +...Colorless liquid. [R12, 36] ODOR: +... Mild, ether-like odor. [R12, 36]; *Slight, rancid odor. [R6]; *Weak, pleasant odor. [R13] BP: *171-172 DEG C [R14] MP: *-70 deg C [R15] MW: *118.20 CTP: *CRITICAL TEMP: 694 DEG F= 368 DEG C= 641 DEG K; CRITICAL PRESSURE: 470 PSIA= 32 ATM= 3.2 MEGANEWTONS/SQUARE M [R16] DEN: *SP GR: 0.9012 @ 20 DEG C/4 DEG C [R14] HTC: *-13,890 BTU/LB= -7720 CAL/G= -323X10+5 JOULES/KG [R16] HTV: *157 BTU/LB= 87.1 CAL/G= 3.65X10+5 JOULES/KG [R16] OWPC: *log Kow= 0.83 [R17] SOL: *SOL IN MOST ORG SOLVENTS, IN MINERAL OIL [R14]; *Mixes in all proportions with acetone, benzene, carbon tetrachloride, ethyl ether, n-heptane and water; miscible in all proportions with many ketones, ethers, alcohols, aromatic paraffin and halogenated hydrocarbons. [R18]; +water solubility = 1X10+6 mg/l [R19] SPEC: *SADTLER REF NUMBER: 2292 (IR, PRISM); 10979 (IR, GRATING) [R20]; *Index of refraction: 1.4198 @ 20 deg C/D [R21]; *Intense mass spectral peaks: 57 m/z (100%), 45 m/z (38%), 41 m/z (31%), 87 m/z (16%) [R22]; *IR: 1052 (Coblentz Society Spectral Collection) [R23]; *NMR: 4023 (Sadtler Research Laboratories Spectral Collection) [R23] SURF: *Surface tension: 27.4 mN/m (=dyn/cm) @ 25 deg C. [R24] VAPD: *4.1 (Air= 1) [R25] VAP: *Vapor pressure = 0.88 mm Hg at 25 deg C [R26] VISC: *At 25 deg C= 2.83 centistokes [R18] OCPP: *Acidity (as acetic acid), % by wt (max) 0.01. [R18] *Blush resistance (@ 27 Deg C 96% rh; Coefficient of expension: 0.00092 cu cm [R24] +hydroxyl radical rate constant = 1.86X10-11 cu-cm/molc sec [R27] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R28] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R28] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R28] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R28] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R28] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R28] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R28] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R28] FPOT: *... Keep away from heat and open flame. [R29] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R30] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R30] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R30] FLMT: +Lower: 1.1% @ 93 deg C; Upper: 12.7% @ 135 deg C [R30] FLPT: +143 DEG F (62 DEG C) (CLOSED CUP) [R30] *Flash point = 69.4 deg C (open cup) and 60.0 deg C (closed cup) [R31] AUTO: +238 deg C [R30] FIRP: *CARBON DIOXIDE OR DRY CHEMICAL FOR SMALL FIRES; ALCOHOL-TYPE FOAM FOR LARGE FIRES. [R16] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Keep run-off water out of sewers and water sources. [R32] REAC: *Incompatibilities: Strong oxidizers, strong caustics. [R33, 155] +Strong oxidizers, strong caustics. [R12, 36] SERI: *Irritation of eyes, nose and throat ... [R33, 155] EQUP: *AIR PACK OR ORGANIC CANISTER RESPIRATOR, RUBBER GLOVES; GOGGLES; CLOTHING TO PREVENT BODY CONTACT WITH LIQ [R16] *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any reasonable probability of eye contact. Employees should wash immediately when skin is wet or contaminated. Remove nonimpervious clothing immediately if wet or contaminated. Provide emergency showers. [R33, 156] +Wear appropriate personal protective clothing to prevent skin contact. [R12, 37] +Wear appropriate eye protection to prevent eye contact. [R12, 37] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R12, 37] +Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. [R12, 37] +Recommendations for respirator selection. Max concn for use: 125 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. [R12, 37] +Recommendations for respirator selection. Max concn for use: 250 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with a tight-fitting facepiece and organic vapor cartridge(s). May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R12, 37] +Recommendations for respirator selection. Max concn for use: 700 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R12, 37] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R12, 37] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R12, 37] OPRM: +Contact lenses should not be worn when working with this chemical. [R12, 37] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R12, 37] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R12, 37] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. [R32] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R32] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R34] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R35] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. 2. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER. WASTE DISPOSAL: 1. BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL AND DISPOSING IN SECURED SANITARY LANDFILL. 2. BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER. [R36] *IN SIMULATED WASTE GAS CONTAINING 1000 PPM ETHYLENE BUTYL MONOBUTYL ETHER WAS ABSORBED BY SPINDLE OIL 88 CONTAINING CALCIUM NAPHTHANATE, A NONIONIC SURFACTANT, AN ANTIOXIDANT AND A STABILIZER. [R37] *ACTIVATED SLUDGE DECOMPOSED ORGANIC SOLVENT CONTAINED IN ABSORBING LIQ OF WASTE GAS FROM PAINTING BOOTHS. ETHYLENE GLYCOL MONOBUTYL ETHER WAS DECOMPOSED BY ACCLIMATED SLUDGE. [R38] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *n-Butoxy ethanol should be atomized into an incinerator, and combustion may be improved by mixing with a more flammable solvent. [R39] *The following wastewater treatment technologies have been investigated for Ethylene glycol monobutyl ether: Concentration process: Activated carbon. [R40] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: 2-Butoxyethanol is a high production volume glycol ether. It is a colorless liquid that is miscible in water and soluble in most organic solvents. 2-Butoxyethanol is used widely as a solvent in surface coatings, such as spray lacquers, quick dry lacquers, enamels, varnishes, varnish removers and latex paint. HUMAN EXPOSURE: Based on limited data, ambient exposures in air are generally in the ug/cu m range. Industrial exposure of the general population to this chemical is most likely from inhalation and dermal absorption during the use of products containing 2-butoxyethanol. Levels of airborne 2-butoxyethanol in occupational settings are typically in the mg/cu m range. The results of in vitro studies indicate that human red blood cells are not as sensitive to the hemolytic effects of 2-butoxyethanol and 2-butoxyacetic acid and also that red blood cells are more sensitive to hemolysis by 2-butoxyacetic acid than to hemolysis by 2-butoxyethanol. ANIMAL STUDIES: 2-Butoxyethanol is readily absorbed following inhalation, oral or dermal exposure. The chemical is metabolized via alcohol and aldehyde dehydrogenases, with the formation of 2-butoxyacetaldehyde and 2-butoxyacetic acid, the principal metabolite, although other metabolic pathways have also been identified. This chemical has moderate acute toxicity and it is irritating to the eyes and skin; it is not a skin sensitizer. The principal effect exerted by 2-butoxyethanol and its metabolite 2-butoxyacetic acid is hematotoxicity, with the rat being the most sensitive species. In rats, adverse effects on the central nervous system, kidneys and liver occur at higher exposure concentrations than do the hemolytic effects. In animals, adverse effects on reproduction and development have not been observed at less than toxic doses. Although the results of in vitro tests for mutagenicity of 2-butoxyethanol were inconsistent, the absence of structural alerts and the negative findings from in vivo studies indicate that 2-butoxyethanol is not mutagenic. [R41] CARC: +WEIGHT-OF-EVIDENCE CHARACTERIZATION: No reliable human epidemiological studies are available that address the potential carcinogenicity of EGBE. ... NTP /the National Toxicology Program/ (1988) reported no evidence of carcinogenic activity in male F344/N rats, and equivocal evidence of carcinogenic activity in female F344/N rats on the basis of increased combined incidences of benign and malignant pheochromocytoma (mainly benign) of the adrenal medulla. They also reported some evidence of carcinogenic activity in male B6C3F1 mice on the basis of increased incidences of hemangiosarcoma of the liver, and some evidence of carcinoma (mainly papilloma). ... because of the uncertain relevance of these tumor increases to humans, the fact that EGBE is generally negative in genotoxic tests and the lack of human data to support the findings in rodents, the human carcinogenic potential of EGBE, in accordance with the recently proposed Guidelines for Carcinogen Risk Assessment (USEPA, 1996), cannot be determined at this time, but suggestive evidence exists from rodent studies. Under existing EPA guidelines (USEPA, 1986), EGBE is judged to be a possible human carcinogen, Group C. HUMAN CARCINOGENICITY DATA: There are currently no human epidemiological studies addressing the potential carcinogenicity of EGBE. [R42] MEDS: *Consider the points of attack (liver, kidneys, lymphoid system, skin, blood, eyes, respiratory system) in placement and periodic physical examinations. [R33, 155] HTOX: *SYMPTOMATOLOGY: 1. Central nervous depression, although probably less prominent than with ethylene glycol. 2. No hypocalcemic tetany or metabolic acidosis with the possible exception of poisonings due to ethylene glycol monomethyl ether. 3. Nausea, vomiting, and sometimes diarrhea. 4. Prominent headache. Later abdominal and lumbar pain and costovertebral angle tenderness. 5. Transient polyuria and then oliguria, progressing to anuria. 6. Acute renal failure ... 7. Less critical pathological lesions may appear in brain, lung, liver, meninges and heart. 8. Observations in animals suggest the remote possibility of pulmonary edema, intravascular hemolysis and bone marrow depression, at least with some ether derivatives of ethylene and diethylene glycols. ... /Ethylene glycol (Group B compounds)/ [R43] *EXPOSURE ... TO HIGH CONCN ... OF ... VAPORS, PROBABLY IN RANGE OF 300-600 PPM FOR SEVERAL HR WOULD BE EXPECTED TO CAUSE RESP AND EYE IRRITATION ... /CNS DEPRESSION/, AND DAMAGE TO KIDNEY AND LIVER. [R44, 3933] *FIRST SIGN OF ORGANIC ABNORMALITY ... RESULTING FROM EXCESSIVE EXPOSURE BY ANY ROUTE LIKELY WOULD BE ABNORMAL BLOOD PICTURE CHARACTERIZED BY ERYTHROPENIA, RETICULOCYTOSIS, GRANULOCYTOSIS, AND LEUCOCYTOSIS. SOMEWHAT MORE INTENSE EXPOSURE WOULD BE LIKELY TO CAUSE FRAGILITY OF ERYTHROCYTES AND HEMATURIA. [R44, 3933] *BONE MARROW DAMAGE. /FROM TABLE/ [R45] *2-Butoxyethanol penetrates the skin readily, and toxic action from excessive skin exposure may be more likely than from vapor inhalation. [R46, 1991.163] *IT APPEARS THAT THIS CHEMICAL IS ONE OF THE FEW MATERIALS TO WHICH HUMAN IS MORE RESISTANT THAN THE USUAL EXPERIMENTAL ANIMALS. THIS APPEARS TO BE DUE, IN PART AT LEAST, TO THE FACT THAT HUMANS ARE MORE RESISTANT THAN ARE MOST LAB ANIMALS TO THE HEMOLYTIC EFFECTS CAUSED BY THE MATERIAL ITSELF OR ITS METABOLITE. [R44, 3937] *... REGARDED AS MOST TOXIC GLYCOL MONOALKYL ETHER USED AS SOLVENT ... . [R1, 610] *THE EFFECTS /OF ALKYL DERIV OF ETHYLENE GLYCOL/ ... UPON THE CNS INCLUDE HEADACHE, DROWSINESS, WEAKNESS, SLURRED SPEECH, RECRUDESCENT STUTTERING, STAGGERING GAIT, TREMOR, AND BLURRED VISION. CHANGES OF PERSONALITY ARE OFTEN NOTED ... THESE CHANGES ARE SUCH THAT THE PATIENT, IN THE ABSENCE OF AN ACCURATE OCCUPATIONAL HISTORY, MAY BE TREATED FOR SCHIZOPHRENIA OR NARCOLEPSY. IN ACUTE POISONING WITH THE ETHYLENE GLYCOL MONOALKYL ETHERS, THERE IS ... RENAL INJURY: ALBUMINURIA AND HEMATURIA. /ETHYLENE GLYCOL MONOALKYL ETHERS/ [R47] *A case of severe poisoning with ethylene glycol butyl ether after massive ingestion is described. Deep coma, metabolic acidosis, hypokalemia hemoglobinuria, oxaluria and a transitory rise in the serum creatinine level were observed. The elimination of the various metabolites butoxyacetic acid and oxalate was assessed in urine and a metabolic pattern for ethylene glycol butyl ether is suggested. [R48] *The effects of 2-butoxyethanol and its metabolites, 2-butoxyacetaldehyde and butoxyacetic acid, on erythrocytes from humans were investigated in vitro. ... Incubation of human blood with butoxyacetic acid showed minimal swelling or hemolysis of erythrocytes with minimal decline in blood ATP levels at butoxyacetic acid concentrations several-fold higher than required to cause complete hemolysis of rat erythrocytes. ... Human erythrocytes are comparatively insensitive to the hemolytic effects of butoxyacetic acid in vitro. [R49] *A case of acute poisoning with ethylene glycol butyl ether is reported in a chronic alcoholic abuser. On admission the 53 yr old patient was comatose with metabolic acidosis, shock and noncardiogenic pulmonary edema confirmed by hemodynamic study. Following supportive treatment and hemodialysis the outcome was favorable. ... [R50] *In several, single, 8 hour exposures of humans at concentrations of 200 or 100 ppm, no objective effects were seen except for urinary excretion of butoxyacetic acid. No increased osmotic fragility was observed in these short term exposures. Subjectively, these concentrations were found to be uncomfortable, and mild eye, nose, and throat irritation followed exposure. [R46, 1991.163] *No clinical signs of adverse effects nor subjective complaints occurred among seven male volunteers exposed at 20 ppm for 2 hours during light physical exercise. [R46, 1991.163] NTOX: *Tests of the liquid by dropping on rabbit eyes induces reddening and swelling of the conjunctiva with slight clouding of the corneal epithelium. The degree of injury judged 24 hours after the application of a single drop has been graded 4 on a scale of 1 to 10. Rabbit eyes in contact with the liquid for eight minutes before irrigation with water have recovered completely in four days. [R51] *ON EXCISED BEEF CORNEA ... /IT REDUCED/ ADHESION OF EPITHELIUM TO STROMA ... . [R51] *... RATS OF DIFFERENT AGES /WERE EXPOSED/ TO VARIOUS CONCN OF VAPOR. ... 1-YR-OLD RATS WERE MORE SUSCEPTIBLE THAN YOUNG, ACTIVELY GROWING RATS. AT ... 375 PPM OLD ADULTS DIED AFTER 7 HR WHILE 6-WK-OLD RATS SURVIVED 8 HR AT 500 PPM. [R44, 3935] *... REPEATED INHALATION STUDIES ... AT HIGH CONCN, RATS EXHIBITED HEMORRHAGE OF LUNG, CONGESTION OF VISCERA, LIVER INJURY, HEMOGLOBINURIA, AND MARKED ERYTHROCYTE FRAGILITY. FEMALES WERE MORE SENSITIVE THAN MALES. [R44, 3935] *GUINEA PIGS ... AT HIGH CONCN, CONGESTION AND CLOUDY SWELLING OF TUBULES OF KIDNEYS ... BUT NO INCR IN FRAGILITY OF ERYTHROCYTES ... @ ANY CONCN STUDIED. MICE WERE ... AS RESISTANT AS GUINEA PIGS, WITH EXCEPTION THAT THEIR ERYTHROCYTES WERE AS FRAGILE AS THOSE OF RAT. [R44, 3935] *... RATS /WERE MAINTAINED/ ... ON DIETS CONTAINING 2.0, 0.5, 0.125, and 0.03% ... AT TOP LEVEL, GROWTH DEPRESSION AND INCR KIDNEY AND LIVER WEIGHTS ... AT 0.5% ... GROWTH DEPRESSION AND INCR LIVER WT ... . [R44, 3933] *... 2 DOGS /WERE/ EXPOSED TO VAPOR CONCN OF 415 PPM 7 HR/DAY, 5 DAYS/WK, FOR 12 WK. ... THERE WAS INCR IN NUMBER OF CALCIUM OXALATE CRYSTALS IN URINE AND ... RETENTION OF UREA IN BLOOD ... . [R44, 3935] *DOGS EXPOSED TO HIGH CONCN SUFFERED CONGESTION OF KIDNEYS AND LUNG, WT LOSS, INCR FRAGILITY OF ERYTHROCYTES, NASAL AND EYE INFECTIONS, APATHY, ANOREXIA, NAUSEA, and ... CHANGES IN CIRCULATING BLOOD. LEUCOCYTES ... INCR. WHEREAS ... HEMOGLOBIN ... DECR. ... INCR IN PLASMA FIBRINOGEN. [R44, 3937] *MONKEYS EXPOSED TO 200 PPM SUFFERED MARKED REDUCTION IN NUMBER OF CIRCULATING RED BLOOD CELLS AND IN HEMOGLOBIN CONCN. ... FEMALE MONKEYS EXCRETED 309 MG OF BUTOXYACETIC ACID OVER A 48-HR PERIOD AFTER RECEIVING THE 48-HR EXPOSURE. [R44, 3937] *CHRONIC. LUNG ... SLIGHT TO MODERATE CONGESTION; SOMETIMES BRONCHOPNEUMONIA. SPLEEN, CONGESTION AND FOLLICULAR PHAGOCYTOSIS ... . [R1, 612] *... BY INHALATION /MEDIAN LETHAL DOSE/, FOR RATS, 432 PPM 7 HR/DAY, 5 DAYS/WK FOR 30 DAYS; FOR GUINEA PIGS, 494 PPM KILLED ONLY 2 OUT OF 10; FOR DOGS, 617 PPM AFTER 13 1/2 HR EXPOSURES IN 2 DAYS. ACUTE. SLUGGISHNESS, ROUGH COAT, PROSTRATION AND ... /CNS DEPRESSION/ IN HIGH CONCN ... CORNEAL OR LENS OPACITY. [R1, 611] *ACUTE. SLUGGISHNESS, ROUGH COAT, PROSTRATION AND ... /SRP: CNS DEPRESSION/ IN ANIMALS DYING FROM ORAL DOSE ... IN MICE ... DYSPNEA WAS CONSTANT SIGN AND WITH HIGH CONCN ... CORNEAL OR LENS OPACITY. [R1, 611] *INHALATION (84 MG/CU M, 6 HR DAILY, 3 DAYS/WK, FOR 4 MO) CAUSED ADAPTATION IN RATS AND MICE, PROBABLY CONSISTING OF CHANGES OF ENZYME SYSTEMS OF ERYTHROCYTES, PROTECTING HEMOGLOBIN AND ERYTHROCYTE MEMBRANE FROM PEROXIDATION. 3-HR, 6 DAYS/WK FAILED TO INDUCE ADAPTATION. [R52] *HIGH DOSES OF ORALLY ADMIN ETHYLENE GLYCOL MONOALKYL ETHERS PRODUCED TESTICULAR ATROPHY AND LEUKOPENIA IN MICE. A DOSE RESPONSE RELATION WAS OBSERVED. /ETHYLENE GLYCOL MONOALKYL ETHERS/ [R53] *Fifty pregnant CD-1 mice were given 1,180 mg/kg/day of ethylene glycol monobutyl ether in water by gavage on days 6-13 of gestation and allowed to deliver. Ethylene glycol monobutyl ether caused 20% mortality in treated dams but had no effect on the offspring of treated animals. [R54] *The reproductive effects of ethylene glycol monomethyl ether and propylene glycol monomethyl ether inhalation were investigated in rats. To determine the effects on testis and hematology, male Wistar rats were exposed to 100 or 300 ppm ethylene glycol monomethyl ether or 200 or 600 ppm propylene glycol monomethyl ether for 6 hr per day for 10 consecutive days in an inhalation chamber. The teratogenic potential on the developing embryo was assessed by exposing pregnant female rats to 100 or 300 ppm ethylene glycol monomethyl ether and 200 or 600 ppm propylene glycol monomethyl ether for 6 hr per day on days 6 to 17 of gestation. Other studies investigated the teratogenic potential of diethylene ethylene monomethyl ether in the postnatal development test, effect on route of administration on teratogenic potential of ethylene glycol monomethyl ether, effect of ethylene glycol monoisopropyl ether on the testis and blood, effect of a single inhalation exposure to ethylene glycol monomethyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monomethyl ether, and ethylene glycol monobutyl ether, and exposure of a single exposure to ethylene glycol monomethyl ether on the testis of male rats. Ethylene glycol monomethyl ether caused testicular atrophy at 300 ppm and showed teratogenic potential at 100 ppm; propylene glycol monomethyl ether did not cause testicular atrophy or affect embryonic development at 600 ppm by inhalation. Diethylene glycol monomethyl ether showed no teratogenic potential when administered subutaneously in rats up to 1,000 ul/kg, whereas ethylene glycol monomethyl ether had effects at 40 ul/kg. Ethylene glycol monomethyl ether caused testicular changes in rats after a single exposure to 600 ppm or more for 4 hr. Ethylene glycol monoethyl ether caused a reduction in testicular weight following a single exposure to saturated vapor of 17 mg/l for 3 hours; ethylene glycol monoisopropyl ether at 15 mg/l and ethylene glycol monobutyl monobutyl ether at 4 mg/l showed no effect on the testis. [R55] *Previous NIOSH studies demonstrated the embryo- and fetotoxicity and teratogenicity of ethylene glycol monoethyl ether applied to the shaved skin of pregnant rats. In the present study ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, and diethylene glycol monoethyl ether were tested in the same experimental model, using distilled water as the negative control and ethylene glycol monoethyl ether as a positive control. Water or undiluted glycols were applied four times daily on days 7 to 16 gestation to the shaved interscapular skin with automatic pipetter. Volumes of ethylene glycol monoethyl ether (0.25 ml), ethylene glycol monoethyl ether acetate (0.35 ml), and diethylene glycol monoethyl ether (0.35 ml) were approximately equimolar (2.6 mmole per treatment). Ethylene glycol monobutyl ether at 0.35 ml four times daily (approximately 2.7 mmole per treatment) killed 10 of 11 treated rats, and was subsequently tested at 0.12 ml (0.9 mmole) per treatment. Ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate treated rats showed a reduction in body weight relative to water controls that was associated with completely resorbed litters and significantly fewer live fetuses per litter. Visceral malformations and skeletal variations were significantly increased in ethylene glycol monoethyl ether and ethylene glycol monoethyl ether acetate groups over the negative control group. No embryotoxic, fetotoxic, or teratogenic effects were detected in the ethylene glycol monobutyl ether or diethylene glycol monoethyl ether treated litters. [R56] *Mice were intubated during gestation and were evaluated for signs of toxicity. In the teratology probe, uterine contents were examined at term. In the postnatal study, offspring were examined and weighed through day 22 postpartum. Ethylene glycol monoethyl ether produced embryo lethality and malformations, and decreased fetal weight at a dose level which was not maternally toxic in the teratology probe. In the postnatal study, ethylene glycol monoethyl ether decreased litter size and neonatal body weight; while litter size continued to decrease beyond neonatal period, body weights of surviving pups were not significantly different from control. Pups exposed prenatally to ethylene glycol monoethyl ether developed kinked tail which was not apparent in fetuses or neonates. Maternally toxic doses levels of ethylene glycol monobutyl ether ethanol were associated with increased embryo lethality in teratology probe studies. In postnatal studies, there were no significant effects on pup growth or survival at maternally toxic dose levels. The teratology probe measures resorption incidence which may be a more sensitive index of prenatal death than number of live born. Neither fetal weight nor neonatal weight reliably predict permanent alteration of growth. [R57] *Structure activity studies with nine glycol alkyl ethers were conducted with a cellular leukemia transplant model in male Fischer rats to measure the effects on neoplastic progression in transplant recipients. Chemicals were given ad libitum in the drinking water simultaneously with the transplants and continued throughout the study. In all 20 million leukemic cells were injected sc into syngeneic rats, which after 60 days resulted in a 10-fold increase in relative spleen weights, a 100-fold increase in white blood cell counts, and a 50% reduction in red blood cell indices and platelet counts. Ethylene glycol monomethyl ether given at a dose of 2.5 mg/ml in the drinking water completely eliminated all clinical, morphological, and histopathological evidence of leukemia, whereas the same dose of ethylene glycol monoethyl ether reduced these responses by about 50%. Seven of the glycol ethers were ineffective as anti-leukemic agents, including ethylene glycol, the monopropyl, monobutyl, and monophenyl ethylene glycol ethers, diethylene glycol, and the monomethyl and monoethyl diethylene glycol ethers. Ethylene glycol monomethyl ether more than double the latency period of leukemia expression and extended survival for at least 21 days. A minimal effective dose for a 50% reduction in the leukemic responses was 0.25 mg/ml ethylene glycol monomethyl ether in the drinking water (15 mg/kg body weight), whereas a 10-fold higher dose of 2-ethylene glycol monoethyl ether was required for equivalent antileukemic activity. In addition, the in vitro exposure of a leukemic spleen mononuclear cell culture to ethylene glycol monomethyl ether caused a dose- and time-dependent reduction in the number of leukemia cells after a single exposure to 1-100 uM concentrations, whereas the ethylene glycol monomethyl ether metabolite, 2-methoxyacetic acid, was only half as effective. [R58] *Studies were conducted on the percutaneous absorption, distribution, excretion, and hemolytic activity of n-butoxyethanol. Rats receiving a subcutaneous dose of (14)C-labeled n-butoxyethanol excreted the radioactivity in the urine (79%), expired air (10%), and feces (0.5%) within 72 hr. Of the organs analyzed, thymus and spleen showed elevated specific radioactivities as compared with blood. A percutaneous application of n-butoxyethanol on rats, under nonocclusive conditions, showed 25-29% absorption within 48 hr. Peak blood levels of n-butoxyethanol occurred at 2 hr after application; butoxyacetic acid was found to be the major metablite. Comparison of in vitro skin penetration data showed the following absorption pattern of n-butoxyethanol: hairless rat much greater than pig greater than human skin. Hemolysis and associated hematological changes were noted in the rats which received single dermal applications of 260-500 mg/kg of n-butoxyethanol. In vitro, butoxy acetic acid showed markedly greater hemolytic ability on rat erythrocytes than did n-butoxyethanol. Human erythrocytes showed no hemolysis when incubated with n-butoxyethanol or butoxy acetic acid at concentrations that are hemolytic to rat erythrocytes. An intravenous dose of 62.5 mg/kg of n-butoxyethanol does not result in hemolysis or hemoglobinuria in the rat. The rat may be an animal model with increased susceptibility to the effects of n-butoxyethanol compared with humans because of its rapid percutaneous absorptive ability and its greater hemolytic sensitivity. [R59] *2-Butoxyethanol causes acute hemolytic anemia in rats, and activation of 2-butoxyethanol to butoxyacetic acid, presumably through the intermediate 2-butoxyacetaldehyde, is a prerequisite for development of hematotoxicity. The effects of 2-butoxyethanol and its metabolites, 2-butoxyacetaldehyde and butoxyacetic acid, on erythrocytes from rats were investigated in vitro. At 20 mM, 2-butoxyethanol caused hemolysis of rat erythrocytes accompanied by a decrease in hematocrit. In contrast, incubation of 2-butoxyacetaldehyde or butoxyacetic acid with rat blood caused time- and concentration-dependent swelling of red blood cells followed by hemolysis; butoxyacetic acid was significantly more efficacious than 2-butoxyacetaldehyde. Addition of aldehyde dehydrogenase and its co-factors potentiated the effect of 2-butoxyacetaldehyde on rat erythrocytes. Incubation of rat blood with butoxyacetic acid or 2-butoxyacetaldehyde cused a time- and concentration-dependent decrease in blood ATP concentration. The decrease in blood ATP was greater with butoxyacetic acid than with 2-butoxycetaldehyde and was not induced by 2-butoxyethanol. Butoxyacetic acid caused no significant changes in the concentration of reduced glutathione and glucose-6-phosphate dehydrogenase in rat erythrocytes. The hemolytic effect of 2-butoxyethanol can be attributed primarily to its metabolite butoxyacetic acid, and hemolysis of rat erythrocytes by butoxyacetic acid or 2-butoxyacetaldehyde is preceded by swelling and ATP depletion. [R49] *Male rats were given ethylene glycol monomethyl ether or ethylne glycol monobutyl ether per os for 4 consecutive days at doses of 100 or 500 mg/kg body wt/day for ethylene glycol monobutyl ether, and 500 or 1000 mg/kg body wt/day for ethylene glycol monobutyl ether. Animals were examined on days 1, 4, 8, and 22 after the final treatment. Both ethylene glycol monomethyl ether and ethylene glycol monobutyl ether produced thymic atrophy and lymphocytopenia and, in the case of ethylene glycol monobutyl ether, neutropenia also. Hemolytic anemia induced by ethylene glycol monobutyl ether resulted in splenic extramedullary hemopoiesis, hyperplasia of both spleen and bone marrow, and reticulocytosis. Apart from residual slight increases in spleen weight, mean red cell volume, and mean corpuscular hemoglobin at the end of the recovery period, other effects were reversible. With ethylene glycol monomethyl ether, reduction in the numbers of circulating red cells was only slight. Treatment with ethylene glycol monomethyl ether also abolished splenic extramedullary hemopoiesis which partially recovered on day 4, followed by a marked response on day 8, and return to the control values on day 22. Femoral bone marrow was hemorrhagic 1 day after treatment with ethylene glycol monomethyl ether which appeared to be associated with sinus endothelial cell damage. By day 4 the histologic appearance of the marrow was normal. Testicular atrophy was also produced in ethylene glycol monomethyl ether-treated animals. Ethylene glycol monomethyl ether and ethylene glycol monobutyl ether differ considerably in the spectrum of toxic changes induced, and apart from testicular atrophy, these changes were largely reversible within a short time of the end of treatment. [R60] *Structurally related alkyl glycol ethers were examined for their ability to block junction-mediated intercellular communication. Interruption of intercellular communication was measured in vitro by an assay that depends on the transfer of metabolites via gap junctions, ie, metablic cooperation. All compounds tested ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, and ethylene glycol monobutyl ether were able to block metabolic cooperation in vitro. The potencies of the compounds were inversely related to the length of the aliphatic chain, the dose required for maximum blockage increasing as the aliphatic chain shortened. Cytotoxicity, as measured by cell survival, was also related to the structure of the compound, generally increasing with increased length of the aliphatic chain. [R61] *Timed-pregnant Fischer 344 rats and New Zealand White rabbits were exposed to ethylene glycol monobutyl ether vapors by inhalation on gestational days 6 through 15 (rats) or 6 through 18 (rabbits) at concentrations of 0, 25, 50, 100 or 200 ppm. The animals were sacrificed on gestational day 21 (rats) or 29 (rabbits). In rats, exposure to 200 or 100 ppm resulted in maternal toxicity (clinical signs, decreased body weight and weight gain, decreased absolute and relative organ weights, decreased food and water consumption and evidence of anemia), embryotoxicity (increased number of totally resorbed litters and decreased number of viable implantations per litter) and fetotoxicity (reductions in skeletal ossification). No increase in fetal malformations was observed in any exposure group relative to controls. At 50 or 25 ppm, there was no maternal, embryo or fetal toxicity (including malformations) in rats. In rabbits, exposure to 200 ppm resulted in maternal toxicity (apparent exposure-related increases in deaths and abortions, clinical signs, decreased weight during exposure and reduced gravid uterine weight at sacrifice) and embryotoxicity (reduced number of total and viable implantations per litter). No treatment-related fetotoxicity was seen. No treatment-related increase in fetal malformations or variations were seen at any exposure concentration tested. There was no evidence of maternal, embryo, or fetal toxicity (including malformations) at 100, 50 or 25 ppm in rabbits. [R62] *Investigated the teratogenicity of five compounds. Each chemical was vaporized and administered to pregnant rats in one to three concentrations for 7 hr/day on gestation days 7 to 15, and dams were sacrificed on day 20. At concentrations which were apparently not maternally toxic, 2-methoxyethanol was highly embryotoxic, producing complete resorptions at 200 ppm; increased resorptions, reduced fetal weights and skeletal and cardiovascular defects occured at both 100 and 50 ppm. 2-Ethoxyethyl acetate at 600 ppm induced complete resorption of litters; 390 ppm reduced fetal weights and induced skeletal and cardiovascular defects, but only a single defect was observed at 130 ppm. 2-Butoxyethanol evidenced slight maternal toxicity at 200 ppm but produced no increase in congenital defects at that concentration. Neither 2-(2-ethoxyethoxy)ethanol (100 ppm) nor 2-methylaminoethanol (150 ppm) was maternally toxic or embryotoxic. Shorter alkyl chained glycol ethers produced greater embryotoxicity than those having longer chains, and the ester produced effects equivalent to the ether. [R63] *In F344 male rats, 2-butoxyethanol causes severe acute hemolytic anemia resulting in significant increase in the concentration of free plasma hemoglobin. Secondary to the hemolytic effects, 2-butoxyethanol also caused hemoglobinuria as well as histopathologic changes in the liver and kidney. The hemolytic effects of 2-butoxyethanol were age dependent with older rats being more sensitive than younger rats. There was a higher portion of the administered dose eliminated as carbon dioxide a higher portion of the administered dose was excreted in the urine of young rats. Analysis of the urinary metabolites showed that the ratio of butoxyacetic acid 2-butoxyethanol glucuronide + 2-butoxyethanol sulfate (previously thought to reflect an activation/detoxification index of 2-butoxyethanol) was higher in old rats. The increase in the activation/detoxification index in older rats is caused by decreased degradation of butoxyacetic acid to carbon dioxide and by depressed urinary excretion of butoxyacetic acid in the urine of older rats. [R64] *2-Butoxyethanol given orally to mice for 5 weeks at a dose of 1000 mg/kg produced no change in absolute or relative testis weights. [R46, 1991.162] *Exposure of pregnant rats at 100 ppm or rabbits at 200 ppm during organogenisis resulted in maternal toxicity and embryotoxicity, including a decrease number of viable implantations per litter. Slight fetotoxicity in the form of poorly ossified or unossified skeletal elements was also observed in rats. Teratogenic effects were not observed in either species. [R46, 1991.162] +... ... Conclusions: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of 2-butoxyethanol in male F344/N rats exposed to 31.2, 62.5 or 125 ppm. There was equivocal evidence of carcinogenic activity of 2-butoxyethanol in female F344/N rats based on incr incidences of benign or malignant pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence of carcinogenic activity of 2-butoxyethanol in male B6C3F1 mice based on incr incidences of hemangiosarcoma of the liver. ... There was some evidence of carcinogenic activity of 2-butoxyethanol in female B6C3F1 mice based on incr incidences of forestomach squamous cell papilloma or carcinoma (mainly papilloma). [R65] HTXV: *The lethal oral dose /of ethylene glycols/ in humans is approximately 1.4 ml/kg, which would be equivalent to approximately 100 ml for a 70-kg person. /Ethylene glycols/ [R66] NTXV: *LD50 Rat oral 1.48 g/kg; [R14] *LD50 Mouse oral 1.2 g/kg; [R67, 315] *LD50 Rabbit oral 0.32 g/kg; [R67, 315] *LD50 Guinea pig oral 1.2 g/kg; [R67, 315] *LD50 Rabbit dermal 400 mg/kg; [R46, 1991.162] ETXV: *LC50 Lepomis macrochirus 1490 ppm/96 hr. (Static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr); [R67, 315] *LC50 Menidia beryllina 1250 ppm/96 hr (static bioassay in synthetic seawater at 23 deg C, mild aeration applied after 24 hr); [R67, 315] *LC50 Crangon crangon (brown shrimp) 800 mg/l/48 hr (range: 600-1000 mg/l). /Conditions of bioassay not specified/; [R67, 314] *LC50 Poecilia reticulata (guppy) 983 ppm/7 day. /Conditions of bioassay not specified/; [R67, 314] NTP: +... 2 Year Study in Rats: Groups of 50 male and 50 female F344/N rats were exposed to 2-butoxyethanol by inhalation at concn of 0, 31.2, 62.5 or 125 ppm 6 hr/day, 5 days per week for 104 weeks. ... 2 Year Study in Mice: Groups of 50 male and 50 female B6C3F1 mice were exposed to 2-butoxyethanol by inhalation at concn of 0, 62.5, 125 or 250 ppm 6 hr/day 5 days per week for 104 weeks. ... Conclusions: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of 2-butoxyethanol in male F344/N rats exposed to 31.2, 62.5 or 125 ppm. There was equivocal evidence of carcinogenic activity of 2-butoxyethanol in female F344/N rats based on incr incidences of benign or malignant pheochromocytoma (mainly benign) of the adrenal medulla. There was some evidence of carcinogenic activity of 2-butoxyethanol in male B6C3F1 mice based on incr incidences of hemangiosarcoma of the liver. ... There was some evidence of carcinogenic activity of 2-butoxyethanol in female B6C3F1 mice based on incr incidences of forestomach squamous cell papilloma or carcinoma (mainly papilloma). [R65] +Ethylene Glycol Monobutyl Ether (EGBE) ... was tested for reproductive toxicity in Swiss CD-1 mice using the RACB protocol. It was part of a series of glycol ethers and congeners evaluated for structure-activity correlations using this design. Data collected on body weights, clinical signs, and food/water consumption during the dose-range-finding segment (Task 1) were used to set concns for the main study (Task 2) at 0.5%, 1.0%, and 2.0% EGBE in drinking water. These concns produced calculated consumption estimates of nearly equal to 0.72, 1.35, and 2.0 g/kg/day. Excessive mortality (65%) was seen in the high-dose females during Task 2; 6/20 females died in the 1% group, and 1/20 in the control and 0.5% groups. Male mice in the middle and high dose groups showed less weight gain during Task 2. Water consumption was reduced in all treatment groups, by approx 50%. The number of live pups/litter was reduced by 52% and 71% in the middle and high dose groups, respectively, and the proportion of pups born alive was reduced in these groups by nearly equal to 40% and 45%. As EGBE concn increased, adjusted pup weight decreased by 5%, 11%, and 16%. At the crossover mating trial, using the controls and the 1.0% EGBE group, EGBE-treated females delivered 34% fewer pups which weighed 12% less than control pups. At necropsy after Task 3, F0 females from the 1.0% EGBE group weighed 10% less than controls, while the kidneys and liver (adjusted for body weight) weighed 17% and 21% more than controls. EGBE-treated F0 males weighed 9% less than controls, with kidneys that weighed 13% more than controls, and testes that weighed 8% less. There were no changes in sperm indices. Due to the reduced fertility in the 1% EGBE group, insufficient animals were available to test the second generation at this dose. Thus, the second generation was evaluated using the 0.5% group and the controls. There was no indication of reduced body weight gain during maturation to mating at 74 ± 10 days of age. While there was no difference between the two groups in the proportion of pairs mating or becoming pregnant, there was a 5% reduction in the weight of the F2 pups. At F1 necropsy, body weights were not different between the groups, although in females , liver weight and kidney weight were increased by 7% and 22%, respectively. In males, liver weight was increased by 9%. In summary, EGBE was a reproductive toxicant, based on reductions in pup weight and litter size, but these occurred only at concns that reduced water intake and fluid consumption, altered liver and kidney weights and/or induced significant lethality (F0's). In F1's, reduced pup weight was seen concomitant with increased liver and kidney weight. [R68] +The present study was conducted to determine whether exposure of pregnant F/344 rats to ethylene glycol monobutyl ether (EGBE) during critical periods of cardiovascular development adversely affected the structure of the fetal heart and great vessels. Ethylene glycol monobutyl ether dissolved in distilled water was administered daily by gavage on either gestational days (gd) 9 through 11 at doses of 0. 30. 100 or 200 mg/kg/day or on gestational days 11 through 13 at doses of 0, 30, 100 or 300 mg/kg/day . The maternal effects of ethylene glycol monobutyl ether given from gestational days 9 through 11 or from gestational days 11 through 13 at doses greater than or equal to 100 mg/kg/day included marked reductions in body weight and/or weight gain, increases in organ weights (kidney and spleen) and severe hematotoxicity. In particular, dramatic reductions in circulating red blood cells, hematocrit and hemoglobin resulted by 24 hr after treatment. By gestational days 20, the hematotoxic effects were nearly reversed. The changes observed in hematological parameters and organ weights in this study are typical of hemolytic anemia and the compensatory hematopoietic response associated with recovery. Following developmental phase-specific dosing of the dams with ethylene glycol monobutyl ether, neither heart nor great vessel defects were observed in fetuses examined near term (gestational days 20). No other indications of embryo/fetal toxicity were observed at the low and middle doses which were either nontoxic (30 mg/kg/day ) or toxic (100 mg/kg/day ) to the dams. The viability of embryos was markedly reduced by ethylene glycol monobutyl ether treatment at 200 mg/kg/day from gestational days 9 through 11, a dose that also produced severe hematotoxicity as well as general toxicity in the dams. In conclusion, development of the F/344 rat was not uniquely sensitive to ethylene glycol monobutyl ether at 30 or 100 mg/kg/day , po, administered on either gestational days 9 through 11 or gestational days 11 through 13. Reduced prenatal viability was noted at 200 mg/kg/day following exposure on gestational days 9 through 11, but not on gestational days 11 through 13. Thus, 100 mg/kg/day was the no-observed-adverse-effect level (NOAEL) for developmental toxicity in this study. The maternal NOAEL was 30 mg/kg/day for both treatment periods. [R69] TCAT: ?Teratogenicity was evaluated in mated Fischer 344 rats (30/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations (number of pregnant rats) of 0 (21), 100 (21), 200 (16) or 300 (24) ppm on gestation days (GD) 6-15 for 6 hrs/day. The rats were sacrificed on GD 21. There were significant differences observed between pregnant treated and control animals in the following: decreased maternal body weight gain and decrease in food consumption (all treated groups during exposure), increased food consumption (200 and 300 ppm groups, post-exposure), decreased water consumption (200 and 300 ppm, exposure period), decreased uterine and liver absolute weights (300 ppm), increased non-viable implantations and percent pre-implantation loss and decreased viable implantations and percent live implantations (300 ppm), increased incidence of ventricular septal defect, and absent and severely shortened innominate artery (300 ppm). There were no significant differences observed between pregnant treated and control animals in the following: post-exposure water consumption, weights of thymus and spleen, relative weights of uterus and liver, numbers of corpora lutea, and total implantations. [R70] ?Teratogenicity was evaluated in pregnant Fischer 344 rats (36/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-15. The rats were sacrificed on GD 21. There were significant differences observed between treated and control animals in the following: increase in number of totally resorbed litters (200 ppm group), increased incidence of clinical observations including cold and pale extremities, abnormal tails, fur and urogenital areas stained, urogenital wetness and encrustation, occult blood (200 ppm), periocular wetness and perinasal encrustation (100 and 200 ppm), decreased body weight (200 ppm), decreased body weight gain (100 and 200 ppm, exposure period, 200 ppm post-exposure period also), decreased food consumption (100 and 200 ppm, exposure period), increased water consumption (100 ppm, post-exposure), decreased gravid uterine weight and increased relative and absolute spleen and relative kidney weights (200 ppm), decreased red blood cell count and mean corpuscular hemoglobin volume and increased mean corpuscular volume and corpuscular hemoglobin level (100 and 200 ppm), increased hemoglobin and hematocrit levels (200 ppm), decreased viable implants and percent live fetuses and increased non-viable implants and embryonic resorptions (200 ppm), increased number of litters with 1 or more cases of unossified skeletal elements (100 and 200 ppm) including anterior arch of the atlas and cervical centra, cervical arches, sternebrae, and proximal phalanges (200 ppm), unossified cervical centrum (100 ppm), and decreased incidence of bilobed cervical centrum 5 (100 and 200 ppm). There were no significant differences observed between treated and control animals in the following: pregnancy rates, early deliveries, dead fetuses, liver and thymus and absolute kidney weights, numbers of corpora lutea, total implants, dead fetuses, pre-implantation loss, fetal sex ratio, mean litter weight, external, visceral, skeletal or total malformations. [R71] ?Teratogenicity was evaluated in pregnant New Zealand white rabbits (24/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-18. The rats were sacrificed on GD 29. There were significant differences observed between treated and control animals in the following: decreased maternal body weight (200 ppm group on GD 15), increased hemoglobin and hematocrit levels (100 ppm group), decreased gravid uterine weight (200 ppm), reduced number of total implants and viable implants/litter (200 ppm), increased number of litters with fusion of papillary muscles in left ventricle (100 ppm), and reduced ossification of sternebra 6 and rudimentary rib (200 ppm). There were no significant differences observed between treated and control animals in the following: maternal mortality, number of spontaneous abortions, pregnancy rates, maternal body weight gain, number of non-viable implants, pre-implantation losses, percent live fetuses, sex ratio, fetal body weights/litter, and number of fetuses or of litters with one or more affected fetuses with pooled external, visceral, skeletal or total malformations. [R71] ?Acute oral toxicity was evaluated in 4 groups of 10 male albino rats (Wistar strain) administered PolySolv EB (ethylene glycol mono-n-butyl ether) by gavage at 0.67, 1.31, 2.56 and 5.0 g/kg dose levels. Mortality was observed within 14 days of dosing in 3 rats at the 1.31 g/kg dose level, 8 rats at the 2.56 g/kg dose level and all rats at the 5.0 g/kg dose level. The LD50 was calculated to be 1.59 g/kg with 95% confidence limits of 1.11 - 2.27 g/kg. Clinical observations include piloerection and lethargy at the 1.31 and 2.56 g/kg dose levels, flaccidity at the 2.56 g/kg dose level, and ataxia at the 5.0 g/kg dose level. Gross necropsy revealed dark liver and kidney in 3, and enlarged kidney in 4 rats at the 1.31 g/kg dose level; red intestine in 1 and blood in the bladder in all rats at the 2.56 g/kg dose level; blood in the bladder in all rats at the 5.0 g/kg dose level. [R72] ?Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS male rats administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not reported). Mortality occurred within 14 days after dosing, but the LD50 value was not reported. Clinical observations included inactivity, labored breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and prostration. Gross necropsy of animals dying within 14 days of dosing revealed bloody urine, and blood in the stomach and intestine. These conditions were not observed in animals surviving through 14 days. [R73] ?Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS CD-1 male mice administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not reported). Mortality occurred within 14 days after dosing, but the LD50 value was not reported. Clinical observations included inactivity, labored breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and prostration. Gross necropsy of animals dying within 14 days of dosing revealed bloody urine and blood in the stomach and intestines. These conditions were not observed in animals surviving through 14 days. [R73] ?Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS male rats administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not reported). Mortality occurred within 14 days after dosing, but the LD50 value was not reported. Clinical observations included inactivity, labored breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and prostration. Gross necropsy of animals dying within 14 days of dosing revealed bloody urine, and blood in the stomach and intestine. These conditions were not observed in animals surviving through 14 days. [R74] ?Acute oral toxicity was evaluated using 5 groups of 5 Charles River COBS CD-1 male mice administered ethlyene glycol mono-n-butyl ether by gavage (dose levels not reported). Mortality occurred within 14 days after dosing, but the LD50 value was not reported. Clinical observations included inactivity, labored breathing, rapid respiration, anorexia, slight to moderate weakness, tremors and prostration. Gross necropsy of animals dying within 14 days of dosing revealed bloody urine and blood in the stomach and intestines. These conditions were not observed in animals surviving through 14 days. [R74] ?Acute oral toxicity was evaluated in groups of male and female Sherman rats (total number not reported) administered single doses of a 10% water dilution of butyl Cellosolve (ethylene glycol mono-n-butyl ether) by gavage (number of dose levels not reported). Mortality was observed within 14 days of dosing. The oral LD50 value for males was calculated (using Thompson's method) to be 2.9 g/kg, and for females, 2.3 g/kg. Clinical observations included sluggishness, rough coat, prostration and narcosis. Gross necropsy revealed congested or hemorrhagic lungs, mottled liver, congested kidneys and bloody urine. [R75] ?Acute oral toxicity was evaluated in groups of 5 rats (sex and strain not reported) administered single doses (method of administration not reported) of ethylene glycol n-butyl ester ether at dose levels of 0.252, 0.5, and 1.0 g/kg. Mortality was observed within 4 days of dosing in 3 animals at 0.5 g/kg and 2 at 1.0 mg/kg; the LD50 was 0.47 g/kg. Clinical observations included drowsiness and blood in the urine. Gross necropsy findings were not reported. [R76] ?Acute oral toxicity was evaluated in groups of 5 male Wistar rats administered single doses of butyl oxide by oral gavage at dose levels of 1.25, 2.50, 5.0, and 10.0 ml/kg of body weight. Mortality was observed within 1 day of dosing in 2 animals of the 2.50 ml/kg group, and in 5 rats of each of the 5.0 and 10.0 ml/kg groups; the LD50 was 2.68 ml/kg of body weight. Clinical observations included bloody saliva, sluggishness, difficult breathing and an unsteady gait. Gross necropsy revealed dark livers, stomach distention, red kidneys and adrenals, and blood was found in the intestines. [R77] ?Acute oral toxicity was evaluated in 5 groups of 3 female CDF Fischer-344 rats receiving ethylene glycol mono-n-butyl ether by oral gavage at dose levels of 130, 250, 300, 500, 1000, or 2000 mg/kg. Mortality was observed at the 2 highest dose levels. The oral LD50 ranged from 1000 and 2000 mg/kg. Clinical observations included staining of perineal region, rough hair coat, lethargy, rapid shallow breathing and palpebral closure. Gross necropsy findings were not reported. [R78] ?Acute dermal toxicity was evaluated in 4 groups of 4 New Zealand white rabbits (sex not reported) administered single doses of PolySolv EB (ethylene glycol mono-n-butyl ether) on clipped and abraded skin at dose levels of 0.25, 0.5, 1.0 and 2.0 g/kg. Mortalities were observed winthin 14 days of dosing in 0/4 rabbits at dose level 0.25 g/kg, 1/4 rabbits at the 0.5 g/kg dose level, and all animals at the two highest dose levels. The Litchfield and Wilcoxon LD50 was calculated to be 0.58 g/kg with 95% confidence limits of 0.31 and 0.85 g/kg. Clinical observations include blood in the urine, yellow cornea, flaccidity, lacrimation and anorexia. Gross necropsy revealed blood in the bladder, as well as discolored liver, kidney and intestines. [R72] ?Acute dermal toxicity was evaluated in rabbits (number, sex distribution and strain not reported) administered single doses (dose levels not reported) of 2-butoxyethanol by open application. The LD50 was 2.0 mL/kg (specific mortalities, clinical observations and gross necropsy not reported). [R79] ?Acute dermal toxicity was evaluated in rabbits (sex and strain not reported) receiving dermal applications of ethylene glycol mono-n-butyl ether at dose levels of 0.2 g/kg (group of 10) or 0.252 g/kg (group of 4). Mortality was observed within 2 to 7 days of dosing in 4 animals of the 0.252 g/kg group. No mortalities were observed at the 0.2 g/kg dose level. A dermal LD50 was not reported. Clinical observations included slight initial weight loss and slight to moderate irritation of the skin at both dose levels. Gross necropsy results were not reported. [R80] ?Acute dermal toxicity was evaluated in groups of 4 male New Zealand white rabbits receiving single applications of butyl oxide to clipped intact skin of the trunk at dose levels of 0.5 and 1.0 ml/kg body weight. Mortality was observed within 1 to 2 days of dosing in 1 animal of the 0.5 ml/kg group and in all animals exposed to 1.0 ml/kg body weight. The LD50 was 0.630 ml/kg body weight (95% confidence limit = 0.386 to 1.03 ml/kg). Erythema and necrosis were noted in the high dose groups. Gross necropsy revealed included blood in the urine, orange-red colored lungs and livers, dark colored spleens, dark red kidneys, orange colored peritoneal and intestines. [R77] ?An acute inhalation toxicity study was conducted with groups of male and female albino Wistar rats (3/sex/group) receiving whole body exposure to the vapors of ethylene glycol monobutyl ether in a dynamic air flow chamber. The vapor was generated in a glass flask containing the test substance maintained at 20 +/- 1 degrees celsius. Maximum exposure was for 7 hours, but if deaths occurred during either the exposure period or observation period, exposures were repeated at shorter intervals. During the 7 hour exposure, no animals died, but 3 females and 1 male animals died between day 1 and day 3 of the 14 day observation period. Therefore the test was repeated, and two additional test were performed at exposure times of 1 and 3 hours. No deaths were reported for the 1 hour group rats and only one 3 hour exposed female animal died on the day 1 of the observation period. Post exposure observations were lethargy (7 and 3 hour group rats), blood in urine (all exposures), piloerection (7 and 3 hour), paleness of eyes and feet (all exposures) and necrosis at the ends of the tail (7 hour). Seven hour group males appeared to recover by day 11; 3 hour males by day 1 and females by days 6-8; and 1 hour males by day 1 and females by day 2. The theoretical saturated concentration of ethylene glycol monobutyl ether at 20 degrees celsius was calculated to be 617ppm and the concentrations by weight loss estimation were calculated to be 769, 771 and 828ppm for the 7, 3 and 1 hour exposure, respectively. [R81] ?Acute 7-hour inhalation toxicity of different industrial formulations of ethylene glycol monobutyl ether (Dowanol EB, n-butyl oxitol - USA (BO-USA), and n-butyl oxitol - Europe (BO-Europe) was evaluated in 3 groups of 4 male albino rabbits (strain not reported) exposed to the nominal concentration of 410 ppm. A fourth group served as negative control. A 1-week observation period followed exposure. The number dead or moribund by group were 3, 1, and 4 in the Dowanol EB, BO-USA, and BO-Europe groups, respectively. Clinical signs reported were poor coordination and loss of equilibrium. Changes in body weight and necropsy results were not reported. [R82] ?Acute 7-hour inhalation toxicity of different industrial formulations of ethylene glycol monobutyl ether (Dowanol EB, n-butyl oxitol - USA (BO-USA), and n-butyl oxitol - Europe (BO-Europe) was evaluated in 3 groups of 2 male beagle dogs exposed to the nominal concentration of 410 ppm. A fourth group served as negative control. A 1-week observation period followed exposure. No dogs died. The only clinical sign reported was salivation during exposure. No body weight changes are mentioned. No animals were sacrificed for necropsy. [R82] ?Acute 7-hour inhalation toxicity of different industrial formulations of ethylene glycol monobutyl ether (Dowanol EB, n-butyl oxitol - USA (BO-USA), and n-butyl oxitol - Europe (BO-Europe) was evaluated in 3 groups of 8 male guinea pigs (strain not reported) exposed to 410 ppm (nominal). A fourth group served as negative control. A 1-week observation period followed exposure. No mortalities were observed. Clinical signs, changes in body weight, and necropsy results are not reported. [R82] ?Acute toxicity was evaluated in groups of 4 female Sprague-Dawley rats receiving a single intraperitoneal injection of n-butyl Oxidol or Dowanol EB Glycol Ether (ethylene glycol monobutyl ether) at dose levels of 200, 252, 316, or 398 mg/kg bw, then observed for two weeks. The LD50 was 252-317 mg/kg bw. All treated rats had bloody urine and nasal porphryin secretion; those treated with the two higher doses of n-butyl Oxidol also displayed tremors. Surviving rats gained weight throughout the recovery period. The authors concluded that both types of ethylene glycol monobutyl ether have similar toxicity when injected intraperitoneally in rats. [R83] ?The effects of ethylene glycol butyl ether (EGBE) at concentration of 0.05, 0.1, 0.25, 0.4, and 0.5% on in vitro human erythrocyte fragility was evaluated employing 0.68% sodium chloride and 37 degrees C incubation. Hemolytic activity was reported to be 1.5, 20.5 and 70.9% at EGBE concentrations of 0.25, 0.4 and 0.5% respectively. This activity was compared to the hemolysis activity of rat, rabbit and dog erythrocytes under the same conditions. Rat hemolytic activity was reported to be 2.5, 51.5 and 62.0% and rabbit activity was 2.8, 83.7, and 72.0% at EGBE concentrations of 0.25, 0.4 and 0.5% respectively. Dog hemolytic activity was 46.8, 36.2, 41.2 and 62.3% at EGBE concentrations of 0.05, 0.1, 0.4, and 0.5% respectively. [R84] ?Subchronic toxicity was evaluated in groups of 10 male Charles River COBS albino rats receiving once daily oral gavage doses of undiluted ethylene glycol monobutyl ether at dose levels of 222, 443, or 885 mg/kg body weight/day, 5 days a week for 6 weeks. Mortality was observed in 2 high dose group rats and 1 middle dose group rat during the treatment period. Clinical observations included lethargy, and red discolored urine. A dose dependent decrease in body weight gain observed throughout the treatment period was only statistically significant (ANOVA, p < 0.05) at the high dose level. Effects on hematological parameters included a dose dependent decrease in hemoglobin concentration, red blood cell count, and mean corpuscular hemoglobin concentrations (MCHC); hemoglobin concentrations and red blood cell counts were reduced (p < 0.05) at all doses, while MCHC was lower (p < 0.05) than control at the middle and high dose levels. Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) showed a dose-dependent increase which was significant (p < 0.05) at all levels for MCH and at the middle and high dose levels for MCV. Slight but significant (p < 0.05) increases were seen in serum glutamic pyruvic transaminase in the high dose group, and alkaline phosphatase was significantly increased in the middle and high dose groups. Relative liver weights were increased (p < 0.05) at all dose levels, while relative weights of the kidneys, heart, brain and spleen were increased in the middle and high dose groups. Gross necropsy examination revealed darkened, enlarged spleens in the middle and high dose groups. Treatment related histopathology included hepatocytomegaly (in the high dose group); focal hemosiderin in livers (high and mid groups); and hyalin droplet degeneration, splenic congestion, minor hemosiderin accumulation in the proximal convoluted tubules of the kidney, hyperkeratosis and acanthosis in the stomach (in all groups). [R85] ?Subchronic oral toxicity was evaluated in 4 groups of 10 male rats (strain not reported) administered ethylene glycol monobutyl ether by gavage at dose levels of 0, 222, 443 and 885 mg/kg/day for 5 days/week over 6 weeks. Mortalities included 2 rats at the 885 mg/kg/day dose level and 1 rat at the 443 mg/kg/day level. Clinical observations included lethargy at the 443 and 885 mg/kg/day treatment levels, as well as rough coat and piloerection at the 885 mg/kg/day dose level. A dose-related weight reduction was observed, but reduced food consumption was significant (statistical test and significance level not reported) only at the 885 mg/kg/day dose level. Dose-related decreases in red blood cell count and in hemoglobin concentration were observed. Elevated liver weights, increased serum alkaline phosphatase concentration (443, 885 mg/kg/day) and increased serum glutamic pyruvic transaminase concentration (885 mg/kg/day) were observed. Serum glucose was reduced in rats at the 885 mg/kg/day treatment level. Gross necropsy revealed enlarged dark spleens at the 443 and 885 mg/kg/day treatment levels. Histopathological evaluation revealed hepatocytomegally and focal hemosiderin in the liver at the two highest dose levels, as well as hemosiderin in the kidney, splenic congestion, and hyperkeratosis and acanthosis in the stomach at all dose levels. Urinalysis was not reported. [R86] ?Subchronic oral toxicity was evaluated in 3 groups of 10 male albino Charles River rats administered diethylene glycol monomethyl ether by gavage at dose levels equivalent to 1/2, 1/4 and 1/8 of the acute LD50 (actual dose levels not reported) 5 days/week for 6 weeks. An additional group of 10 untreated rats was used as a negative control. Compound-related mortality was not observed. The only clinical sign of toxicity was bloody urine and blood around the nares in one rat at the highest dose level. Significant (p < 0.05) weight loss was observed only in rats at the highest treatment level. No treatment-related hematological or clinical biochemistry effects were reported. Reduction in relative testis weight was observed in rats at the highest dose level. Gross necropsy revealed no abnormalities in treated rats, but histopathologic examination revealed testicular atrophy. [R87] ?Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS, CD, BR) given doses of ethylene glycol mono-n-butyl ether equivalent to 0, 1/2, 1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific information regarding doses was not reported), by oral gavage, 5 days/week for six weeks. No effect was noted on mortality. Food consumption and body weights were reduced only in rats from the high-dose group. Dose-related effects were seen on hematological parameters, but not serum chemistry. Relative spleen weights increased in rats from the mid- and high-dose groups, liver weights increased in rats from the high-dose group and smaller than normal thymuses were observed in two rats from the high-dose group. Rats given mid- or high-dose levels had bloody urine, lethargy, unkempt hair coats, piloerection, rales, slight weakness and inactivity. Diffuse hemorrhage of the thymus was observed in one high-dose rat. Rats given the test compound (response to specific dose levels was not reported) had hepatocytomegally, anisokaryosis, and lack of cytoplasmic basophilia in livers, and congestion and extramedullary hematopoiesis in spleens. [R88] ?Subchronic toxicity was evaluated in groups of 10 male albino rats (CR, COBS, CD, BR) given doses of ethylene glycol mono-n-butyl ether equivalent to 0, 1/2, 1/4 or 1/8 of the acute oral LD50 for the test compound in rats (more specific information regarding doses was not reported), by oral gavage, 5 days/week for six weeks. No effect was noted on mortality. Food consumption and body weights were reduced only in rats from the high-dose group. Mean hemoglobin concentration and total erythrocyte count were reduced, and mean corpuscular hemoglobin was increased, in rats from all treatment groups. Rats from the mid- and high-dose groups had increased in mean corpuscular volume and decreased mean corpuscular hemoglobin concentration. Treatment did not alter serum chemistry. Relative spleen weights increased in rats from the mid- and high-dose groups, and liver weights increased and smaller than normal thymuses were observed in rats from the high-dose group. Rats given mid- or high-dose levels had bloody urine, lethargy, unkempt hair coats, piloerection, rales, slight weakness and inactivity. Diffuse hemorrhage of the thymus was observed in one high-dose animal. Rats given the test compound (response to specific dose levels was not reported) had hepatocytomegally, anisokaryosis, and lack of cytoplasmic basophilia in livers, and congestion and extramedullary hematopoiesis in spleens. [R88] ?Subchronic dermal toxicity was evaluated in groups of 20 New Zealand White rabbits (10 male and 10 female) receiving occluded applications of ethylene glycol monobutyl ether at doses of 10, 50 or 150 mg/kg body weight, 5 days/week for 13 weeks. Mortality was observed in 1 low dose group female, 1 mid dose and 1 high dose group male during the treatment period. Clinical observations included red feces, red liquid material on cage lining, anorexia, congestion, nasal discharge, and emaciation. Slight to moderate erythema and edema, along with scaling and flaking were observed at the treatment site. Treatment related changes in food consumption, body weights, or organ to body weight ratios were not observed at any dose level. Additionally, the test article did not induce changes in hematology, or in serum chemistry parameters. Treatment related pathological effects were not observed on gross or microscopic examination of the adrenals, aorta bone, brain, epidymis, esophagus, eyes, gall bladder, heart, intestines, kidneys, liver, lung, lymph node, mammary gland, ovaries, pancreas, parathyroids, pituitary, prostate, sciatic nerve, seminal vesicles, skeletal muscle, spleen, stomach, submandibular salivary gland, testes, thyroids, thymus, tongue, trachea, urinary bladder, uterus, or vagina. [R89] TCAT: ?Subchronic toxicity was evaluated in 3 female and 3 male New Zealand White rabbits exposed to unoccluded doses of diethylene glycol butyl ether as a 1.5% solution in distilled water at a level of 2.0 mg/kg/day for 28 days. There were no mortalities. Clinical observations included slight dermal reaction. Necropsy revealed compound-related abberations in none of the treated animals. [R90] ?Subchronic dermal toxicity was evaluated in 5 groups of 10 New Zealand White rabbits (1:1 sex ratio/group) exposed dermally under occlusive patches to 2-butoxyethanol at nominal dose levels of 0, 0.02, 0.1, 0.2, and 0.4 ml/kg for 6 hours/day, on 9 of 11 consecutive days. Residual test compound was removed with absorbant material, but not washed off, after each exposure. Animals were sacrificed after a 14-day observation period. No treatment-related mortality or ophthalmologic effects were observed. Dose-related progressive erythema, edema, and necrosis were observed at the site of application. Both hemoglobinuria and proteinuria were observed at the 2 highest dose levels, and both were reversible after cessation of dosing. Both reduced red blood cell count and a decrease over time of urinary hemoglobin were observed in the highest dose group. No treatment-related changes were observed in clinical chemistry, body weight, organ weight, or histopathologic data. A gross thickening of the skin at the site of treatment was observed. [R91] ?Subchronic dermal toxicity was evaluated in 4 groups of 20 New Zealand White rabbits (1:1 sex ratio per group) dermally exposed to 0, 10, 50, and 150 mg/kg, respectively. Rabbits were dosed under an occlusive dressing for 6 hours/day, 5 days/week, over a 90-day period. It was not reported whether the site of application was washed after each 6-hour dosing. No treatment-related changes in mortality, clinical signs, food consumption rate, body weight, hematological parameters, serum chemistry, organ weights, gross pathological parameters, or histopathological parameters were observed. [R92] ?Subchronic dermal toxicity was evaluated in groups of 5 male and 5 female New Zealand White rabbits receiving daily dermal (occluded) applications of 1 ml/day of 0, 5, 25, 50, or 100% concentrations of butyl CELLOSOLVE for a total of 9 applications over an 11-day period. There were no treatment-related mortalities. Clinical observations included dermal irritation (necrosis, edema, and erythema). Females in the 100% (undiluted) butyl CELLOSOLVE group displayed significantly reduced (p < 0.05) body weights. Hematological examination revealed significant (p < 0.05) reductions in the mean erythrocyte counts, hemoglobin, and mean corpuscular hemoglobin concentrations and increased mean corpuscular hemoglobin in females administered the undiluted material. Urinalysis revealed hemoglobin in the urine (males at 100%), increased urinary protein levels (males and females at 100%), and the presence of blood (females at 50 and 100%). Clinical biochemical anlaysis was not reported. Gross necropsy findings included thickening of the skin of males at 100%. There were no treatment-related organ/body weight changes. Histopathological examination of the kidneys revealed interstitial nephritis and tubular changes in rabbits exposed to the undiluted material. [R93] ?Subchronic inhalation toxicity was evaluated in 4 groups of Fischer 344 rats exposed by inhalation to ethylene glycol monomethyl ether (butyl CELLOSOLVE) at air concentrations of 0 ppm (15 female, 16 male), 20 ppm (8 female, 8 male), 86 ppm (8 female, 8 male), and 245 ppm (15 female, 16 male), respectively, for 6 hours/day for 9 days. Rats were sacrificed either shortly after the final exposure or after a 14-day observation period. No mortalities were observed. Audible respiration, nasal discharge, and red-stained urine were seen in the highest exposure group. Transient body weight gain decreases occurred in the 2 highest exposure groups. Increases were observed in the 245 ppm group in mean corpuscular volume, nucleated red cells, reticulocytes and lymphocytes (males only), and decreases were seen in erythrocyte count, hemoglobin, and mean corpuscular hemoglobin concentration. Groups exposed to 86 ppm showed an increase in mean corpuscular volume and a decrease in hemoglobin. After the 14-day observation period, only the leukocyte count recovered to control levels. The mean liver/body weight ratio was elevated in females and males of the 2 highest and in the highest exposure groups, respectively. The incidence of gross lesions was not treatment-related. Evaluations of treatment effects on urinalysis, clinical chemistry, and histopathology were not reported. [R94] ?Subchronic inhalation toxicity was evaluated in 4 groups of 32 Fischer 344 rats (1:1 sex ratio per group) exposed by inhalation to ethylene glycol monomethyl ether (butyl CELLOSOLVE) at air concentrations of 0, 5, 25, and 77 ppm for 6 hours/day, 5 days/week over 13 weeks. An interim sacrifice of 6 rats of each sex was executed after 30 exposures. No treatment-related effects were observed in male rats at any exposure level, with respect to mortality, clinical signs (via the Irwin Screen Test), mean body weight, food consumption rate, clinical chemistry, urinalysis, hematology, gross necropsy, and histopathology. Females in the highest exposure group exhibited a transitory depression of weight gain in the first weeks of exposure, as well as minimal reductions in red blood cell count, hemoglobin, and hematocrit. No other treatment-related effects were observed in the females. [R95] ?Hemolysis was evaluated in vitro with human erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.1, 0.25, 0.4, or 0.5% EGBE was 0, 1.5, 20.5, and 70.9%, respectively. [R96] ?Hemolysis was evaluated in vitro with rat erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.1, 0.25, 0.3, 0.4, and 0.5% EGBE was 0, 2.5, 0, 51.5, and 62%, respectively. [R96] ?Hemolysis was evaluated in vitro with dog erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.05, 0.1, 0.4, and 0.5% EGBE was 46.8, 36.2, 41.2, and 62.3%, respectively. [R96] ?Hemolysis was evaluated in vitro with rabbit erythrocytes (suspended in veronal buffered isotonic saline) exposed to ethylene glycol butyl ether (EGBE) for 1 hour. The percent hemolysis for 0.1, 0.25, 0.4, or 0.5% EGBE was 0, 2.8, 83.7, and 72.0%, respectively. [R96] ?In an absorption study, the permeability of human abdominal skin to 2-butoxyethanol was measured in vitro using Franz-type glass diffusion cells. Epidermal layers from human skin were exposed for 8 hours to a solution containing radiolabeled test compound in the donor chamber and the appearance of radioactivity was measured in the receptor chamber. Damage to skin was calculated by comparing the water absorption rates of skin before and after exposure to the test compound. The rate of absorption of the test compound across human skin was 0.20 mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin to water. [R97] ?In an absorption study, the permeability of human abdominal skin to 2-butoxyethanol was measured in vitro using Franz-type glass diffusion cells. Epidermal layers from human skin were exposed for 8 hours to a solution containing radiolabeled test compound in the donor chamber and the appearance of radioactivity was measured in the receptor chamber. Damage to skin was calculated by comparing the water absorption rates of skin before and after exposure to the test compound. The rate of absorption of the test compound across human skin was 0.20 mg/cm2/hr. Exposure to the test chemical did not alter the permeability of skin to water. [R98] ?Metabolism of Dowanol EB (ethylene glycol mono-n-butyl ether) was evaluated in vitro with an equine liver alcohol dehydrogenase assay obtained from the Sigma Chemical Company. The Vmax, Km, and Vmax/Km were 4.06, 1.18X10E-3, and 3.50, respectively. The authors concluded that alcohol dehydrogenase has a high affinity for the test compound, indicating that the test compound is probably metabolized to a significant extent by this enzyme in vivo. [R99] ?Ethylene glycol monobutyl ether (CAS# 111-76-2) was studied for reproductive effects in 50 CD-1 mice when administered by oral gavage for 8 days at 1180 mg/kg/day on gestation days 7 through 14. Observations continued through day 3 postpartum. The dose was selected based on the results of a preliminary maximum tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of 295, 590, 1180, 2365, and 4275 mg/kg administered by oral gavage for 8 days. A water (vehicle) control group was used. The test group included 11 deaths, of which 5 were of pregnant mice, 7 resorbed pregnancies and 24 live births. Chi-square testing showed significant difference (p < 0.01) from the control in the reproductive index (number of females bearing viable litters per number ofpregnant females). ANOVA testing indicated that a trend toward decreased maternal weight and maternal weight changes were not significant and there were no significant changes in litter sizes and litter weight changes between day 1 and day 3 postpartum. [R100] ?Ethylene glycol monobutyl ether (CAS# 111-76-2) was studied for reproductive effects in 50 CD-1 mice when administered by oral gavage for 8 days at 1180 mg/kg/day on gestation days 7 through 14. Observations continued through day 3 postpartum. The dose was selected based on the results of a preliminary maximum tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of 295, 590, 1180, 2365, and 4275 mg/kg/day administered by oral gavage for 8 days. A water (vehicle) control group was used. The test group included 11 deaths of which 5 were of pregnant mice, 7 resorbed pregnancies and 24 live births. Chi-square testing showed significant difference (p < 0.01) from the control in the reproductive index (number of females bearing viable litters per number of pregnant females). ANOVA testing indicated that a trend toward decreased maternal weight and maternal weight changes were not significant and there were no significant changes in litter sizes and litter weight changes between day 1 and day 3 postpartum. [R101] ?A one-generation reproductive toxicity study was conducted with groups of 25 male and 25 female Charles River COBS CD rats administered diethylene glycol butyl ether (DGBE) in deionized water by gavage at a level of 250, 500 or 1000 mg/kg/day. Three groups of males were dosed 60 days prior to mating through to sacrifice and 3 groups of females were dosed 14 days prior to mating, continuing until sacrifice or weaning. Control animals received the vehicle only at a level of 5 ml/kg/day. Treated animals were mated with untreated counterparts and about one-half of the females in each group underwent uterine examinations on gestation day 13. Observations of the treated F0 animals and their offspring included the following: mortality observed in 2 low-dose females, 1 mid-dose male and female and 3 high-dose males and females; excess salivation in high-dose females; reduced body weights in high- dose males; reduction in mean pup body weight during latter stages of lactation in the offspring of high-dose females; and reduction in the mean numbers of uterine implants in high-dose females and females paired with high-dose males. [R102] ?Teratogenicity was evaluated in groups of 6 pregnant CD-1 mice administered ethylene glycol monobutyl ether by oral gavage at doses of 0, 350, 600, 1000, 1500, and 2000 mg/kg on days 8-14 of gestation. Surviving animals were sacrificed on gestation day 18. Maternal mortality was observed in 3 mice at 1500 mg/kg and in all 6 at 2000 mg/kg. Significant reductions in maternal body weights were observed at 1000 and 2000 mg/kg. Clinical signs of maternal toxicity included green-brown or red-brown staining of papers beneath the cages of animals at treatment levels 600 mg/kg and above, while at 1500 and 2000 mg/kg, animals exhibited vaginal discharge, lethargy, abnormal breathing, and the inability of several animals to right themselves. Gross necropsy revealed distention and enlargement of gall bladders (350, 600, 1000 and 1500 mg/kg), enlargement of the spleen (350, 1500 and 2000 mg/kg), and distention of the stomach and intestinal tract (1500 and 2000 mg/kg). Significant changes between dose groups and controls were observed for total resorptions (increased at 1000 and 1500 mg/kg), resorptions/implantation (increased at 1500 mg/kg), and live fetuses/implantation (decreased at 1500 mg/kg). A dose-related increase in resorptions and dead fetuses and decrease in live fetuses was observed. Cleft palates were observed in 4/43 fetuses at 1000 mg/kg and in 1/25 at 1500 mg/kg. [R103] ?Reproductive toxicity was evaluated in groups of 10 pregnant Charles River CD female mice receiving an oral gavage dose of ethylene glycol mono-n-butyl ether at 10 ml/kg body weight on gestation days 7 through 14. Maternal mortality was approximatedly 8% in the test group. Clinical observations and gross necropsy results were not reported. There was a significant reduction (p < 0.05) in the number of live pups per litter, reduced survival, and reduced birth weight among offspring of treated dams. [R104] ?Teratogenicity was evaluated in mated Fischer 344 rats (30/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations (number of pregnant rats) of 0 (21), 100 (21), 200 (16) or 300 (24) ppm on gestation days (GD) 6-15 for 6 hrs/day. The rats were sacrificed on GD 21. There were significant differences observed between pregnant treated and control animals in the following: decreased maternal body weight gain and decrease in food consumption (all treated groups during exposure), increased food consumption (200 and 300 ppm groups, post-exposure), decreased water consumption (200 and 300 ppm, exposure period), decreased uterine and liver absolute weights (300 ppm), increased non-viable implantations and percent pre-implantation loss and decreased viable implantations and percent live implantations (300 ppm), increased incidence of ventricular septal defect, and absent and severely shortened innominate artery (300 ppm). There were no significant differences observed between pregnant treated and control animals in the following: post-exposure water consumption, weights of thymus and spleen, relative weights of uterus and liver, numbers of corpora lutea, and total implantations. [R70] ?Teratogenicity was evaluated in pregnant Fischer 344 rats (36/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-15. The rats were sacrificed on GD 21. There were significant differences observed between treated and control animals in the following: increase in number of totally resorbed litters (200 ppm group), increased incidence of clinical observations including cold and pale extremities, abnormal tails, fur and urogenital areas stained, urogenital wetness and encrustation, occult blood (200 ppm), periocular wetness and perinasal encrustation (100 and 200 ppm), decreased body weight (200 ppm), decreased body weight gain (100 and 200 ppm, exposure period, 200 ppm post-exposure period also), decreased food consumption (100 and 200 ppm, exposure period), increased water consumption (100 ppm, post-exposure), decreased gravid uterine weight and increased relative and absolute spleen and relative kidney weights (200 ppm), decreased red blood cell count and mean corpuscular hemoglobin volume and increased mean corpuscular volume and corpuscular hemoglobin level (100 and 200 ppm), increased hemoglobin and hematocrit levels (200 ppm), decreased viable implants and percent live fetuses and increased non-viable implants and embryonic resorptions (200 ppm), increased number of litters with 1 or more cases of unossified skeletal elements (100 and 200 ppm) including anterior arch of the atlas and cervical centra, cervical arches, sternebrae, and proximal phalanges (200 ppm), unossified cervical centrum (100 ppm), and decreased incidence of bilobed cervical centrum 5 (100 and 200 ppm). There were no significant differences observed between treated and control animals in the following: pregnancy rates, early deliveries, dead fetuses, liver and thymus and absolute kidney weights, numbers of corpora lutea, total implants, dead fetuses, pre-implantation loss, fetal sex ratio, mean litter weight, external, visceral, skeletal or total malformations. [R71] ?Teratogenicity was evaluated in pregnant New Zealand white rabbits (24/group) exposed by inhalation to ethylene glycol mono-butyl ether (EGBE) at nominal concentrations of 0, 25, 50, 100 or 200 ppm on gestation days (GD) 6-18. The rats were sacrificed on GD 29. There were significant differences observed between treated and control animals in the following: decreased maternal body weight (200 ppm group on GD 15), increased hemoglobin and hematocrit levels (100 ppm group), decreased gravid uterine weight (200 ppm), reduced number of total implants and viable implants/litter (200 ppm), increased number of litters with fusion of papillary muscles in left ventricle (100 ppm), and reduced ossification of sternebra 6 and rudimentary rib (200 ppm). There were no significant differences observed between treated and control animals in the following: maternal mortality, number of spontaneous abortions, pregnancy rates, maternal body weight gain, number of non-viable implants, pre-implantation losses, percent live fetuses, sex ratio, fetal body weights/litter, and number of fetuses or of litters with one or more affected fetuses with pooled external, visceral, skeletal or total malformations. [R71] ?An inhalation toxicity study was conducted with groups of 36 mated female F-344 rats exposed to ethylene glycol mono-n-butyl ether at target concentrations (analytical concentrations) of 25 (25), 50 (50), 100 (98), 200 (201), ppm on gestation days (GD) 6-15 for 6 hrs/day. The animals were sacrificed on GD 21. Mortality was not observed. Clinical observations included hematuria, urogenital discharge, red urogenital wetness and encrustations, pale and cold extremities, and necrosis of the tail tip. Maternal toxicity was evident in the high-exposure group by significant changes (p < 0.001) in body weight, body weight gain, gravid uterine weight, and food and water consumption. Absolute and relative spleen weights and relative kidney weights were also increased relative to controls in this group. Toxicity related hematologic observations included significant reductions in erythrocyte count, significant increases in hemoglobin and hematocrit, significant enlargement of red blood cells, increase in hemoglobin per cell, and significant reduction in mean corpuscular hemoglobin concentration. Evidence of maternal toxicity in the 100 ppm dose group included significant changes in the following: weight gain, food consumption, size of red blood cells, and mean corpuscular hemoglobin concentration. Embryotoxicity was indicated in the 200 ppm dose group by a significant increase in number of totally resorbed litters (p < 0.01), a significant decrease in number of viable implantations per litter (p < 0.001) and a significant decrease in percent of live fetuses (p < 0.01). A reduction in skeletal ossification was also observed in these groups. There were no statistically significant increases in the incidence of external, visceral, skeletal, or total malformations in any treatment group relative to controls. [R105] ?An inhalation toxicity was conducted with groups 24 pregnant New Zealand white rabbits of exposed to ethylene glycol mono-n-butyl ether at target concentrations, (analytical concentration) of 25 (25), 50 (50), 100 (98), 200 (201), ppm on gestation days (GD) 6-18 for 6 hrs/day. The animals were sacrificed on GD 29. Mortality was observed in 4 dams in the high-exposure group; however, a significant difference from controls was not observed. Clinical observations included periocular wetness, perinasal wetness and discharge, red fluid on tray, and stained fur. Significantly decreased (p < 0.05) maternal body weight, and gravid uterine weight, and increased number of abortions (4) were observed in the high dose group. A significant reduction (p < 0.05) in the number of total implants and viable implants per litter were observed at the high-exposure level. There were no significant effects on the number of non-viable implants, preimplantation loss, percent live fetuses, sex ratio, or fetal body weight per litter. A significant increase (p < 0.05, Fisher's Exact Test) was observed in unossified sternebra 6 and in the rudimentary rib lumbar 1, bilateraly. No statistically significant increases in the incidence of malformations was observed in any treatment group relative to controls. [R105] ?Teratogenicity was evaluated in groups of 36 pregnant Fischer 344 rats exposed to ethylene glycol monobutyl ether vapors at concentrations of 0, 25, 50, 100, and 200 ppm for 6 hours/day on days 6-15 of gestation. Maternal mortality was not observed and all rats were sacrificed on gestation day 21. Clinical signs of maternal toxicity at 100 and 200 ppm included red straining and wetness of the fur, fluid on trays beneath cages, periocular wetness, and perinasal encrustation. Additional clinical observations at 200 ppm included cold and pale extremities, discoloration and ulceration of the tail tip, and absence of the tail tip. A significant (p < 0.001, Bonferroni t-test) reduction in maternal body weights was observed at 200 ppm, as was the rate of food consumption at 100 and 200 ppm. Hematologic findings included significantly (p < 0.001) reduced hemoglobin and hematocrit values at 200 ppm and red blood cell counts at 100 and 200 ppm. Gross necropsy of dams revealed a significant (p < 0.001) reduction in relative spleen weights. Examination of the uteri revealed significant (p < 0.01) reductions in the numbers of viable implants and resorptions and the percent of live fetuses at 200 ppm. The numbers of corpora lutea, total implants and preimplantation losses and the sex ration were not effected by the material at any concentration. There were no significant differences between control and exposure groups with respect to the incidence of external, visceral, skeletal, or total fetal malformations. [R106] ?Teratogenicity was evaluated in groups of 24 pregnant New Zeland white rabbits exposed to ethylene glycol monobutyl ether vapors at concentrations of 0, 25, 50, 100, and 200 ppm for 6 hours/day on days 6-18 of gestation. Maternal mortality was observed in 4 rabbits at 200 ppm; all surviving rabbits were sacrificed on gestation day 29 and the uteri examined. Clinical signs of maternal toxicity at 100 and 200 ppm included periocular wetness and red fluid on the trays beneath the cages. Additional clinical observations at 200 ppm included staining of the fur and perinasal wetness and discharge. There were no differences between control and treatment groups with respect to maternal body weights, hematological findings, the number of non-viable implants, preimplantation losses, percent live fetuses, sex ratios, or fetal weights. Significant (p < 0.05) reductions in uterine weights and the number of total and viable implants/litter were observed at 200 ppm. The incidence of external, visceral, skeletal, and total fetal malformations at all exposure levels was not significantly different from that of the control group. [R106] TCAT: ?Developmental toxicity was evaluated in groups of 36 female Fischer 344 rats receiving whole-body exposure to ethylene glycol monobutyl ether at vapor concentrations of 0, 25, 50, 100, or 200 ppm, for 6 hours/day, on gestation days 6-15, followed by fetal examination on gestation day 21. Maternal toxicity was observed at the two highest dose levels, including clinical signs, reduced body weight gain, food consumption, and gravid uterine weight, and increased relative spleen and kidney weight. The compound was embryotoxic (increased incidence of resorptions) and fetotoxic (reduced skeletal ossification) at the two highest dose levels, but the incidence of fetal malformations was unchanged at all dose levels. The NOEL was estimated at 50 ppm. [R107] ?Developmental toxicity was evaluated in groups of 24 female New Zealand white rabbits receiving whole-body exposure to ethylene glycol monobutyl ether at vapor concentrations of 0, 25, 50, 100, or 200 ppm, for 6 hours/day, on gestation days 6-18, followed by fetal examination on gestation day 29. Maternal toxicity was observed at the highest dose level, including clinical signs, reduced body weight gain and gravid uterine weight, and increased incidence of mortality and abortion. The compound was embryotoxic (reduced number of viable fetuses) at the highest dose level, but no treatment-related effects were noted with respect to fetotoxicity or fetal malformations. The NOEL was estimated at 100 ppm. [R107] ?Developmental toxicity was evaluated in groups of pregnant rabbits exposed to ethylene glycol monoethyl ether acetate at vapor concentrations of 0, 25, 100, and 400 ppm. Maternal body weight gain and food consumption decreased in the high-dose group. Decreased body weight and retarded skeletal ossification were observed in fetuses from the mid- and high-dose groups; the high dose was also embryotoxic (increased resorptions) and teratogenic (major malformations of the vertebral column). The document summarized this study, and no further information was available regarding experimental methods or results. [R108] ?Developmental toxicity was evaluated in groups of pregnant rats (strain and number per group not reported) exposed to ethylene glycol monobutyl ether at vapor concentrations of 0, 100, 200, or 300 ppm. Maternal toxicity was observed at all dose levels and some fetal effects were noted (not specified). The document summarized this study, and no further information was available regarding experimental methods or results. [R108] ?Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for developmental toxicity. It was administered in 24 pregnant New Zealand white rabbits exposed to 0, 25, 50, 100 or 200 ppm of the test material on days 6-18 of gestation. Maternal weight gains were not significantly altered by treatment. At 200 ppm maternal toxicity was observed, including apparent exposure-related increases in deaths and abortions, clinical signs (periocular wetness, perinasal wetness and discharge), decreased weight during gestation day 15 (p < 0.05) and reduced gravid uterine weight (p < 0.05) at sacrifice. Embryotoxicity was exhibited by a reduced number of total and viable implantations (p < 0.05) per litter. No treatment-related fetotoxicity was observed. No treatment-related increases in fetal malformations or variations were seen at any exposure level. At 200 ppm ethylene glycol monobutyl ether exhibited maternal and embryo toxicity, but no fetotoxicity or teratogenicity. [R109] ?Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for developmental toxicity. It was administered in 24 pregnant New Zealand white rabbits at exposure levels of 0, 25, 50, 100 or 200 ppm of the test material on days 6-18 of gestation. Maternal weight gains were not significantly altered by treatment. At 200 ppm maternal toxicity was observed, including apparent exposure-related increases in deaths and abortions, clinical signs (periocular wetness, perinasal wetness and discharge), decreased weight during gestation day 15 (p < 0.05) and reduced gravid uterine weight (p < 0.05) at sacrifice. Embryotoxicity was exhibited by a reduced number of total and viable implantations (p < 0.05) per litter. No treatment-related fetotoxicity was observed. No treatment-related increases in fetal malformations or variations were seen at any exposure level. At 200 ppm ethylene glycol monobutyl ether exhibited maternal and embryo toxicity, but no fetotoxicity or teratogenicity. [R109] ?Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for developmental toxicity. It was administerd in 36 pregnant Fischer 344 rats per group exposed to 0, 25, 50, 100, or 200 ppm of ethylene glycol monobutyl ether on days 6-15 of gestation. Maternal toxicity was expressed as significant reductions in body weight (p < 0.001) at 200 ppm, weight gain (p < 0.05) during exposure at 100 and 200 ppm, food consumption (p < 0.001) at 100 and 200 ppm, and the presence of hematuria. Embryofetal toxicity included increased numbers of resorbed litters (p < 0.01), decreased numbers of viable implants (p < 0.001), decreased percent of live fetuses (p < 0.01) and delayed ossification (p < 0.05). No statistically significant increases in the incidence of external, visceral, skeletal, or total malformations were observed. At 25 ppm or less there was no maternal, embryo or fetal toxicity. Inhalation exposure to 100 ppm or above of ethylene glycol monobutyl ether caused maternal toxicity, embryotoxicity, and fetotoxicity, but no teratogenicity. [R110] ?Ethylene glycol monobutyl ether (CAS# 111-76-2) was evaluated for developmental toxicity. It was administered in 24 pregnant New Zealand white rabbits exposed to 0, 25, 50, 100 or 200 ppm of ethylene glycol monobutyl ether on days 6-18 of gestation. Maternal weight gains were not significantly altered by treatment. At 200 ppm maternal toxicity was observed, including apparent exposure-related increases in deaths and abortions, clinical signs (periocular wetness, perinasal wetness and discharge), decreased weight during gestation day 15 (p < 0.05) and reduced gravid uterine weight (p < 0.05) at sacrifice. Embryotoxicity was exhibited by a reduced number of total and viable implantations (p < 0.05) per litter. No treatment related fetotoxicity, increases in fetal malformations, or variations were seen at any exposure level. At 200 ppm ethylene glycol monobutyl ether exhibited maternal and embryo toxicity, but no fetotoxicity or teratogenicity. [R110] ?The ability of 2-butoxyethanol to induce mutations at the gene locus coding for hypoxanthine-guanine phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was evaluated in both the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests, nonactivated cultures were treated with 0.0625, 0.125, 0.25, 0.5 or 1.0% butyl cellosolve (v/v) and produced a range of 138.6 to 95.6 relative growth. S9-activated cultures treated with 0.03125, 0.0625, 0.125, 0.25, or 0.5% produced a range of 137 to 84.7% relative growth. None of the culture produced mutant frequencies significantly greater than the solvent control. [R111] ?The frequency of sister chromatid exchange (SCE) was determined in Chinese hamster ovary cells exposed in vitro to butyl cellosolve with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was administered at concentrations of 0.00780, 0.01560, 0.03125, 0.625, 0.125, and 0.25% butyl cellosolve (v/v) both in the presence and absence of metabolic activation. A statistically significant (p < 0.05) increase in SCE's/cell and SCE's/chromosome was not observed in any of the cultures at any concentration. [R111] ?The effects of 2-butoxyethanol were examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, 2-butoxyethanol was tested at concentrations of 0.0001, 0.001, 0.003, 0.01, 0.03, and 0.1% v/v. None of the tested concentrations caused a significant increase in unscheduled DNA synthesis over the solvent (DMSO) control. [R111] ?The ability of 2-butoxyethanol to induce mutations at the gene locus coding for hypoxanthine-guanine phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was evaluated in both the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests, nonactivated cultures were treated with 0.0625, 0.125, 0.25, 0.5 or 1.0% butyl cellosolve (v/v) and produced a range of 138.6 to 95.6 relative growth. S9-activated cultures treated with 0.03125, 0.0625, 0.125, 0.25, or 0.5% produced a range of 137 to 84.7% relative growth. None of the culture produced mutant frequencies significantly greater than the solvent control. [R111] ?The effects of 2-butoxyethanol were examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, 2-butoxyethanol was tested at concentrations of 0.0001, 0.001, 0.003, 0.01, 0.03, and 0.1% v/v. None of the tested concentrations caused a significant increase in unscheduled DNA synthesis over the solvent (DMSO) control. [R111] ?The frequency of sister chromatid exchange (SCE) was determined in Chinese hamster ovary cells exposed in vitro to butyl cellosolve with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was administered at concentrations of 0.00780, 0.01560, 0.03125, 0.625, 0.125, and 0.25% butyl cellosolve (v/v) both in the presence and absence of metabolic activation. A statistically significant (p < 0.05) increase in SCE's/cell and SCE's/chromosome was not observed in any of the cultures at any concentration. [R111] [Bushy Run Research Center; Butyl Cellosolve In Vitro Mutagenesis Studies: 3-Test Battery with Attachments, Cover Sheets and Letter Dated 06/06/89. (1980). EPA Document No. 86-890000946, Fiche No. OTS0520384} In an in vitro sister chromatid exchange assay, chinese hamster ovary cells (CHO-K1-BH4-D1) were exposed to 0.0, 0.0156, 0.03125, 0.0625, 0.125, 0.25% ethylene glycol mono-n-butyl ether, with or without an S-9 metabolic activating system from Arochlor 1254 induced rat liver. Doses were selected based on low cytotoxicity to CHO cells in a preliminary study. No treatment-related effects were seen, either in the presence or absence of a metabolic activating system. [Bushy Run Research Center; Butyl Cellosolve In Vitro Mutagenesis Studies: 3-Test Battery with Attachments, Cover Sheets and Letter Dated 06/06/89. (1980). EPA Document No. 86-890000946, Fiche No. OTS0520384} The ability of butyl cellosolve to induce specific mutations at the gene locus coding for hypoxanthine-guanine phosphoribosyl transferase in Chinese hamster ovary cells (CHO/HGPRT Assay) was evaluated in presence and absence of metabolic activation from Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity tests, non-S9 activated cultures were treated with 0.0625, 0.125, 0.25, 0.5, or 1.0% v/v, and the S9 activated cultures were treated with 0.03125, 0.0625, 0.125, 0.25, or 0.5% v/v. None of the cultures had mutant frequencies significantly greater than the solvent (H2O) control. ?In an in vitro DNA repair assay, hepatocytes from Hilltop-Wistar albino rats were exposed for 2 hours to 0.0001, 0.001, 0.003, 0.01, 0.03, and 0.1% ethyl glycol mono-n-butyl ether, dissolved in DMSO. No metabolic activating system was used. The concentrations used were non-cytotoxic to rat hepatocytes. The level of unscheduled DNA synthesis was determined by measuring the incorporation of 3H-thymidine into cell nuclei DNA or into precipitated DNA, using a liquid scintillation counter. Statistically significant increases in the level of unscheduled DNA synthesis were observed at the two lowest dose-levels, but not at the four highest dose-levels. [R112] ?The mutagenicity of butyl cellosolve (ethylene glycol mono-n-butyl ether) was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537, and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on the results of preliminary bacterial toxicity testing, the material was tested for mutagenicity at concentrations of 0, 2000, 4000, 6000, 8000, 10000, and 15000 ug/plate using the direct plate incorporation method. Butyl cellosolve did not cause a reproducible positive response in any of the bacterial tester strains, either in the presence or absence of added metabolic activation. [R113] ADE: *... ABSORBED VIA SKIN, LUNG, OR GASTROINTESTINAL TRACT. [R47] *... BUTOXYACETIC ACID ... IS EXCRETED IN URINE OF MOST ANIMAL SPECIES AND OF HUMAN BEINGS. ANIMAL TESTS ALSO INDICATE THAT ETHYLENE GLYCOL BUTYL ETHER IS EXCRETED VIA THE LUNG. [R44, 3933] *THEY FOUND 55 MG OF BUTOXYACETIC ACID IN 16 HR URINE SAMPLES OF DOGS EXPOSED TO 385 PPM. ... 100 and 42 MG IN 24-HR URINE SAMPLES FROM 2 DOGS EXPOSED TO 200 PPM OF VAPOR AND 100 and 94 MG IN SIMILAR URINE SAMPLES FROM 2 DOGS EXPOSED TO 100 PPM. ONE OF TWO MONKEYS EXPOSED TO 100 PPM EXCRETED 30 MG ... IN 48-HR PERIOD ... . [R44, 3938] *HUMAN BEINGS EXPOSED 8 HR TO 195 PPM EXCRETED ANYWHERE FROM 6-300 MG BUTOXYACETIC ACID IN 24 HR PERIOD. [R44, 3938] *... ONCE ABSORBED INTO BODY, ESTERS ARE SAPONIFIED AND SYSTEMIC EFFECT IS QUITE TYPICAL OF PARENT GLYCOL OR GLYCOL ETHER. /ETHER-ESTERS OF GLYCOLS/ [R44, 4010] *The percutaneous absorption of 2-butoxyethanol (Butyl cellosolve) was investigated in 5 men. The presence of butoxyethanol in blood and of butoxyacetic acid in urine confirmed that butoxyethanol enters the systemic circulation in man in vivo during dermal exposure. Calculated percutaneous uptake rates ranged from 7 to 96 nmol/min/sq cm. Persons exposing large portions of their skin to butoxyethanol are at risk of absorbing acutely toxic doses. [R114] *The absorption across isolated human abdominal epidermis was measured in vitro. Epidermal membranes were set up in glass diffusion cells. 2-Methoxyethanol was most readily absorbed (mean steady rate 2.82 mg/sq cm/hr) was also apparent for 1-methoxypropan-2-ol. There was a trend of reducing absorption rate with increasing molecular weight or reducing volatility for monoethylene glycol ethers (2-methoxyethanol, 2.82 mg/sq cm/hr; 2-ethoxyethanol, 0.796 mg/sq cm/hr; 2-butoxyethanol, 0.198 mg/sq cm/hr) and also within the diethylene glycol series: 2-(2-methoxyethoxy) ethanol, (0.206 mg/sq cm/hr); 2-(2-ethoxyethoxy) ethanol, (0.125 mg/sq cm/hr) and 2-(2-butoxyethoxy) ethanol, (0.035 mg/sq cm/hr). The rate of absorption of 2-ethoxyethyl acetate was similar to that of the parent alcohol, 2-ethoxyethanol. Absorption rates of diethylene glycol ethers were slower than their corresponding monoethylene glycol equivalents. [R115] *Acute exposure to 2-butoxyethanol causes dose- and age-dependent hemolytic anemia in rats. Butoxyacetic acid is the proximate hemolytic agent and inhibition of alcohol or aldehyde dehydrogenases protected rats against 2-butoxyethanol induced hemolytic anemia. The kinetics of (14)C-2-butoxyethanol metabolism and clearance were studied in control adult (3-4 months old) and old (12-13 months old) male F344 and in adult male F344 rats treated with pyrazole, cyanamide or probenecid. The area under the curve, maximum plasma concentration and systemic clearance of 2-butoxyethanol were dose-dependent. In contrast, there was no effect of dose on half-life (T1/2) or volume of distribution of 2-butoxyethanol. There was no age effect on T1/2, volume of distribution, or systemic clearance of 2-butoxyethanol. However, maximum plasma concentration and area under the curve of 2-butoxyethanol increased as a function of age. Inhibition of 2-butoxyethanol metabolism by pretreatment of rats with pyrazole or cyanamide resulted in an increase in the T1/2 and area under the curve of 2-butoxyethanol, whereas it caused a decrease in the systemic clearance. Furthermore, pyrazole had no effect, whereas cyanamide had decreased volume of distribution of 2-butoxyethanol. [R116] METB: *... METABOLIZED, @ LEAST IN PART, TO BUTOXYACETIC ACID ... . [R44, 3933] *Seventeen persons who were exposed to glycolethers in a varnish production plant, were examined according to their external and internal solvent exposure. The workers in the production plant (n= 12) were exposed to average concentrations of ethoxyethanol, ethoxyethyl acetate, butoxyethanol, 1-methoxypropanol-2, 2-methoxypropyl-1-acetate and xylene of 2.8; 2.7; 1.1; 7.0; 2.8 and 1.7 ppm. Internal exposure was estimated by measuring butoxyethanol in blood as well as ethoxyacetic acid and butoxyacetic acid in urine samples. As expected, the highest values were found in the varnish production. The average post shift concentrations of butoxyethanol, ethoxyacetic acid and butoxyacetic acid were 121.3 ug/l; 167.8 and 10.5 mg/l. The relatively high concentrations of ethoxyacetic acid and butoxyacetic acid in pre-shift samples can be explained by the long half-lives of these metabolites. Most of the glycolethers were taken up through the skin. The authors think that a future tolerable limit value for the concentration of ethoxyacetic acid in urine should be in the order of 100 to 200 mg/l. [R117] *The elimination kinetics of 2-butoxyethanol (ethylene glycol monobutyl ether) were studied in the once-through isolated perfused rat liver system in the presence and absence of ethanol. Dose-dependent Michaelis-Menten kinetics in the elimination of ethylene glycol monobutyl ether were observed. The apparent Michaelis constant range from 0.32 to 0.70 mM while the maximum elimination rate ranged from 0.63 to 1.4 umol/min/g liver. In the presence of 17.1 mM ethanol (0.1%) the extraction ratio of ethylene glycol monobutyl ether decreased from 0.44 to 0.11. Ethylene glycol monobutyl ether is mainly metabolized via oxidation by alcohol dehydrogenase in the rat liver. [R118] *For the glycol ethers 2-methoxyethanol, 2-ethoxyethanol, and 2-butoxyethanol, the effect of alkyl group length on disposition of these three glycol ethers was studied in male F344/N rats allowed access for 24 hr to 2-butoxy(U-(14)C)ethanol, 2-ethoxy (U-(14)C)ethanol, or 2-methoxy(U-(14)C)ethanol in drinking water at three doses (180 to 2590 ppm), resulting in absorbed doses ranging from 100 to 1450 umols/kg body weight. The majority of the (14)C was excreted in urine or exhaled as carbon dioxide. Less than 5% of the dose was exhaled as unmetabolized glycol ether. Distinct differences in the metabolism of the glycol ethers as a function of alkyl chain length were noted. For 2-butoxyethanol 50-60% of the dose was eliminated in the urine as butoxyacetic acid and 8-10% as carbon dioxide; for 2-ethoxyethanol 25-40% was eliminated as ethoxyacetic acid and 20% as carbon dioxide; for 2-methoxyethanol 34% was eliminated as methoxyacetic acid and 10-30% as carbon dioxide. Ethylene glycol, a previously unreported metabolite of these glycol ethers, was excreted in urine, representing approximately 10, 18, and 21% of the dose for 2-butoxyethanol, 2-ethoxyethanol, and 2-methoxyethanol, respectively. Thus, for longer alkyl chain lengths, a smaller fraction of the administered glycol ether was metabolized to ethylene glycol and carbon dioxide. Formation of ethylene glycol suggests that dealkylation of the glycol ethers occurs prior to oxidation to alkoxyacetic acid and, as such, represents an alternate pathway in the metabolism of these compounds that does not involve formation of the toxic acid metabolite. [R119] *Ethylene glycol monobutyl ether was rapidly absorbed in male rats after gavage administration, metabolized, and eliminated. Tissue distribution of ethylene glycol monobutyl ether revealed that ethylene glycol monobutyl ether is distributed to all tissues with the highest levels (detected 48 hr after dosing) detected in the forestomach followed by the liver, kidney, spleen, and the glandular stomach. However, the increase in the tissue concn in rats treated with 500 mg/kg (as compared to that in rats treated with 125 mg/kg ethylene glycol monobutyl ether) was not proportional to the increase in ethylene glycol monobutyl ether dose. The major route of ethylene glycol monobutyl ether elimination was in the urine, followed by (14)CO2 exhalation. The portion of the ethylene glycol monobutyl ether dose eliminated in urine or as (14)CO2 was significantly higher in rats treated with 125 mg/kg than in the rats treated with 500 mg/kg. This indicates that saturation of ethylene glycol monobutyl ether-metabolizing enzymes occurs at the high dose. A small portion (8%) of the administered dose (500 mg/kg) was excreted in the bile in 8 hr after dosing. The major urinary metabolite, butoxyacetic acid, accounted for > 75% of the radioactivity excreted in the urine. The 2nd major metabolite in urine was the glucuronide conjugate of ethylene glycol monobutyl ether. In the bile, the major biliary metabolite was BEG followed by butoxyacetic acid. A small quantity of the radioactivity excreted in the urine of rats treated with the low dose of ethylene glycol monobutyl ether was the sulfate conjugate of ethylene glycol monobutyl ether; however, no BES was detected in the urine of rats treated with the high dose of ethylene glycol monobutyl ether. The following metabolic pathways of ethylene glycol monobutyl ether are identified: oxidation of ethylene glycol monobutyl ether to butoxyacetic acid, conjugation of ethylene glycol monobutyl ether with uridine diphosphate glucuronic acid, and conjugation of ethylene glycol monobutyl ether with the sulfate. [R120] ACTN: *... Ethylene glycol monobutyl ether, and to a greater extent its metabolite, butoxyacetic acid, both increase the osmotic fragility of the erythrocyte. This action appears to be greatest in the rat, mouse, and rabbit and distinctly less in the guinea pig, dog, rhesus monkey, and human. [R44, 3938] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethylene glycol mono-n-butyl ether's production and use as a synthetic intermediate and as a solvent in a variety of applications may result in its release to the environment through various waste streams. If released to soil, ethylene glycol mono-n-butyl ether is expected to have high mobility based on as estimated Koc of 67. Volatilization of ethylene glycol mono-n-butyl ether is not expected to be important from moist soil surfaces but may be important from dry soil surfaces based on an estimated Henry's Law constant of 2X10-8 atm-cu m/mol and a measured vapor pressure of 0.88 mm Hg, respectively. Alcohols and ethers are generally resistant to hydrolysis. Such functional groups do not absorb UV light at environmentally significant wavelengths (> 290 nm) and are commonly used as solvents for obtaining UV spectra. Therefore, direct photolysis will not be an important process. According to several biodegradation tests, aerobic degradation of ethylene glycol mono-n-butyl ether should occur rapidly in soil and water. If released to water, ethylene glycol mono-n-butyl ether is not expected to adsorb to suspended solids and sediment given its estimated Koc value. Ethylene glycol mono-n-butyl ether is expected to be essentially non-volatile from water surfaces because of its Henry's Law constant. An estimated BCF value of 2.5 suggests that bioconcentration of ethylene glycol mono-n-butyl ether will be low in aquatic organisms. If released to the atmosphere, ethylene glycol mono-n-butyl ether will exist as a vapor based on its vapor pressure. Vapor-phase ethylene glycol mono-n-butyl ether is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 20 hours. Particulate-phase ethylene glycol mono-n-butyl ether may be physically removed from the air by wet deposition. The predominant route of exposure to ethylene glycol mono-n-butyl ether is through dermal adsorption; other routes of exposure include ingestion and inhalation of this compound, particularly from household products. (SRC) ARTS: *Ethylene glycol mono-n-butyl ether was listed as a volatile organic emission of silicone caulk(4). Ethylene glycol mono-n-butyl ether is also released to the environment via leachate from municipal landfills and hazardous waste site(1-3). [R121] *Ethylene glycol mono-n-butyl ether's production and use in hydraulic fluids(1), as coupling agent for many water-based coatings(2), to make acetate esters as well as phthalate and stearate plasticizers(2), as a coupling agent to stabilize immiscible ingredients in metal cleaners, textile lubricants, cutting oils, and liquid household products(2), as a solvent for nitrocellulose resins, spray lacquers, quick-drying lacquers, varnishes, enamels, dry-cleaning compounds, varnish removers, textile, mutual solvent for "soluble" mineral oils to hold soap in solution and to improve the emulsifying properties(3), vinyl and acrylic paints(4), in aqueous cleaners to solubilize organic surfactants(4), and as a solvent in cosmetics(5) may result in its release to the environment through various waste streams(SRC). [R122] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 67(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that ethylene glycol mono-n-butyl ether is expected to have high mobility in soil(SRC). Volatilization of ethylene glycol mono-n-butyl ether is not expected to be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 2X10-8 atm-cu m/mole(SRC), using a recommended regression equation(4). Volatilization may be important from dry soil surfaces(SRC) based on an experimental vapor pressure of 0.88 mm Hg(5). Alcohols and ethers are generally resistant to hydrolysis(6). They do not absorb UV light at environmentally significant wavelengths (> 290 nm) and are commonly used as solvents for obtaining UV spectra(3). Therefore, direct photolysis will not be an important process. According to several biodegradation tests, aerobic degradation of ethylene glycol mono-n-butyl ether should occur rapidly in soil(5,7-12). [R123] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 67(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(1), indicates that ethylene glycol mono-n-butyl ether is not expected to adsorb to suspended solids and sediment(SRC) in the water. Ethylene glycol mono-n-butyl ether is expected to be essentially non-volatile from water surfaces based on an estimated Henry's Law constant of 2X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). An estimated BCF value of 2.5(1,SRC), from an experimental log Kow(2), suggests that ethylene glycol mono-n-butyl ether bioconcentration in aquatic organisms will be low(SRC), according to a recommended classification scheme(4). Alcohols and ethers are generally resistant to hydrolysis(5). They do not absorb UV light at environmentally significant wavelengths (> 290 nm) and are commonly used as solvents for obtaining UV spectra(1). Therefore, direct photolysis will not be an important process. According to several BOD biodegradation tests, aerobic degradation of ethylene glycol mono-n-butyl ether should occur rapidly in water(6-12). [R124] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethylene glycol mono-n-butyl ether, which has an experimental vapor pressure of 0.88 mm Hg at 25 deg C(2,SRC), will exist as a vapor in the ambient atmosphere. Vapor-phase ethylene glycol mono-n-butyl ether is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 20 hours(3,SRC). Particulate-phase ethylene glycol mono-n-butyl ether may be physically removed from the air by wet deposition(SRC). [R125] BIOD: *A number of aerobic biological screening studies, which utilized settled waste water, sewage, or activated sludge for inocula, indicate that ethylene glycol mono-n-butyl ether should biodegrade rapidly in the environment(1-4). Five and ten-day Theoretical BOD values were 73% (with acclimation)(1) and 74%(2). The maximum Theoretical BOD reported was 88% for 20 days(2). [R126] *A two-week biodegradation study using 30 mg/l sludge and an ethylene glycol mono-n-butyl ether concentration of 100 mg/l gave a theoretical BOD of 96%(1). The theoretical BODs for ethylene glycol mono-n-butyl ether after 5, 10, and 20 days have been determined to be 5, 57, and 72%(2). Biooxidation of ethylene glycol mono-n-butyl ether using a 20 day BOD test and a 28 day OECD test resulted in 88 and 75% degradation(3). [R127] ABIO: *The rate constant for the vapor-phase reaction of ethylene glycol mono-n-butyl ether with photochemically produced hydroxyl radicals has been experimentally determined to be 1.86x10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 20 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Alcohols and ethers are generally resistant to hydrolysis(2). They do not absorb UV light at environmentally significant wavelengths (> 290 nm) and are commonly used as solvents for obtaining UV spectra(3). Therefore, ethylene glycol mono-n-butyl ether should not undergo hydrolysis or direct photolysis in the environment(SRC). [R128] BIOC: *An estimated BCF value of 2.5 was calculated for ethylene glycol mono-n-butyl ether(SRC), using an experimental log Kow of 0.83(1) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R129] KOC: *The Koc of ethylene glycol mono-n-butyl ether is estimated as approximately 67(SRC), using an experimental log Kow of 0.83(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that ethylene glycol mono-n-butyl ether should have high mobility in soil(SRC). [R130] VWS: *The Henry's Law constant for ethylene glycol mono-n-butyl ether is estimated as 2X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that ethylene glycol mono-n-butyl ether will be essentially nonvolatile from water surfaces(2,SRC). Ethylene glycol mono-n-butyl ether's Henry's Law constant(1,SRC) indicate that volatilization from moist soil surfaces is not expected(SRC). The potential for volatilization of this compound from dry soil surfaces may exist(SRC) based on the measured vapor pressure of 0.88 mm Hg(3). [R131] WATC: *DRINKING WATER: Ethylene glycol mono-n-butyl ether was listed as a contaminant found in drinking water for a survey of US cities including Pomona, Escondido, Lake Tahoe and Orange Co, CA and Dallas, Washington, DC, Cincinnati, Philadelphia, Miami, New Orleans, Ottumwa, IA, and Seattle(1). [R132] *GROUNDWATER: Ethylene glycol mono-n-butyl ether was detected at a concn of 23 ug/l in 1 of 7 groundwater samples collected near "The Valley of Drums", KY(1). A ground water sample from an aquifer underlying a municipal landfill in Norman, OK contained ethylene glycol mono-n-butyl ether(2,3). Ethylene glycol mono-n-butyl ether was qualitatively identified in ground water in Milan, Italy near a paint factory where several underground tanks of solvents were located(4). [R133] *SURFACE WATER: In April 1980, ethylene glycol mono-n-butyl ether was detected in Hayashida River water (the Matsubara area in Tatsuno City, Hyogo Prefecture) at concn of 1310 and 5680 ppb(1). Ethylene glycol mono-n-butyl ether was identified in the Rhine River at Lobith at a concentration of 0.036 ug/l(2). [R134] EFFL: *Ethylene glycol mono-n-butyl ether was identified in 1 and 4 neutral fractions of 33 industrial wastewater effluents at concn of < 10 and < 100 ug/l, respectively(4). Because ethylene glycol mono-n-butyl ether was detected in groundwater receiving municipal landfill leachate, it may be present in other landfill leachates(2,3). Ethylene glycol mono-n-butyl ether was listed as a volatile organic emission of silicone caulk(4). Ethylene glycol mono-n-butyl ether was detected in the emissions of waste incineration plants at 0.23 ug/cu m(5). [R135] ATMC: *INDOOR: According to the National Ambient Volatile Organic Compounds (VOCs) Database, the average daily indoor atmospheric concn of ethylene glycol mono-n-butyl ether is 0.214 ppbv for 14 samples(1). Ethylene glycol mono-n-butyl ether was detected at a concn of 8 ug/cu m in 1 of 6 samples of indoor air from 14 homes of northern Italy(2). Ethylene glycol mono-n-butyl ether was been identified in air from occupational buildings at concentrations of 1.8, 3.4, 3.9, 6.7, 8.5, 16, and 34 ug/cu m, in building exhaust at 6.0 and 13 ug/cu m, and in an elevator shaft at 19 ug/cu m(3). [R136] FOOD: *Ethylene glycol mono-n-butyl ether has been qualitatively identified in the volatile fraction of raw beef(1,2). [R137] OEVC: *Ethylene glycol mono-n-butyl ether was contained in organic solvents with a frequency of occurrence of 0.4%(1). A paint stripping formulation was comprised of 35% ethylene glycol mono-n-butyl ether(2). Ethylene glycol mono-n-butyl ether was not detected in a machine cutting fluid prior to its use; however, the used fluid contained ethylene glycol mono-n-butyl ether at a concn of 0.060 ug/g(3). [R138] *Ethylene glycol mono-n-butyl ether was qualitatively detected in the headspace of liquid wax for marble, ceramic, linoleum, plastic, and varnished wood floors(1). Ethylene glycol mono-n-butyl ether was found in printer's inks used for serigraphy on paper and paper boards at concentrations of 0.1 and 0.4 wt%(2). Ethylene glycol mono-n-butyl ether has been identified as a major component of latex caulk(3). Ethylene glycol mono-n-butyl ether has been identified in a variety of household products including paints, primers and varnishes; all purpose cleaners; window and glass cleaners; engine degreasers; rug and upholstery cleaners; and metal cleaners and polishes(4). [R139] RTEX: *The most probable route of human exposure to ethylene glycol mono-n-butyl ether is by inhalation, dermal contact and ingestion. Workplace exposures have been documented(2-6). Drinking water supplies have been shown to contain ethylene glycol mono-n-butyl ether(1). [R140] *THERE IS ... HAZARD OTHER THAN VAPOR THAT MUST NOT BE OVERLOOKED WHEN HANDLING THIS MATERIAL--THAT OF POSSIBLE ABSORPTION OF TOXIC QUANTITIES THROUGH SKIN, BECAUSE OF LOW VAPOR PRESSURE ... @ ROOM TEMP, HAZARD FROM SKIN ABSORPTION COULD WELL BE GREATER, OR CONTRIBUTE SUBSTANTIALLY TO OVER-ALL HAZARD. [R44, 3938] *FROM INDUST POINT OF VIEW, ONLY ONE CASE OF POSSIBLE SYSTEMIC INJURY WAS THAT OF MAN WHO WAS REPORTED ... AS HAVING HAD TWO ISOLATED ATTACKS OF HEMATURIA, WITH 5 MO INTERVAL. ... HIS EXPOSURE ... INCL BUTYL CARBITOL AS WELL AS BUTYL CELLOSOLVE. [R1, 612] *OCCUPATIONAL EXPOSURES TO BUTYL CELLOSOLVE, ETHANOL, AND XYLENE IN FILAMENT-DRAW DEPARTMENT OF ELECTRICAL RESISTOR MFR FACILITY DID NOT POSE A HEALTH HAZARD. [R141] *NIOSH (NOES Survey as of 3/28/89) has estimated that 1,680,764 workers are potentially exposed to ethylene glycol mono-n-butyl ether in the USA(1). According to the National Ambient Volatile Organic Compounds (VOCs) Database, the median workplace atmospheric concn of ethylene glycol mono-n-butyl ether is 0.075 ppbV for 14 samples(3). Workers at paint stripping operations that used stripping agents containing ethylene glycol mono-n-butyl ether were exposed to it(2). [R142] *Personal exposures to atmospheric ethylene glycol mono-n-butyl ether at a specialty chemical production facility in June of 1981 ranged from undetected levels to 0.1 ppm; indoor air concn within the facility were as high as 1.7 ppm(2). A national survey of workplaces in the Federal Republic of Germany showed that workers were exposed to solvents containing ethylene glycol mono-n-butyl ether with a 0.4% frequency of occurrence(1). [R143] *A study initiated in 1983, which surveyed the workplace atmospheres of 336 businesses in Belgium, showed that ethylene glycol mono-n-butyl ether was present in 25 of 94 air samples taken from sites that utilize printing pastes; 10 of 81 samples from where painting took place; 1 of 20 samples from automobile repair shops; and 17 of 67 samples from sites where various materials such as varnishes, sterilization agents and cleaners are employed(1). The geometric mean concn of ethylene glycol mono-n-butyl ether in the air of printing shops was 4.1 mg/cu m with a range of 1.5 to 17.7 mg/cu m; 18.8 mg/cu m with a range of 3.4 to 93.6 mg/cu m for painting areas; 5.9 mg/cu m for car repair shops; and 8.5 mg/cu m with a range of 0.2 to 1775 mg/cu m for various industries(1). [R144] *Ethylene glycol mono-n-butyl ether was identified as a volatile emission from used machine cutting oils in an automobile manufacturing facility in Japan(1). Non-occupational exposures may occur among populations with contaminated drinking water supplies(2). Because ethylene glycol mono-n-butyl ether is a component of solvent based building materials such as silicone caulk(3), human exposures may occur at construction sites and areas that have undergone remodelling(SRC). [R145] *Exposure of cleaning women and cleaners of cars to ethylene glycol mono-n-butyl ether resulted in urine levels of < 0.1-7.33 ppm (time-weighted averages)(1). It was established that the predominant route of exposure to ethylene glycol mono-n-butyl ether was through skin penetration(1). Ethylene glycol mono-n-butyl ether was identified in air from automotive repair shops in Sydney, Australia in 8 out of 70 samples at an average concentration of 2.0 mg/cu m(2). [R146] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +700 ppm [R12, 36] ATOL: *Ethylene glycol monobutyl ether is exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R147] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 50 ppm (240 mg/cu m). Skin Designation. [R148] +Vacated 1989 OSHA PEL TWA 25 ppm (120 mg/cu m), skin designation, is still enforced in some states. [R12, 360] NREC: *NIOSH recommends reducing exposure to lowest feasible concn and preventing contact with the skin. /Glycol ether/ [R149] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 ppm (24 mg/cu m). Skin. [R12, 36] TLV: +8 hr Time Weighted Avg (TWA): 25 ppm. [R150, 2002.18] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R150, 2002.6] +Notice of Intended Change for 2002: These substances, with their corresponding values and notations, comprise those for which a limit has been proposed for the first time or for which a change in the Adopted value is proposed. In each case, the proposed values should be considered trial values for the year following ratification by the ACGIH Board of Directors. If, during the year, no evidence comes to light that questions the appropriateness of these proposals, the values will be reconsidered for adoption as TLVs. A3; Confirmed animal carcinogen with unknown relevance to humans. [R150, 2002.62] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Ethylene glycol monobutyl ether is produced, as an intermediate or final product, by process units covered under this subpart. [R151] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Ethylene glycol mono-n-butyl ether is included on this list. [R152] FIFR: *Ethylene glycol monobutyl ether is exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R147] FDA: *Ethylene glycol monobutyl ether is an indirect food additive for use only as a component of adhesives. [R153] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *In instances where materials are very soluble in water, samples of air can be taken effectively by scrubbing through water. /Glycol ethers/ [R44, 3910] ALAB: *NIOSH Method 1403. Analyte: Alcohols. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. For 2-butoxyethanol, this method has an estimated detection limit of 0.01 to 0.02 mg/10 liters. The overall precision/RSD is 0.060 and the recovery is 92%. Applicability: This method may be used to determine two or more analytes simultaneously by varying GC conditions (eg, temperature). Interferences: High humidity reduces sampling capacity. Less volatile compounds may displace more volatile compounds on the charcoal. [R154] *DETERMINED IN WASTE WATER BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY. [R155] *Gas chromatography is likely to be the analytical method for final analysis. Infrared absorption is sometimes used. /Glycol ethers/ [R44, 3910] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Jaraczewska W et al; Toxicology of butyl glycol; Med Pr 30 (5) 353 (1979). A review on the toxicity of butyl ethylene glycol, especially its CNS depressant effect and action inducing parenchymatous organ lesions. USEPA; Health effects assessment for glycol ethers pp 90 (1984) EPA/540/1-86/052 Johanson G; Aspects of biological monitoring of exposure to glycol ethers; Toxicol Lett 43 (1-3): 5-21 (1988) Miller RR; Metabolism and Disposition of Glycol Ethers; Drug Metab Rev 18 (1): 1-22 (1987). Tyler TR, Acute and subchronic toxicity of ethylene glycol monobutyl ether, Environ Health Perspect, 185-91 (1984). DHHS/NTP; NTP Technical Report on Toxicity Studies of Ethylene Glycol Ethers 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 26 NIH Publication No. 93-3349 (1993) Toxicology and Carcinogenesis Studies of 2-Butoxyethanol in F344/N Rats and B6C3F1 Mice p.6 Technical Report Series No. 484 (2000) NIH Publication No. 00-3974 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 SO: R1: Browning, E. 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No. 89-890000248, Fiche No. OTS0516782 R104: Department of Health and Human Services; Results of Testing Fifteen Glycol Ethers in a Short-Term In Vivo Reproductive Toxicity Assay With Attachments, EPA Doc. 40-8385037, Fiche No. OTS0521552 R105: Bushy Run Research Center; A Teratologic Evaluation of Ethylene Glycol Monobutyl Ether in Fischer 344 AND New Zealand White Rabbits Following Inhalation Exposure (Final Report) with Cover Letter, (1984), EPA Document No. 40-8478020, Fiche No. OTS0512387 R106: Jefferson Chem Co., Inc.; Teratologic Evaluation of Ethylene Glycol Monobutyl Ether in Fischer 344 Rats and New Zeland White Rabbits Following Inhalation Exposure, (1984), EPA Doc. 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Riihimaki V, Ulfvarson U eds Alan R Liss Inc. (1986) (2) Hahn WJ, Werschulz PO; Evaluation of alternatives to toxic organic paint strippers. NTIS PB86 219-177/AS USEPA 600/S2-86/063 (1986) (3) Yasuhara, A et al; Agric Bio Chem 50: 1765-70 (1986) R139: (1) Knoppel H, Schauenburg H; Environ Intl 15: 413-18 (1989) (2) Rastogi SC; Arch Environ Contam Toxicol 20: 543-47 (1991) (3) Tichenor BA; Environ Intl 15: 389-96 (1989) (4) USEPA; Compilation and Speciation of National Emissions Factors or Consumer/Commercial Solvent Use. Information Compiled to Support Urban Air Toxics Assessment Studies. Research Triangle Park,NC: USEPA Off Air Radiat, Off Air Qual Plan Stand, USEPA/450/2-89/008 NTIS PB89-207203 (1989) R140: (1) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p 397 (1984) (2) Lehmann E et al; pp. 31-41 in Safety and Health Aspects of Organic Solvents. Riihimaki V, Ulfvarson U eds Alan R Liss Inc. (1986) (3) Hahn WJ, Werschulz PO; Evaluation of Alternatives to Toxic Organic Paint Strippers. NTIS PB86 219-177/AS USEPA 600/S2-86/063 (1986) (4) Clapp DE et al; Environ Health Perspective 57: 91-5 (1984) (5) Shah JJ, Heyerdahl EK; National Ambient VOC Database Update USEPA 600/3-88/010 (1988) (6) Yasuhara, A et al; Agric Bio Chem 50: 1765-70 (1986) R141: GILLES ET AL; US NTIS PB REP; ISS PB-273739 (1976) 16 PP R142: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) (2) Hahn WJ, Werschulz PO; Evaluation of Alternatives to Toxic Organic Paint Strippers. NTIS PB86 219-177/AS USEPA 600/S2-86/063 (1986) (3) Shah JJ, Heyerdahl EK; National Ambient VOC Database Update USEPA-600/3-88/010 (1988) R143: (1) Lehmann E et al; pp 31-41 in Safety and Health Aspects of Organic Solvents. Riihimaki V, Ulfvarson U eds Alan R Liss Inc. (1986) (2) Clapp DE et al; Environ Health Perspective 57: 91-5 (1984) R144: (1) Veulemans H et al; Am Indust Hyg Assoc J 48: 671-7 (1987) R145: (1) Yasuhara A et al; Agric Bio Chem 50: 1765-70 (1986) (2) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p 397 (1984) (3) Tichenor BA, Mason MA; JAPCA 38: 264-8 (1988) R146: (1) Vincent R et al; Appl Occup Environ Hyg 8: 580-6 (1993) (2) Winder C, Turner PJ; Am Occup Hyg 36: 385-94 (1992) R147: 40 CFR 180.1001(d) (7/1/94) R148: 29 CFR 1910.1000 (7/1/98) R149: NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988.16 R150: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R151: 40 CFR 60.489 (7/1/94) R152: 40 CFR 716.120 (7/1/94) R153: 21 CFR 175.105 (4/1/93) R154: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994.p. 1403-1 R155: JUNGCLAUS ET AL; ANAL CHEM 48 (13): 1894 (1976) RS: 174 Record 68 of 1119 in HSDB (through 2003/06) AN: 542 UD: 200302 RD: SRP review on 12/09/1987 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: FURFURAL- SY: +Ant-oil,-artificial-; *ARTIFICIAL-ANT-OIL-; *ARTIFICIAL-OIL-OF-ANTS-; +Bran-oil-; *2-FORMYLFURAN-; +Fural-; *FURALDEHYDE-; +ALPHA-FURALDEHYDE-; *2-FURALDEHYDE-; *FURALE-; *2-FURANALDEHYDE-; *FURANCARBONAL-; *2-FURANCARBONAL-; *2-FURANCARBOXALDEHYDE-; *2-FURFURAL-; *FURFURALDEHYDE-; *2-FURFURALDEHYDE-; *FURFURALE- (ITALIAN); *FURFUROLE-; *FURFURYLALDEHYDE-; *2-FURIL-METANALE- (ITALIAN); *FUROL-; *FUROLE-; *ALPHA-FUROLE-; *2-FURYLALDEHYDE-; *Furyl-methanal-; *2-FURYL-METHANAL-; *NCI-C56177-; *PYROMUCIC-ALDEHYDE-; *Quakeral- RN: 98-01-1 MF: +C5-H4-O2 SHPN: UN 1199; Furfural IMO 3.3; Furfural STCC: 49 131 46; Furfural HAZN: U125; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +Furfural is produced from annually renewable agricultural sources /containing pentosans/ such as ... corncobs, cottonseed hulls ... rice hulls ... bagasse ... wood and wood products ... in batch or continuous digestors where the pentosans are hydrolyzed to pentoses and the pentoses subsequently cyclodehydrated to furfural. In all processes, raw material is charged to the digestor and treated with strong inorganic acid. High pressure steam is introduced through the mass and, after attaining operating temperature and pressure, furfural is steam distilled. [R1, p. 11(80) 505] +PREPD FROM PYRIDINE. [R2] FORM: +GRADES: TECHNICAL, REFINED. [R3] +NATURAL, SYNTHETIC, INDUSTRIAL, 98% GRADES [R4] MFS: +Aldrich Chemical Company, Inc, Hq, 940 West St Paul Avenue, Milwaukee, WI 53233, (414) 273-3850 [R5] +Great Lakes Chemical Corporation, Highway 52, North West, West Lafayette, IN 47906, (317) 497-6100; Subsidiary: QO Chemicals, Inc, 2801 Kent Avenue, West Lafayette, IN 47906; Production site: Omaha, NE 68108 [R5] OMIN: +QO CHEMICALS /FORMERLY QUAKER OATS CO, CHEM DIV, WAS THE ONLY USA PRODUCER OF FURFURAL IN 1984/ [R6] +THE HAZARD OF HANDLING FURFURAL RESINS IS SIMILAR TO THAT OF OTHER ALDEHYDE RESINS. [R7, 2666] USE: +Source of furfuryl alcohol, tetrahydrofurfuryl alcohol, furan, tetrahydrofuran, poly(oxytetramethylene) glycol and a variety of synthetic resins; for the extractive distillation of butadiene and other C4 hydrocarbons for the manufacture of synthetic rubber; and for the production of light-colored wood resins [R1, p. 11(80) 508] +CONSTITUENT OF RUBBER CEMENTS [R7, 2665] *SYNTHETIC FLAVORING INGREDIENT [R8] *SOLVENT FOR SYNTHETIC AND NATURAL RESINS, DYES, POLYMERS /FURFURAL AND DERIV/ [R9, 932] *SCREENING TEST FOR URINE: FURFURAL SPOT TEST FOR MEPROBAMATE AND OTHER CARBAMATES [R10] +IN MFR OF FURFURAL-PHENOL PLASTICS SUCH AS DURITE; IN SOLVENT REFINING OF PETROLEUM OILS; PREPN OF PYROMUCIC ACID; SOLVENT FOR NITRATED COTTON, CELLULOSE ACETATE, AND GUMS; IN MFR OF VARNISHES; FOR ACCELERATING VULCANIZATION; AS INSECTICIDE, FUNGICIDE, GERMICIDE; AS REAGENT IN ANALYTICAL CHEMISTRY [R2] +WETTING AGENT IN MFR OF ABRASIVE WHEELS AND BRAKE LININGS, WEED KILLER, ADIPIC ACID AND ADIPONITRILE, ROAD CONSTRUCTION; IN PRODN OF LYSINE; REFINING OF RARE EARTHS AND METALS [R3] +A chemical intermediate in manufacture of furor, hexamethylene diamene, and pyromucic acid. [R11, 1981.3] CPAT: *39% EXPORTED; 3% FOR FURFURYL ALCOHOL; 16% FOR SOLVENT USAGE (INCLUDING 8% FOR LUBRICATING OILS AND 7% FOR BUTADIENE); 9% FOR SYNTHESIS OF TETRAHYDROFURAN; 3% FOR MISC APPLICATIONS (1974) [R12] *48% FURFURYL ALCOHOL; 19% LUBE OIL REFINING; 19% TETRAHYDROFURAN; 5% BUTADIENE EXTRACTION; 9% OTHER (1983) [R6] PRIE: U.S. PRODUCTION: *(1983) 5.22X10+10 g [R6] U.S. IMPORTS: *(1984) 7.26X10+9 g [R13] +(1986) 8.17X10+6 lb [R14] U.S. EXPORTS: *(1983) 9.08X10+9 g [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *AN AMBER-COLORED LIQUID [R9, 931]; *COLORLESS LIQUID WHEN FRESHLY PREPARED [R8]; *Colorless to reddish-brown oily liquid [R15, p. 49-51]; +Colorless to amber liquid ... [Darkens in light and air]. [R16, 150] ODOR: *Almond odor [R15, p. 49-51]; *PECULIAR ODOR SOMEWHAT RESEMBLING THE ODOR OF BENZALDEHYDE [R2]; +... Almond-like odor ... [R16, 150] TAST: *Distinct caramel taste [R17] BP: *161.8 DEG C AT 760 MM HG; 103 DEG C @ 100 MM HG; 67.8 DEG C @ 20 MM HG; 18.5 DEG C @ 1.0 MM HG [R2] MP: +-38.7 deg C [R18, p. C-282] MW: *96.08 [R2] CTP: +Critical temp: 745 deg F= 397 deg C= 670 K; critical pressure: 798 psia= 54.3 atm= 5.50 MN/sq m [R19] DEN: *1.1563 @ 25 DEG C/4 DEG C [R2] HTC: +559.5 KG CAL @ 20 DEG C (LIQUID) [R18, p. D-276] HTV: +107.5 CAL [R3] OWPC: +Log Kow= 0.41 [R20] SOL: +Soluble in chloroform, petroleum ether [R18, p. C-282]; +8.3 wt% in water @ 20 deg C (pure) [R21, 373]; +> 10% in acetone [R22]; +> 10% in benzene [R22]; +> 10% in ether [R22]; +> 10% in ethanol [R22]; +water solubility = 8.3X10+4 mg/l @ 25 deg C [R23] SPEC: +Index of refraction: 1.5261 @ 20 deg C/D [R18, p. C-282]; +SADTLER REFERENCE NUMBER: 113 (IR, PRISM); 35 (IR, GRATING); MAX ABSORPTION (SULFURIC ACID): 280 NM (LOG E= 3.07) (INITIAL) [R24]; *2-Furaldehyde, 99%, exhibits its two strongest infra red absorption bands at wavelengths of 6.0 and 13.3 microns. [R25]; +IR: 6172 (Coblentz Society Spectral Collection) [R22]; +UV: 42 (Sadtler Research Laboratories Spectral Collection) [R22]; +NMR: 95 (Varian Associates NMR Spectra Catalogue) [R22]; +MASS: 200 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R22] SURF: +43.5 DYNES/CM @ 20 DEG C IN CONTACT WITH AIR OR VAPOR [R18, p. F-36] VAPD: *3.3 (Air= 1) [R15, p. 325M-55] VAP: +2.21 mm Hg @ 25 deg C /calculated from experimentally derived coefficients/ [R26] VISC: +2.48 cP @ 0 deg C; 1.49 cP @ 25 deg C [R18, p. F-43] OCPP: +Thermal conductivity: 0.1525 BTU/(hr)(sq ft)(deg F/ft) @ 100 deg F [R21, 372] +Molar volume= 83.19 ml/mole @ 25 deg C [R21, 373] +Carbon tetrachloride/water partition coefficient: 0.23 [R27] +Ionization potential= 9.21 eV [R28] *Vapor diffusion coefficient= 0.087 sq cm/sec at 25 deg C [R21, 372] *Dielectric constant= 38 at 25 deg C [R21, 372] +Specific conductivity= 0.26X10-5 ohm (minimum), 0.37X10-5 ohm (maximum) [R21, 372] +Forms condensation products with many types of cmpd, phenol, amines, urea, etc [R3] +Dipole moment: 2.13 @ 25 deg C (liquid), 3.63 in benzene @ 25 deg C [R29, p. 4-63] +Enthalpy of formation: -47.8 kcal/mole (liquid) [R29, p. 5-22] *TENDS TO DARKEN ON AGE [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R30] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R30] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R30] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. [R30] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R30] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R30] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R30] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R30] FPOT: +Flammability of furfural is comparable to that of kerosene or No 1 fuel oil. [R1, p. 11(80) 507] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R31, p. 325-] +Flammability: 2. 2= Liquids which must be moderately heated before ignition will occur and solids that readily give off flammable vapors. Water spray may be used to extinguish the fire because the material can be cooled to below its flash point. [R31, p. 325-55] +Reactivity: 0. 0= Materials which are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R31, p. 325-55] FLMT: +LOWER 2.1%; UPPER 19.3% (% BY VOL) [R31, p. 325-55] FLPT: +60 DEG C (140 DEG F) (CLOSED CUP) [R31, p. 325-55] AUTO: +316 deg C (600 deg F) [R31, p. 325-55] FIRP: +USE WATER SPRAY, DRY CHEM, "ALCOHOL" FOAM, OR CARBON DIOXIDE. USE WATER TO KEEP FIRE-EXPOSED CONTAINERS COOL. ... /IF LEAK OR SPILL HAS NOT IGNITED/, STOP OR CONTROL THE LEAD, IF THIS CAN BE DONE WITHOUT UNDUE RISK. USE WATER SPRAY TO DISPERSE VAPORS AND TO PROTECT PERSONNEL. CONTROL RUNOFF AND ISOLATE DISCHARGED MATERIAL FOR PROPER DISPOSAL. [R31, p. 49-73] +Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Apply water from as far a distance as possible. [R32] TOXC: +Toxic gases and vapors (such as carbon monoxide) may be released in a fire involving furfural. [R11, 1981.2] EXPL: +Upper: 19.3 % by vol in air; lower: 2.1 % by vol in air [R16, 150] REAC: +Polymerization may occur on contact with strong acids or strong alkalies. Reacts with oxidizing materials. [R31, p. 49-73] *... CAN REACT WITH OXIDIZING MATERIALS. [R33] *AN EXOTHERMIC RESINIFICATION OF ALMOST EXPLOSIVE VIOLENCE CAN OCCUR UPON CONTACT WITH STRONG MINERAL ACIDS OR ALKALIES. [R33] +Strong acids, oxidizers, strong alkalis [Note: May polymerize on contact with strong acids or strong alkalis]. [R16, 150] POLY: +POLYMERIZATION IS GREATLY ACCELERATED BY HOT ALKALI. [R2] ODRT: +Odor index @ 20 deg C= 5260 [R34] +Detection in water: 3.00X10+3 ppb (gas chromatically pure) [R35] +0.0240 mg/cu m (odor low) 20.0 mg/cu m (odor high) [R36] SERI: +Vapor may irritate eyes and respiratory system. Liquid irritates skin ... [R19] EQUP: *PERSONS REQUIRED TO HANDLE FURFURAL ... SHOULD WEAR PERSONAL PROTECTIVE EQUIPMENT TO AVOID SKIN CONTACT, INCLUDING EYE AND FACE PROTECTION AND HAND PROTECTION. WHERE BRIEF EXPOSURE TO HIGH ATMOSPHERIC CONCN IS POSSIBLE WORKERS SHOULD WEAR RESPIRATORY PROTECTIVE EQUIPMENT. [R9, 932] *Employees should be provided with and required to use impervious clothing, gloves, face-shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with furfural. Employees should be provided with and required to use splash-proof goggles where there is any possibility of liquid furfural contacting the eyes. [R11, 1981.2] +Breakthrough times greater than one hour reported by (normally) two or more testers for butyl rubber (butyl) and polyvinyl alcohol (PVA). Some data suggesting breakthrough times of approximately an hour or more for natural rubber (Nat.rub) and neoprene (neop). Breakthrough times less (usually significantly less) than one hour reported by (normally) two or more testers for nitrile rubber (nitrile). No data for neoprene istyrene-butadiene rubber (Neop/SBR), nitrile rubber/polyvinyl chloride (nitrile/PVC), polyurethane (PU), viton, polyvinyl chloride (PVC), chlorinated polyethylene (CPE), and polyethylene (PE). [R37] +Wear appropriate personal protective clothing to prevent skin contact. [R16, 151] +Wear appropriate eye protection to prevent eye contact. [R16, 151] +Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. [R16, 151] +Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous-flow mode. May require eye protection. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R16, 151] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R16, 151] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R16, 151] OPRM: *DURING THE HANDLING OR PROCESSING OF FURFURAL, EXHAUST VENTILATION AND GENERAL VENTILATION SHOULD BE PROVIDED TO KEEP THE ATMOSPHERIC CONCN BELOW RECOMMENDED LEVELS. ... MEASURES TO PREVENT INHALATION HAZARDS WILL NORMALLY BE SUFFICIENT TO PREVENT THE FORMATION OF EXPLOSIVE MIXTURES; THE PRODUCTS SHOULD BE CONFINED AS MUCH AS PRACTICABLE, ESPECIALLY WHEN HEATED, TO PREVENT THE ESCAPE OF VAPOR, AND SOURCES OF IGNITION SHOULD BE ELIMINATED. [R9, 932] +If material /is/ not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to disperse vapors and dilute vapors and dilute standing pools of liquid. Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R32] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R11, 1981.2] +Clothing contaminated with liquid furfural should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of furfural from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the furfural, the person performing the operation should be informed of furfural's hazardous properties. Nonimpervious clothing which becomes contaminated with liquid furfural should be removed immediately and not reworn until the furfural is removed from the clothing. [R11, 1981.2] *Employees who handle liquid furfural should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. [R11, 1981.3] *KEEP AWAY FROM HEAT AND OPEN FLAME. [R33] +Contact lenses should not be worn when working with this chemical. [R16, 151] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. +The worker should immediately wash the skin when it becomes contaminated. [R16, 151] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16, 151] SSL: *TURNS YELLOW TO BROWN ON EXPOSURE TO AIR AND LIGHT AND RESINIFIES (POLYMERIZATION IS GREATLY ACCELERATED BY HOT ALKALI) [R2] +Drum lots may be stored for months without appreciable change in physical properties. [R1, p. 11(80) 507] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R38] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R39] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R40] STRG: +KEEP IN AIRTIGHT CONTAINER ... [R2] *FURFURAL AND ITS DERIVATIVES SHOULD BE STORED IN WELL-VENTILATED AREAS, SHELTERED FROM DIRECT SUNLIGHT AND AWAY FROM HEAT AND OTHER SOURCES OF IGNITION. [R9, 932] +STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM STRONG OXIDIZING MATERIALS, STRONG ALKALIES, AND STRONG ACIDS. OUTSIDE OR DETACHED STORAGE IS PREFERRED. [R31, p. 49-73] +Recommended: low-pressure storage tank, atmospheric < 0.5 psig. [R41] +Storage in either aboveground or underground installations is satisfactory. Because furfural is an excellent solvent and penetrant, care must be taken that all joints are secure and that the pump and valve packings are in good condition. [R1, p. 11(80) 507] CLUP: +1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities, absorb on paper towels. Evaporate in a safe place ... Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. For large quantities, cover with sodium bisulfite, add a small amt of water and mix. ... After 1 hr, flush with large amt of water and wash site with soap solution. [R11, 1981.4] *Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash or cement powder. Add sodium bisulfite (NaHSO3). [R32] +Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. Inject "universal" gelling agent to solidify encircled spill and increase effectiveness of booms. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R32] +Air spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. [R32] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U125, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R42] *Furfural is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. /From table/ [R43] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R44] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R44] +Adsorption and landfill: Furfural may be disposed of: 1) By adsorbing it in vermiculite, dry sand, earth or a similar material and disposing in a secured sanitary landfill. 2) For small quantities, by adsorbing it in vermiculite, dry sand, earth, or a similar material and disposing it in a suitable combustion chamber. 3) For large quantities, by mixing with a flammable liquid (such as acetone) and atomizing in a suitable combustion chamber. Recommendable method: Incineration. Not recommendable method: Evaporation. [R45] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: 2-Furaldehyde is a liquid with a pungent almond-like odor. It is found in trace amounts in a number of dietary sources. HUMAN EXPOSURE: 2-Furaldehyde is present in many food items as a natural product or as a contaminant. Its presence in drinking water and mother's milk has been reported. Measured occupational exposures are available. Generally, airborne exposure in all industries is below 8 mg/cu m. Toxicokinetic data are limited, but there are indications that 2-furaldehyde is readily absorbed via the inhalation and dermal exposure routes. In humans, absorption of the vapor via both lungs and skin has been demonstrated. The metabolism of 2-furaldehyde in humans indicates a majority of the retained dose is excreted as urinary 2-furoylglycine. Furoic acid and furanacrylic acid are also detected as minor metabolites. Dermal absorption from liquid furaldehyde has also been observed. Sin and eye irritation have been reported. No throat or eye irritation was noted in humans exposed to 40 mg/cu m (10 ppm) for 8 hr or 80 mg/cu m (20 ppm) for 4 hr. There are no adequate data available regarding reproductive or developmental effects; hence it is not possible to evaluate the risk to human health for these endpoints. ANIMAL STUDIES: Acute toxicity data from animals are variable; overall, this compound is toxic by inhalation and oral routes, with no clear information about the dermal route. Malignant and benign tumors have been observed in rats and mice following oral exposure for 103 weeks. 2-Furaldehyde is clearly genotoxic in vitro in mammalian cells; although no firm conclusions can be drawn on the genotoxic potential of 2-furaldehyde in vivo, the possibility that the genotoxicity could contribute to the carcinogenic process cannot be discounted. Toxic thresholds for a variety of microorganisms have been reported. Acute LC50's for fish have also been documented. [R46] CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of furfural. There is limited evidence in experimental animals for the carcinogenicity of furfural. Overall evaluation: Furfural is not classifiable as to its carcinogenicity to humans (Group 3). [R47] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R48, 2002.33] MEDS: *Employees should be screened for history of certain medical conditions (listed below) which might place the employee at increased risk from furfural exposure. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of furfural might cause exacerbation of symptoms due to its irritant properties or psychic reflex bronchospasm. Skin disease: Furfural can cause dermatitis on excessive exposure. Persons with existing skin disorders may be more susceptible to the effects of this agent. Kidney disease: Although furfural is not known as a kidney toxin in humans, the importance of this organ in the elimination of toxic substances justifies special consideration in those with possible impairment of renal function. Liver disease: Although furfural is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Any employee developing the above-listed conditions should be referred for further medical examination. [R11, 1981.1] HTOX: +... IRRITANT DERMATITIS, WHICH MAY BECOME ECZEMATOUS, HAS OCCURRED AND CASES OF SKIN SENSITIZATION HAVE BEEN REPORTED. [R9, 932] +May be harmful if absorbed through skin or inhaled. Irritating to eyes, skin, and respiratory system. [R31, p. 49-73] *FURFURAL IS A PHOTOSENSITIZER. [R49] *Workers chronically exposed to the vapor have had complaints of headache, fatigue, itching of the throat, lacrimation, loss of the sense of taste, numbness of the tongue, and tremor. Occupational overexposure is relatively rare due to the liquid's low vapor pressure, and symptoms usually disappear rapidly after removal from exposure. [R50] +... THOUGH MANY MILLIONS OF LB OF FURFURAL HAVE BEEN USED IN SOLVENT AND REFINING OPERATIONS AND IN SYNTHETIC RESIN INDUSTRY DURING A 15-YEAR PERIOD, FURFURAL HAS NOT BEEN CONSIDERED HAZARDOUS TO HEALTH UNDER ORDINARY PLANT CONDITIONS (IE, WITH ADEQUATE VENTILATION). ONLY OCCASIONAL INDIVIDUAL SENSITIVITY WAS ENCOUNTERED. [R51] *Fifty-one workers /employed in a butadiene plant/, exposed to furfural, had their respiratory system examined. Questionnaire studies demonstrated chronic bronchitis in 23.5% of subjects. Spirometric tests do not show subjective complaints. This seems to be related to hypercortisolemia, as experiments on animals indicate that furfural inhalations increase corticosteroid concentrations in blood serum. [R52] +THE VAPOR IS ... A CENTRAL NERVOUS SYSTEM POISON. HOWEVER, ITS LOW VOLATILITY REDUCES ITS TOXIC EFFECT. [R33] +INFORMATION IS CONFLICTING REGARDING THE TOXICITY OF FURFURAL VAPOR. ... /IT HAS BEEN/ CONCLUDED /BY SOME/ THAT THE PHYSIOLOGIC EFFECTS OF THE VAPOR WERE RELATIVELY MILD AND SIMILAR TO THOSE OF BUTYL ALCOHOL. [R51] +Furfural ... /is/ much less irritating than formaldehyde or acrolein. [R7, 2633] *FROM POINT OF VIEW OF COMFORT ... WHEN THE AIR CONTAINED FROM 0.007 TO 0.053 MG FURFURAL PER L OF AIR (1.9 TO 14 PPM) HEADACHES, ITCHING OF THE THROAT, AND RED AND WEEPING EYES OCCURRED. [R51] +Sister-chromatid exchanges (SCE) in human lymphocytes were studied using the FPG (fluorescence plus Giemsa) technique in order to determine the cytogenetic effect of furfural and furfuryl alcohol. The induction of SCE was also investigated in workers occupationally exposed to these solvents that are commonly used in the manufacture of furoic resins. The results obtained from the in vitro treatments show that furfural increased the number of SCE, while furfuryl alcohol did not. In exposed workers, neither of these solvents increased the spontaneous frequency of SCE per metaphase. [R53] NTOX: +/FURFURAL PRODUCES/ CENTRAL NERVOUS DEPRESSION WITH BRAIN LESIONS IN ANIMALS. INGESTED FURFURAL HAS PRODUCED LIVER CIRRHOSIS IN RATS. [R54] *RABBITS EXPOSED TO VAPORS SEVERAL HR DAILY MANIFESTED HEPATIC AND RENAL LESIONS AND MODIFICATIONS IN BLOOD PICTURE. [R9, 932] *... Furfural has a rather high acute toxicity. Inhalation of 260 ppm was fatal to rats but caused no deaths in mice or rabbits. Dogs exposed 6 hr a day for four wk @ 130 ppm suffered liver damage, but at 63 ppm no ill effects were noted. [R51] *GUINEA PIGS IRRITANT EFFECT ON SKIN: SLIGHT /FROM TABLE/ [R7, 2664] *THE INHALATION EXPOSURE OF CATS TO VERY HIGH LEVELS OF FURFURAL (2800 PPM) FOR 30 MIN RESULTED IN DEATH DUE TO PULMONARY EDEMA. [R7, 2665] +ORAL LD50 /FOR FURFURAL/ IN RATS IS BETWEEN 50 and 100 MG/KG AND IP LD50 BETWEEN 20 and 50 MG/KG. THE SYMPTOMS ... APPEAR TO BE THOSE OF WEAKNESS, ATAXIA, AND UNCONSCIOUSNESS. [R7, 2665] +TEST APPLICATION OF 10% AQ SOLN /OF FURFURAL/ ... ON EYES OF ANIMALS HAS CAUSED IMMEDIATE PAIN ... FOLLOWED BY COMPLETE ANESTHESIA OF CORNEA AND CONJUNCTIVA. AT SAME TIME LIDS AND CONJUNCTIVAE BECAME RED AND SWOLLEN, BUT IN TWENTY-FOUR HR EYES RETURNED TO NORMAL. WHEN APPLIED FULL STRENGTH TO RABBIT EYES ... CAUSED IMMEDIATE EDEMA OF CORNEAL EPITHELIUM FOLLOWED BY LOSS OF EPITHELIUM IN SHEETS. SMALL HEMORRHAGES APPEARED IN NICTITATING MEMBRANE, AND EDEMA IN CONJUNCTIVA. [R55] +50% ORAL LD50 DOSE OF FURFURAL IN RATS CAUSED 40% INCR IN LIVER TYROSINE AMINOTRANSFERASE ACTIVITY AND APPROX 50% DECR IN KIDNEY LEVELS OF SAME ENZYME. A 10% LD50 CAUSED NO CHANGE IN LIVER ENZYME AFTER 14 DAYS BUT A 26% DECR IN KIDNEY ENZYME. AT 1X10-4 M, FURFURAL COMPLETELY INHIBITED IN VITRO LIVER AND KIDNEY AMINOTRANSFERASE ACTIVITY WHILE @ 1X10-6 and 1X10-8 M THE ENZYME WAS ACTIVATED IN BOTH TISSUES. [R56] +TOXICITY STUDY IN SYRIAN HAMSTERS EXPOSED TO FURFURAL BY INHALATION TO 20, 115 and 552 PPM 6 HR/DAY, 5 DAY/WK FOR 13 WK. AT HIGHEST CONCN, EYE AND NOSE IRRITATION AND RETARDED GROWTH OCCURRED. ATROPHY AND HYPERPLASIA OF OLFACTORY EPITHELIUM IN NASAL CAVITY WERE ALSO SEEN @ 115 PPM. [R57] +RATS WERE ADMINISTERED DAILY IP INJECTIONS OF 58 MG/KG FURFURAL FOR 30 DAYS. IT CAUSED TIME-REVERSIBLE DECR OF RESP ENZYME ACTIVITY IN KIDNEY MITOCHONDRIA, DECR ENZYME ACTIVITY ASSOC WITH BIOLOGICAL ACTIVITY OF MEMBRANES, INCR IN ACTIVITY OF ENDOPLASMIC RETICULUM AND INTENSIFICATION OF RESPONSE TO ACID PHOSPHATASE. THESE PERTURBATIONS LEAD TO A DEGENERATION OF THE PROCESSES OF REVERSE RESORPTION IN THE MAIN PART OF THE NEPHRONS AND MAY POSSIBLY BE THE CAUSE OF THE FUNCTIONAL INSUFFICIENCY OF THE KIDNEYS. [R58] +INHALATION EXPOSURES TO FURFURAL (200 MG/CU M, 5 HR/DAY, 6 TIMES/WK FOR 12 WK) CAUSED CHANGES IN HYPOTHALAMIC-HYPOPHYSEAL-ADRENAL SYSTEM OF RATS WHICH AFFECTED BODILY ADAPTATION PROCESSES. DECR IN BRAIN NORADRENALINE LEVELS AND ADRENAL GLAND ADRENALINE CONTENT OCCURRED. BRAIN ACETYLCHOLINESTERASE CONCN INCREASED AND URINARY 17-HYDROXYCORTICOSTEROID AND 17-KETOSTEROID EXCRETION DECREASED. [R59] +TEMPORARY DECR IN BRAIN AND HEART ADRENALINE AND NORADRENALINE AND A DECR FOLLOWED BY AN INCR IN ADRENAL ADRENALINE AND NORADRENALINE WERE OBSERVED IN RATS GIVEN A SINGLE 20% LD50 DOSE OF FURFURAL IP. IT ALSO REDUCED 17-HYDROXYCORTICOSTEROIDS ELIMINATION. [R60] +THE MUTAGENIC ACTIVITY OF FURFURAL WAS DETERMINED BY ITS EFFECT ON REVERSION OF HIS MUTATIONS IN SALMONELLA TYPHIMURIUM STRAINS TA98 AND TA100. CONCN OF FURFURAL RANGED FROM ABOUT 1 TO 15 UL/PLATE. IT WAS MUTAGENIC IN TA100 STRAIN BUT NOT IN TA98 STRAIN. A RAT-LIVER MICROSOMAL FRACTION DID NOT INCREASE THE MUTAGENIC ACTVITIY OF FURFURAL IN EITHER STRAIN. [R61] *Cultured Chinese hamster ovary cells were exposed for 3 hr to furan and 6 furan derivatives, incl furfural. Each of the 6 furan derivatives induced a relatively high frequency of chromatid breaks and chromatid exchanges in the absence of a (rat) liver microsomal activation preparation. The clastogenic activity of furfural was increased. [R62] *Exposure of Bombyx mori larvae to 2-furaldehyde, a major volatile component of baldcypress heartwood, (Taxodium distichum), resulted in the in vivo inhibition of enteric microorganism at concn (1-47 ppm) that were released naturally from heartwood. The 7 bacterial and 2 fungal enteric isolates were also inhibited in vitro at the same concn. It is suggested that inhibition of leaf surface microorganisms or in vivo inhibition of silkworm enteric microflora, as a result of indirect action of 2-furaldehyde, exacerbates the growth-inhibitory effects of this cmpd on larvae by reducing the microbial nutritional contribution. The ecological significance of insect enteric microbial inhibition by plant /products/ is discussed. [R63] *Acute and chronic furfural intoxication of rats resulted in enhanced polyphenylalanine formation in hepatic preparations. Protein synthesis in renal preparations was not affected by a single (20 or 50% LD50) dose of furfural, but was inhibited following chronic treatment. A single 50% LD50 dose of furfural did not alter renal, hepatic, or serum cAMP levels. Repeated 10% LD50 doses decr renal cAMP content without affecting its serum or hepatic level. [R64] *Furfural, given to rats orally as a single 50% LD50 (32.5 mg/kg) dose or for 14 days at 6.5 mg/kg/day, had no effect on either brain acetylcholinesterase or serum cholinesterase. [R65] +Furfural at 1X10-8 to 1X10-6 M had no effect on aspartate aminotransferase activity and at 1X10-8 to 1X10-5 M had no effect on alanine aminotransferase activity in rat kidney and liver homogenates. A single dose of furfural at 50% LD50 inhibited aspartate aminotransferase activity in the kidney, but not in the blood serum or liver, of rats. Repeated doses of it at 10% LD50 had no effect on aspartate aminotransferase activity in the kidney, liver, or blood serum. Alanine aminotransferase activity in the kidney, liver, and blood serum were not altered by the single or repeated treatments. [R66] *Furfural was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster using a protocol approved by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of furfural that resulted in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. Furfural was positive at a dose of 100 ppm when administered to males by injection. [R67] *The effects of hepatic cirrhosis on chemical hepatocarcinogenesis were studied in rats using an experimental model for hepatic cirrhosis established by chronic furfural administration ... and N-2-fluorenylacetamide (2-FAA). Sixteen male Wistar rats were fed with 2-FAA feeding 3 cycles, which consisted of 3 weeks consuming 0.03% 2-FAA diet and 1 week basal diet, after 120 days of furfural feeding. Grossly and histologically all livers of experimental animals showed formation of multiple hyperplasic nodules with atypical features in parts. These hyperplastic nodules were positively immunostained with alpha-fetoprotein. On the other hand, none of the livers of 16 rats fed with furfural alone showed formation of hyperplastic changes and only 2 livers of 16 rats fed 2-FAA without preadministration of furfural showed one small hyperplastic nodule each, respectively. These results indicate that the cirrhotic liver induced by chronic furfural feeding has an enhancing effect on 2-FAA chemical hepatocarcinogenesis, and suggests that the presence of hepatic cirrhosis induces increased susceptibility to hepatocarcinogenic stimuli. [R68] +The inhalation of 10 mg/cu m furfural (insecticide, fungicide) by adult rats during three months for five hr/day, six days/wk, for three months did not change the calcium and phosphorus level in serum and in bones, but depressed the activity of alkaline phosphatase in serum. The exposure to furfural of immature rats (6-7 wk old) for 4 wk depressed serum and intestinal mucosal alkaline phosphatase activity, elevated calcium and phosphorus levels in serum with concomitant fall in bones, and decreased in calcium excretion with urine. [R69] +Changes of the liver following either single or repeated oral administration of furfural were studied histopathologically. Following single administration, the livers showed scattered eosinophilic globular formation and increased mitotic figures without zonal or massive necrosis. Both changes were most prominent 6 hr after administration, gradually decreasing in number thereafter. In the repeated administration experiment, furfural was mixed with basal diet for 90 or 120 days. The livers on the 90th day showed cirrhotic changes. In the parenchyma bridging necrosis and hydropic degeneration of hepatocytes were striking. In the livers on the 120th day, pseudolobule formation was more prominent but parenchymal damage reduced. No cancerous or precancerous changes were observed. Cirrhotic changes seen in the chronic experiment resembled Nagayo-Miyake's A-type hepatic cirrhosis in man; evidently, furfural-induced hepatic cirrhosis is an appropriate model of studying the interrelation between hepatic cirrhosis and hepatocarcinogenesis. [R70] +The desmutagenic effects of alpha-hydroxycarbonyl compounds, such as ... furfural, ... and alpha-dicarbonyl compounds ... were investigated against the mutagenic heterocyclic amines, such as Trp-P-1, Trp-P-2, Glu-P-1, Glu-P-2 and IQ. Most of the carbonyl compounds suppressed the mutagenicity of heterocyclic amines for S typhimurium TA98, alpha-dicarbonyl compounds showing a higher desmutagenicity effect than alpha-hydroxycarbonyl compounds. The reaction of carbonyl compounds with mutagenic heterocyclic amines also eliminated the mutagenicity of the former for S typhimurium TA100. [R71] +... Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of furfural for male F344/N rats based on the occurrence of uncommon cholangiocarcinomas in two animals and bile duct dysplasia with fibrosis in two other animals. There was no evidence of carcinogenic activity for female F344/N rats that received doses of 0, 30, or 60 mg/kg furfural. There was clear evidence of carcinogenic activity for male B6C3F1 mice, based on increased incidences of hepatocellular adenomas and hepatocellular carcinomas. There was some evidence of carcinogenic activity in female B6C3F1 mice, based on increased incidences of hepatocellular adenomas. Renal cortical adenomas or carcinomas in male mice and squamous cell papillomas of the forestomach in female mice may have been related to exposure to furfural. [R72] ETXV: +LD50 Agelaius phoeniceus (Redwinged blackbird) oral 98.0 mg/kg; [R73] NTP: +... Toxicology and carcinogenesis studies were conducted by administering furfural (99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 years. Dose for the 2 yr studies were 0, 30, and 60 mg/kg for rats and 0, 50, 100. and 175 mg/kg for mice. Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of furfural for male F344/N rats based on the occurrence of uncommon cholangiocarcinomas in two animals and bile duct dysplasia with fibrosis in two other animals. There was no evidence of carcinogenic activity for female F344/N rats that received doses of 0, 30, or 60 mg/kg furfural. There was clear evidence of carcinogenic activity for male B6C3F1 mice, based on increased incidences of hepatocellular adenomas and hepatocellular carcinomas. There was some evidence of carcinogenic activity in female B6C3F1 mice, based on increased incidences of hepatocellular adenomas. Renal cortical adenomas or carcinomas in male mice and squamous cell papillomas of the forestomach in female mice may have been related to exposure to furfural. [R72] POPL: +/Persons with/ chronic respiratory, skin, kidney, liver diseases /are at increased risk/. [R11, 1981.1] ADE: +ANALYSIS OF EXPIRED AIR OF VOLUNTEERS EXPOSED FOR 8 HR TO VAPOR SHOWED AFTER TERMINATION OF EXPOSURE VERY SMALL PROPORTION (LESS THAN 1%) OF RETAINED FURFURAL IS ELIMINATED BY LUNGS. IT IS METABOLIZED VERY RAPIDLY. HALF-LIFE IS ABOUT 2 TO 2.5 HR. NO FREE FUROIC ACID FOUND. THIS CMPD ENTERS THE BODY ALSO PERCUTANEOUSLY. AT 15 MIN CONTAMINATION OF 1 HAND (UP TO THE WRIST), APPROX THE SAME AMT OF FURFURAL IS ABSORBED AS WOULD BE RETAINED @ AN 8 HR (OR 4 HR) INSPIRATION OF AIR IN CONCN EQUALING MAX ALLOWABLE CONCN. [R74] METB: *THE ALDEHYDE GROUP IS CONVERTED TO AN ACID AND THIS IN TURN IS CONJUGATED WITH GLYCINE. IN DOGS AND RABBITS, FUROIC ACID, FUROYL GLYCINE, AND FURFURACRYLURIC ACID ARE EXCRETED. [R7, 2665] *IT IS METABOLIZED VERY RAPIDLY. CHIEF METABOLITE IS FUROYLGLYCINE, SIDE METABOLITE IS 2-FURANACRYLURIC ACID. NO FUROIC ACID FOUND. [R74] *Furfural and its metabolite furoylglycine were extracted from urine. About 60% of furfural dose orally admin to rats was recovered in urine as furoylglycine, and no urinary furfural was detected. [R75] BHL: +ANALYSIS OF EXPIRED AIR OF VOLUNTEERS EXPOSED FOR 8 HR TO VAPOR SHOWED HALF-LIFE IS ABOUT 2 TO 2.5 HR. [R74] INTC: *Binary mixtures of aldehydes, incl furfural, were tested for toxicity to the protozoan Chilomonas paramecium. Significant incr (eight-fold) in toxicity were found with combinations of crotonaldehyde with furfural, benzaldehyde, and acrolein and acetaldehyde with furfural and acrolein. A lesser potentiation of toxicity (four-fold) was found with furfural and benzaldehyde. [R76] +The alkaline unwinding assay and protection of cleavage sites from the action of various restriction enzymes was used to study the interaction of furfural with DNA. Alkaline unwinding experiments showed that formation of an increasing number of strand breaks in duplex DNA both with increasing furfural concentrations (DNA base pair/furfural molar ratios of 1:1, 1:2, 1:4, 1:8, and 1:16) and with time of reaction (up to 16 hours). At a molar ratio of 1:16 and alkaline unwinding time of 30 min, there were 5.56 breaks per unit DNA. Number of breaks per DNA increased from 1.31 at 1 hr to 29.74 at 16 hr during incubation at a fixed DNA base pair/furfural molar ratio of 1:4 at 37 deg C. Treatment of lambda phase DNA with furfural protected cleavage with restriction endonucleases DraI and SspI but not with ApaI, BssHII and SacII. To define the minimum number of consecutive AT base pairs necessary for the reaction with furfural, the reacted DNA was cleaved with the following restriction enzymes: SspI, EcoRI, NcoI, and MluI. SspI and EcoRI sites were protected against cleavage by these enzymes, but NcoI and MluI showed normal cleavage patterns. These results indicate that the reaction of furfural with double-stranded DNA requires the presence of at least 3-4 consecutive AT base pairs. When DNA was treated with furfural (molar ratio of 1:4, 37 deg C for 2 hr), in the presence of sodium chloride, the number of strand breaks per unit DNA were 4.28 with furfural alone, 2.32 with furfural and 0.1 M sodium chloride, and 1.82 with furfural and 0.2 M sodium chloride. [R77] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: +Furfural is a naturally occuring compound which is also produced commerically. It may be released to the environment as a fugitive emission during its manufacture, formulation, or use in commercial products. Furfural may also be released to the environment in the smoke from burning wood. If released to soil, furfural is expected to display high mobility and it has the potential to leach into groundwater. Limited data suggests that in may undergo biodegradation in soil. Volatilization from the soil surface to the atmosphere may occur; however it is not expected to be a rapid process. If released to water, furfural is expected to undergo microbial degradation, under both aerobic and anaerobic conditions. Acclimation has been found to increase the rate of biodegradation, and high concentrations of furfural inhibit the rate. Furfural is not expected to adsorb to sediment or suspended organic matter, nor is it expected to bioconcentrate in fish and aquatic organisms. Hydrolysis is not expected to be a significant fate process under environmental conditions. In the atmosphere, furfural is expected to exist predominately in the vapor phase. Destruction by the vapor phase reaction with photochemically produced hydroxyl radicals is expected to be an important process with an estimated half-life of 0.44 days. Night time destruction by the vapor phase reaction with nitrate radicals may be an important process in urban areas. Limited data suggests that direct photochemical degradation of furfural may occur in the atmosphere. Atmospheric removal by wet deposition may be a significant process. Occupational exposure to furfural may occur by inhalation or dermal contact during its production, formulation or use, Exposure to the general population may occur by the ingestion of contaminated drinking water or ingestion of food in which it is contained. The general population may also receive exposure to furfural by inhalation of smoke from wood fires, or by inhalation or dermal contact during the use of commercial products which contain this aldehyde. (SRC) NATS: +... FOUND IN SEVERAL ESSENTIAL OILS FROM PLANTS OF THE PINACEAE FAMILY, IN THE ESSENTIAL OIL FROM CAJENNE LINALOE, IN THE OIL FROM LEAVES OF TRIFOLIUM PRATENSE AND TRIFOLIUM INCARNATUM, IN THE DISTILLATION WATERS OF SEVERAL ESSENTIAL OILS SUCH AS AMBRETTE AND ANGELICA SEEDS, IN CEYLON CINNAMON ESSENTIAL OIL, IN PETITGRAIN OIL, YLANG-YLANG, LAVENDER, LEMONGRASS, CALAMUS, EUCALYPTUS, NEROLI, SANDALWOOD, TOBACCO LEAVES, AND OTHERS. [R8] ARTS: +Furfural has numerous commercial applications including the solvent refining of lubricating oils, butadiene, and other organic materials, as a solvent for nitrocellulose, cellulose and shoe dyes, as a synthetic intermediate, as an additive in phenolic and furan polymers, as a wetting agent for the manufacture of abrasives and brake linings, as a weed killer and fungicide, in road construction and metal refining, in flavorings, and as an analytical reagent(1,2,3). It may be released to the environment as a fugitive emission during its production, formulation or use in commercial products. Furfural may also be released to the environment in the smoke of wood burning stoves or fireplaces(SRC). [R78] FATE: +TERRESTRIAL FATE: If released to soil, furfural is expected to display high mobility and it has the potential to leach into groundwater. Volatilization from the soil surface to the atmosphere is expected to occur; however, it is not expected to be a rapid process. Limited data suggests that furfural may undergo microbial degradation in soil. (SRC) +AQUATIC FATE: If released to water, furfural is expected to undergo microbial degradation under both aerobic and anaerobic conditions. The rate of microbial degradation has been found to increase as the microorganisms become acclimated, and high concentrations have been found to inhibit both the degradation of furfural and the degradation of other organic species present. Furfural is not expected to adsorb to sediment or suspended organic matter, nor is it expected to bioaccumulate in fish and aquatic organisms. Hydrolysis under environmental conditions is not expected to be a significant process. Volatilization from water to the atmosphere is expected to occur, although it is not expected to be a rapid process. The estimated half-life for the volatilization of furfural from a model river is 9.9 days(1,2,3,SRC). [R79] BIOD: *Pseudomonas fluorescens, which had been known to be unable to degrade furfural, could utilize 0.03% furfural as a sole C source in a culture with forced aeration. High concn of furfural (greater than 0.1%) had a killing effect on this strain. [R80] +Furfural at an initial concn of 300 mg/L, in solution with phenol and N-methyl-2-pyrolidine, was found to undergo 98% removal in a flow-through laboratory bioreactor using an activated sludge inoculum under aerobic conditions(1). At an initial feed concentration of 1,000 mg/L, degradation was also found to occur. In a static reactor using unacclimated inocula, a lag period of 4 to 7 days was observed(1). Furfural at an initial concn of 200 mg/L COD underwent 96.3% removal (time not given, but less than 120 hours) using a thickened adapted activated sludge under aerobic conditions(2). [R81] +In river die-away studies using water taken from the Great Miami, Little Miami, Ohio Rivers, 1.0 ppm of furfural was completely degraded within 3 days under aerobic conditions(1). The rate of degradation at a higher initial furfural concn was found to be dependent upon the degree of acclimation, and fully acclimatized seeds were found to degrade 25 ppm within 5-12 days(1). Furfural was listed as being confirmed to be well biodegradable using the Japanese MITI test(2,3). Furfural was shown to support the aerobic growth of organisms obtained from soil and grown on phenol(4), suggesting that this compound may biodegrade in soil(SRC). At an initial concn of 1.7 to 20, and 440 ppm, furfural underwent 46% and 17% theoretical biological oxygen demand, respectively, in 5 days using a sewage sludge seed under aerobic conditions(5). [R82] +Unactivated anaerobic organisms obtained from commercial wastewater reactors were found to completely utilize 580 mg/L of furfural in 30 days as measured by the production of methane and CO2; however, it was found that at this furfural concentration the degradation rate of other carbon sources was inhibited(1). At a furfural concn of 1160 g/L, no gas production was observed, although it was not clear if furfural was toxic to the microorganisms or merely inactivated them. Acclimated inocula from the same source were found to remove 99% of an initial 2320 mg/L of furfural in 32 days under anaerobic conditions(1). [R83] ABIO: +An initial furfural concn of 1.5 ppm in distilled water was found to decrease by only 0.1 ppm after 30 days at 20 deg C(1), suggesting that hydrolysis under neutral conditions is not an important process(SRC). High temperatures and long reaction times are necessary for the complete hydrolysis of furfural mineral acids(2). The gas-phase concentration o furfural, obtained as a component of the smoke obtained from burning oak in a wood stove, was found to decrease when irradiated in an experimental chamber equipped both with sun lights and UV lights(3) suggesting that direct photooxidation of furfural may occur in the atmosphere. The rate of disappearance was greater when NOx was added to the system(3). The half-life fo the vapor phase reaction of furfural with photochemically produced hydroxyl radicals is estimated at 0.44 days(4,SRC), which suggests that it will be a significant atmospheric fate process. The night time degradation of the aldehyd group of furfural by the vapor phase reaction with nitrate radicals may be an important process in urban areas where higher concentrations of this oxidant ar expected(5). [R84] BIOC: +Based on the water solubility of furfural, 86,000 mg/L at 25 deg C(1), and its log octanol/water partition coefficient, 0.41(2), respective bioconcentration factors in the range 0.008 - 1.2 can be calculated using an appropriate regression equation(3,SRC). These values suggest that the bioconcentration of furfural in fish and aquatic organisms will be an insignificant process(SRC). [R85] KOC: +Based on the water solubility of furfural, 86,000 mg/L at 25 deg C(1), and its log octanol/water partition coefficient, 0.41(2), respective soil adsorption coefficients in the range of 1 to 40 can be calculated using appropriate regression equations(3,SRC). These values suggest that furfural will display very high mobility in soil(4) and as such it has the potential to leach into groundwater(SRC). [R86] VWS: +Based on a water solubility of 86,000 mg/L at 25 deg C(1), and a vapor pressure of 2.5 mm Hg at 25 deg C(2), a Henry's Law constant of 3.7X10-6 atm cu-m/mol at 25 deg C can be calculated for furfural(3,SRC). Based on this value, the estimated half-life for the volatilization of furfural from a model river 1 m deep flowing at 1 m/sec and a wind speed of 3 m/sec is 9.9 days(3,SRC). This Henry's Law constant also suggests that volatilization from the soil surface to the atmosphere may occur, but it is not expected to be a rapid process(SRC). [R87] WATC: +SURFACE WATER: Furfural was detected in 1 out of 204 surface water samples taken near heavily industrialized sites across the USA (detection limit 1 ppb) at a concentration of 2 ppb(1). Furfural was found in 1 of 13 samples taken in the Lake Michigan basin, 1977, at a concn of 2 ug/L(2). [R88] +DRINKING WATER: Furfural has been identified in the drinking water supplies of the United States and Europe(1). It has been qualitatively detected in the drinking water of Ottumwa, IA(2). [R89] EFFL: +Furfural was detected as an emission from the burning of jack pine, cedar, oak, and ash in a fireplace(1). It was identified in the smoke obtained from the burning of oak(2). Furfural was detected in the wastewater of a synthetic rubber company discharging into the Calcasieu River (or its tributaries), LA, at an approximate concn of 1.7 ug/L(3). Although furfural has been identified in vehicle exhaust emissions, it was not detected in samples taken from the Allegheny Mountain tunnel, PA, 1979(4). Furfural was identified in the spent chlorination liquor from the wood pulping industry which uses the sulfite process(5). The mean concentration of five sulfite evaporator condensates (wastewater) from a paper plant in Bellingham, WA, ranged from 179-471 mg/L, mean 274 mg/L(6). [R90] ATMC: +Furfural was qualitatively detected in indoor air above a floor finished with a natural oil 4-5 months after its application(1). Furfural was qualitatively detected in the air above the Southern Black Forest (Kalbelescheur), Germany, 1984-85(2). [R91] FOOD: +Furfural was identified as the dominant volatile flavor component of beef fried together with vegetables, soy sauce and sugar (Sukiyaki), and it was present in two of the ingredients, beef and soy sauce(1). Furfural has been identified as a volatile flavor component of roasted filberts (nuts)(2), fried bacon(3), nectarines(4), baked potatoes(5), and the neutral fraction of clove essential oil(6). Furfural, as a mixture with 3-hexanol, was identified as a volatile flavor component of mango's preserved for 14 months at -15 deg C, but not in samples of the fresh fruit(7). Identified in the aroma fraction of blue cheese fat(8). [R92] +NON-ALCOHOLIC BEVERAGES, 4.0 PPM; ALCOHOLIC BEVERAGES, 10 PPM; ICE CREAM, ICES, ETC, 13 PPM; CANDY, 12 PPM; BAKED GOODS, 17 PPM; GELATINS AND PUDDINGS, 0.80 PPM; CHEWING GUM, 45 PPM; SYRUPS, 30 PPM. [R8] +... Reported found in rum and toasted coffee. [R8] MILK: +Furfural was qualitatively detected in 2 of 8 samples of mothers milk (detection limits not given) from samples obtained from four urban sites in the USA(1). [R93] RTEX: *Furfural can affect the body if it is inhaled, swallowed, or comes in contact with the eyes or skin. [R11, 1981.1] +NIOSH (NOES Survey 1981- 1983) has statistically estimated that 134,158 workers are exposed to furfural in the USA(1). NIOSH (NOHS survey 1972-1974) has statistically estimated that 15,412 workers are exposed to furfural in the USA(2). [R94] +Occupational exposure to furfural may occur by inhalation or dermal contact during its production, formulation, and use in commercial products. Exposure to the general population may occur by inhalation or dermal contact if commercial products containing this compound are used in the home, or by the ingestion of contaminated water. Ingestion of food containing furfuran is a probable route of exposure. Exposure to the general population may also occur by inhalation of the smoke from wood-burning fireplaces or stoves. (SRC) BODY: +Furfural was qualitatively detected in 2 of 8 samples of mothers milk (detection limits not given) from samples obtained from four urban sites in the USA(1). [R93] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +100 ppm [R16, 150] ATOL: +/Furfural byproduct/ (a granular steam-acid sterilized, lignocellulosic residuum is the extraction of furfural from corn cobs, sugarcane bagasse, cottonseed hulls, oat hulls, and rice hulls) is exempted from the requirement of a tolerance when used as a solid diluent or carrier in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R95] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (20 mg/cu m). Skin Designation. [R96] +Vacated 1989 OSHA PEL TWA 2 ppm (8 mg/cu m), skin designation, is still enforced in some states. [R16, 364] NREC: +After reviewing available literature, NIOSH provided comments to OSHA on August 1, 1988, regarding the "Proposed Rule on Air Contaminants" (29 CFR 1910, Docket No. H-020). In these comments, NIOSH questioned whether the PELs proposed for furfural (TWA 2 ppm (skin)) were adequate to protect workers from recognized health hazards. [R16, 150] TLV: +8 hr Time Weighted Avg (TWA): 2 ppm, skin. [R48, 2002.33] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R48, 2002.6] +Biological Exposure Index (BEI): Determinant: total furoic acid in urine; Sampling Time: end of shift; BEI: 200 mg/g creatinine. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. [R48, 2002.90] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R48, 2002.33] OOPL: +Emergency Response Planning Guidelines (ERPG): ERPG(1) 2 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 10 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 100 ppm (not life threatening) up to 1 hr exposure. [R97] ASTD: +This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Furfural is produced, as an intermediate or final product, by process units covered under this subpart. [R98] CERC: +Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R99] TSCA: +Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2-Furancarboxaldehyde is included on this list. [R100] RCRA: +As stipulated in 40 CFR 261.33, when furfural, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R101] FIFR: +/Furfural byproduct/ (a granular steam-acid sterilized, lignocellulosic residuum is the extraction of furfural from corn cobs, sugarcane bagasse, cottonseed hulls, oat hulls, and rice hulls) is exempted from the requirement of a tolerance when used as a solid diluent or carrier in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R95] FDA: +Furfural is an indirect food additive for use only as a component of adhesives. [R102] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: +NIOSH 2529: Analyte: oxazolidine derivative of furfural; Matrix: air; Sampler: solid sorbent tube (10% 2-hydroxymethyl)piperidine on XAD-2, 120 mg/60 mg); Flow rate: 0.01 to 0.05 l/min; Vol: min 1 l @ 5 ppm, max 12 l; Sample stability: at least 2 wk @ 25 deg C [R103] +NIOSH S17: ANALYTE: FURFURAL-GIRARD T DERIVATIVE; MATRIX: AIR; PROCEDURE: BUBBLER COLLECTION [R104] ALAB: +NIOSH S17: ANALYTE: FURFURAL-GIRARD T DERIVATIVE; MATRIX: AIR; PROCEDURE: DERIVATIZATION WITH GIRARD T REAGENT, HIGH PRESSURE LIQUID CHROMATOGRAPHY, UV @ 12 NM; RANGE: 10.1 TO 40 MG/CU M; PRECISION (RELATIVE STANDARD DEVIATION): 0.054; EST LIMIT OF DETECTION: 20 UG/SAMPLE; INTERFERENCES: OTHER VOLATILE ALDEHYDES OR ACETONE MAY CAUSE SIGNIFICANT INTERFERENCE OR COMPETE WITH FURFURAL FOR REACTION WITH GIRARD T REAGENT. CHROMATOGRAPHIC CONDITIONS CAN BE ADJUSTED TO SEPARATE THE VARIOUS SUBSTANCES. [R104] +NIOSH 2529: Analyte: oxazolidine derivative of furfural; Matrix: air; Technique: gas chromatography, flame ionization detection; Desorption: 2 ml toluene, 30 min ultrasonic; Range: 16 to 640 ug per sample; Precision (relative standard deviation): 0.057; Est limit of detection: 5 ug per sample; Interferences: none have been observed. [R103] +FURFURAL DETERMINED IN INDUSTRIAL AIR BY ALTERNATING-CURRENT POLAROGRAPHY IN PRESENCE OF LITHIUM CHLORIDE WITH TRAPEZOIDAL FORM OF ALTERNATING-CURRENT. DETECTION LIMIT 0.5 UG/ML. DEPENDENCE OF PEAK HEIGHT ON CONCN IS LINEAR BETWEEN 0.5 and 10 UG/ML @ 1.6 VOLTAGE. [R105] +Determination of environmental furfural by gas chromatographic method is considered. [R106] +Determination of furfural in orange juice by a high-performance liquid chromatographic method was discussed. It was necessary to separate furfural from interfering cmpd by distilling the juice. The distillate was injected on a Du Pont Zorbax ODS column. The furfural was eluted with water-methanol (70:30 v/v). Detection was by absorbance at 280 nm. The minimum detectable level of furfural in orange juice is 2 ppb. [R107] +Furfural in distilled liquors is analyzed with steam distillation and UV spectrophotometry at 277 nm, using standard solutions and curves. [R108] CLAB: +GAS-LIQUID CHROMATOGRAPHY METHOD APPLICABLE FOR HUMAN BIOLOGICAL MATERIALS. [R109] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Brune G et al; Ger Offen Patent No 3210911 (9/29/83). Anaerobic treatment of furfural-containing wastewater, useful bacteria and their derivation. Merrill RG et al; Atmos Environ 21 (2): 331-6 (1987). Screening methods for the identification of organic emissions from indoor air pollution sources. Arbetarskyddsstyrelsen 174: 118 (1984). This criteria document is an English version of Arbete och H"alsa 1984:43. It is a compilation of consensus reports on the physical, chemical, and toxilogical properties and methods of determination of potentially hazardous substances, /including furfural/. ... Clayton Environmental Consultants Inc; Medical Management of Chemical Exposures in the Petroleum Industry p.211 (1982). An introduction and description of the petroleum industry is followed by general recommendation for employee health evaluation and medical surveillance, industrial record-keeping and reporting, and data sheets for more than 90 substances which cover: physical data and properties; synonyms; degree of health hazard; exposure limits; toxicity; medical treatment and follow-up; additional comments; biological monitoring. DHHS/NTP; Toxicology and Carcinogenesis Studies of Furfural in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 382 (1990) NIH Publication No. 90-2837 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. 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Technical Report Series No. 382 (1990) NIH Publication No. 90-2837 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R73: Schafer EW Jr, et al; Arch Environ Contam Toxicol 12 (3): 355-82 (1983) R74: FLEK J, SEDIVEC V; INT ARCH OCCUP ENVIRON HEALTH 41 (3): 159-68 (1978) R75: Jodynis-Liebert J, Laboda K; Bromatol Chem Toksykol 15 (1-2): 61-6 (1982) R76: Bringmann G et al; Z Wasser Abwasser Forsch 15 (5): 239-42 (1982) R77: Hadi SM et al; Mutat Res 225 (3): 101-6 (1989) R78: (1) Mckillip WP, Sherman E; Kirk-Othmer Encycl Chem Tech 3rd ed NY: John-Wiley 11: 499-527 (1980) (2) Sax NI, Lewis RJSR; Hawley's Condensed Chemical Dictionary: 11th ed NY: Van Nostrand Reinhold Co p. 546 (1987) (3) Windholz M; The Merck Index: 10th ed Rahweh,NJ: Merck and Co Inc (1983) R79: (1) Amoore JE, Hautala E; J Appl Toxicol 3: 272-90 (1983) (2) Riddick JA et al; Organic Solvents Physical Properties and Methods of Purification: 4th ed Wiley Interscience NY (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw Hill pp. 15-1 to 15-29 (1982) R80: Kim TY et al; Misaengmul Hakhoechi 21 (3): 149-55 (1983) R81: (1) Rowe EH, Tullos LFJR; Hydrocarbon Process 59: 63-5 (1980) (2) Pitter P; Water Res 10: 231-5 (1976) R82: (1) Ettinger MB et al; Proc 8th Industrial Waste Conf: Purdue Univ Ext Ser (1954) (2) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (3) Sasaki S; pp. 283-98 in Aquatic Pollutants Hutzinger O et al Ed Pergamon Press Oxford (1978) (4) Kramer N, Doetsch RN; Arch Biochem Biophys 26: 401-5 (1950) (5) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) R83: (1) Benjamin MM et al; Water Res 18: 601-7 (1984) R84: (1) Ettinger MB et al; Proc 8th Industrial Waste Conf: Purdue Univ Ext Ser (1954) (2) Mckillip WP, Sherman E; Kirk-Othmer Encycl Chem Tech 3rd ed NY: John-Wiley 11: 499-527 (1980) (3) Kleindienst TE et al; Environ Sci Tech 20: 493-501 (1986) (4) Atkinson R; Chem Rev 85: 69-201 (1985) (5) Carter WPL et al; Environ Sci Tech 15: 829-31 (1981) R85: (1) Amoore JE, Hautala E; J Appl Toxicol 3: 272-90 (1983) (2) Hansch C, Leo AJ; Medchem project Issue No. 26: Claremont CA Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 5-1 to 5-30 (1982) R86: (1) Amoore JE, Hautala E; J Appl Toxicol 3: 272-90 (1983) (2) Hansch C, Leo AJ; Medchem project Issue No. 26: Claremont CA Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-1 to 4-33 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R87: (1) Amoore JE, Hautala E; J Appl Toxicol 3: 272-90 (1983) (2) Riddick JA et al; Organic Solvents Physical Properties and Methods of Purification 4th ed NY: Wiley Interscience (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-1 to 15-29 (1982) R88: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters, Appendix: USEPA-560/6-77-015A Washington DC USEPA (1977) (2) Konasewich D et al; Status Report on Organic and Heavy Metal Contaminants in the Lakes Erie, Michigan, Huron and Superior: Great Lakes Water Qual Board (1978) R89: (1) Kool HJ et al; CRC Crit Rev Env Control 12: 307-57 (1982) (2) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 3 USEPA-600/1-84-020 Columbus, OH (1984) R90: (1) Lipart F et al; Environ Sci Technol 18: 326-30 (1984) (2) Kleindienst TE et al; Environ Sci Tech 20: 493-501 (1986) (3) Keith LH; Sci Total Environ 3: 87-102 (1974) (4) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (5) Carlberg GE et al; Sci Total Environ 48: 157-67 (1986) (6) Benjamin MM et al; Water Res 18: 601-7 (1984) R91: (1) Van Nettin C et al; Bull Environ Contam Toxicol 40: 672-7 (1988) (2) Juttner F; Chemosphere 15: 985-92 (1986) R92: (1) Shibamato T et al; J Agric Food Chem 29: 57-63 (1981) (2) Kinlin TE et al; J Agr Food Chem 20: 1021-8 (1972) (3) Ho CT et al; J Agric Food Chem 31: 336-42 (1983) (4) Engel KH et al; J Agric Food Chem 36: 549-53 (1988) (5) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (6) Muchalal M, Crouzet J; Agric Biol Chem 49: 1583-9 (1985) (7) MacLeod AJ, Snyder CH; J Agric Food Chem 36: 137-9 (1988) (8) Day EA, Anderson DF; J Agr Food Chem 13: 2-4 (1965) R93: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) R94: (1) NIOSH; National Occupational Exposure Survey (NOES) (1974) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1983) R95: 40 CFR 180.1001(d) (7/1/88) R96: 29 CFR 1910.1000 (7/1/98) R97: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.25 R98: 40 CFR 60.489 (7/1/89) R99: 54 FR 33419 (8/14/89) R100: 40 CFR 716.120 (7/1/88) R101: 40 CFR 261.33 (7/1/88) R102: 21 CFR 175.105 (4/1/88) R103: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V1 2529-1 R104: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V5 S17-1 R105: ZAITSEVA ZV ET AL; ZH ANAL KHIM 33 (9): 1823-8 (1978) R106: Sidhu KS; Bull Environ Contam Toxicol 28 (2): 250-5 (1982) R107: Marcy JE, Rouseff RL; J Agric Food Chem 32 (5): 979-81 (1984) R108: Association of Official Analytic Chemists. Official Methods of Analysis of the AOAC. 14th ed. Arlington, VA: Association of Official Analytic Chemists, Inc., 1984.,p. 185 9.097 R109: NUYTINCK M ET AL; FARM TIJDSCHR BELG 54 (6): 395-402 (1977) RS: 83 Record 69 of 1119 in HSDB (through 2003/06) AN: 566 UD: 200205 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HEXYLRESORCINOL- SY: *ADROVER-; *ANTASCARIN-; *ASCARICID-; *ASCARINOL-; *CYSTOIDS-ANTHELMINTIC-; *1,3-DIHYDROXY-4-HEXYLBENZENE-; *GELOVERMIN-; *4-HEXYL-1,3-BENZENEDIOL-; *4-HEXYL-1,3-DIHYDROXYBENZENE-; *4-HEXYLRESORCINE-; *4-N-HEXYLRESORCINOL-; *P-HEXYLRESORCINOL-; *4-HEXYLRESORCINOL-; *4-(1-HEXYL)RESORCINOL; *HIDESOL-; *OXANA-; *PRENSOL- RN: 136-77-6 MF: *C12-H18-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF CAPROIC ACID AND RESORCINOL IN THE PRESENCE OF A CATALYST [R1] *PREPD BY REDUCTION OF HEXANOYLRESORCINOL WITH ZINC AMALGAM + DIL HCL: DOHME ET AL, J AM CHEM SOC 48, 1688 (1926); TWISS, IBID 2206; GER PATENT 488,419 and 489,117 (1929 TO SHARP AND DOHME). [R2] FORM: *ST 37, CAPROKOL, CRYSTOIDS, SUCRETS. [R2] *OFFICIAL HEXYLRESORCINOL PILLS...ARE COATED BY PATENTED PROCESS, GELATIN COATING BEING SO TOUGH THAT IT CANNOT BE READILY BROKEN EVEN THOUGH CHEWED. [R3] *DOSAGE FORMS-- PILLS NF: 100 and 200 MG. [R3] *FORMULATION: SORUNEX [R4] MFS: *MERCK AND CO, INC, MERCK CHEM DIV, RAHWAY, NJ [R1] *RSA CORP, ARDSLEY, NY [R1] USE: *MEDICATION *MEDICATION (VET) PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW, HEAVY LIQ BECOMING SOLID ON STANDING @ ROOM TEMP; NEEDLES FROM BENZENE OR PETROLEUM ETHER [R2]; *WHITE, OR YELLOWISH WHITE, NEEDLE-SHAPED CRYSTALS; ACQUIRES BROWNISH PINK TINT ON EXPOSURE TO LIGHT AND AIR [R3] ODOR: *PUNGENT ODOR [R2] TAST: *SHARP ASTRINGENT TASTE [R2] BP: *178-180 DEG C @ 6.7 MM HG [R2] MP: *67.5-69 DEG C [R2] MW: *194.26 [R2] OWPC: +log Kow = 3.45 [R5] SOL: *SOL IN ETHER, CHLOROFORM, ACETONE, ALCOHOL; SLIGHTLY SOL IN PETROLEUM ETHER; SOL IN ABOUT 2000 PARTS WATER; SOL IN VEGETABLE OILS [R2]; *FREELY SOL IN GLYCERIN, BENZENE [R3]; +water solubility = 500 mg/l @ 18 deg C [R6] SPEC: *INDEX OF REFRACTION: ALPHA= 1.513; GAMMA= 1.557 [R7, 308]; +IR: 10856 (Sadtler Research Laboratories IR Grating Collection) [R8]; +UV: 2223 (Sadtler Research Laboratories Spectral Collection) [R8]; +NMR: 3219 (Sadtler Research Laboratories Spectral Collection) [R8] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *CARE SHOULD BE TAKEN THAT PILLS CONTAINING DRUG ARE SWALLOWED WHOLE OR PAINFUL ULCERATION OF ORAL MUCOUS MEMBRANE MAY RESULT. [R3] *...PRODUCES SENSATION OF NUMBNESS WHEN PLACED ON TONGUE... [R3] *...IS IRRITATING TO...RESP TRACT AND TO SKIN, AND ITS SOLN IN ALCOHOL HAS VESICANT PROPERTIES. [R3] *CONCN SOLN CAN CAUSE BURNS OF SKIN, MUCOUS MEMBRANES. [R2] *SOME CUTANEOUS REACTIONS ARE DUE TO HYPERSENSITIVITY. [R9] NTOX: *BECAUSE OF POOR ABSORPTION, SYSTEMIC SYMPTOMS ARE UNUSUAL BUT DAMAGE TO LIVER AND HEART HAS BEEN REPORTED IN DOGS. [R9] *TESTS ON RABBIT EYES HAVE SHOWN THAT SURFACE OF CORNEA CAN BE IRRIGATED FOR 5 MIN WITH 1:10,000 SOLN WITHOUT INJURY, BUT THAT IRRIGATION WITH 1:1,000 SOLN FOR 1-5 MIN CAUSED DIFFUSE EDEMA OF EPITHELIUM, FOLLOWED IN 2 0R 3 HR BY BLUISH STROMAL EDEMA AND HYPEREMIA OF IRIS. [R10] +p-Hexylresorcinol was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). p-Hexylresorcinol was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.300, 1.000, 3.000, 3.300, 10.000, 22.000, 33.000, and 100.000 ug/plate. The highest ineffective dose tested in any S. typhimurium strain was 100.000 ug/plate. At this dose, slight to total clearing of the background bacterial lawn occurred under all test conditions. [R11] +... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally incr incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. ... [R12] NTP: +2 yr toxicology and carcinogenesis studies of 4-hexylresorcinol were conducted by admin 0, 62.5 or 125 mg/kg to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days/wk. Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally incr incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. ... [R12] METB: *HUMAN METABOLITE OF 4-HEXYLRESORCINOL IS ETHEREAL SULFATE. /FROM TABLE/ [R7, 353] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3. 3= MODERATELY TOXIC: PROPABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB). SOMEWHAT LESS TOXIC THAN RESORCINOL OR PHENOL. [R9] THER: +Anti-Infective Agents, Local; Antinematodal Agents; Antiplatyhelmintic Agents [R13] +DOSE-- USUAL, 1 G; MAY REPEAT AT WEEKLY INTERVALS IF NECESSARY. ... USUAL DOSE FOR CHILD IS 100 MG FOR EACH YR OF AGE. [R3] *IT IS COMMONLY EMPLOYED IN 1:1000 SOLN OR GLYCERITE IN MOUTHWASHES OR PHARYNGEAL ANTISEPTIC PREPN. [R14] *MEDICATION (VET): RARE NOW, AS ANTHELMINTIC ESPECIALLY SINCE INTRODUCTION OF DICHLORVOS AND OTHER DRUGS. TOPICALLY IT IS EFFECTIVE BACTERIOSTATIC, BACTERICIDAL, VIRUCIDAL, FUNGISTATIC, AND FUNGICIDAL AGENT @ DIL GREATER THAN 1:1000 (0.1%), ALTHOUGH LATTER IS SAFE TOPICALLY. IN RINGWORM THERAPY WITH AMIOACRIDINIUM= ACRISORCIN... [R4] *MEDICATION (VET): EFFECTIVE AGAINST MANY VIRUSES WHEN AEROSOLED @ 5 MG/CU M. ... ADMINISTER ORALLY IN OIL TO REDUCE LOCAL IRRITATION. [R4] *EFFECTIVE BY ALL PORTALS INCLUDING PERCUTANEOUS ABSORPTION. [R9] *REPORTED USES: IN TREATMENT OF WHIPWORM, HOOKWORM, ASCARIS, OXYURIS, AND DWARF TAPEWORM INFECTIONS [R3] *ANTHELMINTIC IN HUMAN AND VETERINARY MEDICINE; ANTISEPTIC IN MOUTHWASHES AND GARGLES, COUGH AND COLD PREPARATIONS, THROAT PREPARATIONS, CONTRACEPTIVES [R1] *URINARY ANTISEPTIC [R3] *ANTHELMINTIC, TOPICAL ANTISEPTIC [R2] WARN: *HEXYLRESORCINOL SHOULD NOT BE DISPENSED IN ORDINARY, HARD-GELATIN CAPSULES AS THESE QUICKLY BECOME BRITTLE, AND MAY BREAK IN MOUTH CAUSING CAUSTIC BURNS. [R3] *HEXYLRESORCINOL, GIVEN ORALLY, IS INEFFECTIVE BUT WHEN GIVEN BY ENEMA, TEDIOUS AND UNPLEASANT EXPERIENCE FOR PT, THERE IS IMMEDIATE SYMPTOMATIC RELIEF, ALTHOUGH CURES ARE RARELY ATTAINED. [R15] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *ISOLATION AND THIN-LAYER CHROMATOGRAPHY IDENTIFICATION OF HEXYLRESORCINOL. DETERMINATION BY ULTRAVIOLET AND VISIBLE SPECTROPHOTOMETRY. [R16] *METHOD OF TITRATION FOR DETERMINATION OF HEXYLRESORCINOL. [R17] *QUANTITATIVE DETERMINATION OF HEXYLRESORCINOL IN COMMERCIAL ANTISEPTIC SOLN BY HIGH-PRESSURE LIQ CHROMATOGRAPHY. [R18] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Hexylresorcinol in F344/N Rats and B6C3F1 Mice Technical Report Series No. 330 (1988) NIH Publication No. 88-2586 SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 618 R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1174 R4: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 260 R5: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 105 R6: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R7: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 265 R9: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-127 R10: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 548 R11: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R12: Toxicology and Carcinogenesis Studies of 4-Hexylresorcinol in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 330 (1988) NIH Publication No. 88-2586 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R13: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R14: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 991 R15: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 864 R16: BUCHHEISTER MACHMER M; ISOLATION AND THIN-LAYER CHROMATOGRAPHY IDENTIFICATION OF HEXYLRESORCINOL. DETERMINATION BY ULTRAVIOLET AND VISIBLE SPECTROPHOTOMETRY; REV FAC FARM UNIV LOS ANDES 19: 5-51 (1978) R17: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/696-37.126 R18: MUSTO JD ET AL; QUANTITATIVE DETERMINATION OF HEXYLRESORCINOL IN COMMERCIAL ANTISEPTIC SOLN BY HIGH-PRESSURE LIQ CHROMATOGRAPHY; J PHARM SCI 68(2) 240-1 (1979) RS: 11 Record 70 of 1119 in HSDB (through 2003/06) AN: 582 UD: 200303 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: STANNOUS-CHLORIDE- SY: *CI-77864-; *DICHLOROTIN-; *NCI-CO2722-; *STANNOUS-DICHLORIDE-; *Tin-chloride- (SnCl2); *TIN-DICHLORIDE-; *TIN- (II)-CHLORIDE; *Tin- (II)-chloride- (1:2); *TIN-PROTOCHLORIDE-; *Uniston-CR-HT-200- RN: 7772-99-8 RELT: 7001 [Tin Compounds] MF: *Cl2-Sn ASCH: Stannous chloride, dihydrate; 10025-69-1 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepn of anhydrous salt may be by direct reaction of chlorine and molten tin, heating tin in hydrogen chloride gas, or reducing stannic chloride soln with tin metal followed by dehydration. [R1, 124] *Stannous chloride dihydrate is prepared either by treatment of granulated tin with hydrochloric acid followed by evaporation and crystallization or by reduction of stannic chloride soln with a cathode or tin metal followed by crystallization. /stannous chloride, dihydrate/ [R1, 124] IMP: *Absorbs oxygen from air and forms insol oxychloride /dihydrate/ [R2] FORM: *Stannous chloride is available in 2 forms: anhydrous and stannous chloride dihydrate, also called tin crystals or tin salts. [R3, p. 24(97) 124] *Grades: technical; chemically pure; reagent. ... [R4, 1088] *Anhydrous, 99.5% reagent and 99% technical grades. ... [R5] MFS: *Cardinal Companies, L.P., 2010 South Belt Line Blvd., Columbia, SC 29201, (803) 799-7190 [R6] *Elf Atochem North America, Inc, Specialties Chemical Divison; Hq, 2000 Market Street, 21st Floor, Philadelphia, PA 19103-3222, (215) 419-7000; Prodn site: Carollton, KY 41008 [R6] USE: *Powerful reducing agent, particularly in manufacture of dyes; in tanning by galvanic methods; in liquor finishing of wire; in sensitizing of glass before metallizing; as soldering flux; as mordant in dyeing with cochineal; in manufacture of color pigments, pharmaceuticals, sensitized paper, lubricating oil additives; as tanning agent; in removing ink stains; in yeast revivers; reagent in analytical chemistry; as catalyst in organic reactions [R2] *Anhydrous stannous chloride is used extensively in the plating industry and in tin alloy plating. Used as an analytical reducing agent, a reducing agent in inorganic and organic chemicals manufacture and in the photoleaching of dyes, and as a sensitizing agent for nonconductive surfaces before silver coating or other metallization processes. It is also used to sensitize plastics prior to their electroless coating with metals. It is also used as a food additive. [R3, p. V24 (1997)125] PRIE: U.S. IMPORTS: *(1972) 3.89X10+7 G [R7] *(1975) 1.7X10+7 G [R7] *(1986) 96,032 LB [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White, ortho rhombic crystals [R9]; *Orthorhombic crystalline mass or flakes; fatty appearance [R2] ODOR: *Odorless [R10, 1981.1] BP: *623 deg C [R9] MP: *246 deg C [R9] MW: *189.60 [R9] DEN: *3.90 g/cu cm [R9] SOL: *Sol in methyl acetate, isobutyl alcohol; practically insol in petroleum naphtha, xylene [R2]; *SOL IN PYRIDINE, ETHYL ACETATE [R11]; *42.7 g/100 g acetone @ 23 deg C [R1, 124]; *54.4 g/100 g ethyl alcohol @ 23 deg C [R1, 124]; *10.45 g/100 g isobutyl carbinol @ 23 deg C [R1, 124]; *9.61 g/100 g isopropyl alcohol @ 23 deg C [R1, 124]; *9.43 g/100 g methyl ethyl ketone @ 23 deg C [R1, 124]; *3.76 g/100 g isoamyl acetate @ 23 deg C [R1, 124]; *0.49 g/100 g diethyl ether @ 23 deg C [R1, 124]; *0.03 g/100 g mineral spirits @ 23 deg C [R1, 124]; *90 g/100 g water @ 20 deg C [R10, 1981.1]; *Soluble in less than its own weight of water; very soluble in hydrochloric acid (dilute or concn); soluble in alcohol, ethyl acetate, glacial acetic acid, sodium hydroxide solution. [R12] VAP: *3.3 kPa @ 427.9 deg C [R13] OCPP: *Heat of fusion: 14.52 kJ/mol [R9] *Density: 2.71; mp: 37-38 deg C when rapidly heated; decomp on strong heating; sol in less than its own wt of water; very sol in dil or concn hydrochloric acid; sol in alc, ethyl acetate, glacial acetic acid, sodium hydroxide; absorbs oxygen from air and forms insol oxychloride /dihydrate/ [R2] *A white crystalline solid, sol in methanol /Dihydrate/ [R1, 125] *White monoclinic crystals; decomposes @ 37 deg C, density 2.71 g/cu cm, souluble in water, ethanol, NaOH, very soluble in HCl. /Dihydrate/ [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Ignition on contact with bromine trifluoride. [R12] TOXC: *Toxic gases and vapors may be released in a fire involving the tin chlorides and stannous sulfate. [R10, 1981.2] EXPL: *Potentially explosive reaction with metal nitrates. [R12] *Violent reactions with hydrogen peroxide; ethylene oxide; hydrazine hydrate; nitrates; /potassium/; /sodium/. [R12] REAC: *Hydrazine hydrate reacts with stannous chloride to give ... stannous dihydrazinechloride. When this compound is heated, it decomposes explosively. [R14, p. 491-186] *Bromine trifluoride and stannous chloride react with flame. [R14, p. 491-36] *A mixture of /stannous chloride and nitrates/ ... may cause an explosion. [R14, p. 491-124] *A mixture of sodium and /stannous chloride/ ... produces a strong explosion on impact. ... [R14, p. 491-173] *... Anhydrous chlorides of iron, tin, and aluminum ... are some of the the catalysts that may cause liquid ethylene oxide to rearrange and/or polymerize liberating heat. [R14, p. 491-82] *A mixture of stannous chloride and calcium carbide can be ignited with a match, and the reaction proceeds with incandescence. [R14, p. 491-186] *Violent reactions with hydrogen peroxide; ethylene oxide; hydrazine hydrate; nitrates; /potassium/; /sodium/. [R12] *A mixture can be ignited with a match, and reduction to metallic tin proceeds with incandescence. [R15, 205] *Addition of peroxide solutions of above 3% wt strength causes a violent reaction. [R15, 1214] DCMP: *When heated to decomp it emits toxic fumes of Cl- /chloride/. [R12] *Decomposed by hot water. [R4, 1087] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with stannous chloride or liquids containing stannous chloride. [R10, 1981.3] *Employees should be provided with and required to use dust and splash proof goggles where stannous chloride or liquids containing stannous chloride may contact the eyes. [R10, 1981.3] OPRM: *If employees' clothing may have become contaminated with solid stannous chloride ... employees should change into uncontaminated clothing before leaving the work premises. ... Non-impervious clothing which becomes wet with stannous chloride should be removed promptly and not reworn until the stannous chloride is removed from the clothing. [R10, 1981.3] *Clothing contaminated with stannous chloride /or/ stannic chloride ... should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of contaiminant from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the contaminant, the person performing the operation should be informed of contaminant's hazardous properties. [R10, 1981.3] *Skin that becomes contaminated with stannous chloride should be promptly washed to remove any stannous chloride. Employees who handle stannous chloride, stannic chloride ... should wash their hands thoroughly before eating, smoking, or using toilet facilities. [R10, 1981.4] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. STRG: *KEEP TIGHTLY CLOSED, IN A COOL PLACE. /DIHYDRATE/ [R16] *CONTAINERS: BOTTLES; DRUMS. [R4, 1088] CLUP: *If ... stannous chloride ... is spilled or leaked, the following steps should be taken: 1. Ventilate area of spill or leak. 2. Collect spilled or leaked material in the most convenient and safe manner for reclamation or for disposal. ... Liquid containing inorganic tin compounds should be absorbed in vermiculite, dry sand, earth, or a similar material. [R10, 1981.5] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *In this study tin(II), as stannous chloride, is readily taken up by human white blood cells and can cause damage to DNA. Damage was detected in white blood cells after exposure to 10-50 uM tin(II) for 30 minutes at either 0 deg or 37 deg C. [R17] *Organotin compounds examined in this study exhibited a relative order of potency for induction of in vitro hemolysis in human erythrocytes as follows: tri-n-butylitin > tri-n-propyltitn > tetra-n-butyltin > triphenyltin chloride > tri-n-ethyltin bromide > dibutyltin dichloride > stannous chloride > tri-n-methyltin chloride + butyltin chloride dihydroxide. [R18] NTOX: *THERE IS 1 REPORT ... OF PARALYSIS IN DOG AFTER LARGE DOSE (500 MG/KG) OF STANNOUS CHLORIDE IN MILK. [R19] *SEVERE GROWTH RETARDATION AND OTHER SIGNS OF TOXICITY OCCURRED WITH STANNOUS CHLORIDE ... @ FEEDING LEVELS OF 0.3% /TO RATS/. [R20] *DOSE EFFECT OF INORGANIC TIN WAS EXAMINED IN MALE WISTAR RATS ORALLY ADMIN STANNOUS CHLORIDE (1, 3, 10, and 30 MG TIN/KG). EACH DOSE WAS ADMIN 6 TIMES @ 12 HR INTERVALS. DECREASES IN GASTRIC SECRETION, DUODENAL ALKALINE PHOSPHATASE AND HEPATIC PHOSPHORYLASE ACTIVITIES, SERUM CALCIUM CONCN, FEMORAL CALCIUM CONTENT WERE FOUND. AT 3 MG/KG, THE CALCIUM CONTENT IN EPIPHYSIS OF THE FEMUR WAS SIGNIFICANTLY DECREASED BUT NOT AT 1 MG/KG. RESULTS SUGGEST THAT THE CRITICAL ORGAN IN INORGANIC TIN TOXICITY IS BONE. [R21] *WHEN ADMIN ORALLY TO RATS TWICE DAILY FOR 3 DAYS, STANNOUS CHLORIDE (3 MG TIN/100 G) INCR SERUM GLUCOSE CONCN AND DECR SERUM INSULIN LEVEL AFTER A SINGLE ORAL GLUCOSE LOAD (0.2 G/100 %). [R22] *ORAL ADMIN OF STANNOUS CHLORIDE (TWICE A DAY, EACH TIME 30 MG TIN/KG) FOR 3 DAYS DECR CALCIUM CONTENT OF SERUM AND FEMURS IN RATS. 10 DAY ADMIN INCR CALCIUM CONTENT OF KIDNEYS AND PANCREAS, WHILE DECREASING THAT OF SERUM AND FEMURS. [R23] *Mice given single intravenous doses of some radiopharmaceuticals containing stannous chloride as a reducing agent, showed significant inhibition of hepatic azo-reductase and aromatic hydroxylase activity at dose levels which contained as little as 0.2 mg/kg of stannous chloride. Cytochrome p450 content was also reduced significantly. [R24] *Rabbits fed stannous chloride ... at the level of 1 g/animal/wk died in 2 months after suffering from gastritis, degeneration of liver and kidneys, and paralysis of hind limbs. [R25, 184] *Dermal effects from sol acid salts tin difluoride and stannous chloride in skin scratches in the upper epidermis in rabbits produced a destructive reaction with intraepidermal polymorphonuclear leukocyte pustules occurring on each side of the scratch when scratches were covered for 18 hr. Tin difluoride was destructive at lower concn (0.25%) than stannous chloride (1.0%). [R26, 2269] *Test results for mutagenicity of stannous chloride in L5178Y mouse lymphoma cells were negative. [R27] *Test results for cytogenetic effects of stannous chloride in Chinese hamster ovary cells were positive for chromosome aberrations and sister chromatid exchanges. [R28] *Groups of six weanling male Wistar rats were gavaged with 0, 0.03, 1.0 or 3.0 mg tin/kg every 12 hr for 90 days. Tin was administered as stannous chloride in a hydrochloric acid solution. The variables evaluated included enzyme activities in the serum, liver, femur, and kidneys, and calcium content of the femur. Rats gavaged with 3.0 mg/kg had significant decreases in relative weight of the femur, calcium content of the femoral diaphysis and epiphysis, calcium concentration, lactic dehydrogenase and alkaline phosphatase activities in the serum, and succinate dehydrogenase activity in the liver. Significantly reduced succinic hydrogenase activity in the liver and significant reductions in calcium content and acid phosphatase activity in the femur were observed among rats gavaged with 1.0 mg/kg. A ... decrease in the calcium content of the femoral epiphysis was seen in rats treated with 0.3 mg/kg. [R29] *... Moderate testicular degeneration in male Wistar rats fed 1% stannous chloride in the diet for 8 weeks. [R30] *The effects of stannous chloride on brain and muscular cholinesterase was investigated in male Wistar rats. Groups of 30 male rats, averaging 0.365 kg in body weight, were given 0, 0.44 (100 mg/l), 1.11 (250 mg/l) or 2.22 mM (500 mg/l) stannous chloride in drinking water for 1-18 weeks. Groups of five rats were killed and examined after 1, 4, 8, 12, 15, and 18 weeks of treatment. A significant increase in brain acetycholinesterase activity was observed in the high dose group after only 1 week of treatment. Dose related and significant increases in both brain and muscle acetycholinesterase activity were observed among rats exposed to both 1.11 and 2.22 mM stannous chloride after 18 weeks of treatment. Tin concentration in brain tissue rose steadily over the experimental period. [R31] *Ninety rats of the Wister strain were divided into 18 groups (5 animals in each). Stannous chloride was administered to animals by different routes (subcutaneously, intraperitoneally, intragastrically). ... Control animals received 0.9% NaCl. Aminolevulinic acid dehydratase (ALAD) activity was clearly deceased due to the double tin dose (total dose 4 mg Sn/kg), whereas 7 doses (altogether 14 mg Sn/kg) resulted in almost complete enzyme inhibition. ALLAD inhibition in rat blood was similar, whatever the stannous chloride administration route. [R32] *Male Wistar rats were given either 100 mg stannous chloride dihydrate per l (0.44 mM), 250 mg/l (1.11 mM) or 500 mg/l (2.22 mM) in their drinking water for 1-18 weeks. Tin detected by a novel atomic absorption spectrophotometric method accumulated in the cerebrum at the highest dose level (2.22 mM) throughout the experiment. In brain, tin concentrations above the 1.11-mM dose were only found after 15 and 18 weeks/. Tin did not increase in the brain at the 0.44 mM dose level. Blood tin increased promptly after one week at the highest dose (2.22 mM) without further accumulation. Blood tin at the 0.44 mM dose level did not differ from controls. Tin exposure caused a dose dependent increase in the cerebral and muscle acetylcholinesterase activity at the two higher doses. [R33] *The effects of feeding inorganic tin on the gastrointestinal tract were examined in rats. Three groups of male weanling Wistar rats were fed a diet to which 0, 250, or 500 ppm Sn2+ had been added as stannous chloride. A fourth group was subjected to feed restriction by pair feeding with the 500 ppm group. comparison of the data from the tin fed groups with both the control and the reduced diet groups allowed discrimination between effects of reduced feed intake and Sn2+ effects. Independent of the reduced feed intake, Sn2+ affected hemoglobin concentration in the blood and several small intestine parameters. Total length of the small intestine, as well as absolute and relative weights was increased. An increase was also observed in the migration of epithelial cells along the villus, as revealed by (3)H-thymidine incorporation and autoradiography in rats fed 900 ppm Sn2+ for 4 weeks. Stereo-light microscopy and scanning electron microscopy revealed the formation of ridge-like villi due to Sn2+ feeding and a decreased number of villi per unit surface. [R34] *Tin cmpd, both organic and inorganic, were administered to adult male rats by 3 different methods of exposure: ip injection, drinking water, or stomach gavage. The forms of tin used included stannous chloride and trimethyltin chloride with at least 2 different levels of exposure in each group. Responses monitored included wt changes, auditory startling habituation, and maze activity. In addition, Sn concn in organs of sacrificed rats were determined by plasma emission spectroscopy or, in the case of (113)SnCl2 injection, gamma counts. Rats exposed to SnCl2 via ip injections at 6.67 mg Sn/kg showed deficits in the auditory startling habituation tests. Trimethyltin chloride, administered by stomach gavage, was lethal at doses > 8 mg Sn/kg within 4 days after a single exposure. No adverse effects for trimethyltin exposures of < 4 mg Sn/kg were noted, indicating a very steep dose response curve for this cmpd. [R35] *... Inorganic tin, as stannous chloride, /reported/ to be a potent inducer of heme oxygenase in the kidney. ... At sc doses of 2.5 to 25 umol/100 g body wt (0.56 to 5.64 mg stannous chloride dihydrate/100 g), the rate of heme oxidation activity of this organ was ... between 20 and 30 times that of control animals' kidneys, and in some experiments, oxidation activity exceeded 40 times that of control level. ... Microsomal content of cytochrome p450 in the kidney was decreased by an average of 50%. /Dihydrate/ [R26, 2266] *... Under the conditions of this bioassay, stannous chloride was judged not to be carcinogenic for male or female F344/N rats or B6C3F1/N mice, although C-cell tumors of the thyroid gland in male rats may have been associated with the admin of the test chemical. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R36] *... Paralysis was induced in a dog after 14 months of daily admin of stannous chloride (SnCl2) in milk at a dosage of 500 mg/kg. [R37] *In lifeterm feed studies, when mice and rats were provided with stannous chloride (SnCl2) in their water/diets, the incidence of cancers was unaffected. [R38] NTXV: *LD50 Mouse oral 1200 mg/kg; [R25, 183] *LD50 Mouse intraperitoneal 41 mg/kg; [R25, 183] *LD100 Mouse intraperitoneal 66 mg/kg; [R25, 183] *LD50 Rat oral 700 mg/kg; [R25, 183] *LD50 Rat intraperitoneal 52 mg/kg; [R25, 183] *LD100 Dog subcutaneous 159 mg/kg; [R25, 183] *LD50 Dog intravenous 22 mg/kg; [R25, 183] *LD50 Mouse iv 17,800 ug/kg; [R12] *LD50 Rabbit oral 10 g/kg; [R12] NTP: *... The chronic phase of a carcinogenesis bioassay for stannous chloride was conducted by feeding diets containing 1,000 or 2,000 ppm stannous chloride to groups of 50 F344/N rats and 50 B6C3F1/N mice of each sex for 105 wk. Similar groups of untreated rats and mice served as controls. Under the conditions of this bioassay, stannous chloride was judged not to be carcinogenic for male or female F344/N rats or B6C3F1/N mice, although C-cell tumors of the thyroid gland in male rats may have been associated with the admin of the test chemical. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R36] POPL: *Skin disease: Certain inorganic tin cmpd other than oxides are primary skin irritants. Persons with existing skin disorders may be more susceptible to the effects of these agents. [R10, 1981.1] ADE: *The concn of tin in the diaphysis was higher than in the epiphysis both in controls and rats given oral doses of stannous chloride for 28 days. [R39] *The effect of dietary tin on zinc, copper, and iron utilization by rats was studied. Male weanling Sprague-Dawley rats were fed a diet containing 206 ug tin (as stannous chloride)/g feed for 21 days. The rats fed the test diet lost more zinc in feces and retained much lower levels of zinc in tibias and kidneys than rats fed the control diet 1 ug tin/g. Rats fed the tin supplemented diet retained higher levels of tin in kidneys and tibias and lower levels of copper in kidneys than controls. [R40] *Volunteers in a balance experiment given diets containing 0.11 or 49.67 mg tin (as stannous chloride) daily for 20 days appeared to absorb 50 and 3% of the tin, respectively, as estimated from dietary and fecal tin recovery. [R41] *... Rats and rabbits absorbed < 2% of orally administered tin from stannous chloride. [R41] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: *8 hr Time Weighted Avg (TWA): 2 mg/cu m. /Tin oxide and inorganic cmpd, except tin hydride/ [R42, 2002.57] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Tin oxide and inorganic cmpd, except tin hydride/ [R42, 2002.6] WSTD: STATE DRINKING WATER GUIDELINES: +(MN) MINNESOTA 4000 ug/l /Tin/ [R43] +(FL) FLORIDA 4,200 ug/l /Tin/ [R43] FDA: *Stannous chloride is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) any substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient. [R44] *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R45] *Stannous chloride used as a chemical preservative in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R46] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Stannous Chloride in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 231 (1982) NIH Publication No. 82-1787 DHHS/ATSDR; Toxicological Profile for Tin TP-91/27 (1992) SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V24 (1997) R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1501 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R5: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 214 R6: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 940 R7: SRI R8: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-519 R9: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 4-93 R10: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R11: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 1944 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3176 R13: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. 929 R14: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R15: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R16: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1257 R17: McLean JR et al; Chem Biol Interact 46 (2): 189-200 (1983) R18: Gray BH et al; Cell Biol Toxicol 3 (1): 23-38 (1987) R19: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. 325 R20: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-146 R21: YAMAGUCHI M ET AL; TOXICOL LETT (AMST) 5 (3-4): 275-8 (1980) R22: YAMAGUCHI M ET AL; TOXICOL LETT 2 (2): 111-3 (1978) R23: YAMAGUCHI M; NIPPON EISEIGAKU ZASSHI 34 (6): 719-22 (1980) R24: Burba JV; Toxicol Lett 18 (3): 269-72 (1983) R25: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. R26: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R27: NTP; Fiscal Year 1987 Annual Plan p.82 (1987) NTP-87-001 R28: NTP; Fiscal Year 1987 Annual Plan p.88 (1987) NTP-87-001 R29: USEPA; Health Effects Assessment for Tin and Compounds p.9 (1987) EPA/600/8-88/055 R30: USEPA; Health Effects Assessment for Tin and Compounds p.12 (1987) EPA/600/8-88/055 R31: USEPA; Health Effects Assessment for Tin and Compounds p.10 (1987) EPA/600/8-88/055 R32: Zareba G, Chmielnicka J; Ecotox Environ Safety 9 (1): 40-6 (1985) R33: Savolainen H, Valkonen S; Toxicol Lett 30 (1): 35-9 (1986) R34: Janssen PJ et al; Toxicol Appl Pharmacol 78 (1): 19-28 (1985) R35: Hassett JM et al; Trace Subst Environ Health 18: 487-96 (1984) R36: Carcinogenesis Bioassay of Stannous Chloride in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 231 (1982) NIH Publication No. 82-1787 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R37: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1550 R38: Chang, L.W. (ed.). Toxicology of Metals. Boca Raton, FL: Lewis Publishers, 1996 269 R39: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986.,p. V2 575 R40: Greger JL, Johnson MA; Food Cosmet Toxicol 19 (2): 163-6 (1981) R41: USEPA; Health Effects Assessment for Tin and Compounds p.4 (1987) EPA/600/8-88/055 R42: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R43: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R44: 21 CFR 172.108 (4/1/2000) R45: 21 CFR 184.1845 (4/1/2000) R46: 21 CFR 582.3845 (4/1/2000) RS: 28 Record 71 of 1119 in HSDB (through 2003/06) AN: 586 UD: 200201 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GERANYL-ACETATE- SY: *ACETIC-ACID,-GERANIOL-ESTER-; *BAY-PINE- (OYSTER)-OIL; *2,6-DIMETHYL-2,6-OCTADIENE-8-YL-ACETATE-; *TRANS-3,7-DIMETHYL-2,6-OCTADIEN-1-OL,-ACETATE-; *3,7-DIMETHYL-2-TRANS-6-OCTADIENYL-ACETATE-; *TRANS-3,7-DIMETHYL-2,6-OCTADIEN-1-YL-ACETATE-; *TRANS-2,6-DIMETHYL-2,6-OCTADIEN-8-YL-ETHANOATE-; *FEMA-NUMBER-2509.-; *GERANIOL-ACETATE-; *NCI-C54728-; *2,6-OCTADIEN-1-OL, 3,7-DIMETHYL-, ACETATE, (E)-; *2,6-OCTADIEN-1-OL,-3,7-DIMETHYL-,-ACETATE,-TRANS- RN: 105-87-3 MF: *C12-H20-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *a) Constituent of several essential oils; b) By heating geraniol and sodium acetate with acetic anhydride [R1] *N,N-Diethylgeranylamine, when heated with acetic anhydride at reflux temperature in the presence of anhydrous sodium acetate gives geranyl acetate in 59% yield [R2] FORM: *GRADES: TECHNICAL; FCC. [R1] MFS: *Aldrich Chemical Company, Inc., Hq, 940 West St. Paul Avenue, Milwaukee, WI 53233, (414) 273-3850; Production site: Milwaukee, WI 53233. [R3] *Elan Chemical Company, Hq, 268 Doremus Avenue, Newark, NJ 07105, (201) 344-8014; Production site: Newark, NJ 07105. [R3] *Givaudan-Roure Corporation, Hq, 100 Delawanna Avenue, Clifton, NJ 07014; Specialty Division; Production site: Clifton, NJ 07014. [R3] *International Flavors and Fragrances, Inc., Hq, 521 West 57th Street, New York, NY 10019, (212) 765-5500; Production site: Keyport, NJ 07735. [R3] *SCM GLIDCO Organics, Hg, P.O. Box 389, Jacksonville, FL 32201, (904) 768-5800; Production site: Foot of West 61st Street, Jacksonville, FL 32208. [R3] *Union Camp Corporation, Hq, 1600 Valley Road, Wayne, NJ 07470, (201) 628-2000; Bush Boake Allen, Hq, 2051 North Lane Avenue, Jacksonville, Fl 32254, (904) 783-2180; Production site: Jacksonville, FL 32254. [R3] OMIN: *GERANIOL ACETATE WAS HIGHLY ACTIVE AGAINST GROWTH OF KERATINOPHILIC FUNGI. [R4] *REPORTED USES: NON-ALCOHOLIC BEVERAGES 1.6 PPM, ICE CREAM, ICES, E TC 6.5 PPM, CANDY 15 PPM, BAKED GOODS 17 PPM, GELATINS AND PUDDINGS 6.8-7.5 PPM, CHEWING GUM 0.30-1.2 PPM, SYRUPS 1.0 PPM /FROM TABLE/ [R5] USE: *USED AS SYNTHETIC FLAVORING SUBSTANCE AND ADJUVANT [R6] *Used frequently in perfumery to create not only flowery-fruity nuances (example, rose), but also for citrus and lavender notes. A small amount is added to fruit aromas for shading. [R7] *Widely used in perfume compositions as a sweetener and modifier in floral, fruit, herbaceous and Citrusy fragrance types. Used in flavor composition for a great variation of types: Apricot, Apple, Banana, Blackcurrant, Gooseberry, Ginger Ale, Grape, Honey, Lemon, Peach, Pear, Lime, Wine, and in various Spice complexes, Berry variations, and Floral flavor types. [R8] CPAT: *USE IN FRAGRANCES, APPROX 4.54X10+7 GR/YR (1974) [R9] PRIE: U.S. PRODUCTION: *(1985) 5.90X10+7 g [R10] *132,000 kg (1993) [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R5] ODOR: *ODOR OF LAVENDER [R12]; *Sweet, fruity-floral, rosy, somewhat green and remotely Lavender-like odor of moderate tenacity. [R8] TAST: *SWEET LIQ [R12]; *Sweet, fruity, overall nondescript taste with notes resembling those of banana, pear, apple and peach, but not a purely sweet aftertaste. [R8] BP: *Approx. 242 deg C with decomposition. [R13] MW: *196.29 [R7] DEN: *0.9174 @ 15 DEG C/15 DEG C [R13] SOL: *1.8 IN 70% ALCOHOL; SOL IN MOST ORG SOLVENTS [R5]; *INSOL IN WATER AND GLYCEROL [R14]; *MISCIBLE WITH ETHER [R13] SPEC: *INDEX OF REFRACTION: 1.4580-1.4640 @ 20 DEG C; 1.4570-1.4620; SPECIFIC OPTICAL ROTATION: -2.0 DEG TO +3.0 (+ OR -1 DEG) [R5]; *IR: 6944 (Coblentz Society Spectral Collection) [R15]; *NMR: 4240 (Sadtler Research Laboratories Spectral Collection) [R15]; *MASS: 1378 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R15] VAP: *3.3X10-2 mm Hg @ 25 deg C (extrapolated) [R16] OCPP: *ASSAY: 90% MIN; 92% (85% TECHNICAL) [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R17] +Flammability: 1. 1= Includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R17] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R17] FLPT: +> 212 deg F (> 100 deg C) closed cup [R17] FIRP: +"ALCOHOL" FOAM. [R17] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R12] SERI: *IN HUMAN PATCH TEST, GERANIOL @ 32% CONCN WAS SEVERELY IRRITATING AND GERANYL ACETATE MILDLY IRRITATING. [R18] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *IN HUMAN PATCH TEST, GERANIOL @ 32% CONCN WAS SEVERELY IRRITATING AND GERANYL ACETATE MILDLY IRRITATING. [R18] *NONE OF THESE PERFUME ACETATES SEEMS TO HAVE GIVEN RISE TO ANY HEALTH PROBLEMS IN MANUFACTURING, HANDLING, OR IN THEIR END USES. SKIN SENSITIZATION TO THEM APPEARS TO BE RARE. [R19] NTOX: *Geranyl acetate was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Geranyl acetate was tested at doses of 0.001, 0.003, 0.010, 0.033, 0.10, 0.33, 1.0, and 3.3 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Geranyl acetate was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 3.3 mg/plate. [R20] *... Under the conditions of these studies, geranyl acetate was not carcinogenic for F344/N rats or B6C3F1 mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male mice: Negative; Female mice: Negative. [R21] NTXV: *LD50 Rat oral 6.33 g/kg; [R22] NTP: *Carcinogenesis studies of food-grade geranyl acetate (containing approximately 29% citronellyl acetate) were conducted by admin the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 1,000 or 2,000 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 500 or 1,000 mg/kg. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Under the conditions of these studies, geranyl acetate was not carcinogenic for F344/N rats or B6C3F1 mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male mice: Negative; Female mice: Negative. [R21] METB: *ASSUMING THAT THESE TERPENE ESTERS ARE HYDROLYZED TO THE ALCOHOLS, THEY PROBABLY ARE THEN OXIDIZED IN PART TO AN ACID KNOWN AS HILDEBRANDT ACID... IN CASE OF GERANIOL, SOME REDUCED HILDEBRANDT ACID (@ 2-3 DOUBLE BOND) IS ALSO FORMED. [R19] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3(?). 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB). /GERANIOL/ [R23] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Geranyl acetate occurs in varying amounts in many essential oils. Geranyl acetate's production and use in perfume and flavor compositions may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 3.3X10-2 mm Hg at 25 deg C indicates that geranyl acetate will exist solely as a vapor in the ambient atmosphere. Vapor-phase geranyl acetate is degraded in the atmosphere by reaction with ozone and photochemically-produced hydroxyl radicals with estimated half-lives of 19 minutes and 2.2 hours, respectively. If released to soil, geranyl acetate is expected to be immobile based on an estimated Koc of 6500. Geranyl acetate is not expected to volatilize from dry soil surfaces given its extrapolated vapor pressure. Volatilization from moist soil surfaces may be an important fate process given this compound's estimated Henry's Law constant of 2.4X10-3 atm-cu m/mole. However, adsorption to organic matter is expected to attenuate this process. If released into water, geranyl acetate is expected to adsorb to suspended solids and sediment in the water column based upon its estimated Koc. Volatilization from water surfaces may be an important fate process given this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 7.5 hours and 6.6 days, respectively. However, volatilization is expected to be attenuated by adsorption. An estimated BCF of 1500 suggests the potential for bioconcentration in aquatic organisms is very high. Estimated hydrolysis half-lives of 230 and 23 days at pHs 7 and 8, respectively, indicate that hydrolysis is expected to be a slow process. In general, acetates are expected to be readily biodegradable. Occupational exposure to geranyl acetate may occur through inhalation and dermal contact with this compound at workplaces where geranyl acetate is produced or used. The general population may exposed to geranyl acetate via ingestion of foods, and inhalation or dermal contact with consumer products containing this compound. (SRC) NATS: *Geranyl acetate occurs in varying amounts in many essential oils; up to 60% in oils from Callitris and Eucalyptus species, and up to 14% in palmarosa oil(1). A smaller amount occurs in, for example, geranium, citronella, petitgrain, and lavender oils(1). [R24] ARTS: *Geranyl acetate's production and use in perfume and flavor compositions(1) may result in its release to the environment through various waste streams(SRC). [R25] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6500(SRC), determined from an estimated log Kow of 4.5(2,SRC) and a regression-derived equation(3), indicates that geranyl acetate is expected to be immobile in soil(SRC). Volatilization of geranyl acetate from moist soil surfaces may be important(SRC) given an estimated Henry's Law constant of 2.4X10-3 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Adsorption to organic matter is expected to attenuate volatilization(SRC). Geranyl acetate is not expected to volatilize from dry soil surfaces based on a vapor pressure of 3.3X10-2 mm Hg(5). In general, acetates are expected to be readily biodegradable(SRC). [R26] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6500(SRC), determined from an estimated log Kow of 4.5(2,SRC) and a regression-derived equation(3), indicates that geranyl acetate is expected to adsorb to suspended solids and sediment in water(SRC). Geranyl acetate is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 2.4X10-3 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Estimated volatilization half-lives for a model river and model lake are 7.5 hours and 6.6 days, respectively(3,SRC). The volatilization half-life from an environmental pond 2 m deep is estimated to be about 2.3 days ignoring adsorption(5); when considering maximum adsorption the volatilization half-life increases to 51 days(5). According to a classification scheme(6), an estimated BCF of 1500(3,SRC), from an estimated log Kow(2,SRC), suggests that bioconcentration in aquatic organisms is potentially very high(SRC). Estimated hydrolysis half-lives of 230 and 23 days at pHs 7 and 8, respectively(7), indicate that hydrolysis is expected to be a slow process(SRC). In general, acetates are expected to be readily biodegradable(SRC). [R27] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), geranyl acetate, which has a vapor pressure of 3.3X10-2 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase geranyl acetate is degraded in the atmosphere by reaction with ozone and photochemically-produced hydroxyl radicals(SRC); the half-lives for these reactions in air are estimated to be about 19 minutes and 2.2 hours, respectively(3,SRC). [R28] ABIO: *The rate constant for the vapor-phase reaction of geranyl acetate with photochemically-produced hydroxyl radicals has been estimated as 1.8X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2.2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The rate constant for the vapor-phase reaction of geranyl acetate with ozone has been estimated as 8.6X10-16 cu cm/molecule-sec at 25 deg C(1,SRC). This corresponds to an atmospheric half-life of about 19 minutes at an atmospheric ozone concn of 7X10+11 cu cm/molecule-sec at 25 deg C(1,SRC). A base-catalyzed second-order hydrolysis rate constant of 0.35 L/mol-sec (SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 230 and 23 days at pH values of 7 and 8, respectively(2,SRC). [R29] BIOC: *An estimated BCF of 1500 was calculated for geranyl acetate(SRC), using an estimated log Kow of 4.5(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests that bioconcentration in aquatic organisms is potentially very high(SRC). [R30] KOC: *The Koc of geranyl acetate is estimated as approximately 6500(SRC), using an estimated log Kow of 4.5(1,SRC) and a regression-derived equation(2,SRC). According to a classification scheme(3), this estimated Koc value suggests that geranyl acetate is immobile in soil(SRC). [R31] VWS: *The Henry's Law constant for geranyl acetate is estimated as 2.4X10-3 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that geranyl acetate may volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is approximately 7.5 hours(2,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is approximately 6.6 days(2,SRC). The volatilization half-life from an environmental pond 2 m deep is estimated to be about 2.3 days ignoring adsorption(3); when considering maximum adsorption the volatilization half-life increases to 51 days(3). Geranyl acetate's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces may occur(SRC). Geranyl acetate is not expected to volatilize from dry soil surfaces(SRC) based on a vapor pressure of 3.3X10-2 mm Hg(4). [R32] FOOD: *Geranyl acetate was identified, but not quantified as a potent odor compound in extracts of Japanese fresh ginger rhizomes(1). Geranyl acetate was identified as a volatile component in Korean salt-fermented shrimp paste at a mean concentration of 281 ng/g(2). [R33] PFAC: PLANT CONCENTRATIONS: *Geranyl acetate was identified as a volatile compound found in fresh, tree-ripened apricots and a plumcots at concentrations of 4 and 3 ug/kg of fresh fruit tissue, respectively(1). [R34] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 10,503 workers (7,199 of these are female) are potentially exposed to geranyl acetate in the US(1). Occupational exposure to geranyl acetate may occur through inhalation and dermal contact with this compound at workplaces where geranyl acetate is produced or used(SRC). The general population may be exposed to geranyl acetate via ingestion of foods, and inhalation or dermal contact with consumer products containing this compound(SRC). [R35] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Synthetic flavoring substances and adjuvants /for human comsumption/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Geranyl acetate is included on this list. [R36] *Synthetic flavoring substances and adjuvants /for animal drugs, feeds, and related products/ that are generally recognized as safe for their intended use, within the meaning of section 409 of the Act. Geranyl acetate is included on this list. [R37] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GLC STUDIES OF ESSENTIAL OILS. [R38] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Food Grade Geranyl Acetate (71% Geranyl Acetate, 29% Citronellyl Acetate in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 252 (1987) NIH Publication No. 88-2508 SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 558 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V22 723 (1983) R3: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 618 R4: JAIN PC, AGRAWAL SC; NIPPON KINGAKKAI KAIHO 19(2) 197 (1978) R5: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 216 R6: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 703 R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 163 R8: Arctander S; Perfume and Flavor Chemicals (Aroma Chemicals) I (1969) R9: SRI R10: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.121 R11: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-69 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1348 R13: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 747 R14: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 1418 R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 930 R16: Ohe S; Computer Aided Data Book of Vapor Pressure. Data Book Publ Co: Tokyo, Japan (1976) R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-56 R18: MOTOYOSKI ET AL; COSMET TOILETRIES 94(8) 41 (1979) R19: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1864 R20: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R21: Carcinogenesis Studies of Food Grade Geranyl Acetate (71% Geranyl acetate, 29% Citronellyl Acetate) in F344/N Rats and B6C3F1 Mice (Gavage Study). Technical Report Series No. 252 (1987) NIH Publication No. 88-2508 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R22: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 2980 R23: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-168 R24: (1) Bauer K et al; Ullmann's Encycl Indust Chem. NY,NY: VCH Publ A11: 163 (1988) R25: (1) Arctander S; Perfume and Flavor Chemicals (Aroma Chemicals) I 1430 (1969) R26: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals, NY,NY: Lewis Publ, CRC Press p. 171(1997) R27: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) USEPA; EXAMS II Computer Simulation (1987) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) R28: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals, NY,NY: Lewis Publ, CRC Press p. 171 (1997) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R29: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park,CA: SRI International (1987) R30: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R31: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R32: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) (4) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals, NY,NY: Lewis Publ, CRC Press p. 171(1997) R33: (1) Nishimura O; J Agric Food Chem 43: 2941-45 (1995) (2) Cha YJ, Cadwallader KR; J Food Sci 60: 19-24 (1995) R34: (1) Gomez E et al; J Agric Food Chem 41: 1669-76 (1993) R35: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R36: 21 CFR 182.60 (4/1/97) R37: 21 CFR 582.60 (4/1/97) R38: KARLSEN J ET AL; PHARM WEEKBL 106(MAR 19) 293 (1971) RS: 24 Record 72 of 1119 in HSDB (through 2003/06) AN: 591 UD: 200303 RD: Reviewed by SRP on 1/31/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PROPYL-GALLATE- SY: *BENZOIC-ACID,-3,4,5-TRIHYDROXY-,-PROPYL-ESTER-; *GALLIC-ACID,-PROPYL-ESTER-; *NCI-C505888-; *NIPA-49-; *NIPAGALLIN-P-; *PROGALLIN-P-; *N-PROPYL-ESTER-OF-3,4,5-TRIHYDROXYBENZOIC-ACID-; *N-PROPYL-GALLATE-; *N-PROPYL-3,4,5-TRIHYDROXYBENZOATE-; *PROPYL-3,4,5-TRIHYDROXYBENZOATE-; *TENOX-PG-; *3,4,5-TRIHYDROXYBENZENE-1-PROPYLCARBOXYLATE- RN: 121-79-9 MF: *C10-H12-O5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF N-PROPYL ALCOHOL WITH 3,4,5-TRIHYDROXYBENZOIC ACID [R1] MFS: *Eastman Chemical Company, Hq, PO Box 511, Kingsport, TN 37662. (615) 229-2000. Tennessee Eastman Division, PO Box 511, Kingsport, TN 37662. (615) 229-2000. Production Site: Kingsport, TN 37662 [R2] OMIN: *USED IN FOODS RESTRICTED TO 0.02% OF FAT CONTENT. [R3] *...CLEARED FOR USE IN FOOD PACKAGING...BASED ON THE STIPULATION THAT NO MORE THAN 50 PPM OF THE ANTIOXIDANT SHALL BECOME A PART OF THE PACKAGED FOOD. [R4, 216] *THE ANTIOXIDANT FORMULATIONS MOST COMMONLY USED IN EDIBLE PRODUCTS CONTAIN VARIOUS COMBINATIONS OF BHA, BHT, AND/OR PROPYL GALLATE TOGETHER WITH CITRIC ACID IN SUITABLE SOLVENT. [R4, 202] USE: *ANTIOXIDANT OR SYNERGIST TO RETARD OR PREVENT RANCIDITY IN LARD AND OTHER EDIBLE FATS AND OILS; LABORATORY REAGENT [R3] *AS AN ANTIOXIDANT IN FOOD PRODUCTS [R1] *A PRESERVATIVE [R5] *Used as a stabilizer for synthetic vitamin A [R6] CPAT: *APPROXIMATELY 80% AS AN ANTIOXIDANT IN FATS AND OILS; THE REMAINDER AS AN ANTIOXIDANT IN SHORTENING, SALT, BREAKFAST CEREAL, LARD, CHEWING GUM BASE, CANDY, CHICKEN SOUP BASE, FLAVORED BEVERAGES, FROZEN MILK DESSERTS, AND BAKERY PRODUCTS(EST)(1972) [R1] PRIE: U.S. PRODUCTION: *(1972) 5.0X10+7 GRAMS (EST) [R1] *(1975) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE TO CREAMY-WHITE CRYSTALLINE POWDER [R5]; *COLORLESS CRYSTALS [R3]; *NEEDLES IN WATER [R7]; *FINE, IVORY POWDER [R8] ODOR: *ODORLESS [R5] TAST: *SLIGHTLY BITTER TASTE [R5] MP: *130 DEG C [R9] MW: *212.21 [R9] OWPC: +Log Kow = 1.80 [R10] SOL: *At 25 deg C in water 0.35 g/100 ml, in alcohol 103 g/100 g, in ether 83 g/100 g, cottonseed oil at 30 deg C 1.23 g/100 g, in lard at 45 deg C 1.14 g/100 g. [R11] SPEC: *MAX ABSORPTION (ALCOHOL): 275 NM; 9163 (IR, PRISM) [R7]; *IR: 3:1032D (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R12, p. V1 659]; *NMR: 7:32D (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R12, p. V1 659]; *IR: 2023 (Coblentz Society Spectral Collection) [R12, p. V1 234]; *NMR: 18732 (Sadtler Research Laboratories Spectral Collection) [R12, p. V1 234]; *IR: 2:903G (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R12, p. V2 180] OCPP: *Darkens in presence of iron and iron salts. [R11] *Synergic with acids, BHA, BHT. [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- OFHZ: *Slight, when exposed to heat or flame; can react with oxidizing materials. [R8] DCMP: *When heated to decomp it emits tox fumes and smoke. [R8] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *PROPYL GALLATE PRODUCED CONTACT DERMATITIS IN 5 OF 10 PATIENTS. PATIENTS APPLIED 20% IN 70% ETHYL ALC TO FOREARM DAILY FOR 24 DAYS. 5 PATIENTS COMPLAINED OF PRURITUS AND ERYTHEMA. (16 REF.) [R13] *LOW TOXICITY. [R14] *Propyl gallate was investigated in vitro at concn of 0.5, 5.0 and 50 ug/ml employing WI-38 human embryonic lung cells for anaphase abnormalities. ... Propyl gallate was /not/ mutagenic ... . [R15, p. 11 (1993)] *Gallates have been shown to cause contact dermatitis in bakers and other workers handling gallates. Patch tests with lauryl gallate at 0.2% showed a weak positive response in one sensitized individual. Other individuals have suffered recurring episodes of dermatitis, presumably caused by gallates in food products ... . /Gallates/ [R15, p. 14 (1993)] NTOX: *ORAL TOXICITY IN RATS IS LOW (ACUTE LD50= 3.8 G/KG) SYMPTOMS PRODUCED @ THESE LEVELS ARE GASPING RESPIRATION AND TERMINAL CONVULSIONS. [R16] *LEVELS OF 1.1%-2.3% IN DIET WERE NOT TOLERATED BY RATS, DEFINITE STUNTING OF GROWTH RESULTING. ...TUBULAR DAMAGE IN KIDNEYS WAS NOTED...THIS MAY HAVE BEEN RESULT OF SEVERE INANITION. NO EFFECT ON GROWTH OF RATS...AFTER 1 YR ON LEVELS OF 0.001%. ... NO BLOOD OR HISTOLOGICAL CHANGES...FOUND... [R16] *GUINEA PIGS FED 0.01% IN DIET FOR 14 MO ALSO SHOWED NO TOXIC EFFFECTS. DOGS TOLERATED 0.01% IN DIET FOR OVER A YR WITH NO SIGNS OF TOXICITY. [R16] *PROPYL GALLATE HAS A CONTACT SENSITIZATION POTENTIAL COMPARABLE TO THAT OF DINITROCHLOROBENZENE IN GUINEA PIGS. (16 REF.) [R17] *Propyl gallate was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Propyl gallate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.010, 0.033, 0.100, 0.333, and 1.000 mg/plate. The highest ineffective dose tested without noticeable toxicity in any S. typhimurium strain was 0.333 mg/plate. At the high dose, slight to total clearing of the background bacterial lawn occurred under nearly all test conditions. [R18] *Propyl gallate inhibited liver mixed function oxidase (MFO) and demethylase activity when added at concn of 50 to 500 uM to liver microsomal preparations obtained from male Sprague-Dawley rats. Specifically, the cmpd inhibited benzopyrene hydroxylase activity and demethylase activity with ethyl morphine, aminopyrene or benzphetamine as substrate. No induction of mixed function oxidase activity was noted when propyl gallate was injected ip at 300 mg/kg bw 24 hr prior to sacrifice and assay. The microsomes from the treated animals had lower demethylase activity ... . [R15, p. 4 (1993)] *Weanling female Sprague-Dawley rats were fed high polyunsaturated fat, high saturate fat or low fat diets for 1 mo, with or without the addition of 0.3% propyl gallate. Propyl gallate caused no measurable difference in body weights, relative liver weight or liver microsomal protein values. Liver enzyme activity of aniline hydroxylase, aminopyrene N-demethylase and cytochrome-C-reductase were not affected by treatment, nor was the liver concn of cytochrome p450 and microsomal protein. [R15, p. 5 (1993)] *Addition of 24 or 125 umol of propyl gallate to an mixed function oxidase assay system prepared from the tissues of male Sprague-Dawley rats (liver, kidneys, stomach, colon and small intestine) inhibited the oxidation of benzo(a)pyrene ... . [R15, p. 5 (1993)] *Addition of 50 umol of propyl gallate to a rat testis microsomal preparation in the presence of arachidonate stimulated the formation of prostaglandin PGF2. Addition of 0.1 mmol vitamin E instead ... did not results in increased production of any of the prostaglandins. Addition of propyl gallate to similar preparations from vitamin E-deficient rats resulted in an increase in production of PGF2 only. In the female rat both dietary lipid and dietary propyl gallate affect prostaglandin synthesis by mammary gland preparations. ... Propyl gallate stimulates formation of prostaglandin PGF2 in mammary gland from rats fed polyunsaturated fats, but inhibits PGF2 synthesis in rats fed a saturated fat diet. Stimulation of synthesis of different prostaglandins may occur in preparations to which propyl gallate was added exogenously as compared to a dietary source of the cmpd. Changes in levels of PGF2 have been correlated with the susceptibility of rats to mammary tumors induced by 7,12-dimethyl-benzo(a)anthracene ... . [R15, p. 5 (1993)] *Weight gain depression of more than 10% was observed in male rats receiving diets containing 12,500 or 25,000 and in females receiving 25,000 mg propyl gallate/kg feed. Dirty tails, indicating GI disturbance, were noted in both sexes at 25,000 mg propyl gallate/kg feed. In the 25,000 mg/kg feed groups, reddish duodenal mucosa was reported in both sexes, in addition to thickening of the stomach wall with necrosis and ulceration of the mucosal surface of the stomach, and moderate to severe granulomatous inflammatory response in the submucosa and muscular wall of the stomach. No stomach nor duodenal lesions were noted in either sex at 6,000 or 12,500 mg/kg feed ... . [R15, p. 6 (1993)] *A 4 wk oral toxicity study with propyl gallate was performed in rats (6 animals/group/sex) at dose levels of 0, 1,000, 5,000 and 25,000 mg/kg feed. ... In the high-dose group both females and males gained less weight than those in the control group. Hemoglobin concn, packed cell volume, red blood cell concn, mean corpuscular volume and mean corpuscular hemoglobin were lowered in the high-dose group. Consistent with the anemia, an increased extramedullary hematopoiesis and slightly decreased hemosiderosis were noted in the spleen. In kidneys hyperplastic tubuli in the outer medulla were detected. In the liver of the animals of the 5,000 and 25,000 mg/kg feed groups increases in activity of aminopyrine-N-demethylase and glucuronyl-transferase and glutathione-s-transferase and an increase in cytochrome p450 content were detected ... . [R15, p. 7 (1993)] *A toxicity study with propyl gallate in SPF-derived Wistar RIVM:Tox rats (10 animals/group/sex) was performed in which they were fed a semisynthetic diet containing 0, 490, 1,910 or 7,455 mg propyl gallate/kg feed for 13 wk. ... Adverse effects of propyl gallate observed in the high-dose group were effects on the hematopoietic system reflected in the hematological parameters ... and the morphological changes ... in the spleen. The other effects of propyl gallate comprised a decreased incidence of nephrocalcinosis normally seen in female rats on semisynthetic diet, an increased activity of ethoxy-resorufin-o-deethylase (EROD) in the high-dose group and an increased activity of the conjugating enzymes glucuronyl-transferase and glutathione-s-transferase, in the mid and high-dose groups receiving propyl gallate. [R15, p. 7 (1993)] *Propyl gallate fed to guinea-pigs in groups of 20 at a level of 0.02% in the diet for 14 mo caused no observed ill effects ... . [R15, p. 7 (1993)] *A level of 0.01% propyl gallate in the diet was well tolerated by a group of seven dogs over a period of 14 mo ... . [R15, p. 8 (1993)] *Diets containing 0.2% propyl gallate were fed to pigs without observed ill effect; no anemia was observed ... . [R15, p. 8 (1993)] *Groups of 50 mice ... equally divided by sex were maintained on diets containing 0, 0.25 or 1.0% n-propyl gallate for a period of 21 mo. Water intake, food consumption and growth of test animals were comparable to controls. Treated male mice showed a greater percentage survival than control mice at termination. Hematologic measurements ... were similar for test and control animals. At autopsy, a comparison of relative organ/bw showed a reduction in the relative spleen weight of males on the 1% diet. No cmpd-related histopathological changes were observed ... . [R15, p. 8 (1993)] *Chronic toxicity studies were conducted by maintaining groups of 50 F344 rats and 50 B6C3F1 mice of each sex on nutritionally complete diets containing 0%, 0.6%, or 1.2% propyl gallate for 103 weeks. Survival of rats and mice of both sexes was not significantly affected by the administration of this compound. Dosed rats and mice showed growth retardation and reduced feed utilization efficiency. Increased incidence of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate gland were observed in dosed male rats and were considered to be related to propyl gallate administration. Tumors of the preputial gland, islet cell tumors of the pancreas, and pheochromocytoma of the adrenal gland were observed with significantly (p < 0.05) higher incidence in the low-dose male rats; however, there was little evidence of a dose response or of an effect in the high-dose group. Rare tumors (an astrocytoma and u glioma) were found in the brains of two low-dose female rats but none was found in the high-dose group. Malignant lymphoma occurred with a significant (p ~ 0.05) positive trend in male mice and the incidence in the high-dose group was significantly (p < 0.05) higher than that of the concurrent controls. However, the high-dose incidence was not significantly different from the historical control rate for the laboratory that conducted the bioassay. Under the conditions of the bioassay, propyl gallate was not considered to be clearly carcinogenic for F344 rats, although the increased incidence of preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytoma of the adrenal glands in low dose male rats may have been related to compound administration. Thus, the evidence for carcinogenicity in male rats is regarded as being equivocal, while there was no indication of a carcinogenic response in female rats. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice, although the increased incidence of malignant lymphoma in dosed male mice may have been related to administration of the test compound. [R19] *A level of 5% propyl gallate in the diet in a 2-yr chronic toxicity study in rats and mice gave rise to patchy hyperplasia in the ... . At a level of 1%, no difference was noted between test and control animals ... . [R15, p. 9 (1993)] *Groups of 10 male and 10 female rats were fed for 2 yr on diets containing 0, 0.001, 0.01, 0.12, 1.2, or 2.3% propyl gallate. The groups receiving 1.17 and 2.34% propyl gallate showed stunted growth and evidence of renal damage. In the other groups, there was no detectable effect on hemoglobin, erythrocyte or leucocyte levels in the blood, nor on the histopathological appearance of the organs examined ... . [R15, p. 10 (1993)] *... Fed groups of 50 F-344 rats of each sex diets containing 0, 6,000 or 12,000 mg propyl gallate for 105-107 wk. ... Throughout the study, there was a dose-related depression in bw at both dose levels and in both sexes. Mean feed consumption was 94% and 98% of the controls in the low and high-dose males, while the corresponding values for females were 95 and 115% respectively, In males 78% of the controls, 76% of the low-dose and 88% of the high-dose group lived to the end of the study. In females the corresponding values were 78%, 76% and 84% respectively. No treatment-related clinical signs were observed ... in male rats the incidence of three types of neoplasms was increased in the low-dose treatment compared to the control group, namely, phaechromocytoma of the adrenal medulla, islet cell neoplasms of the pancreas and neoplasm of preputial gland origin. Equal or greater increases were not observed in the high-dose male groups. The occurrence of these tumors was not considered to be treatment related. The combined incidence of male rats with follicular cell adenomas or carcinomas of the thyroid was significant (p < 0.05) by the trend test, but the high-dose incidence was not statistically different in any test in direct comparison with the control. In the high-dose females there were 3 mammary adenomas while there were none in the other two groups. ... There was an increase in the incidence of females with endometrial stomal polyps of the uterus with a marginally significant trend. ... Tumors of the brain ... were found in two low-dose female rats. ... The incidence of these tumors in the brain of the low-dose females was not considered to be related to propyl gallate, since none of the high-dose females had this tumor ... . [R15, p. 10 (1993)] *Propyl gallate was fed to rats at concn of 0.035, 0.2 or 0.5% in the diet for 2 successive generations. Neither effects on reproduction performance nor on indices of reproduction were reported. No abnormalities were observed in the organs or tissues of the rats at autopsy ... . [R15, p. 11 (1993)] */Propyl gallate/ was investigated in vivo by the cytogenetic analysis of metaphase cells from the bone marrow of rats (Sprague-Dawley C-D strain). The dosages employed were 5,0, 50.0 and 500 mg/kg bw. Propyl gallate was /not/ mutagenic ... . [R15, p. 11 (1993)] *The genotoxic effect of propyl gallate was studied using Salmonella typhimurium strains TA-1530 and G-46 and Saccharomyces D-3 in presence of absence of metabolic activation. A 0.25% concn was tested. Propyl gallate was non-mutagenic in all tests. [R15, p. 12 (1993)] *In a host-mediated assay, propyl gallate was tested at dose levels equivalent to 5, 50, 500 and 2,000 mg/kg bw in ICR Swiss mice employing, as indicated organisms, Salmonella G-46 and TA-1530 and Saccharomyces D-3. Propyl gallate was non-mutagenic under the conditions of the test. [R15, p. 12 (1993)] *In a dominant lethal test, Sprague-Dawley CD strain male rats were dosed at 5, 50 and 500 mg/kg bw. In an acute study, a single dose was admin with subsequent mating for each of 8 wk. Propyl gallate did not produce any significant dominant lethality. In a subacute study, five daily doses were admin (5 x 5, 5 x 50, 5 x 500 and 5 x 5,000 mg/kg bw). Males were subsequently mated for each of 7 wk. No dominant lethal effects were noted ... . [R15, p. 12 (1993)] *Propyl gallate incorporation into the diet (0.52 and 2%) and fed to male F-344 rats, for 9 days neither affected the morphological appearance of the forestomach squamous epithelium nor induced changes in the (methyl-3H) thymidine labelling index in the fundic region of the forestomach ... . [R20] *Propyl gallate inhibited the genotoxicity of benzo(a)pyrene for Salmonella typhimurium (Strain TA 98), and moderately increased the mutagenicity of aflatoxin B1 for Salmonella typhimurium TA 100 and TA 98 ... . [R15, p. 12 (1993)] *Four-wk old random-bred ICR Swiss male mice were fed diets containing 0, 10, 100, 1,000, or 5,000 mg propyl gallate/kg feed for 3 mo. They were exposed to 50 or 125 rad of whole gamma radiation from a 137-Cs source. Thirty hr after irradiation, animals were scored for micronuclei in polychromatic bone marrow erythrocytes. As compared to controls not give propyl gallate, the propyl gallate-treated animals had an increased incidence of micronuclei of about 1.6-2-fold. However, there was no dose dependence, 10 mg/kg of propyl gallate was as effective in producing radio-sensitization as 5,000 mg/kg feed ... . [R21] *Propyl gallate itself was not mutagenic towards Salmonella typhimurium strains TA 98 and TA 100 in the presence or absence of arochlor-induced rat liver homogenates. Treatment of bacteria (evidently without activation) with propyl gallate and N-acetoxy-AAF or N-methyl-N-nitrosoguanidine resulted in a reduction of mutation rate compared to that observed in the presence of N-acetoxy-AAF or N-methyl-N-nitrosoguanidine alone. By contrast, mixtures of propyl gallates and 4-nitroquinoline oxide or N-hydroxy-AAF showed increased mutagenicity as compared to that observed with the cmpds in the absence of the propyl gallate. The proceeding studies were all done using Salmonella strain TA 100, except that the propyl gallate - 4-nitroquinoline mixture was tested with both Salmonella strains TA 100 and TA 98. Propyl gallate was more efficient at enhancing mutagenesis for Salmonella TA 100 than TA 98. A propyl gallate-aflatoxin B1 mixture was also tested using liver activation from arochlor-treated rats; the addition of propyl gallate substantially reduced the mutagenic activity of aflatoxin B1 ... . [R15, p. 13 (1993)] *Propyl gallate was not mutagenic to Salmonella strains TA 98 or TA 100 with or without activation by liver extracts from arochlor-induced rats. ... These workers observed a small increase in aflatoxin B1 mutagenesis in TA 100 in the presence of propyl gallate ... . [R15, p. 13 (1993)] *Lung adenomas were induced in strain A mice by chronic treatment with nitrite in drinking water and morpholine in food. Addition of gallic acid to the diet resulted in an 86% inhibition of adenoma induction. Dietary gallic acid reduced or did not affect the induction of adenomas by mononitrosopiperazine or nitrosomorpholine given in drinking water, and failed to induce lung adenomas when given alone ... . /Gallic acid/ [R15, p. 13 (1993)] *Weanling (21 day old) female Sprague-Dawley rats were fed with one of three basal diets: polyunsaturated fat (20% corn oil, HPF); saturate fat (18% coconut oil and 2% linoleic acid, HSF); or low fat (2% linoleic acid, LF), with and without 0.3% propyl gallate (PG). At 50 days of age, one half of each group (30 rats/group) received 10 mg of DMBA in 1 ml corn oil p.o. as a tumor inducer. Both the amt of fat and the degree of unsaturation were found to affect the extent of protection against tumorigenesis afforded by propyl gallate, with some protection seen in all three dietary groups. Tumor incidences at 32 wk of age were: HPF, 100%; HSF, 63%; LF, 29%; HPF+PG, 77%; HSF+PG 11%. Tumors grew most rapidly in the HPF group. Propyl gallate did not alter the function of the hepatic mixed oxidase system by induction or inhibition under the dietary conditions used ... . [R15, p. 13 (1993)] *The induction of epidermal ornithine decarboxylase by 12-O-tetradecanoylphorbyl-13 acetate in mouse epidermis was inhibited by the topical application of propyl gallate. Its potency was approx 10% of that of BHA ... . [R15, p. 14 (1993)] *Propyl gallate did not modify tumor development of 1,2-dimethylhydrazine-initiated colon carcinogenesis in F344 rats ... . [R15, p. 14 (1993)] *The promoting activity of 3 antioxidants, alpha-tocopherol, propyl gallate and tertiary butylhydroquinone (TBHQ) in urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in male Fischer 344 rats was examined. Rats, 6 wk old, were treated with 0.05% BBN in the drinking water for 4 wk and then admin 1.50, 0.75 or 0.38% alpha-tocopherol, 1.0% propyl gallate or 2.0% TBHQ in the diet for 32 weeks. The urinary bladder of each animal was examined histologically after the 36-wk experimental period ... alpha-tocopherol and propyl gallate did not demonstrate a promoting effect for urinary bladder lesions ... . [R15, p. 14 (1993)] *Propyl gallate, gallic acid and nordihydroguaiaretic acid were all potent inhibitors of the in vitro mouse spleen cell antibody response as assayed by antisheep erythrocyte plaque-forming cell response. These cmpds also suppressed clone formation in vitro by human WISH or mouse L-cells ... . [R15, p. 14 (1993)] *At concn as low as 5x10-6 M, gallic acid, a metabolite of propyl gallate and tannic acid, suppressed the anti-sheep erythrocyte plaque forming cell response of C57Bl/6 mouse spleen cells when added t cultures as late as 48 hr after antigen addition. Gallic acid induced suppression was reversed by 2-mercaptoethanol added at the same time as, or up to 48 hr after, antigen. Gallic acid also suppressed mitogen induced DNA synthesis of C57Bl/6 T lymphocytes, and this suppression was reversed by 2-mercaptoethanol. Gallic acid had no effect on the response of athymic nude mouse spleen cells to the thymus-independent antigen Escherichia coli 0127:B8, and failed to suppress lipopolysaccharide-induced B lymphocyte DNA synthesis. ... Gallic acid selectively suppresses a macrophage-dependent T lymphocyte function(s). /Gallic acid/ [R22] *Propyl gallate, gallic acid and nordihydroguaiaretic acid were all potent inhibitors of the in vitro mouse spleen cell antibody response as assayed by antisheep erythrocyte plaque-forming cell response. These cmpd also suppressed clone formation in vitro by human WISH or mouse L-cells ... . [R15, p. 14 (1993)] NTXV: *LD50 Rat oral 3,600-3,800 mg/kg bw /From table/; [R15, p. 6 (1993)] *LD50 Mouse oral 2,000-3,000 mg/kg bw /From table/; [R15, p. 6 (1993)] *LD50 Rat ip 380 mg/kg bw /From table/; [R15, p. 6 (1993)] NTP: *A carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 wk. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. ... Under the conditions of this bioassay, propyl gallate was not considered to be carcinogenic for F344/N rats, although there was evidence of an incr proportion of low dose male rats with preputial gland tumors, islet cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the incr incidence of malignant lymphoma in male mice may have been related to dietary admin of propyl gallate. [R23] METB: *PROPYL GALLATE YIELDS GALLIC ACID PROBABLY IN PULLULARIA. [R24] *The available evidence indicates that the gallate esters are hydrolyzed in the body to gallic acid. Most of the gallic acid is converted into 4-O-methyl gallic acid. Free gallic acid or a conjugated derivative of 4-O-methyl gallic acid is excreted in the urine. Conjugation of the 4-O-methyl gallic acid with glucuronic acid was demonstrated ... . [R15, p. 4 (1993)] *In vitro incubations with propyl, octyl and dodecyl gallate were performed using homogenates of liver, mucosa of the small intestine, and contents of caecum/colon as a source of intestinal microflora. The various homogenates were incubated at 37 deg C with the individual gallate esters. At various time points up to 24 hr, samples were taken and analyzed by HPLC. ... All test substances were extensively metabolized by the homogenate of the intestinal mucosa. ... Furthermore, the caecum and colon contents also showed a high metabolic capacity, especially towards propyl gallate. The amt of gallic acid detected in the incubations was always much smaller than the total decrease of the amt of ester. It seems likely that apart from hydrolysis of the ester bond, other biotransformation routes ... are of major importance for all three gallate esters. [R15, p. 4 (1993)] INTC: *Partial protection against liver damage by single oral doses of 2.5 or 0.25 ml/kg of chloroform was provided by ip injection of 150 mg/kg bw of propyl gallate ... . [R15, p. 15 (1993)] *Pregnant New Zealand white rabbits (on gestation day 12) were injected sc with propyl gallate (362-900 mg/kg bw) and hydroxyurea (600-750 mg/kg bw). The materials were injected either simultaneously or mixed over periods of 45 min. The extent of amelioration of the teratogenic effects of hydroxyurea was dependent on the dose of propyl gallate. There was a significant linear decrease in both resorptions and specific malformations with increasing doses of propyl gallate ... . [R15, p. 12 (1993)] *INHIBITED BIOSYNTHESIS OF PGE2 + PGF2 ALPHA FROM ARACHIDONIC ACID BY PROSTAGLANDIN SYNTHETASE FROM BULL SEMINAL VESICLES WITH IC50 OF 103 UM. REDUCES ABILITY OF ARACHIDONIC ACID, ACETYLCHOLINE OR ACETIC ACID TO CAUSE ABDOMINAL CONSTRICTION IN MICE. [R25] *PROPYL GALLATE ADMIN IP PARTIALLY PREVENTED LIVER INJURY INDUCED BY CARBON TETRACHLORIDE (2.5 ML/KG, ORALLY) IN RATS. [R26] *PROPYL GALLATE INHIBITED N-ACETOXY-2-ACETYLAMINOFLUORENE-INDUCED MUTAGENESIS. [R27] *PROPYL GALLATE WAS FOUND TO STABILIZE FUNGIZONE AND TO PROLONG ITS ANTIFUNGAL ACTIVITY AGAINST CANDIDA ALBICANS. [R28] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of propyl gallate are exempted from the requirement of a tolerance when used as an antioxidant in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R29] *Propyl gallate is exempted from the requirement of a tolerance when used as a antioxidant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R30] FIFR: *Residues of propyl gallate are exempted from the requirement of a tolerance when used as an antioxidant in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R29] *Propyl gallate is exempted from the requirement of a tolerance when used as an antioxidant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R30] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A GAS-LIQUID CHROMATOGRAPHIC METHOD FOR MULTIDETERMINATION OF ANTIOXIDANTS IN FATS, OILS, AND DRIED FOOD PRODUCTS. [R31] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Propyl Gallate in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 240 (1982) NIH Publication No. 83-1796 WHO/IPCS; Toxicological Evaluation of Certain Food Additives and Contaminants WHO Food Additives Series 32 (1993) SO: R1: SRI R2: SRI; 1995 - Directory of Chemical Producers USA pg 876 (1995) R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 972 R4: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R5: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1223 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V24 155 (1984) R7: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-199 R8: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2310 R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-76 R10: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 73 R11: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1248 R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R13: KAHN G ET AL; ARCH DERMATOL 109 (APR): 506-9 (1974) R14: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 728 R15: WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Food Additives and Contaminants. R16: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1902 R17: KAHN G ET AL; ARCH DERMATOL 109 (APR) 506-9 (1974) R18: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R19: Abdo KM et al; J Am Coll Toxicol 2 (6): 425 (1983) R20: WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Foods Additives and Contaminants. p. 12 (1993) R21: WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Food Additives and Contamiants. p. 12 (1993) R22: Archer DL et al; Proceedings of the Society for Experimental Biology and Medicine 156: 465 (1977) R23: DHHS/NTP; Toxicology and Carcinogenesis Studies of Propyl Gallate in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 240 (1982) NIH Publication No. 83-1796 R24: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-39 R25: MCDONALD-GIBSON WJ ET AL; BR J PHARMACOL 58 (4): 573-81 (1976) R26: TORRIELLI MV, UGAZIO G; TOXICOL APPL PHARAMCOL 34 (1): 151-69 (1975) R27: ROSIN MP, STICH HF; INT J CANCER; 23 (5): 722-7 (1979) R28: ANDREWS FA ET AL; ANTIMICROB AGENTS CHEMOTHER 11 (4): 615-8 (1977) R29: 40 CFR 180.1001(c) (7/1/94) R30: 40 CFR 180.1001(e) (7/1/94) R31: KLINE DA ET AL; J ASSOC OFF ANAL CHEM 61 (3): 513-9 (1978) RS: 33 Record 73 of 1119 in HSDB (through 2003/06) AN: 606 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ISOAMYL-NITRITE- SY: *AMILNITRIT-; *AMYL-NITRIT-; *AMYL-NITRITE-; *ASPIRAL-; *ISOPENTYL-ALCOHOL,-NITRITE-; *ISOPENTYL-NITRITE-; *3-METHYLBUTANOL-NITRITE-; *3-METHYLBUTYL-NITRITE-; *NITRAMYL-; *NITROUS-ACID,-3-METHYLBUTYL-ESTER-; *PENTANOLI-NITRIS-; *VAPOROLE- RN: 110-46-3 MF: *C5-H11-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ISOAMYL ALCOHOL AND NITROUS ACID [R1] *PREPD BY NITROSATION OF ISOPENTYL ALCOHOL: BEVILLARD, CHOUCROUN, BULL SOC CHIM FRANCE 1957, 337. [R2] FORM: *LIQ IN 0.18 and 0.3 ML CONTAINERS. DRUG MARKETED UNDER GENERIC NAME. [R3] +Grades: NF (75% min); technical [R4] +Usually a mixture of isomers [R5] MFS: *FRANK ENTERPRISES, COLUMBUS, OHIO [R1] +Chemical Dynamics Corp, PO Box 395, Hadley Industrial Plaza, Hadley Road, South Plainfield, NJ 07080, (201)753-5000 [R6] +Burroughs-Wellcome Co, 3030 Cornwallis Rd, Research Triangle Park, NC 27709, (919)248-3000 [R7] OMIN: *INCOMPATIBILITIES: ALCOHOL, ANTIPYRINE, CAUSTIC ALKALIES, ALKALINE CARBONATES, POTASSIUM IODIDE, BROMIDES, FERROUS SALTS. [R2] USE: *CARDIOVASCULAR DILATOR [R1] +Used in perfumes; preparation of diazonium compounds [R4] +Used as a vasodilator in angina therapy in the treatment of hydrogen cyanide and hydrogen sulfide poisonings, and as an industrial chemical and perfume scent [R5] +Used in discotheques to stimulate dancing [R5] *MEDICATION *MEDICATION (VET) CPAT: *100% AS A CARDIOVASCULAR DILATOR (1973) [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] +(1986) ND U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] +(1986) ND U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOWISH, TRANSPARENT LIQ [R2] ODOR: *PECULIAR, ETHEREAL, FRUITY ODOR [R8] TAST: *PUNGENT, AROMATIC TASTE [R8] BP: *97-99 DEG C [R2] MW: *117.15 [R2] DEN: *0.875 @ 25 DEG C/25 DEG C [R2] SOL: *PRACTICALLY INSOL IN WATER; MISCIBLE WITH ETHER, ALCOHOL, CHLOROFORM [R8] SPEC: *INDEX OF REFRACTION: 1.3918 @ 20 DEG C [R9]; *INDEX OF REFRACTION: 1.3871 @ 21 DEG C/D [R2]; *MAX ABSORPTION (CYCLOHEXANE): 224 NM (LOG E= 3.29); 333 NM (LOG E= 1.71); 369 NM (LOG E= 1.83); 384 NM (LOG E= 1.52) [R9]; +IR: 5147 (Sadtler Research Laboratories Spectral Collection) [R10]; +UV: 1398 (Sadtler Research Laboratories Spectral Collection) [R10]; +MASS: 444 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R10]; +Intense mass spectral peaks: 41 m/z, 57 m/z, 70 m/z, 85 m/z [R11] VAPD: *4.0 (AIR=1) [R12] OCPP: *VOLATILE EVEN AT LOW TEMP [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Some may polymerize (P) explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R13] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R13] +Public safety: Call Emergency Response Telephone Number on Shipping Paper first. If Shipping Paper not available or no answer, refer to appropriate telephone number listed on the inside back cover. Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R13] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R13] +Evacuation: Large spill: Consider initial downwind evacuation for at least 300 meters (1000 feet). Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R13] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from the ends of tanks. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R13] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R13] +First aid: Move victim to fresh air. Call emergency medical care. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R13] FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME OR BY SPONTANEOUS CHEM REACTION...CAN REACT WITH OXIDIZING...MATERIAL. [R12] *CAUTION--AMYL NITRITE IS VERY FLAMMABLE. DO NOT USE WHERE IT MAY BE IGNITED. [R8] AUTO: *408 DEG F [R12] FIRP: *ALCOHOL FOAM... [R12] EXPL: *CAUTION: FORMS EXPLOSIVE MIXT WITH AIR OR OXYGEN. [R2] OPRM: *BASIC VENTILATION METHODS ARE LOCAL AND EXHAUST VENTILATION AND DILUTION OR GENERAL VENTILATION. [R12] SSL: *UNSTABLE AND DECOMP ON EXPOSURE TO AIR AND LIGHT [R2] *MOISTURE ACCELERATES DECOMP [R8] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R15] STRG: *KEEP TIGHTLY CLOSED CONTAINERS PROTECTED FROM LIGHT AND IN COOL PLACE. [R2] *MATERIAL...STORED IN /COOL/ PLACES...PROVIDE ADEQUATE VENTILATION...LOCATE STORAGE AREA...AWAY FROM AREAS OF FIRE HAZARD... HIGHLY FLAMMABLE IE REDUCING OR EASILY OXIDIZED MATERIALS MUST BE KEPT APART FROM...OXIDIZING AGENTS, MATERIALS...SUSCEPTIBLE TO SPONTANEOUS HEATING... [R12] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *PROMPT CIRCULATORY COLLAPSE FROM VASODILATION, IN ADDITION TO METHEMOGLOBINEMIA. [R16] *SEE NITRITE. SYMPTOMATOLOGY: 1. PROMPT FALL IN BLOOD PRESSURE. 2. HEADACHE... VERTIGO, PALPITATIONS, AND VISUAL DISTURBANCES. 3. SKIN IS FLUSHED AND PERSPIRING. LATER COLD AND CYANOTIC. 4. NAUSEA AND VOMITING. INGESTION...MAY CAUSE COLIC AND DIARRHEA. 5. SYNCOPE... 6. ...CYANOSIS AND ANOXIA. /NITRITE/ [R16] *SEE NITRITE. SYMPTOMATOLOGY: 7. HYPERPNEA; LATER DYSPNEA AND SLOW BREATHING. 8. PULSE...SLOW, DICROTIC AND INTERMITTENT. 9. INCR INTRAOCULAR TENSION AND INTRACRANIAL PRESSURE. 10. COLLAPSE AND COMA...CONVULSIONS. 11. DEATH DUE TO CIRCULATORY COLLAPSE. /NITRITE/ [R16] *THE DESIRED EFFECTS AND ADVERSE EFFECTS RESULTING FROM ABUSE OF AMYL NITRITE ARE PRESENTED. [R17] *HEART RATE RESPONSES TO INHALATION OF AMYL NITRITE BY PT DURING ACUTE ADRENERGIC BETA BLOCKADE WITH IV PROPRANOLOL VARIED GREATLY FROM PT TO PT BUT BECAUSE OF ITS MARKED HYPOTENSIVE EFFECT IT PROVED TO BE VERY POTENT STIMULUS FOR HEART RATE INCR. [R18, (1978)] NTOX: *INHALATION OF SMALL AMT OF VAPOR CAUSES...IN SOME...ANIMALS SLIGHT MOMENTARY RISE IN INTRAOCULAR PRESSURE. [R19, 134] *LIQ AMYL NITRITE TESTED ON NORMAL RABBIT EYES CAUSES ONLY SLIGHT SUPERFICIAL INJURY. [R19, 135] +Isoamyl nitrite was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Isoamyl nitrite was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.010, 0.033, 0.100, 0.333, 1.000, 3.333, and 6.666 mg/plate. The lowest positive dose tested in any S. typhimurium strain was 0.100 mg/plate in strain TA1535 with 10% rat liver S-9. Slight to total clearing of the background bacterial lawn was exhibited in cultures containing the two highest doses. [R20] ADE: *AMYL NITRITE...RAPIDLY ABSORBED BY SKIN AND RESPIRATORY AND MUCOUS MEMBRANES... [R21] ACTN: *BASIC PHARMACOLOGICAL ACTION OF NITRITES IS TO RELAX SMOOTH MUSCLE. RELAXATION IS NONSPECIFIC... [R22, 728] *IN ANGINA PECTORIS, PAIN IS EASED BY VASODILATION OF CORONARY ARTERIES PRODUCED BY AMYL NITRITE. [R8] *...IN EMERGENCY TREATMENT OF CYANIDE POISONING.../NITRITE/ TEMPORARILY INACTIVATES TOXIC CYANIDE ION BY COMBINING WITH IT TO FORM CYANMETHEMOGLOBIN. FOR THIS PURPOSE, SODIUM NITRITE IS EMPLOYED IV, BUT AMYL NITRITE MAY BE INHALED WHILE SOLN OF SODIUM NITRITE IS BEING PREPARED. [R8] INTC: *...ITS EFFECT CAN BE ANTAGONIZED BY ANY DRUG THAT CAN ACTIVATE SMOOTH MUSCLE UNDER CONSIDERATION. THUS, NITRITE IS FUNCTIONAL ANTAGONIST OF NOREPINEPHRINE, ACETYLCHOLINE, HISTAMINE... /NITRITE/ [R22, 728] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *IN ACTUAL PRACTICE...AMYL NITRITE IS EMPLOYED BUT RARELY, EXCEPT AS VASODILATOR IN TREATMENT OF ATTACKS OF ANGINA PECTORIS. UNUSUAL BUT @ TIMES LIFE-SAVING USE FOR AMYL NITRITE IS EMERGENCY TREATMENT OF CYANIDE POISONING, WHERE NITRITES ARE GIVEN TO PRODUCE METHEMOGLOBIN... [R8] *IT IS...USED IN BRONCHOSPASM AND BILIARY SPASM. [R23] *DOSAGE: 0.18 OR 0.3 ML, INHALATION. [R22, 734] *PATIENTS SHOULD BE IN SITTING POSITION WHILE INHALING AMYL NITRITE. FRAGILE GLASS AMPUL CONTAINING DRUG IS CRUSHED IN HANDKERCHIEF AND VAPORS ARE INHALED. [R23] *MEDICATION (VET): VASODILATOR. USE/D/ TO DILATE SMOOTH MUSCLES AND AS EMERGENCY MEASURE IN CYANIDE POISONING. EFFECTS START WITHIN FEW SECONDS AND LAST ABOUT 10 MIN. [R24] *ALTHOUGH PROMPT RELIEF OF ANGINAL PAIN MAY BE OBTAINED BY INHALATION OF AMYL NITRITE, THIS AGENT IS EXPENSIVE AND IS UNACCEPTABLE TO MANY PT BECAUSE OF ITS UNPLEASANT ODOR AND PRONOUNCED SIDE EFFECTS (HEADACHE, ORTHOSTATIC SYMPTOMS, REFLEX TACHYCARDIA). [R3] *Used by enthusiasts to stimulate highs and intensify sexual orgasms [R5] WARN: *SINCE AMYL NITRITE INCR INTRAOCULAR PRESSURE AS WELL AS THAT OF CEREBROSPINAL FLUID, IT SHOULD BE USED WITH CAUTION IN PT WITH GLAUCOMA OR CEREBRAL HEMORRHAGE. [R23] *UNTOWARD RESPONSES TO THERAPEUTIC USE OF NITRITES ARE...HEADACHE...DIZZINESS, WEAKNESS, AND OTHER MANIFESTATIONS OF CEREBRAL ISCHEMIA ASSOC WITH POSTURAL HYPOTENSION...DRUG RASH...METHEMOGLOBINEMIA. /NITRITES/ [R22, 733] *VET: CAUSES INTENSE AND RAPID LOWERING OF BLOOD PRESSURE AND INCR IN HEART RATE. [R24] *BECAUSE AMYL NITRITE ACTIVATES VAGAL WITHDRAWAL WHICH INCR HEART RATE REGARDLESS OF EXTENT OF BETA BLOCKADE IN THIS STUDY, IT IS CONCLUDED THAT AMYL NITRITE FROM CLINICAL STAND POINT CANNOT BE USED AS TEST TO ASSESS ACCURATELY DEGREE OF BETA BLOCKADE. [R18, (1958)] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NMR ANALYSIS OF PHARMACEUTICALS. DETERMINATION OF AMYL NITRITE IN ITS INHALANT DOSAGE FORM. [R25] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 682 R3: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 25 R4: HAWLEY. CONDENSED CHEM DICTNRY 10TH ED 1981 p.69 R5: GOSSELIN. CTCP 5TH ED 1984 p.II-211 R6: CHEMICALWEEK BUYERS' GUIDE '86 p.383 R7: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.113 R8: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 788 R9: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-399 R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 34 R11: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.84 R12: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 403 R13: U.S. Department of Transportation. 1996 North American Emergency Response Guidebook. A Guidebook for First Responders During the Initial Phase of a Hazardous Materials/Dangerous Goods Incident. U.S. Department of Transportation (U.S. DOT) Research and Special Programs Administration, Office of Hazardous Materials Initiatives and Training (DHM-50), Washington, D.C. (1996).. G-129 R14: 49 CFR 171.2 (7/1/96) R15: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3024 (1988) R16: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-142 R17: SIGELL ET AL; POPPING AND SNORTING VOLATILE NITRITES: A CURRENT FAD FOR GETTING HIGH; AM J PSYCHIATRY 135(10) 1216-18 (1978) R18: NIARCHOS ET AL; AM HEART J 96(1) 47-53 R19: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. R20: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R21: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 237 R22: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R23: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 24:12 R24: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 19 R25: TURCZAN JW, MEDWICK T; NMR ANALYSIS OF PHARMACEUTICALS. 14. DETERMINATION OF AMYL NITRITE IN ITS INHALANT DOSAGE FORM; J PHARM SCI 65(FEB) 235-8 (1976) RS: 17 Record 74 of 1119 in HSDB (through 2003/06) AN: 613 UD: 200301 RD: Reviewed by SRP on 9/23/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ISOBUTYLENE- SY: *GAMMA-BUTYLENE-; *ASYM-DIMETHYLETHYLENE-; *1,1-DIMETHYLETHYLENE-; *ISOBUTENE-; *ISOPROPYLIDENEMETHYLENE-; *2-METHYLPROPENE-; *2-METHYL-1-PROPENE-; *1-PROPENE,-2-METHYL-; *PROPENE,-2-METHYL- RN: 115-11-7 MF: *C4-H8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *RECOVERY FROM C-4 STREAM IN PETROLEUM REFINING [R1] *Obtained from refinery streams by absorption on 65% H2SO4 @ about 15 deg C: Packie, Rupp, US patents 2,424,186, 2,509,885; Draeger, US patent 2,456,260 ... Sepn from mixed C4 stream using 50% H2SO4: British patents 824,573, 858,645 AND French patent 1,337,232 (1959, 1961 and 1963 to Compagnie Francaise de Raffinage ...) [R2] *Prepn from C4 refinery stream by reacting with a lower aliphatic primary alc of up to about 6 carbon atoms and decomposing resultant tertiary ether by contact with low area, solid weakly acid-acting metal oxide catalyst at elevated temp: Verdol, US patent 3,170,000 (1965 to Sinclair). [R2] *Gas mixtures containing considerable isobutene are obtained by fractionation of refinery gases resulting from cracking of petroleum. [R3] MFS: *ARCO Chemical Co., Hq, 3801 W. Chester Pike, Newtown Square, PA 19073; Production site: Bayport, TX 77062 [R4] *Exxon Chemical Co., 13501 Katy Freeway, Houston, TX 77079, (281) 870-6000; Production sites: Baton Rouge, LA 70821; Baytown, TX 77520 [R4] *Texas Petrochemicals Corp., Three Riverway, Suite 1500, Houston, TX 77056, (713) 627-7774; Production site: Houston, TX 77017 [R4] OMIN: *POLYMERIZATION OF ISOBUTYLENE ... LEADS TO FORMATION OF HIGH POLYMERS WITH MOLECULAR WT BETWEEN 15,000 and 500,000. FIRST MEMBERS, WITH MOLECULAR WT UP TO ABOUT 60,000, ARE SYRUPY, BUT PRODUCTS WITH HIGHER MOLECULAR WT ARE RUBBER-LIKE ... [R5] *... CAN BE USED FOR ACID OR BASE RESISTANT LININGS OR FOR MAKING HOSE, SINCE THEY ARE TASTELESS AND ODORLESS, OR FOR TRANSPORTING BEVERAGES (BEER, WINE). /ISOBUTYLENE POLYMERS/ [R5] USE: *Used to produce trimers and other polymers /of isobutylene/; to produce antioxidants for foods; to produce antioxidants for packaging, food supplements, and for plastics [R2] *Prodn of isooctane, high-octane aviation gasoline; tert-butanol methacrylates and other derivatives; copolymer resins with butadiene, acrylonitrile [R3] *Reacted with methanol to produce methyl t-butyl ether [R6] CPAT: *100% AS A CHEM INT, OF WHICH 45% IS USED FOR BUTYL ELASTOMER, 40% FOR POLYBUTENES, 7% FOR DIISOBUTYLENE, 6% FOR POLYISOBUTYLENES, AND 2% FOR DI-TERT-BUTYL P-CRESOL (1973) [R1] PRIE: U.S. PRODUCTION: *(1972) 2.72X10+11 GRAMS [R1] *(1973) 3.5X10+11 GRAMS [R1] *(1984) 4.01X10+11 g [R7] *(1991) 0.97 billion lb [R8] *(1992) 1.29 billion lb [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Easily liquefied gas [R3] ODOR: *Coal gas odor [R3] BP: *-6.9 deg C [R9] MP: *-140.4 deg C [R9] MW: *56.11 [R9] DEN: *0.589 g/cu cm @ 25 deg C [R9] OWPC: *log Kow = 2.34 [R10] SOL: *Very soluble in ethanol and ether; soluble in benzene [R9]; *In water, 263 mg/l @ 25 deg C [R11] SPEC: *Index of refraction: 1.3926 @ -25 deg C [R9]; *SADTLER REF NUMBER: 7858 (IR, PRISM) [R12]; *MAX ABSORPTION: 159 NM (LOG E= 3.9); 184 NM, 188 NM (LOG E= 4.1); 192 NM SHOULDER (LOG E= 3.9); 200 NM SHOLDER (LOG E= 3.9) [R12]; *IR: 8514 (Sadtler Research Laboratories IR Grating Collection) [R13]; *MASS: 26 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R13] VAPD: *1.94 (Air= 1) [R14] VAP: *2,308 mm Hg @ 25 deg C [R15] OCPP: *Reacts easily with numerous materials, polymerizes easily [R3] *TASTELESS AND ODORLESS /ISOBUTYLENE POLYMERS/ [R5] *Henry's Law constant = 0.218 atm cu-m/mol @ 25 deg C [R16] *Hydroxyl radical rate constant = 5.14X10-11 cu-cm/molc sec @ 25 deg C [R17] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: EXTREMELY FLAMMABLE. Will be easily ignited by heat, sparks or flames. Will form explosive mixtures with air. Vapors from liquefied gas are initially heavier than air and spread along ground. Vapors may travel to source of ignition and flash back. Containers may explode when heated. Ruptured cylinders may rocket. [R18] +Health: Vapors may cause dizziness or asphyxiation without warning. Some may be irritating if inhaled at high concentrations. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Fire may produce irritating and/or toxic gases. [R18] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. [R18] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. Always wear thermal protective clothing when handling refrigerated/cryogenic liquids. [R18] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for l600 meters (1 mile) in all directions; also, consider initial evacuation for 1600 meters (1 mile) in all directions. [R18] +Fire: DO NOT EXTINGUISH A LEAKING GAS FIRE UNLESS LEAK CAN BE STOPPED. Small fires: Dry chemical or CO2. Large fires: Water spray or fog. Move containers from fire area if you can do it without risk. Fire involving Tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R18] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. If possible, turn leaking containers so that gas escapes rather than liquid. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Do not direct water at spill or source of leak. Prevent spreading of vapors through sewers, ventilation systems and confined areas. Isolate area until gas has dispersed. CAUTION: When in contact with refrigerated/cryogenic liquids, many materials become brittle and are likely to break without warning. [R18] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. Clothing frozen to the skin should be thawed before being removed. In case of contact with liquefied gas, thaw frosted parts with lukewarm water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R18] FPOT: *A very dangerous fire and explosion hazard when exposed to heat or flame. [R19] AUTO: *869 DEG F (465 DEG C) [R3] FIRP: *To fight fire, stop flow of gas. [R19] EXPL: *LEL: 1.8%; UEL: 9.6% [R19] REAC: *CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R19] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R19] EQUP: *PROTECTIVE CLOTHING, BARRIER CREAMS ... MEDICAL CONTROL ... [R20] OPRM: *VENTILATION CONTROL: THE BASIC VENTILATION METHODS ARE LOCAL EXHAUST VENTILATION AND DILUTION OR GENERAL VENTILATION. [R20] *... SUBSTITUTION OF LESS IRRITATING SUBSTANCES ... REDESIGN OF OPERATIONS ... PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, WORK CLOTHING AND STORAGE FACILITIES ... [R20] SSL: *VOLATILE LIQUID OR EASILY LIQUEFIED GAS. [R3] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R22] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R23] STRG: *... MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMPOSE INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL, WELL VENTILATED PLACE, OUT OF THE DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED ... [R20] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic Treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Anticipate seizures and treat as necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... Treat frostbite with rapid rewarming techniques ... /Aliphatic hydrocarbons and related compounds/ [R24, p. 209-210] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... Treat seizures with diazepam (Valium) ... Use proparacaine hydrochloride to assist eye irrigation ... /Aliphatic hydrocarbons and related compounds/ [R24, 210] HTOX: *BUTYLENE ISOMERS ARE SIMILAR IN PHARMACOLOGICAL ACTIVITY AS ASPHYXIANTS AND WEAK ANESTHETICS. ... ABOUT 4.5 TIMES AS TOXIC AS ETHYLENE. /BUTYLENE ISOMERS/ [R25] *The biotransformation of 2-methylpropene, a gaseous alkene widely used in industry, was investigated in vitro in liver tissue of rats, mice, and humans. Interspecies comparison revealed that the lowest levels of the primary epoxide metabolite were detected in incubations of 2-methylpropene with human liver homogenate, followed by rat and mouse, respectively. Among the human liver samples, however, important interindividual variations were observed. Out of the 16 samples analyzed, only 2 contained measurable epoxide amounts, while in the other samples only traces were detectable. The involvement of rat liver cytochrome P450 2E1 in the activation of 2-methylpropene to its epoxide 2-methyl-1,2-epoxypropane has been established. The lower capacity of the mixed function oxidase system in human liver samples compared to rodents is confirmed. Concerning epoxide detoxifying enzymes, a high microsomal epoxide hydrolase activity was observed in human liver tissue and an intermediate in rat liver, while a low activity was measured in mouse liver. These findings were inversely correlated with the epoxide levels measured in vitro in liver tissue of the three species studied. It can be concluded that, as far as the in vitro metabolism of 2-methylpropene is concerned, neither mouse nor rat represents a good model for the human situation. Although, the same biotransformation pathways are involved, marked quantitative differences in epoxide levels were observed. The results indicate that human liver tissue is exposed in vitro to smaller concentrations of the primary metabolite 2-methyl-1,2-epoxypropane than rodent liver. [R26] NTOX: *2-Methylpropene or isobutene is a gaseous chemical used on a large scale in the synthetic rubber industry. The present review covers the rather scarce literature on 2-methylpropene with respect to its metabolic fate and toxicity in laboratory animals and humans. It has been shown both in vivo and in vitro that 2-methylpropene is metabolized to the primary metabolite 2-methyl-1,2-epoxypropane by rodent and human liver tissue. The formation of this reactive epoxide intermediate is catalyzed by CYP2E1, while epoxide hydrolase and glutathione S-transferase appear to be involved in its inactivation. In rats, the capacity to absorb and metabolize 2-methylpropene is saturable. 2-Methylpropene is oxidized to compounds that are mainly excreted in urine. Data indicate that rodents can tolerate low levels of 2-methylpropene without apparent toxicity. The primary metabolite 2-methyl-1,2-epoxypropane, however, is able to produce genetic damage in both prokaryotic and eukaryotic cells in vitro. 2-Methylpropene is thus not toxic per se but elicits metabolic activation to become potentially harmful. Consequently, the balance between formation and detoxification of 2-methyl-1,2-epoxypropane plays a key role in determining the potential toxicity of the parent compound [R27] *The toxicity of isobutene is similar to that of other lower alkenes. It is a simple asphyxiant and causes CNS depression at higher concentrations. At 30%, it produces no CNS depression in mice, and excitement and CNS depression in 7 to 8 min at 40%, but immediate CNS depression in 2 to 2.25 min at 50%, or in 50 to 60 sec at 60 to 70%. The 2-hr LC50 in the mouse is 415 mg/L and the 4-hr LC50 in the rat is 620 mg/L. [R28, 1247] *... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of isobutene in male F344/N rats based on an incr incidence of follicular cell carcinoma of the thyroid gland. There was no evidence of carcinogenic activity of isobutene in female F344/N rats or male or female B6C3F1 mice exposed to 500, 2,000 or 8,000 ppm. [R29] *The epoxidation of the gaseous alkene 2-methylpropene or isobutene was studied in vitro in rat lung tissue in comparison with rat liver. Pulmonary tissue appears to be less exposed to the toxic epoxide metabolite than is the case for hepatic tissue. The results are correlated with the low capacity of the mixed function oxidase system, expressed by means of the cytochrome p450 content and the 7-ethoxycoumarin O-deethylase activity, to form reactive intermediates. The activities of the principal epoxide detoxifying enzymes glutathione S-transferase and epoxide hydrolase represent only 5-10% of the values measured in rat liver. [R30] *There was a linear relationship between the degree of CNS depression and the cerebral concentrations. [R28, 1247] NTXV: *LC50 Mouse oral 415 mg/L/2 hr; [R28, 1247] *LC50 Rat oral 620 mg/L/4 hr; [R28, 1247] *LC50 Rat ihl 620 g/cu m/4 hr; [R19] *LC50 Mouse ihl 415 g/cu m/2 hr; [R19] NTP: *... Groups of 50 male and 50 female F344/N rats were exposed to isobutene at concn of 0, 500, 2,000 or 8,000 ppm 6 hr/day 5 days/wk for 105 wk. ... Groups of 50 male and 50 female B6C3F1 mice were exposed to isobutene at concn of 0, 500, 2,000 or 8,000 ppm 6 hr/day, 5 days/wk for 105 wk. ... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was some evidence of carcinogenic activity of isobutene in male F344/N rats based on an incr incidence of follicular cell carcinoma of the thyroid gland. There was no evidence of carcinogenic activity of isobutene in female F344/N rats or male or female B6C3F1 mice exposed to 500, 2,000 or 8,000 ppm. [R29] ADE: *FASTED RATS EXHALE THE HYDROCARBONS @ RATE OF APPROX 1.7 NMOL/KG/HR. THROUGH AN IMPROVED ANALYTICAL PROCEDURE OTHER VOLATILE HYDROCARBONS COULD BE DETECTED IN BREATH OF ANIMALS. [R31] *In metabolic studies on rats and mice, inhaled isobutene levels in the brain and parenchymatous organs were similar, but the level in the fatty tissue was significantly higher than in the brain, liver, kidneys, or spleen. [R28, 1247] METB: *The effect of age and gender on the in vitro biotransformation of 2-methylpropene, an alkene metabolized to 2-methyl-1,2-epoxypropane, was studied. The epoxide concentration and the epoxide metabolizing enzymatic activities were investigated in male and female Brown Norway rats of different ages. Liver tissue of senescent rats was exposed to smaller 2-methyl-1,2-epoxypropane concentrations than that of young animals, although changes during ageing were rather modest. With advancing age a feminization of male glutathione S-transferase and cytosolic epoxide hydrolase activities was found, as well as a significant decline of the female microsomal epoxide hydrolase activity and an increase of the cytochrome p450 content in the oldest female rats. [R32] *Total uptake, excretion patterns, and metabolic conversions were studied in rats exposed for up to 6 hr to 0, 2, 40, 400, or 4000 ppm 14(C)isobutene. Absorption of the inhaled isobutene was approximately 8% up to 40 ppm isobutene, but decreased at the higher concentrations. The amount of isobutene metabolized per ppm.hr of exposure was also linear up to 40 ppm but decreased at higher concentrations. Over 90% of the absorbed isobutene was metabolized at exposure concentrations up to 400 ppm, but the exposure to approximately 4000 ppm isobutene resulted in approximately 20% of the absorbed dose exhaled as the unmetabolized isobutene. Two urinary metabolites were identified as isobutenediol and 2-hydroxyisobutyric acid. Two other urinary metabolites were tentatively identified as sulfate conjugates of isobutenediol. [R33] ACTN: */Butenes/ are simple asphyxiants and can be used as anesthetics. /Butenes/ [R28, 1246] INTC: *GAS-LIQUID CHROMATOGRAPHY WAS USED TO STUDY BRAIN HYDROCARBON CONTENT IN RATS AND MICE INHALING MIXTURES OF BUTANE AND ISOBUTYLENE. THERE WAS SUMMATION OF CNS DEPRESSANT EFFECTS OF BUTANE AND ISOBUTYLENE TOWARD POTENTIATION RATHER THAN ANTAGONISM. [R34] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Isobutylene's production and use in the production of polymers, antioxidants and high octane aviation fuel may result in its release to the environment through various waste streams. It is also released to the environment from the exhaust of automobiles and other gasoline powered engines. If released to air, a vapor pressure of 2,308 mm Hg at 25 deg C indicates isobutylene will exist solely as a gas in the ambient atmosphere. Gas-phase isobutylene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone molecules with atmospheric half-lives of about 7.5 and 23 hours respectively. If released to soil, isobutylene is expected to have moderate mobility based upon an estimated Koc of 450. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 0.218 atm-cu m/mole. Isobutylene may volatilize from dry soil surfaces based upon its vapor pressure. Isobutylene was degraded to 1,2-epoxy butane by pure cultures of methanotrophic bacteria, suggesting biodegradation may occur under anaerobic conditions. If released into water, isobutylene is expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 2 and 71 hours, respectively. An estimated BCF of 35 suggests the potential for bioconcentration in aquatic organisms is moderate. Occupational exposure to isobutylene may occur through inhalation and dermal contact with this compound at workplaces where isobutylene is produced or used. The general population may be exposed to isobutylene via inhalation of ambient air. (SRC) NATS: *ISOBUTYLENE IS A COMPONENT OF PETROLEUM AND NATURAL GAS. [R7] ARTS: *Isobutylene's production and use in the production of polymers, antioxidants and high octane aviation fuel(1,2) may result in its release to the environment through various waste streams(SRC). It is also released to the environment from the exhaust of automobiles and other gas powered engines(3-5). [R35] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 450(SRC), determined from a log Kow of 2.34(2) and a regression-derived equation(3), indicates that isobutylene is expected to have moderate mobility in soil(SRC). Volatilization of isobutylene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 0.218 atm-cu m/mole(4). The potential for volatilization of isobutylene from dry soil surfaces may exist based upon a vapor pressure of 2308 mm Hg(5). Isobutylene was degraded to 1,2-epoxy butane by pure cultures of methanotrophic bacteria(6), suggesting biodegradation may occur under anaerobic conditions(SRC). [R36] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 450(SRC), determined from a log Kow of 2.34(2) and a regression-derived equation(3), indicates that isobutylene is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected to occur rapidly(3) based upon the Henry's Law constant of 0.218 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 2 and 71 hours, respectively(SRC). According to a classification scheme(5), an estimated BCF of 35(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). Isobutylene was degraded to 1,2-epoxy butane by pure cultures of methanotrophic bacteria(6), suggesting biodegradation may occur in anaerobic water(SRC). [R37] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), isobutylene, which has a vapor pressure of 2,308 mm Hg at 25 deg C(2), is expected to exist solely as a gas in the ambient atmosphere. Gas-phase isobutylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7.5 hours(SRC), calculated from its rate constant of 5.14X10-11 cu cm/molecule-sec at 25 deg C(3). The rate constant for the gas-phase reaction of isobutylene with ozone has been measured as 1.2X10-17 cu cm/molecule-sec at 25 deg C(4). This corresponds to an atmospheric half-life of about 23 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(4). [R38] BIOD: *Isobutylene was degraded to 1,2-epoxybutane by pure cultures of methanotrophic bacteria(1). [R39] ABIO: *The rate constant for the gas-phase reaction of isobutylene with photochemically-produced hydroxyl radicals has been measured as 5.14X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 7.5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the gas-phase reaction of isobutylene with ozone has been measured as 1.2X10-17 cu cm/molecule-sec at 25 deg C(2). This corresponds to an atmospheric half-life of about 23 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). Isobutylene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). [R40] BIOC: *An estimated BCF of 35 was calculated for isobutylene(SRC), using a log Kow of 2.34(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). [R41] KOC: *The Koc of isobutylene is estimated as 450(SRC), using a log Kow of 2.34(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that isobutylene is expected to have moderate mobility in soil(SRC). [R42] VWS: *The Henry's Law constant for isobutylene is 0.218 atm-cu m/mole(1). This Henry's Law constant indicates that isobutylene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 2 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 71 hours(SRC). Isobutylene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of isobutylene from dry soil surfaces may exist based upon a vapor pressure of 2,308 mm Hg(3). [R43] EFFL: *Isobutylene has been identified, not quantified, in the exhaust of automobiles(1-3). Isobutylene was detected at a concn of 60 and 28 ug/cu m in the emissions of automobiles(4). Isobutylene was detected at concns of 0.14 ppb (87 octane) and 0.13 ppb (89 octane) in automobile exhaust(5). Isobutylene was identified, not quantified, in the effluent of a plastic incineration plant in Japan(6). [R44] ATMC: *URBAN/SUBURBAN: Isobutylene was detected in Porto Alegre, Brazil at concns of 1-15 ug/cu m(1) and in Los Angeles, CA at 2.35 ug/cu m(2). Butenes, including isobutylene, were detected at the following locations in Sweden: outdoor park (0.09 ug/cu m), city streets (0.7-7.7 ug/cu m) and a parking garage (7.7 ug/cu m)(3). Combined isomers of isobutylene and 1-butene were detected in Washington DC at a mean concn of 0.67 ppb and a max concn of 2.25 ppb in 1991(4). Isobutylene was detected at street levels in London, England at a mean concn of 19 ppb(5). Isobutylene was detected in the atmosphere of London, England at concns of 132-1,506 parts per trillion at altitudes between 453 and 758 m(5). Isobutylene was identified, not quantified, in Chicago, IL, Raleigh, NC, Atlanta, GA and Budapest, Hungary(6). Combined isomers of isobutylene and 1-butene were detected in urban areas around Vienna, Austria at mean concns of 9.6 and 10.1 ppb at 2 different sampling locations(7). Isobutylene was detected at a mean concn of 1.2 ppb in urban air samples in England(8). [R45] *SOURCE DOMINATED: Isobutylene was detected in the Caldecott Tunnel, CA at a concn of 0.058 g/L of August 1994 when vehicles were using low oxygenated gasoline and 0.089 g/l in October 1994 when vehicles were using high oxygenated gasoline(1). Combined isomers of isobutylene and 1-butene were detected in the Lincoln Tunnel, NY at a mean concn of 344.9 ppb in 1970 and 89.1 ppb in 1982(2). [R46] *RURAL/REMOTE: Isobutylene was detected at a mean concn of 2 ppb in rural air samples in England and 8.5 ppb in polluted rural air in England(1). [R47] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,861 workers (982 of these are female) are potentially exposed to isobutylene in the US(1). Occupational exposure to isobutylene may occur through inhalation and dermal contact with this compound at workplaces where isobutylene is produced or used(SRC). The general population may be exposed to isobutylene via inhalation of ambient air(SRC). [R48] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Isobutylene is produced, as an intermediate or a final product, by process units covered under this subpart. [R49] FDA: *Isobutylene is an indirect food additive for use only as a component of adhesives. [R50] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SIMPLE, RAPID AND SENSITIVE COLORIMETRIC METHOD WAS DEVELOPED TO DETERMINE ISOBUTYLENE IN AIR. [R51] *GAS CHROMATOGRAPHY WAS USED TO STUDY DISTRIBUTION OF 6 VOLATILE HYDROCARBONS IN MOUSE AND RAT BODY TISSUES. [R52] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Isobutene in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 487 (1998) NIH Publication No. 99-3977 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 879 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 652 R4: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 689 R5: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 34 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V15 412 R7: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 R8: Chem and Engineering News 71 (15): 11 (4/12/93) R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-289 R10: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 9 R11: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-464 R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 355 R14: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 750 R15: Yaws CL; Handbook of Vapor Pressure Vol 1 C1-C4 Compounds. Houston, TX: Gulf Pub Co (1994) R16: Wasik SP, Tsang W; J Phys Chem 74: 2970-6 (1970) R17: Atkinson R; Journal of Physical And Chemical Reference Data. Monograph No 1 (1989) R18: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-115 R19: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1952 R20: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 841 R21: 49 CFR 171.2 (7/1/96) R22: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. R23: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.2070 (1988) R24: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R25: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1204 R26: Cornet M et al; Chem Res Toxicol 8 (7): 987-92 (1995) R27: Cornet M, Rogiers V; Crit Rev Toxicol 27 (3): 223-32 (1997) R28: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R29: DHHS/NTP; Toxicology and Carcinogenesis Studies of Isobutene in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 487 (1998) NIH Publication No. 99-3977 R30: Cornet M et al; Arch Toxicol 70 (1): 64-7 (1995) R31: FRANK H ET AL; TOXICOL APPL PHARMACOL 56 (3): 337 (1980) R32: Cornet M et al; Mech Ageing Dev 74 (1-2): 103-15 (1994) R33: Henderson RF et al; Toxicol Appl Pharmacol 123 (1): 50-61 (1993) R34: SHUGAEV BB; FARMAKOL TOKSIKOL (MOSCOW) 30 (1): 102 (1967) R35: (1) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p. 879 (1996) (2) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Reinhold Co., p. 652 (1993) (3) Williams RL et al; Air Waste Manage Assoc 40: 747-56 (1990) (4) Stump FD et al; Anal Chem 57: 2629-34 (1992) (5) Schuetzle D et al; Environ Health Perspect 4: 3-12 (1994) R36: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Wasik SP, Tsang W; J Phys Chem 74: 2970-76 (1970) (5) Yaws CL; Handbook of Vapor Pressure. Vol 1 C1-C4 Compounds. Houston, TX: Gulf Publ Co (1994) (6) Patel RW et al; in Developments in Industrial Microbiology, Vol 23: 187-205 (1982) R37: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Wasik SP, Tsang W; J Phys Chem 74: 2970-76 (1970) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Patel RW et al; in Developments in Industrial Microbiology, Vol 23: 187-205 (1982) R38: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yaws CL; Handbook of Vapor Pressure. Vol 1 C1-C4 Compounds. Houston, TX: Gulf Publ Co (1994) (3) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (4) Atkinson R, Carter WPL; Chem Rev 84: 437-470 (1984) R39: (1) Patel RW et al; in Developments in Industrial Microbiology, Vol 23: 187-205 (1982) R40: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-470 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R41: (1) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R42: (1) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R43: (1) Wasik SP, Tsang W; J Phys Chem 74: 2970-76 (1970) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Yaws CL; Handbook of Vapor Pressure. Vol 1 C1-C4 Compounds. Houston, TX: Gulf Publ Co (1994) R44: (1) Williams RL et al; Air Waste Manage Assoc 40: 747-56 (1990) (2) Stump FD et al; Anal Chem 57: 2629-34 (1992) (3) Schuetzle D et al; Environ Health Perspect 4: 3-12 (1994) (4) Sawyer RF; Environ Health Perspect 101(Suppl 6): 5-12 (1994) (5) Conner TL et al; J Air Waste Manage Assoc 45: 383-94 (1995) (6) Nishikawa H et al; Chemosphere 25: 1953-60 (1992) R45: (1) Grossjean E et al; Environ Sci Technol 32: 2061-69 (1998) (2) Fraser MP et al; Environ Sci Technol 31: 2356-67 (1997) (3) Loefgren L, Petersson G; Sci Total Environ 116: 195-201 (1992) (4) Hendler AH, Crow WL; Proc Ann Air Waste Manage Assoc 28: 1-17 (1992) (5) Blake NJ et al; J Geophys Res 98: 2851-64 (1993) (6) Haszpra L, Szilagyi I; Atmos Environ 28: 2609-14 (1994) (7) Lanzerstorfer CH, Puxbaum H; Wat Air Soil Pollut 51: 345-55 (1990) (8) Colbeck I, Harrison RM; Atmos Environ 19: 1899-1904 (1985) R46: (1) Kirschstetter TW et al; Environ Sci Technol 30: 661-70 (1996) (2) Lonneman WA et al; Environ Sci Technol 20: 790-96 (1986) R47: (1) Colbeck I, Harrison RM; Atmos Environ 19: 1899-1904 (1985) R48: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R49: 40 CFR 60.489 (7/1/98) R50: 21 CFR 175.105 (4/1/98) R51: LIPINA TG; GIG TR PROF ZABOL 17 (1): 45 (1973) R52: SHUGAEV BB; FARMAKOL TOKSIKOL (MOSCOW) 31 (3): 360 (1968) RS: 38 Record 75 of 1119 in HSDB (through 2003/06) AN: 617 UD: 200303 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALLYL-ISOTHIOCYANATE- SY: *AITC-; *ALLYL-ISOSULFOCYANATE-; *ALLYL-MUSTARD-OIL-; *Allylsenevol-; *ALLYLSENFOEL- (GERMAN); *Carbospol-; +Pesticide-Code:-004901.-; *FEMA-NUMBER-2034-; *ISOTHIOCYANATE-D'ALLYLE- (FRENCH); *3-ISOTHIOCYANATO-1-PROPENE-; *ISOTHIOCYANIC-ACID,-ALLYL-ESTER-; *MUSTARD-OIL-; *NCI-C50464-; *OIL-OF-MUSTARD,-ARTIFICIAL-; *OLEUM-SINAPIS-; *OLEUM-SINAPIS-VOLATILE-; *1-PROPENE,-3-ISOTHIOCYANATO-; *PROPENE,-3-ISOTHIOCYANATO-; *2-PROPENYL-ISOTHIOCYANATE-; *REDSKIN-; *SENFOEL-; *SENF-OEL- (GERMAN); *Synthetic-mustard-oil-; *VOLATILE-MUSTARD-OIL-; *VOLATILE-OIL-OF-MUSTARD- RN: 57-06-7 MF: *C4-H5-N-S SHPN: UN 1545; Allyl isothiocyanate, stabilized IMO 6.1; Allyl isothiocyanate, stabilized MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ALLYL AMINE AND CARBON DISULFIDE IN THE PRESENCE OF MERCURIC CHLORIDE [R1] *BY DISTILLATION OF SODIUM THIOCYANATE AND ALLYL CHLORIDE. [R2] *ISOLATED FROM BRASSICA NIGRA (L) KOCH, CRUCIFERAE (BLACK MUSTARD SEED), OR PREPD FROM ALLYL IODIDE AND POTASSIUM THIOCYANATE [R3] *Prepared by reaction of allyl bromide with ammonium thiocyanate followed by thermal rearrangement. [R4] *Can be prepared by reacting allyl chloride with alkaline earth or alkali rhodanides. [R5] IMP: *In 1972, a food grade was available with the following specifications: 93% min purity; arsenic, 0.0003% max; lead, 0.001% max. It is also required to pass a test for phenol content [R6, p. V36 56] FORM: *GRADES: TECHNICAL. FCC; 93% purity minimum; In 1972 a food grade was available, 93% purity minimum [R6, p. V36 56] MFS: *Quest International, 400 International Drive, Mount Olive, NJ 07828, (201) 691-7100 [R7] OMIN: *THE SEED OF SINAPSIS NIGRA CONTAINS THE GLYCOSIDE, SINIGRIN, WHICH, IN THE PRESENCE OF THE ENZYME MYROSIN, DECOMPOSES TO YIELD ALLYL ISOTHIOCYANATE (VOLATILE OIL OF MUSTARD)... [R8] USE: +For Allyl isothiocyanate (USEPA/OPP Pesticide Code: 004901) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R9] *FLAVORING AGENT; DENATURANT FOR ALCOHOL [R1] *In the manuf /of/ war gas [R3] *A COUNTER-IRRITANT IN MEDICINE; A FUNGICIDE, AN INSECTICIDE FUMIGANT AND A REPELLENT FOR CATS AND DOGS; IN SOME MODEL AIRPLANE CEMENTS TO DETER GLUE SNIFFERS; EXTERNALLY AS A RUBEFACIENT [R10, p. II-352] *An attractant for the cabbage maggot fly Hylemya brassicae. [R11] *REPORTED USE: NON-ALCOHOLIC BEVERAGES 0.02-0.50 PPM; ICE CREAM, ICES, ETC 0.50 PPM; CANDY 0.50 PPM; BAKED GOODS 5.2 PPM; CONDIMENTS 52 PPM; MEATS 87 PPM; SYRUPS 10-88 PPM [R2] *Synthetic flavoring substances and adjuvants: allyl isothiocyanate (artificial mustard oil): overpowering mustard-like odor with stinging taste; spice blends; mustard vegetable flavors, meat-horseradish. [R12] CPAT: *(FLAVORING GRADE) 96% AS A FLAVORING AGENT IN MEATS; 2% IN VARIOUS CONDIMENTS; 1% IN BAKED GOODS; 1% IN PICKLES, NON-ALCOHOLIC BEVERAGES, FROZEN MILK DESSERTS, AND IN OTHER MISC APPLICATIONS (EST) (1976) [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R1] *(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS TO PALE YELLOW, OILY LIQUID [R13] ODOR: *VERY PUNGENT [R14, 45]; *Mustard odor [R5] TAST: *ACRID TASTE [R14, 45] BP: *148-154 DEG C [R14, 45] MP: *-80 DEG C [R15] MW: *99.15 [R14, 45] DEN: *1.013-1.020 [R14, 45] SOL: *SLIGHTLY SOL IN WATER; MISCIBLE WITH ALCOHOL AND MOST ORGANIC SOLVENTS; SOLUBILITY IN 70% ALCOHOL: 1 ML DISSOLVES IN 10 ML [R14, 45]; *SOLUBILITY IN ALCOHOL: 1:8 IN 80% ETHANOL; COMPLETELY MISCIBLE WITH ETHER, CHLOROFORM, AND BENZENE [R2]; *SOL IN CARBON DISULFIDE [R13]; +water solubility = 2,000 mg/l @ 20 deg C [R16] SPEC: *INDEX OF REFRACTION: 1.5268-1.5280 @ 20 DEG C/D; OPTICALLY INACTIVE [R14, 452]; *MAX ABSORPTION (CYCLOHEXANE): 250 NM (LOG E= 3.00); 275 NM (LOG E= 1.65) SHOULDER; SADTLER REFERENCE NUMBER: 1603 (IR, PRISM); 8182 (IR, GRATING); 459 (UV); 3155 (NMR) [R17]; *IR: 2:464D (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R18]; *NMR: 3:177C (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R18] VAPD: *3.41 (AIR= 1) [R19] VAP: +0.493 kPa at 20 deg C (3.7 mm Hg @ 30 deg C) [R20] OCPP: *1 MM HG @ -2 DEG C [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapors may travel to source of ignition and flash back. Substance will react with water (some violently) releasing flammable, toxic or corrosive gases and runoff. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated or if contaminated with water. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +Health: TOXIC; inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns, or death. Bromoacetates and chloroacetates are extremely irritating/lachrymators. Reaction with water or moist air will release toxic, corrosive or flammable gases. Reaction with water may generate much heat which will increase the concentration of fumes in the air. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +Fire: Note: Most foams will react with the material and release corrosive/toxic gases. Small fires: CO2, dry chemical, dry sand, alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. FOR CHLOROSILANES, DO NOT USE WATER; use AFFF alcohol-resistant medium expansion foam. Move containers from fire area if you can do it without risk. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. A vapor suppressing foam may be used to reduce vapors. FOR CHLOROSILANES, use AFFF alcohol-resistant medium expansion foam to reduce vapors. DO NOT GET WATER on spilled substance or inside containers. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Prevent entry into waterways, sewers, basements or confined areas. Small spills: Cover with DRY earth, DRY sand, or other non-combustible material followed with plastic sheet to minimize spreading or contact with rain. Use clean non-sparking tools to collect material and place it into loosely covered plastic containers for later disposal. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Allyl isothiocyanate, stabilized; Allyl isothiocyanate, inhibited/ [R22] FPOT: *Moderate fire risk. [R13] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, incl self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms and waist should be provided. No skin surface should be exposed. [R23] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R23] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R23] FLPT: +115 DEG F (46 DEG C) (CLOSED CUP) [R23] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEMICAL... [R24] REAC: *DANGEROUS...ON CONTACT WITH ACID OR ACID FUMES, IT EMITS HIGHLY TOXIC FUMES OF CYANIDES; CAN REACT WITH OXIDIZING MATERIALS. [R24] *A routine preparation by interaction of allyl chloride and sodium thiocyanate in an autoclave at 5.5 bar exploded violently at the end of the reaction. Peroxides were not present or involved and no other cause could be found, but extensive decomposition occurred when allyl isothiocyanate was heated to 250 deg C in glass ampoules. [R25] DCMP: +When heated to decomp ... emits highly toxic fumes of cyanides. [R24] ODRT: *8X10-3 PPM [R26] SERI: *Allyl isothiocyanate is a liquid having a very pungent irritating odor. ... The vapor is lacrimogenic and can cause keratitis which interferes with vision. [R27] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *...SUBSTITUTION OF LESS IRRITATING SUBSTANCES...REDESIGN OF OPERATIONS...PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, WORK CLOTHING AND STORAGE FACILITIES, PROTECTIVE CLOTHING, AND BARRIER CREAMS. MEDICAL CONTROL... [R28] SSL: *TENDS TO DARKEN ON AGING [R2] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R29] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R30] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R31] STRG: *Containers: 5 lb bottles. [R13] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of allyl isothiocyanate. There is limited evidence in experimental animals for the carcinogenicity of allyl isothiocyanate. Overall evaluation: Allyl isothiocyanate is not classifiable as to its carcinogenicity to humans (Group 3). [R32] HTOX: *THE VAPOR IS LACRIMOGENIC AND CAN CAUSE KERATITIS WHICH INTERFERES WITH VISION. [R27] *A VIOLENT IRRITANT UNLESS DILUTED. ... AQUEOUS SUSPENSIONS ARE MORE IRRITATING THAN OIL SOLUTIONS AND MAY PRODUCE BLISTERS. [R10, p. II-352] *TOXIC BY INGESTION, INHALATION AND SKIN CONTACT. [R13] *Mustard oil did not induce chromosomal aberration in cultured human embryonic lung cells ... . [R33] NTOX: *ACUTE ORAL LD50 OF 10% SOLUTION IN CORN OIL IS 339 MG/KG IN RATS. DEATH OCCURRED BETWEEN 4 HR TO 15 DAYS, AND THE ANIMALS HAD A SCRAWNY APPEARANCE WITH ROUGH FUR AND A PORPHYRIN-LIKE DEPOSIT AROUND THE EYES AND NOSE. [R10, p. II-352] *MUSTARD SEED OIL AND ALLYL ISOTHIOCYANATE CAUSED INCREASES IN ACTIVITIES OF LIVER SUCCINATE DEHYDROGENASE AND LACTATE DEHYDROGENASE OVER CONTROLS WHEN FED AT LEVEL OF 0.3% TO MALE SPRAGUE-DAWLEY RATS. [R34] *Allyl isothiocyanate induces chromosomal aberrations in root-tip cells of Allium cepa. [R33] *Allyl isothiocyanate (purity, 95%) induces mutation in Escherichia coli WP67; this activity requires the presence of an exogenous metabolic system; rodent, goat and monkey liver were tested. [R33] *The correlation of teratogenicity with molecular structure of 16 related chemicals /was studied/. ...Allylisothiocyanate /was not teratogenic to rats on day 12 or 13 at a dosage of 60 mg/kg./ [R35] *Sinapis alba and Sinapis nigra contain the glycosides sinigrin and sinalbin, respectively, which on hydrolysis give rise to the mustard oils isopropyl isothiocyanate and allyl isothiocyanate. Affected animals develop clinical signs including acute gastroenteritis, colic, frothing around the mouth and nose, grunting and diarrhea. Post-mortem examination reveals acute inflammation of the stomach, intestines and kidneys. [R36] *Mustard oil, which contains > 90% allyl isothiocyanate, was tested in a two stage mouse skin assay. Three control groups of 12-16 'S' strain mice (actual strain, age and sex unspecified) received 0.3 ml of 0.1-0.15% 7,12-dimethylbenz(a)anthracene on the skin of the back followed by no treatment (two groups) or 21 days later by twice weekly applications for 12 weeks and weekly applications for 15 weeks of acetone. A fourth group of 16 mice received an initial skin application of 0.3 ml of 0.1% 7,12-dimethylbenz(a)anthracene followed 39 days later by applications of a 3-4% solution of mustard oil in acetone weekly for 20 weeks. The incidence of skin pappillomas among animals surviving to the end of the experiment was 4/21, 1/12 and 1/16 in the combined 7,12-dimethylbenz(a)anthracene control groups with no secondary treatment, in controls receiving 7,12-dimethylbenz(a)anthracene followed by acetone and in treated mice receiving 7,12-dimtheylbenz(a)anthracene and mustard oil, respectively. [R37] *A reduction in blood clotting and prothrombin times, an increase in total plasma and liver triglycerides and cholesterol, and a decrease in D-amino acid oxidase and xanthine oxidase were reported after administration to rats of 0.1% allyl isothiocyanate in the diet for 30 days. [R38] *The teratogenic potential of allyl isothiocyanate was evaluated in mice, rats, hamsters and rabbits. Groups of 23-25 CD-1 mice were treated with 0, 0.3, 6.0, or 28.0 mg/kg body weight allyl isothiocyanate (purity unspecified) in corn oil by oral gavage on gestation days 6-15. Fetuses were examined for malformations on day 20. Groups of 25-27 golden hamsters received doses of 0, 0.2, 1.1, 5.1, or 23.8 mg/kg body weight in corn oil by oral intubation on days 6-10 of gestation. Fetuses were examined on day 14 for malformations. Groups of 11-14 Dutch-belted rabbits received doses of 0, 0.123, 0.6, 2.8, or 12.3 mg/kg body weight in corn oil by oral intubation on days 6-18 of gestation. Fetuses were delivered by caesarean section on day 29. No evidence of maternal toxicity or treatment related malformation was observed in any species. In mice, there appeared to be an increase in dead and resorbed fetuses in the high dose group, although no statistical analysis of the data was presented (at the highest dose level, 38/276 implantation sites were dead or resorbed compared to 15/264 in the control group, and the average number of live pups per litter was 9.92 compared to 11.3). [R38] *Groups of pregnant Wistar rats (29 animals in the control group, five in the low dose and unstated for the high dose groups) were given 0, 60, or 120 mg/kg body weight of allyl isothiocyanate (purity unspecified) in corn oil by oral intubation on days 12 or 13 of gestation as part of an effort to determine structure activity relationships for chemicals similar to the teratogen ethylenethiourea. Despite the occurrence of maternal toxicity at the high dose, no adverse effect on the fetuses was found. [R38] *Two groups of six and eight pregnant Holtzman rats received 50 or 100 mg/kg body weight allyl isothiocyanate (purity unspecified), respectively, by subcutaneous administration (the vehicle was either propylene glycol or distilled water) on days 8 and 9 of gestation. A group of 54 pregnant rats served as controls. Maternal toxicity was evident with the high dose. Fetuses were examined on day 20; those in the low dose group weighed significantly less than controls, while an increase incidence of resorptions was seen in the high dose group. No treatment related malformation was observed. [R38] *Allyl isothiocyanate (purity unspecified) was mutagenic to Salmonella typhimurium TA98 and TA100 using the preincubation procedure; the presence of an exogenous metabolic system (S9) from the livers of polychlorinated biphenyl-induced rats had no effect on this activity. However, addition of an exogenous metabolic system was reported to abolish a weak response in strain TA100 following a modified treatment procedure with allyl isothiocycnate (purity, 99.8%). [R33] *Mustard oil did not induce chromosomal aberration in ... the bone marrow of rats given up to 100 mg/kg body weight. [R33] *Mustard oil, which is reported to contain > 90% allyl isothiocyanate, was reported not be induce "genetic effects" in Saccharomyces cerevisiae in a host mediated assay with mice treated with up to 130 mg/kg body weight. [R33] *The induction by mustard oil of sex lined lethal mutations has been reported in Drosophila melanogaster. It did not induce dominant lethal mutations in rats at levels of up to 100 mg/kg body weight. [R33] *Chemicals were tested for their mutagenic potential in the L5178Y tk + or - mouse lymphoma cell forward mutation assay, using procedures based upon those described by Clive and Spector Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine, 3 ug/ml. The chemicals were tested at least twice. Significant responses were obtained with allyl isothiocyanate. [R39] NTXV: *LD50 Rat oral 339 mg/kg (10% solution in corn oil); [R10, p. II--352] ETXV: *LC50 Pimephales promelas (fathead minnow) 85.6 ug/l/96 hr, flow-through bioassaywith measured concentrations, 25.1 deg C, dissolved oxygen 6.9 mg/l, and pH 7.8; [R40] NTP: +A 2 yr carcinogenesis bioassay of food-grade allyl isothiocyanate (greater than 93% purity) ... was conducted by administering 12 or 25 mg/kg allyl isothiocyanate in corn oil five times per wk by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 wk. Groups of 50 rats and 50 mice of each sex received corn oil alone and served as vehicle controls. ... Under the conditions of this bioassay, allyl isothiocyanate was carcinogenic for male F344/N rats, causing transitional cell papillomas in the urinary bladder. Evidence for associating allyl isothiocyanate with subcutaneous fibrosarcomas in female F344/N rats was equivocal. Allyl isothiocyanate was not carcinogenic for B6C3F1 mice of either sex. [R41] ADE: *Fischer 344 rats and B6C3F mice were used to study the tissue distribution ... of allyl isothiocyanate (purity, > 98%). When measured 15 min after intravenous injection of 25 mg/kg body weight, allyl isothiocyanate derived radioactivity was found at the highest concentration in the urinary bladder of male rats and mice and in the kidneys of male mice; the bladders of males containing five to ten times more radioactivity than the bladders of females. After oral and intravenous administration, most of the radioactivity was cleared through urine (70-80%), while exhaled air (13-15%) and feces (3-5%) contained less. [R33] METB: *Fischer 344 rats and B6C3F mice were used to study the ... metabolism of allyl isothiocyanate (purity, > 98%). ... The major metabolite detected in urine was N-acetyl-S-(N-allylthiocarbamoyl)-L-cysteine. [R33] ACTN: *The irritating and lacrimogenic effects of allyl isothiocyanate have been considered probably related to the reactivity of this compound with sulfhydryl groups of nerve endings ... . [R27] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *IN THE ESSENTIAL OIL FROM SEEDS OF BRASSICA NIGRA KOCH, BRASSICA JUNCEA HOOK AND THOMS, AND THLASPI ARVENSE; IN THE ESSENTIAL OIL FROM ROOTS OF COCHLEARIA ARMORACIA; IN THE SEEDS AND ROOTS OF ALLIARIA OFFICINALIS; IN ONION JUICE; AND IN SEEDS OF VARIOUS CRUCIFERAE. [R2] FOOD: *REPORTED USE: NON-ALCOHOLIC BEVERAGES 0.02-0.50 PPM; ICE CREAM, ICES, ETC 0.50 PPM; CANDY 0.50 PPM; BAKED GOODS 5.2 PPM; CONDIMENTS 52 PPM; MEATS 87 PPM; SYRUPS 10-88 PPM [R2] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: +Workplace Environmental Exposure Level (WEEL): Short-term Exposure Limit (STEL) 1 ppm, 15 min, skin. [R42] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Allyl isothiocyanate is found on List D. Case No: 4097; Pesticide type: Insecticide, fungicide, herbicide, rodenticide, antimicrobial; Case Status: RED Approved 01/94; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document .; Active ingredient (AI): Allyl isothiocyanate; Data Call-in (DCI) Date(s): 02/22/94, 10/13/95; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R43] FDA: *Allyl isothiocyanate is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. [R44] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION OF VOLATILE OIL IN MUSTARD SEED BY (A) GAS CHROMATOGRAPHIC METHOD AND (B) TITRATION METHOD. [R45] *COLORIMETRIC METHOD WAS DEVELOPED FOR DETERMINING ALLYLISOTHIOCYANATE IN PURE SAMPLE. [R46] *Spectrophotometry Detection limit 2.5 ug/ml; GC/FID Detection limit not given; Spectrophotometry (600 nm) Detection limit 20 ug/ml; HPLC/UV Detection limit not given; GC/MS Detection limit not given; GC/FID Detection limit not given; Proton magnetic resonance (PMR) Detection limit not given [R6, p. V36 69] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Allyl Isothiocyanate in F344/N Rats and B6C3F1 Mice (Gavage Study) Technical Report Series No. 234 (1982) NIH Publication No. 83-1790 SO: R1: SRI R2: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 19 R3: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 50 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 2:100 R5: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 154 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R7: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 699 R8: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 211 R9: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Allyl isothiocyanate (57-06-7). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of October 24, 2002. R10: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R11: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA14 311 R12: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 257 R13: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 36 R14: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. R15: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 64th ed. Boca Raton, Florida: CRC Press Inc., 1983-84.,p. C-85 R16: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-356 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 56 R19: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 325M-147 R20: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. 232 R21: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 180 R22: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-155 R23: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-73 R24: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 168 R25: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 432 R26: Fenaroli's Handbook of Flavor Ingredients. Volume 1. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 188 R27: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 70 R28: Sax, N.I. Dangerous Properties of Industrial Materials 3rd. ed. New York: Van Nostrand Reinhold Co., 1968. 387 R29: 49 CFR 171.2 (7/1/96) R30: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 94 R31: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6054 (1988) R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 73 45 (1999) R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 62 (1985) R34: MUZTAR AJ ET AL; NUTR REP INT 19 (6): 829-34 (1979) R35: Shepard, T. H. Catalog of Teratogenic Agents. 3rd ed. Baltimore, MD.: Johns Hopkins University Press, 1980. 141 R36: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 220 R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 60 (1985) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 61 (1985) R39: McGregor DB et al; Environ Mol Mutagen 12 (1): 85-154 (1988) R40: Geiger D.L., D.J. Call, L.T. Brooke. (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales- Promelas). Vol. V. Superior WI: University of Wisconsin-Superior, 1990.66 R41: DHHS/NTP; Carcinogenesis Bioassay of Allyl Isothiocyanate in F344/N Rats and B6C3F1 Mice (Gavage Study) Technical Report Series No. 234 (1982) NIH Publication No. 83-1790 R42: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R43: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.343 (Spring, 1998) EPA 738-R-98-002 R44: 21 CFR 172.515 (4/1/93) R45: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/499 30.026 R46: DEVANI MB ET AL; COLORIMETRY OF ALLYLISOTHIOCYNATE IN MUSTARD SEED; J ASSOC OFF ANAL CHEM 61 (1): 167-8 (1978) RS: 33 Record 76 of 1119 in HSDB (through 2003/06) AN: 619 UD: 200302 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ISOPHORONE- SY: *AI3-00046-; *Caswell-no-506-; *2-CYCLOHEXEN-1-ONE,-3,5,5-TRIMETHYL-; *Pesticide-Code:-047401-; *EPA-Pesticide-Chemical-Code-047401-; *ISOACETOPHORONE-; *ISOFORON-; *ISOFORONE- (ITALIAN); *Isooctopherone-; *ISOPHORON-; *ALPHA-ISOPHORON-; *ALPHA-ISOPHORONE-; *IZOFORON- (POLISH); *NCI-C55618-; *1,1,3-TRIMETHYL-3-CYCLOHEXENE-5-ONE-; *3,5,5-TRIMETHYL-2-CYCLOHEXENE-1-ONE-; *3,5,5-TRIMETHYL-2-CYCLOHEXENONE-; *3,5,5-TRIMETHYL-2-CYCLOHEXEN-1-ONE-; *3,5,5-TRIMETHYL-2-CYCLOHEXEN-1-ON- (GERMAN, DUTCH); *3,5,5-TRIMETIL-2-CICLOESEN-1-ONE- (ITALIAN) RN: 78-59-1 MF: *C9-H14-O STCC: 49 152 78; Isophorone (combustible liquid, not otherwise specified) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ACETONE ... IS PASSED OVER CALCIUM OXIDE, HYDROXIDE OR CARBIDE OR THEIR MIXT AT 350 DEG C AND ATMOSPHERIC PRESSURE, OR IT IS HEATED @ 200-250 DEG C UNDER PRESSURE. ISOPHORONE IS SEPARATED FROM RESULTANT PRODUCTS BY DISTILLATION. [R1, 1763] *Produced by the condensation of acetone in the liquid phase at ca. 200 deg C and 3.6 Mpa in the presence of an aqueous potassium hydroxide solution (ca. 1%). The process steps condensation, separation of unreacted acetone, and hydrolysis of byproducts can be carried out in a single reactor. Reaction in the gas phase at 350 deg C over calcium-aluminum oxide has also been reported. [R2] *Review of preparation and purification: G.S. Salvapati, M. Janardanarao, J. Sci. Ind. Res. 42, 261-267 (1983). [R3] IMP: *It usually contains 1-3% of the isomeric beta-isophorone (3,5,5-trimethyl-3-cyclohexen-1-one). [R2] *COMMERCIAL ISOPHORONE USUALLY CONTAINS SOME UNCONJUGATED ISOMER (UP TO 5%) AND SMALL AMOUNTS (< 1%) OF XYLITONE [R4, p. 13(81) 920] *Beta-isophorone 2-4%, mesitylene (1,3,5-trimethylbenzene) trace, mesityl oxide (2-methyl-2 pentene-4-one) trace, phorone (2,6-dimethyl-2, 5-heptadiene-4-one) trace, isoxylitones trace, water trace. [R5] FORM: *Purity: 98.0% by wt., min. [R6, 668] MFS: *Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817-0001, (203) 794-2000; Production site: Institute, WV 25103 [R7] OMIN: *It is the most powerful solvent for nitrocellulose and "Vinylite" resins. [R6, 6668] USE: *For Isophorone (USEPA/OPP Pesticide Code: 047401) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R8] *SOLVENT FOR LACQUERS AND PLASTICS [R9] *SOLVENT FOR MANY OILS, FATS, GUMS, RESINS, NITROCELLULOSE, AND VINYL-RESIN COPOLYMERS [R1, 1763] *CHEM INT FOR 3,3,5-TRIMETHYLCYCLOHEXANOL, and 3,5-XYLENOL; SPECIALTY SOLVENT [R10] *In solvent mixtures for finishes, for polyvinyl and nitrocellulose resins, stoving lacquers [R11] *Solvent in some printing inks, paints, lacquers, and adhesives [R3] *Intermediate for alcohols; raw material for 3,5-dimethylaniline [R12] *Pesticide manufacture /Former use/ [R12] *Leveling agent (textile printing) [R13] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 4.54X10+5 G [R10] *(1976) GREATER THAN 2.27X10+6 G [R10] *Worldwide production capacity for isophorone currently stands at ca. 50,000 tons annually. [R2] U.S. IMPORTS: *(1984) 9.81X10+8 g [R14] *(1986) 7.44X10+5 lb [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Water-white liquid [R11]; *Colorless to white-liquid. [R16]; *Clear liquid [R3] ODOR: *Peppermint-like odor [R3]; *Camphor-like [R17] BP: *215.32 deg C [R18] MP: *-8.1 deg C [R18] MW: *138.21 [R18] DEN: *0.9255 @ 20 deg C [R18] HTC: *-16,170 BTU/lb= -8,980 cal/g= -376x10+5 J/kg [R17] HTV: *43.4 kJ/mol [R19] OWPC: *log Kow = 1.70 [R20] SOL: *Soluble in ether, acetone, alcohol [R3]; *Has high solvent power for vinyl resins, cellulose esters, ether, and many substances soluble with difficulty in other solvents. [R11]; *In water, 12,000 mg/l @ 25 deg C. [R4, p. V21(1983) 385] SPEC: *UV max (MeOH): 235.5 nm (e 14300) [R3]; *Index of refraction: 1.4766 @ 18 deg C/D [R18]; *MAXIMUM ABSORPTION (ALCOHOL): 236 NM (LOG E= 4.09); SADTLER REF NUMBER: 122 (IR, PRISM) [R21]; *Intense mass spectral peaks: 82 m/z (100%), 138 m/z (17%), 54 m/z (13%), 41 m/z (13%) [R22]; *IR: 36 (Sadtler Research Laboratories IR Grating Collection) [R23]; *UV: 6-247 (Phillip et al., Organic Electronic Spectral Data, John Wiley and Sons, New York) [R24]; *NMR: 7311 (Sadtler Research Laboratories Spectral Collection) [R23]; *MASS: 57756 (NIST/EPA/MSDC Mass Spectral Database, 1990 version) [R24] SURF: *32 dyn/cm @ 20 deg C [R19] VAPD: *4.77 (Air= 1) [R25] VAP: *0.438 mm Hg @ 25 deg C [R26] VISC: *2.62 cP @ 20 deg C [R11] OCPP: *PERCENT IN SATURATED AIR: 0.06 [R1, 1723] *CONVERSION FACTORS: 1 PPM= 5.65 MG/CU M; 1 MG/L= 177 PPM [R27, 455] *Bulk density: 7.7 lb/gal @ 20 deg C [R11] *1 mg/cu m = 0.18 ppm; 1 ppm = 5.65 mg/cu m [R12] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flammable and explosive when exposed to heat or flame. [R28] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R29, p. 325-62] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R29, p. 325-62] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R29, p. 325-62] FLMT: *Lower 0.8% by vol; upper 3.8% [R30, 272] FLPT: *184 DEG F (84 DEG C) CLOSED CUP [R29, p. 325-62] AUTO: *860 deg F; 460 deg C [R29, p. 325-62] FIRP: *Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R30, 273] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R31] *Use water spray to keep fire exposed containers cool. Use flooding quantities of water as fog or spray, dry chemical, foam, or carbon dioxide. [R29, p. 49-80] EXPL: *Flammable and explosive when exposed to heat or flame. [R28] *lower explosive limit: 0.8% upper explosive limit: 3.8% [R28] REAC: *Incompatible with strong oxidizers [R32] *Oxidizers, strong alkalis, amines. [R16] ODRT: *Odor detection in air= 2.00 ppm. Purity not specified. [R33] *Odor recognition in air= 5.40 ppm. Purity not specified. [R33] *1 mg/cu m (odor low); 50 mg/cu m (odor high) [R34] SERI: *... HUMAN VOLUNTEERS EXPOSED AT 40, 85, 200 and 400 PPM ISOPHORONE EXPERIENCED EYE, NOSE, AND THROAT IRRITATION. [R35] *Irritates and burns eyes, nose, mucous membranes, respiratory tract. [R30, 273] *Isophorone vapor (25 ppm) produced irritation to the eyes, nose, and throats of unacclimatized volunteers. [R36, 1850] EQUP: *... Wear appropriate chemical protective gloves, boots and goggles. [R37] *Wear appropriate personal protective clothing to prevent skin contact. [R16] *Wear appropriate eye protection to prevent eye contact. [R16] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection [R16] *Recommendations for respirator selection. Max concn for use: 40 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any supplied-air respirator. May require eye protection. [R16] *Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. [R16] *Recommendations for respirator selection. Max concn for use: 200 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with a tight-fitting facepiece and organic vapor cartridge(s). May require eye protection. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R16] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R16] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R16] OPRM: *Irrigate eyes with water. Wash skin with abundant quantities of water. [R38] *Contact lenses should not be worn when working with this chemical. [R16] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R31] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R31] *The worker should immediately wash the skin when it becomes contaminated. [R16] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16] STRG: *store in a cool, dry, well-ventilated location. Outside or detached storage is preferred. Separate from oxidizing materials. [R29, p. 49-80] CLUP: *If leak or spill has not ignited, use water spray to disperse vapors and to protect men attempting to stop leak. [R30, 273] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surfact flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or comercial sorbents. [R31] *Environmental considerations: Water spill: Use natural barriers or oil spill control booms to limit spill travel. Remove trapped material with suction hoses. [R31] *Environmental considerations: Air spill: Apply water spray or mist ot knock kown vapors. [R31] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *The following wastewater treatment technologies have been investigated for Isophorone. Concentration process: Biological treatment. [R39] *The following wastewater treatment technologies have been investigated for Isophorone. Concentration process: Solvent extraction. [R40] *The following wastewater treatment technologies have been investigated for Isophorone. Concentration process: Activated carbon. [R41] *Spray into incinerator or burn in paper packaging. Additional flammable solvent may be added. [R30, 274] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: Isophorone is a colorless liquid with a peppermint like odor. It is soluble in water and miscible with most organic solvents. HUMAN EXPOSURE: The odor of isophorone can be detected at low concentrations. Eye, nose and throat irritation has been observed along with nausea, headache, dizziness, faintness and inebriation. Dermal and inhalation exposure may occur along with oral exposure from drinking water. ANIMAL STUDIES: Distribution studies in rats using (14)C isophorone showed that 93% of orally administered radioactivity appeared mainly in the urine and expired air within 24 hr. The tissues retaining the highest concentration after this period were the liver, kidney and preputial glands. The metabolites from oral administration of isophorone identified in rabbit urine resulted from the oxidation of the 3-methyl group, reduction of the keto group and hydrogenation of the double bond of the cyclohexene ring, and were eliminated as such or as glucuronide derivatives in the case of the alcohols. In animal studies, data indicate that isophorone is rapidly absorbed through the skin. Acute effects from dermal exposure in rats and rabbits ranged from mild erythema to scabs. Conjunctivitis and corneal damage have been reported following direct application to the eye or exposure to high concentrations of isophorone. In acute and short-term oral studies on rodents at high doses degenerative effects were seen in the liver and CNS depression and some deaths. In a 90 day oral study in beagle dogs (with limited numbers) no effects were seen at doses up to 150 mg/kg body weight per day. Isophorone does not induce gene mutations in bacteria, chromosomal aberrations in vitro, DNA repair in primary rat hepatocytes, or bone marrow micronuclei in mice. Positive effects were observed only in the absence of an exogenous metabolic system in L5178YTK +/- mouse mutagenesis assays as well as in a sister chromatid exchange assay. Isophorone induced morphological transformation in vitro in the absence of an exogenous metabolism system. It did not induce sex linked recessive lethal mutations in Drosophilia. In long term oral toxicity studies in mice and rats, male rats showed several lesions of the kidney, including nephropathy, tubular cell hyperplasia and low incidence of tubular cell adenomas and adenocarcinomas. Isophorone exposure was associated with some neoplastic lesions of the liver, and the integumentary and lymphoreticular systems of male mice, as well non-neoplastic liver and adrenal cortex lesions, but this was not observed in female mice. In /one/ long term inhalation study in rats and rabbits, irritation to eye and nasal mucosa, and lung and liver changes were observed. Very limited studies in rats and mice indicate that isophorone does not affect fertility nor does it cause developmental toxicity in experimental animals. The fact that central nervous system depression occurs in experimental animals could indicate a positive neurotoxic effect. Isophorone also elicited a positive effect in the behavioral despair swimming test. No data on terrestrial animals were available. The available data suggest that isophorone has a low toxicity to aquatic organisms. [R42] CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on no data in humans; limited evidence of carcinogenicity of one tumor type in one sex of one animal species as shown by an increase of preputial gland carcinomas in male rats. The apparent renal tubular cell tumor in the male rat is associated with alpha-2u-globulin, considered to be of questionable relevance to humans. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R43] *A3; Confirmed animal carcinogen with unknown relevance to humans. [R44] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . For contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Ketones and related compounds/ [R45, 237] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Ketones and related compounds/ [R45, p. 237-8] MEDS: *Consider the points of attack (respiratory system, skin) in preplacement and periodic physical examinations. [R32] HTOX: *... HUMAN VOLUNTEERS EXPOSED AT 40, 85, 200, and 400 PPM ISOPHORONE EXPERIENCED EYE, NOSE, AND THROAT IRRITATION. A FEW COMPLAINTS OF NAUSEA, HEADACHE, DIZZINESS, FAINTNESS, INEBRIATION, AND A FEELING OF SUFFOCATION RESULTED FROM 200 and 400 PPM. SYMPTOMS OF IRRITATION AND ... /CNS DEPRESSION/ ACTION DECREASED @ CONCNS OF 40 and 85 PPM. [R35] *In a sensory threshold study ... twelve unconditioned subjects of both sexes were exposed to the vapors of several industrial solvents including isophorone for 15 min periods in a 1,200 cu ft chamber. They found that exposure to isophorone at 25 ppm produced irritation of the eyes, nose, and throat, and that isophorone vapor was considered by the subjects to be the most irritating of all the ketonic solvents tested. The highest tolerable level for an 8 hr isophorone exposure was judged to be 10 ppm by a majority of the subjects. [R46] *... One min exposures to 200 ppm isophorone are intolerable for humans. A concn of 40 ppm was intolerable to half of an unspecified number of human volunteers after 4 min. ... Isophorone did not cause allergic contact sensitization in any of the ten human volunteers. [R47] *NO REPORT OF SYSTEMIC POISONING ... BUT THE VAPOR IS KNOWN TO IRRITATE MUCOUS MEMBRANES. [R9] *Causes smarting of the skin and first-degree burns on short exposure; may cause second-degree burns on long exposure. [R17] *It is irritating at the level of 25 ppm to humans. [R28] *Isophorone is irritating to the eyes and mucous membranes of humans. ... When the exposure duration was 15 min, 10 ppm was tolerated, while 25 ppm produced irritation to the eye, nose, and throat. ... When the exposure duration was 7 min, no irritation was reported at 18 ppm, but the threshold for throat irritation was 35 ppm. Eye and nose irritation occurred at 65 ppm, but not at 35 ppm. ... The subjects were retested after 2 wk, with no significant difference between the trials. [R48] NTOX: *... /FROM WORK ON/ EXPERIMENTAL ANIMALS ... NO EFFECT WHATEVER RESULTED FROM EXPOSURE AT 25 PPM OF ISOPHORONE OF VAPOR. ... 10 RATS AND 10 GUINEA PIGS, WERE EXPOSED 8 HR/DAY FOR 30 DAYS @ CONCN RANGING FROM 25-500 PPM. AT THE HIGHER CONCN THE CHIEF EFFECTS WERE ON THE KIDNEYS. [R35] *ISOPHORONE TESTED BY APPLICATION OF DROP TO RABBIT CORNEAS CAUSES MILD TRANSIENT INJURY, GRADED 4 ON SCALE OF 1 TO 10 AFTER 24 HR. [R49] *BY SC INJECTION, SINGLE INJECTION OF 0.3 G /TO RABBITS/ CAUSED ONLY DIARRHEA, FECES HAVING UNPLEASANT ODOR; AFTER 4 INJECTIONS PRONE POSITION AND LOSS OF REFLEXES, AND DEATH AFTER 8 HR. [R27, 457] *FROM ORAL OR SC ADMIN, PUNCTATE HEMORRHAGES IN STOMACH AND REDDENING OF INTESTINAL MUCOUS MEMBRANE. A TRACE OF ALBUMINURIA WAS FOUND AFTER SC INJECTION OF 0.3 G ... . [R27, 457] *DAILY INJECTION OF 0.2-0.6 G WAS FOLLOWED BY DEATH OF GUINEA PIGS AFTER 6 DAYS DAILY INJECTION ... CAUSED MUCH INCR AMT OF ALBUMINURIA. [R27, 457] *... /AFTER INHALATION BY GUINEA PIGS AND RABBITS/ PETECHIAL AND MASSIVE HEMORRHAGES OF LUNG AND CONGESTION OF STOMACH AND LIVER. ... THE LUNGS SHOWED GENERAL CONGESTION, INCR ALVEOLAR SECRETION, DESQUAMATION, AND IN ABOUT 5% SECONDARY PNEUMONIA. THE KIDNEYS, CONGESTION AND CLOUDY SWELLING. THE LIVER, IN FEW ANIMALS, SHOWED CONGESTION, PARENCHYMAL HEMORRHAGE AND CLOUDY SWELLING. [R27, 458] *Flow-through 96 hr and early-life-stage toxicity tests were conducted with isophorone using fathead minnows as test animals. The 96 hr median lethal concn were 145 and 255 mg/l depending on fish age. No-effect concn from early-life-stage exposures was 14 mg/l. [R50] *Flow-through, acute (96 hr) and early life stage (28 days after hatch) toxicity tests were performed on a saltwater fish, sheepshead minnows. Chemical effects on survival, growth and development were determined. Max acceptable toxicant concn was > 80 and < 156 mg/l. [R51] *CFE albino rat weanlings were divided into 4 groups of 20 males and females each and fed isophorone at 0, 750, 1,500, or 3,000 ppm in the daily diet. Individual body weights, food and cmpd consumption were tabulated weekly. After 4 wk and at 90 days, 5 rats/sex/group were killed and blood was collected for hematological and clinical chemistry determinations. Urine was collected from an additional 5 males and 5 females/group at the same time and was also comprehensively analyzed. The rats sacrificed after 4 wk were examined for gross pathology only; but after 90 days, tissues from 10 rats of each sex from the control and 3,000 ppm groups were examined histologically. The livers and kidneys from 5 rats/sex from the 750 and 1,500 ppm groups were also examined. Two rats died during the study, one in the control group and one in the 3,000 ppm group, of an unspecified infection unrelated to the admin of isophorone. The body weights and food consumption were not significanly affected at the end of the study by feeding isophorone although the body weights of the males in the 3000 group were significantly depressed for several weeks during the study. There was no significant difference between the treated and control groups regarding hematology, blood chemistry, or urinalysis, and no pathological lesions were observed by either gross or microscopic exam. [R52] *Four male and four female beagles were fed isophorone for 90 days at doses of 0, 35, 75, and 150 mg/kg/day, in gelatin capsules (food containing isophorone was refused). The dogs were weighed weekly and bled monthly for hematological blood chemistry evaluation, and urine was collected and analyzed on the same schedule as the blood. All the animals survived the study and were killed after 90 days and examined grossly. Twenty-eight selected tissues from the control and high level (150 mg/kg) groups were examined histologically, as were liver and kidney specimens from the intermediate exposure groups. All dogs survived the study in excellent condition. Food consumption was within normal limits and body weight was not affected by treatment. The hematology, biochemical, and urinalysis tests indicated a lack of adverse effect from 90 doses of isophorone. All organs appeared normal at gross exam and no significant changes in organ weight were produced with the ingestion of isophorone. There was no evidence of any definitive signs of cellular change in any of the tissues examined. [R53] *The existence of a quantitative relation between the % of the incr of convulsion threshold induced by pentetrazole and the log of atmospheric concn of chemicals allowed the calculation of the SCE50 (concn responsible for the 50% incr in convulsion threshold) for pentetrazole in mice. The systematic determination of this index allowed the comparison between different chem concerning their depressant action towards the CNS. The SCE50 value for isophorone is 131. /Units not given/ [R54] *Isophorone was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Isophorone was tested at doses of 0.033, 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, AND TA100) in the presence and absence of rat or hamster liver S-9. Isophorone was negative in these tests and the highest ineffective dose tested in any S typhimurium strain was 10 mg/plate. Toxicity including total clearing of the background lawn occurred in most cultures above the dose of 3.3 mg/plate. [R55] *Isophorone was not mutagenic in strains TA100, TA1535, TA1537, or TA98 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male rat or male hamster liver S9. It was weakly mutagenic in the mouse L5178Y/TK+/i assay in the absence of S9; it was not tested in the presence of S9. It induced sister-chromatid exchanges in the absence of S9 in Chinese hamster ovary cells; it did not induce sister-chromatid exhanges in the presence of Aroclor 1254-induced male rat liver S9, and it did not induce chromosomal aberrations. [R56] *Groups of 10 Male and 10 Female young adult Charles River CD rats were exposed to isophorone at air concns of 0 or 0.25 mg/l (250 mg/cu m), 6 hr/day, 5 days/wk for 4 wk. Results of daily spectroscopic determinations indicated that the average daily exposure was 0.208 mg/l (208 mg/cu m). Body weight measurements and hematological studies were made before exposure and after 4 wk. The rats were killed and gross necropsy was performed. Organ weights were determined for lungs, liver, kidneys, adrenals and spleen. Histological exam of those tissues were performed in 3 males and 3 females/group. The following effects were observed: transient nasal bleeding, increased percentages of lymphocytes, decreased percentages of neutrophils and increased hemoglobin concn in males and females and significantly lower terminal body weights and significantly decreased absolute and relative liver weights of exposed males, compared with controls. [R57] *The mutagenicity of methylated alpha/beta unsaturated ketones for chlorination was studied in vitro. Mesityl oxide and isophorone were chlorinated by adding the cmpds to solns containing sodium hypochlorite in media buffered to a pH of 7.5, 8.5, or 9.5. The conditions were similar to those encountered during wastewater chlorination. Aliquots of the reaction mixture were assayed for mutagenic activity by the Ames/Salmonella assay using strain TA-100. Styrene-oxide was the positive control. Neither mesityl oxide nor isophorone showed mutagenic activity in the absence of chlorination. Aqueous chlorination at pH 9.5 generated mutagens from both cmpds. Increasing the ratio of sodium hypochlorite to isophorone from 0.32 to 1.6 increased the mutagen yield. ... Decreasing the reaction pH decreased the yield of mutagens. With isophorone, the limiting pH was reached between 7.5 and 8.5. ... Mutagen formation could occur by way of a haloform reaction. [R58] *Isophorone ... /was/ tested for potential genotoxicity. The assays ... included ... L5178Y/TK+/- mouse lymphoma assay, ... unscheduled DNA synthesis assay, and micronucleus assay. ... No genotoxicity was found for ... isophorone. [R59] *Male and female rats and mice were dosed with isophorone by gavage for 16 days at doses up to 2000 mg/kg/day, and for 13 wk at doses up to 1000 mg/kg/day. In the 16 day studies, all 2000 mg/kg mice and 3 of 10 2000 mg/kg rats died. Reduced weight gain was noted at 1000 mg/kg. In the 13 wk studies, cmpd related deaths were seen in 1 of 10 female rats and 3 of 10 female mice at the 1000 mg/kg dose. The treatments did not produce gross or histopathological changes. [R36, 1848] *When male and female rats were exposed to 500 ppm isophorone 8 hr/day, 5 days/wk for 6 and 4 months, respectively, a total of 3 of 20 animals died, but the only other reported adverse effects consisted of irritation of the eyes and nose. Eye and nose irritation were also seen in a limited 18 month study in which rats and rabbits were exposed to 250 ppm isophorone for 6 hr/day, 5 days/wk. [R36, 1849] *Rats and guinea pigs exposed to 100-500 ppm isophorone 8 hr/day, 5 days/wk for 6 wk had decreased weight gain. Exposure to 500 ppm produced chronic conjunctivitis and pulmonary inflammation. Kidney damage occurred at the higher concns. There was a concn related incr in mortality. [R36, 1849] *... A concn of 27.8 ppm for 5 min caused a 50% decr in the reflex respiratory rate of mice, an indication of respriatory irritation. [R60] *Slight lung congestion was observed in rats and mice sacrificed immediately after exposure to 619 ppm isophorone for 6 hr, but not in rats or mice sacrificed 14 days after the exposure, suggesting reversibility of the lesion. ... Rats and rabbits that were exposed to isophorone at concns up to 7000 ppm for 5 hr died and had hemorrhagic lungs with vascular dilation of the alveolar capillaries and peribronchial vessels. [R60] *... Groups of 22 female rats and 22 female mice were exposed on gestation days 6-15 to concns of isophorone up to 115 ppm. In rats, dose-related maternal toxicity (alopecia) was seen at all concns (> or = 25 ppm). In addition, rat dams exposed to 115 ppm had lower body weights than controls on some days. No other indications of maternal toxicity were noted. There was a statistically significant reduction in mean crown-rump length among rat fetuses, but not among litters, in the group exposed to 115 ppm. In mice, the only effect noted was that the mean body weight of dams exposed to 115 ppm isophorone was decreased during one day of the treatment period. [R61] *... An early life stage toxicity test was conducted with freshwater fathead minnow Pimephales promelas using concn of 11, 19, 30, 56 and 112 mg isophorone/liter. Survival was affected at a concn of 112 mg/l, but not at 56 mg/l or less; fork length was affected at 30 mg/l but not at 19 mg/l or less; body weight gain was decreased at 19 mg/l or more but not at 11 mg/l. ... A no-observed-effect concn of 14 mg/l /was/ calculated. [R62] *Isophorone and a number of aliphatic ketones have been studied using the mouse behavioral despair swimming test. This test, which was developed for screening antidepressant drugs, is based on the duration of the periods of immobility exhibited by mice when placed in water. Mice were exposed to isophorone at atmospheric concentrations of 508-782 mg/cu m (89-137 ppm) for 4 hr. The ID50 (an estimated concentration producing a 50% reduction in the immobility time) for animals thus exposed was 628 mg/cu m (110 ppm). [R63] *The teratogenicity of isophorone to rats and mice was studied. Groups of 22 confirmed mated females of each species were exposed 6 hr/day on days 6-15 of gestation to atmospheres containing 0, 143, 285, or 656 mg/cu m (0, 25, 50 or 115 ppm) isophorone. At the highest atmospheric concentration there was evidence of maternal toxicity which showed as reduced food consumption, alopecia and cervical or anogenital staining in the rats and reduced body weights in the mice. Comprehensive uterine and fetal examinations did not show any significant differences between animals exposed to isophorone and their respective controls. From the results of this study, it can be concluded that no teratogenic or fetotoxic effect was observed with 656 mg/cu m in F-344 rats and CD-1 mice. [R64] *The daily occluded application shaved and abraded skin of 0.1 or 0.2 ml of isophorone to rats for 8 weeks produced erythema and scabs at the site of application. [R65] NTXV: *LD50 Rat oral 1000-3450 mg/kg; [R66] *LC50 Rabbit dermal 1380 mg/kg; [R66] *LC50 Rat inhalation 7000 mg/cu m/4 hr; [R66] *LD50 Mouse oral 2.0 g/kg; [R36, 1848] *LD50 Rat oral 2.37 g/kg; [R36, 1848] *LD50 Rat and mouse oral > 3200 mg/kg; [R36, 1848] *LD50 Rat oral 2280 mg/kg; [R36, 1848] *LD50 Rat ip 400-800 mg/kg; [R36, 1848] *LD50 Mouse ip 400 mg/kg; [R36, 1848] *LD50 Rabbit dermal 1500 mg/kg; [R36, 1849] ETXV: *LC50 Cyprinodon variegatus (sheepshead minnow) 166,000-295,000 ug/l/96 hr. /Conditions of bioassay not specified/; [R67] *EC50 Selenastrum capricornutum (alga) 122,000 ug/l/96 hr, Toxic Effect: cell number reduced. /Conditions of bioassay not specified/; [R68] *EC50 Selenastrum capricornutum (alga) 126,000 ug/l/96 hr, Toxic Effect: Chlorophyll a synthesis inhibited. /Conditions of bioassay not specified/; [R68] *EC50 Skeletonema costatum (alga) 105,000 ug/l/96 hr, Toxic Effect: cell number reduced. /Conditions of bioassay not specified/; [R68] *EC50 Skeletonema costatum (alga) 110,000 ug/l/96 hr, Toxic Effect: Chlorophyll a synthesis inhibited. /Conditions of bioassay not specified/; [R68] *LC50 Mysidopsis bahia (Mysid shrimp) 12.9 mg/l/96 hr. /Conditions of bioassay not specified/; [R69] *LC50 Pimephales promelas (fathead minnow) 145-255 mg/l/96 hr, flow through exposure. /From table/; [R70] *LC50 Artemia salina (brine shrimp) 430 mg/l/24 hr. /From table; Conditions of bioassay not specified/; [R70] *EC50 Daphnia magna (water flea) 117 mg/l/48 hr, static exposure, immobilization; [R71] NTP: *Toxicology and carcinogenesis studies of isophorone > 94% pure, a widely used solvent and chem intermediate, were conducted by administering 0, 250, or 500 mg isophorone/kg/day by gavage in corn oil to groups of 50 rats and 50 mice of each sex, 5 days/wk for 103 wk. Doses selected for the 2 yr studies were based on 16 day studies in which rats and mice of each sex received doses of 0-2000 mg/kg/day and on 13 wk studies in which rats and mice of each sex received doses ranging from 0 to 1000 mg/kg/day by gavage in corn oil. No chemically related gross or histopathologic effects were observed in the 16 day or 13 wk studied, but 1/5 high-dose male rats, 4/5 high-dose female rats, and all high-dose female mice died. The high dose for the 2 yr studies was set at 500 mg/kg/day for each sex of rats and mice, based mainly on the deaths in the 13 wk studies. Throughout the 2 yr study, the mean body weights of the high-dose male rats averaged 5% lower than those of the vehicle controls. During the second year, the mean body wts of the female high-dose rats averaged 8% lower than those of the vehicle controls, and the high-dose female mice averaged 5% lower. The survival of male mice was also low (16/50; 16/50; 19/50), but there was a significant trend toward increased survival of dosed female mice relative to that of the vehicle controls (26/50; 35/50; 34/50). Dosed male rats showed a variety of proliferative lesions of the kidney ... . Dosed male rats also exhibited increased mineralization of the medullary collecting ducts ... and low-dose male rats showed a more severe nephropathy than is commonly seen in aging rats. Carcinomas of the preputial gland were increased in high-dose male rats ... . With the exception of a moderate increase in nephropathy, ... female rats did not show chem related increased incidences of neoplastic or nonneoplastic lesions. In high-dose male mice, isophorone exposure was associated with increased incidences of hepatocellular adenomas and carcinomas. An increased incidence of lymphomas or leukemias was noted in low-dose male mice. [R72] TCAT: An inhalation teratology study was conducted with pregnant Fisher 344 rats and CD-1 mice receiving whole body exposure to isophorone at nominal concentrations of 0, 25, 50 or 115ppm in a dynamic air flow chamber. At each concentration, 22 rats and 22 mice were exposed for 6hrs/day on days 6-15 of gestation. There was no effect of treatment for all animals as indicated by mortality, gross necropsy observations and uterine implantation data. Maternal toxicity was evident by statistical differences between dosed groups and controls for: mean body weight and food consumption (115ppm group, rats and mice). No statistically significant differences (ANOVA) among control and treatment groups were found for any of the fetal external, visceral or skeletal parameters. [R73] The ability of isophorone to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenesis Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity tests, nine nonactivated cultures treated with 1.3, 1.0, 0.75, 0.56, 0.42, 0.32, 0.24, 0.18 or 0.13 ul/ml were cloned, producing a range of 12 - 111% total growth. Ten S9-activated cultures treated with 0.89, 0.67, 0.50, 0.38, 0.28, 0.21, 0.16, 0.12, 0.089 or 0.067 ul/ml were cloned, producing a range of 9 - 86% total growth. None of the cultures that were cloned produced mutant frequencies which were significantly greater than the mean mutant frequency of the solvent controls (DMSO,acetone). [R74] Isophorone was evaluated for the ability to increase the incidence of micronucleated polychromatic erthrocytes in bone marrow of male and female CD-1 mice treated by single i.p. injection (Micronucleus Test). Groups of 10 mice (5 male, 5 female) were sacrificed 12, 24 and 48 hours following injection of isophorone in corn oil at a dose of 0.54 ml/kg body weight (calculated LD20 dose). The incidence of micronucleated polychromatic erythrocytes and the ratio of normochromatic to polychromatic erythrocytes were not significantly different (p > 0.05.ANOVA) in the treatment groups compared with the vehicle controls, regardless of sacrifice time. [R75] The effect of isophorone was examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, isophorone was tested at concentrations of 0.40 (cytotoxic), 0.20, 0.10, 0.50, 0.01 or 0.0005 ul/ml (no toxic effect). None of the tested concetrations caused a significant increase in the unscheduled DNA synthesis over the solvent control (ethanol). [R76] ?Isophorone (CAS # 78-59-1) was evaluated for developmental toxicity in pregnant Fischer 344 rats (22/exposure level) administered whole-body exposures to 0, 25, 50, and 115 ppm, 6 hours/day on Gestational Days (GD) 6 through 15, then sacrificed on GD 20 for examination of fetal gross external, visceral, and skeletal anomalies. Treatment-related maternal toxicity consisted of significant (Fisher's Exact Test) anorexic reductions in bodyweight (115 ppm), dose-related alopecia, and cervical and anogenital staining. Pregnancy rates and reproductive parameters, including gravid uterine weight, number of corpora lutea, total implantations, viable and non- viable implantations per litter, percent preimplantation loss, percent live fetuses, and sex ratio were unaffected by treatment. No treatment related fetotoxicity or developmental toxicity in excess of that in controls was observed. [R77] ?Isophorone (CAS # 78-59-1) was evaluated for developmental toxicity in pregnant CD-1 mice (22/exposure level) administered whole-body exposures to 0, 25, 50, and 115 ppm, 6 hours/day on Gestational Days (GD) 6 through 15, then sacrificed on GD 18 for examination of fetal gross external, visceral, and skeletal anomalies. Treatment-related maternal toxicity consisted of reduced feed consumption and bodyweight (115 ppm). No further toxic effects were observed with regard to mortality of treated dams, maternal gross pathology, or reproductive parameters. Fetuses of all groups, including controls, exhibited comparable external, visceral, and skeletal malformations/variations. [R77] ?Isophorone (CAS # 78-59-1) was evaluated in pre-reproductive probe study for subchronic, reproductive, and developmental toxicity in pregnant Fischer 344 rats (12/exposure group) administered whole-body exposures to 0, 50, 100, or 150 ppm, 6 hours/day on Gestational Days (GD) 6 through 15. Treatment-related maternal toxicity (150 ppm only) consisted of significant (Dunnett's Test or Dunn's Summed Rank Test, p < 0.05) but transient reductions in mean bodyweight (Day 12), reductions in mean bodyweight gain, alopecia, excessive lacrimation, yellow anogenital staining, and tan, yellow, or red material about the mouth and/or jaw. There was no excess mortality related to treatment, no clinical maternal toxicity observed in any byt the 150 ppm exposure group, and no effect of treatment on pregnancy rates. Upon necropsy, maternal relative (to GD 16 bodyweight minus uterine weight) kidney (50, 150 ppm), liver (50, 100, 150 ppm), and spleen (100, 150 ppm) weights were significantly (p < 0.05) increased. Malformations consisted of a solitary high-dose late resorption with exencephaly. [R78] ?Isophorone (CAS # 78-59-1) was evaluated in pre-reproductive probe study for subchronic, reproductive, and developmental toxicity in pregnant CD-1 mice (12/exposure group) administered whole-body exposures to 0, 50, 100, or 150 ppm, 6 hours/day on Gestational Days (GD) 6 through 15. Treatment-related maternal toxicity (150 ppm only) consisted of significant (Dunnett's Test or Dunn's Summed Rank Test, p < 0.05) reductions in mean bodyweight gains (Day 6-16) and corrected Day 16 bodyweight gains (minus uterus weight); there was no excess mortality related to treatment. Single animals/exposure group exhibited alopecia (100 ppm), excessive salivation (150 ppm), yellow ano-genital staining (150 ppm), and/or tan, yellow, or red material about the mouth and/or jaw (100, 150 ppm). No clinical maternal toxicity was observed in 50 ppm dams and there was no effect of treatment on pregnancy rates in any group. Upon necropsy, maternal absolute and relative (to GD 16 bodyweight minus uterine weight) spleen (150 ppm) weights were significantly (p < 0.05) increased. Malformations (150 ppm litters only) consisted of a late resorption in one litter and 2 live fetuses in another, all exhibiting exencephaly. [R78] ?Isophorone (CAS # 78-59-1) was evaluated for subchronic inhalation toxicity in rats (10/sex/exposure group, breed unspecified) administered whole-body exposures to nominal vapor concentrations of 0, 81, and 203.5 ppm for 6 hours/day, 5 days/week over 2 weeks (10 total exposures). Treatment was associated with progressive signs of clinical toxicity only in 203.5 ppm rats, including eye irritation, nasal discharge, lethargy, irritability, haircoat discoloration, and bloody oral and nasal discharge. Mean bodyweights were significantly diminished in the 203.5 ppm males relative to controls; however, both males and females exhibited increased relative liver weights in association with 203.5 ppm exposures. Relative and absolute lung weights were unaffected by treatment. Upon terminal necropsy, gross lesions were confined to the lungs and consisted of blanched spots to patchy consolidation (203.5 ppm), and pinpoint or patchy hemorrhage (81, 203.5 ppm) to hemorrhagic consolidation (203.5 ppm). Microscopic examination revealed extensive alveolar collapse with surrounding slight to moderate alveolar expansion in 81 ppm males and females, but no significant treatment-induced pulmonary histopathology in 203.5 ppm males or females. Renal, hepatic, and splenic tissues appeared comparable to controls in both treated groups. [R79] ?Isophorone (CAS # 78-59-1) was evaluated for the significance of protein binding and associated cellular proliferation in exposed rat preputial glands, the sites of previously documented increased incidence of carcinomas in exposed male rats. Preputial gland and kidney cytosol isolated from Fischer-344 rats (10/sex/dose group) previously administered single 0, 250 and 500 mg/kg doses of 14C-labeled isophorone by oral gavage 24 hours prior to sacrifice revealed isophorone binding primarily to alpha(2u)globulin (alpha(2u)G) of the preputial gland in both males and females and in the kidney in males, but not females. Upon challenge with SDS elution in labeled isophorone-derived cytosol samples, these bonds were readily dissociated. Conversely, extraction of preputial gland and kidney DNA from rats treated with single 500 mg/kg labeled doses yielded no evidence of isophorone binding to DNA, these negative results confirmed in 32P-postlabeling assays with samples from male and female rats treated for 1 week with 500 mg/kg/day isophorone by oral gavage. Preputial gland acinar cells were heavily and comparably (with no dose-related differences) stained immunohistochemically with anti-alpha(2u)G antibody in both male and female groups (8/sex) treated with 0, 250, and 500 mg/kg by oral gavage on 5 days/week for 1 or 4 weeks. Conversely, in the kidneys of males, treatment intensified and extended the duration of alpha(2u)G activity relative to that indicated by limited immunohistochemical staining of proximal tubule cells in the kidneys of controls. Neither control or treated females exhibited any such evidence of alpha(2u)G in the kidney. Using an identical protocol preceded by the administration of BrdU 2 days earlier, rats (8/sex/dose group) were sacrificed for histologic examination of preputial gland and kidney tissues. Immunohistochemical staining with anti-BrdU antibody revealed a significant (Dunnett's test, p < 0.05) increase in cell proliferation in male preputial glands after 1 week's dosing, that was subsequently reduced to a marginal elevation above controls at 4 weeks. A more dramatic (p < 0.01) increase in cell proliferation was noted in male kidneys in association with both 1 and 4 week's dosing. Female preputial glands, but not kidneys, showed non- significant increased cell proliferation. The authors concluded that, isophorone appears not to be genotoxic and the mechanism of documented preputial gland tumorogenicity in association with chronic oral isophorone may be coincidental (based on historic and control variability) rather than a alpha(2u)G-induced pathology and associated hyperplasia, as this association was transient and inconsistent with that in male rat kidneys. In the male rat kidney, isophorone-related increase in alpha(2u)G activity with increased and sustained cell proliferation suggests a mechanism that is not relevent in humans. [R80] ?Ishophorone (CAS # 78-59-1) was evaluated for chronic toxicity and carcinogenesis in rats and mice (gavage studies), and the results documented in NTP Technical Report, Draft dated 10/84, Series No. 291 (abstract only attached). Fischer 344 rats (50/sex/dosage group) administered doses of 0 (corn oil solvent control), 250, and 500 mg/kg/day by oral gavage for 103 weeks showed decreased weight gain in association with the highest dose only. Upon terminal necropsy of approximately 24 rats/sex/group, treated males were found to have increased incidence of neoplastic lesions in the kidneys (250, 500 mg/kg) and preputial gland (500 mg/kg) relative to controls. Epithelial hyperplasia of the renal pelvis and mineralization of the medullary collecting ducts were also increased in association with doses of 250 and 500 mg/kg. No treatment-related increase in neoplastic or nonneoplastic lesions were identified in females. Statistical analyses of results were not reported. Peer review by NTP Board of Scientific Counselors and a Panel of Experts found no discrepancies in reported results or interpretations of the study authors. [R81] ?Ishophorone (CAS # 78-59-1) was evaluated for chronic toxicity and carcinogenesis in rats and mice (gavage studies), and the results documented in NTP Technical Report, Draft dated 10/84, Series No. 291 (Abstract only attached). B6C3F1 mice (50/sex/dosage group) administered doses of 0 (corn oil solvent control), 250, and 500 mg/kg/day by oral gavage for 103 weeks showed no clinical signs of toxicity. Upon terminal necropsy, treated males, relative to controls, were found to have substantially increased incidence of liver adenomas and carcinomas (500 mg/kg) associated with hepatocytomegaly and coagulative necrosis, and mesenchymal tumors (fibroma, fibrosarcoma, neurofibrosarcoma, or sarcoma) of the integument (500 mg/kg), as well as lymphomas and leukemias of the hematopoietic system (250 mg/kg). No treatment-related neoplastic or non-neoplastic lesions were identified in females. The authors reported equivocal evidence of carcinogenicity in male mice based on the high historical background incidence of these type lesions in this species. Statistical analyses of results were not reported. Peer review by NTP Board of Scientific Counselors and a Panel of Experts found no discrepancies in reported results or interpretations of the study authors. [R81] ?Isophorone (CAS # 78-59-1) was evaluated for clastogenicity in triplicate groups of CD-1 mice (5/sex/treatment group) administered single doses of 0.54 mL/kg in ethanol (maximum tolerated dose in toxicity study) by intraperitoneal injection. Replicate treatment groups were then sacrificed at 12, 24, and 48 hours for harvest of bone marrow with microscopic assessment of treatment-related changes in numbers micronucleated polychromatic erythrocytes. Treatment with isophorone in mice was not associated with increased incidence of chromosome breaks and micronucleated polychromatic erythrocytes relative to ethanol solvent controls. [R82] ?Ishophorone (CAS # 78-59-1) was evaluated for mutagenicity in cultured L5178Y TK+/- mouse lymphoma cells, both in the presence and absence of Aroclor-induced rat liver S-9 metabolic activation. Lymphoma cell cultures with and without metabolic activation, respectively, were tested at several concentrations ranging from 0.067 to 0.89 uL/mL and 0.13 to 1.3 uL/mL corresponding to 9 to 86% and 12 to 111% total growth relative to DMSO solvent controls. Neither activated nor non-activitated cultures responded to treatment (other than the highly toxic) with significantly increased mutation frequencies relative to controls. [R82] ?Isophorone (CAS # 78-59-1) was evaluated for unscheduled DNA synthesis in cultured primary rat liver cells exposed for 18 hours to 10 graduated concentrations from 0.005 to 0.40 uL/mL, corresponding to relative survival indices ranging from 100 to 0. Relative to the EtOH solvent control, rat hepatocytes exposed for 18 hours in vitro with tritiated thymidine (3H- TdR) did not demonstrate increased unscheduled DNA synthesis of significance (mean net labeled nuclear grains increased at least 5 grain counts over control). [R82] ADE: *The demonstrated toxicity of isophorone by oral, inhalation, and dermal exposures indicates that it is capable of passage across epithelial membranes. [R83] *Rabbits and rats treated orally with isophorone excreted unchanged isophorone in the expired air and in the urine. [R84] *Preliminary results of a pharmacokinetic study indicate that rats treated orally with 14C-isophorone excreted 93% of the radiolabel in the urine, expired air and feces in 24 hr. The majority was found in the urine indicating that isophorone was well absorbed. The wide distribution of isophorone in the organs of rats and a rabbit 1-5 hr after dosing by gavage with 4000 mg/kg indicates rapid GI absorption. In two rabbits given a gavage dose of 1000 mg/kg isophorone, a blood level of isophorone of 102 ug/L was found within 10 min. The level increased to 141 ug/L in 30 min and declined to < or = 0.05 ug/L in 21 hr. The results indicate rapid absorption and elimination. The detection of unchanged isophorone and its metabolites in the urine and the observations of systemic toxicity and carcinogenicity in animals exposed orally to isophorone provide qualitative evidence that isophorone is absorbed after oral exposure. [R85] *In rats exposed to 400 ppm isophorone for 4 hr and sacrificed immediately after exposure or 1.5 or 3 hr after exposure, levels of isophorone were highest in all tissues examined (brain, lungs, heart, stomach, liver, spleen, pancreas, kidney, adrenals, testicles, and ovaries) immediately after exposure. Levels ranged from 1.5-74 ug/g tissue wet weight. The levels declined rapidly in males but declined very little in females by 3 hr after exposure. [R85] *Radiolabel was widely distributed in male rats 24 hr after an oral dose of 14C-isophorone in corn oil, with highest levels in the liver, kidney, preputial gland, testes, brain, and lungs. Isophorone was widely distributed to the tissues of rats and a rabbit following treatment with isophorone at a gavage dose of 4000 mg/kg. The rats died within 1-5 hr and the rabbit died within an hr after dosing at which times the tissues were sampled for analysis. in rats, tissue levels of isophorone in ug/g tissue wet weight were as follows: stomach-6213, pancreas-2388, adrenals-1513, spleen-1038, liver-613, brain-378, lung-383, heart-387, kidney-465, testes-275, and ovaries-471. In the rabbit, tissue levels were as follows: stomach-5395, adrenals-1145, ovaries-3000, spleen-545, liver-515, kidney-295, heart-260, and lungs-50. [R86] METB: *... ISOPHORONE IS METABOLIZED IN RABBITS INTO 5,5-DIMETHYLCYCLOHEX-1-EN-3-ONE-1-CARBOXYLIC ACID, WHICH IS EXCRETED IN URINE AS ESTER GLUCURONIDE. [R87] *AFTER ORAL ADMIN OF 1 G/KG ALPHA-ISOPHORONE, RABBIT AND RAT URINE CONTAINED ALPHA-ISOPHORONE, ISOPHOROL, CIS-3,5,5-TRIMETHYLCYCLOHEXANOL, TRANS-3,5,5-TRIMETHYLCYCLOHEXANOL, DIHYDROISOPHORONE, 5,5-DIMETHYLCYCLOHEX-1-EN-3-ONE-1-CARBOXYLIC ACID, AND DIHYDROISOPHORONE GLUCURONIDE. [R88] *The allylic methyl group of isophorone was oxidized to a carboxylic acid group when industrial isophorone was administered orally to rabbits. The product was detected in urine and no other products were identified. [R89] *Rabbits and rats treated orally with isophorone excreted unchanged isophorone in the expired air and in the urine. The urine also contained 3-carboxy-5,5-dimethyl-2-cyclohexene-1-one and glucuronic conjugates of 3,3,5-trimethyl-2-cyclohexene-1-ol (isophorol), 3,5,5,-trimethylcyclohexanone (dihydroisophorone), and cis- and trans-3,5,5-trimethylcyclohexanols. Rat urine contained more dihydroisophorone and less isophorol than did rabbit urine. ... /It was/ proposed that metab of isophorone involves methyloxidation to 3-carboxy-5,5-dimethyl-2-cyclohexene-1-one, reduction of the ketone group to isophorol, reduction of the ring double bond to dihydroisophorone, and dismutation of dihydroisophorone to cis- and trans-3,5,5-trimethylcyclohexanols. [R86] INTC: *Joint toxic action of isophorone with 26 industrial liquid chemicals was examined based on acute LD50 data from oral intubations of female albino rats. ... LD50s were determined for each of the cmpds. Based on the assumption of simple similar action, isophorone exhibited > additive toxicity in combination with 9 cmpds and < additive toxicity in combination with 17 cmpds. The significance of the interactions was determined by modifying the interactive ratios (predicted/observed LC50) so that the distribution approximated normality. Significant interaction was then defined as those ratios which were beyond 1.96 standard deviations from the mean ratio. By this criterion none of the mixtures containing isophorone deviated significantly from the assumption of simple similar action. In a subsequent study, equal volume mixtures of isophorone and propylene oxide showed markedly < additive toxicity, but equitoxic mixtures showed slightly > additive toxicity. An equitoxic mixture was defined as a mixture of chemicals in volumes directly proportional to their respective rat oral LD50 values, so that each component contributed the same degree of toxicity to the mixture. [R47] *... /It was/ reported that inhalation of isophorone for 4 hr by mice increased the threshold for onset of seizures produced by iv admin of pentrazole ... . [R61] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Isophorone's production and use as a solvent for printing inks, lacquers, adhesives, and use as a chemical intermediate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.438 mm Hg at 25 deg C indicates isophorone will exist solely as a vapor in the ambient atmosphere. Vapor-phase isophorone will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 5 hrs. If released to soil, isophorone is expected to have moderate mobility based upon an estimated Koc of 200. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 6.6X10-6 atm-cu m/mole. This compound is not expected to biodegrade rapidly in the environment based upon a 3% theoretical BOD in 2 weeks using an activated sludge inoculum and the Japanese MITI test. If released into water, isophorone is expected to adsorb moderately to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 7 and 52 days, respectively. A BCF of 7 suggests that bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to isophorone may occur through inhalation and dermal contact with this compound at workplaces where isophorone is produced or used. Monitoring data indicate that the general population may be exposed to isophorone via ingestion of contaminated drinking water. (SRC) NATS: *There are no known natural sources of isophorone(1). [R90] ARTS: *Isophorone's production and use as a solvent for printing inks, lacquers, adhesives(1), and use as a chemical intermediate(2) may result in its release to the environment through various waste streams(SRC). [R91] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 200(SRC), determined from a log Kow of 1.70(2), indicates that isophorone is expected to have moderate mobility in soil(SRC). Volatilization of isophorone from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.6X10-6 atm-cu m/mole(SRC), derived from its vapor pressure, 0.438 mm Hg(3), and water solubility, 12,000 mg/l(4). Isophorone is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(3). Biodegradation is not expected to be an important environmental fate process in soil based upon a 3% theoretical BOD in 2 weeks using an activated sludge inoculum and the Japanese MITI test(5). [R92] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 200(SRC), determined from a log Kow of 1.70(2), indicates that isophorone is not expected to adsorb strongly to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 6.6X10-6 atm-cu m/mole(SRC), derived from its vapor pressure, 0.438 mm Hg(4), and water solubility, 12,000 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 7 and 52 days, respectively(SRC). According to a classification scheme(6), a BCF of 7(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation is not expected to be an important environmental fate process in water based upon a 3% theoretical BOD in 2 weeks using an activated sludge inoculum and the Japanese MITI test(7). [R93] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), isophorone, which has a vapor pressure of 0.438 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase isophorone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 hrs(SRC), calculated from its rate constant of 8.1X10-11 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(3). [R94] BIOD: *AEROBIC: Isophorone, present at 100 mg/l, reached 3% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). Removal of isophorone from unacclimated fresh and salt water seeded with settled domestic wastewater was 42 and 9%, respectively, after 20 days(3). Removal of isophorone from wastewater treated by various different biological treatment processes: trickling filter, activated sludge, aerated lagoon, and facultative lagoon was 19, 98, 24, and 30%, respectively(4); therefore this compound is not expected to biodegrade rapidly(SRC). A 100% loss was observed when 5 and 10 mg/l isophorone underwent a 7-day static incubation in the dark at 25 deg C under aerobic conditions using settled domestic wastewater as inoculum(2). Using a multi-level respirometric test protocol employing a sludge microbiota, a half-life of 25 days for 100 mg test compound was determined(5). [R95] ABIO: *The rate constant for the vapor-phase reaction of isophorone with photochemically-produced hydroxyl radicals has been estimated as 8.1X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Isophorone is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2-4) nor to undergo direct photolysis due to the lack of absorption in the environmental UV spectrum (> 290 nm)(5). The rate constant for the vapor-phase reaction of isophorone with ozone has been estimated as 7.4X10-17 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(6). [R96] BIOC: *A BCF of 7 was measured for isophorone in bluegill sunfish(1). The half-life of isophorone in fish tissue was found to be 1 day(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R97] KOC: *The Koc of isophorone is estimated as 200(SRC), using a log Kow of 1.7(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that isophorone is expected to have moderate mobility in soil. [R98] VWS: *The Henry's Law constant for isophorone is estimated as 6.6X10-6 atm-cu m/mole(SRC) derived from its vapor pressure, 0.438 mm Hg(1), and water solubility, 12,000 mg/l(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 7 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 52 days(SRC). Isophorone's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Isophorone is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R99] WATC: *... EPA maintains an inventory of organic compounds that have been isolated and identified in drinking water in the USA. ... Isophorone was ... detected at concentrations as high as 9.5 ug/l. [R100] *GROUNDWATER: Isophorone was detected in groundwater samples collected from the Netherlands at a maximum concn of 10 ug/l(1). [R101] *DRINKING WATER: Isophorone was identified in finished drinking water from: Cincinnati, OH - Oct 1978 and Jan 1980; Philadelphia, PA - Feb 1976; Ottumwa, IA - Sept 1976; and Seattle, WA - Nov 1976(1). During the USEPA 1974 National Organics Reconnaissance Survey (NORS) isophorone was detected in 1 of 10 finished drinking water supplies(2). Approximately 0.02 ug/l was found in drinking water from Cincinnati, OH(2). Trace levels were detected in Philadelpha, PA drinking water during Aug 1977(3). The compound was detected in drinking water from New Orleans, LA during 1974, with a max concn of 2.9 ug/l(4). [R102] *SURFACE WATER: Data from the USEPA STORET Data Base indicates that of 795 water samples, 1% tested positive for isophorone with a median concn of < 10 ug/l(1). During Aug 1977 in the Delaware River, Pennsylvania at river mile 106, 108, and 110, isophorone concentrations were found to be 3, 0.6 and < 0.01 ug/l, respectively(2). Isophorone was detected in the St. Joseph River, Michigan and not detected in the Cuyahoga River, Ohio(3). USEPA National Urban Runoff Program (NURP) results as of July 1982 indicate that isophorone was found in runoff in 1 of 19 cities across USA(4). 10 ug/l was detected in urban runoff of Washington, DC(4). Samples collected on the St. Lawrence River in the region of Quebec, Canada in June, 1987 contained isophorone at a conc of 69 ng/l(5). [R103] EFFL: *According to the USEPA STORET Data Base, of 1272 effluent samples, 1.6% tested positive for isophorone, with a median concn of < 10.0 ug/l(1). Isophorone has been found in the treated wastewater from the following industries: iron and steel mfg, 1 of 5 samples pos, concn 170 ug/l; coil coating, 5 of 31 samples pos, max concn 560 ug/l, mean concn 120 ug/l; foundries, 7 of 7 samples pos, max concn 28 ug/l, mean concn 12 ug/l; photographic equipment and supplies, 2/4 samples pos, max concn 10 ug/l, mean concn 10 ug/l; paint and ink formulation, 1 of 1 samples pos, concn < 7 ug/l; automobile tire plant, 40 ug/l; and oil shale retorting, 340-5800 ug/l(2-4). The influent and effluent of the Philadelphia (PA) Northeast Sewage Treatment plant during Aug 1977 were 100 and 10 ug/l, respectively(5). Isophorone was tested for but not detected (detection limit of 1.0 ug/l) in tire leachates from tire plugs soaked 31 days in fresh water from Lake Mead, NV(6). Analysis of New York City municipal wastewaters was conducted from 1989 to 1993(7). Isophorone was detected once in 1989 and 1991 in influent samples at a concn of 5 ug/l (2% detection), and in a 1991 effluent sample at a concn of 8 ug/l (1% detection)(7). The compound was detected at a concn of 10.4 ug/l in leachate from a municipal landfill in Japan(8). According to a Danish study, isophorone was detected not quantified in waste exudate analysis of garden waste(9). Municipal landfill leachate concn of isphorone as reported in the literature range from a low of 3.18 pg/l to 16 mg/l, detected in 13 of 26 samples at a median concn of 76 ug/l(10). Isophorone has been detected in the effluents from latex and chemical plants in Alabama, but no levels were reported. [R104] SEDS: *SEDIMENT: Isophorone was qualitatively identified in sediment/soil/water samples taken from Love Canal in Niagara Falls, NY during 1980(1). According to the USEPA STORET Data Base, of 318 sediment samples tested, 0% were positive for isophorone(2). The compound was detected in sediments taken from Lake Pontchartrain (LA), concn range 0.98-12 ng/g (ppb) dry wt(3). [R105] ATMC: *SOURCE DOMINATED: Isophorone has been detected in coal fly ash at a concentration of 490 ug/g(1). [R106] FOOD: *Isophorone was detected in apricots (Prunus armeniaca) and plums (Prunus salicina, Lindl.) at 17, 4, an 11 mg/kg in 3 of 3 apricots and at 1 mg/kg in 1 of 2 plums(1). [R107] PFAC: FISH/SEAFOOD CONCENTRATIONS: *The USEPA STORET Data Base reports that of 123 samples of biota, 0% were positive for isophorone(1). Whole fish samples collected from nearshore tributaries and the Grand Traverse Bay on Lake Michigan in the fall of 1993 tested positive for isophorone, at a mean concn range of not detected to 3.61 mg/kg wet weight(2). Isophorone was not detected in Great Lakes fish collected from the Sheboygen (WI), Milwaukee (WI), Kinninkinnic (WI), Fox (WI), Black (OH), Menominnee (WI), Wolf (WI), Ashtabula (OH) rivers, and Chequamegon Bay (Lake Superior, WI)(3). Bottomfish collected in 1981 from Old Town Dock area, Commencement Bay in Tacoma WA tested positive for isophorone at a max concn of 0.92 ppm(4). [R108] OEVC: *Isophorone is present in printer's inks used for serigraphy, concn not specified(1). [R109] RTEX: *Certain occupations (particularly individuals who are exposed to isophorone as a solvent) have elevated levels of exposure relative to the general population. [R47] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 47,097 workers (10,353 of these are female) are potentially exposed to isophorone in the US(1). Occupational exposure to isophorone may occur through inhalation and dermal contact with this compound at workplaces where isophorone is produced or used(SRC). Monitoring data indicate that the general population may be exposed to isophorone via ingestion of contaminated drinking water(SRC). [R110] *Concentration of isophorone in breathing zone samples from an isophorone manufacturing plant (Exxon Chemical) were reported to range from 0.01-0.63 ppm, mean concn 0.07 ppm(1). Time-weighted average (TWA) concentration in breathing zones and workplace air of a screen printing plant ranged from 8.3-23 ppm and 3.5-14.5 ppm, respectively(2). Up to 25.7 ppm was detected in air of a silk screen printing plant in Pittsburgh, PA(3). Concentration of isophorone in breathing zone samples from a decal manufacturing plant in Ridgefield, NJ was 0.7-14 ppm(4). [R111] *The occupational exposures to isophorone occur by inhalation or dermal contact and mainly occur in the printing industry. [R112] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *200 ppm [R16] ATOL: *Isophorone is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R113] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 25 ppm (140 mg/cu m). [R114] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 4 ppm (23 mg/cu m). [R16] TLV: *Ceiling Limit: 5 ppm. [R44] *A3; Confirmed animal carcinogen with unknown relevance to humans. [R44] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Isophorone is produced, as an intermediate or a final product, by process units covered under this subpart. [R115] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Isophorone is included on this list. [R116] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 100 ug/l [R117] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 40 ug/l [R117] +(ME) MAINE 140 ug/l [R117] +(MN) MINNESOTA 100 ug/l [R117] +(NH) NEW HAMPSHIRE 140 ug/l [R117] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R118] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R119] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Isophorone is included on this list. [R120] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. [R121] FIFR: *Isophorone is exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practice as inert (or occasionally active) ingredents in pesticide formulations applied to growing crops only. [R113] FDA: *Isophorone is listed as an indirect food additive for use only as a component of adhesives. [R122] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Activated charcoal, Ambersorb XE-348, and Amberlites XAD-2, XAD-4, and XAD-7 were evaluated as solid adsorbents for work-room air sampling of acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl n-butyl ketone, cyclohexanone, and isophorone. Activated charcoal had good capacity for the compounds investigated, but most ketones decomposed on this adsorbent during storage. Ambersorb XE-348 also showed good capacity for most of the ketones and decomposition was insignificant. [R123] *NIOSH Method 2508. Analyte: isophorone; sampler: solid sorbent tube (petroleum-based charcoal, 100 mg/50 mg); flow rate: 0.01-1 l/min; vol: -min: 2 l, -max: 25 l; sample stability: at least 7 days @ 25 deg C. [R124] ALAB: *NIOSH Method 2508. Isophorone. Technique: Gas chromatography, FID. The working range for this method is 0.35 to 70 ppm (2 to 400 mg/cu m) for a 12-L air sample. Estimated limit of detection: 0.02 mg per sample. [R124] *Isophorone has been determined in water by gas chromatography and mass spectrometry. [R125] *EPA Method 609-A. Nitroaromatics and Isophorone in Wastewater by Gas Chromatography with Electron Capture Detection. Detection limit = 16.000 ug/l. [R126] *EPA Method 609-B. Nitroaromatics and Isophorone in Wastewater by Gas Chromatography with Flame Ionization Detection. Detection limit = 5.7 ug/l. [R126] *EPA Method 625. Protocol for the Analysis of Base/Neutral and Acid Extractable (BNA) Organic Priority Pollutants in Industrial and Municipal Wastewater. Detection limit = 2.2 ug/l. [R126] *EPA Method 625-S. Analysis of Extractable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. Detection limit = 2.2 ug/l. [R126] *EPA Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. Detection limit = 5.00 ug/kg. [R126] *OSW Method 8270B-S. Determination Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Estimated Quantitation Limit = 660.000 ug/kg. [R126] *OSW Method 8090-ECD. Nitroaromatics and Cyclic Ketones by Gas Chromatography with an Electron Capture Detector. Detection limit = 16.000 ug/l. [R126] *EPA Method SFSAS_16. Method Analysis of Sediment for General Organics by Mechanical Dispersion Extraction. Limit of Quantitation = 40 ug/kg. [R126] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Isophorone (1980) EPA 440/5-80-056 USEPA; Health and Environmental Effects Profile for Isophorone (1986) ECAO-CIN-P162 DHHS/ATSDR; Toxicological Profile for Isophorone (1989) ATSDR/TP-89/15 DHHS/NTP; Toxicology and Carcinogenesis Studies of Isophorone in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 291 (1986) NIH Publication No. 86-2547 SO: R1: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA15 (1990) 88 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 887 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R5: USEPA; Ambient Water Quality Criteria Doc: Isophorone p.A-2 (1980) EPA 440/5-80-056 R6: Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991. R7: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 693716 R8: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Isophorone (78-59-1). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of September 26, 2001. R9: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-184 R10: SRI R11: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 631 R12: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley and Sons. New York, NY. 2001 1340 R13: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 513 R14: BUREAU OF THE CENSUS US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-359 R15: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-526 R16: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 178 R17: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R18: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-131 R19: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V14 (1995) 981 R20: Veith GD et al; pp. 116-29 in Aquatic Toxicology. Easton JG et al, eds. Amer Soc Test Mat ASTM STP 707 (1980) R21: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-354 R22: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 379 R23: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 796 R24: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V3 2317 R25: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1161 R26: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R27: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R28: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1971 R29: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R30: Prager, J.C. Environmental Contaminant Reference Databook Volume 2. New York, NY: Van Nostrand Reinhold, 1996. R31: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. 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Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.397 R38: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 228 R39: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-35 (1982) R40: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-110 (1982) R41: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-146 (1982) R42: Environmental Health Criteria 174 Isophorone. pp.1-22 (1995) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. 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(1984), EPA Document No. 40-8555049, Fiche No. OTS0507224 R74: Microbiological Associates; L5178Y TK+/- Mouse Lymphoma Mutagenicity Assay, (1984), EPA Document No. 40-8455047, Fiche No. OTS0507222 R75: Microbiological Associates, Inc.; Activity of Isophorone in the Micronucleus Cytogenetic Assay in Mice, Final Report, (1984), EPA Document No. 40-8455047, Fiche No. OTS0507222 R76: Microbiological Associates; Unscheduled DNA Synthesis in the Rat Primary Hepatocytes, Final Report, (1984), EPA Document No. 40-8455047, Fiche No. OTS0507222 R77: Chem Mfgs Assn; Inhalation Teratology Study in Rats and Mice, Test Material: MRD-83-237; 11/20/84; EPA Doc No. FYI-AX-0485-0355; Fiche No. OTS0000355-1 R78: Chem Mfgs Assn; Inhalation Teratology Probe Study in Rats and Mice; 01/25/84; EPA Doc No. 40-8455042; Fiche No. OTS0507219 R79: Exxon Chemical Americas; Comparison of Subacute Inhalation Toxicities of Three Ketones; 08/05/66; EPA Doc No. 86960000030; Fiche No. OTS0572860 R80: Union Carbide Corp; Mechanistic Studies on Isophorone and Preputial Gland Carcinomas; 03/25/97; EPA Doc No. 86970000764; Fiche No. OTS0558974 R81: Union Carbide Corp; Isophorone - Significance of the Toxicology and Carcinogenicity in Fischer 344 Rats and B6C3F1 Mice; 04/12/85; EPA Doc No. 88- 920009340; Fiche No. OTS0571092 R82: Chem Mfgs Assn; Voluntary Testing Program Under Section 4 of the Toxic Substances Control Act Submission of Test Data Vol III: Isophorone Mutagenicity Studies; 10/10/84; EPA Doc No. FYI-OTS-1084-0355, Fiche No. OTS0000355-0 R83: USEPA; Ambient Water Quality Criteria Doc: Isophorone p.C-5 (1980) EPA 440/5-80-056 R84: DHHS/ATSDR; Toxicological Profile for Isophorone p.46-7 PB90-180225 (1989) R85: DHHS/ATSDR; Toxicological Profile for Isophorone p.45 TP-89/15 (1989) R86: DHHS/ATSDR; Toxicological Profile for Isophorone p.46 TP-89/15 (1989) R87: The Chemical Society. 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USEPA-600/2-82-001a (1981) (3) Jungclaus GA et al; Anal Chem 48: 1894-6 (1976) (4) Hawthorne SB, Sievers RE; Environ Sci Tech 18: 483-90 (1984) (5) Sheldon LS, Hites RA; Environ Sci Technol 13: 574-9 (1979) (6) Nelson SM et al; Bull Environ Contam Toxicol 52: 574-81 (1994) (7) Stubin AI et al; Water Environ Res 68: 1037-44 (1996) (8) Yasuhara A et al; Kankyo Kagaku 3: 356-7 (1993) (9) Wilkins K, Larsen K; Chemosphere 32: 2049-55 (1996) (10) Roy WR; pp. 411-46 in Contaminated Groundwaters. Adriano DC et al, eds. Northwood, UK: Sci Rev (1994)(11) Shackelford WM, Keith LH; Frequency of organic compounds identified in water. Athens, GA: USEPA 600/4-76-062 p. 626 (1976) R105: (1) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) (2) Staples CA et al. Environ Toxicol Chem 4: 131-42 (1985) (3) McFall JA et al; Chemosphere 14: 1561-9 (1985) R106: (1) Harrison FL et al; Environ Sci Tech 19: 186-93 (1985) R107: (1) Gomez E et al; J Agric Food Chem 41: 1669-76 (1993) R108: (1) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) (2) Camanzo J et al; J Great Lakes Res 13: 296-309 (1987) (3) DeVault DS; Arch Environ Contam 14: 587-594 (1985) (4) Nicola RN et al; J Environ Health 49: 342-7 (1987) R109: (1) Rastogi SC; Arch Environ Contam Toxicol 20: 543-7 (1991) R110: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R111: (1) USEPA; Exxon Chemical Americas. Office of Toxic Substances Microfiche No. 206267 (1982) (2) Samimi B; Amer Ind Hyg Assoc J 43: 858-62 (1982) (3) Kominsky JR; National Institute of Occupational Safety and Health (NIOSH) Health Hazard. Report No. HE78-107-563 NTIS PB 81-14371 (1981) (4) Lee SA, Frederick L; NIOSH Health Hazard. Report No. HHE80-103-827 NTIS PB82-189226 (1982) R112: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 1121 R113: 40 CFR 180.1001(d) (7/1/2001) R114: 29 CFR 1910.1000 (7/1/2001) R115: 40 CFR 60.489 (7/1/2001) R116: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R117: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R118: 40 CFR 401.15 (7/1/2001) R119: 40 CFR 302.4 (7/1/2001) R120: 40 CFR 716.120 (7/1/2001) R121: 40 CFR 712.30 (7/1/2001) R122: 21 CFR 175.105 (4/1/2001) R123: Levin JO, Carleborg L; Ann Occup Hyg 31 (1): 31-8 (1987) R124: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R125: Eichelberger JW et al; Anal Chem 55 (9): 1471-9 (1983) R126: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 96 Record 77 of 1119 in HSDB (through 2003/06) AN: 622 UD: 200302 RD: Reviewed by SRP on 1/31/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALLYL-BROMIDE- SY: *BROMALLYLENE-; *1-BROMO-2-PROPENE-; *3-BROMOPROPENE-; *3-BROMO-1-PROPENE-; *3-BROMOPROPYLENE-; *1-PROPENE,-3-BROMO-; *PROPENE,-3-BROMO-; *2-PROPENYL-BROMIDE- RN: 106-95-6 MF: *C3-H5-Br SHPN: UN 1099; ALLYL BROMIDE IMO 3.2; ALLYL BROMIDE MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF HYDROGEN BROMIDE AND ALLYL ALCOHOL; PARTIAL DEHYDROBROMINATION OF DIBROMOPROPANE AND SEPARATION OF ISOMERS [R1] *...FROM HYDROBROMIC ACID AND ALLYL ALCOHOL; FROM TRIPHENYLPHOSPHITE, ALLYL ALCOHOL AND BENZYL BROMIDE. [R2] FORM: *GRADES: TECHNICALLY PURE (95% MINIMUM PURITY BY BROMINE TITRATION). [R3] *Grades or Purity: Commercial [R4] MFS: *Columbia Organic Chemical Co, Inc, PO Box 1045, Camden, SC 29020, (803) 425-17867. Production site: Cassatt, SC 29032. [R5] USE: *MFR OF OTHER ALLYL COMPOUNDS [R2] *INSECTICIDAL FUMIGANT [R6] *CHEM INT IN ORGANIC SYNTHESIS, FOR RESINS (COPOLYMER WITH SULFUR DIOXIDE) AND FRAGRANCES [R1] *Contact poison [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS TO LIGHT YELLOW LIQUID [R3] ODOR: *UNPLEASANT, PUNGENT [R2] BP: *71.3 DEG C @ 760 MM HG [R2] MP: *-119 DEG C [R2] MW: *120.99 [R2] DEN: *1.398 @ 20 DEG C/4 DEG C [R2] HTC: *(est) 6700 BTU/lb= 3700 cal/g= 150X10+5 J/kg [R4] HTV: *(est) 110 BTU/lb= 59 cal/g= 2.5X10+5 J/kg [R4] OWPC: +log Kow = 1.79 [R8] SOL: *SLIGHTLY SOLUBLE IN WATER; MISCIBLE WITH ALCOHOL, CHLOROFORM, ETHER, CARBON DISULFIDE, CARBON TETRACHLORIDE [R2]; *Water solubility = 3835 mg/l at 25 deg C [R9] SPEC: *INDEX OF REFRACTION: 1.46545 @ 20 DEG C/D [R2]; *SADTLER REFERENCE NUMBER: 2539 (IR, PRISM) [R10]; *IR: 6163 (Coblentz Society Spectral Collection) [R11]; *UV: 5-9 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R11]; *NMR: 24 (Varian Associates NMR Spectra Catalogue) [R11]; *MASS: 473 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R11] SURF: *26.9 dynes/cm= 0.0269 N/m @ 20 deg C [R4] VAPD: +4.17 (AIR= 1) [R12, p. 49-14] OCPP: *Liquid-Water Interfacial Tension: (est) 40 dynes/cm= 0.040 N/m @ 20 deg C; Ratio of Specific Heats of Vapor (Gas): 1.1210 [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R13] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R13] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R13] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R13] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R13] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R13] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R13] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R13] FPOT: +Flammable and combustible liquid. [R12, p. 49-14] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R12, p. 325-12] +Flammability: 3. 3= Includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R12, p. 325-12] +Reactivity: 1. 1= Includes materials that are normally stable, but may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R12, p. 325-12] FLMT: +PERCENT BY VOL: LOWER: 4.4%; UPPER: 7.3%. [R12, p. 325-12] AUTO: +563 DEG F (295 DEG C) [R12, p. 325-12] FIRP: +WATER MAY BE INEFFECTIVE. [R12, p. 325-12] +USE DRY CHEMICAL, FOAM, CARBON DIOXIDE, OR WATER SPRAY. WATER MAY BE INEFFECTIVE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. APPROACH FIRE FROM UPWIND TO AVOID HAZARDOUS VAPORS AND TOXIC DECOMP PRODUCTS. [R12, p. 49-14] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R14] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame - consider evacuation of one-third (1/3) mile radius. [R14] TOXC: +COMBUSTION BY-PRODUCTS INCLUDE HYDROGEN BROMIDE. [R12, p. 49-14] OFHZ: +VAPORS ARE HEAVIER THAN AIR AND MAY TRAVEL TO A SOURCE OF IGNITION AND FLASH BACK. [R12, p. 49-14] EXPL: +Lower (4.4%), Upper (7.3%) [R12, p. 49-14] *Vapor may explode if ignited in an enclosed area. [R4] REAC: +Reacts with oxidizing materials, alkalies. [R12, p. 49-14] DCMP: +WHEN STRONGLY HEATED, THEY EMIT HIGHLY TOXIC FUMES OF /BROMIDES/. /BROMIDES/ [R15] POLY: +Polymerization may be caused by elevated temperature, oxidizers, peroxides. [R12, p. 49-14] SERI: *Irritation of eyes and respiratory tract. [R16] EQUP: *Goggles and face shield; protective clothing; self-contained breathing apparatus for high vapor concn. [R4] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to disperse vapors and dilute standing pools of liquid. [R14] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective clothing. [R14] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R14] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R17] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R18] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R19] STRG: +SEPARATE FROM OXIDIZING MATERIALS, ALKALIES. STORE IN COOL, DRY, WELL-VENTILATED LOCATION. [R12, p. 49-14] *KEEP TIGHTLY CLOSED. [R20] CLUP: +Spill or leak procedures: Releases may require isolation or evacuation. Eliminate all ignition sources. Stop or control the leak, if this can be done without undue risk. Use appropriate foam to blanket release and supress vapors. Absorb in noncombustible material for proper disposal. [R12, p. 49-14] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: +Causes severe eye and skin burns. Serious health hazard. May be harmful if absorbed through skin or inhaled. Irritating to eyes, skin, and respiratory system. [R12, p. 49-14] *Allyl bromide induced unscheduled DNA synthesis in HeLa cells. [R21] *...Is irritating to the eyes and respiratory passages. [R22] NTOX: *ONE OF THE MOST TOXIC OF THE HALOGENATED HYDROCARBONS, CAUSING DEATHS IN EXPERIMENTAL ANIMALS EXPOSED FOR 4 HR TO CONCENTRATIONS AS LOW AS 1 MG/L. ... DEATHS IN ANIMALS ARE APPARENTLY DUE TO LUNG INJURY, BUT SURVIVORS RECOVER WITHOUT SEQUELAE. [R6] *ALLYLATION OF A RIBONUCLEOSIDE MIXTURE WITH ALLYL BROMIDE IN DIMETHYLFORMAMIDE (DMF) RESULTED IN MODIFICATION OF ADENOSINE, GUANOSINE, AND CYTIDINE, BUT NOT URIDINE. IN 0.4 MOLAR POTASSIUM ACETATE, NO ALLYLATION OF RIBONUCLEOSIDES OCCURRED WITH ALLYL BROMIDE. NO ALLYLATION OF YEAST RIBOSOMAL AND TRANSFER RNA WAS OBSERVED ON TREATMENT WITH ALLYL BROMIDE IN POTASSIUM ACETATE; HOWEVER, IN DIMETHYLFORMAMIDE (DMF), ALLYLATION OCCURRED, BUT INVOLVED ONLY GUANINE, 7-ALLYLGUANINE BEING FORMED. [R23] *REACTIVITY OF ALLYL BROMIDE WAS DETERMINED BY MEASURING RATE CONSTANT OF REACTION WITH 4-(4-NITROBENZYL)PYRIDINE IN ACETOPHENONE TO FORM QUATERNARY AMMONIUM PRODUCTS, AND COMPARED WITH IP LD50 VALUES OF BROMO CMPD IN MICE. ALLYL BROMIDE HAD MUCH GREATER TOXICITY THAN DID THE ALKYL BROMIDES. [R24] *A SERIES OF CMPD, EACH CONTAINING AN ALLYLIC MOIETY, WAS TESTED USING SALMONELLA TYPHIMURIUM IN A MODIFIED AMES MUTAGENICITY ASSAY SYSTEM. THEIR MUTAGENIC ACTIVITY DECREASED AS FOLLOWS: ALLYL METHANESULFONATE, ALLYL IODIDE, ALLYL BROMIDE, AND ALLYL CHLORIDE. [R25] *Allyl bromide induced mutations in the Ames test. [R26] *Allyl ... bromide ... /was/ investigated for /its/ ... properties as sensory irritants in mice. The concn of the chemical necessary to depress the respiratory rate by 50% (RD50) within the first 10 minutes of exposure due to irritation of the upper respiratory tract ... /was/ 257 ppm. No pulmonary irritation was observed for allyl bromide ... . [R27] TCAT: ?Toxicity of 3-bromopropene (BP) with respect to testicular changes was evaluated in male albino Wistar rats (10/treated group, 20 in arachis oil vehicle control group) exposed orally to BP by gavage at dosage levels of 15 or 60 mg/kg/day for 14 days. On day 15, the animals were sent for pathological examination. Significant differences between treated and control animals were observed only in reduced body weights (high-dose level). No significant differences between treated and control animals were observed in the following: testes weights, morphology, or detailed macroscopic and microscopic examination of the kidneys, testes, epididymides, ductuli efferentes, and vasa deferentes. [R28, ] ?3-Bromopropene (CAS # 106-95-6) was evaluated for subchronic oral toxicity. The test substance was administered by oral gavage to 10 male rats/group for 14 days at 15 mg/kg or 60 mg/kg. Additional groups were exposed to the control vehicles (water or arachis oil) or the positive control, glycerol-a-monochlorohydrin. At 60 mg/kg, signs of compound-related intoxication included excessive salivation in a small number of animals, severe gastric irritation, reduced body weights, and reduced body weight gains. Exposure caused no morphological changes of the reproductive tract and no significant changes in mean testes weights. [R29] ?Toxicity of 3-bromopropene (BP) with respect to testicular changes was evaluated in male albino Wistar rats (10/treated group, 20 in arachis oil vehicle control group) exposed orally to BP by gavage at dosage levels of 15 or 60 mg/kg/day for 14 days. On day 15, the animals were sent for pathological examination. Significant differences between treated and control animals were observed only in reduced body weights (high-dose level). No significant differences between treated and control animals were observed in the following: testes weights, morphology, or detailed macroscopic and microscopic examination of the kidneys, testes, epididymides, ductuli efferentes, and vasa deferentes. [R28] METB: */ALLYL BROMIDE/...DOSED SC TO MALE RATS /WAS/...METABOLIZED INTO ALLYLMERCAPTURIC ACID, S-ALLYLCYSTEINE, AND S-ALLYLCYSTEINE S-OXIDE. 3-HYDROXYPROPYLMERCAPTURIC ACID WAS /PROBABLY/ A METABOLITE... [R30] *S-ALLYL-L-CYSTEINE WAS ISOLATED FROM URINE OF RATS DOSED WITH ALLYL BROMIDE. [R31] *Urinary excretion of 3-hydroxypropylmercapturic acid (S-(3-hydroxypropyl)-N-acetyl-L-cysteine) following exposure to allylic compounds was studied in rats to examine the possibility of using 3-hydroxypropylmercapturic acid (S-(3-hydroxypropyl)-N-acetyl-L-cysteine) as a biological marker of exposure to allylic compounds that were metabolized to acrolein and excreted as 3-hydroxypropylmercapturic acid (S-(3-hydroxypropyl)-N-acetyl-L-cysteine) in the urine. Male Sprague Dawley rats were given ... 120 mg/kg allylbromide ... by gavage. Twenty four hour urine samples were collected for the next 48 hours and analyzed for 3-hydroxypropylmercapturic acid (S-(3-hydroxypropyl)-N-acetyl-L-cysteine) by HPLC. ... Total urinary excretion of 3-hydroxypropylmercapturic acid (S-(3-hydroxypropyl)-N-acetyl-L-cysteine) as a percentage of the dose ... averaged ... 3.0 percent for allylbromide ... . [R32] *Wistar rats were administered carbon 14 labeled ... allyl bromide ... orally. Urine, feces, exhaled carbon dioxide, and air were collected and analyzed for metabolites. The major metabolite found after treatment with ... allylbromide was S-carboxyethyl mercapturic acid. [R33] INTC: *IN RATS, CYSTEINE MAGNESIUM NITRATE AND CYSTEINE MAGNESIUM ACETATE ADMIN IP RESULTED IN 17-33% HIGHER SURVIVAL RATE FOLLOWING ALLYL BROMIDE POISONING THAN DID CYSTEINE ADMIN. CYSTEINE MAGNESIUM BROMIDE WAS AS EFFECTIVE AS CYSTEINE AGAINST ALLYL BROMIDE POISONING. [R34] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Allyl bromide's use in the synthesis of other allyl compounds and as a contact poison could result in its release to the environment through various waste streams. Allyl bromide should have very high mobility in soil. Volatilization of allyl bromide is expected from both moist and dry soils. In water, allyl bromide is expected to volatilize rapidly with estimated half-lives of 3.3 hours and 4.38 days from a model river and a model lake, respectively. Hydrolysis of allyl bromide is expected to be an important fate process with an experimental half-life of 12 hours. Allyl bromide's water solubility of 3835 mg/l indicates that bioconcentration and adsorption to sediment are not expected to be important in aquatic systems. Biodegradation of allyl bromide may be an important fate process in both soil and aquatic conditions based on a BOD dilution test. Allyl bromide will exist in the vapor phase in the ambient atmosphere. If released to the atmosphere, it will degrade by reaction with photochemically produced hydroxyl radicals with an estimated half-life of approximately 19 hours. It will also react with atmospheric ozone with estimated half-life of 7.28 days. Removal of allyl bromide from the atmosphere can occur though wet deposition. Exposure to allyl bromide can occur through dermal contact, inhalation, and ingestion. (SRC) ARTS: *Allyl bromide's use in the synthesis of other allyl compounds(1) and as a contact poison(2) could result in its release to the environment through various waste streams(SRC). [R35] FATE: *TERRESTRIAL FATE: If released to soil, allyl bromide should have very high mobility(3) in soil based on estimated Koc values of 44 and 47(1,2). Biodegradation of allyl bromide is expected to be an important fate process based on a BOD dilution test(6). Volatilization of allyl bromide is expected from moist and dry soils based on an estimated vapor pressure of 136 mm Hg at 25 deg C(4) and an estimated Henry's Law constant of 0.011 atm-cu m/mole(5). [R36] *AQUATIC FATE: Allyl bromide is expected to volatilize rapidly from water(2) based upon an estimated Henry's Law constant of 0.011 atm-cu m/mol(1,SRC). Based on this Henry's Law constant the volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 3.3 hours(2,SRC). The volatilization half-life from a model lake (1 meter deep) can be estimated to be about 4.38 days(2,SRC). Biodegradation of allyl bromide may be an important fate process based on a BOD dilution test(3). Hydrolysis of allyl bromide is expected to be an important fate process with an experimental half-life of 12 hours(4). Allyl bromide's water solubility of 3835 mg/l(5) indicates that aquatic bioconcentration and adsorption to sediment are not expected to be important(SRC). [R37] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of 136 mm Hg at 25 deg C(1), allyl bromide will exist in the atmosphere in the vapor phase(2). It will degrade in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of 19 hours, and with atmospheric ozone with an estimated half-life of 7.28 days(3). Removal of allyl bromide from the atmosphere can occur through wet deposition(SRC). [R38] BIOD: *Using a standard BOD dilution test and an inoculum from a sanitary waste treatment facility, a theoretical BOD of 56% and 74% was observed over a 5 day incubation period, with stirring and seeding adaptation, respectively(2). [R39] ABIO: *The rate constant for the vapor-phase reaction of allyl bromide with photochemically produced hydroxyl radicals has been estimated to be approximately 20.25X10-12 cu cm/molecule-sec at 25 deg C, which corresponds to an atmospheric half-life of about 19 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The reaction rate of allyl bromide with atmospheric ozone has been estimated to be 0.1575X10-17 cu meter/molecule-sec which corresponds to an atmospheric half-life of 7.28 days at an ozone concentration of 7X10+11 molecules/cu centimeter(1,SRC). Significant reductions of allyl bromide in the presence of sulfite were observed (89%), reaction kinetics were highly pH dependent and modeled as first order: 0.11720 per minute at pH 8.1, 0.11755 per minute at pH 10.0, and not significant at pH 3(2). The neutral hydrolysis rate constant for allyl bromide is given as 1.674X10-5 per second with a half-life of 12 hours(3,4). At 25 deg C, allyl bromide undergoes neutral hydrolysis at an observed rate of 1.698X10-5 per second(5). [R40] BIOC: *Based upon an experimental water solubility of 3835 mg/l(1), the BCF of allyl bromide can be estimated to be approximately 6 from a regression-derived equation(2). This estimated BCF value suggests that bioconcentration in aquatic organisms will not be an important fate process(SRC). [R41] KOC: *Using a structure estimation method based on molecular connectivity indexes, the Koc for allyl bromide can be estimated to be about 44(1,SRC). The Koc for isopropyl bromide can also be estimated to be about 47(SRC) based on an experimental water solubility of 3835 mg/L(3) and a regression derived equation(2). According to a suggested classification scheme(4), these estimated Koc values suggest that allyl bromide has very high soil mobility. [R42] VWS: *The Henry's Law constant for allyl bromide can be estimated to be 1.11X10-2 atm-cu m/mole using a structure estimation method(1). Another study calculated the Henry's Law for isopropyl bromide to be 5.87X10-3 atm-cu meter/mol(2). These values of the Henry's Law constant indicate that volatilization of allyl bromide from water is rapid(4). Based on the Henry's Law constant value of 1.11X10-2 atm-cu meter/mole(1), the volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 3.3 hours(4,SRC). The volatilization half-life from a model lake (1 meter deep) can be estimated to be about 4.38 days(4,SRC). [R43] ATMC: *SOURCE DOMINATED: Allyl bromide was detected in the atmosphere at two source dominated sites in Arkansas: over El Dorado at a mean concentration of 7.1X10-1 ppbv (from a total 51 samples with only one sample reported at a concentration of 6.7 ppbv), and over Magnolia at a mean concentration of 3.0X10-1 ppbv (from a total 17 samples with only one sample reported at a concentration of 2.5 ppbv)(1). Allyl bromide was detected in ambient air surrounding Arkansas Chemical Incorp. in El Dorado, AR at three different locations at concentrations of 70, trace, and 29.7 ng/cu meter on September 20, 1976(2). Allyl bromide was also detected in ambient air surrounding Great Lakes Corp. El Dorado, AR at concentrations of 8.4, trace, 8, 2.5 and 24.8 (water tower) ng/cu meter(2). Allyl bromide was also detected in ambient air surrounding Michigan Chemical Corp. El Dorado, AR at concentrations of trace, 3.2, and 32.9 (15-18 ft elevation) ng/cu meter(2). Allyl bromide was also detected in ambient air surrounding Ethyl Corp. Magnolia, AR at concentrations of 9.4 and 15.8 ng/cu meter(2). [R44] RTEX: *Occupational exposure to allyl compounds, such as allyl bromide, can occur through dermal contact, inhalation, and ingestion(1). [R45] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for allyl bromide. Route: topical; Species: mice. [R46] SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 49 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 39 R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 491 R6: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-113 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V4 256 (1978) R8: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 5 R9: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-463 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 181 R12: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R13: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-131 R14: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 42 R15: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 518 R16: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 22 R17: 49 CFR 171.2 (7/1/96) R18: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 94 R19: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3055 (1988) R20: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 44 R21: Schiffmann D et al; Cancer Lett 20 (3): 263-9 (1983) R22: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 69 R23: BOLLACK C, EBEL JP; BULL SOC CHIM BIOL 50 (12): 2351-62 (1968) R24: FISCHER GW ET AL; J PRAKT CHEM 320 (1): 133-9 (1978) R25: EDER E ET AL; BIOCHEM PHARMACOL 29 (7): 993-8 (1980) R26: Schiffmann D et al; Induction of Unscheduled DNA Synthesis in HeLa Cells by Allylic Compounds; Cancer Lett 20 (3): 263-9 (1983) R27: Nielsen GD, Bakbo JC; Acta Pharmacol Toxicol (Copenh) 57 (2): 106 (1985) R28: Tunstall Lab, Shell Oil Co.; Toxicity of Fine chemicals: Preliminary Studies for the Detection of Testicular Changes in Rats. (1979), EPA Document No. 878216424, Fiche No. OTS0510352 R29: SHELL OIL CO; Toxicity of Fine Chemicals: Preliminary Studies for the Detection of Testicular Changes in Rats with Cover Letter Dated 042586; 11/08/79; EPA Doc. No. 878216424; Fiche No. OTS0510352 R30: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 433 R31: KAYE CM ET AL; XENOBIOTICA 2 (2): 129-39 (1972) R32: Sanduja R et al; J Appl Toxicol 9 (4): 235 (1989) R33: Eder E et al; Archives of Toxicol 60 (1-3): 182 (1987) R34: VASILEVA ZA ET AL; FIZIOL AKT VESHCHESTVA 9: 52-4 (1977) R35: (1) Budavari S et al; The Merck Index 11th ed Rahway, NJ: Merck and Co Inc (1989) (2) Stenger VA; in Kirk-Othmer Encycl Chem Tech 3rd ed NY, NY: Wiley 4: 256 (1978) R36: (1) Meylan WM et al; Environ Sci Technol 28: 459-65(1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Lyman WJ; pg 31 in Environmental Exposure from Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton, FL: CRC Press (1985) (5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (6) Bridie AL et al; Water Res 13: 627-30 (1979) R37: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington,DC: Amer Chem Soc p.15-15 to 15-29 (1990) (3) Bridie AL et al; Water Res 13: 627-30 (1979) (4) Mabey W, Mill T; J Phys Chem Ref Data 2: 383-415 (1978) (5) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) R38: (1) Lyman WJ; pg 31 in Environmental Exposure from Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton, FL: CRC Press (1985) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R39: (1) Bridie AL et al; Water Res 13: 627-30 (1979) R40: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Bauman L, Stenstrom MK; Environ Sci Technol 23: 232-6 (1989) (3) Mabey W, Mill T; J Phys Chem Ref Data 2: 383-415 (1978) (4) Macalady DL, Schwarzenbach RP; Chem Exposure Predict. Calamari D (ed). Lewis Publ Boca Raton, FL Chpt 3 pp. 27-46 (1993) (5) Robertson RE, Scott JMW; J Chem Soc 1961: 1596-604 (1961) R41: (1) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-10 (1990) R42: (1) Meylan WM et al; Environ Sci Technol 28: 459-65(1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R43: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Yaws C et al; Chem Engin November 1991: 179-85 (1991) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) R44: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. Menlo Park, CA: Atmospheric Science Center. SRI International. Contract 68-02- 3452. 198 pp. (1982) (2) Pellizzari ED et al; Environmental Monitoring Near Industrial Sites: Brominated Chemicals Part . Washington, DC: USEPA. Office of Toxic Substances (1978) R45: (1) Parmeggiani L; Encycl Occup Health and Safety 3rd ed Geneva, Switzerland: International Labour Office pg 128 (1983) R46: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.20 RS: 34 Record 78 of 1119 in HSDB (through 2003/06) AN: 669 UD: 200303 RD: Reviewed by SRP on 1/31/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SACCHARIN- SY: *ANHYDRO-O-SULFAMINEBENZOIC-ACID-; *1,2-Benzisothiazolinone,-1,1-Dioxide-; *1,2-BENZISOTHIAZOLIN-3-ONE,-1,1-DIOXIDE-; *3-BENZISOTHIAZOLINONE-1,1-DIOXIDE-; *1,2-BENZISOTHIAZOL-3(2H)-ONE, 1,1-DIOXIDE; *BENZOIC-SULFIMIDE-; *O-BENZOIC-SULFIMIDE-; *O-BENZOSULFIMIDE-; *BENZOSULFINIDE-; *BENZOSULPHIMIDE-; *O-BENZOSULPHIMIDE-; *BENZO-2-SULPHIMIDE-; *BENZO-SULPHINIDE-; *O-BENZOYL-SULFIMIDE-; *Benzoylsulfonic-Imide-; *O-BENZOYL-SULPHIMIDE-; *1,2-DIHYDRO-2-KETOBENZISOSULFONAZOLE-; *2,3-DIHYDRO-3-OXOBENZISOSULFONAZOLE-; *GARANTOSE-; *GLUCID-; *GLUSIDE-; *HERMESETAS-; *3-HYDROXYBENZISOTHIAZOLE-S,S-DIOXIDE-; *INSOLUBLE-SACCHARIN-; *KANDISET-; *NATREEN-; *SACARINA-; *SACCHARIMIDE-; *SACCHARINA-; *SACCHARIN-ACID-; *SACCHARINE-; *SACCHARIN-INSOLUBLE-; *SACCHARINOL-; *SACCHARINOSE-; *SACCHAROL-; *SAXIN-; *SUCRE-EDULCOR-; *SUCRETTE-; *O-SULFOBENZIMIDE-; *O-SULFOBENZOIC-ACID-IMIDE-; *2-Sulphobenzoic-Imide-; *SYKOSE-; *ZAHARINA- RN: 81-07-2 MF: *C7-H5-N-O3-S HAZN: U202; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. ASCH: Sodium saccharin; 128-44-9; Calcium saccharin; 6485-34-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *TOLUENE IS REACTED WITH CHLOROSULFONIC ACID TO FORM O-TOLUENESULFONYL CHLORIDE, WHICH IS CONVERTED TO THE SULFONAMIDE WITH AMMONIA. THE METHYL GROUP IS THEN OXIDIZED WITH DICHROMATE YIELDING O-SULFAMYLBENZOIC ACID WHICH, WHEN HEATED, FORMS THE CYCLIC IMIDE. [R1] *A mixture of toluenesulfonic acids is converted into the sodium salt then distilled with phosphorus trichloride and chlorine to obtain the o-toluene sulfonyl chloride which, by means of ammonia, is converted into o-toluenesulfamide. This is oxidized with permanganate, treated with acid, and saccharin crystallized out. [R2] *Saccharin and sodium saccharin are produced commercially in the USA only by the Maumee process. Methyl anthranilate (made either by the methylation of anthranilic acid, the reaction of phthalic anhydride with ammonia, sodium hypochlorite and methanol, or the reaction of isatoic anhydride with methanol) is diazotized by treatment with sodium nitrite and hydrochloric acid to form 2-carbomethoxybenzenediazonium chloride. Sulfonation of this produces 2-carbomethoxybenzenesulfinic acid, which is converted to 2-carbomethoxybenzenesulfonyl chloride with chlorine. Amidation of this sulfonylchloride, followed by acidification, forms saccharin, which is treated with either sodium hydroxide or sodium bicarbonate to produce sodium saccharin. Calcium saccharin can be produced by the reaction of calcium hydroxide with saccharin. [R3] IMP: *Sodium bicarbonate is added to provide water solubility. [R2] *o- and p-Toluenesulfonamide; 1,2-benzisothiazol-1,1-dioxide; 1,2-benzisothiazoline-1,1-dioxide; 3-aminobenzisothazol-1,1-dioxide; 5- and 6-chlorosaccharin; ammonium saccharin; methyl saccharin; diphenyl sulfone; ditolylsulphone isomers; o- and p-sulfamoylbenzoic acid; o-chlorobenzoic acid; o-sulfobenzoic acid (and ammonium salt); n-tetracosane; bis(4-carboxyphenyl)sulfone; toluene-2,4-disulfonamide; saccharin-o-toluenesulfonamide; saccharin-6-sulfonamide; N-methyl-o-toluene-sulfonamide; methyl-o-chlorobenzoate; 4,4'-dibenzoylsulfone; 2- or 3-carboxy thiaxanthone-5-dioxide; o-sulfobenzamide; methyl-o-sulfamoylbenzoate; methyl-N-methylsulfamoylbenzoate; saccharin-o-toluenesulfoxylimide; and other /Reported impurities in saccharin and sodium saccharin/ [R4] FORM: *WHILE ACID FORM OF SACCHARIN IS WELL-RECOGNIZED ARTICLE OF COMMERCE, SALTS ARE PRODUCTS ACTUALLY USED IN FORMULATION OF FOODS AND BEVERAGES. ... CALCIUM ... AMMONIUM AND OTHER SALTS HAVE BEEN PREPD AND USED TO LIMITED EXTENT. ... CALCIUM ... MUST MEET USP SPECIFICATIONS IN TERMS OF PHYSICAL PROPERTIES AND IMPURITIES. [R5, 526] *Grades: Commercial; CP /Chemically pure: A grade designation signifying a minimum of impurities, but not 100% pure/; USP /United States Pharmacopeia/; FCC /Food Chemicals Codex/. [R2] *Assugrin vollsuss (also contains sodium cyclamate). [R6] *Available in the USA as saccharin insoluble powder FCC (Food Chemicals Codex): 98-101% active ingredient on an anhydrous basis, a maximum of 100 mg/kg toluenesulphonamides, 30 mg/kg selenium, 10 mg/kg heavy metals (as lead) and 3 mg/kg arsenic ... available in the USA as a USP grade containing 98-101% active ingredient on an anhydrous basis. [R6] MFS: *PMC, Inc, Hq, 12243 Brandford St, PO Box 1367, Sun Valley, CA 91352, (818) 896-1101; PMC Specialties Group Division, 20525 Center Ridge Rd, Rocky River, OH 44116; Production site 501 Murray Rd, Cincinnati, OH 45217 [R7] OMIN: *SWEETENING AGENT IN AROMATIC CASCARA SAGRADA FLUID EXTRACT AND HIGHLY ALCOHOLIC PREPN. ... IT IS USED AS SWEETENING AGENT IN VEHICLES, CANNED FOODS, BEVERAGES, AND IN DIETS FOR DIABETICS TO REPLACE SUCROSE. RELATIVE SWEETENING POWER OF SACCHARIN IS INCR BY DILUTION. [R1] *Industrial grade sodium saccharin is reportedly used as a brightener in nickel-plating baths, as an antistatic agent in plastics and textiles, as a polymer modifier and accelerator in photosensitive dispersions, and as a light fastness aid in nylon dyes. /Sodium saccharin/ [R8] *NAS has stated that saccharin is a weak carcinogen in animals and a potential human carcinogen. Products containing it must have a warning label. [R2] *Sodium saccharin FCC (Food Chemicals Codex) is available in the USA in four grades: spray-dried, containing 3.0% moisture; powder, containing 5.0-5.8% moisture; pelletized, containing 10.5-11.5% moisture; and granular, containing 14.0-15.0% moisture. Each of these grades meets or exceeds the following Food Chemicals Codex specifications: 98-101% active ingredient on an anhydrous basis, 3-15% water, 100 mg/kg toluenesulphonamides, 30 mg/kg selenium, 10 mg/kg heavy metals (as lead) and 3 mg/kg arsenic. /Sodium saccharin/ [R9] *SACCHARIN IS DISSOLVED IN EQUIMOLAR QUANTITY OF AQ SODIUM HYDROXIDE AND THE SOLN IS CONCN TO CRYSTALLIZATION. /SODIUM SALT/ [R1] *SACCHARIN IS REACTED WITH SEMIMOLAR QUANTITY OF CALCIUM HYDROXIDE IN AQ MEDIUM AND RESULTING SOLN IS CONCN TO CRYSTALLIZATION. /CALCIUM SALT/ [R1] *In 1977 and later amended in 1984, the FDA ruled that the use of saccharin as a food an beverage additive would be permitted on an interim basis and use was considerably reduced. [R10] USE: *NON-CALORIC SYNTHETIC SWEETENER IN TABLETS, LIQ PRODUCTS, SOFT DRINKS, DIETETIC FOODS, MISC PHARMACEUTICALS, CHEWING GUM, TOOTH PASTE, SMOKELESS TOBACCO PRODUCTS; ELECTROPLATING BATH ADDITIVE; CATTLE FEED ADDITIVE; ANTISEPTIC (FORMER USE); PRESERVATIVE TO RETARD FERMENTATION OF FOOD (FORMER USE). [R11] *Saccharin has been used in the sweetening of pharmaceutical tablets and in processing of tobacco. [R8] *In 1976, 77% of all forms of saccharin consumed in the US was added to food(1). In particular, 45% was used in soft drinks, 18% in table top sweeteners, and 14% in other foods such as fruits, premixes, juices, sweets, chewing gums and jellies. Typical concn of saccharin in sugar substitutes, carbonated soft drinks, jams and jellies, and chewing gum are 13.5 mg/teaspoon, 5.5 mg/fluid ounce, 4.5 mg/teaspoon and 2.2 mg/stick, respectively. [R12] CPAT: *The USA consumption pattern for saccharin (all forms) in 1976 has been estimated as follows: 77% in food uses: 45% in soft drinks, 18% in 'tabletop' sweetener, and 14% in other foods such as fruits, premixes, juices, sweets, chewing gum and jellies; and 23% in nonfood items: 10% in cosmetics such as toothpaste, mouthwash and lipstick, 7% in pharmaceuticals such as coatings on pills, 2% in smokeless tobacco products such as chewing tobacco and snuff, 2% in electroplating, 1% in cattle feed and 1% in miscellaneous uses. /Saccharin and its salts/ [R8] *In 1976, 23% of all forms of saccharin consumed in the US was added to non-food items. In particular, 10% was used in cosmetics such as toothpaste, mouthwash and lipstick; 7% in pharmaceuticals such as coatings on pills; 2% in smokeless tobacco such as chewing tobacco and snuff; 2% in electroplating; 1% in cattle feed and 1% in miscellaneous uses. [R13] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 2.18X10+9 G (EST-INCL SALT) [R11] *(1982) AT LEAST 2.00X10+9 G (EST) [R11] *(1985) Not reported [R14] U.S. IMPORTS: *(1977) 1.35X10+9 G [R11] *(1982) 1.34X10+9 G [R11] *(1985) 8.07X10+8 g. [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Monoclinic crystals [R16, 1430]; *WHITE CRYSTALS OR WHITE CRYSTALLINE POWDER. [R1] ODOR: *ODORLESS OR HAS FAINT AROMATIC ODOR. [R1] TAST: *In dil aq soln it is 500 times as sweet as sugar; sweet taste detectable in 1:100,000 diln. [R16, 1430]; *Bitter, metallic aftertaste [R16, 1430] MP: *228.8-229.7 deg C [R16, 1430] MW: *183.19 [R17] DEN: *0.828 [R16, 1430] DSC: *pKa= 1.31 @ 25 deg C for the conjugate acid [R18] HTC: *@ const vol: 4753.1 cal/g [R16, 1430] OWPC: *log Kow= 0.91. [R19] PH: *Acid to litmus; pH of 0.35% aq soln 2.0 [R16, 1430] SOL: *1 g dissolves in 290 ml water, 25 ml boiling water, 31 ml alc, 12 ml acetone, and in about 50 ml glycerol; freely sol in soln of alkali carbonates; slightly sol in chloroform, ether [R16, 1430]; *DISSOLVED BY DIL SOLN OF AMMONIA, SOLN OF ALKALI HYDROXIDES [R1]; *In water, 4300 mg/l at 25 deg C. [R20] SPEC: *MAX ABSORPTION (0.1 N NAOH): BROAD PEAK @ 267.3 NM (E= 1570) [R21]; *SADTLER REF NUMBER: 322 (IR, PRISM); 110 (IR, GRATING) [R22]; *IR: 5038 (Coblentz Society Spectral Collection) [R23]; *UV: 15734 (Sadtler Research Laboratories Spectral Collection) [R23]; *NMR: 6667 (Sadtler Research Laboratories Spectral Collection) [R23]; *MASS: 4335 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R23] OCPP: *Perfect 100 cleavage; acicular crystals by vacuum sublimation. [R16, 1460] *1 G SOL IN 2.6 ML WATER, 4.7 ML ALC /CALCIUM SALT/. [R1] *SOL: 30.5 G/100 G 92.5% ETHANOL-WATER MIXT @ 25 DEG C; 35.1 G/100 G PROPYLENE @ 25 DEG C; 36.3 G/100 ML GLYCOL @ 25 DEG C; 13.3 G/100 ML GLYCERIN @ 25 DEG C. /CALCIUM SALT/ [R5, 529] *FREELY SOL IN WATER. /AMMONIUM SALT/ [R24] *1 g dissolves in 1.2 ml water, about 50 ml alc. /Sodium salt/ [R16, 1460] *SOL: 2.6 G/100 G 92.5% ETHANOL-WATER @ 25 DEG C; 44.7 G/100 G PROPYLENE @ 25 DEG C; 46.2 G/100 ML GLYCOL @ 25 DEG C; 55.8 G/100 G GLYCERIN @ 25 DEG C. /SODIUM SALT/ [R5, 529] *INDEX OF REFRACTION: 1.480 (ALPHA), GREATER THAN 1.523 (BETA), 1.692 (GAMMA) /CALCIUM SALT/ [R25, 298] *INDEX OF REFRACTION: 1.560 (ALPHA); 1.642 (BETA); 1.733 (GAMMA). /SODIUM SALT/ [R25, 323] *Aq soln are neutral or alkaline to litmus, but not to phenolphthalein; effloresces in dry air. /Sodium salt/ [R16, 1460] *Sublimes in vacuum. [R17] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *WHEN HEATED TO DECOMP IT EMITS TOXIC FUMES OF SO(X) AND NO(X). [R26] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R27, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R27, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R27, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R27, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R27, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R27, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R27, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R27, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R27, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R27, 1979.11] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R27, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R27, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R27, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R27, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U202, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R28] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R29] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R27, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R27, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R27, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R27, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R27, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated saccharin for carcinogenicity. According to their analysis, the weight-of-evidence for saccharin is group C, which is based on inadequate evidence in humans and limited evidence in animals. As a group C chemical, saccharin is considered to be possibly carcinogenic to humans. [R30] *Evaluation: There is inadequate evidence in humans for the carcinogenicity of saccharin salts used as sweeteners. There is sufficient evidence in experimental animals for the carcinogenicity of sodium saccharin. There is inadequate evidence in experimental animals for the carcinogenicity of saccharin (acid form) and calcium saccharin. Overall evaluation: In making the evaluation, the Working Group concluded that sodium saccharin produced urothelial bladder tumors in rats by a non-DNA reactive mechanism that involves the formation of a urinary calcium phosphate containing precipitate, cytotoxicity and enhanced cell proliferation. The mechanism is not relative to humans because of critical interspecies differences in urine composition. Saccharin and its salts are not classifiable as to the carcinogenicity to humans (Group 3). [R31] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R27, 1979.23] HTOX: *LARGE DAILY DOSES MAY ... PRODUCE GASTRIC HYPERACIDITY. [R32] *A SURVEY OF BLADDER CANCER PATIENTS AND CONTROLS WITHOUT BLADDER CANCER SHOWED THAT IN GENERAL BLADDER CANCER RISK WAS NOT INCREASED BY NONNUTRITIVE SWEETENER SACCHARIN AND CYCLAMATE USE. ADJUSTING FOR SMOKING HABITS, OCCUPATION, AGE, RACE, SEX, DIABETES MELLITUS, ETC DID NOT LEAD TO SIGNIFICANT CORRELATIONS BETWEEN THE SWEETENER USE AND BLADDER CANCER. [R33] *THE RELATION BETWEEN CANCER OF THE LOWER URINARY TRACT AND USE OF ARTIFICIAL SWEETENERS CYCLAMATES AND SACCHARIN WAS EVALUATED IN A CASE CONTROL STUDY OF 592 PATIENTS, AGED 21 TO 89 YR, WITH LOWER URINARY TRACT CANCER (94% OF WHOM HAD BLADDER TUMORS) and 536 CONTROLS CHOSEN FROM THE GENERAL POPULATION OF THE STUDY AREA. IN THOSE WHO HAD USED SUGAR SUBSTITUTES AND DIETETIC BEVERAGES, THE RELATIVE RISK OF LOWER URINARY TRACT CANCER WAS ESTIMATED TO BE 0.9, AS COMPARED WITH ONE IN NONUSERS OF ARTIFICIAL SWEETENERS. AMONG MEN, THE RELATIVE RISK WAS 0.8 IN THOSE WHO HAD USED SUGAR SUBSTITUTES. AMONG WOMEN, THE CORRESPONDING RELATIVE RISKS WERE 1.6 and 1.5. INCREASING FREQUENCY OR DURATION OF USE OF ARTIFICIAL SWEETENERS WAS NOT CONSISTENTLY ASSOCIATED WITH INCREASING RELATIVE RISK. THIS STUDY SUGGESTS THAT, AS A GROUP, USERS OF ARTIFICIAL SWEETENERS HAVE LITTLE OR NO EXCESS RISK OF CANCER OF THE LOWER URINARY TRACT. [R34] *POSITIVE ASSOC BETWEEN USE OF ARTIFICIAL SWEETENERS, PARTICULARLY SACCHARIN, AND RISK OF BLADDER CANCER IN MALES WAS OBSERVED IN CASE CONTROL STUDY OF 480 MEN AND 152 WOMEN IN 3 PROVINCES IN CANADA. [R35] *... No increase in spontaneous abortions among women taking saccharin. [R36] *...reported 5 patients in whom oral administration of 0.1 g saccharin caused pruritis and oedematous papules on the trunk and limbs. [R37] NTOX: *GROUPS OF 50 MALE AND 50 FEMALE 30-DAY OLD CHARLES-RIVER CD RATS WERE FED EITHER A CONTROL DIET OR A DIET CONTAINING 5% SODIUM SACCHARIN PREPD BY THE MAUMEE PROCESS ... AND FREE OF ORTHO-TOLUENESULFONAMIDE. SURVIVAL WAS NOT AFFECTED BY TREATMENT. BLADDER TUMORS (BENIGN AND MALIGNANT) WERE OBSERVED IN 1/36 CONTROL MALES AND 7/38 MALE RATS FED SACCHARIN WHICH SURVIVED 87 WK OR MORE THE TIME IN WHICH THE FIRST TUMOR WAS OBSERVED ... IN ADDN, 1 TREATED MALE AND 2 TREATED FEMALES HAD UROTHELIAL TUMORS OF THE KIDNEY PELVIS AND 1 TREATED MALE HAD URETHRAL TUMOR; NO OTHER UROTHELIAL TUMORS WERE OBSERVED IN CONTROLS. /SODIUM SALT/ [R38] *ADDN OF 0.5% SODIUM SACCHARIN TO THE DIET REDUCED THE GROWTH RATE OF RATS OVER A 38-DAY PERIOD. THE FEEDING OF 0.065 G/KG BODY WT/DAY SODIUM SACCHARIN TO DOGS FOR 11 MO PRODUCED NO TOXIC EFFECTS OTHER THAN OCCASIONAL STOOL SOFTENING. ... ADMIN OF 1% SODIUM SACCHARIN IN DRINKING-WATER AND/OR FOOD DECR WT GAIN AND CAUSED DEATH IN RATS FED REDUCED FOOD RATIONS. /SODIUM SALT/ [R39] *RABBITS ARE KILLED BY ORAL DOSES OF 8 TO 10 G/KG, PRESUMABLY AS RESULT OF GASTROENTERITIS. [R32] *CHRONIC ADMIN OF SACCHARIN IN DRINKING WATER TO SYRIAN GOLDEN HAMSTERS, UP TO MAX TOLERATED DOSE LEVEL, FAILED TO INDUCE EXCESS OF TUMORS, NOR WERE ANY URINARY BLADDER TUMORS FOUND. [R40] *SUBACUTE TOXICITY WITH SODIUM SACCHARIN WAS EVALUATED BY FEEDING AT DIETARY LEVEL OF 2000 PPM TO BOTH BEAGLE DOGS AND ALBINO RATS. DOGS WERE MAINTAINED ON TEST DIETS FOR 16 WK, RATS FOR 13 WK. NO SIGNS OF PHARMACOTOXIC RESPONSE TO THE TEST MATERIAL WAS OBSERVED. /SODIUM SACCHARIN/ [R41] *MAINLY TESTED AS ITS SODIUM SALT, SACCHARIN HAS BEEN FOUND TO BE WEAKLY MUTAGENIC IN SALMONELLA @ HIGH DOSES, IN DROSOPHILA @ MODERATE DOSES, AND IN MICE @ MODERATE TO HIGH DOSES. CMPD IS WEAK CHROMOSOME BREAKER IN ONION ROOT TIPS AND IN CHINESE HAMSTER CELLS. FOR MOST OF THESE, AND FOR OTHER TEST SYSTEMS AS WELL, A NUMBER OF DOUBTFUL OR NEG RESULTS HAVE BEEN REPORTED. IT IS SUGGESTED THAT THE OBSERVED CONTRAINDICATIONS MIGHT BE RELATED TO THE OCCURRENCE OF VARYING AMT OF IMPURITIES. /SODIUM SACCHARIN/ [R42] *IN MALE MICE INJECTED IP WITH 1, 2, OR 4 G SACCHARIN PER KG BODY WT OR RECEIVING DURING A 100 DAY PERIOD 20 G OF SACCHARIN PER LITER OF DRINKING WATER AND TESTED FOR MUTAGENICITY, YIELDED NEG RESULTS. IT IS CONCLUDED THAT THE POS FINDINGS REPORTED IN THE LITERATURE WERE PROBABLY DUE TO THE MUTAGENIC ACTIVITY OF SACCHARIN IMPURITIES. [R43] *MALE AND FEMALE WISTAR RATS WERE ADMIN SODIUM SACCHARIN FOR LIFE (2 YR) EITHER IN THE DRINKING WATER OR DIET. A CONTROL GROUP RECEIVED SACCHARIN-FREE DIET AND DRINKING WATER. MILD UROTHELIAL HYPERPLASIAS DEVELOPED FROM 85 WK IN RATS OF BOTH SEXES RECEIVING SACCHARIN, THE INCIDENCE WAS STATISTICALLY SIGNIFICANT IN BOTH THE BLADDERS AND KIDNEYS OF RATS RECEIVING THE HIGHER DOSE IN DIET, BUT IN KIDNEYS ONLY RECEIVING THE LOWER DOSE IN DRINKING WATER. TELANGIECTASIA OF THE VASA RECTA WAS SIGNIFICANT IN RATS OF BOTH SEXES. A VERY LOW INCIDENCE OF BLADDER TUMORS, EXCLUSIVELY IN MALES RECEIVING THE HIGHER DOSE WAS SEEN FROM 95 WK. THE POSSIBILITY THAT SACCHARIN MAY PROMOTE, OR ENHANCE, THE DEVELOPMENT OF LATENT TUMOR CELLS ALREADY PRESENT IS CONSIDERED. /SODIUM SACCHARIN/ [R44] *NO EFFECTS ON REPRODUCTION WERE OBSERVED IN 20 MICE RECEIVING 194 MG/KG BODY WT SACCHARIN DAILY FOR 180 DAYS. ORAL DOSES OF UP TO 600 MG/KG BODY WT PER DAY SACCHARIN OR ITS SODIUM SALT GIVEN OVER THE TOTAL ORGANOGENESIS PHASE HAVE NOT BEEN FOUND TO INDUCE MALFORMATIONS OR OTHER EMBRYOTOXIC EFFECTS IN MICE, RATS, RABBITS. [R45] *A HIGHLY PURIFIED PREPN OF SACCHARIN ... CAUSED A SIGNIFICANT, DOSE-RELATED INCR IN CHROMOSOME ABERRATIONS (BREAKS, GAPS, TRANSLOCATIONS AND RING FORMATIONS) IN CHINESE HAMSTER OVARY (CHO) CELLS IN THE PRESENCE OF LIVER HOMOGENATE. IT WAS REPORTED ... THAT CHROMATID BREAKS AND GAPS WERE ALSO INDUCED IN CHO-K1 CELLS TREATED WITH SODIUM SACCHARIN ... ABERRATIONS HAVE BEEN INDUCED BY SACCHARIN AND ITS SODIUM SALT IN OTHER CHINESE CELL LINES. [R46] *... SACCHARIN THAT IS CLAIMED TO HAVE PRODUCED BLADDER TUMORS CONTAINS O-TOLUENESULFONAMIDE AS IMPURITY. ANOTHER TYPE OF SACCHARIN, MFR BY DIFFERENT PROCESSES NOT CONTAINING THIS IMPURITY, HAS FAILED TO INDUCE TUMORS WHEN FED @ HIGH LEVELS TO RATS. [R47] *Saccharin was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Saccharin was tested at doses of 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Saccharin was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 10 mg/plate. [R48] *Male Sprague-Dawley CD rats were exposed to a series (8 to 10) of sequential daily training trials, with 120 min access to a drinking solution containing 0.2% saccharin on half the trials, according to a counterbalanced repeating ABBA design. During the test period, the rats' maintenance chow was replaced by the same chow flavored with 0.8% (by wt) non-nutritive chicken or chocolate flavor. Preference for a flavored food paired with a drinking solution was inferred from a 2-choice test conducted on the day after the last training trial. All rats were given both flavored foods simultaneously. Intake of each was measured after 0.5, 1, 2, 4, and 24 hr. Relative to trials with a different flavored food and only water to drink, food intake was increased by drinking 0.2% saccharin. There was no correlation between the vol of saccharin ingested and the incr in feeding produced by saccharin. [R49] *Rats were exposed to a series (8 to 10) of sequential daily training trials, with 30 to 120 min access to a drinking solution (0.2% saccharin) on half the trials, according to a counterbalanced repeating ABBA design. During the test period, the rats' maintenance chow was replaced by the same chow flavored with 0.8% (by wt) non-nutritive chicken or chocolate flavor. Learning was unnecessary for the feeding response, as rats that drank saccharin increased food intake whether or not their food contained saccharin contingent flavor cues. However, learning helped support and maintain the response, as rats repeatedly given flavored food together with saccharin to drink later increased intake when given the flavored food without saccharin (ie in extinction). The rewarding or hedonic effects of the immediate or sensory properties of saccharin were not responsible for its effects on feeding, as drinking saccharin before but not after eating flavored food increased food intake and food preference. Furthermore, hungry rats developed an aversion to flavored food paired with saccharin ingestion when the quantity of food was limited. [R50] *Rats were exposed to a series (8 to 10) of sequential daily training trials, with 30 to 120 min access to a drinking solution (0.2% saccharin) on half the trials, according to a counterbalanced repeating ABBA design. The results show that cephalic phase insulin response could be dissociated from food intake in three ways. (1) Drinking saccharin increased the food intake and food preference of rats with sham surgery or celiac vagotomy, but not hepatic vagotomy; it produced a short lived increase in plasma insulin levels in all three groups, but the insulin response of both the celiac vagotomy and hepatic vagotomy was attenuated relative to the sham surgery group. (2) Rats increased food intake even when a 90 min interval was imposed between drinking saccharin and eating food although insulin and glucose levels returned to normal within 30 min of drinking saccharin. (3) Streptozotocin induced diabetes did not affect the increased feeding response to saccharin. [R51] *... Tested pregnant mice with saccharin and found no evidence of teratogenicity. The mice received up to 25 mg/kg daily from the 6th through the 15th day. Cyclamate up to 250 mg/kg was also given without producing fetal changes. Reported no teratogenic effects in the rat fetus when the mother received 25 mg /kg from day 6 through 15 gestation. Also found no teratogenicity in long term studies in mice. In the male offspring of rats maintained on a diet of 7.5% saccharin an increase in bladder neoplasms was found. No increase was found with a diet containing 5% saccharin. [R36] *... Studied embryofetotoxicity of possible intermediates or contaminants of commercially prepared saccharin. Administered orally to rats at 0.1% of the diet, O-toluenesulfonamide was devoid of toxicity, O-sulfobenzoic acid increased the number of fetal resorptions sightly, but O-sulfamoylbenzoic acid, and especially NH-4 O-sulfobenzoic acid markedly increased resorptions. [R36] *Six chemicals, diethylhexyl phthalate, ethanol, cyclohexylamine, sodium saccharin, cadmium chloride and triflupromazine, were suggested to be unique germ cell mutagens by the GeneTox Workgroups of the USEPA. If this is a correct classification it would have major consequences when screening for mutagenicity and when labelling genotoxic substances. However, re-evaluation of the GeneTox literature, including some more recent publications, has failed to find substantive evidence that any of these chemicals have been unequivocally established as having unique mutagenic activity in germ cells. For diethylhexyl phthalate, sodium saccharin and triflupromazine the evidence for genotoxic/mutagenic effects is questionable, in both germinal and somatic cells. Ethanol and cadmium chloride showed clastogenic activity, but it was not restricted to germ cells. Both, ethanol and cadmium salts, appear to induce aneuploidy. The unconfirmed clastogenic effect of cyclohexylamine was restricted to rats, but it occurred in both bone marrow and spermatogonia. Therefore, the general observation that rodent germ cell mutagens are also genotoxic in somatic cells in vivo remains valid. /Sodium saccharin/ [R52] *In an attempt to define the role of exposure to sodium saccharin during early life on the subsequent development of bladder tumors, ... /a study was developed to/ compare the responses of male rat pups to exposure to 5% dietary sodium saccharin initiated at parturition with those to exposure initiated at weaning. ... /The study/ also compared the effects of exposure from parturition to sodium saccharin given in a low carbohydrate diet with those of sodium saccharin in rat chow. Sodium saccharin ingestion by the dam was associated with low saccharin concentrations in the pups' urine and had no effect on the cecal or bladder mass in the suckling pups. In the 10 wk after weaning, the rats ingesting sodium saccharin in chow showed decreased weight gain and increases in feed consumption, mass of cecal contents and tissue, urine output, bladder mass, relative water consumption (g water consumed/g feed consumed) and bladder hyperplasia. Except for bladder hyperplasia these effects were generally greater in the rats exposed to sodium saccharin from parturition than in those exposed only from weaning. The animals exposed to sodium saccharin in the low carbohydrate diet had the highest level of urinary saccharin but showed no bladder hyperplasia. /Sodium saccharin/ [R53] *Sodium saccharin, potassium saccharin, calcium saccharin and the free acid when fed to young male rats at a level of about 200 umol/g diet all produced an equivalent increase in the cecal enlargement indicating that this phenomenon was due to the saccharin ion and not the accompanying cation. The sodium and potassium salts caused greater polydipsia and polyuria than the calcium or free acid forms. Simple hyperplasia of the bladder was noted in the rats ingesting the sodium and potassium salts but not in those ingesting the calcium or free acid forms. The difference in urine and bladder response to the salt forms is not attributable to the difference in the total urinary saccharin or the urinary concentration of saccharin. These results suggest that excess water absorption from the lower bowel and the concomitant bladder responses are dependent upon monovalent cation absorption but independent of saccharin absorption. [R54] *To ascertain whether the bladder mass increase and epithelial hyperplasia induced by 5% dietary sodium saccharin in short-term experiments with rats are caused by increased urinary excretion of indican associated with this treatment, the responses of the urine and bladder induced by 1.5% indole ingestion were compared with those induced by 5% sodium saccharin and 1.5% indole + 5% sodium saccharin. Indole and sodium saccharin, when fed alone, produced equivalent increased in bladder mass and both compounds induced epithelial hyperplasia, but indole ingestion was associated with much greater urinary indican (5 mg/g diet ingested) than was sodium saccharin (0.3 mg/g diet ingested). When indole and sodium saccharin were ingested together, the bladder mass increase was additive, but the epithelial hyperplasia was not exacerbated over that observed with each alone, and the urinary indican was equivalent to that produced by indole alone. These findings suggest that a high level of urinary indican excretion is associated with an increase in bladder mass and epithelial hyperplasia (indole treatment) but indicate that the relatively low urinary indican level obtained by sodium saccharin feeding alone is unlikely to be responsible for the bladder responses noted with this compound. /Sodium saccharin/ [R55] *Three methods used to detect proliferative changes in the rat urothelium, light microscopy, scanning electron microscopy, and autoradiography, were compared for their sensitivity in detecting changes produced by administration of sodium saccharin. Weanling male F344 rats were fed sodium saccharin as 0, 3, 5, or 7.5% of the diet, and the bladders were evaluated after 4, 7 and 10 wks of feeding. Light microscopic changes and increase in labeling index were seen at all time points in rats fed 7.5% sodium saccharin, but not at the lower doses. A slight increase in labeling index was also observed at 10 wks in the 5.0% /group/. Scanning electron microsopic changes were evident as early as 4 wks with increasing severity at the 3, 5, and 7.5% doses. This study demonstrates that the hyperplastic response of the urothelium to sodium saccharin administration varies with dose and time, and that observation by scanning electron microscopy is the most sensitive of the three methods evaluated for detecting these changes. /Sodium saccharin/ [R56] *Sodium saccharin has been reported to promote the development of urinary bladder tumors in rats following low doses of several carcinogens. To evaluate the generality of this effect between species, an initiation-promotion study was conducted in mice. Weanling female BALB/c mice were initiated with 200 ppm dietary 2-acetylaminofluorene for 90 days. Following a 2 week period of control diet, saccharin was administered at 0, 0.1, 0.5 1.0, and 5.0% in the diet for the remainder of the 132 week study. An elevated incidence of persistent bladder transitional cell hyperplasia and a low incidence of urothelial and hepatocellular tumors indicated that these organs achieved an adequate dose of the initiator. However, sodium saccharin dosing did not result in an increased incidence of tumors in either the bladder or liver and is therefore not considered to be a promoter of carcinogenesis at these sites in the mouse. Furthermore, sodium saccharin exhibited a modest inhibitory effect on the rate of development of lymphomas in both initiated and noninitiated animals. Interspecies difference in the bladder tumorigenic effect of sodium saccharin and their association with differences in urinary tract physiology are discussed. /Sodium saccharin/ [R57] *Since both sodium L-ascorbate and sodium saccharin promote two-stage bladder carcinogenesis in rats, synergism of the two chemicals was investigated with special reference to the role of urinary pH and sodium+ concentration. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk and then treated with basal diet containing 5% sodium saccharin, 5% sodium L-ascorbate, 5% sodium saccharin plus 5% sodium L-ascorbate, 5% L-ascorbic acid, 5% sodium saccharin plus 5% L-ascorbic acid, or no added chemical for 32 wk. Treatment with sodium saccharin or sodium L-ascorbate alone significantly increased the induction of neoplastic and preneoplastic lesions of the bladder. Sodium saccharin plus sodium L-ascorbate also induced these bladder lesions significantly when compared with the controls, and the number of lesions was greater than the sum of the lesions in the group treated with sodium saccharin alone or sodium L-ascorbate alone. In contrast, the induction of carcinomas and papillomas in rats treated with sodium saccharin plus sodium L-ascorbate produced an elevation of urinary pH and sodium+ concentrations, although the increases were not different from those in rats fed sodium saccharin or sodium L-ascorbate alone. Sodium saccharin plus L-ascorbic acid, however, did not cause elevation of urinary pH, although it increased urinary sodium+ concentration. Thus, the bladder carcinogenesis promotion by sodium saccharin was synergized by sodium L-ascorbate and inhibited by L-ascorbic acid. This modulation was associated with changes of urinary pH and Na+ concentration. /Sodium saccharin/ [R58] *When male rats of certain strains are fed a diet with 3% or more sodium saccharin, their urinary bladders developed epithelial hyperplasia and a greater incidence of tumors. Since the daily dose of saccharin is high, a link between tumor formation and the disruption of urothelial physiologic and biochemical processes has been sought. ... Male and female Sprague-Dawley rats were fed a saccharin free or 7.5% sodium saccharin diet for 1 month. Excised bladders were mounted in flux chambers and exposed to Krebs-Ringer bicarbonate solution or urine. Bioelectric properties and (22)Na, (36)Cl, and (14)C mannitol or (3)H mannitol undirectional fluxes were measured by conventional techniques. No differences were noted between bladders from male and female animals or between sodium saccharin-fed animals and animals fed the saccharin-free diet. When both surfaces of the epithelium were exposed to Krebs-Ringer bicarbonate solution, transepithelial dc conductance fell over 4 hr to 50% of the initial value. Conductance averaged 1.4 ms/sq cm. Transepithelial potential difference was usually lumen negative and averaged 0.7 mV. Unidirectional permeability coefficients for (36)Cl, (22)Na, and radiomannitol were symmetric, proportional to conductance, and followed a rank order compatible with unrestricted passive diffusion. Exposure of the bladder lumen to urine from animals fed saccharin-free or sodium saccharin diet hyperpolarized the transepithelial potential difference by more than 5 mV and raised conductance nearly threefold. Permeability coefficients remained symmetric and compatible with passive diffusion. Exposure of the lumen to solutions with the potassium+, sodium+, and chlorine concentrations and osmolality of urine simulated the conductance and potential difference effects of urine. ... /Results suggest/ that sodium saccharin feeding or urine with saccharin does not uniquely affect the permeability of the excised preparation. Small hydrophilic solutes appear to cross bladder epithilium through paracellular channels which increase in aggregate area during exposure of the lumen to urine. The hyperpolarization induced by lumenal urine is the consequence of the transepithelial potassium+ gradient. /Sodium saccharin/ [R59] *The tumor-promoting activities of sodium cyclamate and sodium saccharin were investigated in an assay based on the induction of epithelial foci exhibiting enhanced growth potential in a rat bladder explant culture system. An initiating, non-focus- inducing dose was defined for the carcinogen N-methyl-N-nitrosourea to make promotion studies possible. Saccharin induced epithelial foci when added to cultures pretreated with an initiating dose of N-methyl-N-nitrosourea, and also increased the incidence of foci in cultures treated with transforming doses of N-methyl-N-nitrosourea. Cyclamate was found to induce a high incidence of foci when added to cultures by itself. When N-methyl-N-nitrosourea and cyclamate treatments were combined, an additive effect could be detected. These results indicate that both cyclamate and saccharin can contribute to epithelial transformation in this system. /Sodium saccharin/ [R60] *Aqueous salt solutions containing sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, calcium chloride, ammonium chloride, or sodium saccharin are mutagenic in yeast when logarithmic growth of cells is interrupted by exposure to a 0.5-2.0 M salt solution. Stationary-phase cells are not mutated by this treatment. When placed in an enriched medium with the salt, the stationary-phase cells grow after a prolonged lag period. The compounds tested (sodium chloride, potassium chloride, and sodium saccharin), under conditions in which growth in medium can take place exhibit an antimutagenic response as measured by the compartmentalization test. The antimutagenic action of salt solutions in yeast is concentration-dependent. Unlike the mutagenic action of these compounds, which approximates an osmolality-dependent response, the antimutagenic action seems to be correlated with toxicity as measured by growth rate reduction at increasing concentrations of the compounds. For example, sodium saccharin and sodium chloride exhibit almost identical osmolalities; however, 0.3 M sodium saccharin reduces the growth rate much more than does 0.3 M sodium chloride. At these same molar concentrations, the spontaneous mutation rate for histidine prototrophy is, for the control, 6.2x10-8 mutations/cell/generation, 3.5x10-8 with 0.3 M sodium chloride, and 1.7x10-8 with 0.3 M sodium saccharin. /Sodium saccharin/ [R61] *Saccharin, administered to male albino rats at a dose of 65 mg/kg body weight/day (weak dose) for a total period of 39 weeks resulted in a distinct decrease in the hepatic alkaline phosphatase (AkP, 86%), lactate dehydrogenase (LDH, 28%) and glutamate pyruvate transaminase (GPT, 67%) activities. The glutamate oxaloacetate transaminase (GOT) activity, however, increased 3.05 fold after 26 weeks of saccharin administration. The urea content showed 3.26% fold increase during the first 13 weeks of saccharin administration, which normalized subsequently. The cholesterol content and DNA content increased 7.7 fold and 2.6 fold after 26 weeks of saccharin administration. The soluble protein and RNA content, on the other hand, decreased 63% and 35% during the first 26 weeks of saccharin administration. After strong dose (260 mg/kg body wt/day) administration, various biochemical parameters followed the same pattern as for the weak dose, except for the extent of damage and for the DNA content, which decreased significantly when compared to weak dose experiment. Both concentrations of saccharin caused hypertrophy of hepatic cell, its nucleus and nucleoli in addition to excessive vacuolation. The number of nuclei/cell remained unaltered, whereas number of nucleoli/nucleus increased significantly after saccharin intoxication. [R62] *... While exposure to rodents during only the adult phase provided qualitatively similar results, early neonatal exposure typically provided slightly higher incidences of tumors, and decreased latency to tumor onset in certain scientific studies. In a series of studies recently performed by the NIEHS with three known animal carcinogens, neonatal or adult exposure produced similar tumors in similar tissues. The food additive saccharin, which shows bladder tumors, and eugenol reliably produced tumors only with neonatal exposure. Implications for carcinogenicity testing of food additives are discussed in light of these experimental findings. [R63] NTOX: *The tumor suppressor gene p53 encodes a nuclear phosphoprotein which is critical for cell cycle control and prevention of uncontrolled cell proliferation that can lead to cancer. Previous studies have shown that cells respond to DNA damage by increasing their levels of p53, which then acts to prevent replication of damaged DNA. ... The epigenetic (non-DNA-reactive) carcinogens azathioprine and saccharin, as well as two substances generally considered to be non-carcinogens, dimethylsulfoxide and benzethonium chloride, had no effect on p53 protein levels of treated cells. Measurement of the cytotoxic effects of each of these chemicals led to the conclusion that p53 protein induction is not a general, non-specific consequence of the cytotoxic effect of these genotoxins. [R64] *In studies primarily designed to evaluate the effects of saccharin and silicate on the urinary bladders of rodents, hemorrhage of the glandular stomach was observed in high incidence. It occurred in young rats with high doses of saccharin (7.5% sodium saccharin; 6.3% acid saccharin), with no difference between male and female F344 rats fed during ages 5 to 15 weeks, no difference between sodium saccharin and acid saccharin, and was reversible, even with continued saccharin administration. Sodium silicate (0.38, 1.13, 2.26% of the diet) had no influence on gastric hemorrhage. Iron deficiency anemia has been observed in young rats fed high dietary levels of saccharin, and the present results suggest that gastric hemorrhage contributes to its etiology. [R65] *The incidence of sodium saccharin (NaS)-associated bladder tumors in male rats increases when exposure to high doses begins in utero or at birth compared with treatment after weaning. The present experiment evaluated the effect of sodium saccharin exposure on selected physiological parameters in young second generation rats. 6-wk-old male and female Sprague-Dawley rats were placed on either a diet supplemented with 7.5% sodium saccharin or an untreated diet, and mated 4-6 wk later. Treatment was continued through lactation and the offspring were weaned on to the same diet. Body weights were significantly depressed in sodium saccharin-treated litters by 4 days after birth, and were 35% lower than controls by 30 days when the animals were killed. sodium saccharin treatment of the offspring was associated with an increase in faecal moisture content and caecal content weight, changes in several urinary analytes, a 50% increase in serum cholesterol a 10-fold increase in serum triglycerides and decreases in serum and hepatic vitamins. In addition, sodium saccharin-treated dams and pups were anaemic. Relatively few differences between males and females were noted, but significant inter-litter differences existed. The numerous physiological changes indicate that 7.5% dietary sodium saccharin exceeds the maximum tolerated dose for weanling rats. [R66] *A previous study in our laboratory demonstrated that 30-day-old Sprague-Dawley rats exposed to 7.5% sodium saccharin (NaS) since conception differ from untreated rats in several physiological parameters. In the present study, to determine the dose response of the changes associated with sodium saccharin treatment, animals were evaluated at 30 days post-birth, after treatment with dietary levels of 0, 1, 3 or 7.5% sodium saccharin since conception. Most physiological consequences of sodium saccharin treatment in the weanling rat, including anaemia and reductions in serum folate and vitamin A concentrations, were dose dependent. Serum vitamin E, cholesterol and triglyceride concentrations were decreased at the two lower doses of sodium saccharin but were significantly increased with 7.5% sodium saccharin. The no-effect level (NOEL) was similar for physiological effects and for bladder tumor production in two-generation studies (1% sodium saccharin in the diet). The reversibility of the effects of 7.5% sodium saccharin was examined in 90-day-old rats. The increases in lipids and vitamin E were reversible. Although values for hematological parameters and serum vitamin A remained significantly reduced at 90 days, changes were less severe than at 30 days. Histological examinations revealed that the effects of 7.5% dietary sodium saccharin on the bladder were negligible, indicating that the physiological changes observed in the young rat are probably not directly related to the production of bladder tumors. [R67] *The present paper describes the possible clastogenic activity of the following synthetic sugar substitutes, such as cyclamate in daily doses of 11 and 110 mg/kg, saccharin, 5 and 50 mg/kg, acesulfam, 15 and 150 mg/kg, sucralose, 15 and 150 mg/kg, aspartame, 40 and 400 mg/kg, orally given to C57Bl/6 mice during 5 days. No clastogenic activity was found in the compounds tested. [R68] NTXV: *LD50 Mouse oral 17 g/kg; [R26] ETXV: *LC50 Pimephales promelas (fathead minnow) 30 day old 18.3 g/l/96 hr. (confidence limit 16.4 - 20.4 g/l). Dilution factor: 0%, 20%, 40%, 60%, 80% and 100% of the stock solution. Behavioral observations were not recorded. Increased alkalinity values were due to a reaction between the titrant and toxicant. /Saccharin, sodium salt hydrate/; [R69] NTP: +Sodium saccharin (NaSac) ... was tested for potential effects on reproduction and fertility in Swiss CD-1 mice using the RACB protocol. Data on food and water consumptions, body weights, and clinical signs from the dose-range-finding study (Task 1) were used to set exposure concns for the continuous cohabitation phase (Task 2) at 1.25, 2.5, and 5% weight/volume in the drinking water. While water consumption was decreased at the high dose by nearly equal to 10-20%, it was increased at the low and middle dose levels by nearly =40% and 20%, respectively. Consequently, the high dose animals gained slightly less weight during Task 2. Measures of body weights and water consumption allowed the calculation of daily exposure estimates: 3.5, 5.9, and 8.1 g/kg/day. In Task 2, 3, 0, 1, and 8 mice died in the control, low, middle, and high dose groups, respectively. The increased mortality at 5% NaSac was attributed to complications of dehydration. For the surviving pairs, there was no reduction in the mean number of litters/pair, although at the high dose, the number of live pups/litter decreased by 16% and the pup weight adjusted for litter size was decreased by 6%. There was no decr in the viability of the offspring. These effects were considered secondary to the decreased water intake seen at the high dose, and since the middle dose level had a relative incr in intake and showed no reproductive toxicity, Task 2 was judged to be essentially negative for reproductive toxicity, and the evaluation of the second generation was performed with only the controls and the middle dose level. Thus, the last litter from the control and middle dose groups was nursed, weaned, and reared to mating at nearly equal to 70-80 days of age. There was no effect of exposure to NaSac on viability or growth to weaning, or on body weights at the start of the cohabitation wk. Water consumption was increased by nearly =30 in the 2.5% NaSac group, although this did not translate to a change in body weight. In the mating trial, there were no differences due to NaSac consumption in the percent of F1 pairs mating or delivering a litter, or in the number, weight, or viability of pups in that litter. After the F2 pups were evaluated and discarded, the F1 controls and 2.5% NaSac-exposed mice were killed and necropsied. There were no differences between the groups in terminal body weights or organ weights. The concn, % motile, or % morphologically abnormal sperm in the epididymis were unchanged by NaSac exposure, as was the length or characteristics of the estrous cycle. In summary, NaSac reduced fertility only at a concn that also significantly reduced water consumption and increased mortality. At concns that increased water consumption, there were no measurable effects on reproductive performance or necropsy endpoints. /Sodium saccharin/ [R70] POPL: *The risk of potential occupational exposure exists for workers involved in the production of saccharin or its salts, in the manufacture and formulation of saccharin-containing products, and during the packaging of the consumer products. [R71] ADE: *TRANSPLACENTAL TRANSFER OF ... (14)C-SACCHARIN ADMIN BY IV INFUSION TO RHESUS MONKEYS IN LATE PREGNANCY, WAS RAPID, BUT SLIGHT. (14)C WAS CLEARED MORE SLOWLY FROM FETAL THAN FROM MATERNAL BLOOD, AND WAS DISTRIBUTED IN ALL FETAL TISSUES EXAMINED ... WAS ONLY BIOTRANSFORMED TO LIMITED EXTENT AND WAS RAPIDLY EXCRETED ... . [R72] *... SACCHARIN IS RAPIDLY EXCRETED UNCHANGED: ALMOST ENTIRELY IN URINE OF TREATED GUINEA PIGS, and 70% IN URINE, 30% IN FECES OF TREATED RATS. [R73] *IN 3 VOLUNTEERS, 85-92% OF DOSES OF 1 G 3(14)C-SACCHARIN ADMIN ORALLY FOR 21 DAYS WAS EXCRETED UNCHANGED IN THE URINE WITHIN 24 HR; NO METABOLITES WERE FOUND. WITHIN 48 HR, 92.3% OF A DOSE OF 500 MG (14)C-SACCHARIN WAS EXCRETED IN THE URINE AND 5.8% IN THE FECES. [R37] *TISSUE LEVELS, INCLUDING BLADDER, KIDNEY, AND LIVER, OF SACCHARIN WERE DETERMINED IN RATS DURING TWO-GENERATION FEEDING STUDIES. [R74] *THE KINETICS OF DIETARY SACCHARIN WERE DETERMINED IN 6 HEALTHY WOMEN WHO USED SACCHARIN CONTAINING PRODUCTS IN THEIR DIET AND WERE ASKED TO TAKE DIVIDED EQUAL DOSES OF SACCHARIN EVERY 6 HR TO MAINTAIN THEIR AVERAGE DAILY INTAKE (100-300 MG) FOR 3 DAYS. AT THE END OF THIS PERIOD, EACH SUBJECT TOOK A SINGLE DOSE THAT WAS EQUAL TO ONE DIVIDED DOSE. SACCHARIN CONCN IN PLASMA AND URINE SAMPLES WERE USED TO ASSESS THE KINETIC PROFILE. SACCHARIN ABSORPTION WAS RAPID WITH MAXIMUM CONCN IN PLASMA IN 0.5-1.0 HR. MAXIMUM PLASMA CONCN AND AREAS UNDER THE PLASMA CONCN-TIME CURVES WERE PROPORTIONAL TO DOSE. RENAL CLEARANCE EXCEEDED GLOMERULAR FILTRATION RATE IN ALL CASES AND APPROXIMATED RENAL PLASMA FLOW WHEN CORRECTED FOR THE SACCHARIN FREE FRACTION IN PLASMA. MEAN ELIMINATION T/2 WAS 7.5 HR AND MEAN APPARENT VOLUME OF DISTRIBUTION WAS 264 LITERS. THE KINETIC PARAMETERS INDICATE THAT SACCHARIN IS DISTRIBUTED AS A FUNCTION OF LEAN RATHER THAN TOTAL BODY MASS; THIS OBSERVATION SUGGESTS THAT THERE MAY BE ONE OR MORE HIGH RETENTION COMPARTMENTS FOR SACCHARIN. [R75] METB: *... 3-(14)C-SACCHARIN WAS EXCRETED UNCHANGED, MAINLY IN THE URINE (85-92% IN 24 HR) BY ADULT HUMAN SUBJECTS, BOTH BEFORE AND AFTER TAKING 1 G OF SACCHARIN DAILY FOR 21 DAYS; NO METABOLITE OF SACCHARIN WAS FOUND. THESE RESULTS WERE AMPLY CONFIRMED IN ANIMAL EXPERIMENTS, IN WHICH ORALLY ADMIN (14)C-SACCHARIN WAS EXCRETED ENTIRELY UNCHANGED BY RATS ON A NORMAL DIET AND BY RATS ON A DIET CONTAINING 1% and 5% OF SACCHARIN FOR UP TO 12 MO. 80-90% OF THE DOSE WAS EXCRETED IN THE URINE, 10-20% IN THE FECES; NO (14)CO2 WAS FOUND IN THE EXHALED AIR, AND NO (14)CO3(2-) OR 2-SULFAMOYLBENZOIC ACID IN THE URINE. [R76] *YIELDS IN MONKEYS SULFAMOYLBENZOIC ACID AND O-SULFOBENZOIC ACID. /FROM TABLE/ [R77] *EXPOSURE OF MALE CHARLES RIVER CDI RATS TO 5% SACCHARIN DIET IN UTERO AND THROUGHOUT WEANING, DID NOT INDUCE DETECTABLE METABOLISM. NO METABOLITES WERE DETECTED IN URINE OF NORMAL RATS GIVEN TRACER DOSE. PRETREATMENT WITH 3-METHYLCHOLANTHRENE DID NOT INDUCE SACCHARIN METABOLISM. [R78] INTC: *IT IS NOW WELL ESTABLISHED THAT THE INTERACTION OF MULTIPLE ENVIRONMENTAL FACTORS MAY INCR THE INCIDENCE OF SOME HUMAN CANCERS MORE THAN EXPOSURE TO A SINGLE CARCINOGEN. WITH AN IN VIVO EXPERIMENTAL RAT MODEL, SYNERGISTIC EFFECT IN BLADDER CARCINOGENESIS BETWEEN A SUBCARCINOGENIC DOSE OF THE STRONG BLADDER CARCINOGEN, N-METHYL-N-NITROSOUREA AND SACCHARIN WAS DEMONSTRATED. [R79] *CHRONIC RAT FEEDING STUDIES WERE CONDUCTED ON A 10:1 CYCLAMATE/SACCHARIN MIXT. THE TEST MIXT WAS FED AT DIETARY LEVELS DESIGNED TO FURNISH 500, 1120, and 2500 MG/KG TO GROUPS OF 35 MALE AND 45 FEMALE RATS. THE ONLY POS FINDING WHICH PROVED TO HAVE CRUCIAL SIGNIFICANCE WAS THE OCCURRENCE OF PAPILLARY CARCINOMAS IN THE BLADDERS OF 12 OF THE 70 RATS FED THE MAX DIETARY LEVEL OF THE MIXT (EQUIV TO ABOUT 2500 MG/KG) FOR PERIODS RANGING FROM 78 TO 105 WK. [R80] *N-METHYL-N-NITROSOUREA WAS USED AS INITIATING CARCINOGEN AND GREATLY INCR YIELD OF BLADDER CANCERS IN SACCHARIN TREATED RATS. SACCHARIN IS A WEAK INITIATOR BUT A POWERFUL PROMOTER OF CARCINOGENESIS IN THE RAT BLADDER. [R81] *IN THE PRESENCE OF SACCHARIN, HYPERPLASIA INDUCED BY A SINGLE DOSE OF N-METHYL-N-NITROSOUREA (MNU) PERSISTED. FOLLOWING 3 MULTIPLE DOSES OF MNU IN THE PRESENCE OF SACCHARIN, SPINDLE CELL HYPERPLASIA WAS INDUCED SIMILAR TO THAT SEEN WITH MULTIPLE DOSES OF MNU ALONE, ALTHOUGH NUCLEI APPEARED MORE PLEOMORPHIC AND HYPERCHROMATIC IN THE PRESENCE OF SACCHARIN. [R82] *WATER-DEPRIVED MICE WERE INJECTED WITH LITHIUM CHLORIDE OR SODIUM CHLORIDE 15 MINUTES BEFORE THEY WERE ALLOWED TO DRINK EITHER WATER OR 0.1% SACCHARIN. THE SODIUM CHLORIDE INJECTIONS PRODUCED A DOSE-DEPENDENT INCREASE IN INTAKE OF BOTH FLUIDS. HOWEVER, THE HIGHER DOSAGES OF LITHIUM CHLORIDE PRODUCED A SELECTIVE DEPRESSION OF FLUID INTAKES. SACCHARIN INTAKES WERE DEPRESSED FOR LESS THAN 1 HR BUT WATER INTAKES WERE NOT AFFECTED. LITHIUM CHLORIDE INJECTIONS ALSO DEPRESSED GENERAL ACTIVITY AND PRODUCED AN APPARENT SHIFT OF WATER FROM BLOOD INTO CELLS. THE LITHIUM CHLORIDE-INDUCED DEPRESSION OF SACCHARIN INTAKE WAS NOT SIGNIFICANTLY INFLUENCED BY EXTENSIVE PREVIOUS EXPERIENCE WITH THE DRINKING FLUID. /DOSES NOT SPECIFIED IN SOURCE/ [R83] *The short term food intake of male Sprague-Dawley CD rats was increased by drinking hyposmotic 0.2% saccharin dissolved in water and decr by drinking 0.2% saccharin dissolved in 0.9% NaCl. In addition, rats showed a sustained incr in saccharin induced food intake after antidiuretic hormone treatment (im injection of 0.1 Units/kg Pitressin tannate in 1 ml/kg oil vehicle), which was designed to exacerbate their positive water balance. Rats drinking only 2 ml 0.2% saccharin solution increased food intake. Also, gastric intubation of similar vol of water produced a small, transient incr in feeding behavior, which was apparent after the first intubation only and could not be preserved by adding water contingent flavors to the food. Hydration had no observable influence on the acquisition of flavored food preference. [R84] *Various compounds were screened for antipromoter activity in bladder carcinogenesis in rats with a view to using them clinically to inhibit postoperative intravesical ectopic tumor growth of superficial papillary bladder cancer. Their inhibitions of the effect of sodium saccharin in maintaining increased agglutinability of bladder cells by concanvalin A were examined in 4-week tests. The compounds found to inhibit the effect of saccharin were alpha-tocopherol, ascorbic acid, aspirin, all-trans aromatic retinoid, alpha-difluoromethylornithine, sodium cyanate and p,p'-diamo-diphenylmethane. Considering the toxicities of some of these chemicals, ascorbic acid and alpha-difluoromethylornithine were concluded to be the most promising for future clinical trials. [R85] *Effects of retinoids and inhibitors of arachidonic acid metabolism on tumor promoter induced soft agar colony formation of mouse epidermal cells and rat bladder cells were evaluated. Topical application of retinoic acid, an anti-tumor promoter, to female SENCAR mouse skin inhibited 12-O-tetradecanylphorbol-13-acetate-induced soft agar colony formation of mouse epidermal cells, an event proposed to be essential for tumor promotion. Effects of dietary retinyl acetate, nordihydroguaiaretic acid and quinacrine hydrochloride on colony formation of rat bladder cells were then examined. Male Fischer 344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosoamine for 3 weeks, followed immediately by the administration for 9 weeks of 5% sodium saccharin supplemented with or without 0.5% retinyl acetate, 0.1% nordihydroguaiaretic acid or 0.1% quinacrine hydrochloride. Saccharin-induced colony growth was significantly inhibited by the administration of retinyl acetate or nordihydroguaiaretic acid, suggesting that these two agents have anti-tumor promoting effects on rat bladder carcinogenesis. Thus, the colony-forming assay might be useful for early detection of anti-tumor promoters of skin and bladder. [R86] *Since both sodium L-ascorbate and sodium saccharin promote two-stage bladder carcinogenesis in rats, synergism of the two chemicals was investigated with special reference to the role of urinary pH and sodium+ concentration. ... The bladder carcinogenesis promotion by sodium saccharin was synergized by sodium L-ascorbate and inhibited by L-ascorbic acid. This modulation was associated with changes of urinary pH and Na+ concentration. /Sodium saccharin/ [R58] *The tumor-promoting activities of sodium cyclamate and sodium saccharin were investigated in an assay based on the induction of epithelial foci exhibiting enhanced growth potential in a rat bladder explant culture system. An initiating, non-focus- inducing dose was defined for the carcinogen N-methyl-N-nitrosourea to make promotion studies possible. Saccharin induced epithelial foci when added to cultures pretreated with an initiating dose of N-methyl-N-nitrosourea, and also increased the incidence of foci in cultures treated with transforming doses of N-methyl-N-nitrosourea. Cyclamate was found to induce a high incidence of foci when added to cultures by itself. When N-methyl-N-nitrosourea and cyclamate treatments were combined, an additive effect could be detected. These results indicate that both cyclamate and saccharin can contribute to epithelial transformation in this system. /Sodium saccharin/ [R60] *Saccharin is an artificial sweetener commonly used in the formulation of food and beverages. Sodium saccharin-induced mutagenicity is detectable in human RSa cells by estimation of cloning efficiency of ouabain-resistant mutant cells and determination of K-ras codon 12 mutation in genomic DNA, analyzed by PCR and differential dot-blot hybridization. However, in this study no phenotypic or genetic mutations were detected in RSa cells cultured with human IFN (HuIFN)- a before sodium saccharin treatment. The suppressive effect was lessened by transient treatment with antipain immediately after sodium saccharin treatment. Elevation of antipain-sensitive protease activity was found, furthermore, in RSa cells cultured with human IFN-alpha and subsequently treated with sodium saccharin. Thus, antipain-sensitive protease induction in cells tested here may be involved in suppression of the mutagenicity of saccharin by human IFN-alpha. [R87] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Saccharin's production and use as a non-nutritive sweetener may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.4X10-7 mm Hg at 25 deg C indicates saccharin will exist in both the vapor and particulate phases. Vapor-phase saccharin will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3 days. Particulate-phase saccharin will be removed from the atmosphere by wet and dry deposition. If released to soil, saccharin is expected to have high mobility based upon an estimated Koc of 75. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.2X10-9 atm-cu m/mole. If released into water, saccharin is not expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests bioconcentration in aquatic organisms is low. This compound has the potential to chemically hydrolyze in aqueous environments to o-sulfamoylbenzoic acid and ammonium o-sulfobenzoic acid, but the kinetics of the potential hydrolysis are unknown. The importance of biodegradation in soil and water is unkown, but amides are usually susceptible to microbial metabolism. Occupational exposure to saccharin may occur through inhalation of dust particles and dermal contact with this compound at workplaces where saccharin is produced or used. The general population may be exposed through the ingestion of food products such as soft drinks, table sweeteners and candy that contain this product. (SRC) NATS: *Saccharin, sodium and calcium saccharin and o-toluenesulphonamide do not occur as natural products. [R88] ARTS: *Saccharin's production and use as a non-nutritive sweetener(1) may result in its release to the environment through various waste streams(SRC). [R89] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 75(SRC), determined from a log Kow of 0.91(2) and a regression-derived equation(3), indicates that saccharin is expected to have high mobility in soil(SRC). Volatilization of saccharin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Saccharin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-7 mm Hg(SRC), determined from a fragment constant method(5). The importance of biodegradation in soil and water is unkown, but amides are usually susceptible to microbial metabolism(6). [R90] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 75(SRC), determined from a log Kow of 0.91(2) and a regression-derived equation(3), indicates that saccharin is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(3,SRC), from its log Kow(2) suggests the potential for bioconcentration in aquatic organisms is low(SRC). This compound has the potential to chemically hydrolyze in aqueous environments to o-sulfamoylbenzoic acid and ammonium o-sulfolbenzoic acid(6), but the kinetics of the potential hydrolysis are unknown(SRC). The importance of biodegradation in soil and water is unkown, but amides are usually susceptible to microbial metabolism(7). [R91] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), saccharin, which has an estimated vapor pressure of 6.4X10-7 mm Hg at 25 deg C(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase saccharin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3 days(SRC) from its estimated rate constant of 5.9X10-12 cu cm/molecule-sec at 25 deg C(3). Particulate-phase saccharin may be removed from the air by wet and dry deposition(SRC). [R92] BIOD: *The importance of biodegradation of saccharin in soil and water is unknown, but amides are usually susceptible to microbial metabolism(1). [R93] ABIO: *The rate constant for the vapor-phase reaction of saccharin with photochemically-produced hydroxyl radicals has been estimated as 5.9X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The respective acid and alkaline hydrolysis products of saccharin are o-sulfamoylbenzoic acid and ammonium o-sulfobenzoic acid(2). Rate data for the hydrolysis of saccharin in aqueous solutions were not located in the available literature(SRC). However, saccharin is stable in aqueous solution for most normal food applications, especially beverages. Therefore, saccharin is not expected to hydrolyze rapidly in environmental media(SRC). [R94] BIOC: *An estimated BCF of 3 was calculated for saccharin(SRC), using a log Kow of 0.91(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R95] KOC: *The Koc of saccharin is estimated as approximately 75(SRC), using a log Kow of 0.91(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that saccharin is expected to have high mobility in soil(SRC). [R96] VWS: *The Henry's Law constant for saccharin is estimated as 1.2X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that saccharin is expected to be essentially nonvolatile from water surfaces(2). Saccharin's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is not expected(SRC). Saccharin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.4X10-7 mm Hg(SRC), determined from a fragment constant method(3). [R97] RTEX: *The most probable route of human exposure to saccharin is by the ingestion of foods that it was added to as a sweetening agent(1). [R98] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 224,753 workers (95,731 of these are female) are potentially exposed to saccharin in the US(1). Occupational exposure to saccharin may occur through inhalation of dust particles and dermal contact with this compound at workplaces where saccharin is produced or used(SRC). The general population may be exposed through the ingestion of food products such as soft drinks, table sweeteners and candy that contain this product(SRC). [R99] AVDI: *The average daily intake of saccharin through food for the Finnish population was estimated to be 15 mg, based on a survey of the population of Finland(1). [R100] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R101] RCRA: *U202; As stipulated in 40 CFR 261.33, when saccharin, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /Saccharin and salts/ [R102] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A SCHEME IS SUGGESTED FOR ANALYSIS OF MIXT OF SACCHARIN SODIUM, CYCLAMATE SODIUM AND SORBITOL. PROCEDURE DEPENDS ON: DETERMINATION OF SACCHARIN SODIUM BY PREPARATION OF SILVER SACCHARINATE. [R103] *GLC DETERMINATION OF SACCHARIN IN PHARMACEUTICAL PRODUCTS. [R104] *A REVERSE PHASE HIGH PRESSURE LIQ CHROMATOGRAPHIC METHOD IS PRESENTED FOR THE SIMULTANEOUS SEPARATION AND DETERMINATION OF SACCHARIN, SODIUM BENZOATE, AND CAFFEINE IN SOFT DRINKS, FRUIT JUICES, FRUIT COCKTAILS, FRUIT PUNCHES, COFFEE, AND ARTIFICIAL SWEETENER CONCENTRATES. [R105] *DETERMINATION OF SACCHARIN IN FOOD AND DRUGS BY COLUMN CHROMATOGRAPHY. [R106] *Gravimetric, differential pulse polarographic, and sublimation methods have been described for determination of saccharin in food. [R107, p. 405/20.202-20] *Thin layer chromatographic method is used to identify saccharin in nonalcoholic beverages. UV spectrometry can be used at 254 nm for determination. [R107, p. 400/20.174] *Saccharin is quantitated in soda beverages by liquid chromatography using acetic acid solution as mobile phase. Artificial colors or sorbates may interfere. [R107, p. 231/12.018] *Various gas chromatographic methods for determination of saccharin in soft drinks, chewing gums, multivitamin tablets, pharmaceutical preparations, tooth paste, and sweetened wine have been described. [R6] CLAB: *Gas chromatography/Electron Capture detection (GC/ECD) is used for determination of saccharin in blood. Limit of detection is 10 ug/l. [R3] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicity of Food Additives (Excluding Antioxidants), January 1978-July 1989. Govt Reports Announcements and Index (GRA and I) Issue 6 (1990). This bibliography contains citations concerning the toxicity of food additives, incl saccharin, and their effects on the liver, kidneys, bladder, and other organs. Arnold DL, Boyes BG; The Toxicological Effects Of Saccharin in Short-Term Genotoxicity Assays. Mutat Res 221 (2): 69-132 (1989). U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1,B3 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting Saccharin (81-07-2); Reason: ... The majority opinion of the Report on Carcinogens review groups was to recommend that saccharin be removed from the Report on Carcinogens. There is evidence for the carcinogenicity of saccharin in rats but less convincing evidence in mice. Studies indicate that the observed urinary bladder cancers in rats are related to the physiology of the rat urinary system including urinary pH, osmolality, volume, and that the presence of a precipitate, and urothelial damage with attendant hyperplasia following consumption of diets containing sodium saccharin of 3% or higher with inconsistent findings at lower dietary concn. The factors thought to contribute to tumor induction by sodium saccharin in rats would not be expected to occur in humans. The mouse data are inconsistent and require verification by additional studies. Results of several epidemiology studies indicate no clear association between saccharin and urinary bladder cancer. Although it is impossible to absolutely conclude that it poses no threat to human health, sodium saccharin is not reasonably anticipated to be a human carcinogen under conditions of general usage as an artificial sweetner. /Sodium saccharin/ SO: R1: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1236 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1017 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 123 (1980) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 113 (1980) R5: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 111 (1980) R7: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 642 R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 125 (1980) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 119 (1980) R10: CFR 1988; Code of Federal Regulations Food and Drugs 21: Part 180.1 and 180.37 (1988) R11: SRI R12: IARC; Monographs of the Evaluation of the Carcinogenic Risk of Chemicals to Humans 22: 111-71 (1980) R13: IARC; Saccharin 22: 111-71 (1980) R14: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.125 R15: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1985 p.1-564 R16: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R17: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-66 R18: Serjeant EP, Dempsey B; Ionisation constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. NY,NY: Pergamon (1979) R19: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 27 R20: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R21: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1321 R22: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-485 R23: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 271 R24: Weed Science Society of America. Herbicide Handbook. 4th ed. Champaign, IL: Weed Science Society of America, 1979. of America, 1979. 371 R25: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R26: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 348 R27: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R28: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R29: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-15 (1981) EPA 68-03-3025 R30: USEPA; Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to Cercla Section 102 (Final) p.42 (1988) EPA/600/8-89/053 R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 73 607 (1999) R32: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-406 R33: KESSLER II; HEALTH SUGAR SUBSTITUTES PROC ERGOB CONF SUGAR SUBSTITUTES: 85 (1979) R34: MORRISON AS, BURING JE; N ENGL J MED 302 (MAR 6): 537 (1980) R35: HOWE GR ET AL; LANCET 2 (SEP 17): 578 (1977) R36: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 510 R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 151 (1980) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 135 (1980) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 144 (1980) R40: ALTHOFF J ET AL; CANCER LETT 1 (1): 21 (1975) R41: KENNEDY GL JR ET AL; TOXICOLOGY 6 (2): 133 (1976) R42: KRAMERS PG; MUTAT RES 32 (1): 81 (1975) R43: LEONARD A, LEONARD ED; J ENVIRON PATHOL TOXICOL 2 (4): 1047 (1979) R44: CHOWANIEC J, HICKS RM; BR J CANCER 39 (4): 355 (1979) R45: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 145 (1980) R46: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V22 149 (1980) R47: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 722 R48: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R49: Tordoff MG, Friedman MI; Appetite 12 (1): 1-10 (1989) R50: Tordoff MG, Friedman MI; Appetite 12 (1): 23-36 (1989) R51: Tordoff MG, Friedman MI; Appetite 12 (1): 37-56 (1989) R52: Adler ID, Ashby J; Mutat Res 212 (1): 55-66 (1989) R53: Anderson RL et al; Food Chem Toxicol 26 (11-12): 899-907 (1988) R54: Anderson RL et al; Food Chem Toxicol 26 (8): 665-9 (1988) R55: Anderson RL et al; Food Chem Toxicol 27 (12): 777-9 (1989) R56: Cohen SM et al; Scanning Microsc 4 (1): 135-42 (1990) R57: Frederick CB et al; Fundam Appl Toxicol 12 (2): 346-57 (1989) R58: Fukushima S et al; Cancer Res 50 (14): 4195-8 (1990) R59: Gatzy JT et al; Toxicol Appl Pharmacol 100 (3): 424-39 (1989) R60: Nicholson LJ, Jani H; Int J Cancer 42 (2): 295-8 (1988) R61: Parker KR, von Borstel RC; Basic Life Science 52: 367-71 (1990) R62: Shakoori AR et al; Pakistan Journal of Zoology 27 (1): 1-13 (1995) R63: Hattan DG; International Journal of Toxicology 17 (3): 337-53 (1998) R64: Yang J, Duerksen-Hughes P; Carcinogenesis 19 (6): 1117-25 (1998) R65: Okamura T et al; Toxicology Letters 74 (2): 129-40 (1994) R66: Garland EM et al; Food Chem Toxicol 29 (10): 657-67 (1991) R67: Garland EM et al; Food Chem Toxicol 29 (10): 669-79 (1991) R68: Durnev AD et al; Vapor Med Khim 41 (4): 31-3 (1995) R69: Geiger D.L., Call D.J., Brooke L.T. (eds). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Vol. IV. Superior Wisconsin: University of Wisconsin-Superior, 1988.141 R70: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Sodium Saccharin (CAS #128-44-9): Reproduction and Fertility Assessment in CD-1 Mice When Administered in Drinking Water, NTP Study No. RACB83072 (April 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R71: U.S. Department of Health and Human Services/National Toxicology Program; 8th Report on Carcinogens p. 189 (1998) R72: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 150 R73: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 349 R74: SWEATMAN TW, RENWICK AG; TOXICOL APPL PHARMACOL 62 (3): 465 (1982) R75: COLBURN WA ET AL; CLIN PHARMACOL THER 30 (OCT): 558 (1981) R76: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 419 R77: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. S-1 R78: SWEATMAN TW, RENWICK AG; SCIENCE 205 (4410): 1019 (1979) R79: HICKS RM, CHOWANIEC J; CANCER RES 37 (8 PT 2): 2943 (1977) R80: OSER BL ET AL; TOXICOLOGY 4 (3): 315 (1975) R81: HICKS RM ET AL; TOXICOLOGY RESEARCH PROJECTS DIRECTORY 04: 10 (1979) R82: EL-GERZAWI S ET AL; J NATL CANCER INST 69 (3): 577 (1982) R83: HAMBURGER JN, KUTSCHER CL; PHARMACOL BIOCHEM BEHAV 10 (5): 651 (1979) R84: Tordoff MG, Friedman MI; Appetite 12 (1): 11-21 (1989) R85: Kakizoe T et al; Jpn J Cancer Res 79 (2): 231-5 (1988) R86: Kanamaru H et al; Jpn J Cancer Res 79 (9): 1043-7 (1988) R87: Suzuki N, Suzuki H; Cancer Research 55 (1): 4253-6 (1995) R88: IARC MONOGRAPHS 1972-PRESENT V22 p.128 R89: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Reinhold Co., p. 1017 (1993) R90: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) (6) Boethling RS et al; Environ Sci Technol 28: 459-65 (1994) R91: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Budvari S; Merck Index, 12th ed, Whitehouse Station, NJ Merck and Co. p. 1430 (1996) (7) Boethling RS et al; Environ Sci Technol 28: 459-65 (1994) R92: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R93: (1) Boethling RS et al; Environ Sci Technol 28: 459-65 (1994) R94: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Budvari S; Merck Index, 12th ed, Whitehouse Station, NJ Merck and Co. p 1430 (1996) R95: (1) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R96: (1) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995)(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R97: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) R98: (1) IARC; Saccharin 22: 111-71 (1980) R99: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R100: (1) Hemminki K, Vainio H; IARC Sci Publ 59: 37-45 (1984) R101: 40 CFR 302.4 (7/1/97) R102: 40 CFR 261.33 (7/1/97) R103: AMER MM ET AL; PHARMAZIE 33 (JUL): 435 (1978) R104: RATCIHK EM, VISWANATHAN V; J PHARM SCI 64 (JAN): 133 (1975) R105: SMYLY DS ET AL; J ASSOC OFF ANAL CHEM 59 (JAN): 14 (1979) R106: ALARY J ET AL; BULL TRAV SOC PHARM LYON 25 (1-2-3-4):65 (1981) R107: Association of Official Analytic Chemists. Official Methods of Analysis of the AOAC. 14th ed. Arlington, VA: Association of Official Analytic Chemists, Inc., 1984. RS: 97 Record 79 of 1119 in HSDB (through 2003/06) AN: 672 UD: 200303 RD: Reviewed by SRP on 2/28/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SALICYLIC-ACID- SY: *O-HYDROXYBENZOIC-ACID-; *2-HYDROXYBENZOIC-ACID-; *PSORIACID-S-STIFT-; *RETARDER-W-; *RUTRANEX-; *SALICYLIC-ACID-COLLODION-; *SALONIL- RN: 69-72-7 RELT: 652 [ACETYLSALICYLIC ACID] (Analog and metabolic precursor) MF: *C7-H6-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF DRY, POWDERED SODIUM PHENATE WITH EXCESS CARBON DIOXIDE TO PRODUCE SODIUM SALICYLATE SOLUTION, WHICH IS ACIDIFIED TO OBTAIN SALICYLIC ACID [R1] *MADE SYNTHETICALLY BY HEATING SODIUM PHENOLATE WITH CARBON DIOXIDE UNDER PRESSURE. [R2] *SOME IS ... MADE BY SAPONIFYING CERTAIN NATURAL OILS SUCH AS BIRCH OR GAULTHERIA. [R3] *NOVEL METHOD BY MICROBIAL OXIDN OF NAPHTHALENE. [R2] *... PRODUCED BY REACTION OF CARBON DIOXIDE ON PHENOL ... . [R4] FORM: *SALICYLIC ACID, U.S.P.: Generic. Powder. SalAc (GenDerm). Lotion (for acne) containing salicylic acid 2% in 180 ml containers. SALICYLIC ACID COLLODION, U.S.P. 40% SALICYLIC ACID PLASTER, U.S.P.: Numerous commercial products are available for wart and callus treatment. Selected concentrations (usually 5% to 17%) can be compounded by a pharmacist. [R5, 1031] *AVAILABLE MIXTURES: Duofilm (Stiefel), Salactic Film (Pedinol), Viranol (American Dermal). Flexible collodion containing salicylic acid 16.7% and lactic acid 16.7% in 10 ml (Firanol only) and l15 ml containers. Hydrisalic (Pendinol), Keralyt (Westwood). Gel containing salicylic acid 6% in a propylene glycol and alcohol vehicle in 30 g containers. Occlusal (GenDerm). Salicylic acid 17% in a polyacrylic vehicle in 15 ml containers. Occlusal-HP (GenDerm). Salicylic acid 26% in a polyacrylic vehicle in 10 ml containers. [R5, 1031] *BENZOIC AND SALICYLIC ACIDS OINTMENT: Mixture available under the name Whitfield's Ointment in 30, 45, and 454 g containers (nonprescription). [R5, p. 1031] MFS: *Hilton-Davis Co, Hq, 2235 Langdon Farm Rd, Cincinnati, OH 45237, (513) 841-4000 [R6] *Kalama Chemical Inc, Hq, The Bank of California Center, Suite 1110, Seattle, WA 98164, (206) 682-7890; Production site: Garfield, NJ 07026 [R6] OMIN: *SIMPLE FREE PHENOLIC ACIDS REPORTED IN WHEAT FRACTIONS. SALICYLIC ACID /FROM TABLE/ [R7] *INCOMPATIBILITY: IRON SALTS, SPIRIT NITROUS ETHER, LEAD ACETATE, IODINE. [R2] *INCOMPATIBILITIES: SALICYLIC ACID IS INCOMPATIBLE WITH USUAL VANISHING CREAM DUE TO FACT THAT CREAMS OF THIS TYPE ARE BASED ON FORMATION OF EMULSION WITH AID OF SOAP. [R3] USE: *AS PRESERVATIVE OF FOOD PRODUCTS, BUT ITS USE FOR THIS PURPOSE IS FORBIDDEN IN SOME COUNTRIES; MFR METHYL SALICYLATES, ACETYLSALICYLIC ACID, AND OTHER SALICYLATES; AS REAGENT IN ANALYTICAL CHEMISTRY; MEDICINE: TOPICAL KERATOLYTIC; VET: EXTERNALLY AS ANTISEPTIC AND ANTIFUNGAL AGENT, AND FOR VARIOUS SKIN CONDITIONS; HAS BEEN USED INTERNALLY IN EQUINE GASTRIC TYMPANY [R2] *CHEMICAL INTERMEDIATE IN SYNTH OF ASPIRIN, SALICYLATE ESTERS AND SALTS, AND RUBBER RETARDERS; DYESTUFF INTERMEDIATE [R1] *MEDICATION *MEDICATION (VET) CPAT: *CHEMICAL PROFILE: Salicylic Acid. Aspirin, 65%; salicylate esters and salts, 20%; foundry resins, 7%; miscellaneous, including rubber retarder and dystuffs intermediate, 8%. [R8] *CHEMICAL PROFILE: Salicylic acid. Demand: 1986: 35.5 million lb; 1987: 35.8 million lb; 1991 /projected/: 37.0 million lb. [R8] *CHEMICAL PROFILE: Salicylic acid. Aspirin, 60%; salicylate esters and salts, 20%; phenolic resins, 10%; miscellaneous, 10%. [R9] *CHEMICAL PROFILE: Salicylic acid. Demand: 1989: 27 million lb; 1990: 270 million lb; 1994 /projected/: 27 million lb. (Includes imports, which totaled 2.35 million lb. last year; exports are negligible.) [R9] PRIE: U.S. PRODUCTION: *(1972) 2.53X10+10 GRAMS [R1] *(1975) 1.39X10+10 GRAMS (TECH GRADE) [R1] U.S. IMPORTS: *(1972) NEGLIGIBLE [R1] *(1975) 2.02X10+8 GRAMS (TECH GRADE) [R1] U.S. EXPORTS: *(1972) NEGLIGIBLE [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE, FINE, NEEDLE-LIKE CRYSTALS, OR FLUFFY, WHITE CRYSTALLINE POWDER [R3]; *Needles in water; monoclinic prisms in alcohol [R10] ODOR: *SYNTHETIC ACID IS ODORLESS [R3] TAST: *IT HAS SWEETISH, AFTERWARD ACRID, TASTE [R3] BP: *ABOUT 211 DEG C @ 20 MM HG [R2] MP: *157-159 DEG C [R2] MW: *138.12 [R2] DEN: *1.443 @ 20 DEG C/4 DEG C [R10] DSC: +pKa = 2.97 [R11]; *pKa: 3.00 [R12]; *pKa= 2.97 and 13.4 [R13] OWPC: +log Kow= 2.26 [R14] PH: *2.4 (SATURATED AQ SOLN) [R2] SOL: *1 G DISSOLVES IN: 460 ML WATER, 15 ML BOILING WATER, 2.7 ML ALCOHOL, 3 ML ACETONE, 42 ML CHLOROFORM, 3 ML ETHER, 135 ML BENZENE, 52 ML OIL TURPENTINE, CA 60 ML GLYCEROL, CA 80 ML FATS OR OILS [R2]; *SLIGHTLY SOL IN TOLUENE; SOL IN CARBON TETRACHLORIDE [R15]; *Water solubility: 2,059 mg/L at 25 deg C [R16] SPEC: *MAX ABSORPTION (0.5 N SODIUM HYDROXIDE ): 235 NM (A= 680, 1%, 1 CM); 300 NM [R17, 818]; *MAX ABSORPTION (ALCOHOL): 207 NM (LOG E= 4.46); 236 NM (LOG E= 3.85); 303 NM (LOG E= 3.57); SADTLER REF NUMBER: 17414 (IR, PRISM); 328 (IR, GRATING); 671 (UV) [R15]; *IR: 5154 (Coblentz Society Spectral Collection) [R18]; *UV: 5-91 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R18]; *MASS: 87 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R18]; *Intense mass spectral peaks: 64 m/z, 92 m/z, 120 m/z, 138 m/z [R19]; *INDEX OF REFRACTION: 1.565 [R10] VAPD: *4.8 (AIR= 1) [R20] VAP: +8.2X10-5 mm Hg at 25 deg C /calculated from experimentally derived coefficients/ [R21] OCPP: *SUBLIMES @ 76 DEG C; WHEN RAPIDLY HEATED @ ATM PRESSURE IT DECOMP INTO PHENOL AND CARBON DIOXIDE; SALICYLIC ACID OR ITS SALTS ARE COLORED REDDISH EVEN BY MEREST TRACES OF FERRIC SALTS; SOLUBILITY IN WATER INCR BY SODIUM PHOSPHATES, BORAX, ALKALI ACETATES OR CITRATES [R2] */Salicylic acid is/ incompatible with iodine, iron salts, and oxidizing substances. [R22] *1 MM HG @ 113.7 DEG C [R23] *Henry's Law constant= 7.34X10-9 atm-cu m/mole @ 25 deg C (SRC) SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT WHEN EXPOSED TO HEAT OF FLAME; CAN REACT WITH OXIDIZING MATERIALS [R23] NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R24] +Flammability: 1. 1= Includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R24] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R24] FLMT: +Lower 1.1% @ 392 deg F [R24] FLPT: +315 DEG F (157 DEG C) (CLOSED CUP) [R24] AUTO: +1004 DEG F (540 DEG C) [R24] FIRP: *WATER, FOAM, CARBON DIOXIDE, DRY CHEM [R23] +Water or foam may case frothing ... to liquids having flash points above 212 deg F (100 deg C) ... Does not indicate water or fire fighting foam should not be used. The frothing may be violent and could endanger any fire fighters located too close to the burning liquids, particularly when solid streams of, water are directed onto the hot, burning liquid. On the other hand, a carefully applied water spray has frequently been used to achieve extinguishment by deliberately causing frothing only on the surface of the liquid; the foaming action blankets the surface of the liquid and extinguishes the fire by excluding oxygen. This tactic is expecially successful with high viscosity liquids. [R24] EXPL: *DUST IS EXPLOSIVE IN AIR ... . [R23] REAC: *Incompatability: Iron salts, spirit nitrous ether, lead acetate, iodine. [R25] DCMP: *When heated to decomp it emits acrid smoke. [R25] SERI: */Salicylic acid/ ... dust irritates the nostrils. [R22] SSL: *GRADUALLY DISCOLORS IN SUNLIGHT [R2] STRG: *Salicylic acid should be stored in well-closed containers. Salicylic acid collodion should be stored in tight containers at 15-30 deg C. Because the collodion is flammable, it should not be stored near heat or an open flame. Salicylic acid plaster should be stored in well-closed containers, preferably at 15-30 deg C. The Trans-Ver-Sal plaster should be stored at a temperature less than 37.8 deg C. [R13] *KEEP PROTECTED FROM LIGHT. [R2] DISP: *Salicyclic acid is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *ABSORPTION OF SALICYLATE FROM GASTROINTESTINAL TRACT CAN BE REDUCED BY EMESIS, GASTRIC LAVAGE, ADMIN OF ACTIVATED CHARCOAL, OR COMBINATION OF THESE. /SALICYLATES/ [R27, 652] *TREATMENT IS LARGELY SYMPTOMATIC ... SALICYLATE MEDICATION IS WITHDRAWN AS SOON AS INTOXICATION IS SUSPECTED. THE PATIENT SHOULD BE ... HOSPITALIZED ... / and / BLOOD SHOULD BE OBTAINED FOR PLASMA SALICYLATE DETERMINATIONS AND ACID-BASE AND ELECTROLYTE STUDIES. /SALICYLATES/ [R27, 652] *MEASURES TO RID BODY RAPIDLY OF SALICYLATE. ... SHOULD BE UNDERTAKEN IMMEDIATELY. ... DIURESIS WITH ALKALINIZING SOLN APPEARS TO BE BETTER THAN ALKALI ALONE ... . /SALICYLATES/ [R27, 652] *IF PATIENT PRESENTS WITH ACIDOSIS, CORRECTION OF LOW BLOOD PH IS ESSENTIAL. ... BICARBONATE SOLN SHOULD BE INFUSED IV TO COMBAT ACIDOSIS AND, IF POSSIBLE, TO MAINTAIN ALKALINE DIURESIS. /SALICYLATES/ [R27, 652] *HYPERTHERMIA AND DEHYDRATION ARE THE IMMEDIATE THREATS TO LIFE, AND THE INITIAL THERAPY MUST BE DIRECTED TO THEIR CORRECTION AND TO MAINTENANCE OF ADEQUATE RENAL FUNCTION. EXTERNAL SPONGING WITH TEPID WATER SHOULD BE PROVIDED QUICKLY TO ANY CHILD WHO HAS RECTAL TEMP OVER 104 DEG F. ADEQUATE AMT OF IV FLUIDS MUST BE GIVEN PROMPTLY. /SALICYLATES/ [R27, 652] *IF POTASSIUM DEFICIENCY OCCURS ... IT SHOULD BE TREATED BY ADDING CATION TO IV FLUIDS ONCE IT HAS BEEN DETERMINED URINE FORMATION IS ADEQUATE. PLASMA TRANSFUSION MAY BE BENEFICIAL. ESPECIALLY IF SHOCK SYNDROME INTERVENES. /SALICYLATES/ [R27, 652] *ANY ATTEMPT TO OBTUND SALICYLATE-INDUCED HYPERVENTILATION BY GIVING BARBITURATE OR NARCOTIC IS DANGEROUS AND MAY ... LEAD TO RESP ACIDOSIS AND COMA. /SALICYLATES/ [R28, 337] *IN SEVERE INTOXICATION, HEMODIALYSIS IS THE MOST EFFECTIVE MEASURE AVAILABLE ... HEMODIALYSIS SHOULD BE CONSIDERED IN PATIENTS WITH SALICYLATE CONCENTRATIONS ABOVE 1000 UG/ML, IN THOSE WITH SEVERE ACID BASE DISTURBANCES ... AND WHO ARE DETERIORATING DESPITE ... THERAPY, AND IN THOSE /WITH/ ASSOCIATED SERIOUS DISEASE. /SALICYLATES/ [R27, 652] *FOR THE TREATMENT OF ALLERGIC RESPONSES, EPINEPHRINE IS THE DRUG OF CHOICE. [R28, 337] *HEMORRHAGIC PHENOMENA MAY NECESSITATE WHOLE-BLOOD TRANSFUSION AND VITAMIN K. /SALICYLATES/ [R27, 652] HTOX: */DIMINISHED ABILITY OF CONJUGATING SALICYLIC WITH GLUCURONIC ACIDS/ ... APPEARS TO OBTAIN IN INFANTS WITH CONGENITAL NON-HEMOLYTIC JAUNDICE, SUCH AS CRIGLER-NAJJAR SYNDROME ... DRUGS WHICH ARE NORMALLY CONJUGATED WITH GLUCURONIC ACID MAY AGGRAVATE KERNICTERUS IN THESE INDIVIDUALS BY FURTHER IMPEDING CONJUGATION OF BILIRUBIN. [R29, 159] *MILD CHRONIC SALICYLATE INTOXICATION IS TERMED SALICYLISM. ... SYNDROME INCLUDES HEADACHE, DIZZINESS, RINGING IN THE EARS, DIFFICULTY IN HEARING, DIMNESS OF VISION, MENTAL CONFUSION, LASSITUDE, DROWSINESS, SWEATING, THIRST, HYPERVENTILATION, NAUSEA, VOMITING, AND OCCASIONALLY DIARRHEA. A MORE SEVERE DEGREE OF SALICYLATE INTOXICATION IS CHARACTERIZED BY MORE PRONOUNCED CNS DISTURBANCES (INCLUDING GENERALIZED CONVULSIONS AND COMA), SKIN ERUPTIONS, AND MARKED ALTERATIONS IN ACID-BASE BALANCE. /SALICYLATES/ [R27, 651] *SALICYLIC ACID IS QUITE IRRITATING TO SKIN AND MUCOSA AND DESTROYS EPITHELIAL CELLS. ... SALTS OF SALICYLIC ACID ARE INNOCUOUS TO UNBROKEN SKIN; HOWEVER, IF FREE ACID IS RELEASED IN STOMACH, GASTRIC MUCOSA MAY BE IRRITATED. [R27, 649] *ABSORPTION OF LARGE AMT CAN CAUSE ... ABDOMINAL PAIN, INCR RESPIRATION, ACIDOSIS ... MAY CAUSE SKIN RASHES IN SENSITIVE INDIVIDUALS. [R2] *Two patients died after more than 50% of their body areas had been painted twice with an alcoholic solution of salicylic acid 20.7% for tinea infection. The deaths were preceded by symptoms typical of salicylate poisoning. [R22] *The study was undertaken to determine the distribution of aspirin and its metabolites in the semen of humans after an oral dose of aspirin. Each of seven healthy male volunteers given a single oral dose of 975 mg of aspirin on an empty stomach together with 200 ml of water. Timed samples of blood and semen were obtained from each subject, and the concentrations of aspirin, salicylic acid, and salicyluric acid determined by a specific high-performance liquid chromatographic assay. The mean peak concentration of aspirin was 6.5 ug/ml in plasma (range, 4.9-8.9 ug/ml), reached in 26 min (range, 13-33 min). The half-life of aspirin was 31 min concentration ratio of aspirin (semen/plsama) was 0.12 (except for one subject in whom it was 0.025). The mean peak concentration of salicylate in plasma was 49 ug/ml (range, 42-62 ug/ml), reached in 2.5 hr (range, 2.0-2.8 hr). Salicylate distributed rapidly into semen and maintained a concentration ratio (semen/plasma) of 0.15. Salicyluric acid acid (the glycine conjugate of salicylic acid) was found in the semen. Its high concentration in some subjects' semen (four times the concurrent plasma concentration) was attributed to contamination of semen sample with residual urine, containing salicylurate, in the urethra of those who urinated after the dose of aspirin. Possible side effects of aspirin and salicylate in semen include adverse effects on fertility, male-medicated teratogenesis, dominant lethal mutations, and hypersensitivity reactions in the recipients. [R30] *A 72 yr old man with psoriasis and end-stage renal disease was treated with a topical cream containing 10% salicylic acid. The patient presented with encephalopathy and subsequently developed hypoglycemia refractroy to infusions of large amounts of glucose. A serum salicylate concentrations was elevated at 3.2 mmol/l. Emergency hemodialysis was accompanied by rapid lowering of serum salicylate concentration and resolution of refractory hypoglycemia. Salicylate is well absorbed across normal and diseased skin. Salicylate markedly impairs gluconeogenesis and increases glucose utilization, resulting in hypoglycemia. ... [R31] NTOX: *REPEATED APPLICATION MAY CAUSE IRRITATION. [R32, 973] *SPLASH OF 3 % SOLN IN COLLODION AND SPLASH OF 3 % IN MIXT OF ALCOHOL AND GLYCERIN ... SHOWN TO CAUSE MUCH IRRITATION AND MODERATE INJURY TO CONJUNCTIVA. [R33] *SALICYLATE MAY ... CAUSE GASTRIC ULCERATION AND EVEN HEMORRHAGE IN EXPTL ANIMALS ... /SALICYLATE/ [R28, 330] *TREATMENT OF TRANSPLANTED HIND LIMB-BUDS CAUSED REDN IN LENGTH, WT, AND VOL OF DEVELOPING LIMB-BUDS. APPARENT LOOSENING OF BASAL MEMBRANE WAS OBSERVED. [R34] *IT WAS TERATOGENIC WHEN INJECTED SC INTO PREGNANT RAT. IT MAY BIND MINERALS IN MATERNAL FETAL ENVIRONMENT MAKING THEM INSUFFICIENTLY AVAIL FOR NORMAL BIOCHEM FUNCTIONS OF DEVELOPING FETUS. [R35] *IT INHIBITED RNA POLYMERASE AND INCORPORATION OF LABELED 5-(3)H-OROTIC ACID AND 6-(3)H-THYMIDINE INTO WHOLE 13 and 16 DAY RAT FETUSES. [R36] *RATS FED 0.4% IN DIET ON GESTATION DAYS 8-14 SHOWED TEMPORARY BODY WT LOSS, SALIVATION AND PILOERECTION; HIGH MORTALITY AND GROWTH RETARDATION IN FETUSES. PUPS FED 0.2% SHOWED MINOR CERVICAL BONE CHANGES. [R37] *RECENT STUDY HAS CONFIRMED PREVIOUS REPORTS THAT ... SALICYLIC ACID AND METAL-CHELATING AGENT EDTA /ETHYLENEDIAMINETETRACETIC ACID/ WERE TERATOGENIC IN RATS. [R38] *PENTOBARBITAL /SRP: CNS DEPRESSION/ IN MICE WAS ENHANCED AFTER PRE-TREATMENT WITH ... SALICYLIC ACID. [R39] *In rats, Mg deficiency caused a moderate hearing loss, measured by means of evoked potentials at 10 and 20 kHz, which was repaired after refeeding a normal diet. Application of 700 mg/kg salicylic acid or injection of 5x100 mg/kg gentamicin also caused a reversible hearing loss in normally fed rats. Treatment of Zn deficient rats with salicylic acid produced a stronger although reversible hearing loss than in normally fed salicylate treated rats. Treatment of Mg deficient rats with gentamicin induced a strong hearing loss that was nearly complete and irreversible in 9 of 25 rats. [R40] *Oral application of 700 mg/kg salicylic acid to pregnant and non-pregnant female rats caused an increase of serum Mg2+ and a decrease of serum Ca2+ concentration. The salicylate effect was drastically enhanced by Zn deficiency. The increase in serum Mg2+ is probably caused by the nephrotoxicity of salicylate. The decrease of serum Ca2+ concentration is combined with an increase of parathyroid hormone concentration in serum. Probably, salicylate and Zn deficiency inhibit Ca2+ mobilization by parathyroid hormone in bone. [R41] ADE: */FOUR TO FIVE PERCENT IS EXCRETED IN URINE AS 3,5-DIHYDROXYGENTISIC ACID/. /FROM TABLE/ [R17, 375] */IT/ ... IS METABOLIZED ... TO SALICYLURIC ACID (15 % OF DOSE IN MAN), AND WITH GLUCURONIC ACID TO GIVE ... O-CARBOXYPHENYLGLUCURONIDE (20 %) AND O-HYDROXYBENZOYLGLUCURONIDE (5 %). ... HYDROXYLATION ... /GIVES/ GENTISIC ACID (1-5 %), AND TRACES OF 2,3-DIHYDROXYBENZOIC AND 2,3,5-TRIHYDROXYBENZOIC ACIDS, and 60 % OF DOSE ... EXCRETED UNCHANGED. [R42, 175] *SALICYLATE ABSORPTION OCCURS BY PASSIVE DIFFUSION PRIMARILY OF NONDISSOCIATED LIPID-SOL MOLECULES (SALICYLIC ACID AND ACETYLSALICYLATIC ACID) ACROSS GI MEMBRANES AND HENCE IS INFLUENCED BY GASTRIC PH. ... A RISE IN PH ALSO INCR SOLUBILITY OF SALICYLATE, AND THE OVERALL EFFECT IS TO ENHANCE ABSORPTION. [R27, 649] *EFFECT OF DRUG PKA AND GASTRIC PH ON ABSORPTION OF DRUGS FROM RAT STOMACH. PKA 3.0; 61 % SALICYLIC ACID IN 0.1 N HYDROCHLORIC ACID ABSORBED IN 1 HR, 13 % IN SODIUM BICARBONATE, PH 8. /FROM TABLE/ [R29, 27] *PHYSICAL CHARACTERISTICS AND PERMEABILITY COEFFICIENTS FOR DRUGS MAINLY IONIZED @ PH 7.4 WITH RESPECT TO ENTRY INTO CEREBROSPINAL FLUID. SALICYLIC ACID PKA 3.0; % UN-IONIZED @ PH 7.4 0.004-0.01; BLOOD-CEREBROSPINAL FLUID PERMEABILITY COEFFICIENT (MIN-1) 0.0026-0.006. /FROM TABLE/ [R29, 82] *CLEARANCE GREATER IN ALKALINE URINE. /FROM TABLE/ [R29, 124] *... SALICYLIC ACID ... WAS REPUTED TO APPEAR IN HUMAN SWEAT ... . [R29, 142] *5-6 MO PREGNANCY INTERRUPTED: 96 MIN AFTER ADMIN, LEVELS IN MOTHER AND FETUS BLOOD ALMOST EQUAL. HIGHEST LEVELS IN FETUS KIDNEY, LOWEST IN BRAIN. IN AMNIOTIC FLUID, ONLY TRACES OF SALICYLIC ACID WERE FOUND. [R43] *[TJALVE H ET AL; ARCH INT PHARMACODYN THER 203 (1): 142-150 (1973)] IN MOTHER CONCN HIGH IN BLOOD, LIVER, KIDNEY, PERITONEAL, PLEURAL AND SYNOVIAL FLUID OF JOINTS @ SHORT AND EXCRETORY ORGANS @ LATE TIME INTERVALS. HIGH CONCN OF RADIOACTIVITY IN PLACENTA, PASSED TO FETUS. FETAL RADIOACTIVITY INCR RELATIVE TO THAT IN MOTHER @ LONG TIME INTERVALS. DISTRIBUTION OF RADIOACTIVITY SIMILAR EXCEPT IN VITREOUS BODY OF EYE--FETUS HIGH AND MOTHER LOW ACCUM: IN LUNGS THE REVERSE WAS THE CASE. [R42, 175] *This drug is absorbed readily and is excreted slowly in the urine. [R5, 1030] METB: *... METABOLIZED BY MAN AND OTHER MAMMALS BY CONJUGATION WITH GLYCINE TO ... SALICYLURIC ACID (15 % OF DOSE IN MAN), AND WITH GLUCURONIC ACID TO GIVE ... O-CARBOXYPHENYLGLUCURONIDE (20 %) AND O-HYDROXYBENZOYLGLUCURONIDE (5 %). ... HYDROXYLATION ... /GIVES/ ... TRACES OF 2,3-DIHYDROXYBENZOIC AND 2,3,5-TRIHYDROXYBENZOIC ACIDS ... . [R42, 175] *... SALICYCLIC ACID IS METABOLIZED INTO CATECHOL BY PSEUDOMONAS ENZYME, SALICYLATE HYDROXYLASE, A FLAVOPROTEIN REQUIRING NADH2 /NICOTINAMIDE ADENINE DINUCLEOTIDE/ AND OXYGEN [R42, 119] *... SALICYLIC ... /ACID IS/ METABOLIZED BY CONJUGATION @ BOTH CARBOXYL AND HYDROXYL GROUPS, AND BY HYDROXYLATION OF AROMATIC RING TO GIVE SMALL AMT OF GENTISIC ACID (2,5-DIHYDROXYBENZOIC ACID) AND PROTOCATECHURIC ACID (3,4-DIHYDROXYBENZOIC ACID) RESPECTIVELY. [R42, 142] *YIELDS SALICYLOYL-B-D-GLUCURONIC ACID IN RABBIT; YIELDS PYROCATECHURIC ACID IN RABBIT; YIELDS PHENOL IN GLOMERELLA; YIELDS SALICYLALDEHYDE IN NEUROSPORA; YIELDS SALICYLIC ACID GLUCOSIDE IN BEAN; YIELDS O-HYDROXYHIPPURIC ACID IN MAN. /FROM TABLE/ [R44, p. S-4] *YIELDS O-CARBOXYPHENYL-B-D-GLUCURONIDE IN MAN; IN RABBIT; YIELDS O-CARBOXYPHENYL SULFATE IN RAT. /FROM TABLE/ [R44, p. S-3] *The study was undertaken to determine the distribution of aspirin and its metabolites in the semen of humans after an oral dose of aspirin. Each of seven healthy male volunteers given a single oral dose of 975 mg of aspirin on an empty stomach together with 200 ml of water. Timed samples of blood and semen were obtained from each subject, and the concentrations of aspirin, salicylic acid, and salicyluric acid determined by a specific high-performance liquid chromatographic assay. The mean peak concentration of aspirin was 6.5 micrograms/ml in plasma (range, 4.9-8.9 micrograms/ml), reached in 26 minutes (range, 13-33 minutes). The half-life of aspirin was 31 minutes. The concentration ratio of aspirin (semen/plsama) was 0.12 (except for one subject in whom it was 0.025). The mean peak concentration of salicylate in plasma was 49 micrograms/ml (range, 42-62 micrograms/ml), reached in 2.5 hours (range, 2.0-2.8 hours). Salicylate distributed rapidly into semen and maintained a concentration ratio (semen/plasma) of 0.15, Salicyluric acid acid (the glycine conjugate of salicylic acid) was found in the semen. Its high concentration in some subjects' semen (four times the concurrent plasma concentration) was attributed to contamination of semen sample with residual urine, containing salicylurate, in the urethra of those who urinated after the dose of aspirin. ... [R30] *1. Metabolism of aspirin was studied in 10 human volunteers who took a therapeutic dose (600 mg) by mouth and in nine patients who took aspirin in overdose. 2. Salicyluric acid was the major urinary metabolite in volunteers (63.1 + or - 8.4% of dose in 0-8 hr). In overdose patients, salicyluric acid in urine was decreased (30.0 + or - 8.2%, 0-24 hr, P less than 0.001) and there was increased elimination of salicyclic acid (34.1%, P less than 0.005), salicyl acyl glucuronide (14.4%, P less than 0.05) and gentisuric acid (5.3%). 3. Metabolism of orally administered 14(C) aspirin in rats over a 10-fold dose range (10-100 mg/kg) resulted in excretion of 81-91% dose in urine in the first 24 hr. Salicyclic acid was the major urinary metabolite (43-51% dose). Excretion of salicyluric acid decreased with increasing dose, whereas gentisic acid and salicyl phenolic and acyl glucuronides increased. 4. The profile of aspirin metabolites was qualitatively similar in man and rat but there were quantitative differences. Limited capacity to form salicyluric acid was observed in both species. Dependence on this pathway in rat was low and was compensated by increased utilization of other routes; dependence on salicyluric acid formation in man was high and in overdose, compensation by other routes was incomplete. /Aspirin/ [R45] ACTN: *Conc exceeding 3% are keratolytic ... . [R5, 1030] *... KERATOLYTIC ACTION. ... TISSUE CELLS SWELL, SOFTEN, AND ULTIMATELY DESQUAMATE. [R3] INTC: *PERCUTANEOUS ABSORPTION OF HYDROCORTISONE AND SALICYLIC ACID WAS FOUND TO BE GREATER WHEN DIMETHYL SULFOXIDE WAS PRESENT. HOWEVER, EFFECT ON ... ACID WAS GREATER @ LOW PH VALUES, AND POSITIVE ACTION OF DIMETHYL SULFOXIDE APPEARED TO BE DUE PARTLY TO ITS ABILITY TO INCR SOLUBILITY OF UN-IONIZED DRUG. [R46] *PENTOBARBITAL /SRP: CNS DEPRESSION/ IN MICE WAS ENHANCED AFTER PRE-TREATMENT WITH ... SALICYLIC ACID ... SALICYLIC ACID ... SHOWN TO DECR PLASMA-PROTEIN BINDING OF DIPHENYLHYDANTOIN IN MAN ... . [R39] *In rats, magnesium deficiency caused a moderate hearing loss, measured by means of evoked potentials at 10 and 20 kHz, which was repaired after refeeding a normal diet. Application of 700 mg/kg salicylic acid or injection of 5 x 100 mg/kg gentamicin also caused a reversible hearing loss in normally fed rats. Treatment of zinc deficient rats with salicylic acid produced a stronger although reversible hearing loss than in normally fed salicylate treated rats. Treatment of magnesium-deficient rats with gentamicin induced a strong hearing loss that was nearly complete and irreversible in 9 of 25 rats. [R40] *Corticosteroids have been reported to decrease the plasma concentrations of salicylate when salicylates have been administered chronically at high doses. In the present study, two single, oral doses of sodium salicylate, 10 mg kg-1 were administered to six adult subjects with a variety of inflammatory conditions both before and during treatment with daily oral doses of prednisone (12-60 mg). Concomitant prednisone therapy did not increase the whole body clearance of single doses of salicylate in these subjects (0.0275 + or - 0.08 kg/hr before prednisone; 0.0247 + or - 0.03 kg/hr during prednisone therapy; P greater than 0.05). These results indicate that corticosteroids do not alter the clearance of single doses of salicylate in man. [R47] *The effects of aspirin on the pharmacokinetics of niacin (nicotinic acid) were studied in 6 healthy male subjects (aged 20-30 yr) who received an intravenous infusion of 0.075 to 0.1 mg/kg/min nicotinic acid for 6 hr and an oral tablet of 1 g aspirin 120 min after the beginning of the nicotinic acid infusion. Plasma samples were analyzed for nicotinic acid, nicotinuric acid and salicylic acid. After aspirin administration, an immediate marked decrease of nicotinuric acid levels and an increase in nicotinic acid levels were observed. It was suggested that aspirin caused a concentration dependent decrease in total nicotinic acid clearance which resulted in the saturation of the nicotinuric acid conjugation pathway. [R48] *Oral application of 700 mg/kg salicylic acid to pregnant and non-pregnant female rats caused an increase of serum magnesium(2+) and a decrease of serum calcium(2+) concentration. The salicylate effect was drastically enhanced by zinc deficiency. The increase in serum magnesium(2+) is probably caused by the nephrotoxicity of salicylate. The decrease of serum calcium(2+) concentration is combined with an increase of parathyroid hormone concentration in serum. Probably, salicylate and zicn deficiency inhibit calcium(2+) mobilization by parathyroid hormone in bone. [R41] *Aspirin (acetylsalicylic acid) is metabolically converted to salicylic acid by the action of carboxylesterases. Although metabolic drug interactions involving aspirin are theoretically possible, there appear to have been no studies to date which have shown conclusively that aspirin hydrolysis is altered by coadministered drugs. However, a number of treatments are known to affect the rate or extent of aspirin absorption, including activated charcoal, antacids, cholestyramine and metoclopramide. Caffeine and metoprolol have been reported to increase peak salicylic acid concentration following aspirin administration, and coadministration of dipyridamole and aspirin results in higher plasma aspirin concentrations. The mechanism(s) responsible for these latter observations remains unknown. Salicylic acid is extensively bound to plasma albumin, and many of the reported drug interactions involve displacement of the coadministered drug from plasma protein. Protein binding displacement appears to be the basis of salicylic acid interactions with diclofenac, flurbiprofen, ibuprofen, isoxicam, ketoprofen, naproxen, phentoin and tolmetin. Following displacement of these agents increased clearance of total drug occurs, and consequently the plasma concentration of total drug decreases. Although generally not measured, unbound concentration of the interacting drug should not be markedly altered. Salicylic acid also increases total plasma clearance of fenoprofen but, unlike the interactions with the other propionic acid non-steroidals, plasma protein binding displacement does not appear to be involved. Induction of fenoprofen metabolism is a possibility, although there is no firm evidence from other studies that salicylate is able to induce the metabolism of coadministered drugs. Since salicylic acid is extensively metabolised, it is not surprising that it is able to inhibit the metabolism of certain coadministered drugs and chemicals, an effect which has been reported for salicylamide, valproic acid, m-xylene, and zomepirac. The interactions with salicylamide, m-xylene and zomepirac are probably competitive in nature since mutual inhibition of salicylic acid metabolism occurs. There is an additional component of protein binding displacement in the interactions with valproic acid and zomepirac, resulting in increased unbound drug concentration. Certain coadministered drugs (or chemicals) may alter the metabolism of salicylic acid; inhibition of its metabolism has been demonstrated following treatment with benzoic acid, salicylamide, m-xylene, zomepirac and possibly cimetidine. In contrast, salicylic acid elimination is enhanced in oral contraceptive steroid users and by corticosteroid treatment. Oral contraceptive steroids induce both salicylic acid glucuronidation and salicylurate formation. Induction of metabolism has also been proposed to account for the the effect of corticosteriods, but this is [R49] *Two elderly patients, who were chronically receiving aspirin, developed lethargy, incontinence, and confusion after dosing with acetazolamide. Unbound plasma acetazolamide concentrations were elevated and plasma protein binding was reduced, suggesting an interaction with aspirin. In vitro studies demonstrated a concentration dependent effect of salicylate on acetazolamide binding to serum proteins. At a therapeutic serum acetazolamide level of 8.0 ug/ml, the unbound percentage of acetazolamide in serum was 3.3% and increased to 11.0% and 30.0%, with serum salicylate levels of 200 and 386 ug/ml, respectively. Furthermore, the apparent association constant of acetazolamide for binding to serum proteins was decreased by 58% and 86% of its control value at these respective salicylate concentrations. The maximal binding capacity of serum for acetazolamide was not affected by salicylate. Pharmacokinetic studies in four volunteers showed that the plasma protein binding and renal clearance of actazolamide were significantly reduced during chronic salicylate dosing. Salicylate appears to competitively inhibit the plasma protein binding of acetazolamide and simultaneously to inhibit acetazolamide renal tubular secretion. [R50] *Furosemide is a loop diuretic which has been found to be ototoxic in humans and experimental animals. The ototoxic effects seem to be directed primarily towards the stria vascularis, since its shrinkage ad extracellular edema have been observed in correlation with electrophysiologic changes. The present study was designed to examine the interaction of sodium salicylate and furosemide on the cochlear microstructures. Chinchillas weighing 400-600 g were used in all tests performed. The endocochlear potential (EP) was monitored continuously through a microelectrode inserted through the basilar membrane. A control group of animals was injected with 0.5 saline iv 30 min before 25 mg/kg furosemide was given. The experimental group of animals was injected with 50 mg/kg sodium salicylate iv 30 min before 25 mg/kg furosemide. The control animals were found to have a mean decrease in endocochlear potential of 61.1 + or - 7.0 mV. In contrast, the experimental group had very little alteration of the endocochlear potential following furosemide injection (18.7 + or - 3.9 mV). These findings suggest that sodium salicylate markedly reduces the ototoxic effect of furosemide. This effect may be mediated by an alteration of local or systemic prostaglandin metabolism, or may be due to inhibition of organic acid uptake in the cochlea. /Sodium salicylate/ [R51] *SALICYLIC ACID ... SHOWN TO DECR PLASMA-PROTEIN BINDING OF DIPHENYLHYDANTOIN IN MAN ... . [R39] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents; Antifungal Agents; Keratolytic Agents [R52] *Used to remove thick calluses and splinters. [R5, 1030] *Used to treat superficial fungal infections. [R5, 1030] *... ESPECIALLY USEFUL IN TREATMENT OF TINEA PEDIS (ATHLETE'S FOOT) AND TINEA CAPITIS (RINGWORM OF SCALP). [R3] *SALICYLIC ACID WITH COCOA BUTTER IN PETROLATUM ROSE WATER OINTMENT IS USED AS EMOLLIENT, KERATOLYTIC, AND ANTIPRURITIC AGENT FOR SENILE SKIN, DRY SKIN, AND SHEET RASH. [R53] *MEDICATION (VET): SALICYLIC, ACID, USP, HAS LOW GERMICIDAL AND FUNGICIDAL ACTIVITY. ... MAINLY USED WITH OTHER DRUGS IN DERMATOLOGIC PREPN FOR ITS KERATOLYTIC ACTIVITY. [R32, 866] *MEDICATION (VET): ... MAIN APPLICATION IS IN TREATMENT OF CHRONIC SUPERFICIAL DERMATOMYCOSIS. [R32, 973] *MEDICATION (VET): ITS PRINCIPAL USE INTERNALLY IS IN CATTLE AS ANTIFERMENTATIVE AGENT. FOR THIS PURPOSE, ORAL DOSE ... HAS BEEN USED IN CATTLE TO DECR AMT OF GAS PRODUCED BY BACTERIAL FERMENTATION. EFFICACY ... AS ANTIFERMENTATIVE AGENT IN CATTLE DOES NOT APPEAR TO HAVE BEEN FIRMLY ESTABLISHED. [R32, 357] *MEDICATION (VET): HAD BEEN USED INTERNALLY IN EQUINE GASTRIC TYMPANY. [R2] *Salicylic acid is used topically for its keratolytic effect in controlling seborrheic dermatitis of the body and scalp, psoriasis of the body and scalp, dandruff, and other scaling dermatoses. The drug is also used topically for its keratolytic and caustic effect in the removal of common and plantar warts, corns, and calluses. Salicylic acid has also been used in the treatment of localized hyperkeratosis, such as occurs on the palms and soles. [R13] *Salicylic acid has bacteriostatic and fungicidal actions. It is applied externally, usually as a 1 to 5% dusting-powder, lotion, or ointment, for the treatment of chronic ulcers, dandruff, eczema, psoriasis, hyperhydrosis, and parasitic skin diseases. It is also used in conjunction with many other agents, such as benzoic acid, coal tar, resorcinol, and sulfur. [R22] *Concentrations of salicylic acid 0.5% to 2% are safe and effective in the treatment of acne ... . Salicylic acid 3% to 6% in an ointment base is useful in dandruff, seborrheic dermatitis, and psoriasis. This concentration in a gel vehicle with propylene glycol 60% (Hydrisalic, Keralyt) is particularly effective when applied under occlusive dressings to treat ichtyosis ... . [R5, 1030] *A novel use of a salicylic acid 40% disk occluded with an adhesive strip has been described for the removal of splinters. The application of the disk to the splinter site for 12 hours is reported to be especially useful in children with splinters not easily accessible in order to avoid the adverse infective and psychological effects associated with traumatic mechanical extraction. [R5, 1030] *To remove calluses, the ointment is applied at bedtime and washed off in the morning. ... The collodion solution is applied to corns ... . [R5, 1030] WARN: *SALICYLIC ACID ... IS SO IRRITATING THAT IT CAN ONLY BE USED EXTERNALLY ... [R27, 644] *ABSORPTION OF LARGE AMT CAN CAUSE VOMITING, ABDOMINAL PAIN, INCR RESPIRATION, ACIDOSIS, MENTAL DISTURBANCES. MAY CAUSE SKIN RASHES IN SENSITIVE INDIVIDUALS. [R2] *Not effective in a zinc oxide paste because it forms zinc salicylate, which is pharmacologically inactive. [R5, 1030] *Salicylic acid should not be applied over large areas, in high concn, or for prolonged periods to extremities, especially in diabetics, infants, young children, or in patients with peripheral vascular disease; acute inflammation, ulceration and even fatalities may occur after such use. [R5, 1030] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Salicylic acid occurs naturally in many microorganisms and plants. It may be involved in photochemical polymerization of fulvic and humic materials, of which it is a minor constituent. Anthropogenic releases may occur via effluents at sites where it is produced or used in the manufacture of aspirin, foundry and phenolic resins, rubber retarders, dyestuffs and medicines. Salicylic acid and the salicylate ion will occur in pH dependent proportions. Above pH 5, virtually all salicylic acid will exist as the salicylate ion. Adsorption, volatilization and bioconcentration are not expected to be important environmental fate processes. Biodegradation is expected to be the dominant removal mechanism from soil and water. It may also undergo photochemical degradation in sunlit environmental media. In air, it is expected to exist in both the vapor and particulate phase. Vapor phase reaction with photochemically produced hydroxyl radicals may be important (estimated half-life of 1.2 days). Removal by wet and dry deposition can also occur. A probable human exposure would be occupational exposure. Common non-occupational exposures include ingesting contaminated drinking water supplies and certain foods and beverages such as fruits, fruit juices and wines. Infants may ingest it with milk from nursing mothers that have consumed aspirin. Exposures can occur in urban atmospheres and during recreational activities at contaminated waterways. (SRC) NATS: *Free salicylic acid occurs naturally in plants in very small amounts(1). It is also produced by microbes such as Actinomycetes, the bacteria, Aerobacter aerogens, and the fungus, Penicillium griseofulvum(2). Hence, it has been identified as a constituent of fulvic(3) and humic acids(4) contained in natural waters and soil. Salicylic acid has been isolated from the roots, stem and leaves, blossoms, and fruit of Spiracea ulmaria(1), and is contained in the sapwood of Pinus radiata(2). Salicylic acid occurs in tulips, hyacinths, violets and in common fruits such as apples, oranges, plums, and grapes(1). The occurrence of salicylic acid in fruits also accounts for its presence in most wines(1) and probably fruit juices(SRC). In general, methyl salicylate and salicyl alcohol occur in greater quantities in plants along with salicylic acid(1). Both forms are also more common than salicylic acid; they occur in a greater number of species including poplar (Populus), willow (Salix), birch (Betula), beech (Fagus) and wintergreen (Gaultheria proumbens)(1). [R54] ARTS: *Salicylic acid may be released to the environment via effluents at sites where it is produced or used in the manufacture of aspirin, foundry and phenolic resins (i.e. fiber glass, brake liners and binders for grinding wheels), rubber retarders, dyestuffs and medicines (salicylic acid USP (US Pharmacopeia) is an antiseptic, disinfectant, and antifungal and keratolytic agents)(1). Salicylic acid may also be released to the aquatic environment in wastewater discharges from textile and paper mills(2), timber products, organic chemical and plastic manufacturing facilities(3), municipal garbage incinerators(4) and sewage treatment facilities(5). [R55] FATE: *TERRESTRIAL FATE: With a pKa of 2.97(1), salicylic acid and its conjugate base, the salicylate ion, will exist in extremely acidic soils in varying proportions that are pH dependent. Above pH 5, virtually all salicylic acid will exist as the salicylate ion(2). Anions generally do not volatilize or undergo adsorption to the extent of their neutral counterparts(2). Both the vapor pressure and the Henry's Law constant indicate that volatilization of salicylic acid from soil should not be an important fate process. Biodegradation is expected to be the dominant removal mechanism from terrestrial environments. A soil grab sample study showed that salicylic acid biodegraded rapidly under differing sets of agricultural practices in Pahokee muck soil(3). Adsorption should not compete with biodegradation; calculated Koc values (65 to 404)(2) indicate a high to medium mobility class for salicylic acid in soil(4). Photochemical data in water(5) suggests that salicylic acid may possibly photodegrade and polymerize to form humic materials in sunlit soil surfaces(SRC). [R56] *AQUATIC FATE: With a pKa of 2.97(1), salicylic acid and its conjugate base, the salicylate ion, will exist in extremely acidic natural waters in varying proportions that are pH dependent. Above pH 5, virtually all salicylic acid will exist as the salicylate ion(2), which can not volatilize from water or adsorb to particulate matter to the extent of their neutral counterparts(2). A calculated Henry's Law constant of 7.34X10-9 atm-cu m/mole at 25 deg C(SRC) suggests that volatilization of salicylic acid from natural bodies of water will not be an important fate process(2). The potential for salicylic acid to bioconcentrate in aquatic organisms or partition from the water column to organic matter contained in sediments and suspended solids is low, based on estimated values of log BCF (0.92 to 1.49) and Koc (65 to 404)(2). However, salicylic acid has been detected in river and sea sediments(3). [R57] *AQUATIC FATE: The dominant removal mechanisms of salicylic acid from aquatic systems are expected to be biodegradation and possibly photooxidation reactions. Extensive aqueous screening test data has shown that salicylic acid should biodegrade rapidly upon acclimation under both aerobic and anaerobic conditions(1-9). [R58] *AQUATIC FATE: Half-lives of 30 to 142 days have been calculated(SRC) for the photochemical reaction of salicylic acid and the salicylate with hydroxyl radicals in full intensity sunlit natural waters(1-3). Limited evidence suggests that salicylic acid, via photochemical processes, is involved in polymerization of fulvic acids in natural waters(4). [R59] *ATMOSPHERIC FATE: Based on a vapor pressure of 8.2X10-5 mm Hg at 25 deg C(1), salicylic acid is expected to exist in both the vapor and particulate phase in ambient air(2). For gaseous salicylic acid in the atmosphere, vapor phase reactions with photochemically produced hydroxyl radicals may be important. The reaction rate constant was estimated to be 1.32X10-11 cu cm/molecule-sec at 25 deg C, which corresponds to an atmospheric half-life of about 1.2 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(3,SRC). Limited monitoring data has shown that physical removal from air by wet deposition (rainfall, dissolution in clouds, etc.)(4) and dry deposition of particulate matter can occur(5-6). [R60] BIOD: *River die-away tests pertaining to the biodegradation of salicylic acid in natural waters were not located in the available literature. Only one soil grab sample test was located, which showed that salicylic acid biodegraded rapidly under differing sets of agricultural practices in Pahokee muck soil(1). In October, soil planted to grass, fallow soil and soil with sugar cane cover at 25 deg C, 43, 17 and 21% of the radiolabeled salicylic acid was emitted as CO2/cu cm of soil/min(1). In January, 26, 7 and 11% of the starting material was emitted as CO2/cu cm of soil/min(1). [R61] *A number of aerobic biological screening studies, which utilized settled waste water, sewage, or activated sludge for inocula, have demonstrated that salicylic acid is readily biodegradable upon acclimation(1-7). In 14 hrs, 87% of 1000 ppm salicylic acid was degraded by an activated sludge acclimated to concns equal to the starting material(3). Also, > 90% of the starting salicylic acid degraded within 4 days of acclimation during the Zahn-Wellens screening method(7). Five day BOD:ThOD ratios were 38% and 98% for unacclimated(1) and acclimated(4) cultures, respectively. In 14 days, 94% of 150 ppm salicylic acid degraded(2). Similar 14 day BOD tests were used to calculate half-lives ranging from 7.5 to 9.5 hrs after lag periods of 10 to 20 days(6). According to the Japanese MITI screening procedure, salicylic acid is readily biodegradable(5). [R62] *A few anaerobic screening studies have demonstrated that salicylic acid is biodegraded readily upon acclimation under anaerobic conditions(1-2). [R63] ABIO: *Experimental data pertaining to the hydrolysis of salicylic acid was not located in the available literature. Nevertheless, hydrolysis is not expected to be an important environmental fate process because the salicylic acid molecule does not contain any hydrolyzable groups(1). Measured rate constants for the reaction of salicylic acid with hydroxyl radicals in water at room temperatures and pH 2 range from 1.2-2.0X10+10 L/mole-sec(2). A much wider range of rate constants has been measured for the salicylate ion. An identical value of 5.6X10+9 L/mole-sec has been reported for the reaction of salicylate ion with hydroxyl radicals in water at room temperatures (18 to 25 deg C) and pHs of 9(3) and 10.7(4). At pH 7, the rate constant ranged from 1.2-2.0X10+10 L/mole-sec(10). Assuming the hydroxyl radical concentration in full intensity sunlit natural water is 1.0X10-17 mole/L(5), calculated half-lives for the photochemical reaction of salicylic acid and the salicylate ion with hydroxyl radicals in water under conditions of continuous full intensity sunlight would range from approximately 30 to 47 and 40 to 142 days(SRC). [R64] *Radiolabeled salicylic acid solutions of 5 and 100 mg/L were irradiated by a high pressure mercury lamp (Philips HPK 125) with a pyrex cooling jacket(1). About 1% of the starting material was degraded to CO2 within 30 min; other photolytic products included quinone-like compounds and singlet oxygen(1). The presence of green algae (Scenedesmus subspicatus) increased the rate of reaction; about 4% CO2 was formed in 30 min. Further photochemical processes involved polymerization and the formation of fulvic acids(1). Hence, salicylic acid may be a precursor to humic material synthesis when exposed to sunlight in natural waters(1). The rate constant for the reaction of salicylic acid with photochemically produced hydroxyl radicals in air has been estimated to be 1.32X10-11 cu-cm/molecule-sec at 25 deg C(2,SRC). Based upon an average yearly atmospheric hydroxyl radical concentration of 5.0X10+5 molecules/cu-cm in a typical atmosphere(2), the corresponding half-life for salicylic acid would be about 1.2 days(SRC). [R65] BIOC: *Based on a water solubility of 2,059 mg/L at 25 deg C(1) and a log Kow of 2.26(2), the respective bioconcentration factors (log BCF) of 0.92 and 1.49 have been calculated for salicylic acid using recommended regression-derived equations(3). These BCF values indicate the potential for salicylic acid to bioconcentrate in aquatic organisms is low(SRC). [R66] KOC: *Based on a water solubility of 2,059 mg/L at 25 deg C(1) and a log Kow of 2.26(2), a Koc of 65 and 404 have been calculated for salicylic acid using various regression-derived equations(3,SRC). These Koc values indicate a high to medium mobility class for the undissociated salicylic acid in soil(4). However, with a pKa of 2.97(5), salicylic acid and its conjugate base, the salicylate ion, will exist in varying proportions that are pH dependent. [R67] VWS: *With a pKa of 2.97(1), salicylic acid and its conjugate base, the salicylate ion, will exist in extremely acidic environmental media in varying proportions that are pH dependent. Above pH 5, virtually all salicylic acid will exist as the salicylate ion(2). Ions are not expected to volatilize from water(2). The Henry's Law constant of 7.34X10-9 atm-cu m/mole for salicylic acid has been calculated from the water solubility (2,059 mg/L at 25 deg C)(3) and vapor pressure (8.2X10-5 mm Hg at 25 deg C)(4). Based on this Henry's Law constant, volatilization of salicylic acid from acidic natural bodies of water and moist soils is not expected to be an important fate process(2). [R68] WATC: *DRINKING WATER: Salicylic acid was identified as a constituent of humic material contained in the drinking water supply of Warsaw, Poland(1). It was also qualitatively identified as a contaminant of an English drinking water supply derived from a lowland river and ground waters(2). [R69] *SURFACE WATER: Salicylic acid was identified as a constituent of fulvic acid contained in the surface water of Lake Singletary, NC(2). Relatively polluted water samples from the Futago (16 Dec 1975), Ohkuri (29 April 1976), Nogawa (16 Dec 1975), and Kototoi Rivers (9 July 1975) near Tokyo, Japan contained salicylic acid at concns of 0.06, 0.09. 0.10, and 0.07 ug/L, respectively(1). It was also detected in 3 water samples from the Chohfu River, Japan at concns of 0.09 (16 Dec 1975), 0.05 (29 Aug 1976), 0.10 (21 Dec 1977), and 0.30 (4 March 1978) ug/L(1). At rather pristine sites, surface waters of the Ogasawara Islands, Japan (24 August 1974-6 August 1975), salicylic acid concentrations were similar where it was detected (0.06, 0.06, 0.05, 0.07, 0.06, 0.07 and 0.07 ug/L(1). However, the polluted waters had a greater frequency of detection which lead to a greater overall average concn of 0.05 ug/L, as opposed to an average concn of 0.01 ug/L at the pristine sites(1). [R70] *RAIN/SNOW: Salicylic acid was qualitatively listed as a contaminant in precipitation(1). [R71] EFFL: *Salicylic acid may be released to the aquatic environment in wastewater discharges from industry(4) and sewage treatment facilities(3). In response to the June 1976 consent decree, the EPA surveyed the wastewaters of 46 industrial categories for 129 priority pollutants. Salicylic acid was detected in 2 of 21 industrial categories of wastewater effluents(4). Extract from the wastewater of a timber products mill contained salicylic acid at an average concn of 3,687 mg/L(4). Extract from the wastewater of a organic chemical and plastic manufacturing facility contained salicylic acid at an average concn of 5 mg/L(4). Salicylic acid was detected in the wastewater effluent of a municipal garbage incinerator in Tokyo, Japan (26 June 1975) at a concn of 0.2 ug/L(1). In 1972, salicylic acid was detected in the wastewater effluent of a Kraft paper mill in Georgia on 2 of 4 separate occasions at a concns of 0.005 and 0.010 mg/L(2). [R72] SEDS: *SOIL: Soil at Metropolitan University, Tokyo, Japan contained salicylic acid at a concn of 0.06 ug/g(1). SEDIMENT: Salicylic acid was detected in sediments from 4 surface waters in Japan and sea sediments. Sediments from Lake Haruna, Tama River, Komagari Reservoir and Yatsuse River contained salicylic acid at average concns of 0.6, 0.1, 0.06 and 0.2 ug/g, respectively(2). Sediments from the Gulf of Mexico contained salicylic acid at an average concn of 0.02 ug/g(2). [R73] ATMC: *URBAN: Atmospheric fallout at Metropolitan University, Tokyo, Japan contained salicylic acid at concns of 0.6, 1.0, 0.8, 0.3, 1.0, 1.0 ug/sq m/day for 6 samples(1). SUBURBAN: Salicylic acid was identified as a component of airborne particulate matter collected at Tsukuba, Japan (60 Km NE of Tokyo)(2). [R74] FOOD: *Salicylic acid occurs in common fruits such as apples, oranges, plums, and grapes, which accounts for its presence in most wines(1) and probably fruit juices(SRC). [R75] PFAC: PLANT CONCENTRATIONS: *Salicylic acid has been isolated from the roots, stem and leaves, blossoms, and fruit of Spiracea ulmaria(1), and is contained in the sapwood of Pinus radiata(2). Salicylic acid occurs in tulips, hyacinths, violets and in common fruits such as apples, oranges, plums, and grapes(1). [R76] RTEX: *The most probable human exposure to salicylic acid would be occupational exposure, which may occur through dermal contact or inhalation at places where it is produced or used. The National Occupational Exposure Survey (NOES as of 3/28/89) has estimated that 46,769 U.S. workers are potentially exposed to salicylic acid in the workplace(1). The most common non-occupational exposures are likely to result from the ingestion of contaminated drinking water supplies(2,3) and certain foods and beverages such as fruits, fruit juices and wines(4). Infants may ingest salicylic acid and the salicylate ion with milk from nursing mothers that have consumed aspirin(5). Non-occupational exposures may also occur through inhalation of urban atmospheres, and by dermal contact and ingestion during recreational activities at contaminated waterways(SRC). [R77] BODY: *Salicylic acid was detected in the breast milk of 2 nursing mothers within 1 hour of aspirin (acetylsalicylic acid) ingestion; concns ranged from 0.2-1.5 and 0.27-1.0 mg/L(1). The salicylate ion was also detected in breastmilk from 6 nursing mothers between the ages of 24 and 32 who ingested aspirin(1). [R78] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *A tolerance of zero is established for residues of salicyclic acid in milk from dairy animals. [R79] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Salicyclic acid is produced, as an intermediate or a final product, by process units covered under this subpart. [R80] FIFR: *Product registrations which once contained active ingredients incl salicyclic acid have previously been amended to remove the ingredient from the formula or have been cancelled for other reasons ... These ingredients will be removed from Reregistration List D effective 90 days after publication of this notice ... and will not be considered further for reregistration. [R81] FDA: *A tolerance is established for residues of salicyclic acid in milk from dairy animals. [R79] *Salicyclic acid used as a preservative only is an indirect food additive for use only as a component of adhesives. [R82] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *ASSAY FOR PURITY: TABLE 962.21B. ... MICROCHEMICAL TEST FOR SYNTHETICS: SYNTHETIC SALICYLIC ACID; SOLVENT HYDROCHLORIC ACID (1 + 3); CONCN ... DRY POWDER; REAGENT BROMIDE-BROMATE SOLN; DESCRIPTION OF TESTS AND CRYSTALS: STIR FEW CRYSTALS INTO 1 DROP OF HYDROCHLORIC ACID. ADD 1 DROP REAGENT. FINE NEEDLES APPEAR TO GROW FROM CRYSTALS OF SALICYLIC ACID. [R83, p. 15/539] *ASSAY FOR PURITY: TABLE 962.21B. MICROCHEMICAL TEST FOR SYNTHETICS: SYNTHETIC SALICYLIC ACID, CONCN DRY POWDER, REAGENT LEAD TRIETHANOLAMINE, DESCRIPTION OF TESTS AND CRYSTALS: STIR FEW CRYSTALS INTO 1 DROP REAGENT. RODS OR NEEDLES GROW FROM CRYSTALS OF SALICYLIC ACID. [R83, p. 15/539] *ASSAY FOR PURITY: TABLE 962.21B. ... MICROCHEMICAL TESTS FOR SYNTHETICS: SYNTHETIC SALICYLIC ACID, SOLVENT 2% TRIETHANOLAMINE, CONCN ... 1:100 TO 1:200, REAGENT SILVER NITRATE, DESCRIPTION OF TESTS AND CRYSTALS: SMALL, IRREGULAR PLATES; FEW SHORT RODS. [R83, p. 15/539] *JORRISEN TEST. DISSOLVE ... MATERIAL IN 10 ML OF WATER BY HEATING. COOL. ADD 5 DROPS ... 10 % POTASSIUM NITRITE, 2 DROPS GLACIAL ACETIC ACID AND 1 DROP ... 10 % COPPER SULFATE. BOIL ... 2 MIN. SALICYLATE ... INDICATED BY RED COLOR. [R84] *THIN LAYER CHROMATOGRAPHY. [R17, 788] *GAS LIQUID CHROMATOGRAPHY ANALYSIS. [R17, 808] *Salicylic acid in food and beverages using Qualitative Tests and Colorimetric method. [R83, p. 15/1155-6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for salicyclic acid. Route: topical; Species: mice. [R85] SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1324 R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 725 R4: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 31 R5: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. R6: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 764 R7: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 713 R8: Kavaler AR; Chemical Marketing Reporter 231 (9): 50 (1987) R9: Kavaler AR; Chemical Marketing Reporter 237 (11): 50 (1990) R10: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-455 R11: Serjeant EP, Dempsey B; Ionisation constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. New York, NY: Pergamon pp.989 (1979) R12: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1838 R13: McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990). 2057 R14: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 29 R15: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-191 R16: SRC; Yalkowsky SH; Arizona Data Base of Water Solubility (1989) R17: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 225 R19: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.182 R20: National Fire Protection Guide. Fire Protection Guide on Hazardous Materials. 10 th ed. Quincy, MA: National Fire Protection Association, 1991.,p. 325M-83 R21: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R22: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 277 R23: Sax, N.I. 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R30: Kershaw RA et al; J Clin Pharmacol 27 (4): 304-9 (1987) R31: Raschke R et al; Arch Intern Med 151 (3): 591-3 (1991) R32: Jones, L.M., et al. Veterinary Pharmacology and Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. R33: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 796 R34: SULEIMAN SA, BAKER JR; PROC IOWA ACAD SCI 78 (1): 20-23 (1971) R35: KOSHAKJI RP, SCHULERT AR; BIOCHEM PHARMACOL 22 (3): 407-16 (1973) R36: JANAKIDEVI K, SMITH MJ H; J PHARM PHARMACOL 22 (4): 249-52 (1970) R37: TANAKA S ET AL; SHOKUHIN EISEIGAKU ZASSHI 14 (6): 549-57 (1973) R38: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 665 R39: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 440 R40: Gunther T et al; Biol Trace Elem Res 16 (1): 43-50 (1988) R41: Gunther T et al; Biol Trace Elem Res 16 (2): 129-35 (1988) R42: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. R43: ELIS J ET AL; INT J CLIN PHARMACOL BIOPHARM 16 (8): 365-7 (1978) R44: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976. R45: Patel DK et al; Xenobiotica 20 (8): 847-54 (1990) R46: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 426 R47: Day RD et al; Br J Clin Pharmacol 26 (3): 334-7 (1988) R48: Ding RW et al; Clin Pharmacol Ther 46 (Dec): 642-647 (1989) R49: Miners JO; Clin Pharmacokinet 17 (5): 327-44 (1989) R50: Sweeney KR et al; Clin Pharmacol Ther 40 (5): 518-24 (1986) R51: Rybak LP et al; Arch Otorhinolaryngol 243 (3): 180-2 (1986) R52: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R53: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 84:28 R54: (1) Erickson SH; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 20: 500-24 (1982) (2) Matsumoto G; Water Res 16: 551-7 (1982) (3) Christman RF et al; Sci Total Environ 47: 195-210 (1985) (4) Naumczyk J et al; Water Res 23: 1593-7 (1989) R55: (1) Erickson SH; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 20: 500-24 (1982) (2) Keith LH; Environ Sci Technol 10: 555-64 (1976) (3) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey. Contract No. 68-03-2867. Athens, GA: USEPA Environ Res Lab (1982) (4) Matsumoto G; Water Res 16: 551-7 (1982) (5) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) R56: (1) Serjeant EP, Dempsey B; IUPAC Chemical Data Series No. 23 NY: Pergamon Press (1979) (2) Lyman WJ et al; Handbook of Chemical Property Estimation NY: McGraw-Hill pp. 4-6, 6-1 to 6-27, 15-15 to 15-29 (1982) (3) Tate RL III; Appl Environ Microbiol 37: 1085-90 (1979) (4) Swann RL et al; Res Rev 85: 16-28 (1983) (5) Wang WH et al; Chemosphere 17: 1197-204 (1988) R57: (1) Serjeant EP, Dempsey B; IUPAC Chemical Data Series No. 23 NY: Pergamon Press (1979) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp.. 4-6, 6-1 to 6-27, 15-15 to 15-29 (1982) (3) Matsumoto G, Hanya T; Atmospheric Environment 14: 1409-19 (1980) R58: (1) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (2) Garrison AW; Analytical Studies of Textile Wastes presented before the Division of Water, Air and waste Chemistry. Am Chem Soc Div Water Air Waste Chem Unpub Work (1969) (3) Lund FA, Rodriquez DS; J Gen Appl Microbiol 30: 53-61 (1984) (4) Pitter P; Water Res 10: 231-5 (1976) (5) Sasaki S; pp. 283-98 in Aquatic Pollutants Hutzinger O et al, eds Oxford: Pergamon Press (1978) (6) Urano K, Kato Z; J Hazardous Materials 13: 147-59 (1986) (7) Zahn R, Wellens H; Z Wasser Abwasser Forsch 13: 1-7 (1980) (8) Shelton DR, Tiedje JM; Development of Tests for Determining Anaerobic Biodegradation Potential USEPA-560/5-81-013, NTIS PB84-166495 (1981) (9) Shelton DR, Tiedje JM; App Env Microbiol 47: 850-7 (1984) R59: (1) Buxton GV et al; J Phys Chem Ref Data 17: 517-882 (1988) (2) Anbar M, Neta P; Int J Appl Radiation Isotopes 18: 493-523 (1967) (3) Dorfman LM, Adams GE; Reactivity of the Hydroxyl Radical in Aqueous Solution Washington DC: Natl Bureau Standards NSRD-NBS-46 (1973) (4) Wang WH et al; Chemosphere 17: 1197- 204 (1988) R60: (1) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Cmpds, Design Inst for Phys Prop Data, Am Inst for Phys Prop Data, (1985) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) (4) Mazurek MA, Simoneitt BRT; Organic Components in Bulk and Wet-only Precipitation CRC Critical Review Environ Control 16: 140 (1986) (5) Matsumoto G, Hanya T; Atmospheric Environment 14: 1409-19 (1980) (6) Yokouchi Y, Ambe Y; Atmos Environ 20: 1727-34 (1986) R61: (1) Tate RL III; Appl Environ Microbiol 37: 1085-90 (1979) R62: (1) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (2) Garrison AW; Analytical Studies of Textile Wastes. Div Water, Air Waste Chem Am Chem Soc Div Water Air Waste Chem Unpub Work (1969) (3) Lund FA, Rodriquez DS; J Gen Appl Microbiol 30: 53-61 (1984) (4) Pitter P; Water Res 10: 231-5 (1976) (5) Sasaki S; pp. 283-98 in Aquatic Pollutants Hutzinger O et al, eds Oxford: Pergamon Press (1978) (6) Urano K, Kato Z; J Hazardous Materials 13: 147-59 (1986) (7) Zahn R, Wellens H; Z Wasser Abwasser Forsch 13: 1-7 (1980) R63: (1) Shelton DR, Tiedje JM; Development of Tests for Determining Anaerobic Biodegradation Potential USEPA 560/5-81-013, NTIS PB84-166495 (1981) (2) Shelton DR, Tiedje JM; App Env Microbiol 47: 850-7 (1984) R64: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 7-4 (1982) (2) Buxton GV et al; J Phys Chem Ref Data 17: 517-882 (1988) (3) Anbar M, Neta P; Int J Appl Radiation Isotopes 18: 493-523 (1967) (4) Dorfman LM, Adams GE; Reactivity of the Hydroxyl Radical in Aqueous Solution Washington DC: Natl Bureau Standards NSRD-NBS-46 (1973) (5) Mill T; Science 207: 886-7 (1980) R65: (1) Wang WH et al; Chemosphere 17: 1197-204 (1988) (2) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) R66: (1) Yalkowsky SH; Arizona Data Base of Water Solubility (1989) (2) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-10 (1982) R67: (1) Yalkowsky SH; Arizona Data Base of Water Solubility (1989) (2) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-9, 6-1 to 6-27 (1982) (4) Swann RL et al; Res Rev 85: 16-28 (1983) (5) Serjeant EP, Dempsey B; IUPAC Chemical Data Series No 23 NY: Pergamon Press (1979) R68: (1) Serjeant EP, Dempsey B; IUPAC Chemical Data Series No. 23 NY: Pergamon Press (1979) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 6-1 to 6-27, 15-15 to 15-29 (1982) (3) Yalkowsky SH; Arizona Data Base of Water Solubility (1989) (4) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Cmpds, Design Inst for Phys Prop Data, Am Inst for Phys Prop Data, NY (1989) R69: (1) Naumczyk J et al; Water Res 23: 1593-7 (1989) (2) Crathorne B et al; Environ Sci Technol 18: 797-802 (1984) R70: (1) Matsumoto G; Water Res 16: 551-7 (1982) (2) Christman RF et al; Sci Total Environ 47: 195-210 (1985) R71: (1) Mazurek MA, Simoneitt BRT; Organic Components in Bulk and Wet-only Precipitation CRC Critical Review Environ Control 16: 140 (1986) R72: (1) Matsumoto G; Water Res 16: 551-7 (1982) (2) Keith LH; Environ Sci Technol 10: 555-64 (1976) (3) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (4) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey. Contract No. 68-03-2867. Athens, GA: USEPA Environ Res Lab (1982) R73: (1) Matsumoto G, Hanya T; J Chromat 193: 89-94 (1980a) (2) Matsumoto G, Hanya T; Atmos Environ 14: 1409-19 (1980) R74: (1) Matsumoto G, Hanya T; Atmos Environ 14: 1409-19 (1980) (2) Yokouchi Y, Ambe, Y; Atmos Environ 20: 1727-34 (1986) R75: (1) Erickson SH; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 20: 500-24 (1982) R76: (1) Erickson SH; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 20: 500-24 (1982) (2) Matsumoto G; Water Res 16: 551-7 (1982) R77: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) (2) Naumczyk J et al; Water Res 23: 1593-7 (1989) (3) Crathorne B et al; Environ Sci Technol 18: 797-802 (1984) (4) Erickson SH; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley 20: 500-24 (1982) (5) Cone MV et al; Chemicals Identified in Human Breast Milk: A Literature Search. USEPA-560/5-83-009, NTIS PB84-118538, pp. 125 (1983) R78: (1) Cone MV et al; Chemicals Identified in Human Breast Milk: A Literature Search. USEPA-560/5-83-009, NTIS PB84-118538, pp. 125 (1983) R79: 21 CFR 556.590 (4/1/90) R80: 40 CFR 60.489 (7/1/90) R81: 56 FR 50423 (10/4/91) R82: 21 CFR 175.105 (4/1/91) R83: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R84: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 328 R85: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 69 Record 80 of 1119 in HSDB (through 2003/06) AN: 695 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-AZIDE- SY: *U-3886-; *AZIDE-; *AZIUM-; *AZOTURE-DE-SODIUM- (FRENCH); *Hydrazoic-acid,-sodium-salt.-; *KAZOE-; *NATRIUMAZID- (GERMAN); *NATRIUMMAJIDE- (DUTCH); *NSC-3072-; *SMITE-; *SODIUM-AZIDE-; *SODIUM,-AZOTURE-DE- (FRENCH); *SODIUM,-AZOTURO-DI- (ITALIAN) RN: 26628-22-8 MF: *N3-Na SHPN: UN 1687; Sodium azide IMO 6.1; Sodium azide STCC: 49 234 65; Sodium azide HAZN: P105; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN: ... PREPARED BY REACTING SODIUM METAL WITH AMMONIA USING FERRIC CHLORIDE AS THE CATALYST TO FORM SODIUM AMIDE. THE SODIUM AMIDE IS THEN REACTED WITH NITROUS OXIDE TO FORM THE SODIUM AZIDE. [R1, 441] *REACTION OF SODIUM WITH LIQUID AMMONIA IN THE PRESENCE OF A CATALYST (EG, FERRIC NITRATE), AND TREATMENT OF THE RESULTING SLURRY WITH NITROUS OXIDE UNDER PRESSURE. [R2] *... Ammonia is fed into molten sodium metal, which is contained in a closed steel vessel, at 350 deg C ... the resulting liquid sodium amide is converted to sodium azide ... by reaction with dinitrogen monoxide at ca. 230 deg C in a horizontal nickel reactor. ... The solid mixture is known as crude azide. ... dissolved in water and the resulting solution is clarified and then evaporated in vacuum. [R3, p. VA13 194] FORM: *TECHNICAL SALT; 15% GRANULAR SODIUM AZIDE (SMITE 15 G). [R4] *GRADES OF PURITY: PURE: 99+%; PRACTICAL GRADE [R5] *Nucleating agents may be added during precipitation to produce free-flowing crystals or rounded agglomerates required for the large-scale, automatic loading of detonators. The presence of hydrophilic polymeric substances also tends to eliminate the small possibility of spontaneous explosions occurring during the precipitation process. Wetting agents may also be added [R6, p. V9 571] MFS: *American Azide Corporation, 10622 West 6400N, PO Box 629, Cedar City Utah, 84721, (435) 865-5000 [R7] OMIN: *... PURIFICATION: RECRYSTALLIZE FROM HOT WATER. [R1, 441] *Sodium azide is insensitive but highly toxic. Contact must be avoided with acid, with which it forms the dangerous hydrazoic acid, and with copper, lead, cadmium, silver, mercury, or their alloys, with which sensitive azides may be formed. Nucleating agents may be added during precipitation to produce free flowing crystals or rounded agglomerates required for the large-scale, automatic loading of detonators. The presence of hydrophilic polymeric substances also tends to eliminate the small possibility of spontaneous explosions occurring during the precipitation process. Wetting agents may also be added [R8, p. V10 19] *With sodium azide, salts of secondary nitroparaffins rearrange to N-substituted amides [R8, p. V17 210] *Sodium azide shows many of the same phenomena as the alkali halides in regard to photochromism [R6, p. V6 125] USE: *... In the prepn of hydrazoic acid, lead azide, pure sodium. [R9] *Herbicide, fungicide, nematocide, soil fumigant [R10] *PREPLANT INCORPORATION: THIS MODE OF APPLICATION ... USED WITH THE HIGHER LEVELS OF SODIUM AZIDE FOR BROAD-SPECTRUM WEED CONTROL AND GENERAL "FUMIGANT" ACTION AGAINST SOIL MICROORGANISMS AND INSECTS. ... POSTEMERGENCE: AQ SPRAY ... USED TO DEFOLIATE COTTON AND AS A DIRECT TREATMENT TO CONTROL WEEDS IN TOLERANT CROPS. [R1, 438] *FOR CONTROL OF AQUATIC WEEDS IN RICE; FOR CONTROL OF DISEASES IN PEANUTS, TOMATOES, GREEN BEANS, STRAWBERRIES, ORNAMENTALS, AND MANY OTHER FRUIT AND VEGETABLE CROPS; FOR SOIL FUMIGATION AND TURF RENOVATION. [R4] *SODIUM AZIDE IS A BROAD-SPECTRUM BIOCIDE, SHOWING FUNGICIDAL, BACTERICIDAL, NEMATICIDAL AND INSECTICIDAL ACTIVITY. [R1, 439] *Intermediate in organic synthesis [R11] *... Used for stabilization of aqueous prealbumin in fractions (isolated from human serum) during storage.... [R12] *... The preparation of human blood samples for analysis of acetaldehyde and ethanol ... . [R13] *... Enhancement of interleukin-2 production. [R14] *A /diagnostic/ method using sodium azide ... is proposed as a new and simple means of measuring tocopherol deficiency in erythrocyte membranes. [R15] *As preservative for laboratory reagents ... As propellant for inflating automotive safety bags. [R9] *One of the reagents required for the determination of dissolved oxygen in polluted water is a soln of sodium azide in 50% sulfuric acid. [R16, 1361] *The chemical industry has used sodium azide as a retarder in the manufacture of sponge rubber, to prevent coagulation of styrene and butadiene latexes stored in contact with metals, and to decompose nitrites in the presence of nitrates. [R17] *Used as a preservative for seeds and wine; used by lumber industry to limit the growth of enzymes responsible for formation of brown stain on sugar pine; used by Japanese beer industry to prevent growth of a fungus which darkens its product [R18] *Air-bag inflation, preservative in diagnostic medicinals, intermediate in explosive manufacture [R19] *... Starting material for other metal azides. ... Used in automobile safety devices, e.g. steering-wheel air bags ... . [R3, p. VA13 195] *Used in the Curtis reaction for the production of amines. [R3, p. VA13 193] *Sensitive probe for studies of the electrostatic interactions between charged sites in myoglobin. [R20] *... Preservative found in manufactured antisera. [R21] *PRESERVATIVE IN DIAGNOSTIC MEDICINALS [R2] PRIE: U.S. PRODUCTION: *1974 - less than 1,000 lb (est) [R11] *(1978) NO EVIDENCE OF COMMERCIAL PRODN IN U.S. [R2] *(1982) NO EVIDENCE OF COMMERCIAL PRODN IN U.S. [R2] U.S. IMPORTS: *(1977) AT LEAST 9.08X10+6 G [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless hexagonal crystals [R9]; *Colorless to white, crystalline solid [Note: Forms hydrazoic acid (HN3) in water]. [R22, 280] ODOR: *Odorless [R3, p. VA13 193] MP: *275 deg C (decomp) [R3, p. VA13 193] MW: *65.010 [R23] CORR: *VERY CORROSIVE TO ALUMINUM, MODERATE TO COPPER AND LEAD [R24] DEN: *1.846 @ 20 DEG C [R23] DSC: *pK= 4.8, aq solns contains NH3 which escapes readily at 37 deg C. [R9] SOL: *Slightly soluble in ethanol, insoluble in ethyl ether [R23]; *Insol in ether; sol in liq ammonia [R9]; *Sol 40.16% @ 10 deg C, and 41.7% @ 17 deg C in water [R9]; *Slightly sol in alcohol @ 25 deg C [R9]; *In water, 41.0 g/100 ml @15 deg C [R3, p. VA13 193] VAP: *1 Pa @ 20 deg C [R25] OCPP: *DECOMP @ 275 DEG C TO SODIUM AND NITROGEN. DECOMP IN VACUUM. [R26] *Sodium azide reacts vigorously with water. [R3, p. VA13 194] *Thermal decomposition occurs at 300 deg C with formation of sodium metal and nitrogen. [R3, p. VA13 193] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R27] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R27] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R27] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R27] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R27] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R27] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R27] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R27] FPOT: *NOT CONSIDERED FLAMMABLE UNLESS HEATED ABOVE 300 DEG C. [R1, 439] FIRP: *Stay upwind. Use water spray to "knock down" dust. Isolate and remove discharged material. ... Cool exposed containers with water. [R5] *If material on fire or involved in fire: use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. [R28] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame - consider evacuation of one-half (1/2) mile radius. [R28] TOXC: *Poisonous gases may be produced when heated. [R5] *Products of the combustion of sodium azide /during air-bag inflation/ are nitrogen gas (which inflates the rubberized nylon bag), ash (black dust), and small particles of sodium hydroxide that may quickly convert by reaction with carbon dioxide and water vapor in the air to sodium carbonate and sodium bicarbonate. These products may produce ocular injuries and facial burns. [R29, 1388] OFHZ: *Containers may explode in fire. [R5] EXPL: *INSENSITIVE TO IMPACT, IT DECOMPOSES, SOMETIMES EXPLOSIVELY, ABOVE MP, PARTICULARLY IF HEATED RAPIDLY. [R16, 1360] REAC: *Interaction of barium carbonate and sodium azide to form cyanide ion requires careful control of temp at 630 deg C to prevent explosions. [R16, 1360] *The product of interaction /of sodium azide and trifluoroacryloyl fluoride/ was an unidentified highly explosive solid. [R16, 335] *Carbon disulfide and aqueous solutions of metal azides interact to produce metal azidodithioformates most of which are explosive, with varying degrees of power and sensitivity to shock or heat /metal azides/. [R16, 197] *Nitrogen-diluted bromine vapor passed over silver or sodium azide formed bromine azide, and often caused explosions /metal azides/. [R16, 100] *Forms explosion-sensitive materials with some metals such as lead, silver, mercury, and copper. [R5] *A SOLUTION OF SODIUM AZIDE IN COPPER PIPE WITH LEAD JOINTS FORMED COPPER AZIDE AND LEAD AZIDE, BOTH DETONATING CMPD. [R30] *REACTION OF SODIUM AZIDE AND CHROMYL CHLORIDE IS AN EXPLOSIVE ONE. [R30] *MIXTURE OF SODIUM AZIDE AND BENZOYL CHLORIDE REACTS SPONTANEOUSLY WITH EVOLUTION OF HEAT IN A POTASSIUM HYDROXIDE SOLN. [R30] *THE REACTION OF SODIUM AZIDE AND STRONG NITRIC ACID IS ENERGETIC. [R30] *DURING PREPN OF METHYL AZIDE FROM REACTION OF /DIMETHYL SULFATE AND SODIUM AZIDE/...A VIOLENT EXPLOSION OCCURRED. APPARENTLY THE PH WAS ALLOWED TO FALL BELOW 5. AT THIS ACIDITY HYDRAZOIC ACID, A POWERFUL EXPLOSIVE, READILY FORMS. [R30] */SODIUM AZIDE AND/ DIBROMOMALONONITRILE...REACT TO PRODUCE A PRODUCT THAT IS EXTREMELY SENSITIVE TO LIGHT SHOCK. [R30] *EFFLUENT FROM AUTOMATIC BLOOD-ANALYZERS IN WHICH 0.01-0.1% SODIUM AZIDE SOLN ARE USED, MAY LEAD OVER SEVERAL MONTHS TO FORMATION OF EXPLOSIVE HEAVY METAL AZIDES IN BRASS, COPPER OR LEAD PLUMBING LINES... [R16, 1361] *ADDITION OF WATER TO SODIUM AZIDE WHICH HAD BEEN STRONGLY HEATED CAUSED VIOLENT REACTION. THIS WAS ATTRIBUTED TO FORMATION OF METALLIC SODIUM OR SODIUM NITRIDE IN AZIDE. [R16, 1362] *Brass plates exposed to sodium azide solution during several months in soil percolation tests and then dried caused explosions, due to formation of copper and/or zinc azides. [R16, 1361] *During repairs to a metal thermostat bath in which sodium azide soln had been used as a preservative, a violent explosion occurred. [R16, 1361] *Acids, metals, water. [R22, 280] *Violent reaction with ... barium carbonate, sulfuric acid ... (CH3)2SO4 ... Incompatible with ... ammonium chloride + trichloroacetonitrile, phosgene, cyanuric chloride, 2,5-dinitro-3-methylbenzoic acid + oleum ... [R31, 2948] DCMP: *... Appears to be susceptible to photodecomposition by solar radiation. Photolysis ... may result in metal nitrides initially, with the eventual formation of the free metal and nitrogen gas. [R32] *When heated to 275 to 300 deg C in air, the solid crystals decompose with the evolution of nitrogen gas, leaving a residue of sodium oxide. [R17] *READILY DECOMPOSED BY IRRADIATION [R1, 438] *When heated to decomp ... emits very toxic fumes of /nitrogen oxides and disodium oxide/. [R31, 2948] EQUP: *AVOID BREATHING OF DUST OR VAPOR BY WEARING APPROVED BUREAU OF MINES RESP PROTECTION. ... GLOVES AND GOGGLES SHOULD BE WORN. [R1, 439] */NIOSH certified respirator/; protective clothing; goggles. [R5] *Wear appropriate personal protective clothing to prevent skin contact. [R22, 280] *Wear appropriate eye protection to prevent eye contact. [R22, 280] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R22, 280] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R22, 280] OPRM: *Contact lenses should not be worn when working with this chemical. [R22, 280] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *May be dangerous if it enters water intakes. Notify local health and wildlife officials. Notify operators of nearby water intakes. [R5] *The worker should immediately wash the skin when it becomes contaminated. [R22, 280] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R22, 280] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R22, 280] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. [R28] *Personnel protection: Avoid breathing dusts, and fumes from burning material. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. ... If contact with the material anticipated, wear appropriate chemical protective equipment. [R28] SSL: *UNLIMITED SHELF LIFE. ... STABLE AT TEMP BELOW 300 DEG C. [R33] *... Stable in water in the absence of light.... [R32] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R34] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R35] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R36] STRG: *Storage temperature: ambient. [R5] DISP: *At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Put into approved storage containers and ship to an approved disposal area. [R37] *Disposal may be accomplished by reaction with sulfuric acid solution and sodium nitrate in a hard rubber vessel. Nitrogen dioxide is generated by this reaction and the gas is run through a scrubber before it is released to the atmosphere. Controlled incineration is also acceptable (after mixing with other combustible wastes) with adequate scrubbing and ash disposal facilities. [R38] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. /As sodium azide or as hydrazoic acid vapor/ [R39] ANTR: *Basic treatment: Establish a patent airway. Suction it' necessary. Watch for signs of respiratory insufficiency and assist respirations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 1 hum. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Sodium azide (NaN3) and related compounds/ [R40, 162] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Early intubation, at the first sign of upper airway obstruction, may be necessary. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema... . Treat seizures with diazepam (Valium) ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Sodium azide (NaN3) and related compounds/ [R40, 163] HTOX: */CASE OBSERVED/ A CHEMIST WAS ACIDIFYING 10 G...IN A MALFUNCTIONING HOOD. ... FEW MIN EXPOSURE, HE DEVELOPED DIZZINESS, WEAKNESS, BLURRED VISION, SLIGHT SHORTNESS OF BREATH, AND A /FAINT FEELING/...MODERATE REDUCTION IN BLOOD PRESSURE AND BRADYCARDIA. ...RECOVERY IN ONE HR WITH NO...SYMPTOMS. [R41, 2211] *AN ADULT LAB TECHNICIAN ... ACCIDENTALLY SWALLOWED 150 MG OF SODIUM AZIDE IN AQ SOLN EXPERIENCED BREATHLESSNESS AND TACHYCARDIA WITHIN 5 MIN. NAUSEA, VOMITING, HEADACHE, RESTLESSNESS AND DIARRHEA ... WITHIN 15 MIN. LATER POLYDIPSIA, ECG CHANGES AND LEUKOCYTOSIS ... COMPLETE RECOVERY REQUIRED MORE THAN 10 DAYS ... [R42] *"SEVERAL GRAMS" PRODUCED COLLAPSE AND DEATH WITHIN 40 MIN IN ... ADULT. PATHOLOGIC FINDINGS WERE LIMITED TO SWELLING OF THE BRAIN AND LUNGS AND MILD FATTY DEGENERATION OF THE LIVER ... IN A SINGLE CLINICAL CASE OF ACUTE AZIDE POISONING, NITRITE-INDUCED METHEMOGLOBINEMIA HAD NO DISCERNIBLE BENEFIT. /AZIDE SALTS/ [R42] *IN HUMAN LYMPHOCYTES EXPOSED 4 HR TO 10-3 TO 10-7 MOLAR, CONCN ABOVE 10-4 MOLAR INDUCED LETHALITY. LOWER CONCN PRODUCED NO SIGNIFICANT INCR IN SISTER CHROMATID EXCHANGE (SCE). IT WOULD APPEAR THIS MUTAGEN DOES NOT INCR SCE AND/OR BREAK CHROMOSOMES. [R43, (1981)] *Male patient ... accidentally drank a solution containing 50 to 60 mg of sodium azide. Within 5 min he collapsed and briefly lost consciousness. The patient complained of nausea, a severe headache, and feeling hot. After 1 hr , all symptoms had disappeared except for the headache which lingered until the next morning. [R44] *A technician in a hematology lab ingested an estimated 5 to 10 mg of sodium azide. She complained of headache, sweating, and faintness within 5 min of exposure. The complaints dissipated shortly thereafter. [R45] *A lab technician accidentally ingested what was estimated to be a "very small amount" of sodium azide. Symptoms of tachycardia, hyperventilation, and hypotension were observed. The authors note that the minimal hypotensive dose in humans lies between 0.2 and 0.4 ug/kg. [R45] *MUTAGENICITY: MUTATION RESEARCH 87: 143 (1981). MAMMALIAN CYTOGENETICS - IN VITRO LEUKOCYTE OR LYMPHOCYTE STUDIES, HUMAN: NEGATIVE. [R46] *Label: Poison [R47] *Azide exposure may induce cough, conjunctivitis, CNS depression (seizures, collapse, muscle flaccidity, hyporeflexia, coma, fixed pupils, blurred vision, headache, dizziness), GI stimulation (nausea, vomiting, diarrhea), vascular smooth muscle relaxation (hypotension and reflex tachycardia), and a pungent odor. This may later be followed by lactic acidosis and death in a few days. /Azide/ [R29, 1387] *Cardiovascular toxicity consists of arteriolar vasodilation, hypotension, syncope, angina, and tachycardia. Neurologic symptoms can include syncope, headache, muscular weakness, decreased reflexes, seizures and coma. Respiratory toxicity can involve respiratory failure and pulmonary edema. Methemoglobinemia can occur due to oxidation of hemoglobin similar to nitrites. Clinical signs and symptoms of toxicity are dose dependent. [R48, 533] *Ingestions of 40 mg and less have produced headache. Doses of up to 60 mg have resulted in syncope and hypotension. Doses of 80-150 mg have resulted in angina, dyspnea, tachycardia, nausea, vomiting, diarrhea, and headache. [R48, 533] *Demyelination of nerves can occur in chronic large doses. [R48, 535] NTOX: *MUTAGENICITY: [MUTATION RESEARCH 76: 169 (1980)] ESCHERICHIA COLI WP2 - REVERSE MUTATION STUDIES: QUESTIONABLE; ESCHERICHIA COLI WP2,UVRA - REVERSE MUTATION STUDIES: NEGATIVE. [R46] *Repeated ip injections in rats (5 to 10 mg/kg every 15 to 30 min for 3 to 6 hr) result in severe intoxication; some survivors show injury and demyelination of nerve fibers in the central nervous system and testicular damage, but no lesions of liver or kidney. [R49] *Monkeys given 26 mg/kg intravenously had reduced blood pressure, convulsions, unconsciousness, vascular congestion, apnea, and 30% mortality. Cerebellar damage and ataxia in survivors were also seen. [R49] *AZIDE INHIBITS RESP OF BOVINE CORNEA, PRESUMABLY BY POISONING CYTOCHROME OXIDASE. [R50, 828] *SYMPTOMS OBSERVED IN ANIMALS AFTER RELATIVELY LARGE DOSES ARE RESP STIMULATION AND CONVULSIONS, THEN DEPRESSION AND DEATH. WITH LOWER DOSES...THERE IS A CONSISTENT PROMPT TRANSIENT FALL IN BLOOD PRESSURE. ... ASSOC HEMATURIA AND CARDIAC IRREGULARITIES...OBSERVED. ...1 MG/KG IV IN CATS...PRODUCE HYPOTENSION... [R41, 2210] *SUBACUTE TOXICITY: IN A TERATOGENIC STUDY EMPLOYING ALBINO RATS TREATED ORALLY WITH TECHNICAL SODIUM AZIDE AT DOSE LEVELS OF 0.5, 1.5, OR 5.0 MG/KG ... DAILY DURING GESTATION DAYS 6 THROUGH 15, NO TERATOGENIC EFFECTS DUE TO AZIDE WERE FOUND. [R1, 441] *TEN ALBINO RATS EXPOSED TO DUST OF 16% GRANULAR SODIUM AZIDE @ A CONCN OF 4.23 MG/L AIR FOR 4 HR EXHIBITED PTOSIS AND PROSTRATION, AND ONE ANIMAL DIED. [R1, 441] *Lesions also in the optic nerves and tracts have been reported in several rats surviving two or three days after being poisoned severely with azide. If azide concentration is great enough degeneration of rod cells is histologically demonstrable. [R50, 829] *SODIUM AZIDE TREATMENT OF PEA SEEDS INDUCED MUTANT YIELD IN M2 GENERATION COMPARABLE TO THAT PRODUCED BY GAMMA RAYS, BUT WITH FEWER STUNTED OR DEFORMED PLANTS. [R51] *EXPOSURE OF GERMINATED BARLEY SEEDS TO 10-3 MOLAR NAN3 FOR 2 HR RESULTED IN UNIDENTIFIED METABOLITE, WHICH WAS MUTAGENIC TO S TYPHIMURIUM TA 1530. [R52] *... AZIDE STIMULATES CAROTID BODY CHEMORECEPTORS ... AND INHIBITS HEME-TYPE ENZYMES SUCH AS CATALASE, PEROXIDASE AND CYTOCHROME OXIDASE. /AZIDE SALTS/ [R42] *CHINESE HAMSTER K1 CELLS EXPOSED 2 HR TO CONCN RANGING FROM 10-3 TO 10-7 MOLAR. THEY WERE SENSITIVE TO CONCN ABOVE 10-5 MOLAR; @ LOWER CONCN NO SIGNIFICANT INCR IN SISTER CHROMATID EXCHANGE (SCE) FREQUENCY. THIS MUTAGEN APPEARS NOT TO INCR SCE AND/OR BREAK CHROMOSOMES. [R43, (1981).] *Sodium azide induced a high frequency of mutations ... in barley seeds. [R53] *Sodium azide is a potent mutagen of salmon sperm DNA in an acidic environment. [R53] *African violet plants are susceptible to sodium azide-induced mutagenesis. [R53] *Sodium azide effectively reverts S. typhimurium strain TA1530, indicating that it is a base substitution mutagen. It is ineffective on strains ... which are frameshift mutants. [R53] *Sodium azide treatment has been shown to slightly increase the frequency of penicillin- and streptomycin-resistant mutants in Staphylococcus aureus. [R53] *In a chronic rat study in which the maximum tolerated dose (unspecified) and half that level were given in the diet or by gastric intubation twice weekly for 18 months,... sodium azide was determined to be noncarcinogenic. [R53] *Bioassay studies indicate that 10 ppm sodium azide in the soil significantly reduces germination and growth in tested plants. At levels below 10 ppm, germination is often delayed, but normal growth occurs ... [R32] *... In S. typhimurium ... the induction of base-pair substitutions was independent of pH. [R54] *... DNA synthesis inhibition testing and mutagenicity testing suggest that treatment with /sodium azide/ does not induce DNA damage in human and Chinese hamster cells. The cytostatic effect /observed/ is probably not accompanied by a genotoxic effect. [R55] */Sodium azide/ treatment of rice seeds for 4 hr induced chlorophyll-deficient mutants, with the frequency of mutation increasing linearly with azide concn. ... Although hydration of the seeds by a moderate amount of presoaking enhanced the mutagenicity of /sodium azide/, prolonged soaking had an adverse effect. [R56] */Sodium azide is/ effective in controlling stickleback, but not toxic to sockeye salmon (Oncorhynchus nerka), chinook salmon (O. tschawytscha), steelhead (Salmo gairdneri), and other marketable fish. [R57] *A microtiter hemolytic assay was utilized to determine sodium azide modulation of B6C3F1 and C3H mouse serum complement levels in vivo and in vitro. Sodium azide does not affect mouse complement levels in vivo /but/ suppresses in vitro complement hemolytic activity. [R58] *... Sodium azide is capable of inducing nondisjunction but may not induce point mutations. ... Sodium azide does not induce somatic crossing over and chromosome breaks in soybeans. [R59] *DNA synthesis and cell division in S. typhimurium was inhibited as was RNA and protein synthesis in ascites ovary carcinoma cells. [R44] *Uptake of glucose /from purified suspensions of mycobacterium leprae/ was inhibited by ... sodium azide. [R60] *WHEN APPLIED TO SEED EMBRYOS AND IN SOME ENTERIC BACTERIA, AZIDES HAVE BEEN SHOWN TO BE POTENT MUTAGENS, PRODUCING ... BASE SUBSTITUTION MUTATIONS AND NO CHROMOSOME ABERRATIONS. [R1, 440] *Sodium azide was mutagenic in the Salmonella/microsome test with TA1535 and TA100 strains, but mutagenicity was decreased by Arochlor-induced rat liver S9 mix. Azide mutagenicity is pH-dependent; its activity is decreased or lost by lowering pH. [R61] *... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of sodium azide in male or female F344/N rats administered 5 or 10 mg/kg. [R62] *When male and female F344 rats were given 0, 5, 10, 20, 40, or 80 mg/kg sodium azide, 5 days/wk for 2 wk, all rats given the two highest doses became lethargic and then died. Two of the five females given 20 mg/kg sodium azide also died; increased liver-to-body-weight ratios were recorded in the males. [R63, 1991.1403] *Intramuscular injection of 8-10 mg/kg in monkeys produced convulsions and apnea and resulted in the deaths of many of these animals. Among those who survived, ataxia developed secondary to the lesions in the cerebellar cortex; repeated administration caused necrosis and demyelination of the optic nerves and destruction of the caudate nucleus and putamen of the lenticular nucleus. [R63, 1991.1403] *Sterility has been produced in male mice given sodium azide. [R63, 1991.1404] HTXV: *DNA inhibition human fibroblast 50 mg/L. [R64] NTXV: *DNA repair Escherichia coli mutation dose 5 gm/L; [R64] *TDLo rat oral 2,730 mg/kg/78 wk continuous; [R64] *TD rat oral 5,460 mg/kg/78 wk continuous; [R64] *LD50 rat oral 27 mg/kg; [R64] *LD50 Mouse oral 27 mg/kg; [R31, 2947] *LD50 Mouse iv 19 mg/kg; [R31, 2947] *LD50 Rabbit skin 20 mg/kg; [R31, 2947] *LD50 Bird, type not specified oral 23,700 ug/kg; [R31, 2947] ETXV: *EC50 SIMOCEPHALUS 8.4 MG/L/96 HR @ 15 DEG C (95% CONFIDENCE LIMIT 6.1-12.2 MG/L), FIRST INSTAR /TECHNICAL MATERIAL, 98%/; [R65] *LC50 G FASCIATUS 6.4 MG/L/96 HR @ 21 DEG C (95% CONFIDENCE LIMIT 4.6-8.9 MG/L), MATURE /TECHNICAL MATERIAL, 98%/; [R65] *LC50 PTERONARCYS 8.0 MG/L/96 HR @ 15 DEG C (95% CONFIDENCE LIMIT 5.7-11.0 MG/L), SECOND YEAR CLASS /TECHNICAL MATERIAL, 98%/; [R65] *LC50 RAINBOW TROUT 0.8-1.6 MG/L/96 HR @ 13 DEG C, WT 1.4 G /TECHNICAL MATERIAL, 98%/; [R65] *LC50 BLUEGILL 0.8 MG/L/96 HR @ 18 DEG C, WT 0.4 G /TECHNICAL MATERIAL, 98%/; [R65] *EC50 DAPHNIA PULEX 4.2 MG/L/96 HR @ 15 DEG C (95% CONFIDENCE LIMIT 2.8-6.2 MG/L), FIRST INSTAR /TECHNICAL MATERIAL, 98%/; [R65] *LC50 G FASCIATUS 5.0 MG/L/96 HR @ 21 DEG C (95% CONFIDENCE LIMIT 3.7-6.8 MG/L), FIRST INSTAR /TECHNICAL MATERIAL, 98%/; [R65] *LC50 BLUEGILL 0.7 MG/L/96 HR @ 18 DEG C, WT 0.6 G /TECHNICAL MATERIAL, 98%/; [R65] *Aquatic toxicity: TLm bluegill 1.5 ppm/24 hr/fresh water; [R5] *Heritable translocation insects oral mutation dose 100 mg/L; [R64] *The mutagenic effect was observed /in Scenedesmus acutus/ at exposure (1-2 hr) to 0.05-0.8% sodium azide; [R66] NTP: *Toxicology and carcinogenicity studies were conducted by administering sodium azide (greater than 99% pure) in distilled water by gavage to groups of male and female F344/N rats ... 5 days per week for ... 2 years. ... Two year studies were conducted by administering 0, 5, or 10 mg/kg sodium azide to groups of 60 male and 60 female rats. ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of sodium azide in male or female F344/N rats administered 5 or 10 mg/kg. [R62] TCAT: ?Sodium azide (CAS # 26628-22-8) was evaluated for subchronic toxicity and neurotoxicity in dogs (breed, number unspecified) administered oral doses of 1, 3, and 10 mg/kg/day (duration unspecified). On 27th and terminal (unspecified) weeks of study ataxia was reported in 2 high-dose females and 1 mid-dose male. Treatment was also associated with altered clinical chemistry values including depressed alkaline phosphatase levels in all male and most female groups, decreased LDH in all treated males, and decreased serum glutamic oxalocetic transaminase in most treated animals. Bodyweights, relative organ weights, food consumption, ophthalmic and neurological examinations, hematology, urinalysis, and gross pathology showed no toxic effects. A draft pathology report subsequently documented compound-related histomorphologic changes in mid and anterior cerebrum of affected females, characterized by gliosis, conspicuous vasculature from endothelial swelling and condensation of the neuropil, and demyelination with degenerative changes in the caudate nucleus. This submission included a summarized version of this study only; no further information or data was provided. [R67] ADE: *... ABSORBED BY SEEDS AND PLANT ROOTS AND TO A LESSER DEGREE BY PLANT EPICOTYLS. ... READILY TRANSPORTED ACROPETALLY IN PLANT XYLEM. [R1, 439] *...RAPIDLY ABSORBED FROM THE GI TRACT AND FROM INJECTION SITES... [R41, 2210] *... For treatment of foot rot /in the bovine hoof/ ... the penetration rate ... of sodium azide /is/ less than 0.05 to 0.24 mm per hr. ... Inclusion of sodium lauryl sulfate in treatments enhanced the penetration rate of ... azide approx 6-fold. [R68] METB: *... SHORT HALF LIFE IN PLANTS. ... DEGRADED BY 2 PATHS--AZIDE ION CAN BE OXIDIZED BY NATURAL PLANT OXIDIZING AGENTS SUCH AS NITRITES, OR HYDRAZOIC ACID COULD BE FORMED ... and ... REACT WITH ORG ACIDS TO FORM AZIDES ... WHICH THEN DECOMP BY THE CURTIUS REARRANGEMENT, FOLLOWED BY REACTION OF THE RESULTING ISOCYANATE WITH H2O RELEASING N2 AND CO2. [R1, 439] BHL: *... SHORT HALF LIFE IN PLANTS. [R1, 439] ACTN: */SRP: Sodium azide, which activates guanylate cyclase, stimulates catecholamine release from perfused dog adrenals. ... /Results suggest the involvement of the Ca(2+) influx mechanism in the secretory action of sodium azide. [R69] *Sodium azide /is/ an inhibitor of mitochondrial ATPase. ... [R70] *Sodium azide is a broad-spectrum, metabolic poison that interferes with oxidation enzymes and inhibits phosphorylation. Although the effects in these systems are complex, there is general agreement that azide causes a dissociation of phosphorylation and cellular respiration. [R38] *Sodium azide functions as a metabolic poison in plants. ... Following penetration and accumulation ... in soybean and oat roots ..., the result is a strong increase in the release of soluble organic substances from the roots ... suggesting a direct interaction of sodium azide with the protein components of cellular membranes. [R32] *Stomatal movement in excised leaves is retarded in the presence of sodium azide, however, stomatal closure is not affected ... /suggesting/ that sodium azide works indirectly on stomata by initially affecting photosynthetic processes. [R32] *... Through disruption of the energy transfer enzymes, sodium azide inhibited cilia movement and phagocytosis in Tetrahymena pyriformis. [R44] INTC: *ADDITION OF MAMMALIAN LIVER MICROSOMAL PREPN (S-9 FRACTION) (50 MUL) REDUCED MUTAGENICITY OF NA AZIDE (0.625-5 MUG) TO SALMONELLA TYPHIMURIUM. DEACTIVATION CORRELATED WITH AMT OF S-9 FRACTION. [R71] *Addition of even small amounts of sodium azide to preparations of blood serum lipoproteins ... intensified peroxidation of their lipids. [R72] */The/ activity /of, the antibody, anti-I cold auto-agglutinin/ is enhanced in the presence of ... sodium azide. [R73] *Sodium azide /inhibits/ the activity of the peroxidase conjugates. [R74] *Sodium azide in combination with CO induced sex-linked recessive lethal mutations in Drosophila melanogaster. [R53] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ FATE: *Aquatic Fate: Photolysis of sodium azide may result in metal nitrides initially, with the eventual formation of the free metal and nitrogen gas. [R75] ABIO: *THE DISSIPATION OF AZIDES IN SOIL IS NOT BY MICROBIAL ACTION BUT IS STRICTLY A CHEM PROCESS ACCELERATED BY INCREASING ACIDITY AND ELEVATED TEMP. ... DISSIPATES ... RAPIDLY IN SOILS BY OXIDN OR BY REACTION OF HYDRAZOIC ACID WITH SOIL ORG ACIDS TO FORM AZIDES OF THESE ACIDS WHICH ... DECOMP BY THE CURTIUS REARRANGEMENT. [R1, 440] *Sodium azide is stable in water in the absence of light but appears to be susceptible to photo-decomposition by solar radiation. Photolysis of sodium azide may result in metal nitrides initially, with the eventual formation of the free metal and nitrogen gas. [R75] RTEX: *The largest potential exposure is that to automotive workers, repairmen and wreckers if inflatible airbags are installed on all passenger cars and if sodium azide is used as the inflation chemical. [R17] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: *Vacated 1989 OSHA PEL Ceiling limit 0.1 ppm (as HN3), skin designation; Ceiling limit 0.3 mg/cu m (as NaN3), skin designation, is still enforced in some states. [R22, 371] NREC: *Recommended Exposure Limit: Ceiling Value: 0.1 ppm (as HN3), skin. [R22, 280] *Recommended Exposure Limit: Ceiling Value: 0.3 ppm (as NaN3), skin. [R22, 280] TLV: +Ceiling Limit: 0.29 mg/cu m. /As sodium azide/ [R39] +Ceiling Limit: 0.11 ppm. /As hydrazoic acid vapor/ [R39] +A4; Not classifiable as a human carcinogen. /As sodium azide or as hydrazoic acid vapor/ [R39] OOPL: *Australia: peak limitation 0.3 mg/cu m, as sodium azide; peak limitation 0.1 ppm as hydrazoic acid (1990); Federal Republic of Germany: for sodium azide, 0.2 mg/cu m, short-term exposure values in preparation; for hydrazoic acid, 0.1 ppm, short-term level 0.2 ppm, 5 min, 8 times per shift (1992); United Kingdom: 10-min STEL 0.3 mg/cu m as sodium azide; 10-min STEL 0.1 ppm as hydrazoic acid vapor (1991). [R63, 1991.1405] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R76] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Sodium Azide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R77] RCRA: *P105; As stipulated in 40 CFR 261.33, when sodium azide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R78] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *PRODUCT ANALYSIS: ... IN DISTILLATION ASSEMBLY /TREAT SAMPLE/ WITH DIL PHOSPHORIC ACID SOLN LIBERATING HYDRAZOIC ACID. ... DISTILLED ... INTO A FERRIC NITRATE REAGENT WHICH FORMS A FERRIC ACID COLOR COMPLEX WHICH CAN BE MEASURED COLORIMETRICALLY ... [R1, 441] *A quantitative methemoglobin diffusion method /is used/ for determining sodium azide in wine ... /using/ a Widmark apparatus ... the optical density of /methemoglobin/ is read on a spectrophotometer at 572 and 700 nm and the difference is plotted on a diagram with a /sodium azide/ scale from 0-3 mg/l. ... [R79] CLAB: *Sodium azide, used for stabilization of aqueous prealbumin fractions (isolated from human serum) during storage, was detected in lyophilized prealbumin fractions by high-performance liquid chromatography. The mobile phase was o-phthalic acid (1X10-3 M) in distilled, deionized water (> or + 2 M omega resistivity) adjusted with pyridine to pH 3.5. ... The detection limit was 0.2 mug/injection and the correlation coefficient was 0.9996. This assay procedure is specific for azide ion and proteins do not interfere in the detection. [R12] *A microtiter hemolytic assay was utilized to determine sodium azide modulation of B6C3F1 and C3H mouse serum complement levels in vivo and in vitro. [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NIOSH Profile, SRI, 2/77 NIOSH Profile (Azides, Inorganic) SRC, 10/81 NIOSH Current Intelligence Bulletin 13, (1976) USEPA Chemical Hazard Information Profile (1977) EPA 560/11-80-011 DHHS/NTP; Toxicology and Carcinogenesis Studies of Sodium Azide in F344/N Rats (Gavage Studies) Technical Report Series No. 389 (1991) NIH Publication No. 91-2844 SO: R1: Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983. R2: SRI R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R4: Farm Chemicals Handbook 1981. Willoughby, Ohio: Meister, 1981.,p. C-29 R5: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R7: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 879 R8: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R9: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1471 R10: Farm Chemicals Handbook 1999. Willoughby, OH: Meister Publishing Co., 1999.,p. C-355 R11: USEPA; Chemical Hazard Information Profile: Sodium Azide p.237 (1977) EPA 560/11-80-011 R12: Mackie H et al; J Chromatog 242(1): 177-80 (1982) R13: DeMaster EG et al; Alcoholism (NY) 7(4): 436-42 (1983) R14: Feldman SP et al; Blood 61(4): 815-8 (1983) R15: Feo CJ; CR Seances Acad Sci 295(3): 227-30 (1982) R16: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R17: Sittig M; Handbook of Toxic and Hazardous Chemicals p.602 (1981) R18: SITTIG. HDBK TOX AND HAZARD CHEM AND CARCINOGENS 2ND ED 1985 p.793 R19: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1010 R20: Aldrich; Catalog Hdbk Fine Chem p.972 (1984) R21: Reviron M et al; Vox Sang 46(4): 211-6 (1984) R22: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R23: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 4-85 R24: Weed Science Society of America. Herbicide Handbook. 4th ed. Champaign, IL: Weed Science Society of America, 1979. of America, 1979. 412 R25: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA13 (89) 193 R26: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. B-124 R27: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R28: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 969 R29: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R30: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-176 R31: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R32: USEPA; Chemical Hazard Information Profile: Sodium Azide p.242 (1977) EPA 560/11-80-011 R33: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 439 R34: 49 CFR 171.2 (7/1/99) R35: IATA. Dangerous Goods Regulations. 40th Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 1999. 208 R36: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6254 (1998) R37: DLA/DOD; Hazardous Materials Info System #6810-01-003-1078 (1982) R38: Sittig M; Handbook of Toxic and Hazardous Chemicals p.603 (1981) R39: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.53 R40: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R41: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R42: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-115 R43: ARENAZ P AND NILAN RA; MUTAT RES 88(2) 217 R44: USEPA; Chemical Hazard Information Profile: Sodium Azide p.240 (1977) EPA 560/11-80-011 R45: USEPA; Chemical Hazard Information Profile: Sodium Azide p.241 (1977) EPA 560/11-80-011 R46: GENE-TOX Program: Current Status of Bioassay in Genetic Toxicology. U.S. Environmental Protection Agency, Washington, DC. Office of Toxic Substances and Pesticides. (For program information, contact Environmental Mutagen Information Center, Oak Ridge National Laboratory, Post Office Box Y, Oak Ridge, Tennessee 37830. Telephone (615) 574-7871) R47: Bureau of Explosives; Hazardous Matls Regs of DOT p.80 (1984) ICC No. BOE-6000D R48: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. R49: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 3426 R50: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R51: SANDER ET AL, MUTAGENIC EFFECTS OF SODIUM AZIDE AND GAMMA IRRADIATION IN PISUM, ENVIRON EXP BOT 17(1) 43 (1977). R52: OWAIS WM ET AL, A MUTAGENIC IN VIVO METABOLITE OF SODIUM AZIDE, MUTAT RES 53(3) 355 (1978). R53: USEPA; Chemical Hazard Information Profile: Sodium Azide p.239 (1977) EPA 560/11-80-011 R54: Tomlinson CR; Mutat. Res. 85(3): 185-6 (1981) R55: Slamenova D, Gabelova A; Mutat Res 71(2): 263-67 (1980) R56: Sarma et al; Environ Exp Bot 19(2): 117-21 (1979) R57: MacPhee C, Cheng FF; US Patent No. 4,221,782 (1980) R58: Johnson KW et al; Toxicol Appl Pharmacol 73(3): 559-63 (1984) R59: De Serres FJ, Hollaender A; Chemical Mutagens Vol 4 p.157 (1976) R60: Khanolkar SR; J Gen Microbiol 128(pt 2): 423-5 (1982) R61: De Flora S; Carcinogenesis 2: 283-98 (1981) R62: Toxicology and Carcinogenesis Studies of Sodium Azide in F344/N Rats (Gavage Studies). Technical Report Series No. 389 (1991) NIH Publication No. 91-2844 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R63: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R64: NIOSH; Current Awareness Listing (1984) R65: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office, 1980.12 R66: Nikolov N, Khubavenska N; Genetika (Moscow) 18(11): 1803-5 (1982) R67: PPG Indus Inc; Results of Toxicity Studies on Sodium Azide and Potassium Azide; 10/11/83; EPA Document No. 888400557; Fiche No. OTS0503918 R68: Malecki JC, McCausland IP; Res Vet Sci 3(2): 192-7 (1982) R69: Dohi T et al; Eur J Pharmacol 94(3-4): 331-5 (1983) R70: Doucet A, Katz AI; Am J Physiol 242(4): F346-52 (1982) R71: DE FLORA S, METABOLIC DEACTIVATION OF MUTAGENS IN SALMONELLA-MICROSOME TEST, NATURE (LONDON) 271(5644) 455 (1978) R72: Formaciuk VE; Vpor Med Khim 28(6): 110-3 (1982) R73: Reviron M et al; Vox Sang 46(4): 211-16 (1984) R74: Richardson TC et al; J Clin Pathol 36(4): 411-414 (1983) R75: USEPA; Chemical Hazard Information Profile: Sodium Azide p.242 (1977) EPA-560/11-80-011 R76: 40 CFR 302.4 (7/1/99) R77: 40 CFR 355 (7/1/99) R78: 40 CFR 261.33 (7/1/99) R79: Villa P et al; Ig, Mod 72(3): 321-35 (1979) RS: 52 Record 81 of 1119 in HSDB (through 2003/06) AN: 707 UD: 200211 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CARVONE- SY: *CARVOL-; *1-CARVONE-; *2-CYCLOHEXEN-1-ONE, 2-METHYL-5-(1-METHYLETHENYL)-; *FEMA-NUMBER-2249-; *KARVON-; *P-MENTHA-6,8-DIEN-2-ONE-; *6,8(9)-P-MENTHADIEN-2-ONE; *1-METHYL-4-ISOPROPENYL-DELTA(6)-CYCLOHEXEN-2-ONE; *NCI-C55867-; *DELTA(SUP 6,8)-(9)-TERPADIENONE-2 RN: 99-49-0 MF: *C10-H14-O ASCH: D-Carvone; 2244-16-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *D-CARVONE IS USUALLY PREPARED BY FRACTIONAL DISTILLATION OF OIL CARAWAY; ALSO FROM DILLSEED AND DILLWEED OILS, BUT THIS TYPE DIFFERS IN ODOR AND FLAVOR. /D-FORM/ [R1] *PREPN FROM ALPHA-PINENE. [R2] *SYNTHESIS OF L-CARVONE FROM D-LIMONENE. FROM L-ALPHA-PINENE. /L-FORM/ [R2] *SYNTHESIS OF DL-CARVONE FROM DL-ALPHA-TERPINYL ACETATE. /DL-FORM/ [R2] FORM: *ASSAY: 97% MIN (AS KETONE CONTENT) /L-FORM/; 95% MIN /D-FORM/ [R1] *GRADES: FCC (BOTH D- AND L-FORMS); TECHNICAL /D- AND L-FORM/ [R3] *THE PROPORTION OF CARVONE IN HERB OIL HAS BEEN REPORTED TO VARY FROM 6 TO 44%, DEPENDING ON THE GEOGRAPHICAL ORIGIN ... WHILE THE AMOUNT OF CARVONE IN THE OIL OF DILL SEEDS IS MORE CONSTANT, 40-55% [R4] *THE MAIN CONSTITUENT/OF CARAWAY OIL/IS d-CARVONE (60-70%) [R5] *THE MAIN CONSTITUENT/OF SPEARMINT OIL/IS 1-CARVONE (ca 50-70%) [R6] MFS: *Penta Manufacturing Company, Hq, PO Box 1448, Fairfield, NJ 07007. (201) 740-2300. Production site: Fairfield, NJ 07007 [R7] *Quest International, Hq, 400 International Drive, Mount Olive, NJ 07828. (201) 691-7100. Production site: Mount Olive, NJ 07828 [R7] *Ungerer and Company, Hq, 4 Bridgewater Lane, Lincoln Park, NJ 07035. (201) 628-0600. Chemical Division, 100 North Commerce Way, Bethlehem, PA 18017 (610) 868-7266. Production site: Bethlehem, PA 18017 [R7] *Givaudan-Roure Corporation, 100 Delawanna Avenue, Clifton, NJ 07014 (201) 365-8000. Specialty Division. /L-Carvone/ [R7] *SCM GLIDCO Organics, Hq, PO Box 389, Jacksonville, FL 32201 (904) 768-5800 or (800) 231-6728. Production site: Jacksonville, FL 32201. /L-Carvone/ [R7] OMIN: *GROUND CARAWAY SEED YIELDS UP TO 7% OF VOLATILE OIL, HAVING UP TO 60% CARVONE AS PRINCIPAL CONSTITUENT... [R8] *KETONE DERIVED FROM TERPENE DIPENTENE. IT IS OPTICALLY ACTIVE, OCCURRING NATURALLY IN BOTH D- AND L-FORMS. [R3] *METHOD OF PURIFICATION: RECTIFICATION. [R3] */IN/ NON-ALCOHOLIC BEVERAGES 850 PPM; ALCOHOLIC BEVERAGES 130 PPM; ICE CREAM, ICES, ETC 120 PPM; CANDY 180 PPM; BAKED GOODS 110 PPM. [R1] *TO ENHANCE FLAVOR OF CERTAIN FOODS. WIDE VARIETY OF SPICES AND NATURAL AND SYNTHETIC FLAVORS /SUCH AS CARVOL/ ARE USED IN PROCESSED FOODS... WITHOUT THEM THERE WOULD BE NO SUCH FOODS AS SPICE CAKE, GINGERBREAD, OR SAUSAGE. /FROM TABLE/ [R9] USE: *AS OIL OF CARAWAY; FLAVORING LIQUEURS; IN PERFUMERY AND SOAPS [R2] *CARMINATIVE [R2] *MOST (-)-CARVONE IS USED FOR ENHANCING MINT FLAVORS AND AROMAS FOR USE IN DENTIFRICES, CONFECTIONS, PHARMACEUTICALS AND ODORANTS [R10] *FLAVORS USEFUL IN: KUMMEL LIQUOR, PICKLE, SPICE FLAVORS, SPEARMINT FLAVORS. [R11] PRIE: U.S. PRODUCTION: *WORLDWIDE PRODUCTION OF (-)-CARVONE IS ca 270-365 t/yr (1981 DATA) [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to slightly yellow liquid [R12] MW: *150.21 [R2] SOL: *Sol in alcohol, ether, chloroform, propylene glycol, mineral oils; insol in glycerol [R3]; *Water solubility = 1300 mg/L at 25 deg C [R13] OCPP: *SADTLER REFERENCE NUMBER: 6626 (IR, PRISM); 271 (NMR, VARIAN) /D-FORM/ [R14] *SADTLER REFERENCE NUMBER: 21371 (IR, PRISM) /L-FORM/ [R14] *SPEARMINT ODOR /L-FORM/; ODOR REMINISCENT OF CARAWAY /D-FORM/ [R1] *RYE BREAD ODOR AND TASTE /D-FORM/ [R11] *LIQUID; BP: 230-231 DEG C @ 763 MM HG; DENSITY: 0.9652 @ 15 DEG C/15 DEG C; INDEX OF REFRACTION: 1.4988 @ 20 DEG C/D; SPECIFIC OPTICAL ROTATION: -62.46 DEG @ 20 DEG C/D /L-FORM/ [R2] *LIQUID; BP: 230-231 DEG C; DENSITY: 0.9645 @ 15 DEG C/15 DEG C /DL-FORM/ [R2] *SLIGHTLY SOL IN HOT WATER; SOL IN ETHER, CHLOROFORM; MAX ABSORPTION (ALCOHOL): 235 NM (LOG E= 3.93), 318 NM (LOG E= 1.62) /DL, L AND D FORMS/ [R14] *LIQUID; BP: 230 DEG C @ 755 MM HG; DENSITY: 0.965 @ 20 DEG C/4 DEG C; INDEX OF REFRACTION: 1.4989 @ 20 DEG C/D; SPECIFIC OPTICAL ROTATION: +61.2 DEG @ 20 DEG C/D /D-FORM/ [R2] *COLORLESS TO PALE STRAW COLORED LIQ; SOL IN 70% ALC: 1:2 /L-FORM/ [R1] *COLORLESS TO LIGHT YELLOW LIQ; SOL IN 60% ALC: 1:5 /D-FORM/ [R1] *MISCIBLE WITH ALC; INDEX OF REFRACTION: 1.5003 @ 20 DEG C/D /DL-FORM/ [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *The terpene 1-carvone is one of the main constituents of spearmint oil. The sensitizing potential of 1-carvone has been considered low, but it has occasionally caused contact allergy in users of spearmint toothpaste and chewing gum. 1-Carvone is also an oxidation product of d-limonene that occurs in solvents used increasingly in industry. /It was concluded/ 1-carvone 5% pet. in the standard patch test series. In the first year, 541 patients were tested and 15 (2.77%) had positive, and 12 doubtful positive (?+) reactions to 1-carvone. The strongest reactions were observed in 9 patients with concomitant Compositae sensitivity. The key clinical features and other contact allergies of the patients are presented. When retesting with 1-carvone in the same or lower concentrations, only 2 out of 8 patients had positive reactions. Possible reasons for this discrepancy are discussed in terms of cross-reactions, concomitant sensitization, excited skin syndrome, irritancy and facilitated immunological response. [R15] *Food or flavoring intolerance has been demonstrated in 14 out of 80 patients with oro-facial granulomatosis. Provoking molecules include cinnamaldehyde, carvone and piperitone, although a wide range of food or flavorings may be implicated. The nature of the reaction is not understood but does not seem to involve an IgE mediated response. At present the only reliable way of detecting specific provoking factors is by the use of an elimination diet. [R16] *Cheilitis was observed in a 74 year old patient after use of a new toothpaste which occurred after several weeks despite withdrawal of the paste. Positive patch testing with the toothpaste confirmed suspect contact sensitization. The cause was the main component of the flavor additive i.e., the terpene ketone L-carvone. Due to the characteristic flavor it is contained in many mint and peppermint oils. In this case it also caused the recurrences by sucking of refreshment lozenges. L-Carvone is also contained in most chewing gums and should thus be considered etiologically in cases of cheilitis and stomatitis. [R17] NTOX: *CARVONE CAUSED TRANSIENT DEPRESSION OF CENTRAL NERVOUS SYSTEM ACTIVITY IN MICE. [R18] *CARVONE WAS AMONG VARIOUS ORG CMPD NOT FOUND TO BE MUTAGENIC USING SALMONELLA TYPHIMURIUM (TA 98, TA 100, TA 1535, AND TA 1537) WITH AND WITHOUT S-9 FROM AROCLOR-INDUCED RATS @ 3 UMOL/PLATE. [R19] *NO MUTAGENIC ACTIVITY WAS DETECTED WHEN DIRECT URINE SAMPLES FROM RATS ADMIN CARVONE WERE ASSAYED WITH SALMONELLA TYPHIMURIUM TA100 AND TA98 EITHER IN PRESENCE OR ABSENCE OF BETA-GLUCURONIDASE. [R20] *The monoterpene d-carvone is present in a large number of commonly used essential oils. Recently, it has been found to induce the activity of detoxifying enzymes and inhibit nitrosamine-induced carcinogenesis. To explore the structure-activity relationship, a series of carvone compounds were tested for their ability to induce increased activity of glutathione S-transferase in several tissues of A/J mice. The parent compound d-carvone exhibited the highest activity as an inducer in all of the tissues. The alpha,beta-unsaturated ketone system in d-carvone appeared to be critical for the high enzyme-inducing activity, which proved the hypothesis that many anticarcinogenic enzyme inducers are Michael reaction acceptors containing olefinic bonds conjugated with electron withdrawing groups. The effects of the carvone compounds on the tissue glutathione level were also determined. Several compounds were found to elevate GSH level significantly in the mouse forestomach, while d-carvone decreased GSH level in most of the tissue. Since the anticarcinogenic activity has been found to correlate with the ability to induce increased activity of detoxifying enzymes, carvone compounds can be a class of potential chemopreventive agents. [R21] +... ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of d-carvone in male or female B6C3F1 mice administered 375 or 750 mg/kg, 5 days/wk for 2 yr. [R22] NTP: *Groups of 50 male and 50 female B6C3F1 mice were administered 0, 375, or 750 mg/kg d-carvone in corn oil by gavage, 5 days/wk for 103 wk. ... Under the conditions of these two yr gavage studies, there was no evidence for the carcinogenic activity of d-carvone for male or female B6C3F1 mice. ... [R23] METB: *...KETONES (EG CARVONE AND MENTHONE) ARE REDUCED TO SECONDARY ALC WHICH ARE THEN EXCRETED AS GLUCURONIDES. [R24] INTC: *Naturally occurring compounds belonging to the two chemical groups were studies for their capacities to inhibit N-nitrosodiethylamine-induced carcinogenesis in female A/J mice. One group consists of organosulfur compounds found in Allium species, including garlic, onions, leeks, and shallots, and the other, two monoterpenes, i.e., d-limonene and d-carvone. In these experiments d-limonene and D-carvone were tested and reduced forestomach tumor formation by slightly over 60% and pulmonary adenoma formation by about 35%. The results of these studies provide evidence of an increasing diversity of naturally occurring compounds having the capacity to inhibit nitrosamine carcinogenesis. [R25] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Carvone's production and use as a flavoring liqueur, in perfumery and soaps, and as a carminative may result in its release to the environment through various waste streams. Carvone is found naturally in caraway and dill seed oils, mandarin seed oil, spearmint oil, and gingergrass oil. If released to soil, carvone will have high mobility in soil. Volatilization of carvone may be important from moist and dry soil surfaces. Insufficient data are available to determine the rate or importance of biodegradation of carvone in soil. If released to water, carvone will not adsorb to suspended solids and sediment in the water. Carvone may volatilize from water surfaces with estimated half-lives for a model river and model lake of 17.5 hours and 9 days, respectively. An estimated BCF value of 11 suggests that carvone will not bioconcentrate in aquatic organisms. Insufficient data are available to determine the rate or importance of biodegradation of carvone in water. If released to the atmosphere, carvone will exist in the vapor phase in the ambient atmosphere. Vapor-phase carvone is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals; the half-life for this reaction in air is estimated to be about 2.7 hours. Vapor-phase carvone may also react with ozone, the half-life for this reaction in air is estimated to be about 3.2 hours. Particulate-phase carvone may be physically removed from the air by wet and dry deposition. The general population can be exposed to carvone through various foodstuffs. (SRC) NATS: *OPTICALLY ACTIVE AND INACTIVE FORMS HAVE BEEN REPORTED AMONG CONSTITUENTS OF ABOUT 70 ESSENTIAL OILS. [R1] *DEXTRO FORM IS PRESENT IN CARVI, ANETHUM GRAVEOLENS, ANETHUM SOWA, LIPPIA CARVIODORA, MENTHA ARVENSIS, ETC. /D-FORM/ [R1] *LEVO FORM IS PRESENT IN MENTHA VIRIDIS VAR CRISPA, MENTHA LONGIFOLIA FROM SOUTH AFRICA, EUCALYPTUS GLOBULUS, AND SEVERAL MINT SPECIES. /L-FORM/ [R1] *RACEMIC FORM IS PRESENT IN GINGER GRASS, LITSEA GUATEMALEUSIS, LAVENDER, AND ARTEMISIA FERGANENSIS. /RACEMIC OR DL-FORM/ [R1] *D-Carvone is found in caraway seed and dill seed oil and it has been isolated from mandarin peel oil (citrus reticulata blanco, rutaceae)(1). L-Carvone is found in spearmint and kuromoji oils and DL-carvone is found in gingergrass oil(1). [R26] ARTS: *Carvone's production and use as a flavoring liqueur, in perfumery and soaps, and as a carminative(1) may result in its release to the environment through various waste streams(SRC). [R26] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 85(SRC), determined from an experimental water solubility(2) and a recommended regression-derived equation(3), indicates that carvone will have high mobility in soil(SRC). Volatilization of carvone may be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 7.7X10-5 atm-cu m/mole(4,SRC), and from dry soil surfaces(SRC) based on an estimated vapor pressure of 0.16 mm Hg(5,SRC). Insufficient data are available to determine the rate or importance of biodegradation of carvone in soil(SRC). [R27] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 85(SRC), determined from an experimental water solubility(2) and a recommended regression-derived equation(3), indicates that carvone may not adsorb to suspended solids and sediment(SRC) in the water. Carvone may volatilize from water surfaces based on an estimated Henry's Law constant of 7.7X10-5 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Estimated half-lives for a model river and model lake are 17.5 hours and 9 days, respectively(3,SRC). An estimated BCF value of 11(3,SRC), from an experimental water solubility(2), suggests that bioconcentration of carvone will be low in aquatic organisms(SRC) according to a recommended classification scheme(5). Insufficient data are available to determine the rate or importance of biodegradation of carvone in water(SRC). [R28] *ATMOSPHERIC FATE: According to a suggested classification scheme(1), an estimated vapor pressure of 0.16 mm Hg at 25 deg C(2,SRC) indicates that carvone will exist in the vapor phase in the ambient atmosphere. Vapor-phase carvone is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2.7 hours(3,SRC). Vapor-phase carvone may also react with ozone(SRC), the half-life for this reaction in air is estimated to be about 3.2 hours(3,SRC). Particulate-phase carvone may be physically removed from the air by wet and dry deposition(SRC). [R29] ABIO: *The rate constant for the vapor-phase reaction of carvone with photochemically produced hydroxyl radicals has been estimated as 1.41X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2.7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Carvone may also react in the atmosphere with ozone with an estimated rate constant of 8.6X10-17 cu cm/molecule-sec(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 3.2 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(1,SRC). [R30] BIOC: *An estimated BCF value of 11 was calculated for carvone(SRC), using an experimental water solubility of 1300 mg/l(1) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms will be an low(SRC). [R31] KOC: *The Koc of carvone is estimated as approximately 84.6(SRC), using an experimental water solubility of 1300 mg/L(1) and a regression- derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that carvone has high mobility in soil(SRC). [R32] VWS: *The Henry's Law constant for carvone is estimated as 7.7X10-5 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that carvone will volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 17.5 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 9 days(2,SRC). Carvone's vapor pressure, 0.16 mm Hg(3,SRC) and Henry's Law constant(1,SRC) indicate that volatilization from dry and moist soil may occur(SRC). [R33] FOOD: *Carvone has been detected as a volatile component of roasted filberts(1) and in concentrated aqueous orange essences(2). [R34] PFAC: PLANT CONCENTRATIONS: *GROUND CARAWAY SEED YIELDS UP TO 7% OF VOLATILE OIL, HAVING UP TO 60% CARVONE AS PRINCIPAL CONSTITUENT... [R8] RTEX: *Through its use as a flavoring liqueur, in perfumery and soaps, and as a carminative(1) the general population can be exposed to carvone through various foodstuffs(SRC). [R35] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *d- or l- carvone (carvol) used as a synthetic flavoring substance or adjuvant in food for human consumption is generally recognized as safe when used in accordance with good manufacturing practice. [R36] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GAS CHROMATOGRAPHY, MASS SPECTROSCOPY, IR, AND NMR SPECTRA. [R37] *PARAMAGNETIC RESONANCE ASSAY OF CARVONE IN CARAWAY AND DILL OILS. [R38] *COLORIMETRIC DETERMINATION OF CARVONE IN VOLATILE OILS. [R39] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Carvone in B6C3F1 Mice (Gavage Studies) Technical Report Series No. 381 (1990) NIH Publication No. 90-2836 SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 87 R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 286 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 227 R4: HUOPALHTI R, LINKO, RR; J AGRIC FOOD CHEM 31: 331-3 (1983) R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 322 (1980) R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 328 (1980) R7: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 616 R8: Merory, J. Food Flavorings: Composition, Manufacture, and Use. 2nd ed. Westport, Conn.: Avi Publishing Co., 1968. 121 R9: Arena, J. M. Poisoning: Toxicology, Symptoms, Treatments. Fourth Edition. Springfield, Illinois: Charles C. Thomas, Publisher, 1979. 708 R10: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V22 745 (1983) R11: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 263 R12: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 172 R13: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) R14: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-241 R15: Paulsen E et al; Contact Dermatitis 29 (3): 138-43 (1993) R16: Patton DW et al; Br J Oral Maxillofac Surg 23 (4): 235-42 (1985) R17: Hausen BM; Dtsch Med Wochenschr 109 (8): 300-2 (1984) R18: LE BOURHIS B, SOENEN AM; FOOD COSMET TOXICOL 11 (1): 1 (1973) R19: FLORIN I ET AL; TOXICOLOGY 15: 219 (1980) R20: ROCKWELL P, RAW I; NUTR CANCER 1 (4): 10 (1979) R21: Zheng GQ et al; J Agric Food Chem 40 (5): 751-5 (1992) R22: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Carvone in B6C3F1 Mice (Gavage Studies) p.3 Technical Report Series No. 381 (1990) NIH Publication No. 90-2836 R23: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Carvone in B6C3F1 Mice (Gavage Studies) Technical Report Series No. 381 (1990) NIH Publication No. 90-2836 R24: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 149 R25: Wattenberg LW et al; Cancer Res 49 (10): 2689-92 (1989) R26: (1) Budavari S; The Merck Index 11th ed Rahway, NJ: Merck and Co Inc p. 286 (1989) R27: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R28: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R29: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R30: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R31: (1) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R32: (1) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R33: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R34: (1) Kinlin TE et al; J Agr Food Chem 20: 1021-8 (1972) (2) Moshonas MG, Shaw PE; J Agric Food Chem 38: 2181-4 (1990) R35: (1) Budavari S; The Merck Index 11th ed Rahway, NJ: Merck and Co Inc (1989) R36: 21 CFR 182.60 (4/1/93) R37: CHENNOUFI R ET AL; RIV ITAL EPPOS 62 (7): 353 (1980) R38: MOSSA JS ET AL; SPECTROSC LETT 13 (1): 49 (1980) R39: KARAWYA MS ET AL; J ASSOC OFF ANAL CHEM; 62 (2): 250 (1979) RS: 24 Record 82 of 1119 in HSDB (through 2003/06) AN: 722 UD: 200302 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: RESORCINOL- SY: *Caswell-#723-; *BENZENE,-M-DIHYDROXY-; *M-BENZENEDIOL-; *1,3-BENZENEDIOL-; *M-DIHYDROXYBENZENE-; *1,3-DIHYDROXYBENZENE-; *M-DIOXYBENZENE-; *Pesticide-Code:-071401-; *M-HYDROXYPHENOL-; *3-HYDROXYPHENOL-; *EPA-pesticide-code-071401-; *RESORCIN-; *RESORCINE- RN: 108-46-3 MF: *C6-H6-O2 SHPN: UN 2876; Resorcinol IMO 6.1; Resorcinol STCC: 49 667 74; Resorcinol HAZN: U201; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *It can be made in several other ways, by destructive distillation of brazilin or by fusion of galbanum, ammoniac, sagapenum, asafetida, or acroides with caustic potash. [R1, 1587] *Reaction of benzene with sulfuric acid to form m-benzenedisulfonic acid which is then converted to its disulfonate sodium salt by treatment with sodium sulfite. In a second step, this salt is heated to 350 deg C in the presence of sodium hydroxide yielding the sodium resorcinate and sodium sulfite. After sulfuric acid work-up ... the rescorcinol is estracted and isolated in a 94% yield ... [R2, 998] *Hydroperoxidation of m- or p-diisopropylbenzene. This is an important industrial route to resorcinol... [R2, 998] IMP: *TECHNICAL /USP/ GRADE RESORCINOL HAS 99% MIN RESORCINOL CONTENT AND CONTAINS SMALL AMT OF PHENOL AND CATECHOL AS IMPURITIES. IN JAPAN, TECHNICAL RESORCINOL HAS ... FP OF 108.5 DEG C MIN; 0.5% MAX WATER; and 0.1% MAX RESIDUE ON IGNITION. CHIEF IMPURITIES ARE OTHER HYDROQUINONE ISOMERS. [R3] *Maximum limits of impurities: Residue after ignition (0.01%), Insoluble matter (0.005%), Acidity (0.02%), Diresorcinol and Phenol (0.001%). [R4] FORM: *Grades: USP; technical [R2, 1008] */Available/ as an ointment, cream, or lotion in concentrations of 1 to 10%. It is also used as compound resorcinol ointment, which contains 6% resorcinol. Resorcinol monoacetate gradually liberates resorcinol and, therefore, exerts a milder but more lasting action. It is used for the same purposes as resorcinol. Resorcinol monoacetate is compounded with sulfur in preparations for seborrhea. [R5, 970] *Castellani Paint /topical antifungal agent/ contains resorcinol, basic fuchsin, phenol, acetone and alcohol [R6, p.1377] *Night Cast Formula R /medicated acne mask/ contains 2% resorcinol, 8% sulfur and 31% alcohol [R6, p.1696] *Resinol ointment and Resinol greaseless cream /contain/ 2.0% resorcinol [R5, p. V-541] *Resulfolin /contains/ 3% resorcinol monoacetate [R5, p. V-451] MFS: *INDSPEC Chemical Corp., Hq, 411 7th Ave., Suite 300, Pittsburgh, PA 15219, (412) 765-1200; Production site: Petrolia, PA 16050 [R7] OMIN: *SPECIFICATIONS FOR USP GRADE ARE: 99-100.5% ACTIVE INGREDIENT; MELTING RANGE, 109-111 DEG C; 1% MAX WT LOSS ON DRYING OVER SILICA GEL FOR 4 HR; 0.05% MAX IGNITION RESIDUE; AND CONTAINING NO PHENOL OR CATECHOL (USA PHARMACOPEIAL CONVENTION, INC, 1975). [R3] *MODIFICATION OF ITS USE AS WATERPROOF PLYWOOD GLUE (RESORCINOL-FORMALDEHYDE) WITH GELATIN HAS PRODUCED GOOD MULTIPURPOSE GLUE FOR USE ON CUT TISSUES AND SECURING PROSTHESES. [R8] USE: *For Resorcinol (USEPA/OPP Pesticide Code: 071401) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R9] *In tanning; manufacturing resins, resin adhesives, hexylresorcinol, p-amino salicyclic acid, explosives, and dyes. [R10] *Used primarily in the rubber industry for tires and reinforced rubber products (conveyer belts, driving belts) and in high-quality wood adhesvies... It is also used in the preparation of dyes and pharmaceuticals, as a cross-linking agent for neoprene and a rubber tackifier, and in cosmetics. [R11] *In photography [R1, 1587] *Chemical intermediate used in oxidation hair dyes [R12] *CHEMICAL INTERMEDIATE IN SYNTH OF RESORCINOL-FORMALDEHYDE RESINS, RESIN PROGENITORS, WOOD ADHESIVE RESINS [R13] *MEDICATION *MEDICATION (VET) *Resorcinol is an indirect food additive polymer for use as a basic component of single and repeated use food contact surfaces. ... For use only as a reactive adjuvant substance employed in the production of gelatin-bonded cord composition for use in lining crown closures. ... [R14] CPAT: *The primary consumer (more than 50%) is the rubber industry. [R15, 114] *42% FOR RESORCINOL-FORMALDEHYDE RESINS AND RESIN PROGENITORS; 31% EXPORTED; 15% FOR WOOD ADHESIVE RESINS; 12% FORMISC APPLICATIONS (1970) [R13] *In 1977, the United States use of resorcinol was 65% in the manufacture of rubber products, 20% in wood adhesives, and 15% for miscellaneous uses. [R16] PRIE: U.S. PRODUCTION: *(1972) 1.48X10+10 GRAMS [R13] *(1974) 1.6X10+10 GRAMS (EST) [R13] *(1986) ND *Worldwide production of resorcinol in 1994 was estimated to be 30,000-35,000 tons. [R11] U.S. IMPORTS: *(1972) 4.27X10+7 G [R13] *(1975) 4.54X10+4 G [R13] *(1984) 8.83x10+8 g [R17] U.S. EXPORTS: *(1972) 4.59X10+9 G [R13] *(1975) 6.30X10+8 G [R13] *(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White needle-like crystals [R10]; *NEEDLES FROM BENZENE; PLATES FROM WATER [R18, p. C-480]; *Rhombic tablets and pyramids [R1, 1587]; *POWDER [R19]; *White needles, plates, crystals, flakes, or powder [Note: Turns pink on exposure to air or light, or contact with iron]. [R20] ODOR: *Faint, characteristic odor [R1, 1589] TAST: *Sweetish taste followed by bitter taste [R1, 1589] BP: *280 deg C [R10] MP: *109-111 deg C [R10] MW: *110.11 [R10] DEN: *1.2717 [R21] DSC: *pKa = 9.32 [R22] HTC: *-2710 kJ/mol @ 25 deg C [R15, 111] OWPC: *log Kow = 0.80 [R23] PH: *pH = 5.2 [R10] SOL: *1 g dissolves in 0.9 ml water at room temperature, 0.2 ml water @ 80 deg C, 0.9 ml alcohol; freely sol in ether, glycerol; slightly sol in chloroform [R10]; *Sol in water, alcohol, ether and acetic acid [R18, 48058]; *Sol in DMSO at greater than or equal to 100 mg/ml at 18 deg C. [R24]; *Sol in acetone at greater than or equal to 100 mg/ml at 18 deg C. [R24]; *In water, 7.17X10+5 mg/l @ 25 deg C. [R25] SPEC: *SADTLER REFERENCE NUMBER: 467 (IR, PRISM); 125 (IR, GRATING); MAX ABSORPTION (ALC): 220 NM (LOG E= 3.79); 276 NM (LOG E= 3.33) [R26]; *Resorcinol, 98%, exhibits its two strongest infra red absorption bands at wavelengths of 3.0 and 8.6 microns. [R27]; *IR: COB 1112 (Coblentz Society Spectral Collection) [R28]; *UV: 2572 (Sadtler Research Laboratories Spectral Collection) [R28]; *NMR: 6672 (Sadtler Research Laboratories Spectral Collection) [R28]; *MS: WILEY 351 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R28] VAPD: *3.79 (air= 1); % in saturated air: 2.64% by vol @ 25.1 deg C; density of saturated air: 1.0739 (air= 1) [R1, 1587] VAP: *4.89X10-4 mm Hg @ 25 deg C [R29] OCPP: *Crystals; MP 109.1 deg C /USP XX/ [R2, 1009] *Flakes /Technical/ [R2, 1009] *1 MG/L= 222.3 PPM; 1 PPM= 0.00450 MG/L @ 25 DEG C 760 MM HG [R30] *Resorcinol crystallizes in the orthorhombic hemimorphic system, and its crystals are colorless, triboluminescent, and piezoelectric. X-ray diffraction measurements indicate that resorcinol crystallizes in the form which is converted to the BETA form at 74 deg C; the latter is more dense (d= 1.33 g/cu cm), as a result of hydrogen bonding between oriented molecules in the crystal lattice. [R16] *Vapor pressure = 1 mm Hg @ 108.4 deg C [R31, 2869] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R32] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R32] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R32] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R32] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R32] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R32] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R32] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R32] FPOT: *COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME [R31, 2870] NFPA: *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R33] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R33] FLMT: *Lower flammable limit: 1.4% @ 392 deg F (200 deg C) by volume [R33] FLPT: *261 deg F (Closed cup) [R31, 2869] AUTO: *1126 DEG F (608 DEG C) [R33] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. [R34] */Use/ water, foam, dry chemical, or carbon dioxide [R35] OFHZ: *Water may cause frothing [R35] EXPL: *Containers may explode in fire. [R35] *Potentially explosive reaction with concentrated nitric acid. [R31, 2870] REAC: *INCOMPATIBILITIES: ACETANILIDE, ALBUMIN, ALKALIES, ANTIPYRINE, CAMPHOR, FERRIC SALTS, MENTHOL, SPIRIT NITROUS ETHER, URETHAN. [R36] *Can react with oxidizing materials [R31, 2870] *Aquatic reactions: auto-oxidation at 25 deg C: t1/2: 1612 hours at pH 9.0 [R37, 1043] *Resorcinol and its derivatives are only slowly attacked by periodate, but reaction with hydrogen peroxide in presence of tungstic oxide yields maleic acid. [R38] *Hydroquinone, resorcinol, and catechol react with ammonia to give the corresponding p-, m-, and o-aminophenol. [R38] *Hydroquinone, resorcinol, and catechol react with formaldehyde under both acidic and basic conditions to give methyol derivatives which undergo condensation to yield high molecular weight condensation products; resorcinol has the highest reactivity of the three and has its most important use in this reaction. [R38] *Acetanilide, albumin, alkalis, antipyrine, camphor, ferric salts, menthol, spirit nitrous ether, strong oxidizers and bases [Note: Hygroscopic (i.e., absorbs moisture from the air)]. [R20] *Potentially explosive reaction with concentrated nitric acid. [R31, 2870] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R31, 2870] ODRT: *Odor threshold concentration (detection): 6.0 mg/l [R37, 1044] SERI: *It is irritating to the eyes and skin. [R1, 1588] EQUP: *Wear chemical goggles, rubber gloves and protective clothing. [R39] *Wear appropriate personal protective clothing to prevent skin contact. [R20] *Wear appropriate eye protection to prevent eye contact. [R20] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R20] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. [R20] *Remove contaminated clothing and shoes. [R35] *The worker should immediately wash the skin when it becomes contaminated. [R20] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R20] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R20] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. [R34] *Personnel protection: Avoid breathing vapors or dusts. Avoid bodily contact with the material. ... If contact with the material anticipated, wear appropriate chemical protective clothing. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. ... [R34] SSL: *HYGROSCOPIC [R40] *VOLATILIZES @ LOWER TEMP THAN BP; SLIGHTLY VOLATILE WITH STEAM. [R36] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R41] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R42] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R43] STRG: *PROTECT FROM LIGHT [R36] CLUP: *Environmental consideration: Water spill: Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R34] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. [R34] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U201, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R44] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R45] *Chemical Treatability of Resorcinol; Concentration Process: Activated Carbon; Chemical Classification: Phenols; Scale of Study: Batch Flow/Laboratory Scale; Type of Wastewater Used: Pure Compound; Influent Concentration: 100 ppb; Results of Study: 100% reduction; 0% desorbed from carbon by elutriation with solvent (Calgon FS-300 used. Solvent included pentane-acetone, diethyl ether, methylene chloride-acetone, chloroform-acetone and acetone). [R46] *Chemical Treatability of Resorcinol; Concentration Process: Resin Adsorption; Chemical Classification: Phenols; Scale of Study: Batch Flow/Laboratory Scale Type of Wastewater Used: Pure Compound; Influent Concentration: 100 ppb; Results of Study: 100% reduction; 60% desorbed from resin by elutriation with solvent (Amberlite XAD-2 used. Solvents included pentane-acetone, diethyl ether, methylene chloride-acetone, chloroform-acetone and acetone). [R47] *Chemical Treatability of Resorcinol; Concentration Process: Activated Carbon; Chemical Classification: Phenol; Scale of Study: Batch Flow and Lab Scale; Type of Wastewater Used: Pure compound; Results of Study: 100% reduction; 35% desorbed from resin by elutriation with solvent. [R48] *Chemical Treatability of Resorcinol; Concentration Process: Resin Adsorption; Chemical Classification: Phenol; Scale of Study: Batch Flow and Lab Scale; Type of Wastewater Used: Pure compound; Study: 100% reduction; 6% desorbed from carbon by elutriation with solvent. [R49] *Dissolve in a combustible solvent and incinerate. Recommendable methods: Incineration and use as a boiler fuel. Peer review: Dissolve in light fuel. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R50] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of resorcinol were available. There is inadequate evidence in experimental animals for the carcinogenicity of resorcinol. Overall evaluation: Resorcinol is not classifiable as to its carcinogenicity to humans (Group 3). [R51] *A4. A4= Not classifiable as a human carcinogen. [R52] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Administer activated charcoal ... . Do not use emetics. Cover skin burns with dry, sterile dressings after decontamination ... . Maintain body temperature. /Penols and related compounds/ [R53, p. 243-4] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... Treat seizures with diazepam (Valium). ... Use proparacaine hydrochloride to assist eye irrigation ... . /Phenols and related compounds/ [R53, 244] *For poisoning, treat symptomatically. Get medical advice. [R31, 2870] MEDS: *Perform complete blood count, urinalysis, studies of liver and kidney functions annually. [R39] HTOX: *APPLICATION OF 3-25% SOLN OF RESORCINOL TO SKIN MAY CAUSE REDNESS, ITCHING, DERMATITIS, EDEMA OR CORROSION OF AFFECTED AREA. INGESTION OF 8 G ... BY CHILD RESULTED IN HYPOTHERMIA, HYPOTENSION, DECR RESPIRATION, TREMORS, ICTERUS AND HEMOGLOBINURIA ... [R54] *Pathology reported for humans includes marked siderosis of the spleen and marked tubular injury in the kidney, fatty changes and edema of the liver, degenerative changes in the kidney, fatty changes of the heart muscle, moderate enlargement and pigmentations of the spleen, and edema and emphysema of the lungs. [R1, 1588] *Cutaneous application of solutions or salves containing from 3 to 25% of this compound may result in local hyperemia, itching, dermatitis, edema, corrosion, and the loss of the superficial layers of the skin. ... May be associated with ... enlargement of regional lymph glands, restlessness, methemoglobinemia, cyanosis, convulsions, tachycardia, dyspnea, and death. [R1, 1589] *IRRITATING TO SKIN, MUCOUS MEMBRANES. ABSORPTION CAN CAUSE METHEMOGLOBINURIA, CYANOSIS, CONVULSIONS, DEATH. [R36] *SOMETIMES ASSOC WITH ... HEINZ BODIES AND HEMOLYSIS. [R5, p. II-191] *RESORCINOL HAS BEEN REPORTED TO BE LESS TOXIC THAN PHENOL OR CATECHOL BY INGESTION OR SKIN PENETRATION. [R55, 1991.1333] *42 workers from the motorcycle section in an Italian tire making plant were given dermatological exams and skin tests using substances issued from the factory. Skin test results were negative in all subjects. All the groups showed areas of rusty red pigmentation of various color intensities and dimensions, mainly in the thenar and hypothenar eminences, on the pulps of all the fingers, and in some cases of the flexor surface of the fingers and on the palms of both hands. In some cases the lesions were accompanied by a thin layer of desquamation. A clinical diagnosis of pigmentary dermatosis with a slight irritant component, probably due to an external cause was made. Only 8 subjects (19%) reported skin or allergic pathology, or both; but all had used a new cmpd recently. Analysis of the cmpd used showed an incr in resorcinol. [R56] *Oral ingestion of resorcinol may cause methemoglobinemia, cyanosis, and convulsions; dermal exposure has been reported to cause dermatitis, hyperemia, and pruritis. [R55, 1991.1335] *... Resorcinol ... /has/ caused goiter in human beings when applied to the abraded skin. [R57] NTOX: *WHEN TESTED BY REPEATED SKIN APPLICATION, RESORCINOL SHOWED NO CARCINOGENIC EFFECT IN MICE. [R58] *RESORCINOL WAS NOT MUTAGENIC TO SALMONELLA TYPHIMURIUM STRAINS TA 1535, TA1537, TA98 OR TA100 IN PRESENCE OR ABSENCE OF RAT LIVER POSTMITOCHONDRIAL SUPERNATANT FRACTION @ DOSE OF UP TO 1000 UG/PLATE ... INDUCE CHROMOSOME ABERRATIONS OR KARYOTYPIC EFFECTS IN ALLIUM CEPA ... CHARA ZEYLANICA ... AND TULBAGHIA VIOLACES ... (MCCANN ET AL, 1975) [R59] *TESTS OF 10% SOLN ON RABBIT EYES HAVE CAUSED PAIN, CONJUNCTIVAL INFLAMMATION, AND VASCULARIZATION OF CORNEA. DRY, POWDERED RESORCINOL APPLIED TO RABBIT EYES INDUCED NECROSIS SUFFICIENT TO CAUSE PERFORATION OF CORNEA IN SOME AND EXTENSIVE VASCULARIZATION IN OTHERS ... [R60] *... NO TOXIC EFFECTS WERE NOTED WHEN RATS, GUINEA PIGS, AND RABBITS WERE EXPOSED 6 HR/DAY FOR 2 WK TO RESORCINOL AT 34 MG/CU M (8 PPM). [R55, 1991.1334] *Chemical test results proved negative for heritable genetic effects in Drosphilia ... . (Sex linked recessive lethal) [R61] *Dyes were administered by gavage to pregnant Sprague-Dawley rats on gestation Days 6 through 15 at doses ranging from 12.5 to 500 mg/kg. No overt signs of toxicity were observed during the treatment period. The high dose for resorcinol, which exceeded a 100-fold exaggeration of human exposure, did not produce a significant reduction in maternal weight gain. An evaluation of fetal external, visceral, and skeletal anomalies revealed no statistically significant differences between dye-treated and vehicle control groups. Administration of 100,000 units of vitamin A, the positive control, on Day 9 of gestation resulted in a significant increase in abnormal fetuses. [R62] *Resorcinol had extremely small inhibitory effects on the photosynthesis presumably due to its poor oxidation to the corresponding quinone under the physiological conditions compared to o- and p-dihydroxyphenols. Photosynthesis was inhibited at 8x10-5 M concentration of phenols. [R63] *Resorcinol had ED50 values ranging from 2.4 to 22.0 mumol when tested for embryotoxicity on three day chicken embryos. [R64] *... Resorcinol is slightly to moderately toxic. Subchronic feeding and dermal studies ... produced no significant effects. A chronic dermal study was uneventful. Significant skin effects were observed in mice, but not in rabbits, following dermal application of resorcinol at 5%. At 10% resorcinol solution was not irritating to guinea pigs. ... Resorcinol was not photoallergenic to guinea pigs but was a sensitizer at 10%. Resorcinol ... was nonmutagenic in microbial and tissue culture assays for mutagenicity. Topically applied hair dyes containing Resorcinol was negative for carcinogenicity. Resorcinol showed no cocarcinogenic potential when tested on mice and rats. ... Resorcinol was a mild skin irritant and rare sensitizer in clinical testing, but not when tested on nonclinical groups. On the basis of the available animal and clinical data, it is concluded that resorcinol ...is safe as a cosmetic ingredient in the present practices of use and concentrations. [R65] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of resorcinol in male F344/N rats given 112 or 225 mg/kg or female F344/N rats given 50, 100 or 150 mg/kg. There was no evidence of carcinogenic activity of resorcinol in male or female B6C3F1 mice given 112 or 225 mg/kg. [R66] *IN AN INHALATION TOXICITY TEST, AEROSOL (RESORCINOL-WATER) CONCN AS HIGH AS 7800 MG/CU M (1733 PPM) FOR A 1-HR PERIOD AND AS HIGH AS 2800 MG/CU M FOR AN 8-HR PERIOD CAUSED NO DEATHS OR LESIONS ATTRIBUTABLE TO INHALATION OF THE AEROSOL AT GROSS AUTOPSY. [R55, 1991.1333] *After F344/N male and female rats received 12 oral doses of resorcinol dissolved in water at 0, 27, 55, 110, 225, or 450 mg/kg by intubation, 5 days/wk over 17 days, tachypnea and hyperexcitability ensued within 30 min of dosing and resolved within 2 hr in those animals given doses > or = 55 mg/kg/day. [R55, 1991.1333] *Application of 0.1 gram of resorcinol into the eyes of rabbits caused discomfort, conjunctivitis, and corneal ulcerations which were not reversible. [R55, 1991.1333] *Application of 0.5 gram of resorcinol moistened with saline to intact or abraded skin of rabbits for up to 24 hr caused reactions varying from no irritation to moderate irritation of the intact skin and from no irritation to necrosis of the abraded skin. [R55, 1991.1333] *Subcutaneous injection of 154 mg/kg in rats produced myxedema and goiter; however, a similar injection of 50 mg/kg failed to produce any such disturbances in rat thyroid. [R55, 1991.1333] *Groups of 15 male Fischer 344 rats, six weeks of age, were given resorcinol (purity unspecified) at concentrations of 0 or 0.2% in the diet for 22 weeks either after ligation on one ureter to enhance bladder carcinogenesis or after exposure to 0.05% N-nitrosobutyl-N-(4-hydroxybutyl)amine in the drinking water for two weeks followed by ureteric ligation to initiate bladder carcinogenesis. All animals were killed at 24 weeks. Resorcinol administration did not affect body weight. resorcinol alone did not induce bladder lesions and did not increase the incidence of any type of tumor when given after the initiator. [R67] *Groups of 16 male Fischer 344 rats, six weeks of age, were given resorcinol (purity, > 99%) at concentrations of 0 or 0.8% in the diet for 51 weeks. Other groups were given 0 or 0.8% resorcinol in the diet for 51 weeks beginning one week after oral gavage of 50 mg/kg body weight N-methyl-N'-nitro-N-nitrosoguanidine to initiate gastric carcinogenesis. Resorcinol reduced the body weights of rats given no initiator and of those given initiator. Resorcinol alone induced a low incidence of mild hyperplasia in the forestomach, but no forestomach tumors. Resorcinol given after the initiator did not increase the incidence of forestomach papillomas or squamous-cell carcinomas induced by the initiator. [R68] *Groups of 10 or 20 male Fischer 344 rats, six weeks of age, were given resorcinol (purity, > 99.5%) at concentrations of 0 or 0.8% in the diet for 36 weeks either alone or after exposure to 0.05% N-nitrosobutyl-N-(4-hydroxybutyl)amine in the drinking water for four weeks to initiate bladder carcinogenesis. Resorcinol did not affect body or bladder weight either when given alone or after initiator. Resorcinol exposure alone did not induce bladder lesions. Feeding of resorcinol after initiation did not increase the incidence or multiplicity of bladder neoplasms resulting from initiation. [R69] *Groups of 15 or 20 six week old male Wistar/Crj rats were given resorcinol (purity unspecified) at concentrations of 0, 0.8% in the diet for 36 weeks alone or starting one week after exposure to 0.1% N-nitrosoethyl-N-hydroxyethylamine in the drinking water for three weeks to initiate liver and kidney carcinogenesis. The final body weight of rats given resorcinol were lower than those of rats given basal diet alone or with initiator. Resorcinol also increased the relative liver and kidney weights. resorcinol treatment after initiation did not affect the incidence of liver or kidney tumors induced by the initiator, but reduced the multiplicity of liver tumors. [R69] *Resorcinol did not induce gene mutations in Salmonella typhimurium or in Escherichia coli strains in either the presence or absence of an exogenous metabolic activation system. [R70] *The effects of the adipocyte-derived hormone leptin on glucose metabolism in hepatocytes were investigated. Incubation of hepatocytes from Wistar rats with leptin for 16 h caused a dose-dependent increase in incorporation of [14C]glucose into glycogen, with a maximal effect at 30 nmol/l leptin. This effect of leptin was observed over a range of glucose concentrations (10-25 mmol/l) and was associated with stimulation of net glycogen deposition. It was not counteracted by mercaptopicolinate, an inhibitor of phosphoenolpyruvate carboxykinase, indicating that it is not due to increased gluconeogenic flux. Leptin also enhanced the short-term stimulation of glycogen synthesis by insulin. These effects of leptin were associated with inhibition of phosphorylase a, which occurred after 4 h of exposure to leptin. Culture with leptin for 16 h did not affect the activities of glucose-6-phosphatase or glucokinase or the activation state of glycogen synthase. Leptin did not affect glycolysis determined from the detritiation of [3-(3)H]glucose. The inhibitory effects of leptin on phosphorylase a were counteracted by short-term incubation with glucagon but were additive with the inhibitory effects of insulin and also with the inhibition caused by resorcinol (25 pmol/l), which inhibits phosphorylase kinase by a mechanism analogous to the antidiabetic drug proglycosyn. These results show that leptin has additive effects with insulin in inhibiting phosphorylase and stimulating glycogen storage in hepatocytes, indicating that these hormones act by separate but convergent mechanisms. It is concluded that the primary action of leptin in hepatocytes is to enhance glycogen storage. This may be an important compensatory mechanism for the inhibition of insulin secretion. [R71] *The increase in brain iron associated with several neurodegenerative diseases may lead to an increased production of free radicals via the Fenton reaction. Intracellular iron is usually tightly regulated, being bound by ferritin in an insoluble ferrihydrite core. The neurotoxin 6-hydroxydopamine (6-OHDA) releases iron from the ferritin core by reducing it to the ferrous form. Iron release induced by 6-OHDA and structurally related compounds and two other dopaminergic neurotoxins, 1-methyl-4-phenylpyridinium iodide (MPP+) and 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), were compared, to identify the structural characteristics important for such release. 1,2,4-Trihydroxybenzene (THB) was most effective in releasing ferritin-bound iron, followed by 6-OHDA, dopamine, catechol, and hydroquinone. Resorcinol, MPP , and TaClo were ineffective. The ability to release iron was associated with a low oxidation potential. It is proposed that a low oxidation potential and an ortho-dihydroxyphenyl structure are important in the mechanism by which ferritin iron is mobilized. In the presence of ferritin, both 6-OHDA and THB strongly stimulated lipid peroxidation, an effect abolished by the addition of the iron chelator deferoxamine. These results suggest that ferritin iron release contributes to free radical-induced cell damage in vivo. [R72] *Several genetically engineered mouse models are currently being examined for potential use in cancer hazard identification. We have undertaken an interlaboratory comparison of the performance of the CB6F1-Tg rasH2 transgenic mouse in cancer bioassays concurrently conducted in the United States and Japan. Chemicals selected for study included known human carcinogens (melphalan and cyclosporin A) and known rodent carcinogens (p-cresidine and vinyl carbamate) tested at carcinogenic doses, and non-carcinogens (p-anisidine and resorcinol) tested at appropriate high doses. Because of abdominal adhesions caused by the intraperitoneal dosing vehicle, melphalan was excluded from the study results. The remaining five studies showed similar results between the two laboratories conducting each study. Vinyl carbamate gave the strongest positive response inducing lung adenomas and carcinomas and splen ic hemangiosarcomas. p-Cresidine was considered positive for urinary bladder transitional neoplasia. Cyclosporin A, p-anisidine, and resorcinol were negative in all studies. [R73] NTXV: *Lethal Oral Dose in Rat: 0.37 g/kg (approx); [R37, 1044] *Lethal Oral Dose in Rabbit: 0.75 g/kg (approx); [R37, 1044] *Lethal Oral Dose in Guinea Pig: 0.37 g/kg (approx); [R37, 1044] *LD50 Rat oral 980 mg/kg; [R55, 1991.1333] *LD50 Rabbit dermal 3.36 g/kg; [R55, 1991.1333] *LD50 Rat oral 301 mg/kg; [R31, 2869] *LD50 Mouse ip 215 mg/kg; [R31, 2869] *LD50 Mouse subcutaneous 213 mg/kg; [R31, 2869] *LD50 Rat oral 0.98 g/kg; [R1, 1588] *LD50 Rabbit dermal 3.36 g/kg; [R1, 1588] ETXV: *LC50 Pimephales promelas (fathead minnow): 88.6 mg/l/24 hr /Conditions of bioassay not specified/; [R37, 1044] *LC50 Pimephales promelas (fathead minnow): 72.6 mg/l/48 hr /Conditions of bioassay not specified/; [R37, 1044] *LC50 Pimephales promelas (fathead minnow): 53.4 mg/l/96 hr /Conditions of bioassay not specified/; [R37, 1044] *LC50 Palaemonetes pugio (grass shrimp): 170 mg/l/24 hr /Conditions of bioassay not specified/; [R37, 1044] *LC50 Palaemonetes pugio (grass shrimp): 78 mg/l/48 hr /Conditions of bioassay not specified/; [R37, 1044] *LC50 Palaemonetes pugio (grass shrimp): 42 mg/l/96 hr /Conditions of bioassay not specified/; [R37, 1044] NTP: *... Toxicology and carcinogenicity studies were conducted by administering resorcinol (> 99% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 2 yr. Two Year Studies: ... Groups of 60 male rats and male and female mice were admin 0, 112, or 225 mg/kg resorcinol in deionized water by gavage, five days/wk for up to 104 wk. Groups of 60 female rats were initially administered the same doses as male rats, but by wk 22 of the study 16 of the high-dose females had died. Consequently, the female rat study was restarted using doses of 0, 50, 100, or 150 mg/kg. ... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence oJ carcinogenic activity of resorcinol in male F344/N rats given 112 or 225 mg/kg or female F344/N rats given S0, 100 or 150 mg/kg. There was no evidence of carcinogenic activity of resorcinol in male or female B6C3F1 mice given 112 or 225 mg/kg. [R66] POPL: *... Individuals with liver, kidney, or blood diseases. [R39] ADE: *Resorcinol is readily absorbed from the gastroenteric tract and, in a suitable solvent, is readily absorbed through the human skin. The compound is excreted in the urine, as are other phenols, in a free state and conjugated with hexuronic, sulfuric, or other acids. [R1, 1588] *A dose of 112 mg/kg of (14)C resorcinol was orally administered to 3 male and 3 female Fischer 344 rats. After one day, the animals were sacrificed, and major tissues and excretory products were analyzed to determine the fate of the resorcinol. Only trace amounts of the compound were found in any tissue and there was no evidence of specific organ accumulation. More than 90% of the total administered dose was recovered from the excreta in 24 hr. The primary route of excretion was in the urine. Only 1 to 2% of the dose was eliminated in the feces and less than 0.1% was eliminated as CO2. Cannulation of the common bile duct followed by iv injection of 11.2 mg/kg resorcinol indicated that excretion in bile was rapid and underwent enterohepatic circulation to be excreted in the urine. Less than 50% of the parent compound was excreted in the urine, most was in the form of four metabolites. The major metabolite of resorcinol was a glucuronide conjugate (approximately 70%). One metabolite was identified as a sulfate conjugate (10-20%), one was identified as a diconjugate with glucuronide and sulfate (5-10%), and one, present in small quantities (less than 2%), was suggested to be a diglucuronide conjugate. Repeated exposure of both sexes to daily doses of 225 mg/kg for 5 days did not alter the rate or relative metabolite ratio of resorcinol excretion. [R74] *The US EPA calculated a permeability coefficient for resorcinol through human skin of 1.5 X 10^-3 cm/hr, based primarily on the percutaneous transfer of 2.4 X 10^-4 cm/hr measured in vitro using human cadaver abdominal epidermis. [R55, 1991.1334] *Resorcinol absorbed very slightly under normal conditions and the absorption was lower when applied to the scalp than to clean shaven skin due to a strong fixation by the hair. The results were somewhat similar in humans, rhesus monkeys and guinea pigs. [R75] *Pharmacokinetic data on resorcinol were obtained from studies in the rat. The drug, administered in an aqueous solution, rapidly cleared plasma via urine and did not accumulate in tissues. In the urine, the major metabolite of resorcinol was its glucuronide. Repeated dosing for 30 days with maximum tolerated daily doses of 100 mg/kg did not alter pharmacokinetic parameters, nor did it cause overt toxic signs or adverse reactions. The animals' body weight, blood values, levels of serum T3 and T4, and the gross and microscopic appearance of the thyroid gland and spinal cord remained within normal limits throughout the study. [R76] METB: *IT YIELDS 3-AMINO-3,4-DIHYDRO-7-HYDROXYCOUMARIN, 2,4-DI- HYDROXY-L-PHENYLALANINE, M-HYDROXY-BETA-D-FUCOSIDE, AND M-HYDROXY- PHENYL-BETA-D-GLUCOSIDE IN ESCHERICHIA /FROM TABLE/ [R77, p. R-1] *IT YIELDS M-HYDROXYPHENYL-ALPHA-D-GLUCOSIDE AND HYDROXYQUINOL IN ASPERGILLUS: PRIDHAM JB, CHEM IND (1961) 1172; SIMONART AND VERACHTERT, BULL SOC CHIM BIOL, 51, 919 (1969); YIELDS M-HYDROXYPHENYL SULFATE AND M-HYDROXYPHENYL-BETA-D-GLUCURONIDE IN RABBITS. /FROM TABLE/ [R77, p. R-1] *RESORCINOL YIELDS M-METHOXYPHENOL IN STREPTOMYCES. /FROM TABLE/ [R77, p. R-2] *In the urine, the major metabolite of resorcinol was its glucuronide. [R76] *At least 50% of the absorbed resorcinol underwent enterohepatic circulation /after a single oral intubation of 112 to 225 mg/kg in F344 rats/. Resorcinol underwent conjugation in vivo, with the gluconuride accounting for 70% of the urinary metabolites and the remainder being composed of the monosulfate, diglucuronide, and mixed sulfate-glucuronide conjugates. [R55, 1991.1334] *Essential to anaerobic aromatic metabolism is the replacement of all the oxygen-dependent steps by an alternative set of novel reactions and the formation of different central intermediates (e.g. benzoyl-CoA) for breaking the aromaticity and cleaving the ring; notably, in anaerobic pathways, the aromatic ring is reduced rather than oxidised. The two-electron reduction of benzoyl-CoA to a cyclic diene requires the cleavage of two molecules of ATP to ADP and P1 and is catalysed by benzoyl-CoA reductase. After nitrogenase, this is the second enzyme known which overcomes the high activation energy required for reduction of a chemically stable bond by coupling electron transfer to the hydrolysis of ATP. The alicyclic product cyclohex-1,5-diene-1-carboxyl-CoA is oxidised to acetyl-CoA via a modified beta-oxidation pathway; the ring structure is opened hydrolytically. Some phenolic compounds are anaerobically transformed to resorcinol (1,3-dihydroxybenzene) or phloroglucinol (1,3,5-trihydroxybenzene). These intermediates are also first reduced and then as alicyclic products oxidised to acetyl-CoA. This review gives an outline of the anaerobic pathways which allow bacteria to utilize aromatics even in the absence of oxygen. [R78] ACTN: *... RESORCINOL ... AND CERTAIN OTHER AGENTS SOFTEN KERATIN, LOOSEN CORNIFIED EPITHELIUM, AND CAUSE SWELLING AND SOFTENING EVEN OF VIABLE CELLS. EPIDERMIS EASILY DESQUAMATES, THUS RIDDING AREA OF INVADING FUNGI AND MAKING UNDERLYING LAYERS MORE ACCESSIBLE TO MEDICATION OR SURGICAL DEBRIDEMENT. [R79] *PHENOLS OXIDIZABLE TO QUINONES CAUSE CESSATION OF PROTOPLASMIC STREAMING IN NITELLA AND ELODEA CANADENSIS, ALSO INHIBITING ADENOSINE TRIPHOSPHATASE ACTIVITY. /PHENOLS/ [R80] INTC: *The micronucleus test using mouse bone marrow polychromatic erythrocytes was used to study the extent of which benzo(a)pyrene (BP) mutagenicity was inhibited by mixtures of simple phenols (resorcinol and pyrogallol) with and without the complex hindered-phenol antioxidant ... 2,6-di-tert-butyl-4-methylphenol. Mixtures of these phenolic compds inhibited benzo(a)pyrene mutagenicity more effectively than did the individual constituents. One can assume that the simple phenols regenerated in the presence of 2,6-di-tert-butyl-4-methylphenol from the tissue-oxidized forms incr the formation of detoxified or less mutagenic metabolites of benzo(a)pyrene. [R81] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *ANTIFUNGAL, ANTIBACTERIAL, MILDLY KERATOLYTIC AND LOCAL IRRITANT AGENT. IT IS EMPLOYED IN TREATMENT OF RINGWORM, ECZEMA, PSORIASIS, SEBORRHEIC DERMATITIS, ACNE ROSACEAE, ETC. [R19] *RESORCINOL MAY BE USED IN PREPN FOR REMOVAL OF CORNS, WARTS, CALLOUSES, ETC AND IN TREATMENT OF ATHLETE'S FOOT. [R19] *MEDICATION (VET): KERATOLYTIC, ANTIPRURITIC, ANTISEPTIC, SURFACTANT. ... USE: ... IN VARIOUS LOTIONS, CREAMS, AND OINTMENTS. TOPICALLY, ON ECZEMAS AND OTITIS EXTERNA OF DOGS. POOR ANTISEPTIC IN PRESENCE OF PARTICULATE MATTER. BEST AS AEROSOL SPRAY GERMICIDE. [R8] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Resorcinol's production and use in the rubber industry, tanning, manufacturing resins, resin adhesives, chemical intermediate, explosives, and dyes may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 4.9X10-4 mm Hg at 25 deg C indicates resorcinol will exist solely as a vapor in the ambient atmosphere. Vapor-phase resorcinol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 1.9 hours. The vapor-phase reaction of resorcinol with nitrate radicals may also be an important atmospheric removal process in urban areas at night, but the rate of this reaction is not known. If released to soil, resorcinol is expected to have high mobility based upon an estimated Koc of 65. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 9.9X10-11 atm-cu m/mole. Biodegradation is expected to be an important environmental fate process for resorcinol. Complete degradation of resorcinol occurred in 8 days (as determined by a 100% UV absorbancy loss) in a mineral salts medium using a silt loam soil inocula while the half-life of resorcinol in an aerobic screening test ranged from 0.16 to 0.24 days using activated sludge. If released into water, resorcinol is not expected to adsorb to suspended solids and sediment based upon its estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 2 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process due to a lack of hydrolyzable functional groups. Occupational exposure to resorcinol may occur through dermal contact at sites where the compound is produced or used as a chemical intermediate in the manufacture of other chemicals. The general population may be exposed through the use of consumer products such as some hair dyes which may contain this compound. (SRC) NATS: *Resorcinol does not occur in nature as such(1). [R82] ARTS: *Resorcinol's production and use in the rubber industry(1), tanning, manufacturing resins, resin adhesives, hexylresorcinol, p-aminosalicyclic acid, explosives, and dyes(2) may result in its release to the environment through various waste streams(SRC). [R83] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 65(SRC), determined from a log Kow of 0.8(2) and a regression-derived equation(3), indicates that resorcinol is expected to have high mobility in soil(SRC). Volatilization of resorcinol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 9.9X10-11 atm-cu m/mole(SRC) derived from its vapor pressure, 4.9X10-4 mm Hg(4), and water solubility, 7.2X10+5 mg/l(5). Resorcinol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 4.9X10-4 mm Hg(4). Complete degradation of resorcinol occurred in 8 days(6) (as determined by a 100% UV absorbancy loss) in a mineral salts medium using a silt loam soil inocula while the half-life of resorcinol in an aerobic screening test ranged from 0.16 to 0.24 days(7) using activated sludge. [R84] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 65(SRC), determined from a log Kow of 0.8(2) and a regression-derived equation(3), indicates that resorcinol is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 9.9X10-11 atm-cu m/mole(SRC) derived from its vapor pressure, 4.9X10-4 mm Hg(4), and water solubility, 7.2X10+5 mg/l(5). According to a classification scheme(6), an estimated BCF of 2(SRC) derived from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). The major degradation processes for resorcinol in natural water may be biodegradation and photooxidation. A number of biological screening studies have found resorcinol to be readily biodegradable. By analogy to other phenol compounds, resorcinol may react relatively rapidly in sunlit natural water with photochemically produced oxidants such as hydroxyl and peroxy radicals; typical half-lives for hydroxyl radical and peroxy radical reaction with phenol are on the order of 100 and 19.2 hours of sunlight, respectively(8). [R85] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), resorcinol, which has a vapor pressure of 4.9X10-4 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase resorcinol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 hours(SRC), calculated from its rate constant of 2.0X10-10 cu cm/molecule-sec at 25 deg C(SRC), estimated with a structure estimation method(3). The vapor-phase reaction of resorcinol with nitrate radicals may be an important atmospheric removal process in urban areas at night(4), but the rate of this reaction is not known. [R86] BIOD: *AEROBIC: Complete degradation of resorcinol occurred in 8 days (as determined by a 100% UV absorbancy loss) in a mineral salts medium using a silt loam soil inocula(1). A 5-day 61% theoretical BOD was measured using a sewage inocula(2). Resorcinol was determined to be readily biodegradable using the Japanese MITI protocol(3,4). A 95% degradation was observed over a 0.4-day incubation period using a Warburg respirometer and an acclimated activated sludge inocula(5). A 6-day 21% theoretical BOD was observed using a Warburg respirometer and an activated sludge acclimated to aniline(6). A 12-hr theoretical BOD of 33-39% was observed using a Warburg respirometer and activated sludge acclimated to either phenol, catechol, or benzoic acid(7). A 5-day COD removal of 90% was measured in an activated sludge system(8). The half-life of resorcinol in an aerobic screening test ranged from 0.16 to 0.24 days using activated sludge acclimated to cresols(9). Half-lives of 0.5 and 4.5 hours were determined for initial concentrations of 20 and 120 ppm resorcinol, respectively, in a treatment plant simulation study over a 1-hr incubation period using inoculum from a coke wastewater treatment plant(10). Degradation of 95% in 1 day and 90% in 8 days was observed in a biological treatment simulation using activated sludge and initial concns of 138 and 500 ppm, respectively(11). Using a Warburg respirometer and a mixed-culture of bacteria adapted to phenol, 95% of initial resorcinol was degraded in 1 to 2 days(12). [R87] *ANAEROBIC: Resorcinol was readily degraded (95% utilization based on TOC) in an anaerobic reactor(1). A 98% of theoretical methane formation was observed in an anaerobic-water screening test using inoculum from one waste treatment facility, but no methane formation was observed using inoculum from a second treatment facility(2).The degradation of resorcinol was examined using anaerobic denitrifying enrichments established in sediments from an estuarine tidal strait in New Jersey(4). Resorcinol half-lives were found to range between 1 and 7 days(4). Activated sludge from an oxidation ditch treating domestic wastewater was separately acclimated to mixed feeds containing m-nitrobenzene sulphonate and resorcinol, m-aminophenol and resorcinol, and catechol and resorcinol(5). Biodegradation half-lives for the three separate feed mixtures were approximately 9 hours, 2.5 hours, and 10 hours, respectively(5). The biodegradation of resorcinol was studied in an upflow anaerobic filter(6). Biodegradation half-lives were found to range from 30 to 250 days, varying with substrate organic loadings(6). [R88] ABIO: *The rate constant for the vapor-phase reaction of resorcinol with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The vapor-phase reaction of resorcinol with nitrate radicals may be an important atmospheric removal process in urban areas at night(2), but the rate of this reaction is not known. Phenols are generally resistant to aqueous environmental hydrolysis(3); therefore, resorcinol is not expected to hydrolyze in water(SRC). As a class, phenols react relatively rapidly in sunlit natural water via reaction with photochemically produced hydroxyl radicals and peroxy radicals(4); typical half-lives for hydroxyl radical and peroxy radical reaction are on the order of 100 and 19.2 hours of sunlight, respectively(4). Resorcinol does not absorb UV light at wavelengths above 295 nm at low concns in methanol or acidic aqueous solution(5,6). However, in dilute alkaline solutions, resorcinol does absorb UV light above 295 nm(6); resorcinol has a pKa of 9.15(6) which indicates that it will increasingly dissociate with an increase of pH. These data suggest that direct photolysis in environmental waters will not occur under acidic conditions, but may potentially occur in alkaline waters(SRC). Resorcinol crystals acquire a pink tint when exposed to light and air(7). [R89] BIOC: *An estimated BCF of 2 was calculated for resorcinol(SRC), using a log Kow of 0.8(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R90] KOC: *The Koc of resorcinol in a clay loam soil from the Michigan State University Soils Research Farm was measured to be 10.36(1). The Koc of resorcinol is estimated as 65(SRC), using a measured log Kow of 0.8(2) and a regression-derived equation(3). According to a classification scheme(4), this estimated Koc value suggests that resorcinol is expected to have high mobility in soil. [R91] VWS: *The Henry's Law constant for resorcinol is estimated as 9.9X10-11 atm-cu m/mole(SRC) based upon its vapor pressure, 4.9X10-4 mm Hg(1), and water solubility, 7.2X10+5 mg/l(2). This Henry's Law constant indicates that resorcinol is expected to be essentially nonvolatile from water surfaces(3). Resorcinol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 4.9X10-4 mm Hg(1). [R92] WATC: *GROUND WATER: Resorcinol was found as a pollutant in filtered ground water at a waste treatment plant(1). [R93] *SURFACE WATER: Resorcinol was found as a pollutant in filtered surface water at a waste treatment plant(1). [R93] EFFL: *The concn of resorcinol in the condensate water from a coal gasification facility in Grand Forks, ND ranged from not detected (no analytical detection limit reported) to 60 ppm between Jun 1980 and Apr 1982(1). A resorcinol level of 1000 ppm was detected in wastewater from a synthetic coal conversion process(2). Resorcinol has been found in effluents associated with coal gasification and conversion, coal-tar production and shale oil processing and from the combustion of wood(3). [R94] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 100,792 workers (56,465 of these are female) are potentially exposed to resorcinol in the US(1). Occupational exposure to resorcinol may occur through dermal contact at sites where the compound is produced or used as a chemical intermediate in the manufacture of other chemicals(SRC). [R95] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (45 mg/cu m). [R20] *Recommended Exposure Limit: 10 Min Short-Term Exposure Limit: 20 ppm (90 mg/cu m). [R20] TLV: *8 hr Time Weighted Avg (TWA) 10 ppm; Short Term Exposure Limit (STEL) 20 ppm [R52] *A4: Not classifiable as a human carcinogen. [R52] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Resorcinol is produced, as an intermediate or a final product, by process units covered under this subpart. [R96] WSTD: STATE DRINKING WATER GUIDELINES: +(ME) MAINE 140 ug/l [R97] CWA: +Resorcinol is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R98] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R99] RCRA: *U201; As stipulated in 40 CFR 261.33, when resorcinol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R100] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC Method 942.21. Resorcinol in hair lotions. Bromate titration. [R101] *EAD Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. [R102] *OSW Method 3640A. Gel Permeation Chromatography (GPC) Cleanup Procedure. [R102] *SFSAS Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. Detection limit= 2 mg/kg. [R102] CLAB: *... RESORCINOL, EXTRACTED FROM TISSUE SAMPLES /BY GAS CHROMATOGRAPHY/; KOEMPE, B, A GLC-SYSTEM FOR IDENTIFICATION OF UNKNOWN DRUG IN FORENSIC CHEMISTRY, ARCH B, A GLC-SYSTEM FOR IDENTIFICATION OF UNKNOWN DRUG IN FORENSIC CHEMISTRY, ARCH PHARM CHEM SCI, 2, 145-152 (1974). [R103] *A high-performance liquid chromatography technique, requiring only a simple ethanol extraction, is described for the detection of free resorcinol in plasma and urine at concentrations as low as 0.5 mug/mL. The method gives recoveries of > 90% with good reproducibility. Using this method, the percutaneous absorption and metabolic disposition of resorcinol were studied following the exaggerated repeated topical application of resorcinol (800 mg/day) to 3 volunteers. After 2 wk oftreatment, an average of 1.64% (range 0.47-2.87%) of the resorcinol dose was excreted in 24 hr urines. No resorcinol was detected in any of the blood samples collected after 1, 2, 3, and 4 wk of drug application. 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Thomas Publisher, 1986. 792 R61: NTP; Fiscal Year 1986 Annual Plan p.72 (1986) NTP-86-086 R62: DiNardo JC et al; Toxicol Appl Pharmacol 78 (1): 163-6 (1985) R63: Kozitskaya VN; Eksp Vodn Toksikol 9: 40-51 (1984) R64: Korhonen A et al; Acta Pharmacol Toxicol 52 (2): 95-9 (1983) R65: Anonymous; J Am Coll Toxicol 5 (3): 167-204 (1986) R66: Toxicology and Carcinogenesis Studies of Resorcinol in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 403 (1992) NIH Publication No. 92-2858 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R67: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1121 (1999) R68: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 20 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Yaws CL; Handbook of Vapor Pressure. Vol 2 - C5 to C7 Compounds. Houston, TX: Gulf Pub Co (1994) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (6) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (7) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 13: 59-65 (1984) R85: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 20 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Yaws CL; Handbook of Vapor Pressure. Vol 2 - C5 to C7 Compounds. 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Reference Book TSU-No. 3 (1978) (5) Lund FA, Rodriguez DS; J Gen Appl Microbiol 30: 53-61 (1984) (6) Malaney GW; J Water Pollut Control Fed 32: 1300-11 (1960) (7) McKinney RE et al; Sew Indust Wastes 28: 547-57 (1956) (8) Pitter P; Water Res 10: 453-60 (1976)(9) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 13: 59-65 (1984) (10) Chmielowski J et al; Pol Arch Hydrobiol 22: 327-44 (1975) (11) Gubser H; Gas, Wasser, Abwasser 49: 175-81 (1969) (12) Tabak HH et al; J Bacteriol 87: 910-9 (1964) R88: (1) Chou WL et al; Biotechnol Bioeng Smyp 8: 391-414 (1979) (2) Horowitz A et al; Dev Ind Microbiol 23: 435-44 (1982) (4) Milligan PW, Haggblom MM; Environ Toxicol Chem 17: 1456-1561 (1998) (5) Deshpande SD, Chakrabarti T; Indian J Environ Hlth 30: 215-221 (1989) (6) Swaminathan K et al; J Environ Sci Health 5: 655-672 (1991) R89: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Atkinson R; Environ Sci Technol 21: 1123-6 (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY, NY: McGraw-Hill p. 7-4 (1982) (4) Mill T, Mabey W; pp. 208-11 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (5) Sadtler; 2572 UV. 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Re-evaluation of some organic chemicals, hydrazine and hydrogen peroxide (Part three). 71: 1119-31 (1999) R95: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R96: 40 CFR 60.489 (7/1/2000) R97: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R98: 40 CFR 116.4 (7/1/2000) R99: 40 CFR 302.4 (7/1/2000) R100: 40 CFR 261.33 (7/1/2000) R101: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 366 R102: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R103: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V15 166 (1977) R104: Yeung D et al; J Chromatogr 224 (3): 513-18 (1981) RS: 79 Record 83 of 1119 in HSDB (through 2003/06) AN: 732 UD: 200303 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-CHLORATE- SY: *ASEX-; *ATRATOL-; *Chlorate-de-sodium-; *CHLORATE-SALT-OF-SODIUM-; *CHLORAX-; *CHLORIC-ACID,-SODIUM-SALT-; *CHLORSAURE- (GERMAN); *Defol-; *De-Fol-Ate-; *Ortho-C-1-Defoliant-; *ORTHO-C-1-DEFOLIANT-AND-WEED-KILLER-; *Dervan-; *DESOLET-; *DREXEL-DEFOL-; *Dropleaf-; +Pesticide-Code:-073301.-; *EVAU-SUPER-; *FALL-; *GRAIN-SORGHUM-HARVEST-AID-; *GRANEX-O-; *Harvest-Aid-; *B-HERBATOX-; *KM-; *KUSA-TOHRU-; *KUSATOL-; *Leafex-2-; *Leafex-3-; *NATRIUM-CHLORAAT- (DUTCH); *NATRIUM-CHLORAT- (GERMAN); *OXYCIL-; *SHED-A-LEAF-; *SHED-A-LEAF-'L'-; *Soda-chlorate-; *SODIO- (CLORATODI)- (ITALIAN); *SODIUM- (CHLORATEDE)- (FRENCH); *SODIUM-CHLORATE- (NACLO3); *TRAVEX-; *Tumbleaf-; *Tumbleleaf-; *UNITED-CHEMICAL-DEFOLIANT-NO-1-; *Val-Drop-; *Weed-Killer- RN: 7775-09-9 MF: *Cl-Na-O3 SHPN: UN 1495; SODIUM CHLORATE (SODA CHLORATE) UN 2428; SODIUM CHLORATE, AQUEOUS SOLUTION IMO 5.1; Sodium chlorate, aqueous solution, Soda chlorate, STCC: 49 187 43; Sodium chlorate (chlorate of soda) 49 187 65; Sodium chlorate and sodium chloride, in water solution (oxidizing material) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Produced from sodium chloride by electrolysis. [R1, 1473] IMP: *Impurities: sodium chloride and chromium [R2, (1979)] FORM: +USEPA/OPP Pesticide Code 073301; Trade Names: Altacide, Chlorax, Drop-leaf, Fall, Tumbleaf, Shed-a-leaf'l'. [R3] *WP 40% ACTIVE, LIQ 4, 19 AND 28% ACTIVE. DUST 12-33% ACTIVE. POWDER FROM 99% ACTIVE. ALSO FORMULATED WITH BORATES, CALCIUM CHLORIDE, MAGNESIUM CHLORIDE, MONURON, 2,4-D AND OTHERS. MAY BE MIXED WITH SODIUM CHLORIDE TO REDUCE FIRE HAZARD. MONOBOR-CHLORATE (US BORAX)- FORMULATION OF SODIUM BORATE AND SODIUM CHLORATE, EFFECTIVE AGAINST JOHNSONGRASS AND OTHER WEEDY GRASSES ON NON-CROP LAND. [R4] *DREXEL DEFOL 6 CONTAINS 6 LB/GAL OF SODIUM CHLORATE PLUS A FIRE RETARDANT. [R5] *The chlorate of commerce is about 99% pure. [R1, 1473] *Grades: technical; CP; crystals; powder. [R6] *Leafex, Liquid Ureabor, De-Fol-Ate, Drop-Leaf, Fall, and Kusatol [R7] *Sodium chlorate of technical grade is: NaClO3, 99.5% min; sodium chloride, 0.12% max; moisture, 0.20% max; clear solution [R2] *Some sodium chlorate is shipped as a solution containing sodium chloride, ca 200 g/l (15 wt%, 3.4 M); sodium chlorate, ca 350 g/l (26 wt%, 3.3 M); and chromium, 130 ppm [R2] *Water-soluble powder [R8] *Mixed formulations: (sodium chlorate +) atrazine; atrazine + 2,4-D; atrazine + sodium metaborate; bromacil + sodium metaborate; diuron + sodium metaborate [R9] *Mixtures with fire depressants to reduce fire hazard. Mixtures include: ... Sodium chlorate + sodium metaborate. [R10] MFS: *442 Corporation, PO Box 76, Perdue Hill, AL 36470, (334)575-3510 [R11] *CXY Chemicals U.S.A. Inc, 12450 Greenspoint Dr, Suite 1350, Houston, TX 77060, (281)876-2267; Production Site: Taft, LA 70057 [R11] *Eka Nobel Inc., 1519 Johnson Ferry Rd, Suite 200, Marietta, GA 30062, (404) 578-0858, (800) 241-3900; Production sites: Moses Lake, WA 98837; Columbus, MI 39702 [R11] *Elf Atochem North America Inc, Three Parkway, Philadelphia, PA 19102, (215) 587-7000; Basic Chemicals Div; Production sites: Portland, OR 97208 [R11] *Georgia Gulf Corp, PO Box 105197, Atlanta, GA 30348, (404) 395-4500; Production site: Plaquemine, LA 70764 [R11] *Huron Tech Corp, PO Box 189, Delco, NC 28436, (919) 655-3845; Production sites: Augusta, GA 30906 [R11] *Kerr-McGee Corporation, Kerr-McGee Center, PO Box 25861, Oklahoma City, OK 73125, (405) 270-1313; Production sites: Hamilton, MS 39746; Henderson, NV 89015 [R11] *Sterling Pulp Chemicals, Inc, 5700 Hunt Rd, Valdosta, GA 31606, (912)244-6780 [R11] *Western Electrochemical Company, PO Box 629, Cedar City, UT 84720, (435)865-5000 [R11] OMIN: *Sodium chlorate is a strong oxidizing agent in plants, and also may act to block protein sulfation. It is bioactivated to the highly phytotoxic chlorite ion by reducing activity of nitrate reductase. [R12, 274] *Soil applications ... Best for sterilant effect, however, it can be sprayed or applied dry to soil or plants. [R7] *Two ppm sodium chlorate controlled Skeletonema, Cymodium, and Hornellia in seawater in 7 days. [R13] *Not compatible with herbicides which are susceptible to oxidation. [R10] USE: +For Sodium chlorate (USEPA/OPP Pesticide Code: 073301) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R3] *Oxidizer in mfr dyes; explosives and matches; dyeing and printing fabrics; tanning and finishing leather; pharmaceutic aid (oxidizing agent). [R1, 1474] *Semi-permanent soil sterilant herbicide, harvest aid. [R7] *Oxidizing agent and bleach (especially to make chlorine dioxide) for paper pulps; ore processing; to make perchlorates. [R6] *Uranium processing, rocket fuel oxidant, and as an intermediate for potassium chlorate and perchlorates. [R14] *Used in toothpastes and mouthwashes and ... weedkillers. [R15, 303] *USED AS HERBICIDE FOR MORNING GLORY, ST JOHNSWORT, RUSSIAN KNAPWEED, CANADA THISTLE, AND JOHNSONGRASS. [R16, 442] *Substitute for potassium chlorate, being more soluble in water; ... flares, and pyrotechnics; recovery of bromine from natural brines; ... textile mordant. [R6] *For control of both grasses and broadleaf weeds, annual and perennial, and to kill trees and stumps. Kills all plant growth except moss. ... [R7] *Used on railroad beds for seasonal weed control. [R17] *Total weed control on non-crop land, applied at up to 600 kg/ha. Also used as a defoliant and desiccant in cotton, safflowers, sunflowers, lupins, alfalfa, clover, field beans, soya beans, flax, rice, etc. Has a soil-sterilant effect. [R10] *Production of chloric acid [R18] *As a sweetening agent in oil refineries [R19, 4498] CPAT: *Paper bleaching, 85%; Other chlorates and perchlorates, 6%; Uranium, 4%; Agriculture, 3%; Miscellaneous, 2% (1984) [R20] *CHEMICAL PROFILE: Sodium Chlorate. Wood pulp bleaching, 88%; other chlorates, perchlorates and chlorites, 8%; herbicide, 2%; miscellaneous, including water treatment and uranium mining, 2%. [R21] *CHEMICAL PROFILE: Sodium chlorate. Demand: 1986: 675,000 tons; 1987: 730,000 tons; 1991 /projected/: 825,000 tons. [R21] *Wood pulp bleaching 95%, other chlorates perchlorates and chlorites, 3%; miscellaneous including herbicides, water treatment, and uranium mining, 2%. [R22] *Demand for sodium chlorate from the U.S. and Canada was 1.6 million tons in 1995, 1.75 million tons in 1996 and is estimated to be 2.1 million tons in 2000. [R22] PRIE: U.S. PRODUCTION: *(1984) 2.68X10+11 g [R23] *(1991) 6.39x10+5 ton [R24] U.S. IMPORTS: *(1984) 1.24X10+11 g [R25] U.S. EXPORTS: *(1984) 1.72X10+9 g [R26] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS; CUBIC OR TRIGONAL CRYSTALS [R27]; *White powder [R28]; *Pale yellow to white crystals [R12, 273]; *Colorless powder [R10]; *Colorless crystals or white granules [R29, 379] ODOR: *Odorless [R1, 1473] TAST: *Salty taste [R12, 273] BP: *122 deg C [R30, 99] MP: *248 deg C [R1, 1473] MW: *106.45 [R19, 4497] CORR: *CORROSIVE TO ZINC AND MILD STEEL [R4] DEN: *2.5 g/ml [R19, 4497] PH: *Aqueous solution is neutral [R1, 1474] SOL: *SOL IN LIQ AMMONIA, GLYCERIN [R27]; *Sol in about 1 ml cold, 0.5 ml boiling water, about 130 ml alc, about 50 ml boiling alc; sodium chloride diminishes its solubility in water [R1, 1475]; *Water solubility = 9.59X10+5 mg/l @ 20 deg C [R31]; *790 g/l (in water) @ 0 deg C; 2,300 g/l (in water) @ 100 deg C. In 90% alcohol 16 g/kg, soluble in glycerol [R10]; *In water, 1X10+6 mg/l @ 20 deg C [R12, 273] SPEC: *INDEX OF REFRACTION: 1.513 [R27] SURF: *9.07X10-2 N/m @ 538.15 K VISC: *7.78X10-3 Pa.s @ 525 K OCPP: *At 300 deg C liberates oxygen; entirely decomp at higher temp [R1, 1473] *White, odorless, crystalline solid /Technical sodium chlorate/ [R7] *Potent oxidizing agent, reacting with organic materials, so creating a serious fire hazard with splashed clothing. [R10] *Releases ClO2 in presence of heat. [R19, 4496] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: These substances will accelerate burning when involved in a fire. Some may decompose explosively when heated or involved in a fire. May explode from heat or contamination. Some will react explosively with hydrocarbons (fuels). May ignite combustibles (wood, paper, oil, clothing, etc.). Containers may explode when heated. Runoff may create fire or explosion hazard. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +Health: Inhalation, ingestion or contact (skin, eyes) with vapors or substance may cause severe injury, burns, or death. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may cause pollution. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +Fire: Small fires: Use water. Do not use dry chemicals or foams. CO2, or Halon may provide limited control. Large fires: Flood fire area with water from a distance. Move containers from fire area if you can do it without risk. Do not move cargo or vehicle if cargo has been exposed to heat. Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +Spill or leak: Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Do not get water inside containers. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Small liquid spills: Use a non-combustible material like vermiculite, sand or earth to soak up the product and place into a container for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Following product recovery, flush area with water. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Sodium chlorate; Sodium chlorate, aqueous solution/ [R32] FPOT: *STRONG OXIDIZER-MIXING WITH OTHER MATERIALS CAN PRODUCE FLAMMABLE ... MIXTURES. ... CLOTHING CONTAMINATED ... SHOULD NOT BE BURNED WITH ORDINARY PLANT WASTES IN INCINERATOR OR UNDER STEAM BOILERS. SODIUM CHLORATE MUST BE USED WITH WATER SOLUBLE FIRE RETARDANT SUCH AS SODIUM METABORATE, SODA ASH, MAGNESIUM CHLORIDE, OR UREA. [R33] *AS POWERFUL OXIDIZING AGENT, IT SUBSTANTIALLY ENHANCES INFLAMMABILITY OF COMBUSTIBLE DRIED PLANT TISSUE. [R34] *Dangerous fire risk, strong oxidant, contact with organic materials may cause fire. [R6] *Clothing and vegetation contamination with chlorate or its solutions are dangerously flammable. [R16, 442] *Mixtures of sodium chlorate and combustible materials are readily ignited; mixtures with finely divided combustible materials can react explosively. [R29, 379] *Mixtures with ammonium salts, powdered metals, phosphorus, silicon, sulfur or sulfides are readily ignited ... . Paper impregnated with the chlorate can be ignited by static sparks. ... With the chlorate over a period of time may ignite ... . [R29, 379] FIRP: *Fire extinguishing agents not to be used: fire blankets. [R35] *If material on fire or involved in fire: Flood with water. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. [R36, 972] *Personnel protection: ... Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R36, 072] *If material on fire or involved in fire: Flood with water. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. /Sodium chlorate, solution/ [R36, 972] OFHZ: *Behavior in fire: Melts, then decomposes to give oxygen gas that increases the intensity of fire. [R35] EXPL: *Following a violent explosion during a fire involving 67 tons of drummed sodium chlorate, experiments confirmed that pure sodium chlorate would decompose explosively under intense fire conditions. [R37] *Sodium chlorate should not be used in the hydroxylation of alkenes to diols in the presence of potassium osmate if the diol is to be distilled from the reaction mixture; explosive oxidation may occur. ... Mixtures with ammonium salts, powdered metals, phosphorus, silicon, sulfur or sulfides are readily ignited and potentially explosive. ... A mixture /of sodium chlorate and nitrobenzene/ is powerfully explosive. ... Mixtures with fibrous or absorbent organic materials (charcoal, flour, shellac, sawdust, sugar) are hazardous and can be caused to explode by static friction or shock. ... A mixture /of sodium chlorate and phosphorus/ explodes violently. ... Addition of concentrated sulfuric acid causes explosion of the chlorate generated. ... Wood in contact with the chlorate over a period of time may ignite or explode. [R29, 379] *It can explode on contact with flame or sparks (static discharge) ... May react explosively with ... alkenes + potassium osmate, aluminum + rubber, ... grease, leather, ... nonmetals, sulfides, cyanides, cyanoborane oligomer, ... organic matter, paint + polyethylene, ... sodium phosphinate. [R38, 2954] REAC: *Must not be triturated with any combustible substance. [R6] *The potential for explosive combustion of mixture of sodium chlorate based herbicides with other combustible agricultural materials was determined. [R37] *Reacts explosively, either as a solid or a liquid, with all organic matter and some metals. [R35] *Violent reaction or ignition with aluminum, ammonium sulfate, Sb2S3, arsenic, arsenic trioxide, 1,3-bis(trichloromethylbenzene) + heat, carbon, charcoal, MnO2, phosphorus, potassium cyanide, osmium + heat, paper, ... thiocyanates, triethylene glycol + wood, ... zinc. Can also react violently with ... paper, metal sulfides, dibasic organic acids, organic matter. [R38, 2954] *APPROX 0.2 JOULES IMPACTS ARE SUFFICIENT TO CAUSE EXPLOSIONS OF UNCONFINED SODIUM CHLORATE ON RUSTY STEEL SURFACE. EFFECTS WERE EXAMINED OF SAWDUST, COPPER ACETATE, DRY WHITE PAINT FLAKES, AND CHOPPED POLYTHENE FILM ON INCIDENCE OF EXPLOSIONS OF SODIUM CHLORATE. [R39] *TEXTILES SOAKED WITH MIXT THAT COMBINE AGROSAN (SODIUM CHLORATE) AND ANFORSTAN (POTASSIUM CHLORATE) WITH WOFATOX-KONZENTRAT 50 (METHYL PARATHION) ARE CAPABLE OF EXPLOSIVE COMBUSTION @ ROOM TEMP. [R40] +Mixtures containing more than 10% sodium chlorate are sufficiently combustible to be hazardous al low relative humidity. Mixtures of sodium chlorate with organic material such as charcoal, sugar, flour or shellac may be ignited by friction or shock. [R41] *A bulk cargo of sodium chlorate became hot while being transported in a tank that had previously contained ammonium thiosulfate. Under controlled laboratory conditions, a small quantity of ammonium thiosulfate in sodium chlorate could be made to decompose explosively. [R41] *Arsenic trioxide and sodium chlorate form a spontaneously flammable mixture. [R41] +Chlorates when brought in contact with sulfuric acid are likely to cause fire or explosions. [R41] DCMP: *When heated to decomp it emits toxic fumes of /hydrogen chloride, disodium oxide/. [R38, 2954] SERI: *When used as a pesticide, sodium chlorate may cause irritation of skin, eyes, or respiratory tract. [R28] EQUP: *... DUST RESPIRATORS MAY BE NECESSARY /CHLORATES/ [R42] *... Should include overalls, hand and arm protection such as plastic gloves, a washable head covering and foot protection such as rubber boots. /Chlorates/ [R42] *Do not wear leather gloves or shoes. Wear rubber boots and apron to avoid contact with clothing. [R16, 442] *Safety glasses or vented safety goggles, impermeable gloves, washable clothing with pants over rubber boots or shoes. [R33] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Wood should be avoided in the structure and floors of the buildings and in the plant or equipment where chlorates are handled, and a copious water supply should be available for extinguishing fire. ... The /chlorate/ dust should be reduced to a minimum ... . /Chlorates/ [R42] *CARE SHOULD BE TAKEN TO AVOID IMPREGNATION OF CLOTHING WITH CHLORATES. ALL CONTAMINATED CLOTHING SHOULD BE KEPT WET AND CHANGED IMMEDIATELY AND WASHED BEFORE RE-USE. [R33] *Do not use oils, greases, or protective creams on skin. [R43] *Cloth, leather, wood and paper are extremely flammable when impregnated by ... chlorates. Special consideration must be given, therefore, to personal protective equipment; working clothes worn by chlorate workers should be washable and should not be worn away from the immediate work area; they should be washed and rinsed each day. /Chlorates/ [R42] *Remove contaminated clothing promptly and wash it thoroughly with water. Do not get on floor. ... Do not smoke while handling. [R16, 442] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. [R36, 972] *Personnel protection: ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R36, 972] *If material not on fire and not involved in fire: Keep sparks, flames, and othersources of ignition away. Keep material out of water sources and sewers. /Sodium chlorate, solution/ [R36, 972] *Personnel protection: ... Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Sodium chlorate, solution/ [R36, 973] *Evacuation: If fire becomes uncontrollable consider evacuation of one-third mile radius. /Sodium chlorate, solution/ [R36, 973] *Avoid contact with skin, eyes and clothing. Wear nitrile rubber gloves, laboratory coat, and eye protection /when cleaning spills/. [R29, 380] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *STABLE @ NORMAL TEMP AND WHEN KEPT ISOLATED FROM OTHER MATERIALS [R16, 443] *At about 300 deg C liberates oxygen; entirely decomp at higher temp. [R44] *Stable at normal temperatures if no acidic or oxidizable substances or ammonium salts are present. [R9] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R45] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R46] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R47] STRG: *STORE IN COOL, DRY, FIRE RESISTANT AREA; SEPARATE FROM ... SOLVENTS, OILS, ORGANIC SUBSTANCES ... SULFIDES, POWDERED METALS ... . DO NOT CONTAMINATE FOOD OR FEEDSTUFFS BY STORAGE. [R33] *Keep out of contact with organic matter or other oxidizable substances. [R44] *Keep away from fire and flammable materials. [R9] *When not in use, keep tightly closed in original metal container. ... Store ... separately from ... strong acids. [R16, 442] *Sodium chlorate reacts with organic materials in the presence of sunlight. [R48, 565] CLUP: *SWEEP UP SPILLS IMMEDIATELY INTO METAL CONTAINERS. [R33] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *SODIUM CHLORATE SHOULD NOT BE DISPOSED OF INTO WATERWAYS AS FISH AND PLANT LIFE MAY BE AFFECTED. [R33] */Laboratory/ spillage disposal: Scoop the chlorate into a container and transport to the fume hood. Add to suficient water to give an approximately 10% solution. Follow the waste disposal procedure. Wash the site of the spillage thoroughly with soap and water. [R29, 380] */Laboratory/ waste disposal: Prepare a 10% aqueous solution of the waste sodium chlorate. For each 10 ml of solution, slowly, and with stirring, add 18 ml of a 10% solution of sodium bisulfite (this allows about 50% excess of reducing agent). The continued presence of chlorate can be detected by adding, to 3 ml of the solution, a freshly prepared solution of potassium iodide (100 mg) in 3 ml of 3 M sulfuric acid (prepared by cautiously adding 0.5 ml of concn acid to 2.5 ml of cold water). Add sodium bifulfite solution until the test is negative. Neutralize the acidic solution with sodium carbonate and discard into the drain with at least 50 times its volume of water. [R29, 380] *CONTAINER DISPOSAL: DO NOT USE CONTAINER. DESTROY BY CRUSHING AND BURYING IN SAFE PLACE. DO NOT BURN. [R16, 442] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *A case of severe sodium chlorate poisoning was observed within 5 hr after suicidal ingestion of 150-200 g. Treatment with methylene blue and ascorbic acid did not prevent massive hemolysis with disseminated intravascular coagulation. Hypercoagulation and hyperfibrinolysis was treated successfully with exchange transfusions, heparin and fresh plasma. During the 1st hr, 70 mmol chlorate were excreted before complete renal failure occurred which required hemodialysis for several weeks. Clinical observations and in vitro experiments provided evidence that methylene blue was effective only in the early stages of chlorate poisoning. The following treatment was suggested: gastric lavage, exchange transfusion, bicarbonate infusion, hemodialysis, anticoagulation with heparin and substitution of clotting factors if necessary. [R49] *Treatment of severe methemoglobinemia includes supportive measures (iv fluids, oxygen) and prompt removal of the suspected agent from the GI tract or skin. ... Exchange transfusion has been advocated by some workers. [R15, 303] *In case of irritation of the skin or mucous membranes, the area should be thoroughly flushed with water. Every effort should be made to remove the material if ingestion has occurred. There is no specific antidote, but oxygen, peritoneal dialysis, and exchange transfusions may be lifesaving even after a dose as high as 40 g. Dialysis is important because 95% of small doses of chlorate are excreted by the kidney, but larger doses so injure that organ that the body is almost powerless to remove to poison unaided. [R48, 566] *Obviously ill patients should be evaluated for the adequacy of airway, ventilation, and circulation. Methemoglobin levels, complete blood count, serum electrolytes, and creatinine should be drawn immediately after the establishment of adequate ventilation and an iv line. The patient should receive cardiac monitoring and supplemental oxygen. Watch carefully for signs of hyperkalemia (widening of the QRS and PR prolongation) on the ECG. ... The usual measures of gut decontamination (lavage, activated charcoal, cathartics) may be useful within the first several hr after exposure. ... Sodium chlorate is freely dialyzable, and hemodyalysis or early exchange transfusion is recommended, particularly when renal failure is present. Such procedures may prevent the ensuing hemolysis, which may be fatal. ... Sodium thiosulfate either orally or iv (2-5 g in 200 ml of 5% sodium bicarbonate) inactivates chlorate ion and is a potentially useful antidote on the basis of anecdotal reports. Methemoglobin can be reduced to hemoglobin by iv methylene blue; however, methylene blue may have minimal effect in the treatment of chlorate intoxication. [R50] *Treatment of sodium chlorate poisoning should include the use of gastric lavage and saline purgatives to remove the poison. Methemoglobinemia can be treated with iv administered methylene blue. The recommended dose in the cow is 2 g in the form of a 2% aqueous solution. In the dog, blood transfusion, iv glucose, egg albumin orally, and inhalation of oxygen may also be useful. [R51, 30] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. /Chlorates and related cmpds/ [R52, 410] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Chlorates and related cmpds/ [R52, p. 410-11] HTOX: */IN CHLORATE POISONING/ HEINZ BODIES ARE OFTEN PRESENT AND ... MANY OF THE ERYTHROCYTES CLUMP AND ARE BROKEN UP. LATTER EFFECT PRODUCES EMBOLI AND EXCRETION OF BLOOD PIGMENTS BY KIDNEY, WITH RESULTING DARK-COLORED URINE. /CHLORATES/ [R53, 158] *DEATH /FROM CHLORATE POISONING/ OCCURS WITHIN A FEW HR TO FEW DAYS. ... DEATH IS DUE TO SEVERE METHEMOGLOBINEMIA OR TO ACUTE NEPHRITIS. /CHLORATES/ [R53, 159] *CAUSES SKIN IRRITATION AND ULCERATION OF NASAL SEPTUM. ORAL INGESTION MAY PRODUCE ABDOMINAL PAIN, NAUSEA, VOMITING, DIARRHEA, PALLOR, BLUENESS, SHORTNESS OF BREATH, UNCONSCIOUSNESS AND COLLAPSE. [R16, 443] *13 YR OLD BOY INGESTED WHITE CRYSTALS, 6 HR LATER HE BECAME ILL WITH RIGORS, ABDOMINAL PAIN, VOMITING AND DIARRHEA. URINE WAS DARK WITH BLOOD CLOTS. 3 DAYS LATER RENAL FAILURE WAS PRESENT. [R54] *Sodium chlorate and potassium chlorate ... are potent oxidants, and accidental or intentional ingestion has resulted in fatal methemoglobinemia as well as hemolysis. They are also toxic to GI tract, liver and kidney. [R15, 302] *A 29 year old man ingested about 20 g of sodium chlorate (230 mg chlorate/kg body weight). He became cyanotic, and his hemoglobin dropped to 11 g/100 ml within 24 hr; methemoglobin and methemoalbumin were detected in his plasma. He was anuric for 14 days, then gradually improved, and he was released from the hospital after 6 wk. [R30, 102] *14 cases of sodium chlorate poisoning was reported. The patients' ages ranged from 3 to 55 years. Doses estimated to be in excess of 100 g or 79 g as chlorate ion were uniformly fatal. One 46 year old woman given supportive therapy died 20 hours after a dose estimated to be 15 g (218 mg chlorate/kg body wt). This was the lowest dose found to be fatal in these cases. Another female of unreported age died 5 days after ingesting 30 g (436 mg chlorate/kg body weight) despite treatment with methylene blue, peritoneal dialysis, and exchange transfusion. However, an 18 yr old male survived a dose estimated at 100 g (1.45 g chlorate/kg body wt) after treatment with methylene blue, exchange transfusion, and hemodialysis. Cyanosis was seen in 50% of the patients, abdominal pain in 36%, diarrhea in 21%, dyspnea in 21%, anuria within 48 hr in 50%, coma in 12%, and methemoglobinemia in 93%, 64% died. [R30, 102] *Ingestion of relatively large quantities may be fatal. [R16, 443] *... Near-fatal poisoning occurred when a 13 year old boy "tasted" crystals of /sodium chlorate/ which he found in his father's shed. In spite of intensive treatment, recovery did not begin until about the 15th day and required a little over 40 days. [R48, 565] *Poisoning is characterized by gastritis (nausea, vomiting, and pain), anoxia, (cyanosis, collapse, and terminal convulsions) secondary to methemoglobinemia, possible liver injury, and nephritis (lumbar pain and oliguria). Nephritis presumably is the direct result of chlorate ion as well as secondary to the destruction of corpuscles. The blood pressure tends to fall and the heartbeat becomes irregular. The liver and spleen may be enlarged and tender. The urine, if any, is brown or black in color and contains casts, red cells, free hemoglobin, and methemoglobin. The blood is brownish in color, and the plasma contains free hemoglobin and free methemoglobin. The red cell count is very low and the white cell count high. Onset may be delayed as much as 12 hr. Death from sodium chlorate poisoning has occurred from 4 hr to 34 days after ingestion with an average of just over 4 days. [R48, 566] *Dermal absorption associated with agricultural use of sodium chlorate is not sufficient to cause systemic poisoning. Even by mouth, a large dose is required to produce illness. [R48, 566] *Sodium chlorate is a powerful oxidizing agent that causes methemoglobinemia, hemolytic anemia, and direct nephrotoxic effects. Coma and death within a few hr can result from either tissue hypoxia (severe methemoglobinemia), hyperkalemia from massive hemolysis, or acute renal failure compounded by hemoglobinuria. ... Within 2-24 hr, GI symptoms develop including nausea, vomiting, diarrhea, and abdominal pain. After absorption, hemoglobin rapidly oxidizes to methemoglobin, leading to cyanosis, dyspnea, and coma in severe cases. Intravascular hemolysis also can occur. [R50] *Swallowing solution or solid results in nausea, vomiting, and abdominal pain, and possibly kidney damage. [R29, 380] NTOX: *ALTHOUGH THE CAUSE OF DEATH FROM INGESTION ... SEEMS TO BE THE FORMATION OF METHEMOGLOBIN WITH CONSEQUENT TISSUE ANOXIA, THE RATE OF FORMATION OF METHEMOGLOBIN FROM HEMOGLOBIN IS RELATIVELY SLOW ... AND OTHER SIGNS USUALLY PRECEDE THE CYANOSIS AND DYSPNEA ASSOCIATED WITH METHEMOGLOBINEMIA. THESE ARE STAGGERING, PURGING, EVIDENCE OF ABDOMINAL PAIN, HEMOGLOBINURIA, AND HEMATURIA ... IN ACUTE POISONING /BY INGESTION OF/ LARGE AMOUNTS. ... DEATH MAY OCCUR SUDDENLY WITHOUT OBVIOUS SYMPTOMS. IN SUCH CASES, THE HISTORY OF SUDDEN DEATH, TOGETHER WITH THE APPEARANCE OF "TARRY" BLOOD EXUDING FROM NOSTRILS, ANUS AND VULVA, MAY LEAD TO CONFUSION WITH ANTHRAX. [R55, 39] *... POISONING OF 15 CATTLE WITH 6 DEATHS /WAS RECORDED/ FOLLOWING APPLICATION OF ... SODIUM CHLORATE TO ... A FIELD. IN ANOTHER CASE, 2 CATTLE DIED AND OTHERS SHOWED SYMPTOMS AFTER APPROXIMATELY 0.4 KG OF SODIUM CHLORATE HAD BEEN SCATTERED ONTO A PASTURE TO KILL THISTLES. SODIUM CHLORATE SPRAYS SEEM TO HAVE LOWER TOXICITY FOR SHEEP THAN FOR CATTLE, FOR NO HARMFUL EFFECTS WERE OBSERVED IN SHEEP GRAZING PLOTS, HEAVILY SPRAYED WITH HERBICIDE, OVER A PERIOD OF 7 DAYS. [R55, 38] *SODIUM CHLORATE SHOWED ORAL LD OF ABOUT 2 G/KG IN DOGS. ORAL DOSE OF 1 G/KG RESULTED IN SEVERE METHEMOGLOBINEMIA AND DEATH OF ANOTHER DOG WITH PRE-EXISTING CHRONIC INTERSTITIAL NEPHRITIS. [R56] *TOXICITY OF CHLORATE TO DOMESTIC ANIMALS: HORSE 250 G LETHAL; COW 500 G LETHAL; CALF 260 MG/KG NO EFFECT; CALF 525 MG/KG NO EFFECT; COW 0.1-0.25 G/KG FOR 5 DAYS DARK BROWN URINE, METHEMOGLOBINEMIA. TOXICITY OF CHLORATE FOR DOMESTIC ANIMALS: COW 0.06-0.18 G/KG FOR 3 DAYS ANOREXIA, WATERY FECES, COW WENT DOWN; SHEEP 10 G OR MORE PRODUCES METHEMOGLOBINEMIA; CHICKEN 5 G/KG LETHAL; DOGS 0.5-2.0 G/KG LD50 IN 2-4 DAILY DOSES. [R57] *Phytotoxic to all crops. [R9] *The minimum lethal dose is of the order of 1 g/kg body wt in cattle, 1.5-2.5 g/kg body wt in sheep, and 5 g/kg body wt in poultry. ... Although the cause of death following chlorate ingestion appears to be the tissue anoxia resulting from methemoglobinaemia, the rate of methemoglobin formation is relatively slow and other signs usually precede cyanosis and dyspnea. These include staggering, purging, evidence of abdominal pain, hemoglobinuria, and hematuria. In acute chlorate poisoning, death may occur suddenly, without development of obvious clinical signs. In such cases, the history of sudden death, together with the appearance of 'tarry' blood exuding from the nostrils, anus, and vulva, may lead to confusion with anthrax. ... The post-mortem changes associated with chlorate poisoning include a characteristic dark, chocolate brown colored blood, with more or less pronounced brownish discoloration of the organs and tissues. In chlorate poisoning, methemoglobin formation continues after death. [R51, 29] *Poisoned dogs showed post mortem evidence of marked splenic congestion and moderately severe chronic interstitial nephritis. Peak blood methemoglobin levels occurred 1 hr following iv administration of 0.5 g/kg body wt of sodium chlorate, while in animals which died the values were still rising 5 hr after sodium chlorate administration. [R51, 30] HTXV: *Death invariably follows a dose of 100 g. [R58] NTXV: *LD50 Rat oral 1200 mg/kg; [R28] *LD50 Mouse ip 596 mg/kg; [R48, 565] *LD50 Mouse oral 8350 mg/kg; [R38, 2953] *LD50 Rabbit oral 7200 mg/kg; [R38, 2954] ADE: */CHLORATES/ ... ARE READILY ABSORBED FROM THE ALIMENTARY TRACT, BUT NOT FROM THESKIN. /CHLORATES/ [R53, 158] *CHLORATE ... IS RAPIDLY EXCRETED UNCHANGED BY THE KIDNEYS, EXCRETION BEING COMPLETE IN 2 DAYS. /CHLORATES/ [R53, 159] *IT IS READILY ABSORBED THROUGH BOTH ROOTS AND LEAVES AND MAY BE TRANSLOCATED THROUGHOUT PLANT. [R59] *Absorbed through the roots and foliage, with translocation basipetally in the xylem, as the phloem tissue is killed. The rate of respiration is increased, catalase activity decreased, and the plant's food reserves are depleted. [R9] ACTN: *The effects of sodium chlorate on human erythrocytes were studied in vitro. A concn dependent lag phase was seen before methemoglobin was formed. After prolonged incubation, methemoglobin could no longer be reduced with methylene blue. Several other effects were observed: increased permeability to cations, increased resistance to hypotonic hemolysis, and prolonged filtration time through polycarbonate membranes. This suggests an increased membrane rigidity due to membrane protein polymerization, as demonstrated by SDS polyacrylamide gel electrophoresis. Simultaneously, erythrocyte enzymes were inactivated, primarily glucose 6-phosphate dehydrogenase, which is necessary for the therapeutic effect of methylene blue. This explains the inefficacy of methylene blue in the treatment of chlorate poisoning. [R60] *In the body it produces methemoglobin, a process involving the conversion of iron from the normal ferrous state to the ferric state. In addition, chlorate destroys red blood corpuscles, liberating hemoglobin and other proteins. The intact red cell has considerable power to reduce methemoglobin, but the mechanism apparently cannot operate after hemolysis. [R48, 565] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *A dose of 5-10 g can prove fatal in adults, as can a dose of 2 g in small children. [R9] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ FATE: *AT 300 KG/HECTARE, /SODIUM CHLORATE/ GIVES CONTROL FOR ABOUT 0.5 YR BUT IS LEACHED BY HIGH RAINFALL. [R61] *IT IS SOL IN WATER TO 75% AND IS MOST PERSISTENT IN AREAS OF LOW RAINFALL WHERE IT MAY REMAIN TOXIC AS LONG AS 5 YR. [R59] *Terrestrial fate: Remains in soil for 0.5 to 5 years, depending upon rate of application, soil type, fertility, organic matter content, moisture, and weather conditions. [R9] ABIO: */SODIUM CHLORATE/ IS A POTENT OXIDIZING AGENT REACTING WITH ORGANIC MATERIALS. [R61] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Sodium chlorate is exempted from the requirement of atolerance for residues in or on the following raw agricultural commodities when used as a defoliant, desiccant, or fungicide in accordance with good agricultural practice: beans (dry, edible); corn (fodder, forage, and grain); cottonseed; flaxseed; flax (straw); guar beans; peas (southern); peppers (chili); rice (including straw); safflower (grain); sorghum (grain, fodder, and forage); soybeans; and sunflower seed. [R62] WSTD: STATE DRINKING WATER GUIDELINES: +(ME) MAINE 7 ug/l /Chlorate ion/ [R63] FIFR: *Sodium chlorate is exempted from the requirement of atolerance for residues in or on the following raw agricultural commodities when used as a defoliant, desiccant, or fungicide in accordance with good agricultural practice: beans (dry, edible); corn (fodder, forage, and grain); cottonseed; flaxseed; flax (straw); guar beans; peas (southern); peppers (chili); rice (including straw); safflower (grain); sorghum (grain, fodder, and forage); soybeans; and sunflower seed. [R62] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Sodium chlorate is found on List D. Case No: 4049; Pesticide type: Herbicide, antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): sodium chlorate; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R64] FDA: *Sodium chlorate is an indirect food additive for use only as a component of adhesives. [R65] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 7300. Analyte: Sodium Matrix: Air. Sampler: Filter (0.8-um, cellulose ester membrane). Flow Rate: 1 to 4 l/min. Sample Size: 500 liters. Shipment: Routine. Sample Stability: Stable. /Sodium/ [R66] ALAB: *COLORIMETRIC METHOD DEVELOPED FOR DETERMINATION OF CHLORATE RESIDUES IN SOIL IS DESCRIBED AT 533 NM. [R67] *PRODUCT ANALYSIS IS EITHER BY REACTION WITH ACIDIFIED POTASSIUM BROMIDE AND POTASSIUM IODIDE FOLLOWED BY TITRATION WITH SODIUM THIOSULFATE, OR BY ADDING EXCESS OF IRON(II) SALT AND TITRATION WITH POTASSIUM DICHROMATE. [R68] *For macro analysis use Methods Clearing House Method 3300; National Formulary 1X p. 398 (1950) [R12, 274] *Product analysis is by titration (CIPAC Handbook, 1970, 1, 626; ibid., 1992, E, 197-201; Herbicides 1977, p 41). Residues in soil may be determined by colorimetry of a derivative. [R10] *Analysis of residual chlorate herbicides bu ion chromatography in water and soil. /Chlorate herbicides/ [R69] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for sodium chlorate is in progress. Route: dosed-water feed; Species: water disinfection byproducts, rats and mice. [R70] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 641 R3: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Sodium chlorate (7775-09-9). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of October 24, 2002. R4: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 518 R5: Farm Chemicals Handbook 1984. Willoughby, Ohio: Meister Publishing Co., 1984.,p. C-208 R6: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1052 R7: Farm Chemicals Handbook 1998. Willoughby, OH: Meister Publishing Co., 1998.,p. C-356 R8: Augustin-Beckers PWM et al; Rev Env Contam Tox 137: 1-82 (1994) R9: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A294/AUG 87 R10: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 1110 R11: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 888 R12: Ahrens, W.H. Herbicide Handbook of the Weed Science Society of America. 7th ed. Champaign, IL: Weed Science Society of America, 1994. R13: Algicide composition; Jpn Kokai Tokkyo Koho PATENT NO 81 49309 05/02/81 (Nippon Soda Co, Ltd) R14: Chem Purch 19(8): 17-21 (1983) R15: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. R16: Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983. R17: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 346 (1980) R18: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V5 (93) 999 R19: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R20: CHEMICAL PROFILE: Sodium Chlorate, 1984 R21: Kavaler AR; Chemical Marketing Reporter 231 (21): 50 (1987) R22: Chemical Marketing Reporter; Chemical Profile Sodium Chlorate. June 17, 1996. NY,NY: Schnell Pub Co (1996) R23: BUREAU OF THE CENSUS. CURRENT INDUSTRIAL REPORTS: INORGANIC CHEMICALS 1984 p.5 R24: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 944 R25: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-351 R26: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-9 R27: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 4-98 R28: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 61 R29: Armour, M.A. Hazardous Laboratory Chemicals Disposal Guide. Boca Raton, FL: CRC Press Inc., 1991. R30: National Research Council. Drinking Water and Health. Volume 7. Washington, DC: National Academy Press, 1987. R31: Shiu WY et al; Rev Environ Contam Toxicol 116: 15-187 (1990) R32: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-140 R33: Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-315 R34: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 3. New York: Marcel Dekker, Inc., 1977. 114 R35: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R36: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. R37: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 988 R38: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R39: LAMB JA; SODIUM CHLORATE EXPLOSION; CHEM BR 15 (3): 125-6 (1979) R40: REIMER B; NACHR PFLANZENSCHUTZ DDR 30 (10): 202-5 (1976) R41: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-178 R42: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 458 R43: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R44: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1359 R45: 49 CFR 171.2 (7/1/96) R46: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997.,p. 212-3 R47: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.5072, 5072-1 (1988) R48: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. R49: Steffen C, Seitz R ; Arch Toxicol 48 (4): 281-8 (1981) R50: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1642 R51: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. R52: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R53: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. R54: STARVOU A ET AL; PRACTITIONER 221 (1323): 397-9 (1978) R55: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. R56: SHEAHAN BJ ET AL; RES VET SCI 12 (4): 387-9 (1971) R57: BUCK ET AL; CLINICAL AND DIAGNOSTIC VETERINARY TOXICOLOGY, 2ND ED, 167-8 (1976) R58: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 1097 R59: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 35 R60: Singelmann E et al; Toxicology 30 (2): 135-47 (1984) R61: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 749 R62: 40 CFR 180.1020 (7/1/91) R63: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R64: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.316 (Spring, 1998) EPA 738-R-98-002 R65: 21 CFR 175.105 (4/1/97) R66: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 7300-1 R67: REIFENSTEIN H, HEINISCH E; ARCH PFLANZENSCHUTZ 7 (1): 79-85 (1971) R68: Worthing, C. R. (ed.). Pesticide Manual. 6th ed. Worcestershire, England: British Crop Protection Council, l979. 477 R69: Kikuchi M et al; Sendai-shi Eisei Kenkyushoho (19): 267-70 (1990) R70: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 51 Record 84 of 1119 in HSDB (through 2003/06) AN: 734 UD: 200211 RD: Reviewed by SRP on 5/6/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-CYANIDE- SY: *M-44-cyanide-capsules-; *Caswell-No-758-; *CIANURO-DI-SODIO- (ITALIAN); *CYANIDE-OF-SODIUM-; *CYANOGRAN-; *CYANURE-DE-SODIUM- (FRENCH); *CYMAG-; *EPA-Pesticide-Chemical-Code-074002-; *HYDROCYANIC-ACID,-SODIUM-SALT-; *KYANID-SODNY- (CZECH) RN: 143-33-9 MF: *C-N-Na SHPN: UN 1689; Sodium cyanide, solid or solution IMO 6.1; Sodium cyanide, solid or solution STCC: 49 232 27; Sodium cyanide solution 49 232 28; Sodium cyanide, solid HAZN: P106; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. D003; /SRP:/ A waste containing sodium cyanide may (or may not) be characterized a hazardous waste following testing for the reactivity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. ASCH: Cyanide ion; 57-12-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Sodium cyanide can be prepared by heating sodium amide with carbon, by melting sodium chloride and calcium cyanamide together in an electric furnace ... [R1, 3127] *Molten sodium, ammonia and charcoal react to give a high grade (98%) sodium cyanide [R2, p. V7 765] FORM: *Powder [R3] *Grades: 30% soln; 73-75%; 96-98%; reagent; technical; briquettes granular. [R4] *The cyanide of commerce is 95-98% pure. [R5, 1475] *Mixtures of sodium cyanide with sodium chloride or carbonate for special uses are also marketed. [R5, 1475] *M-44 cyanide capsules; Pelletted/tabletted; 88.78% sodium cyanide (74002) [R6] *Sodium cyanide; crystalline; 99% sodium cyanide (74002) [R6] MFS: *Cyanco Co., P.O. Box 1999, Winnemucca, NV 89446 (702)623-1214; Production site: Winnemucca, NV 89446 [R7, 852] *Degussa-Huls, Corp., 65 Challenger Rd., Ridgefield Park, NJ 07660, (201)641-6100; Production site: Theodore, AL 36590 [R7, 852] *DuPont, Hq, 1007 Market St., Wilmington, DE 19898, (302)774-1000; DuPont Specialty Chemicals, DuPont Performance, Specialty, and Fine Chemicals; Production site: Memphis, TN 38127 [R7, 882] *FMC Corp., 200 East Randolph Dr., Chicago, IL 60601, (312)861-6000; Chemical Products Group; Alkali Chemicals Division; Production site: Green River, WY [R7, 882] *Sterling Chemicals, Inc., Hq, 1200 Smith St., Suite 1800, Houston, TX 77002, (713) 650-3700; Production site: Texas City, TX 77590 [R7, 882] OMIN: *U.S.: For use only by trained persons with permit or license. [R3] USE: */Former use/ Fumigating citrus and other fruit trees, ships, railway cars, warehouses [R5, 157] */FORMER USE/ AS RODENTICIDE [R8] *Cleaning metals; mfr of dyes and pigments, nylon int, chelating cmpd; extracting gold and silver from ores. [R4] *For rabbit, rat burrows and holes; termite nests [R3] *COMPONENT OF ELECTROPLATING SOLUTIONS, EG, FOR ZINC; COMPONENT OF SALTS FOR CASE HARDENING OF STEEL; AGENT FOR EXTRACTION OF GOLD AND SILVER FROM ORES; DEPRESSANT IN FROTH FLOTATION SEPARATION OF ORES; CHEM INT FOR PHENYLGLYCINE [R9] *Manufacture of hydrocyanic acid and many other cyanides [R5, 1475] *Chemical uses are in 5 general categories: dyes, including optical brighteners; agricultural chemicals; pharmaceuticals; chelating or sequestering agents; and specialties, preparation of nitriles, carbylamines, cyano fatty acids, and heavy metal cyanides, misc uses include heat-treating, metal stripping, and compounds for clearing smut [R2, p. V7 766] *Used as a single and multidose poison on pastures, range land, and forest lands for coyote, fox and wild dog. /M-44 cyanide capsules/ [R6] *Used as an insecticide and miticide for postharvest application for non-stored commodity of citrus or fumigation of trucks (feed/food-full). /Sodium cyanide, crystalline/ [R6] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 1.14X10+11 G [R9] U.S. IMPORTS: *(1978) 7.01X10+9 G [R9] *(1982) 7.45X10+9 G [R9] *(1985) 8.32X10+9 g [R10] *(1986) 2.77x10+7 lb [R11] U.S. EXPORTS: *(1978) 9.66X10+9 G [R9] *(1982) 9.96X10+9 G [R9] *(1985) 1.23X10+10 g [R12] *(1987) 9,031,377 lb [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White cubic crystals [R14]; *WHITE SOLID IN FORM OF GRANULES, FLAKES, OR EGGS (RESEMBLING CHICKEN EGGS) [R15]; *White, granular or crystalline solid. [R16] ODOR: *Odorless when perfectly dry, emits odor of hydrogen cyanide when damp [R5, 1475]; *Faint odor of bitter almonds [R17, 975]; *Faint almond-like odor. [R16] BP: *1496 deg C [R1, 3127] MP: *563 deg C [R14] MW: *49.0 [R5, 1475] CORR: *Corrosive to aluminum. [R18] DEN: *1.595 g/cu cm @ 20 deg C [R19] HTV: *3041 J/g [R2, p. V7 766] PH: *Aq soln strongly alkaline [R4] SOL: *48 G/100 CC WATER @ 10 DEG C [R20]; *82 G/100 CC WATER @ 35 DEG C [R20]; *Slightly sol in alcohol [R4] SPEC: *INDEX OF REFRACTION: 1.452 [R20] VAP: *1 mm Hg @ 817 deg C; 10 mm Hg @ 983 deg C [R1, 3127] VISC: *4 cP @ 30 deg C (26% aqueous soln) [R21, p. 7(79) 321] OCPP: *Soln readily dissolves gold and silver in presence of air [R5, 1475] *DELIQUESCES [R20] *Absorbs water from the air forming a syrup [R17, 975] *Heat of capacity: 1.40 @ 25-72 deg C; heat of fusion: 179 J/g; heat of formation: -89.9X10+3 J/mole (exothermic); heat of solution: -1548 J/mole; hydrolysis constant: 2.51X10-5 @ 25 deg C [R2, p. V7 766] *When heated in a dry carbon dioxide atmosphere, sodium cyanide fuses without much decomposition. Thermal dissociation of sodium cyanide has been studied in an atm of helium at 600-1050 deg C and in an atm of nitrogen at 1050-1255 deg C. It has been shown that vapor phase over melt contains decomposition products. [R21, p. 7(79) 321] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns, or death. Reaction with water or moist air will release toxic, corrosive or flammable gases. Reaction with water may generate much heat which will increase the concentration of fumes in the air. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R22, p. G-157] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Vapors may accumulate in confined areas (basement, tanks, hopper/tank cars etc.). Substance will react with water (some violently), releasing corrosive and/or toxic gases. Reaction with water may generate much heat which will increase the concentration of fumes in the air. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated or contaminated with water. [R22, p. G-157] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R22, p. G-157] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R22, p. G-157] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R22, p. G-157] +Fire: Note: Most foams will react with the material and release corrosive/toxic gases. Small fires: CO2 (except for Cyanides), dry chemical, dry sand, alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Use water spray or fog; do not use straight streams. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R22, p. G-157] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. A vapor suppressing foam may be used to reduce vapors. DO NOT GET WATER INSIDE CONTAINERS. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Prevent entry into waterways, sewers, basements or confined areas. Small spills: Cover with DRY earth, DRY sand, or other non-combustible material followed with plastic sheet to minimize spreading or contact with rain. Use clean non-sparking tools to collect material and place it into loosely covered plastic containers for later disposal. [R22, p. G-157] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R22, p. G-157] +Table of Water-Reactive Materials Which Produce Toxic Gases: Materials Which Produce Large Amounts of Toxic-by-Inhalation (TIH) Gas(es) When Spilled in Water: Name of Material: Sodium cyanide, Toxic Vapor (TIH) Produced: hydrogen cyanide. [R22, p. TABLE] +Table of Initial Isolation and Protective Action Distances (Sodium Cyanide when spilled in water): Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.5 kilometers (0.3 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 155 meters (500 feet); then, PROTECT persons Downwind during DAY 1.6 kilometers (1.0 miles) and NIGHT 4.2 kilometers (2.6 miles). [R22, p. TABLE] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R23] +Flammability: 0. 0= This degree includes any material that will not burn. [R23] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R23] FIRP: *Carbon dioxide fire extinguishers must not be used where cyanide salts are present. /Cyanide salts/ [R24] *Wear chemical protective suit with self-contained breathing apparatus. [R25] *Avoid carbon dioxide extinguishers. Extinguish fire using agent suitable for surrounding fire. Use water spray to keep fire-exposed containers cool. [R23] *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Use foam, dry chemical, or carbon dioxide. Use water spray to knock-down vapors. /Sodium cyanide solution/ [R17, 975] *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use foam, dry chemical, or carbon dioxide. Do not use water on material itself. If large quantities of combustibles are involved, use water in flooding quantities as spray and fog. Use water spray to knock-down vapors. /Sodium cyandie, solid/ [R17, 976] TOXC: *Toxic oxides of nitrogen are produced in fires involving this material. /Sodium cyanide solution; sodium cyanide, solid/ [R17, 975] OFHZ: +Not combustible, but if involved in a fire decomposes to produce hydrogen cyanide and oxides of nitrogen. [R23] EXPL: *Explodes if melted with nitrite or chlorate at about 450 deg C. [R26] REAC: *Violent reaction with fluorine /gas/, magnesium, nitrates, nitric acid ... [R26] *Hydrogen cyanide and mercury (II) cyanide: The cyanide, /mercury(II) cyanide/, is a friction-and impact-sensitive explosive and may initiate detonation of liquid hydrogen cyanide. Other metal cyanides are similar. /Metal cyanides/ [R27] *Dangerous; on contact with acid, acid fumes, water, or steam ... will produce toxic and flammable vapors of CN- and sodium oxide. [R26] *Cyanide may react with carbon dioxide in ordinary air to form toxic hydrogen cyanide gas. /Cyanide/ [R28, 1981.3] *Fusion of mixtures of metal cyanides with metal chlorates, perchlorates, or nitrates ... causes a violent explosion. /Metal cyanides/ [R29] *Contact with acids and acid salts causes immediate formation of toxic and flammable hydrogen cyanide gas. ... /Cyanides/ [R28, 1981.3] *Strong oxidizers (such as acids, acid salts, chlorates and nitrates) [Note: Absorbs moisture from the air forming a syrup]. [R16] DCMP: *... If involved in a fire decomposes to produce hydrogen cyanide and oxides of nitrogen. [R23] SERI: *Irritating to skin, eyes, and respiratory system. [R23] EQUP: *WHERE SKIN CAN BE EXPOSED ... PROTECTIVE CLOTHING, INCLUDING IMPERVIOUS HAND PROTECTION SHOULD BE PROVIDED. ... /CYANIDES/ [R30, 576] *Wear special protective clothing and positive pressure self-contained breathing apparatus. [R23] *Respirator Selection: Less than or equal to 25 mg/cu m: (1) Filter type respirators, approved for toxic dust, with half-mask (not applicable for calcium cyanide). (2) Chemical cartridge respirators with replaceable cartridge for toxic dusts and acid gases; With half-mask. Maximum service life 4 hr. Less than or equal to 50 mg/cu m: (1) Full-face gas mask, chest or back mounted type, with industrial size canister for toxic dust and hydrocyanic acid gas. Maximum service life 2 hr. (2) Type C supplied air-respirator, continuous-flow or pressure-demand type (positive pressure) with full facepiece. (3) Type A supplied-air respirator, (hose mask with blower) with full facepiece. Greater than 50 mg/cu m: (1) Self-contained breathing apparatus with positive pressure in full facepiece. (2) Combination supplied-air respirator pressure-demand type with auxiliary self-contained air supply. Emergency (no concentration limit): (1) Self-contained breathing apparatus with positive pressure in facepiece. (2) Combination supplied-air respirator, pressure-demand type, with auxiliary self-contained air supply. Evacuation or Escape (no concentration limit): (1) Self-contained breathing apparatus in demand or pressure-demand mode (negative or positive pressure). (2) Full-face gas mask, front or back mount type with industrial size canister for toxic dust and hydrocyanic acid gas. /Cyanide salts/ [R31] *Chemical safety goggles shall be worn by employees engaged in any operation wherein there is danger or likelihood that dusts or solutions of cyanide salts will come into contact with the eye. Full-length face shields with forehead protection shall be worn by employees engaged in any operation wherein there is danger or likelihood that dusts, molten salts, or solutions of cyanide salts may contact the face. /Cyanide salts/ [R32] *... Rubber gloves /should be worn/ when handling cyanide solutions ... [R25] *Wear appropriate personal protective clothing to prevent skin contact. [R16] *Wear appropriate eye protection to prevent eye contact. [R16] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R16] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R16] *Recommendations for respirator selection. Max concn for use: 25 mg/cu m. Respirator Class(es): Any supplied-air respirator. Any self-contained breathing apparatus with a full facepiece. [R16] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full face piece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R16] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister /SRP: rebreather or oxygen generating/ providing protection against the compound of concern and having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R16] OPRM: *If material not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. /Sodium cyanide solution/ [R17, 975] *If material not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Use water spray to knock-down vapors. Do not use water on material itself. /Sodium cyanide, solid/ [R17, 976] *Personnel protection: ... If contact with the material anticipated, wear appropriate chemical protective clothing. /Sodium cyanide, solid/ [R17, 976] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Sodium cyanide solution; sodium cyanide, solid/ [R17, 975] *When cyanide salts are used in fused salt baths, mechanical local exhaust ventilation should be provided to control any cyanide emissions. /Cyanide salts/ [R33] *Eyewash facilities and emergency showers shall be provided in areas where contact with ... cyanide salts as either solids or solutions is likely. Work clothing which has been contaminated by absorption of, or contact with, cyanide shall be thoroughly laundered before it is worn again. /Hydrogen cyanide and cyanide salts/ [R34] *If the clothing is to be laundered or otherwise cleaned to remove the cyanide, the person performing the operation should be informed of cyanide's hazardous properties. /Cyanides/ [R28, 1981.3] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *PERSONS WHO WORK WITH AND AROUND CYANIDE PREPN SHOULD BE GIVEN SPECIFIC DETAILED INSTRUCTIONS ON MANAGEMENT OF CYANIDE POISONING. /CYANIDES/ [R35, 905] *Food storage, preparation, and eating shall be prohibited in areas where HCN is used. Smoking and the carrying of tobacco and other smoking materials shall also be prohibited in these areas. Clean and sanitary lunchroom facilities, if provided, must be in non-exposure areas. ... Clothing-change and locker-room facilities shall be provided in a non-exposure area. Workers should be encouraged to shower after work and to change work clothing frequently. Showers and basin washing facilities shall be located in the locker-room area. /Hydrogen cyanide or cyanide salts/ [R34] *ATTENTION TO ... VENTILATION IS NECESSARY. ... BECAUSE OF THE LOW PERMISSIBLE EXPOSURE LEVEL ... COMPLETE ENCLOSURE OF PROCESS IS RECOMMENDED. ... THOSE WORKING WITH CYANIDE SALTS SHOULD BE INSTRUCTED THAT CONTACT WITH ACIDS WILL RELEASE HYDROGEN CYANIDE. WHERE EXPOSURE POTENTIAL EXISTS, WORKERS SHOULD BE TRAINED TO RECOGNIZE THE ODOR OF HYDROGEN CYANIDE AND WHEN ... DETECTED, WORK AREA SHOULD BE EVACUATED IMMEDIATELY. /CYANIDES/ [R30, 576] *Contact lenses should not be worn when working with this chemical. [R16] *The worker should immediately wash the skin when it becomes contaminated. [R16] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R16] *ALL CONTAINERS ... SHOULD BE KEPT COVERED OR IN EXHAUSTED HOOD WHEN NOT IN USE. ANY PROCESS THAT MAY RELEASE HYDROGEN CYANIDE SHOULD BE MECHANICALLY EXHAUSTED, WITH PROVISION FOR HIGHER RATE DURING EMERGENCIES. DIRECT READING INSTRUMENTS FOR DETERMINATION OF HYDROCYANIC ACID ARE AVAILABLE. /CYANIDES/ [R30, 576] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Two physician's treatment kits shall be immediately available to trained medical personnel at each plant where there is a potential for the release of, accidental or otherwise, or for contact with, hydrogen cyanide or cyanide salts. ... First-aid kits shall be immediately available at workplaces where there is potential for the release, accidental or otherwise, of hydrogen cyanide or a potential for exposure to cyanide salts. ... Pertinent medical records shall be maintained ... /SRP: for the duraton of employment plus 50 years [29 CFR 1910.1020]/ following the last exposure to hydrogen cyanide or cyanide salts. /Hydrogen cyanide and cyanide salts/ [R36] SSL: *AQ SOLN ... RAPIDLY DECOMPOSES ON STANDING. [R37] *Aqueous solutions of sodium cyanide are slightly hydrolyzed (Kh= 2.5X10-5) at ordinary temperatures to produce hydrogen cyanide. [R38] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R39] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R40] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R41] STRG: *Store in a cool, dry, well-ventilated location. Separate from water, acids, carbon dioxide. [R23] *Cyanide salts as solids must be stored in sealed or tightly closed containers. No hooks should be used in handling cyanide containers. ... Storage areas must be adequately ventilated to ensure that cyanide concentrations do not exceed the recommended workplace environmental limits. /Cyanide salts/ [R24] *ALL CONTAINERS OF CYANIDE SALTS SHOULD BE KEPT COVERED OR IN EXHAUST HOOD WHEN NOT IN USE. /CYANIDES/ [R30, 576] *Cyanide salts as solids or solutions must be ... protected from corrosion or damage. They should be stored so there is no contact with nitrate-nitrite mixtures or peroxides. /Cyanide salts/ [R21, p. 7(79) 326] CLUP: *WASTE CYANIDE SALTS FROM CASE HARDENING OF STEEL ARE DESTROYED BY REACTING THE SALTS AT 650-700 DEG C WITH WASTE FERRIC HYDROXIDE SLUDGES FROM VARIOUS SOURCES. /CYANIDE SALTS/ [R42] *Environmental considerations - Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. /Sodium cyanide, solid/ [R17, 976] *Environmental considerations - Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash or cement powder. Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. /Sodium cyanide solution/ [R17, 975] *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. Vapor knock down water is corrosive or toxic and should be diked for containment. /Sodium cyanide solution; sodium cyanide, solid/ [R17, 975] *Environmental considerations - Water spill: Add dilute caustic soda (sodium hydroxide). Add calcium hypochlorite ... Adjust pH to neutral (pH= 7). /Sodium cyanide solution; sodium cyanide, solid/ [R17, 975] *Spills of sodium cyanide ... solids may be shoveled carefully into containers, with care being taken that cyanide dust is not dispersed into the air. The residue after shoveling, or small spills, may be removed by dry vacuuming or flushing with a liberal quantity of water. [R43] *The electrodialysis through polyethylene membranes is used by the Legrand Copper Plating Co at Limoges, France to recover 3000 kg copper and 3400 kg sodium cyanide annually from wastewaters. [R44] *If cyanide is spilled ... 1. Ventilate area of spill. 2. Collect spilled material in the most convenient and safe manner for reclamation or for treatment in a cyanide disposal system. [R28, 1981.5] *REMOVAL OF COPPER, NICKEL, ZINC, CADMIUM AND CYANIDE FROM PLATING WASTEWATER BY ELECTROFLOTATION IS DISCUSSED. /CYANIDES/ [R45] *Keep water away from release. Avoid contact with dust, mist, or solution. Do not create dust. Prompt cleanup and removal are necessary. Shovel into suitable dry container. Control runoff and isolate discharged material for proper disposal. [R23] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D003; P106, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R46] *Cyanide salts should not be flushed into any drain which may contain or subsequently receive acid waste. ... Cyanide process waste solutions and flushings from spills should be passed through a cyanide waste disposal system. /Cyanide salts/ [R33] *Sodium cyanide is a poor candidate for incineration. [R47] *SMALL AMOUNTS OF AMMONIUM CHLORIDE-BUFFERED, AQUEOUS SODIUM CYANIDE WERE DECONTAMINATED WITH CALCIUM HYPOCHLORITE AT LESS THAN OR EQUAL TO 12 DEGREES, WHILE LARGER AMOUNTS OF CYANIDE WASTE WERE TREATED WITH HYPOCHLORITE FROM ANY SOURCE AT PH 10 TO CONVERT CYANIDE ION TO CYANATE ION. [R48] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic Treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 l/min. Administer amyl nitrite ampules as per protocol and physician order ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Cyanide and related compounds/ [R49, p. 387-8] *Advanced Treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer cyanide antidote kit as per protocol and physician order ... . Monitor and treat cardiac arrhythmias if necessary ... . Consider vasopressors to treat hypotension without signs of hypovolemia ... . Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Cyanide and related compounds/ [R49, 388] *Although a variety of agents are effective antidotes in the experimental animal (nitrites, dimethylaminophenol, cobalt EDTA, hydroxocobalamin, stroma-free methemoglobin solutions, pyruvate, thiosulfate, sulfur sulfanes, mercaptopyruvate, oxygen) only the three-step Eli-Lilly cyanide kit is approved in the US. /Cyanide/ [R50, 1481] */SRP: For patients treated with nitrites:/ Measurement of methemoglobin may be useful for assessing exposure. However, methemoglobin levels may be artificially low if not analyzed within a few hours after drawing the blood. Methemoglobin levels have been found to correlate with clinical symptoms in most cases. /Cyanide/ [R51, 912] *The use of the combination consisting of 4 g of hydroxoycobalamin and 8 g of sodium thiosulfate as an antidote in cases of cyanide poisoning is reviewed. The antidote, which has been used in France since 1970, has proved to be nontoxic and therefore can be given in cases where the diagnosis of cyanide poisoning is not absolutely certain. On the other hand, the Lilly Cyanide Antidote Kit, which has been approved for use in the USA for the same purpose, has been shown to be toxic and its use requires caution. The antidotal effectiveness of the association of hydroxoycobalamin and sodium thiosulfate has been demonstrated in mice and other animal species poisoned with cyanide. Most animal studies reveal a strong antidotal synergism between the two agents. In France, the efficacy of the antidotal combination has been proved in patients who have ingested as much as 1.5 g of potassium cyanide and have blood cyanide levels on the order of 15 ug/ml. In the USA, the antidotal combination is designated as an orphan drug by the FDA and studies have been started to validate its safety and efficacy before being approved for use in this country. /Cyanide/ [R52] MEDS: *Preplacement and annual medical examinations shall include: An initial or interim work and medical history with special attention to skin disorders and those non-specific symptoms, such as headache, nausea, vomiting, dizziness or weakness, that may be associated with chronic exposure. A physical examination giving particular attention to skin, thyroid, and the cardiovascular and upper respiratory systems. ... Two physicians treatment kits shall be immediately available to trained medical personnel at each plant where there is a potential for the release of, accidental or otherwise, or for contact with, hydrogen cyanide or cyanide salts. ... First-aid kits shall be immediately available at workplaces where there is potential for the release, accidental or otherwise, of hydrogen cyanide or a potential for exposure to cyanide salts. ... Pertinent medical records shall be maintained for 5 years following the last exposure to hydrogen cyanide or cyanide salts. /Cyanide salts/ [R36] *Initial medical examination /should include/: a complete history and physical examination ... to detect existing conditions that might place the exposed employee at incr risk and to establish a baseline for future health monitoring. ... Examination of cardiovascular, nervous, and upper resp systems, and thyroid should be stressed. The skin should be exam for evidence of chronic disorders. ... The aforementioned medical exam should be repeated on an annual basis. ... /Cyanides/ [R28, 1981.1] *Pre-placement and periodic examinations should include the cardiovascular and central nervous systems, liver and kidney function, blood, history of fainting and dizzy spells. Blood cyanide levels may be useful during acute intoxication. Urinary thiocyanate levels have been used but are nonspecific and are elevated in smokers. /Cyanides/ [R53] *Arterial Blood Gases: Arterial blood gases may be useful for monitoring of metabolic acidosis that can occur from cyanide poisoning. /Cyanide/ [R51, 912] *EKG Measurement: EKG monitoring may be useful since changes have been found with cyanide exposure. /Cyanide/ [R51, 912] *The assessment of cyanide exposure can be accomplished through measurement of cyanide. Most information found in the literature regarding monitoring for absorption of cyanide preferred the measurement of blood cyanide. ... Blood Reference Ranges: Normal - non-smokers, < 0.02 ug/ml; smokers, average 0.041 ug/ml; Exposed - Levels of < 0.2 ug/ml have been found to be non-toxic; however, levels of 0.5 - 1.0 ug/ml have been associated with tachycardia and flushing. Toxic - Levels of 1.0 - 2.5 ug/ml have been associated with obtundation; coma and respiratory depression with levels greater than 2.5 ug/ml; death with values greater than 3 ug/ml. Serum or Plasma Reference Ranges: Normal - cyanide: nonsmoker, 0.004 ug/ml; smoker, 0.006 ug/ml; Exposed - not established; Toxic - cyanide; greater than 0.1 ug/ml. Urine Reference Ranges: Normal - not established; Exposed - not established; Toxic - not established. /Cyanide/ [R51, 911] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. /Cyanide/ [R51, 913] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. /Cyanide/ [R51, 913] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. /Cyanide/ [R51, 913] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. /Cyanide/ [R51, 914] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. /Cyanide/ [R51, 914] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell Assessment ... Visual Assessment ... Facial and Trigeminal Nerve Assessment ... Vestibular Assessment ... Hearing Assessment. /Cyanide/ [R51, 914] HTOX: *SYMPTOMATOLOGY: 1. Massive doses may produce, without warning, sudden loss of consciousness and prompt death from respiratory arrest. With smaller but still lethal doses, the illness may be prolonged for 1 or more hours. 2. Upon ingestion, a bitter, acrid, burning taste is sometimes noted, followed by a feeling of constriction or numbness in the throat. Salivation, nausea and vomiting are not unusual ... 3. Anxiety, confusion, vertigo, giddiness, and often a sensation of stiffness in the lower jaw. 4. Hyperpnea and dyspnea. Respirations become very rapid and then slow and irregular. Inspiration is characteristically short while expiration is greatly prolonged. 5. The odor of bitter almonds may be noted on the breath or vomitus ... 6. In the early phases of poisoning, an increase in vasoconstrictor tone causes a rise in blood pressure and reflex slowing of the heart rate. Thereafter, the pulse becomes rapid, weak, and sometimes irregular. ... A bright pink coloration of the skin due to high concentrations of oxyhemoglobin in the venous return may be confused with that of carbon monoxide poisoning. /Cyanide/ [R54, p. III-126] *SYMPTOMATOLOGY: 7. Unconsciousness, followed promptly by violent convulsions, epileptiform or tonic, sometimes localized but usually generalized. Opisthotonos and trismus may develop. Involuntary micturition and defecation occur. 8. Paralysis follows the convulsive stage. The skin is covered with sweat. The eyeballs protrude, and the pupils are dilated and unreactive. The mouth is covered with foam, which is sometimes bloodstained. ... The skin color may be brick red. Cyanosis is not prominent in spite of weak and irregular gasping. In the unconscious patient, bradycardia and the absence of cyanosis may be key diagnostic signs. 9. Death from respiratory arrest. /Cyanide/ [R54, p. III-127] *MOST SPECIFIC PATHOLOGICAL FINDING IN ACUTE CASES /OF CYANIDE POISONING/ IS BRIGHT RED COLOR OF VENOUS BLOOD. THIS IS STRIKING, VISIBLE EVIDENCE OF INABILITY OF TISSUE CELLS TO UTILIZE OXYGEN ... VENOUS BLOOD IS ONLY ABOUT 1 VOL % LOWER IN OXYGEN CONTENT THAN ARTERIAL BLOOD ... /CYANIDES/ [R1, 3125] *WORKERS IN ELECTROPLATING INDUST HAVE SHOWN DERMATITIS TO BE A PROBLEM. ALSO REPORTED WERE ITCHING, SCARLET RASH, PAPULES ... IRRITATION OF NOSE, LEADING TO OBSTRUCTION, BLEEDING, SLOUGHS, AND IN SOME CASES PERFORATION OF SEPTUM. /CYANIDES/ [R30, 575] *... ENLARGED THYROID GLANDS /WERE REPORTED/ IN WORKERS EXPOSED TO CYANIDE SALTS IN HEAT TREATMENT OF METALS. IT WAS SUGGESTED THAT ABSORPTION OF CYANIDE DUST AND HYDROGEN CYANIDE PRODUCED BY HYDROLYSIS OF CYANIDE SALTS, WAS FOLLOWED BY METABOLISM TO THIOCYANATE, AND THAT FAILURE TO ELIMINATE THIS ... CAUSED GOITROGENIC EFFECT. /CYANIDE SALTS/ [R55] *... IT IS POSSIBLE FOR CYANIDE TO CAUSE BLINDNESS AND TO DAMAGE OPTIC NERVES AND RETINA. /CYANIDE/ [R56] *A STUDY WAS UNDERTAKEN TO ASSESS THE HEALTH STATUS OF WORKERS EXPOSED TO CYANIDE FUMES AND AEROSOLS IN A FACTORY. CYANIDE LEVELS WERE MEASURED IN THE WORK ENVIRONMENT AND IN BLOOD AND URINE. SMOKERS HAD HIGHER CONCENTRATIONS THAN NON-SMOKERS. THE HIGHEST LEVELS WERE 0.8 and 0.2 MG/CU M IN BREATHING ZONE AND GENERAL WORKROOM ATMOSPHERE, RESPECTIVELY. THE WORKERS COMPLAINED OF TYPICAL CYANIDE POISONING IN SPITE OF THE LOW CONCN. ... /CYANIDES/ [R57] *THE TLV FOR ALKALI CYANIDES ... IS BASED ON ADDED IRRITATION CAUSED BY ALKALINITY, SUFFICIENT TO RESULT IN EPISTAXIS (NOSEBLEED) AND NASAL ULCERATION. AIR CONCN OF CYANIDE FROM ALKALI CYANIDES PRODUCING THIS EFFECT (NOSEBLEED) DID NOT GREATLY EXCEED 5 PPM. /ALKALI CYANIDES/ [R58] *Cyanides are absorbed from the skin and mucosal surfaces and are ... dangerous when inhaled because toxic amt are ... absorbed through bronchial mucosa and alveoli. Symptoms, which /may/ occur ... are giddiness, headache, palpitation, dyspnea, and unconsciousness. There may be some evidence of local irritation from the salts and nausea and vomiting. ... Central nervous depression. ... Early electrocardiographic changes may include atrial fibrillation, ectopic ventricular beats, and abnormal QRS complex with T wave originating high on the R wave. Sinus bradycardia is a common presenting sign. As cyanide levels in the blood rise, ataxia develops and is followed by coma, convulsions, and death. /Cyanides/ [R59] *Signs and symptoms of acute cyanide poisoning reflect cellular hypoxia and are often nonspecific. Onset of symptoms depends on dose, route, and duration of exposure. Inhalation produces ... flushing, headache, tachypnea, and dizziness ... irregular stridulous breathing, coma, seizure, and death ... /Cyanide/ [R50, 1478] *WHEN ABSORBED, /CYANIDE/ ... REACTS READILY WITH ... CYTOCHROME OXIDASE IN MITOCHONDRIA; CELLULAR RESPIRATION IS THUS INHIBITED AND CYTOTOXIC HYPOXIA RESULTS. ... RESPIRATION IS /INITIALLY/ STIMULATED ... A TRANSIENT STAGE OF CNS STIMULATION WITH HYPERPNEA AND HEADACHE IS OBSERVED; FINALLY THERE ARE HYPOXIC CONVULSIONS AND DEATH DUE TO RESPIRATORY ARREST. /CYANIDE/ [R60, 1642] *SODIUM CYANIDE PRODUCES ALL TYPICAL SYMPTOMS OF OTHER SOURCES OF CYANIDE ION. IT CAN PRODUCE ACUTE SYMPTOMS BY INHALATION AND BY SKIN ABSORPTION AS WELL AS BY INGESTION. FATAL DOSAGE BY ORAL INGESTION WILL VARY CONSIDERABLY DEPENDING ON WHETHER OR NOT FOOD IS PRESENT IN STOMACH, ETC. IT IS PROBABLY ON ORDER OF 1-2 MG/KG ... [R1, 3127] *VOLATILE CYANIDES /SRP: AND ALL AIRBORNE CYANIDE SALTS/ RESEMBLE HYDROCYANIC ACID PHYSIOLOGICALLY, INHIBITING TISSUE OXIDN AND CAUSING DEATH THROUGH ASPHYXIA. CYANOGEN IS PROBABLY AS TOXIC AS HYDROCYANIC ACID ... /CYANIDES/ [R61] *In minimal lethal doses, cyanide affects primarily the central nervous system. Cyanide initially stimulates the peripheral chemoreceptors, causing increased respirations. It also promotes slowing of the heart by stimulating the carotid body receptors. The electrical activity of the brain may stop while the heart is still beating. /Cyanide/ [R50, 1478] *The most common symptoms of a long-term cyanide exposure that has exceeded current standards have been headache, dizziness, nausea or vomiting, and a bitter or almond taste. Mild abnormalities of vitamin B12, folate, and thyroid function have been noted, but symptoms did not correlate with these changes. Other excessive exposures to cyanide have resulted in psychosis and thyroid enlargement without symptoms of thyroid dysfunction. Several clinical syndromes have been associated with chronic cyanide toxicity ... . These diseases may be due to high cyanide levels, impaired cyanide detoxification mechanisms, nutritional deficiencies, or some combination of these factors. /Cyanide/ [R50, 1479] *In serious poisonings, the skin is cold, clammy, and diaphoretic. Cyanosis may be a late finding, since poor tissue utilization of oxygen results in elevated venous oxygen levels. Retinal veins and arteries may appear similar in color because of the elevated venous oxygen level. /Cyanide/ [R50, 1479] *Depression of the cardiovascular system requires cyanide doses higher than those necessary for depression of the CNS. Initial tachycardia occurs followed by bradycardia.. Dysrhythmias and hypotension often precede peripheral vascular collapse. The ECG may display striking ischemic changes; pulmonary edema may complicate severe intoxications. /Cyanide/ [R50, 1479] *The CNS is the most sensitive target organ of cyanide poisoning, with early stimulation followed by CNS depression. Early symptoms include lightheadedness, giddiness, tachypnea, nausea, vomiting, feeling of neck constriction and suffocation, confusion, restlessness, and anxiety. Initial tachypnea results from direct stimulation of carotid body chemoreceptors followed by respiratory depression. Severe cyanide poisonings progress to stupor, coma, opisthotonus, convulsions, fixed dilated pupils, and death. /Cyanide/ [R50, p. 1478-9] *Workers, such as electroplaters and picklers, who are daily exposed to cyanide solutions may develop a "cyanide" rash, characterized by itching and by mascular, papular, and vesicular eruptions. [R26] *Exposure to small amounts of cyanide compounds over long periods of time is reported to cause loss of appetite, headache, weakness, nausea, dizziness, and symptoms of irritation of the upper respiratory tract and eyes. [R26] *Because cyanide salts are rapidly absorbed from mucous membranes, symptoms following acute inhalation of or mucous membrane contact with toxic concentrations of cyanide salts may begin within seconds to a few minutes after exposure. [R62] NTOX: *CYANIDES SUCH AS ... HYDROGEN CYANIDE, POTASSIUM CYANIDE AND SODIUM CYANIDE ARE ACUTELY POISONOUS, INTERFERING WITH METABOLIC PROCESSES AND CAUSING RAPID DEATH. IN SEVERE POISONING, PUPILS ARE CHARACTERISTICALLY WIDELY DILATED. [R63] *Acute systemic toxicity of hydrogen cyanide, sodium cyanide, and potassium cyanide by instillation into the inferior conjunctival sac was investigated in rabbits. LD50 value of hydrogen cyanide was 0.103 mmol/kg. Signs of toxicity appeared rapidly and death occurred within 3 to 12 min after instillation of cyanide into the conjunctival sac of the rabbit. Thus, following ocular instillation, cyanides may be absorbed across the conjunctival blood vessels in amounts sufficient to produce systemic toxicity. [R64] *THE TERATOGENIC POTENTIAL OF SODIUM CYANIDE WAS EVALUATED IN THE GOLDEN HAMSTER. INFUSION WAS BY MEANS OF SC IMPLANTED OSMOTIC MINIPUMPS BETWEEN DAYS 6 AND 9 OF GESTATION. INFUSION OF SODIUM CYANIDE AT DOSE RATES OF 0.126, 0.1275, AND 0.1295 MMOL/KG/HR PRODUCED HIGH INCIDENCES OF MALFORMATIONS AND RESORPTIONS IN THE OFFSPRING. MOST COMMON ANOMALIES WERE NEURAL TUBE DEFECTS, INCLUDING EXENCEPHALY AND ENCEPHALOCELE. OTHERS OCCURRED LESS FREQUENTLY AND INCLUDED HYDROPERICARDIUM AND CROOKED TAIL. A TOTAL DOSE EQUIVALENT TO 30-40 TIMES THE ACUTE SC LD50 DOSE WAS ADMIN BY INFUSION TO THESE ANIMALS BEFORE SIGNS OF MATERNAL TOXICITY APPEARED. [R65] *WILD COYOTES WERE TESTED IN ACUTE ORAL TOXICITY TESTS AND TOXIC-COLLAR TESTS USING THE COMPOUNDS SODIUM CYANIDE AND DIPHACINONE. FIVE COYOTES RECEIVED 4, 8, 16, 32, OR 64 MG/KG SODIUM CYANIDE BY ORAL SYRINGE IN THE ACUTE TEST. RESULTS SHOWED SURVIVAL OF THE ONE ANIMAL GIVEN 4 MG/KG; THE OTHERS DIED WITHIN 2 MINUTES AFTER DOSING. IN TOXIC-COLLAR EXPERIMENTS 6 COYOTES WERE ALLOWED TO ATTACK SHEEP FITTED WITH COLLAR CONTAINING EITHER DIPHACINONE OR SODIUM CYANIDE. ONLY 1 OF THE COYOTES THAT PUNCTURED A SODIUM CYANIDE COLLAR INGESTED A LETHAL DOSE OF THE POISON, WHEREAS 3 COYOTES THAT PUNCTURED DIPHACINONE COLLARS ALL RECEIVED LETHAL AMOUNTS OF THE ANTICOAGULANT. [R66] *IN EXPTL ANIMALS, DEMONSTRATION OF EFFECTS OF CYANIDE POISONING ON RETINA AND OPTIC NERVE HAS BEEN SUCCESSFUL PRINCIPALLY WITH ACUTE SEVERE, NEAR-LETHAL OR LETHAL POISONINGS. /CYANIDES/ [R56] *IN RABBITS, AFTER SUBLETHAL DOSES OF CYANIDE, CHANGES IN ELECTRORETINOGRAM HAVE BEEN OBSERVED. /CYANIDE/ [R63] *The significance of various physiological factors contributing to the pathogenesis of experimental cyanide encephalopathy, such as the systemic atrial blood pressure, venous pressure, common carotid blood flow, and local blood flow of the cerebral grey and white matters, and blood gas including pH, is examined. The histology and topography of the brain damage was also analyzed. Twenty-one cats were divided into four groups. The animals in groups 1, 2, and 3 were subject to continuous infusion of 0.2% sodium cyanide soln and to the ensuing hypotension below 100 mm Hg by administering a ganglion-blocking drug and by respiratory arrest. Severe damage developed in the deep cerebral white matter, corpus callosum, pallidum, and substantia nigra, but the damage of the cerebral cortex and hippocampus was not remarkable. The animals in group 4 that were subject to sodium cyanide infusion without significant hypotension (> 100 mm Hg), but to the same degree of acidosis as that of the other groups, had similar morphological changes, but to a lesser degree. Apparently, the pathophysiological factors of tissue hypoxia and subsequent hypotension operated in cyanide leucoencephalopathy. The topography selectivity related to the characteristic cerebral vascular system, and the severity of the white matter lesions, was related to the intensity of both hypoxia and hypotension during cyanide infusion, but not to the extent of acidosis, total dose of cyanide, or duration of its infusion. ... [R67] *... The acute toxicity of 11 chemicals to rainbow trout (Salmo gairdneri) fry (average weight 1 g) that had been reared for about 8 wk on 1 of 5 diets. Chemicals tested against the fish included sodium cyanide. Responses of the fish to the chemicals were consistent in all 5 groups. No group demonstrated superior resistance to these chemicals. Diet appears to have little influence on the sensitivity of young rainbow trout to chemicals in acute toxicity tests. [R68] *Intact neutrophils killed opsonized Actinobacillus actinomycetemcomitans under aerobic and anaerobic conditions, and the kinetics of these reactions indicated that both oxidative and nonoxidative mechanisms were operative. Oxidative mechanisms contributed significantly, and most of the killing attributable to oxidative mechanisms was inhibited by sodium cyanide, which suggested that the myeloperoxidase-hydrogen peroxide-chloride system participated in the oxidative process. [R69] *The participation of afferents from carotid and aortic bodies in the hyperventilation caused by cytotoxic hypoxia was assessed in pentobarbitone-anesthetized cats. Dose-response curves for the ventilatory effects induced by iv injections of sodium cyanide were obtained before and after successive denervations of peripheral chemoreceptors, in different sequences. Bilateral aortic neurotomy or unilateral carotid neurotomy did not affect significantly the minimal sensitivity to the drug, although maximal reactivity was reduced in some cats. After bilateral carotid neurotomy, with preservation of aortic nerves, sensitivity was reduced, but hyperventilation was still provoked by large doses of cyanide. Bilateral aortic neurotomy and bilateral carotid neurotomy abolished the ventilatory responses to the drug. In cats with bilateral aortic neurotomy and unilateral carotid neurotomy, ventilatory responses had a high degree of correlation with increases of carotid chemosensory discharges in the range between approximately 200% of control and the gasping threshold. Thus, the aortic bodies of the cat play a significant role in the hyperventilation produced by cytotoxic hypoxia, although it is less marked than that induced through the carotid bodies. [R70] *In 6 animals breathing spontaneously through the intact upper airway, iv administration of respiratory stimulants (sodium cyanide or nicotine) produced a dose-related decrease in upper airway resistance. In 9 animals, upper airway resistance was measured across the isolated upper airway. The stimulants produced a dose-related decrease in upper airway resistance. In both preparations inspiratory resistance fell at lower doses than expiratory resistance. Eventually a dose could be given which resulted in comparable, minimal values of resistance during both inspiration and expiration. Pharmacological challenge resulted in a change in the route of airflow (from nose only to nose-and-mouth breathing) as well a change in caliber of the airway at the level of the naso-pharynx and hyoid appendage. In anesthetized dogs, respiratory stimulants will decrease upper airway resistance by increasing activation of upper airway muscles which may enlarge the airway, change the route of flow, and thus overcoming collapsing forces produced by increased chest wall muscle activation. [R71] *The renal vasodilatory effects of cholinergic drugs, and the relation between hemodynamic and natriuretic changes, were investigated by comparing intrarenal infusions of sodium cyanide to that of acetylcholine in 5 mongrel dogs. Infusion of /each/ compound resulted in immediate and ipsilateral increases in the fractional excretion of sodium, potassium, calcium and magnesium. Each agent increased the renal plasma flow to the same extent. Regression plots of the relation between changes in sodium excretion and changes in renal plasma flow were similar for both agents. [R72] *In cats, reflex hyperpnea produced by sodium cyanide was mediated by both carotid and aortic nerves and the response was greater when both carotid nerves were intact than when only 1 was intact. [R73] *... In explanted chick embryos ... sodium cyanide above a concn of 5x10-3 M inhibited development of the central nervous system with less effect on heart development. [R74] *Toxic effects of zinc cyanide complexes were similar to those of sodium cyanide, whereas adult Leptomysis Mediterranean was less sensitive to sodium cyanide (LC50 88 ug cyanide/l) and zinc cyanide complexes than to cadmium cyanide complexes. This may be due to toxic effects of cadmium besides those of cyanide. The invertebrates are more sensitive to cyanide than fish which are used at present as standard aqueous indicator organisms. [R75] *IF ... ANIMALS ... HAVE EATEN CYANOGENIC PLANTS, CLINICAL SIGNS MAY VARY FROM MILD TACHYPNEA AND APPARENT ANXIETY TO SEVERE PANTING, GASPING, AND BEHAVIORAL ALARM. OTHER SIGNS INCL SALIVATION, MUSCLE TREMORS, LACRIMATION, URINATION AND DEFECATION, SEVERE COLIC, EMESIS, PROSTRATION, ... CLONIC CONVULSIONS, MYDRIASIS, AND RAPID DEATH. ... MUCOUS MEMBRANES ARE ... PINK AND BLOOD IS CHERRY RED AND MAY NOT CLOT. RED COLOR IS DUE TO HYPEROXYGENATION THAT OCCURS WHILE THE ANIMAL IS DYING. THERE MAY BE AGONAL HEMORRHAGES ON HEART. GI TRACT AND LUNG MAY HAVE CONGESTION AND PETECHIAL HEMORRHAGES. /CYANOGENIC PLANTS/ [R76] *IN THE CASE OF HYDROCYANIC ACID AND CYANIDES /IN VERY HIGH DOSES/, DEATH USUALLY OCCURS /IN ANIMALS/ WITHIN A FEW SECONDS: THERE MAY BE CONVULSIONS, PARALYSIS, STUPOR, AND CESSATION OF RESPIRATION BEFORE THAT OF HEARTBEATS. /CYANIDES/ [R77] *Except for the more sensitive invertebrate species, such as Daphnia pulex and Gammarus pseudolimnaeus, invertebrate species are usually more tolerant of cyanide than are freshwater fish species, which have most acute values clustered between 50 to 200 ug/l. A long-term survival and two life cycle test with fish gave chronic values of 7.9, 14, and 16 ug/l, respectively, with Gammarus pseudolimnaeus being comparable to fish in sensitivity and isopods being considerably more tolerant. /Free cyanide: HCN and CN-/ [R78] *... /THERE IS A/ COMBINED EFFECT OF PULMONARY EDEMA AND THE INTERFERENCE OF CELLULAR METABOLISM BY THE CYANIDE RADICAL. /CYANIDE ION/ [R79] *The LD50s of sodium cyanide for black vulture (Coragyps atratus), American kestrel (Falco sparverius), Japanese quail (Coturnix japonica), domestic chicken (Gallus domesticus), eastern screech owl (Otus asio), and European starling (Sturnus vulgaris) were 4.8, 4.0, 9.4, 21, 8.6, and 17 mg/kg, respectively. The LD50s for the flesh eating birds (vulture, kestrel, and owl) were lower (4.0-8.6 mg/kg) than LD50s for birds (quail, chicken, starling) that feed predominantly on plant material (9.4-21 mg/kg). [R80] *Salmonella typhimurium strain (OASS positive) synthesize a toxic but non mutagenic metabolite from cyanide and O-acetylserine. Salmonella typhimurium mutant DW379 (OASS deficient) is neither able to carry out this reaction in vitro nor produce the toxic metabolite in vivo. L-Cysteine reverses the cyanide metabolite mediated inhibition and thus allows OASS positive strains to grow in medium containing cyanide and O-acetylserine. The toxic metabolite is ninhydrin-positive, adheres strongly to the cation-exchange column, and migrates in thin layer chromatography to an Rf value similar to that of beta-cyanoalanine. [R81] *The major detoxification pathway for cyanide (CN) in many species is a biotransformation to the less toxic thiocyanate (SCN). Hepatic thiosulfate: cyanide sulfurtransferase (rhodanese) is the principal enzyme demonstrating in vitro catalytic activity. Despite the assumed importance of the hepatic enzyme for cyanide detoxification in vivo, the effects of liver damage (surgical or chemical) on cyanide lethality in animals have not been examined previously. Male CD-1 mice were pretreated with carbon tetrachloride (CCl4, 1 ml/kg, ip) 24 hr prior to the administration of sodium cyanide (NaCN). In other experiments, carbon tetrachloride was given in the same doses at both 48 hr and 24 hr prior to sodium cyanide. Hepatotoxicity was documented by elevated serum glutamicpyruvic transaminase (SGPT) activity, by histologic evaluation of the extent of cellular necrosis, by electron microscopy of the mitochondrial fraction, and by the increased duration of zoxazolamine-induced paralysis. Lethality was not changed by carbon tetrachloride pretreatments when sodium cyanide was given alone in doses of 4 or 6 mg/kg or at a dose of 10.7 mg/kg following sodium thiosulfate (1 g/kg, ip). A statistically significant protective effect was exhibited by carbon tetrachloride when sodium cyanide was given at a dose of 16 mg/kg following the administration of sodium thiosulfate. Rhodanese activity as measured in mitochondrial preparations fractionated from the livers of mice pretreated with carbon tetrachloride was not different from that in animals given the corn oil vehicle even though electron micrographs showed extensive mitochondrial damage. No difference in cyanide lethality was evident between sham operated mice and partially (2/3) hepatectomized mice at 24 hr post-surgery. [R82] *In cats, a dose of 1.2 mg/kg was fatal; Dogs a dose of 2.25 mg/kg caused death in 48 hours. In monkeys a dose of 0.8 mg/kg altered ECG patterns, similar to humans. [R83] *Glomus cells of the rabbit excised carotid body were slightly depolarized by sodium cyanide, a response that occurred slowly and with a gradual onset. In contrast, dopamine and acetylcholine strongly depolarized the cells. The membrane potential responses to sodium cyanide appeared to be indirect. [R84] *The swimming performance of guinea pigs was degraded following administration of sodium cyanide at doses which were not lethal for individual animals. Decrements in performance were observed two minutes following subcutaneous administration of sodium chloride, were maximal at 8-16 min and, at the highest dose tested, did not return to control levels until 64-128 min. Pretreatment with p-aminopropiophenone at a dose inducing 7-15% methemoglobinemia, 15-19 minutes after administration, protected animals against the effects of sodium cyanide upon swimming performance. However, the protection decreased as the interval between p-aminopropiophenone and NaCN was increased from 15 to 75 minutes. [R85] NTXV: *Inorganic cyanides are acutely toxic compounds, for example, the LD50 in the rat is 15 mg/kg for sodium cyanide ..; [R86] *LD50 Rat oral 6440 ug/kg; [R26] *LD50 Rat ip 4300 ug/kg; [R26] *LD50 Mouse ip 5881 ug/kg; [R26] *LD50 Mouse sc 3660 ug/kg; [R26] *LD50 Mouse un 10 mg/kg; [R26] *LD50 Rabbit intramuscular 1666 ug/kg; [R26] *LD50 Rabbit ocular routes 5048 ug/kg; [R26] POPL: *WORKERS WITH CHRONIC DISEASES OF KIDNEYS, RESPIRATORY TRACT, SKIN OR THYROID ARE AT GREATER RISK OF DEVELOPING TOXIC CYANIDE EFFECTS THAN ARE HEALTHY WORKERS. /CYANIDES/ [R30, 576] ADE: *IN 30 DAYS, 72% OF (14)C FROM AN IP DOSE OF (14)C-CYANIDE TO MICE WAS EXCRETED IN URINE AND FECES, 25% IN EXPIRED AIR AND 3% WAS RETAINED IN ANIMALS. PEAK EXCRETION OCCURRED WITHIN 10 MIN IN EXPIRED AIR AND WITHIN 6-24 HR IN URINE AND FECES. /CYANIDE/ [R87] *CYANIDES ARE RAPIDLY ABSORBED FROM SKIN AND ALL MUCOSAL SURFACES AND ARE MOST DANGEROUS WHEN INHALED, BECAUSE TOXIC AMT ARE ABSORBED THROUGH BRONCHIAL MUCOSA AND ALVEOLI. /CYANIDES/ [R59] *THE CYANIDE ION IS READILY ABSORBED AFTER ORAL OR PARENTERAL ADMIN. PROLONGED LOCAL CONTACT WITH CYANIDE SOLN ... MAY RESULT IN ABSORPTION OF TOXIC AMT THROUGH SKIN. PART OF ABSORBED CYANIDE IS EXCRETED UNCHANGED BY THE LUNG. LARGER PORTION ... IS CONVERTED BY SULFURTRANSFERASE RELATIVELY NONTOXIC TO THIOCYANATE ION. /CYANIDE/ [R35, 904] *As estimated in rats given 30 mg sodium cyanide intraperitoneally over a period of 8 days, 80 percent of the total cyanide is excreted in the urine in the form of thiocyanate. [R88] *Cyanide is distributed to all organs and tissues via the blood, where its concn in red cells is greater than that in plasma by a factor of two or three. /Cyanides/ [R89] *Once absorbed into the body, cyanide can form complexes with heavy metal ions. /Cyanide/ [R90] *Acute systemic toxicity of hydrogen cyanide, sodium cyanide, and potassium cyanide by instillation into the inferior conjunctival sac was investigated in rabbits. LD50 value of hydrogen cyanide was 0.103 mmol/kg. Signs of toxicity appeared rapidly and death occurred within 3 to 12 min after instillation of cyanide into the conjunctival sac of the rabbit. Thus, following ocular instillation, cyanides may be absorbed across the conjunctival blood vessels in amounts sufficient to produce systemic toxicity. [R64] *Inhalation of cyanide salt dusts is dangerous because the cyanide will dissolve on contact with moist mucous membranes and be absorbed into the bloodstream. /Cyanide salts/ [R91] *Cyanide is concentrated in red blood cells at a RBC/plasma ratio is 100/l. The volume of distribution of cyanide ion is approximately 1.5 l/kg. About 60% if CN- in plasma is protein bound. /Cyanide/ [R50, 1478] METB: *OPOSSUMS WERE DOSED WITH SODIUM CYANIDE BY ... STOMACH TUBE. ... ANALYSIS INDICATED THAT MAJOR ROUTE OF DETOXICATION ... WAS BY CONVERSION TO THIOCYANATE, WHICH WAS EXCRETED IN URINE. TRACES OF 2-IMINO-4-THIAZOLIDINE CARBOXYLIC ACID WERE OBSERVED IN CRUDE CONCENTRATED EXTRACT OF URINE. [R92] *... CYANIDE ION IS CONJUGATED WITH SULFUR TO FORM THIOCYANATE. ... CONJUGATION IS CATALYZED BY THE ENZYME RHODANESE WHICH IS WIDELY DISTRIBUTED IN MOST ANIMAL TISSUES EXCEPT BLOOD, LIVER BEING PARTICULARLY ACTIVE. ... THE RHODANESE MECHANISM IS CAPABLE OF DETOXICATING ONLY LIMITED AMT OF CYANIDE, SUCH AS ARE FORMED DURING NORMAL METAB. /ANOTHER SULFUR DONOR IS 3-MERCAPTOPYRUVATE. THE ENZYME, MERCAPTOSULFUR TRANSFERASE IS LOCALIZED IN CYTOSOL./ /CYANIDE/ [R93] *Salmonella typhimurium strain (OASS positive) (OASS, O-acetylserine sulfhydrylase) synthesize a toxic but non-mutagenic metabolite from cyanide and O-acetylserine. Salmonella typhimurium mutant DW379 (OASS deficient) is neither able to carry out this reaction in vitro nor produce the toxic metabolite in vivo. L-Cysteine reverses the cyanide metabolite mediated inhibition and thus allows OASS positive strains to grow in medium containing cyanide and O-acetylserine. The results suggest that the enzyme O-acetylserine sulfhydrylase catalyzes the reaction of cyanide and O-acetylserine to form the toxic metabolite. This metabolite from ninhydrin-positive, adheres strongly to the cation-exchange column, and migrates in thin layer chromatography to an Rf value similar to that of beta-cyanoalanine. [R81] */ONE OF/ THE MAJOR MECHANISMS FOR REMOVING CYANIDE FROM THE BODY IS ITS ENZYMATIC CONVERSION, BY THE MITOCHONDRIAL ENZYME RHODANESE (TRANSSULFURASE), TO THIOCYANATE, WHICH IS RELATIVELY ... /LESS TOXIC/. /CYANIDE/ [R60, 1643] *FACTORS THAT INCR LIKELIHOOD OF HYDROGEN CYANIDE POISONING FROM INGESTION OF CYANOGENIC PLANTS INCLUDE: (1) LARGE AMT OF FREE HYDROGEN CYANIDE AND CYANOGENIC GLYCOSIDE IN PLANT, (2) RAPID INGESTION; (3) INGESTION OF A LARGE AMT OF PLANT, and (4) RUMINAL PH AND MICROFLORA THAT CONTINUE TO HYDROLYZE GLYCOSIDE /SRP: TO RELEASE HYDROGEN CYANIDE/ RAPID INTAKE OF PLANT ... EQUIV TO ABOUT 4 MG HYDROGEN CYANIDE/KG OF BODY WT IS CONSIDERED TO BE LETHAL AMOUNT OF PLANT MATERIAL. ... /CYANOGENIC PLANTS/ [R76] *RUMINANTS ARE MORE SUSCEPTIBLE TO POISONING BY CYANOGENIC PLANTS /SRP: WHICH RELEASE HYDROGEN CYANIDE/ THAN ARE HORSES AND PIGS ... /CYANOGENIC PLANTS/ [R77] BHL: *Half-life for the conversion of cyanide to thiocyanate from a non-lethal dose in man is between 20 min and 1 hr. /Cyanide/ [R94] ACTN: *CYANIDE HAS A VERY HIGH AFFINITY FOR IRON IN THE FERRIC STATE. WHEN ABSORBED, /CYANIDE/ ... REACTS READILY WITH TRIVALENT IRON OF CYTOCHROME OXIDASE IN MITTCHONDRIA; CELLULAR RESPIRATION IS THUS INHIBITED AND CYTOTOXIC HYPOXIA RESULTS. SINCE UTILIZATION OF OXYGEN IS BLOCKED, VENOUS BLOOD IS OXYGENATED AND IS ALMOST AS BRIGHT RED AS ARTERIAL BLOOD. RESPIRATION IS STIMULATED BECAUSE CHEMORECEPTIVE CELLS RESPOND AS THEY DO TO DECREASED OXYGEN. A TRANSIENT STAGE OF CNS STIMULATION WITH HYPERPNEA AND HEADACHE IS OBSERVED; FINALLY THERE ARE HYPOXIC CONVULSIONS AND DEATH DUE TO RESPIRATORY ARREST. /CYANIDE/ [R60, 1642] *SINGLE DOSES OF CYANIDE PRODUCE ALTERATIONS IN PATTERN OF BRAIN METABOLITES CONSISTENT WITH DECR IN OXIDATIVE METABOLISM AND INCR IN GLYCOLYSIS. DECR IN BRAIN GAMMA-AMINOBUTYRIC ACID ... HAVE BEEN ASCRIBED TO CYANIDE INHIBITION OF GLUTAMIC ACID DECARBOXYLASE. /CYANIDE/ [R54, p. III-126] *THE CORTICAL GRAY MATTER, HIPPOCAMPUS (H1), CORPORA STRIATA, AND SUBSTANTIA NIGRA ARE COMMONLY AFFECTED. ... CYANIDE ALSO HAS PROPENSITY FOR DAMAGING WHITE MATTER, PARTICULARLY CORPUS CALLOSUM. CYANIDE INHIBITS CYTOCHROME OXIDASE AND PRODUCES CYTOTOXIC ANOXIA, BUT ALSO CAUSES HYPOTENSION THROUGH ITS EFFECTS ON HEART. /CYANIDE/ [R95] *Evoked release of transmitter at the squid giant synapse was examined under conditions where the calcium ion concentration in the presynaptic terminal was manipulated by inhibitors of calcium sequestration. Simultaneous intracellular recordings of presynaptic and postsynaptic resting action potentials were made during bath application of various metabolic inhibitors including sodium cyanide. Cyanide reversibly depressed the post-synaptic potential. The progressive reduction of post-synaptic potential amplitude was accompanied by a reversible increase in synaptic delay. The time course of block of the post-synaptic potential was similar for different agents and dependant on the rate of presynaptic activity (30-40 min at 0.01 Hz). Recovery of the post-synaptic action potential following block by cyanide was obtained within 40 min. Synaptic depression by the metabolic inhibitors does not result from changes in the presynaptic resting or action potentials, nor from a change in post-synaptic receptor sensitivity. The post-synaptic response to local ionophoresis of L-glutamate was unchanged following the inhibition of evoked release of transmitter by cyanide. Injections of EDTA into presynaptic terminals poisoned by cyanide produced transient increases in post-synaptic potential amplitude, suggesting that cyanide is having its effect through raising intracellular calcium rather than lowering ATP. Control experiments injecting EDTA into unpoisoned nerve terminals showed no apparent effect on evoked transmitter release. [R96] *The effects of carotid body chemoreceptor stimulation by sodium cyanide on respiration and phrenic nerve activity were studied in intact and vagotomized rabbits. In intact animals an intracarotid injection of 30 ug of sodium cyanide resulted in an elevation of phrenic nerve activity and a rapid onset of respiratory excitation associated with an increase in respiratory rate and the response was markedly potentiated after vagotomy. The change in respiratory rate was primarily due to a decrease in expiration time in intact animals, whereas it resulted from a pronounced decrease in inspiration time in vagotomized animals. Apparently, a suppressive effect of the vagus nerve on carotid body chemoreceptor reflex occurred. An induction of a continuous increase in phrenic nerve activity accompanied by apneustic respiration by intracarotid dopamine was another evidence to support the /observation/. [R97] *The major detoxification pathway for cyanide in many species is a biotransformation to the less toxic thiocyanate. Hepatic thiosulfate: cyanide sulfurtransferase (rhodanese) is the principal enzyme demonstrating in vitro catalytic activity. Despite the assumed importance of the hepatic enzyme for cyanide detoxification in vivo, the effects of liver damage (surgical or chemical) on cyanide lethality in animals have not been examined previously. Male CD-1 mice pretreated with carbon tetrachloride (CCl4, 1 mg/kg, ip 24 hr prior to the administration of sodium cyanide. In other experiments carbon tetrachloride was given in the same doses at both 48 hr and 24 hr prior to sodium cyanide. Hepatotoxicity was documented by elevated serum glutamic pyruvic transaminase (SGPT) activity, by histologic evaluation of the extent of cellular necrosis, by electron microscopy of the mitochondrial fraction, and by the increased duration of zoxazolamine-induced paralysis. Lethality was not changed by carbon tetrachloride pretreatments when sodium cyanide was given alone in doses of 4 or 6 mg/kg or at a dose of 10.7 mg/kg following sodium thiosulfate (sodium sulfide, 1 g/kg, ip). A small but statistically ... protective effect was exhibited by CCl4 when sodium cyanide was given at a dose of 16 mg/kg following the administration of sodium sulfide. Rhodanese activity as measured in mitochrondrial preparations fractionated from the livers of mice pretreated with carbon tetrachloride was not different from that in animals given the corn oil vehicle even through electron micrographs showed extensive mitochondrial damage. No difference in cyanide lethality was evident between sham-operated mice and partially (2/3) hepatectomized mice at 24 hr post-surgery. An intact healthy liver does not appear to be essential for cyanide detoxification in mice whether or not thiosulfate is also given. Because rhodanese activity was slightly but ... higher in mitochondria lysed by Triton X-100 than in intact mitochondria, the mitochondrial membrane may constitute a barrier to sodium sulfide. [R98] *Presumably, the accumulation of cyanide in erythrocytes is a reflection of its binding to methemoglobin. [R99] *The cyanide ion (CN-) ... forms complexes with a number of other chemicals (eg, in tissues) and has a strong affinity for cobalt. /Cyanide ion/ [R76] *Human lymphocytes were irradiated by (60)Co gamma-rays after 0, 10, 20, 35, 45, 48, and 49.5 hr of incubation. Immediately after irradiation sodium cyanide, sodium fluoride, or monoiodoacetic acid was given for 2.5 hr. Non irradiated cells were subject to the same treatments. Chromosomal aberrations were analyzed in metaphase cells of the first mitosis. When administered alone, all chemicals increased the frequency of chromatid aberrations. The special analysis showed that these chemicals were not mutagens in a strict sense, as the observed increase of aberration frequency was due to inhibition of repair process, which increased the probability of manifestation of spontaneous changes (so-called "pseudomutagenesis"). The same chemicals increased the frequency of radiation-induced aberrations during two periods of mitotic cycle, namely, in the end of the G1 stage and in the G2 stage. [R100] */CYANIDE/ ... REACTS ... WITH TRIVALENT IRON OF CYTOCHROME OXIDASE IN MITOCHONDRIA TO FORM THE CYTOCHROME OXIDASE-CN COMPLEX ... THE CYTOCHROME-OXIDASE-CN COMPLEX IS DISSOCIABLE; THE MITOCHONDRIAL ENZYME SULFURTRANSFERASE ... MEDIATES TRANSFER OF SULFUR FROM THIOSULFATE TO CYANIDE ION. THUS, THIOCYANATE IS FORMED ... KINETIC STUDIES INDICATE THAT THE CLEAVAGE OF THE THIOSULFATE SULFUR-SULFUR BOND IS THE RATE-LIMITING STEP IN THIS REACTION. RELATIVELY MINOR PATHWAYS INCL COMBINATION WITH CYSTINE TO FORM 2-IMINO-THIAZOLIDINE-4-CARBOXYLIC ACID, OXIDATION TO CARBON DIOXIDE AND FORMATE, AND FORMATION OF CYANOCOBALAMIN. /CYANIDE/ [R60, 1642] INTC: *FASTED MONGREL DOGS WERE SUBJECTED TO SODIUM THIOSULFATE INFUSION FOLLOWED BY SODIUM CYANIDE ADMIN (1 MG/KG) 30 MIN LATER. A PHARMACOKINETIC MODEL SHOWED THAT SODIUM THIOSULFATE INCREASED THE RATE OF CONVERSION OF CYANIDE TO THIOCYANATE BY A FACTOR OF 36.5; ALSO, IT REDUCED THE APPARENT VOLUME OF DISTRIBUTION OF CYANIDE. [R101] *ATTEMPTS WERE MADE TO EVALUATE THE EFFECTS OF PRETREATMENT WITH AIR AND OXYGEN EITHER ALONE OR IN VARIOUS COMBINATIONS WITH SODIUM NITRITE AND/OR SODIUM THIOSULFATE ON THE PHYSIOLOGIC DISPOSITION OF SODIUM (14)C-CYANIDE IN MICE. OXYGEN EITHER ALONE OR IN COMBINATION WITH SODIUM THIOSULFATE ... ENHANCED THE RESPIRATORY EXCRETION WHEN COMPARED WITH AIR. SODIUM THIOSULFATE ACCELERATED THE INITIAL RATE, BUT NOT THE TOTAL AMOUNT OF RADIOACTIVITY EXCRETED. THE CUMULATIVE RECOVERY OF RADIOACTIVE GASES WAS ... GREATER WITH GROUPS RECEIVING OXYGEN EITHER ALONE OR WITH SODIUM THIOSULFATE. NO SIGNIFICANT DIFFERENCES BETWEEN VARIOUS EXPERIMENTAL GROUPS WERE NOTED IN THE TOTAL AMOUNT OF URINARY RADIOACTIVITY EXCRETED OR THE TOTAL BODY RETENTION OF RADIOACTIVITY. [R102] *Previous reports indicated that prophylactic protection against cyanide intoxication in mice can be enhanced by administration of chlorpromazine when it is given with sodium thiosulfate. The mechanism of potentiation of sodium thiosulfate by chlorpromazine was studied alone and in combination with sodium nitrite. Although chlorpromazine was found to induce a hypothermic response, the mechanism of enhancement of the antagonism of cyanide by chlorpromazine does not correlate with the hypothermia produced. Various other possible mechanisms were investigated, such as rate of methemoglobin formation, enzymatic activity of rhodanese and cytochrome oxidase, and alpha-adrenergic blockade. The alpha-adrenergic blocking properties of chlorpromazine may provide a basis for its antidotal effect, since this protective effect can be reversed with an alpha-antagonist, methoxamine. /Cyanide/ [R103] *The effects of tribuyltin and sodium cyanide on hemolysis in human erythrocytes are described. Tributyltin has a sharp cut take off concentration for induction of hemolysis. A 5 uM concentration of tributyltin induces hemolysis and 1 uM or less does not in erythrocyte suspensions with lysis are sigmoidal indicating a complex molecular mechanism leading to lysis. Ten mM sodium cyanide plus 1 uM tributyltin does not stimulate hemolysis rates above levels observed with 10 mM sodium cyanide alone. Five nM sodium cyanide plus hemolytic concentrations of tributyltin stimulates hemolysis rates synergistically compared with either cyanide or tributyltin alone. Ultrastructurally, hemolytic concentrations of tribuyltin can be visualized in the electron microscope by osmium staining during fixation as electron dense spheres penetrating the lipid bilayer of the erythrocyte plasma membrane. Ten mM sodium cyanide plus 25 uM tributyltin increases slightly the size of osmiophilic structures in erythrocyte membranes compared with those spheres seen in cells exposed to 25 uM tribuyltin alone. Sodium cyanide is the only compound tested that stimulates tributyltin induced hemolysis. [R104] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *In bacteria, cyanide production has been observed in Chromobacterium violaceum and certain species of Pseudomonas. /Cyanide/ [R105] ARTS: *Material containing cyanide compounds disposed of on land may lead to elevated levels of cyanide in underlying strata and in groundwater. /Cyanides/ [R106] FATE: *Aquatic Fate: The alkali metal salts are very soluble in water, and as a result, they readily dissociate into their respective anions and cations upon release to water. The resulting cyanide ion may then form hydrogen cyanide or react with various metals present in natural water. If the cyanide ion is present in excess, complex metallocyanides may form; however, if metals are prevalent, simple metal cyanides may form. [R107] RTEX: */IN ELECTROPLATING/ ... SODIUM BATH CONTAINS SODIUM CYANIDE ... ... [R108] *... SYMPTOMS OF CHRONIC DISEASE ... REPORTED IN ELECTROPLATERS AND SILVER POLISHERS AFTER SEVERAL YEARS OF EXPOSURE. /CYANIDES/ [R30, 575] *AMONG FUMIGATORS ... CYANIDE POISONING IS RECOGNIZED ... /CYANIDES/ [R30, 575] *DERMATITIS ... IN WORKERS CHRONICALLY EXPOSED TO CYANIDE SOLN. ELECTROPLATERS SUFFER FROM SUCH IRRITATION. /CYANIDE SOLN/ [R109] BODY: *Cyanide is present in normal healthy human organs at concentrations ranging up to 0.5 mg/kg. /Cyanide/ [R110] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *25 mg/cu m (as CN) [R16] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 mg/cu m). Skin Designation. /Cyanides, as CN/ [R111] NREC: *Recommended Exposure Limit: 10 Min Ceiling Value: 4.7 ppm (5 mg/cu m). [R16] TLV: *Ceiling limit 5 mg/cu m, skin [R112] OOPL: *Inorganic cyanide standards: Bulgaria 0.3 mg/cu m; Czechoslovakia 3-15 mg/cu m; Finland 7 mg/cu m; Federal Republic of Germany 5 mg/cu m; Hungary 0.3 mg/cu m; Poland 0.3 mg/cu m; Romania 0.3 mg/cu m; USSR 0.3 mg/cu m; and Yugoslavia 5 mg/cu m. /Calcium, potassium, sodium, Cyanide salts/ [R113] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 200 ug/l /Cyanide ion/ [R114] FEDERAL DRINKING WATER GUIDELINES: +EPA 200 ug/l /Cyanide ion/ [R114] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 220 ug/l /Cyanide ion/ [R114] +(ME) MAINE 154 ug/l /Cyanide ion/ [R114] +(MN) MINNESOTA 100 ug/l /Cyanide ion/ [R114] CWA: +Sodium cyanide is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R115] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R116] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Sodium cyanide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100 lbs. [R117] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R118] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Sodium cyanide is included on this list. [R119] *Manufacturers and processors of sodium cyanide are required to conduct chemical fate and terrestrial effects tests under TSCA section 4. [R120] RCRA: *P106; As stipulated in 40 CFR 261.33, when sodium cyanide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R121] */SRP:/ D003; A solid waste containing sodium cyanide may become characterized as a hazardous waste when subjected to testing for reactivity as stipulated in 40 CFR 261.23, and if so characterized, must be managed as a hazardous waste. [R122] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA 1988 were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Sodium cyanide is found on List C. Case No: 3086; Pesticide type: rodenticide; Case Status: Reregistration Eligibility Decision Approved 9/94, PB95-173514 - OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): sodium cyanide; Data Call-in (DCI) Date(s): 9/30/92; AI Status: Reregistration Eligibility Decision Completed - OPP has completed a Reregistration Eligibility document for the case/AI. [R123] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Analyte: Sodium; Matrix: air; Sampler: filter (0.8 um cellulose membrane); Flow rate: 1-4 l/min; Vol: min: 13 l, max: 2000 l; Stability: stable /Elements, Sodium/ [R124] ALAB: *ION SELECTIVE ELECTRODE: FRANK, ROSE AND RISEMAN; ANAL CHEM (44) 2227 (1972); FLUOROMETRY: DANCHIK AND BOLTZ; ANAL CHIM ACTA (49) 567 (1970); GAS CHROMATOGRAPHY: VALENTOUR, AGGARWAL AND SUNSHINE; ANAL CHEM (46) 924 (1974); ION SELECTIVE ELECTRODE, FLUOROMETRY, AND CHROMATOGRAPHY USED TO DETERMINE SODIUM CYANIDE. *A GAS CHROMATOGRAPHIC METHOD FOR DETERMINING RESIDUES OF SODIUM CYANIDE IN VEGETATION AND SOIL IS PRESENTED. SOIL PLOTS WERE TREATED WITH 0.88 G OF SODIUM CYANIDE. VERY SMALL AMOUNTS WERE FOUND IN THE VEGETABLE AND SOIL SAMPLES TAKEN 2 DAYS AFTER TREATMENT INDICATING THE CONTAMINATION OF THE ENVIRONMENT FROM THE USE OF M-44 CARTRIDGES WHICH CONTAIN SODIUM CYANIDE IS NOT LIKELY TO OCCUR. [R125] *Color reaction: Oxidation of hemoglobin to methemoglobin, which reacts with cyanide to form cyanomethemoglobin. This compound has a characteristic red color and a characteristic absorption spectrum. /Total Cyanide/ [R126] *Colorimetric method: Pyridine-pyrazolone. /Total Cyanide/ [R127] *Seven methods for the analysis of simple cyanides have been investigated including: 1) An ion-exchange procedure; 2) A continuous flow distillation; 3) An EDTA electrode method; 4) The AISI aeration method; 5) An EDTA aeration method; 6) The modified Roberts-Jackson method; and 7) The EPA method for Cyanides Amenable to Chlorination. Of all the seven procedures studied, the modified Roberts-Jackson method is the best. It gives complete recovery for all but one of the simple cyanides without decomposing the complex cyanides. ... It has the unique ability to perform accurately in the presence of both sulfide and thiocyanate. A lower limit of 2 ppb + or - 1 ppb is possible with a precision of + or - 10% above 10 ppb. ... The ligand-exchange procedure appears to be the most advantageous method of analysis of total cyanides. /Total Cyanides/ [R128] *EPA Method 9010: Colorimetric, Manual. Method 9010 is used to determine the concentration of inorganic cyanide in an aqueous waste or leachate. The method detects inorganic cyanides that are present as either simple soluble salts or complex radicals. It is used to determine values for both total cyanide and cyanide amenable to chlorination; it is not intended to determine if a waste is hazardous by the characteristic of reactivity. The cyanide, as hydrocyanic acid, is released by refluxing the sample with strong acid and distillation of the hydrogen cyanide into an absorber-scrubber containing sodium hydroxide solution. The cyanide ion in the absorbing solution is then manually determined colorimetrically by converting the cyanide to cyanogen chloride by reaction with chloramine-T at a pH less than 8 without hydrolyzing the cyanate. ... Color is formed on addition of the pyridine-barbituric acid reagent. In a single laboratory, using mixed domestic and industrial waste samples at concentrations of 0.06, 0.13, 0.28, and 0.62 mg cyanide/l, the standard deviations were + or - 0.005, + or - 0.007, + or - 0.031, and + or - 0.094, respectively. In a single laboratory, using mixed industrial and domestic waste samples at concentrations of 0.28 and 0.62 mg cyanide/l, recoveries were 85% and 102%, respectively. /Total and Amenable Cyanide/ [R129] *REVIEW WHICH DISCUSSES THE METHODS AND LIMIT OF DETECTIONS OF CYANIDE IN NATURAL AND TREATED WATERS, INDUST EFFLUENTS, BIOLOGIC FLUIDS AND SOLIDS: GAS CHROMATOGRAPHY (25 NG/ML), FLUOROMETRY (1 PPB), ION-SELECTIVE ELECTRODES (25 UG/L) AND ABSORPTION SPECTROPHOTOMETRY (1-5 UG/L). /TOTAL CYANIDE/ [R130] *Indirect atomic absorption spectrometric analysis: (1) The complex dicyano-bis-(1,10-phenanthroline)-iron (II) is formed and then extracted into chloroform. The chloroform is evaporated and the residue is taken up in ethanol. The ethanol solution is aspirated directly into the flame, and iron equivalent to a known amount of cyanide is then determined. (2) The second method is based on precipitating silver cyanide, then determining the excess silver ion in the supernatant by atomic absorption spectrometry. /Total Cyanide/ [R131] CLAB: *CYANIDE MAY BE LIBERATED FROM BIOLOGICAL FLUIDS /BLOOD, URINE/ BY ACIDIFICATION. THE EVOLVED CYANIDE IS ABSORBED IN ALKALI AND SODIUM CYANIDE THUS FORMED IS QUANTITATIVELY DETERMINED BY MEASURING THE ABSORBANCE OF CHROMOPHORES FORMED BY INTERACTION OF THE CYANIDE ION WITH SUITABLE REAGENTS ... /ANOTHER/ PROCEDURE PRESENTS A SENISITIVE GAS CHROMATOGRAPHIC METHOD FOR DETERMINATION OF CYANIDE IN BIOLOGICAL SPECIMENTS, BASED ON ITS CONVERSION TO CYANOGEN CHLORIDE USING CHLORAMINE-T. /TOTAL CYANIDE/ [R132] *A FLUOROMETRIC MICRODIFFUSION METHOD IS DESCRIBED FOR DETERMINING CYANIDE IN BIOLOGICAL FLUIDS. THIS DETECTION IS BASED ON THE PRODUCTION OF FLUORESCENCE BY THE TREATMENT OF CN WITH P-BENZOQUINONE. /TOTAL CYANIDE/ [R133] *GAS CHROMATOGRAPHIC DETERMINATION OF CYANIDES IN BIOLOGICAL SPECIMENS BASED UPON ITS CONVERSION TO CYANOGEN CHLORIDE USING CHLORAMINE-T (SODIUM P-TOLUENE SULFONCHLORAMIDE) IS DISCUSSED. /TOTAL CYANIDE/ [R134] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts (1976) DHEW Pub. NIOSH 77-108 Nat'l Research Council Canada; Effects of Cyanides on Aquatic Organisms with Emphasis Upon Fresh Water Fishes (1982) NRCC No.19246 Health Effects Assessment for Sodium Cyanide Report; Iss EPA/540/1-86/012 Sodium cyanide; potassium cyanide: Cahiers de notes documentaries 118: 133-138 (1985) DHHS/ATSDR; Toxicological Profile for Cyanide (Update) TP-92/09 (1993) USEPA; Ambient Water Quality Criteria Doc: Cyanide (1984) EPA 440/5-84-028 USEPA; Ambient Water Quality Criteria Doc: Cyanides (1980) EPA 440/5-80-037 DHHS/NTP; NTP Technical Report on Toxicity Studies of Sodium Cyanide Administered in Drinking Water to F344/N Rats and B6C3F1 Mice Rpt No. 37 (1993) NIH Publication No. 94-3386 SO: R1: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. 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Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 94 R88: Wood JL, Cooley SL; J Biol Chem 218: 449 (1956) as cited in USEPA; Ambient Water Quality Criteria Doc: Cyanides p.C-14 (1980) EPA 440/5-80-037 R89: USEPA; Ambient Water Quality Criteria Doc: Cyanides p.C-9 (1980) EPA 440/5-80-037 R90: NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.45 (1976) DHEW Pub. NIOSH 77-108 R91: USEPA; Ambient Water Quality Criteria Doc: Cyanides p.C-7 (1980) EPA 440/5-80-037 R92: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.85 R93: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 96 R94: Feldstein M, Klendshoj NC; J Lab Chin Med 44: 166-70 (1954) as cited in NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.45 (1976) DHEW Pub. NIOSH 77-108 R95: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 372 R96: Adams DJ et al; J Physiol 369: 145-159 (1985) R97: Matsumoto S et al; Arch Int Pharmacodyn Ther 252 (2): 298-306 (1981) R98: Rutkowski JV et al; Toxicology 38 (3): 305-14 (1986) R99: USEPA; Ambient Water Quality Citeria Doc: Cyanides p.C-9 (1980) EPA 440/5-80-037 R100: Luchnik NV et al; Genetika (Moskva) 21 (2): 252-61 (1985) R101: SYLVESTER DM ET AL; PROC WEST PHARMACOL SOC 24: 135 (1981) R102: BURROWS GE ET AL; J TOXICOL ENVIRON HEALTH 10: 181-89 (1982) R103: Kong A et al; Toxicol Appl Pharmacol 71 (3): 407-13 (1983) R104: Gray BH et al; J Appl Toxicol 6 (4): 263-70 (1986) R105: Nat'l Research Council Canada; The Effect of Cyanides on Aquatic Organisms with Emphasis Upon Fresh Water Fishes p.47 (1976) NRCC No.19246 R106: Nat'l Research Council Canada; The Effect of Cyanides on Aquatic Organisms with Emphasis Upon Fresh Water Fishes p.49 (1982) NRCC No.19246 R107: DHHS/ATSDR; Toxicological Profile for Cyanide (Draft) p.76 (1/88) R108: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. 164 R109: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 224 R110: NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.48 (1976) DHEW Pub. NIOSH 77-108 R111: 29 CFR 1910.1000 (7/1/99) R112: American Conference of Governmental Industrial Hygienists. Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents Biological Exposure Indices for 1999. Cincinnati, OH: ACGIH, 1999. 42 R113: NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.190 (1976) DHEW Pub. NIOSH 77-108 R114: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R115: 40 CFR 116.4 (7/1/99) R116: 40 CFR 302.4 (7/1/99) R117: 40 CFR 355 (7/1/99) R118: 40 CFR 712.30 (7/1/99) R119: 40 CFR 716.120 (7/1/99) R120: 40 CFR 799.5000 (7/1/99) R121: 40 CFR 261.33 (7/1/99) R122: 40 CFR 261.23 (7/1/99) R123: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.257 (Spring, 1998) EPA 738-R-98-002 R124: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V1 7300-1 R125: OKUNO I ET AL; BULL ENVIRON CONTAM TOXICOL 22 (3): 386-90 (1979) R126: NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.97 (1976) DHEW Pub. NIOSH 77-108 R127: NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.98 (1976) DHEW Pub. NIOSH 77-108 R128: USEPA; Development and Evaluation of Procedures for the Analyis of Simple Cyanides, Total Cyanide, and Thiocyanate in Water and Wastewater p.1 (1983) EPA 600/S4-83-054 R129: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R130: USEPA; REVIEWS OF ENVIRONMENTAL EFFECTS OF POLLUTANTS: V. CYANIDE P.28 (1978) EPA-600/1-78-027 R131: Danchik RS, Botz DF; Anal Chim Acta 49: 567-69 (1970) as cited in NIOSH; Criteria Document: Hydrogen Cyanide and Cyanide Salts p.99 (1976) DHEW Pub. NIOSH 77-108 R132: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 113 R133: MORGAN R ET AL; PROC WEST PHARMACOL SOC 19: 392-96 (1976) R134: VALENTOUR ET AL; ANAL CHEM 46: 924 (1974) RS: 104 Record 85 of 1119 in HSDB (through 2003/06) AN: 757 UD: 200303 RD: Reviewed by SRP on 02/06/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-NITRITE- SY: *Diazotizing-salts-; *DUSITAN-SODNY- (CZECH); *ERINITRIT-; *FILMERINE-; *NATRIUM-NITRIT- (GERMAN); *NCI-C02084-; *NITRITE-DE-SODIUM- (FRENCH); *Nitrito-sodico- (Spanish); *NITROUS-ACID,-SODIUM-SALT-; *ANTI-RUST-; *SYNFAT-1004- RN: 7632-00-0 MF: *H-N-O2.Na SHPN: UN 1500; Sodium nitrite IMO 5.1; Sodium nitrite STCC: 49 187 47; Sodium nitrite ASCH: Nitrite; 14797-65-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY HEATING SODIUM NITRATE UNTIL IT FUSES ... ADDING SUFFICIENT METALLIC LEAD TO COMPLETELY REDUCE NITRATE TO NITRITE. ... MIXT IS LIXIVIATED WITH WATER, FILTERED, PARTIALLY EVAPORATED, AND ALLOWED TO CRYSTALLIZE. [R1] *REACTION OF NITROGEN OXIDES WITH AQUEOUS SODIUM HYDROXIDE. [R2] *Formed by burning sodium in nitric oxide. [R3] FORM: *96-98% SODIUM NITRITE. [R4] *GRADES: REAGENT; TECHNICAL; USP; FCC. [R5] MFS: +E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Gibbstown, NJ 08027. [R6] +Henley Manufacturing Inc, Hq, 11255 N Torrey Pines Road, La Jolla, CA 92037, (619) 455-9494; General Chemical Corporation, 90 E Halsey Road, Parsippany, NJ 07054-0393; Production sites: Route 13, Claymont, DE 19703 (Delaware Valley Works); Syracuse (Solvay), NY 13209. [R6] +Hummel Chemical Company, Incorporated, Hq, PO Box 250, South Plainfield, NJ 07080, (201) 754-1800; Croton Corp, 10 Harmich Rd, South Plainfield, NJ 07080-4804; Production site: South Plainfield, NJ 07080. [R6] +The Proctor and Gamble Co, Hq, 301 E Sixth St, PO Box 599, Cincinnati, OH 45201, (513) 983-5607; Subsidiary: Richardson-Vicks, Inc, One Far Mill Crossing, Shelton, CT 06484, (203) 929-2500; JT Baker, Inc, subsidiary, (201) 859-2151; Production site: 222 Red School Lane, Phillipsburg, NJ 08865 [R6] +G Frederick Smith Chemical Company, PO Box 23214, Columbus, OH 43223, (614) 881-5501; Production site: 867 McKinley Ave, Columbus, OH 43222 [R6] OMIN: *INCOMPATIBILITIES: ACETANILIDE, ANTIPYRINE, CHLORATES, HYPOPHOSPHITES, IODIDES, MERCURY SALTS, PERMANGANATES, SULFITES, TANNIC ACID, VEGETABLE ASTRINGENT DECOCTIONS, INFUSIONS OR TINCTURES. [R4] *Addition of sodium nitrite to meat that accounts for 7% of the entire US food supply is generally believed to have reduced the risk of botulism in humans to almost zero. Nitrite retards the growth of botulinum spores, which are prevalent in food. [R7] USE: *COMPONENT OF HEAT-TRANSFER SALTS; CHEM IN METAL TREATMENT AND FINISHING OPERATIONS; COMPONENT OF DETINNING SOLUTION AND MULTIPURPOSE GREASES; AGENT FOR RECOVERY OF TIN FROM SCRAP. [R2] *Serves as an anticorrosion inhibitor for multipurpose greases. [R8] *Used as a photobleach to eliminate solarization. [R9] *Fertilizer /minor use/ [R10] *Diazotization (by reaction with hydrochloric acid to form nitrous acid), rubber accelerators, color fixative and preservative in cured meats, meat products, fish; pharmaceuticals, photographic and analytical reagent, dye manufacture. [R5] +MEDICATION +MEDICATION (VET) *HAS BEEN FOUND EFFECTIVE ... AS PRESERVATIVE FOR FISH WHEN INCORPORATED IN ICE AT A LEVEL OF 0.1-0.5%. [R11, 155] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 5.0X10+9 G [R2] U.S. IMPORTS: *(1978) 3.94X10+9 G [R2] *(1982) 4.68X10+9 G [R2] *(1984) 8.14X10+9 g [R12] U.S. EXPORTS: *(1984) 4.03X10+11 g /Sodium compounds, NSPF/ [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS-YELLOW RHOMBOHEDRAL PRISMS [R14]; *WHITE OR SLIGHTLY YELLOW GRANULES, RODS, OR POWDER [R4]; *SLIGHTLY YELLOWISH OR WHITE CRYSTALS, PELLETS, STICKS OR POWDER [R5] TAST: *MILD, SALINE TASTE [R1] MP: *271 DEG C [R4] MW: *69.00 [R4] DEN: *2.26 [R4] PH: *AQ SOLN IS ALKALINE, PH ABOUT 9 [R4] SOL: *SOL IN 1.5 PARTS COLD, 0.6 PARTS BOILING WATER. [R4]; *0.3 G/100 CC ETHER AT 20 DEG C; 4.4 G/100 CC METHANOL AT 20 DEG C; 3 G/100 CC ABS ALC AT 20 DEG C; VERY SOL IN AMMONIA. [R14] OCPP: *HYGROSCOPIC [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: These substances will accelerate burning when involved in a fire. Some may decompose explosively when heated or involved in a fire. May explode from heat or contamination. Some will react explosively with hydrocarbons (fuels). May ignite combustibles (wood, paper, oil, clothing, etc.). Containers may explode when heated. Runoff may create fire or explosion hazard. [R15] +Health: Inhalation, ingestion or contact (skin, eyes) with vapors or substance may cause severe injury, burns, or death. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may cause pollution. [R15] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R15] +Fire: Small fires: Use water. Do not use dry chemicals or foams. CO2, or Halon may provide limited control. Large fires: Flood fire area with water from a distance. Move containers from fire area if you can do it without risk. Do not move cargo or vehicle if cargo has been exposed to heat. Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R15] +Spill or leak: Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Do not get water inside containers. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Small liquid spills: Use a non-combustible material like vermiculite, sand or earth to soak up the product and place into a container for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Following product recovery, flush area with water. [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R15] FPOT: *MODERATE; A STRONG OXIDIZING AGENT. IN CONTACT WITH ORGANIC MATTER WILL IGNITE BY FRICTION. [R16] +SODIUM NITRITE AT 460 DEG F IN CONTACT WITH FIBER DRUMS IN WHICH IT IS SHIPPED UNDERGOES VIGOROUS DECOMP REACTION PRODUCING PROPELLANT-TYPE BURNING UNTIL CARTON IS CONSUMED. [R17] *SODIUM NITRITE SOLN IS USED TO INHIBIT ... POLYMERIZATION OF BUTADIENE IN PROCESSING PLANT. IF CONCN NITRITE SOLN (5%) ARE USED, BLACK SLUDGE IS PRODUCED WHICH, WHEN DRY, WILL IGNITE AND BURN ... . [R18, 1060] EXPL: *EXPLODES WHEN HEATED TO OVER 1000 DEG C ... . [R16] */AMINOGUANIDINE SALTS/ INTERACTION, WITHOUT ADDN OF ACID, PRODUCES TETRAZOLYLGUANYLTRIAZENE ('TETRAZENE'), A PRIMARY EXPLOSIVE OF EQUAL SENSITIVITY TO MERCURY(II) AZIDE, BUT MORE READILY INITIATED. ... MIXT OF SODIUM ... NITRITES AND VARIOUS CYANIDES EXPLODE ON HEATING. SUCH MIXT HAVE BEEN PROPOSED AS EXPLOSIVES ... MIXT OF SODIUM NITRITE AND PHTHALIC ACID OR ANHYDRIDE EXPLODE VIOLENTLY ON HEATING. ... ADDN OF SOLID NITRATE TO MOLTEN AMIDE CAUSES IMMEDIATE GAS EVOLUTION, FOLLOWED BY VIOLENT EXPLOSION. [R18, 1060] *MIXTURE /OF SODIUM NITRITE AND SODIUM THIOCYANATE/ EXPLODES ON HEATING. ... FUSION OF UREA (2 MOL) WITH SODIUM ... NITRITE (1 MOL) TO GIVE HIGH YIELDS OF CYANATE MUST BE CARRIED OUT EXACTLY AS DESCRIBED TO AVOID RISK OF EXPLOSION. [R18, 1062] *INTERACTION OF NITRITES WHEN HEATED WITH METAL AMIDOSULFATES ('SULFAMATES') MAY BECOME EXPLOSIVELY VIOLENT OWING TO LIBERATION OF NITROGEN AND STEAM. MIXT WITH AMMONIUM SULFAMATE FORM AMMONIUM NITRATE WHICH DECOMP VIOLENTLY AROUND 80 DEG C. [R18, 1060] +VIOLENT EXPLOSION OCCURS IF AN AMMONIUM SALT IS MELTED WITH NITRITE SALT. ... WHEN SODIUM NITRITE AND THIOSULFATE MIXT WAS HEATED TO EVAPORATE TO DRYNESS, VIOLENT EXPLOSION OCCURRED. ... SOLN OF POTASSIUM AND SODIUM NITRITE IN LIQ AMMONIA FORM DISODIUM NITRITE, WHICH IS VERY REACTIVE AND EASILY EXPLOSIVE. ... LITHIUM REACTS WITH SODIUM NITRITE TO FORM LITHIUM SODIUM HYDRONITRITE, A CMPD WHICH DECOMP VIOLENTLY AROUND 100-130 DEG C. [R17] *SHOCK MAY EXPLODE THEM ... . /NITRITES/ [R16] REAC: *... /THEY/ CAN REACT VIGOROUSLY WITH REDUCING MATERIALS. /NITRITES/ [R16] DCMP: +... WHEN HEATED TO DECOMP, ... EMITS HIGHLY TOXIC FUMES OF /NITROGEN OXIDES AND DISODIUM OXIDE/. [R19] *DECOMP ABOVE 320 DEG C; DECOMP EVEN BY WEAK ACIDS WITH EVOLUTION OF BROWN FUMES OF NITROGEN OXIDE. [R4] SSL: *VERY SLOWLY OXIDIZES TO NITRATE IN AIR. [R4] *SOLN OF SODIUM NITRITE ARE UNSTABLE AND SHOULD BE PREPARED DIRECTLY BEFORE USE; CANNOT BE DISPENSED IN ACIDIC VEHICLES. [R20] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R22] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R23] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *THE TWO BASIC ACTIONS OF SODIUM NITRITE IN VIVO ARE RELAXATION OF SMOOTH MUSCLE, ESP OF SMALL BLOOD VESSELS, AND IN TOXIC DOSES THE CONVERSION OF HEMOGLOBIN TO METHEMOGLOBIN. [R24, p. III-314] *SIGNS AND SYMPTOMS OF NITRITE POISONING INCLUDE INTENSE CYANOSIS, NAUSEA, VERTIGO, VOMITING, COLLAPSE, SPASMS OF ABDOMINAL PAIN, TACHYCARDIA, TACHYPNEA, COMA, CONVULSIONS AND DEATH. INJECTION AND INFLAMMATION OF GASTRIC AND INTESTINAL MUCOSA ARE DESCRIBED AT AUTOPSY. /INORGANIC NITRITE SALTS/ [R24, p. II-315] *SYMPTOMATOLOGY: PROMPT FALL IN BLOOD PRESSURE. HEADACHE WHICH IS PERSISTENT AND THROBBING, WITH ASSOC PALPITATIONS AND VISUAL DISTURBANCES. SKIN IS FLUSHED AND PERSPIRING, LATER COLD AND CYANOTIC. INGESTION OF NITRITES MAY CAUSE COLIC AND DIARRHEA. ... HYPERPNEA; LATER DYSPNEA AND SLOW BREATHING. ... INCR INTRAOCULAR TENSION AND INTRACRANIAL PRESSURE. /NITRITE/ [R24, p. II-323] *ACUTE NITRATE TOXICITY IS ALMOST ALWAYS SEEN IN INFANTS RATHER THAN ADULTS WHEN IT RESULTS FROM INGESTION OF WELL WATERS AND VEGETABLES HIGH IN NITRATES. ... /IT WAS/ DEDUCED THAT INFANTS WERE PRONE TO UPSET STOMACHS AND ACHLORHYDRIA. AS RESULT, STOMACH PH INCREASED IN ALKALINITY ALLOWING NITRATE-REDUCING ORGANISMS TO ENTER AND TO REDUCE NITRATES TO NITRITES. A GASTRIC PH ABOVE 4 SUPPORTS NITRATE-REDUCING ORGANISMS. ... IMMATURE ENZYME SYSTEMS MAY ALSO BE OF IMPORTANCE. ... FETAL HEMOGLOBIN (HEMOGLOBIN F) IS OXIDIZED BY NITRITE TO METHEMOGLOBIN AT RATE TWICE AS RAPID AS ADULT HEMOGLOBIN (HEMOGLOBIN A). FURTHERMORE, ENZYMATIC CAPACITY OF ERYTHROCYTES OF NEWBORN INFANTS TO REDUCE METHEMOGLOBIN TO HEMOGLOBIN APPEARS LESS THAN THAT OF ADULTS. DIFFERENCE IS PROBABLY DUE TO DEVELOPMENTAL DEFICIENCY IN ACTIVITY OF DPNH-METHEMOGLOBIN REDUCTASE (DIPHOSPHOPYRIDINE NUCLEOTIDE). AS OPPOSED TO ADULTS, SEVERAL CLINICAL, PHYSIOLOGIC AND METABOLIC FACTORS PREDISPOSE INFANTS TO DEVELOPMENT OF METHEMOGLOBINEMIA AND ACUTE NITRATE POISONING. /NITRITE/ [R25] *A 78 year old man was found comatose, apneic, and asystolic after closed-spaced smoke inhalation. He was successfully resuscitated to pulse and blood pressure at the scene. A cyanide component to the poisoning was suspected and two 300 mg doses of sodium nitrite were administered, resulting in significant hypotension. Although high methemoglobin levels were not induced, when added to simultaneously obtained carboxyhemoglobin levels, the total amount of non-oxygen transporting hemoglobin remained nearly constant for about 4-1/2 hr before hyperbaric oxygen therapy could be administered. The patient later died in multi-organ system failure. Admission whole blood cyanide level was only 0.34 ug/ml. These sodium nitrite adverse effects can be avoided by slow intravenous infusion and by administering only recommended doses. In smoke inhalation victims with suspected cyanide poisoning, sodium thiosulfate should be administered first, and sodium nitrite withheld until after the patient is receiving hyperbaric oxygen therapy. When available, hydroxocobalamin (which neither induces methemoglobinemia nor causes hypotension) may be the specific cyanide antidote of choice for victims of smoke inhalation. [R26] NTOX: *NITRITE CONVERTS HEMOGLOBIN ... INTO METHEMOGLOBIN ... . IF THIS CHANGE IS SUFFICIENTLY COMPLETE ANIMALS MAY DIE OF TISSUE ANOXIA; CLINICAL SIGNS ARE SEEN WHEN ABOUT 20% OF HEMOGLOBIN IS CONVERTED INTO METHEMOGLOBIN AND BECOME PROGRESSIVELY MORE SEVERE AS PROPORTION INCREASES, DEATH OCCURRING WHEN LEVEL REACHES ABOUT 80%. /INORGANIC NITRITE SALTS/ [R27, 66] *FASTING INCREASES SUSCEPTIBILITY TO ... NITRITE POISONING ... . CATTLE FED ON AN ADEQUATE DIET CAN TOLERATE ... INTAKE OF ... NITRITE SUFFICIENT TO CAUSE A 50% CONVERSION OF HEMOGLOBIN TO METHEMOGLOBIN ... . /INORGANIC NITRITE SALTS/ [R27, 67] *SINGLE DOSE OF 30 MG/KG OF SODIUM NITRITE IV CAUSED METHEMOGLOBINEMIA IN DOGS. /FROM TABLE/ [R28] *... RUMINANTS AND MINK IN NORWAY WERE REPORTED TO HAVE MALIGNANT LIVER LESIONS AFTER EATING RATION THAT CONTAINED FISH MEAL PRESERVED BY ADDITION OF NITRITE. /INORGANIC NITRITE SALTS/ [R11, 154] *A long-term feeding study was carried out in rats with sodium nitrite. The test substance was administered as part of a reduced-protein diet to groups of 50, 6 wk old, male F344 rats at dose levels of 0.2 or 0.5% (w/w) sodium nitrite for up to 115 wk. In the first week of treatment the following hematological parameters were reduced: red blood cell count continued to fall for 8 wk, then slowly returned to normal by wk 52. A dose-related reduction was noted in both the incidence and time of onset of lymphomas, leukemias and testicular interstitial cell tumors. Leukemias were only found in animals with lymphoma, indicating an association between the two lesions. Under the conditions described in this study, sodium nitrite was found not to be carcinogenic when fed to rats in the diet for up to 115 wk, but rather that the incidence of tumors was reduced in a dose-related manner, which corelated with a similar trend in body weights. [R29] *Pregnant ICR mice were given drinking water containing sodium nitrite at a concn of either 100 or 1000 mg/l on days 7-18 of gestation. There were no significant differences between treated and control groups in measures of developmental toxicity, eg, litter size, fetal weight and number of resorbed or dead fetuses. The incidences of external and skeletal malformations in fetuses of treated groups were not significantly different from those in the controls. No significant increase was observed in the frequency of gaps and breaks of liver cell chromosomes in fetuses exposed in utero to sodium nitrite. Teratogenic and mutagenic effects of sodium nitrite were absent in mice at the doses used. [R30] *Effects of nitrate (doses of 600 and 1200 mg/kg/day during 14 days) and sodium nitrite (60 and 120 mg/kg/day during 14 days) on germ cells of male mice were investigated /by/ ... stomach intubation. The germ cell stages analysed were spermatids (for the heritable effects) and differentiating and stem cell spermatogonia (for direct effects). A lack of heritable translocation, sperm abnormalities, as well as morphological changes, such as changes in the eyes, coat color, testes and body weight, was demonstrated in F1 males originating from treated P males. Significant effects in treated males were found with respect to: (1) sex chromosomal univalency in the diakinesis metaphase I stage after the treatment of stem spermatogonia (both doses of sodium nitrate and the higher dose of sodium nitrite), (2) sperm head abnormalities after treatment of differentiating spermatogonia (the higher dose of sodium nitrite and both doses of sodium nitrate), and (3) fertility after treatment of spermatids (the higher dose of sodium nitrite). Nonmutagenic effects and possible carcinogenic potential of the tested doses are discussed. [R31] *TESTING OF SODIUM NITRITE ON RABBIT CORNEAS BY APPLICATION OF 0.08 MOLAR SOLN AFTER REMOVAL OF CORNEAL EPITHELIUM, OR BY INJECTION INTO STROMA, HAS CAUSED NO LOCAL INJURY. [R32] *... MICE CHRONICALLY EXPOSED TO SODIUM NITRITE AT 1,000 and 2,000 MG/L IN DIRNKING WATER SHOWED REDUCED MOTOR ACTIVITY. EEG RECORDINGS FROM IMPLANTED ELECTRODES REVEALED MAJOR CHANGES IN BRAIN ELECTRIC ACTIVITY IN RATS RECEIVING NITRITE AT 100-2,000 MG/L. ... CHRONIC EXPOSURE OF RATS TO SODIUM NITRITE AT 2,000 and 3,000 MG/L IN DRINKING FOR 2 YR WAS ASSOCIATED WITH DISTINCT PATHOLOGIC CHANGES IN HEART AND LUNG TISSUES. [R25] *... RATS RECEIVED SODIUM NITRITE AT 100 MG/KG IN DRINKING WATER DAILY DURING THEIR ENTIRE LIFE SPAN OVER THREE GENERATION; NO EVIDENCE OF CHRONIC TOXICITY, CARCINOGENICITY, OR TERATOGENICITY ... FOUND. [R25] *... SEVERE TOXICOSIS IN PREGNANT SOWS WITH 21 TO 35 MG OF SODIUM NITRITE/KG SC. TREATMENT PERFORMED ON VARIOUS SINGLE DAYS DURING 1ST 100 DAYS OF GESTATION DID NOT PRODUCE ANY FETAL DEFECTS. FETAL METHEMOGLOBIN REMAINED AT VERY MUCH LOWER LEVEL THAN THAT IN MOTHER. *MAMMALIAN CYTOGENETICS - IN VIVO OOCYTE OR EARLY EMBRYO STUDIES: POSITIVE. *SISTER CHROMATID EXCHANGE - IN VITRO CHROMOSOMAL EFFECT STUDIES, NON-HUMAN: POSITIVE. *DNA REPAIR-DEFICIENT BACTERIAL TEST: NEGATIVE. *The Drosphila wing somatic mutation and recombination test was applied to a series of chemicals to determine its suitability in genotoxicity screening. Chronic feeding of three day old larvae with a concentration of 72.5 mM sodium nitrite led to a positive result for the small single spots in two independent experiments. Data on induction of large single spots and twin spots were inconclusive. [R33] *MINIMUM LETHAL DOSE OF ... SODIUM NITRITE /IN CATTLE ESTIMATED TO BE/ 0.15-0.17 G/KG. ... PIGS ARE MORE SUSCEPTIBLE TO NITRITE POISONING THAN CATTLE AND SHEEP MIN LETHAL DOSE BEING OF ORDER OF 70 TO 75 MG/KG (32 TO 34 MG/LB) IN FORM OF SODIUM NITRITE ... . [R27, 67] +Groups of 50 male and 50 female F344/N rats were exposed to 0, 750, 1500 or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 35, 70 or 130 mg/kg to males and 40, 80 or 150 mg/kg to females) in drinking water for 2 yr. ... Groups of 50 male and 50 B6C3F1 female mice were exposed to 0, 750, 1500 or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 60, 120 or 220 mg/kg to males and 45, 90 or 165 mg/kg to females) in drinking water for 2 yr. CONCLUSIONS: Under the conditions of this 2 yr drinking water study, there was no evidence of carcinogenic activity of sodium nitrite in male or female F344/N rats exposed to 750, 1500, or 3000 ppm. There was no evidence of carcinogenic activity in male B6C3F1 mice exposed to 750, 1500 or 3000 ppm. There was equivocal evidence of carcinogenic activity of sodium nitrite in female B6C3F1 mice based on positive trend in the incidences of squamous cell papilloma or carcinoma (combined of the forstomach). [R34] NTP: +Sodium nitrite administered via drinking water, was tested for its effects on fertility and reproduction in Swiss CD-1 mice according to the continuous breeding protocol. Based on results of dose-finding studies, 0.06, 0.12, and 0.24% weight/volume sodium nitrite concns were chosen to investigate effects on fertility and reproduction. Male and female mice were continuously exposed for a 7 day precohabitation and a 98 day cohabitation period (Task 2). Sodium nitrite treatment had no effect on fertility or any of the reproductive parameters. The water consumption in the 0.24% group was consistently lower but this had no effect on F0 body weights. Since the response was negative in Task 2, the cross-over mating trial (Task 3) to determine the sex affected by chemical treatment was not conducted. The F1 pups from control and 0.24% groups were weaned for second generation studies. Live male and female pup weights were significantly lower on postnatal days 7, 14, and 21 in the 0.24% group. At sexual maturity, fertility was not affected in the F1 mice nor were body weights decreased in either sex. At necropsy, absolute cauda epididymis weight was lower in the treated group by 9%. Based on the results of the present study, it is concluded that sodium nitrite is not a reproductive toxicant in Swiss CD-1 mice at the levels tested. [R35] +Groups of 50 male and 50 female F344/N rats were exposed to 0, 750, 1500 or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 35, 70 or 130 mg/kg to males and 40, 80 or 150 mg/kg to females) in drinking water for 2 yr. ... Groups of 50 male and 50 B6C3F1 female mice were exposed to 0, 750, 1500 or 3000 ppm sodium nitrite (equivalent to average daily doses of approximately 60, 120 or 220 mg/kg to males and 45, 90 or 165 mg/kg to females) in drinking water for 2 yr. CONCLUSIONS: Under the conditions of this 2 yr drinking water study, there was no evidence of carcinogenic activity of sodium nitrite in male or female F344/N rats exposed to 750, 1500, or 3000 ppm. There was no evidence of carcinogenic activity in male B6C3F1 mice exposed to 750, 1500 or 3000 ppm. There was equivocal evidence of carcinogenic activity of sodium nitrite in female B6C3F1 mice based on positive trend in the incidences of squamous cell papilloma or carcinoma (combined of the forstomach). [R34] POPL: *ACUTE NITRATE TOXICITY IS ALMOST ALWAYS SEEN IN INFANTS RATHER THAN ADULTS WHEN IT RESULTS FROM INGESTION OF WELL WATERS AND VEGETABLES HIGH IN NITRATES. ... /IT WAS/ DEDUCED THAT INFANTS WERE PRONE TO UPSET STOMACHS AND ACHLORHYDRIA. AS RESULT, STOMACH PH INCREASED IN ALKALINITY ALLOWING NITRATE-REDUCING ORGANISMS TO ENTER AND TO REDUCE NITRATES TO NITRITES. A GASTRIC PH ABOVE 4 SUPPORTS NITRATE-REDUCING ORGANISMS. ... IMMATURE ENZYME SYSTEMS MAY ALSO BE OF IMPORTANCE. ... FETAL HEMOGLOBIN (HEMOGLOBIN F) IS OXIDIZED BY NITRITE TO METHEMOGLOBIN AT RATE TWICE AS RAPID AS ADULT HEMOGLOBIN (HEMOGLOBIN A). FURTHERMORE, ENZYMATIC CAPACITY OF ERYTHROCYTES OF NEWBORN INFANTS TO REDUCE METHEMOGLOBIN TO HEMOGLOBIN APPEARS LESS THAN THAT OF ADULTS. DIFFERENCE IS PROBABLY DUE TO DEVELOPMENTAL DEFICIENCY IN ACTIVITY OF DPNH-METHEMOGLOBIN REDUCTASE (DIPHOSPHOPYRIDINE NUCLEOTIDE). AS OPPOSED TO ADULTS, SEVERAL CLINICAL, PHYSIOLOGIC AND METABOLIC FACTORS PREDISPOSE INFANTS TO DEVELOPMENT OF METHEMOGLOBINEMIA AND ACUTE NITRATE POISONING. /NITRITE/ [R25] ADE: *... TRANSPLACENTAL PASSAGE OF NITRITE OCCURRED IN PREGNANT RATS GIVEN DOSES AT 2.5-50 MG/KG ORALLY ... . [R25] *IN MICE GIVEN 400, 800, OR 1200 MG SODIUM NITRITE ORALLY IN DRINKING WATER 99.1 TO 99.5% OF THE DOSE WAS ELIMINATED. THE REMAINING NITRITE WAS TRANSFORMED INTO NITRATE AND RECOVERED FROM THE LIVER AND MUSCLE. [R36] ACTN: *The effects of acidified sodium nitrite a releaser of nitric oxide, combined with human superoxide dismutase were investigated in a 6 hr model of myocardial ischemia (MI) with repertusion in open-chest, anesthetized cats. Acidified sodium nitrite + human superoxide dismutase together exert significant protection on the myocardium subjected to ischemia and repertusion injury. Sodium nitrite may act synergisticaly with human superoxide dismutase to prolong the action of nitric oxide scavenging free radicals that inactivate nitric oxide. [R37] INTC: *RESULTS OF FEEDING TESTS WITH RATS PROVIDE FURTHER EVIDENCE THAT INGESTION OF SECONDARY AND TERTIARY AMINES WITH NITRITE (INCL SODIUM NITRITE) CAN LEAD TO FORMATION OF SIGNIFICANT AMT OF CARCINOGENIC N-NITROSO CMPD IN STOMACH. [R38] *HAMSTER FED AN AMINOPYRINE/SODIUM NITRITE MIXT IN DRINKING WATER SHOWED A HIGH INCIDENCE OF INTRAHEPATIC BILE DUCT TUMORS. [R39] *FORMATION OF N-NITROSO COMPOUNDS IN MOUSE STOMACH FROM EQUIMOLAR DOSES OF SODIUM NITRITE AND SECONDARY AMINES OR ALKYLUREA DERIV GIVEN SIMULTANEOUSLY BY STOMACH TUBE WAS ESTIMATED, BY MEASURING MUTAGENIC ACTIVITY OF CMPD IN IP HOST-MEDIATED ASSAY WITH USE OF SALMONELLA TYPHIMURIUM TA1950 AS GENETIC INDICATOR SYSTEM. HIGHEST MUTAGENICITY WAS EXERTED BY PIPERAZINE DIHYDROCHLORIDE PLUS NITRITE, WHILE AMITROLE PLUS NITRITE WAS ONLY WEAKLY MUTAGENIC. RESULTS ARE COMPARED WITH THOSE OBTAINED IN LONG-TERM CARCINOGENESIS STUDIES WITH SODIUM NITRITE PLUS AMINES. [R40] *CARCINOGENICITY OF SODIUM NITRITE AND METHYLGUANIDINE SINGLY AND TOGETHER WERE EXAMINED IN RATS. HEMANGIOMAS AND BILE DUCT ADENOMAS OF LIVER, HEPATOCELLULAR CARCINOMA, HEMANGIOSARCOMA AND SPINDLE CELL SARCOMA WERE FOUND IN RATS FED CONTINUOUSLY ON PELLET DIET CONTAINING 0.16% SODIUM NITRITE AND 0.16% METHYLGUANIDINE. HEMANGIOMAS AND BILE DUCT ADENOMAS OF LIVER WERE FOUND IN RATS FED PELLET DIET OF 0.16% SODIUM NITRITE. ONLY 1/5 RATS FED DIET CONTAINING 0.16% METHYLGUANIDINE DEVELOPED HEMANGIOMA. [R41] *... VASODILATATION /FROM NITRITES/ IS NOT BLOCKED BY ... ANY RECOGNIZED DRUG ... PROBABLY EPINEPHRINE AND RELATED COMPOUNDS SHOULD BE STRICTLY PROHIBITED; THEY INTENSIFY ARTERIOLAR CONSTRICTION ... WITH RESULT THAT TISSUE BLOOD FLOW IS FURTHER COMPROMISED. /INORGANIC NITRITE SALTS/ [R24, p. II-84] *MORPHOLINE (10 G/KG) IN THE DIET AND SODIUM NITRITE (2 G/L) IN THE DRINKING WATER WERE ADMIN FOR LIFE TO RATS WITHOUT (GROUP 1) OR WITH (GROUP 2) SODIUM ASCORBATE (22.7 G/KG) IN THE DIET. GROUP 3 WAS UNTREATED. GROUP 2 SHOWED A LOWER LIVER TUMOR INCIDENCE WITH A LONGER LATENCY THAN GROUP 1, INDICATING A 78% INHIBITION BY SODIUM ASCORBATE OF IN VIVO N-NITROSOMORPHOLINE (NMOR) FORMATION. THE INCIDENCE OF FORESTOMACH PAPILLOMAS WAS 3% IN GROUP 1, 38% IN GROUP 2, and 8% IN GROUP 3. THE DIFFERENCE BETWEEN GROUPS 1 and 2 WAS NOT SIGNIFICANT DUE TO THE SHORTER LIFE-SPAN OF GROUP 1. [R42] *LARGER DOSES (15.2 MG/KG) OF SODIUM CYANIDE IN SHEEP WERE EFFECTIVELY ANTAGONIZED BY EITHER 660 MG/KG SODIUM THIOSULFATE ALONE OR IN COMBINATION WITH 1.5 MG/KG P-AMINOPROPIOPHENONE OR 22 MG/KG SODIUM NITRITE. [R43] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antidotes; Food Preservatives; Indicators and Reagents; Mutagens [R44] *Has been used as a vasodilator; as a circulatory (blood pressure) depressant and to relieve smooth muscle spasm. [R4] *ANTIDOTE FOR CYANIDE POISONING. [R4] +MEDICATION (VET): IN CYANIDE POISONING. [R4] */Cyanide antidote:/ Adults, oxygen therapy should be initiated and amyl nitrite inhaled from the crushable ampules for 30 seconds of every minute until an intravenous route is established. Amyl nitrite then is discontinued and all of the sodium nitrite (300 mg) in the 10 ml ampule is administered intravenously. The 12.5 g of sodium thiosulfate contained in the 50 ml ampule is then administered intravenously. If symptoms persist, a second dose of sodium nitrite (one-half the amount of the first dose) should be given 30 minutes later. Children, oxygen therapy is initiated; 0.33 ml/kg of sodium nitrite solution is administered, followed immediately by 1.65 ml/kg of sodium thiosulfate solution. [R45] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Present in brines. [R46] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Sodium nitrite (not more than 3% of pesticide formulation) is exempted from the requirement of a tolerance when used as a stabilizer or inhibitor in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R47] *The food additive sodium nitrite may be safely used in or on specified foods: (1) As a color fixative in smoked cured tunafish products so that the level of sodium nitrite does not exceed 10 ppm (0.001%) in the finished product; (2) As a preservative and color fixative, with or without sodium nitrate, in smoked, cured sablefish, smoked, cured salmon, and smoked, cured shad so that the level of sodium nitrite does not exceed 200 ppm in the finished products; (3) As a preservative and color fixative, with sodium nitrate, in meat-curing prepn for the home curing of meat and meat products (incl poultry and wild game), with directions for use which limit the amt of sodium nitrite to not more than 200 ppm in the finished meat product. [R48] *Sodium nitrite may be safely used in canned pet food containing meat and fish in accordance with the following conditions: It is used or intended for use alone as a preservative and color fixative in canned pet food containing fish, meat, and fish and meat byproducts so that level of sodium nitrite does not exceed 20 ppm. [R49] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 1000 ug/l /Nitrite/ [R50] FEDERAL DRINKING WATER GUIDELINES: +EPA 1000 ug/l /Nitrite/ [R50] STATE DRINKING WATER GUIDELINES: +(ME) MAINE 1000 ug/l /Nitrite/ [R50] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R51] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R52] FIFR: *Sodium nitrite (not more than 3% of pesticide formulation) is exempted from the requirement of a tolerance when used as a stabilizer or inhibitor in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R47] FDA: *Sodium nitrite is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. Tolerances are established for sodium nitrite as a color fixative in smoked cured sablefish, smoked, cured salmon and smoked cured shad; and as a preservative and color fixative, with sodium nitrate, in meat-curing prepn for the home curing of meat and meat products (incl poultry and wild game). [R48] *Sodium nitrite is an indirect food additive for use only as a component of adhesives. [R53] *Closure with sealing gaskets may be safely used on containers intended for use in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food. Substances that may be employed in the manufacture of closure-sealing gaskets incl sodium nitrite. Limitations (expressed as % by wt of closure-sealing gasket composition): 0.2%; for use only in annular ring gaskets applied in aqueous dispersions to closures for containers having a capacity of not < 5 gal. [R54] *Rubber articles intended for repeated use may be safely used in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting, or holding food. Substances employed in the preparation of rubber articles incl sodium nitrite (total not > 5% by wt of rubber product). [R55] *Sodium nitrite /is/ subject to prior sanctions issued by the USDA for use as color fixatives and preservative agents, with or without sodium or potassium nitrate, in the curing of red meat and poultry products. [R56] *Tolerances are established for canned pet food containing meat and fish. [R57] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method. Analyte: Sodium. MATRIX: Air. Sampler: Filter (0.8-um, cellulose ester membrane) Flow Rate: 1 to 4 liter/min. Sample Size: 500 liters. SHIPMENT: Routine. Sample Stability: Stable. /Sodium/ [R58] ALAB: *HYDRAZINE METHOD, APPLICABLE IN PRESENCE OR ABSENCE OF NITRATES OR CHLORIDES, IS USED TO DETERMINE NITRITES IN DRUG TABLETS BY TITRATION WITH IODINE. /NITRITES/ [R59, p. 681/36.105] *COLORIMETRIC METHOD FOR DETERMINATION OF ... NITRITE IN CURED MEAT. /NITRITE/ [R11, 155] *MODIFIED JONES REDUCTOR USED TO DETERMINE NITRATE AND NITRITE IN CHEESES CONTAINING GREATER THAN OR EQUAL TO 1 PPM NITRITE. /NITRATES AND NITRITES/ [R59, p. 310/16.278-2832] *TITRATION WITH SODIUM THIOSULFATE USED TO DETERMINE NITRITES (INCLUDING SODIUM NITRITE) IN DRY CURE MIX OR CURING PICKLE PRESERVATIVES. [R59, p. 385/20.090-092] *DETERMINED COLORIMETRICALLY IN GUNSHOT RESIDUES BY METHOD BASED ON DIAZOTIZATION-COUPLING REACTION BETWEEN SULFANILIC ACID AND ALPHA-NAPHTHYLAMINE FOLLOWED BY MEASURING ABSORBANCE AT 534 NM. [R60] *Nitrates and Nitrites in Meat; xylenol Method - To determine nitrates and nitrites in meat and meat products by comparing color of extract with standard nitrate curve prepared at 450 nm. /Nitrates and nitrites/ [R59, p. 436/24.041] *Colorimetric Method - Nitrites in cured meat is determined by color of extract at 540 nm and compared with standard nitrite curve. /Nitrites/ [R59, p. 436/24.044] *NIOSH Method 7300-1: Analyte: Sodium. Matrix: Air. Procedure: Inductively Coupled Argon Plasma, atomic emission spectroscopy. For sodium this method has an estimated detection limit of 1 ug per 500 liter air sample. The overall precision/RSD is 0.045 at 1000 ug/filter and the recovery is 101% at 100 ug/ filter. Applicability: The working range of this method is 0.005 to 2.0 mg/cu m for sodium in 500 liter air sample. Interferences are the primary interferences. /Sodium/ [R58] *Atomic Absorption Spectrophotometric Method - Method can be used to determine sodium in water at wavelength of 589.0 nm. Flame gases are air-acetylene. This method has a sensitivity of 0.005-0.2 mg/l. This method is applicable to determination of 1-200 mg sodium/l in surface and saline waters, and domestic and industrial wastes. /Sodium/ [R59, p. 632/33.107-110] *Method 325B. Flame Emission Photometric. Trace amounts of sodium can be determined by flame emission photometry at a wavelengh of 589 nm. Detection limit is 100 ug/l. /Sodium/ [R61] *Method 305: Emission spectroscopy for the determination of sodium in water and wastewater samples using an inductively coupled plasma source. The exact choice of emission line is related to sample matrix and instrumentation. A typically used emission line for sodium in water is a wavelength of 589.0 nm, with an expected detection limit of 30 ug/l. /Sodium/ [R62] *Direct Aspiration Atomic Absorption Spectrometry is used for the determination of sodium. Using air-acetylene as the flame gas at a wavelength of 589.0 nm. /Sodium/ [R63] *NIOSH Method 173: Analyte: Trace metals; Procedure: Atomic absorption spectrometry. Samples are treated with nitric acid to ash the organic matrix and to dissolve the metal present in the sample. The analysis is subsequently made by atomic absorption spectrometry. The relative standard deviation of the method is 3%. This method has the sensitivity of 0.015 ug/m, detection limit of 0.0002 ug/ml, over a range of 0.5-5.0 ug/ml to 21-210 ug/cu m. /Sodium/ [R64] *EPA Method 9200: Nitrate. Method 9200 is applicable to the analysis of ground water, drinking, surface, and saline waters, and domestic and industrial wastes. Modification can be made to remove or correct for turbidity, color, salinity, or dissolved organic compounds in the sample. The applicable range of concentration is 0.1 to 2 mg nitrate-nitrogen/l of sample. This method is based upon the reaction of the nitrate ion with brucine sulfate in a 13 N sulfuric acid solution at a temperature of 100 deg C. The color of the resulting complex is measured at 410 nm. Temperature control of the color reaction is extremely critical. Twenty-seven analysts in fifteen laboratories analyzed natural-water samples containing increments (as nitrogen, nitrate) of 0.16, 0.19, 0.08, and 1.24 mg/l with the precision as the standard deviation of 0.092, 0.083, 0.245, and 0.214 mg/l, respectively. /Nitrate/ [R65] *Method 418C: Reduction Method. This method uses commercially available cadmium granules treated with copper sulfate to form a copper coating. The nitrite produced is determined by diazotizing with sulfanilamide and coupling with N-(1-naphthyl)-ethylenediamine to form a highly colored azo dye that is measured colorimetrically. The applicable range of this method is 0.01 to 1.0 mg nitrate-nitrogen/l. The method especially is recommended for nitrate levels below 0.1 mg nitrogen/l where other methods lack adequate sensitivity. /Nitrate/ [R66] *Method 418D: Chromotropic Acid Method. Two moles of nitrate react with one mole of chromotropic acid to form a yellow reaction product with maximum absorbance at 410 nm. The maximum color develops within 10 min and is stable for 24 hr. The method is recommended for the concn range 0.1 to 5 mg nitrate ion-nitrogen/l. A synthetic sample containing 1.00 mg nitrate ion-nitrogen/l was analyzed by 5 laboratories with a relative standard deviation of 8% and relative error of 3%. /Nitrate/ [R67] *Method 418E: Devarda's Alloy Reduction Method. This method is recommended for oxidized nitrogen concn greater than 2 mg/l. In this technique, nitrate ion and nitrite ion are reduced to ammonia under hot alkaline conditions in the presence of a reducing agent, Devarda's alloy (an alloy of 50% copper, 45% aluminum and 5% zinc). The reduction is carried out in a kjeldahl distillation apparatus. Under hot alaline conditions, the ammonia formed distills and is trapped in a receiving flask containing boric acid. The ammonia can be determined either by direct nesslerization or acidimetrically. /A separate determination of nitrogen dioxide should be made and subtracted, otherwise the result is reported as "total oxidized nitrogen."/ The recovery of 200 to 400 ug nitrate ion-nitrogen from partially treated effluents was found to average 96% with a coefficient of variation of 7.7%. /Nitrate/ [R68] *EPA Method 7770: Atomic Absorption, Direct Aspiration for the determination of sodium in solution. Preliminary treatment of waste water, ground water, extraction procedure (EP) extracts, and industrial waste is always necessary because of the complexity and variability of the sample matrix. The performance characteristics for an aqueous sample free of interferences are: optimum concentration range of 0.03-1 mg/l with a wavelength of 589.6 nm, a sensitivity of 0.002 mg/l, and a detection limit of 0.015 mg/l. /Sodium/ [R65] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NAS/NRC; Nitrates, An Environmental Assessment 723 pp. (1978) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the technical report on sodium nitrite is in the galley/camera ready copy stage of development. Route: dosed-water feed; Species: rats and mice. NTP TR No 495. [R69] SO: R1: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 779 R2: SRI R3: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V21 p.186 R4: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1365 R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1067 R6: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 957 R7: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 1100 R8: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V14 p.503 R9: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V17 p.634 R10: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V10 p.56 R11: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R12: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-351 R13: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-93 R14: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-131 R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-140 R16: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2442 R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-182 R18: Bretherick, L. Handbook of Reactive Chemical Hazards. 2nd ed. Boston MA: Butterworths, 1979. R19: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2981 R20: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 782 R21: 49 CFR 171.2 (7/1/96) R22: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 214 R23: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.5077, 5064 (1988) R24: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R25: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 420 R26: Hall AH et al; J Toxicol Clin Exp 9 (1): 3-9 (1989) R27: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. R28: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2416 R29: Grant D, Butler WH; Food Chem Toxicol 27 (9): 565-72 (1989) R30: Shimada T; Arch Environ Health 44 (1): 59-63 (1989) R31: Alvanti CD et al; Mutat Res 204 (4): 689-95 (1988) R32: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 840 R33: Graf U et al; Mutat Res 222 (4): 359-73 (1989) R34: Toxicology and Carcinogenesis Studies of Sodium Nitrite in F344/N Rats and B6C3F1 Mice p.8 Technical Report Series No. 495 (2001) NIH Publication No. 01-3954 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R35: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Sodium Nitrite (CAS No. 7632-00-0) in CD-1 Swiss Mice, NTP Study No. RACB88071 (December 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 8, 2002 R36: CANTONI C ET AL; ARCH VET ITAL 32 (1-2): 7 (1981) R37: Johnson G et al; Am Heart J l119 (3): 530-7 (1990) R38: LIJINSKY W, TAYLOR HW; FOOD COSMET TOXICOL 15 (4): 269 (1977) R39: BERGMAN F, WAHLIN T; ACTA PATHOL MICROBIOL SCAND, SECT A 89A (3): 241 (1981) R40: BRAUN R ET AL; CANCER RES 37 (12): 4572 (1977) R41: MATSUKURA N ET AL; Z KREBSFORSCH KLIN ONKOL 90 (1): 87 (1977) R42: MIRVISH SS ET AL; J NATL CANCER INST 71 (1): 81-5 (1983) R43: BURROWS GE; VET HUM TOXICOL 23 (1): 22 (1981) R44: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R45: American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986. 1646 R46: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V11 p.159 R47: 40 CFR 180.1001(d) (7/1/88) R48: 21 CFR 172.175 (4/1/90) R49: 21 CFR 573.700 (4/1/90) R50: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R51: 40 CFR 116.4 (7/1/88) R52: 54 FR 33419 (8/14/89) R53: 21 CFR 175.105 (4/1/90) R54: 21 CFR 177.1210 (4/1/90) R55: 21 CFR 177.2600 (4/1/90) R56: 21 CFR 181.34 (4/1/90) R57: 21 CFR 575.700 (4/1/90) R58: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 7300-1 R59: Association of Official Analytic Chemists. Official Methods of Analysis of the AOAC. 14th ed. Arlington, VA: Association of Official Analytic Chemists, Inc., 1984. R60: PETRACO N ET AL; FORENSIC SCI INT 18 (1): 85 (1981) R61: Franson, MA (Ed). Standard Methods for the Examination of Water and Wastewater P.246-249 (1985) R62: Franson MA (Ed): Standard Methods for the Examination of Water and Wastewater p.181 (1985) R63: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.154 (1985) R64: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. 173-1 Vol. 3 R65: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R66: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.394 (1985) R67: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.397-8 (1985) R68: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.398-9 (1985) R69: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 48 Record 86 of 1119 in HSDB (through 2003/06) AN: 768 UD: 200211 RD: Reviewed by SRP on 5/7/1998 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged also to retrieve the record named SELENIUM COMPOUNDS, which has additional information relevant to this title chemical. For general information on the toxicity and environmental fate of selenium ions and selenium compounds, refer to the SELENIUM COMPOUNDS record; for information on the metal itself, refer to the SELENIUM, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-SELENITE- SY: *DISODIUM-SELENITE-; *DISODIUM-SELENIUM-TRIOXIDE-; *NATRIUMSELENIT- (GERMAN); *SELENIOUS-ACID,-DISODIUM-SALT-; *SELENIOUS-ACID- (H2SEO3),-DISODIUM-SALT RN: 10102-18-8 RELT: 6909 [SELENIUM COMPOUNDS] MF: *H2-O3-Se.2Na SHPN: UN 2630; SODIUM SELENITE IMO 6.1; Sodium selenite STCC: 49 233 50; Sodium selenite HAZN: D010; A waste containing selenium (such as sodium selenite) may (or may not) be characterized a hazardous waste following testing by the Toxicant Extraction Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. (see 40 CFR 261). MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by evaporating an aqueous solution of sodium hydroxide and selenious acid between 60 and 100 deg C; by heating a mixture of sodium chloride and selenium oxide. [R1] *By neutralizing selenious acid with sodium carbonate and crystallizing. [R2] FORM: *BO-SE INJECTION IS EMULSION OF SELENIUM-TOCOPHEROL FOR ... WHITE MUSCLE DISEASE ... IN /ANIMALS/ ... SODIUM SELENITE 2.19 MG/ML. [R3, p. 16/40] *E-SE INJECTION IS EMULSION OF SELENIUM-TOCOPHEROL FOR ... MYOSITIS ... SYNDROME IN HORSES. EACH ML CONTAINS: SODIUM SELENITE ... 5.48 MG ... [R3, p. 16/46] *L-SE INJECTION IS EMULSION OF SELENIUM-TOCOPHEROL FOR ... WHITE MUSCLE DISEASE (SELENIUM-TOCOPHEROL DEFICIENCY) ... IN LAMBS AND ... BABY PIGS. EACH ML CONTAINS: SODIUM SELENITE ... 0.55 MG ... [R3, p. 16/50] *MU-SE /INJECTION/ IS EMULSION OF SELENIUM-TOCOPHEROL FOR ... DEFICIENCY SYNDROME IN WEANLING CALVES AND BREEDING BEEF CATTLE. EACH ML CONTAINS: SODIUM SELENITE ... 10.95 MG ... [R3, p. 16/51] *SELETOC IS COMBINATION SELENIUM TOCOPHEROL FOR USE IN ... CERTAIN ARTHROPATHIES IN DOGS. INJECTION: EACH ML CONTAINS: SODIUM SELENITE ... 2.19 MG ... MINICAPS: EACH CAPSULE CONTAINS: SODIUM SELENITE ... 0.55 MG ... CAPSULES: EACH CAPSULE CONTAINS: SODIUM SELENITE ... 2.19 MG. [R3, p. 16/59] *Technical grade [R4] MFS: *Ajay North America, LLC, Hq, P.O. Box 127, 1400 Industry Road, Powder Springs, GA 30073-0127, (770) 943-6202; Production site: Powder Springs, GA 30073. [R5] *The Prince Manufacturing Company, Hq, 700 Lehigh Street, Bowmanstown, PA 18030, (610) 852-2345; Production sites: 700 Lehigh Street, Bowmanstown, PA 18030; P.O. Box 1009, Radio Road, Quincy, IL 62306, (217) 222-8854. [R5] OMIN: *IN 1974 US FDA APPROVED USE OF SODIUM SELENITE ... IN FEED OF SWINE, TURKEYS AND GROWING CHICKENS UP TO 16 WK OF AGE; PERMISSIBLE LEVELS ARE 0.1 MG/KG IN SWINE AND CHICKEN FEEDS AND 0.2 MG/KG IN TURKEY FEEDS. PURPOSE OF THESE ADDITIVES IN FEED IS TO PREVENT SELENIUM DEFICIENCIES, WHICH CAN RESULT IN DECR GROWTH RATES, DISEASE AND DEATH. [R6] USE: *REMOVING GREEN COLOR FROM GLASS DURING ITS MFR; ALKALOIDAL REAGENT [R1] *REAGENT IN BACTERIOLOGY; TESTING GERMINATION OF SEEDS; DECORATING PORCELAIN [R2] *MEDICATION *MEDICATION (VET) PRIE: U.S. IMPORTS: *(1984) 6.52X10+8 g [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *TETRAGONAL PRISMS [R1]; *White tetragonal crystals. [R8] BP: *Decomposes [R9, 1981.2] MP: *710 deg C (1310 deg F) (decomposes) [R9, 1981.2] MW: *172.94 [R1] DEN: *Specific gravity: 3.1 (water = 1) [R9, 1981.2] SOL: *INSOL IN ALCOHOL [R1]; *85 g/100 g water at 20 deg C [R9, 1981.2]; *Insoluble in ethanol. [R8] OCPP: *FREELY SOLUBLE IN WATER TO FORM A SLIGHTLY ALKALINE SOLN /PENTAHYDRATE/ [R10] *Selenites are less soluble than the corresponding selenates and are easily reduced to elemental selenium. /Selenites/ [R11] *ACICULAR CRYSTALS; LOSES WATER OF CRYSTALLIZATION IN DRY AIR /SODIUM SELENITE, PENTAHYDRATE/ [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R12] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R12] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R12] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R12] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R12] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R12] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R12] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R12] FIRP: *Extinguish fire using agent suitable for type of surrounding fire. Material itself does not burn or burns with difficulty. Use water in flooding quantities as fog. Use foam, dry chemical or carbon dioxide. Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R13] TOXC: *Toxic gases and vapors may be released in a fire involving ... sodium selenite. [R9, 1981.3] DCMP: *710 deg C (1310 deg F) (decomposes) [R9, 1981.2] *When heated to decomp ... emits toxic fumes of /selenium and disodium oxide./ [R14] EQUP: *Wear appropriate chemical protective gloves, boots and goggles. [R13] OPRM: *Where there is any possibility of exposure of an employee's body to selenium, selenium oxychloride, sodium selenite, sodium selenate, selenium dioxide, or liquids containing these compounds, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. [R9, 1981.4] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with selenium, sodium selenite, or sodium selenate. [R9, 1981.4] *Non-impervious clothing which becomes contaminated with selenium, sodium selenite, sodium selenate, selenium dioxide or liquids containing these compounds should be removed promptly and not reworn until the contaminant is removed from the clothing. [R9, 1981.4] *Skin Exposure: If selenium or its inorganic compounds get on the skin, immediately wash the contaminated skin. If selenium, sodium selenite, sodium selenate, or selenium dioxide soak through the clothing, remove the clothing immediately and wash the skin. If irritation persists after washing, get medical attention. [R9, 1981.5] *Keep material out of water sources and sewers. Avoid breathing dusts and fumes from burning material. Keep upwind. Avoid bodily contact with the material. [R13] SSL: *STABLE IN AIR [R15] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R16] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R17] CLUP: *Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be contained with a flexible impermeable membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. [R18] *Water spill: Adjust pH to neutral (pH 7). If dissolved, apply sodium sulfide (Na2S) solution to precipitate heavy metals. Allow to aerate. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R18] *1. VENTILATE AREA OF SPILL. 2. COLLECT SPILLED MATERIAL IN MOST CONVENIENT AND SAFE MANNER AND DEPOSIT IN SEALED CONTAINERS FOR RECLAMATION OR FOR DISPOSAL IN A SECURED SANITARY LANDFILL. LIQ CONTAINING SELENIUM AND ITS INORGANIC CMPD SHOULD BE ABSORBED IN VERMICULITE, DRY SAND, EARTH, OR SIMILAR MATERIAL. [R9, 1981.4] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *EXPTL THERAPY: PROTECTIVE EFFECTS OF THIOSULFATE, SULFATE, OR AMINO ACIDS AGAINST SELENOSIS IN RATS ARE NOT PREDICTIVE OF PROTECTIVE OR THERAPEUTIC EFFECTS AGAINST ACUTE SELENOSIS IN SWINE. IN PARENTERAL ADMIN, THEY ARE CONTRAINDICATED FOR TREATMENT OF SELENOSIS IN SWINE. [R19] MEDS: *The following medical procedures should be made available to each employee who is exposed to selenium and its inorganic compounds at potentially hazardous levels: 1. Initial Medical Examination: A complete history and physical examination: The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Persons with a history of asthma, allergies, or known sensitization to selenium, or with a history of other chronic respiratory disease, gastrointestinal disturbances, disorders of liver or kidneys or recurrent dermatitis would be expected to be at increased risk from exposure. Examination of the eyes, respiratory system, liver, kidneys, and blood should be stressed. The skin should be examined for evidence of chronic disorders. Special consideration should be given to women of childbearing age since the possibility that selenium may be teratogenic might place these women in a high risk group. Urinalysis: Proper function of the kidneys is necessary to validate levels of selenium in the urine. A urinalysis should be obtained to include at a minimum specific gravity, albumin, glucose, and a microscopic /examination of/ centrifuged sediment. Liver function tests: Selenium causes liver damage and tumors in animals. A profile of liver function should be obtained by using a medically acceptable array of biochemical tests. The aforementioned medical examinations should be repeated on an annual basis. /Selenium and its inorganic compounds/ [R9, 1981.1] HTOX: *... PORPHYRINURIA ACCOMPANYING SEVERE SKIN LESIONS IN A GLASS WORKER, WHO HAD INHALED DUST OF SELENIUM AND SODIUM SELENITE, WAS /ASSUMED/ ASSOCIATED WITH A LATENT DISPOSITION ACTIVATED BY ACTION OF SELENIUM. [R20, 293] */In 1983 Chinese report/ ... a 62 yr old man with moderate dietary intake of selenium who took about 0.9 mg selenium as sodium selenite per day to maintain his health. After 2 yr, his blood and hair levels were 0.179 ug/ml and 0.828 ug/mg, respectively, and it was noticed that he had thickened fragile nails. It was concluded that a daily intake of about 1 mg selenium as selenite can be toxic, and that selenite selenium produces toxic reactions more readily than cereal selenium /(SRP: brewers yeast)/. [R21, p. V2 502] *Human whole blood cultures were exposed to selenium dioxide and selenium in other valence states. The ability of the Se cmpd to induce sister chromatid exchanges in decreasing order of their effectiveness were: Se, selenium dioxide, sodium selenide, sodium selenite, and sodium selenate. [R22] *Long term Exposure: Prolonged exposure to selenium, sodium selenite, sodium selenate, or selenium dioxide may cause paleness, coated tongue, stomach disorders, nervousness, metallic taste and a garlic odor of the breath. [R9, 1981.1] *Four employees exposed to barium and sodium selenite in the glass industry suffered from dermatitis and/or conjunctivitis. In two cases an irritant pathogenesis was assumed; in the other two cases both patients developed an allergic contact dermatitis in part with papulo-follicular morphology. Sodium selenite 0.1% in petrolatum is suitable for patch testing. [R23] *Sodium selenite induces substantial DNA damage in human fibroblasts. This damage appears to consist of the true DNA breaks rather than alkali labile sites and do not arise via free oxygen radical production. Cloning efficiency and DNA strand breakage show dramatically enhanced sensitivity to selenite if the treatments are carried out in the presence of reduced glutathione or, to a lesser degree, serum, supporting the notion that a glutathione selenite conjugant is required for activation to a genotoxic form. In addition, the notion that selenium anticarcinogenicity involves enhancement of cellular DNA repair, has been examined. No evidence for enhancement (or inhibition) of repair of methyl methanesulfonate, UV or bleomycin induced DNA damage was observed in human fibroblasts treated with selenite. [R24] *Morpholfunctional changes in HeLa cell culture following treatment with various concentrations of selenium ion during 2, 4 and 24 hr are described. Variations in mitotic index, duration of separate mitotic stages and a profile of pathologic mitoses were established. Inhibition of cell entry into the S phase of mitotic cycle and modifications of RNA and protein synthesis after treatment with 0.1 and 0.25 ppm of the trace element was shown autoradiographically. Increased destruction of cell monolayer following contact with selenium was demonstrated by light, scanning and transmission electron microscopy. [R25] *SELENIOUS ACID WAS TESTED FOR THE CAPACITY TO INDUCE CHROMOSOME ABERRATIONS IN CULTURED HUMAN LEUKOCYTES. WHEN DETERMINED BY THE AMT OF TOTAL ABERRATION YIELD ON AN EQUIMOLAR BASIS, THE EFFICIENCY TO INDUCE CHROMOSOME ABERRATIONS WAS IN THE ORDER SELENIOUS ACID > SODIUM SELENITE > SELENIUM OXIDE > SELENIC ACID > SODIUM SELENATE. [R26] *... The tumoricidal activity of four currently available selenium forms /was studied/ against a human leukemia cell line. ... Only selenocystine and sodium selenite showed antitumor activity, and these were also the only compounds which demonstrated significant redox chemistry, including depletion of cellular glutathione, stimulation of glutathione reductase, and stimulation of oxygen consumption. ... [R27] *A 62 year old man with a moderate dietary intake of selenium who took about 0.9 mg selenium as sodium selenite per day to maintain his health. After 2 years, his blood and hair levels were 0.179 ug/mL and 0.828 ug/mg, respectively, ... and had thickened fragile nails. ... Daily intake of about 1 mg selenium as selenite can be toxic, and that selenite selenium produces toxic reactions more readily than cereal selenium. [R21, 502] *A 15 year old girl drank selenate solution that contained 1160 mg selenium. She was forced to vomit after 20 min, and was treated with vitamin C and dimercaprol. She developed only slight symptoms (minor arches, irritability and garlic breath). Nevertheless, the initial serum level was 3.1 ug/mL. After two days the serum level was 0.21 ug/mL. There were also minor ECG changes, and tests showed slightly abnormal liver function. [R21, 499] *... A 57 yr old female ... took daily doses of tablets that accidentally contained about 31 mg selenium (probably the major amount in the form of selenite). After approx 11 days she noted marked hair loss which eventually developed into alopecia. ... Two wk later, she noted white horizontal streaking on her fingernails, tenderness and swelling of the finger tips, and purulent discharge. Over a 3 wk period all fingernails were affected, and one fingernail was lost. She had periodic episodes of nausea and vomiting, a sour milk breath odor and felt increased fatigue. ... She had consumed 77 tablets. Four days after the last tablet her serum selenium level was 0.528 ug/ml. /Selenite/ [R21, p. V2 500] *... In human patients with acute myocardial infarction, serum selenite /concn from iv sodium selenite/ were lower than those in controls; this was especially true in the patients with reduced left ventricular function and cardiogenic shock. There was an inverse correlation between serum selenium content and the mortality rate. [R28] NTOX: *SHEEP FED WITH ASTRAGALUS PRUSSI CONTAINING 45.4 PPM OF ORGANIC SELENIUM AT A LEVEL OF 0.33 MG/KG/DAY DIED IN 5-6 DAYS, BUT OTHERS FED AT SAME LEVEL OF SELENIUM IN FORM OF SODIUM SELENITE WERE APPARENTLY NORMAL AFTER 90 DAYS. ACUTE POISONING /MAY ARISE/ ... FROM OVERDOSAGE WITH SODIUM SELENITE GIVEN TO LAMBS TO PREVENT NUTRITIONAL MUSCULAR DYSTROPHY. LD50 ... IS 1.9 MG SELENIUM/KG ... ORALLY, 0.455 ... IM ... ANIMALS SHOW DEPRESSION, ATAXIA, AND DYSPNEA; PULMONARY CONGESTION AND EDEMA, AND DEGENERATIVE CHANGES IN LIVER AND KIDNEY ... LETHAL DOSE SODIUM SELENITE ... PARENTERALLY IN PIG IS 1.2-3.5 MG SELENIUM/KG. CLINICAL SIGNS ... DEPRESSION, VOMITING, ATAXIA AND RAPID PULSE ... . [R29] *SODIUM SELENITE ... TESTED ON RABBIT EYES @ CONCN 0.003-0.05 MOLAR BY APPLICATION TO CORNEA AFTER REMOVAL OF EPITHELIUM OR BY INJECTION INTO CORNEAL STROMA ... CAUSED VERY SEVERE INJURY. [R30] *... THE ADDITION OF 6.4 MG/KG ... OF SELENIUM AS SODIUM SELENITE TO THE DIET OF RATS CAUSED SIGNIFICANT GROWTH DEPRESSION, LIVER CIRRHOSIS AND SPLENOMEGALY ... DIETS CONTAINING 8.0 MG/KG OR MORE CAUSED ... ANEMIA, PANCREATIC ENLARGEMENT, ELEVATED SERUM BILIRUBIN LEVELS AND AFTER 4 WK, DEATH. [R31, 564] *... ANEMIA PRODUCED IN RATS BY FEEDING SODIUM SELENITE @ 5-15 PPM /SRP: OF DIET/ WAS DUE TO HEMOLYSIS. SYNTHESIS OF NEW RED CELLS APPEARED UNAFFECTED. [R32, 358] *... ORAL ADMIN OF AQ SOLN OF SODIUM SELENITE TO RABBITS @ ... 0.005 MG SE/KG BODY WT FOR 7.5 MO RESULTED IN INCR CONCN OF GLUTATHIONE IN BLOOD, DECR ACTIVITY OF SUCCINIC DEHYDROGENASE IN LIVER, AND SOME IMPAIRMENT OF EXCRETORY FUNCTION OF LIVER AND KIDNEYS. INCR NUMBER AND EXTENT OF DENTAL LESIONS WAS OBSERVED IN RATS WHOSE MOTHERS RECEIVED HIGH LEVELS OF SODIUM SELENITE IN ... DRINKING WATER (5-10 MG/L) DURING PREGNANCY AND LACTATION AND WHICH WERE SUBSEQUENTLY EXPOSED TO HIGH SELENIUM DRINKING WATER OVER A PERIOD OF 120 DAYS. [R31, 565] *CATARACT WAS INDUCED BY ADMINISTRATION OF A SINGLE DOSE OF SODIUM SELENITE TO SUCKLING RATS. [R33] *Dose dependent fetocidal effects and fetal growth retardation were observed in mothers injected SC with sodium selenite on day 12 of gestation. On day 12, abortion occurred only at 58.8 umol/kg sodium selenite, whereas on day 16 it occurred at both 27.2 and 40.0 umol/kg. [R34] *Sodium selenite and choline selenite were equitoxic in sheep when tested at 500, 620, 650, and 800 ug Se/kg. Most of the treated sheep died after a single dose. A rapid and weak pulse and respiratory distress were observed in the treated sheep. Hematologic alterations, eg elevated blood urea-N, and microscopic lesions in the lungs and kidneys were observed. Females were more sensitive to Se toxicity than males. [R35] *The study was designed to investigate the effect of sodium selenite (Na2SeO3), sodium selenide (Na2Se), and sodium selenate (Na2SeO4) on induction of sister chromatid exchange (SCE) in the Chinese hamster V79 cell line in the presence and absence of S9 mixture. The most potent SCE inducer in the presence of the S9 mixture was sodium selenite (Na2SeO3). [R36] *The myocardial mitochondrial alterations induced by IP sodium selenite (Na2SeO3) admin in guinea pigs were dose-dependent. The lesions were characterized by swelling, disruption of cristae, and marked cavitation of space. [R37] *Acute and chronic effects of selenium as sodium selenite given as a supplement in drinking water of Sprague Dawley rats for 35 days, 1 yr and 2 yr were compared. For the 35 day study, the groups were untreated controls and rats supplemented with 1, 48, and 64 ppm selenium. Selenium toxicity was apparent in microscopic pathology showing liver congestion, fatty degeneration of parenchymal cells and necrosis. Untreated controls were compared with rats receiving 4 ppm selenium in the drinking water. Liver glutathione peroxidase was 1/2 and selenium levels in the selenium treated rats were 2 fold compared to controls. [R38] *Groups of about 100 male and female weanling Long Evans rats were given 2 mg/l selenium as sodium selenite ... in drinking water (eq to about 4.5 mg/kg of diet) until they were 1 yr of age when the dose was raised to 3 mg/l. A group of 105 controls received no selenium in drinking water. After 58 days ... male rats receiving 2 mg/l sodium selenite were transferred to sodium selenate, since 50% of the animals had died; surviving animals in this group were killed after 596 days and no tumors observed. ... In 32 female selenite treated rats killed between 662-691 days, 4 malignant tumors were found (12.5%). Of the 65 control rats examined, 20 had tumors (30.8%) 11 of which were malignant (16.9%). ... an evaluation of results was not possible because not all autopsied animals were examined histologically and because treated animals lived longer than controls ... (avg lifespan of control males and females was 813 and 814 days and that of treated animals 847 and 929 days, respectively) (Schroeder and Mitchener, 1971a). [R39] *IN MAMMALIAN SYSTEMS, INORG SELENIUM USUALLY IS NOT INCORPORATED INTO AMINO ACIDS ... ALTHOUGH THERE IS SOME EVIDENCE OF INCORPORATION OF SELENIUM FROM SODIUM SELENITE INTO A RABBIT PROTEIN. [R32, 353] *The feasibility of using selenite ion (selenium dioxide (SeO2) or sodium selenite (Na2SeO3)) as a systemic deer repellent for the protection of Douglas fir seedlings is evaluated. When applied to the soil, the selenium (Se) is absorbed by the seedling roots, transported to the foliage, and thereafter volatilized. Acute phytotoxicity is observed only when Se foliar concn exceed 100 ppm, while animal repellency is demonstrated at concn as low as 1-2 ppm. ... [R40] *The subacute toxicity of selenium was tested by feeding sodium selenite to Syrian hamsters at dietary levels of 0.1, 1, 5, 10 or 20 ppm selenium for 42 days. General health, survival and organ weights were not adversely affected at any of the dose levels. Weight gain and food intake were relatively low in males fed the highest dose level. The differences from the control values were not statistically significant and there was no similar effect in females. Hamsters fed 10 or 20 ppm retained considerable higher levels of selenium in the liver than did the controls. Microscopic examination of the liver revealed degenerative changes in males and females in the 20 ppm group. The nontoxic effect level of selenium fed in the diet for 42 days to Syrian hamsters was found to be 10 ppm, equivalent to an intake of about 0.7 mg selenium/kg body weight/day. [R41] *Acute sodium selenite toxicosis was evaluated in 20 female crossbred sheep, 8 to 14 mo of age. Five groups of 4 sheep each were given 0.4, 0.6, 0.7, 0.8, or 1.0 mg selenium/kg body weight IM. The LD50 for sodium selenite was 0.7 mg selenium/kg body weight with a standard error of 0.035 over a 192 hr observation period. The most evident clinical signs were dyspnea and depression. At necropsy, the most consistant lesion in animals which received 0.7, 0.8, and 1.0 mg selenium/kg body weight were edematous lungs and pale mottled hearts. Highest tissue selenium concentrations in declining order found in the liver, kidney and heart. [R42] *Subcutaneous injection of sodium selenite into young rats produces a nuclear cataract within 72 hours. A three fold elevation in lens calcium and a two fold increase in lens inorganic phosphate have been found to precede opacification. Scanning electron micrographs suggested weakened cell-to-cell adhesion in the cataractous nuclear zone. [R43] *Sodium selenite was fed in the diet in concentrations of 3, 1 or 0.50 ppm to hybrid type chicks for 4 weeks from the age of 7 days. The chemical's effects on growth and tissues were investigated. One and 3 ppm dietary levels of selenium caused depression of growth, fatty change, focal necrosis, congestion of the sinusoids and slight fibroplasia in the liver, congestion and degeneration and/or necrosis of the cells of the proximal renal tubules and of the cardiac muscle fibers and hemorrhage in the thigh and breast. These changes were accompanied by an increase in the activity of sorbitol and glutamic dehydrogenases (SDH and GDH) and in the concentration of potassium, and a decrease in the levels of total protein, calcium and zinc in the serum. Susceptibility to hemorrhage and damage to kidneys and liver persisted for 3 weeks after the test diet was withdrawn. One half of 1 ppm selenite meal produced no adverse effects on the chicks. [R44] *... Moderate doses of sodium selenite did not affect the growth of the placenta and fetus significantly /in mice/, whereas high doses of selenite resulted in a large percentage of abortions. ... [R45] *Testis structure and functions were monitored in male Wistar rats chronically exposed to various levels of sodium selenite (Na2SeO3) in drinking water (4, 8 or 16 ppm). The most remarkable testicular changes were observed in the 16 ppm group: intertubular edema, oligospermia, scattered foci of degenerated spermatids were found. In addition, marked changes in several specific enzymes /decrease in sorbitol dehydrogenase, increases in gamma-glutamyl transpeptidase and beta-glucuronidase/ of testicular cells occurred along with a significant reduction of mean tubular diameters, mean tubular areas and mean tubular perimeters. [R46] *The effect of sodium selenite on the body temperature of adult male ICR mice was examined. Sodium selenite (10-60 umol/kg) administration subcutaneously resulted in a transient and dose dependent hypothermia at ambient temperatures of 20 and 30 deg C. Reduced oxygen consumption accompanied the changes in body temperature. In addition, sodium selenite treated mice exhibited transient cold seeking behavior in the thermogradient. This sodium selenite induced hypothermia was very similar to those induced by ethanol, tetrahydrocannabinol, triethyltin, sulfolane, and chlordimeform in that these all were transient, dependent on temp, and not counteracted by behavioral thermoregulation. From these results, involvement of neural afferent or integral pathways is suggested. Further, acute mortality of sodium selenite injected mice was enhanced with the elevation of temp, as in the case of the chemicals mentioned above. [R47] *In a study designed to examine the long term effects of inorganic selenium (IV) on early life stages of rainbow trout (Salmo gairdneri), survival was significantly reduced at selenium concentrations of 47 and 100 ug/l /administered as sodium selenite/ after 90 days of exposure. Length and weight were significantly reduced after 90 days of exposure to 100 ug/l. ... Analysis of trout backbone indicated little change in bone development with exposure to selenium (IV) with one exception; calcium concentrations were significantly decreased in fish exposed to 12 ug/l of selenium. Results ... indicate that a recommended safe level of 10 ug/l for inorganic selenium would not significantly affect growth and survival of rainbow trout; however, concentrations of selenium near this level can reduce the levels of calcium in the backbones of trout. [R48] *The acute toxicities of sodium selenite (Na2SeO3) and sodium selenate (Na2SeO4) to Daphnia magna were determined in defined culture at 22 deg C. For adults, the 48 hr median lethal concn (LC50) values were 0.68 ppm selenium as selenite. [R49] *Isolated hepatocytes incubated with selenite (30-100 uM) exhibited changes in the glutathione redox as shown by an increase in oxygen consumption, oxidation of glutathione and loss of NADPH. Selenite (50 uM) raised oxygen consumption within the 1 hr and induced a partial depletion of thiols with a concomitant increase in oxidized glutathione, as well as a decrease in NADPH levels within 2 hr. With 100 uM selenite more pronounced effects were obtained such as a total depletion of thiols. This concentration of selenite also lysed cells within 3 hr. Arsenite, mercuric chloride and potassium cyanide prevented the increase in oxygen uptake, counteracted loss of thiols and delayed selenite induced lysis. p-Tert-butylbenzoic acid, an inhibitor of gluconeogenesis, decreased selenite dependent oxygen consumption and potentiated the effect on NADPH levels as well as the toxic effect. Finally, methionine further enhanced oxygen consumption by selenite and also delayed loss of thiols and potentiated selenite toxicity. These results indicated that selenite catalyzed a reduction of oxygen in glutathione dependent redox cycles with NADPH as an electron donor. With subtoxic concentrations of selenite (50 uM) there were indications that oxygen reduction was terminated by selenite biotransformation to methylated metabolites. With toxic concentrations of selenite (100 uM) it appeared that oxygen reduction was eventually limited by the capacity of the cell to regenerate NADPH. [R50] *The effects of sodium selenite administration on the appetites of male mice were studied. When compared to phosphate-buffered saline, mice challenged with SS at 30 umol/kg sc, fed more frequently and had greater gastric content over 4 hr than did controls. A dose related effect was noted for two different age groups of mice (9 wk and 17 wk) in that 10 umol sodium selenite/kg had no effect on gastric content at 3 hr post injection, but 30 umol sodium selenite/kg significantly increased gastric content. No age-related difference was demonstrated for this effect. Using quantitation of gastric contents at 3 hr post injection, a chronological comparison revealed that morning (0650 hr) injection of sodium selenite significantly increased the hyperphagic effect of sodium selenite relative to a challenge administered at 1150 hr. Mice receiving 30 umol sodium selenite/kg and deprived of food consumed wooden bedding equivalent to twice the gastric content of mice in the control group. [R51] *ANIMAL TESTS INDICATE THAT SELENITE IS MORE TOXIC THAN SELENATE. [R52] *Selenite cataract is a fairly recently described, experimental animal model for cataract. Selenite cataract has been extensively characterized histologically and biochemically. The model has been particularly useful for studies on the roles of calcium accumulation and lens proteolysis in cataract formation. This review describes current knowledge of the biochemical mechanism for selenite cataract and indicates how the model may be used for further understanding of cataractogenesis in general. [R53] *Rats receiving selenium compounds (generally sodium selenite) in their diets show acute, subacute, and chronic pathologic pictures entirely similar to those seen in rats fed poisonous field-grown grain... . Rats that received selenium (as sodium selenate) at a dietary level of 100 ppm ate little food and all died in 8-16 days; those receiving 50 ppm all died in 10-97 days. A dietary level of 15 ppm was tolerated for 72 days or more, but food intake was about half of normal. All rats survived a dietary level of 7.5 ppm (about 0.37 mg/kg/day) for 6 months, and their growth was normal. [R54] NTXV: *LD50 Lamb oral 119 mg/kg; [R29] ADE: *Absorption of selenite is from the duodenum. Monogastric animals have a higher intestinal absorption than ruminants, probably because selenite is reduced to an insoluble form in rumen. Over 90 percent of milligram doses of sodium selenite may be absorbed by man and widely distributed in organs, with highest accumulation initially in liver and kidney, but appreciable levels remain in blood, brain, myocardium, and skeletal muscle and testis. [R55] *EXCRETION BY LUNG HAS FOLLOWED SC INJECTION ... IN ANIMALS ... SODIUM SELENITE ... IS ELIMINATED BY LUNG ... RAPIDLY AND IN ... GREATER AMT, 17-52% OF ADMIN AMT BEING EXHALED WITHIN 8 HR ... . [R20, 288] *IN MAN ABOUT 93% OF SELENIUM WAS ABSORBED WHEN MG DOSES SODIUM SELENITE WERE ADMIN IN AQUEOUS SOLUTION. THUS, HUMANS, LIKE RATS APPEAR TO HAVE NO HOMEOSTATIC CONTROL TO LIMIT GI ABSORPTION OF LARGE AMOUNTS OF SELENITE. [R31, 560] *... Injected subcutaneously single doses of 0.1-0.7 ug of labelled sodium selenite per kg body weight to mice and found that 15 min and 1 hr later liver contained about 17 and 30% of the admin dose, respectively, but 24 hr later only 3.7%. [R31, 560] *IN SWINE, FECAL EXCRETION OF SELENIUM WAS ABOUT 5 TIMES GREATER WHEN SODIUM SELENITE WAS ADMIN ORALLY THAN ... IV, ALTHOUGH TOTAL EXCRETION WAS THE SAME, REGARDLESS OF ROUTE OF ADMIN. ... SWINE ABSORB SELENIUM BETTER THAN SHEEP, AND THE GREATER FECAL EXCRETION BY SHEEP MAY BE DUE TO BACTERIAL REDN OF SELENITE TO INSOL ... SE. [R32, 352] *(75)Se concn and excretion was studied after admin of (75)Se labeled selenite to male rats during ontogeny. The concn of (75)Se in individual organs decreases with increasing age. The largest differences between young and adults were in the quantity and quality of excreted substances. During 2 hr after admin of 20 umol selenite/kg, young rats excreted 2.4% of the dose, essentially in the urine only, while adults excreted a total of 11%, distributed equally in breath and urine. The part excreted as methylated metabolites was 0.1% of the admin dose in young and 6.3% in adult rats. [R56] *Metal selenide accumulations were demonstrated in the anterior pituitary of the rat by a histochemical technique at light and electron microscopic levels. After administration of sodium selenite either by drinking water (2.5 to 15 ppm) or by ip injection (5 to 20 mg/kg body wt), intracellular accumulations were found in secretory granules and lysosomes of the somatotrophs, thyrotrophs, corticotrophs, and the gonadotrophs. The amount of countable deposits increased with increasing doses, whether selenite was given in drinking water or by ip injections. Localization of deposits was independent of route of administration. Following a single ip injection of 5 mg sodium selenite/kg, a steadily increasing amount of visible deposits was seen throughout the first week. After this peak the deposits started to decrease but could still be found after 2 weeks. Selenium may possibly create bonds to endogenous zinc in the anterior pituitary as has been suggested for the brain. [R57] *Selenium is excreted chiefly in the urine but about 3- 10% is metabolized and excreted by the lungs, and there is some fecal excretion even when sodium selenate is administered subcutaneously ... . When sodium selenite is administered in the same way, 17-52% is exhaled within 8 hr ... . [R54] *SELENITE DISTRIBUTION WITHIN THE LIVER CELL HAS BEEN DETERMINED. MORE THAN HALF IS IN THE CYTOSOL AND DEPENDING ON DOSE AND DIET, THE REST IS VARIABLY DISTRIBUTED IN OTHER FRACTIONS; INJECTED SELENITE IS FOUND MORE IN MITOCHONDRIA THAN IN MICROSOMES OR NUCLEI ... /SELENITE/ [R32, 351] *The excretion pattern of a single exposure to selenite appears to have at least two phases: a rapid initial phase with as much as 15 to 40 percent of the absorbed dose excreted in the urine the first week. There is expotential excretion of the remainder of the dose with a half life of 103 days. /Selenite/ [R55] *SELENIUM CAN REPLACE SULFUR IN NORMAL SULFUR AMINO ACIDS AND SELENITE CAN ALSO BIND TO SULFUR AMINO ACIDS. /SELENITE/ [R58] METB: *... EVIDENCE SUGGESTS THAT RABBITS AND RATS CAN CONVERT SELENITE INTO SELENOCYSTEINE TO SOME EXTENT WHICH IS THEN INCORP INTO TISSUE PROTEINS. [R31, 561] *The addition of sodium selenite (Na2SeO3) to the drinking water of mice for 14 days resulted in the formation of dimethylselenide and also dimethyldiselenide in the breath. Exhalation seems to be a minor form of selenium elimination. [R59] *...EVIDENCE SUGGESTS THAT RABBITS AND RATS CAN CONVERT SELENITE INTO SELENOCYSTEINE TO SOME EXTENT WHICH IS THEN INCORP INTO TISSUE PROTEINS. /SELENITE/ [R31, 561] *TRIMETHYL SELENONIUM ION /IS/...MAJOR EXCRETORY PRODUCT OF SELENIUM METAB IN RATS FED /COMPD INCL/ SELENITE... /SELENITE/ [R60] *Selenium compounds are biotransformed to excretable metabolite, and when given in high doses, a major fraction is excreted within a few days. Major metabolites are methylated selenides, and trimethylselenonium has been identified in rat urine after administration of ... selenite ... /Selenium compounds/ [R21, p. V2 494] *When selenium is consumed as selenomethionine or other organic forms that occur naturally in foods, it is released as selenite by postabsorptive catabolism. /Selenite/ [R61] *Selenite is reductively metabolized by animals to dimethylselenide that requires reduced glutathione. /Selenite/ [R62] BHL: *The excretion pattern of a single exposure to selenite appears to have at least two phases: a rapid initial phase with as much as 15 to 40 percent of the absorbed dose excreted in the urine the first week. There is expotential excretion of the remainder of the dose with a half life of 103 days. /Selenite/ [R55] ACTN: *... Dietary selenium, as sodium selenite, ... appeared to act by enhancing potential conjugative detoxication pathways, rather than by decreasing the potential activation of chemicals via the hepatic cytochrome p450 system. [R63] *Selenium exists in a number of forms with differing valence states, some of which have shown antitumor activity. The tumoricidal activity of four currently available selenium forms against a human leukemia cell line /was studied/. ... Only selenocystine and sodium selenite showed antitumor activity, and these were also the only compounds which demonstrated significant redox chemistry, including depletion of cellular glutathione, stimulation of glutathione reductase, and stimulation of oxygen consumption. ... [R27] *The effects of sodium selenite and sodium selenate on DNA and RNA synthesis have been examined using intact HeLa cells, isolated nuclei and extracted polymerases. Selenate had no effect on any of the systems examined. Selenite inhibited DNA synthesis in intact cells and in isolated nuclei, and to a limited extent also inhibited DNA polymerase alpha. Selenite also inhibited RNA synthesis in intact cells and alpha-amanitin resistant RNA synthesis in isolated nuclei (ie, synthesis catalyzed by RNA polymerase I and III). It had no effect on alpha-amanitin sensitive synthesis (catalyzed by RNA polymerase II) at concentrations up to 500 uM. However, transcription of exogenous DNA by extracted RNA polymerase II (as well as by polymerase I and II) was inhibited by selenite. [R64] *Influence of sodium selenite on functioning of the systems of intracellular generation and detoxication of active oxygen compounds in hepatocarcinogenesis induced by diethylnitrosamine has been studied in rats. It has been shown that the duration of latent period initiated by ions of ferrous iron chemiluminescence of homogenate of the liver rather objectively reflects the state of the functioning of the systems in charge of the formation and utilization of free radicals of oxygen in a cell. It is supposed that one of the mechanisms of anticarcinogenic action of selenium is connected with its antioxidant functions in the organism and consists in the increase of the activity of superoxide dismutase and selenium dependent glutathione peroxidases, providing a reliable level of enzymatic protection of normal cells from ... active oxygen. [R65] *...TOXICITY OF SE IS GENERALLY THE RESULT OF EXCESSIVE ACCUM OF SELENITE ION, AN OXIDANT WHICH MAY INTERFERE WITH GLUTATHIONE METAB. /SELENIUM COMPOUNDS/ [R60] *SELENIUM CAN REPLACE SULFUR IN NORMAL SULFUR AMINO ACIDS AND SELENITE CAN ALSO BIND TO SULFUR AMINO ACIDS. /SELENITE/ [R58] *Lipid peroxidation in silver treated mice was assayed by measuring the malonaldehyde content of liver, kidneys, and brain tissue. Groups of 5 mice received either 2 daily ip injections each of 2 mg/kg sodium selenite pentahydrate (Na2SeO3.5H2O) on successive days or 2 daily sc injections of 0.1 ml saline. Forty eight hr after the last Se injection, the Se treated group and 1 of the control groups received 20 mg/kg silver lactate ip and the other control group received a sodium lactate injection. Livers were analyzed 3 hr after the injection of silver. In a control experiment, 1 group of mice received sodium selinite and another group saline and livers were analyzed 51 hr after the last Se injection. Pretreatment of mice with Se resulted in a significant increase of silver induced lipid peroxidation in liver, when compared with animals exposed to silver alone (p < 0.001) or with controls (p < 0.001). The doses of selenium used in the experiment did not increase or decrease lipid peroxidation. /Sodium selenite pentahydrate/ [R66] *The objectives of this study were a) to compare the efficacy of inorganic or organic selenium compounds in protecting against mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene; in rats and b) to study the interaction of vitamin C with either selenite (inorganic) or seleno-DL-methionine (organic) in chemoprevention. Control Sprague Dawley rats were fed a purified 5% corn oil diet containing 0.1 ppm selenium. Selenite or seleno-DL-methionine was added to the basal diet in concentrations of 2, 3, or 4 ppm starting 1 week after 7,12-dimethylbenz(a)anthracene administration. The inhibitory response in mammary tumorigenesis with selenium supplementation was dose dependent. Both selenium compounds were found to be equally efficacious in prophylaxis, although at the 4 ppm level a slight reduction in growth was observed. /Selenite/ [R67] INTC: *The highest lead concn (1 mM) reduced the percentage of selenite absorbed from the in situ ligated duodenal loop, but did not influence the retention of the orally admin cmpd. [R68] *Three days after pretreatment of rats of both sexes with sodium selenite (2.4 mg Se/kg ip), the duration of pentobarbital induced hypnosis was potentiated in males but not in females. [R69] *Acute treatment with sodium selenite effectively reduces bromobenzene hepatotoxicity in male rats. [R70] *The effects of cadmium, mercury, and three different chemical forms of selenium (selenite, selenocystine, and selenomethionine) on ram spermatozoa motility and oxygen consumption in vitro were studied over a 4 mo period. Concentrations of 10(-6) to 10(-2) M cadmium and mercury were injurious to spermatozoa as indicated by depressed motility and reduced oxygen uptake. Equimolar concentrations of selenium as selenite, selenocystine, or selenomethioine counteracted the toxicity of cadmium and mercury at low concentrations (10(-5) and 10(-6) M) but not at higher concentrations (10(-4) to 10(-2) M). ... [R71] *Male Porton Wistar rats were tested to determine the protection exerted by selenite, selenomethionine, selenium, or biological selenium (in the form of the liver soluble fraction from animals treated with sodium selenite) against the toxic effects of mercury. Mercury was given as mercuric chloride, injected subcutaneously in doses of 2.5, or 7.5 umoles/kg. The animals received equimolar doses of selenium compounds at the time of treatment with mercury. A reduction in the level of mercury in the urine was recorded 48 hours after treatment with both biological selenium and selenomethionine. Treatment with selenite induced a greater decrease in the levels of urinary mercury, together with a significant reduction of the levels of mercury in the kidney. The activity of alkaline phosphatase in urine and the levels of plasma urea nitrogen recorded in animals treated with mercury in doses of 2.5 or 5 umoles/kg were lowest in the rats treated with selenium, followed by biological selenium, and selenite in that order. The degree of necrosis seen in the proximal kidney tubules of animals treated with 5 or 7.5 umoles/kg mercury showed the same pattern, while in animals treated with the lowest dose of mercury necrotic damage was slight. These results support the hypothesis that the protective effect of selenium against mercury renal toxicity is due to the formation of mercury selenide. [R72] *The biotransformation efficiency of alkylmercurial compounds was studied in rat liver, kidneys, blood, and brain after 2 week administration of methylmercuric chloride and ethylmercuric chloride at doses of 0.25 or 2.5 mg mercuric ion/kg, alone or in combination with sodium selenite at a level of 0.5 mg selenium/kg. Simultaneously, the level of metallothionein like proteins and endogenous copper was monitored in tissues of control rats and intoxicated rats. Regardless of the dose, the highest concentrations of inorganic mercury from both the alkylmercurials was found in the rat kidneys. Sodium selenite had a variable effect on the amount of inorganic mercury liberated, depending on the organ and the molar ratio of mercury:sodium selenite administered. A statistically significant increase in the levels of metallothionein like and endogenous copper, compared with control group, was found only in the kidneys of intoxicated rats. This increase was dependent on the concentration of inorganic mercury liberated by biotransformation of alkylmercurials. The observed changes appeared when the level of inorganic mercury exceeded 10 ug mercury/g tissue and reached a plateau at about 40 ug mercury/g tissue. In the presence of selenium the plateau of metallothionein like and endogenous copper levels were not observed in the kidneys, regardless of the amount of inorganic mercury liberated. [R73] *Repeated doses of sodium selenite were administered to rats receiving repeated (IV or PO) doses of 0.25 or 2.5 mg Hg/kg methylmercuric chloride. Sodium selenite (0.5 mg/kg) was observed to alter the distribution of methylmercuric chloride among tissues as well as among subcellular fractions of kidneys and liver. An excess of selenium resulted in a twofold decrease in the mercury content of kidneys and a similar increase in the mercury content of brain. [R74] *The clastogenic effects of selenium were studied in short-term lymphocyte cultures. ... Cells from non-smoking, healthy individuals were exposed to individual agents and combinations of the four agents (sodium arsenite, lead acetate, sodium sulfite and sodium selenite) and the cells were analysed for chromosome aberrations and sister chromatid exchanges. Selenium showed an antagonistic (protective) effect against the other agents. No synergistic effects were found, and the interactions between arsenic, lead and sulfur dioxide were mainly antagonistic. ... Mixed exposure from copper smelters, and other mixed exposures where arsenic, lead and sulfur dioxide are involved, may cause less genetic damage than expected and that an adequate dietary supplement of selenium may reduce the genotoxic effects of these chemicals. [R75] *The protection offered by selenium against the genetic damage caused by lead was investigated using 145 female laboratory bred white rats, Rattus norvegicus. Rats were exposed to lead acetate at concentrations of 2.5 mg/100 g body weight (mg/100 g). Some animals also received sodium selenite at concentrations of 0.012, 0.024, 0.031, or 0.047 mg/100 g. Rats were treated for 5, 10 or 15 days and sacrificed on days 6, 11, and 16. Acute exposures were at 20 mg/100 g lead acetate and 0.188 mg/100 g selenite given immediately after or 1 hour before or after the lead salt. Bone marrow cells were examined for chromosome abnormalities. The clastogenic effects of chronic treatment with lead acetate were reduced by very small quantities of sodium selenite when given concurrently. The most effective protection was obtained with the 0.024 mg/100 g selenite dose. ... When administered 1 hour after lead acetate, the selenium salt had no protective effect and all the rats died. However, when selenium was given 1 hour before lead exposure, protective action was observed. ... [R76] *Male Sprague Dawley rats were tested to determine the effects of cadmium and selenium on the glutathione metabolism of Leydig and Sertoli cells in the testis and to determine whether the increase in the activity of glutathione peroxidase is associated with the increase in the concentration of heme in the cells. ... The effects of cadmium on rat testis were suppressed by the prior administration of sodium selenite, which also suppressed the increased in the activity of glutathione peroxidase. [R77] *Weanling male Sprague-Dawley rats were used to determine the effects of selenium (Se) supplementation on cadmium (Cd) toxicity manifestations and renal Cd retention. Biological interactions of Se with sulfur (S) supplied as sulfate were also studied. The animals (8/group) were fed (5-6 wk) a Torula yeast based Se deficient diet. For some groups, the basic diet was supplemented with 0.5 mg/kg Se. Supplemental Cd was added to the distilled, deionized drinking water (25 mg/l), and S, supplied as sulfate (2%) was added to the basic diet. Animals on a diet supplemented with Se showed the following: (a) significant weight increase; (b) relative kidney weight reduction; (c) large increases in heart and kidney selenoenzyme glutathione peroxidase activity. Relative heart weight, blood hemoglobin, and systolic blood pressure levels were not affected by Se. Se-supplemented diets to which Cd was added caused significant (p < 0.005) weight increases in rats. Heart weight increases caused by Cd were reduced in the group fed supplemental Se. [R78] *Male ICR mice, a group of 5, were ip injected with sodium arsenite (5.0 mg As/kg body weight) and selenite (5.3 mg Se/kg body weight) to determine their interaction in regard to the amount of induced zinc-thionein. Injection of selenite caused the production of a large amount of hepatic zinc thionein. When selenite was co-administered with sodium arsenite the level of zinc-thionein was approximately one fifth that observed with selenite alone, and was about equal to the level induced by arsenite alone. [R79] *The effect of sodium selenite on renal toxicity and antitumor activity of cis-diamminedichloroplatinum (CDDP) repeatedly admin to mice inoculated with Ehrlich ascites tumor cells was examined. The growth of Ehrlich ascites tumor cells was inhibited by selenite given in combination with CDDP. [R80] *Sodium selenite (6.3 mg/kg ip) injected 2 hr prior to the admin of cisplatin (14 mg/kg ip) in mice prevented the increase of blood urea nitrogen induced by the toxic effect of cisplatin on the kidney. [R81] *The effects of exposure to selenium and nickel on the frequency of pulmonary adenomas induced by urethan in mice were investigated. Groups of female Swiss cross mice were exposed every other day for 15 weeks to either 3 ug/ml sodium selenite or to 100 ug/ml nickelous chloride in drinking water. Other groups were exposed on successive days to both metals. After 3 weeks of treatment, the mice were administered 1.5 mg/kg of urethan ip. The mice were killed at the end of the 15 week period. Mice exposed to nickel or selenium showed no clinical toxicity and no difference in wt gain compared to controls. Sleep time induced by urethan (a measure of urethan metabolism and excretion) was significantly reduced by selenium exposure but not nickel exposure. Exposure to selenium alone did not significantly affect the size or number of urethan induced adenomas. Exposure to nickel alone increased adenoma size but had no effect on tumor number. Combined selenium and nickel exposure appeared to produce more tumors than the corresponding single metal exposure treatments. Interactions associated with tumor size and tumor number following combined selenium and nickel exposure, suggests that the immunological and carcinogenic or anticarcinogenic actions of nickel and selenium differ considerably from the corresponding mechanism controlling urethan induced carcinogenesis. [R82] *The chemopreventive efficacies of selenate, selenite, selenium dioxide, selenomethionine and selenocystine were examined during the promotion phase of carcinogenesis in the 7,12-dimethylbenz(a)anthracene-induced mammary tumor model in rats. Each agent was added to the diet of a final concentration of 3 ppm selenium. In general, there was no significant difference in the potency of these five selenium compounds in inhibiting the development of mammary tumors. The interaction of vitamin E (500 ppm) with either selenite or selenomethionine was further characterized in a second carcinogenesis study. Results of this experiment suggested that vitamin E enhanced the protective effect of selenite but not that of selenomethionine. In an attempt to explore the synergistic mechanism of selenium and vitamin E, the effects of these two agents on mitogen induced blastogenesis and natural killer cytotoxic activity were also investigated. No consistent changes in these in vitro immune functions were detected resulting from supranutritional feeding of either selenite or vitamin E or both. ... /Selenite/ [R83] *The objectives of this study were a) to compare the efficacy of inorganic or organic selenium compounds in protecting against mammary tumorigenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA); in rats and b) to study the interaction of vitamin C with either selenite (inorganic) or seleno-DL-methionine (organic) in chemoprevention. Control Sprague Dawley rats were fed a purified 55 corn oil diet containing 0.1 ppm selenium. Selenite or seleno-DL-methionine was added to the basal diet in concentrations of 2, 3, or 4 ppm starting 1 week after DMBA administration. The inhibitory response in mammary tumorigenesis with selenium supplementation was dose dependent. Both selenium compounds were found to be equally efficacious in prophylaxis, although at the 4 ppm level a slight reduction in growth was observed. /Selenite/ [R67] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ BION: *Selenium is an integral component of glutathione peroxidase, an enzyme that metabolizes hydroperoxides. [R84] */SELENIUM/ ... IS ... AN ESSENTIAL ELEMENT IN PREVENTING LIVER NECROSIS IN RATS AND EXUDATIVE DIATHESIS IN CHICKS ... IT IS A ... REQUIREMENT FOR MAX GROWTH. ... DIETARY FACTOR KNOWN AS FACTOR 3 IS AN ORG CMPD CONTAINING SELENIUM AND ... IS REPLACEABLE BY SELENITE IN UG QUANTITIES ... /SELENIUM CMPD/ [R20, 287] THER: *EXPTL USE: DIETARY SODIUM SELENITE @ 1 PPM MARKEDLY REDUCED THE NUMBER OF PAPILLOMAS INDUCED BY COMBINATION OF DMBA CROTON OIL AND BY BENZO(A)PYRENE. [R32, 365] *EXPTL USE: PROPHYLACTIC ADMIN OF 1 MG/KG SE AS SODIUM SELENITE DECREASED THE BLOOD PRESSURE RISE IN RATS WITH RENAL HYPERTENSION. [R85] *MEDICATION (VET): /IN DEFICIENCY STATE TREATMENT/ ... INORG COMPLEXES ... SUCH AS SODIUM SELENITE ARE ... USED. ... CHIEF INDICATIONS ARE IN: MUSCULOSKELETAL DISORDERS: STIFF LAMB DISEASE; WHITE MUSCLE DISEASE ... MYOSITIS, AZOTURIA ... PARAPLEGIA, METASTATIC CALCIFICATION OF MUSCLE, ARTHRITIC AND RHEUMATIC SYNDROMES. DERMATITIS: PRURITIS, EXUDATIVE OR HYPERTROPHIC SYNDROMES. ... CARDIOVASCULAR DISEASES: CALCIFICATION, ENDOCARDITIS, MYOCARDITIS, EDEMATOUS CONDITIONS, CARDIAC NECROSIS, AND MULBERRY HEART DISEASE (SWINE). REPRODUCTIVE PROBLEMS: INFERTILITY ... TESTICULAR ATROPHY, ABORTION OR FETAL DEATH ... PREMATURE BIRTHS, RETAINED PLACENTA ... DECR HATCHABILITY ... [R86] *Exptl Use: Sodium selenite (Na2SeO3) injected ip increased the longevity of mice inoculated with L1210 cells. Admin of 40 ug selenium as sodium selenite daily for 7 days resulted in a 65% increase in longevity of mice inoculated with (10)5 L1210 cells. Selenium admin as sodium selenite was shown to be more effective in increasing the longevity of L1210 inoculated mice than was treatment with selenocystine, or selenomethionine. Sodium selenite treatment at 20, 30, or 40 ug/day in mice inoculated with (10)2 cells resulted in 50, 80, or 90% cures, respectively. [R87] *Orally admin sodium selenite has been found to be extremely effective in reducing, but not completely eliminating Keshan Disease, an endemic cardiomyopathy associated with severe Se deficiency in the Peoples Republic of China. [R88] *MEDICATION (VET): Selenium, vitamin E capsules. (a) Specifications, The capsules contain 2.19 mg of sodium selenite (equivalent to 1 mg of sodium selenium) and 56.2 mg of vitamin E (68 IU) (as d-alpha tocopheryl acid succinate) or 0.548 mg of sodium selenite (equivalent to 0.25 mg of selenium and 14 mg of vitamin E (17 IU) (as d-alpha tocopheryl acid succinate). (b) Conditions of use. (1) The drug is intended for use as an aid in alleviating and controlling inflammation, pain, and lameness associated with certain arthropathies in dogs. (2) The capsules are administered orally with the larger capsules administered at a dosage level of 1 capsule per 20 lb of body weight to a maximum of 5 capsules with the dosage repeated at 3 day intervals until a satisfactory therapeutic response is observed. A maintenance dosage is then administered consisting of 1 capsule per 40 lb of body weight, with a minimum of 1 capsule, given every 3 days, or longer, as required to maintain improvement or an asymptomatic condition. For dogs under 20 lb of body weight, the small capsules are administered orally at a dosage level of 1 per 5 lb of body weight with a minimum of 1 capsule which dosage is repeated at 3 day intervals until a satisfactory response is observed then a maintenance regimen is initiated with 1 capsule per 10 lb of body weight, minimum of 1 capsule, every 3 days, or 7 days, or longer as required to maintain continued improvement or an asymptomatic condition. (3) Federal law restricts this drug to use by or on the order of a licensed veterinarian. [R89] *MEDICATION (VET): Mineral supplement and nutritional source of selenium for domestic animals, especially chickens and swine [R4] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Selenium, sodium selenite, sodium selenate, or selenium dioxide can affect the body if they are inhaled, if they come in contact with the eyes or skin, or if they are swallowed. Selenium oxychloride and selenium dioxide may enter the body through the skin. [R9, 1981.1] *... by ingestion. [R18] *... PORPHYRINURIA ACCOMPANYING SEVERE SKIN LESIONS IN A GLASS WORKER, WHO HAD INHALED DUST OF SELENIUM AND SODIUM SELENITE, WAS /ASSUMED/ ASSOCIATED WITH A LATENT DISPOSITION ACTIVATED BY ACTION OF SELENIUM. [R20, 293] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.2 mg/cu m. /Selenium compounds, as Se/ [R90] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Sodium selenite is included on this list. [R91] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 50 ug/l /Selenium/ [R92] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 45 ug/l /Selenium/ [R92] +(ME) MAINE 10 ug/l /Selenium/ [R92] +(MN) MINNESOTA 30 ug/l /Selenium/ [R92] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Selenium and compounds/ [R93] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free telephone number of the NRC is (800) 424-8802; In the Washington metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.6 (section IV. D.3.b). [R94] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Sodium selenite is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100/10,000 lbs. [R95] RCRA: *D010; A solid waste containing selenium (such as sodium selenite) may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R96] FDA: *The food additive selenium fed as a nutrient in the form of sodium selenite or sodium selenate may be safely used on chickens, swine, turkeys, sheep, beef cattle, dairy cattle, and ducks when used in accordance of prescribed conditions. [R97] *Specifications and conditions for use of sodium selenite vitamin E capsules are given. [R89] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Whiting RF et al; Mutagenic and Antimutagenic Activities of Selenium Compounds in Mammalian Cells; Selenium Biol Med, Proc Int Symp, 2nd: 325-30 (1981). A review with 7 ref on the mutagenicity and antimutagenicity of sodium selenite and selenocystine in mammalian cells. WHO; Evaluation of The Available Toxicity Data On Selenium (1987). Properties and analysis; sources, levels and transport in the environment; human exposure; metabolism; animal studies; effects on man; evaluation of the health risks; quantitative assessment of exposure. NTIS; Govt Reports Announcements and Index (GRA and I), Issue 14 (1987). This bibliography contains citations concerning the toxicity, carcinogenicity, environmental pollution, and other hazards and adverse effects of selenium. The detection, characterization, analytical methods, and removal from the environment are discussed. Pollution from coal fired and geothermal power plants are considered. (This updated bibliography contains 349 citations, none of which are new entries to the previous edition.) [Najael; Revue g'en'erale de s'ecurite - RGS 63: 65-72 (1987). Information note on the harmful effects of selenium compounds. Physical and chemical properties of selenium and its principal compounds; uses; pathology and toxicology (irritation of the skin and mucous membranes; these irritations are compensable under French law); radioactive selenium; fire hazards; French regulations; protection. Environ Health Criteria: Selenium 58 (0): 1-306 (1987) Olson OE; J Am Coll Toxicol 5 (1): 45-70 (1986). A review with 208 refs in which the toxicity of selenium and its cmpd is discussed. Buell DN; Semin Oncol 10 (3): 311-21 (1983). Clinical and metabolic features of the trace element selenium and the full spectrum of its animals and human toxicity have been reviewed. USEPA; Chemical Safety Information Sheet: Sodium Selenite (1985) DHHS/NTP; NTP Toxicity Studies of Sodium Selenate and Sodium Selenite Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 38 NIH Publication No. 94-3387 (1994) SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1482 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1068 R3: Aronson, C.E. (ed.). Veterinary Pharmaceuticals and Biologicals, 1982-1983. Edwardsville, Kansas: Veterinary Medicine Publishing Co., 1983. R4: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 212 R5: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 895 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 248 (1975) R7: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-352 R8: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 4-87 R9: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R10: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2131 R11: US Dept of Interior/Fish and Wildlife Service Contaminant Reviews; Selenium Hazards to Fish, Wildlife, and Invertebrates: A Synoptic Review Biol Rept No (85)1.5 p.3 (1985) R12: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-151 R13: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 993 R14: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2995 R15: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1241 R16: 49 CFR 171.2 (7/1/96) R17: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 209 R18: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.640 R19: HATCH RC ET AL; AM J VET RES 40 (12): 1808-11 (1979) R20: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. R21: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986. R22: Ray JH, Altenburg LC; Mutat Res 78 (3): 261-6 (1980) R23: Richter G et al; Derm Beruf Unwelt 35 (5): 162-4 (1987) R24: Snyder RD; Cancer Lett 34 (1): 73-81 (1987) R25: Avtsyn AP et al; Vopr Onkol 32 (8): 77-89 (1986) R26: NAKAMURO K ET AL; MUTAT RES 40: 177-84 (1976) R27: Batist G et al; Cancer Res 46 (11): 5482-5 (1986) R28: Peters HJ et al; Math Naturwiss Reihe 35 (2): 195-204 (1986) R29: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 71 R30: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 935 R31: Friberg, L., G.R. Nordberg, and V.B. Vouk. Handbook on the Toxicology of Metals. New York: Elsevier North Holland, 1979. R32: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R33: OSTADALOVA I ET AL; EXPERIENTIA (BASEL) 34 (2): 222-3 (1978) R34: Yonemoto J et al; Teratology 28 (3): 333-40 (1983) R35: Soffietti G et al; Arch Vet Ital 34 (5): 65-79 (1983) R36: Sirianni SR, Huang CC; Cancer Lett (Shannon, Ireland) 18 (1): 109-16 (1983) R37: Dini G et al; Exp Mol Pathol 36 (34): 326-32 (1982) R38: Jacobs M, Forst C; J Toxicol Environ Health 8 (4): 575-86 (1982) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 251 (1975) R40: Allan GG et al; For Ecol Manage 7 (3): 163-81 (1984) R41: Beems RB, van Beek L; Food Chem Toxicol 23 (10): 945-7 (1985) R42: Blodgett DJ, Bevill RF; Vet Hum Toxicol 29 (3): 233-6 (1987) R43: Bunce G E et al; Curr Eye Res 3 (2): 315-20 (1984) R44: Dafalla R, Adam SE; Vet Hum Toxicol 28 (2): 105-8 (1986) R45: Hau J et al; Lab Anim 21 (1): 26-30 (1987) R46: Nebbia C et al; Res Commun Chem Pathol Pharmacol 58 (2): 183-97 (1987) R47: Watanbe C, Suzuki; Toxicol Appl Pharmacol 86 (3): 372-9 (1986) R48: Hunn JB et al; Water Res 21 (2): 233-8 (1987) R49: Johnston PA; Aquat Toxicol 10 (5-6): 335-52 (1987) R50: Anundi I et al; Chem Biol Interact 50 (3): 277-88 (1984) R51: Ohba T et al; Toxicol Lett 39 (2-3): 275-81 (1987) R52: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 208 R53: Shearer TR et al; Curr Eye Res 6 (2): 289-300 (1987) R54: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 558 R55: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 719 R56: Ostadalova I et al; Arch Toxicol 49 (3-4): 247-52 (1982) R57: Thorlacius-Ussing O, Danscher G; Toxicol Appl Pharmacol 81 (1): 67-74 (1985) R58: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 977 R59: Jiang S et al; Experientia 39 (3): 293-4 (1983) R60: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. 244 R61: Olson et al; Phytochem 9: 1181-88 (1970) R62: Combs CF, Combs SB; Ann Rev Nutr 4: 257-80 (1984) R63: Davies MH et al; Drug Nutr Interact 5 (3): 169-79 (1987) R64: Frenkel GD; Toxicol Lett 25 (2): 219-23 (1985) R65: Babenko GA et al; Eksp Onkol 8 (4): 31-3 (1986) R66: Rungby J; Toxicology 45: 135-42 (1987) R67: Ip C; JNCI 77 (1): 299-303 (1986) R68: Mykkanen H, Humaloja T; Biol Trace Elem Res 6 (1): 11-7 (1984) R69: Schnell RC, Early JL; Res Commun Chem Pathol 32 (3): 561-4 (1981) R70: Merrick BA et al; Toxicol Appl Pharmacol 72 (1): 102-10 (1984) R71: Alabi NS et al; Biol Reprod 33 (4): 911-9 (1985) R72: Magos L et al; Arch Toxicol 60 (6): 422-6 (1987) R73: Brze'znicka EA, Chmielnicka J; Environ Health Perspect 60: 423-31 (1985) R74: Brze'znicka EA, Chmielnicka J; Environ Health Perspect 60: 411-21 (1985) R75: Beckman L, Nordenson I; Hum Hered 36 (6): 397-401 (1986) R76: Chakraborty I et al; Toxicol Lett 37 (1): 21-26 (1987) R77: Chung AS, Maines MD; Biochem Pharmacol 36 (8): 1367-72 (1987) R78: Christensen MJ et al; Arch Environ Contam Toxicol 16 (6): 717-22 (1987) R79: Maitani T et al; Toxicol Lett 39 (1): 63-70 (1987) R80: Naganuma A et al; J Pharmacobio-Dyn 7 (3): 217-20 (1984) R81: Antidotes for antitumor Platinum Drugs; Jpn Kokai Tokkyo Koho Patent No 83 96024 06/07/83 (Stockel, Richard F) R82: Blakely BR; J Appl Toxicol 7 (6): 387-90 (1987) R83: Ip C, White G; Carcinogenesis 8 (12): 1763-6 (1987 R84: Rotruck et al; Science 179: 588-90 (1973) R85: HILSE H ET AL; ACTA PHYSIOL PHARMACOL BULG 5 (3): 47-50 (1979) R86: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 522 R87: Milner JA, Hsu CY; Cancer Res 41 (5): 1552-6 (1981) R88: Combs GF, Combs SB; Ann Rev Nutr 4: 257-80 (1984) R89: 21 CFR 520.2100 (4/1/88) R90: 29 CFR 1910.1000 (7/1/98) R91: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R92: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R93: 40 CFR 401.15 (7/1/87) R94: 51 FR 34534 (9/29/86) R95: 40 CFR 355 (7/1/97) R96: 40 CFR 261.24 (7/1/96) R97: 21 CFR 573.920 (4/1/88) RS: 75 Record 87 of 1119 in HSDB (through 2003/06) AN: 779 UD: 200302 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-BROMIDE- SY: *M-B-R-98-; *AI3-01916-; *Bercema-; *Tri-Brom-; *BROM-METHAN- (GERMAN); *BROMOMETANO- (ITALIAN); *BROMOMETHANE-; *Brom-O-Sol-; *BROMUR-DI-METILE- (ITALIAN); *BROMURE-DE-METHYLE- (FRENCH); *BROOMMETHAAN- (DUTCH); *Caswell-No-555-; *CURAFUME-; *Detia-Gas-Ex-M-; *Dowfume-MC-2-; *Dowfume-MC-33-; *Dowfume-MC-2-Soil-Fumigant-; *EDCO-; *EMBAFUME-; *Brom-O-Gas-; *Brom-O-Gas-Methyl-Bromide-Soil-Fumigant-; *HALON-1001-; *HALTOX-; *ISCOBROME-; *KAYAFUME-; *MB-; *MBC-Soil-Fumigant-; *MBC-33-Soil-Fumigant-; *MBX-; *Dowfume-MC-2R-; *Dowfume-MC-2-Fumigant-; *MEBR-; *Metabrom-; *METHANE,-BROMO-; *Meth-O-Gas-; *METHOGAS-; *Superior-Methyl-Bromide-2-; *METHYLBROMID- (GERMAN); *Methyl-fume-; *METYLU-BROMEK- (POLISH); *MONOBROMOMETHANE-; *PESTMASTER-; *Pestmaster-Soil-Fumigant-1-; *Drexel-Plant-Bed-Gas-; *ROTOX-; *TERABOL-; *Terr-O-Gas-; *ZYTOX- RN: 74-83-9 MF: *C-H3-Br SHPN: UN 1062; Methyl bromide, liquid (including up to 2% chloropicrin) IMO 2.3; Methyl bromide NA 1581; Methyl bromide and more than 2% chloropicrin mixtures, liquid UN 1647; Methyl bromide ethylene dibromide mixtures, liquid NA 1955; Methyl bromide and nonflammable, nonliquefied compressed gas mixture, liquid (including up to 2% chloropicrin) IMO 6.1; Methyl bromide ethylene dibromide mixtures, liquid STCC: 49 214 38; Methyl bromide and ethylene dibromide mixture, liquid 49 214 37; Methyl bromide and more than 2% chloropicrin mixture, liquid 49 214 39; Methyl bromide and nonflammable nonliquefied compressed gas mixture, liquid 49 214 40; Methyl bromide, liquid (including up to 2% chloropicrin) HAZN: U029; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ESTERIFICATION OF METHANOL WITH HYDROGEN BROMIDE. [R1] *ADDITION OF SULFURIC ACID TO SODIUM BROMIDE AND METHANOL WITH THE METHYL BROMIDE REMOVED BY DISTILLATION. [R1] *Action of bromine on methanol in the presence of phosphorus, with subsequent distillation. [R2] *... PROPOSED PROCESSES INVOLVE THE REACTION OF HYDROGEN BROMIDE WITH EXCESS METHYL CHLORIDE AT 400-500 DEG C AND THE THERMAL OR PHOTOCHEMICAL REACTION OF BROMINE CHLORIDE WITH METHANE. [R3] IMP: *Methyl bromide is sold as the essentially pure cmpd, 99.5% minimum purity, with not more than 0.010% water and 0.001% acidity as HBr. [R4] FORM: *FORMULATIONS INCLUDE MIXTURES WITH ETHYLENE DIBROMIDE OR OTHER FUMIGANTS, WITH OR WITHOUT CHLOROPICRIN /UP TO 2%/ TO SERVE AS WARNING AGENT, AND HYDROCARBONS AS INERT DILUENTS. [R3] *(BROMO-O-GAS): METHYL BROMIDE 98%, CHLOROPICRIN 2% [R5, p. V-101] *Dowfume MC-2: methyl bromide 98%/wt, chloropicrin 2%/wt. Dowfume MC-33: methyl bromide 67%/wt, chloropicrin 33%/wt [R5, p. V-202] *MBC Soil Fumigant: 68.6% methyl bromide, 1% chloropicrin, petroleum hydrocarbons 30.0%. MBC-33 Soil Fumigant: methyl bromide 67%, chloropicrin 33%. [R5, p. V-394] *Pestmaster Soil Fumigant-1 /is/ trademark for a mixture of methyl bromide 98%, chloropicrin 2%. [R6] *Grades: Technical; pure (99.5% minimum) [R2] *Mixtures (methyl bromide+) chloropicrin; GA (gas) [R7] *Terr-O-Gas 100%, 98%, 80%, 75%, 70%, 67%, 57%, 50%, 45%, 33%. [R8] *Bromo-O-Gas and M-B-R 98; solution-ready to use, 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Brom-O-Gas (contains 1% chloropicrin), pressurized gas; 99.0% methyl bromide, 1.0% chloropicrin. [R9] *Brom-O-Gas Methyl Bromide Soil Fumignt, 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Drexel Plant Bed Gas, pressurized gas; 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Dowfume MC-2R, solution-ready to use; 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Methyl Bromide Rodent Fumigant (with chloropicrin), pressurized gas; 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Tri-Brom, pressurized gas; 99.0% methyl bromide. [R9] *Superior Methyl Bromide-2, solution-ready to use; 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Dowfume MC-2 Fumigant, solution-ready to use; 98.0% methyl bromide, 2.0% chloropicrin. [R9] *Methyl Bromide Rodent Fumigant (with chloropicrin) [R9] *USEPA/OPP Pesticide Code: 522200 [R10] *Pesticide Code: 053201 [R11] *M-B-C Fumigant [R12] MFS: *Albemarle Corp., 451 Florida St., Baton Rouge, LA 70801, (225) 288-8011; Production site: Magnolia, AR 71753 [R13] *Great Lakes Chemical Corp., One Great Lakes Blvd., P.O. Box 2200, West Lafayette, IN 47906, (765) 497-6100; Production site: El Dorado, AR 71730 [R13] OMIN: *It is ordinarily marketed as a condensed liquid (which may have a warning agent added) in a pressurized container. [R14] *... SINCE CHEM IS A GAS AT ORDINARY TEMP IT IS APPLIED FROM CONTAINERS INTO WHICH IT HAS BEEN COMPRESSED AS A LIQUID. IT READILY VAPORIZES @ TEMP ORDINARILY ENCOUNTERED IN FUMIGATING. [R15] *THE BAN ON ETHYLENE DIBROMIDE AS A SOIL FUMIGANT HAS BOLSTERED METHYL BROMIDE'S PREDOMINANCE IN THE MARKET. [R16] *DOW CLOSED ITS 21 MILLION LB PLANT AT MIDLAND, MI IN AUGUST, 1983. [R16] *Because of its toxicity, there has been considerable concern against distributing this gas in small fire extinguishers. [R17] *It is packed in glass ampoules (up to 50 ml), in metal cans and cylinders for direct use. [R18] USE: *For Methyl bromide (USEPA/OPP Pesticide Code: 053201) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R11] *In ionization chambers, degreasing wool, extracting oils from nuts, seeds, and flowers. [R17] *Fumigant used to treat soil a wide range of grains, and other commodities, mills warehouses, and houses. [R19, 4022] *... Has been used as a refrigerant and fire extinguisher; ... . [R20, 1991.945] *Used for insect and rodent control in space and commodity fumigations; for preplant soil fumigation (only with chloropicrin) to control nematodes, insects, weed seeds and fungi. [R21] *Used in food sterilization for pest control in fruits, vegetables, dairy products, nuts, and grain; as solvent in aniline dyes. [R22, 1981.3] *As methylating agent, especially for prepn of antipyrine and other pharmaceuticals. [R23] *The first recorded use of methyl bromide occurred in the last /part of the/ 19th century: It was used as a medicinal agent to destroy malignant tissue and as an anesthetic in dentistry. [R24] *Used as a /fungicide,/ nematicide, herbicide (unspecified), herbicide (terrestrial), and an insecticide and miticide against nematodes and weeds (preemergence) through soil fumigation treatment for fumigation of storage areas (feed/food-full) and domestic dwellings (indoor). [R9] *FOR CONTROL OF TERMITES IN STRUCTURES. [R25] *Disinfestation of potatoes, tomatoes, and other crops; organic synthesis; extraction solvent for vegetable oils. [R2] CPAT: *65% SOIL FUMIGANT, 15% SPACE FUMIGANT, 10% CHEMICAL PROCESSES, 10% EXPORTS (1985). [R16] *CHEMICAL PROFILE: Methyl Bromide. Soil fumigant, 55%; space and structural fumigant, 10%; chemical processes, 10%; grain and commodity fumigant, 5%; exports, 20%. [R26] *CHEMICAL PROFILE: Methyl bromide. Demand: 1987: 41 million lb; 1988: 42 million lb; 1992 /projected/: 47 million lb (Includes exports; in addition, 5 million to 7 million lb were imported from Israel in 1987). [R26] *Between the period of 1990-93 and 1995, the estimated annual use of methyl bromide was 3.7X10+7 lbs in the United States. [R27] PRIE: U.S. PRODUCTION: *(1984) 2.04X10+10 G (EST) [R1] U.S. IMPORTS: *(1982) 7.35X10+8 G (EST) [R28] U.S. EXPORTS: *(1984) 2.13X10+9 g [R29] *(1987) 9,116,674 lb [R30] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless gas [Note: A liquid below 38 degrees F. Shipped as a liquefied compressed gas]. [R31, 200] ODOR: *Usually odorless; sweetish, chloroform-like odor at high concn [R17]; *Methyl bromide has practically no odor or irritating effects in low concentration and therefore does not provide any warning of physiologically dangerous concentrations. [R32] TAST: *Burning taste [R17] BP: *3.5 deg C [R33, p. 3-205] MP: *-93.66 deg C [R17] MW: *94.94 [R17] CORR: *Corrosive to aluminum, magnesium and their alloys [R18] *In presence of moisture, corrosive to tin, zinc, and other alloys. [R34] *When dry (< 100 ppm water), methyl bromide is inert toward most materials of construction. Aluminum, magnesium, zinc, and alloys of these metals should not be used because under some conditions dangerous pyrophoric compounds may be formed. Many nonmetallic materials are also useful for handling methyl bromide, but nylon and polyvinyl chloride should be avoided. [R4] CTP: *Critical temp: 194 deg C; Critical pressure: 83.4 atm [R35] DEN: *1.730 @ 0 deg C/4 deg C (liq); 3.974 g/l @ 20 deg C (gas) [R17] HTC: *-787.0 kJ/mol [R36, 525] HTV: *23.26 kJ/mol @ 25 deg C [R36, 523] OWPC: *log Kow= 1.19 [R37] SOL: *13.4 G/L WATER @ 25 DEG C [R38]; *Sol in ether [R33, p. 3-205]; *Freely sol in benzene, carbon tetrachloride, carbon disulfide. [R17]; *Miscible in ethanol, chloroform [R39]; *In water, 15,200 mg/l @ 25 deg C [R40] SPEC: *MAX ABSORPTION (GAS): 204 NM (LOG E= 2.26) [R41]; *Index of refraction: 1.4218 @ 20 deg C [R33, p. 3-205]; *IR: 10972 (Sadtler Research Laboratories IR Grating Collection) [R39]; *UV: 5-2 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R39]; *MASS: 821 (NIST/EPA/MSDC Mass Spectral Database 1990 Version); 548 (Atlas of Mass Spectral Data, J Wiley and Sons, NY) [R39] SURF: *24.5 dynes/cm= 0.0245 N/m at 15 deg C [R12] VAPD: *3.3 (Air= 1) [R42] VAP: *1620 mm Hg @ 25 deg C [R43] EVAP: *Greater than 1 (butyl acetate= 1) [R22, 1981.2] VISC: *0.397 cP @ 0 deg C [R17] OCPP: *1 MG/L= APPROX 257 PPM AND 1 PPM= APPROX 3.89 MG/CU M @ 25 DEG C, 760 TORR [R19, 4023] *Specific heat @ -96.6 deg C: 0.165 cal/g/deg C; @ -13.0 deg C: 1.97 cal/g/deg C; @ 25 deg C: 0.107 cal/g/deg C; forms cryst hydrate below 4 deg C [R17] *Heat of fusion: 15.05 cal/g= 62.97 J/g= 5,978 J/mol [R44] *Ratio of specific heats of vapor: 1.247 [R12] *It weighs 14.45 lb/gal at 0 deg C [R45, 160] *Dielectric constant: 1.0068 @ 100 deg C (gas); 9.82 @ 0 deg C [R46, p. 4-48] *Thermal conductivity: 0.574 at 0 deg C [R45, 162] *Specific heat of liquid at 0 deg C: 0.12 cal/g [R47] *Transition Point: -99.4 deg C; Absolute density of gas at 101.325 kPa at 25 deg C: 3.974 kg/cu m; Critical volume: 1.639 d cu m/kg; Critical density: 0.610 kg/d cu m; Critical compressibility factor: 0.209; Heat of transition at -99.4 deg C = 1.195 kcal/kg [R48] *Reacts with some metals (aluminum); alkylating agent [R49] *Dipole moment: 1.79 (gas) [R46, p. 4-48] *Heat of formation (Gibbs): -6.75 kcal/mole; Heat of formation (enthalpy): -9.02 kcal/mole [R46, p. 5-7] *Saturated liquid density: 107.700 lb/cu ft at 35 deg F; Liquid heat capacity: 0.198 Btu/lb-feet at 35 deg F; Liquid thermal conductivity: 0.700 Btu-inch/hr-sq ft-F at 30 deg F; Saturated vapor pressure: 27.710 lb/sq in at 70 deg F; Saturated vapor density: 0.46270 lb/cu ft at 70 deg F; Ideal gas heat capacity: 0.106 Btu/lb-F at 75 deg F [R12] *... It forms a crystalline hydrate with ice water. [R7] *Viscosity= 0.22 centistokes at 0 deg C [R21] *Easily liquefied gas or volatile liquid [R2] *Heat of vaporization: 23.91 kJ/mol at 3.5 deg C; 22.81 kJ/mol at 25 deg C (extrapolated) [R33, p. 6-109] *Hydroxyl radical reaction rate constant = 4.02X10-14 cu cm/molecule sec @ 25 deg C [R50] *Henry's Law constant = 7.34X10-3 atm-cu m/mole @ 25 deg C [R51] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of methyl bromide stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this colorless, nearly odorless gas may occur from its use as a fumigant for soil, grain and other commodities, as a solvent, methylating agent, and extracting agent. Effects from exposure may include contact burns to the skin and eyes, dizziness, headache, nausea, respiratory irritation, ventricular fibrillation, pulmonary edema (sometimes delayed 4 to 5 days), convulsions, coma, and death. The OSHA PEL is set at a ceiling limit of 20 ppm, with a notation that skin contact is to be prevented. The ACGIH has recommended a TWA of 5 ppm. Levels should be controlled by local exhaust ventilation, with a continuous monitoring system to warn of excursions. In activities or situations where over-exposure may occur, wear a self-contained breathing apparatus with a full facepiece, and full chemical protective clothing (including gloves and boots) which is specifically recommended by the shipper or producer to prevent skin contact with methyl bromide. If contact should result, immediately flush affected skin or eyes with running water for at least 15 minutes. Remove contaminated clothing and shoes at the site. While methyl bromide does not ignite easily, it may burn with the production of irritating and poisonous gases. Also, containers may explode violently in the heat of a fire. Fires involving methyl bromide may be extinguished with dry chemical, CO2, Halon, or standard foam. Water spray, if used, should be applied with caution because it may cause frothing. Dike runoff from fire-control water. Methyl bromide should be stored in dry, well-ventilated areas, away from sources of ignition, direct sunlight, and sources of physical damage. Choice of containers should take into account methyl bromide's reactivity with aluminum, magnesium, tin, zinc, and other alloys. Certain methods of shipment are forbidden for methyl bromide. Consult with the regulatory requirements of the US Department of Transportation for detailed shipping and labelling instructions. If methyl bromide should spill or leak from a small container or pressurized cylinder, first remove ignition sources, then ventilate the spill area and stop the leak. Isolate the area 75 feet in all directions from the spill. For a large spill, water spray or mist may be necessary to knock down vapor. Dike any surface flow with soil or sandbags to keep the material out of water sources or sewers. Absorb bulk liquid with fly ash or cement powder. Before implementing land disposal of waste methyl bromide, consult with environmental regulatory agencies for guidance. DOT: +Health: TOXIC; may be fatal if inhaled or absorbed through skin. Vapors may be irritating. Contact with gas or liquefied gas may cause burns, severe injury and/or frostbite. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control may cause pollution. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Fire or explosion: Some may burn, but none ignite readily. Vapors from liquefied gas are initially heavier than air and spread along ground. Containers may explode when heated. Ruptured cylinders may rocket. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Many gases are heavier than air and will spread along ground and collect in low or confined areas (sewers, basements, tanks). Keep out of low areas. Ventilate closed spaces before entering. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Fire: Small Fires: Dry chemical or CO2. Large Fires: Water spray, fog or regular foam. Do not get water inside containers. Move containers from fire area if you can do it without risk. Damaged cylinders should be handled only by specialists. Fire involving tanks: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Do not direct water at source of leak or safety devices; icing may occur. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. Do not touch or walk through spilled material. Stop leak if you can do it without risk. If possible, turn leaking containers so that gas escapes rather than liquid. Prevent entry into waterways, sewers, basements or confined areas. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Do not direct water at spill or source of leak. Isolate area until gas has dispersed. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with liquefied gas, thaw frosted parts with lukewarm water. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Keep victim under observation. Effects of contact or inhalation may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Methyl bromide; Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid; Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. G-123] +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. G-151] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.3 kilometers (0.2 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 95 meters (300 feet); then, PROTECT persons Downwind during DAY 0.5 kilometers (0.3 miles) and NIGHT 1.4 kilometers (0.9 miles). [R52, p. TABLE] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.5 kilometers (0.3 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 125 meters (400 feet); then, PROTECT persons Downwind during DAY 1.3 kilometers (0.8 miles) and NIGHT 3.1 kilometers (1.9 miles). /Methyl bromide and chloropicrin mixtures; Methyl bromide and more than 2% chloropicrin mixture, liquid/ [R52, p. TABLE] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.2 kilometers (0.1 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.3 kilometers (0.2 miles) and NIGHT 0.5 kilometers (0.3 miles). /Methyl bromide and ethylene dibromide mixture, liquid/ [R52, p. TABLE] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.3 kilometers (0.2 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 95 meters (300 feet); then, PROTECT persons Downwind during DAY 0.5 kilometers (0.3 miles) and NIGHT 1.4 kilometers (0.9 miles). /Methyl bromide and nonflammable, nonliquefied compressed gas mixture/ [R52, p. TABLE] FPOT: *NON-FLAMMABLE IN AIR, BUT BURNS IN OXYGEN. [R53] *Flame propagation is narrow range of 13.5-14.5% by vol in air. [R19, 4023] *Not ordinarily considered to be combustible; however, it will burn in air in the presence of a high energy source of ignition and within a narrow flammability range. [R54, p. 49-86] *Mixtures of 10-15% with air may be ignited with difficulty. [R55] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R54, p. 325-67] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R54, p. 325-67] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R54, p. 325-67] FLMT: *Lower flammable limit: 10% by volume; Upper flammable limit: 16% by volume [R54, p. 325-67] FLPT: *NONE [R55] AUTO: *537 Deg C [R19, 4023] FIRP: *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Extinguish fire using agent suitable for surrounding fire. Use flooding quantities of water as fog. Use water spray to keep fire-exposed containers cool. [R54, p. 49-86] *Extinguishant: Stop flow of gas. [R22, 1981.2] */Wear/ self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode /during fire fighting/. [R22, 1981.5] *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Use foam, dry chemical, or carbon dioxide. [R56] TOXC: *Toxic gases and vapors (such as hydrogen bromide and carbon monoxide) may be released in a fire involving methyl bromide. [R22, 1981.2] EXPL: *LOWER 13.5%; UPPER 14.5%. [R55] *Moderately explosive when exposed to sparks or flame. Forms explosive mixtures with air within narrow limits at atmospheric pressure, with wider limits at higher pressure. The explosive sensitivity of mixtures with air may be increased by the presence of aluminum; magnesium; zinc; or their alloys. [R55] REAC: *Contact with aluminum or strong oxidizers may cause fires and explosions. [R22, 1981.2] *Aluminum, magnesium, strong oxidizers. [Note: Attacks aluminum to form aluminum trimethyl which is SPONTANEOUSLY flammable.] [R31, 200] *Metallic components of zinc, aluminum and magnesium (or their alloys) are unsuitable...with bromomethane because of the formation of pyrophoric Grignard-type compounds. ...A severe explosion /is attributed/ to ignition of a bromomethane-air mixture by pyrophoric methylaluminum bromides produced by corrosion of an aluminum component. [R57] *Forms explosive mixtures with air within narrow limits at atmospheric pressure, but wider at higher pressure. [R55] DCMP: *Thermal decomposition products of methyl bromide from contact with a hot surface or open flame include the irritant gases hydrogen bromide, bromine, and carbon oxybromide, as well as carbon dioxide and carbon monoxide. [R58] *When heated to decomposition it emits toxic fumes of /hydrogen bromide/. [R55] ODRT: *In mg/cu m: odor low 80; odor high 4,000 [R59] *Low threshold= 80 mg/cu m, High threshold= 4000 mg/cu m [R60] SERI: *Contact of the skin with high concns of vapor or with liquid methyl bromide produces a tingling and burning sensation. [R32] *Corrosive to skin; can produce severe burns. [R55] *Liquid can cause eye and skin burns. [R38] EQUP: *PERSONAL PROTECTION SHOULD CONSIST OF AIRLINE MASKS SUPPLIED BY PLANT COMPRESSED AIR, POSITIVE PRESSURE HOSE MASKS SUPPLIED BY EXTERNALLY LUBRICATED BLOWERS, OR SELF-CONTAINED RESPIRATORY APPARATUS. CANISTER-TYPE GAS MASKS ARE ALSO USEFUL EXCEPT IN EMERGENCY SITUATIONS WHERE ... CONCN MAY EXCEED 20,000 PPM. [R61, 331] *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (8-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with liquid methyl bromide. ... Employees should be provided with and required to use splash-proof safety goggles where liquid methyl bromide may contact the eyes. [R22, 1981.3] *Respiratory protection: 200 ppm or less: Any supplied air respirator. Any self contained breathing apparatus; 1000 ppm or less: Any supplied air respirator with a full facepiece, helmet, or hood. Any self contained breathing apparatus with a full facepiece; 2000 ppm or less: A Type C supplied air respirator operated in pressure-demand or other positive pressure mode; > 2000 ppm or entry and escape from unknown concns: Self contained breathing apparatus with a full facepiece operated in pressure demand or other positive pressure mode, or a combination respirator which includes a Type C supplied air respirator with a full facepiece operated in pressure demand, or other positive pressure or continuous flow mode and an auxillary self contained breathing apparatus operated in pressure-demand or other positive pressure mode; Escape: Any gas mask providing protection against organic vapors, or any self contained breathing apparatus. [R22, 1981.5] *Gas masks are relatively ineffective because methyl bromide and methyl chloride penetrate the skin readily. [R62, 151] *The breakthrough time for polyethylene is less (usually significantly less) than 1 hr reported by (normally) two or more testers. Some data (usually from immersion tests) suggesting breakthrough times for chlorinated polyethylene > 1 hr are not likely. [R63] *Wear appropriate personal protective clothing to prevent skin contact. /Liquid/ [R31, 200] *Wear appropriate eye protection to prevent eye contact. /Liquid/ [R31, 200] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] /Liquid/ [R31, 200] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R31, 200] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Classes: Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R31, 200] *Methyl bromide is an odorless volatile liquid which rapidly disperses and penetrates rubber and clothes. [R64] OPRM: *In industrial operations regularly using methyl bromide, it is advisable to have some kind of warning or monitoring system for continuous analysis of the air. In fumigation operations, suitable analytical equipment is required and personnel must have proper protective equipment for that operation. [R19, 4022] *IF POSSIBLE, ANY PROCESS INVOLVING BROMOMETHANE SHOULD BE ISOLATED FROM OPERATOR OR CARRIED OUT UNDER EFFICIENT LOCAL EXHAUST VENTILATION. [R61, 331] *It must be used by only individuals who are well acquainted with proper methods of handling and fully cognizant of the consequences of exposure to excessive amounts. [R19, 4022] *EMERGENCY SHOWERS OR WASHING FACILITIES SHOULD BE AVAILABLE IMMEDIATELY. [R61, 331] *Clothing contaminated with liquid methyl bromide should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of methyl bromide from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the methyl bromide, the person should be informed of methyl bromide's hazardous properties. Where there is any possibility of exposure of an employee's body to liquid methyl bromide, facilities for quick drenching of the body should be provided within the immediate work area for emergency use. Non-impervious clothing which becomes contaminated with liquid methyl bromide should be removed immediately and not reworn until the methyl bromide is removed from the clothing. Skin that becomes wet with liquid methyl bromide should be immediately washed or showered with soap or mild detergent and water to remove any methyl bromide. [R22, 1981.3] *Leaks of methyl bromide vapor from process lines may be detected by applying soap water solution to the site of a /potential/ leak; Leaks will be evident by formation of bubbles. ... [R65] *Avoid tight clothing, jewelry, gloves, and boots when handling methyl bromide. Methyl bromide may be trapped inside and cause skin irritation or injury. [R66] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Contact lenses should not be worn when working with this chemical. [R31, 200] *If methyl bromide in liquid form or in high concentrations comes in contact with the eyes, the eyes should be irrigated immediately with copius quantities of water for a minimum of 15 minutes. The eyelids should be held apart during the irrigation to insure contact of the water with all tissues of the eyes and lids. Medical attention should be obtained promptly. [R32] *In case of contamination of shoes or other articles of clothing with liquid methyl bromide, all such clothing must be removed at once and the skin washed with copious quantities of water and then with a 2% aqueous solution of sodium bicarbonate. The contaminated clothing must not be worn again until washed thoroughly and dried. Skin lesions should be bathed in sodium bicarbonate solution and the blisters should be treated like second degree thermal burns. [R32] *The worker should immediately wash the skin when it becomes contaminated. /Liquid/ [R31, 200] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R31, 200] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Methyl bromide is a gas that is heavier than air and constitutes a hazard in confined spaces. [R64] *If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R56] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R56] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R56] SSL: *Heat /contributes to instability/. [R22, 1981.2] *Hydrolyzed very slowly in water, more rapidly in alkaline media. [R38] *Decomp in water with half-life of 67.8 hr @ 100 deg C ... [R49] */Methyl bromide/ is stable and noncorrosive. [R67, 668] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R68] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R69] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R70] STRG: *Maintain the temp constantly lower than 40 deg C. [R71, 329] *Store cylinders upright, secured to a rack or wall to prevent tipping. Cylinders should not be subjected to rough handling or mechanical shock such as dropping, bumping, dragging, or sliding. ... Replace safety cap and valve protection bonnet when cylinder is not in use. When cylinder is empty, close valve, screw safety cap on to valve outlet, and replace protection bonnet before returning to shipper. [R66] *Store in a cool, dry, well-ventilated location. Outside or detached storage is preferred for cylinders. Isolate from active metals. [R54, p. 49-86] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. STOP FLOW OF GAS. IF SOURCE OF LEAK IS A CYLINDER AND LEAK CANNOT BE STOPPED IN PLACE, REMOVE THE LEAKING CYLINDER TO A SAFE PLACE IN THE OPEN AIR, REPAIR THE LEAK OR ALLOW THE CYLINDER TO EMPTY. 4. IF IN THE LIQ FORM, ALLOW TO VAPORIZE. [R22, 1981.4] *Releases may require isolation or evacuation. Approach release from upwind. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors and protect personnel. Control runoff and isolate discharged material for proper disposal. [R54, p. 49-86] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U029, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R72, (7/1/2000)] *Controlled incineration with adequate scrubbing and ash disposal facilities. [R73] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R74] *"Pour onto vermiculite, sodium bicarbonate or a soda-ash mixture (90-10). Mix and shovel into paper boxes. Place in an open incinerator. Cover with scrap wood and paper. Ignite with an excelsior train; stay on upwind side or pump into a closed incinerator with afterburner." "Dissolve in a flammable solvent. Spray into the fire box of an incinerator equipped with afterburner and scrubber" but methyl bromide gas is very toxic and incineration by a layman appears to be too hazardous. Methyl bromide is apparently degraded rapidly in the sunlight in air and a preferable disposal procedure for the layman would be to release small amt slowly to the atmosphere in a well ventilated outdoor location. Recommendable methods: Incineration and evaporation. Peer-review: Methyl bromide is a toxic gas and incineration may be difficult to arrange safely unless an efficient method of feeding the gas into the incinerator can be arranged. Incineration requires dilution with excess fuel. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R75] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R76] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R76] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U029, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R72, (7/1/91)] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of methyl bromide. There is limited evidence in experimental animals for the carcinogenicity of methyl bromide. Overall evaluation: Methyl bromide is not classifiable as to its carcinogenicity in humans (Group 3). [R77] *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Inadequate human and animal data: a single mortality study from which direct exposure associations could not be deduced and studies in several animal species with too few animals, too brief exposure or observation time for adequate power. Bromomethane has shown genotoxicity. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Inadequate. [R78] *A4. Not classifiable as a human carcinogen. [R79] ANTR: *In a /methyl bromide/ poisoned man suffering from action myoclonus, the condition was controlled by diazepam (60 mg/day). However, because of severe somnolence, the treatment was changed to clonazepam at ... . This treatment was effective; the somnolence disappeared, and the myoclonus decreased conspicuously. Clonazepam produced mild improvement in another case with action myoclonus. Although /dimercaprol/ has been used for treating methyl bromide poisoning, there is no evidence that it was beneficial. Treatment of a poisoning case with acetylcysteine was concluded to be not harmful and possibly beneficial. [R67, 671] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . /Bromine, methyl bromide, and related compounds/ [R80, 404] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Consider vasopressors to treat hypotension without signs of hypovolemia (refer to shock protocol in Section Three). Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Bromine, methyl bromide, and related compounds/ [R80, 405] *N-acetylcysteine may restore depleted glutathione stores... . Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encepholopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, ECG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. [R81] *The high affinity of methyl bromide for sulfhydryl groups may have a role in its toxic action. Sulfhydryl agents may thus be beneficial as antidotes in poisoning with methyl bromide. [R82] MEDS: *Evaluate the central nervous system, respiratory tract, and skin in preplacement and periodic examinations. [R83] *Physical exam of exposed personnel every 6 months with special attention to CNS, and incl determination of bromide in blood. [R71, 330] *Initial Medical Examination: A complete history and physical examination: The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. A careful history and examination of the nervous and respiratory systems should be stressed. The skin should be examined for evidence of chronic disorders. ... Periodic Medical Examination: The aforementioned medical examinations should be repeated on an annual basis except that an X-ray is necessary only when indicated by the results of pulmonary function testing. [R84] *The assessment of methyl bromide exposure can be accomplished through measurement of bromide. Due to the rapid clearance of bromide, the correlation between serum bromide levels and severity of effects appears to be best when measurements are performed within the first 1-2 days of exposure. Serum or Plasma Reference Ranges: Normal - less than 15 mg/l; Exposed - Levels up to 80 mg/l have occurred without obvious clinical signs.; Toxic - Levels of 150-400 mg/l have been observed in people with moderate to severe symptoms. [R85, 843] *Renal Function Tests /include/ ... Urine Albumin ... Urinary Beta-2-Microglobulin and/or Retinal Binding Protein (RBP) ... Urinary Alpha and Pi Isoenzymes of Glutathione S-Transferase ... Urinary Enzyme N-Acetylglucosaminidase ... /and/ Routine Urinalysis. [R85, 884] *Liver Function Tests: ... Biochemical tests - Enzymes that reflect cholestasis: alkaline phosphatase (AP), 5'-nucleotidase (5'-NT) /and/ leucine aminopeptidase (LAP); ... Enzymes that detect direct hepatic damage: aspartate aminotransferase (AST) /and/ alanine aminotransferase (ALT). ... Clearance tests - indocyanine green ... antipyrine test ... /and/ serum bile acids. [R85, 845] *Respiratory Symptom Questionnaires: Questionnaires published by the American Thoracic Society (ATS) and the British Medical Research Council have proven useful for identifying people with chronic bronchitis. Certain pulmonary function tests such as the FEV1 have been found to be better predictors of chronic airflow obstruction. [R85, 846] *Chest Radiography: Chest radiographs are widely used to assess pulmonary diesase. They are useful for detecting early lung early lung cancer in asymptomatic people, and especially for detecting of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, experts' views on the risk-to-benefit ratio in detection of pulmonary disease conflict, so routine annual chest x-rays are not recommended for all people. [R85, 846] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. [R85, 846] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. [R85, 846] HTOX: *CHRONIC EXPOSURE CAN CAUSE CNS DEPRESSION OR KIDNEY INJURY ... . [R53] */In handling methyl bromide in drug industry/ ... severe itching, dermatitis was observed. ... Liq ... can cause severe corneal burns but vapors do not appear to be irritating. [R19, 4022] *Symptomatology (3-12 hr after inhalation of vapor): 1. Dizziness and headache. 2. Anorexia, nausea, vomiting, and abdominal pain. 3. Lassitude, profound weakness, slurring of speech, and staggering gait. 4. Transient blurring of vision, diplopia, sometimes strabismus and even temporary blindness. 5. Mental confusion, mania, tremors, and epileptiform convulsions. ... 6. Rapid respiration, associated with signs of severe pulmonary edema, cyanosis, pallor and collapse. ... 7. Coma, areflexia and death from respiratory or circulatory collapse. 8. Low-level subacute vapor exposures have produced a syndrome of persistent numbness in the hands and legs, impaired superficial sensation, muscle weakness, unsteadiness of gait and absent or hypoactive distal tendon reflexes. 9. Late sequelae incl bronchopneumonia after severe pulmonary lesions, renal failure with anuria due to tubular degeneration, and severe weakness with or without evidence of paralysis. These difficulties ... subside within a few wk or mo, and complete recovery is the rule. ... Jaundice and other evidence of mild hepatic injury are noted occasionally. [R5, p. III-282] *SUFFICIENT PERCUTANEOUS ABSORPTION ... CAN OCCUR TO PRODUCE DEATH IN MAN, AND IF EVAPORATION IS DELAYED ... IT IS INTENSE VESICANT ON ... SKIN. BLISTERS PRODUCED ... ARE ENORMOUS BUT RARELY DEEP ENOUGH TO DESTROY ENTIRE SKIN LAYER. [R5, p. III-280] *AUTOPSY IN CASE IN WHICH THERE HAD BEEN BLURRING OF VISION AND APPEARANCE OF FLICKERING LIGHTS, DOUBLE VISION, AND PAIN BEHIND EYES SHOWED MANY MINUTE HEMORRHAGES THROUGHOUT BRAIN, HEART, SPLEEN, AND KIDNEYS. [R86, 609] *IN 35 METHYL BROMIDE FUMIGATORS EXAMINED, SLIGHT EEG CHANGES (IN 10 SUBJECTS) AND SMALL INCR IN SERUM TRANSAMINASES WERE FOUND WHICH COULD BE RELATED TO BROMIDE CONCN IN BLOOD. [R87] *THREE CASES OF METHYL BROMIDE POISONING ARE DISCUSSED. A 6 YR OLD BOY HAD CONVULSIONS AND BECAME COMATOSE FOLLOWING EXPOSURE TO METHYL BROMIDE. HIS INITIAL EEG SHOWED IRREGULAR WAVES BUT AFTER 3 WK RETURNED TO NORMAL. HIS GRANDMOTHER SHOWED SIGNS OF CONFUSION ACCOMPANIED BY NAUSEA, VOMITING, SEIZURES AND COMA. HER EEG WAS AFFECTED BUT NORMALIZED 2 YR AFTER THE INCIDENT. GRANDFATHER'S SYMPTOMS CONSISTED OF NAUSEA AND CONFUSION. HIS AWAKE EEG WAS INITIALLY IRREGULAR BUT THE SLEEP EEG WAS NORMAL. [R88] *AFTER SPRAYING METHYL BROMIDE IN STOREROOM OF A HOME, SPASMS OCCURRED IN ALL 4 RESIDENTS, A GIRL 11 YR OF AGE HAD FREQUENT APPEARANCE OF GENERAL MYOCLONIA WHICH WAS FOLLOWED BY COMA. AFTER THE DISAPPEARANCE OF MYOCLONIA, A PERIODIC HIGH AMPLITUDE SLOW WAVE DISCHARGE APPEARED ON THE ELECTROENCEPHALOGRAM. CHARACTERISTIC ACTION MYOCLONIA REMAINED ON THE RIGHT UPPER EXTREMITY. SERUM CONCN OF BROMIDE ION DID NOT SHOW ANY CORRELATION WITH CLINICAL PICTURE (SUGGESTING THAT TOXICITY ... IS DUE TO THE METHYL BROMIDE GROUP RATHER THAN THE BROMIDE ION.) [R89] *Human experience indicates that acute fatal intoxication can result from exposures to vapor levels as low as 1164 to 1552 mg/cu m, and harmful effects can occur at 388 mg/cu m or more. Systemic poisoning has been reported to occur from a two week exposure (8 hr/day) at about 136 mg/cu m. Symptoms generally increase in severity with increasing levels of exposure and may vary somewhat according to exposure circumstances and individual susceptibility. In sublethal poisoning cases a latency period of 2 to 48 hr (usually about 4 to 6 hr) occurs between exposure and onset of symptoms. [R90] *A case of fatal methyl bromide poisoning in a 68 yr old male scrapdealer was reported. The subject discharged several obsolete fire extinguishers containing methyl bromide into the atmosphere and proceeded to scrap them. Several hrs later he developed twitching of the arms and became ataxic. On physical exam he had painful, epileptiform tonic, clonic spasms of the face, trunk, and limbs but was fully conscious during these episodes. Anticonvulsant treatment with diazepam, phenytoin, iv chlormethiazole and nitrous oxide by inhalation had no effect on convulsions. Muscle paralysis was induced with pancuronium and positive pressure ventilation begun. EEG showed centroencephalic spike discharges. After 7 days the generalized convulsions had ceased and ventilation was discontinued. There was some neurological improvement over the following week. Despite anticoagulant treatment the patient died 16 days after admission from pulmonary emboli. Serum bromide concn ranged from 130-480 mg/100 ml. [R91] */Early medicinal/ uses did not last long because of the tendency of methyl bromide to cause throat irritation, to induce vomiting, and to release free bromine, in addition, several deaths were attributed to its medicinal use. [R92] *The case of action myoclonus following acute methyl bromide intoxication was characterized by marked changes in the inferior colliculi and moderate or mild abnormalities of thalamus, griseum centrale mesencephali, nucleus centralis superior, nucleus reticularis tegmenti pontis, nuclei pontis, and dentatus. [R93] *... Exposure of human lymphocyte cultures to 4.3% methyl bromide for 100 sec increased the frequency of sister chromatid exchanges from 10.0 to 16.8%. [R94] *Chronic methyl bromide toxicity usually is limited to CNS although mild elevation of serum hepatic aminotransferase levels has been reported in industrial workers. A fumigator chronically exposed to methyl bromide developed paresthesia of the extremities, dysesthesias, and visual impairment secondary to optic atrophy. Mild neurologic dysfunction (eg, decreased finger sensitivity, reduced cognitive performance, and behavioral abnormalities) was detected in a study of soil fumigators. [R95] *Bromomethane is a CNS depressant and may involve pyschic, motor and GI disturbances. In light poisoning cases effects may be limited to mild neurological and GI disturbances, with recovery in a few days. Moderate cases involve the CNS further, with more extensive neurological symptoms and usual disturbance. Recovery may be prolonged for weeks or months, with persisting symptoms and/or disturbed function. [R96] *Severe poisoning cases also involve a latent period and similar initial symptoms, with development of disturbed speech and gait, incoordination, tremors that may develop to convulsions, psychic disturbances. Recovery can be quite protracted with persisting neurological disorders. [R96] *In fatal cases the convulsions may become more intense and frequent, with unconscious periods. Death may occur in a few hours from pulmonary edema or in one to three days from circulatory failure. Pathology often includes hyperemia, edema, and inflammation in lungs and brain. Degenerative changes occur in the kidneys, liver and/or stomach, and perhaps the brain; although brain changes are usually more functional in character. [R97] *A case of brief skin exposure (spray) to liquid bromomethane, quickly decontaminated, did not produce a burn, but resulted in severe, delayed neuromuscular disturbances (twitching, fits, convulsions) and permanent brain damage (cerebellum and pyranedal tract). [R97] *The signs and symptoms of methyl bromide poisoning vary according to the degree of exposure. In most instances, the onset of the symptoms is delayed and this latent period varies from 1/2 to several hrs and occasionally 12, 24, or 48 hr. The symptoms may be fatigue, headache, dizziness, nausea and vomiting, disturbances of hearing, vision, mental confusion, muscular weakness, collapse, respiratory difficulties and coma. Death is usually due to lung damage, but damage to the CNS may accompany pulmonary damage. [R32] *Exposure to low, but harmful, concns of methyl bromide over a period of time results in a varied picture of signs and symptoms. In order of frequency of occurrence, these symptoms are: visual disturbances, disturbances of speech, numbness of the extremities, mental confusion, hallucinations, tremors, coma and frequent fainting attacks. Most symptoms disappear in a few days /after/ the exposure /is terminated/, but numbness of the extremities and visual disturbances may persist from 2-5 mo. [R32] *NO REASONS HAVE BEEN ADVANCED FOR COMPLETE SPARING OF LUNGS IN SOME CASES WHERE BRAIN DAMAGE HAS BEEN BOTH SEVERE AND PERMANENT. SEVERE NEUROLOGICAL SIGNS SEEM TO BE DEPENDENT ON A SUDDEN EXPOSURE TO HIGH CONCN FOLLOWING CONTINUOUS SLIGHT EXPOSURE. [R61, 330] *METHYL BROMIDE IS A DANGEROUS CUMULATIVE POISON WITH DELAYED SYMPTOMS OF CENTRAL NERVOUS SYSTEM INTOXICATION THAT MAY APPEAR AS LONG AS SEVERAL MONTHS AFTER EXPOSURE. [R98] *Fatal poisoning has ... resulted from exposures to relatively high concn of methyl bromide vapors (from 8600 to 60000 ppm). [R55] *When used as a fumigant for various foodstuffs in the past, methyl bromide caused more fatalities among California workmen than any other agricultural chemical. [R5, p. III-280] *The toxic effects of aliphatic chlorinated, brominated, fluorinated and iodinated hydrocarbons, alcohols, acids, and thioacids, were reviewed, with emphasis on their action at the level of the CNS in both man and experimental animals as well as their metab and effects on other organs. Methyl iodide, methyl bromide, methyl chloride and ethyl chloride were shown to induce signs, symptoms, or lesions of the cerbellum in both humans and experimental animals. [R99] *The effects of exposure of the skin to high concentrations of methyl bromide were studied in 6 cases, who had been unintentionally exposed. Exposure to high concentrations of methyl bromide (approximately 40 g/cu m) for 40 min can lead to redness and blistering of the skin. This cannot be prevented by wearing standard protective clothing. Skin lesions show a preference for relatively moist skin areas. Plasma bromide levels were highest immediately following exposure (mean 9.0 + or - 12.4 mg/l) and fell in subsequent hours (mean 6.8 + or - 2.3 mg/l 12 hr after the exposure). No systemic effects were noted in this series. [R100] *Neurobehavioral functions affected by methyl bromide exposure were evaluated in California structural and soil fumigators using methyl bromide and sulfuryl fluoride. Sampling data revealed that structural fumigators are exposed for up to 1.5 hr/day to 0-2.2 ppm methyl bromide and/or 10-200 ppm sulfuryl fluoride, and soil fumigators can be exposed to 2.3 ppm methyl bromide over an 8 hr day. Subjects were grouped for statistical analysis on the basis of exposure history: Those exposed primarily (80% or more of the work period with exposure potential) to methyl bromide (n= 32), primarily to sulfuryl fluoride (24), or to a combination of methyl bromide and sulfuryl fluoride (40-60% of each) for a minimum of one year (18), and those not exposed to high concentrations of any chemicals (29 Referents). Fumigators using methyl bromide reported a significantly higher prevalence of 18 symptoms consistent with methyl bromide toxicity than did referents. Methyl bromide fumigators did not perform as well as referents on 23 of 27 behaviorial tests (chosen to reflect methyl bromide effects), and were significantly lower on one test of finger sensitivity and one of cognitive performance. [R101] *A 32 year old fumigationassistant developed systemic and neuro-ophthalmic manifestation of methyl bromide poisoning, including increased serum bromide level (6.6 mg/100 ml), paresthesias and burning dysesthesia on his hands and feet, and visual impairment. Ocular examination showed mild bilateral decrease in vision, temporal optic nerve head pallor, severely attenuated visual-evoked response amplitudes and normal latencies, a normal electroetinogram, an abnormal electrooculogram, and a severe deuteranomalous (green) defect on Farnsworth-Munsell 100 hue testing. His vision had not improved 12 mo after the initial exposure. [R102] *A technique was described which used sister chromatid exchanges in human peripheral blood lymphocyte cultures to assess the genotoxic potential of vapors. Cultures were exposed to 4.3% methylbromide. Methylbromide increased sister chromatid exchange frequency from 9.90 to 16.84 per cell. [R103] *High concns of methyl bromide can produce rapid unconsciousness during exposure, leading to a prompt "anesthetic" death. However, anesthesia plays no part in the great majority of cases, which are characterized by delayed onset, a great variety of symptoms, and delayed recovery, if death does not occur. The delay in onset usually is several hours, but a delay of only a few min and a delay of 48 hr have been observed. In fatal cases with delayed onset, death generally occurs within 4-6 hr but sometimes after 24-48 hr. In rare instances, death may be delayed as much as 18 days. The cause of death in these cases usually is circulatory failure. [R67, 670] *...Two cases of testicular cancer mortality versus 0.11 expected (SMR= 1.799, p < 0.05) among workers exposed to organic bromides /were reported/. ...Based on the recorded work histories, the only known shared potential exposure was methyl bromide. [R104] *Characteristically during exposure to the gas there are no warning sensations, but after a latent period of several hr the victim has headache, nausea, vomiting, vertigo, and staggering. He may then also have lacrimation from irritation of the eyes, and may experience blurring and diplopia. Transient dimming of vision and blindness for twelve hr has been reported associated with severe nausea and vomiting, but with recovery within a few days. In other cases, nystagmus on lateral gaze, diplopia, and blurring of vision, especially when attempting to read, have been associated with the general neurologic disturbances. In severe cases, convulsion, delirium, and sometimes mania ensue, followed by collapse and possible death. Patients who recover may have a protracted period of apathy and depression, incoordination, tremors, and bothersome visual complaints. As a rule those who recover eventually recover completely. [R86, 607] *In a carefully studied case in 1937, a man exposed to methyl bromide while filling fire extinguishers did not develop symptoms until 48 hr later; then he began to have vertigo, aphasia, and ataxia. At the end of a week, when speech was improving, he noted that the contour of objects appeared blurred. His amblyopia became worse, approaching almost complete blindness in a few days. At the same time, vertigo became worse, and one arm was paralyzed. Three weeks after exposure he began to discern objects better, and there was general improvement. At a month, vision in both eyes could not be improved beyond 5/10 with glasses, but the pupils and fundi were normal. There appeared to be weakness of accommodation (requiring 3.5 D for near vision), and central scotomas were found for green, but not for white. By two months, vision in each eye improved to 8/10, and only 1.5 D was required for near vision. His other neurologic disturbances had also subsided. [R86, 609] *... A man exposed to pure methyl bromide gas for about half an hour became weak and stupified, unable to walk, but able to crawl out of the room. He saw lights doubled, and they appeared to dance in front of this eyes. He could not place his hands on things accurately. He had neither headache nor vomiting, but in the next few days ataxia increased so that he could scarely stand, and he had marked intention tremor of the hands. The eyes appeared normal externally, and he made no complaint of ocular irritation. The optic nerveheads were described as abnormally red. The retinal arteries seemed normal, but the veins were distended and tortuous. In one eye a retinal hemorrhage slightly larger than the disc extended from the nervehead inferiorly along the course of the verve fibers. Visual acuity varied from 3/4 to 1. There seemed to be slight paresis of abduction in each eye, but psychic disturbance made testing difficult, and the patient complained not only of doubled vision, but of seeing things four or five fold. Ataxia and psychic symptoms became more severe, wth hallucinations of hearing and vision, epileptiform attacks and periods of coma. The hemorrhage in the fundus spread, and it was postulated that the patient must have small hemorrhages in various parts of the central nervous system. [R86, 608] *Local contact of methyl bromide with the eye either as concentrated vapor or as a splash of liquid has resulted in no more than transient irritation and conjunctivitis in the few cases in which this accident has been observed. [R86, 616] *Methyl bromide is reported to be eight times more toxic on inhalation than ethyl bromide. Moreover, because of its volatility, it is a much more frequent cause of poisoning. Death following acute poisoning is usually caused by its irritant effect on the lungs. In chronic poisoning, death is due to injury to the CNS. ... In addn, to injury to the lung and CNS, the kidneys may be damaged, with development of albuminuria and, in fatal cases, cloudy swelling and/or tubular degeneration. The liver may be enlarged. There are no characteristic blood changes. [R55] *Signs and symptoms of chronic exposures include those from acute exposure plus visual and hearing disorders, numbness or tingling in the extremities, incoordination, ataxia, and loss of consciousness. Psychologic symptoms have been associated with chronic exposure, including loss of initiative, depressed libido, personality changes, hallucinations, and an intolerance to alcohol. [R64] *The concn immediately dangerous to life and health (IDLH) is 2000 ppm, and at this concn, methyl bromide produces pulmonary edema, seizures, and death. [R64] *Both acute and chronic exposure can result in behavioral toxicity manifested by psychosis, delirium, hallucinations, aggression, and mania. Cases of homicidal ideation and acute psychosis have been described following serious exposures. [R64] *SUFFICIENT PERCUTANEOUS ABSORPTION ... CAN OCCUR TO PRODUCE DEATH IN MAN, AND IF EVAPORATION IS DELAYED ... IT IS INTENSE VESICANT ON ... SKIN. BLISTERS PRODUCED ... ARE ENORMOUS BUT RARELY DEEP ENOUGH TO DESTROY ENTIRE SKIN LAYER. LIKE OTHER VESICANTS ... METHYL BROMIDE INHIBITS SKIN GLYCOLYSIS AT HEXOKINASE LEVEL. [R5, p. III-280] *Methyl bromide poisoning is difficult to confirm because routine laboratory testing has not been reliable. Measurable levels of the parent agent are rapidly reduced, probably as a result of direct tissue chemical reaction. Serum bromide levels have been used as an indirect measure of exposure and/or toxicity but are inconsistent. Recently special testing has shown that protein adducts formed after exposure to methyl bromide may be a better measure of significant exposure. The S-methylcysteine adduct was used to confirm acute methyl bromide toxicity 10 weeks after an exposure. [R105] *CASE REPORT: We describe a case of early peripheral neuropathy and central nervous system toxicity as a result of acute predominantly dermal exposure to methyl bromide. A 32-year-old male was admitted after an accidental predominantly dermal exposure to methyl bromide while fumigating soil for pest control. The patient suffered dermal burns and vesicles on the upper and lower limbs. One week following exposure, he developed progressive weakness of the lower limbs, ataxia, paresthesiae of both legs and the left arm, hyperactive tendon reflexes in the lower limbs, and left Babinski sign. Nerve conduction velocity testing was compatible with axonal neuropathy. The patient recovered gradually from his burns. Three months postexposure he showed no signs of central nervous system toxicity, but the peripheral neuropathy was still present. Neurological effects primarily referable to the central nervous system following severe inhalation of methyl bromide have frequently been reported. The patient described in this study developed an unusual early peripheral neuropathy following dermal exposure. Peripheral neuropathy can be an outcome of methyl bromide intoxication, but is usually a late sequela of acute central nervous system toxicity or an aftereffect of repetitively inhaled chronic exposure. In this case, exposure to methyl bromide through abraded skin caused early peripheral neuropathy and central nervous system toxicity. [R106] NTOX: *INHALATION EXPOSURE AT 100 PPM FOR 2-3 WK RESULTED IN DEATH OR SERIOUS SYMPTOMS AMONG RATS, GUINEA PIGS AND MONKEYS. ... RATS AND GUINEA PIGS SHOWED NO DEMONSTRABLE TOXIC EFFECTS WHEN EXPOSED AT 64 PPM 7-8 HR A DAY OVER A PERIOD OF 6 MO. RABBITS RESPONDED WITH PULMONARY IRRITATION AND PARALYSIS, WHEREAS MONKEYS DISPLAYED CONVULSIONS AT THE SAME DOSE. AT 33 PPM, RABBITS STILL SHOWED IRRITATION OF LUNGS AND PARALYSIS, BUT OTHER SPECIES WERE NOT AFFECTED. ALL SPECIES TOLERATED 16 PPM WITHOUT EVIDENCE OF INJURY. [R107] *8-hr survival dose for rats was ... approximately 1 mg/l (260 ppm). Rats survive 5200 ppm for 6 min and 2600 ppm for 24 min. The 6-hr survival dose for rabbits is approx 2 mg/l (520 ppm). ... These authors /also/ studied rats, rabbits, guinea pigs, and monkeys. They described the response of most animals as typically one of lung irritation. If exposure was severe enough, this resulted in lung edema and usually a typical confluent bronchial pneumonia. [R19, 4024] *AT 0.25 MG/L (66 PPM) RATS SHOWED ... NO RESPONSE FROM 6 MO PERIOD OF REPEATED EXPOSURES. ... RABBITS, HOWEVER, DEVELOPED ... PARALYSIS AND SOME PULMONARY DAMAGE. MONKEYS EXPOSED AT THIS LEVEL DEVELOPED A PARALYSIS COMPARABLE TO THAT SEEN IN RABBITS. [R108] *Methyl bromide was mutagenic to Salmonella typhimurium TA100 when tested at concn of 0.02-0.2% in desiccators in absence of an exogenous metabolic system. ... A commercial prepn of methyl bromide (tested @ 0.5-5 g/cu m in a closed container) was mutagenic to Salmonella typhimurium TA1535 AND TA100 (but not to TA1538 or TA98) and to Escherchia coli WP2 hcr in the absence of an exogenous metabolic system. An aqueous soln of methyl bromide (tested @ 0.5-6 mM) induced mutations to streptomycin independence in Escherchia coli SD-4. [R109] *NEUROBEHAVIORAL EFFECTS OF CHRONIC AND SUBCHRONIC EXPOSURE OF RABBITS AND RATS TO METHYL BROMIDE WERE STUDIED. ONE GROUP OF RATS AND RABBITS WAS EXPOSED TO 65 PPM FOR A TOTAL EXPOSURE OF FOUR 25 HR WEEKS, OR 100 HR, AND RATS WERE EXPOSED TO 55 PPM FOR A TOTAL EXPOSURE OF THIRTYSIX 30 HR WEEKS. EXPOSURE TO 65 PPM FOR FOUR WK SIGNIFICANTLY REDUCED EYE BLINK RESPONSES AND NERVE CONDUCTION VELOCITY IN RABBITS BUT HAD NO EFFECT ON RATS. [R110] *TOXIC EFFECT IN RATS OF METHYL BROMIDE VAPOR WAS ASSESSED BY A CONDITIONED TASTE AVERSION REGIME. RATS KEPT UNDER A WATER DEPRIVATION SCHEDULE FOR 7 DAYS WERE PERMITTED ACCESS TO 0.3% (WT/VOL) SODIUM SACCHARIN SOLN AND WERE EXPOSED TO METHYL BROMIDE AT 0, 25, 50 and 100 PPM FOR 4 HR. THREE DAYS AFTER EXPOSURE, A DOSE-DEPENDENT SACCHARIN AVERSION WAS NOTED IN THE TREATED ANIMALS. [R111] *TEN WK OLD MALE WISTAR RATS WERE EXPOSED BY INHALATION TO 200 OR 300 PPM OF METHYL BROMIDE FOR 4 HR/DAY, 5 TIMES/WK FOR 3 WK. RELATIVELY PROLONGED DYSFUNCTION OF THE PERIPHERAL NERVES AND DISTURBANCE IN SPONTANEOUS CIRCADIAN RHYTHM ACTIVITY WERE FOUND IN RATS EXPOSED TO THE 300 PPM DOSE. NO MACROSCOPIC OR MICROSCOPIC ABNORMALITIES WERE FOUND IN CNS OR IN THE PERIPHERAL NERVES. [R112] *... Exposing a rabbit eye to pure methyl bromide gas for 1 and 1/2 min resulted in an immediate loss of surface luster, followed in several hours by a loss of corneal epithelium and much edema of the conjunctivae and lids. The cornea became opaque ... . [R22, 1981.2] *Extremely phytotoxic. ... Not dangerous to bees when used as described. [R38] *It was reported ... that oral admin of 25 and 50 mg/kg body wt methyl bromide (purity unspecified) in peanut oil, admin by gavage for periods of 20, 60, 90 and 120 days, caused ulceration and epithelial hyperplasia of the forestomach in rats (number, strain, age, wt and sex unspecified) without evidence of malignancy. (The Working Group noted that the level of detail provided was inadequate for evaluation of carcinogenicity). [R113] *Toxic responses in rabbits administered bromomethane sc (in oil) at 20-120 mg/kg included limb paralysis, cessation of drinking, reduced urine excretion. Levels > 50 mg/kg sharply increased the blood bromide level and reduced platelets, serotonin, and water content. [R114] *Methyl bromide applied under plastic to soil organisms at concentrations of 300 g/cu m killed all insects. Some soil nematodes and mites survived in small numbers. [R115] *A 100% mortality rate occurred in Aspergillus ochraceus, Aspergillus flavus, Penicillium citrinum, Penicillium chrysogenum, and Penicillium cyclopium when fumigated with methyl bromide at a concentration of 120 mg/l for 4 hr. However 40% of an Aspergillus niger population retained its viability at this concentration. [R116] *Methyl bromide injected under plastic at 448 kg/ha did not eradicate nematodes or fanleaf virus carried by nematodes, but did reduce both /organisms/ to acceptable levels in a California vineyards. [R117] *Application of 300 and 400 lb/acre resulted in good control of Xiphinema index and the root rot nematode. [R116] *Methyl bromide at 436 lb/acre under plastic reduced nematode populations and resulted in increased wheat and barley yields. Methyl bromide at 857 kg/ha decreased nematode larvae in potato fields, and at 977 kg/ha in a greenhouse controlled nematodes to a depth of 40 cm and resulted in increased tomato yields. [R118] *Methyl bromide was found to be 0.81 times more toxic to Aonidiella aurantii than hydrogen cyanide. [R119] *Mutagenic effects were observed in Drosophila melanogaster exposed to concentrations of 0.004 and 0.002 mmole/l after 30 and 90 hr exposures. [R120] *Klebsiella pneumoniae tested in a fluctuation test, without metabolic activation showed mutagenic effects at concentrations in air of 4.75 g/cu m (0.05 mmole/l) and higher. [R120] *Cats fed fumigated peanuts /containing methyl bromide/ at 0.5 to 1.25 mg/day for 4 months showed no changes in motor responses. [R121] *Dogs fed fumigated pelleted food in doses equal to 35, 75 and 150 mg/kg/day for 6 to 8 wk were observed for 1 yr. Animals /which/ received 35 or 75 mg/kg/day showed no or minimal evidence of toxicity. Animals fed 150 mg/kg/day showed lethargy, occasional salivation, and diarrhea, but no changes in blood chemistry, hematology, urinary values, or histology. [R121] *A study on horses, goats and cattle fed hay contaminated with 6800 to 8400 ppm methyl bromide following fumigation showed difficulty in walking, locomotor impairment, listlessness, and /in some instances/ death. [R121] *Cattle fed pelleted food containing 170, 511, 1062, 2633, and 4650 ppm methyl bromide for 49 days showed signs of intoxication (uncoordinated movement and gait), and recumbency. [R122] *A laboratory study was conducted to determine the acute toxic effects in Swiss Webster mice after a one hr inhalation exposure to methyl bromide. Groups of 6 mice were exposed to 0, 0.87, 1.72, 2.20, 2.70, 3.50, 3.82, 4.70, 5.77, or 5.93 mg/l. Animals exposed to 3.50 mg/l or more exhibited kidney lesions. Animals with exposure to 2.20 or 2.70 mg/l showed decreased lung and liver weight. Liver lesions appeared in animals exposed to 4.70 mg/l. Animals exposed to 5.77 mg/l developed decreased motor coordination. The 1 hr LC50 for methyl bromide in mice was 4.68 mg/l (1200 ppm). The dose response curve was quite steep and the LC10 to LC90 of mortality was within a doubling of concentration. [R123] *Methyl bromide was evaluated in the L5178Y mouse lymphoma cell TK gene mutation assay at a dose range of 0-2.5 ug/ml. The test protocol used met criteria established for this assay by the Gene Tox Program. The chemical was positive at the 2.5 ug/ml dose level without metabolic activation. [R124] *Seeds of beans (Phaseolus vulgaris), with a moisture content of 8.10 and 13.80%, were treated with methyl bromide and placed in multiwall Kraft paper bags and stored at room temperature. Methyl bromide reduced both germination and vigor. Seeds with the higher moisture content were more susceptible than those with lower moisture. [R125] *... Micronuclei were induced in bone marrow cells of Fischer 344 rats and BDF1 mice and in peripheral blood cells of BDF1 mice exposed to methyl bromide by inhalation for 6 hr/day, 5 days/wk for 2 wk. In mice, the incidence of polychromatic erythrocytes with micronuclei in the bone marrow increased by 10 fold in males (200 ppm; 776 mg/cu m) and by 6 fold in females (154 ppm; 600 mg/cu m), and those in peripheral blood increased by 32 fold in males (200 ppm) and by 3 fold in females (154 ppm). In rats, the increases were 10 fold in males (338 ppm, 1211 mg/cu m) and 3 fold in females (338 ppm) /in bone marrow/. [R94] *The available data for halomethanes indicate that acute toxicity to freshwater aquatic life occurs at concentrations as low as 11,000 ug/l. ... No data are available concerning the chronic toxicity of halomethanes to sensitive freshwater aquatic life. /Halomethanes/ [R126] *The available data for halomethanes indicate that acute and chronic toxicity to saltwater aquatic life occur at concentration as low as 12000 and 6400 ug/l, respectively. ... A decrease in algal cell numbers occur at concentrations as low as 11,500 ug/l. /Halomethanes/ [R126] *Groups of cattle were fed oat hay from a bromomethane fumigated field or pelleted ration containing sodium bromide added at various concentrations. The hay contained bromide ion at concentrations of 6800 to 8400 mg/l. Groups fed the hay and highest dose rate of bromide in pelleted ration developed signs of CNS toxicity (motor incoordination) at 10 to 12 days of exposure. Serum bromide levels and neurologic signs were markedly reduced two weeks after termination of exposure. /Bromide ion/ [R127] *Methyl bromide (soil fumigant) administered by oral gavage as a solution in arachis oil was carcinogenic to rats in a 90 day experiment. In 13 of 20 animals of the highest dose group, 50 mg methyl bromide/kg body wt, squamous cell carcinomas of the forestomach developed. All animals of this group showed a marked diffuse hyperplasia of the epithelium of the forestomach. A less pronounced hyperplasia was observed in high and lower incidence with, respectively, 10 and 2 mg methyl bromide/kg body wt. The lowest dose, 0.4 mg methyl bromide/kg body wt was without effects. [R128] *Rats received a single 8 hr exposure to methyl bromide, and the amines and metabolities were separated by a reverse-phase HPLC and were quantified via native fluorescence. An exposure to 100 ppm methyl bromide decreased tissue levels of dopamine and norepinephrine in all brain areas at 0 or 2 hr following exposure. Homovanillic acid and 3-methoxy-4-hydroxyphenylglycol contents were significantly increased in almost all brain regions. In a second study, rats were exposed to four concentrations of methyl bromide ranging from 31-250 ppm, and monoamine and metabolite levels in brain regions measured immediately after the exposure. There were dose-dependent decreases of dopamine and norepinephrine, and increases in homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. Less clear changes in serotonin and 5-hydroxyindoleacetic acid contents were observed. [R129] *Groups of 10 male F344 rats (11-13 wk old) were exposed to 0, 90, 175, 250, or 325 ppm methyl bromide 6 hr/day for 5 days. Animals were anesthetized with phenobarbital then perfusion fixed 1-2 hr after the last exposure or in extremis (325 ppm, 4 days) with Karnovsky's fixative and selected tissues were processed for light microscopy. With the exception of the nasal passages, tissues were selected on the basis of previous studies with methyl chloride. The principal clinical signs, confined to the 250 and 325 ppm groups, were diarrhea, hemoglobinuria, and, in a few cases, gait disturbances and convulsions. A dose-dependent vacuolar degeneration of the zona fasciculata of the adrenal glands, cerebellar granule cell degeneration, and nasal olfactory sensory cell degeneration were seen in all concn groups except at 90 ppm. Cerebral cortical degeneration and minor alterations in testicular histology were seen only in the 325 ppm group. Hepatocellular degeneration was confined to the 250 and 325 ppm groups. No changes were seen in the kidney or epididymis. [R130] *The reproductive effects of methyl bromide in the male rat were studied. Adult male F344 rats (11-13 wk) were exposed by inhalation to 0 or 200 ppm methyl bromide 6 hr/day for 5 days (first day of exposure= day 1). Ten animals from each group were anesthetized with pentobarbital and terminated on days, 1, 3, 5, and 8. Additional, 5 males from each group were killed on days 6, 10, 17, 24, 38, 52, and 73. Plasma testosterone concn was reduced during and immediately following exposure (days 1, 3, 5, and 6), but returned to control levels by day 8. Nonprotein sulfhydryl content of the liver and testis was reduced during exposure but returned to control levels by day 8 (3 days postexposure). No other reproductive indexes, including testis wt, daily sperm production, cauda epididymal sperm count, sperm morphology, percentage motile sperm, linear sperm velocity, and epididymal and testicular histology were affected by methyl bromide exposure at any time point examined. [R131] *1,2-Dichloroethane and methyl bromide were tested for mutagenicity in Drosophila melanogaster by inhalation exposure; both cmpd were mutagenic (standard sex-linked recessive lethal mutation) but the mutagenic affect of methyl bromide was most pronounced at the postmeiotic germ cell stage. Prolonged expsoure to the cmpd at lower concn caused mutation rates similar to those of higher concn at shorter exposure periods. [R132] *Methyl bromide concn which induce neurotoxic effects were studied in the rabbit, a species known to be sensitive to this cmpd. Rabbits were exposed via inhalation to 27 ppm methyl bromide over a period of 8 mo for a total exposure duration of 900 hr. Biweekly neurobehavioral tests failed to uncover any untoward consequences of the exposures. Long term exposures to methyl bromide, in the present concn range, are tolerated by this species. After subchronic exposures to 65 ppm methyl bromide, rabbits developed severe neuromuscular losses and had impaired blink reflexes and body weights. The symptoms partially subsided within 6-8 wk after removal from the exposure. [R133] *The acute toxicity of methyl bromide to carp was determined in experiments with a 4 hr exposure period. The 4 hr median lethal concn was calculated at approximately 17 mg/l ie, the order of magnitude of actually encountered peak concn in surface water. The concn effect curve was very steep and the response was somewhat delayed. Morphological damage to the gill epithelium, indicative of alkylation of cell membranes, was the most pronounced effect of methyl bromide. It consisted of initial swelling of the lymphatic space and vaculizaiton of the epithelial cells, followed by disintegration of the epithelium and invasion of leukocytes. [R134] *Six week old male Wistar rats were treated with the agent by gavage at the rate of 50 mg/kg five times per week, either for 13 weeks with a 12 week recovery period or continuously for a period of 25 weeks. Treatment caused significant reduction in weight gain; stoppage of treatment resulted in significantly greater body weight gain as compared to rats on continuous treatment. The stomach of rats treated for 13 weeks had numerous abdominal adhesions. The forestomach at the greater curvature adhered to the liver, spleen and diaphragm and was extremely contracted. Animals treated up to 25 weeks presented similar features while the stop treatment group still had peritoneal adhesions, but the stomach was less contracted. In methyl bromide treated rats, microscopy revealed inflamation, fibrosis, acanthosis and pseudoepithelimatous hyperplasia of the forestomach. Mild acanthosis of the esophagus was evident after 25 weeks of continuous exposure. Discontinuation of methyl bromide was associated with a forestomach epithelium that had fewer cell layers than that of the continuous treatment group and a lower incidence of hyperplastic lesions. One animal in the 25 week group had a severe dysplastic lesion with high mitotic activity, which was classified as an early carcinoma. [R135] *Effects of methyl bromide on organ systems were measured with specific attention given to body weight changes, organ weight changes, general condition and hematological changes, residual bromide ion concentration and histopathological changes in male Sprague Dawley rats exposed to methyl bromide through inhalation at concentrations of 502, 622, 667, 699, and 896 ppm. Single exposures were for 4 hr periods. Additional rats were exposed to 701, 767, 808, 817, and 832 ppm concentration levels. Subacute toxicity exposures were at 150, 200, 300, or 400 ppm. The median lethal concentration for rats after 4 hr exposure was 780 ppm. In subacute and chronic toxicity studies neurological manifestations of paralysis of extremities and ataxia were noted after 300 ppm and 400 ppm exposure. Necrosis in the brain occurred at 400 ppm. Necrosis of the heart occurred at all concentrations. At 200, 300, and 400 ppm exposures, the kidney had the highest concentration. An unknown biochemical mechanism results in the metabolism of methyl bromide to bromide ion. Liver concentrations of methyl bromide were lower than either the liver or the brain. At 150 ppm levels the total lipid and nonesterified fatty acids in blood had decreased. Exposure to 150 ppm caused small focal necroses and fibrosis replacement in the heart muscle. [R136] *The fumigant methyl bromide was evaluated for genotoxicity in the somatic wing spot assay of Drosophila melanogaster. Third instar larvae trans-dihybrid for mwh and flr3 were exposed to varying concentrations (0-16 mg/l) of the gas for 1 hr. Following this exposure via inhalation, the larvae were placed into vials containing Instant Medium. Seven days after the exposure, the adult flies in the vials were collected and their wings were scored under 400X magnification for the presence of clones appeared as mwh-flr3 twin spots and single spots of either mwh or flr3 phenotype. Exposure to methyl bromide was found to result in the positive induction of both twin spots and large (greater than 2 cells) single spots. For each endpoint, a significant exponential association was obtained between concentration and frequency of spots per wing. Methyl bromide was found to be a negative inducer of small (1-2 cells) single spots at all concentrations except 16 mg/l where a positive effect was observed. [R137] *The SOS umu test has been used for the detection of DNA damaging agents. The SOS function inducibility of volatile chemicals (propylene oxide, methyl bromide, and ethylene dibromide). All chemicals tested induced SOS function in a dose related manner. [R138] *The subacute effects of continuous exposure to methyl bromide on the heart, liver, lung, and blood were examined in male Sprague Dawley rats. Animals were exposed through continuous inhalation for 3 weeks of 1, 5, or 10 ppm methyl bromide. Rats were sacrificed within 1 hr after end of exposure, and organs were weighed and biochemical examinations were performed on the blood and the homogenates of heart, liver, and lung. No differences were seen between rats given the 1 ppm concentration and control rats. Rats in the 5 ppm group showed several changes; blood glucose, thymus weight, and creatine phosphokinase decreased, while blood hemoglobin, reduced glutathione, serum total protein, and glutamic pyruvic transaminase increased after exposure. Animals receiving 10 ppm showed many changes. An increase was observed in: serum glutamic oxaloacetic transaminase, lactate dehydrogenase, total protein, blood hemoglobin, reduced glutathione, and glutamic pyruvic transaminase. Decreases were noted in: serm cholinesterase, creatine phosphokinase, triglyceride, free cholesterol lactate, blood glucose, heart lactate, glucose, free fatty acids and glyocgen. [R139] *Methyl bromide was positive for induction of gene mutations in Salmonella typhimurium strain TA100, with and without exogenous metabolic activation; negative results were obtained with TA98 in this assay. In vivo, methyl bromide induced sister chromatid exchanges in bone marrow cells and micronuclei in periphral erythrocytes of female mice exposed by inhalation for 14 days. No significant incr in either sister chromatid exchanges or micronuclei was observed in male or female mice exposed to methyl bromide by inhalation for 4, 8, or 12 wk. [R140] *Decreased eyeblink reflex and hind limb paralysis associated with decreased sciatic and ulnar nerve conduction velocities were observed in rabbits exposed for 4 wk to 65 ppm methyl bromide. Only partial recovery was observed in these rabbits 6-8 weeks after cessation of exposure. [R67, 669] *Methyl bromide was not teratogenic to rats exposed to 20 or 70 ppm for 7 hr/day, 5 days/wk, for 3 weeks prior to mating and daily through gestation day 19. In the same study, rabbits exposed to 70 ppm methyl bromide showed severe neurotoxicity and mortality. However at 20 ppm, no maternal toxicity, fetotoxicity, or teratogenic effects were elicited. [R67, 670] *Experimental exposure of a rabbit's eye to pure methyl bromide gas at room temperature for one and one half minutes caused immediate loss of surface luster, followed in several hours by loss of corneal epithelium, and much edema of the conjunctivae and lids. A day later the corneal stroma was bluish, much swollen, and nearly opaque, but within five days the cornea started to clear. This was much more severe exposure than would occur by accident. [R86, 610] *In the 29-month study male and female-rats were exposed to 0, 3, 30, or 90 ppm of methyl bromide gas 6 hr/days 5 days/week. Ten rats per sex were killed at 13, 52, and 104 weeks for interim information. Mortality was increased at week 114 but only in the 90 ppm group, which also had lowered body weights. Increased incidences of degenerative and hyperplastic changes in the nasal olfactory epithelium were observed in a dose-related manner in all groups. The lesions did not appear to progress with time. Exposure to 90 ppm was associated with an increased incidence of thrombi and myocardial degeneration-in the hearts and hyperkeratosis in the esophagus and forestomach. [R19, 4026] *Groups of 50 male and 50 female Fischer 344/DuCrj rats, six weeks of age, were administered methyl bromide (purity, > 99.9%) by whole body inhalation at concentrations of 0 (controls), 4, 20 or 100 ppm (0, 16, 78 or 389 mg/cu m) for 6 hours per day on five days per week for 104 weeks. At week 105, all surviving animals were killed. Necropsy was performed on all animals and all organs were examined histologically. Survival at week 104 was 34/50, 34/50, 31/50 and 33/50 in control, low-, mid- and high-dose males and 42/49, 38/50, 39/50 and 41/50 in control, low-, mid- and high dose females, respectively. The incidence of adenomas of the pituitary gland was significantly increased in high-dose males compared with controls (16/50, 23/50, 19/50 and 30/50 in control, low-, mid-, and high-dose, respectively; p < 0.01, chi-square test). In females, no increase in the incidence of tumors related to treatment was observed. [R141] *Alkylation of guanine-N-7 in DNA of liver and spleen was observed after treatment of male CBA mice with (14)C methyl bromide (4.9-5.0 mCi/mmole) by inhalation. [R94] *Rats were exposed to 290 or 495 ppm methyl bromide gas for 6 h/day, 3 times/wk for 4 to 8 wk. Creatine kinase (CK), aspartate aminotransferase (ASAT), and lactate dehydrogenase (LDH) activities and bromide ion concentrations were measured in eight regions of the brain. Methyl bromide gas inhibited CK activities in all regions of the brain, though the inhibition tended to be smallest in the cerebellum (hemisphere and vermis) and largest in the brainstem (hypothalamus, midbrain, and medulla oblongata). The dose of methyl bromide to inhibit CK activities was lower than that to damage the central nervous system histologically. No inhibition of ASAT or LDH activities was seen except for a slight inhibition of these in striatum. Inhibition of CK activities did not increase clearly on increasing dose (290 to 495 ppm) or on prolonging exposure period (4 to 8 wk). Although 50% recovery of CK activities and the half-life of bromide ion agreed well in the medulla oblongata, changes in CK activities and bromide ion concentrations did not correlate otherwise. Thus, inhibition of CK activities in brain appears to be a sensitive indicator of methyl bromide intoxication, and may be related to genesis of its neurotoxicity. The inhibition seems to be caused by methyl bromide itself rather than by bromide ion. When effects on enzyme activities in brain homogenate were examined in vitro by bubbling with methyl bromide gas, CK inhibition was seen within 15 s of exposure. Dithiothreitol suppressed the CK inhibition, whereas N-acetylcysteine did not. These observations suggest that methyl bromide may attack sites in the CK molecule different from those attacked by ethylene oxide or acrylamide. [R142] NTOX: *We used the inhalation of methyl bromide gas to produce a near-complete destruction of the rat olfactory epithelium and analyzed the reinnervation of the bulb during reconstitution of the epithelium. The degeneration of olfactory axons elicits a transient up-regulation of glial cell proliferation and glial fibrillary acidic protein expression in the olfactory nerve and olfactory nerve layer of the bulb. Anterograde transport after intranasal infusion of wheat germ agglutinin conjugated horseradish peroxidase demonstrates that the first nascent axons reach the bulb within the first week after lesion. Subsequently, a massive wave of fibers arrives at the bulb between 1 and 2 weeks postlesion, and enters the glomeruli between 2 and 3 weeks postlesion. However, the olfactory projection does not stabilize until 8 weeks after lesion judging from the return in growth associated protein-43 expression to control levels. The extent of reinnervation after lesion is correlated with the completeness with which the epithelium reconstitutes itself. In rats that are lesioned while fed ad libitum, there is near-complete reconstitution of the neuronal population, and the projection onto the bulb fills the glomerular layer in its entirety. However, in rats that are lesioned while food restricted, a significant fraction of olfactory epithelium becomes respiratory during its reconstitution, and the population of reinnervating fibers is less. As a consequence, the posterior half of the bulb remains hypoinnervated overall and denervated at its caudal margin. ... Accordingly, we hypothesize that the persistence of a significant population of pre-existing neurons is needed to preserve receptotopy during reinnervation. In addition, the results suggest that in the face of massive turnover and a reduced afferent population, there is a tendency for reinnervating axons to fill available synaptic space. [R143] *Methyl bromide, is neurotoxic in humans and other mammals. To study its short-term effects on neurons, it was applied in aqueous solution to hippocampal slices of young rats (1.4 and 0.7 mM; for 8 minutes). Extracellular field recordings and intracellular microelectrode recordings from CA1 pyramidal neurons showed that the neurons stay viable for at least one hour after application of the mono-halomethane. However, a moderate, but consistent, irreversible decrease in synaptic excitability was observed. The intracellular recordings indicate that this may be attributed to a decrease in excitatory postsynaptic potentials. No effects were observed at 0.7 mM methyl bromide. Bromide, in a dose-dependent, partly reversible manner (during one hour), produced a similar decrease in excitability. Quantitatively, the action of bromide at 0.5 mM resembled the one seen with methyl bromide at the concentration of 1.4 mM. Since methyl bromide did not induce electrophysiologic changes consistent with evidence of neurotoxicity during one hour of observation it is concluded that it lacks immediate toxic effects on hippocampal rat neurons. Its neurotoxicity may be entirely due to metabolites or other indirect effects. The slight decrease in excitability may be due to the effect of bromide that is set free as tissue proteins and other cell molecules are methylated. [R144] *Methyl bromide was experimentally exposed to a 12 cm2 area of the back skin of Wistar rats for 30 s, and for 1, 3, and 5 min, and time courses of both changes in plasma bromide concentration and of histopathological changes were examined. The concentration of plasma bromide ion showed a sharp increase immediately after the exposure in all exposed groups, reaching a peak level after 1 hr, then decreased rapidly. The ion level gradually decreased after 72 hr to 1 week, and returned to a normal level after 4 to 8 weeks. Calculating from a regressive curve, the biological half lives of plasma bromide ion were 5.0 days to 6.5 days. Histopathologically, the impairments to the epidermal cells, fibroblasts and blood vessels were observed in the early phase. These cellular changes could be due to the direct cytotoxicity of the compound. In the next phase, newly infiltrating cells showed degeneration and necrosis. Subsequently, an impairment of the collagen bundles was observed. [R145] *Average human exposure resulting from consumption of methyl bromide (MB)-fumigated food has been estimated to be 0.00125 mg/kg/day. A 1-yr feeding study in beagle dogs was conducted as a safety study, in which the high-dose diet was intended to yield a methyl bromide dose of at least 100 times the calculated human dietary exposure. Diets were fumigated with MB and fed to the dogs daily, except for weekends and holidays. MB consumption each feeding day was calculated as a time weighted average (TWA) that accounted for the rate of degassing from the fumigated diet and the rate of feed consumption during the feeding period. TWA compound consumption in the low-, mid- and high-dose groups, respectively, averaged 0.06 + or - 0.02, 0.13 +/- 0.03 and 0.28 + or - 0.08 mg/kg/day in males and 0.07 + or - 0.03, 0.12 + or - 0.03 and 0.27 + or - 0.09 mg/kg/day in females. Clinical observations, body weight and feed consumption, ophthalmology, clinical pathology, urinalysis, organ weights and macroscopic and microscopic pathology were comparable in control and MB-treated dogs. Under the conditions of this study, the no-observed-effect level (NOEL) for MB was at least 0.28 mg/kg/day, or approximately 200 times the expected average human dietary exposure. [R146] *Teratogenicity studies of methyl bromide, a widely used fumigant, were conducted in rats and rabbits. Methyl bromide was dissolved in corn oil and administered orally to groups of 24 copulated female Crj:CD (SD) rats at dose levels of 0 (corn oil), 3, 10 or 30 mg/kg/day on days 6-15 of gestation and to groups of 18 artificially inseminated female Kbl:JW rabbits at 0, 1, 3 or 10 mg/kg/day on days 6-18 of gestation. Maternal rats and rabbits were euthanized on respective days 20 and 27 of gestation. Foetuses were examined for survival, growth and teratological alterations. Maternal toxicity was evident in the high-dose groups for both species. In these groups, maternal body weight gains and food consumption were significantly decreased during the dosing and post-dosing periods. Necropsy of maternal rats also revealed erosive lesions in the stomach and the surrounding organs. However, no treatment-related adverse effects were found in foetuses of the treated groups for both rat and rabbit studies. ... Methyl bromide was not foetotoxic or teratogenic to rat and rabbit foetuses up to dose levels of 30 and 10 mg/kg/day, respectively, at which maternal toxicity was evident for both species. [R147] NTXV: *LC100 Rat inhalation 0.63 mg/l air/6 hr; [R38] *LC50 Mouse inhalation 4.68 mg/l/hr (1200 ppm/1 hr); [R148] *LC100 Guinea pig 7760-11640 mg/cu m; [R149] *LC50 Rat 780 ppm/4 hr; [R136] *LD50 Rat oral 214 mg/kg; [R55] *LC50 Rat inhalation 302 ppm/8 hr; [R55] *LC50 Mouse inhalation 1540 mg/cu m/2 hr; [R55] ETXV: *LC50 Lepomis macrochirus (bluegill) 11 ppm/96 hr (static bioassay in fresh water at 23 deg C, mild aeration applied after 24 hr); [R150] *LC50 Menidia beryllina (tidewater silverside) 12 ppm/96 hr (static bioassay in synthetic seawater at 23 deg C, mild aeration applied after 24 hr); [R150] *LD50 Coleoptera 4.505 mg/l/24 hr; [R151] NTP: *Groups of 70 B6C3F1 mice of each sex were exposed to methyl bromide by inhalation at 0, 10, 33, or 100 ppm for 6 hr per day, 5 days per week for up to 103 weeks. Additional groups of 16 mice were included for neurobehavioral evaluations thorughout the 2 year studies. By 20 weeks (139 days), 27 males and 7 females exposed to 100 ppm had died and methyl bromide exposure was discontinued for the remaining mice in this dose group. Ten female mice from the 100 ppm group predesignated for the 15 month interim evaluation were killed on schedule and all other high dose animals were allowed to live to term (24 mo) fore evaluation of chronic toxicity and carcinogenicity. Clinical signs indicative of neurotoxicity, including tremors, abnormal posture, tachypnea, and hind leg paralysis, persisted in these high dose mice until the end of the studies. ... Final mean body weights of surviving 100 ppm males and females were markedly lower (33% and 31%) than those of the controls. Neurobehavioral changes occurred in male and female mice initially exposed to 100 ppm methyl bromide, with more pronounced changes observed in males. In general, these animals were less active and manifested a heightened sensitivity in the startle response than mice in other dose groups. ... Exposure to methyl bromide was not carcinogenic under the conditions of these studies. However, there was an increase in the incidence of several nonneoplastic lesions in the brain, heart, bone (sternum), and nose. Degenerative changes in the cerebellum and cerebrum occurred in males and females exposed to 100 ppm. Myocardial degeneration and cardiomyopathy were observed in the hearts of mice exposed to 100 ppm. An increased incidence of sternal dysplasia was seen in treated animals, particularly in those exposed to 100 ppm. An increased incidence of olfactory epithelial necrosis and metaplasia within the nasal cavity was seen in the mice exposed to 100 ppm, particularly males. [R140] TCAT: ?Methyl bromide (CAS # 74-83-9) was evaluated for subchronic oral toxicity in male Wistar rats (10 rats/treatment group) administered gavage doses in peanut oil of 0, 25, or 50 mg/kg/day, 5 days/week for approximately 90 and 120 days (an additional rat was included in each 90- day treatment group). Two additional 90-day treatment groups (10 rats/dose level), respectively, were allowed 60- and 30-day recovery before necropsy. Supplemental groups (10 rats/dose level) of control and high dosed (50 mg/kg/day) rats also received treatment for approximately 30, 60, and 90 days, the 90-day groups undergoing gastrotomy prior to terminal necropsy. Relative to both control and low dose rats, 50 mg/kg/day oral dosing for 30 days was associated with lethargy, decreased feeding efficiency with weight loss, increased water consumption, soft stool, and some abdominal distention. Gross lesions predominated in the peritoneum and nonglandular stomach and included both nonspecific diffuse and focal changes of the gastric mucosa, atrophy of the surface squamous epithelium, and multiple adhesions of the gastric serosa to adjacent organs. Hyperplasia consisted of acanthosis and hyperkeratosis, with epithelial projections ("pegs") in all rats of this group; fibrotic lesions of the tunica muscularis and fibrotic serosa adhesions contained duct-like structures as well. These changes were statistically significant in association with treatment (irrespective of dose) relative to control and length of exposure, but did not demonstrate a dose-related significance (incidence differences between treated groups was not significant by Duncan's multiple range test). Increased fibrosis of the lamina propria and lymphocytic infiltrates of the glandular stomach were statistically significant (p < /= 0.05, Duncan's multiple range test) overall in the high-dose group, but were considered secondary to necrosis. Regression of lesions of the squamous epithelial portion of the stomach upon treatment cessation confirmed a reparable hyperplastic response to oral methyl bromide. Further, cessation of treatment was associated with recovery of generalized bodyweight and growth loses in treated rats relative to controls. No treatment-related malignancy was noted. [R152] ?In orientative study, methyl bromide (CAS # 74-83-9) was evaluated for subacute inhalation toxicity in male SPF Wistar rats (6/dose level) which received whole-body exposures to doses of 0, 150, 375, and 750 mg/cu m, 6 hours/day, on 5 and 3 days in 2 consecutive weeks. Exposure to 750 mg/cu m was associated with marked growth retardation, tremors, and motor incoordination. All treated rats had dose-related reduction in absolute and increase in relative brain weight compared with controls. Histologic examination showed pulmonary hyperemia with focal hemorrhage in 3/6 rats of 750 mg/cu m exposures. In range-finding tests, rats (6/sex/exposure level) were exposed to concentrations of 0, 70, 200, or 600 mg/cu m methyl bromide, 5 days/week for 3 weeks and 7 days of a fourth week. Exposures to 600 mg/m3 was associated with anorexia, stunted growth, and death (3/6 females, 5/6 males). This group also exhibited uprighting and balancing anomalies, while 3/6, 6/6, and 6/6 of low-, mid-, and high-concentration groups had abnormal gait. Elevated serum SGPT and alkaline phosphatase activity characterized the clinical chemistry and there was evidence of disrupted blood morphology. Histologic examination revealed lesions of the heart including diffuse fatty vacuolization and degeneration of myocardial fiber, and hyperemic lungs with marked alveolar dilation in 600 mg/cu m rats. Some animals exhibited interstitial pneumonia. This study reports a NOAEL of 70 mg/cu m. [R153] ?Methyl bromide (CAS # 74-83-9) was evaluated for chronic inhalation toxicity and carcinogenicity in Wistar rats (90/sex/group) which received whole-body exposure to nominal concentrations of 0, 3, 30, and 90 ppm for 6 hours/day, 5 days/week, for up to 29 months. Ten of each sex/group were sacrificed for interim pathology assessments at 13, 52 and 104 weeks, and 10 rats/sex/group removed from study at Week 41 received behavioral evaluation. High dose animals showed slightly increased mortality, slightly diminished bodyweights, and reduced brain weights in both males and females. The reduction in brain weight was statistically significant in females, but not in males. No other distinct clinical observations and no changes in hematology, biochemistry, or urine were noted throughout the study. Increased incidence of hemothorax was observed in dead and moribund 90 ppm rats. On microscopic evaluation, increased incidence of slight hyperplasia and degenerative lesions of the dorsomedial nasal epithelium was significantly (Fischer exact probability test) dose related. These changes did not appear to progress with time. Increased hyperkeratosis was observed in the esophagus of 30 ppm males and and both esophagus and forestomach of 90 ppm males and females, but the increase reached statistical significance in the esophagus of 90 ppm males. The incidence of cardiac thrombosis was also significantly increased in 90 ppm males and females, respectively, at 105 weeks and 29 months. The significantly increased myocardial degeneration with cartilaginous metaplasia (3 ppm females, 90 ppm males) also increased in severity with length of exposure, that change significant in 90 ppm females but not in the males. No dose or treatment-related neoplastic lesions were identified in any treatment group at any assessment throughout the study. [R154] ?Methyl bromide (CAS # 74-83-9) was evaluated for chronic inhalation toxicity and carcinogenicity in Wistar rats (90/sex/treatment level) administered exposures (protocol unspecified) to 0, 3, 30, or 90 ppm for 6 hours/day, 5 days/week, for up to 29 months. Ten of each sex/treatment group were sacrificed for interim assessments at 13, 52 and 104 weeks. This report by Dr. Jerry F. Hardisty of Experimental Pathology Laboratories, Inc. primarily constitutes confirmation of the original study pathologist's conclusions. Upon specific reexamination of nasal cavity specimens in groups sacrificed at 52 and 104 weeks, incidence of basal cell hyperplasia of olfactory epithelium in the dorsi-medial nasal cavity in low dose groups did not reach statistical significance (Fischer's exact probability test) relative to controls. Such changes in mid- and high-dose rats were significantly related to exposure level; however, a low level exposure established the inhalation NOEL of 3 ppm for this study, contrary to original study conclusions. The reviewer also found the incidence, but not the severity, of these lesions to increase with time. [R155] ?Methyl bromide (CAS # 74-83-9) was evaluated in 2 rabbits (breed unspecified) for daily urinary excretion of Br associated with each of 5 initial daily 0 and 60 ppm exposures (exposure terms unspecified) in metabolic chambers. These values were compared to those of 2 rabbits from initial onset of exposure-related paralysis upon Days 14 and 20 of 60 ppm exposures, respectively. Values for mg Br/cc urine were initially comparable at 0.029 and 0.027, rose to 0.035 and 0.036 mg Br/cc following a first exposure, and rose again successively with each daily exposure to respective 5- and 3-day maximal values of 0.085 and 0.059 mg Br/cc. These values ranged from 0.011 to 0.019 ave. mg Br/cc/day in control rabbits. Initial values were 0.094 and 0.086 mg Br/cc in just-paralyzed rabbits, and 3- day values averaged 0.107 and 0.109 mg Br/cc/day. Subsequently, these animals deteriorated as to preclude their initial water and food consumption (and urination). [R156] ?Methyl bromide (CAS # 74-83-9) was evaluated in rabbits (2/treatment group, breed unspecified) for urinary excretion of formic acid associated with daily 0 and 60 ppm atmospheric exposures (of unspecified duration). Relative to controls, rabbits administered daily methyl bromide exposures until paralyzed or moribund excreted no formic acid of significance in the urine. [R157] ?Methyl bromide (CAS # 74-83-9) was evaluated in 5 and 9 rabbits (breed unspecified), respectively, of repeated 0 or 60 ppm atmospheric exposures, 8 hours/day, for toxicity-related methanol in blood, muscle, liver, kidney, lung, brain, and/or urine. The exposures were repeated until treatment-related paralysis or death ensued (18 to 26 exposures). No methanol of significance was detected in blood, tissues, or urine of controls or in rabbits of MeBr- associated paralysis or death. [R158] ?Methyl bromide (CAS # 74-83-9) was evaluated in 2 and 4 cavies (breed unspecified), respectively, of repeated 0 or 60 ppm inhalation exposures, 8 hours/day, for toxicity-related methanol in blood. The exposures were repeated to induce overt treatment-related toxicity; however, a total of 145-146 total exposures in 214-215 days produced no clinical toxicity and no methanol of significance in the sampled blood of MeBr-exposed cavies relative to controls. [R158] ?Methyl bromide (CAS # 74-83-9) was evaluated in 5 control and 8 MeBr-paralyzed rabbits (breed unspecified), respectively, of daily 0 and 60 ppm exposures (20-30 days' repeated inhalation exposures, protocol unspecified) for blood/tissue distribution of Br. Relative to average levels of 0.618 mg Br/100 cc blood, and 0.04, 0.50, 0.55, 0.44, and 0.00 mg Br/100 g dryweight muscle, liver, brain, kidney and lung of control rabbits, levels in the respective tissues of paralyzed rabbits were 11.1 mg/cc in the blood (approximately 20X), and 3.27, 11.3, 9.9, 22.7, and 26.0 mg/100 g tissue dryweights. Following cessation of treatment, the return of these values to normal in 2 paralyzed rabbits paralleled their improved general appearance and behavior on Recovery Days 27 and 64. [R159] ?Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in groups of 48, 25, 23, 23, and 23 pregnant RIV-TOX rats, respectively, administered daily gavage doses of 0, 0.5, 5, 25, and 50 mg/kg bodyweight from Gestational Days 5 through 20. Dose-related maternal toxicity associated with 25 and 50 mg/kg regimens was characterized by significantly (student's T test, p < 0.05) diminished weight gain at Treatment Days 14 and 3, respectively. Otherwise, all clinical toxicity was confined to the high dose dams, including perivaginal blood, diarrhea, lethargy, piloerection, morbidity (4/23 dams killed in extremis), and death (1 dam). Pathologic inspection of the early lethalities revealed poor general condition with swollen abdomens and no changes in heart or lungs, their death apparently related to inflammation and perforation of the peritoneum arising in the stomach. Each dam had implantations or early resorptions, one with live embryos. No treatment-related reductions in bodyweight attended the clinical condition of pregnant females with live fetuses at caesarian, and placental weights, fetal weights, sex ratios, and gross morphology were comparable to controls in all dose groups; numbers of fetuses were comparable to controls in both pregnant and pregnant with live fetus determinations of all treated dams. Of the 43, 21, and 18 initially-pregnant dams in control, 25 mg/kg, and 50 mg/kg dose groups, 1, 3, and 18 (100%) were without live fetuses upon terminal caesarian. Relative to controls, the abortive pregnancies in 25 mg/kg (3/21) and 50 mg/kg (18/18) dams were associated with normal numbers of implantations and pre- implantation losses, and diminished maternal bodyweight, decreased corpora lutea, and increased early resorptions. Upon terminal necropsy, dams of the 2 highest treatment groups exhibited dose-related incidence and levels of plastic peritonitis arising from the stomach to involve diaphragm, liver, spleen, left adrenal gland, kidney, and pancreas. The nonglandular stomach had thickened walls characterized by hyperplasia and hyperkeratosis with ulceration and fibrosis of underlying tissues in extreme cases (50 mg/kg) and adhesions to the adjacent organs. Pending fetal skeletal and tissue analyses, the authors suggested that concurrence of dose-related maternal toxicity and early resorptions and otherwise normal reproductive parameters in treated pregnant rats indicated a lack of embryotoxicity. [R160] ?Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in female Wistar rats (38-42/treatment group) administered whole-body exposures to 0, 20, and 70 ppm, 7 hours/day, 5 days/week, for 3 weeks, mated, then exposed 7 hours/day for the initial 19 days of gestation. Additional groups received either low or high-level exposures pre- or post-conception, with exposure to filtered air only as the complement pre- or post-conception exposures. On Gestational Day 21, all rabbits were subjected to terminal necropsy with caesarian section. Significantly depressed bodyweights during post-conception high-level exposures in previously exposed dams resolved to near normal relative to air/air pre- and post-conception exposed controls; no further untoward effects or pathological change related to inhalation exposure of any concentration, with or without pretreatment. Histopathologic changes in lungs (25% random sampling) included mononuclear and focal granulomatous inflammatory lesions of questionable etiology, but the incidence was not related to exposure level. Other lesions included hydronephrosis, and hepatic inflammation and necrosis. Pregnancy rates, fetal size, sex ratio, fecundity, and embryotoxicity appeared comparable to air/air controls. The incidence of slight ossification reductions in fetuses did not correlate to exposure level. Authors reported minimal maternal toxicity and no notable embryotoxicity associated with repeated inhalation exposure to concentrations of 20 or 70 ppm in rats. [R161] ?Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in artificially inseminated virgin female New Zealand rabbits (24/exposure group) administered whole-body exposures to 0, 20, and 70 ppm, 7 hours/day on the initial 24 days of gestation. All exposures were discontinued on Day 15 due to clinical toxicity in high dose animals, including marked anorexic weight loss and generalized signs of distress, progressing to convulsive movements, hind-limb paresis, and death (24/25 by GD 30). No maternal toxicity was noted in low dose does. On terminal necropsy, the solitary surviving high-level rabbit had a significantly small (relative and absolute) liver relative to controls. Microscopic examination revealed mononuclear and inflammatory lesions of the lungs, neither their incidence or severity correlated to dose level. No lesions of kidney, liver, or uterus were identified. Pregnancy rates (calculated among lethalities as well as survivors) were not significantly affected by treatment and no significant treatment-related differences in fetal weight or length were documented; however, the fetuses of the sole high-dose litter were dramatically smaller than those of both negative control and low dose groups. Since fetal effects accompanied severe maternal toxicity and were not noted in low-dose groups, the authors reported no treatment-related embryotoxicity per se. [R161] ?Methyl bromide (CAS # 74-83-9) was investigated for subhchronic inhalation toxicity in pregnant New Zealand White Rabbits in two range-finding tests for planned developmental toxicity study. Daily exposures to concentrations of 0, 50, 70, and 140 ppm in the second probe resulted in generalized moribund condition in high dose does, such that treatment was halted on Study Day 17. No clinical toxicity was noted at lower level exposures. Upon histologic examination of 7 brain and spinal cord tissue samples of each exposure group, all rabbits of the 140 ppm group exhibited multifocal brain lesions including bilateral necrosis or spongiosis and inflammation of the midbrain meninges; the spinal cords showed no treatment- related lesions. No neurologic lesions were identified among rabbits of other exposure groups. Gross lesions observed in 140 ppm rabbits included decreased ingesta, fecal soiling of the perineum, pulmonary atelectasis and congestion, focal hepatic blanching, erosions and/or ulcers of the gastric glandular mucosa, and distended bladder (urine). These lesions were not apparent at lower exposure levels. No reproductive data were presented. [R162] ?Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in 2-part study with artificially inseminated rabbits (26/group) administered whole-body exposures to 0, 20, 40, or 80 ppm for 6 hours/day on gestational days 6-19. The initial trial reported significant maternal toxicity in 80 ppm does, and significant developmental toxicity (fetal malformations) consisting of agenesis of caudal lung lobes and gall bladders, and fused sternebrae. Potential confounding factors in assessing developmental toxicity included hereditary predisposition to malformations via the females or a common source of semen inseminating the 8 females of litters lacking gall bladders. In a second study, groups of 18 pregnant does (not inseminated with suspect semen) were exposed to either 0 or 80 ppm and 18 does (inseminated only with suspect semen) were an unexposed control group. Treatment-related maternal toxicity and reduced fetal bodyweights per litter were not associated with increased percent fetal malformation (fetal skeletal exams were not done) in the 80 ppm group, although incidence of missing gall bladders in 80 ppm fetuses was nearly 5X that in negative controls; the naive control group litters had fewer malformations than either the negative control or 80 ppm group litters. The protocol and findings were evaluated and validated by Dr. Rochelle Tyl, Senior Program Director, Reproductive and Developmental Toxicology, Research Triangle Institute. Both the study authors and Dr. Tyl concluded that fetal effects might be attributed to maternal toxicity at 80 ppm, as such fetal effects and maternal toxicity were not observed at lower concentrations. Dr. Tyl additionally provided historical control data regarding fetal fused sternebrae associated with maternal toxicity (irrespective of chemical, route, or dose). A NOAEL for both does and conceptuses was 40 ppm under the conditions of this study, and neither study authors nor reviewer considered the results indicative of developmental toxicity per se. [R163] ?Methyl bromide (CAS # 74-83-9) was evaluated for developmental toxicity in two-part study with artificially inseminated rabbits (26/group) administered whole-body exposures to nominal concentrations of 0, 20, 40, or 80 ppm for 6 hours/day on gestational days 6-19. On Day 28, all surviving does were necropsied for examination of maternal visceral organs, pregnancy status, and any fetal developmental anomalies. The initial trial reported significant (Dunnett's test, p < 0.05) clinical toxicity in 80 ppm does (13/26), including decreased feces, lethargy, right-sided head tilt, ataxia, and lateral recumbency with reductions of bodyweight and/or bodyweight gain. Treatment did not significantly affect relative or absolute maternal organ weights or reproductive parameters including pregnancy weight, gravid uterine weight, number of implantations, preimplantation loss, resorption rate, litter size, fetal sex ratio, or fetal body weights relative to controls. Fetal malformations (80 ppm litters only) included agenesis of caudal lung lobes and gall bladders, and fused sternebrae. Incidence of fused sternebrae and absence of gall bladders in 80 ppm fetuses was statistically significant. Of these, the former is historically attributable to maternal toxicity, while the significance of absent fetal gall bladders was potentially confounded by hereditary predisposition to malformations via the females and/or the common source of semen conceiving the litters lacking gall bladders. A second study employed groups of 18 pregnant does (inseminated with nonsuspect semen) exposed for 6 hours daily to either 0 or 80 ppm and 18 does (inseminated only with suspect semen) as a naive control group. The observed treatment-related maternal toxicity, reduced gravid uterine weights, and reduced fetal bodyweights per litter in 80 ppm litters were not associated with significantly increased percent total fetal malformation (skeletal examinations were not performed). The incidence of missing gall bladders in 80 ppm fetuses, however, was nearly 5X that in negative controls, and the naive control group litters had fewer malformations than either the negative control or 80 ppm group litters. Likewise, agenesis of caudal lung lobes could not be causally related to heredity factors of the suspect semen in the earlier study, but also was not decisively related to treatment since malformations also occurred among chamber control fetuses. As neither fetal effects nor maternal toxicity were observed at lower concentrations, the authors concluded that developmental effects were likely attributable to maternal toxicity at 80 ppm rather than developmental toxicity per se. [R164] ?Methyl bromide (CAS # 74-83-9) was evaluated for genotoxicity in cultured Chinese hamster ovary cells (3 x 375,000 cells/tube) gassed for 20 seconds at concentrations of 0, 1, 6, 13, and 26 ppm, sealed, and incubated for 18 hours. After transfer to fresh medium with bromodeoxyuridine, cells were gassed 3 times in 48 hours, until metaphase spreads could be examined for sister chromatid exchange (SCE). Exposure to MeBr vapor was associated with a significant (by linear regression analysis) dose-related increased rate of SCE in chinese hamster ovary cells. [R165] ?Methyl bromide (CAS # 74-83-9) was evaluated in 4 assays for mutagenicity in Saccharomyces cerevisiae D3 in modified protocol using methyl bromide in a gas-tight desiccator at concentrations ranging from 0.005 to 5.000%, 0.05 to 0.30%, 0.10 to 0.40%, and 0.075 to 0.40%. Toxicity in the first assay was associated with concentrations of 0.5% and above, but not with a 0.05% concentration. In the second assay, recombinations occurred at concentrations of 0.3%, the highest concentration, both in the presence and absence of metabolic activation (Aroclor 1254-induced mouse liver S-9 fraction). The third assay documented increased recombinations, both with and without metabolic activation, at concentrations of 0.2, 0.3, and 0.4%, but these were not clearly dose-related. In the final assay, a dose-related increase in mitotic recombinants was observed both with and without S-9 induction, and produced toxicity at the highest dose of 0.4%. The authors concluded that, MeBr induces mitotic recombination in Saccharomyces cerevisiae with and without metabolic activation in vitro. [R166] POPL: *... Individuals with psychiatric, neurologic disorders, and diseases of skin, lung, liver, and kidneys. [R71, 330] ADE: *Methyl bromide is absorbed readily through the lungs. There has been suggestions that it can be absorbed through the human skin, but experience so far has not shown absorption through the skin to be an important factor in methyl bromide intoxication. The major problem is inhalation. [R19, 4026] *... SERUM BROMIDE LEVELS ACHIEVED IN SERIOUS CASES OF METHYL BROMIDE POISONING ARE CONSIDERABLY LOWER THAN THOSE REQUIRED FOR POISONING BY INORGANIC BROMIDES. IT HAS BEEN SUGGESTED THAT THIS MAY BE DUE TO GREATER LIPID SOLUBILITY OF METHYL BROMIDE AND HENCE GREATER PENETRATION INTO THE BRAIN. [R167] *Upon absorption, blood levels of residual nonvolatile bromide increase, indicating rapid uptake of bromomethane or its metabolites. Bromomethane is rapidly distributed to various tissues and is broken down to inorganic bromide. Storage, only as bromides, occurs mainly in lipid-rich tissues. [R168] *Elimination of bromomethane is rapid initially, largely through the lung as bromomethane. The kidneys eliminate /most of the remaining bromomethane/ bromide in the urine. Final elimination may take longer, accounting in part for its prolonged toxicity. [R169] *The disposition of methyl bromide was studied following various routes of exposure. Recoveries of oral and ip doses indicated little radioactivity persisted in the body after 3 days with urine being the major route of excretion. No changes in respiratory pattern occurred. Pulmonary absorption after inhalation exposure was linear over a dose range from 50 to 10,400 nmoles (14)C methyl bromide/l of air for 6 hr, decreasing only at higher doses. Expired CO2 was the dominant excretory product. After 60 hours 25% of the dose remained in the body of rats. [R170] *In rats fed bromomethane fumigated diets with residual bromide levels, higher tissue bromide levels were /found/ in their eyes, lung, blood, spleen, and testes, while /the/ lowest tissue levels were in /the/ fat, skeletal muscle, bone, and liver. [R169] *Uptake of methyl bromide and pathways for excretion of (14)C were investigated in male Fischer 344 rats after nose only inhalation of 50, 300, 5700, or 10,400 nmoles (1.6 to 310 ppm) of (14)C methyl bromide/l of air for 6 hr. Fractional uptake of methyl bromide decreased at the highest concentrations, with 37 and 27% of the inhaled methyl bromide absorbed, compared to 48% at the lower levels. Total methyl bromide adsorbed was 9 or 40 umol/kg body wt after exposure to 50 or 300 nmol/l, respectively. Exhaled (14)CO2 was the dominant route of excretion, with from 1.2 to 110 umol (50% of amount absorbed) exhaled, and was described by a two component negative exponential function; 85% was exhaled with a half-life of 4 hr, and the remaining 15% was exhaled with a half-life of 17 hr. [R171] *Male Fischer 344 rats were exposed nose only to a vapor concentration of 337 nmol (14)C methyl bromide/l air (9.0 ppm, 25 degrees C, 620 torr) for 6 hr. Urine, feces expired air, and tissues were collected for up to 65 hr after exposure. Elimination of (14)C as (14)CO2 was the major route of excretion with about 47% (3900 nmol/rat) of the total (14)C methyl bromide absorbed excreted by this route. Radioactivity was widely distributed in tissues immediately following exposure /with highest (14)C concentrations (in nmol equivalent/g) of: lung (250), adrenal (240), kidney (180), liver (130), and nasal turbinates (110)/. [R172] *Absorption of methyl bromide by the lung was rapid and exhibited first order kinetics without a saturable component following exposure of rats to 100-3000 ppm (390-11640 mg/cu m). [R109] *After oral admin of 100 mg/kg body wt methyl bromide to rats, approx 45% was exhaled within 4 hr. Following ip admin to 120-180 mg/kg body wt in hourly divided doses, a total of 24-45% was exhaled. [R109] *Following either oral or intraperitoneal admin of 250 umole/kg body wt (24 mg/kg body wt) (14)C methyl bromide to rats, 14-17% of the radioactivity remained in the body after 72 hr. Expiration of (14)C carbon dioxide amounted to 32% and 45%, respectively, and the respective urinary excretion of (14)C radioactivity was 43% and 16%. Less than 3% of the radioactivity was excreted in feces. In animals with bile duct cannulations, 46% of the radioactivity of the oral dose appeared in the bile over a 24 hr period. [R109] *Male Fischer 344 rats were given 250 umol/kg of (14)C labeled methyl bromide by either oral or ip administration. Urine, feces, and expired air were collected and at the end of 72 hr the rats were sacrificed and tissues analyzed to determine (14)C excretion and tissue distribution. After ip administration of methyl bromide, the dominant route of excretion was exhalation of (14)CO2, with 46% of the dose exhaled as (14)CO2. In contrast, urinary excretion of (14)C was the major route of elimination (43% of the dose) when methyl bromide was given orally. Very little of the (14)C appeared in the feces (< 3% of the dose) regardless of route of administration. In rats with bile duct cannulations, 46% of an oral dose appeared in the bile over a 24 hr period. Collection of bile significantly decreased the exhaltion of (14)CO2 and (14)C excreted in urine compared to controls. At 72 hr after oral or ip administration, 14-17% of the (14)C remained in the rats, with liver and kidney being the major organs of retention. [R173] *The effects of exposure to the skin to high concentrations of methyl bromide were studied in 6 cases, who had been unintentionally exposed. Expsoure to high concentrations of methyl bromide (approximately 40 g/cu m) for 40 min can lead to redness and blistering of the skin. ... Plasma bromide levels were highest immediately following exposure (mean 9.0 + or - 1.4 mg/l) and fell in subsequent hours (mean 6.8 + or - 2.3 mg/l 12 hr after the exposure). [R100] *Methyl bromide is one of the most important pesticides for the control of insects, fungi and nematodes. Serum bromide has been proposed as a biomonitor for occupational exposure to methyl bromide. Therefore, a ... novel, sensitive photometric method was developed for the determination of serum bromide at concentrations relevant for such exposure. Further possible applications are monitoring of intoxication victims and halothane narcosis. ... We have established a mean serum bromide level of 4.13 + or - S.D. 1.05 mg/l (n/64) in a group of healthy female and male volunteers not knowingly exposed to bromide or bromine containing organics. Serum of a subject accidently exposed to methyl bromide revealed a bromide level of 11.5 mg/l serum, while two individuals exposed to methyl iodide had no elevated levels. A group of 30 agricultural workers showed a mean serum bromide level of 15.33 + or - S.D. 1.90 mg/l at the end of the methyl bromide application season. [R174] *INTRODUCTION: Methyl bromide has been responsible for deaths that usually occur from its accidental inhalation during fumigation. ... /This study reports on/ ... an accidental fatality that occurred after methyl bromide seeped through underground conduits from a fumigated building to an adjacent guest house on the same property. The patient developed refractory seizures, intermittent fever, and multiorgan system failure before dying 19 days after exposure. The initial serum bromide was 27 mg/dl. Postmortem analysis detected methyl bromide concentrations of 2.9 mg/dl in the blood, 1.7 mg/dl in the bile, 24 micrograms/g in the liver, and 28 micrograms/g in the adipose tissue. [R175] METB: *... EXCRETION IS ... BY LUNGS AS UNCHANGED METHYL BROMIDE. A SIGNIFICANT AMT OF METHYL BROMIDE, HOWEVER, IS METABOLIZED IN THE BODY AND APPEARS AS INORGANIC BROMIDE, WHICH IS EXCRETED IN URINE. [R108] *Although the exact mechanism has not been well studied, part of the absorbed methyl bromide is ... metabolized to 5-methylcysteine, which is excreted in the urine. [R95] *The fat-soluble methyl bromide, methyl chloride, and methyl iodide enter cells, where hydrolysis to methanol and halogen ion occurs. [R62, 150] *In human erythrocytes in vitro, methyl bromide is consumed, probably with formation of a glutathione conjugate. The reaction involves a glutathione S-transferase enzyme that metabolized methyl halides. This enzyme has not been found in erythrocytes of mouse, rat, cattle, sheep, pig or rhesus monkey. The enzyme is present only in part of the human population: among 45 people investigated, only 27 conjugated glutathione with methyl bromide. The enzyme is erythrocytes of conjugators is different from other glutathione S-transferases with respect to substrate specificity, affinity chromatography, and inhibition characteristics; it has been designated as glutathione S-transferase 0. [R176] BHL: *Uptake of methyl bromide and pathways for excretion of (14)C were investigated in male Fischer 344 rats after nose only inhalation of 50, 300, 5700, or 10,400 nmol (1.6 to 310 ppm) of (14)C methyl bromide/l of air for 6 hr. ... 85% was exhaled with a half-life of 4 hr, and the remaining 15% was exhaled with a half-life of 17 hr. [R171] ACTN: *METHYL BROMIDE METHYLATES SH GROUPS OF CYSTEINE, GLUTATHIONE, AND SEVERAL SH-CONTAINING ENZYMES. [R167] *Methyl bromide is a delayed pulmonary irritant which, on hydrolysis, produces methanol and hydrobromic acid. Metabolism to methanol may contribute to neurologic and visual changes, although methylation of sulfhydryl groups in vital enzymes currently is the favored mechanism of action. [R95] *RATS WERE EXPOSED TO METHYL BROMIDE FOR 24 HR OR 3 WEEKS CONTINUOUSLY. NOREPINEPHRINE (NE), DOPAMINE (DA), SEROTONIN, ACETYLCHOLINE (ACH), CYCLIC AMP AND CYCLIC GMP CONTENTS IN DISSECTED BRAIN REGIONS WERE MEASURED AFTER EXPOSURE. IT PRODUCED REMARKABLE REDUCTION IN NE CONTENTS OF HYPOTHALAMUS AND CORTEX + HIPPOCAMPUS @ 100 PPM OR HIGHER CONCN AFTER 24 HR EXPOSURE AND AT 10 PPM AFTER 3 WK EXPOSURE. METHYL BROMIDE MIGHT ENHANCE STIMULATION OF DOPAMINE RECEPTORS AND WEAKEN THE STIMULATION OF ACETYLCHOLINE RECEPTORS IN THE BRAIN. [R177] *The toxicity of bromomethane is mediated by the bromomethane molecule itself and its reaction with tissues (methylation of sulfhydryl groups in critical cellular proteins and enzymes), rather than by the bromide ion residue resulting from breakdown of the parent compound. Bromomethane readily penetrates cell membranes while the bromide ion does not. Intracellular bromomethane reactions and decomposition result in inactivation of intracellular metabolic processes, disturbed function, and irritative, irreversible, or paralytic consequences. [R169] *The present study reports a procedure developed for the identification and quantitative analysis of the adducts formed by interaction of methyl bromide with human hemoglobin, based on combined analysis by electrospray mass spectrometry and automated Edman degradation of either intact globin chains or tryptic peptides of globin chains. The procedure has allowed identification of the reactive sites in human hemoglobin. ... The results obtained represent the basis for the complete structural characterization of the modified hemoglobin and demonstrate the usefulness of the proposed analytical approach for the evaluation of the degree of alkylation and the identification of modified amino acids in proteins. [R178] INTC: *After exposure to 63, 125, 188, or 250 ppm methyl bromide for eight hours in rats, concentrations as low as 63 ppm enhanced the sleep-inducing potency of thiopental, but methyl bromide exerted no effect on thiopental metabolism. The body temperature and body weight gain were decreased at exposure to concentrations of 125 ppm or higher, and locomotor activity was reduced at 188 ppm or higher. These effects were reversible; 24 hr after the exposure, locomotor activity and body temperature were almost the same as in control rats. [R179] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl bromide's production and use as a soil and space fumigant and in disinfestation of crops results in its direct release to the environment. Methyl bromide's production and use in organic synthesis and as an extraction solvent for vegetable oils may result in its release to the environment through various waste streams. Because of the environmental problems associated with methyl bromide, a number of countries including the United States, have banned or will ban its production and use. The bulk of the methyl bromide detected in the environment is believed to be released from oceans; the gross flux of methyl bromide to the atmosphere from the oceans is 39X10+9 g/yr. If released to air, a vapor pressure of 1,620 mm Hg at 25 deg C indicates methyl bromide will exist in the gas phase. Gas-phase methyl bromide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is about one year. Methyl bromide is not expected to undergo direct photolysis due to the lack of absorption in the environmental UV spectrum (> 290 nm). If released to soil, methyl bromide is expected to have very high mobility based upon Koc values ranging from 9 to 22. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 7.34X10-3 atm-cu m/mole. Methyl bromide volatilizes from dry soil surfaces based upon its vapor pressure. Chemical reactions, likely nucleophilic substitutions on soil organic matter, are the predominant pathway through which methyl bromide degrades in soil. If released into water, methyl bromide is not expected to adsorb to suspended solids and sediment based upon its range of Koc values. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.0 hrs and 3.9 days, respectively. An estimated BCF of 2 suggests the potential for bioconcentration in aquatic organisms is low. Chemical hydrolysis is the primary degradation mechanism for methyl bromide in water; its chemical hydrolysis rate constant at 25 deg C and pH 7 is 4.1X10-7 1/sec which translates into a half-life of 20 days. Occupational exposure to methyl bromide may occur through inhalation and dermal contact with this compound at workplaces where methyl bromide is produced or used. Farm workers may be exposed to methyl bromide during its use as a soil disinfectant. Monitoring data indicate that the general population may be exposed to methyl bromide via inhalation of ambient air containing methyl bromide. (SRC) NATS: *The bulk of the methyl bromide detected in the environment is believed to be released from oceans(1,2). Mean aquatic production of methyl bromide was estimated at 15X10+10 g/yr(3). Of the methyl bromide produced in the ocean, 60-75% of it is destroyed in situ, with the remainder being emitted to the atmosphere(3). The gross flux of methyl bromide to the atmosphere from the oceans is 39X10+9 g/yr(3). Global biomass burning could contribute an avg of 30X10+9 g (range, 10X10+9-50X10+9 g) of methyl bromide annually to the atmosphere(3). [R180] ARTS: *Methyl bromide's production and use as a soil and space fumigant(1); and in the disinfestation of crops(1) is expected to result in its direct release to the environment(SRC). Methyl bromide's production and use in organic synthesis and as an extraction solvent for vegetable oils(1) may result in its release to the environment through various waste streams(SRC). In 1992, emissions of industrially produced methyl bromide from soil fumigation, durable disinfestation, perishable disinfestation, and structural disinfestation ranged from 16.7-47.3 Gg (where Gg = 10+9 g), 4.8-8.4 Gg, 5.4-6.0 Gg, and 2.0-2.1 Gg, respectively(2). Methyl bromide may be released in auto exhaust when ethylene dibromide is used in leaded gasoline by catalytic decomposition of ethylene dibromide(3). Methyl bromide may also be released in exhaust fumes from turbines(4). [R181] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values ranging from 9 to 22(2) indicate that methyl bromide is expected to have very high mobility in soil(SRC). Volatilization of methyl bromide from moist soil surfaces is an important fate process(SRC) given a Henry's Law constant of 7.34X10-3 atm-cu m/mole(3). The volatilization of methyl bromide from dry soil surfaces is an important removal mechanism from soil(SRC) based upon a vapor pressure of 1,620 mm Hg at 25 deg C(4). In soil, chemical reactions, likely nucleophilic substitutions on soil organic matter, were identified as the predominate pathway through which methyl bromide was degraded(5). For example, methyl bromide reacts rapidly with aniline (a model used to simulate reactions with organic matter in soil) compared to direct hydrolysis with water(5); the degradation half-lives of methyl bromide with water and aniline are 20 days and 2.9 days at 24 deg C, respectively(5). The oxidation of 14C-methyl bromide to 14CO2 was measured in field experiments with soils collected from two strawberry plots fumigated with mixtures of methyl bromide and chloropicrin(6). Degradation of methyl bromide by chemical and/or biological processes accounted for 20 to 50% of the loss of methyl bromide during fumigation(6) with the remainder of methyl bromide loss due to volatilization(SRC). [R182] *AQUATIC FATE: Based on a classification scheme(1), Koc values ranging from 9 to 22(2), indicate that methyl bromide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected based upon a Henry's Law constant of 7.34X10-3 atm-cu m/mole(3). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are 1.0 hrs and 3.9 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 2(SRC), from its log Kow(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Chemical hydrolysis is the primary degradation mechanism for methyl bromide in water(SRC). The hydrolysis rate constant of methyl bromide at 25 deg C and pH 7 is 4.1X10-7 1/sec which translates into a half-life of 20 days(8). Another hydrolysis rate constant for methyl bromide is 3X10-7 1/sec at 25 deg C(9), which translates into a half-life of 26.7 days(SRC). The products of methyl bromide hydrolysis are methanol and bromide ion(9). [R183] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methyl bromide, which has a vapor pressure of 1,620 mm Hg at 25 deg C(2), will exist in the gas phase(SRC). Gas-phase methyl bromide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is about one year (SRC), calculated from its rate constant of 4.0X10-14 cu cm/molecule-sec at 25 deg C(3). Methyl bromide is not expected to undergo direct photolysis due to the lack of absorption in the environmental UV spectrum (> 290 nm)(4). Upward diffusion of methyl bromide to the stratosphere is believed to be the dominant loss mechanism of this compound from the troposphere(4). In the stratosphere, into which lower wavelength light can penetrate, photolysis is expected to be the predominant removal mechanism of methyl bromide(4). [R184] BIOD: *ANAEROBIC: Methyl bromide was anaerobically degraded in salt marsh sediments after chemical reaction with abundant free sulfide(1). The product of this nucleophilic substitution reaction was methanethiol, which underwent further chemical and bacterial reactions to form dimethyl sulfide(1). [R185] *The oxidation of 14C-methyl bromide to 14CO2 was measured in field experiments with soils collected from two strawberry plots fumigated with mixtures of methyl bromide and chloropicrin(1). Degradation of methyl bromide by chemical and/or biological processes accounted for 20 to 50% of the loss of methyl bromide during fumigation(1). Oxidation was by direct bacterial attack of methyl bromide and not of methanol (a product of chemical hydrolysis)(1). Repeated addition of methyl bromide to live soils resulted in higher rates of removal, suggesting that soil bacteria used methyl bromide as an electron donor for growth(1). Methylotrophic bacteria are capable of oxidizing methyl bromide(2,3). Methyl bromide was oxidized to formaldehyde by a soluble methane monooxygenase isolated from Methylbacterium SP. CRL-26(4). Cell-free extracts and whole cell suspensions of Methylococcus capsulatus oxidized methyl bromide to formaldehyde(3,5), but Methylococcus capsulatus was unable to grow on methyl bromide(3). [R186] ABIO: *The rate constant for the vapor-phase reaction of methyl bromide with photochemically-produced hydroxyl radicals is 4.0X10-14 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about one year at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). The rates of removal of methyl bromide from the atmosphere by Cl and NO3 radicals, and by cloud and rain water are negligible(2). The hydrolysis rate constant of methyl bromide at 25 deg C and pH 7 ranges from 3X10-7 to 4.1X10-7 1/sec(3,4) which translates into half-lives of about 20 to 26.7 days(SRC). The products of methyl bromide hydrolysis are methanol and bromide ion(5). The total degradation rate for methyl bromide in seawater ranges from 8-42% day-1 for a temperature range of 20 to 30 deg C; the reaction with Cl-ions is around 6.5 times that of the reaction with water(2). For example, at a sea water surface temperature of 21.9 deg C and a chloride concn of 0.56 mol/l, the calculated degradation half-life of methyl bromide in sea water is 4 days; at 35 deg C, the half-life is 22 hrs(6). Methyl bromide is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm)(5). The half-live for direct photolysis of methyl bromide is 150,000 days(7). However, with the upward diffusion of methyl bromide from the troposphere to stratosphere into which lower wavelength light can penetrate, photolysis is expected to be the primary removal mechanism(5). In soil, chemical reactions, likely nucleophilic substitutions on soil organic matter, were identified as the primary pathway through which methyl bromide was degraded(8). For example, methyl bromide reacts rapidly with aniline (a model used to simulate reactions with organic matter in soil) compared to direct hydrolysis with water(8); the degradation half-life of methyl bromide with aniline is 2.9 days at 24 deg C(8). [R187] BIOC: *An estimated BCF of 2 was calculated for methyl bromide(SRC), using a log Kow of 1.19(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R188] KOC: *The Koc of methyl bromide ranges from 9 to 22(1). According to a classification scheme(2), these Koc values suggest that methyl bromide is expected to have very high mobility in soil(SRC). The adsorption coefficient, Kd, for methyl bromide was below measurable for Greenfield sandy loam, Linne clay loam, and Carsetas loamy sand soils; Kd was equal to 0.2 for potting mix soil(3). [R189] VWS: *The Henry's Law constant for methyl bromide is 7.34X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that methyl bromide is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.0 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 3.9 days(SRC). A volatilization half-life of 72 min for methyl bromide was obtained by an experiment in which 100 ppm of methyl bromide was placed in a 39.4 cm aeration cylinder and air bubbled through for 4 hr(3). The mass transfer coefficient of methyl bromide is 22.56 cm/hour at 25 deg C(3), and this value was used to calculate a volatilization half-life of 3.1 hr for methyl bromide from 1 m of water(2). Methyl bromide's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The volatility of methyl bromide from treated soils (initial concn 2,733 ug/g soil; soil moisture = -33 kPa) incubated at 15 deg C, 25 deg C, and 35 deg C were 32%, 35%, and 54%, respectively(4); more than 86% of the total methyl bromide flux occurred within 3 hrs at all three temperatures(4). The volatility increased significantly with increasing soil moisture(4). A measured 4%, 35%, and 65% of the applied methyl bromide volatilized from soil samples with -300 kPa, -33 kPa, and -3 kPa soil moisture content, respectively(4). Volatilization of methyl bromide from dry soil surfaces occurs(SRC) based upon a vapor pressure of 1,620 mm Hg(5). Using a soil screening model, the half-lives for the volatilization of methyl bromide from 1 and 10 cm were estimated to be 0.2 and 0.5 days, respectively(6). [R190] WATC: *SEAWATER: Concentrations of methyl bromide in seawater collected off Dorset, UK, in 1975 ranged from 1.5 to 3.9 ug/l(1). Mean concn in surface seawater in the eastern Pacific at 40 deg N to 32 deg S latitude was approx 1.2 ng/l(1). [R191] *SURFACE WATER: The near shore water concn at Point Reyes, CA, USA, was 0.14 ug/l(1). Surface water in a greenhouse crop growing region of Malines-Antwerp, Belgium, was sampled for levels of bromide ion before, during and after soil treatment with methyl bromide(1). Accumulation of bromide ion was noted downstream of some brooks; however, the max concn was 9.6 mg/l(1). In rivers, only a very slight increase of bromide ion was noted during periods of intensive leaching, and the concn did not exceed 1 mg/l except at one site where levels ranging from 1.1 to 4.4 mg/l were thought to be due to the presence of seawater(1). Methyl bromide was detected in 1.4% of 941 water samples and the median methyl bromide concentration was < 10.0 ug/l(1). [R192] *DRINKING WATER: Methyl bromide has been detected but not quantified in drinking water from Miami, FL(1), and three unidentified U.S. drinking waters(2). [R193] *GROUNDWATER: Methyl bromide was detected but not quantified in New Jersey groundwater(1). [R194] EFFL: *Methyl bromide was detected in 1.4% of 1,317 samples and the median methyl bromide concentration was < 10.0 ug/L(1). [R195] SEDS: *The annual global soil uptake estimate for methyl bromide is 6.5X10+9 g/yr, 21.7X10+9 g/yr, 9.7X10+9 g/yr, 1.7X10+9 g/yr, 2.7X10+9 g/yr, and 42X10+9 g/yr for tropical forest and savanna soils, temperate forest and woodland shrubland soils, temperate grassland soils, boreal forest soils, and cultivated land, respectively(1). The annual total global soil sink for methyl bromide is 42X10+9 g/yr(1). [R196] ATMC: *Average levels in air at ten urban sites in the USA ranged from 41 to 259 part per trillion (159-1005 ng/cu m). ... The background concn from natural sources at surface level at 40 deg N latitude is estimated to be 78 ng/cu m (20 part per trillion). ... Measurements over the eastern Pacific (40 deg N AND 32 deg S latitude) showed mean air concentrations of 23 part per trillion (89 ng/cu m). Measurements of 5 bromine-containing trace gases in Point Barrow, AK, showed that the monthly avg concn of methyl bromide was higher in the summer (15 parts per trillion; 58.2 ng/cu m) than in the winter (9 parts per trillion; 35 ng/cu m). [R197] *URBAN/SUBURBAN: The avg concn of methyl bromide in Northern California in 1975 ranged from 116-205 ng/cu m near the shore; in Standford Hills, CA, the avg concn was 60 ng/cu (sampling date, 11/75); in Point Reyes, CA, the avg concn was 360 ng/cu m (sampling date, 12/75)(1). The avg concn of methyl bromide in Houston, TX was 388 ng/cu m (sampling date, 5/80); in St. Louis, MO, the avg concn was 314 ng/cu m (sampling dates, 1-7/80); in Staten Island, NY, the avg concn was 326 ng/cu m (sampling dates, 3-4/81); in Pittsburgh, PA, the avg concn was 159 ng/cu m, (sampling date, 4/81); in Chicago, IL, the avg concn was 182 ng/cu m, (sampling date, 4/81)(2). The avg concn of methyl bromide in Los Angeles, CA was 419 ng/cu m (sampling date, 5/76); in Palm Springs, CA, the avg concn was 93.1 ng/cu m (sampling data, 5/76); in Yosemite, CA, the avg concn was 19.4 ng/cu m (sampling date, 5/76)(3). The mean concn of methyl bromide in Los Angeles, CA was 947 ng/cu m (sampling date, 4/79); in Phoenix, AZ, the mean concn was 260 ng/cu m (sampling dates, 4-5/79); in Oakland, CA, the mean concn was 210 ng/cu m (sampling dates, 6-7/79)(4). Along the Southern California coast, the monthly mean concn of methyl bromide ranged from not detected to 2170 ng/cu m (sampling dates, 11/82-12/83)(5). [R198] *RURAL/REMOTE: In 1990, the estimated background concentration of methyl bromide was 0.039 ug/cu-m(1). In the Northwest USA, the concn of methyl bromide was 19 ng/cu m (sampling dates, 12/74-2/75)(2). In Washington State, the concn of methyl bromide ranged from 1.9 to 3.5 ng/cu m (sampling date, 1976)(3); in Barrow, AK, the monthly avg concn ranged from 35 to 57 ng/cu m(4). In Norway, the concn of methyl bromide was 56 ng/cu m in the Spring 1983(5). The concn of methyl bromide in the stratosphere (44 deg N) ranged from 0.388 to 3.88 ng/cu m (sampling date, 9/80)(6). In the Arctic, the concn of methyl bromide was 42.7 ng/cu m in March-April 1983(7). [R199] *SOURCE DOMINATED: The California Air Resources Board conducted ambient air monitoring of pesticides(1); monitoring was done in several communities in a county of high use during the month of expected peak pesticide use in order to assess general population exposure(1). In July 1995, the mean concn of methyl bromide was 4.1 ug/cu m (number of sites, 3; max concn, 4.4 ug/cu m) in communities near application sites(1); the max concn of methyl bromide at application-sites was 3,500 ug/cu m(1). [R200] FOOD: *Methyl bromide was found infrequently in leaf and stem vegetables(1). Reported methyl bromide residues in fumigated wheat, flour, raisins, corn, sorghum, cottonseed meal, rice, and peanut meal were reduced to less than 1 mg/kg within a few days(2). No residual methyl bromide was found in asparagus, avocados, peppers, or tomatoes after two-hour fumigation at 320 mg methyl bromide/cu m air(2). Only trace amounts were present in wheat flour and other products fumigated at 370 mg/cu m methyl bromide after nine days of aeration(2). Methyl bromide residues in longhorn cheese (outer 1/4 inch) were between 62 and 78 mg/kg after 0.5 hr of ventilation; between 40 and 54 mg/kg after 4 hr of ventilation; and between 20 and 9 mg/kg after 24 hr of ventilation(3). [R201] RTEX: */INVESTIGATORS/ ... REPORTED THAT TESTS IN DATE PROCESSING AND PACKING HOUSES, WHERE NUMBER OF EMPLOYEES HAD BEEN STRICKEN, SHOWED VALUES RANGING UP TO 100 PPM IN GENERAL WORKROOM AIR, UP TO 500 PPM NEAR WALLS OF INEFFECTIVELY SEALED CHAMBERS, AND OVER 1000 PPM @ BREATHING ZONE OF WORKERS ENTERING CHAMBER TO REMOVE FUMIGATED FRUIT. [R20, 1991.948] *... Some common operations in which exposure to methyl bromide may occur ... are: use in food sterilization for pest control ... in organic synthesis as methylating agent ... as selective solvent in aniline dyes and in laboratory procedures. [R22, 1981.3] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 5,603 workers (975 of these are female) are potentially exposed to methyl bromide in the US(1). The NOES Survey does not include farm workers(SRC). Occupational exposure to methyl bromide may occur through inhalation and dermal contact with this compound at workplaces where methyl bromide is produced or used(SRC). Farm workers may be exposed to methyl bromide during its use as a soil disinfectant(SRC). During soil disinfection in greenhouses, methyl bromide concn varied between 30 and 3,000 ppm(2). Exposure levels of applicators were greatly dependant on the fumigation techniques(2). Monitoring data indicate that the general population may be exposed to methyl bromide via inhalation of ambient air containing methyl bromide(SRC). Higher exposure may occur near agricultural areas where it is used as a soil fumigant(SRC). For example, in July 1995, the mean concn of methyl bromide was 4.1 ug/cu m (number of sites, 3; max concn 4.4 ug/cu m) in communities near application sites(3). [R202] AVDI: *AIR INTAKE: Assume 0 to 0.04 ug/cu m(1), 0 to 0.8 ug(SRC). [R203] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers methyl bromide to be a potential occupational carcinogen. [R31, 200] ATOL: *Tolerances are established for residues of inorganic bromides (calculated as Br) in or on the following food commodities which have been fumigated with the antimicrobial agent and insecticide methyl bromide after harvest (with the exception of strawberries): alfalfa, hay (post-H), 50.0 ppm; almonds (post-H), 200.0 ppm; apples (post-H), 5.0 pp; apricots (post-H), 20.0 ppm; artichokes, Jerusalem (post-H), 30.0 ppm; asparagus (post-H), 100.0 ppm; avocados (post-H), 75.0 ppm; barley (post-H), 50.0 ppm; beans (post-H), 50.0 ppm; beans, green (post-H), 50.0 ppm; beans, lima (post-H), 50.0 ppm; beans, snap (post-H), 50.0 ppm; beets, garden, root (post-H), 30.0 ppm; beets, sugar, roots (post-H), 30.0 ppm; blueberries (post-H), 20.0 ppm; Brazil nuts (post-H), 200.0 ppm; bush nuts (post-H), 200.0 ppm; butternuts (post-H), 200.0 ppm; cabbage (post-H), 50.0 ppm; cantaloupes (post-H), 20.0 ppm; carrots (post-H), 30.0 ppm; cashews (post-H), 200.0 ppm; cherries (post-H), 20.0 ppm; chestnuts (post-H), 200.0 ppm; cippolini, bulbs (post-H), 50.0 ppm; citrus citron (post-H), 30.0 ppm; cocoa beans (post-H), 50.0 ppm; coffee beans (post-H), 75.0 ppm; copra (post-H), 100.0 ppm; corn (post-H), 50.0 ppm; corn (pop) (post-H), 240.0 ppm; corn, sweet (K+CWHR) (post-H), 50.0 ppm; cottonseed (post-H), 200.0 ppm; cucumbers (post-H), 30.0 ppm; cumin, seed (post-H), 100.0 ppm; eggplants (post-H), 20.0 ppm; filberts (hazelnuts) (post-H), 200.0 ppm; garlic (post-H), 50.0 ppm; ginger, roots (post-H), 100.0 ppm; grapefruit (post-H), 30.0 ppm; grapes (post-H), 20.0 ppm; hickory nuts (post-H), 200.0 ppm; honeydew melons (post-H), 20.0 ppm; horseradish (post-H), 30.0 ppm; kumquats (post-H), 30.0 ppm; lemons (post-H), 30.0 ppm; limes (post-H), 30.0 ppm; mangoes (post-H), 20.0 ppm; muskmelons (post-H), 20.0 ppm; nectarines (post-H), 20.0 ppm; oats (post-H), 50.0 ppm; okra (post-H), 30.0 ppm; onions (post-H), 20.0 ppm; oranges (post-H), 30.0 ppm; papayas (post-H), 20.0 ppm; parsnips, roots (post-H), 30.0 ppm; peaches (post-H), 20.0 ppm; peanuts (post-H), 200.0 ppm; pears (post-H), 5.0 ppm; peas (post-H), 50.0 ppm; peas, blackeyed (post-H), 50.0 ppm; pecans (post-H), 200.0 ppm; peppers (post-H), 30.0 ppm; pimentos (post-H), 30.0 ppm; pineapples (post-H), 20.0 ppm; pistachio nuts (post-H), 200.0 ppm; plums (post-H), 20.0 ppm; pomegranates (post-H), 100.0 ppm; potatoes (post-H), 75.0 ppm; pumpkins (post-H), 20.0 ppm; quinces (post-H), 5.0 ppm; radishes (post-H), 30.0 ppm; rice (post-H), 50.0 ppm; rutabagas (post-H), 30.0 ppm; rye (post-H), 50.0 ppm; salsify, roots (post-H), 30.0 ppm; sorghum, grain (post-H), 50.0 ppm; soybeans (post-H), 200.0 ppm; squash, summer (post-H), 30.0 ppm; squash, winter (post-H), 20.0 ppm; squash, zucchini (post-H), 20.0 ppm; strawberries (pre- and post-H), 60.0 ppm; sweet potatoes (post-H), 75.0 ppm; tangerines (post-H), 30.0 ppm; timothy, hay (post-H), 50.0 ppm; tomatoes (post-H), 20.0 ppm; turnips, roots (post-H), 30.0 ppm; walnuts (post-H), 200.0 ppm; watermelons (post-H), 20.0 ppm; wheat (post-H), 50.0 ppm. [R204] *Inorganic bromide may be present as a residue in certain processed foods in accordance with the following conditions: (i) When inorganic bromide residues are present as a result of fumigation of the processed food with methyl bromide or from such fumigation in addition to the authorized use of methyl bromide on the source raw agricultural commodity, as provided for in this part, the total residues of inorganic bromides (calculated as Br) shall not exceed the following levels: (A) 400 ppm in or on dried eggs and processed herbs and spices. (B) 325 ppm in or on parmesan cheese and roquefort cheese. (C) 250 ppm in or on concentrated tomato products and dried figs. (D) 125 ppm in or on processed foods other than those listed above. (ii) When inorganic bromide residues are present in fermented malt beverages in accordance with 21 CFR 172.730(a)(2), the amount shall not exceed 25 ppm (calculated as Br). (iii) Where tolerances are established on both the raw agricultural commodities and processed foods made therefrom, the total residues of inorganic bromides in or on the processed food shall not be greater than those designated in paragraph (a)(2) of this section, unless a higher level is established elsewhere in this part. [R205] *Tolerances are established for residues of inorganic bromides (calculated as Br) as follows: (i) 400 ppm for residues in or on milled fractions for animal feed from barley, corn, grain sorghum (milo), oats, rice, rye, and wheat, resulting directly from fumigation with methyl bromide or from carryover and concentration of residues of inorganic bromides fro fumigation of the grains with methyl bromide. [R206] *A tolerance with regional registration, as defined in section 180.1(n), is established for residues of inorganic bromides (calculated as Br) in or on the following food commodity grown in soil fumigated with methyl bromide. Ginger, roots (pre- and post-H), 100 ppm. [R207] *Tolerances are established for residues of inorganic bromides (calculated as Br) in or on the following raw agricultural commodities grown in soil fumigated with combinations of chloropicrin, methyl bromide, and propargyl bromide. No tolerances are established for chloropicrin since it has been established that no residue of this substance remains in the raw agricultural commodity: broccoli, 25 ppm; cauliflower, 25 ppm; eggplants, 60 ppm; muskmelons, 40 ppm; peppers, 25 ppm; pineapples, 25 ppm; strawberries, 25 ppm; and tomatoes, 40 ppm. [R208] *Tolerances with regional registration, as defined in 180.1(n), are established for residues of inorganic bromides (calculated as Br) in or on the following agricultural commodities grown in soil fumigated with combinations of chloropicrin, methyl bromide, and propargyl bromide: asparugus, 300 ppm; lettuce, 300 ppm; and onions (dry bulb), 300 ppm. [R209] *A tolerance with regional registration, as defined in 180.1(n), is established for residues of inorganic bromides (calculated as Br) in or on the following raw agricultural commodity grown in soil fumigated with combinations of methyl bromide and chloropicrin. No tolerance is established for chloropicrin since it has been established that no residue of this substance remains in the raw agricultural commodity when formulations containing chloropicrin at 2 percent or less are used: ginger, roots (pre- and post-H), 100 ppm. [R210] OSHA: *Permissible Exposure Limit: Table Z-1 Ceiling value: 20 ppm (80 mg/cu m). Skin designation. [R211] *Vacated 1989 OSHA PEL TWA 5 ppm (20 mg/cu m), skin designation, is still enforced in some states. [R31, 367] NREC: *NIOSH considers methyl bromide to be a potential occupational carcinogen. [R31, 200] *NIOSH recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R31, 200] TLV: *8 hr Time Weighted Avg (TWA) 1 ppm, skin [R212, 2001.40] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R212, 2001.6] *A4. Not classifiable as a human carcinogen. [R212, 2001.40] OOPL: *Occupational level in West Germany= 20 ppm (mg/cu m) (1978); in Elkins= 10 ppm (mg/cu m) (1959) Occupational level in East Germany= 13 ppm (mg/cu m) (1973); in USSR= 0.25 ppm (mg/cu m) (1966) Occupational level in ANSI= 15 ppm (mg/cu m) (1970); in Sweden= 15 ppm (mg/cu m) (1978) [R213] *Australia: TWA 60 mg/cu m (1978); Belgium: TWA 60 mg/cu m (1978); Finland: TWA 60 mg/cu m, STEL 90 mg/cu m (1981); France: TWA 20 mg/cu m (1985); Germany, Federal Republic: TWA 20 mg/cu m (1985); Hungary: TWA 10 mg/cu m (1974); Italy: TWA 60 mg/cu m (1978); The Netherlands: TWA 60 mg/cu m; Ceiling limit: Poland 5 mg/cu m (1976); Romania 80 mg/cu m; Yugoslavia 80 mg/cu m (1971). /From table/ [R214] *Emergency Response Planning Guidelines (ERPG): ERPG(1) Not appropriate; ERPG(2) 50 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 200 ppm (not life threatening) up to 1 hr exposure. [R215] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Methyl bromide is produced, as an intermediate or final product, by process units covered under this subpart. [R216] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Methyl bromide is included on this list. [R217] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 10 ug/l [R218] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.19 ug/l [R218] +(MA) MASSACHUSETTS 10 ug/l [R218] +(ME) MAINE 10 ug/l [R218] +(MN) MINNESOTA 10 ug/l [R218] +(WI) WISCONSIN 10 ug/l [R218] CWA: +For the maximum protection of human health from the potential carcinogenic effects due to exposure to bromomethane, the ambient water concentration should be zero based on the non-threshold assumption for this chemical. However, zero level may not be attainable at the present time. Therefore, the levels which may result in incremental increase of cancer risk over the lifetime are estimated at 1X10-5, 1X10-6 and 1X10-7. The corresponding recommended criteria are 1.9 ug/l, 0.19 ug/l, and 0.019 ug/l, respectively. If the above estimates are made for consumption of aquatic organisms only, excluding consumption of water, the levels are 157 ug/l, 15.7 ug/l, and 1.57 ug/l, respectively. [R219] +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Halomethanes (including methyl bromide)/ [R220] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R221] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Methyl bromide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R222] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Bromomethane is included on this list. [R223] RCRA: *U029; As stipulated in 40 CFR 261.33, when methyl bromide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R224] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Methyl bromide is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0335; Pesticide type: insecticide, antimicrobial; Registration Standard Date: 08/01/86; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): methyl bromide; Data Call-in (DCI) Date(s): 09/20/91, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R225] *... Pesticide products containing the active ingredients specified below have been classified for restricted use and are limited to use by or under the direct supervision of a certified applicator. Active ingredient: methyl bromide; Formulation: All formulations in containers greater than 1.5 lb; Use pattern: All uses; Classification: Restricted; Criteria influencing restriction: Other hazards, accident history. [R226] *... Pesticide products containing the active ingredients specified below have been classified for restricted use and are limited to use by or under the direct supervision of a certified applicator. Active ingredient: methyl bromide; Formulation: Containers with not more than 1.5 lb of methyl bromide with 0.25% to 2.0% chloropicrin as an indicator. Use pattern: Single applications (nondomestic use) for soil treatment in closed system. Classification: Unclassified. [R226] *... Pesticide products containing the active ingredients specified below have been classified for restricted use and are limited to use by or under the direct supervision of a certified applicator. Active ingredient: methyl bromide; Formulation: Container with not more than 1.5 lb having no indicator. Use pattern: All uses. Classification: Restricted. Criteria influencing restrictions: Other hazards, accident history. [R226] *Tolerances are established for residues of inorganic bromides (calculated as Br) in or on the following food commodities which have been fumigated with the antimicrobial agent and insecticide methyl bromide after harvest (with the exception of strawberries): alfalfa, hay (post-H); almonds (post-H); apples (post-H), 5.0 pp; apricots (post-H); artichokes, Jerusalem (post-H); asparagus (post-H); avocados (post-H); barley (post-H); beans (post-H); beans, green (post-H); beans, lima (post-H); beans, snap (post-H); beets, garden, root (post-H); beets, sugar, roots (post-H); blueberries (post-H); Brazil nuts (post-H); bush nuts (post-H); butternuts (post-H); cabbage (post-H); cantaloupes (post-H); carrots (post-H); cashews (post-H); cherries (post-H); chestnuts (post-H); cippolini, bulbs (post-H); citrus citron (post-H); cocoa beans (post-H); coffee beans (post-H); copra (post-H); corn (post-H); corn (pop) (post-H); corn, sweet (K+CWHR) (post-H); cottonseed (post-H); cucumbers (post-H); cumin, seed (post-H); eggplants (post-H); filberts (hazelnuts) (post-H); garlic (post-H); ginger, roots (post-H); grapefruit (post-H); grapes (post-H); hickory nuts (post-H); honeydew melons (post-H); horseradish (post-H); kumquats (post-H); lemons (post-H); limes (post-H); mangoes (post-H); muskmelons (post-H); nectarines (post-H); oats (post-H); okra (post-H); onions (post-H); oranges (post-H); papayas (post-H); parsnips, roots (post-H); peaches (post-H); peanuts (post-H); pears (post-H); peas (post-H); peas, blackeyed (post-H); pecans (post-H); peppers (post-H); pimentos (post-H); pineapples (post-H); pistachio nuts (post-H); plums (post-H); pomegranates (post-H); potatoes (post-H); pumpkins (post-H); quinces (post-H); radishes (post-H); rice (post-H); rutabagas (post-H); rye (post-H); salsify, roots (post-H); sorghum, grain (post-H); soybeans (post-H); squash, summer (post-H); squash, winter (post-H); squash, zucchini (post-H); strawberries (pre- and post-H); sweet potatoes (post-H); tangerines (post-H); timothy, hay (post-H); tomatoes (post-H); turnips, roots (post-H); walnuts (post-H); watermelons (post-H); wheat (post-H). [R204] *Inorganic bromide may be present as a residue in certain processed foods in accordance with the following conditions: (i) When inorganic bromide residues are present as a result of fumigation of the processed food with methyl bromide or from such fumigation in addition to the authorized use of methyl bromide on the source raw agricultural commodity, as provided for in this part, the total residues of inorganic bromides (calculated as Br) shall not exceed the following levels: (A) in or on dried eggs and processed herbs and spices. (B) in or on parmesan cheese and roquefort cheese. (C) in or on concentrated tomato products and dried figs. (D) in or on processed foods other than those listed above. (ii) ... inorganic bromide residues are present in fermented malt beverages in accordance with 21 CFR 172.730(a)(2) ... (calculated as Br). (iii) Where tolerances are established on both the raw agricultural commodities and processed foods made therefrom, the total residues of inorganic bromides in or on the processed food shall not be greater than those designated in paragraph (a)(2) of this section, unless a higher level is established elsewhere in this part. [R205] *Tolerances are established for residues of inorganic bromides (calculated as Br) as follows: (i) residues in or on milled fractions for animal feed from barley, corn, grain sorghum (milo), oats, rice, rye, and wheat, resulting directly from fumigation with methyl bromide or from carryover and concentration of residues of inorganic bromides fro fumigation of the grains with methyl bromide. [R206] *A tolerance with regional registration, as defined in section 180.1(n), is established for residues of inorganic bromides (calculated as Br) in or on the following food commodity grown in soil fumigated with methyl bromide. Ginger, roots (pre- and post-H). [R207] *Tolerances are established for residues of inorganic bromides (calculated as Br) in or on the following raw agricultural commodities grown in soil fumigated with combinations of chloropicrin, methyl bromide, and propargyl bromide. No tolerances are established for chloropicrin since it has been established that no residue of this substance remains in the raw agricultural commodity: broccoli; cauliflower; eggplants; muskmelons; peppers; pineapples; strawberries; and tomatoes. [R208] *Tolerances with regional registration, as defined in 180.1(n), are established for residues of inorganic bromides (calculated as Br) in or on the following agricultural commodities grown in soil fumigated with combinations of chloropicrin, methyl bromide, and propargyl bromide: asparugus; lettuce; and onions (dry bulb). [R209] *A tolerance with regional registration, as defined in 180.1(n), is established for residues of inorganic bromides (calculated as Br) in or on the following raw agricultural commodity grown in soil fumigated with combinations of methyl bromide and chloropicrin. No tolerance is established for chloropicrin since it has been established that no residue of this substance remains in the raw agricultural commodity when formulations containing chloropicrin at 2 percent or less are used: ginger, roots (pre- and post-H). [R210] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Measurements to determine employee ceiling exposure are best taken during periods of max expected airborne concn of methyl bromide. Each measurement should consist of a 15 min sample or series of consecutive samples totaling 15 min in the employee's breathing zone. Sampling may be performed by collection of vapors using an adsorption tube. [R22, 1981.2] *NIOSH Method 2520. Analyte: Methyl bromide. Matrix: Air. Sampler: Solid sorbent tubes (two petroleum charcoal tubes, 400 mg and 200 mg). Flow Rate: 0.01 to 1 l/min. Sample Size: 5 liters. Shipment: Routine. Sample Stability: Greater than 7 days at 90 deg C. [R227] *OSW Method 8010. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw cap VOA vial equipped with a Teflon faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R228] ALAB: *MIXTURES WITH CHLOROPICRIN ARE ANALYZED BY IR SPECTROSCOPY. [R38] *METHYL BROMIDE IN AIR WAS ANALYZED BY DIRECT INJECTION ONTO A TRAPPING TUBE FILLED WITH TENAX GAS CHROMATOGRAPHY AND OPERATED AT 25 OR 0 DEG C. AMOUNTS AS LOW AS 35 NG CAN BE DETERMINED. THIS GC METHOD CAN ALSO BE USED TO DETERMINE METHYL BROMIDE DESORPTION FROM FUMIGATED WHEAT; 0.3 PPB WAS DESORBED IN 24 HR FROM 1 G WHEAT AERATED FOR 30 DAYS. [R229] *A RAPID HEADSPACE ASSAY FOR METHYL BROMIDE IN GRAPEFRUIT WAS DEVELOPED USING GC/ECD. [R230] *A automated headspace GC method has been developed for determination of methyl bromide in wheat, flour, cocoa and peanuts. A sample of the headspace is withdrawn and analyzed on a GC equipped with an ECD. The detection limit of the method was 0.4 ppb. The coefficient of variation (CV) was 6.5% for wheat, 8.3% for flour, 3.3% for cocoa and 11.6% for peanuts. [R231] *Matrix: Cereal grains and other foods. Analyte: Methyl bromide. Assay procedure: GC/ECD. Limit of detection: 10 ug/kg. /From table/ [R232] *NIOSH Method 2520. Analyte: Methyl bromide. Matrix: Air. Procedure: GC, flame ionization detector. For methyl bromide this method has an estimated detection limit of 0.01 mg sample. The precision/RSD is 0.053 at 0.4 to 1.6 mg/sample. Applicability: The working range is 40 to 400 mg/cu m (10 to 100 ppm) for a 5 liter air sample. Interferences: None known. [R227] *EPA Method 1624. Isotope Dilution Purge and Trap Gas Chromatography/Mass Spectrometry. This method is applicable for the determination of volatile organic compounds in municipal and industrial discharges. By adding a known amount of an isotopically labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If isotopically labeled compounds are not available, an internal standard method is used. Under the prescribed conditions for both the isotopically labeled and unlabeled bromomethane the method has a minimum detection level of 50 and 50 ug/l with no interferences present. [R233] *OSW Method 8240. GC/MS for the determination of volatile organics. This method can be used to quantify most volatile organic compounds including bromomethane that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. The Practical Quantitation Limit for bromomethane is 10 ug/l in ground water and 10 ug/kg in low soil/sediment. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R228] *OSW Method 8260. GC/MS for the determination of volatile organic compounds. This method can be used to quantitate most volatile organic compounds including bromomethane that have boiling points below 200 deg C and are insoluble or slightly soluble in water. Under the prescribed conditions for bromomethane the method has a detection limit of 0.11 ug/l, a percent recovery of 95%, and a percent relative standard deviation of 8.2% using a wide bore capillary column; and a detection limit of 0.06 ug/l, a percent recovery of 99%, and a percent relative standard deviation of 7.2% using a narrow bore capillary column. [R228] *AREAL Method IP-1A. Determination of Volatile Organic Compounds (VOCs) in Indoor Air Using Stainless Steel Canisters. This method is applicable to specific VOCs in indoor air that have been tested and determined to be stable when stored in pressurized and subatmospheric pressure canisters. Detection limit unspecified. [R234] *AREAL Method TO-14. This method is applicable to specific VOCs that have been tested and determined to be stable when stored in pressurized and subatmospheric pressure canisters. Detection limit unspecified. [R234] *APHA Method 6200-B. Volatile Organics in Water by Purge and Trap Capillary-Column Gas Chromatographic/Mass Spectrometric Method. This method is useful for the determination of purgeable organics in industrial and municipal wastes. Detection limit unspecified. [R235, p. 6-21] *APHA Method 6200-C. Volatile Organics in Water by Purge and Trap Capillary- Column Gas Chromatographic Method. Detection limit = 0.103 ug/l (Electrolytic conductivity detector). [R235, p. 6-26] *CLP Method LC_VOA. Analysis of Water for Low Concentration Volatile Organic Compounds by Gas Chromatography/Mass Spectroscopy. This method is applicable to drinking water and well water, and ground water sources around Superfund sites. Detection limit = 1 ug/l. [R234] *CLP Method MC_VOA. Analysis of Volatile Organics in Multi-Concentration Water Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to water from hazardous waste sites. Detection limit = 10 ug/l. [R234] *EMSLC Method 502.1. Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. Detection limit unspecified. [R234] *EMSLC Method 502.2-ELCD. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. Detection limit = 1.1 ug/l. [R234] *EMSLC Method 502.2-PID. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. Detection limit unspecified. [R234] *EMSLC Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. This method is applicable to finished drinking water, raw source water, and drinking water in any treatment stage. Detection limit unspecified. [R234] *EMSLC Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. This method is applicable to surface water, ground water, and drinking water in any treatment stage. Detection limit = 0.11 ug/l. [R234] *EMSLC Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. This method is applicable to municipal and industrial discharges as provided under 40 CFR 136.1. Detection limit = 1.2 ug/l. [R234] *EMSLC Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. This method is applicable to the determination of purgeable organics in industrial and municipal discharges. Detection limit unspecified. [R234] *EMSLC Method 624-S. Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. This method is used for qualitative and quantitative analysis of purgeable (volatile) organic compounds in municipal and industrial wastewater treatment sludges. Detection limit unspecified. [R234] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). This method is applicable to various type of samples, regardless of water content, including ground water, aqueous sludge, caustic liquors, acid liquors, waste solvents, and oily waste. Detection limit = 10 ug/l. [R234] *CLP Method MC_VOA-LS. Analysis of Volatile Organics in Low Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to soil and sediment from hazardous waste sites. Detection limit = 10 ug/kg. [R234] *CLP Method MC_VOA-MS. Analysis of Volatile Organics in Medium Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. This method is applicable to soil and sediment from hazardous waste sites. Detection limit = 1200 ug/kg. [R234] *EAD Method 1624-S. Volatile Organic Compounds by Isotope Dilution GCMS. This method is applicable to the analysis of soils and sludges for VOCs. Detection limit = 11 ug/kg. [R234] *OSW Method 5021. Volatile Organic Compounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. This is a general purpose method for the preparation of volatile organic compounds (VOCs) in soils/sediments and solid wastes for determination by gas chromatography/mass spectrometry (GC/MS). The method is applicable to a wide range of organic compounds that have sufficiently high volatility to be effectively removed from soil samples using an equilibrium headspace procedure. Detection limit unspecified. [R234] CLAB: *Matrix: Serum, plasma and blood. Sample prepn: Analyze 5-ml sample directly. Assay procedure: Neutron activation analysis. Limit of detection: < 5 ug/g. /From table/ [R232] *Determination of bromide contents in blood and hair of workers exposed to methyl bromide by radioactivity analysis method. 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New York, NY: Van Nostrand Reinhold Co., 1983. 836 R151: USDA/Forest Service; Pesticide Background Statements Vol II Fungicides and Fumigants p.MB/C-28 (1986) R152: Great Lakes Chem Co; The Subchronic Effects of Oral Methyl Bromide Administration in the Rat (Volume I); 12/01/86; EPA Doc No. 86-870000749; Fiche No.OTS0516557 R153: Ethyl Corporation; Brief Inhalation Test with Methyl Bromide in Rats; 11/01/80; EPA Doc No. 86-870001201; Fiche No. OTS0516104 R154: DuPont Chem Co; Chronic (29-Month) Inhalation Toxicity and Carcinogenicity Study of Methyl bromide in Rats; 01/01/87; EPA Doc No. 88-920008788; Fiche No. OTS0546338 R155: Chem Mfgs Assn; Chronic (29-Month) Inhalation Toxicity and Carcinogenicity Study of Methyl Bromide in Rats, Reexamination of Nasal Cavity; 07/21/97; EPA Doc No. 88970000251; Fiche No. OTS0559186 R156: Dow Chem Co; Toxicity of Methyl bromide Vapors - Bromide Analyses on Urine from Control Rabbits and Rabbits Exposed to 60 ppm Methyl Bromide; 02/11/38; EPA Doc No. 86-870002140; Fiche No. OTS0515929 R157: Dow Chem Co; Toxicity of Methyl Bromide Vapors - Formic Acid Analyses on Urine from Control Rabbits and Rabbits Exposed to 60 ppm Methyl Bromide and to 5,000 ppm Methyl Alcohol; 02/14/38; EPA Doc No. 86-870002141; Fiche No. OTS0515930 R158: Dow Chem Co; Toxicity of Methyl Bromide Vapors - Methanol Analyses on Blood, Tissues and Urine from Control Animals and from Animals Exposed to 60 ppm Methyl Bromide; 01/25/38; EPA Doc No. 86-870002142; Fiche No. OTS0515931 R159: Dow Chem Co; Toxicity of Methyl Bromide Vapors - Bromide Analyses on Tissues from Control Animals and from Animals Exposed to 60 ppm Methyl Bromide; 12/10/37; EPA Doc No. 86-870002143; Fiche No. OTS0515932 R160: Ethyl Corporation; Teratogenicity Study of Methyl Bromide Dosed Orally (translation from the German); 01/01/81; EPA Doc No. 86-870001186; Fiche No. OTS0516089 R161: NIOSH; Teratologic Assessment of Butylene Oxide and Methyl Bromide, NIOSH Technical Report #81-124; 07/01/81; EPA Doc No. 40-8175008; Fiche No. OTS0509931 R162: Dow Chem Co; Methyl Bromide Inhalation Teratology Probe Study in New Zealand White Rabbits (Draft Pathology); 08/02/89; EPA Doc No. FYI-OTS-0889-0712; Fiche No. OTS0000712 R163: Methyl Bromide Industry Panel; Letter from the Methyl Bromide Industry Panel to USEPA Submitting Supplemental Information Concerning the 8EHQ-1189-0844S Submission on Methyl bromide; 02/26/91; EPA Doc No. 89-910000184; Fiche No. OTS0522340-2 R164: Methyl Bromide Industry Panel; Methyl Bromide Inhalation Teratology Study in New Zealand White Rabbits, Final Report; 06/18/90; EPA Doc No. 89-910000053; Fiche No. OTS0522340-3 R165: Ethyl Corp; 01/28/80; Summary and Data on the Methyl Bromide Mutagenicity Study; 01/28/80; EPA Doc No. 86-870001200; Fiche No. OTS0516103 R166: SRI International; In Vitro Microbiological Mitotic Recombination Assay of Methyl bromide Using S.cerevisiae D3. (Final Report); 02/01/80; EPA Doc No. 86-870001203; Fiche No. OTS0516106 R167: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 567 R168: USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-21 (1980) EPA 440/5-80-051 R169: USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-22 (1980) EPA 440/5-80-051 R170: NTP; Fiscal Year 1985 Annual Plan p.148 (1985) NTP-85-055 R171: Medinsky MA et al; Toxicol Appl Pharmacol 78 (2): 215-25 (1985) R172: Bond JA et al; Toxicol Appl Pharmacol 78 (2): 259-67 (1985) R173: Medinsky MA et al; Toxicol 32 (3): 187-96 (1984) R174: Muller M et al; Toxicol Lett 107 (1-3): 155-9 (1999) R175: Horowitz BZ et al; J Toxicol Clin Toxicol 36 (4): 353-7 (1998) R176: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 725 (1999) R177: HONMA T ET AL; NEUROBEHAV TOXICOL TERATOL 4 (5): 521-4 (1982) R178: Mamone G et al; Rapid Commun Mass Spectrom 12 (22): 1783-92 (1998) R179: Honma T et al; Toxicol Appl Pharmacol 81 (2): 183-91 (1985) R180: (1) Singh HB et al; J Air Pollut Cont Assoc 27: 333-6 (1977) (2) Singh HB et al; J Geophys Res 88: 3684-90 (1983) (3) Butler JH, Rodriguez JM; pp. 28-90 in The Methyl Bromide Issue. Bell CH et al, eds. NY, NY: John Wiley and Sons (1996) R181: (1) Lewis RJ Sr, ed; Hawley's Condensed Chem Dict. 13th ed. NY, NY: John Wiley and Sons Inc, p. 729 (1997) (2) Butler JH, Rodriguez JM; pp. 28-90 in The Methyl Bromide Issue. Bell CH et al, eds. NY, NY: John Wiley and Sons (1996) (3) Singh HB et al; Atmospheric Measurements of Selected Toxic Organic Chemicals USEPA-600/3-80-072 (1980) (4) Graedel TE; Chemical Compounds in the Atmosphere. NY, NY: Academic Press, p. 325 (1978) R182: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) USDA; ARS Pesticide Properties Database on Methyl Bromide (74-83-9). Available from the Database Query page at http://wizard.arsusda.gov/acsl/textfiles/METHYL_BROMIDE as of July 17, 2001. (3) Yates SR, Gan J; J Agric Food Chem 46: 755-61 (1998) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng. NY, NY: Hemisphere Pub Corp (1989) (5) Gan J, Yates SR; J Agric Food Chem 44: 4001-8 (1996) (6) Miller LG et al; Appl Environ Microbiol 63: 4346-54 (1997) R183: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) USDA; ARS Pesticide Properties Database (Methyl Bromide). Available from the Database Query page at http://wizard.arsusda.gov/acsl/textfiles/METHYL_BROMIDE as of July 17,2001. (3) Yates SR, Gan J; J Agric Food Chem 46: 755-61 (1998) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (9) Castro CE, Belser NO; J Agric Food Chem 29: 1005-8 (1981) R184: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng. NY, NY: Hemisphere Pub Corp (1989) (3) Atkinson R; J Phys Chem Ref Data. Monograph 1 (1989) (4) Robbins DE; Geophys Res Lett 3: 213-6 (1976) (5) Altshuller AP; Comments on the Lifetimes of Organic Molecules in Air. USEPA-600/9-80-003 (1980) R185: (1) Oremland RS et al; Environ Sci Technol 28: 514-20 (1994) R186: (1) Miller LG et al; Appl Environ Microbiol 63:4346-54 (1997) (2) Haber CL et al; Science 221: 1147-53 (1983) (3) Stirling DI, Dalton J Gen Microbial 116: 227-83 (1980) (4) Patel RN et al; Appl Environ Microbial 44: 1130-37 (1982) (5) Stirling DI, Dalton H; Fems Microbial Lett 5: 315-8 (1979) R187: (1) Atkinson R; J Phys Chem Ref Data. Monograph 1 (1989) (2) Butler JH, Rodriguez JM; pp. 28-90 in The Methyl Bromide Issue. Bell CH et al, eds. NY, NY: John Wiley and Sons (1996) (3) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (4) Castro CE, Belser NO; J Agric Food Chem 29: 1005-8 (1981) (5) Robbins DE; Geophys Res Lett 3: 213-6 (1976) (6) Jeffers PM, Wolfe NL; Geophys Res Lett 23: 1773-6 (1996) (7) Verschueren K; Handbook of Environmental Data on Organic Chemicals. NY, NY: John Wiley and Sons 2: 1459 (2001) (8) Gan J, Yates SR; J Agric Food Chem 44: 4001-8 (1996) R188: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R189: (1) USDA; ARS Pesticide Properties Database on Methyl Bromide (74-83-9). Available from the Database Query page at http://wizard.arsusda.gov/acsl/textfiles/METHYL_BROMIDE as of July 17, 2001. (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Gan J, Yates SR; J Agric Food Chem 44:4001-8 (1996) R190: (1) Yates SR, Gan J; J Agric Food Chem 46: 755-61 (1998) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Nelly WB; Predicting the Flux of Organics Across the Air/Water Interface. Control Hazard Materials Spills Proc Nat Conf 3rd pp. 197-200 (1976) (4) Rice PJ et al; Environ Toxicol Chem 15: 1723-9 (1996) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (6) Jury WA et al; J Environ Qual 13: 573-9 (1984) R191: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: WHO 41: 192 (1986) R192: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: WHO 41: 192 (1986) (2) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R193: (1) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982) (2) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Drinking Water. USEPA-600/4-76-062 (1976) R194: (1) Greenburg M et al; Environ Sci Technol 16: 14-9 (1982) R195: (1) Staples CA et al; Environ Technol Chem 4: 131-42 (1985) R196: (1) Shorter JH et al; Nature 377: 717-9 (1995) R197: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 192 (1986) R198: (1) Singh HB et al; J Air Pollut Cont Assoc 27: 332-6 (1977) (2) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) (3) Singh HB et al; Atmospheric Distributions, Sources and Sinks of Selected Halocarbon, Hydrocarbons, SF6 and N2O USEPA-600/S3-81-032 (1979) (4) Singh HB et al; Atmos Environ 15: 601-12 (1981) (5) Shikiya JG et al; Proc APCA Ann Mtg 77: 1-21 (1984) R199: (1) Rosenbaum AS et al; J Air Waste Mange Assoc 49:1138-52 (1999) (2) Grimsrud EP, Rasmussen RA; Atmos Environ 9: 1014-7 (1975) (3) Harsch DE, Rasmussen RA; Anal Lett 10: 1041-7 (1977) (4) Rasmussen RA, Khail MA; Geophys Res Lett 11: 433-6 (1984) (5) Hov O et al; Geophys Res Lett 11: 425-8 (1984) (6) Fabia P et al; Nature 294: 733-5 (1981) (7) Berg WW et al; Geophys Res Lett 11: 429-32 (1984) R200: (1) Baker LW et al; Environ Sci Technol 30: 1365-8 (1996) R201: (1) Duggan RE et al; Pesticide Residue Levels in Food in the U.S. from July 1, 1969 to June 30, 1976, FDA and AOAC (1983) (2) Dennis NM et al; J Econ Entomol 65: 1753 (1972) (3) USEPA; Ambient Water Quality Criteria Doc: Halomethanes. USEPA/440/5-80-051 p. C-10 (1980) R202: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: WHO 41: 192 (1986) (3) Baker LW et al; Environ Sci Technol 30: 1365-8 (1996) R203: (1) Rosenbaum AS et al; J Air Waste Mange Assoc 49: 1138-52 (1999) R204: 40 CFR 180.123(a)(1) (7/1/2001) R205: 40 CFR 180.123(a)(2) (7/1/2001) R206: 40 CFR 180.123(a)(3) (7/1/2001) R207: 40 CFR 180.123(c) (7/1/2001) R208: 40 CFR 180.199(a) (7/1/2001) R209: 40 CFR 180.199(b) (7/1/2001) R210: 40 CFR 180.199(c) (7/1/2001) R211: 29 CFR 1910.1000 (7/1/2001) R212: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R213: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.377 R214: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 191 (1986) R215: American Industrial Hygiene Association. The AIHA 2001 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. AIHA Press, Fairfax, VA. 2001. 25 R216: 40 CFR 60.489 (7/1/2001) R217: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R218: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R219: USEPA; Quality Criteria for Water 1986: Halomethanes (May 1,1986) EPA 440/5-86-001 R220: 40 CFR 401.15 (7/1/2001) R221: 40 CFR 302.4 (7/1/2001) R222: 40 CFR 355 (7/1/2001) R223: 40 CFR 716.120 (7/1/2001) R224: 40 CFR 261.33 (7/1/2001) R225: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.132 (Spring, 1998) EPA 738-R-98-002 R226: 40 CFR 152.175 (7/1/2001) R227: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R228: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R229: DUMAS T; J ASSOC OFF ANAL CHEM 65 (4): 913-5 (1982) R230: KING JR ET AL; J AGRIC FOOD CHEM 29 (5): 1003-5 (1981) R231: Devries JW et al; J Assoc Off Anal Chem 68 (6): 1112-6 (1985) R232: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 195 (1986) R233: 40 CFR 136, App. A (7/1/91) R234: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R235: American Public Health Association, American Water Works Association, Warer Environment Federation. M.A.H. Franson (ed.); Standard Methods for the Examination of Water and Wastewater 20th ed., Washington, D.C. 1998. R236: Ohmori S, Hirata M; Jpn J Ind Health 24: 119-25 (1982) RS: 226 Record 88 of 1119 in HSDB (through 2003/06) AN: 792 UD: 200211 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SUCCINIC-ANHYDRIDE- SY: *BERNSTEINSAUREANHYDRID- (GERMAN); *BUTANEDIOIC-ANHYDRIDE-; *DIHYDRO-2,5-FURANDIONE-; *2,5-DIKETOTETRAHYDROFURAN-; *2,5-FURANDIONE,-DIHYDRO-; *NCI-C55696-; *SUCCINIC-ACID-ANHYDRIDE-; *SUCCINYL-ANHYDRIDE-; *SUCCINYL-OXIDE-; *TETRAHYDRO-2,5-DIOXOFURAN- RN: 108-30-5 MF: *C4-H4-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HYDROGENATION OF MALEIC ANHYDRIDE OR FUMARIC ACID; HEATING OF SUCCINIC ACID AT ELEVATED TEMP AND PRESSURE [R1] *...BY TREATING SUCCINIC ACID WITH DIKETENE, SUCCINYL CHLORIDE OR ACETIC ANHYDRIDE, OR BY REACTING DIETHYL ESTER WITH BORON CHLORIDE. [R2, p. V15 266] FORM: *GRADE: DISTILLED. [R3] *...AVAILABLE IN US AS COMMERCIAL GRADE CONTAINING @ LEAST 99.5% OF PURE CHEMICAL, WITH MAX OF 0.5% UNSATURATED COMPD...0.15% CHLORIDES, 0.04% SULFATES... and 20 MG/KG HEAVY METALS. [R2, p. V15 266] +Flake [R4] MFS: +Buffalo Color Corp, Hq, 959 Route 46 East Suite 403, Parsippany, NJ 07054, (201) 316-5600; Production site: Buffalo, NY 14240 [R5] +Chemical Dynamics Corp, Hq, 3001 Hadley Rd, South Plainfield, NJ 07080, (201) 753-5000 [R5] OMIN: *ANHYD DENTIFRICES CONTAINING AN ACID ANHYDRIDE TO MAINTAIN SWEETENER STABILITY REPORTED. TOOTHPASTE CONTAINING 0.50 PARTS SUCCINIC ANHYDRIDE IS AN EXAMPLE. [R6] *LOW RATE OF HYDROLYSIS...TO ACID IS...ADVANTAGE DURING MIXING OF DOUGH, SINCE 1 OF REQUIREMENTS OF LEAVENING ACIDULANT IS NOT TO REACT WITH SODA IN MIXT UNTIL PRODUCT IS PLACED IN OVEN. ...RATE OF HYDROLYSIS INCR.../@ HIGHER TEMP/, LEAVING SALT...WITH NUTRIENT PROPERTIES. [R7, 233] *SUCCINIC ANHYDRIDE IS...VERY USEFUL DEHYDRATING AGENT FOR REMOVAL OF SMALL AMT OF MOISTURE IN...DRY FOOD MIXT WHICH ARE LATER TO BE ADMIXED WITH WATER. ...IT IS CAPABLE OF TAKING UP 20% OF ITS WT OF WATER, AND THE ACID FORMED IS DESIRABLE FLAVORING AGENT IN MANY FOODS. [R7, 233] *...USED IN MFR OF POLYMERIC MATERIALS, PHARMACEUTICALS, AGRICULTURAL CHEMICALS, DYESTUFFS, PHOTOGRAPHIC CHEMICALS, SURFACE-ACTIVE AGENTS, LUBRICANT ADDITIVES, FIRE-RETARDANTS FOR PAPER AND IN FOOD INDUST. [R2, p. V15 266] *...USED IN MFR OF PHARMACEUTICAL PRODUCTS SUCH AS CHEMOTHERAPEUTIC AGENTS, VITAMINS, STEROIDS, ANTIHEMORRHAGIC DRUGS, ANTICONVULSANTS AND MUSCLE RELAXANTS. ...USED IN MFR OF N-DIMETHYLAMINOSUCCINAMIC ACID, PLANT GROWTH REGULATOR...AND MAY ALSO BE USED IN MFR OF INSECT REPELLANTS AND HERBICIDES. [R2, p. V15 267] *...USED IN MFR OF SILVER HALIDE PHOTOGRAPHIC EMULSIONS; ANTHRAQUINONE DYES...DRYING OILS; LUBRICANT ADDITIVES...COMPONENTS OF SURFACTANTS...AND DEMULSIFYING AGENTS; FABRIC-TREATMENT CHEM...FOOD STARCH MODIFIER; NOT MORE THAN 4% SUCCINIC ANHYDRIDE MAY BE USED IN US FOR ESTERIFYING FOOD STARCHES... [R2, p. V15 267] USE: *ACIDULANT IN PROCESSED FOODS [R7, 232] *DEHYDRATING AGENT IN DRY FOOD MIXTURES [R7, 233] *CHEM INT FOR ADHESIVES, DYES; ELASTOMERS FOR SPECIAL TUBINGS, CABLE COVERINGS, AND EXTRUDED ARTICLES [R1] *MFR OF CHEMICALS, PHARMACEUTICALS, ESTERS; HARDENER FOR RESINS [R3] *CROSSLINKING AGENT FOR EPOXY RESINS, AND ION EXCHANGE MEMBRANES; PROBABLY CHEM INT FOR ITS 2,2-DIMETHYLHYDRAZIDE; CHEM INT FOR PAINT DRYING OILS, SUCCINYLATED MONOGLYCERIDE FOOD EMULSIFIERS, SILVER HALOID PHOTOGRAPHIC EMULSIONS, VITAMIN A, SULFA DRUGS, ALKYD RESINS, RESINS FOR SAFETY GLASS, COATINGS, PLASTICIZERS [R1] +Used as a food additive to modify starches [R8] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R1] *(1975) PROBABLY GREATER THAN 9.08X10+5 G [R1] +(1986) ND U.S. IMPORTS: *(1972) 4.5X10+6 G (PRINCPL CUSTOMS DISTS) [R1] *(1974) 2.7X10+6 G (PRINCPL CUSTOMS DISTS) [R1] +(1984) 1.99X10+9 g /Organic acid anhydrides/ [R9] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] +(1984) 2.07X10+8 g /Anhydrides, Acyl Halides, and their derivatives/ [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEEDLES FROM ALC; RHOMBIC PYRAMIDS FROM CHLOROFORM OR CARBON TETRACHLORIDE [R11]; *COLORLESS OR LIGHT-COLORED NEEDLES OR FLAKES [R3] ODOR: *ODORLESS [R7, 233] TAST: *BURNING TART TASTE [R7, 233] BP: *261 DEG C @ 760 MM HG [R12] MP: *119.6 DEG C [R12] MW: *100.08 DEN: *1.503 [R12] HTC: *-369.0 KCAL/MOLE [R7, 233] SOL: *INSOLUBLE IN WATER [R11]; *IN ETHANOL @ 25 DEG C: 2.56 G/100 ML; IN ETHER @ 25 DEG C: 0.64 G/100 ML; IN CHLOROFORM @ 25 DEG C: 0.87 G/100 ML [R7, 233]; *SOL IN CARBON TETRACHLORIDE [R12] SPEC: +MAX ABSORPTION (BENZENE): 278 NM (LOG E= 3.15); SADTLER REF NUMBER: 5150 (IR, PRISM) [R11]; +IR: 449 (Sadtler Research Laboratories IR Grating Collection) [R13]; +MASS: 243 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R13] VAP: +vapor pressure = 2.85X10-6 mm Hg @ 25 deg C /extrapolated/ [R14] OCPP: *REACTS WITH SULFYDRYL GROUP OF CYSTEINE IN NEUTRAL AQ SOLN [R2, p. V15 265] *BULK DENSITY: 47.2 LB/CU FT [R7, 233] *HYDROLYZES VERY SLOWLY, REQUIRING MORE THAN 30 MIN TO CONVERT AGITATED AQ SUSPENSION TO SUCCINIC ACID @ 21 DEG C [R7, 232] *SUBLIMES @ 115 DEG C AND 5 MM PRESSURE, @ 92 DEG C AND 1.0 MM PRESSURE [R12] +vapor pressure = 1 MM HG AT 92 DEG C [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME. [R15] DCMP: +When heated to decomp ... emits acrid smoke and fumes. [R16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R17] HTOX: *MODERATELY TOXIC AND IRRITANT. [R3] NTOX: *SUCCINIC ANHYDRIDE RATED 8 ON RABBITS EYES. MOST SEVERE INJURIES HAVE BEEN RATED 10. [R18] *6 MALE RATS...TREATED TWICE WEEKLY...FOR 65 WK (TOTAL DOSE, 260 MG). SC SARCOMAS DEVELOPED @ INJECTION SITE IN ALL 3 RATS THAT SURVIVED 93-106 WK. NO TUMORS OCCURRED IN 24 CONTROLS... [R2, p. V15 268] *SUCCINIC ANHYDRIDE DID NOT INDUCE REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA1535, TA1537, TA98 AND TA100 EITHER IN PRESENCE OR ABSENCE OF RAT LIVER POST-MITOCHONDRIAL SUPERNATANT. [R2, p. V15 268] *SUCCINIC ANHYDRIDE COMPLETELY INHIBITED ANAEROBIC CO2 PRODN BY INTACT BREWER'S YEAST CELLS, BUT HAD ONLY 10% INHIBITION IN CASE OF SUCCINIC ANHYDRIDE ON CO2 PRODN IN LYOPHILIZED YEAST PREPN. [R19] *SUCCINIC ANHYDRIDE PRODUCED TRANSPLANTABLE LOCAL TUMORS IN ALL SURVIVING RATS. ARACHIS OIL, USED AS VEHICLE FOR PRECEDING COMPD, WAS NONCARCINOGENIC IN 0.5 ML DOSES IN RATS, WHEREAS IN MICE THERE WAS 1 CASE OF MAMMARY ADENOMA FOLLOWING DOSES OF 0.1 ML. [R20] +... Conclusions: Under the conditions of these 2 yr studies, there was no evidence of carcinogenic activity of succinic anhydride for male or female F344/N rats given 50 or 100 mg/kg succinic anhydride. There was no evidence of carcinogenic activity for male B6C3F1 mice given 38 or 75 mg/kg succinic anhydride or for female B6C3F1 mice given 75 or 150 mg/kg. [R21] NTP: +... Toxicology and carcinogenesis studies were conducted by administering suspensions of succinic anhydride (97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... Doses for the two yr studies were 0, 50, or 100 mg/kg to groups of 60 rats of each sex; 0, 38, or 75 mg/kg to groups of 50 male mice; and 0, 75, or 150 mg/kg to groups of 50 female mice. Succinic anhydride was administered as a suspension in corn oil by gavage, 5 days/wk week for 103 wk. Conclusions: Under the conditions of these 2 yr studies, there was no evidence of carcinogenic activity of succinic anhydride for male or female F344/N rats given 50 or 100 mg/kg succinic anhydride. There was no evidence of carcinogenic activity for male B6C3F1 mice given 38 or 75 mg/kg succinic anhydride or for female B6C3F1 mice given 75 or 150 mg/kg. [R21] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TITRATION METHOD BASED ON REACTION OF SUCCINIC ANHYDRIDE WITH MORPHOLINE HAS BEEN USED FOR DETERMINING ITS PURITY, WITH AN ACCURACY OF +-1%. COLORIMETRIC DETERMINATION IS BASED ON REACTION OF SUCCINIC ANHYDRIDE WITH 2-NITROPHENYLHYDRAZINE IN BASIC MEDIUM. [R2, p. V15 267] *METHOD FOR DETERMINING ANHYDRIDES...BASED ON FLUORESCENCE OF CONDENSATION PRODUCT OF SUCCINIC ANHYDRIDE AND 2-CARBOXY-ISONITROSOACETANILIDE. LIMITS OF DETECTION ARE 5X10-10-5X10-9 M/LITER, WITH ERROR OF 15-25%, DZIOMKO VM ET AL; NEW LUMINESCENT METHOD FOR DETERMINATION OF ACYLATING AGENTS, ZH ANALYT KHIM, 24, 1969, 927-930. [R2, p. V15 268] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Succinic Anhydride in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 373 (1990) NIH Publication No. 90-2828 SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R3: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 823 R4: CHEMCYCLOPEDIA 1986 p.113 R5: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 969 R6: BARTH JB; US PATENT NO 3939261 02/17/76 (COLGATE-PALMOLIVE CO) R7: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R8: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V11 p.161 R9: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-357 R10: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-78 R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-501 R12: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1148 R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 313 R14: Perry RH, Green D; Perry's Chemical Engineer's Handbook. Physical and Chemical Data. New York, NY: McGraw-Hill 6th ed (1984) R15: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 998 R16: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2477 R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 72 (1987) R18: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 1180 R19: BOHN B, BROSSMER R; FEBS (FED EUR BIOCHEM SOC) LETT 42 (1): 18 (1974) R20: DICKENS F, JONES HE H; BR J CANCER 19(2) 392 (1965) R21: Toxicology and Carcinogenesis Studies of Succinic Anhydride in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 373 (1990) NIH Publication No. 90-2828 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 RS: 11 Record 89 of 1119 in HSDB (through 2003/06) AN: 797 UD: 200302 RD: Reviewed by SRP on 5/7/1998 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SULFISOXAZOLE- SY: *ALPHAZOLE-; *AMIDOXAL-; *5-(P-AMINOBENZENESULFONAMIDO)-3,4-DIMETHYLISOXAZOLE; *5-(4-AMINOPHENYLSULFONAMIDO)-3,4-DIMETHYLISOXAZOLE; *AZO-GANTRISIN-; *BENZENESULFONAMIDE, 4-AMINO-N-(3,4-DIMETHYL-5-ISOXAZOLYL)-; *CHEMOUAG-; *3,4-DIMETHYL-5-SULFANILAMIDOISOXAZOLE-; *DORSULFAN-WARTHAUSEN-; *ENTUSUL-; *GANTRISIN-; *GANTRISONA-; *GANTROSAN-; *ISOXAMIN-; *NCI-C50022-; *NEAZOLIN-; *NEOXAZOL-; *NORILGAN-S-; *PANCID-; *RENOSULFAN-; *ROXOSUL-TABLETS-; *SOSOL-; *SOXISOL-; *SOXO-; *SOXOMIDE-; *STANSIN-; *V-SUL-; *SULBIO-; *SULFADIMETHYLISOXAZOLE-; *SULFAFURAZOL-; *SULFAFURAZOLE-; *SULFAGAN-; *SULFAISOXAZOLE-; *SULFALAR-; *SULFANILAMIDE, N(1)-(3,4-DIMETHYL-5-ISOXAZOLYL)-; *SULFANILAMIDE, N(SUP 1)-(3,4-DIMETHYL-5-ISOXAZOLYL); *5-SULFANILAMIDO-3,4-DIMETHYLISOXAZOLE-; *SULFASOL-; *SULFAZIN-; *SULFOXOL-; *SULPHAFURAZOLUM-; *SULPHAISOXAZOLE-; *SULPHOFURAZOLE-; *SULSOXIN-; *THIASIN-; *UNISULF-; *URISOXIN-; *URITRISIN-; *UROGAN- RN: 127-69-5 MF: *C11-H13-N3-O3-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...BY ACTION OF P-ACETAMINOBENZENESULFONYL CHLORIDE ON 3,4-DIMETHYL-5-AMINOISOXAZOLE FOLLOWED BY DEACETYLATION [R1] *p-Acetylaminobenzenesulfonyl chloride is reacted with 3,4-dimethyl-5-aminoisoxazole followed by deacteylation. [R2] FORM: *SULFISOXAZOLE, USP (GANTRISIN, SK-SOXAZOLE, AND OTHERS)...AVAILABLE IN 500 MG TABLETS FOR ORAL USE. ...ALSO...VAGINAL CREAM (10%). [R3, 1111] *Gantrisin (Hoffmann-La Roche), SK-Soxazole (Smith Kline and French). [R2] MFS: *Hoffmann-La Roche, 340 Kingsland Street, Nutley, NJ 07110, (800)526-0189. Production site: Nutley, NJ 07110 /Sulfisoxazole, acetyl/ [R4] USE: *MEDICATION (VET) *MEDICATION *CHEM INT FOR SULFISOXAZOLE DERIVATIVES [R5] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 4.54X10+5 GRAMS [R5] *(1975) GREATER THAN 4.54X10+5 GRAMS [R5] U.S. IMPORTS: *(1972) 2.64X10+7 GRAMS [R5] *(1975) 1.43X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White to slightly yellowish crystalline powder [R6] ODOR: *ODORLESS [R7, p. V24 276] TAST: *Bitter [R6] MP: *194 DEG C [R6] MW: *267.31 [R6] DSC: *PKA 4.7 [R8, 112]; *pKa= 5 [R6] OWPC: *log Kow = 1.01 [R9] PH: *ACID TO LITMUS [R1] SOL: *SOL IN ALCOHOL [R6]; *INSOL IN PETROLEUM ETHER; FREELY SOL IN ACETONE [R8, 112]; *SOL IN DIETHYL ETHER (1 IN 800); SOL IN 5% AQ SODIUM BICARBONATE (1 IN 30) [R7, p. V24 276]; *1 G IN ABOUT 6700 ML WATER; SOL IN DIL HYDROCHLORIC ACID; 1 G IN ABOUT 10 ML BOILING ALCOHOL [R10, 1111]; *In water, 300 mg/l at 25 deg C. [R11] SPEC: *INDEX OF REFRACTION: 1.605 (ALPHA), 1.642 (BETA), 1.697 (GAMMA); OPTIC SIGN + ; +- ELONGATION; AXIAL ANGLE LARGE [R8, 327]; *MAX ABSORPTION (ACID SALT): 264 NM (A= 406, 1%, 1 CM); (BASE SALT): 253 NM (A= 1232, 1%, 1 CM) [R8, 283] OCPP: *191 deg C [R12] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of sulfoxides and nitroxides. [R13] SSL: *IN AIR SENSITIVE TO LIGHT; UNSTABLE IN ALKALINE SOLN [R8, 113] *COMMERCIALLY AVAILABLE PREPN MUST BE PROTECTED FROM LIGHT AND MOISTURE, INCL RELATIVE HUMIDITY IN EXCESS OF 60%, AND HAVE EXPIRATION DATES FROM 2 TO 5 YR FOLLOWING DATE OF MFR [R14] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Inadequate evidence of carcinogenicity in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R15] HTOX: *IN HYPOTHESIS-SEEKING STUDY...NO SIGNIFICANT EXCESS OF ANY CANCER WAS OBSERVED IN 11659 SUBJECTS WHO HAD RECEIVED SULFAFURAZOLE. FOLLOW-UP WAS FOR A MINIMUM OF 3 YEARS... [R7, p. V24 281] *Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Therapy should be discontinued at the first appearance of skin rash or any serious side/adverse effects. /Sulfonamides/ [R16, 2695] *...has been shown to transfer into the amniotic fluid during early fetal life. ...no increase in the defect rate when mothers were treated in the first trimester. ...of 796 offspring of mothers treated in the first 4 lunar months of pregnancy...no increase in malformation rate. [R7, p. V24 P280] *Fewer than 0.1% of patients receiving sulfisoxazole suffer serious toxic reactions. [R17, 1060] *The effect of unconjugated bilirubin on the morphology and haemolysis of human erythrocytes was accomplished under distinct incubation conditions: (i) hypotonic medium, with bilirubin concentrations ranging from 1 x 10(-9) to 1 x 10(-4) mol/l; (ii) isotonic medium, with 171 mumol/l bilirubin, in the absence of albumin (aggregating conditions), using non-separated and age-fractionated erythrocytes; (iii) isotonic medium, with 171 mumol/l bilirubin, in the presence of a surplus of human serum albumin (non-aggregating conditions), and using sulfisoxazole as a bilirubin displacer (bilirubin/albumin and sulfisoxazole/albumin molar ratios of 0.5 and 4.0, respectively). Our data showed that low concentrations of bilirubin (1 x 10(-7) to 1 x 10(-5) mol/l) protect against hypotonic haemolysis and induce crenation, while higher bilirubin concentrations induce haemolysis and lead to membrane disruption. When aggregating conditions were used, these phenomena were reproduced, the younger cells being significantly more susceptible to crenation while the older erythrocytes showed increased susceptibility to haemolysis. In non-aggregating conditions, haemolysis was virtually absent, though crenation was evident. Based on the above observations we conclude that the first step of erythrocyte bilirubin toxicity is crenation due to an expansion of the outer membrane leaflet by bilirubin mono-anion location. This effect is more evident in younger cells and explains the protection against the hypotonic haemolysis. Insertion of bilirubin deeper into the bilayer, facilitated by higher concentrations (> or = 1 x 10(-4) mol/l) and cell age, produces an unstable situation, where bilirubin acid aggregation is apparently the main cause for hemolysis and cell destruction. [R18] *Drug-dependent IgG antibodies (DDab) induced by sulfamethoxazole (SMX) and sulfisoxazole (SIX) were identified by flow cytometry in 15 patients who developed thrombocytopenia while taking one of these medications. Fourteen of the 15 drug-dependent IgG antibodies were specific solely for the glycoprotein (GP) IIb/IIIa complex, and 13 of these reacted wholly or in part with epitopes present only on the intact glycoproteinIIb/IIIa heterodimer. None of 12 sulfamethoxazole-induced drug-dependent IgG antibodies cross-reacted with sulfisoxazole, but one of three sulfisoxazole-induced antibodies reacted with sulfamethoxazole. Each of 10 sulfamethoxazole-induced drug-dependent IgG antibodies tested reacted with the N1-acetyl metabolite of sulfamethoxazole, but only one reacted fully with the N4-acetyl derivative. Detection of the sulfamethoxazole- and sulfisoxazole-dependent antibodies was facilitated by using bovine serum albumin (BSA) to achieve suspension of these weakly soluble drugs in an aqueous medium. Our findings indicate that drug-dependent IgG antibodies induced by sulfamethoxazole and sulfisoxazole, in contrast to those induced by quinidine and quinine, are mainly specific for glycoproteinIIb/IIIa and react preferentially with calcium-dependent epitopes present only on the intact glycoproteinIIb/IIIa heterodimer. [R19] NTOX: *STUDIES WITH GUNN RAT, A STRAIN WITH DEFICIENT BILIRUBIN-GLUCURONIDATION MECHANISM, SHOWED THAT KERNICTERUS COULD BE POTENTIATED...BY SULFISOXAZOLE... [R20, 683] *...TOXIC EFFECT, REPORTED BY VET, IS BILATERAL KERATOCONJUNCTIVITIS IN ABOUT 4% OF CANINE PT...WITHIN 1 WK AFTER BEGINNING TREATMENT WITH SULFISOXAZOLE. [R10, 1106] *GROUPS OF 50 MALE AND 50 FEMALE 7-WK-OLD B6C3F MICE RECEIVED BY GAVAGE, 0, 500 OR 2000 MG/KG BODY WT SULFAFURAZOLE (USP GRADE) SUSPENDED IN 0.5% AQUEOUS CARBOXYLCELLULOSE, 7 DAYS/WK FOR 103 WK; ADDN CONTROL GROUP...UNTREATED. ... SURVIVAL RATE...SIMILAR IN ALL GROUPS. ...NO SIGNIFICANT DIFFERENCES /IN TUMOR INCIDENCE/... [R7, p. V24 276] *...MICE AND RATS...ADMIN 1000 MG/KG BODY WT SULFAFURAZOLE ORALLY ON DAYS 7-12 AND 9-14 OF PREGNANCY, RESPECTIVELY, SIGNIFICANT INCR IN CLEFT PALATE AND SKELETAL DEFECTS WAS FOUND IN OFFSPRING OF BOTH SPECIES; IN ADDN, MANDIBULAR DEFECTS...PRESENT IN RAT FETUSES... [R7, p. V24 276] *SULFAFURAZOLE WAS NOT MUTAGENIC IN E COLI SD-4-73 WHEN TREATED IN ABSENCE OF METABOLIC ACTIVATION SYSTEM... [R7, p. V24 276] *Studies in mice given daily oral doses of up to 18 times the highest recommended human daily dose of 103 weeks, and rats given 4 times the highest recommended human daily dose have not shown that sulfisoxazole is carcinogenic in either male or female mice or rats. [R16, 2694] *Bacterial mutagenicity studies with sulfisoxazole have not been done. However, sulfisoxazole has not been shown to be mutagenic when tested in Escherichia coli Sd-4-73 strains in the absence of a metabolic activating system. [R16, 2694] *Studies in rats given daily doses of 7 times the highest recommended daily dose have not shown that sulfisoxazole causes adverse effects on mating behavior, conception rate, or fertility index (percent of animals pregnant). [R16, 2694] *An oral dose of 1 g/kg bw was absorbed rapidly in mice, and peak plasma levels of approximately 2.0 mg/ml were achieved 1 hour after administration. In dogs, 75-82 and 88-96% of oral (a 250 mg tablet) and i.v. (9 mg/kg bw) doses were recovered, respectively, in the urine within 24 hours. [R7, p. V24 P280] *The effect of sulfisoxazole on the propofol response has been investigated in an animal model. Doses of propofol (0, 50, 75, and 100 mg/kg intraperitoneal route) were administered to control (n=36) and sulfisoxazole pretreated mice (n=36). The impairment of righting reflex and struggle response were evaluated before and 5, 10, 15, 20, 30, 40, 50 and 60 minutes after propofol administration. Ten minutes after administration of the different doses of propofol, total plasma concentration was measured in both groups by high performance liquid chromatography. Protein binding displacement was evaluated in vitro by the ultrafiltration technique. Pretreatment with sulfisoxazole produced an important enhancement in the effect of propofol in both tests. This change was reflected in a significant increase in the area under the time-effect curve (p < 0.001) and in a shift of the log dose-effect relationship to the left. Sulfisoxazole itself did not produce any effect on either test. ED50 for the righting reflex was significantly reduced from 114 mg/kg to 64 mg/kg in sulfisoxazole pretreated groups and it fell from 87 mg/kg to 43 mg/kg for the struggle response test. No changes in the total plasma concentration and protein binding were observed. On the basis of these results, it was concluded that a clinical interaction could be expected but this cannot be explained by an alteration in the protein binding. [R21] *Rhodium (II) trifluoroacetate (TFARh), rhodium (II) trifluoroacetate adduct with sulfadiazine (TFARh.Sd) and rhodium (II) acetate adduct with sulfisoxazole (RhSx) were tested in mice for acute toxicity, antitumoral activity against Ehrlich ascites carcinoma and for viability of Ehrlich tumor cells in culture. At ip doses up to 60 mumol/kg (40-70 and 59 mg/kg, respectively), these compounds had no toxic effects up to 14 days. At ip doses of 10 mumol/kg/day for 5 days, Rhodium (II) trifluoroacetate and Rhodium (II) trifluoroacetate adduct with sulfadiazine significantly increased the survival rate of mice bearing Ehrlich ascites cells (probability of survival to the end of 34th day, controls = 0.23, Rhodium (II) trifluoroacetate adduct with sulfadiazine = 0.74). No significant effect was observed for rhodium (II) acetate adduct with sulfisoxazole. In vitro, these rhodium complexes at 40 uM significantly increased the number of dead cells in cultured Ehrlich tumor cells. [R22] *This study compares the responses of rat and chick limb bud micromass cultures to chemical treatment. Eight chemicals, of diverse structure, potency and mechanism, were tested, using two endpoints: extractable alcian blue stain as a measure of differentiation to chondrocytes, and extractable neutral red stain as an index of proliferation. Each chemical reduced differentiation and proliferation in a concentration-related manner, IC50s, concentrations that reduced staining by 50%, ranged from 10 nM (colchicine) to 4 mM (acetazolamide). Rat and chick responses to acetazolamide, colchicine and diazepam were indistinguishable. For diphenylhydramine and sulfisoxazole, concentration-response curves were very similar, but rat IC50s were half that of chick. For two chemicals, concentration-response curves were very similar, but rat IC50s were half that of chick. For two chemicals, concentration-response slopes were markedly steeper for chick; in the case of beta-aminopropionitrile, IC50s were similar, but rat cultures were three-fold more sensitive than chick to cytosine arabinoside. 6-Aminonicotinamide gave a U-shaped response curve, for both endpoints and both species, so IC50s may be misleading, but the IC50 for proliferation was lower for chick (0.6 uM) than rat (4uM). In vivo and in vitro parameters for validation of development toxicity screens are contentious. Diphenhydramine apart, these chemicals can be teratogenic in vivo, although their 'hazard' can be debated. An IC50-proliferation/IC50-differentiation ratio greater than 2 has been suggested to predict specific developmental toxicity. Only sulfisoxazole and 6-aminonicotinamide has significantly different IC50s for proliferation and differentiation, with ratios of 4.4 (both species), and 10.4 for rat and 1.9 for chick, respectively. All other ratios were close to 1. The general consistency of this ratio, and the concentration-responses, in the two species suggests that the chick is a viable alternative to laboratory mammals, but the predictive ability of micromass remains to be determined. [R23] *Pneumocystis carinii pneumonitis was effectively prevented in 90% of immunosuppressed rats by the administration of 100 mg of erythromycin and 300 mg/kg/day of sulfisoxazole. All of the untreated control and erythromycin-treated animals developed the infection and 80% of rats given sulfisoxazole alone had the pneumonitis. A similar pattern of response occurred when the drugs were used therapeutically for rats with established P.carinii pneumonitis. The erythromycin and sulfisoxazole ratio of 1:3 was the most effective of several dose combinations tested. The established safety record from three decades of clinical use of this drug combination plus the broad spectrum of coverage for other causes of diffuse pneumonitis such as Chlamydia, Mycoplasma, and Legionella warrant further study of erythromycin-sulfisoxazole in AIDS patients. [R24] NTXV: *LD50 Rabbit oral 20 g/kg; [R13] *LD50 Rabbits oral > 1.0 g/kg bw; [R25] *LD50 Rat oral 10 g/kg; [R13] *LD50 Mice oral 6.8 g/kg bw; [R26] NTP: *A bioassay of sulfisoxazole for possible carcinogenicity was conducted by admin the chemical by gavage to Fischer 344 rats and B6C3Fl mice. Groups of 50 rats of each sex and 50 mice of each sex were admin sulfisoxazole suspended in aqueous 0.5% carboxymethyl cellulose 7 days/wk at one of two doses, either 100 or 400 mg/kg body weight for the rats and either 500 or 2,000 mg/kg for the mice. Vehicle controls consisted of groups of 50 rats of each sex and 50 mice of each sex that were administered only the aqueous 0.5% carboxymethyl cellulose. Untreated controls consisted of groups of 50 rats of each sex and 50 mice of each sex. The dosed groups of the rats and mice were administered the chemical by gavage for 103 wk, then observed for 1 to 3 additional wk; the vehicle control groups were similarly administered 0.5% carboxymethyl cellulose alone. All surviving rats and mice were /sacrificed/ at wk 104 to 106. ... It is concluded that under the conditions of this bioassay, sulfisoxazole was not carcinogenic for either Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R27] ADE: *PLASMA PROTEIN BINDING OF SULFISOXAZOLE IN THE RAT DECR IN THE PRESENCE OF ITS MAJOR METABOLITE, 4-N-ACETYL-SULFISOXAZOLE. THIS RESULTED IN AN INCR IN THE TOTAL CLEARANCE AND APPARENT VOL OF DISTRIBUTION OF SULFISOXAZOLE. HOWEVER, BOTH TOTAL AND RENAL CLEARANCE OF UNBOUND DRUG FROM THE BODY WERE DECR, INDICATING THAT THE ABILITY TO METABOLIZE AND RENALLY ELIMINATE SULFISOXAZOLE IS DECR BY THE PRESENCE OF ITS MAJOR METABOLITE. [R28] *ACCORDING TO PATENTS CITED, SOLUBILITY @ PH 5 TO 7 IS SO HIGH THAT NEITHER COMPD ITSELF NOR ITS N(4)-ACETYL DERIV IS DEPOSITED IN KIDNEYS. [R1] *AFTER SINGLE IM OR ORAL (2 G) DOSES, PEAK PLASMA LEVELS OF 121-185 UG/ML...OBTAINED AFTER 2 HR AND DRUG HAS BIOLOGICAL T/2 OF 4.6-7.8 HR. [R20, 182] *RENAL CLEARANCE OF SULFISOXAZOLE AND ITS METABOLITE IS A FUNCTION OF GLOMERULAR FILTRATION, ACTIVE TUBULAR SECRETION, AND PASSIVE REABSORPTION IN DOGS AND IN MAN... [R20, 183] *SULFISOXAZOLE IS DISTRIBUTED ONLY IN EXTRACELLULAR BODY WATER...FOLLOWING ORAL DOSE OF 2-4 G, PEAK CONCN IN PLASMA OF 100-250 UG/ML ARE FOUND IN 2-4 HOURS. ... FROM 28 TO 35% SULFISOXAZOLE IN BLOOD AND ABOUT 30% IN URINE IS IN ACETYLATED FORM. APPROX 95% OF SINGLE DOSE IS EXCRETED BY KIDNEY IN 24 HR. CONCN OF DRUG IN URINE...GREATLY EXCEED THOSE IN BLOOD AND MAY BE BACTERICIDAL. [R17, 1060] *IT IS SECRETED INTO PROSTATIC FLUID, BUT...NOT KNOWN WHETHER IT IS SECRETED INTO OTHER GENITOURINARY FLUIDS. [R10, 1111] *AFTER SYSTEMIC ADMIN OF ADEQUATE DOSE...SULFISOXAZOLE ATTAIN/S/ CONCN IN CSF THAT MAY BE EFFECTIVE IN MENINGEAL INFECTIONS. AT STEADY STATE, CONCN RANGES BETWEEN 10 AND 80% OF THAT IN THE BLOOD. [R17, 1059] *THE SERUM PROTEIN BINDING OF SULFISOXAZOLE WAS DETERMINED IN FULL-TERM NEWBORN INFANTS AND THEIR MOTHERS IMMEDIATELY AFTER DELIVERY. IT WAS BOUND MORE EXTENSIVELY IN INFANT SERUM THAN IN MATERNAL SERUM. THERE WERE NEG CORRELATIONS BETWEEN FREE FRACTION OF DRUG AND ALBUMIN CONCN IN SERUM OF MOTHERS. [R29] *THE SERUM PROTEIN BINDING OF SULFISOXAZOLE WAS DETERMINED IN PREGNANT WOMEN AT 7 TIME PERIODS DURING PREGNANCY AND AT 2 TIME PERIODS POSTPARTUM, AND IN NONPREGNANT WOMEN OF CHILDBEARING AGE. DRUG BINDING WAS DETERMINED BY EQUIL DIALYSIS AT 37 DEG C AGAINST AN EQUAL VOL OF 0.13 MOLAR SODIUM PHOSPHATE BUFFER, PH 7.4, TO WHICH 200 MCG/ML SULFISOXAZOLE HAD BEEN ADDED. THE SERUM FREE FRACTION VALUES ROSE DURING PREGNANCY, PRIMARILY AFTER 15 WK OF GESTATION, AND REMAINED ELEVATED FOR AT LEAST 1-5 DAYS POSTPARTUM. IT SHOWED A NEG CORRELATION BETWEEN FREE FRACTION VALUES AND SERUM ALBUMIN CONCN DURING PREGNANCY. [R30] *SIX LACTATING WOMEN, AGES 19-27 YR, WERE GIVEN 4 ORAL DOSES OF SULFISOXAZOLE, ONE G EVERY 6 HR, DURING THE FIRST 24 HR OF THE COLLECTION PERIOD. HALF-LIVES IN MILK WERE 7.2 HR FOR SULFISOXAZOLE (I) AND 8.9 HR FOR ITS MAJOR METABOLITE, N4-ACETYLSULFISOXAZOLE (II). THE MILK TO SERUM RATIO FOR II WAS APPROX FOURFOLD THAT FOR I, REFLECTING THE GREATER DIFFUSION OF THE METABOLITE INTO MILK. TOTAL I RECOVERED IN BREAST MILK DURING THE 48 HR COLLECTION PERIOD ACCOUNTED FOR LESS THAN 1% OF THE MATERNAL DOSE IN ALL PT, WITH A MEAN RECOVERY OF 0.45%. THE DRUG WAS SECRETED PREDOMINANTLY AS THE ACETYLATED METABOLITE, WHICH COMPRISED 77% OF TOTAL DRUG RECOVERED, WHEREAS 23% APPEARED AS THE PARENT COMPD. [R31] *PLASMA CONCN OF TOTAL AND UNBOUND SULFISOXAZOLE WERE FOLLOWED AFTER SINGLE IV AND ORAL DOSES OF 1 G AND DURING A 500-MG FOUR-TIMES-A-DAY DOSING REGIMEN IN HEALTHY MALES. SATURABLE PLASMA PROTEIN BINDING WAS OBSERVED AT TOTAL CONCN GREATER THAN 80-100 MG/L. THE CLEARANCE WAS 18.7 ML/MIN FOR TOTAL DRUG AND 232 ML/MIN FOR UNBOUND DRUG. RENAL ELIMINATION ON THE AVG ACCOUNTED FOR 49% OF THE CLEARANCE. THE APPARENT VOL OF DISTRIBUTION FOR TOTAL DRUG WAS 10.9 L AND 136 L FOR UNBOUND DRUG, INDICATING THAT SULFISOXAZOLE IS PRIMARILY DISTRIBUTED EXTRACELLULARLY. ACCUMULATION OF N4-ACETYLSULFISOXAZOLE DURING MULTIPLE DOSING DID NOT AFFECT THE DISPOSITION OF SULFISOXAZOLE. THE BIOAVAILABILITY FOR AN ORAL DOSE WAS 0.95. [R32] *INTESTINAL BYPASS SURGERY IN MORBIDLY OBESE FEMALES (110-150 KG) HAD NO PERMANENT EFFECT ON THE RATE OR AMT OF SULFISOXAZOLE ABSORPTION. LOSS OF WT OF UP TO 44% BY AN INDIVIDUAL OVER A YEAR'S TIME HAD NO EFFECT ON THE APPARENT VOLUMES OF DISTRIBUTION OR OTHER PHARMACOKINETIC PARAMETERS OF SULFISOXAZOLE OR ITS METABOLITE N4-ACETYLSULFISOXAZOLE. [R33] *IN SPITE OF A DECR IN THE PLASMA PROTEIN BINDING OF SULFISOXAZOLE IN UNDERNOURISHED HUMAN SUBJECTS IN COMPARISON TO WELL NOURISHED SUBJECTS, THERE WAS NO CHANGE IN THE ACTUAL VOL OF DISTRIBUTION OR THE HALF-LIFE OF THIS DRUG IN THESE SUBJECTS. [R34] *SULFISOXAZOLE (66 MG/KG/DAY) WAS ADMIN ORALLY TO DOGS AT 8-HR INTERVALS FOR 5 CONSECUTIVE 8-HR TEST PERIODS. MEAN 8-HR URINE CONCN WERE 1466 MUG/ML. THE MEAN 8-HR PERCENTAGES OF THE DOSES OF DRUG ELIMINATED IN ACTIVE FORM IN THE URINE WERE 65.5%. [R35] *THE RATE OF EXCRETION OF SULFISOXAZOLE IN RAT SUBMAXILLARY SALIVA WAS HIGHER THAN IN RAT PAROTID SALIVA AND THOSE IN RAT PAROTID SALIVA WERE 4-7 TIMES HIGHER THAN IN HUMAN PAROTID SALIVA. THESE FINDINGS CONFIRMED SOME FUNCTIONAL DIFFERENCES IN THE SPECIES OF ANIMAL AND KINDS OF GLAND WITH REGARDS TO THE EXCRETION OF THE DRUG INTO SALIVA. [R36] *...readily absorbed from the GI tract. Peak plasma concentrations occurring at 1-4 hr and ranging from 11.2-25 mg/dL have been reported following administration of single oral or IM doses of 2-4 g of sulfisoxazole. [R14] *SULFONAMIDES ARE ELIMINATED FROM BODY PARTLY AS SUCH AND PARTLY AS METABOLIC PRODUCTS. LARGEST FRACTION IS EXCRETED IN URINE, AND HALF LIFE ... IS THUS DEPENDENT ON RENAL FUNCTION. SMALL AMT ARE ELIMINATED IN FECES AND IN BILE, MILK, AND OTHER SECRETIONS. /SULFONAMIDES/ [R17, 1059] *ALL SULFONAMIDES ARE BOUND IN VARYING DEGREE TO PLASMA PROTEINS, PARTICULARLY TO ALBUMIN. EXTENT ... IS DETERMINED BY HYDROPHOBICITY ... AND ITS PKA ... IN GENERAL, SULFONAMIDE IS BOUND TO SOMEWHAT GREATER EXTENT IN ACETYLATED THAN IN FREE FORM. /SULFONAMIDES/ [R17, 1059] *SULFONAMIDES ARE DISTRIBUTED THROUGHOUT ALL TISSUES OF BODY. ... READILY ENTER PLEURAL, PERITONEAL, SYNOVIAL, OCULAR, AND SIMILAR BODY FLUIDS, AND MAY REACH CONCN THAT ARE 50-80% OF SIMULTANEOUSLY DETERMINED BLOOD CONCN. ... ATTAIN CEREBROSPINAL FLUID CONCN THAT ARE EFFECTIVE IN MENINGEAL INFECTIONS. /SULFONAMIDES/ [R17, 1059] *SULFONAMIDES READILY PASS THROUGH PLACENTA AND REACH FETAL CIRCULATION. EQUILIBRIUM BETWEEN MATERNAL AND FETAL BLOOD IS USUALLY ESTABLISHED WITHIN 3 HR AFTER SINGLE ORAL DOSE. CONCN ATTAINED IN FETAL TISSUES ARE SUFFICIENT TO CAUSE BOTH ANTIBACTERIAL AND TOXIC EFFECTS. /SULFONAMIDES/ [R17, 1059] *... THIS CLASS OF DRUGS IS RAPIDLY AND ADEQUATELY ABSORBED FROM GI TRACT. INDEED, AGENT CAN OFTEN BE FOUND IN URINE WITHIN 30 MIN AFTER ITS ORAL INGESTION. SMALL INTESTINE IS MAJOR SITE OF ABSORPTION, BUT SOME OF DRUG IS ABSORBED FROM STOMACH. /SULFONAMIDES/ [R17, 1059] METB: *IN MAN IT IS EXCRETED IN URINE AS UNCHANGED SULFISOXAZOLE (56%), N(4)-ACETYL DERIVATIVE (18%), N(4)-GLUCURONIDE (3.4%), N(4)-SULFATE (1.0%) AND A SECOND GLUCURONIDE WHICH IS PROBABLY N(2)-GLUCURONIDE OF SULFISOXAZOLE. [R37] *SULFISOXAZOLE...FORMED FROM N-ACETYLSULFISOXAZOLE METABOLIZES TO SULFISOXAZOLE-N(4)-BETA-D-GLUCURONIDE IN MAN. UNO, T AND KONO, M, YAKUGAKU ZASSHI, 82, 1660 (1962), ALSO 81, 72 (1961). /FROM TABLE/ [R38] *The sulfonamides undergo metabolic alterations in vivo, especially in the liver. The major metabolic derivative is the N4-acetylated sulfonamide. /Sulfonamides/ [R17, 1059] BHL: *~ 6 hr [R7, p. V24 P280] ACTN: *SULFONAMIDES ARE STRUCTURAL ANALOGS AND COMPETITIVE ANTAGONISTS OF PARA-AMINOBENZOIC ACID (PABA), AND THUS PREVENT NORMAL BACTERIAL UTILIZATION OF PABA FOR THE SYNTHESIS OF FOLIC ACID (PTEROYLGLUTAMIC ACID, PGA). /SULFONAMIDES/ [R17, 1058] *...SULFONAMIDES ARE COMPETITIVE INHIBITORS OF BACTERIAL ENZYME RESPONSIBLE FOR THE CORPORATION OF PABA /PARA-AMINOBENZOIC ACID/ INTO DIHYDROPTEROIC ACID, THE IMMEDIATE PRECURSOR OF FOLIC ACID. SENSITIVE MICROORGANISMS ARE THOSE THAT MUST SYNTHESIZE THEIR OWN PGA /PTEROYLGLUTAMIC ACID/. /SULFONAMIDES/ [R17, 1058] INTC: *...SULFISOXAZOLE...REPORTED TO INTERACT WITH SULFONYLUREAS /ACETOHEXAMIDE, CHLORPROPAMIDE, TOLAZAMIDE, TOLBUTAMIDE/ IN MANNER SIMILAR TO SULFAPHENAZOLE /IE, ENHANCES ACTION OF TOLBUTAMIDE AND MAY CAUSE SYMPTOMS OF SEVERE HYPOGLYCEMIA IN DIABETIC PT/. [R39, 250] *...ADMIN OF SULFISOXAZOLE (40 MG/KG IV)...PRIOR TO THIOPENTAL REDUCED DOSAGE OF THIOPENTAL REQUIRED FOR HYPNOSIS AND ANESTHESIA BY 20 and 40% RESPECTIVELY, IN 33 PT. ...PRETREATMENT...ALSO SHORTENED TIME TO AWAKENING. MECHANISM...MAY BE RELATED TO DISPLACEMENT OF THIOPENTAL FROM PLASMA PROTEIN BINDING SITES... [R39, 601] *EFFICACY OF SULFONAMIDES IS GENERALLY ENHANCED WHEN DRUGS ARE USED IN COMBINATION WITH FOLIC ACID ANTAGONIST TRIMETHOPRIM. /SULFONAMIDES/ [R10, 1105] *IN STUDIES OF THE EFFECTS OF SUGARS AND OSMOTIC PRESSURE ON THE INTESTINAL ABSORPTION OF SULFISOXAZOLE BY THE RAT WHEN 80 MG/KG WAS ADMIN IN HYPERTONIC SOLN, THE RECIPROCAL OF OSMOTIC PRESSURE WAS CORRELATED WITH BOTH AREAS UNDER THE BLOOD SULFISOXAZOLE CONCN VERSUS TIME CURVE AND MAX BLOOD SULFISOXAZOLE CONCN. NO CORRELATIONS WERE OBSERVED USING IT IN HYPOTONIC SOLN. THUS, OSMOTIC PRESSURE OF THE FORMULATION MUST BE TAKEN INTO ACCOUNT SINCE THE OSMOTIC PRESSURE OF HYPERTONIC SOLN MIGHT AFFECT DRUG ABSORPTION FROM ITS DOSAGE FORM. [R40] *THE PHARMACOKINETICS OF SULFISOXAZOLE WERE STUDIED IN CONTROL RATS AND IN RATS TREATED FOR 5 DAYS WITH A DAILY 100 MG/KG DOSE OF PHENOBARBITAL. THE HALF-LIFE, STEADY STATE APPARENT VOL OF DISTRIBUTION, AND CENTRAL APPARENT VOL OF DISTRIBUTION WERE SIGNIFICANTLY LOWER, AND TRANSPORT AND URINARY EXCRETION RATE CONSTANTS WERE HIGHER IN PHENOBARBITAL TREATED RATS. [R41] *THE PROTHROMBIN TIME OF A 66-YR-OLD WOMAN RECEIVING WARFARIN SODIUM BECAME ELEVATED 2 DAYS AFTER BEGINNING SULFISOXAZOLE THERAPY FOR A URINARY TRACT INFECTION. [R42] *These medications /coumarin- or indandione-derivative anticoagulants; hydantoin anticonvulsants or oral antidiabetic agents/ may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy. /Sulfonamides/ [R16, 2695] *Concurrent use of bond marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered. /Sulfonamides/ [R16, 2695] *Concurrent long-term use of sulfonamides /with estrogen-containing, oral contraceptives/ may result in increased incidence of breakthrough bleeding and pregnancy. /Sulfonamides/ [R16, 2695] *Concurrent use /of cyclosporine/ with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentration and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored. /Sulfonamides/ [R16, 2695] *Concurrent use /of hemolytics/ with sulfonamides may increase the potential for toxic side effects. /Sulfonamides/ [R16, 2695] *Concurrent use /of hepatotoxic medications/ with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored. /Sulfonamides/ [R16, 2695] *In acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended. /Sulfonamides/ [R16, 2695] *The effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations. /Sulfonamides/ [R16, 2695] *Since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy. /Sulfonamides/ [R16, 2695] *To examine the absorption of cefadroxil from the human oral cavity, a buccal absorption test was carried out using 7 healthy volunteers (ages 21-34 yr); similar absorption experiments were performed in the hamster cheek pouch. In human oral mucosa but not in the keratinized hamster cheek oral mucosa, buccal absorption of cefadroxil demonstrated saturation and competitive inhibition by cephalexin, but not by sulfisoxazole. It was concluded that aminocephalosporin antibiotics are absorbed from the non-keratinized region of the human oral cavity via a specialized transport mechanism. [R43] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents /SRP: Antibacterial/ [R44] *MEDICATION (VET): ...PRIMARY USE IN TREATMENT OF URINARY TRACT INFECTIONS IN DOG AND CAT. ...PROVED EFFECTIVE IN CONTROLLING...INFECTIONS CAUSED BY ESCHERICHIA COLI, PROTEUS VULGARIS, PSEUDOMONAS AERUGINOSA, AND GRAM-POSITIVE COCCI. [R45] *MEDICATION (VET): VERY USEFUL FOR CHRONIC ADMIN (30 DAYS) IN CELLULITIS, DERMATITIS, OR CYSTITIS IN CATS...USUALLY @ 1/2 RECOMMENDED DOSAGE AFTER INITIAL OPTIMUM COURSE OF THERAPY. ...COMPATIBLE WITH METHENAMINE. USED PARENTERALLY WITH OTHER SULFONAMIDES, AND OCCASIONALLY IN INTRAMAMMARY PREPN MIXT, OPHTHALMIC "POWDERS"...AND OTHER MISC TOPICAL TREATMENTS FOR EARS, WOUNDS, ETC. [R46, 577] *IT...MAY BE USED IN PREVENTION OF MENINGITIS. ...TREATMENT OF...TRACHOMA, INCLUSION CONJUNCTIVITIS, NOCARDIOSIS, CHANCROIDS AND CHLOROQUININE-RESISTANT MALARIA. [R7, p. V24 276] *SULFISOXAZOLE IS PRESENTLY PREFERRED OVER OTHER SULFONAMIDES BY MOST CLINICIANS, WHEN A RAPIDLY ABSORBED AND RAPIDLY EXCRETED SULFONAMIDE IS INDICATED. [R17, 1060] *Sulfonamides are indicated in the treatment of chancroid caused by Hemophilus ducreyi. however, other agents such as erythromycin and ceftriaxone, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in the treatment of endocervical and urethral infections caused by Chlamydia trachomatis. However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in the treatment of neonatal inclusion conjunctivitis caused by chlamydia trachomatis. However, other agents, such as erythromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated as adjunctive therapy in the treatment of chloroquine-resistant Plasmodium falciparum. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in the prophylaxis of meningitis caused by susceptible strains of Neisseria meningitidis. However, other agents, such as rifampin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in the treatment of nocardiosis caused by Nocardia asteroides. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in combination with other antibacterials in the treatment of otitis media caused by susceptible strains of H. influenza, streptococci, and pneumococci. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfisoxazole is indicated in the prophylaxis of rheumatic fever associated with group A beta-hemolytic streptococcal infections. However, other agents, such as penicillin, are considered to be first line agents. /NOT included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in combination with pyrimethamine in the treatment of toxoplasmosis caused by Toxoplasma gondii. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in the treatment of ocular trachoma caused by Chlamydia trachomatis. However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R16, 2693] *Sulfonamides are indicated in the treatment of acute, uncomplicated urinary tract infections caused by susceptible bacteria. Because sulfamethizole produces low plasma levels and is rapidly eliminated, it is recommended only for use in urinary tract infections, not systemic infections. Sulfadiazine is not recommended for the treatment of urinary tract infections because of its relatively lower urine solubility and the increased chance of crystalluria; other, more soluble agents, such as sulfisoxazole, are generally preferred. /Included in US product labeling/ [R16, 2693] *Sulfonamides are used in the treatment of lymphogranuloma venereum caused by Chlamydia species. However, other agents, such as doxycycline and erythromycin, are considered to be first line agents. /Sulfonamides; NOT included in US product labeling/ [R16, 2693] *A study evaluating antibiotic prescribing patterns for 7357 children, ages < 11 yr, with their first case of otitis media (OM) in at least 9 mos, who were covered by the Tennessee Medicaid program, is reported. Amoxicillin was prescribed 53% of the time, followed by cefaclor; all first-line antibiotics (amoxicillin, ampicillin, erythromycin-sulfisoxazole; trimethoprim-sulfamethoxazole) accounted for 64% of the prescriptions, but only one-fourth of the costs. The highest use of first-line therapy was associated with children under 3 yr of age; children without prior antimicrobial therapy, recent upper respiratory tract infection, or recent sinusitis; children seen by emergency department physicians; and children seen by urban physicians. Medicaid would have saved $68,250 if first-line therapy had been used for all children having their first occurrence of otitis media in the fourth quarter of the study yr. The savings to the state were estimated at $300,000 or more in the study yr had first-line therapy been used for most first occurrences of otitis media in all 4 quarters plus even a small percentage of the estimated 30,000 remaining repeat otitis media cases. [R47] *The effectiveness of long-term sulfonamide therapy was compared with surgical insertion of ventilation tubes (VTs) in the treatment of otitis media with effusion (OME) in 125 children (aged 2.5-7 yr) who were randomly assigned to 75 mg/kg/day of sulfisoxazole for 6 mos (medical treatment) or bilateral insertion of ventilation tubes (surgical treatment). A significantly greater proportion of medical subjects (67%) than surgical subjects (48%) were treatment failures at 6, 12, or 18 mos. Surgical subjects had significantly better hearing at 2 and 4 mos but not at 6, 12, and 18 mos. A significantly greater proportion of surgical subjects (50%) experienced complications of treatment than did medical subjects (9%). Thirty-three percent of candidates for ventilation tube placement did not require surgery when treated with a 6-month course of sulfisoxazole. It was concluded that a 6-month trial of sulfonamide is recommended for children with otitis media with effusion before considering ventilation tube placement. [R48] *Pneumocystis carinii pneumonitis was effectively prevented in 90% of immunosuppressed rats by the administration of 100 mg of erythromycin and 300 mg/kg/day of sulfisoxazole. All of the untreated control and erythromycin-treated animals developed the infection and 80% of rats given sulfisoxazole alone had the pneumonitis. A similar pattern of response occurred when the drugs were used therapeutically for rats with established P.carinii pneumonitis. The erythromycin and sulfisoxazole ratio of 1:3 was the most effective of several dose combinations tested. The established safety record from three decades of clinical use of this drug combination plus the broad spectrum of coverage for other causes of diffuse pneumonitis such as Chlamydia, Mycoplasma, and Legionella warrant further study of erythromycin-sulfisoxazole in AIDS patients. [R49] WARN: *TOPICAL APPLICATION OF SULFONAMIDES CAN CAUSE SENSITIZATION AND THESE AGENTS ARE INACTIVATED BY BLOOD AND PUS WHEN USED BY THIS ROUTE. /SULFONAMIDES/ [R50, 1312] *...BECAUSE LIPID SOLUBILITY...IS LOW, ITS ANTIBACTERIAL POTENCY IS LOW. IT ALSO DOES NOT PENETRATE CELL AND PASS BARRIERS AS WELL AS MOST SULFONAMIDES. CONSEQUENTLY, IT IS NOT ALWAYS EFFECTIVE AGAINST SYSTEMIC INFECTIONS WHICH ARE SENSITIVE TO OTHER SULFONAMIDES. [R10, 1111] *VET: WARNING: INSURE ADEQUATE FLUID INTAKE. USE CAUTIOUSLY (BUT VERY USEFUL) IN RENAL DISEASE. VITAMIN K NEEDS MAY NEED MONITORING WITH LONG-TERM AND/OR HIGH DOSAGE. [R46, 578] *HEMOLYTIC ANEMIA...OBSERVED IN PT WITH OR WITHOUT DEFICIENCY OF ERYTHROCYTIC GLUCOSE-6-PHOSPHATE DEHYDROGENASE... THIS HAZARD SHOULD BE BORNE IN MIND IF...FAMILY HISTORY OF G6PD DEFICIENCY...OCCURS MOST COMMONLY IN BLACKS AND PEOPLE OF MEDITERRANEAN ETHNIC GROUPS. [R50, 1309] *SULFISOXAZOLE...MUST BE USED WITH CAUTION IN PT WITH IMPAIRED RENAL FUNCTION. LIKE ALL OTHER SULFONAMIDES.../IT/ MAY PRODUCE HYPERSENSITIVITY REACTIONS, SOME OF WHICH ARE POTENTIALLY LETHAL. [R3, 1110] *MANY BACTERIA BECOME HIGHLY RESISTANT TO SULFONAMIDES DURING THERAPY. ONCE RESISTANCE DEVELOPS, CROSS RESISTANCE TO OTHER SULFONAMIDES IS USUAL. RESISTANCE MAY BE MINIMIZED BY INITIATING TREATMENT PROMPTLY WITH ADEQUATE DOSES AND CONTINUING...FOR SUFFICIENT PERIOD TO ERADICATE INFECTION. /SULFONAMIDES/ [R50, 1308] *DRUG FEVER IS A COMMON UNTOWARD MANIFESTATION OF SULFONAMIDE TREATMENT... INCIDENCE APPROXIMATES 3% WITH SULFISOXAZOLE. ...GENERALLY SUDDEN IN ONSET AND DEVELOPS BETWEEN SEVENTH AND TENTH DAY OF...ADMIN. [R3, 1114] *USE OF SULFISOXAZOLE HAS BEEN ASSOC WITH CLINICAL ACTIVATION OF QUIESCENT SYSTEMIC LUPUS ERYTHEMATOSUS. [R3, 1113] *LESS THAN 0.1% OF PT RECEIVING SULFISOXAZOLE SUFFER SERIOUS TOXIC REACTIONS. BECAUSE OF ITS RELATIVELY HIGH SOLUBILITY IN URINE.../IT/ ONLY INFREQUENTLY PRODUCED HEMATURIA OR CRYSTALLURIA (0.2 TO 0.3%) AND RISK OF ANURIA IS SMALL. ...IT IS ADVISABLE THAT PT TAKING THIS DRUG INGEST AN ADEQUATE QUANTITY OF WATER. [R17, 1060] *INCIDENCE OF RENAL TOXICITY IS LOWER THAN THAT CAUSED BY SULFADIAZINE OR SULFONAMIDE MIXTURES. [R10, 1111] *Maternal Medication usually Compatible with Breast-Feeding: Sulfisoxazole: Reported Sign or Symptom in Infant or Effect on Lactation: Caution in infant with jaundice or G-6-PD /glucose-6-phosphate dehydrogenase/ deficiency, and ill, stressed, or premature infant; appears in infant's milk. /from Table 6/ [R51] *POTENTIAL ADVERSE EFFECTS ON FETUS: May cause jaundice and kernicterus in fetus. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Excreted in low concentrations. Cited by U.S. Pharmacopeia Dispensing Information to be contraindicated in first 2 months of life because of risk of kernicterus, but American Academy of Pediatrics considers safe for breast-feeding. Sulfonamides may cause hemolytic anemia in G6PD /glucose 6-phosphate dehydrogenase/ deficient infants. COMMENTS: Trimethoprimsulfamethoxazole may interfere with folic acid metabolism. FDA Category: C (C = Studies in laboratory animals have revealed adverse effects on the fetus (teratogenic, embryocidal, etc.) but there are no controlled studies in pregnant women. The benefits from use of the drug in pregnant women may be acceptable despite its potential risks, or there are no laboratory animal studies or adequate studies in pregnant women.) /Sulfonamides/ /from table II/ [R52] *Sulfonamides should not be used in the treatment of Group A beta-hemolytic streptococcal tonsillopharyngitis since they may not eradicate streptococci and therefore may not prevent sequelae such as rheumatic fever. /Sulfonamides/ [R16, 2693] *Sulfonamides are also not effective in treating rickettsial, viral, tuberculous, actinomycotic, fungal, or mycoplasmal infections. They are also not effective in the treatment of shigellosis. /Sulfonamides/ [R16, 2693] *Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis, use of sulfonamides is contraindicated in infants up to 2 months of age. Sulfonamides compete for bilirubin binding sites on plasma albumin, increasing the risk of kernicterus in the newborn. Also, because the acetyltransferase system is not fully developed in the newborn, increased blood concentrations of the free sulfonamide can further increase the risk of kernicterus. /Sulfonamides/ [R16, 2694] *Elderly patients may be at increased risk of severe side/adverse effects. Severe skin reactions, generalized bone marrow depression, and decreased platelet count (with or without purpura) are the most frequently reported severe side/adverse effects in the elderly. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients who are receiving diuretics, primarily thiazides, concurrently with sulfamethoxazole. The potential for these problems should also be considered for elderly patients taking other sulfonamide medications. /Sulfonamides/ [R16, 2694] *The leukopenic and thrombocytopenic effects of sulfonamides may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. /Sulfonamides/ [R16, 2694] *Patients with acquired immunodeficiency syndrome (AIDS) may have a grater incidence of side/adverse effects, especially rash, fever, and leukopenia, than do non-AIDS patients. /Sulfonamides/ [R16, 2695] *Effects...acute and reversible myopia; most common ocular side effect, conjunctivitis, optic neuritis, and photosensitivity [R53] *PRIMARY FACTOR RESPONSIBLE FOR RENAL DAMAGE...PRODUCED BY OLDER SULFONAMIDES IS FORMATION AND DEPOSITION OF CRYSTALLINE AGGREGATES IN KIDNEYS...URETERS, OR BLADDER... ANURIA AND DEATH MAY OCCUR IN PT IN WHOM NO...CRYSTALLURIA OR HEMATURIA CAN BE DETECTED AND IN WHOM LESION FOUND...IS TUBULAR NECROSIS... /SULFONAMIDES/ [R3, 1113] *FOCAL OR DIFFUSE NECROSIS OF LIVER DUE TO DIRECT DRUG TOXICITY OR SENSITIZATION OCCURS IN LESS THAN 0.1% OF PT. HEADACHE, NAUSEA, VOMITING, FEVER, HEPATOMEGALY, JAUNDICE...USUALLY APPEAR 3 TO 5 DAYS AFTER SULFONAMIDE ADMIN IS STARTED AND SYNDROME MAY PROGRESS TO ACUTE YELLOW ATROPHY AND DEATH. /SULFONAMIDES/ [R17, 1062] *HYPERSENSITIVITY REACTIONS. AMONG SKIN AND MUCOUS MEMBRANE MANIFESTATIONS...ARE MORBILLIFORM, SCARLATINAL, URTICARIAL, ERYSIPELOID, PEMPHIGOID, PURPURIC, AND PETECHIAL RASHES, AND ERYTHEMA NODOSUM, ERYTHEMA MULTIFORME OF STEVENS-JOHNSON TYPE... /SULFONAMIDES/ [R17, 1062] *EFFECT UPON EYE MOST COMMONLY PRODUCED BY SYSTEMICALLY ADMIN SULFONAMIDE DRUGS HAS BEEN ACUTE AND COMPLETELY REVERSIBLE MYOPIA. /SULFONAMIDES/ [R54] *The sulfonamides readily cross the placenta to the fetus during all stages of gestation. Equilibrium with maternal blood is usually established after 2-3 hr., with fetal levels averaging 70-90% of maternal. Significant levels may persist in the newborn for several days after birth when given near term. The primary danger of sulfonamide administration during pregnancy is manifested when these agents are given close to delivery. Toxicities that may be observed in the newborn include jaundice, hemolytic anemia and, theoretically, kernicterus./Sulfonamides/ [R55, 795] *Sulfonamides are excreted into breast milk in low concentrations. [R55, 797] *Adverse reactions severe enough to require discontinuation of sulfafurazole administration occurred with an incidence of 3.1% in a series of 1002 treated patients. Skin rashes, eosinophilia and drug fever were the common manifestations. [R7, p. V24 P280] *DRUG ERUPTIONS OCCUR MOST OFTEN AFTER FIRST WEEK OF THERAPY... FEVER, MALAISE, AND PRURITUS ARE FREQUENTLY PRESENT SIMULTANEOUSLY. ... SYNDROME SIMILAR TO SERUM SICKNESS...FEVER, JOINT PAIN, URTICARIAL ERUPTIONS, CONJUNCTIVITIS, BRONCHOSPASM, AND LEUKOPENIA ARE OUTSTANDING FEATURES. ... FOCAL OR DIFFUSE NECROSIS OF LIVER DUE TO DIRECT DRUG TOXICITY OR SENSITIZATION OCCURS... HEADACHE, NAUSEA, VOMITING, FEVER, HEPATOMEGALY, JAUNDICE, AND LAB EVIDENCE OF HEPATOCELLULAR DYSFUNCTION...SYNDROME MAY PROGRESS TO ACUTE YELLOW ATROPHY AND DEATH. /SULFONAMIDES/ [R17, 1062] *AMONG OTHER UNTOWARD EFFECTS...ARE GOITER AND HYPOTHYROIDISM, ARTHRITIS, AND VARIOUS NEUROPSYCHIATRIC DISTURBANCES. ... PERIPHERAL.../PRC: NEUROPATHY/ IS VERY RARE. /SULFONAMIDES/ [R3, 1114] *DEVELOPMENT OF ACUTE HEMOLYTIC ANEMIA...MAY NOT BE DEPENDENT ON DOSAGE OR CONCN OF DRUG IN PLASMA. ...EPISODE OCCURS...USUALLY IN FIRST WEEK OF THERAPY. ...VERTIGO...PALLOR, HEPATOSPLENOMEGALY, AND SHOCK MAY DEVELOP SUDDENLY. ... ACUTE RENAL TUBULAR NECROSIS MAY FOLLOW HEMOGLOBINURIA. /SULFONAMIDES/ [R3, 1113] *AMONG SKIN AND MUCOUS MEMBRANE MANIFESTATIONS...ARE MORBILLIFORM, SCARLATINAL, URTICARIAL, ERYSIPELOID, PEMPHIGOID, PURPURIC, AND PETECHIAL RASHES... /SULFONAMIDES/ [R17, 1062] *AGRANULOCYTOSIS...CAN FOLLOW USE OF...SULFONAMIDES. ... COMPLETE SUPPRESSION OF BONE-MARROW ACTIVITY WITH PROFOUND ANEMIA, GRANULOCYTOPENIA, AND THROMBOCYTOPENIA IS EXTREMELY RARE OCCURRENCE WITH SULFONAMIDE THERAPY. ... IT MAY BE FATAL. ... PRIMARY FACTOR RESPONSIBLE FOR RENAL DAMAGE...IS FORMATION AND DEPOSITION OF CRYSTALLINE AGGREGATES IN KIDNEYS, CALYCES, PELVIS, URETERS, OR BLADDER... ANURIA AND DEATH... /SULFONAMIDES/ [R3, 1113] *Early recognition of trimethoprim and sulfonamide-induced aseptic meningitis is important because drug cessation leads to rapid clinical improvement. We present clinical and laboratory findings in two typical cases. In both cases, MRI revealed previously undescribed diffuse white matter abnormalities that resolved within a few months. These MRI findings are important because they may aid in early diagnosis of this condition in the appropriate clinical setting. In addition, the white matter abnormalities suggest an encephalitic component in addition to the meningitis. [R56] *Lyell syndrome following administration of erythromycin-sulfafurazole and morniflumate (letter; comment) [R57] *We identified 40 patients (25 men and 15 women) who developed calculi composed totally or partially of sulfonamides (acetylsulfamethoxazole, sulfadiazine, and acetylsulfisoxazole) between 1980 and 1987. The incidence of sulfonamide stones is less than 1% of stones. Patient characteristics were determined from questionnaires sent to the patients and attending physicians. The majority of patients developed symptoms 1 to 4 weeks after beginning sulfonamide therapy. The bladder was the most common stone location. Obstruction of the urinary system by the acetyl derivatives of the drug is the most serious consequence of sulfonamide therapy. Early recognition of drug-related stones is essential to protect patients from recurrences, reduce the risk of renal complications, and avoid continuing ineffective therapeutic regimens. [R58] *BACKGROUND: The role of T lymphocytes in mediating drug eruptions is uncertain. METHODS: Twenty-four patients with eruptions induced by sulfonamide-related drugs were studied to detect lymphocyte reactivity to drugs. Both the lymphocyte transformation test and limiting dilution analysis were used as assays for drug-reactive lymphocytes. Peripheral blood lymphocytes were expanded in interleukin-2 and tested for reactivity to sulfamethoxazole and furosemide. RESULTS: The lymphocyte transformation test results to sulfamethoxazole, sulfisoxazole, and furosemide were found to be generally unreliable with a high rate of false-negative and false-positive results. However, as determined by limiting dilution analysis, sulfamethoxazole-reactive lymphocytes were detected in the peripheral blood of one patient at a frequency of 1/172,000. This is within the lower range of frequencies of urushiol-reactive T cells in the peripheral blood of patients with allergic contact dermatitis to urushiol (poison ivy). Two sulfonamide-reactive lymphocyte lines were cultured from two patients. Both lines proliferated in response to sulfamethoxazole but not in response to furosemide, suggesting that furosemide dose not cross-react with the sulfonamides. CONCLUSIONS: Lymphocytes reactive to sulfamethoxazole were detected at low frequencies in the peripheral blood of three patients with drug eruptions secondary to administration of sulfamethoxazole. [R59] *A 44 yr old hispanic female was admitted to our hospital on 3/2/94 with a case of possible CNS toxoplasmosis and salmonella bacteremia. That same day, she was started on pyrimethamine 100 mg/day. The liver enzymes were normal. On 3/15/94, sulfisoxazole 4 g/day was added. On 3/16/94, ciprofloxacin 500 mg/day was added for antimicrobial coverage. On 3/18/94, the patient presented with increase in her liver enzymes. On 3/21/94, sulfisoxazole was discontinued. The liver enzyme tests came back to normal gradually. The patient expired on 3/25/94 due to poor prognosis and poor response to antibiotic therapy but unrelated to the adverse drug reactions. [R60] *With a few notable exceptions, most antibiotics can be used with relative safety during pregnancy. Moreover, none of the antibiotics to data has been shown to be teratogenic, although tetracycline may cause yellow-brown discoloration of the deciduous teeth (a fetal effect). Thus, antibiotics should not be withheld from the pregnant woman, especially when indicated for serious, life-threatening infections. [R61] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R62] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *RESONANCE RAMAN SPECTROMETRY WAS APPLIED TO THE DETERMINATIONS OF 8 COLORLESS SULFONAMIDE DRUGS THAT EXHIBITED NO RESONANCE RAMAN EFFECT WITH ARGON ION LASER EXCITATION. THE LIMITS OF DETECTION WERE APPROX 2X10-8 MOLES. SULFISOXAZOLE GAVE COLORED DERIV IN A COMMON CHEM REACTION SYSTEM, AND THE RESONANCE RAMAN SPECTRA OF THE DERIV HAD CHARACTERISTIC SPECTRAL PATTERNS. [R63] *A HIGH PRESSURE LIQUID CHROMATOGRAPHIC METHOD WAS DEVELOPED FOR IDENTIFICATION AND DETERMINATION OF SULFISOXAZOLE IN TABLET, LIQUID, AND OINTMENT DOSAGE FORMS. [R64] *REVERSED-PHASE THIN-LAYER CHROMATOGRAPHY SEPARATION OF 10 KINDS OF SYNTHETIC SULFONAMIDE ANTIBACTERIALS INCL SULFISOXAZOLE IS DESCRIBED. [R65] *A REVERSED-PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) METHOD IS USED TO QUANTITATE N1-ACETYLSULFISOXAZOLE AND THE RELATED MFG IMPURITY SULFISOXAZOLE. A TLC PROCEDURE IS DESCRIBED TO COMPLEMENT THE HPLC QUANTITATION. [R66] *N-BROMOPHTHALIMIDE WAS USED IN DETERMINATION OF SULFISOXAZOLE BY TITRATION. [R67] *THE 25 MHZ NATURAL ABUNDANCE (13)C-NMR SPECTRA ARE REPORTED FOR SULFA DRUGS INCL SULFISOXAZOLE. [R68] *TWO SIMPLE AND SENSITIVE COLORIMETRIC PROCEDURES FOR DETERMINATION OF 8 SULFONAMIDES IN PURE AND TABLET FORM ARE DESCRIBED. [R69] *A POLAROGRAPHIC METHOD FOR THE MICRODETERMINATION OF SULFUR IN ORG SULFUR DRUGS WAS APPLIED SATISFACTORILY TO THE DETERMINATION OF VARIOUS SULFONAMIDES IN COMMERCIAL SAMPLES SUCH AS TABLETS. [R70] *AOAC 983.29. Sulfisoxazole in Drug Tablets, Solutions, and Ointments. Liquid Chromatographic method. [R71] CLAB: *ANALYTICAL METHODS FOR SULFAFURAZOLE. SAMPLE MATRIX: PLASMA. ASSAY PROCEDURE: HIGH PERFORMANCE LIQUID CHROMATOGRAPHY WITH UV DETECTION. LIMIT OF DETECTION: 2.0 MG/L. PENG GW ET AL; RES COMMUN CHEM PATHOL PHARMACOL 18: 233 (1977). [R7, p. V24 278] *AN AUTOMATED COLORIMETRIC METHOD FOR DETERMINATION OF SULFISOXAZOLE IN HUMAN PLASMA AND URINE WAS DEVELOPED AND TESTED IN VITRO AND IN VIVO. THE LOWER LIMIT OF DETECTION WAS 2 MCG/ML. [R72] *A HIGH-PRESSURE LIQ CHROMATOGRAPHIC METHOD THAT USES A MOBILE PHASE WITH THE PH AND IONIC STRENGTH ADJUSTED TO THAT OF BLOOD IS DESCRIBED. THE MOBILE PHASE WAS METHANOL-WATER (5 AND 95%) FOR SULFONAMIDES. THE METHOD PROVIDES QUICK AND RELIABLE LIPOPHILICITY MEASUREMENT. [R73] *SULFONAMIDES WERE DETERMINED IN SWINE LIVER BY COLLISION-INDUCED DISSOCIATION/MASS ANALYZED ION KINETIC ENERGY SPECTROMETRY. [R74] *THE TECHNIQUE OF DIRECT LIQ INTRODUCTION (DLI) LIQ CHROMATOGRAPHY/MASS SPECTROMETRY/MASS SPECTROMETRY (LC/MS/MS) IS USED TO STUDY SULFA DRUGS INCL SULFISOXAZOLE. RESULTS ARE DESCRIBED FOR THE ANALYSIS OF A RAW ORG EXTRACT OF RACEHORSE URINE AND PLASMA CONTAINING RESIDUES OF ADMIN SULFADIMETHOXINE. [R75] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP TR No 138; Route: oral, gavage; Species: rats and mice. NTIS No PB288779/AS. [R76] Storer RD et al; Mutation Research 368 (2): 59-101 1996. Revalidation of the in vitro alkaline elution/rat hepatocyte assay for DNA damage: Improved criteria for assessment of cytotoxicity and genotoxicity and results for 81 compounds. Berman S; New England Journal of Medicine 332: 1560-1565 June 8, 1995. 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Washington, DC: Association of Analytical Chemists, 1990,p. 569-70 R72: WEINFELD RE, LEE TL; J PHARM SCI 68 (NOV): 1387 (1979) R73: BRENT DA ET AL; J MED CHEM 26 (7): 1014 (1983) R74: BRUMLEY WC ET AL; ANAL CHEM 55 (8): 1405 (1983) R75: HENION JD ET AL; ANAL CHEM 54 (3): 451 (1982) R76: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.27 RS: 64 Record 90 of 1119 in HSDB (through 2003/06) AN: 809 UD: 200302 RD: SRP review on 02/19/1988 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLENEDIAMINE-TETRAACETIC-ACID- SY: *ACETIC ACID, 2,2',2'',2'''-(1,2-ETHANEDIYLDINITRILO)TETRAKIS-; *ACETIC ACID, (ETHYLENEDINITRILO)TETRA-; *ACIDE-ETHYLENEDIAMINETETRACETIQUE- (FRENCH); *AI3-17181-; *Caswell-No-438-; *CELON-A-; *CELON-ATH-; *CHEELOX-; *CHEELOX-BF-ACID-; *CHEMCOLOX-340-; *COMPLEXON-II-; *3,6-DIAZAOCTANEDIOIC ACID, 3,6-BIS(CARBOXYMETHYL)-; *EDATHAMIL-; *EDETIC-; *EDETIC-ACID-; *EDTA-; *EDTA-ACID-; *EDTA- (CHELATINGAGENT); *ENDRATE-; *EPA-Pesticide-Chemical-Code-039101-; *N,N'-1,2-ETHANEDIYLBI-; *Ethylenebisiminodiacetic-Acid-; *ETHYLENEDIAMINETETRAACETIC-ACID-; *ETHYLENEDIAMINE-N,N,N',N'-TETRAACETIC-ACID-; *GLYCINE, N,N'-1,2-ETHANEDIYLBIS(N-(CARBOXYMETHYL)-; *HAVIDOTE-; *METAQUEST-A-; *NERVANAID-B-ACID-; *NULLAPON-B-ACID-; *NULLAPON-BF-ACID-; *PERMA-KLEER-50-ACID-; *SEQUESTRENE-AA-; *SEQUESTRIC-ACID-; *SEQUESTROL-; *TETRINE-ACID-; *TITRIPLEX-; *TRICON-BW-; *TRILON-BW-; *Universne-Acid-; *VERSENE-; *VERSENE-ACID-; *VINKEIL-100-; *WARKEELATE-ACID- RN: 60-00-4 RELT: 4072 [DISODIUM CALCIUM EDTA]; 5003 [TETRASODIUM EDTA] MF: *C10-H16-N2-O8 SHPN: NA 9117; Ethylenediaminetetraacetic acid; EDTA STCC: 49 669 10; Ethylenediaminetetraacetic acid ASCH: Trisodium ethylenediaminetetraacetate trihydrate; 150-38-9 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ETHYLENEDIAMINE WITH FORMALDEHYDE AND SODIUM CYANIDE OR HYDROGEN CYANIDE FOLLOWED BY HYDROLYSIS TO PRODUCE TETRASODIUM SALT. [R1] *ETHYLENEDIAMINE IS CONDENSED WITH SODIUM MONOCHLOROACETATE WITH AID OF SODIUM CARBONATE. AQ SOLN OF REACTANTS IS HEATED TO ABOUT 90 DEG C FOR 10 HR, THEN COOLED AND ACIDIFIED WITH HYDROCHLORIC ACID WHEREUPON THE ACID PRECIPITATES. SALTS OF ACID ARE KNOWN AS EDETATES. [R2, 1260] *Heating tetrahydroxyethylethylenediamine with sodium hydroxide or potassium hydroxide with calcium oxide catalyst. [R3] MFS: +Ciba-Geigy Corporation, Hq, Saw Mill River Road, Ardsley, NY 10502, (914) 478-3131; Dyestuffs and Chemicals Division; Production site: McIntosh, AL 36553 [R4, 521] +Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 [R4, 430] +W R Grace and Co, Hq, Grace Plaza, 1114 Ave of the Americas, New York, NY 10036, (212) 819-5500; Grace Specialty Chemicals Co; Organic Chemicals Division, 55 Hayden Ave, Lexington, MA 02173; Production site: Poisson Ave, Nashua, NH 03061 [R4, 521] OMIN: *IN DOGS, IN DISSOLUTION THERAPY OF BILE DUCT STONES WITH EDTA SOLN THE PH VALUE HAD TO BE SHIFTED TO VALUES AROUND 9 AND ADMIXTURE OF AMINO ACIDS AND BILE SALTS SEEMED TO IMPROVE DISSOLUTION CONDITIONS. AN ALKALINE MILIEU OF PH 9.5 PER SE DID NOT CAUSE TISSUE TOXICITY. [R5] *ADDITION OF EDTA TO CONTACT LENS STORING AND RINSING SOLN PREVENTS THE INACTIVATION OF THE PROTEIN REMOVER WHICH IS PRESENT IN THE FORMULATION. [R6] *THE VASE-LIFE OF CUT FLOWERS STORED AT LOW TEMP WAS EXTENDED BY TREATING THE FLOWERS, ESPECIALLY CARNATIONS, BEFORE STORING WITH SOLN CONTAINING EDTA, SILVER NITRATE, SODIUM THIOSULFATE, AND SUCROSE. [R7] *THE CONCENTRATION OF EDTA-TRIS USED AS LAVAGE TO TREAT OTITIS EXTERNA, CYSTITIS OR OTHER PERSISTENT INFECTIONS IN DOGS AND CATS, WAS FOUND TO PREVENT THE GROWTH OF PSEUDOMONAS AERUGINOSA, STAPHYLOCOCCUS AUREUS AND BETA STREPTOCOCCI WHEN PRESENT IN GROWTH MEDIA. [R8] *EDETIC ACID HAS INCR ANTIBACTERIAL EFFECTS OF BENZALKONIUM AND CHLOROCRESOL, AS WELL AS PREVENTING RESISTANCE IN VITRO TO NEOMYCIN BY RESISTANT STRAINS OF STAPHYLOCOCCUS AUREUS. COPPER, MANGANESE, ZINC UTILIZATION IN CHICKS IS ENHANCED BY PRIOR CHELATION WITH EDETIC ACID. [R9] *ACID, RATHER THAN ANY SALT, IS FORM MOST POTENT IN REMOVING CALCIUM FROM SOLN. IT MAY BE ADDED TO SHED BLOOD TO PREVENT CLOTTING. IT IS ALSO USED IN PHARMACEUTICAL ANALYSIS AND REMOVAL OR INACTIVATION OF UNWANTED IONS IN SOLN. [R2, 1260] *EDTA /ETHYLENEDIAMINETETRAACETIC ACID/ WAS USED AS ANAL REAGENT AND AS CHEM IN MFR OF DYES AS EARLY AS 1935. [R10] USE: *AS ANTIOXIDANT IN FOODS [R11] *CHELATING AGENT IN BOILER AND COOLING WATER, DETERGENTS FOR HOUSEHOLD AND TEXTILE USE, INDUST GERMICIDES, AND METAL CUTTING FLUIDS; CHEM INT FOR MICRONUTRIENTS FOR AGRICULTURAL PURPOSES; BLEACHING AGENT IN COLOR FILM PROCESSING; CHELATING AGENT IN ELECTROLESS NICKEL PLATING; ETCHING AGENT IN METAL FINISHING AND SEMICONDUCTOR PRODN; CHELATING AGENT IN WOOD PULPING PROCESSES; ACTIVATOR IN BUTADIENE-STYRENE COPOLYMERIZATION; CHELATING AGENT IN FOOD, PHARMACEUTICALS AND COSMETICS AND FOR GAS SCRUBBING; COMPONENT OF BLOOD ANTICOAGULANTS [R1] +MEDICATION +MEDICATION (VET) +Liq soaps, shampoos, agricultural chem sprays; metal plating, decontamination of radioactive surfaces, metal deactivator in vegetable oil, oil emulsions, pharmaceutical products, etc; eluting agent in ion exchange, to remove insoluble deposits of calcium and magnesium soaps; in textiles to improve dyeing, scouring; clarification of liq, analitical chemistry, spectrophotometric titration, aid in reducing blood cholesterol, food additive (preservative) [R3] *Use in cadmium determination [R12, p. V4 393] *Use in cerium titration [R12, p. V5 324] *Use in dietary fiber analysis [R12, p. V7 634] *Is effective in detaching biofilm [R13] *ETHYLENEDIAMINETETRAACETIC ACID (EDTA, EDATHAMIL), ITS SODIUM SALT (DISODIUM EDETATE, NA2EDTA), and ... CLOSELY RELATED CMPD HAVE BEEN USED AS INDUSTRIAL AND ANALYTICAL REAGENTS BECAUSE THEY CHELATE MANY DIVALENT AND TRIVALENT METALS. [R14, 1619] *... EDTA ... AIDS IN THE FLAVOR RETENTION OF STORED BEVERAGES AND ... HAS BEEN SHOWN EFFECTIVE IN CONTROLLING CORROSION IN CANNED CARBONATED BEVERAGES. ... EXPERIMENTALLY, OFF-FLAVOR /IN WHOLE MILK/ HAS BEEN SHOWN TO BE SUPPRESSED BY ADDING TO MILK AT LEAST 5 PARTS OF EDTA PER PART COPPER. ... EDTA ENHANCES THE FOAMING PROPERTIES OF RECONSTITUTED SKIM MILK. ... EDTA WILL RETARD NITRIC OXIDE-HEMOGLOBIN FORMATION IN CURED MEATS BY CONTROLLING THE EFFECTS OF METAL IONS. [R15] *MOST OF THE OFFICIAL DRUGS CONTAINING CALCIUM AND THE ZINC CONTENT OF ZINC STEARATE ARE ANALYZED BY TITRATION WITH A STANDARD EDTA SOLUTION. [R2, 183] CPAT: *ESSENTIALLY 100% AS A CHELATING AGENT (INCLUDES FREE ACID PLUS SALTS) [R1] PRIE: U.S. PRODUCTION: *(1979) 4.49X10+9 G [R1] *(1982) 2.82X10+9 G [R1] *(1985) 4.49X10+9 g [R16] U.S. IMPORTS: *(1978) ND [R1] *(1982) ND [R1] *(1987) ND U.S. EXPORTS: *(1978) ND [R1] *(1982) ND [R1] *(1987) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE CRYSTALLINE POWDER [R2, 1260]; *Colorless crystals [R3] MP: *Decomp at 240 deg C [R17, 1314] MW: *292.28 [R11] DSC: +pKa = 0.26 [R18] SOL: *0.50 G/L IN WATER AT 25 DEG C [R11]; *SOL IN SOLN OF ALKALI HYDROXIDES [R2, 1260]; *Insol in common organic solvents [R3]; +water solubility = 1X10+3 mg/l @ 25 deg C [R19] SPEC: +IR: 2:303F (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R20]; +NMR: 3:2D (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R20] OCPP: *DECOMP AT 220 DEG C [R11] *Neutralized by alkali metal hydroxides to form a series of water-soluble salts containing from one to four alkali metal cations. [R3] *Decomposition at 240 deg C [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Some may burn but none ignite readily. Those substance designated with a "P" may polymerize explosively when heated or involved in a fire. Containers may explode when heated. Some may be transported hot. [R22] +Health: Inhalation of material may be harmful. Contact may cause burns to skin and eyes. Inhalation of asbestos dust may have a damaging effect on the lungs. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control may cause pollution. [R22] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. [R22] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R22] +Evacuation: Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R22] +Fire: Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Do not scatter spilled material with high pressure water streams. Dike fire-control water for later disposal. Fire involving tanks: Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from engulfed in fire tanks. [R22] +Spill or leak: Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent dust cloud. Avoid inhalation of asbestos dust. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Small spills: Take up with sand or other noncombustible absorbent material and place into containers for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Cover powder spill with plastic sheet or tarp to minimize spreading. Prevent entry into waterways, sewers, basements or confined areas. [R22] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R22] DCMP: *When heated to decomp it emits toxic fume of /nitrogen oxides/. [R17, 1341] SSL: *FREE ACID IS LESS STABLE THAN ITS SALTS, DECARBOXYLATES ABOVE 150 DEG C; STABLE ON STORAGE ... [R11] DISP: *At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. [R23] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *... The free acid or the sodiun salt of ... /ethylenediamine tetraacetic acid/ are rather toxic ... the less toxic calcium disodium form ... is more frequently used. [R24] NTOX: */ETHYLENEDIAMINETETRAACETIC ACID/ ... PRODUCED LOWERED SERUM CALCIUM LEVELS, IF ADMIN RAPIDLY TO ANIMALS. CHANGE IN SERUM CALCIUM WAS SMALL OR ABSENT FOLLOWING GRADUAL DOSING. [R10] *... TWENTY TO 40 MG EDTA INJECTED DURING EMBRYOGENESIS CAUSED TAIL DEFECTS AND POLYDACTYLY IN RAT FETUSES. ... CLEFT PALATE, BRAIN AND EYE DEFECTS AND SKELETAL ANOMALIES /WERE PRODUCED/ IN RAT FETUSES EXPOSED TO 2 OR 3% EDTA IN THE DIET AFTER DAY 6 OF GESTATION. BY ADDING 1000 PPM OF ZINC TO THE EXPERIMENTAL DIET PREVENTED THE DEFECTS. [R25] *EDTA LEADS TO MORPHOLOGICAL CHANGES OF CHROMATIN AND CHROMOSOME STRUCTURE IN PLANT AND ANIMAL CELLS. A WEAK INDUCTION OF GENE MUTATIONS HAS BEEN REPORTED. [R26] *UNICELLULAR ALGA, POTERIOOCHROMONAS MALHAMENSIS, WAS EXPOSED TO INORG LEAD OR TRIETHYL LEAD AND SIMULTANEOUSLY TREATED WITH LEAD ANTIDOTES. SOME OF THE ANTIDOTES ALONE SLIGHTLY TO SEVERELY INHIBITED ALGAL GROWTH (BAL, EDTA, AND SALTS). [R27] *THE EFFECT OF EDTA (ETHYLENEDIAMINETETRAACETATE) ON THE ANTIMICROBIAL ACTIVITY OF 10% SODIUM SULFACETAMIDE SOLUTIONS WAS EVALUATED IN THIS STUDY BY KILL RATE AND MINIMUM CONCN (MIC). EDTA IMPROVES THE KILL RATE, BUT NOT THE MIC, FOR THE PSEUDOMONAS, SERRATIA, AND CANDIDA SPECIES REGARDLESS OF THE PRESERVATIVE. [R28] *THE INFLUENCE OF CHELATING AGENTS ON THE TOXICITY OF OXYGEN AT ELEVATED TENSION WAS STUDIED IN MICE. NO INCREASE IN TOXIC EFFECTS WAS OBSERVED AFTER ADMIN OF EDTA. [R29] *THE EFFECTIVENESS OF EDTA AND VARIOUS CHELATING AGENTS FOR RELEASING GLUTATHIONE FROM ITS CADMIUM COMPLEXES IN HEMOLYZED ERYTHROCYTES WAS STUDIED. EDTA WAS EFFECTIVE. [R30] *TOTAL MYOCARDIAL CALCIUM CONTENT OF RATS TREATED WITH ADRIAMYCIN WAS VERY HIGH. TREATMENT WITH EDTA DECREASED CALCIUM LEVELS ALMOST TO NORMAL VALUES; HOWEVER THE HISTOLOGICAL ADRIAMYCIN-INDUCED CARDIAC ALTERATIONS WERE NOT PREVENTED. [R31] *CONGENITAL DEFECTS IN THE QUAIL WERE PRODUCED WITH EDTA. [R25] ETXV: *Toxicity Threshold (Cell Multiplication Inhibition Test) Entosiphon sulcatum (protozoa) 36 mg/l /Conditions of bioassay not specified/; [R32] *Toxicity Threshold (Cell Multiplication Inhibition Test) Uronema parduczi Chatton-Lwoff (protozoa) 17 mg/l /Conditions of bioassay not specified/; [R32] *Toxicity Threshold (Cell Multiplication Inhibition Test) Scenedesmus quadricauda (green algae) 11 mg/l /Conditions of bioassay not specified/; [R32] *Toxicity Threshold (Cell Multiplication Inhibition Test) Microcystis aeruginosa (algae) 76 mg/l /Conditions of bioassay not specified/; [R32] *LC50 (Lepomis macrochirus) bluegill 159 mg/l/96 hr; 96 hr no adverse effect level: 100 mg/l /Static bioassay/; [R32] *Toxicity Threshold (Cell Multiplication Inhibition Test) Pseudomonas putida (bacteria) 105 mg/l /Conditions of bioassay not specified/; [R32] NTP: +A bioassay of the chelating agent trisodium ethylenediaminetetracetate trihydrate for possible carcinogenicity was conducted by admin the test material in feed to Fischer 344 rats and B6C3F1 mice. The chem was admin to 560 males and 50 females of each species at low and high concn, 3,750 and 7,500 ppm, for 103 wk. Matched control groups were composed of 20 males and 20 females of each species. No cmpd related signs of clinical toxicity were noted. Although a variety of tumors occurred among test and control animals of both species, no tumors were related to treatment. Since survival was satisfactory and showed no consistent variation among test and control groups, the absence of treatment related tumors could not be attributed to early mortality. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. /Trisodium ethylenediaminetetraacetate trihydrate/ [R33] ADE: *EDTA is essentially not metabolized by the human body and it is rapidly excreted in the urine. About 50% of EDTA admin iv is excreted within 1 hr and 90% within 7 hr. EDTA and its metal chelates do not permeate the cellular membrane to a significant extent; thus most of the EDTA remains in the extracellular fluids until excreted into the urine. [R24] ACTN: *ALL KNOWN PHARMACOLOGICAL EFFECTS OF EDTA RESULT FROM FORMATION OF CHELATES WITH DIVALENT AND TRIVALENT METAL /IONS/ IN THE BODY. [R14, 1620] *EFFECTS ON RAT LIVER GLUCOCORTICOID RECEPTOR IN VITRO WAS STUDIED. AT 4 DEG C, 10 MMOLE EDTA HAD A STABLIZING EFFECT ON UNBOUND HEPATIC GLUCOCORTICOID RECEPTORS. APPARENTLY, ENDOGENOUS METAL IONS ARE INVOLVED IN THE PROCESSES OF GLUCOCORTICOID-RECEPTOR COMPLEX STABILIZATION AND TRANSFORMATION. [R34] *Ethylenediaminetetraacetic acid incr the absorption of a number of agents. This effect is nonspecific because EDTA incr the absorption of bases, acids, and neutral cmpd. It appears that by chelating calcium, EDTA causes a general incr in membrane permeability. [R35] INTC: *... INCR ABSORPTION OF DRUGS ... OCCURS IN PRESENCE OF ... ETHYLENEDIAMINETETRAACETIC ACID (EDTA). WHEN GIVEN ORALLY ... (100-500 MG/KG IN RATS), THE CHELATOR INCR ... RATE OF ABSORPTION OF HEPARIN, SULFOPOLYGLUCIN, MANNITOL, INULIN, DECAMETHONIUM, SULFANILIC ACID ... PHENOL RED, ALL LIPID-INSOL SUBSTANCES WHICH ORDINARILY ARE POORLY ABSORBED FROM GI TRACT. THE WIDE VARIETY OF THE CHEMICAL STRUCTURES OF THESE SUGGESTS THAT THE CHELATING AGENT IS ACTING IN A NONSPECIFIC WAY AND IS NOT AFFECTING THE PHYSICAL OR CHEMICAL STATE OF THE COMPOUNDS WITHIN THE INTESTINE ... /THERE IS/ DIRECT EVIDENCE THAT EDTA ACTS BY INCREASING THE PERMEABILITY OF THE INTESTINAL EPITHELIUM ... PERHAPS EDTA ALTERS PERMEABILITY BY INCREASING THE SIZE OF THE MEMBRANE PORES OR BY WIDENING THE SPACES BETWEEN THE EPITHELIAL CELLS THROUGH THE REMOVAL OF CALCIUM IONS. [R36] *THE EFFECTS OF EDTA ON CONTRACTILE RESPONSES OF HAMSTER CREMASTER ARTERIOLES AND RAT AORTIC STRIPS TO EPINEPHRINE (EPI) OR NOREPINEPHRINE (NOR) WERE EXAMINED. COMPARABLE CONTRACTILE RESPONSES WERE ELICITED BY LOWER EPI OR NOR CONCN IN PRESENCE THAN IN ABSENCE OF EDTA. INDIVIDUAL RESPONSES WERE MAINTAINED IN THE PRESENCE OF EDTA BUT RAPIDLY DECLINED IF EDTA WAS NOT PRESENT. APPARENTLY, OXIDATION OF EPI AND NOR REDUCES APPARENT VASCULAR REACTIVITY AND EDTA PREVENTS OR DELAYS THE REDUCTION. [R37] *EDTA INFLUENCES CHROMOSOME BREAKAGE BY MUTAGENIC AGENTS. WHEN APPLIED IN COMBINATION WITH CHEMICAL MUTAGENS, EDTA ENHANCES MUTAGEN-INDUCED ABERRATION FREQUENCIES. THIS HAS BEEN DEMONSTRATED FOR MANY GENE LOCI IN DROSOPHILA MELANOGASTER, CHLAMYDOMONAS REINHARDI, NEUROSPORA CRASSA AND ZEA MAYS. EDTA INTERFERES WITH DNA REPAIR PROCESSES THAT TAKE PLACE AFTER EXPOSURE TO MUTAGENS. IN ESCHERICHIA COLI OR MICROCOCCUS RADIODURANS AS WELL AS IN CHINESE HAMSTER CELLS, THE FAST REPAIR COMPONENT DETECTABLE AFTER TREATMENT WITH IONIZING RADIATION OR BLEOMYCIN IS INHIBITED BY EDTA. [R26] *... vanadium toxicity in chicks was alleviated by feeding ... ethylenediaminetetraacetic acid ... [R38] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anticoagulants; Antidotes; Chelating Agents [R39] +MEDICATION (VET): PHARMACEUTIC AID (CHELATING AGENT) IN LEAD AND HEAVY METAL POISONING IN FARM ANIMALS. [R11] *EDTA HAS BEEN SUCCESSFULLY USED IN THE TREATMENT OF LEAD AND VANADIUM POISONING. IN VIVO STUDIES IN RATS REVEAL SOME BENEFICIAL EFFECTS OF EDTA IN COPPER POISONING. /CALCIUM DISODIUM EDTA/ [R40] *PRELIMINARY RESULTS FROM THE USE OF EDTA PLUS ZINC AS THERAPY OF LEAD INTOXICATION ARE DISCUSSED. /CALCIUM DISODIUM EDTA/ [R41] *EDTA LEAD-MOBILIZATION TEST HAS PROVED TO BE A SENSITIVE INDICATOR OF EXCESSIVE BODY STORES OF LEAD. THIS TEST WAS USED TO EVALUATE CUMULATIVE PAST LEAD ABSORPTION IN 48 MEN DIAGNOSED AS HAVING ESSENTIAL HYPERTENSION, A DISEASE CONSIDERED A POSSIBLE COMPLICATION OF LEAD POISONING. /CALCIUM DISODIUM EDTA/ [R42] *5 AGENTS INCLUDING EDTA WERE EVALUATED FOR THEIR ABILITY TO DETOXIFY PERIODONTALLY INVOLVED DISEASED HUMAN TOOTH ROOT SURFACES. EXPOSURE TO 15% EDTA PARTIALLY ELIMINATED THE ENDOTOXIN. [R43] *PRETREATMENT OF THE HUMAN TEETH WITH EDTA-STRONTIUM CHLORIDE AT PH 6 DECREASED THE DISSOLUTION OF ENAMEL BY A SUBSEQUENT ACID ETCHING. [R44] +Treatment of chlorosis. [R3] +Use externally in solution or paste to treat skin lesions in chromium-exposed electroplating workers; in endodontic therapy [R24] WARN: *Although chelation therapy with EDTA has been found effective in chronic lead intoxication, there are some doubts whether it is valid for the treatment of acute lead poisoning, esp in the case of lead encephalopathy, where the admin of the chelant has occasionally triggered the deterioration of clinical conditions. ... There is a possibility that most side effects of EDTA are due to the chelation of endogenous essential metals, esp of zinc, and that supplementation of zinc during chelation therapy may be effective in reducing the toxicity of this chelant. /Calcium disodium EDTA/ [R24] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *The primary sources of ethylenediamine tetraacetic acid (EDTA) released to the environment are probably domestic sewage and industrial effluents because of EDTA's detergent chelating applications. Other sources of release to the environment may include use of herbicides containing EDTA and land disposal of products which contain EDTA. If released to soil, EDTA is expected to complex with trace metals and alkaline earth metals present in the soil, thereby causing an increase in the total solubility of the metals. EDTA may eventually predominate as the Fe(III) chelate in acidic soils and as the Ca chelate in alkaline soils. Biodegradation of EDTA in aerobic soils is the dominant removal mechanism, although biodegradation in anaerobic soils is negligible. In various soils common values for mineralization of 2-4 ppm EDTA are 13-45% after 15 weeks and 65-70% after 45 weeks. EDTA and its chelates are expected to leach readily through soil and significant volatilization from soil is not expected. If released to water, EDTA is expected to complex with trace metals and alkaline earth metals. Biodegradation of EDTA is expected to take place relatively slowly under aerobic conditions and to be negligible under anaerobic conditions. Cometabolism has been suggested as the mechanism for EDTA biodegradation. Compounds identified as possible biodegradation products of the ammonium ferric chelate of EDTA are as follows: ethylenediamine triacetic acid (ED3A), iminodiacetic acid (IDA), N,N-ethylenediamine diacetic acid (N,N-EDDA), N,N'-EDDA, ethylenediamine monoacetic acid (EDMA), nitrilotriacetic acid (NTA) and glycine. EDTA may react with photochemically generated hydroxyl radicals (half-life 229 days) and it may photodegrade. The following photodegradation products of Fe(III)-EDTA have been identified: carbon monoxide, formaldehyde, ED3A, N,N-EDDA, N,N'-EDDA, IDA, EDMA and glycine. EDTA is not expected to bioaccumulate in aquatic organisms, adsorb to suspended solids or sediments or volatilize from water surfaces. If released to the atmosphere, EDTA should adsorb to particulate matter and appears to have the potential to photolyze. The most probable routes of human exposure to EDTA are ingestion and dermal contact since EDTA is used as a food additive, in herbicides, in pharmaceuticals and in a variety of consumer products (see also USE). Workers involved in the manufacture or use of EDTA may be exposed by inhalation or dermal contact. (SRC) NATS: *Ethylenediamine tetraacetic acid (EDTA) is not expected to occur naturally in the environment(SRC). ARTS: *The primary sources of ethylenediamine tetraacetic acid (EDTA) released to the environment are probably domestic sewage and industrial effluents(1,SRC). EDTA has numerous industrial applications and may be released from a wide variety of industrial sources (1,SRC). Detergent preparations are probably the predominant source of EDTA found in domestic sewage, contributing an estimated 100 ppb to the total concentration of EDTA in average sewage streams, and smaller amounts probably originate from food and other consumer products containing EDTA(1). Other sources of release to the environment may include use of herbicides containing EDTA and land disposal of products which contain EDTA(SRC). [R45] FATE: *TERRESTRIAL FATE: If released to soil, ethylenediamine tetraacetic acid (EDTA) is expected to complex with trace metals and alkaline earth metals present in the soil, thereby causing an increase in the total solubility of the metals. EDTA may eventually predominate as the Fe(III) chelate in acidic soils and as the Ca chelate in alkaline soils. Biodegradation of EDTA in aerobic soils is the dominant removal mechanism although biodegradation is negligible in anaerobic soils. In various aerobic soils common values for mineralization of 2-4 ppm EDTA are 13-45% after 15 weeks and 65-70% after 45 weeks. EDTA chelates of Cu, Zn, Cd, Mn, Ca, and Fe have been found to degrade equally in soil, while Ni-EDTA has been found to degrade more slowly. EDTA and its chelates are expected to readily leach through soil and significant volatilization from soil is not expected. (SRC) *AQUATIC FATE: If released to water, ethylenediamine tetraacetic acid (EDTA) is expected to complex with trace metals and alkaline earth metals present in water thereby causing an increase in the total solubility of the metals. Results of biodegradation screening studies indicate that biodegradation of EDTA in aerobic waters would take place relatively slowly and would be negligible under anaerobic conditions. Compounds identified as possible biodegradation products of the ammonium ferric chelate of EDTA are as follows: ethylenediamine triacetic acid (ED3A), iminodiacetic acid (IDA), N,N-diethylenediamine diacetic acid (N,N-EDDA), N,N'-EDDA, ethylenediamine monoacetic acid (EDMA), nitrilotriacetic acid (NTA) and glycine(1). EDTA may react with photochemically generated hydroxyl radicals (half-life 229 days(2,3)) and it may photodegrade. The following photodegradation products of Fe(III)-EDTA have been identified: carbon monoxide, formaldehyde, ED3A, N,N-EDDA, N,N'-EDDA, IDA, EDMA, and glycine(4,5). EDTA is not expected to bioaccumulate in aquatic organisms, adsorb to suspended solids or sediments or volatilize from water surfaces. (SRC) [R46] *ATMOSPHERIC FATE: If released to the atmosphere, ethylenediamine tetraacetic acid (EDTA) should adsorb to particulate matter and appears to have the potential to photolyze(SRC). BIOD: *Aerobic degradation of 20 mg/l ethylenediamine tetraacetic acid (EDTA) inoculated with activated sludge was observed to be < 5% after 21 days. Removal was attributed to biodegradation after comparing results to those found in sterilized solutions(1). Results of some aerobic biodegradation screening studies are as follows: Sturm test, initial concn approx. 10 mg/l, after 28 days 28% theo CO2 evolved; Modified OEDC test, initial concn 3-20 mg/l, acclimation 10 days, after 19 days incubation 10% DOC removed; Closed Bottle test, initial concn approx 1 mg/l, after 30 days 3% TBOD consumed(2). EDTA incubated in E aerobic sediments was 9-15% decomposed after 10 weeks(3). Cometabolism has been suggested as the mechanism for EDTA biodegration(3). Compounds identified as possible biodegration products of the ammonium ferric chelate of EDTA by a mixed microbial population from an aerated lagoon are: ethylenediamine triacetic acid (ED3A), iminodiacetic acid (IDA), N,N-ethylenediamine diacetic acid (N,N-EDDA), N,N'-EDDA, nitrilotriacetic acid (NTA), and glycine. In this study little or no degration was observed in sterilized cultures(4). Negligible biodegradation of EDTA is reported under anaerobic conditions in sediment and soil(3). The extent of biodegradation of EDTA in soils is reported to vary among soils with biodegradation rates depending upon environmental conditions such as pH, soil texture, microbial population as well as others(5). In various aerobic soils, common values for 2-4 ppm of added EDTA mineralized were 13 to 45% after 15 weeks and 65 to 70% after 45 weeks(5). After 7 weeks incubation of 4 ppm EDTA in soil under aerobic conditions at 20 deg C 6.5% CO2 evolved and in autoclaved soil 0.5% CO2 evolved(3). EDTA chelates of Cu, Zn, Cd, Mn, Ca and Fe were equally degraded in soil after 18 days, (approx 20% CO2 evolved) while Ni-EDTA degraded more slowly (11% CO2 evolved)(3). !o [R47] ABIO: *Ethylenediamine tetraacetic Acid (EDTA) is capable of complexing with most of the important trace metals and alkaline earth metals in the environment, thus causing an increase in the total solubility of the metals(1). Analysis of cation-EDTA equilibria reactions suggests that EDTA will eventually predominate as the iron (III) (Fe) chelate in acidic soils and as the calcium (Ca) chelate in alkaline soils(2). EDTA, particularly as the Fe(III) chelate, is known to photodegrade(2). The following photodegradation products of Fe(III)-EDTA have been identified: carbon monoxide, formaldehyde, ethylenediaminetriacetic acid (ED3A), iminodiacetic acid (IDA), N,N-ethylendiaminediacetic acid (N,N-EDDA), N,N'-EDDA, ethylenediaminediacetic acid (EDMA) and glycine(2,3). The half-life for EDTA reacting with photochemically produced hydroxyl radicals in water has been calculated to be 229 days using a measured reaction rate constant of 3.5X10+9 mol/l sec(4) and an ambient hydroxyl radical concn of 1X10-17 mol/l(5). The half-life for EDTA vapor in the atmosphere reacting with photochemically generated hydroxyl radicals has been calculated to be 3.01 days using a calculated reaction rate constant of 3.34X10+5 cu cm/molecule sec at 25 deg C and an ambient hydroxyl radical concn of 8.0X10+5 mol/l(6). [R48] +The rate of photolysis of the iron(III) complex of ethylenediamine tetraacetic acid was analyzed. An aqueous solution of the complex was illuminated in a Xenotest 1200 apparatus. Using a sun spectrum from 60 deg N (Stockholm latitude), the half-life was calculated to be 11.3 min for the 1:1 complex dissolved in the top layer of a water body and illuminated at the yearly max of sunlight in the specified area. [R49] BIOC: *On the basis of carbon-14 retention, the whole body bioconcentration factor (BCF) for ethylenediamine tetraacetic acid (EDTA) in bluegill (Lepomis macrochirus) has been measured to be < 2(1). Based on a water solubility of 500 mg/l for EDTA at 25 deg C (2), a BCF of 19 has been calculated(SRC). These BCF values suggest that EDTA will not bioaccumulate in aquatic organisms(SRC). [R50] KOC: +Ethylenediamine tetraacetic acid (EDTA) and complexes of EDTA with alkaline earth metals and trace metals have exhibited negligible adsorption to silica, humic acid, kaolin, kaolinite (only EDTA studied), river sediments and humus solids(1,2). EDTA is reported to readily leach in soil(3). [R51] VWS: *Essentially complete dissociation of ethylenediamine tetraacetic acid (EDTA) under environmental conditions (pH 5-10) as indicated by pKa1=0.26, pKa2=0.96, pKa3=2.60 and pKa4=2.76(1), suggests that volatilization from water or soil would not be significant(SRC). No volatilization of EDTA was detected during a degradation study in soil(2). [R52] WATC: +During 1974, ethylenediamine tetraacetic acid (EDTA) was identified in the Lea River (England) at concentrations ranging from approximately zero to 1120 ppb(1). [R45] EFFL: +During 1974, ethylenediamine tetraacetic acid (EDTA) was identified in the effluent from the Rye Meads (England) sewage treatment plant at concentrations ranging from 200 ppb to 1200 ppb(1). [R45] RTEX: *The most probable routes of human exposure to ethylenediamine tetraacetic acid (EDTA) would be ingestion and dermal contact since EDTA is used as a food additive, in herbicides, in pharmaceuticals and in a variety of consumer products. Workers involved in the manufacture or use of EDTA may be exposed by inhalation and dermal contact. (SRC) *A National Occupational Hazard Survey (NOHS) (1973-74) estimates that 122,438 workers are exposed to ethylenediamine tetraacetic acid (EDTA)(1). A more recent (1985) National Occupational Exposure Survey (NOES) estimates that 36,067 workers are exposed to EDTA; however, this figure does not include the number of workers exposed to tradename products containing EDTA(2). [R53] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *FAO/WHO ACCEPTABLE DAILY INTAKE: 0-2.5 MG/KG BODY WT. [R54] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R55] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5,000 lb or 2270 kg. The toll free telephone number of the NRC is (800) 424-8802; in the Washington metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.6 (section IV. D.3.b). [R56] FIFR: *Unless designated as an active ingredient in accordance with paragraph (b) or (c) of this section, this substance, when used in antimicrobial products, is considered inert, having no independent pesticidal activity. The percentage of such an ingredient shall be included on the label in the total percentage of inert ingredients. [R57] FDA: *Ethylenediamine tetraacetic acid is an indirect food additive for use only as a component of adhesives. [R58] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EDTA IN PICKLED VEGETABLES WAS IDENTIFIED BY GAS-LIQ CHROMATOGRAPHY AND CONFIRMED BY MASS FRAGMENTOGRAPHY AFTER CONVERSION TO ITS TETRAMETHYL ESTER. [R59] *A SPECTROPHOTOMETRIC METHOD FOR DETERMINING EDTA IN FRESHWATER IS PRESENTED. THE SENSITIVITY OF THE METHOD IS 10 UG. [R60] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: HART JR; COSMET TOILETRIES 98 (4): 54-8 (1983); USE OF EDTA-TYPE CHELATING AGENTS AND THEIR SALTS IN SHAMPOOS, LIQUID SOAPS, SKIN CLEANERS, CREAMS AND LOTIONS, AND OTHER PRODUCTS ARE REVIEWED. NTP TR No 011; Route: oral in feed; Species: rats and mice. NTIS No PB270938/AS. /Trisodium ethylenediaminetetraacetate trihydrate/ [R61] SO: R1: SRI R2: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 486 R4: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. R5: LEUSCHER U ET AL; FALK SYMP 33 (BILE ACIDS CHOLESTEROL HEALTH DIS): 407-11 (1983) R6: LUDWIG G, SUNDERDICK R; CAN PATENT NUMBER 1150907 8/2/83 (TIMUS EUROCON KONTAKTLINSEN GMBH UND CO, K-G) R7: RUDNICKI RM ET AL; POL PATENT NUMBER 2/25/83 (INSTYTUT SADOWNICTWA, SKIERNIEWICE) R8: WOOLEY RE, JONES MS; VET MICROBIOL 8 (3): 271-80 (1983) R9: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 193 R10: Hayes, W. J., Jr. Toxicology of Pesticides Baltimore: Williams and Wilkins, 1975. 420 R11: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 508 R12: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R13: National Research Council. Drinking Water and Health, Volume 4. Washington, DC: National Academy Press, 1981.,p. 117 R14: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. R15: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 286 R16: USITC, SYN ORG CHEM-US PROD/SALES 1985 p.245 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R18: Serjeant EP, Dempsey B; Ionisation constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. New York, NY: Pergamon pp.989 (1979) R19: Wolf K, Gilbert PA; EDTA-Ethylene Diamine Tetraacetic Acid; In: The Handbook of Environmental Chemistry Vol 3 Part F; Hutzinger O, Editor; Springer-Verlag: Heidelberg, Germany pp 243-59 (1992) R20: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 622 R21: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 431 R22: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-171 R23: SRP R24: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 443 R25: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 227 R26: HEINDORFF K ET AL; MUTAT RES 115 (2): 149-73 (1983) R27: RODERER G; CHEM BIOL INTERACT 46 (2): 247-54 (1983) R28: HOULSBY RD ET AL; J PHARM SCI 72 (12): 1401-3 (1983) R29: RENNER G, KRAMER HJ; INT J CLIN PHARMACOL, THER TOXICOL 21 (3): 115-7 (1983) R30: RABENSTEIN DL ET AL; BIOCHIM BIOPHYS ACTA 762 (4): 531-41 (1983) R31: DECORTI G ET AL; CANCER LETT 19 (1): 77-83 (1983) R32: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 641 R33: Bioassay of Trisodium Ethylenediaminetetraacetate Trihydrate (EDTA) for Possible Carcinogenicity. Technical Rpt Series No. 11 (1977) R34: HUBBARD JR, KALIMI M; J STEROID BIOCHEM 19 (2): 1163-7 (1983) R35: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 55 R36: LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971. 35 R37: MAXWELL LC ET AL; MICROVASC RES 26 (1): 81-8 (1983) R38: National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980. 353 R39: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R40: RANA SV, KUMAR A; INT J TISSUE REACT 5 (2): 187-92 (1983) R41: BOSCOLO P ET AL; MED LAV 74 (5): 370-5 (1983) R42: BATUMAN V ET AL; N ENGL J MED 309 (1): 17-21 (1983) R43: SARBINOFF JA ET AL; J PERIODONTOL 54 (2): 77-80 (1983) R44: CURZON ME J, SPECTOR PC; CARIES RES 17 (3): 249-52 (1983) R45: (1) Gardiner J; Water Res 10: 507 (1976) R46: (1) Belly RT et al; Appl Microbiol 29: 787 (1975) (2) Dorfman LM, Adams GE; Reactivity of the Hydroxyl Radical in Aqueous Solution, NTIS COM-73-50623 (1973) (3) Mill T et al; Science 207: 886 (1980) (4) Tiedje JM; J Environ Qual 6: 21 (1977) (5) Means JL et al; Environ Poll Ser B Chem Phys 1: 45 (1980) R47: (1) Boatman RJ et al; Environ Tox Chem 5: 233 (1986) (2) Gerike P, Fischer WK; Ecotox Environ Safety 3: 159 (1979) (3) Tiedje JM; Appl Microbiol 30: 327 (1975) (4) Belly RT et al; Appl Microbiol 29: 787 (1975) (5) Tiedje JM; J Environ Qual 6: 21 (1977) R48: (1) Gardiner J; Water Res 10: 507 (1976) (2) Tiedje JM; J Environ Qual 6: 21 (1977) (3) Means JL et al; Environ Poll Ser B Chem Phys 1: 45 (1980) (4) Dorfman LM, Adams GE; Reactivity of the Hydroxyl Radical in Aqueous Solution, NTIS COM-73-50623 (1973) (5) Mill T et al; Science 207: 886 (1980) (6) GEMS; Graphical Exposure Modeling System. FAP. Fate of Atmos Pollut (1986) R49: Svenson A et al; Chemosphere 18 (9-10): 1805-8 (1989) R50: (1) Bishop WE, Maki AW; pp 61-77 in Aquatic Toxicology, Eaton JG ed. ASTM STP 707 (1980) (2) Merck Index, An Encyclo Chem Drugs 10th ed. p.508 (1983) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY p.5-5 (1982) R51: (1) Gardiner J; Water Res 10: 507 (1976) (2) Haas CN, Horowitz ND; Water, Air Soil Poll 27: 131 (1986) (3) Cheng SM et al; Can J Soil Sci 52: 337 (1972) R52: (1) Serjeant EP, Dempsey B; p.989 in Ionisation Constants of Org Acids in Aqueous Solution Pergamon Press NY (1979) (2) Tiedje JM; J Environ Qual 6: 21 (1977) R53: (1) RTECS; Current Awareness File (1984) (2) NIOSH; National Occupational Exposure Survey (NOES) Sept 20 (1985) R54: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 600 R55: 40 CFR 116.4 (7/1/87) R56: 50 FR 13456 (4/4/85) R57: 40 CFR 162.60 (7/1/86) R58: 21 CFR 175.105 (4/1/86) R59: WILLIAMS DT; J ASSOC OFF ANAL CHEM 57 (6): 1382-85 (1974) R60: KAISER K LE; WATER RES 7 (10): 1465-73 (1973) R61: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.28 RS: 39 Record 91 of 1119 in HSDB (through 2003/06) AN: 818 UD: 200201 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ASCORBIC-ACID- SY: *ADENEX-; *ALLERCORB-; *ANTISCORBUTIC-VITAMIN-; *L-ASCORBIC-ACID-; *L-(+)-ASCORBIC ACID; *ASCORVIT-; *CANTAN-; *CANTAXIN-; *CATAVIN-C-; *CEBICURE-; *CEBIONE-; *CECON-; *CEGIOLAN-; *CELIN-; *CERGONA-; *CESCORBAT-; *CETAMID-; *CEVALIN-; *CEVATINE-; *CEVIMIN-; *CE-VI-SOL-; *CEVITAMIC-ACID-; *CEVITAN-; *CEVITEX-; *CIAMIN-; *CIPCA-; *CONCEMIN-; *DAVITAMON-C-; *3-KETO-L-GULOFURANOLACTONE-; *L-3-KETOTHREOHEXURONIC-ACID-LACTONE-; *LAROSCORBINE-; *LEMASCORB-; *LIQUI-CEE-; *NCI-C54808-; *3-OXO-L-GULOFURANOLACTONE- (ENOL FORM); *PLANAVIT-C-; *PROSCORBIN-; *REDOXON-; *RIBENA-; *SCORBU-C-; *TESTASCORBIC-; *C-VIMIN-; *VITACEE-; *VITACIMIN-; *VITACIN-; *VITAMIN-C-; *VITASCORBOL-; *XITIX-; *L-XYLOASCORBIC-ACID- RN: 50-81-7 MF: *C6-H8-O6 ASCH: Ascorbic acid (DL); 62624-30-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *COMMERCIALLY AVAILABLE VITAMIN IS PRODUCED BY SYNTHESIS: ...STARTS WITH D-GLUCOSE...CONVERTED TO D-SORBITOL BY HYDROGENATION. D-SORBITOL...YIELD/S/ L-SORBOSE BY OXIDN... THEN CARBOXYL GROUP...INTRODUCED AT C1. ... RESULTING DIACETONE-2-KETO-L-GULONIC ACID...HEATED WITH HCL TO GIVE ASCORBIC ACID. [R1] *...FROM SORBOSE BY OXIDIZING WITH NITROGEN PEROXIDE: GISVOLD, US PATENT 2,702,808 (1955 TO UNIVERSITY OF MINNESOTA). [R1] FORM: *GRADES: USP; FCC [R2] MFS: *Hoffman-La Roche, Inc., 340 Kingsland Street, Nutley, NJ 07110 (201)235-5000. Production Site: Belvidere, NJ 07823. [R3] *MERCK AND CO, INC, MERCK CHEM DIV, RAHWAY, NJ [R4] *Pfizer, Inc., Chemical Division, 235 East 42nd Street, New York, NY 10017 (212)573-2323. Production Site: Groton, CT 06340. [R3] *Takeda Chemical Producers USA, Inc., 101 Takeda Drive, Wilmington, NC 28401, (901) 762-8666 [R5] OMIN: *1 UNIT (USP OR INTERNATIONAL) IS THE VITAMIN C ACTIVITY OF 0.05 MG OF THE USP ASCORBIC ACID REFERENCE STANDARD. [R1] *...BECAUSE OF ASCORBIC ACID'S SENSITIVITY TO OXIDATION...ITS STABILITY IN FOODS HAS RECEIVED MORE ATTENTION THAN THAT OF OTHER VITAMINS. ... ASCORBIC ACID OXIDASE IS PRESENT IN A VARIETY OF PLANT FOODS AND MAY BE RESPONSIBLE FOR SIGNIFICANT LOSSES IF NOT INACTIVATED DURING TISSUE MACERATION. [R6, 101] *STABILITY...IN POTATO PRODUCTS HAS BEEN OF INTEREST SINCE THEY ARE A SIGNIFICANT DIETARY SOURCE IN MANY COUNTRIES. REDUCED ASCORBIC ACID DECR 50% IN POTATOES STORED THREE MONTHS - FROM 25 TO 13 MG/100 G. ADDN DEGRADATION OCCURS DURING COOKING AND WASHING - FROM 13 TO 6 MG/100 G. [R6, 101] *LOSS DURING STORAGE OF FRESH VEGETABLES IS TEMPERATURE DEPENDENT AS WELL AS RATE OF...DEHYDRATION DEPENDENT... FRESH AND FROZEN BROCCOLI RETAINED ABOUT THE SAME PERCENTAGE OF THEIR ORIGINAL ASCORBIC ACID, 65-79%, WHEN COOKED. ...WAS STABLE IN FROZEN BROCCOLI AFTER 36 WEEKS AT 0 DEG F. [R6, 102] *INCOMPATIBILITIES: VITAMIN C SHOULD NOT BE FORMULATED WITH SODIUM SALICYLATES, SODIUM NITRITE, THEOBROMINE SODIUM SALICYLATE, METHENAMINE. [R1] *ASCORBIC ACID SYNTHESIS IS STIMULATED BY MANY DRUGS AND BY POLYCYCLIC HYDROCARBONS. MECHANISM...UNKNOWN, BUT MAY BE CONNECTED WITH INCR LEVELS OF UDP-GLUCOSE DEHYDROGENASE AND UDP-GLUCURONYL TRANSFERASE OBSERVED ON ENZYME INDUCTION /IN ANIMALS/. [R7] USE: *AS ANTIOXIDANT IN FOODSTUFFS, TO PREVENT RANCIDITY; TO PREVENT BROWNING OF CUT APPLES AND OTHER FRUIT [R1] *OXIDANT IN BREAD DOUGH; ABSCISSION OF CITRUS FRUIT IN HARVESTING; REDUCING AGENT IN ANALYTICAL CHEMISTRY [R2] +PRESERVATIVE FOR FOODS, PRINCIPALLY CURED MEATS [R4] +MEDICATION (VET) +MEDICATION CPAT: *CHEMICAL PROFILE: Ascorbic Acid. Pharmaceutical preparations; 65%; food and beverages, 30%; exports, 5%. [R8] *CHEMICAL PROFILE: Ascorbic acid. Demand: 1986: 30 million lb; 1987: 31 million lb; 1991 /projected/: 34.5 million lb. [R8] *CHEMICAL PROFILE: Ascorbic acid. Pharmaceutical preparations, 55%; food and beverages, 35%; animal feed, 10%. [R9] *CHEMICAL PROFILE: Ascorbic acid. Demand: 1989: 31 million lb; 1990: 32 million lb; 1994 /projected/: 35 million lb. (Includes imports of about 13 million lb, and excludes exports, which run between 1 million and 4 million lb.) [R9] *Humans cannot synthesize L-ascorbic acid and thus must consume vitamin C from exogenous sources. [R10] PRIE: U.S. PRODUCTION: *(1972) 7.08X10+9 GRAMS [R4] *In 1979, ca 10,000 metric tons/yr of L-ascorbic acid was produced. [R10] U.S. IMPORTS: *(1972) 2.5X10+9 GRAMS [R4] *(1975) 2.13X10+9 GRAMS (INCL SALTS) [R4] U.S. EXPORTS: *(1972) 2.27X10+8 GRAMS [R4] *(1975) 7.76X10+7 GRAMS [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS (USUALLY PLATES, SOMETIMES NEEDLES, MONOCLINIC SYSTEM) [R1]; *WHITE TO SLIGHTLY YELLOW CRYSTALS OR POWDER [R11, 156] ODOR: *Odorless [R12] TAST: *PLEASANT, SHARP, ACIDIC TASTE [R1] MP: *190-192 DEG C (SOME DECOMP) [R1] MW: *176.12 [R1] CTP: *Critical temperature = 783 deg K; critical pressure = 5.29X10+6 Pa. [R13] DEN: *1.65 [R1] DSC: +pK1 = 4.17; pK2 = 11.57 [R14] HTV: *The heat of vaporization is 1.487X10+8 J/kmol at 465.15 deg K. [R13] OWPC: *Log Kow = -2.15 @ 23 deg C; log Kow = -2.00 @ 37 deg C [R15] PH: *pH = 3 (5 mg/mL); pH = 2 (50 mg/mL) [R1] SOL: *1 G DISSOLVES IN: 30 ML ALCOHOL, 50 ML ABSOLUTE ALCOHOL, 100 ML GLYCEROL USP, 20 ML PROPYLENE GLYCOL; SOL IN WATER: 80% AT 100 DEG C, 40% AT 45 DEG C; INSOL IN ETHER, CHLOROFORM, BENZENE, PETROLEUM ETHER, OILS, FATS, FAT SOLVENTS [R1]; *1 g dissolves in about 3 ml of water. [R12]; *The solubility in g/ml is 0.33 in water, 0.033 in 95 wt% ethanol, 0.02 in absolute ethanol, 0.01 in glycerol USP, 0.05 in propylene glycol. [R10] SPEC: *INDEX OF REFRACTION: 1.5101-1.5204 AT 25 DEG C/D [R16]; *SPECIFIC OPTICAL ROTATION (1 G IN 100 ML WATER): +20.5 TO +21.5 DEG @ 25 DEG C/D; MAX ABSORPTION (ACID SOLUTION): 245 NM; 265 NM (NEUTRAL SOLUTION); SPECIFIC OPTICAL ROTATION (1 G IN 100 ML METHANOL): +48 DEG AT 23 DEG C/D /L-ASCORBIC ACID/ [R1]; *SPECIFIC OPTICAL ROTATION (1 G IN 100 ML WATER): +24 DEG AT 20 DEG C/D; MAX ABSORPTION (WATER): 244 NM (LOG E= 3.98); SADTLER REF NUMBER: 13217 (IR, PRISM); 470 (IR, GRATING); 3455 (UV); 3126 (NMR) [R17]; *MASS: 838 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R18]; *Intense mass spectral peaks: 85 m/z, 116 m/z, 176 m/z [R19] SURF: *4.039X10-2 N/m [R13] VAP: *7.9179 Pa @ 465.15 deg K [R13] OCPP: *POSSESSES RELATIVELY STRONG REDUCING POWER, DECOLORIZES MANY DYES; FORMS STABLE METAL SALTS [R1] *UV: 6-83 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) /Ascorbic acid (DL)/ [R18] *NMR: 464 (Varian Associates NMR Spectra Catalogue) /Ascorbic acid (DL)/ [R18] *IR: 470 (Sadtler Research Laboratories IR Grating Collection) /Ascorbic acid (D+)/ [R18] *UV: 3455 (Sadtler Research Laboratories Spectral Collection) /Ascorbic acid (D+)/ [R18] *NMR: 3126 (Sadtler Research Laboratories Spectral Collection) /Ascorbic acid (D+)/ [R18] *MASS: 838 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /Ascorbic acid (D+)/ [R18] *Melting point = 465.15 deg K, decomposes. [R13] *The liquid molar volume is 0.1248 cu m/kmol [R13] *Ascorbic acid is stable in the dry state but is easily oxidized in aqueous solution in the presence of air. Oxidation is accelerated by heat, light, alkalies, oxidative enzymes, and traces of copper and iron. [R13] +pKa = 4.70 @ 10 deg C [R20] +log Kow = -1.64 [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Ascorbic acid injection has been reported to be incompatible with many drugs. Compatibility depends on several factors (eg, concentration of the drugs, specific diluents used, resulting pH, temperature). [R22] DCMP: *In concentrations greater than 100 mg/ml , ascorbic acid may undergo decomposition with the production of carbon dioxide. ... [R22] OHAZ: *In concentrations greater than 100 mg/ml , ascorbic acid may undergo decomposition with the production of carbon dioxide. Since increased pressure may develop after prolonged storage, ampuls containing ascorbic acid injections should be opened carefully. [R22] SSL: *STABLE TO AIR WHEN DRY; IMPURE PREPN AND IN MANY NATURAL PRODUCTS VITAMIN OXIDIZES ON EXPOSURE TO AIR AND LIGHT. AQUEOUS SOLUTIONS ARE RAPIDLY OXIDIZED BY AIR, ACCELERATED BY ALKALIES, IRON, COPPER [R23] STRG: *Solutions of ascorbic acid are rapidly oxidized in air and in alkaline media; the drug should be protected from air and light. [R22] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Withdraw use of vitamins in large doses unless clinically indicated by randomized double-blind placebo-controlled studies. Treat symptomatically. [R24] HTOX: *DOSES ON THE ORDER OF SEVERAL G ON AN EMPTY STOMACH MAY PROVOKE GASTRIC DISTRESS AND DIARRHEA. [R25] *REPEATED APPLICATION OF 10% SOLN...TO EYES OF PATIENTS...CAUSED NO INJURY. [R26] *WHILE SERIOUS TOXICITY FROM ADMIN OF VITAMIN C IS...UNCOMMON, UNTOWARD EFFECTS...REPORTED. ...DIARRHEA. ACIDIFICATION OF URINE...MAY CAUSE PRECIPITATION OF CYSTINE AND OXALATE STONES IN URINARY TRACT... HIGH DOSES... TAKEN DURING PREGNANCY...REPORTED TO CAUSE SCURVY IN INFANTS REMOVED FROM THIS ENVIRONMENT BY BIRTH. [R27] *LARGE DOSES CAUSED A DISRUPTION OF PSYCHOLOGICAL FUNCTIONING RESULTING IN DECR REACTION TIMES AND PSYCHOMOTOR COORDINATION. [R28] *LONG-TERM ADMINISTRATION OF DOSES OF 3 TO 30 G PER DAY HAS RESULTED IN NO SERIOUS TOXICITY; ONLY DIARRHEA WAS OBSERVED AS A SIDE EFFECT. [R11, 159] *Vitamin C in overdosage may be associated with diarrhea and may predispose to renal oxalate calculi. A single 45 g dose of intravenous ascorbic acid, a metabolic precursor of oxalate, administered to a 58 year old woman as adjuvant therapy for primary amyloidosis and the nephrotic syndrome, resulted in the development of acute renal failure secondary to tubular obstruction, with calcium oxalate crystals and a serum ascorbic acid level of 15.4 mg/dl (normal 0.4-2.0 mg/dl). She was hemodialyzed, and later developed ventricular fibrillation and died. [R24] *Vitamin C increases iron adsorption and may be dangerous in patients with hemochromatosis, thalassemia, or sideroblastic anemia. Ascorbic acid has induced hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. Four grams of ascorbic acid produced a 200% increase in fractional uric acid clearance in one study. Ascorbic acid in large doses (4-8 g) may result in a diminution of uric acid excretion which may in turn precipitate an acute gouty arthritis in predisposed individuals. [R24] NTOX: *MUTAGENICITY: MUTATION RESEARCH 87: 17 (1981). SISTER CHROMATID EXCHANGE - IN VITRO CHROMOSOMAL EFFECT STUDIES, HUMAN: POSITIVE; NON-HUMAN: POSITIVE. [R29] *SUBCONJUNCTIVAL INJECTIONS OF 1 ML OF 10% SOLN DAILY FOR 10 DAYS IN RABBITS CAUSED NO SIGNIFICANT IRRITATION. [R26] *...1000 MG...BY MOUTH TO PREGNANT MICE AND RATS FROM DAY 6 THROUGH DAY 15...NO ADVERSE EFFECTS ON CONCEPTUS. [R30] *REACTION PRODUCT OF L-TRYPTOPHAN AND L-ASCORBIC ACID CAUSED DNA DAMAGE TO BACILLUS SUBTILIS, AND MUTATION IN SALMONELLA TYPHIMURIUM TA100 BUT NOT TA98. [R31] *GUINEA PIGS WERE GIVEN ORAL SUPPLEMENTS OF 250, 500, and 1000 MG DAILY FOR 9 WK. FOOD INTAKE WAS DEPRESSED AND BODY WT WERE LOWER IN 1000 MG GROUP. KIDNEY WT WERE ALSO LOWER. PHOTOMICROGRAPHS OF KIDNEY SHOWED INCR DILATION OF ARCUATE VEINS AND ARTERIES IN 500 MG AND 1000 MG GROUPS. [R32] NTP: *A carcinogenesis bioassay of L-ascorbic acid (> 97% pure was conducted by administering diets containing 25,000 or 50,000 ppm L-ascorbic acid to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 wk. Controls consisted of 50 untreated rats and 50 untreated mice of each sex. ... Under the conditions of this bioassay, L-ascorbic acid was not carcinogenic for male or female F344/N rats or male or female B6C3F1 mice. /L-Ascorbic acid/ [R33] ADE: *Ascorbic acid is readily absorbed from the intestine, and absorption of dietary ascorbate is nearly complete. When vitamin C is given in a single oral dose, absorption decreases from 75% at 1 gram to 20% at 5 grams. [R34, 1548] *Ascorbic acid is present in the plasma and is ubiquitously distributed in the cells of the body. Concentrations of the vitamin in leukocytes are sometimes taken to represent those in tissue and are less susceptible to depletion than is the plasma. The white blood cells of healthy adults have concentrations of about 27 ug of ascorbic acid per 10(8) cells. It would be noted that the amount of ascorbic acid in leukocytes may be inversely related to their number, and estimates of ascorbic acid status may be falsely low in patients with leukocytosis in whom white-cell ascorbate is measured. Concentrations in plasma also vary with intake. Adequate ingestion is associated with concentrations over 0.5 mg/dl (28 um), whereas concentrations of 0.15 mg/dl (8.5 um) are seen in individuals with frank scurvy. [R34, 1548] *The fat-soluble vitamins ... C ... are absorbed from the skin ... . [R35] METB: *ASCORBIC ACID-2-SULFATE HAS ALSO BEEN IDENTIFIED AS METABOLITE OF VITAMIN C IN HUMAN URINE. [R34, 1548] *Ascorbate is oxidized to CO2 in rats and guinea pigs, but considerably less conversion can be detected in man. One route of metabolism of the vitamin in man involves its conversion to oxalate and eventual excretion in the urine; dehydroascorbate is presumably an intermediate. [R34, 1548] BHL: *VITAMIN C HAS A 96 HR HALF-LIFE IN GUINEA PIGS. [R36, 651] INTC: *OXYTOCIN DECREASES THE RATE OF PLACENTAL TRANSMISSION OF ASCORBIC ACID. [R37] *BIOLOGICAL T/2 OF SALICYLAMIDE WAS DECREASED SOMEWHAT BY IV ASCORBIC ACID AND MORE BY ORAL ASCORBIC ACID, PLASMA LEVELS OF SALICYLAMIDE AND GLUCURONIDE METABOLITE INCREASED WHILE LEVELS OF SULFATE METABOLITE DECREASED. [R38] *WOMAN ON LOGYNON (ETHINYL ESTRADIOL + LEVONORGESTREL) BLED HEAVILY STARTING 2-3 DAYS AFTER LAST DOSE OF ASCORBIC ACID DAILY; NO BLEEDING WITHOUT LATTER. THIS MAY BE WITHDRAWAL EFFECT DUE TO DECR IN ETHINYL ESTRADIOL LEVELS IN PLASMA WHEN ASCORBIC ACID WAS STOPPED. [R39] *AFTER INGESTION OF 2.0 G ASCORBIC ACID AND BREAKFAST, PLASMA LEVELS OF ASCORBIC ACID ROSE FROM FASTING CONCN OF 7.5 +/- 0.8 NG/ML @ 0900 HR TO A PEAK OF 26.9 +/- 2.0 NG/ML @ 1500 HR. INGESTION WITH ETHANOL LOWER PLASMA ASCORBIC ACID CONCN FOR AT LEAST 24 HR. [R40] *CYPROTERONE ACETATE IP EVERY 3RD DAY FOR 15 DAYS TO TOADS RESULTED IN HYPERTROPHY, DEGRANULATION AND VACUOLIZATION OF BASOPHIL TYPE 2 GONADOTROPHS AND INCR NUMBER OF CHROMOPHOBES AND ACIDOPHILS IN PARS DISTALIS. ASCORBIC ACID ADMIN RESTORED SECRETORY MATERIAL IN GONADOTROPHS. [R41] *THE DEPRESSION OF GROWTH OF GUINEA PIGS RESULTING FROM ADMIN OF 50 PPM DIETARY POLYCHLORINATED BIPHENYLS WAS AMELIORATED BY INCREASING DIETARY INTAKE OF ASCORBIC ACID (30-2000 PPM). INCR IN SERUM CHOLESTEROL AND PHOSPHOLIPID AND HEPATIC LIPID PEROXIDN WERE ALSO SUPPRESSED BY LARGER AMT. [R42] *ASCORBIC ACID, A REDUCING AGENT, POTENTIATED THE ACTIVATION OF RAT LUNG SOL GUANYLATE CYCLASE BY SODIUM NITROPRUSSIDE 4.5 TO 9-FOLD. [R43] *TREATMENT OF THE CELLS WITH 6-HYDROXYDOPAMINE (6-OHDA) AND ASCORBIC ACID DECR CYTOTOXICITY OF 6-OHDA FOR SARCOMA CELLS AND INCR TOXICITY FOR NEUROBLASTOMA CELL LINES. [R44] *Large doses of ascorbic acid (but not sodium ascorbate) may lower urinary pH and cause renal tubular reabsorption of acidic medications with concurrent administration; alkaline medications may exhibit decreased reabsorption. [R45, 434] *Doses of 10 grams or more a day of ascorbic acid have been reported to impair gastrointestinal absorption of /coumarin- or indandione-derivative anticoagulants. [R45, 435] *Concurrent use /with cellulose sodium phosphate/ may result in metabolism of ascorbic acid to oxalate. [R45, 435] *Concurrent use /of deferoxamine/ with ascorbic acid may enhance tissue iron toxicity, especially in the heart, causing cardiac decompensation; therefore, this regimen should be used with caution in older patients; the need for ascorbic acid supplementation should be completely documented by measurements of iron excretion before and after supplements, and the oral dose of ascorbic acid should be given an hour or two after the deferoxamine infusion has been initiated when adequate concentrations of deferoxamine have been achieved. [R45, 435] *Concurrent use /of disulfiram/ with ascorbic acid, especially with chronic use or high doses, amy interfere with the disulfiram-alcohol interaction. [R45, 435] *Marked acidification of urine resulting from use of large doses of ascorbic acid may accelerate renal excretion of mexiletine. [R45, 435] *Large doses of ascorbic acid may destroy vitamin B12; patients should be advised to avoid ingestion of large doses within 1 hour of oral vitamin B12. [R45, 435] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *1(?)= PRACTICALLY NON-TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) ABOVE 15 G/KG, MORE THAN 1 QT FOR 70 KG PERSON (150 LB). HUMAN POISONINGS ARE UNKNOWN AND EVEN RELIABLE ESTIMATES OF LETHAL DOSE IN ANIMALS ARE RARE. [R25] BION: *Requirements for all vitamins and most minerals are increased during breast-feeding. [R45, 434] *Some unusual diets (eg, reducing diets that drastically restrict food selection) may not supply minimum daily requirements for ascorbic acid. Supplementation is necessary in patients receiving total parenteral nutrition (TPN) or undergoing rapid weight loss or, in those with malnutrition, because of inadequate dietary intake. [R45, 434] */STATE OF DEFICIENCY/: Requirements may be increased and/or supplementation may be necessary in the following persons or conditions (although clinical deficiencies are usually rare): alcoholism, burns, cancer, prolonged diarrhea, prolonged exposure to cold temperatures, prolonged fever, gastrectomy, chronic hemodialysis, hyperthyroidism, ileal resection, infants receiving unfortified formulas, continuing infection, intestinal diseases, manual labor, heavy, for long periods of time, peptic ulcer, smokers, continuing stress, surgery, continuing trauma, tuberculosis. [R45, 434] *Deficiency of ascorbic acid may lead to scurvy. [R45, 434] *STATE OF DEFICIENCY: ...EARLY HYPOVITAMINOSIS C INCL MALAISE, IRRITABILITY, EMOTIONAL DISTURBANCES, ARTHRALGIA, HYPERKERATOSIS OF HAIR FOLLICLES, NOSEBLEEDS AND PETECHIAL HEMORRHAGES. [R46, 827] *STATE OF DEFICIENCY: PATHOLOGY IS MANIFEST IN MOST BODY TISSUES, ESP THOSE OF MESODERMAL ORIGIN (IE, COLLAGEN, GROWING BONES, TEETH, BLOOD VESSELS). ... DEFECTIVE GROUND SUBSTANCE IS FORMED AND ... SCAR TISSUE /FORMATION/ IS DELAYED. CAPILLARY FRAGILITY...WITH DEFECTIVE CALCIFICATION OF CARTILAGE CAUSES SUBPERIOSTEAL HEMORRHAGES ... . [R47, 2167] *STATE OF DEFICIENCY: A NORMOCYTIC OR MACROCYTIC ANEMIA, WHICH IS MULTIFACTORIAL IN ORIGIN IS COMMMON. RARELY, MEGALOBLASTIC ANEMIA IS OBSERVED (ONLY ASSOCIATED WITH A DEFICIENCY OF BOTH ASCORBIC AND FOLIC ACIDS). IF UNTREATED, HYPOTENSION, CONVULSIONS, COMA, AND DEATH OCCUR. [R47, 2167] *STATE OF DEFICIENCY (VET): CHRONIC PARTIAL DEFICIENCY IN GUINEA PIGS PRODUCES A RHEUMATOID ARTHRITIS... VITAMIN C CAN NO LONGER REVERSE THE HISTOPATHOLOGY AT THIS POINT AND LESIONS APPEAR TO BE AN INDIRECT EFFECT OF THE DEFICIENCY ON CORTICOSTEROID PRODN BY ADRENALS. [R36, 651] *STATE OF DEFICIENCY (VET): DEFICIENT MONKEYS SC, IM, AND SUBPERIOSTEAL HEMORRHAGE, THINNING, AND NECROSIS OF PERIODONTAL TISSUES, PERIORBITAL HEMORRHAGES, JOINT DEFORMATION, AS WELL AS OTHER SCORBUTIC SYMPTOMS. MEGALOBLASTIC ANEMIA IN CHIMPANZEES...MAY BE DUE TO SECONDARY FOLIC ACID DEFICIENCY. [R36, 651] *A deficiency in the intake of vitamin C can lead to scurvy. Cases of scurvy are encountered among elderly people living alone, alcoholics, drug addicts, and others with inadequate diets, including infants. [R34, 1549] *Scurvy may occur in infants receiving formula diets prepared at home with inadequate concentrations of ascorbic acid. The infant is irritable and resents being touched because of pain. The pain is caused by hemorrhages under the periosteum of the long bones, and the resulting hematomas are often visible as swellings on the shafts of these bones. [R34, 1549] *The daily intake of ascorbic acid must equal the amount that is excreted or destroyed by oxidation. Healthy adult human subjects lose 3 to 4% of their body store daily. To maintain a body store of 1500 mg of ascorbic acid or more in an adult man, it would thus be necessary to absorb approximately 60 mg daily. Values for vitamin C requirements of other age groups are based on similar reasoning. [R34, 1549] *Under special circumstances, more ascorbic acid appears to be required to achieve normal concentrations in the plasma. Thus, South African miners have been observed to require 200 to 250 mg of vitamin C daily to maintain a plasma concentration of 0.75 mg/dl (43 um). Concentrations of ascorbate in plasma are lowered by the use of cigarettes and of oral contraceptive agents, but the significance of these changes is unclear. Requirements can increase in certain diseases, particularly infectious diseases, and also following surgery. [R34, 1549] THER: +Antioxidants; Free Radical Scavengers [R48] *Ascorbic acid has been used to treat methemoglobinemia. /NOT included in US product labeling/ [R45, 434] *Ascorbic acid or sodium ascorbate has been used to increase iron excretion by improving chelation during deferoxamine therapy. /NOT included in US product labeling/ [R45, 434] *Ascorbic acid and sodium ascorbate are indicated for prevention and treatment of ascorbic acid deficiency states. Ascorbic acid deficiency may occur as a result of inadequate nutrition but does not occur in healthy individuals receiving an adequate balanced diet. Dietary improvement is preferred over supplementation whenever possible. /Included in US product labeling/ [R45, 434] *Vitamin C is used for the treatment of ascorbic acid deficiency, especially frank scurvy, which occurs rather infrequently in infants and in adults. [R34, 1549] *A potential role for ascorbic acid in the treatment of cancer has not been proven. Ascorbic acid is not useful for treatment of pyorrhea or gingival infections, hemorrhagic states, hematuria, retinal hemorrhages, immune system dysfunction, or mental depression not related to ascorbic acid deficiency. Ascorbic acid has not been proven effective for treatment of dental caries, anemia, acne, asthma, infertility, aging, atherosclerosis, peptic ulcer, tuberculosis, schizophrenia, dysentery, collagen disorders, fractures, skin ulcers, hay fever, or drug toxicity, nor for prevention of vascular thrombosis or the common cold. Note: There are insufficient data to show that ascorbic acid may reduce the occurrence of certain types of cancer. [R45, 434] *EXPTL USE: IN FORTY LEAD-BURDENED MOTHERS URINARY EXCRETION OF 5-AMINOLEVULINIC ACID DECR BY 65%, THE LEAD CONTENT OF PLACENTA BY 90% AND LEAD CONTENT OF MOTHER'S MILK BY 15% COMPARED WITH CONTROLS WHO HAD NOT RECEIVED COMBINED CALCIUM PHOSPHATE AND ASCORBIC ACID THERAPY. [R49] *EXPTL USE: THE ADVERSE EFFECTS, INCR MORTALITY, GROWTH RETARDATION, ENZYMATIC CHANGES IN LIVER AND KIDNEY, AND MG2+-DEPENDENT ATPASE OF LIVER MITOCHONDRIA, PRODUCED BY CHLORDANE WERE COUNTERACTED BY L-ASCORBIC ACID SUPPLEMENTATION. [R50] *EXPTL USE: COVALENT BINDING OF ACETAMINOPHEN METAB TO MOUSE HEPATIC MICROSOMES WAS INHIBITED BY ASCORBIC ACID. THE POSSIBLE APPLICATION OF THIS STUDY IS THE USE OF ASCORBIC ACID IN PREVENTION AND TREATMENT OF ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MAN. [R51] *EXPTL USE: STUDY MADE ON EFFECT OF ADMIN VIT-C, AN ENHANCER OF PROSTAGLANDIN 1 (PGE1 SYNTH), ON GLUCOSE TOLERANCE OF DIABETIC PT. VIT-C IMPROVED GLUCOSE TOLERANCE. THE BENEFICIAL EFFECT OF VIT-C CAN BE ATTRIBUTED TO ITS STIMULATORY ACTION ON PGE1 SYNTH. [R52] +MEDICATION (VET): USEFUL IN REPTILES AND LIZARDS TO OVERCOME SCORBUTIC NECROTIC MOUTH LESIONS. ...VALUE IN RHINOTRACHEITIS OF CATS. SCURVY-LIKE SYNDROMES RESPONSIVE TO VITAMIN C...REPORTED IN DOGS. [R36, 652] +MEDICATION (VET): TO SUPPLEMENT LOW ADRENAL LEVELS DURING PERIODS OF STRESS, SHOCK, AND INFECTIONS. IT AIDS IN FORMATION OF CARTILAGE, CALLUSES, OSSIFICATION AND THE HEALING OF FRACTURES, WOUNDS, AND BURNS. ...MAY HELP COUNTER SOME OF THE ALLERGIC ASPECTS OF PULMONARY EMPHYSEMA IN CATTLE. [R36, 651] +MEDICATION (VET): PROGRESSIVE STIFFNESS AND 'DOWNER' SYNDROME IN CATTLE HAS RESPONDED TO AND BREEDING EFFICIENCY HAS...IMPROVED IN SOME COWS WITH INJECTIONS... [R36, 651] +MEDICATION (VET): WEAK SCOURING BABY CALVES (NON-RUMINATING) MAY RESPOND TO ORAL DOSAGE AND HIGH PARENTERAL DOSAGE HAS REVERSED AN APPARENT AVITAMINOSIS C IN CALVES. ... HAS SHOWN DISTINCT BENEFITS WHEN ADDED TO SELENIUM THERAPY FOR WHITE MUSCLE DISEASE IN KIDS (GOATS). [R36, 651] +MEDICATION (VET): ...IN COMBATTING THE STRESSES OF RACING OR RESP DISEASE IN HORSES. ... IN PIGS THE VITAMIN INCR ABSORPTION OF ORAL IRON... BABY PIGS WITH...SKIN SCURVY...RESPONDED TO ORAL SUPPLEMENTATION... [R36, 651] +MEDICATION (VET): ...FOR POULTRY /IT/ HELPS PREVENT EXTREME BODY TEMP IN RESPONSE TO ENVIRONMENTAL HEAT AND COLD STRESSES. EGGSHELL QUALITY, EGG WT, AND FERTILITY OF HENS...IMPROVED...(100 G/TON OF FEED). DIARRHEA IN CAPTIVE ROE DEER RESPONDED TO PARENTERAL VITAMIN C EXCEPT IN ADVANCED CASES. [R36, 651] +MEDICATION (VET): ...IN PROPHYLAXIS AND TREATMENT OF SYSTEMIC TOXICITY IN DOGS DURING HEARTWORM THERAPY WITH ARSENAMIDE, ETC. ...ALSO ENHANCES IRON ABSORPTION IN DOGS. RAT AND DOG TRIALS SHOW 6-10 MG OF VITAMIN C IN BLOOD CAN OVERCOME THE ANTICOAGULANT EFFECT OF 5 UNITS OF HEPARIN. [R36, 652] +MEDICATION (VET): ...USEFUL IN DETOXIFICATION OF TOXINS AND A LARGE NUMBER OF DRUGS. [R36, 652] *ASCORBIC ACID FACILITATES ABSORPTION OF IRON BY KEEPING IRON IN REDUCED FORM. A FEW MICROCYTIC ANEMIAS RESPOND TO ASCORBIC ACID TREATMENT, WHICH MAY BE...DUE TO IMPROVED ABSORPTION OF IRON. [R53, 947] *ASCORBIC ACID (BUT NOT SODIUM ASCORBATE) CAN BE USED AS ALTERNATIVE /URINARY ACIDIFIER/...IF AMMONIUM CHLORIDE IS NOT TOLERATED OR IS CONTAINDICATED. DOSES OF 0.5-2 G EVERY 4 HR ARE RECOMMENDED; HOWEVER, THE DESIRABLE ALTERATION IN URINARY PH IS NOT ALWAYS OBTAINED...EVEN AT THE HIGHER DOSE LEVELS. [R46, 1439] *ORAL ADMIN OF MEGADOSE OF ASCORBIC ACID (1 G/DAY) WAS NOT EFFECTIVE IN ELEVATING SERUM HIGH-DENSITY LIPOPROTEIN-BOUND CHOLESTEROL IN NORMAL ADULT MEN. [R54] +MEDICATION (VET): FEED ADDITIVES WITH ANTIOXIDANT PROPERTIES SUCH AS ASCORBIC ACID HAD NO PROTECTIVE EFFECT AGAINST MONOCROTALINE LETHALITY AND HEPATOTOXICITY IN MICE. [R55] *FOR PROPHYLAXIS OR CORRECTION OF DEFICIENCY, VITAMIN C MAY BE GIVEN AS FRESH OR FROZEN ORANGE JUICE (CONTAINS APPROX 0.5 MG/ML OF ASCORBIC ACID). CRYSTALLINE ASCORBIC ACID IS SUITABLE ALTERNATIVE; ORAL ADMIN IS PREFERRED, BUT THE VITAMIN MAY BE GIVEN IM OR IV ... . [R47, 2168] *Ascorbic acid should generally be administered orally or nasogastrically, if the patient is seen while the chromium compound is still in the stomach. Ascorbic acid has been shown to ameliorate the effects of topical human exposure to chromates, and to reduce toxicity following ingestion in rats if given within 2 hours of exposure. [R56] *A series of three carefully designed studies in Canada /were carried out/ to test whether vitamin C plays any role in the prevention and treatment of the common cold. No obvious effect on the incidence of headcolds was seen from the administration of ascorbic acid, although there was a slight reduction in the number of days of missed work. Many other studies have yielded negative or inconsistent results. [R34, 1549] +PROPHYLAXIS AND TREATMENT OF SCURVY [R57] WARN: *... INCREASES IRON ABSORPTION AND, THUS, LARGE DOSES MAY BE DANGEROUS IN PATIENTS WITH ... HEMOCHROMATOSIS, THALASSEMIA, OR SIDEROBLASTIC ANEMIA. MILD HEMOLYSIS HAS BEEN REPORTED IN PATIENTS WITH /ERYTHROCYTE/ G6PD DEFICIENCY ...; IN ONE PATIENT, ACUTE HEMOLYSIS RESULTED IN DISSEMINATED INTRAVASCULAR COAGULATION, ACUTE RENAL FAILURE, AND DEATH ... . [R47, 2168] *POSSIBILITY THAT ASCORBIC ACID IN AMT OF 4 TO 12 G DAILY MAY LEAD TO FORMATION OF URATE AND CYSTINE STONES THROUGH PRECIPITATION HAS BEEN MENTIONED. [R11, 159] *Requirements for all vitamins and most minerals are increased during pregnancy; however, they should be provided by an adequate diet. Many physicians recommend that pregnant women receive multivitamin and mineral supplements, especially those pregnant women who do not consume an adequate diet and those in high risk categories (ie, women carrying more than one fetus, heavy cigarette smokers, and alcohol and drug abusers). Taking excessive amounts of a multivitamin and mineral supplement may be harmful to the mother and/or fetus and should be avoided. [R45, 434] *Studies have not been done in either animals or humans and problems in humans have not been documented with intake of normal daily requirements. Ascorbic acid crosses the placenta. However, ingestion of large quantities of ascorbic acid during pregnancy may result in increased requirements and scurvy in the neonate. [R45, 434] *Excessive use of chewable ascorbic acid tablets may cause breakdown of enamel and increased incidence of caries. [R45, 434] *Side/Adverse Effects: Those indicating need for medical attention: Incidence dose-related: Kidney stones, oxalate (side or lower back pain). Note: Occasionally prolonged doses of ascorbic acid in excess of 1.0 g per day may cause precipitation of oxalate stones in the urinary tract in patients with renal disease, especially those on hemodialysis, or in patients with a history of renal stones. [R45, 435] *Side/Adverse Effects: Those indicating need for medical attention only if they continue or are bothersome: Incidence less frequent or rare: Dizziness or faintness - with rapid intravenous administration. With high doses: Diarrhea - with oral doses greater than 1 gram per day; flushing or redness of skin; headache; increase in urination, mild - with doses greater than 600 mg per day; nausea or vomiting; stomach cramps. [R45, 435] *Any benefit that might be derived from /megadoses/ of ascorbic acid seems small when weighed against the expense and the risks of the megadosage treatment. The latter include formation of kidney stones resulting from the excessive excretion of oxalate, rebound scurvy in the offspring of mothers taking high doses, and a similar phenomenon when subjects who are consuming large amounts of vitamin C suddenly stop. These rebound phenomena are presumably due to induction of pathways of ascorbic acid metabolism as a result of the preceding high dosage. [R34, 1550] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *WIDELY DISTRIBUTED IN THE PLANT AND ANIMAL KINGDOM. GOOD SOURCES ARE CITRUS FRUITS, HIP BERRIES, ACEROLA, FRESH TEA LEAVES. ISOLATED FROM THE ADRENAL CORTEX OF OX AND LATER FROM LEMONS AND PAPRIKA... [R23] *CITRUS FRUITS, TOMATOES, POTATOES AND CABBAGE ARE THE BEST DIETARY SOURCES. [R6, 91] *VITAMIN C IS FOUND IN ALL LIVING PLANT CELLS, IS SYNTHESIZED DURING GERMINATION OF SEEDS AND IS...CONCENTRATED IN RAPIDLY GROWING PARTS OF PLANT. IT IS PRESENT IN ALL ANIMAL TISSUES...ONLY GUINEA PIGS, PRIMATES...FEW EXOTIC ANIMAL SPECIES, AND MAN ARE UNABLE TO MEET...NEEDS BY SYNTHESIS...RELY UPON DIETARY SOURCE. [R53, 948] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Ascorbic acid used as a chemical preservative in food for human consumption is generally recognized as safe when used in accordance with good manufacturing practice. [R58] *Ascorbic acid used as a dietary supplement in food for human consumption is generally recognized as safe when used in accordance with good manufacturing practice. [R59] *Ascorbic acid used as a nutrient in food for human consumption is generally recognized as safe when used in accordance with good manufacturing practice. [R60] *Ascorbic acid used as a chemical preservative in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R61] *Ascorbic acid used as a nutrient and/or dietary supplement in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R62] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R63] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TITRIMETRIC DETERMINATION OF ASCORBIC ACID WITH CHLORAMINE-T USING OXAZINE DYES AS INDICATORS. [R64] *DETERMINATION BY TITRATION WITH INDOPHENOL. [R65] *ASCORBIC ACID WAS DETERMINED BY FOLLOWING ITS REDN OF CU2+-NEOCUPROINE CHELATE TO CU+-NEOCUPROINE CHELATE BY ATOMIC ABSORPTION SPECTROPHOTOMETRY. [R66] *ASCORBIC ACID WAS TITRATED WITH 0.05 NORMAL CE(SO4)2 IN 0.1 NORMAL H2SO4 + CONCENTRATED H3PO4 WITH COLORLESS 0.1% PERPHENAZINE AS INDICATOR. THE PRECISION OF THE INDICATOR WAS HIGHER THAN THAT OF THE CURRENTLY USED FERROINE OR N-PHENYLANTHRANILIC ACID. [R67] *Photometric assay of total ascorbic acid (ascorbic acid plus dehydroascorbic acid) by conversion of the vitamin to its 2,4-dinitrophenylhydrazone. [R12] *Both gas-liquid (glc) and high performance liquid chromatographic (hplc) have been used for the assay of ascorbic acid. [R10] *AOAC Method 984.26. Vitamin C (Total) in Food. Semiautomated Fluorometric Method. [R68, 1060] *AOAC Method 967.22. Vitamin C (Ascorbic Acid) in Vitamin Preparations. Microfluorometric Method. Ascorbic acid is oxidized to dehydroascorbic acid in presence of Norit. Oxidized form is reacted with 0-phenylenediamine to produce fluorophor having activation max. at ca 350 nm and fluorescence max. at ca 430 nm. Fluorescence intensity is proportional to concentration. [R68, 1059] *AOAC Method 967.21. Vitamin C (Ascorbic Acid) in Vitamin Preparations and Juices. 2,4-Dichloroindophenol Titrimetric Method. Ascorbic acid reduces oxidation-reduction indicator dye, 2,4-dichloroindophenol, to colorless solution. At end point, excess unreduced dye is rose pink in acid solution. Vitamin is extracted and titration is performed in presence of HPO3-HOAc or HPO3-HOAc-H2SO4 solution to maintain proper acidity for reaction and to avoid autoxidation of ascorbic acid at high pH. [R68, 1059] *AOAC Method 985.33. Vitamin C (Reduced Ascorbic Acid) in Ready- to-Feed Milk-Based Infant Formula. 2,6-Dichloroindophenol Titrimetric Method. Ascorbic acid is estimated by titration with colored oxidation-reduction indicator, 2,6-dichlororindophenol. EDTA is added as chelating agent to remove Fe and Cu interferences. [R68, 1108] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW OF ASCORBIC ACID INHIBITION OF N-NITROSO COMPOUND FORMATION. [R69] DHHS/NTP; Carcinogenesis Bioassay of L-Ascorbic Acid (Vitamin C) in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 247 (1983) NIH Publication No. 83-2503 SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 130 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 99 R3: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 724 R4: SRI R5: Kavaler AR; Chemical Marketing Reporter. 237(9): 42 (1990) R6: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R7: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 349 R8: Kavaler AR; Chemical Marketing Reporter 231 (2): 46 (1987) R9: Kavaler AR; Chemical Marketing Reporter 237 (9): 42 (1990) R10: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V24 26 R11: Osol, A., and R. Pratt. (eds.). The United States Dispensatory. 27th ed. Philadelphia: J.B. Lippincott, 1973. R12: Chase et al; Remington's Pharmaceutical Sciences 14th ed. Mack Publ Co. Easton, PA p. 1036 (1970) R13: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R14: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 140 R15: Rose RC; Biochim Biophys Acta 924: 254-256 (1987) R16: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 295 R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-129 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 117 R19: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.250 R20: Kortum G et al; Dissociation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry. London: Butterworth (1961) R21: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 22 R22: McEvoy, G.K. (ed.). American Hospital Formulary Service--Drug Information 94. Bethesda, MD: American Society of Hospital Pharmacists, Inc. 1994 (Plus Supplements). 2407 R23: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 111 R24: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 557 R25: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-266 R26: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 120 R27: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1567 R28: BENTON D; THE INFLUENCE OF LARGE DOSES OF VITAMIN C ON PSYCHOLOGICAL FUNCTIONING; PSYCHOPHARMACOLOGY (BERLIN) 75(1) 98 (1981) R29: GENE-TOX Program: Current Status of Bioassay in Genetic Toxicology. U.S. Environmental Protection Agency, Washington, DC. Office of Toxic Substances and Pesticides. (For program information, contact Environmental Mutagen Information Center, Oak Ridge National Laboratory, Post Office Box Y, Oak Ridge, Tennessee 37830. Telephone (615) 574-7871) R30: Shepard, T. H. Catalog of Teratogenic Agents. 3rd ed. Baltimore, MD.: Johns Hopkins University Press, 1980. 89 R31: KANAMORI ET AL; YAKUGAKU ZASSHI 101(7) 596 (1981) R32: KEITH ET AL; NUTR INT 24(4) 811 (1981) R33: DHHS/NTP; Toxicology and Carcinogenesis Studies of L-Ascorbic Acid in F344/N Rats and B6C3F1 Mice Technical Report Series No. 247 (1983) NIH Publication No. 83-2503 R34: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R35: Hayes, W.J., Jr., E.R. Laws Jr., (eds.). Handbook of Pesticide Toxicology Volume 1. General Principles. New York, NY: Academic Press, Inc., 1991. 139 R36: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. R37: LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971. 96 R38: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 25 R39: MORRIS ET AL; BR MED J 283(AUG 15) 503 (1981) R40: FAZIO ET AL; AM J CLIN NUTR 34(11) 2394 (1981) R41: HUSSAIN ET AL; INDIAN J EXP BIOL 19(11) 1061 (1981) R42: KATO ET AL; J NUTR 111(10) 1727 (1981) R43: LAD ET AL; BIOCHEM BIOPHYS RES COMMUN 103(2) 629 (1981) R44: REYNOLDS CP, PEREZ-POLO JR; ASCORBIC ACID ENHANCES THE CYTOTOXIC EFFECT OF 6-HYDROXYDOPAMINE FOR HUMAN NEUROBLASTOMA CELL LINES; NEUROSCI LETT 26(2) 151 (1981) R45: USP Convention. USPDI-Drug Information for the Health Care Professional. 14th ed. Volume I. Rockville, MD: United States Pharmacopeial Convention, Inc., 1994. (Plus Updates). R46: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. R47: American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994. R48: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R49: ALTMANN ET AL; WIEN MED WOCHENSCHR 131(12) 311 (1981) R50: CHATTERJEE ET AL; INT J VITAM NUTR RES 51(3) 254 (1981) R51: LAKE ET AL; TOXICOL APPL PHARMACOL 60(2) 229 (1981) R52: SANDHYA P, DAS UN; IRCS MED SCI: LIBR COMPEND 9(7) 618 (1981) R53: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R54: JOHNSON ET AL; NONRESPONSIVENESS OF SERUM HIGH-DENSITY LIPOPROTEIN-CHOLESTEROL TO HIGH DOSE ASCORBIC ACID ADMIN IN NORMAL MEN; AM J CLIN NUTR 34(10) 2088 (1981) R55: MIRANDA ET AL; CHEM BIOL INTERACT 37(1-2) 95 (1981) R56: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 893 R57: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1579 R58: 21 CFR 182.3013 (4/1/93) R59: 21 CFR 182.5013 (4/1/93) R60: 21 CFR 182.8013 (4/1/93) R61: 21 CFR 582.3013 (4/1/93) R62: 21 CFR 582.5013 (4/1/93) R63: 21 CFR 200-299, 300-499, 820, and 860 (4/1/93) R64: RAO NV, RAO KM; TITRIMETRIC DETERMINATION OF ASCORBIC ACID WITH CHLORAMINE-T USING OXAZINE DYES AS INDICATORS; J INDIAN CHEM SOC 58(11) 1127 (1981) R65: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/829 45.051 R66: KIDANI ET AL; INDIRECT DETERMINATION OF MICROAMOUNTS OF MEDICINAL DRUGS BY ATOMIC-ABSORPTION SPECTROMETRY--MEASUREMENT OF L-ASCORBIC ACID; MIKROCHIM ACTA 2(3-4) 329 (1981) R67: PUZANOWSKA-TARASIEWICZ ET AL; FARM POL 37(5) 271 (1981) R68: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R69: MIRVISH SS; ASCORBIC ACID INHIBITION OF N-NITROSO COMPOUND FORMATION IN CHEMICAL, FOOD, AND BIOLOGICAL SYSTEMS; INHIBITION TUMOR INDUCT DEV: 101 (1981) RS: 43 Record 92 of 1119 in HSDB (through 2003/06) AN: 830 UD: 200208 RD: Reviewed by SRP on 3/2/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TALC- SY: *AGALITE-; *ALPINE-TALC-USP,-BC-127-; *ASBESTINE-; *CI-77718-; *DESERTALC-57-; *EMTAL-596-; *FIBRENE-C-400-; *FRENCH-CHALK-; *Hydrous-magnesium-silicate-; *LO-MICRON-TALC-USP,-BC-2755-; *MISTRON-2SC-; *MISTRON-FROST-P-; *MISTRON-RCS-; *MISTRON-STAR-; *MISTRON-SUPER-FROST-; *MISTRON-VAPOR-; *MP-12-50-; *MP-25-38-; *MP-45-26-; *NCI-CO6008-; *Nonasbestiform-talc-; *Nonfibrous-talc-; *SNOWGOOSE-; *Soapstone-; *Steatite-; *Steatite-talc-; *STEAWHITE-; *SUPREME-; *SUPREME-DENSE-; *TALC-; *TALC,-NON-ASBESTOS-FORM-; *TALC- (POWDER); *TALCUM- RN: 14807-96-6 MF: *H2-O3-Si 3/4Mg MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OPEN PIT OR UNDERGROUND MINING OF NATURAL TALC AND PROCESSING BY CRUSHING, WASHING, DRYING, AND MILLING [R1] *... VARIABLE AMT OF OTHER MINERAL SUBSTANCES ... ARE SEPARATED FROM ... /TALC/ BY MECHANICAL MEANS, SUCH AS FLOTATION OR ELUTRIATION. TALC IS THEN FINELY POWDERED, TREATED WITH BOILING DIL HCL, WASHED WELL, AND DRIED. [R2, 1266] IMP: *Impurities: dolomite; calcite; iron oxide; carbon; quartz; and manganese oxide [R3] *Tremolite [R4] FORM: *GRADES: CRUDE; WASHED; AIR-FLOATED; USP; FIBROUS (99.5%, 99.95%). [R5] *Talc, when it is isolated as a pure mineral, has a composition of 63.6% SiO2, 21.89% MgO, and 4.75% H2O. However, as an industrial commodity, talc rarely approaches theoretical purity. [R6] *When the ultra fine grinds are used (Mistron grades), they contribute to large surface areas, are non-reactive with sensitive toxicants and can be used in wettable powders. [R7] OMIN: *NATURAL HYDROUS MAGNESIUM SILICATE. COMPACT, MASSIVE VARIETIES MAY BE CALLED STEATITE IN DISTINCTION FROM THE FOLIATED VARIETIES, WHICH ARE CALLED TALC. SOAPSTONE IS AN IMPURE VARIETY OF STEATITE. [R5] *TALC IS NONADSORBENT TO MATERIALS IN SOLN AND IS CHEMICALLY INERT MEDIUM FOR FILTERING ANY LIQ, PROVIDED IT HAS BEEN PURIFIED FOR THIS PURPOSE AND IT IS NOT IMPALPABLY FINE VARIETY WHICH WILL PASS THROUGH FILTER PAPER. [R2, 1384] *SLOWLY DISAPPEARING AS POPULAR POWDER VEHICLE FOR MAJOR WOUND THERAPEUTIC INGREDIENTS. [R8] *TALC SHOULD NEVER BE USED AS DUSTING POWDER FOR SURGICAL GLOVES. [R9] */SRP: FORMER USE/ MEDICATED OR PERFUMED TALC (MAINLY MAGNESIUM SILICATE) IS WIDELY USED AS DUSTING POWDER UNDER NAME TALCUM POWDER. [R9] *The lumps are also known as soapstone or steatite. /Talc is/ finely powdered native hydrous magnesium silicate. [R10] *It is a hydrous magnesium silicate, Mg3SiO10(OH)2, theoretically 31.7% MgO, 63.5% SiO2, and 4.8% H2O. [R3] *Containers: 50 lb paper bags; 200 lb multiwall bags; bulk. [R11] *EMULSIFIED OIL WAS REMOVED FROM WASTEWATER BY STIRRING WITH TALC. [R12] USE: *ADDITIVE TO CLAY IN CERAMIC MFR AND PAPER COATINGS, FOR ROOFING MATERIALS [R1] *CARRIER AND DILUENT FOR INSECTICIDES; FILLER AND PIGMENT FOR PAINTS AND ELASTOMERS; ADDITIVE IN MFR OF REFRACTORIES [R1] */SRP: FORMER USE/ DUSTING POWDER, EITHER ALONE OR WITH STARCH OR BORIC ACID, FORMEDICINAL AND TOILET PREPN; EXCIPIENT AND FILLER FOR PILLS, TABLETS AND FOR DUSTING TABLET MOLDS; CLARIFYING LIQ BY FILTRATION; AS PIGMENT IN PAINTS, VARNISHES, RUBBER; FILLER FOR PAPER, RUBBER, SOAP; GLOVE AND SHOE POWDER; IN FIREPROOF AND COLD WATER PAINTS FOR WOOD, METAL AND STONE; LUBRICATING MOLDS AND MACHINERY; ELECTRIC AND HEAT INSULATOR [R10] *CERAMICS; COSMETICS AND PHARMACEUTICALS; FILLER IN PAINTS, PUTTY, PLASTER, OILCLOTH; ABHERENT; SLATE PENCILS AND CRAYONS [R5] *VET: TOPICALLY, ON VULVA FOLD PYODERMAS OF DOGS AS PROTECTANT. [R8] CPAT: *(INCL SOAPSTONE AND PYROPHYLLITE): 20% AS ADDITIVE IN CERAMIC MFR; 15% AS FILLER OR PIGMENT FOR PAINTS; 7% AS ADDITIVE IN PAPER COATINGS; 5% AS CARRIER OR DILUENT FOR INSECTICIDES; 4% AS ADDITIVE FOR ROOFING MATERIALS; 3% AS ADDITIVE FOR TOILET PREPARATIONS; 2% AS FILLER FOR ELASTOMERS; and 44% FOR OTHER USES IN PLASTICS, STUCCO, FLOOR TILE, FOUNDRY FACINGS, RICE POLISHING, CRAYONS, ART SCULPTURE, REFRACTORIES, ASPHALT, TEXTILES, BRICKS, ENAMEL COATING, FERTILIZER, INSULATED WIRE AND CABLE, JOINT CEMENT (1975) [R1] *Ceramics, 37%; Paints, 19%; Paper, 10%; Roofing, 9%; Plastics, 7%; Cosmetics, 5%; Rubber, 3%; insecticides, 1%; and other, 9% (1985) [R13] PRIE: U.S. PRODUCTION: *(1972) 1.0X10+12 G (+ SOAPSTONE, PYROPHYLLITE) [R1] *(1975) 8.45X10+11 GRAMS (SALES) [R1] *(1985) 1.11X10+12 g /Talc and pyrophillite/ [R13] U.S. IMPORTS: *(1972) 2.6X10+10 G (+ SOAPSTONE, PYROPHYLLITE) [R1] *(1975) 2.09X10+10 GRAMS [R1] *(1985) 3.09X10+10 g /Talc and pyrophillite/ [R13] U.S. EXPORTS: *(1972) 1.6X10+11 G (+ SOAPSTONE, PYROPHYLLITE) [R1] *(1975) 1.92X10+11 GRAMS [R1] *(1985) 2.56X10+11 g /Talc and pyrophillite/ [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE TO GRAYISH-WHITE, VERY FINE CRYSTALLINE POWDER [R10]; *Apple-green powder; luster pearly or greasy; feel greasy [R5]; +White powder. [R14] ODOR: *ODORLESS [R10]; +Odorless. [R14] MW: *96.49 [R15] DEN: *2.7-2.8 [R5] SOL: *INSOL IN WATER, COLD ACIDS OR IN ALKALIES [R10] OCPP: *UNCTUOUS, AND ADHERES READILY TO THE SKIN [R10] *MOHS HARDNESS 1-1.5 (MAY BE HARDER WHEN IMPURE) [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *MEASURES FOR HEALTH PROTECTION OF WORKERS EXPOSED TO TALC DUSTS INCL ... USE OF RESPIRATORY PROTECTIVE DEVICES ... . [R16] +Recommendations for respirator selection. Max concn for use: 10 mg/cu m. Respirator Class(es): Any dust and mist respirator. /Containing no asbestos and less than 1% quartz/ [R17, 293] +Recommendations for respirator selection. Max concn for use: 20 mg/cu m. Respirator Class(es): Any dust and mist respirator except single-use and quarter-mask respirators. Any supplied-air respirator. /Containing no asbestos and less than 1% quartz/ [R17, 293] +Recommendations for respirator selection. Max concn for use: 50 mg/cu m. Respirator Class(es): Any powered, air-purifying respirator with a dust and mist filter. Any supplied-air respirator operated in a continuous flow mode. /Containing no asbestos and less than 1% quartz/ [R17, 293] +Recommendations for respirator selection. Max concn for use: 100 mg/cu m. Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. /Containing no asbestos and less than 1% quartz/ [R17, 293] +Recommendations for respirator selection. Max concn for use: 1000 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a pressure-demand or other positive-pressure mode. /Containing no asbestos and less than 1% quartz/ [R17, 293] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. /Containing no asbestos and less than 1% quartz/ [R17, 293] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Containing no asbestos and less than 1% quartz/ [R17, 293] OPRM: *MEASURES FOR HEALTH PROTECTION OF WORKERS EXPOSED TO TALC DUSTS INCL WETTING IN EXTRACTIVE PROCESSES, PROVISION OF ADEQUATE EXHAUST VENTILATION ... IN MILLING AND PACKING OPERATIONS, SUPPLEMENTED BY USE OF RESPIRATORY PROTECTIVE DEVICES BY WORKERS AND PERIODIC MEDICAL EXAM ... INCL CHEST X-RAYS, PULMONARY FUNCTION TESTS ... AND EKG ... . [R16] +Contact lenses should not be worn when working with this chemical. [R17, 293] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *THERE IS LITTLE QUESTION BUT THAT THE DUST OF NONFIBROUS TALC, CONSISTING ALMOST ENTIRELY OF PLATIFORM TALC CRYSTALS AND CONTAINING NO ASBESTOS, CARRIES A RELATIVELY SMALL RESPIRATORY HAZARD THAT MUST BE CONTROLLED. THE DEGREE TO WHICH CONTROLS SHOULD BE APPLIED TO TALC DUST SHOULD DEPEND UPON ITS ASBESTOS CONTENT. [R18, 1986.553] SSL: *HIGH RESISTANCE TO ACIDS, ALKALIES AND HEAT [R5] CLUP: *1. VENTILATE AREA OF SPILL. 2. COLLECT SPILLED MATERIAL IN THE MOST CONVENIENT AND SAFE MANNER FOR RECLAMATION OR FOR DISPOSAL IN A SECURED SANITARY LANDFILL. [R19] DISP: *Landfill [R20, 825] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. /Talc containing no asbestos fibers; particulate matter containing no asbestos and < 1% crystalline silica; respirable fraction/ [R21] HTOX: *66 INDIVIDUALS ... HAD BEEN EXPOSED TO DUST IN 2 MILLS AND MINES HANDLING GEORGIA STEATITE TALC (SOAPSTONE) WITH 10% TREMOLITE CONTENT; THEY FOUND NO PNEUMOCONIOSIS IN THOSE WHO WORKED @ AVG DUST CONCN OF 17 MILLION PARTS/CU FT, BUT SEVERE AND DISABLING CASES WERE ... IN GROUPS WORKING @ AVG DUST CONCN OF 135-300 MPPCF. [R22] *ALTHOUGH TALC IS BENIGN SUBSTANCE WHEN APPLIED TO INTACT SKIN, IT CAN INDUCE SEVERE GRANULOMATOUS REACTIONS WHEN INTRODUCED INTO WOUNDS OR OPERATIVE FIELD. [R9] *CLINICAL PICTURE IS NONSPECIFIC WITH CHEST X-RAY PICTURES OF DIFFUSE BILATERAL CHANGES WITH VARYING DEGREES OF WIDE-SPREAD NODULATION, USUALLY WITH THICKENED PLEURA. SECONDARY INFECTION ALTERS X-RAY PICTURE ... LUNG FUNCTION ABNORMALITIES ... SHOWED ... VENTILATORY FUNCTION AND DIFFUSING CAPACITY ARE IMPAIRED. [R23, 441] *DYSPNEA ON EFFORT AND COUGH ARE PRESENTING SYMPTOMS. ... CYANOSIS AND CLUBBING WITH INCR DYSPNEA ... ACID FAST INFECTION, EMPHYSEMA, AND RIGHT HEART DISEASE ARE COMPLICATIONS OF TALC PNEUMOCONIOSIS. [R23, 441] *CASES ... ARISE AFTER MANY YR OF EXPOSURE TO TALC USED IN CABLE AND RUBBER MFR. THRUN INDOLENT COURSE, STEADILY PROGRESSING TO TERMINAL BOUTS OF RESPIRATORY AND/OR CARDIAC FAILURE. TALC BODIES- VERY LIKE ASBESTOS BODIES- MAY BE FOUND IN SPUTUM AS EVIDENCE OF EXPOSURE. [R23, 441] *TALC CAUSES PLEURAL SCLEROSIS AND FIBROSIS @ SITE OF LUNG PARENCHYMA AND LYMPH NODES. /FROM TABLE/ [R24] *Talc ... used as a dusting powder for surgeons' gloves, has induced granulomas in and about the eye. Talc employed in fulling of cloth is said to have caused conjunctival inflammation resulting in symblepharon, severe enough to require surgery in some instances. [R25] *HILAR ADENOPATHY AND LAMINATED NODULAR FIBROSIS, IF PRESENT, INDICATES MODIFIED REACTION TO TALC INITIATED BY PRESENCE OF FREE SILICA. COR PULMONALE IS OFTEN MAJOR COMPLICATION AND MECHANISM OF DEATH. [R16] *... AN ADVANCED FIBROSIS INCIDENCE RATE OF 14.5% /WAS FOUND/ IN A STUDY COVERING 221 TREMOLITE TALC MINERS AND MILLERS. THE DUST TO WHICH THESE WORKERS WERE EXPOSED WAS LARGELY FIBROUS TALC, AND THIS PHYSICAL CHARACTERISTIC WAS CONSIDERED TO BE RESPONSIBLE FOR THE PATHOLOGY OF THE LUNG LESION, PARTICULARLY BECAUSE OF ITS RESEMBLANCE TO ASBESTOSIS. /FIBROUS TALC/ [R26] *MINERS AND MILLERS OF TALC CONTAINING ASBESTIFORM AMPHIBOLES IN NEW YORK STATE DEMONSTRATE EXCESSIVE MORTALITY DUE TO NONMALIGNANT RESPIRATORY DISEASE AND BRONCHOGENIC CANCER WITH THE OBSERVED DEATHS 380 AND 270% RESPECTIVELY HIGHER THAN THE EXPECTED DEATH RATES. MOST OF THE BRONCHOGENIC CANCER DEATHS AMONG MINERS AND MILLERS OCCUR WITHIN 10-28 YEARS OF THE ONSET OF THEIR EMPLOYMENT. [R27] *Microscopic analyses were conducted on lymph node dust samples from 12 deceased Austrian workers who had been exposed occupationally to dust of talc and other mineral impurities in a talc deposit for many years. The scanning electron microscopic examination of real and irregularly shaped fibers at at a magnification of 6000x resulted in an average concentration that was increased slightly in comparison to "normal" lungs. Fibers were rather short with a mean length of 3 um. There was reasonable agreement between the grade of pneumoconiosis and the mineralogical analyses. [R28] *TALC WITH LESS THAN 1% ASBESTOS IS MAINLY REGARDED AS A NUISANCE DUST. PROLONGED OR REPEATED EXPOSURE CAN PRODUCE A FORM OF PULMONARY FIBROSIS (TALC PNEUMOCONIOSIS) WHICH MAY BE DUE TO ASBESTOS CONTENT. [R29] *THERE IS LITTLE QUESTION BUT THAT THE DUST OF NONFIBROUS TALC, CONSISTING ALMOST ENTIRELY OF PLATIFORM TALC CRYSTALS AND CONTAINING NO ASBESTOS, CARRIES A RELATIVELY SMALL RESPIRATORY HAZARD THAT MUST BE CONTROLLED. THE DEGREE TO WHICH CONTROLS SHOULD BE APPLIED TO TALC DUST SHOULD DEPEND UPON ITS ASBESTOS CONTENT. HOWEVER, DIFFICULTIES ARISE IN ATTEMPTING TO DIFFERENTIATE BETWEEN CLEAVAGE FRAGMENTS OF PRISMATIC OR ACICULAR HABIT, NONASBESTOS FIBERS, AND ASBESTOS FIBERS. ALTHOUGH EXPERIMENTAL EVIDENCE INDICATES THAT CARCINOGENICITY IS ASSOC WITH THIN LONG FIBER, IE FIBERS LESS THAN 0.5 UM WIDE AND GREATER THAN 8 UM LONG, MORE THAN 90% OF THE FIBERS COUNTED ... IN THE DUST TO WHICH TALC MINERS WERE EXPOSED WERE LESS THAN TO 5 UM LONG. IT APPEARS THAT MOST OF THE FIBERS THAT ARE COUNTED IN TALC DUST, IE PARTICLES WITH AN ASPECT RATIO GREATER THAN 3:1 AND GREATER THAN 5 UM LONG ARE NOT ASBESTOS. [R18, 1986.553] *... ON THE BASIS OF 15 CASES WITH FIVE POSTMORTEM EXAMINATIONS ... ASBESTOTIC BODIES WERE ALMOST INVARIABLY PRESENT IN THE FIBROTIC AREAS IN CASES OF TALCOSIS AND NOTED A DEGREE OF SIMILARITY BETWEEN ASBESTOSIS AND PNEUMOCONIOSIS DUE TO TALC. [R26] *One hundred sixteen female residents of western Washington State with serous and mucinous borderline ovarian tumors diagnosed between 1980 and 1985 were questioned on their use of hygienic powders. A sample of 158 control women from the same counties were identified through random digit dialing and were interviewed as well. Women who used deodorizing powders alone or in combination with other talc containing powders had 2.8 times the risk (95% confidence interval 1.1 to 11.7) of women who had not had perineal exposure to powder. The risk associated with the use of talc containing powders or cornstarch after bathing was 1.2. Women who reported any use of talc containing powder or cornstarch on sanitary napkins had a risk about double (2.2) that of women who reported no talc use. Comparing cases and controls by the type of powder used, there was no excess risk of borderline tumors among women who applied unspecified talcum powder to the perineum. [R30] *Cumulative lung damage; Pneumoconiosis (talcosis) /Talc (total)/ [R31] *Increased respiratory morbidity /was reported/ ... among workers exposed to talc. [R32] *Talc as a lubricant in surgical gloves was reported to escape into the body cavity and induce granulomas. Starch was then substituted. [R33, 529] *Talc particles are smaller than 1 um. These particles are respirable and produce an intense inflammatory response characterized by cough, rhinitis, dyspnea, and vomiting. [R33, 906] *Several cases of baby talc aspiration have been reported in children who received large doses of talc over the mouth and nose. [R33, 909] *... The clinical signs and symptoms include dyspnea, cough, chest pain, and weakness. Most ... reports have noted the similarity of talc-induced pneumoconiosis to asbestosis. Early studies suggested that tremolite, rather than pure talc, was the primary pathogenic agent. [R20, 824] *LUNG FUNCTION TESTS PERFORMED ON GROUP OF TALC MINERS AND MILLERS EXPOSED FOR AVG OF 23 YR TO TALC ADMIXED WITH TREMOLITE AND ANTHOPHYLLITE INDICATED PRESENCE OF RESTRICTIVE AND/OR OBSTRUCTIVE BREATHING DISORDER ASSOCIATED WITH IMPAIRED DIFFUSION CAPACITY OF CARBON MONOXIDE ACROSS ALVEOLAR MEMBRANE. [R16] *The toxic effects of talc are dependent on the route, dose and properties of the talc involved. ... Talc commonly contains other minerals ... including some instances several forms of asbestos and silica. [R34] *Respiratory distress syndrome, which can be fatal, has been described in children following massive accidental inhalation of talcum powder ... Acute bronchitis and bronchiolitis were found in a 22 month old boy who died following accidental inhalation of talc. [R34] *A variety of pathological effects arise from iv use of talc containing drugs by addicts. These include micronuclear pulmonary opacities, angiothrombotic pulmonary hypertension and conglomerate pulmonary lesions. [R34] *One reasonably large, representative, well controlled study of exposure in the rubber industry to Vermont talc, reported to have a low content of silica and fibers, showed significantly increased respiratory symptoms and impaired ventilatory function but no radiographic abnormality. [R35] *Four distinct forms of pulmonary disease caused by talc have been defined. The first form, talcosilicosis, is caused by talc mined with high silica content mineral. Findings in this form are identical with those of silicosis. Talcoasbestosis closely resembles asbestosis and is produced by crystalline talc, generally inhaled with asbestos fibers. Pathologic and radiographic abnormalities are virtually identical with those of asbestosis, including calcifications and malignant tumor formation. The third form, talcosis, caused by inhalation of pure talc, may include acute or chronic bronchitis as well as interstitial inflammation; radiographically, it appears as interstitial reticulations or small, irregular nodules, typical of small airway obstruction. The fourth form, due to iv administration of talc, is usually associated with abuse of oral medications and production of vascular granulomas manifested by consolidations, large nodules, and masses. Radiographic abnormalities associated with talc can be predicted when there is sufficient history of the nature of exposure, including the region of origin of the talc in cases of inhalation. Radiographic changes, such as diaphragmatic plaques, often attributed to both talc and asbestos have not been documented to be caused by talc alone. [R36] *The hypothesis whether the use of talc in genital hygiene increases the risk for epithelial ovarian cancer was tested. 235 White women diagnosed with epithelial ovarian cancer between 1984-1987 at ten Boston metropolitan area hospitals and 239 population-based controls of similar race, age, and residence were interviewed. Overall, 49% of cases and 39% of controls reported exposure to talc, via direct application to the perineum or to undergarments, sanitary napkins, or diaphragms, which yielded a 1.5 odds ratio for ovarian cancer (95% confidence interval 1.0-2.1). Among women with perineal exposure to talc, the risk was significantly elevated in the subgroups of women who applied it: 1) directly as a body powder (odds ratio 1.7, 95% confidence interval 1.1-2.7), 2) on a daily basis (odds ratio 1.8, 95% confidence interval 1.1-3.0), and 3) for more than 10 yr (odds ratio 1.6, 95% confidence interval 1.0-2.7). The greatest ovarian cancer risk associated with perineal talc use was observed in the subgroup of women estimated to have made more than 10,000 applications during yr when they were ovulating and had an intact genital tract (odds ratio 2.8, 95% confidence interval 1.4-5.4); however, this exposure was found in only 14% of the women with ovarian cancer. These data support the concept that a lifetime pattern of perineal talc use may increase the risk for epithelial ovarian cancer but is unlikely to be the etiology for the majority of epithelial ovarian cancers. [R37] *A 31 yr old woman, a heroin addict for ten yr, and infected by the human immunodeficiency virus (HIV) for one year, was admitted to the intensive care unit for respiratory failure (PaO2 = 40 mmHg and PaCO2 = 14.8 mmHg, despite breathing pure oxygen). She had been followed up for 6 mo for increasing dyspnea due to chronic core pulmonale for which no satisfactory explanation had been put forward. Artificial ventilation was completely inefficient. She died within a few hours. Postmortem lung biopsy revealed talc particles within interalveolar walls and alveolar macrophages as well as the expected alterations in blood vessels. Pulmonary hypertension due to talc microemboli is a well-known cause of respiratory failure in heroin addicts. Such a diagnosis should not be overlooked in a patient infected with HIV. Respiratory failure may not be only due to opportunist infections, or tumors related to the HIV infection. [R38] *A case of baby powder inhalation, causing adult respiratory distress syndrome in a 16 mo old girl, with follow-up after six yr is reported. Pulmonary function studies in the child and her monozygotic twin, used as a control, were normal. The testing consisted of diffusing capacity to carbon monoxide and body plethysmography, thelatter performed prior to and following an exercise challenge. A review of the literature of talcum aspiration indicates that the management of this condition is largely supportive. The long term effects of baby powder inhalation remain unknown, since serial follow-up studies are not available. [R39] *... Mortality data was collected to assess possible hazardous working conditions of talc mining employees. There were 710 white males who had worked one day or more between 1947 and 1978. Vital status was determined for the entire cohort and the cause of death was determined for all but 5 individuals. Followup was ascertained through 1983 at which time 161 of the members of the cohort were dead. When compared to US white male mortality rates, there were statistically significant increases in all causes combined, all nonmalignant respiratory disease, and lung cancer. The standardized mortality ratio for lung cancer was slightly higher for the workers with tenure of employment less than 1 year compared to workers with greater than 1 year. The lung cancer risk was higher in those with 20 or more yr of latency than in those with less than 20 yr of latency. The standard mortality ratio for nonmalignant respiratory disease was significantly elevated among those with more than 1 year of tenure. The magnitude of the risk for both lung cancer and nonmalignant respiratory disease indicated that the workplace exposures at the company were in part associated with these excesses in mortality. According to the authors, the results support the findings of an excess risk for lung cancer and nonmalignant respiratory disease observed in these workers in 1980. [R40] *Seventeen cases of talc pneumoconiosis were examined pathologically and mineralogically to ascertain whether a true talc pneumoconiosis existed and also to compare these results in primary, secondary, and tertiary exposures. Mineralogic analyses were performed on wet tissue or tissue blocks by a variety of techniques, including analytical transmission electron microscopy and x-ray diffraction. Overall, the pathologic appearance of the tissues was similar in primary, secondary, and teritary exposures, although ferruginous bodies and foreign body giant cells were not always present in cases caused by secondary exposures. Mixed dust fibrotic lesions were found in two cases in which there were substantial quantities of quartz present. There was great variation in the minerals found within the lung tissues. Several cases showed significant quantities of mica and kaolin in addition to talc. One case consisted predominantly of mica and in fact could be regarded as mica pneumoconiosis; this diagnosis was correctly attributed because of the mineralogic findings. Tremolite fibrers were found in only two cases. Substantial quantities of crocidolite and amosite fibers were found in one case. This study shows that talcosis frequently represents disease associated with a variety of minerals and that talc is a common denominator. It shows also the usefulness of lung dust mineral analysis, particularly in secondary industries, for evaluating the cause of a pathologic reaction when exposures are especially complex [R41] *Acute inhalation exposure to talc causes symptoms such as cough, dyspnea, sneezing, vomiting, andcyanosis. Talc which is water insoluble dries up the mucous membranes of the tracheobronchial trees. This results in impairment of ciliary function. Inhaling large quantities of talc can result in obstruction of the small airways in addition to drying the mucous membranes, leading to respiratory distress syndrome or death. Although there have been few studies, it was estimated that there are probably a few thousand cases of infants inhaling talc each year. Creams and lotions should be used in place of sprinkling baby powder. Clinical studies of iv drug abusers ... have shown that iv injection of pills containing psychoactive agents and talc as a binder can result in microemboli forming in small pulmonary arteries, arterioles, and capillaries. This can result in granuloma formation, impaired pulmonary function, and death. Iv injection of talc containing formulations has been shown to predispose users to infections. [R42] *The respiratory health outcomes were examined for miners and millers who worked in the New York or Vermont talc industries. The risk of malignant disease of the lung was not increased for millers but was significantly increased, 4.5 fold, for talc miners in both locations. No difference was noted in risk between miners and millers of New York and of Vermont. The risk of nonmalignant respiratory disease was significantly increased for Vermont talc millers but not for New York talc millers. The risks for nonmalignant respiratory disease for miners were calculated to be 4.1 and 3.6 for those from New York and Vermont, respectively. Influenza or pneumonia caused the death of one New York State talc worker but no Vermont talc miner or miller. Mesothelioma caused the death of one New York State talc man 15 yr after hire which followed 28 yr in mining and construction, and of one Vermont talc man. The talc mined in New York has been described as asbestiform talc while the Vermont talc has been described as nonasbestiform talc. The mortality patterns of the workers appear inconsistent with that classification. [R43] *The patterns of hepatic injury associated with various minerals were studied in seven patients. The subjects included one patient who was a sandblaster (silica by inhalation), one patient who was a dental laboratory technician (silica and chromium-cobalt alloy by inhalation), one patient with inhalational talcum powder abuse, and four chronic iv drug abusers (talc by iv injection). In all cases, the liver was examined by light and polarizing microscopy, and by scanning electron microscopy with energy-dispersive x-ray microanalysis. In the two patients with silica exposure, silica-containing sclerohyaline nodules were diffusely present in portal tracts and lobules. Both chromium cobalt alloy and silica were present in the dental technician. In contrast, in all cases of talc exposure, aggregates of talc-laden macrophages were present in portal and centrilobular areas. Three iv drug abusers and the talcum powder abuser had histologic evidence of chronic hepatitis, most probably of viral etiology. It was concluded that mineral type plays an important role in the pathogenesis and fibrogenesis of hepatic lesions.Compared with silica, talc primarily elicits a macrophage response without granuloma formation or fibrosis. Hepatic silicosis is a rare complication in dental laboratory technicians, and chromium-cobalt alloy may contribute to hepatic injury and fibrosis in this setting. [R44] *A case of talc induced lung disease was described. A 65 yr old nonsmoking female with a 2 mo history of nonproductive cough and progressive dyspnea was hospitalized. She had worked for 25 yr lubricating rubber sheets with talc, and had been retired for 8 yr. The work area had been poorly ventilated. Physical examination showed only fine bilateral basal end inspiratory crackles. Except for a mildly depressed single breath carbon monoxide transfer factor, pulmonary function was normal. No chest x-ray abnormalities were detected. Blood gas analysis revealed hypoxemia. Bronchoalveolar lavage was performed and revealed substantial lymphocytosis. An open lung biopsy showed numerous peribronchiolar granulomas with foreign body giant cells that contained talc crystals. The patient was treated with prednisone which resulted in a rapid improvement in symptoms. The prednisone therapy was discontinued after 3 mo. The patient's symptoms recurred 1 mo after discontinuing prednisone. Bronchoalveolar lavage supplemented by T cell subset analysis was performed again. This revealed lymphocytosis as before with a predominance of T8+ cells relative to T4+ cells. The patient was restarted on prednisone, and improved and remained symptom free. It is suggested that the pathogenesis of talc related pulmonary disease may be similar to that of hypersensitivity pneumonitis and mixed dust disease. Bronchoalveolar lavage may be useful for differentiating talc related disease from other granulomatous disorders. [R45] *A case of bronchiolitis in a patient with talcosis was described. A 43 year old Finnish talc miner was hospitalized with dyspnea, cough, and phlegm. He had worked as a talc loader since 1960. Dust exposures at his workplace had averaged 86 mg/cu m until 1976, after which time they were reduced to 3.5 mg/cu m due to improvements in dust control. The patient reported using paper masks only occasionally. He had smoked 20 cigarettes a day for 21 yr. He was not atopic. He reported that his symptoms decreased on weekends. Pulmonary function testing revealed a restrictive ventilatory defect and impaired diffusing capacity. No clinical or chest x-ray abnormalities were noted. Testing with fungal, bacterial, and viral agents produced negative results. He was treated with the bronchodilator salbutamol for 3 mo and then reexamined. He complained of dyspnea and wheeze after breathing dust at work, during exercise, and when breathing cold air. He was treated off and on during the next year with salbutamol and theophylline with only intermittent improvement. He was hospitalized after 1 year with progressive dyspnea, cough, and fever. A chest x-ray revealed diffuse densities in the mid and lower lung fields. A transbronchial biopsy demonstrated a granulomatous infiltration with macrophages that contained birefringent material. An open lung biopsy revealed bronchiolitis. Energy dispersive x-ray analysis of dust laden macrophages revealed the presence of talc. The patient returned to work where he used a helmet type respirator irregularly. He continued to have mild dyspnea, cough, and phlegm until his retirement in 1986. It was concluded that this is the first known case of bronchiolitis occurring in a patient with talcosis. Further studies are needed to determine whether the bronchiolitis in this case represents a general phenomenon in workers exposed to talc dust. [R46] *A hospital based case-control study of the association between fiber exposure and the development of epithelial ovarian cancer was performed. Genital and respiratory fiber exposures were ascertained from incident cases (N = 77) and age-race matched controls (N = 46) using a structured questionnaire. Cases were ascertained between 1981 and 1985. An increased risk was observed for exposure to talc on sanitary napkins (odds ratio = 4.79, 95% confidence interval, = 1.29-17.79), genital fiber exposure from different sources for a long (cumulative exposure : 37.4 yr) length of time (odds ratio = 2.35, 95% confidence interval = 0.95-5.80), and occupational fiber exposure in relatives (odds ratio = 2.81, 95% confidence interval = 0.90-8.75). A negative association was observed for antecedent tubal ligation (odds ratio = 0.15, 95% confidence interval = 0.027-0.88). [R47] *Cancer incidence and cause specific mortality were studied in a male cohort of 94 talc miners and 295 talc millers, exposed to non-asbestiform talc with low quartz content. No excess risk was found compared with national age-specific incidence. Six cases of lung cancer occurred versus 6.49 expected (miners: observed 2, expected 1.27; millers: observed 4, expected 5.22). There were 3 deaths due to non-malignant respiratory disease against 10.9 expected (miners: observed 1, expected 2.5; millers: observed 2, expected 8.4). Mesothelioma, tuberculosis, or pneumoconiosis were not recorded as causes of death. Pneumoconiosis was noted as a contributory cause in three cases (silicosis two, talcosis one). [R48] NTOX: *TALC ALONE FAILED TO INDUCE RESP TUMORS, GRANULOMAS OR MESOTHELIAL PROLIFERATION WHEN ADMIN TO SYRIAN GOLDEN HAMSTERS. [R49] *ITALIAN TALC PRODUCED FIBROSIS IN LUNGS OF RATS. THE RATS WERE EXPOSED TO 10.8 MG/CU M FOR 3, 6, AND 12 MONTHS. TWO ADENOMATA OCCURRED IN RATS EXPOSED 12 MONTHS TO TALC. [R50] *The relationship between the inhalation exposure concentration of talc and the resulting lung burdens and histologic lesions was studied using groups of 20 F344/Crl rats and 20 B6C3F1 mice (10 male and 10 female) exposed to 1 of 3 concentrations of asbestos free talc for 6 hr/day, 5 days/wk for 4 wk. Controls were exposed to filtered air using the same schedule. The pulmonary retention of talc and the development of pulmonary pathology were evaluated. The mass median aerodynamic diameter of the talc aerosol was 3.0 um with a geometric standard deviation of 1.9. The mean exposure concentrations for rats were 0, 2.3, 4.3 and 17 mg talc/cu m. Lung burdens in rats averaged 0, 0.07, 0.17 and 0.72 mg talc/g lung after the 20 day inhalation exposure; thus, the amount retained in the lung per unit of exposure concentration increased with increasing concentration. Mean exposure concentrations for the mice were 0, 2.2, 5.7 and 20.4 mg of talc/cu m, which resulted in lung burdens of 0, 0.10, 0.29 and 1.0 mg talc/g lung; thus, the relationship between exposure concentration and the amount retained in the lung was approximately constant. [R51] *Talc has been injected experimentally into the anterior chambers of eyes of rabbits and monkeys. In rabbit eyes talc causes pseudohypopyon, which has been observed for two weeks, but by four weeks disappeared, and remnants of talc found later histologically in the iris and angle of the anterior chamber appeared to be producing no granulomatous reaction. ... In monkey eyes talc in the anterior chamber has induced persistent glaucoma. [R25] *Groups of 25 male and 25 female Wistar rats, ten weeks of age, received about 50 mg/kg body weight per day commercial talc (characteristics unspecified) in the diet or standard diet for life (average survival, 649 days). No significant difference in tumor incidence was found in comparison with controls. [R52] *A group of 16 male and 16 female Wistar derived rats, 21-26 weeks of age, were exposed to 100 mg Italian talc (grade 00000; ready milled; mean particle size, 25 um; containing 92% talc, 3% chlorite, 1% carbonate minerals and 0.5% quartz) per day per rat in the diet for five months and then maintained on basal diet for life (average survival, 614 days). A control group of 16 rats was fed basal diet. No difference in tumor incidence was found between the two groups. [R52] *Three groups of 50 male and 50 female Syrian golden hamsters, four weeks old, were exposed to an aerosol of talc baby powder, prepared from Vermont talc by flotation (95% w/w platy talc with trace quantities of magnesite, dolomite, chlorite and rutile), for 3, 30 or 150 min/day on five days a week for 30 days. The mean total aerosol conc was 37.1 mg/cu m, with a mean respirable fraction of 9.8 mg/cu m and a mass median aerodynamic diameter of 4.9 um. Two further groups of hamsters, seven weeks old, were exposed to talc aerosol for 30 or 150 min/day for 300 days or until death. The mean total aerosol conc was 27.4 mg/cu m, with a mean respirable fraction of 8.1 mg/cu m and a mass median aerodynamic diameter of 6 um. Two control groups of 25 males and 25 ffemales were sham exposed. No primary neoplasm was found in the respiratory system of any hamster. The incidence of alveolar cell hyperplasia was 25% in the groups exposed to aerosol for 30 and 150 min/day for 300 days, compared with 10% in the control group. [R53] *A group of 40 female Wistar rats, eight to 12 weeks of age, received four ip injections of 25 mg granular talc in 2 ml saline at weekly intervals. A group of 80 female rats injected with saline served as controls. The rats were observed until spontaneous death or sacrifice (average survival time after injection, 602 days). A mesothelioma was observed in 1/36 talc-exposed rats after 587 days compared with none in 72 controls. [R54] *Two experiments were conducted to determine whether contact with latex or vinyl examination gloves affects canine spermatozoal motility. In experiment 1, semen was collected by digital manipulation from each of 5 dogs, and initial spermatozoal motility was assessed. The ejaculate was divided into 5 equal subsamples of 2 ml each, then randomly assigned to a control group, or treated with a 0.5 sq cm piece of latex or vinyl glove with or without talcum powder. After such exposure, spermatozoal motility was assessed at 1 and 5 min. Talcum powder within latex or vinyl glove treatments had no significant effect on spermatozoal motility at either period. Spermatozoal motility in samples did not differ between the control and vinyl glove groups; however, latex glove treated samples were found to have a significant (p < 0.05) decrease in spermatozoal motility at 1 and 5 min. In experiment 2, the effects of latex and vinyl gloves on canine spermatozoal motility during a sham laboratory manipulation was performed. Three ejaculates of approximately 10 ml were collected from each of 5 dogs and randomly assigned, within each dog, to be either a control (no glove exposure) or allowed to briefly contact either a latex or vinyl glove during sample manipulation. Spermatozoal motility was assessed for each sample immediately prior to and at 1 min after manipulation. Exposure of semen to latex gloves significantly (p < 0.05) decreased sample spermatozoal motility, whereas vinyl glove exposure had a minimal (p > 0.05) effect. [R55] *The genotoxicity of three samples of talc has been determined using in vitro cell systems previously developed for testing asbestos fibres. The talc samples used consisted of particles of respirable size in order to test the effect of particles likely to be deposited in the lung. Genotoxicity was tested in cultures of rat pleural mesothelial cells using genotoxicity assays for unscheduled DNA synthesis and sister chromatid exchanges. The effects were compared with those obtained with negative controls (attapulgite and anatase) and positive controls (chrysotile and crocidolite asbestos). In contrast to asbestos, none of the talc samples, nor the negative controls, induced enhancement of unscheduled DNA synthesis and sister chromatid exchanges in treated cultures in comparison with the untreated cultures. [R56] *In order to evaluate biological effects of Austrian and Italian talc, pulmonary and hemolytic tests as well as pathomorphological examinations were performed. 120 Wistar rats divided into 5 groups were given intratracheally 50 mg of the examined talc dust suspended in 0.5 ml of 0.9 sodium chloride. The control group received one 0.5 ml dose of sodium chloride. The observation periods were 6 and 9 mo. Then the biochemical tests for hydroxyproline content in the lung were carried out along with pathomorphotic tests to evaluate the fibrogenic activity of the talcs examined. In animals the intratracheal insufflation of talc dust causes inflammatory changes within the bronchi and lungs. On the basis of biochemical examination of lung homogenates, the differences in the hydroxyproline content were determined. After 6 mo the symptoms of chronic inflammation and cellular modules developed. Within another 3 mo the symptoms of chronic atrophic inflammation in the bronchi were observed and cellular modules containing dust particles were detected in the lung. Hemolytic test revealed a slightly higher degree of aggressiveness of the Austrian talc. [R57] *The dynamics of the acute phase response and osteoblast trabecular surface in rats was investigated with sc inflammation provoked by magnesium silicate (talc). The first visible indicator of the acute phase response was a rapid and profound hypozincemia, paralleled by a decrease in metaphyseal trabecular surfaces covered with osteoblasts in long bones. Both the intensity of serum acute phase response and the decrease in osteoblast trabecular surface were directly proportional to the number of granulomas. Alterations in bone metabolism were specific for the inflammation, whereas mild hypozincemia and decrease in mononuclear and increase in polymorphonuclear peripheral white blood cell fractions developed in animals pair-fed with rats bearing two or four granulomas. Rats with talc granulomatosis had high serum ACTH and corticosterone levels, but neither adrenalectomy nor high doses of hydrocortisone could revert bone alterations in talc injected animals. Glucocorticoids were necessary for the development of hypozincemia and hypercupremia seen in talc granulomatosis, as well as for normal bone metabolism. Inhibition of prostaglandin synthesis had no effect on bone alterations and serum acute phase response in rats bearing talc induced granulomas. It was concluded that the decrease in bone formation constitutes an important aspect of the host acute phase response in a rat model of talc granulomatosis. [R58] *The aim of this work was to study the anatomical and pathological reaction and the mechanism of the formation of the pleural symphysis during pleural talcosis. The experiment was performed on fifteen dogs of similar breed, divided into three groups of five subjects each. After thoracoscopy under general anaesthesia, 2 ml of intrapleural physiological saline were injected in group (controls) and 2 or 4 ml of talc granules in group II and III. A drainage tube was positioned at the end of the examination. One dog in each group was sacrificed on the 1st, 2nd, 7th, 15th, and 30th days post-thoracoscopy. At autopsy a detailed macroscopic study was carried out and some biopsies were taken for histology. In the control group, the inflammatory reaction was very moderate and rapidly disappeared whereas in the groups treated with talc, the talc led to an exudate of several millimeters the exudate of inflammatory reaction was acute and early and involved the pleural in particular on the costal surface and was more moderate on the visceral surface and only involved the lung to a thickness of 2 or 3 mm and a few peripheral alveolar spaces. The granulomatous reaction occurred later (from the 3rd day) and was accompanied by the formation of a symphysis by the deposition and coagulation of fibrin which continued from the 7th to the 15th day, and became solid on the 30th day post-thoracoscopy. There was no significant difference between the two groups treated with talc, implying that the reaction was linked to the talc and was independent of the dose used. [R59] *Lung deposition and the effects of subchronic exposure to talc were studied in rats and mice. F344/Crl rats were exposed to aerosols containing 2.3, 4.3, or 17 mg/cu m talc 6 hr/day, 5 days/wk for 4 wk. B6C3F1 mice were similarly exposed to 2.2, 5.7, or 20.4 mg/cu m talc aerosols. The animals were observed for clinical signs of toxicity, and were killed 24 hr after the last exposure; the lungs were removed and analyzed for talc. Mathematical models simulating chronic talc exposure utilizing the data were used to predict long term accumulations of talc in rodent and human lungs. Lungs from other animals were removed and examined for histopathological changes. No clinical signs of toxicity were seen. Talc accumulated in the lungs in a dose dependent manner. The average talc lung burdens in rats ranged from 0 to 0.72 mg/g lung tissue and in mice from 0 to 1.0 mg/g. No exposure related lung lesions other than slight diffuse increases in the number of free macrophages containing talc particles within the alveolar spaces of rats and mice exposed to the highest doses were seen. Talc lung burdens of 2 to 3 mg/g were predicted to occur in rats and mice exposed to 17 mg/cu m talc for 2 yr. In human lungs equilibrium talc lung burdens of approximately 2 mg/g were predicted to occur after 4 yr of exposure to 2 mg/cu m talc, the threshold limit value. It was concluded that the predicted long term talc lung burdens are significantly lower than those obtained experimentally. This could reflect impaired pulmonary clearance. Caution should be exercised when predicting lung burdens from short term exposures to talc concentrations of 2 mg/cu m or greater. [R60] +... CONCLUSIONS: Under the conditions of these inhalation studies, there was some evidence of carcinogenic activity of talc in male F344/N rats based on an increased incidence of benign or malignant pheochromocytomas of the adrenal gland. There was clear evidence of carcinogenic activity of talc in female F344/N rats based on increased incidences of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or malignant pheochromocytomas of the adrenal gland. There was no evidence of carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18 mg/cu m. [R61] NTP: +... Toxicology and carcinogenicity studies of talc (non-asbestiform, cosmetic grade), a finely powdered hydrous magnesium silicate, were conducted by exposing groups of F344/N rats to aerosols for 6 hr/day, 5 days/wk for up to 113 wk (males) or 122 wk (females). Groups of B6C3Fl mice were exposed similarly for up to 104 wk. LIFETIME STUDY IN RATS: Groups of 49 or 50 male and 50 female rats were exposed to aerosols of 0, 6, or 18 mg/cu m talc until mortality in any exposure group reached 80% (113 wk for males and 122 wk for females). ... These exposure concentrations provided a dose equivalent of 0, 2.8, or 8.4 mg/kg/day for male rats and 0, 3.2, or 9.6 mg/kg/day for female rats. ... The talc aerosols had a median mass aerodynamic diameter of 2.7 um in the 6 mg/cu m chamber and a median diameter of 3.2 um in the 18 mg/cu m chamber, with geometric standard deviations of 1.9 um. However, there was a 7 wk period beginning at study wk 11 during which the chamber concn for the 18 mg/cu m rats varied from approximately 30 to 40 mg/cu 3 because of difficulties with the aerosol concn monitoring system. Further, there was a 12 wk period beginning at approximately wk 70 during which there were difficulties in generating the talc aerosol, and the chamber concn for rats and mice were substantially lower than the target concn. 2-YEAR STUDY IN MICE: Groups of 47 to 49 male and 48 to 50 female mice were exposed to aerosols containing 0, 6, or 18 mg/cu m talc for up to 104 wk. ... These exposure concentrations provide a dose equivalent of 0, 2, or 6 mg/kg/day for male mice and 0, 1.3, or 3.9 mg/kg/day for female mice. ... The talc aerosols had a median mass aerodynamic diameter of 3.3 um with a geometric standard deviation of 1.9 um in the 6 mg/cu m. CONCLUSIONS: Under the conditions of these inhalation studies, there was some evidence of carcinogenic activity of talc in male F344/N rats based on an increased incidence of benign or malignant pheochromocytomas of the adrenal gland. There was clear evidence of carcinogenic activity of talc in female F344/N rats based on increased incidences of alveolar/bronchiolar adenomas and carcinomas of the lung and benign or malignant pheochromocytomas of the adrenal gland. There was no evidence of carcinogenic activity of talc in male or female B6C3F1 mice exposed to 6 or 18 mg/cu m. [R61] ADE: *FOREIGN BODY GRANULOMAS CONTAINING TALC FIBERS ARE TO BE FOUND IN LUNG, PLEURA, DIAPHRAGM, PERICARDIUM, AND GASTRIC WALL ... . [R23, 441] *... Transmission electron microscopy and energy dispersive X-ray spectroscopy /was used to analyze/ the total fibrous and nonfibrous mineral content of the lungs of a series of 14 male smokers with lung cancer but with no history of occupational dust exposure, and of a series of 14 control men matched by age, smoking history and general occupational class. The average conc of mineral fibers and nonfiberous particles were 3.8 and 2.0 times higher in the group with cancer. Kaolinite, talc, mica, feldspars and crystalline silica comprised the majority of fibrous and nonfibrous particles in both groups. [R35] INTC: *EQUAL AMT OF TALC MIXED WITH BENZO(A)PYRENE ADMIN TO SYRIAN GOLDEN HAMSTERS PRODUCED PAPILLOMAS, SQUAMOUS CELL CARCINOMAS AND UNDIFFERENTIATED TUMORS OF LARYNX, TRACHEA AND LUNGS. IT APPEARS TALC IS DEVOID OF CARCINOGENIC ACTIVITY, BUT INFLUENCES POLYCYCLIC HYDROCARBONS. [R49] *CHRONIC IRRITATION REACTION, FIBROSIS AND GRANULOMA FORMATION WERE OBSERVED HISTOLOGICALLY AFTER A SINGLE APPLICATION OF TALC AND ZINC OXIDE ON THE WOUNDED SKIN OF RATS. [R62] *This nested case control study assessed the relationship of lung cancer and time exposed to talc, while controlling for smoking, other talc exposures, and nontalc exposures. There were 22 lung cancer cases (91% smokers and 9% former smokers) and 66 controls (27% nonsmokers, 9% former smokers, and 64% smokers). Smokers were at sixfold increased risk compared to nonsmokers and ex-smokers. When stratified by smoking status, risk of lung cancer decreased with talc tenure and remained negative when excluding cases with < 20 years' latency and short-term workers. These data suggest that nontalc exposures are not confounding risk factors while smoking is, and that temporal and exposure response relationships are consistent with a smoking etiology but not an occupational etiology for lung cancer. [R63] *Subcutaneous inflammation induced by magnesium silicate (talc) leads to the suppression of bone elongation, osteoblast insufficiency, and subsequent bone loss in rats. Since bone and immunological changes in talc granulomatosis are similar to those observed in zinc deficiency, we investigated the kinetics of zinc tissue distribution and the efects of zinc supplementation on the development of bone loss in rats with talc induced inflammation. Decrease in serum zinc concentration was observed between 5 and 15 hr in rats with talc granulomatosis. It was paralleled by the accumulation of zinc in the liver and rapid disappearance of osteoblasts from the trabecular bone surfaces. However, talc injected rats supplemented parenterally and orally with zinc sulfate exhibited a decrease in osteoblast trabecular surface comparable to that of unsupplemented rats bearing granulomas despite normalized serum zinc concentrations. Zinc supplementation slightly increased osteoblast trabecular surface in all supplemented groups, but this effect was not significant. It was concluded that zinc is the earliest indicator of the acute phase response in rats with talc granulomatosis. Although zinc appears to be important for the normal function of bone cells, there is no causative relationship between acute zinc deficiency and decreased osteoblast number and activity in rats with talc granulomatosis. [R64] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *NATIVE TALC, CALLED SOAPSTONE OR FRENCH CHALK, IS FOUND IN VARIOUS PARTS OF WORLD ... EXCELLENT QUALITY IS OBTAINED FROM NORTH CAROLINA ... MANCHUKUO (MANCHURIA). NATIVE TALC IS USUALLY ACCOMPANIED BY VARIABLE AMT OF OTHER MINERAL SUBSTANCES. [R2, 1266] *TALC IS A MINERAL PRODUCT, THE COMPOSITION OF WHICH VARIES WIDELY FROM ONE GEOLOGICAL DEPOSIT TO ANOTHER AND EVEN WITHIN THE SAME DEPOSIT. THE MAIN COMPONENT IS A CRYSTALLINE HYDRATED SILICATE OF MAGNESIUM. [R18, 1986.550] *The term talc ... covers a wide range of natural minerals, most of which are high magnesium silicates. It is a hydrous magnesium silicate, Mg3SiO10(OH)2, theoretically 31.7% MgO, 63.5% SiO2, and 4.8% H2O. The mineral talc is usually, although not always, a main constituent of mineral mixtures offered commercially as talc. [R3] *Minerals commonly associated with talc are tremolite (CaMg3(SiO3)4), serpentine (2MgO.2SiO2.2HsO), anthophyllite (Mg7.(OH)2.(Si4O11)2), magnesite, mica, and chlorite. The latter is a talclike mineral in which varying proportions of aluminium are substituted for magnesium in the brucite layer. Prochlorite, for example, is 9MgO.3Al2O3.5SiO2.8H2O [R3] RTEX: *... MIGRATES TO FOOD FROM PACKAGING MATERIALS. [R29] *Talc milling processes do not usually alter the mineral composition of the talc mixture delivered to the mill, but rather produce a talc with different physical properties dependent on particle size. Exposure to talc dust occurs during mining, crushing, separating, bagging, loading and in end-use facilities, such as rubber dusting and addition of talcs to ceramic clays and glazes. Since industrial talc is a misture of various associated minerals, occupational exposure is to a mixture of mineral dusts. [R65] *TO DATE ... NO REPORTS OF SIGNIFICANT RISK OF LUNG CANCER IN WORKERS EXPOSED TO ENOUGH TALC TO CAUSE PULMONARY FIBROSIS. IT MAY BE THAT SUCH NEOPLASTIC EFFECT HAS NOT BEEN NOTED BECAUSE NUMBER OF WORKERS EXPOSED TO ENOUGH TALC IS FAR SMALLER THAN NUMBER EXPOSED TO ASBESTOS. [R23, 442] *POTENTIAL OCCUPATIONAL EXPOSURES INCL COSMETIC WORKERS, PAINT MAKERS, PAPER MAKERS, POTTERY MAKERS, RUBBER CABLE COATERS, RUBBER TIRE MAKERS, TALC MILLERS, TALC MINERS, AND TALC POWDER MAKERS. [R66] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +1000 mg/cu m /Containing no asbestos and less than 1% quartz/ [R17, 292] OSHA: +Table Z-3 8-Hour Time Weighted Avg: 20 million particles per cubic feet of air (mppcf). /Talc (not containing asbestos) containing less than 1% quartz/ [R67] NREC: +Recommended Exposure Limit: 10 Hr Time Weighted Avg: 2 mg/cu m (resp). /Containing no asbestos and less than 1% quartz/ [R17, 292] TLV: +8 hr Time Weighted Avg (TWA): 2 mg/cu m. /Talc containing no asbestos fibers; particulate matter containing no asbestos and < 1% crystalline silica; respirable fraction/ [R21] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Talc containing no asbestos fibers; particulate matter containing no asbestos and < 1% crystalline silica; respirable fraction/ [R21] +A4; Not classifiable as a human carcinogen. /Talc containing no asbestos fibers; particulate matter containing no asbestos and < 1% crystalline silica; respirable fraction/ [R21] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *DETERMINATION OF MIN AMT OF 10 SELECTED MINERALS MOST COMMONLY FOUND IN ATMOSPHERIC PARTICULATES BY X-RAY DIFFRACTOMETRY. DETECTION LIMIT WAS 0.4 UG/SQ CM FOR TALC. [R68] ALAB: *SEVERAL BATCHES OF TALC FROM DIFFERENT GEOGRAPHICAL REGIONS WERE ANALYZED BY ATOMIC ABSORPTION SPECTROSCOPY AND THE ACID-SOLUBLE AND ACID-INSOLUBLE CATION CONTENT DETERMINED. [R69] *Talc determination by IR spectrography. [R70] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: KINGLAKE V; SOAP PERFUM COSMET 54 (AUG): 399 (1981). THE SOURCE OF TALC AND ITS USE IN THE FORMULATION OF BABY POWDERS, COSMETIC POWDERS, DRY SHAMPOOS, BLEACHING MASKS AND ANTIPERSPIRANTS ARE DISCUSSED. DHHS/NTP; Toxicology and Carcinogenesis Studies of Talc in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 421 (1993) NIH Publication No. 93-3152 Merchant JA; Human Epidemiology: A review of Fiber Type and Characteristics in the Development of Malignant and Nonmalignant Disease. Environ Health Perspect 88: 287-93 (1990). Consideration of the human epidemiology of diseases arising from exposure to naturally occurring and man made mineral fibers encompasses the several forms of asbestos (chrysotile, crocidolite, amosite, anthophyllite, tremolite-actinolite), other naturally occurring silicates (talc, sepiolite, erionite, attapulgite, vermiculite, and wollastonite), and man made mineral fibers (glass continuous filament, glass/rock/slag insulation wools, ceramic and other refractory fibers, and glass microfibers). Dutch Expert Committee for Occupational Standards; Health-based Recommended Occupational Exposure Limit for Talc Dusts. Ministerie van Sociale Zaken en Werkgelegenheid, Directoraat-Generaal van de Arbeid), Postbus 90804, 2509 LV Den Haag, Netherlands, 57. Talc is a hydrous magnesium silicate. Two different groups of talc dust must be distinguished: cosmetic grade talc and industrial grade talc. Feigin DS; Misconceptions Regarding the Pathogenicity of Silicas and Silicates. J Thoracic Imaging 4 (1): 68-80 (1989). The pathogenicity of silicas and silicates was reviewed, with emphasis on talc. Particular attention was given to the controversies surrounding the results of inhalation of talc and other silicates, with an emphasis on exposures from nonmining settings. One controversy involved the definition of silicates and silicas. Particle shape and size have been important elements in these definitions. Distinctions between fibrous and nonfibrous silicates were not entirely clear. Hajjar NP et al; Health Assessment Document for Talc. Govt Reports Announcements and Index (GRA and I), Issue 24 (1992). Talc is made up of pulverized, foliated, hydrous magnesium silicates from minerals with low crystalline silica content. Approximately 1.25 million short tons of talc were produced in the United States in 1989. The largest end uses of talc are in ceramics and paint; 5% is used in cosmetics. SO: R1: SRI R2: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V22 523 (1983) R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V22 525 (1983) R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1113 R6: Lefond SJ, ed; Industrial Minerals and Rocks, 5th ed V2 p.1275 (1983) R7: Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-330 R8: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 321 R9: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 953 R10: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1429 R11: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. ,p. 835 R12: TREATMENT OF WASTEWATER CONTAINING OIL; JPN KOKAI TOKKYO KOHO PATENT NUMBER 80 70307 05/27/80 (MATSUSHITA ELECTRIC INDUSTRIAL COMPANY, LTD) R13: BUREAU OF MINES. MINERAL COMMODITY SUMMARIES 1986 p.156 R14: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 292 R15: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8303 R16: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 2142 R17: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R18: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists R19: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R20: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R21: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.55 R22: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)242 R23: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. R24: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 266 R25: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 878 R26: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3029 R27: BROWN DP ET AL; DUSTS DIS (PROC CONF OCCUP EXPOSURES FIBROUS PART DUST THEIR EXT ENVIRON): 317 (1979) R28: Friedrichs, KH; Am Ind Hyg Assoc J 48 (7): 626-33 (1987) R29: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2496 R30: Harlow BL, Weiss NS; Am J Epidemiol 130 (2): 390-4 (1989) R31: Cralley, L.J., L.V. Cralley (eds.). Patty's Industrial Hygiene and Toxicology. Volume III: Theory and Rationale of Industrial Hygiene Practice. 2nd ed., 3A: The Work Environment. New York, NY: John Wiley Sons, 1985.182 R32: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 1001 R33: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V42 207 (1987) R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V42 208 (1987) R36: Feigin DS; AJR Am J Roentgenol 146 (2): 295-301 (1986) R37: Harlow BL et al; Obstet Gynecol 80 (1): 19-26 (1992) R38: Magnan A et al; Ann Fr Anesth Reanim 10 (1): 74-6 (1991) R39: Reyes de la Rocha S, Brown MA; Pediatr Emerg Care 5 (1): 43-8 (1989) R40: Brown DP et al; Govt Reports Announcements and Index (GRA and I), Issue 15 (1991) R41: Gibbs AE et al; Hum Pathol 23 (12): 1344-54 (1992) R42: Hollinger MA; Toxicology Letters 52 (2): 121-7( 1990) R43: Lamm SH, Starr JA; Proc VIIth Intern Pneumoconioses Conference, Part II. Pittsburgh, PA, August 23-26, 1988. DHHS (NIOSH) Publication No. 90-108 Part II, 1576-81 (1990) R44: Liu YC et al; Hum Pathol 22 (11): 1120-7 (1991) R45: Redondo AA et al; Thorax 43 (12): 1019-21 (1988) R46: Reijula K et al; Br J Indust Med 48 (2): 140-2 (1991) R47: Rosenblatt KA et al; Gynecol Oncol 45 (1): 20-5 (1992) R48: Wergeland E et al; Am J Ind Med 17 (4): 505-13 (1990) R49: STENBACK F, ROWLAND J; SCAND J RESPIR DIS 59 (3): 130 (1978) R50: WAGNER JC ET AL; DUSTS DIS (PROC CONF OCCUP EXPOSURES FIBROUS PART DUST THEIR EXT ENVIRON): 389 (1979) R51: Pickrell JA et al; Environ Res 49 (2): 233-45 (1989) R52: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V42 199 (1987) R53: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 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Technical Report Series No. 421 (1993) NIH Publication No. 93-3152 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R62: FUKAWA K ET AL; YAKUGAKU ZASSHI 102 (JAN): 89 (1982) R63: Gamble JF; Int Arch Occup Environ Health 64 (6): 449-56 (1993) R64: Marusic A et al; Biol Trace Elem Res 29 (2): 165-73 (1991) R65: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V42 193 (1987) R66: Arena, J.M. Poisoning: Toxicology-Symptoms Treatments. Third Edition. Springfield, Illinois: Charles C. Thomas, 1974. 291 R67: 29 CFR 1910.1000 (7/1/98) R68: PLOWMAN C; ANALYST (LONDON) 103: 982 (1978) R69: CLOUX JL ET AL; J PHARM BELG 37 (1): 27 (1982) R70: Heidermanns G, Jonas C; Staub - Reinhalt Luft 49 (1): 17-24 (1989) RS: 67 Record 93 of 1119 in HSDB (through 2003/06) AN: 852 UD: 200211 RD: Reviewed by SRP on 08/07/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRANITROMETHANE- SY: *METHANE,-TETRANITRO-; *NCI-C55947-; *TNM- RN: 509-14-8 MF: *C-N4-O8 SHPN: UN 1510; Tetranitromethane IMO 5.1; Tetranitromethane HAZN: P112; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... BY NITRATION OF ACETYLENE WITH NITRIC ACID TO FORM TRINITROMETHANE, THE MIXT OF TRINITROMETHANE AND NITRIC ACID BEING CONVERTED TO TETRANITROMETHANE BY SULFURIC ACID AT ELEVATED TEMP. [R1, 4156] *Tetranitromethane is formed by the quantitative reaction between potassium nitroform and nitryl chloride in ether. [R2] MFS: +Hummel Chemical Company, Incorporated, Hq, PO Box 250, South Plainfield, NJ 07080, (201) 754-1800; Production site: 10 Harmich Rd, South Plainfield, NJ 07080 [R3] OMIN: *Has been proposed as irritant war gas. [R4] USE: *Rocket fuel, as an oxidant or monopropellant; qualitative test for unsaturated compounds; diesel fuel booster; organic reagent. [R5] *... As explosive in admixture with toluene. To increase cetane number of diesel fuels. Reagent for detecting the presence of double bonds in organic cmpd. [R4] PRIE: U.S. PRODUCTION: *(1977) GREATER THAN 4.54X10+5 G [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW LIQUID [R4]; *COLORLESS OILY FLUID [R1, 4155]; +Colorless to pale-yellow liquid or solid (below 57 degrees F). [R7] ODOR: *ACRID BITING ODOR [R1, 4157]; +Pungent odor. [R7] BP: *126 deg C @ 760 mm Hg; 40 deg C @ 25.8 mm Hg; 30 deg C @ 14.9 mm Hg; 20 deg C @ 8.4 mm Hg; 13.8 deg C @ 5.7 mm Hg; 0 deg C @ 1.9 mm Hg [R4] MP: *13.8 DEG C [R4] MW: *196.04 [R8] CORR: *Attacks iron, copper, brass, zinc, rubber [R4] DEN: *1.6229 @ 20 DEG C/4 DEG C [R4] OWPC: *log Kow= -0.791 (est) [R9] SOL: *INSOL IN WATER; SOL IN ETHANOL AND ETHER [R10]; *FREELY SOL IN ALCOHOLIC POTASSIUM HYDROXIDE [R4] SPEC: *INDEX OF REFRACTION: 1.4384 @ 20 DEG C/D [R10]; *INDEX OF REFRACTION: 1.4358 @ 25 DEG C/D [R4]; *IR: 6408 (Coblentz Society Spectral Collection) [R11]; *MASS: 1116 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R11] VAPD: *0.8 (AIR= 1) [R1, 4143] VAP: +vapor pressure = 8.42 mm Hg @ 25 deg C [R12] VISC: *1.76 CENTIPOISES @ 20 DEG C [R4] OCPP: *DENSITY: 1.638 @ 25 DEG C/4 DEG C /TECHNICAL/ [R4] *Powerful oxidizing agent [R5] *Henry's Law constant: 2.55X10-5 atm-cu m/mole (calc) [R13] +vapor pressure = 13 MM HG AT 25 DEG C [R1, 4143] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: May explode from friction, heat or contamination. These substances will accelerate burning when involved in a fire. May ignite combustibles (wood, paper, oil, clothing, etc.). Some will react explosively with hydrocarbons (fuels). Containers may explode when heated. Runoff may create fire or explosion hazard. [R14, p. G-143] +Health: TOXIC; inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns, or death. Fire may produce irritating and/or toxic gases. Toxic fumes or dust may accumulate in confined areas (basement, tanks, hopper/tank cars, etc.). Runoff from fire control or dilution water may cause pollution. [R14, p. G-143] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R14, p. G-143] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R14, p. G-143] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R14, p. G-143] +Fire: Small fires: Use water. Do not use dry chemicals or foams. CO2 or Halon may provide limited control. Large fires: Flood fire area with water from a distance. Do not move cargo or vehicle if cargo has been exposed to heat. Move containers from fire area if you can do it without risk. Do not get water inside containers: a violent reaction may occur. Cool containers with flooding quantities of water until well after fire is out. Dike fire-control water for later disposal. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R14, p. G-143] +Spill or leak: Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Use water spray to reduce vapors or divert vapor cloud drift. Prevent entry into waterways, sewers, basements or confined areas. Small spills: Flush area with flooding quantities of water. Large spills: DO NOT CLEAN-UP OR DISPOSE OF, EXCEPT UNDER SUPERVISION OF A SPECIALIST. [R14, p. G-143] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R14, p. G-143] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.3 kilometers (0.2 miles) and NIGHT 0.5 kilometers (0.3 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 60 meters (200 feet); then, PROTECT persons Downwind during DAY 0.6 kilometers (0.4 miles) and NIGHT 1.3 kilometers (0.8 miles). [R14, p. TABLE] TOXC: *Toxic gases and vapors (such as oxides of nitrogen and carbon monoxide) may be released in a fire involving tetranitromethane. [R15] EXPL: *SEVERE, WHEN SHOCKED OR EXPOSED TO HEAT. IT CAN FORM VERY POWERFUL EXPLOSIVES WHEN MIXED WITH OTHER HIGH EXPLOSIVES WHICH ARE SOMEWHAT OXYGEN-DEFICIENT. [R16, 1156] *HIGHLY EXPLOSIVE IN PRESENCE OF IMPURITIES. [R4] *TETRANITROMETHANE (SELF-REACTIVE): THIS CMPD IS A WEAK BUT HIGHLY SENSITIVE EXPLOSIVE. [R17] REAC: *HYDROCARBONS EXPOSED TO /IT/ FORM EXCEEDINGLY SENSITIVE EXPLOSIVES. [R17] +Hydrocarbons, alkalis, metals, oxidizers, aluminum, toluene, cotton [Note: Combustible material wet with tetranitromethane may be highly explosive]. [R18, 304] DCMP: *... WHEN HEATED TO DECOMPOSITION, IT EMITS HIGHLY TOXIC FUMES OF /NITROGEN OXIDES/. [R16, 1156] SERI: *Skin irritant. [R4] *THIS MATERIAL IRRITATES EYES AND RESPIRATORY PASSAGES. [R16, 2550] EQUP: *WORKERS SHOULD BE PROVIDED WITH RESPIRATORY PROTECTIVE EQUIPMENT AND SKIN PROTECTION. [R19] +Wear appropriate personal protective clothing to prevent skin contact. [R18, 305] +Wear appropriate eye protection to prevent eye contact. [R18, 305] +Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R18, 305] +Recommendations for respirator selection. Max concn for use: 4 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any chemical cartridge respirator with a full facepiece and cartridge(s) providing protection against the compound of concern. Only nonoxidizable sorbents allowed (not charcoal). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Only nonoxidizable sorbents allowed (not charcoal). Any powered, air-purifying respirator with cartridge(s) providing protection against the compound of concern. Eye protection needed. Only nonoxidizable sorbents allowed (not charcoal). Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R18, 305] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R18, 305] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern. Only nonoxidizable sorbents allowed (not charcoal). Any appropriate escape-type, self-contained breathing apparatus. [R18, 305] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Apparatus in which /tetranitromethane is/ produced or processed should be of the sealed type ... Measures against fires and explosions are also necessary. [R19] +Contact lenses should not be worn when working with this chemical. [R18, 305] +The worker should immediately wash the skin when it becomes contaminated. [R18, 305] +Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R18, 305] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R18, 305] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R20] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R21] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R22] STRG: *EXTREMES OF HEAT OR COLD, OF AIR DRYNESS OR OF MOISTURE IN STORAGE, ROUGHNESS OR CAREFULNESS WITH WHICH HANDLED, LENGTH OF TIME STORED / and / ... OUT OF ... ORIGINAL CONTAINER BEFORE USED ... HAVE VITAL INFLUENCE ON BEHAVIOR OF COMMERCIAL EXPLOSIVE. /EXPLOSIVES/ [R16, 1156] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. COLLECT FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR MATERIAL. AVOID SHOCK AND FRICTION IF LIQUID SPILLS ON COMBUSTIBLE MATTER SUCH AS WOOD AND PAPER. [R15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P112, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R23] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R24] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of tetranitromethane. There is sufficient evidence in experimental animals for the carcinogenicity of tetranitromethane. Overall evaluation: Tetranitromethane is possibly carcinogenic to humans (Group 2B). [R25] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R26, 2002.57] ANTR: *If solid or liquid tetranitromethane or strong concentrations of tetranitromethane vapors get into the eyes, wash eyes immediately with large amounts of water, lifting the lower and upper lids occasionally. If irritation is present after washing, get medical attention promptly. [R15] MEDS: *General medical supervision, including periodic medical exam of workers is also recommended. [R19] HTOX: *THIS MATERIAL IRRITATES EYES AND RESPIRATORY PASSAGES AND DOES SERIOUS DAMAGE TO THE LIVER. ... IT CAN CAUSE PULMONARY EDEMA ... METHEMOGLOBINEMIA, AND FATTY DEGENERATION OF THE LIVER AND KIDNEYS. [R16, 2550] *SYMPTOMS EXPERIENCED IN THE LABORATORY PRODUCTION OF TETRANITROMETHANE WERE IRRITATION OF EYES, NOSE AND THROAT FROM ACUTE EXPOSURES AND, AFTER MORE PROLONGED INHALATION, HEADACHE AND RESPIRATORY DISTRESS. [R1, 4157] *... CHRONIC SIGNS AND SYMPTOMS INCLUDED HEADACHE, WEARINESS AND PNEUMONIA. AFTER PROLONGED EXPOSURE CENTRAL NERVOUS SYSTEM AND HEART WERE AFFECTED. [R27] *The effect of tetranitromethane on the cortisol binding activity of human transcortin was investigated. This reagent induced a decr of activity concomitant with nitration of L-tyrosine residues. An oxidation of sulfhydryl groups was also observed, but had no implication on cortisol binding. A single essential tyrosine per molecule of transcortin seems implicated in cortisol binding. [R28] *Toxic by ingestion, inhalation, and skin absorption. [R5] NTOX: *FROM ANIMAL EXPERIMENTS IT HAS BEEN FOUND THAT CONCENTRATIONS AS LOW AS 0.1 PPM HAVE PROVED RAPIDLY FATAL, AND THAT CONCENTRATIONS OF 3.3 TO 25.2 PPM PRODUCED VERY RAPID AND MARKED IRRITATION OF MUCOUS MEMBRANES OF EYES, MOUTH, AND UPPER RESPIRATORY TRACT. [R16, 2550] *FIRST SIGNS /OF INHALATION EXPOSURE IN ANIMALS/ ARE INCREASED PREENING, CHANGE IN RESPIRATORY PATTERN, ... EYE IRRITATION, ... RHINORRHEA, GASPING AND SALIVATION. SYMPTOMS PROGRESS TO CYANOSIS, EXCITEMENT, AND DEATH @ HIGHER CONCN. METHEMOGLOBINEMIA ... RESULTS OF PATHOLOGICAL EXAM OF ANIMALS DYING FROM ACUTE EXPOSURES WERE ... LUNG IRRITATION WITH DESTRUCTION OF EPITHELIAL CELLS, VASCULAR CONGESTION, PULMONARY EDEMA, AND EMPHYSEMA WITH TRACHEITIS AND BRONCHOPNEUMONIA. NONSPECIFIC CHANGES IN THE LIVER AND KIDNEY WERE OBSERVED ... [R1, 4156] *... TWO DOGS AND 19 RATS /WERE EXPOSED/ TO 6.35 PPM FOR 6 HR A DAY, 5 DAYS A WEEK, FOR 6 MO. ELEVEN ... RATS DIED ... WITH ... PULMONARY IRRITATION, EDEMA, AND PNEUMONIA. SOME INITIAL ANOREXIA WAS OBSERVED IN THE DOGS. REPEATED EXAM DID NOT REVEAL ANEMIA, HEINZ BODIES, METHEMOGLOBINEMIA, OR BIOCHEMICAL DISTURBANCES. RATS SURVIVING 6.35 PPM FOR 6 MO DEVELOPED PNEUMONITIS AND BRONCHITIS OF A MODERATE DEGREE, WHEREAS THOSE DYING DEVELOPED MORE SEVERE PNEUMONIA. [R1, 4157] */EXPOSURE OF CATS TO TETRANITROMETHANE AT/ CONCN RANGING FROM 3.3 to 25.2 PPM CAUSED MARKED IRRITATION OF MUCOUS MEMBRANES, ACUTE PULMONARY EDEMA, MILD METHEMOGLOBINEMIA, AND PROBABLY FATTY DEGENERATION OF LIVER AND KIDNEYS, AND WERE FATAL USUALLY AFTER A FEW HR EXPOSURE. AT CONCN BETWEEN 0.1 AND 0.4 PPM ... MILD IRRITATION OF EYES WAS NOTED. [R27] *THE RELATION AMONG STRUCTURE, TOXICITY, AND ANTIMICROBIAL ACTIVITY OF NITROALKANES AND THEIR ALPHA-HALO DERIVATIVES WERE STUDIED. THE IP LD50 VALUES OF 32 NITROALKANES AND HALONITROALKANES WERE DETERMINED IN MICE, AND THE INHIBITORY CONCENTRATIONS OF THE COMPOUNDS WERE OBTAINED USING ESCHERICHIA COLI AND STAPHYLOCOCCUS AUREUS AS TEST ORGANISMS. SUBSTITUTION OF NITRO BY METHYL GROUP IN METHANE AND ETHANE DERIVATIVES LOWERED TOXICITY. BROMO-SUBSTITUTED NITROALKANES WERE MORE TOXIC THAN THEIR CHLORO ANALOGS. DERIVATIVES OF NITROETHANE SHOWED GREATER ANTIBACTERIAL ACTIVITY THAN DERIVATIVES OF NITROMETHANE. /NITROALKANES AND HALONITROALKANES/ [R29] *Dominant transforming genes were detected in lung tumors from Fischer 344 rats and C57BL/6 X C3H F1 mice chronically exposed by inhalation to tetranitromethane, a highly volatile compound used in several industrial processes. The rat lung neoplasms were classified as adenocarcinomas, squamous cell carcinomas (epidermoid carcinomas), or adenosquamous carcinomas. The mouse lung tumors were classified as papillary adenocarcinomas or adenomas. In both species, the tumors were morphologically similar to lung tumors in humans. The transfection assay using NIH/3T3 mouse fibroblasts detected transforming genes in 74% (14 of 19) of the rat lung tumors and in 100% (4 of 4) of the mouse lung tumors. Southern blot analysis indicated that transforming gene was an activated K-ras protooncogene in both species. The first exon of the K-ras gene in normal DNA and in DNA from two cell lines transformed by tumor DNA was compared by cloning and sequencing the gene. Experiments showed that there was a GC----AT transition in the second base of the 12th codon of the K-ras oncogene in the two transfectant DNAs. Oligonucleotide hybridization indicated that all of the rat and mouse transfectants had this activating lesion. Additional tumor DNA was then tested for the presence of a mutated allele with the GC----AT transition. All of the rat tumors tested and all of the mouse tumors tested had this mutation present. Hybridization using the normal oligonucleotide sequence around the 12th codon indicated that the normal allele was also present in the majority of the tumors, suggesting that the loss of normal allele is not necessary for the developing of neoplasia. One rat lung tumor had no normal allele present, possibly suggesting that this tumor could have been in a more advanced stage than the other tumors. This is the first study to detect activated protooncogenes in rodent tumors induced under conditions which mimic human exposure to chemical in the workplace. Tetranitromethane may exert its carcinogenic action by both activation of the K-ras oncogene and stimulation of cell proliferation by its irritant properties. [R30] *The nitrosating agent tetranitromethane and the nitrosation production of 3-nitro-L-tyrosine were tested for mutagenic activity in the Salmonella/mammalian microsome assay. Tetranitromethane showed strong genotoxic activity: it was mutagenic in all tester strains used (TA97, TA98, TA100, and TA102). The maximum mutagenic activity was reached between 16 and 32 ug/plate using the standard plate test; higher amounts led to distinct bactericidal effects. The mutagenicity was independent of an in vitro activation system. In the preincubation assay an increased bactericidal effect was observed. In contrast to tetranitromethane, 3-nitro-L-tyrosine, the nitrosation product, was non-mutagenic and non-toxic in the standard plate test and with the preincubation method up to 5000 ug/plate with and without S9 mix and with all tester strains used. Although tetranitromethane is a strong direct-acting mutagen, its nitrosating effect on proteins does led to non-genotoxic nitro products of tyrosine in proteins. [R31] NTXV: *LC50 Rat /inhalation 1230 ppm/ 36 min; [R15] *LD50 Rat oral 130 (83-205) mg/kg (95% confidence limit) /From table/; [R1, 4157] *LD50 Mouse oral 375 (262-511) mg/kg (95% confidence limit) /From table/; [R1, 4157] *LD50 Rat iv 12.6 (10.0-15.9) mg/kg (95% confidence limit) /From table/; [R1, 4157] *LD50 Mouse iv 63.1 (45.0-88.7) mg/kg (95% confidence limit) /From table/; [R1, 4157] NTP: *Male and female F344/N rats were exposed to tetranitromethane by inhalation at 0, 2, or 5 ppm/6 hr/day, 5 days/wk for 2 yr. Male and female B6C3F1 mice were exposed to tetranitromethane by inhalation at 0, 0.5, or 2 ppm 6 hr/day, 5 days/wk for 2 yr. ... Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of tetranitromethane for male and female F344/N rats and male and female B6C3F1 mice, based on increased incidences of alveolar/bronchiolar neoplasms in both species and squamous cell carcinomas of the lung in rats. [R32] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Tetranitromethane may be released to the environment as a result of its manufacture and use as a rocket fuel, diesel fuel booster, organic reagent, and as an explosive in admixture with toluene. It may be released to the environment as a result of the production of TNT since it is a byproduct in the production of this explosive. If tetranitromethane is released to soil, it will be expected to be very highly mobile. Based upon a measured vapor pressure of 8.4 mm Hg at 20 deg C, volatilization from dry near-surface soil or other surfaces may be important processes. No data were located concerning biodegradation or hydrolysis of tetranitromethane in soil. If released to water, it will be expected to be subject to volatilization based upon an estimated Henry's Law constant. The volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 2.1 days. The volatilization half-life from a model pond has been estimated to be 24 days. It will not be expected to adsorb to sediment or suspended particulate matter based upon the estimated Koc or to bioconcentrate in aquatic organisms based upon an estimated BCF of 0.15. No data were located concerning biodegradation, direct photolysis, hydrolysis or oxidation of tetranitromethane in aqueous media. If it is released to the atmosphere, it will expected to exist almost entirely in the vapor phase based upon its vapor pressure. It should not be susceptible to photooxidation via vapor phase reaction with photochemically produced hydroxyl radicals. Exposure to tetranitromethane will be primarily occupational, via inhalation and dermal routes. (SRC) ARTS: *Tetranitromethane may be released to the environment as a result of its manufacture and use(SRC). It has been investigated as a rocket fuel, diesel fuel booster, organic reagent, and as an explosive in admixture with toluene(1,2). It has been proposed to be a component of war gases(2). It may be released as a result of the production of TNT since it is a byproduct in the production of this explosive(3). [R33] FATE: *TERRESTRIAL FATE: If tetranitromethane is released to soil, it will be expected to be very highly mobile based upon(3,SRC) an estimated Koc of 8.8(1,2,SRC) and, therefore, it may leach to groundwater(3,SRC). Based upon a measured vapor pressure of 8.4 mm Hg at 20 deg C(4), volatilization from dry near-surface soil or other surfaces may be important processes(SRC). No data were located concerning biodegradation or hydrolysis of tetranitromethane in soil(SRC). [R34] *AQUATIC FATE: If tetranitromethane is released to water, it will be expected to be subject to volatilization based upon a Henry's Law constant which was estimated(1,SRC) from a vapor pressure of 8.4 mm Hg at 20 deg C(2) and an estimated water solubility of 8.5X104 mg/L at 25 deg C(1,3,SRC). It will not be expected to adsorb to sediment or suspended particulate matter based upon an estimated Koc of 8.8(1,3,SRC) or to bioconcentrate in aquatic organisms based upon an estimated BCF of 0.15(1,3,SRC). No data were located concerning biodegradation, direct photolysis, hydrolysis or oxidation of tetranitromethane in the environment(SRC). [R35] *ATMOSPHERIC FATE: If tetranitromethane is released to the atmosphere, it will be expected to exist almost entirely in the vapor phase(1) based upon a reported vapor pressure of 8.4 mm Hg at 20 deg C(2). It should not be susceptible to photooxidation via vapor phase reaction with photochemically produced hydroxyl radicals(3,SRC). [R36] ABIO: *Tetranitromethane has been estimated to be inert to reaction with photochemically produced hydroxyl radicals in the atmosphere(1). Since tetranitromethane absorbs UV light at wavelengths > 290 nm(2), it may be susceptible to direct photolysis(SRC). [R37] BIOC: *An estimated BCF of 0.15 can be calculated(1,SRC) from an estimated log Kow of -0.791(2). This estimated BCF indicates that tetranitromethane will not be expected to bioconcentrate in aquatic organisms(SRC). [R38] KOC: *An estimated Koc of 8.8 can be calculated(1,SRC) from an estimated log Kow(2). This estimated Koc indicates that tetranitromethane will not be expected to adsorb to soils, sediment, and suspended particulate matter(3,SRC) and that the compound will be expected to exhibit very high mobility in soil(3). [R39] VWS: *Based upon an estimated water solubility of 8.5X10+4 mg/l, calculated(1,SRC) from an estimated log Kow of -0.791(2,SRC) using a recommended regression equation(1,SRC), and a vapor pressure of 8.4 mm Hg at 20 deg C(3), the Henry's Law constant for tetranitromethane has been calculated to be 2.55X10-5 atm-cu m/mole(1,SRC). The volatilization half-life from a model river (1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 2.1 days(1,SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be 24 days(4,SRC). Based upon its vapor pressure(3), volatilization of tetranitromethane from surfaces and near-surface dry soil may be important processes(SRC). [R40] RTEX: *Exposure to tetranitromethane will be primarily occupational, via inhalation and dermal routes of exposure. (SRC) *DYSPNEA, COUGH, AND DIZZINESS IN MEN HANDLING CRUDE TNT HAS BEEN ATTRIBUTED TO TETRANITROMETHANE ... . [R41] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,445 workers are potentially exposed to tetranitromethane in the USA(1). [R42] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +4 ppm [R18, 304] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1 ppm (8 mg/cu m). [R43] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 ppm (8 mg/cu m). [R18, 304] TLV: +8 hr Time Weighted Avg (TWA): 0.005 ppm. [R26, 2002.57] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R26, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R26, 2002.57] OOPL: *USSR: 0.04 ppm (1967) [R27] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R44] +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Tetranitromethane is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R45] RCRA: *P112; As stipulated in 40 CFR 261.33, when tetranitromethane, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R46] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method S224. Analyte: Tetranitromethane. Matrix: Air. Procedure: Collection in ethyl acetate/impingers. Flow Rate: 1 l/min. Sample Size: 250 liters. [R47] ALAB: *NIOSH Method S224. Analyte: Tetranitromethane. Matrix: Air. Procedure: Gas chromatography/alkali-flame ionization detection. Method Evaluation: Method was validated over the range of 2.70 to 11.5 mg/cu m using a 250 liter sample. Method detection limit: not given. Precision (CVt): 0.076. Applicability: Under the conditions of sample size (250 liter) the useful range is 1 to 16 mg/cu m. Interferences: Any compound which has the same retention time as the analyte at the operating conditions described in this method is an interference. [R47] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: KINKEAD ER ET AL; TOXIC HAZARDS EVALUATION OF FIVE ATMOSPHERIC POLLUTANTS FROM ARMY AMMUNITION PLANTS; US NTIS, AD REPORT, AD-A043957 PP 39 (1977). TOXIC HAZARDS OF 5 ATMOSPHERIC POLLUTANTS FROM ARMY AMMUNITION PLANTS ARE EVALUATED. DHHS/NTP; Toxicology and Carcinogenesis Studies of Tetranitromethane in F344 Rats and B6C3F1 Mice (Inhalation Studies) Report #386 (1990) NIH Pub # 90-2841 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V15 974 (1981) R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 1030 R4: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1455 R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1139 R6: SRI R7: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 304 R8: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 84/8401 R9: SRC; CLOGP3; PCGEMS Graphical Exposure Modeling System USEPA (1986) R10: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-350 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 842 R12: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. R13: SRC; Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 2-14, 15-15 to 15-29 (1982) R14: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000 R15: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R16: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R17: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 491M-210 R18: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R19: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1451 R20: 49 CFR 171.2 (7/1/96) R21: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 219 R22: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.5086 (1988) R23: 40 CFR 240-280, 300-306, 702-799 (7/1/90) R24: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-10 (1981) EPA 68-03-3025 R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 65 468 (1996) R26: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R27: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.567 R28: Le Gaillard F et al; Biochimie 64 (2): 153-58 (1982) R29: FRIDMAN AL ET AL; KHIM-FARM ZH 10 (6): 53 (1976) R30: Stowers SJ et al; Cancer Res 47 (12): 3212-29 (1987) R31: Wuergler FE et al; Mutat Res 244 (1): 7-14 (1990) R32: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tetranitromethane in F344 Rats and B6C3F1 Mice (Inhalation Studies) Report #386 (1990) NIH Pub # 90-2841 R33: (1) Hawley GG; Condensed Chemical Dictionary 10th ed NY: Van Nostrand Reinhold p. 1010 (1981) (2) Merck; The Merck Index 10th ed Rahway, NJ: Merck and Co p. 9061 (1983) (3) Ryon MG et al; Database Assessment of the Health and Environmental Effects of Munition Production Waste Products. Final Rpt ORNL-6018 NTIS DE84-016512 pp. 217 (1984) R34: (1) Lyman WJ et al; Handbook of Chem Property Estimation Methods NY: McGraw-Hill pp. 4-9, 15-9 to 15-31 (1982) (2) CLOGP3; PCGEMS Graphical Exposure Modeling System USEPA (1986) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Boublik T et al Vapor Pressures of Pure Substances. Elsevier NY (1984) R35: (1) Lyman WJ et al; Handbook of Chem Property Estimation Methods NY: McGraw-Hill pp. 2-14, 4-9, 5-5, 15-9 to 15-31 (1982) (2) Boublik T et al; Vapor Pressures of Pure Substances. Elsevier NY (1984) (3) CLOGP3; PCGEMS Graphical Exposure Modeling System USEPA (1986) R36: (1) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (2) Boublik T et al; Vapor Pressures of Pure Substances. Elsevier NY (1984) (3) Atkinson R; Intern J Chem Kinetics 19: 799-828 (1987) R37: (1) Atkinson R; Intern J Chem Kinetics 19: 799-828 (1987) (2) Carpenter BH et al; Specific Air Pollutants From Munitions Processing and Their Atmospheric Behavior Vol 3 Final Report (NTIS AD-A060147). Research Triangle Park, NC: Res Triangle Park, pp. 139 (1977) R38: (1) Lyman WJ et al; Handbook of Chem Property Estimation Methods NY: McGraw-Hill pp. 5-5 (1982) (2) CLOGP3; PCGEMS Graphical Exposure Modeling System USEPA (1986) R39: (1) Lyman WJ et al; Handbook of Chem Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (2) CLOGP3; PCGEMS Graphical Exposure Modeling System USEPA (1986) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R40: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 2-14, 15-15 to 15-29 (1982) (2) CLOGP3; PCGEMS Graphical Exposure Modeling System USEPA (1986) (3) Boublik T et al; Vapor Pressures of Pure Substances. Elservier NY (1984) (4) USEPA; EXAMS II Computer Simulation (1987) R41: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 319 R42: (1) NIOSH; The National Occupational Exposure Survey (NOES) (1983) R43: 29 CFR 1910.1000 (7/1/98) R44: 40 CFR 302.4 (7/1/90) R45: 40 CFR 355 (7/1/97) R46: 40 CFR 261.33 (7/1/90) R47: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V3 S224-1 RS: 39 Record 94 of 1119 in HSDB (through 2003/06) AN: 860 UD: 200302 RD: Reviewed by SRP on 5/6/2000 NT: This record contains information specific to the title compound. Those with an interest in this record are strongly encouraged also to retrieve the record on NICKEL COMPOUNDS which has additional, general information relevant to the toxicity and environmental fate of nickel ions and nickel compounds. For information on the metal itself, refer to the NICKEL, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NICKEL-CHLORIDE- SY: *NICKEL- (2+)-CHLORIDE; *NICKEL-CHLORIDE- (NICL2); *NICKEL-DICHLORIDE-; *NICKEL- (II)-CHLORIDE; *NICKEL- (II)-CHLORIDE- (1:2); *NICKELOUS-CHLORIDE- RN: 7718-54-9 RELT: 6933 [NICKEL COMPOUNDS]; 1096 [NICKEL, ELEMENTAL] MF: *Cl2-Ni STCC: 49 663 64; Nickel chloride MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepn: nickel chloride may be prepared from nickel oxide by chlorination or by reaction with hydrogen chloride. [R1] *REACTION OF NICKEL POWDER OR NICKEL OXIDE WITH HYDROCHLORIC ACID FOLLOWED BY EVAPORATION; PASSAGE OF CHLORINE GAS OVER HEATED NICKEL [R2] *Action of hydrochloric acid on nickel [R3] FORM: *Technical, 99+%. [R4] *-10 mesh and -60 mesh, 99.5 and 99.999% purity grades; 6 lb/gal electrodeless nickel grade; high purity soln suitable for printed circuit and other plating and metal treating applications; liquid grades; crystal and powder grades [R5] MFS: *Atotech USA Inc., 1750 Overview Drive, Rock Hill, SC 29730, (803)817-3500; Production site: Rock Hill, SC 29730 [R6] *Chemtech Products Inc., 1630 Des Peres Road, Suite 210, St. Louis, MO 63131, (314)965-7100; Production site: St. Louis, MO 63131 [R6] *GFS Chemicals Inc., P.O. Box 245, Powell, OH 43065, (740)881-5501; Production site: Columbus, OH 43222 [R6] *IMC/Americhem, One Pitcairn Place, 165 Township Line Road, Jenkintown, PA 19046-3593, (215)517-6000; Production site: Shelby, NC 28152-0648 [R6] *Mallinckrodt Baker, Inc., 675 McDonnell Blvd., PO Box 5840, St. Louis, MO 63134, (314)654-2000; Production site: Phillipsburg, NJ 08865 [R6] *McGean Rohco, Inc., Republic Building, Suite 1100, 25 Prospect Ave. West, Cleveland, OH 44115, (216)441-4900; Production site: Cleveland, OH 44105 [R6] *OMG Fidelity Chemical Products, Corp., 470 Frelinghuysen Ave., Newark, NJ 07114, (973)242-4110; Production site: Newark, NJ 07114 [R6] *OM Group, Inc., World Headquarters, 50 Public Square, 3800 Terminal Tower, Cleveland, OH, 44113, (216)781-0083; Production site: Franklin, PA 16323 [R6] *Phibro-Tech, Inc., One Parker Plaza, Fort Lee, NJ 07024, (201)944-6000; Production site: Sewaren, NJ 07077 [R6] USE: *For nickel plating cast zinc; mfr sympathetic ink; absorbent for NH3 in gas masks [R7] *Used for nickel plating cast zinc; agent in electrolytic refining of nickel; chemical intermediate for nickel catalysts and complex nickel salts; absorber of ammonia gas in industrial gas masks; catalyst in diarylamine and silicon tetrachloride production; agent in electrodeless plating of nickel; agent in tin-nickel alloy plating. Fungicide; control of rust and rustlike disease /SRP: former use/. [R8, 867] *Electroplated nickel coatings, reagent chemical [R3] *... /has/ been used successfully for control of rust and rust-like diseases. /SRP: former use/ [R9] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 5.09X10+8 G [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Yellow scales; ... golden yellow [R8, 867]; *Brown scales [R3]; *Golden yellow [R10] ODOR: *None [R8, 867] BP: *Sublimes @ 973 deg C; deliquesces [R8, 1117] MP: *1001 deg C [R11] MW: *129.60 [R7] DEN: *3.51 [R11] SOL: *Soluble in ethanol and ammonium hydroxide, insoluble in ammonia [R8, 867]; *64.2 g/100 cc water @ 20 deg C [R8, 867]; *87.6 g/100 cc water @ 100 deg C [R8, 868]; *SOL IN ETHANOL AND AMMONIUM HYDROXIDE [R12]; *INSOLUBLE IN AMMONIA [R12]; *16.2 wt% in ethylene glycol at 20 deg C [R13]; *0.8 G/100 ML HYDRAZINE @ 20 DEG C [R13]; *Water solubility: 2.54X10+6 mg/l @ 20 deg C [R14] VAP: *1 mm Hg at 671 deg C (solid) [R8, 868] OCPP: *Green, deliquescent crystals or crystal powder, monoclinic, structure reported to be trans-(NiCl2(H2O)4.2H2O, sol in about one part water, in alcohol /Hexahydrate/ [R7] *Golden-yellow, sublimable in absence of air, readily absorbs NH3. /Anhydr salt/ [R7] *Aq soln is acid; pH about 4. /Hexahydrate/ [R7] *Heat of Solution: 8.8 Btu/lb= 4.9 cal/g= 0.21x10+5 J/kg [R4] *Heat of fusion: 142.5 cal/g [R4] *Green scales, sol in water, alcohol, and ammonium hydroxide /Hexahydrate/ [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R15] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R15] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R15] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R15] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R15] FPOT: *Nonflammable [R16] FIRP: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty). Use foam, dry chemical, or carbon dioxide. Keep run-off water out of sewers and water sources. [R17, 760483] TOXC: *Toxic gases and vapors (such as nickel carbonyl) may be released in a fire involving nickel ... /Nickel and sol nickel cmpd/ [R18] EXPL: *A MIXTURE OF POTASSIUM AND ... /NICKEL CHLORIDE/ PRODUCES A STRONG EXPLOSION ON IMPACT ... . [R19] DCMP: *When heated to decomp it emits very toxic fumes of /hydrogen chloride/. [R20] *Toxic gases and vapors (such as nickel carbonyl) may be released ... in the decomp of nickel cmpd. /Nickel and sol nickel cmpd/ [R18] SERI: *Inhalation of dust causes irritation of nose and throat. Dust irritates eyes ... . [R4] EQUP: *Goggles or face shield; protective gloves; Bureau of Mines approved respirator; protective clothing. [R4] OPRM: *Personnel protection: Keep upwind. Avoid breathing dusts and fumes from burning material. ... Avoid contact with the material. [R17, 760] *If material not involved in fire: Keep material out of water sources and sewers. [R17, 760] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. /Nickel metal and other compounds, as Ni/ [R21, 225] *The worker should wash daily at the end of each work shift. /Nickel metal and other compounds, as Ni/ [R21, 225] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Nickel metal and other compounds, as Ni/ [R21, 225] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Nickel metal and other compounds, as Ni/ [R21, 225] STRG: *Use ambient storage temp and open venting. [R4] *KEEP WELL CLOSED. [R10] CLUP: *Nickel is removed from waste water containing nickel chloride by using membrane electrodialysis with a cell thickness 0.77 mm and flow rate 1.18 ml/min. [R22] */Precipitator is/ effective for controlling ... /nickel chloride/ discharged on the ground or into water. [R23] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *... Nickel chloride is a water soluble salt. ... Respiratory absorption with secondary GI absorption of nickel (insoluble and soluble /salts/) is the major route of entry during occupational exposure. A significant quantity of inhaled material is swallowed following mucocillary clearance from the respiratory tract. Poor personal hygiene and work practices can contribute to GI exposure. Percutaneous absorption is negligible, quantitatively, but is important in the pathogenesis of contact hypersensitivity. Absorption is related to the solubility of the compound, followed the general relationships nickel carbonyl > soluble nickel compounds > insoluble nickel compounds. ... Studies in which nickel was administered via inhalation are limited. Studies on hamsters and rats ... /with/ soluble nickel chloride ... /absorption was/ rapid. ... Nickel chloride injected ip into mice and rats caused a rapid decr in body temperature. Nickel chloride given orally, or by inhalation, has been reported to decr iodine uptake by the thyroid /gland/. ... Nickel chloride affects the T-cell system and suppresses the activity of natural killer cells. Parenteral administration of nickel chloride ... has been reported to cause interuterine mortality and decr weight gain in rats and mice. ... Nickel chloride /did not/ induce tumors of the peritoneal cavity in rats after repeated administration. /Another study reported that/ ... nickel chloride which had not induced local tumors in im studies, were tested using repeated ip administration, ... elicited a carcinogenic response. ... Cases of nickel poisoning ... /have been reported/ in electroplaters who accidentally ingested water contaminated with ... nickel chloride. [R24] CARC: *Evaluation: There is sufficient evidence in humans for the carcinogenicity of nickel sulfate, and of the combinations of nickel sulfides and oxides encountered in the nickel refining industry. There is inadequate evidence in humans for the carcinogenicity of metallic nickel and nickel alloys. There is sufficient evidence in experimental animals for the carcinogenicity of metallic nickel, nickel monoxides, nickel hydroxides and crystalline nickel sulfides. There is limited evidence in experimental animals for the carcinogenicity of nickel alloys, nickelocene, nickel carbonyl, nickel salts, nickel arsenides, nickel antimonide, nickel selenides and nickel telluride. There is inadequate evidence in experimental animals for the carcinogenicity of nickel trioxide, amorphous nickel sulfide and nickel titanate. The Working Group made the overall evaluation on nickel compounds as a group on the basis of the combined results of epidemiological studies, carcinogenicity studies in experimental animals, and several types of other relevant data, supported by the underlying concept that nickel compounds can generate nickel ions at critical sites in their target cells. Overall evaluation: Nickel compounds are carcinogenic to humans (Group 1). Metallic nickel is possibly carcinogenic to humans (Group 2B). /Nickel compounds/ [R25] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 t0 15 L/min. Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Nickel and related compounds/ [R26, p. 371-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Consider drug therapy for pulmonary edema ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Nickel and related compounds/ [R26, 372] HTOX: *Nickel chloride (NiCl2) produces a dose dependent depression of proliferation and mitotic rate ... in 2 human cell lines, HeLa and diploid embryonic fibroblasts ... /Additional effects included/ ... increasing release of intracellular lactic dehydrogenase ...; /increased/ lactic acid production; /reduced/ plating efficiency, DNA synthesis, protein synthesis, RNA synthesis. ... Serum constituents, notably albumin, bind the metal effectively and inhibit cellular uptake. [R27] *Cells from the CHO-K1-Chinese hamster fibroblast line and human lymphocytes from the peripheral blood of a male subject were used to evaluate subtoxic doses of insoluble metal compounds in the sister chromatid exchange assay. While NTA did not induce sister chromatid exchange in the CHO cell line, soluble compounds of cadmium chloride, potassium dichromate, mercury chloride, and nickel chloride significantly increased sister chromatid exchange in CHO cells, establishing a clear dose effect relationship. Equimolar concentrations of NTA did not enhance sister chromatid exchange induction by metals. The NTA/metal complexes, once formed, were genetically active at extremely low concentrations. The enhancement of the genetic activity was not pH dependent. These effects were also demonstrated in the presence of sodium, magnesium and calcium ions in concentrations largely exceeding those of the genotoxic metal cationic and anionic forms. [R28] *Thirty-two workers in an electroplating plant accidentally drank water contaminated with nickel sulfate and nickel chloride (1.63 g nickel/l). Twenty workers rapidly developed symptoms (e.g., nausea, vomiting, abdominal discomfort, diarrhoea, giddiness, lassitude, headache, cough, shortness of breath) that typically lasted a few hours, but persisted for 1-2 days in 7 cases. The nickel doses in workers with symptoms were estimated to range from 0.5 to 2.5 g. In 15 exposed workers, who were investigated on day 1 after exposure, serum-nickel concentrations ranged from 12.8 to 1340 ug/l (average 286 ug/l) with urinary nickel concentrations ranging from 0.23 to 37.1 mg/l (average 5.8 mg/l) compared with control values for nickel-plating workers of 2.0-6.5 ug/l (average 4.0 ug/l) for serum nickel and 22-70 ug/l (average 50 ug/l) for urinary nickel. Laboratory tests showed transiently elevated levels of blood reticulocytes (7 workers), urine-albumin (3 workers), and serum-bilirubin (2 workers) ... . [R29] *When aqueous solutions of nickel chloride were applied to the back, the threshold concentrations for irritancy were 1% with occlusion and 10% without occlusion ... . [R30] NTOX: *... NICKEL CHLORIDE IS LETHAL TO DOGS WHEN IV ADMIN IN A SINGLE DOSE OF 10-20 MG/KG, THE CARDIAC AND RESPIRATORY NERVE CENTERS ARE AFFECTED; GROSS CHANGES CONSIST OF EDEMA, HEMORRHAGE, AND DEGENERATION OF THE HEART MUSCLE, BRAIN, LUNG, LIVER, AND KIDNEY. [R31, 1825] *... CHLORIDE OF INHALED NICKEL ... GREATLY INCREASED THE VISCOSITY OF LUNG WASHINGS /IN RATS/, @ APPROXIMATELY THE SAME EXPOSURE LEVEL (100 UG NICKEL/CU M). MOST PROMINENT EFFECT OF ... THE CHLORIDE WAS HYPERPLASIA OF THE BRONCHIOLAR AND BRONCHIAL EPITHELIUM WITH PERIBRONCHIAL LYMPHOCYTIC INFILTRATION. [R31, 1825] *... NICKEL CHLORIDE, NICKEL SULFATE, AND NICKEL NITRATE /WERE NOT/ ... MUTAGENIC IN A STUDY OF MUTATION IN STREPTOMYCIN DEPENDENT E COLI STRAIN ... SIMILAR NEGATIVE RESULTS WERE FOUND ON TESTING BACTERIOPHAGE T4 WITH NISO4 DURING PHAGE REPLICATION IN T4 INFESTED E COLI ... [R31, 1829] *FISCHER FEMALE RATS HAD PROTEINURIA AFTER SINGLE IP DOSE OF NICKEL CHLORIDE (34-85) MOLES/KG AND ALPHA-AMINOACIDURIA AFTER IP DOSE OF 68 and 85 MOLES/KG. RETURNED TO NORMAL BY DAY 5. [R32] *RATS GIVEN NICKEL CHLORIDE (16 MG NI/KG) IM DURING EARLY GESTATION CAUSED INCR EMBRYO DEATH AND IMPAIRED FETAL GROWTH AT DOSES THAT DID NOT CAUSE MATERNAL MORTALITY. [R33] *EMBRYOS GROWN IN 10-3 TO 10-2 MOLAR NICKEL CHLORIDE CLEAVED AT A NORMAL RATE AND FORMED BLASTULAE BUT DID NOT GASTRULATE. [R34] *MICE IMMUNIZED IP WITH SHEEP RBC WERE TREATED WITH NICKEL CHLORIDE. INJECTIONS WITH 9.26-12.34 UG NICKEL ION/G CAUSED SIGNIFICANT IMMUNOSUPPRESSION. [R35] *SINGLE IP OR INTRATRACHEAL INJECTION OF NICKEL CHLORIDE IN RATS CAUSED RAPID TRANSIENT INCR IN SERUM GLUCOSE AND DECR IN SERUM INSULIN AND GLYCOSURIA. INSULIN INHIBITION MAY BE DUE TO NICKEL IN PITUITARY. [R36] *SUBCUTANEOUS INJECTION OF NICKEL CHLORIDE (20 and 10 MG/KG) LED TO PROFOUND AND CONSISTENT INCR OF CIRCULATING PROLACTIN LEVELS AFTER 1 DAY AND LASTED FOR 4 DAYS IN MALE RATS. HAS EFFECTS ON ENDOCRINE SYSTEM AND IS MEDIATED THROUGH NEUROENDOCRINE SYSTEM. [R37] *ADMIN OF NICKEL CHLORIDE TO PREGNANT MICE ON 7TH-11TH DAY OF GESTATION RESULTED IN SIGNIFICANT EMBRYOTOXIC EFFECTS SUCH AS INCR RESORPTION RATE, DECR FETAL WT, DELAY IN SKELETAL OSSIFICATION AND HIGH INCIDENCE OF MALFORMATION. [R38] *NICKEL CHLORIDE INDUCED DNA STRAND BREAKS IN CULTURED CHINESE HAMSTER OVARY CELLS. [R39] *SC INJECTION OF NICKEL(II) CHLORIDE INTO RABBITS (5 MG METAL/KG) INHIBITED ADP INDUCED PLATELET AGGREGATION IN PLASMA SAMPLES TAKEN AT VARIOUS TIMES AFTER INJECTION. [R40] *Injection of 2 or 4 mg nickel chloride produced prompt elevations in plasma glucose and glucogen levels which returned to normal 2-4 hr afterwards in normal, adrenalectomized, and hypophysectomized rats. [R41] *Nickel chloride given orally to rats at 0.5 to 5.0 mg/kg/day for two to four weeks or by inhalation (0.05 to 0.5 mg/cu m) significantly decreased iodine uptake by the thyroid, the effect being more pronounced for inhaled nickel. [R42] *Rats given a single 19 mg/kg dose of nickel chloride or an oral 225 ppm long term exposure in water had 4 fold increases in serum glucose, hyperlipidemia, and insulin resistance, with elevated serum triglycerides. [R43] *In rats given a 250 mg/kg ip injection of nickel chloride as a single dose 3-6 hr before sacrifice, ATP-ase activity in brain capillaries was abolished. [R44] *18 guinea pigs were given nickel chloride by ip injection at a dose of 4 umol/100 g (about 5 mg/kg) eighteen controls received injections of saline only. Urinary corticoid excretions in animals treated with nickel chloride was almost twice that of controls. [R45] *Dose related increases in /metallothionein/ concn were observed in liver and kidney of /male Fischer/ rats killed 17 hr after injection of nickel chloride (NiCl2) (0.25-0.75 mmol/kg, sc). Repeated administration of nickel chloride (0.1 mmol/kg ip) on 4 successive days, with sacrifice 3 days after last treatment, increased metallothionein concn 1.4 fold in liver and kidneys ... . [R46] *Nickel chloride produces a dose dependent depression of proliferation and mitotic rate ... in ... V-79 Chinese hamster cells and in L-A mouse fibroblasts. /Additional effects included/ ... increasing release of intracellular lactic dehydrogenase ...; /increased/ lactic acid production; /reduced/ plating efficiency, DNA synthesis, protein synthesis, RNA synthesis. ... Serum constituents, notably albumin, bind the metal effectively and inhibit cellular uptake. [R27] *Intratracheal instillation of nickel chloride (0.1 or 1.0 umol/lung) inhibited the p-nitroanisole O-demethylase activity (30 and 54%, respectively) ... in isolated, ventilated and perfused rat lung preparations. [R47] *Nickel chloride caused substantial induction of DNA repair synthesis at ... 100 uM ... in cultured Syrian hamster embryo and Chinese hamster ovary cells. Repair synthesis was detected at concn ... which result in no detectable damage to DNA. [R48] *Nickel chloride (NiCl2) ... injected into chicken eggs at dosages ranging from 0.02-0.7 mg/egg ... at days 0, 1, 2, 3, and 4 of incubation ... /produced dose related effects including/, exencephaly, everted viscera, short and twisted neck and limbs, microphthalmia, hemorrhage, and reduced body size. The toxicity and teratogenicity of NiCl2 was the highest in the embryos treated at day 2. [R49] *Female C3H/HeJ or CD-1 mice were infected with a sublethal dose of murine cytomegalovirus and then exposed to nickel chloride (NiCl2) or cadmium chloride intramuscularly (im) or by inhalation. Effects of these treatments on disease susceptibility, virus augmented and spontaneous natural killer cell activity, and virus induction of interferon were determined. NiCl2 (20 mg/kg, im) enhanced mortality due to murine cytomegalovirus in both mouse strains, and a reduction in virus augmented natural killer cell activity was seen at doses as low as 10 mg NiCl2/kg. Effects on natural killer activity did not appear to be due to effects on interferon production since neither of the metal treatments caused a depression of this response. [R50] *Acute thymic involution ocurred in male, Fischer-344 rats following a single injection of nickel chloride (0.5 mmol/kg, sc). In nickel treated rats, the mean thymic weight was significantly decreased at 24 hr, continued to diminish at 48 hr, and reached 24% of the control value at 72 hr post injection. The ratio of thymic weight to body weight (mg/g) decreased from 1.24 + or - 0.05 (SD) in control rats to 0.30 + or - 0.05 in nickel treated rats at 72 hr post injection (p < 0.01). The mean concentration of thymic lipoperoxides was unchanged at 24 hr, increased 2 fold at 48 hr, and reached 8 times the control value at 72 hr after nickel chloride injection. Sections of thymus from nickel treated rats showed moderate to profound depletion of cortical lymphocytes at 72 hr post injection. Marked degenerative changes were noted in cortical lymphocytes, with pyknosis and karyorrhexis; swelling and vacuolation were evident in thymic reticular epithlial cells. [R51] *The effects of lead acetate, nickel chloride and sodium selenite on resistance to experimentally induced Klebsiella pneumoniae infection was investigated in mice, with particular emphasis on the interference of the time of toxic exposure with the infectious challenge. A single intraperitoneal dose of 24 mg/kg lead or 4 mg/kg nickel enhanced the resistance of mice to Klebsiella pneumoniae when administered 24 hr before the infectious challenge, whereas host resistance was impaired when the same dose was injected 5 hr after the infectious challenge. A 3 day pretreatment with 8 or 12 mg/kg lead enhanced host resistance but 0.5 or 1 mg/kg nickel decreased it. In all cases, sodium selenite increased the resistance of mice toward infection. [R52] *Rabbits were exposed to 0.6 mg/cu m of nickel as nickel chloride for one month; alveolar macrophages were lavaged and divided into three fractions by elutriation. Laminated structures in the macrophages were related to fraction number so that the fractions with the largest cells contained the highest number of structures. Lysozyme activity decreased in unfractionated as well as in fractionated macrophages from nickel exposed rabbits. The decrease was most pronounced in the fraction with the smallest macrophages and smallest number of laminated structures. [R53] *Male Sprague-Dawley rats injected subcutaneously with nickel chloride show significantly increased lipoperoxidation (as indicated by the presence of thiobarbituric acid chromogens) in the liver, kidney, and lung and dose related increases in hepatotoxicity (as measured by serum aspartate-aminotransferase). Cojugated dienes in hepatic microsomal lipids were increased by ten fold in rats given 750 micromol/kg nickel chloride, compared to paired controls. Rats given 500 micromol/kg nickel chloride exhale significant amounts of ethane and ethylene at 13 to 16 and 20 to 23 hr post injection. Erythrocyte deformability was significantly reduced in rats bled 24 or 48 hr after injection of 750 micromol/kg nickel chloride. Plasma lipoperoxide concentrations significantly increase by 24 or 48 hr in rats given 250 to 750 micromol/kg nickel chloride. When pretreated with three antioxidants, sodium ascorbate, promethazine hydrochloride, or selenium dioxide, followed by 500 microg/kg nickel chloride, the increase of thiobarbituric acid chromogens in rat kidney homogenates was partially suppressed by selenium dioxide. The other antioxidants had no effect. [R54] *Inbred male or female Fischer-344 rats, 60 days old, received a single intramuscular injections of 10 to 20 mg/lg nickel chloride in the thigh to determine whether the rat immune system responds in a manner similar to that of the mouse. Significant decreases in body weight were noted at 15 or 20 mg/kg along with decreased spleen weights at the higher dose level. Rat demonstrated suppression of natural killer cell activity similar to that previously observed in mice. This suppression allowed the development of lung tumors following the injection of syngeneic tumor cells. Suppression of natural killer cell activity was temporary, and recovery to normal activity occurred within a few days. T-cell mediated responses, which were suppressed in mice, were elevated in the rat, but not significantly. T-cell responses such as lymphoproliferation in response to the T-cell mitogens concanavalin-A and phytohemagglutinin and the T-cell and B-cell pokeweed mitogen, as well as the primary antibody response to the T-cell dependent antigen sheep red blood cells, were elevated in treated rats. [R55] *The chelating efficacy of triethylenetetraamine, glutathione and the macrocyclic drugs, cyclam and cyclam s, for nickel (Ni chloride) was studied in 6-wk-old female albino rats. The drugs were injected sc (20 rats/dose) with 250, 500, and 1000 umol/kg 60 min after a single sc injection of NiCl2 (500 umol/kg) that caused 100% mortality within 6 hr. At a 1:0.5 mol (nickel:chelating drug) all drugs reduced mortality. To compare the ability of the drugs to enhance urinary excretion, groups (n= 5) were injected with (63) Ni (250 umol Ni/kg containing 400 uCi) 60 min prior to injection of 500 umol of chelator (saline as a control). With the exception of glutathione effects on urinary Ni excretion, all drugs significantly (p < 0.05) enhanced urinary and biliary excretion of Ni. Urinary excretion of Ni at 72 hr was highest for cyclam. To compare the efficacy of the drugs in reducing Ni body burden and the comparative affinity for other trace metals, 8 rats were treated with 500 umol Ni/kg body wt 60 min prior to injection of chelator at 1:0.5, 1:1, or 1:2 ratios. The animals were killed 72 hr after injection and hepatic and renal Ni content determined. At all Ni:chelator ratios, cyclam was most effective at reducing liver and kidney Ni concentrations. At the highest ratio (1:2) triethylenetetraamine produced significant depletion (there was an increase in hepatic Zn) in liver and kidney trace metal (Cu, Fe, Mn, Zn) concentrations that were not observed with cyclam or cyclam s. The prophylactic effect of the drugs on Ni poisoning were studied by injecting chelator (1000 umol/kg) 60 min prior to 500 umol/kg of Ni (n= 40/chelator) and observing survival for 17 days (n= 20); 20 rats were given a second injection of Ni after 72 hr and survival observed for 14 days. Rats receiving cyclam or cyclam s had longer mean survival time than those receiving triethylenetetraamine or glutathione. [R56] *The ability of calcium chromate, nickel sulfate, and nickel chloride to induce chromosomal aberrations in Chinese hamster ovary and C3H1OT1/2-mouse cell lines was investigated. Chinese hamster ovary and C3H1OT1/2 cells were grown in monolayer culture and exposed to various concentrations of nickel and chromium compounds for various time periods. Nickel chloride and nickel sulfate induced chromosomal aberrations primarily in heterochromatin in both cell lines, while calcium chromate showed no preference for heterochromatin or euchromatin. Nickel compounds also showed a preferential effect on the condensation state of the heterochromatic long arm of X-chromosome, this effect was more dramatic with nickel sulfate. No effect was observed with calcium chromate. [R57] *The effects of exposure to selenium and nickel on the frequency of pulmonary adenomas induced by urethan in mice were investigated. Groups of female Swiss cross mice were exposed every other day for 15 weeks to either 3 ug/ml sodium selenite or to 100 ug/ml nickelous chloride in drinking water. Other groups were exposed on successive days to both metals. After 3 weeks of treatment, the mice were administered 1.5 mg/kg of urethan ip. The mice were killed at the end of the 15 week period. Mice exposed to nickel or selenium showed no clinical toxicity and no difference in wt gain compared to controls. Sleep time induced by urethan (a measure of urethan metabolism and excretion) was significantly reduced by selenium exposure but not nickel exposure. Exposure to selenium alone did not significantly affect the size or number of urethan induced adenomas. Exposure to nickel alone increased adenoma size but had no effect on tumor number. Combined selenium and nickel exposure appeared to produce more tumors than the corresponding single metal exposure treatments. Interactions associated with tumor size and tumor number following combined selenium and nickel exposure, suggests that the immunological and carcinogenic or anticarcinogenic actions of nickel and selenium differ considerably from the corresponding mechanism controlling urethan induced carcinogenesis. [R58] *Nickel chloride inhalation ... enhances viral respiratory infection in mice ... . [R59] *Cells from the CHO-K1-Chinese hamster fibroblast line and human lymphocytes from the peripheral blood of a male subject were used to evaluate subtoxic doses of insoluble metal compounds in the sister chromatid exchange assay. While NTA did not induce sister chromatid exchange in the CHO cell line, soluble compounds of cadmium chloride, potassium dichromate, mercury chloride, and nickel chloride significantly increased sister chromatid exchange in CHO cells, establishing a clear dose effect relationship. Equimolar concentrations of NTA did not enhance sister chromatid exchange induction by metals. The NTA/metal complexes, once formed, were genetically active at extremely low concentrations. The enhancement of the genetic activity was not pH dependent. These effects were also demonstrated in the presence of sodium, magnesium and calcium ions in concentrations largely exceeding those of the genotoxic metal cationic and anionic forms. [R28] *... Investigated the uptake of nickel chloride and its effects on the development of sea urchin embryos. After fertilization, sea urchin eggs exhibited incr rates of nickel uptake that appeared to be a result of an active transport mechanism. When exposed to 59-590 mg nickel/l, gastrulation of embryos was prevented. Embryos grown in 0.59-5.9 mg nickel/l were able to gastrulate, but failed to develop dorsoventral symmetry. [R60] *Ip admin of nickel chloride to mice and rats caused a rapid decr of body temp ... The nickel chloride treatment resulted in hypothermia that lasted for more than 1 hr, with a reduction in colonic temp of 3-4 deg C at 20 deg C ambient temp. The Ni2+ induced hypothermia was accentuated at lower ambient temp (10 deg C) and ameliorated at higher ambient temp (30 deg C). [R61] NTXV: *LD50 4 day old chick embryo 0.20 mg/egg; [R62] *LD50 8 day yolk sac injected eggs 2.38 mg/egg; [R62] *LD50 8 day old chorioallantoic membrane injected egg 0.33 mg/egg; [R62] *LD50 rat female ip 29 mg/kg /From table./; [R63] *LD50 rat female pregnant im 71 mg/kg /From table./; [R64] ETXV: *LC50 (Philodina acuticornus) rotifer static unmeasured 2,900 ug/l 96 hr (in water hardness of calcium carbonate 25 mg/l); [R65] *LC50 Daphnia magna (cladoceran) static unmeasured 510 ug/l 48 hr (in water hardness of calcium carbonate 45 mg/l); [R66] *LC50 Daphnia magna 0.13 mg/l 3 week. /Conditions of bioassay not specified/; [R67] *Reproductive impairment Daphnia magna 30-95 ug/l/64 hr. /Conditions of bioassay not specified/; [R66] *LC50 Daphnia magna 1,120 ug/l (in water hardness of calcium carbonate 44 mg/l) 48 hr. /Conditions of bioassay not specified/; [R66] *LC50 Salmo gairdneri 50 ug/l 28 days (in water hardness of calcium carbonate 93-105 mg/l); [R68] *LC50 Micropterus salmoides (embryo) 2,020 ug/l 8 days (in water hardness of calcium carbonate 98-105 mg/l); [R69] *LC50 Carassius auratus 2,140 ug/l 7 days (in water hardness of calcium carbonate 195 mg/l); [R70] *LC50 Ambystoma opacum 420 ug/l 8 days (in water hardness of calcium carbonate 195 mg/l); [R71] *LC50 Gastrophyrne carolinensis 50 ug/l 7 days (in water hardness of calcium carbonate 195 mg/l); [R69] *LC50 Capitella capitata > 50,000 ug/l/96 hr. /Conditions of bioassay not specified/; [R72, (1979)] *LC50 Capitella capitata > 50,000 ug/l/7 days. /Conditions of bioassay not specified/; [R72, (1978)] *LC50 Pandalus montagui 200,000 ug/l/48 hr; [R73] *LC50 Carcinus maenus 300,000 ug/l/48 hr; [R73] *TLm fathead minnow 96 hr: soft water, 5.18 ppm; hard water, 42.4 ppm. /Conditions of bioassay not specified/; [R4] ADE: *THE KIDNEYS SHOWED LARGEST AMT OF NICKEL/G IN MALE RATS 6 HR AFTER INTRATRACHEAL INJECTION OF 1 MG NICKEL AS NICKEL CHLORIDE, FOLLOWED BY LUNG, ADRENAL, LIVER, PANCREAS, SPLEEN, HEART, AND TESTIS IN ORDER. [R36] *TETA, 0.75 MMOL/KG IM ADMIN TO FISCHER RATS IMMEDIATELY PRIOR TO (63)NICKEL CHLORIDE, 0.068 OR 0.10 MMOL/KG IP OR IM. RENAL CLEARANCE WAS EST TO BE GREATER THAN 20 TIMES NONCHELATED-(63)NICKEL. [R74] *AFTER SINGLE IP INJECTION OF NICKEL CHLORIDE (17 OR 816 UG NICKEL/ANIMAL, RESP) INTO RATS OR RABBITS, (63)NICKEL ION RAPIDLY CLEARED PLASMA OR SERUM FIRST 2 DAYS AND SLOWER NEXT 5 DAYS. [R75] *SOL NICKEL CHLORIDE ... RAPIDLY CLEARED AFTER INTRATRACHEAL INJECTION /IN RATS/. BY 72 HR, 90% OF INJECTED NICKEL ... EXCRETED, MAINLY (75%) IN THE URINE. ... 6 HR AFTER /ONE/ INTRATRACHEAL INJECTION OF 1 MG NICKEL CHLORIDE, KIDNEYS SHOWED GREATEST AMT OF NI/G. /THEN/ ... LUNG, KIDNEYS ... PANCREAS, SPLEEN, HEART, TESTES. [R31, 1834] *AFTER SINGLE INJECTION ADMIN TO FEMALE WISTAR RATS, SOL NICKEL CHLORIDE WAS READILY DISTRIBUTED THROUGHOUT BODY AND RAPIDLY CLEARED. AFTER PULMONARY EXPOSURE, RAPIDLY ABSORBED FROM SITE. [R76] *After an ip injection of 50 uci nickel chloride ((63)NiCl2) into a 16 day pregnant mouse, nickel appeared rapidly in connective tissue, prominent sites ... 72 hr after injection included the visceral yolk sac, lung, GI tract and kidneys. Nickel crossed the placental barrier /and/ was distributed throughout the embryo... . [R77] *The binding of cultured Chinese hamster ovary cells /following/ treatment of cultured cells with nickel chloride ((63)NiCl2) at 10 ug/ml for 3 days /was/ selective ... to protein. Cellular proteins contained 100 times more (63)nickel bound than the respective RNA or DNA fractions. [R78] *Male Sprague-Dawley rats were exposed to nickel chloride aerosols of 90 ug/cu m or 400 ug/cu m using a head only exposure system. The rate of nickel removal from the lung was described by michaelis Menten kinetics. The amount of nickel remaining in the lung at half maximal clearance was 894 ng/g after acute nickel exposure and 1,380 ng/g after repeated exposure. The maximum velocity of nickel clearance from the lung was 31.3 and 34.6 ng/g per hour after acute and chronic exposure, respectively. The lung burdens for nickel were linearly related to the chamber concentration and were estimated according to the assumption that aerosol deposition occurred according to zero order kinetics. The deposition rate was determined according to an equation based upon the respiratory rate, frequency, and chamber aerosol concentration. The rate of nickel removal from the lung was estimated using an equation based on the maximal velocity of clearance and the amount of nickel remaining in the lung at half maximal clearance. Lung nickel burdens were simulated by computer models based on these equations. The assumption of a saturable removal mechanism provided a reasonable fit to the composite data. [R79] *The saturable nature of soluble nickel compounds clearance from the lung was studied by repeated exposures of rats to respirable submicron size nickel arosols. Using Michaelis-Menten type kinetics for removal of nickel lung burdens and a constant rate of deposition, the lung nickel burdens were simulated by computer. Male Sprague-Dawley rats were exposed for 2 hr/day to nickel chloride aerosols at either 90 or 400 micrograms nickel/cu m for up to 14 days. The particle size of the aerosol ranged from 0.7 to 0.9 micron mass median aerodynamic diameter with a geometric standard deviation of 1.2-1.4. A steady state nickel lung burden was observed at 90 micrograms/cu m, as predicted from computer modeling, while lung burdens continued to increase with repeated exposure to 400 micrograms nickel/cu m. The best fit for the experimental data was obtained with a maximum clearance velocity of 34.6 ng nickel/g X hr and a Michaelis-Menten constant for transport of 1380 ng nickel/g. The percentage of submicron nickel chloride aerosols retained in the lung was 6.9%. [R79] *In rats that had received 1 mg nickel, admin intratracheally as a single dose of (63)nickel chloride, most of the admin dose was found in the kidney (53%) and the lung (30%), the rest being distributed among the adrenals, liver, pancreas, spleen, heart, and testes ... . As clearance by 3 days was faster in the kidney, the lungs became the organ with the highest (63)Ni level (64% of the total amt deposited; kidney: 19%). Lung clearance within 6 hr was 27%, which means that 70% of the material originally deposited had been absorbed. [R80] *Appreciable amt of radioactive nickel, admin to male rats intratracheally as the chloride (1.27 ug nickel), were absorbed ... Twenty-one days after exposure, the only measurable activity was in the lungs and kidneys. For example, 1 day after exposure, 29% of the initial burden was retained in the lungs, decr to 0.1% on day 21. [R80] *... Nickel, given orally to rats as the chloride in the drinking water (0.005, 0.5, or 5 mg/l), was eliminated mainly in the feces ... Intubation in rats of (63)nickel chloride in 0.1 N hydrochloric acid led to 3-6% absorption of the labelled nickel, regardless of the admin dose (1.8 ug/animal, or 4, 16, and 64 mg nickel/kg body weight). From these two studies ... it can be concluded that very little nickel in water or beverages is bioavailable ... Large doses are required to overcome the intestinal absorption-limiting mechanism. [R81] *In a study on dermal absorption ... applied (63)nickel chloride (40 uCi) to the shaven flanks of guinea pigs and reported that a small amt of the applied dose passed through the skin and appeared in the plasma. After 4, 12, and 24 hr exposure, 0.005, 0.07, and 0.05%, respectively, of the total (63)Ni dose were found in the plasma, and 0.009, 0.21, and 0.51%, respectively, of the absorbed nickel, were measured in urine. In excised skin, levels of 1.94, 7.30, and 5.33%, respectively, were found. [R82] *Using micro-autoradiography of (63)nickel chloride exposed skin (2 uCi; periods of 1/2-48 hr, shaved flanks of guinea pigs) ... also found that the radioactive nickel accumulated within 1 hr in the highly keratinized areas, the stratum corneum, and hair shafts, showing a route of entry via the hair follicles and sweat glands. Incr radioactivity was also measured in the serum and urine. [R82] METB: *The effects of nickel on hepatic glutathione and the enzymes glutathione reductase, glutathione-peroxidase, glutathione-S-transferase, and gamma-glutamyl-transpeptidase were investigated in female albino rats. Three groups of rats were sacrificed 16, 24, or 72 hr after a subcutaneous injection of nickel as nickel chloride at a level of 200 micromol/kg. Four groups of rats were sacrificed 16 hr after a single subcutaneous injection of either 50, 100, 200, or 400 micromol/kg nickel chloride. The single dose of 200 micromol/kg nickel chloride increased glutathione levels and glutathione reductase and glutathione-S-transferase activity at 16 and 24 hr post treatment. Glutathione peroxidase and gamma-glutamyl-transpeptidase activity were reduced at 16 and 24 hr. The effect on enzyme activity was dose dependent at all levels of nickel chloride. Glutathione levels were decreased at 50 micromol/kg relative to the control values but increased with increasing nickel levels. [R83] *Induction of heme oxygenase in liver, kidney, and other organs of rodents is a nonspecific, toxic response to parenteral administration of numerous metal compounds. Cobalt and cadmium ions are especially potent inducers of heme oxygenase in rat liver; tin ion, nickel ion, and arsenic ion, are potent inducter of enzyme in rat adrenal. Rat spleen testis, and brain are relatively refractory to metal induction of heme oxygenase activity; in testicular microsomes from cadmium ion-treated rats, heme oxygenase activity is markedly inhibited. Metal induction of heme oxygenase requires de novo synthesis of mRNA and protein, based on 1) experiments with metabolic inhibitrors (actinomycin d, puromyci, and cycloheximide) and 2) translation assays of heme oxygenase mRNa. Heme oxygenase induction by metals is generally suppressed by treatments with SH compounds (for example, cysteine and glutathione) and enhanced by agents that deplete tissue SH levels (for example, diethyl maleate). Administration of DDC exerts a pronounced synergistic effect on Ni2+ induction of heme oxygenase activity in rat tissues, attributable in part to enhanced cellular uptake of nickel. Induction of heme oxygenase activity in rat tissues, attributable in part to enhanced cellular uptake of nickel. Induction of heme oxygenase is not sustained during repeated daily treatments of rats with nickel chloride. [R84] BHL: *The biological half-life /in fetal tissues of mice/ was calculated to be 8.9 hr in the rapid phase and 33 hr in the slow phase. [R85] ACTN: *... Cell growth was selectively blocked in S-phase by ... 1-60 uM ... nickel chloride. [R86] *SC INJECTION OF NICKEL(II) CHLORIDE INTO RABBITS (5 MG METAL/KG) INHIBITED ADP INDUCED PLATELET AGGREGATION IN PLASMA SAMPLES TAKEN @ VARIOUS TIMES AFTER INJECTION. [R87] *The mechanism of nickel mediated increases in hepatic lipid peroxidation was studied. Eighteen female albino rats were administered a single subcutaneous dose of 200 nickel chloride. A second group of 24 rats was divided into four subgroups and given 50, 100, 200, and 400 uM/kg nickel chloride. Increased lipid peroxidation and glutathione and iron concentrations were proportional to dose at 16 and 24 hr. Glutathione peroxidase activity decreased at the low dose but rose at higher nickel chloride concentrations. Lipid peroxidation was inhibited by exogenous ethylenediaminetetraacetic acid, sodium azide, ethanol, sodium benzoate, and histidine, but was unaffected by superoxide benzoate, and histidine, but was unaffected by superoxide-dismutase and catalase. The administration of Ni resulted in the accumulation of hepatic iron and glutathione peroxidase activity. [R88] INTC: *The effect of complexans (NTA; EDTA) on the toxicity of nickel chloride ... to carp (Cyprinus carpio), and the accumulation of metals in fish at lethal level concentrations was studied. The toxicity of nickel salts to carp was relatively lower ... /and/ the inhibition of nickel accumulation by the presence of complexans was recognized throughout the fish, but no significant decrease of mortality was seen. [R89] *Nickel chloride induction of /metallothionein/ in liver and kidneys /of male Fischer rats/ was inhibited by cycloheximide (2 mg/kg, ip). [R46] *Synergistic induction /of microsomal heme oxygenase activity/ was observed in liver and kidneys of rats killed after administration of sodium diethyldithiocarbamate and nickel chloride (NiCl2) at all dosage combinations (diethyldithiocarbamate dosages: 0.33 to 1.33 mmol/kg, im, 17 hr before death; NiCl2 dosages: 0.125 and 0.25 mmol/kg, sc, 17 hr before death). At the highest dosages ... the dual treatments induced heme oxygenase activity 11 fold in liver and 16 fold in kidneys ... at the same dosage given /alone/ ... NiCl2 induction was 1.3 fold in liver and 6 fold in kidneys. [R90] *Sodium diethyldithiocarbamate caused a retention and redistribution of (63)nickel chloride in the tissues /and/ DL-penicillamine decreased the (63)nickel ion concn in the tissues ... of mice injected with (63)nickel chloride. [R91] *By simultaneous exposure to increasing concn of manganese chloride, the toxic effect of nickel chloride (NiCl2) ... on the ciliary activity in mouse trachea in an organ culture ... was reduced. At these nickel concn /0.5 and 2.0 mM NiCl2/, optimal protection was obtained by approx half the molar concn of manganese chloride. [R92] *Addition of ... nickel chloride ... to a soln of tetracycline hydrochloride ... decreased the antimicrobial activity ... in in vitro tests. [R93] *Tetradecylamine in combination with ... nickel chloride ... produced a greater antiplaque effect than the sum of the effects produced by either alone. [R94] *After a single intraperitoneal injection of 20 mg/kg silver lactate, lipid peroxidation was significantly increased in mouse liver 3, 12 and 48 hr after exposure. Malondialdehyde levels in kidney and brain were not significantly affected. Pretreatment with 2 mg/kg sodium selenite ip for 2 days increased silver induced lipid peroxidation in the liver. Liver from mice treated with 20 mg/kg silver lactate followed by an injection of 35 micrograms/kg nickel chloride had significantly higher contents of malondialdehyde than did livers from mice treated with either silver or nickel alone. [R95] *The effects of exposure to selenium and nickel on the frequency urethan (51796) induced pulmonary adenomas in mice were investigated. Groups of female Swiss-cross mice were exposed every other day for 15 weeks to either 3 ug/ml nickelous chloride in drinking water. Other groups were exposed on successive days to both metals. After 3 weeks of treatment, the mice were administered 1.5 milligrams per gram of urethan intraperitoneally. Mice exposed to nickel or selenium showed no clinical toxicity and no difference in weight gain compared to controls. Sleep time induced by urethan (a measure of urethane metabolism and excretion) was significantly reduced by selenium exposure but not Ni exposure. Exposure to Se alone did not significantly affect the size or number of urethan induced adenomas. Exposure to nickel alone increased adenoma size but had no effect on tumor number. Combined selenium and nickel exposure appeared to produce more tumors than the corresponding single metal treatments. There were also significant interactions associated with tumor size. [R96] *The uptake of (14)C by the green algae, Selenastrum capricornutum, was inhibited by free nickel ... ions. In the presence of the chelator, nitrilotriacetic acid, the inhibition ... was reduced. Thus, the toxicity of metals may be reduced or increased by the presence of chelators. [R97] *In a two-stage carcinogenesis assay, orally administered nickel chloride enhanced the renal carcinogenicity of N-ethyl-N-hydroxyethyl nitrosamine in rats, but not the hepatocarcinogenicity of N-nitrosodiethylamine, the gastric carcinogenicity of N-methyl-N-nitro-N-nitrosoguanidine, the pancreatic carcinogenicity of N-nitrosobis(2-oxopropyl)amine, or the skin carcinogenicity of 7,12-dimethylbenzanthracene ... . [R98] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ FATE: *AQUATIC FATE: Nickel chloride is water soluble and would be expected to release divalent nickel into the water. [R99] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers nickel metal and other compounds (as Ni) to be a potential occupational carcinogen. /Nickel metal and other compounds (as Ni)/ [R21, 224] OSHA: *Vacated 1989 OSHA PEL TWA 0.1 mg/cu m is still enforced in some states. /Nickel metal and other compounds (as Ni), soluble/ [R21, 368] *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1 mg/cu m. /Nickel, soluble cmpd, as Ni/ [R100] NREC: *NIOSH considers nickel metal and other compounds (as Ni) to be a potential occupational carcinogen. /Nickel metal and other compounds (as Ni)/ [R21, 224] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Nickel metal and other compounds (as Ni)/ [R21, 224] *Recommended Exposure Limit: 10 Hr TWA 0.015 mg/cu m. /Nickel metal and other compounds (as Ni)/ [R21, 224] TLV: *8 hr Time Weighted Avg (TWA) 0.1 mg/cu m, inhalable fraction. A4. A4= Not classifiable as a human carcinogen. /Nickel, soluble compounds, as Ni/ [R101, 51] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R101, 6] OOPL: *Max allowable concn (MAX) USSR 0.005 mg/cu m as Ni /Nickel salts and aerosols/ [R102] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Nickel chloride is included on this list. [R103] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 100 ug/l /Nickel/ [R104] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 150 ug/l /Nickel/ [R104] +(MA) MASSACHUSETTS 100 ug/l /Nickel/ [R104] +(ME) MAINE 150 ug/l /Nickel/ [R104] +(MN) MINNESOTA 100 ug/l /Nickel/ [R104] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Nickel and compounds/ [R105] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R106] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; Chemical selection Profile: Nickel Chloride (1979) SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 83 (1976) R2: SRI R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 786 R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 198 R6: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 759 R7: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1117 R8: Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995. R9: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 (80) 493 R10: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 933 R11: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 4-73 R12: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. B-110 R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 79 (1976) R14: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 628 R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-151 R16: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 820 R17: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. R18: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.3 R19: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 491M-167 R20: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2406 R21: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R22: Chen C et al; Hua Hsueh Iss 2: 31-6 (1979) R23: Ecology and Environment Inc. Toxic Substance Storage Tank Containment. Park Ridge, NJ: Noyes Publications, 1985. 253 R24: Environmental Health Criteria 108: Nickel. pp. 17-22 (1991) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V49 410 (1990) R26: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R27: Skreb Y, Fisher AB; Zentralbl Bakteriol Mikrobiol Hyg 178 (5-6): 432-45 (1984) R28: Montaldi A et al; Toxicol Environ Chem 14 (3): 183-200 (1987) R29: WHO; Environ Health Criteria 108: Nickel p.258 (1991) R30: WHO; Environ Health Criteria 108: Nickel p.263 (1991) R31: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R32: GITLITZ PH ET AL; TOXICOL APPL PHARMACOL 34 (3): 430-40 (1975) R33: SUNDERMAN FW ET AL; TOXICOL APPL PHARMACOL 43 (2): 381-90 (1978) R34: TIMOURIAN H ET AL; J EXP ZOOL 182 (3): 379-87 (1972) R35: GRAHAM JA ET AL; ENVIRON HEALTH PERSPECT 12: 109-13 (1975) R36: CLARY JJ; TOXICOL APPL PHARMACOL 31 (1): 55-65 (1975) R37: CLEMONS EK ET AL; TOCIXOL APPL PHARMACOL 61 (3): 343-8 (1981) R38: LU CC ET AL; TERATOLOGY 19 (2): 137-42 (1979) R39: ROBISON SH ET AL; CANCER LETT 15 (1): 35-40 (1982) R40: FIEDLER H, HERRMAN I; FOLIA HAEMATOL (LEIPZIG) 96 (2): 224-30 (1971) R41: Horak E, Sunderman FW; Toxicol Appl Pharmacol 32: 316 (1975) R42: Lestrovoi AP et al; Gig Sanit 10: 105 (1974) R43: Clary JJ, Viganti I; Toxicol Appl Pharmacol 25: 467 (1973) R44: Joo F; Nature 219: 1378 (1968) R45: Sobel H et al; Proc Soc Exp Biol Med 104: 86-8 (1960) R46: Sunderman FW Jr, Fraser CB; Ann Clin Lab Sci 13 (6): 489-95 (1983) R47: Williams SJ, Menzel DB; Toxicol Appl Pharmacol 64 (3): 431-8 (1982) R48: Robison SH et al; Cancer Lett 17 (3): 273-9 (1983) R49: Gilani SH, Marano M; Arch Environ Contam Toxicol 9 (1): 17-22 (1980) R50: Daniels MJ et al; Fundam Appl Toxicol 8 (4): 443-53 (1987) R51: Knight JA et al; Res Commun Chem Pathol Pharmacol 55 (3): 291-302 (1987) R52: Laschi-Loquerie A et al; Immunopharmacol Imunotoxicol 9 (2-3): 235-41 (1987) R53: Johansson A et al; Br J Ind Med 44 (1): 47-52 (1987) R54: Sunderman FW; Toxicol Environ Chem 15 (1-2): 59-69 (1987) R55: Smialowicz RJ et al; Toxicology 44 (3): 271-81 (1987) R56: Athar M et al; Fundam Appl Toxicol 9 (1): 26-33 (1987) R57: Sen P et al; Cancer Research 47 (8): 2142-7 (1987) R58: Blakely BR; J Appl Toxicol 7 (6): 387-90 (1987) R59: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986.,p. V2 472 R60: WHO; Environ Health Criteria 108: Nickel p.161 (1991) R61: WHO; Environ Health Criteria 108: Nickel p.180 (1991) R62: Ridgway LP, Karnofsky DA; Ann NY Acad Sci 55: 203-15 (1952) R63: WHO; Environ Health Criteria 108: Nickel p.??? (1991) R64: WHO; Environ Health Criteria 108: Nickel p.181 (1991) R65: Buikema AL et al; Water Res Bull Amer Water Resource Assoc 10: 648 (1974) R66: Biesinger KE, Christensen GM; J Fish Res Board Canada 29: 1691 (1972) R67: Beisinger KE, Christensen GM; J Fish Res Board Canada 29: 1691 (1972) R68: Birge WJ et al; in Surface Mining and Fish/Wildlife needs in the eastern United States; Samuel DE ed, (1978) FWS/OBS-78/81 R69: Birge WJ et al; Surface Mining and Fish/Wildlife Needs in the Eastern United States by Samuel DE ed (1978) FWS/OBS-78/81 R70: Birge WJ; In Energy and Environmental Stress in Aquatic Systems by Thorp JA, Gibbons JW, eds (1978) R71: Birge WJ; In Energy and Environmental Stress in Aquatic Systems by Throp JA, Gibbons JW, eds (1978) R72: Petrich SM, Reish DJ; Bull Envir Contam Tox 23: 698 R73: Portmann JE; Helogolander Wiss Meeresunters 17: 247 (1968) R74: SUNDERMAN FW ET AL; TOXICOL APPL PHARMACOL 38 (1): 177-88 (1976) R75: ONKELINX C ET AL; RES COMMUN CHEM PATHOL PHARMACOL 6 (2): 663-76 (1973) R76: ENGLISH JC ET AL; AM IND HYG ASSOC J 42 (7): 486-92 (1981) R77: Olsen I, Jonsen J; Toxicology 12: 165-72 (1979) R78: Harnett PB et al; Toxicol Appl Pharmacol 64 (1): 20-30 (1982) R79: Menzel DB et al; Toxicol Lett 38 (1-2): 33-43 (1987) R80: WHO; Environ Health Criteria 108: Nickel p.107 (1991) R81: WHO; Environ Health Criteria 108: Nickel p.110 (1991) R82: WHO; Environ Health Criteria 108: Nickel p.115 (1991) R83: Ahar M et al; Res Comm Chem Pathol Pharmacol 57 (3): 421-4 (1987) R84: Sunderman FW; Ann NG Acad Sci 514: 65-80 (1987) R85: WHO; Environ Health Criteria 108: Nickel p.118 (1991) R86: Costa M et al; Res Commun Chem Pathol Pharmacol 38(3): 405-19 (1982) R87: FIEDLER H ET AL; FOLIA HAEMATOL (LEIPZIG) 96 (2): 224-30 (1971) R88: Athar M et al; Biochemical and Biophysical Res Comm 147 (3): 1276-81 (1987) R89: Muramoto S; J Envir Sci Health 18 (6): 787-96 (1983) R90: Sunderman FW Jr et al; Toxicol Appl Pharm 71 (3): 436-44 (1983) R91: Oskarsson A, Tjalve H; Arch Toxicol 45 (1): 45-52 (1980) R92: Paulsen G et al; Res Commun Chem Pathol Pharm 32 (3): 525-34 (1981) R93: Gupta RP et al; Inorg Chem Acta 32 (2): 95-6 (1979) R94: Ritchey TW; Eur Pat Appl Patent No 11663 (1980) R95: Rungy J; Toxicology 45 (2): 135-42 91987) R96: Blakley Br; J Appl Toxicol 7 (6): 387-90 (1987) R97: Laegreid M et al; Complexation Trace Met Nat Waters Proc Int Symp p.419-24 (1984) R98: WHO; Environ Health Criteria 108: Nickel p.252 (1991) R99: USEPA; Quality Criteria for Water (1976) as cited in NTP; Chem Selection Profile: Nickel Chloride p.2 (1979) R100: 29 CFR 1910.1000 (7/1/99) R101: American Conference of Governmental Industrial Hygienists. Guide to Occupational Exposure Values - 1999. Cincinnati, OH: 1999. R102: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1438 R103: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R104: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R105: 40 CFR 401.15 (7/1/99) R106: 40 CFR 302.4 (7/1/99) RS: 65 Record 95 of 1119 in HSDB (through 2003/06) AN: 893 UD: 200303 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIETHANOLAMINE- SY: *AMINE,-TRIETHYL,-2,2',2''-TRIHYDROXY-; *DALTOGEN-; *ETHANOL,-2,2',2''-NITRILOTRI-; *ETHANOL,-2,2',2''-NITRILOTRIS-; *NITRILOTRIETHANOL-; *NITRILO-2,2',2''-TRIETHANOL-; *2,2',2''-NITRILOTRIS(ETHANOL); *STEROLAMIDE-; *STING-KILL-; *THIOFACO-T-35-; *TRIETHANOLAMIN-; *TRIETHANOLAMIN-NG-; *TRIETHYLAMINE,-2,2',2''-TRIHYDROXY-; *TRIETHYLOLAMINE-; *TRIHYDROXYTRIETHYLAMINE-; *TRIS- (HYDROXYETHYL)AMINE; *TRIS(2-HYDROXYETHYL)AMINE; *TROLAMINE- RN: 102-71-6 MF: *C6-H15-N-O3 ASCH: Triethanolamine hydrochloride; 637-39-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ETHYLENE OXIDE AND EXCESS AMMONIA, FOLLOWED BY FRACTIONATION [R1, p. VA10 4] *PRODUCED ALONG WITH MONO- AND DIETHANOLAMINE BY AMMONOLYSIS OF ETHYLENE OXIDE. [R2, 9586] FORM: *COMMERCIAL PRODUCT CONTAINS UP TO 25% DIETHANOLAMINE AND UP TO 5% MONOETHANOLAMINE. ... GRADES: TECHNICAL; REGULAR; 98%; USP. [R3] *A FLAME RETARDANT FINISH FOR COTTON CONTAINS 3% TRIETHANOLAMINE [R4, p. V10 433] *OPAQUE SUN SCREENS CONTAIN 0.5 wt% OF TRIETHANOLAMINE [R4, p. V7 154] *A TYPICAL HAND, FACE AND BODY LOTION CONTAINS 0.80% TRIETHANOLAMINE [R4, p. V7 150] *85%, 99%, NF industrial, Commercial grades (equiv wt 147-150), low-freeze grade. [R5] MFS: *Dow Chemical U.S.A., Hq, 2020 Dow Center, Midland, MI 48674, (517)636-1000; Manufacturing site: Main Street, Midland, MI 48667, P.O. Box 150, Plaquemine LA 70764(mono-, di- and triethanolamines) [R6, 588] *Occidental Petroleum Corp., Hq, 10889 Wilshire Boulevard, Suite 1500, Los Angeles, CA, 90024,(310) 879-1700, Petrochemicals, Ethylene Oxide and Derivatives Division; Manufacturing site: Bayport, TX 77000 (mono-, di- and triethanolamines) [R6, 588] *Texaco Chemical Company, Hq, 3040 Post Oak Blvd, P.O. Box 27707, Houston, TX 77056, (713) 961-3711; Manufacturing site: 6001 Highway 366, P.O. Box 847, Port Neches, TX 77651(mono-, di- and triethanolamines) [R6] *Union Carbide Corp, Industrial Chemicals Division Hq, Old Ridgebury Rd, Danbury, CT 06817, (203) 794-2000; Manufacturing site: Seadrift, TX 77983 (mono-, di- and triethanolamines) [R6, 588] *ICI AMERICAS, INC., CONCORD PIKE AND MURPHY RD, WILMINGTON, DE 19897, (302)575-3000 [R7, 1984] OMIN: *GENERAL INDUSTRY PRODUCTION RATIOS ARE TRIETHANOLAMINE 37%; MONOETHANOLAMINE 32% AND DIETHANOLAMINE 31% [R7, 1984] *Annual capacity = 1,035 million pounds [R6, 588] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R8] *CHEMICAL INTERMEDIATE FOR SALTS OF FATTY ACIDS (ANIONIC SURFACTANTS), ALKYL BENZENESULFONATE ANIONIC SURFACTANTS, ALKYL SULFATES (ANIONIC SURFACTANTS), HERBICIDE 2,4-D TRIETHANOLAMINE SALT, HERBICIDE TRIETHANOLAMINE-COPPER COMPLEX; SOLVENT FOR NATURAL RUBBER; CUTICLE REMOVER AND SOFTENER [R9] *INTERMEDIATE, IN MAKING EMULSIONS, SOLVENT, MFR OF SYNTHETIC RESINS; PHARMACEUTIC AID (ALKALIZING AGENT); INCREASING PENETRATION OF ORG LIQUIDS INTO WOOD AND PAPER; IN PRODN OF LUBRICANTS FOR TEXTILE INDUSTRY; INTERMEDIATE IN MFR OF SURFACE ACTIVE AGENTS, TEXTILE SPECIALTIES, WAXES, POLISHES, HERBICIDES, PETROLEUM DEMULSIFIERS, TOILET GOODS, CEMENT ADDITIVES, CUTTING OILS. IN MAKING EMULSIONS WITH MINERAL AND VEGETABLE OILS, PARAFFIN AND WAXES. SOLVENT FOR CASEIN, SHELLAC, DYES ... . [R2, 1521] *FATTY ACID SOAPS USED IN DRYCLEANING, COSMETICS, HOUSEHOLD DETERGENTS, AND EMULSIONS; WOOL SCOURING; TEXTILE ANTIFUME AGENT AND WATER-REPELLENT; DISPERSION AGENT; CORROSION INHIBITOR; SOFTENING AGENT, HUMECTANT, AND PLASTICIZER; INSECTICIDE; CHELATING AGENT; RUBBER ACCELERATOR. [R3] *USED AS A SUBSTITUTE FOR POTASSIUM HYDROXIDE IN CUTICLE REMOVERS AND SOFTNERS [R4, p. V7 163] *USED AS A CHELATING AGENT [R4, p. V5 344] *USED IN AMINO RESIN ADHESIVES FORMULATIONS TO NEUTRALIZE EXCESS CATALYST ACID [R4, p. V2 448] *USED TO PREPARE PIPERAZINE [R4, p. V2 298] *USED IN THE RECOVERY OF HYDROGEN SULFIDE FROM SOUR NATURAL GASES AND SOUR CRUDE PETROLEUMS [R4, p. V22 267] *USED AS AN INITIATOR FOR POLY TRIOL PRODUCTION [R4, p. V19 249] *Component of corrosion inhibitors, particularly coolants for automobile engines, as well as drilling and cutting oils. Also employed as additives in lubricants. [R1, p. VA10 6] *Aqueous solutions of triethanolamine are used as milling additives in cement production. In addition to assisting the milling process, triethanolamine also improves the flow properties and setting behavior of the cement. [R1, p. VA10 6] *Liquid detergents are based primarily on triethanolamine. [R1, p. VA10 6] *Insecticide, Antimicrobial [R10] CPAT: *DETERGENTS (INCLUDING TEXTILE, TOILET GOODS, METAL AND OTHER SPECIALTY SURFACTANTS), 35%; GAS CONDITIONING AND PETROLEUM USE, 30%; METAL WORKING, 15%; TEXTILES, 10%; MISCELLANEOUS (INCLUDING AGRICULTURAL INTERMEDIATES AND CEMENT GRINDING AIDS) AND EXPORTS, 10% (1984) /ETHANOLAMINES/ [R7, 1984] *Surfactants, 40%; gas purification, 25%; metals, 17%; textiles, 8%; other, including cement grinding oils, agricultural chemicals, 10% (mono-, di- and triethanolamines) [R7, 9/28/92] PRIE: U.S. PRODUCTION: *(1972) 4.57X10+10 G [R9] *(1975) 4.06X10+10 G [R9] *(1984) 6.34X10+10 g [R11] *1992 sales: 81.38 million kilograms valued at $79,092,000. [R12] *(1991) Demand: 640 million pounds, includes exports, but not imports. In addition, an estimated 100 to 200 million pounds were consumed in internal operations. (mono-, di- and triethanolamines) [R7, 9/28/92] *(1992) Demand: 660 million pounds(mono-, di- and triethanolamines) [R7, 9/28/92] U.S. IMPORTS: *(1972) 6.36X10+7 G (MONO, DI AND TRI) [R9] *(1975) 2.03X10+9 G(MONO, DI, TRIETHANOLAMINES) [R9] *(1984) 1.40X10+9 g/MONO, DI, AND TRIETHANOLAMINE/ [R13] *(1991) 17 million pounds (mono-, di- and triethanolamines) [R7, 9/28/92] U.S. EXPORTS: *(1991) 230 million pounds (mono-, di- and triethanolamines) [R7, 9/28/92] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *VISCOUS LIQUID [R2, 1521]; *COLORLESS TO PALE YELLOW [R14] ODOR: *SLIGHT AMMONICAL ODOR [R2, 1521] BP: *335.4 DEG C @ 760 MM HG [R2, 1521] MP: *21.57 deg C [R2, 1521] MW: *149.19 CTP: *Critical temperature = 514.3 deg C; critical pressure = 24.2 mm Hg [R15] DEN: *1.1242 @ 20 DEG C/4 DEG C; 1.0985 @ 60 DEG C/4 DEG C [R2, 1521] DSC: *pKa @ 25 DEG C: 7.76 [R15] HTV: *16.127 kcal/mol @ boiling point [R15] OWPC: +log Kow = -1.00 [R16] PH: *0.1 N AQ SOLN: 10.5; STRONG BASE [R2, 1521] SOL: *MISCIBLE WITH WATER, METHANOL, ACETONE; SOL @ 25 DEG C IN BENZENE, 4.2%; IN ETHER, 1.6%; IN CARBON TETRACHLORIDE, 0.4%; IN N-HEPTANE, LESS THAN 0.1% [R2, 1521]; *SOL IN CHLOROFORM [R3]; *SLIGHTLY SOL IN PETROLEUM ETHER [R17] SPEC: *INDEX OF REFRACTION: 1.4852 @ 20 DEG C/D [R2, 1521]; *IR: 6371 (Coblentz Society Spectral Collection) [R18]; *NMR: 7209 (Sadtler Research Laboratories Spectral Collection) [R18]; *MASS: 103 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R18] SURF: *0.0484 N/m @ 20 deg C [R1, p. VA10 2] VAPD: *5.1 (AIR= 1) [R19] VAP: *3.59x10-6 mm Hg @ 25 deg C (calc from exper derived coeffic) [R20] VISC: *@ 25 DEG C: 3.5X10+10 CENTIPOISE; @ 60 DEG C: 65.7 CENTIPOISE [R2, 1521] OCPP: *CRYSTALS FROM ETHANOL; MP: 177 DEG C /TRIETHANOLAMINE HYDROCHLORIDE/ [R2, 1521] *Heat of fusion = 6.500 kcal/mol [R15] *Heat capacity = 74.1 cal/K-mol [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Fire hazard: Slight, when exposed to heat or flame. [R21] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R22] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R22] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R22] FLPT: *190.5 deg C (Open cup) [R23] *355 deg F (closed cup) [R24] FIRP: *Wear goggles and self-contained breathing apparatus. Extinguish with dry chemical, alcohol foam, or carbon dioxide. Water may be ineffective on fire. Water or foam may cause frothing. Cool exposed containers with water. [R24] EQUP: *Goggles or face shield; rubber gloves and boots. [R24] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *VERY HYGROSCOPIC; TURNS BROWN ON EXPOSURE TO AIR AND LIGHT [R25] CLUP: *Overspread sufficient sodium bisulfate and sprinkle water. Drain into a sewer with abundant water. [R23] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *(a) Dissolve in combustible solvent such as alcohols, etc. Burn in an open furnace by igniting from a safe distance with the utmost care or sprinkle into the fire chamber of the furnace with afterburner and scrubber. (b) Pour into a sodium bisulfate in a large evaporating dish. Sprinkle water and neutralize. ... [R23] *The following wastewater treatment technologies have been investigated for Triethylene glycol: Concentration process: Activated carbon. [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Since most cosmetics ingested are nontoxic, only supportive care and perhaps dilution are required. The decision to induce emesis depends on the product toxicity, quantity ingested, time since exposure, patient's weight, and presence of symptoms. Most ingestions of cosmetics do not require emesis. /Cosmetics/ [R27] HTOX: *... CONSIDERED TO HAVE LOW ACUTE AND CHRONIC TOXICITY. ... IF DELETERIOUS EFFECTS WERE TO OCCUR IN MAN ... THESE WOULD PROBABLY BE ACUTE IN NATURE AND DUE TO ITS ALKALINITY RATHER THAN ITS INHERENT TOXICITY. [R28, 3169] *LOW TOXICITY. [R29] *Triethanolamine and diethanolamine produce mild skin irritation only in concentrations above 5%; little skin sensitization develops. [R27] *No industrial injuries have been recorded. Toxic effects are predicted to be limited to mild skin irritation. [R30] *The ingestion of several ounces can probably be tolerated by man, but unless the liquid is partly neutralized with acid, alkali burns of the mouth, pharynx and esophagus are likely. [R31] NTOX: *The principal toxic effect in animals has been ascribed to alkalinization (systemic alkalosis), ... /and/ functional signs of transient liver injury have been described in animals after sublethal doses. Gross pathology has been limited to the GI tract in fatal oral poisonings in rats and guinea pigs. [R31] *TESTED BY APPLICATION OF A DROP TO RABBIT EYES, ... IT CAUSED MODERATE, PRESUMABLY TRANSIENT INJURY, GRADED 5 ON A SCALE OF 1 TO 10 AFTER 24 HR, AND IN ANOTHER TEST CAUSED NEGLIGIBLE IRRITATION. [R32] *WHEN TESTED ON RABBIT EYES IN 0.023 MOLAR AQ SOLN BY CONTINUOUS APPLICATION FOR 15 MIN AFTER REMOVAL OF CORNEAL EPITHELIUM TO FACILITATE PENETRATION ... FOUND SOLN ADJUSTED TO PH 10 WAS ESSENTIALLY NONINJURIOUS. SAME SOLN ADJUSTED TO PH 11 CAUSED MODERATE CORNEAL SWELLING AND HYPEREMIA OF IRIS AND CONJUNCTIVA ... . [R33] *... IV INJECTIONS OF MONO-, DI-, AND TRIETHANOLAMINES IN DOGS RESULTED IN INCR BLOOD PRESSURE, DIURESIS, SALIVATION, AND PUPILLARY DILATATION. ... LARGER DOSES PRODUCED SEDATION, COMA, AND DEATH FOLLOWING DEPRESSION OF BLOOD PRESSURE AND CARDIAC COLLAPSE. MONOETHANOLAMINE WAS THE MOST EFFECTIVE AND TRIETHANOLAMINE THE LEAST EFFECTIVE. [R28, 3167] *IN A 90-DAY SUBACUTE FEEDING EXPT WITH RATS, THE MAX DOSE PRODUCING NO EFFECT WAS 0.08 G/KG DAILY. MICROSCOPIC LESIONS AND DEATHS OCCURRED @ 0.73 G/KG, and 0.17 G/KG PRODUCED ALTERATIONS IN LIVER AND KIDNEY WEIGHTS. APPLICATIONS OF 5 OR 10% SOLN TO RABBIT OR RAT SKIN DID NOT PRODUCE IRRITATION. [R28, 3169] *Groups of 50 6-wk-old F344/DUCRJ rats were given triethanolamine (TEA) dissolved in distilled drinking water at dose levels of 0 (controls), 1, or 2% ad libitum for 104 weeks. The dose levels in females were reduced by half from week 69 because of associated nephrotoxicity. Moribund, dead, and surviving rats, terminated at week 113, were autopsied and the following organs examined histopathologically: brain, spinal cord, nerves, pituitary, thyroid, parathyroid, thymus, lung, trachea, heart, liver, spleen, pancreas, adrenals, kidney, bladder, salivary glands, tongue, esophagus, stomach, small and large intestine, rectum, gonads, accessory sex organs, mammary, lymph nodes, skin, muscle, sternum, bone, eyes, and nasal cavity. Tumor varieties and incidence in all groups were similar to those spontaneously occurring in this strain, without statistically significant increases. Renal damage was examined in the treated groups, and nodular hyperplasia, pyelonephritis, and papillary necrosis were observed. Under the conditions of this study, triethanolamine was not carcinogenic in F344 rats but was toxic to the kidneys. [R34] *In a 90 day dermal study /on mice/ doses of triethanolamine up to 2.3 g/kg/day produced only slight epidermal hyperplasia at the site of application but no other systemic effects. [R35] *Triethanolamine has not been found to have any skin sensitizing activity in guinea pig skin sensitization tests. ... Ten guinea pigs were exposed by dermal application of 8,000 mg triethanolamine/kg body weight, 5 day/wk. All animals died after 2 to 17 applications, and pathologic changes were observed in the kidneys, liver, lungs, adrenals and peritoneum. This study indicates that dermal absorption of triethanolamine in guinea pigs is sufficient to produce systemic toxicity. [R36, 444] *Fourteen day repeated dose studies of triethanolamine in F344 rats and B6C3F1 mice were performed by inhalation, drinking water, or dermal routes of exposure. Exposures for both species in the inhalation study were 0, 0.125, 0.25, 0.5, 1.0 or 2.0 g/cu m, 6 hr/day, 5 days/wk, for 2 wk (10 exposures). The only histopathologic observation was a minimal acute inflammation of the laryngeal submucosa in rats and mice. In the oral study, concentrations of triethanolamine in drinking water (adjusted to pH 7.4) were 0, 0.5, 1.0, 2.0, 4.0, and 8.0 g/100 ml. Water consumption was significantly reduced in the 4 and 8% dose groups of rats and mice. No compound-related gross or microscopic lesions were observed in the liver or kidneys of rats; cytoplasmic vacuolization of hepatocytes was observed in the high dose groups of male and female mice. Dose levels of triethanolamine in the dermal study were 0, 0.14, 0.28, 0.56, 1.13 and 2.25 g/kg for rats and 0, 0.21, 0.43, 0.84, 1.69, and 3.37 g/kg for mice. Triethanolamine was applied as the undiluted compound, 5 days/wk for 2 wk. Chronic active necrotizing inflammation of the skin at the application site was observed at a greater frequency and severity in dosed rats than in dosed mice. [R36, 445] *Triethanolamine was embryotoxic when injected into three day chick embryos. ... Triethanolamine did not produce a significant increase in the incidence of malformations (3 malformations per 110 treated eggs compared to 1 malformation per 100 acetone control eggs). [R36, 445] *In a battery of short-term tests, triethanolamine did not induce mutations in bacteria (Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538 or Escherichia coli strains WP2 and WP2 uvrA in the presence or absence of S-9 fractions prepared from livers of Aroclor-induced rats), mitotic gene conversion in Saccharomyces cerevisae JD1 cells, or chromosomal damage in cultured rat liver RAL4 cells. ... Triethanolamine was inactive in inducing revertants to histidine prototrophy in the excision repair deficient Bacillus subtilis strain TKJ5211 with or without rat liver S-9 preparations. [R36, 446] *... An increased incidence of malignant lymphomas, particularly thymic lymphomas, developed in female but not male ICR-JCL mice fed diets containing 0.03 or 0.3% (w/w) triethanolamine throughout their lifespan compared to controls. The triethanolamine containing diets were prepared by heating mixtures of mouse feed plus triethanolamine for 40 min at 100 deg C. The incidences of malignant tumors in lymphoid tissues were 2.8% (1/36), 19% (7/37), and 25% (9/36), respectively. [R36, 447] *... There were no increases in the incidences of neoplasms in male and female B6C3F1 mice dosed with 1% or 2% triethanolamine in their drinking water for 78 wk compared to controls. [R36, 447] *... The compound is less irritating to skin and mucous membranes than most amines. [R31] *The carcinogenic potential of triethanolamine was examined in B6C3Fl-mice. The mice were exposed to drinking water containing 0, 1 or 2% triethanolamine. After 82 weeks surviving mice were sacrificed. Body weights in animals receiving 2% ethanolamine were lower than controls by week 60 for females and during the first 20 weeks for male mice. Water consumption of male mice receiving 1% triethanolamine was slightly higher than that of female mice. Total intakes of triethanolamine for 82 weeks were 26.9 and 37.3 grams/mouse in the low dose group and 62.8 and 63.6 grams/mouse in the high dose group for females and males, respectively. No significant increases were noted in any organ weights. Tumors developed in the liver, lung, hematopoietic system, Harderian gland, mammary gland, kidney, spleen, subcutis, thyroid gland, adrenal gland, pituitary gland, and uterus in the control and in each treatment group. No dose related increase of the incidence of any tumor was seen. /It was/ concluded that the chronic toxicity study documented a lack of carcinogenic activity of triethanolamine in B6C3F1-mice. [R37] *The carcinogenic potential of triethanolamine given in the drinking water over a two year period was investigated using F344-rats. There appeared to be no increase in the incidence of any specific tumors over the corresponding control group. However, a positive trend was noted in the occurrence hepatic tumors (neoplastic nodule or hepatocellular carcinoma) in males and of uterine endometrial sarcomas and renal cell adenomas in females by trend analysis tests. Histologically, all tumors observed in this study were similar to the spontaneous tumors observed in earlier studies. Toxic lesions of the liver associated with triethanolamine administration were not observed, although nonneoplastic lesions, which are common in aging F344-rats, were noted in the liver of both control and experimental groups. The absolute and relative kidney weights, however, increased significantly and dose dependently in the treated groups of both sexes. Macroscopically, kidneys were enlarged, granular on the surface, and anemic in color. In addition, mineralization of the renal papilla, nodular hyperplasia of the pelvic mucosa, and pyelonephritis with or without papillary necrosis were observed more frequently and dose dependently in the treated groups than in controls, while there were no tumors in the renal pelvis of any of the groups. /It was/ concluded that triethanolamine is not carcinogenic in F344-rats when given continuously in the drinking water for 2 years, although it is toxic to the kidneys, especially in females. [R38] +... 2 Year Study in Rats: ... CONCLUSIONS: Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of triethanolamine in male F344/N rats based on a marginal incr in the incidence renal tubule cell adenoma. There was no evidence of carcinogenic activity in female F344/N rats receiving 63, 125 or 250 mg triethanolamine/kg body weight. The study in male and female B6C3F1 mice was inadequate, because of the presence of a Helicobacter hepaticus infection complicated interpretation of the relationship between triethanolamine admin and liver neoplasms in these animals. [R39] NTXV: *LD50 Rat oral 8,680 mg/kg; [R21] *LD50 Mouse ip 1,450 mg/kg; [R21] *LD50 Guinea pig oral 8,000 mg/kg; [R21] ETXV: *LC50 Pimephales promelas (fathead minnow) 11.8 mg/l/96 hr (95% confidence limit 10.6 - 13.0 mg/l), flow-through bioassay with measured concentrations, 25.7 deg C, dissolved oxygen 7.3 mg/l, and pH 7.8; [R40] NTP: +... 2 Year Study in Rats: ... Triethanolamine doses selected for the 2 yr study in F344/N rats were 32, 63 and 125 mg/kg for males and 63, 125 and 250 mg/kg for females. Groups of 60 male and 60 female rats were topically admin triethanolamine in acetone 5 days/wk for 103 wk. ... 2 Year Study in Mice: ... Triethanolamine doses selected for the 2 yr study in mice were 200, 630 and 2,000 mg/kg for males and 100, 300 and 1,000 mg/kg for females. Groups of 60 male and 60 female mice were topically admin triethanolamine in acetone 5 days/wk for 103 wk. CONCLUSIONS: Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of triethanolamine in male F344/N rats based on a marginal incr in the incidence renal tubule cell adenoma. There was no evidence of carcinogenic activity in female F344/N rats receiving 63, 125 or 250 mg triethanolamine/kg body weight. The study in male and female B6C3F1 mice was inadequate, because of the presence of a Helicobacter hepaticus infection complicated interpretation of the relationship between triethanolamine admin and liver neoplasms in these animals. [R39] +... Although triethanolamine is a skin, eye, and mucous membrane irritant, no information could be found on its sensitizing potential. Triethanolamine was ... prepared in an acetone:olive oil mixture (4:1) which also served as the vehicle. Primary irritancy studies indicated that all concentrations of triethanolamine tested (up to 30%) were non-irritating. Female B6C3F1 mice were sensitized dermally to either 3%, 10%, or 30% solutions of triethanolamine daily for 5 consecutive days and challenged 7 days later with a 30% solution. A 0.5% solution of 1-fluoro-2,4-dinitrobenzene ... was used as a positive control. Site preparation included dermabrasion as well as intradermal injections of Freund's complete adjuvant into some mice. ... The irritancy response was determined by monitoring extravasation of 125I-bovine serum albumin into the treated area. The contact hypersensitivity response was assessed by monitoring the infiltration of 125I-iododeoxyuridine labeled cells into the challenge site and the mouse ear swelling test. ... There were no treatment-related effects on survival or body weights. There were no statistically significant or dose-related hypersensitivity responses to triethanolamine observed by either the radioisotopic method or the ear swelling test, with or without Freund's complete adjuvant. The positive response with 0.5% 1-fluoro-2,4-dinitrobenzene is shown for comparison ... . Under these experimental conditions, no statistically significant group or dose-dependent contact hypersensitivity responses to triethanolamine were observed in mice by dermal exposure. [R41] ADE: *In a dermal pharmacokinetic study, (14)C-triethanolamine was absorbed more slowly and less extensively in F344 rats than in C3H/HeJ mice. 48 hr after dermal application of (14)C-triethanolamine to mice (1,000 mg/kg dose), about 60% of the radioactivity was recovered from the urine and about 20% was recovered in the feces; less than 10% of the radioactivity was found in skin at the site of application. It was concluded that triethanolamine does not undergo extensive biotransformation in mice, since greater than 95% of the radioactivity recovered from the urine was identified as the parent compound. [R36, 443] *Triethanolamine was rapidly absorbed in orally dosed rats, and subsequently excreted mainly as unchanged parent compound in the urine. 24 hr after oral administration of triethanolamine (single dose of 2-3 mg/kg), 53% and 20% of the administered dose was recovered as the parent compound in the urine and feces, respectively. [R36, 443] BHL: *The blood half-life of triethanolamine equivalents after iv injection (1 mg/kg) or dermal application (1000 mg/kg) of (14)C-triethanolamine in mice was about 9.5 hr. [R36, 443] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *2= SLIGHTLY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 5-15 G/KG, BETWEEN 1 PINT AND 1 QT FOR 70 KG PERSON (150 LB). [R31] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Triethanolamine may be released to the environment in emissions or effluents resulting from its manufacture, transport, disposal, and use as a chemical intermediate in the manufacture of surfactants, detergents, herbicides, corrosion inhibitors and other products and as a processing aide. In soil and water, triethanolamine will biodegrade fairly rapidly following acclimation (half-life on the order of days to weeks). In soil, residual triethanolamine may leach. In the atmosphere triethanolamine is expected to exist partly in the vapor phase and partly in particulate form. Triethanolamine vapor is expected to react with photochemically generated hydroxyl radicals in the atmosphere (estimated half-life 4 hours). Wet and dry deposition may also be an important removal processes. The most probable route of exposure to triethanolamine is dermal contact with personal care products (i.e. soaps, cosmetics, emollients), household detergents and other surfactants, and lubricating fluids which contain this compound. (SRC) ARTS: *Triethanolamine may be released to the environment in emissions or effluents resulting from its manufacture, transport, disposal, and use as a chemical intermediate in the manufacture of surfactants, personal care products, detergents, herbicides, and corrosion inhibitors, especially in coolants for automotive engines and additives for lubricating fluids, for cutting oils and for milling cement(1-4). [R42] FATE: *TERRESTRIAL FATE: If released to soil, triethanolamine is expected to biodegrade fairly rapidly following acclimation (half-life on the order of days to weeks). Residual triethanolamine may leach. Volatilization from soil is not expected to be an important fate process. (SRC) *AQUATIC FATE: If released to water, triethanolamine should biodegrade. The half-life of this compound is expected to range from a few days to a few weeks depending, in large part, on the degree of acclimation of the system. Bioconcentration in aquatic organisms, adsorption to suspended solids and sediments, and volatilization are not expected to be important fate processes in water. (SRC) *ATMOSPHERIC FATE: Based on a vapor of 3.59X10-6 mm Hg at 25 deg C(3), triethanolamine is expected to exist partly in the vapor phase and partly adsorbed to particulates in the atmosphere(2,SRC). Triethanolamine vapor is expected to react with photochemically generated hydroxyl radicals in the atmosphere (estimated half-life 4 hours). The complete miscibility of triethanolamine in water(1) suggests that this compound may also be removed from the atmosphere in precipitation. Dry deposition may be an important removal process for triethanolamine adsorbed on particles(SRC). [R43] BIOD: *Triethanolamine was biodegraded in a river die-away at an initial concn 50 ppm, the results in 10 day test being 70% Theoretical Biochemical Oxygen Demand with acclimated Kanawha River water as seed and sewage as inoculum(1). In a BOD test in water using a sewage inoculum, triethanolamine added at an initial concn 2.5 ppm and run for 5, 10, 15, and 20 days exhibited 0, 0.8, 3.5, and 6.8% Theoretical Biochemical Oxygen Demand, respectively(2). Another BOD test in water using sewage inoculum and run for 20 days resulted in 66% Theoretical Biochemical Oxygen Demand for triethanolamine(3). Using synthetic sea water and sewage inoculum, a 20 day run showed 69% Theoretical Biochemical Oxygen Demand for triethanolamine(3). Using effluent from a biological sanitary waste treatment plant as an inoculum in BOD water, triethanolamine in a 5 day test resulted in 5% Theoretical Biochemical Oxygen Demand (unadapted) and 28% Theoretical Biochemical Oxygen Demand (adapted)(4). Triethanolamine at an initial concn of 500 ppm added to BOD water with an activated sludge inoculum and subjected to a 15 day acclimation period with a 10 day test period resulted in 22% Theoretical Biochemical Oxygen Demand(5). [R44] *Using the Zahn-Wellens test, triethanolamine added initial concn equivalent to 1000 mg/L COD and run for 14 days exhibited 89% degradation, using a non-adapted activated sludge inoculum(1). Another Zahn-Wellens test, using and initial triethanolamine concn equivalent to 400 ppm carbon (C), and runf for 8 days, showed 82% dissolved organic carbon (DOC) removal, activated sludge inoculum(2). In a Sturm test using a sewage inoculum, triethanolamine at initial concn equivalent to 10 ppm carbon (C) using a 14 day acclimation period period, resulted in 91% carbon dioxide (CO2) evolution and 100% dissolved organic carbon (DOC) removal after 28 dyas(2). Triethanolamine at an initial concn equivalent to 3-20 ppm carbon (C) in the Organization of Economic Cooperation Development (OECD) test using a sewage inoculum, resulted in 96% dissolved organic carbon (DOC) removal after 19 days(2). [R45] *Using a Modified Closed Bottle test, 2 ppm of triethanolamine resulted in 9% Theoretical Biochemical Oxygen Demand after 30 days, using an enriched sewage inoculum(1). However, in a prolonged closed bottle test, triethanolamine proved to be readily biodegradable with 73 and 78% of the Theoretical Oxygen Demand being expressed after 28 and 42 days, respectively(3). The French Association for Standardization (AFNOR) using sewage inoculum and triethanolamine at an initial concn of equivalent to 40 ppm carbon (C), resulted in 97% dissolved organic carbon (DOC) removal after 42 days(1). The Japanese Ministry of International Trade and Industry MITI test with an activated sludge inoculum and using 100 ppm triethanolamine resulted in < 30% Theoretical Biochemical Oxygen Demand after 14 days(2). [R46] ABIO: *The half-life for triethanolamine vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 4 hours based on an estimated reaction rate constant of 10.4X10-11 cu cm/molecules-sec at 25 deg C and an average ambient hydroxyl concentration of 5X10+5 molecules/cu cm(1,SRC). [R47] BIOC: *A bioconcentration factor (BCF) of < 1 was estimated for triethanolamine based on a log Kow of -1.59(1,2,SRC). An experimentally determined BCF was < 3.9(4). These BCF values and triethanolamine's complete solubility in water suggest that this compound does not bioconcentrate in aquatic organisms(3,SRC). [R48] KOC: *A soil adsorption coefficient (Koc) of 3 was estimated for triethanolamine based on a log Kow of -1.59 using a regression equation(1,2,SRC). This Koc value and the complete miscibility of triethanolamine in water suggests that this compound would be extremely mobile in soil and would not adsorb appreciably to suspended solids and sediments in water(3,4,SRC). [R49] VWS: *Henry's Law Constant for triethanolamine has been estimated to be less than 1X10-7 atm-cu m/mol at 25 deg C using a method of structural contributions to intrinsic hydrophilic character(1,SRC). This value suggests that volatilization of triethanolamine from water and moist soil would be negligible(2,SRC). [R50] RTEX: *The most probable route of exposure to triethanolamine is dermal contact with personal care products (i.e. soaps, cosmetics, emollients), household detergents and other surfactants, and lubricating fluids which contain this compound(1,2,SRC). The chief risk in industry would be from direct local contact of the skin or eyes with the undiluted, unneutralized fluid(3). [R51] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,198,609 workers are potentially exposed to triethanolamine in the USA(1). Ninety-eight percent of these exposures are with tradename products containing triethanolamine. [R52] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of amine salts of alkyl (C8-C24) benzene-sulfonic acid (..., and triethanolamine) are exempted from the requirement of a tolerance when used as a surfacant or related adjuvants of surfacants in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R53] *Residues of triethanolamine are exempted from the requirement of a tolerance when used as a stabilizer or inhibitor for formulations used before crop emerges from soil in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R53] *Amine salts of alkyl (C8-C24) benzene- sulfonic acid (..., triethanolamine) is exempted from the requirement of a tolerance when used as a surfacant or related adjuvants of surfacants in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R54] TLV: +8 hr Time Weighted Avg (TWA): 5 mg/cu m. [R55, 2002.58] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R55, 2002.6] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R56] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Triethanolamine is included on this list. [R57] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Triethanolamine is found on List C. Case No: 3145; Pesticide type: Insecticide, Antimicrobial; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Triethanolamine; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R8] *Residues of amine salts of alkyl (C8-C24) benzene-sulfonic acid (..., and triethanolamine) are exempted from the requirement of a tolerance when used as a surfacant or related adjuvants of surfacants in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R53] *Residues of triethanolamine are exempted from the requirement of a tolerance when used as a stabilizer or inhibitor for formulations used before crop emerges from soil in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R53] *Amine salts of alkyl (C8-C24) benzene- sulfonic acid (..., triethanolamine) is exempted from the requirement of a tolerance when used as a surfacant or related adjuvants of surfacants in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R54] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NIOSH Method 3509 Aminoethanol Compounds II Issue 5/15/89. Ion chromatography, ion pairing. Working range 0.1-5 ppm for 100 mL sample. Limit of detection 0.02 mg/sample, limit of quantitation 0.06 mg/sample. [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology and Carcinogenesis Studies of Triethanolamine in F344/N Rats and B6C3F1 Mice p.6 Technical Report Series No. 449 (1999) NIH Publication No. 00-3365 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The mid-1998 issue indicates that pathology quality assessment of the two year study for triethanolamine is in progress. Route: topical; Species: mice. [R59] SO: R1: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1179 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R5: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1994. 116 R6: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. R7: CHEMICAL PROFILE: ETHANOLAMINES R8: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.282 (Spring, 1998) EPA 738-R-98-002 R9: SRI R10: USEPA/OPP; Status of Pesticides in Reregistration and Special Review p.216 (Mar, 1992) EPA 700-R-92-004 R11: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.254 R12: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994.p. 3-133 R13: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-355 R14: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1256 R15: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 706 R16: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 25 R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-110 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 759 R19: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 2005 R20: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. 2065 R21: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2653 R22: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-88 R23: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 542 R24: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R25: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1241 R26: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-3-E-22 (1982) R27: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 907 R28: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R29: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 881 R30: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 707 R31: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-106 R32: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 944 R33: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 1050 R34: Maekawa A et al; J Toxicol Environ Health 19:345-357 (1986) R35: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 781 R36: Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990. R37: Konishi Y et al; Fundam and Appl Toxicol 18 (1): 25-9 (1992) R38: Maekawa A et al; J of Toxicol and Environ Health 19 (3): 345-57 (1986) R39: Toxicology and Carcinogenesis Studies of Triethanolamine in F344/N Rats and B6C3F1 Mice p.6 Technical Report Series No. 449 (1999) NIH Publication No. 00-3365 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R40: Geiger D.L., D.J. Call, L.T. Brooke. (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales- Promelas). Vol. V. Superior WI: University of Wisconsin-Superior, 1990.137 R41: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of Triethanolamine (CAS No. 102-71-6) Contact Hypersensitivity Studies in Female B6C3F1 Mice, NTP Study No. IMM90005 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 21, 2002 R42: (1) Liepins R et al; Industrial Process Profiles for Environmental Use. USEPA-600/2-77-023f NTIS PB-281 478 pp. 6-386 to 6-387 (1977) (2) Hawley GG; The Condensed Chemical Dictionary 10th ed NY: Van Nostrand Reinhold p. 1045 (1981) (3) Mullins RM; Kirk-Othmer Encycl Chem Tech 3rd ed NY: Wiley-Interscience 1: 959 (1978) (4) Hammer H et al; pp 1-6 in Ullman's Encycl Indust Chem A10 NY,NY: VCH Publ (1987) R43: (1) Dow Chemical; The Alkanolamine Handbook Midland, MI: Dow Chemical (1980) (2) Eisenreich SJ et al; Environ Sci Tech 15: 30-8 (1981) (3) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds. NY,NY: Amer Inst Phys Prop Data (1989) R44: (1) Mills EJ, Stack VT; Proc 9th Ind Waste Conf Eng Bull Purdue Univ: Ext Ser 9: 449-64 (1955) (2) Lamb CB, Jenkins GF; pp. 326-39 in Proc 8th Ind Waste Conf Purdue Univ (1952) (3) Price KS et al; J Water Poll Contr Fed 46: 63-77 (1974) (4) Bridie AL et al; Water Res 13: 627-30 (1979) (5) Gannon JE et al; Microbios 23: 7-18 (1978) R45: (1) Zahn R, Wellens H, Z Wasser Abwasser Forsch 13: 1-7 (1980) (2) Gerike P, Fischer WK; Ecotox Environ Safety 3: 159-43 (1979) R46: (1) Gerike P, Fischer WK; Ecotox Environ Safety 3: 159-43 (1979) (2) Kawasaki M, Ecotox Environ Safety 4: 444-54 (1980) (3) VanGinkel CG, Stroo CA; Ecotox Environ Saf 24: 319-27 (1992) R47: (1) Atkinson R; Inter J Chem Kinet 19: 799-828 (1987) R48: (1) GEMS; Graphical Exposure Modeling System CLOG3 (1986) (2) Lyman WJ et al; p. 5-5 in Handbook of Chemical Property Estimation Methods NY: McGraw-Hill (1982) (3) Dow Chemical; The Alkanolamines Handbook Midland, MI: Dow Chemical (1980) (4) Chemical Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chem Ind Ecol-Toxicol Info Center. ISBM 4-89074-101-1 (1992) R49: (1) Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (3) Dow Chemical; The Alkanolamines Handbook Midland, MI: Dow Chemical (1980) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R50: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-12 to 15-32 (1982) R51: (1) Hawley GG; The Condensed Chemical Dictionary 10th ed NY: Van Nostrand Reinhold p. 1045 (1981) (2) Chemical Marketing Reporter; Chemical Profile: Ethanolamine NY: Schnell Publishing Nov 10 (1986) (3) Am Conf Gov Ind Hyg; Appendix: Documentation of the Threshold Limit Values and Biological Exposure Indices 5th ed. p. 3169 Cincinnati, OH (1986) R52: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R53: 40 CFR 180.1001(c) (7/1/92) R54: 40 CFR 180.1001(e) (7/1/92) R55: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R56: 40 CFR 712.30 (7/1/92) R57: 40 CFR 716.120 (7/1/92) R58: NIOSH R59: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 48 Record 96 of 1119 in HSDB (through 2003/06) AN: 894 UD: 200211 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PENTACHLOROPHENOL- SY: *AI3-00134-; *Caswell-No.-641-; *Chlon-; *DOWICIDE-7-; *Dowicide-7-Antimicrobial-; *Dowicide-EC-7-; *Dura-Treet-II-; *EP-30-; *EPA-Pesticide-Chemical-Code-063001-; *Forpen-50-Wood-Preservative-; *FUNGIFEN-; *GRUNDIER-ARBEZOL-; *LAUXTOL-; *LIROPREM-; *NCI-C55378-; *NCI-C56655-; *Ontrack-WE-Herbicide-; *Osmose-Wood-Preserving-Compound-; *PCP-; *PENCHLOROL-; *Pentachlorphenol- (German); *Penta-Concentrate-; *Penta-Ready-; *Penta-WR-; *PERMASAN-; *Santophen-20-; *Ortho-Triox-Liquid-Vegetation-Killer-; *Watershed-Wood-Preservative-; *Weed-and-Brush-Killer-; *Woodtreat- RN: 87-86-5 RELT: 761 [PENTACHLOROPHENOL, SODIUM SALT] (Analog); 1724 [HEXACHLOROBENZENE]; 2863 [PENTACHLOROBENZENE] (Analog) MF: *C6-H-Cl5-O SHPN: UN 3155; Pentachlorophenol IMO 6.0; PENTACHLOROPHENOL UN 2761; Organochlorine pesticides, solid, toxic, not otherwise specified (compounds and preparations) UN 2762; Organochlorine pesticides, liquid, flammable, toxic, not otherwise specified, flashpoint less than 23 deg C (compounds and preparation) UN 2995; Organochlorine pesticides, liquid, toxic, flammable, not otherwise specified, flashpoint 23 deg C or more. UN 2996; Organochlorine pesticides, liquid, toxic, not otherwise specified. IMO 3.0; Organochlorine pesticides, liquid, flammable, toxic not otherwise specified, flashpoint less than 23 deg C. IMO 6.1; Organochlorine pesticides, solid or liquid, toxic, flammable, not otherwise specified, flashpoint 23 deg C or more. STCC: 49 613 80; Pentachlorophenol HAZN: D037; A waste containing pentachlorophenol may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. F027; A hazardous waste from nonspecific sources when a component of a discarded unused formulation. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by the chlorination of 2,4,5-trichlorophenol. [R1] *Pentachlorophenol is produced commercially in the USA by direct chlorination of phenol with chlorine gas in the presence of a catalyst at gradually rising temperatures up to 200 deg C. Other contaminants formed in pentachlorophenol production are isomers of hexa, hepta, and octachlorodibenzo-para-dioxin and isomers of tetra, penta, hexa, hepta, and octachlorodibenzofuran. [R2] *Pentachlorophenol is prepared either by catalytic chlorination of phenol or by alkaline hydrolysis of hexachlorobenzene. [R3] IMP: *Technical PCP has been reported to contain chlorodiphenylethers, chlorodibenzo-p-dioxins, chlorodibenzofurans, and hydroxychlorodiphenylethers; the octachlorodibenzo-p-dioxin content is typically 500-1500 ppm. [R4, 1465] *Fourteen technical pentachlorophenol and three sodium pentachlorophenate samples were obtained from several manufacturers and analyzed for various chlorinated phenolic impurities. Reversed-phase liquid chromatography with an electrochemical (coulometric mode) detector was used for qualitative and quantitative determinations. 2,4-Dichlorophenol, 3,5-dichlorophenol, 2,3,4-trichlorophenol, 2,4,6-trichlorophenol, 3,4,5-trichlorophenol, 2,3,5,6-tetrachlorophenol, 2,3,4,6-tetrachlorophenol, and 2,3,4,5-tetrachlorophenol were detected as contaminants in the various samples. [R5] *Commercial pentachlorophenol (PCP) contains significant quantities of tetrachlorophenol (TCP). The ratio of PCP to TCP in Dowicide G-ST, a commercial PCP formulation, was 2.5 + or - 0.1. [R4, 1465] *COMMERCIAL GRADE PCP CONTAINS 88.4% PCP, 4.4% TETRACHLOROPHENOL, 6.2% HIGHER-CHLORINATED PHENOXYPHENOLS, LESS THAN 0.1% TRICHLOROPHENOL AND VARIOUS DIBENZO-P-DIOXINS AND DIBENZOFURANS. /SRP: 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN HAS NOT BEEN FOUND./ [R6, 750] *The identification of 2-bromo-3,4,5,6-tetrachlorophenol, a halogenated phenol, in commercial pentachlorophenol samples is described. The concentration of the phenol impurity in the samples was on the order of 0.1%. [R7] *... Pentachlorophenol available after about 1973 contained only 1 ppm of the hexachloro- and 26 ppm of the octachlordibenzo-p-dioxin. [R8, 474] *Impurities in commercial pentachlorophenol preparations are as follows: tetrachlorophenol, 4.4-10.2%; trichlorophenol, less than or equal to 1%; chlorinated phenoxyphenols, 5-6.2%; octachlorodibenzodioxin, 5.5-3600 mg/kg; heptachlorodibenzodioxin, 0.6-520 mg/kg; hexachlorodibenzodioxin, < 0.03-100 mg/kg; octachlorodibenzofuran, < 0.1-260 mg/kg; heptachlorodibenzofuran, < 0.1-400 mg/kg; hexachlorodibenzofuran, < 0.03-90 mg/kg; pentachlorodibenzofuran, < 0.03-40 mg/kg; and tetrachlorodibenzofuran < 0.02-0.45 mg/kg. In addition, chlorinated cyclohexenones and cyclohexadienones, hexachlorobenzene and polychlorinated biphenyls are found. [R9] *The 1,2,3,6,7,9-, 1,2,3,6,8,9-, 1,2,3,6,7,8-, and 1,2,3,7,8,9- isomers of hexachlorodibenzo-p-dioxin have been detected in technical-grade pentachlorophenol. The 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxins predominated in commercial samples of technical-grade pentachlorophenol (Dowicide 7) and sodium pentachlorophenate. Octachlorodibenzo-p-dioxin is present in relatively high amounts in unpurified technical-grade [R10] *2,3,7,8-Tetrachlorodibenzo-p-dioxin has been confirmed only once in commercial pentachlorophenol samples. [R10] FORM: *The cmpd may be used alone or in combination with other agents such as ... 2,4-dinitrophenol, sodium fluoride, the dichromate salts, sodium arsenate, or arsenious oxide. [R11, 383] *Grades or Purity: 86-100%. [R12] *Dowicide EC-7: Pentachlorophenol 88%; Other chemicals 12%. [R13] *Penta Concentrate contains 9.7 lbs/gal PCP /Los Angeles Chemical Co/ [R14] *Penta Ready contains 5.3% PCP /Los Angeles Chemical Co/ [R14] *Penta WR contains 5.0% PCP /Los Angeles Chemical Co/ [R14] *The formulated product is available as granules, wettable powder and oil-miscible liquid...pentachlorophenol is also formulated as blocks, pellets, prills, and concentrates. [R9] *For the treatment of wood in the USA, pentachlorophenol is usually administered as a 5% solution in a mineral spirit solvent, such as No. 2 fuel oil or kerosene, or in dichloromethane, isopropyl alcohol, or methanol. Formulations may also contain co-solvents and anti-blooming agents. MFS: *Vulcan Materials Co, Hq, PO Box 530390, Birmingham, AL 35253, (205) 877-3000; Vulcan Chemicals Group, PO Box 530390, Birmingham, AL 35253; Production site: Wichita, KS 67277 [R15] OMIN: *Once used in tremendous volumes as an insecticide and fungicide in preserving wood products, /pentachlorophenol/ is being phased out of use because of the discovery that many commercial products were contaminated by polychlorinated dibenzodioxins and dibenzofurans, predominantly by hexa-, hepta-, and octachlorinated congeners. [R16] USE: *AS A MOLLUSCICIDE [R17] *TO INHIBIT FERMENTATION IN VARIOUS MATERIALS [R18] *Used as a preharvest defoliant on selected crops /Former/ [R19, p. C-194] *In various products, pentachlorophenol has been used as a herbicide, algacide, defoliant, wood preservative, germicide, fungicide, and molluscicide. As a wood preservative, it is commonly applied as a 0.1% solution in mineral spirits, NO 2 fuel oil, or kerosene. It is used in pressure treatment of lumber at 5% concentration. Weed killers contain higher concentrations. PCP is no longer available for over-the-counter sale in the USA. [R20] *Insecticide for termite control; pre-harvest defoliant; general herbicide. Has been recommended for use in the preservation of wood, wood products, starches, dextrins, glues. [R21] *The main commercial use of pentachlorophenol is as a wood preservative...it is used as a fungicide to protect wood from fungal decay and wood-boring insects...it is used as a pre-harvest defoliant in cotton and as a general pre-emergence, non-selective contact herbicide...it has been used as a bactericide in drilling fluids, as a fungicide in adhesives and textiles and for slime control in pulp and paper manufacture...pentachlorophenol has also been used to control the snails that are the hosts of schistosomiasis. [R22] *Pentachlorophenol is used to control termites and, frequently, as an ester (such as pentachlorophenyl laurate) to protect wood from fungal rots and wood-boring insects, and as a general herbicide. The sodium salt is used as a general disinfectant, e.g. for trays in mushroom houses. [R23] CPAT: *Wood Preservative, 90%; Sodium Pentachlorophenate, 10% (1983) [R1] *In the USA, it was estimated that 97% of the pentachlorophenol usage was as a wood preservative, 1% as a general herbicide and the remainder for miscellaneous smaller applications. [R22] PRIE: U.S. PRODUCTION: *(1975) 1.79X10+10 G [R24] *(1980) 2.12X10+10 G [R24] *2.04X10+10 g [R1] *Four manufacturers in the USA produced a total of 18,000-23,000 tonnes of pentachlorophenol annually from 1945 to 1978. Less than 14,000 tonnes were produced in 1980 by two manufacturers. In 1987, about 12,000 tonnes were produced by the sole US producer. [R22] U.S. IMPORTS: *(1980) 1.49X10+8 G [R24] *(1982) 5.47X10+7 G [R24] *(1983) 274,730 lb [R11, 383] U.S. EXPORTS: *(1978) 1.11X10+9 G [R24] *(1983) 8.89X10+8 G [R24] *1.83X10+9 G [R25] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS CRYSTALS (TECH; DARK GREY) [R23]; *Colorless to light-brown flakes or crystals [R26]; *White monoclinic, crystalline solid [R27, 953]; *Needle-like crystals [R21]; *Colorless to white crystalline solid. [R28] ODOR: *PHENOLIC ODOR [R26]; *VERY PUNGENT ODOR ONLY WHEN HOT [R21]; *Benzene-like odor. [R28] TAST: *Taste threshold of 30 ug/l. [R29] BP: *309-310 DEG C (DECOMP) [R21] MP: *174 deg C (monohydrate); 191 deg C (anhydrous) [R26] MW: *266.34 [R21] CORR: *Noncorrosive in absence of moisture [R30, 641] DEN: *1.978 AT 22 DEG C/4 DEG C [R21] DSC: *pKa= 4.70 [R31] HTV: *16,742.6 gcal/gmole [R32, p. C-672] OWPC: *log Kow= 5.12 [R33] SOL: *In water, 14 mg/l at 26.7 deg C. [R34]; *SLIGHTLY SOL IN PETROLEUM ETHER [R35]; *SOL IN MOST ORGANIC SOLVENTS; SLIGHTLY SOL IN PARAFFINS [R30, 641]; *Sol in ether [R32, p. C-414]; *Sol in dilute alkali, carbitol, cellosolve [R36]; *2 g/100 g in carbon tetrachloride at 20 deg C [R37, ()1981]; *8.5 g/100 g in o-dichlorobenzene at 20 deg C [R37, (1981)]; *3.1 g/100 g in diesel oil @ 20 deg C [R37, (1981)]; *32 g/100 g in pine oil @ 20 deg C [R37, (1981)]; *1.5 g/100 g in Stoddard solvent @ 20 deg C [R37, (1981)]; *In acetone: 50 g/100 g @ 25 deg C [R38]; *In benzene: 15 g/100 g @ 25 deg C [R38]; *In diacetone alcohol: 190 g/100 g @ 25 deg C [R38]; *In ethanol (95%): 120 g/100 g @ 25 deg C [R38]; *In methanol: 180 g/100 g @ 25 deg C [R38]; *In isopropanol: 85 g/100 g at 25 deg C [R38]; *In ethylene glycol: 11 g/100 g @ 25 deg C [R38]; *Water Solubility: 5 mg/l in water @ 0 deg C; 14 mg/l in water @ 20 deg C; 35 mg/l in water @ 50 deg C; 85 mg/l in water @ 70 deg C [R4, 1466] SPEC: *MAX ABSORPTION (ALCOHOL): 300.5 NM (LOG E= 3.4); 308 NM (LOG E= 3.4); SADTLER REFERENCE NUMBER: 279 (IR, PRISM); 96 (IR, GRATING) [R35]; *Intense mass spectral peaks: 266 m/z (100%), 268 m/z (70%), 264 m/z (68%), 165 m/z (54%) [R39]; *IR: 3657 (Coblentz Society Spectral Collection) [R40]; *UV: 112 (Sadtler Research Laboratories Spectral Collection) [R40]; *MASS: 1889 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R40]; *Intense mass spectral peaks: 200 m/z, 228 m/z [R41]; *Infrared (prism(279)); grating (96), ultraviolet (112) and nuclear magnetic resonance (proton (39667); C-13 (26001)) spectral data have been reported. [R26] VAPD: *9.20 (air= 1) [R27, 953] VAP: *0.00011 mm Hg at 25 deg C [R42] OCPP: *DENSITY OF SATURATED AIR: 1.0000011 (AIR= 1); PERCENT IN SATURATED AIR: 0.0000145% BY VOLUME AT 20 DEG C; 1 MG/L IS EQUIVALENT TO 91.9 PPM AND 1 PPM IS EQUIVALENT TO 0.01088 MG/L AT 25 DEG C [R43, 1606] *Henry's Law constant = 2.45X10-8 atm-cu m/mole [R44] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC, inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R45, p. G-154] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. [R45, p. G-154] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R45, p. G-154] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY, it is not effective in spill situations. [R45, p. G-154] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R45, p. G-154] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R45, p. G-154] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R45, p. G-154] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R45, p. G-154] +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R45, p. G-131] +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R45, p. G-151] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R46] +Flammability: 0. 0= This degree includes any material that will not burn. [R46] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R46] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. Material itself does not burn or burns with difficulty. [R47] +Extinguish fire using agent suitable for surrounding fire. Use dry chemical, foam, carbon dioxide, or water spray. Water may be ineffective. Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Use water spray to keep fire-exposed containers cool. [R46] TOXC: *Hydrogen chloride, chlorinated phenols, and carbon monoxide may be released upon decomposition. [R48, 1981.2] REAC: *Contact with strong oxidizers may cause fires or explosions. [R48, 1981.2] +Reacts with acids, alkalies, oxidizing materials, and other organic materials. [R46] +Strong oxidizers, acids, alkalis. [R49, 242] DCMP: *Hydrogen chloride, chlorinated phenols, and carbon monoxide may be released upon decomposition. [R48, 1981.2] +Decomposes to produce hydrogen chloride and other irritants and toxic gases. [R46] ODRT: *Odor thresholds for PCP soln at 30 deg and 60 deg C were 857 and 12,000 ug/l, respectively. [R50] *Detection: 1.6 mg/l. [R27, 954] SERI: *Dust or vapor irritates skin. ... [R12] +Eye and skin irritant. [R46] *All chlorophenol ... dusts are ... irritating to the respiratory tract. /Chlorophenols/ [R51] *Dust and vapor of pentachlorophenol are irritating to the eyes, causing lacrimation. [R52] EQUP: *Wear rubber gloves ... and overalls. [R36] *Five commercial glove materials were tested for permeation using two pentachlorophenol (PCP) formulations. When challenged with a 4.3% PCP in diesel oil soln, both Dayton Flexible Products Triflex (PVC) and the Best 64 NFW (natural rubber) gloves exhibited breakthrough times 30 sec after exposure. The Playtex #835 (latex/neoprene) glove exhibited breakthrough after 60 min, but showed a 5-fold greater rate of permeation than the Dayton and the Best glove. Neither the Edmont Sol-Vet (nitrile rubber) not the Granet Glo-Gluv (PVC) gloves had been permeated after testing for 8 and 16 hr, respectively. ... The results show that different gloves offer differing resistance to permeation by PCP based upon the composition of the gloves and the PCP formulation tested. [R53] +Recommendations for respirator selection. Max concn for use: 2.5 mg/cu m: Respirator Classes: Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust, mist, and fume filter. May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust, mist, and fume filter. May require eye protection. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R49, 243] +Recommendations for respirator selection. Emergency or planned entry into unknown concn or IDLH conditions: Respirator Classes: Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R49, 243] +Recommendations for respirator selection. Escape from suddenly occuring respiratory hazards: Respirator Classes: Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R49, 243] +Wear appropriate personal protective clothing to prevent skin contact. [R49, 243] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +Wear appropriate eye protection to prevent eye contact. [R49, 243] +Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R49, 243] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R49, 243] *Decontamination: Wear positive-pressure SCBA and protective equipment specified by references such as the DOT Emergency Response Guidebook or the CANUTEC Initial Emergency Response Guide. If special chemical protective clothing is required, consult the chemical manufacturer or specific protective clothing compatibility charts. Delay entry until trained personnel and proper protective equipment are available. Remove patient from contaminated area. Quickly remove and isolate patient's clothing, jewelry, and shoes. Gently brush away dry particles and blot excess liquids with absorbent material. Rinse patient with warm water, 30 deg C/86 deg F, if possible. Wash patient with Tincture of Green soap or a mild liquid soap and large quantities of water. Refer to decontamination protocol in Section Three. [R54, 317] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R55, 1979.8] OPRM: *ALL CLOTHING WORN DURING ONE SPRAYING OPERATION SHOULD BE LEFT AT WORKPLACE AND LAUNDERED BEFORE REUSE. WASHING WITH SOAP AND WATER IS MUST BEFORE EATING, DRINKING OR SMOKING. AT END OF EACH DAY, WORKMEN SHOULD SHOWER AND CHANGE INTO CLEAN CLOTHING. [R43, 1612] *Penta Concentrate: Vapor will cause injury if adequate ventilation is not insured. Do not use this product indoors or any other confined areas where vapors may concentrate ... [R19, p. C-244] +Contact lenses should not be worn when working with this chemical. [R49, 243] *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. [R47] *Avoid breathing vapors. Keep upwind. Wear boots, protective gloves, and goggles. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R47] *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be contained with a flexible impermeable membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. [R47] *Environmental considerations: Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates or greater concentration. [R47] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R49, 243] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R49, 243] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R49, 243] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R55, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R55, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R55, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R55, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R55, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R55, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R55, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R55, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R55, 1979.11] SSL: *STABLE; PROLONGED HEATING ABOVE 200 DEG C PRODUCES TRACES OF OCTACHLORODIBENZO-PARA-DIOXIN. [R56] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R57] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R58] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R59] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R55, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R55, 1979.13] STRG: *Temperature: ambient. [R12] *Venting: open. [R12] +Store in cool, dry, well ventilated location. Separate from acids, alkalies, oxidizing materials, and other organic materials. [R46] *Penta Ready, Penta WR: Keep container closed. Do not leave in sunshine. Do not use, pour, spill, or store near heat or open flame. Destroy or return this container when empty. Do not reuse empty container. [R19, p. C-194] *Penta Concentrate: Not for use or storage around the house. [R19, p. C-194] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R55, 1979.13] CLUP: *1) VENTILATE AREA OF SPILL. 2) COLLECT SPILLED MATERIAL IN MOST CONVENIENT AND SAFE MANNER AND DEPOSIT IN SEALED CONTAINERS FOR RECLAMATION OR ... DISPOSAL ... LIQ CONTAINING PENTACHLOROPHENOL SHOULD BE ABSORBED IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL. [R48, 1981.4] *Biological treatment is principal secondary treatment method but other ... methods employed at some wood preservative plants are carbon absorption, membrane filtration ... and oxidation by chlorine, hydrogen peroxide, and ozone. The reduction in concn of pentachlorophenol ... /in biological treatment/ is thought to occur by adsorption upon biomass rather than by degradation. [R60] *Avoid contact with solid and dust. Keep people away. Stop discharge if possible. Isolate and remove discharged material. Notify local health and pollution control agencies. [R12] *Survey report six case histories employing EPA's hazardous materials spills treatment trailer are reviewed. The trailer's ... treatment system has three mixed-media filters and three activated carbon columns to remove suspended, precipitated, and organic soluble materials. Spills of PCB, pentachlorophenol, kepone, tremide (chlordane, heptachlor, aldrin, and dieldrin), toxaphene, and dinitrobutylphenol were treated by the EPA trailer, which was generally successful in mitigating environmental effects by filtering and carbon-adsorption. 90% removal was achieved for 21 of 23 compounds. [R61] *Adsorption studies for the removal of the pesticide pentachlorophenol found in a number of water supplies were carried out using various materials including kaolinite, bentone SD-3 and powdered activated carbon. It was found that adsorption on kaolinite was negligible, whereas bentone SD-3 presented an adsorption efficiency from 10 to 100 fold less than equivalent quantities of powdered activated carbon. The effect of the pH on the removal of pentachlorophenol by activated carbon was studied. The removal efficiency of pentachlorophenol by activated carbon is better in acidic media. A clear dependence of adsorption on the pH appeared to be the result of a marked variation on the pesticide solubility as a function of the pH. Adsorption of pentachlorophenol/phenate (5 mg/l) diminishes markedly at pH values above the pKa of this weak acid (equal to 5.9 : 0.1) when the pentachlorophenol exists almost entirely in ionic form in aqueous solution, and is enhanced at low pH when the percentage of molecular species (whose concentration can be determined from pKa value) becomes significant. These remarks and the adsorptive capacities (163 mg.g-1 = 0.6 mmol/g at pH = 5.2 and 79 mg/g = 0,3 mmol/g at pH = 12.7), suggest a negative interaction between pentachlorophenol and activated carbon which seems to be confirmed by the results with bentone SD-43 (tables 1 to 4), and the values of the electrokinetic potential of these materials. This study emphasizes the effect of organic coadsorbates (eg, dissolved humic substances and the pesticide lindane) on the adsorption capacity of activated carbon for pentachlorophenol. Two different natural organic matters were studied as coadsorbates: purified humic acids from a commercial source (at 10 mg/l) and fulvic acids extracted from a top soil horizon (at 20 mg/l). Pentachlorophenol absorption was not affected by humic acids, whereas an increase of adsorption seemed to be observed in the presence of fulvic acids. Pentachlorophenol does not affect the adsorption of the humic acids, but improves slightly the removal of fulvic acids. This suggests an association between the two kinds of organic compounds, the resulting complex, fulvic acids/pentachlorophenol, being more adsorbed than the compounds themselves. The coadsorbate lindane (0.65 mg/l) which is easily adsorbed by activated carbon seemed also to improve slightly the removal efficiency of pentachlorophenol by activated carbon. [R62] *Chemical analyses revealed that polycyclic aromatic hydrocarbons and other organic compounds were present in a perennial freshwater stream that flowed through the abandoned American Creosote works and into Pensacola Bay, Florida. Moreover, groundwater pumped from a well depth of 21 m at a location adjacent to the site was heavily contaminated with polycyclic aromatic hydrocarbons and other organics. A study was conducted to determine the efficacy of ultrafiltration for removal of organics from groundwater at this USEPA, Super Fund site. Ultrafiltration reduced the concentration of total identified organics from 210.0 mg/l in groundwater to 1.5 mg/l in the post filtration permeate. Tests for toxicity/teratogenicity in embryonic inland silversides, Menidia beryllina; and Microtox 15 min EC50's were conducted with: (1) streamwater, (2) untreated groundwater, (3) feedwater used in the ultrafiltration system and (4) permeate water that passed through the ultrafiltration system. Concentration of 100% streamwater caused significant (alpha : 0.05) teratogenic responses in fish embryos and larvae; the Microtox EC50 was 3.7% streamwater. Groundwater and feedwater caused significant embryo toxic or teratogenic responses at concentrations of 100, 10, and 1%; the Microtox EC50's were 0.85 and 0.48%, respectively. In contrast, only 100% permeate water caused significant increases in terata, compared to the control response; at 10 and 1% concentration > 90% of hatched larvae appeared normal. The Microtox EC50 was 30% permeate water. [R63] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R55, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers D037; F027 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R64] *Pentachlorophenol is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Incineration (600 deg to 900 deg) coupled with adequate scrubbing and ash disposal facilities. [R65] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. [R66] *The following wastewater treatment technologies have been investigated for pentachlorophenol: Concentration process: Biological Treatment. [R67] *The following wastewater treatment technologies have been investigated for pentachlorophenol: Concentration process: Solvent Extraction. [R68] *Before draining, aqueous soln of low concn must be purified of the poisonous pentachlorophenol by filtering methods such as adsorption of the harmful material by activated charcoal. After this step, the charcoal is regenerated by controlled oxidation in a rotary kiln incinerator installation (600-900 deg C). The escaping hydrogen chloride gas is removed by scrubbers. Concentrated wastes are destroyed in special waste incinerators which have suitable installations to scrub the liberated hydrogen chloride gas. Recommendable method: Incineration. Not recommendable methods: Discharge to sewer, open burning and use as fuel. Peer-review: Dissolve in excess solvent before burning. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R69] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R55, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R55, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R55, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R55, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R55, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is limited evidence in humans for the carcinogenicity of combined exposures to polychlorophenols and their sodium salts. ... There is sufficient evidence in experimental animals for the carcinogenicity of pentachlorophenol. Overall evaluation: Combined exposures to polychlorophenols or to their sodium salts are possibly carcinogenic to humans (Group 2B). /Polychlorophenols and sodium salts/ [R70] *CLASSIFICATION: B2; probable human carcinogen BASIS FOR CLASSIFICATION: The classification is based on inadequate human data and sufficient evidence of carcinogenicity in animals: statistically significant increases in the incidences of multiple biologically significant tumor types (hepatocellular adenomas and carcinomas, adrenal medulla pheochromocytomas, and malignant pheochromocytomas, and/or hemangiomas) in one or both sexes of B6C3F1 mice using two different preparations of pentachlorophenol. In addition, a high incidence of two uncommon tumors (adrenal medulla pheochromocytomas and hemangiomas/hemangiosarcomas) was observed with both preparations. The classification is supported by mutagenicity data, which provides some indication that pentachlorophenol has clastogenic potential. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R71] +A3: Confirmed animal carcinogen with unknown relevance to humans. [R72, 2002.47] ANTR: *If poisoning has been caused by contamination of body surfaces, bathe and shampoo contaminated skin and hair promptly and thoroughly with soap and water, or water alone if soap is not available. Wash the chemical from skin folds and from under fingernails. Contaminated clothing should be promptly removed, bagged, and not returned until it has been thoroughly laundered. Contaminated leather shoes should be discarded. The possibility that pesticide has contaminated the inside surfaces of gloves, boots, and headgear should be kept in mind. [R73] *Flush chemical from eyes with copious amounts of clean water. Obtain medical attention if irritation or other injury persists. [R73] *Systemic poisoning must be treated by controlling body temperature, providing oxygen, maintaining hydration, and relieving agitation. Reduce elevated body temperature by physical means. Administer sponge baths and cover victim with cool blankets. In fully conscious patients, administer cold, sugar-containing liquids by mouth as tolerated. Do not administer atropine, aspirin, or other salicylates to control hyperthermia. ... Administer oxygen continuously by mask to minimize tissue anoxia. Unless there are manifestations of cerebral or pulmonary edema or of inadequate renal function, administer intravenous fluids to restore hydration and support physiologic mechanisms for heat loss and toxicant disposition. Monitor serum electrolytes, adjusting IV infusions to stabilize electrolyte concentrations. Follow urine contents of albumin and cells, and keep an accurate hourly record of intake/output to forestall fluid overload if renal function declines. ... In severe poisonings, monitor pulmonary ventilation carefully to insure adequate gas exchange, and monitor cardiac status by ECG to detect arrhythmias. The toxicant itself and severe electrolyte disturbances may predispose to arrhythmias and myocardial weakness. ... [R74] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . Rapid body cooling may be necessary in case of hyperthermia. Use of salicylates is contraindicated. /Pentachlorophenol and related compounds/ [R54, 318] *Advances treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's to treat dehydration. Watch for signs of fluid overload, cerebral edema, and pulmonary edema. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Pentachlorophenol and related compounds/ [R54, 318] MEDS: *Whole Blood: Reference Ranges: Normal - Not established; Exposed - Not established; Toxic - Not established. The assessment of pentachlorophenol exposure can be accomplished through measurement of free pentachlorophenol. However, the reference ranges found in the literature were for pentachlorophenol in serum or plasma, which appears to be the better specimen for analysis. Pentachlorophenol exists primarily in the plasma, thus analysis of this specimen would be more sensitive. [R75, 1909] *Serum or Plasma: The assessment of pentachlorophenol exposure can be accomplished through measurement of free pentachlorophenol. However, other compounds such as hexachlorobenzene and lindane may be metabolized to pentachlorophenol in the body, which can confound the identification of exposure. Hemolysis of the blood specimen will have no effect on the analysis, since pentachlorophenol is present in red cells in a negligible amount. Reference Ranges: Normal - Background levels of up to 0.1 mg/l have been found in people in the general population with no recognized exposure to pentachlorophenol; Exposed - BEI (sampling time is end of shift, measured as free pentachlorophenol): 5 mg/l. Serum levels of pentachlorophenol below 1.3 mg/l have not been associated with any adverse health effect. Pentachlorophenol concentrations in serum/plasma that have been found to correlate with workplace air concentrations are as follows: Pentachlorophenol air levels 0.05 and 0.1 mg/cu m correlate to serum/plasma pentachlorophenol levels (sampling time not fixed) of 1000 and 1700 ug/L, respectively; Toxic - Serum levels of pentachlorophenol ranging from 23 to 162 mg/L have been reported in cases of fatal overexposure. [R75, 1909] *Urine: The assessment of pentachlorophenol exposure can be accomplished through measurement of total pentachlorophenol (free and conjugated), which has been found to correlate well with air levels. However, other compounds such as hexachlorobenzene and lindane may be metabolized to pentachlorophenol in the body, and may also cause elevated pentachlorophenol levels. Exposure to these pesticides should be ruled out when evaluating urinary levels. Reference Ranges: Normal - Average concentration approximately 0.063 mg/L, but has been found to be up to 0.100 mg/L in people with no recognized exposure to pentachlorophenol; Exposed - BEI (sampling time is prior to the last shift of workweek, measured as total pentachlorophenol): 2 mg/g creatinine. Pentachlorophenol concentrations in urine that have been found to correlate with workplace air concentrations are as follows: pentachlorophenol air levels of 0.05 and 0.10 mg/cu m correlate to urine pentachlorophenol levels (sampling time not fixed) of 300 and 600 ug/L, respectively; Toxic - Not established. [R75, 1910] *Urine Albumin: Albuminuria has been shown to be a specific marker of glomerular dysfunction. Tubular damage, however, can also result in increased levels of albumin in the urine. [R75, 1911] *Urinary Beta-2-Microglobulin and/or Retinal Binding Protein: Measurements for the presence of either of these low molecular weight proteins are useful in detection of early impairment of proximal tubular function. However, beta-2-microglobulin is unstable at urinary pH less than 6, and may degrade in the bladder prior to collection and subsequent neutralization of the urine sample. Measurement of retinal binding protein appears to be a better marker for early tubular dysfunction due to its stability in the urine subsequent to collection and analysis. However, retinal binding protein is produced in the liver and not a constitutive protein of the kidney, so that its presence in the kidney provides only indirect evidence of tubular damage. [R75, 1912] *Urinary Alpha () and Pi () Isoenzymes of Glutathione S-Transferase: Radio-immunological and Elisa techniques have been developed for quantitation of and isoenzymes of glutathione S-transferase, which are constitutive proteins in the kidney. The isoenzyme is located only in the proximal tubule, while the isoenzyme is located in the distal convoluted tubule, the loop of Henle, and the collecting ducts of the kidney. Damage to epithelial cell membranes can result in the increased excretion of these isoenzymes in the urine. This test for assessing renal tubular damage appears to have many advantages over other available tests, such as: (1) the and isoenzymes are constitutive proteins in the kidney; (2) these isoenzymes are stable in the urine, (3) the test is simple and reproducible; and (4) due to selective localization of the isoenzymes, differential diagnosis of specific tubular damage is possible. In addition, increased levels of these isoenzymes were seen in patients previously exposed to nephrotoxicants where conventional tests for kidney function were normal, indicating a high degree of sensitivity. [R75, 1912] *Urinary Enzyme N-acetylglucosaminidase: This lysosomal enzyme has shown promise in assessment of subclinical nephrotoxic injury. This enzyme is not normally filtered at the glomerulus due to its high molecular weight. In the absence of glomerular injury, this enzyme will be detected in the urine as a result of leakage or exocytosis from damaged, stimulated, or exfoliated renal cells. The sensitivity of measurement for this enzyme has not been thoroughly studied, but it's usefulness has shown some promise. However, this enzyme is unstable at urinary ph greater than 8, which could diminish the sensitivity of the measurement due to enzyme degradation. [R75, 1912] *Routine Urinalysis: Performing a routine urinalysis including parameters such as specific gravity, glucose, and a microscopic examination may be useful for assessing renal toxicity. [R75, 1912] *Biochemical Tests: Enzymes that reflect cholestasis - alkaline phosphatase, 5'-nucleotidase, leucine aminopeptidase; ... Enzymes that detect direct hepatic damage - aspartate aminotransferase, alanine aminotransferase. [R75, 1913] *Clearance Tests: Indocyanine green; Antipyrine test; Serum bile acids. [R75, 1913] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV 1 have been found to be better predictors of chronic airflow obstruction. [R75, 1914] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. [R75, 1914] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. [R75, 1914] *Sputum Cytology: Sputum cytology along with chest radiographs have been the standard procedures for detecting early lung cancer in asymptomatic patients. Sputum cytology has been found to be useful for detection of central tumors, especially squamous carcinomas. For this test to be effective, exfoliated respiratory mucosal cells must be present in the expectorated specimen. Pooling of sputum collected over 2-3 days may enhance the sensitivity of this test by increasing the yield of exfoliated cells in the specimen. [R75, 1915] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. [R75, 1915] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. [R75, 1915] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell assessment - standardized odor threshold and identification testing; Visual assessment -standard acuity tests, visual field tests, contrast sensitivity, and color vision measurements (vision assessment); Facial and Trigeminal Nerve assessment - blink reflex (pontogram); Vestibular assessment - pure tone audiometry for bone- and air-conducted sounds, threshold decay at 4 kHz, speech discrimination and speech reception thresholds, tympanograms and acoustic thresholds, electronystagmograms; Hearing assessment - audiometry testing. [R75, 1915] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R55, 1979.23] HTOX: *INGESTION CAUSES INCR THEN DECR OF RESP, BLOOD PRESSURE, URINARY OUTPUT; FEVER; INCR BOWEL ACTION; MOTOR WEAKNESS, COLLAPSE WITH CONVULSIONS AND DEATH. CAUSES LUNG, LIVER, KIDNEY DAMAGE; CONTACT DERMATITIS. ... DUST CAUSES SNEEZING. [R76] *MOST IMPORTANT EFFECT OF PENTACHLOROPHENOL INHALATION IS ACUTE POISONING CENTERING IN CIRCULATORY SYSTEM WITH ACCOMPANYING HEART FAILURE. ... DUSTS ARE PARTICULARLY IRRITATING TO EYES AND NOSE IN CONCN GREATER THAN 1 MG/CU M. SOME IRRITATION OF NOSE MAY OCCUR AT 0.3 MG/CU M. ... SURVIVORS OF ... INTOXICATION SUFFER ... VISUAL DAMAGE AND ACUTE TYPE OF SCOTOMA. OTHER DAMAGE INCL ACUTE INFLAMMATION OF CONJUNCTIVA AND CHARACTERISTICALLY SHAPED CORNEAL OPACITY, CORNEAL NUMBNESS AND SLIGHT MYDRIASIS. [R17] *Immersion of hands for 10 min in a 0.4% soln caused pain and inflammation. [R77] *Dust and mist concn greater than 1.0 mg/cu m resulted in painful irritation of upper respiratory tract in persons not previously exposed to pentachlorophenol. Violent sneezing and coughing accompanied exposure. Conditioned persons tolerated concn up to 2.4 mg/cu m. [R77] *Chronic exposure in workers resulted in elevated bilirubin and creatine phosphokinase. Higher prevalence of gamma mobility c-reactive protein in sera. [R78] *Five cases of pentachlorophenol poisoning, including 2 fatalities, occurred in two small wood preservative plants ... fever ... severe hyperpyrexia ... increased anion gap and renal insufficiency. ... Pentachlorophenol may uncouple oxidative phosphorylation, resulting in a poisoning syndrome characterized by hyperpyrexia, diaphoresis, tachycardia, tachypnea, abdominal pain, nausea and even death. [R79] *Repeated exposure to commercial (technical grade) pentachlorophenol preceded aplastic anemia in four patients and pure red cell aplasia in two. Two patients developed concomitant or subsequent Hodgkin's disease and acute leukemia ... . [R80] *Chromosome analyses were carried out on peripheral lymphocytes from 22 male workers employed at a pentachlorophenol producing factory. ... A small but significant increase in the frequency of dicentrics and acentrics was observed. ... [R81] *Workers (3 women, 15 men) in a pentachlorophenol processing factory, with a mean activity of processing pentachlorophenol for 12 years were studied. ... Pentachlorophenol levels in plasma ranged from 0.02-1.5 ug/l, median 0.25 ug/l, and in urine 13-1224 ug/l, median 112 ug/l or 11-2111 ug/g creatinine, median 111 ug/g creatinine. ... Individual evaluation of the toxicological and neurophysiological results gave /indications/ that in some cases decreased nerve conduction velocity was caused by chronic exposure to pentachlorophenol. [R82] *A cytogenetic study was performed on 20 healthy workers exposed to pentachlorophenol in concentrations ranging from 1.2 to 180 ug/cu m (maximum concentration at the workplace is 500 ug/cu m) for 3 to 34 years. Pentachlorophenol was determined in the blood plasma of all probands, yielding concentrations between 23 and 775 ug/l (Biological Tolerance Value is 1000 ug/l). In vitro pentachlorophenol up to 90 mg/l was added to phytohemagglutinin-stimulated lymphocytes of normal healthydonors without any effect on sister chromatid exchange or chromosomal aberrations, whereas a slow down of cell proliferation could be detected in the presence of 60 mg pentachlorophenol/l. [R83] *A series of studies of chronically exposed workers has been conducted in Hawaii. The first involved workers in wood treatment plants and farmers or pest-control operators. Elevation of serum enzyme levels, ie, serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase, and lactic dehydrogenase, and low-grade infections or inflammations of the skin, eye, and respiratory tract were found in the exposed groups. In a /separate/ study, plasma protein levels were found to be elevated in exposed, as compared with unexposed, workers. [R11, 388] *ALTHOUGH PENTACHLOROPHENOL IS HIGHLY TOXIC IN ITS OWN RIGHT, SOME STUDIES SUGGEST THAT CONTAMINANTS MAY BE RESPONSIBLE FOR /SRP: SOME OF THE POISONOUS POTENTIAL OF/ THE TECHNICAL GRADE. COMPARISON OF EFFECTS OF TECHNICAL VERSUS PURIFIED PCP INDICATED THAT ONLY TECHNICAL GRADE PRODUCED CHLORACNE, CHICK EDEMA, HEPATIC PORPHYRIA AND INCR RELATIVE LIVER WT. TECHNICAL GRADE WAS ALSO MUCH MORE ACTIVE AS LIVER ENZYME INDUCER. [R84] */NRC Safe Drinking Water Committee/ ... noted that the toxicity of pentachlorophenol is increased by impurities contained in the technical product. For example, the No Observed Effect Level for pure pentachlorophenol is 3 mg/kg/day; however, the No Observed Effect Level for technical pentachlorophenol is 1 mg/kg/day, indicating increased toxicity due to impurities. [R11, 396] *The general population is more susceptible during hot weather. [R48, 1981.1] *Individuals emptying bags of prilled (granular) or powder formulations of pentachlorophenol and of sodium pentachlorophenol are at an incr oncogenic risk. [R85] *SEVERAL AREAS IN PENTACHLORPHENOL TOXICOLOGICAL PROFILE, SUCH AS CARCINOGENESIS AND MUTAGENESIS, ARE NOT COMPLETE. WITH REGARD TO OCCUPATIONAL EXPOSURES, PRECAUTIONS SHOULD BE TAKEN TO AVOID DIRECT CONTACT AND AIR LEVELS SHOULD BE KEPT WITHIN ACCEPTABLE LEVELS. [R86] *A case of a 33 yr old man who died following occupational exposure to pentachlorophenol is presented. Postmortem examination revealed cerebral edema and fatty degeneration of the viscera. [R87] *A longitudinal study was performed to examine whether chronic occupational exposure to pentachlorophenol or its compounds causes measurable alterations in the conduction velocity in peripheral nerves as an adverse effect. In total, the results of nerve conduction velocity determinations in 1980 and 1984 in 10 subjects (7 men, 3 women) who had been exposed for an average of 16 years (range 4-24) were available. The concentrations of pentachlorophenol in the air at the workplace varied between 0.3 and 180 ug/cu m and were thus below the maximum allowed concn (MAK value) of 500 ug/cu m. The biological monitoring carried out showed the following results: pentachlorophenol in the serum: 38-1270 ug/l; pentachlorophenol in urine 8-1224 ug/l. Compared with the upper normal limits pentachlorophenol in the serum 150 ug/l, pentachlorophenol in the urine 60 ug/l), distinct internal exposure to pentachlorophenol has resulted in some of the employees. Determinations of the nerve conduction velocity of motor and sensory nerve fibers (ulnar, median, peroneal, and sural nerve) were always in the normal range. A significant difference in the nerve conduction velocity for the period 1980-4 could not be detected. In addition, the correlation analyses did not show any hints of dose-effect relations. It is concluded that occupational exposure to pentachlorophenol over several years in the concentrations observed probably do not lead to any adverse effects on the peripheral nervous system. [R88] *Three case reports of skin lesions associated with exposure to pentachlorophenol in wood preservatives were described. Since pentachlorophenol and its sodium salt are commonly used in wood preservatives, paints, and disinfectants due to their fungicidal, insecticidal, bactericidal, herbicidal, and molluscicidal properties, exposure can occur in both occupational and non-occupational settings. The cases described involved two males and one female, all of whom were caucasian. Serum pentachlorophenol levels were measured in each individual. In non-exposed individuals, normal levels did not exceed 15 ug/l. The first case was that of a 41 year old man diagonosed as having pemphigus vulgaris. Exposure was attributed to a bookcase which had been treated with pentachlorophenol. Serum levels of pentachlorophenol varied from 10 to 47 ug/l in this patient, and clinical improvement was associated with decreased serum levels. A 28 year old female also diagnosed as having pemphigus vulgaris. Exposure in this case was ascribed to rafters in her home which had been treated with pentachlorophenol. Serum pentachlorophenol levels ranged from 10.8 to 114 ug/l, and also tended to decline with periods of clinical improvement. The third case was that of a 35 year old male who suffered from urticaria. Exosure in this case occurred when the patient had treated wood framework. Serum pentachlorophenol levels varied from 20.9 to 96 ug/1 in this individual. The role of pentachlorophenol in the pathogenesis of these cases is not understood. The ... possible mechanisms could include direct toxic effects, photoreactivity, or induced changes in epidermal immunology. [R89] *A 32 year old white male was seen at a university dermatology clinic complaining of an acneform eruption of 6 months duration. The patient was part owner of a firm that constructed piers for small boat marinas. The lumber used was pretreated with pentachlorophenol. Within about 9 months after beginning work, he noted a papular acneform eruption that occurred over the entire body. The eruption was characterized by multiple, small yellow/white papules. Areas most involved included the malar regions of the face, post auricular area, the trunk, buttocks, thighs, and lower legs. Some of papules were inflamed. A trephine punch biopsy of one of the papules showed a small epithelial lined cystic structure that communicated with the surface. The lining epithelium was composed of atrophic, but normal appearing, epidermis. Contained within the cyst was keratin-like material. The condition was diagnosed as chloracne. The patient's condition improved after 6 weeks oral treatment with isoretinoin. The patient remained asymptomatic for the ensuing 2 years of observation. The patient returned to work wearing appropriate protective clothing. A sample of pentachlorophenol used by the firm and samples of treated wood were analyzed for octachlorodibenzodioxin. Samples from the surface of the lumber contained about ten to 40 times the amount of octachlorodibenzodioxin as did the wood itself. The undiluted pentachlorophenol contained 1600 ppm octachlorodibenzodioxin. It was concluded the patient developed chloracne after exposure to pentachlorophenol treated lumber. The octachlorodibenzodioxin containing surface residue seemed to be the major source of the intoxication. [R90] *... Liquid or solid causes smarting of skin and first-degree burns on short exposure; may cause secondary burns on long exposure. [R12] *The most important effect of pentachlorophenol inhalation is acute poisoning centering in the circulatory system with accompanying heart failure. [R17] *Industrial hygiene experience shows that pentachlorophenol and its sodium salt are capable of inducing discomfort and local as well as systemic effects. Dusts are particularly irritating to the eyes and nose in concentrations greater than 1 mg/cu m. Some irritation of the nose may occur at 0.3 mg/cu m. Hardened workers can tolerate up to 2.4 mg/cu m. Pentachlorophenol is highly poisonous with a wide range of acute action but no pronounced cumulative properties. [R91, 1991.1178] *The survivors of pentachlorophenol intoxication suffer with impairments in autonomic function, circulation, visual damage, and an acute type of scotoma. Other damage included acute inflammation of the conjunctiva and characteristically shaped corneal opacity, corneal numbness, and slight mydriasis. Other symptoms involve excessive sweating, tachycardia, tachypnea, respiratory distress, hepatic enlargement, and metabolic acidosis. [R91, 1991.1179] +Symptoms of overexposure include an increase followed by a decrease in respiration, blood pressure, and urinary output; fever; increase in bowel action; motor weakness; and collapse with convulsions and death. [R46] *Chlorophenols appear to be mildly hepatotoxic, and studies in animals indicate that pentachlorophenol may reduce humoral and cell-mediated immunity as well as act as a cocarcinogen. /Chlorophenols/ [R92] *Evaluation of lymphocyte phenotype frequencies, functional responses, serum immunoglobulin levels, and autoantibodies was completed for 38 individuals (ie, 10 families) who were exposed to pentachlorophenol in manufacturer treated log houses. Comparison of subjects with controls revealed that the exposed individuals had activated T cells, autoimmunity, functional immunosuppression, and B cell dysregulation. Autoimmunity was evidenced by elevation of TA1 phenotype frequencies and a 21% incidence of anti-smooth muscle antibody. Functional immunosuppression was evidenced by the significantly reduced responses to all mitogens tested and to allogeneic lymphocytes in the mixed lymphocyte culture test. There was a significant elevation of CD10, and an 18% increase or decrease in serum immunoglobulins was noted. A striking anomaly was the enhanced natural killer activity found in exposed females but not in males. [R93] *A mortality study was conducted in a cohort of 2283 plywood mill workers employed for at least one year between 1945 and 1955 in this industry. There were 570 deaths in this cohort, which was only 74% of the number expected based on comparable US mortality figures. A statistically nonsignificant excess of deaths was observed for lymphatic and hematopoietic cancer excluding leukemia (standard mortality ratio (SRM)=156). The greatest excess was for multiple myeloma (SRM=333). The excess mortality due to lymphatic and hematopoietic cancer excluding leukemia was highest after 20 yr duration of employment and latency. The workers were potentially exposed to formaldehyde, but there were no deaths due to nasal cancer. A subcohort of 818 workers involved in drying or gluing operations and exposed to formaldehyde and pentachlorophenol was also studied. Based on small numbers, statistically nonsignificant increased risks of death from Hodgkin's disease (SRM=333) and lymphosarcoma (SRM=250) were observed. The authors recommend further surveillance of the plywood mill worker cohort. [R94] *The occurrence of chloracne among pentachlorophenol (PCP) workers was evaluated, and the risk of chloracne among workers who had records of direct skin contact with PCP was assessed. The workers had been employed at a facility which had produced PCP from 1938 through 1978. Of the 926 hourly workers in the study cohort, 666 had medical records available and were employed in 1953 or later; 65 had a diagnosis of chloracne, of which 47 were thought to be associated with PCP. The increase in duration of exposure did not appear to be related to the increased risk of chloracne. Episodes of direct skin contact with PCP were reported throughout the history of the facility. The workers with independent records of direct skin exposure had overall a four fold increase in the risk of developing chloracne compared with workers who did not have records of direct skin contact. Eight of the 13 cases had only one episode of direct skin contact with PCP prior to the diagnosis of chloracne, three cases had two episodes, and two cases had three episodes. The interval between the latest episode of direct skin contact and the diagnosis of chloracne for these 13 cases ranged from about 7 weeks to about 14 years. Four of the 13 cases occurred within 6 months of contact, four occurred between 1 and 2 years after the skin contact. Two occurred between 2 and 3 years after contact and three occurred more than 10 years after exposure. The authors conclude that exposure to PCP contaminated with hexachlorinated, heptachlorinated, and octachlorinated dibenzo-p-dioxins and dibenzofurans was associated with the occurrence of chloracne. [R95] *Pentachlorophenol (PCP) and its sodium salt are frequently used in wood preservatives. Little is known about the effects on man when being chronically exposed. Only vague skin symptoms, such as rashes, acne and cutaneous infections were described. We present two cases of pemphigus vulgaris with a known non-occupational chronic PCP exposure. The clinical course and the titer of pemphigus antibodies roughly correlate with the PCP levels in serum. In one case of chronic urticaria the exacerbations also run parallel to the PCP serum levels and increased anti-skin antibodies, without any manifestation of pemphigus vulgaris. The role of PCP as one of the causes provoking pemphigus vulgaris and chronic urticaria with raised anti-skin antibodies is discussed. [R96] *A cytogenetic study was performed on 20 healthy workers exposed to pentachlorophenol (PCP) in concentrations ranging from 1.2 to 180 ug/cu m (Maximum Concentration at the workplace is 500 ug/cu m) for 3 to 34 years. PCP was determined in the blood plasma of all probands, yielding concentrations between 23 and 775 ug/l (Biological Tolerance Value is 1000 ug/l). In vitro PCP up to 90 mg/l was added to phytohaemagglutinin stimulated lymphocytes of normal healthy donors without any effect on sister chromatid exchange (SCE) or chromosomal aberrations (CA), whereas a slowdown of cell proliferation could be detected in the presence of 60 mg PCP/l. In vivo we neither observed a relation between PCP concentrations and the number of SCE nor an increase of CA. [R97] *Aplastic anemia, pure red cell aplasia, leukemia, lymphoma and other hematologic disorders have followed exposure to products containing the pesticide pentachlorophenol (PCP). Information in a 25-year compilation of documented case reports is summarized, involving industrial and home exposure and accidental poisoning in a nursery. The potential hematologic, mutagenic and carcinogenic effects of PCP and its dioxin-dibenzofuran contaminants also are reviewed. Owing to widespread contamination of the environment by PCP products, and latent periods of up to several decades after exposure before these disorders become manifest clinically, it is necessary to consider their etiologic or contributory role. These issues continue to surface in toxic tort litigation relative to causation. [R98] *Pentachlorophenol (PCP) is a substance whose widespread use, mainly in wood protection and pulp and paper mills, has led to a substantial environmental contamination. This in turn accounts for a significant exposure of the general human population, with rather high exposure levels being attained in occupational settings. Investigations on the genotoxic activity of PCP have given rise to divergent results which would seem to make an evaluation difficult. By grouping them into 3 categories a somewhat clearer picture, allowing finally an (admittedly tentative) assessment, can be obtained. PCP does seem to be at most a weak inducer of DNA damage: it produces neither DNA-strand breaks nor clear differential toxicity to bacteria in rec-assays in the absence of metabolic activation. Also in SCE induction no increase can be observed in vivo, while PCP is found marginally active in a single in vitro experiment. Metabolic activation, however, leads to prophage induction and to DNA strand breaks in human lymphocytes, presumably through the formation of oxygen radicals. A possible further exception in this area might be the positive results in the yeast recombination tests, although their inadequate reporting makes a full evaluation difficult. PCP does not seem to induce gene (point) mutations, as most bacterial assays, the Drosophila sex-linked recessive lethal test and in vitro assays with mammalian cells did not demonstrate any effects. Marginally positive results were obtained in the mammalian spot test in vivo and in one bacterial test; the positive result in the yeast assay for cycloheximide resistance is fraught somewhat with its questionable genetic basis. PCP does, however, induce chromosomal aberrations in mammalian cells in vitro and in lymphocytes of exposed persons in vivo. Those in vivo results that were unable to provide evidence of chromosomal damage are hampered either by methodological inadequacies or by too low exposure levels. The (rodent) metabolite tetrachlorohydroquinone might be a real genotoxic agent, capable of binding to DNA and producing DNA strand breaks; this activity is probably due to semiquinone radical formation and partly mediated through active oxygen species. Since this compound has not been tested in the common bacterial and mammalian mutagenicity assays, the few ancillary results on this substance cannot be used in a meaningful human risk assessment of PCP. Furthermore, this metabolite has only been produced by human liver microsomes in vitro, but has not been detected in exposed humans in vivo. [R99] *Urinary PCP was monitored in male volunteers exposed to Fungifen solution which is a readily accessible pharmaceutical product containing 1% of PCP as active ingredient, and is recommended for the local treatment of interdigital mycoses. PCP absorbed readily through the skin and its elimination was slow. After the topical application of Fungifen, maximumlevels of urine PCP ranged from 109 to 1290 ug/l. In a single case a peak value of 3200 ug/l was measured. At the same time, PCP could be detected in the saliva, too. Urinary preexposure levels (ranged around 10 ug/l) were reached within 75 and 90 days, respectively. Maximum urinary levels represent exposures corresponding to occupational ones, known from other studies. The toxicity of PCP as well as the health risk of the Fungifen use to the great masses of the people (including pregnant women and children) are discussed. [R100] *Immune parameters were examined in 188 patients who were exposed for more than 6 mo to pentachlorophenol containing pesticides. Blood levels of pentachlorophenol, lymphocyte populations, in vitro responses to mitogenic and allogenic stimulation, plasma neopterin levels, plasma cytokine and cytokine receptors were determined. Impaired in vitro lymphocyte stimulation responses were impaired in 65% of the patients. ... Impaired lymphocyte stimulation incr significantly with levels of pentachlorophenol that exceeded 10 ul/l (p < 0.05). Patients who had high levels of pentachlorophenol and abnormal lymphocyte stimulation also had incr proportions of blood monocytes in blood (p < 0.05), as well as incr IL-8 serum levels (p < 0.02). Eleven patients had abnormal mitogen stimulation experienced decr CD4/CD8 ratios of < 1.0; 5 of these patients had decr CD4+ lymphocyte counts of < 500/ul, and 3 patients had incr plasma neopterin of > 15 nmol/l. ... This indicates that incr levels of pentachlorophenol in blood can lead to severe T lymphocyte dysfunction. [R101] *Excessively treated interior surfaces may be a source of exposure sufficient to cause irritation of eyes, nose, and throat. [R20] NTOX: *TOXICITY OF PENTACHLOROPHENOL TO SHEEP AND CALVES HAS BEEN EXAMINED ... MIN ACUTE LETHAL DOSE RATE WAS FOUND TO BE APPROX 120 and 140 MG/KG RESPECTIVELY IN THE 2 SPECIES. ... DEATH OCCURRED IN 2 TO 14 HR. MOST PROMINENT CLINICAL SIGN WAS ACCELERATED BREATHING ... WHICH DISTINGUISHED DOSED ANIMALS FROM CONTROLS 1 TO 2 HR AFTER /ORAL/ DRENCHING. BADLY AFFECTED ANIMALS STOOD SWAYING, WITH HEAD LOWERED, PANTED NOISILY, AND MADE LITTLE ATTEMPT TO MOVE WHEN APPROACHED. SALIVATION WAS OBSERVED IN CALVES AND COAT FELT DAMP. RECOVERY FROM THIS STAGE ... WAS RAPID AND COMPLETE. IN FATAL CASES, COMPLETE COLLAPSE OCCURRED, ANIMALS LYING WITH LEGS LIMP AND PANTING VIGOROUSLY THROUGH OPEN MOUTH. ASPHYXIAL TREMORS, BUT NO CONVULSIONS, SET IN JUST BEFORE DEATH. [R102] *POST MORTEM, ACUTELY POISONED SHEEP /FROM ORAL DRENCHING/ SHOWED GENERALIZED CONGESTION. LYMPH NODES APPEARED ENLARGED AND EDEMATOUS. THERE WERE HEMORRHAGES IN EPICARDIUM AND ALONG AORTA. LUNG SHOWED ISOLATED AREAS OF COLLAPSE AND GENERALIZED CONGESTION. BLOOD SPLASHES WERE OCCASIONALLY SEEN ON DIAPHRAGM. STOMACH, INTESTINES, LIVER AND KIDNEY SOMETIMES SHOWED MILD CONGESTION. BLADDER INVARIABLY EMPTY. [R102] *PURIFIED AND COMMERCIAL GRADES ... GIVEN ORALLY TO /SPRAGUE-DAWLEY/ RATS AT DOSES RANGING FROM 5-10 MG/KG BODY WT/DAY AT VARIOUS INTERVALS DURING DAYS 6-15 OF PREGNANCY. SIGNS OF EMBRYOTOXICITY AND FETOTOXICITY ... RESORPTIONS, SC EDEMA, DILATED URETERS AND ANOMALIES OF SKULL, RIBS, VERTEBRAE AND STERNEBRAE WERE OBSERVED AT INCIDENCE WHICH INCR WITH DOSE. EARLY ORGANOGENESIS ... MOST SENSITIVE PERIOD. NO-EFFECT ... LEVEL OF COMMERCIAL GRADE WAS 5 MG/KG/BODY WT/DAY; PURIFIED PENTACHLOROPHENOL GIVEN AT SAME ... LEVEL CAUSED ... SIGNIFICANT INCR IN INCIDENCE OF DELAYED OSSIFICATION OF SKULL BONES BUT NO OTHER EFFECT ON ... DEVELOPMENT. INGESTION OF 3 MG/KG BODY WT/DAY OF COMMERICALLY AVAILABLE PURIFIED GRADE HAD NO EFFECT ON REPRODUCTION, NEONATAL GROWTH, SURVIVAL OR DEVELOPMENT. [R103] *A single 60 mg/kg body wt oral dose of purified pentachlorophenol was given to pregnant Charles River CD strain rats on days 8, 9, 10, 11, 12, or 13 of gestation. Treatment on days 9 or 10 had the greatest effect on fetotoxicity. [R11, 392] *SIX GROUPS OF 27 MALE AND ... FEMALE WEANLING SPRAGUE-DAWLEY (SPARTAN SUBSTRAIN) RATS ... GIVEN LAB CHOW ... CONTAINING PENTACHLOROPHENOL (SAMPLE XD-9108.002: PENTACHLOROPHENOL 90.4%; TETRACHLOROPHENOL 10.4%; TRICHLOROPHENOL LESS THAN 0.1%; HEPTA- AND OCTACHLORODIBENZO-P-DIOXINS ABOUT 21 MG/KG; HEXA- AND HEPTACHLORODIBENZOFURANS ABOUT 5.2 MG/KG; AND HEXACHLOROBENZENE 400 MG/KG) TO PROVIDE ... LEVELS OF 0, 1, 3, 10 OR 30 MG PCP/KG BODY/DAY. PENTACHLOROPHENOL WAS DISSOLVED IN ANISOLE AND CONCN ... ADJUSTED ON A MONTHLY BASIS TO MAINTAIN DESIGNATED DOSE LEVELS ... GROUPS OF 27 MALE AND 27 FEMALE CONTROLS ... RECEIVED LAB CHOW CONTAINING ANISOLE ONLY. FEMALE RATS WERE MAINTAINED ON TEST DIETS FOR 24 MO, BUT THE MALE/S/ ... WERE TAKEN OFF ... AFTER 22 MO BECAUSE OF HIGH MORTALITY ...THE TOTAL AND INDIVIDUAL TUMOR INCIDENCES BY SITES, TIMES OF APPEARANCE ... AND AVG NUMBERS ... PER ANIMAL (PREDOMINANTLY BENIGN NEOPLASMS) WERE NOT SIGNIFICANTLY DIFFERENT FROM THOSE OBSERVED IN CONTROL RATS. THE NUMBER OF RATS WITH TUMORS/THOSE EXAM WERE, IN MALES: 11/27 (CONTROLS), 13/26 (1 MG/KG), 13/27 (3 MG/KG), 12/27 (10 MG/KG), 11/27 (30 MG/KG); IN FEMALES: 27/27 (CONTROLS), 26/27 (1 MG/KG), 25/27 (AT ALL OTHER DOSES). [R104] *GROUPS OF 18 MALE AND ... FEMALE (C57BL/6XC3H/ANF)F1 MICE AND 18 MALE AND FEMALE (C57BL/6XAKR)F1 MICE RECEIVED ... DOWCIDE-7 (IMPURITIES UNSPECIFIED) ... /AT/ 46.4 MG/KG BODY WT IN 0.5% GELATIN AT 7 DAYS OF AGE BY STOMACH TUBE AND SAME AMT (NOT ADJUSTED FOR INCR BODY WT) DAILY UP TO 4 WK OF AGE; SUBSEQUENTLY, THE MICE WERE FED 130 MG/KG /PPM/ DIET UNTIL ... 78 WK OF AGE AT WHICH TIME 16, 18, 17 and 16 MICE WERE STILL ALIVE IN THE 4 GROUPS, RESPECTIVELY. TUMORS DEVELOPED IN 3/18, 4/18, 3/17 AND 2/18 MALE AND FEMALE ... MICE; THESE INCIDENCES WERE NOT SIGNIFICANTLY GREATER THAN IN 79-90 NECROPSIED MICE OF EACH SEX AND STRAIN, WHICH HAD EITHER BEEN UNTREATED OR HAD RECEIVED GELATIN ONLY. [R105] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF)F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR)F1 MICE ... GIVEN SINGLE SC INJECTIONS OF 46.4 MG/KG BODY WT ... (DOWCIDE-7; IMPURITIES UNSPECIFIED) IN CORN OIL AT 28 DAYS OF AGE AND WERE OBSERVED UP TO 78 WK OF AGE, AT WHICH TIME 14, 18, 18 and 16 MICE IN THE 4 GROUPS, RESPECTIVELY WERE STILL ALIVE. NEG CONTROL GROUPS CONSISTED OF ANIMALS THAT WERE EITHER UNTREATED OR RECEIVED GELATIN, CORN OIL OR DIMETHYLSULFOXIDE AND COMPRISED 141 MALES AND 154 FEMALES OF THE FIRST STRAIN AND 161 MALES AND 157 FEMALES OF THE SECOND STRAIN. THE INCIDENCES OF HEPATOMAS (4/17) IN MALES OF 1ST STRAIN WAS SIGNIFICANTLY INCR ... OVER THAT IN CONTROLS (9/141). [R104] *Acute and chronic toxicity to saltwater aquatic life occur at concentrations as low as 53 and 34 ug/l, respectively. [R106] *Twenty one day chronic mortality of Daphnia magna was produced at 320 ug/l, but not at 180 ug/l. [R107] *IN FEEDING EXPT WITH DROSOPHILA MELANOGASTER, 7 MILLIMOLAR PENTACHLOROPHENOL FAILED TO INDUCE SEX-LINKED RECESSIVE LETHALS IN MEIOTIC AND POSTMEIOTIC STAGES OF MALE GERM CELLS. IN LATERAL ROOTS OF VICIA FABA SEEDLINGS TREATED WITH 43.5-174 MG/L ... THERE WAS INCR IN FREQUENCY OF ABNORMAL CELL DIVISIONS (EG, STICKINESS AND LAGGING OF CHROMOSOMES AND CHROMOSOME FRAGMENTATION); THESE ABNORMALITIES WERE MORE FREQUENT DURING METAPHASE THAN IN EARLIER STAGES AND, IN GENERAL, INCR WITH INCR CONCN. [R108] *The no observable effect level for fetal resorption in pregnant Sprague Dawley female rats was 5.8 mg/kg/day of commercial grade pentachlorophenol and 15 mg/kg/day of purified pentachlorophenol. Measurements were also taken on fetal body weight and crown rump length, both of which decreased with increasing dose. The no observable effect level for these parameters was 15 mg/kg/day for both commercial grade and purified pentachlorophenol. [R109] *Pregnant Syrian golden hamsters given daily oral doses of pentachlorophenol (unspecified purity) ranging from 1.25 to 20 mg/kg from days 5 to 10 of gestation experienced an increase in fetal deaths and resorptions. The no effect level was 2.5 mg/kg/day. [R11, 392] */Pentachlorophenol/ ... (0, 5, 50, or 500 ppm) /was administered/ to Sprague-Dawley rats in the diet beginning with the rats own weaning through the weaning of their pups. ... Significant effects /were observed/ on the immune system (as indicated by decreased antibody titers, decreased delayed hypersensitivity to oxazolone, and increased peritoneal macrophage numbers) and reduced ethylnitrosourea-induced transplacental carcinogenesis. [R11, 392] *... Effects /were/ observed ... on the central nervous system in rabbits after 60 days of exposure to subcutaneous doses of 5%, 10% and 25% of the minimum lethal dose (275 mg/kg body wt). Nervous system lesions were seen in all dose groups. Neurochemical effects were observed in 30 male Wistar rats given 20 mg/l concn of technical grade pentachlorophenol in drinking water for 3 to 14 wk. Thirty controls were also studied. ... The main effects seen in the rat brain were transient biochemical effects ... . [R11, 391] *In a 160 day study, cattle fed 20 mg/kg doses of technical pentachlorophenol for 42 days, followed by 15 mg/kg/day for the remainder of the study, had decreased wt gain, progressive anemia, and immune effects. Only minimal adverse effects were observed after exposure to analytical grade pentachlorophenol. [R11, 390] *PENTACHLOROPHENOL WAS EMBRYOTOXIC AND FETOTOXIC /TO SPRAGUE-DAWLEY RATS/ @ DOSES OF COMMERCIAL AND PURE PENTACHLOROPHENOL OF 15 MG/KG AND ABOVE. ... DELAYED OSSIFICATION OF SKULL WAS OBSERVED AFTER TREATMENT WITH PURE PENTACHLOROPHENOL. ORAL ADMIN ... TO HAMSTERS ON DAYS 5-10 OF GESTATION PRODUCED FETAL DEATH AND/OR RESORPTIONS AT 5 MG/KG/DAY AND ABOVE. [R6, 753] *PROVED NEGATIVE IN SEX-LINKED LEVEL TEST IN DROSOPHILA ... . [R6, 753] *The effects of pure and technical grade pentachlorophenol on primary cultured rat hepatocytes were compared to determine if contaminants of commercial preparations of pentachlorophenol increased its toxicity. Hepatocytes isolated from adult Sprague-Dawley rats were incubated with analytical /grade/ pentachlorophenol of 99% purity, technical grade pentachlorophenol, or its sodium salt, which contains only minor concentrations of technical impurities. Monooxygenase activity was markedly induced by technical grade pentachlorophenol in a concentration dependent pattern, with a maximum response of approximately 14 fold seen at concentrations of 30 to 50 micromoles. Monooxygenase induction was much less marked after exposure to 50 micromoles sodium salt of technical pentachlorophenol, only 2.7 fold, and was barely detectable after exposure to 50 micromoles 99% purity pentachlorophenol. Phase II metabolism of monooxygenase product was equally inhibited by pretreatment with any of the pentachlorophenol preparations. Cell membrane damage, assessed by leakage of LDH into the culture medium, was also observed with all the pentachlorophenol preparations tested. These results indicated that monooxygenase induction was attributable to technical impurities, while cytotoxic effects were caused by the pentachlorophenol itself. [R110] *The teratogenic activities of highly purified pentachlorophenol and pentachloroanisole, administered in the diet of Sprague Dawley rats of both sexes, at the rate of 4, 13 or 43 mg/kg and 4, 12 or 41 mg/kg/day, respectively, for a period of 181 days, were investigated. Pregnant females treated with pentachlorophenol ate more food than untreated controls. As compared to controls, dams treated with the highest doses of both compounds had a lower body wt on day 0 of gestation and gained less weight during their pregnancy. Animals treated with the highest dose of pentachlorophenol gained less weight during pregnancy than controls. Embryonic deaths were recorded following treatment with pentachlorophenol at the rate of 43 mg/kg/day, while lower doses of the compound induced dose related reductions in body wt. At the rate of 13 mg/kg/day only, pentachlorophenol reduced the crown to rump length and increased the skeletal alterations of the fetus. Decreased numbers of corpora lutea and embryonic death were recorded following the administration of pentachlorophenol at the rate of 4 and 41 mg/kg/day. At the same dose pentachlorophenol reduced the body wt and the crown to rump length of male fetuses, while their female counterparts were not affected. Neither pentachlorophenol nor pentachloroanisole affected the soft tissue of the animals. Results indicate the pentachlorophenol is slightly more toxic than pentachloroanisole in Sprague Dawley rats. [R111] *In a 7 day experiment, food conversion efficiency (as g of growth/g of food eaten) in fry of largemouth bass was significantly affected in a concentration-dependent fashion at concentration of pentachlorophenol > 10 ug/l; with exposure to increasing pentachlorophenol concn > 10 ug/l, there was a significant concentration-related reduction in total length of largemouth bass at the end of a 57 day exposure. For the length data, the threshold response value was 25.2 ug/l which was very close to that of the food-coversion efficiency value (23.4 ug/l). When comparing pentachlorophenol induced mortality, behavioral responses, length at the end of a long-term exposure, and food-conversion efficiency, the latter two are the most sensitive indicators of pentachlorophenol effects on fish. [R112] *Rainbow trout were exposed for 4 or 8 days to various types of toxicants, each applied to the test water at a high sublethal concn. The activity of liver UDP-glucuronosyltransferase was assayed from the submitochondrial fraction using p-nitrophenol as an aglycone. Activity of UDP-glucuronosyltransferase was inhibited ... by pentachlorophenol, a toxicant regularly found in effluents of the pulp and paper industry. [R113] *The induction of mutation of the hypoxanthine-guanine phosphoribosyl transferase locus and cytotoxicities of 6 different chlorophenols (2,4- and 2,6-dichlorophenol, 2,4,5- and 2,4,6-trichlorophenol, 2,3,4,6-tetrachlorophenol and pentachlorophenol) were examined in V79 Chinese hamster cells without exogenous metabolic activation. The chlorophenols were cytotoxic to V79 cells, but fail to produce significant increases in the frequency of 6-thioguanine-resistant mutants. [R114] *Largemounth bass Micropterus salmoides were reared over their first 8 weeks of free-swimming life in uncontaminated control water or in water containing one of five concentrations of pentachlorophenol ranging from 1.6 to 88 ug/l. Over the final 3 weeks of the study, fish reared in concentrations of 67 and 88 ug pentachlorophenol/l performed significantly fewer feeding acts (orientations, bites) and had a lower rate of prey capture than did control fish. However, fish in high concentrations spent significantly more time swimming than did control fish, which indicated that exposure to pentachlorophenol made them hyperactive. By inhibiting energy intake while inducing higher energy expenditures, pentachlorophenol may reduce survival of young largemouth bass over the winter. [R115] *The immunosuppressive effects produced by exposure to technical grade pentachlorophenol were compared with those produced by purified pentachlorophenol both in vitro and in vivo in mice. Female B6C3F1 mice were administered daily doses of 10, 30, or 100 mg/kg technical grade pentachlorophenol, or corn oil via gastric intubation for 14 days. Animals were sacrificed the day after the last dose, and antibody responses to multiple antigenic stimuli were measured in spleen cell suspensions from the mice. There were no differences in the antibody responses in the spleen cell suspensions from technical grade pentachlorophenol or purified pentachlorophenol treated animals as compared to controls. When mice were immunized with sheep erythrocytes on day 10 or 11 of the 14 day exposure period, there was a dose dependent suppression of the immunoglobulin-M antibody response to sheep erythrocytes in spleen cells from mice treated with technical grade pentachlorophenol. No changes were observed in the antibody responses of spleen cells from mice to purified pentachlorophenol which were immunized during exposure. When added directly to spleen cell cultures from untreated mice, both technical grade pentachlorophenoland purified pentachlorophenol suppressed the in vitro antibody responses and were cytotoxic to the spleen cells. The in vitro antibody assay is of limited value in studying the mechanism of immunosuppression by technical grade pentachlorophenol, and that technical grade pentachlorophenol induced immunosuppression cannot be attributed to a direct effect on immunocompetent cells. [R116] *The effects of chronic dietary exposure to technical grade pentachlorophenol on humoral immune responses in mice were examined. Primary and secondary splenic antibody responses to the T-dependent antigen, sheep red blood cells, were examined in mice using the Hemolytic Antibody Isotope Release assay. To assess the direct effects of technical grade pentachlorophenol on B cells, the splenic plaque-forming cell response and serum antibody titers to the T-independent antigen, dinitrophenyl Ficoll, were examined. Technical grade pentachlorophenol exposure altered the kinetics and the magnitude of the humoral antibody responses to sheep red blood cells and dinitrophenyl Ficoll. Peak splenic antibody production and serum antibody responses were dose-dependently suppressed by technical grade pentachlorophenol exposure. IgM responses appeared to be more sensitive to technical grade pentachlorophenol induced suppression than the IgG response. Significant depresssion of the IgM anti-sheep red blood cells splenic hemolytic antibody isotope release response was apparent as early as 2 wk after initiation of technical grade pentachlorophenol exposure and persisted for at least 8 wk after terminination of technical grade pentachlorophenol feeding. Liver weight and serum lactate dehydrogenase and alanine aminotransferase levels were significantly elevated during technical grade pentachlorophenol exposure and returned to control levels after a 4-6 wk recovery period. The immunotoxic effect of pentachlorphenol on humoral immunity was observed only in animals exposed to technical grade pentachlorphenol known to be contaminated with significant levels of other chlorinated phenols as well as nonphenolic impurities including chlorinated dioxins, furans, and diphenyl ethers. Animals exposed to analytical grade pentachlorophenol did not exhibit depressed humoral immunity. [R117] *The rat embryo was shown to be most susceptible to the toxic effect of pentachlorophenol during the early phases of organogenesis. [R91, 1991.1177] */Mean oral/ LD50 for female mallards at age 3 mo was 380 mg/kg and for female pheasants at age 3-6 mo, 504 mg/kg./ Signs of intoxication: Polydipsia and regurgitation (in mallards), tachypnea, wing shivers or twitching, jerkiness, shakiness, ataxia, imbalance, tremors, and spasms. Signs appeared as soon as 10 min and mortalities in mallards usually occurred between 2 and 24 hr after treatment and in pheasants between 3 and 5 days after treatment. However, one pheasant died after about 3 hr and one died between 10 and 12 days after treatment. Remission took up to 2 wk. [R118] *By means of controlled laboratory experiments it was established that timber treatment fluids containing gamma hexachlorocyclohexane and pentachlorophenol and used according to manufacturers' recommendations rapidly cause the death of pipistrelle bats roosting in contact with timber treated between six weeks and 14 months previously. The chemicals responsible are presumably ingested when the bats groom their fur after they have been in contact with the treated timber. Bats prevented from establishing such bodily contact took longer to die indicating that absorption of the vapor phase of the tested chemicals also takes place across the skin or respiratory epithelium. Acrylic resin reduces the lethal effect when used as a sealant over wood treated with gamma-hexachlorocyclohexane and pentachlorophenol, but polyurethane varnish does not. It has also been established that no obvious harm is caused to bats roosting for 16 to 22 weeks in contact with timber treated with the synthetic pyrethroids permethrin, cypermethrin and deltamethrin at concentrations which have previously proved effective for the control of wood boring beetles. Similarly, no obvious harm is caused to bats roosting for 13 weeks in contact with timber treated with the fungicides borester 7 and zinc octoate. However, greater mortality was recorded in bats housed in cages treated with the fungicide tributyltin oxide than in control groups. It is clear from these results that synthetic pyrethroids should replace gamma-hexachlorocylcohexane for the treatment of wood boring beetles in bat roosts. A high priority should be accorded to replacing pentachlorophenol with a fungicide which is not toxic to bats. [R119] *The suitability of ejaculated bovine spermatozoa as an in vitro model of the assessment of the cytotoxic potential of chemicals was evaluated using several endpoints: swimming activity, adenine nucleotide content, membrane integrity and oxygen consumption. A series of chlorophenols inhibited sperm motion (motility and velocity) in a concentration dependent manner. This could be determined quantitatively and reproducibly by means of videomicrography and automatic computer image analysis. The sper immobilizing potency increased with increasing chlorination and was positively correlated with lipophilicity. Concentrations which reduced the percentage of moving sperm to 50% of controls ranged from 43 muM for pentachlorophenol to 1440 muM for 4-monochlorophenol. Determinations of adenine nucleotides and percentages of viable cells revealed qualitative differences between the action of pentachlorophenol and the lower chlorinated phenols. While the latter decreased the total adenine nucleotide contents and the percentage of unstained cells in parallel to motion inhibition, no such changes occurred after exposure to immobilizing concentrations of pentachlorophenol. Penta-, tetra-, and trichlorinated phenols stimulated cellular respiration, indicating their uncouping activity, at concentrations lower than those necessary for motion inhibition. The results indicate that bovine spermatozoa may become a useful in vitro model for the toxicological evaluation of chemicals providing quantitative as well as qualitative data. [R120] *The acute toxicity of a technical formulation of pentachlorophenol and pure pentachlorophenol to three age classes of Daphnia magna, and adult Daphnia pulex and Daphnia galeata mendotae was determined by static toxicity tests. The influence of a number of factors on toxicity of pentachlorophenol was also examined. The 48 hr LC50 estimates for adult daphnids of the three species exposed to pure pentachlorophenol were 1.78, 4.59 and 0.51 mg/l, respectively, while those for the technical formulation were 2.57, 3.66 and 0.33 mg/l, respectively. There was little difference in toxicity between the technical and pure pentachlorophenol; however, toxicity of both forms of pentachlorophenol was influenced by duration of exposure, age (and/or size) and species of test organism and pH of the test solution. Pentachlorophenol caused a toxic response over a very narrow range of concentrations, with the greatest response occurring immediately between 0 and 24 hr. Pure pentachlorophenol was equally toxic to all age classes of Daphnia magna but susceptibility to technical pentachlorophenol decreased with maturation. Daphnia galeata mendotae was ten times more sensitive than Daphnia pulex to pentachlorophenol. Pure pentachlorophenol was significantly more toxic to Daphnia magna at pH 5.5 than 7.0 with mean 48 hr LC50 values of 0.082 and 1.78 mg pentachlorophenol/l, respectively. At 12 deg C, the toxicity of both forms of pentachlorophenol to Daphnia galeata mendoate and Daphnia pulex did not differ significantly from that at 20 deg C; however, technical pentachlorophenol was significantly more toxic to Daphnia magna at 12 deg C for an exposure duration of 48 hr. There was no effect of test container size (100, 250, 600 and 1,000 ml) on the toxicity of pentachlorophenol to Daphnia magna at 20 deg C with the lower pH of 5.5, suggesting that adsorption to glassware was not a factor in availability of pentachlorophenol to test organisms. Beaker size had no effect on the toxicity of pentachlorophenol to Daphnia pulex at 20 deg C with test solutions having a pH of 7.0-8.0. [R121] *In this investigation the effects of chlorophenols on rat liver mitochondrial respiratory parameters were determined and compared to the toxicities of those compounds in a variety of biological systems currently being used for toxicity testing. Mitochondrial fractions were exposed to six concentrations of five different chlorophenols in a semiclosed, 2 ml reaction vessel. Respiratory parameters were measured polarographically with an oxygen electrode and compared to control experiments. The toxicity of the chlorophenols, as measured by the concentration reducing the respiratory control ratio of the control to 50%, increased with increasing chloro substitution. The concentrations reducing the respiratory control ratio of the control to 50% ranged from 599 muM with 2 chlorophenol to 0.110 muM with pentachlorophenol. The RCR50 concentrations for the five chlorophenols were compared to six physicochemical parameters for the same chlorophenols; high degrees of correlation between the the concentrations reducing the respiratory control ratio of the control to 50% and the physicochemical parameters were found (r : 0.890). The highest correlation coefficient obtained was with the n-octanol/water partition coefficient (r = 0.991), indicating that the ability of chlorophenols to partition into the lipid mitochondrial membrane plays a significant role in eliciting its toxic effects. The concentrations reducing the respiratory control ratio of the control to 50% were also compared to nine currently existing short-term toxicity tests. High degrees of correlation were obtained with several of the tests, including algal, bacterial, and fish bioassays. This suggests that the uncoupling of oxidative phosphorylation may be the major mechanism by which chlorophenols cause toxicity to intact cells as well as more complex organisms. The use of mitochondrial respiratory parameters appears to offer a complementary approach as a short term toxicity test for this class of compounds. Further development and testing with a variety of other toxicants is suggested. [R122] NTOX: *GF-Scale cells, a fibroblastic cell line derived from the scale of golfish, were used for the determination of the cytotoxicity of chlorophenols and the quantitative structure-activity relationship studies. As the cytotoxicity end point, the amount of neutral red retained by viable cells after exposure to chemicals was quantified. The sequence of cytotoxicity based on the concentration of chemicals that reduced uptake of neutral red by 50% was penta-chloro > 2,4,5-trichloro > 2,3,4-trichloro > 2,3,4,6-tetrachloro > 3,5-dichloro > 3,4-dichloro > 2,4-dichloro > 2,5-dichloro > 2,3-dichloro > 2,4,6-trichloro > 3-chloro > 4-chloro > 2,6-chloro > phenol. The in vitro cytotoxicity of these chemicals was found to be significantly correlated to their in vivo acute toxicity to aquatic species, and the concentrations of chemicals that reduced uptake of neutral red by 50% were correlated with six physiochemical parameters of chlorophenols. N-Octanol/water partition coefficient gave the best correlation in simple linear regression analysis, as is frequently stated in toxicity studies with aquatic animals. Multiparametric linear regression equations yielded improved correlation coefficients and predictive capabilities, including the n-octanal/water partition coefficient and pKa. These results suggest that in vitro fish cytotoxicity assays using the GF-Scale cell line are useful for ecotoxicity screening of aquatic pollutants. [R123] *Effects of administration of equimolar doses of hexachlorobenzene and its metabolites pentachlorophenol and tetrachlorohydroquinone on serum thyroxine and triiodothyronine levels in rats were studied. Furthermore, it was investigated whether the observed effects were related to the serum levels of hexachlorobenzene or pentachlorophenol. Rats received either corn oil (controls) or hexachlorobenzene, pentachlorophenol or tetrachlorohydroquinone in a single equimolar intraperitoneal dose of 0.056 mmol/kg. Results indicated that hexachlorobenzene did not alter serum thyroxine and triiodothyronine levels for a period up to 96 hr after dosing. In contrast, pentachlorophenol and tetrachlorohydroquinone were both capable of reducing serum thyroxine levels with a maximum effect between 6 and 24 hr after exposure. Tetrachlorohydroquinone was more effective in repressing triiodothyronine than thyroxine blood levels. Dose response experiments were carried out in order to obtain insight into the sensitivity of the observed effects. Rats received different doses of pentachlorophenol or tetrachlorohydroquinone intraperitoneally. The reductions of thyroxine levels by pentachlorophenol were inversely related to serum pentachlorophenol levels in exposed animals, based on the toxicokinetics and dose response profiles. Furthermore, pentachlorophenol serum levels after hexachlorobenzene administration appeared too low to cause an effect. The results of this study indicate that not hexachlorobenzene itself, but rather its metabolites pentachlorophenol and tetrachlorohydroquinone may be involved in reduced serum thyroid hormone levels after hexachlorobenzene administration. [R124] *Bluegill sunfish (Lepomis macrochirus), exposed to a 22 day subchronic exposure of pentachlorophenol at concentrations of approximately 20 and 75% of the 96 hr LC50, showed significant reductions in food conversion efficiency measured during the last 10 days of exposure. Bluegills exposed to a 3 day acute spill mimicking exposure of pentachlorophenol at a concentration of approximately 100% of the 96 hr LC50 failed to show a significant reduction in food conversion efficiency measured during the 10 days following exposure. Bluegill sunfish exposed to pentachlorophenol at continuous low level concentrations are at a greater risk for decreased growth than those exposed to a more concentrated short term pulse of toxicant. [R125] *To evaluate the toxicities of 37 xenobiotics detected in drinking water, primary cultures of rat hepatocytes were treated with the xenobiotics at a concentration of 0.5 mM. The toxicities were assessed by four cellular markers: leakage of intracellular lactate dehydrogenase activity, glycogenolytic activity as a specific function of hepatocytes, intracellular glutathione content, and observations of cytopathic effects. The cytotoxic assay revealed that pesticides of xenobiotics used in the current study were the most toxic at muM levels, that phenolic compounds had potent toxicity for the cultured cells while benzoic compounds did not, and that 3 carbon compounds with substitution of hydrogen to bromine or chlorine at both positions 1 and 3 were highly toxic. The order of hepatotoxicity on the basis of IC50 was, 1,3-dichloro-2-propanone > pentachlorophenol : 1,2-dibromo-3-chloro-propane > hepatachlor > 2,4,6-trichlorophenol : 2,4,6-tribromophenol. Since lag times were observed for the expression of cytotoxicity by the pesticides, biotransformation appeared important for the toxicity. Currently the concentration of pesticides is very low in the environment, and therefore the possibility of causing an impact on human health is low. However, the long lifetime and high lipophilicity of pesticides give them the potential to become some of the greatest environmental toxicants. [R126] *The inhibition of methane production by Methanosaeta concilii GP6, Methanospirillum hungatei GP1, Methanobacterium espanolae GP9, and Methanobacterium bryantii during short term (6 hr) exposure to eight benzene ring compounds was studied. The concentration that caused 50% inhibition of the methane production rate was dependent on the species and the toxicant. Pentachlorophenol was the most toxic of the tested compounds, with an IC50 of less than 8 mg/liter for all species except Methanospirillum hungatei. Abietic acid was the next most toxic compound for all the species, with an IC50 in the range of 1,225 to 32,400 mg/liter. 3-Chlorobenzoate was substantially more toxic (IC50, 450 to 1,460 mg/liter) than benzoate. The inhibition by benzene, phenol, vanillic acid, and toluene was intermediate to that of pentachlorophenol and benzoate. Long term incubation (days) studies to determine effect on growth indicated that all eight compounds were usually much more toxic than predicted from the short term data. In these latter studies, there was generally a good correlation in the observed inhibition as determined from growth and methane production. [R127] *The toxicity of polychlorinated aromatic compounds was studied. Polychlorinated aromatic compounds in corn oil were administered to adult male and female albino mice, NMRJ strain, orally or by intraperitoneal injection. The median lethal dose for pentachlorophenol was 3.85 mg/mouse by the oral route and 1.75 mg/mouse by ip injection, for pentachloroanisole the values were 9.50 and 8.40, for tetrachlorocatechol 9.50 and 4.80, for tetrachlorohydroquinone 11.0 and 0.85, and for tetrachlororesorcinol the median lethal doses were 22.0 and 10.5 mg/mouse, respectively. After oral administration, pentachlorophenol was found to be the most toxic compound. After intraperitoneal administration, tetrachlorohydroquinone was found to be the most toxic compound. The animals that received 12 mg oral or ip single doses of tetrachlorodimethoxybenzenes did not die. Oral or ip single doses of tetrachlorobenzenediol-diacetates also produced no death. The groups of males dosed orally with tetrachlorohydroquinone, those dosed with tetrachlororesorcinol-diacetate, and the groups of males and females dosed intraperitoneally with tetrachlororesorcinol-diacetate showed a slower growth in body weight than controls. Microscopic examination of spleen, kidney, liver and lung tissue indicated unspecific bronchitis and inflammatory reaction in the hilar fat tissue in liver and slight infiltrates of lymphoid cells in some animals. [R128] *The effects of pure and technical grade pentachlorophenol on primary cultured rat hepatocytes were compared to determine if contaminants of commercial preparations of pentachlorophenol increased its toxicity. Hepatocytes isolated from adult Sprague Dawley rats were incubated with analytical pentachlorophenol of 99 percent purity, technical grade pentachlorophenol, or its sodium salt (technical grade pentachlorophenol sodium salt), which contains only minor concentrations of technical impurities. Monooxygenase activity was markedly induced by technical grade pentachlorophenol in a concentration dependent pattern, with a maximum response of approximately 14 fold seen at concentrations of 30 to 50 micromoles. Monooxygenase induction was much less marked after exposure to 50 micromoles technical grade pentachlorophenol sodium salt, only 2.7 fold, and was barely detectable after exposure to 50 micromoles analytical pentachlorophenol. Phase II metabolism of monooxygenase product was equally inhibited by pretreatment with any of the pentachlorophenol preparations. Cell membrane damage, assessed by leakage of lactate dehydrogenase into the culture medium, was also observed with all the pentachlorophenol preparations tested. These results indicated that monooxygenase induction was attributable to technical impurities, while cytotoxic effects were caused by the pentachlorophenol itself. The authors conclude that the measurement of monooxygenase activity in cultured rat hepatocytes may provide a method of detecting enzyme inducers as contaminants in complex industrial chemicals. [R110] *A study was designed to define the activity ranges of different chlorinated phenols in the series from monochlorophenol to pentachlorophenol in bacteria; to define the effect of these compounds on growth and viability parameters, correlating experimental findings with those obtained by enzymatic activities; and to define the relationships between toxicity and some physicochemical properties of these compounds. Escherichia coli was grown in the presence of test agents and assayed for growth and dehydrogenase and beta-galactosidase activities. Under these experimental conditions, the lag time to initiation of acclimation of growing cultures to phenol was 3 hours, while for chlorinated compounds it was about 2 hours longer. No effect of chlorine substituent number or concentration was seen. Toxicities of phenol, monochlorophenols, and polychlorophenols were differentiated by plotting specific growth rates, normalized to controls, against different concentrations. The validity of dehydrogenase activity in determining the toxicity of various phenol compounds by discriminating among different compounds was also demonstrated. Specific growth rate and dehydrogenase activity gave the best responses for quantitating toxicity and were compared for each phenol compound. The relative toxicity values showed that for both parameters the values obtained were lower than 10 for monochlorophenols and higher than 25 for polychlorinated phenols. A dependence of toxicity on phenol ionization constants was also noted. The authors conclude that use of specific growth rates and dehydrogenase activity in Escherichia coli is valid for evaluation of chemical toxicities of halogenated phenol compounds. [R129] *The acute oral median lethal dose of technical grade pentachlorophenol was investigated in developing Sprague Dawley rats from 10 to 134 days old. Signs of acute toxicity included ataxia developing about 15 minutes after dosing, followed by rapidly developing motor weakness, hyperpyrexia, and rapid breathing about 25 minutes after dosing. Most deaths occurred either between 20 minutes and 2 hours, or between 4 hours and 8 hours following dosing. Those animals who recovered had little salivation, rectal temperatures only 1 to 3 degrees F above normal, and began to recover after 8 hours. Rats who were 10 to 20 days of age and not yet weaned and adult rats aged 70 to 134 days old formed the two most susceptible groups, far more susceptible than were juveniles aged 25 to 50 days, to the toxic effects of pentachlorophenol. The LD50 increased 4.4 times from postnatal day ten to postnatal day 25, plateaued from day 25 to 50, and decreased 2.8 times from day 50 to 134. The physiological reasons for the developmental susceptibility as evidenced in this study were not known. The authors suggest that functional changes in both the kidney and liver may be contributing factors. [R130] *The effect of pentachlorophenol on microsomal mixed function oxidases was studied in cattle. Four adult lactating Holstein cattle were fed 0.2 mg/kg technical grade pentachlorophenol for 75 to 84 days, followed by 2 mg/kg for 56 to 60 days. Twelve adult nonlaboratory Holstein cattle were administered 0, 0.1, 1.0, or 10.0 mg/kg purified pentachlorophenol for 95 days. The pentachlorophenol was administered directly into the rumen by way of a permanent cannula. Fifteen male calves were administered 1, 2, 10, or 20 mg/kg technical grade or purified pentachlorophenol from 5 to 43 days of age. The animals were observed for clinical signs of toxicity; they were killed at the end of the dosing period and the liver and lungs were removed and weighed. Liver and lung microsomes were prepared and assayed for benzo(a)pyrene-hydroxylase, ethoxycoumarin-O-deethylase, hexobarbital-hydroxylase, ethylmorphine-N-demethylase, aminopyrine-N-demethylase, cytochrome-P450(448), or cytochrome-b5. None of the adult cattle exhibited clinical signs of toxicity. Liver and lung weights were significantly elevated in cattle given technical grade pentachlorophenol. Liver and lung benzo(a)pyrene-hydroxylase was significantly increased in these animals. Purified pentachlorophenol had no effect on any enzyme activities. Toxic effects such as growth impairment and mortality were observed in calves fed 10 and 20 mg/kg pentachlorophenol. Liver weights were significantly increased. No toxic effects were seen in calves fed pure pentachlorophenol. Cytochrome-P450(448) and cytochrome-b5 were significantly increased by 10 mg/kg technical or pure pentachlorophenol. Technical grade pentachlorophenol at 1 and 10 mg/kg induced benzo(a)pyrene-hydroxylase and ethoxycoumarin-O-deethylase. The 10 mg/kg dose of purified pentachlorophenol also stimulated these enzymes. The /results suggest/ that pentachlorophenol induces organ enlargement and stimulates cytochrome-P450(448) and certain mixed function oxidases. Benzo(a)pyrene-hydroxylase is the most inducible enzyme. The effects observed with technical grade pentachlorophenol are attributed to chlorinated dioxin and furan impurities. Newborn cattle are more susceptible to the inducing properties of pentachlorophenol and its impurities than adults. [R131] *The effects of phenol and pentachlorophenol on axonal conduction and ganglionic transmission were studied in vitro. Desheathed sciatic nerves from toads (Caudiverbera caudiverbera) were incubated with up to 10 mM phenol, pentachlorophenol, or procaine (as a reference compound) for 20 minutes. The extent of axonal conduction block was determined by measuring the compound action potentials evoked by supramaximal stimulation. Desheathed sciatic nerve preparations were incubated with 0.3 to 3 mM pentachlorophenol for 20 minutes, following which the preparations were placed in fresh medium. Compound action potentials were measured for up to 60 minutes to assess the reversibility of the block. Sheathed or desheathed nerve preparations were incubated with 3 mM pentachlorophenol at pHs 7.0 and 9.0 to assess the effect of pH on the axonal block. Phenol, pentachlorophenol, and procaine induced axonal conduction block in a dose dependent manner. The doses for causing a 50% block were phenol 6.30 mM, pentachlorophenol 1.00 mM, and procaine 2.00 mM. The block was irreversible. Shifting the pH of the medium from 7.0 to 9.0 in the absence of pentachlorophenol caused a nonsignificant axonal conduction block. When pentachlorophenol was present the same pH change caused a significant decrease in the axonal block. The eighth ganglia from the paravertebral chain of C-caudiverbera spinal cords were incubated with 0.003 to 0.03 mM pentachlorophenol at pH 7.0 and 9.0. In some experiments 0.1 mM 3,4-diaminopyridine was present. The effects on synaptic transmission were assessed by measuring compound action potentials as before. Pentachlorophenol induced a synaptic transmission block that was dose dependent and irreversible. The pentachlorophenol induced block at pH 9.0 was significantly less than at pH 7.0. 3,4-Diaminopyridine antagonized the effect of pentachlorophenol. The authors conclude that pentachlorophenol, procaine, and phenol are able to block axonal conduction in toad nerve fibers, with PCP showing a much greater potency than procaine or phenol. [R132] *The effects of chlorophenols on the function and viability of rat hepatocytes were studied in vitro. Primary hepatocytes obtained from male Sprague Dawley rats were cultured and incubated with PCP, 2,3,4,5-tetrachlorophenol (TCP), 2,4,5-trichlorophenol (TrCP), 2,4-dichlorophenol (DCP), or 4-chlorophenol (chlorophenol) for 1 hr at concn of 0 to 1X10-3 M. The effects on phase I and phase II metabolism of 7-ethoxycoumarin (7EC) were assessed by determining the concentrations for inhibiting 7-ethoxycoumarin-deethylase activity and depleting intracellular ATP content by 50 percent. The cultures were assayed for leakage of lactate dehydrogenase (LDH) into the medium. The EC50s for inhibiting phase I 7EC metabolism were: PCP, 37.5 uM; TCP, 34.6 uM; TrCP, 36.4 uM; DCP, 87.8 uM; and clorophenol, 215.2 uM. The corresponding EC50s for phase II 7EC metabolism were 6.5, 22.8, 22.0, 30.9, and 48.4 uM, respectively. The EC50s for depleting cellular ATP were: PCP, 6.4 uM; TCP, 18.4 uM; TrCP, 25.9 uM; DCP, 185.8 uM; and chlorophenol, 1334.1 uM. None of the compounds caused a significant leakage of LDH into the medium. When compared with published values of their octanol/water partition coefficients, the log of the EC50s were linearly correlated with the log of their partition coefficients. The /results indicate/ that short term exposure to chlorophenols severely disrupts the metabolic function of primary cultured rat hepatocytes at concentrations that do not affect cell membrane integrity. Primary cultures of rat hepatocytes are a suitable model for evaluating the short term toxicity of chlorinated phenols in vitro. [R133] *Phenol and the 19 isomers of chlorophenol were evaluated in the Microscreen Prophage Induction Assay to characterize the genotoxicity of these agents. Seven of the isomers induced prophage lambda in the presence of S9, with 2,3,4-trichlorophenol, 2,4,5-trichlorophenol, and 3,4,5-trichlorophenol being about ten times as potent as 2,3,6-trichlorophenol, 2,4,6-trichlorophenol, and pentachlorophenol. Medium potency was demonstrated by 2,3,4,5-tetrachlorophenol. Structurally, the more potent isomers had one or no chlorine atoms in the ortho position to the hydroxyl group. The less potent isomers had two chlorine atoms ortho to the hydroxyl group. None of the 20 compounds was mutagenic in Salmonella. However, the prophage induction results agreed with earlier results that most of these seven isomers were clastogenic, were associated with cancer and chromosomal aberrations in humans, and were carcinogenic in rodents. The /results/ suggest that the metabolism of the parent isomer to a chlorohydroquinone is an important step in the genotoxicity of these isomers. This chlorohydroquinone can form a chlorobenzosemiquinone in the presence of oxygen. Free radicals can then be produced that can cause DNA strand breaks, resulting in prophage induction in Escherichia coli or possibly the chromosomal aberrations associated with human exposure to chlorophenols. [R134] *An investigation was conducted to examine the competition of various chlorinated phenol congeners with the thyroxine (T4) binding site of transthyretin (TTR). Specifically, attempts were made to determine whether the T4 binding site of TTR could be occupied by hydroxylated chlorinated aromatic compounds using chlorinated phenol congeners as model compounds in a competition assay with (125)I labeled T4. 2,3-Dichlorobenzene, 3,4,3',4'-tetrachlorobiphenyl, 4-hydroxybiphenyl, and phenol were inefficient competitors. The chlorinated phenols which were tested were all competitors for the T4 binding site of TTR. The most effective competitor was pentachlorophenol (PCP), following in decreasing order by trichlorophenols, dichlorophenols, and monochlorophenols. When the chlorine was present in both ortho positions to the hydroxyl group, the competitor was more efficient. The relative affinity of binding of PCP to TTR was twice that of T4. PCP mainly decreased the affinity constant while the binding capacity was not altered. This indicated a competitive type of inhibition. PCP competed successfully with T4 sites on albumin as well with a relative affinity of 0.25. The binding of T4 to thyroid binding globulin was much less affected by PCP interference. /Results suggest/ that a specific interaction of chlorophenols exists with the T4 binding site of TTR. [R135] *The effect of pentachlorophenol (PCP) and its metabolite tetrachlorohydroquinone (TCH) were tested on growth, RNA, protein and ribosome syntheses, and ribosome content in yeast cells. Cells exposed to increasing concentrations of PCP show increasing inhibition to RNA and ribosome synthesis, and to cell growth. TCH causes a delay of the growth of the cell culture (prolongation of the lag phase) but does not cause inhibition. After treatment with TCH the maximum of the RNA synthesis was retarded, but subsequently reached nearly the same level as the untreated control cells. On ribosome synthesis and ribosome content, treatment with increasing concentrations of PCP, as well as of TCH, leads to a substantial decrease in ribosomal synthesis and, finally, total inhibition. Parallel to this, the content of free and membrane-bound ribosomes is diminished. PCP exhibits a stronger effect than TCH. The protein synthesis is only slightly reduced after treatment with PCP or TCH (with concentrations up to 20 ug/ml). [R136] *Rainbow trout were exposed for 4 or 8 days to various types of toxicants, each applied to the test water at a high sublethal concentration. The activity of liver UDP-glucuronosyltransferase (UDP-GT) was assayed from the submitochondrial fraction using p-nitrophenol as an aglycone. Activity of UDP-GT was inhibited by 2,4,6-trichlorophenol, pentachlorophenol and dehydroabietic acid, all toxicants regularly found in effluents of the pulp and paper industry. The heavy metals cadmium and zinc, the polychlorinated biphenyl, Pyralene 3010, and chloroform did not affect UDP-GT activity. The slimicide N-methyl-dithiocarbamate (Vapam) significantly increased the enzyme activity. [R137] *It is shown that p-tetrachlorohydroquinone (TCH), the metabolite of the environmental chemical pentachlorophenol (PCP), is more toxic to cultured CHO cells than PCP, and that it causes DNA single-strand breaks and/or alkali-labile sites at concentrations of 2-10 microgram/ml as demonstrated by the alkaline elution technique. [R138] NTOX: *Chronictoxicity test procedures (static, with renewal) were used to determine the chronic toxicity of sublethal concentrations of a technical formulation of pentachlorophenol (PCP) and pure pentachlorophenol to Daphnia magna. Test organisms 48 + or - 12 h old were exposed for their entire lifespan (ie, until death) to 0.01, 0.05, 0.1 and 0.5 mg technical PCP/L and 0.01, 0.087 and 0.1 mg pure PCP/L. Criteria used to assess chronic toxicity were mean time to appearance of the primiparous instar in the brood chamber, mean number of days to release of the first brood, mean number of broods produced per female, mean brood size per female, mean number of reproductive days, mean number of young produced per reproductive day per female and survivorship. Pentachlorophenol differentially affected maturation and reproduction but not survivorship or longevity. Mean number of broods produced per daphnid, length of the reproductive period, longevity and survivorship were insensitive criteria relative to mean time to appearance of the primiparous instar, time to release of first brood, brood size, and number of young produced per daphnid per reproductive day. Generally, there was little difference in toxicity of the three concentrations of pure PCP, for they significantly reduced mean brood size and rate of reproduction of young and significantly but differentially affected maturation. Technical PCP, at the highest concentration of 0.5 mg/L, significantly reduced mean brood size and the rate of production of young, and significantly delayed both time to appearance of the primiparous instar and release of the first brood. When differences in toxicity occurred, generally, pure PCP was more toxic than comparable concentrations of technical PCP. Although enhanced maturation was observed there was no compensatory reproduction. [R139] *Chlorinated phenols represent a major component of hazardous oily and wood-preserving wastes that are widely distributed in chemical dumpsites throughout the United States. Pentachlorophenol has been reported to be highly embryolethal and embryotoxic in rats. However, data pertaining to the developmental toxicities of other important chlorophenols are limited. In this study, the toxicities of phenol, chlorophenol homologues and their isomers, selected phenyl acetates, anisoles, sodium phenates, and tetrachlorobenzoquinones (a total of 38 chemicals) were evaluated using cultures of Hydra attenuata. Developmental hazard index (A/D ratio) was determined for selected test chemicals (ie, those chemicals which resulted in an early toxic endpoint at the lowest whole-log concentration in the adult hydra assay). These same chemicals were evaluated at equimolar concentration in postimplantation rat whole embryo culture. Hydra attenuata and whole embryo culture studies demonstrated a linear relationship between toxicity and the degree of chlorine substitution with pentachlorophenol > 2,3,4,5-tetrachlorophenol > 2,3,5-trichlorophenol > 3,5-dichlorophenol > 4-chlorophenol > phenol. The developmental hazard index A/D ratios from the Hydra attenuata assay were approximately 1 for all of the chemicals tested. Findings from the whole embryo culture assay indicated similar results based on growth, gross morphology, and DNA and protein content of embryos. The results obtained in the Hydra attenuata and whole embryo culture assays suggest that the chlorinated phenols are not potent teratogens. The combination of Hydra attenuata and whole embryo culture may facilitate the rapid detection and ranking of hazardous chemicals associated with complex mixtures of chemical wastes. [R140] *This study investigated impairment of oxidative phosphorylation in mitochondria isolated from the liver of hexachlorobenzene treated rats. Partial and reversible uncoupling of the phosphorylative process was found in liver mitochondria from rats dosed with hexachlorobenzene for 60 days. Pentachlorophenol, endogenously formed by hexachlorobenzene metabolism was detected in the mitochondria at a concn of 0.3-0.4 nmol/mg protein. Based on the effect of pentachlorophenol, added in vitro at a similar concn to that found in vivo, it was concluded that the uncoupling of oxidative phosphorylation under the experimental conditions was almost completely due to the presence of pentachlorophenol. [R141] *This study investigated the extent of impairment in function parameters of liver mitochondria from rats treated for 60 days with hexachlorobenzene. A constant amount of mitochondrial uncoupling was found throughout the treatment period. At the same time a nearly constant amount of pentachlorophenol was detected in these mitochondria. In contrast, the level of mitochondrial porphyrins increased progressively. There was good correlation between the concentration of mitochondrial pentachlorophenol and the degree of uncoupling of oxidative phosphorylation. [R142] NTXV: *LD50 Rat male oral 146 mg/kg; [R143] *LD50 Rat female oral 175 mg/kg; [R143] *LD50 Rat oral 210 mg/kg; [R144] *LD50 Rat dermal 96-330 mg/kg; [R91, 1991.1177] ETXV: *LC50 Tubifex tubifex 286, 619, and 1294 ug/l/24 hr at pH values of 7.5, 8.5, and 9.5, respectively; [R145] *TLm Carassius auratus (goldfish) flow through bioassay at 25 deg C/96 hr: 0.22 mg/l; 120 hr: 0.253 mg/l; 336 hr: 0.189 mg/l; [R27, 956] *TLm Lepomis macrochirus (bluegill) flow through bioassay at 25 deg C 30 hr: 0.303 mg/l; 243 hr: 0.251 mg/l; 406 hr: 0.188 mg/l; [R27, 956] *LC50 Trout, flow through bioassay 48 hr: 0.25 mg/l; 96 hr: 0.23 mg/l; 10 day: 0.23 mg/l at 15 deg C; [R27, 956] *LC50 (Brachydanio rerio) Zebra fish, flow through bioassay 48 hr: 1.24 mg/l; 96 hr: 1.13 mg/l; 10 days: 1.08 mg/l at 25 deg C; [R27, 956] *LC50 (Jordanella floridae) Flagfish, flow through bioassay 48 hr: 1.82 mg/l; 96 hr: 1.74 mg/l; 10 d: 1.74 mg/l at 25 deg C; [R27, 956] *LC50 (Channa gachua) Freshwater fish, static test (test solutions changed every 24 hr) 24 hr: 0.79 mg/l; 48 hr: 0.56 mg/l; 72 hr: 0.43 mg/l; 96 hr: 0.39 mg/l; [R27, 956] *LC50 Pimephales promelas (fathead minnows) 4 wk old, 0.222 + or - 0.021 mg/l/24 hr /Conditions of bioassay not specified/; [R27, 956] *LC50 Pimephales promelas (fathead minnows) 7 wk old, 24 hr: 0.245 + or - 0.039 mg/l; 96 hr: 0.230 + or - 0.03 mg/l /Conditions of bioassay not specified/; [R27, 956] *LC50 Pimephales promelas (fathead minnows) 11 wk old, 24 hr: 0.232 + or - 0.052 mg/l; 96 hr: 0.222 + or - 0.3 mg/l. /Conditions of bioassay not specified/; [R27, 956] *LC50 Pimephales promelas (fathead minnows) 14 wk old, 24 hr: 0.200 + or - 0.016 mg/l; 96 hr: 0.190 + or - 0.0 mg/l. /Conditions of bioassay not specified/; [R27, 956] *LC50 Poecilia reteculata Guppy 0.38 ppm/24 hr at pH 7.3 /Conditions of bioassay not specified/; [R27, 956] *LC50 ONCORHYNCHUS TSHAWYTSCHA (CHINOOK SALMON) 68 UG/L/96 HR AT 10 DEG C (95% CONFIDENCE LIMIT 48-95 UG/L) WT 1 G. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CACO3 AND ALKALINITY OF 30-35 MG/L; [R146] *LC50 SALMO GAIRDNERI (RAINBOW TROUT) 52 UG/L/96 HR AT 11 DEG C (95% CONFIDENCE LIMIT 48-56 UG/L) WT 1 G. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CACO3 AND ALKALINITY OF 30-35 MG/L; [R146] *LC50 PIMEPHALES PROMELAS (FATHEAD MINNOW) 205 UG/L/96 HR AT 20 DEG C (95% CONFIDENCE LIMIT 179-234 UG/L) WT 1.1 G. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CACO3 AND ALKALINITY OF 30-35 MG/L; [R146] *LC50 ICTALURUS PUNCTATUS (CHANNEL CATFISH) 68 UG/L/96 HR AT 20 DEG C (95% CONFIDENCE LIMIT 58-80 UG/L) WT 0.8 G. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CACO3 AND ALKALINITY OF 30-35 MG/L; [R146] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) 32 UG/L/96 HR AT 15 DEG C (95% CONFIDENCE LIMIT 23-44 UG/L) WT 0.4 G. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CACO3 AND ALKALINITY OF 30-35 MG/L; [R146] *LC50 COLINUS VIRGINIANUS (BOBWHITE) 10 DAYS OLD, ORAL (5-DAY DIET) APPROX 3400 PPM; [R147] *LC50 COTURNIX JAPONICA (JAPANESE QUAIL) 20 DAYS OLD, ORAL (5-DAY DIET) 5204 PPM (95% CONFIDENCE LIMIT 4536-6034 PPM); [R147] *LC50 PHASIANUS COLCHICUS (RING-NECKED PHEASANT) 16 DAYS OLD, ORAL (5-DAY DIET) 4331 PPM (95% CONFIDENCE LIMIT 3926-4787 PPM); [R147] *LC50 ANAS PLATYRHYNCHOS (MALLARD DUCKS) 10 DAYS OLD, ORAL (5-DAY DIET) APPROX 4500 PPM; [R147] *EC50 Thalassia testudinum (seagrass) flow through bioassay 0.74 ppm/40 hr; [R148] *LC50 CYPRINODON VARIEGATUS (SHEEPHEAD MINNOWS) 1 DAY OLD, 329 UG/L/96 HR, STATIC TEST; [R149] *LC50 CYPRINODON VARIEGATUS (SHEEPSHEAD MINNOWS) 2 WK OLD, 392 UG/L/96 HR, STATIC TEST; [R149] *LC50 CYPRINODON VARIEGATUS (SHEEPSHEAD MINNOWS) 4 WK OLD, 240 UG/L/96 HR, STATIC TEST; [R149] *LC50 (CYPRINODON VARIEGATUS) SHEEPSHEAD MINNOWS, 6 WK OLD, 232 UG/L/96 HR, STATIC TEST; [R149] *LC50 (LYMNAEA ACUMINATA) PULMONATE SNAILS, STATIC BIOASSAY, 0.16 MG/L (95% CONFIDENCE LIMIT 0.138-0.186 MG/L); [R150] *LD50 Coturnix japonica (Japanese quail) oral 5139 ppm (95% confidence limit 4149-6365 ppm); [R151] *LC50 (Viviparus bengalensis) Freshwater pond snails 0.840 mg/l/96 hr static bioassay; [R152] *LD50 Mallard 3 mo female oral 380 mg/kg (mean); [R118] *LD50 Pheasant 3-6 mo female oral 504 mg/kg (mean); [R118] NTP: *Carcinogenicity bioassays were conducted utilizing 0, 100, or 200 ppm technical grade pentachlorophenol or 0, 100, 200, or 600 ppm (Dowicide EC-7, a technical grade formulation) fed to groups of 50 male and 50 female /B6C3F1 mice. ... Under the conditions of these two yr studies, there was clear evidence of carcinogenic activity for male B6C3F1 mice fed diets containing technical grade pentachlorophenol, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was some evidence of carcinogenic activity for female B6C3F1 mice exposed to technical grade pentachlorophenol, as shown by increased incidences of hemangiosarcomas and hepatocellular carcinomas. /Also/, there was clear evidence of carcinogenic activity for male B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms. There was clear evidence of carcinogenic activity for female B6C3F1 mice exposed to pentachlorophenol, EC-7, as shown by increased incidences of adrenal medullary and hepatocellular neoplasms and hemangiosarcomas. [R153] POPL: *INDIVIDUALS SUFFERING FROM KIDNEY AND LIVER DISEASES ... SHOULD /BE PROTECTED FROM/ OCCUPATIONAL EXPOSURE. [R43, 1612] ADE: *Rapid absorption of pentachlorophenol has been reported in rodents, monkeys, and humans following oral, dermal, or inhalation exposure. ... The major tissue deposits vary somewhat between species. In humans whose deaths were not related to pentachlorophenol exposure, the liver (containing pentachlorophenol residues of 0.067 ug/g), kidney, brain, spleen, and fat (0.013 ug/g) appeared to be major deposition sites. In the mouse, the gall bladder is a principal storage site. In the rat, it is the kidney. [R11, 385] *WHEN WORKER EXPOSURE TO PENTACHLOROPHENOL AT WOOD TREATMENT PLANT WAS MEASURED OVER 5 MO PERIOD, SERUM AND URINE LEVELS ... WERE 348.4 TO 3963 UG/L AND 41.3 TO 760 UG/L, RESPECTIVELY. PENTACHLOROPHENOL RESIDUES IN WORKPLACE AIR WERE IN THE RANGE OF 5.1 TO 15275.1 NG/CU M. [R105] *(14)C-PCP WAS ADMIN TO MICE BY SC OR IP INJECTION. MOST OF THE ACTIVITY (72-83%) WAS EXCRETED IN URINE IN 4 DAYS; ABOUT HALF, IN 24 HR; AND ONLY TRACE (0.05%), IN EXPIRED AIR. HIGH ACTIVITY OBSERVED IN GALLBLADDER AND ITS CONTENTS, WALL OF STOMACH FUNDUS, CONTENTS OF GI TRACT AND LIVER. [R154, l974.287] *ENTEROHEPATIC CIRCULATION OF PENTACHLOROPHENOL OCCURS IN MONKEYS AND MICE. IN RATS, IT IS FOUND MAINLY IN PLASMA PROTEIN; LIVER AND KIDNEY HAVE HIGHEST TISSUE CONCN. PLASMA HALF-LIVES AT 10 MG/KG BODY WT DOSE WERE ABOUT 15 HR IN RATS AND 78 HR IN MACACA MULATTA MONKEYS. [R108] *UNLESS RENAL AND LIVER FUNCTIONS ARE IMPAIRED, PENTACHLOROPHENOL IS RAPIDLY ELIMINATED FROM BLOOD AND TISSUES. [R155] *PENTACHLOROPHENOL HAS BEEN DETECTED IN HUMAN BLOOD PLASMA AT LEVELS OF 15.69 TO 15.86 UG/L IN HEMODIALYZED PATIENTS AND 15.0 UG/L IN PERSONS USED AS CONTROL. IT ALSO HAS BEEN DETECTED IN URINE, SEMINAL FLUID (20-70 UG/KG) AND FINGERNAILS OF NON-OCCUPATIONALLY EXPOSED INDIVIDUALS. PENTACHLOROPHENOL WAS FOUND IN 85% OF 416-418 SAMPLES OF URINE COLLECTED FROM GENERAL POPULATION ... MAX LEVEL WAS 193 UG/L AND MEAN LEVEL 6.3 UG/L. ... URINE SAMPLES TAKEN AT 25 FACTORIES USING PENTACHLOROPHENOL ... SHOWED THAT AVG WORKER'S EXPOSURE TO PENTACHLOROPHENOL IN AIR WAS 0.013 MG/CU M, WITH MAX RANGE OF 0.004-1.000 MG/ CU M, AND LEVEL IN URINE RANGED FROM 0.12 TO 9.68 MG/L. [R156] *Small amounts have been shown to cross the placenta. [R157] *Plasma and urinary pentachlorophenol was measured in 209 workers who had occupational exposure to wood preservatives containing this compound and 101 workers not exposed occupationally to pentachlorophenol. Workers were examined for chloracne and blood concentrations of bilirubin, gamma-glutamyltransferase, cholesterol and high-density lipoproteins were determined. All the occupationally exposed groups showed evidence of pentachlorophenol absorption; highest mean concentrations were found in timber treatment operatives (6.0 mmol/l for plasma and 274 nmol/mmol of creatinine for urine). [R158] *Pentachlorophenol was given orally to ... volunteers at single doses of 3.9, 4.5, 9, and 18.8 mg. Daily urinary excretion of pentachlorophenol and pentachlorophenol conjugated to glucuronic acid was monitored using gas chromatography with electron capture detection. Based on first order elimination kinetics an elimination half-life of 20 days was derived. To eliminate interference by the uncontrolled absorption of pentachlorophenol from the environment 0.98 mg (13)C-pentachlorophenol was taken by one of the volunteers. Pentachlorophenol levels in urine and plasma were determined using mass spectrometry with negative chemical ionization. An elimination half-life of 17 days was found in both urine and blood. The collected data were used to calculate the clearance of pentachlorophenol: a value of 0.07 m1/min was found. The long elimination half-life of pentachlorophenol is explained by the low urinary clearance due to the high plasma protein binding (> 96%) and the tubular reabsorption. The pH-dependency of the elimination of pentachlorophenol was investigated, and a distinct increase in the daily excretion was observed following alkalinization by oral administration of sodium bicarbonate. In order to elucidate the role of the enterohepatic circulation as a possible pool for pentachlorophenol in humans, the bile of cholelithiasis patients with postoperative T-drainage was investigated for pentachlorophenol and compared with the corresponding urine and plasma levels, but no accumulation of pentachlorophenol in the enterohepatic circulation could be observed. The daily elimination and plasma levels of pentachlorophenol in a group of individuals without a specific exposure were found to range from 10 to 48 ug/day and 19 to 36 ug/1, respectively. [R159] *Urine from 230 Finnish sawmill workers exposed to a combination of 2,3,4,6-tetrachlorophenol (80%), 2,4,6-trichlorophenol (10-20%), and pentachlorophenol (5%), was analyzed for the sum of the three chemicals as chlorophenols. Samples were collected at the end of the work shift. Workers were divided into the following exposure groups according to work tasks: primarily skin exposure (n= 112), primarily respiratory tract exposure (n= 34), and equal exposure by both routes (n= 84). Air concentrations at the workplace and amount of time spent with skin contact were not studied. There was no control group; values were compared to the nonexposed Finnish population level of < 0.1 umol/l. Skin absorption was the most effective route of exposure as reflected by urinary chlorophenol concentrations. The median concentration in workers with skin absorption was 7.8 umol/l (range 0.1 to 210.9 umol/l) and was significantly different from that in workers with the respiratory tract as the main route of exposure (median concentration 0.9 umol/l; range 0.1 to 13.3 umol/l; p < 0.001) and from those with both routes of equal importance (1.4 umol/l; range 0.1 to 47.8 umol/l; p < 0.001). /Tri-, Tetra-, and Pentachlorophenols/ [R160] *The compounds are readily absorbed from the gastroenteric tract and from parenteral sites of injection. /Chlorophenols/ [R43, 1615] *Plasma half-life in man is 30.2 + or - 4.0 hr. Half-lives for elimination of pentachlorophenol and pentachlorophenol-glucuronide from the urine are 33.1 + or - 4.5 and 12.7 + or - 5.4 hr, respectively. [R161] *The dependence of bats in Britain on houses as roosts may result in them being exposed to pesticides used in remedial timber treatments. Pentachlorophenol and permethrin are used as a fungicide and a insecticide for timber treatment, respectively. The present study investigated toxicity and distribution in body tissues of these two pesticides in pipistrelle bats. Four groups of nine to ten bats were kept in separate outdoor flight enclosures and were provided with roost boxes treated with either pentachlorophenol only, permethrin, pentachlorophenol/permethrin mixture or solvent only (control). At the start of the experiment, mean (: standard error) pentachlorophenol and permethrin concentrations on the surface of wooden blocks that had been treated in the same way as roost boxes were 69.32 : 6.76 mg/g (n = 6) and 3.3 : 1.6 mg/g (n = 3), respectively. All bats exposed to pentachlorophenol and pentachlorophenol/permethrin treated boxes died within 24 and 120 hr, respectively; nine out of the ten controls survived the 32 day experimental period (p < 0.001; both groups compared with control). Bats exposed to permethrin treated boxes survived as well as controls. Mean (: standard error) carcass pentachlorophenol concentration (excluding deposits on fur) of bats exposed to pentachlorophenol and pentachlorophenol/permethrin treated boxes was 13.11 : 2.52 ug/g body wt (n = 20). Pentachlorophenol burdens on fur were positively correlated with total weight of Pentachlorophenol in the carcass (p < 0.001). Pentachlorophenol was present in fat depots, liver, kidney and the remainder of the body which, despite containing low pentachlorophenol concentrations, was the main pentachlorophenol reservoir (66.4 : 5.0% of carcass pentachlorophenol load; n = 20). Total pentachlorophenol in the carcass was significantly correlated with lipid weight (p < 0.005). Permethrin was not detectable in body washes and tissues of bats exposed to pentachlorophenol/permethrin mixture or permet. [R162] *A pilot study was conducted to determine the overall efficiency of transdermal penetration of pentachlorophenol and tetrachlorophenol applied to human cadaver skin. Two commercially available wood preservatives were tested, one diesel oil based and the other a water based product. To simulate human exposure conditions at the workplace, small doses were used. The objective was to document the portion of applied dose which permeated the skin and to examine the effect of vehicle or formulation on the relative and absolute absorption of the chlorinated compounds. The penetration of the diesel oil preparations was 62% for pentachlorophenol and 63% for tetrachlorophenol. In the case of the aqueous based preparation, penetration was 16% for sodium-pentachlorophenate and 33% for sodium tetrachlorophenate. The incomplete recovery of each compound may have been due in part to the irreversible binding or unfavorable partitioning of the chlorophenols which would be consistent with the lipophilic character of these compounds. [R163] *The excretion and conjugation of chlorophenols were studied in workers exposed to 2,4,6-tri-, 2,3,4,6-tetra-, and pentachlorophenolates, the main components of the chlorophenolate product manufactured by direct chlorination of phenol. The workers were exposed in two different saw mills in which sodium chlorophenolate was used for treatment of lumber during the warm season. Urine specimens were collected at the end of the treatment season as well as at the start of a new treatment period in the spring. Serum specimens were collected towards the end of the treatment period. Total and unconjugated chlorophenols were analyzed with a GC method. The maximal concentrations of urinary 2,4,6-tri-, 2,3,4,6-tetra- and pentachlorophenol at the end of the lumber-treatment period were 1-11.8, 3.4-17.3, and 0.2-0.9 umol/l, respectively, and the average apparent half-times calculated using a one compartment model were 18 hr, 4.3 days and 16 days, respectively. For 2,3,4,6-tetrachlorophenol, the data of some subjects showed a better fit with a two compartment model; the corresponding half-times were 5.3 and 26 days. During the continuous-exposure period the average serum levels of tetra- and pentachlorophenol were rather similar before and after the working day: 2.79 + or - 1.78 umol/l for tetrachlorophenol and 0.85 + or - 0.4 umol/l for pentachlorophenol. Renal clearance values for tetra- and pentachlorophenol were related to urine flow and indicated tubular reabsorption. At low concentrations, sulfate conjugation was dominant. With increasing chlorophenol concentrations the proportion of glucuronide conjugation was increased, especially for pentachlorophenol. [R164] *1. Interspecies variability in the metabolism of pentachlorophenol (PCP) was investigated by exposing rainbow trout, fathead minnows, sheepshead minnow, firemouth, and goldfish to water-borne (14)C-PCP for 64 hr. 2. The amounts of metabolites in bile and exposure water were species-dependent; all of the metabolites excreted into the water were sulfate conjugates while bile was enriched in glucuronide conjugates. 3. Biliary excretion accounted for less than 30% of the total PCP metabolites. 4. Biliary metabolites alone were a poor indication of the metabolites produced and of the major routes of elimination. [R165] METB: *... MAJOR METABOLITE OF HCB /HEXACHLOROBENZENE/ ... . [R166, 327] *FOLLOWING SINGLE ORAL DOSE OF PENTACHLORO-(14)C-BENZENE (0.5 MG/KG) TO RHESUS MONKEYS ... /7% WAS EXCRETED/ AS PENTACHLOROPHENOL ... IN URINE. [R166, 346] *PENTACHLOROPHENOL ... IS DECHLORINATED IN VIVO AND IN VITRO IN RAT TO TETRA- AND TRI-CHLOROHYDROQUINONE ... DECHLORINATION IS MEDIATED BY LIVER-MICROSOMAL ENZYMES, AND THEIR ACTIVITY IS ENHANCED BY PRE-TREATMENT WITH SEVERAL WELL-KNOWN INDUCERS OF CYTOCHROME P450. ... PHARMACOKINETIC STUDY OF SINGLE ORAL DOSAGE (0.1 MG/KG) ... IN HUMAN SUBJECTS ... REVEALED NO METABOLITES WERE DETECTED APART FROM GLUCURONIDE OF PCP (ABOUT 12%). [R166, 327] *BACTERIAL ISOLATE, RELATED TO SAPROPHYTIC CORYNEFORM BACTERIA, WAS ABLE TO METABOLIZE PENTACHLOROPHENOL AS SOLE SOURCE OF CARBON AND ENERGY. PENTACHLOROPHENOL WAS RAPIDLY METABOLIZED TO CO2. IN CULTURES OF TRICHODERMA VIRGATUM, PENTACHLOROPHENOL WAS METHYLATED TO FORM PENTACHLOROANISOLE. SIMILARLY, PENTACHLOROANISOLE WAS FORMED FROM PENTACHLOROPHENOL BY PENICILLIUM SP AND CEPHALOASCUS FRAGRANS. [R154, l974.288] *THE PROTOPORPHYRIN ENZYME PEROXIDASE, DETECTED IN SNAILS, CATALYZED OXIDATION OF PENTACHLOROPHENOL TO 2,2',3,3',5,5',6,6'-OCTACHLOROBIPHENYLQUINONE. [R154, l974.287] *... MOST OF PENTACHLOROPHENOL TRANSFERRED TO HEPATOPANCREAS /IN GOLDFISH/ WAS DETOXIFIED BY SULFATE CONJUGATION OR BY DECOMPOSITION. EXCRETION ... WAS IN FORM OF CONJUGATE IDENTIFIED AS PENTACHLOROPHENYLSULFATE. [R167] *The metabolism of pentachlorophenol is generally similar in mammalian species. In rodents, more than 40% is excreted in urine unchanged. The remainder is excreted as tetrachlorohydroquinone and glucuronide conjugates of pentachlorophenol. In limited studies of humans, pentachlorophenol, tetrachlorohydroquinone, and pentachlorophenol glucuronide have been found in urine. In vivo retention of pentachlorophenol by lipid-containing tissues may be attributable to conjugation with fatty acids. [R11, 385] *Unchanged pentachlorophenol is excreted in the urine of rabbit, rat, mouse, and monkey. In addition to free pentachlorophenol, rats excrete tetrachloro-p-hydroquinone and trichloro-p-hydroquinone. ... Both metabolites as well as the parent cmpd are excreted free and as glucuronides. [R8, 474] *The biotransformation of pentachlorophenol in man and animals takes place by conjugation, hydrolytic dechlorination, and reductive dechlorination. Further species dependent reactions are oxidation and methylation. The reaction with glutathione results in the formation of conjugates and cleavage of glycine and glutamate gives cysteine conjugates. Acetylation of the amino group of the cysteinyl moiety in mammals gives mercapturic acids. The metabolic pathways leading to dechlorinated derivatives may be mediated by the reaction with glutathione as the presence of the N-acetyl-S-(pentachlorophenyl)cysteine. [R168] *The metabolism of pentachlorophenol and its covalent binding to protein and DNA were tested in the microsomes of Wistar rats of both sexes pretreated with hexachlorobenzene, phenobarbital, 3-methylcholanthrene, or isosafrole. Pentachlorophenol when incubated with microsomes, was converted into tetrachloro-1,2-hydroquinone and tetrachloro-1,4-hydroquinone. Isosafrole increased the rate of conversion 7 times as compared to control microsomes, while hexachlorobenzene, pentachlorophenol and 3-methylcholanthrene increased the rate of conversion 2 to 3 times. The fact that pentachlorophenol and hexachlorobenzene accounted for the production of tetrachloro-1,4-hydroquinone and tetrachloro-1,2-hydroquinone in a ratio of about 2, as compared to a ratio of about 1.3 for 3-methylcholanthrene and isosafrole, and the fact that this ratio decreased with increasing concentrations of pentachlorophenol in microsomes from hexachlorobenzene treated rats, were indicative of the involvement of the various cytochrome p450 isoenzymes. The covalent binding of pentachlorophenol to protein was inhibited by ascorbic acid, with a subsequent increase in the production of tetrachlorohydroquinones. The rate of covalent protein binding was constant, regardless of variation in the rate of conversion observed in the mirosomes of rats treated with various inducers. DNA binding was conversion dependent and was lower than protein binding. The addition of DNA did not affect the formation of soluble metabolites. [R169] *The metabolism of pentachlorophenol in animals and man was reviewed. Tetrachlorophenols, 2,3,5,6-tetrachloro-1,4-benzoquinone, 2,3,4-trichlorophenol, 2,3,5-trichloro-1,4-hydroquinone, and their glucuronide conjugates were found in animals and man. Also identified were pentachlorophenylacetate, pentachloroanisole, and pentachlorophenylsulfate. The biotransformation of pentachlorophenol in man and animals takes place by conjugation, hydrolytic dechlorination, and reductive dechlorination. Further species dependent reactions are oxidation and methylation. The reaction with glutathione results in the formation of conjugates and cleavage of glycine and glutamate gives cysteine conjugates. Acetylation of the amino group of the cysteinyl moiety in mammals gives mercapturic acids. The metabolic pathways leading to dechlorinated derivatives may be mediated by the reaction with glutathione as the presence of the N-acetyl-S-(pentachlorophenyl)cysteine would indicate. The results of metabolic in vivo studies on hexachlorobenzene, pentachloronitrobenzene, pentachlorobenzene, and pentachlorophenol indicate that one pathway stems from hexachlorobenzene and pentachloronitrobenzene via sulfur containing conjugates to thiophenolic derivatives and to chlorinated benzenes, primarily to pentachlorobenzene. Another pathway transforms pentachlorophenol to less chlorinated phenols. The authors state that pentachlorophenol is a metabolite of various environmental chemicals and is itself metabolized. Therefore there is no direct relationship between the level of pentachlorophenol in body fluids and the degree of exposure. [R170] BHL: *Absorbed by goldfish from water and rapidly excreted as a sulfate conjugate. Biological half-life of approx 10 hr. [R171] *Biological half-life for excretion in the Rhesus monkey was 41 and 92 hr in males and females, respectively. [R172] *Half-life for absorption in man following ingestion of 1.0 mg/kg was 1.3 + or - 0.4 hr. Peak plasma concn of 0.248 mg/l occurred at 4 hr. [R173] *In humans, urinary excretion half-lives following chronic exposure are significantly longer than after single high-dose exposure (20 days versus 10 hr). [R11, 386] *PLASMA HALF-LIVES OF 10 MG/KG BODY WT DOSE WERE ABOUT 15 HR IN RATS AND 78 HR IN MACACA MULATTA MONKEYS. [R108] ACTN: *CHLORINATED PHENOLS ... ARE VERY EFFECTIVE (... IN VITRO) AS UNCOUPLERS OF OXIDATIVE PHOSPHORYLATION. THEY THUS PREVENT INCORPORATION OF INORGANIC PHOSPHATE INTO ATP WITHOUT EFFECTING ELECTRON TRANSPORT. AS A RESULT OF THIS ACTION, WHICH IS BELIEVED TO OCCUR @ MITOCHONDRIAL /MEMBRANE/, CELLS CONTINUE TO RESPIRE BUT SOON ARE DEPLETED OF ATP NECESSARY FOR GROWTH. /CHLOROPHENOLS/ [R174] *The chlorophenols ... act at the sites of adenosine triphosphate production and decrease or block it without blocking the electron transport chain. Thus the poisons uncouple phosphorylation from oxidation. Free energy from the electron transport chain then converts to more body heat. As body temp rises, heat-dissipating mechanisms are overcome and metabolism is speeded. More adenosine diphosphate and other substrates accumulate, and these substrates stimulate the electron transport chain further. The electron transport chain responds by using up more and more available oxygen (increasing oxygen demand) in an effort to produce adenosine triphosphate but much of the free energy generated is liberated as still more body heat. Oxygen demand quickly overcomes oxygen supply, and energy reserves become depleted. /Chlorophenols/ [R175] *... PENTACHLOROPHENOL ... CAUSES /SIGNIFICANT/ UNCOUPLING OF OXIDATION AND PHOSPHORYLATION CYCLES IN TISSUES. THIS PRODUCES ... INCR BASAL METABOLIC RATE AND MARKED TEMP INCR. IN VITRO TESTS HAVE SHOWN THAT 1X10-6 TO 1X10-3 (OR GREATER) MOLAR CONCN ... UNCOUPLE OXIDATIVE PHOSPHORYLATION, INHIBIT MITOCHONDRIAL AND MYOSIN ADENOSINE TRIPHOSPHATASE, INHIBIT GLYCOLYTIC PHOSPHORYLATION, INACTIVATE RESPIRATORY ENZYMES AND CAUSE GROSS DAMAGE TO MITOCHONDRIA. [R43, 1610] *Pentachlorophenol induces microsomal enzymes. However, in vitro studies of rat liver microsomes have shown that pentachlorophenol inhibits microsomal detoxification enzymes by disturbing electron transport from flavins to cytochromes. [R11, 386] *... EFFECTIVE UNCOUPLER OF OXIDATIVE PHOSPHORYLATION. ... AT LOW CONCN (10-5 M) PCP PREVENTS THE UPTAKE OF INORGANIC PHOSPHATE ASSOCIATED WITH THE OXIDATION OF ALPHA-KETOGLUTARATE. IN PHOSPHATE-DEFICIENT SYSTEMS, ALPHA-KETOGLUTARATE OXIDATION IS STIMULATED BY PENTACHLORPHENOL. PENTACHLOROPHENOL GREATLY ENHANCES LIBERATION OF INORG PHOSPHATE FROM ATP IN FRESH MITOCHONDRIAL PREPN, BUT ... NO EFFECT UPON ATPASE PREPARED FROM DISINTEGRATED MITOCHONDRIA. ... SUGGEST/ED/ EFFECT OF PCP MAY BE ONE OF ALTERING PERMEABILITY OF MITOCHONDRIA RATHER THAN DIRECT EFFECT ON ATPASE. [R176] *A study of magnesium(2+)-ATPase and sodium(+), potassium(+)-ATPase from various tissues of the rat revealed very complex reactions, suggesting that pentachlorophenol uncouples oxidative phosphorylation at low concn and inhibits it at high concn and that sodium(+), potassium(+)-ATPase is the locus of action of the poison. [R8, 475] *The effects of sublethal doses of pentachlorophenol on the membranes of mammalian cells in cultures were studied using electron spin resonance and fluorescence depolarization techiques. Chinese hamster fibroblasts (V79-S171-W1) were exposed to pentachlorophenol at a concn of 282 micromoles/l for 24 hr. Plasma membrane isolated from pentachlorophenol treated cells demonstrated a 50% increase in fluidity. Pentachlorophenol apparently reduced the interchain hydrophobic forces contributing to bilayer stability. Similar changes were noted for preparations of total cell membrane, suggesting that the toxicant is highly mobile and can access intracellular membranes and plasmalemma. Experiments indicated that pentachlorophenol partitioned well into the bilayer and exhibited little, if any, amphipathic orientation. Toxicant transfer from cell surface to internal membranes apparently occurred through endocytosis and fusion of endocytotic vesicles with internal membranes. The content of phospholipid phosphate per cell was decreased by up to 50% following 24 hr treatments with pentachlorophenol. However, no significant change was noted in fatty acid composition of the membranes and only a very small change occurred in the sterol fatty acid ratio. The /results/ concluded that fatty acids are not selectively depleted from the membranes, and that the lipid bilayer is altered by phospholipase-C, which cleaves the phospholipid headgroup to form 1,2-diacylglycerol. It is noted that the extensive fluidization of membranes and the decline in phospholipid phosphate are manifestations of sublethal damage. [R177] INTC: *The toxicity to Pseudomonas fluorescens was greater when pentachlorophenol and 2,3,4,5-tetrachlorophenol were given sequentially than when pentachlorophenol alone was given. The antioxidant butylated hydroxyanisole enhances the toxicity of pentachlorophenol to Pseudomonas fluorescens. [R11, 386] *Hexachlorobenzene (HCB) at 1000 ppm and 99% pure pentachlorophenol (PCP) at 500 ppm admin to female Wistar rats for up to 8 wk resulted in an increased accumulation of pentachlorophenol in the liver. Pentachlorophenol ... accelerated the onset of hepatic porphyria by hexachlorobenzene. [R11, 386] *Pretreatment with pentachlorophenol inhibits the carcinogenic effect of hydroxyamine acids and the hepatoxicity of N-hydroxy-2-acetylaminofluorene. [R11, 386] */Pentachlorophenol/ ... enhances the transplacental carcinogenicity of ethylnitrosourea. [R11, 392] *The organochlorine pesticide, pentachlorophenol, a potent sulfotransferase inhibitor, reportedly reduces the binding of 2,6-dinitrotoluene, an industrial hepatocarcinogen to hepatic DNA by 95% after a single ip injection. Activation of 2,6-dinitrotoluene to genotoxic metabolites involves enzymes in both the liver and the intestinal flora. Since pentachlorophenol also has bactericidal activity and induced hepatic mixed function oxidase activity after longer treatment, the effect of pentachlorophenol on intestinal enzyme and the biotransformation of 2,6-dinitrotoluene to genotoxic metabolites was studied after 1, 2, 4, and 5 weeks of treatment. Male Fischer 344 rats were dosed daily, by gavage, with either 20 mg/kg pentachlorophenol or the peanut oil vehicle. After 1, 2, 4, and 5 wk, select control and treated aniamls were injected orally with 75 mg/kg 2,6-dinitrotoluene and transferred to metabolism cages, where urine was collected for 24 hr and tested for mutagenic activity in the Ames Salmonella typhimurium reversion assay. At 2 and 4 wk, six control and six treated animals were sacrificed and nitroreductase, azo reductase, beta-glucuronidase, dechlorinase, and dehydrochlorinase activities were analyzed in homogenates of the small intestine, large intestine, and cecum. At 5 wk, hepatic DNA adduct formation was assayed by the (32)P postlabeling of DNA. Results from this study indicated that pentachlorophenol accelerated the biotransformation of 2,6-dinitrotoluene genotoxic metabolites and potentiated the formation of 2,6-dinitrotoluene induced DNA adducts in the liver. This is the first report of a chemical interaction leading to increased DNA adduct formation and indicates that chemical interactions could be important to risk assessment since they alter the relationship between exposure, dose, and the effect of genotoxicants. [R178] *The aim of the present work was to explore the possibility that pentachlorophenol influences the behavior of the resting Na efflux in single muscle fibers from the barnacle, Balanus nubilus. It is shown here that pentachlorophenol causes a transitory rise in the sodium efflux in both unpoisoned and ouabain poisoned fibers and that the response is dose dependent, the minimal effective concentration in ouabain treated fibers being less than 1X10-6 M. The efficacy of pentachlorophenol is significantly greater than that of 2,3,4-trichlorophenol. 2,3-Dichlorophenol is ineffective. This is also the case with phenol. [R179] *2,6-Dinitrotoluene (2,6-DNT) and pentachlorophenol (PCP) are used for industrial purposes and are found in the environment as hazardous contaminants. Because concurrent exposure to both compounds can occur, it is of interest to determine if organochlorine compounds potentiate the effect of nitroaromatic chemicals. CD-1 mice were treated with PCP (42.8 mg/kg) for 4 weeks. On weeks 1, 2, and 4 after the initial PCP dose, mice were treated p.o. with 2,6-DNT (75 mg/kg) and 24 hr urines were collected. After concentration, the urines were tested for their mutagenic activity in Salmonella typhimurium strain TA98 without metabolic activation in a microsuspension bioassay. A significant increase (P less than .05) in mutagenicity was observed in urines from mice treated with 2,6-DNT alone and in combination with PCP. By week 4, mice that received both 2,6-DNT and PCP excreted urine that was more mutagenic than that from animals which received only 2,6-DNT. At weeks 2 and 4, mice were sacrificed and intestinal enzyme activities (nitroreductase, azo reductase, beta-glucuronidase, dechlorinase, and dehydrochlorinase) were quantitated. The enhanced genotoxicity observed in urines from 2,6-DNT/PCP-treated mice coincided with a decrease in nitroreductase and an increase in beta-glucuronidase activities in the small intestine. [R180] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Pentachlorophenol's production and use in the US as an industrial wood preservative for utility poles, cross arms, and fenceposts, and other items, that consume about 97% of its production, may result in its release to the environment through various waste streams(SRC). If released to air, a vapor pressure of 0.00011 mm Hg at 25 deg C indicates pentachlorophenol will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase pentachlorophenol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 29 days. Pentachlorophenol may also be degraded in the vapor phase by direct photolysis. Particulate-phase pentachlorophenol will be physically removed from the atmosphere by wet and dry deposition. If released to soil, the mobility of pentachlorophenol (pKa of 4.70) is expected to be based upon the soil pH. In light and heavy loam soils, Koc values for the total dissociated phenol was calculated to be 1250 and 1800, (classified as low mobility) respectively, while for the undissociated species, the Koc is 25,000 (classified as immobile). 25 to 51% of the added pentachlorophenol in terrestrial microcosms was detected in the air, suggesting that evaporation from soil of the formulated pesticide does occur. Photolysis of the dissociated form from moist soil surfaces may also occur with as much as 55% of added pentachlorophenol photodegraded in a sandy clay loam soil in 14 days. Both aerobic and anaerobic biodegradation rates are expected to be sensitive to the concn of pentachlorophenol present in both soil and water. Max mineralization rates of 0.3 to 0.5 mg/kg-day were reported for pentachlorophenol at 30 mg/kg soil with 82% of the added pentachlorophenol recovered as CO2 in 7 months. Less than 2% of the added pentachlorophenol was mineralized in 7 months when it was present at 100 mg/kg. Biodegradation has been reported using a non-adapted river sediment, required a lag period of 11 days with complete degradation by day 17. A biodegradation rate of < 5 ng/L-day was reported for pentachlorophenol in a variety of natural waters. If released into water, pentachlorophenol is expected to adsorb to suspended solids and sediment in water based upon its measured Koc values. Volatilization from water surfaces is not expected to be an important fate process based on a field study of an artificial stream in which < 0.006% of the added pentachlorophenol was lost by volatilization. BCF values from approximately 100 to 1000 indicate that bioconcentration of pentachlorophenol in aquatic organisms is high. Bioconcentration is expected to be pH dependent with greater accumulation at lower pH values. Occupational exposure to pentachlorophenol may occur via dermal contact, primarily in situations where workers use this compound as a preservative or are in contact with treated wood products. The general population will be exposed primarily from ingesting food contaminated with pentachlorophenol. (SRC) NATS: *It has been suggested that pentachlorophenol is a product of fungus metabolism(1). [R181] ARTS: *PENTACHLOROPHENOL HAS BEEN DETECTED IN 9/65 COMMERCIAL SAMPLES OF PAINTS USED ON CHILDREN'S TOYS AT LEVELS OF 100 TO 2700 MG/KG; AND IN WOOD-SHAVING LITTER FROM CHICKEN HOUSES AT LEVELS OF 0.6 TO 83 MG/KG (FRESH) and 0 TO 4.1 MG/KG (AFTER 8 WK). [R105] *Pentachlorophenol has been detected in: (1) river water and effluent water from a chlorinated biological sewage treatment plant; (2) the effluent waters from various manufacturing and processing plants; (3) well water. [R182] */Pentachlorophenol/ has ... been detected in: (1) sewage influent and effluent water of cities at levels, of 1-5 ug/l; (2) a river, at levels of 0.1-0.7 ug/l; (3) rain- snow-, and lake-water at levels of 2-284, 14 and 10 ng/l; (4) creek- water containing industrial discharges at levels of 0.1-10 mg/l [R182] *After treatment of greenhouse soil with pentachlorophenol at levels of 15 and 45 kg/ha, residues in the soil were 20.4 and 69.1 mg/kg, respectively. [R182] *Pentachlorophenol's production and use in the US as an industrial wood preservative for utility poles, cross arms, and fenceposts, and other items that consume about 97% of its production(1,2) may result in its release to the environment through various waste streams(SRC). Other uses that may lead to its release include the manufacture of sodium pentachlorophenolate (3) and minor uses as a fungicide, bactericide, algicide, and herbicide for crops, leathers and textiles(1,2). Pentachlorophenol's use on wood is "restricted" and its non-wood use is undergoing special review by EPA(4). [R183] FATE: *TERRESTRIAL FATE: Results of an environmental partitioning model indicate that pentachlorophenol partitions mainly in soil (96.5%)(1). Since pentachlorophenol has a pKa value of 4.70(2), its adsorptivity will be strongly dependent on pH. Based on a classification scheme(3), Koc values for the total dissociated phenol of 1250 and 1800 for light and heavy loam soils, respectively, and 25,000 for the undissociated species(4), indicate that pentachlorophenol is expected to have low to no mobility in soil, depending on the pH(SRC). A survey of 4 RCRA sites that contained wood-preserving plants with surface impoundments indicated that all had some groundwater contamination extending down 20 to 60 ft(5). Both aerobic and anaerobic biodegradation rates are expected to be sensitive to the concn of pentachlorophenol present in the soil(SRC). Max mineralization rates of 0.3 to 0.5 mg/kg-day were reported for pentachlorophenol at 30 mg/kg soil with 82% of the added pentachlorophenol recovered as CO2 in 7 months(6). Less than 2% of the added pentachlorophenol was mineralized in 7 months when it was present at 100 mg/kg(6). Mineralization of pentachlorophenol (initially at 30 mg/kg) in a pristine sandy loam soil did not occur while a pristine peaty soil mineralized 13% of a 30 mg/kg spike of pentachlorophenol in 4 months(6). [R184] *TERRESTRIAL FATE: Volatilization of pentachlorophenol from moist soil surfaces is not expected to be important(1,SRC) given a Henry's Law constant of 2.45X10-8 atm-cu m/mole(2). However, significant amounts (25-51%) of pentachlorophenol in terrestrial microcosms have been detected in the air(3-4), which suggests that evaporation from soil of the formulated pesticide will be significant(5). Pentachlorophenol is not expected to volatilize from dry soil surfaces based on a vapor pressure of 1.1X10-4 mm Hg(6). Photolysis of the dissociated form on moist soil surfaces may be a significant process(7). As much as 55% of added pentachlorophenol was photodegraded in a sandy clay loam soil in 14 days with conditions present to increase rates of evaporative flux(7). [R185] *AQUATIC FATE: Based on a classification scheme(1), Koc values ranging from 1250 to 25,000, depending on the pH(2), indicate that pentachlorophenol is expected to adsorb to suspended solids and sediment in water(SRC). Adsorption is expected to be greater under acidic conditions(3,SRC). Both aerobic and anaerobic biodegradation rates are expected to be sensitive to the concn of pentachlorophenol present in the water column(SRC). Aerobic biodegradation of pentachlorophenol, using a non-adapted river sediment, required a lag period of 11 days with complete degradation by day 17; intermediate products of 3,5-dichlorophenol, 3,4,5-trichlorophenol, 2,3,4,5-tetrachlorophenol were reported(4). Increasing the concn of pentachlorophenol, from 1 to 10 mg/l, increased the time required for complete biodegradation(4). The rate of pentachlorophenol mineralization in the relatively unpolluted water of Long Island Sound and water from several sites in the Hudson Estuary in summer was very low (< 5 ng/l/day)(5). Pentachlorophenol is not expected to volatilize from water surfaces(6,SRC) based on a Henry's Law constant of 2.45X10-8 atm-cu m/mole(7). This agrees with a field study in an artificial stream in which < 0.006% of the added pentachlorophenol was lost by volatilization(8). [R186] *AQUATIC FATE: Photolysis of the dissociated form in water may be a significant process(1,2). In water at pH 7.3, 90% degradation occurred in 10 hr with sunlight while at pH 3 (mostly the undissociated form), 40% degradation occurred in 90 hr(2). Both the temperature and pH are expected to influence the loss of pentachlorophenol from water surfaces; at pH 5, the half-life is 328 hours (30 deg C) while at pH 6, the half-life is 3120 hours(3). According to a classification scheme(4), BCF values from approximately 100 to 1000(5-8) indicate that bioconcentration of pentachlorophenol in aquatic organisms is high(SRC). Bioconcentration is expected to be pH dependent with greater bioconcentration at lower pH values(9). [R187] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pentachlorophenol, which has a vapor pressure of 1.1X10-4 mm Hg at 25 deg C(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase pentachlorophenol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 29 days(3,SRC). In addition, vapor phase pentachlorophenol may be directly photolysed. Particulate-phase pentachlorophenol may be physically removed from the air by wet and dry deposition(SRC). [R188] BIOD: *The acute toxicity of pentachlorophenol (PCP) was determined at pH levels 4, 6, 9 to the midge, Chironomus riparius, with the findings that PCP is of greatest toxicity at pH 4 and of least toxicity at pH 9. This differential toxicity is attributable to variations in uptake levels at the respective pH levels. At pH 4, PCP is fully protonated and therefore highly lipophilic. The amount of [14C]PCP present in the midges at 24 hr is thus highest at pH 4. Conversely, at pH 9, the compound is completely ionized. The reduction in lipophilicity at pH 9 decreases the ability of the compound to penetrate into the midge, thereby decreasing the observed toxicity of the compound. [R189] *The 2nd year of a 2-year study of the fate of pentachlorophenol in outdoor artificial streams focused on details of microbial degradation by a combination of in situ and laboratory measurements. Replicate streams were dosed continuously at pentachlorophenol concentrations of 0, 48, and 144 ug/l, respectively, for an 88 day period during the summer of 1983. Pentachlorophenol was degraded both aerobically and anaerobically. Aerobic degradation was more rapid than anaerobic degradation. Mineralization of pentachlorophenol was concommitant with pentachlorophenol disappearance under aerobic conditions, but lagged behind loss of the parent molecule under anaerobic conditions. Biodegradation in the streams, or in specific stream compartments such as the sediment or water column, was characterized by an adaptation period (3-5 weeks for the stream as a whole, and reproducible from the previous year), which was inversely dependent on the concentration of pentachlorophenol and microbial biomass. The adaptation in the streams could be attributed to the time necessary for selective enrichment of an initially low population of pentachlorophenol degraders on surface compartments. The extent of biodegradation in the streams (percent loss of initial concentration of pentachlorophenol) increased with increasing pentachlorophenol input, which was explicable by an increase in the pentachlorophenol degrader population with increasing pentachlorophenol concentration. The sediment zone most significant to overall pentachlorophenol biodegradation was the top 0.5 to 1 cm layer as shown by pentachlorophenol migration rates and depth profiles of degrader density within the sediment. Pentachlorophenol profiles in sediment cores taken during and after the adaptation period for degradation showed that diffusion of pentachlorophenol into the sediment was rate limiting to degradation in this compartment. [R190] *Screening biodegradability tests give conflicting results(1-7); pentachlorophenol does biodegrade but may require several weeks for acclimation(3-7). Using an acclimated pentachlorophenol-degrading culture, half-lives of 85 (lag time of 27 hours) and 420 (lag time of 220 hours) hours were reported for aerobic and anaerobic conditions, respectively(8). 1% of the theoretical BOD was reached in 28 days during the Modified MITI test with pentachlorophenol initially at 100 mg/l and using an activated sludge inoculum(9). Acclimation of microbial communities to pentachlorophenol appears to increase tolerance to pentachlorophenol and/or select for pentachlorophenol-tolerant microorganisms(10). Pentachlorophenol, at an initial concn of 300-500 ug/l, had a half-life of 2.6 days using a sludge inoculum(11). At this concn, no lag phase was seen(11). [R191] *Avg first-order rate constants of 0.006, 0.002, 0.005 per hour were measured for pentachlorophenol at an initial concn of 5 ug/L, 10 ug/l and 10 mg/l, respectively, in a SCAS test using synthetic sewage with a sludge retention time of 10 days(1). An avg first-order rate constant of 0.021 per hour was measured for pentachlorophenol at an initial concn of 10 ug/L in a SCAS test using domestic sewage with a sludge retention time of 10 days(1). Avg first-order rate constants of 0.006 and 0.027 per hour were measured for pentachlorophenol at an initial concn of 10 mg/l and 10 ug/l, respectively, in a SCAS test using domestic sewage with a sludge retention time of 20 days(1). Pentachlorophenol, initially present at 890 ug/l, was found at 0.39 ug/l in the effluent of an activated sewage sludge treatment plant; dewatered sludge contained 0.16 mg/kg pentachlorophenol(2). 41 and 60% removal was reported for pentachlorophenol in a trickling filter system (49 ug/l in secondary sludge) and during activated sludge treatment (99 ug/l in secondary sludge), respectively(3). After 6 months of operation, a lab-scale fixed film reactor was able to remove about 60% of the initially added pentachlorophenol; if glucose was added then removal reached 98%(4). Biodegradation of pentachlorophenol stopped when the sludge retention time was < 8 days(5). Laboratory scale activated sludge reactors run under continuous flow conditions gave minimum and max first-order rate constants for the removal of pentachlorophenol of 0-2 and 1-24 per g/MLSS/day(6). Six municipal wastewater treatment plants were monitored for their ability to remove pentachlorophenol; 0.46, 0.43 (influent, effluent concns); 0.75, 0.50; 0.76, 0.65; 0.73, 0.62; 0.67, 0.41; 0.51, 0.19, were reported for the six treatment plants(7). [R192] *Pentachlorophenol was added to both non-adapted river sediment and to river sediment which had been adapted to 2,4-dichlorophenol and 3,4-dichlorophenol (over a one year period) and incubated under anaerobic conditions(1). A lag period of 11 days with complete degradation by day 17 was reported for the non-adapted culture; the lag period was 9 days with complete degradation by day 13 days for the adapted culture(1). Intermediate products of 3,5-dichlorophenol, 3,4,5-trichlorophenol, 2,3,4,5-tetrachlorophenol were reported(1). Increasing the concn of pentachlorophenol, from 1 to 10 mg/l, increased the time required for complete biodegradation. Complete biodegradation at pH 7 and 8 required 13 and 3 days, respectively; only 20% biodegradation was reported by day 19 for cultures incubated at pH 6(1). No significant biodegradation of pentachlorophenol-contaminated soil (4 to 7 mg/kg soil) was reported in the first 6 days of aerobic incubation; over the next 12 days, an avg of 87% of the initial concn was lost with an avg rate of degradation of 0.32 mg/kg-day during the first 19 days and 0.64 mg/kg-day for day 12 to 19(2). Anaerobic biodegradation of a pentachlorophenol-contaminated soil resulted in an initial increase in pentachlorophenol concns due to desorption; this was followed by a period of dechlorination giving 2,3,4,5- and 2,3,5,6-tetrachlorophenol as initial metabolites(2). Mineralization of pentachlorophenol in contaminated soil was measured at 30 mg/kg and 100 mg/kg soil; max rates of 0.3 to 0.5 mg/kg-day were reported for the lower concn with 82% of the added pentachlorophenol recovered as CO2 in 7 months(3). Less than 2% of the added pentachlorophenol was mineralized in 7 months when it was present at 100 mg/kg(3). Mineralization of pentachlorophenol (initially at 30 mg/kg) in a pristine sandy loam soil did not occur while a pristine peaty soil mineralized 13% of a 30 mg/kg spike of pentachlorophenol(3). The order of pentachlorophenol dechlorination in anaerobic sediment is ortho to produce 2,3,4,5-tetrachlorophenol, ortho to produce 3,4,5-trichlorophenol, meta to produce 2,4-dichlorophenol, and para or ortho to produce 2-chlorophenol or 4-chlorophenol(4). Less than 0.2% of the initially added pentachlorophenol was degraded to CO2 in 5 weeks following inoculation with pentachlorophenol-contaminated soil(5). [R193] *Little biodegradation was noted in 40 days in a river die-away study or in stream sediment(1). However, approximately 6% biodegradation occurred in aerobic soil in 160 days(2) while no biodegradation occurred in anaerobic soil(2). Other studies in soil have suggested greater biodegradation under anaerobic conditions producing pentachloroanisole and tri- and tetrachlorophenols(3-4). A study of biodegradation in estuarine sediment indicated that pH (test conditions= pH 5, 6.5, 8, 9) and redox potential (test conditions= -250, 0, +250, +500 MV) considerably affected degradation; significant biodegradation (70%-35 days, 17 day lag period) was only noted at pH 6.5 and 8.0 at redox potential of +500 MV(5). [R194] *Half-life in soil is approximately weeks to months(1-3). The main degradation products of pentachlorophenol in soil are 2,3,7,8-tetrachlorophenol and CO2(4). In an artificial stream, microbial degradation became significant after 3 weeks and accounted for 26-46% removal(5). Pentachlorophenol mineralization in the relatively unpolluted water of Long Island Sound and water from several sites in the Hudson Estuary in summer was also very low (< 5 ng/l per day)(6). 3 and 5 ppm PCP were completely degraded in 38 and 57 days, respectively, when incubated in Pennsylvania and Virginia unsaturated soils taken at 4 and 4.5 m depths(7). [R195] ABIO: *Pentachlorophenol does not appear to oxidize or hydrolyze under environmental conditions; however, photolysis of the dissociated form in water may be an important process(1,2). Pentachlorophenol has a pH-dependent absorption max of 303 nm(8). A measured half-life for the photolysis of pentachlorophenyl has been reported to be 0.86 hrs(7). In water at pH 7.3, 90% degradation occurred in 10 hr with sunlight while at pH 3 (mostly undissociated form), 40% degradation occurred in 90 hr(2). Reported half-lives for photodegradation of the dissociated form have included 0.2 hr (10 cm deep)(1), 3.5 hr(2), 4.75 hr (300 cm deep)(1), and 10 days(3). Products of photodegradation include 2,3-dichloromaleic acid, 2,3,5,6- and 2,3,4,6-tetrachlorophenol, tetrachlororesorcinol, tetrachlorocatechol, some benzoquinones(2-3), and possibly dioxins(5). Photolysis in a solution of H2O-CH3CN using 290 nm wavelengths and a pH of 12 produces the photoproduct 2-methyl-4,5,6,7-tetrachlorobenazole(6). Half-lives of 24 minutes, 30.9 minutes, and 635 minutes were reported for aqueous solutions of pentachlorophenol under direct sunlight, under a clear plastic sheet, and under a black plastic sheet, respectively(9). As much as 55% of added pentachlorophenol was photodegraded in a sandy clay loam soil in 14 days with conditions present to increase rates of evaporative flux(9). Little loss of pentachlorophenol was noted in dry soils or soils covered with black plastic. Photodegradation rates are lower than aqueous rates due to the attenuation of light by natural chromophores(9). A second-order rate constant of 9.36X10+7 per M-sec was reported for the reaction of pentachlorophenol with singlet oxygen(10). [R196] *The rate constant for the vapor-phase reaction of pentachlorophenol with photochemically-produced hydroxyl radicals has been estimated as 5.5X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 29 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R197] BIOC: *Pentachlorophenol is expected to bioconcentrate because of its low water solubility(13). The bioconcentration factor (BCF) is expected to be dependent upon the pH of the water; pentachlorophenol has a pKa of 4.70(12) indicating that in most environmental waters, it will be mainly present as the anion(SRC). BCF values varied from 2 at pH 10, to 56 at pH 7, to 132 at pH 5.5 in goldfish(1). Levels of pentachlorophenol in pike from an acidified lake (pH=5.2)varied from 2.05 to 8.72 ng/g fresh weight (geometrical mean=3.95 ng/g) while concns in pike from non-acidified lakes (pH~ 8) ranged from 1.50 to 3.21 ng/g fresh weight (geometrical mean=2.19)(11). Other reported BCF values are 776 in fathead minnow(2); 251-5370 in rainbow trout(3-4); 5-50 in sheepshead minnows(5); 295 in mosquito fish(6); 708(8) and 977(7) in zebra fish; and 417 in golden orfe(8). According to a classification scheme(14), these BCF values suggest the potential for bioconcentration in aquatic organisms is generally high(SRC). The accumulation increased with temperature in golden orfe and decreased with temperature in zebra fish(8). BCF values of 39-198 and 45-224 were measured in an 8-week carp study with pentachlorophenol concns of 30 and 3 ug/l, respectively(9). BCF values of 214 in Jordanella floridae and 380-1698 in Oryzias latipes were reported for pentachlorophenol(7). A BCF value of 13 was measured in bluegill muscle in an 8-day study(10). [R198] *The BCF of pentachlorophenol in humans was measured from daily intake of pentachlorophenol and measured concn in different tissues, giving the following results: 5.7, 3.3, 1.4, 1.4, and 1.0 in liver, brain blood, spleen and adipose tissue respectively(1). Calculation using a linear one compartment pharmacokinetic model yielded similar results(2). Eichhornia crassipes, an aquatic plant, had measured BCF values of 114 and 156 in leaves and roots, respectively(3). BCF values of 10000 to 45000 were measured in zebra mussels(4). Freshwater mussel Anodonta anatina and Pseudanodonta complanata, exposed to pentachlorophenol, had wet-weight based BCF values of 80-120 and 61-85, respectively(5). Passive uptake of pentachlorophenol was reported in Chironomus riparius, a midge; uptake was greater when sediment was present(6). A BCF value of 458 was measured in Chironomus riparius (midge) exposed to pentachlorophenol at 9 ug/l in a 16 hour static phase; a depuration rate was determined in a flow-through system as 55 ml/g-hr(7). [R199] KOC: *Pentachlorophenol has a tendency to adsorb to soil and sediment; calculated Koc=1000(1), measured sediment Koc=3,000-4,000(2). Adsorption of pentachlorophenol to oxidized sediment is greater than to reduced sediment(2). Adsorption to soil and sediment appears to be pH dependent, with stronger adsorption under acid conditions(3). Approximately 15% of the dose in an artificial freshwater stream adsorbed to sediments(4). An accidental spill in a lake resulted in pentachlorophenol in the sediment(5). After a 180 day microcosm experiment using radioactive substrate, 40 to 43% of the radioactivity was present in the sediments(6). [R200] *Since pentachlorophenol has a pKa of 4.70(8), its adsorptivity will be strongly dependent on pH. The Freundlich adsorption constant for 6 Dutch soils are (soil (% organic carbon, pH) log KF, 1/N): humic sand (1.7%, 3.4) 2.2, 0.9; humic sand (2.2%, 4.9) 2.2, 0.9; humic-rich sand (3.2%, 4.7) 2.6, 1.0; peat (29.8%, 4.6) 3.3, 0.8; light loam (0.9%, 7.5) 1.1, 0.9; heavy loam (1.7%, 7.1) 1.5, 0.8(1). For loam soil where pH > pKa, significant contribution from the phenolate ion can be expected. The Koc values for the total dissociated phenol was calculated to be 1250 and 1800 for light and heavy loam, respectively, while for the undissociated species, the Koc is 25,000(1). Koc values of 2285 (pH 4.9), 4267 (pH 5.0), 6224 (pH 5.9), 3684 (pH 4.6), 121681 (pH 3.5), 121810 (pH 3.9), 97471 (pH 3.7), 1586 (pH 5.0), 4109 (pH 5.1), 4009 (pH 5.5), 123563 (pH 3.5) were measured for pentachlorophenol(2). According to a classification scheme(7), these Koc values indicate that pentachlorophenol is expected to have slight to no mobility in soil where the pH is acidic(SRC). The fraction of pentachlorophenol which is sorbed decreases linearly with pH to a pH of 6; above pH 6, significant adsorption of the anion again occurs, contributing as much as 20% of the total adsorption effect at pH 8(3). K values for a Bjuv clay (12% organic C) and an aquifer soil (0.02% organic C) were 433 and 86 at pH 3.0, respectively, and 167 and 50 at pH 6.5, respectively(3). K values for a bentonite clay of 72 and 34 were measured at pH 3.0 and 6.5, respectively(3). The nonionized form of pentachlorophenol had a K value of 3.63 ml/g in a sandy aquifer material (0.13% organic C) (Koc=2792)(4). K values measured at pH 7 for a Guishan sandy loam (organic C=1.4%) and a Shulin clay loam (organic C=2.0%) were 2.56 (Koc=183) and 7.03 (Koc=352), respectively(5). The Koc for pentachlorophenol was measured for five soils (foc from 0.07 to 2.96%; 3 sands, 1 loamy sand, 1 loam)(6). At pH 4, 7, and 10, the Koc values ranged from 10091-40120 (avg=19675), 178-1956 (avg=651), and 126-942 (avg=501), respectively(6). These Koc values indicate that pentachlorophenol, while expected to have low to no mobility in acidic soils, has higher mobility when soils are basic(SRC). [R201] *Koc values of 241 and 433 were measured for the upper (pH=6.1; organic C=1.38%) and lower (pH=6.5; organic C=0.36%) horizon, respectively, of a Menfro silt loam soil(1). The addition of humic acid to this soil resulted in a linear increase in adsorption of pentachlorophenol(1). In situ Koc values from 4.2 to 560 were measured in an aquifer (foc=0.007) at pH values ranging from 7.2 to 8.5(2). K values of 10.367, 13.955, 0.463, and 26.883 were measured in a quartz, calcite, kaolinite, and montmorillonite suspension, respectively; the ionized form of pentachlorophenol was dominant in this study(3). Retardation factors of 4.7 and 1.0 were measured for pentachlorophenol in a Eustis soil (0.37% organic C) column with water and methanol, respectively, used as the mobile phase(4). Kf values of 120 (Koc=3243), 125 (Koc=2049), 57 (Koc=703), and 714 (Koc=4577) cu dm/kg were measured for a sandy soil (organic C=3.7%), a sandy soil (organic C=6.1%), an OECD artificial soil (organic C=8.1%), and a peaty sand (organic C=15.6%), respectively(5). Koc values of 2727, 2647, 100, 52, 208, and 115 were measured at pH 7 (foc=0.0066), pH 6.6 (foc=0.68), pH 5.3 (foc=0.012), pH 6.4 (foc=0.0087), pH > 10 (foc=0.039), and pH > 10 (foc=0.039), respectively, in column studies(2). In batch studies, Koc values of 718 and 597 were measured at pH > 7 (foc=0.0039) and pH 7.5 (foc=0.034), respectively(2). [R202] *Kp values (as l/g suspended solids) were determined for pentachlorophenol using microbial biomass as the sorbent; values of 2.44, 0.98, 0.66, 0.44, and 0.35 were measured at pH values of 4, 5, 6, 7, and 8, respectively(1). Koc values of 5337, 6887, 1487, and 2087 were measured for natural dissolved organic matter at < 0.1 mg/l DOC (pH 5.4), natural dissolved organic matter at 15 mg/l DOC (pH 5.4), natural dissolved organic matter at < 0.1 mg/l DOC (pH 6.1), and natural dissolved organic matter at 15 mg/l DOC (pH 6.1), respectively, in an aquifer sand column with groundwater as the mobile phase(2). [R203] VWS: *The low water solubility (14 ppm)(1) and moderate vapor pressure (0.00011 torr at 20 deg C)(2) would suggest that evaporation from water is not rapid, especially at natural pH values where pentachlorophenol is present in the dissociated form (pKa=4.70)(2). The Henry's Law constant for pentachlorophenol was measured as 2.45X10-8 atm-cu m/mole(3). This Henry's Law constant indicates that pentachlorophenol is expected to be essentially nonvolatile from water surfaces(4,SRC). This agrees with a field study in an artificial stream in which < 0.006% of the added pentachlorophenol was lost by volatilization(5). Both the temperature and pH influence the loss of pentachlorophenol from water surfaces; at pH 5, the half-life is 328 hours (30 deg C) while at pH 6, the half-life is 3120 hours(6). [R204] *Pentachlorophenol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is not expected(2,SRC). However, significant amounts (25-51%) of pentachlorophenol in terrestrial microcosms have been detected in the air(3-4), which suggests that evaporation from soil of the formulated pesticide will be significant(5). Pentachlorophenol is not expected to volatilize from dry soil surfaces based on a vapor pressure of 1.1X10-4 mm Hg(6). [R205] WATC: *GROUNDWATER: Germany - 6.9% occurrence(1). Pentachlorophenol was detected in groundwater in monitoring program in California, Oregon and Minnesota(2). In Minnesota 3% of wells monitored by the Agriculture Department had detectable pentachlorophenol with a max level of 0.64 ppb. In Oregon, 1.4% of tested wells contained pentachlorophenol and the max concn was 0.12 ppb(2). Concns of pentachlorophenol in groundwater were 1047 and 152 ppb at Havertown PCP site, Havertown, PA(3) and Doepke disposal site, Holliday, KS, respectively(4). The leaking of pentachlorophenol from a sawmill dip tank in British Columbia resulted in the contamination of a shallow aquifer at peak concns of 20 to 63 mg/l; the nearby Okanagan River received contaminated groundwater with a travel time of 47 days (for 122 m distance)(5). Groundwater from Visalia, CA was heavily contaminated with pentachlorophenol(6). At the Pensacola site, a former wood treatment plant in Florida resulted in the contamination of an underlying aquifer with pentachlorophenol at concns from 0.0 to 3.53(6). Pentachlorophenol was detected at a max concn of 40 ug/l in the Biscayne aquifer study area(7). Pentachlorophenol was detected in one groundwater supply site in Atlantic Canada at 11 ug/l(8). Groundwater was contaminated with pentachlorophenol (maximum concn=0.01% solution) from a wood treatment facility in Florence, SC(9). [R206] *DRINKING WATER: Pentachlorophenol was detected in drinking water at the following concns and locations: 0.04-0.28 ug/l, Corvallis, OR; 0.07 ug/l (mean of 108 samples from the National Organics Monitoring Survey); and < 1 to 800 ppb (avg of 227 ppb) in 7 water wells in Oroville, CA(1). [R207] *SURFACE WATER: Netherlands - 5 rivers - 0.41 to 9.9 ppb(1,2) Japan - urban rivers 0.1 to 10 parts/trillion(3); Willamette R, Oregon 0.1-0.7 ppb(4), Lake Erie 0-1.7 ppb(5). Pentachlorophenol concns in the Weser River and estuary (0.05-0.5 ug/l; Germany), German Bight (< 0.002-0.026 ug/l), Ruhr River (< 0.1-0.2 ug/l; Germany), River Rhine (0.1 ug/l; Cologne, Germany), Tama River (0.01-0.9 ug/l; Tokyo, Japan), Sumida River (1-9 ug/l; Tokyo, Japan), River Rhine(in 1976 and 1977, mean=0.7, 1.1 ug/l, respectively; The Netherlands), River Meuse, The Netherlands (in 1976 and 1977, 0.3, and 0.8 ug/l, respectively; The Netherlands), 124 sampling points in South Africa(not detected to 0.85 ug/l), an estuary in Galveston Bay, Texas (not detected to 0.01 ug/l), and in a pond in Mississippi (< 1 to 82 ug/l; contaminated by waste from pole-treatment facility)(6). Rivers and streams from the Zagreb, Croatia area contained pentachlorophenol at concns from 2 to 23 ng/l (N=10; median=2 ng/l)(7). Lakes in the Zagreb area contained from < 1 to 5 ng/l (N=13; median= < 1 ng/l)(7). Water sampled along a gradient from the Iggesund pulp mill, Sweden, contained pentachlorophenol at 43 to 1080 ng/l, with the higher concn reported for a sampling point very close to the source(8). An upstream location from a pulp mill contained pentachlorophenol at 0.007 ug/l while downstream locations had concns from 0.019 to 0.049 ug/l(9). [R208] *SURFACE WATER: Pentachlorophenol was reported at seven surface water supplies in a study of municipal water supply sources in Atlantic Canada from 0.002 to 0.021 ug/l during one sampling period(1). Pentachlorophenol was the only halogenated phenolic compound found in more than 20% of the raw water samples from 40 potable water treatment plants across Canada in the fall and winter samples at levels up to 53 ng/l with mean values of 1.9 and 2.8 ng/l, respectively(4). Pentachlorophenol was detected in the Isipingo River and the Isipingo Estuary, Republic of South Africa, at concns from 0.1 to 3.79 ug/l(2). Concns of pentachlorophenol from 0.040 to 5.26 ug/l (higher concn from a sample close to the water intake plant) were measured in Pyhaoja Brook, Finland; the water was apparently affected by a sawmill operation(3). [R209] *SEAWATER: Germany 0.02-1.30 parts/trillion(1). Four sites located in the Scheldt estuary in North West Belgium and South West Netherlands had concns of 0.1, 0.18, and 0.02 ppb, respectively(3). [R210] EFFL: *Oregon cities sewage treatment plant effluent 1-4 ppb(1). Detected in the effluents of the following industries (industry - max concn, ppb): auto and other laundries - 27, coal mining - 3, iron and steel manufacturing - 25, leather tanning and finishing - 3100, electrical/electronic components - 10, foundries - 140, photographic equipment/supplies - 350, pharmaceutical manufacturing - 110, paint and ink formulation - 490, pulp and paperboard mills - 1400, rubber processing - 10, steam electric power plants - 6.5, textile mills - 15, timber products processing - 8300(2). 4.6 ppb mean concn reported for organic manufacturing/plastics(2). Waste from a municipal compositions facility on Long Island, NY has a concentration range of 7-210 ppb(3). Effluent from a pulp and paper bleach plant, aerated lagoon, and treated effluent discharging into a river on site contained concentrations of pentachlorophenol of 3.1, 1.3 and 0.6 ppb, respectively(4). Primary-treated and municipal wastewater from the Iona Island treatment plant in Vancouver, British Columbia, Canada contained pentachlorophenol concentrations ranging from 0.4-13.2 ppb(5). [R211] *Raw effluent from several wood-treatment plants contained pentachlorophenol at concns of 25 to 150 mg/l(1). Influent and effluent from a sewage plant in Corvallis, OR contained pentachlorophenol at 1-5 ppb and 1-4 ppb, respectively(1). Pentachlorophenol was measured in the waste from the production of sodium pentachlorophenol at 51 g/kg waste(2). Pentachlorophenol was present in a treated pulp mill effluent from Finland at 0.3 ug/l(3). A typical concn of pentachlorophenol in sewage sludge was reported as 1 to 5 mg/kg dry weight(4). Bleachery effluents in a pulp and paper mill using chlorine dioxide substitution at 60% and 100% chlorine dioxide, contained pentachlorophenol at 2 and 0.5 ug/l; secondary treated mill effluents using this procedure contained pentachlorophenol at less than 1 ug/l at both chlorine dioxide concns(5). Pentachlorophenol was detected in both free and chemically bound residues in effluents from the chlorine (3.01 and 6.09 ug/l, respectively) and alkali extraction (9.23 and 9.93 ug/l, respectively) phases of chlorobleaching of pine kraft pulp(6). Pentachlorophenol was not detected in influent and effluent of a pulp mill treatment system and was not detected in discharge water samples; however, it was detected in biosludge samples at 6.06 and 12.1 ng/g for free and bound residues, respectively(7). [R212] *Pentachlorophenol was detected in 8 samples of leachate (median=0.06, mean=0.21, max=1.1 ug/l) collected from municipal and industrial landfills in Finland(1). Samples from yard waste composting facilities contained pentachlorophenol at concns from not detected to 91 ng/g; samples collected from municipal solid waste composting programs contained pentachlorophenol from 73 to 430 ng/g; samples collected from a facility that composts municipal solid waste with dewatered sewage sludge contained pentachlorophenol from 190 to 960 ng/g(2). [R213] *Pyrolysis of low molecular weight polyvinyl chloride, in order to determine the effect of incinerator operations, resulted in the production of several compounds, including pentachlorophenol(1). The 1990 Toxics Release Inventory reported that 12 tons of pentachlorophenol were released to the air per year(2). During incineration of pulp and paper mill biosludges in a pilot-scale circulating fluidized bed incineration plant, pentachlorophenol was released in the flue gases at concns from 0.10 to 0.74 ug/normalized cu-m(3). Flue gas from two sites at a municipal waste incineration plant, after an electrostatic precipitator and after a wet scrubber, contained pentachlorophenol at 0.5 and 0.4 ug/normalized cu-m, respectively(4). Flue gas from the stack of the second combustion line at a hazardous waste incinerator in Biebesheim, Germany, contained pentachlorophenol at 0.68 and 0.34 ng/normalized cu m(5). Pentachlorophenol was detected in waste samples collected following two municipal landfill fires at concns from -0.1 to 0.38 ug/g dry weight(6). Flue or ventilation emissions from a metal reclamation plant in Sweden contained pentachlorophenol at 0.1, 0.4, 2.0, 0.1, and 0.2 ug/normalized cu m from the aluminum smelting, car shredding, turnings drying, sink and float separation and ring crusher processes(7). [R214] SEDS: *SEDIMENT: Mississippi R outlet 1.6 ppm near spill(1), Bremerhaven, Germany 0.095-20 ppb(2), German rivers 0.2-8 ppb(3), Portland, ME 9 coastal sites, all pos, 0.01-2.4 ppb(4). SOIL: Abandoned sawmill site near a wood-preserving site in Finland - 390 ppm(5). Gas Works Parks, Seattle, Wash - 0.052 ppm(6); Lipar landfill, Manutua, Township, Gloucester Co., NJ - 2033 ppb(7). At several freshwater and marine sites in British Columbia, Canada, which received effluents from the wood-treatment industry, avg pentachlorophenol levels in the sediments ranged from not detectable to 590 ug/kg, while the corresponding range for the overlying waters was from not detectable to 7.3 ug/l(8). Pentachlorophenol concns in sediments upstream from the Kinleith pulp and paper mill ranged from 0.5 to 5.5 ng/g; downstream concns ranged from 11 to 13 ng/g near to the mill and from 0.41 to 1.6 ng/g further downstream(9). Pentachlorophenol was present in sediment collected from sediment traps placed both upstream and downstream from a pulp mill; upstream concns ranged from 0.05 to 0.06 and downstream concns from 0.04 to 0.06 ug/g dry matter(10). Sediment concns at the same sampling locations contained pentachlorophenol at 0.040 to 0.050 ug/g dry matter at upstream locations and from 0.060 to 0.110 ug/g dry matter at downstream locations(10). A marine sediment collected in a harbor on the west coast of Norway contained pentachlorophenol at unreported concns(11). [R215] *Soil samples from four sites near a pentachlorophenol-production facility in Switzerland contained 25 to 140 ug/kg (dry weight) at depths of 0-10 cm and 33-184 ug/kg at 20-30 cm(1). Soil from Finnish sawmills was heavily contaminated with up to 45.6 mg/kg at 0-5 cm depth near the treatment basin and up to 0.14 mg/kg in the area for storing treated wood. The background level was 0.012 mg/kg. Avg pentachlorophenol levels in soil samples at 2.5, 30.5, and 152.5 cm from poles treated with pentachlorophenol were 658, 3.4, and 0.26 mg/kg, respectively(1). Concns of pentachlorophenol ranged from 0.012 to 0.227 ug/g dry weight in the sediment of Pyhaoja Brook, Finland; this stream has been apparently affected by the operation of a sawmill(2). Sediment samples collected from 3 sites, the basin of a bleached kraft mill effluent treatment lagoon, from a location in the effluent drain midway between this basin and the effluent outfall point, and from a location immediately downstream of the outfall point contained pentachlorophenol at 1045, 173, and 160.0 ug of Cl/g dry weight(3). [R216] ATMC: *Pentachlorophenol was detected in two air samples from a single location at a median concn of 1 ng/cu m(1). Bolivia and Antwerp, Belgium 0.023-0.70 parts/trillion(2). Detected in Hamburg, Germany - 0.67 parts/trillion(3). [R217] *INDOOR: An estimation of children's (age 6 months to 5 years) exposure to pentachlorophenol by respiration and household dust in nine homes ranged from not detected-1.4 ug/day and < 0.01 to 0.33 ug/day, respectively(2). In a pilot EPA study of non-occupational exposure to pesticides, nine households in an urban-suburban area of Jacksonville, FL, an area of high pesticide use, were monitored(3). Pentachlorophenol was detected indoors in two households and outdoors in one household. [R218] FOOD: *US daily intake - % pos (ug): 1971 - 0.6% (0.03 ug), 1972-0, 1973 - 2.5% (0.7 ug), 1974 - 3.0% (0.8 ug), 1975 - 5.4% (2.0 ug), 1976 - 0.8% (1.0 ug)(1). Results from the US FDA's Adult Total Diet Study in which the typical 14-day diet of a 16-19 yr male was collected throughout the US from market basket composite samples in 12 food groups (Fiscal Year-average intake (ug/kg body wt/day)) are: FY79 0.006, FY 80 0.040, FY 81/82 0.052(2). An analogous study for infants and toddlers calculated that in FY 81/82, that daily pentachlorophenol input per unit body weight was 0.023 and 0.079 ug/kg, respectively(2). In the 1988 Total Diet Study, the intake of pentachlorophenol in ug/kg body wt/day was 0.0004, 0.0002, and 0.0003 for a 6-11 month old, 14-16 yr male, and 60-65 yr female, respectively(3). For the FY 81/82 Adult Total Diet Survey, 27 cities were sampled. In FY 81/82, there were 48 positive samples out of the 27 composites from each of the 12 food groups containing pentachlorophenol levels up to 0.024 ppm(2). The avg 70 kg man would have an avg intake of 3.62 ug/day(2). The food groups that contained pentachlorophenol are (class, avg concn number of positives): meat, fish and poultry, 0.0037 ppm 14 positives; grain and cereal products, 0.0048 ppm 12 positives; oils and fats, 0.0072 ppm 18 positives; and sugar and adjuncts, 0.0010 ppm, 4 positives(2). Mean daily intake of pentachlorophenol from 1984-1986, determined during the FDA's Total Diet Study, was reported as 0.0169. 0.0379, 0.0135, 0.0183, 0.0130, 0.0156, 0.0108, and 0.0127 ug/kg body weight/day for a 6- 11 month old child, a 2 year old child, a 14-16 year old female, a 14-16 year old male, a 25-30 year old female, a 25-30 year old male, a 60-65 year old female and a 60-65 year old male, respectively(4). Intake of pentachlorophenol found in the Total Diet Study analyses for 1986 to 1991 were reported as 0.0009, 0.0014, 0.0005, 0.0008, and 0.0007 ug/kg body weight/day for a 6-11 month old child, a 2 year old child, a 14-16 year old male and female, a 25-30 year old female and a 60-65 year old male and female, and a 25-30 year old male, respectively(5). In a 10 year Revised Market Basket Study from 1982 to 1991, pentachlorophenol was detected 485 times in 128 different foods at an avg concn of 0.0073 ug/g(6). [R219] PFAC: PLANT CONCENTRATIONS: *Surface wax of pine needles in Sweden, collected in 1984 to 1986, contained pentachlorophenol at about 1 ng/g in downwind locations (from a 1983-1984 spraying program in the former East Germany); upwind needle concns (considered background) were reported as 0.48 ng/g(1). Surface wax of pine needles collected from a series of stations in West Germany, Denmark, Norway, and Sweden contained pentachlorophenol from 0.6 to 7.3 ng/g fresh weight(2). Pine needle samples collected from Regina, Saskatoon, and Yellowgrass in Saskatchewan, Canada, contained pentachlorophenol at an avg concn of 0.93 ng/g with a standard deviation of 0.49 ng/g (concentration range of 0.42 to 2.08 ng/g)(3). Rice samples taken from fields which had been exposed to the effluent of a kraft pulp and paper mill in Vietnam, contained pentachlorophenol at concns from not detected to 0.02 ug/kg dry weight(4). Rice samples taken from a nearby field which had not received waste effluents from the mill contained pentachlorophenol at concns from not detected to 0.04 ug/kg dry weight(4). [R220] FISH/SEAFOOD CONCENTRATIONS: *Not detected in meat, fish and poultry in market basket surveys(1). New Brunswick, Canada fish 0.5-4 ppb, White shark liver - 10.8 ppb, (2). Wabash R, IN - composite fish samples - detected, not quantified(3). Fish 0.35-59 ppm(4). Gulf of Mexico, TX - flounder, killifish, shrimp, crab and squid 2.6-7.5 ppb(5). [R221] *Mussels obtained from Lake Vanaja in Finland contained pentachlorophenol at 180 to 260 ng/g lipid weight; mussels collected from the River Kymijoki contained pentachlorophenol at concns less than 20-24 ng/g lipid weight(1). Perch, caught along a gradient outside two pulp mills at Norrsundet and Iggesund, contained pentachlorophenol at concns from 140 to 920 ng/g bile (lower number represents fish caught 10 km from the mill) and 30 to 840 ng/g bile (lower value for low exposure to effluent material), respectively(2). In a second experiment at Iggesund, perch bile contained from 56 to 1100 ng/g with larger concns reported for fish caught closer to the pulp mill(2). Mountain whitefish collected below a pulp and paper mill, then transferred upstream of the mill for eight days during a depuration phase, contained pentachlorophenol at concns from not detected to 0.1 ug/g in fish bile samples(3). Limited longnose sucker fish samples and other mountain whitefish collected below the mill ranged from not detected-0.20 and from not detected-1.0 ug/g fish bile, respectively(3). Fillets from longnose sucker fish and mountain whitefish collected immediately downstream from the paper mill during spring 1991 contained pentachlorophenol at concns from not detected to 4.00 ug/g(3). Pentachlorophenol was not detected in any collected fish in the fall 1991 sampling period(3). Bile obtained from goldfish collected from a New Zealand hydrolake, which received a bleached kraft mill discharge, contained pentachlorophenol at concns of 0.24-1.23 and 3.94-8.22 ug/g dry weight for locations upstream of the outfall and downstream of the discharge point, respectively(4). 9.1 km downstream of the discharge point pentachlorophenol concns in goldfish bile were 0.17 ug/g dry weight(4). [R222] ANIMAL CONCENTRATIONS: *In Canada, 6.6% of 881 pork liver samples contained pentachlorophenol at concns > 0.1 mg/kg, max concn=0.72 mg/kg(1). 2% of 51 beef liver samples contained pentachlorophenol at concns > 0.1 mg/kg, max concn=0.35 mg/kg. Only one sample out of 214 chicken and 68 turkey liver samples contained pentachlorophenol at a concn > 0.1 mg/kg(1). Birds 0.04-0.49 ppm, snails 36-8 ppm; dairy cattle in pentachlorophenol treated barn 58-1136 ppb(2); bird eggs 0.36-0.51 ppb(3). [R223] *IN THE STATE OF MICHIGAN, HERDS OF DAIRY CATTLE WERE CONTAMINATED WITH PENTACHLOROPHENOL USED TO TREAT WOOD OF BARNS WHERE THEY WERE HOUSED AND FROM FEED BINS TREATED WITH PENTACHLOROPHENOL; THE CONTAMINATING PENTACHLOROPHENOL WAS SAID TO CONTAIN 1 TO 1000 MG/KG DIOXIN. PCP LEVELS IN 18 COWS RANGED FROM 58 TO 1136 UG/KG. PENTACHLOROPHENOL HAS BEEN FOUND IN BLOOD OF 8 SUCH HERDS. [R156] MILK: *Not detected in milk in market basket surveys(1). [R224] *1 SAMPLE OF MILK WAS FOUND TO CONTAIN 0.09 MG/KG. [R156] OEVC: *One of three new cotton T-shirt samples, tested for the presence of pentachlorophenol, contained this compound at 2000 ng/g (detection limit=10 ng/g)(1). Mean concns of pentachlorophenol in samples from nine homes were reported as 0.48 ug/sq m, 0.03 ug/sq m, 0.02 ug/sq m, 0.02 ug, 0.05 ug/cu m, 0.03 ug/g, 0.02 ug/g, and 0.02 ug/g for house dust, PUF roller (carpet dust), investigator hand, child hand rinse, air, entryway soil, walkway soil, and play area soil, respectively(2). Pentachlorophenol was measured in raw wood (3 of 15 samples positive; 0.25 mg/kg max), wood packings and pallets (3 of 39 samples positive; 0.90 mg/kg max), interior decoration (21 of 30 samples positive; 11.6 mg/kg max), beams (4 of 22 samples positive; 0.32 mg/kg max), windows (64 of 68 samples positive; 163.3 mg/kg max), fences and stakes (13 of 14 samples positive; 0.70 mg/kg max), cable-drums (4 of 10 samples positive; 1.32 mg/kg max), and recycling chips (8 of 9 samples positive; 4.43 mg/kg max)(3). 9 of 65 paints used in children's toys(1); wood-shaving litter from a chicken house(4). [R225] RTEX: *NIOSH's National Occupational Exposure Survey (NOES) (1981-83) has statistically estimated that 22,107 workers, including 3,881 women, are exposed to pentachlorophenol in the USA(1). The NIOSH survey indicates that major occupational exposure is to workers in the electric services industry (wood preservative)(2). 25 wood preservative factories avg 0.012 ppb(2). Elevated levels were found in workers' urine and serum(2). Aerial spraying of farm crops gave rise to levels of pentachlorophenol of 0.9 mg/cu m in the cockpit of the spray plane, 38 mg/cu m in the vicinity of the signal man and 1-4 mg/cu m outside the treated field(3). At a sawmill in Finland, urine from exposed workers contained pentachlorophenol at concns from not detected to 15.9 ng/mg creatinine(4). [R226] *Major human exposure will be workers or other people who handle or breathe air near wood that has been preserved with pentachlorophenol and through consumption of food that contains the pesticide(SRC). General water and air contamination are not likely sources of human exposure. Results of an environmental partitioning model indicate that ingestion of food accounts for 99.9% of human exposure to pentachlorophenol(1,SRC). [R227] AVDI: *Pentachlorophenol partitions mainly into soil (96.5%), and food chains, especially fruits, vegetables and grains, account for 99.9% of human exposure to pentachlorophenol. The long-term, avg daily intake of pentachlorophenol is estimated to be 16 ug/day(1). Air intake (assume 0) - 0; Water intake (assume 0) - 0; Food intake - 0.014(2), 3.6(3), 16(4) ug(SRC). [R228] BODY: *BLOOD: 15 ppb(1), 10-120 ppb in users of PCP-contaminated water(2). Serum of 123 residents of PCP-treated log homes ranged from 69-1340 ppb, 420 ppb mean, while 34 controls ranged from 15-75 ppb, 40 ppb(3). Serum levels in 25 occupationally-exposed workers in 5 workplaces ranged from 26 to 84,900 ppb(3). Medium serum PCP levels in 4 of the workplaces ranged from 83 to 490 ppb, while in the chemical packaging area of a chemical plant it was 62,000 ppb(3). Avg serum concn (of pentachlorophenol) of 7 workers continuously exposed to chlorophenols at 2 saw mills was 0.84-0.85 ppm(4). Concns of pentachlorophenol in the blood serum and urine of workers involved either with the production of pentachlorophenol or with the treatment of wood with pentachlorophenol have been measured(5). Urine of workers responsible for lumber dipping, spraying or brushing contained pentachlorophenol at mean concns from 1.31 to 2.83 mg/l (blood serum mean=5.14 mg/l); urine from an individual in the office at a lumber yard contained 0.06 mg/l pentachlorophenol (blood serum mean=0.65 mg/l). Individuals involved with pentachlorophenol production had mean blood serum and urine levels of 0.72-2.38 mg/l and 4.73 mg/l, respectively(5). Adipose tissue from 58 people (not occupationally exposed) from southern and northern Finland contained pentachlorophenol at a median concn of 0.002 ug/g residue fat; 75-81.8% of the samples were positive(6). 84.6% of the liver samples were positive for pentachlorophenol with a median concn of 0.004 ug/g(6). [R229] *HUMAN MILK: Bavaria, Germany - 0.03-2.83 ppb - 21 donors(1). Milk from 10 to 20 Swedish women, from 1972 to 1989, contained pentachlorophenol at 0.0125 to 0.036 ug/g fat(8). URINE: 85% pos over 400 samples 6.3 ppb mean, 193 ppb max(2). Urine of 118 residents of PCP-treated log homes ranged from 1-340 ppb, 69 ppb mean, while 143 controls ranged from 1-7 ppb, mean 3.4 ppb(3). All urine samples from 197 Arkansas children contained pentachlorophenol(4). The median and max pentachlorophenol concn was 14 and 240 ppb. SEMINAL FLUID: 20-70 ppb(2), 100-200 ppb(5). ADIPOSE TISSUE: 250-500 ppb(5), 23 ppb(6). The mean levels of pentachlorophenol in samples collected from the general population in Barcelona, Spain, in 1982-83 were 25 ng/ml (50 samples) in urine and 21.9 ng/ml (100 samples) in serum(7). All 87 urine samples collected randomly in Saskatchewan, Canada, contained pentachlorophenol at concns from 0.5 to 9.1 ng/mL (detection limit=0.2 ng/ml; avg=1.6 ng/ml and median=1.3 ng/mL)(9). A second study of 38 urine samples from "normal, healthy" humans living in Saskatchewan, Canada, reported pentachlorophenol concns from 0.1 to 3.6 ng/ml with an avg concn of 0.9 ng/ml and a median concn of 0.5 ng/ml(9). [R230] *Pentachlorophenol was detected during hand wipe studies of 5 children living on 3 different farms; concns ranged from 9 to 99 ng(1). The National Human Monitoring Program for Pesticides, USEPA, has shown that ~85% of all human urine samples contain pentachlorophenol at a mean of 0.0063 ppm and a max of 0.193 ppm(2). Avg concns of pentachlorophenol in tissue samples obtained from 8 humans from western Oregon were as follows: testis, 1.087 ppm; kidney, 0.953 ppm; prostate, 0.838 ppm; liver, 0.592 ppm; omentum fat, 0.029 ppm; subcutaneous fat, 0.017 ppm; perinephric fat, 0.016 ppm(2). [R231] *A study of serum and urine pentachlorophenol (87865) (PCP) concentrations in persons living in log homes and workers occupationally exposed to PCP was conducted. The study group consisted of 35 persons exposed to PCP in six workplaces and 123 persons living in 45 homes constructed of PCP treated logs. The comparisons consisted of 143 persons living in conventional homes and not occupationally exposed to PCP. Urine and blood samples were collected and analyzed for PCP. Among the comparisons, urine PCP concentrations ranged from 1 to 17 ppb, mean 3.4 ppb. Serum samples from 34 comparisons ranged from 15 to 75 ppb, mean 40 ppb. In persons living in PCP treated log homes, serum PCP concentrations ranged from 69 to 1340 ppb, mean 420 ppb. The serum PCP concentrations decreased with increasing age. Subjects in the 2 to 7 year old group had significantly higher serum PCP concentrations than those over 15 years old. The serum PCP concentrations in children 2 to 15 years old averaged 1.7 to 2.0 times that of their parents. Repeat blood samples taken from ten persons residing in homes in which the logs were coated with a sealant showed that sealing the logs resulted in decreased serum PCP concentrations. Urine PCP concentrations ranged from 1 to 340 ppb, mean 69 ppb. When the urine PCP concentrations were corrected for creatinine concentrations, they correlated well with the serum PCP concentrations. Serum PCP concentrations in the PCP workers ranged from 26 to 84900 ppb. The lowest concentrations occurred in workers constructing homes from PCP treated logs and the highest in workers exposed to PCP in chemical factories. Urine PCP concentrations in four workers ranged from 2400 to 13800 ppb, mean 10000 ppb. [R232] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +2.5 mg/cu m [R49, 242] ADI: *EPA RfD= 0.03 mg/kg [R233] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 0.5 mg/cu m. Skin Designation. [R234] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.5 mg/cu m, skin. [R49, 242] TLV: +8 hr Time Weighted Avg (TWA): 0.5 mg/cu m, skin [R72, 2002.47] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R72, 2002.6] +Biological Exposure Index (BEI): Determinant: total pentachlorophenol in urine; Sampling Time: prior to last shift of workweek; BEI: 2 mg/g creatinine. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. [R72, 2002.92] +A3: Confirmed animal carcinogen with unknown relevance to humans. [R72, 2002.47] +Biological Exposure Index (BEI): Determinant: free pentachlorophenol in plasma; Sampling Time: end of shift; BEI: 5 mg/l. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. [R72, 2002.92] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Chlorophenols is produced, as an intermediate or final product, by process units covered under this subpart. /Chlorophenols/ [R235] +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Pentachlorophenol is included on this list. [R236] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 1 ug/l [R237] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 220 ug/l [R237] +(ME) MAINE 1 ug/l [R237] +(MN) MINNESOTA 3 ug/l [R237] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. [R238] +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R239] +The criterion level for pentachlorophenol in water is 30 ug/l. [R240] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R241] RCRA: *D037; A solid waste containing pentachlorophenol may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R242] *F027; Discarded unused formulations containing tri-, tetra-, or pentachlorophenol or discarded unused formulations containing compounds derived from these chlorophenols are classified as a hazardous waste from a nonspecific source and must be managed according to Federal and/or State hazardous waste regulations. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (see 40 CFR 261.5). [R243] FIFR: *Criteria of concern: oncogenicity, mutagenicity, and teratogenicity. Action: In order to avoid concellation, registrants must adhere to the terms and conditions of the Federal Register notices for ... pentachlorophenol ... . Application: Wood preservatives (wood uses only). References: 49 FR 28666 July 13, 1984; 51 FR 1334 January 10, 1986. [R244] *Criteria of concern: oncogenicity, mutagenicity, and teratogenicity. Action: Cancelled, all products for pentachlorophenol products used in paper mills in the wet end of the paper making process ... Cancelled, any of the retained registrations for pentachlorophenol uses in cooling towers, pulp paper mills, and oil wells ... . Application: Wood preservatives (nonwood uses only). References: 50 FR 41943 October 16, 1985; 53 FR 5524 February 24, 1988; 53 FR 24787 June 30, 1988. [R244] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Pentachlorophenol is found on List B. Case No: 2505; Pesticide type: insecticide, fungicide, antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Pentachlorophenol; Data Call-in (DCI) Date(s): 01/06/92, 08/04/88, 05/30/86; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R245] FDA: *Pentachlorophenol is an indirect food additive for use only as a component of adhesives. [R246] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Commercially available air sampling tubes were evaluated for personnel sampling of several pesticides. Commercial Chromosorb 102 sorbent air sample tubes designed into 66 and 33 mg portions separated by either glass wool or polyurethane plugs were used. [R247] *This paper presents the analytical results of personal breathing zone, area air, and surface wipe samples collected at a typical pentachlorophenol manufacturing plant. The personal breathing zone samples showed that workers were exposed to hexachlorobenzene concentrations ranging from less than 0.0001 to 0.12 mg/cu m. Area air samples taken throughout the manufacturing plant showed that hexachlorobenzene concentrations ranged from less than 0.0001 to 0.63 mg/cu m. Surface wipe samples showed contamination ranging from less than 0.1 to 3.7 micrograms/wipe. [R2] *EPA Method 8040. For the detection of phenolic compounds, a representative sample (solid or liquid) is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Maximum sample holding time until extraction is 7 days, after extraction is 40 days. [R248] *NIOSH Method 5512. Analyte: Pentachlorophenol. Matrix: Air. Sampler: Filter and bubbler (mixed cellulose ester membrane with stainless steel backup screen/ethylene glycol). Flow Rate: 0.5 to 1.0 l/min: Sample Size: 180 liters. Shipment: Place filter in bubbler containing 15 ml ethylene glycol after sampling. Sample Stability: At least 8 days at 25 deg C. [R249, p. 5512-1] *NIOSH Method 230. Analyte: Pentachlorophenol. Matrix: Urine. Procedure: Benzene extraction. Flow Rate: Not given. Sample Size: 2 ml. [R250, p. 230-1] *NIOSH Method 5297. Analyte: Pentachlorophenol. Matrix: Air. Procedure: Filter and bubbler collection, ethylene glycol, extraction. Flow Rate: 1 to 5 l/min. Sample Size: 180 liters. [R250, p. 5297-1] *NIOSH Method 8303. Analyte: Pentachlorophenol. Specimen: Urine end of shift mid to late in work week. Volume: 100 ml in polyethylene bottle. Preservative: 2 to 3 drops concentrated hydrochloric acid acid after collection. Shipment: Ship frozen in dry ice. Sample Stability: 40 days if kept frozen. [R249, p. 8303-1] *NIOSH Method 8001. Analyte: Pentachlorophenol. Specimen: Whole blood in 5 ml tubes. Volume: 5 ml. Preservative: None. Shipment: Polyethylene shippers with sample container kept at 10 deg C. Sample Stability: Unknown. [R249, p. 8001-1] ALAB: *DETECTED IN RIVER AND WASTE WATERS BY UV AND IR SPECTROPHOTOMETRY. DETECTED IN SEDIMENT, SEWAGE AND SOIL BY GAS CHROMATOGRAPHY WITH ELECTRON CAPTURE DETECTION. [R251] *Negative chemical ionization mass spectrometry has been used to examine a commercial pentachlorophenol formulation in a series of environmental and human samples. [R27, 953] *PENTACHLOROPHENOL WAS DETECTED IN WOOD SHAVINGS (10 UG/KG) BY GAS CHROMATOGRAPHY/ELECTRON CAPTURE DETECTION. EXTRACTION/CLEANUP PROCEDURE: DIGEST (POTASSIUM HYDROXIDE), ACIDIFY, STEAM DISTILL, EXTRACT (TOLUENE), ETHYLATE. [R252] *Product analysis is by titration with alkali. Residues may be determined by colorimetry of derivatives. [R30, 642] *EPA Method 3540. Soxhlet Extraction. A solid sample is mixed with anhydrous sodium sulfate and extracted using an appropriate solvent in a Soxhlet extractor. The sample is then dried and concentrated using a Kuderna-Danish apparatus. This is a procedure for extracting nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. [R253] *EPA Method 3550. Sonication Extraction. A 2- to 3-g solid sample is mixed with anhydrous sodium sulfate to form a free-flowing powder, then solvent extracted using a horn-type sonicator, followed by vacuum filtration or centrifugation for organic components of equal or less than 20 mg/kg. This method is applicable to the extraction of nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. Interferences include chlorofluorocarbons and methylene chloride. [R253] *EPA Method 8040. Method for the determination of phenols in solid waste by gas chromatography with flame ionization detection (FID) or derivatization to pentafluorobenzyl- bromide (PFB) derivatives followed by gas chromatography with electron capture detection (ECD). ECD is used to reduce detection limits of some phenols and/or interferences. Under the prescribed conditions for pentachlorophenol, the method detection limit is 0.59 ug/l using FID and 7.4 ug/l using ECD. Precision and method accuracy were found to be directly related to analyte concentration and essentially independent of the sample matrix. [R253] *EPA Method 8250. Packed Column Gas Chromatography/Mass Spectrometry Technique for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soil, and groundwater. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride and capable of being eluted with derivatization as sharp peaks from a gas chromatographic packed column. Under the prescribed conditions, pentachlorophenol has a detection limit of 3.6 ug/l. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R253] *EPA Method 515. Capillary Column Gas Chromatography with electron capture detection for the determination of chlorinated herbicides in drinking water. For pentachlorophenol the estimated detection limit is 0.0005 ug/l, and the method detection limit is not given. Using the packed column, mean recovery is 63% with a standard deviation of 11% with a spike level of 1.01 ug/l in reagent water. Using a capillary column, mean recovery, standard deviation, and spike level are not given. [R254] *Method 6420 B. Liquid - Liquid Extraction GC with flame ionization detection or derivatization and ECD. The method is applicable to the determination of a wide variety of phenols including pentachlorophenol. The method detection limit is 7.4 ug/l using flame ionization detection and 0.59 ug/l using ECD. [R255] *Method 6420 C. Liquid - Liquid Extraction GC/MS for the determination of phenols including pentachlorophenol in water and wastewater. For pentachlorophenol the method detection limit is 3.6 ug/l. Precision and method bias were found to be related directly to the compound concentration and essentially independent of the sample matrix. [R256] *EPA Method 604. GC Method with flame ionization detection. This method is applicable for analysis of phenols including pentachlorophenol in municipal and industrial discharges. Under the prescribed conditions for pentachlorophenol, the method has a detection limit of 7.4 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R257] *EPA Method 625. GC/MS for the analysis of acid/base/neutral extractables including pentachlorophenol in municipal and industrial discharges. Under the prescribed conditions for pentachlorophenol, the method has a detection limit of 3.6 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. Interferences: PCBs. [R257] *EPA Method 1625. Isotope Dilution Capillary Column GC/MS for the determination of semivolatile organic compounds in municipal and industrial discharges. By adding a known amount of an isotopically labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If isotopically labeled compounds are not available, an internal standard method is used. Under the prescribed conditions for both the isotopically labeled and unlabeled pentachlorophenol, the method has a minimum detection level of 50 ug/l. [R257] *EPA 8270. Capillary Column GC/MS. This method is used for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and groundwater. This method is applicable to quantify most acidic, basic, and neutral organic compounds that are soluble in methylene chloride and are capable of being eluted without derivatization as sharp peaks from a capillary column (DB-5 or equivalent). The Practical Quantitation Limit for pentachlorophenol is 50 ug/l in ground water and 3300 ug/kg in low soil/sediment. The precision and a method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R253] *NIOSH Method 3297. Analyte: Pentachlorophenol. Matrix: Air. Procedure: HPLC Method Evaluation: Method was validated over the range of 0.2654 to 1.131 mg/cu m using a 190 l sample. Method detection limit: Not given. Precision (CVT): 0.072. Interferences: No specific interferences. [R250, p. 3297-1] *Most of the analytical methods used today involve acidification of the sample to convert pentachlorophenol to its nonionized form, extraction into an organic solvent, possible cleaning by back-extraction into a basic solution, and determination by gas chromatography with ECD or other chromatographic methods as ester or ether derivatives. Depending on sampling procedures and matrices, detection limits as low as 0.05 ug/cu m in air and 0.01 ug/L in water can be achieved. [R10] *AREAL Method IP-8. Determination of Organochlorine Pesticides in Indoor Air. Range= 0.01 ug/cu m indoor air. [R258] *AREAL Method TO-10. Determination of Organochlorine Pesticides In Ambient Air Using Low Volume Polyurethane Foam (PUF) Sampling With Gas Chromatography/ Electron Capture Detector (GC/ECD). [R259] *CLP Method LC_SV. The Analysis of Water for Low Concentration Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry. Contract required quantitation limit=20 ug/l. [R260] *CLP Method MC_SVOA. Analysis of Semivolatile Organics in Multi- Concentration Water Samples by Gas Chromatography with a Mass Spectrometer. Contract required quantitation limit= 20 ug/l. [R260] *EAD Method 1653. Chlorinated Phenolics in Wastewater by In-situ Acetylation and GCMS. Method detection limit= 0.280 ug/l. [R260] *EMSLC Method 515.1. Determination of Chlorinated Acids in Water by Gas Chromatography with an Electron Capture Detector. Revision 4.0. Estimated detection limit= 0.076 ug/l. [R261] *EMSLC Method 525.1. Determination of Organic Compounds in Drinking Water by Liquid-Solid Extraction and Capillary Column Gas Chromatography and Mass Spectrometry. Revision 2.2. Method detection limit=0.30 ug/l. [R261] *EMSLC Method 555. Determination of Chlorinated Acids in Water by High Performance Liquid Chromatography with a Photodiode Array Ultraviolet Detector. Revision 1.0. Method detection limit= 1.6 ug/l. [R262] *NCASI Method CP-85.01. Determination of Chlorinated Phenolics in Water by In-Situ Acetylation using Gas Chromatography with Electron Capture Detection. Lower detection limit= 0.6 ug/l. [R260] *OSW Method 8151. Determination of Chlorinated Herbicides by GC Using Methylation Or Pentafluorobenzylation Derivatization: Capillary Column Technique. Estimated detection limit= 0.076 ug/l; 0.160 ug/kg in soil/waste. [R263] *EAD Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. Method detection limit= 210 ug/kg. [R260] *CLP Method MC_SVOA. Analysis of Semivolatile Organics in Low Concentration Soil Samples by Gas Chromatography with a Mass Spectrometer. Contract required quantitation limit= 830 ug/kg; 25000 ug/kg (for medium concentrations). [R260] *EPA-B Method PMD-PCP. Determination of Pentachlorophenol by High Performance Liquid Chromatography. [R260] *EPA-B Method PMD-PCP. Determination of Pentachlorophenol by Gas Chromatography (FID-IS) Using On-Column Derivatization with MSFTA. [R260] *FDA Method 221.1. Method for Chlorophenoxy Acids and Pentachlorophenol by Gas Chromatography. [R260] *FDA Method 221.1. Method for Chlorophenoxy Acids and Pentachlorophenol by Gas Chromatography. [R260] *NIOSH Method 8001. Determination of Pentachlorophenol in Blood by Gas Chromatography with Electron Capture Detection. Range= 0.01 ug/ml. [R264] *NIOSH Method 8303. Determination of Pentachlorophenol in Urine by Gas Chromatography with Electron Capture Detection. [R264] *NIOSH Method 5512. Determination of Pentachlorophenol by High Performance Liquid Chromatography with UV Detection. Detection limit= 0.010 ug/cu m. [R264] *AOAC Method 985.24. Pentachlorophenol in Gelatin. Gas Chromatographic Method. [R265] CLAB: *A method incorporating hydrolysis is essential to relate pentachlorophenol urinary excretion to absorbed dose. HPLC with a fixed wavelength detector at 313 nm was used. [R266] *Chlorinated phenols in urine are ... detected by electron-capture gas chromatography using a double support-bonded diethylene glycol succinate column ... Avg recoveries of > 80% were obtained. /Chlorinated phenols/ [R267] *DETECTED IN /NON-HUMAN/ MILK (5 UG/KG); BIOLOGICAL TISSUE (0.1 UG/KG); HUMAN ADIPOSE TISSUE (5 UG/KG), PLASMA (20 UG/L), BLOOD AND URINE (10 UG/L) BY GAS CHROMATOGRAPHY FITTED WITH ELECTRON CAPTURE DETECTION. [R268] *Negative chemical ionization mass spectrometry has been used to examine a commercial pentachlorophenol formulation in a series of environmental and human samples. [R27, 953] *Pentachlorophenol has been found to be present in human adipose tissue as an ester of palmitic acid. Levels of pentachlorophenol in human fat tissue range from 4-250 ppb. Current extraction procedures do not hydrolyze the ester bond, eliminating pentachlorophenol present in ester form. New procedures for extraction and simultaneous monitoring of pentachlorophenol and palmitoylpentachlorophenol or a procedure designed that would hydrolyze palmitoylpentachlorophenol before extraction of pentachlorophenol would accurately assess pentachlorophenol exposure. [R269] *A GC method for determining pentachlorophenol in biological fluids was developed. Samples analyzed were urine, water, serum, or fish, tissue. Urine and water samples were digested at 100 deg C for 1 hr in a sealed vial and later were extracted with toluene. Serum samples were acidified and then digested and extracted as above. Fish tissue washomogenized, acidified to pH 2, and rehomogenized; the emulsion was extracted with methylene chloride, extracted with alkali, and finally with toluene and digested as above. All samples were treated with an internal standard, diluted as appropriate, and subjected to gas chromatography at 300 deg C using fused silica capillary columns. Samples were injected at 1 microliter volume and detection of compounds was facilitated by electron capture at 350 deg C. A calibration standard of pure pentachlorophenol was run; the time of chromatographic run was 1 hr. Good resolution was achieved. Concentrations as low as 0.5 ppb wre detected by this method. The precision of the method was 1.2% for pentachlorophenol. The upper limit of detection was 200 ppb. Samples of water, urine, serum, and fish tissue contained a detectable concentration. Corrections were made to compensate for instrument drift. This method offers high sensitivity and precision for examining pentachlorophenol. [R270] *A gas chromatographic procedure for determining pentachlorophenol in blood and urine was described. Two ml samples of urine and 10 ml samples of blood were used. Theblood and urine samples were analyzed on a GC column fitted with a (63)Ni electron capture detector. [R271] *NIOSH Method 230. Analyte: Pentachlorophenol. Specimen: Urine. Procedure: Gas chromatography. For pentachlorophenol this method has a working range from 20 to 180 ug for a 2 -ml urine sample. The precision/RSD is 0.15 (est). Applicability: In urine. Interference: Chlorinated or other electrophilic organic compounds having the same chromatographic retention time as pentachlorophenol. [R272] *NIOSH Method 8303. Analyte: Pentachlorophenol. Specimen: Urine end of shift, mid to late in work week. Procedure: Gas chromatography, electron capture detector. For pentachlorophenol this method has an estimated detection limit of 1 ug/l/sample. The presision/RSD is 0.03 and the recovery is 0.947. The working range is 1 to 1000 ug/l for a 100-ml sample. Applicability: This method measures free and conjugated pentachlorophenol after hydrolysis and is useful when monitoring chronic pentachlorophenol exposure via skin contact, ingestion or inhalation. Urine contains about 82% free pentachlorophenol and 13% pentachlorophenol glucuronide. Interferences: Numerous potential interferences from urine include chloronaphthylenes, polychlorinated biphenyls and diuron. [R249, p. 8303-1] *NIOSH Method 8001. Analyte: Pentachlorophenol. Specimen: Whole blood in 5 ml tubes. Procedure: Gas chromatography, electron capture detector. For pentrachlorophenol this method has an estimated detection limit of 0.001 ug pentachlorophenol/ml blood. The presision/RSD is 0.02 and the recovery is 90%. The working range is 0.01 to 1 ug pentachlorophenol/ml blood for a 5-ml sample. Interferences: Chloronaphthalenes, polychlororinated biphenyl and diuron are also hexane-extractable but are separated from pentachlorophenol by column. [R249, p. 8001-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: ARSENAULT RD; PROC AM WOOD-PRESERV ASSOC 72: 122-48 (1976). REVIEW WITH 118 REFERENCES ON ENVIRONMENTAL FATE, INDUSTRIAL SAFETY AND RESP BREAKDOWN PRODUCTS OF PENTACHLOROPHENOL. U.S. Dept of Int, Fish and Wildlife Serv; Metabolism of Pesticides-Update III U.S. Dept Int Special Sci Report- Wildlife No 232 (1980) NRC ASSOC COMM SCI CRITERIA ENVIRON QUAL CAN; CHLORINATED PHENOLS: CRITERIA FOR ENVIRONMENTAL QUALITY; NATL RES COUNC CAN ASSOC COMM SCI CRITERIA ENVIRON QUAL PUBL, ISSUE (18578): 17-191 (1982) USEPA; Pentachlorophenol (Non-Wood Uses): Special Review Document No. 2/3 (1987) EPA/540/9-87/124 USEPA; Ambient Water Quality Criteria Document: Pentachlorophenol (1986) EPA 440/5-86/009 O'Donoghue JL; Neurotox Ind Commer Chem 2: 139-53 (1985). A review with 157 references on the neurotoxicity of phenol, pentachlorophenol, hexachlorophene, and 2,4-dichlorophenoxyacetic acid. USEPA; Drinking Water Criteria Doc: Pentachlorophenol (Final Draft) (1984) EPA/600/X-84/177-1 Exon JH; Vet Hum Toxicol 26 (6): 508-20 (1984). A review of chlorinated phenols. NCI/DCE; Monograph on Human Exposure to Chemicals in the Workplace: Pentachlorophenol. SRC-TR-84-535 (1984) Contract N01-CP-26002-03. The report presents a summary and evaluation of information relevant to an occupational hazard assessment of pentachlorophenol. Grimm HG; VDI-Ber 609: 69-88 (1987). Review of pentachlorophenol pollution along with human exposure data. Rosner G; Staub-Reinhalt Luft 47 (7-8): 198-203 (1987). A review of pentachlorophenol-dioxin health hazards. Choudhury H et al; Toxicol Indust Health 2 (4): 483-571 (1986). The Environmental Protection Agency (EPA) health and environmental effects profile of pentachlorophenol is presented. Physical and chemical properties of pentachlorophenol are summarized. Production and uses of pentachlorophenol are discussed. ... Govt Reports Announcements and Index 15: 1-74 (1987) NTIS/PB87-859914. This bibliography contains citations concerning laboratory and field studies regarding the toxicity of the pesticide pentachlorophenol. Topics include dosage effects, uptake, bioaccumulation, and metabolism by various organisms, detection methods, and synergistic effects with other harmful compounds. Cases of human poisoning and occupational hazards associated with pentachlorophenol are also treated. Alberta Community and Occupat Health, Medical Servics; Medical Monitoring of Workers Exposed to Pentachlorophenol p.8 (12/86). This guideline is for the prevention of adverse effects and includes /the following/: background on pentachlorophenol; entry, metabolism and excretion; health effects; protective measures; health and biological monitoring; treatment of pentachlorophenol intoxication. Govt Reports Announcements and Index 19: 1-64 (1987) NTIS/PB-87-863767. This bibliography contains citations concerning toxicological studies of pentachlorophenol and its effects on humans, aquatic and laboratory animals, and livestock. Topics include pentachlorophenol determination and analysis methods, pentachlorophenol accumulation in animals, assessment and control of PCP contamination in waters and soils, health risk assessment of pesticides and insecticides, and pentachlorophenol degradation and decomposition techniques. Biochemical studies of occupational exposure and clinical reports are included. Govt Reports Announcements and Index 18: 1-38 (1987) NTIS/PB87-863528. This bibliography contains citations concerning toxicology studies of pentachlorophenol and its effects on humans, and aquatic and laboratory animals. Topics include pentachlorophenol determination and analysis methods, water quality criteria, health risk assessment of pentachlorophenol pesticides and insecticides, human exposure in the workplace and hazard assessment, and techniques of pentachlorophenol degradation and destruction. Reports on pentachlorophenol wood preservatives are also included. Smejtek P; J Membr Sci 33 (2): 249-68 (1978). A discussion and review ... on the membrane toxicity of pentachlorophenol, a herbicide and wood preservative. Experimental data on membrane-pentachlorophenol interactions from multiple studies were compared. These data include membrane electroconductivity, toxicity, microelectrophoresis, and spectrophotometry. DHHS/ATSDR; Toxicological Profille for Pentachlorophenol (Update) (1994) ATSDR/TP-93/13 DHHS/NTP; Toxicology and Carcinogenesis Studies of Two Pentachlorophenol Technical Grade Mixtures in B6C3F1 (Feed Studies) Mice Technical Report Series No. 349 (1989) NIH Publication No. 89-2804 SO: R1: CHEMICAL PRODUCTS SYNOPSIS: Pentachlorophenol, 1983 R2: Marlow DA; IARC Sci Publ 77: 161-9 (1986) R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V53 374 (1991) R4: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. 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Weinheim, Federal Republic of Germany. 1985.446 R42: Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants p 87-4 EPA-440/4-79-029b (1979) R43: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R44: Hellman H; Fresenius' Z Anal Chem 328: 475-79 (1987) R45: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000 R46: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 49-101 R47: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 829 R48: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R49: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R50: USEPA; Ambient Water Quality Criteria Doc: Pentachlorophenol p.C-32 (1980) EPA 440/5-80-065 R51: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 869 (1981) R52: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 706 R53: Silkowski JB et al; Am Ind Hyg Assoc J 45 (8): 501-4 (1984) R54: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R55: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). 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Food and Drug Administration, Washington, DC (1989) (4) Hattermer-Frey HA, Travis CC; Arch Environ Contam Toxicol 18: 482-9 (1989) R229: (1) IARC; Some Halogenated Hydrocarbons 20: 303-25 (1979) (2) Morgade C et al; Bull Environ Contam Toxicol 24: 257-64 (1980) (3) Cline RE et al; Arch Environ Contam Toxicol 18: 475-81 (1989) (4) Pekari K et al; Int Arch Occup Environ Health 63: 57-62 (1991) (5) IARC; Occupational Exposures in Insecticide Application, and Some Pesticides 53: 371-402 (1991) (6) Mussalo-Rauhamaa H et al; Sci Total Environ 83: 161-72 (1989) R230: (1) Gebefugi I, Korte F; Chemosphere 12: 1055-60 (1983) (2) IARC; Some Halogenated Hydrocarbons 20: 303-25 (1979) (3) Cline RE et al; Arch Environ Contam Toxicol 18: 475-81 (1989) (4) Hill RH Jr et al; Arch Environ Contam Toxicol 18: 469-74 (1989) (5) Kuehl DW, Dougherty RC; Environ Sci Technol 14: 447-9 (1980) (6) Morgade C et al; Bull Environ Contam Toxicol 24: 257-64 (1980) (7) IARC; Occupational Exposures in Insecticide Application, and Some Pesticides 53: 371-402 (1991) (8) Noren K; Sci Total Environ 139/140: 347-55 (1993) (9) Thompson TS, Treble RG; Bull Environ Contam Toxicol 56: 520-26 (1996) R231: (1) Geno PW et al; Arch Environ Contam Toxicol 30: 132-38 (1996) (2) Wagner SL et al; Arch Environ Contam Toxicol 21: 596-606 (1991) R232: Cline RE et al; Archives of Environmental Contamination and Toxicology 18 (4): 475-81 (1989) R233: USEPA/OPP; Health Effects Div RfD/ADI Tracking Report p.44 (8/26/91) R234: 29 CFR 1910.1000 (7/1/98) R235: 40 CFR 60.489 (7/1/97) R236: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R237: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R238: 40 CFR 401.15 (7/1/90) R239: 40 CFR 116.4 (7/1/90) R240: USEPA; Ambient Water Quality Criteria Doc: Pentachlorophenol p.C-39 (1980) EPA 440/5-80-065 R241: 40 CFR 302.4 (7/1/97) R242: 40 CFR 261.24 (7/1/97 R243: 40 CFR 261.31 (7/1/97) R244: Environmental Protection Agency/OPTS. Suspended, Cancelled, and Restricted Pesticides. 5th Ed. Washington, DC: Environmental Protection Agency, February 1990. R245: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.197 (Spring, 1998) EPA 738-R-98-002 R246: 21 CFR 175.105 (4/1/91) R247: Thomas TC, Nishioka YA; Bull Environ Contam Toxicol 35 (4): 460-5 (1985) R248: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R249: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R250: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R251: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 310 (1979) R252: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 312 (1979) R253: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R254: USEPA; Methods for the Determination of Organic Compounds in Finished Drinking Water and Raw Source Water (1986) R255: Franson MA, ed; Standard Methods for the Examination of Water and Wastewater, 17th ed p.6-137 (1989) R256: Franson MA, ed; Standard Methods for the Examination of Water and Wastewater, 17th ed. p.6-146 (1989) R257: 40 CFR 136, App. A (7/1/90) R258: USEPA/Atmospheric Research and Exposure Assessment Laboratory; Compendium of Methods for the Determination of Air Pollutants in Indoor Air, Draft, September 1989, Frank McElroy, U.S. Environmental Protection Agency, Atmospheric Research and Exposure Assessment Laboratory (MD-77), Research Triangle Park, NC 27711 as cited in USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC #4082. Rockville, MD: Government Institutes (1997) R259: USEPA/Atmospheric Research and Exposure Laboratory (AREAL); Compendium of Methods for the Determination of Toxic Organic Compounds in Ambient Air (1988) EPA/600/4-89/017 R260: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC #4082. Rockville, MD: Government Institutes (1997) R261: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water, EPA/600/4-88/039, December 1988, Revised July 1991 R262: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water, Supplement II, EPA/600/R-92/129, August 1992 R263: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R264: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R265: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. V1 308 R266: Drummond I et al; Int Arch Occup Environ Health 50 (4): 321-8 (1982) R267: Edgerton TR et al; Anal Chem 52 (11): 1774-7 (1980) R268: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 311 (1979) R269: Ansari GAS et al; Bull Environ Contam Toxicol 34 (5): 661-7 (1985) R270: Kalman DA; J Chromatog Sci 22 (10): 452-5 (1984) R271: Atuma SS, Okor DI; Bull Environ Contam Toxicol 35 (3): 406-10 (1985) R272: Aronson, C.E. (ed.). Veterinary Pharmaceuticals and Biologicals, 1982-1983. Edwardsville, Kansas: Veterinary Medicine Publishing Co., 1983.,p. 230-1 RS: 312 Record 97 of 1119 in HSDB (through 2003/06) AN: 924 UD: 200303 RD: Reviewed by SRP on 11/07/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIETHANOLAMINE- SY: *AMINE,-DIETHYL,-2,2-DIHYDROXY-; *BIS- (HYDROXYETHYL)AMINE; *BIS(2-HYDROXYETHYL)AMINE; *DEA-; *DIAETHANOLAMIN- (GERMAN); *DIETHANOLAMIN- (CZECH); *N,N-DIETHANOLAMINE-; *DIETHYLAMINE,-2,2'-DIHYDROXY-; *DIETHYLOLAMINE-; *2,2'-DIHYDROXYDIETHYLAMINE-; *Di(2-hydroxyethyl)-amine; *DIOLAMINE-; *ETHANOL,-2,2'-IMINOBIS-; *ETHANOL,-2,2'-IMINODI-; *2-((2-HYDROXYETHYL)AMINO)ETHANOL; *2,2'-IMINOBISETHANOL-; *IMINODIETHANOL-; *2,2'-IMINODIETHANOL-; *2,2'-IMINODI-1-ETHANOL-; *NCI-C55174- RN: 111-42-2 MF: *C4-H11-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ETHYLENE OXIDE AND EXCESS AMMONIA, FOLLOWED BY FRACTIONATION OF THE THREE ETHANOLAMINES (MONO, DI, AND TRI) [R1] FORM: *DIETHANOLAMINE CONDENSATES ARE OFFERED COMMERCIALLY AS ONE MOLE OF FATTY ACID WITH 2 MOLES OF DIETHANOLAMINE [R2] MFS: *ALLIED CHEM CORP, SPECIALTY CHEMS DIV, ORANGE, TEX (ON STAND-BY) (MONO, DI, AND TRIETHANOLAMINES) [R1] *DOW CHEM USA, FREEPORT, TEX, MIDLAND, MICH (MONO, DI, AND TRIETHANOLAMINES) [R1] *OLIN CORP, DESIGNED PRODUCTS DIV, BRANDENBURG, KY (MONO, DI, AND TRIETHANOLAMINES) [R1] *TEXACO INC, JEFFERSON CHEM CO, INC, SUBSID, PORT NECHES, TEX (MONO, DI, AND TRIETHANOLAMINES) [R1] *UNION CARBIDE CORP, CHEMS AND PLASTICS DIV, SEADRIFT, TEX (MONO, DI, AND TRIETHANOLAMINES) [R1] OMIN: *DIETHANOLAMINE CAN BE USED WITH CRACKING GASES AND COAL OR OIL GASES WHICH CONTAIN CARBONYL SULFIDE THAT WOULD REACT WITH MONOETHANOLAMINE. /IT IS USED/ IN MFR OF SURFACE ACTIVE AGENTS USED IN TEXTILE SPECIALTIES, HERBICIDES, PETROLEUM DEMULSIFIERS. [R3] *GENERAL INDUSTRY PRODUCTION RATIOS ARE TRIETHANOLAMINE 37%; MONOETHANOLAMINE 32% AND DIETHANOLAMINE 31% [R4] USE: *PRODUCTION OF LUBRICANTS FOR THE TEXTILE INDUSTRY; AS RUBBER CHEMICALS INTERMEDIATE; HUMECTANT AND SOFTENING AGENT; IN ORG SYNTH; /IT IS USED/ AS EMULSIFIER AND DISPERSING AGENT IN VARIOUS AGRICULTURAL CHEMICALS, COSMETICS, AND PHARMACEUTICALS. [R3] *CUTTING OILS, SHAMPOOS, CLEANERS AND POLISHES [R5] *SOLUBILIZER FOR 2,4-D [R6, 2065] *CHEM INT FOR FATTY ALKANOLAMIDES FOR LIQUID DETERGENTS AND TEXTILE CHEM; GAS CONDITIONING AGENT; CHEM INT FOR MORPHOLINE, FOR FATTY ACID SALT EMULSIFIERS, FOR ALKYL SULFATE SALT EMULSIFIERS [R1] *DEHYDRATION OF DIETHANOLAMINE PRODUCES MORPHOLINE [R7] *DIETHANOLAMINE IS USED WITH SULFOLANE IN THE SULFINOL PROCESS TO ABSORB CARBON DIOXIDE AND HYDROGEN SULFIDE GASES [R8] CPAT: *(FOR MONO, DI, AND TRIETHANOLAMINE) 46% AS AN INT FOR DETERGENTS (INCLUDING TEXTILES, TOILET GOODS, METALS AND OTHER SPECIALTY SURFACTANT USES); 28% IN GAS CONDITIONING AND PETROLEUM USE; 6% AS A CHEM INT FOR MORPHOLINE; 20% FOR MISC APPLICATIONS (INCLUDING EMULSION POLISHES AND HERBICIDES) (1975) [R1] *DETERGENTS (INCLUDING TEXTILE, TOILET GOODS, METAL AND OTHER SPECIALTY SURFACTANTS), 35 PERCENT; GAS CONDITIONING AND PETROLEUM USE, 30 PERCENT; METAL WORKING, 15 PERCENT; TEXTILES, 10 PERCENT; MISCELLANEOUS (INCLUDING AGRICULTURAL INTERMEDIATES AND CEMENT GRINDING AIDS) AND EXPORTS, 10 PERCENT (1984) /ETHANOLAMINES/ [R9] PRIE: U.S. PRODUCTION: *(1972) 4.59X10+10 G [R1] *(1975) 3.89X10+10 G [R1] *(1983) 7.54X10+10 g [R10] U.S. IMPORTS: *(1972) 6.36X10+7 G (MONO, DI, AND TRI) [R1] *(1975) 2.03X10+9 G (MONO, DI, AND TRI) [R1] *(1984) 1.40X10+9 G /MONO, DI, TRIETHANOLAMINE/ [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PRISMS [R12]; *USUALLY OFFERED AS A VISCOUS LIQUID [R3]; *CRYSTALLINE SOLID [R3]; +Colorless crystals or a syrupy, white liquid (above 82 degrees F). [R13] ODOR: *MILD AMMONIACAL [R3]; +Mild, ammonia-like odor. [R13] BP: *268.8 DEG C @ 760 MM HG [R3] MP: *28 DEG C [R14] MW: *105.14 DEN: *1.0966 @ 20 DEG C/4 DEG C [R14] DSC: *pKa= 8.88 [R6, 2040] OWPC: *log Kow= - 1.43 (est) [R15] PH: *PH OF 0.1 N AQUEOUS SOLN: 11.0 [R3] SOL: *VERY SOL IN ALC [R14]; *MISCIBLE WITH WATER, METHANOL WATER; SOL IN BENZENE: 4.2% @ 25 DEG C; IN ETHER: 0.8% @ 25 DEG C; IN N-HEPTANE: LESS THAN 0.1% @ 25 DEG C; IN CARBON TETRACHLORIDE: LESS THAN 0.1% @ 25 DEG C [R3] SPEC: *INDEX OF REFRACTION: 1.4753 @ 30 DEG C/D [R3]; *SADTLER REFERENCE NUMBER: 5830 (IR, PRISM) [R12]; *IR: 5638 (Coblentz Society Spectral Collection) [R16]; *NMR: 6575 (Sadtler Research Laboratories Spectral Collection) [R16]; *MASS: 313 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R16] VAPD: *3.65 (AIR= 1) [R17] VAP: *1.4X10-4 mm Hg at 25 deg C [R18] VISC: *351.9 CENTIPOISES @ 30 DEG C; 53.85 CENTIPOISES @ 60 DEG C; DIPOLE MOMENT: 2.81 [R3] OCPP: *DELIQUESCENT PRISMS; ONE USA GAL WEIGHS 9.09 LB @ 30 DEG C [R3] *VAPOR PRESSURE: LESS THAN 0.01 MM HG @ 20 DEG [R6, 2065] *Henry's Law constant= 3.9X10-11 atm-cu m/mol at 25 deg C (est) [R19] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *FIRE HAZARD: SLIGHT, WHEN EXPOSED TO HEAT OR FLAME; CAN REACT WITH OXIDIZING MATERIALS. [R20] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R21] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R21] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R21] FLPT: *134 deg C (Open cup) [R22] +342 deg F (172 deg C) (OC) [R21] AUTO: +1224 DEG F (662 DEG C) [R21] FIRP: *Use water spray, dry chemical, alcohol foam or carbon dioxide fire extinguishing agent. Use water to keep fire-exposed containers cool, to disperse the vapors, to flush spills away from exposure, to dillute spills to nonflammable mixtures and to prevent the spread of fires. [R22] REAC: +Oxidizers, strong acids, acid anhydrides, halides [Note: Reacts with carbon dioxide in the air. Hygroscopic (i.e., absorbs moisture from the air). Corrosive to copper, zinc, and galvanized iron]. [R23, 104] SERI: *Slight irritation of skin and mucous membranes. [R22] EQUP: *Wear butyl rubber gloves, general cartridge respirators and overalls. [R22] +Wear appropriate personal protective clothing to prevent skin contact. [R23, 105] +Wear appropriate eye protection to prevent eye contact. [R23, 105] +Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R23, 105] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R23, 105] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R23, 105] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R23, 105] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R23, 105] +Contact lenses should not be worn when working with this chemical. [R23, 105] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Since most cosmetics ingested are nontoxic, only supportive care and perhaps dilution are required. The decision to induce emesis depends on the product toxicity, quantity ingested, time since exposure, patient's weight and presence of symptoms. Most ingestions of cosmetics do not require emesis. Cationic surfactants, perborates, and substantial essential oil ingestions that exceed one to two swallows of pure solution may benefit from emesis. The risk of ethanol exposures that produce serum ethanol levels higher than 50 mg/l may be reduced if the patient receives syrup of ipecac within 1 hour. ... The use of syrup of ipecac should be considered in ingestions of hydrocarbons containing glues (eg, toluene) only when the total dose of hydrocarbon exceeds 1 to 2 ml/kg. /Ethanols/ [R24] HTOX: *BY ANALOGY WITH TRIETHANOLAMINE, DIETHANOLAMINE PROBABLY HAS LOW TOXICITY. [R25] *Diethanolamine produce mild skin irritation only in concentration above 5%; little skin sensitization develops. [R24] NTOX: *... INTRAVENOUS INJECTIONS OF ... DIETHANOLAMINE IN DOGS RESULTED IN INCREASED BLOOD PRESSURE, DIURESIS, SALIVATION, AND PUPILLARY DILATATION. ... LARGER DOSES PRODUCED SEDATION, COMA AND DEATH FOLLOWING DEPRESSION OF BLOOD PRESSURE AND CARDIOVASCULAR COLLAPSE. [R26, 3167] *ACUTE AND SUBACUTE ORAL TOXICITY ... FOR RATS IS ... GREATER THAN THAT FOR MONOETHANOLAMINE. ... MAXIMUM DAILY DOSE HAVING NO EFFECT OVER 90-DAY PERIOD IS 0.02 G/KG. DAILY DOSE OF 0.17 G/KG OVER SAME PERIOD PRODUCES MICROSCOPIC PATHOLOGY AND DEATHS AND /DOSE OF/ 0.09 G/KG CAUSES CHANGES IN LIVER OR KIDNEY WEIGHTS. [R26, 3169] *TEN PER CENT SOLUTIONS APPLIED TO RABBITS' SKIN CAUSED REDNESS. HIGHER CONCENTRATIONS CAUSED INCREASING INJURY. [R26, 3169] *UNDILUTED LIQUID AND 40% SOLN PRODUCE SEVERE EYE BURNS WHEREAS 15% PRODUCES MINOR DAMAGE. [R26, 3169] *IN ANIMALS GIVEN FATAL ORAL DOSES ... PATHOLOGY IS FOUND WITHIN GI TRACT. [R27] *ACUTE TOXICITY STUDIES SHOW THAT DIRECT CONTACT MAY IMPAIR VISION AND DENATURE SKIN UPON REPEATED APPLICATION. [R28] *APPLIED TO RABBIT CORNEA, LIQ MAY CAUSE MODERATE INJURY, GRADED 5 ON SCALE OF 1 TO 10 AFTER 24 HR, BUT IF LIQ IS WASHED OFF WITH WATER WITHIN FEW MIN, INJURY IS SLIGHT AND EYES RETURN TO NORMAL WITHIN 24 HR. [R29] *GIVEN TO RATS REPEATEDLY @ 330 MG/KG/DAY DIETHANOLAMINE CAUSED SIGNIFICANT INHIBITION OF PHOSPHATIDYL CHOLINE AND ETHANOLAMINE. REDUCTION OF CHOLINE AND ETHANOLAMINE INCORPORATION OCCURRED IN LIVER AND SYNTHESIS OF ETHANOLAMINE PHOSPHOGLYCERIDES DECLINED. [R30] *Marine diatoms (Skeletonema costatum, 10,000 cells/ml) were exposed to a series of 5 or more concn of diethanolamine for 5 days (replicated 3 times). At 548.2 mg/l diethanolamine caused a 50% reduction in the number of cells per ml, and 522.8 mg/l caused a 50% reduction in total cell volume. The no observed effect level (NOEL) was 216 mg/l for both cell measurements. [R31] +... CONCLUSIONS: Under the conditions of these 2 yr dermal studies, there was no evidence of carcinogenic activity of diethanolamine in F344/N rats admin 16, 32 or 64 mg/kg diethanolamine or in female F344/N rats admin 8, 16 or 32 mg/kg. There was clear evidence of carcinogenic activity of diethanolamine in male and female B6C3F1 mice based on incr incidences of liver neoplasms in males and females and incr incidences of renal tubule neoplasms in males. [R32] HTXV: *The estimated fatal dose of diethanolamine in humans is 20 g. [R33, 406] NTXV: *LD50 Rat oral 710 mg/kg; [R22] *LD50 Mouse ip 2,300 mg/kg; [R22] *LD50 Rat acute oral 1.82 g/kg; [R34] *LD50 Rabbit acute dermal 11.9 ml/kg; [R34] *LD50 Mouse sc 3,553 mg/kg; [R33, 403] ETXV: *TLm Mosquito fish 1800 mg/l/24 hr in turbid Oklahoma water /Conditions of bioassay not specified/; [R34] *TLm Bluegill sunfish 2100 mg/l/24 hr in tap water /Conditions of bioassay not specified/; [R34] *LC50 Goldfish 800 mg/l/24 hr at pH 9.6 /Conditions of bioassay not specified/; [R34] *LC50 Goldfish > 5000 mg/l/24 hr at pH 7 /Conditions of bioassay not specified/; [R34] NTP: +Rats: Groups of 50 male F344/N rats were admin 0, 16, 32 or 64 mg diethanolamine/kg body weight in ethanol dermally for 2 yr. Groups of 50 female F344/N rats were admin 0, 8, 16 or 32 mg diethanolamine/kg body weight in ethanol dermally for 2 yr. Mice: Groups of 50 male and 50 female B6C3F1 mice were admin 0, 40, 80 or 160 mg diethanolamine/kg body weight in ethanol dermally for 2 yr. ... Under the conditions of these 2 yr dermal studies, there was no evidence of carcinogenic activity of diethanolamine in F344/N rats admin 16, 32 or 64 mg/kg diethanolamine or in female F344/N rats admin 8, 16 or 32 mg/kg. There was clear evidence of carcinogenic activity of diethanolamine in male and female B6C3F1 mice based on incr incidences of liver neoplasms in males and females and incr incidences of renal tubule neoplasms in males. [R32] +... Diethanolamine (DEA) was ... selected for immunotoxicity studies /using female B6C3F1 mice/. ... Female B6C3F1 mice were administered diethanolamine daily for 14 days at doses of 100, 300 and 600 mg/kg. Diethanolamine was administered by gavage as a solution in sterile distilled water. ... Mice exposed to diethanolamine at doses up to and including 600 mg/kg did not have significant decreases in body weight or body weight changes when evaluated over the two week exposure period. While the thymus, spleen, and kidney were unaffected by the diethanolamine exposure, the liver (42%) weights were dose dependently increased. No effects were observed on leukocyte numbers, leukocyte differentials, mean corpuscular volume, mean corpuscular hemoglobin or mean corpuscular hemoglobin concentrations. However, the erythroid elements, erythrocytes (16%), hemoglobin (17%), hematocrit (18%) and reticulocytes (59%) were all dose dependently decreased. Serum chemistries were unaffected by diethanolamine exposure. ... Exposure to diethanolamine increased the number of B-cells (30%), and decreased the number of CD4+CD8- (18%) T-cell subsets. Total T-cells and the other T-cell subsets were not affected. Diethanolamine produced a dose-dependent decrease (58%) in the antibody-forming cell response to sheep erythrocytes at a 800 mg/kg exposure level. The proliferative response to mitogens, both Con A and LPS, were not affected. Furthermore, the proliferative response to F(ab)2 + BSF-1 was not affected nor was the proliferative response to allogeneic cells as evaluated in the MLR. Over all, the natural killer cell response was not affected; however, a dose-dependent decrease was observed in the CTL response (14%) when evaluated at the highest (25:1) effector/target ratio. A dose-dependent decrease in the cytotoxicity (21%) of resident macrophages resulted following diethanolamine exposure. However, the cytotoxicty of resident macrophages stimulated with gamma interferon was not affected nor was the cytotoxicity of peptone-elicited macrophages with or without stimulation. Peritoneal cell differentials were not affected following diethanolamine exposure. In the three host resistance studies conducted, host resistance to Listeria monocytogenes was not affected, while a decrease in host resistance was observed to Streptococcus pneumoniae and in the B16F10 melanoma tumor model ... . A no-effect level for diethanolamine in the female B6C3F1 mouse could not be established since the lowest dose administered significantly decreased the cytotoxic T lymphocyte (CTL) activity, and produced an increase in tumor burden following challenge with the B16F10 melanoma tumor. [R35] +... Female Sprague-Dawley-derived (CD(R)) rats were dosed by gavage with DEA (50, 125, 200, 250 or 300 mg/kg body weight/day) or vehicle (Pico water) on gestational days (gd) 6 through 19. The dose volume was 5ml/kg. Dose selection was based upon a previous developmental toxicity screening study in mice and general toxicity studies in mice and rats ... . In this study, 12 timed-mated rats were assigned per group. Dams were monitored at regular intervals throughout gestation and lactation for clinical signs, food and water intake, and body weight. At scheduled termination on postnatal day (pnd) 21, the following were recorded: maternal clinical condition; body, liver and paired kidney weights; and number of uterine implantation sites. Naturally delivered offspring were monitored for clinical condition on pnd 0, 4, 7, 14 and 21. Numbers of live or dead pups per litter and individual live pup body weights were recorded on pnd 0, 4, 7, 14 and 21. Gross (external) morphology was examined on pnd 0, and major organs were examined for gross pathology at scheduled necropsy on pnd 7 (culling) or pnd 21 (termination). The calculated LD10 was 218 mg/kg/day under the conditions of this study. At 200 mg/kg/day, one pregnant female was euthanized moribund on gd 22. One pregnant female at 250 mg/kg/day was euthanized moribund on gd 21 and another pregnant female in the same group was found dead on gd 15. At 300 mg/kg/day, excessive toxicity included a 26% reduction in maternal body weight (gd 12), tremors, lethargy and piloerection. Two females were sacrificed moribund on gd 11, and the remaining females in this group were terminated by gd 15. The following description of results therefore excludes the 300 mg/kg/day group. Maternal relative feed intake was decreased at greater than or equal to 200 mg/kg/day from gd 6 to 9, 9 to 12 and 12 to 15. At 250 mg/kg/day, feed intake was transiently decreased from pnd 0 to 4. Maternal relative water intake was reduced at 125 and 250 mg/kg/day from gd 9 to 12. Otherwise, maternal relative feed and water intakes were comparable to or greater than controls. Maternal body weight was decreased on gd 12 and pnd 4 at 200 mg/kg/day, and on gd 12, 15, 18, 20 and pnd 4 at 250 mg/kg/day. Maternal liver weight (absolute or relative) was unaffected on pnd 21. Maternal kidney weight (absolute or relative) showed an increasing trend, and absolute kidney weight was significantly elevated at greater than or equal to 125 mg/kg/day. On pnd 0, postimplantation loss was noted for 2, 6, 3, 17 and 51% of implantation sites per litter in the control through 250 mg/kg/day groups, respectively, and this increase was statistically significant at greater than or equal to 200 mg/kg/day. From pnd 0 to 4, postnatal mortality occurred in 0, 0.6, 1.8, 2.8 and 13.4% of pups per live litter in the control through 250 mg/kg/day groups, respectively, and this increase was statistically significant at greater than or equal to 125mg/kg/day. There were no statistically significant effects on the incidence of postnatal mortality for pnd 4 to 7, 7 to 14 or 14 to 21. Pup body weight per litter was reduced at greater than or equal to 200 mg/kg/day for one or more timepoints. No treatment-related morphological anomalies were detected upon external examination and no treatment-related gross pathology was detected at necropsy. In summary, CD(R) rats were dosed by gavage with DEA (0, 50, 125, 200, 250 or 300mg/kg/day) from gd 6-19. Maternal effects included reduced body weight or weight gain (greater than or equal to 200 mg/kg/day), increased absolute kidney weight (greater than or equal to 125 mg/kg/day), altered feed intake (greater than or equal to 200 mg/kg/day) and water intake (greater than or equal to 125 mg/kg/day). Postimplantation mortality (pnd 0) was elevated at greater than or equal to 200 mg/kg/day, and early postnatal mortality (pnd 0 to 4) was increased at greater than or equal to 125 mg/kg/day. Pup body weight was reduced at greater than or equal to 200 mg/kg/day. Thus, maternal and developmental toxicity NOAELs were 50 mg/kg/day and the LOAELs were 125 mg/kg/day. [R36] METB: *Treatment of Wistar or Sherman rats with diethanolamine caused increases in the formation of hepatic phospholipids. In addition, dietary administration led to incorporation of ethanolamine into hepatic phospholipids, and repeated oral administration of diethanolamine in drinking water (one to three wk) at a dose of 320 mg/kg/day was found to reduce the level of incorporation of ethanolamine and choline into hepatic and renal phospholipids in Sprague-Dawley rats. [R33, 403] *Dermal absorption of diethanolamine is suggested to occur in rats since N-nitrosodiethanolamine was excreted in the urine of male Sprague-Dawley rats which had been administered diethanolamine by dermal application and given nitrite in their drinking water. [R33, 403] ACTN: *DIETHANOLAMINE WHICH INTERFERES WITH PHOSPHOLIPID METAB PRODUCED A LOSS OF MITOCHONDRIAL INTEGRITY AFTER SUBACUTE ADMIN TO SPRAGUE-DAWLEY RATS. [R37] *DIETHANOLAMINE INHIBITED IN VITRO SYNTHESIS OF PHOSPHATIDYL CHOLINE AND PHOSPHATIDYL ETHANOLAMINE IN RAT LIVER TISSUE. [R30] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ WARN: *The concentration of the three ethanolamines in cosmetic formulations should not exceed 5% in products intended for prolonged contact with the skin. In addition, diethanolamine should not be used in products containing N-nitrosating agents, since it may be nitrosated to form N-nitrosodiethanolamine, a liver and nasal cavity carcinogen. [R33, 406] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Diethanolamine (DEA) may be released to the environment in emissions or effluents from sites of its manufacture or industrial use, from disposal of consumer products which contain this compound, and from application of agricultural chemicals in which this compound is used as a dispersing agent. In soil and water, DEA is expected to biodegrade fairly rapidly following acclimation (half-life on the order of days to weeks). N-Nitrosodiethanolamine is a metabolite of diethanolamine. In soil, DEA should leach. In the atmosphere, diethanolamine is expected to exist almost entirely in the vapor phase. Reaction with photochemically generated hydroxyl radicals is expected to be the dominant removal mechanism (half-life 4 hours). This compound may also be removed from the atmosphere in precipitation. The most probable route of exposure to DEA is dermal contact with personal care products (i.e. soaps, shampoos, cosmetics), detergents and other surfactants containing this compound. Workers may be exposed to DEA by inhalation during the use of lubricating-cooling liquids in various processes in machine building and metallurgy (cutting, die stamping, grinding, extrusion, die casting, etc.) (SRC) ARTS: *Diethanolamine may be released to the environment in emissions or effluents from sites of its manufacture or industrial use, from disposal of consumer products which contain this compound, in the utilization of lubricating liquids in various processes in machine building and metallurgy (cutting, die stamping, grinding, extrusion, die casting, etc.), and from application of agricultural chemicals in which this compound is used as a dispersing agent(1,2,3,SRC). [R38] FATE: *TERRESTRIAL FATE: If released to soil, diethanolamine (DEA) is expected to biodegrade fairly rapidly following acclimation (half-life on the order of days to weeks). DEA is expected to leach in soil. However, protonated DEA may adsorb to humic material in suspended solids and sediments. Volatilization from soil surfaces is not expected to be an important fate process. (SRC) *AQUATIC FATE: If released to water, diethanolamine (DEA) should biodegrade. The half-life of this compound is expected to range from a couple of days to a few weeks depending, in large part, on the degree of acclimation of the system. N-Nitrosodiethanolamine is a metabolite of DEA. Protonated DEA may adsorb to humic material in suspended solids and sediments. Bioconcentration in aquatic organisms and volatilization are not expected to be important fate processes in water. (SRC) *ATMOSPHERIC FATE: Based on a vapor pressure of 1.4X10-4 mm Hg at 25 deg C(1), diethanolamine (DEA) is expected to exist almost entirely in the vapor phase in the atmosphere(2,SRC). Reaction with photochemically generated hydroxyl radicals is expected to be the dominant removal mechanism (half-life 4 hours). The complete solubility of DEA in water suggests that this compound may also be removed from the atmosphere in precipitation(SRC). [R39] BIOD: *TESTED FOR BIODEGRADABILITY EMPLOYING BACTERIUM ISOLATED FROM CUTTING FLUID AND A SEWAGE POPULATION. SHOWED THAT DIETHANOLAMINE WAS DEGRADABLE, BEING OXIDIZED TO MEANINGFUL EXTENT. [R40] *Grab sample (stream water), initial concn 21 mg/L, 210 ug/L and 21 ng/L, 4 days - 5, 55, and 32% mineralization, respectively(1). Grab sample (lake water), initial concn 0.001 ppm, 14 day - 31 and 1.2% mineralization, Cayuga Lake water and North Lake (acidic) water, respectively(2). [R41] *Sewage die-away, initial concn 0.001 ppm, 20 days 53% mineralization, sewage inoculum(1). N-Nitrosodiethanolamine has been identified as a metabolite of diethanolamine in natural water samples and sewage(1). Die-away, initial concn 50 ppm, 10 day 90% Theoretical Biochemical Oxygen Demand, acclimated Kanawha River water as seed, sewage inoculum(2). BOD water, initial concn 2.5 ppm, 5, 10,15, and 20 days - 0.9, 1.4, 3.5, and 6.8% Theoretical Biochemical Oxygen Demand, respectively, sewage inoculum(3). BOD water, 20 day 88% Theoretical Biochemical Oxygen Demand, sewage inoculum(4). Synthetic sea water 20 day 76% Theoretical Biochemical Oxygen Demand, sewage inoculum(4). BOD water, 5 day 2% Theoretical Biochemical Oxygen Demand (unadapted) and 77% Theoretical Biochemical Oxygen Demand (adapted), inoculum was effluent from a biological waste treatment plant(5). BOD water, initial concn 500 ppm, 10 day 97% Theoretical Biochemical Oxygen Demand, acclimated activated sludge inoculum(6). BOD water, initial concn equivalent to 100 ppm carbon (C), 5 day 97% COD removal, activated sludge inoculum(7). [R42] *Zahn-Wellens, initial concn equivalent to 400 ppm carbon (C), 3 day 94% dissolved organic carbon (DOC) removal, activated sludge inoculum(1). Sturm - carbon dioxide (CO2) evolution, initial concn equivalent to 10 ppm carbon, 28 days 91% carbon dioxide evolution and 100% dissolved organic carbon removal, acclimated sewage inoculum(1). Organization of Economic Cooperation Development (OECD), initial concn equivalent to 3-20 ppm carbon, 19 day 100% dissolved organic carbon removal, sewage inoculum(1). Modified Closed Bottle, initial concn 2 ppm, 30 day 94% Theoretical Biochemical Oxygen Demand, enriched sewage inoculum(1). French Association for Standardization (AFNOR) , initial concn equivalent to 40 ppm carbon, 28 and 42 days - 97 and 98% dissolved organic carbon removal, respectively, sewage inoculum(1). Japanese Ministry of International Trade and Industry (MITI), initial concn equivalent to 50 ppm carbon, 14 days 3% Theoretical Biochemical Oxygen Demand, activated sludge inoculum(1). Japanese Ministry of International Trade and Industry, initial concn 100 ppm, 14 days 74.6% Theoretical Biochemical Oxygen Demand (ammonia endproduct) and 51.4% Theoretical Biochemical Oxygen Demand (nitrogen dioxide endproduct) activated sludge inoculum(2). [R43] ABIO: *The half-life for diethanolamine vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 4 hours based on an estimated reaction rate constant of 8.9X10-11 cu cm/molecules-sec at 25 deg C and an average ambient hydroxyl concentration of 5X10+5 molecules/cu cm(1,SRC). [R44] BIOC: *A bioconcentration factor (BCF) of < 1 was estimated for diethanolamine (DEA) based on a log Kow of - 1.43(1,2,SRC). This BCF value and complete solubility of DEA in water suggest that this compound does not bioconcentrate significantly in aquatic organisms(3,SRC). [R45] KOC: *A soil adsorption coefficient (Koc) of 4 was estimated for diethanolamine based on a log Kow of -1.43(1,2,SRC). This Koc value and the complete solubility of DEA in water suggests that this compound would be extremely mobile in soil and would not adsorb appreciably to suspended solids and sediments in water(3,4,SRC). However, diethanolamine is a base (pKa 8.97 at 25 deg C(5)) and may exist in the protonated form under environmental conditions (pH 5-9). Protonation may result in greater adsorption and less mobility than its water solubility or log Kow indicate. Futhermore, diethanolamine has been shown to adsorb to humic acid which may be contained in soils and sediments(6). The adsorption of diethanolamine on humic acid changed very slightly from pH 4-8, (40-45% adsorption)(6). [R46] VWS: *The Henry's Law constant for diethanolamine can be estimated to be 3.9X10-11 atm-cu m/mol at 25 deg C using a chemical structure estimation method(1,SRC). This value of Henry's Law constant suggest that diethanolamine is essentially nonvolatile from water(2). [R47] EFFL: *Diethanolamine has been quantitatively detected as a volatile compound of lubricating-cooling liquids at a concn range of 0.25-0.40 mg/cu m(1). [R48] RTEX: *The most probable route of exposure to diethanolamine (DEA) is dermal contact with personal care products (i.e. soaps, shampoos, cosmetics), detergents and other surfactants which contain this compound(1,2,3,SRC). Workers may be exposed to DEA by inhalation during the use of lubricating liquids in various processes in machine building and metallurgy (cutting, die stamping, grinding, extrusion, die casting, etc)(4). [R49] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 1,284,534 workers are potentially exposed to diethanolamine (DEA) in the USA(2). NIOSH (NOES Survey 1981-1983) has statistically estimated that 573,025 workers are potentially exposed to DEA in the USA(1). [R50] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Diethanolamine is exempted from the requirement of a tolerance when used as a stabilizer for formulations used before crop emerges from soil in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R51] OSHA: +Vacated 1989 OSHA PEL TWA 3 ppm (15 mg/cu m) is still enforced in some states. [R23, 363] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 3 ppm (15 mg/cu m). [R23, 104] TLV: +8 hr Time Weighted Avg (TWA): 2 mg/cu m, skin. [R52, 2002.28] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R52, 2002.6] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Diethanolamine is included on this list. [R53] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Diethanolamine is included on this list. [R54] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R55] FIFR: *Diethanolamine is exempted from the requirement of a tolerance when used as a stabilizer, inhibitor for formulations used before crop emerges from soil in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R51] FDA: *Diethanolamine is an indirect food additive for use only as a component of adhesives. [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Diethanolamine is sampled from air on a glass fiber filter coated with 1-naphthylisothiocyanate, resulting in the formation of a substituted thiourea in situ. [R57] *NIOSH Method 3509. Analyte: Diethanolamine. Sampler: Impinger (15 ml 2mM hexanesulfonic acid). Flow Rate: 0.5 to 1 l/min: Sample Size: 100-liter. Shipment: Routine. Sample Stability: Stable at least 3 weeks @ 20 deg C. [R58] ALAB: *GAS CHROMATOGRAPHIC METHOD WAS DEVELOPED FOR QUANTITATIVE DETERMINATION OF DIETHANOLAMINE. [R59] *DETERMINATION OF ETHANOL- AND ISOPROPANOLAMINES IN AIR @ PPB LEVELS. DERIV ARE SEPARATED BY GAS CHROMATOGRAPHY WITH FLAME IONIZATION DETECTION. [R60] *A high performance liquid chromatography method for the determination of diethanolamine is described. Recovery of the thiourea from the coated filter spiked with the amine is 86-96%. The sensitivity of this method is 0.01 ppm and the precision, measured as the mean relative standard deviation (coefficient of variation) in the spiking experiment is 4%. [R57] *NIOSH Method 3509. Analyte: Diethanolamine Procedure: Ion chromatography, ion pairing. For diethanolamine this method has an estimated detection limit of 7 to 20 ug/sample. The precision/RSD is 0.064. Applicability: The working range for diethanolamine is 0.09 to 7 ppm (0.4 to 30 mg/cu m) for a 100 liter sample. Interferences: Large amines do not elute under these analytical conditions and do not interfere. [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: MOREL C ET AL; TOXICOLOGICAL CARD. 147. DIETHANOLAMINE; CAH NOTES DOC (97) 655: (1979). SUMMARY COVERS PHYS AND CHEM PROPERTIES OF DIETHANOLAMINE, HAZARDS IN USE, AND CURRENT LEGISLATION IN FRANCE AFFECTING IT. RECOMMENDATIONS ARE MADE FOR ITS STORAGE AND HANDLING, AND MEDICAL TREATMENT IN CASE OF ACCIDENTS. DHHS/NIOSH Screening of Priority Chemicals for Reproductive Hazards. Diethanolamine (CAS No. 111-42-2) (1987), NTIS PB89-139067 DHHS/NTP; NTP Technical Report on Toxicity Studies of Diethanolamine Administered Topically and in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 20 NIH Publication No. 92-3343 (1992) SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V22 373 (1983) R3: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 491 R4: CHEMICAL PROFILE: ETHANOLAMINE, 1984 R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 386 R6: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R7: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 298 (1978) R8: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 901 (1980) R9: CHEMICAL PROFILE: ETHANOLAMINES, 1984 R10: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.254 R11: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-355 R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-106 R13: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 104 R14: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-214 R15: SRC; Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985); Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-5 (1982) R16: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 554 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 571 R18: SRC; Dow Chemical; The Alkanolamine Handbook Midland, MI: Dow Chemical (1980) R19: SRC; Meylan WM, Howard PH; Environ Toxicol and Chem 10: 1283-93 (1991) R20: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 640 R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-36 R22: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 172 R23: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R24: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 907 R25: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-73 R26: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R27: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-106 R28: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.197 R29: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 333 R30: BARBEE SJ, HARTUNG J; TOXICOL APPL PHARMACOL 47 (3): 421 (1979) R31: Cowgill UM et al; Environ Toxicol Chem 8 (5): 451-5 (1989) R32: Toxicology and Carcinogenesis Studies of Diethanolamine in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 478 (1999) NIH Publication No. 99-3968 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R33: Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990. R34: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 519 R35: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of Diethanolamine (CAS No. 111-42-2) in Female B6C3F1 Mice, NTP Study No. IMM98011 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 19, 2002 R36: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity Screen for Diethanolamine (CAS No. 111-42-2) Administered by Gavage to Sprague-Dawley (CD(R)) Rats on Gestational Days 6 through 19: Evaluation of Dams and Pups through Postnatal Day 21, NTP Study No. TER96001 (December 22, 1999) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R37: BARBEE SJ, HARTUNG R; TOXICOL APPL PHARMACOL 47 (3): 431 (1979) R38: (1) Liepins R et al; Industrial Process Profiles for Environmental Use. USEPA-600/2-77-023f NTIS PB-281 478 pp. 6-386 to 6-387 (1977) (2) Windholz M ed; The Merck Index 10th ed Rahway, NJ: Merck and Co p. 451 (1983) (3) Berezkin VG, Drugov S; Zavod Lab 52: 16-9 (1986) R39: (1) Dow Chemical; The Alkanolamine Handbook Midland, MI: Dow Chemical (1980) (2) Eisenreich SJ et al; Environ Sci Tech 15: 30-8 (1981) R40: GANNON JE ET AL; MICROBIAL DEGRADATION OF DIETHANOLAMINE AND RELATED COMPOUNDS; MICROBIS 23(91) 7 (1978) R41: (1) Boethling RS, Alexander M; Environ Sci Tech 13: 989-91 (1979) (2) Yordy JR, Alexander M; J Environ Qual 10: 266-70 (1981) R42: (1) Yordy JR, Alexander M; J Environ Qual 10: 266-70 (1981) (2) Mills EJ, Stack VT; Proc 9th Ind Waste Conf Eng Bull Purdue Univ: Ext Ser 9: 449-64 (1955) (3) Lamb CB, Jenkins GF; pp 326-39 in Proc 8th Ind Waste Conf Purdue Univ (1952) (4) Price KS et al; J Water Poll Contr Fed 46: 63-77 (1974) (5) Bridie AL et al; Water Res 13: 627-30 (1979) (6) Gannon JE et al; Microbios 23: 7-18 (1978) (7) Pitter P; Water Res 10: 63-77 (1976) R43: (1) Gerike P, Fischer WK; Ecotox Environ Safety 3: 159-73 (1979) (2) Kitano M; OECD Tokyo Meeting Reference Book Tsu-No. 3 (1978) R44: (1) Atkinson R; Inter J Chem Kinet 19: 799-828 (1987) R45: (1) Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-5 (1982) (3) Dow Chemical; The Alkanolamines Handbook Midland, MI: Dow Chemical (1980) R46: (1) Hansch C, Leo AJ; Medchem Project Issue no. 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (3) Dow Chemical; The Alkanolamines Handbook Midland, MI: Dow Chemical (1980) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) Chremos G, Zimmerman HJKR; Texas J Sci 11; 467-70 (1959) (6) Sithole BB, Guy RD; Environ Int 11: 499-504 (1985) R47: (1) Meylan WM, Howard PH; Environ Toxicol and Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-12 to 15-32 (1982) R48: (1) Berezkin VG, Drugov S; Zavod Lab 52: 16-9 (1986) R49: (1) Hawley GG; The Condensed Chemical Dictionary 10 th ed NY: Van Nostrand Reinhold p 342 (1981) (2) Chemical Marketing Reporter; Chemical Profile: Ethanolamine NY: Schnell Publishing Nov 10 (1986) (3) Windholz M ed; The Merck Index 10th ed Rahway, NJ: Merck and Co p 451 (1983) (4) Berezkin VG, Drugov S; Zavod Lab 52: 16-9 (1986) R50: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1974) R51: 40 CFR 180.1001(d) (7/1/91) R52: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R53: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R54: 40 CFR 716.120 (7/1/91) R55: 40 CFR 712.30 (7/1/91) R56: 21 CFR 175.105 (4/1/91) R57: Levin JO et al; Ann Occup Hyg 33 (2): 175-80 (1989) R58: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 3509-1 R59: O'CONNELL AW; ANAL CHEM 49 (MAY): 835 (1977) R60: LANGVARDT PW, MELCHER RG; ANAL CHEM 52 (4): 669 (1980) RS: 44 Record 98 of 1119 in HSDB (through 2003/06) AN: 939 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLOROACETIC-ACID- SY: *ACETIC-ACID,-CHLORO-; *ACIDE-CHLOROACETIQUE- (FRENCH); *ACIDE-MONOCHLORACETIQUE- (FRENCH); *ACIDOMONOCLOROACETICO- (ITALIAN); *CHLORACETIC-ACID-; *ALPHA-CHLOROACETIC-ACID-; *CHLOROACETIC-ACID,-SOLID- (DOT); *CHLOROETHANOIC-ACID-; *MONOCHLOORAZIJNZUUR- (DUTCH); *MONOCHLORACETIC-ACID-; *MONOCHLORESSIGSAEURE- (GERMAN); *MONOCHLOROACETIC-ACID-; *MONOCHLOROACETIC-ACID-SOLUTION- (DOT); *MONOCHLOROETHANOIC-ACID-; *NCI-C60231- RN: 79-11-8 MF: *C2-H3-Cl-O2 SHPN: UN 1750; Chloroacetic acid, solution UN 1751; Chloroacetic acid, solid IMO 8.0; Chloroacetic acid, liquid or solution, molten, solid UN 3250; Chloroacetic acid, molten STCC: 49 314 44; Chloroacetic acid, liquid or solution 49 314 16; Chloroacetic acid, solid ASCH: Sodium chloroacetate; 3926-62-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Made by chlorination of glacial acetic acid in presence of small amt of sulfur or iodine; also by hydrolysis of trichloroethylene with 90% sulfuric acid. [R1] *Action of chlorine on acetic acid in the presence of acetic anhydride, phosphorus, or sulfur. [R2] *Reaction of chloroacetyl chloride with water. [R3, p. V1 165] IMP: *High purity 99+% chloroacetic acid will contain less than 0.5% of either acetic acid or dichloroacetic acid. Other impurities that may be present in small amounts are water and hydrochloric acid. [R3, p. V1 165] *Technical grade is about 90% pure. [R4, 186] FORM: *Grades: Technical; Medicinal; 99.5% Pure. [R2] *80% solution of chloroacetic acid [R3, p. V1 165] MFS: *Dow Chemical USA, 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Midland, MI 48667 [R5, 521] *Hercules Inc., Hercules Plaza, Wilmington, DE 19894 (302) 594-5000, Aqualan, 1313 N. Market St., Wilmington, DE 19899-8740, (302) 594-6600; Production site: Hopewell, VA 23860. [R5, 521] *Niacet Corp., 400 47th St., Niagara Falls, NY 14304 (716)285-1474; Production site: Niagara Falls, NY 14304 [R5, 521] *Pfizer, Inc., 235 East 42nd St., New York, NY 10017, (212) 573-2323, Chemical Division; Production site: Groton, CT 06340. [R5, p. `521] OMIN: *IT ... HAS BACTERIOSTATIC PROPERTIES BUT IS CONSIDERED TOO HAZARDOUS FOR USE IN FOODS. [R6, 1795] *A major disadvantage of the chlorination process is residual acetic acid and overchlorination to dichloroacetic acid...chloroacetic acid is usually purified by crystallization. [R3, p. V1 165] *Of the three monoclinically prismatic structures, alpha, beta, and gamma, and possibly the delta form, the alpha form is the most stable and the most important industrially. [R7] USE: *CHEM INT FOR PHARMACEUTICALS, EG, VITAMIN A [R8] *CHEM INT FOR INDIGOID DYES [R8] *Herbicide. Manufacture various dyes and other organic chemicals. [R1] *Herbicide, preservative, bacteriostat, intermediate in production of carboxymethylcellulose; ethyl chloroacetate; glycine; synthetic caffeine; sarcosine; thioglycolic acid; EDTA; 2,4-D; 2,4,5-T. [R2] *Mainly used in the manufacture of cellulose ethers, herbicides, and thioglycolic acid. Also used for the manufacture of glycine, amphoteric surfactants, and cyanoacetic acid. [R3, p. V1 167] *MEDICATION *Used as feedstock and as an intermediate in the manufacture of malonic acid. [R9] CPAT: *CHEM INT FOR SODIUM CARBOXYMETHYLCELLULOSE, 60%; FOR HERBICIDES, 30%; FOR OTHER DERIVATIVES (EG, GLYCINE, THIOGLYCOLIC ACID, PHARMACEUTICALS, AND INDIGOID DYES), 10% (1979) [R8] *CHEMICAL PROFILE: Chloroacetic acid. Cellulose ethers, mainly carboxymethylcellulose (CMC), 29%; herbicides, 27%; miscellaneous, including thioglycolic acid, surfactants, cyanoacetic acid, phenoxyacetic acid, glycine, and chloroacetic acid esters, 44%. [R10] *CHEMICAL PROFILE: Chloroacetic acid. Demand: 1994: 77.5; million pounds; 1995: 79 million pounds; 1999: 85 million pounds (includes imports, which were 31 million pounds in 1993; exports are negligible). [R10] PRIE: U.S. PRODUCTION: *(1978) 3.50X10+10 G [R8] *(1982) PROBABLY GREATER THAN 6.81X10+6 G [R8] *Produced at a rate of more than 300,000 tons annually. [R11] U.S. IMPORTS: *(1978) 1.25X10+10 G [R8] *(1982) 1.35X10+10 G [R8] *The majority of imported chloroacetic acid is produced in Germany. [R3, p. V1 165] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MONOCLINIC PRISMS [R12]; *Colorless or white crystals [R1]; *Colorless to light-brownish crystals [R2] ODOR: *Characteristic penetrating odor similar to vinegar [R13] BP: *All 3 forms /alpha, beta, gamma/ boil at 189 deg C [R1] MP: *alpha 63 deg C; beta 55-56 deg C; gamma 50 deg C [R1] MW: *94.50 [R1] CORR: *Corrosive to metals. [R14] CTP: *Critical temperature: 686.0 K; critical pressure: 5.78X10+6 Pa [R15] DEN: *1.4043 @ 40 deg C/4 deg C /Chloroacetic acid, beta/ [R16] DSC: *pKa = 2.87 [R17] HTC: *715.9 kJ/mol [R7] HTV: *250 btu/lb= 139 cal/g= 5.82 x 10+5 J/Kg [R13] OWPC: *log Kow= 0.22 [R18] SOL: *SLIGHTLY SOLUBLE IN CHLOROFORM [R12]; *Sol in benzene, alcohol, chloroform, and ether. [R1]; *Sol in ethanol, diethyl ether [R19]; *Soluble in carbon disulfide [R2]; *6.14X10+6 mg/l in water at 25 deg C [R20]; *Solubility (g/100 g solvent): water = 614; acetone = 257; methylene chloride = 51; benzene = 26; carbon tetrachloride = 2.75 [R3, p. V1 165] SPEC: *Index of refraction: 1.4300 @ 55 DEG C/D [R15]; *SADTLER REF NUMBER: 2094 (IR, PRISM) [R12]; *MAX ABSORPTION (ALCOHOL): 218 NM (LOG E= 1.7) SHOULDER [R12]; *IR: 5567 (Coblentz Society Spectral Collection) [R21]; *NMR: 128 (Sadtler Research Laboratories Spectral Collection) [R21]; *MASS: 196 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R21] SURF: *35.17 dyn/cm at 100 deg C [R3, p. V1 165] VAPD: *3.26 (Air= 1) [R22] VAP: *6.50X10-2 mm Hg at 25 deg C [R20] VISC: *1.29 cP at 100 deg C [R3, p. V1 165] OCPP: *This compound absorbs water from the air and forms a syrup. [R14] *IR: 5567 (Coblentz Society Spectral Collection) /Chloroacetic acid (beta)/ [R21] *MASS: 196 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Chloroacetic acid (beta)/ [R21] *IR: 5567 (Coblentz Society Spectral Collection) /Chloroacetic acid (gamma)/ [R21] *MASS: 196 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Chloroacetic acid (gamma)/ [R21] *The commercial material melts at 61-63 deg C, boiling range 186-191 deg C. [R2] *Heat capacity = 181 J/mol deg K at 100 deg C; Heat of formation = -490.1 kJ/mol at 100 deg C; Heat of sublimation = 88.1 kJ/mol at 25 deg C. [R3, p. V1 165] *Heat of fusion at the melting point = 1.2285X10+7 J/kmol [R15] *Degree of dissociation in water (potentiometric): 1.52X10-3 at 25 deg C [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chloroacetic acid, liquid; Chloroacetic acid, molten; Chloroacetic acid, solid; Chloroacetic acid, solution/ [R23] FPOT: *Combustible liquid when exposed to heat or flame. [R24] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R25] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R25] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R25] FLPT: *259 deg F (126 deg C) (Closed cup) [R25] AUTO: *GREATER THAN 932 DEG F (GREATER THAN 500 DEG C). [R25] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use water spray to knock-down vapors. /Chloroacetic acid, liquid/ [R26, 236] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. /Chloroacetic acid, solid/ [R26, 237] *To fight fire, use water spray, fog, mist, dry chemical, foam. [R24] REAC: *HIGHLY REACTIVE CHEMICALLY REACTS WITH AMMONIA TO FORM GLYCINE AND WITH ANILINE TO FORM A PRECUSOR FOR INDIGO DYES. [R27] DCMP: *WHEN HEATED TO DECOMP, IT EMITS TOXIC FUMES OF /HYDROGEN CHLORIDE./ [R24] SERI: *Irritating to skin, mucous membranes. [R1] EQUP: *PERSONAL PROTECTIVE EQUIPMENT ... WORN BY PERSONS ENGAGED IN THE OPERATIONS, AND EYE PROTECTIVE EQUIPMENT AND RESP PROTECTIVE EQUIPMENT ... AVAILABLE FOR USE WHEN NECESSARY. /HALOGENATED ACETIC ACIDS/ [R28] *FULL PROTECTIVE CLOTHING, INCL SELF-CONTAINED BREATHING APPARATUS, COAT, PANTS, GLOVES, BOOTS, AND BANDS AROUND LEGS, ARMS AND WAIST ... PROVIDED. NO SKIN SURFACE ... EXPOSED. [R29] OPRM: *STRICT PRECAUTIONS ... NECESSARY FOR ... HANDLING. ... SHOULD BE PREPARED AND USED IN ENCLOSED PLANT, THE OPENINGS IN WHICH SHOULD BE LIMITED TO THE NECESSITIES OF MANIPULATION. EXHAUST VENTILATION ... APPLIED TO ENCLOSURE TO THE ENCLOSURE TO ENSURE THAT FUMES OR DUST DO NOT ESCAPE ... /HALOGENATED ACETIC ACIDS/ [R28] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. /Chloroacetic acid, liquid/ [R26, 237] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective clothing. /Chloroacetic acid, liquid/ [R26, 237] *Personnel protection: Avoid breathing vapors. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. ... If contact with the material anticipated, wear appropriate chemical protective clothing. /Chloroacetic acid, solid/ [R26, 237] *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Neutralize spilled material with crushed limestone, soda ash, or lime. /Chloroacetic acid, solid/ [R26, 237] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R30] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R31] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R32] STRG: *KEEP WELL CLOSED AND IN A COOL PLACE. [R1] CLUP: *WASTE WATER CONTAINING CHLOROACETIC ACID CAN BE TREATED WITH AMMONIA, AMMONIUM SALTS OR AMINES WHICH SPLIT OFF AMMONIA AT REACTION TEMP AND AFTER THESE STEPS SUSPENDED SOLIDS SEPARATE. [R33] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist respirations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Activated charcoal is not effective ... . Do not attempt to neutralize because of exothermic reaction. Cover skin bums with dry, sterile dressings after decontamination ... . /Organic acids and related compounds/ [R34, p. 152-3] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Early intubation, at the first sign of upper airway obstruction, may be necessary. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Organic acids and related compounds/ [R34, 153] MEDS: *ALL PERSONS EXPOSED TO REPEATED CONTACT OR HANDLING APPRECIABLE QUANTITIES SHOULD BE UNDER CAREFUL MEDICAL SUPERVISION. [R6, 1796] HTOX: *MONOCHLOROACETIC ACID CAN PRODUCE LOCAL REACTIONS OF ... EYE, OR RESPIRATORY TRACT, AS MIGHT BE EXPECTED FROM ITS IONIZATION CONSTANT. ... IT IS LUNG ... IRRITANT. [R6, 1796] */SRP: WITH MOLTEN/ MONOCHLORACETIC ACID CAUSES ONLY RUBEFACTION IF SKIN IS QUICKLY WASHED WELL, BUT DEATH MAY FOLLOW IF MORE THAN 3% OF SKIN IS INVOLVED. [R35] *MONOCHLOROACETIC ACID ... VAPORS APPEAR IN ONE INSTANCE TO HAVE CAUSED CORNEAL EPITHELIAL INJURY. [R36] *THE HALOGENATED ACETIC ACIDS CAUSE SEVERE DAMAGE TO THE SKIN AND MUCOUS MEMBRANES ... /HALOGENATED ACETIC ACIDS/ [R28] *SYMPTOMATOLOGY (after ingestion or skin contact): 1) Corrosion of mucous membranes of mouth, throat, and esophagus, with immediate pain and dysphagia. The necrotic areas are at first grayish white but soon acquire a blackish discoloration and sometimes a shrunken or wrinkled texture; the process is described as a "coagulation necrosis." 2) Epigastric pain, which may be associated with nausea and the vomiting of mucoid and "coffee-ground" material. At times, gastric hemorrhage may be intense, and the vomitus then contains fresh blood. Profound thirst. 3) Ulceration of all membranes and tissues with which the acid comes in contact ... . 4) Circulatory collapse with clammy skin, weak and rapid pulse, shallow respirations, and scanty urine. Circulatory shock is often the immediate cause of death. 5) Asphyxial death due to glottic edema. 6) Late esophageal, gastric and pyloric strictures and stenoses, which may require major surgical repair, should be anticipated. Signs of obstruction commonly appear within a few weeks but may be delayed for months and even years. Permanent scars may also appear in the cornea, skin and oropharynx. 7) Uncorrected circulatory collapse of several hours' duration may lead to renal failure and ischemic lesions in the liver and heart. [R37, p. II-102] NTOX: *CHLOROACETIC ACID ADMIN TO MOUSE WAS NONTUMORIGENIC. ROUTE: ORALLY; DURATION OF STUDY: 540 DAYS; DOSE: 46.4 MG/KG. [R38] *IN RATS 24 HR LD50 FOR MONOCHLOROACETATE WAS 108 MG/KG. MEDIAN TIME TO DEATH 480 MIN. MONOCHLOROACETATE INHIBITED (14)CARBON-ACETATE OXIDN. MONOCHLOROACETATE APPARENT KI= 9X10-7 MOLAR. MONOCHLOROACETATE DECR SULFHYDRYL CONCN IN KIDNEY AND LIVER BUT DID NOT DECR CYSTEINE SULFHYDRYL CONCN IN VITRO. /MONOCHLOROACETATE/ [R39] *WITH CHLOROACETIC ACID, NO ENHANCEMENT OF MUTATION FREQUENCY COULD BE DETECTED IN BASE-PAIR SUBSTITUTION TEST DIRECTLY IN SALMONELLA TYPHIMURIUM TA1535. [R40] *CHLOROACETIC ACID INHIBITED INCORPORATION OF (14)CARBON FROM (14)CARBON-LABELED ALANINE INTO GLUCOSE IN LIVER SLICES. [R41] *CHLOROACETIC ACID YIELDED MUTANT COUNTS SIGNIFICANTLY GREATER THAN CONTROL LEVELS IN ONE TEST WITH S9 MIXT IN MOUSE LYMPHOMA CELLS L5178Y TK+/- TO TK-/- MUTATION ASSAY. [R42] *During incidents of accidental poisoning, the lowest estimated fatal dosages of sodium chloroacetate were 17-68 mg/kg body weight in cattle, and 39-70 mg/kg in sheep. /Sodium monochloroacetate/ [R43] *Chloroacetic acid was evaluated for mutagenicity using the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Chloroacetic acid was tested at doses of 0.01, 0.033, 0.10, 0.333, 1.0, 2.0, and 3.333 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of a rat or hamster liver S-9. Chloroacetic acid was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 3.333 mg/plate. Slight clearing of the background bacterial lawn occurred at the high dose in all strains. [R44] *Chloroacetic acid was evaluated for its mutagenic potential in the L5178Y TK+/TK- mouse lymphoma forward mutation assay using established procedures. Three experiments were conducted, all without metabolic activation. The dose levels tested in these experiments ranged from 0-800 ug/ml. One experiment was discarded; however significant mutagenic responses were obtained from the remaining two experiments. Thus, chloroacetic acid was positive in these tests and the lowest effective dose tested was 400 ug/ml. [R45] *Groups of twenty 6 to 24 hr old daphnids (Daphnia magna) were exposed to varying concn of chloroacetic acid for 24 or 48 hr. The effective concn (EC) was defined as the concn at which daphnids lost the ability to swim. For chloroacetic acid after 24 hr exposure, the EC50 was 99, the EC0 was 81 and the EC100 was 107 mg/l; corresponding 48 hr EC values were 77, 55, and 107 mg/l, respectively. [R46] *21-day Daphnia reproduction tests were conducted in line with the provisional procedure proposed by the Federal Environmental Agency (Umweltbundesamt, FRG), as of Jan 1, 1984. Groups of twenty, 24 hr old Daphnia magna Straus were exposed to 0.032 to 100 mg/l monochloroacetic acid in semi-static test vessels. Parent animals in the test and control vessels had to be pipetted 3 times/wk in freshly prepared test and control media at the corresponding concn level. The no observed effect concn (NOEC) was determined from the parameters of mortality of the parent animals, reproduction rate and appearance of the first offspring during the test period. In preliminary acute Daphnia tests, the 24 hr EC50 was 96 mg/l for chloroacetic acid, the EC0 was 85 mg/l. The nominal 21 day no observed effect concn was 32 mg/l. [R47] *... Pretreatment of /male mice of ddY strain/ with either diethyldithiocarbamate or carbon disulfide ... did not prevent the hypothermia induced by monochloroacetic acid. ... [R48] *... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity for monochloroacetic acid in male or female F344/N rats given 15 or 30 mg/kg. There was no evidence of carcinogenic activity for monochloroacetic acid in male or female B6C3F1 mice given 50 or 100 mg/kg. [R49] *Toxic to poultry. ... Toxic to bees. [R4, 187] NTXV: *LD50 Rat oral 76 mg/kg; [R1] *LD50 Mouse oral 255 mg/kg; [R1] *LD50 Guinea pig oral 80 mg/kg; [R1] *LD50 Rat sc 5 mg/kg; [R24] *LD50 Rat iv 55 mg/kg; [R24] *LD50 Mouse oral 165 mg/kg; [R24] *LD50 Mouse sc 250 mg/kg; [R24] ETXV: *Tubifex tubifex (worm) perturbation concn, 150 mg/l; [R50, 448] *Vorticella campanula (protozoan) perturbation concn, 9 mg/l; [R50, 448] *Paramecium caudatum (protozoan) toxic, 150 mg/l; [R50, 448] *Gammarus pulex (water shrimp) perturbation concn, 30 mg/l; [R50, 449] *Chironomus plumosus (midge) perturbation concn, 140 mg/l; [R50, 449] *Trutta iridea (fish) perturbation concn, 20 mg/l /Conditions of bioassay not specified/; [R50, 449] *Cyprinus carpio (carp) pertubation concn, 14 mg/l /Conditions of bioassay not specified/; [R50, 449] NTP: *... Toxicology and carcinogenicity studies were conducted by admin monochloroacetic acid (99% pure) in deionized water by gavage to ... at 0, 15, or 30 mg/kg ... to groups of 70 F344/N rats of each sex, and 0, 50 or 100 mg/kg, admin to groups of 60 B6C3F1 mice of each sex for 2 yr. ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity for monochloroacetic acid in male or female F344/N rats given 15 or 30 mg/kg. There was no evidence of carcinogenic activity for monochloroacetic acid in male or female B6C3F1 mice given 50 or 100 mg/kg. [R49] TCAT: ?Summary information indicates that monochloroacetic acid (CAS # 79-11-8) was evaluated for acute inhalation toxicity in rats (sex, strain, and number not reported) by exposure to the test substance in the form of saturated vapor for a period of 1 minute. The use of controls was not reported. There were no mortalities. Clinical signs and necropsies were not reported. [R51] ?Summary information indicates that monochloroacetic acid (CAS # 79-11-8) was evaluated for acute inhalation toxicity in rats (sex, strain , and number not reported) by exposure to the test substance in the form of saturated vapor for a period of 10 minutes. The use of controls was not reported. There were no mortalities. Clinical signs and necropsies were not reported. [R51] ?Summary information indicates that monochloroacetic acid (CAS # 79-11-8) was evaluated for acute inhalation toxicity in mice (sex, strain, and number not reported) by exposure to the test substance in the form of saturated vapor for a period of 1 minute. The use of controls was not reported. There were no mortalities. Clinical signs and necropsies were not reported. [R51] ?Summary information indicates that monochloroacetic acid (CAS # 79-11-8) was evaluated for acute inhalation toxicity in mice (sex, strain, and number not reported) by exposure to the test substance in the form of saturated vapor for a period of 10 minutes. The use of controls was not reported. There were no mortalities. Clinical signs and necropsies were not reported. [R51] ?Summary information indicates that monochloroacetic acid (CAS # 79-11-8) was evaluated for acute inhalation toxicity in guinea pigs (sex, strain, and number not reported) by exposure to the test substance in the form of saturated vapor for a period of 1 minute. The use of controls was not reported. There were no mortalities. Clinical signs and necropsies were not reported. [R51] ?Summary information indicates that monochloroacetic acid (CAS # 79-11-8) was evaluated for acute inhalation toxicity in guinea pigs (sex, strain, and number not reported) by exposure to the test substance in the form of saturated vapor for a period of 10 minutes. The use of controls was not reported. There were no mortalities. Clinical signs and necropsies were not reported. [R51] ADE: *SCREENING TESTS INDICATED ABSORPTION THROUGH SKIN. [R6, 1796] *AFTER (14)C-LABELED CHLOROACETIC ACID (0.07-0.10 G/KG, IP) ADMIN TO RATS, 82-88% RADIOACTIVITY FOUND IN URINE AND 8% IN EXPIRED AIR WITHIN 3 DAYS. [R52] METB: *2 PATHWAYS SUGGESTED FOR METAB IN MOUSE: MAJOR: S-CARBOXYMETHYL-GLUTATHIONE FORMED IS CONVERTED TO S-CARBOXYMETHYLCYSTEINE, PART OF WHICH GOES TO THIODIACETIC ACID; MINOR: ENZYMATIC HYDROLYSIS OF CARBON-CHLORIDE BOND GIVING GLYCOLIC ACID, THEN OXIDIZED TO CARBON DIOXIDE. [R53] INTC: *... Pretreatment of /male mice of ddY strain/ with either diethyldithiocarbamate or carbon disulfide ... did not prevent the hypothermia induced by monochloroacetic acid. ... [R48] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG, BETWEEN 1 TEASPOON AND 1 OZ FOR 70 KG PERSON (150 LB). [R37, p. II-198] THER: */FORMER USE/: PHENOL ... HAS BEEN ESSENTIALLY REPLACED BY MONO-, BI-, AND TRICHLOROACETIC ACIDS FOR REMOVAL OF ACTINIC, SENILE, AND SEBORRHEIC KERATOSES. [R54] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Chloroacetic acid's production and use in the manufacture of cellulose ethers, mainly carboxymethylcellulose (CMC), herbicides, thioglycolic acid, surfactants, cyanoacetic acid, phenoxyacetic acid, glycine, and chloroacetic acid esters may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 6.5X10-2 mm Hg at 25 deg C indicates chloroacetic acid will exist solely as a vapor in the ambient atmosphere. Vapor-phase chloroacetic acid will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 20 days. If released to soil, chloroacetic acid is expected to have very high mobility based upon an estimated Koc of 1.2. Chloroacetic acid is readily biodegraded in screening studies using a sewage or acclimated sludge inoculum; greater than 70-90% degradation was reported in 5-10 days. Degradation is increased by acclimation and involves dechlorination. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.32X10-9 atm-cu m/mole. Chloroacetic acid will not volatilize from dry soil surfaces based upon its vapor pressure. If released into water, chloroacetic acid is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Chloroacetic acid was mineralized in river water with 73% conversion to carbon dioxide in 8-10 days at 29 deg C. In contrast, no biodegradation was reported for chloroacetic acid in either river water or seawater samples after a 3 day incubation. Aqueous solutions of ferric ions and chloroacetic acid are degraded by light with wavelengths greater than 300 nm; chloroacetic acid was photolyzed at a rate of 2X10-7 einstein/sec-ml. Chloroacetic acid does not absorb UV radiation above 290 nm appreciably and would therefore not directly photolyze. It very slowly photodechlorinates in air-saturated solutions. The rate decreases after a few hours. Direct photodechlorination is much lower in the absence of oxygen. The presence of sensitizers such as p-cresol and tryptophan that generate superoxide radicals increases the rate of photodechlorination by up to 16-fold. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to chloroacetic acid may occur through inhalation and dermal contact with this compound at workplaces where chloroacetic is produced or used. The general population may be exposed to chloroacetic acid through consumption of drinking water, as it is a disinfectant by-product found in some drinking waters as a result of the chlorination process. (SRC) ARTS: *Chloroacetic acid's production and use in the manufacture of cellulose ethers, mainly carboxymethylcellulose (CMC), herbicides, thioglycolic acid, surfactants, cyanoacetic acid, phenoxyacetic acid, glycine, and chloroacetic acid esters(1) may result in its release to the environment through various waste streams(SRC). [R55] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.2(SRC), determined from a log Kow of 0.22(2) and a regression-derived equation(3), indicates that chloroacetic acid is expected to have very high mobility in soil(SRC). Volatilization of chloroacetic acid from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.32X10-9 atm-cu m/mole(SRC) from its vapor pressure, 6.50X10-2 mm Hg(4), and water solubility, 6.14X10+6 mg/l(4). Chloroacetic acid is not expected to volatilize from dry soil surfaces(SRC) based upon it's vapor pressure(4). Chloroacetic acid is readily biodegraded in screening studies using a sewage or acclimated sludge inoculum; greater than 70-90% degradation was reported in 5-10 days(5-9). Degradation is increased by acclimation(8,9) and involves dechlorination(9). Biodegradation occurs in soil; however, under acidic conditions at low temperature chloroacetic acid is comparatively resistant(10). [R56] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.2(SRC), determined from a log Kow of 0.22(2) and a regression-derived equation(3), indicates that chloroacetic acid is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.32X10-9 atm-cu m/mole(SRC) from its vapor pressure, 6.50X10-2 mm Hg(6), and water solubility, 6.14X10+6 mg/l(6). A pKa of 2.87(7) indicates chloroacetic acid will exist almost entirely in the ionized form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process. According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow(2), and a regression-derived equation(5), suggests the potential for bioconcentration in aquatic organisms is low. Chloroacetic acid was mineralized in river water with 73% conversion to carbon dioxide in 8-10 days at 29 deg C(8). No biodegradation was reported for either river water or seawater samples after a 3 day incubation(9); this time period may have been too short to allow for acclimation(SRC). Chloroacetic acid does not absorb UV radiation above 290 nm appreciably(10) and would therefore not directly photolyze(SRC). It very slowly photodechlorinates in air-saturated solutions with < 0.4% being converted to free chloride when irradiated for 11 hours in a laboratory photoreactor at 300 nm(10). Direct photodechlorination is much lower in the absence of oxygen(10). The presence of sensitizers such as p-cresol and tryptophan that generate superoxide radicals increases the rate of photodechlorination by up to 16-fold(10). [R57] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), chloroacetic acid, which has a vapor pressure of 6.50X10-2 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase chloroacetic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 20 days(SRC), calculated from its rate constant of 7.9X10-13 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). [R58] BIOD: *AEROBIC: Chloroacetic acid, at 100 mg/l, was 65% degraded in 21 days using an activated sludge inoculum(1). CO2 evolution was 14-24% and 73% of the theoretical amount possible at a chloroacetic acid concentration of 4.5 and 9.0 mg carbon/l, respectively, after a 7 day incubation with an activated sludge inoculum(2). Chloroacetic acid was completely degraded in the closed bottle test (at 5 mg/l), the Modified OECD Screening Test (at 5 mg C/l), and the Zahn-Wellens Test (at 1000 mg/l)(3). Chloroacetic acid is degraded in laboratory biodegradation tests using sewage or acclimated sludge inocula with greater than 70-90% degradation being reported in 5-10 days(4-7,9). Degradation is increased by acclimation(7,9) and involves dechlorination(7). Mineralization occurs in river water with 73% of the chemical being converted to carbon dioxide in 8-10 days at 29 deg C(8). The biodegradability of chloroacetic acid, at 10 ppm, was measured in both river water and seawater using the cultivation method; no biodegradation was reported for both samples after a 3 day incubation(10). Based on these results, this compound was determined to be difficult to degrade(10). [R59] ABIO: *The rate constant for the vapor-phase reaction of chloroacetic acid with photochemically-produced hydroxyl radicals has been estimated as 7.9X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 20 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Based on a measured pKa of 2.87(2), chloroacetic acid is expected to almost completely exist in its ionized state at environmental pH values(SRC). Chloroacetic acid does not absorb UV radiation above 290 nm appreciably(3) and would therefore not directly photolyze(SRC). It very slowly photodechlorinates in air-saturatedsolutions with < 0.4% being converted to free chloride when irradiated for 11 hours in a laboratory photoreactor(3). Direct photodechlorination is much lower in the absence of oxygen(3). The presence of sensitizers such as p-cresol and tryptophan that generate superoxide radicals increases the rate of photodechlorination by up to 16-fold(3). Hydrolysis was negligible during the course of these experiments(3). [R60] BIOC: *An estimated BCF of 3 was calculated for chloroacetic acid(SRC), using a log Kow of 0.22(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R61] KOC: *The Koc of chloroacetic acid is estimated as 1.2(SRC), using a log Kow of 0.22(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that chloroacetic acid is expected to have very high mobility in soil. [R62] VWS: *The Henry's Law constant for chloroacetic acid is estimated as 1.32X10-9 atm-cu m/mole(SRC) from its vapor pressure, 6.50X10-2 mm Hg(1), and water solubility, 6.14X10+6 mg/l(1). This Henry's Law constant indicates that chloroacetic acid is expected to be essentially nonvolatile from water surfaces(2). Chloroacetic acid's estimated Henry's Law constant(1) indicates that volatilization from moist soil surfaces will not occur(SRC). Chloroacetic acid is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 6.5X10-2 mm Hg(1). [R63] WATC: *DRINKING WATER: Drinking water samples collected from Philadelphia, PA (in 1976), Ottumwa, IO (in 1976), and Seattle, WA (in 1976) contained chloroacetic acid at unreported concentrations(1). Finished drinking water from the Philadelphia Suburban Water Co, the Metropolitan Water District of Southern California, and the cities of Houston, TX and Corpus Christi, TX contained chloroacetic acid at below detection limits, 1.17 ug/l, 1.29 ug/l, and below detection limits, respectively (unreported detection limits)(2). Water samples collected from 35 drinking water treatment facilities during 1988 contained chloroacetic acid at concentrations ranging from < 1.0 to 1.2 ug/l(3). [R64] *SURFACE WATER: Chloroacetic acid was found in river water, canal water, and seawater at a min-max, median concn of < 0.029-6.31, 0.832 ug/l, < 0.029-8.78, 1.75 ug/l, and < 0.029-0.32, 0.051 ug/l, respectively, in Tokyo, Japan(1). [R65] *RAIN/SNOW/FOG: Rainwater samples collected in Zurich, Switzerland in the summer of 1993 measured concentrations of chloroacetic acid exceeding 500 ng/l(1). [R66] EFFL: *Effluent from a Blue Plains, Washington, DC advanced waste treatment plant contained chloroacetic acid at unreported concentrations(1). Chloroacetic acid was measured in the flue gases from the municipal incinerator at Boras, Sweden at concentrations from 3.2 to 7.8 ug/cu m(2). Kraft pulp mill bleach plant effluents contained chloroacetic acid from 1-4 g/ton pulp(3). Chloroacetic acid was detected in the spent chlorination liquor from the bleaching of sulphite pulp at concentrations ranging from 0.1 to 0.7 g/ton pulp(4). Chloroacetic acid emitted into the air is mainly from manufacturing processes(5). Chloroacetic acid has been detected in Canadian drinking water as a by-product of the processes used by water treatment plants(6). [R67] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 11,176 workers (1960 of these are female) are potentially exposed to chloroacetic acid in the US(1). Occupational exposure to chloroacetic acid may occur through inhalation and dermal contact with this compound at workplaces where chloroacetic acid is produced or used(SRC). The general population may be exposed to chloroacetic acid through consumption of drinking water, as it is a disinfectant by-product found in some drinking waters as a result of the chlorination process(SRC). [R68] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 0.3 ppm, skin; Short-term Exposure Limit (STEL) 1 ppm, 15 min, skin. [R69] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Chloroacetic acid is produced, as an intermediate or a final product, by process units covered under this subpart. [R70] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Chloroacetic acid is included on this list. [R71] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 60 ug/l /Haloacetic acids/ [R72] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 14 ug/l [R72] CERC: *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Chloroacetic acid is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100/10,000 lbs. [R73] *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R74] FDA: *Chloroacetic acid is an indirect food additive for use only as a component of adhesives. [R75] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2008. Analyte: Chloroacetic acid. Matrix: Air. Sampler: Solid sorbent tube (silica gel, 100 mg/50 mg, with glass wool plugs). Flow Rate: 0.05 to 0.2 l/min. Sample Size: 1 to 100 liters. Shipment: Routine. Sample Stability: At least 7 days at 25 deg C. [R76] ALAB: *SPECTROPHOTOMETRIC ESTIMATION OF WINE AND OTHER SUBSTRATES LACKS SPECIFICITY BECAUSE OF CONTAMINANTS SUCH AS PHENOXYACETIC ACID HERBICIDES. [R77] *AOAC Method 942.10. Titrimetric method for determination of monochloroacetic acid in nonalcoholic beverages and wines. [R78] *NIOSH Method 2008. Determination of Chloroacetic Acid by Ion Chromatography. For use with air samples. Detection limit = 4X10-4 mg/cu m. [R79] *APHA Method 6233-B. Haloacetic Acids and Trichlorophenol in Water by Micro Liquid-Liquid Extraction and Gas Chromatography. Analysis of drinking water by capillary GC/ECD. MDL = 0.082 ug/l. [R80] *EMSLC Method 552. Determination of Haloacetic Acids in Drinking Water by Liquid-Liquid Extraction, Derivatization, and Gas Chromatography with Electron Capture Detection. Analysis of drinking water by capillary GC/ECD. MDL = 0.052 ug/l. [R80] *EMSLC Method 552.1. Determination of Haloacetic Acids in Drinking Water by Ion-Exchange Liquid-Solid Extraction, and Gas Chromatography with Electron Capture Detection. Revision 1.0. Analysis of drinking water by capillary GC/ECD. MDL = 0.21 ug/l. [R80] *AOAC Method 949.09. Monofluoroacetic Acid Pesticide Residues by Qualitative Test (Sodium Salt, 1080). For use with food samples. [R78, 305] *AOAC Method 942.09. Monochloroacetic Acid in Liquids and Preservatives. Method gives procedures for the Optical-Crystallographic Properties of Barium Salt Test, the Indigo Test, and the Pyridine Test. [R78, 1149] *AOAC Method 942.1. Monochloroacetic Acid in Nonalcoholic Beverages and Wines. Titrimetric Method. [R78, 1150] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Chemical Profile: Chloroacetic acid (1985). Aspects covered in this data sheet: exposure limitations; personal protective equipment; fire hazards; fire fighting; disposal; first aid; spills. DHHS/NTP; Toxicology and Carcinogenesis Studies of Monochloroacetic Acid in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 396 (1992) NIH Publication No. 92-2851 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 352 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 251 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994. R5: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. R6: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 538 R8: SRI R9: Hashimoto S et al; Environ Toxicol Chem 17: 798-805 (1998) R10: Kavaler AR; Chemical Marketing Reporter. April 17 (1995) R11: Reimann S et al; Environ Sci Technol 30: 2340-44 (1996) R12: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-203 R13: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R14: Bureau of Explosives; Emergency Handling of Haz Matl in Surface Trans p.120 (1981) R15: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R16: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-6 R17: Serjeant, E.P., Dempsey B.; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23, 1979. New York, New York: Pergamon Press, Inc. R18: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 4 R19: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 223 R20: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V1 171-8 R21: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 418 R22: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 773 R23: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R24: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 722 R25: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-25 R26: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. R27: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 46 R28: International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998.,p. 104.13 R29: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978. 50 R30: 49 CFR 171.2 (7/1/99) R31: IATA. Dangerous Goods Regulations. 40th Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 1999. 127 R32: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6097-1, 6097-2 (1998) R33: OPAVSKY W AND MACPHERSON E; GER OFFEN PATENT NUMBER 2430193 1/15/76 (WACKER-CHEMIE GMBH) R34: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R35: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 137 R36: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 640 R37: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R38: Hayes, W. J., Jr. Toxicology of Pesticides Baltimore: Williams and Wilkins, 1975. 160 R39: HAYES ET AL, TOXICOL APPL PHARMACOL 26 (1): 93 (1973) R40: RANNUG ET AL, CHEM BIOL INTERACT 12 (3-4): 251 (1976) R41: DOEDENS D AND J ASHMORE; BIOCHEM PHARMACOL 21 (12): 1745 (1972) R42: AMACHER DE AND TURNER GN; MUTAT RES 97 (1): 49 (1982) R43: Quick MP; Vet Rec 113: 155-156 (1983) R44: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R45: McGregor DB et al; Environ Mutagen 9: 143-60 (1987) R46: Kuhn R et al; Water Res 23 (4): 495-99 (1989) R47: Kuhn R et al; Water Res 23 (4): 501-10 (1989) R48: Masuda Y, Nakayama N; Toxicol Appl Pharmacol 71 (1): 42-53 (1983) R49: Toxicology and Carcinogenesis Studies of Monochloroacetic Acid in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 396 (1992) NIH Publication No. 92-2851 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R50: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. R51: Industrial Bio-Test Laboratories; Letter from Hercules Incorporated to USEPA Submitting Information on Monochloroacetic Acid with Attachments, (1978), EPA Doc. No. 8EHQ-0578-0154PS, Fiche No. OTS0200536 R52: YLLNER S; ACTA PHARMACOL TOXICOL 30 (1-2): 69 (1971) R53: YLLNER, S; ACTA PHARMACOL TOXICOL 30 (1-2): 69 (1971) R54: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 907 R55: (1) Kavaler AR; Chemical Marketing Reporter. Chemical Profile: Chloroacetic acid. April 17 (1995) R56: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Amer Chem Soc, Washington, DC. p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Freiter ER; Kirk-Othmer Encycl Chem Tech 3rd ed NY, NY: John Wiley 1: 171-8 (1978) (5) Zahn R, Wellens H; Z Wasser Abwasser Forschung 13: 1-7 (1980) (6) Zahn R, Wellens H; Chemiker Z 98: 228-32 (1974) (7) Dias FF, Alexander M; Appl Microbiol 22: 1114-8 (1971) (8) Jacobson SN, Alexander M; Appl Environ Microbiol 42: 1062-6 (1981) (9) Thom NS, Agg AR; Proc Roy Soc London B 189: 347-57 (1975) (10) Jensen HL; Tidsskr Planteavl 63: 470-99 (1959) R57: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. nn (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Franke C et al; Chemosphere 29: 1501-4 (1994) (5) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (6) Freiter ER; Kirk-Othmer Encycl Chem Tech 3rd ed. NY, NY: Wiley 1: 171-8 (1978) (7) Serjeant EP, Dempsey B; Ionisation constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. NY, NY: Pergamon pp. 989 (1979) (8) Boethling RS, Alexander M; Appl Environ Microbiol 37: 1211-6 (1979) (9) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (10) Draper WM, Crosby DG; J Agric Food Chem 31: 734-37 (1983) R58: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (1) Freiter ER; Kirk-Othmer Encycl Chem Tech 3rd Ed 1: 171-8 (1978) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R59: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Struijs J, Stoltenkamp J; Ecotoxicol Environ Safety 19: 204-11 (1990) (3) Gerike P, Gode P; Chemosphere 21: 799-812 (1990) (4) Zahn R, Wellens H; Z Wasser Abwasser Forschung 13: 1-7 (1980) (5) Zahn R, Wellens H; Chemiker Z 98: 228-32 (1974) (6) Dias FF, Alexander M; Appl Microbiol 22: 1114-8 (1971) (7) Jacobson SN, Alexander M; Appl Environ Microbiol 42: 1062-6 (1981) (8) Boethling RS, Alexander M; Appl Environ Microbiol 37: 1211-6 (1979) (9) Thom NS, Agg AR; Proc Roy Soc London B 189: 347-57 (1975) (10) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) R60: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993 (2) Serjeant EP, Dempsey B; Ionization Constants of Organic Acids in Aqueous Solution. IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press (1979) (3) Draper WM, Crosby DG; J Agric Food Chem 31: 734-37 (1983) R61: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R62: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17- 28 (1983) R63: (1) Freiter ER; Kirk-Othmer Encycl Chem Tech 3rd ed, NY, NY: John Wiley 1: 171-8 (1978) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15- 29 (1990) R64: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. Analysis Results for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank Concentrates. USEPA-600/1-84-020A (NTIS PB85-128221). Columbus, OH: Columbus Labs. Health Eff Res Lab (1984) (2) Cowman GA, Singer PC; Environ Sci Technol 30: 16-24 (1996) (3) Krasner SW et al; J Amer Water Works Assoc 81: 41-53 (1989) R65: (1) Hashimoto S et al, Environ Toxicol Chem 17: 798-805 (1998) R66: (1) Reimann S et al, Environ Sci Technol 30: 2340-44 (1996) R67: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. Analysis Results for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank Concentrates. USEPA-600/1-84-020A (NTIS PB85-128221). Columbus, OH: Columbus Labs. Health Eff Res Lab (1984) (2) Mowrer J, Nordin J; Chemosphere 16: 1181-92 (1987) (3) Lindstrom K, Osterberg F; Environ Sci Technol 20: 133-138 (1986) (4) Carlberg GE et al; Sci Total Environ 48: 157-67 (1986) (5) Shareef GS et al; Hazardous/Toxic Air Pollutant Control Technology: A Literature Review. USEPA-600/2-84-194. (NTIS PB85-137107). Research Triangle Park, NC: Radian Corp (1984) (6) Williams DT et al; Chemosphere 34: 299-316 (1997) R68: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R69: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.40 R70: 40 CFR 60.489 (7/1/99) R71: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R72: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R73: 40 CFR 355 (7/1/99) R74: 40 CFR 302.4 (7/1/99) R75: 21 CFR 175.105 (4/1/99) R76: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2008-1 R77: BALUJA ET AL; ARCH ENVIRON CONTAM TOXICOL 1 (4): 375 (1973) R78: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R79: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R80: USEPA; EMMI. Environmental Monitoring Methods Index. Version 2.0. NTIS PB-95-502415 (1995) RS: 61 Record 99 of 1119 in HSDB (through 2003/06) AN: 945 UD: 200302 RD: Reviewed by SRP on 1/31/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYL-VANILLIN- SY: *BENZALDEHYDE,-3-ETHOXY-4-HYDROXY-; *BOURBONAL-; *ETHAVAN-; *ETHOVAN-; *3-ETHOXY-4-HYDROXYBENZALDEHYDE-; *ETHYLPROTAL-; *ETHYLPROTOCATECHUIC-ALDEHYDE-; *ETHYLVANILLIN-; *4-HYDROXY-3-ETHOXYBENZALDEHYDE-; *PROTOCATECHUIC-ALDEHYDE-ETHYL-ETHER-; *QUANTROVANIL-; *VANILLAL-; *VANILLIN,-ETHYL-; *VANIROM-; *VANIROME- RN: 121-32-4 MF: *C9-H10-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM SAFROLE BY ISOMERIZATION TO ISOSAFROLE AND...OXIDATION TO PIPERONAL. THE METHYLENE LINKAGE IS...BROKEN BY HEATING PIPERONAL IN AN ALCOHOLIC SOLN OF POTASSIUM HYDROXIDE; FINALLY THE RESULTING PROTOCATECHUALDEHYDE IS REACTED WITH ETHYL ALCOHOL. [R1] *FROM GUAETHOL BY CONDENSATION WITH CHLORAL TO YIELD 3-ETHOXY-4-HYDROXYPHENYL TRICHLOROMETHYL CARBINOL. THIS IS THEN BOILED WITH AN ALCOHOLIC SOLN OF POTASSIUM HYDROXIDE OR SODIUM HYDROXIDE ACIDIFIED, AND EXTRACTED WITH CHLOROFORM TO YIELD ETHYL VANILLIN... [R1] *...ETHYL VANILLIN.../IS/ PREPARED FROM CELLULOSE INDUSTRY WASTE PRODUCTS (LIGNIN) BY THE SULFITE PROCESS OR OBTAINED FROM GUAIACOL OR EUGENOL. [R2] *BY REACTING O-ETHOXYPHENOL WITH FORMALDEHYDE AND P-NITROSODIMETHYLANILINE IN THE PRESENCE OF ALUMINUM AND WATER. IT MAY ALSO BE PREPD BY APPLICATION OF REIMER-TIEMANN REACTION TO O-ETHOXYPHENOL. [R3] *GA KIRKHGOF, RUSSIAN PATENT 44,929 (NOV 1935), CHEM ABSTR 32, 2961 (1938); CN GENEFF, US PATENT 2,154,979 (APR 18, 1939), CHEM ABSTR 33, 5415 (1939). [R4, 1695] FORM: *Grades: NF /National Formulary/; FCC /Food Chemicals Codex/. [R5] MFS: *Rhone-Poulenc, Inc, Hq, 52 Vanderbilt Avenue, New York NY 10017, (201) 297-0100; Specialty Group, CN 5266, Princeton, NJ 08543; Production sites: Freeport, TX 7541; New Brunswick, NJ 08901 [R6] OMIN: *REPORTED USES: NON-ALCOHOLIC BEVERAGES, 20 PPM; ALCOHOLIC BEVERAGES, 100 PPM; ICE CREAM, ICES, ETC, 47 PPM; CANDY, 65 PPM; GELATINS AND PUDDINGS, 74 PPM; CHEWING GUM, 110 PPM; ICINGS AND TOPPINGS, 140-200 PPM; CHOCOLATE, 250 PPM; IMITATION VANILLA EXTRACTS, 28000 PPM. [R1] *FLAVORING POWER IS 2-4 TIMES STRONGER THAN VANILLIN [R1] *IT IS A SUBSTANCE WHICH MIGRATES TO FOOD FROM PACKAGING MATERIALS... [R7] *FEMA NUMBER 2464 [R1] *E MATHER AND WE HAMER, BRITISH PATENT 453,482 (SEPT 4, 1936), CHEM ABSTR 31, 1039 (1937); E MATHER AND WE HAMER, US PATENT 2,199,748 (MAY 7, 1940), CHEM ABSTR 34, 5854 (1940); F BOEDECKER AND H VOLK, US PATENT 2,062,205 (NOV 24, 1936), CHEM ABSTR 31, 701 (1937). [R4, 1695] USE: *In perfumery [R8] *USED AS A CHEMICAL INTERMEDIATE [R4, 1695] *FLAVORING AGENT IN VANILLA AND CHOCOLATE FLAVORED FOODS [R9] *... Replacement or fortifier of vanillin. [R5] CPAT: *100% AS A FLAVORING AGENT (1976) [R9] PRIE: U.S. PRODUCTION: *(1972) 1.27X10+7 GRAMS [R9] *(1975) GREATER THAN 4.5X10+7 GRAMS [R9] U.S. IMPORTS: *(1972) 6.93X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R9] *(1976) 1.06X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Fine, crystalline needles [R10]; *WHITE OR SLIGHTLY YELLOWISH CRYSTALS [R3]; *Colorless flakes [R8] ODOR: *INTENSE VANILLA [R1] TAST: *SWEET [R1] BP: *285 DEG C [R1] MP: *77.5 deg C [R11] MW: *166.18 [R11] OWPC: *log Kow = 1.61 @ 28 deg C [R12] PH: *SOLUTIONS ARE ACID TO LITMUS [R3] SOL: *SLIGHTLY SOL IN WATER (1.3% @ 50 DEG C) [R1]; *Sol in ethanol, ether, benzene [R11]; *Sol in glycerol, propylene glycol [R8]; *Solubility in 95% alcohol about 1 g/2 ml [R8]; *FREELY SOL IN SOLN OF FIXED ALKALI HYDROXIDES [R3]; *In water, 2,822 mg/l @ 25 deg C [R12] SPEC: *INDEX OF REFRACTION: 1.485 (ALPHA); GREATER THAN 1.733 (GAMMA) [R13]; *SADTLER REFERENCE NUMBER: 5178 (IR, PRISM); 211 (IR, GRATING); 318 (UV) [R14]; *IR: 3725 (Coblentz Society Spectral Collection) [R15, p. V1 140]; *UV: 17152 (Sadtler Research Laboratories Spectral Collection) [R15, p. V1 140]; *NMR: 1320 (Sadtler Research Laboratories Spectral Collection) [R15, p. V1 140]; *MASS: 1083 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R15, p. V1 140]; *MASS: 4250 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R15, p. V1 619] VAP: *1.04X10-5 mm Hg @ 25 deg C [R16] OCPP: *CONVERSION FACTORS: 1 PPM IS EQUIV TO 6.78 MG/CU M; 1 MG/L IS EQUIV TO 147.2 PPM @ 25 DEG C, 760 MM HG [R4, 1696] *ODOR DETECTION IN WATER: 1.00X10-1 PPM [R17, 497] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Incompatible with oxidizing materials, BI3. /Ethers/ [R18, 1500] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R18, 1611] SERI: *A human skin irritant. [R18, 1610] *... Highly irritating action on the eyes and mucous membranes of the respiratory tract. /Aldehydes/ [R18, 84] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *NOT STABLE; IN CONTACT WITH IRON OR ALKALI, IT EXHIBITS A RED COLOR AND LOSES ITS FLAVORING POWER [R1] *AFFECTED BY LIGHT [R19] STRG: *... Should not be stored near powerful oxidizers or in areas of high fire hazard. They should be kept cool and the containers electrically grounded to avoid sparks. /Ethers/ [R18, 1500] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Administer activated charcoal ... . Dilution may be contraindicated because it may increase absorption. Do not use emetics ... . Cover skin burns with dry sterile dressings after decontamination ... . /Phenols and Related compounds/ [R20, p. 243-4] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Phenols and Related Compounds/ [R20, 139] HTOX: *...WHEN TESTED AS 2% IN PETROLATUM, ETHYL VANILLIN PRODUCED MILD IRRITATION AFTER 48-HR CLOSED-PATCH TEST IN 25 HUMAN SUBJECTS. [R17, 497] *In a volunteer study, ethyl vanillin (EV) demonstrated no sensitizing potential but was a skin irritant. [R21] NTOX: */RESEARCHERS/...ADMIN TO RABBITS BY INTUBATION SINGLE DOSES...AS 4 OR 5% SOLUTIONS IN MILK. ...DOSES OF 3.0 G/KG OR MORE...WERE LIKELY TO BE LETHAL. TYPICAL SIGNS OF INTOXICATION...WERE INCREASED RESPIRATION, LACRIMATION, DYSPNEA, COLLAPSE AND DEATH IN COMA. NO CONVULSIONS WERE OBSERVED. [R4, 1697] *.../RESEARCHERS ADMIN/ APPROXIMATELY 300 MG/KG...INTRAGASTRICALLY TO RATS TWICE A WEEK FOR 14 WEEKS WITHOUT SIGNS OF ILLNESS. [R4, 1697] *WHEN 20 MG/KG/DAY FED TO RATS FOR 18 WK NO EFFECTS PRODUCED, WHEREAS RATS FED 64 MG/KG/DAY FOR 10 WK SHOWED REDN IN GROWTH RATE AND MILD CARDIAC, RENAL, HEPATIC, LUNG, SPLEEN, AND STOMACH INJURIES. [R17, 497] *WHEN...ETHYL VANILLIN WAS ADMINISTERED SC TO RATS IN SINGLE DOSES AS A 4% SOLN IN MILK, DOSES OF 1.8 G/KG OR MORE WERE LIKELY TO BE LETHAL... [R17, 483] *...COMPARATIVE ACUTE IP TOXICITIES OF VANILLIN, ETHYL VANILLIN, AND THEIR ORTHO ISOMERS ON MOUSE /LD50 0.75 G/KG/ AND GUINEA PIG /LD50 1.14 G/KG/. .../ETHYL VANILLIN AND ETHYL O-VANILLIN/ WERE STRONG CONVULSIVE AGENTS... [R17, 483] *...LETHAL DOSES OF VANILLIN ADMIN IP /TO RABBITS/ CAUSED...DROP IN BLOOD PRESSURE / and /...DOUBLING OF RESPIRATION RATE. .../RESPIRATION/ RETURNED TO NORMAL.../BUT/ BLOOD PRESSURE CONTINUED TO FALL...CAUSING DEATH. ...ETHYL VANILLIN PRODUCED.../SIMILAR/ EFFECTS...BUT...GRADUALLY. [R4, 1698] *NEITHER 20,000 /2%/ and 50,000 PPM /5%/ OF ETHYL VANILLIN FED TO MALE RATS IN DIET FOR 1 YR, NOR 5000, 10,000, and 20,000 PPM /2%/ FED TO MALE AND FEMALE RATS IN DIET FOR 2 YR PRODUCED ANY EFFECTS. [R17, 497] *Ethyl vanillin was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Ethyl vanillin was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, 6.000, and 8.000 mg/plate. The highest ineffective dose tested without appreciable toxicity in any S. typhimurium strain was 6.000 mg/plate in strains TA1537 and TA98 without activation. At this dose, strains TA100 and TA1535 exhibited some clearing of the background bacterial lawn when tested without activation. Slight to total clearing of the background lawn was observed at the high dose. [R22] *Acute oral toxicity was low by the oval route in rats and rabbits although a high oral dose caused central nervous system effects and coma in rats and rabbits. In rats and rabbits treated by multiple oral dosing, cellular changes were seen in the heart, lungs, liver and kidneys. A limited long term feeding study generated no evidence of carcinogenicity. Ethyl vanillin did not cause structural damage to mammalian chromosomes in vivo on in vitro. It was non mutagenic in the bacterial Ames test and did not induce heritable mutations in fruit files. [R21] NTXV: *LD50 Rat oral 1590 mg/kg; [R18, 1610] *LD50 Mouse ip 750 mg/kg; [R18, 1610] *LD50 Guinea pig ip 1140 mg/kg; [R18, 1610] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethyl vanillin's production and use as a flavoring agent and in perfumery may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 1X10-5 mm Hg at 25 deg C indicates ethyl vanillin will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase ethyl vanillin will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 12 hours. Particulate-phase ethyl vanillin will be removed from the atmosphere by wet and dry deposition. If released to soil, ethyl vanillin is expected to have moderate mobility based upon an estimated Koc of 180. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 8.1X10-10 atm-cu m/mole. Ethyl vanillin is not expected to volatilize from dry soil surfaces based upon its vapor pressure. A 52.9% of the theoretical BOD was achieved in 5 days with a sewage inoculum, suggesting that biodegradation may be rapid in the environment. If released into water, ethyl vanillin is expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 10 suggests bioconcentration in aquatic organisms is low. Occupational exposure to ethyl vanillin may occur through inhalation and dermal contact with this compound at workplaces where ethyl vanillin is produced or used. The general population may be exposed to ethyl vanillin via dermal contact with perfumes and ingestion of food products that contain this compound as a flavorant. (SRC) NATS: */IT IS/ NOT REPORTED FOUND IN NATURE. [R1] ARTS: *Ethyl vanillin's production and use as a flavoring agent(1) and in perfumery(2) may result in its release to the environment through various waste streams(SRC). [R23] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 180(SRC), determined from a log Kow of 1.61(2) and a regression-derived equation(3), indicates that ethyl vanillin is expected to have moderate mobility in soil(SRC). Volatilization of ethyl vanillin from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 8.1X10-10 atm-cu m/mole(SRC), determined from its experimental values for vapor pressure, 1X10-5 mm Hg at 25 deg C(4), and water solubility, 2,822 mg/l at 25 deg C(2). Ethyl vanillin is not expected to volatilize from dry soil surfaces(SRC) based upon its measured vapor pressure(4). A 52.9% of the theoretical BOD was achieved in 5 days with a sewage inoculum(5), suggesting that biodegradation may be rapid in the environment(SRC). [R24] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 180(SRC), determined from a log Kow of 1.61(2) and a regression-derived equation(3), indicates that ethyl vanillin is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 8.1X10-10 atm-cu m/mole(SRC) determined from its experimental values for vapor pressure, 1X10-5 mm Hg at 25 deg C(4), and water solubility, 2,822 mg/l at 25 deg C(2). According to a classification scheme(5), an estimated BCF of 10(3,SRC), from its log Kow(2) suggests the potential for bioconcentration in aquatic organisms is low(SRC). A 52.9% of the theoretical BOD was achieved in 5 days with a sewage inoculum(6), suggesting that biodegradation may be rapid in the environment(SRC). [R25] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethyl vanillin, which has a vapor pressure of 1X10-5 mm Hg at 25 deg C(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase ethyl vanillin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 12 hours(SRC) from its estimated rate constant of 3.3X10-11 cu cm/molecule-sec at 25 deg C(SRC), determind by a fragment constant estimation method(3). Particulate-phase ethyl vanillin may be removed from the air by wet and dry deposition(SRC). [R26] BIOD: *A 52.9% of the theoretical BOD was achieved in 5 days with a sewage inoculum(1), suggesting that biodegradation may be rapid in the environment(SRC). [R27] ABIO: *The rate constant for the vapor-phase reaction of ethyl vanillin with photochemically-produced hydroxyl radicals has been estimated as 3.3X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 12 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Ethyl vanillin is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). [R28] BIOC: *An estimated BCF of 10 was calculated for ethyl vanillin(SRC), using a log Kow of 1.61(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF value suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R29] KOC: *The Koc of ethyl vanillin is estimated as approximately 180(SRC), using a log Kow of 1.61(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that ethyl vanillin is expected to have moderate mobility in soil(SRC). [R30] VWS: *The Henry's Law constant for ethyl vanillin is estimated as 8.1X10-10 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 1X10-5 mm Hg(1), and water solubility, 2,822 mg/l(2). This Henry's Law constant indicates that ethyl vanillin is expected to be essentially nonvolatile from water surfaces(3). Ethyl vanillin's estimated Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces is not expected(SRC). Ethyl vanillin is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R31] SEDS: *Ethyl vanillin was identified, not quantified, in suspended sediment from Singletary Lake, NC(1). [R32] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 18,034 workers (5,059 of these are female) are potentially exposed to ethyl vanillin in the US(1). Occupational exposure to ethyl vanillin may occur through inhalation and dermal contact with this compound at workplaces where ethyl vanillin is produced or used(SRC). The general population may be exposed to ethyl vanillin via dermal contact with perfumes and ingestion of food products that contain this compound as a flavorant(SRC). [R33] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Ethyl vanillin is included on this list. [R34] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R35] FDA: *Substances migrating to food from paper and paperboard products used in food packaging that are generally recognized as safe for their intended use, within section 409 of the Act. Ethyl vanillin is included on this list. [R36] *Synthetic flavoring substances and adjuvants /for human consumption/ that are generally recognized as safe for their intended use, withn the meaning of section 409 of the Act. Ethyl vanillin is included on this list. [R37] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *...ETHYL VANILLIN CAN BE TRAPPED FROM THE AIR BY SCRUBBING WITH METHANOL. ... SOLUTIONS CAN BE ANALYZED BY ULTRAVIOLET SPECTROPHOTOMETRY. STRONG ABSORPTION BANDS OCCUR FROM...310 AND 278 NM. ...IN THE RANGE 0.01 MG/100 ML METHANOL CAN BE MEASURED ACCURATELY WHEN A 10-CM CELL IS USED. [R4, 1696] *AOAC 966.13. Vanillin and ethyl vanillin in vanilla extract. Paper chromatographic method. [R38, 891] *AOAC 955.31. Vanillin, ethyl vanillin and coumarin in vanilla extract. Chromatographic separation method. [R38, 892] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: REVIEW WITH 13 REFERENCES. [R39] BIBRA working group, Ethyl vanillin, Toxicity profile; The British Industrial Biological Research Association; 4 (1967). In a volunteer study, ethyl vanillin (EV) demonstrated no sensitizing potential but was a skin irritant. SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 196 R2: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 1456 R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1230 R4: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 501 R6: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 622 R7: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 675 R8: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 654 R9: SRI R10: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 1691 R11: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-18 R12: Jin L et al; Chemosphere 35: 2707-12 (1997) R13: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 306 R14: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-142 R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R16: Yaws CL; Handbook of Vapor Pressure. Vol 3: C8-C28 Compounds. Houston,TX: Gulf Pub Co (1994) R17: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R18: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R19: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 369 R20: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R21: BIBRA working group; Toxicity profile. The British Industrial Biological Research Association; 4 (1967) R22: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R23: (1) Fenaroli's Handbook of Flavor Ingredients Volume 2. Furia TE, Bellanca N Eds. 2nd ed. Cleveland,OH: The Chemical Rubber Co (1975) (2) Budvari S; Merck Index, 12th ed, Whitehouse Station, NJ Merck and Co. p 654 (1996) R24: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Jin L et al; Chemosphere 35: 2707-12 (1997) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Yaws CL; Handbook of Vapor Pressure Vol 3 C8-C28 Compounds. Houston,TX: Gulf Publ Co (1994)(5) Babeu L, Vaishnav DD; J Indust Microb 2: 107-15 (1987) R25: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Jin L et al; Chemosphere 35: 2707-12 (1997) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Yaws CL; Handbook of Vapor Pressure Vol 3 C8-C28 Compounds. Houston,TX: Gulf Publ Co (1994) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Babeu L, Vaishnav DD; J Indust Microb 2: 107-15 (1987) R26: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yaws CL; Handbook of Vapor Pressure Vol 3 C8-C28 Compounds. Houston,TX: Gulf Publ Co (1994) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R27: (1) Babeu L, Vaishnav DD; J Indust Microb 2: 107-15 (1987) R28: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R29: (1) Jin L et al; Chemosphere 35: 2707-12 (1997) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R30: (1) Jin L et al; Chemosphere 35: 2707-12 (1997) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R31: (1) Yaws CL; Handbook of Vapor Pressure Vol 3 C8-C28 Compounds. Houston,TX: Gulf Publ Co (1994) (2) Jin L et al; Chemosphere 35: 2707-12 (1997) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R32: (1) Christman RF et al; Sci Total Environ 47: 195-210 (1985) R33: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R34: 40 CFR 716.120 (7/1/97) R35: 40 CFR 712.30 (7/1/97) R36: 21 CFR 182.90 (4/1/97) R37: 21 CFR 182.60 (4/1/97) R38: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R39: OPDYKE DL J; FRAGRANCE RAW MATERIALS. ETHYL VANILLIN; FOOD COSMET TOXICOL 13(1) 103 (1975) RS: 26 Record 100 of 1119 in HSDB (through 2003/06) AN: 949 UD: 200208 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GLUTARALDEHYDE- SY: *ALDESEN-; *CIDEX-; *1,3-Diformylpropane-; *Pesticide-Code:-043901-; *GLUTARAL-; *GLUTARALDEHYD- (CZECH); *GLUTARDIALDEHYDE-; *GLUTARIC-ACID-DIALDEHYDE-; *GLUTARIC-ALDEHYDE-; *GLUTARIC-DIALDEHYDE-; *HOSPEX-; *NCI-C55425-; *PENTANEDIAL-; *1,5-PENTANEDIAL-; *1,5-PENTANEDIONE-; *SONACIDE- RN: 111-30-8 MF: *C5-H8-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *THE 1:1 DIELS-ALDER ADDUCT OF ACROLEIN AND VINYL ALKYL ETHER IS HYDROLYZED YIELDING GLUTARALDEHYDE AND ALKANOL. [R1, 1102] *Prepared by heating 2-ethoxy-3,4-dihydro-2H-pyran with aq HCl [R2] FORM: *USEPA/OPP Pesticide Code 043901; Trade Names: Cidex, component of; Odix, component of; Aldesan; Alhydex; Glutaralum; Hospex; NCI-C55425; Sonacide; Coldcide-25 Microbiocide Concentrate; GKN-O Microbiocide Concentrate (043901+069104+069154). [R3] *IT HAS BEEN MARKETED AS 2% ALKALINE SOLN IN 70% ISOPROPANOL... [R4, 994] *CIDEX (ARBROOK) TOPICAL: SOLN (AQ) 2%. [R5] *Grades: 99%; 50% biological soln; 25% soln. [R6, 541] *EMPLOYED AS 25% SOLN IN WATER FOR EMBALMING FLUID. [R7, p. II-125] *2% AQ SOLN BUFFERED WITH 0.3% SODIUM CARBONATE TO PH OF 7.5-8.5 IS USEFUL FOR DISINFECTION AND STERILIZATION OF ENDOSCOPIC INSTRUMENTS AND PLASTIC AND RUBBER APPARATUS USED FOR INHALATION THERAPY AND ANESTHESIA. [R5] *Electron microscopy grade is highly purified [R8] *Biocide; supplied in acid solution and subsequently buffered to pH 8 [R9] MFS: *Polysciences, Inc., 400 Valley Rd., Warrington, PA 18976, (800) 523-2575; Production site: Warrington, PA 18976 [R10] *Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817-001, (203) 794-2000; Production site: Institute, WV 25103 [R10] *Vinings Industries, Inc., 245 TownPark Drive, Suite 200, Kennesaw, GA 30144, (800) 347-1542; Production site: Marietta, GA 30060 [R10] OMIN: *COST AND LACK OF STABILITY ARE IMPORTANT DRAWBACKS TO ITS USE. [R5] *NEITHER ALKALINE NOR ACIDIC SOLN IS DAMAGING TO MOST SURGICAL INSTRUMENTS. ALKALINE DEPOSITS POLYMERIC FILM AFTER FEW HR. [R4, 994] *...SUPERIOR TO FORMALDEHYDE AS STERILIZING AGENT. ... /AS 2% ALKALINE SOLN IN 70% ISOPROPANOL/...PERIOD OF 10 HR IS NECESSARY TO STERILIZE DRIED SPORES. ...ACIDIC /GLUTARALDEHYDE/ SOLN KILLS DRIED SPORES IN 20 MIN... [R4, 944] USE: *For Glutaraldehyde (USEPA/OPP Pesticide Code: 043901) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R3] *EMBALMING FLUID [R7, p. II-123] *Intermediate; cross-linking protein and polyhydroxy materials; tanning of soft leathers [R6, 542] *CHEM INT FOR ADHESIVES, SEALANTS, ELECTRICAL PRODUCTS [R11] *In sterilization of endoscopic instruments thermometers, rubber or plastic equipment which cannot be heat sterilized [R2] *Used as a biocide in the oil industry [R9] *The most popular enzyme cross-linking reagent; microbiol cells are also cross-linked with glutaraldehyde to yield cell pellets [R12] *Skin disinfectant [R13] *DISINFECTANT THAT IS VERY GOOD NOT ONLY AGAINST VEGETATIVE BACTERIA BUT ALSO AGAINST SPORES. ITS EFFICACY AGAINST FUNGI AND VIRUSES IS GOOD. ...DISINFECTANT OF CHOICE FOR COLD STERILIZATION OF SURGICAL INSTRUMENTS BUT IS BEING DISPLACED BY ETHYLENE OXIDE... GLUTARALDEHYDE AEROSOLS ARE ALSO USED TO "STERILIZE" HOSPITAL ROOMS; OPERATING AREAS, ETC. ACID GLUTARALDEHYDE IS MORE EFFECTIVE THAN ALKALINE GLUTARALDEHYDE... [R1, 1103] *Disinfectant [R14] *Gelatine hardening agent; biocide (cosmetics, water treatment, oilfield applications); leather tannive auxiliary [R15] *MEDICATION *TISSUE FIXATION PRIE: U.S. PRODUCTION: *(1974) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R11] *(1976) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R15]; *Oil [R2] ODOR: *Pungent odor [R16, 152] BP: *188 deg C (decomp) [R17] MP: *FP: -14 deg C [R6, 541] MW: *100.13 [R18] DEN: *0.72 [R6, 541] SOL: *Miscible in ethanol and water; sol in benzene [R17]; *SOL IN ETHER [R19] SPEC: *Index of refraction: 1.4338 @ 25 deg C [R2]; *MASS: NIST 1116 (NIST/EPA/MCDC Mass Spectral Database 1990 Version) [R20] VAPD: *3.4 (AIR= 1) [R21] VAP: *0.6 mm Hg at 30 deg C [R22] OCPP: *CONVERSION FACTORS: 1 MG/L= 245 PPM; 1 PPM= 4.1 MG/CU M [R21] *Hydroxyl radical reaction rate constant = 2.38X10-11 cu cm/molecule-sec @ 25 deg C [R23] *Polymerizes in water to a glassy form which regenerates the dialdehyde on vacuum distillation. [R2] *VP = 17 mm Hg @ 20 deg C; FP = -7 deg C /25% aqueous solution/; FP = -14 deg C /50% aqueous solution/ [R24] *VP = 17 mm Hg @ 20 deg C; FP = -7 deg C /25% aqueous solution/ [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Strong oxidizers, strong bases [Note: Alkaline solutions of glutaraldehyde (i.e., activated glutaraldehyde) react with alcohol, ketones, amines, hydrazines and proteins]. [R16, 152] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R25] SERI: *A severe skin and eye irritant in humans. [R25] *Contact with liquid causes severe irritation of eyes and irritation of skin. [R26] *Eye and respiratory irritation are noted at a level of 0.3 ppm. [R27] EQUP: *Goggles or face shield; rubber gloves. [R26] *Neoprene or butyl rubber gloves are protective. Latex rubber gloves are not as protective. [R28] *Wear appropriate personal protective clothing to prevent skin contact. [R16, 153] *Wear appropriate eye protection to prevent eye contact. [R16, 153] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R16, 153] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R16, 153] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Containment of vapors and prevention of skin contact are important industrial hygiene principles to help avoid sensitization of the skin and respiratory irritation and/or asthma. Proper skin protection must be provided as well as ventilation controls. [R28] *The worker should immediately wash the skin when it becomes contaminated. [R16, 153] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16, 153] *Contact lenses should not be worn when working with this chemical. [R16, 153] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SSL: *ACID GLUTARALDEHYDE IS MORE STABLE THAN ALKALINE GLUTARALDEHYDE [R1, 1103] *STABLE IN LIGHT, OXIDIZES IN AIR, POLYMERIZES IN HEAT [R1, 1103] *ALKALINE SOLUTION DEPOSITS POLYMERIC FILM AFTER FEW HR [R4, 994] *GLUTARAL LOSES ACTIVITY WITHIN 2 WK AFTER PREPN [R29, 1620] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R30] ANTR: *Skin that becomes contaminated with glutaraldehyde should be washed immediately or showered. [R27] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Aggressive airway management may be necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aldehydes and related compounds/ [R31, p. 234-35] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Intubation should be considered at the first sign of upper airway obstruction caused by edema. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Treat seizures with diazepam ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aldehydes and related compounds/ [R31, 235] HTOX: *WATER SOLNS OF ... GLUTARALDEHYDE ... ARE RELATIVELY STRONG IRRITANTS TO THE SKIN OR EYES. THEIR LOWER VAPOR PRESSURES, HOWEVER, REDUCE THE LIKELIHOOD THAT INHALATION WOULD BE A SUBSTANTIAL ROUTE OF EXPOSURE. [R32, 311] *...SEVERE EYE, PLUS NOSE AND THROAT IRRITATION WERE FELT BY OPERATOR AND INVESTIGATORS /IN COLD-STERILIZING PROCEDURE/, WHO ALSO EXPERIENCED SUDDEN HEADACHE. [R19] *IT CAN...CAUSE SENSITIZATION (ALLERGIC CONTACT DERMATITIS) FROM OCCASIONAL OR INCIDENTAL OCCUPATIONAL EXPOSURE. [R19] *Nine medical and nursing staff (4 male, 5 female) working in a endoscopy unit (with 2% glutaraldehyde on the disinfecting trolley) were offered a questionnaire to determine the symptoms associated with glutaraldehyde. Eight members of the staff (3 male, 5 female), who had been affected by the vapor, underwent clinical assessment, including details of any history of atopy. None of the staff affected had any previous history of allergy. Air samples obtained by a personal sampler over a period of 1 hr, from the breathing zone of the nurse carrying a cold sterilization process, contained 0.12 ppm glutaraldehyde. Air at the corridor bench contained 0.05 ppm. Clinical manifestations included watering of eyes, rhinitis, dermatitis, respiratory difficulty, nausea and headache. [R33] *Although glutaraldehyde is a weak allergen, the vapors from glutaraldehyde may act as an irritant to bronchial and laryngeal mucous membranes, and prolonged exposure could produce localized edema and other symptoms suggestive of an allergic response. [R28] *In a study simulating a complete cold sterilizing procedure lasting 12 min, the integrated sample of activated, 2% aqueous sol resulted in 0.38 ppm of glutaraldehyde measured at the operator's breathing zone. Although some irritation was recorded throughout this procedure, it was not until the end of the operation, when the equipment undergoing sterilization was being air-hose dried, that severe irritation of the eye, nose, and throat was experienced by the operator and by the investigators, who also experienced sudden headaches. [R34, 1991.703] *A 33 year old respiratory technologist developed occupational asthma as a result of exposure to glutaraldehyde. The case was documented by preshift and postshift spirometry, appropriate changes in peak expiratory flow rate, provocative concentration causing a 20% fall in forced expiratory volume in 1 second, and workplace challenge test. The subject had a history of asthma as a child with mild symptoms, readily relieved by bronchodilators. As an adult, she had symptoms briefly following colds. At age 29 she began working in a bronchoscopy unit at a local hospital; her asthma worsened since that time and she was using an albuterol inhalant three to four times a day. The subject also intermittently received courses of prednisone for acute exacerbations. The subject assisted physicians in fiberoptic bronchoscopy and also cleaned bronchoscopes after use with Sporicidin which contained 3.6% glutaraldehyde, 7% phenol, and 1.2% sodium-phenolate. Cleaning was performed in a small room with no ventilation. Sporicidin was placed in a basin that was not covered during cleaning. After diagnosis, the subject continued work but no longer performed the cleaning operation. As a result, her symptoms have decreased and she has been able to gradually reduce the dose of inhaled beclomethasone to 500 ug/day without recurrence. Lung function tests have returned to normal levels. [R35] *This letter reports two cases of work-related asthma in radiographers, each case attributable to a different agent. Tests on one patient revealed an asthmatic response on exposure to glutaraldehyde, a hardener used during developing, while tests on the other showed adverse reactions to fixative chemicals. Although it is likely that, under the best conditions, concentrations of glutaraldehyde in radiographic departments are below the occupational exposure standard, higher levels may occur during maintenance or where ventilation is inadequate. Concern about respiratory disease has been expressed within the radiography profession. [R36] *A case of contact allergic dermatitis due to occupational exposure to benzalkonium chloride and glutaraldehyde in a dental nurse was described. A 36 year old female dental nurse with an intensely itchy eczena on her hands, forearms, upper arms, and face was examined. The eczema began on her hands and forearms 4 months previously and gradually spread to her upper arms and face. She was patch tested with the standard Italian allergen series, a nurse series, and products she used at work. She reacted to thiuram mix and nickel sulfate in the standard series, glutaraldehyde and benzalkonium chloride in the nurse series, and three products she used at work (Sanipull, Ster-l, and Cidex). Sanipull contained 1% benzalkonium chloride, Ster-l contained glutaraldehyde, and Cidex contained 2% acidic glutaraldehyde. The reactions to benzalkonium chloride and glutaraldehyde and the products containing these were judged to reflect her current symptoms. The reactions to nickel sulfate and thiuram mix were judged to reflect episodes of contact dermatitis induced by jewelry and latex rubber gloves. /It was/ concluded that cases like this can be expected to become more common since benzalkonium chloride and glutaraldehyde are being used more frequently to sterilize dental and other medical instruments and equipment. [R37] *Proctitis has been reported after the use of glutaraldehyde as a disinfectant of flexible sigmoidoscopes. Within hours of an exam patients may have acute tenesmus and bloody diarrhea. The prognosis is good. Recovery follows in a few weeks. [R27] NTOX: *IRRITANT EFFECT ON SKIN OF RABBITS IS MODERATE. /FROM TABLE/ [R32, 312] *... A 25% AQ SOLN ON RABBIT EYES, CAUSED SEVERE INJURY, GRADED 9 ON A SCALE OF 10. A 1% SOL QUICKLY ABOLISHES THE B-WAVE OF THE RABBIT RETINA IN VITRO. [R38] *18 6-8 wk old male and female mice of various strains (Swiss, Balb/c, DBA/2, CBA, C57B1/6, and B6D2F1) received a topical application of 10% glutaraldehyde in ethanol on both sides of the right ear on days 0 and 2, and a scapular sc injection of 0.05 ml of complete Freunds adjuvant on day 2. On day 9, left ear thickness was measured immediately before topical application of 1% glutaraldehyde in ethanol, on both sides of the ear, and again 24 hr later (day 10). A statistically significant incr in ear thickness was seen. [R39] *Solutions of 1 and 2% glutaral destroy Bacillus anthracis spores more rapidly than 4% formaldehyde. ... In addition to sporicidal activity glutaral has inactivated enteroviruses and other viruses. [R40] *Alkanes, alcohols, ketones, and aldehydes reported not to produce neurotoxicity after chronic and subchronic exposures. Test substance: Glutaraldehyde, Species: Rat, Route: Water, Exposure conditions: 0.25, 0.5, and 1.0% in drinking water for 11 weeks. /From table/ [R41] *Percutaneous lethal dose in rabbits 0.6 g/kg. [R42] *... When mice were exposed at 8 and 33 ppm (33 and 133 mg/cu m) of alkalinized glutaraldehyde for 24 hr, the animals reacted with distinctly nervous behavior, panting and washing of the face and limbs, with symptoms disappearing after a few hours. Fifty percent of the mice in each group were sacrificed immediately postexposure, and the remaining animals were killed the following day. Lungs and kidneys showed no histopathologic damage, but the livers of the mice exposed at 33 ppm showed definite signs of toxic hepatitis, possibly reversible, since it was present to somewhat lesser degree in the animals necropsied one day postexposure. [R34, 1991.703] *... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of glutaraldehyde in male or female F344/N rats exposed to 250, 500 750 ppb. There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 62.5, 125 or 250 ppb. [R43] NTXV: *LD50 Rat oral 134 mg/kg; [R25] *LD50 Rabbit skin 2,560 mg/kg; [R25] *LD50 Rat oral 0.82 g/kg; [R32, 312] *LD50 Rabbit skin 0.64 ml/kg; [R32, 312] *LC50 Rat inhalation 5000 ppm/4 hr exposure; [R34, 1991.703] *LD50 Rat oral 1.30 ml/kg 50% aqueous soln (w/w); [R34, 1991.704] *LC50 Rat (male) inhalation 24 ppm/ 4 hr; [R34, 1991.704] *LC50 Rat (female) inhalation 40 ppm/ 4 hr; [R34, 1991.704] *LD50 Rat oral 1.87 ml/kg 25% aqueous soln (w/w); [R34, 1991.704] *LD50 Rat oral 3.3 ml/kg 5% aqueous soln (w/w); [R34, 1991.704] *LD50 Rat oral 12.3 ml/kg 1% aqueous soln (w/w); [R34, 1991.704] *LD50 Rat oral 96.1 mg/kg 2% Cidex formulation; [R34, 1991.704] *LD50 Mouse oral 100 mg/kg; [R34, 1991.704] *LD50 Mouse oral 1300 mg/kg 25% olive oil soln; [R34, 1991.704] *LD50 Mouse (male) oral 122 mg/kg 2% Cidex formulation; [R34, 1991.704] *LD50 Rabbit oral 1.59 ml/kg 50% aqueous soln (w/w); [R34, 1991.704] *LD50 Rabbit oral 8.0 ml/kg 25% aqueous soln (w/w); [R34, 1991.704] *LD50 Rabbit oral > 16 ml/kg 5% aqueous soln (w/w); [R34, 1991.704] *LD50 Rat sc 2390 mg/kg; [R34, 1991.704] *LD50 Mouse (male) sc 1430 mg/kg; [R34, 1991.704] *LD50 Rat ip 17900 ug/kg; [R34, 1991.704] *LD50 Mouse ip 13900 ug/kg; [R34, 1991.704] *LD50 Rat iv 15300 ug/kg; [R34, 1991.704] *LD50 Mouse iv 15400 ug/kg; [R34, 1991.704] *LD50 Rat iv 9800 ug/kg; [R25] NTP: *... 2 yr study in rats: Groups of 50 male and 50 female F344/N rats were exposed to 0, 250, 500 or 750 ppb glutaraldehyde vapor by inhalation 6 hr/day 5 days/wk for 104 wk. ... 2 yr study in mice: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 62.5, 125 or 250 ppb glutaraldehyde vapor by inhalation, 6 hr/day 5 days/wk for 104 wk. ... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was no evidence of carcinogenic activity of glutaraldehyde in male or female F344/N rats exposed to 250, 500 750 ppb. There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 62.5, 125 or 250 ppb. [R43] ADE: *Material balance and pharmacokinetic studies were conducted with rats and rabbits including iv or topical dosing with [14C]glutaraldehyde. IV dosing resulted in radiochemical recovery from 86% to 101%. Principal route of recovery was as CO2 at 22% to 80% of the admin dose (7%-28% urinary, 0.2%-5% feces). Epicutaneous dosing resutled in radiochemical recovery primarily in the skin at the site of application (31%-61%) with no consistent accumulation in any other tissue. Rabbits absorbed 33% to 53% of the epicutaneously administered dose and rats absorbed 4.1% to 8.7%. Pharmacokinetic studies indicated percutaneous radiochemical absorption of 0.3% to 2.1% for rats and 2.5% to 15.6% for rabbits under conservative study conditions that are likely to overestimate potential human exposure conditions. [R34, 1991.704] METB: *... The probable major metabolic pathway /is/ initial oxidation to the corresponding mono- or dicarboxylic acid by aldehyde dehydrogenase and then further oxidation of the acidic intermediate to carbon dioxide. [R34, 1991.704] ACTN: *Cross-linking of the peptidoglycan in the bacterial cell wall with intermolecular bonding between techoic acid chains and glutaraldehyde may cause a partial sealing and contraction of the outer cell envelope. [R27] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3-4. 3= MODERATELY TOXIC, PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OUNCE AND 1 PINT FOR 70 KG PERSON (150 LB). 4=VERY TOXIC, PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG, BETWEEN 1 TEASPOON AND 1 OUNCE FOR 70 KG PERSON (150 LB). [R42] THER: *Disinfectants; Fixatives [R44] *...USED ON LIVING TISSUES IN TREATMENT OF WARTS AND HYPERHIDROSIS. [R5] *Glutaral 2% in a buffered solution (pH 7.5) ... has an anhidrotic effect when applied to the palms and soles but not the axillae. [R29, 1213] *IT...POSSESSES TUBERCULOCIDAL ACTION. [R5] WARN: *This disinfectant may cross-react with formaldehyde. [R29, 1620] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Occupational exposure to health care workers is common. [R28] *Sensitization has occurred mainly through its use as a cold sterilizing solution in hospitals and dental clinics where medical and allied professionals including x-ray film handlers may be exposed to activated glutaraldehyde in concentrations of 0.13-2%. [R28] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- NREC: *Recommended Exposure Limit: Ceiling value: 0.2 ppm (0.8 mg/cu m). [R16, 152] TLV: +Ceiling Limit: 0.05 ppm, sensitizer. /Activated and inactivated/ [R30] +A4; Not classifiable as a human carcinogen. [R30] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R45] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Pentanedial is included on this list. [R46] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Glutaraldehyde is found on List B. Case No: 2315; Pesticide type: fungicide, antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Glutaraldhyde; Data Call-in (DCI) Date(s): 06/10/91, 07/15/92, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R47] FDA: *Microcapsules for flavoring substances. Microcapsules maybe safely used for encapsulating discrete particles of flavoring substances that are generally recognized as safe for their intended use or are regulated under this part, in accordance with the following conditions: ... Component: glutaraldehyde; Limitation: as cross-linking agent for insolubilizing a coacervate of gum araabic and gelatin. [R48] *Glutaraldehyde is an indirect food additive for use only as a component of adhesives. [R49] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *OSHA Method No. 64 Glutaraldehyde Issue June 1987. HPLC/UV Reliable quantitation limit = 18 ug/cu m. [R50] *NIOSH Method 2531. Determination of Glutaraldehyde by High Performance Liquid Chromatography with UV Detection. This method is applicable to air samples. Detection limit = 0.01 mg/cu m. [R51] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of Glutaraldehyde Administered by Inhalation to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 25 NIH Publication No. 93-3348 (1993) Toxicology and Carcinogenesis Studies of Glutaraldehyde in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 490 (1999) NIH Publication No. 99-3980 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 SO: R1: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 761 R3: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Glutaraldehyde (111-30-8). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R4: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R5: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 894 R6: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. R7: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976. R8: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1994. 82 R9: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA16 (1990) 567 R10: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 654 R11: SRI R12: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA9 (1987) 386 R13: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA8 (1987) 555 R14: Farm Chemicals Handbook 2001. Willoughby, Ohio: Meister 2001.,p. C 210 R15: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 450 R16: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R17: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-240 R18: Howard PH, Neal M; Dictionary of Chemical Names and Synonyms. Boca Raton, FL: Lewis Publishers, p. I-263 (1992) R19: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)447 R20: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V4 3838 R21: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1981 R22: Heisler SL, Friedlander SK; Atmos Environ 11: 157-168 (1977) R23: Atkinson R; J Phys Chem Ref Data Monograph 1 p. 137 (1989) R24: Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991. 511 R25: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1734 R26: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R27: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1219 R28: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 983 R29: American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994. R30: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.34 R31: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R32: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R33: Jachuck SF et al; J Soc Occup Med 39 (2): 69-71 (1989) R34: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R35: Chan-Yeung M et al; Journal of Allergy and Clinical Immunology 91 (5): 974-8 (1993) R36: Cullman P et al; Lancet 340 (8833): l477 (1992) R37: Cusano F, Luciano S; Contact Dermatitis 28 (2): 127 (1993) R38: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 462 R39: Descotes J; J Toxicol Cutan Ocular Toxicol 7 (4): 263-72 (1988) R40: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 714 R41: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume II. Boca Raton, FL: CRC Press, Inc., 1985. 81 R42: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-187 R43: Toxicology and Carcinogenesis Studies of Glutaraldehyde in F344/N Rats and B6C3F1 Mice p.5 Technical Report Series No. 490 (1999) NIH Publication No. 99-3980 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R44: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R45: 40 CFR 712.30 (7/1/2000) R46: 40 CFR 716.120 (7/1/2000) R47: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.184 (Spring, 1998) EPA 738-R-98-002 R48: 21 CFR 172.230 (4/1/2000) R49: 21 CFR 175.105 (4/1/2000) R50: OSHA; Analytical Methods Manual. 2nd ed., Part 1 Organic Substances, Vol I Meth 1-28, Vol II, meth 29-54, Vol III Meth 55-80. Jan 1990. Vol IV Meth 81-102, Apr 1993. US Dept Labor Occupational Safety and Health, Admin, Direct Tech Supp, OSHA Technical Center, Salt Lake City, Utah R51: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 34 Record 101 of 1119 in HSDB (through 2003/06) AN: 972 UD: 200302 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-CHLOROACETOPHENONE- SY: *ACETOPHENONE,-2-CHLORO-; *CAF-; *CAP-; *Chemical-Mace-; *Chloroacetophenone-; *ALPHA-CHLOROACETOPHENONE-; *OMEGA-CHLOROACETOPHENONE-; *1-CHLOROACETOPHENONE-; *CHLOROMETHYL-PHENYL-KETONE-; *2-Chloro-1-phenylethanone-; *CN-; *ETHANONE,-2-CHLORO-1-PHENYL-; *MACE-; *MACE- (LACRIMATOR); *NCI-C55107-; *Phenacylchloride-; *PHENYLCHLOROMETHYLKETONE-; *"Tear-gas"- RN: 532-27-4 MF: *C8-H7-Cl-O SHPN: UN 1697; Chloroacetophenone liquid or solid. IMO 6.1; Chloroacetophenone liquid or solid MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *From chloroacetylchloride, benzene, and aluminum chloride. [R1] *Prepn: R. Scholl, H. Korten, Ber 34: 1902 (1901); H. Rheinboldt, M. Perrier, J Am Chem Soc 69: 3148 (1947); Schaefer, Sonnenberg, J Org Chem 28: 1128 (1963) [R2] *Prepared by chlorination of acetophenone with selenium oxychloride [R3] *Acetophenone (alpha chlorination) [R4] FORM: *CHEMICAL MACE CONSISTS OF A POTENT LACRIMATOR, CHLOROACETOPHENONE (0.9-1.2%) DISSOLVED IN A MIXTURE OF TRICHLOROTRIFLUOROETHANE (70-80%), 1,1,1-TRICHLOROETHANE (5%), AND HYDROCARBONS RESEMBLING KEROSENE (APPROX 4%). [R5, 884] *93% Purity grade [R6] OMIN: *A chem warfare agent with lacrimatory properties [R2] USE: *For 2-Chloroacetophenone (USEPA/OPP PC Code: 018001) there are 0 labels match. /SRP: Not registered for current use in the U.S./ [R7] *... ALCOHOL DENATURANT (FORMER USE) [R8] *Pharmaceutical intermediate; riot control gas [R1] *Obsolete in military use, common in police agency mixtures of tear gas; principal ingredient in the riot agent under the tradename MACE, Methylchloroform chloro ACEtophenone [R3] *Because of its strong lacrimating capacity, /it's/ used as a riot-control agent and in personal protective devices. [R9, 1991.264] PRIE: U.S. IMPORTS: *(1977) AT LEAST 4.99X10+6 G [R8] *(1981) 4.50X10+5 G (PRINCPL CUSTMS DISTS) [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crystals from dil alc, carbon tetrachloride, or light petroleum [R2]; *Colorless to gray crystalline solid. [R10, 60]; *White crystals [R1] ODOR: *IN VERY LOW CONCN IN AIR IT HAS AN ODOR RESEMBLING APPLE BLOSSOMS [R11]; *Sharp, irritating odor. [R10, 60] BP: *244-245 deg C [R2] MP: *58-59 deg C; also reported as 54 deg C (Macy) and 56.5 deg C (Rheinboldt, Perrier) [R2] MW: *154.60 [R2] DEN: *1.324 @ 15 deg C [R2] HTC: *-9,340 BTU/LB= -5,190 CAL/G= -217X10+5 JOULES/KG (EST) [R12] SOL: *Practically insol in water; freely sol in alcohol, ether and benzene. [R2]; *Sol in acetone and carbon disulfide [R1] SPEC: *MAX ABSORPTION (HEXANE): 246 NM (LOG E= 3.92); 280 NM (LOG E= 3.00); 291 NM (LOG E= 286); 329 NM (LOG E= 1.83) [R13]; *IR: 1169 (Coblentz Society Spectral Collection) [R14]; *MASS: 507 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R14] VAPD: *5.32 (Air= 1) [R15] VAP: *5.4X10-3 mm Hg @ 20 deg C [R2] OCPP: *MP: 20 deg C; BP: 237 deg C [R1] *Must be mixed with alcohol or ether to be used as a liquid aerosol. To be used in normal form as a smoke, it must be heated in the presence of a secondary burning agent either mixed in with the powder or burned in close proximity, such as in a thermal grenade. [R3] *Vapor pressure: 0 deg C, 0.0026 mm Hg; 20 deg C, 0.0041 mm Hg; 52 deg C, 0.152 mm Hg. [R3] *Solid density at 20 deg C = 1.318 g/cc; liquid density at 58 deg C = 1.187 g/cc [R3] *Decomposes at 248 deg C; flashpoint is very high and does not interfere with use [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chloroacetophenone; Chloroacetophenone, liquid; Chloroacetophenone, solid/ [R16] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R17] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R17] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R17] FLPT: *244 deg F (118 deg C) (Closed cup) [R17] REAC: *Water, steam, strong oxidizers [Note: Slowly corrodes metals]. [R10, 60] *Combustible when exposed to heat or flame. [R18, 724] DCMP: *DANGEROUS WHEN HEATED TO DECOMPOSITION IT EMITS TOXIC FUMES OF /HYDROGEN CHLORIDE./ [R18, 724] ODRT: *0.1 MG/CU M [R19] *Odor low: 0.1020 mg/cu m; Odor high: 0.15 mg/cu m /Alphachloroacetophenone/ [R20] SERI: *IRRITATION THRESHOLDS RANGE FROM 0.15-0.4 MG/CU M; LACRIMATION THRESHOLDS FROM 0.3-0.4 MG/CU M [R19] *Irritant to eyes in concentration of 0.3 ppm. ... [R21] *... The substance is an irritant to the upper respiratory tract and the skin. [R9, 1991.264] *Accidental overexposure of the eyes ... can result in permanent partial opacity (leukoma); under ordinary exposure ... the severe conjunctivis, corneal haziness, and pain, ... are not permanent. [R9, 1991.265] EQUP: *FULL FACE ORGANIC CANISTER MASK; SELF CONTAINED BREATHING APPARATUS; RUBBER GLOVES; PROTECTIVE CLOTHING. [R22] *Wear appropriate personal protective clothing to prevent skin contact. [R10, 61] *Wear appropriate eye protection to prevent eye contact. [R10, 61] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R10, 61] *Recommendations for respirator selection. Max concn for use: 3 mg/cu m. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Any supplied-air respirator. [R10, 61] *Recommendations for respirator selection. Max concn for use: 7.5 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Eye protection needed. [R10, 61] *Recommendations for respirator selection. Max concn for use: 15 mg/cu m. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern and having a high-efficiency particulate filter. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R10, 61] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R10, 61] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern and having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R10, 61] OPRM: *Contact lenses should not be worn when working with this chemical. [R10, 61] *The worker should immediately wash the skin when it becomes contaminated. [R10, 61] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R10, 61] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R10, 61] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R23] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R24] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R25] CLUP: *1. VENTILATE AREA OF SPILL. 2. FOR SMALL QUANTITIES, SWEEP ONTO PAPER OR OTHER SUITABLE MATERIAL, PLACE IN AN APPROPRIATE CONTAINER AND BURN IN SAFE PLACE (SUCH AS A FUME HOOD). LARGE QUANTITIES MAY BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN A FLAMMABLE SOLVENT (SUCH AS ALCOHOL) AND ATOMIZE IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R26] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *1. BY MAKING PACKAGE OF ALPHA-CHLOROACETOPHENONE IN PAPER OR OTHER FLAMMABLE MATERIAL AND BURNING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. 2. BY DISSOLVING ALPHA-CHLOROACETOPHENONE IN A FLAMMABLE SOLVENT (SUCH AS ALCOHOL) AND ATOMIZING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . For contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Ketones and related compounds/ [R27, 237] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Ketones and related compounds/ [R27, p. 237-8] HTOX: *SYMPTOMS INCL TEARING, BURNING OF THE EYES AND DIFFICULTY IN BREATHING, BUT SELDOM ANY PERSISTENT OR PERMANENT DISABILITY. HIGH CONCN MAY LEAD TO ... ACUTE PULMONARY EDEMA AFTER LATENCIES OF 8 HR TO SEVERAL DAYS. FIRST AND PERHAPS SECOND DEGREE BURNS OF SKIN MAY OCCUR, PARTICULARLY IF IN CONTACT WITH ABRADED AREAS. [R11] *A PECULIAR, SHORT LIVED (45 MIN) RAPIDLY DEVELOPING TOLERANCE OCCURS TO /2-CHLOROACETOPHENONE/ WHEN EXPOSURE CONCN ... HIGH TO CAUSE PROFUSE LACRIMATION AND OTHER SIGNS OF IRRITATION; PERSISTENCE OF CYANIDE IN THE ATMOSPHERE LEADS TO CESSATION OF SYMPTOMS. CROSS TOLERANCE RAPIDLY DEVELOPS ALSO TO BROMBENZYL CYANIDE, CHLOROPICRIN, CHLOROCROTONALDEHYDE, ETHYL-CHLOROFORMATE AND TRICHLOROMETHYL FORMATE. ... TWO REPORTS SUGGEST THAT INDIVIDUALS CAN BE SENSITIZED TO ... /2-CHLOROACETOPHENONE/ WITH CROSS OVER REACTIONS WITH O-CHLOROBENZILIDINE MALONONITRILE. SENSITIZATION WAS MORE READILY PRODUCED AND REACTIONS MORE SEVERE WITH ... /2-CHLOROACETOPHENONE/. [R9, 1991.264] *... 12 PATIENTS ... SPRAYED IN THE EYES WITH CHEM MACE ... @ DISTANCE OF 6-12 INCHES ... HAD INJURIES OF EPITHELIUM OF CORNEA AND CONJUNCTIVA DEMONSTRABLE BY STAINING WITH FLUORESCEIN ... 9/12 HEALED IN 72 HR. THE OTHER 3 HAD MORE EXTENSIVE EPITHELIAL INJURY WHICH TOOK 14-21 DAYS TO HEAL COMPLETELY ... IN 1 EYE A SUPERFICIAL STROMAL OPACITY ... /PERSISTED/ FOR 5 MO, BUT THIS WAS SUPERFICIAL AND LOCATED PERIPHERALLY IN THE CORNEA. [R5, 885] *Skin reactions of sensitized guinea pigs to challenging doses of chloroacetophone included erythema, edema, induration, necrosis, and eschar formation. [R9, 1991.265] *ACCIDENTAL OVEREXPOSURE OF EYES ... CAN RESULT IN PERMANENT PARTIAL OPACITY. [R9, 1991.264] *Some prisoners sprayed with 2-chloroacetophenone during a disturbance at San Quentin Prison in April 1981 required hospitalization because of severe laryngotracheobronchitis, chemical skin burns, conjunctivitis, and apparent allergic reactions. [R28] *Solid chloroacetophenone also caused significant damage to the cornea, iris, conjunctiva, and eyelids ... . [R9, 1991.277] *The uses of tear gas, its toxicity, and treatment for exposure were reviewed. The two compounds most commonly used in recent years were identified as omega-chloroacetophenone (CN) and o-chlorobenzylidenemalononitrile (CS). Previous reports and reviews of tear gas usage and exposure effects were considered. The results of a survey of tear gas use in civil disturbances in Seoul, Korea were summarized. The agent used in these events was identified as CS; in exposed persons near exploding tear gas canisters, effects included penetration trauma, skin burns, and impaired lung function. The Korean medical community was not found to have access to information necessary for treating those who were exposed. A similar report of tear gas use in Gaza and the West Bank of Israel was cited. The development of CS as the predominant tear gas agent, and its use in riot control and in Vietnam was described, as was its toxicology. Inhalation studies showing an association between high level CS exposure and pneumonitis, pulmonary edema, heart failure, hepatic damage, and death were cited. The use of tear gas in enclosed spaces, or detonating gas grenades or canisters directly into crowded gatherings could result in exposures to much higher levels that use in the open. Studies of long term pulmonary and genotoxic effects were appraised as inconclusive, and the lack of reproductive epidemiologic studies was noted. CS was hypothesized to be genotoxic, due to its ability to alkylate sulfhydryl groups. The toxicity of CN was compared to CS. Treatment for CS and CN exposures was described, including skin washes, supportive pulmonary therapy, and observation. The authors conclude that there is a need for further investigations into the toxicological potential of tear gas chemicals. [R29] NTOX: *AT HIGH CONCN ... PERMANENT OPACIFICATION, ULCERATION WITH VASCULARIZATION AND PERFORATIONS CAN BE PRODUCED IN THE EYES OF LAB ANIMALS. POSSIBLE SYSTEMIC MANIFESTATIONS INCL AGITATION, MIOSIS, COMA, AREFLEXIA AND FATTY INFILTRATION OF LIVER. [R30] *... LIQ RESIDUE @ ATMOSPHERIC PRESSURE OBTAINED FROM SPRAY CANS OF CHEM MACE ... DROPPED DIRECTLY ON THE EYES OF UNANESTHETIZED ANIMALS CAUSED LOSS OF CORNEAL EPITHELIUM AND CLOUDING OF THE STROMA, BUT THESE HEALED IN 3-10 DAYS. IF RABBITS WERE ANESTHETIZED BEFORE /APPLICATION/ THE REACTION WAS MUCH MORE SEVERE, CONSISTING OF GREATER STROMAL EDEMA, DEVELOPMENT OF CORNEAL OPACITY, IRIDOCYCLITIS, AND HYPOPYON, WITH SERIOUS DEGENERATIVE CHANGES IN THE CORNEAS IN SOME ANIMALS. [R5, 884] *THE TOXICITY OF ALPHA-CHLOROACETOPHENONE IN TEST ANIMALS IS DESCRIBED AND DATA ARE EXTRAPOLATED TO HUMANS. NO CARCINOGENICITY COULD BE FOUND, ALTHOUGH CMPD WAS EMBRYOTOXIC AND DID CAUSE ALLERGIC SENSITIZATION. [R31] *1-CHLOROACETOPHENONE CAUSED CONTACT SENSITIZATION OR DELAYED HYPERSENSITIVITY IN GUINEA PIGS BY TOPICAL OR INTRADERMAL ADMIN. IT IS MORE IRRITATING TO SKIN AND MORE ALLERGENIC WHEN ADMIN AS MACE THAN IN ACETONE. INTRADERMAL ADMIN CAUSED ERYTHEMA, EDEMA, INDURATION, NECROSIS; DERMAL APPLICATION CAUSED THE SAME EFFECTS PLUS ESCHAR. [R32] *RABBIT EYES DOSED WITH 1-CHLOROACETOPHENONE 1-10% IN POLYETHYLENE GLYCOL 300 SOLN SHOWED INFLAMMATION, CORNEAL DAMAGE (5-10% SOLN), KERATITIS, INCR IN CORNEAL THICKNESS AND INTRAOCULAR TENSION. SOLID FORM: SIMILAR BUT MORE SEVERE EFFECTS. USING AEROSOL: CONJUNCTIVAL AND LID IRRITATION. [R33] *Chloroacetophenone was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. The chemical was tested at doses of 0, 0.3, 1, 3, 10, 33, 100, and 333 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor induced rat or hamster liver S9. Chloroacetophenone was negative in these tests and the highest ineffective dose level tested (not causing a complete clearing of the background lawn) in any Salmonella tester strain was 100 ug/plate. [R34] *Incubation of chick embryos in the primitive streak stage with 0.5-3 mM 2-chloroacetophenone for 15-120 minutes increased the frequency of abnormalities in the nervous system, including improper differentiation and incomplete closure of the brain. Well differentiated closed neural tubes were observed in embryos incubated with 2-chloroacetophenone and subsequently exposed to sulfhydryl agents. Embryos incubated at the head process stage with 2-chloroacetophenone showed normal development. Thus, the inhibitory effect of 2-chloroacetophenone on morphogenesis of the nervous system in chick embryos was reversible. [R35] *2-Chloroacetophenone ... increased incidence of epidermal papillomas in skin of mice previously given dermal applications of 0.3 ml of 0.15% 9,10-dimethyl-1,2-benzanthracene dissolved in acetone. Twenty-one days after exposure to 9,10-dimethyl-1,2-benzanthracene, mice received applications of 0.3 ml of 0.4%-0.8% 2-chloroacetophenone in acetone twice per week for 12 weeks and then once per week for 15 weeks. Twenty epidermal neoplasms were observed in 9/12 mice that received the 9,10-dimethyl-1,2-benzanthracene plus 2-chloroacetophenone applications, compared with 1 neoplasm in 12 control mice that received 9,10-dimethyl-1,2-benzanthracene followed by dermal applications of acetone on the same dosing schedule. Epidermal hyperplasia was also observed at the site of application of 2-chloroacetophenone. [R36] *2-Chloroacetophenone toxicity may be due to the alkylation and consequent inhibition of sulfhydryl-containing enzymes because inhibition of lactate dehydrogenase activity by 2-chloroacetophenone in vitro was not reversed by glutathione and because intravenous administration of sodium thiosulfate did not protect rats from lethal doses of 2-chloroacetophenone given by intraperitoneal injection. [R28] *2-Chloroacetophenone was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In cytogenetic tests with CHO (Chinese hamster ovary) cells, 2-chloroacetophenone did not induce sister chromatid exchanges with or without activation, but a weak positive increase in chromosomal aberrations was observed in the absence of metabolic activation. [R37] *The biochemical changes in blood samples of rats at different intervals after O-Chloracetophenone (CN) and Dibenz (b,f)-1,4 oxazepine (CR) were studied. After a single subacute (1/10 LC50) exposure, both the compounds induced hyperglycaemia which was abolished within 24 h. The level of plasma urea was unaltered. CR exposed animals did not show any significant changes in plasma GOT, acid and alkaline phosphase activities at different intervals. However, in CN exposed animals, a significant elevation of the activities of GOT, GPT, acid and alkaline phosphatase was observed at different intervals. All the parameters became normal within seven days after the exposure. Inhalation of CN aerosols can thus lead to tissue damaging effects in rats. [R38] HTXV: *A 10 MINUTE EXPOSURE TO 0.85 MG/L IS ESTIMATED TO BE LETHAL IN MAN. [R11] NTXV: *LD50 Rat oral 127 mg/kg; [R39] *LD50 Rabbit oral 118 mg/kg; [R39] *LD50 Guinea pig oral 158 mg/kg; [R39] *LD50 Mouse iv 81 mg/kg; [R39] *LD50 Rat ip 36 mg/kg; [R39] *LD50 Guinea pig iv 17 mg/kg; [R40] *LD50 Rat oral 1820 mg/kg; [R18, 723] NTP: *Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to air containing 2-chloroacetophenone vapor for ... 2 years. ... Groups of 60 rats of each sex were exposed to a vapor of 0 (chamber control), 1 or 2 mg/cu m (0, 15, or 0.3 ppm) 2-chloroacetophenone, 6 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed to 0 (chamber control), 2, or 4 mg/cu m (0, 3, or 0.6 ppm) on the same schedule. ... Fibroadenomas of the mammary gland occurred in female rats with positive trends, and the incidence in the 2 mg/cu m group was greater than that in chamber controls (control, 12/50; 1 mg/cu m, 19/50; 2 mg/cu m, 23/50). The incidences of adenomas or adenocarcinomas of the mammary gland were not increased in the exposed groups. Minimal to mild suppurative inflammation of the nasal mucosa was observed at increased incidences in exposed male rats. Hyperplasia and squamous metaplasia of the nasal respiratory epithelium were observed at increased incidences in exposed male and female rats. In mice, squamous metaplasia of the respiratory epithelium of the nasal passage was seen in four females and two males exposed to 4 mg/cu m 2-chloroacetophenone. Inflammation, ulcers, and squamous hyperplasia of the forestomach were observed at increased incidences in exposed female rats. There were no exposure related increased incidences of neoplastic lesions in mice. [R41] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Chloroacetophenone's production and use as an intermediate in pharmaceuticals and as an ingredient in chemical MACE may result in its release to the environment through various waste streams. It may be directly released to the environment during its use as a riot control gas. If released to air, a vapor pressure of 5.4X10-3 mm Hg at 25 deg C indicates 2-chloroacetophenone will exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase 2-chloroacetophenone will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 8 days. The UV spectrum for a hexane solution of 2-chloroacetophenone shows absorbency maxima occurring at 291 and 329 nm which indicates that 2-chloroacetophenone may directly photolyze in the environment. If released to soil, 2-chloroacetophenone is expected to have high mobility based upon an estimated Koc of 90. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 3.5X10-6 atm-cu m/mole. 2-Chloroacetophenone will not volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 2-chloroacetophenone is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 14 and 110 days, respectively. An estimated BCF of 1 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is expected to occur very slowly; products are hydrochloric acid and hydroacetophenone. Occupational exposure to 2-chloroacetophenone may occur through dermal contact with this compound at workplaces where 2-chloroacetophenone is produced or used. The use of "Chemical Mace" to disable attackers causes direct exposure to 2-chloroacetophenone through eye and skin contact and inhalation. (SRC) ARTS: *2-Chloroacetophenone's production and use as an intermediate in pharmaceuticals(1) and as an ingredient in chemical MACE(2) may result in its release to the environment through various waste streams(SRC). It may be directly released to the environment during its use as a riot control gas(1). [R42] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 90(SRC), determined from a structure estimation method(2), indicates that 2-chloroacetophenone is expected to have high mobility in soil(SRC). Volatilization of 2-chloroacetophenone from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.5X10-6 atm-cu m/mole(SRC), determined using a fragment constant estimation method(3). 2-Chloroacetophenone undergoes hydrolysis very slowly; products are hydrochloric acid and hydroacetophenone(5). 2-Chloroacetophenone is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 5.4X10-3 mm Hg(4). Insufficient data are available to predict the importance of biodegradation or other degradation processes in soil(SRC). [R43] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 90(SRC), determined from an estimation method(2), indicates that 2-chloroacetophenone is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 3.5X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 14 and 110 days, respectively(SRC). 2-Chloroacetophenone undergoes hydrolysis, but very slowly; products are hydrochloric acid and hydroacetophenone(8). According to a classification scheme(5), an estimated BCF of 1(SRC), from an estimated log Kow of 1.93(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is extremely low. Insufficient data are available to predict the importance of biodegradation in water(SRC). [R44] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2-chloroacetophenone, which has a vapor pressure of 5.4X10-3 mm Hg at 25 deg C(2), is expected to exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase 2-chloroacetophenone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 8 days(SRC), calculated from its estimated rate constant of 1.74X10-12 cu cm/molecule-sec at 25 deg C(3). The UV spectrum for a hexane solution of 2-chloroacetophenone shows absorbency maxima occurring at 291 and 329 nm(4) which indicates that 2-chloroacetophenone may directly photolyze in the environment(SRC); the potential importance of direct photolysis is not known because kinetic rate data are not available(SRC). [R45] BIOD: *Inoculation of a sterile solution (containing 6% glucose, 4% peptone, 4% yeast extract, 4% malt extract, and 100 mg 2-chloroacetophenone) with Cryptococcus macerans for a 2-day period yielded the corresponding chlorohydrin and 2-chloro-1-phenylethanol(1). [R46] ABIO: *The rate constant for the vapor-phase reaction of 2-chloroacetophenone with photochemically-produced hydroxyl radicals has been estimated as 1.74X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 8 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). 2-Chloroacetophenone undergoes hydrolysis, but very slowly; products are hydrochloric acid and hydroacetophenone(2). The UV spectrum for a hexane solution of 2-chloroacetophenone shows absorbency maxima occurring at 291 and 329 nm(3) which indicates that 2-chloroacetophenone may directly photolyze in the environment(SRC); the potential importance of direct photolysis is not known because kinetic rate data are not available(SRC). [R47] BIOC: *An estimated BCF of 1 was calculated for 2-chloroacetophenone(SRC), using an estimated log Kow of 1.93(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is extremely low. [R48] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 2-chloroacetophenone can be estimated to be 90(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2-chloroacetophenone is expected to have high mobility in soil. [R49] VWS: *The Henry's Law constant for 2-chloroacetophenone is estimated as 3.5X10-6 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2-chloroacetophenone is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 14 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 110 days(SRC). 2-Chloroacetophenone's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). 2-Chloroacetophenone is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 5.4X10-3 mm Hg(3). [R50] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,293 workers (1,411 of these are female) are potentially exposed to 2-chloroacetophenone in the US(1). Occupational exposure to 2-chloroacetophenone can occur at workplaces where 2-chloroacetophenone is produced or used through inhalation of dusts and vapors and through skin contact(2). The use of "Chemical Mace" to disable attackers causes direct exposure to 2-chloroacetophenone through eye and skin contact and inhalation(SRC). [R51] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *15 mg/cu m [R10, 60] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.05 ppm (0.3 mg/cu m). [R52] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.3 mg/cu m (0.05 ppm). [R10, 60] TLV: *8 hr Time Weighted Avg (TWA) 0.05 ppm [R53, 24] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R53, 6] *A4. A4= Not classifiable as a human carcinogen. [R53, 24] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 2-Chloroacetophenone is included on this list. [R54] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R55] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R56] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2-Chloroacetophenone is included on this list. [R57] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 291. Analyte: 2-chloroacetophenone. Matrix: Air. Procedure: Adsorption on Tenax gas chromatography, thermal desorption. Flow Rate: 0.01- 0.2 l/min. Sample Size: 12 liters. [R58] ALAB: *NIOSH Method 291. Analyte: 2-chloroacetophenone. Matrix: Air. Procedure: Gas chromatography/flame ionization detector. Method Evaluation: Method was validated over the range of 0.18 to 0.62 mg/cu m using a 12 liter sample. Method detection limit: 20 ng. Precision (CVt): 0.061. Interferences: None identified. [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: SCHREMPF A; CHEMICAL MACE- HOW DANGEROUS IS CHLOROACETOPHENONE?; CHEM UNSERER ZEIT 12 (5): 146 (1978). A REVIEW, WITH 59 REFERENCES, OF THE TOXICOLOGY AND CHEMISTRY OF THE LACRIMATOR MACE. Hu H et al; J Am Med Assoc 262 (5): 660-663 (1989). The uses of tear gas, its toxicity, and treatment for exposure were reviewed. The two compounds most commonly used in recent years were identified as omega-chloroacetophenone and o-chlorobenzylidenemalononitrile. Previous reports and reviews of tear gas usage and exposure effects were considered. Danto BL; Medical Problems and Criteria Regarding Use of Tear Gas by Police; Am J Forensic Med Pathol 8 (4): 317-22 (1987). This paper addresses the basic types of gas in terms of their chemistry, uses, and medical side effects and complications. Two types of gases namely, chloroacetophenone (CN) and orthochlorobenzylidenemalontrile (CS) are discussed in terms of basic properties, unique advantages, and possible harm to the body. DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 379 (1990) NIH Publication No. 90-2834 HIST: *DURING THE DERAILMENT OF A TRAIN CARRYING CHLORINE IN CANADA IN 1979, THE GROUND LEVEL CHLORINE WAS CONFINED TO A NARROW RIBBON OR PLUME DOWNWIND OF THE SITE. AMONG OTHERS, 2-CHLOROACETOPHENONE WAS DETECTED IN THE PLUME WHICH RESULTED FROM THE LEAK-RELATED FIRE. [R59] SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 251 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 353 R3: Compton JAF; Military Chemical and Biological Agents. Chemical and Toxicological Properties. Caldwell, NJ: Telford Press p. 215 (1987) R4: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 195 R5: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R6: Kuney, J.H. (ed.). CHEMCYCLOPEDIA 90. Washington, DC: American Chemical Society, 1990. 109 R7: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on 2-Chloroacetophenone (532-27-4). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of June 14, 2000. R8: SRI R9: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R11: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-96 R12: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R13: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-99 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 31 R15: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 450 R16: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-25 R18: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R19: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values, 4th ed., 1980. Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.83 R20: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R21: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 117 R22: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R23: 49 CFR 171.2 (7/1/96) R24: IATA. Dangerous Goods Regulations. 41st Ed.Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2000. 133 R25: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6099 (1988) R26: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R27: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R28: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.14 Technical Report Series No.379 (1990) NIH Pub No.90 2834 R29: Hu H et al; J of the American Medical Association 262 (5): 660-3 (1989) R30: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-68 R31: ELSKAMP DM W; TOXIC PROPERTIES OF CN AND CS; REPORT (MBL-1976-14) (1976) R32: CHUNG CW, GILES AL JR; J IMMUNOL 109 (2): 284 (1972) R33: BALLANTYNE B ET AL; ARCH TOXICOL 34 (3): 183 (1975) R34: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R35: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.15 Technical Report Series No.379 (1990) NIH Pub No.90-2834 R36: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.15 Technical ReportSeries No.379 (1990) NIH Pub No.90-2834 R37: DHHS/NTP; Toxicology and Carcinoigenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.4 Technical ReportSeries No. 379 (1990) NIH Pub No. 90-2834 R38: Husain K et al; Indian J Med Res Sect B 94 (FEB): 76-9 (1991) R39: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.13 Technical ReportSeries No.379 (1990) NIH Pub No.90-2834 R40: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.13 Technical Report Series No.379 (1990) NIH Pub No.90-2834 R41: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.4 Technical Report Series No. 379 (1990) NIH Pub No. 90-2834 R42: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons, Inc. p. 251 (1997) (2) Compton JAF; Military Chemical and Biological Agents. Chemical and Toxicological Properties. Caldwell, NJ: Telford Press p. 215 (1987) R43: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Budavari S ed; The Merck Index. 12th ed Whitehouse Station, NJ: Merck and Co., p. 353 (1996) (5) Compton JAF; Military Chemical and Biological Agents. Chemical and Toxicological Properties. Caldwell, NJ: Telford Press p. 215 (1987) R44: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. Boca Raton, FL: Lewis p. 370 (1997) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Compton JAF; Military Chemical and Biological Agents. Chemical and Toxicological Properties. Caldwell, NJ: Telford Press p. 215 (1987) R45: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Budavari S ed; The Merck Index. 12th ed Whitehouse Station, NJ: Merck and Co., p. 353 (1996) (3) Atkinson R; Environ Sci Technol 21: 1014-22 (1987) (4) Weast RC; Handbook of Chemistry and Physics 60th ed. Boca Raton, FL: CRC Press p. C-99 (1979) R46: (1) Imuta M et al; J Org Chem 45: 3352-5 (1980) R47: (1) Atkinson R; Environ Sci Technol 21: 1014-22 (1987) (2) Compton JAF; Military Chemical and Biological Agents. Chemical and Toxicological Properties. Caldwell, NJ: Telford Press p. 215 (1987) (3) Weast RC; Handbook of Chemistry and Physics 60th ed. Boca Raton, FL: CRC Press p. C-99 (1979) R48: (1) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. Boca Raton, FL: Lewis p. 370 (1997) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R49: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R50: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Budavari S ed; The Merck Index. 12th ed Whitehouse Station, NJ: Merck and Co., p. 353 (1996) R51: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Parmeggiani L; Encyl Occup Health and Safety 3rd ed. Geneva, Switzerland: International Labour Office p. 1170-3 (1983) R52: 29 CFR 1910.1000 (7/1/99) R53: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R54: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R55: 40 CFR 302.4 (7/1/99) R56: 40 CFR 712.30 (7/1/99) R57: 40 CFR 716.120 (7/1/99) R58: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. 291-1 R59: LANE DA, THOMSON BA; MONITORING A CHLORINE SPILL; PROC INT TECH CONF TOXIC AIR CONTAM: 141-55 (1981) RS: 50 Record 102 of 1119 in HSDB (through 2003/06) AN: 993 UD: 200201 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CITRAL- SY: *3,7-DIMETHYL-2,6-OCTADIENAL-; *FEMA-NUMBER-2303-; *2,6-OCTADIENAL,-3,7-DIMETHYL- RN: 5392-40-5 MF: *C10-H16-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DEHYDROGENATION OF A GERANIAL-NERAL MIXTURE OBTAINED FROM BETA-PINENE [R1] *SYNTHESIS FROM ISOPRENE. [R2] *PRINCIPAL CONSTITUENT OF LEMON GRASS OIL AND CAN BE ISOLATED BY FRACTIONAL DISTILLATION. OBTAINED SYNTHETICALLY BY OXIDATION OF GERANIOL, NEROL, OR LINALOOL BY CHROMIC ACID. [R3] FORM: *GERANIAL: 2-TRANS-3,7-DIMETHYL-2,6-OCTADIEN-1-AL; NERAL: 2-CIS-3,7-DIMETHYL-2,6-OCTADIEN-1-AL. [R4] *GRADES: TECHNICAL; PURE; FCC [R3] *COMMERCIAL MATERIAL IS A MIXTURE OF ALPHA AND BETA ISOMERS. [R3] *CITRAL FROM NATURAL SOURCES IS A MIXTURE OF TWO GEOMETRIC ISOMERS, GERANIAL AND NERAL. SEPARATION OF ISOMERS. [R2] MFS: *Bell Flavors and Fragrances Inc, Hq, 500 Academy Drive, Northbrook, IL 60062, (708) 291-8300; Production site: Los Angeles, CA 90039 [R5] *Givaudan-Roure Corp, Hq, 100 Delawanna Ave, Clifton, NJ 07014, (201) 365-8000; Specialty Division; Production site: Clifton, NJ 07014 [R5] *SCM GLIDCO Organics Group, PO Box 389, Jacksonville, FL 32201; Production site: Foot of West 61st St, Jacksonville, FL 32208 [R5] *Ungerer and Co, Hq, 4 Bridgewater Lane, Lincoln Park, NJ 07035, (201) 628-0600; Chemical Division, 110 North Commerce Way, Bethlehem, PA 18017 (610) 868-7266. Production site: Bethlehem, PA 18017 [R5] *Union Camp Corp, Hq, 1600 Valley Rd, Wayne, NJ 07470, (201) 628-2000; Bush Boake Allen, P.O. Box 37617, Jacksonville, FL 32236, (904) 783-2180 or (800) 874-9220. Production site: Jacksonville, FL 32236. [R5] OMIN: *WILL CAUSE DISCOLORATION OF WHITE SOAPS AND ALKALINE COSMETICS. [R2] USE: *INTERMEDIATE FOR OTHER FRAGRANCES [R3] *IN SYNTHESIS OF VITAMIN A, IONONE AND METHYLIONONE; FLAVOR, FOR FORTIFYING LEMON OIL; IN PERFUMERY FOR ITS CITRUS EFFECT IN LEMON AND VERBENA SCENTS, IN COLOGNE ODORS, IN PERFUMES FOR COLORED SOAPS [R2] PRIE: U.S. PRODUCTION: *(1972) 1.32X10+7 G (SALES OF CITRAL A) [R1] *(1973) 3.95X10+7 G (SALES OF CITRAL A) [R1] U.S. IMPORTS: *(1972) 7.59X10+6 G [R1] *(1975) 5.90X10+7 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- ODOR: *STRONG, LEMON-LIKE [R4] TAST: *CHARACTERISTIC BITTERSWEET [R4] BP: *Boiling point = 226-228 deg C. [R6] MP: *Melting point < -10 deg C. [R6] MW: *152.23 DEN: *0.891-0.897 @ 15 deg C [R3] PH: *ACID VALUE: 5.0 MAX [R4] SOL: *In 5 volumes of 60% alcohol, in all proportions of benzyl benzoate, diethyl phthalate, glycerol, propylene glucol, mineral oil, fixed oils, + 95% alcohol; insol in water. [R3]; *Water solubility = 1.34X10+3 mg/L at 37 deg C [R7] SPEC: *Refractive index = 1.4860-1.4900 @ 20 deg C, not optically active [R3] OCPP: *MAX ABSORPTION (ALCOHOL): 237 NM (LOG E= 4.16) /GERANIAL, NERAL/ [R8] *BP: 91-92 DEG C @ 2.6 MM HG; DENSITY: 0.8869 @ 20 DEG C/4 DEG C; INDEX OF REFRACTION: 1.48690 @ 20 DEG C/D /NERAL/ [R2] *SWEETER THAN GERANIAL; SEMICARBAZONE: MP: 171 DEG C /NERAL/ [R2] *SEMICARBAZONE: MP 164 DEG C /GERANIAL/ [R2] *VAPOR PRESSURE: 5 MM HG @ 91-95 DEG C /GERANIAL/ [R9, 1976] *LIGHT OILY LIQUID; MISCIBLE WITH ETHER, BENZYL BENZOATE, PROPYLENE GLYCOL, DIETHYL PHTHALATE, GLYCEROL, MINERAL OILS, ALC, ESSENTIAL OILS; PRACTICALLY INSOL IN WATER /GERANIAL AND NERAL/ [R2] *INDEX OF REFRACTION: 1.4892 @ 20 DEG C/D; DENSITY: 0.8888 @ 20 DEG C/4 DEG C; BP: 92-93 DEG C @ 2.6 MM HG /GERANIAL/ [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R10] +Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R10] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R10] FLPT: +195 DEG F (91 DEG C) (CLOSED CUP) [R10] FIRP: *If material on fire or involved in fire: Use foam, dry chemical, or carbon dioxide. cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Keep run-off water out of sewers and water sources. [R11] EXPL: *It is rather endothermic. [R12] OPRM: *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Use water spray to knock-down vapors. [R11] *Personnel protection: Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. [R11] SSL: *NOT STABLE TO ALKALIES AND STRONG ACIDS [R13] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *IRRITANT EFFECT OF 19 OILS AND 20 SYNTHETIC PERFUMES USED IN COSMETICS WERE TESTED ON SKIN OF 50 MALE VOLUNTEERS. CITRAL @ 32% CONCN WAS THE MOST IRRITATING OF PERFUMES IN HUMAN PATCH TEST. [R14] *The low molecular weight aldehydes, the halogenated aliphatic aldehydes, and the unsaturated aldehydes are particularly irritating. The mucus membranes of the nasal and oral passages and the upper respiratory tract are affected, producing a burning sensation, an increased ventilation rate, bronchial constriction, choking, and coughing. The eyes tear, and a burning sensation is noted on the skin of the face. During low exposures, the initial discomfort may abate after 5 to 10 minutes but will recur if exposure is resumed after an interruption. /Aldehydes/ [R15, 2633] *RECENT OUTBREAK OF HAND ECZEMA AMONGST CLEANING PERSONNEL AFTER INTRODUCTION OF NEW, LEMON-SCENTED DETERGENT. CITRAL PROVED TO BE STRONG PRIMARY IRRITANT @ HIGHER TEMP. [R16] NTOX: *Citral once was alleged to cause increase in intraocular pressure in monkeys, but this has not been confirmed, nor has an influence on intraocular pressure been found in rabbits. [R17] *CITRAL WAS OVICIDAL TO FRESHLY LAID EGGS OF DYSDERCUS CINGULATUS, AND INHIBITED EMBRYONIC GROWTH IN OLDER EGGS, RESULTING IN DEFORMED DEAD IMAGOES FOUND IN EGGSHELL OR IMAGOES WHICH DIED WHILE COMING OUT OF THE EGGSHELL. [R18] *CITRAL INDUCED MICROPHTHALMOS IN 3-DAY-OLD CHICK EMBRYOS BY INTRAAMNIOTIC INJECTION. IN SEVERE CASES CHANGES WERE IN IPSILATERAL PART OF HEAD. CORNEAL EPITHELIUM LOST ITS CONTINUITY AND LENS SHOWED DEGENERATIVE CHANGES WITH SPHEROPHAKIA. HYPERPLASIA OF CORNEA AND RETINA. [R19] *MATURE FEMALE RATS TREATED WITH CITRAL EITHER TOPICALLY FOR 60 OR 100 DAYS OR BY IP INJECTIONS SHOWED MARKED DECR IN NUMBER OF NORMAL FOLLICLES/SECTION, BECAUSE OOCYTES DEGENERATED. REDUCTION IN IMPLANTATION NUMBER AND LITTER SIZE AND INCR POST-IMPLANTATION FETAL DEATH. [R20] *TREATMENT OF RATS FOR 3 DAYS WITH CITRAL INCR ENZYME AND CYTOCHROME P-450 LEVELS. [R21] *CITRAL CAUSED TERATOGENIC EFFECT WHEN ADMIN BY INJECTION AT CONCN OF 0.001-0.1 MOL TO CHICK EMBRYOS. MORPHOLOGICAL MALFORMATION OCCURRED MAINLY IN CRANIOFACIAL AREA, AS WELL AS OTHER PARTS OF BODY. [R22] *Citral was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using a standard protocol approved by the National Toxicology Program. Citral was tested at doses of 0, 1, 3, 10, 33, 50, 100, and 160 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Citral was negative in these tests and the highest ineffective dose level tested without clearing of the background lawn in any Salmonella tester strain was 33 ug/plate. [R23] *A study was under taken to investigate the embryofeto-toxic potential of citral in the rat. Citral (60; 125; 250; 500 and 1000 mg/kg) in corn oil was given orally to Wistar rats from day 6 to 15 of pregnancy. On day 21 of pregnancy, the number of resorptions and implantation sites were recorded. A transient decrease in weight gain from days 6 to 11 of gestation at the lowest doses and a reduction in body weight minus uterine weight at term at the highest doses indicated that citral was maternally toxic over the dose range tested. A slight but statistically significant increase in the ratio of resorptions per implantations was observed with 60 and 125 mg/kg body weight. Doses higher than 125 mg/kg reduced dose-dependently the ratio of pregnant per mated female. Signs of fetal growth retardation and a higher incidence of minor skeletal abnormalities were found in doses higher than 60 mg/kg. No increase in the frequency of visceral anomalies was found at any dose level, but an increase in fetal spleen weight was observed in doses higher than 125 mg/kg. The no-observed adverse effect level for embryofeto-toxicity is lower than 60 mg citral/kg body weight p.o. [R24] *A study of the potential effects of microencapsulation on the toxicity of citral was conducted in 14 day continuous feeding studies with both sexes of F344 rats and B6C3Fl mice. Toxicity by the feeding route was compared with that from bolus doses of the neat chemical in corn oil administered by gavage. Both sexes of rats and mice were given diet containing 0, 0.63, 1.25, 2.5, 5 and 10% citral microcapsules. These feed formulations were equivalent to daily doses of 0, 142, 285, 570, 1140 and 2280 mg citral/kg body weight for rats and 0, 534, 1068, 2137, 4275 and 8550 mg citral/kg body weight for mice. The daily gavage doses were 0, 570, 1140 and 2280 mg citral/kg body weight for both sexes of rats, and 0, 534, 1068 and 2137 mg citral/kg body weight for both sexes of mice. Citral microcapsules administered in the diet did not cause mortality in mice or rats. Toxicity was confined to decreases in body weight at the 10% concentration in mice, at the 5 and 10% concentrations in rats, and decreases in absolute weights of the liver, kidney and spleen at the 10% concentration in rats. The only histopathological change observed was minimal to mild hyperplasia and/or squamous metaplasia of the respiratory epithelium in the anterior portion of the nasal passages of rats fed 5 or 10% citral microcapsules. By contrast, citral gavage caused mortality in five out of five male and female mice at 2137 mg/kg body weight, and in two out of five male mice at 1068 mg/kg body weight. There were dose-related increases in absolute liver weights of male and female mice. Cytoplasmic vacuolization of hepatocytes occurred in all female mice gavaged with 1068 and 2137 mg citral/kg body weight, and in male mice from the 2137 mg/kg dose group. Necrosis, ulceration and/or acute inflammation of the forestomach occurred in the high-dose mice of both sexes. Inflammation and/or hyperplasia of the forestomach occurred in about half of the male and female mice dosed with 1068 mg citral/kg. Citral gavage at doses that were equivalent to up to 10% in the diet (2280 mg/kg body weight) did not cause toxicity in rats, except for minimal hyperplasia of the squamous epithelium of the forestomach in high-dose males. [R25] *To investigate potential mammalian developmental toxicity, pregnant Sprague-Dawley rats were exposed to citral by inhalation for 6 hr/day on gestation days 6-15 at mean concentrations of 0, l0 or 34 ppm as vapor, or 68 ppm as an aerosol/vapor mixture. On gestation day 20, the fetuses were evaluated for gross, visceral and skeletal malformation. Exposure to 68 ppm was maternally toxic, with reduced body-weight gains, ocular opacity, breathing difficulty, nasal discharge and salivation noted in the dams. No maternal toxicity was seen at the lower vapor exposure levels. The number of corpora lutea, implantations, resorptions, fetal viability, litter size, and sex ratio were not adversely affected by citral at any exposure level tested, and no exposure-related malformations were observed. At a maternally toxic exposure level, a slight reduction in mean fetal body weight and a slight increase in the incidence of hypoplastic bones were noted. Citral does not produce developmental toxicity in the rat when administered by inhalation at concentrations up to a maternally toxic exposure level. [R26] *Locally applied retinol is metabolized to retinoic acid in mouse epidermis in vivo. To characterize the oxidation system, the ability of soluble extracts of hairless mouse epidermis to convert retinol and retinal into retinoic acid /was investigated/. The extracts oxidized retinol to retinoic acid in two steps catalyzed by two NAD+-dependent enzymes. The first enzyme catalyses the reversible oxidation of retinol to retinal and is an alcohol dehydrogenase isoenzyme. The second enzyme oxidizes retinal to retinoic acid. Retinol oxidation by epidermal extracts was inhibited by the alcohol dehydrogenase inhibitor 4-methylpyrazole and by citral. Citral significantly inhibited retinoic acid formation from retinol in the epidermis in vivo. [R27] *The short-term effects of citral on the liver have been studied in two strains of rat. Hepatomegaly was accompanied in citral-treated rats by an altered distribution of lipid and glycogen in the liver and peroxisome proliferation occurred in a manner of that associated with some hypolipidaemic compounds. Specific biochemical markers supported the morphological changes in the peroxisomes. Cyanide-insensitive palmitoyl CoA oxidation showed, at the maximum fourfold and threefold inductions in Wistar albino and Long Evans hooded rats, respectively. In addition, induction of cytochrome p450 levels was greater in the Long Evans than in the Wistar rats the maximal increases recorded being 81 and 27% respectively. No alterations in plasma triglycerides or total cholesterol were detected. The differential induction of the mixed-function oxides system and the differential proliferation of peroxisomes in these two strains of rat suggest that citral may be metabolized differently in the two strains. peroxisomal and possibly also mitochondrial changes are involved in the action of citral on lipid metabolism. [R28] *Immunocytochemical characterization of several epithelial markers using the PAP technique was analyzed during different stages of induced prostatic hyperplasia in rats. Intact adolescent rats 142 days old were treated with citral (3,7 dimethyl-2,6 octadienal) for l0, 30 and 100 days and their ventral prostate compared to untreated matched-age animals. Among the epithelial markers studied, the prostatic specific acid phosphatase was present in hyperplastic prostates of rats. The immunoreaction showed a fair correlation with the severity of lesion and duration of treatment. The prostatic specific antigen showed equally immunoreactive in both control and treated rats. The hyperplastic and normal rat prostates did not show immunoreactivity towards the other epithelial cell markers such as epithelial membrane antigen, carcinoembrionic antigen and alpha-fetoprotein antisera. Prostatic specific acid phosphatase and to a lesser extent prostatic specific antigen might represent valuable markers for comparative studies of prostatic hyperplasia in rodents. [R29] TCAT: ?3,7-Dimethyl-2,6-octadienal (CAS # 5392-40-5) was evaluated for dermal sensitization. The test substance was applied at a dosage of 0.5 ml to the occluded upper arms of 42 human subjects. The final challenge application applied two patches, one to the original site and one to a site not previously sensitized. No evidence of primary irritation or sensitization was observed. [R30] ?3,7-Dimethyl-2,6-Octadienal (CAS # 5392-40-5) was evaluated for primary dermal irritation. The test substance was applied (undiluted) at a dosage level of 0.5 ml to 6 New Zealand albino rabbits for 24 hours. Clinical signs included moderate erythema and edema, and loosening of the scab edges in 14-17 days, showing injury in depth. The test substance was determined to be corrosive. [R31] ?A case report for 3,7-Dimethyl-2,6-Octadienal (CAS # 5392-40-5) was submitted because of an adverse health effect from an Exxon employee who complained of "congestion, nausea, headaches, sore throat, eyes burning, tightness in chest", during the run of lemon scent bags containing the product "lemon scent resin concentrate". The product contains one material, Citral, which is know to have sensitizing potential. Citral is a skin irritant and may be capable of eliciting skin allergies (delayed contact hypersensitivity). Further claims of adverse health effects were alleged from a clerical employee in the Clinton, Massachusetts plant who suffered a "distinct allergic reaction" to the scent of a raw material used in the manufacture of the subject chemical. The employee saw a physician at the time of the incident, who "administered a shot which reduced the swelling, and after a few minutes returned her breathing to normal". The allergic response is similar to "anaphylactic shock". [R32] ?3,7-Dimethyl-2,6-Octadienal (CAS # 5392-40-5) was evaluated for genotoxicity. Tests for cytogenetic effects were performed in chinese hamster ovary cells. The test substance was negative for induction of chromosome aberrations (CA) and positive for induction of sister chromatid exchanges (SCE). No further information was submitted. [R33] ADE: *IN RAT AND MOUSE ORALLY ADMIN CITRAL WAS RAPIDLY ABSORBED FROM GI TRACT, RESULTING IN UNIFORM DISTRIBUTION OF LABEL THROUGHOUT BODY OF MOUSE BY 12 HR. RADIOACTIVITY WAS EXCRETED RAPIDLY, MAJOR ROUTE BEING URINARY TRACT. NO EVIDENCE FOR LONG-TERM STORAGE IN BODY. [R34] *The disposition of citral was studied in male Fischer rats after iv, po, and dermal treatments. The pattern of distribution and elimination was the same after iv or oral exposure. Urine was the major route of elimination of citral-derived radioactivity, followed by feces, (14)C02, and expired. However, after dermal exposure, relatively less of the material was eliminated in the urine and more in the feces, suggesting a role for first-pass metabolism through the skin. Citral was almost completely absorbed orally; due to its extreme volatility, much of an applied dermal dose was lost. The citral remaining on the skin was fairly well absorbed. No effect of oral dose, from 5 to 500 mg/kg, was detected on disposition. Although the feces was a minor route of excretion, approximately 25% of the administered dose was eliminated via the bile within 4 hr of an iv dose. The metabolism of citral was both rapid and extensive. Within 5 min of an iv dose, no unmetabolized citral could be detected in the blood. Repeated exposure to citral resulted in an increase in biliary elimination, without any significant change in the pattern of urinary, fecal, or exhaled excretion. This suggests that citral may induce at least one pathway of its own metabolism. The rapid metabolism and excretion of this compound suggest that significant bioaccumulation of citral would not occur. [R35] METB: *CITRAL...IN EXPERIMENTAL ANIMALS...IS CONVERTED IN PART TO THE SO-CALLED HILDEBRANDT ACID IN WHICH A DOUBLE OMEGA OXIDATION HAS TAKEN PLACE. [R9, 1979] *Aldehydes are readily oxidized to organic acids, which, in turn, can serve as substrates for fatty acid oxidation pathways and the Krebs cycle. ... Oxidation of aldehydes is catalyzed by aldehyde dehydrogenase, which has been found in the brain, erythrocytes, liver, kidney, heart, and placenta. /Aldehydes/ [R15, 2635] *... The detoxification of aldehydes can be seen to proceed basically via two routes: (1) an oxidation to yield readily metabolized acids; (2) inactivation by reaction with sulfhydryl groups, particularly glutathione. Under conditions that either deplete glutathione levels, or that result in an inhibition of aldehyde dehydrogenase (for example, Antabuse treatment), the acute and chronic effects of aldehyde toxicity might be more fully expressed. /Aldehydes/ [R15, 2637] *Citral is a naturally occurring aliphatic aldehyde of the terpene series and is an isomeric mixture of geranial and neral. In this study, urinary metabolites of citral in male F344 rats were characterized. Stereospecific oxidation of citral at the C-8 methyl was investigated, as was the hydrolytic sensitivity of biliary and urinary metabolites. For metabolite identification, urine was collected over dry ice for 24 hr after a single po 500 mg/kg dose of (l4)C citral. Elimination in urine was rapid, with approximately 50% of the dose excreted within 24 hr. Citral was rapidly metabolized and excreted as metabolites, including several acids and a biliary glucuronide. Seven urinary metabolites were isolated and identified: 3-hydroxy-3,7-dimethyl-6-octenedioic acid; 3,8-dihydroxy-3,7-dimethyl-6-octenolc acid; 3,9-dihydroxy-3,7-dimethyl-6-octenolc acid; E- and Z-3,7-dimethyl-2,6-octadienedioic acid; 3,7-dimethyl-6-octenedioic acid; and E-3,7-dimethyl-2,6-octadienoic acid. Although citral is an alpha,beta-unsaturated aldehyde and has the potential of being reactive, the urinary metabolites of citral appear to arise from metabolic pathways other than nucleophilic addition to the double bond. [R36] *Reports of the in vivo metabolism of citral suggest that a primary route of metabolism is conversion to the corresponding acid presumably by aldehyde dehydrogenases. In the present study, hepatic mitochondrial and cytosolic fractions were prepared from male Sprague-Dawley rats to assess in vitro metabolism of citral. Evidence of aldehyde dehydrogenases-mediated citral oxidation was not seen in either subcellular fraction. On the contrary, citral was found to be a potent inhibitor of acetaldehyde oxidation by the low-KM mitochondrial form of aldehyde dehydrogenases. Measurement of the in vitro acetaldehyde oxidation rates of this isozyme in the presence of citral lead to the estimation of a Ki of 360 nM. It was observed that citral was readily reduced to the corresponding alcohol by alcohol dehydrogenase in the cytosolic fraction. The reduction of citral in the presence of NADH proceeded at two distinct rates. It is possible that the differential alcohol dehydrogenase-mediated reduction rates of citral are the result of varying affinities for the enzyme of two citral, isomers, geranial (trans) and neral (cis). [R37] *Citral inhibit the formation of retinoic acid from retinol in mouse epidermis. Since skin-carcinogenesis is sensitive to retinoid status, and retinoic acid may be the active form of vitamin A in the epidermis, citral was tested for its ability to modulate tumor promotion in a two-stage skin-carcinogenesis study in hairless mice. The dorsal skins of female skh/hrl mice were initiated with O.l umol dimethylbenzanthracene, and tumors were promoted by twice-weekly application of l0 nmol of tetradecanoylphorbol-13-acetate (TPA) for 20 weeks. Prior to each TPA application groups were dosed with 0, l umol or 10 umol citral. Citral had a dose-dependent inhibitory effect on tumor-production in the TPA promoted groups. At 10 weeks of promotion the percentage of mice with tumors were 88%, 72% and 60%, for the 0, 1 and l0 umol citral treated groups, and the numbers (mean + or- SD) of tumors per affected animal were 7.3 + or - 6.6, 3.9 + or - 4.2, and 3.7 + or - 3.5, respectively. At 15 weeks of promotion the tumor incidence was 96%, 96% and 84%, respectively, and the number of tumors per affected animal were 9.5 + or - 6.8, 7.2 + or - 4.6 and 4.5 + or - 3.3, respectively. The mice in the high dose citral group had significantly fewer tumors. When the study was terminated at 20 weeks of promotion all mice had at least one tumor, but the number of tumors per affected mouse were lower in the citral treated groups. [R38] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Citral's production and use in the synthesis of vitamin A, ionone, and methylionone, as a flavor, in perfumery, in cologne, in soaps, and as an intermediate for other fragrances may result in its release to the environment through various waste streams. If released to the soil, citral will have high mobility. Volatilization of citral may be important from moist soil surfaces. Biodegradation of citral may be an important removal process in soil based on a four-week sludge study. If released to water, citral may adsorb to suspended solids and sediment. Citral may volatilize from water surfaces with estimated half-lives for a model river and model lake of 1.2 and 12 days, respectively. An estimated BCF value of 250 suggests that bioconcentration in aquatic organisms will be high. Biodegradation of citral may be an important removal process in water based on a four-week sludge study. If released to the atmosphere, citral will exist in the vapor phase in the ambient atmosphere. Vapor-phase citral is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 2.8 hours. Vapor-phase citral is also degraded in the atmosphere by reaction with ozone with an estimated half-life of about 37 minutes. Citral may be physically removed from the air by wet deposition. The general population can be exposed to citral in foodstuffs based on its natural existence in lemon grass, lemons, and oranges and its use as a flavor, in perfumery, in cologne, and in soaps. Occupational exposure to aldehydes, such as citral, can occur through dermal contact, inhalation, and ingestion. (SRC) NATS: *CONSTITUENT (75 TO 85%) OF OIL OF LEMON GRASS, THE VOLATILE OIL OF CYMBOPOGON CITRATUS (DC) STAPF, OR OF CYMBOPOGON FLEXUOSUS (NEES) STAPF, GRAMINEAE. ALSO PRESENT TO A LIMITED EXTENT IN OILS OF VERBENA, LEMON, AND ORANGE. [R2] *...FOUND IN: LITSEA CITRATA (APPROX 90%), LITSEA CUBEBA BLUME (APPROX 70%), LINDERA CITRIODORA (APPROX 65%), BACKHOUSIA CITRIODORA (APPROX 95-97%), CALYPRANTHES PARRICULATA (APPROX 62%), LEPTOSPERMUM LIVERSIDGEIVAR A LEAVES (APPROX 70-80%), AND OCIMUM GRATISSIUMUM (APPROX 66.5%). ALSO PRESENT IN LEMON (2-5%), LIME (6-9%), AND CITRUS AURANTIFOLIA LEAVES (PETITGRAIN, APPROX 36%). [R4] ARTS: *Citral's production and use in the synthesis of vitamin A, ionone, and methylionone, as a flavor, in perfumery, in cologne, in soaps(1), and as an intermediate for other fragrances(2) may result in its release to the environment through various waste streams(SRC). [R39] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 150(SRC), determined from a structure estimation method(2), indicates that citral will have high mobility in soil(SRC). Volatilization of citral may be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 4.35X10-5 atm-cu m/mole(3,SRC). Biodegradation of citral may be an important removal process in soil based on a two-week sludge study(4). [R40] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 150(SRC), determined from a structure estimation method(2), indicates that citral may adsorb to suspended solids and sediment(SRC) in the water. Citral may volatilize from water surfaces based on an estimated Henry's Law constant of 4.35X10-5 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Estimated half-lives for a model river and model lake are 1.2 and 12 days, respectively(4,SRC). An estimated BCF value of 250(4,SRC), from an estimated log Kow(5,SRC), suggests that bioconcentration in aquatic organisms will be high(SRC) according to a recommended classification scheme(6). Biodegradation of citral may be an important removal process in water based on a two-week sludge study(7). [R41] *ATMOSPHERIC FATE: According to a suggested classification scheme(1), an estimated vapor pressure of 0.09 mm Hg at 25 deg C(2,SRC) indicates that citral will exist in the vapor phase in the ambient atmosphere. Vapor-phase citral is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2.8 hours(3,SRC). Vapor-phase citral is also degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be about 37 minutes(3,SRC). Particulate-phase citral may be physically removed from the air by wet deposition(SRC). [R42] BIOD: *A four week biodegradation study using 100 mg/l sludge and a citral concentration of 30 mg/L gave a 88-94% theoretical BOD(1). [R43] ABIO: *The rate constant for the vapor-phase reaction of citral with photochemically produced hydroxyl radicals has been estimated as 1.4X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2.8 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The rate constant for the vapor-phase reaction of citral with ozone has been estimated as 4.4X10-16 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 37 minutes at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(1,SRC). Reaction with nitrate radicals in the atmosphere may also be important(1,SRC). [R44] BIOC: *An estimated BCF value of 250 was calculated for citral(SRC), using an estimated log Kow of 3.45(1,SRC) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is high(SRC). [R45] KOC: *Using a structure estimation method based on molecular connectivity indexes(1), the Koc for citral can be estimated to be about 150(SRC). According to a recommended classification scheme(2), this estimated Koc value suggests that citral has high mobility in soil(SRC). [R46] VWS: *The Henry's Law constant for citral is estimated as 4.35X10-5 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that citral will volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 1.2 days(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 12 days(2,SRC). Citral's Henry's Law constant(1,SRC) indicates that volatilization from moist soil may occur(SRC). [R47] FOOD: *NON-ALCOHOLIC BEVERAGES 9.2 PPM; ICE CREAM, ICES, ETC 23 PPM; CANDY 41 PPM; BAKED GOODS 43 PPM; CHEWING GUM 170 PPM. [R4] RTEX: *The general population can be exposed to citral in foodstuffs based on its natural existence in lemon grass, lemons, and oranges(1) and its use as a flavor, in perfumery, in cologne, and in soaps(1). [R48] *Occupational exposure to aldehydes, such as citral(SRC), can occur through dermal contact, inhalation, and ingestion(1). [R49] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 65,227 workers are potentially exposed to citral in the USA(1). [R50] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Citral used as a synthetic flavoring substance or adjuvant in food for human consumption is generally recognized as safe when used in accordance with good manufacturing practice. [R51] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *CITRAL OFFICIAL FINAL ACTION. COLORIMETRY. [R52] *HSLC PROCEDURE WAS FASTER AND MORE CONVENIENT THAN GLC FOR CITRAL DETERMINATION. [R53] *ON ACIDIFICATION WITH METHANOLIC H2SO4, PERMANENT MEASURABLE GREEN COLOR IS DEVELOPED WITH CITRAL. QUANTITATIVE THIN LAYER CHROMATOGRAPHY WAS ALSO ADOPTED FOR DETERMINATION OF CITRAL IN VOLATILE OILS MAKING USE OF PROPOSED COLOR REACTION. [R54] *GAS CHROMATOGRAPHIC ANALYSIS OF CITRAL. [R55] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that citral is on the list of post peer review technical reports in progress. Route: microencapsulation in feed; Species: rats and mice. NTP TR No 505. [R56] SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 362 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 286 R4: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 99 R5: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 618 R6: Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R7: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) R8: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-251 R9: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R10: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-27 R11: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 262 R12: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 528 R13: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 299 R14: MOTOYOSHI K ET AL; COSMET TOILET 94 (AUG): 41 (1979) R15: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R16: ROTHENBORG HW ET AL; CONTACT DERMATITIS 3 (1): 37 (1977) R17: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 241 R18: OSMANI Z ET AL; INDIAN J EXP BIOL 15 (8): 666 (1977) R19: ABRAMOVICI A ET AL; DEV NEUROSCI 1 (3-4): 177 (1978) R20: TOAFF ME ET AL; J REPROD FERTIL 55 (2): 347 (1979) R21: PARKE DV, RAHMAN H; BIOCHEM J 113 (2): 12 (1969) R22: ABRAMOVICI A; ADV EXP MED BIOL 27 161 (1972) R23: Zeiger E et al; Environ Mutagen 9:1-110 (1987) R24: Nogueira A C MA et al; Toxicol 96 (2): 105-13 (1995) R25: Dieter MP et al; Food Chem Toxicol 31 (7): 463-74 (1993) R26: Gaworski CL et al; Food Chem Toxicol 30 (4): 269-75 (1992) R27: Connor MJ, Smit MH; Biochem J 244 (2): 489-92 (1987) R28: Jackson GM et al; Food Chem Toxicol 25 (7): 505-13 (1987) R29: Massas R et al; Histol Histopathol 6 (2) 183-9 (1991) R30: Repeated Insult Patch Test of Group Number 79, NRA-01-0229(-----)C (Final Report) with Attachments and Cover Letter Dated 112591 (Sanitized); 02/23/72; EPA Doc. No. 86-920000249S; Fiche No. OTS0535066 R31: MONSANTO CO; Initial Submission: Toxicity Studies on: Citral with Cover Letter Dated 08/13/92; 06/12/78; EPA Doc. No. 88-920007532; Fiche No. OTS0538615 R32: QUANTUM CHEMICAL CORP; Letter From Quantum Chemical Corp to USEPA Regarding Adverse Health Effects as a Result of Exposure to Lemon Scent Resin with Attachments and Cover Letters Dated 04/07/88 and 11/16/87; 04/07/88; EPA Doc. No. FYI-OTS-0488-0609P; Fiche No. OTS0000609-0 R33: GIVAUDAN CORP; National Toxicology Program Fiscal Year 1985 Annual Plan; 03/01/85; EPA Doc. No. 86-870001798; Fiche No. OTS0516404 R34: PHILLIPS JC ET AL; FOOD COSMET TOXICOL 14 (6): 537 (1976) R35: Diliberto JJ et al; Drug Metab Dispos 16 (5): 721-7 (1988) R36: Diliberto JJ et al; Drug Metab Dispos 18 (6): 866-75 (1990) R37: Boyer CS, Petersen DR; Drug Metab Dispos 19 (1) 81-6 (1991) R38: Connor MJ; Cancer Lett 56 (l): 25-8 (1991) R39: (1) Budavari S; The Merck Index 11th ed. Rahway, NJ: Merck and Co Inc pg. 362 (1989) (2) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary 12th ed. NY, NY: Van Nostrand Rheinhold Co pg. 286 (1993) R40: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R41: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10, 15-1 to 15-29 (1990) (5) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R42: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R43: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R44: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R45: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R46: (1) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) R47: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R48: (1) Budavari S; The Merck Index. 11th ed. Rahway,NJ: Merck and Co Inc pg. 362 (1989) R49: (1) Parmeggiani L; Encycl Occup Health and Safety 3rd ed Geneva, Switzerland: International Labour Office pg. 122-3 (1983) R50: (1) NIOSH; National Occupational Exposure Survey (1983) R51: 21 CFR 182.60 (4/1/93) R52: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/316 19.073 R53: RABINOWITZ I ET AL; INT CONGR ESSENT OILS (PAP) 6TH, 98, 29 PP (1974) R54: KARAWYA MS ET AL; AN ACAD BRAS CIENC 44 (SUPPL): 161 (1972) R55: ABD ALLAH MA ET AL; NAHRUNG 19 (3): 195 (1975) R56: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 40 Record 103 of 1119 in HSDB (through 2003/06) AN: 1002 UD: 200210 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIETHYLENETETRAMINE- SY: *ARALDITE-HARDENER-HY-951-; *ARALDITE-HY-951-; *N,N'-BIS(2-AMINOETHYL)ETHYLENEDIAMINE; *DEH-24-; *1,8-DIAMINO-3,6-DIAZAOCTANE-; *3,6-DIAZAOCTANE-1,8-DIAMINE-; *1,2-ETHANEDIAMINE, N,N'-BIS(2-AMINOETHYL)-; *ETHYLENEDIAMINE, N,N'-BIS(2-AMINOETHYL)-; *HY-951-; *TECZA-; *TETA-; *1,4,7,10-TETRAAZADECANE-; *TRIEN- RN: 112-24-3 MF: *C6-H18-N4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ETHYLENE DICHLORIDE AND AMMONIA UNDER CONTROLLED CONDITIONS [R1] FORM: *GRADES: TECHNICAL; ANHYDROUS. [R2] MFS: +Air Products and Chemicals, Inc, Hq, PO Box 538, Allentown, PA 18195, (215) 481-4911; Industrial Chemicals Division; Production site: St Gabriel, LA 70776 [R3] +Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 [R3] USE: *IN DETERGENTS; SYNTHESIS OF DYESTUFFS, PHARMACEUTICALS [R2] +MEDICATION (VET) +MEDICATION *CHEM INT FOR IMIDAZOLINE AND AMINOAMIDE SURFACTANTS, WATER SOL PLASTIC FILMS AND POLYAMIDE RESINS; CURING AGENT IN VULCANIZATION OF ALKYL ACRYLATE POLYMERS, METHACRYLONITRILE POLYMERS AND COPOLYMERS; HARDENER FOR LIQUID EPOXY RESINS [R1] PRIE: U.S. PRODUCTION: *(1972) 8.2X10+9 GRAMS [R1] *(1975) 1.36X10+6 GRAMS [R1] U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MODERATELY VISCOUS, YELLOWISH LIQUID [R4] BP: *266-267 DEG C @ 760 MM HG [R5] MP: *12 DEG C [R5] MW: *146.24 [R6, 2039] DEN: *0.9818 @ 20 DEG C/20 DEG C [R6, 2039] PH: *STRONGLY BASIC (PH 10 IN 1% AQ SOLN) [R7, 146] SOL: *SOL IN ALCOHOL, ACID [R5]; *COMPLETE SOLUBILITY IN WATER [R6, 2039] SPEC: *INDEX OF REFRACTION: 1.4971 @ 20 DEG C/D; SADTLER REF NUMBER: 532 (IR, PRISM) [R5]; +IR: 15546 (Sadtler Research Laboratories IR Grating Collection) [R8] VAPD: *5.04 (AIR= 1) [R6, 2039] VAP: *LESS THAN 0.01 MM HG, 20 DEG C [R6, 2039] OCPP: *CONVERSION UNITS: 1 MG/L= 167 PPM, 1 PPM= 5.98 MG/CU M [R6, 2039] *WT 8.2 LB/GAL @ 20 DEG C [R2] *CAN REACT WITH OXIDIZING MATERIALS [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R9] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R9] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R9] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R9] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R9] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R9] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R9] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R9] FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME. [R4] NFPA: *HEALTH 3. 3= MATERIALS EXTREMELY HAZARDOUS TO HEALTH BUT AREAS MAY BE ENTERED WITH EXTREME CARE. FULL PROTECTIVE CLOTHING, INCL SELF-CONTAINED BREATHING APPARATUS, COAT, PANTS, GLOVES, BOOTS, AND BANDS AROUND LEGS, ARMS AND WAIST...PROVIDED. NO SKIN SURFACE SHOULD BE EXPOSED. [R10] *FLAMMABILITY 1. 1= MATERIALS...MUST BE PREHEATED BEFORE IGNITION CAN OCCUR. WATER MAY CAUSE FROTHING IF IT GETS BELOW SURFACE OF LIQUID AND TURNS TO STEAM. HOWEVER, WATER FOG GENTLY APPLIED TO SURFACE WILL CAUSE FROTHING WHICH WILL EXTINGUISH THE FIRE. [R10] *REACTIVITY 0. 0= MATERIALS WHICH (IN THEMSELVES) ARE NORMALLY STABLE EVEN UNDER FIRE EXPOSURE CONDITIONS AND WHICH ARE NOT REACTIVE WITH WATER. NORMAL FIRE FIGHTING PROCEDURES MAY BE USED. [R10] FLPT: *290 DEG F [R6, 2039] AUTO: *640 DEG F. [R4] FIRP: *CARBON DIOXIDE, DRY CHEMICAL, ALCOHOL FOAM. [R4] EQUP: *B) PROTECT HANDS WITH RUBBER GLOVES AND...BARRIER CREAMS. /ALIPHATIC AMINES/ [R7, 147] OPRM: *.../IT WAS/ CONCLUDED THAT CONTROL PROBLEM WAS PRIMARILY ONE OF PREVENTING DIRECT SKIN CONTACT. SUCCESSFUL CONTROL REQUIRES GOOD PERSONNEL TRAINING AND SCRUPULOUS HANDLING TECHNIQUES. [R6, 2061] *C) DECR CONCN OF AMINE VAPOR BY GOOD VENTILATION. AMINES WITH HEAVY VAPOR... SHOULD BE DRAWN OFF BY DESCENT. D) EMPLOYEES PRONE TO SENSITIZATION OR LIVER DEFICIENCY...REMOVED FROM SHOPS HANDLING HARDENERS. /ALIPHATIC AMINES/ [R7, 147] SSL: *VOLATILE [R11] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R12] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R13] STRG: *IN GENERAL, MATERIALS...TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS...SHOULD BE STORED IN COOL...VENTILATED PLACE, OUT OF...SUN, AWAY FROM...FIRE HAZARD...BE PERIODICALLY INSPECTED AND MONITORED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED... [R14] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: *WORKMEN...MEDICALLY EXAM @ REGULAR INTERVALS. /ALIPHATIC AMINES/ [R7, 147] HTOX: *EXPOSURE TO THE HOT VAPOR RESULTS IN RESPIRATORY TRACT IRRITATION AND ITCHING OF THE FACE WITH ERYTHEMA AND EDEMA. [R6, 2061] *...MARKED SENSITIZATION /NOTED/ IN 6-20 WORKMEN EMPLOYED IN ELECTRICAL EQUIPMENT...FACTORY. THIS SHOWED ITSELF AS SERIOUS SKIN LESIONS, VESICULAR PAPULAR ECZEMA, SOMETIMES WEEPING, LOCALIZED PARTICULARLY ON HANDS, FOREARMS, AND GENITAL AND INGUINAL REGIONS, TOGETHER WITH FACIAL EDEMA. [R7, 166] NTOX: *ACUTE TOXICITY IN RABBITS: SKIN IRRITATION GRADE 6. 6= MORE NECROSIS FROM UNDILUTED, LESS THAN EDEMA FROM 10%. /FROM TABLE/ [R6, 2046] *THERE WERE NO DEATHS IN RATS EXPOSED TO SATURATED VAPOR FOR 4 HR. /FROM TABLE/ [R6, 2046] *...RATED 5 ON RABBIT EYES. /MOST SEVERE INJURIES HAVE BEEN RATED 10/. [R15] *IN NONPREGNAT RATS TREATED DERMALLY WITH TRIETHYLENETETRAMINE STABILIZER, GAMMA-GLUTAMYLTRANSPEPTIDASE ACTIVITY IN KIDNEYS AND AMINOTRANSFERASES ACTIVITY IN LIVER INCR. ACETYLCHOLINESTERASES ACTIVITY IN BRAIN WAS INHIBITED. [R16] *TRIETHYLENETETRAMINE STABILIZER WAS ADMIN DERMALLY TO PREGNANT RATS. ASPARTATE AMINOTRANSFERASE ACTIVITY IN LIVER WAS INHIBITED. MORPHOLOGICAL CHANGES IN INTERNAL ORGANS WERE SIMILAR TO THOSE IN NONPREGNANT RATS. HYPEREMIA OF LIVER AND KIDNEYS. [R16] *COLD-CURING RESIN HARDENERS WERE EXAMINED REGARDING THEIR SENSITIZATION CAPACITY BY GUINEA PIG MAXIMIZATION TEST. THE PHENOL-ACCELERATED ADDUCT OF TRIETHYLENETETRAMINE SENSITIZED NEARLY HALF OF THE ANIMALS. [R17] *ORAL LD50 FOR MICE, RATS AND RABBITS 1600, 4300 and 5500 MG/KG RESPECTIVELY. CUMULATION COEFFICIENTS IN 4 MO SUBACUTE TEST WERE 3.5 and 8 FOR 0.1 and 0.05 LD50 RESPECTIVELY. STIMULATION OF CNS DECR. HIPPURIC ACID, HEMOGLOBIN AND PROTEINS DECR. PEROXIDASE INHIBITED MORE THAN CATALASE. [R18] *0.8 OR 4.0 MG/KG DAILY FOR 10 MO INCR CNS EXCITABILITY AND STIMULATED TACTILE REFLEXES. ANTITOXIC, CARBOHYDRATE AND PROTEIN FUNCTIONS OF LIVER DISTRUBED. THRESHOLD DOSE OF CHRONIC TOXICITY 0.8 MG/KG. CUMULATION COEFFICIENT FOR CHRONIC TOXICITY 1.3. (MICE, RATS, RABBITS; ORALLY) [R18] *CONSIDERABLE CACHEXIA, WIDE CUTANEOUS ALTERATIONS IN PLACE OF TRIETHYLENETETRAMINE SMEARING, FATTY LIVER DEGENERATION AND KIDNEY AND BRAIN CONGESTION OBSERVED IN PREGNANT AND NONPREGNANT GUINEA PIGS. WIDE NECROTIC CHANGES IN PLACENTA AND FETAL DEATH IN PREGNANT ANIMALS. [R19] +Triethylenetetramine was found to be positive when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Triethylenetetramine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The lowest positive dose tested in any S. typhimurium strain was 0.033 mg/plate in strain TA100 without activation. In this strain, the low dose almost doubled the number of positive in TA1535, TA1537, and TA98 both with and without activation. A positive response was also exhibited in strain TA100 with activation. [R20] POPL: *EMPLOYEES PRONE TO SENSITIZATRION OR LIVER DEFICIENCY...REMOVED FROM SHOPS HANDLING HARDENERS. /ALIPHATIC AMINES/ [R7, 147] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antidotes; Chelating Agents; Indicators and Reagents [R21] +MEDICATION (VET): EXPTL USE: BASAL URINE COPPER EXCRETION BY RATS WAS INCR FROM 65.1 TO 357.1 OR 305.9 NMOL/24 HR BY TRIETHYLENETETRAMINE DIHYDROCHLORIDE (100 MG ORALLY). [R22] +MEDICATION (VET): EXPTL USE COPPER MOBILIZING EFFECT OF 16 SUBSTANCES WAS STUDIED IN RATS. TRIETHYLENETETRAMINE SHOWED MOST EFFICACY. [R23] +MEDICATION (VET): EXPTL USE 0.75 MMOL/KG WAS ADMIN IP TO RATS PRIOR TO ADMIN OF (63)NICL2. TRIETHYLENETETRAMINE (TETA) REDUCED PLASMA (63)NI CONCN AND INCR URINE EXCRETION DURING 6 HR AFTER INJECTION OF (63)NICL2, COMPARED TO CONTROLS THAT RECEIVED ONLY (63)NICKEL CHLORIDE. [R24] +MEDICATION (VET): EXPTL USE IN NICKEL POISONED RATS KILLED 6 HR AFTER TRIETHYLENETETRAMINE (TETA) ADMIN, (63)NI CONCN IN LIVER, KIDNEY, SPLEEN, LUNG AND HEART AVG 3.4, 0.72, 0.27. 0.22 and 0.12 TIMES CORRESPONDING CONCN IN CONTROLS. [R24] +MEDICATION (VET): EXPTL USE TRIETHYLENETETRAMINE (TETA) CHELATED NI IN POISONED RATS. RESULTS SUPPORT HYPOTHESIS THAT COMBINED ADMIN OF TETA AND (63)NICL2 RESULTED IN PARTITION OF POOL OF (63)NI BETWEEN 2 COMPONENTS: (63)NI-TETA COMPLEX AND NONCHELATED (63)NI. [R25] +MEDICATION (VET): EXPTL USE CHELATION IN NICKEL POISONED RATS. RENAL CLEARANCE OF (63)NI-TRIETHYLENETETRAMINE (TETA) EST TO BE MORE THAN 20 TIMES THAT OF NONCHELATED (63)NI. ADMIN OF TETA REDUCED NICKEL-INDUCED PROTEINURIA AND AMINOACIDURIA. [R24] +MEDICATION (VET): EXPTL USE SIX CHELATING DRUGS ADMIN TO RATS IM AT EQUIMOLAR DOSAGES IN ORDER TO COMPARE EFFECTIVENESS IN PREVENTION OF DEATH AFTER SINGLE PARENTERAL INJECTION OF NICL2. TRIETHYLENETETRAMINE AND D-PENICILLAMINE WERE MOST EFFECTIVE ANTIDOTES. [R26] +MEDICATION (VET): EXPTL USE RATS ADMIN SINGLE IV INJECTION OF AQ SOLN OF METAL SALTS AND SINGLE IM INJECTION OF TRIETHYLENETETRAMINE (TETA). TETA WAS EXTREMELY EFFECTIVE IN REDUCING PLASMA CONCN OF (63)NI FOLLOWED BY THAT OF (59)FE, (54)MN AND (113)SN. [R27] +MEDICATION (VET): EXPTL USE IN THIS STUDY 2,3,2-TETRAMINE, BY GAVAGE OR IV, WAS MOST EFFECTIVE AGENT FOR INDUCING CUPRURESIS IN BOTH NORMAL AND COPPER LOADED RATS. IF HUMANS CAN TOLERATE IT, IT COULD BE USED FOR MGMNT OF DISORDERS CHARACTERIZED BY COPPER ACCUMULATION. [R28] *EXPTL USE: DIHYDROCHLORIDE SALT TOLERATED WITHOUT SIDE EFFECTS APPROX 2.5 YR BY GIRL UNABLE TO TOLERATE D-PENICILLAMINE IN SPITE OF STEROID COVERAGE. RESPONSE WOULD SUGGEST THAT IT IS SAFE AGENT FOR TREATMENT OF WILSON'S DISEASE WHEN INTOLERANCE TO PENICILLAMINE EXISTS. [R29] *EXPTL USE: CASE REPORT OF PT WITH WILSON'S DISEASE, WITH INTOLERANCE TO D-PENICILLAMINE, TREATED WITH DIHYDROCHLORIDE SALT (TRIEN). ITS PHARMACOKINETIC PROPERTIES AS SHOWN BY SERUM COPPER PROFILE, COPPER MOBILIZATION AND EXCRETION ARE DIFFERENT FROM D-PENICILLAMINE [R30] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: +Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 1 ppm, skin. [R31] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 883 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 1044 R4: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 1052 R5: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-532 R6: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R7: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 395 R9: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R10: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 325M-180 R11: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 643 R12: 49 CFR 171.2 (7/1/96) R13: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.8230 (1988) R14: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 1195 R15: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 1184 R16: WOYTON ET AL; TOXICOL APPL PHARMACOL 32(1) 5 (1975) R17: THORGEIRSSON A; ACTA DERM-VENEREOL 58(4) 332 (1978) R18: STAVREVA M; KHIG ZDRAVEOPAZ 22(2) 179 (1979) R19: SZACKI ET AL; ARCH IMMUNOL THER EXP 22(1) 123 (1974) R20: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R21: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R22: GIBBS K, WALSHE JM; CLIN SCI MOL MED 53(4) 317 (1977) R23: PLANAS-BOHNE F; TOXICOL APPL PHARMACOL 50(2) 337 (1979) R24: SUNDERMAN ET AL; TOXICOL APPL PHARMACOL 38(1) 177 (1976) R25: SUNDERMAN ET AL; TOXICOL APPL PHARMCOL 38(1) 177 (1976) R26: HORAK ET AL; RES COMMUN CHEM PATHOL PHARMACOL 14(1) 153 (1976) R27: DWIVEDI ET AL; CHEMOSPHERE 7(11) 925 (1978) R28: BORTHWICH ET AL; J LAB CLIN MED 95(4) 575 (1980) R29: HASLAM ET AL; DEV PHARMACOL THER 1(5) 318 (1980) R30: HARDERS H, COHNEN E; PROC R SOC MED 70(SUPPL 3) 10 (1977) R31: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.41 RS: 18 Record 104 of 1119 in HSDB (through 2003/06) AN: 1003 UD: 200208 RD: Reviewed by SRP on 1/20/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIFLURALIN- SY: *L-36352-; *AGREFLAN-; *AGRIFLAN-24-; *BENZENAMINE, 2,6-DINITRO-N,N-DIPROPYL-4-(TRIFLUOROMETHYL)-; *CRISALIN-; *DIGERMIN-; *2,6-DINITRO-N,N-DIPROPYL-4-(TRIFLUOROMETHYL)BENZENAMINE; *2,6-DINITRO-N,N-DI-N-PROPYL-ALPHA,ALPHA,ALPHA-TRIFLUORO-P-TOLUIDINE-; *2,6-DINITRO-6-TRIFLUORMETHYL-N,N-DIPROPYLANILIN- (GERMAN); *4-(DI-N-PROPYLAMINO)-3,5-DINITRO-1-TRIFLUOROMETHYLBENZENE; *N,N-DI-N-PROPYL-2,6-DINITRO-4-TRIFLUOROMETHYLANILINE-; *N,N-DIPROPYL-4-TRIFLUOROMETHYL-2,6-DINITROANILINE-; *ELANCOLAN-; *LILLY-36,352-; *NCI-C00442-; *NITRAN-; *OLITREF-; *SU-SEGURO-CARPIDOR-; *P-TOLUIDINE,-ALPHA,ALPHA,ALPHA-TRIFLUORO-2,6-DINITRO-N,N-DIPROPYL-; *TREFICON-; *TREFLAM-; *TREFLAN-; *Treflan-EC-; *TREFLANOCIDE-ELANCOLAN-; *TRIFLUORALIN-; *ALPHA,ALPHA,ALPHA-TRIFLUORO-2,6-DINITRO-N,N-DIPROPYL-P-TOLUIDINE-; *TRIFLURALINE-; *TRIFUREX-; *TRIKEPIN-; *TRIM- RN: 1582-09-8 MF: *C13-H16-F3-N3-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 4-TRIFLUORO-2,6-DINITROCHLOROBENZENE AND DIPROPYLAMINE IN THE PRESENCE OF SODIUM CARBONATE [R1] FORM: *USEPA/OPP Pesticide Code 036101; Trade Names: Treflan. [R2] *EMULSIFIABLE CONCENTRATE (4 LB TRIFLURALIN PER US GAL), GRANULAR 5%. PRODUCT TO CONTAIN LESS THAN 1 PPM NITROSAMINE BY EPA ORDER. [R3] MFS: *Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268, (317) 337-3000; Production site: not listed [R4] OMIN: *TRIFLURALIN IS TOLERATED AT 0.05 PPM BY MOST CROPS; EXCEPTIONS ARE ALFALFA HAY (0.2 PPM), CARROTS (1 PPM), AND MUNG BEANS (2 PPM). [R5, 547] *DETERMINATION OF GAS CHROMATOGRAPH AMENABLE NITROSAMINES IN HERBICIDE FORMULATIONS. N-NITROSODIPROPYLAMINE WAS DETECTED IN TRIFLURALIN FORMULATIONS USING THERMAL ENERGY ANALYZER AFTER SEPARATION BY GAS CHROMATOGRAPHY OR HPLC. IDENTITY OF THE CMPD WAS CONFIRMED BY MASS SPECTROMETRY. RESULTS INDICATE THAT FORMULATIONS OF AMINE SALTS CAN FORM NITROSAMINES ON STORAGE, AND NITROSAMINES CAN BE FORMED IN PREPN OF NITROANILINE BASED HERBICIDES. [R6] USE: *For Trifluralin (USEPA/OPP Pesticide Code: 036101) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R2] *Herbicide [R7] CPAT: *SELECTIVE HERBICIDE FOR GRASSES AND BROADLEAF WEEDS, OF WHICH 52% IS USED ON SOYBEANS, 40% ON COTTON, 8% ON OTHER FIELD CROPS, VEGETABLES, FRUIT, NUTS, NURSERY CROPS, ALFALFA, PASTURE LAND, AND SUMMER FALLOW, and 2% AS SELECTIVE HERBICIDE IN OTHER APPLICATIONS (1972) [R1] *(1975) 9.86X10+9 GRAMS (CONSUMPTION) [R1] PRIE: U.S. PRODUCTION: *(1972) 9.53X10+9 GRAMS [R1] U.S. IMPORTS: *(1972) NEGLIGIBLE [R1] U.S. EXPORTS: *(1972) 1.82X10+9 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Yellow crystals [R7]; *YELLOW-ORANGE PRISMS [R3] ODOR: +NO APPRECIABLE ODOR [R8, 471] BP: *139-140 deg C @ 4.2 mm Hg [R7] MP: *46-47 deg C [R7] MW: *335.28 [R7] CORR: *Technical not corrosive [R9, 297] DEN: *1.36 @ 22 deg C [R10, 1248] OWPC: *log Kow= 5.34 [R11] SOL: *Solubility @ 25 deg C: > 100 g/100 ml acetone; 81 g/100 ml xylene [R9, 297]; *SOLUBILITY @ 25 DEG C: 7 G/100 ML ETHANOL [R12, 448]; *Sol at 25 deg C: > 100 g/100 ml acetonitrile; > 100 g/100 ml choloroform; 82 g/100 ml dimethylformamide; 83 g/100 ml dioxane; 5-6.7 g/100 ml hexane; 3-3.4 g/100 ml methanol; 44 g/100 ml methyl cellosolve; 88 g/100 ml methyl ethyl ketone [R9, 297]; *Slightly sol in water (0.0024 g/100 ml) [R7]; *In water, 18.4 mg/l @ 25 deg C, pH= 5 [R10, 1248] SPEC: *Intense mass spectral peaks: 306 m/z (100%), 264 m/z (97%), 43 m/z (95%), 41 m/z (35%) [R13] VAP: *4.58X10-5 mm Hg @ 25 deg C [R10, 1248] OCPP: *Henry's Law constant= 1.03X10-4 atm-cu m/mol @ 20 deg C [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *TECHNICAL MATERIAL IS NOT FLAMMABLE. FOR FORMULATED CONCENTRATE USE ORDINARY PRECAUTIONS FOR VOLATILE SOLVENTS. [R12, 449] DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen fluoride and nitrogen oxides/. [R15, 1378] *Susceptible to decomposition by ultraviolet radiation. [R16] SERI: *Cause eye irritation. May cause skin sensitization reactions in certain individuals. [R17] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *SHELF LIFE OF CONCENTRATE IS MORE THAN 2 YR [R12, 449] *STABLE IN PURE STATE, IN LIQ OR IN GRANULAR FORMULATIONS [R3] *Stable though susceptible to decomposition by ultraviolet radiation. [R16] STRG: *THIS PRODUCT IS STABLE UNDER NORMAL STORAGE CONDITIONS FOR A MINIMUM OF 3 YR WHEN STORED IN ADEQUATE PACKING IN METAL CONTAINERS WITH POLYETHYLENE LINING, AT ROOM TEMP. THE BIOLOGICAL ACTIVITY OF DIGERMIN REMAINS PRACTICALLY UNVARIED FOR 2 YR UNDER ENVIRONMENTAL CONDITIONS, PROVIDED THE PRODUCT IS STORED IN ITS UNOPENED AND UNDAMAGED ORIGINAL CONTAINERS, AND IN SHADED AND POSSIBLY WELL-AIRED PLACES. AVOID FREEZING. STORE ABOVE 40 DEG F. DO NOT STORE NEAR HEAT OR FLAME. [R18] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Trifluralin is resistant to oxidation, and acid and alkaline hydrolysis. The major environ effect of concern in the disposal of trifluralin is its toxicity to fish. Trifluralin is known to be strongly adsorbed onto the soil and is resistant to movement by water, and burial in specially designated landfills or isolated areas away from water supplies is the procedure recommended for the disposal of small quantities of trifluralin. For the decontamination of trifluralin containers, the National Agricultural Chemical Association triple rinse and drain procedure is recommended. Rinse soln from containers can be poured into the spray tank for application. Trifluralin bags should be destroyed when empty and disposed of through regular refuse collection system or buried in an isolated area away from water supplies. Recommendable method: Landfill. Not recommendable methods: Discharge to sewer, and thermal destruction. [R19] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of trifluralin. There is limited evidence in experimental animals for the carcinogenicity of technical grade trifluralin. Overall evaluation: Trifluralin is not classifiable as to its carcinogenicity to humans (Group 3). [R20] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Classification is based on the induction of urinary tract tumors (renal pelvis carcinomas and urinary bladder papillomas) and thyroid tumors (adenomas/carcinomas combined) in one animal species (F344 rats) in one study. Trifluralin is structurally similar to ethalfluralin, a carcinogen in the rat. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R21] ANTR: *Skin decontamination: Skin contamination should he treated promptly by washing with soap and water. Contamination of the eyes should be treated immediately by prolonged flushing of the eyes with large amounts of clean water. If dermal or ocular irritation persists, medical attention should be, obtained without delay. [R22] *Gastrointestinal decontamination: Ingestion of these herbicides are likely to be followed by vomiting and diarrhea due to their irritant properties. Management depends on: (1) the best estimate of the quantity ingested, (2) time elapsed since ingestion, and (3) the clinical status of the subject. Activated charcoal is probably effective in limiting irritant effects and reducing absorption of most or all of these herbicides. Aluminum hydroxide antacids may be useful in neutralizing the irritant actions of more acidic agents. Sorbitol should be given to induce catharsis if bowel sounds are present and if diarrhea has not already commenced. Dehydration and electrolyte may be severe enough to require oral or intravenous fluids. There are no specific antidotes for poisoning by these herbicides. In the case of suicidal ingestions, particularly, the possibility must always be kept in mind that multiple toxic substances may have been swallowed. If large amounts of herbicide have been ingested and the patient is seen an hour of the ingestion, gastrointestinal decontamination should be considered. If the amount of ingested herbicides was small, if effective emesis has already occurred, or if treatment is delayed, administer activated charcoal and sorbitol mouth. [R22] *Intravenous fluids: If serious dehydration and electrolyte depletion have occurred as a result of vomiting and diarrhea, monitor blood electrolytes and fluid balance and administer intravenous infusions of glucose, normal saline, Ringer's solution, or Ringer's lactate to restore extracellular fluid volume and electrolytes. Follow this with oral nutrients as soon as fluids can be retained. [R22] HTOX: *SINCE 1969, 16 EPISODES OF TRIFLURALIN POISONING HAVE BEEN REPORTED. THERE HAVE BEEN NO FATALITIES, AND ONLY 1 CASE REQUIRED HOSPITALIZATION. 10 OF 16 CASES INVOLVED SYMPTOMS THAT APPEARED TO BE RELATED TO THE SOLVENT, RATHER THAN TRIFLURALIN ITSELF. [R5, 548] *SUMMARY TOXICITY STATEMENT /ACUTE/= MODERATE VIA ORAL ROUTE. MODERATE= MAY CAUSE REVERSIBLE OR IRREVERSIBLE CHANGES TO EXPOSED TISSUE, NOT PERMANENT INJURY OR DEATH; CAN CAUSE CONSIDERABLE DISCOMFORT. [R23] NTOX: *RABBITS EXPOSED TO 500 MG OF TECHNICAL TRIFLURALIN IN STD DRAIZE SKIN IRRITATION STUDY HAD SCORE OF 0, INDICATING NO DERMAL IRRITATION. TECHNICAL TRIFLURALIN ALSO CAUSED NO DAMAGE WHEN TESTED IN RABBIT EYES. [R5, 549] *IN 10-DAY STUDY OF CATTLE, SHEEP, AND CHICKENS ORALLY TREATED WITH TRIFLURALIN ... NO-ADVERSE-EFFECT DOSAGE WAS 100 MG/KG/DAY ... . [R5, 549] *HARLAN RATS (6 MALES AND 6 FEMALES IN EACH GROUP) WERE FED TECHNICAL TRIFLURALIN AT 20, 200, 2000, and 20,000 PPM IN DIET FOR 2 YR. AT HIGHEST DOSAGE LEVEL, RATS SHOWED SIGNIFICANT GROWTH RETARDATION AND BILE DUCT PROLIFERATION AND SURVIVED MAX OF 460 DAYS. IN ALL OTHER GROUPS ... NO SIGNIFICANT DIFFERENCES BETWEEN TREATED ANIMALS AND CONTROLS ... . [R5, 549] *TECHNICAL GRADE TRIFLURALIN DID NOT INDUCE POINT MUTATIONS IN SALMONELLA/MAMMALIAN MICROSOME ASSAY OR STIMULATION OF UNSCHEDULED DNA SYNTHESIS, BUT INDUCED AN INCR OF MITOTOC CROSSING-OVER IN ASPERGILLUS NUDULANS. A PURIFIED SAMPLE SHOWED NO GENETIC ACTIVITY WHEN TESTED IN THE SAME GENETIC SYSTEM. [R24] *IN TERATOLOGY STUDIES THERE WAS NO EFFECT WITH: RATS AT 2000 MG/KG DIET; DOGS AT 1000 MG/KG DIET; RABBITS AT 1000 MG/KG BODY WT DAILY. [R25] *... 8 MONGREL DOGS WERE GIVEN DAILY ORAL DOSES IN CAPSULES OVER 2-YR PERIOD. 1 MALE AND 1 FEMALE IN EACH GROUP WERE GIVEN 2.5 MG/KG, 5 MG/KG, and 25 MG/KG. 2 FEMALES WERE GIVEN 10 MG/KG. THERE WERE NO ADVERSE EFFECTS @ ANY DOSAGE. [R5, 550] *IN 3-YR STUDY, PUREBRED BEAGLES WERE GIVEN TRIFLURALIN ORALLY @ 10 and 25 MG/KG. EACH TREATMENT GROUP INCL 2 ANIMALS OF EACH SEX, AND CONTROL GROUP WAS ESTABLISHED WITH 3 ANIMALS OF EACH SEX. AT 25 MG/KG, INCR LIVER:BODY-WEIGHT RATIO WAS OBSERVED. THEREFORE, NO-ADVERSE-EFFECT DOSAGE WAS CONSIDERED TO BE 10 MG/KG. [R5, 550] *CHICKENS, WHICH ARE SENSITIVE TO CATARACTOGENIC PROPERTIES OF COMPOUNDS, WERE EXPOSED TO TRIFLURALIN. THERE WAS NO EFFECT IN TRIFLURALIN-TREATED CHICKENS ... [R5, 549] *ORAL TOXICITY /FEMALE MALLARD DUCKS AND MALE PHEASANTS 3-4 MO OF AGE/ ACUTE SYMPTOMS: VERY MILD ATAXIA ONLY. [R26] *OCCURRENCE OF VERTEBRAL DYSPLASIA IN BROWN TROUT SALMO TRUTTA WAS ATTRIBUTED TO PREEMERGENCE HERBICIDE, ACTIVE INGREDIENT TRIFLURALIN, WHICH WAS ACCIDENTALLY DISCHARGED INTO STREAM. [R27] *OF 19 HERBICIDES INCUBATED AT 1 TO 100 PPM FOR 7 DAYS WITH EARTHWORMS IN SAND SOIL SAMPLES, ONLY 100 PPM TRIFLURALIN CAUSED MORTALITY, KILLING ALL WORMS. [R28] *The dinitroanilines /including trifluralin/ are considered to be moderately persistent herbicides in the soil. They are generally considered to have a very low degree of toxicity to mammals and are degraded in the environment to products without significant adverse effects on organisms. [R29] *Examples of dinitroanilines include ... trifluralin ..., the oral LD50 value /for rats/ ... is > 10,000 mg/kg. Not only /does this/ cmpd have a low acute toxicity in mammals, but rats and dogs showed no ill effect when fed a dietary level of 1,000 ppm for 2 years. [R30] *TRIFLURALIN AFFECTS PHYSIOLOGICAL GROWTH PROCESSES ASSOC WITH SEED GERMINATION. [R8, 473] *Trifluralin (2,6-dinitro-N,N-di-N-propyl-alpha,alpha,alpha-trifluoro-p-toluidine) is the active ingredient in the herbicide TREFLAN. The potential developmental toxicity of trifluralin was evaluated in rats and rabbits. Pregnant rats and rabbits were dosed once daily by gavage on gestation days 6-15 and 6-18, respectively. Doses for rats were 0, 100, 225, 475, and 1000 mg/kg; doses for rabbits were 0, 100, 225, 500 and 800 mg/kg. Cesarean sections performed on rats and rabbits on gestation days 20 and 28, respectively. In rats, maternal toxicity was indicated at the 475 and 1000 mg/kg dose levels by depression of body weight gain and food consumption. Fetal viability and morphology were not adversely affected at any dose level. Developmental toxicity was indicated at the 1000 mg/kg dose level by depressed fetal weight. The no observed effect levels for maternal and developmental toxicity in the rat were 225 and 475 mg/kg, respectively. The A/D /adult to developmental/ ratio in rats was less than 1. In rabbits, maternal toxicity was indicated at the 225, 500, and 800 mg/kg dose levels by abortions and/or deaths in conjunction with depression of body weight gain and food consumption. Developmental toxicity was indicated at the 500 and 800 mg/kg dose levels by depressed fetal viability and weight. Fetal morphology was not adversely affected at any dose level. The no observed efect levels for maternal and developmental toxicity in the rabbit were 100 and 225 mg/kg, respectively. The A/D /adult to developmental/ ratio in rabbits was less than 1. Based on these data, trifluralin did not exhibit selective toxicity toward the developing conceptus. [R31] NTXV: *LD50 Rat oral > 10,000 mg/kg; [R16] *LD50 Mouse oral 500 mg/kg; [R16] *LD50 Rabbit oral > 2000 mg/kg; [R16] *LD50 Dog oral > 2000 mg/kg; [R16] *LD50 Chicken oral > 2000 mg/kg; [R16] *LD50 Mouse acute oral 5,000 mg/kg; [R32, 430] *LD50 Rat oral 1930 mg/kg; [R15, 1377] *LD50 Rat skin > 5,000 mg/kg; [R15, 1377] *LD50 Mouse oral 3197 mg/kg; [R15, 1377] *LD50 Dog oral > 2000 mg/kg; [R15, 1377] *LD50 Rabbit oral > 2000 mg/kg; [R15, 1377] *LD50 Rat oral 0, 100, 225, 475, and 1000 mg/kg; [R31] *LD50 Rabbit oral 0, 100, 225, 500 and 800 mg/kg; [R31] ETXV: *THE 24 HR MEDIAN LETHAL CONCN (LC50) OF TRIFLURALIN FOR MOSQUITOFISH AND JUVENILE CRAWFISH WERE 28 and 13 PPM. THE 96 HR LC50 WAS 12 PPM; [R33] *LC50 SIMOCEPHALUS 900 UG/L/48 HR @ 15 DEG C (95% CONFIDENCE LIMIT 651-1,245 UG/L), FIRST INSTAR /TECHNICAL MATERIAL, 95.9%/ STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 DAPHNIA MAGNA 560 UG/L/48 HR @ 21 DEG C (95% CONFIDENCE LIMIT 320-1000 UG/L), FIRST INSTAR /TECHNICAL MATERIAL, 95.9%/ STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY Ff 30-35 MG/L; [R34, 1980.79] *LC50 DAPHNIA PULEX 625 UG/L/48 HR @ 15 DEG C (95% CONFIDENCE LIMIT 446-876 UG/L), FIRST INSTAR /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 GAMMARUS FASCIATUS 2,200 UG/L/96 HR @ 21 DEG C (95% CONFIDENCE LIMIT 1,400-3,400 UG/L), MATURE /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 PTERONARCYS 2,800 UG/L/96 HR @ 15 DEG C (95% CONFIDENCE LIMIT 2,100-3,700 UG/L), SECOND YR CLASS /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 RAINBOW TROUT 41 UG/L/96 HR @ 12 DEG C (95% CONFIDENCE LIMIT 26-62 UG/L), WT 0.8 G /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 FATHEAD MINNOW 105 UG/L/96 HR @ 18 DEG C (95% CONFIDENCE LIMIT 83-134 UG/L), WT 0.8 G /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 CHANNEL CATFISH 2,200 UG/L/96 HR @ 22 DEG C (95% CONFIDENCE LIMIT 1,420-3,410 UG/L), WT 0.8 G /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.79] *LC50 BLUEGILL 58 UG/L/96 HR @ 22 DEG C (95% CONFIDENCE LIMIT 47-70 UG/L), WT 0.8 G /TECHNICAL MATERIAL, 95.9%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.80] *LC50 LARGEMOUTH BASS 75 UG/L/96 HR @ 18 DEG C (95% CONFIDENCE LIMIT 65-87 UG/L), WT 0.7 G /EMULISIFIABLE CONCENTRATE, 46%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.80] *LC50 GOLDFISH 145 UG/L/96 HR @ 18 DEG C (95% CONFIDENCE LIMIT 108-195 UG/L), WT 1.0 G /EMULISIFIABLE CONCENTRATE, 46%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R34, 1980.80] *LC50 Channel catfish 417 ug/l/96 hr /Conditions of bioassay not specified/; [R35] *LC50 Bluegill 0.019 ppm/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Rainbow trout 0.011 ppm/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Gammarus lacustris 2200 ug/l/96 hr /Conditions of bioassay not specified/; [R35] *LC50 Gammarus fasciatus 1000 ug/l/96 hr /Conditions of bioassay not specified/; [R35] *LC50 Daphnia magna 560 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Daphnia pulex 240 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Simocephalus serrulatus 450 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Cypridopsis vidua 250 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Asellus brevicaudus 200 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Palaemonetes kodiakensis 1200 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Orconectes nais 50,000 ug/l/48 hr /Conditions of bioassay not specified/; [R35] *LC50 Pteronarcys californica 3000 ug/l/96 hr /Conditions of bioassay not specified/; [R35] *LC50 Cyprinodon variegatus 190 ug/l/96 hr /Conditions of bioassay not specified/; [R35] *LC50 Coturnix oral > 5,000 ppm (95% confidence interval); [R36] *LC50 Rainbow trout young 10-40 ug/l/96 hr and young bluegill sunfish 20-90 ug/l/96 hr; bluegill sunfish 19 ppb for 48 hr and rainbow trout 11 ppb for 48 hr; [R32, 428] NTP: *A bioassay for possible carcinogenicity of technical grade trifluralin was conducted using Osborne-Mendel rats and B6C3F1 mice. Analysis of the technical product established the presence of 84 to 88 ppm dipropylnitrosamine. The product was admin in the feed, at either of two concn, to groups of 50 male and 50 female animals of each species. 50 animals of each sex were placed on test as controls for the rat bioassay, while 20 of each sex were utilized as controls on the mouse study. The time weighted avg high and low dietary concentrations of trifluralin were, respectively, 8,000 and 4,125 ppm for male rats, 7,917 and 4,125 ppm for female rats, 3,744 and 2,000 ppm for male mice, and 5,192 and 2,740 ppm for female mice. After a 78 wk treatment period, there was an additional observation period of 33 wk for rats and 12 wk for mice. For female mice the association between incr dosage and elevated incidence of hepatocellular carcinomas was significant (0/20, 12/47, and 21/44 of the control, low dose, and high dose, respectively) as was the relationship between dose and incidence of alveolar/bronchiolar adenomas. Significance of incidence for both types of tumors was supported by tests for significance at each dose level. Squamous cell carcinomas of the stomach were observed in dosed female mice, but not in controls. Although incidences of these tumors were not statistically significant, they are unusual lesions in B6C3F1 mice and are considered treatment related. Neoplasms observed in treated rats were types that have occurred spontaneously in this strain and were apparently unrelated to trifluralin treatment. Evaluation of the results of this bioassay, technical grade trifluralin is a carcinogen in female B6C3F1 mice, being associated with incr incidences of hepatocellular carcinomas, alveolar/bronchiolar adenomas and squamous cell carcinomas of the forestomach. Sufficient evidence was not provided for the carcinogenicity or tumorigenicity of trifluralin in male B6C3F1 mice or Osborne-Mendel rats. Evaluation of the results of this bioassay indicates that technical grade trifluralin is a carcinogen in female B6C3F1 mice, being associated in these animals with an elevated incidence of hepatocellular carcinomas, alveolar/bronchiolar adenomas and squamous cell carcinomas of the forestomach. Sufficient evidence was not provided for the carcinogenicity or tumorigenicity of trifluralin in male B6C3F1 mice or in Osborne-Mendel rats of either sex. Levels of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Positive. [R37] ADE: *APPROX 80% OF INGESTED CMPD WAS EXCRETED IN FECES, REMAINDER IN URINE /OF RATS AND DOGS STUDIED/. [R5, 548] *SALMON PARR SALMO SALAR WERE SUBJECTED TO HIGH INITIAL CONCN OF TRIFLURALIN AND THEN MAINTAINED IN CLEAR WATER FOR 12 MO. SOME WERE REMOVED AT PRESELECTED INTERVALS FOR EXAM BY X-RAY AND CHEM ANALYSIS. HALF-LIFE OF TRIFLURALIN IN SALMON PARR WAS 40.5 DAYS. [R27] METB: *MAJOR METABOLITES /FOUND IN URINE AND FECES OF TREATED RUMINANTS/ WERE UNIDENTIFIED POLAR COMPD, BUT N',N'-DIPROPYL-3-NITRO-5-TRIFLUOROMETHYL-ORTHO-PHENYLENEDIAMINE AND N(4)N(4)-DIPROPYL-ALPHA,ALPHA,ALPHA-TRIFLUOROTOLUENE-3,4,5-TRIAMINE WERE ALSO FORMED. [R38] *TRIFLURALIN IS DEALKYLATED IN RUMEN /OF DAIRY ANIMALS/, LOSING 1 OR BOTH PROPYL GROUPS; NITRO GROUPS ARE REDUCED TO 1 OR 2 AMINO GROUPS. 2 TYPES OF REACTIONS OCCUR SIMULTANEOUSLY, LEADING TO A TRIFLUOROMETHYLTRIAMINOBENZENE. [R5, 548] *METAB IN VITRO BY RAT LIVER MICROSOMES INDICATES ALIPHATIC HYDROXYLATION, N-DEALKYLATION, REDN OF A NITRO GROUP, AND CYCLIZATION TO BE MAJOR METABOLIC ROUTES. A BENZIMIDAZOLE METABOLITE WAS FORMED. [R39] *The predominant metabolic pathways appear to be hydroxylation of alkyl groups or N-dealkylation. To a lesser extent, a cyclized compound, benzimidazole, and the reduction product of a nitro group, an amine, are also included in the pathways. ... [R40] INTC: *MICE WERE FED TRIFLURALIN AT 1000, 1500 and 2000 PPM IN DIET FOR 12 OR 14 WEEKS. TUMORS WERE INDUCED BY ADMIN 8 MG OF BENZO(A)PYRENE ORALLY AT TWO TIME PERIODS. INHIBITION OF TUMORIGENESIS IN LUNG AND FORESTOMACH BY TRIFLURALIN WAS OBSERVED WHEN IT WAS FED IN DIET 1 WK BEFORE OR 1 DAY FOLLOWING EXPOSURE TO BENZO(A)PYRENE. [R41] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Trifluralin's use as a herbicide has resulted in its direct release to the environment. If released to air, a vapor pressure of 4.58X10-5 mm Hg at 25 deg C indicates trifluralin will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase trifluralin will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals; the half-life for this reaction in the air is estimated to be 16 hours. Direct photolysis is expected to be an important environmental fate process based upon the observed half-life for trifluralin in July sunlight which ranged from 25-60 minutes. Particulate-phase trifluralin will be removed from the atmosphere by wet and dry deposition. If released to soil, trifluralin is expected to have moderate to no mobility in soils based on Koc values in the range of 397 to 16,851 measured in soils. Volatilization from moist soil surfaces may be an important fate process based upon an experimental Henry's Law constant of 1.03X10-4 atm-cu m/mole. Trifluralin was volatilized 16%, 28% and 40% in dry, moist and flooded soils over a 32 day incubation period. Biodegradation is expected to be an important environmental fate process in the environment. Trifluralin was degraded with half-lives of 189, 202, and 116 days in sandy loam, clay loam, and loam soils, respectively, when incubated aerobically in the dark at 22 deg C for 364 days. If released into water, trifluralin is expected to adsorb to suspended solids and sediment based upon its Koc values. Volatilization from water surfaces may be an important environmental fate process based upon this compound's experimental Henry's Law constant. Volatilization half-lives for a model river and model lake are 0.5 days and 12 days, respectively. Photolysis in sunlit surface waters may be an important environmental fate process for this compound, based upon a direct photolysis half-life of 22 minutes in near surface water, latitude 40 deg N in the summer. Trifluralin is stable to hydrolysis. Experimental BCF values ranging from 1,689 to 9,586 suggest the potential for bioconcentration in aquatic organisms is very high. Occupational exposure to trifluralin may occur through inhalation of dust particles and dermal contact with this compound at workplaces where trifluralin is produced or used. Monitoring data indicate that the general population may be exposed to trifluralin via ingestion of contaminated food. (SRC) ARTS: *Trifluralin's use as a herbicide(1) has resulted in its direct release to the environment(SRC). [R42] FATE: *TRIFLURALIN WAS MORE PERSISTENT IN SOIL (PH 6.56) THAN METRIBUZIN. HALF-LIFE OF TRIFLURALIN WAS 38 DAYS FOR 670 G/HA AND 61 DAYS FOR 1100 G/HA. [R43] *TERRESTRIAL FATE: Based on a classification scheme(1), experimental Koc values ranging from 397 to 16,851(2-8) indicate that trifluralin is expected to have moderate to no mobility in soil(SRC). Volatilization of trifluralin from moist soil surfaces may be an important fate process(SRC) given a Henry's Law constant of 1.03X10-4 atm-cu m/mole(9). Trifluralin is known to rapidly volatilize from both moist and dry soils to the atmosphere(10-13), although the volatilization rate is greater for moist soils(14). Trifluralin was volatilized 16%, 28% and 40% in dry, moist and flooded soils over a 32 day incubation period(10). The persistence of trifluralin in soil has been estimated at 6 months(16) and > 40 weeks(15). Its persistence is less in southern climates than in northern ones(16). [R44] *AQUATIC FATE: Based on a classification scheme(1), Koc values ranging from 397 to 16,851(2-8) indicate trifluralin is expected to adsorb to suspended solids and sediment. Volatilization from water surfaces may be expected(9) based upon experimental data(10) and a Henry's Law constant of 1.03X10-4 atm-cu m/mole(12), although its strong adsorption to sediment and suspended organic matter may attenuate the rate of this process(SRC). Using this Henry's Law constant and an estimation method(9), volatilization half-lives for a model river and model lake are 0.5 days and 12 days, respectively, when adsorption is ignored(SRC). Trifluralin is not expected to hydrolyze in water(11). According to a classification scheme(13), experimental BCF factors ranging from 1,689 to 9,586(14-17) suggest the potential for bioconcentration in aquatic organisms is very high. The experimental half-life for the direct photolysis of trifluralin in near surface water, latitude 40 deg N in the summer is 22 min(18). [R45] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trifluralin, which has an experimental vapor pressure of 4.58X10-5 mm Hg(2) at 25 deg C, will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase trifluralin is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 16 hours(SRC), calculated from its rate constant of 24X10-12 cu cm/molecule-sec at 25 deg C(SRC), determined using a structure estimation method(3). Particulate-phase trifluralin may be removed from the air by wet and dry deposition(SRC). If released to the atmosphere, trifluralin is expected to undergo rapid photolytic degradation; the observed half-life for trifluralin in July sunlight ranged from 25-60 min(4). In the presence of ozone, the rate of this reaction increases(5,6). [R46] BIOD: *AEROBIC: Trifluralin biodegrades faster in anaerobic soils than in aerobic soils(1). Trifluralin degraded with half-lives of 189, 202, and 116 days in sandy loam, clay loam, and loam soils, respectively, when incubated aerobically in the dark at 22 deg C for 364 days(2). Seven degradates of trifluralin have been identified(2): alpha-alpha-alpha-trifluoro-2,6,-dinitro-N-propyl-p-toluidine; alpha-alpha-alpha-trifluoro-5-nitro-4-propyl-toluene-3,4-diamine; 2-ethyle-7-nitro-1-propyl-5-(trifluoromethyl)benzimidazole-3-oxide; 2-ethyl-7-nitro-1-propyl-5-(trifluoromethyl) benzimidazole; 2-ethyl-7-nitro-5-(trifluoromethyl)benzimidazole; alpha-alpha-alpha-trifluoro-2,6-dinitro-p-cresol; 2,2'-azoybis(alpha-alpha-alpha-trifluoro-6-nitro-N-propyl-p-toluidine(2). These degradates were identified in test samples at maximum concns (% applied radioactivity) of 2.8-4.6%, 1.5-2.1%, 0.1-0.3%, 0.5-1.0%, 2.1-2.6%, 0.1-2.7%, and 0.8-3.0%, respectively(2). During the testing period of about one year, trifluralin parent declined to less than 25% of applied radioactivity in all soils(2). At the same time volatile and unextractable residues increased to 22% and about 45% of applied radioactivity(2). In another laboratory study, the estimated half-life for the biodegradation of 1,000 ppm trifluralin in soil was 405 days under aerobic conditions(3). Trifluralin, which was added to soil obtained from a pesticide disposal site, did not biodegrade in 157 days under aerobic conditions(4). Aerobic biodegradation of trifluralin proceeds through an initial dealkylation followed by reduction of the nitro groups(5). The trifluoromethyl group of trifluralin appears to remain intact in all major metabolites and is eventually oxidized to the carboxylic acid(6). In a 14-day environmental chamber study with a 14 hr photoperiod, degradation of 10 ppm trifluralin, present as a mixture with metolachlor and atrazine, was shown to occur in non-vegetated soil (47% degradation) but not to the extent of the Kochia scoparia rhizosphere soil (70% degradation), suggesting that the rhizosphere of certain plant species may facilitate microbial degradation(7). [R47] *Trifluralin at an initial concn of 100 ug/l underwent 49% removal when incubated with primary sewage effluent under aerobic conditions; under anaerobic conditions it underwent 91% removal during the same time period(1). Incubation of radiolabled trifluralin with sediment samples under aerobic conditions resulted in a concn reduction equal to 1/4 its original value after 10 days; the microbial community was not found to adapt to trifluralin(2). The concn of trifluralin in shake flask tests containing either natural water or a sediment water slurry were found to decrease; the rate of decrease was less in sterilized flasks(3). [R48] *ANAEROBIC: Trifluralin biodegrades faster in anaerobic soils than in aerobic soils(1). Trifluralin degraded with half-lives of 22-59 days in sandy loam, loam, and clay loam soils incubated anaerobically in the dark at 22 deg C for 60 days following an aerobic incubation period of 30 days(2). In another laboratory study, the estimated half-life for the biodegradation of 1,000 ppm trifluralin in soil was 211 days under anaerobic conditions(3). Degradation under anaerobic conditions initiates with nitro group reduction followed by dealkylation(4). The major degradates identified were(2): alpha-alpha-alpha-trifluoro-5-nitro-N4,N4-dipropyl-toluene-3,4-diamine (which reached a maximum concn of 5.4% and 13.2% of the applied radioactivity in sandy loam soil and clay loam soil, respectivily, at Day 60 following flooding, and 11.6% in the loam soil at Day 30 following flooding); 7-amino-2-ethyl-1-propyl-5-(trifluoromethyl)benzimidazole (which reached 7.3% in sandy loam soil and 8.3% in loam and clay loam soils at Day 60 following flooding); alpha-alpha-alpha-trifluoro-N4-N4-dipropyltoluene-3,4,5-triamine (which reached 0.3% in sandy loam soil, 4.1% in loam soil, and 2.6% in clay loam soil). [R49] ABIO: *The rate constant for the vapor-phase reaction of trifluralin with photochemically-produced hydroxyl radicals has been estimated as 24X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 16 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Trifluralin is stable to hydrolysis(2). [R50] *Trifluralin underwent approx 10-15% loss when soil TLC plates incorporated with the pesticide were exposed to the July sun for 6 days(1). Photodecomposition of trifluralin in water leads to the formation of highly polar products via N-dealkylation, nitro reduction and cyclization(2). Photolysis of water suspensions of trifluralin under summer sunlight leads to the formation of mono and di-dealkylated products, the corresponding benzimidazole and its N-oxide and the corresponding phenol(3). In both laboratory and field gas-phase photolysis studies the same products were produced(4-5). The half-life for the gas-phase photolysis of trifluralin in the laboratory was 1 hour(6). The observed half-life for trifluralin when irradiated by July sunlight ranged from 25-60 min(7). Trifluralin was found to photodegrade to 50% of applied concn after 30 min irradiation to light of wavelengths above 290 nm(8). Vapor-phase photolysis rates for trifluralin were determined by sunlight irradiation; half-lives were found to range from 19 to 74 minutes. Simultaneous irradiation of methanolic solutions produced half-lives of 17 to 25 min(9). Sunlight photolysis of trifluralin adsorbed to soil TLC plate resulted in 18.4% removal in 7 days(10), although in the field it is not believed that direct photolysis on the soil surface can compete with volatilization(11,12). The rate of the gas-phase photolysis of trifluralin was found to increase in the presence of ozone(13). The experimental half-life for the direct photolysis of trifluralin in near surface water, latitude 40 deg N in the summer is 22 min(14). No change in the loss rate of trifluralin from soil was observed with changing pH, indicating that pH dependent hydrolysis was not occurring(15). [R51] BIOC: *Fish bioconcentration factors estimated from field data were: sauger (Stizostedion canadense), 5,421, shorthead redhorse (Moxostoma macrolepidolum), 2,832, and golden redhorse (M. erthrurum), 1,689, and an experimental value of 3,261 for fathead minnows (Pimephales promelas)(1). An experimental fish bioconcentration factor of 4,570, species not stated, has been reported for trifluralin(2). The bioconcentration factor for trifluralin in topmouth gudgeon (Pseudorasbora parva) has been reported as 3,162(3). Mean bioconcentration factors accumulated in bluegill sunfish exposed to 0.0059 ppm trifluralin ranged from 2,041 to 9,586(4). According to a classification scheme(3), these BCF values suggest the potential for bioconcentration in aquatic organisms is very high(SRC). [R52] KOC: *Koc values of trifluralin have been experimentally determined to range from 397 to 16,851(1-7). According to a classification scheme(8), this range of Koc values suggests trifluralin is expected to be moderately mobile to immobile in soil. An experimental soil adsorption coefficient of 30,550 was determined for trifluralin using Georgia pond sediment(9). Trifluralin was immobile in soil TLC experiments using 14 different soils that ranged from sandy loam to silty clay(10). In a laboratory screening study, trifluralin did not leach past 30 cm in 100 days(11-12). It was estimated that it would take 1580 yrs for trifluralin to leach through soil to a depth of 3 m(12). Trifluralin was detected at 86% of 28 agrochemical dealership sites in Iowa at a max concn of 14,200 ug/l(13). [R53] VWS: *The Henry's Law constant for trifluralin is 1.0X10-4 atm-cu m/mole(1). This Henry's Law constant indicates that trifluralin is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 12 hours if adsorption is neglected(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 12 days if adsorption is neglected(SRC). The volatilization from a model pond is about 8 yrs when adsorption is considered(4). Trifluralin's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). In a laboratory study, trifluralin underwent 24% volatilization loss from a Lakeland soil in 3 hours; the rate of volatilization increased with increasing soil moisture(5).Volatilization losses for trifluralin amounted to approx 16% after 32 days in dry soil, approx 28% loss in moist soil and 40% loss in flooded soil(6). In an ecosystem model mimicking a Northern prairie wetland, trifluralin underwent approx 15% loss due to volatilization in 42 days(7). In a laboratory study, trifluralin underwent 5% evaporative losses in 10 days when incorporated to 10 cm depth in soil samples(8). The measured rate for volatilization of trifluralin from nonadsorbent sand was 3 kg/ha/day(9). [R54] WATC: *TRIFLURALIN WAS DETECTED IN FINISHED WATER IN US ... [R5, 548] *GROUNDWATER: Trifluralin was detected in well water samples at a concn of 41 ug/l in 1 out of 179 wells from farms in an agricultural area in Ontario, Canada, 1984-86(1,2). Trifluralin has been qualitatively detected in groundwater samples in 4 states(3). It was detected in 1 of 1443 wells monitored in NE, at a concn of 0.42 ppb(4). In a survey of U.S. groundwater quality, trifluralin was detected in samples from KS, MD, MS, and NE as a result of normal use at a mean and maximum concn of 2.20 ppb and 0.40 ppb, it was detected in ND as a result of a point source contamination at 0.03 ppb and in KS from unknown origin at a maximum and mean concn of 5.40 ppb and 3.09 ppb(5). Trifluralin was detected in 3 groundwater samples collected from a small residential community in South-Central Connecticut, the average detected concn was 0.04 ug/l(6). Trifluralin was detected in 1 of 62 lake and river/stream sites sampled from 1989 to 1991 in a 4 county region of Arkansas at a maximum concn of 1.3 ug/l(7). Trifluralin was detected in groundwater samples at 65% of 28 agrochemical dealership sites in Iowa at a max concn of 58 ug/l(8). [R55] *SURFACE WATER: The concn of trifluralin in the Ochre and Turtle River, Canada, 1984, ranged from < 0.6 to 3.3 ug/cu m and < 0.5 to 5.2 ug/cu m(1). Water samples taken from the Wabash River, IN, 1974, 8 km downstream from a pesticide manufacturing facility contained 874 parts/per trillion trifluralin(2). It was detected in Mississippi River water samples obtained 20 miles below Memphis, TN, 1984, at a concn of 19 ng/l(3). Trifluralin has been detected in water from Lake Erie and Lake Michigan watersheds(4). Its concn in the Wabash River, 1975, ranged from 3.12 ug/l to 548 ug/l < 1 mile from a pesticide manufacturing facility(5). The concn of trifluralin in the Shell Creek, NE, 1988, after a spring storm event ranged from trace to 0.5 ug/l(6). Trifluralin was detected in 3 of 69 samples of natural waters from various regions of Greece, at concns ranging from < 0.005 to 0.01 ug/l(7). Trifluralin was detected in seawater, ice and fog condensate samples taken from the Bering and Chukchi Seas during the summer of 1993(8). Trifluralin concns ranged from < 0.34 to 1150 pg/l in seawater and ice samples while fog condensate concns ranged from < 0.1 to < 0.3 ng/l. Trifluralin was detected in air and surface water samples at different elevations in California's Sequoia National Park during the summer of 1996; trifluralin concn ranges detected for air and surface waters were 0.03 to 0.64 ng/cu m and non-detectable to 108.12 ng/l, respectively(9). [R56] *DRINKING WATER: Trifluralin was qualitatively detected in raw and finished drinking water obtained from the Llobregat River, Barcelona, Spain(1). [R57] *RAIN/SNOW: The concn of trifluralin in "brown snow", snow contaminated by a long range transport event, 1988, was 764 pg/l(1). Trifluralin was detected in winter-spring rain/snow precipitation from Sequoia National Park and Lake Tahoe Basin at concns ranging from 0.5 to 2 ng/l(2). [R58] EFFL: *The concn of trifluralin in wastewater samples from a pesticide manufacturer in Barcelona, Spain, 1984, was 2 ppm(1). The estimated total discharges of trifluralin into the Ochre and Turtle Rivers, Canada, 1984, from the surrounding watershed are 119 and 37 g/yr(2). [R59] SEDS: *SOIL: Trifluralin was detected in soil samples from the corn belt states IL, IA, MN, MO, and OH, 1970, at concns of 0.01-0.08 ppm, 0.02-0.06 ppm, 0.09-0.33 ppm, 0.03 ppm and 0.08 ppm, respectively(1). Trifluralin was detected in 52 of 1533 soil samples from 37 states during the Natl Soils Monitoring Program, FY 1972, at 0.01-1.29 ppm, mean concn < 0.01 ppm(2). During FY 1973, it was found in 81 of 1483 sites at 0.01-1.86 ppm, mean concn 0.01 ppm(3) and FY 1970 it was found in 8 of 178 sites, 0.01-0.09 ppm mean concn < 0.01 ppm(4). Residues of trifluralin in soil samples from a pesticide disposal pit in CA, 1985, ranged from < 10-1104 ppm(5). Trifluralin was detected in and around 20 Illinois retail agrichemical facilities that were flooded in 1993 at median on and off-site concns of 0.71 mg/kg and 0.04 mg/kg, respectively(6). Trifluralin was detected at 86% of 28 agrochemical dealership sites in Iowa at a max concn of 14,200 ug/l(7). [R60] ATMC: *SOURCE DOMINATED: Trifluralin was found in 5 of 56 air samples 275 m from a formulation plant in TN at a mean concn of 10.2 ng/cu m (range 0-30.3 ng/cu m)(1). [R61] *SUBURBAN/RURAL: Trifluralin was detected in 3 of 11 air samples taken from Pekin, IL, 1980, at concns ranging from 1.3 to 5.0 ng/cu m(1). In a survey of 14 U.S. states, trifluralin was not detected in 787 samples taken in 1970, 7.9% of 667 samples in 1971 (mean concn 0.2 ng/cu m), and 4.59% of 1025 samples in 1972 (mean concn 0.1 ng/cu m)(2). [R62] FOOD: *IN ANNUAL MARKET BASKET SURVEYS CONDUCTED BY FOOD AND DRUG ADMIN, TRIFLURALIN RESIDUES HAVE NEVER BEEN DETECTED... [R5, 547] *Trifluralin was qualitatively detected in domestic and imported agricultural commodities in the FDA's pesticide residue monitoring program, FY 83-86(1). The FDA found residues of trifluralin in 3 of 6391 domestic agricultural commodity samples and 1 of 12044 imported samples, 1981-6, at concns ranging from 0.10 to 1.0 ppm and 1.0 ppm, respectively(2-3). For 1988, trifluralin was found in 4 of 13980 samples but it was not detected in 13085 samples from 1989(4). [R63] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Trifluralin was qualitatively detected in dead carp taken from the Llobregat River, Barcelona, Spain, 1984(1). Fish obtained from the Wabash River, IN, had the following mean trifluralin levels: sauger, 10.2 ppm, shorthead redhorse, 5.38 ppm, and golden redhorse, 3.21 ppm(2). [R64] RTEX: *... NO DISCERNIBLE HAZARDS FROM TECHNICAL TRIFLURALIN; SOLVENT SYSTEM IN EMULSIFIABLE CONCENTRATES MAY BE IRRITATING TO SKIN AND EYES. PERSONNEL WHO FORMULATE OR APPLY TRIFLURALIN HAVE NOT EXPERIENCED DISCOMFORT OR UNTOWARD EFFECTS. [R12, 451] *DISCOVERY OF THE VOLATILE NITROSAMINE, N-NITROSODI-N-PROPYLAMINE AS CONTAMINANT OF TRIFLURALIN, PROMPTED INVESTIGATION INTO POSSIBLE EXPOSURE OF FIELD WORKERS. SAMPLING AND ANALYTICAL TECHNIQUES USED DEMONSTRATED A LOW LEVEL OF EXPOSURE POTENTIAL. [R65] *Occupational exposure to trifluralin may occur by inhalation or dermal contact during its production, formulation, or application as a herbicide(SRC). Dermal exposure to trifluralin by farmworkers may also occur long after initial exposure as this compound has been found to be adsorbed to clothing even after numerous washings(1,2). Trifluralin residues ranging from 1.6 to 11.9 ng/sq cm were found on cotton overalls which were worn for four seasons and washed after every day of use(1). The general population may be exposed to trifluralin by dermal and inhalation exposure from lawn products and by ingestion of contaminated agricultural products(3) or the ingestion of fish caught in contaminated waters(4). [R66] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *THE FAO/WHO HAS NOT ESTABLISHED ACCEPTABLE DAILY INTAKE OF TRIFLURALIN OR ANY OTHER DINITROANILINE HERBICIDE. [R5, 547] ATOL: *Tolerances are established for residues of the herbicide and plant growth regulator trifluralin (alpha, alpha, alpha- trifluoro-2,6-dinitro-N,N-dipropyl-p-toludine) in or on the following raw agricultural commodities: Alfalfa, hay 0.2 ppm; asparagus 0.05 ppm; barley, hay 0.05 ppm; barley, straw 0.05 ppm; bean, mung, sprouts 2.0 ppm; carrot, roots 1.0 ppm; corn, field, grain 0.05 ppm; corn, field, stover 0.05 ppm; corn, field, forage 0.05 ppm; cotton, undelinted seed 0.05 ppm; cress, upland 0.05 ppm; flax, seed 0.05 ppm; fruit, citrus, group 0.05 ppm; fruit, stone group 0.05 ppm; grain, crops, except corn, sweet and rice grain 0.05 ppm; grapes 0.05 ppm; hops 0.05 ppm; legumes, forage 0.05 ppm; nut, tree, group 0.05 ppm; peanut 0.05 ppm; peppermint, tops 0.05 ppm; rapeseed 0.05 ppm; safflower seed 0.05 ppm; sorghum, fodder 0.05 ppm; sorghum, forage 0.05 ppm; spearmint, tops 0.05 ppm; sugarcane, cane 0.05 ppm; sunflower seed 0.05 ppm; vegetable, curcurbit, group 0.05 ppm; vegetable, fruiting, group 0.05 ppm; vegetables, leafy 0.05 ppm; vegetables, root (exc. carrots) 0.05 ppm; vegetables, seed and pod 0.05 ppm; wheat, grain 0.05 ppm; and wheat, straw 0.05 ppm. [R67] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Trifluralin is included on this list. [R68] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 5 ug/l [R69] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 2 ug/l [R69] +(ME) MAINE 2 ug/l [R69] +(WI) WISCONSIN 7.5 ug/l [R69] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R70] FIFR: *Tolerances are established for residues of the herbicide and plant growth regulator trifluralin (alpha, alpha, alpha- trifluoro-2,6-dinitro-N,N-dipropyl-p-toludine) in or on the following raw agricultural commodities: Alfalfa, hay; asparagus; barley, hay; barley, straw; bean, mung, sprouts; carrot, roots; corn, field, grain; corn, field, stover; corn, field, forage; cotton, undelinted seed; cress, upland; flax, seed; fruit, citrus, group; fruit, stone group; grain, crops, except corn, sweet and rice grain; grapes; hops; legumes, forage; nut, tree, group; peanut; peppermint, tops; rapeseed; safflower seed; sorghum, fodder; sorghum, forage; spearmint, tops; sugarcane, cane; sunflower seed; vegetable, curcurbit, group; vegetable, fruiting, group; vegetables, leafy; vegetables, root (exc. carrots); vegetables, seed and pod; wheat, grain; and wheat, straw. [R67] *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Trifluralin is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0179; Pesticide type: Herbicide (growth regulator); Registration Standard Date: 04/01/87; Case Status: RED Approved 09/95; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Trifluralin; Data Call-in (DCI) Date(s): 03/03/95, 04/30/96; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R71] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Analytical method for residue determination requires extraction of crop tissue or soil with a solvent ... removal of interfering substances on florisil column, and determination by gas chromatography utilizing electron affinity detector. [R9, 299] *AOAC Method 973.13. Benfluralin or trifluralin in pesticide formulations. Ultraviolet spectroscopic method. [R72, 179] *AOAC Method 973.4. Benfluralin or trifluralin in pesticide formulations. Gas chromatographic method. [R72, 180] *A QUANTITATIVE GAS LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY PROCEDURE FOR DETERMINING TRIFLURALIN RESIDUES IN SOIL IS DESCRIBED. [R73] *A SENSITIVE MULTIRESIDUE METHOD IS PRESENTED FOR DETECTION OF 7 NATURAL HERBICIDES (INCL TRIFLURALIN) IN NATURAL WATERS WITH PRACTICAL DETECTION LIMITS BETWEEN 5 and 100 NG/L. [R74] *... TRIFLURALIN DETERMINATION IN FORMULATIONS BY GC, AFTER EXTRACTION WITH WATER, WITH DIISOBUTYL PHTHALATE AS INTERNAL STD. SHOWS DATA FOR 3 TYPICAL FORMULATIONS. [R3] *A method was developed for the simultaneous extraction of trifluralin, methyl paraoxon, methyl parathion, fenvalerate and 2,4-D dimethylamine salt in pond water using a solid-phase C18 column. For trifluralin analysis, after elution from the C18 column the eluate was cleaned up with activated alumina (less than 10 min contact time). A 1 ug spike of trifluralin dissolved in 5 ml solvent and allowed to remain in contact with 2 g alumina for 30 min resulted in a 25% loss of trifluralin. Analysis was then made on a capillary gas chromatograph equipped with an electron-capture detector. Simultaneous extractions of trifluralin, methyl paraoxon, methyl parathion, fenvalerate and 2,4-D dimethylamine salt were obtained from 500 g fortified pond water (from wetlands in ND). At 1.0, 0.1, 0.01, and 0.001 ppm trifluralin, percent recoveries were 91 + or - 4.5, 90 + or - 5.3, 92 + or - 9.7 and 79 + or - 3.8%, respectively. Median recovery for trifluralin was 91%. [R75] *Product analysis is by gas liquid chromatography with FID. Residues are determined by gas liquid chromatography with electron capture detector. [R10, 1249] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; Bioassay of Trifluralin for Possible Carcinogenicity CAS No. 1582-09-8 Report # 034 (1978). NIH Pub # 78-834. USEPA; Health Advisories for 50 Psticides (Including Trifluralin) (1988) PB88-245931. Documents summarize health effects of 50 pesticides including trifluralin. Topics discussed include: General effects and properties; Pharmacokinetics; Health effects in humans and animals; Quantification of toxicological effects; Other criteria and standards, Analytical methods and treatment technologies. SO: R1: SRI R2: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Trifluralin (1582-09-8). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of Sept 8, 2000. R3: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 580 R4: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 793 R5: National Research Council. 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Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 159 R14: Rice CP, Chernyak SM; pp. 439-44 in Organohalogen Compd Vol 24 (Dioxin 95, 15th Inter Symp Chlor Dioxins Relat Cmpds). Edmonton, Canada, August 21-25 (1995) R15: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R16: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 832 R17: Farm Chemicals Handbook 1991. Willoughby, OH: Meister, 1991.,p. C-312 R18: Farm Chemicals Handbook 1981. Willoughby, Ohio: Meister, 1981.,p. C-243 R19: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 292 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 53 530 (1991) R21: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Trifluralin (1582-09-8) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R22: U.S. Environmental Protection Agency/Office of Prevention, Pesticides, and Toxic Substances. Reigart, J.R., Roberts, J.R. Recognition and Management of Pesticide Poisonings. 5th ed. 1999. EPA Document No. EPA 735-R-98-003, and available in electronic format at: http://www.epa.gov/pesticides/safety/healthcare123 R23: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 1055 R24: BENIGNI R ET AL; ANN IST SUPER SANITA 18 (1): 123 (1982) R25: Worthing, C. R. (ed.). Pesticide Manual. 6th ed. Worcestershire, England: British Crop Protection Council, l979. 537 R26: U. S. Department of the Interior, Fish and Wildlife Service, Bureau of Sport Fisheries and Wildlife. Handbook of Toxicity of Pesticides to Wildlife. Washington, D. C.: U. S. Government Printing Office, 1970.118 R27: WELLS DE, COWAN AA; ENVIRON POLLUT SER A ECOL BIOL 29 (4): 249 (1982) R28: MARTIN NA; THE EFFECTS OF HERBICIDES USED ON ASPARAGUS ON THE GROWTH RATE OF THE EARTHWORM ALLOLOBOPHORA CALIGINOSA; PROC NZ WEED PEST CONTROL CONF 35TH: 328 (1982) R29: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. 881 R30: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 541 R31: Byrd RA, Markham JK; Teratology 41 (5): 542-3 (1990) R32: Montgomery, J.H.; Agrochemicals Desk Reference 2nd ed. Lewis Publishers, Boca Raton, FL 1997 R33: NAQVI SM, LEUNG T; BULL ENVIRON CONTAM TOXICOL 31 (3): 304 (1983) R34: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office R35: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 1159 R36: Hill, E.F. and Camardese, M.B. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix. Fish and Wildlife Technical Report 2. Washington, DC: United States Department of Interior Fish and Wildlife Service, 1986.137 R37: Bioassay of Trifluralin for Possible Carcinogenicity (1978) Technical Rpt Series No. 34 DHEW Pub No. (NIH) 78-834, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R38: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 308 R39: NELSON JO ET AL; PESTIC BIOCHEM PHYSIOL 7 (1): 73 (1977) R40: Aizawa, H. Metabolic Maps of Pesticides. New York, NY: Academic Press, 1982. 28 R41: TRIANO EA ET AL; FED PROC 41 (3): 1548 (1982) R42: (1) Budavari S, ed; The Merck Index. 12th ed Whitehouse Station, NJ: Merck and Co., Inc., p. 1650 (1996) R43: CAMPANHOLA C ET AL; PESQUI AGROPECU BRAS 17 (4): 565 (1982) R44: (1) Swann RL et al; Re Rev 85: 17-28 (1983) (2) Gerstl Z, Mingelgrin U; J Environ Sci Health B19: 297-312 (1984) (3) Kanazawa J; Environ Tox Chem 8: 477-84 (1989) (4) Kenaga EE; Ecotox Environ Safety 4: 26-38 (1980) (5) Ahrens WH, ed; Herbicide Handbook of the Weed Sci Soc Amer. 7th ed. 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June 19-24. Air and Waste Management Assoc, 94-TP45B.08 (1994) R61: (1) Lewis RG, Lee RE; pp. 5-51 in Air Pollut From Pestic and Agric Processes Lee RE, ed. Boca Raton, FL: CRC Press Inc (1976) R62: (1) Carey AE, Kutz FW; Environ Monit Assess 5: 155-63 (1985) (2) Kutz FW et al; pp. 95-137 in Air Pollut From Pestic and Agric Processes Lee RE, ed Boca Raton, FL: CRC Press Inc (1976) R63: (1) Yess NJ et al; J Assoc Anal Chem 74: 273-80 (1991) (2) Hundley ET et al; J Assoc Off Anal Chem 71: 875-92 (1988) (3) Luke MA et al; J Assoc Off Anal Chem 71: 415-20 (1988) (4) Minyard JP Jr, Roberts WE; J Assoc Anal Chem 74: 438-52 (1991) R64: (1) Rivera J et al; Int J Environ Anal Chem 24: 183-91 (1986) (2) Spacie A; Diss Abstr Int B 36: 4367 (1975) R65: DAY EW JR ET AL; ENVIRON SCI TECHNOL 16 (3): 131 (1982) R66: (1) Stone JF, Stahr HM; J Environ Health 51: 273-6 (1989) (2) Rigakis KB et al; Agric Forest Bull 10: 24-7 (1987) (3) Yess NJ et al; J Assoc Anal Chem 74: 273-80 (1991) (4) Spacie A; Diss Abstr Int B 36: 4367 (1975) R67: 40 CFR 180.207 (7/1/2000) R68: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R69: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R70: 40 CFR 302.4 (7/1/2000) R71: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.155 (Spring, 1998) EPA 738-R-98-002 R72: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R73: DOWNER GB ET AL; J AGRIC FOOD CHEM 24 (6): 1223 (1976) R74: LEE HB, CHAU AS Y; J ASSOC OFF ANAL CHEM 66 (3): 651 (1983) R75: Swineford DM, Belisle AA; Environ Toxicol Chem 8 (6): 465-8 (1989) RS: 70 Record 105 of 1119 in HSDB (through 2003/06) AN: 1008 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-ANTHRANILATE- SY: *O-AMINOBENZOIC-ACID,-METHYL-ESTER-; *2-AMINOBENZOIC-ACID-METHYL-ESTER-; *ANTHRANILIC-ACID,-METHYL-ESTER-; *BENZOIC-ACID,-2-AMINO-,-METHYL-ESTER-; *O-CARBOMETHOXYANILINE-; *2-(METHOXYCARBONYL)ANILINE; *METHYL-O-AMINOBENZOATE-; *METHYL-2-AMINOBENZOATE-; *NEROLI-OIL,-ARTIFICIAL- RN: 134-20-3 MF: *C8-H9-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *SYNTHETICALLY BY ESTERIFYING ANTHRANILIC ACID WITH METHYL ALCOHOL IN PRESENCE OF HYDROGEN CHLORIDE. [R1] FORM: *GRADES: TECHNICAL; FCC. [R2] MFS: ?BASF Corp, Hq, 8 Campus Drive, Parsippany, NJ 07054; Subsidiary: Fritzsche Dodge and Olcott, Inc, 76 Ninth Avenue, New York, NY 10011, (212) 929-4100; Production site: Merry Lane and Passaic Avenue, East Hanover, NJ 07936 [R3] ?Bell Flavors and Fragrances Inc, Hq, 500 Academy Drive, Northbrook, IL 60062, (312) 291-8300; Production sites: Northbrook, IL 60062; Oakland, NJ 07436 [R3] ?Givaudan Corp, Hq, 100 Delawanna Ave, Clifton, NJ 07014, (201) 365-8000; Chemicals Division; Production site: Clifton, NJ 07014 [R3] ?PMC, Inc, Hq, 12243 Brandford St, PO Box 1367, Sun Valley, CA 91352, (818) 896-1101; PMC Specialties Group Division, 20525 Center Ridge Rd, Rocky River, OH 44116; Production site: 501 Murray Rd, Cincinnati, OH 45217 [R3] ?Ungerer and Co, Hq, 4 Bridgewater Lane, Lincoln Park, NJ 07035, (201) 628-0600; Chemical Division, 650 Union Blvd, Totowa, NJ 07512 [R3] OMIN: *USED IN NON-ALCOHOLIC BEVERAGES AT 16 PPM; ALCOHOLIC BEVERAGES AT 0.20 PPM; ICE CREAM, ICES, ETC 21 PPM; CANDY 56 PPM; BAKED GOODS 20 PPM; GELATINS AND PUDDINGS 23 PPM; CHEWING GUM 2,200 PPM. [R4] */BECAUSE IT DOES NOT ABSORB UV RADIATION AND HAS LOW MOLAR ABSORPTIVITY IT IS USED AS A SUNSCREEN AND/...IN COMBINATION WITH OTHER SUNSCREENS OR LIGHT-PROTECTIVES. ...DOSE: 5% IN CREAMS, LOTIONS OR OINTMENTS. [R5] *FEMA NUMBER 2682. [R6] USE: *AS PERFUME FOR OINTMENTS; MFR SYNTHETIC PERFUMES [R1] *FLAVORING [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS [R1]; *COLORLESS TO PALE-YELLOW LIQUID WITH BLUISH FLUORESCENCE [R2] ODOR: *GRAPE-TYPE ODOR [R2]; *ORANGE FLOWER ODOR [R4] TAST: *SLIGHTLY BITTER, PUNGENT TASTE [R4] BP: *256 DEG C @ 760 MM HG [R7] MP: *24-25 DEG C [R1] MW: *151.16 [R1] DEN: *1.168 @ 20 DEG C/4 DEG C [R1] SOL: *SLIGHTLY SOL IN WATER; FREELY SOL IN ALCOHOL OR ETHER [R1]; *SOL IN FIXED OILS, PROPYLENE GLYCOL, VOLATILE OILS [R2] SPEC: *INDEX OF REFRACTION: 1.5810 @ 25 DEG C/D [R7]; *MAX ABSORPTION (ALCOHOL): 248 and 341 NM (LOG E= 3.7); SADTLER REF NUMBER: 897 (IR, PRISM); 280 (IR, GRATING); 1200 (UV) [R7]; +IR: 1234 (Coblentz Society Spectral Collection) [R8]; +UV: 280 (Sadtler Research Laboratories Spectral Collection) [R8]; +NMR: 1200 (Sadtler Research Laboratories Spectral Collection) [R8]; +MASS: 1-7 (Archives of Mass Spectral Data, John Wiley and Sons, New York) [R8] OCPP: *CONGEALING POINT: 23.8 DEG C, 24 DEG C [R4] *IT HAS LOWEST MOLAR ABSORPTIVITY OF ALL SUNSCREENS AND DOES NOT ABSORB THROUGHOUT THE NEAR-ULTRAVIOLET RANGE [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FLPT: *ABOVE 212 DEG F [R9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *ITS ACUTE ORAL TOXICITY IN RAT IS LOW, ABOUT 3-5 G/KG. ...TOLERATED IN DIET OF RATS IN CHRONIC FEEDING...AT 0.3% BUT NOT AT 1.0%, AT WHICH LEVEL...SLIGHT HISTOLOGICAL CHANGES IN KNDNEY AND INCR LIVER AND KIDNEY WT WERE SEEN. ...7-HR EXPOSURE OF RATS TO ATMOSPHERES SATURATED AT 100 DEG C CAUSED...ONLY TRANSIENT WT LOSS. [R10] *IT IS ONLY SLIGHT SKIN IRRITANT IN RABBIT AND GUINEA PIG, BUT MAY CAUSE EYE IRRITATION IN CONCN FORM. [R10] +Methyl anthranilate was found to be negative when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Methyl anthranilate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.100, 0.333, 1.000, and 1.800 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 1.800 mg/plate. At this dose, slight to total clearing of the background bacterial lawn occurred under all test conditions. [R11] METB: *METABOLISM OF THIS ESTER DOES NOT APPEAR TO HAVE BEEN ESTABLISHED, BUT IT APPEARS PROBABLE THAT IT WOULD IN PART BE HYDROLYZED AND THE ACID THEN EXCRETED AS AN ESTER GLUCURONIDE. [R10] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *REPORTED FOUND IN SEVERAL ESSENTIAL OILS: NEROLI, ORANGE, BERGAMONT, LEMON, MANDARIN, JASMINE, TUBEROSE, GARDENIA, CHAMPACA, YLANG-YLANG AND OTHERS; ALSO IN JUICE AND OIL OF VITIS LABRUSCA. /FROM TABLE/ [R4] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *121.101. LIMITATIONS: GRAS, SYNTHETIC FLAVOR AND ADJUVANT [R6] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *BEVERAGES: NONALCOHOLIC AND CONCENTRATES. COLORIMETRIC ANALYSIS APPLICABLE TO SAMPLES CONTAINING LESS THAN 500 MG/L. GRAVIMETRIC ANALYSIS APPLICABLE TO SAMPLES CONTAINING EQUAL TO OR GREATER THAN 500 MG/L. [R12] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 787 R2: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 560 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 655 R4: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 346 R5: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 729 R6: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 888 R7: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-183 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 100 R9: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 325M133 R10: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1899 R11: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R12: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/204 12.024 RS: 7 Record 106 of 1119 in HSDB (through 2003/06) AN: 1024 UD: 200211 RD: Reviewed by SRP on 1/31/1998 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged also to retrieve the record named VANADIUM COMPOUNDS, which has additional, general information on the toxicity and environmental fate of vanadium ions and vanadium compounds. For information on the metal itself, refer to the VANADIUM, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: VANADIUM-PENTOXIDE- SY: *ANHYDRIDE-VANADIQUE- (FRENCH); *CI-77938-; *DIVANADIUM-PENTAOXIDE-; *DIVANADIUM-PENTOXIDE-; *Vanadic-acid-anhydride-; *VANADIC-ANHYDRIDE-; *VANADIO,-PENTOSSIDO-DI- (ITALIAN); *VANADIUM-OXIDE- (V2O5); *Vanadium-Pentaoxide-; *VANADIUMPENTOXID- (GERMAN); *VANADIUM,-PENTOXYDE-DE- (FRENCH); *VANADIUMPENTOXYDE- (DUTCH); *WANADU-PIECIOTLENEK- (POLISH) RN: 1314-62-1 RELT: 6911 [VANADIUM COMPOUNDS] MF: *O5-V2 SHPN: UN 2862; Vanadium pentoxide HAZN: P120; Vanadium Pentoxide MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *(A) ALKALI OR ACID EXTRACTION FROM VANADIUM MINERALS. (B) BY IGNITING AMMONIUM METAVANADATE. (C) FROM CONCN FERROPHOSPHORUS SLAG BY ROASTING WITH SODIUM CHLORIDE, LEACHING WITH WATER, AND PURIFICATION BY SOLVENT EXTRACTION FOLLOWED BY PRECIPITATION AND HEATING. [R1] *PURE (99.6%) VANADIUM PENTOXIDE IS MADE BY CALCINING AMMONIUM METAVANADATE [R2] *Production: iron-vanadium ore (calcination/water leaching/solvent extraction/precipitation/calcination); spent oil-refining catalysts/boiler fly-ash (solvent extraction/precipitation/calcination); phosphoric acid, crude (solvent extraction/hydrorefining; co-produced with yellow cake); uranium ore (leaching/solvent extraction/hydrorefining; co-produced with yellow cake). [R3] *Vanadium in iron ores is recovered in some cases by roasting and leaching the ground ore in a manner similar to that used for carnotite ore. In other cases the ore is smelted to produce pig iron which contains the vanadium. When the pig iron is converted to steel, the vanadium is recovered in a rich slag containing 5 to 25% vanadium pentoxide. The slag is then processed by a roasting and leaching procedure to extract the vanadium in the form of red cake. The vanadium in phosphate rock is recovered in ferrophosphorus during the production of elemental phosphorus by electric furnace smelting. The ferrophosphorus contains 3-7% vanadium and is processed further by roasting and leaching to recover the vanadium. /Vanadium/ [R4, 2014] FORM: *Commercial: 98-99%. [R5] *GRADES: COMMERCIAL AIR-DRIED; COMMERCIAL FUSED; CHEMICAL PURITY AIR-DRIED; CHEMICAL PURITY FUSED. [R1] MFS: *Gulf Chemical and Metallurgical Corporation, Hq, 302 Midway Road, P.O. Box 2290, Freeport, TX 77541, (409) 233-7882; Production site: Freeport, TX 77541 [R6] *Kerr-McGee Chemical Corporation, Hq, Kerr-McGee Center, P.O. Box 25861, Oklahoma City, OK 73125, (405) 270-1313; Production site: Soda Springs, ID 83276 [R6] *Umetco Minerals Corp., Hq, P.O. Box 669, Blanding, UT 84511, (801) 678-2221; Production site: White Mesa Mill, Blanding, UT 84511 [R6] *U.S. Vanadium Corporation, Hq, 30 Main Street, Danbury, CT 06810, (203) 790-1555; Production site: Hot Springs, AR 71901-8801 [R6] OMIN: *METHOD OF PURIFICATION: ALKALI SOLN, PRECIPITATION AS AMMONIUM METAVANADATE AND IGNITION TO VANADIUM PENTOXIDE. [R1] *Vanadium pentoxide was one of several catalysts used for the reduction of nitrogen oxides in flue gases. [R7] *V2O5 is the principal starting material for the production of all vanadium compounds. [R8] USE: *CHEMICAL INTERMEDIATE; PRINCIPALLY A CHEM INT FOR VANADIUM ALLOYS AND COMPOUNDS; OXIDATION CATALYST IN MANY INDUSTRIAL SYNTHESIS PROCESSES; CATALYST IN MANUFACTURE OF SULFURIC ACID (CONTACT PROCESS); OXIDATION CATALYST IN AUTOMOBILE CATALYTIC CONVERTERS; ADDITIVE TO GLASS FOR SCREENING UV RADIATION [R9] *Catalyst for oxidation of sulfur dioxide in sulfuric acid manufacture ferrovanadium, catalyst for many organic reactions, ceramic coloring material, vanadium salts, inhibiting UV transmission in glass, photographic developer, dyeing textiles. [R1] *For the manufacture of yellow glass; depolarizer. [R10] *Used as an oxidation catalyst for the production of sulfuric acid from sulfur dioxide, phthalic anhydride from naphthalene or 2-xylene, maleic anhydride from benzene or n-butane/butene, adipic acid from cyclohexanol/cyclohexanone, and acrylic acid from propane. Minor amounts are used in the production of oxalic acid from cellulose and of anthraquinone from anthracene. Used to lower the melting point of enamel frits for the coating of aluminum substrates. Further uses are as a corrosion inhibitor in the carbon dioxide scrubbing solutions of the Benfield and related processes for the production of hydrogen from hydrocarbons, as cathode in primary and secondary (rechargeable) lithium batteries, as UV absorbent in glass, in YVO4. [R11] PRIE: U.S. IMPORTS: *(1985) 6.0X10+5 lb (ores, slag, residues); 1.6X10+6 lb (ferrovanadium) [R12] *(1986) 4.0X10+6 lb (ores, slag, residues); 1.1X10+6 lb (ferrovanadium) [R12] *(1987) 4.5X10+6 lb (ores, slag, residues); 6.8X10+5 lb (ferrovanadium) [R12] *(1988) 4.8X10+6 lb (ores, slag, residues); 6.7X10+5 lb (ferrovanadium) [R12] *(1992) 2.06X10+5 kg; (1991) 1.33X10+5 kg [R8] *(1990) estimated 3.7X10+5 lb; (1989) 4.07X10+5 lb; (1988) 4.82X10+5 lb; (1987) 4.57X10+5 lb; (1986) 8.24X10+5 lb /Vanadium pentoxide, anhydride/ [R13] U.S. EXPORTS: *3.14X10+9 g [R14] *(1984) 2.4X10+4 lb (ores); 6.7X10+5 lb (ferrovanadium) [R12] *(1985) 5.0X10+3 lb (ores); 6.4X10+5 lb (ferrovanadium) [R12] *(1986) 1.7210+5 lb (ores); 8.2X10+5 lb (ferrovanadium) [R12] *(1990) estimated 1.9X10+6 lb; (1989) 4.62X10+6 lb; (1988) 1.37X10+6 lb; (1987) 1.64X10+6 lb /Vanadium pentoxide, anhydride/ [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW TO RUST-BROWN ORTHORHOMBIC CRYSTALS [R10]; +Yellow-orange powder or dark-gray flakes dispersed in air. [R15] ODOR: +Odorless. [R15] BP: *1750 deg C (3182 deg F) (decomp) [R16, 1981.1] MP: *690 DEG C [R10] MW: *181.88 [R10] DEN: *3.357 AT 18 DEG C [R1] SOL: *1 G/125 ML WATER [R10]; *SOL IN CONCN ACIDS, ALKALIES; INSOL IN ALCOHOL [R10]; *SOL IN ACETONE [R17] SPEC: *INDEX OF REFRACTION: 1.46, 1.52, 1.76 [R18] VAP: *Approx 0 at 20 deg C (68 deg F) [R16, 1981.2] OCPP: *LOSES OXYGEN REVERSIBLY IN THE REGION 700-1125 DEG C; ITS ACID SOLN ARE REDUCED BY SULFUR DIOXIDE, ZINC + HYDROCHLORIC ACID AND BY EVAPORATION WITH HYDROCHLORIC ACID; FORMS RED AND YELLOW SOLUTIONS IN CONCENTRATED ACIDS; FORMS VANADATES IN ALKALIES [R10] *... Vanadium pentoxide has been reported to catalyze the oxidation of carcinogenic hydrocarbons, benzo(a)pyrene, 7,12-dimethylbenzanthracene, 3-methylcholanthrene, 1,2,5,6-dibenzanthracene, and 2-acetylaminofluorene. [R4, 2021] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of vanadium pentoxide stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal contact), exposure to this odorless, yellow-to-orange, crystalline substance may occur from its use as an intermediate for vanadium alloys and compounds, as an oxidation catalyst (eg, in manufacture of sulfuric acid, and in automobile catalytic converters), in photographic development, in dyeing textiles, in ceramic coloring, from vanadium mining and processing, and from the cleaning of oil-fired boilers, combustion chambers, gas turbines, and firebrick linings. Effects from exposure may include burns to the skin and eyes,tracheitis, bronchitis, emphysema, pulmonary edema, or bronchial pneumonia. The ACGIH has extablished a TLV TWA of 0.05 mg/cu m for vanadium fume and respirable dust (as vanadium pentoxide). OSHA has set this same limit as a final rule to become effective December 31, 1992. Engineering controls (including process enclosure and exhaust ventilation) should be used to limit vanadium pentoxide exposure. In activities and situations where over-exposure may occur, wear protective clothing specifically recommended by the shipper or producer to prevent skin contact with vanadium pentoxide, and a self-contained breathing apparatus. Safety showers and eyewash fountains should be located in areas where exposures are likely. If contact should occur, flush exposed eyes with copious amounts of tepid water for at least 15 minutes, and wash exposed skin with soap and water. Contaminated clothing should be removed and left at the work site for cleaning. While vanadium pentoxide does not ignite easily, it may burn with the production of acrid smoke and fumes. Also, containers may explode in the heat of a fire. For fires involving vanadium pentoxide, extinguish with dry chemical, CO2, Halon, water spray, fog, or standard foam. Fight the fire from a maximum distance, and dike fire control water to prevent the material from entering water sources or sewers. Vanadium pentoxide should be stored i n tightly closed containers, away from moisture, heat, sparks, or flames, and incompatibles such as chlorine trifluoride, lithium, or peroxyformic acid. Vanadium pentoxide may be shipped domestically via air, rail, road, or water. Small spills of vanadium pentoxide may be collected and placed in clean, dry containers for later disposal (liquid solutions are taken up with sand ornoncombustible absorbent). Large spills on land should be contained in excavated pits or other holding areas. Solids should be covered with a plastic sheet. Spills into bodies of water should be neutralized with agricultural lime, crushed limestone, or sodium bicarbonate, and mechanical dredges used to remove immobilized masses. DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R19] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R19] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R19] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R19] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R19] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R19] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R19] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R19] FPOT: *Not flammable. [R5] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use "alcohol" foam, dry chemical or carbon dioxide. Keep run-off water out of sewers and water sources. [R20] REAC: +The reaction of lithium and vanadium pentoxide occurs around 400 deg C; the temperature then rises rapidly to 768 deg C. [R21] +Lithium, chlorine trifluoride. [R22, 328] SERI: *Vanadium pentoxide dust may cause irritation of the eyes ... and respiratory tract. [R16, 1981.2] *... Extensive evidence exists that vanadium dust (usually the pentoxide) is severely irritating to the mucous membranes of the eyes, nose, throat and respiratory tract. /Vanadium dust/ [R23] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, dust resistant safety goggles, face shields (eight inch minimum), and other appropriate clothing necessary to prevent repeated or prolonged skin contact with vanadium pentoxide dust. [R16, 1981.4] +Wear appropriate personal protective clothing to prevent skin contact. /Dust/ [R22, 329] +Wear appropriate eye protection to prevent eye contact. /Dust/ [R22, 329] +Recommendations for respirator selection. Max concn for use: 0.5 mg/cu m). Respirator Class(es): Any air-purifying respirator with a high-efficiency particulate filter. May require eye protection. Any supplied-air respirator. May require eye protection. /Dust/ [R22, 329] +Recommendations for respirator selection. Max concn for use: 1.25 mg/cu m). Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with a high-efficiency particulate filter. May require eye protection. /Dust/ [R22, 329] +Recommendations for respirator selection. Max concn for use: 2.5 mg/cu m). Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. /Dust/ [R22, 329] +Recommendations for respirator selection. Max concn for use: 35 mg/cu m. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. /Dust/ [R22, 329] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Dust/ [R22, 329] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Dust/ [R22, 329] *Respirator selection, upper limit devices recommended by NIOSH for vanadium pentoxide dust. For concn up to 0.5 mg/cu m, use high efficiency particulate filter; or any supplied air respirator; or any self contained breathing apparatus. For concn up to 1.25 mg/cu m, use any supplied air respirator operated in a continuous flow mode; or any powered air purifying respirator with a high efficiency particulate filter. For concn up to 2.5 mg/cu m, use any air purifying full facepiece respirator with a high efficiency particulate filter; or any self contained breathing apparatus with a full facepiece; or any supplied air respirator with a full facepiece and powered air purifying respirator with a tight fitting facepiece and a high efficiency particulate filter. For concn up to 70 mg/cu m, use any supplied air respirator with a full facepiece and operated in a pressure demand or other positive pressure mode. For entry into IDLH or unknown concentration, use any self contained breathing apparatus with a full facepiece and operated in a pressure demand or other positive pressure mode; or any supplied air respirator with a full facepiece and operated in a pressure demand or other positive pressure mode in combination with an auxiliary self contained breathing apparatus operated in pressure demand or other positive pressure mode. For escape conditions, use any air purifying full facepiece respirator with a high efficiency particulate filter; or any appropriate escape type self contained breathing apparatus. [R24] OPRM: *It is important to prevent the inhalation of airborne particulate vanadium pentoxide. For use as a catalyst, vanadium pentoxide can be produced in an agglomerated or pelleted form which is dust free; however, vibration in the plant may, in time, reduce a certain proportion to dust. In the processes associated with the manufacture of metallic vanadium, and in the sieving of used catalyst during maintenance operations, the escape of dust should be prevented by the enclosure of the process and by the provision of exhaust ventilation. ... Where possible, on load cleaning should be improved to reduce the need for workers to enter furnaces; where off load cleaning proves essential, methods such as water lancing, which do not necessitate physical entry, should be tried. [R25, 2241] +Contact lenses should not be worn when working with this chemical. /Dust/ [R22, 329] *Personnel protection: Keep upwind. Avoid breathing dusts, and fumes from burning material. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. [R20] *If material not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. [R20] *Non-impervious clothing which becomes contaminated ... should be removed promptly and not reworn until the vanadium dust is removed from the clothing. Skin that becomes contaminated ... should be promptly washed or showered to remove any pentoxide dust. [R16, 1981.4] +SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. /Dust/ [R22, 329] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Dust/ [R22, 329] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R26] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R27] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R28] CLUP: *1. Ventilate area of spill. 2. Collect spilled /dust/ material in the most convenient and safe manner for reclamation, or for disposal in a secured sanitary landfill. [R16, 1981.6] *If potentially hazardous amounts of vanadium pentoxide fume are inadvertently released, ventilate the area of the release to disperse the fume. [R16, 1981.5] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P120, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R29] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. /Vanadium pentoxide, as V2O5, dust or fume; respirable fraction/ [R30, 2002.60] ANTR: *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A AND B/ [R31] *For advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A AND B/ [R31] MEDS: *Workers should be given pre-employment medical examinations to ensure that persons suffering from chronic respiratory disease are /to be protected from/ vanadium pentoxide, and exposed workers should receive regular periodical examination. [R25, 2241] HTOX: *WHEN INHALED, CHIEF EFFECTS OF VANADIUM PENTOXIDE ARE ON RESP PASSAGES. TRACHEITIS, BRONCHITIS, EMPHYSEMA, PULMONARY EDEMA, OR BRONCHIAL PNEUMONIA MAY BE OBSERVED, BUT NO SPECIFIC CHRONIC LUNG LESIONS HAVE BEEN DESCRIBED. ... IN STUDYING EFFECTS OF EXPOSURE TO RESPIRABLE VANADIUM PENTOXIDE DUST IN FIVE HUMAN VOLUNTEERS ... SEVERE UPPER RESP TRACT IRRITATION IN FORM OF PERSISTENT PRODUCTIVE COUGH AT AN AVERAGE CONCN OF 0.2 MG/CU M DURING SINGLE 8 HR EXPOSURE /WAS FOUND/. [R32] *VANADIUM PENTOXIDE APPEARS TO BE THE ONLY VANADIUM CMPD FOR WHICH OCULAR DISTURBANCES HAVE BEEN REPORTED. THE DUST CAUSES A SENSATION OF BURNING AND IRRITATION OF EYES AND SIGNS OF CONJUNCTIVITIS, ACCOMPANIED BY IRRITATION OF THE NOSE AND THROAT. RESP IRRITATION OCCURS AT LOWER CONCN THAN DOES OCULAR IRRITATION. [R33] *INHIBITION OF ATPASE BY VANADIUM PENTOXIDE WAS STUDIED IN MICROSOMAL FRACTIONS AND TISSUE HOMOGENATES OF HUMAN KIDNEY. ENZYME IN TISSUE HOMOGENATES WAS MORE RESISTANT TO VANADIUM THAN MICROSOMAL ENZYME FROM SAME TISSUES. [R34] *... skin ... /is/ irritated by the dust or by contact with an acid soln of vanadium pentoxide; eczematous lesions have occurred ... [R16, 1981.3] *Four cases are described in which workers from a vanadium pentoxide refinery presented with symptoms of acute toxicity. The patients presented with green discoloration of the tongue, upper respiratory symptoms and asthma. One patient continued to wheeze 8 wk after his last exposure. Vanadium cmpd appear to be capable of inducing asthma in previously normal subjects. [R35] *... /Studies indicate/ little probability of vanadium pentoxide dust producing pneumoconiosis. [R4, 2021] *Workers exposed to vanadium pentoxide for only a few days may develop irritation of the conjunctivae, rhinitis, dryness of the throat, hoarseness, bronchitis with coughing and wheezing, dyspnea, and pneumonitis. [R36] *Eighteen workers who were exposed to vanadium pentoxide dust at concentrations in excess of 0.5 mg/cu m for a period of up to 2 weeks developed acute respiratory symptoms which persisted for nearly 2 weeks after removal from exposure; vanadium was demonstrable in urine at elevated levels, and it continued to be excreted for up to 14 days after exposure had ended. Controlled human exposure to vanadium pentoxide at a concentration of 0.1 mg/cu m for 8 hours produced mucous formation in the lungs and cough which subsided within 3 days, while a concentration of 0.25 mg/cu m caused a loose cough which persisted for 7-10 days The peak urinary vanadium concentration observed was 130 ug/l at 3 days after exposure; vanadium was undetectable in all urine specimens by 7 days following exposure. [R37] *... Vanadium poisoning in workers was /studied/. The men were primarily exposed to vanadium oxide dust and fume. They had a dry, irritating cough, blood stained sputum, and anemia preceded by an increased erythrocyte count, pallor, anorexia, emaciation, albuminuria and casts, hematuria, tremors, eye irritation, vertigo, hysteria, and depression. Tuberculosis often developed, sometimes resulting in death. [R38] *BOILER CLEANERS EXPOSED TO VANADIUM TRIOXIDE OR VANADIUM PENTOXIDE AT CONCENTRATIONS OF 2-85 MG/CU M SHOWED RESPIRATORY IRRITATION; THOSE EXPOSED TO 30-104 MG/CU M SHOWED INTOXICATION (USED RESPIRATORS TO SOME EXTENT). /FROM TABLE/ [R39, p. V2 650] *A greenish black discoloration of the tongue is a characteristic manifestation of the toxic action of vanadium. That it is not merely a deposit of the metal or its salts on the surface of the tongue is shown by the fact that though it disappears within 2 to 3 days of cessation of exposure, it cannot be removed by cleaning. ... /It has been/ suggested that it might be due to the reduction of the pentoxide to trioxide, and to the formation of green salts by the action of ptyalin and bacteria in the mouth; ... [R40, 345] *Ammonium metavanadate and vanadium pentoxide in 0.5 and 0.8% solutions, respectively, representing approx saturated solutions, do not irritate the skin. [R4, 2022] *Inhalation of vanadium pentoxide produced 10-32 mg V/cu m for 2-5 days and caused respiratory irritation, tremors, and discolored tongue. /From table/ [R41] *Inhalation of vanadium pentoxide and vanadium trioxide for 1-5 yr ... produced asthma in 3 of 20 workers. [R42] *No evidence of effects was found among boiler cleaners working in an atmosphere containing vanadium pentoxide at an average concentration of 99.6 mg/cu m. They noted that the lack of effects was probably because of the gauze filter masks worn over the nose and mouth and because of the intermittent cleaning operation that occurred only one or two times each month. [R43] *250 workers exposed to levels of vanadium pentoxide ranging from 0.02-3.2 mg/cu m (mean= 0.844 mg/cu m) over an 8 yr period. Conjunctivitis, tracheobronchitis and contact dermatitis were the most prevalent clinical observations. No changes in hematology, pulmonary function, or blood pressure were noted, although a transient increase in blood pressure was reported in some individuals who did not take proper precautions in areas of high vanadium levels. ... Concluded that exposure to vanadium pentoxide caused no permanent adverse systemic effects in spite of the observation that there were some chronic changes in the mucous membranes. [R44] *In a vanadium factory in Sweden, workers were exposed to vanadium pentoxide at concentrations ranging from 0.05-5.58 mg/cu m. Vanadium was detected in the blood and urine of exposed individuals, and some of the workers had developed eczema or a hypersensitivity to vanadium detectable with a skin patch test. Severe respiratory irritation was the most prevalent symptom, but slight changes in blood, hemoglobin concentrations, heart palpitations upon exertion, weakness and neuroasthenic symptoms were observed occasionally. Blood pressure was not increased and there were no gastrointestinal or urinary tract symptoms and no discoloration of the tongue; chronic changes, such as pneumonoconiosis, fibrosis or emphysema, were not detected. [R45] *Severe respiratory tract irritation occurred in at least 74 of 100 boilermakers after exposure to high levels of vanadium pentoxide welding fumes during oil-to-coal conversion of a power plant in Massachussetts. Most frequent symptoms were productive cough, sore throat, dyspnea on exertion and chest pain or discomfort. ... The median latency period between starting work and onset of symptoms was 7 days. Wheezing, rhonchi, rales, and hoarseness were found in workers examined by physicians. Urinalysis was negative in the three workers tested. ... Exposure was caused mainly by carrying out welding work in unventilated confined spaces. Vanadium fume exposure levels varied from 0.05 to 5.3 mg/cu m. The OSHA exposure limit for is 0.05 mg/cu m. [R46] *Since vanadium itself is considered nontoxic, there is little hazard associated with mining; however, exposure to the more toxic compounds, especially the oxides, can occur during smelting and refining. Exposure may also occur in conjunction with oil fired furnace flues. [R47] *Nasal catarrh or nose bleeding, observed in gas turbine workers, in boiler cleaners, and in process workers has been a prominent initial symptom. This, with soreness of the throat and chest, is described as belonging to a primary group of symptoms with an onset between a half and 1 hr after starting work. Dry cough, wheezing and dyspnea on exertion appear after a period of 6-24 hr. Bronchitis, mainly of an acute nature is considered to be a prominent symptom, lasting from a few days to more than 2 months. ... Cases of bronchopneumonia and lobar pneumonia, probably of combined chemical and bacterial origin (vanadium pneumonitis) and 1 case of pleurisy /have been observed/. [R40, 344] *Conjunctivitis, upper airway irritation, bronchoconstriction (cough develops within 24 hours), mucosal discoloration (greenish-black tongue) [R48] *Occupational asthma has also been documented in workers in a vanadium pentoxide refinery. [R49] *Sixty three employees out of 79 making vanadium pentoxide from magnetite ore /were studied/. Pulmonary function tests showed no differences compared with unexposed controls, despite previous exposure of the vanadium workers for an average of 11 years to concentrations in the range of 0.1 to 3.9 mg/cu m. Wheezing was more common among the vanadium workers, and pneumoconiosis was not observed. A characteristic histologic feature of the nasal mucosa of vanadium workers as being "a zonelike subepithelial infiltrate of mononuclear cells" /was also described/. [R49] *... Vanadium workers are more susceptible to colds and other respiratory illnesses than others. Vanadium salts are quite toxic for alveolar macrophytes in vitro. Toxicity was related to the extent of dissolution of particles of venadium pentoxide, divanadium trioxide, and vanadium dioxide. In view of the important role of the alveolar macrophage in pulmonary defense, studies suggest that exposure to vanadium may impair the lung resistance to respiratory infection. /Vanadium, vanadium oxides/ [R23] *Acute exposure to vanadium oxide dusts in associated with acute upper and lower airway irritation. Conjunctivitis, rhinitis, and pharyngitis commonly occur within 0.5 hor of exposure and up to 12 hours after the exposure. Cough, sneezing, dyspnea, and substernal soreness occur with more severe exposures. A green-black discoloration of the tongue occurs with some exposures. The discoloration occurs from simple exposure of the tongue mucosa to vanadium powder. /Vanadium oxide dusts/ [R50] NTOX: *VANADIUM PENTOXIDE DUST /WAS FOUND/ TO BE LETHAL TO RABBITS FOLLOWING SINGLE, 7 HR EXPOSURE TO 205 MG OF V2O5/CU M. THE ANIMALS DIED OF PULMONARY EDEMA, PRESUMABLY FROM COMBINED NONSPECIFIC IRRITANCY AND SPECIFIC TOXICITY OF VANADIUM PENTOXIDE. DIETARY V2O5 IS LESS TOXIC THAN SODIUM METAVANADATE MONOHYDRATE (NAVO3.H2O) BY A FACTOR OF 2, BUT IS TOXIC AT 100 PPM VANADIUM TO RATS FED CASEIN DIET, WHEREAS IT REQUIRED 1000 PPM VANADIUM IN OPTIMAL DIET TO PRODUCE DEFINITE SIGNS OF TOXICITY. ... V205 WAS INGESTED FOR A LIFETIME, 2.5 YR, BY RATS AND DOGS AT LEVELS OF 10 AND 100 PPM VANADIUM WITH ... /ONLY/ REDUCED HAIR CYSTINE VALUES. [R51] *VANADIUM PENTOXIDE IN DRINKING WATER @ LEVEL OF 5% CAUSES MARKED ANOREXIA, AND DEATH WITHIN 10 WK /IN LAB ANIMALS/ [R52] *PULMONARY ALVEOLAR MACROPHAGES FROM DOGS, RABBITS, AND RATS WERE EXPOSED IN VITRO FOR 20 HR TO VANADIUM PENTOXIDE. A SIGNIFICANT DECREASE IN THE ACTIVITY PRESENT IN PHOSPHOLIPID OCCURRED AT VANADIUM CONCENTRATIONS THAT AFFECTED VIABILITY OF MACROPHAGES FROM ALL THREE SPECIES. [R53] *Two vanadium cmpd, vanadyl sulfate (VOSO4) and vanadium pentoxide (V2O5), and fly ash from an oil fueled power plant were dissolved or suspended in culture medium over a range of concn and hamster tracheal epithelia were exposed for 1 hr/day, for 9 consecutive days. Explants treated with vanadyl sulfate (VOSO4) either decreased ciliary activity or produced ciliostasis depending on the concn and length of exposure. Early morphological alterations consisted of vacuolization of both nuclei and cytoplasm. Similar changes were observed in cultures exposed to vanadium pentoxide (V2O5); however, the cytotoxicity appeared earlier and was more pronounced. [R54] +Vanadium pentoxide (0, 1.0, 2.0, 10.0, 15.0, 20.0 umol V/100 g body wt) was administered via oral intubation (in water) to weanling male Wistar rats (60-65 g; 3 wk old) for 3 days. 15 and 20 umol V/100 g caused a significant increase in serum calcium concn. Bone alkaline phosphatase activity was increased significantly by 1-20 umol V/100 g, while bone acid phosphatase activity was not altered significantly. Bone DNA content was increased significantly by 1-10 umol V/100 g. Bone calcium content was not altered significantly by admin of vanadium. The increase in serum calcium concn caused by admin of V (20 umol/100 g) was prevented completely by simultaneous injection of zinc sulfate (15.3 umol Zn/100 g) for 3 days, although zinc alone did not have any effects. [R55] *FATTY CHANGES WITH PARTIAL CELL NECROSIS IN LIVER HAVE BEEN OBSERVED IN RATS AND RABBITS AS RESULT OF LONG TERM INHALATION EXPOSURE TO VANADIUM PENTOXIDE, TRIOXIDE, AND CHLORIDE (10-70 MG/KG, 2 HR/DAY, 9-12 MO). OTHER EFFECTS INCL A MARKED REDUCTION IN ALBUMIN/GLOBULIN RATIO IN SERUM, AND DRASTIC REDUCTION IN LIVER TISSUE RESP. [R39, p. V2 652] *... /It was/ discovered that rats admin vanadium pentoxide in diet (25-1000 mg vanadium/kg) had a lower content of cystine in hair than controls, indicating inhibition of cystine synthesis. Such inhibition should affect metabolic processes involving cystine, eg, biosynthesis of coenzyme A. This was confirmed ... /in an expt which/ demonstrated a reduction of coenzyme A in the liver of rats admin sodium vanadate (single ip injection, 5-10 mg/kg, or dietary concn 500 mg/kg), and ... /in an expt which/ showed in vitro inhibition of cholesterol synthesis from (14)C-acetate in rat and rabbit liver in the presence of vanadyl sulfate (about 1 mmol/l vanadium). Vanadyl sulfate also inhibits the synthesis of cholesterol from mevalonic acid but not from squalene, a subsequent intermediate in the biosynthesis of cholesterol. [R39, p. V2 654] *Group of five male Wistar rats were treated with vanadium pentoxide at levels of 0, 25 or 50 ppm of dietary vanadium for 35 days, at which time levels were increased to 100 and 150 ppm, respectively, for the two treated groups and continued for an additional 68 days. At the end of 103 days, the rats ingesting vanadium pentoxide gained more weight than the control rats, although food consumption was reported to be similar in all groups. There was a decrease in the amount of cysteine in the hair of the rats exposed to the high level of vanadium pentoxide. [R56] *... Vanadium pentoxide or ammonium metavanadate ... inhibit the respiratory chain but have no effect on oxidative phosphorylation of kidney mitochondria in rat. [R57] *The effects of vanadium on the lipid peroxide level in mouse lung, kidney and liver was investigated by short term inhalation of vanadium pentoxide aerosol (80 mg/sq m as vanadium pentoxide, 1 hr), a single oral and a single ip administration of sodium vanadate (170 mumol/kg body weight as sodium vanadate. ... Thiobarbituric acid value, an index of lipid peroxidation, increased in the liver after inhalation and in the kidney and liver after ip administration at 0.5-3 hr, 0.5-18 hr and 7-18 hr, respectively. The elevation of thiobarbituric acid value in the liver was recognized when hepatic glutathione concentrations was as high as 60-70% of control values. [R58] *The effects of soluble compounds and oxides of /10 elements/ on oxidative metabolism and membrane integrity of rabbit alveolar macrophages were studied by 24 hr in vitro exposure. Oxidative metabolism induced by phagocytosis of opsonized zymosan was measured by hydrogen peroxide and O2- release and by chemiluminescence in the presence of luminol. Membrane integrity was estimated by extracellular LDH activity. Metallic ions and oxides inhibited the release of active oxygen species. Cadmium, arsenic, and vanadium pentoxide were the most toxic elements as measured by all parameters. ... [R59] *The effects of acute vanadium pentoxide exposure on pulmonary function were investigated in monkeys. Sixteen male Macaca fascicularis monkeys were exposed to vanadium pentoxide dust by acute, whole body inhalation at 0.5 or 5.0 mg/cu m vanadium pentoxide at a 1 week interval. Bronchoalveolar lavage was conducted after pulmonary function testing of each animal was completed. ... Acute inhalation of vanadium pentoxide dust caused impairment in pulmonary function at an aerosol concentration of 5.0 mg/cu m vanadium pentoxide but not at 0.5 mg/cu m vanadium pentoxide. No significant changes in dynamic compliance forced volume concentration, total lung capacity, or the diffusion capacity for carbon monoxide were observed. There was a significant increase in the total number of cells in bronchoalveolar lavage fluid 1 day after acute inhalation of vanadium pentoxide dust. The increase in the number of cells by differential counting occurred through a marked increase in the absolute number and relative percentage of polymorphonuclear leukocytes. ... Air flow limitation ... in monkeys acutely exposed to vanadium pentoxide dust ... is associated with an increased total cell count in bronchoalveolar lavage recovered from the lungs. [R60] *A quantitative method for evaluating rabbit alveolar macrophage function utilizing chemiluminescence was described. The method was evaluated with vanadium pentoxide. ... Alveolar macrophages obtained from adult New Zealand white rabbits were incubated with 3 to 12 ug/ml vanadium pentoxide. ... The macrophages were activated with a standardized opsonized zymosan preparation or a polyacrylamide bead preparation to which gamma-immunoglobulin and luminol were chemically bound, 100 microliters of cell suspension containing 200,000 cells being used. The cells were assayed in a device which quantitatively detected photon emission due to respiratory burst activity. The method was compared with semiquantitative procedures that utilized phagocytosis of immunoglobulin coated beads and reduction of a nitro-blue-tetrazolium dye. Chemiluminescence of the macrophages decreased linearly with increasing vanadium pentoxide concentration. The inhibition could be correlated with decreased phagocytic capacity. Dye reduction and phagocytic efficiency also decreased with increasing vanadium pentoxide concentration; however, these methods were less sensitive than the chemiluminescence assay. [R61] *Rats were intratracheally given vanadium pentoxide or the pot dust collected in a fire-box of a mazut-fired stove. Vanadium pentoxide content in the dust was about 58%. Intratracheal /admin/ was carried out every other week. ... Dose of administered dust was equivalent in respect of vanadium pentoxide content. ... /Admin/ of two kinds of dust, ... increased lung mass and /increased/ lung hydroxyproline content. Roentgenograms revealed similar, subtle pulmonary alterations in animals under investigation, both after the administration of vanadium pentoxide and the pot dust. [R62] *Rats were intraperitoneally given vanadium pentoxide in a single dose of 1/5, 1/15, and 1/45 of LD50. ... Inhibition of liver microsomal monooxygenase system components: benzo(a)pyrene aryl hydroxylase, cytochrome c, cytochrome b5 and cytochrome p450 nicotinamide adenine dinucleotide phosphate reductase, was found. ... [R63] *In in vitro experiments, /vanadium/ compounds inhibit the microsomal fraction aryl 4-hydroxylase and lysosomal fraction acid phosphatase activities in the rat liver. In in vivo chronic experiments rats were 6 or 12 times exposed to vanadium pentoxide ... by intratracheal /admin/ ... . Intoxication with vanadium pentoxide caused the aryl 4-hydroxylase activity to decrease. Contrary to the vitro results, acid phosphatase activity tended to increase. [R64] *Rats fed a diet containing 100 ug V/kg grew more slowly than those having 0.5 mg V/kg in their diet. ... Rats consuming less than 10 ug V/kg in their diet was impaired slightly in the third generation and markedly in the fourth generation (reduced number of pups and increased neonatal mortality compared with that of controls). [R65] *An unspecified number of rats and mice were exposed to 1-2 mg/cu m of vanadium pentoxide for 6 hours/day for 3 months. No effects on growth rate, lung size, blood chemistry or histology were reported in the mice or rats exposed to 0.1-0.4 mg/cu m of vanadium pentoxide. At the higher concentration, however, the rats had a decreased growth rate and enlarged lungs and the mice had thickened alveolar walls and congested lung. [R66] *Daily ip admin of vanadium pentoxide or at a dose of 1 mg/kg for 14 days produced no marked change in pulmonary protein, glycogen and phospholipid levels in adult male rats. Increasing the vanadium pentoxide content to 4 mg/kg decreased lung phospholipid content. The 1 mg/kg dose of vanadium pentoxide produced a significant rise in glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, while the higher vanadium pentoxide dose failed to alter the enzyme activity. [R67] ADE: *VANADIUM PENTOXIDE IS READILY ABSORBED FROM LUNG INTO BLOODSTREAM ... [R68] *DEPOSITION OF VANADIUM IN TISSUES OF RATS, FOLLOWING 6 MO OF DAILY, 6 HR INHALATION OF VANADIUM PENTOXIDE DUST, 0.2 MICRON MMD /MEDIAN MASS DIAMETER/, @ LEVEL OF 0.5 MG OF V/CU M, AMOUNTED TO 30 UG V/G IN LUNG, 0.8 UG/G IN KIDNEY, 0.6 UG/G IN SPLEEN, AND ONLY 0.14 UG/G IN LIVER. ELIMINATION FROM THESE ORGANS WAS ... SLOW ... EVIDENCE OF VANADIUM EXPOSURE WAS STILL FOUND IN THE LUNG, KIDNEY, AND SPLEEN 20 WK POSTEXPOSURE. [R4, 2026] *Intratracheally instilled (48)V vanadium pentoxide was rapidly cleared from rat lungs into blood, liver, and bone; 40% of the recovered (48)V was excreted, primarily in urine by day 3, while the skeleton accounted for 30% by day 7. The behavior of instilled (48)V VO2Cl was similar to that of (48)vanadium pentoxide. Uptake of gavaged (48)V vanadium pentoxide was 2.6% of admin dose. Skeleton, lung, kidney and liver were primary targets for intratracheally instilled vanadium, with uptake being greater intratracheally than by oral route. [R69] *Serum and urinary vanadium (vanadium) concn were investigated in 8 men exposed to vanadium pentoxide dust. Creatinine adjusted urinary vanadium concn correlated with serum vanadium concn but not with vanadium contents of factory air. Urinary vanadium excretion decreased significantly with the time the workers spent away from exposure. Most absorbed vanadium was excreted in the urine within 1 day after a long term moderate exposure to vanadium dust. [R70] *Several studies have reported that vanadium was identified in the blood, feces and, in most studies, the urine of some, but not all, workers after occupational exposure to vanadium pentoxide dust, indicating that absorption occurred as a result of vanadium pentoxide inhalation. [R71] *Young adult rats were exposed via inhalation or intratracheal instillation to oxides of arsenic, beryllium, cadmium, cobalt, lead, selenium, vanadium, and ytterbium. ... The lung clearance varied widely for these compounds, and the times to remove 50% of the initial burden ranged from 18 min vanadium to 400 days for beryllium. Arsenic, cadmium, lead, selenium, and vanadium were initially soluble in lung, but a small fraction (1-20%) remained there over the long term. ... Arsenic, selenium, and vanadium translocated to carcass and bone. ... In general, the aqueous solubility of these compounds was a poor predictor for behavior in vivo because of their interaction with metabolic processes. Of the metal oxides tested for acute lethality following pulmonary deposition, cadmium was most toxic, followed by selenium, vanadium, and arsenic. [R72] *Vanadium was determined in urine and blood of two workers (workers 1 and 2 with direct exposure to vanadium pentoxide) and 13 fellow workers (with indirect or no vanadium exposure), and the results were compared by means of personal and stationary sampling of vanadium in air. Worker 1, a foreman with the heaviest exposure to vanadium, had a green tongue, complained of frequent productive coughing, and excreted 47 to 124 ng/ml vanadium in his late morning and mid-afternoon urine. Worker 2, a helper to the foreman with less exposure, had no green tongue or subjective complaints, and excreted no vanadium at a measurable level even in his mid-shift urine. No vanadium was detected in urine samples from other workers, nor in blood from all workers including workers 1 and 2. [R73] *IN AN EXPTL STUDY IN WHICH HUMANS WERE EXPOSED TO VANADIUM OXIDE DUST, WITH TESTS BEING RUN BEFORE, DURING, AND AFTER EXPOSURE, THE GREATEST AMOUNT OF VANADIUM WAS FOUND IN URINE 3 DAYS AFTER EXPOSURE; NONE WAS DETECTABLE AFTER A WEEK. FECAL VANADIUM WAS AT A MAX OF 0.003 MG/G; NONE WAS DETECTED AFTER 2 WK. [R68] *The distribution in mouse lung, kidney and liver was investigated by short term inhalation of vanadium pentoxide aerosol (80 mg/sq m as vanadium pentoxide, 1 hr), a single oral and a single ip administration of sodium vanadate (170 mumol/kg body weight as sodium vanadate. ... The highest distribution of vanadium was found in the lung in /the case of/ inhalation and in the kidney in case of oral and ip administration. ... Vanadium concentration in ... /lung, kidney, and liver/ tissues reached maximum value at 3 hr after administration and decreased rapidly within 18 hr, and then decreased slowly. /Sodium vanadate/ [R58] *The retention of soluble versus less soluble compounds of vanadium was evaluated in rat lungs after intratracheal instillation. Male Sprague-Dawley rats were injected intratracheally with ... preparations containing 0.2 mg of either radioactive vanadium pentoxide or sodium orthovanadate. ... Blood and organ samples /were/ obtained at 1, 7, and 28 days after treatment. ... Lungs treated with vanadium pentoxide retained 29, 22, and 13% of the injected compound at the three respective times after treatment. Radioactivity in liver remained relatively constant throughout the observation period of 28 days. Radioactivity increased between 1 and 28 days after treatment in spleen, bone, muscle, heart, brain, and testes, but not blood and kidneys, for which peaks were reached at 1 day following treatment. Lungs treated with orthovanadate retained only 11, 3, and 1% after 1, 7, and 28 days, respectively. Radioactivity levels declined rapidly within 1 day in every organ except brain, in which it remained at a constant low level. ... Disappearance of vanadium from the lungs is largely influenced by its initial chemical form, and that the low solubility of the pentoxide may determine its disposition. ... The relatively longer retention of vanadium pentoxide in lungs may have direct implications for pulmonary injury, including tracheobronchitis and bronchopneumonia, that has been reported to be induced by this compound. [R74] *When pregnant rats were injected with (48)V2O5, vanadium accumulated in the material bones, teeth, liver, renal cortex, lung, and mammary glands, as well as in the fetus. [R75] *Evaluated three groups of vanadium mining and process workers in Peru who had been employed for 1-10 yr. The control group (n=37) was not exposed to vanadium pentoxide in the workplace; the second group (n=39) was exposed to a low level of vanadium pentoxide ranging from 0.004-2.116 mg V/cu m; the third group (n=39) was exposed to a high level of vanadium pentoxide ranging from 0.078-58.82 mg v/cu m. ... Vanadium levels detected in the urine appeared to be significantlly higher in the workers occupationally exposed to high levels of vanadium pentoxide. Vanadium levels (median 0.017 mg/l) in the urine from workers exposed to low concentrations of vanadium pentoxide appeared similar to those levels (median 0.016 mg/l) in the urine from controls. Median V content in blood was 0.041, 0.036, and 0.031 mg/100 cc in high exposure, low exposure and the control groups, respectively. [R76] ACTN: *Vanadium pentoxide evoked rhythmic and tonic contractions of the normal and reserpinized rat isolated vas deferens. Vanadium induced contractions were blocked by calcium ion deprivation, nifedipine, magnesium ion, manganese ion, nickel ion, and cobalt ion, indicating the involvement of a loosely bound or extracellular calcium dependent mechanism. It is still unclear whether this calcium translocation was related, or not, to changes in sodium ion potassium ion dependent ATPase activity. Since ouabain blocked the action of vanadyl or vanadate noncompetitively, it is concluded that vanadium cmpd and ouabain induce their effects by interacting with different sites in vas deferens, both of which may or may not be located on the sodium ion, potassium ion dependent ATPase enzyme complex. [R77] INTC: *Intratracheal admin of vanadium pentoxide (V2O5) (0.2 LD50) or dust (1/16 LD50) suspended in physiological soln (12 times in 2 wk intervals) in rats inhibited the respiratory chain of liver mitochondria. Vitamin A alleviated part of this phenomenon, whereas vitamin C had only an insignificant beneficial effect on the respiration rate. [R78] *The effect of vanadium on bone metabolism was investigated in the femoral diaphysis of weanling rats. Vanadium pentoxide (1.0-20.0 mumol vanadium/100 g b wt) was administered orally for 3 days. The dose of 15.0 and 20.0 mumol vanadium/100 g caused a significant increase in serum calcium concentration. Bone alkaline phosphatase activity was increased significantly by the dose of 1.0-20.0 mumol vanadium/100 g, while bone acid phosphatase activity was not altered significantly. Bone DNA content was increased significantly by the dose of 1.0-10.0 mumol vanadium/100 g. Bone calcium content was not altered significantly by administration of vanadium. The increase in serum calcium concentration caused by administration of vanadium (20.0 mumol/100 g) was prevented completely by simultaneous injection of zinc sulfate (15.3 mumol zinc/100 g) for 3 days, although zinc alone did not have any effect. Administration of zinc (15.3 mumol/100 g) produced an appreciable increase in bone alkaline phosphate activity, DNA content, and calcium content. These increases were not enhanced significantly by simultaneous injection of vanadium (2.0 and 20.0 mumol vanadium/100 g). ... Zinc can prevent the /manifestation/ of the toxic effect of vanadium with higher doses /of vanadium./ [R79] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ WARN: *INGESTION OF VANADIUM COMPOUNDS (VANADIUM PENTOXIDE) FOR MEDICINAL PURPOSES PRODUCED GI DISTURBANCES, SLIGHT ABNORMALITIES OF CLINICAL CHEMISTRY RELATED TO RENAL FUNCTION, AND NERVOUS SYSTEM EFFECTS. [R80] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Although ores containing small amounts of vanadium are rather widely distributed throughout the world, the most important ones are found in the Western Hemisphere. During the 1970s domestic USA sources (mine production and recovery) have been largely confined to four states, Colorado, Arkansas, Idaho, AND Utah. The chief vanadium ores in uranium bearing sandstones are carnotite (K2O.2UO3.V2O5.3H2O), roscoelite (CaO.3V2O5.9H2O), and vanadinite (Pb(PbCl)(V2O4)). In all, more than 65 vanadium ores have been described, but all except 5 or 6 are of secondary origin formed by oxidation or weathering. Other potential sources are weathered shale, 1% vanadium pentoxide, and oil crudes, up to 3.72 ug vanadium/ml. [R4, 2013] ARTS: *... Flue gas deposits from oil fired furnaces may contain over 50% vanadium pentoxide. [R25, 2240] ATMC: *... The maximum concentration of vanadium pentoxide found in the breathing zone of workers at a steel plant was 0.078 mg/cu m (0.044 mg V/cu m); most values were less than 0.01 mg/cu m (0.0056 mg V/cu m). [R81] RTEX: *Occupational exposure to vanadium containing dusts is encountered in the mining of vanadium bearing ores. Most of the vanadium bearing ores in the United States come from Arkansas, Colorado, and Idaho while foreign sources include South Africa, Chile, and the USSR. In milling, exposure to vanadium containing dust can occur near the production sites of numerous vanadium compounds, particularly vanadium pentoxide and, to a lesser extent, the vanadates. Numerous exposures to vanadium compounds have occurred during the cleaning of oil fired burners, where the dust is generated from the residual oil ash of high vanadium content oil. [R82] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 4,468 workers (541 of these are female) are potentially exposed to vanadium pentoxide in the US(1). [R83] *Vanadium is present in all fuel oils and it remains in the residue after the more volatile fractions have been distilled. After combustion it appears as the pentoxide, which, when mixed with water, forms an acid solution irritating to the skin and eyes. The men who clean oil fired boilers and combustion chambers and the bricklayers who renew the firebrick linings are exposed to large amounts of dust, containing 6.1 to 12.7% of vanadium while those who clean the deposit on the outside of the heat exchanger tubes of gas turbines may be exposed to dust containing from 11-20% of vanadium. [R40, 344] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +35 mg/cu m (as V) [R22, 328] OSHA: +Permissible Exposure Limit: Table Z-1 Ceiling value: 0.5 mg/cu m. /Respirable dust, as V2O5/ [R84] +Permissible Exposure Limit: Table Z-1 Ceiling value: 0.1 mg/cu m. /Fume, as V2O5/ [R84] +Vacated 1989 OSHA PEL TWA 0.05 mg V2O5/cu m is still enforced in some states. /Vanadium dust, resp/ [R22, 373] +Vacated 1989 OSHA PEL Ceiling limit 0.05 mg V2O5/cu m is still enforced in some states. /Vanadium fume/ [R22, 373] NREC: +Recommended Exposure Limit: 15 Min Ceiling Value: 0.05 mg V/cu m. /Dust/ [R22, 328] TLV: +8 hr Time Weighted Average: 0.05 mg/cu m /Vanadium pentoxide, as V2O5, dust or fume; respirable fraction/ [R30, 2002.60] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Vanadium pentoxide, as V2O5, dust or fume; respirable fraction/ [R30, 2002.6] +A4; Not classifiable as a human carcinogen. /Vanadium pentoxide, as V2O5, dust or fume; respirable fraction/ [R30, 2002.60] +Biological Exposure Index (BEI): Determinant: vanadium in urine; Sampling Time: end of shift at end of workweek; BEI: 50 ug/g creatinine. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. [R30, 2002.94] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 7 ug/l /Vanadium/ [R85] +(FL) FLORIDA 49 ug/l /Vanadium/ [R85] +(MN) MINNESOTA 50 ug/l /Vanadium/ [R85] +(WI) WISCONSIN 30 ug/l /Vanadium/ [R85] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R86] RCRA: *P120; As stipulated in 40 CFR 261.33, when vanadium pentoxide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R87] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 7504: Analyte: vanadium pentoxide; Matrix: air; Sampler: cyclone + filter (10-mm nylon cyclone + 5-um polyvinylchloride membrane); Flow rate: 1.7 l/min; Vol: 200 l at 0.5 mg/cu m minimum, 1000 l maximum. [R88] ALAB: *AIR BY COLORIMETRY: SNELL FD, SNELL CT; COLORIMETRIC METHODS OF ANALYSIS 2: 3RD ED, D VAN NOSTRAND CO INC, PRINCETON, NJ, 1949. SPECTROPHOTOMETRY: DANIEL EP ET AL; IND ENG CHEM, ANAL ED 14: 921 (1942). [R89] *NIOSH 7504: Analyte: vanadium pentoxide; Matrix: air; Technique: X-ray powder diffraction; Range: 0.1 to 2 mg vanadium/sample. The method was evaluated using spiked and generated samples of vanadium pentoxide. With the spiked samples, using the 31.05 deg line and loadings of 433 to 699 ug/filter, the overall relative standard deviation was 8.3% with an avg bias of -7.3%. Five sets of generated samples, ranging from 184 to 2400 ug vanadium pentoxide per filter, gave an avg bias of 10.12% with a pooled relative standard deviation of 6.9%. The samples were generated using an aerosol which had been sized using a cyclone with characteristics similar to the 10 mm nylon cyclone; however, individual 10 mm nylon cyclones on the cassettes were not used. The 10 mm nylon cyclones must be tightly sealed and used carefully; otherwise, serious imprecision may be introduced. The method will determine vanadium pentoxide, vanadium trioxide, and ammonium metavanadate on the same sample. [R88] *NIOSH 7504: Analyte: vanadium pentoxide; Matrix: air; Technique: X-ray powder diffraction; Range: 0.1 to 2 mg vanadium/sample. The method was evaluated using spiked and generated samples of vanadium pentoxide. With the spiked samples, using the 31.05 deg line and loadings of 433 to 699 ug/filter, the overall relative standard deviation was 8.3% with an avg bias of -7.3%. Five sets of generated samples, ranging from 184 to 2400 ug vanadium pentoxide per filter, gave an avg bias of 10.12% with a pooled relative standard deviation of 6.9%. The samples were generated using an aerosol which had been sized using a cyclone with characteristics similar to the 10 mm nylon cyclone; however, individual 10 mm nylon cyclones on the cassettes were not used. The 10 mm nylon cyclones must be tightly sealed and used carefully; otherwise, serious imprecision may be introduced. The method will determine vanadium pentoxide, vanadium trioxide, and ammonium metavanadate on the same sample. [R88] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Nat'l Research Council Canada; Effects of Vanadium in the Canadian Environment (1980) NRCC No. 18132 NIOSH; Criteria Document: Vanadium (1980) DHEW Pub. NIOSH 77-222 Nechay BR; Ann Rev Pharmacol Toxicol 24: 501-24 (1984). Mechanisms of action concerning vanadium. DHHS/ATSDR; Toxicological Profile for Vanadium (1992) ATSDR/TP-91/30 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study on vanadium pentoxide is scheduled for peer review. Route: inhalation; Species: rats and mice. NTP TR No 507. [R90] SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1209 R2: CONSIDINE. CHEMICAL AND PROCESS TECHNOL ENCYC p.1128 (1974) R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 937 R4: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R5: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R6: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 971 R7: Catalyst composition for reduction of nitrogen oxides in fluel gas with ammonia; Jpn Kokai Tokkyo Patent 81 48248 05/01/81 (NGK Insulators, Ltd) R8: Hilliard HE; pp. 1447-66 in Minerals Yearbook, Vol 1 Metals and Minerals, United States Department of the Interior, Bureau of Mines (1992) R9: SRI R10: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1692 R11: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA27 380 R12: BUREAU OF MINES. MINERAL COMMODITY SUMMARIES P.176 (1989) R13: Bureau of Mines; Mineral Commodity Summaries p. 178 (1991) R14: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, p.2-94 (1984) R15: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 328 R16: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. B-140 R18: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-142 R19: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-151 R20: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 1105 R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-109 R22: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R23: Nat'l Research Council Canada; Effects of Vanadium in the Canadian Environment p.53 (1980) NRCC No. 18132 R24: Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995. 1146 R25: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R26: 49 CFR 171.2 (7/1/96) R27: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 228 R28: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6246 (1988) R29: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R30: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R31: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R32: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.620 R33: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 970 R34: NECHAY BR, SAUNDERS JP; J ENVIRON PATHOL TOXICOL 2 (2): 247-62 (1978) R35: Musk AW, Tees JG; Med J Aust 1 (Feb 20): 183-4 (1982) R36: Sjoberg SG; Acta Med Scand 154: 381-6 (1956) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 275 (1980) R37: Zenz C, Berg BA; Arch Env Health 14: 709-12 (1967) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 276 (1980) R38: Duthon WF; JAMA 1: 1648 (1911) as cited in NIOSH; Criteria Document: Vanadium p.21 (1977) DHEW Pub. NIOSH 77-222 R39: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986. R40: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. R41: Williams N; Br J Ind Med 9: 50-5 (1952) as cited in NIOSH; Criteria Document: Vanadium p.78 (1980) DHEW Pub. NIOSH 77-222 R42: Roshchin IV et al; Gig Tr Prof Zabal 28: 25-9 (1964) as cited in NIOSH; Criteria Document: Vanadium p.78 (1980) DHEW Pub. NIOSH 77-222 R43: McTurk et al; Ind Med Surg 25: 29-36 (1956) as cited in NIOSH; Criteria Document: Vanadium p.36 (1977) DHEW Pub. NIOSH 77-222 R44: Tebrock HE, Machle W; Occup Med 10: 692-6 (1968) as cited in USEPA; Health Assessment Document: Vanadium p.12 (1987) EPA-600/8-88-061 R45: Sjoberg SG; Am Med Assoc Arch Ind Health 11: 505-12 (1955) as cited in USEPA; Health Assessment Document: Vanadium p.11 (1987) EPA-600/8-88-061 R46: Levy BS et al; J Occupat Med 26 (8): 567-70 (1984) R47: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 914 R48: Kimbrough, R.D., P. Grandjean, D.D. Rutstein. Clinical Effects of Environmental Chemicals. New York, NY: Hemisphere Publishing Corp., 1989. 30 R49: Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. 826 R50: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 904 R51: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 2328 R52: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 75 R53: SHERIDAN CJ ET AL; ANNU RESP INHALATION TOXICOL RES INST (LOVELACE FOUND MED EDUC RES): 294-8 (1978) R54: Schiff LJ, Graham JA; Environ Res 34 (2): 390-402 (1984) R55: Yamaguchi M et al; Res Exp Med 189 (1): 47-53 (1989) R56: Mountain JT; Arch Ind Hyg Occup Med 8: 406 (1953) as cited in USEPA; Health Assessment Document: Vanadium p.7 (1987) EPA-600/8-88-061 R57: Zychlinski L; Bromatol Chem Toksykol 19 (1): 42-7 (1986) R58: Ueno S et al; Eisei Kagaku 33 (2): 129-35 (1987) R59: Labedzka A et al; Environ Res 48 (2): 255-74 (1989) R60: Knecht EA et al; Amer Rev Resp Dis 132 (6): 1181-5 (1985) R61: Brennan PC, Kirchner FR; Environ Res 37 (2): 452-60 (1985) R62: Czarnowski W; Bromatol Chem Toksykol 19 (2): 113-7 (1986) R63: Kugaczewska M et al; Bromatol Chem Toksykol 20 (3-4): 169-74 (1987) R64: Cempel M et al; Bromatol Chem Toksykol 18 (1): 41-5 (1985) R65: Hopkins LL, Mohr HE; Fed Proc 33 (6): 1773-5 (1974) as cited in Nat'l Research Council Canada; Effects of Vanadium in the Canadian Environment p.51 (1980) NRCC No. 18132 R66: Sugiura S; Shikoku Igaku Zasshi: 34 (5): 209-19 (1978) as cited in USEPA; Health Assessment Document: Vanadium p.9 (1987) EPA-600/8-88-061 R67: Kacew S et al; Toxicol Lett 11 (1-2): 119-24 (1982) R68: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 297 R69: Conklin AW et al; Toxicol Lett 11 (1-2): 199-204 (1982) R70: Kiviluoto M et al; Int Arch Occup Environ Health 48 (3): 251-6 (1981) R71: USEPA; Health Assessment Document: Vanadium p.4 (1987) EPA-600/8-88-061 R72: Rhoads K, Sanders CL; Environ Res 36 (2): 359-78 (1985) R73: Kawai T et al; Int Arch Occup Environ Health 61 (4): 283-7 (1989) R74: Sharma RP et al; Toxicol Indust Health 3 (3): 321-9 (1987) R75: Nat'l Research Council Canada; Effects of Vanadium in the Canadian Environment p.49 (1980) NRCC No. 18132 R76: Vintinner FJ et al; Am Med Assoc Arch Ind Health 12: 653-56 (1955) as cited in USEPA; Health Assessment Document: Vanadium p.12-13 (1987) EPA-600/8-88-061 R77: Garcia AG et al; Eur J Pharmacol 70 (1): 17-23 (1981) R78: Czarnowski W et al; Bromatol Chem Toksykol 15 (4): 279-85 (1982) R79: Yamaguchi M et al; Res Exp Med 189 (1): 47-54 (1989) R80: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 628 R81: Nat'l Research Council Canada; Effects of Vanadium in the Canadian Environment p.28 (1980) NRCC No. 18132 R82: NIOSH; Criteria Document: Vanadium p.18 (1977) DHEW Pub. NIOSH 77-222 R83: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R84: 29 CFR 1910.1000 (7/1/98) R85: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R86: 40 CFR 302.4 (7/1/96) R87: 40 CFR 261.33 (7/1/96) R88: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 7504-1 R89: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 665 R90: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 74 Record 107 of 1119 in HSDB (through 2003/06) AN: 1035 UD: 200211 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: VINYL-TOLUENE- SY: *BENZENE,-ETHENYLMETHYL-; *Methylethenylbenzene-; *METHYLSTYRENE-; *NCI-C56406-; *ALPHA,-BETA-STYRENE-; *STYRENE,-AR-METHYL-; *STYRENE,-METHYL-; *Tolylethylene-; *Vinyltoluene- RN: 25013-15-4 RELT: 6503 [4-VINYLTOLUENE] (Mixture Component) MF: *C9-H10 SHPN: UN 2618; Vinyl toluene inhibited (mixed isomers) IMO 3.3; Vinyl toluene inhibited (mixed isomers) STCC: 49 122 75; Vinyl toluene, inhibited ASCH: 2-Vinyltoluene; 611-15-4; 3-Vinyltoluene; 100-80-1 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Vinyltoluene is produced from ethylbenzene via zinc oxide catalyzed dehydrogenation reaction. [R1] *Vinyl toluene is commercially produced by the catalytic dehydrogenation of a mixture of 3-ethyltoluene and 4-ethyltoluene to the corresponding mixture of methylstyrenes, known commercially as vinyltoluene, and then polymerized to poly(vinyltoluene) [R2] *Toluene is alkylated with ethylene, and the resulting ethyltoluene is dehydrogenated to yield vinyltoluene. [R3, 386] *Toluene + ethylene (Friedel-Crafts alkylation/dehydrogenation) [R4] IMP: *Commercial vinyltoluene product: 99.2 wt% min, polymer, 25 ppm max; para-tert-butylcatechol (inhibitor), 10-15 ppm or 45-55 ppm [R5] FORM: *Usually occurs as a mixture of rarely the o-, and mainly the m- and p-isomers at 50 to 70% and 30 to 45%, respectively. [R6] *Typical chemical analysis of vinyltoluene: purity, 99.6% (by wt); polymer content, none; phenyl acetylene, 58 ppm; aldehydes as CHO, 10 ppm; peroxides as hydrogen peroxide, 5 ppm; chlorides as chloride, 5 ppm; TBC, 12 ppm; m-vinyltoluene 60% (by wt); p-vinyltoluene, 40% (by wt). [R7, 987] *A commercial vinyltoluene mixture of meta- and para-vinyltoluene, usually with 56-60 meta, 40-45% para and 1% ortho [R5] *Commercial vinyltoluene product: 99.2 wt% min, polymer, 25 ppm max; para- tert-butylcatechol (inhibitor), 10-15 ppm or 45-55 ppm [R5] MFS: *Deltech Corporation, Hq, 550 Route 206, Bedminster, NJ 07921, (908) 781-1100; Production site: Baton Rouge, LA 70800 [R8] OMIN: *Vinyltoluene, comprising a mixture of about 33% para- and 67% meta- methylstyrene, was marketed for about 30 yr by Dow Chemical and also by Cosden [R9] USE: *Polystyrene/alkyl/epoxy ester resin comonomer; reactive diluent (unsaturated polyester resins) [R3, 986] *Resin modifier in unsaturated polyester resins [R3, 986] *Block backing component for radioactive waste; as an insecticide component [R6] *Used to make copolymers with oil-modified alkyds for surface coatings [R10] *Vinyltoluene undergoes cross-linking when irradiated with UV light /to form polyvinyltoluene/. [R11] *Vinyltoluene is used in quick-dry coatings. [R12] *Reactive monomer; used in the coatings industry as a modifier for drying oils and oil-modified alkyds; used as a replacement for styrene in unsaturated polyester resins; used as a copolymer with styrene to increase the operating temperature range of paints, coatings and varnishes. [R13] CPAT: *APPROX 50% AS A CHEM INTERMED FOR UNSATURATED POLYESTER RESINS; APPROX 40% AS A CHEM INTERMED FOR ALKYD COATING RESINS; APPROX 10% AS A CHEM INTERMED FOR DRYING OILS (1976 EST) [R14] PRIE: U.S. PRODUCTION: *(1976) APPROX 2.27X10+10 G (EST) [R14] *NO DATA (1992) [R15] *Annual production is in the range of 18,000-23,000 tons/yr [R3, 386] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R4] ODOR: *Strong, disagreeable odor. [R16, 332] BP: *168 deg C [R4] MP: *-77 deg C [R4] MW: *118.18 [R4] CTP: *Critical temperature: 382 deg C; Critical pressure: 4.19 MPa [R7, 986] DEN: *0.890 @ 25 deg /25 deg C [R17] HTC: *-4816.54 kJ/mol of gas at constant pressure at 25 deg C [R7, 986] HTV: *426.10 J/g at 25 deg C; 349.24 J/g at boiling point [R7, 986] SOL: *Sol in methanol, ether [R18]; *Soluble in acetone, carbon tetrachloride, benzene, diethyl ether, n-heptane, ethanol [R19]; *Miscible with oxygenated solvents [R4]; *In water, 89 mg/l @ 25 deg C [R20] SPEC: *Index of refraction: 1.534 @ 34 deg C [R17] SURF: *31.66 dynes/cm @ 20 deg C [R7, 986] VAPD: *4.08 (air= 1) [R21, p. 325-13] VAP: *1.5 mm Hg @ 20 deg C [R22] VISC: *0.837 cP @ 20 deg C [R7, 986] OCPP: *Critical volume, 3.33 ml/g; critical density, 0.30 g/ml; specific heat of vapor, 1.2284 J/g deg K at 25 deg C; heat of formation, 115.48 kJ/mol of liquid at 25 deg C; heat of polymerization, +66.9 + or - 0.2 KJ/mol; shrinkage upon polymerization, 12.6% by vol; cubical coefficient of expansion, 9.361X10-4 at 20 deg C [R7, 986] *IR: 178 (Coblentz Society Spectral Collection); UV: 1-256 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York); MASS: 2022 (NIST/EPA/MSDC Mass Spectral Database, 1990 version); 450 (Atlas of Mass Spectral Data, John Wiley and Sons) /2-Vinyltoluene/ [R23, p. V1 959] *IR: 15063 (Sadtler Research Laboratories Prism Collection); UV: 4418 (Sadtler Research Laboratories Spectral Collection); MASS: 2023 (NIST/EPA/MSDC Mass Spectral Database, 1990 version); 185 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /3-Vinyltoluene/ [R23, p. V1 960] *Boiling Pt = 167.7 deg C (commercial mixture, meta and para), 169.8 deg C (ortho), 171.6 deg C (meta), 172.8 deg C (para); Density = 0.898 g/ml at 20 deg C (commercial mixture, meta and para), 0.904 g/ml at 20 deg C (ortho), 0.911 g/ml at 20 C (meta and para); Freezing pt = -77 deg C (commercial mixture); Conversion factor: mg/cu m = 4.83 x ppm [R5] *VP: 1.6 mm Hg [220 Pa] at 25 deg C /commercial mixture, meta and para- vinyltoluene/; 1.8 mm Hg [240 Pa] at 25 deg C /ortho and para-vinyltoluene/; 1.9 mm Hg [260 Pa] at 25 deg C /meta-vinyltoluene/; 1.1 mm Hg [147 Pa] at 20 deg C [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Vinyltoluene, inhibited/ [R24] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Vinyltoluene, inhibited/ [R24] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Vinyltoluene, inhibited/ [R24] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Vinyltoluene, inhibited/ [R24] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Vinyltoluene, inhibited/ [R24] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Vinyltoluene, inhibited/ [R24] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Vinyltoluene, inhibited/ [R24] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Vinyltoluene, inhibited/ [R24] FPOT: *Flammable when exposed to heat or flame. [R25] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R21, p. 325-93] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R21, p. 325-93] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R21, p. 325-93] FLMT: *Lower flammable limit: 0.8%; Upper flammable limit: 11% [R21, p. 325-93] FLPT: *60 deg C (open cup) [R26, 1991.1717] *60 deg C (Cleveland open-cup) [R19] AUTO: *1000 deg F (538 deg C) [R21, p. 325-93] FIRP: *USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. FIGHT FIRE FROM PROTECTED LOCATION OR MAXIMUM POSSIBLE DISTANCE. [R21, p. 49-137] *Evacuation: If fire becomes uncontrollable or container is exposed to direct flame; consider evacuation of one-third (1/3) mile radius. /Vinyltoluene, inhibited/ [R27] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. /Vinyltoluene, inhibited/ [R27] TOXC: *When heated to decomposition, it emits acrid smoke and irritating fumes. [R25] EXPL: *Explosive range in air 1.9 to 6.1% [R19] REAC: *Oxidizers, peroxides, strong acids, iron or aluminum salts [Note: Usually inhibited with tert-butyl catechol to prevent polymerization]. [R16, 332] DCMP: *When heated to decomposition, it emits acrid smoke and irritating fumes. [R25] POLY: *Hazardous polymerization may occur. [R21, p. 49-137] ODRT: *Odor low 240 mg/cu m; Odor high 240 mg/cu m; Irritating concn 240 mg/cu m. [R28] *Human subjects noted ... strong, objectionable odor at 300 ppm; and strong, tolerable odor at 200 ppm. At 50 ppm, the odor was detectable ... The odor was reported to be undetectable at less than 10 ppm. [R26, 1991.1719] SERI: *Eye and skin irritant. [R21, p. 49-137] *Vinyltoluene is a skin, nose, and eye irritant. [R29, 220] EQUP: *Wear appropriate chemical protective gloves, boots and goggles. /Vinyltoluene, inhibited/ [R30] *Wear appropriate personal protective clothing to prevent skin contact. [R16, 333] *Wear appropriate eye protection to prevent eye contact. [R16, 333] *Recommendations for respirator selection. Max concn for use: 400 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s). May require eye protection. Any powered, air-purifying respirator with organic vapor cartridge(s). May require eye protection. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R16, 333] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R16, 333] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R16, 333] OPRM: *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Vinyltoluene, inhibited/ [R27] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock-down vapors /Vinyltoluene, inhibited/ [R27] *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent ... eye contact. Employees should wash promptly when skin is wet or contaminated. Remove nonimpervious clothing promptly if wet or contaminated. [R31] *The worker should immediately wash the skin when it becomes contaminated. [R16, 333] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16, 333] *Contact lenses should not be worn when working with this chemical. [R16, 333] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R32] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R33] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R34] STRG: *Outside or detached storage is preferred. Store in a cool, dry, well-ventilated location. Store away from heat, oxidizing materials, and sunlight. Separate from acids, oxidizing materials, peroxides, and metal salts. [R21, p. 49-138] CLUP: *Absorb on paper. Evaporate on a glass or iron dish in hood. Burn the paper. [R35] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Incineration /is a suggested method of disposal/. [R31] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of vinyl toluene. There is evidence suggesting lack of carcinogenicity of vinyl toluene in experimental animals. Overall evaluation: Vinyl toluene is not classifiable as to its carcinogenicity to humans (Group 3). [R36] *A4; Not classifiable as a human carcinogen. [R37] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R38, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatic hydrocarbons and related compounds/ [R38, 182] *If vinyl toluene gets into the eyes, wash eyes immediately with large amounts of water, lifting the lower and upper lids occasionally. Get medical attention as soon as possible. Contact lenses should not be worn when working with this chemical. [R39] *If vinyl toluene gets in the skin, promptly flush the contaminated skin with water. If vinyl toluene soaks through the clothing, remove the clothing immediately and flush the skin with water. When there is skin irritation, get medical attention. [R39] *If a person breathes in large amounts of vinyl toluene, move the exposed person to fresh air at once. If breathing has stopped, perform artificial respiration. Keep the affected person warm and at rest. Get medical attention as soon as possible. [R39] *If vinyl toluene has been swallowed, do not induce vomiting. Get medical attention immediately. [R39] MEDS: *Employees should be screened for history of certain medical conditions which might place the employee at increased risk from vinyl toluene exposure. Kidney disease: Although vinyl toluene is not known as a kidney toxin in humans, the importance of this organ in the elimination of toxic substances justifies special consideration in those with possible impairment of renal function. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway disease, the breathing of vinyl toluene might cause exacerbation of symptoms due to its irritant properties or ... bronchospasm. Liver disease: Although vinyl toluene is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Skin disease: Vinyl toluene is a defatting agent and can cause dermatitis on prolonged exposure. Persons with pre-existing skin disorders may be more susceptible to the effects of this agent. [R39] HTOX: *VINYLTOLUENE (40% PARA-, 60% META-ISOMERS) WAS TESTED FOR POTENTIAL TO INDUCE CHROMOSOME ABERRATIONS AND SISTER CHROMATID EXCHANGE IN PHYTOHEMAGGLUTININ-STIMULATED HUMAN LYMPHOCYTES CULTURED FOR 48 HR (ABERRATION ANALYSIS) OR 72 HR (SISTER CHROMATID EXCHANGE ANALYSIS). THE TREATMENTS WERE CARRIED OUT 24 HR (ABERRATIONS) OR 48 HR (SISTER CHROMATID EXCHANGE) BEFORE HARVEST. THE TOXICITY OF VINYLTOLUENE WAS SIMILAR TO THAT OF STYRENE. CHROMOSOME ABERRATIONS WERE OBSERVED IN CELLS TREATED WITH 0.33 TO 4.00 MMOLAR VINYLTOLUENE. LIKE STYRENE, VINYLTOLUENE IS CONVERTED IN VITRO TO REACTIVE METABOLITES, PRESUMABLY EPOXIDES. [R40] *Human subjects noted ocular and upper respiratory tract irritation at a 400 ppm vinyl toluene concn; strong, objectionable odor at 300 ppm; and strong, tolerable odor at 200 ppm. At 50 ppm, the odor was detectable, but there was no irritation of mucous membranes. The odor was reported to be undetectable at less than 10 ppm. [R26, 1991.1719] *The main toxic effect of vinyl toluene is irritation of the eyes, upper respiratory tract, and skin. With prolonged and repeated contact and absorption of high doses, there may be depression of the central nervous system. [R39] *Central nervous system effects, such as depression, poor memory, slow visuomotor performance and electrophysiological changes, have often been associated with heavy occupational exposures to vinyl toluenes. Information is not available on human exposure to vinyl toluene alone. [R41] *... In human lymphocytes exposed in whole blood cultures, vinyl toluene induced both sister chromatid exchange and chromosomal aberrations in a dose-dependent manner, in the absence of exogenous metabolic activation. The induction of sister chromatid exchange was dependent on the number of erythrocytes present. Significant increases in the frequencies of sister chromatid exchange were observed in human lymphocytes exposed in whole blood cultures to ortho, meta and para isomer. The strongest responses were seen with the meta and para isomers, which are the dominant species in vinyl toluene. [R42] NTOX: *The single oral rat LD50 of a meta- and para-isomer mixture was 4 g/kg. When animals received 92 to 100 seven- to eight-hour inhalation exposures of the mixture at 1250 ppm, there was an increase in renal and hepatic weights and fatty degeneration of the liver. Some mortality occurred in exposed rats, but all guinea pigs, rabbits, and monkeys survived. Similar exposures at 600 ppm were well tolerated, and all animals appeared normal as judged by body weight gain, hematology, organ weight, gross and microscopic examination of tissues, blood urea nitrogen, and the results of qualitative urinanalyses. [R26, 1991.1717] *MALE C57BL/6 MICE WERE TREATED IP WITH SINGLE DOSE OF VINYLTOLUENE (100, 200, 300, OR 500 MG/KG BODY WT; 4-5 ANIMALS/GROUP) OR OLIVE OIL (CONTROLS). SIGNIFICANT INCR IN MICRONUCLEATED POLYCHROMATIC ERYTHROCYTES WAS OBSERVED AT 200, 300, and 500 MG/KG; AND AT 100, 200, and 300 MG/KG A SLIGHT DECREASE IN RATIO OF POLYCHROMATIC TO NORMOCHROMATIC ERYTHROCYTES WAS SEEN. THERE WAS NO INCREASE IN NORMOCHROMATIC CELLS WITH MICRONUCLEI. [R43] *SHORT-TERM EXPT WITH IP INJECTIONS OF VINYLTOLUENE IN RATS, MICE, AND CHINESE HAMSTERS SHOWED TIME- AND DOSE-DEPENDENT /DECREASES/ IN GLUTATHIONE CONTENT IN THE LIVER AND KIDNEYS. BOTH OVERALL DRUG OXIDN REACTIONS (O-DEETHYLATIONS OF ETHOXYCOUMARIN AND ETHOXYRESORUFIN) AND UDP-GLUCURONOSYLTRANSFERASE ACTIVITY IN LIVER WERE ENHANCED. THE HIGHEST DOSE (500 MG/KG) DECREASED ACUTELY (WITHIN 6 HR) CYTOCHROME P450 CONTENT AND 7-ETHOXYCOUMARIN O-DEETHYLASE ACTIVITY IN MOUSE LIVER MICROSOMES. THE MOUSE WAS MORE VULNERABLE THAN THE RAT TO VINYLTOLUENE-INDUCED DEPRESSION OF NONPROTEIN SULFHYDRYL GROUPS. [R44] *VINYLTOLUENE (72% PARA AND 28% ORTHO ISOMERS) EXHIBITED A /CNS DEPRESSANT/ EFFECT ... DURING EXPOSURE OF MICE, RATS, GUINEA PIGS, AND RABBITS BY VARIOUS ROUTES (ORAL, INHALATION, AND SKIN). DURING REPEATED EXPOSURE FOR 1 MO VINYLTOLUENE HAD SOME EFFECT ON THE CNS OF MICE, AND DURING CHRONIC INHALATION AT 0.03 MG/L IT CAUSED REDN IN WT OF MICE AND SYMPTOMS OF INTOXICATION IN THE OFFSPRING OF GUINEA PIGS. THE LIQUID FORM IRRITATED THE SKIN AND MUCOUS MEMBRANES OF EYES. [R45] *Vinyltoluene has been tested by application of a drop to rabbit eyes and found to cause slight transient conjunctival irritation, but no injury of the cornea demonstrable by staining with fluorescein. [R46] *Subchronic inhalation of 6 ppm (29 mg/cu m) by guinea pigs for 4 months produced teratogenic effects. /From table/ [R47] *In rats an inhalation exposure to vinyltoluene at concentrations of 100 and 300 ppm for 12 wk (6 hr/day 5 day/wk) decreased motor conduction velocity in the tail and also the amplitude of the evoked motor action potential, while no such changes occurred at 50 ppm. Changes in brain enzymes have also been reported in rats exposed to vinyltoluene inhalation. [R29, 221] *Vinyltoluene inhalation (1250 ppm, 7-8 hr/day for 92-100 days) increases kidney and liver weights and causes fatty degeneration /of these organs/ in rats, guinea pigs, rabbits, and monkeys. Exposure to 600 ppm did not cause any microscopic or macroscopic organ changes. A 12-wk inhalation admin of 300 ppm vinyl toluene causes slight increase in secondary lysosomes in the rat liver. [R29, 221] *An open field method to assess functional effects of low concentrations of solvent exposure in animals was tested. Male Sprague Dawley rats and male Wistar rats were exposed to 100 to 500 ppm solvent vapor in inhalation chambers for 4 days, 6 hours a day or for 4 to 15 weeks, 5 days a week, 6 hours a day. Some animals received perorally 15 to 20 percent ethanol in drinking water. After long term or short term exposures, animals were tested as naive or habituated to the open field. There were statistically significant behavioral changes in naive animals after short term exposure to vinyltoluene; to short and long term exposure to sytrene, ethylbenzene, and xylene and to long term but not short term exposure to turpentine. In habituated animals, statistically significant changes occurred from long and short term exposures to sytrene and ethanol only. Statistically significant changes in behavior occurred from long term but not short term exposures to xylene, xylene and ethanol, and possibly toluene. No behavioral changes occurred after short term or long term exposure to styrene or vinyltoluene. The time course and nature of the effects varied with the solvents. Habituation to the test situation increased the reliability of the method, but changed the nature and sensitivity of the test. It was concluded that the open field test sensitively indicates changes in spontaneous behavior especially when the situation is stressful or there is simultaneous ethanol treatment. [R48] *Vinyltoluene is a less volatile homolog of styrene, a neurotoxic chemical. Sixty male Wistar rats were exposed to vinyltoluene vapor at 50, 100 or 300 ppm solvent concentration 6 hr daily, 5 days a week for up to 15 weeks. Twenty control rats were similarly sham exposed. Motor conduction velocity of the tail nerve decreased significantly after exposure for 12 weeks to 100 or 300 ppm and the amplitude of evoked motor action potential decreased also. This effect was reproducible in another series of 15 rats exposed to similar concentrations for 11 weeks. Acid proteinase activity in the cerebral homogenate increased at 8 weeks in 300 ppm rats and at 15 weeks in 100 ppm rats. Succinate dehydrogenase activity was below the control range in all exposed groups. Two small protein fractions appeared in the electrophoretograms of axons taken from exposed rats at the end of the experiment. Electrophysiological changes typical of axonal degeneration and a change in the axonal proteins coincided in rats exposed to 100 or 300 ppm of vinyltoluene, while exposure to 50 ppm had no electrophysiological effects. [R49] *Male rats were exposed to vinyltoluene vapor after pretreatment with polychlorinated biphenyl. Brain and body solvent burdens were in a linear relationship to the exposure level although it changed between the two weeks while the solvent accumulated in the perirenal fat. The pretreatment caused a significantly smaller burden in the fat samples. Lysosomal acid proteinase was above the control range in the brain homogenate in the highest exposure, while glutathione peroxidase and 2',3'-cyclic nucleotide 3'-phosphohydrolase showed a dose-dependent decrease in the homogenate during the first week. Acid proteinase activity in the glial cells increased above the control range only in the polychlorinated biphenyl pretreated rats in the first week. Azoreductase increased in the glial cells above the control range only in the first week, and the pretreatment augmented the increase very significantly. All biochemical effects were largely abolished within two weeks of solvent-free period with the exception of an increase in the cerebral RNA at the highest dose level. Vinyltoluene can cause more pronounced neurochemical effects compared to styrene, xylene, or toluene at similar exposure levels. [R50] *Male rats were exposed by inhalation to vinyltoluene at 50, 100 or 300 ppm for 8, 12 or 15 wk. Vinyltoluene was metabolized to glutathione conjugates via the formation of electrophilic intermediates. This metabolic pathway was suggested by the decreased hepatic nonprotein SH content, with a concomitant increase in the urinary excretion of thioethers. The excretion of thioethers showed no saturation phenomena, suggesting that the formation of electrophilic intermediates capable of conjugating with glutathione was fairly linear, at least with exposure to vinyltoluene vapor up to 300 ppm. The slight increase in the activities of hepatic drug biotransformation enzymes (7-ethoxycoumarin O-deethylase, UDP-glucuronosyltransferase) observed after 8 wk of exposure to vinyltoluene vapor disappeared by wk 15 irrespective of the continued intermittent inhalation of vinyltoluene. Histological study revealed that /hepatocyte/ cell size had decreased in the rat exposed to vinyltoluene. [R51] *In male Sprague Dawley rats, motor and sensory conduction velocities of the tail nerve decreased significantly as a result of oral administration of 400 and 200 mg/kg of 2,5 hexanedione once daily, 5 days a week for up to 7 and 15 weeks, respectively; and of whole-body exposure to 300 ppm of vinyltoluene for 6 hr daily, 5 days a week for up to 21 weeks. Exposure to 100 ppm of vinyltoluene did not cause any significant impairment of tail nerve function throughout the 21 week exposure period. Significant changes in motor and sensory conduction velocities were consistently observed for weeks 4 and 2, respectively, in 2,5-hexanedione treated rats. Changes resulting from exposure to 300 ppm of vinyltoluene were reported intermittently from week 15. Significant linear relationships were established between the length of treatment with 2,5-hexanedione, length of exposure to 300 ppm of vinyltoluene, and the extent of impairment of tail nerve function. Structural damage of the sciatic nerves was only seen in 2,5-hexanedione treated rats. It is concluded that vinyltoluene can be regarded as an airborne chemical which leads to the development of a borderline experimental neuropathy at a level of 300 ppm. [R52] *The effects of vinyltoluene on nerve function was studied in rats. Male Wistar rats were exposed to 0, 50, 100, or 300 ppm vinyltoluene vapor 6 hr daily, 5 days a week for up to 15 weeks. Motor conduction velocities and evoked motor action potentials of the tail nerve were measured 4, 8, 12, or 15 weeks after exposure. Selected animals were killed at the same times. Myelin deprived axons from the spinal cord were isolated and were analyzed for protein composition by polyacrylamide disc gel electrophoresis. Motor conduction velocity and the amplitudes of the evoked motor action potential were significantly reduced by 100 or 300 ppm vinyltoluene after exposure for 12 weeks. No significant changes were seen before 12 weeks. Two small protein fractions appeared in the electrophoretograms of the exposed axons after 15 weeks of exposure. The 50 ppm vinyltoluene dose caused no electrophysiological effects. The results are consistent with an axonal type of nerve degeneration. The neurotoxic effects of vinyltoluene are more pronounced than those seen in previous studies with styrene. [R53] *Fifteen-Day Studies: Rats were exposed to 0, 200, 400, 800, or 1,300 ppm vinyl toluene, and mice were exposed to 0, 10, 25, 50, 100, or 200 ppm /by inhalation for 6 hr per day for 10 days over a 15-day period/. All rats lived to the end of the studies. The mean body weights at necropsy of rats exposed to 400-1,300 ppm were 13% -19% lower than that of controls for males and 9%-13% lower for females. Most male rats exposed to 1,300 ppm had centrilobular necrosis and focal inflammatory cell infiltration of the liver, whereas minimal centrilobular vacuolization of the liver was seen in all female rats exposed to 1,300 ppm. Dysplasia of the bronchial epithelial lining, chronic bronchitis, and lymphoid hyperplasia of the lung were observed in all rats exposed to 1,300 ppm. Three of five male mice exposed to 200 ppm vinyl toluene died before the end of the studies. Four of five male mice exposed to 200 ppm had moderate-to-severe hepatocellular necrosis; all female mice exposed to 200 ppm had hyperplasia of the epithelium of the intrapulmonary bronchi and centrilobular necrosis, vacuolization, and inflammatory cell infiltrates in the liver. [R54] *Thirteen-Week Studies: Rats were exposed to 0, 25, 60, 160, 400, or 1,000 ppm vinyl toluene /by inhalation for 6 hr per day, 5 days per week for 13 weeks (64 exposures)/. All rats lived to the end of the studies. The final mean body weights of rats exposed to 400-1,000 ppm were 8%-19% lower than that of controls for males and 6%-12% lower for females. Relative liver weights for rats at 1,000 ppm were significantly greater than those for controls. The severity of nephropathy was increased in male rats exposed to 160, 400, or 1,000 ppm. Compound-related lesions were not observed in female rats. Mice were exposed to 0, 10, 25, 60, or 160 ppm vinyl toluene /by inhalation, on the same schedule as of rats/. The final mean body weights of mice exposed to 25-160 ppm were 12%-20% lower than that of controls for males and 13%-16% lower for females. Inflamation of the lung was observed in 5/10 male and 3/9 female mice exposed to 160 ppm. Metaplasia of the nasal turbinates was seen in all exposed groups. [R55] *Vinyl toluene did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Vinyl toluene was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells in the absence of S9; it was not tested with S9. Vinyl toluene did not induce sister chromatid exchanges or chromosomal aberrations in CHO cells with or without S9. [R56] *Groups of 60 male and 60 female Swiss mice, six weeks old, were administered 0 (control), 10, 50, or 250 mg/kg body weight vinyl toluene (purity, > 99%; 96.8% para isomer and 3% meta isomer) by gastric intubation in olive oil once a day on five days a week for 78 weeks. The study was terminated at 83 weeks, when the survival rate was reduced to less than 50% in at least one group. There was no treatment-related effect on survival of female mice or on body weight in mice of either sex; survival of male mice was reduced in treated groups, but /it was/ concluded that both the chemical and amyloidosis were causal factors in the increased mortality (survival data not provided). There was no significant treatment-related increase in either the percentage of mice with malignant tumors or with benign and malignant tumors combined or in the number of malignant tumors per mouse. [R57] *Groups of 60 or 90 male and 60 or 90 female Sprague Dawley rats, six weeks old, were administered 10, 50, 250, or 500 mg/kg body weight vinyl toluene (purity, > 99%; 96.8% para isomer and 3% meta isomer) by gastric intubation in olive oil once a day on five days a week for 108 weeks. Control groups of 60 male and 60 female rats received olive oil alone. Five rats from the 500 mg/kg group were killed at 54 and 107 weeks. The study was terminated at 123 weeks when the survival rate was reduced to less than 50% in at least one group. Survival of male rats receiving 250 and 500 mg/kg body weight was reduced (exact data not provided). There was no treatment-related effect on survival in female rats or on body weights of male or female rats and no treatment-related increase in either the percentage of rats with malignant tumors or with benign and malignant tumors combined nor in the number of malignant tumors per rat. [R57] *Vinyl toluene was not mutagenic to Salmonella typhimurium. It did not induce sex-linked recessive lethal mutations in Drosophila melanogaster, treated either by feeding liquid vinyl toluene (up to 500 ppm (mg/kg) for one or three days) or by exposure to the gas at up to 300 ppm (1,450 mg/cu m) for five days. [R42] *Vinyl toluene induced forward mutations at the tk locus of mouse L5178Y lymphoma cells in the absence of an exogenous metabolic activation system, but only at a single, highly toxic dose. [R42] */Vinyl toluene/ induced neither sister chromatid exchange nor chromosomal aberrations in Chinese hamster ovary cells ... . [R42] *Vinyl toluene increased the frequency of micronuclei in mouse bone-marrow erythrocytes in vivo. [R42] *Results of long term carcinogenicity studies on styrene, styrene oxide, and para-methylstyrene in Sprague-Dawley rats and Swiss mice were presented. Styrene was admin to rats by inhalation, ingestion and injection. Styrene oxide was admin to rats by ingestion. para-Methylstyrene was admin to rats and mice by ingestion. Styrene exposure produced a higher incidence of total malignant tumors in the group exposed at 100 ppm by inhalation. This was not due to the increase of any specific type of tumor. A higher incidence of total benign and malignant mammary tumors and malignant mammary tumors was reported in the females of all groups exposed to styrene through inhalation. The incidence of malignant mammary tumors was treatment related. Lower incidence of total benign and malignant tumors and of total mammary tumors was noted in rats treated by ingestion at the highest dose level as a consequence of increased mortality. A dose related increase in total and malignant tumors was noted in groups treated with styrene oxide primarily due to forestomach neoplasias. In the forestomach, styrene oxide produced squamous cell carcinomas, papillomas, and acanthomas and precursor lesions. para-Methylstyrene was not shown to be carcinogenic. [R58] *Adult male rabbits were exposed to high concentratlons (750 ppm, 12 hr/day for 7 days of toluene, xylenes, styrene, ethylbenzene, vinyltoluene (3-methylstyrene), and 7-methyl-styrene vapors or were dosed with 4 mM/kg/day ip of hippuric, methylhippuric, mandelic, phenylglyoxylic, 7-methyl-mandelic acids. Styrene, vinyltoluene and ethylbenzene caused a marked depletion of striatal and tuberoinfundibular dopamine. Such an effect was also caused by treatment with phenylglyoxylic and mandelic acids. Dopamine depletion was associated with an increase in homovanilic acid concn in the same regions. These results indicate that dopamine metabolism is a target for the neurotoxic effects of some monocyclic aromatic hydrocarbons and their metabolites, a lateral vinyl or ethyl chain being crucial for the structure activity relationship of such compounds. [R59] *In male Sprague-Dawley rats, motor and sensory conduction velocities (MNCV and SNCV) of the tail nerve decreased significantly as a result of oral administration of 400 and 200 mg/kg of 2,5- hexanedione (2,5-HD) once daily, 5 days/week for up to 7 and 15 weeks, respectively; and of whole body exposure to 300 ppm of vinyl toluene for 6 hr daily, 5 days/wk for up to 21 weeks. Exposure to 100 ppm of vinyltoluene did not cause any significant impairment of tail nerve function throughout the 21 wk exposure period. Significant changes in MNCV and SNCV were consistently observed for weeks 4 and 2, respectively, in 2,5-hexanedione treated rats. Changes resulting from exposure to 300 ppm of vinyltoluene were reported intermittently from week 15. Significant linear relationships were established between the length of treatment with 2,5-hexanedione, length of exposure to 300 ppm of vinyltoluene, and the extent of impairment of tail nerve function. Structural damage of the sciatic nerves was only seen in 2,5-hexanedione treated rats. ... [R60] *Efforts were made to clarify the molecular basis of styrene toxicity on the dopaminergic systems and to evaluate whether the same mechanism was common to other solvents. Groups of male New Zealand rabbits were exposed to 750 ppm toluene, xylene, styrene, ethylbenzene, vinyltoluene, 7-methyl-styrene, or fresh air (control group). A significant depletion in both striatal and tubero infundibular dopamine was caused by styrene, ethylbenzene, and vinyltoluene. Methylation of the aromatic ring of styrene did not change its activity, whereas methylation of the side chain drastically reduced its effect on dopamine. Treatment carried out with the main metabolites of aromatic solvents indicated that acidic metabolites of some solvents caused striatal and tubero infundibular dopamine depletion. Present data suggested a chemical reaction between dopamine and some acidic metabolites. The active metabolites have an alpha-keto acid as the side chain or as a part of their molecule. These keto acids condense nonenzymatically with dopamine. [R61] NTXV: *LD50 Rat oral 4000 mg/kg; [R35] *LD50 Mouse oral 3.16 g/kg; [R47] *LD50 Rat oral 2255 mg/kg; [R25] *LD50 Rat ip 2324 mg/kg; [R25] NTP: *Nonneoplastic and Neoplastic Effects in the 2-Yr Studies: Groups of 49 or 50 rats of each sex were exposed to 0, 10, or 300 ppm vinyl toluene by inhalation, 6 hr/day, 5 days/wk for 103 wks. Groups of 50 mice of each sex were exposed to 0, 10, or 25 ppm on the same schedule. Degenerative and nonneoplastic proliferative lesions of the nasal mucosa were observed at increased incidences in exposed rats. These lesions included diffuse hyperplasia (goblet cell) of the respiratory epithelium with intraepithelial mucous cysts and focal erosion of the olfactory epithelium with cystic dilation (cysts) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homogenous eosinophilic cytoplasm in the olfactory epithelium occurred at increased incidences in exposed female rats. Neoplasms of the nasal mucosa were not seen in male or female rats. [R62] TCAT: ?Vinyl toluene (CAS # 25013-15-4, mixed isomers) was evaluated for chronic inhalation toxicity and carcinogenicity in F344/N rats (49 or 50/sex/group) administered whole body exposures to concentrations of 0 (chamber control), 100, or 300 ppm, 6 hours/day, 5 days/week, for 103 weeks. Upon terminal necropsy, all tissues were inspected for gross lesions with only high dose, control animals, and low dose animals dying within the first 21 months of treatment receiving full microscopic examination. Gross lesions from any dose group and specific target organs (nasal passage and lungs) from low dose groups were also examined for treatment-related histopathology. A prevalence analysis of Dinse and Lagakos was used to dissociate tumor incidence and mortality in logistic regression analysis of dose-response significance. Treatment had no apparent effect on survival in either males or females, but was associated with an average 4-11% depression in bodyweights (300 ppm males; 100, 300 ppm female). This report did not define statistical significance limits for these weight decrements. Degenerative and nonneoplastic proliferative changes of the nasal mucosa increased significantly (p < 0.05) in association with both treatment regimens relative to negative controls. Treatment-related non-neoplastic lesions of the olfactory epithelium included hyperplasia and eosinophilia (100, 300 ppm females), metaplasia (100 ppm males), erosion (100 ppm males), and cysts (300 ppm males and females); hyperplasia and cysts of the respiratory epithelium were significantly increased in all groups exposed to vinyl toluene. The authors noted in particular the erosion of olfactory epithelium along the dorsal meatus with replacement by respiratory epithelium, the olfactory Bowman's glands replaced by ciliated columnar cells. No neoplasms of the nasal passage were statistically attributable to treatment, and all other lesions in treated rats were within the range of historic or study controls. [R63] ?Vinyl toluene (CAS # 25013-15-4, mixed isomers) was evaluated for chronic inhalation toxicity and carcinogenicity in B6C3F1 mice (50/sex/group) administered whole body exposures to 0 (chamber control), 10, or 25 ppm, 6 hours/day, 5 days/week, for 103 weeks. Upon terminal necropsy, all tissues were inspected for gross lesions with only high dose, control animals, and low dose animals dying within the first 21 months of treatment receiving full microscopic examination. Gross lesions from all dose groups and the presumed target organs (nasal passage and lungs) from low dose groups were also examined for treatment-related histopathology. A prevalence analysis of Dinse and Lagakos was used to dissociate tumor incidence and mortality in logistic regression analysis of dose-response significance. Treatment had no apparent effect on survival in either males or females. The 25 ppm exposures were associated with an average 10-23% depression in bodyweights, while 10 ppm exposures generally reduced bodyweights less than 10%. This report did not define statistical significance limits for these weight decrements. Degenerative and inflammatory changes of the nasal mucosa and lungs/bronchioles increased significantly (p < 0.01) in all vinyl toluene groups relative to negative controls: Non- neoplastic lesions included hyperplasia of the nasal respiratory epithelium (replacement of olfactory epithelium Bowman's cells with ciliated columnar cells) and chronic active inflammation of both the nasal epithelium and the bronchioles. There was also evidence of neural atrophy in the submucosa of the nasal passage. No excess of neoplasms relative to controls was identified in the examined tissues of any treatment group. Rather, incidence of neoplasms of alveola/bronchiole and hematopoietic system in males and of the liver in females were significantly diminished in association with exposures to 25 ppm for 2 years. [R63] ADE: *The main exposure route is via inhalation. Minor routes of absorption are via the skin and gastrointestinal tract. [R29, 218] *Male Wistar rats inhaling 300 ppm (1,450 mg/cu m) vinyl toluene for one week or 50, 100, and 300 ppm (240, 480 and 1,450 mg/cu m) for 8-12 weeks showed a dose-dependent increase in the urinary excretion of thioethers. [R41] *After ortho-, meta- and para-vinyl toluenes were injected intraperitoneally into male albino Wistar rats, 11 urinary metabolites were distinguished /para-vinylbenzoic acid, para-vinylbenzoyl glycine, vinyltoluene-7,8-oxide, para-methylphenyl acetaldehyde, para-methylphenylacetic acid, para-methylphenylacetyl glycine, para-methylphenylethylene glycol, para-methylmandelic acid, para-methylbenzoic acid, para-methylphenylglyoxylic acid, para-methylbenzoyl glycine/. The main metabolites were similar to the corresponding styrene metabolites and included ethylene glycol, mandelic acid, glyoxylic acid derivatives and N-acetylcysteine and glucuronide conjugates. Over 90% of the recovered metabolites were excreted within 24 hours. N-Acetylcysteine derivatives substituted at carbon 8 greatly exceeded (> 80%) those substituted at carbon 9 in Sprague Dawley rats, in spite of steric hindrance by the methyl group. [R41] *At the dose of 50 mg/kg 55% of the dose was detected as urinary metabolites within 23 hr, mainly within the first 6 hr. The amounts of the excreted metabolites expressed as per cent of injected dose (250 mg/kg or 500 mg/kg) were lower than that caused by 50 mg/kg, and a noticeable amount of the total sums were excreted within 11-23 hr; this suggests that excretion was still continued with the dose of 250 and 500 mg/kg 23 hr after the injection. [R64] *Male rats were exposed to vinyltoluene vapor after pretreatment with polychlorinated biphenyl. Brain and body solvent burdens were in a linear relationship to the exposure level although it changed between the two weeks while the solvent accumulated in the perirenal fat. The pretreatment caused a significantly smaller burden in the fat samples. [R50] METB: *LIKE STYRENE, VINYLTOLUENE AND 4-METHOXY-BETA-CHLOROSTYRENE ARE CONVERTED IN VITRO TO REACTIVE METABOLITES, PRESUMABLY EPOXIDES. [R65] *Vinyltoluene is excreted mainly in urine in the form of its metabolites. The major metabolites which have been detected in rats after a single ip dose of vinyltoluene were p-methylmandelic acid, p-methylglyoxylic acid, p-methylebenzoic acid, p-methylbenzoylglycine, p-methylphenylacetylglycine, p-vinylbenzoylglycine, p-methylphenylacetic acid, p-methylphenylacetylglycine, p-vinylbenzoyl acid and thioethers (N-acetyl-S-(2-(p-tolyl-2-hydroxyethyl)) cysteine and N-acetyl-S-(1-(tolyl)-2-hydroxyethyl)cysteine). A large proportion of the metabolites were as thioethers at low doses of vinyltoluene than at high doses (50 mg/kg/body weight vs 350-500 mg/kg/body weight, when given ip). With the exception of p-vinylbenzoic acid and p-vinylbenzoylglycine all other metabolites are formed by cytochrome p450-dependent oxidation of vinyltoluene with vinyltoluene-7,8-oxide (p-methylphenylethylene-7,8-oxide) as an intermediate. [R29, 220] *Vinyltoluene binds in vitro to cytochrome p450 producing a type I spectral change with a spectral dissociation constant of 0.53 mM/nmol cytochrome p450 in rats. Vinyltoluene is mainly oxidized by a cytochrome p450-catalyzed mono-oxygenase system into p-vinyltoluene-7,8-oxide (p-methylphenylethylene oxide) which binds in vitro with nucleic acids, both with guanosine and with 4-(p-nitrobenzyl)-pyridine. p-Vinyltoluene formed its major alkyl adduct at N-7 guanosine. p-Vinyltoluene epoxide is either conjugated with glutathione or hydrolyzed by epoxide hydrolase for further conjugation. [R29, 218] *Both inhalation and ip administrations of vinyltoluene increase mono-oxygenase enzyme activities and UDP glucuronosyltransferase activity in the rat liver and also slightly in the rat and Chinese hamster kidneys, although changes were not always dose-dependent. Concomitantly with the depletion of hepatic glutathione there is an increase in urinary thioether excretion after vinyltoluene administration. [R29, 220] *Metabolism of vinyltoluene was studied in rats after injecting different doses of vinyltoluene. The main metabolites excreted in urine of rats after vinyltoluene treatment were thioethers, p-methylmandelic acid; p-methylphenylglyoxylic acid; p-methylbenzoyl glycine; p-methylphenylacetyl glycine; and p-vinylbenzoyl glycine. The highest excretion rate was obtained with doses of 50, 250 and 500 mg/kg within the 1st 6 hr. The dose of 500 mg/kg did not increase the excretion rates of these metabolites compared to the dose of 250 mg/kg, suggesting that the metabolic pathways begin to be saturated with the amount of 250 mg/kg. At the dose of 50 mg/kg 55% of the dose was detected as urinary metabolites within 23 hr, mainly within the first 6 hr. The amounts of the excreted metabolites expressed as per cent of injected dose (250 mg/kg or 500 mg/kg) were lower than that caused by 50 mg/kg, and a noticeable amount of the total sums were excreted within 11-23 hr; this suggests that excretion was still continued with the dose of 250 and 500 mg/kg 23 hr after the injection. The excretion of all analyzed metabolites of vinyltoluene was prevented by the pretreatment of the rats with 1-phenylimidazole, an inhibitor of cytochrome p450 monooxygenases. These metabolites were evidently formed as catalyzed by cytochrome p450. The structure of the analyzed metabolites suggest that the main reactive intermediate of vinyltoluene is vinyltoluene-7,8-oxide. The amounts of the excreted metabolites showed that the main detoxification pathways of vinyltoluene-7,8-oxide were the conjugation with reduced glutathione and hydration to diols. Pretreatment of the rats with polychlorinated biphenyl increased the excretion rates of metabolites. The polychlorinated biphenyl pretreatment rats excreted less thioethers (62%) compared to the rats treated only with the same amount of vinyltoluene whereas the total sum of the other metabolites was about the same in both groups. Polychlorinated biphenyl apparently change the metabolism of vinyltoluene to some other pathway which could be glucuronide because polychlorinated biphenyl increased the activity of UDP glucuronosyltransferae in a dose-dependent manner. [R64] *Male rats were exposed by inhalation to vinyltoluene at 50, 100 or 300 ppm for 8, 12 or 15 wk. Vinyltoluene was metabolized to glutathione conjugates via the formation of electrophilic intermediates. This metabolic pathway was suggested by the decreased hepatic nonprotein SH content, with a concomitant increase in the urinary excretion of thioethers. The excretion of thioethers showed no saturation phenomena, suggesting that the formation of electrophilic intermediates capable of conjugating with glutathione was fairly linear, at least with exposure to vinyltoluene vapor up to 300 ppm. The slight increase in the activities of hepatic drug biotransformation enzymes (7-ethoxycoumarin O-deethylase, UDP-glucuronosyltransferase) observed after 8 wk of exposure to vinyltoluene vapor disappeared by wk 15 irrespective of the continued intermittent inhalation of vinyltoluene. [R51] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Vinyl toluene's production and use as an comonomer and resin modifier may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 1.5 mm Hg at 20 deg C indicates vinyl toluene will exist solely as a vapor in the ambient atmosphere. Vapor-phase vinyl toluene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone; the half-lives for these reactions in air are estimated to be 7 and 2 hrs, respectively. Vinyl toluene may absorbs light in the environmental UV spectrum and has the potential for direct photolysis. If released to soil, vinyl toluene is expected to have low mobility based upon an estimated Koc of 820. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 2.6X10-3 atm-cu m/mole. Vinyl toluene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, vinyl toluene is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hr and 4 days, respectively. BCFs of 32 and 35 for the p- and m- isomers, respectively, suggest the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to vinyl toluene may occur through inhalation and dermal contact with this compound at workplaces where vinyl toluene is produced or used. Monitoring data indicate that the general population in some locations may be exposed to vinyl toluene via inhalation of contaminated air and ingestion of contaminated drinking water. (SRC) ARTS: *Vinyl toluene's production and use as an comonomer with styrene(1) and resin modifier in unsaturated polyester resins(2) may result in its release to the environment through various waste streams(SRC). Vinyl toluene isomers may also be released to the environment in engine exhaust, wood smoke and emissions from the combustion of polyethylene and polystyrene polymers(3-5). Exhaust gas from motor boat engines has been found to pollute waterways with vinyl toluene isomers(6). o-Vinyl toluene has been identified as a biodegradation product of o-ethyltoluene(7). [R66] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 820(SRC), determined from a structure estimation method(2), indicates that vinyl toluene is expected to have low mobility in soil(SRC). Volatilization of vinyl toluene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.6X10-3 atm-cu m/mole(SRC), derived from its vapor pressure, 1.5 mm Hg(2), and water solubility, 89 mg/l(3). The potential for volatilization of vinyl toluene from dry soil surfaces may exist(SRC) based upon its vapor pressure(2). [R67] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 820(SRC), determined from a structure estimation method(2), indicates that vinyl toluene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 2.6X10-3 atm-cu m/mole(SRC), derived from its vapor pressure, 1.5 mm Hg(2), and water solubility, 89 mg/l(3). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are 1 hrs and 4 days, respectively(SRC). According to a classification scheme(5), BCFs of 32 and 35 for the p- and m- isomers, respectively(6), suggest the potential for bioconcentration in aquatic organisms is moderate(SRC). [R68] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), vinyl toluene, which has a vapor pressure of 1.5 mm Hg at 20 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase vinyl toluene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC); the half-lives for these reactions in air are estimated to be 7 and 2 hrs, respectively(SRC), calculated from rate constants of 5.3X10-11 and 1.4X10-16 cu cm/molecule-sec, respectively at 25 deg C(SRC) derived using a structure estimation method(3). [R69] ABIO: *The rate constant for the vapor-phase reaction of vinyl toluene with photochemically-produced hydroxyl radicals has been estimated as 5.3X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 7 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of vinyl toluene with ozone has been estimated as 1.4X10-16 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 hrs at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). Vinyl toluene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). Vinyltoluene (m- and p- isomers) in organic solvents has been found to exhibit slight absorption of UV light in the environmentally significant range (wavelength > 290 nm)(4) which suggests that vinyltoluene may be susceptible to photolysis in the environment(SRC). [R70] BIOC: *Bioconcentration factors of 32 for p-vinyltoluene and 35 for m-vinyltoluene have been measured in goldfish(1). According to a classification scheme(2), these BCFs suggest bioconcentration in aquatic organisms is moderate(SRC). [R71] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for vinyl toluene can be estimated to be 820(SRC). According to a classification scheme(2), this estimated Koc value suggests that vinyl toluene is expected to have low mobility in soil(SRC). [R72] VWS: *The Henry's Law constant for vinyl toluene is estimated as 2.6X10-3 atm-cu m/mole(SRC) derived from its vapor pressure, 1.5 mm Hg(1), and water solubility, 89 mg/l(2). This Henry's Law constant indicates that vinyl toluene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 1 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4 days(SRC). Vinyl toluene's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of vinyl toluene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 1.5 mm Hg(1). [R73] WATC: *DRINKING WATER: Vinyltoluene (isomer not specified) was tentatively identified in drinking water collected from the Torresdale water treament plant in Philiadelphia, PA in Nov. 1976(1). Vinyltoluene (isomer not specified) has reportedly been found in drinking water in Germany(2). [R74] *SURFACE WATER: Vinyltoluene (isomer not specified) has been identified in water samples collected from the River Lee in Great Britian(1). Vinyltoluene (o-, m-, and p- isomers) was identified in water samples which were collected in Aug 1984 from Lake Constance (Germany) following a period of heavy boat traffic. The concentration of o-vinyltoluene in water samples collected throughout the day varied between 3-70 mg/l. Emissions from the motor boat engines were identified as the primary source of volatile organic compounds found in the water(2). [R75] EFFL: *o-Vinyltoluene was identified in concentrates of advanced waste water treatment plant effluents collected from plants in Lake Tahoe, CA in Oct 1974, Pomona, CA in Sept-Oct. 1974 and June 1975, and Orange County, CA in Feb 1976(1). Vinyltoluene (isomer not specified) has been detected in effluent from 6 out of 63 USA industrial plants at concentrations which ranged from < 10 to > 100 ug/l(2). Vinyltoluene has been detected in exhaust emissions from spark-ignition engines (o-, m-, and p-isomers)(3,4), wood smoke (m-isomer)(5), emissions from the incineration of polyethylene and polystyrene polymers (o-, m-, and p-isomers)(6,7) and volatile emissions from polychloroprene-based building materials (o-isomer)(8). [R76] ATMC: *o-Vinyltoluene has been identified in indoor air of homes in Washington, DC and Chicago, IL(1). Trace levels of vinyltoluene (isomer not specified) were detected in air samples collected in Nitro, WV during Sept 1977(2). [R77] PFAC: PLANT CONCENTRATIONS: *o-Vinyltoluene has been identified in the essential oil of a Mississippi salt marsh plant(1). [R78] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 25,353 workers (3,889 of these are female) are potentially exposed to vinyl toluene in the US(1). Occupational exposure to vinyl toluene may occur through inhalation and dermal contact with this compound at workplaces where vinyl toluene is produced or used(SRC). Monitoring data indicate that the general population in some locations may be exposed to vinyl toluene via inhalation of contaminated air(2,3) and ingestion of contaminated drinking water(4). [R79] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *400 ppm [R16, 332] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (480 mg/cu m). [R80] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 100 ppm (480 mg/cu m). [R16, 332] TLV: *8 hr Time Weighted Avg (TWA): 50 ppm; 15 min Short Term Exposure Limit (STEL): 100 ppm. [R37] *A4; Not classifiable as a human carcinogen. [R37] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Vinyl toluene is produced, as an intermediate or a final product, by process units covered under this subpart. [R81] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. [R82] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Vinyl toluene is included on this list. [R83] FDA: *Vinyl toluene is an indirect food additive for use only as a component of adhesives. [R84] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1501. Analyte: Vinyl toluene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.20 l/min. Sample Size: 10-24 liters. Shipment: No special precaution. Sample Stability: Not given. [R85] ALAB: *NIOSH Method 1501. Hydrocarbons, Aromatic. Analyte: Vinyl toluene Matrix: Air. Procedure: Gas Chromatography, flame ionization detection. For vinyl toluene this method has an estimated detection limit of 0.001 to 0.01 mg/sample. The precision/RSD is 0.008. Applicability: This method is for peak, ceiling and time-weighted average determination of aromatic hydrocarbons. Interferences: Alcohols, ketones, ethers, and halogenated hydrocarbons are possible interferences. [R85] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Health and Environmental Effects Profile for Methyl Styrenes (1987) ECAO-CIN-G006 O'Donoghue JL; p.127-37 in Neurotoxicity of Industrial and Commercial Chemicals; O'Donoghue JL, ed (1985). The toxic effects of toluene and styrene in humans and in experimental animals were reviewed. DHHS/NTP; Toxicology and Carcinogenesis Studies of Vinyl toluene (Mixed Isomers) in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 375 (1990) NIH Publication No. 90-2830 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V9 397 (1978) R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA13 256 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V24 (1997) R4: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 950 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 374 (1994) R6: Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley and Sons. New York, N.Y. (2001).,p. V4 315 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V22 (1997) R8: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 768 R9: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V23 270 R10: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 123 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V19 616 (1980) R12: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 41 (1978) R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 375 (1994) R14: SRI R15: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994. R16: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R17: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1172 R18: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.630 R19: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V21 794 (1983) R20: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V21 (1978) 770 R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R22: Weber RC et al; Vapor pressure distribution of selected organic chemicals. Cincinnati, OH: USEPA-600/2-81-021 p. 39 (1981) R23: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994. R24: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-130 R25: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3383 R26: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R27: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 1113 R28: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R29: Snyder, R. (ed.) Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume 1: Hydrocarbons. Amsterdam - New York - Oxford: Elsevier, 1987. R30: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1992.952 R31: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 926 R32: 49 CFR 171.2 (7/1/2000) R33: IATA. Dangerous Goods Regulations. 42nd Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2001. 241 R34: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3392 (1998) R35: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 556 R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 60 384 (1994) R37: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.60 R38: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R39: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R40: NORPPA H; CARCINOGENESIS (LOND) 2 (3): 237-42 (1981) R41: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 380 (1994) R42: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 382 (1994) R43: NORPPA H; TOXICOL LETT (AMST) 8 (4-5): 247-52 (1981) R44: HEINONEN T, VAINIO H; BIOCHEM PHARMACOL 29 (19): 2675-9 (1980) R45: KRYNSKAYA IL ET AL; GIG SANIT 34 (9): 40-5 (1969) R46: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 978 R47: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 1359 R48: Junnila MA; Proceedings of the Fourth Finnish Soviet Joint Symposium, Institute of Occupational Health, Helsinki p.98-105 (1984) R49: Seppalainen AM, Savolainen H; Neurotoxicology 3 (1): 36-43 (1982) R50: Savolainen H, Pfaffli P; Arch Environ Contam Toxicol 10 (4): 511-7 (1981) R51: Heinonen T et al; Acta Pharmacol Toxicol 51 (1): 69-75 (1982) R52: Gagnaite F et al; Toxicol Lett (AMST) 30 (1): 27-34 (1986) R53: Seppalainen AM, Savolainen H; Archives of Toxicology Supplement 5: 100-2 (1983) R54: DHHS/NTP; Toxicology and Carcinogenesis Studies of Vinyl toluene (Mixed Isomers) (65% - 71% meta-isomer and 32% - 35% para-isomer) in F344/N Rats and B6C3F1 Mice (Inhalation studies); p.3 (1990) Technical Report Series No. 375 NIH Pub No. 90-2830 R55: DHHS/NTP; Toxicology and Carinogenesis Studies of Vinyltoluene (Mixed Isomers) (65% - 71% meta-isomer and 32% - 35% para-isomer) in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.3,19 (1990) Technical Report Series No. 375 NIH Pub No. 90-2830 R56: DHHS/NTP; Toxicology and Carcinogenesis Studies of Vinyltoluene (Mixed Isomers) (65% - 71% meta-isomer and 32% - 35% para-isomer) in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.4 (1990) Technical Report Series No. 375 NIH Pub No. 90-2830 R57: IARC. 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V60 378 (1994) R58: Conti B et al; Ann NY Acad Sci 534: 203-34 (1988) R59: Romanelli A et al; J Appl Toxicol 6 (6): 431-6 (1986) R60: Nicot T et al; Toxicol Lett 30 (1): 27-34 (1986) R61: Mutti A; Toxicol 49 (1): 77-82 (1988) R62: DHHS/NTP; Toxicol and Carcinogenesis Studies of Vinyltoluene (mixed isomers) (65%-71% meta-isomer and 32%-35% para-isomer) in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.3-4 (1990) Technical Report Series No. 375 NIH Pub No. 90-2830 R63: Deltech Corp; NTP Technical Report on the Toxicology and Carcinogenesis Studies of Vinyl Toluene in F344/N Rats and B6C3F1 Mice (Inhalation Studies); 03/31/90; EPA Doc No. 86940000408; Fiche No. OTS0572511 R64: Heinonen T; Biochem Pharmacol 33 (10): 1585-94 (1984) R65: NORPPA H; CARCINOGENESIS 2 (3): 237-42 (1981) R66: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: WHO 60: 375 (1994) (2) Ozokwelu ED; Kirk-Othmer Encycl Chem Tech 4th ed. NY, NY: John Wiley and Sons 24: 386 (1997) (3) Fleming RD; Effect of Fuel Composition on Exhaust Emissions from a Spark-Ignition Engine NTIS PB 194942 (1970) (4) Kleindienst TE et al; Environ Sci Tech 20: 493-501 (1986) (5) Hawley-Fedder RA et al; J Chromatogr 314: 263-73 (1984) (6) Juttner F; Z Wasser Abwasser Forsch 21: 36-39 (1988) (7) Kappelar T, Wuhrmann K; Water Res 12: 335-42 (1978) R67: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Weber RC et al; Vapor pressure distribution of selected organic chemicals. Cincinnati, OH: USEPA-600/2-81-021 p. 39 (1981) (3) Lewis PJ et al; Kirk-Othmer Encycl Chem Tech. 3rd. NY, NY: Wiley 21: 770-801 (1978) R68: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Weber RC et al; Vapor pressure distribution of selected organic chemicals. Cincinnati, OH: USEPA-600/2-81-021 p. 39 (1981) (3) Lewis PJ et al; Kirk-Othmer Encycl Chem Tech. 3rd. NY, NY: Wiley 21: 770-801 (1978) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984) R69: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Weber RC et al; Vapor pressure distribution of selected organic chemicals. Cincinnati, OH: USEPA-600/2-81-021 p. 39 (1981) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R70: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (4) Atkinson R; Intern J Chem Kinet 19: 799-828 (1987) R71: (1) Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R72: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R73: (1) Weber RC et al; Vapor pressure distribution of selected organic chemicals. Cincinnati, OH: USEPA-600/2-81-021 p. 39 (1981) (2) Lewis PJ et al; Kirk-Othmer Encycl Chem Tech. 3rd. NY, NY: Wiley 21: 770-801 (1978) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R74: (1) Suffet IH et al; Water Res 14: 853-67 (1980) (2) Kool HJ et al; Crit Environ Control 12: 307-57 (1982) R75: (1) Waggott A; Chem Water Reuse 2: 55-99 (1981) (2) Juttner F; Z Wasser Abwasser Forsch 21: 36-39 (1988) R76: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol. 2. USEPA 600/1-84-020B. NTIS PB85- 128239 p. 180 (1984) (2) Perry DL et al; Identification of Organic Compounds in Industrial Effluent Discharges NTIS PB 294794 p. 42 (1979) (3) Fleming RD; Effect of Fuel Composition on Exhaust Emissions from a Spark-Ignition Engine NTIS PB 194942 (1970) (4) Fleming RD; Effect of Fuel Composition from a Spark- Ignition Engine Bartlesville, OK: US Bureau of Mines (1970) (5) Kleindienst TE et al; Environ Sci Tech 20: 493-501 (1986) (6) Hawley-Fedder RA et al; J Chromatogr 315: 201-10 (1984) (7) Hawley-Fedder RA et al; J Chromatogr 314: 263-73 (1984) (8) Kiselev AV et al; Chromatogr 17: 539-44 (1983) R77: (1) Jarke FM et al; ASHRAE Trans 87: 153-66 (1981) (2) Erickson MD, Pellizzari ED; Analysis of Organic Air Pollutants in the Kanawha Valley, WV and the Shenandoah Valley, VA. USEPA 903/9-78-007. NTIS PB 286141 pp. 17, 47 (1978) R78: (1) Mody NV et al; Phytochem 14: 599-601 (1975) R79: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Jarke FM et al; ASHRAE Trans 87: 153-66 (1981) (3) Erickson MD, Pellizzari ED; Analysis of Organic Air Pollutants in the Kanawha Valley, WV and the Shenandoah Valley, VA. USEPA 903/9-78-007. NTIS PB 286141 pp. 17, 47 (1978) (4) Suffet IH et al; Water Res 14: 853-67 (1980) R80: 29 CFR 1910.1000 (7/1/2001) R81: 40 CFR 60.489 (7/1/2001) R82: 40 CFR 712.30 (7/1/2001) R83: 40 CFR 716.120 (7/1/2001) R84: 21 CFR 175.105 (4/1/2001) R85: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 83 Record 108 of 1119 in HSDB (through 2003/06) AN: 1036 UD: 200211 RD: Reviewed by SRP on 12/10/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MONURON- SY: *3-(4-CHLOOR-FENYL)-1,1-DIMETHYLUREUM (DUTCH); *CHLOREA-; *CHLORFENIDIM-; *N-(4-CHLOROPHENYL)-N',N'-DIMETHYLUREA; *N-PARA-CHLOROPHENYL-N',N'-DIMETHYLUREA-; *1-PARA-CHLOROPHENYL-3,3-DIMETHYLUREA-; *3-PARA-CHLOROPHENYL-1,1-DIMETHYLUREA-; *1-(4-CHLOROPHENYL)-3,3-DIMETHYLUREA; *3-(4-CHLOROPHENYL)-1,1-DIMETHYLUREA; *1-(4-CHLORO PHENYL)-3,3-DIMETHYLUREE (FRENCH); *3-(4-CHLOR-PHENYL)-1,1-DIMETHYL-HARNSTOFF (GERMAN); *3-(4-CLORO-FENIL)-1,1-DIMETIL-UREA (ITALIAN); *CMU-; *CMU-WEEDKILLER-; *CNV-Weed-Killer-; *N,N-DIMETHYL-N'-(4-CHLOROPHENYL)UREA; *N-Dimethyl-N'-(4-chlorophenyl)urea; *1,1-DIMETHYL-3-(PARA-CHLOROPHENYL)UREA; *Karmex-W-; *KARMEX-MONURON-HERBICIDE-; *KARMEX-W-MONURON-HERBICIDE-; *LIROBETAREX-; *MONUROUN-; *MONUROX-; *MONUURON-; *NCI-C02846-; *Rosuran-; *TELVAR-MONURON-WEEDKILLER-; *TELVAR-W-MONURON-WEEDKILLER-; *UREA, N'-(4-CHLOROPHENYL)-N,N-DIMETHYL-; *UREA, 3-(P-CHLOROPHENYL)-1,1-DIMETHYL-; *Urea, 3-(4-Chlorophenyl)-1,1-dimethyl; *USAF-P-8-; *USAF-XR-41- RN: 150-68-5 MF: *C9-H11-Cl-N2-O ASCH: Monuron trichloroacetate; 140-41-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF P-CHLOROPHENYL ISOCYANATE WITH DIMETHYLAMINE [R1] *PREPD BY REACTING P-CHLOROPHENYL ISOCYANATE WITH DIMETHYLAMINE [R2] *p-Chloroaniline in dioxane or another inert solvent with anhydrous hydrogen chloride and phosgene at 70-75 deg C forms p-chlorophenyl isocyanate, which at 25 deg C with dimethylamine gives monuron. [R3] FORM: *WETTABLE POWDER (80% ACTIVE COMPONENT); WATER SUSPENSION 2.8 LB/GALLON ACTIVE INGREDIENT. [R4] *Wettable powder (800 g monuron/kg). Mixtures include: Urox, granular (55, 110 or 220 g monuron-TCA/kg), oil miscible liquid, oil/water miscible concentrate oil/water miscible concentrate, (monuron-TCA + 2,4-D) > . [R5, 585] *(Monuron +) amitrole. [R6] *Monuron is available in the US as a technical grade product, as a wettable powder containing @ 80% of the chemical and as granular formulations containing 2.4-8%. Granular formulations containing both monuron and trichloroacetic acid are also available, with several concentrations of each ai. [R7] OMIN: *RESIDUES OF 1-7 MG/KG WERE TOLERATED ON ... FRUITS AND VEGETABLES. AS OF JULY 1973 ... MONURON IS NO LONGER REGISTERED FOR USE ON ANY AGRICULTURAL CROP (US EPA, 1975). [R7] *... DIFFERENTIAL METAB IS ONE OF MAJOR FACTORS RESPONSIBLE FOR SELECTIVITY OF PHENYLUREA HERBICIDES. IN PARTICULAR, COTTON EXHIBITED REMARKABLE ABILITY TO DEGRADE MONURON ... IN CONTRAST TO CERTAIN MONOCOTYLEDONOUS PLANT SPECIES ... DIFFERENCES IN METAB ... BASED ON DIFFERENT RATES OF DEGRADATION AND NOT ON DIFFERENCES IN BIOCHEMICAL TRANSFORMATION PATHWAYS. [R8, 272] *IT IS RECOMMENDED @ 10 TO 30 KG AI/HA FOR TOTAL WEED CONTROL OF NON-CROP AREAS; 5 TO 10 KG AI/HA SUFFICES FOR ANNUAL MAINTENANCE. [R5, 584] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R9] *The only known use of monuron is as a broad-spectrum herbicide for the control of many grasses and herbaceous weeds on non-cropland areas, such as right-of-way, industrial sites and drainage ditch banks. [R10] *AS A SOIL STERILANT MONURON IS PREFERRED ON MEDIUM TO HEAVY SOILS AND UNDER INTERMEDIATE RAINFALL CONDITIONS. AT STERILANT DOSAGES IT CONTROLS A WIDE RANGE OF ANNUAL AND PERENNIAL GRASSES AND BROADLEAF WEEDS ON NONCROP AREAS. /FORMER USE/ [R11] *A plant growth regulator. [R12] *... Sugarcane flowering suppressant. [R12] CPAT: *100% AS HERBICIDE FOR USE ON CROPS (1971) [R1] PRIE: U.S. PRODUCTION: *(1971) 3.7X10+7 G (CONSUMPTION) [R1] *(1975) 9.1X10+7 G (CONSUMPTION) [R1] U.S. IMPORTS: *(1972) 5.1X10+7 G (PRINCPL CUSTMS DISTS) [R1] *(1975) 6.94X10+7 G (PRINCPL CUSTMS DISTS) [R1] *(1973) 6.5x10+7 g [R7] U.S. EXPORTS: *(1973) 4.5X10+7 g [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE PLATES FROM METHANOL [R13]; *THIN RECTANGULAR PRISMS FROM METHANOL [R2]; *Platelets [R14] ODOR: *SLIGHT ODOR [R2]; *Odorless solid [R12] MP: *170.5-171.5 DEG C [R2] MW: *198.65 [R2] CORR: *NON-CORROSIVE [R6] DEN: *1.27 @ 20 DEG C/20 DEG C [R5, 584] OWPC: *log Kow= 1.94 (est) [R15] PH: *6.26 SATURATED AQ SOLUTION [R2] SOL: *VERY SLIGHTLY SOL IN NUMBER 3 DIESEL OIL; MODERATELY SOL IN METHANOL, ETHANOL, PRACTICALLY INSOL IN HYDROCARBON SOLVENTS [R2]; *SLIGHTLY SOL IN OIL AND POLAR SOLVENTS [R16, 524]; *Solubility (ppm): water 230 (@ 25 deg C), acetone 52,000 (@ 27 deg C), benzene 2900 (@ 27 deg C) [R17]; *Sol in benzene: 3 g/kg at 27 deg C [R6] SPEC: *MAX ABSORPTION: 247 NM [R18]; *Intense mass spectral peaks: 72 m/z (100%), 198 m/z (19%), 73 m/z (7%), 200 m/z (6%) [R19]; *IR: 10667 (Sadtler Research Laboratories Prism Collection) [R20]; *UV: 20884 (Sadtler Research Laboratories Spectral Collection) [R20]; *NMR: 16056 (Sadtler Research Laboratories Spectral Collection) [R20]; *MASS: 161 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R20] VAP: *0.067 mPa @ 25 deg C [R5, 584] OCPP: *COMMERCIAL PRODUCT MELTS @ 176-177 DEG C [R2] *VAPOR PRESSURE: 178X10-5 MM HG @ 100 DEG C [R2] *DECOMP @ 185-200 DEG C [R4] *The rate of hydrolysis at room temp and pH 7 is negligible ... . [R5, 584] *Monuron-TCA is a crystalline solid; mp 78-81 deg C. Solubility (room temperature): 918 mg/l water; 400 g/kg 1,2-dichloroethane; 177 g/kg methanol; 91 g/kg xylene. It is acidic in reaction and incompatible with alkaline materials. /Monuron Trichloroacetate/ [R5, 584] *... Used at 10-15 kg/ha for total weed control of uncropped areas. /Monuron Trichloroacetate/ [R5, 584] *Henry's Law constant= 5.72X10-10 atm-cu m/mole (est). [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *... NON-FLAMMABLE. [R22] FIRP: *Self-contained breathing apparatus, rubber gloves, hats, suits, and boots must be worn. [R23] DCMP: *When heated to decomposition it emits very toxic fumes of oxides of nitrogen and /hydrogen/ chloride ions. [R24] EQUP: *PROTECT SKIN AND HAIR ... USE ONLY APPROVED RESPIRATORY PROTECTIVE EQUIPMENT, WHEN LABEL DIRECTIONS ADVISE NEED. /HERBICIDES/ [R25] *Wear rubber gloves for all handling. [R23] OPRM: *AVOID INHALING ANY DUST, SPRAY MIST AND STRONG VAPOR. /HERBICIDES/ [R25] SSL: *Negligible hydrolysis at room temp in neutral solutions. [R7] *STABLE TOWARDS MOISTURE AND OXIDATION @ ROOM TEMP [R22] *ELEVATED TEMP AND MORE ACID OR ALKALINE CONDITIONS APPRECIABLY RAISE RATE OF HYDROLYSIS [R2] *DRY FORMULATIONS ARE STABLE UNDER NORMAL STORAGE CONDITIONS [R11] *Stable toward oxygen and moisture under ordinary conditions at neutral pH. [R2] STRG: *Keep in well ventilated area. [R23] DISP: *Treatment at elevated temp by acid or base yields dimethylamine and 3,4-dichloroaniline. Hydrolysis is not recommended as a disposal procedure because of the generation of the toxic product, 3,4-dichloraniline and dimethylamine. Recommendable method: Incineration. Not recommendable method: Hydrolysis. Peer review: Incineration in a unit with effluent gas scrubbing is recommendable. (Peer-review conclusions of an IRPTC expert consultation May 1985)) [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No data were available from studies in humans. There is limited evidence in experimental animals for the carcinogenicity of monuron. Overall evaluation: Monuron is not classifiable as to its carcinogenicity to humans (Group 3). [R27] ANTR: *1. SKIN CONTAMINATION SHOULD BE REMOVED PROMPTLY BY WASHING WITH SOAP AND WATER. CONTAMINATION OF THE EYES SHOULD BE TREATED IMMEDIATELY BY PROLONGED FLUSHING OF THE EYES WITH COPIOUS AMOUNTS OF CLEAN WATER. IF DERMAL OR OCULAR IRRITATION PERSISTS, MEDICAL ATTENTION SHOULD BE OBTAINED WITHOUT DELAY. /OTHER HERBICIDES/ [R28] *2. INGESTIONS OF THESE HERBICIDES ARE LIKELY TO BE FOLLOWED BY VOMITING AND DIARRHEA DUE TO THE IRRITANT PROPERTIES OF MOST OF THE TOXICANTS. ... A. IF LARGE AMOUNTS OF HERBICIDE HAVE BEEN INGESTED, AND IF THE PATIENT IS FULLY ALERT, INDUCE EMESIS WITH SYRUP OF IPECAC, FOLLOWED BY SEVERAL GLASSES OF WATER. DOSAGE FOR ADULTS AND CHILDREN OVER 12 YEARS: 30 ML; DOSAGE FOR CHILDREN UNDER 12 YEARS 15 ML. WHEN VOMITING HAS STOPPED, GIVE ACTIVATED CHARCOAL. ADD SORBITOL TO THE CHARCOAL SLURRY UNLESS DIARRHEA HAS ALREADY COMMENCED. IF, FOR SOME REASON, THE PATIENT IS NOT FULLY ALERT, PUT IN PLACE A CUFFED ENDOTRACHEAL TUBE TO PROTECT THE AIRWAY, THEN ASPIRATE AND LAVAGE THE STOMACH WITH A SLURRY OF ACTIVATED CHARCOAL. LEAVE A QUANTITY OF CHARCOAL, WITH SORBITOL, IN THE STOMACH BEFORE WITHDRAWING THE STOMACH TUBE. REPEATED ADMINISTRATION OF CHARCOAL AT HALF OR MORE THE INITIAL DOSAGE EVERY 2-4 HOURS MAY BE BENEFICIAL. /OTHER HERBICIDES/ [R29] *2. B. IF THE AMOUNT OF INGESTED HERBICIDES WAS SMALL, IF EFFECTIVE EMESIS HAS ALREADY OCCURRED, OR IF TREATMENT IS DELAYED, ADMINISTER THE ACTIVATED CHARCOAL AND SORBITOL BY MOUTH. C. IF SERIOUS DEHYDRATION AND ELECTROLYTE DEPLETION HAVE OCCURRED AS A RESULT OF VOMITING AND DIARRHEA, MONITOR BLOOD ELECTROLYTES AND AND FLUID BALANCE AND ADMINISTER INTRAVENOUS INFUSIONS OF GLUCOSE, NORMAL SALINE RINGER'S SOLUTION, OR RINGER'S LACTATE TO RESTORE EXTRACELLULAR FLUID VOLUME AND ELECTROLYTES. FOLLOW THIS WITH ORAL NUTRIENTS AS SOON AS FLUIDS CAN BE RETAINED. FLUIDS SERVE TO SUPPORT EXCRETION OF THE TOXICANTS. D. SUPPORTIVE MEASURES ARE ORDINARILY SUFFICIENT FOR SUCCESSFUL MANAGEMENT OF EXCESSIVE EXPOSURES TO THESE HERBICIDES. /OTHER HERBICIDES/ [R29] NTOX: *OF LOW MAMMALIAN TOXICITY ... RATS FED WITH 500 MG/KG/DAY SURVIVED 10 TREATMENTS BUT SHOWED LOSS OF WT. RATS MAINTAINED FOR 6 WK ON DIET CONTAINING 0.5, 0.05 and 0.005% ... SHOWED DEPRESSED GROWTH EFFECTS @ 0.05% LEVEL. 33% PASTE NON-IRRITANT TO GUINEA PIGS WITH NO SIGNS OF SENSITIZATION. [R4] *FOUR GROUPS OF 30 MALE AND 30 FEMALE 4 WK OLD ALBINO RATS (ROCHESTER, EX-WISTAR) WERE FED DIETS CONTAINING 0 (CONTROL), 0.0025, 0.025 OR 0.25% MONURON FOR UP TO 2 YR. ... 24 TUMORS (MAINLY LYMPHOMAS AND MAMMARY FIBROADENOMAS) OCCURRED IN GROUP KILLED @ 2 YR, AND ABOUT 30 RATS DIED WITH TUMORS BEFORE 2 YR. TOTAL TUMOR INCIDENCE WAS REPORTED TO BE WITHIN RANGE OF THAT IN CONTROL RATS OF THAT COLONY. [R30] *... 50 RANDOM-BRED MALE RATS ... GIVEN 450 MG/KG MONURON IN FOOD DAILY FOR 18 MO ... TUMORS OCCURRED IN 14 RATS AND INCL 2 STOMACH TUMORS, 1 MALIGNANT TUMOR OF INTESTINE, 1 HEPATOMA, 2 LIVER CELL CARCINOMAS, 2 ALVEOLAR CARCINOMAS, 4 SMALL CELL CARCINOMAS OF LUNG AND 2 SEMINOMAS. ... NO TUMORS ... IN 50 CONTROLS ... . [R30] *... 25 C57BL MICE ... WERE GIVEN 6 MG/ANIMAL MONURON IN MILK BY STOMACH TUBE WEEKLY FOR 13 MO, AT WHICH TIME THE 25 SURVIVORS WERE KILLED. ... 7 HAD TUMORS, COMPRISING 1 LYMPHOMA OF THE INTESTINE, 2 HEPATOMAS, 2 LIVER CELL CARCINOMAS, 1 LUNG TUMOR, and 1 MALIGNANT KIDNEY TUMOR. ... ONE HEPATOMA OCCURRED AMONG C57BL CONTROLS ... . [R31] *... 25 RANDOM BRED ... MICE WERE GIVEN 6 MG/ANIMAL MONURON IN MILK BY STOMACH TUBE WEEKLY FOR 13 MO, AT WHICH TIME THE 23 SURVIVORS WERE KILLED. ... A TOTAL OF 13 TUMORS OCCURRED ... COMPRISING 1 STOMACH ADENOCARCINOMA, 4 HEPATOMAS, 4 HEPATOCELLULAR CARCINOMAS, 2 LUNG TUMORS AND 2 MALIGNANT KIDNEY TUMORS. ... NO TUMORS OCCURRED IN ... RANDOM-BRED CONTROLS ... . [R31] *... 18 MALE AND 18 FEMALE (C57BL/6XAKR)F1 MICE RECEIVED COMMERCIAL MONURON (95% PURE) ... 215 MG/KG BODY WT ... AT SEVEN DAYS OF AGE BY STOMACH TUBE AND THE SAME AMOUNT DAILY UP TO 4 WK OF AGE; SUBSEQUENTLY, THE MICE WERE GIVEN 517 MG/KG OF DIET. THE EXPERIMENT WAS TERMINATED WHEN THE MICE WERE ABOUT 78 WK OF AGE, AT WHICH TIME 16 and 17 MICE, RESPECTIVELY, WERE STILL ALIVE. ... TUMOR INCIDENCES WERE COMPARED WITH THOSE IN 90 /CONTROL/ NECROPSIED MICE OF EACH SEX. ... TUMORS OCCURRED IN 6/16 NECROPSIED MALES (6 LUNG ADENOMAS) AND 3/17 NECROPSIED FEMALES (1 RETICULUM CELL SARCOMA AND 2 LUNG ADENOMAS). TUMOR INCIDENCES WERE SIGNIFICANTLY DIFFERENT ONLY FOR LUNG ADENOMAS IN MALES ... (6/16 COMPARED WITH 9/90) ... . [R31] *REPEATED DOSES IN RATS PRODUCE ANEMIA. METHEMOGLOBINEMIA MAY OCCUR IF METABOLIC HYDROLYSIS PRODUCED P-CHLOROANILINE. [R32] *MONURON AND ITS CONGENERS INDUCED BACK MUTATIONS IN SALMONELLA TYPHIMURIUM (AMES TEST), MICRONUCLEI IN MOUSE BONE MARROW CELLS, AND INHIBITION OF TESTICULAR DNA SYNTHESIS (DSI TEST) IN MICE. [R33] *IN SHRIMP (PALAEMON ELEGANS) MONURON WAS NOT TOXIC AT 0.1 MG/L. TOXIC CONCENTRATIONS TO THE MOLLUSK CERASTODERMA LAMARCKI WERE TABULATED; MAXIMUM PERMISSIBLE CONCENTRATION OF MONURON WAS 0.00001 MG/L. [R34] *Monuron was not mutagenic in Salmonella strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254-induced rat liver S9. Monuron did induce chromosomal aberrations and sister chromatid exchanges in cultured Chinese hamster ovary cells. [R35, 88-2522] *Anemia and methemoglobinemia have been produced in experimental animals. [R2] *Phytotoxic. Contact with desired plants should be avoided. [R6] *Non irritating and non sensitizing to skin (guinea pigs) ... . [R6] *Female Sprague Dawley rats were given monuron (250-1000 mg/kg diet) for 14 mo. The final body wt was similar to those of controls. No treatment related effects on organ weights were observed at autopsy, except for a dose related increase in spleen wt. The proportion of hemoglobin in the form of methemoglobin increased in the dose group and resulted in a secondary anemia with changes in the morphology of erythrocytes. Hemoglobin adducts of aromatic amines released from the herbicide were present at dose related levels in rats treated with monuron. Compound related lesions were observed histologically in treated rats, with increased pigmentation (hemosiderin) in the spleen, reflecting the response to the hemolytic anemia and methemoglobinemia induced by the herbicides. Pigment deposition consisting of golden brown granules in the cytoplasm of the tubular epithelium in the kidney and in the Kupffer cells in the liver were observed. The hemotoxic effects that were observed may indicate that the formation of adducts between hemoglobin and the parent aromatic amines released metabolically has a role in the splenic toxicity of this compound. [R36] *A phage induction assay for screening chlorinated pesticides was described based on the Microscreen phage induction system. The pesticides tested included monuron. The Eschericia coli strains used were WP2S(lambda), which is a lambda lysogen of WP2S(trpE, uvrB), and SR714(trpE, uvrD3) as the indicator strain. Phage induction was tested with and without S9 activation by an assay of plaque formation. Monuron did not induce prophage. Monuron was positive in carcinogenicity in rodents but tested negative in both microbial assays. [R37] NTXV: *LD50 Rat oral 3600 mg monuron/kg; [R5, 584] *In diet: rats and dogs: no effect level: 250-500 ppm; [R38] ETXV: *LC50 BOBWHITE QUAIL GREATER THAN 5000 PPM/5 DAYS (AGE 17 DAYS, NO MORTALITY TO 5000 PPM); [R39] *LC50 JAPANESE QUAIL GREATER THAN 5000 PPM/5 DAYS (AGE 12 DAYS, NO MORTALITY AT 1250 PPM, 7% AT 2500 PPM, 21% AT 5000 PPM); [R39] *LC50 RING-NECKED PHEASANT 4682 PPM/5 DAYS (AGE 15 DAYS, 95% CONFIDENCE LIMIT 3902-5746 PPM); [R39] *LC50 MALLARD DUCK GREATER THAN 5000 PPM/5 DAYS (AGE 10 DAYS, NO MORTALITY AT 1250 PPM, 10% AT 2500 PPM, 10% AT 5000 PPM); [R39] *LC50 Japanese quail (Coturnix japonica), 14 days old, oral (5 day ad libitum in diet) > 5,000 ppm; [R40] NTP: *Carcinogenesis studies of monuron (greater than 99% pure), ... were conducted by feeding diets containing 0, 750, or 1,500 ppm monuron to groups of 50 F344/N rats of each sex ... for 103 wk. Survivors then were fed a control diet for 1 week, killed, and examined. Throughout most of the studies, mean body weights of dosed rats of each sex were lower than those of the controls. Survival rates of low dose female rats ... were increased relative to those of the controls. Nonneoplastic changes associated with the long-term administration of monuron to rats included renal tubular cell cytomegaly, mainly involving the proximal convoluted tubules in male and female rats, and dose-related hepatic cytoplasmic changes in male rats.In the 104 wk study, the kidneys and liver of male rats were the primary tissues affected. Under the conditions of these 2 yr feed studies, there was clear euidence of carcinogenicity for male F344/N rats in that monuron caused increased incidences of tubular cell adenocarcinomas of the kidney, tubular cell adenomas of the kidney, and neoplastic nodules or carcinomas (combined) of the liver. Monuron induced cytomegaly of the renal tubular epithelial cells in both male and female F344/N rats. [R41] *Carcinogenesis studies of monuron (greater than 99% pure), ... were connducted by feeding diets containing ... 0, 5000, or 10000 ppm to groups of 50 B6C3F1 mice of each sex for 103 weeks. Survivors then were fed a control diet for 1 week, killed, and examined. Throughout most of the studies, mean body weights of dosed ... mice of each sex were lower than those of the controls. Survival rates of ... high dose male and female mice were increased relative to those of the controls. In male mice, dose-related decreases occurred in the incidences of hepatocellular carcinomas (6/50 5/49; 2/50) and hepatocellular adenomas or carcinomas (12/50; 8/49; 6/50); incidences of hepatocellular tumors in low dose female mice were reduced, but the decreases were not dose related. The incidences of malignant lymphomas were reduced in dosed female mice (16/50; 8/50; 7/50). Under the conditions of these 2 year feed studies ... there was no evidence of carcinogenicity for female F344/N rats or for male or female B6C3FI mice. Monuron was not mutagenic in Salmonella strains TA98, TA100, TA1535, or TA1537 in the presence or absence of Aroclor 1254 induced rat liver S9. Monuron did induce chromosomal aberrations and sister chromatid exchanges in cultured Chinese hamster ovary cells. [R35, 88-252] ADE: *SUBSTITUTED UREAS ARE READILY ABSORBED BY PLANT ROOTS AND TRANSLOCATED TO ACCUMULATE IN LEAVES ... THEY DO NOT PENETRATE READILY THROUGH LEAVES. [R42, 51] *AFTER ADMIN OF 175 MG/KG BODY WT/DAY FOR 60 DAYS OR OF 0.1-20.0 MG/KG BODY WT FOR 6 MO, TISSUE RETENTION OF MONURON-RELATED SUBSTANCES OCCURRED /MOST/ IN LUNGS, /DECR RESPECTIVELY IN/ HEART, LIVER, BRAIN AND KIDNEYS, MILK, BONE MARROW AND THYROID GLAND. [R43] *IN RATS GIVEN 875 MG/KG BODY WT ORALLY, PEAK BLOOD CONCN OCCURRED 2 HR AFTER DOSING ... CMPD WAS DISTRIBUTED EVENLY THROUGHOUT BODY. [R43] METB: *3-(P-CHLOROPHENYL)-1,1-DIMETHYLUREA YIELDS IN COTTON 3-(P-CHLOROPHENYL)-1-HYDROXYMETHYL-1-METHYLUREA; ALSO YIELDS 3-(P-CHLOROPHENYL)-1-METHYLUREA. /FROM TABLE/ [R44] *COTTON PLANTS DEGRADED MONURON TO MONOMETHYLMONURON AND P-CHLORO-PHENYLUREA BY SUCCESSIVE DEMETHYLATIONS AND THEN TO P-CHLOROANILINE BY HYDROLYSIS OF AMIDE BOND. [R45] *IN MAMMALS, MONURON IS METABOLIZED (I) BY OXIDATIVE N-DEMETHYLATION, (II) BY HYDROXYLATION OF AROMATIC NUCLEUS AND (III) BY FISSION OF UREA RESIDUE TO GIVE CHLOROANILINE DERIVATIVES. [R43] *YIELDS OF VARIOUS METABOLITES INDICATE THAT HYDROXYLATION FAVORS 2-POSITION RATHER THAN 3-POSITION. PHENOLIC METABOLITES WERE EXCRETED IN URINE AS CONJUGATES. 4-CHLORO-2-HYDROXYANILINE WAS EXCRETED AS THE N-ACETYL CMPD 2-ACETAMINO-5-CHLOROPHENOL. [R43] *... URINARY METABOLITES ... IN RATS ARE N-(4-CHLOROPHENYL)-N'-METHYLUREA, N-(4-CHLOROPHENYL)UREA (14% OF DOSE), N-(2- HYDROXY-4-CHLOROPHENYL)-N',N'-DIMETHYLUREA, N-(2-HYDROXY-4-CHLO ROPHENYL)-N'-METHYLUREA (1.5%), N-(2-HYDROXY-4-CHLOROPHENYL)UREA (6.5%), 2-ACETAMINO-5-CHLOROPHENOL AND N-(3-HYDROXY-4-CHLOROPHENYL)UREA (2.2%). [R43] *N-Hydroxymethylation of monuron causes the formation of beta-D-glucoside, and other polar, unknown methanol-soluble metabolites and insoluble residues in higher plants. The terminal demethylation product is p-chlorophenylurea. [R46] */Undergoes/ ... metabolism via the liver microsomes. [R47] *Sweet orange seedlings took up monuron and metabolized it to 3-(4- chlorophenyl)-l-methylurea and 4-chlorophenylurea. Water soluble metabolites developed over the period of one day to 10 weeks of exposure. TLC, IR, MS and enzymatic hydrolysis indicated that monuron was conjugated with fructose. [R48] *Incubation of monuron with Rhizopus japonicus produced 1-(4-chlorophenyl)3-methylurea. [R49] *Young leaves were cut from 2 week old plants of bean (Phaseolus vulgaris var Black Valentine) and corn (Zea mays L. var. Batam Cross) and exposed to carbonyl-(l4)C-labeled monuron in water. After monuron uptake by the leaves, analyses showed the presence in both plants of: 1-(4-chlorophenyl)-3-methylurea; 4-chlorophenylurea; an unidentified conjugate: and l,l-dimethyl-3-(2-hydroxy-4-chlorophenyl) urea. Although the conjugates were not identified, these studies indicated the presence of a monuron-polypeptide larger than 5000 and three glucose conjugates. The latter were identified as mono-beta-D-glucose conjugates of 2-hydroxy-4-chlorophenylurea; l-(2-hydroxy-4-chlorophenyl)-3-methylurea; and l,l-dimethyl-3-(2-hydroxy-4-chlorophenyl) urea. [R49] ACTN: *SUBSTITUTED UREAS ... IN LEAVES ... CAUSE COLLAPSE OF PARENCHYMA VESSELS. ... THEY INHIBIT PHOTOSYNTHESIS ... AND ARE POWERFUL INHIBITORS OF OXIDATION OF WATER TO OXYGEN (HILL REACTION) ... SUGGESTED THAT MONURON BLOCKS PHOTOSYNTHESIS AT SITE OF ELECTRON TRANSFER BY FLAVIN MONONUCLEOTIDE ... . [R42, 51] INTC: *IN PRESENCE OF MODERATE AMT OF CARBARYL, DEGRADATION /OF MONURON IN COTTON PLANTS/ BEYOND MONO-DEMETHYLATION WAS INHIBITED. ... 4-BENZOTHIOPHENE-N-METHYLCARBAMATE WAS AS EFFECTIVE AS CARBARYL. [R45] *FLAVINS (FLAVINMONONUCLEOTIDE) HAVE BEEN SHOWN TO CAUSE PHOTOINACTIVATION OF PHENYLUREAS, SUCH AS MONURON, IN VITRO. [R42, 256] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Monuron is a herbicide recommended for use in non-crop areas for total control of weeds, and it would be released to the environment as a result of this use. Monuron's registration with EPA for use as a herbicide was cancelled in 1977, and therefore if its is still manufactured, it would be manufactured for export. In soil, monuron is transformed to its metabolites primarily by biodegradation. The half-life of monuron in field soils ranges from less than 30 days to 166 days. Monuron has a moderate mobility in most soils. Although biodegradation is slow, it is probably the major degradative pathway in water. Loss of monuron due to hydrolysis and volatilization will not be important processes. However, some loss may result due to photolysis in surface layers of water. Monuron is not expected to bioconcentrate in aquatic organisms. The reaction with hydroxyl radicals with an estimated half-life of 5.5 hr may be the most important loss process for vapor phase monuron in the atmosphere. Removal of atmospheric monuron may also occur by dry and wet deposition. Monuron is not registered for use in the US and therefore exposure of applicators, other workers to monuron will be limited. (SRC) NATS: *Monuron is not known to occur naturally(1). [R50] ARTS: *Since monuron is commercially produced and used as a herbicide(1), it will be released to the environment during the manufacture and particularly during the use of the herbicide(SRC). Accidental spills during loading/unloading and shipment will also release monuron in the environment(SRC). [R51] FATE: *TERRESTRIAL FATE: Biodegradation appears to be the major process by which monuron may be lost from most soils(1-2). The loss of monuron from soil surface by photolysis may account for a small fraction of loss of monuron as most of the monuron would move deeper into soil with rain(1). Volatilization loss of monuron from dry soil or wet soils should not be important(1). Monuron may moderately leach in most soils(3-4). Depending on the nature of soil and climatic conditions, the field half-life of monuron in soil range from less than 30 days to 166 days(5-7). [R52] *AQUATIC FATE: At low concns (on the order of ug/l), the major process for the loss of monuron from water appears to be biodegradation(1-2). Neither hydrolysis nor any other chemical reaction is important for the loss of monuron in water(1,3). Monuron may photolyze in surface layers of water where sunlight penterates(1). The photolysis half-life of monuron in aqueous solution by natural sunlight is estimated to be 15 days(4). Photolysis is accelerated by the presence of surfactants(5). Based upon the low vapor pressure(6) and high water solubility(7), monuron should not volatilize from water. Monuron is not expected to bioconcentrate in aquatic organisms(7). [R53] *ATMOSPHERIC FATE: Based upon on its vapor pressure, 5.03X10-7 mm Hg at 25 deg C(1), monuron is expected to be present partially in the vapor phase and partially in the particulate form in air(2,SRC). Vapor phase monuron will react with photochemically produced hydroxyl radicals with a half-life of 6.7 hr(3-4). Monuron may also be removed from the atmosphere by dry and wet deposition(SRC). [R54] BIOD: */INVESTIGATORS/ ... WERE ABLE TO ISOLATE FROM BROOKSTON SILTY CLAY LOAM A BACTERIUM OF GENUS PSEUDOMONAS WHICH UTILIZED MONURON AS SOLE SOURCE OF CARBON. [R8, 231] *Several pure cultures of bacteria including Pseudomonas, Xanthomonas, Sarcina, and Bacillus and fungi including Penicillium and Aspergillus are capable of degrading monuron(1-3). The major process for the loss of monuron from water is biodegradation(3). At a concentration of 6-7 mg/l, no loss of monuron by mixed microorganisms from river water and sewage was observed in 16 wk(5). However, in a soil-water system, appreciable biodegradation occurred after 16 weeks and 15% of monuron was recovered after 128 wk(4). At an initial concn of 10 ug/l in sewage water, monuron started to mineralize on day 45 and about 20% of monuron mineralized by day 84(6). No mineralization of monuron was observed in 84 days at a concn of 10 mg/l(6). Besides carbon dioxide, products with chromatographic characteristics of 4-(chlorophenyl)urea and 4-chloroaniline were also identified(6). [R55] *Monuron is lost from soil primarily through biodegradation(1,3). Monuron loss from two soils was about 40% in 22 wk at a concn of 4 ppm(1). In a clay loam soil, approx. 10% of monuron mineralized to carbon dioxide in 90 days(1). Hydroxylation products of monuron have been identified in soil(5). Except for most heavily treated soils (above 16 lbs/acre), approx. 90% of monuron disappeared in 1 yr. During the second year, loss averaged about 62%(3). Monuron's degradation is a function of application rate(2). Biodegradation is favored by high temperature adequate moisture and high soil organic matter content(2). When monuron was incubated with sediments from a pond under anaerobic conditions, no ring-substituted products were detected in 73 days(4). Therefore, monuron may persist in soil and sediments under anaerobic conditions(SRC). [R56] ABIO: *Monuron was stable in sterile aqueous solution at pH values normally found in natural waters(1). solution of monuron in the dark was found to be stable towards chemical reactions(2). The disappearance of monuron in soil by non-biological degradation was concluded to be unimportant in most cases(2). When a 88.3 ppm aqueous solution of monuron was exposed to sunlight, 83% loss was observed in 48 days(2). The half-life for the photodegradation of aqueous solution of monuron in natural sunlight has been estimated to be 15 days(5). Addition of surfactants enhanced the photolysis rate of monuron in solution(3). Five substituted biphenyl photoproducts were identified from the photolysis of monuron(4). Besides these biphenyl photoproducts, demethylated, completely monodemethylated, and a phenolic product, 3-(2-hydroxy-4-chlorophenyl)-1,1-dimethylurea have been isolated as photoproducts of monuron(6-7). [R57] *Based on an estimation method(1-2), the rate constant for reaction of monuron with hydroxyl radicals in the atmosphere is 3.8X10-11 cu cm/molecule-sec(SRC). If the 12 hr daylight average concentration of hydroxyl radicals in the atmosphre is assumed to be 1.5X10-6 radicals/cu cm(1), the half-life of this reaction would be 6.7 hr(SRC). [R58] *The 4-halogen substituent was replaced by hydroxyl when linuron and monuron wereexposed to sunlight in aqueous solutions; demethylation also occured. Monuron, on irradiation in water under aerobic conditions, gives 3-(4-chloro-2-hydroxyphenyl)-1,1-dimethylurea, together with 1,3-bis(p-chlorophenyl)urea and a number of oxidized and polymeric compounds. 1,3-Bis(p-chlorophenyl)urea may be formed by a reaction which proceeds via an ioscyanate intermediate; dimethylamine is eliminated from monuron to form p-chlorophenyl isocyanate, which can react with free p-chloroaniline. [R59] *When incubated with the fungus Cunninghamella echinulata Thaxter, monuron yielded 3-(4-chlorophenyl-methylurea and 4-chlorophenylurea. [R48] *UV irradiation of saturated aqueous solutions of monuron produced the following identified compounds: 3-(4-chlorophenyl)-1-formyl-1-methylurea; 3-(4-chlorophenyl)-1-methylurea; 3-(4-hydroxyphenyl)-1-formyl-methylurea; 4,4'-dichlorocarbanilide; 3-(4-hydroxyphenyl)-dimethylurea; 3-(4-chloro-2-hydroxyphenyl)- dimethylurea; the dimer, 3-[4-(N-(N',N'-dimethylaminocarbonyl)-4'-chloroanilino)phenyl]- dimethylurea; the p-hydroxy dimer; a dihydroxy dimer; the monodealkylated dimer; and tentatively a trimeric product. [R48] *Saturated aqueous solutions of monuron were treated with ferrous sulfdte + hydrogen peroxide (Fenton's reagent). Products were characterized spectroscopically: 3-(4-hydroxyphenyl)- dimethylurea; 4-chlorophenylurea; 3-(4-chlorophenyl)-1-methylurea; 4-chloro-2hydroxyphenylurea; 3-(4-chloro-2-hydroxyphenyl)-1-methylured; 3-(4- chloro-2-hydroxyphenyl)-dimethylurea; 4-chloro-2-henzoxazolinone; 4-chloro-2,4'-dihydroxycarbanilide; and 4-chloro-4'-hydroxycarbdnilide. [R48] BIOC: *From its water solubility and a regression equation, the bioconcentration factor (BCF) for monuron in aquatic organisms has been estimated to be 29(1). Based on a log Kow value of 1.94(2) and a regression equation(3), the BCF value can be estimated to be 17(SRC). Both these values indicate that bioconcentration of monuron in aquatic organisms should not be important(1,SRC). The low rate of uptake and fast depuration (depuration half-life of 0.45 days) of monuron from catfish (Ictalurus melas)(4) also indicates that bioconcentration will not be important(SRC). [R60] KOC: *The Koc values for monuron determined from experimental adsorption isotherms or estimated using recommended regression equations range from 83 to 225(1-6). According to a suggested classification scheme(9), Koc values of this magnitude indicate that monuron is moderately to highly mobile in soil. Soil thin layer chromatographic studies also indicate that monuron is moderately mobile in soil(5,7). The adsorption of monuron in soil is virtually independent of pH and clay content of soil, but the adsorption increases with increase in organic carbon content(6,8). However, other investigators concluded that the adsorption of monuron increases with an increase in the clay content of soil(10). [R61] VWS: *Volatilization from water should not be important transport process for monuron. Based on a value of Henry's Law constant of 5.72X10-10 atm-cu m/mole estimated from the ratio of vapor pressure(2) and water solubility(1), the volatilization half-life of monuron from a 1 m deep model river flowing at a speed of 1 m/sec and a wind speed of 5 m/sec is estimated to be about 165 yr(3,SRC). If the effect of sorption is considered, the half-life will be even longer. The volatilization half-life of monuron from 1 to 10 cm soil depth has been estimated to be about 160-170 days(4). The volatilization of monuron coevaporating with water vapor in soil was found to be insignificant(5). Therefore, the loss of monuron due to volatilization from both dry and wet soil should not be an important environmental fate process(SRC). [R62] WATC: *GROUNDWATER: Monuron was detected in one groundwater sample from a rural area in Ontario, Canada that was contaminated with the herbicide as a result of a spill(1). [R63] MILK: *IN RATS GIVEN 875 MG/KG BODY WT ORALLY, ... MONURON RELATED MATERIAL WAS ... SECRETED INTO MILK OF LACTATING ANIMALS. [R43] RTEX: *Monuron is not registered for use in the U.S. and therefore there should be no exposure of monuron by field applicators and formulators(SRC). If monuron is manufactured for export, occupational exposure of workers involved in manufacturing and loading monuron would most likely be through dermal contact. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Monuron is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0045; Pesticide type: Herbicide; Registration Standard Date: 06/30/83,07/01/83; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Monuron; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R9] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *PRODUCT ANALYSIS IS BY HYDROLYSIS AND TITRATION OF THE 4-CHLOROANILINE WITH PERCHLORIC ACID. RESIDUE ANALYSIS IS BY ALKALINE HYDROLYSIS, AND COLORIMETRIC DETERMINATION OF THE 4-CHLOROANILINE, BY GLC AND HPLC. [R6] *RAPID BIOLUMINESCENCE METHOD CAPABLE OF DETERMINING LOW CONCN OF PHOTOSYNTHESIS-INHIBITING HERBICIDES, SUCH AS MONURON, IN WATER AND SOIL ... . [R31] *Sample matrix: Specified fruit and vegetables. Sample preparation: Alkaline hydrolysis to release para-chloroaniline; diazotize; couple with N-(1-naphthyl) ethylene-diamine; clean-up and separate resulting dyes on cellulose column. Assay procedure: TLC. [R64] *Sample matrix: Residues. Sample preparation: Hydrolyse to para-chloroaniline using sodium hydroxide; distil; acidify distillate; wash with hexane or dichloromethane; neutralize; extract with hexane. Assay procedure: GC with FID. [R64] *COLORIMETRIC REACTION, SPECTROPHOTOMETRY @ 560 NM, FOR DETERMINATION OF MONURON. [R16, 525] *GC HAS BEEN USED TO DETERMINE MONURON AND ITS HYDROLOSIS PRODUCTS. ... TLC SCREENING TEST FOR PHENYLUREA HERBICIDES /INCLUDING MONURON/ THAT INHIBIT CERTAIN ENZYMIC ACTIVITIES /HAVE BEEN DESCRIBED/. [R10] *Product analysis of monuron is by hydrolysis and titration of the liberated amine and of monuron-TCA by infrared spectrometry. Residues of monuron may be determined by GLC. [R5, 585] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Monuron in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 266 (1988) NIH Publication No. 88-2522 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 985 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 319 (1980) R4: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 406 R5: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. R6: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A286/Aug 87 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 168 (1976) R8: Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975. R9: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.134 (Spring, 1998) EPA 738-R-98-002 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 169 (1976) R11: Farm Chemicals Handbook 1983. Willoughby, Ohio: Meister Publishing Co., 1983.,p. C-162 R12: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 797 R13: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-509 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 167 (1976) R15: Hansch C, Leo AJ; Medchem Project. Issue No 26. Claremont, CA: Pomona College (1985) R16: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R17: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 320 (1980) R18: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 812 R19: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 201 R20: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 416 R21: Worthing CR; The Pesticide Manual. 8th ed., The Lavenham Press Ltd. Lavenham, Suffolk p. 584-5 (1987) R22: Worthing, C. R. (ed.). Pesticide Manual. 6th ed. Worcestershire, England: British Crop Protection Council, l979. 368 R23: Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. 9:1 (1989) R24: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 757 R25: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 667 R26: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 296 R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 53 478 (1991) R28: MORGAN DP; RECOGNITION AND MANAGEMENT OF PESTICIDE POISONINGS. 4TH ED, P.87 EPA 540/9-88-001. WASHINGTON, DC: U.S. GOVERNMENT PRINTING OFFICE, MARCH 1989 R29: MORGAN DP; RECOGNITION AND MANAGEMENT OF PESTICIDE POISONINGS. 4TH ED, P.88 EPA540/9-88-001. WASHINGTON, DC: U.S. GOVERNMENT PRINTING OFFICE, MARCH 1989 R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 171 (1976) R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 170 (1976) R32: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-332 R33: SEILER JP; PESTIC BIOCHEM PHYSIOL 12 (2): 183 (1979) R34: KASYMOV AG ET AL; IZV AKAD NAUK AZ SSR, SER BIOL NAUK 4: 92 (1980) R35: DHHS/NTP; Toxicology and Carcinogenesis Studies of Monuron in F344/N Rats and B6C3F1 Mice (Feed Studies) p. 4 (1988) Technical Rpt Series No. 266 NIH Pub No. R36: Wang SW et al; Food Chem Toxicol 31 (4): 285-95 (1993) R37: Houk VS, DeMarini DM; Mutation Research 182 (4): 193-201 (1987) R38: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 383 R39: U.S. Department of the Interior, Fish and Wildlife Service, Bureau of Sports Fisheries and Wildlife. Lethal Dietary Toxicities of Environmental Pollutants to Birds. Special Scientific Report - Wildlife No. 191. Washington, DC: U.S. Government Printing Office, 1975.28 R40: Hill, E.F. and Camardese, M.B. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix. Fish and Wildlife Technical Report 2. Washington, DC: United States Department of Interior Fish and Wildlife Service, 1986.105 R41: DHHS/NTP; Toxicology and Carcinogenesis Studies of Monuron in F344/N Rats and B6C3F1 Mice (Feed Studies) p.4 (1988) Technical Rpt Series No. 266 NIH Pub No. 88-252 R42: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. R43: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 172 (1976) R44: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. C-40 R45: Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974.385 R46: Aizawa, H. Metabolic Maps of Pesticides. New York, NY: Academic Press, 1982. 124 R47: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. 1114 R48: Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 566 R49: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.298 R50: (1) IARC; IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Some Carbamates, Thiocarbamates and Carbazides, Vol 12. Lyon, France: Inter Agency Res Cancer p. 167-76 (1976) R51: (1) Worthing CR; The Pesticide Manual. 8th ed., The Lavenham Press Ltd. Lavenham, Suffolk p. 584-5 (1987) R52: (1) Hill GD et al; Agron J 47: 93-104 (1955) (2) Birk LA; Can J Agr Sci 35: 377-87 (1955) (3) Reinbold KA et al; Adsorption of Energy-related Organic Pollutants: A Literature Review, PB 80-105117, Springfield, VA: NTIS (1979) (4) Rhodes RC et al; J Agr Food Chem 18: 524-8 (1970) (5) Jury WA et al; Rev Environ Contam Toxicol 99: 119-64 (1987) (6) Domsch KH; Plant Soil 76: 367-78 (1984) (7) Haque R, Freed VH; Res Rev 52: 89-116 (1974) R53: (1) Hill GD et al; Agron J 47: 93-104 (1955) (2) Wang YS et al; J Agric Food Chem 33: 495-9 (1985) (3) El-Dib MA, Aly OA; Water Res 10: 1055-9 (1976) (4) Tanaka FS et al; Pestic Sci 16: 265-70 (1985) (5) Tanaka FS et al; J Agric Food Chem 29: 227-30 (1981) (6) Worthing CR; The Pesticides Manual. 8th ed., The Lavenham Press Ltd. Lavenham, Suffolk p. 584-5 (1987) (7) Bailey GW, White JL; Res Rev 32: 29-92 (1970) R54: (1) Worthing CR; The Pesticide Manual. 8th ed. The Lavenham Press Ltd. Lavenham, Suffolk p. 584-5 (1987) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-38 (1981) (3) Atkinson R; Environ Toxicol Chem 7: 435-42 (1988) (4) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R55: (1) Abel AL; World Crops 9: 328-30 (1957) (2) Murray DS et al; Weed Sci 17: 52-55 (1969) (3) Hill GD et al; Agron J 47: 93-104 (1955) (4) Frank PA; Weeds 14: 219-22 (1966) (5) El-Dib MA, Aly OA; Water Res 10: 1055-9 (1976) (6) Wang YS et al; J Agric Food Chem 33: 495-9 (1985) R56: (1) Hill GD et al; Agron J 47: 93-104 (1955) (2) Crafts AS, Drever H; Weeds 8: 12-8 (1960) (3) Birk LA; Can J Agr Sci 35: 377-87 (1955) (4) Attaway HH et al; J Environ Sci Health B17: 683-99 (1982) (5) Martin JP, Ervin JO; Decomposition and Transformation of Herbicides in Soils. Proc 22nd Ann. Calif Weed Conference. pp. 83-108 (1970) R57: (1) El-Dib MA, Aly OA; Water Res 10: 1055-9 (1976) (2) Hill GD et al; Agron J 47: 93-104 (1955) (3) Tanaka FS et al; J Agric Food Chem 29: 227-30 (1981) (4) Tanaka FS et al; Chemosphere 13: 927-32 (1984) (5) Tanaka FS et al; Pestic Sci 16: 265-70 (1985) (6) Crosby DG; pp. 835-90 in Herbicides 2nd ed. Kearney PC, Kaufman DD (eds), Vol 2. NY: Marcel Dekker, Inc (1976) (7) Marcheterre L et al; Rev Environ Contam Toxicol 103: 61-123 (1988) R58: (1) Atkinson R; Environ Toxicol Chem 7: 435-42 (1988) (2) Meylan WM, Howard PH; Chemosphere 2293-9 (1993) R59: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 321 (1980) R60: (1) Kenaga EE; Ecotox Environ Safety 4: 26-38 (1980) (2) Hansch C, Leo AJ; Medchem Project. Issue No 26. Claremont, CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods: Amer Chem Soc Washington, DC p. 5-5 (1990) (4) Ellegehau et al; Ecotox Environ Safety 4: 134-57 (1980) R61: (1) Kenaga EE; Ecotox Environ Safety 4: 26-38 (1980) (2) Rao PSC et al; Soil Crop Sci Soc Florida Proc 44: 1-8 (1985) (3) Gerstl Z, Helling S; J Environ Sci Health B22: 55-69 (1987) (4) Li W et al; Res J Water Pollut Control Fed 62: 16-26 (1990) (5) Reinbold KA et al; Adsorption of Energy-related Organic Pollutants: A Literature Review, PB 80-105117, Springfield, VA: NTIS (1979) (6) Hance RJ; Weed Res 5: 98-107 (1965) (7) Rhodes RC et al; J Agr Food Chem 18: 524-8 (1970) (8) Hance RJ; Can J Soil Sci 49: 357-64 (1969) (9) Swann RL et al; Res Rev 85: 17-28 (1983) (10) Helling CS; Soil Sci Soc Amer Proc 35: 743-8 (1971) R62: (1) Bailey GW, White JL; Res Rev 32: 29-92 (1970) (2) Worthing CR; The Pesticide Manual. 8th ed., The Lavenham Press Ltd. Lavenham, Suffolk p. 584-5 (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Amer Chem Soc Washington, DC p. 15-21 (1990) (4) Jury WA et al; J Environ Qual 13: 573-9 (1984) (5) Jury WA et al; Rev Environ Contam Toxicol 99: 119-64 (1987) R63: (1) Frank R et al; Arch Environ Contam Toxicol 16: 9-22 (1987) R64: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V53 468 (1991) RS: 47 Record 109 of 1119 in HSDB (through 2003/06) AN: 1097 UD: 200302 RD: SRP review on 08/03/1990 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,1'-AZOBIS(FORMAMIDE) SY: *ABFA-; *AZ-; *1,1'-AZOBISCARBAMIDE-; *AZOBISCARBONAMIDE-; *AZOBISCARBOXAMIDE-; *1,1'-AZOBISFORMAMIDE-; *AZODICARBAMIDE-; *AZODICARBOAMIDE-; *AZODICARBONAMIDE-; *AZODICARBOXAMIDE-; *AZODICARBOXYLIC-ACID-DIAMIDE-; *AZODIFORMAMIDE-; *1,1'-AZODIFORMAMIDE-; *DELTA(1,1')-BIUREA; *CELOGEN-AZ-; *CELOGEN-AZ-130-; *CELOGEN-AZ-199-; *CHKHZ-21-; *CHKHZ-21R-; *DIAZENEDICARBOXAMIDE-; *FICEL-EP-A-; *FORMAMIDE,-1,1'-AZOBIS-; *GENITRON-AC-; *GENITRON-AC-2-; *GENITRON-AC-4-; *GENITRON-EPC-; *KEMPORE-R-125-; *KEMPORE-60/40-; *KEMPORE-125-; *LUCEL-ADA-; *NCI-C55981-; *PINHOLE-ACR-3-; *PINHOLE-AK-2-; *PORAMID-K-1-; *POROFOR-505-; *POROFOR-ADC/R-; *POROFOR-CHKHZ-21-; *POROFOR-CHKHZ-21R-; *POROFOR-LK-1074- (BAYER); *UNIFOAM-AZ-; *UNIFOAM-AZH-25- RN: 123-77-3 MF: *C2-H4-N4-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF HYDRAZINE AND AN ALKALI CYANATE (OR UREA) FOLLOWED BY OXIDATION USING EITHER CHLORINE, CHROMIC ACID, A NITRATE IN THE PRESENCE OF A CATALYST, OR SODIUM CHLORATE IN THE PRESENCE OF AMMONIUM METAVANADATE [R1] FORM: *GRADES: TECHNICAL, FCC /FOOD CHEMICAL CODEX/ [R2] MFS: ?Avery, Inc, Hq, PO Box 2610, New Bruswick, NJ 08904; Uniroyal Chemical Company, Inc; Production site: Geisamer, AL 70734 [R3] ?Fairmont Chemical Company, Inc, 117 Blanchard Street, Newark, NJ 07105, (201) 344-5790 [R4] OMIN: *AMONG BLOWING AGENTS (SUBSTANCES EVOLVING NITROGEN OR CARBON DIOXIDE AND CAUSING SWELLING) ... AZODICARBONAMIDE (POROFOR-LK 1074, BAYER) EVOLVES NITROGEN FROM 190 DEG C UPWARDS. [R5, 149] *A FORMULATION WITH PYNAMIN 1 AND AZODICARBONAMIDE 5 G IN CONTAINER OF 100 G CALCIUM OXIDE AND 40 G WATER GAVE 86.7% VOLATILIZATION OF INSECTICIDE; 6.3% WITHOUT THE FOAMING AGENT. [R6] *BETA-WHITLOCKITE FOR DENTAL AND SURGICAL PROSTHETIC MATERIALS: SEDIMENT IS MIXED WITH EGG ALBUMIN AND AZODICARBOXAMIDE, LEFT OVERNIGHT, THEN SINTERED. THE CERAMIC WHEN IMPLANTED IN DOGS WAS RESORBED IN 2 MO, REPLACED BY DENSE BONE TISSUE. [R7] *IN FRANCE AZODICARBONAMIDE IS ON AUTHORIZED LISTS OF PRODUCTS WHICH MAY COME IN CONTACT WITH FOODSTUFFS AND IN USA IT MAY BE USED AS A FOOD ADDITIVE. [R5, 411] *MIXTURE OF A RODENTICIDE AND GAS-FORMING CMPD IS INDIRECTLY HEATED BY A THERMOGENIC CMPD; FUMIGANT FORMED IS FREE FROM FIRE HAZARD. MIXTURE CONTAINS WARFARIN, AZODICARBONAMIDE, AND HYDROXYPROPYLCELLULOSE. [R8] USE: *BLOWING AGENT FOR SYNTHETIC AND NATURAL RUBBER AND ETHYLENE-VINYL ACETATE COPOLYMERS; FOR POLY(VINYLCHLORIDE) CMPD AND THERMOPLASTIC URETHANE ELASTOMERS; FOR POLYOLEFIN RESINS; ACRYLIC AND ACETAL POLYMERS AND POLYETHYLENE; FOR ACRYLONITRILE-BUTADIENE-STYRENE RESINS AND HIGH IMPACT POLYSTYRENE SHEETING [R1] *AGING AND BLEACHING INGREDIENT IN CEREAL FLOUR,UP TO 45 PPM. [R9] *FOAMING AGENTS MAY BE ADDED TO INCR POROSITY OF PLASTICS WHICH NORMALLY FOAM OR TO CREATE FOAMED STRUCTURES FROM PLASTICS WHICH HAVE NO INHERENT FOAMING PROPERTIES. ... MOST COMMON COMMERCIAL CHEMICAL FOAMING AGENT IS AZOBISFORMAMIDE. [R10] *AZODICARBONAMIDE AND CYSTINE ARE USED IN IMPREGNATION SOLN FOR CATALYST PRODN FOR AUTO EXHAUST GAS PURGING. [R11] *... USED IN COMMERCIAL BAKING. [R12] *1,1-Azobis(formamide) is an indirect food additive polymer for use as a basic component of single and repeated use food contact surfaces. [R13] CPAT: *100% AS A BLOWING AGENT FOR VARIOUS POLYMERS (1975) [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 1.36X10+6 G [R1] *(1976) PROBABLY GREATER THAN 4.54X10+6 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Orange-red crystals [R14]; *YELLOW POWDER [R2] MP: *225 DEG C [R14] MW: *116.08 DEN: *1.65 @ 20 DEG C/20 DEG C [R2] SOL: *SLIGHTLY SOL IN ETHER; INSOL IN ORGANIC SOLVENTS [R15]; *SOL IN DIMETHYL SULFOXIDE [R2]; *Sol in hot water; insol in cold water, alcohol [R14] OCPP: *Hydrolyzes at high temperatures to nitrogen, carbon dioxide, and ammonia. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flammable [R14] DCMP: *... 1,1'-azobisformamide, which like all azo compounds yields nitrogen when heated to decomposition. [R16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: Azodicarbonamide is a synthetic chemical that exists at ambient temperatures as a yellow orange crystalline soild. It is poorly soluble in water. HUMAN EXPOSURE: Studies in humans have concentrated soley on the ability of this chemical to induce asthma and skin sensitization. Evidence that azodicarbonamide can induce asthma in humans has found from bronchial challenge studies with symptomatic individuals and from health evaluations of employees at workplaces where this cgemical is manufactured or used. On the basis that this chemical is a human asthmagen and the concentrations required to induce asthma in a non-sensitive individual or to provoke a response in a sensitive individual is unknown, it is concluded that there is a risk to human health under present occupational exposure conditions. Exposure of the general public to this chemical could notbe evaluated because of the lack of data. ANIMAL STUDIES: Toxicokinetic data on azodicarbonamide are limited, but the chemical appears to be well absorbed by the inhalation and oral routes of in rodents. Substantial quantities of the substance remain unabsorbed from the gastrointestinal tract and are passed out in the feces. The compound is readily converted to biurea (hydrazocarbonamide), the only breakdown product identified, and it is likely that systemic exposure is principally to this derivative rather than to the parent compound. Elimination of this compound and hydrazocarbonamide is rapid, occurring predominantly via the urine, and there is very little systemic retention of hydrazocarbonamide. Azodicarbonamide is of low acute toxicity and does not cause skin, eye or respiratory tract irritation in experimental animals. Results from a poorly conducted skin sensitization study were negative, and there was no evidence of an asthmatic type response in guinea pigs in one study. Repeated oral exposures resulted in the appearance of pyelonephritis with casts and crystalline deposits in renal tubuli in several species. The dose levels required to induce these effects were high. This compound was found to be a mutagen in bacterial systems, there was no evidence this effect would be expressed in vivo. The carcinogenicity and reproductive toxicity of azodicarboxamide have not been examined in detail, but no tumorigenic or antifertility effects were observed in early studies in which animals were treated wit the breakdown product hydrazocarbonamide. Developmental toxicity has not been studied. No observed effect concentrations (NOECs) for fish and the water flea have been reported. [R17] HTOX: *POSSIBLE PULMONARY REACTIVITY OF INHALED FINELY GROUND AZODICARBONAMIDE (EXPOSURE OF PLANT WORKERS TO RESPIRABLE DUST IN THE MG/CU M RANGE) IS DISCUSSED. [R18] NTOX: *AZODICARBONAMIDE (USED AS FLOUR-MATURING AGENT) DID NOT ALTER APPEARANCE, BEHAVIOR, GROWTH, FOOD EFFICIENCY, HEMATOLOGIC FINDING, BLOOD CHEM, AND URINE CHANGES IN DOGS AND RATS, MAINTAINED FOR 2 YR ON BREAD OR FLOUR TREATED WITH 10 TIMES THE NORMAL CONCN. [R19] *1-YR DIET LEVELS OF 5 and 10% CAUSED A SLIGHT DEPRESSION IN GROWTH, WT AND FOOD INTAKE IN MALE RATS, WHILE IN DOGS IT INDUCED RENAL PATHOLOGY WITHIN 4 MO AND DEATH IN 28-45 WK. DOGS HAD BIUREA CALCULI IN KIDNEY, URETERS AND BLADDERS (DOSE 1000 TIMES GREATER THAN THE USE LEVEL). [R19] *RATS GIVEN AZODICARBONAMIDE, 5 OR 10% OF THE DIET FOR 10 DAYS OR 4 WK HAD LOWER THYROIDAL IODINE UPTAKE AND SERUM PROTEIN BOUND IODINE THAN CONTROLS. IT HAD NO GOITROGENIC EFFECT, NOR DID IT INCR SERUM TSH. AMT ADMIN WERE MUCH HIGHER THAN THOSE USED IN COMMERCIAL BAKING. [R12] *Azodicarbonamide was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Azodicarbonamide was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.0333, 0.100, 0.3333, 1.000, 3.333, and 10.000 mg/plate. The lowest positive dose tested was 0.100 mg/plate in strain TA1535 without metabolic activation. A positive response was seen in strain TA100 at 0.3333 mg/plate without activation and at 1.000 mg/plate with activation. [R20] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *The food additive azodicarbonamide may be safely used in food in accordance with the following prescribed conditions: (a) It is used or intended for use: (1) As an aging and bleaching ingredient in cereal flour in an amount not to exceed 2.05 g per 100 lb of flour (0.0045 %; 45 ppm). (2) As a dough conditioner in bread baking in a total amount not to exceed 0.0045 % (45 ppm) by weight of the flour used, including any quantity of azodicarbonamide added to flour. [R21] FDA: *Tolerances are established for the food additive azodicarbonamide as an aging and bleaching ingredient in cereal flour and as a dough conditioner in bread baking. [R21] *Rubber articles intended for repeated use may be safely used in producing, manufacturing, packing, processing, preparing, treating, packaging, transporting or holding food, subject to the provisions of this section. Substances employed in the preparation of rubber articles include azodicarbonamide (total not to exceed 5 % by wt of rubber product) as a chemical blowing agent. [R13] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Azodicarbonamide is determined in air with increased sensitivity by treating the sample with alkaline Nessler reagent at room temperature, followed by spectrophotometric determination. [R22] *A HPLC method with UV detection was used for the determination of low mol wt amides in pharmaceutical matrixes. The method was based on Zorbax C8 or Alltech C18 column, mobile phase consisting of 3-5% MeCN in 0.1M phosphate buffer, and flow rate of 1-1.5 ml/min at the room temperature. By strongly retaining the sample matrix and allowing the amide analyte to elute, the method can be generally applied to many types of org matrix for pharmaceutical and agricultural products. /Amides/ [R23] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 110 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 935 R4: USITC. SYN ORG CHEM-U.S. PROD/SALES 1988 p.15-14 R5: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R6: KASHIHARA ET AL; FUMIGANT INSECTICIDE COMPOSITION CONTAINING FOAMING AGENTS; JP KOKAI TOKKYO KOHO PATENT 78109945 9/26/78 (EARTH CHEM CO, LTD) R7: JARCHO M, SALSBURY R; GER OFFEN PATENT 2855368 7/5/79 (STERLING DRUG, INC) R8: KASHIWARA ET AL; JPN KOKAI TOKKYO KOHO PATENT 80 43047 3/26/80 (EARTH CHEM CO, LTD) R9: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 797 R10: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 344 R11: SAKAI ET AL; IMPREGNATION SOLN FOR CATALYST PRODN FOR AUTO EXHAUST GAS PURGING, JPN KOKAI TOKKYO KOHO PATENT 79 78389 6/22/79 (MITSUI MINING AND SMELTING CO, LTD) R12: GAFFORD ET AL; J CLIN ENDOCRINOL METAB 32 (5): 659-62 (1971) R13: 21 CFR 177.2600(c)(4)(ix) (4/1/88) R14: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 132 R15: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-137 R16: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 23(83) 915 R17: World Health Organization/International Programme on Chemical Safety. Concise International Chemical Assessment Document No. 16. Azodicarbonamide p.4 (1999) R18: FERRIS ET AL; J OCCUP MED 19 (6): 424-5 (1977) R19: OSER ET AL; TOXICOL APPL PHARMACOL 7 (3): 445-72 (1965) R20: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R21: 21 CFR 172.806 (4/1/88) R22: Balis EP; USSR Patent No. 544892 (1/30/77) R23: Snorek SV et al; J Chromatog 458: 287-93 (1988) RS: 13 Record 110 of 1119 in HSDB (through 2003/06) AN: 1102 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-DICHLOROPROPANE- SY: *BICHLORURE-DE-PROPYLENE- (FRENCH); *ALPHA,BETA-DICHLOROPROPANE-; *Dichloro-1,2-propane-; *DWUCHLOROPROPAN- (POLISH); *ENT-15,406-; *Pesticide-Code-029002.-; *NCI-C55141-; *Propane,-1,2-dichloro-; *Propylenedichloride-; *ALPHA,BETA-PROPYLENE-DICHLORIDE- RN: 78-87-5 RELT: 6298 [DICHLOROPROPANE-DICHLOROPROPENE MIXTURE] (Mixture); 4341 [DICHLOROPROPANE] (Mixture) MF: *C3-H6-Cl2 SHPN: UN 1279; 1,2-Dichloropropane IMO 6.1; Propylene dichloride STCC: 49 092 69; Dichloropropane HAZN: U083; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Chlorination of propylene [R1] *From propyl chloride and antimony pentachloride [R2] *Action of chlorine on propylene [R3] IMP: *WATER-O.O5% MAX, OXYGEN COMPOUNDS-0.1% MAX [R4] FORM: *USEPA/OPP Pesticide Code 029002; Trade Names: Mixture, component of; Nemex, component of; Vidden D, component of; Vorlex, component of (with 029001 and 068103). [R5] *DOWFUME EB-5 (7.2% ETHYLENE DIBROMIDE, 29.5% PROPYLENE DICHLORIDE, 63.6% CARBON TETRACHLORIDE). EMULSIONS UP TO 100% ACTIVE INGREDIENT. [R6] *DICHLOROPROPANE, DISTILLED-MIN 99.5% [R4] *Telone 2 contains about 92% 1,3-dichloropropene and 3 to 5% 1,2-dichloropropane. [R7] *1,2-Dichloropropane has been marketed in combination with chloropicrin. [R8] *DOW-421 (4 PARTS O-DICHLOROBENZENE, 2 PARTS PROPYLENE DICHLORIDE, 1 PART ETHYLENE DICHLORIDE) [R9, p. III-141] *Grade: Refined [R3] *Reported as a component of insecticidal fumigants [R10] MFS: *Dow Chemical USA, 2030 Dow Center, Midland, MI 48674, (517) 832- 1150; Production sites: Freeport, TX 77541; Plaquemine, LA 70765 [R11] OMIN: *Production of 1,2-dichloropropane and of DD mixture has been discontinued by the Dow Chemical Co [R12] USE: *For 1,2-Dichloropropane (USEPA/OPP Pesticide Code: 029002) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R5] *Livestock (in DD mixt); solvent in plastics, resins, and metals indust, int in rubber processing [R1] *Oil and fat solvent; in dry cleaning fluids; in degreasing, in insecticidal fumigant mixtures. [R13] *Intermediate for perchloroethylene and carbon tetrachloride; lead scavenger for antiknock fluids; solvents for fats and oils, waxes, gums, and resins; solvent mixture for cellulose esters and ethers; scouring compounds; spotting agents; metal degreasing agents. [R3] *Soil fumigant for nematodes /Former use/ [R3] CPAT: *(For agricultural uses) 50% used alone as an insecticide for stored grain; 48% in DD mixture as an insecticide on crops; 2% in DD mixture as an insecticide for livestock and in other agricultural applications (DD mixture consists of 1,3-dichloropropene, 3,3-dichloropropene, 1,2-dichloropropane, 2,3-dichloropropene, and related C3 chlorinated hydrocarbons) (1975) /SRP: D-D no longer in production/ [R1] PRIE: U.S. PRODUCTION: *(1972) 1.85X10+10 G (SALES) [R1] *(1975) 3.82X10+10 G [R1] *(1980) 3.50X10+10 g [R14] *(1988) NO DATA PROVIDED [R15] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R3] ODOR: *Sweet [R16]; *Chloroform-like odor. [R17, 268] BP: *96.4 deg C; (-3.7 deg C at 10 mm Hg) [R18] MP: *-100.4 deg C [R18] MW: *112.99 [R13] CORR: *... It will attack some forms of plastics, rubber, and coatings. [R19, 1981.2] DEN: *1.159 @ 25 deg C/25 deg C [R13] HTC: *-7300 Btu/lb= -4100 cal/g= -170x10+5 J/kg (est) [R16] HTV: *8,428.5 g cal/g mole (multiply by 4.184 for J/g mole) [R20, p. C-671] OWPC: *log Kow = 1.98 [R21] SOL: *Sol in alcohol, ether, benzene and chloroform [R18]; *Miscible with org solvents [R13]; *In water, 2,800 mg/l @ 25 deg C [R22] SPEC: *Sadtler reference number: 3208 (IR, Prism); 10981 (IR, Grating); 30 (NMR, VARIAN) [R23]; *Index of refraction: 1.4388 at 20 deg C/D [R13]; *IR: 5994 (Coblentz Society Spectral Collection) [R24]; *NMR: 30 (Varian Associates NMR Spectra Catalogue) [R24]; *MS: NIST 3459 (NIST/EPA/MCDC Mass Spectral Database 1990 version); WILEY 370 (Atlas of Mass Spectral Data) [R24] SURF: *29 dynes/cm = 0.029 N/m at 20 deg C [R16] VAPD: *3.9 (AIR= 1) [R25] VAP: *53.3 mm Hg @ 25 deg C [R26] EVAP: *Greater than 1 (butyl acetate= 1) [R19, 1981.2] OCPP: *Wt/gal: 9.6 lb @ 20 deg C [R3] *Heat of Fusion: 13.53 cal/g (56.61 J/g; 6,396 J/mol) [R20, p. C-666] *Air pollution factors: 1 mg/cu m = 0.21 ppm, 1 ppm = 4.62 mg/cu m. Saturation concn: 258 g/cu m @ 20 deg C, 393 g/cu m @ 30 deg C [R25] *Henry's Law constant = 2.82X10-3 atm-cu m/mole @ 25 deg C [R27] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R28] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R28] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R28] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R28] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R28] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R28] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R28] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R28] FPOT: *DESPITE LOW FLASH POINT IT DOES NOT CATCH FIRE READILY IN INDUSTRIAL APPLICATIONS. [R29] *A flammable liquid and bery dangerous fire hazard when exposed to heat or flame. [R30, 2807] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R31, p. 325-82] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R31, p. 325-82] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R31, p. 325-82] FLMT: *Lower flammable limit: 3.4% by volume; Upper flammable limit: 14.5% by volume [R31, p. 325-82] FLPT: *60 deg F (16 deg C) (Closed cup) [R31, p. 325-82] AUTO: *1035 DEG F [R31, p. 325-82] TOXC: *Toxic gases and vapors (such as carbon monoxide and hydrogen chloride) may be released in a fire involving propylene dichloride. [R19, 1981.2] REAC: *Contact with ... strong acids may cause decomposition. ... With strong oxidizing agents may cause fires or explosions. [R19, 1981.2] *Orthodichlorobenzene had been mixed with ethylene dichloride and ... /1,2-propylene dichloride/. This mixture dissolved the oxide coating from the aluminum containing vessel. Subsequent reaction between the aluminum vessel and the chlorinated olefins caused rupture of the vessel. [R31, p. 491-14] *Strong oxidizers, strong acids, active metals. [R17, 268] *A virtually unvented aluminum tank containing a 4:1:2 mixture of o-dichlorobenzene, 1,2-dichloroethane, and 1,2-dichloropropane exploded violently 7 days after filling. [R32] *Reacts with aluminum to form aluminum chloride. This reaction, when confined, and lead to explosion. [R30, 2807] DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen chloride/. [R30, 2808] ODRT: *... Human subjects described the odor as "strong" at 130 to 190 ppm and "not noticeable" at 15 to 23 ppm. [R19, 1981.2] SERI: *Vapor is irritating to eyes, nose, and throat. ... Liquid is irritating to skin and eyes. [R16] EQUP: *... Rubber gloves, ... protective coveralls, and rubber footwear. [R16] *Breakthrough times for dichloropropane on chlorinated polyethylene are less (usually significantly) than one hour as reported by two or more testers. [R33] *Wear appropriate personal protective clothing to prevent skin contact. [R17, 269] *Wear appropriate eye protection to prevent eye contact. [R17, 269] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R17, 269] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R17, 269] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL at any detectable cocentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R17, 269] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R17, 269] OPRM: *Contact lenses should not be worn when working with this chemical. [R17, 269] *Employees should be provided with and required to use impervious clothing, gloves, face shields (8 inch min), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact ... . Clothing wet with liquid ... should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of propylene dichloride from the clothing. ... Any clothing which becomes wet with liquid .... should be removed immediately and not reworn until propylene dichloride is removed ... . Employees should be provided with and required to use splash-proof safety goggles where liquid ... may contact the eyes. [R19, 1981.4] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *The worker should immediately wash the skin when it becomes contaminated. [R17, 269] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R17, 269] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *Sensitive to heat. [R34] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R35] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R36] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R37] CLUP: *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be collected and atomized in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. Propylene dichloride should not be allowed to enter a confined space, such as a sewer, because of the possibility of an explosion. [R19, 1981.3] *1,2-Dichloropropane ... could be removed by several mechanisms, the most important being stripping, biodegradation, and a combination of each. [R38] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U083, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R39] *1,2-Dichloropropane is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Incineration, preferably after mixing with another combustible fuel, care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R40] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R41] *Propylene dichloride may be disposed of by atomizing in a suitable combustion chamber equipped with an appropriate gas cleaning device. [R19, 1981.3] *Due to their volatility and inflammability, 1,2-dichloropropane and dichloropropane-containing wastes cannot be dumped. They therefore have to be destroyed in special waste incinerators. Because of the high content of hydrogen chloride and possibly phosgene in the flue gases, extensive safety and cleaning precautions have to be taken. Dichloropropane-containing wastes are, therefore, generally burned /in international waters/. Recommendable methods: Incineration and evaporation. Peer review: Evaporation may be recommendable for small amounts. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R42] *Incineration: Dissolve in a combustible solvent, scatter the spray of the solution into the furnace with afterburner and alkali scrubber. [R42] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *IDENTIFICATION: 1,2-Dichloropropane is a liquid. It is soluble in water, ethanol, and ethyl ether. When heated, it emits highly toxic fumes of phosgene. 1,2-dichloropropane is used in furniture finish, dry cleaning fluid, and paint remover, gum processing, metal degreasing, oil processing, and as a rubber- and wax-making agent, and a chemical intermediate int he production of tetrachloroethylene and carbon tetrachloride. HUMAN EXPOSURE: Exposure of the general population to 1,2-dichloropropane via air and water is unlikely, except in areas where there is extensive use of 1,2-dichloropropane and "MIX D/D" in agriculture. The risk to the general population is negligible. Several cases of acute poisoning have been reported due to accidental or intentional (suicide) over-exposure to 1,2-dichloropropane. Effects have been mainly on the central nervous system, liver, and kidneys. Hemolytic anemia and disseminated intravascular coagulation have also been reported. In one case, delirium progressed to irreversible shock, cardiac failure, and death. Occupational exposures can be via both skin and inhalation. Several cases of dermatitis and skin sensitization have been reported in workers using solvent mixtures containing 1,2-dichloropropane. ANIMAL STUDIES: The acute oral toxicity of 1,2-dichloropropane in experimental animals is low. Short-term, oral toxicity studies of 1,2-dichloropropane in mice and rats showed growth inhibition, clinical toxic signs associated with central nervous system depression, and/or increased mortality at dose levels of 250 mg/kg body weight per day or higher. Studies did not indicate any teratogenic activity of 1,2-dichloropropane at oral dose levels up to 125 mg/kg body weight in the rat and 150 mg/kg body weight in the rabbit. In a carcinogenicity study on mice administered 125 or 250 mg 1,2-dichloropropane/kg body weight by gavage, a dose-related increase in the incidence of liver adenomas was observed. 1,2-Dichloropropane administered orally to rats is rapidly eliminated. Urine is the major route of elimination. Unchanged 1,2-dichloropropane is not found in urine. Three major urinary metabolites have been identified. 1,2-Dichloropropane can also be oxidized to lactate with resultant carbon dioxide or acetyl co-enzyme A production. [R43] CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of 1,2-dichloropropane were available. There is limited evidence in experimental animals for the carcinogenicity of 1,2-dichloropropane. Overall evaluation: 1,2-Dichloropropane is not classifiable as to its carcinogenicity to humans (Group 3). [R44] *A4. A4= Not classifiable as a human carcinogen. [R45] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . /Dichloropropane, dichloropropene, and related compounds/ [R46, 297] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Dichloropropane, dichloropropene, and related compounds/ [R46, 298] *Stabilization: Treatment is largely supportive. Watch for respiratory depression and arrhythmias. Obtain arterial blood gases. Administer oxygen if there is evidence of altered mental status or dyspnea. Treat hypotension with volume expansion and vasopression. Use lidocaine or beta-blockers for ventricular arrhythmias. Skin: Remove contaminated clothing. Wash affected area with soap and copious amounts or water. Eye: Irrigate the eye for 15-20 min. Obtain a consultation if symptoms persist. Oral: Most of the halogenated solvents ingested in quantities of 1-2 swallows may be partially removed by ipecac-induced emesis if admin within a few hr to a patient who has not lost the gag reflex, is not seizing, is not markedly lethargic, or is not in coma. Observe the patient in the upright position to lessen the possibility of aspiration. Activated charcoal is probably ineffective. Inhalation: Move from the contaminated area. Provide a source of oxygen and prepare for mechanical ventilation. If the patient is unconscious and the pulse is absent, initiate CPR measures. Enhancement of Elimination: Maintain good ventilation. Hemodialysis or hemoperfusion are not likely to be useful because of the high lipophilic properties of these solvents. Antidote: N-acetylcysteine may restore depleted glutathione stores, but no adequate clinical studies are available to validate this possible treatment. Supportive Care: Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encephalopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, EKG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. /Halogenated hydrocarbons/ [R47] *1. FLUSH contaminating fumigants from the skin and eyse with copious amounts of water or saline for at least 15 minutes. Some fumigants are corrosive to the cornea and may cause BLINDNESS. Specialized medical treatment should be obtained promptly following removal of toxicant by copious flushing with clean water. Skin contamination may cause BLISTERING and deep chemical burns. Absorption of some fumigants across the skin may be sufficient to cause systemic poisoning in the absence of fumigant inhalation. For all these reasons, decontamination of eyes and skin must must be IMMEDIATE and THROUGH. 2. REMOVE victims of fumigant inhalation to FRESH AIR immediately. Even though initial symptoms and signs are mild, keep the victim quiet, in a semi-reclining position. Minimum pohysical activity limits the likehood ofpulmonary edema. 3. If victim is not breathing, clear the airway of secretions and RESUSCITATE with positive poressure oxygen apparatus. If this is not available, use chest compression to sustain respiration. If victim is pulseless, employ cardiac resuscitation. 4. If PULMONARY EDEMA is evident, there are several measures avilable to sustain life. Medical judgement must be relied upon, however, in the management of each case. The following procedures are generally recommended: A. Put the victim in a SITTING position with a backrest. B. Use intermittent and/or continuous positive pressure OXYGEN to relieve hypoxemia. ... C. Slowly administer FUROSEMIDE, 40 mg, or SODIUM ETHACRYNATE, 50 mg, to reduce venous load by inducing diuresis. ... D. Morphine in small doses (5-10 mg), slowly, iv to allay anxiety and promote deeper respiratory excursions. E. Administer AMINOPHYLLINE (0.25-0.50 gm) slowly, iv. ... F. Digitalization may be considered, but there is a serious risk of arrhythmias in an anoxic and toxic myocardium. G. TRACHEOSTOMY may be necessary in some cases to facilitate aspiration of large amounts of pulmonary edema fluid. H. Epinephrine, atorpine, and expectorants are generally not helpful, and may complicate treatment. I. Watch for RECURRENT PULMONARY EDEMA, even up to 2 weeks after the initial episode. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. 5. Combat SHOCK by placing victim in the Trendelenburg position and administering plasma, whole blood, and/or electrolyte and glucose solutions intravenously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. 6. Control CONVULSIONS. Seizures are most likely to occur in poisonings by methyl bromide, hydrogen cyanide, acrylonitrile, phosphine, and carbon disulfide. ... /Fumigant poisoning/ [R48] MEDS: *Recommended medical surveillance: 1) Initial medical screening: Employees should be screened for history of certain medical conditions ... which might place employee at incr risk ... /such as/ skin disease, ... liver disease, ... kidney disease, ... and chronic resp disease ... 2) Periodic medical exam: Any employee developing the above-listed conditions should be referred for further medical exam. [R19, 1981.1] *Evaluate the skin, liver, and renal function on a periodic basis, as well as cardiac and respiratory status and general health. [R49] HTOX: *HUMAN EYE INJURY FROM SPRAY OF 1,2-DICHLOROPROPANE OCCURRED WHEN PIPELINE BURST AND SPRAYED ONE SIDE OF FACE OF WORKMAN. SMARTING OF EYE ON THAT SIDE PERSISTED FOR SEVERAL HR. CORNEAL EPITHELIUM WAS DAMAGED IN SEVERAL SMALL AREAS IN PALPEBRAL FISSURE, BUT RECOVERY WAS PROMPT WITH NO SPECIAL TREATMENT. [R50] *... The effects of 1,2-dichloropropane poisoning in humans. Symptoms incl headache, vertigo, lacrimation, and irritation of the mucous membrane. Changes in the blood are similar to those of marked anemia. [R51] *Propylene dichloride may cause dermatitis by defatting the skin. More severe irritation may occur if it is confined against the skin by clothing. Undiluted, it is moderately irritating to the eyes, but does not cause permanent injury. [R49] *3 cases of 1,2-dichloropropane intoxication were examained. Case 1, a 28 yr old male accidentally ingested a stain remover containing 1,2-dichloropropane and was admitted to the hospital where blood, kidney, and liver tests were performed. After 2 days, renal failure developed, forced diuresis was carried out, and tests were repeated. Case 2, a 20 yr female, was admitted to the hospital with vomiting, abdominal pain, widespread ecchymoses, hematuria, and metrorrhagia. Symptoms regressed and lab tests were performed. 9 months later, the patient was readmitted with oliguria, epistaxis, hematuria, metrorrhagia, and conjucntival hemorrhages. The patient had been sniffing a stain remover containing 1,2-dichloropropane on both occasions. Lab tests were performed. The patient was given fresh blood and plasma transfusions and underwent hemodiafiltration. Case 3, a 55 yr old female suffering from membranoproliferative glomerulonephritis and on home dialysis, was admitted to the hospital 3 days after cleaning with a solvent containing 1,2-dichloropropane. During the 3 days, she developed anorexia, abdominal pain, and nocturnal sweating. Laboratory tests were performed. Hemodialysis was continued in the hospital. Testing showed that all cases had acute renal and hepatic injury, hemolytic anemia, and disseminated intravascular coagulation. Case 1 died after seven days from septic shock. Case 2 was discharged after 3 wk with complete recovery of renal and function and normal coagulation tests. The hemolytic activity and disseminated intravascular coagulation of Case 3 disappeared after 1 wk. Liver disease improved. Biliary and liver echography did not show pathological findings. /It was/ concluded that wide use of 1,2-dichloropropane in commercial solvents could be a dangerous and unknown source of intoxication. [R52] *... In the subjects poisoned by mixtures rich in 1,2-dichloropropane ... cytoplasmic and mitochondrial enzymes appeared in the serum, indicating a severe lesion of the cytoplasmic and mitochondrial membranes. Lysosomal enzymes appeared in the serum of 2 cases indicating a diffuse and irreversible liver cell necrosis. [R53] *2 case reports of dermatitis due to 1,2-dichloropropane were described. 1 woman had worked for 6 yr on the production of various plastic products from polypropylene, polystyrene, metaplex, and bakelite. The second woman had worked for 4 yr producing bakelite parts for cars. Both patients were exposed to Siliform, and had developed dermatitis on the feet and hands. Skin tests with 1% dichloropropane were positive in both women, and one woman also reacted to Siliform. The Siliform aerosol contained 7.4% dichloropropane along with various other components. [R54] *Pertinent clinical and experimental studies of nutritional factors affecting the toxicity of ... /1,2-dichloropropane/ ... were reviewed and it was concluded that a well-balanced diet, containing protein, adequate for growth or the maintenance of optimal weight and nitrogen balance, a moderate amt of fat (10-15%), and a high content of carbohydrates, will afford maximal protection against poisoning. [R55] *The odor may be adequate to warn against /non-reocurring/ acute injury, but it appears doubtful ... it will prevent excessive repeated exposure. [R56, 4167] *A study was made of 10 cases of allergic contact dermatitis from 1,2-dichloropropane occurring on the fingers and hands of painters or metalworkers in the engineering industry from 1985-1988. All patients had occupational contact with solvent mixtures containing 10-40% of 1,2-dichloropropane. Patch testing of the patients, as well as of 120 comparison subjects was carried out with 1, 2, 5, 10, and 20% concn of 1,2-dichloropropane in petrolatum. Results of patch testing demonstrated an allergic response in all 10 patients, with a reactivity threshold at 2% concn in almost all cases (7 cases). Comparison subjects were negative to all concn of 1,2-dichloropropane, except for 2 cases with slight erythematous reaction to the 20% 1,2-dichloropropane concn. It was concluded that the dermatitis is caused by delayed hypersensitivity to 1,2-dichloropropane, and that discontinuance of exposure produced quick resolution of dermatitis. [R57] *Human exposures resulting in toxicity indicate that the main target organs are liver and kidney. Sublethal exposure also causes CNS depression. [R58] *Ingestion of cleaning solvent (50 ml) containing 1,2-dichloropropane (other components not known) by a man produced coma followed by delirium, irreversible shock, cardiac failure, and death. Histopathologically, centri- and medio-lobular hepatic necrosis was found. [R59] *Toxic hepatitis with portal hypertension has been described in a 49 yr old man, who ingested 1,2-dichloropropane in an attempted suicide. [R59] *Symptomatology: 1A) Inhalation, high vapor concn: gasping, refusal to breathe, coughing, substernal pain, and extreme respiratory distress at vapor concn over 1500 ppm. Irritation of eyes and upper respiratory mucosa appears promptly after exposure to concentrated vapors. Lacrimation and headache are prominent. Coma may occur rapidly. B) Inhalation, low vapor concn: central nervous depression and moderate irritation of respiratory system. Headache is frequent. 2) Dermal: severe skin irritation with marked inflammatory response of epidermis and underlying tissues. 3) Oral: acute gastrointestinal distress with pulmonary congestion and edema. Central nervous depression, perhaps even in the absence of impaired oxygen uptake. 4) By any route, possible late injuries to liver, kidneys and heart. 5) After inhalation exposures, malaise, headache, chest and abdominal discomfort and irritability have been reported to persist for several weeks and perhaps for several years. [R9, p. III-142] NTOX: *PROPYLENE DICHLORIDE ON OPEN SKIN CAUSES ONLY MILD IRRITATION. ... /IT/ CAUSES ... PAIN AND IRRITATION WHEN SPLASHED INTO EYES OF RABBITS ... [R56, 4158] *... Repeated inhalation of propylene dichloride in concn of 1000 ppm caused deaths among dogs after 24 exposures, among guinea pigs after 22 exposures, while some rats died after 7 exposures. ... Severe liver damage was main finding in animals which died. Under conditions of these expt, propylene dichloride appeared more toxic than carbon tetrachloride, but less ... /toxic/ than ethylene dichloride. [R60] */WHEN/ APPLIED BY DROP TO RABBIT CORNEAS IT WAS FOUND MODERATELY INJURIOUS ... EXPOSURE OF GUINEA PIGS TO 2200 PPM IN AIR FOR MANY HR UNTIL MOST /WERE/ DEAD CAUSED LACRIMATION AND SWELLING OF LIDS AND CONJUNCTIVA, ... BLUISH DISCOLORATION OF CORNEAS AND INFECTION DEVELOPED. RABBITS EXPOSED TO SAME CONDITIONS SHOWED LITTLE IRRITATION. [R61] *MICE INHALING 4.8 TO 26.0 MG 1,2-DCP/L INITIALLY EXPERIENCED GENERAL AGITATION AND DECR COORDINATION OF MOVEMENTS, FOLLOWED BY SLUGGISHNESS, AMYOTONIA, AND SPORADIC CLONIC SPASMS, FOLLOWED BY LOSS OF RIGHTING REFLEX. IN MICE, 4 HR AFTER CONTINUOUS INHALATION EXPOSURE TO 2 MG/L, CATALASE AND ACETYLCHOLINESTERASE ACTIVITY CHANGES OCCURRED. [R62] *35 albino rats inhaled a 1 ug/l concn of 1,2-dichloropropane for 7 days. This caused unidirectional changes in the fatty cell system, apparent in an increased functional activity of fatty cells (an adaptation reaction), and the appearance of degeneration and disintegration of fatty cells into conglomerates (an injury reaction). [R63] *In this experimental study on the toxicology of propylene dichloride (1,2-dichloropropane), rats, guinea pigs, and dogs received from 128-140 7 hr inhalation exposures to 400 ppm of 1,2-dichloropropane. These were given 5 days/wk. No ill effects were observed that could be attributed to the exposures except for decreased weight gain by the exposed rats. Histological exam showed no changes specifically attributable to dichloropropane. [R64] *Animals were exposed to 1,2-dichloropropane via inhalation for 94 continuous days, at a concn of 9 mg/cu m ... caused a change in the functional state of the CNS, blood enzyme activity, structural shifts in the liver, lung, and corpuscle cell system, and the disruption of bioenergetic processes in the liver, lung, and adrenal glands, as well as changes in the DNA synthesizing system of the liver. [R65] *1,2-Dichloropropane was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild-type males were treated with concns of 1,2-dichloropropane that result in approx 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concns of 1,2-dichloropropane tested by injection (4200 ppm) or feeding (7200 ppm) were negative in this assay. [R66] */WHEN/ APPLIED BY DROP TO RABBIT CORNEAS IT WAS FOUND MODERATELY INJURIOUS ... [R50] *Signs of acute 1,2-dichloropropane toxicity include CNS depression and irritation of the eyes and respiratory tract. ... Acute inhalation of 1,2-dichloropropane increases the levels of serum glutamate- oxalacetate transaminase and glutamate-pyruvate transaminase. ... Liver damage was reported in rats following short-term exposure by inhalation to 1,2-dichloropropane, and in female Fischer 344/N rats and male B6C3F mice following admin by gavage for 103 wk. [R67] *1,2-Dichloropropane (practical grade) was tested in two laboratories in preincubation assays in Salmonella typhimurium in the presence and absence of a metabolite system (S9) from the livers of Arocolor-induced rats or hamsters at doses of 10-10,000 ug/plate. In both laboratories, a low, but reproducible incr in mutation frequency was obtained with strain TA100 in the absence of S9. Results with strain TA1535 were equivocal, and negative results were obtained with strains TA1537 AND TA98. [R67] *In a plate assay, 1,2-dichloropropane (purity unspecified) (tested at doses up to 100 umol/plate) was not mutagenic to Salmonella typhimurium TA100 in the presence or absence of S9 from Aroclor-induced rats. [R68] *In a plate assay, 1,2-dichloropropane (analytical grade; tested at 1-10 ul/plate) was mutagenic to Salmonella Typhimurium TA1535 AND TA100. The presence of Aroclor-induced rat-liver S9 reduced the mutagenic effect. Similar results were obtained with one dose (10 ul/plate) in strains TA1535 AND TA100 in a spot test; strains TA1537, TA1538 AND TA98 gave negative reponses. The same sample (tested at 2-100 ul/plate) did not induce streptomycin-resistant mutants were induced in Aspergillus nidulans in both a plate assay and a spot test at concns of 100-400 ul/plate. [R68] *1,2-Dichloropropane (> 99% pure) did not induce crossing-over, mitotic nondisjunction or haploidization in Aspergillus nidulans in a plate incorporation assay. ... /Only a single, nontoxic dose (154 mM) was tested/ [R68] *Adult male Sprague-Dawley rats were dosed by gavage with 0, 100, 250, 500 or 1000 (750 in the 13 wk study) mg/kg bw 1,2-dichloropropane/day, for up to 10 days or for 13 wk. In the single dose study, the main effects were a reduction in body weight gain and CNS depression; morphological changes were restricted to centrilobular hepatocytes in rats of the 500 and 1000 mg/kg bw dose groups. Non-protein sulfhydryl (thiols) were decreased in the liver and increased in the kidney. Over the 10 day period, resistance to hepatotoxicity developed, but there was clear evidence of hemolytic anemia and hemosiderosis. In the 13 wk study, many deaths occurred in the groups given 500 and 750 mg/kg bw, but none occurred in the lower dose groups. There was limited hepatotoxicity and no apparent nephrotoxicity, while splenic hemosiderosis was evident in most rats of all dose groups. [R58] *Pregnant Sprague-Dawley rats and New Zealand White rabbits were dosed orally (gavage) with 1,2-dichloropropane on gestation days 6-15 and 7-19, respectively. Maternal toxicity in both rats and rabbits was observed at doses of 125 mg/kg bw and 150 mg/kg bw, respectively. At these maternally toxic doses only, there were increases in the incidence of delayed ossification of the skull of the fetuses. No teratogenic effects were observed in either rats or rabbits. [R69] *Groups of 5 male and 5 female B6C3F1 mice were admin (by gavage) 1, 125, 250, 500, 1000 or 2000 mg 1,2-dichloropropane (99.4%)/kg bw, in corn oil. The doses were given for 14 consecutive days (range-finding study) followed by 1 day of observation. all male mice in the 100 and 2000 mg/kg group died. Also 3 out of 5 males receiving 500 mg/kg and 4 out of 5 females receiving 1000 mg/kg died. No growth inhibition was seen in the surviving animals. Groups of 10 male and 10 female B6C3F1 mice were then admin 1,2-dichloropropane (99.4%) in corn oil, by gavage, 5 days/wk for 13 wk, at doses of 0, 30, 60, 125, 250, or 500 mg/kg bw. Mortality was not significantly increased, and mean body weight changes were not dose-related. No compound-related histopathological changes were found at the highest dose level. [R70] *Groups of 5 male and 5 female F344/N rats were admin 1,2-dichloropropane (99.4%) at 0, 125, 250, 500, 1000, and 2000 mg/kg bw, in corn oil, by gavage, for 14 consecutive days (range-finding study) followed by 1 day of observation. All rats receiving the highest dose level died. Growth inhibition was seen in the surviving animals in the 1000 mg/kg group. At necropsy, renal medullae were red in the 2000 mg/kg group, not in lower dose levels. Groups of 10 male and 10 female F344/N rats were then admin 1,2-dichloropropane (99.4%) in corn oil, by gavage, 5 days/wk for 13 wk at doses of 0, 60, 125, 250, 500, or 1000 mg/kg bw. All animals admin 1000 mg/kg and half of the males admin 500 mg/kg died. Growth inhibition was seen in the 500 mg/kg group. Centrilobular congestion of the liver occurred in the 1000 mg/kg group and 2 females of this group showed hepatic changes and centrilobular necrosis. Lower dose levels did not produce effects. [R70] *A 2-wk study of 1,2-dichloropropane (99.9%) was conducted using groups of 10 Fischer 344 rats/sex to select doses for a subsequent 13-wk study. Dose levels were 0 (corn oil), 300, or 500 mg/kg bw/day (by gavage) for 14 days. Data were obtained on body weight, clinical effects, body temperature, functional observational battery, motor activity, hematology, liver, kidney, and spleen weights, gross pathology and histological exam of the liver and kidneys. In both groups, transient clinical effects (tearing, blinking, and lethargy) were seen, and body weights were significantly decreased. The body temperatures of treated animals in both groups, recorded 1 hr after dosing on day 13, were decreased by 0.3-0.5 deg C. No effects on motor activity and hematology were noted. Liver and kidney weights were increased and spleen weight decreased. Histopathological changes (prominent nucleoli of hepatocytes in the centrilobular region, degeneration and necrosis of the liver cells) were found in the livers of animals in both the treated groups. [R71] *Groups of 30 male and 30 female Sprague-Dawley rats each were provided with drinking-water containing 1,2-dichloropropane (99.9%) at concns of 0, 0.24, 1, or 2.4 g/l (w/v) (equivalent to 0, 33.6, 140, or 336 mg/kg bw) over 2 generations. A concn of 2.4 g/l represented the maximum practicable attainable concn, based on solubility. Adult rats were evaluated for body weights, water and feed consumption, reproductive performance, and gross pathological and histological changes. The litters were evaluated for size, neonatal growth, and survival. Decreases in water consumption reflective of rejection because of unpalatability, were observed at all levels tested in both sexes in the F0 AND F1 generations. These decreases in water consumption resulted in significantly lower body weights in both generations admin 2.4 g/l. These differences in water consumption and body weights were also evident among the females during gestation and/or lactation. The 0.24 g/l dose level had a minor effect on water consumption and body weights, but no adverse effects on the animals. No treatment-related gross pathological changes were noted in any dose group and histological changes were limited to increased hepatocellular granularity in both sexes in both generations at all dose levels. There were no histological changes in the reproductive tracts of either sex in either generation. Reproductive function, measured by fertility and litter size, was unaffected. The decreases in water consumption among females at 2.4 g 1,2-dichloropropane/l resulted in significantly lower neonatal body weights and slightly increased neonatal mortality in their litters. The neonatal effects were considered secondary to the substantial decreases in maternal water consumption, rather than a direct effect of the substance. There were no neonatal effects at the 2 lower concns. The NOAEL for adults is 0.24 g/l, and the reproductive NOAEL is 1 g/l (equivalent to 140 mg/kg bw). [R72] *In cytogenic studies using Chinese hamster ovary cells, 1,2-dichloropropane (99.4%) caused both chromosome aberrations and sister chromatid exchanges. Dose levels tested were 0.46-1.50 and 0.113-1.13 mg/ml, respectively. [R73] *The effects of a single dose of 1,2-dichloropropane of 2 ml/kg bw (by gavage) on the intracellular glutathione (GSH) content of the liver, kidneys, and blood of male Wistar rats (180-250 g) /were investigated/. 1,2-Dichloropropane, admin orally, caused a significant depletion of GSH within 24 hr of treatment, followed by a slow recovery, approaching normal levels after 96 hr. The GSH depletion was associated with a marked incr in serum GOT, GPT, 5'-nucleotidase, gamma-glutamyl transpeptidase, alkaline phosphatase, urea, and creatinine and a significant degree of hemolysis. The admin of L-buthionine-S,R sulfoximine (BSO) (0.5 g/kg bw, ip), 4 hr before 1,2-dichloropropane treatment, resulted in a significant degree of hemolysis. The admin of a GSH precursor, N-acetylcysteine (NAC), ip, at 250 mg/kg bw, 2 and 16 hr after 1,2-dichloropropane treatment, prevented the loss of cellular GSH and reduced the extent of injury in the target tissues. There was a correlation between the depletion of liver GSH and the incr in GOT, GPT, and 5'-nucleotidase, between the depletion of GSH in the kidneys and the incr in serum urea and creatinine, and the depletion of GSH in blood and the occurrence of hemolysis. [R74] NTXV: *LC50 Mouse inhalation 720 ppm/10 hr; [R67] *LDf50 Guinea pig oral 2000-4000 mg/kg; [R12] *LC50 Rat inhalation 14,000 mg/cu m/8 hr; [R75, 91986)] *LD50 Rat dermal 9 ml/kg; [R75, (1986)] *LD50 Rat oral 1.19 ml/kg; [R29] *LD50 Rat oral 1947 mg/kg; [R30, 2807] *LD50 Mouse oral 860 mg/kg; [R30, 2807] *LD50 Rabbit skin 8750 mg/kg; [R30, 2807] ETXV: *TLm Shrimp > 100 ppm/48 hr /Conditions of bioassay not specified/; [R76] *LC50 Poecilia reticulata (guppy) 116 ppm/7 days /Conditions of bioassay not specified/; [R76] *LC50 Lepomis macrochirus 320 ppm/96 hr; In fresh water at 23 deg C, mild aeration applied after 24 hr; [R76] *LC50 Menidia beryllina 240 ppm/96 hr; In synthetic seawater at 23 deg C, mild aeration applied after 24 hr; [R76] *LC50 Daphnia magna (cladorecan) 52,500 ug/l/96 hr; [R77] *LC50 Pimephales promelas (fathead minnow) 139,300 ug/l/96 hr /Conditions of bioassay not specified/; [R77] *MATC P. promelas 6-11 ug/l (est) /Conditions of bioassay not specified/; [R78] *LC50 Pimephales promelas (fathead minnow) 127 mg/l/96 hr (confidence limit 119 - 135 mg/l), flow-through bioassay with measured concentrations, 24.1 deg C, dissolved oxygen 8.9 mg/l, hardness 44.8 mg/l calcium carbonate alkalinity 39.6 mg/l calcium carbonate and pH 7.03; [R79] NTP: *Carcinogenesis studies of 1,2-dichloropropane were conducted by administering the chemical in corn oil by gavage to groups of 50 female F344/N rats and 50 male and 50 female B6C3F1 mice at doses of 125 or 250 mg/kg body weight and to groups of 50 male F344/N rats at doses of 62 or 125 mg/kg body weight. Doses were administered 5 times per week for 103 weeks. There was no evidence of carcinogenicity for male F344/N rats receiving 62 or 125 mg/kg. For female rats, there was equivocal evidence of carcinogenicity in that 250 mg/kg of 1,2-dichloropropane caused a marginally increased evidence of adenocarcinomas in the mammary gland. These borderline malignant lesions occurred concurrent with decreased survival and reduced body weight gain. There was some evidence of carcinogenicity for male and female B6C3F1 mice exposed to 1,2-dichloropropane, as indicated by increased incidences of hepatocellular neoplasms, primarily adenomas. [R80] POPL: *Persons with existing skin disorders may be more susceptible to the effects of this agent ... /as well as/ persons with impaired liver function. ... Special consideration /should be given/ before exposing persons with impaired renal function. ... In persons with impaired pulmonary function, especially those with obstructive airway diseases, the breathing of propylene dichloride might cause exacerbation of symptoms due to its irritant properties. [R19, 1981.1] ADE: *Rats receiving single oral doses of 1,2-dichloro(1-(14)C)propane excreted about 50% in the urine and 5% in feces in 24 hr. There was little further excretion over the next 72 hr. A total of 19% of the dose was excreted as (14)CO2 and 23% as other volatile substances. At 96 hr, 5% remained in the carcass. [R81] *Male and female Fischer 344 rats were either exposed to atmospheres of 5, 50 or 100 ppm (23, 230 or 460 mg/cu m) of singly labeled 1,2-dichloro((14)C))propane for a 6 hr period or dosed orally once with 1 or 100 mg/kg bw or on 7 consecutive days with 1 mg/kg bw. During inhalation exposure, maximum blood concns were reached after 2 hr, the values being approx 0.06, 0.9 and 4.0 ug/g blood, respectively. Once exposure stopped, 1,2-dichloropropane was rapidly eliminated from blood. Analysis of expired air provided evidence for saturation of metab, the proportion of expired 1,2-dichloro((14)C)propane increasing with dose. For both gavage and inhalation admin, the principal routes of elimination were urine (37-65%) and expired air (18-40%), most of the radioactivity being eliminated within 24 hr, irrespective of the route or sex. Tissues, feces and the cage wash accounted for < 11%, about 10% and about 4% of the dose, respectively. [R81] *Groups of 5 male Wistar rats (200 g) were admin ip, 0, 10, 25, 50, 100, 250, or 500 mg 1,2-dichloropropane (97%)/kg bw in 0.5 ml corn oil for 5 days (once daily) or for 4 wk (5 days/wk). Urinary mercapturic acid excretion was monitored. A significant incr in mercapturic acid excretion was observed at all dose levels, with no further incr during the treatment: at lower doses, a return to baseline values occurred within 48 hr of the end of the treatment. Mercapturic acid excretion at the end of wk 2, 3, and 4 was significantly lower than that observed at the end of the first wk. [R82] METB: *... 1,2-DICHLOROPROPANE ... IS PARTLY METABOLIZED TO CO2, /UNCHANGED/ 1,2-DICHLOROPROPANE AS WELL AS CO2 METABOLIZED 1,2-DICHLOROPROPANE ARE EXCRETED /IN EXPIRED AIR/. [R9, p. III-142] *It has been shown that rat liver microsomes in vitro are capable of metabolizing 1,2-dichloropropane. [R56, 4164] *The metabolism of 1,2-dichloropropane and its proposed intermediate metabolite 1-chloro-2-hydroxypropane were studied. Sprague-Dawley rats received labeled dichloropropane in ip doses of 100 mg/kg, or by continuous oral dosing at 20 mg/kg per day for four days, while labeled 1-chloro-2-hydroxypropane was administered via ip injections at doses of 100 mg/kg. Urine was collected without fecal contamination for analysis via thin layer chromatography. During in vitro studies, a reaction was carried out in an oxidizing system using 1,2-dichloropropane as the substrate. ... The major urinary metabolite of 1,2-dichloropropane was N-acetyl-S-(hydroxypropyl)cysteine, with 2 minor metabolites, beta-chlorolactate and N-acetyl-S-(2,3-dihydroxypropyl)cysteine. Aside from N-acetyl-S-(2-hydroxypropyl)cysteine, a known urinary metabolite of 1-chloro-2-hydroxypropane, beta-chloroacetaldehyde and beta-chlorolactate were also identified as urinary 1-chloro-2-hydroxypropane metabolites ... /It was/ concluded that 1,2-dichloropropane oxidation to 1-chloro-2-hydroxypropane, ultimately resulting in the production of N-acetyl-S-(2-hydroxypropyl)cysteine, is suggested as the pathway of 1,2-dichloropropane metabolism in rats. The major detoxicating pathway of 1-chloro-2-hydroxypropane is epoxidation to 1,2-epoxypropane, which can either conjugate with glutathione or be hydrolyzed to propane-1,2-diol. [R83] *1,1-Dichloropropane and 1,2-dichloropropane are enzymatically dechlorinated by an enzyme located in hepatic microsomes. This system requires reduced nicotinamide adenine dinucleotide phosphate and oxygen, and is inducible by phenobarbital and benzpyrene, but not by methylcholanthrene. The optimum pH of the system is 8.2. [R84] *The major urinary metabolite found after oral dosing was N-acetyl-S-(2-hydroxypropyl)-L-cysteine. Identified minor metabolites were beta-chlorolactate and N-acetyl-S-(2,3-dihydroxypropyl)-L-cysteine. [R81] *1,2-Dichloropropane is metabolized to form a variety of metabolic products. Dichloropropane oxidation yielded the mercapturic acid, N-acetyl-S-(2-hydroxypropyl)cysteine. Three mercapturic acid metabolites were identified in the urine of Fischer 344 rats (110-140 g) admin 1,2-dichloropropane orally (100 mg/kg bw) or by inhalation (466 mg/cu m/6 hr). These cmpds are N-acetyl-S-(2-hydroxypropyl)-L-cysteine, N-acetyl-S-(2-oxo-propyl)-L-cysteine and N-acetyl-S-(1-carboxyethyl)-L-cysteine. Fischer 344 rats were given a single oral dose of deuterium (D6)-labeled dichloropropane (105 mg/kg bw) in a mechanistic study conducted to determine whether the conjugated metabolites are generated through a sulfonium ion intermediate. The results suggest that dichloropropane undergoes oxidation either prior to, or subsequent to, glutathione conjugation. There was no evidence to support the existence of a sulfonium intermediate in the formation of the 2-hydroxypropyl-mercapturic acid metabolite of dichloropropane. Instead, this metabolite is thought to arise via the direct oxidation of 1,2-dichloropropane, either prior to, or following, conjugation with glutathione. [R74] INTC: *MALE RATS EXPOSED 4 HR TO VARIOUS CONCN TO TETRACHLOROETHYLENE SINGLY AND IN COMBINATION WITH 1,2-DICHLOROPROPANE SHOWED MARKEDLY ELEVATED GLUTAMIC OXALACETIC TRANSAMINASE, GLUTAMIC PYRUVIC TRANSAMINASE AND ORNITHINE CARBAMYL TRANSFERASE. [R85] *Weanling Wistar rats, fed for several weeks on low protein choline-deficient diets, were more susceptible to the effects of inhalation of 4660 mg 1,2-dichloropropane/cu m than rats on a control diet. This increased susceptibility could be corrected by dietary supplements of 1-methionine or 1-cysteine plus choline chloride. [R86] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Dichloropropane's production and use as a solvent may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 53.3 mm Hg at 25 deg C indicates 1,2-dichloropropane will exist solely as a vapor in the ambient atmosphere. In the past, 1,2-dichloropropane was directly released to the environment as a component of the insecticide D-D. Vapor-phase 1,2-dichloropropane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 36 days. Photolysis is not expected to be an important environmental fate process as vapor-phase photolysis under simulated sunlight did not occur after prolonged exposure. If released to soil, 1,2-dichloropropane is expected to have very high mobility based upon a Koc of 47. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 2.82X10-3 atm-cu m/mole. 1,2-Dichloropropane may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation is not expected to be an important environmental fate process in soil or water given a 0% theoretical BOD using the MITI test. If released into water, 1,2-dichloropropane is not expected to adsorb to suspended solids and sediment based upon the Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively. A BCF range of 0.5 to 6.9 suggests bioconcentration in aquatic organisms is low. The hydrolytic half-life of 1,2-dichloropropane is expected to be 6 months to several years. Occupational exposure to 1,2-dichloropropane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloropropane is produced or used. Monitoring data indicate that the general population may be exposed to 1,2-dichloropropane via inhalation of ambient air, ingestion of drinking water, and dermal contact with consumer products containing 1,2-dichloropropane. (SRC) ARTS: *1,2-Dichloropropane's production and use as a solvent(1) may result in its release to the environment through various waste streams(SRC). In the past, 1,2-dichloropropane was directly released to the environment as a component of the insecticide D-D(2). [R87] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 47(2), indicates that 1,2-dichloropropane is expected to have very high mobility in soil(SRC). Volatilization of 1,2-dichloropropane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 2.82X10-3 atm-cu m/mole(3). The potential for volatilization of 1,2-dichloropropane from dry soil surfaces may exist(SRC) based upon a vapor pressure of 53.3 mm Hg(4). Biodegradation is not expected to be an important environmental fate process in soil given a BOD of 0% theoretical using the MITI test(5). In a closed system using fresh soil at 15 deg C, a mean half-life of 52 days was measured for 1,2-dichloropropane(6). [R88] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 47(2), indicates that 1,2-dichloropropane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3), based upon a Henry's Law constant of 2.82X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively(SRC). The hydrolytic half-life of 1,2-dichloropropane is expected to be 6 months to several years(5). According to a classification scheme(6), a BCF range of 0.5-6.9(7), suggests bioconcentration in aquatic organisms is low(SRC). Biodegradation is not expected to be an important environmental fate process in water given a 0% theoretical BOD using the MITI test(7). [R89] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-dichloropropane, which has a vapor pressure of 53.3 mm Hg at 25 deg(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichloropropane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 36 days(SRC), calculated from its rate constant of 4.42X10-13 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Vapor-phase photolysis under simulated sunlight did not occur after prolonged exposure(4). [R90] BIOD: *Partial chemical oxidation of biorefractory cmpds by ozone treatment prior to biological oxidation was studied. 1,2-Dichloropropane is not biodegradable, but it can be made biodegradable with ozonation. [R91] *AEROBIC: The total degradation of 1,2-dichloropropane in soil at normal field rates was extremely slow as compared to 2,3-, cis- and trans-1,3-dichloropropene(1). In a closed system using fresh soil at 15 deg C, a mean half-life of 52 days was measured for 1,2-dichloropropane as opposed to mean half-lives of 26, 13, and 8, respectively(1). 1,2-Dichloropropane is reported to be degraded during biological treatment provided suitable acclimation is achieved(2,5). However, in a bench scale continuous flow activated sludge reactor with an 8 hr retention time, 1,2-dichloropropane was entirely removed by stripping(3). It was reported to be degradation resistant in a 2 week screening test that utilizes a mixed inoculum of soil, surface water and sludge(4). 42% degradation was achieved in 7 days when incubated with sewage seed(6). There was evidence of only slight biodegradation in 20 weeks (as evidenced by 5% of the radioactivity remaining unextracted from a medium loam soil) and it was stable in a sandy loam soil for 12 weeks when incubated in a closed container(7). No volatile degradation products were detected from treated soil(7). 1,2-Dichloropropane, present at 100 mg/l, reached 0% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(8). [R92] ABIO: *The rate constant for the vapor-phase reaction of 1,2-dichloropropane with photochemically-produced hydroxyl radicals has been estimated as 4.4X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 36 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The hydrolytic half-life of 1,2-dichloropropane is expected to be 6 months to several years(2). 1,2-Dichloropropane is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). Vapor-phase photolysis under simulated sunlight did not occur after prolonged exposure(3). [R93] BIOC: *BCF ranges of 1.2-3.2 and 0.5-6.9 were measured for 1,2-dichloropropane at concns of 0.4 mg/l and 0.04 mg/l, respectively(1). According to a classification scheme(2), these BCF values suggest bioconcentration in aquatic organisms is low(SRC). [R94] KOC: *The Koc for 1,2-dichloropropane is 47 in a silt loam(1). According to a classification scheme(2), this Koc value suggests that 1,2-dichloropropane is expected to have high mobility in soil. It sorbs to clay minerals in dry soil but desorbs as the soil absorbs moisture(2). In the areas of the US where 1,2-dichloropropane was used as a fumigant, the soil is generally sandy with low organic carbon content and would probably have little impact on reducing mobility due to soil adsorption(2). [R95] VWS: *The Henry's Law constant for 1,2-dichloropropane is 2.82X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that 1,2-dichloropropane is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 3 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). 1,2-Dichloropropane's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,2-dichloropropane from dry soil surfaces may exist(SRC) based upon a vapor pressure of 53.3 mm Hg(3). The mean half-life of 1,2-dichloropropane in dissipation studies using soils not previously fumigated with D-D was 52 days(4). The rate changed by a factor of approximately 2 for every 10 deg C change in the environmentally important range of 2 deg C to 20 deg C(4). [R96] WATC: *HIGHEST CONCN FOUND IN FINISHED (DRINKING) WATER WAS LESS THAN 1.0 UG/L. /FROM TABLE/ [R97] *Local monitoring has found levels as high as 1200 ug/l in shallow wells near sites where 1,2-dichloropropane has been used as a soil fumigant. [R98] *... Has been surveyed for in the Ground Water Supply Survey ... found in approx 1-2% of rural wells at levels around 1 ug/l. [R99] *GROUNDWATER: Found in 3 MD wells, 30 Long Island, NY wells, and over 60 CA wells at levels ranging from 1-50 ppb(1). Minnesota: Found in groundwater under 8 of 13 municipal landfills with suspected groundwater contamination - 0.5-43 ppb and 1 of 7 other municipal landfills - 1.1 ppb(2). 1,2-Dichloropropane is the second most frequent groundwater pesticidal contaminant in California(3). It has been detected in 75 wells at concns ranging up to 1200 ppb in 9 countries(3). Not detected in groundwater underlying the Amphenol metal plating facility in Broadview, IL at a detection limit of 1 ppb(4). Detected in groundwater 83 days after application with 92%, 1,3-dichloropropene(5). Identified in groundwater under a leaky storage tank of a paint factory(6). 1,2-Dichloropropane was not found above the detection limit of 0.16 ug/l in 3 well samples from the Big Creek watershed, Ontario, Canada, an agricultural area with historic use of 1,3-dichloropropane(7). In a survey of untreated ambient groundwater of the US from 1985 to 1995, 1,2-dichloropropane was detected in 0.8% of 406 wells in urban areas at a median concn of 0.2 ug/l and in 0.9% of 2,542 wells in rural areas at a median concn of 0.5 ug/l(8). Atmospheric deposition was shown not to be a source of 1,2-dichloropropane using surficial Kirkwood-Cohansey aquifer samples in southern New Jersey(9). 1,2-Dichloropropane was identified not quantified in a survey conducted during 1989 of the groundwater in the vicinity of the Ciba-Geigy Superfund site near Toms River in Ocean County, NJ(10). 32 of 40 piezometers at 13 sites in the Canadian portion of the Abbotsford aquifer showed detectable levels of 1,2-dichlorpropane during testing conducted from July 1991 through June 1994; the avg concn was 2.23 ug/l with a max concn of 7.07 ug/l(11). Of US 1,834 groundwater samples, 1,2-dichloropropane was detected in 1.14% at a max concn of 7.50 ug/l(12). [R100] *DRINKING WATER: 1,2-Dichloropropane has been identified in drinking water in the US: 11 water utilities along the Ohio River 0.1 ppb mean, 0.1 ppb max, 1.6% positive(1). The Netherlands: maximum concn in tap water derived from bank-filtered Rhine River water was 300 parts per trillion(2). In a US Groundwater Supply Survey, of 945 supplies derived from groundwater chosen both randomly and on the basis that they may contain VOC's, 13 samples were positive; the median concn of positive samples was 0.9 ppb, with a 21 ppb max(4). 1,2-Dichloropropane was detected, not quantified in 11 of 1,396 wells sampled from 38 counties in the 1995 California well water survey(5). [R101] *SURFACE WATER: 1,2-Dichloropropane was reported in surface waters as follows: Lake Ontario (95 stations) 4 stations had concns ranging from 210-440 parts per trillion and 15 others have trace quantities(1). Lower Niagara River (16 stations) 4 stations had concns ranging from 7-55 parts per trillion and 5 other stations had trace quantities(1). Ohio River 1977/78 (141 samples) 19 positive, 0.1 ppb max, Ohio River tributaries (95 samples) 5 positive, 0.8 ppb maximum(2). Ohio River 1980/81 (11 stations 4972 samples) 8.8% of samples positive, 28 samples between 1-10 ppb and 1 sample > 10 ppb(3). 14 heavily industrialized river basins in US: 5 of 204 sites positive including those in the Illinois River Basin, Delaware River Basin and Hudson River Basin 1-2 ppb(4). Rhine River (km 865) < 1 ppb(5). Detected in the Niagara and Genesee Rivers (NY) but not in the open waters of Lake Ontario(6). 1,2-Dichloropropane was not found above the detection limit of 0.16 ug/l in 4 samples from the Big Creek watershed, Ontario, Canada, an agricultural area with historic use of 1,3-dichloropropane(7). [R102] EFFL: *Municipal landfill leachate tested in MN resulted in 3 of 6 samples testing positive for 1,2-dichloroethane at a concn range of 2.0-81 ppb as was 1 of 5 samples in WI, concn of 54 ppb(1). National Urban Runoff Program in which 86 samples from 19 cities throughout the US were analyzed: detected only in Eugene OR at 3 ppb, 1% frequency of detection nationwide(2). Industries (mean concn) whose effluents contain 1,2-dichloropropane include photographic equipment/supplies (10 ppb) organic chemical manufacturing/plastics (25 ppb), and paint and ink formulation (210 ppb)(3). 1,2-Dichloropropane was not detected, detection limit of 1 ug/l, in leachate from samples of reclaimed asphalt pavement from asphalt plants throughout Florida(4). 1,2-Dichloropropane was detected not quantified in emissions from wax paste for furniture, floors, and linoleum and from liquid floor wax(5). [R103] SEDS: *1,2-Dichloropropane was detected at concn up to 12.2 ppb throughout much of a 24-foot soil core collected from a field with recent documented use of Telone II(1). Not detected in boring in Anoka sandplain near Minneapolis and upgradient of an asphalt lined municipal solid waste landfill which had polluted groundwater, but 2.0 ppb was found in clay boring upgradient of landfill in SW Minnesota which had contaminated the groundwater(2). Detected in Love Canal sediment/soil/water samples(3). Found in soil cores in California as far as 7m down at 0.2-2.2 ppb(4). [R104] ATMC: *... Reported in urban air at low levels, approx 100 parts per trillion. [R99] *URBAN/SUBURBAN: 1,2-Dichloropropance was detected in 396 US samples at a median concn of 57 parts per trillion, 110 parts per trillion max(1). Seven US cities sampled round-the-clock for 1-2 weeks resulted in a range of mean concns of 21-78 parts per trillion(2). Houston, TX had highest mean value with highest values at night or early morning and low values in afternoon(2). Samples from Delft and Vlaardingin, The Netherlands showed a mean concn of 140 parts per trillion, 3000 parts per trillion max(4). The California Air Monitoring Program (24-hr sampling at four sites throughout the year) reported 2% of samples above the quantitation limit (0.2 parts per trillion), while most positive values were near the quantitation limit; one monthly mean in Riverside was 1.1 ppb(5). Samples from Portland, OR taken during 7 rain events had a 1,2-dichloropropane concn of 4.4-8.4 parts per trillion in the gas phase(8). [R105] *RURAL/REMOTE: Air samples from the Island of Terschelling, The Netherlands, contained 1,2-dichloropropane at a concn of 60 parts per trillion mean, 1500 parts per trillion, maximum(1). [R106] *SOURCE DOMINATED: 1,2-Dichloropropane was detected in 26 US samples at a median concn of 120 parts per trillion, 130 parts per trillion max(1). Samples from Niagara Falls, NY contained a trace with 22% of the samples positive; Baton Rouge, LA samples contained a range of 0-40 ppb, with 38% of samples positive(2). Traces of 1,2-dichloropropane were detected outside 2 of 9 homes of Love Canal, NY residents(3). A 24-hr, 3 month survey of 10 source-oriented sites in Philadelphia, PA, (31 samples) showed a mean concn of 259 parts per trillion(4). [R107] RTEX: *Inhalation of vapor, ingestion, eye, and skin contact [R49] *... Common operations in which /occupational/ exposure to propylene dichloride may occur ... /incl/ use as soil fumigant, ... use in cleaning, degreasing, and spot removal operations incl paint and varnish removal, use during rubber compounding and vulcanizing operations, use during extraction processing of fats, oils, lactic acid, and petroleum waxes, use in mfr of tetrachloroethylene and propylene oxide, and use as an additive and lead scavenger in antiknock fluids. [R19, 1981.3] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,944 workers (1,022 of these are female) are potentially exposed to 1,2-dichloropropane in the US(1). The NOES Survey does not include farm workers. Occupational exposure to 1,2-dichloropropane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloropropane is produced or used(SRC). Monitoring data indicate that the general population may be exposed to 1,2-dichloropropane via inhalation of ambient air, ingestion of drinking water, and dermal contact with this compound and other products containing 1,2-dichloropropane(SRC). [R108] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *400 ppm; NIOSH considers propylene dichloride to be a potential occupational carcinogen. [R17, 268] ATOL: *Propylene dichloride is exempted from the requirement of a tolerance when used as a solvent for formulations used before crop emerges from soil in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R109] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 75 ppm (350 mg/cu m). [R110] NREC: *NIOSH considers propylene dichloride to be a potential occupational carcinogen. [R17, 268] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R17, 268] TLV: *8 hr Time Weighted Avg (TWA) 75 ppm; 15 min Short Term Exposure Limit (STEL) 110 ppm [R111] *A4: Not classifiable as a human carcinogen. [R111] OOPL: *Romania: 40 ppm; East Germany: 10 ppm; Poland: 10 ppm; USSR: 2 ppm; Bulgaria: 2 ppm. [R60] *Vapor hazard index for volatile chemicals is a measure of the amount by which a saturated atmosphere would exceed the TLV. It is defined as concn of saturated vapor divided by TLV times 1000; and it is temperature dependent. The vapor hazard index for 1,2-dichloropropane is 0.7 at 20 deg C. [R112] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Propylene dichloride is produced, as an intermediate or a final product, by process units covered under this subpart. [R113] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,2-Dichloropropane is included on this list. [R114] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l [R115] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 5 ug/l [R115] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.56 ug/l [R115] +(CT) CONNECTICUT 5 ug/l [R115] +(ME) MAINE 5 ug/l [R115] +(MN) MINNESOTA 5 ug/l [R115] +(WA) WASHINGTON 3 ug/l [R115] CWA: +1,2-Dichloropropane is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R116] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1,000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R117] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2-Dichloropropane is included on this list. [R118] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R119] *Manufacturers and processors of 1,2-dichloropropane are required to conduct (1) Health effects testing incl (a) neurotoxicity testing, (b) mutagenic effects studies, (c) developmental toxicity testing, and (d) pharmacokinetic studies; (2) Environmental effects testing incl (a) mysid acute and chronic toxicity tests, (b) algal acute toxicity testing and (c) daphnid chronic toxicity testing under TSCA section 4. [R120] RCRA: *U083; As stipulated in 40 CFR 261.33, when propylene dichloride, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R121] FIFR: *Propylene dichloride is exempted from the requirement of a tolerance when used as a solvent for formulations used before crop emerges from soil in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R109] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1013. Analyte: 1,2-dichloropropane. Matrix: Air. Sampler: Solid sorbent tube (petroleum charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min. Sample Size: 0.1 to 3.5 liters. Sample Stability: Stable for less than or equal to 26 days at 25 deg C in the dark. [R122] *EPA Method 8010. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw-cap vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R123] ALAB: *Purge-and-trap analysis using fused silica capillary column gas chromatography/mass spectrometry was evaluated for the analysis of priority pollutants. Using EPA volatile organic performance evaluation samples, as unknown test materials, satisfactory precision (8.5%) and excellent accuracy (98.5% and 102% recoveries) were achieved. The capillary column was much faster than the packed column (13 min compared to 33 min) and overcame difficulties normally encountered with samples having excessive complexity, very large concn spread among components, or high concn of high-boiling components. [R124] *Dichloropropane at the nanogram per liter level in water was determined by capillary gas chromatography with electron capture detection using an improved analytical headspace method. [R125] *Dichloropropane in the atmosphere was detected by using specific gas chromatographic detectors and mass spectrometry in selected ion monitoring mode. [R126] *NIOSH Method 1013. Analyte: 1,2-dichloropropane. Matrix: Air. Procedure: Gas chromatography, with electolytic conductivity detector. For 1,2-dichloropropane this method has an estimated detection limit of 0.1 ug/sample. The precision/RSD is 0.031 at 0.5 to 520 ug/sample. Applicability: The working range is 0.05 to 130 ppm (0.25 to 600 mg/cu m) for a 2-liter air sample. Interferences: 1,2-dichloroethane cannot be resolved from 1,2-dichloropropane with a carbowax packed column. They were resolved with a carboulax capillary column. [R122] *AOB Method VG-001-01. Volatile Organics in Soil Gas - Adsorbent Tube Method. Quantitation limit = 20 ng/l. [R127] *EPA Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. Minimum level = 10 ug/l. [R127] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. Method detection limit = 6 ug/l. [R127] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. Method detection limit = 0.040 ug/l. [R127] *EPA Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. Method detection limit = 0.20 ug/l. [R127] *EPA Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. Revision 4.0. Method detection limit = 0.040 ug/l. [R127] *EPA Method 502.2-ELCD. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. Method detection limit = 0.010 ug/l. [R127] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Estimated quantitation limit = 5.0 ug/l. [R127] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. Method detection limit = 0.040 ug/l. [R127] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/ATSDR; Toxicological Profile for 1,2-Dichloropropane (1989) ATSDR/TP-89/12 DHHS/NTP; Toxicology and Carcinogenesis Studies of 1,2-Dichloropropane in F344/N Rats and B6C3F1 Mice Technical Report Series No. 263 (1986) NIH Publication No. 86-2519 WHO: Environmental Health Criteria 146: 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures (1993) HIST: *... DOW 421 (4 PARTS O-DICHLOROBENZENE, 2 PARTS PROPYLENE DICHLORIDE, 1 PART ETHYLENE DICHLORIDE) WAS INVOLVED IN MASS POISONING. THREE THOUSAND GALLONS ... WERE LIBERATED INTO NARROW COURTYARD CONTAINING 45 MEN WHEN TANK CAR EXPLODED. ... SIX MEN WHO DEVELOPED SEVERE RESP COMPLICATIONS WERE TREATED AS 1 GROUP. ALTHOUGH COUGHING AND CHOKING WERE INITIAL SYMPTOMS, THESE SUBSIDED ON TERMINATION OF EXPOSURE AND WERE REPLACED BY PERIOD OF QUIESCENCE (4-6 HR). DURING THIS PERIOD MUCH OF THE LINING OF ... RESP TRACTS WAS ... DESTROYED ... OVER SUCCEEDING 2-3 DAYS, PULMONARY EDEMA, ATELECTASIS, EMPHYSEMA AND BRONCHOPNEUMONIA WERE ... PRESENT, AS WAS TACHYCARDIA AND OCCASIONAL ATRIAL PREMATURE BEATS. 3 PATIENTS DIED ... ONLY 1 OF 3 SURVIVORS SHOWED RESIDUAL IMPAIRMENT OF RESP TRACT FUNCTION. /DOW 421/ [R9, p. III-141] SO: R1: SRI R2: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994. 1349 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 934 R4: MOBAY. 1,2-DICHLOROPROPANE, DISTILLED (DCP), TECHNICAL BULLETIN-UNDATED R5: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on 1,2-Dichloropropane (78-87-5). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R6: Spencer, E.Y. Guide to the Chemicals Used in Crop Protection. 6th ed. 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Amer Inst Hydrol. Alexandria, VA; Water Environ Fed (1993) (11) Grove G et al; Water Qual Res J Canada 33: 51-71 (1998) (12) Kolpin DW et al; Ground Water 38: 858-63 (2000) R101: (1) Ohio River Valley Water Sanit Comm; Water Treatment Process Modifications for Trihalomethane Control and Organic Substances in the Ohio River 10/76-8/79 (1979) (2) Piet GJ, Morra CF; pp. 31-42 in Artificial Groundwater Recharge. Huisman L, Olsthorn TN, eds. Pitman Pub (1983) (3) Kopfler FC et al; Adv Environ Sci Technol 8(Fate Pollut Air Water Environ): 419-33 (1977) (4) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) (5) CA EPA; Sampling for pesticide residues in California well water. 1995 update of the Well Inventory Data Base. Sacramento, CA: CA EPA EH95-06 (1995) R102: (1) Kaiser KLE et al; J Great Lakes Res 9: 212-23 (1983) (2) Ohio River Valley Water Sant Comm; Assessment of Water Quality Conditions, Ohio River Mainstream 1978-9 (1980) (3) Ohio River Valley Sanit Comm; Assessment of Water Quality Conditions Ohio River Mainstream 1980-81 (1982) (4) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollut in Surface Waters p. 75 Washington, DC: USEPA-560/6-77-015 (1977) (5) Malle KG; Z Wasser-Abwasser Forsch 17: 75-81 (1984) (6) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem Vol.I (1983) (7) Merriman JC et al; Bull Environ Contam Toxicol 47: 572-9 (1991) R103: (1) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) (2) Cole RH et al; J Water Pollut Control Fed 56: 898-908 (1984) (3) USEPA; Treatability Manual I Treatability Data. Washington, DC: USEPA-600/2-82-001A (1981) (4) Brantley AS, Townsend TG; Environ Eng Sci 16: 105-16 (1999) (5) Knoppel H, Schauenburg H; Environ Inter 15: 413-8 (1989) R104: (1) Ali SM et al; Am Chem Soc Div Environ Chem 191st Natl Meet 26: 41 (1986) (2) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) (3) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) (4) Cohen SZ et al; ACS Symp Ser 259: 297-325 (1984) R105: (1) Brodzinsky R, Singh HB; Volatile organic chemicals in the atmosphere: an assessment of available data. Menlo Park, CA: Atmos Sci Center, SRI Inter 68-02-3452 p. 198 (1982) (2) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) (4) Guicherit R, Schulting FL; Sci Total Environ 43: 193-219 (1985) (5) Shikiya J et al; p. 21 in Proc APCA Annu Meet 77th Vol I 84-1.2 (1984) (8) Ligocki MP et al; Atmos Environ 19: 1609-17 (1985) R106: (1) Guicherit R, Schulting FL; Sci Total Environ 43: 193-219 (1985) R107: (1) Brodzinsky R, Singh HB; Volatile organic chemicals in the atmosphere: an assessment of available data. Menlo Park, CA: Atmos Sci Center, SRI Inter 68-02-3452 p. 198 (1982) (2) Pellizzari ED et al; Formulation of Prelim Assess of Halogenated Org Compounds in Man and Environ Media USEPA-560/13-79-006 p. 469 (1979) (3) Barkley J et al; Biomed Mass Spectrom 7: 139-47 (1980) (4) Sullivan DA et al; p. 15 in Proc APCA Annu Meet 78th Vol 2, 85-17.5 (1985) R108: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R109: 40 CFR 180.1001(d) (7/1/2000) R110: 29 CFR 1910.1000 (7/1/2000) R111: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001.49 R112: Pitt MJ; Chem Ind (London) (20): 804-6 (1982) R113: 40 CFR 60.489 (7/1/2000) R114: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R115: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R116: 40 CFR 116.4 (7/1/2000) R117: 40 CFR 302.4 (7/1/2000) R118: 40 CFR 716.120 (7/1/2000) R119: 40 CFR 712.30 (7/1/2000) R120: 40 CFR 799.1550 (7/1/2000) R121: 40 CFR 261.33 (7/1/2000) R122: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R123: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R124: Dreisch FA, Munson TO; J Chromatogr Sci 21 (3): 111-8 (1983) R125: Comba ME, Kaiser K LE; Int J Environ Anal Chem 16 (1): 17-32 (1983) R126: Possanzini M et al; Comm Eur Communities, Rep (Eur 7624, Phys-Chem Behav Atmos Pollut): 76-81 (1982) R127: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 105 Record 111 of 1119 in HSDB (through 2003/06) AN: 1109 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,3-DICHLOROPROPENE- SY: *Telone-C-; *D-D-92-; *1,3-D-; *GAMMA-CHLOROALLYL-CHLORIDE-; *3-CHLOROPROPENYL-CHLORIDE-; *DCP-; *Dedisol-C-; *cis,trans-1,3-Dichloropropene-; *Dichloro-1,3-propene-; *1,3-DICHLOROPROPENE-1-; *1,3-DICHLORO-2-PROPENE-; *ALPHA,GAMMA-DICHLOROPROPYLENE-; *1,3-DICHLOROPROPYLENE-; *1,3-dichloro-1-propylene-; *Di-Trapex-; *Di-Trapex-CP-; *Dorlone-; *Pesticide-Code-029001-; *NCI-C03985-; *Nematox-; *Nemex-; *Caswell-No.-324A-; *EPA-Pesticide-Chemical-Code-029001-; *1-Propene,-1,3-dichloro-; *PROPENE,-1,3-DICHLORO-; *Telone-; *Telone-C17-; *Telone-II-; *Vidden-D-; *Vorlex-; *Vorlex-201- RN: 542-75-6 RELT: 6298 [DICHLOROPROPANE-DICHLOROPROPENE MIXTURE] (Mixture); 6293 [DICHLOROPROPENE] (MIXTURE); 1504 [TRANS-1,3-DICHLOROPROPENE] (Mixture Component); 1503 [CIS-1,3-DICHLOROPROPENE] (Mixture Component); 39 [EPICHLOROHYDRIN] (Contaminant) MF: *C3-H4-Cl2 SHPN: UN 2047; Dichloropropenes IMO 3.3; Dichloropropenes HAZN: U084; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Usual industrial prepn is from 1,3-dichloro-2-propanol by dehydration with phosphorus oxychloride or with phosphorus pentaoxide in benzene. [R1] *Prepd from 1,2,3-trichloropropane with sodium hydroxide. ... from 3-chloro-2-propen-1-ol with phosphorus trichloride. From acrolein with phosphorus pentachloride /and from 3,3-dichloropropene by isomerization with concn hydrochloric acid/. From 3,3-dichloropropene by isomerization with concentrated hydrochloric acid. [R1] *Made by the high temperature chlorination of propylene to yield allyl chloride as a primary product. The 1,3-dichloropropene is separated from the heavy ends after removal of allyl chloride as an overhead product in distillation. /1,3-Dichloropropene mixture/ [R2] *Propylene + chlorine (high-temperature chlorination; by-product of allyl chloride production) [R3] *The compounds cis- and trans-1,3-dichloropropene arise from a secondary reaction of allyl chloride, in which a further hydrogen atom is substituted by chlorine. [R4] IMP: *OTHER CHLORINATED HYDROCARBONS MAY BE PRESENT AS IMPURITIES AND STABILIZERS. THESE INCLUDE CHLOROPICRIN, ISOMERS OF DICHLOROPROPENE, DICHLOROPROPANE, AND EPICHLOROHYDRIN. /1,3-DICHLOROPROPENE MIXTURE/ [R5] *2,3-Dichloropropene may be present at up to 6.5% [R6] FORM: *USEPA/OPP Pesticide Code 029001; Trade Names: Mixture, componenet of; Vidden D, component of; Nemex, component of; Telone; NCI-CO3985; Telone II; Vorlex, component of (with 029002 and 068103). [R7] *Liquid ready-to-use: 78.3 to 94.0% multiple and single active ingredient products, respectively. [R8] *The commercial formulation is a mixture of (E)- and (Z)-isomers. It is used in a mixture with 1,2-dibromoethane (Dorlone) or with 1,2-dichloropropane (D-D Soil Fumigant, Nemex, Telone, AND Vidden D). [R9, 162] *FORMULATIONS OF 1,3-DICHLOROPROPENE INCLUDE THOSE BY DOW CHEMICAL CO UNDER THE TRADEMARKS "TELONE" (78.5% 1,3-DICHLOROPROPENE, 20.5% 1,2-DICHLOROPROPANE AND RELATED COMPOUNDS), "TELONE II" (92% 1,3-DICHLOROPROPENE), AND "TELONE C17" (76.3% 1,3-DICHLOROPROPENE, 17.1% CHLOROPICRIN) /SRP: FORMER FORMULATION/ [R10] *AMOUNTS OF 1,3-DICHLOROPROPENE HAVE CHANGED OVER THE YEARS WITH THE INTRODUCTION OF NEWER FORMULATIONS (55% IN DD MIXTURE, 78% IN TELONE, 85% IN TELONE C AND 92-98% IN TELONE II) /SRP: FORMER FORMULATION/ [R5] *Telone II contains approximately 89% cis- and trans-1,3-dichloropropene, 2.5% 1,2-dichloropropene, 1.5% of a trichloropropene isomer, and 1.0% epichlorhydrin. /Telone/ [R11] *Tech product is 92-97% pure. It is a mixture of approximately equal quantities of (E)- and (Z)- isomers. [R12, 366] *Mixtures: (1,3-dichloropropene +) 1,2-dichloropropane [R12, 366] MFS: *Dow AgroSciences LLC, 9330 Zionsville Rd., Indianapolis, IN 46268, (317) 337-3000; Production site: Freeport, TX 775411 [R13] OMIN: *1,3-DICHLOROPROPENE WAS INTRODUCED /AS A PESTICIDE/ IN 1956. [R9, 162] *EPICHLOROHYDRIN (1 TO 2%) IS OFTEN ADDED TO STABILIZE MATERIAL AND TO PREVENT CORROSION. [R14] *DICHLOROPROPENE WILL REPLACE MANY FORMER USES OF ETHYLENE DIBROMIDE [R15] *1,3-Dichloropropene has been shown to react with biological materials (cow's milk, potatoes, humus-rich soil) to produce 3-chloroallyl methyl sulfide. [R16] USE: *For 1,3-Dichloropropene (USEPA/OPP Pesticide Code: 029001) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R7] *(1995) 7th most commonly used pesticide in U.S. agricultural crop production [R17] *Organic synthesis [R18] *In manufacture of pesticides [R1] *Nematicide [R19] *... EFFECTIVE IN CONTROL OF ROOT KNOT NEMATODES IN SANDY AND LOAM SOILS AT 20 USA GAL/ACRE (MARSH SOILS REQUIRED DOUBLE THIS AMT) AT SOIL TEMP OF 40-80 DEG F. [R20] *Pre-plant soil fumigant [R21] *Non-food use pesticide [R8] CPAT: *IT IS USED AS A NEMATOCIDE (SOIL FUMIGANT) AS FOLLOWS: 80% ON SUGAR BEETS; 8% ON TOBACCO; 7% ON POTATOES; 5% ON TOMATOES AND PEACH TREES (1975) [R22] *SOIL FUMIGANT FOR USE ON COTTON AND POTATOES-48%; VEGETABLES, TOBACCO AND SUGAR BEETS-38%; FLORAL, ORNAMENTAL, TREEFRUITS, TURF, MISC CROPS-14% (1984) [R15] *(1990-1995) 24,130,000 lbs active ingredient applied [R8] *The California State Department of Agriculture reported that in 1971 approximately 1,285 metric tons of pesticide containing 1,3-dichloropropene were used in that state. [R23] *(1995) 17-19.5X10+6 kg active ingredient [R17] PRIE: U.S. PRODUCTION: *(1974) 9.1X10+9 G [R22] *(1983) 1.63X10+10 g [R15] *(1979) Europe: 6-7 kilotons/yr (est) [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Amber liquid [R3]; *Colorless to straw-colored liquid [R24, 100] ODOR: *Pungent odor [R3]; *Sharp, sweet, irritating, chloroform-like odor. [R24, 100] BP: *108 deg C [R1] MP: *< -50 deg C [R12, 366] MW: *110.97 [R1] CORR: *Corrosive to aluminum, magnesium, and alloys of these metals [R25] *IT APPARENTLY REACTS WITH CERTAIN MATERIALS SUCH AS RUBBER, LEATHER, AND FUR TO FORM A STRONG ODOR. [R14] DEN: *1.220 @ 25 deg C [R1] HTC: *6900 BTU/lb= 3900 cal/g= 160x10+5 J/kg (est) [R26] HTV: *113 BTu/lb= 62.8 cal/g= 2.63x10+5 J/kg (est latent heat) [R26] OWPC: *log Kow = 1.82 [R12, 366] SOL: *Miscible with hydrocarbons, halogenated solvents, esters, and ketones. [R12, 366]; *Soluble in toluene, acetone, octane. [R18]; *In water, 2,800 mg/l @ 20 deg C [R27] SPEC: *Index of refraction: 1.4735 @ 22 deg C/D [R1] SURF: *31.2 dynes/cm= 0.0312 N/m @ 24 deg C [R26] VAPD: *3.8 (AIR= 1) [R28, p. 325-35] VAP: *34 mm Hg @ 25 deg C [R27] EVAP: *50% after 31 minutes from water at 25 deg C of 1 ppm solution [R29] OCPP: *Conversion factor: 1 ppm = 4.54 mg/cu m [R24, 100] *Specific gravity = 1.209 mg/l @ 25 deg C [R8] *Colorless to straw-colored liquid, pungent, sweet, penetrating odor; boiling point 104 deg C; specific gravity 1.211 (25 deg C0; vapor pressure 28 mm Hg (20 deg C); solubility in water approx 0.1%. /Technical/ [R19] *Soluble in hydrocarbon, halogenated solvents; esters, ketones. /DD-92 (trade name)/ [R19] *Henry's Law constant = 3.55X10-3 atm-cu m/mole @ 20 deg C [R30] *Hydroxyl radical reaction rate constant = 1.12X10-11 cu cm/molecule-sec @ 25 deg C /isomer avg/ [R31] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Dichloropropenes/ [R32] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Dichloropropenes/ [R32] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Dichloropropenes/ [R32] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. /Dichloropropenes/ [R32] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Dichloropropenes/ [R32] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Dichloropropenes/ [R32] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Dichloropropenes/ [R32] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Dichloropropenes/ [R32] FPOT: *Flammable liquid. /1,3-Dichloropropene (cis and trans)/ [R28, p. 49-52] *A flammable liquid and dangerous fire hazard when exposed to heat, flame, or oxidizers. [R33] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R28, p. 325-35] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R28, p. 325-35] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R28, p. 325-35] FLMT: *Lower flammable limit: 5.3% by volume; Upper flammable limit: 14.5% by volume [R28, p. 325-35] FLPT: *25 deg C (Abel closed cup) [R34, 308] *35 deg C (open cup) [R28, p. 325-35] FIRP: *Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Stop flow of liquid before extinguishing fire. Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R28, p. 49-52] TOXC: *Toxic and irritating gases may be generated /upon burning/ include hydrogen chloride. /1,3-Dichloropropene (cis and trans)/ [R26] *Combustion may produce irritants and toxic gases. Combustion by-products include hydrogen chloride. [R28, p. 49-52] OFHZ: *VAPORS ARE HEAVIER THAN AIR AND MAY TRAVEL TO A SOURCE OF IGNITION AND FLASH BACK. [R28, p. 49-52] EXPL: *lower, 5% and upper, 14.5% by vol in air /46% cis and 53% trans with 1% other materials, primarily epichlorohydrin/ [R14] REAC: *... /CIS-TRANS MIXTURE/ REACTS READILY WITH ALUMINUM, ALUMINUM ALLOYS, OTHER ACTIVE METALS AND SOME METAL SALTS AND HALOGENS. [R14] *Aluminum, magnesium, halogens, oxidizers [Note: Epichlorohydrin may be added as a stabilizer]. [R24, 100] *Reacts vigorously with oxidizing materials. [R33] DCMP: *DT50 11.3 day (pH 5-9, 20 deg C). [R34, 308] *When heated to decomposition it emits toxic fumes of /hydrogen chloride/. [R33] ODRT: *At 3 ppm: odor detected by 7 of 10 volunteers; at 1 ppm: odor detected by 7 of 10 volunteers [R35] SERI: *Severely irritating to skin, eyes, and mucous membranes. Prolonged contact with skin can cause severe burns. [R34, 308] *Irritating to skin, eyes and respiratory tract. [R28, p. 49-52] *Highly irritating to skin, eyes and all mucous membranes. [R36] EQUP: *NIOSH or MSHA approved respiratory protection must be worn when Telone II is exposed to atmosphere or when conducting operations which vent to atmosphere. When in use, canisters or cartridges must be replaced daily or sooner if specified by manufacturer or at first sign of odor breakthrough, whichever ... /occurs/ first. NIOSH approved cartridges, such as Welsh 7400-IL, will be adequate for short term situations ... as ... above. /Telone II/ [R37] *When very high concn of vapors ... expected (such as large spills in poorly ventilated areas) a self-contained or air-supplied respirator should be used. ... There are no protective clothing materials that are "completely" impervious. Rubber, vinyl protective gear, thin layers of polyethylene (minimum 1 mil), give short-term protection and must be immediately discarded upon contamination. Heavy (3 mil) polyethylene, rubber, neoprene provide longer term protection. [R37] *One-piece, long-sleeve, long pant coveralls, liquid proof hat, gloves, boots, and goggles or face shield. Product rapidly penetrates leather, and rubber boots should be worn. [R38] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R39, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R24, 101] *Wear appropriate eye protection to prevent eye contact. [R24, 101] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R24, 101] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R24, 101] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R24, 101] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R24, 101] OPRM: *When handling or working with Telone II, wear clean body covering incl gloves and heavy footwear. Immediately remove contaminated coverings. Aerate and wash all protective clothing and gear thoroughly after use. ... If /protective/ gear becomes contaminated, immediately wash with soap and water. Never wear protective gear having odor of Telone II. Wash and aerate all protective gear thoroughly after use until all odor is gone. Destroy all contaminated leather goods. Observe all safety precautions on label. [R37] *... Whenever exposed to the atmosphere or when it is suspected that vapor is present in the atmosphere, approved respiratory protection must be used; also by tractor drivers, field applicators during calibration, filling operations and during small spills, repairs, transfers, sampling, or when working in poorly ventilated areas. [R38] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R39, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R39, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R39, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R39, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R39, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R39, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R39, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R39, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R39, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *The worker should immediately wash the skin when it becomes contaminated. [R24, 101] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R24, 101] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. [R24, 121] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. SSL: *Stable under normal conditions. [R34, 308] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R40] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R41] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R42] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R39, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R39, 1979.13] STRG: *Keep container in a well-ventilated place. Keep away from sources of ignition, no smoking. Take precautionary measures against static discharges. [R43] *Do not contaminate food, feedstuffs, drugs, domestic water, seeds, plants, fertilizers, or other pesticide chemicals. Do not ship or store with food, feeds, drugs, or clothing. Avoid heat, open flame; do not flame-cut or weld containers. Do not handle or store on containers made of aluminum magnesium, or alloys of these metals. Store in tightly-closed original container in cool, well aired, secure area away from dwellings, or foodstuffs. Outside, store drums on sides to avoid accumulation of rain water in recessed areas. Triple rinse containers and dispose of rinsate in field just treated. After aeration dispose of containers by state or local approved procedures. Do not pollute surface or underground water supplies. [R38] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R39, 1979.13] *Outside or detached storage is preferred. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Separate from oxidizing materials and active metals. [R28, p. 49-52] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R39, 1979.15] *Eliminate all ignition sources. Approach release from upwind. Stop or control the leak, if this can be done without undue risk. Control runoff and isolate discharged material for proper disposal. [R28, p. 49-52] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U084, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R44] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R39, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R39, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R39, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R39, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by the solubility of the agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4-(4-nitrobenzyl)pyridine. /Chemical Carcinogens/ [R39, 1979.17] *A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R45] *Mix with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. Recommendable methods: Incineration and evaporation. Peer review: Evaporation may be recommendable for small amt. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R46] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *IDENTIFICATION: 1,3-Dichloropropene is a colorless to amber colored liquid with a penetrating, irritating, chloroform-like odor. It has been widely used in agriculture as a pre-plant soil fumigant for the control of nematodes in vegetables, potatoes, and tobacco. It often appears as part of a mixture also including 1,2-dichloropropane. Application is primarily by soil injection. In water, 1-3-dichloropropene is likely to disappear rapidly, because of its relatively low water solubility and high volatility. HUMAN EXPOSURE: The exposure of the general population through air, water, or food is unlikely. Occupational exposure is likely to be through inhalation and via the skin. Irritation of the eyes and the upper respiratory mucosa appears promptly after exposure. Dermal exposure caused severe skin irritations. Inhalation may result in serious signs and symptoms of poisoning with lower exposures resulting in depression of the central nervous system and irritation of the respiratory system. Some poisoning incidents have occurred in which persons were hospitalized with signs and symptoms of irritation of the mucous membrane, chest discomfort, headache, nausea, vomiting, dizziness and, occasionally, loss of consciousness and decreased libido The fertility status of workers employed in the production of chlorinated three-carbon compounds was compared with a control group. There was no indication of an assocation between decreased fertility and exposure. ANIMAL STUDIES: The acute oral toxicity of 1,3-dichloropropene in animals is moderate to high. Acute dermal exposure is moderately toxic. Acute intoxication showed central nervous and respiratory system involvement. Severe reactions were seen in rabbit skin and eye irritation tests. Degeneration of the olfactory epithelium and hyperplasia were seen in inhalation studies with mice and rats. Cis- and trans-1,3-dichloropropene and mixtures were mutagenic in bacteria with, and without, metabolic activation. In mice, increased incidences of hyperplasia of the urinary bladder, the forestomach, and the nasal mucosa were observed. There was an increase in the incidence of benign lung tumors. Some toxic changes in the olfactory mucosa of the nasal cavity were also seen in rats, but no increase in tumor incidence. The major metabolic route of elimination of 1,3-dichloropropene is via conjugation with glutathione. [R47] CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of 1,3-dichloropropene were available. There is sufficient evidence in experimental animals for the carcinogenicity of mixed isomers of 1,3-dichloropropene (technical grade). Overall evaluation: 1,3-Dichloropropene (technical grade) is possibly carcinogenic to humans (Group 2B). [R48] *WEIGHT-OF-EVIDENCE CHARACTERIZATION: Human data are inadequate for assessment of the potential human carcinogenicity of 1,3-dichloropropene because the only human data available are case studies. In chronic animal bioassays, 1,3-dichloropropene produced tumors in F344 rats (forestomach, liver) and B6C3F1 mice (forestomach, urinary bladder, and lung) at high gavage doses, liver tumor in F344 rats at lower dietary doses, and benign lung tumors in male mice exposed via inhalation. Although 1,3-dichloropropene elicited a positive response for mutagenicity in bacterial assays with the addition of S9, the most compelling evidence for mutagenicity is the isolation of mutagenic epoxide metabolites from mouse liver at high (~LD50) doses. Thus, under the current Risk Assessment Guidelines (USEPA, 1987), 1,3-dichloropropene is a B2, probable human carcinogen, because of the lack of data in humans and sufficient evidence of carcinogenicity in animals. Although the available human data are inadequate, 1,3-dichloropropene is characterized as "likely" to be a human carcinogen in accordance with the Proposed Guidelines for Carcinogen Risk Assessment (USEPA, 1996). This characterization is based on tumors observed in chronic animal bioassays for both inhalation and oral routes of exposure. Although the chronic dietary and inhalation bioassays suggest that tumors may not occur at low doses, a nonlinear mechanism of tumor formation is not supported by the available mechanistic data. In fact, the mutagenic properties of 1,3-dichloropropene suggest a genotoxic mechanism of action. The mutagenic properties and the absence of data to support a nonlinear mechanism of tumor formation require that the quantitative assessment default to a linear model. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R49] *A4. Not classifiable as a human carcinogen. [R50] ANTR: *1. FLUSH contaminating fumigants from the skin and eyse with copious amounts of water or saline for at least 15 minutes. Some fumigants are corrosive to the cornea and may cause BLINDNESS. Specialized medical treatment should be obtained promptly following removal of toxicant by copious flushing with clean water. Skin contamination may cause BLISTERING and deep chemical burns. Absorption of some fumigants across the skin may be sufficient to cause systemic poisoning in the absence of fumigant inhalation. For all these reasons, decontamination of eyes and skin must must be IMMEDIATE and THOROUGH. 2. REMOVE victims of fumigant inhalation to FRESH AIR immediately. Even though initial symptoms and signs are mild, keep the victim quiet, in a semi-reclining position. Minimum physical activity limits the likehood of pulmonary edema. 3. If victim is not breathing, clear the airway of secretions and RESUSCITATE with positive pressure oxygen apparatus. If this is not available, use chest compression to sustain respiration. If victim is pulseless, employ cardiac resuscitation. 4. If PULMONARY EDEMA is evident, there are several measures available to sustain life Medical judgement must be relied upon, however, in the management of each case. The following procedures are generally recommended: A. Put the victim in a SITTING position with a backrest. B. Use intermittent and/or continuous positive pressure OXYGEN to relieve hypoxemia. ... C. Slowly administer FUROSEMIDE, 40 mg, or SODIUM ETHACRYNATE, 50 mg, to reduce venous load by inducing diuresis. ... D. Morphine in small doses (5-10 mg), slowly, iv to allay anxiety and promote deeper respiratory excursions. E. Administer AMINOPHYLLINE (0.25-0.50 gm) slowly, iv. ... F. Digitalization may be considered, but there is a serious risk of arrhythmias in an anoxic and toxic myocardium. G. TRACHEOSTOMY may be necessary in some cases to facilitate aspiration of large amounts of pulmonary edema fluid. H. Epinephrine, atorpine, and expectorants are generally not helpful, and may complicate treatment. I. Watch for RECURRENT PULMONARY EDEMA, even up to 2 weeks after the initial episode. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. 5. Combat SHOCK by placing victim in the Trendelenburg position and administering plasma, whole blood, and/or electrolyte and glucose solutions intravenously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. 6. Control CONVULSIONS. Seizures are most likely to occur in poisonings by methyl bromide, hydrogen cyanide, acrylonitrile, phosphine, and carbon disulfide. ... /Fumigant poisoning/ [R51] *7. If a FUMIGANT LIQUID OR SOLID has been INGESTED less than several hours prior to treatment, quantities remaining in the stomach must be removed as effectively as possible by gastric intubation, aspiration, and lavage, after all possible precautions have been taken to protect the respiratory tract from aspirated gasric contents. A. Put in place a cuffed ENDOTRACHEAL TUBE prior to gastric intubation. Administer OXYGEN, using a mechanical ventilator if respiration is depressed. B. Lavage the stomach with a slurry of ACTIVATED CHARCOAL in saline or water. Leave a volume of the slurry in the stomach with an appropriate dose of sorbitol as cathartic ... . C. If treatment is delayed and if the patient remains fully alert, adminisiter activated charcoal and sorbitol orally. ... Repeated administration of charcoal at half or more the initial dosage every 2-4 hours may be beneficial. D. Do not give vegetable or animal fats or oils, which enhance gastrointestinal absorption of many of the fumigant compounds. 8. Intravenous infusions of GLUCOSE are valuable in limiting the heptotoxicity of many substances. Monitor central venous pressure to avoid precipitating, or aggravating, pulmonary edema by fluid overload. The victim should be watched closely for indications of delayed or recurrent pulmonary edema, and for bronchopneumonia. Fluid balance should be monitored, and urine sediment should be checked regularly for indications of tubular injury. Measure serum alkaline phosphatase, LDH, ALT, AST, and bilirubin to assess liver injury. 9. HEMOPERFUSION OVER ACTIVATED CHARCOAL has been used in managing a case of carbon tetrachloride poisoning with apparent success. ... 10. EXTRACORPOREAL HEMODIALYSIS may be needed to regulate extracellular fluid composition if renal failure supervenes. It is probably not very effective in removing lipophilic fumigant compounds from blood, but is, of course, effective in controlling extracellular fluid composition if renal failure occurs. /Fumigant poisoning/ [R51] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . /Dichloropropane, dichloropropene, and related compounds/ [R52, 297] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Dichloropropane, dichloropropene, and related compounds/ [R52, 298] *Stabilization: Treatment is largely supportive. Watch for respiratory depression and arrhythmias. Obtain arterial blood gases. Administer oxygen if there is evidence of altered mental status or dyspnea. Treat hypotension with volume expansion and vasopression. Use lidocaine or beta-blockers for ventricular arrhythmias. Skin: Remove contaminated clothing. Wash affected area with soap and copious amounts or water. Eye: Irrigate the eye for 15-20 min. Obtain a consultation if symptoms persist. Oral: Most of the halogenated solvents ingested in quantities of 1-2 swallows may be partially removed by ipecac-induced emesis if admin within a few hr to a patient who has not lost the gag reflex, is not seizing, is not markedly lethargic, or is not in coma. Observe the patient in the upright position to lessen the possibility of aspiration. Activated charcoal is probably ineffective. Inhalation: Move from the contaminated area. Provide a source of oxygen and prepare for mechanical ventilation. If the patient is unconscious and the pulse is absent, initiate CPR measures. Enhancement of Elimination: Maintain good ventilation. Hemodialysis or hemoperfusion are not likely to be useful because of the high lipophilic properties of these solvents. Antidote: N-acetylcysteine may restore depleted glutathione stores, but no adequate clinical studies are available to validate this possible treatment. Supportive Care: Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encephalopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, EKG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. /Halogenated hydrocarbons/ [R53] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R39, 1979.23] *The assessment of 1,3-dichloropropene exposure can be accomplished through measurement of 1,3-dichloropropene. /Whole Blood/ test can be useful for identification of exposure, However, there were no studies located that demonstrated a correlation between blood levels and exposure levels or onset of adverse clinical effects. ... The assessment of exposure can be accomplished through measurement of the N-acetyl cysteine conjugate, mercapturic acid. /Urinary/ levels of the metabolite have been found to correlate well with blood levels of 1,3-dichloropropene. However, no reference levels for this metabolite have been found to correlate with environmental exposure levels or the onset of adverse effects. [R54, 519] *Respiratory Symptom Questionnaires: Questionnaires published by the American Thoracic Society (ATS) and the British Medical Research Council have proven useful for identifying people with chronic bronchitis. Certain pulmonary function tests such as the FEV1 have been found to be better predictors of chronic airflow obstruction. [R54, 520] *Chest Radiography: Chest radiographs are widely used to assess pulmonary disease. They are useful for detecting early lung cancer in asymptomatic people, and especially for detecting peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such asbestos, experts' views on the risk-to-benefit ratio in detection of pulmonary disease conflict, so routine annual chest x-rays are not recommended for all people. [R54, 520] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. Spirometry, for the measurement of FVC (forced vital capacity) AND FEV1 (forced expiratory volume in 1 sec), has been found to be the most reproducible and least variable test of pulmonary function. [R54, 520] HTOX: *Seven of 10 volunteers detected 1,3-dichloropropene at an air concn of 3 ppm; some reported fatigue of the sense of smell after few minutes. The same proportion of volunteers detected 1 ppm, but odor was noticeably fainter. ... /It has caused/ edema, redness, and necrosis of skin /from exposure during use/. [R55] *Prolonged contact with skin will cause severe burns. [R56] *Case reports of hematologic neoplasms following intoxicating exposure to the agricultural chemical 1,3-dichloropropene were examined. In two firefighters, lymphomas appeared simultaneously several years after a simultaneous exposure at the site of a chemical spill. In both, the tumor was refractory to standard regimens of treatment, and the subjects died within a few months of one another. Leukemia developed in a farmer a few months after an initial extended daily exposure during application of the chemical to the soil. The farmer suffered from a smoldering leukemia until after a second series of daily exposures, one year later, when the leukemia became extremely aggressive. Both patterns, immediate and delayed, were recognized in the epidemiology of chemical carcinogenesis. The exposed firefighters did not develop any malignant neoplasms at the time of the report. [R57] *The effect of a common nematocide soil fumigant mixture on human skin was studied in farmers. The mixture contained 1,3-dichloropropene, 1,2-dichloropropane, and epichlorohydrin. Three cases of skin contact were examined. Patch testing was performed with ingredients of the mixture at 1 percent in acetone (concentration producing no reaction in five volunteers) and with the 20 standard allergens of the International Contact Dermatitis Research Group. Patient 1 received two 1 week exposures 1 year apart and developed an itching erythematous rash. Patient 2 developed the rash after a single exposure. Patient 3 was employed spraying pesticides on a daily basis for 10 years between /the months/ September and January. After 7 years he developed dermatitis on his arms, face, and ears which subsided upon avoidance of the nematocide. Patch testing with 1 percent produced allergic reactions in patient 1 (with spongiosis, lymphocyte infiltration and migration) but not in patients 2 and 3; however, comparisons also showed reaction to a concentration of 10% in acetone after 24 hours and blistering was noted afterward. The /results indicate/ that volunteers, as well as patients 2 and 3, experienced reactions to the mixture as a primary irritant. [R58] *Forty-six people were treated for exposure to 1,3-dichloropropene fumes following a traffic accident in 1975 involving spillage of 4500 liters of a formulated product. Twenty-four of these, 3 of whom had lost consciousness, were hospitalized overnight with symptoms including headache, irritation of mucous membranes, and chest discomfort. All patients took showers and were given iv fluids and 3 received oxygen and corticosteroids because of chest pain and cough. Eleven of 41 persons tested had slightly higher than average serum SGOT AND/or SGPT values, which reverted to normal within 48-72 hr, except for 5 who still had slightly higher then average SGOT values. Follow-up interviews with patients 1-2 wk later revealed symptoms including headache, abdominal and chest discomfort, and malaise. One was diagnosed as having had pneumonia. Symptoms were reported more frequently in those most heavily exposed to the fumes. Patient interviews conducted approx 2 yr after the accident revealed complaints of headache, chest pain or discomfort, and "personality changes" (fatigue, irritability, difficulty in concentrating, or decreased libido). Two had undergone cardiac catheterizations but their arteriograms were normal. There was no correlation of these long-persisting symptoms with intensity of exposure. [R55] *AFTER EXPOSURE TO CONCN VAPORS. LACRIMATION IS PROMINENT. ... SEVERE SKIN IRRITATION WITH MARKED INFLAMMATORY RESPONSE OF EPIDERMIS AND UNDERLYING TISSUES /FROM DERMAL EXPOSURES/. /DICHLOROPROPENES/ [R59, p. III-142] *Highly irritating to skin, eyes and all mucous membranes. [R36] *A case of sensitization to DD-95 with a nematocide containing approximately 95% 1,3-dichloropropene. A 44 yr old male process operator in a Dutch pesticide manufacturing facility developed an acute bullous dermatitis on the dorsae of both feet. He denied any chemical exposure. Patch testing with an augmented European standard allergen series produced positive reactions to wood tars and thimerosal, which were considered clinically irrelevant. A year later he developed an identical dermatitis. He remembered soiling his shoes with DD-95 the day before. He also recalled soiling his shoes with DD-95 before the earlier incident. He was patch tested with DD-95 at concn of 0.005, 0.03, 0.1, 0.5, 1, and 2% in petrolatum. All concn produced a positive response after 2 and 3 days. Patch testing 20 volunteers with 0.05% DD-95 produced negative results. It was concluded that the patient was probably sensitized to DD-95 after the initial exposure. Since DD-95 is toxic and a potent sensitizer, farmers and operators employed at pesticide manufacturing facilities who develop dermatoses should be patch tested with DD-95 as well as standard allergen series. [R60] *The effects of subchronic exposure to 1,3-dichloropropane on liver and kidney function in employees of the Dutch flower bulb industry were examined. The study was part of a larger environmental and biological monitoring study of 1,3-dichloropropene in the Dutch flower bulb culture industry. The cohort consisted of 14 commercial applicators who used 1,3-dichloropropene in soil fumigation operations in the Bollenstreek region of the Netherlands. Venous blood and spot urine samples were collected from the subjects at the start of the bulb culture season in July and after the season ended in October. The effects on liver function were assessed by determining serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma-glutamyl transpeptidase, alkaline phosphatase, and total bilirubin. The effects on kidney function were evaluated by measuring serum beta2-microglobulin and creatinine and urinary albumin, retinol binding protein), beta-galactosidase, and alanine aminopeptidase. Blood glutathione concn and erythrocyte glutathione-S-transferase activity were determined to evaluate the effect on blood glutathione conjugation capacity. Data from the environmental monitoring study indicated that the fumigators were exposed to time weighted average 1,3-dichloropropene concn of 1.9 to 18.9 mg/cu m, which exceeded the Dutch standard of 5 mg/cu m 30% of the time. A decrease in serum total bilirubin concn was the only parameter of liver function to be significantly affected by 1,3-dichloropropene. Urine albumin and retinol binding protein concn were significantly increased and serum creatinine concn was significantly decreased during the spraying season. Blood glutathione concn and erythrocyte glutathione-S-transferase activity were significantly decreased by 1,3-dichloropropene over the spraying season. The authors suggest that exposure to 1,3-dichloropropene over a spraying season may induce a subclinical nephrotoxic effect. The decreases in glutathione and glutathione-S-transferase values indicate that 1,3-dichloropropene affects glutathione conjugating capacity. [R61] *1,3-D is metabolized by conjugation with glutathione and is excreted primarily as a mercapturic acid conjugate. This urinary metabolite has been detected in workers exposed to 1,3-D vapor during fumigation. Applicator exposure was studied using personal air monitoring of 1,3-D, and monitoring of urinary excretion of the mercapturic acid metabolite and the excretion of the renal tubular enzyme, N-acetyl glucosaminidase (NAG). Urinary excretion of the metabolite correlated well with exposure to 1,3-D. Four workers ( out of 15 studied) had clinically elevated activity of NAG in any of their urine collections after baseline. Nine workers showed > 25% increases in NAG excretion when compared to baseline. Dichloropropene air exposure products of > 700 mg min/cu m or excretion of the metabolite > 1.5 mg/day distinguished abnormally high daily excretion of NAG. These data demonstrate a relationship between air exposure and dose, and a possible subclinical nephrotoxic effect in workers handling 1,3-D. [R62] *A 27 year old previously healthy male worker who accidentally drank a solution containing 1,3-dichloropropene (mixture of cis- and trans-isomers) developed gastrointestinal distress, adult respiratory distress syndrome, hematological and hepatorenal functional impairment, and died 40 hours after ingestion. [R63] *Symptomatology: 1A) Inhalation, high vapor concn: gasping, refusal to breathe, coughing, substernal pain, and extreme respiratory distress at vapor concn over 1500 ppm. Irritation of eyes and upper respiratory mucosa appears promptly after exposure to concentrated vapors. Lacrimation and headache are prominent. Coma may occur rapidly. B) Inhalation, low vapor concn: central nervous depression and moderate irritation of respiratory system. Headache is frequent. 2) Dermal: severe skin irritation with marked inflammatory response of epidermis and underlying tissues. 3) Oral: acute gastrointestinal distress with pulmonary congestion and edema. Central nervous depression, perhaps even in the absence of impaired oxygen uptake. 4) By any route, possible late injuries to liver, kidneys and heart. 5) After inhalation exposures, malaise, headache, chest and abdominal discomfort and irritability have been reported to persist for several weeks and perhaps for several years. [R59, p. III-142] NTOX: *WHEN FED TO RATS IN SINGLE DOSES AS 2.5% SOLN IN CORN OIL ... LIVER APPEARED TO BE PRINCIPAL SITE OF INJURY. DOSES OF 0.5 G/KG AS A 25% SOLUTION IN PROPYLENE GLYCOL WERE LETHAL TO RABBITS WHEN APPLIED TO SKIN BENEATH CUFF FOR 24 HR. DEATH FROM INHALATION WAS USUALLY ASSOC WITH SEVERE LUNG INJURY. [R59, p. II-168] *When fed by gavage to groups of rats at 0, 1, 3, 10, or 30 mg/kg body wt, 6 days/wk for 13 wk it was concluded ... /that/ 3 to 10 mg/kg was a nontoxic effect level. ... The relative wt of kidneys ... were incr at 30 mg/kg/day in both sexes and in males at 10 mg/kg/day. [R64, 4228] *WHEN 1,3-DICHLOROPROPENE INSTILLED INTO EYES OF RABBITS AND THEN WASHED FROM ONE EYE BY STREAM OF FLOWING TAP WATER, SEVERE CONJUNCTIVAL IRRITATION WAS SEEN IN 4 OF 6 RABBITS AND SLIGHT TO MODERATE CORNEAL INJURY WAS SEEN IN 2 OF THEM WITHIN 24 HR. INJURY GRADUALLY HEALED BY 8TH DAY. IN MOST INSTANCES, WASHING WITH WATER WAS EFFECTIVE IN AVERTING INJURY. [R9, 162] *BRIEF EXPOSURE TO CONCN ABOVE 2700 PPM WERE IRRITATING TO EYES AND NOSE OF RATS AND CAUSED SEVERE LUNG, NASAL, LIVER, AND KIDNEY INJURY. RATS WERE KILLED BY 2 HR of EXPOSURE TO 1000 PPM, BUT OTHERS SURVIVED 1 HR OF SUCH EXPOSURE. A PECULIAR GARLICKY ODOR WAS NOTED ON ... /THOSE/ EXPOSED TO 700 PPM OR GREATER. SINGLE EXPOSURE OF 7 HR TO 400 PPM WAS LETHAL TO GUINEA PIGS AND SEVERELY INJURIOUS TO RATS. [R9, 162] *EXPOSURE OF RATS AND GUINEA PIGS TO VAPOR CONCN OF ... 50 OR 11 PPM, 7 HOURS/DAY, 5 DAYS/WEEK FOR 1 MONTH PRODUCED LIVER AND KIDNEY INJURY. [R9, 162] *MALE RATS EXPOSED TO MIXED ISOMERS OF 1,3-DICHLOROPROPENE AT CONCN OF 3 PPM FOR 7 HR/DAY, 5 DAYS/WK FOR 6 MO SHOWED SLIGHT, REVERSIBLE CHANGE IN KIDNEYS. NO CHANGE WAS DETECTED IN RATS KILLED 3 MO AFTER LAST EXPOSURE. FEMALE RATS, MALE AND FEMALE RABBITS, MALE AND FEMALE GUINEA PIGS, AND FEMALE DOGS SHOWED NO ADVERSE EFFECT ... AT 1 PPM (4.5 MG/CU M). [R9, 162] *Necrosis and edema occurred when liquid 1,3-dichloropropene was confined on skin of rabbits but if allowed to evaporate the effect was greatly reduced. [R64, p. 4226-7] *Subchronic inhalation toxicity data on 1,3-dichloropropene are contradictory. Older data indicate commercial product studied ... (1958-1975) was quite irritating and hepatotoxic, but data developed on currently produced fumigants indicate considerably less hepatotoxicity. ... In early subacute study ... considerable liver and kidney injury /were/ evident grossly in small groups of rats exposed 19 times to 50 ppm, 7 hr/day in a 28-day period. Studies with more recently produced product, Telone II soil fumigants (47% cis, 45% trans, the balance related cmpd), indicate considerably lower toxicity /in/ Fischer 344 rats and CD-1 mice ... exposed 7 hr/day, 5 days/wk for 13 wk to 0, 93, 32, or 12 ppm. Exposures resulted only in failure to gain wt (high dose rats and female mice) and focal histomorphological changes of epithelium of nasal septums and turbinates in high dose rats of both sexes as well as female rats exposed to 32 ppm. Female, but not male mice, exposed to 93 ppm showed similar effects. [R64, 4226] *THE TOXICITY OF MIXED ISOMERS OF 1,3-DICHLOROPROPENE, WHEN REPEATEDLY INHALED AT LOW CONCN (1 OR 3 PPM) FOR SIX MO WAS INVESTIGATED. RATS, GUINEA PIGS, RABBITS, AND DOGS RECEIVED 7 HR DAILY EXPOSURES 5 DAYS PER WK TO 1 PPM FOR 6 MO WITH NO ADVERSE EFFECT. THE ONLY EFFECT IN ANY GROUP EXPOSED TO 3 PPM WAS SLIGHT, APPARENTLY REVERSIBLE CHANGE SEEN MICROSCOPICALLY IN KIDNEYS OF MALE RATS EXPOSED 7 OR 4 HR/DAY. [R65] *In a test conducted on a mixed assemblage of emerald shiners and fathead minnows exposed to 1,3-dichloropropene, 100% of the fish survived 3 days at 1,000 ug/l, and none survived at 10,000 ug/l. [R66] *Four preparations of 1,3-dichloropropene were assayed for mutagenic activity before and after silicic acid chromatography. None of the preparations retained mutagenic activity after chromatography, but each contained direct acting mutagenic polar impurities in the Ames test. The specific mutagenic activities of the unpurified samples appeared to be detected by the mutagenic activities of their polar impurities. A mixture of mutagenic polar impurities could be regenerated by refluxing a purified preparation for 6 hr. The fraction of polar impurities from one of the preparations was analyzed by GC/MS. Although its composition was too complex to characterize completely, two known mutagens, epichlorhydrin and 1,3-dichloro-2,2-propanol, were tentatively identified. [R67] *Telone was tested over a range of 7 doses in the mouse to assess their testicular toxicity. Measures of potential toxicity were sperm morphology, sperm counts and morphology testicular weights. Each pesticide was injected intraperitoneally in a single dose on each of 5 days. Testicular toxicity was assessed at 35 days. None of the pesticides tested, including the known human male testicular toxin, DBCP, produced statistically significant differences in the parameters from vehicle injected controls. [R68] *1,3-Dichloropropene at 20 ug/ml of air, killed 100% of microsclerotia after incubation for 30 hr, and at 100 ug/g of soil moisture after incubation for 3 days. Higher temperatures increased the toxicity. [R69] *Telone II (technical grade 1,3-dichloropropene) was evaluated in chronic toxicology/carcinogenicity studies using Fischer-344 rats and B6C3F1 mice of both sexes. Doses administered were 0, 25, or 50 mg/kg to rats (52 rats of each sex per dose group) and 0, 50, or 100 mg/kg to mice (50 mice of each sex per dose group). Telone II was given in corn oil by gavage 3 times per week for 104 weeks. Ancillary studies were conducted in which 5 rats of each sex in each dose group were killed and necroscopied after 9, 16, 21, 24, or 27 months. There was a significant increase (0.001 < p < 0.05) over controls in neoplastic lesions of the forestomach (male and female rats, female mice), urinary bladder (female mice), lung (female mice), and liver (male rats). The presence of 1% epichlorohydrin, a direct acting mutagen and carcinogen added as a stabilizer may have influenced the development of forestomach lesions. [R70] *1,3-Dichloropropene (DCP) was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster using a standard protocol approved by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of 1,3-dichloropropene that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. 1,3-Dichloropropene was positive at a dose of 5,570 ppm when administered to males by feeding. [R71] *1,3-Dichloropropene (DCP), which has found widespread use as a soil fumigant, was evaluated for its potential effects on embryonal and fetal development in rats and rabbits. Pregnant Fischer 344 rats and New Zealand White rabbits were exposed to 0, 20, 60, or 120 ppm of 1,3-dichloropropene for 6 hr/day during gestation days 6-15 (rats) or 6-18 (rabbits). Exposure-related decreases in maternal weight gain and feed consumption were observed in rats at all treatment levels. Decreased weight gain was also observed among rabbits at 60 and 120 ppm. A slight, but statistically significant, increase in the incidence of delayed ossification of the vertebral centra in rats exposed in utero to 120 ppm of 1,3-dichloropropene was considered of little toxicologic significance in light of the maternal toxicity observed at this exposure concentration. No evidence of a teratogenic or embryotoxic response was observed in either species at any exposure level /up to 120 ppm/ tested. [R72] *... 1,3-Dichloropropene administered by intraperitoneal injections of 0 to 75 mg/kg/day for 5 days had no effect on sperm count, sperm morphology, or testicular weights in mice. [R73] *The effects of 1,3-Dichloropropene (DCP) upon the trypsin, trypsin inhibitor, amylase, and lipase activities in the blood serum of albino rats /were investigated/. Animals were fed daily doses of 0.1, 0.5, and 2.5 mg of 1,3-dichloropropene/kg bw for 6 months. The results showed that ... trypsin activity increased through the 6 months of admin, while the activity of trypsin inhibitor decreased after the second month of admin. Also blood lipase activity permanently increased, while amylase tended to be reduced. [R74] *Not toxic to bees when used as directed. [R34, 309] *Groups of albino rats were fed daily oral doses of 2.2 and 55 mg of 1,3-dichloropropene (DCP)/kg /body weight/ for 30 days. The results showed that by day 30 of admin the excretory liver function was altered, as evidenced by pigment circulation in the blood, raised thymol test values, cholesterol level, and the stimulated increase of fructose 1-monophosphate aldolase. [R75] *An oral dose of 3500 mg/kg /in dogs/ caused staggering, partial /CNS depression/ and death within 24 hr. [R76] *Rats were exposed to 3 ppm (13.6 mg/cu m) for periods of 0.5, 1, 2, or 4 hr/day, 5 day/wk for 6 mo. Only the rats exposed for 4 hr/day showed ... cloudy swelling of the tubular epithelium. [R77] *... The acute toxicity /of 1,3-dichloropropene/ to saltwater aquatic life occurs at concn as low as 790 mg/l. [R78] *The effectiveness of 1,3-dichloropropene applied at various rates and horizontal chisel spacing was evaluated for control of cotton (Gossypium) root rot caused by Phymatotrichum omnivorum. With 281 l/ha applied in 48 cm horizontal chisel spacing, cotton lint yield was 724 kg/ha, as compared with 250 kg/ha for the check. The fumigant treatments delayed infection by the fungus and reduced the number of infected plants as compared with the check. A 2 wk delay in plant mortality is sufficient for the short-season cultivars to set and mature a near-normal crop. [R79] *The subchronic reproductive toxicity of DD, a mixture of 1,3-dichloropropene and 1,2-dichloropropane, was studied in rats. Wistar rats were exposed by inhalation to 0, 10, 30, or 90 ppm DD 6 hr daily 5 days a wk for 10 wk. Selected male rats from each exposure group were mated with unexposed virgin females during wk 3, 5, 8, and 10 of exposure. On the 12th day after mating, each female was killed and examined for numbers of corpora lutea, uterine implantation, and resorption sites. After the 10 wk exposure period, selected females from each exposure group were mated with unexposed males. Gestation lengths were recorded. After delivery, the number of live and dead pups was recorded on postnatal days 0, 1, and 4. The litters were weighed on postnatal days one and four. Other animals were killed 10 to 22 hr, 5 wk, or 7 wk after exposure ended and necropsied. Semen samples were examined for sperm abnormalities. Vaginal smears were taken and stained to evaluate estrus cycle activity. DD exerted no adverse effects on sperm morphology or estrus cycling activity. None of the measured reproductive parameters were affected by DD. Kidney and liver weights were slightly increased in rats of either sex exposed to 90 ppm DD. No other treatment related gross or histopathologic changes were seen. /DD/ [R80] *Toxicology and carcinogenesis studies of Telone II (a soil fumigant containing approx 89% cis- and trans-1,3-dichloropropene, 2.5% 1,2-dichloropropane, 1.5% of a trichloropropene isomer, and 1.0% epichlorohydrin) were conducted by administering the commercial-grade formulation in corn oil by gavage to groups of 52 male and 52 female F344/N rats at doses of 0, 25, or 50 mg/kg and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 25, or 50, 100 mg/kg. Doses were administered three times per week for 104 weeks. Ancillary studies were conducted in which dose groups containing five male and five female rats were killed after receiving Telone II for 9, 16, 21, 24, or 27 months. The primary organs affected were the forestomach (rats and mice), urinary bladder (mice), lung (mice), and liver (rats). Compound related non-neoplastic lesions included basal cell or epithelial hyperplasia of the forestomach (rats and mice), epithelial hyperplasia of the urinary bladder (mice), and kidney hydronephrosis (mice). Neoplastic lesions associated with administration of Telone II included squamous cell papillomas of the forestomach, squamous cell carcinoma of the forestomach, transitional cell carcinoma of the urinary bladder, alveolar/bronchiolar adenomas, and neoplastic nodules of the liver. Development of lesions in the forestomach (basal cell hyperplasia and squamous cell papilloma) was observed to be time dependent. The results of the scheduled kills supported the findings of the carcinogenesis studies. /Telone II (Technical grade 1,3-Dichloropropene, containing 1.0% epichlorohydrin as a stabilizer)/ [R81] *Adult Fischer 344-rats and New-Zealand-White rabbits were used to determine the effect of the inhalation of 1,3-dichloropropene in concn ranging from 20 to 120 ppm. The rats were exposed to 1,3-dichloropropene from gestation days six to 15, while the rabbits were exposed to the product from gestation days six to 18. At all dose levels, reduction in maternal body weight and decreased feed consumption were evident. Rats exposed in-utero to 120 ppm 1,3-dichloropropene had a slight but significant increase in the incidince of delayed ossification of the vertebral centra, but there was no consistent evidence of teratogenic or embryotoxic effects in either species, regardless of the dose. The appearance and behavior of the exposed animals were not altered, and there was no mortality attributable to treatment. [R82] *The reproductive and developmental effects of inhaled 1,3-dichloropropene were studied using Fischer 344 rats. The F0 generation animals were exposed by inhalation to 0, 10, 30, or 90 ppm 1,3-dichloropropene for 6 hr/day, 5 days/wk for 10 wk before mating and for 6 hr/day, 7 days/wk during mating, gestation, and lactation. Weaned F1 rats followed the same dosing regimen. The animals were evaluated for fertility, pup survival, length of gestation, litter size, pup body wt, pup sex ratio, gross pathology, and histological alterations. 1,3-dichloropropene exposure had no significant effect on either behavior or clinical appearance of the animals. A decrease in body wt during the exposure period was observed for all F0 and F1 males and females treated at the 90 ppm level. No significant changes in mating, conception, gestation period, cohabitation time required for mating, pup survival, pup body wt, litter size, or pup appearance were determined following 1,3-dichloropropene treatment, nor were any treatment related histopathological changes observed in male or female reproductive tissues. The exposure of adult male an female rats to 90 ppm 1,3-dichloropropene produced characteristic stress lesions in the nasal mucosa. The authors conclude that the inhalation of 1,3-dichloropropene vapors does not adversely affect the reproduction and neonatal development in Fischer 344 rats. [R83] *A series of mutation experiments was carried out with Drosophila melanogaster using inhalation exposure. 1,2-Dichloroethane and 1,2-dibromoethane were active in the sex-linked recessive lethal assay, whereas dichloromethane, dibromomethane, 1,2-dichloropropane an 1,3-dichloropropane were not. Compared to 1,2-dibromoethane, 1,2-dichloroethane is a less potent mutagen in the sex-linked recessive lethal assay system. For both compounds, there is no evidence of a clear-cut dose-rate effect. 1,2-Dichloroethane and dichloromethane were also investigated in the somatic mutation and recombination test, with results similar to those from the sex-linked recessive lethal assay. For 1,2-dichloroethane the genetic activity profile was further analyzed by carrying out a sex-chromosome loss assay and a complementation analysis of a series of induced recessive lethal mutations. A review of the use of inhalation in mutagenicity assays with Drosophila shows that this route of exposure is an effective one. Especially with chronic exposure times, rather low exposure concn can be detected. With compounds of intermediate volatility inhalation is not superior to other modes of administration; nor is it likely to be sensitive enough for in situ monitoring. [R84] *The subchronic reproductive toxicity of D-D, a mixture of 1,3-dichloropropene and 1,2-dichloropropane, was studied in rats. Wistar rats were exposed by inhalation to 0, 10, 30, or 90 ppm 1,3-dichloropropene/1,2-dichloropropane 6 hr daily 5 days a wk for 10 wk. Selected male rats from each exposure group were mated with unexposed virgin females during wk 3, 5, 8, and 10 of exposure. On the 12th day after mating, each female was killed and examined for numbers of corpora lutea, uterine implantation, and resorption sites. After the 10 wk exposure period, selected females from each exposure group were mated with unexposed males. Gestation lengths were recorded. After delivery, the number of live and dead pups was recorded on postnatal days 0, 1, and 4. The litters were weighed on postnatal days one and four. Other animals were killed 10 to 22 hr, 5 wk, or 7 wk after exposure ended and necropsied. Semen samples were examined for sperm abnormalities. Vaginal smears were taken and stained to evaluate estrus cycle activity. 1,3-Dichloropropene/1,2-dichloropropane exerted no adverse effects on sperm morphology or estrus cycling activity. None of the measured reproductive parameters were affected by 1,3-dichloropropene/1,2-dichloropropane. Kidney and liver wt were slightly increased in rats of either sex exposed to 90 ppm 1,3-dichloropropene/1,2-dichloropropane. No other treatment related gross or histopathologic changes were seen. It was concluded that subchronic inhalation of 1,3-dichloropropene/1,2-dichloropropane at concn up to 90 ppm does not affect the reproductive system of rats of either sex. [R85] *A comprehensive chronic inhalation toxicity and oncogenicity bioassay was performed on rats treated with 1,3-dichloropropene. 1,3-Dichloropropene was used as an agricultural pesticide and inhalation was thought to be the major route of human exposure. Male and female Fischer 344 rats and B6C3F1 mice were exposed to 1,3-dichloropropene by inhalation for 6 hr/day, 5 days/wk for up to 24 mo. Concn of 0, 5, 20, and 60 ppm 1,3-dichloropropene vapors were used. No clinical signs indicative of toxicity and no significant differences in survival were observed between any groups of either sex of rats or mice. There were no apparent increases in palpable masses due to exposure to 1,3-dichloropropene. Data from urinalysis and hematological and biochemical studies of 1,3-dichloropropene treated animals showed no signs of toxicity. Gross pathological exam of treated rats revealed no apparent exposure related effects. In mice, morphological alterations involving the urinary bladder and lung were attributed to 1,3-dichloropropene exposure. Hyperplasia of the transitional epithelium of the urinary bladder was observed in nearly all female mice exposed to 60 ppm 1,3-dichloropropene for 12 and 24 mo and in some female mice exposed to 20 ppm for 12 and 24 mo. An incr in benign bronchioloalveolar adenomas was seen in male mice exposed to 60 ppm 1,3-dichloropropene. There were no statistically significant increases in primary, benign, or malignant tumor incidence in exposed rats. Nasal tissue of mice exposed to 20 or 60 ppm and of rats exposed to 60 ppm for 24 mo showed morphological alterations consisting mainly of hypertrophy and hyperplasia. It was concluded that the results clearly demonstrate a dramatic difference between the tumorigenic response of rats and mice to inhaled 1,3-dichloropropene versus that observed in a previous gavage bioassay and state that this finding is significant because most human exposure is by inhalation of vapor and not by ingestion. [R86] *The role of the chlorinated alkane solvent effect on the inhibition of hepatic triglyceride secretion was investigated using male Swiss Webster mice and male Sprague Dawley rats. Triglycerides were measured in serum of treated animals or in supernatants of isolated hepatocytes exposed to solvents and tritiated glycerol. Two hours following carbon tetrachloride injection, triglyceride levels were reduced significantly to 42% o control values and to 15% by 8 hr. Methylene chloride caused a more rapid decline in serum triglyceride concn. Significant dose related decreases in serum triglyceride levels at 2 hr followed the administration of 1-chloropropane, 1-chlorobutane, 1-chloropentane, 1-chlorohexane, 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, and 1,5-dichloropentane. The shorter chain, less lipid soluble solvents were the more potent at decreasing triglyceride secretion in vivo. In freshly prepared isolated hepatocyte systems, the relationship between 50% inhibitory concn and lipid solubility was opposite to that observed in vivo. The more lipid soluble solvents were the more potent at decreasing secretion in vitro. The authors suggest from this finding that nonspecific solvent effects on membrane integrity may be important in the inhibition of triglyceride secretion. The chlorinated alkane induced development of fatty liver through inhibition of triglyceride secretion may be related to lipid solubility of the chemical rather than to its metabolism to free radicals. [R87] *A comprehensive study was made of the subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fischer 344 rats and B6C3F1 mice were exposed to target concn of 0, 10, 30, 90, and 150 ppm 1,3-dichloropropene for 6 hr/day, 5 days/wk, for 13 wk. Animals were observed for signs of toxicity twice daily on exposure days and were weighed approx weekly. After exposure, surviving animals were sacrificed and examined by clinical laboratory, gross necroscopic, and histopathologic studies. No treatment related deaths were observed. Dose related decreases in body wt were seen in both species. No significant treatment related changes in clinical chemistry, hematology, and urinalysis profiles were noted, except those which could be related to reduced growth. Both sexes of rats and mice showed treatment related histological changes in nasal mucosa. Female mice had urinary bladder alterations and female rats had uterine changes. Dose related slight degeneration of nasal olfactory epithelium and/or mild nasal respiratory epithelial hyperplasia were observed in all animals exposed to the 2 highest doses and in 2 of 10 male rats exposed to 30 ppm. High exposure group mice showed some focal areas of respiratory metaplasia. Uterine changes in rats were suggestive of hypoplasia and were attributed to growth retardation. Female mice in the 2 highest exposure groups had diffuse moderate hyperplasia of the urinary bladder transitional epithelium. The authors conclude that nasal mucosa of rats and mice and urinary bladder of female mice are potential target tissues of inhaled 1,3-dichloropropene. [R88] *Adult Fischer 344 rats and New Zealand White rabbits were used to determine the effect of the inhalation of 1,3-dichloropropene in concns ranging from 20-120 ppm. The rats were exposed to 1,3-dichloropropene from gestation days 6-15, while the rabbits were exposed to the product from gestation days 6-18. At all dose levels, reduction in maternal body wt and decreased feed consumption were evident. Rats exposed in utero to 120 ppm 1,3-dichloropropene had a slight but significant incr in the incidence of delayed ossification of the vertebral centra, but there was no consistent evidence of teratogenic or embryotoxic effects in either species, regardless of the dose. The appearance and behavior of the exposed animals were not altered, and there was no mortality attributable to treatment. It was concluded that exposure of pregnant rats and rabbits to 1,3-dichloropropene in concns of up to 120 ppm during the embryonic period does not present a teratogenic risk for either species, and that the slight fetal toxicity observed is seen at a 1,3-dichloropropene level which also induces evident maternal toxicity. [R89] NTOX: *Subchronic studies were also performed with rats, rabbits, and guinea pigs, involving exposures to 1 or 3 ppm for 125-130 times over a period of 185 days. Male rats exposed to 3 ppm exhibited cloudy swelling of the renal tubular epithelium. Female rats exhibited slight but statistically significant increases liver-to-body weight ratio. [R62] *F344 rats of each sex were gavaged with Telone in corn oil at doses of 0, 25, and 50 mg/kg/day 3 times/wk. No incr mortality occurred in treated animals. Elevated incidence of the following tumors were observed at the highest dose tested: (a) forestomach squamous cell papillomas in males and females; (b) forestomach squamous cell papillomas and carcinomas combined in males and (c) liver neoplastic nodules in males. The incr incidence of forestomach tumors was accompanied by a positive trend for forestomach basal cell hyperplasia in male and female rats of both treated groups (25 and 50 mg/kg/day). B6C3F1 mice of each sex were gavaged with Telon II in corn oil at doses of 0, 50, and 100 mg/kg/day 3 times/wk for 104 wk. A total of 50 mice/sex were used for each dose group. Due to excessive mortality in control male mice from myocardial inflammation approx 1 yr after the initiation of the study (a time when neoplastic lesions would not be expected to occur), conclusions pertaining to oncogenicity were based on both concurrent control data as well as on available NTP historical control data. Elevated incidence of the following tumors were observed either at the highest dose level tested or at both dose levels tested: (a) forestomach squamous cell papillomas or papillomas and carcinomas combined in males and females, and squamous cell carcinomas in females; (b) urinary bladder transitional cell carcinomas in males and females; and (c) lung adenomas, and adenomas and carcinomas combined in males and females. [R62] *During /acute inhalation/ exposure and observation periods, the following symptoms were observed: partial closing of the eyes, pilo-erection, salivation, lacrimation, lethargy, diarrhea, reduction in respiratory rate, irregular respiratory movements (lung congestion was observed in dead animals) and hunched posture, brown staining of fur and fur loss, and reddening of ears, tail, and feet. Pathological signs were cardiopulmonary failure, acute tubular necrosis in the kidneys, and local effects on the respiratory tract. [R90] *The following signs of toxicity were observed after oral admin: hunched posture, lethargy, pilo-erection, decreased respiratory rate, ptosis, diarrhea, diuresis, ataxia, tip-toe gait, red/brown staining around the snout, tremors, emaciation, and pallor of the extremities. Hemorrhages and congestion were found in the lungs and GI tract. The livers showed patchy areas of pallor. [R90] *After dermal application, the signs of intoxication were: diarrhea, lethargy, hunched posture, decreased respiratory rate, with lacrimation, salivation, ataxia or abasia, loss of righting reflex, diuresis, and red/brown staining around the eyes, snout, or mouth. The lungs and GI tract showed hemorrhages and irritation. Signs of skin irritation manifested by edema, eschar formation, or subcutaneous hemorrhage were apparent. [R91] *Technical grade 1,3-dichloropropene (containing 1.0% epichlorohydrin) was tested for carcinogenicity by gavage in one experiment in mice and in one experiment in rats. In mice, it produced dose related increases in the incidence of benign and/or malignant tumors of the urinary bladder, lung and forestomach. In male rats, it produced dose-related increases in the incidence of benign and malignant tumors of the forestomach. [R92] *Treatment.with buthionine sulfoximine (0.2 m in 0.58% NaCl, 4 ml/kg body weight (to inhibit glutathione synthesis) 4 hr before dosing. with 1,3-dichloropropene or with diethyl maleate (3.1 m in corn oil, 0.4 ml/kg body weight) (to deplete glutathione) or corn oil itself 1 hour before dosing with 1,3-dichloropropene at 50 and 75 mg/kg body weight, resulted in elevations of N-acetylglucosaminidase excretion. In contrast, treatment with aminooxyacetic acid (0.125 m in 0.85 % NaCl, 4 ml/kg body weight) (which inhibits beta lyase activity) 1 hour before 1,3-dichloropropene injection prevented the 1,3-dichloropropene induced release of N-acetylglucosaminidase from the renal tubule. These results suggest that the nephrotoxic effects of 1,3-dichloropropene may be mediated through the mercapturic acid metabolites in the kidney, rather than glutathione depletion. [R93] *1,3-Dichloropropene was administered to male and female Fischer 344 rats and B6C3F1 mice for 13 weeks (0, 5, 15, 50 or 100 mg/kg bw per to rats or 0, 15, 50, 100 or 175 mg/kg bw per day to mice) in the diet by mixing a microencapsulated formulation of 1,3-dichloropropene into animal feed (microencapsulated in a 80/20% starch) sucrose matrix; 1,3-dichloropropene consisted of 50.7% cis, 45.1% trans isomers). There was a decrease in the body weights of male and female rats ingesting more than 5 and 15 mg/kg bw per day, respectively, and a decrease in body weights of mice in all treatment groups relative to controls. A low degree of basal cell hyperplasia in the nonglandular portion of the stomach of male and female rats exposed to more than 15 mg/kg bw per day was also observed, but the severity of the damage was somewhat diminished after a four week recovery period during which the rats were not exposed to 1,3-dichloropropene. [R93] NTXV: *LD50 Rat oral 140 + or - 25 mg/kg; [R94] *LD50 Mouse oral 300 + or - 27 mg/kg; [R94] *LD50 Rabbit dermal 2100 + or - 260 mg/kg; [R94] *LD50 Rabbit dermal 504 mg/kg; [R95] *LC50 Rat inhalation 2.7-3.07 mg/l air/4 hr; [R34, 308] *LD50 Rat percutaneous 1200 mg/kg; [R34, 308] *LD50 Rat (male) oral 713 mg/kg /a 92% product (a cis:trans mixture) when fed as a 10% soln in corn oil/; [R14] *LD50 Rat (female) oral 470 mg/kg /a 92% product (a cis:trans mixture) when fed as a 10% soln in corn oil/; [R14] *LD50 Rat skin 775 mg/kg; [R33] *LD50 Rat ip 175 mg/kg; [R33] *LC50 Mouse inhalation 4650 mg/cu m/2 hr; [R33] *LD50 Mouse (CD1) oral 215 mg/kg bw /From table/; [R96] *LD50 Mouse (JCL:ICR, male) oral 640 mg/kg bw /From table/; [R96] *LD50 Mouse (JCL:ICR, female) oral 640 mg/kg bw /From table/; [R96] *LD50 Rat (Fischer 344) oral 94 mg/kg bw /From table/; [R96] *LD50 Rat (CD) oral 127 mg/kg bw /From table/; [R96] *LD50 Rat (Wistar, male) oral 560 mg/kg bw /From table/; [R96] *LD50 Rat (Wistar, female) oral 510 mg/kg bw /From table/; [R96] *LC50 Rat (Wistar) inhalation 3309.7 mg/cu m/4 hr /From table/; [R97] *LC50 Rat (Fischer 344, male) inhalation 3041.8 mg/cu m/4 hr /From table/; [R97] *LC50 Rat (Fischer 344, female) inhalation 3337.8 mg/cu m/4 hr /From table/; [R97] *LC50 Rat (Crb:CD(SD)Br, male) inhalation 4880.5 mg/cu m/4 hr /From table/; [R97] *LC50 Rat (Crb:CD(SD)Br, female) inhalation 5402.6 mg/cu m/4 hr /From table/; [R97] *LD50 Mouse (JCL:ICR) dermal > 1.211 g/kg bw /From table/; [R91] *LD50 Mouse (JCL:ICR, male) subcutaneous 0.33 g/kg bw /From table/; [R91] *LD50 Mouse (JCL:ICR, female) subcutaneous 0.345 g/kg bw /From table/; [R91] ETXV: *LC50 DAPHNIA MAGNA (WATER FLEA) 90 UG/L/48 HR AT 21 DEG C, 1ST INSTAR (95% CONFIDENCE LIMIT 63-129 UG/L) /TECHNICAL MATERIAL, 100%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R98] *LC50 PIMEPHALES PROMELAS (FATHEAD MINNOW) 4100 UG/L/96 HR AT 18 DEG C, WT 0.9 G (95% CONFIDENCE LIMIT 3390-4970 UG/L) /TECHNICAL MATERIAL, 100%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R98] *LC50 MICROPTERUS SALMOIDES (LARGEMOUTH BASS) 3650 UG/L/96 HR (IN HARD WATER, 272 PPM CALCIUM CARBONATE) AT 18 DEG C, WT 1.0 G (95% CONFIDENCE LIMIT 3520-3780 UG/L) /TECHNICAL MATERIAL, 100%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R98] *LC50 STIZOSTEDION VITREUM (WALLEYE) 1080 UG/L/96 HR AT 18 DEG C, WT 1.3 G (95% CONFIDENCE LIMIT 990-1180 UG/L) /TECHNICAL MATERIAL, 100%/. STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L; [R98] *LC50 Mallard duck > 10,000 mg/kg in a 5 day diet; [R34, 308] *LC50 Bobwhite quail > 10,000 mg/kg in a 5 day diet; [R34, 308] *LC50 Rainbow trout 3.9 mg/l/96 hr /Conditions of bioassay not specified/; [R34, 308] *LC50 Lepomis macrochirus (bluegill sunfish) 6060 ug/l/96 hr /Unmeasured static bioassay/; [R99] *LC50 Mysidopsis bahia (mysid shrimp) 790 ug/l/96 hr /Unmeasured static bioassay/; [R99] *LC50 Cyprinodon variegatus (sheepshead minnow) 1770 mg/l/96 hr /Unmeasured static bioassay/; [R99] *EC50 Daphnia magna 6150 ug/l/48 hr /Unmeasured static bioassay/; [R99] *EC50 Selenastrum capricornutum (freshwater alga) 4950 ug/l/96 hr (effected Chlorophyll A production) /Conditions of bioassay not specified/; [R100] NTP: *Toxicology and carcinogenesis studies of Telone II (a soil fumigant containing approx 89% cis- and trans-1,3-dichloropropene, 2.5% 1,2-dichloropropane, 1.5% of a trichloropropene isomer, and 1.0% epichlorohydrin) were conducted by administering the commercial-grade formulation in corn oil by gavage to groups of 52 male and 52 female F344/N rats at doses of 0, 25, or 50 mg/kg and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 25, or 50, 100 mg/kg. Doses were administered three times per week for 104 weeks. Ancillary studies were conducted in which dose groups containing five male and five female rats were killed after receiving Telone II for 9, 16, 21, 24, or 27 months. The primary organs affected were the forestomach (rats and mice), urinary bladder (mice), lung (mice), and liver (rats). Compound related non-neoplastic lesions included basal cell or epithelial hyperplasia of the forestomach (rats and mice), epithelial hyperplasia of the urinary bladder (mice), and kidney hydronephrosis (mice). Neoplastic lesions associated with administration of Telone II included squamous cell papillomas of the forestomach, aquamous cell carcinoma of the forestomach, transitional cell carcinoma of the urinary bladder, alveolar/bronchiolar adenomas, and neoplastic nodules of the liver. Development of lesions in the forestomach (basal cell hyperplasia and squamous cell papilloma) was observed to be time dependent. The results of the scheduled kills supported the findings of the carcinogenesis studies. /Telone II (Technical grade 1,3-Dichloropropene, containing 1.0% epichlorohydrin as a stabilizer)/ [R81] ADE: *Absorption through skin occurred particularly when the liquid was confined or when in propylene glycol solution which retarded evaporation. [R64, 4227] *... Significant differences are apparent in the elimination rates of the cis and trans /isomers/ of 1,3-dichloropropene. /cis- and trans-1,3-Dichloropropene/ [R101] *Kinetic data on the uptake of vapors of technical grade 1,3-dichloropropene (DCP) and resultant cis- and trans-1,3-dichloropropene blood concns were obtained in rats exposed to 30, 90, 300, or 900 ppm 1,3-dichloropropene for 3 hr. The uptake of 1,3-dichloropropene did not incr proportionately with increasing exposure concn due to an exposure level related decr in the respiratory ventilatory frequency of rats exposed to > or = 90 ppm 1,3-dichloropropene and the saturation of metab of 1,3-dichloropropene by rats exposed to > or = 300 ppm 1,3-dichloropropene. Absorption of inhaled 1,3-dichloropropene occurred primarily in the lower respiratory tract, although a small amount of the chemical was absorbed via the nasal mucosa, a known target tissue of inhaled 1,3-dichloropropene in rats. Following absorption, both isomers of 1,3-dichloropropene were, at < or = 300 ppm exposure levels, rapidly eliminated from the bloodstream (3-6 min half-life). In addn, data obtained in rats exposed to 300 ppm 1,3-dichloropropene revealed that this rapid elimination phase was followed by a slower elimination phase having a 33-34 min half-life. Rats exposed to 900 ppm vapors also eliminated 1,3-dichloropropene in a biphasic manner; however, in this case the blood half-life of 1,3-dichloropropene during the initial phase of excretion was 14-27 min. Exposure of 90 ppm 1,3-dichloropropene also produced a significant decr in renal (31%) and hepatic (41%), but not pulmonary, nonprotein sulfhydryl content. [R102] *A biological monitoring study was carried out in the Dutch flower-bulb culture to determine the relationship between respiratory occupational exposure to Z- and E-1,3-dichloropropene and urinary excretion of two mercapturic acid metabolites, N-acetyl-S-(Z- and E-3-chloropropenyl-2)-L-cysteine. Urinary excretion of N-acetyl-S-(Z-3-chloropropenyl-2)-L-cysteine and N-acetyl-S-(E-3-chloropropenyl-2)-L-cysteine, either based on excretion rates or on creatinine excretion, followed first order elimination kinetics after exposure. Urinary half-lives of elimination were 5.0 + or - 1.2 hr for N-acetyl-S-(Z-3-chloropropenyl-2)-L-cysteine and 4.7 + or - 1.3 hr for N-acetyl-S-(E-3-chloropropenyl-2)-L-cysteine and were not statistically significantly different. Calculated coefficients of variation indicated that the half-life of elimination of N-acetyl-S-(Z-3-chloropropenyl-2)-L-cysteine and N-acetyl-S-(E-3-chloropropenyl-2)-L-cysteine were quite consistent inter- and intra-individually. Strong correlations (r > 0.93) were observed between respiratory 8 hour time weighted average (TWA) exposure to Z- and E-1,3-dichloropropene and complete cumulative urinary excretion of N-acetyl-S-(Z-3-chloropropenyl-2)-L-cysteine and N-acetyl-S-(E-3-chloropropenyl-2)-L-cysteine. Z-DCP yielded three times more mercapturic acid than E-1,3-dichloropropene, probably due to differences in metabolism. Z-1,3-dichloropropene and E-1,3-dichloropropene were excreted 45 and 14% as their respective mercapturic acid metabolites. A respiratory 8 hour TWA exposure to the Dutch occupational exposure limit of 5 mg M(-3) 1,3-Dichloropropene would result in a complete cumulative excretion of 14.4 mg (95% confidence interval: 11.7 - 17.0 mg) N-acetyl-S-(Z-3-chloropropenyl-2)-L-cysteine and 3.2 mg (95% confidence interval: 2.3-4.1 mg) N-acetyl-S-(E-3-chloropropenyl-2)-L-cysteine. [R103] *Groups of 8 adult Fischer 344 rats/sex were given non radiolabelled 1,3-dichloropropene at 5 mg/kg bw, in corn oil, by gavage, for 14 consecutive days, prior to a single dose of 5 mg 14C-1,3-dichloropropene/kg bw (actual 4.5 mg) (uniformly labeled) (96.3%; 53.3% cis- and 43.0% trans-), administered to 5 out of the 8 rats on day 15. The remaining 3 rats/sex were sacrificed. The distribution of radioactivity found in the tissues (4-6%) of repeatedly dosed rats, 2 rats of each sex, which had not been previously dosed, received a single gavage dose of 5 mg 14C-1,3-dichloropropene/kg bw. The urine was the major route of elimination of the radioactivity derived from 14C-1,3-dichloropropene, which ranged from 60-65% of the administered dose in 48 hr in the rats with repeated doses and a single dose. Elimination of 1,3-dichloropropene as 14/carbon dioxide/ was approx (average) 26% of the administrated radioactivity with about 4-5% of the dose eliminated in the feces, for all groups. [R104] *In rats, 1,3-dichloropropene is absorbed rapidly, after either inhalation or oral administration, and is eliminated principally by metabolism (glutathione conjugation) within 24-48 hours. [R105] METB: *The major urinary metabolite in rats given 1,3-dichloro-2-propene was a mercapturic acid. [R59, p. III-142] *The biotransformation to sulfur containing products of the Z-isomers and E-isomers of 1,3-dichloropropene administered ip in combination to male Wistar-rats was investigated. The presence of mercapturic acids in the urine of the animals was determined using GC with nitrogen and sulfur selective detection (GC-NDP AND GC-FDP, respectively) AND GC/MS with negative chemical ionization and single ion detection. Quantification of mercapturic acids in the urine of animals treated with the dichloropropene isomers in doses of 5 ug each, was achieved with the use of GC-NDP AND GC-FPD, while GC/negative chemical ionization/MS detected only the mercapturic acids generated by doses = 25 ug or higher, due to the interference of endogenous products. Both products tested are metabolized via glutathione conjugation, with the generation of 2 major mercapturic acid conjugates, and that all three analytical procedures tested are useful for the determination of human exposure to low levels of 1,3-dichloropropene. [R106] *A study of the relationship between air dichloropropene (DCP) concns and urinary excretion of N-acetyl-S-(cis-3-chloroprop-2-enyl)cysteine (3CNAC) AND N-acetylglucosaminidase (NAG) in DCP fumigators was conducted. The study group consisted of male dichloropropene applicators. Breathing zone samples were analyzed for dichloropropene. Urine samples were collected before and at various times after application and analyzed for 3CNAC AND NAG. Air DCP concns ranged from 0.26-9.39 mg/cu m, mean 2.56 mg/cu m. Duration of exposure ranged from 120-697 min. This yielded DCP air exposure products of 62-3700 mg/cu m/min. 24 hr urinary excretion of 3 CNAC ranged from 0.50-9.17 mg, mean 2.57 mg. 24 hr 3CNAC excretion correlated well with the DCP air exposure product, correlation coefficient 0.854. The correlation was improved when the next morning urine samples were used, correlation coefficient 0.914. The overall mean excretion of NAG was 2.63 mU/mg creatinine. 4 subjects had NAG values above 4 mU/mg, a value considered to be clinically abnormal. 9 subjects had increases in NAG activity that averaged 25% higher than the baseline value. 3CNAC concns in the next morning urine were positively correlated with 24 hr excretion of NAG. [R107] *The relationship between the concn of inhaled 1,3-dichloropropene and urinary excretion of the mercapturic acid conjugate was examined. Male Sprague Dawley rats were exposed nose only to 1,3-dichloropropene at dose levels of 0, 40, 106, 284, 398 or 788 ppm for 1 hr. Exposures were conducted in a nose only exposure system housed in a carcinogen glove box. The volume of urine excreted per rat in the 24 hr period after exposure to 1,3-dichloropropene was significantly affected only after exposure to 284 ppm. The excretion levels of the mercapturic acid conjugate N-acetyl-S(cis-3-chloroprop-2-enyl)cysteine at all exposure concn were significantly different from controls. With increasing exposure concn from 0 to 284 ppm, N-acetyl-S(cis-3-chloroprop-2-enyl)cysteine levels increased; from 284 to 789 ppm, N-acetyl-S(cis-3-chloroprop-2-enyl)cysteine levels were not significantly different. The authors conclude that at the lower exposure levels, urinary excretion of N-acetyl-S(cis-3-chloroprop-2-enyl)cysteine was dependent on 1,3-dichloropropene concn. [R108] *Levels of glutathione in various tissues were studied in male Sprague-Dawley rats following acute inhalation exposure to 1,3-dichloropropene for 1 hr in a dynamic, nose only system. Glutathione content was determined in nasal tissue, heart, kidney, liver, lung, and testes. No 1,3-dichloropropene was detected in the blood of rats 2 hr after exposure to up to 955 ppm 1,3-dichloropropene. When one rat was exposed to 100 mg/kg 1,3-dichloropropene orally, both cis and trans isomers of 1,3-dichloropropene were detected in the blood 2 hr after exposure. Nasal tissue glutathione content was decreased to 27% of control at 5 ppm 1,3-dichloropropene, to 23% at 31 ppm, to 18% at 71 ppm, and to 12% at 223 ppm. In lung tissue, glutathione content remained relatively constant at 68 to 82% of control after exposure of 2-955 ppm 1,3-dichloropropene. Exposure to up to 955 ppm 1,3-dichloropropene had little or no effect on the glutathione levels of heart and testes. Significantly decreased glutathione levels in heart, lung, liver, and testes were observed after exposure to 1716 ppm 1,3-dichloropropene. A concn dependent decr of glutathione levels in the liver was observed for exposure between 772 and 1716 ppm 1,3-dichloropropene. No change in lung wet wt was observed for any exposure. Serum lactate dehydrogenase activity, when measured 6 hr after 1,3-dichloropropene exposure, was decreased only for the highest 1,3-dichloropropene concn. The results showed that, at least at low levels, 1,3-dichloropropene was detoxified by conjugation to glutathione in nasal tissue. [R109] *Oral admin of 1,3-dichloropropene to rats or mice resulted in significant, dose-related reductions in the levels of non-protein sulfhydryls (NPS) (indicator of tissue glutathione concn) in the forestomach and to a lesser extent in the glandular stomach and liver. [R110] *1,3-Dichloropropene was given in doses of 0, 25, 50 and 75 mg/kg body weight intraperitoneally to male fischer 344 rats. Excretion of the metabolite N-acetyl-S-(cis-3-chloroprop-2-enyl)-L-cysteine increased in a dose-dependent manner from 0 to 50 mg/kg 1,3-dichloropropene, but no further increase was seen at the 75 mg/kg dose, suggesting that, at higher doses, the metabolism pathway may be saturated or impaired. [R63] *The major urinary metabolite in rats given 1,3-dichloro-2-propene was a mercapturic acid. Apparently the chlorine in the 1-position is removed prior to conjugation with cysteine. Formation of a glutathione conjugate was shown in an in vitro system. Although this conjugation appears to require the enzyme hepatic glutathione transferase /while/ many other molecules with electrophilic centers also form glutathione conjugates nonenzymatically. ... Perhaps alkylation of critical proteins is the molecular basis of the widespread visceral lesions in D-D poisoning. [R59, p. III-142] *The metabolism of cysteine S-conjugates of both cis- and trans-1,3-dichloropropene in the presence of rat kidney microsomes and purified flavin-containing monooxygenase from hog liver was investigated in vitro. Preliminary studies with isolated rat kidney cells demonstrated that cysteine S-conjugates were quite toxic to the cells in a process which was consistent with a role of the flavin-containing monooxygenase in the bioactivation of the nephrotoxins. Putative S-oxide metabolites of cysteine S-conjugates were chemically synthesized, and diastereomers were separated and identified by spectroscopic means. The metabolic products of cysteine S-conjugates were identified by comparing the chemical properties of the metabolites with authentic synthetic cysteine S-conjugate S-oxides. Surprisingly, S-conjugate S-oxygenase activity was not observed with rat kidney microsomes but was present when cysteine S-conjugates were incubated with the highly purified flavin containing monooxygenase from hog liver. The kinetic parameters indicated that considerable S-oxygenase stereoselectivity and structural selectivity was observed: cis cysteine S-conjugates were preferred substrates and N-acetylation of cysteine S-conjugates decreased substrate activity. S-Oxygenation was considerably diastereoselective and diastereoselectivity was much greater for cysteine S-conjugates with higher Vmax values. Cysteine S-conjugate S-oxides were not indefinitely stable, and under certain conditions, the S-oxides underwent a (2,3)-sigmatropic rearrangement to acrolein. Formation of acrolein or other electrophilic products from S-(chloropropenyl)cysteine conjugate S-oxides may contribute to the renal effects observed for S-(chloropropenyl)cysteine conjugates. Thus, cytotoxicity studies with isolated rat proximal tubular cells or LLC-PK1 cells treated with cysteine S-conjugates showed a time and dose-dependent decrease in cell viability. Reduction of renal cytotoxicity of cysteine S-conjugates in the presence of methimazole, an alternate substrate competitive inhibitor of the flavin containing monooxygenase, suggested that this enzyme may contribute to the renal effects of 1,3-dichloropropene. [R111] BHL: *Following absorption, both isomers of 1,3-dichloropropene were, at less than or equal to 300 ppm exposure levels, rapidly eliminated from the bloodstream (3-6 min half-life). In addition, data obtained in rats exposed to 300 ppm 1,3-dichloropropene revealed that this rapid elimination phase was followed by a slower elimination phase having a 33-34 min half-life. Rats exposed to 900 ppm vapors also eliminated 1,3-dichloropropene in a biphasic manner; however, in this case the blood half-life of 1,3-dichloropropene during the initial phase of excretion was 14 to 27 min. [R112] ACTN: *An increase in concentration of rat liver homogenate fraction (S9) in the metabolizing system (S9 mix) enhances mutagenicity for 1,3-dichloropropene and 2,3-dichloro-1-propene. According to the effects of the enzyme inhibitors SKF525, 1,1,1-trichloropropene-2,3-oxide and cyanamide, the allylic chloropropenes fall into 3 groups distinguished by their mode of metabolic activation by S9 mix. 1,3-Dichloropropene is hydrolyzed to the corresponding allylic alcohol which can be oxidized to the respective acroleins (hydrolytic oxidative pathway). Structural parameters like chloro substitution of the central C atom of the substituted induced polarization of the C as cis/trans isomerism might be responsible for different substrate properties for the enzymes involved in allylic chloropropene metabolism, thus determining different degrees of activation by either one or both pathways. [R113] *Computed molecular properties were compared with experimental mutagenic potentials of some allylic compounds. The computational results suggest that the primary mechanism of action involves the SN1 formation of allylic cations which then react with nucleophilic centers of nucleic acid bases. The usefulness of computed properties in estimating the degree of alkylating activity and mutagenicity was evaluated. In general, stability of the allylic carbocation intermediate and the degree of charge delocalization in the allyl system correlate well with observed mutagenic potentials. [R114] *To investigate the mechanism of 1,3-dichloropropene induced hepatotoxicity, we studied effects of modulation in concn or activities of glutathione, glutathione S-transferase, cytotchrome p-450 on 1,3-dichloropropene toxicity in mice. Piperonyl butoxide was used to inhibit cytochrome p-450 and buthionine sulfoximine to inhibit glutathione synthesis. 1,3-dichloropropene (300 mg/kg) administered with a stomach tube significantly increased plasma glutamate oxaloacetate transaminase and glutamate pyruvate transaminase activities as well as hepatic centrilobular swelling 15 hr after administration. No significant changes were observed at 100 mg/kg 1,3-dichloropropene. Piperonyl butoxide pretreatmen significantly suppressed the elevation of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase activities caused by 300 mg/kg 1,3-dichloropropene. This pretreatment significantly increased 1,3-dichloropropene concn in the liver. The piperonyl butoxide pretreatment decreased cytochrome p450 content in liver microsomes but prevented further reduction of cytochrome p-450 after 1,3-dichloropropene treatment. With buthionine sulfoximine pretreatment plasma glutamate oxaloacetate transaminase activity significantly increased in animals receiving 100 mg/kg 1,3-dichloropropene, whereas liver glutathione content and glutathione-S-transferase activity decreased. This pretreatment also significantly increased 1,3-dichloropropene concn in the liver. Cysteine administered 2 hr after 1,3-dichloropropene treatment by which time 1,3-dichloropropene in the liver had disappeared did not decrease the cytochrome p-450 content induced by 1,3-dichloropropene, although it prevented the elevation of glutamate oxaloacetate transaminase and glutamate pyruvate transaminase activities and increased hepatic glutathione concn. These results suggest 1,3-dichloropropene is biotransformed via cytochrome p450, the metabolites induced liver damage and glutathione plays an important role in the detoxification of 1,3-dichloropropene. [R115] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,3-Dichloropropene's production and use as a soil fumigant and nematicide may result in its direct release to the environment. If released to air, a vapor pressure of 34 mm Hg at 20 deg C indicates 1,3-dichloropropene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,3-dichloropropene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2 days. 1,3-Dichloropropene reacts with sunlight in the presence of free hydroxyl radicals with an estimated photolysis half-life of 7 to 12 hrs. If released to soil, 1,3-dichloropropene is expected to have very high mobility based upon a Koc range of 20-42. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 3.55X10-3 atm-cu m/mole. 1,3-Dichloropropene may volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation in soil and aquatic systems may occur based on half-lives in soil of 3-4 weeks. The cis- and trans-isomers of 1,3-dichloropropene are hydrolyzed in wet soil to the corresponding 3-chloroallyl alcohol, with the 3-chloroallylacrylic acid as the hydrolytic end-product. If released into water, 1,3-dichloropropene is not expected to adsorb to suspended solids and sediment based upon the Kocs. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively. An estimated BCF of 5 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to 1,3-dichloropropene may occur through inhalation and dermal contact with this compound at workplaces where 1,3-dichloropropene is produced or used. Monitoring data indicate that the general population may be exposed to 1,3-dichloropropene via ingestion of drinking water. Those people residing in certain farming regions may be exposed to 1,3-dichloropropene via inhalation of air in the immediate vicinity during application. (SRC) ARTS: *The California State Department of Agriculture reported that in 1971 approximately 1,285 metric tons of pesticide containing 1,3-dichloropropene were used in that state. It can be estimated that approximately 72 tons, or 8%, of 1,3-dichloropropene were lost to the atmosphere. [R23] *1,3-Dichloropropene's production and use as a soil fumigant(1) and nematicide(2) is expected to result in its direct release to the environment(SRC). Emissions, due to its rapid diffusion and comparatively slow degradation in soil, can result in degradation of air quality in application areas(3). [R116] FATE: *Terrestrial Fate: Although field applications of 1,3-dichloropropene have shown between 15 and 80% decomposition, the large amount that can be absorbed (80 to 90%) can result in considerable residues existing months after application is completed. [R117] *TERRESTRIAL AND ATMOSPHERIC FATE: Fumigant mixtures of ... 1,3-dichloropropene are applied to the soil in liquid form, usually by means of a chisel applicator. Small amounts of these mixtures escape into the atmosphere by natural diffusion up through the soil profile, and some may leak into the atmosphere from the soil surface through inadequately sealed chisel shank holes. An estimate of the total amount of cis-dichloropropene lost to the atmosphere after a typical application of Telone R to a 30.5 cm depth in a warm, moist, sandy loam soil would amount to approximately 5 to 10%. [R23] *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 20-42(2), indicate that 1,3-dichloropropene is expected to have very high mobility in soil(SRC). Volatilization of 1,3-dichloropropene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 3.55X10-3 atm-cu m/mole(3). The potential for volatilization of 1,3-dichloropropene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 34 mm Hg(4). The hydrolysis rate is temperature dependent, with half-lives of 1.5-20 and 91-100 days at 29 and 2 deg C, respectively, reported for the cis-isomer(5). Biodegradation in soil may be an important environmental fate process based on a half-life of 3-4 weeks(6). [R118] *AQUATIC FATE: Based on a classification scheme(1), Kocs ranging from 20-42(2) indicate that 1,3-dichloropropene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(4) based upon a Henry's Law constant of 3.55X10-3 atm-cu m/mole(5). Using this Henry's Law constant and an estimation method(4), volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively(SRC). 1,3-Dichloropropene undergoes hydrolysis in aqueous solution producing 3-chloroallyl alcohol(11). The half-life of the cis-isomer in aqueous solution is 20 days(11). The cis- and trans-isomers of 1,3-dichloropropene are hydrolyzed in wet soil to the corresponding 3-chloroallyl alcohol(6), with the 3-chloroallylacrylic acid as the hydrolytic end-product(6). The hydrolysis rate is temperature dependent, with half-lives of 1.5-20 and 91-100 days at 29 and 2 deg C, respectively, reported for the cis-isomer(7). According to a classification scheme(8), an estimated BCF of 5(SRC), from its log Kow of 1.82(3) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation in aquatic systems may be an important environmental fate process based on a half-life in soil of 3-4 weeks(10). [R119] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,3-dichloropropene, which has a vapor pressure of 34 mm Hg at 20 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,3-dichloropropene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 days(SRC), calculated from its cis-/trans- average rate constant of 1.12X10-11 cu cm/molecule-sec at 25 deg C(SRC), determined using a structure estimation method(3). 1,3-Dichloropropene reacts with sunlight in the presence of free hydroxyl radicals with an estimated photolysis half-life of 7 to 12 hrs(4). [R120] BIOD: *THE TOTAL DEGRADATION OF 1,2-DICHLOROPROPANE AND 1,3- and 2,3-DICHLOROPROPENES IN SOIL AT NORMAL FIELD RATES WAS EXTREMELY SLOW. THE HALF-LIFE OF 2,3-DICHLOROPROPENE WAS 4 TIMES AS LONG AS THOSE OF THE OTHER COMPOUNDS TESTED. [R121] *Eight months after D-D soil fumigant was applied to muck and sandy loam soils in August during field studies, residues of 1.8 and 4.8 ppm of the cis and trans isomers were found in the muck soil and 0.03 and 0.39 ppm were found in the sandy loam(2). Residues persisted > 91 days in the sandy soil of a tree nursery and were also found in neighboring irrigation wells. 1,3-Dichloropropene was injected 0.2 m deep into the soil of three flower bulb fields during summer. Based on soil samples collected at depths of 0-0.6 m, half-lives, for the cis and trans isomers were determined to be about 4 days(3). Half-lives of both isomers in soil at 20 deg C have been estimated to range between 3 and 25 days(1). [R122] *In screening tests, 55% of 1,3-dichloropropene is degraded by a sewage inoculum in 7 days(1). It is also attacked by soil bacteria(2). Twelve weeks after labeled cis- or trans-1,3-dichloropropene was added to soil and stored in sealed containers, 19% of the cis and 18% of the trans isomers remained in sandy loam and 10% of cis and 22% of trans isomer remained in medium loam(3). After 20 weeks, 5% and 4% of the cis and trans isomer, respectively, remained in sandy loam and 3% and 14%, respectively remained in the medium loam(3). The half-life of the applied dichloropropenes were 3-4 weeks(3). It was possible that some of the parent compound was lost by volatilization(3). 14C-1,3-Dichloropropene, added at 100 ug/g soil and incubated aerobically in the dark at 25 deg C, displayed half-lives of 1.8, 12.3, and 61 days using Wahiawa silt clay, Catlin silt loam, and Fuquay loamy sand, respectively(4). Degradation products were 3-chloroallyl alcohol, 3-chloroacrylic acid, numerous minor carboxylic acid metabolites, and carbon dioxide(4). Degradation of 1,3-dichloropropene was greatly enhanced in amended soils compared to the unamended soil, and the degree of acceleration varied with the type as well as the rate of amendment. Compost manure was more effective in stimulating 1,3-dichloropropene degradation than a less decomposed biosolid-manure mix; the acceleration in compost manure-amended soils was a combined result of enhanced chemical and microbial degradation, since sterilization only partially reduced the enhanced degradation(5). Complete mineralization, based on chloride release, can be a matter of years however(6). 5 ug/ml test compound added to a sediment sample from a drainage ditch at an agricultural field station in Marcham, England was readily converted to 3-chloropropionic acid(7). [R123] ABIO: *The rate constant for the vapor-phase reaction of 1,3-dichloropropene (mixed isomers) with photochemically-produced hydroxyl radicals has been estimated as 1.12X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.6 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The half-lives of trans- and cis-1,3-dichloropropene with respect to ozone were 12 and 52 days, respectively(2). The products were formyl chloride and chloroacetaldehyde, chloroacetic acid, HCl, CO, CO2, and formic acid(2). The cis- and trans-isomers of 1,3-dichloropropene are hydrolyzed in wet soil to the corresponding 3-chloroallyl alcohol(4), with the 3-chloroallylacrylic acid as the hydrolytic end-product(4). The hydrolysis rate is temperature dependent, with half-lives of 1.5-20 and 91-100 days at 29 and 2 deg C, respectively, reported for the cis-isomer(5). 1,3-Dichloropropene reacts with sunlight in the presence of free hydroxyl radicals with an estimated photolysis half-life of 7 to 12 hrs(6). [R124] *Ozone reacts with cis- and trans-1,3-dichloropropene yielding half-lives of 74 and 17 days respectively (assuming an ozone concn of 7.2X10+11 molecules/cc)(1). Hydroxyl-radicals also react with cis- and trans-1,3-dichloropropene by addition to the double bond yielding half-lives of 50 and 29 hr, respectively (assuming a hydroxyl radical concn of 5X10+5 molecules/cu cm)(1). 1,3-Dichloropropene undergoes hydrolysis in aqueous solution producing 3-chloroallyl alcohol(2). The half-life of the cis-isomer in aqueous solution is 20 days(2). The rate of hydrolysis is enhanced by the presence of soil by a factor of 1.4 when the soil/solution ratio is 0.5. Mixtures of higher soil content enhance the hydrolysis rate to about the same extent, and at best three-fold(2). Results of another laboratory study and a field study indicate a hydrolysis half-life in soil of greater than 69 days(3). It is additionally reported that disappearance is more rapid in clay soils than sandy ones, but no rates were given(4). [R125] BIOC: *Estimated weighted average BCF 1.91 for the edible portion of all freshwater and estuarine aquatic organisms consumed by Americans. (The estimation method was given). /1,3-Dichloropropene (cis and trans)/. [R126] *Estimated steady state BCF 4.84 (from table). /1,3-Dichloropropene (cis and trans)/. [R127] *An estimated BCF of 5 was calculated for 1,3-dichloropropene(SRC), using a log Kow of 1.82(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R128] KOC: *The measured Koc was 23 and 26 for the cis and trans isomers, respectively(1). The average Koc for 3 soils with % organic carbon of 3.19, 10.4, and 55.1% was 27 and 28 for cis- and trans-1,3-dichloropropene, respectively(2). The adsorption onto soil from the vapor is greater for the trans than the cis isomer(3). The adsorption isotherm for the vapor/soil system is linear. The average max Koc values were 20 for sand, 25 for loamy sand, and 41 and 42 for two clay soils(3). According to a classification scheme(4), these Koc values suggest that 1,3-dichloropropene is expected to have very high mobility in soil. [R129] *Adsorption is higher in dry soils than in moist soil(2). However, water-saturated soils have air passageways blocked and fumigant movement is decreased(2). This is illustrated by a 20-day study in which the 1,3-dichloropropene diffused to > .46 m in a silty clay loam with 23% moisture (dry wt) and > 1.20 m in the same soil when the moisture content was 7.7%(2). The concentration of 1,3-dichloropropene was monitored at ground level and at 42 inches above ground after fumigant was applied to a pineapple field at a depth of 18 inches(1). 1,3-Dichloropropene levels were relatively constant (20-50 ppb) at ground level for 6 days after fumigation; after 9 days the concn steadily declined to < 0.1 ppb after 27-30 days. A light rain at day 6 temporarily increased the release of the fumigant 100-fold(1). The reduced adsorption due to increased soil moisture, resulted in a transfer of fumigant from soil to water at or near the soil surface, after which evaporation occured. At 42 inches above ground level, 1,3-dichloropropene was still detectable and was probably drifting in from other fields(1). [R130] VWS: *Lab experiments were conducted concerning the principal factors which influence volatilization of 1,3-dichloropropene from soil. Four independent variables were considered: soil type, soil moisture, soil temperature, and dose of the chemical applied to the soil. Soil temperature was the most important variable affecting volatilization loss of 1,3-dichloropropene, with 36.97, 88.69, and 71.03% recovered in n-hexane after 72 hours at 5, 15, and 25 deg C, respectively(1), followed by soil moisture. Air dried soil, air-dried plus 4% water, and air-dried plus 8% water resulted in 39.68, 60.93, and 64.45% total recovered in n-hexane, respectively, after 144 hours. Soil type and 1,3-dichloropropene concn in the soil had only a small influence on nematicide volatilization, with 36.81, 29.46, and 39.47% recovered in sandy-clay, sandy-silt, and sand, repestively, after 48 hours. Soil type had only a small influence on nematicide volatilization, with 36.81, 29.46, and 39.47% recovered in sandy-clay, sandy-silt, and sand, repestively, after 48 hours. 1,3-Dichloropropene concn in the soil did not influence volatilization to a great extent. Preliminary experiments on the effect of air flow rate and air humidity, indicated that these variables are additional factors affecting volatilization loss of 1,3-dichloropropene from the soil(1). [R131] *The Henry's Law constant for 1,3-dichloropropene is 3.55X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that 1,3-dichloropropene is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 3 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). 1,3-Dichloropropene's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,3-dichloropropene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 34 mm Hg(3). About 50% of 1,3-dichloropropene applied at a concn of 198 kg active ingredient/ha was found to have evaporated from laboratory test soil plots over a period of about 1 month(4). The evaporation of 1,3-dichloropropene from ditch water samples from Letcombe Brook, Marcham, England, had a half-life of less than 5 hrs(5). [R132] WATC: *HIGHEST CONCN FOUND IN FINISHED (DRINKING) WATER WAS LESS THAN 1.0 UG/L. [R133] *GROUNDWATER: 1,3-Dichloropropene was not detected in monitoring wells underlying the Amphenol metal plating plant in Broadview, IL, detection limit of 1 ppb(1). It was detected in groundwater 68 days after application with 92% 1,3-dichloropropene at 140 l/ha but not at 94 l/ha(2). Samples from Minnesota: cis-isomer found in groundwater under 1 of 13 municipal landfill with suspected groundwater contamination but not under 7 other municipal landfills(3). [R134] *DRINKING WATER: 1,3-Dichloropropene (isomer not specified) has been identified in drinking water in the US(1). Municipal wells in areas of CA where Telone or D-D had been applied for over 15 years (54 wells, 65-1200 ft deep in 5 counties) were sampled however the compound was not detected at the quantitation limit of 0.1 ppb(2). It was identified, not quantitated in New Orleans drinking water(3). 1,3-Dichloropropene was not detected at < 0.1 ug/l in 42 raw and 42 treated water samples from 9 Canadian municipalities located along the Great Lakes(4). It was not detected in the Denver, CO water reuse plant influent or effluent between Oct 1, 1985 and March 31, 1986. The influent to this plant is unchlorinated secondary effluent from a municipal wastewater treatment plant(5). [R135] *SURFACE WATER: The USEPA STORET Data Base reports a mean 1,3-dichloropropene concn of 6.07 ppb, 320 ppb maximum based on 1675 observations(1). [R136] *RAIN/SNOW: In October, 1982, cis- and trans-1,3-dichloropropene were detected in the aqueous phase of rain water collected in Portland, OR at concns of 10 and 2 ng/l, respectively(1). [R137] EFFL: *Based on the National Urban Runoff Program in which 86 samples from 19 cities throughout the US were analyzed, 1,3-dichloropropene was detected only in Eugene, OR at 1-2 ppb, which was a 2% frequency of detection nationwide(1). 1,3-Dichloropropene has been detected in wastewater from organic chemicals manufacturing/plastics (79 ppb mean)(2). 1 out of 5 samples of municipal landfill leachate in WI was positive, reporting a concn of 18 ppb (cis isomer) but not detected in 6 samples of municipal landfill leachate in MN(3). Influent of a textile wastewater plant contained 2 ppb of the cis-isomer while effluent from the plant contained 6 ppb of the cis-isomer and 6 ppb of the trans-isomer(4). Influent to a municipal waste treatment plant contained no 1,3-dichloropropene, but following superchlorination a mean concn of 10 ppb was detected in the liquid sludge(4). Air concns in air above pineapple fields in Kunia, Oahu, Hawaii were 1,600 ug/cu m at 2 days dropping to 400 ug/cu m at 5 days post treatment after an application rate of 224 L/ha using commercial fumigation equipment(5). [R138] SEDS: *SOIL: Data from the USEPA STORET Data Base reports a 5.44 ppb mean, 500 ppb maximum on dry weight basis of 341 observations(1). [R136] ATMC: *... SINCE IT IS GENERALLY INJECTED INTO SOIL AT DEPTHS OF 15 TO 30 CM AIRBORNE CONCN ARE GENERALLY WELL BELOW 0.5 PPM EVEN WHEN MEASURED IN MIDDLE OF FUMIGATED FIELD. [R64, 4225] *URBAN/SUBURBAN: 2 of 11 samples from Baton Rouge, LA tested positive with a trace and 2.2 parts per trillion 1,3-dichloropropene(1). [R139] *RURAL/REMOTE: 1,3-Dichloropropene was not detected in 7 samples from the Grand Canyon(1). [R139] *SOURCE DOMINATED: 1,3-Dichloropropene concns were reported in samples from the US (4 sites, 16 points) at 7.3 parts per trillion median, 570 parts per trillion maximum (isomer unspecified)(1). One source area, Freeport, TX, that has a mean concn of 170 parts per trillion is a site of 1,3-dichloropropene manufacturing(1). [R140] PFAC: FISH/SEAFOOD CONCENTRATIONS: *The USEPA STORET Data Base (146 observations) 0.19 ppm mean, 20.0 ppm maximum(1). [R141] RTEX: *... /IT/ IS ABSORBED FROM SKIN AS WELL AS FROM RESP AND GI SYSTEMS. [R9, 162] *EXPOSURE OCCURS PRINCIPALLY DURING MANUFACTURING OR DURING BULK HANDLING. [R64, 4225] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,162 workers (33 of these are female) are potentially exposed to 1,3-dichloropropene in the US(1). The NOES Survey does not include farm workers. Occupational exposure to 1,3-dichloropropene may occur through inhalation and dermal contact with this compound at workplaces where 1,3-dichloropropene is produced or used(SRC). Hawaiian pineapple field workers were found to be exposed to 1,3-dichloropropene at avg concns (for various job categories) ranging between 7-1019 ppb(2). Respiratory exposure tests to cis- and trans-isomers showed a time-weighted avg concn range of 1.9 to 18.9 mg/cu m among field applicators working in the Dutch flower-bulb industry(3). On 30% of the working days tested, the Dutch occupational exposure limit of 5 mg/cu m was exceeded(3). Monitoring data indicate that the general population may be exposed to 1,3-dichloropropene via ingestion of drinking water(SRC). Those people residing in certain farming regions may be exposed to 1,3-dichloropropene via inhalation of air in the immediate vicinity during application(SRC). [R142] BODY: *Dichloropropene was detected in one of 8 samples of mother's milk from 4 urban areas in the USA but the isomer was not specified(1). /Dichloropropene/ [R143] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers 1,3-dichloropropene to be a potential occupational carcinogen. [R24, 100] ADI: *OPP RfD= 0.0003 mg/kg; EPA RfD= 0.0003 mg/kg [R144] OSHA: *Vacated 1989 OSHA PEL TWA 1 ppm (5 mg/cu m), skin designation, is still enforced in some states. [R24, 362] NREC: *NIOSH considers 1,3-dichloropropene to be a potential occupational carcinogen. [R24, 100] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R24, 100] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 ppm (5 mg/cu m), skin. [R24, 100] TLV: *8 hr Time Weighted Avg (TWA) 1 ppm, skin [R145] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R145] *A3: Confirmed animal carcinogen with unknown relevance to humans. [R145] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,3-Dichloropropene is included on this list. [R146] WSTD: STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 0.5 ug/l [R147] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 1 ug/l [R147] +(MA) MASSACHUSETTS 0.5 ug/l [R147] +(ME) MAINE 2 ug/l [R147] +(MN) MINNESOTA 2 ug/l [R147] +(WI) WISCONSIN 0.2 ug/l [R147] CWA: +1,3-Dichloropropene is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R148] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R149] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1-Propene, 1,3-dichloro- is included on this list. [R150] RCRA: *U084; As stipulated in 40 CFR 261.33, when 1,3-dichloropropene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R151] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. 1,3-Dichloropropene is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0328; Pesticide type: Fungicide (nematicide); Registration Standard Date: 09/18/86; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): 1,3-Dichloropropene; Data Call-in (DCI) Date(s): 09/28/90, 02/26/91, 10/13/95, 06/11/96; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R152] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Trapping method for soil fumigants, including 1,3- dichloropropene, in the atmosphere using solid adsorbents. [R153] ALAB: *Determination of fumigants and related chemicals, including 1,3-dichloropropene, in fatty and nonfatty foods by GC. [R154] *Product and residue analysis is by gas liquid chromatography. [R12, 367] *Trace analysis of organic priority pollutants by high resolution gas chromatography and selective detectors (flame-ionization detection, electron-capture dectection, nitrogen-phosphate detection, and mass spectrometry) application to municipal wastewater and sludge. [R155] *Determination of volatile organic cmpds in fish samples by vacuum distillation and fused silica capillary gas chromatography/mass spectrometry. [R156] *1,3-DICHLOROPROPENE (1,3-DCP), 1,2-DIBROMOETHANE AND 1,3-DIBROMO-3-CHLOROPROPANE WERE CONCURRENTLY DETERMINED IN FOODS BY EXTRACTION WITH ACETONITRILE, PARTITIONING INTO HEXANE, COLUMN CHROMATOGRAPHY ON FLORISIL AND GAS LIQUID CHROMATOGRAPHY WITH ELECTRON-CAPTURE DETECTION. MINIMUM DETECTABLE LIMITS WAS EST TO BE 3 PPB FOR 1,3-DICHLOROPROPENE. [R157] *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile organics. This method can be used to quantify most volatile organic compounds including 1,3-dichloropropene that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R158] *EPA Method 624. Purge and Trap Gas Chromatography/Mass Spectrometry for the analysis of purgeable organics including 1,3-dichloropropene in the municipal and industrial discharges. Under the prescribed conditions for 1,3-dichloropropene, the method detection limit is not determined as defined by EPA. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R159] *Rapid determination of fumigant and industrial chemical residues, including 1,3-dichloropropene, in food using GC. [R160] *OSW Method 0031. Sampling Method for Volatile Organic Compounds. Sampling train. Incinerator. Target detection limit = 0.100 ug/cu m. [R161] *EPA Method PMD-CKA. Determination of Chloropicrin and 1,3-Dichloropropenes by Gas Chromatography. Gas chromatograph with thermal conductivity detector. Detection limit not specified. [R161] *APHA Method 6040-B. Constituent Concentration in Water by Closed-Loop Stripping and Gas Chromatographic/Mass-Spectrometric Analysis. Instrument detection limit = 2.0 ng/l. CLAB: *A rapid, simple and specific gas chromatography and gas chromatography mass spectroscopy methods are described for determining cis- and trans-1,3-dichloropropene in rat blood at 5.88 and 5.35 ng/ml, respectively, with gas chromatography, and 51.8 (cis) and 47.1 ng/ml (trans) with the gas chromatography mass spectroscopy method. The gas chromatography column was 20% Carbowax 20M on Chromasorb WAW (80-100 mesh). Mass spectroscopy with selected ion (m/z 77) monitoring was used. The chromatographic column combined with MS was a glass column containing HNU Synerg C-1H. The mean recovery of the cis- and trans-isomers from blood (gas chromatography method) was 89.7 and 90.5%, respectively. /cis and trans-1,3-Dichloropropene/ [R162] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Dangerous Prop Ind Mater Rep 6 (4): 63-70 (1986). Reviews dichloropropene safety, toxicology and health hazards. DHHS/NTP; Toxicology and Carcinogenesis Studies of Telone II (Technical Grade 1,3-Dichloropropene Containing 1.0% Epichlorohydrin as a Stabilizer) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 269 (1985) NIH Publication No 85-2525 Albrecht WN; Hazard Evaluation of Technical Assistance Branch, National Institute for Occupational Safety and Health, Cincinati Ohio. Toxicology and hazard assessment of 1,3-dichloropropene (Telone II). Arch Environ Health 42 (5): P292-6 (1987). Potential adverse health effects from occupational exposure to 1,3-dichloropropene are reviewed and hazards assessed. Albrecht WN; Toxicology and hazard assessment of 1,3-dichloropropene (Telone II).; Arch Environ Health 42 (5): 292-6 (1987). Potential adverse health effects from occupational exposure to 1,3-dichloro-propene are reviewed and hazards assessed. Further toxicologic evaluations should be conducted using only high-purity material that is free from possibly confounding impurities and stabilizers. Safety considerations when handling the material are included. Anon; Pesticide Fact Sheet Number 95: 1,3-Dichloropropene; Govt Reports Announcements and Index (GRA and I), Issue 02 (1987). The document contains up-to-date chemical information, including a summary of the Agency's regulatory position and rationale, on a specific pesticide or group of pesticides. A Fact Sheet is issued after one of the following actions has occurred. (1) Issuance or reissuance of a registration standard, (2) Issuance of each special review document, (3) Registration of a significantly changed use pattern, (4) Registration of a new chemical, or (5) An immediate need for information to resolve controversial issues relating to a specific chemical or use pattern. Anon; 1,3-Dichloropropene Position Document 1. Govt Reports Announcements and Index (GRA and I), Issue 04, 1992. A Special Review Document addresses the risks and benefits of pesticide products containing 1,3-dichloropropene. The Agency has determined that the use of products containing the subject active ingredient may meet or exceed a risk criterion described in 40 CFR Part 154. Potential hazards will be examined further to determine the nature and extent of the risk, and considering the benefits of th subject active ingredient, whether such risks cause unreasonable adverse effects on the environment. Pub. in Federal Register, v51 n195, 8 Oct 86. WHO: Environmental Health Criteria 146: 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures (1993) U.S Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Services, Research Triangle Park, NC. (2000) HIST: *IN COLLISION BETWEEN 2 TRUCKS ... A TANK CARRIED BY ONE ... RUPTURED AND ... SPILLED ... APPROX 4542 L OF 1,3-DICHLOROPROPENE ... AN EST 80 PERSONS ... WERE EXPOSED TO VAPOR. ... MOST COMMON SIGNS AND SYMPTOMS WERE: HEADACHE IN 6 ... IRRITATION OF MUCOUS MEMBRANES IN 5, DIZZINESS IN 5, AND CHEST DISCOMFORT IN 4. THREE PERSONS REPORTEDLY HAD LOST CONSCIOUSNESS AT SCENE OF ACCIDENT. ... ELEVEN OF 41 ... TESTED HAD SLIGHTLY ELEVATED SGOT AND/OR SGPT VALUES. WITHIN 48-72 HR, VALUES ... REVERTED TO NORMAL IN 8 OF THEM ... BUT 5 STILL HAD SLIGHTLY ELEVATED SGOT. [R9, 163] *Forty-six people were treated for exposure to 1,3-dichloropropene fumes following a traffic accident in 1975 involving spillage of 4500 liters of a formulated product. Twenty-four of these, 3 of whom had lost consciousness, were hospitalized overnight with symptoms including headache, irritation of mucous membranes, and chest discomfort. All patients took showers and were given iv fluids and 3 received oxygen and corticosteroids because of chest pain and cough. Eleven of 41 persons tested had slightly higher than average sperm SGOT AND/or SGPT values, which reverted to normal within 48-72 hr, except for 5 who still had slightly higher then average SGOT values. Follow-up interviews with patients 1-2 wk later revealed symptoms including headache, abdominal and chest discomfort, and malaise. One was diagnosed as having had pneumonia. Symptoms were reported more frequently in those most heavily exposed to the fumes. Patient interviews conducted approx 2 yr after the accident revealed complaints of headache, chest pain or discomfort, and "personality changes" (fatigue, irritability, difficulty in concentrating, or decreased libido). Two had undergone cardiac catheterizations but their arteriograms were normal. There was no correlation of these long-persisting symptoms with intensity of exposure. [R55] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 520 R2: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. 291 R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 289 R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. 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Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Dilling WL; Environ Sci Technol 11: 405-9 (1977) (4) Woodbridge AP, Sherren AJ; in Brighton Crop Prot Conf., Pest Dis. 2: 823-8 (1992) (5) Yon DA et al; Pestic Sci 32: 147-59 (1991) R133: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 799 R134: (1) IT Corporation; Preliminary Site Assess, TSCA Health and Safety Studies 8D Submission #878216382 (2) Loria R et al; Plant Dis 70: 42-5 (1986) (3) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) R135: (1) Kopfler FC et al; Adv Environ Sci Technol 8: 419-33 (1977) (2) Maddy KT et al; Bull Environ Contam Toxicol 29: 354-9 (1982) (3) Dowty B et al; Science 187: 75-7 (1975) (4) Otson R; Intern J Environ Anal Chem 31: 41-53 (1987) (5) Rogers SE et al; J Wat Poll Control Fed 59: 722-32 (1987) R136: (1) Smith JW et al; Health and Environ Effects Profile on 1,3-Dichloropropene, Final Draft, SRC-TR-85-090 (1985) R137: (1) Mazurek MA, Simoneit BRT; Critical Rev in Environ Control Vol. 16; Boca Raton, FL: CRC Press p. 27 (1986) R138: (1) Cole RH et al; J Water Pollut Control Fed 56: 898-908 (1984) (2) USEPA; Treatability Manual I.12.14-1 to I.12.14-5 USEPA-600/282-001A (1981) (3) Sabel GV, Clark TP; Waste Manag Research 2: 119-30 (1984) (4) Krijgsheld KR, van der Gen A; Chemosphere 15: 861-80 (1986) (5) Schneider RC et al; pp. 104-15 in Fumigants. Seiber JN et al, eds., Washington, DC: Amer Chem Soc (1997) R139: (1) Pellizzari ED et al; Formulation of Prelim Assess of Halogenated Organ Compounds in Man and Environ Media USEPA-560/13-79-006 (1979) R140: (1) Brodzinsky R, Singh HB; Volatile Organic Chem in the Atmosphere, An Assess of Available Data pp. 198 (1982) R141: (1) Smith JW et al; Health and Environ Effects Profile on 1,3-Dichloropropene Final Draft, SRC-TR-85-090 (1985) R142: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Albrecht WN; Arch Environ Health 42: 286-91 (1987) (3) Brouwer DH et al; Arch Environ Contam Toxicol 20: 1-5 (1991) R143: (1) Pellizzari ED et al; Environ Contam Toxicol 28: 322-8 (1982) R144: USEPA/OPP; Health Effects Div RfD/ADI Tracking Report p.21 (8/26/91) R145: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001.27 R146: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R147: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R148: 40 CFR 116.4 (7/1/2000) R149: 40 CFR 302.4 (7/1/2000) R150: 40 CFR 716.120 (7/1/2000) R151: 40 CFR 261.33 (7/1/2000) R152: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.151 (Spring, 1998) EPA 738-R-98-002 R153: Watanabe T; Bunseki Kagaku 39 (6): T77-T81 (1990) R154: Daft JL; J Agric Food Chem 37 (2): 560-4 (1989) R155: Gibbai M et al; Anal Chem Sym Ser 13 (1): 41-52 (1983) R156: Hiatt MH; Anal Chem 53 (9): 1541-3 (1983) R157: NEWSOME WH, PANOPIO LG; J AGRIC FOOD CHEM 25 (5): 998-1000 (1977) R158: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R159: USEPA/SCC; Environmental Monitoring Methods Index p.144 (1992) R160: Daft JL; J Assoc Off Anal Chem 71 (4): 748-60 (1988) R161: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R162: Kastl PE, Hermann EA; J Chromator 265 (2): 277-83 (1983) RS: 173 Record 112 of 1119 in HSDB (through 2003/06) AN: 1118 UD: 200303 RD: Reviewed by SRP on 1/31/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-ETHYL-1-HEXANOL- SY: *ETHYLHEXANOL-; *2-ETHYLHEXANOL-; *2-ETHYLHEXYL-ALCOHOL-; *1-HEXANOL,-2-ETHYL-; *OCTYL-ALCOHOL- RN: 104-76-7 MF: *C8-H18-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HYDROGENATION OF 2-ETHYL-1-HEXENAL AT 200 DEG C USING A COPPER OR NICKEL CATALYST [R1] *(A) OXO PROCESS, FROM PROPYLENE AND SYNTHESIS GAS. (B) ALDOLIZATION OF ACETALDEHYDE OR BUTYRALDEHYDE, FOLLOWED BY HYDROGENATION. GRADE: TECHNICAL. [R2, 494] *2-Ethyl hexanol is produced in 4 steps: (1) aldolization of butyraldehyde and subsequent dehydration; (2) separation of aldolization solution; (3) hydrogenatioon of intermediate product 2-ethyl-2-hexenal; (4) fractionization of 2-ethylhexanol. The butyraldeyde required for step 1 is made by the hydroformylation of propene (oxo process). [R3] FORM: *Liquid grade, 99% grade, 99.5% grade [R4] MFS: *Aristech Chemical Corporation, Hq, 600 Grant Street, Pittsburgh, PA 15219-2704; (412) 433-2747; Production site: Pasadena, TX 77501 [R5] *BASF Corporation, Hq, 3000 Continental Drive - North, Mount Olive, NJ 07828-1234; (201) 426-2800; Industrial Organics; Production site: 602 Copper Road, Freeport, TX 77541 [R5] *Eastman Chemical Company, Hq, PO Box 511, Kingsport, TN 37662' (615) 229-2000; Tenessee Eastman Division; Production site: Longview, TX 75607 [R5] *Shell Chemical Co, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production site: Deer Park, TX 77536 (Houston Plant) [R5] *Union Carbide Corp, Hq, Old Ridgebury Rd, Danbury, CT 06817, (203) 794-2000; Solvents and Intermediates Division; Production site: Texas City, TX 77591 [R5] OMIN: *UNLESS SPECIFIED AS NORMAL (OR PRIMARY) OCTYL OR CAPRYLIC ALCOHOL, BRANCHED CHAIN ISOMER 2-ETHYLHEXYL ALCOHOL IS PROBABLY MEANT, BECAUSE IT IS MORE COMMON IN COMMERCE. [R6] *Low production costs for butyraldehyde in modern large-scale plants and the lower price of propene as compared with ethylene mean that the oxo route for the manufacture of 2-ethylhexanol will be given preference for economic reasons. [R3] *NON-ALCOHOLIC BEVERAGES 10.0 PPM; ICE CREAM, ICES, ETC 10.0 PPM; CANDY 10.0 PPM; CHEWING GUM 10.0 PPM. /FROM TABLE/ [R7] USE: *MERCERIZING TEXTILES; AS SOLVENT FOR DYES, RESINS, OILS; ALSO CLAIMED TO POSSESS ANTIFOAMING PROPERTIES [R8] *PLASTICIZER FOR PVC RESINS; WETTING AGENT; ORG SYNTH; SOLVENT MIXTURES FOR NITROCELLULOSE, PAINTS, LACQUERS, BAKING FINISHES [R2, 494] *INKS; RUBBER; PAPER; LUBRICANTS; PHOTOGRAPHY; DRY CLEANING [R2, 494] CPAT: *78% AS A CHEM INT FOR VINYL PLASTICIZERS; 10% AS A CHEM INT FOR 2-ETHYLHEXYL ACRYLATE; 12% IN OTHER APPLCNS(1975) [R1] *CHEMICAL PROFILE: 2-Ethylhexanol. Plasticizers, 49%; (dioctyl phthalate, 36%; dioctyl adipate, 6%; trioctyltrimellitate, 4%; other plasticizers, 3%); 2-ethylhexyl acrylate, 13%; 2-ethylhexyl nitrate (cetane improver), 5%; lube additive, 3%; surfactant, 1%; miscellaneous, 4%; exports, 25%. [R9] *CHEMICAL PROFILE: 2-Ethylhexanol. Demand: 1986: 570 million lb; 1987: 630 million lb; 1991 /projected/: 615 million lb (Includes exports, but not imports, which were 43 million lb in 1986). [R9] *Plasticizers, 60% (dioctyl phthalate, 38%; dioctyl adipate, 7%, trioctyl trimellitate, 6%; other plasticizers, including dioctyl terephthalate, 9%); 2-ethylhexyl acrylate, 17%; 2-ethylhexyl nitrate (cetane improver), 7%; lube additive, 4%; surfactants, 3%; solvent, 2%; miscellaneous, including mining applications, 7%. [R10] PRIE: U.S. PRODUCTION: *(1972) 2.27X10+11 GRAMS [R1] *(1975) 1.76X10+11 GRAMS [R1] *Demand 685 million pounds in 1992 and 700 million pounds in 1993. (Includes exports, but not imports) [R11] U.S. IMPORTS: *(1972) NEGLIGIBLE [R1] *(1993) 20 million pounds [R11] U.S. EXPORTS: *(1972) 2.36X10+10 GRAMS (EST) [R1] *85 to 150 pounds per year. [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R8] ODOR: *MILD, OILY, SWEET, SLIGHTLY FLORAL ODOR REMINISCENT OF ROSE [R7]; *Intense and unpleasant [R12] TAST: *SWEET, FATTY-FLORAL TASTE WITH FRUITAL NOTE [R7]; *Intense and unpleasant [R12] BP: *184.34 deg C [R13, 259] MP: *FP: -76 DEG C [R14] MW: *130.22 [R8] CTP: *Critical temperature = 339.8 deg C; Critical pressure 2.76 MPa [R3] DEN: *0.8344 @ 20 DEG C/20 DEG C [R8] HTC: *-1263.81 kcal/mol @ 25 deg C [R13, 239] HTV: *10.8 kcal/mol @ boiling point [R13, 239] SOL: *SOL IN ABOUT 720 PARTS WATER, IN MANY ORG SOLVENTS [R8]; *880 mg/l @ 25 deg C in water [R15] SPEC: *INDEX OF REFRACTION: 1.4300 @ 20 DEG C/D [R8]; *Intense mass spectral peaks: 57 m/z (100%), 43 m/z (41%), 41 m/z (40%), 55 m/z (28%) [R16]; *IR: 10974 (Sadtler Research Laboratories IR Grating Collection) [R17]; *NMR: 98 (Sadtler Research Laboratories Spectral Collection) [R17]; *MASS: 271 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R17] VAPD: +4.5 (AIR= 1) [R18] VAP: *0.36 MM HG @ 20 DEG C [R2, 493] VISC: *9.8 centapoise @ 20 deg C [R13, 239] OCPP: *WT/GAL: 6.9 LB @ 20 DEG [R2, 493] *% IN SATURATED AIR: 0.0066 @ 20 DEG C; DENSITY OF "SATURATED" AIR: LESS THAN 1.001 (AIR= 1) [R19, 1463] *1 MG/L APPROX= 187.8 PPM AND 1 PPM APPROX= 5.32 MG/CU M @ 25 DEG C, 760 MM HG [R19, 1463] *Vapor pressure = 0.1360 mm Hg @ 25 deg C /Calculated from experimentally-derived coefficients/ [R20] *Dielectric constant = 7.7 @ 20 deg C [R3] *Standard heat of fusion = -103.46 kcal/mol @ 25 deg C [R13, 239] *Heat capacity = 73.45 cal/deg K-mol @ 25 deg C [R13, 239] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Keep run off water out of sewers and water sources. [R21] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R18] +Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R18] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R18] FLMT: +(% BY VOL) 0.88% (LOWER), 9.7% (UPPER) [R18] AUTO: +448 DEG F (231 DEG C) [R18] FIRP: *Foam, carbon dioxide, and dry chemical. [R22] OFHZ: *Moderate, when exposed to heat or flame; reacts with oxidizers. [R22] DCMP: *When heated to decomp it emits acrid smoke and fumes. [R22] EQUP: *Personnel protection: ... Wear appropriate chemical protective gloves, boots, and goggles. [R21] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock down vapors. [R21] *Personnel protection: Avoid breathing vapors. Keep upwind. Wear appropriate chemical protective gloves, boots, and goggles. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R21] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *NO APPARENT INJURY HAS BEEN REPORTED FROM ITS USE IN INDUSTRY. IT IS MODERATELY IRRITATING TO SKIN AND SLIGHTLY TOXIC WHEN INGESTED... [R23] *SYMPTOMATOLOGY: 1. CNS: HEADACHE, MUSCLE WEAKNESS, GIDDINESS, ATAXIA, CONFUSION, DELIRIUM, COMA. 2. GI: NAUSEA, VOMITING, DIARRHEA (ODOR OF ALCOHOL IN EXCRETA). 3. IRRITATION OF SKIN, EYES, THROAT- FROM VAPOR OR LIQUID. COUGH AND DYSPNEA. 4. DEATH FROM RESP FAILURE. /ALCOHOLS, HIGHER/ [R6] *SYMPTOMATOLOGY: 5. DISTURBANCES OF CARDIAC RHYTHM. 6. OCCASIONAL COMPLICATION: A. GI HEMORRHAGE; B. RENAL DAMAGE WITH GLYCOSURIA; C. LIVER DAMAGE; D. CARDIAC FAILURE; E. PULMONARY EDEMA. /ALCOHOLS, HIGHER/ [R6] *ONLY SCANTY INFORMATION IS AVAILABLE ABOUT HIGHER HOMOLOGUES OF ALIPHATIC ALCOHOL SERIES, BUT ANIMAL DATA ESTABLISH THAT LETHALITY DOES NOT CONTINUE TO INCR WITH INCREASING CHAIN LENGTH. /ALCOHOLS, HIGHER/ [R6] *ALIPHATIC ALCOHOLS WITH 8 CARBONS (OCTANOLS) ARE LESS TOXIC. THUS CAPRYLIC ALCOHOL (OCTANOL-2) AND IMPORTANT INDUSTRIAL SOLVENT 2-ETHYLHEXYL ALCOHOL (2-ETHYLHEXANOL-2) RESEMBLE BUTYL ALCOHOLS IN ACUTE TOXICITY... . /ALCOHOLS, HIGHER/ [R6] *... Laboratory workers exposed to EH (among other substances) reported headaches, dizziness, fatigue and GI disorders; also that exposed workers had slightly decreased blood pressure during the day. [R24, p. 51 (1993)] NTOX: *...RATED 5 ON RABBIT EYES. ...TESTED EXTERNALLY ON EYES OF RABBITS AND...RATED NUMERICALLY ON SCALE OF 1-10 ACCORDING TO DEGREE OF INJURY ... AFTER 24 HR /OBSERVATION/, PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA. MOST SEVERE INJURIES HAVE BEEN RATED 10. [R25] *2-Ethyl-1-hexanol (ETH) was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Forty-nine pregnant CD-1 mice were given 1525 mg/kg/day 2-ethyl-1-hexanol in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. 2-Ethyl-1-hexanol was lethal to 30% of the dams. Maternal weight and the number of viable litters were reduced. A decrease in litter size, percent survival, and birth weight/gain was observed in pups from treated animals. [R26] *Gavage admin of 1 mmol/kg bw/day EH (approx 130 mg/kg bw/day) to 5 male Wistar rats for 14 days was not associated with liver peroxisome proliferation ... . [R24, p. 37 (1993)] *... Admin of 2% EH in the diet (approx 1,000 mg/kg bw/day) to 5 male Fischer 344 rats for 3 wk was reported to cause peroxisome proliferation and significant increases in the activities of liver catalase and carnitine acetyltransferase ... . [R24, p. 37 (1993)] *When gavage doses of 0, 100, 320, or 950 mg/kg bw/day EH were administered to male and female Fischer 344 rats (5/sex/group) for 21 days, significant hepatomegaly at 950 mg/kg bw/day, significant increases in cyanide-insensitive palmitoyl CoA oxidation (a marker for peroxisome proliferation) in males (dose-related, 320 and 950 mg/kg bw/day) and females (950 mg/kg bw/day), and significant increases in lauric acid hydroxylase activity in males and females at 950 mg/kg bw/day were shown. As well, electron microscopy showed only a slight increase in the number of peroxisomes in hepatocytes of high-dose rats ... . [R24, p. 37 (1993)] *Groups of five male and five female Alderley Park rats and mice were gavaged with 0, 140, 350, 700, 1050, or 1750 mg/kg bw/day 2-ethyl-1-hexanol for 14 days. Rats in the high-dose group exhibited toxic effects (not specified) and died or were killed during the course of the study. Dose-related increases in relative liver weights of rats and mice were observed; the increases were statistically significant in rats at 700 and 1050 mg/kg bw/day, in male mice at 700, 1050, and 1750 mg/kg bw/day, and in female mice at 1750 mg/kg bw/day. 2-Ethyl-1-hexanol administration resulted in a nearly linear dose-related induction of peroxisomal B-oxidation (measured as palmitoyl CoA oxidation activities) in both rats and mice, although the dose(s) at which this effect was statistically significant were not stated ... . [R24, p. 37 (1993)] *Activity of succinic dehydrogenase was increased and activity of lactic dehydrogenase was decreased after 12 daily dermal applications of 2 ml/kg bw undiluted 2-ethyl-1-hexanol to the shaved skin of the rat. 2-Ethyl-1-hexanol-treated rats had significantly lower bw than control rats 17 days after dermal application of 2-ethyl-1-hexanol was terminated ... . [R24, p. 38 (1993)] *Microsomal p450 content increased and glucose-6-phosphatase activity decreased in rat liver microsomal pellets following oral admin of 2-ethyl-1-hexanol to the intact animal. Admin of 2-ethyl-1-hexanol increased alcohol dehydrogenase activity demonstrated histochemically in the centrilobular area of the liver, the number of microbodies, the dilatation of the smooth endoplasmic reticulum, and the number of microperoxisomes in the hepatocytes of rats ... . [R24, p. 38 (1993)] *Concn of 2-ethyl-1-hexanol ranging from 2.5-15 mM significantly inhibited the activities of rat liver aminopyrine N-demethylase (approx 60% inhibition at 15 mM 2-ethyl-1-hexanol) and aniline hydroxylase (approx 50% inhibition at 15 mM 2-ethyl-1-hexanol) in vitro ... . [R24, p. 38 (1993)] *... Reported that 0.1 or 0.5 mM 2-ethyl-1-hexanol did not induce palmitoyl CoA oxidase activity (a marker for peroxisome proliferation) in rat hepatocytes in vitro ... . [R24, p. 38 (1993)] *The activity of carnitine acetyltransferase (a peroxisomal enzyme) in rat liver cells in vitro was significantly induced (approx 9X level in untreated cultures) by 1 mM 2-ethyl-1-hexanol but not by 0.2 mM 2-ethyl-1-hexanol ... . [R24, p. 38 (1993)] *In an in vitro test system using viable plugs from periportal or pericentral regions of rat liver, ... demonstrated that incubation of these plugs with 2-ethyl-1-hexanol (0.1 to 3 mM) decreased urea synthesis in a dose-related manner (up to 80% inhibition at 800 uM oxygen) and caused extensive cell damage (assessed by lactate dehydrogenase leakage) ... . [R24, p. 38 (1993)] *Rabbits given 0, 0.2, 0.4, 0.6, 0.8, 1.6, or 3.2 x 10 -5 mol/kg 2-ethyl-1-hexanol (0.26 to 4.16 mg/kg bw iv) had dose-related increases in heart rate and frequency of respiration. However, when EH was admin to dogs (doses reported as 4.05 and 8.10 mol/kg iv), no cmpd-related hypotensive effects were seen. Finally, when rabbits and rats were given acute iv doses of 2-ethyl-1-hexanol (doses not provided), direct toxic damage to the heart and smooth muscle elements of the blood vessels was observed ... . [R24, p. 38 (1993)] *Doses of 0, 100, 330, 1,000, or 1,500 mg 2-ethyl-1-hexanol/kg bw/day were administered by gavage for 11 days (9 administrations) to groups of 10 male and 10 female C3B6F1 mice. Effects clearly related to administration of the test substance occurred in male and female mice receiving 330, 1,000, or 1,500 mg/kg bw/day. One male mouse receiving 330 mg/kg bw/day for 11 days showed ataxic gait and piloerection following the administration of the 8th dose, but these symptoms were reported to have disappeared by the next day. Two male and two female mice receiving 330 mg/kg bw/day were reported to have acanthosis in the mucous membrane of the forestomach that was usually associated with hyperkeratosis and was once associated with focal inflammatory edema in the submucosa. One female mouse receiving 1,000 mg 2-ethyl-1-hexanol/kg bw/day showed abdominal position and loss of consciousness; the mouse died later the same day; microscopic examination revealed tubular dilatation in the renal cortex and centrilobular fatty infiltration in the liver of this mouse. Also, the following significant effects were reported to be associated with administration of 1,000 mg/kg bw/day for 11 days: 1) increased absolute stomach weights in males and females; 2) increased liver-to-bw ratio for males; 3) increased stomach-to-bw ratio for females; 4) foci in the forestomach of 3 males and 2 females; 5) hyperkeratosis and focal or multifocal acanthosis and inflammatory edema in the submucosa of the forestomach of males and females, including focal or multifocal ulceration of the mucous membrane of a few males and females; and 6) hypertrophy of hepatocytes in one male and one female. Males (9/10) and females (6/10) receiving 1,500 mg 2-ethyl-1-hexanol/kg bw/day for 11 days had clinical signs such as ataxia and lethargy, some animals also had piloerection, and a few animals showed abdominal or lateral position and loss of consciousness; one male and four females died during the study. Microscopic evaluation showed tubular dilatation and nephrosis in the renal cortices of males and females that died intercurrently, and centrilobular fatty infiltration in the liver of females that died intercurrently. The following statistically significant effects were reported, associated with administration of 1,500 mg 2-ethyl-1-hexanol/kg bw/day: 1) increased absolute liver and stomach weights in males and females; 2) increased organ-to-bw ratios for stomach and liver in males and females; 3) increased organ-to-brain weight ratios for stomach and liver in males and females; 4) foci in the forestomach of 7/10 males and 5/10 females; 5) hyperkeratosis and focal or multifocal acanthosis and inflammatory edema in the submucosa of the forestomach of most males and females, including focal or multifocal ulceration of the mucous membrane in a few males and females; 5) hypertrophy of hepatocytes in the liver of males and females, including focal necrosis of liver cells in one male and one female; and 7) bilateral tubular giant cells in the testicular tubules of two males ... . [R24, p. 40 (1993)] *Doses of 0, 25, 125, 250, or 500 mg 2-ethyl-1-hexanol/kg bw/day were admin by gavage to groups of 10 male and 10 female B6C3F1 mice for 3 mo. Animals in the 250 and 500 mg/kg bw/day groups showed toxic effects related to admin of the test cmpd. For male mice receiving 250 mg/kg bw/day, statistically significant increased stomach-to-bw ratio was observed. Statistically significant effects observed in animals receiving 500 mg 2-ethyl-1-hexanol/kg bw/day included: a) increased stomach-to-bw ratio in males and 2) slight focal or multifocal acanthosis in the mucosa of the forestomach of 2/10 males and 1/10 female ... . [R24, p. 41 (1993)] *Doses of 0, 100, 330, 1,000, or 1,500 mg 2-ethyl-1-hexanol/kg bw/day were administered by gavage for 11 days (9 applications) to groups of 10 male and 10 female Fischer 344 rats. Clear toxic effects occurred in the male and female rats receiving 330, 1,000, or 1,500 mg/kg bw/day. Female rats receiving 330 mg/kg bw/day for 11 days had increased kidney-to-bw ratios, but not increased absolute kidney weights or kidney-to-brain weight ratios. Microscopic findings included inflammatory edema in the forestomach of one female rat and decreased thymus size (microscopic examination) in 1 female and 2 male rats. Male and female rats receiving 1,000 mg 2-ethyl-1-hexanol/kg bw/day had reduced feed consumption, body weight, and body weight gain compared to control rats. Some rats in this dose group showed ataxia and apathy; a single rat showed piloerection and the genital region of one rat was smeared with urine. The following statistically significant effects were also reported to be associated with administration of 1,000 mg/kg bw/day for 11 days: a) serum cholesterol and reticulocytes in rats of both sexes were reduced; b) absolute spleen weights of rats of both sexes were reduced; c) absolute liver weights of male and female rats were increased; d) organ-to-bw ratios for stomach, liver and kidneys were increased for male and female rats; e) brain-to-bw ratio was increased in female rats; f) spleen-to-bw ratios were reduced in male and female rats; g) liver-to-brain weight ratios were increased in male and female rats; h) spleen-to-brain weight ratios were decreased in male and female rats; i) foci were reported in the forestomachs of 2 males; j) hyperkeratosis and focal or multifocal acanthosis in the mucous membrane of the forestomach of most male and female rats, as well as epithelial degeneration, ulceration and subcutaneous inflammatory edema; k) parenchymal involution of lymphoreticular tissue in the spleens of 5 female rats; l) decreased thymus size in 2 males and 5 females (microscopic evaluation); m) lymphocyte depletion in the thymus of 5 females and lymphocyte necrosis in the thymus of 4 females. Male and female rats receiving 1,500 mg 2-ethyl-1-hexanol/kg bw/day showed reduced feed consumption, body weight, and body weight gain compared to control rats. All animals in the dose group demonstrated ataxia and lethargy, some animals showed abdominal or lateral position and appeared to be unconscious, almost all animals had piloerection, and a few rats had genital regions smeared with urine. The following statistically significant effects were also reported to be associated with administration of 1,500 mg 2-ethyl-1-hexanol/kg bw/day: a) reduced serum cholesterol, glucose, and reticulocytes in male and female rats; b) increased serum alanine aminotransferase in male rats; c) decreased absolute spleen, brain, and adrenal weights and increased absolute liver and stomach weights in male and female rats; d) increased organ-to-body weight ratios for stomach, liver, kidney, and brain in male and female rats, decreased spleen-to-bw ratios for male and female rats, increased adrenal-to-bw ratio for male rats, and increased lung-to-bw ratio for female rats; e) increased organ-to-brain weight ratios forliver and stomach in rats of both sexes, decreased spleen-to-brain weight ratio for male and female rats, and decreased adrenal-to-brain weight ratio in female rats. Foci were reported in the forestomach of 4 male and 7 female rats dosed with 1,500 mg 2-ethyl-1-hexanol/kg bw/day. Microscopic findings at this dose level were reported to include: a) hyperkeratosis and focal or multifocal acanthosis in the mucous membrane of the forestomach of all male and female rats, as well as epithelial degeneration, ulceration, and subcutaneous inflammatory edema in some animals; b) slight hypertrophy of hepatocytes in the liver of 8 males and 8 females; c) focal hepatocellular necrosis in 1 female and 2 male rats; d) parenchymal involution of lymphoreticular tissue in the spleen of 9 male and 9 female rats; e) decreased thymus size in 10 male and 9 female rats; and f) lymphocyte depletion in the thymus of 9 male and 8 female rats and lymphocyte necrosis in the thymus of 1 male and 6 female rats ... . [R24, p. 41 (1993)] *Doses of 0, 25, 125, 250, or 500 mg 2-ethyl-1-hexanol/kg bw/day were administered by gavage to groups of 10 male and 10 female Fischer 344 rats for 3 months. Animals in the 250 and 500 mg/kg bw/day groups showed toxic effects. For animals receiving 250 mg/kg bw/day, statistically significant effects were reported to include: a) decreased serum alkaline phosphatase and glucose in male rats and decreased serum alanine aminotransferase in female rats; b) increased liver-to-bw ratios in male and female rats and increased stomach-to-bw ratio in female rats; and c) decreased fat deposition of the liver cells of male rats. Statistically significant effects observed in animals receiving 500 mg 2-ethyl-1-hexanol/kg bw/day included: a) decreased body weight and body weight gain in male and female rats; b) decreased serum alanine aminotransferase, glucose, and cholesterol in male and female rats, increased reticulocytes in male and female rats, decreased serum alkaline phosphatase in male rats, and increased serum protein and albumin in male rats; c) increased absolute liver weights in male and female rats and increased absolute stomach weights in female rats; d) increased organ-to-body weight ratios for liver and stomach in male and female rats; and e) increased organ-to-brain weight ratios for liver and stomach in male and female rats. Slightly elevated single or multiple foci were observed in the mucosa of the forestomach of male and female rats receiving 500 mg/kg bw/day. Macroscopic findings at this dose level were reported to include: a) focal or multifocal acanthosis in the mucosa of the forestomach of 1 male and 5 female rats; b) acanthosis of the whole mucosa, ballooning degeneration of the epithelia, and inflammatory edema in the submucosa of 1 male rat; and c) decreased fat deposition in the liver and fewer animals with fatty infiltration of the lobular periphery of the liver compared to vehicle-control rats ... . [R24, p. 42 (1993)] *Five male Wistar-derived rats were administered 1 mmol/kg/day (approximately 130 mg/kg bw/day) 2-ethyl-1-hexanol dissolved in polyethylene glycol 300 (10 ml/kg/day) by gavage for 14 days; 10 control rats were administered the gavage vehicle alone. At the end of the treatment period, rats were killed and blood was withdrawn for analysis of plasma cholesterol and triglyceride levels; livers and testis were weighed, liver samples were taken for light and electron microscopy, and the remaining liver was homogenized for determination of total catalase and CN-insensitive palmitoyl CoA oxidation. No major pathological signs of hepatotoxicity were observed, although slight centrilobular hypertrophy (controls: 4/10 rats; 2-ethyl-1-hexanol-treated: 2/5), slight/moderate glycogen vacuolization (controls: 9/10; 2-ethyl-1-hexanol-treated: 5/5), and slight/moderate centrilobular "fat" vacuolation (controls: 9/10; 2-ethyl-1-hexanol-treated: 1/5) were reported in control and 2-ethyl-1-hexanol-treated rats. Administration of 2-ethyl-1-hexanol had no significant effect on body weight gain, liver-to-body-weight ratio, testis-to-body-weight ratio, number of peroxisomes/504 square micrometers liver, serum catalase activity, serum cholesterol, or serum triglycerides. In addition, 0.1 mM 2-ethyl-1-hexanol had no effect on acyl CoA oxidase activity after 72 hrs in vitro culture with rat hepatocytes ... . [R24, p. 43 (1993)] *Gavage administration of 1335 mg/kg bw/day 2-ethyl-1-hexanol in corn oil to 6 male Wistar albino rats for 7 days resulted in significantly increased liver-to-body-weight ratio (control: 3.5 + or - 0.1 g/100 g bw; 2-ethyl-1-hexanol-treated: 4.9 + or - 0.1 (p < 0.001)), decreased glucose-6- phosphatase activity (control: 24 + or - 2 ug/min/mg microsomal protein; 2-ethyl-1-hexanol-treated: 15 + or - 1 (p < 0.01)), increased biphenyl 4-hydroxylase activity (control: 1.6 + or - 0.1 umol/hr/g liver; 2-ethyl-1-hexanol-treated: 2.1 + or - 0.1 (p < 0.01)), and increased microsomal cytochrome p450 content (control: 0.07 + or - 0.003 delta-E 450-500 nm/mg microsomal protein; 2-ethyl-1-hexanol-treated: 0.1 + or - 0.004 (p < 0.001)) ... . [R24, p. 43 (1993)] *2-Ethyl-1-hexanol (0, 50, 200, or 750 mg/kg bw/day) was administered by gavage to groups of 50 male and 50 female B6C3F, mice five days per week for a period of 18 months. The purity of the test substance was reported to be greater than 99.87%. The gavage vehicle was doubly distilled water containing 5 mg Polyoxyl 35 castor oil per 100 ml. An additional control group of 50 male and 50 female rats was gavaged with double distilled water only. All rats received 10 ml/kg bw test substance emulsion, vehicle or double distilled water per dose. ... Mice were housed singly and feed and water were available ad libitum throughout the study. At the initiation of dosing, mice were 49 days old; mean body weight of males was 23 g (range 21-26 g) and mean body weight of females was 19 g (range 17-23 g). At the end of the study, non-fasted mice were decapitated under CO2 anaesthesia. The general health of the test animals was checked daily, and test animals were examined and palpated once a week. Mice were weighed weekly during the first 13 weeks, then every four weeks for the duration of the study. Feed consumption was determined for a period of one week every four weeks during the study. Blood samples were drawn from the tail vein of all surviving animals for hematological examination at 12 months and at the end of the study. Animals that survived to the end of the study were necropsied; tissues and organs were subjected to gross and microscopic pathology examination. No 2-ethyl-1-hexanol-related changes were observed in mice administered 50 or 200 mg/kg bw/day 2-ethyl-1-hexanol for 18 months. In mice administered 750 mg/kg bw/day, the following effects were observed: 1) decreased body weight gain in males (approximately 26%) and females (24%) that was associated with a substantial reduction in feed consumption (males: decreased from about 9% to 20%; females: decreased from about 9% to 30%); 2) increased mortality in males (vehicle controls: 4%; 2-ethyl-1-hexanol-treated: 30%) and females (vehicle controls: 8%; 2-ethyl-1-hexanol-treated: 30%); 3) treatment-related hematological changes, including slightly increased polymorphonuclear neutrophils in males and females (males: controls - 19.8 + or - 5.9% (12 mo) and 20.5 + or - 7.6% (18 mo); 750 mg/kg bw/day - 26.4 + or - 9.1% (12 mo) and 26.9 + or - 13.5% (18 mo))(females: controls - 20.6 + or - 5.6% (12 mo) and 22.6 + or - 10.7% (18 mo); 750 mg/kg bw/day - 24.2 + or - 5.4 (12 mo) and 25.1 + or - 9% (18 mo)) and slightly decreased lymphocytes in males and females (males: controls - 77 + or - 6.9% (12 mo) and 76.6 + or - 7.6% (18 mo); 750 mg/kg bw/day - 69.1 + or - 9% (12 mo) and 70.6 + 13.2% (18 mo)); and 4) treatment-related, but not statistically significant, increased focal hyperplasia of the epithelium of the forestomach in males (controls - 1/50; 50 mg/kg bw/day - 1/50; 200 mg/kg bw/day - 1/50; 750 mg/kg bw/day - 5/50) and females (controls - 1/50; 50 mg/kg bw/day - 1/50; 200 mg/kg bw/day - 0/50; 750 mg/kg bw/day - 4/50). Also, a slight increase in the incidence of hepatocellular carcinomas in high-dose females was statistically significant when compared to the incidence in vehicle control females but not when compared to the incidence inwater-gavaged control females (vehicle control - 0/50; 50 mg/kg bw/day - 1/50; 200 mg/kg bw/day- 3/50; 750 mg/kg bw/day - 5/50). No statistically significant increase in tumor incidence occurred in male mice. 2-Ethyl-1-hexanol is not oncogenic in the mouse under the conditions of this study ... . [R24, p. 43 (1993)] *... 2-Ethyl-1-hexanol was administered by gavage (vehicle: distilled water containing 5 mg polyoxyl 35 castor oil per 100 ml) to two groups of male and female B6C3Fl mice at 750 mg/kg bw/day. A control group of 10 males and 10 females was gavaged with the vehicle only for 13 months; a second (non-recovery) group of 10 males and 10 females was gavaged with 2-ethyl-1-hexanol for 13 months, 5 days/week; a third (recovery) group of 50 males and 50 females was gavaged with 2-ethyl-1-hexanol for 13 months, 5 days/wk, then gavaged with the vehicle only for 5 months, 5 days/wk. Mice were killed at the end of the treatment periods - 13 months for groups one and two; 18 months for group three - and subjected to gross pathological assessment. The general health of the test animals was checked daily, and animals were examined and palpated once a week. Body weights were determined once a week during the first 13 wk of the study, then once every four weeks. Feed consumption was determined one week in every four weeks throughout the study. Microscopic examination of tissues and organs was performed only on mice that died during the study. Administration of 750 mg/kg bw/day 2-ethyl-1-hexanol to male and female mice for 13 months caused increased mortality in males and females (males: control - 0%, non-recovery - 30%, recovery - 22% during the first 13 months; females: control - 0%, non-recovery - 20%, recovery - 16% during the first 13 months). For the non-recovery mice and recovery mice during treatment with 2-ethyl-1-hexanol, feed consumption was significantly decreased compared to control mice (at 13 months, males: control - 4.7 + or - 0.4 g/day, non-recovery - 3.7 + or - 0.5 g/day, recovery - 4.4 + or - 0.6 g/day; females: control - 6.0 + or - 1.3 g/day, non-recovery - 5.6 + or - 1.5 g/day, recovery - 5.8 + or - 1.0 g/day); following the 5 month recovery period, feed consumption for mice in the recovery group was in the same range as feed consumption for control mice (males: control - 4.8 + or - 0.9 g/day, recovery - 4.9 + or - 0.8 g/day; females: control - 6.3 + or - 1.3 g/day, recovery - 5.9 + or - 1.1 g/day). For the non-recovery mice and recovery mice during treatment with 2-ethyl-1-hexanol, body weight gain was significantly decreased (at 13 months, males: control - 40.9 + or - 2.7 g, non-recovery - 36.7 + or - 2.8 g, recovery - 38.7 + or - 3.2 g; females: control - 38.7 + or - 5.4 g, non-recovery - 33.8 + or - 4.4 g, recovery - 34.9 + or - 4.8 g); following the 5 month recovery period, body weight gain of female mice that had been gavaged with 2-ethyl-1-hexanol for 13 weeks was still significantly decreased compared to control mice (males: control - 42.7 + or - 3.5 g, recovery - 42.4 + or - 3.6 g; females: control - 41.1 + or - 5.6 g, recovery - 36.9 + or - 5.1 g). Some statistically significant changes in organ weights and masses or foci in liver and stomach were observed to be associated with 2-ethyl-1-hexanol administration; these were similar to changes noted in the results of the carcinogenicity study ... . [R24, p. 44 (1993)] NTOX: *2-Ethyl-1-hexanol (0, 50, 100, or 150 mg/kg bw/day /SRP: Also 500 mg/kg bw/day/) was administered by gavage to groups of 50 male and 50 female Fischer 344 rats five days/week for a period of 24 months. ... At the initiation of dosing, rats were 42 days old; mean body weight of males was 103 g (range 86-128 g) and mean body weight of females was 81 g (range 64-95 g). ... No compound-related changes were associated with administration of 50 mg/kg bw/day for 24 months; however, body weights and body-weight gains of rats receiving 50, 150, or 500 mg 2-ethyl-1-hexanol/kg bw/day were decreased in a statistically significant dose-dependent manner compared to vehicle control rats. At the end of the study, body weights were about 5%, 11%, and 23% below control values and body weight gains were about 8%, 16%, and 33% below control values, respectively. ... An 2-ethyl-1-hexanol-associated increase in mortality was observed for female mice of the high-dose group only (males: vehicle controls - 34%, 50 mg/kg bw/day - 46%, 150 mg/kg bw/day - 32%, 500 mg/kg bw/day - 38%; females: vehicle controls - 28%, 50 mg/kg bw/day - 28%, 150 mg/kg bw/day - 26%, 500 mg/kg bw/day - 52%). For rats receiving 100 mg/kg bw/day, the study reported a) statistically significant reductions in body weight (males: 11 %; females: 9%) and body weight gain (males: 16%; females: 12%) compared to vehicle control rats and b) slightly increased numbers of animals with clinical symptoms and incidences of symptoms (frequency/animals) such as poor general condition (100 mg/kg bw/day: males - 69/15; vehicle control: males - 62/12), labored breathing (100 mg/kg bw/day: males - 4/1, females - 30/5; vehicle control: males - 2/1, females - 9/3), piloerection (100 mg/kg bw/day: males - 17/1; vehicle control: males - O/O), and genital regions smeared with urine (100 mg/kg bw/day: females - 31/4; vehicle controls: females - 0/0). ... The following treatment-related changes were observed in rats dosed with 500 mg/kg bw/day 2-ethyl-1-hexanol for 24 months: a) statistically significant reductions in body weight gain for males (33%) and females (31%); b) increased incidences of male and female rats with clinical symptoms (frequency/animals) such as poor general condition (500 mg/kg bw/day: males - 200/14, females - 248/21; vehicle control: males - 62/12, females - 34/8), labored breathing (500 mg/kg bw/day: males - 41/4, females - 75/12; vehicle control: males - 2/1, females - 9/3), piloerection (500 mg/kg bw/day: males - 67/2, females - 21/5; vehicle control: males - 0/0, females - 2/1), and/or genital region smeared with urine (500 mg/kg bw/day: males - 13/1, females - 502/21; vehicle control: males - 0/0, females 44/6); and c) statistically significant increased mortality in dosed females as reflected in the number of animals that died or were sacrificed in a moribund condition during the study (52%) compared with vehicle control females (28%). Male rats dosed with 500 mg/kg bw/day had slightly increased anisocytosis, predominantly microcytosis at 12 months, but not at 18 nor 24 months, compared to vehicle control males. No malignant tumors were detected in high-dose animals that died before scheduled termination and the sum of primary tumors, benign tumors and malignant tumors was remarkably lower in the high-dose group compared to both control groups of rats. Thus, 2-ethyl-1-hexanol was not oncogenic in the rat under conditions of this assay ... . [R24, p. 45 (1993)] *... 2-Ethyl-1-hexanol was administered by gavage (vehicle: distilled water containing 5 mg polyoxyl 35 castor oil per 100 ml) to two groups of male and female Fischer 344 rats at 500 mg/kg bw/day. A control group of 10 males and 10 females was gavaged with the vehicle only for 18 months; a second (non-recovery) group of 10 males and 10 females was gavaged with 2-ethyl-1-hexanol for 18 months, 5 days/week; a third (recovery) group of 50 males and 50 females was gavaged with 2-ethyl-1-hexanol for 18 months, 5 days/week, then gavaged with the vehicle only for 6 months, 5 days/week. Rats were killed at the end of the treatment periods - 18 months for groups one and two; 24 months for group three - and subjected to gross pathological assessment. The general health of the test animals was checked daily, and animals were examined and palpated once a week. Body weights were determined once a week during the first 13 weeks of the study, then once every four weeks. Feed consumption was determined one week in every four weeks throughout the study. Microscopic examination of tissues and organs was performed only on rats that died during the study. Administration of 500 mg/kg bw/day 2-ethyl-1-hexanol to male and female rats for 18 months caused slightly increased mortality in females (control - 20%, non-recovery - 40%, recovery - 34% during the first 18 months) and decreased feed consumption in males (maximum decrease of approximately 12%). For the non-recovery rats and recovery rats during treatment with 2-ethyl-1-hexanol, body weight gain was significantly decreased (at 18 months, males: control - 298.7 + or - 19.6 g, non-recovery - 215.4 + or - 21.3 g, recovery - 211.2 + or - 22.4 g; females: control - 149.9 + or - 19.8 g, non-recovery - 128.7 + or - 21.7 g, recovery - 128.5 + or - 18.3 g); following the 6 month recovery period, body weight gains of males and females that had been gavaged with 2-ethyl-1-hexanol for 18 weeks had partially recovered but were still significantly decreased compared to controls (males: control - 266.5 + or - 30.7 g, recovery - 216.1 + or - 23.0 g; females: control -177.5 + or - 27.0 g, recovery - 150.6 + or - 21.5 g). The following changes were observed in rats that had been gavaged with 500 mg/kg bw/day 2-ethyl-1-hexanol for 18 months compared to control rats: 1) a greater number of animals and/or a higher incidence of clinical symptoms such as poor general condition, labored breathing, and genital region smeared with urine in males and females; 2) statistically significant decreases in the absolute weights of brain (males and females) and stomach (males); 3) statistically significant decreases in organ-to-body weight ratios of brain (males and females), liver (males and females), kidneys (males and females), stomach (males and females), and testes ... . [R24, p. 47 (1993)] *The response of mixed cultures of Sertoli and germ cells prepared from Sprague-Dawley rat testes to model testicular toxicants was studied. After incubation of the cultures with 2 x 10 -4 M 2-ethyl-1-hexanol for 24 hrs, no increase was observed in the normal rate of germ cell detachment from Sertoli cells into the culture medium ... . [R24, p. 48 (1993)] *Effects of 2-ethyl-1-hexanol on rat testes were examined in vivo and in vitro. No testicular damage was observed in male Sprague-Dawley rats given oral doses of 2.7 mmol 2-ethyl-1-hexanol/kg bw/day for 5 days and incubation with 2-ethyl-1-hexanol (0-100 uM for 24 or 48 hr) did not enhance detachment of germ cells from primary mixed cultures of rat Sertoli and germ cells ... . [R24, p. 48 (1993)] *2-Ethyl-1-hexanol did not increase lactate and pyruvate concn in the medium of in vitro cultures of rat Sertoli cells. Such increases are considered to be indicators of altered Sertoli cells function assoc with Sertoli-cell toxicants ... . [R24, p. 48 (1993)] *Pregnant CD-1 mice were gavaged on gestation days 6-13 with 1525 mg/kg bw/day 2-ethyl-1-hexanol in corn oil; control mice were gavaged with corn oil; dams were allowed to litter. Admin of 2-ethyl-1-hexanol caused statistically significant (p < 0.05) decreased maternal bw gain (control: 7.0 + or - 2.5 g; 2-ethyl-1-hexanol: 3.9 + or - 3.2 g), decreased number of viable litters (control: 33/34; 2-ethyl-1-hexanol: 11/20), decreased liveborn per litter (control: 9.9 + or - 2.4; 2-ethyl-1-hexanol: 6.8 + or - 3.4), decreased birth weight (control: 1.6 + or - 0.1 g/pup; 2-ethyl-1-hexanol: 1.4 + or - 0.2 g/pup) and weight gain for pups (control: 0.6 + or - 0.1 g/pup; 2-ethyl-1-hexanol: 0.3 + or - 0.2 g/pup) ... . [R24, p. 48 (1993)] *Pregnant Wistar rats were admin undiluted di(2-ethylhexyl)phthalate (DEHP; 12.5 or 25 mmol/kg bw), 2-ethyl-1-hexanol (6.25 or 12.5 mmol/kg bw, approx equivalent to 800 and 1600 mg/kg bw), or 2-ethylhexanoic acid (EA; 6.25 or 12.5 mmol/kg bw) by gavage on day 12 of gestation. Control rats were not gavaged (untreated controls). Caffeine (150 mg/kg) was dissolved in water and injected ip in some pregnant rats of each group. Rats were killed on day 20 of gestation; following Caesarean section, implantation sites were determined in situ and the number of dead or resorbed fetuses was determined. Live fetuses were removed and examined; internal and external soft tissue and skeletal malformations were recorded. At least seven litters for each experimental condition were analyzed. Administration of each test compound resulted in statistically significant, dose-related increases in malformed live fetuses ... 2-ethyl-1-hexanol: 6.25 mmol/kg bw (7 litters) - 2.0 + or - 1.3%, 12.5 mmol/kg bw (7 litters) - 22.2 + or - 14.7% ... compared to controls (no malformed live fetuses in 7 litters). Defects in fetuses following treatment with 2-ethyl-1-hexanol included hydronephrosis (7.8% of live fetuses), tail defects (4.9% of live fetuses), limb defects (9.7% of live fetuses), and other defects (1.0% of live fetuses). For each test compound, caffeine was reported to potentiate (increase) the percent of malformed live fetuses. However, administration of test compounds did not significantly affect the percentage of dead and resorbed fetuses compared to controls. No maternal effects associated with the test compounds were reported ... . [R24, p. 48 (1993)] *The developmental toxicity of dermally applied 2-ethyl-1-hexanol was studied in Fischer 344 rats; results of a dose range-finding study for the developmental toxicity study were also included. In the dose range-finding study 0, 420, 840, 1680, or 2520 mg/kg bw/day 2-ethyl-1-hexanol (undiluted) was applied to the clipped dorsal skin of pregnant F344 rats (8 rats/group); a positive dermal control group (2-methoxyethanol) and a sham-treated (deionized water) dermal control group were included in the study. In the developmental toxicity study, 0, 252, 840, or 2520 mg/kg bw/day 2-ethyl-1-hexanol (undiluted) was applied to the clipped dorsal skin of pregnant F344 rats (25/group); a positive dermal control group (2-methoxyethanol) and a sham-treated (deionized water) dermal control group also were included in this study. Body weights were recorded on gestation days 0, 6, 9, 12, 15, and 21; feed consumption was estimated for 3-day intervals from gestation days 0-21. Skin irritation was measured before and after each 6-hr application period. Surviving females were killed on gestation day 21; uterine and liver weights (both studies) and weights of spleen, adrenals, kidneys, and thymus (developmental toxicity study) were recorded. Corpora lutea and uterine implantation sites were counted; ovaries, cervices, vaginas, and abdominal and thoracic cavities were examined grossly. All live and dead fetuses and resorption sites were noted. Live fetuses were sexed, weighed, and examined for external, visceral, and skeletal malformations and variations. All pregnant females treated with 2-ethyl-1-hexanol survived. Clinical findings for 2-ethyl-1-hexanol-treated pregnant rats were limited to body weight changes, skin irritation, and nasal and ocular effects. Decreased body weight gain was observed in the dose range-finding study for gestation days 6-15 at doses of 1680 (10.1 + or - 7.1 g) and 2520 mg/kg bw/day 2-ethyl-1-hexanol (10.7 + or - 4.8 g) compared to sham-treated control rats (18.9 + or - 6.4 g). In the main study, weight gain was statistically significantly decreased for gestation days 6-9 at 2520 mg/kg bw/day 2-ethyl-1-hexanol (0.1 + or - 2.4 g) compared to sham-treated controls (3.3 + or - 1.2 g), and was somewhat, but not statistically significantly, decreased at 840 mg/kg bw/day 2-ethyl-1-hexanol. No significant changes in feed consumption were reported at any treatment level of 2-ethyl-1-hexanol in either study throughout gestation (data not given). 2-Ethyl-1-hexanol-related irritation effects at the treatment site were identified as mild, and included exfoliation, encrustation and erythema for all treatment groups in both studies; edema was not observed. Gestational effects were observed for neither study at any dose of 2-ethyl-1-hexanol applied dermally. Also, dermal administration of 2-ethyl-1-hexanol was not associated with external, visceral, or skeletal malformations. Dermally applied 2-ethyl-1-hexanol does not produce developmental or teratogenic effects when administered at doses associated with demonstrable maternal toxicity ... . [R24, p. 49 (1993)] *With one exception, the results of various (14 total) in vitro genotoxicity assays on 2-ethyl-1-hexanol were of negative results, including a dominant lethal assay, a chromosomal aberration assay, and a mutagenicity assay on rat urinary metabolites of 2-ethyl-1-hexanol. /From table/ [R24, p. 50 (1993)] NTXV: *LC50 Guinea pig inhalation > 227 ppm/6 hr /From table/; [R24, p. 39 (1993)] *LD50 Guinea pig dermal > 8300 mg/kg bw /From table/; [R24, p. 39 (1993)] *LD50 Rabbit dermal 1986 mg/kg bw /From table/; [R24, p. 39 (1993)] *LC50 Mouse > 227 ppm/6 hr /From table/; [R24, p. 39 (1993)] *LD50 Mouse ip 780 mg/kg bw /From table/; [R24, p. 39 (1993)] *LD50 Mouse iv 1670 mg/kg /From table/; [R24, p. 39 (1993)] *LC50 Rat inhalation > 227 ppm/6 hr /From table/; [R24, p. 39 (1993)] *LD50 Rat iv 1670 mg/kg bw /From table/; [R24, p. 39 (1993)] *LD50 Rat oral 2053 mg/kg bw /From table/; [R24, p. 39 (1993)] *LD50 Rat ip 650 mg/kg bw /From table/; [R24, p. 39 (1993)] NTP: +... Microencapsulated 2-ethylhexanol (0%, 0.009%, 0.03%, or 0.09% in feed) was provided on gestational days (gd) 0 to 17 ad libitum to timed-mated CD-1(R) mice (28/group). At sacrifice (gd 17),the number of ovarian corpora lutea and uterine implantation sites, including resorptions, and dead or live fetuses, were recorded. ... No dams died, delivered early or were removed from study. Pregnancy rate was high (93-96%) and equivalent across all groups. One litter at 0% was fully resorbed; all other pregnant animals had live litters at scheduled necropsy. The numbers of live litters evaluated were 27 at 0.009 and 0.03% and 26 at 0 and 0.09% 2-ethylhexanol. There was no treatment-related maternal toxicity observed in this study. Maternal body weights, weight gains (absolute or corrected for gravid uterine weight), gravid uterine weight and liver weight (absolute or relative to body weight) were unaffected. Food consumption (g/kg/day and g/day) was significantly increased for gd 0-3 at 0.09% and unaffected for all other time points evaluated. The calculated consumption of 2-ethylhexanol, based on gestational food consumption was 0 (0 mmol/kg), 17 (0.13 mmol/kg), 59 (0.46 mmol/kg) and 191 mg/kg/day (1.49 mmol/kg), for the 0, 0.009, 0.03 and 0.090% groups, respectively. There were no effects of exposure to dietary 2-ethylhexanol on any gestational parameters. The number of corpora lutea, uterine implantation sites (live, dead, resorbed), pre- and post implantation loss, sex ratio (%, males) and live fetal body weight per litter (all fetuses or separately by sex) were all equivalent across all groups. There were also no treatment-related changes in the incidence of individual, external, visceral, skeletal or total malformations or variations. In conclusion, there were no maternal or developmental toxic effects of 2-ethylhexanoldietary exposure throughout gestation at any concentration tested, in contrast to the qualitatively similar maternal and developmental toxicity previously reported for di(2-ethylhexyl)phthalate ... and mono(2-ethylhexyl)phthalate (NTP, 1990) at approximately equimolar doses administered under comparable experimental conditions. The present study therefore indicates that 2-ethylhexanol plays essentially no role in the expression of di(2-ethylhexyl)phthalate-induced maternal and developmental toxicity. [R27] TCAT: ?Micronuclei induction in strain B6C3F1 mouse polychromatic erythrocytes (PCE's) was evaluated after intraperitoneal injection of 2-ethyl hexanol (purity not reported) to groups of 12 mice (6 male, 6 female). Harvest of bone marrow PCE's was performed 30 hours after mice received a single acute dose, or 24 hours after mice received the second of 2 administrations (24 hours apart) of 2-ethyl hexanol at 456 mg/kg. Differences in the percentages of micronucleated PCE's were evaluated by the Student t-test for males and females, both separately and pooled, independently for the two treatment schemes. With one exception, there was no significant difference in percent micronucleated PCE's between animals dosed with 2-ethyl hexanol and the corresponding negative control. The exception was the multiple treatment males, whose percentage was increased at a statistically significant level (0.01 < = P < = 0.05). The investigators stated that they did not believe this effect to be biologically significant because of the observation of unusually low percentages of micronucleated PCE's in the corresponding control group. [R28] ?The morphological transforming potential of 1.5, 1.125, 0.75, 0.375 or 0.188 ul/ml 2-ethyl hexanol (purity not reported) administered in vitro to Balb/C-3T3 cells was evaluated open vessel conditions. No statistically significant (using the Bailey modification of the Students t-test) increase in transformation rates were observed at any concentration. The effect of 2- ethyl hexanol on colony formation in the concomitant cytotoxicity assay was not dose related; the investigators postulated that this was due to volatilization and the transformation trial was repeated using 0.162, 0.129, 0.086, 0.043 or 0.011 ul/ml under closed vessel conditions. No statistically significant (using Bailey modification of Students t-test) increase in transformation rates were observed at any concentration . Colony formation in the concomitant closed vessel cytotoxicity test ranged from 106.7% of control at 0.0117 ul/ml to 37.5% at 0.175 ul/ml. [R29] ?The frequency of reversion to HIS+ phenotype was determined in Salmonella strains TA1535, TA1537, TA1538, TA98 and TA100 exposed in vitro to 2-ethylhexanol (purity not reported). No statistically significant increase in mutation frequency was observed at dosages of up to 1.8 ul/plate in the presence or absence of rat liver S9 metabolic activation. In a separate toxicity test using the TA100 strain, 80% toxicity was observed at 1.8 ul/plate in the absence of metabolic activation. [R30] ?The frequency of forward mutation was determined at the HGPRT locus of Chinese Hamster Ovary K-1 cells exposed in vitro to 2-ethylhexanol (purity not reported). Concentrations of up to 350 nl/ml did not induce any statistically significant changes in the mutant frequency in the absence of rat liver S9 metabolic activation. No statistically significant mutagenic activity was observed at levels up to 200 nl/ml in the presence of metabolic activation. In tests with and without metabolic activation, 2-ethylhexanol was observed to decrease cell survival in a dose-related manner; in the absence of metabolic activation the relative survival was 16.3% at the 350 nl/ml dose level, in the presence of activation the relative survival was 25.1% at the 200 nl/ml dose level. [R31] ?The ability of 2-ethyl-1-hexanol (2-EH) to cause chromosome aberrations in Chinese hamster ovary (CHO) cells in vitro was evaluated in the presence and absence of induced rat liver S9 activation. Based on preliminary toxicity tests, nonactivated cultures treated with 5, 10, 20, 50, 100, 200, 500, 1000, 2000 and 5000 nl/ml 2-EH in 1% aqueous acetone (insoluble material present in the highest 4 concentrations) were cloned, producing a cloning efficiency ranging from 103.3% to 0% (0% cloning efficiency observed for highest 4 concentrations). Assays at the same concentrations with metabolic activation produced cloning efficiency ranging from 102.7% to 0% (0% cloning efficiency observed for the highest 4 concentrations). The test material did not induce dose-related increases in the mutant frequency at any of the concentrations used in these tests, either with or without activation. [R32] ?The ability of 2-ethylhexanol to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) in the presence of added metabolic activation by Arochlor-induced rat liver hepatocytes was evaluated. Based on preliminary clonal toxicity determinations (exposure time=24 hrs), di-2-ethylhexanol was tested at 180, 144 and 96 nl/ml, with cell survival ranging from 72.0-3.7% relative to the solvent control (acetone). The test material did not induce the appearance of a significant number of transformed foci. [R33] ?2-Ethylhexanol was examined for mutagenic activity in Salmonella typhimurium tester strains TA1535, TA1538, TA1537, TA98, TA100 in the presence and absence of metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was not mutagenic at concentrations ranging from 0.002 to 1.8 ul/plate with or without activation. In a preliminary cytotoxicity assay, the percent relative survival decreased from 72.7% at 1.2 ul/plate to 8.2% at 2.3 ul/plate. [R34] ?The mutagenic effect of 2-ethylhexanol was evaluated in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 with and without metabolic activation provided by rat liver S9 fraction. The method used for inducing liver enzyme activity was not reported. Additionally, the investigators did not report the exact method for administering the test article, but stated that a volatile containment apparatus was used. 2-Ethylhexanol was administered at levels from 0.41 to 1.77 ug/plate and was not found to be mutagenic in the presence or absence of activation. In a preliminary cytotoxicity test, the concentrations used for the mutagenicity assay were shown to be toxic to cells. [R35] ?The mutagenicity of urine from Sprague-Dawley rats dosed daily by gavage for 15 days with 2,000 mg/kg of 2-ethylhexanol was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Modified Ames Test), both in the presence and absence of Aroclor-induced rat liver S9 metabolic activation and beta-glucuronidase/aryl sulfatase. Cultures were dosed with up to 2 ml of urine using direct plating procedures. The urine of rats treated with 2-ethylhexanol did not cause a positive response under any of the test conditions. [R36] ?The ability of 2-ethylhexanol to cause forward mutations at the HGPRT locus in Chinese Hamster Ovary cells was evaluated in the presence and absence of metabolic activation provided by Aroclor-induced rat liver S9 fraction. In the absence of activation, an increase in mutant frequency that just achieved statistical significance ( p < = 0.01 ) was observed at 200 nl/ml after administration of test article at concentrations ranging from 20 to 300 nl/ml, however, duplicate cultures did not show this effect and the mutant frequency was reported to be similar to controls. In the presence of activation, administration of 100 to 400 nl/ml resulted in slight statistically significant increases in mutant frequencies at 250 nl/ml and 400 nl/ml, but again duplicate cultures did not show this effect and the mutant frequency was reported to be similar to controls. The percent relative survival was 19.6% at 400 nl/ml in the presence of activation, and 68.2% at 300 nl/ml in the absence of activation. [R37] ?The morphological transforming potential of 96, 144, or 180 nl/ml 2- ethyl hexanol (purity not reported) administered in vitro to Balb/C-3T3 cells in the presence of freshly isolated rat liver hepatocytes was evaluated. 2-ethyl hexanol did not induce the appearance of a statistically significant (by use of Bailey modified Students t-test) number of transformed foci at the concentrations tested. In a concomitant cytotoxicity test, the test range was found to include survival rates of approximately 72.0% at the low dose, to 3.7% at the high dose. [R38] ?The mutagenicity of 2-ethyl hexanol was evaluated in the dominant lethal assay. Based on preliminary toxicity determinations, three groups of 25 male ICR/SIM mice received 250, 500 or 1000mg/kg (maximum tolerated dose) of test material orally by gavage for five consecutive days. After treatment, 20 animals per treatment group were chosen to be mated with two virgin females per week for eight consecutive weeks. Females mated with treated males had statistically significant (t-test) increases in the average number of dead implants (mid dose only), dead/total implant ratios (mid and high doses), and death indices (mid and high doses) during week one. However, effects were attributed to extremely low values for the negative control females. Total implants per pregnant female were reduced during week six for mid dose groups and high dose groups during week 8. The high dose implant reduction was not accompanied by a significant reduction in live implants or an increase in dead implants. 2-Ethyl hexanol was not considered to have demonstrated a significant mutagenic effect in the dominant lethal assay. [R39] ?2-Ethyl-1-hexanol (CAS # 104-76-7) was evaluated for carcinogenicity. The test substance was administered by oral gavage to B6C3F1 mice (50/sex/group) at a dosage level of 50, 200, and 750 mg/kg body weight for 5 days a week for 18 months. In the 750 mg/kg group, clinical and hematological findings included increased mortality, reduced body weight gain, reduced feed consumption, slight increase in polymorphonuclear neutrophils, and a slight decrease in lymphocytes. Pathological findings at 750 mg/kg, include a slight increase in focal hyperplasia of the epithelium of the forestomach; and a slight increase in hepatocellular carcinomas in the females. At 50 and 200 mg/kg, there were no substance-related changes. The test substance was determined to be non-oncogenic. [R40] ?2-Ethyl-1-hexanol (CAS # 104-76-7) was evaluated for chronic oral toxicity and carcinogenicity. The test substance was administered by oral gavage to Fischer F-344 rats (50/sex/group) at a dosage level of 50, 150, and 500 mg/kg body weight for 5 days a week for 24 months. At 150 mg/kg and above, clinical signs included reduced body weight gain, labored breathing, and piloerection. In the 500 mg/kg level, there was increased mortality by 52% and an increased incidence of bronchopneumonia. The test substance was determined to be non-oncogenic. [R41] ADE: *EFFICIENTLY ABSORBED FOLLOWING ORAL ADMIN, RAPIDLY EXCRETED IN RESP CO2 (6-7%), FECES (8-9%) AND URINE (80-82%), WITH ESSENTIALLY COMPLETE ELIMINATION 28 HR AFTER ADMIN; ONLY ABOUT 3% EXCRETED UNCHANGED. [R42] *Two adult male CD-strain rats (300 g) were gavaged with radiolabeled 2-ethyl-1-(14)C-hexanol ((14)C-2-ethyl-1-hexanol; 1 uCi; 8.8 ug) in cottonseed oil. Two others were given the same amount of (14)C-EH and cottonseed oil, but also were given 0.1 ml (0.64 mmol) of unlabeled 2-ethyl-1-hexanol. Following administration of the test substance, rats were housed in metabolism cages with ad libitum access to feed and water; expired CO2, urine, and feces were collected every hour for 28 hrs. Most (99.8%) of the orally administered radioactivity was accounted for by radioactivity in expired CO2, urine, feces, an ethanol wash of the metabolism cage at the end of the experiment, heart, brain, liver, kidneys, and "residual carcass." 2-Ethyl-1-hexanol was efficiently absorbed following oral administration and rapidly excreted in respired CO2 (6-7%), urine (80-82%), and feces (8-9%); elimination was essentially complete by 28 hrs. The major urinary metabolite of 2-ethyl-1-hexanol in the rat was shown to be 2-ethylhexanoic acid through acid extraction of urine. This metabolite can undergo partial B-oxidation and decarboxylation to produce (14)CO2 and 2- and 4-heptanone (in the urine). Other urinary metabolites of 2-ethyl-1-hexanol were identified as 2-ethyl-5-hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, and 2-ethyl-1,6-hexanedioic acid. Approximately 3% of the parent compound was excreted unchanged. [R24, p. 35 (1993)] *An in vitro dermal absorption study of 2-ethyl-1-hexanol and seven other cmpd was conducted with full thickness rat skin and human stratum corneum. The ratio of the rate of absorption of EH through rat and human skin (rat/human) was reported to be 5.8, indicating that rat skin is more permeable to 2-ethyl-1-hexanol than is human skin. Damage to skin by dermal application of 2-ethyl-1-hexanol was defined as the ratio of the permeability constant for 3-H2O after contact with 2-ethyl-1-hexanol to the permeability constant for 3-H2O before application. Ratios for human skin (1.5 + or - 0.4 and 3.7 + or - 2.1) and rat skin (31.9 + or - 5.1) indicated that dermal application of 2-ethyl-1-hexanol damages rat skin more than human skin ... . [R24, p. 36 (1993)] *Excretion balance studies were conducted on female Fischer 344 rats (4 animals/group) following acute oral doses of 50 or 500 mg/kg bw (14)C-2-ethyl-1-hexanol and repeated oral doses of 50 mg/kg bw/day (14)C-2-ethyl-1-hexanol for 14 days; results of acute gavage doses of 500 mg/kg bw (14)C-2-ethyl-1-hexanol administered neat and as aqueous suspensions containing 5 mg Polyoxyl 35 castor oil/100 ml were compared. Dermal exposures to (14)C-2-ethyl-1-hexanol (1 g/kg bw applied dose) for 6 hr and iv exposures to 1 mg/kg bw (14)C-2-ethyl-1-hexanol were also studied. Acute oral doses of 50 or 500 mg/kg bw and repeated oral doses of 50 mg/kg bw/day showed similar excretion balance profiles of (14)C, with some evidence of metabolic saturation at the high dose. No evidence of metabolic induction was reported following repeated dosing. All oral doses were rapidly eliminated during the first 24 hours after dosing, predominantly in the urine. Approximately 5% of the dermal dose was absorbed. A majority of the oral and dermal doses were eliminated as glucuronides of oxidized metabolites of 2-ethyl-1-hexanol principally glucuronides of 2-ethyladipic acid, 2-ethylhexanoic acid, 5-hydroxy-2-ethylhexanoic acid, and 6-hydroxy-2-ethylhexanoic acid. Only trace amounts of unchanged 2-ethyl-1-hexanol were eliminated in the urine. Bioavailability of 2-ethyl-1-hexanol orally administered with the gavage vehicle was slightly greater than bioavailability of 2-ethyl-1-hexanol administered alone ... . [R24, p. 36 (1993)] METB: *...NEARLY 90% OF DOSE OF 2-ETHYLHEXANOL, WHEN INGESTED BY RABBITS IS EXCRETED IN URINE CONJUGATED WITH GLUCURONIC ACID (ALPHA-ETHYLHEXANONYLGLUCURONIDE). [R19, 1464] *IN RATS AMT OF LABEL RECOVERED IN (14)CO2 MATCHED AMT OF UNLABELED 2-HEPTANONE + 4-HEPTANONE RECOVERED FROM URINE: BOTH TYPES MAY BE DERIVED FROM MAJOR URINARY METABOLITE 2-ETHYLHEXANOIC ACID, BY DECARBOXYLATION FOLLOWING PARTIAL BETA-OXIDN. [R42] *The major urinary metabolite of 2-ethyl-1-hexanol in the rat was shown to be 2-ethylhexanoic acid through acid extraction of urine. This metabolite can undergo partial B-oxidation and decarboxylation to produce (14)CO2 and 2- and 4-heptanone (in the urine). Other urinary metabolites of 2-ethyl-1-hexanol were identified as 2-ethyl-5- hydroxyhexanoic acid, 2-ethyl-5-ketohexanoic acid, and 2-ethyl-1,6-hexanedioic acid. Approximately 3% of the parent compound was excreted unchanged. [R24, p. 35 (1993)] *Rats and other mammals hydrolyze orally ingested DEHP (di-(2-ethylhexyl)phthalate, a plasticizer in food-contact materials) to (EH) and MEHP (mono-(2-ethylhexyl)phthalate) prior to absorption of (mono-(2-ethylhexyl)phthalate) by the intestine ... . [R24, p. 36 (1993)] *... Studied the metabolism of 8 mg (14)C-2-ethyl-1-hexanol in rats and 200 mg (14)C-2-ethyl-1-hexanol in rabbits following ip injection. The major urinary metabolite in rats was 2-ethylhexanoyl glucuronide; 2-ethyl-1-hexanol and 2-ethyl hexanoic acid were also identified in rat urine. In rabbits, the major urinary metabolite also was 2-ethylhexanoyl glucuronide; 2-ethylhexanoyl glucuronide; 2-ethyl-2,3-dihydroxyhexanoic acid and 2-ethyl-1-hexanol were also identified in rabbit urine ... . [R24, p. 36 (1993)] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3(?). 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT FOR 70 KG PERSON (150 LB). [R6] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Ethylhexanol may be released to the environment as emission or in wastewater as a result of its manufacture, transport, storage, disposal and use as a chemical intermediate in the manufacture of plasticizers and other chemicals. It is also a plant volatile and may be released naturally into air. If released in soil, it would be expected to leach and readily biodegrade after some acclimation. Some volatilization may occur from both moist and dry soil. If released in water, 2-ethylhexanol will volatilize; the estimated half-life in a model river is 1.7 days. It is readily biodegradable in screening tests and one river die-away test and should biodegrade. Adsorption to sediment and bioconcentration in fish is not expected to be important. In the atmosphere, 2-ethylhexanol will occur as a vapor and react with photochemically produced hydroxyl radicals. Its estimated half-life in the atmosphere is 1.2 days. Since it is moderately water soluble, it may also be washed out of the atmosphere by rain. Occupational exposure to 2-ethylhexanol may occur via inhalation and dermal contact. The general population may be exposed to 2-ethylhexanol by ingesting some fruits, in which it occurs naturally, and drinking water and also from indoor air. (SRC) NATS: *2-Ethylhexanol is a naturally occuring plant volatile that has been identified in a variety of fruits(1-4). [R43] ARTS: *2-Ethylhexanol may be released to the environment as emission or in wastewater(SRC) as a result of its manufacture, transport, storage, disposal and use as a chemical intermediate in the manufacture of plasticizers (e.g.dioctyl phthalate), 2-ethylhexyl acrylate (plastics, coatings), 2-ethylhexyl nitrate (cetane improver), lube additives, surfactants, and solvents(2). 2-Ethylhexanol may be formed during the chlorination of water and wastewater(1,8) and the combustion of PVC plastics(3) and may be released in these processes(SRC). 2-Ethylhexanol is also found in emissions from some carpeting(4,5,7). It was emitted from a polyamide carpet with latex backing and a silicone-based sealant(4). In another study, 2-ethylhexanol was emitted from a nylon carpet with PVC backing, but not from 3 other nylon carpets with polypropylene or polyurethane backing and SBR latex(5). 2-Ethylhexanol may leach from defective high density polyethylene water pipe(6). In a German study, approximately 20% of the piping studied (264 samples) was defective and the total release time for this piping may exceed several months under low flow conditions(6). [R44] FATE: *TERRESTRIAL FATE: 2-Ethylhexanol is estimated to have a Koc value of 105(SRC), determined using its water solubility, 880 mg/L(2), and a recommended regression equation(3,SRC), which indicates that it will be highly mobile in soil(1,SRC). 2-Ethylhexanol's vapor pressure, 0.136 mm Hg at 25 deg C(4), and estimated Henry's Law constant, 2.65X10-5 atm-cu m/mole(2,4,SRC), suggest that some volatilization may occur from both dry and moist soil(SRC). 2-Ethylhexanol is expected to biodegrade in soil because it is readily degradable in aerobic screening tests(5-7) and degraded when incubated in soil from a waste site(7). [R45] *AQUATIC FATE: If released in water, 2-ethylhexanol may be lost by volatilization since its volatilization half-life from a model river is estimated to be 1.7 days(3,SRC). This half-life is derived using a Henry's Law constant, 2.65X10-5 atm-cu m/mole(SRC), derived from its vapor pressure, 0.136 mm Hg(1), and water solubility, 880 mg/L(2). Its estimated Koc, 105, and BCF, 13, both estimated from its water solubility(2) and regression equations(3,SRC) indicate that adsorption to sediment and bioconcentration in aquatic organisms will not be an important transport processes(SRC). 2-Ethylhexanol is expected to biodegrade in water because it is readily degradable in aerobic screening tests(4-6) and degraded in river water after a few days of acclimation in one study(7). [R46] *Based on its vapor pressure of 0.136 mm Hg at 25 deg C(3), 2-ethylhexanol will occur in the atmosphere primarily as a vapor(2,SRC). It reacts with photochemically-produced hydroxyl radicals resulting in an estimated atmospheric half-life of 1.2 days(1,SRC). Since it is moderately water soluble, 880 mg/L(4), it may also be washed out of the atmosphere by rain(SRC). [R47] BIOD: *2-Ethylhexanol readily biodegrades in aerobic screening tests, especially with some acclimation. It was readily biodegradable in the 2-week screening test of the Japanese Ministry International Trade and Industry (MITI), a BOD test utilizing a mixed inoculum of activated sludge, sewage and surface water(4). In BOD tests, 100% degradation occurred in 24 hours using an industrial wastewater (acclimated) inoculum(1), while no degradation occurred after 24 hours and 100% degradation occurred after 135 hours using a municipal wastewater (unacclimated) seed(1). In another BOD test, using a sewage seed, 26%, 75%, 78%, and 86% of the theoretical BOD was exerted after 5, 10, 15, and 20 days, respectively(2). When the test was repeated in synthetic seawater, the respective results were 58%, 64%, 84%, and 100% of the theoretical BOD consumed(2). After 5 days, 41.5% of theoretical BOD was consumed using an inoculum of mixed microbial cultures(5). Thirty-one percent of 2-ethylhexanol degraded when incubated with soil from a waste disposal site for 21 days; 52% degradation occurred when the sample was amended with a source of nitrogen(3). Only 5% degradation occurred when the test was conducted under anaerobic conditions(3). [R48] *When 2-ethylhexanol was added to river water at 18-19 deg C, it started to degrade after a 3-4 day lag(1). The BOD consumed after 8 and 9 days was 30% and 59% of the theoretical BOD(1,SRC). [R49] ABIO: *2-Ethylhexanol has a vapor pressure of 0.136 mm Hg at 25 deg C(3) and therefore will exist primarily as the vapor in the atmosphere(2,SRC). Vapor-phase 2-ethylhexanol reacts with photochemically-produced hydroxyl radicals with an estimated rate constant of 13.0X10-12 cu cm/molecule-sec(1,SRC). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of 2-ethylhexanol in the atmosphere would be 1.2 days(SRC). 2-Ethylhexanol is resistant to hydrolysis because of the lack of hydrolyzable functional groups(4,SRC). [R50] BIOC: *An estimated BCF value of 13 was calculated for 2-ethylhexanol(SRC), using its water solubility, 880 mg/L(1), and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this low BCF value suggests that bioconcentration in aquatic organisms will not be an important fate process(SRC). [R51] KOC: *The Koc for 2-ethylhexanol is estimated to be 105(SRC), using its water solubility, 880 mg/L(1), and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that 2-ethylhexanol will have high mobility in soil(SRC). [R52] VWS: *The Henry's Law constant for 2-ethylhexanol calculated from its vapor pressure, 0.136 mm Hg(1), and water solubility, 880 mg/L (2), is 2.65X10-5 atm-cu m/mole(SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated to be 1.7 days(3,SRC). Similarly, its volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated to be 16 days(3,SRC). 2-Ethylhexanol's vapor pressure(1) and Henry's Law constant(1,2,SRC) suggest that some volatilization may occur from both dry and moist soil(SRC). [R53] WATC: *DRINKING WATER: 2-Ethylhexanol was identified in drinking water in the following cities: Poplarville, MS; Cincinnati, OH; Philadelphia, PA; Ottuma, IA; and Seattle, WA(4). 2-Ethylhexanol was identified in raw water treated with either liquid or gaseous chlorine dioxide, chlorine, FeCl2 followed by dual media filtration, but not in raw water or raw water treated with liquid or gaseous chlorine dioxide alone(1). Therefore, 2-ethylhexanol may be formed in some drinking water during chlorination(SRC). 2-Ethylhexanol in bottled water in glass and PET containers from lots showing similar and unpleasant organoleptic characteristics (12 samples of each): 2.1-10.9 ug/l, 5.5 ug/l mean (glass containers) and not detected (DL 0.5 ug/l) (PET containers)(2). The gaskets of the caps of all 24 containers contained 2-diethylhexyl phthalate from the same lot. The authors suggest that the 2-ethylhexanol was a contaminant in the gasket material and that during the 35-45 day period between bottling and analysis, the 2-ethylhexanol may have biodegraded in the PET containers, that favor biodegradation, but not in the glass containers(2). 2-Ethylhexanol was found in drinking water in a pilot study of personal exposure in New Jersey(3). [R54] *SURFACE WATER: 2-Ethylhexanol was detected in 2 of 5 samples taken from the Delaware River, near Philadelphia, PA at 3 and 5 ppb(6). A 1989 monitoring study of five sites in the Rhine delta in The Netherlands found 2-ethylhexanol at Lobith (0.025 ug/L) and Maassluis (0.026 and 0.011 ug/L) on the main stream of the Rhine and at Haringvliet, a semi-stagnant lake (0.023 ug/L)(1). It was also found in the Caroni River (Trinidad)(4), the Hayashida River (Tatsuma City, Japan the site of the leather industry) at 111 ppb(3), the Kanawaha River at Nitro, WV(2), and the Jinsha River in China(5). [R55] EFFL: *2-Ethylhexanol was detected in emissions from a medium-sized incinerator burning polyvinyl chloride (PVC)(1). The concentrations of 2-ethylhexanol in the exhaust gas was 11 and 43 ug/cu m when the combustion chamber was controlled at about 630 and 800 deg C, respectively. Gas emanating from a municipal landfill site contained 6200 ppb of 2-ethylhexanol(2). 2-Ethylhexanol was also detected in air above the sedimentation tank of a water treatment plant(9). 2-Ethylhexanol is one of the 99 most frequently identified compounds at Superfund sites with 131 occurrences in EPA's Contract Laboratory Program's (CLP) Analytical Results Database(5). It was found in leachate from a waste disposal site in The Netherlands; the landfill was in the acidification (anaerobic fermentation stage) of degradation(4). It was found in leachate from simulated waste disposal sites during the acid to methane stage of decomposition(6). 2-Ethylhexanol was present, but not quantified, in effluent from advanced wastewater treatment plants in the following cities: Lake Tahoe, CA; Pomona, CA; Orange County, CA; and Washington, DC (Blue Plains)(3). It was found in effluent from a polyester fiber finishing plant(7) and rug and carpet plants(9). [R56] *In a comprehensive survey of wastewater from 4000 industrial and publicly owned treatment works (POTWs) sponsored by the Effluent Guidelines Division of the U.S. EPA, 2-ethylhexanol was identified in discharges of the following industrial category (positive occurrences, median concn in ppb): timber products (4; 451.1), leather tanning (1; 156.8), iron and steel mfg (2; 53.5), petroleum refining (6; 40.4), nonferrous metals (7; 88.7), paint and ink (31; 189.3), printing and publishing (5; 211.2), ore mining (4; 210.3), coal mining (2; 17.7), organics and plastics (11; 546.7), inorganic chemicals (4; 2.4), textile mills (4; 91.5), plastics and synthetics (5; 57.0), pulp and paper (4; 25.9), rubber processing (2; 3208.0), auto and other laundries (5; 145.3), pesticides manufacture (2; 1089.5), pharmaceuticals (3; 31.3), explosives (11; 72.8), foundries (4; 19.8), aluminum (1; 65.1), electronics (13; 95.7), oil and gas extraction (1; 51.8), organic chemicals (34; 52.5), mechanical products (8; 226.0), transportation equipment (3; 346.4), amusements and athletic goods (1; 1145.6), synfuels (1; 12.6), publicly owned treatment works (59; 50.4), rum industry (1; 84.3)(1). Industries with highest effluent concns above 1 ppm were: mechanical products, 56.9 ppm; organics and plastics, 11.1 ppm; rubber processing, 6.1 ppm; paint and ink, 4.4 ppm; pharmaceuticals, 3.5 ppm; pesticides manufacture 2.1 ppm; ore mining 1.8 ppm; nonferrous metals, 1.7 ppm; publicly owned treatment works 1.6 ppm; plastics and synthetics, 1.2 ppm; explosives, 1.1 ppm; amusements and athletic goods, 1.1 ppm; auto and other laundries, 1.0 ppm(1). [R57] SEDS: *2-Ethylhexanol was detected, but not quantified in mid-channel sediment in the Saskatchewan River, 8 and 20 km downstream from Nipawin, Saskatchewan, Canada(1). [R58] ATMC: *INDOOR AIR: In a study of 230 West German homes between 1985-1986, 2-ethylhexanol was found at concns ranging from < 1.0-10 ug/cu m with a mean of 2 ug/cu m(1). The number of positive samples and the detection limit were not reported. 2-Ethylhexanol was not detected in eight personal air samples from subjects in Bayonne, NJ(2). [R59] FOOD: *2-Ethylhexanol is a volatile found in fruits, such as cassava(1), apricots(2), plums(2), apples(3), and nectarines(4). It is also a meat flavor volatile and has been identified in raw beef(5), duck meat(6) and fried bacon(7). [R60] PFAC: PLANT CONCENTRATIONS: *2-Ethylhexanol is a plant volatile which has been identified in cassava(1), apricots(2), plums(2), apples(3), and nectarines(4). The amount of 2-ethylhexanol emitted from immature apples is not substantially different from that emitted from apples at different post-harvest periods(3). [R43] FISH/SEAFOOD CONCENTRATIONS: *2-Ethylhexanol was identified in mussels, mytilus edulis, in Denmark(1). It constituted 0.3% of the volatile components in the extracts. Since 2-ethylhexyl phthalate has a half-life of approximately 3.5 days in M. edulis(1), the 2-ethylhexanol may be a metabolite of 2-ethylhexyl phthalate which is extensively used as a plasticizer, rather than being ingested directly from the water(SRC). [R61] MILK: *Of the 8 samples of mother's milk analyzed from US cites, 2-ethylhexanol was found in 1 (Pittsburgh, PA)(1). [R62] OEVC: *Used machine cutting-fluid emulsion contained 0.057 ppm of 2-ethylhexanol(1). The chemical was not detected in fresh cutting fluid. [R63] RTEX: *The general population may be exposed to 2-ethylhexanol by ingesting some fruits, in which it occurs naturally, and drinking water and also from indoor air. Exposure may be related to leaching of 2-ethylhexanol from plastics(1,4) or emissions from carpeting(2,3,5). Occupational exposure may occur via inhalation and dermal contact(SRC). [R64] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 33,621 workers are exposed to 2-ethylhexanol in the USA(1). [R65] BODY: *2-Ethylhexanol was detected in 17.6% of 387 samples of expired air from 54 study subjects selected from urban areas who were normal, healthy and nonsmoking; the geometric mean concn was 4 ng/L of expired air at 25 deg C(1). It was not detected in twelve breath samples from subjects in Bayonne, NJ(3). 2-Ethylhexanol was found in 1 of 8 samples (Pittsburgh, Pa) of mother's milk collected from various US cities(2). In a national study in FY 82, 2-ethylhexanol was found in 7 of 46 composite samples of adipose tissue(4). The age distribution of positive composites was (age, fraction positive samples): 0-14, 1/12; 15-44, 4/17; 45+, 2/17. [R66] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of 2-ethyl-1-hexanol (not more than 2.5% of pesticide formulation) are exempted from the requirement of a tolerance when used as a solvent or adjuvant of surfactants in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R67] *2-Ethylhexanol is exempted from the requirement of a tolerance when used as a cosolvent, defoamer, or solvent for all pesticides used before crop emerges from soil and in herbicides before or after crop emerges in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R68] *2-Ethyl-1-hexanol (not more than 2.5% of pesticide formulation) is exempted from the requirement of a tolerance when used as a solvent, adjuvant, or surfactant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R69] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2-ethyl-1-hexanol is included on this list. [R70] *Manufacturers and processors of 2-ethylhexanol are required to conduct specific chemical tests as required under TSCA section 4. [R71] FIFR: *Residues of 2-ethyl-1-hexanol (not more than 2.5% of pesticide formulation) are exempted from the requirement of a tolerance when used as a solvent or adjuvant of surfactants in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R67] *2-Ethylhexanol is exempted from the requirement of a tolerance when used as a cosolvent, defoamer, or solvent for all pesticides used before crop emerges from soil and in herbicides before or after crop emerges in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R68] *2-Ethyl-1-hexanol (not more than 2.5% of pesticide formulation) is exempted from the requirement of a tolerance when used as a solvent, adjuvant, or surfactant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R69] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION OF PHTHALATE CONTAMINANTS IN IV SOLUTIONS STORED IN PVC BAGS BY GC-SINGLE-ION MONITORING MASS SPECTROMETRY. [R72] *Capillary column GC with FID detection. Linear response over 0-50 ug/ml, the range of concentrations considered. Limit of determination 0.5 ug/l. [R12] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Food Additives and Contaminants. (1993) SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA10 137 R4: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1995.,p. 211-2 R5: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 602 R6: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-118 R7: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 174 R8: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 600 R9: Kavaler AR; Chemical Marketing Reporter 232 (18): 54 (1987) R10: Kavaler AR; Chemical Marketing Reporter. NY,NY: Schnell Pub Co., Inc., November 22, 1993 p 41 (1993) R11: Kavaler AR; Chemical Marketing Reporter. NY,NY: Schnell Pub Co, Inc, November 22, 1993 p 41 (1993) R12: Vitali M et al; J AOAC Internat 76: 1133-7 (1993) R13: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. R14: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 363 R15: Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) R16: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 5 R17: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 720 R18: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-52 R19: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R20: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R21: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 451 R22: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1356 R23: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 74 R24: WHO; Environ Health Criteria Number 32: Toxicological Evaluation of Certain Food Additives and Contaminants. R25: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1035 R26: Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987) R27: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of 2 Ethylhexanol (CAS NO. 104-76-7) in CD-1 Swiss Mice, NTP Study No. TER90029 (May 15, 1991) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R28: Litton Bionetics, Inc.; Mutagenicity evaluation of 2-ethyl hexanol (2-EH) in the Mouse Micronucleus Test, final report. (1982), EPA Document No. 40-8226118, Fiche No. OTS0508477 R29: Litton Bionetics, Inc.; Evaluation of 2-ethyl hexanol (2-EH) in the In Vitro Transformation of Balb/3T3 Cells Assay, Final report. (1982), EPA Document No. 40-8226118, Fiche No. OTS0508477 R30: Litton Bionetics, Inc.; Mutagenicity evaluation of 2-ethyl hexanol (2-EH) in the Ames Salmonella/Microsome Plate Test, final report. (1982), EPA Document No. 40- 8226118, Fiche No. OTS0508477 (Correction of solvent control volumes and means, standard deviations found in: Litton Bionetics, Inc.; Mutagenicity evaluation of 2-ethyl hexanol (2-EH) in the Ames Salmonella/Microsome Plate Test, addendum to the final report. (1983), EPA Document No. 40-8326129, Fiche No. OTS0508481) R31: Litton Bionetics Inc.; Evaluation of 2-ethylhexanol (2-EH) in the CHO/HGPRT forward mutation assay, final report. (1985), EPA Document No. 40-8526196, Fiche No. OTS0508501 R32: Litton Bionetics, Inc.; Evaluation of 2-Ethylhexanol (2-EH) in the CHO/HGPRT Forward Mutation Assay, Final Report. (1985), EPA Document No. 40-8526196, Fiche No. OTS0508501 R33: Litton Bionetics, Inc.; Evaluation of 2-Ethylhexanol in the In Vitro Transformation of Balb/3T3 Cells with Metabolic Activation by Primary Rat Hepatocytes. (1983), EPA Document No. 40-8426085, Fiche No. OTS0508486 R34: Litton Bionetics, Inc.; Mutagenicity Evaluation of 2-Ethyl Hexanol in the Ames Salmonella/Microsome Plate Test, Final Report (1982), EPA Document No. 40-8226118, Fiche No. OTS0508477 R35: Eastman Kodak Co.; Bacterial Mutagenicity Testing of Urine from Rats Dosed with 2-Ethylhexanol Derived Plasticizers (1984), EPA Document No. 878213941, Fiche No. OTS0206391 R36: Eastman Kodak Company; Bacterial Mutagenicity Testing of Urine from Rats Dosed with 2-Ethylhexanol Derived Plasticizers, (1984), EPA Document No. 878213941, Fiche No. OTS0206391 R37: Litton Bionetics, Inc.; Evaluation of 2-Ethylhexanol (2-EH) in the CHO/HGPRT Forward Mutation Assay, Final Report (1985), EPA Document No. 40-8426139, Fiche No. OTS0508498 R38: Litton Bionetics, Inc.; Evaluation of 2-ethylhexanol in the In Vitro Transformation of Balb/3T3 Cells with Metabolic Activation by Primary Rat Hepatocytes, addendum to the final report of July 1983. (1983), EPA Document No. 40-8426085, Fiche No. OTS0508486 R39: SRI International; Dominant Lethal Study of Three Compounds, Final Report, (1981), EPA Document No. 878210249, Fiche No. OTS0206260 R40: CHEM MFGS ASSN; The Oncogenic Potential of 2-Ethylhexanol in Mice After Administration by Gavage (Aqueous Emulsion) for 18 Months With Cover Letter Dated 01/16/92 AND Attachment; 12/20/92; EPA Doc. No. 40-9211171; Fiche No. OTS0540337 R41: CHEM MFGS ASSN; The Oncogenic Potential of 2-Ethylhexanol in Rats After Administration by Gavage (Aqueous Emulsion) for 24 Months With Cover Letter Dated 02/11/92 With Attachment; 01/24/92; EPA Doc. No. 40-9211172; Fiche No. OTS0540339 R42: ALBRO PW; XENOBIOTICA 5 (10): 625-36 (1975) R43: (1) Dougan J et al; J Sci Food Agric 34: 874-84 (1983) (2) Gomez E et al; J Agric Food Chem 41: 1669-76 (1993) (3) Mattheis JP et al; J Agric Food Chem 39: 1902-6 (1991) (4) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) R44: (1) Richardson SD et al; Environ Sci Technol 28: 592-9 (1994) (2) Kavaler AR; Chemical Marketing Reporter; NY,NY: Schnell Pub Co., Inc., November 22, 1993 p 41 (1993) (3) Nishikawa H et al; Chemosphere 25: 1953-60 (1992) (4) Wolkoff P; Indoor Air 3: 291-7 (1993) (5) Hodgson AT et al J Air Waste Manage Assooc 43: 316-24 (1993) (6) Anselme C et al; Sci Tot Environ 47: 371-84 (1985) (7) Pleil JD, Whiton RS; Appl Occup Environ Hyg 5: 693-9 (1990) (8) Gould JP et al; pp. 525-39 in Water Chlorination: Environ Impact Health Eff Vol 4 (1983) R45: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (5) Price KS et al; J Water Pollut Contr Fed 46: 63-77 (1974) (6) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (7) Vaishnav DD et al; Chemosphere 16: 695-703 (1987) (8) Francis AJ; pp. 415-29 in IAEA-SM-257/72 Vienna, Austria: Inter Atomic Energy Agency (1982) R46: (1) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (2) Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc Chapt 4, 5, 15 (1990) (4) Price KS et al; J Water Pollut Contr Fed 46: 63-77 (1974) (5) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (6) Vaishnav DD et al; Chemosphere 16: 695-703 (1987) (7) Hammerton C; J Appl Chem 5: 517-24 (1955) R47: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Bidleman TF Environ Sci Technol 22: 361-7 (1988) (3) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (4) Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) R48: (1) Gaffney PE; J Water Pollut Control Fed 48: 2731-7 (1976) (2) Price KS et al; J Water Pollut Contr Fed 46: 63-77 (1974) (3) Francis AJ; pp. 415-29 in IAEA-SM-257/72 Vienna, Austria: Inter Atomic Energy Agency (1982) (4) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (5) Vaishnav DD et al; Chemosphere 16: 695-703 (1987) R49: (1) Hammerton C; J Appl Chem 5: 517-24 (1955) R50: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Bidleman TF Environ Sci Technol 22: 361-7 (1988) (3) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 7 (1982) R51: (1) Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R52: (1) Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R53: (1) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (2) Amidon GL et al; J Pharm Sci 63: 1858-66 (1974) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R54: (1) Richardson SD et al; Environ Sci Technol 28: 592-9 (1994) (2) Vitali M et al; J AOAC Internat 76: 1133-7 (1993) (3) Wallace LA et al; Environ Res 35: 293-319 (1984) (4) Lucas SV et al; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol 1 USEPA-600/1-84-020A (1984) R55: (1) Hendriks AJ et al; Water Res 28: 581-98 (1994) (2) Rosen AA et al; J Water Pollut Control Fed 35: 777-82 (1963) (3) Yasuhara A et al; Environ Sci Technol 15: 570-3 (1981) (4) Moore RA, Karasek FW; Int J Environ Anal Chem 17: 203-21 (1984) (5) He Z et al; Fenzi Huaxue 14: 93-7 (1986) (6) Sheldon LS, Hites RA; Environ Sci Technol 12: 1188-94 (1978) R56: (1) Nishikawa H et al; Chemosphere 25: 1953-60 (1992) (2) Brosseau J, Heitz M; Atmos Environ 28: 285-93 (1994) (3) Lucas SV et al; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol 1 (1984) EPA-600/1-84-020A (4) Harmsen J; Water Res 17: 699-705 (1983) (5) Eckel WP; In: Amer Chem Soc, Div Environ Chem, Preprint Ext Abract, 208th ACS Natl Mtg, vol 34, pp. 67-9 (1994) (6) Fresenius W et al; In: Amer Chem Soc, Div Environ Chem, Preprint Ext Abract, 208th ACS Natl Mtg, vol 34, pp. 596-9 (1994) (7) Gordon AW, Gordon M; Trans Ky Acad Sci 42: 149-57 (1981) (8) Hangartner M; Intern J Environ Anal Chem 6: 161-9 (1979) (9) Gaffney PE; J Water Pollut Control Fed 48: 2731-7 (1976) R57: (1) Shackelford WM et al; Analyt Chim Acta 146: 15-27 (supplemental data) (1983) R58: (1) Samoiloff MR et al; Environ Sci Technol 17: 329-34 (1983) R59: (1) Otson R, Fellin P; Gaseous Pollutants: Characterization and Cycling, JO Nriagu, ed. pp. 335-421 John Wiley and Sons (1992) (2) Wallace LA et al; Environ Res 35: 293-319 (1984) R60: (1) Dougan J et al; J Sci Food Agric 34: 874-84 (1983) (2) Gomez E et al; J Agric Food Chem 41: 1669-76 (1993) (3) Mattheis JP et al; J Agric Food Chem 39: 1902-6 (1991) (4) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) (5) King MF et al; J Agric Food Chem 41: 1974-81 (1993) (6) Wu CM, Liou SE; J Agric Food Chem 40: 838-41 (1992) (7) Ho CT et al; J Agric Food Chem 31: 336-42 (1983) R61: (1) Rasmussen T et al; Chemosphere 27: 2123-5 (1993) R62: (1) Erickson MD et al; Aquisition and Chemical Analysis of Mother's Milk for Selected Chemical Substances USEPA 560/13-80-029 (1980) R63: (1) Yashuhara A, Morita M; Chemosphere 16: 2559-65 (1987) R64: (1) Vitali M et al; J AOAC Internat 76: 1133-7 (1993) (2) Wolkoff P; Indoor Air 3: 291-7 (1993) (3) Hodgson AT et al J Air Waste Manage Assooc 43: 316-24 (1993) (4) Anselme C et al; Sci Tot Environ 47: 371-84 (1985) (5) Pleil JD, Whiton RS; Appl Occup Environ Hyg 5: 693-9 (1990) R65: (1) NIOSH; National Occupational Exposure Survey (1989) R66: (1) Krotoszynski BK et al; J Anal Toxicol 3: 225-34 (1979) (2) Erickson MD et al; Aquisition and Chemical Analysis of Mother's Milk for Selected Chemical Substances USEPA 560/13-80-029 (1980) (3) Wallace LA et al; Environ Res 35: 293-319 (1984) (4) Onstot JD et al; Characterization of HRGC/MS Unidentified Peaks from the Broad Scan Analysis of the FY82 NHATS Composites Vol I (1987) EPA 68-02-4252 R67: 40 CFR 180.1001(c) (7/1/94) R68: 40 CFR 180.1001(d) (7/1/94) R69: 40 CFR 180.1001(e) (7/1/94) R70: 40 CFR 716.120 (7/1/94) R71: 40 CFR 799.1645 (7/1/94) R72: ULSAKER GA, HOEM RM; ANALYST (LONDON) 103 (1231): 1080-3 (1978) RS: 99 Record 113 of 1119 in HSDB (through 2003/06) AN: 1139 UD: 200302 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,4-DICHLOROPHENOL- SY: *A13-00078-; *DCP-; *2,4-DCP-; *4,6-DICHLOROPHENOL-; *NCI-C55345-; *PHENOL,-2,4-DICHLORO- RN: 120-83-2 RELT: 4240 [2,6-DICHLOROPHENOL] (Contaminant) MF: *C6-H4-Cl2-O SHPN: UN 2020; Chlorophenols, solid IMO 6.1; Chlorophenol, liquid or solid HAZN: U081; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Synthesis of 2,4-dichlorophenol ... through the chlorination of the monochlorophenols. [R1] *Preparation by chlorination of phenol; by chlorination of o-chlorophenol or p-chlorophenol; from 2,4-dinitrophenol. [R2] *Industrially it is obtained by chlorinating phenol, p-chlorophenol, o-chlorophenol, or a mixture of these compounds in cast-iron reactors. The chlorinating agent may be chlorine or sulfuryl chloride in combination with a Lewis acid. [R3] IMP: *Technical grade contains 2,6-dichlorophenol (8.0%) [R4, 493] *... Chlorinated 2-phenoxyphenols, chlorinated diphenyl ethers, and chlorinated dibenzofurans occur as impurities in technical grade of chlorophenols. /Chlorophenols/ [R5] MFS: *Dow Chemical U.S.A., Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1150; Production site: Main Street, Midland, MI 48667. [R6] OMIN: *Among all the dichlorophenols, 2,4-dichlorophenol is produced in the greatest quantity. [R3] USE: *IN SYNTHESIS OF ANTIHELMINTHIC BITHIONOL SULFOXIDE [R7] *... 2,4-DCP is used as a feedstock for the manufacture of ... certain methyl cmpd used in mothproofing, antiseptics and seed disinfectants. 2,4-DCP is also reacted with benzene sulfonyl chloride to produce miticide or further chlorinated to pentachlorophenol, a wood preservative. [R8] *Key intermediate in the synthesis of the herbicide 2,4-D. [R2] *Organic synthesis. [R9] *Dyestuffs intermediate. [R10] *Used in manufacturing 2,4-D and 2,4-DP. [R3] PRIE: U.S. PRODUCTION: *(1977) 4.04X10+9 G (SALES ONLY) [R11] *(1982) PROBABLY GREATER THAN 4.54X10+6 G [R11] *1,991,000 kg (1976) [R12] U.S. IMPORTS: *(1977) 5.00X10+5 G (PRINCPL CUSTMS DISTS) [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS CRYSTALS OR NEEDLES [R13]; *HEXAGONAL NEEDLES FROM BENZENE [R14, p. C-410]; *WHITE SOLID [R9]; *Pale yellow solid [R10] ODOR: *Strong medicinal [R15] BP: *210 DEG C [R9] MP: *45 DEG C [R9] MW: *163.00 [R16] DEN: *1.383 AT 60 DEG C/25 DEG C [R13] DSC: *pKa = 7.89 [R17] HTV: *13,230.4 gcal/gmole [R14, p. C-672] OWPC: *log Kow= 3.06 [R18] SOL: *SOL IN CARBON TETRACHLORIDE [R9]; *In water, 4.50X10+3 mg/l at 20 deg C. [R19]; *Soluble in ethanol, benzene, and ethyl ether. [R16]; *Soluble in aqueous alkali, oxygenated and chlorinated solvents. [R10] SPEC: *MAX ABSORPTION (0.1 N NaOH): 304 NM (LOG E= 3.50); SADTLER REFERENCE NUMBER: 1315 (IR, PRISM) [R20]; *IR: 1320 (Coblentz Society Spectral Collection) [R21]; *UV: 9786 (Sadtler Research Laboratories Spectral Collection) [R21]; *MASS: 1027 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R21] VAPD: *5.62 [R13] VAP: *0.12 mm Hg at 25 deg C [R22] OCPP: *Heat of fusion: 29.46 cal/g= 123.26 J/g= 20,091 J/mol [R14, p. C-667] *2,4-DCP can produce objectionable odors when present in water at extremely low levels. [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Chlorophenols, liquid or solid/ [R23] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Chlorophenols, liquid or solid/ [R23] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Chlorophenols, liquid or solid/ [R23] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Chlorophenols, liquid or solid/ [R23] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chlorophenols, liquid or solid/ [R23] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Chlorophenols, liquid or solid/ [R23] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Chlorophenols, liquid or solid/ [R23] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chlorophenols, liquid or solid/ [R23] FPOT: *COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME. [R13] *Behavior in fire: Solid melts and burns. [R15] NFPA: +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R24] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R24] FLPT: *200 deg F (open cup); 237 deg F (closed cup) [R15] +237 deg F (114 deg C) (open cup) [R24] FIRP: *ALCOHOL FOAM, FOAM, CARBON DIOXIDE, DRY CHEMICAL. [R13] *Cool exposed containers with water. [R15] *Wear goggles, self-contained breathing apparatus, and rubber overclothing (including gown); /when fighting a fire involving 2,4-Dichlorophenol/ [R15] TOXC: *WHEN HEATED TO DECOMPOSITION, OR ON CONTACT WITH ACID OR ACID FUMES, IT EMITS HIGHLY TOXIC FUMES OF CHLORIDES. [R13] OFHZ: *Fire extinguishing agents: water or foam may be used even though frothing occurs. [R15] EXPL: *During vacuum fractionation of the mixed dichlorophenols produced by partial hydrolysis of trichlorobenzene, rapid admission of air to the receiver caused the column contents to be forced down into the boiler at 210 deg C, and a violent explosion ensued. /Dichlorophenol mixed isomers/ [R25] REAC: *... CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R13] *... ON CONTACT WITH ACID OR ACID FUMES, IT EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. [R13] DCMP: *WHEN HEATED TO DECOMPOSITION ... IT EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. ... [R13] ODRT: *Odor detection in water: 2.10X10-1 ppm (chemically pure) [R26] *In air: 0.21 ppm /Purity not specified/ [R4, 493] *Detection in water: 0.04 mg/l; 0.002 mg/l; 0.0003 mg/l /Purity not specified/ [R4, 493] *In air: low 1.4007 mg/cu m; high 1.4007 mg/cu m /Purity not specified/ [R27] EQUP: *BUREAU OF MINES APPROVED RESPIRATOR, RUBBER GLOVES, AND CHEMICAL GOGGLES. [R15] *Wear ... protective clothing ... and safety shoes. [R28] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. /Chlorobenzene/ [R29] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R30] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R31] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R32] STRG: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. CLUP: *Phenolic cmpd in waste water are oxidized with hydrogen peroxide catalyzed by Fe(+3)-Fe(+2). When the wt ratio of phenol: hydrogen peroxide is 1:3 and iron 5-100 ppm, more than 95% of the phenols are removed in 30 min from a 500 ppm phenol soln at pH 5-6 and 25-50 deg C. /Phenolic cmpd/ [R33] *ACTIVATED CARBON IS A GOOD METHOD FOR REMOVING CHLOROPHENOLS FROM WATER. COMPETITIVE ADSORPTION OCCURS BETWEEN CHLOROPHENOLS AND HUMIC SUBSTANCES PRESENT IN NEARLY ALL MUNICIPAL WATER SUPPLIES. THIS COMPETITION DECR THE CAPACITY OF CARBON FOR CHLOROPHENOLS. /CHLOROPHENOLS/ [R34] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U081, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R35] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. [R36] *The following wastewater treatment technologies have been investigated for 2,4-dichlorophenol: biological treatment, solvent extraction, and resin adsorption. [R37] *Dissolve in a combustible solvent and incinerate in a furnace equipped with afterburner and scrubber. Recommendable method: Incineration. Not recommendable method: Discharge to sewer. Peer-review: Incinerate at high temp. PCDDs may be formed. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R38] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is limited evidence in humans for the carcinogenicity of combined exposures to polychlorophenols or to their sodium salts. There is evidence suggesting lack of carcinogenicity of 2,4-dichlorophenol in experimental animals. ... Overall evaluation: Combined exposures to polychlorophenols or to their sodium salts are possibly carcinogenic to humans (Group 2B). /Polychlorophenols and their sodium salts/ [R39] ANTR: *For advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: To keep open, "minimal flow rate"/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Treat seizures with diazepam (Valium). ... Use proparacaine hydrochloride to assist eye irrigation ... . /Phenols and related compounds/ [R40] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Administer activated charcoal ... . Dilution may be contraindicated because it may increase absorption. Do not use emetics ... . Cover skin burns with dry, sterile dressings after decontamination ... . Maintain body temperature. /Phenols and related compounds/ [R40] MEDS: *Whole Blood: Reference Ranges: Normal - Not established; Exposed - Not established; Toxic - Not stablished. [R41] *Serum or Plasma: Reference Ranges: Normal - Not established; Exposed - Not established; Toxic - Not stablished. [R41] *Urine: Reference Ranges: Normal - None detected; Exposed - Not established; Toxic - Not established. [R41] HTOX: *SYMPTOMATOLOGY: 1. Burning pain in mouth and throat. White necrotic lesions in mouth, esophagus and stomach. Abdominal pain, vomiting ... and bloody diarrhea. 2. Pallor, sweating, weakness, headache, dizziness, tinnitus. 3. Shock: Weak irregular pulse, hypotension, shallow respirations, cyanosis, pallor, and a profound fall in body temperature. 4. Possibly fleeting excitement and confusion, followed by unconsciousness. ... 5. Stentorous breathing, mucous rales, rhonchi, frothing at nose and mouth and other signs of pulmonary edema are sometimes seen. Characteristic odor of phenol on the breath. 6. Scanty, dark-colored ... urine ... moderately severe renal insufficiency may appear. 7. Methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia have been reported. ... 8. Death from respiratory, circulatory or cardiac failure. 9. If spilled on skin, pain is followed promptly by numbness. The skin becomes blanched, and a dry opaque eschar forms over the burn. When the eschar sloughs off, a brown stain remains. /Phenol/ [R42] *STRONG IRRITANT TO TISSUE; MODERATELY TOXIC BY INGESTION. [R43] *2,4-DCP can produce objectionable odors when present in water at extremely low levels. [R8] *The toxicity of chlorophenols tends to increase as the level of chlorination is increased. /Chlorophenols/ [R44] *An occupational study of 4459 workers exposed to 2,4-dichlorophenol and 4-chloro-o-cresol based phenoxy herbicides, in addition to other pesticides and chemical intermediates was conducted. In male workers, significant increases in relative risk ratios for lung cancer, rectal cancer, and soft tissue sarcomas were reported; for females, there were increases in the relative risk of cervical cancer. /The researchers/ considered only the soft tissue sarcoma incidence to be of significance because it was also found to be elevated in several other occupational studies involving exposures to phenoxy herbicides. In addition to the problem of exposure to a mixture of chemicals, the small cohort sizes in all of these studies obscures the significance of the findings. [R45] *Solid or dust will burn the skin and eyes. [R15] NTOX: *IN RATS ORAL, SUBCUTANEOUS, AND INTRAPERITONEAL LETHAL DOSES OF THE CHLOROPHENOLS PRODUCE SIMILAR SIGNS OF POISONING. ORAL ADMINISTRATION, HOWEVER, RESULTS IN FATAL POISONING IN SMALLER DOSAGE AND IN A SHORTER PERIOD OF TIME THAN SC ADMINISTRATION. RESTLESSNESS AND AN INCREASED RATE OF RESPIRATION APPEAR A FEW MINUTES AFTER ADMIN OF O- AND M-CHLOROPHENOLS AND ARE FOLLOWED A FEW MINUTES LATER BY A RAPIDLY DEVELOPING MOTOR WEAKNESS. TREMORS, CLONIC CONVULSIONS (WHICH CAN BE INDUCED BY NOISE OR TOUCH), DYSPNEA AND COMA SET IN PROMPTLY AND CONTINUE UNTIL DEATH. SIMILAR SIGNS ARE PRODUCED BY P-CHLOROPHENOL, BUT THE CONVULSIONS ARE MORE SEVERE. 2,4- and 2,6-DICHLOROPHENOLS AND 2,4,6- and 2,4,5-TRICHLOROPHENOLS PRODUCE THESE SIGNS ALSO, BUT DECREASED ACTIVITY AND MOTOR WEAKNESS DO NOT APPEAR QUITE SO PROMPTLY. THE TREMORS ARE MUCH LESS SEVERE, BUT IN THIS CASE, ALSO, THEY CONTINUE UNTIL A FEW MINUTES BEFORE DEATH. /CHLOROPHENOLS/ [R46, p. 1613-15] *IN A 6-MO FEEDING STUDY IN WHICH MALE MICE WERE FED DIETS CONTAINING 2,4-DICHLOROPHENOL AD LIBITUM (0, 45, 100, and 230 MG/KG/DAY) /INVESTIGATORS/ ... OBSERVED NO ADVERSE CHANGES IN GROWTH RATE, HEMATOLOGY, SERUM SGOT AND SGPT, OR BEHAVIOR UP TO THE MAXIMUM DOSAGE LEVEL OF 230 MG/KG/DAY. THEY DID FIND SLIGHT ABNORMALITIES IN LIVER HISTOPATHOLOGY IN ANIMALS RECEIVING HIGHEST DOSAGE. THEY REGARDED 100 MG/KG/DAY AS THE MAXIMUM NO-EFFECT LEVEL. [R47] *... 0.2-2000 MG/L /ADMIN/ IN DRINKING WATER PRODUCED NO EFFECTS, EITHER ON CHOLINESTERASE ACTIVITY OR ON SERUM GLUTAMIC OXALOACETIC TRANSAMINASE (SGOT) IN RATS. [R48, 726] *A THERMOSTABLE SUBSTANCE WAS PRESENT IN LIVERS OF HEXACHLOROBENZENE INTOXICATED RATS WHICH WAS CAPABLE OF DECREASING HEPATIC PORPHYRINOGEN CARBOXYLYASE ACTIVITY FROM NORMAL RATS. OF THE SERIES OF CHEMICALS TESTED, 2,4-DICHLOROPHENOL WAS ONE OF THE CHEMICALS THAT EFFECTIVELY INHIBITED NORMAL HEPATIC PORPHYRINOGEN CARBOXYLYASE ACTIVITY WHEREAS HEXACHLOROBENZENE APPEARED TO HAVE NO EFFECT. [R49] *ZEBRA FISH (BRACHYDANIO RERIO) EXPOSED TO PULP BLEACHING WASTE PRODUCED EGGS WITH A HIGHER INITIAL MORTALITY THAN THAT OF CONTROL EGGS. HATCHABILITY WAS DECREASED AND THE NEXT GENERATION SHOWED A SOMEWHAT LOWERED WASTEWATER TOLERANCE. INCREASED CONCENTRATIONS OF 2,4-DICHLOROPHENOL, 2,4,6-TRICHLOROPHENOL, and 3,4,5-TRICHLOROGUAIACOL WERE FOUND IN THE EXPOSED FISH. [R50] *STUDIES OF THE ACUTE TOXICITY OF 2,4-DICHLOROPHENOL, TRICHLOROPHENOLS, TETRACHLOROPHENOLS, AND PENTACHLOROPHENOL TO GRASS SHRIMP AT KNOWN STAGES OF THE MOLT CYCLE SHOWED THAT, WITH THE EXCEPTION OF 2,4-DICHLOROPHENOL, THE VARIOUS CHLOROPHENOLS WERE MORE TOXIC TO MOLTING SHRIMP THAN TO NONMOLTING, INTERMOLT SHRIMP. IN GENERAL, THE TOXICITY OF CHLOROPHENOLS COULD NOT BE CORRELATED TO EITHER THE NUMBER OF CHLORINE ATOMS OR TO THE PKA VALUES OF THESE CHLOROPHENOLS. [R51] *EMBRYOS OF FATHEAD MINNOWS WERE MORE RESISTANT TO PHENOL, 2,4-DIMETHYLPHENOL, 2,4-DICHLOROPHENOL, AND PENTACHLOROPHENOL THAN WERE LARVAL OR JUVENILE LIFE STAGES. GROWTH OF 28 DAY OLD FISH WAS THE MOST SENSITIVE INDICATOR OF STRESS DURING EXPOSURES TO PHENOL, 2,4-DIMETHYLPHENOL, AND PENTACHLOROPHENOL, WHEREAS SURVIVAL WAS THE MOST SENSITIVE INDICATOR OF TOXIC EFFECTS FROM 2,4-DICHLOROPHENOL. BASED ON THESE EFFECTS, THE ESTIMATED MAX ACCEPTABLE TOXICANT CONCN FOR FATHEAD MINNOWS IN LAKE SUPERIOR WATER LIES BETWEEN 290 and 460 UG/L FOR 2,4-DICHLOROPHENOL. VALUES FOR OTHER COMPOUNDS ARE GIVEN. [R52] *IN A CLOSED SYSTEM, THE MOST TOXIC COMPOUNDS TO EMBRYO-LARVAL STAGES OF FISH WERE 2,4-DICHLOROPHENOL, CAPACITOR 21, CHLOROBENZENE, AND PHENOL. CHLOROPHENOL AT 90 UG/L PRODUCED COMPLETE LETHALITY OF TROUT EGGS. THE 3 OTHER COMPOUNDS GAVE LOG PROFIT LC50 (MEDIAN LETHAL CONCN) OF 2-70 UG/L WHEN TROUT STAGES WERE EXPOSED IN HARD WATER AND LETHAL CONCENTRATION (1%) WERE 0.3, 1.0 and 1.7 UG/L FOR PHENOL, CAPACITOR 21, and 2,4-DICHLOROPHENOL. WHEN BASS AND GOLDFISH AT DIFFERENT STAGES WERE EXPOSED TO CHLOROBENZENE, LETHAL CONCENTRATION (1%) WERE 8-33 UG/L. COMPARED TO OTHER SPECIES, TROUT DEVELOPMENTAL STAGES EXHIBITED THE GREATEST SENSITIVITY. [R53] *Weanling female Sprague-Dawley rats were given 3 ppm, 30 ppm, or 300 ppm of 2,4-dichlorophenol (2,4-DCP) in drinking water from 3 weeks of age through breeding and parturition. The females were bred to untreated males at 90 days of age and the offspring were studied (prenatal-exposure experiment or group 1). In another experiment, the rats were treated in the same manner as in group 1 but the exposure was continued throughout lactation and weaning until the termination of the experiment at about 24 mo (pre- and postnatal exposure experiment or group 2). Each treatment group consisted of 12-22 breeding females and 48-52 offspring of both sexes. In group 1 (prenatal exposure), litter sizes of rats treated with 300 ppm of 2,4-DCP were significantly smaller than controls. The percent of stillborn pups tended to increase at all doses of 2,4-DCP. Survival to weaning was significantly less at 30 ppm of 2,4-DCP. In group 2, antibody levels to keyhole limpet hemocyanin in the serum of rats exposed to 2,4-DCP were consistently greater than controls, and significantly different from controls at the 300 ppm dose. Delayed-type hypersensitivity responses in 2,4-DCP exposed rats were significantly suppressed when compared with controls. Liver weights were significantly increased in rats exposed to 300 ppm 2,4-DCP in comparison with controls. Spleen weights of 2,4-DCP exposed rats were greater than controls, and thymus weights were smaller than controls. In group 2, tumor incidence, latency, or type in male and female rats exposed to 2,4-DCP was not significantly different from that in controls. The number of red blood cells and the hemoglobin levels were generally increased in rats treated with 300 ppm 2,4-DCP, compared with the controls. [R54] *Effects on mitosis and meiosis in flower buds and root cells of vetch included meiotic alterations of chromosome stickiness, lagging chromosomes, and anaphase bridges when flower buds were sprayed with 0.1 M 2,4-DCP. Mitotic changes of chromosome stickiness, lagging chromosomes, disintegration, bridging, disturbed prophase and metaphase, and occasional cytomyxis (a cellular discharge) were seen in root cells exposed to 62.5 mg/l of 2,4-DCP. [R55] */In a study using fathead minnows (Pimephales promelas) the/ affected fish lost schooling behavior, were hypoactive, swam upside down, had deformities, and lost equilibrium prior to death. The dosage was between 0 mg/l for control groups and 15.0 mg/l for the highest dosed group. [R56] *A review of volatile organic contaminant data was presented. Volatile organic contaminants of water were evaluated for acute oral toxicity, 14 day repeated dosing toxicity, taste aversion, 90 day subchronic toxicity, and multigeneration effects in mice. The cmpd studied were halomethanes and chlorophenols. All cmpd caused apparent central nervous system depression and behavior changes. The liver and possibly the immune system were sensitive target organs, and male mice were more sensitive than females. /Halomethanes and chlorophenols/ [R57] *Isolated mouse ova were exposed to in vitro penetration after prior exposure to dichlorophenols. None of the agents affected sperm motility. /Dichlorophenols/ [R58] *BF-2 cells, an established cell line derived from bluegill sunfish (Lepomis macrochirus) were exposed to 18 organic toxicants /including 2,4 DCP/, with cytotoxicity being assayed by the neutral red technique. ... Published in vivo LC50 values were identified for 11 of the 18 test agents and, with the exception of 2,4-dinitrophenol, there was a good correlation between the in vitro cytotoxicity of the test agents and their in vivo waterborne acute toxicity. The potencies of the substituted phenolics and chlorinated toluenes as determined by the in vitro cytotoxocity assay correlated strongly with their log octanol/water partition coefficients (log P). ... [R59] *The acute oral LD50 of 2,4-dichlorophenol (2,4-DCP) employing corn oil as vehicle was determined to be 1352 mg/kg for female and 1276 mg/kg for male CD-1 mice. CD-1 mice of both sexes were exposed to 2,4-DCP in drinking water containing 10% emulphor for 90 days at concentrations of 0.2, 0.6 and 2.0 mg/ml providing theoretical daily doses of 50, 150, and 500 mg/kg. These concentrations resulted in mean daily doses of 50, 143 and 491 mg/kg for females and 40, 114 and 383 mg/kg for males. ... There were no biologically significant differences in body weight gain, ... terminal organ weights, or organ weight ratios in either sex. Hematological differences were observed in males only and included an increase in total number of leukocytes (high dosage) and an increase in polymorphonuclear leukocytes (low dosage). Clinical chemistry parameters were altered in females only and included a decrease in creatinine (low dosage), and increase in blood urea nitrogen /creatinine ratio (mid dosage), and an increase in ALP (high dosage). ... Administration of 2,4-DCP to CD-1 mice of both sexes for 90 days at mean doses of 40-491 mg/kg per day in drinking water did not elicit either consistent compound-related or dose-dependent significant toxicological effects. [R60] *The induction of mutation at the hypoxanthine-guanine phosphoribosyl transferase locus and cytotoxicities of 6 different chlorophenols /including 2,4-DCP/ were examined in V79 Chinese hamster cells without exogenous metabolic activation. The chlorophenols were cytotoxic to V79 cells, but failed to produce significant increases in the frequency of 6-thioguanine-resistant mutants. [R61] *The relative toxic responses to 27 selected phenols in 96 hr acute flow through Pimephales promelas (fathead minnow) and 48-60 hr chronic static Tetrahymena pyriformis (ciliate protozoan) test systems were evaluated. Log Kow-dependent linear regression analyses revealed that the data from each test system consisted of 2 linear equations. The less toxic chem form a relation which models polar /depression/; these chem are slightly more active than the baseline toxicity of nonionic /depressant/ chem. The more toxic chem form a relation which model uncoupling of oxidative phosphorylation. Regression analysis of fathead minnow toxicity (log median lethal concn (mol/l)) vs Tetrahymena pyriformis toxicity (log of the 48-60 hr 50% inhibitory concn (BR), mmol/l) showed good correlation between the 2 systems. [R62] *Tested chlorophenols for mutagenicity using the Salmonella mammalian microsome Ames assay in both activated and non-activated systems. The following dichlorophenol isomers were tested and reported as non-mutagenic in both test systems: 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dichlorophenols. [R63] *Male ICR mice maintained on a diet of 2,000 ppm 2,4-dichlorophenol for 6 mo (230 mg/kg/day) exhibited reversible hepatic changes (mild histological lesions in the liver). [R64] *... 2,4-DCP represents a potential threat to aquatic and terrestrial life, including man. [R8] *Chlorine atoms on the ortho position weakened the activity of mono- and dichlorophenols as oxidative inhibitors. /Mono and dichlorophenols/ [R65] NTXV: *Toxicity Threshold (Cell Multiplication Inhibition Test) Pseudomonas putida (bacteria) 6 mg/l; [R4, 494] *LD50 Guinea pig oral 500-1000 mg/kg; [R4, 494] *LD50 Mouse oral 1134 mg/kg; [R4, 494] *LD50 Male Rats (single oral dose) 2830 (2050-3890) mg/kg; [R66] *The acute oral LD50 of 2,4-dichlorophenol (2,4-DCP) employing corn oil as vehicle was determined to be 1276 mg/kg for male CD-1 mice; [R60] *The acute oral LD50 of 2,4-dichlorophenol (2,4-DCP) employing corn oil as vehicle was determined to be 1352 mg/kg for female; [R60] ETXV: *Toxicity Threshold (Cell Multiplication Inhibition Test) Entosiphon sulcatum (protozoa) 0.5 mg/l /Conditions of bioassay not specified/; [R4, 494] *Toxicity Threshold (Cell Multiplication Inhibition Test) Uronema parduczi Chatton-Lwoff (protozoa) 1.6 mg/l /Conditions of bioassay not specified/; [R4, 494] *Toxicity Threshold (Cell Multiplication Inhibition Test) Scenedesmus quadricauda (green algae) 3.6 mg/l /Conditions of bioassay not specified/; [R4, 494] *Toxicity Threshold (Cell Multiplication Inhibition Test) Microcystis aeruginosa (algae) 2 mg/l /Conditions of bioassay not specified/; [R4, 494] *LC50 Poecilia reticulata (guppy) 4.2 ppm/24 hr at pH 7.3 /Conditions of bioassay not specified/; [R4, 494] *LC50 Goldfish 7.8 ppm/24 hr; amt found in dead fish at 8 ppm: 268 ug/g /Conditions of bioassay not specified/; [R4, 494] *LC50 Daphnia magna (cladoceran) 2610 ug/l/48 hr /Static bioassay/; [R67] *LC50 Pimephales promelas (fathead minnow, juvenile) 8230 ug/l/96 hr /Flow-through bioassay/; [R68] *LC50 Lepomis macrochirus (bluegill) 2020 ug/l/96 hr /Static bioassay/; [R69] *LC50 Pimephales promelas (fathead minnow) 7.75 mg/l/96 hr, (30 days old), confidence limit 7.47-8.05. Test conditions: Water temp= 25.4 deg C, dissolved oxygen= 7.9 mg/l, water hardness= 45.2 mg/l calcium carbonate, alkalinity= 42.1 mg/l calcium carbonate, tank volume= 41 l, additions= 10.3 V/D, pH= 7.38 (0.08) /Conditions of bioassay not specified/; [R56] NTP: *... Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity for male F344/N rats fed diets containing 2,500 or 5,000 ppm 2,4-dichlorophenol. There was no evidence of carcinogenic activity for male and female B6C3F1 mice fed diets containing 5,000 or 10,000 ppm 2,4-dichlorophenol. [R70] ADE: *... READILY ABSORBED FROM GASTROINTESTINAL TRACT AND FROM PARENTERAL SITES OF INJECTION. /CHLOROPHENOLS/ [R46, 1615] *THE METABOLISM AND DISTRIBUTION OF 2,4-DICHLOROPHENOL (2,4-DCP) WERE STUDIED IN RAT AFTER IV ADMIN OF 10 MG/KG. HIGHEST CONCN WAS FOUND IN KIDNEY, FOLLOWED BY LIVER, FAT, AND BRAIN. 2,4-DCP IS METABOLIZED TO GLUCURONIDE AND OTHER CONJUGATES. THE PARENT CMPD AND ITS CONJUGATES WERE RAPIDLY ELIMINATED FROM BODY. HALF-LIFE OF 2,4-DCP AND ITS CONJUGATES IN PLASMA, FAT, BRAIN, LIVER, AND KIDNEY RANGED FROM 4 TO 30 MIN. VOL OF DISTRIBUTION OF 2,4-DCP IN PLASMA WAS 3.7 L/KG. TISSUE/PLASMA RATIOS INDICATED THAT 2,4-DCP HAS A GREATER AFFINITY FOR KIDNEY. [R71] *Because of their high lipid solubility and low ionization at physiological pH, dichlorophenols would be expected to be readily absorbed following ingestion. /Dichlorophenols/ [R72] *In vivo incorporated bovine urine and adipose reference meterials were prepared by oral administration of lindane, 1,2-dichlorobenzene, 2,4-dichlorophenol, 1,2,3,4-tetrachlorobenzene, and pentachlorophenol to cows. The tissues and fluids obtained were homogenized and analyzed for administered compounds and major metabolites. Virtually all of the 20 g dose of 2,4-dichlorophenol was eliminated in the urine within 24 hr following administration. ... The urine samples were found to be reasonably stable with chlorophenol concentrations remaining constant over four freeze/thaw cycles. ... [R73] *Analysis for 2,4-DCP (a metabolite of Nemacide) in laying hens fed /dietary levels of/ technical grade Nemacide O-(2,4-dichlorophenyl)-O,O-diethyl phosphorothioate at 50, 100, 200, and 800 ug/g for 55 weeks resulted in detection of 2,4-DCP residues in liver and yolk, but not in muscle or fat. In hens studied, liver 2,4-DCP concentration decreased as the dosage of Nemacide was decreased. The highest mean liver level of 2,4-DCP found in hens was 0.56 ug/g, identical to a mean level of 0.56 ug/g found in the kidneys of cattle fed 300 ug 2,4-DCP/g of feed. [R74] METB: *2,4-DICHLOROPHENOL IS EXCRETED AS A CONJUGATE OF GLUCURONIC ACID. UP TO 16% MAY BE EXCRETED AS SULFATE IN URINE OF RABBITS. [R48, 725] *Mice were given (14)C labeled gamma- or beta-benzene hexachloride by intraperitoneal injection, and the appearance of metabolites in the urine was monitored. 2,4-DCP and 2,4-DCP conjugates were found and identified primarily as glucuronides and sulfates. [R75] *The uptake and metabolism of (14)C-labeled 2,4-dichlorophenol was studied in the isolated perfused rat liver. The uptake of radioactivity in liver increased 6.6% in the presence of ATP and 14.9% in the presence of ATP and galactosamine. This increase in the uptake of radioactivity was indicative of maintaining the integrity of liver cells. The glucuronide conjugate of 2,4-DCP in bile was derivatized by permethylation and characterized by gas chromatography-mass spectrometry. Two unusual metabolites were isolated from the liver and perfusate by extraction with hexane. The gas chromatogram of these metabolites gave peaks at the retention times 12.0 and 15.5 min, and were characterized by mass spectrometry. The fragmentation pattern of these metabolites confirmed their identity as dichloromethyoxyphenols. [R76] *... Various chlorophenols /including 2,4-dichlorophenol/ are formed as intermediate metabolites during the microbiological degradation of the herbicides 2,4-D AND 2,4,5-T and pesticides Silvex, Ronnel, lindane and benzene hexachloride. /Chlorophenols/ [R77] BHL: *2,4-Dichlorophenol (2,4-DCP) /half-lives/ were studied in the rat after iv administration of 10 mg/kg. The half-lives of 2,4-DCP and its conjugates in plasma, fat, brain, liver, and kidney ranged from 4-30 min. [R78] ACTN: *2,4-DCP inhibits oxidative phosphorylation in rat liver mitochondria and rat brain homogenates. [R79] *CHLORINATED PHENOLS ... ARE VERY EFFECTIVE (... IN VITRO) AS UNCOUPLERS OF OXIDATIVE PHOSPHORYLATION. THEY THUS PREVENT INCORPORATION OF INORGANIC PHOSPHATE INTO ATP WITHOUT EFFECTING ELECTRON TRANSPORT. AS A RESULT OF THIS ACTION, WHICH IS BELIEVED TO OCCUR @ MITOCHONDRIAL /MEMBRANE/, CELLS CONTINUE TO RESPIRE BUT SOON ARE DEPLETED OF ATP NECESSARY FOR GROWTH. /CHLOROPHENOLS/ [R80] INTC: *... TOPICAL APPLICATION OF 0.3% DIMETHYLBENZANTHRACENE IN BENZENE AS AN INITIATOR AND 20% (312 MG/KG) 2,4-DICHLOROPHENOL FOR 39 WK PROMOTED PAPILLOMAS AND CARCINOMAS IN MICE. [R48, 726] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,4-Dichlorophenol's production and use in organic synthesis may result in its release to the environment through various waste streams. However, the major source of 2,4-dichlorophenol in the environment is the degradation of the phenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). If released to air, a vapor pressure of 0.12 mm Hg at 25 deg C indicates that 2,4-dichlorophenol will exist solely as a vapor in the ambient atmosphere. Vapor-phase 2,4-dichlorophenol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 15 days. 2,4-Dichlorophenol has been detected in rainwater from Portland and Beaverton, OR; therefore, physical removal from air by means of wet deposition may be an important fate process. The direct photolysis half-life of 2,4-dichlorophenol in the protonated form (pH=5) was determined to be 25 minutes and in the anion form (pH=9) was determined to be 3 minutes. If released to soil, 2,4-dichlorophenol is expected to have low to moderate mobility based upon Koc values of 263, 661, and 708. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 3.5X10-6 atm-cu m/mole. Volatilization from dry soil surfaces should not be important given the vapor pressure of this compound. Biodegradation studies have shown that 2,4-dichlorophenol is degradable under both aerobic and anaerobic conditions. 79-82% of initial 2,4-dichlorophenol was degraded in a clay loam soil during 12-14 days of aerobic incubation and 45-73% of initial 2,4-dichlorophenol was degraded in a stream sediment system during 15-30 days of aerobic incubation. Study results revealed that 2,4-dichlorophenol inhibited gas production in digested sewage sludge after an incubation period of 56 days, 0 to 30% mineralization in freshwater swamp sediment after an incubation period of 56 days, and 0 to 30% mineralization in marine sediment after an incubation period of 96 days. In addition, aerobic degradation of 2,4-dichlorophenol produced 4-chlorophenol as the major product. 2,4-Dichlorophenol, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum. If released into water, 2,4-dichlorophenol is expected to adsorb to suspended solids and sediment in water based on the Koc. Volatilization from water surfaces may be an important fate process based on its Henry's Law constant. Estimated half-lives from a model river and model lake are 70 days and 514 days, respectively. Volatilization from water and moist soil surfaces may be attenuated by adsorption to soil. The estimated volatilization half-life, excluding adsorption to sediment, from a model pond 2 m deep is estimated as approximately 94 days. The estimated volatilization half-life from a model pond 2 m deep including adsorption to sediment is estimated with a range of 166 to 306 days. 39-84% of initial 2,4-dichlorophenol was degraded in a stream water during 40 days of aerobic incubation. At a concn of 100-1000 ppb in aerated and buffered (pH 7) lake water, 97.5-100% degradation occurred within 16-30 days after incubation; in unaerated and unbuffered lake water (predominantly anaerobic conditions), 49.4-80% degradation occurred within 43 days after incubation. Using anaerobic water conditions and an unacclimated digester sludge inocula from a municipal sewage plant, 100% of initial 2,4-dichlorophenol was degraded in 28 days of inoculation. Since the pKa of 2,4-dichlorophenol is 7.89, 2,4-dichlorophenol will exist in water and sediment in a partially dissociated state which may affect its transport and reactivity in water and sediment. A BCF range of 7.1 to 69 in carp suggests bioconcentration in aquatic organisms is low to moderate. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to 2,4-dichlorophenol may occur through inhalation of this compound at workplaces where 2,4-dichlorophenol is produced or used. The general population may be exposed to 2,4-dichlorophenol via inhalation of ambient air, ingestion drinking water, ingestion of fish, and dermal contact with products containing 2,4-dichlorophenol. (SRC) ARTS: *PHENOL PRESENT IN WASTE OR SURFACE WATERS CONTAINING CHLORINE ADDED AS A DISINFECTANT IS CHLORINATED TO FORM, AMONG OTHER CHLOROPHENOLS, 2,4-DICHLOROPHENOL. [R81] *2,4-Dichlorophenol is present in 2,4-dichlorophenoxyacetic acid manufacturing wastes. [R82] *Contamination of cocoa powder by chlorophenols and chloroanisoles adsorbed from packaging materials was investigated. Aq suspensions prepared from cocoa powder were sour and had an intense moldy off odor and a strong disinfectant aftertaste. 2,6-dichlorophenol was one of the 5 chlorophenols found in contaminating sack. Concn of 2,6-dichlorophenol in cocoa powder and packaging materials of contaminating sack and normal sack were, for: contaminating sack: 7 ug/kg cocoa powder, 100 ug/kg glued seams, and 41 ug/kg paper sacking; normal sack: less than 1 ug/kg cocoa powder, 4 ug/kg glued seams, less than 1 ug/kg paper sacking /2,6-dichlorophenol/. 2,6- and 2,4-Dichlorophenol, 2,4,6-trichlorophenol, and 2,3,4,6-tetrachlorophenol were present in the tainted cocoa powder in such high concn that they would be expected to taint beverages and other food items prepared from it. The packaging material was the most likely source of the contamination. However, it is possible that the 2,6-dichlorophenols in the cocoa powder were derived from the microbial metabolism of chlorophenoxyacetic acid herbicides, which are still used in some cocoa-producing countries. [R83] *Biologically treated effluent samples from nine Canadian bleached softwood kraft mills were analyzed for chlorinated phenolic content. Chlorinated phenols, including 2,4-DCP, present in effluent discharged from bleached kraft mills are not expected to contribute an off-odor to recipient waters. the effluents from a hazardous waste inciner [R84] *Chlorination of polluted and natural water can produce chloro-compounds and chlorophenols which would be undesirable substances in drinking water. /Chlorophenols/ [R85] *2,4-Dichlorophenol's production and use in organic synthesis(1) may result in its release to the environment through various waste streams(SRC). Most of the known environmental emissions of 2,4-dichlorophenol result from water effluents generated at sites of its production and use as a chemical intermediate(2); although minor in comparison to water effluents, atmospheric emissions also occur at these production and use sites(2). Release to soil can occur through application of pesticides (such as 2,4-D, silvex, 2,4,5-T, etc) which may contain impurities of 2,4-dichlorophenol or may metabolize in the soil to produce 2,4-dichlorophenol(1). 2,4-Dichlorophenol has been detected in atmospheric emissions from the combustion of municipal solid waste, coal, wood, and peat(3-5). 2,4-Dichlorophenol has been detected in wastewaters from bleaching processes at pulp mills(3). Chlorination of water containing organic material can result in the formation of dichlorophenols, such as 2,4-dichlorophenol(6,7). [R86] FATE: *AQUATIC FATE: The consequences of contamination of the aquatic environment by chlorophenols /including ... 2,4-dichlorophenol/, have been evaluated by extensive review of the available scientific data. The chlorophenols generally exert moderate toxic effects to mammalian and aquatic life, although toxicity to fish upon long-term exposure may be considerable, as has been found for 2,4-dichlorophenol. Persistence is low when adapted microflora is present, capable of biodegrading these compounds, but may become moderate to high depending on the environmental conditions. Bioaccumulation is expected to be low. A striking feature of these chlorophenols is their strong organoleptic effect. /Chlorphenols/ [R87] *Pseudomonas strains capable of mineralizing 2,4-dichlorophenol (DCP) and p-nitrophenol in culture media were isolated from soil. One DCP-metabolizing strain mineralized 1.0 and 10 ug of DCP but not 2.0 to 300 ng/ml in culture. When added to lake water containg 10 ug of DCP per ml, the strain mineralized DCP only after 6 days. The strain did not grow or metabolize DCP when inoculated into sterile lake water, but did so when the system was amended with glucose. The bacterium grew in sterile DCP-amended sewage, although not causing appreciable mineralization of the test compound. ... A second DCP-utilizing pseudomona failed to mineralize DCP when added to the surface of sterile soil, although activity was evident if the inoculum was mixed with the soil. [R88] *Atmospheric Fate: The atmospheric half-life of 2,4-dichlorophenol for the oxidation of vapor-phase ... by photochemically generated hydroxyl radicals is approximately 7 days. This value was calculated using estimated reaction rate constants of 1.53x10-12 cu m molecule-sec for 2,4-dichlorophenol at 25 deg C and an ambient hydroxyl radical concn of 8.0x10+5 molecules/cu m. [R89] *... Moist soil incubation with 2,4-dichlorophenol showed more decomposition in clay and sandy loam, than in clay loam. Small amounts of dichloroanisole were formed. [R90] *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 263 in lake sediment, 661 in river sediment and 708 in aquifer material(2) indicate that 2,4-dichlorophenol is expected to have low to moderate mobility in soil(SRC). Volatilization of 2,4-dichlorophenol from moist soil surfaces is expected to be important(SRC) based on an estimated Henry's Law constant of 5.5X10-6 atm-cu m/mole(SRC), calculated using a vapor pressure of 0.12 mm Hg(4) and a water solubility of 4500 mg/l(5). 2,4-Dichlorophenol is not expected to volatilize from dry soil surfaces based on a vapor pressure of 0.12 mm Hg(4). Since the pKa of 2,4-dichlorophenol is 7.89(6), it will exist in water and sediment in a partially dissociated state which may effect its transport and reactivity in water and sediment(SRC). In highly alkaline soils (pH 10), it will be primarily in the ionized form and has been observed to be poorly adsorbed to soil under such conditions(7). Non-dissociated 2,4-dichlorophenol is expected to undergo more adsorption than the ionized form(7,8). At 0-4 deg C, 79-82% of initial 2,4-dichlorophenol was degraded in a clay loam soil during 12-14 days of aerobic incubation while 0-1% was degraded in sterile soil controls(9); at 0-20 deg C, 45-73% of initial 2,4-dichlorophenol was degraded in a stream sediment system during 15-30 days of aerobic incubation while 21% was degraded in sterile sediment controls over 30 days(9). Subsurface microcosm studies using soils from PA and VA determined that initial 2,4-dichlorophenol concns were biologically attenuated to non-detectable levels in less than 4 months(10). [R91] *AQUATIC FATE: Based on a classification scheme(1), Koc values of 263 in lake sediment, 661 in river sediment and 708 in aquifer material(2) indicate that 2,4-dichlorophenol is expected to adsorb to suspended solids and sediment in water(SRC). 2,4-Dichlorophenol is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 5.5X10-6 atm-cu m/mole(SRC), calculated using a vapor pressure of 0.12 mm Hg(4) and a water solubility of 4500 mg/l(5). Estimated volatilization half-lives for a model river and model lake are 9 days and 67 days, respectively(3,SRC). The volatilization half-life from an environmental pond 2 m deep is estimated to be 94 days ignoring adsorption(6); when considering maximum adsorption the volatilization half-life increases to a range of 166 days to 306 days(6). According to a classification scheme(7), a BCF range of 7.1 to 69 in carp(8), suggests the potential for bioconcentration in aquatic organisms is low to moderate(SRC). However, BCF does vary for 2,4-dichlorophenol depending upon species. The BCF of 2,4-dichlorophenol in goldfish ranged from 34 to 100 and in algae ranged from 257 to 263(2,9); the BCF in fish was 100(2) and in trout was 10(9). At 0-20 deg C, 39-84% of initial 2,4-dichlorophenol was degraded in a stream water during 40 days of aerobic incubation while 35-60% was degraded in sterile stream water controls over 40 days(10). At a concn of 100-1000 ppb in aerated and buffered (pH 7) lake water, 97.5-100% degradation occurred in 16-30 days of incubation(11); in unaerated and unbuffered lake water (predominantly anaerobic conditions), 49.4-80% degradation occurred in 43 days of incubation(11). Using anaerobic water conditions and an unacclimated digester sludge inocula from a municipal sewage plant, 100% of initial 2,4-dichlorophenol was degraded in 28 days of inoculation(12). Hydrolysis is not expected to be an important fate process due to lack of hydrolyzable functional groups(3). [R92] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,4-dichlorophenol, which has a vapor pressure of 0.12 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 2,4-dichlorophenol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 15 days(3,SRC). Direct photolysis in air may be possible, but kinetic rate data specific to air are not available to predict its relative significance. 2,4-Dichlorophenol has been detected in rainwater from Portland and Beaverton, OR(4,5); therefore, physical removal from air by means of wet deposition may have some importance(SRC). [R93] BIOD: *Biological Oxygen Demand (BOD): 100%, 5 days [R15] *... Decomp rate in soil suspensions: 9 days for complete disappearance ... [R94] *When activated sludge was exposed to 2,4-dichlorophenol at levels of 100 mg/l of sludge, 75 percent of the chemical disappeared in two days, and essentially 100 percent was gone in five days. [R95] *The rates of photolysis and microbial degradation of phenol, p-chlorophenol, 2,4-dichlorophenol, 2,4,5-trichlorophenol, and pentachlorophenol in estuarine water were determined. Photolysis was the primary transformation process for the polychlorinated phenols, with photolysis rate constants in surface estuarine water ranging from 0.3 to 1.2 per hour and half-lives ranging from 0.6 to 3 hr. Dichlorophenol photolysis rates were 20-80% higher in estuarine water than in distilled water, indicating a photosensitized reaction. There was no microbial (dark) degradation of polychlorinated phenols during short incubation periods (up to 3 days). The photoproducts of polychlorinated phenols were rapidly degraded by microbes. Microbial degradation was the primary process for transformation of phenol and p-chlorophenol. In the summer the microbial and photolysis transformation rate constants for phenol were 0.03 (half-life= 28 hr) and 0.016 per hour (half-life= 43 hr), respectively. Winter photolysis and microbial degradation rates were lower than the summer values. [R96] *The kinetics of mineralization of (14)C-labeled phenol and aniline were measured at initial concentrations ranging from 0.32 to 2,000 ng and 0.30 ng to 500 ug/g of soil, respectively. ... The ... two-compartment model provided the best fit for the mineralization of concentrations of phenol below 100 ng/g. ... It is concluded that models derived from the Monod equation, including the first-order model, do not adequately describe the kinetics of mineralization of low concentrations of chemicals added to soil. [R97] *The reductive biodegradation of a variety of haloaromatic substrates was monitored in samples from 2 sites within a shallow anoxic aquifer and was compared with freshwater sediment and sewage sludge. The metabolic capacity existing in methane-producing aquifer material was very similar to that in sediment, because 3 of 4 chlorobenzoates, 5 of 7 chlorophenols, and 1 of 2 chlorophenoxyacetate herbicides were reductively dehalogenated in both types of incubations. 2,4-D was first converted to a dichlorophenol before dehalogenation occurred. Sewage sludge microorganisms dehalogenated 4 of 7 chlorophenols tested and degraded both phenoxyacetate herbicides by first converting them to the corresponding chlorophenols, but the micoroorganisms did not transform the chlorobenzoates. In general, the same suite of initial metabolites was produced from a test substrate in all types of samples, as confirmed by cochromatograph of the intermediates with authentic material. The aquifer microbiota from a sulfate-reducing site was unable to significantly degrade any of the haloaromatics substrates tested. Biological removal of the sulfate in samples from this site permitted dehalogenation of a model substrate, whereas stimulation of methanogenesis without removal of sulfate did not. Thus, dehalogenating microorganisms were present at this site but their activity was at least partially inhibited by the high sulfate levels. [R98] *The fate and effects of ... 2,4-dichlorophenol (DCP) added to North Sea coastal plankton communities enclosed by large plastic bags were studied in three experiments of 4 to 6 weeks duration. The biodegradation of the compounds was studied in laboratory experiments using water from concentrations of 0.1-1.0 mg X liter-1, disappeared from the water in the enclosures in 5 to 23 days ... . Degradation rates were generally comparable to those found in laboratory tests with the same water. ... DCP was probably removed by a combination of biodegradation, photodegradation, and/or chemical degradation. Results indicated that biodegradation rates could be limited by lack of inorganic nutrients, leading to much lower degradation rates than would be expected from routine laboratory tests. ... Addition of 0.3 mg/l ... DCP inhibited the phtyoplankton growth rate slightly. The 1 mg/l ... or DCP inhibited the phytoplankton, changed the species composition, and also influenced the zooplankton. In two of the three experiments 1 mg/l DCP resulted in a temporary lowering of bacterial numbers following the addition. In one experiment inhibitory effects were found after ... DCP had disappeared from the water, pointing to the formation of a more toxic intermediate during the degradation of the compounds. The laboratory tests also indicated the formation of relatively stable intermediates. The concentrations causing the effects in the different bag experiments were quite similar. This indicated that, although the development of the plankton communities during the different experiments was different, the concentrations resulting in ecological effects are quite reproducible. [R99] *Using a static-culture flask-screening procedure with a settled wastewater inoculum, 2,4-dichlorophenol was found to be significantly degradable with rapid microbial adaptation as 99-100% of initial concn were degraded within 7 days(1). Using a Warburg respirometer and phenol-adapted bacteria (bacteria isolated from garden soil, river mud, compost and waste lagoon sediment), 95% of initial 2,4-dichlorophenol (200 ppm) was degraded within 7-10 days(2). Based on COD determination, 98% of initial 2,4-dichlorophenol was degraded in a BOD system with an activated sludge inoculum during a 20-day inoculation period(3). First order disapperance rate was observed in a small stream with resect to either distance or time of flow, average half-life of about 4 hrs; however the absence of seasonal variability over several ecological zones suggests that the rate controlling factor is not biological(6). Complete ring degradation of 2,4-dichlorophenol occurred within 5 days in a BOD system using an activated sludge inocula(4). Anaerobic degradation studies using two different freshwater pond sediments determined that 100% of initial 2,4-dichlorophenol was degraded within 4 weeks(5). [R100] *AEROBIC: 2,4-Dichlorophenol, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum(1). Sulfate-reducing bacteria produced 80 to 95% degradation of 2,4-dichlorophenol at concn levels of 60 mg/l or lower after 7 days(2). Under aerobic conditions, 2,4-dichlorophenol was completely degraded in the presence of sanitary landfill leachate after 25 days(3). Aerobic cultures of activated sludge, amended with a methanotrophic soil enrichment, was enriched on phenol and toluene and was able to rapidly degrade 2,4-dichlorophenol(4). [R101] *ANAEROBIC: An anaerobic gas production test of sewage sludge, a freshwater swamp sediment and a marine sediment was conducted. Results revealed 2,4-dichlorophenol inhibited gas production in digested sewage sludge after an incubation period of 56 days, 0 to 30% mineralization in freshwater swamp sediment after an incubation period of 56 days, and 0 to 30% mineralization in marine sediment after an incubation period of 96 days(1). The anaerobic degradation potential of 2,4-dichlorophenol in primary digesting sludge, expressed as net gas potential (NPG) was determined to be -90%, which corresponds to a chemical which inhibits biodegradation(2). Anaerobic degradation of 2,4-dichlorophenol between 5 and 72 deg C was investigated. Reductive 2,4-dichlorophenol dechlorination occurred only in the temperature range between 5 and 50 deg C. In freshwater sediment samples from two sites and at all tested temperatures from 5 to 50 deg C, 2,4-dichlorophenol was degraded to 4-chlorophenol(3). The rate of 2,4-dichlorophenol transformation in anaerobic estuarine sediment was determined to be 0.045/day, which corresponds to a half-life of 15.3 days(4). [R102] ABIO: *IN AQUATIC ENVIRONMENT 2,4-D (2,4-DICHLOROPHENOXYACETIC ACID) IS DECOMPOSED TO 2,4-DICHLOROPHENOL BY SUNLIGHT AND THEN TO SIMPLER CMPD. [R48, 725] *2,4-Dichlorophenol was decomposed by ultraviolet light, and the rate of photolysis in distilled water decreased as pH decreased. Degradation of 50 percent of 2,4-dichlorophenol by ultraviolet light was accomplished in two minutes at pH 9.0, in five minutes at pH 7.0, and in 34 minutes at pH 4.0. [R103] *The rate constant for the vapor-phase reaction of 2,4-dichlorophenol with photochemically-produced hydroxyl radicals has been determined to be 1.06X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 15 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 2,4-Dichlorophenol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). The direct photolysis half-life of 2,4-dichlorophenol in the protonated form (pH = 5) was determined to be 25 minutes and in the anion form (pH = 9) was determined to be 3 minutes(3). Riboflavin slightly increased the rate of 2,4-dichlorophenol photodecomposition to 7 minutes at pH 7; the rate of this photolysis increased with increasing pH(3). Brief UV (300 nm) photolysis greatly facilitated the removal of 2,4-dichlorophenol from sewage through accelerated mineralization and binding of polar products; the half-life for 2,4-dichlorophenol degradation was determined to range from 1.68 to 9.63 minutes(4). A quantum yield of approximately 0.10 was observed for the irradiation of an aqueous solution of the anionic form of 2,4-dichlorophenol while the quantum yield for the molecular form was only 0.01-0.02(5); in addition, the absorption max occurred at 304 nm for the anionic form and 282 nm for the molecular form(5). Using a quantum yield of 0.12 (a value determined via measurements of 15 different laboratories), the direct photolysis lifetime of 2,4-dichlorophenol in the top millimeters of a natural aquatic system under mid-day sunlight conditions at a latitude of 40-50 deg N has been calculated to be 0.075 hours(6). 2,4-Dichlorophenol could no longer be detected in an aqueous solution after 10 days of solar irradiation under conditions of good aeration(7). [R104] *Based on exposure to midday sunlight for 4 hr in sealed flasks, the photodegradation half-life of 2,4-dichlorophenol has been estimated to be 0.8- 3.0 hr (summer-winter) in distilled water and 0.7-2.0 hr (summer-winter) in estuarine water at pH 7.7(1). The rate constant for the reaction of 2,4- dichlorophenol with singlet oxygen in water at 19 deg C has been measured to vary from 7X10+5 (pH 5.5) to 1.2X10+8 (pH 9.0) liters/mole-sec, with the rate of reaction increasing as the degree of dichlorophenol ionization increases(2); assuming a singlet oxygen concn of 4X10-14 M in natural water(2), the half-life at pH 8 under midday sunlight is approximately 62 hr(2); singlet oxygen concns of 1X10-12 M can be formed in some natural waters(3). The rate constant for the reaction of 2,4-dichlorophenol with peroxy radicals in sunlit natural water has been estimated to be 1X10+7 liters/mole-hr(3); assuming a peroxy radical concn of 1X10-9 M in natural water(3), the half-life can be estimated to 69.3 hr(SRC). [R105] BIOC: *A BCF range of 7.1 to 69 was determined for 2,4-dichlorophenol in carp and 8 weeks exposure(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low to moderate(SRC). However, BCF does vary for 2,4-dichlorophenol depending upon species. The BCF of 2,4-dichlorophenol in goldfish ranged from 34 to 100 and in algae ranged from 257 to 263(3,4); the BCF in fish was 100(3) and in trout was 10(4). [R106] KOC: *The Koc of 2,4- dichlorophenol ranged from approximately 200 to 5000 in soil adsorption studies using five mineral soils(1,SRC); the most important factors controlling the degree of adsorption were pH and percentage of iron oxide in the soil(1). In batch soil adsorption experiments conducted at pH 10, 2,4-dichlorophenol exhibited a soil equilibrium partition coefficient (Kp) of 0.0+/-0.5 indicating that adsorption was not occurring(2); 2,4-dichlorophenol has a pKa of 7.8 at 20 deg C which indicates that it will exist predominantly in the ionized form at pH 10(2); ionized phenols will generally not sorb to neutral or negatively charged soil organic matter as well as the non-dissociated form(2); the degree of dichlorophenol adsorption in soils has a pH dependence(2). The adsorption of the dichlorophenol isomers (including 2,4-dichlorophenol) onto Wyoming bentonite clay was found to be pH dependent with maximum adsorption occurring when ionization of the isomers was less than 50% based on pKa values(3). A 2,4-dichlorophenol Koc of 126 was measured in a clay loam soil from Michigan State University(4). [R107] *The Koc of 2,4-dichlorophenol in fine and coarse sediment (from Lake Zoar, CT) was determined to range from 3130 to 3990 at pHs of 6.21-6.35 when the compound is primarily in the non-ionized state(1). The Koc of non-ionized 2,4-dichlorophenol in a lake sediment, a river sediment, and an aquifer material was found to range from 266 to 715(2). Monitoring of the Weser estuary in Germany found a ratio of 650 for the concn of 2,4-dichlorophenol (and 2,5-dichlorophenol) in the sediment to the concn in the water(3); a ratio of 117 was found for the concn in suspended matter to concn in water pH not stated(3). [R108] *The Koc of 2,4-dichlorophenol has been determined to be 263 in lake sediment, 661 in river sediment and 708 in aquifer material(1). According to a classification scheme(2), these Koc values suggest that 2,4-dichlorophenol is expected to have low to moderate mobility in soil(SRC). A study determined that 26.31% of 2,4-dichlorophenol was adsorbed on suspensions of aluminum-pillared montmorillonite; the study concluded that the adsorption of chlorophenols increases as the number of chlorines in their molecules increases(3). [R109] VWS: *Its low vapor pressure and non-volatility from alkaline solutions would cause it to be only slowly removed from surface water via volatilization. [R110] *The dissipation of 2,4-dichlorophenol from natural lake waters at a buffered pH of 7 with initial 2,4-DCP concentrations of 100, 500, and 1000 ug/l, the percentages of 2,4-DCP remaining at 9 days were 0, 0.34, and 46, respectively. By contrast, initial concentrations of 100, 500, and 1000 ug/l in unaerated and unbuffered waters resulted in percentages of 40, 51.6 and 56, respectively, remaining at 17 days. [R111] *The Henry's Law constant for 2,4-dichlorophenol is estimated as 5.5X10-6 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.12 mm Hg(1), and water solubility, 4500 mg/l(2). This Henry's Law constant indicates that 2,4-dichlorophenol is expected to volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 9 days(3,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 67 days(3,SRC). However, this model underestimates the volatilization half-life of 2,4-dichlorophenol since it does not take into account the effects of adsorption. A Koc range of 263 to 708(2) suggests that volatilization could be greatly attenuated by adsorption to suspended solids and sediments in water(SRC). This is apparent from the results of two EXAMS model runs, one in which the effect of adsorption was considered (half-life of 166 days in a model pond 2 m deep(4,SRC)) and one in which the effect of adsorption was ignored (half-life of 94 days in a model pond 2 m deep(4,SRC)). 2,4-Dichlorophenol's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces may occur(SRC). 2,4-Dichlorophenol is not expected to volatilize from dry soil surfaces(SRC) based on a vapor pressure of 0.12 mm Hg(1). [R112] WATC: *... CHLOROPHENOLS IN SEWAGE, STREAM WATER AND TAP WATER IN THE VICINITY OF SEOUL, KOREA FROM JAN TO SEPT, 1979 WAS STUDIED. CHLORINATED PHENOLS CAN BE PRODUCED BY THE CHLORINATION OF PHENOL WITH HYPERCHLORITE IN WATER. CHLOROPHENOLS IDENTIFIED FROM TAP WATER IN SEOUL DURING THE SUMMER OF 1979 WERE: O-CHLOROPHENOL 0.042 PPB; 2,6-DICHLOROPHENOL 0.033 PPB; 2,4-DICHLOROPHENOL 0.003 PPB. [R85] *GROUNDWATER: Samples collected on September 9, 1980 from an uncontaminated well bordering a US Army installation site in Bristol, RI revealed that the average concn of 2,4-dichlorophenol was 26 ug/l(1). An average 2,4-dichlorophenol concn of 248 ug/l was found in leachate samples from a hazardous waste landfill(2). 2,4-Dichlorophenol was identified in groundwater samples taken from the Ville Mercier site (12 different locations) in southern Quebec, Canada, in concns ranging from not detected to 3.3 ug/l(3). 2,4-Dichlorophenol was detected in 6 of 10 groundwater samples (concentration of 3.2-79.7 ppb) taken from two wells (between Oct 1981 and Mar 1983) in the vicinity of an abandoned creosote facility in Conroe, TX(4). 2,4-Dichlorophenol was detected in groundwater associated with an Australian quarry receiving organic waste dumping(5). [R113] *DRINKING WATER: The presence of 2,4-dichlorophenol was investigated in drinking water samples collected in the area of Zagreb, Yugoslavia in June and July 1986; concns of 2,4-dichlorophenol ranged from < 8 to 17 ng/l in the municipal water supply and < 8 to 30 ng/l in private wells(1). 2,4-Dichlorophenol has been identified, but not quantified, in a study conducted in the early 1980's as a contaminant in drinking water in 113 USA cities(2). [R114] *SURFACE WATER: An analysis of the USEPA STORET Database determined that 2,4-dichlorophenol was positively detected in 0.4% of 876 effluent reporting stations at a median level below 10 ppb(1). 2,4-Dichlorophenol (plus 2,5-dichlorophenol) levels of 1.8 ug/kg were detected in water samples taken from the Weser estuary in Germany on Aug 21, 1978(2). A 2,4-dichlorophenol level of 0.45 ppb was found in the Rhine River in 1978(3). Max levels of 0.59 and 0.35 ppb were detected in the Rhine at Lobith, Netherlands in 1976 and 1977, respectively(4). The concn of 2,4-dichlorophenol in a section of the Isipingo River and Isipingo Estuary, Natal, Republic of South Africa, sampled on April 3 and May 8, 1991, ranged from 0.1 to 10.0 ug/l(1). [R115] *SEAWATER: Seawater from the Gulf of Bothnia (Sweden) was found to contain 2,4-dichlorophenol levels of 2-400 ng/l from samples collected on Sept 13, 1982 and Nov 3, 1983(1); the presence of chlorophenols in the seawater was attributed to effluent discharges from a sulfate pulp mill(1). [R116] *RAIN/SNOW: An average 2,4-dichlorophenol concn of 1.3 ng/l (range of 0.56-2.5 ng/l) was detected in rainwater of Portland, OR during monitoring between Feb and Apr 1984(1). Levels of 0.55-20 ng/l were detected in rainwater collected in suburban Beaverton, OR in Feb and Apr 1982(2). [R117] EFFL: *2,4-DICHLOROPHENOL IS A MAJOR COMPONENT OF PULP MILL EFFLUENTS FORMED DURING THE MULTI-STEP BLEACHING OF CELLULOSE TO REMOVE COLORED LIGNIN CONSTITUENTS. [R118] *An analysis of the USEPA STORET Database determined that 2,4-dichlorophenol was positively detected in 3.0% of 1319 effluent reporting stations at a median level below 10 ppb(1). 2,4-Dichlorophenol levels of 2-11 ng/l were detected in waste liquors from Finnish pulp mills in 1983(2); levels of 234 and 570 ng/g were found in combustion ash from two municipal refuge incinerators(2). A 2,4-dichlorophenol concn of 0.1 ng/g was detected in particle effluents from coal-fired power plants(3). Combustion effluents from the combustion of municipal solid waste, wood wastes, and peat have been found to contain 2,4-dichlorophenol(4). [R119] *2,4-Dichlorophenol was detected in raw sludge and treated sludge, concns unknown, in samples taken from 37 water pollution control plants in Ontario, Canada between January and July 1986(1). The concn of 2,4-dichlorophenol, a by-product of wood pulp chlorination, in Canadian pulp mill effluents was determined to range from 95 to 99 ug/l(2). The concn of 2,4-dichlorophenol in waste liquors of pine kraft pulp bleaching stages ranged from < 2 to 52.7 ug/l(3). In a review of pulp mills, the concn of 2,4-dichlorophenol found in secondary treated mill effluents using chlorine dioxide substitution ranged from 1.0 to 5.0 ug/l(4). [R120] SEDS: *Soils (clay, clay loam, and sandy loam) were incubated with (14)C-ring-labeled 2,4-D in flasks. Breakdown was > 70% within 10 days, at 20 degree. (14)CO2 accounted for 30-42% of the applied (14)C. 2,4-Dichloroanisole and 2,4-dichlorophenol were formed, accounting for < 10% of the applied (14)C. ... [R90] *The concn of 2,4-dichlorophenol in river sediments above and below the effluent discharges of two New Zealand pulp and paper mills on the Tarawera River was determined to range from 0.4 to 1.3 ng/g(1). The concn of 2,4-dichlorophenol in soil at an abandoned sawmill in Finland was determined to be 1200 ug/kg dry soil(2). 2,4-Dichlorophenol (plus 2,5-dichlorophenol) levels of 1.17 mg/kg were detected in sediment samples taken from the Weser estuary in Germany on Aug 21, 1978(3). 2,4-Dichlorophenol conc. of 15-23 mg/kg (dry weight) were found in sediments of a Finnish lake receiving bleaching effluents from kraft pulp mills(4). Levels of 10-2580 ug/kg were detected in the soil of two Finnish sawmills which used chlorophenolic fungicides(5). Sediment samples collected from Lake Ketelmeer in the Netherlands during Mar 1979-Mar 1980 contained max and median concns of 10 and 4.4 ug/kg, respectively(6). The concn of 2,4-dichlorophenol on suspended sediment collected from the effluent of kraft pulp mills in rivers of Alberta, Canada from summer 1990 to fall 1992 ranged from 0.005 to 1 ug/g(7). Sediment samples collected 1 km from the discharge of a kraft mill south of the city of Hudiksvall, Norway from 1985 to 1989 were found to contain 0.13 ug/g of 2,4-dichlorophenol(8). [R121] ATMC: *SOURCE DOMINATED: The emission of 2,4-dichlorophenol from two municipal waste incineration facilities in Germany was detected at a concn of 2.39 ug/cu-m(1). The avg emission of 2,4-dichlorophenol from a hazardous waste incinerators across the nation as of 1992 has been determined to be 0.004 tons/yr; the 95% percentile concn levels were determined to be 0.5 ng/l(2). URBAN/SUBURBAN: An avg 2,4-dichlorophenol gas-phase concn of 1.5 ng/cu m (range of 0.60-2.3 ng/cu m) was detected in the air of Portland, OR during monitoring between Feb and Apr 1984(3). [R122] PFAC: PLANT CONCENTRATIONS: *Total DCP content in oat and soybean plants increased for approximately three weeks when the soil contained a DCP concentration of 0.07 ug/g. As these plants grew, the total tissue content of DCP remained relatively constant but decreased as the plants matured. At the time of harvest, oats contained 0.01 ug of DCP per gram of plant tissue, and soybeans contained 0.02 ug/g. [R123] *A field study of industrial organic uptake by growing crops was conducted during 1990 at the St. David Coal Refuse Pile Reclamation Site, Fulton County, IL; 2,4-dichlorophenol was detected in coal refuse and plant materials, concns unknown(1). [R124] FISH/SEAFOOD CONCENTRATIONS: *2,4-Dichlorophenol was identified, but not quantified, in various fish collected from Lake Michigan and tributary streams during 1983(1). The concn of 2,4-dichlorophenol in the bile of perch (Perca fluviatilis) collected from bleach pulp mill effluents from the Baltic Sea in 1984 and 1985 ranged from 240 to 7700 ng/g bile(2). The concn of 2,4-dichlorophenol in fish collected upstream and downstream from a bleached kraft mill in the St. Maurice River, Quebec on August 14 and 18, 1989 ranged from 7 to 20 ug/l(3). The concn of 2,4-dichlorophenol in the bile of goldfish (Crassius auratus) collected from bleached kraft mill discharge from Lake Maraetai, New Zealand ranged from not detected to 2.65 ug/g bile (dry weight)(2). 2,4-Dichlorophenol levels ranging from 0.29 to 9.0 mg/kg were detected in seven species of fish (sturgeon, tomcod, shad, flounder, smelt, spiny dogfish, sea alewife) taken from the Saint John River-Harbor area during June-Aug 1977(4). The concn of 2,4-dichlorophenol in fish collected from the effluent of bleached kraft pulp mills in rivers of Alberta, Canada from summer 1990 to fall 1992 ranged from 0.1 to 14.0 ug/g in mountain whitefish and longnose sucker(5). [R125] ANIMAL CONCENTRATIONS: *2,4-Dichlorophenol concns of 372 and 1017 ng/g were found in liver and kidney samples from white-tailed eagles collected in Finland from 1980-1982(1). [R126] OEVC: *The concn of 2,4-dichlorophenol in the urine of 197 Arkansas children ranged from 7 to 200 ppb(1). [R127] RTEX: *Absorption of 2,4-dichlorophenol (2,4-DCP) by biological tissues may occur upon exposure to 2,4-DCP either dissolved in water or associated with suspended matter or sediments in water. [R128] *Dichlorophenol isomers are absorbed through the skin and from the gut. /Dichlorophenol isomers/ [R129] *The ... group expected to be at risk for high exposure to 2,4-DCP is industrial workers involved in the manufacturing or handling of 2,4-DCP and 2,4-D pesticide. [R8] *Workers employed in wood treatment plants, tanneries, textile plants, and pulp and paper mills, as well as pesticide spray operators, are potentially at risk from exposure to chlorophenols and to impurities in chlorophenol products. /Chlorophenols/ [R130] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 63 workers (23 of these are female) are potentially exposed to 2,4-dichlorophenol in the US(1). Occupational exposure to 2,4-dichlorophenol may occur through inhalation with this compound at workplaces where 2,4-dichlorophenol is produced or used(SRC). The general population may be exposed to 2,4-dichlorophenol via inhalation of ambient air, ingestion of drinking water, ingestion of fish, and dermal contact with vapors and other products containing 2,4-dichlorophenol. [R131] BODY: *The mean value of 2,4-dichlorophenol in the urine of humans exposed to specific pesticides has been reported to be 203 ug/l(1). The urine from 5 randomly selected workers from a Finnish sawmill contained 2,4-dichlorophenol levels of 0.15-1.35 mg/l(2). [R132] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Chlorophenols are produced, as intermediates or final products, by process units covered under this subpart. /Chlorophenols/ [R133] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 20 ug/l [R134] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 21 ug/l [R134] +(FL) FLORIDA 4 ug/l [R134] +(ME) MAINE 20 ug/l [R134] +(MN) MINNESOTA 20 ug/l [R134] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Chlorinated phenols/ [R135] +The USEPA /has/ determined ambient water quality criteria of ... 0.3 ug/l for 2,4-dichlorophenol, based upon organoleptic (taste threshold) data. ... [R136] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R137] RCRA: *U081; As stipulated in 40 CFR 261.33, when 2,4-dichlorophenol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R138] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *EPA Method 604: Grab samples of water in municipal and industrial discharges must be collected in glass containers, 1 l or 1 qt amber glass, fitted with a screw cap lined with Teflon, except that the bottles must not be prerinsed with sample before collection. Fill the sample bottles, and if residual chlorine is present, add 80 mg of sodium thiosulfate per liter of sample and mix well. All samples must be iced or refrigerated from the time of collection until analysis. All samples must be extracted within 7 days of collection and completely analyzed within 40 days of extraction. Extraction is performed by adding 60 ml of methylene chloride to the sample in a separatory funnel and shaking. The combined extract is then concentrated using a Kuderna-Danish concentrator. [R139] *EPA Method 1625: Collect water samples in municipal and industrial discharges in glass containers, amber, 1.1 l minimum with threaded caps lined with Teflon. Maintain samples at 0-4 deg C from the time of collection until extraction. If residual chlorine is present, add 80 mg sodium thiosulfate per liter of water. Extraction is performed by adding methylene chloride to the samples in a continuous liquid-liquid extractor and concentrated with a Kuderna-Danish apparatus. Begin sample extraction within seven days of collection, and analyze all extracts within 40 days of extraction. [R139] *A two stage air sampling tube for use at hazardous waste sites was described. The tube was developed by the Environmental Response Team and Hazardous Materials Branch of the Environmental Protection Agency for sampling at sites where unknown and multiple contaminants may be present. The sampler consisted of a two stage glass sampling tube, 8 mm outside diameter and 6 mm inside diameter. The front section was filled with 100 mg of 20/35 mesh Tenax-GC and the back stage with 200 mg of 20/40 mesh Chromosorb-102. The tube was intended to be used with an air sampling pump capable of drawing air at flow rates of 10 to 50 ml/minute against vacuums of 0.5 to 5.0 cm of water. In practice, both sections were to be Soxhlet extracted with pentane for 6 hours, followed by 6 hours of extraction by methanol, and purging with dry nitrogen at 250 or 300 deg C at a flow rate of 30 ml/min for 12 hours. The tube was designed to be used with a thermal desorber, cryogenic trap, and capillary gas chromatography/mass spectrometry system. Experimental research used in developing the tube was described. Chemicals used in developing the sampler were ... 2,4-dichlorophenol. ... [R140] ALAB: *2,4-DICHLOROPHENOL FORMED ACETATE ESTER BY DIRECT ADDITION OF ACETIC ANHYDRIDE WHICH PROVIDED FOR IMPROVED GAS CHROMATOGRAPHIC CHARACTERISTICS AND QUANTITATIVE RECOVERY FROM AQ SOLN. STABLE ACETATE ESTER CAN BE ANALYZED USING STD GC COLUMNS SUCH AS OV-17 OR OV-101, ND. [R141] *A LIQUID CHROMATOGRAPHIC SYSTEM, CAPABLE OF SELECTIVELY DETECTING INDIVIDUAL PHENOLIC COMPOUNDS AT 1 PPB LEVELS IN WATER IS DESCRIBED. A POLYMERIC-CATION-EXCHANGE RESIN COLUMN, ACIDIC ACETONITRILE-WATER ELUENT AND AN ELECTROCHEMICAL DETECTOR CONTAINING UNIQUE C-BLACK/POLYETHYLENE TUBULAR ANODE ARE EMPLOYED. /PHENOLIC COMPOUNDS/ [R142] *Determination in water: Methylene chloride extraction followed by gas chromatography with flame ionization or electron capture detection or gas chromatography plus mass spectrometry. [R8] *EPA Method 604: A gas chromatography method for the analysis of 2,4-dichlorophenol in municipal and industrial discharges, consists of a glass column, 1.8 m x 2 mm ID, packed with Supelcoport (80/100 mesh) coated with 1% SP-1240DA, with flame ionization detection, and nitrogen as the carrier gas at a flow rate of 30 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column injection temperature is 80 deg C programmed immediately at 8 deg C/min to a final temperature of 150 deg C. This method has a detection limit of 0.39 ug/l and an overall precision of 0.18 times the average recovery + 0.62, over a working range of 12.0 to 450 ug/l. [R139] *EPA Method 625: A gas chromatographic/mass spectrometry method for the analysis of 2,4-dichlorophenol in municipal and industrial discharges, consists of a glass column, 1.8 m x 2 mm ID, packed with Supelcoport (100/120 mesh) coated with 3% SP-2250, with the detection performed by the mass spectrometer, and helium as the carrier gas at a flow rate of 30 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 50 deg C for 4 minutes and then programmed immediately at 8 deg/min to a final temperature of 270 deg C. This method has a detection limit of 2.7 ug/l and an overall precision of 0.21 times the average recovery + 1.28, over a working range of 5 to 1300 ug/l. [R139] *EPA Method 1625: An isotope dilution gas chromatography/ mass spectrometry method for the determination of semivolatile organic compounds in municipal and industrial discharges is described. This method is designed to meet the survey requirements of Effluent Guidelines Division (EGD) and the National Pollution Discharge Elimination System (NPDES). Under the prescribed conditions, unlabeled 2,4-dichlorophenol has a minimum level of 10 ug/l and a mean retention time of 947 sec. The labeled compound has a minimum level of 10 ug/l, a mean retention time of 944 sec, and a characteristic primary m/z of 162/167. This method has an initial precision of 12 ug/l and an accuracy of 85-131 ug/l for the unlabeled compound, while the labeled compound has an initial precision of 28 ug/l, an accuracy of 38-164, and a labeled compound recovery of 24-260%. [R139] *A gas-liquid chromatographic procedure is described for the identification of 32 substituted phenols. This method involves a simple and reproducible derivation step which forms stable phenol pentafluorobenzyl ethers for which the electron capture detector is highly sensitive. /Substituted phenols/ [R143] *Direct determination of trace amounts of chlorophenols in freshwater, waste water and seawater was studied. /Chlorophenols/ [R144] *Separation of free chlorophenol isomers on non-polar and polar quartz capillary columns was studied. /Chlorophenol isomers/ [R145] *EPA Method 8040: Phenols: Extracted samples are analyzed using gas chromatography with flame ionization detector. Under the prescribed conditions, 2,4-dichlorophenol has a detection limit of 0.39 ug/l, a retention time of 4.30 min, and an overall precision of 0.18 times the average recovery + 0.62 ug/l, over a working range of 12-425 ug/l. [R146] *EPA Method 8250: Gas chromatography/mass spectrometry for Semivolatile Organics: Packed Column Technique: Extracted samples are analyzed using gas chromatography coupled with mass spectrometry. Under the prescribed conditions, 2,4-dichlorophenol has a detection limit of 2.7 ug/l, a retention time of 9.8 min, and an overall precision of 0.21 times the average recovery + 1.28 ug/l, over a working range of 5-1300 ug/l. [R146] *EPA Method 8270: Gas chromatography/mass spectrometry for Semivolatile Organics: Capillary Column Technique: Extracted samples are analyzed using gas chromatography coupled with mass spectrometry. Under the prescribed conditions, 2,4-dichlorophenol has a retention time of 9.48 min and an overall precision of 0.21 times the average recovery + 1.28 ug/l, over a working range of 5-1300 ug/l. [R146] *A gas chromatographic procedure is described for the analysis of a variety of substituted phenols /including 2,4-DCP/ from water samples. ... The phenols were extracted, derivatized, and quantified by flame ionization and electron capture detection. Toluene gave a better extraction efficiency than acetone, hexane, dichloromethane, and ethylacetate, yielding essentially the same recovery from spiked well water samples as direct acetylation with acetic anhydride. Between 5 and 35 ng/ml of different phenols were detected. The heptafluorobutyryl derivatives possessed high electron capture sensitivity, ranging from 0.1 to 7.6 pg of individual phenols. The practical detection limit was from 0.01 to 0.20 ng/ml. [R147] *... The use of packed columns was explored for the gas chromatographic separation and identification of 19 chlorophenol congeners after acetylation. Numerous mixtures of polar or nonpolar packings with either of 2 commercial Bentone 34 mixtures were tested. A mixture of 5% OV-101, 1.75% Bentone 34 on Chrom W-HP (100/120) mixed with twice its weight of 3% OV-225 on 100/120 Supelcoport separated all 19 congeners. /Chlorophenols/ [R148] *A method was described which permitted the analysis of chlorinated phenols in aqueous samples at ng/l concentrations. Extraction was carried out by homogenization with dichloromethane, clean-up by sample concentration and back extraction with alkali and derivatization for capillary gas chromatograph/electron capture detection by extractive alkylation with pentafluorobenzoyl chloride. The method was applied to municipal waste water sludge and soil leachate and the concentrations found were reported. Eight chlorinated phenols /including 2,4-DCP/ were spiked into these samples and the mean recovery was 70% with a relative SD of 7-15%, dependent upon sample matrix. [R149] *A method is presented for the simultaneous determination of a wide range of carboxylic acids and phenols in water. Extractive alkylation is used with the tetrabutylammonium ion as counter ion and pentafluorobenzylbromide as alkylating agent. Extracts are analyzed by glass capillary gas chromatography and electron capture detection. Using a 1 ml water sample, the detection limit is 1-10 ug/l. /Chlorophenols/ [R150] *Chlorophenols were separated by high pressure liquid chromatography with UV detection (280 nm) in conjunction with electrochemical detection. /Chlorophenols/ [R151] *Detection of trace chlorophenol residues in environmental samples by quadrapole mass spectrometry with selected-ion monitoring is described. /Chlorophenols/ [R152] *A new gas chromatography column was developed that overcomes problems of incomplete separation in the determination of phenols, and permits quantitative analysis at the nanogram level of 11 priority pollutants: including 2,4-dichlorophenol. Gas liquid solid chromatography was selectd for its high selectivity and suitability for the elution of polar compounds. When graphitized carbon black was used as the adsorbent, the elution of polar compounds was very selective and linear. The problem of high retention times was solved by coating the packing material with monolayers of a nonpolar liquid phase. Use of an acidic phase to coat the adsorbent solved the problem of the presence of some chemically active adsorption sites; trimesic-acid was preferred. Chromatograms of industrial water from an olive oil extraction plant polluted by phenols showed that elution of water is very fast and does not affect column performance. The packed column officially used in the United State gave less effective separation. A capillary column required 50 percent higher analysis time. [R153] *EPA Method 8040: Phenols. For the detection of phenolic compounds, a representative sample (solid or liquid) is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Maximum sample holding time after extraction is 40 days. Samples are extracted using the appropriate techniques and are analyzed by gas chromatography using the solvent flush technique, with detection achieved with a flame ionization detector. For the preparation of pentafluorobenzylbromide derivatives, additional cleanup procedures for electron capture gas chromatography is provided. Under the prescribed conditions, 2,4-dichlorophenol has a detection limit of 0.39 ug/l, a limit for the standard deviation of four measurements of 25.1 ug/l, and a range of the average recovery of 59.7-103.3 ug/l. [R146] *EPA Method 8250: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Packed Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water samples. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride, including the title compound, and capable of being eluted without derivatization as sharp peaks from a gas chromatographic packed column. For base/neutral compound detection, a 2 m by 2 mm ID stainless or glass column packed with 3% SP-2250-DB on 100/120 mesh Supelcoport or equivalent is used. For acid compound detection, a 2 m by 2 mm ID glass column packed with 1% SP-1240-DA on 100/120 mesh Supelcoport or equivalent is used. A representative sample is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Under the prescribed conditions, 2,4-dichlorophenol has a detection limit of 2.7 ug/l, a range for the average recovery of four measurements of 52.5-121.7 ug/l, and a limit for the standard deviation of 26.4 ug/l. [R146] *EPA Method 8270: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Capillary Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride, including the title compound, and are capable of being eluted without derivatization as sharp peaks from a 30 m by 0.25 mm ID (or 0.32 mm ID) 1 um film thickness silicon-coated fused silica capillary column (J and W Scientific DB-5 or equivalent)). A representative sample is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Under the prescribed conditions, 2,4-dichlorophenol has a retention time of 9.48 min, a range for the average recovery of four measurements of 52.5-121.7 ug/l, and a limit for the standard deviation of 26.4 ug/l. [R146] *Soxhlet extraction with pentane for 6 hr, followed by six hours of extraction with methanol, and purging with dry nitrogen at 250 or 300 deg C at a flow rate of 30 ml/min for 12 hr. The tube was designed to be used with a thermal desorber, cryogenic trap, and capillary gas chromatography/mass spectrometry system. [R140] *APHA Method 6420-BB: Phenols in Water by Gas Chromatography: Phenols in Water by Liquid-Liquid Extraction and Gas Chromatography; GC flame ionization detection, wastewater, detection limit of 0.680 ug/l. [R154] *EMSLC Method 625-S: Organics in Sludge - Base/Neutral and Acid: Organics in Sludge - Base/Neutral and Acid; GC mass spectrometry detection, determination of the base, neutral, and acid-extractable organic compounds in sludge, detection limit of 2.70 ug/l. [R154] *EAD Method 1625-S: Semivolatiles - Soil, GC/MS: Semivolatile Organic Compounds by Isotope Dilution GCMS; GC mass spectrometry detection, soil, detection limit of 120 ug/kg. [R154] *SFSAS Method 16: Organics in Sediment: Analysis of Sediment for General Organics by Mechanical Dispersion Extraction; GC mass spectrometry detection, sediment, detection limit of 100 ug/kg. [R154] *SFSAS Method 29: Organics in Biological Tissue: Extraction and Analysis of Organics in Biological Tissue; GC mass spectrometry detection, biological tissue, detection limit of 2.0 mg/kg. [R154] *SFSAS Method 6: Organics in Fish: Analysis of Fish for General Organics by Solvent Extraction; GC mass spectrometry detection, fish, detection limit not specified. [R154] CLAB: *URINE SAMPLES FROM OCCUPATIONALLY EXPOSED PERSONS CAN BE ANALYZED BY GC ON GLASS COLUMN CONTAINING 60/80 MESH TENAX GC USING FLAME IONIZATION DETECTORS. DETECTION LIMITS RANGE FROM 0.1 MG/L FOR PHENOL TO 1 MG/L FOR DICHLOROPHENOLS. /PHENOLS AND DICHLOROPHENOLS/ [R155] *CHLORINATED PHENOLS IN URINE ARE ISOLATED BY SORPTION ONTO SMALL COLUMN OF MACRORETICULAR RESIN. THE PHENOLS WERE ELUTED FROM COLUMN WITH 2-PROPANOL IN HEXANE; SOLN CONCENTRATED AND THE PHENOLS WERE SEPARATED AND ANALYZED BY GC. /CHLORINATED PHENOLS/ [R156] *A METHOD IS DESCRIBED FOR THE CONFIRMATION OF CHLOROPHENOLS IN HYDROLYZED URINE (HUMAN) USING GAS CHROMATOGRAPHY AND LIQ CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION. /CHLOROPHENOLS/ [R157] *BLOOD SERUM FROM 58 FEMALES FROM DADE COUNTY, FL WERE ANALYZED FOR PRESENCE OF 2,4-DICHLOROPHENOL AND OTHER PHENOLIC COMPOUNDS BY GLC. ... FAUCET SAMPLES FROM 12 OF THE CHLORINATED AND 10 FROM NON-CHLORINATED DRINKING WATER SUPPLIES AND 10 SAMPLES OF ADIPOSE TISSUE FROM AUTOPSIES WERE ALSO ANALYZED. NO 2,4-DICHLOROPHENOL WAS FOUND. TRICHLOROPHENOL WAS DETECTED IN WATER AND BIOLOGICAL TISSUES. [R158] *A METHOD FOR THE DETECTION AND CONFIRMATION OF TRACE AMOUNTS OF CHLOROPHENOL RESIDUES IN ENVIRONMENTAL AND BIOLOGICAL SAMPLES BY QUADRUPOLE MASS SPECTROMETRY WITH SELECTED-ION MONITORING (SIM) IS DESCRIBED. USE OF SIM ELIMINATES BACKGROUND INTERFERENCE WHICH ALLOWS IDENTIFICATION OF CHLOROPHENOL RESIDUES IN HUMAN URINE. PHENOL CONCENTRATIONS AS LOW AS 1.0 PMOL/ML URINE GAVE PEAKS THAT WERE DISCERNIBLE BY SIM. /CHLOROPHENOL/ [R152] *A gas chromatographic method is described that is sensitive and specific for the simultaneous determination of 10 chlorinated phenols /in urine samples/: 2,6-, 2,4-, 2,3-, and 3,4-dichlorophenol; 2,4,6-, 2,4,5-, and 3,4,5-trichlorophenol; 2,3,4,6- and 2,3,4,5-tetrachlorophenol; and pentachlorophenol. ... The method is based on the hydrolysis of the phenolic compounds in urine and subsequent derivatization with acetic anhydride. To determine the accuracy and precision of the method, pooled urine from unexposed persons spiked with definite amounts of each chlorophenol was analyzed. Concentrations were between 58 and 220 ug/l. Recoveries ranged between 87 and 119%. The coefficients of variation were between 4.4 and 10.1%. The detection limit for each chlorophenol in urine ranged between 4.9 and 18.6 ug/l. [R159] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; KOZAK VP ET AL; REVIEWS OF THE ENVIRONMENTAL EFFECTS OF POLLUTANTS: XI. CHLOROPHENOLS; 519 PAGES (1979) EPA-600/1-79-012. THIS PAPER DISCUSSES THE HEALTH AND ENVIRONMENTAL EFFECTS, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS, BIOLOGICAL ASPECTS (HUMAN AND NON-HUMAN), ENVIRONMENTAL DISTRIBUTION AND TRANSFORMATION AND ENVIRONMENTAL INTERACTIONS OF CHLOROPHENOLS AND THEIR CONSEQUENCES. AVAILABLE DATA INDICATE THAT CHLOROPHENOLS DO NOT POSSESS TUMORIGENIC, MUTAGENIC OR TERATOGENIC PROPERTIES. 2,4-DICHLOROPHENOL MAY PROMOTE TUMORS IN MICE. /CHLOROPHENOLS INCLUDING 2,4-DCP/ ETHYLBENZENE, PHENOL, 2,4-DICHLOROPHENOL, 2,4,5-TRICHLOROPHENOL, AND PENTACHLOROPHENOL AND THE LIST OF TOXIC POLLUTANTS OF THE CLEAN WATER ACT; FED REGIST 46 (5): 2267-73 (1981). DATA ON AQUATIC PERSISTENCE, DEGRADABILITY, AND TOXICITY TO FISH, FRESHWATER INVERTEBRATES, MAMMALS AND HUMANS ARE GIVEN SUPPORTING THE RETENTION OF ETHYLBENZENE, PHENOL, 2,4-DICHLOROPHENOL, 2,4,5-TRICHLOROPHENOL AND PENTACHLOROPHENOL ON THE TOXIC POLLUTANT LIST OF THE CLEAN WATER ACT. TSCA CHIPs present a preliminary assessment of 2,4-dichlorophenol's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404 or (800) 424-9065 Toxicology Review: Science of the Total Environment 2 (4): 305 (1974) Nat'l Research Council Canada; Chlorinated Phenols (1982) NRCC No. 18578 Scientific Criteria Document For Standard Development. Chlorinated Phenols In The Aquatic Environment No. 2-84 (1984) Environmental Protection Service. Chlorophenols and Their Impurities in the Canandian Environment Report EPS 3-EC-81-2 (1981) USEPA; Reviews of the Environmental Effects of Pollutants: XI Chlorophenols (1979) EPA 600/1-79-012 USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol (1980) EPA 440/5-80-042 Arch Toxicol Suppl Vol 8, Iss Recept Other Targets Toxic Subst: 481-7 (1985). Prediction of toxicity using quantitative structure-activity relationships Ahlborg UG, Thunberg TM; Crit Rev Toxicol 7 (1): 1-36 (1980) Chlorinated phenols, their occurrence, toxicity, metabolism and environmental impact are discussed. USEPA; Health Effects Assessment for 2-chlorophenol and 2,4-dichlorophenol (1987) EPA/600/8-88/052. Anon; Dangerous Prop Ind Mater Rep 7(3): 70-86 (1987). Review of dichlorophenol safety, toxicology, and health hazard. Krijgsheld KR, Van der Gen A; Chemosphere 15 (7 ): 825-860 (1986). 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New York, NY: Van Nostrand Reinhold Co., 1996. 703 R95: Ingols RS et al; J Water Pollut Control Fed 38: 629 (1966) as cited in USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol p.C-4 (1980) EPA 440/5-80-042 R96: Hwang HM; Environ Sci Technol 20 (910): 1002-7 (1986) R97: Scow KM et al; Appl Environ Microbiol 51 (5): 1028-35 (1986) R98: Gibson SA, Sulfita JM; Appl Envrion Microbiol 52 (4): 681-8 (1986) R99: Kuiper J, Hanstveit AO; Ecotoxicol Environ Safety 8 (1): 15-33 (1984) R100: (1) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (2) Tabak HH et al; J Bacteriol 87: 910-9 (1964) (3) Pitter P; Water Res 10: 231-5 (1976) (4) Ingols RS et al; J Water Pollut Control Fed 38: 629-35 (1966) (5) Rogers JE, Halet DD; Amer Chem Soc Div Environ Chem Preprints, New Orleans, LA 27: 699-701 (1987) (6) Carey JH et al; Can J Physiol Pharmacol 62: 971-5 (1984) R101: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Dronamraju MM, Bhattacharya SK; pp. 360-64 in Applied Biotechnology for Site Remediation. Pap Int Symp, In-Situ On-Site Bioreclam. 2nd. Hinchee REL et al, eds. Boca Raton,FL: Lewis Pub (1993) (3) Lyngkilde J et al; pp. 91-100 in Contaminated Soils, K Wolf and WJ van den Brink, eds. Kluwer Academic Pub (1988) (4) Ryding JM et al; Water Res 28: 1897-1906 (1994) R102: (1) Madsen T et al; Chemosphere 31: 4243-58 (1995) (2) Battersby NS and Wilson V; Appl Environ Microbiol 55: 433-39 (1989) (3) Kohring GW et al; Appl Environ Microbiol 55: 348-53 (1989) (4) Masunaga S et al; Environ Sci Technol 30: 1253-60 (1996) R103: Aly OM, Faust SD; J Agric Food Chem 12: 541 (1964) as cited in USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol p.C-4 (1980) EPA 440/5-80-042 R104: (1) Atkinson R; Journal of Physical And Chemical Reference Data. Monograph No 1 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Larson RA et al; Environ Toxicol Chem 8: 1168-70 (1989) (4) Miller RM et al; Environ Sci Tech 22: 1215-19 (1988) (5) Boule P et al; Chemosphere 13: 603-12 (1984) (6) Lemaire J et al; Chemosphere 14: 53-77 (1985) (7) Crosby DG, Tutass HO; J Agric Food Chem 14: 596-9 (1966) R105: (1) Hwang H et al; Environ Sci Technol 20: 1002-7 (1986) (2) Scully FE Jr, Hoigne J; Chemosphere 16: 681-94 (1987) (3) Mabey WR et al; Aquatic Fate Proces Data for Organic Priority Pollutants. USEPA-440/4-81-014. p. 28, 251-2 (1981) R106: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) (3) Shiu WY et al; Chemosphere 29: 1155-224 (1994) (4) Suntio LR et al; Chemosphere 17:1249-90 (1988) R107: (1) Artiola-Fortuny J, Fuller WH; Soil Sci 133: 218-27 (1982) (2) Johnson RL et al; Ground Water 5: 652-66 (1985) (3) Miller RW, Faust SD; Environ Lett 4: 211-33 (1973) (4) Boyd SA; Soil Sci 134: 337-43 (1982) R108: (1) Isaacson PJ, Frink CR; Environ Sci Technol 18: 43-48 (1984) (2) Schellenberg K et al; Environ Sci Technol 18: 652-7 (1984) (3) Eder G, Weber K; Chemosphere 9: 111-8 (1980) R109: (1) Shiu WY et al; Chemosphere 29: 1155-224 (1994) (2) Swann RL et al; Res Rev 85: 23 (1983) (3) Danis TG et al; pp. 148-151 in Environmental Behavior of Pesticides, Regulatory Aspects. Copin A et al, eds. Rixensart,Belgium: European Study Service (1994) R110: USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol p.A-2 (1980) EPA 440/5-80-042 R111: Aly Om, Faust SD; J Agric Food Chem 12: 541 (1964) as cited in USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol p.C-3 (1980) EPA 440/5-80-042 R112: (1) Shiu WY et al; Chemosphere 29: 1155-224 (1994) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) USEPA EXAMS II Computer Simulation (1987) R113: (1) Beltis K et al; Chemical Analysis Support: Limited Analysis of Bristol, Rhode Island Well Water Samples. US Army Tox Hazard Mat Agency, Aberdeen Proving Ground, MD. Report No. DRXTH-TE-CR-2135, AD-A120-636 (1982) (2) Forst C et al; Chemosphere 26: 1355-36 (1993) (3) Pakdel H et al; pp. 381-421 in Groundwater Contamination and Analysis at Hazardous Waste Sites. S Lesage and RE Jackson, eds. NY,NY: Marcel-Dekker, Inc (1994) (4) Bedient PB et al; Ground Water 22: 318-29 (1984) (5) Stepan S et al; Austral Water Resources Council Conf Ser 1: 415-24 (1981) R114: (1) Fingler S and Drevenkar V; Toxicol Environ Chem 17: 319-28 (1988) (2) Kraybill HF; J Environ Sci Health C1: 175-232 (1983) R115: (1) Staples CR et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Eder G, Weber K; Chemosphere 9: 111-8 (1980) (3) Malle KG; Z Wasser-Abwasser Forsch 17: 75-81 (1984) (4) Wegman RCC, Hofstee AWM; Water Res 13: 651-7 (1979) {5) Grobler DF et al; Marine Poll Bull 32: 572-75 (1996) R116: (1) Xie TM et al; Environ Sci Technol 20: 457-63 (1986) R117: (1) Leuenberger C et al; Environ Sci Technol 19: 1053-8 (1985) (2) Mazurek MA, Simoneit BRT; CRC Critical Reviews in Environ Control 16: 49 (1986) R118: LANDNER L ET AL; BULL ENVIRON CONT TOXICOL 18: 663 (1977) R119: (1) Staples CR et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Paasivirta J e al; Chemosphere 14: 469-91 (1985) (3) Junk JA et al; p. 109-23 in ACS Symp Ser 319 (1986) (4) Oberg T et al; Chemosphere 16: 2451-65 (1987) R120: (1) Canviro Consultants; Thirty Seven Municipal Water Pollution Control Plants, Pilot Monitoring Study Volume 1. Interim Report. Ontario Ministry of the Environment Water Resources Branch. ISBN 0-7729-4900-X. pp 97 (1988) (2) Lee B et al; J Assoc Off Anal Chem 72: 979-84 (1989) (3) Paasivirta J et al; Chemosphere 24: 1253-58 (1992) (4) Solomon K et al; A Review and Assessment of the Ecological Risks Associated With the Use of Chlorine Dioxide for the Bleaching of Pulp. Prepared for the Alliance for Environmental Technology. 75 pp. (1993) R121: (1) Judd MC et al; Chemosphere 33: 2209-20 (1996) (2) Kitunen VH, Salkinoja MS; Chemosphere 20: 1671-77 (1990) (3) Eder G, Weber K; Chemosphere 9: 111-8 (1980) (4) Salkinoja-Salonen MS et al; In: Current Perspectives in Microbiology, Klug MJ, Reddy CA eds. pp 668-72. Nat Acad Sci (1984) (5) Valo R et al; Chemosphere 13: 835-44 (1984) (6) Wegman RCC, Vandenbroek HH; Water Res 17: 227-30 (1983) (7) Owens JW et al; Chemosphere 29: 89-109 (1994) (8) Kvernheim AL; Chemosphere 27: 733-45 (1993) R122: (1) Jay K and Stieglitz; Chemosphere 30: 1249-60 (1995) (2) Dempsey CR; J Air Waste Management Assoc 43: 1374-79 (1993) (3) Leuenberger C et al; Environ Sci Technol 19: 1053-8 (1985) R123: Isensee AR, Jones GE; J Agric Food Chem 19: 1210 (1971) as cited in USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol p.C-9 (1980) EPA 440/5-80-042 R124: (1) Webber MD et al; J Environ Qual 23: 1019-26 (1994) R125: (1) Camanzo J et al; J Great Lakes Res 13: 296-309 (1987) (2) Soderstrom M et al; Chemosphere 28: 1701-19 (1994) (3) Hodson P et al; Environ Toxicol Chem 11: 1635-51 (1992) (4) New Brunswick Res and Prod Council; Bioaccumulation of Toxic Compounds in Pulpmill Effluents by Aquatic Organisms in Receiving Waters. PAR Project Report 675-1. Fredericton, New Brunswick (1978) (5) Owens JW et al; Chemosphere 29: 89-109 (1994) R126: (1) Paasivirta J et al; Chemosphere 14: 469-91 (1985) R127: (1) Hill RH et al; Arch Environ Contam Toxicol 18: 469-74 (1989) R128: USEPA; Ambient Water Quality Criteria Doc: 2,4-Dichlorophenol p.C-1 (1980) EPA 440/5-80-042 R129: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Phenols p.C-30 (1980) EPA 440/5-80-032 R130: Nat'l Research Council Canada; Chlorinated Phenols p.77 (1982) NRCC No. 18578 R131: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R132: (1) Fatiadi AJ; Environ International 10: 175-205 (1984) (2) Kitunen V et al; Intern J Environ Anal Chem 20: 13-28 (1985) R133: 40 CFR 60.489 (7/1/97) R134: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R135: 40 CFR 401.15 (7/1/88) R136: USEPA: Health Effects Assessment; 2-Chlorophenol and 2,4-Dichlorophenol EPA/600/8-88/052 p.12 (1987) R137: 40 CFR 302.4 (7/1/97) R138: 40 CFR 261.33 (7/1/97) R139: 40 CFR 136 (7/1/88) R140: Turpin RD et al; Fifth National Conference on Management of Uncontrolled Hazardous Waste Sites p.81-84 (1984) R141: COUTTS RT ET AL; J CHROMATOGR 179 (2): 291-300 (1979) R142: ARMENTROUT DN ET AL; ANAL CHEM 51 (7): 1039-45 (1979) R143: Lee HB, Chau AS Y; J Assoc Off Anal Chem 66 (4): 1029-38 (1983) R144: Abrahamsson K, Xie TM; J Chrom 279: 199-208 (1983) R145: Korhonen IO O; J Chrom 303 (1): 197-205 (1984) R146: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R147: Bengtsson G; J Chrom Sci 23 (9): 397-401 (1985) R148: Cline RE, Needham LL; J Anal Toxicol 8 (6): 282-4 (1984) R149: Buisson R SK et al; J Chromatogr Sci 22 (8): 339-42 (1984) R150: Fogelqvist E et al; J High Resolut Chromatogr Commun 3 (11): 568-74 (1981) R151: Aakerblom M, Lindgren B; J Chromatogr 258: 302-6 (1983) R152: Hargesheimer EE, Coutts RT; J Assoc Off Anal Chem 66 (1): 13-21 (1983) R153: Margani F et al; Anal Chem 58 (14): 3261-3263 (1986) R154: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R155: VAN ROOSMALEN PB ET AL; INT ARCH OCCUP ENVIRON HEALTH 45 (1): 57-62 (1980) R156: EDGERTON TR ET AL; ANAL CHEM 52 (11): 1774-7 (1980) R157: LORES EM ET AL; J CHROMATOGR SCI 19 (9): 466-9 (1981) R158: MORGADE C ET AL; BULL ENVIRON CONTAM TOXICOL 24 (1): 257-64 (1980) R159: Angerer J et al; Int Arch Occup Environ Health 48 (4): 319-24 (1981) RS: 124 Record 114 of 1119 in HSDB (through 2003/06) AN: 1156 UD: 200302 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-NITROANILINE- SY: *Para-aminonitrobenzene-; *1-AMINO-4-NITROBENZENE-; *ANILINE,-P-NITRO-; *ANILINE,-4-NITRO-; *AZOAMINE-RED-ZH-; *AZOFIX-RED-GG-SALT-; *AZOIC-DIAZO-COMPONENT-37-; *BENZENAMINE,-4-NITRO-; *CI-AZOIC-DIAZO-COMPONENT-37-; *CI-DEVELOPER-17-; *CI-37035-; *DEVELOPER-P-; *DEVOL-RED-GG-; *DIAZO-FAST-RED-GG-; *FAST-RED-P-BASE-; *FAST-RED-2G-BASE-; *FAST-RED-BASE-2J-; *FAST-RED-BASE-GG-; *FAST-RED-GG-BASE-; *FAST-RED-GG-SALT-; *FAST-RED-MP-BASE-; *FAST-RED-P-SALT-; *FAST-RED-2G-SALT-; *FAST-RED-SALT-2J-; *FAST-RED-SALT-GG-; *NAPHTOELAN-RED-GG-BASE-; *NCI-C60786-; *P-NITRANILINE-; *4-NITRANILINE-; *NITRAZOL-CF-EXTRA-; *P-NITROANILINA- (POLISH); *Para-nitroaniline-; *4-NITROBENZENAMINE-; *P-NITROPHENYLAMINE-; *PNA-; *RED-2G-BASE-; *SHINNIPPON-FAST-RED-GG-BASE- RN: 100-01-6 RELT: 1132 [2-NITROANILINE] (METABOLITE); 2570 [3-NITROANILINE] MF: *C6-H6-N2-O2 SHPN: UN 1661; Nitroanilines (o-, m-, p-) IMO 6.1; Nitroanilines (o-, m-, p-) STCC: 49 215 30; Nitroaniline HAZN: P077; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *AMMONOLYSIS OF P-NITROCHLOROBENZENE; OR BY NITRATION OF ACETANILIDE FOLLOWED BY HYDROLYSIS. [R1] *FROM ACETANILIDE; BY SCHMIDT REACTION. [R2] *PREPARED FROM THE REACTION OF GAMMA-GLUTAMYL-P-NITROANILIDE WITH GAMMA-GLUTAMYL TRANSPEPTIDASE. [R3, p. V3 757] IMP: *A CO-PRODUCT OF THE GAMMA-GLUTAMYL TRANSPEPTIDASE REACTION IS GLUTAMYLGLYCYLGLYCINE. [R3, p. V3 757] MFS: *E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Deepwater, NJ 08023 [R4] *Monsanto Co, Hq, 800 N Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Monsanto Chemical Co, Production site: Sauget, IL 62201 [R4] USE: +MEDICATION (VET) +CHEM INT FOR ANTIOXIDANTS, DYES, PIGMENTS, GASOLINE GUM INHIBITORS [R1] *COUPLES WITH 2-NAPHTHOL TO FORM PIGMENT RED 1. [R5] *USED IN DIAZOTIZED FORM TO RETAIN THE FASTNESS OF DYES AFTER WASHINGS. [R6, (1972)] *USED TO PRODUCE AZO DYE ACID VIOLET 3. [R6, (1972)] *USED TO PRODUCE AZO DYE ACID GREEN 20. [R6, (1972)] *USED TO PRODUCE AZO DYE DIRECT YELLOW 44. [R6] *USED AS AN INTERMEDIATE FOR PRODUCING P-PHENYLENEDIAMINE. [R3, p. V2 439] */4-Nitroaniline/ is used ... as a corrosion inhibitor. [R7] CPAT: *40% AS AN INT FOR ANTIOXIDANTS; 20% AS AN INT FOR GASOLINE GUM INHIBITORS; 20% AS AN INT FOR DYES AND PIGMENTS; 7% IN PHARMACEUTICAL AND VETERINARY USE; 13% IN MISC APPLICATIONS(1968). [R1] PRIE: U.S. PRODUCTION: *(1973) 4.77X10+9 G (DEMAND EST) [R1] *(1975) 3.93X10+9 G [R1] U.S. IMPORTS: *(1972) 1.1X10+7 G (PRINCPL CUSTMS DISTS) [R1] *(1975) 1.23X10+9 G [R1] *(1983) 5.72X1O+8 g [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW MONOCLINIC NEEDLES [R9, 2467]; *BRIGHT YELLOW POWDER [R2]; *Bright yellow, crystalline powder. [R10] ODOR: *Faint ammonia; slightly pungent [R11]; *Odorless [R12, 1981.2]; *Slight ammonia-like odor. [R10] TAST: *Burning sweet taste [R9, 2467] BP: *332 DEG C [R2] MP: *146 DEG C [R2] MW: *138.12 [R2] CORR: *Will attack some forms of plastics, coatings, and rubber. [R12, 1981.2] DEN: *1.424 AT 20 DEG C/4 DEG C [R13, p. C-73] DSC: *pKa = 1.01 [R14]; *pKa = 2.05 [R15] HTC: *-9,920 Btu/lb= -5,510 cal/g= -231x10+5 J/kg [R11] HTV: *17,220.2 GCAL/GMOL [R13, p. C-672] OWPC: *Log Kow = 1.39 [R16] PH: *pH = 6.7 [R17] SOL: *1 G/1250 ML WATER [R2]; *SOL IN ACETONE, CHLOROFORM; VERY SOL IN METHYL ALC [R13, p. C-73]; *1 G/45 ML BOILING WATER [R2]; *1 G/25 ML ALCOHOL [R2]; *1 G/30 ML ETHER [R2]; *SOL IN BENZENE [R2]; *0.08 g/100 g water at 18.5 deg C. [R12, 1981.2]; *Solubility in water 390 ppm at 20 deg C. [R18]; *Water Solubility = 724 mg/l @ 25 deg C [R19]; *Water Solubility = 600 mg/l at 25 deg C [R20] SPEC: *MAX ABSORPTION (95% ETHANOL): 374 NM (E= 151, 1%, 1 CM) [R21]; *MAX ABSORPTION (ALCOHOL): 227 NM SHOULDER (LOG E= 3.86); 375 NM (LOG E= 4.19); SADTLER REFERENCE NUMBER: 8451 (IR, PRISM) [R22]; *IR: 2257 (Coblentz Society Spectral Collection) [R23]; *UV: 2243 (Sadtler Research Laboratories Spectral Collection) [R23]; *NMR: 9378 (Sadtler Research Laboratories Spectral Collection) [R23]; *MASS: 87 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R23] VAPD: *4.77 (air= 1) [R24] VAP: *4X10-3 mm Hg at 25 deg C [R25] EVAP: *Evaporation rate (butyl acetate= 1): 22.6 [R12, 1981.2] OCPP: *Vapor Pressure = 1 mm Hg @ 142.4 deg C [R26] *IG Heat of Formation = 5.95X10+7 Joules/kmol [R27] *Liquid molar volume is 0.129 cu m/kmol [R27] *Heat of fusion at melting point = 2.11X10+7 Joules/kmol SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Nitroanilines/ [R28] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Nitroanilines/ [R28] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Nitroanilines/ [R28] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitroanilines/ [R28] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitroanilines/ [R28] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Nitroanilines/ [R28] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Nitroanilines/ [R28] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitroanilines/ [R28] FPOT: *Combustible when exposed to heat or flame. [R29] *COMBUSTIBLE. IN PRESENCE OF MOISTURE CAUSES NITRATION OF ORG MATERIALS AND MAY RESULT IN SPONTANEOUS IGNITION. [R13, p. 49-67] *Process errors led to discharge of copious amt of nitrous fumes into glass reinforced plastic ventilation duct above diazotization vessel. On 2 occasions fires were caused in the duct by vigorous reaction of the dinitrogen tetraoxide with nitroaniline dusts in the duct. [R30, 1354] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, incl self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms and waist should be provided. No skin surface should be exposed. [R31, p. 49-95] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R31, p. 49-95] +Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R31, p. 49-95] FLPT: *329 DEG F (OPEN CUP) (MOLTEN SOLID) [R11] *199 deg C (closed cup) [R12, 1981.2] AUTO: *180 deg C (356 deg F) [R12, 1981.2] TOXC: *Toxic oxides of nitrogen may form in fire. [R11] REAC: *An ammonical soln of 4-nitroaniline containing ammonium chloride was being treated with 50% sodium hydroxide soln to displace ammonia. In error, double the amt required to give usual 10% of free alkali was added, and during subsequent degassing operation (heating to 130 deg C under pressure, followed by depressuring to vent ammonia), complete conversion to sodium 4-nitrophenoxide occurred. ... /When/ separated by centrifuging, it was then heated to dry ... when it decomposed violently and was ejected through the vessel opening. ... Some of the tautomeric aci-nitroquinonoid salt may have been produced during the drying operation. [R30, 586] *Incompatible with reducers. [R32, 650] *Incompatabilities: Strong oxidizers and moisture may result in spontaneous heating. [R12, 1981.2] *FORMS WATER SOL SALTS WITH MINERAL ACIDS. [R33] +Strong oxidizers, strong reducers, (Note: May result in spontaneous heating of organic materials in the presence of moisture.) [R34, 226] DCMP: +Explosive decomposition may occur under fire conditions. [R31, p. 49-96] +When heated to decomp it emits toxic /nitrogen oxides./ [R35] SERI: *Eye Irritation Level: ... Is mildly irritating to the eyes and may cause some corneal damage. [R12, 1981.2] *Dust: irritating to eyes, nose and throat; solid: irritating to skin and eyes [R11] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face-shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with solid 4-nitroaniline or liquids containing 4-nitroaniline. Employees should be provided with and required to use dust and splash-proof safety goggles where there is any possibility of liquid 4-nitroaniline or solids containing 4-nitroaniline contacting the eyes. [R12, 1981.2] +Wear appropriate personal protective clothing to prevent skin contact. [R34, 227] +Wear appropriate eye protection to prevent eye contact. [R34, 227] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readiliy available, whereas in others, the availability of water from a sink or hose could be considered adequate.) [R34, 227] +Recommendations for respirator selection. Max concn for use: 30 mg/cu m. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R34, 227] +Recommendations for respirator selection. Max concn for use: 75 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R34, 227] +Recommendations for respirator selection. Max concn for use: 150 mg/cu m. Respirator Class(es): Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R34, 227] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards. Respirator Class(es): Any air-purfying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister in combination with a dust, mist, and fume filter. Any appropriate escape-type, self-contained breathing apparatus. [R34, 227] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concentrations of IDLH conditions. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R34, 227] +Recommendations for respirator selection. Max concn for use: 300 mg/cu m. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R34, 227] OPRM: *Employees should wash immediately with soap when skin is wet or contaminated and daily at the end of each work shift. Work clothing should be changed daily if ... contaminated. Remove non-impervious clothing immediately if wet or contaminated. Provide emergency showers. [R32, 651] +Contact lenses should not be worn when working with this chemical. [R34, 227] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Ample ventilation of work area or with piped air respirator. Extreme sanitary and clean work area and of the personnel is necessary. [R36] *Eating and smoking should not be permitted in areas where liquid 4-nitroaniline is handled, processed, or stored. [R12, 1981.3] *Employees who handle solid 4-nitroaniline or liquids containing 4-nitroaniline should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. [R12, 1981.3] *Clothing contaminated with liquid 4-nitroaniline should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of 4-nitroaniline from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the 4-nitroaniline, the person performing the operation should be informed of 4-nitroaniline's hazardous properties. Non-impervious clothing which becomes contaminated with liquid 4-nitroaniline should be removed immediately and not reworn until the 4-nitroaniline is removed from the clothing. [R12, 1981.2] *In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mine Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. [R12, 1981.2] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R34, 227] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R34, 227] +The worker should immediately wash the skin when it becomes contaminated. [R34, 227] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location, and weather conditions. [R37] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Use water spray to knock down vapors. [R37] *Personnel protection: Avoid breathing dusts and fumes from burning material. Keep upwind. Avoid bodily contact with the material. Do not handle broken packages unless wearing personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R37] +The worker should wash daily at the end of each work shift. [R34, 227] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R38] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R39] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R40] STRG: +Store in a cool, dry, well-ventilated location. Separate from acids, oxidizing materials, and reducing agents. [R31, p. 49-96] CLUP: *1. Ventilate area of spill. 2. For small quantities, sweep onto paper or other suitable material, place in an appropriate container and burn in a safe place (such as a fume hood). Large quantities may be reclaimed; however, if this is not practical, dissolve in a flammable solvent (such as alcohol) and atomize in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. [R12, 1981.2] *EFFECTIVENESS OF PURIFICATION OF P-NITROANILINE WASTE WATER CONTAMINANTS WAS INCREASED BY USING PSEUDOMONAS FLUORESCENS 5/7 IN AERATING PURIFIERS WITH THE ADDITION OF NUTRIENT SALTS IN WASTE WATERS. [R41] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P077, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R42] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R43] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R44, 2002.44] MEDS: *Consider the points of attack (blood, heart, lungs and liver) in preplacement and periodic physical examinations. [R32, 651] *Routine checking of lips, tongue and nail beds of exposed personnel for signs of cyanosis. /Protect/ from exposure those individuals with anemia, cardiovascular or pulmonary diseases. [R36] HTOX: *Para-nitroaniline is a potent methemoglobin-inducing agent and given sufficiently high or prolonged exposures, hemolysis can occur. Prolonged exposure may also result in liver damage. [R45, 1991.1094] *... SEVERAL CASES OF POISONING AMONG MEN WHO SWEPT UP SPILLED ... POWDER IN ... HOLD OF A SHIP. ONE MAN, WHO ALREADY HAD LIVER DISEASE, BECAME JAUNDICED AND DIED. THE OTHERS BECAME CYANOTIC AND COMPLAINED OF HEADACHE, SLEEPINESS, WEAKNESS, AND RESPIRATORY DISTRESS. [R45, 1991.1094] *Symptomatology: 1. Lips, tongue, and mucous membranes navy blue to black; skin slate gray, all without signs of cardiac or pulmonary insufficiency. 2. Severe headache, nausea, sometimes vomiting, dryness of throat. 3. Central nervous symptoms: confusion, ataxia, vertigo, tinnitus, weakness, disorientation, lethargy, drowsiness, and finally, coma. Convulsions may occur but appear to be uncommon. 4. Cardiac effects: heart blocks, arrhythmias, and shock. 5. Death, although uncommon, is usually due to cardiovascular collapse and not resp paralysis. 6. Urinary signs and symptoms may incl painful micturition, hematuria, hemoglobinuria, and renal insufficiency (usually mild). 7. A late acute hemolytic episode should be anticipated at 6 to 8 days after ingestion. /Aniline/ [R46, p. II-197] *... P-NITROANILINE /FOUND/ IN SOME SAMPLES OF RED WAX CRAYONS AND IN SOME SAMPLES OF THE PARA-RED DYE ... /IS SUSPECTED OF BEING/ RESPONSIBLE FOR ... POISONING OF CHILDREN WHO ATE SUCH CRAYONS. [R45, 1991.1094] *More toxic than aniline and probably more toxic than nitrobenzene. [R46, p. II-209] *A powerful methemoglobin former causing anoxia. ... Chronic exposure may cause jaundice and anemia. [R9, 2468] +Serious health hazard. May be harmful if absorbed through skin or inhaled. Symptoms of overexposure include irritability, vomiting, diarrhea, cyanosis, ataxia, tachycardia, convulsions, respiratory arrest, and anemia. [R31, p. 49-96] NTOX: *METHEMOGLOBIN WAS PRODUCED IN DOGS GIVEN SINGLE DOSE OF 15 MG/KG BY IV ADMINISTRATION. /FROM TABLE/ [R9, 2416] *ADMIN TO RAT INITIALLY DECR BLOOD SH GROUP, GLUTATHIONE, AND OTHER THIOL SYSTEMS OF ERYTHROCYTE CYTOPLASM LEVELS. HEME OXIDN AND HEMOGLOBIN DESTRUCTION LEADING TO ERYTHROCYTE HEMOLYSIS AND ANEMIA FOLLOWED. FERROGEN GAVE FERROHEME, HEMOGLOBIN PPT AS HEINZ BODIES. [R47] *4-Nitroaniline was found to be a frameshift mutagen in Salmonella typhimurium strain TA1538. The chemical was also toxic to TA1538. [R48] *p-Nitroaniline was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Fifty pregnant CD-1 mice were given 1200 mg/kg/day p-nitroaniline in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. p-Nitroaniline caused maternal death and reduced body weight. It decreased the number of viable litters and reduced pup viability and percent survival. [R49] *The teratogenic potential of para-nitroaniline and para-nitrochlorobenzene was studied in rats and rabbits. Pregnant Sprague-Dawley rats were administered 25 to 250 mg/kg per day para-nitroaniline or 5 to 45 mg/kg/day para-nitrochlorobenzene on days 6 through 19 of gestation. All animals were observed for clinical signs of toxicity. Surviving rats and rabbits were killed on days 20 or 30, respectively. Maternal spleen weights were recorded. The uterine horns were examined for the number and location of viable and non viable fetuses and resorptions. Fetuses were removed and examined for decreased body weight gain, urogenital staining, and increased spleen weights. An increased number of resorptions and decreased fetal body weights were observed. Fetal skeletal and soft tissue abnormalities were seen. The lower doses caused no teratogenic effects but caused signs of maternal toxicity. In rabbits, the 125 mg/kg/day dose of para-nitroaniline caused a high degree of maternal mortality. No fetotoxic or teratogenic effects were observed. Para-nitrochlorobenzene caused no fetotoxicity or teratogenic effects. Fetal effects were observed with para-nitroaniline and para-nitrochlorobenzene only at doses that caused severe maternal toxicity. This suggests that there is a causal relationship between toxicity and subsequent fetal effects. Para-nitrochlorobenzene and para-nitroaniline should not be labeled as teratogenic as the fetal effects cannot be dissociated from the maternal effects. [R50] *For evaluation of subchronic toxicity of the two single-ring nitroaromatics, p-nitroaniline and p-nitrochlorobenzene, groups of 10 male and 10 female Sprague-Dawley rats were exposed to an aerosol/vapor of p-nitroaniline in isopropanol at target concentrations of 0, 10, 30, or 90 mg/cu m or to p-nitrochlorobenzene vaporized from a solution in ethylene glycol monoethyl ether at target concentrations of 0, 5, 15, or 45 mg/cu m for 6 hr/day, 5 days/week for 4 weeks. Clinical signs of toxicity, body weights, results of ophthalmoscopic exam, hematology and clinical chemistry tests, organ weights, gross and histopathological changes were recorded. Exposure to p-nitroaniline or p-nitrochlorobenzene resulted in a dose-related increase in blood methemoglobin levels. Mean spleen weights (absolute and relative to body weight) were significantly increased at the high dose levels in the two studies. A slight increase in spleen weights was also observed at the low concentration level in the p-nitroaniline study. Microscopic changes were observed mainly in the spleen and included and increase in intensity of extramedullary hematopoiesis and hemosiderosis with both compounds. Neither p-nitroaniline nor p-nitrochlorobenzene exhibited significant toxicological effects other than those of methemoglobinemia, anemia, and splenic changes classically associated with nitroaromatics at levels significantly above presently accepted occupational standard. ... Data suggest that the current threshold limit values for p-nitroaniline which is 3 mg/cu m will provide adequate protection to the workers. [R51] *p-Dinitrobenzene, p-nitroaniline, and p-nitroacetanilide were examined for mutagenic action in Salmonella typhimurium strains TA98, TA98NR, TA1538NR. p-Nitroaniline and p-nitroacetanilide were not mutagenic in these tester strains. [R52] *Heme metabolism and porphyrin metabolism disorders caused by poisoning by aromatic nitro compounds and amino compounds were investigated. The pathological nature of such disorders was assessed. Contents of methemoglobin, sulfhemoglobin, oxyhemoglobin, sulfhydryl blood groups, and Heinz bodies in the blood were determined. The concentration of coproporphyrin-3 was determined as an indicator porphyrin metabolism. Compounds having the most hematoxic effect were aniline; meta-chloroaniline; para-chloroaniline; meta-nitroaniline; para-nitroaniline; aminotoluenes; and nitrochlorobenzenes. Least hemotoxic were isomer nitrotoluenes, o-chloro-p-nitroaniline, and isomer nitrochlorobenzenes. Intoxication with aniline, nitrobenzene, p-chloroaniline, m-chloroaniline, and isomer nitrochlorobenzenes most affected porphyrin in metabolism. [R53] *Three nitroanilines and 9 nitroaminophenols were tested for their ability to induce mutations in Salmonella typhimurium strains TA1535, TA100, TA1537, TA1538, and TA98. The compound p-nitroaniline was also inactive in all tests with the possible exception of that in strain TA98 in the presence of S9 mix, where it was either very weakly mutagenic or nonmutagenic. [R54] *The toxic effects of aniline, p-chloroaniline, nitrobenzene (NB), p-nitrochlorobenzene, p-nitroaniline, o-nitroaniline, o-chloroparanitroaniline, p-chloro-o-nitroaniline, o-nitrotoluene, m-nitrotoluene, dinitrotoluene, and trinitrotoluene were investigated on the hemoglobin content of rats. Male white rats were administered 20% of the median lethal dose (LD50) of compounds daily for 30 days; dinitrotoluene and trinitrotoluene were administered as 10% of the LD50. After 5 days, most of the compounds inactivated the respiratory blood pigment. Based on the intensity of methemoglobinemia, compounds were ranked according to their effect from greater to lesser: p-nitroaniline, p-nitrochlorobenzene, p-chloroaniline, aniline, nitrobenzene, aniline, dinitrotoluene. All of the compounds studied with the exception of o-nitrotoluene and o-nitroaniline suppressed the respiratory function of the blood. [R55] *Nineteen nitro compounds, including p-nitroaniline, were evaluated for mutagenicity, using a modification of the standard Salmonella typhimurium mutagenicity assay. A preincubation protocol was used which incorporated flavin mononucleotide (FMN) to facilitate nitro reduction. The mutagenic activity of p-nitroaniline was greater in Salmonella typhimurium TA98 than TA100. In the standard plate test, little or no mutagenicity was detected with or without rat liver S9. p-Nitroaniline was more mutagenic when hamster rather than rat liver S9 was used. The presence of flavin mononucleotide in the S9 mix was a necessary condition for optimal mutagenic activity. [R56] *... Groups of male and female mice were administered the chemical in corn oil by gavage at doses of 0, 10, 30, 100, 300, or 1000 mg/kg bw, 5 days/wk for 2 wk (14-day studies) or 0, 1, 3, 10, 30, or 100 mg/kg day, 5 days/wk for 13 wk (13-wk studies). In the 14-day studies, all mice that received 1000 mg/kg/day died from cmpd-related toxicity by day 4. The hematologic and pathologic findings in the mice receiving p-nitroaniline were characteristic of a process of accelerated erythrocyte destruction associated with methemoglobinemia and Heinz body formation and a physiologic, compensatory reaction to maintain erythrocyte mass. The methemoglobin concentrations of all dosed groups were significantly greater than those of the concurrent controls. The total erythrocyte counts of male and females receiving 100 or 300 mg/kg/day and of females receiving 30 mg/kg/day were significantly reduced compared with the concurrent controls. The reticulocyte counts of male mice receiving 300 mg/kg and of females receiving 100 or 300 mg/kg/day were significantly greater than those of the controls. No gross lesions associated with p-nitroaniline administration were observed. Increased extramedullary hematopoeisis in males and females and in the Heinz bodies as well as increased Kuppfer cell pigmentation were the only histopathologic changes associated with exposure to p-nitroaniline. In the 13-wk studies, there were no deaths associated with exposure to p-nitroaniline. The hematologic finding were consistent with those of the 14-day studies; most of the changes occurred in the 30 and 100 mg/kg/day dose groups. Histopathologic changes associated with administration of p-nitroaniline occurred in the spleen (hematopoiesis and pigmentation), liver (golden-brown pigment in Kuppfer cells of male mice), and bone (bone marrow hyperplasia in male mice but not in females). [R45, 1991.1093] *... Gave p-nitroaniline in corn oil by gavage to rats at doses of 0, 0.25, 1.5, or 9 mg/kg/day for 2 yr. This chronic administration of p-nitroaniline produced statistically significant increases in methemoglobin concentrations and decreased erythrocyte counts at 1.5 and 9 mg/kg/day. None of the doses studied produced either a general increase in tumors or any increase in splenic fibrosarcomas. [R45, 1991.1093] *Following intubation of 30 or 100 mg/kg/day in male mice, an increased incidence of hepatic hemangiosarcomas and an increased incidence of hemangioma or hemangiosarcoma (combined) at all sites were recorded. ... Concluded that there was equivocal evidence for the carcinogenicity of p-nitroaniline in male mice. There was no evidence of carcinogenicity of p-nitroaniline in female mice at any or the doses. [R45, 1991.1094] *... Evaluated the potential reproductive toxicity of oral p-nitroaniline by administering 0, 0.25, 1.5, or 9 mg/kg/day to groups of male and female rats (F0) for 14 wk before mating, during mating, throughout gestation, and during lactation. Rats from the F1 generation were given the same dose levels of p-nitroaniline for 18 wk through lactation; F2 pups were observed through weaning. A slight reduction in the rate of pregnancy was observed in the high-dose F0 group, but no other differences between F0 and F1 groups were observed. [R45, 1991.1094] TCAT: ?The teratogenicity of 4-nitroaniline (NA) was evaluated in pregnant New Zealand White rabbits (18 females/group) orally exposed to NA in corn oil vehicle by gavage at dose levels of 0, 15, 75 or 125 mg/kg/day on gestation days (GD) 7-19. Surviving females were sacrificed on GD 30. No significant differences between treated and control animals were observed in the following: maternal mortality, pregnancy rates, mean maternal body weight change, uterine implantation data, mean percentages of resorptions, live fetuses to implants ratios, maternal spleen weight, mean number of fetuses and fetal weight, number of fetuses with ossification variations, fetal externally visible malformations, fetal skeletal malformations, and most fetal soft tissues examined (see below). Two high-dose group fetuses did not have a gallbladder (11.1% frequency) whereas the reported frequency of gallbladder variations was 0.9% (representing data for 8000 fetuses) and the historical frequency of rabbit fetuses with no gallbladders in the laboratory which performed these tests is 0.1% (representing 3541 fetuses). It is unclear in the report whether this observation was determined to be statistically significant. [R57] ?Teratogenicity was evaluated in pregnant Charles River CD rats (24 mated females/group) orally exposed to 4-nitroaniline (NA) in corn oil vehicle at dose levels of 0, 25, 85 or 250 mg/kg/day on gestation days (GD) 6-19. All females were sacrificed on GD 20. Significant differences between treated and control animals were observed in the following: decreased maternal body weight gain (high-dose group), increased incidence of yellow staining of the fur (mid- and high-dose groups), increased mean number of resorptions and percentage of resorptions to implants (high-dose group), increased absolute and relative maternal spleen weights and frequency of spleen lesions, including dark coloration and/or pitted surface (mid- and high dose groups), decreased mean fetal weights of both sexes (mid- and high dose groups), increased incidence of fetal ossification variations (high-dose group), and increased incidence of fetuses with external, soft tissue or skeletal malformations (high-dose group; predominant effects included kinked or shortened tails, absence of kidney or ureter, and fused ribs). No significant difference between treated and control animals was observed with respect to maternal mortality. [R58] ?p-Nitroaniline was examined for mutagenic activity in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without Aroclor-induced rat liver S9 fraction metabolic activation. In plate incorporation assays, significant ( Bartletts and Students-T tests, p < 0.01 ) mutagenic activity was observed at test article concentrations of 1.5, 3, 4, and 5 mg/plate in the absence of activation. In the presence of activation, a mutagenic effect was observed at p-Nitroaniline concentrations of 1 and 3 mg/plate, however, statistical evaluation of results showed significance only at the p < 0.03 level. The test article was reported not to elicit toxicity to tester strain TA100 at levels up to and including 10 mg/ml, which was the highest dose tested. In spot tests using tester strains TA100, TA1535, TA1537, or TA98, p-nitroaniline was not mutagenic in the presence or absence of Aroclor-induced rat liver, or CD-1 strain mouse liver S9 fraction metabolic activation. [R59] ?The frequency of mutations at the HGPRT locus was determined in Chinese Hamster Ovary cells exposed to concentrations of 62.5, 125, 250, 500 and 750 ug/ml p-nitroaniline in the absence and presence of Aroclor-induced rat liver S9 fraction metabolic activation. In an initial assay, a slight but statistically significant ( Snee and Irr, p < = 0.01 ) increase in mutation frequency was observed at the 62.5 and 500 ug/ml level with activation, and at the 62.5 ug/ml level without activation, however, dose response was not observed. The experiment was repeated and no significant mutagenic effects were observed in the presence or absence of activation. In a preliminary cytotoxicity screen, p-nitroaniline was reported to cause 100% cell death at concentrations of 1000 ug/ml with activation, while 13.2% relative survival was observed at this concentration without activation. [R60] ?The frequency of forward mutations was determined at the thymidine kinase (TK) locus of the mouse lymphoma L5178Y cell line exposed in vitro to p-nitroaniline with and without the presence of Aroclor induced rat liver S9 metabolic activation. A significant ( Students T-test, p < 0.01 ) mutagenic response was observed in cells exposed to concentrations ranging from 5 to 50 ug/ml in the presence of activation, while exposure to 100 and 200 ug/ml was excessively cytotoxic. In the absence of activation, p-nitroaniline was tested at concentrations ranging from 200 to 800 ug/ml and a significant mutagenic effect was observed at the 650 and 700 ug/ml concentrations, while 800 ug/ml proved excessively cytotoxic. Differential toxicity of the test article in the presence and absence of rat liver S9 was also reported in preliminary range finding assays. [R61] ?The effect of 4-nitroaniline was examined in the rat hepatocyte primary culture/DNA repair assay. Fischer F344 rat liver hepatocytes were exposed to concentrations of test article ranging from 0.1665 to 5,000 ug/ml for 18 to 20 hours. Net grain counts greater than 5 were observed at concentrations of 1.665 and 5 ug/ml, however, the effect was not dose related. 4-Nitroaniline was observed to be toxic to cells at concentrations of 500 ug/ml and higher during the test. [R62] ?The fate of 14-C-4-nitroaniline (14C-NA) was studied in male and female Sprague-Dawley rats (3/sex) exposed by gavage to a dose level of 6.10-7.76 mg/kg (14C-NA). Urine, feces, and expired air were collected at intervals of 0-8, 8-16, 16-24, 24-48, and 48-72 hrs following dosing. Animals were sacrificed at 72 hrs following dosing. The majority of the 14C-activity was found in the urine (98.24-97.96% of the dose) and most of this was excreted in the 0-8 hr period. The amount of 14-activity found in the feces ranged from 3.78-5.83% of the dose. The total amount of 14C-activity found in the expired air ranged from 0.01-0.07% of the dose. The tissues were not analyzed for 14C-activity at necropsy since the entire dose was excreted in the urine and feces. [R63] ADE: *It is absorbed through the skin. [R9, 2468] *... ABSORBED ... BY INHALATION OF DUST OR VAPOR. [R64] *The disposition of 14(C)-labeled p-nitroaniline was studied in male rats following oral or iv admin. The clearance of 14(C) p-nitroaniline-derived radioactivity from various tissues was rapid and followed a 2-component decay curve. The whole-body half-life of p-nitroaniline was approximately 1 hr. Within 3 days, clearance of p-nitroaniline-derived radioactivity from the body was almost complete. 14(C) p-nitroaniline was rapidly cleared by metabolism to 9 metabolites which were excreted primarily in the urine and to a lesser extent in the feces. Most (56%) of the urinary radioactivity was in the form of sulfate conjugates of 2 metabolites of p-nitroaniline. [R65] *The percutaneous absorption of nitrobenzene, p-nitroaniline, 2,4-dinitrochlorobenzene, 2-nitro-p-phenylenediamine, and 4-amino-2-nitrophenol was studied in vivo and in vitro. The compounds were applied to shaved abdominal skins of Rhesus-monkeys at a concentration of 4 ug/sq cm. Five day urine samples were collected and analyzed for the compounds. Radiolabeled nitrobenzene, p-nitroaniline, 2-4-dinitrochlorobenzene, 2-nitro-p-phenylenediamine, or 4-amino-2-nitrophenol were applied to excised human skin at a dose of 4 ug/sq cm using a diffusion cell technique. Penetration of radioactivity through the skin was monitored for the next 24 hours. The compounds rapidly penetrated excised human skin, the greatest penetration occurring in the first 2 hours after exposure. The ability of the compounds to penetrate human skin ranked in decreasing order of permeability and corrected for evaporation was 4-amino-2-nitrophenol, nitrobenzene, p-nitroaniline, 2,4-dinitrochlorobenzene, and 2-nitro-p-phenylenediamine. The corresponding rank for penetration of monkey skin was 4-amino-2-nitrophenol, p-nitroaniline, 2,4-dinitrochlorobenzene, 2-nitro-p-phenylenediamine, and nitrobenzene. [R66] METB: *GIVEN ORALLY OR IP IN DOSES OF 20-40 MG/KG IN RATS, ANALYSIS OF 24-HR URINE SAMPLES SHOWED THAT 4-NITROANILINE WAS EXCRETED PARTLY UNCHANGED AND ALSO AS 4-PHENYLENEDIAMINE AND 2-AMINO-5-NITROPHENOL. [R67] *The principal rat liver microsomal metabolite of 4-nitroaniline was isolated by high performance liquid chromatography and characterized as 2-amino-5-nitrophenol. Pretreatment of rats with phenobarbital and 3-methylcholanthrene increased the rate of conversion of 4-nitroaniline to 2-amino-5-nitrophenol by 2- and 4-fold, respectively. [R68] *14(C) labeled m-dinitrobenzene was administered to rabbits in oral doses or by subdermal injection of 50 to 100 mg/kg. Within 2 days, 65 to 93 percent of 14(C)-dinitrobenzene was excreted in urine and 1 to 5 percent was excreted in feces. The major metabolites found in urine were m-nitroaniline and m-phenylenediamine, which comprised 35 percent of the m-dinitrobenzene dose, and 2,4-diaminophenol and 2-amino-4-nitrophenol, with 31 and 14 percent of the dose, respectively. Only trace amounts of 2,4-dinitrophenol were found in urine. The remaining metabolites were: 4-amino-2-nitrophenol, m-nitrophenylhydroxylamine, and unchanged m-dinitrobenzene. Subcutaneous administration of m-dinitrobenzene did not lessen the amounts of reduction products appearing in the urine, indicating that reduction was not caused by intestinal bacteria. [R69] *The metabolism of radiolabeled dinitrobenzene isomers was compared in hepatocytes and hepatic subcellular fractions isolated from male rats. Under aerobic conditions, reduction was the major metabolic pathway for m-dinitrobenzene and p-dinitrobenzene in hepatocytes with m-nitroaniline and p-nitroaniline accounting for 74.0 and 81.0% respectively, of the radioactivity present after a 30-minute incubation. The major metabolite of o-nitrobenzene in similar incubations was S-(2-nitrophenyl)glutathione which represented 48.1% of the total radioactivity. o-Nitroaniline accounted for 29.5% of the radioactivity. [R70] *P-NITROANILINE WAS FOUND IN LIVER IN A CASE OF HUMAN POISONING WITH ... RODENTICIDE VACOR 1-(3-PYRIDYLMETHYL)-3-(4-NITROPHENYL)UREA. [R71] BHL: *The whole-body half-life of p-nitroaniline was approximately 1 hr. [R65] ACTN: *THE RELATIVE MUTAGENIC ACTIVITIES OF AMINOANILINES HAVE BEEN ATTEMPTED TO BE RELATED TO PARAMETERS REFLECTING POTENTIAL FOR N-HYDROXYLATION AND STABILITY OF THE ARYLNITRENIUM IONS. BOTH CHLORO AND THE NITRO GROUPS DEACTIVATE THE AMINE GROUP TO N-HYDROXYLATION AND THE RING TO EPOXIDATION, AND NO ACTIVE PRODUCTS FROM CYTOCHROME P450 WOULD BE PREDICTED. THE ACTIVITY OF THE NITRO DERIVATIVES IS PRESUMED TO BE DUE TO TRANSFORMATION OF THE NITRO GROUP ITSELF TO AN ACTIVE MUTAGENIC SPECIES BY OTHER ENZYME SYSTEMS. /AMINOANILINES/ [R72] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +MEDICATION (VET): IN VET MEDICINE FOR POULTRY [R1] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4-Nitroaniline may be released to the environment from process and waste emissions involved in its production or use as a chemical intermediate and through stack emissions from hazardous waste incineration. 4-Nitroaniline has been detected in various samples of Rhine River water, wastewater effluent, incinerator stack effluent, and in waste landfill leachate. If released to soil, 4-nitroaniline will undergo a covalent chemical bonding with humic materials which can result in its chemical alteration to a latent form and prevent leaching. However, based on experimental and estimated Koc values, 4-nitroaniline has high to very high soil mobility. Photodegradation may occur on soil surfaces exposed to sunlight. Based on its Henry's Law constant and its vapor pressure, 4-nitroaniline is not expected to volatilize from moist or dry soils. If released to water, 4-nitroaniline will covalently bind with humic materials in the water column and sediments. Photodegradation in the aquatic environment may be possible. Aquatic hydrolysis, volatilization, and bioconcentration are not environmentally important. Various biological screening tests suggest that 4-nitroaniline is generally resistant to biodegradation. If released to the atmosphere, 4-nitroaniline will react rapidly (estimated half-life of 1.2 days) with sunlight-produced hydroxyl radicals. Humans will be primarily exposed to 4-nitroaniline by dermal contact or inhalation in occupational settings. (SRC) ARTS: *4-Nitroaniline may be released to the environment as fugitive emissions or in wastewater from its production or use as a chemical intermediate. It may also be emitted to the environment in stack effluents from hazardous waste incineration(SRC). 4-Nitroaniline has been detected in various samples of Rhine River water(1), wastewater effluent(2), incinerator stack effluent(3), and in waste landfill leachate(4). [R73] *... P-NITROANILINE /FOUND/ IN SOME SAMPLES OF WAX CRAYONS ... . [R74] FATE: *TERRESTRIAL FATE: When released to soil, 4-nitroaniline will undergo a covalent chemical binding with humic materials which can result in its chemical alteration to a latent form and tight adsorption(1). When covalently bound in this latent form, significant leaching in soil systems is not generally expected to occur(1). This covalent bonding proceeds in two steps; a rapid and reversible binding followed by a slower and much less reversible reaction(1). Leaching in soil may be possible prior to the occurrence of the slower binding reaction(1). Based on experimental and estimated Koc values of 52 to 117(2-6), 4-nitroaniline has high to very high soil mobility(7). 4-Nitroaniline on soil surfaces exposed to sunlight may be susceptible to photodegradation(8). Various biological screening tests suggest that 4-nitroaniline is generally resistant to biodegradation(9-17). 4-Nitroaniline is not expected to volatilize from moist or dry soils(SRC). [R75] *AQUATIC FATE: The half-life of 4-nitroaniline in the water column of the Rhine River has been estimated to be 3.8 days based on water monitoring data collected near Lobith Netherlands(1). If released to water, 4-nitroaniline will undergo chemical bonding with humic materials and clay in the water column and in the sediment(2). 4-Nitroaniline near the water surface may be susceptible to degradation by direct photolysis and photooxidation(3). Various biological screening tests suggest that 4-nitroaniline is generally resistant to biodegradation(4-12). Aquatic hydrolysis, volatilization, and bioconcentration are not environmentally important, based upon the lack of hydrolyzable functional groups, low Henry's Law constant, and high water solubility(13,SRC). [R76] *ATMOSPHERIC FATE: If released to the ambient atmosphere, 4-nitroaniline will exist primarily in the vapor phase, although a minor fraction can be expected to partition to atmospheric particulates, based on its extrapolated vapor pressure of 3.2X10-6 mm Hg at 20 deg C(1,SRC). Vapor-phase reaction with sunlight-produced hydroxyl radicals (estimated half-life of 1.2 days) should rapidly remove 4-nitroaniline from the atmosphere(2). Direct photolysis may also contribute to its atmospheric transformation(SRC). Physical removal of particulates containing adsorbed 4-nitroaniline may be accomplished via dry and wet deposition(SRC). [R77] BIOD: *P-NITROANILINE AT CONCN 250-1000 MG/L WAS DEGRADED BY A MIXT OF PSEUDOMONAS FLUORESCENS AND BACILLUS VALINOVORUS. [R78] *CANDIDA WERE USED FOR THE DESTRUCTION OF P-NITROANILINE IN WASTEWATERS OF THE ANILINE-DYE INDUSTRY. [R79] *BACTERIA OF THE GENERA PSEUDOMONAS AND BACILLUS, ACTIVELY DECOMPOSING P-NITROANILINE, WERE ISOLATED FROM THE BIOFILM ADAPTED TO P-NITROANILINE AND THE ACTIVATED SLUDGE (A LABORATORY MODEL OF THE BIOLOGICAL CONSTRUCTION). [R80] *The mono-nitroanilines were found to be markedly more resistant to biological degradation, as compared to aniline, using Warburg respirometer procedures(1). 4-Nitroaniline was determined to be non-biodegradable using the Japanese MITI protocol(2). No biodegradation of 4-nitroaniline was observed at concn of 25-30 ppm upon incubation with adapted activated sludge for 20 days(3). Degradation of 4-nitroaniline in a mineral salts solution, with a soil inoculum, was in excess of 64 days(4). No biodegradation occurred over a 240 hr period in an electrolytic respirometer study(5). Only limited biooxidation of 4-nitroaniline was observed in respirometric tests utilizing phenol-adapted bacteria(6). [R81] *In a 2-week closed bottle biodegradation study, using 100 mg/L 4-nitroaniline and 30 mg/L sludge, 4-nitroaniline had a theoretical BOD of 0 percent(1). Using a concentration of 50 mg/L, para-nitroaniline was biodegraded in an aerobic sewage seed samples after a lag period of about 20 days(2). [R82] *A strain of Pseudomonas, isolated from soil, grew slowly on p-nitroaniline as a sole source of carbon. o-Nitroaniline was not degradable as sole sources of carbon. [R83] ABIO: *Aromatic amines and nitro compounds are generally resistant to environmental hydrolysis(1); the mono-nitroanilines are not expected to hydrolyze significantly under natural aquatic conditions(2). The mono-nitroanilines absorb sunlight above 290 nm and have been shown to photodegrade when irradiated with sunlight; however, sufficient kinetic rate data are not available to predict direct photolysis rates in the natural environment(2). The half-life for the vapor-phase reaction of 4-nitroaniline with sunlight produced hydroxyl radicals in a typical ambient atmosphere has been estimated to be about 1.2 days based on an estimated reaction rate constant of 1.3X10-11 cu cm/molecule-sec at 25 deg C(3). The reaction of 4- nitroaniline, for example, with manganese dioxide may represent a pathway for transformation of aniline and other primary amines in acidic mineralogical and soil/water environments in the absence of oxygen and substantial microbial activity(4). However, p-nitroaniline was found to be particularly unreactive towards manganese dioxide(4). After a reaction period of 12 hours, there was only 5% disappearance of the compound at pH 4 and the experimental rate constant was ~0.01 L/mol minute(4). [R84] BIOC: *Based on a log Kow of 1.39(1), the log bioconcentration factor for 4-nitroaniline can be estimated to be 0.83 from a recommended regression- derived equation(2). Based on an experimental water solubility of 728 mg/L(3), the BCF of 4-nitroaniline can also be estimated to be 15 from a regression derived equation(2). In a 6-week bioconcentration test, the BCF factor of 4-nitroaniline was 2.9-3.6 at a concentration of 0.5 mg/L and < 10 at a concentration of 0.05 mg/L(4). 4-Nitroaniline was found to have no or low bioaccumulation potential in carp (fish) during laboratory studies(5). In a bioconcentration study using zebrafish and a 4-nitroaniline concentration of 0.21 umol/L, the BCF was measured to be 4.4(6). These experimental and estimated BCF factors suggest that bioconcentration in aquatic organisms may not be an important fate process(SRC). [R85] KOC: *Soil adsorption studies using four silt loam soils and a 2-hour adsorption period determined a mean log Kom of 1.49 (which corresponds to a Koc of 53.7) for 4-nitroaniline(1). Another study cites the log Kom of 4-nitroaniline as 1.64 which corresponds to a Koc value of 75.2(2). Koc values for 4-nitroaniline have been observed to be 87 and estimated to be 75.9(3). Using a structure estimation method based on molecular connectivity indexes, the Koc for 4-nitroaniline can be estimated to be approximately 52(4). The Koc has also been estimated to be approximately 117 based on an experimental water solubility of 728 mg/L(5) and a regression derived equation(6). According to a suggested classification scheme(7), these experimental and estimated Koc values suggest that 4-nitroaniline has high to very high soil mobility. Aromatic anilines have been observed to undergo rapid and reversible covalent bonding with humic materials in aqueous solution; the initial binding reaction is followed by a slower and much less reversible reaction believed to represent the addition of the amine to quinoidal structures followed by oxidation of the product to give an amino-substituted quinone; these processes represent pathways by which aromatic amines may be converted to latent forms in the biosphere(8). [R86] VWS: *The Henry's Law constant for 4-nitroaniline can be estimated to be 1.81X10-8 atm cu meter/mole using a structure estimation method(1). This value of Henry's Law constant indicates that 4-nitroaniline is essentially non-volatile from water(2). [R87] WATC: *SURFACE WATER: 4-Nitroaniline was detected at a concn of 1 ppb in water from the Rhine River in the Netherlands, but was not detected in associated tapwater(1). A concentration of 1 ppb 4-nitroaniline was identified in water taken from the Rhine River near Lobith, Netherlands(2). 4-Nitroaniline was detected at several locations in Rhine River water at concentrations of 0.018 to 0.261 ug/L(3). [R88] EFFL: *Raw wastewater collected from a US dye manufacturing plant on the Black River, South Carolina in July 1976 contained 270 ppb nitroaniline (isomers unspecified); the final treated effluent contained no detectable levels of nitroaniline(1). 4-Nitroaniline was qualitatively detected in a stack effluent from a hazardous waste incinerator(2). 4-Nitroaniline has been detected in waste landfill leachates from various locations throughout the United States, however, concentrations were not given(3). 4-Nitroaniline was tested for in tire leachate water but not detected at a detection limit of 1.0 ug/L(4). [R89] RTEX: *Humans will be primarily exposed to 4-nitroaniline by dermal contact or inhalation in occupational settings. (SRC) *2813 Workers are potentially exposed to 4-nitroaniline based on statistical estimates derived from the NIOSH survey conducted between 1972-74 in the USA(1). 1448 Workers are potentially exposed to 4-nitroaniline based on statistical estimates derived from the NIOSH survey conducted between 1981-83 in the USA(2). [R90] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +300 mg/cu m [R34, 226] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 1 ppm (6 mg/cu m). Skin Designation. [R91] +Vacated 1989 OSHA PEL TWA 3 mg/cu m, skin designation, is still enforced in some states. [R34, 368] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 3 mg/cu m (skin). [R34, 226] TLV: +8 hr Time Weighted Avg (TWA): 3 mg/cu m, skin. [R44, 2002.44] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R44, 2002.6] +A4; Not classifiable as a human carcinogen. [R44, 2002.44] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R44, 2002.91] OOPL: *The Soviet limit is 0.1 mg/cu m ... West Germany adopted the 6 mg/cu m value as its MAK. [R74] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). These standards implement Section 111 of the Clean Air Act and are based on the Administrator's determination that emissions from the SOCMI cause, or contribute significantly to, air pollution which may reasonably be anticipated to endanger public health or welfare. The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. p-Nitroaniline is produced, as an intermediate or final product, by process units covered under this subpart. These standards of performance become effective upon promulgation but apply to affected facilities for which construction or modification commenced after January 5, 1981. [R92] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R93] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R94] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Benzenamine, 4-nitro, is included on this list. [R95] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Nitroaniline is included on this list. [R95] RCRA: *P077; As stipulated in 40 CFR 261.33, when p-Nitroaniline, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R96] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A known volume of air is drawn through a tube containing silica gel to trap the aromatic amines present. [R97, p. V1 168-1] ALAB: *A KNOWN VOLUME OF AIR IS DRAWN THROUGH A MIXED CELLULOSE ESTER MEMBRANE FILTER TO TRAP P-NITROANILINE AEROSOL. THIS METHOD IS NOT APPLICABLE FOR SAMPLING ENVIRONMENTS WHERE SIGNIFICANT P-NITROANILINE VAPOR MAY BE PRESENT. THE FILTER IS TRANSFERRED TO A SAMPLE JAR AND EXTRACTED IN 5 ML OF ISOPROPANOL. AN ALIQUOT IS INJECTED INTO A HIGH PERFORMANCE LIQUID CHROMATOGRAPH EQUIPPED WITH A VARIABLE WAVELENGTH UV DETECTOR SET AT 375 NM. THE METHOD WAS VALIDATED OVER RANGE OF 3.90 TO 12.88 MG/CU M AT ATMOSPHERIC TEMP AND PRESSURE OF 25 DEG C AND 762.5 MM HG, USING A 90-L SAMPLE. THE METHOD MAY BE EXTENDED TO HIGHER VALUES BY FURTHER DIL OF SAMPLE SOLN. THE DETECTION LIMIT IS EST TO BE AT LEAST 10 UG/ML. PRECISION IS 0.054. [R97, p. V5 S7-1] *A KNOWN VOL OF AIR IS DRAWN THROUGH A TUBE CONTAINING SILICA GEL TO TRAP THE AROMATIC AMINES PRESENT. THE SILICA GEL IS TRANSFERRED TO A GLASS-STOPPERED TUBE AND TREATED WITH ETHANOL. AN ALIQUOT OF DESORBED AROMATIC AMINES IN ETHANOL IS INJECTED INTO A GAS CHROMATOGRAPH. PEAK AREAS ARE DETERMINED AND COMPARED WITH CALIBRATION CURVES OBTAINED FROM THE INJECTION OF STANDARDS. THE LOWER LIMIT OF THIS METHOD USING A FLAME IONIZATION DETECTOR IS 0.01 MG/SAMPLE OF ANY ONE OF THE CMPD WHEN THE SAMPLE IS DESORBED WITH 5 ML ETHANOL AND A 10-UL ALIQUOT IS INJECTED INTO THE GAS CHROMATOGRAPH. SENSITIVITY FOR P-NITROANILINE IS 5 TIMES LESS. THE UPPERLIMIT IS AT LEAST 14 MG/SAMPLE. /AROMATIC AMINES IN AIR/ [R97, p. V1 168-1] *AIRBORNE VAPORS OF P-NITROANILINE ARE IDENTIFIED BY GAS CHROMATOGRAPHY USING A SILICONE OV-25 COLUMN. [R98] *Determination of p- and o-nitroanilines in wastewater by two-wavelength spectrophotometric method was discussed. [R99] *Method 8270: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Capillary Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride, including the title compound, and are capable of being eluted without derivatization as sharp peaks from a 30 m by 0.25 mm ID (or 0.32 mm ID) 1 um film thickness silicon-coated fused silica capillary column (J and W Scientific DB-5 or equivalent)]. A representative sample is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Under the prescribed conditions, 4-Nitroaniline has a retention time of 16.90 min. [R100] *NIOSH Method 5033, p-Nitroaniline; HPLC with UV Detection, Estimated LOD = 20 ug/sample [R101] CLAB: *IDENTIFICATION OF P-NITROANILINE IN HUMAN LIVER TISSUE IS PERFORMED BY DIFFERENTIAL PULSE POLAROGRAPHY. [R102] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Rickert DE; Toxicity of Nitroaromatic Compounds 1-295 Hemisphere Publising Corp (1985). Papers presented in 1982, cover: occurrence and uses of nitroaromatic compounds in industry; carcinogenicity, mutagenicity and teratogenicity of the compounds; interaction of the compounds with DNA; sex, strain and species differences in rodent response to nitrobenzene; mammalian and bacterial metabolism of nitroaromatics; skin penetration; absence fo reduced fertility among chemical plant workers exposed to dinitrotoluene and toluene G diamine; subclinical effects of trinitrotoluene; risk assessment. Santodonato J et al; Monographs on Human Exposure to Chemicals in the Workplace: Nitroanilines 1-26 (1985). This report summarizes and evaluates toxicologic information relevant to an occupational hazard assessment of nitroanilines, including chemical and physical properties, production and use, extent of occupational exposure, pharmacokinetics, animal carcinogenicity and mutagenicity, and epidemiological studies. DHHS/NTP; Toxicology and Carcinogenesis Studies of p-Nitroaniline in B6C3F1 Mice (Gavage Studies) Technical Report Series No. 418 (1993) NIH Publication No. 93-3149 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1042 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 780 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V17 840 (1982) R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V8 305 R7: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.491 R8: USITC. IMPORTS OF BENZENOID CHEM AND PROD 1983 p.23 R9: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 226 R11: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R12: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R13: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 67th ed. Boca Raton, FL: CRC Press, Inc., 1986-87. R14: Bintein S, Devillers J; Chemosphere 28: 1171-88 (1994) R15: Larson RA et al; Environ Toxicol Chem 8: 1165-70 (1989) R16: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R17: Bintein S, Devillers J; Chemosphere 28:1171-88 (1994) R18: Hashimoto Y et al; Chemosphere 11: 991-1003 (1982) R19: Suzuki T; J Computer-Aided Molecular Design 5: 149-66 (1991) R20: Yalkowski SH, Dannenfelser RM; AQUASOL DATABASE of Aqueous Solubility. 5th ed. Tucson, AZ Univ of Arizona, College of Pharmacy (1990) R21: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 2156 R22: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-117 R23: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 83 R24: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 325M-74 R25: Dixon D, Rissmann E; Physical-Chemical Properties and Categorization of RCRA Wastes According to Volatility. Springfield, VA: Versar, Inc. pp 129 USEPA-450/3-85-007 (1985) R26: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2007 R27: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R28: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R29: DANGER PROPS INDUS MATER 8TH ED 1992 R30: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R31: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R32: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R33: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 945 R34: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R35: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2424 R36: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 367 R37: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 769 R38: 49 CFR 171.2 (7/1/96) R39: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 184 R40: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6183 (1988) R41: ROTMISTROV MN ET AL; BIOCHEMICAL REMOVAL OF P-NITROANILINE FROM WASTE WATERS; USSR PATENT NO 467037 04/15/75 (INSTITUTE OF COLLOIDAL AND WATER CHEMISTRY, ACADEMY OF SCIENCES, UKRAINIAN SSR) R42: 40 CFR 240-280, 300-306, 702-799 (7/1/92) R43: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-9 (1981) EPA 68-03-3025 R44: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R45: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R46: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R47: VASILENKO NM, ZVEZDAI VI; FIZIOL PATOL OBMENA PORFIRINOV GEMA, MATER SIMP 1ST: 60-3 (1974) R48: Malca-Mor L, Stark AA; Appl Environ Microbiol 44 (4): 801-8 (1982) R49: Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987) R50: Nair RS et al; Toxicity of Nitroaromatic Compounds 61-85 (1985) R51: Nair RS et al; Fundam Appl Toxicol 6 (4): 618-27 (1986) R52: Corbett MD et al; Carcinog 6 (5): 727-32 (1985) R53: Vasilenko NM, Zvezdai VI; Fiziol Patol Obmena Porfirinov Gema Mater Simp 60-3 (1974) R54: Shahin MM; Imt J Cosmet 7 (6): 277-89 (1985) R55: Vasilenko NM et al; Sovremennye Problemy Biokhim Dykhaniza Klin Mater Voes Konf 1: 411-3 (1972) R56: Dellarco VL, Prival MJ; Environ Mol Mutagen 13 (2): 116-27 (1989) R57: Bio/dynamics Inc.; A Teratogenicity Study in Rabbits with p-Nitroaniline, Final Report. (1982)), EPA Document No. 878211841, Fiche No. OTS0206222 R58: Bio/dynamics Inc.; A Teratogenicity Study with p-Nitroaniline in Rats, Final Report. (1980), EPA Document No. 878211846, Fiche No. OTS0206222 R59: Monsanto Co.; Salmonella Mutagenicity Assay of p-Nitroaniline, DA-79-257 (1980), EPA Document No. 878211039, Fiche No. OTS0206222 R60: Pharmakon Research International, Inc.; CHO/HGPRT Mammalian Cell Forward Gene Mutation Assay (1984), EPA Document No. 878214479, Fiche No. OTS0206580 R61: Stanford Research Institute International; An Evaluation of Mutagenic Potential of p-Nitroaniline Employing the L5178Y TK +/- Mouse Lymphoma Assay (1982), EPA Document No. 878211853, Fiche No. OTS0206222 R62: Pharmakon Research Intl, Inc.; Rat Hepatocyte Primary Culture/DNA Repair Test (1983), EPA Document No. 878214478, Fiche No. OTS0206580 R63: Bio/Dynamics Inc.; Absorption, Distribution and Elimination of 14C-Labeled p-Nitroaniline in the Rat. (1980), EPA Document No. 878211843, Fiche No. OTS0206222 R64: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 145 R65: Chopade HM, Matthews HB; Fundam Appl Toxicol 4 (3): 485-93 (1984) R66: Bronaugh RL, Maibach HI; Toxicity of Nitroaromatic Compounds 141-8 (1985) R67: MATE C ET AL; FOOD COSMET TOXICOL 5 (5): 657-63 (1967) R68: Anderson MM et al; Drug Metab Dispos 12 (2): 179-85 (1984) R69: Parke DV; Biochem J 78: 262-71 (1981) R70: Cossum PA, Rickert DE; Drug Metab Dispos 13 (6): 664-8 (1985) R71: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 438 R72: LOEW GH ET AL; J ENVIRON PATHOL TOXICOL 2 (4): 1069-78 (1979) R73: (1) Hendricks AJ et al; Wat Res 28: 581-98 (1994) (2) Games LM, Hites RA; Anal Chem 49: 1433-40 (1977) (3) James RH et al; J Air POllut Contol Assoc 35: 959-69 (1985) (4) Brown KW, Donnelly KC; Haz Waste Haz Mat 5: 1-26 (1988) R74: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.430 R75: (1) Parris GE; Environ Sci Technol 14: 1099-106 (1980) (2) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (3) Sabljic A; Environ Sci Tech 21: 358-66 (1987) (4) Bahnick DA, Doucette WJ; Chemosphere 17: 1703-15 (1988) (5) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (6) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (7) Swann RL et al; Res Rev 85: 17-28 (1983) (8) USEPA; Health and Environmental Effects Document for Nitroanilines (o-, m-, p-) ECAO-CIN-P114 (Final Draft) p.7 (1985) (9) Malaney GW; J Water Pollut Control Fed 32: 1300-11 (1960) (10) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances; OECD Tokyo Meeting, Reference Book TSU-No. 3 (1978) (11) Pitter P; Water Res 10: 231-5 (1976) (12) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1960) (13) Urano K, Kato Z; J Haz Mat 13: 147-59 (1986) (14) Chambers CW et al; J Water Pollut Control Fed 35: 1517-28 (1963) (15) Chemical Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center (1992) (16) Klopman G et al; J Chem Inf Comput Sci 32: 474-82 (1992) (17) Young JC, Affleck SB; Eng Bull Purdue Univ, Eng Ext Ser 1: 154-64 (1974) R76: (1) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) (2) Parris GE; Environ Sci Technol 14:1099-1106) (3) USEPA; Health and Environmental Effects Document for Nitroanilines (o-, m-, p-) ECAO-CIN-P114 (Final Draft) p.7 (1985) (4) Malaney GW; J Water Pollut Control Fed 32: 1300-11 (1960) (5) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances; OECD Tokyo Meeting, Reference Book TSU-No. 3 (1978) (6) Pitter P; Water Res 10: 231-5 (1976) (7) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1960) (8) Urano K, Kato Z; J Hazard Materials 13: 147-59 (1986) (9) Chambers CW et al; J Water Pollut Control Fed 35: 1517-28 (1963) (10) Chemical Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center (1992) (11) Klopman G et al; J Chem Inf Comput Sci 32: 474-482 (1992) (12) Young JC, Affleck SB; Eng Bull Purdue Univ, Eng Ext Ser 1: 154-64 (1974) (13) Lyman WJ et al; Handbook of Chemical Estimation Methods. Washington,DC: Amer Chem Soc (1990) R77: (1) Ferro D, Piacente V; Thermochimica Acta 90: 387-9 (1985) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R78: UDOD VM, PODORVAN NI; NAUCHN OSN TEKHNOL OBRAB VODY 2: 151-2 (1975) R79: UDOD VM, PODORVAN NI; NAUCHN OSN TEKHNOL OBRAB VODY 2: 145-7 (1975) R80: UDOD VM ET AL; MIKROBIOLOGIYA 41 (2): 213-6 (1972) R81: (1) Malaney GW; J Water Pollut Control Fed 32: 1300-11 (1960) (2) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances; OECD Tokyo Meeting, Reference Book TSU-No. 3 (1978) (3) Pitter P; Water Res 10: 231-5 (1976) (4) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1960) (5) Urano K, Kato Z; J Hazard Materials 13: 147-59 (1986) (6) Chambers CW et al; J Water Pollut Control Fed 35: 1517-28 (1963) R82: (1) Chemical Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN (1992) (2) Young JC, Affleck SB; Eng Bull Purdue Univ, Eng Ext Ser 1: 154-64 (1974) R83: Zeyer J, Kearney PC; J Agric Food Chem 31 (2): 304-8 (1983) R84: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p.7-4 (1982) (2) USEPA; Health and Environmental Effects Document for Nitroanilines (o-,m-,p-) ECAO-CIN-P114 (Final Draft) p.7 (1985) (3) Meylan WM, Howard PH; Chemosphere 26:2293-9 (1993) (4) Laha S, Luthy RG; Environ Sci Technol 24: 363-373 (1990) R85: (1) Hansch C, Leo AJ; Medchem Project Issue No. 26 Pomona College, Claremont CA (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw-Hill p.5-4, 5-10 (1982) (3) Gross PM, Saylor JH; J Amer Chem Soc 53: 1744-51 (1931) (4) Chemical Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center (1992) (5) Sasaki S; p 283-98 in Aquatic Pollutants: Transformation and Biological Effects; Hutzinger O et al eds Oxford: Peragamon Press (1978) (6) Kalsch W et al; Chemosphere 22: 351-363 (1991) R86: (1) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (2) Sabljic A; Environ Sci Tech 21: 358-66 (1987) (3) Bahnick DA, Doucette WJ; Chemosphere 17: 1703-15 (1988) (4) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (5) Gross PM, Saylor JH; J Am Chem Soc 53: 1744-51 (1931) (6) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (7) Swann RL et al; Residue Reviews 85: 17-28 (1983) (8) Parris GE; Environ Sci Technol 14: 1099-106 (1980) R87: (1) Meylan WM, Howard PH: Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc p 15-15 to 15-29 (1990) R88: (1) Piet GH, Morra CF; p.31-42 in Artificial Groundwater Recharge; Huisman L and Olsthorn TN eds, Pitman Pub (1983) (2) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) (3) Hendricks AJ et al; Wat Res 28: 581-598 (1994) R89: (1) Games LM, Hites RA; Anal Chem 49: 1433-40 (1977) (2) James RH et al; J Air Pollut Control Assoc 35: 959-69 (1985) (3) Brown KW, Donnelly KC; Hazardous Waste and Hazardous Materials 5: 1-26 (1988) (4) Nelson SM et al; Bull Environ Contam Toxicol 52: 574-581 (1994) R90: (1) NIOSH; National Occupational Hazard Survey (1974) (2) NIOSH; National Occupational Exposure Survey (1983) R91: 29 CFR 1910.1000 (7/1/98) R92: 40 CFR 60.489 (7/1/94) R93: 40 CFR 302.4 (7/1/94) R94: 40 CFR 712.30 (7/1/94) R95: 40 CFR 716.120 (7/1/94) R96: 40 CFR 261.33 (7/1/94) R97: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R98: WOOD GO, ANDERSON RG; J AM IND HYG ASSOC 36 (7): 538-48 (1975) R99: Wang S, Chen J; Huanjing Kexue 3 (4): 50-2 (1982) R100: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R101: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R102: OSTERYOUNG JG ET AL; FATE PEST LARGE ANIM (SYMP CENT MEET ACS): 253-65 (1977) RS: 82 Record 115 of 1119 in HSDB (through 2003/06) AN: 1157 UD: 200302 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-NITROPHENOL- SY: *P-HYDROXYNITROBENZENE-; *4-HYDROXYNITROBENZENE-; *NCI-C55992-; *NIPHEN-; *4-NITROFENOL- (DUTCH); *P-NITROPHENOL-; *PARANITROFENOL- (DUTCH); *PARANITROFENOLO- (ITALIAN); *PARANITROPHENOL-; *PHENOL,-P-NITRO-; *PHENOL,-4-NITRO-; *PNP- RN: 100-02-7 RELT: 6296 [NITROPHENOLS] (Mixture); 2592 [P-NITROPHENOL SODIUM SALT] (Analog) MF: +C6-H5-N-O3 SHPN: UN 1663; Nitrophenols IMO 6.1; Nitrophenols STCC: 49 633 94; Nitrophenol HAZN: U170; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... SYNTHESIZED COMMERCIALLY BY HYDROLYSIS OF APPROPRIATE CHLORONITROBENZENE ISOMER WITH AQUEOUS SODIUM HYDROXIDE AT ELEVATED TEMP. [R1, 230] *Action of dilute nitric acid on phenol @ low temp ... Separated /from o-nitrophenol/ by steam distillation; also para-isomer is produced from p-chloronitrobenzene. [R2] FORM: *FLAKE, TECHNICAL GRADES [R3] *TECHNICAL; PURE [R4] MFS: *Solutia Inc., 10300 Olive Blvd., St. Louis, MO 63141-7893, (314)674-1000; Production site: Anniston, AL 36201 [R5] OMIN: +THERE ARE THREE ISOMERS OF NITROPHENOL, O-,M- AND P- ISOMERS [R6] USE: *As indicator in 0.1% alcohol soln; pH range: 5.6 colorless, 7.6 yellow [R7] *FUNGICIDE [R8] +CHEM INTERMEDIATE FOR THE INSECTICIDES METHYL PARATHION AND ETHYL PARATHION, AZO AND SULFUR DYES, N-ACETYL-P-AMINOPHENOL; CHEM INTERMEDIATE FOR LEATHER PRESERVATIVES [R9] *AS SUBSTRATE FOR ANALYSIS OF UDP-GLUCURONYL TRANSFERASE [R1, 233] +BACTERICIDE [R10] *Leather treatment agent, production of acetominophen. [R11] CPAT: +87% AS A CHEM INTERMED FOR METHYL AND ETHYL PARATHION; 13% IN OTHER APPLICATIONS (EST) (1971) [R9] +/IN MANUFACTURE OF/ ETHYL AND METHYL PARATHIONS, 84%; N-ACETYL-P-AMINOPHENOL (APAP), 8%; MISC, INCL DYESTUFFS AND LEATHER TREATMENT, 8% [R12] +CHEMICAL PROFILE: p-Nitrophenol. Acetaminophen (n-acetyl-p-aminophenol or APAP), 55%; exports, 35%; leather tanning, dyestuffs oxydianiline and miscellaneous uses, 10%. [R13] +CHEMICAL PROFILE: p-Nitrophenol. Demand: 1986: 22 million lb; 1987: 23 million lb; 1991 /projected/: 25 million lb (Includes exports; imports are negligible). [R13] *Demand: 1989: 22 million lbs; 1990: 22.5 million lbs; 1994: 25.5 million lbs [R14] PRIE: U.S. PRODUCTION: +(1972) 1.59X10+10 G [R9] +(1975) PROBABLY GREATER THAN 9.08X10+5 G [R9] *(1984) 1.5X10+10 g (DEMAND) [R12] +(1986) 5.9X10+7 lb [R15] U.S. IMPORTS: *(1972) 7.31X10+8 G (PRINCPL CUSTMS DISTS) [R9] *(1975) 1.44X10+9 G (PRINCPL CUSTMS DISTS) [R9] +1.02X10+5 lb [R16] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to slightly yellow crystals [R7]; *YELLOW TO BROWN SOLID [R17] ODOR: *Odorless [R18] TAST: *Sweetish, then burning taste [R7]; *TASTE /THRESHOLD/ CONCENTRATION 43.4 MG/L. [R1, 230] BP: +279 DEG C (DECOMPOSES) [R19] MP: *113-114 deg C [R7] MW: *139.11 [R20, p. 3-258] DEN: *1.270 @ 20 deg C/D [R7] DSC: *pka= 7.15 @ 25 deg C [R21] HTC: *-8870 BTU/LB= -4930 CAL/G= -206X10+5 J/KG [R17] OWPC: *log Kow= 1.91 [R22] SOL: *Freely sol in alcohol, chloroform, ether; sol in soln of fixed alkali hydroxides and carbonates [R7]; *Very sol in ethanol, ether, and acetone [R20, p. 3-258]; *32.8 G/L IN WATER @ 40 DEG C [R1, 231]; *10,000 mg/l @ 15 deg C [R23]; *16,000 mg/l in water @ 25 deg C [R23]; *269,000 mg/l in water @ 90 deg C [R23] SPEC: +MAX ABSORPTION (METHANOL): 310 NM (LOG E= 4.00); SADTLER REF NUMBER: 5887 (IR, PRISM), 506 (IR, GRATING) [R24]; +Intense mass spectral peaks: 139 m/z (100%), 65 m/z (87%), 109 m/z (31%), 93 m/z (31%) [R25]; +IR: 5952 (Coblentz Society Spectral Collection) [R26]; +UV: 1684 (Sadtler Research Laboratories Spectral Collection) [R26]; +NMR: 6814 (Sadtler Research Laboratories Spectral Collection) [R26]; +MASS: 88 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R26] VAP: *0.005 mm Hg @ 20 deg C [R27] OCPP: *Heat of fusion: 18.25 kJ/mol [R20, p. 6-134] *Sublimes [R7] +FOR ... /FOR ODOR, TASTE, AND COLOR THRESHOLD/ CONCENTRATIONS ... 58.3, 43.4, ND 0.24 MG/L, RESPECTIVELY. [R1, 230] *Henry's Law constant = 1.3X10-8 atm-cu m/mol @ 20 deg C [R28] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 4-nitrophenol stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, dermal absorption), exposure to this odorless, colorless to yellow, crystalline substance, may occur from its use as a fungicide for leather products, or as a chemical intermediate in the syntheses of methyl and ethyl parathion. Effects from exposure may include burns to the skin and eyes, headache, dizziness, shock, unconsciousness, and death from cardiac or pulmonary failure. Contact with 4-nitrophenol should be protected against by wearing butyl rubber gloves, boots, chemical protective clothing which is specifically recommended by the shipper or producer, and a dust mask, organic vapor canister respirator, or in emergency situations, a self-contained breathing apparatus. If contact does occur, immediately flush affected skin or eyes with running water for at least 15 minutes, and remove and isolate contaminated clothing at the site. While 4-nitrophenol does not ignite easily, it can burn, emitting toxic oxides of nitrogen. Also, containers may explode in the heat of a fire. For small fires involving 4-nitrophenol, extinguish with dry chemical, CO2, Halon, water spray, or standard foam, and for large fires, use water spray, fog, or standard foam. Runoff from fire control water may give off poisonous gases or cause pollution, and should be controlled by diking, as necessary. 4-Nitrophenol should be stored in a cool, ventilated, fireproofed area, away from oxidizing agents, oxidiazable materials, and sources of ignition and physical damage. Small spills of 4-nitrophenol may be taken up (if liquid, with sand or other noncombustible absorbent) and placed into containers for later disposal. Large spills should be contained in pits, or other holding areas that are sealed with an impermeable flexible membrane liner. Solids should be covered with a plastic sheet. Liquids should be neutralized wih slaked lime, crushed limestone, or sodium bicarbonate, and diked, if necessary, to prevent runoff from entering water sources or sewers. Spills of 4-nitrophenol in water may need to be trapped at the bottom with sand bag barriers, activated charcoal applied, and the trapped material removed with suction hoses, mechanical dredges, or lifts. Prior to implementing permanent land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance. Also, 4-nitrophenol is a potential candidate for rotary kiln or fluidized bed forms of incineration. DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Nitrophenols/ [R29] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Nitrophenols/ [R29] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Nitrophenols/ [R29] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitrophenols/ [R29] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitrophenols/ [R29] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Nitrophenols/ [R29] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Nitrophenols/ [R29] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitrophenols/ [R29] FPOT: *... Will burn even in absence of air. [R17] +AROMATIC NITROCOMPOUNDS ARE FLAMMABLE ... /AROMATIC NITROCMPD/ [R30] *Nitrophenol is combustible though it may take some effort to ignite. /Nitrophenol/ [R31] FIRP: *If material on fire or involved in fire: Use water in flooding quantities as fog. Solid streams of water may spread the fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. /Nitrophenol/ [R31] *Use water spray, dry chemical, foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Fight fire from protected location or maximum possible distance. [R32] TOXC: *Toxic oxides of nitrogen are produced during combustion of this material. /Nitrophenol/ [R31] REAC: *Mixtures with diethyl phosphite may explode when heated. [R33] *Interaction in absence of solvent in a stirred flask heated by a regulated mantle led to a runaway reaction and explosion. [R34, 496] *Solid mixtures of 4-nitrophenol with potassium hydroxide (1:1.5 mol) readily deflagrate, at the rapid rate of 30 cm/min. [R34, 607] DCMP: *DECOMPOSES VIOLENTLY @ 279 DEG C ... [R17] *When heated to decomposition it emits toxic fumes of nitroxides. [R33] *Its exothermic decomposition causes a dangerously fast pressure increase. [R33] OHAZ: *Its exothermic decomposition causes a dangerously fast pressure increase. [R33] ODRT: +58.3 MG/L [R1, 230] *Detection in air: 2.3 mg/cu m [R35, 919] *Detection in water: 2.5 mg/l [R35, 919] SERI: +Dust: irritating to eyes, nose and throat; ... solid: irritating to skin and eyes [R17] *Irritating to skin, eyes, and respiratory system. [R32] EQUP: *BUTYL RUBBER GLOVES; SIDE-SHIELD SAFETY GLASSES; /NIOSH APPROVED RESPIRATOR/ OR SELF-CONTAINED BREATHING APPARATUS [R17] OPRM: +... Clean work clothes should be supplied daily; showers should be taken prior to changing to street clothes. ... Appropriate type respirators with organic vapor canisters should be provided in areas of concn of dust or vapors. /Nitrophenols/ [R6] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. /Nitrophenol/ [R31] *Personnel protection: Avoid breathing vapors or dusts. ... Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Nitrophenol/ [R31] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R36] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R37] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R38] STRG: +... KEEP ALL FLAMMABLES AWAY FROM AREA WHERE OXIDIZING AGENTS ARE STORED. ... AREA ... KEPT COOL AND VENTILATED, AND SHOULD BE FIREPROOFED. [R39] *Store in a cool, dry, well-ventilated location. Separate from alkalies and oxidizing materials. [R32] CLUP: *Land Spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. Neutralize with agricultural lime, crushed limestone, or sodium bicarbonate. /Nitrophenol/ [R31] *Water Spill: Neutralize with agricultural lime, crushed limestone, or sodium bicarbonate. If material is dissolved, in the region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Nitrophenol/ [R31] *Shovel into suitable dry container. [R32] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U170, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R40] +Potential candidate for rotary kiln incineration, with a temperature range of 820 to 1,600 deg C and a residence time of hours. Also a potential candidate for fluidized bed incineration, with a temperature range of 450 to 980 deg C and a residence time for liquids and gases; seconds: solids; longer. [R41] *Nitrophenol is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. /SRP: Incineration must be controlled./ Care must be taken to maintain complete combustion at all times. Incineration of large quantities may require scrubbers to control the emission of NOx. /Nitrophenol cmpd/ [R42] +Chemical Treatability of 4-nitrophenol; Concentration Process: biological treatment; Chemical Classification: Phenols; Scale of Study: unknown; Type of Wastewater Used: pure compound (one solute in a solvent); Results of Study: 95% reduction based on chemical oxygen demand; rate of biodegradation 17.5 mg chemical oxygen demand/g hr; (Activated sludge process). [R43] *Chemical Treatability of 4-nitrophenol; Concentration Process: biological treatment; Chemical Classification: phenols; Scale of Study: unknown; Type of Wastewater Used: Industrial wastewater; Results of Study: less than or equal to 99.5% reduction. (Powder activated carbon and activated sludge treatment.) [R43] +Chemical Treatability of 4-nitrophenol; Concentration Process: resin adsorption; Chemical Classification: phenols; Scale of Study: unknown; Type of Wastewater Used: Industrial wastewater; results of Study: Effluent concentration reduced to 1-5 ppm by cross-linked polystyrene adsorbent resin; (Effluent from parathion manufacturer. 4% aqueous caustic soda (2 BV) followed by water rinse used as regenerant). [R44] +Chemical Treatability of 4-nitrophenol; Concentration Process: resin adsorption; Chemical Classification: phenols; Scale of Study: continuous flow and laboratory scale; Type of Wastewater Used: Industrial wastewater; Results of Study: Effluent concentration reduced to 5.0-6.0 ppm for 32 BV Resin capacity was about 40 g/l. Efficient ethanol regeneration; (Amberlite XAD-7 20 ml columns used with experimental runs of up to 40 BV) [R44] +The effectiveness of various wastewater treatment processes (ie, use of activated sludge, powdered activated carbon added to activated sludge, a granular activated carbon column, and a resin column) in removing the major pollutants from wastewater from the pharmaceutical industry was studied on a field pilot plant scale. The addition of powdered activated carbon to activated sludge produced a better effluent than the extended aeration of activated sludge. However, the powdered activated carbon pilot plant did not always produce a better effluent than the granular activated carbon plant. In general, the granular activated carbon pilot plant produced a better effluent than the resin column. [R45] +Controlled incineration. Care must be taken to maintain complete combustion at all times. Incineration of large quantities may require scrubbers to control the emission of NO(x). Alternatively, nitrophenols may be recovered from wastewaters. Recommendable method: Incineration. Not recommendable method: Discharge to sewer. [R46] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: The nitrophenol isomers are water soluble solids that are moderately acidic in water as a result of disassociation. 2-Nitrophenol is used as an intermediate in the synthesis of a number of organophosphate pesticides and some medical products. HUMAN EXPOSURE: 2-Nitrophenol is slightly irritating to the skin but non-irritating to the eye. ANIMAL/PLANT STUDIES: There is limited information concerning the toxicological profile for 2-nitrophenol. A dose dependent increase in the formation of methemaglobin was seen in cats after oral exposure to 2-nitrophenol. This compound has not been fully tested for genotoxicity. Insufficient data are available on 2-nitrophenol to allow any conclusions to be made about its possible mutagenicity. In one study, which had several limitations, no skin tumors were noted after dermal application of 2-nitrophenol over 12 weeks. Carcinogenicity studies using the oral or inhalation routes were not available for 2-nitrophenol. In an oral study with rats, 2-nitrophenol induced developmental effects in the offspring only at doses that also produced maternal toxicity. In these studies, the fetuses were not examined for internal malformations. From valid test results available on the toxicity of 2-nitrophenol to various aquatic organisms, the nitrophenols can be classified as substances exhibiting moderate to high toxicity in the aquatic compartment. The lowest effect concentration for Scenedesmus subspicatus, 96 hr EC50: 0.39 mg/l 2-nitrophenol. The available data indicate only a moderate toxicity potential of nitrophenols in the terrestrial environment. [R47] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes if immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . Rapid body cooling may be necessary in case of hyperthermia. Salicylates are contraindicated. /Dinitrophenol and related compounds/ [R48, p. 300-1] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's to treat dehydration. Watch for signs of fluid overload and pulmonary edema. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Dinitrophenol and related compounds/ [R48, 301] MEDS: *Liver and renal function and blood should be evaluated in placement or periodic examinations. /Nitrophenols/ [R6] +Excretion of 4-nitrophenol, a metabolite of the organophosphorous pesticides, parathion, methylparathion, O-ethyl O-(p-nitrophenyl) phenyl phosphorothioic acid (EPN), and decapthion is a good indicator of human exposure to these pesticides. [R49] HTOX: *Symptomatology: 1. Burning pain in mouth and throat. White necrotic lesions in mouth, esophagus and stomach. Abdominal pain, vomiting ... and bloody diarrhea. 2. Sweating, weakness, headache, dizziness, tinnitus. 3. Shock: Weak irregular pulse, hypotension, shallow respiration, cyanosis, and profound fall in body temp. 4. Possibly fleeting excitement (delirium), followed by unconsciousness. Convulsions are rarely seen except in children. 5. Stertorous breathing, mucous rales, rhonchi, frothing at nose and mouth ... pulmonary edema are sometimes seen. Characteristic odor of phenol on breath. 6. Scanty, dark-colored or "smokey" urine. If death does not occur promptly, moderately severe renal insufficiency may appear. 7. Methemoglobinemia, Heinz bodies, hemolytic anemia and hyperbilirubinemia have been reported occasionally. 8. Death from resp, circulatory or cardiac failure. 9. If spilled on skin, pain is followed promptly by numbness. Skin becomes blanched, and a dry opaque eschar forms over the burn. When eschar sloughs off, a brown stain remains. /Phenol/ [R8] *IN STUDY OF N-ACETOXY-2-ACETYLAMINOFLUORENE-INDUCED REPAIR SYNTHESIS IN HYDROXYUREA-TREATED HUMAN DIPLOID FIBROBLASTS (WI-38), A TUMOR PROMOTER, PHENOL, INHIBITED DNA REPAIR SYNTHESIS ONLY @ HIGH CONCN; THE ANALOG 4-NITROPHENOL DID SO @ MUCH LOWER CONCN. [R50] *POISONINGS ARE ASSUMED TO RESEMBLE BOTH PHENOL AND ANILINE. [R8] +Inhalation or ingestion causes headaches, drowsiness, nausea, and blue color in lips, ears, and fingernails (cyanosis). ... Contact with eyes causes irritation. ... Can be absorbed through intact skin to give same symptoms as for inhalation. [R17] NTOX: *[MUTAGENICITY: MUTATION RESEARCH 87: 211 (1981)] DNA REPAIR-DEFICIENT BACTERIAL TESTS: POSITIVE. [R51] *HAS EXPTL PRODUCED HYPERTHERMIA, METHEMOGLOBINEMIA AND CNS DEPRESSION. [R39] +P-NITROPHENOL @ 21 MMOL IN 1% DIMETHYLSULFOXIDE SOLVENT TESTED ON SACCHAROMYCES CEREVISIAE FOR INDUCTION OF MITOTIC GENE CONVERSION. TREATMENT TIME 30 HR, 29% SURVIVAL. CONVERTANTS/1X10+5 SURVIVORS @ ADE2 AND TRP5 LOCI: 8.82 and 2.01, RESPECTIVELY; CONTROLS: 0.45 and 0.27, RESPECTIVELY. [R52] +... 4-Nitrophenol ... shown to inhibit porcine heart maleate dehydrogenase in vitro, and depressed rectal temp have been observed in rats receiving any of the three isomeric nitrophenols. ... /4-Nitrophenol possesses/ distinct cumulative properties. Chronic admin of any of the mononitrophenols to mammals caused alterations of neurohumoral regulation and pathological changes including colitis, enteritis, hepatitis, gastritis, hyperplasia of the spleen, and ... /neuropathy/. Limiting doses for the disruption of conditioned reflex activity were established as ... 0.00125 mg/kg for 4-nitrophenol. [R1, 241] *SYMPTOMS ... IN ANIMALS INCLUDE SHORTNESS OF BREATH, AND INITIAL STIMULATION FOLLOWED BY PROGRESSIVE DEPRESSION. [R1, 239] *4-NITROPHENOL SHOWED NEGATIVE MUTAGENIC ACTIVITY IN HOST-MEDIATED ACTIVITY IN MICE USING SALMONELLA TYPHIMURIUM AND SERRATIA MARCESCENS INDICATOR ORGANISMS. ... EXAMINED MITOTIC EFFECT OF MONONITROPHENOL ISOMERS IN ROOT TIPS OF ALLIUM CEPA. ALL THREE CMPD INDUCED MITOSIS IN ROOT TIPS, BUT ONLY 4-NITROPHENOL INDUCED DETECTABLE CHROMOSOME FRAGMENTATIONS. [R1, 242] +P-NITROPHENOL DID NOT YIELD MUTANT COUNTS SIGNIFICANTLY HIGHER THAN CONTROL LEVELS WHEN TESTED IN THE PRESENCE OF 5% VOL/VOL 9000XG POSTMITOCHONDRIAL SUPERNATANT FRACTION (S9) FROM LIVERS OF UNTREATED SPRAGUE DAWLEY RATS. [R53] +FLOW-THROUGH, ACUTE (96 HR) AND EARLY LIFE STAGE (28 DAYS AFTER HATCH) TOXICITY TESTS /SRP: ON C VARIEGATUS (SHEEPSHEAD MINNOWS)/ REVEALED THAT MAX ACCEPTABLE TOXICANT CONCN (MATC) FOR 4-NITROPHENOL WAS GREATER THAN 10 BUT LESS THAN 16 MG/L, WITH AN APPLICATION FACTOR OF 0.31-0.50. [R54] *ITS TOXICITY IS IDENTICAL TO THAT OF O-NITROPHENOL. O-NITROPHENOL CAUSES CENTRAL AND PERIPHERAL VAGUS STIMULATION, CNS DEPRESSION, METHEMOGLOBINEMIA, AND DYSPNEA IN ANIMAL EXPERIMENTATION. [R55] *Mutagenicity in the Salmonella test: negative; < 0.02 revertant colonies/nmol; 70 revertant colonies at 500 ug/plate [R35, 920] +... 4-Nitrophenol is the most toxic of the mononitrophenols. [R56] +Fifty pregnant CD-1 mice were given 400 mg/kg/day of p-nitrophenol in corn oil by gavage on days 6-13 of gestation and allowed to deliver. p-Nitrophenol produced 18% mortality in treated dams; no toxic effects were observed in the offspring of treated animals. [R57] +The present study has examined biochemical mechanisms by which butylated hydroxyanisole increases the glucuronidation of xenobiotics. Male and female Swiss Webster mice received butylated hydroxyanisole in the diet (1% w/w) for 10 days (600 to 800 mg/kg/day). Hepatic UDP-glucuronosyltransferase activities were increased toward specific substrates in native and detergent activated microsomes. In general, butylated hydroxyanisole increased glucuronidation toward group 1 substrates (1-naphthol and 4-nitrophenol) 36 to 141% whereas no changes were found with a group 2 (chloramphenicol) or a group 3 substrate (digitoxigenin monodigitoxoside). [R58] +4-Nitrophenol concn > or = to 10 mg/l were chronically toxic to Daphnia magna under both static renewal and flow-through conditions. Although growth and reproduction of the daphnids were both substantially better in the flow-through test, the 4-nitrophenol concn that caused significant impacts on the populations were the same in both systems. [R59] +The relative toxic response to 27 selected phenols in 96 hr acute flow-through Pimephales promelas (fathead minnow) and 48-60 hr chronic static Tetrahymena pyriformis (ciliate protozoan) test systems were evaluated. Log Kow dependent linear regression analyses revealed that the data from each test system consisted of 2 linear equations. The less toxic chemicals form a relation which models polar CNS depression; these chemicals are slightly more active than the baseline toxicity of nonionic chemicals. The more toxic chemicals form a relation which models upcoupling of oxidative phosphorylation. Regression analysis of fathead minnow toxicity (log median lethal concn (mol/l)) vs Tetrahymena pyriformis toxicity (log of the 48-60 hr 50% inhibitory concn (BR), mmol/l) showed good correlation between the 2 systems. An exception is 4-nitrophenol which is more active in the Tetrahymena system than in the fathead minnow /system/. [R60] +The process of wet oxidation breaks down organic substances in aqueous solution at elevated temperature and pressures. Experimental wet oxidations were carried out on pure solutions of phenol, 2-chlorophenol and 4-nitrophenol. After 1 hr wet oxidation, final concentrations of these compounds averaged 3% of their concentrations in the starting solutions. The toxicities of the starting compounds and the residual toxicity of the end product solutions were measured with 48 hr acute toxicity tests using Daphnia magna. The solutions of end products were all less toxic than the starting solutions by factors of 10-120. The end product solutions were more toxic than would have been predicted from the known concentration of initial compound remaining in the solution of end products. [R61] +Chlorella pyrenoidosa (alga) 25,000 ug/l/3 days, Toxic effect: Inhibition of chlorophyll synthesis /From table/ [R62] +... CONCLUSIONS: Under the conditions of these 18-month dermal studies there was no evidence of carcinogenic activity in male or female Swiss-Webster mice receiving 40, 80, or 160 mg/kg p-nitrophenol. [R63] *ITS TOXICITY IS /SIMILAR/ /TO/ ... O-NITROPHENOL. /O-NITROPHENOL CAUSES CENTRAL AND PERIPHERAL VAGUS STIMULATION, CNS DEPRESSION, METHEMOGLOBINEMIA, AND DYSPNEA IN ANIMAL EXPERIMENTATION./ [R55] *... Toxicology and carcinogenesis studies of p-nitrophenol (greater than 97% pure) were conducted by dermal application to male and female Swiss-Webster mice for 18 months. Dermal application was selected as the route of chemical administration because of possible skin absorption from p-nitrophenol-treated leather footwear. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 18-MONTH STUDIES: Groups of 60 Swiss-Webster mice of each sex received p-nitrophenol in acetone applied to the interscapular skin. Doses of 0, 40, 80, or 160 mg/kg p-nitrophenol were administered to mice 3 days per week for 78 weeks. At the end of the study, survival rates of mice receiving 0, 40, 80, or 160 mg/kg p-nitrophenol were 29/60,17/60, 26/60, and 24/60 for males and 35/60, 26/60, 33/60, and 27/60 for females. Deaths after 60 weeks were caused by generalized amyloidosis and secondary kidney failure. The severity of amyloidosis was similar among dosed and control animals. At the end of the study, the final mean body weights of the dosed groups of each sex were similar to those of the controls. No biologically significant lesions were observed that were related to the dermal administration of p-nitrophenol. GENETIC TOXICOLOGY: p-Nitrophenol was not mutagenic in Salmonella typhimurium (strains TA100, TA1535, TA1537, and TA98) with or without exogenous metabolic (S9) activation, or in germ cells of male Drosophila melanogaster administered p-nitrophenol in feed or by injection. In Chinese hamster ovary cells, no induction of sister chromatid exchanges was observed with or without S9, but a significant increase in chromosomal aberrations occurred in trials conducted with S9. CONCLUSIONS: Under the conditions of these 18-month dermal studies there was no evidence of carcinogenic activity in male or female Swiss-Webster mice receiving 40, 80, or 160 mg/kg p-nitrophenol. [R64] */The authors/ evaluated genotoxic and cytotoxic effects of the three non-mutagenic and non-carcinogenic compounds p-nitrophenol, D-menthol and sodium N-lauroyl sarcosine which have previously been shown to induce DNA double strand breaks (DNA dsb) secondary to induced cytotoxicity. /The authors/ tested whether genotoxic effects in the alkaline single cell gel test (comet assay) may be confounded by cytotoxicity-induced DNA double strand breaks. Cell viability was determined at the end of the treatment using the fluorescein diacetate/ethidium bromide-assay and plating efficiency was used as an indicator of long-term survivability. Experiments with V79 Chinese hamster cells and human white blood cells revealed negative results in the comet assay despite strong cytotoxic effects. However, cells with extremely fragmented DNA ('clouds') occurred but were excluded from the evaluation under the principle that they represent dead cells. /The authors/ also noticed a significant loss of cells at cytotoxic concentrations that might be attributed to the induction of highly fragmented DNA which is lost during electrophoresis. Since the comet assay allows the determination of DNA effects on the single cell level, a confounding effect of cytotoxicity on test results can be avoided. [R65] NTXV: +LD50 Rat oral 620 (450-850) mg/kg; [R66] *LD50 Mouse oral 380 mg/kg; [R33] *LD50 Mouse ip 75 mg/kg; [R33] *42% Mortality Carassius auratus (goldfish) 8000 ug/l/8 hr; [R67] *Lethal threshold (pollutant concn causing the onset of cell multiplication inhibition) Crangon septemspinosa (shrimp) 26,400 ug/l/96 hr; [R67] *Lethal threshold (pollutant concn causing the onset of cell multiplication inhibition) Mya arenaria (clam, soft shell) 29,400 ug/l/96 hr; [R67] *50% Growth Inhibition Chlorella vulgaris 6,950 ug/l/80 hr; [R62] *Toxicity threshold (pollutant concn causing the onset of cell multiplication inhibition) Microcystis aeruginosa (alga) 6,000 ug/l/8 days; [R68] *Toxicity threshold (pollutant concn causing the onset of cell multiplication inhibition) Scenedesmus quardricauda (alga) 7,400 ug/l/8 days; [R68] ETXV: +TLm Vairon (distilled water) 4-6 mg/l/6 hr; (hard water) 30-33 mg/l/6 hr /Conditions of bioassay not specified/; [R35, 920] *LC50 Lepomis macrochirus (bluegill) 8,280 ug/l/24 hr /Static, unmeasured bioassay/; [R69] +LC50 Daphnia magna (Cladoceran) 35,000 ug/l/24 hr /Conditions of bioassay not specified/; [R70] +LC50 Pimephales promelas (fathead minnow) 64.6 (58.4-71.5) mg/l 24 hr, wt 84 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R71] +LC50 Pimephales promelas (fathead minnow) 54.4 (49.7-59.5) mg/l 48 hr, wt 84 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R71] +LC50 Pimephales promelas (fathead minnow) 44.1 (40.7-47.8) mg/l 72 hr, wt 84 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R71] +LC50 Pimephales promelas (fathead minnow) 41.0 (37.7-44.6) mg/l 96 hr, wt 84 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 98%; [R71] NTP: +... Toxicology and carcinogenesis studies of p-nitrophenol (greater than 97% pure) were conducted by dermal application to male and female Swiss-Webster mice for 18 mo. Dermal application was selected as the route of chemical administration because of possible skin absorption from p-nitrophenol treated leather footwear. ... 18-MONTH STUDIES: Groups of 60 Swiss-Webster mice of each sex received p-nitrophenol in acetone applied to the interscapular skin. Doses of 0, 40, 80, or 160 mg/kg p-nitrophenol were administered to mice 3 days/wk for 78 wk. ... CONCLUSIONS: Under the conditions of these 18-month dermal studies there was no evidence of carcinogenic activity in male or female Swiss-Webster mice receiving 40, 80, or 160 mg/kg p-nitrophenol. [R63] POPL: +... Individuals with cardiovascular, renal, or pulmonary disease and those with anemia are probably more subject to poisoning by nitrophenol. /Nitrophenols/ [R6] ADE: *WHEN P-NITROPHENOL WAS ADMIN TO THE SEA URCHIN, ELIMINATION OF THE PARENT CMPD WAS MAJOR PATHWAY FOR REDUCING BODY BURDEN. [R72] +Based on the rapid urinary elimination of the mononitrophenols, the compounds may be restricted primarily to the blood and urine following absorption by humans. /Mononitrophenols/ [R73] +... Shown to permeate the skin and produce damage at threshold concentration of 0.9 percent (wt/vol). [R73] *EXCRETION BY MICE, RATS, RABBITS, AND GUINEA PIGS IS ... RAPID. MOST DOSES WERE COMPLETELY ELIMINATED FROM BLOOD WITHIN 2 HR AFTER ADMIN. RATES @ WHICH 4-NITROPHENOL DISAPPEARED FROM BLOOD DECR IN FOLLOWING DESCENDING ORDER: MOUSE, RABBIT, GUINEA PIG, RAT, AND MONKEY. [R1, 232] +Nitrophenols are readily absorbed through intact skin and by inhalation. ... /Nitrophenols/ [R6] +Mononitrophenols are readily absorbed by the gastrointestinal tract and rapidly excreted primarily in the urine. ... Elimination of 4-nitrophenol by monkey following oral and ip doses of 20 mg/kg ... complete within 5 hr. [R1, 232] *Rana temporaria and Xenopus laevis excrete 90-95% dose, and metabolize 50-65% dose of phenol, 4-nitrophenol, and 2-methylphenol within 24 hr, to about the same extent. Kinetic data for the excretion of phenols from both species fit a 2 compartment model. The elimination constants of Rana and Xenopus are not significantly different. Metabolism is mostly conjugation by glucuronidation and sulfation of the original phenols. Additionally, oxidations leading to dihydroxyphenols and benzoic acid from 2-methylphenol, and reduction of 4-nitrophenol, occur, followed by conjugation. There is an important difference between the metabolite patterns of Rana and Xenopus in that the latter is unable to glucuronidate phenols. As the amt of metabolites produced is similar in both species, Xenopus compensates for its inability to glucuronidate by increasing other metabolites. [R74] *The distribution of phenol (108952), p-cyanophenol (767000), p-nitrophenol (100027), p-hydroxybenzoic-acid (99967), and p-heptyloxyphenol (13037860) after intraperitoneal (ip) and dermal exposure was examined. Young female Fischer-344-rats were exposed to radiolabeled phenol and p-substituted phenol congeners via ip administration at a dose of 2.5 ug or dermal administration at a dose of 5 ug. ... Following ip administration, urinary excretion rates ranged from 8% of the dose per hour for heptyloxyphenol to 20 to 25% of the dose per hour for phenol, cyanophenol, hydroxybenzoic-acid, and nitrophenol. After 120 hr, 87% to 97% and 1% to 4% of the phenol, cyanophenol, hydroxybenzoic-acid, and nitrophenol doses were excreted in the urine and feces, respectively. ... Carcasses contained 0.5% of the phenol, cyanophenol, and nitrophenol doses and 7% to 10% of the heptyloxyphenol and hydroxybenzoic-acid doses. After dermal administration, urinary excretion rates ranged from 0.4% of the dose per hour for hydroxybenzoic-acid to 10% of the dose per hour for phenol. After 120 hr, urinary and fecal excretion of the phenol, cyanophenol, and nitrophenol doses ranged from 65% to 77% and 1% to 3% of the dose, respectively. ... After 120 hr, dermal absorption ranged from less than 2.3% of the hydroxybenzoic-acid dose to 80% of the phenol dose. ... The ionization potential of the p-substituted functional group may affect the dermal absorption of phenol congeners. [R75] METB: +... EXCRETION OF 4-NITROPHENOL FROM 19 YR OLD FEMALE FOLLOWING SUICIDAL ORAL DOSE OF NITROBENZENE /REPORTED/. LARGE QUANTITIES ... DETECTED IN URINE. [R1, 235] +IN VIVO STUDIES WITH NITROPHENOLS ... META-AND PARA-NITROPHENOL ARE REDUCED MORE READILY THAN THE ORTHO ISOMER ... [R76] *P-NITROPHENOL YIELDS P-NITROPHENYL-BETA-D-GALACTOSIDE IN GUINEA PIGS. YIELDS P-NITROPHENYL-ALPHA-D-GLUCOSIDE IN ASPERGILLUS. /FROM TABLE/ [R77] *P-NITROPHENOL YIELDS P-AMINOPHENOL IN RAT, BASS, CARP, CATFISH, LAMPREY, PERCH, PIKE, SALMON, STURGEON. YIELDS P-AMINOPHENOL AND P-NITROPHENYL SULFATE, 4-NITROCATECHOL IN RABBIT. /FROM TABLE/ [R77] *SULFATE CONJUGATION OF 4-NITROPHENOL ... IS DECR DURING PREGNANCY IN RABBITS ... AND INCR WITH AGE IN RAT, GUINEA PIG, AND HUMANS ... RELATIVE RATES OF GLUCURONIDE VERSUS SULFATE CONJUGATION OF 4-NITROPHENOL MAY DEPEND ON LEVELS OF PHENOL PRESENT. [R1, 233] *P-NITROPHENOL GLUCURONIDATION WAS SHOWN TO OCCUR IN THE KIDNEY AND LUNG OF THE RAT IN VIVO, WHEREAS SULFONATION OCCURRED ALMOST EXCLUSIVELY IN THE LIVER. [R78] +IN MAN AND CHICKEN, P-NITROPHENOL (PNP) IS EXCRETED ALMOST ENTIRELY IN URINE AS P-NITROPHENYL SULFATE AND P-NITROPHENYLGLUCURONIDE. IN FASTED, UNANESTHETIZED CHICKEN DURING INFUSION OF (14)C-P-NITROPHENOL @ RATE OF 100 NMOL/MIN/KG, A MINIMUM OF 38% OF CONJUGATION OF P-NITROPHENOL OCCURRED IN THE KIDNEY. [R79] +Metabolism of mononitrophenols probably occurs via one of three mechanisms in humans. The major route of mononitrophenol metabolism is undoubtedly conjugation and the resultant formation of either glucuronide or sulfate conjugates. /Mononitrophenols/ [R80] *To investigate the in vivo xenobiotic metabolism of three p-nitrophenol derivatives, rice field crayfish were exposed to 0.1 to 0.01 mg/l (14)C substrate solutions for 15 hr. At apparent steady state uptake, the crayfish were transferred to a recycling flow-through metabolism chamber for 24 hr where the depurated products were collected and concentrated on a column of Amberlite XAD-4 resin. The tissue absorption and distribution of (14)C compounds at the apparent steady state and post depuration periods were measured by complete tissue combustion and recovery of evolved (14)CO2. The structure and concentration of metabolites in resin and soft tissue extracts were determined by cochromatography with authentic standards in high performance liquid chromatography and TLC systems. The crayfish rapidly absorbed the radiolabeled chemical from solution and depurated metabolites of oxidation were the beta-D-glucosides of the free phenols, with lesser amounts of the corresponding sulfate esters. [R81] +SPF Wistar rats of both sexes were /used/ to determine the effect of sex differences on the sulfation of 4-nitrophenol. Following the administration of a single dose of 4-nitrophenol 35% was excreted in the urine of the animals in the form of 4-nitrophenyl sulfate and 40% in the form of the glucuronide, with no difference between sexes. [R82] *The metabolism of 5 phenols in zebra fish (Brachydanio rerio) was studied after uptake from the medium. The results showed no qualitative differences to other cyprinid fish species, only the oxidation rate seemed to be lower. Only the glucuronide and sulfate conjugates were detected as metabolites of 4-nitrophenol, 4-chlorophenol, and pentachlorophenol. [R83] +The effect of dibutyryl cyclic adenosine 3',5'-monophosphate on metabolism of p-nitroanisole and aniline was studied in isolated rat hepatocytes. Initial studies indicated that in vitro addition of dibutryryl cyclic adenosine 3',5'-monophosphate to hepatocytes increased metabolism of both p-nitroanisole and aniline as determined by the production of oxidized metabolites, p-nitrophenol and p-aminophenol, respectively. After enzymic hydrolysis with beta-glucuronidase and arysulfatase, dibutryryl cyclic adenosine 3',5'-monophosphate increased accumulation of p-nitrophenol formed from p-nitroanisole by inhibiting further metabolism via conjugation reactions. Further studies using p-nitrophenol directly as substrate confirmed the finding and revealed that glucuronidation was more sensitive to the inhibitory effect of dibutyryl cyclic adenosine 3',5'-monophosphate than was sulfation. The 8-bromo derivative of cyclic adenosine 3',5'-monophosphate was more potent than dibutyryl cyclic adenosine 3',5'-monophosphate at inhibiting glucuronidation, whereas cyclic adenosine 3',5'-monophosphate and dibutyryl cyclic guanosine 3',5'-monophosphate were without effect. Noncyclic adenine nucleotides (5'-ATP, 5'-ADP, 5'-AMP) also altered p-nitroanisole and p-nitrophenol metabolism. Adenosine triphosphate and adenosine diphosphate increased p-nitrophenol accumulation from p-nitroanisole while adenosine and adenosine mono-phosphate inhibited glucuronidation of p-nitrophenol. Dibutyryl cyclic adenosine 3',5'-monophosphate was further found to decrease UDP-glucuronic acid levels in a concn dependent manner without disrupting the redox state (NAD+/NADH) in hepatocytes. [R84] +The in vitro rate of hepatic microsomal activation of parathion to paraoxon was significantly reduced in mice at 19 days of gestation when compared to nonpregnant controls. Total hepatic metabolism of parathion was determined during in situ perfusion of livers from pregnant and nonpregnant mice. Levels of parathion, paraoxon, and p-nitrophenol in the perfusate after 45 min of perfusion did not differ significantly between livers from the pregnant and nonpregnant groups. [R85] +The effects of acute and subacute administration of diiosopropyl fluorophosphate and acute administration of soman, sarin, and tabun on UDP-glucuronyltransferase activity towards 4-nitrophenol, 4-methylumbelliferone, phenolphthalein and testosterone in rat liver microsomes were investigated. Twenty four hr after a single injection of diisopropyl fluorophosphate the activity of UDP-glucuronyltransferase towards 4-nitrophenol and 4-methylumbelliferone was inhibited, and the inhibitory effect continued for 3 days. The activity had recovered by 7 days after injection. After daily diisopropyl fluorophosphate injections, the activity of UDP-glucuronyltransferase towards 4-nitrophenol and 4-methylumbelliferone was decreased to the same level as found following acute treatment with diisopropyl fluorophosphate. The in vitro addition of diisopropyl fluorophosphate to liver microsomes did not affect UDP-glucuronyltransferase activity towards 4-nitrophenol. In the 3-methylcholanthrene pretreatment group, diisopropyl fluorophosphate inhibited only the UDP-glucuronyltransferase activity towards 4-nitrophenol and 4-methylumbelliferone. On the other hand, in the phenobarbital pretreatment group, diisopropyl fluorophosphate did not inhibit the UDP-glucuronyltransferase activity towards 4-nitrophenol and 4-methylumbelliferone. [R86] +Enzymic azoreduction of the hepatocarcinogen, dimethylaminoazobenzene and glucuronidation of its ring hydroxylation product, 4'-hydroxy-dimethylaminoazobenzene by hepatic microsomal fractions in vitro were studied during an 8 day period of hepatic regeneration following partial hepatectomy in Wistar rats. Azoreduction of dimethylaminoazobenzene and its N-demethylated metabolites did not change during hepatic regeneraton in contrast to N-demethylation of these dyes which is profoundly suppressed during regeneration. UDP-glucuronosyltransferase activity towards 4'-hydroxy-dimethylaminoazobenzene was partially depressed during the regeneration period, but the depression was considerably less than that for bilirubin. Transferase activity towards 4-nitrophenol, after initial depression, returned to normal after the third day of partial hepatectomy. In Gunn rats, microsomal UDP-glucuronosyltransferase activity towards bilirubin was undectectable, whereas transferase activity toward 4-nitrophenol was 50% of normal. Addition of diethylnitrosamine in vitro restored transferase activity towards 4-nitrophenol to normal levels, but the activity towards bilirubin was unaffected. Gunn rat UDP-glucuronosyltransferase activity towards 4'-hydroxy-dimethylaminoazobenzene was 25% of normal and was partially activated upon addition of diethylnitrosamine in vitro. Treatment with clofibrate or beta-naphthoflavone induced hepatic microsomal bilirubin and 4-nitrophenol specific UDP-glucuronosyltransferase activities, respectively; both agents induced transferase activity towards 4'-hydroxy-dimethylaminoazobenzene Triiodothyronine, which induces 4'-nitrophenol-specific UDP-glucuronosyltransferase and depresses bilirubin-specific UDPG, had little effect on 4'-hydroxy-dimethylaminoazobenzene UDP-glucuronosyltransferase activity. [R87] +Male Fischer rats were fed a diet ad libitum containing eugenol (4-allyl-2-methoxyphenol) to observe its effects on liver drug-detoxifying enzymes such as UDP-glucuronyltransferase, UDP-glucose dehydrogenase and glutathione S-transferase. Liver weights affected significantly by a diet containing 3% euqenol (wt/wt) for 13 wk. The activities of UDP-glucuronyltransferase of liver microsomes toward various xenobiotic substances such as 4-nitrophenol, 1-naphthol, 4-hydroxybiphenyl and 4-methylumbelliferone were enhanced by dietary administration of eugenol, but the activity of UDP-glucuronyltransferase toward its endogenous substrate, bilirubin, was not changed. Dose response relationships between the enhancement of UDP-glucuronyltransferase activities toward these xenobiotics and the dose of eugenol were observed. The induced higher activities of UDP-glucuronyltransferase toward these xenobiotics were maintained during 13 wk of eugenol treatment. Similar results on UDP-glucose dehydrogenase and glutathione S-transferase activities in the liver cytosol were obtained by dietary administration of eugenol, while no effect on cytochrome p450 content in the liver microsomes from the rats fed the eugenol diet was observed during 13 wk. [R88] *Western blot analyses of liver microsomes from 13 male and 12 female monkeys demonstrated that in each sample a variable amount of a cytochrome P450 (P450) protein, likely monkey P450 2E1, cross-reacted with anti-rat P450 2E1 antibodies. ... Involvement of monkey 2E1 in the oxidation of typical substrates for 2E1 from other species, such as dimethylnitrosamine , p-nitrophenol, chlorzoxazone, and aniline, was investigated. ... Inhibition experiments showed that chlorzoxazone and p-nitrophenol hydroxylations were immunoinhibited by 60-80% by anti-rat P450 2E1 and were inhibited by the prototypical 2E1 inhibitor 4-methylpyrazole with IC50 values of 1.5 and 13 ugM, respectively. In conclusion, the findings provide evidence that P450 2E1 is constitutively and equally expressed in male and female monkey liver and it exerts a major role only in hydroxylation of chlorzoxazone and p-nitrophenol. [R89] *Monooxygenase enzymatic activities were measured in liver and kidney microsomes of control and ethanol-treated rats. ... Ethanol treatment increased the liver and renal hydroxylations of chlorzoxazone and 4-nitrophenol. [R90] *... Cytochrome P450 2E1 mRNA has been identified in the rat prostate and testis by reverse transcription PCR, southern blotting, and DNA sequencing. P450 2E1 protein from rat testis could be detected with immunoblot analysis, but was not detected in the prostate. The hydroxylation of p-nitrophenol, known to be mediated by P450 2E1, was demonstrated by HPLC measurement of product formation in microsomal fractions from the rat testis, but again not from prostate. Exposure of rats to pyridine resulted in a 2.9-fold increase of p-nitrophenol hydroxylation by testicular microsomes. Diethyldithiocarbamate, a selective mechanism-based inhibitor of P450 2E1, or a P450 2E1 monoclonal antibody, caused marked inhibition of testicular microsomal p-nitrophenol hydroxylase activity. These results indicate that cytochrome P450 2E1 is present in the rat testis, and that it is elevated by treatment of the animals with pyridine. Thus, the presence and inducibility of cytochrome P450 2E1 in the testis may be of significance in the bioactivation of environmental chemicals to genotoxic metabolites. [R91] *4-Nitrophenol 2-hydroxylation activity was previously shown to be mainly catalyzed by P450 2E1 in animal species and humans. As this chemical compound is widely used as an in vitro probe for P450 2E1, this study was carried out to test its catalytic specificity. First, experiments were carried out on liver microsomes and hepatocyte cultures of rat treated with different inducers. Liver microsomes from pyrazole- and dexamethasone-treated rats hydroxylated p-nitrophenol with a metabolic rate increased by 2.5- and 2.7-fold vs control. Dexamethasone treatment increased the hepatic content of P450 3A but not that of P450 2E1. Two specific inhibitors of P450 3A catalytic activities, namely, ketoconazole and troleandomycin (TAO), inhibited up to 50% of 4-nitrophenol hydroxylation in dexamethasone-treated rats but not in controls. Hepatocyte cultures from dexamethasone-treated rats transformed p-nitrophenol into 4-nitrocatechol 7.8 times more than controls. This catalytic activity was inhibited by TAO. Similarly, hepatocyte cultures from pyrazole-treated rats hydroxylated p-nitrophenol with a metabolic ratio increased by about 8-fold vs control. This reaction was inhibited by diethyl dithiocarbamate and dimethyl sulfoxide, both inhibitors of P450 2E1. Second, the capability of human P450s other than P450 2E1 to catalyze the formation of 4-nitrocatechol was examined in a panel of 13 human liver microsomes. Diethyl dithiocarbamate and ketoconazole reduced 4-nitrophenol hydroxylase activity by 77% (:11) and 13% (:16), respectively. Furthermore, the residual activity following diethyl dithiocarbamate inhibition was significantly correlated with seven P450 3A4 catalytic activities. Finally, the use of human cell lines genetically engineered for expression of human P450s demonstrated that P450 2E1 and 3A4 hydroxylated 4-nitrophenol with turnovers of 19.5 and 1.65 min-1, respectively. In conclusion, P450 3A may make a significant contribution to 4-nitrophenol hydroxylase activity in man and rat. [R92] *The metabolic capacity of rat brain slices for m-dinitrobenzene (99650) was assessed /in/ male Fischer-344-rats ... Slices from both brain stem or forebrain (400 um thick) or liver tissue (control) were incubated with a 0.2 mM m-dinitrobenzene containing medium for 2 hours. The m-dinitrobenzene was metabolized in the two brain tissues and the liver tissue. No metabolism occurred in heat inactivated tissues. Metabolic disposal of m-dinitrobenzene was 1.05+/-0.11 umol/g wet weight per hour in the liver, 0.49+/-0.05 umol/g wet weight per hour in brain stem, and 0.44+/0.05 umol/g wet weight per hour in the forebrain. The main metabolite produced by both brain and liver slices was m-nitroaniline (99092), which represented 57 to 66% of the disposal of m-dinitrobenzene. In the liver, 2-aminophenol (95556), 4-aminophenol (123308), 4-nitrophenol (100027), or 2-nitrophenol (88755) was produced, but they were not detected in the brain slices. Nitrosonitrobenzene (17122213) was detected in slices from both parts of the brain, but not in the liver slices. In the presence of m-dinitrobenzene the glucose consumption of brain slices was significantly increased; 26% in the brain stem and 17.9% in the cerebral cortex, which may have been a precytotoxic effect. ... The brain has considerable nitroreductive capacity towards m-dinitrobenzene and that in-situ reduction of m-dinitrobenzene may be responsible for its neurotoxicity. [R93] *The activities of xenobiotic metabolizing enzymes measured in the liver of freshwater vendace (Coregonus albula) varied with the seasons. The determinations were made at a constant temperature (18 deg C) and at the environmental (water) temperature, in which the fish were caught. UDP-glucuronosyltransferase activity, p-nitrophenol as substrate, increased slowly before spawning and just after the event the activity rose to much higher levels. It did not show any thermal compensation during water cooling in the autumn. [R94] ACTN: +Nitrophenols inhibit the microbial growth of natural aquatic systems because they uncouple the metabolic process of oxidative phosphorylation. /Nitrophenols/ [R95] +The effects of phenobarbital treatment on the biotransformation of parathion by intact mouse liver were investigated, and the subsequent effect of phenobarbital on the acute toxicity of parathion were examined. Daily intraperitoneal treatment of male Hla(SW)BR Swiss Webster mice with 80 mg/kg phenobarbital for 4 days induced hepatic cytochrome p450 content, as well as hepatic oxidative activation and oxidative detoxification of parathion, while antagonizing the acute toxicity of parathion without directly affecting tissue cholinesterase activities. Perfusion of mouse livers from control and phenobarbital treated mice resulted in the generation of paraoxon, p-nitrophenol, and p-nitrophenyl sulfate, and p-nitrophenyl glucuronide; phenobarbital increased production of p-nitrophenol, p-nitrophenyl glucuronide, and p-nitrophenyl sulfate from livers perfused with parathion but had no effect on the production of paraoxon. [R96] *Nitrophenols interfere with normal metabolism by uncoupling oxidative phosphorylation. For the mononitrophenols, the order of severity of effects is 4- > 3- > 2-nitrophenol. [R97] INTC: *... ABILITY OF GUNN RATS TO FORM GLUCURONIDE OF P-NITROPHENOL WAS STRONGLY ENHANCED AFTER PHENOBARBITAL TREATMENT. [R98] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4-Nitrophenol's production and use in the manufacture of methyl and ethyl parathion, N-acetyl-p-aminophenol (acetominophen), dyestuffs as well as a leather treatment agent may result in its release to the environment through various waste streams. It is a photooxidation product of nitrobenzene in air and aromatic hydrocarbons such as benzene, toluene, and phenanthrene with nitric oxide in air. It is emitted in vehicular exhaust from both gasoline and diesel engines. 4-Nitrophenol is also a degradation product of parathion and an impurity in the parathion formulation Thiophos and, therefore, will be released during the application of the insecticide. If released to air, a vapor pressure of 0.005 mm Hg at 20 deg C indicates 4-nitrophenol will exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-nitrophenol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 4 days. 4-Nitrophenol was 39 % mineralized when exposed to light greater than 290 nm over a 17 hour period, suggesting that photodegradation may be an important fate process. If released to soil, 4-nitrophenol is expected to have high mobility based upon a log Koc value of 1.7. Volatilization from moist soil surfaces is not expected based upon a Henry's Law constant of 1.3X10-8 atm-cu m/mole at 20 deg C. 4-Nitrophenol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. The biodegradation half-life of 4-nitrophenol in an acidic soil was reported as 2.5 days and the biodegradation half-life in a basic soil was reported as 10.2 days. If released into water, 4-nitrophenol is not expected to adsorb to suspended solids and sediment in the water column based upon the Koc value. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's Henry's Law constant. A pKa of 7.15 indicates 4-nitrophenol will partially exist in the ionized form in water and moist soils and the anion will not volatilize. The biodegradation half-life of 4-nitrophenol was reported as 18 hours and 6.8 days in aerobic and anaerobic waters, respectively. Photolysis in surface waters is expected to occur based on photolysis half-lives of 5.7, 6.7, and 13.7 days at pH 5, 7, and 9, respectively. BCF values of 2-79 measured in fish suggest bioconcentration in aquatic organisms is low to moderate. Occupational exposure to 4-nitrophenol may occur through inhalation and dermal contact with this compound at workplaces where 4-nitrophenol is produced or used. The general population may be exposed to 4-nitrophenol via inhalation of ambient air and ingestion of contaminated water. (SRC) ARTS: *4-Nitrophenol's production and use in the manufacture of methyl and ethyl parathion, N-acetyl-p-aminophenol (acetominophen), dyestuffs as well as a leather treatment agent may result in its release to the environment through various waste streams(1). It is a photooxidation product of nitrobenzene in air(2) and aromatic hydrocarbons such as benzene, toluene, and phenanthrene with nitric oxide in air(5). It is emitted in vehicular exhaust from both gasoline and diesel engines(5). 4-Nitrophenol is also a degradation product of parathion(3) and an impurity in the parathion formulation Thiophos and, therefore, will be released during the application of the insecticide(4). [R99] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a log Koc value of 1.7(2) indicates that 4-nitrophenol is expected to have high mobility in soil(SRC). Volatilization of 4-nitrophenol from moist soil surfaces is not expected to be an important fate process(SRC) given a Henry's Law constant of 1.3X10-8 atm-cu m/mole(3). The pKa of 4-nitrophenol is 7.15(4), indicating that this compound will partially exist in the ionized form in moist soils and the anion will not volatilize(SRC). 4-Nitrophenol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.005 mm Hg at 20 deg C(5). The biodegradation half-life of 4-nitrophenol in an acidic soil was reported as 2.5 days and the biodegradation half-life in a basic soil was reported as 10.2 days(6). [R100] *AQUATIC FATE: Based on a classification scheme(1), a log Koc value of 1.7(2) indicates that 4-nitrophenol is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon the Henry's Law constant of 1.3X10-8 atm-cu m/mole at 20 deg C(4). The pKa of 4-nitrophenol is 7.15(5), indicating that this compound will partially exist in the ionized form in water and the anion will not volatilize(SRC). According to a classification scheme(6), BCF values in the range of 2 to 79 in fish(7,8) suggest bioconcentration in aquatic organisms will be low to moderate. The biodegradation half-life of 4-nitrophenol was reported as 18 hours and 6.8 days in aerobic and anaerobic waters, respectively(9). When 4-nitrophenol in water was exposed to sunlight, the half-life was 5.7, 6.7, and 13.7 days at pH 5, 7, and 9, respectively(10). [R101] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-nitrophenol, which has a vapor pressure of 0.005 mm Hg at 20 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-nitrophenol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 days(SRC) from its rate constant of 4.4X10-12 cu cm/molecule-sec at 25 deg C(3). 4-Nitrophenol adsorbed to silica gel was 39% mineralized when exposed to light greater than 290 nm over a 17 hour period(4). [R102] BIOD: +Pseudomonas strains capable of mineralizing 2,4-dichlorophenol and p-nitrophenol (PNP) in culture media were isolated from soil. A Pseudomonas able to mineralize 5.0 ug p-nitrophenol/ml in culture did not mineralize the compound in sterile or nonsterile lake water. The bacterium destroyed p-nitrophenol in sterile sewage and enhanced p-nitrophenol mineralization in nonsterile sewage. When added to the surface of sterile soil, the bacterium mineralized little of the p-nitrophenol present at 5.0 ug/g, but it was active if mixed well with the sterile soil. [R103] +During the years 1978-1981 both the European Economic community and the Organization for Economic Cooperation and Development organized various interlaboratory comparison programs on standardized screening methods to study the biodegradability of chemicals in water. While the ring test results were generally rather heterogenous, one of the compounds studied, 4-nitrophenol, turned out to be particularly problematic as the compound was found either easily biodegradable or not biodegradable by various laboratories in various tests. This paper describes some more detailed studies on 4-nitrophenol degradation in two different tests, the modified Organization for Economic Cooperation screening test (MOST test) and the Zahn-Wellens test, respectively. The test variable investigated include inoculum characteristics and pretreatment, test duration, and 4-nitrophenol concentration. The results are discussed in relation to toxicity and degradation pathways of 4-nitrophenol. [R104] +A study was conducted of possible reasons for acclimation of microbial communities to the mineralization of organic compounds in lake water and sewage. The acclimation period for the mineralization of 2 ng of p-nitrophenol (PNP) per ml of sewage was eliminated when the sewage was incubated for 9 days, with no added substrate. The acclimation period for the mineralization of 2 ng but not 200 ng or 2 ug of p-nitrophenol/ml was eliminated when the compound was added to lake water that had been first incubated in the laboratory. Mineralization of p-nitrophenol by Flavobacterium sp was detected within 7 hr at concentrations of 20 ng/ml to 2 micrograms/ml but only after 25 hr at 2 ng/ml. p-Nitrophenol utilizing organisms began to multiply logarithmically after 1 day in lake water amended with 2 ug of p-nitrophenol/ml, but substrate disappearance was only detected at 8 days, at which time the numbers were approaching 10(5) cells per ml. The addition of inorganic nutrients reduced the length of the acclimation period from 6 to 3 days in sewage and from 6 days to 1 day in lake water. The prior degradation of natural organic materials in the sewage and lake water had no effect on the acclimation priod for the mineralization of p-nitrophenol, and naturally occurring inhibitors that might delay the mineralization were not present. The length of the acclimation phase for the mineralization of 2 ng of p-nitrophenol/ml was shortened when the protozoa in sewage were suppressed by eucaryotic inhibitors added to lake water. [R105] *SCREENING TESTS: 4-Nitrophenol is a benchmark chemical for biodegradability test and therefore there are numerous results on its behavior in screening tests. The results of the biodegradability screening studies are conflicting, ranging from no degradation to rapid degradation using soil, sewage, activated sludge, sediment, and freshwater inocula. The results are roughly divided between 4-nitrophenol biodegrading moderately slowly and rapidly; acclimation is generally important(1-12,14) while some of the conflicting results may be due to differences in concentrations of the test chemical, inocula, toxicity at higher concentrations(3), or insufficient acclimation. Many results were obtained in interlaboratory comparisons in which different laboratories report 0 and 100% degradation for the same test(1). The importance of acclimation is illustrated in results of 100% degradation in 15 and 3 days without and with acclimation, respectively; the latter also at much higher concentration levels(2). At very low concentration levels (parts per trillion range), mineralization is achieved without a lag period(12). 4-Nitrophenol biodegrades rapidly in simulated biological treatment plants, but only after adequate acclimation(2,4,5,13). [R106] *AEROBIC: As the concn of 4-nitrophenol in Mardin silt loam soil was increased from 1 ppb to 50 ppm the lag period increased and time for 10% mineralization increased from 5 hr to 40 hr(1). When 2 ppm of 4-nitrophenol was incubated in agricultural topsoil at 10 deg C, the half-life was 0.7-1.2 days under aerobic conditions(2). In subsoil the half-life was 40 days under aerobic conditions when the soil moisture was at 79% field capacity(2). The biodegradation of 4-nitrophenol in agricultural soil is greatly increased by pretreatment of the soil with 4-nitrophenol, and decreased by the presence of some fertilizers, fungicides, and herbicides(3). The experiments which showed this involved monitoring the rate of mineralization of ring-labeled parathion in which 4-nitrophenol is an intermediate(3). The addition of captafol, maneb, and benomyl reduced the mineralization after 3 wk from 6.4-41% of controls while PCNB had no effect(3). Pretreatment of the soil with 4-nitrophenol increased the amount mineralized after 1 day from 2 to 34%(3). Amending with 100 ppm-N ammonium sulfate and potassium nitrate reduced the 3 wk mineralization 83 and 35%, respectively, although ammonium nitrate did not have a similar effect(3). 4.3% of the theoretical BOD was observed for 4-nitrophenol in sludge over a 2 week incubation period(4). A half-life of about 8 days was observed for 4-nitrophenol in a laboratory batch microcosm incubated with sediment and groundwater(5). 4-Nitrophenol was degraded over 80 % in an aerobic groundwater/sediment microcosm from a landfill during a 60 day incubation period(6). First-order rate constants of 0.09/day to 0.5/day were determined for 4-nitrophenol in aerobic aquifer material(7), corresponding to half-lives of about 1-8 days(SRC). The biodegradation half-life of 4-nitrophenol in an acidic soil was reported as 2.5 days and the biodegradation half-life in a basic soil was reported as 10.2 days(8). [R107] *AEROBIC: In die-away tests in which a chemical is added to a water sample from a site, 4-nitrophenol degrades rapidly with acclimation and half-lives decrease with increasing concn of 4-nitrophenol. Typical half-lives are: approximately 1.5 days in the Vistula River in Warsaw, Poland for 5-20 ppm of chemical(2), 7.6 days, mean value calculated in 5 ponds(8); 50% mineralization in 300 hr at 1 ppm increasing to 700 hr at 0.5 ppb including a 250 hr lag in a eutrophic lake(4); and 58% mineralization in 14 days in an oligotropic lake for 1 ppb of chemical(3). When 4-nitrophenol was incubated in freshwater/sediment eco-cores from 5 sites along the Escabia River in Florida, 10-63% mineralization occurred in 160 hr including a 40-120 hr lag(6). However, when the eco-cores were preexposed, there was no longer a lag and 12-58% mineralization occurred in 80 hr(6). Similarly in eco-cores from a freshwater pond, 4-nitrophenol disappeared within 80 hours in previously treated cores and within 15 hr when treated a third time(1). At the time of disappearance approximately 40-50% of the nitrophenol had mineralized(1). Mineralization was much slower in eco-cores from a salt marsh than from a river, 9-21% in 250 hr versus 46-49% in 100 hr in the freshwater system(7). The half-life was 348-1225 days in salt water from three sites in Pensacola Bay(5) although the half-lives were decreased to 9-291 days by the addition of sediment from the site into the test flasks and to 13-20 days in eco-cores from the same sites(5). When initially dosed, 4-nitrophenol disappeared slowly from a laboratory microcosm (100% disappearance in 7.5 days) and a test pond, however on redose 10 days after initial treatment, it disappeared within a day(1). Nine months after the study, the microbial community in the pond had apparently reverted as an acclimation period was again required before the 4-nitrophenol degraded(1). The biodegradation half-life of 4-nitrophenol was reported as 18 hours and 6.8 days in aerobic and anaerobic waters, respectively(9). [R108] *ANAEROBIC: 4-Nitrophenol was completely mineralized in 1 week in an anaerobic sewage sludge(1) and was 75-100% mineralized in 56 days in another sludge(2). 4-Nitrophenol was degraded 51 % and 70 % in 2 flooded soils over a 10 day incubation period(3). No biodegradation of 4-nitrophenol was observed under denitrifying conditions during a 30 day incubation period(4). 4-Nitrophenol was degraded over 90 % in an anaerobic groundwater/sediment microcosm from a landfill during a 10 day incubation period(5). When 4-nitrophenol was incubated with an estuarine sediment suspension from the Louisiana Gulf Coast, only 7% mineralization occurred under anaerobic conditions in 10 days(6). When 2 ppm of 4-nitrophenol was incubated in agricultural topsoil at 10 deg C, the half-life was 14 days under anaerobic conditions(7). [R109] ABIO: +... Has been detected as a photo-alteration product of parathion following application to cotton plants. [R110] *The rate constant for the vapor-phase reaction of 4-nitrophenol with photochemically-produced hydroxyl radicals has been measured as 4.4X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 4 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 4-Nitrophenol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). 4-Nitrophenol adsorbed to silica gel was 39% mineralized when exposed to light greater than 290 nm over a 17 hour period(3). A pKa of 7.15(4), indicates that 4-nitrophenol will partially exist in the ionized form in the environment. The rate constant for the reaction between singlet oxygen and 4-nitrophenol in surface waters was measured as 2.6X10+6 l/mol-s at 27 deg C(5). This corresponds to a photolysis half-life of about 77 days at a singlet oxygen concn of 4X10-14 mol/l(5). When 4-nitrophenol in water was exposed to sunlight, the half-life was 5.7, 6.7, and 13.7 days at pH 5, 7, and 9, respectively(6). The presence of substances like nitrite and nitrate ions in the water results in the formation of hydroxyl radicals under illumination which can react with 4-nitrophenol(7) to form 1,4-hydroquinone and 1,4-benzoquinone(8). In laboratory experiments, the half-life, which was 16 hr for direct photolysis, was reduced to 1.2 and 3.5 hr in the presence of nitrite and nitrate ions(7). [R111] BIOC: *BCF values of 2 to 8 were measured for carp exposed to 0.2 mg/l of 4-nitrophenol over a 6 week incubation period(1). BCF values of 3 to 5 were measured for carp exposed to 0.02 mg/l of 4-nitrophenol over a 6 week incubation period(1). The BCF value of 4-nitrophenol was reported as 79 in fathead minnows(2) and 58 in golden orfe(3). According to a classification scheme(4), these BCF values suggest bioconcentration in aquatic organisms is low to moderate. [R112] KOC: +The sorption of benzoic acid, nitrobenzene, 4-nitrophenol, 2,4-dichlorophenoxyacetic acid, and naphthalene was determined for 10 Danish soils in laboratory studies. Measured equilibrium isotherms were of nonlinear Freundlich type for nearly all combinations of soil test compounds. Adsorption was significantly correlated with the organic carbon content of the soils tested. No significant correlations with pH and cation exchange capacity were observed. [R113] *The Koc of 4-nitrophenol was reported as 55 in Brookston clay loam(1) and the log Koc was reported as 1.7 in a second study(2). According to a classification scheme(3), these Koc values suggest that 4-nitrophenol is expected to have high mobility in soil. [R114] VWS: *The Henry's Law constant for 4-nitrophenol is 1.3X10-8 atm-cu m/mole at 20 deg C(1). This Henry's Law constant indicates that 4-nitrophenol is not expected to volatilize from water surfaces(2). The pKa of 4-nitrophenol is 7.15(3), indicating that this compound will partially exist in the ionized form in water and moist soils and the anion will not volatilize(SRC). 4-Nitrophenol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.005 mm Hg at 20 deg C(4). [R115] WATC: *GROUNDWATER: 4-Nitrophenol was detected in groundwater of Ville Mercier, Quebec, Canada at 0.3-6.5 ug/l(1). 4-Nitrophenol was detected at concns of 5.8-84 ug/l in groundwater at a former munitions plant in Saxony, Germany(2). 4-Nitrophenol was detected in groundwater of a waste treatment plant (0.002-0.014 ug/l) and a landfill (0.002-0.003 ug/l) in Cape Cod, MA(3). 4-Nitrophenol was detected in the Biscayne Aquifer, FL at 200 ug/l(4). [R116] *DRINKING WATER: 4-Nitrophenol was identified, not quantified, in drinking water of Taiwan(1) and the US(2). [R117] *SURFACE WATER: Ambient water concentrations reported in the USEPA's STORET data base, 1980-82 (807 samples) 0.0% pos(1). Not detected in the Lake Erie or Lake Michigan basin(2). [R118] *SURFACE WATER: 4-Nitrophenol was identified, not quantified, in natural waters of Taiwan(1). 4-Nitrophenol was detected in the Potomac River, Virginia at a concn of less than 10 ug/l(2). [R119] *RAIN/SNOW: 4-Nitrophenol was identified, not quantified, in rainwater in Yokohama, Japan(1). 4-Nitrophenol was detected in the rain and snow of Hannover, Germany at concns of 0.49-17.1 ug/l(2). 4-Nitrophenol was detected in the rain and clouds of the Vosges mountains, France at concns of 1.11-16.27 ug/l (mean, 2.95 ug/l)(3). [R120] EFFL: *Effluent concns reported in the USEPA's STORET database, 1980-1982 identified, not quantified in 42 out of 1,318 samples(1). 4-Nitrophenol was detected in the treated effluents of the following industries: electrical/electronic components (< 22 ppb mean, 35 ppb max), organic chemicals manufacturing/plastics (190 ppb max), petroleum refining (< 1 ppb max), and textile mills (< 10 ppb max)(2). Additionally the raw wastewater of the following industries not listed above contained 4-nitrophenol (industry (concn)): auto and other laundries (14 ppb mean), aluminum forming (18 ppb max) metal finishing (10 ppb max), and photographic equipment/supplies (57 ppb max)(2). 4-Nitrophenol was detected in Long Island, NY, Washington, DC, Little Rock, AK, and Eugene, OR in the range 1-19 ppb, with a 9% frequency of detection according to the National Urban Runoff Program in which 19 cities and metropolitan councils across the USA (51 catchments) were sampled(3). 4-Nitrophenol was identified, not quantified, from a hazardous waste incinerator in Germany(4). 4-Nitrophenol was detected in the effluent of 17 refineries in the US at concns of less than 50 ug/l(5). 4-Nitrophenol was detected in the exhaust of vehicles without catalytic converters at concns of 0.1-1.0 ug/l of exhaust(6). Exhaust from gasoline and diesel engines contained trace amounts and 2.5 ppb of 4-nitrophenol, respectively(7). 4-Nitrophenol was detected in untreated septage (0.16 ug/l), untreated wastewater (0.091-0.22 ug/l) and treated septage/wastewater (0.034-0.12 ug/l) in Cape Cod, MA(8). [R121] SEDS: *4-Nitrophenol was detected in soil of Ville Mercier, Quebec, Canada at 2.6-70,400 ug/kg(1). 4-Nitrophenol was identified, not quantified, in 6 of 302 soil samples reported in the USEPA's STORET data base, 1980-82(2) and in soil/sediment samples from Love Canal, NY(3). [R122] ATMC: *URBAN/SUBURBAN: 4-Nitrophenol was detected in Yokahama, Japan at concns of 5.1-42 ppm. 4-Nitrophenol was detected in the atmosphere of Boise, ID at concns of less than 0.04 ng/cu m to 2.7 ng/cu m(2). 4-Nitrophenol was detected in Great Dun Fell, Germany at concns of less than 0.05 ng/cu m to 20.4 ng/cu m(3). 4-Nitrophenol was detected in Portland, OR at concns of 11-34 ng/cu m (mean, 24 ng/cu m) in 1984(4). [R123] FOOD: *Lettuce sprayed with parathion (0.5 lb/acre) contained 0.061 ppm 4-nitrophenol at harvest on the trimmed head(1). [R124] PFAC: FISH/SEAFOOD CONCENTRATIONS: *4-Nitrophenol was identified, not quantified, in fish from Lake Michigan tributaries and embayments(1). [R125] RTEX: *POSSIBLE SOURCES OF HUMAN EXPOSURE TO 4-NITROPHENOL CAN ... RESULT FROM MICROBIAL OR PHOTODEGRADATION OF THE PARATHIONS OR FROM IN VIVO METABOLISM FOLLOWING INGESTION OF PARATHION OR OTHER SIMILAR ORGANOPHOSPHATE INSECTICIDES. [R1, 230] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,155 (1,533 of these are female) workers are potentially exposed to 4-nitrophenol in the US(1). Occupational exposure to 4-nitrophenol may occur through inhalation and dermal contact with this compound at workplaces where 4-nitrophenol is produced or used or where the pesticide parathion is used(SRC). The general population may be exposed to 4-nitrophenol via inhalation of ambient air and ingestion of contaminated water(SRC). [R126] BODY: *Health and Nutrition Examination Survey II: 4-Nitrophenol was identified, not quantified, in the urine of 168 of 6,990 persons that had been exposed to methyl and ethyl parathion(1). Parathion sprayers had detectable levels of 4-nitrophenol of 1.587-8.571 ug/ml in urine(2). [R127] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 4-Nitrophenol is included on this list. [R128] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 60 ug/l [R129] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 15 ug/l [R129] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Nitrophenols/ [R130] +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R131] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R132] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Nitrophenol is included on this list. [R133] RCRA: *U170; As stipulated in 40 CFR 261.33, when p-nitrophenol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R134] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SEPARATION OF PARATHION AND P-NITROPHENOL. READ ABSORBANCE OF EACH SOLN IN PHOTOELECTRIC COLORIMETER (400-450 NM) OR SPECTROPHOTOMETER (405 NM) AGAINST H2O AS REFERENCE. PLOT ABSORBANCE AGAINST CONCN IN MG/ML. [R135] +High-performance liquid chromatography separation by isocratic elution of a wide range of substituted phenols, incl the priority pollutants, was investigated. /Substituted phenols/ [R136] +Detection limits by Thin-Layer Chromatography are described for substituted phenols in water. /Substituted phenols/ [R137] +A reversed phase high pressure liquid chromatography method for resolution of phenolic cmpd was presented. A new derivation reaction was developed employing diazotized 4-aminobenzonitrile. The products of the reaction could be extracted in n-butanol, allowing preconcentration and clean-up steps. /Phenolic compounds/ [R138] +EPA Method 604: A gas chromatographic method for the analysis of 4-nitrophenol in municipal and industrial discharges, consists of a glass column, 1.8 m x 2 mm ID, packed with Supelcoport (80/100 mesh) coated with 1% SP-1240DA, with flame ionization detection, and nitrogen as the carrier gas at a flow rate of 30 ml/min, is an EPA approved method. A sample injection volume of 2 to 5 ul is suggested, the column injection temperature is 80 deg C programmed immediately at 8 deg C/min to a final temperature of 150 deg C. This method has a detection limit of 2.8 ug/l and an overall precision of 0.19 times the average recovery + 4.79, over a working range of 12.0 to 450 ug/l. [R139] +EPA Method 625: A gas chromatographic/mass spectrometry method for the analysis of 4-nitrophenol in municipal and industrial discharges, consists of a glass column, 1.8 m x 2 mm ID, packed with Supelcoport (100/120 mesh) coated with 3% SP-2250, with the detection performed by the mass spectrometer, and helium as the carrier gas at a flow rate of 30 ml/min, is an EPA approved method. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 50 deg C for 4 minutes and then programmed immediately at 8 deg/min to a final temperature of 270 deg C. This method has a detection limit of 2.4 ug/l and an overall precision of 0.44 times the average recovery + 3.24, over a working range of 5 to 1300 ug/l. [R139] *EPA Method 1625: An isotope dilution gas chromatography/ mass spectrometry method for the determination of semivolatile organic compounds in municipal and industrial discharges, this method is designed to meet the survey requirements of Effluent Guidelines Division (EGD) and the National Pollution Discharge Elimination System (NPDES). Under the prescribed conditions, unlabeled 4-nitrophenol has a minimum level of 50 ug/l and a mean retention time of 1354 sec. This method has an initial precision of 42 ug/l and an accuracy of 62-146 ug/l for the unlabeled compound. [R139] +HIGH PRESSURE LIQ CHROMATOGRAPHIC METHOD CAPABLE OF IDENTIFYING NG/L QUANTITIES OF PHENOLIC CMPD IN WATER WAS DESCRIBED. SEPARATION WAS ACCOMPLISHED BY USING A MICROPAK 5 U C18 COLUMN WITH ACETIC ACID/WATER/ACETONITRILE ELUENT. DUAL UV DETECTION PROVIDED CONFIRMATORY INFORMATION. /Phenolic cmpd/ [R140] +A LIQUID CHROMATOGRAPHIC SYSTEM, CAPABLE OF SELECTIVELY DETECTING INDIVIDUAL PHENOLIC COMPOUNDS AT 1 PPB LEVELS IN WATER IS DESCRIBED. A POLYMERIC-CATION-EXCHANGE RESIN COLUMN, ACIDIC ACETONITRILE-WATER ELUENT AND AN ELECTROCHEMICAL DETECTOR CONTAINING UNIQUE C-BLACK/POLYETHYLENE TUBULAR ANODE ARE EMPLOYED. 1 PPB LEVELS WERE DETECTED. /PHENOLIC CMPD/ [R141] +A gas-liquid chromatographic procedure is described for the identification of 32 substituted phenols. This method involves a simple and reproducible derivation step which forms stable phenol pentafluorobenzy ethers for which the electron capture detector is highly sensitive. /Substituted phenols/ [R142] *Method 3630B. Silica Gel Cleanup Method. [R143] *Method 3650B. Acid-Base Partitioning Cleanup. [R143] *EPA Method 8040: Phenols. For the detection of phenolic compounds, a representative sample (solid or liquid) is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Maximum sample holding time after extraction is 40 days. Samples are extracted using the appropriate techniques and are analyzed by gas chromatography using the solvent flush technique, with detection achieved with a flame ionization detector (FID). For the preparation of pentafluorobenzylbromide (PFB) derivatives, additional cleanup procedures for electron capture gas chromatography /are/ provided. Under the prescribed conditions, 4-nitrophenol has a detection limit of 2.8 ug/l, a limit for the standard deviation of four measurements of 19.0 ug/l, and a range of the average recovery of 22.7-100.0 ug/l. [R144] *Method 8041. Phenols by Gas Chromatography: Capillary Column Technique. [R143] *Method 8250A. Determination of Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry. [R143] *EPA Method 8270: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Capillary Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride, including the title compound, and are capable of being eluted without derivatization as sharp peaks from a 30 m by 0.25 mm ID (or 0.32 mm ID) 1 um film thickness silicon-coated fused silica capillary column (J and W Scientific DB-5 or equivalent). A representative sample is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Under the prescribed conditions, 4-nitrophenol has a retention time of 15.80 min, a range for the average recovery of four measurements of 13.0-106.5 ug/l, and a limit for the standard deviation of 47.2 ug/l. [R144] +A chromatographic micro method for determining trace amounts of substituted phenols in water was described. Samples, 0.5 to 1.0 ml, were extracted with toluene. The toluene layer was removed and the extracted phenols were derivatized with heptafluorobutyric anhydride. Excess heptafluorobutyric anhydride was removed by adding 100 microliters of 1 molar sodium hydroxide. An aliquot of the toluene layer was injected into a gas chromatograph fitted with an electron capture detector. The method was used to determine the concentration of phenols in a ground water microcosm, designed for studying the pattern and fate of pollutants. The microcosm was essentially a 4 by 20 sq cm glass column aseptically filled with nondisturbed soil cores and operated with a water flow rate of 2 centimeters per day. The well water supplying the soil was spiked with 1 mg/l in 10 mirograms per liter of phenols such as 2-fluorophenol, 2,4-dimethylphenol, phenol, 2,4,6-trichlorophenol, 4-nitrophenol, and p-cresol. Between 5 and 34 ng/ml of different phenols were detected. Loss of the original concentration of individiual phenols as a result of sorption and degradation was detectable. The detection limit of the phenols was generally 0.01 to 0.20 ng/ml. [R145] +A new gas chromatography column was developed that overcomes problems of incomplete separation in the determination of phenols, and permits quantitative analysis at the nanogram level of 11 priority polutants: 2-chlorophenol; 4-chloro-3-methylphenyl; 2-nitrophenol; 4-nitrophenol; 2,4,6-trichlorophenol; pentachlorophenol; 2-methyl-4,6-dinitrophenol; 2,4-dinitrophenol; phenol; 2,4-dimethylphenol; and 2,4-dichlorophenol. Gas liquid solid chromatography was selected for its high selectivity and suitability for the elution of polar compounds was very selective and linear. The problem of high retention times was solved by coating the packing material with morolayers of a nonpolar liquid phase. Use of an acidic phase to coat the adsorbent solved the problem of the presence of some chemically active adsorption sites; trimesic acid was preferred. Chromatograms of industrial water from an olive oil extraction plant polluted by phenols showed that the elution of water is very fast and does not effect column performance. The packed column officially used in the United States gave less effective separation. A capillary column required 50% higher analysis time. [R146] CLAB: *HYDROLYZED URINE SAMPLE IS EXTRACTED WITH ORGANIC SOLVENT WHICH IN TURN IS REEXTRACTED WITH ALKALI. THIS ALKALINE SOLN IS REACTED WITH O-CRESOL AND TITANIUM TRICHLORIDE TO YIELD SOLN WHOSE ABSORBANCE IS FUNCTION OF P-NITROPHENOL CONCN. [R147] +Pretreated samples (eg homogenized fish samples) were analyzed by gas chromatography for the micro determination of o-, m-, and p-nitrophenol. Recoveries ranged from 88 to 96%. [R148] +In connection with the toxicologic analysis of a number of parathion intoxications a method for determination for free and conjugated forms of p-nitrophenol (p-NP) as the main metabolite of parathion in blood and urine was established. Quantification of conjugates is based on their hydrolysis followed by detection of p-NP using a sensitive high performance liquid chromatography method. Hydrolysis of both p-nitrophenol glucuronide and p-nitrophenol sulfate is performed by specific enzymes and also by mineral acid, the latter is also found to be highly selective under definite conditions. The two hydrolysis methods applied showed a good correlation. The levels of free and conjugated p-NP in series of blood and urine samples were established after survival from two parathion intoxications. The individual levels of p-nitrophenol sulfate and p-nitrophenol glucuronide in both cases are discussed in respect of results made by other authors in this field. [R149] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol (1980) EPA 440/5-80-063 Dean BJ; Mutat Res 47: 75-97 (1978). A review with 90 references on the mutagenicity, biotransformations, and toxicity of benzene, toluene, xylene, and phenols including o-nitrophenol. Bablch H, Borenfreund E; Environ Res 42 (1): 229-37 (1987). BF-2 cells, an established cell line derived from bluegill sunfish, (Lepomis macrochirus), were exposed to 18 organic toxicants, with cytotoxicity being assayed by the neutral red technique. DHHS/ATSDR; Toxicological Profile for Nitrophenols: 2-Nitrophenol, 4-Nitrophenol (1992) TP-91/23 DHHS/NTP; Toxicology and Carcinogenesis Studies of p-Nitrophenol in Swiss-Webster Mice (Dermal Studies) Technical Report Series No. 417 (1993) NIH Publication No. 93-3148 USEPA; Ambient Water Quality Criteria Doc: Nitrophenols (1987) EPA 600/8-88/050 SO: R1: National Research Council. Drinking Water and Health, Volume 4. Washington, DC: National Academy Press, 1981. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 830 R3: CHEMCYCLOPEDIA 1985 p.103 R4: WEISS. HAZARD CHEM DATA BOOK 1980 p.667 R5: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 772 R6: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 664 R7: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1138 R8: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-197 R9: SRI R10: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 375 R11: Chemical Marketing Reporter; Chemical Profiles (8/13/90) R12: CHEMICAL PROFILE: P-NITROPHENOL, (1984) R13: Kavaler AR; Chemical Marketing Reporter 232 (13): 50 (1987) R14: Chemical Marketing Reporter; Chemical Profile p-Nitrophenol. August 13, 1990 NY,NY: Schnell Pub Co (1990) R15: SRI. DIRECTORY OF CHEMICAL PRODUCERS-USA 1987, p.819 R16: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-494 R17: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R18: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2034 R19: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. C-414 R20: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996. R21: Serjeant EP, Dempsey B; Ionisation constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. NY,NY: Pergamon pp. 989 (1979) R22: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 18 R23: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1399 R24: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-432 R25: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 147 R26: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 70 R27: Schwarzenbach R et al; Environ Sci Technol 22: 83-92 (1988) R28: Tremp J et al; Water Air Soil Pollut 68: 113-12 (1993) R29: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R30: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1451 R31: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 780 R32: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 49-98 R33: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2455 R34: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R35: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R36: 49 CFR 171.2 (7/1/96) R37: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 187 R38: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6186 (1988) R39: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. 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Mosby Lifeline. 1994. R49: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.C-10 (1980) EPA 440/5-80-063 R50: POIRIER MC; DISS ABSTR INT B 37: 5493 (1977) R51: GENE-TOX Program: Current Status of Bioassay in Genetic Toxicology. U.S. Environmental Protection Agency, Washington, DC. Office of Toxic Substances and Pesticides. (For program information, contact Environmental Mutagen Information Center, Oak Ridge National Laboratory, Post Office Box Y, Oak Ridge, Tennessee 37830. Telephone (615) 574-7871) R52: FAHRIG R; IARC SCI PUBL 10: 161-81 (1974) R53: AMACHER DE, TURNER GN; MUTAT RES 97 (1): 49 (1982) R54: WARD GS ET AL; J TOXICOL ENVIRON HEALTH 8 (1-2): 225-40 (1981) R55: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 974 R56: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.C-19 (1980) EPA 440/5-80-063 R57: Hardin BD et al; Terat Carcin Mut 7: 29-48 (1987) R58: Hazelton GA et al; Toxicol Appl Pharmacol 78 (2): 280-90 (1985) R59: Francis PC et al; Bull Environ Contam Toxicol 36 (5): 730-7 (1986) R60: Schultz TW et al; Ecotoxicol Environ Saf 12 (2): 146-53 (1986) R61: Keen B, Baillod CR; Water Res 19 (6): 762-72 (1985) R62: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.B-13 (1980) EPA 440/5-80-063 R63: Toxicology and Carcinogenesis Studies of p-Nitrophenol in Swiss Webster Mice (Dermal Studies). Technical Report Series No. 417 (1993) NIH Publication No. 93-3148 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R64: NTP; Toxicology and Carcinogenesis Studies of p-Nitrophenol in Swiss-Webster mice (Dermal Studies) p. 165 (1993) R65: Hartmann A, Speit G; Toxicol Lett 90 (2-3): 183-8 (1997) R66: Vernot EH et al; Toxicol and Appl Pharm 42: 417-23 (1977) R67: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.B-17 (1980) EPA 440/5-80-063 R68: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.B-15 (1980) EPA 440/5-80-063 R69: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.B-3 (1980) EPA 440/5-80-063 R70: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.B-16 (1980) EPA 440/5-80-063 R71: Holcombe GW et al; Environ Pollut 35 (Series A): 367-81 (1984) R72: LANDRUM PF, CROSBY DG; XENOBIOTICA 11 (5): 351-61 (1981) R73: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.C-13 (1980) EPA 440/5-80-063 R74: Goerge G et al; Xenobiotica 17 (11): 1293-8 (1987) R75: Hughes MF, Hall LL; Food and Chemical Toxicology 35 (7): 697-704 (1997) R76: Testa, B. and P. 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N-18 R78: MACHIDA M ET AL; BIOCHEM PHARMACOL 31 (5): 787-91 (1982) R79: DIAMOND GL, QUEBBEMANN AJ; DRUG METAB DISPOS 9 (5): 402-9 (1981) R80: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.C-14 (1980) EPA 440/5-80-063 R81: Foster GD, Crosby DG; Environ Toxicol Chem 5 (12): 1059-70 (1986) R82: Meerman JHN et al; Biochem Pharmacol 36 (16): 2605-8 (1987) R83: Kasokat T et al; Xenobiotica 17 (10): 1215-21 (1987) R84: Shipley LA et al; Drug Metab Dispos 14 (5): 526-31 (1986) R85: Weitman SD et al; Dev Pharmacol Ther 9 (1): 23-31 (1986) R86: Watanabe HK et al; Biochem Pharmacol 35 (3): 455-60 (1986) R87: Raza H et al; Xenobiotica 17 (6): 669-77 (1987) R88: Yokota H et al; Biochem Pharmacol 37 (5): 799-802 (1988) R89: Amato G et al; Drug Metab Dispos 26 (5): 483-9 (1998) R90: Amet Y et al; Alcoholism Clinical and Experimental Research 22 (2): 455-62 (1998) R91: Jiang Y et al; Biochemical and Biophysical Research Communications 246 (3): 578-83 (1998) R92: Zerilli A et al; Chemical Research in Toxicology 10 (10): 1205-12 (1997) R93: Hu H-L et al; Neurotoxicology 18 (2): 363-70 (1997) R94: Lindstrom-Seppa P; Aquat Toxicol 6 (4): 323-32 (1985) R95: Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979.p. 90-5 R96: Sultatos LG; Toxicol Appl Pharmacol 86 (1): 105-11 (1986) R97: USEPA; Nitrophenols: Hazard Profile (Draft) p.18 (1980) R98: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 581 R99: (1) Chemical Marketing Reporter; Chemical Profile p-Nitrophenol. Aug 13, 1990. NY,NY: Schnell Pub Co (1990) (2) Graedel TE; Chem Compounds in the Atmos, Academic Press NY p 297 (1978) (3) Metcalf RL; Kirk-Othmer Encycl Chem Tech 3rd ed NY,NY: Wiley 13: 438 (4) Archer TE; J Agric Food Chem 23: 858-60 (1975) (5) Nojima K et al; Chem Pharm Bull 31: 1047-51 (1983) R100: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Borisover MD, Graber ER; Chemosphere 34: 1761-76 (1997) (3) Tremp J et al; Water Air Soil Pollut 68: 113-123 (1993) (4) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. IUPAC Chemical Data Series No 23. NY, NY: Pergamon Press pp. 989 (1979) (5) Schwarzenbach R et al; Environ Sci Technol 22: 83-92 (1988) (6) Loehr RC; Treatability Potential for EPA Listed Hazardous Wastes in Soil. Ada, OK: Robert S Kerr Environ Res Lab, USEPA/600/2-89/011 (1989) R101: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Borisover MD, Graber ER; Chemosphere 34: 1761-76 (1997) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Tremp J et al; Water Air Soil Pollut 68: 113-123 (1993) (5) erjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. IUPAC Chemical Data Series No 23. NY, NY: Pergamon Press pp. 989 (1979) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (8) Call DJ et al; Arch Environ Contam Toxicol 9: 699-714 (1980) (9) Capel PD, Larson SJ; Chemosphere: 30: 1097-1107 (1995) (10) Hustert K et al; Chemosphere 10: 995-8 (1981) R102: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Schwarzenbach R et al; Environ Sci Technol 22: 83-92 (1988) (3) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (4) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) R103: Goldstein RM et al; Appl Environ Microbiol 50 (4): 977-83 (1985) R104: Nyholm M et al; Ecotoxicol Environ Safety 8 (5): 451-70 (1984) R105: Wiggins BA et al; Appl Environ Microbiol 53 (4): 791-6 (1987) R106: (1) Organ Econ Coop Devel; OECD Chemical Testing Programme, Expert Group Degradation/Accumulation 1: 141 (1979) (2) Dojlido JR; Investigations of Biodeg and Toxicity of Organic Compound pp 118 USEPA 600/2-79-163 (1979) (3) Kool HJ; Chemosphere 13: 751-61 (1984) (4) Gerike P, Fischer WK; Ecotox Environ Safety 3: 159-73 (1979) (5) Means JL, Anderson SJ; Water Air Soil Poll 16: 301-15 (1981) (6) Rott B et al; Chemosphere 11: 531-8 (1982) (7) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (8) Spain JC et al; Appl Environ Microbiol 48: 944-50 (1984) (9) Haller HD; J Water Pollut Control Fed 50: 2771-7 (1978) (10) Schmidt-Bleek F et al; Chemosphere 11: 383-415 (1982) (11) Schefer W, Waelchli O; Z Wasser Abwasser Forsch 13: 205-9 (1980) (12) Rubin HE et al; Appl Environ Microbiol 43: 1133-8 (1982) (13) Wilderer P; AICHE Symp Ser 77: 205-13 (1981) (14) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 12: 37-46 (1983) R107: (1) Scow KM et al; Appl Environ Microbiol 51: 1028-35 (1986) (2) Loekke H; Environ Pollut Ser A 38: 171-81 (1985) (3) Lichtenstein E; Fate of Persistence of (14)C Residues in Different Soils. Internatl Atomic Energy Agency, Vienna IAEA-R-2032-F, NTIS DE83704120. pp. 1-20 (1982) (4) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (5) Nielsen PH, Christensen; J Contam Hydrol 17: 55-67 (1994) (6) Christensen TH et al; pp. 1/207-1/214 in Proc ISWA Int Congr Exhib 7th Yokohama, Japan: ISWA International Congr (1996) (7) Nielsen PH et al; Environ Sci Technol 30: 31-37 (1996) (8) Loehr RC; Treatability Potential for EPA Listed Hazardous Wastes in Soil. Ada,OK: Robert S Kerr Environ Res Lab USEPA/600/2-89/011 (1989) R108: (1) Spain JC et al; Appl Environ Microbiol 48: 944-50 (1984) (2) Dojlido JR; Investigations of Biodeg and Toxicity of Organic Compound. USEPA 600/2-79-263 pp. 118 (1979) (3) Rubin HE et al; Appl Environ Microbiol 43: 1133-8 (1982) (4) Jones SH, Alexander M; Appl Environ Microbiol 51: 891-7 (1986) (5) Van Veld PA, Spain JC; Chemosphere 12: 1291-1305 (1983) (6) Spain JC, Van Veld PA; Appl Environ Microbiol 45: 428-35 (1983) (7) Spain JC et al; Appl Environ Microbiol 40: 726-34 (1980) (8) Paris DF et al; Appl Environ Microbiol 45: 1153-5 (1983) (9) Capel PD, Larson SJ; Chemosphere: 30: 1097-1107 (1995) R109: (1) Boyd SA et al; Appl Environ Microbiol 46: 50-4 (1983) (2) Shelton DR, Tiedje JM; Appl Environ Microbiol 47: 850-7 (1984) (3) Sudhakar-Barik, Sethunathan N; J Environ Qual 7: 349-52 (1978) (4) O'Conner OA, Young LY; Environ Sci Technol 30: 1419-28 (1996) (5) Christensen TH et al; pp. 1/207-1/214 in Proc ISWA Int Congr Exhib 7th Yokohama, Japan: ISWA International Congr (1996) (6) Siragusa GR, Delaune RD; Environ Toxicol Chem 5: 175-8 (1986) (7) Loekke H; Environ Pollut Ser A 38: 171-81 (1985) R110: USEPA; Ambient Water Quality Criteria Doc: Nitrophenol p.C-7 (1980) EPA 440/5-80-063 R111: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) (4) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. IUPAC Chemical Data Series No 23. NY,NY: Pergamon Press pp. 989 (1979) (5) Tratnyek, PG Holgne J; Environ Sci Technol 25: 1596-1604 (1991) (6) Hustert K et al; Chemosphere 10: 995-8 (1981) (7) Kotzias D et al; Naturwissenschaften 69: 444-5 (1982) (8) Suarez C et al; Tetrahedron Lett 8: 575-8 (1970) R112: (1) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Call DJ et al; Arch Environ Contam Toxicol 9: 699-714 (1980) (3) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) R113: Lokke H; Ecotoxicol Environ Safety 8 (5): 395-409 (1984) R114: (1) Boyd SA; Soil Science 134: 337-43 (1982) (2) Borisover MD, Graber ER; Chemosphere 34: 1761-76 (1997) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R115: (1) Tremp J et al; Water, Air Soil Pollut 68: 113-123 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. IUPAC Chemical Data Series No 23. NY,NY: Pergamon Press pp. 989 (1979) (4) Schwarzenbach R et al; Environ Sci Technol 22: 83-92 (1988) R116: (1) Pakdel H et al; pp. 381-421 in Groundwater Contamination and analysis at Hazardous Waste sites, Lesage S, Jackson RE eds., NY,NY: Marcel Dekker Inc (1994) (2) Lewin U et al; Chromatographia 45: 91-98 (1997) (3) Rudel RA; Environ Sci Technol 32: 861-869 (1998) (4) Canter LW, Sabatini DA; Intern J Environ Studies 46: 35-57 (1994) R117: (1) Wang YJ, Lin JK; Arch Environ Contam Toxicol 28: 537-42 (1995) (2) Garrison AW et al; in Pergamon Ser Environ Sci 1(Aquat Pollut: Transform Biol Eff 1997): 39-68 (1978) R118: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem 1: 195 (1983) R119: (1) Wang YJ, Lin JK; Arch Environ Contam Toxicol 28: 537-42 (1995) (2) Hall LW et al; Aquatic Toxicol 10: 73-99 (1987) R120: (1) Grosjean D Sci Total Environ 100: 367-414 (1991) (2) Alber M et al; Fres Z Anal Chem 334: 540-45 (1989) (3) Levsen K et al; Intern J Environ Anal Chem 52: 87-97 (1993) R121: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) USEPA; Treatability Manual 1: I.8.6-1 to I.8.6-5 USEPA 600/8-80-042 (1980) (3) Cole RH et al; J Water Pollut Control Fed 56: 898-908 (1984) (4) Jay K, Stieglitz L; Chemosphere 30: 1249-60 (1995) (5) Snider EH, Manning FS; Environ Int 7: 237-58 (1982) (6) Tremp J et al; Water Air Soil Pollut 68: 113-23 (1993) (7) Nojima K et al; Chem Pharm Bull 31: 1047-51 (1983) (8) Rudel RA; Environ Sci Technol 32: 861-869 (1998) R122: (1) Pakdel H et al; pp. 381-421 in Groundwater Contamination and Analysis at Hazardous Waste Sites, Lesage S, Jackson RE eds., NY,NY: Marcel Dekker Inc (1994) (2) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (3) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) R123: (1) Nojima K et al; Chem Pharm Bull 31: 1047-51 (1983) (2) Nishioka MG, Lewtas J; Atmos Environ 26A: 2077-87 (1992) (3) Luttke J, Levsen K; Atmos Environ 16: 2649-55 (1997) (4) Kelly TJ et al; Ambient Concentration Summeries For Clean Air Act Title III Hazardous Air Pollutants. Research Triangle Park,NC: USEPA/600/R-94/090 (1993) R124: (1) Archer TE; J Agric Food Chem 23: 858-60 (1975) R125: (1) Camanzo J et al; J Great Lakes Res 13: 296-309 (1987) R126: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R127: (1) Carey AE, Kutz FW; Environ Assess 5: 155-63 (1985) (2) Denga N et al; Bull Environ Contam Toxicol 55: 296-302 (1995) R128: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R129: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R130: 40 CFR 129 (7/1/88) R131: 40 CFR 116.4 (7/1/88) R132: 40 CFR 302.4 (7/1/97) R133: 40 CFR 716.120 (7/1/97) R134: 40 CFR 261.33 (7/1/97) R135: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 14/133 6.479 R136: Buckman NG et al; J Chromatog 284 (2): 441-6 (1984) R137: Thielemann H; Acta Hydrochim Hydrobiol 7 (1): 123-4 (1979) R138: Baiocchi C et al; Chromatographia 15 (10): 660-4 (1982) R139: 40 CFR 136 (7/1/87) R140: REALINI PA; J CHROMATOGR SCI 19 (3): 124-36 (1981) R141: ARMENTROUT DN ET AL; ANAL CHEM 51 (7): 1039-45 (1979) R142: Lee HB, Chau AS Y; J Assoc Off Anal Chem 66 (4): 1029-38 (1983) R143: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R144: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R145: Bengtsson G; J Chromatog Sci 23 (9): 397-401 (1985) R146: Mangani F et al; Analytical Chemistry 58 (14): 3261-3 (1986) R147: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 284 R148: Kawata K et al; Niigata-Ken Kogai Kenkyusho Kenkyu Hokoku 5: 11-4 (1981) R149: Michalke P; Z Rechtsmed 92 (2): 95-100 (1984) RS: 117 Record 116 of 1119 in HSDB (through 2003/06) AN: 1158 UD: 200302 RD: Reviewed by SRP 05/08/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-NITROTOLUENE- SY: *BENZENE,-1-METHYL-4-NITRO-; *P-METHYLNITROBENZENE-; *1-METHYL-4-NITROBENZENE-; *4-METHYLNITROBENZENE-; *NCI-9579-; *P-NITROTOLUENE-; *Nitrotoluenos- (Spanish); *4-NITROTOLUOL-; *TOLUENE,-P-NITRO- RN: 99-99-0 RELT: 6301 [NITROTOLUENES] MF: *C7-H7-N-O2 SHPN: UN 1664; Nitrotoluenes IMO 6.1; Nitrotoluenes STCC: 49 631 32; p-Nitrotoluene 49 631 55; Nitrotoluene ASCH: 4-Methyl-2-nitrophenol; 119-33-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM TOLUENE BY NITRATION AND SEPARATION BY FRACTIONAL DISTILLATION. [R1] MFS: +First Mississippi Corp, Hq, 700 North St, PO Box 1249, Jackson, MS 39205, (601) 948-7550; Subsidiary: First Chemical Corp, (601) 949-0246; Production site: Pascagoula, MS 39567 [R2] +E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Freon Products Division; Production site: Deepwater, NJ 08023 [R2] USE: *SYNTHESIS OF INTERMEDIATES AND EXPLOSIVES [R3, 2473] *CHEM INT FOR P-TOLUIDINE, STILBENE DYES, DINITROTOLUENES, P-NITROBENZALDEHYDE, P-NITROBENZOIC ACID. [R4] *FOR PRODUCTION OF TOLUIDINE, FUCHSIN, AND VARIOUS SYNTHETIC DYES. [R1] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 4.54X10+5 G [R4] *(1975) GREATER THAN 4.54X10+5 G [R4] *(1981) 7.0x10+9 G /CALCULATED/ [R5] *(1983) 2.0X10+10 G /ORTHO- AND PARA- ISOMERS COMBINED/ [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOWISH CRYSTALS [R6]; *COLORLESS RHOMBIC NEEDLES [R3, 2474]; *ORTHORHOMBIC CRYSTALS FROM ALCOHOL AND ETHER [R7, p. C-520]; +Crystalline solid. [R8] ODOR: *Weak aromatic [R9]; *Bitter almond [R10]; +Weak aromatic odor. [R8] BP: *238.3 DEG C @ 760 MM HG [R7, p. C-520] MP: *53-54 DEG C [R6] MW: *137.14 [R7, p. C-520] DEN: *1.1038 @ 75 deg/4 deg C [R7, p. C-520] HTC: *897.0 kgcal @ 20 deg C (liquid); 888.6 kgcal @ 20 deg C (solid) [R7, p. D-276] HTV: *11,915.0 gcal/gmole [R7, p. C-676] OWPC: *log Kow= 2.37 [R11] SOL: *SOL IN ALCOHOL, BENZENE, ETHER, CHLOROFORM, ACETONE [R6]; *SOL IN CARBON TETRACHLORIDE, PYRIMIDINE, TOLUENE [R12]; *0.004 g/100 g of water at 20 deg C. [R13, 1981.2]; *Water Solubility: 442 mg/l at 30 deg C [R14] SPEC: *INDEX OF REFRACTION: 1.5346 @ 62.5 DEG C [R3, 2474]; *SADTLER REF NUMBER: 4693 (IR, PRISM); 438 (IR, GRATING); MAX ABSORPTION (HEXANE): 265 NM (LOG E= 4.02) [R12]; *IR: 5633 (Coblentz Society Spectral Collection) [R15]; *UV: 1293 (Sadtler Research Laboratories Spectral Collection) [R15]; *NMR: 677 (Sadtler Research Laboratories Spectral Collection) [R15]; *MASS: 714 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R15] SURF: *36.83 dynes/cm @ 60 deg C; 35.64 dynes/cm @ 70 deg C [R10] VAPD: *4.72 (AIR = 1) [R3, 2474] VAP: *0.1 mm Hg at 20 deg C [R16] OCPP: *% IN SATURATED AIR: 0.17 @ 65 DEG C [R3, 2474] *Boiling point 105 deg C @ 9 mm Hg [R17] *VAPOR PRESSURE: 1.3 MM HG AT 65 DEG C [R3, 2474] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 4-nitrotoluene stem from its toxicologic properties and explosivity. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this bitter-almond-smelling, white-to-yellowish, crystalline substance may occur from its manufacture and use in the synthesis of dinitrotoluene, trinitrotoluene, and various azo and sulfur dye intermediates such as p-toluidine, p-nitrobenzaldehyde and 4-nitro-2-chlorotoluene. Effects from exposure may include contact burns to the skin and eyes, headache, weakness, dizziness, nausea, shortness-of-breath, tachycardia, and methemoglobinemia. The onset of symptoms may be delayed up to 4 hours. OSHA has set a time-weighted-average (TWA) limit of 2 ppm as a final rule to become effective December 31, 1992. Local exhaust ventilation should be applied to control airborne 4-nitrotoluene to permissible limits. In activities and situations where over-exposure may occur, wear a positive pressure self-contained breathing apparatus and chemical protective clothing which is specifically recommended by the shipper or manufacturer. If contact should occur, irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes, and wash exposed skin thoroughly with soap and water. Contaminated clothing should be removed and left at the site for cleaning. While 4-nitrotoluene does not ignite easily, it may burn with the production of irritating or poisonous gases. Also, containers of this substance may explode violently in the heat of a fire. For fires involving 4-nitrotoluene, extinguish with dry chemical, CO2, water spray, fog, or standard foam. Fight fire from as far a distance as possible, and if fire is advanced, evacuate the area. Dike fire control water. 4-Nitrotoluene should be stored away from sources of ignition, heat, strong oxidizers, and sulfuric acid. Small spills of 4-nitrotoluene should be carefully shovelled into a clean, dry container and covered loosely (liquid solutions are taken up with vermiculite, dry sand, or earth). Large dry spills on land should be covered with a plastic sheet to prevent dissolving in the rain or firefighting water, until removal is possible. Large liquid solution spills on land should be diked far ahead of the spill and not allowed to enter water sources or sewers. Spills into bodies of water should be trapped at the bottom with sand bag barriers and removed with suction hoses, or treated with activated carbon and the resulting immobilized masses removed with mechanical dredges or lifts. DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R18] FPOT: *Low fire hazard. /Nitrotoluene/ [R19] *... Contact with strong oxidizers or sulfuric acid may cause fires ... /Nitrotoluene/ [R13, 1981.2] NFPA: +Health 3. 3= Materials extremely hazardous to health, but areas may be entered with extreme care. Full protective clothing, including self-contained breathing apparatus, rubber gloves, boots and bands around legs, arms, and waist should be provided. No skin surface should be exposed. /Nitrotoluenes/ [R20, p. 49-99] +Flammability: 1. 1= Materials that must be preheated before ignition can occur. Water may cause frothing of liquids with this flammability rating number if it gets below the surface of the liquid and turns to steam. However, water spray gently applied to the surface will cause a frothing which will extinguish the fire. Most combustible solids have a flammability rating of 1. /Nitrotoluenes/ [R20, p. 49-99] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R20, p. 49-99] FLMT: +lower: 1.6% [R20, p. 49-99] FLPT: *106 DEG C; 223 DEG F (CLOSED CUP) [R3, 2474] AUTO: +734 deg F (390 deg C) [R20, p. 49-99] FIRP: +Use dry chemical, carbon dioxide, or water spray. Water streams or foam may cause frothing. Use water spray to keep fire-exposed containers cool. Approach fire from upwind to avoid hazardous vapors and toxic decomposition products. Extinguish fire using agent suitable for surrounding fire. [R20, p. 49-99] *Use water in flooding quantities as fog; Cool all affected containers with flooding quantities of water, apply water from as far a distance as possible, solid streams of water may be ineffective. /Nitrotoluene/ [R21] TOXC: *Toxic gases and vapors (such as oxides of nitrogen and carbon monoxide) may be released in a fire involving nitrotoluene. /Nitrotoluene/ [R13, 1981.2] REAC: *INCOMPATIBLE /WITH/ SULFURIC ACID; TETRANITROMETHANE. [R19] +para-Nitrotoluene and sulfuric acid exploded @ 80 deg C. [R20, p. 491-132] *Nitrotoluene will attack some forms of plastics, rubber, and coatings. /Nitrotoluene/ [R13, 1981.2] *... Contact with strong oxidizers or sulfuric acid may cause fires and explosions. [R13, 1981.2] +Strong oxidizers, sulfuric acid. [R22, 232] DCMP: *Decomposes violently at 279 deg C and will burn even in absence of air. [R10] SERI: *Irritating to eyes, nose and throat. [R10] EQUP: *Wear butyl rubber gloves, protective clothing and shoes, and self-contained breathing apparatus. [R23] *Respirators may be used when engineering and work practice controls are not technically feasible ... Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... Respirators permitted are those that have been approved by the Mine Safety and Health Admin ... or by the NIOSH. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (8-inch min), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with solid or liq nitrotoluene. ... Employees should be provided with and required to use dust- and splash-proof safety goggles where solid or liq nitrotoluene may contact the eyes. /Nitrotoluene/ [R13, 1981.2] +Wear appropriate personal protective clothing to prevent skin contact. [R22, 233] +Wear appropriate eye protection to prevent eye contact. [R22, 233] +Recommendations for respirator selection. Max concn for use: 20 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R22, 233] +Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R22, 233] +Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R22, 233] +Recommendations for respirator selection. Max concn for use: 200 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R22, 233] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R22, 233] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R22, 233] OPRM: +Contact lenses should not be worn when working with this chemical. [R22, 233] *Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain water flow as necessary. /Nitrotoluene/ [R21] *Avoid breathing vapors or dusts. Do not handle broken packages without protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R21] *... A complete respiratory protection program should be instituted which incl regular training, maintenance, inspection, cleaning, and evaluation. ... Non-impervious clothing which becomes contaminated ... should be removed ... and not reworn until nitrotoluene is removed. Eating and smoking should not be permitted in areas where solid nitrotoluene is handled, processed, or stored. Employees who handle solid or liq nitrotoluene should wash ... hands thoroughly with soap or mild detergent and water before eating or smoking. /Nitrotoluene/ [R13, 1981.2] +The worker should immediately wash the skin when it becomes contaminated. [R22, 233] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R22, 233] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R22, 233] +SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: */Heat contributes/ ... to instability. /Nitrotoluene/ [R13, 1981.2] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R24] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R25] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R26] STRG: +Store in a cool, dry, well-ventilated location. Separate from acids, alkalies, oxidizing materials, and reducing agents. [R20, p. 49-99] CLUP: *1) Ventilate area of spill or leak. For small quantities of liq nitrotoluene, absorb on paper towels. For small quantities of solid nitrotoluene, sweep onto paper or other suitable material. Remove to safe place (such as fume hood) and burn. Large quantities of liq nitrotoluene can be collected and atomized in suitable combustion chamber equipped with appropriate effluent gas cleaning device. Large quantities of solid nitrotoluene can be reclaimed; ... If not practical, dissolve in flammable solvent (such as alcohol) and atomize in suitable combustion chamber equipped with appropriate effluent gas cleaning device. /Nitrotoluene/ [R13, 1981.3] *Land Spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with plastic sheet to prevent dissolving in rain or fire fighting water. /Nitrotoluene/ [R21] *Water Spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom, remove trapped material with suction hoses. If dissolved, apply activated carbon at ten times the spilled amount in region of 10 ppm or greater concentration. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Nitrotoluene/ [R27] DISP: *1) For liq nitrotoluene, by absorbing it in vermiculite, dry sand, earth or similar material and disposing in secured sanitary landfill. 2) By atomizing liq nitrotoluene in suitable combustion chamber equipped with appropriate effluent gas cleaning device. 3) By making packages of solid nitrotoluene in paper or other suitable material or by dissolving in a flammable solvent (such as alcohol) and burning in a suitable combustion chamber equipped with appropriate effluent gas cleaning device. /Nitrotoluene/ [R13, 1981.3] *The following wastewater treatment technologies have been investigated for 4-nitrotoluene: Concentration process: Biological treatment. [R28] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of nitrotoluenes. There is inadequate evidence in experimental animals for the carcinogenicity of ... 4-nitrotoluene. ... Overall evaluation: Nitrotoluenes are not classifiable as to their carcinogenicity to humans (Group 3). [R29] MEDS: *Initial Medical Exam: A complete history and physical exam: ... Exam of blood, nervous system, GI system, and cardiovascular system should be stressed. Skin should be exam for evidence of chronic disorders. ... A complete blood count should be performed, including red cell count, a white cell count, a differential count of stained smear, as well as hemoglobin and hematocrit. Periodic Medical Exam: The ... /initial medical exam/ should be repeated on an annual basis. Methemoglobin determinations should be performed if overexposure is suspected or signs and symptoms of toxicity occur. /Nitrotoluene/ [R13, 1981.1] *Routine checking of lips, tongue, and nail beds of exposed personnel for signs of cyanosis. /Nitrotoluene/ [R23] HTOX: *TOXICITY IDENTICAL WITH O-NITROTOLUENE. O-NITROTOLUENE PRODUCES METHEMOGLOBIN CAUSING HYPOXIA, BUT OF LOW POTENCY. IT IS ALSO SUSPECTED OF CAUSING ANEMIA IN CHRONIC EXPOSURES. [R3, 2474] *... Cases of poisoning from nitrotoluene are uncommon. Some authorities considered it only slightly toxic, esp in comparison with nitrobenzene. There is some evidence that the different isomers vary ... in toxicity. ... It is stated that nitrotoluene is a methemoglobin former of apparently low grade. /Nitrotoluene/ [R30] *... The onset of symptoms of methemoglobinemia is insidious and may be delayed up to 4 hours; headache is commonly the first symptom and may become quite intense as the severity of methemoglobinemia progresses. ... Cyanosis develops early in the course of intoxication, first the lips, the nose, and the ear lobes, and is usually recognized by fellow workers. ... Until the methemeglobinemia concentration approaches approximately 40%, the individual usually feels well, has no complaints, and will insist that nothing is wrong . ... Over 40% ... weakness and dizziness; at up to 70% ... there may be ataxia, dyspnea on mild exertion, tachycardia, nausea, vomiting, and drowsiness. /Nitrotoluene/ [R13, 1981.1] *TOXIC BY INHALATION, INGESTION, SKIN ABSORPTION. [R1] NTOX: *WHEN ADMIN ORALLY AT DOSES CORRESPONDING TO 0.1-0.2 LD50 VALUES IN RATS FOR 1-3 MO, THE HEMOTOXICITY OF TOLUENE DERIV DECR IN THE ORDER: TRINITROTOLUENE, DINITROTOLUENE, M-NITROTOLUENE, P-NITROTOLUENE, AND O-NITROTOLUENE. THEY CAUSED ANEMIA ACCOMPANIED BY RETICULOCYTOSIS AND A DECR IN THE LEVEL OF SH-GROUPS AND AN INCR OF FIBRINOGEN IN THE BLOOD. [R31] *The mutagenicities of the o, m, and p-isomers of nitrotoluene ... were tested with or without S9 mix and norharman in the Salmonella assay system. None of the compounds were mutagenic without norharman. ... The induction of mutagenesis with norharman was strong for the o-isomer, weak for the p-isomer, and was not observed for the m-isomer. [R32] *Synthetic condensate wastewater prepared to simulate the composition of condensate wastewater from TNT manufacture and containing 32 compounds showed acute toxic concentrations for bluegills (Lepomis macrochirus), scud (Hyalella azteca), and green algae (Selenastrom capricornutum) of 7.1 mg/l, 22.8 mg/l, and 10 mg/l respectively. [R33] *To determine whether hepatic macromolecular covalent binding of mononitrotoluene isomers to hepatic DNA in vivo was decreased by inhibitors of sulfotransferase, male Fischer-344 rats were given a single oral dose of ring-U-(14)C-labeled 2-, 3-, or 4-nitrotoluene, and were killed at various times thereafter. Livers were removed and analyzed for total and covalently bound radiolabel. Maximal concentrations of total radiolabel were observed between 3 and 12 hr after the dose, and there were no large differences among the 3 isomers in peak concentrations achieved. Covalent binding to hepatic macromols was maximal 12 hr after administration for all 3 isomers. Thereafter, concn of administration for all 3 isomers. Thereafter, concn of covalently bound 2-nitrotoluene derived material were always 2-6 times higher than those of 3- or 4-nitrotoluene derived material. When DNA was isolated from livers of rats given mononitrotoluene isomers 12 hr previously, only 2-nitrotoluene was observed to covalently bind at concns above the limits of detection of the assay. The covalent binding of 2-nitrotoluene, but not that of 3- or 4-nitrotoluene, to both total hepatic macromols and DNA was markedly decreased by prior administration of pentachlorophenol or 2,6-dichloro-4-nitrophenol. Covalent binding to hepatic DNA was decreased by > 96%. Thus, 2-nitrotoluene, but not 3- or 4-nitrotoluene, induces DNA excision repair. Furthermore, 2-nitrotoluene, like the hepatocarcinogen 2,6-dinitrotoluene, may require the action of sulfotransferase for its conversion to a species capable of covalently binding to hepatic DNA. [R34] +... 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 1,250, 2,500 or 5,000 ppm p-nitrotoluene (equivalent to avg daily doses of approx 55, 110, 240 mg/kg p-nitrotoluene/kg bw to males and 60, 125 or 265 mg/kg to females for 105 wk. ... 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0, 1,250, 2,500 or 5,000 ppm p-nitrotoluene (equivalent to avg daily doses of approx 170, 345 or 690 mg/kg to males and 155, 315 or 660 mg/kg to females) for 105 or 106 wk. CONCLUSIONS: Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity of p-nitrotoluene in male F344/N rats based on incr incidences of subcutaneous skin neoplasms. There was some evidence of carcinogenic activity of p-nitrotoluene in female F344/N rats based on incr incidences of clitoral gland neoplasms. There was equivocal evidence of carcinogenic activity of p-nitrotoluene in male B6C3F1 mice based incr incidences of alveolar/bronchiolar neoplasms. There was no evidence of carcinogenic activity of p-nitrotoluene in female B6C3F1 mice exposed to 1,250, 2,500 or 5,000 ppm. [R35] ETXV: *The log of the lowest concn of 4-nitrotoluene tested that significantly (p < 0.01) lowered the population growth constant of Daphnia after 21 days was 1.61 umol/l. This same concn was the lowest concn to significantly (p < 0.01) lower the mean length of Daphnia after 21 days; [R36, (1989] *The log of the concn of 4-nitrotoluene causing a decr of 50% in the maximum density (yield) of Chlorella pyrenoidosa populations after 96 hr exposure (96 hr EC50) was 2.21 umol/l; [R36, (1989)] *The log of the concn of 4-nitrotoluene causing a 50% decr of Photobacterium phosphoreum bioluminescence after 15 min of exposure was 1.90 umol/l; [R36, (1989)] *The log of the 48 hr immobilization concn (IC50) of Daphnia magna was 2.14 umol/l for 4-nitrotoluene in static tests. Using a semi-static procedure, the log of the 21 day IC50 was 1.71 umol/l for 4-nitrotoluene; [R36, (1989)] NTP: +... 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 1,250, 2,500 or 5,000 ppm p-nitrotoluene (equivalent to avg daily doses of approx 55, 110, 240 mg/kg p-nitrotoluene/kg bw to males and 60, 125 or 265 mg/kg to females for 105 wk. ... 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were fed diets containing 0, 1,250, 2,500 or 5,000 ppm p-nitrotoluene (equivalent to avg daily doses of approx 170, 345 or 690 mg/kg to males and 155, 315 or 660 mg/kg to females) for 105 or 106 wk. CONCLUSIONS: Under the conditions of these 2-year feed studies there was equivocal evidence of carcinogenic activity of p-nitrotoluene in male F344/N rats based on incr incidences of subcutaneous skin neoplasms. There was some evidence of carcinogenic activity of p-nitrotoluene in female F344/N rats based on incr incidences of clitoral gland neoplasms. There was equivocal evidence of carcinogenic activity of p-nitrotoluene in male B6C3F1 mice based incr incidences of alveolar/bronchiolar neoplasms. There was no evidence of carcinogenic activity of p-nitrotoluene in female B6C3F1 mice exposed to 1,250, 2,500 or 5,000 ppm. [R35] POPL: *Persons with blood disorders may be at increased risk from exposure. /Nitrotoluene/ [R13, 1981.1] ADE: +May be harmful if absorbed through skin or inhaled. [R20, p. 49-99] METB: *YIELDS P-NITROBENZYL ALCOHOL IN RABBITS. ... YIELDS P-NITROBENZYL ALCOHOL IN RATS AND MICE ... . /FROM TABLE/ [R37] *EEL LIVER HOMOGENATES METABOLIZE METHYL GROUP OF P-NITROTOLUENE, MODEL CMPD OF TOLUENE, MORE SLOWLY THAN RAT LIVER HOMOGENATES. [R38] *COMPARATIVE STUDIES ON ANILINE HYDROXYLATION AND P-NITROTOLUENE HYDROXYLATION BY THE LIVER ARE PRESENTED. [R39] *VERTEBRATE LIVER ENZYMES AND INTACT GRASS GRUBS OXIDIZED METHYL GROUPS OF P-NITROTOLUENE INTO CARBOXY GROUPS @ DIFFERENT RATES. [R40] *... The metabolism and excretion of 2-, 3-, and 4-nitrotoluene were studied in male Fischer 344 rats. ... The major metabolites excreted in urine in 72 hr after administration of 4-nitrotoluene were: 4-nitrobenzoic acid (28% of the dose), 4-acetamidobenzoic acid (27% of the dose) and 4-nitrohippuric acid (13% of the dose). [R41] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *The major sources of release of 4-nitrotoluene to the environment appear to be production and use facilities and plants which produces this compound as a by-product. This would include manufacturers of dinitrotoluene, trinitrotoluene and azo and sulfur dye intermediates such as p-toluidine, p-nitrobenzaldehyde and 4-nitro-2-chlorotoluene. 4-Nitrotoluene may also enter the environment from the disposal of waste products containing p-nitrotoluene. If released to soil, 4-nitrotoluene should be resistant to oxidation and chemical hydrolysis. This compound is reported to biodegrade under anaerobic conditions to form toluidine and one study on 4-nitrotoluene under aerobic conditions in mineral salts and a mixed culture of soil microorganisms resulted in persistence > 64 days. 4-Nitrotoluene is expected to be moderately to highly mobile in soil and to volatilize slowly from dry soil surfaces. If released to water, 4-nitrotoluene would be susceptible to photolysis, volatilization (estimated half-life 25 hours in water 1 m deep flowing 1 m/sec with a wind speed of 3 m/sec) and possibly aerobic biodegradation provided suitable acclimation has taken place. Oxidation, chemical hydrolysis, adsorption to suspended solids and sediments and bioaccumulation in aquatic organisms are not expected to be significant aquatic fate processes. Toluidine has been identified as an anaerobic biodegradation product of 4-nitrotoluene; however, insufficient data are available to indicate the significance of anaerobic biodegradation as a possible removal mechanism. Based on monitoring data, the half-life of 4-nitrotoluene in a river 4 to 5 m deep has been estimated to be 2.7 days. If released to the atmosphere, p-nitrotoluene is expected to exist almost entirely in the vapor phase. The dominant removal mechanisms would be reaction with photochemically generated hydroxyl radicals (estimated half-life 19.9 days) and direct photolysis. 4-Methyl-2-nitrophenol is a photoproduct of 4-nitrotoluene. The most probable routes of human exposure to 4-nitrotoluene are inhalation and dermal contact of workers involved in the production and use of this compound, dinitrotoluene and trinitrotoluene. (SRC) ARTS: *4-Nitrotoluene may be released to the environment by manufacturers of dinitrotoluene, trinitrotoluene and various azo and sulfur dye intermediates such as p-toluidine, p-nitrobenzaldehyde and 4-nitro-2-chlorotoluene(1,SRC). 4-Nitrotoluene may also enter the environment from the disposal of waste products in which it is contained(SRC). [R42] FATE: *TERRESTRIAL FATE: If released to soil, 4-nitrotoluene should be resistant to oxidation and chemical hydrolysis. This compound is reported to biodegrade under anaerobic conditions to form toluidine and one study on 4-nitrotoluene under aerobic conditions in mineral salts and mixed culture of soil microorganisms resulted in persistence > 64 days. 4-Nitrotoluene is expected to be moderately to highly mobile in soil and volatilize slowly from dry soil surfaces(SRC). 0.5 ug/l 4-nitrotoluene was detected in Rhine River water before infiltration and less than 0.01 ug/l (detection limit) was found after bank filtration (filtration time = 1-12 months) and after dune filtration (filtration time = 2-3 months)(1). [R43] *AQUATIC FATE: Based on monitoring data, the half-life of 4-nitrotoluene in a river 4 to 5 m deep has been estimated to be 2.7 days(1). If released to water, 4-nitrotoluene would be susceptible to photolysis, volatilization (estimated half-life 25 hr in water 1 m deep flowing 1 m/sec with a wind speed of 3 m/sec) and possibly aerobic biodegradation provided suitable acclimation has taken place. Oxidation, chemical hydrolysis, adsorption to suspended solids and sediments and bioaccumulation in aquatic organisms are not expected to be significant fate processes. Toluidine has been identified as an anaerobic biodegradation product of 4-nitrotoluene; however, insufficient data are available to indicate the significance of anaerobic biodegradation as a possible removal mechanism(SRC). [R43] *ATMOSPHERIC FATE: If released to the atmosphere 4-nitrotoluene is expected to exist almost entirely in the vapor phase(1,SRC). The dominant removal mechanisms would be reaction with photochemically generated hydroxyl radicals (estimated half-life 19.9 days)(2) and direct photolysis. 4-Methyl-2-nitrophenol is a photoproduct of 4-nitrotoluene(SRC). [R44] BIOD: *100 ppm 4-nitrotoluene inoculated with 30 ppm activated sludge under aerobic conditions at 25 deg C was < 30% degraded after 2 week(1,2). 4-Nitrotoluene (200 mg/l COD) inoculated with adapted activated sludge under aerobic conditions at 20 deg C underwent 98% degradation in 5 days as measured by COD removal(3). 4-Nitrotoluene should be degraded by biological sewage treatment provided suitable acclimation can be achieved(5). 10 ug/l 4-nitrotoluene inoculated in mineral salts and a mixed culture of soil microorganisms under aerobic conditions persisted > 64 days as measured by UV absorbance(4). In general, anaerobic biodegradation of nitroaromatic compounds results in the reduction of the nitro group to an amino group(6). Toluidine has been identified as an anaerobic biodegradation product of 4-nitrotoluene(7). [R45] ABIO: *FAP. Fate of Atmos Pollut (1986)] Chemical hydrolysis and oxidation of 4-nitrophenol are not expected to be important removal processes since this compound contains no functional groups which are susceptible to these types of reactions(1,SRC). Absorption of UV light in the environmentally significant range (> 290 nm) by 4-nitrotoluene in cyclohexane(2), indicates that the potential exists for photolysis in water and air(SRC). Irradiation (at > 300 nm) of 4-nitrotoluene vapor in air for 5 hr resulted in 38% loss of 4-nitrotoluene initially present and formation of 4-methyl-2-nitrophenol (6.1% yield)(3). The half-life for 4-nitrotoluene vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 19.9 days based on a reaction rate constant of 8.05X10-13 cu cm/molecules-sec at 25 deg C and an ambient hydroxyl radical concn of 5.0X10-5 molecules/cu cm(4). [R46] BIOC: *The bioconcentration factor (BCF) for 4-nitrotoluene has been measured to be less than 100 in carp (Carprinus carpio)(1,2). BCF values of 37 and 20 have been calculated based on a log octanol/water partition coefficient (log Kow) of 2.37 and a measured water solubility of 442 mg/l at 30 deg C(3,4,5,SRC). These BCF values suggest that 4-nitrotoluene will not bioaccumulate significantly in aquatic organisms(SRC). [R47] KOC: *The soil adsorption coefficient for 4-nitrotoluene has been calculated to be 464 and 153 based on a log octanol/water partition coefficient (log Kow) of 2.37 and a measured water solubility of 442 mg/l at 30 deg C, respectively(1,2,3,SRC). These Koc values suggest that 4-nitrotoluene would be moderately to highly mobile in soil and would adsorb slightly to suspended solids and sediments in water(4,SRC). [R48] VWS: *Henry's Law constant for 4-nitrotoluene has been calculated to be 5X10-5 atm-cu m/mole at 25 deg C using a method of structural contributions to compounds with intrinsic hydrophilic character(1,SRC). Based on this value for Henry's Law constant the volatilization half-life of 4-nitrotoluene from water 1 m deep, flowing 1 m/sec with a wind speed of 3 m/sec has been calculated to be 25 hr (2,SRC). A vapor pressure of 0.1 mm Hg at 20 deg C for 4-nitrotoluene suggests that this compound will volatilize slowly from dry soil surfaces(3,SRC). [R49] WATC: *During 1974, 2- and 4-nitrotoluene were detected in the river Waal (Netherlands), avg concn 4.5 ug/l, max concn 18.1 mg/l, and in the river Maas (Netherlands), max concn 0.3 ug/l(1). 4-Nitrotoluene has been detected in Rhine River water at a concn of 10 ug/l(2). [R50] EFFL: *4-Nitrotoluene has been found in the effluent from a plant manufacturing trinitrotoluene (TNT) in Radford, VA, 0.12 to 9.2 mg/l detected(1). 4-Nitrotoluene has been detected in the wastewater resulting from the production and purification of 2,4,6-trinitrotoluene, 0.01 to 0.17 mg/l detected, 43% of samples pos(2). 4-Nitrotoluene has also been detected in the raw effluent from a plant manufacturing dinitrotoluene, 8.8 mg/l detected, and in a waste treatment lagoon of a chemical company, 0.04 mg/l(1). [R51] ATMC: *4-Nitrotoluene has been detected in the ambient air at the Dupont plant in Deepwater, NJ at a concn ranging from 59 to 89 ng/cu m(1). [R52] RTEX: *The most probable routes of human exposure to 4-nitrotoluene are inhalation and dermal contact of workers involved in the production and use of this compound, dinitrotoluene and trinitrotoluene. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +200 ppm [R22, 232] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 5 ppm (30 mg/cu m). Skin designation. /Nitrotoluene, all isomers/ [R53] +Vacated 1989 OSHA PEL TWA 2 ppm (11 mg/cu m), skin designation, is still enforced in some states. /Nitrotoluene, all isomers/ [R22, 369] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2 ppm (11 mg/cu m), skin. [R22, 232] TLV: +8 hr Time Weighted Avg (TWA): 2 ppm, skin. /Nitrotoluene, all isomers/ [R54, 2002.45] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Nitrotoluene, all isomers/ [R54, 2002.6] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R54, 2002.91] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R55] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *4-NITROTOLUENE WAS REMOVED FROM AIR BY ABSORPTION ON FLUIDIZED BED AND DETERMINED BY THIN-LAYER CHROMATOGRAPHY. [R57] *A METHOD WAS DEVELOPED FOR DETERMINING O- AND P-NITROTOLUENE IN SOLN AND IN AIR BASED ON REDUCTION TO TOLUIDINE. [R58] *KNOWN MIXT OF O-NITROTOLUENE, M-NITROTOLUENE, AND P-NITROTOLUENE IN AIR OF INDUSTRIAL INSTALLATIONS WERE ANALYZED BY GAS CHROMATOGRAPHY. THE MINIMUM CONCN OF THE ISOMERS WAS 1X10-6 G/ML, TIME FOR EACH DETERMINATION 10 MIN, AND THE ABSOLUTE ERROR 9%. [R59] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of o-, m-, and p-Nitrotoluenes Administered in Dosed Feed to F344/N Rats and B6C3F1 Mice Toxicity Rpt Series No. 23 NIH Publication No. 93-3346 (1992) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that p-nitrotoluene is on the list of post peer review technical reports in progress. Route: dosed feed; Species: rats and mice. NTP TR No 498. [R60] SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 834 R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 809 R3: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R4: SRI R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. 929 R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1051 R7: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R8: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 232 R9: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 670 R10: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R11: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, June 1984. 76 R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-527 R13: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R14: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 866 R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 369 R16: Verschueren K; Handbook of Environmental Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY (1983) R17: Keith, L.H., D.B. Walters, (eds.). Compendium of Safety Data Sheets for Research and Industrial Chemicals. Parts I,II,and III. Deerfield Beach, FL: VCH Publishers, 1985. 1274 R18: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-152 R19: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1885 R20: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R21: Bureau of Explosives; Emergency Handling of Haz Matl in Surface Trans p.375 (1981) R22: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R23: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 381 R24: 49 CFR 171.2 (7/1/96) R25: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 187 R26: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6187 (1988) R27: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.501 R28: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-46 (1982) R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 66 430 (1996) R30: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.444 R31: KOVALENKO II; FARMAKOL TOKSIKOL (KIEV) 8: 137-40 (1973) R32: Suzuki J et al; Mutat Res 120 (2-3): 105-110 (1983) R33: Liu DHW et al; ASTM Spec Tech Publ 802 (Aquat Toxicol Hazard Assess): 135-50 (1983) R34: Rickert DE et al; Chem-Biol Interact 52 (2): 131-9 (1984) R35: Toxicology and Carcinogenesis Studies of p-Nitrotoluene in F344/N Rats and B6C3F1 Mice p.5-6 Technical Report Series No. 498 (2002) NIH Publication No. 02-4432 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R36: Deneer JW et al; Aquat Toxicol 15 (1): 83-98 R37: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. N-25 R38: OHMORI S ET AL; PHYSIOL CHEM PHYS 7 (5): 477-80 (1975) R39: IKEDA M ET AL; JAP J PHARMACOL 22 (4): 479-91 (1972) R40: HOOK GER, SMITH JN; BIOCHEM J 102: 504-10 (1967) R41: Chism JP et al; Drug Metab Dispos 12 (5): 596-602 (1984) R42: (1) Dunlap KL; Kirk-Othmer Encycl of Chem Technol 3rd ed. Vol 15 pp 930 (1981) R43: (1) Zoeteman et al; Chemosphere 9: 231-49 (1980) R44: (1) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (2) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) R45: (1) Kawasaki M; Ecotox Env Safety 4: 444-54 (1980) (2) Sasaki S; pp 283-98 in Aquatic Pollut, Transformation and Bio Effects, Hutzinger O, Van Leytoeld LH, Zoeteman BCJ eds (1978) (3) Pitter P; Water Res 10: 231-5 (1976) (4) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (5) Thom NS, Agg AR; Water Res 10: 231-5 (1976) (6) McCormick NG et al; Appl Environ Microb 31: 949-58 (1976) (7) Hallas LE, Alexander M; Appl Environ Microb 45: 1234-41 (1983) R46: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY pp 7-4 (1982) (2) Sadtler Res Lab; Sadtler Standard UV Spectra No.1293 (1961) (3) Nojima K, Kanno S; Chemosphere 6: 371-6 (1977) (4) Atkinson R; Int Chem Kinet 19: 799-828 (1987) R47: (1) Kawasaki M; Ecotox Env Safety 4: 444-54 (1980) (2) Sasaki S; pp 283-98 in Aquatic Pollut, Transformation and Bio Effects, Hutzinger O, Van Leytoeld LH, Zoeteman BCJ eds (1978) (3) Hansch C, Leo AJ; Medchem Project Issue No 26 Pomona College Claremont CA (1985) (4) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY (1983) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY pp 5-5 (1982) R48: (1) Hansch C, Leo AJ; Medchem Project Issue No 26 Pomona College Claremont CA (1985) (2) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY (1983) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY pp 4-9 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R49: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-7 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY chpt 15 (1982) (3) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY (1983) R50: (1) Meijers AP, Van Der Leer CR; Water Res 597-604 (1976) (2) Piet GJ, Morra CF; pp 31-42 in Artificial Groundwater Recharge, Huisman L, Olsthorn TN eds (1983) R51: (1) Howard PH et al; Investigation of Selected Potential Environ Contam, Nitroaromatics USEPA 560/2-76-010 (1976) (2) Spanggord RJ et al; Environ Sci Tech 16: 229-32 (1982) R52: (1) Pellizzari ED; Quantification of Chlorinated Hydrocarbons in Previously Collected Air Samples pp 46 USEPA 450/3-78-112 (1978) R53: 29 CFR 1910.1000 (7/1/98) R54: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R55: 40 CFR 116.4 (7/1/90) R56: 40 CFR 302.4 (7/1/90) R57: PILENKOVA II ET AL; GIG TR PROF ZABOL ISS 1: 43-4 (1980) R58: KURENKO LT; GIG TR PROF ZABOL 16 (4): 60-1 (1972) R59: IVANYUK EG, KOLIEVSKAYA YA; ZAVOD LAB 43 (2): 157-8 (1977) R60: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 51 Record 117 of 1119 in HSDB (through 2003/06) AN: 1179 UD: 200302 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N,N-DIMETHYLANILINE- SY: *ANILINE,-N,N-DIMETHYL-; *BENZENAMINE,-N,N-DIMETHYL-; *(DIMETHYLAMINO)BENZENE; *DIMETHYLANILINE-; *N,N-DIMETHYLBENZENEAMINE-; *DIMETHYLPHENYLAMINE-; *N,N-DIMETHYLPHENYLAMINE-; *DWUMETYLOANILINA- (POLISH); *NCI-C56428-; *VERSNELLER-NL-63/10- RN: 121-69-7 RELT: 43 [ANILINE] (Analog) MF: *C8-H11-N SHPN: UN 2253; N,N-Dimethylaniline IMO 6.1; N,N-Dimethylaniline MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Made by heating aniline, methyl alcohol, and sulfuric acid under pressure, the sulfate formed being converted by sodium hydroxide to the free base. [R1, 547] *By heating a mixture of aniline, aniline hydrochloride, and methyl alcohol (free from acetone) in an autoclave and distilling. [R2] *Dimethylaniline is produced by passing dimethyl ether and aniline vapor over highly activated aluminum oxide at 230-295 deg C [R3] FORM: *Grades: Technical, reagent, 99.9% pure [R2] *Basic Blue 1; Basic Blue 9; Basic Blue 54; Basic Green 4; Basic Red 22; Basic Violet 1; Basic Violet 3; 4,4'-bis(dimethylamino)benzophenone; bis(p-dimethylaminophenyl)methane; p-dimethylaminobenzaldehyde; N,N-dimethyl-p-nitrosoaniline; tetryl [R4] MFS: *Buffalo Color Corp., Hq, 959 Route 46 East, Suite 201, Parsippany, NJ 07054, (973) 316-5600; Production site: Buffalo, NY 14240 [R5] *DuPont, 1007 Market St., Wilmington DE 19898, (302)774-1000; DuPont Specialty Chemicals, DuPont Performance, Specialty, and Fine Chemicals; Production Site: Deepwater, NJ 08023 [R5] USE: *Manufacture of ... Michler's ketone ... As reagent for methanol, methyl furfural, hydrogen peroxide, nitrate, alcohol, formaldehyde [R1, 548] *... catalytic hardener in certain fiberglass resins. [R6] *CHEMICAL INT FOR VANILLIN, DYES; ACTIVATOR FOR POLYESTERS; SOLVENT [R7] *Dyes, intermediates, solvent, manufacture of vanillin, stabilizer (acid acceptor), reagent [R2] *Unsaturated polyester resin curing accelerator; extraction solvent (sulphur dioxide refining); acylation reagent [R4] PRIE: U.S. PRODUCTION: *(1972) 3.67X10+9 GRAMS (SALES) [R7] *(1975) 4.6X10+9 GRAMS [R7] U.S. IMPORTS: *(1976) 2.0X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Pale-yellow, oily liquid [Note: A solid below 36 degrees F]. [R8, 112]; *Yellowish to brownish, oily liquid [R2] ODOR: *Amine-like odor. [R8, 112] BP: *193.54 deg C [R9] MP: *2.50 deg C [R9] MW: *121.18 [R1, 547] CTP: *Critical temperature: 414 deg C; critical pressure: 3.63X10+3 kPa [R9] DEN: *0.956 @ 20 deg C/4 deg C [R2] DSC: *pKa= 5.15 @ 25 deg C [R10, p. 8-54] HTV: *5.14X10+7 J/kmol @ 2.50 deg C [R9] OWPC: *log Kow= 2.31 [R11] SOL: *Freely sol in alcohol, chloroform, ether [R1, 548]; *Sol in acetone, benzene, org solvents [R6]; *Sol in oxygenated and chlorinated solvents [R4]; *Soluble in ethanol, ethyl ether, and acetone [R10, p. 3-22]; *Water solubility of 1454 ppm at 25 deg C [R12] SPEC: *Index of refraction: 1.5582 @ 20 deg C/D [R2]; *MAX ABSORPTION (ALC): 235 NM (LOG E= 4.1); 251 NM (LOG E= 4.11); 293 NM (LOG E= 3.2); SADTLER REFERENCE NUMBER: 6 (IR, PRISM); 4 (IR, GRATING) [R13]; *IR: 6951 (Coblentz Society Spectral Collection) [R14]; *UV: 3 (Sadtler Research Laboratories Spectral Collection) [R14]; *NMR: 1 (Sadtler Research Laboratories Spectral Collection) [R14]; *MASS: 490 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R14]; *Intense mass spectral peaks: 106 m/z, 121 m/z [R15] SURF: *3.83X10-3 N.m @ 2.50 deg C [R9] VAPD: *4.17 (Air= 1) [R16] VAP: *0.70 mm Hg @ 25 deg C [R9] VISC: *1.89X10-3 Pa.s @ 2.50 deg C [R9] OCPP: *SOLIDIFIES +2 DEG C [R17] *VAPOR PRESSURE: 1 MM HG @ 29.5 DEG C [R18] *Hydroxyl radical rate constant = 1.48X10-10 cu cm/molecule-sec @ 25 deg C [R19] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R20] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R20] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R20] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R20] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R20] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R20] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R20] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R20] FPOT: *Flammable liquid when exposed to heat, flame, or oxidizers. [R21] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R22, p. 325-41] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R22, p. 325-41] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R22, p. 325-41] FLPT: *145 DEG F (63 DEG C) (CLOSED CUP) [R22, p. 315-41] AUTO: *700 DEG F [R22, p. 325-41] FIRP: *TO FIGHT FIRE, USE FOAM, CARBON DIOXIDE, DRY CHEMICAL. [R21] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Keep run-off water out of sewers and water sources. [R23, 395] TOXC: *... Toxic gases and vapors (such as carbon monoxide and oxides of nitrogen) may be released in a fire involving dimethylaniline ... [R24, 1991.482] REAC: *Explodes on contact with benzoyl peroxide or diisopropyl peroxydicarbonate. [R21] *Strong oxidizers, strong acids, benzoyl peroxide. [R8, 112] *Addition of 1% of dimethylaniline to diisopropyl peroxydicarbonate caused instant explosion. [R25] *Explodes on contact with benzoyl peroxide or diisopropyl peroxydicarbonate. [R21] DCMP: *When heated to decomposition it emits highly toxic fumes of aniline and nitroxides. [R21] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R8, 113] *Wear appropriate eye protection to prevent eye contact. [R8, 113] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R8, 113] *Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any supplied-air respirator. [R8, 113] *Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R8, 113] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R8, 113] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R8, 113] OPRM: *Contact lenses should not be worn when working with this chemical. [R8, 113] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Clothing which becomes soaked with aniline should be promptly removed. /Aniline/ [R26, 1981.4] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *The worker should immediately wash the skin when it becomes contaminated. [R8, 113] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R8, 113] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Do not use water. [R23, 396] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. [R23, 396] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] STRG: *IN GENERAL, MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED ... INCOMPATIBLE MATERIALS SHOULD BE ISOLATED FROM EACH OTHER. [R30] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *DIMETHYLANILINE MAY BE DISPOSED OF: 1) BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR A SIMILAR MATERIAL ... 2) BY ATOMIZING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R26, 1981.] *The following wastewater treatment technologies have been investigated for N,N-dimethylaniline: Concentration process: Activated carbon. [R31] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of N,N-dimethylaniline. There is limited evidence in experimental animals for the carcinogenicity of N,N-dimethylaniline. Overall evaluation: N,N-dimethylaniline is not classifiable as to its carcinogenicity to humans (Group 3). [R32] +A4; Not classifiable as a human carcinogen. [R33, 2002.29] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aniline and related compounds/ [R34, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Monitor cardiac rhythm and treat arrhythmias as necessary... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation... . /Aniline and related compounds/ [R34, 207] HTOX: *ABSORBED THROUGH INTACT SKIN TO PRODUCE DANGEROUS METHEMOGLOBINEMIA. [R35, p. II-209] *... Dimethylaniline ... /is/ less toxic than aniline ... Two workers showed symptoms very similar to aniline poisoning. One of the workers ... collapsed immediately, was unconscious for 8 hr, and complained of visual disturbances, noise in the ears, and intense abdominal pain. [R24, 1991.484] *... THERE IS A CONSIDERABLE LAG IN METHEMOGLOBIN APPEARANCE, FOLLOWING ADMIN TO NEARLY ALL SPECIES IN VIVO. [R36] *CLOSELY RESEMBLES ANILINE IN ITS TOXICITY WITH PERHAPS MORE PROMINENT CENTRAL NERVOUS DEPRESSION. [R35, p. II-208] *Clinical signs of intoxication with N,N-dimethylaniline in man are headaches, cyanosis, dizziness, labored breathing, paralysis and convulsions. [R37, 194] *... Depressant effect of dimethylaniline on the nervous system appears to be greater than that of aniline. [R24, 1991.484] NTOX: *A SINGLE DOSE TO DOGS OF DIMETHYLANILINE 50 MG/KG BY STOMACH TUBE CAUSED METHEMOGLOBIN FORMATION. /FROM TABLE/ [R38] *DIMETHYLANILINE TESTED ON RABBIT EYES CAUSED MODERATE INJURY, GRADED 5 ON SCALE OF 10. /MOST SEVERE INJURIES HAVE BEEN RATED 10/. [R39] *AMINE OXIDASE ACTIVITY IS MUCH HIGHER SHORTLY BEFORE AND AFTER BIRTH THAN ACTIVITY OF CYTOCHROME P450-DEPENDENT OXIDN. SINCE N-OXIDATION OF SECONDARY AND TERTIARY AMINES MAY LEAD TO FORMATION OF POTENTIALLY TOXIC METABOLITES, NEWBORNS MAY BE MORE SUSCEPTIBLE THAN ADULTS. [R40] *RATS INHALING DIMETHYLANILINE AT 0.3 MG/CU M FOR 24 HOURS/DAY FOR 100 DAYS SHOWED SIGNIFICANT CHANGES IN THE CENTRAL NERVOUS SYSTEM, BLOOD, AND LIVER, INCLUDING CHANGES IN THE CORRELATION OF MUSCLE ANTAGONIST CHRONAXY, A REDUCED NUMBER OF ERYTHROCYTES AND HEMOGLOBIN, INCREASED METHEMOGLOBIN LEVEL, RETICULOCYTOSIS, LEUKOPENIA, HYPOPROTEINEMIA, A REDUCED SULFHYDRYL GROUP CONTENT IN THE SERUM, AND ACCUMULATION OF PYRUVIC ACID IN THE LIVER AND SERUM. DIMETHYLANILINE INCREASED THE COPROPORPHYRIN URINARY EXCRETION AND REDUCED THE ADRENAL ASCORBIC ACID LEVEL. DIMETHYLANILINE AT 0.005 MG/CU M DID NOT CHANGE THE ABOVE PARAMETERS. [R41] *... DIRECT FORMATION OF METHEMOGLOBIN ... /FROM/ N,N-DIMETHYLANILINE. [R42] *N,N-dimethylaniline was found to be negative when tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program (NTP). N,N-dimethylaniline was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 3.000, 10.000, 33.000, 100.000, and 333.000 ug/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 333.000 ug/plate. [R43] *N,N-Dimethylaniline was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Fifty pregnant CD-1 mice were given 365 mg/kg/day N,N-dimethylaniline in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. N,N-Dimethylaniline had no toxic effect in the dams or in their offspring for the parameters assayed. [R44] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of N,N-dimethylaniline for male F344/N rats, as indicated by the increased incidences of sarcomas or osteosarcomas(combined) of the spleen. There was no evidence of carcinogenic activity of N,N-dimethylaniline for female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 yr. There was no evidence of carcinogenic activity of N,N-dimethylaniline for male B6C3F1 mice given 15 or 30 mg/kg body weight by gavage for 2 yr. There was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for female B6C3F1 mice, as indicated by an incr incidence of squamous cell papillomas of the forestomach. Both rats and mice could have tolerated doses higher than those used in these studies. [R45] *Oral or sc administration of 2 g of N,N-dimethylaniline/kg body weight caused weakness, tremors, tonic and clonic convulsions, slowing of respiration and finally death to guinea pigs. [R37, 193] *Splenomegaly was observed in Fischer 344 rats and B6CF1 mice given a daily dose of up to 500 mg of N,N-dimethylaniline/kg body weight 5 days/wk for 13 wk. Microscopic examination revealed the presence of hemosiderosis and hematopoiesis in the spleens, livers, and kidneys of treated rats and mice. Bone marrow hyperplasia was noted in treated rats but not mice. [R37, 193] NTXV: *LD50 Rat oral 1.41 ml/kg; [R1, 548] *LD50 Rabbit skin 1770 mg/kg; [R21] ETXV: *LC50 Pimephales promelas (fathead minnow) 78.2 mg/l/96 hr (confidence limit 74.2 - 82.4 mg/l), flow-through bioassay with measured concentrations, 23.4 deg C, dissolved oxygen 7.0 mg/l, hardness 43.5 mg/l calcium carbonate, alkalinity 43.4 mg/l calcium carbonate, and pH 7.38; [R46, 1984.297] *EC50 Pimephales promelas (fathead minnow) 75.2 mg/l/96 hr (confidence limit 70.1 - 80.7 mg/l), flow-through bioassay with measured concentrations, 23.4 deg C, dissolved oxygen 7.0 mg/l, hardness 43.5 mg/l calcium carbonate, alkalinity 43.4 mg/l calcium carbonate, and pH 7.38. Effect: loss of equilibrium; [R46, 1984.297] *LC50 Pimephales promelas (fathead minnow) 52.6 g/l/96 hr (confidence limit is not relevant), flow-through bioassay with measured concentrations, 25.3 deg C, dissolved oxygen 5.9 mg/l, hardness 43.5 mg/l calcium carbonate, alkalinity 46.0 mg/l calcium carbonate, and pH 7.63; [R46, 1984.299] *EC50 Pimephales promelas (fathead minnow) 52.6 mg/l/96 hr (confidence limit is not relevant), flow-through bioassay with measured concentrations, 25.3 deg C, dissolved oxygen 5.9 mg/l, hardness 43.5 mg/l calcium carbonate, alkalinity 46.0 mg/l calcium carbonate, and pH 7.63. Effect: loss of equilibrium; [R46, 1984.299] NTP: *... Toxicology and carcinogenesis studies were conducted by administering N,N-dimethylaniline (greater than 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 2 yr. ... Two yr studies were conducted by administering 0, 3 or 30 mg/kg N,N-dimethylaniline in corn oil by gavage, 5 days/wk for 103 wk, to groups of 50 rats of each sex. ... Groups of 50 mice of each sex were administered 0, 15, or 30 mg/kg on the same schedule. Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of N,N-dimethylaniline for male F344/N rats, as indicated by the increased incidences of sarcomas or osteosarcomas(combined) of the spleen. There was no evidence of carcinogenic activity of N,N-dimethylaniline for female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 yr. There was no evidence of carcinogenic activity of N,N-dimethylaniline for male B6C3F1 mice given 15 or 30 mg/kg body weight by gavage for 2 yr. There was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for female B6C3F1 mice, as indicated by an incr incidence of squamous cell papillomas of the forestomach. Both rats and mice could have tolerated doses higher than those used in these studies. [R45] TCAT: ?N,N-dimethylaniline (DMA, CAS # 121-69-7) was evaluated for acute dermal toxicity in New Zealand White rabbits (2/sex/group) administered single occluded 2.0 ml applications of either DMA neat, 6 g/L DMA in 1% H2SO4, and 0.03 g/L DMA in 1% H2SO4, upon intact skin for 24 hours. The study allowed specifically for assessment of chemicotoxic asphyxiation and attendant hematological changes. All treated animals survived the 7-day study and overt respiratory effects were limited to 3-day hyperpnea in 1/2 male rabbits of a 6 g/L dose. Examination of hematological parameters prior to treatment and at 24 hours afterward found no treatment-related changes in hemoglobin, hematocrit, or erythrocyte values. Methemoglobin levels, however, were found markedly elevated immediately following treatment (24 hours) in all rabbits of undiluted doses only. While these values indicated some recovery 5 days post-treatment, they were still notably higher than baseline values. Upon 7th day gross necropsy, one each of the male and female rabbits of the neat dose and 1 female of a 6.0 g/L diluted dose also exhibited bright red or mottled tan lungs. Study authors reported that gross pathology was sporadic and comparable to that in control animals (data from control animals were not provided with this submission). [R47] POPL: *... NEWBORNS MAY BE MORE SUSCEPTIBLE THAN ADULTS. [R40] ADE: *DIMETHYLANILINE IS READILY ABSORBED THROUGH THE SKIN ... [R24, 1991.483] *... Readily absorbed ... by inhalation of vapors. [R48] METB: *... N,N-DIMETHYLANILINE ... HAS BEEN SHOWN TO BE DEMETHYLATED BY RAT LIVER PREPN. [R49] *N,N-DIMETHYLANILINE IN RAT AND PIG YIELDS N,N-DIMETHYLANILINE-N-OXIDE. /FROM TABLE/ [R50] *URINARY METABOLITES OF N,N-DIMETHYLANILINE PRODUCED IN DOGS WERE 4-AMINOPHENOL, 4-(METHYLAMINO)PHENOL, 4-(DIMETHYLAMINO)PHENOL, 2-AMINOPHENOL, AND N-METHYLANILINE. [R51] *CARBON MONOXIDE DIMINISHED MAX VELOCITY OF N-OXIDE FORMATION FROM N,N-DIMETHYLANILINE IN RABBIT LIVER MICROSOMES. [R52] *EVIDENCE FOR EXISTENCE OF ALTERNATE METABOLIC ROUTES OF N-OXIDN OF CMPD BY RABBIT LIVER MICROSOMES IS GIVEN. ONE PATHWAY INVOLVES CYTOCHROME P450-LINKED MIXED FUNCTION OXIDASE SYSTEM AND OTHER INVOLVES MIXED FUNCTION AMINE OXIDASE. [R53] *EXISTENCE OF 424 NM ABSORBANCE 20 MIN AFTER N-OXIDE WAS ADDED TO SAMPLE AGREED WITH PRODN OF MEASURABLE AMT OF N-METHYLANILINE. [R54] *N-DEMETHYLATION OF DIMETHYLANILINE WAS INHIBITED BY SKF 525A. [R55] *HEPATIC MICROSOMES PREPARED FROM RED-WINGED BLACKBIRDS AND ALBINO RATS WERE INCUBATED WITH N,N-DIMETHYLANILINE IN COMPLETE INCUBATION MIXTURES AT PH 7.9 AND 37 DEG C FOR 10 MINUTES. FORMALDEHYDE AND N,N-DIMETHYLANILINE-N-OXIDE PRODUCED FROM N,N-DIMETHYLANILINE WERE MEASURED. REDWINGS HAD SIGNIFICANTLY LOWER N-DEMETHYLATION ACTIVITIES THAN RATS, AND REDWINGS HAD ONLY MARGINAL OR NO N-OXIDATION ACTIVITIES. HEPATIC MICROSOMES FROM REDWINGS DID NOT FURTHER METABOLIZE THE N-OXIDE. [R56] *MICROSOMES FROM THE CORPORA LUTEA OF PIGS IN ESTRUS CYCLE N-OXYGENATED N,N-DIMETHYLANILINE AS RAPIDLY AS LIVER MICROSOMES. LOWER OXYGENATING ACTIVITIES WERE SEEN WITH MICROSOMES FROM OTHER TISSUES. [R57] *THE INCUBATION OF N,N-DIMETHYLANILINE WITH FORTIFIED GUINEA PIG HEPATIC MICROSOMAL PREPARATIONS PRODUCED N,N-DIMETHYLANILINE N-OXIDE, N-METHYLANILINE, ANILINE, N,N-DIMETHYLAMINOPHENOL, N-METHYL-4-AMINOPHENOL, AND 4-AMINOPHENOL. THE FORMATION OF N-METHYL-4-AMINOPHENOL OCCURRED BY 4-HYDROXYLATION OF N,N-DIMETHYLANILINE IN THE PRESENCE OF CYTOCHROME P450. [R58] *N-DEMETHYLATION AND N-OXIDATION WERE THE MOST IMPORTANT ROUTES OF METABOLISM OF N-ALKYL-N-METHYLANILINES BY RAT LIVER MICROSOMES; N-OXIDATION OF N,N-DIMETHYLANILINE WAS LINEAR OVER A 60-MINUTE INCUBATION WHEREAS N-DEMETHYLATION WAS LINEAR OVER ONLY THE FIRST 15-20 MINUTES. [R59] *HUMAN FETAL LIVER MICROSOMES CATALYZED THE N-OXIDATION OF A TERTIARY AMINE, N,N-DIMETHYLANILINE. THE REACTION WAS DEPENDENT UPON THE REDUCED FORM OF NICOTINAMIDE-ADENINE DINUCLEOTIDE PHOSHPATE BUT WAS NOT INHIBITED BY CARBON MONOXIDE. THE RESULTS AGREED WITH THOSE OBTAINED FROM STUDIES ON N-OXIDATION OF SECONDARY AND TERTIARY AMINES BY ANIMAL LIVER MICROSOMES, WHICH SHOWED THAT THIS REACTION PROBABLY PROCEEDS INDEPENDENTLY OF CYTOCHROME P450. [R60] *FOLLOWING PRETREATMENT OF ADULT NONPREGNANT RABBITS WITH MINERALOCORTICOID DEOXYCORTICOSTERONE, MICROSOMAL DMA METABOLISM IN LUNG SHOWED AN INCR OF 50% BUT NOT IN LIVER. [R61] *PCP WAS FOUND TO INTERFERE WITH THE MICROSOMAL METABOLISM OF N,N-DIMETHYLANILINE. [R62] *IN NONPREGNANT RABBITS ADMIN OF TESTOSTERONE PROPIONATE DID NOT AFFECT LIVER OR LUNG MICROSOMAL N,N-DIMETHYLANILINE METAB; HOWEVER, AFTER TREATMENT WITH GLUCOCORTICOID DEXAMETHASONE ACETATE THERE WAS 40-60% INCR IN DEMETHYLASE AND N-OXIDASE ACTIVITIES. [R61] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The lowest lethal dose reported of humans is 50 mg/kg. [R24, 1991.484] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *N,N-Dimethylaniline's production and use in dyes, intermediates, solvents, manufacture of vanillin, stabilizers (acid acceptor), and reagents may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.70 mm Hg at 25 deg C indicates that N,N-dimethylaniline will exist solely as a vapor in the ambient atmosphere. Vapor-phase N,N-dimethylaniline will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl and ozone radicals; the half-lives for these reactions in air is estimated to be 2.6 and 29.4 hrs. Night-time reaction with nitrate radicals may also contribute to the atmospheric transformation of N,N-dimethylaniline. Exposure of a dilute aqueous solution of N,N-dimethylaniline to fluorescent lamps having a continuous spectrum from 300-400 nm resulted in a 50% degradation in approximately 14 min; extrapolation of this rate to environmental photolysis in sunlight is not possible; however, this reactivity suggests that direct photolysis may have some importance in the environment. If released to soil, N,N-dimethylaniline is expected to have moderate mobility based upon an estimated Koc of 182. A pKa value of 5.15 suggests that N,N-dimethylaniline will exist partially in the protonated form in moist soils and the protonated form of N,N-dimethylaniline is expected to bind strongly to soil surfaces. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 5.7X10-5 atm-cu m/mole. N,N-Dimethylaniline is not expected to volatilize from dry soil surfaces based upon its vapor pressure. The results of various screening studies suggest that N,N-dimethylaniline is not readily biodegradable in either soil or water; however, acclimated inocula are apparently capable of degrading the compound. Reaction with sunlight produced singlet oxygen in aqueous environments may be a major degradation process based on a half-life of 9.6 hrs. If released into water, N,N-dimethylaniline is expected to adsorb slightly to sediment and suspended solids in water based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process for the neutral species based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 12 hrs and 9.5 days, respectively. The protonated form of N,N-dimethylaniline does not volatilize from water surfaces. A BCF ranging from 3-13 suggests bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to N,N-dimethylaniline may occur through inhalation and dermal contact with this compound at workplaces where N,N-dimethylaniline is produced or used. (SRC) ARTS: *N,N-Dimethylaniline's production and use as in dyes, intermediates, solvents, manufacture of vanillin, stabilizer (acid acceptor), and reagents(1) may result in its release to the environment through various waste streams(SRC). [R63] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 182(2), indicates that N,N-dimethylaniline is expected to have moderate mobility in soil(SRC). A pKa value of 5.15(3) suggests that N,N-dimethylaniline will exist partially in the protonated form in moist soils and the protonated form of N,N-dimethylaniline is expected to bind strongly to soil surfaces. Volatilization of the neutral species of N,N-dimethylaniline from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.7X10-5 atm-cu m/mole, from its vapor pressure, 0.70 mm Hg(4), and water solubility, 1450 mg/l(5). N,N-Dimethylaniline is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). Exposure of a dilute aqueous solution of N,N-dimethylaniline to fluorescent lamps having a continuous spectrum from 300-400 nm resulted in a 50% degradation in approximately 14 min(6); extrapolation of this rate to environmental photolysis in sunlight is not possible; however, this reactivity suggests that direct photolysis of N,N-dimethylaniline on soil surfaces may have some importance(SRC). The results of various screening studies suggest that N,N-dimethylaniline is not readily biodegradable; however, acclimated inocula are apparently capable of degrading the compound(7). [R64] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 182(2), indicates that N,N-dimethylaniline is expected to adsorb slightly to sediment and suspended solids in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 5.7X10-5 atm-cu m/mole from its vapor pressure, 0.70 mm Hg(4), and water solubility, 1450 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 12 hrs and 9.5 days, respectively(SRC). A pKa of 5.15(6) suggests that N,N-dimethylaniline will exist partially in the protonated form in the aqueous environments and the protonated form of N,N-dimethylaniline is not expected to volatilize from water. The results of various screening studies suggest that N,N-dimethylaniline is not readily biodegradable; however, acclimated inocula are apparently capable of degrading the compound(7). In a study using two microbial populations, one that was acclimated to N,N-dimethylaniline and one that was not, 72% of N,N-dimethylaniline still remained after a 7 day exposure with the non-acclimated microbes while only 0.15% N,N-dimethylaniline remained after 7 days with the acclimated microbes(8). N,N-Dimethylaniline is degraded in aqueous environments by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in water is estimated to be 34 days(SRC), calculated from its rate constant of 1.4X10+10 cu cm/molecule-sec(8). Exposure of a dilute aqueous solution of N,N-dimethylaniline to fluorescent lamps having a continuous spectrum from 300-400 nm resulted in a 50% degradation in approximately 14 min(9); extrapolation of this rate to environmental photolysis in sunlight is not possible; however, this reactivity suggests that direct photolysis in aqueous media may have some importance(SRC). According to a classification scheme(10), a BCF ranging from 3-13(11), suggests the potential for bioconcentration in aquatic organisms is low. [R65] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), N,N-dimethylaniline, which has a vapor pressure of 0.70 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase N,N-dimethylaniline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl and ozone radicals(SRC); the half-lives for these reactions in air are estimated to be 2.6 and 29.4 hrs(SRC), respectively, calculated from their rate constant of 1.48X10-10 cu cm/molecule-sec(3) and 9.1X10-18 cu cm/molecule-sec(4) at 25 deg C. Night-time reaction with nitrate radicals may also contribute to the atmospheric transformation of N,N-dimethylaniline(4). Exposure of a dilute aqueous solution of N,N-dimethylaniline to fluorescent lamps having a continuous spectrum from 300-400 nm resulted in a 50% degradation in approximately 14 min(5); extrapolation of this rate to environmental photolysis in sunlight is not possible; however, this reactivity suggests that direct photolysis in air may have some importance(SRC). [R66] BIOD: *AEROBIC: Using a mixed municipal/industrial activated sludge, 0-3% of N,N-dimethylaniline was removed over a 6 hr period at a concn of 20 mg/l(1). When an industrial activated sludge that was adapted to N,N-dimethylaniline was used, 100% of the total organic carbon was removed after 6 days at a conc of 400 mg/l(1). However, this test indicates that stripping may be the most important elimination process since there was no indications that biodegradation had occurred(1). In another test, both a municipal non-acclimated and an acclimated activated sludge were used to study the biodegradation. The non-acclimated sludge reached less than 10% of its ThOD after 28 days at a concn of 50-200 mg/l of N,N-dimethylaniline while at the same concn, the acclimated sludge reached 22% of its ThOD in 5 days(1). N,N-Dimethylaniline, present at 100 mg/l, reached 0% of its theoretical BOD in 2 weeks using an activated sludge inocula at 30 mg/l and the Japanese MITI test(2). The biodegradation pathway for N,N-dimethylaniline is believed to begin by enzymatic attack of one of the methyl group attached to the nitrogen(3). Two biodegradation experiments were conducted to study the increase in degradability between an acclimated and non-acclimated bacteria culture(4). Microorganisms were obtained as mixed liquor suspended solids from the secondary aeration basins of an industrial wastewater treatment plant(4). One bacteria culture was introduced to N,N-dimethylaniline in nine stages where the concn was steadily increased whereas the other culture was given no prior acclimation(4). At the end of a 7 day exposure, 72% of N,N-dimethylaniline still remained in the non-acclimated culture as opposed to only 0.15% in the acclimated culture(4). [R67] ABIO: *The rate constant for the vapor-phase reaction of N,N-dimethylaniline with photochemically-produced hydroxyl radicals is 1.48X10-10 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 2.6 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of N,N-dimethylaniline with ozone has been experimentally determined to be 9.1X10-18 cu cm/molecule-sec at room temperature which corresponds to an atmospheric half-life of 29.4 hrs at an atmospheric concn of 7.2X10+11 ozone molecules/cu cm(2). The presence of high concns of nitrate radicals in night-time air may also contribute to the atmospheric degradation of N,N-dimethylaniline(2). Exposure of a dilute aqueous solution of N,N-dimethylaniline to fluorescent lamps having a continuous spectrum from 300-400 nm resulted in a 50% degradation in approximately 14 min(3); extrapolation of this rate to environmental photolysis in sunlight is not possible; however, this reactivity suggests that direct photolysis may have some importance in the environment(SRC). Aromatic amines are generally resistant to aqueous environmental hydrolysis(4); therefore, N,N-dimethylaniline is not expected to hydrolyze in water(SRC). N,N-dimethylaniline is degraded in aqueous environments by reaction with photochemically-produced hydroxyl radicals(SRC); the rate constant for this reaction is 1.4X10+10 cu cm/molecule-sec(5). This corresponds to an aqueous half-life of about 34 days at an aqueous concn of 1.0X10-17 hydroxyl radicals per cu cm(5). The rate constant for the reaction between N,N-dimethylaniline and singlet oxygen has been determined to be 1X10+8 l/mole-sec(6); assuming the steady-state concn of singlet oxygen in natural water is 2X10-13M(6), the half-life for this reaction can be estimated to be 9.6 hrs(SRC). [R68] BIOC: *The BCF for N,N-dimethylaniline ranges from 3-13 based on experimental results using carp over a 48 hr period in a static system(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R69] KOC: *The Koc value for the neutral species of N,N-dimethylaniline has been reported as 182(1). According to a classification scheme(2), this Koc value suggests that N,N-dimethylaniline is expected to have moderate mobility in soil. Also, a pKa value of 5.15(3) suggests that N,N-dimethylaniline will exist partially in the protonated form in moist soils and the protonated form of N,N-dimethylanilne is expected to bind strongly to soil surfaces(SRC). [R70] VWS: *The Henry's Law constant for N,N-dimethylaniline is estimated as 5.7X10-5 atm-cu m/mole(SRC) from its vapor pressure, 0.70 mm Hg(1), and water solubility, 1450 mg/l(2). This Henry's Law constant indicates that N,N-dimethylaniline is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 12 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 9.5 days(SRC). N,N-Dimethylaniline's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). N,N-Dimethylaniline is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). A pKa value of 5.15(4), suggests that N,N-dimethylaniline will exist partially in the protonated form in aqueous environments and the protonated form of N,N-dimethylaniline is not expected to volatilize from water or moist soil surfaces(SRC). [R71] EFFL: *Sludge from the Muskegon County Wastewater Management Treatment System in Michigan had an average concn of 223 ug/kg of N,N-dimethylaniline(1). [R72] SEDS: *SOIL: In field plot study, sludge, with an average conc of 223 ug/kg of N,N-dimethylaniline, from an industrial wastewater treatment system was applied to 10 ft sq plots(1). The sludge was allowed to dry for 5 days and was subsequently tilled to a 6 in depth(1). Following this treatment, the concn of N,N-dimethylaniline was studied at various depths in the soil profile. N,N-Dimethylaniline was only detected in the top 15.2 cm at 5, 122, and 241 days after application at an average concn of 24, 19, and 30 ug/kg, respectively(1). [R72] PFAC: PLANT CONCENTRATIONS: *N,N-Dimethylaniline was detected, concn not specified, in cold-pressed orange oil from the peel of fresh Florida oranges(1). [R73] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 30,480 workers (7,448 of these are female) are potentially exposed to N,N-dimethylaniline in the US(1). Occupational exposure to N,N-dimethylaniline may occur through inhalation and dermal contact with this compound at workplaces where N,N-dimethylaniline is produced or used(SRC). [R74] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *100 ppm [R8, 112] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (25 mg/cu m). Skin Designation. [R75] *Vacated 1989 OSHA PEL TWA 5 ppm (25 mg/cu m); STEL 10 ppm (50 mg/cu m), skin designation, is still enforced in some states. [R8, 363] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 ppm (25 mg/cu m). [R8, 112] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 10 ppm (50 mg/cu m), skin. [R8, 112] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm; 15 min Short Term Exposure Limit (STEL): 10 ppm, skin. [R33, 2002.29] +A4; Not classifiable as a human carcinogen. [R33, 2002.29] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R33, 2002.91] OOPL: *Australia: 5 ppm, STEL 10 ppm, skin (1990); Federal Republic of Germany: 5 ppm, short-term level of 10 ppm, 30 min, 4 times per shift, skin, carcinogen group B, justifiably suspected of having carcinogenic potential (1990); Sweden: 2 ppm, short-term value 4 ppm, skin (1987); United Kingdom: 5 ppm, 10-min STEL 10 ppm, skin (1991). [R24, 1991.484] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. N,N-Dimethylaniline is produced, as an intermediate or a final product, by process units covered under this subpart. [R76] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. N,N-Dimethylaniline is included on this list. [R77] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 12,500 ug/l [R78] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R79] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Dimethylaniline is included on this list. [R80] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2002. Analyte: N,N-dimethylaniline. Matrix: Air. Sampler: Solid sorbent tube (silica gel, 150 mg/75 mg). Flow rate: 0.02 to 1.0 liter/min. Sample Size: 3 to 30 liters. Shipment: Routine. Sample Stability: Not available. [R81] ALAB: *THIN-LAYER CHROMATOGRAPHIC SEPARATION AND IDENTIFICATION OF TERTIARY AROMATIC AMINES AND THEIR N-OXIDES. [R82] *DETERMINATION IS BY GAS CHROMATOGRAPHY. [R83] *AFTER ABSORPTION AND SEPN, IDENTIFICATION IS BY GAS CHROMATOGRAPHY. [R84] *HIGH-PRESSURE LIQ CHROMATOGRAPHY ON BONDED OCTADECYLSILANE SUPPORTS FOR SEVERAL CMPD GIVEN. [R85] *COLORIMETRIC DETERMINATION AND DETECTION OF TERTIARY AMINES. [R86] *DETERMINATION IN PENICILLINS BY GC-MS. [R87] *CHEMICAL IONIZATION MASS SPECTROMETRY USING AMMONIA AND AMMONIA-D3 AS REAGENT GASES IS USED TO DIFFERENTIATE NITROGEN-CONTAINING COMPOUNDS. [R88] *NIOSH Method 2002. Amines, aromatic. Analyte: N,N-Dimethylaniline Matrix: Air. Procedure: Gas Chromatography, Flame Ionization Detection. For N,N-dimethylaniline this method has an estimated detection limit of 0.01 mg sample. The precision/RSD is 0.090. Applicability: Applicability of this method for simultaneous determination of analytes has not been investigated. Interferences: None known. Silica gel has greatly reduced capacity at high humidity. [R89] *EAD Method 1665. Semi-Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by Isotope Dilution GC/MS. Detection limit= 10 ug/l. [R90] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of N,N-Dimethylaniline in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 360 (1989) NIH Publication No. 90-2815 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 396 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA2 (85) 310 R4: Ashford, R.D. 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Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-115 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 76 R15: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.152 R16: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 804 R17: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 430 R18: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1132 R19: Atkinson R; J Phys Chem Ref Data, Monograph 1 (1989) R20: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R21: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1297 R22: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R23: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. R24: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R25: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 761 R26: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 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Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R35: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R36: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2415 R37: Snyder, R. (ed.). Ethyl Browning's Toxicity and Metabolism of Industrial Solvents. 2nd ed. Volume II: Nitrogen and Phosphorus Solvents. Amsterdam-New York-Oxford: Elsevier, 1990. R38: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 950 R39: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1031 R40: WIRTH PJ, THORGEIRSSON SS; BIOCHEM PHARMACOL 27 (4): 601 (1978) R41: MARKOSYAN TM; GIG SANIT 34 (3): 7 (1969) R42: UEHLEKE H; INT CONGR PHARMACOL 5: 204 (1972) R43: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R44: Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987) R45: Toxicology and Carcinogenesis Studies of N,N-Dimethylaniline in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 360 (1989) NIH Publication No. 90-2815 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R46: Brooke, L.T., D.J. Call, D.T. Geiger and C.E. Northcott (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Superior, WI: Center for Lake Superior Environmental Studies Univ. of Wisconsin Superior R47: ELF Atochem North America Inc; An Acute Toxicity Study in Rabbits of Three Concentrations of Topically-Administered N,N-dimethylaniline; 09/27/82; EPA Document No. 86950000388; Fiche No. OTS0557828 R48: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 708 R49: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 88 R50: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-87 R51: KIESE M, RENNER G; NAUNYN-SCHMIEDEBERG'S ARCH PHARMACOL 283 (2): 143 (1974) R52: HLAVICA P, KEHL M; HOPPE-SEYLER'S Z PHYSIOL CHEM 355 (12): 1508 (1975) R53: HLAVICA P, KEHL M; PROC INT SYMP, 3RD, 346 (1977) R54: HLAVICA P, AICHINGER G; PROC INT SYMP 2ND: 195 (1978) R55: KITAGAWA H ET AL; CHEM PHARM BULL 20 (4): 650 (1972) R56: PAN HP ET AL; LIFE SCI 17 (5): 819 (1975) R57: HEINZE E ET AL; BIOCHEM PHARMACOL 19 (3): 641 (1970) R58: GOODERHAM NJ, GORROD JW; ADV EXP MED BIOL 136B, ISSUE BIOL REACT INTERMED -2, CHEM MECH BIOL EFF PART B: 1109 (1982) R59: GORROD JW ET AL; XENOBIOTICA 9 (1): 17 (1979) R60: RANE A; CLIN PHARMACOL THER 15 (1): 32 (1974) R61: DEVEREUX TR, FOUTS JR; DRUG METAB DISPOS 3 (4): 254 (1975) R62: ARRHENIUS E ET AL; CHEM BIOL INTERACT 18 (1): 35 (1977) R63: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons, Inc. p. 396 (1997) R64: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (3) Lide DR; CRC Handbook of Chemistry And Physics 76th Ed; CRC Press; Boca Raton, FL; p. 8-54 (1998) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) (6) Kondo M; Simulation Studies of Degradation of Chemicals in the Environment Office of Health Studies, Environment Agency, Japan (1978) (7) Watson HM; Environ Tox Chem 12: 2023-30 (1993) R65: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) (6) Lide DR; CRC Handbook of Chemistry And Physics 76th Ed; CRC Press; Boca Raton, FL; p. 8-54 (1998) (7) Watson HM; Environ Tox Chem 12: 2023-30 (1993) (8) Buxton, GV et al; J Phys Chem Ref Data 17: 513-759 (1988) (9) Kondo M; Simulation Studies of Degradation of Chemicals in the Environment Office of Health Studies, Environment Agency, Japan (1978) (10) Franke C et al; Chemosphere 29: 1501-14 (1994) (11) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 3-23 (1992) R66: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Atkinson R; J Phys Chem Ref Data, Monograph 1 (1989) (4) Atkinson R et al; Environ Sci Technol 21: 64-72 (1987) (5) Kondo M; Simulation Studies of Degradation of Chemicals in the Environment Office of Health Studies, Environment Agency, Japan (1978) R67: (1) Prager JC; Environmental Contaminant Reference Databook. NY, NY: Van Nostrand Reinhold, 1: 171-3 (1995) (2) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 3-23 (1992) (3) James MO; Chem Plant Prot 9: 153-189 (1994) (4) Watson HM; Environ Tox Chem 12: 2023-30 (1993) R68: (1) Atkinson R; J Phys Chem Ref Data, Monograph 1 (1989) (2) Atkinson R et al; Environ Sci Technol 21: 64-72 (1987) (3) Kondo M; Simulation Studies of Degradation of Chemicals in the Environment Office of Health Studies, Environment Agency, Japan (1978) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY, NY: McGraw-Hill p. 7-4 (1982) (5) Buxton, GV et al; J Phys Chem Ref Data 17: 513-759 (1988) (6) Haag WR, Hoigne J; pp. 1011-20 in Water Chlorination: Chem Environ Impact Health Eff, Proc Conf. Jolley RLL, ed (1985) R69: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 3-23 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R70: (1) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Lide DR; CRC Handbook of Chemistry And Physics 76th Ed; CRC Press; Boca Raton, FL; p. 8-54 (1998) R71: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (2) Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) Lide DR; CRC Handbook of Chemistry And Physics 76th Ed; CRC Press; Boca Raton, FL; p. 8-54 (1998) R72: (1) Demirjian YA et al; J WPCF 59: 32-38 (1987) R73: (1) Thomas AF, Bassols F; J Agric Food Chem 40: 2236-2243 (1992) R74: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R75: 29 CFR 1910.1000 (7/1/99) R76: 40 CFR 60.489 (7/1/99) R77: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R78: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R79: 40 CFR 712.30 (7/1/99) R80: 40 CFR 716.120 (7/1/99) R81: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2002-1 R82: DAMANI LA ET AL; J CHROMATOGR 155 (2): 337 (1978) R83: SAWICKI E; HEALTH LAB SCI 12 (4): 394 (1975) R84: WOOD GO, ANDERSON RG; J AM IND HYG ASSOC 36 (7): 538 (1975) R85: MCCALL JM; J MED CHEM 18 (6): 549 (1975) R86: YAMAMOTO M, UNO T; CHEM PHARM BULL 24 (9): 2237 (1976) R87: CHOI JK, PARK MK; ARCH PHARMACOL RES 4 (2): 85 (1981) R88: BUCHANAN MV; ANAL CHEM 54 (3): 570 (1982) R89: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R90: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 64 Record 118 of 1119 in HSDB (through 2003/06) AN: 1240 UD: 200303 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: OLEIC-ACID- SY: *K-52-; *L'ACIDE-OLEIQUE- (FRENCH); *CENTURY-CD-FATTY-ACID-; *ELAIC-ACID-; *EMERSOL-210-; *EMERSOL-211-; *EMERSOL-213-; *EMERSOL-233LL-; *EMERSOL-6321-; *EMERSOL-221-LOW-TITER-WHITE-OLEIC-ACID-; *EMERSOL-220-WHITE-OLEIC-ACID-; *FEMA-NUMBER-2815.-; *GLYCON-RO-; *GLYCON-WO-; *GROCO-2-; *GROCO-4-; *GROCO-6-; *GROCO-5L-; *HY-PHI-1055-; *HY-PHI-1088-; *HY-PHI-2066-; *HY-PHI-2088-; *HY-PHI-2102-; *METAUPON-; *NEO-FAT-90-04-; *NEO-FAT-92-04-; *CIS-DELTA(9)-OCTADECENOIC ACID; *CIS-OCTADEC-9-ENOIC-ACID-; *Z-9-OCTADECENOIC-ACID-; *9-OCTADECENOIC-ACID-; *9,10-OCTADECENOIC-ACID-; *CIS-OLEIC-ACID-; *DELTA(9)-CIS-OLEIC ACID; *OLEINE-7503-; *OLEINIC-ACID-; *PAMOLYN-100-; *RED-OIL-; *CIS-DELTA(SUP 9)-OCTADECENOIC ACID; *TEGO-OLEIC-130-; *VOPCOLENE-27-; *WECOLINE-OO- RN: 112-80-1 RELT: 5001 [PALMITIC ACID] (Metabolic Precursor); 2000 [STEARIC ACID] (Metabolic Precursor) MF: *C18-H34-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HYDROLYTIC SPLITTING OF TALLOW, FOLLOWED BY FRACTIONAL DISTILLATION AND SOLVENT CRYSTALLIZATION [R1] *OBTAINED BY HYDROLYSIS OF VARIOUS ANIMAL AND VEGETABLE FATS AND OILS. SEPARATION FROM OLIVE OIL BY DOUBLE FRACTIONATION VIA UREA ADDUCTS [R2] *DERIVED FROM HYDROLYSIS AND DISTILLATION OF TRIOLEIN. [R3] *FREE FATTY ACID IS OBTAINED FROM THE GLYCERIDE BY HYDROLYSIS, STEAM DISTILLATION AND SEPARATION BY CRYSTALLIZATION OR SOLVENT EXTRACTION. FILTRATION FROM PRESS CAKE RESULTS IN OLEIC ACID OF COMMERCE (RED OIL) WHICH IS PURIFIED AND BLEACHED FOR SPECIFIC USES. [R4] FORM: *GRADES: VARIETY OF TECHNICAL GRADES; GRADE FREE FROM CHICK EDEMA FACTOR; USP; FCC; 99+%. A PURIFIED TECHNICAL OLEIC ACID CONTAINING 90% OR MORE OLEIC, 4% MAXIMUM LINOLEIC AND 6% MAXIMUM SATURATED ACIDS IS AVAIL. [R4] *SEVERAL GRADES ... AVAILABLE IN COMMERCE, VARYING ... PALE YELLOW TO RED BROWN AND DEPENDING ON AMT OF STEARIC, ETC, SATURATED ACID PRESENT, BECOMING TURBID AT 8-16 DEG C. THE ACID OF COMMERCE USUALLY CONTAINS 7-12% SATURATED ACIDS ... STEARIC, PALMITIC ... LINOLEIC, ETC, UNSATURATED ACIDS. [R2] MFS: *Henkel Corporation, Hq, The Triad, Suite 200, 2200 Renaissance Boulevard, Gulph Mills, PA 19406, (215) 270-8100; Production sites: Emery Group, 11501 Northlake Dr, PO Box 429557 Cincinnati, OH 45249 (513) 630-7300; Western Operations, 5568 East 61st St, City of Commerce, CA 90022 (212) 912-8144 [R5] *Hercules Incorporated, Hq, Hercules Plaza, Wilmington, DE 19894, (302) 594-5000; Paper and Technology Group; Production site: Franklin, VA 23851 [R5] *Unichema North America, Hq, 4650 South Racine Ave, Chicago, IL 60609, (312) 376-9000 [R5] *Westvaco Corp, Hq, 299 Park Ave, New York, NY 10171, (212) 688-5000; Chemical Division, PO Box 70848, Charleston Heights, SC 29415; Oleochemicals Department; Production site: Charleston Heights, SC 29415 [R5] *Witco Corp, Hq, 520 Madison Ave, New York, NY 10022-4236 (212) 605-3800; Oleochemicals Group; 755 Crossover Lane, Memphis, TN 38117-4907 (901) 684- 7000; Production sites: Memphis, TN 38108 and Newark, NJ 07105 [R5] *Woburn Chemical Company, Hq, 190 19th Avenue, Paterson, NJ 07504 (201) 345- 8660 [R5] OMIN: *... CONSISTS CHIEFLY OF (Z)-9-OCTADECENOIC ACID ... USUALLY CONTAINS VARIABLE AMT OF OTHER FATTY ACIDS PRESENT IN TALLOW SUCH AS LINOLENIC AND STEARIC ACIDS. [R6] *HEAVY METALS AND CALCIUM SALTS FORM INSOLUBLE OLEATES. IODINE SOLN ARE DECOLORIZED BY FORMATION OF IODINE ADDITION CMPD OF OLEIC ACID. [R6] *EMULSIONS OF 10% FAT (INTRALIPID 10%) ARE PREPD FROM REFINED SOY BEAN OIL, EGG-YOLK PHOSPHOLIPIDS, AND GLYCERIN. THE MAJOR FATTY ACIDS ARE LINOLEIC, OLEIC, PALMITIC, AND LINOLENIC. THE PREPN IS ISOTONIC AND MAY BE ADMIN INTO A PERIPHERAL VEIN ... IN PARENTERAL ALIMENTATION. [R7] *OLEIC ACID ... MOST ABUNDANT OF ALL NATURAL FATTY ACIDS. [R3] *OBTAINED AS BY-PRODUCT IN MFR OF SOLID STEARIC AND PALMITIC ACIDS USED IN MANUFACTURE OF CANDLES, STEARATES, AND OTHER PRODUCTS. CRUDE OLEIC ACID IS KNOWN AS "RED OIL," STEARIC AND PALMITIC ACIDS BEING SEPARATED BY COOLING MIXTURE AND FILTERING. [R6] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R8] *PREPN OF TURKEY RED OIL, SOFT SOAP AND OTHER OLEATES; USED IN POLISHING CMPD; WATERPROOFING TEXTILES [R2] *IN OILING WOOL; MFR DRIERS; THICKENING LUBRICATING OILS [R2] *DEFOAMING AGENT IN WET-PROCESS PHOSPHORIC ACID PROCESS [R9] *MFR SOAP AND DETERGENTS [R3] *PREPN BENZYL BENZOATE LOTION, GREEN SOAP, AND OLEATE SALTS OF BASES [R6] *CHEM INT FOR METALLIC AND AMINE SOAPS; PELARGONIC ACID, AZELAIC ACID, NITROGEN DERIVS; ANIONIC AND NONIONIC SURFACTANTS, PLASTICIZERS; TEXTILE CHEMICALS; WAXES [R1] *IN RODENT EXTERMINATION /BARIUM OLEATE/; PHARMACEUTIC AID (SOLVENT) [R2] *SOLVENT FOR OTHER OILS, FATTY ACIDS AND OIL-SOLUBLE MATERIALS [R4] *OINTMENTS; COSMETICS; ORE FLOTATION; FOOD-GRADE ADDITIVES [R4] *VET: EMULSIFER [R10] *IN HAND CREAMS, LOTIONS, AND LINIMENTS, WHERE IT SERVES AS AN ANTIFREEZE FOR GELS IN COLD CLIMATES [R10] *MEDICATION: IN FAT EMULSION FOR PARENTERAL ALIMENTATION [R7] *COMPOSITION IN WHEAT FLOUR FATTY ACIDS: 11.5%. [R11] *USEFUL IN BUTTER, CHEESE, BANANA, AND MEAT FLAVORS. [R12] *... A DEFOAMING AGENT IN WET-PROCESS PHOSPHORUS ACID PROCESS, IT IS REPORTED TO ENLARGE GYPSUM CRYSTALS 75% AND THUS AID IN FILTRATION STEP. [R9] PRIE: U.S. PRODUCTION: *(1972) 6.4X10+10 GRAMS [R1] *(1975) 5.36X10+10 GRAMS [R1] *(1984) 2.93X10+8 g [R13] U.S. IMPORTS: *(1972) 4.2X10+8 GRAMS [R1] *(1975) 4.17X10+8 GRAMS [R1] U.S. EXPORTS: *(1984) 2.70X10+8 g [R14] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS OR NEARLY COLORLESS LIQ (ABOVE 5-7 DEG C) [R2]; *YELLOWISH, OILY LIQUID [R3]; *WATER-WHITE LIQUID [R6] ODOR: *PECULIAR LARD-LIKE ODOR [R6] TAST: *PECULIAR LARD-LIKE TASTE [R6] BP: *286 DEG C @ 100 MM HG [R2] MP: *16.3 DEG C [R15, p. 3-355] MW: *282.45 CTP: *Critical pressure = 30 atm [R16] DEN: *0.895 @ 25 DEG C/25 DEG C [R2] DSC: *pKa = 5.02 in aqueous solution at 25 deg C [R16] HTC: *At constant volume; delta Ec = -2.663.9 kcal/mol at 25 deg C [R16] HTV: *16.1 kcal/mol at boiling [R16] SOL: *PRACTICALLY INSOL IN WATER; SOL IN CHLOROFORM; ETHER; FIXED AND VOLATILE OILS; ALCOHOL; BENZENE [R2]; *MISCIBLE IN ACETONE; CARBON TETRACHLORIDE; METHANOL [R15, p. 3-355]; *SOL IN MOST ORGANIC SOLVENTS [R4] SPEC: *INDEX OF REFRACTION: 1.463 @ 18 DEG C/D; 1.4585 @ 26 DEG C/D [R2]; *MAX ABSORPTION (HEXANE): 185 NM (LOG E= 3.8) [R15, p. 3-355]; *IR: 915 (Sadtler Research Laboratories Prism Collection) [R17]; *NMR: 70 (Sadtler Research Laboratories Spectral Collection) [R17]; *MASS: 1863 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R17] SURF: *32.8 dyne/cm at 20 deg C; 27.94 dyne/cm at 90 deg C; 21.6 dyne/cm at 180 deg C [R16] VAP: *5.46X10-7 mm Hg at 25 deg C [R18] VISC: *25.6 CENTIPOISE @ 30 DEG C [R15, p. 6-145] OCPP: *IODINE NUMBER: 89.9; ACID VALUE: 198.6; SOLIDIFICATION @ 4 DEG C TO CRYSTALLINE MASS [R2] *AT ATMOSPHERIC PRESSURE DECOMPOSES WHEN HEATED @ 80-100 DEG C [R2] *CONGEALS @ TEMP NOT ABOVE 10 DEG C [R6] *REACTS WITH ALKALIES TO FORM SOAPS; OXIDIZED TO VARIOUS DERIVATIVES BY NITRIC ACID, POTASSIUM PERMANGANATE, AND OTHER AGENTS [R6] *SAPONIFICATION VALUE: 196-206 [R4] *Viscosity = 38.80 mN-s/m2 at 20 deg C; 27.64 mN-s/m2 @ 25 deg C. [R19] *Boiling Point - Decomposes at 360 deg C and 1 atm [R16] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 0. 0= Materials that on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R20] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R20] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R20] FLPT: *390-425 deg F (open cup) [R21] +372 DEG F (189 DEG C) (CLOSED CUP) [R20] AUTO: +685 DEG F (363 DEG C) [R20] FIRP: *Use water spray, dry chemical, foam or carbon dioxide. Water or foam may cause frothing. Water spray may be used to flush spills away from exposures. [R22] REAC: *The improved preparation of 1,4-octadecanolactone involves heating oleic acid (or other C18 acids) with 70% perchloric acid to 115 deg C. This is considered to be a potentially dangerous method. [R23, 961] *Shortly after mixing /aluminum and oleic acid/, an explosion occurred, but this could not be repeated. The acid may have been peroxidized. [R23, 29] SERI: *Irritating to skin and eyes. [R21] EQUP: *Impervious gloves; goggles or face shield; impervious apron. [R21] *Wear rubber gloves, face shield, coveralls, full body shields and self-contained breathing apparatuses ... . [R24] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *ON EXPOSURE TO AIR, ESPECIALLY WHEN IMPURE, IT OXIDIZES AND ACQUIRES YELLOW TO BROWN COLOR AND RANCID ODOR [R25] STRG: *Keep containers closed and store in cool and dark places. [R24] CLUP: *Cover with soda ash or sodium bicarbonate. Mix and add water. Neutralize and drain into a drain with sufficient water. [R24] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Charge directly or after dissolving in a flammable solvent into the furnace with afterburner. [R24] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *Neutrophils from healthy volunteers were isolated and incubated with albumin-bound oleic acid. Standard in vitro function tests including phagocytosis, bactericidal activity, and chemotaxis were performed after the incubation. Oleic acid caused no changes in bactericidal activity and only moderate decreases in phagocytosis and chemotaxis at high conc. [R26, 4966] *Oleic acid in human blood reversibly altered the shape of erythrocytes, led to the reduction of viscosity of the blood in vitro, and reduced the erythrocyte sedimentation rate. [R26, 4966] NTOX: *... Oleic acid or neutralized sodium oleate injected into the corneas of rabbits caused the eyes to become inflamed within a few hours, to develop corneal abscess within a few days, and to become extensively scarred and vascularized. There was necrosis in the immediate region of the injection, and formation of fat droplets in surviving surrounding corneal cells. [R27] *UNDILUTED, IT IS A DEPILATORY ON MICE AND RABBITS. [R10] *THE FREE ACID IN VACCINES (... MANNIDE MONOOLEATE) HAS BEEN ASSOCIATED WITH STERILE ABSCESSES. [R10] *Oleic acid was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Oleic acid was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.300, 1.000, 3.300, 10.000, 33.000, 100.000, and 333.000 ug/plate. The highest ineffective dose tested in any S. typhimurium strain was 333.000 ug/plate. Slight clearing of the background bacterial lawn occurred at 10.000 ug/plate in cultures without activation (the highest dose tested without S-9). In cultures tested with activation, clearing of the background lawn was not seen until the dose reached 333.000 ug/plate. [R28] *Dogs received weekly injections of 0.09 g/kg of oleic acid over a period of 1 to 3 months and responded with a variety of pulmonary changes. Early changes were thromboses and cellular necrosis. These changes were followed by a repair stage with proliferation of type 2 cells and fibrotic foci in subpleural areas. A later change was pulmonary fibrosis. The extent of lesions was related to the number of oleic acid injections. [R26, 4965] *The effect of oleic acid on insulin secretion was studied in the isolated perfused rat pancreas. In the absence of glucose a continuous infusion of oleic acid (1500 uM) induced a biphasic insulin release. The results suggest that high conc of oleic acid stimulate insulin release from the isolated perfused rat pancreas and modulate the insulin response to arginine or glucose. [R26, 4965] *THERE WAS AN INCREASE IN OLEIC ACID OF LECITHIN IN ALCOHOLICS, (OBSERVED IN BOTH LECITHIN AND TRIGLYCERIDES), AS COMPARED TO NORMALS. [R29] *% COMPOSITION OF OLEIC ACID IN LIPID FRAGMENTS DECREASED WITH METHYLMERCURY CHLORIDE (DOSAGE: 1-10 MG/KG) EXCEPT FOR THAT IN PHOSPHOLIPIDS OF KIDNEY OF RATS RECEIVING LOWEST DOSE. [R30] *SODIUM HYDROCORTISONE 21-PHOSPHATE (5 MG/KG, IP, DAILY FOR 14 DAYS) LOWERED THE PERCENTAGE OF OLEIC ACID. [R31] *WITHIN 30-60 SECONDS AFTER IMPLANTATION OF POLYMETHYL METHACRYLATE BONE CEMENT, OLEIC ACID CONTENT DOUBLED IN VENA CAVA BLOOD. [R32] *RATS WERE GIVEN IV INJECTIONS OF 3% METHYLNITROSOUREA (60 MG/KG) FOR 6 CONSECUTIVE DAYS. PHOSPHATIDYLCHOLINE AND PLASMALOGEN WERE CHARACTERIZED BY A DIMINISHED CONTENT OF OLEIC ACID (18:1). [R33] *FREE OLEIC ACID IN PLASMA WAS INCREASED IN 12 HEALTHY MALE VOLUNTEERS TREATED WITH DAILY ORAL DOSES OF HYDROCHLOROTHIAZIDE 100 MG, CHLORTHALIDONE 100 MG, OR FUROSEMIDE 80 MG FOR 3 WEEKS IN CROSS-OVER TRIAL. [R34] *OLEIC ACID CONJUGATE OF DDT WAS RETAINED IN VIVO IN LIVERS AND SPLEEN OF MALE AND FEMALE RATS GIVEN CHRONIC IP DDT INJECTIONS. [R35] *The capacity of stearic, monochlorostearic, dichlorostearic and oleic acids to cause membrane damage was measured as their ability to induce leakage of adenosine triphosphate (ATP) from mammalian tumour cells in vitro. Chlorinated stearic acids, and oleic acid, caused ATP leakage at lower concentrations than normal stearic acid. The membrane disturbing properties are suggested to be a result of the different molecular geometries of the chlorinated stearic acids and oleic acid, compared to non-chlorinated stearic acid. [R36] *It has recently been shown that the infusion of oleic acid into the rat pancreaticobiliary duct causes a reproducible and long-lasting atrophy of exocrine pancreas. The effects of this pancreatic atrophy on non-invasive pancreatic function tests have not been fully characterized. This study was undertaken to determine which pancreatic function test was most useful in determining pancreatic insufficiency in this model. Pancreatic insufficiency (PI) was induced in male Wistar rats by oleic acid infusion and three pancreatic function tests were compared in these animals and saline controls. The coefficient of fat absorption on a 5 or 45% fat diet and bentiromide testing could not differentiate animals with or without pancreatic insufficiency but fecal chymotrypsin levels were excellent discriminators. All animals with pancreatic insufficiency had fecal-chymotrypsin levels below 67 U/g feces whereas all saline controls were above this level. [R37] *The influence of various dietary constituents--phenethylisothiocyanate (PEITC), oleic acid (OA), triolein (TO), and vitamin A (ROL)--on the genotoxic activity of nitrosamines (NDMA, NDELA, NPYR) was investigated. For this purpose differential DNA repair assays with Escherichia coli K-12 strains were performed in vitro and in vivo with mice. Under in vitro conditions (liquid holding), all compounds reduced nitrosamine induced DNA-damage in the indicator bacteria in the dose range 1-10 ug/ml, the ranking order of efficiency being pheneethylisothiocyanate greater than vitamin A greater than or equal to triolein. [R38] *O1eic acid injection produces acute lung injury and pulmonary hypertension in adult animals. In other types of acute lung injury, such as that caused by E coli endotoxin, metabolites of arachidonic acid are important mediators of pulmonary hypertension. Oleic acid /was injected/ into awake, chronically instrumented newborn lambs. The hemodynamic response of lambs to injection of oleic acid alone was compared to their response after pretreatment with either FPL57231, a putative leukotriene receptor antagonist, or indomethacin, a cyclooxygenase synthesis inhibitor. Oleic acid caused acute pulmonary hypertension associated with an increase in protein-rich lung lymph fluid. Systemic hemodynamic effects were variable. FPL57231 completely blocked the oleic acid induced pulmonary hypertension while indomethacin significantly attenuated the response. Therefore, metabolites of arachidonic acid metabolism appear to be important mediators of oleic acid induced pulmonary hypertension in newborn lambs. [R39] ADE: *METABOLISM OF TRITIATED OLEIC ACID WAS STUDIED IN RATS DURING 600 DAYS. DURING FIRST 4 DAYS, HALF ACTIVITY IS FIXED TO WATER AND HALF IS STORED IN ADIPOSE TISSUE WHICH IT LEAVES QUICKLY, THEN MORE SLOWLY WITH T/2 OF ABOUT 200 DAYS. [R40] METB: *The normal metabolic pathway of palmitic and stearic acids in mammals produces oleic acid. Oleic acid, on a series of elongation and desaturation steps, may be converted into longer chain eicosatrienoic and nervonic acid. [R26, 4966] INTC: *LOW CONCN OF ... OLEIC ACID ... CAUSED CONSIDERABLE INCREASE IN THE INTESTINAL ABSORPTION OF AMORPHOUS AND POLYMORPHIC CHLORAMPHENICOL IN THE CAT. [R41] *LIVER TRITIATED-LABELED OLEATE SHOWED ACCUMULATION OF NEWLY SYNTHESIZED TRIGLYCERIDES WITHOUT ANY EFFECT ON PHOSPHOLIPIDS, AFTER SINGLE INJECTION OF CEROUS CHLORIDE IN RATS. [R42] *ALTERATIONS IN PHOSPHOLIPID COMPOSITION IN BRAIN AND HEART OCCURS IN RESPONSE TO ETHANOL IN THOSE STRAINS OF MICE THAT SHOW RAPID TOLERANCE TO ETHANOL. AN INCREASE IN LIVER PHOSPHOLIPIDS CONTAINING OLEIC ACID WERE FOUND IN ALL STRAINS. [R43] *AFTER 16 MIN OF BRAIN ISCHEMIA IN RATS, BRAIN OLEATE INCREASED 2.5-FOLD. POSTISCHEMIA THERAPY WITH THIOPENTAL ACCELERATED THE RATE OF FALL OF BRAIN OLEATE. [R44] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *1. 1= PRACTICALLY NONTOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) ABOVE 15 G/KG, MORE THAN 1 QT (2.2 LB) FOR 70 KG PERSON (150 LB). [R45] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Oleic acid occurs as a natural product in the essential oils of various plants. It has been identified in various foods, such as brown rice and beef. Oleic acid is released to the atmosphere in emissions from tobacco smoke, biomass combustion, coal/refuse combustion, veneer drying, and cooking hamburger meat. It is also released in wastewater effluents from pulp and paper mills, olive oilproduction, and waste treatment plants. If released to the atmosphere, oleic acid will degrade by reaction with photochemically produced hydroxyl radicals (estimated half-life of about 5 hours). It may be physically removed from air by dry deposition. If released to soil or water, oleic acid is expected to biodegrade; a variety of biodegradation screening studies have demonstrated that oleic acid biodegrades. However, the rate of biodegradation may be diminished due to concurrent adsorption (estimated Koc of 38,000). Occupational exposure to oleic acid occurs primarily through dermal contact. The general population is exposed to oleic acid through consumption of food, consumption of drinking water, and dermal contact with cosmetics and ointments in which it is contained. (SRC) NATS: *Oleic acid is a natural constituent of cotton seed oil, linseed oil, peanut oil, coconut oil, palm kernel oil, olive oil, corn oil, palm oil, rapeseed oil, soybean oil, sunflower oil, herring oil, sardine oil, whale oil, beef tallow(1), and brown rice(2). Furthermore, oleic acid can be released in runoff from its natural sources(3) and in emissions from biomass combustion(4). [R46] ARTS: *DETECTED IN THE AIR AT A DETROIT FREEWAY EXCHANGE, A NEW YORK CITY HIGHWAY TRAFFIC LOCATION AND IN A RESIDENTIAL AREA IN BELGIUM [R47] *Oleic acid is released in emissions from tobacco smoke and veneer drying(2). It is also released to the environment in fly ash emissions from coal/refuse combustion(3). Oleic acid can be released in urban runoff(1). It is released in pulp and paper mill effluents, as well as publically owned treatment work (POTW) effluents(3-5). Cooking extra-lean and regular hamburger releases oleic acid to the air(6). [R48] FATE: *TERRESTRIAL FATE: Biodegradation is expected to be the dominant fate process in soil based on half-lives of 0.2 and 0.66 days in screening tests(1-2,SRC). An estimated Koc of 38,000(4,SRC) suggests that oleic acid, in the undissociated form, will be immobile in soil(5). Based on the pKa value of 5.02(3), oleic acid will be 99% dissociated at pH 7(SRC) and no data are available to determine whether the oleate ion will adsorb to soil less strongly than by its estimated Koc. [R49] *AQUATIC FATE: Several screening studies(1-6) indicate that oleic acid will rapidly biodegrade in aquatic ecosystems(SRC). Adsorption to sediment (estimated Koc of 38,000) and bioconcentration in aquatic organisms (estimated BCF of 44,000) are expected to be important transport processes for the undissociated form of oleic acid in water systems(8,SRC). Based on the pKa value of 5.02(7), oleic acid will be 99% dissociated at pH 7(SRC). Volatilization from water may be important from shallow, rapidly moving waters (estimated half-life from a model river is 1.6 days(8,SRC)). [R50] *ATMOSPHERIC FATE: Based on an experimental vapor pressure of 5.46X10-7 mm Hg at 25 deg C(1), oleic acid will exist in both the vapor and particulate phases in the ambient atmosphere(2); monitoring data support this estimate(4). Vapor-phase oleic acid is degraded by reaction with photochemically formed hydroxyl radicals in the ambient atmosphere; the half-life for this reaction in air can be estimated to be about 5 hours(3,SRC). Oleic acid has been found on airborne particulate matter(5-6) which would suggest removal from air via dry deposition(SRC). [R51] BIOD: *A 47 and 52 theoretical %BOD for oleic acid (initial concn of 1,000 ppm) was measured under aerobic conditions over a period of 5 days in screening tests at 20 deg C using sewage inoculum(1). A biodegradation half-life of 0.66 days was measured for oleic acid at an initial concn of 100 ppm with an aerobic Warburg respirometer at 25 deg C using activated sludge inocula(2). In another screening study a first order rate constant was measured to be 0.12 1/hr for oleic acid (initial concn of 100 ppm) which corresponds to a biodegradation half-life of 0.2 days(5). Oleic acid at initial concns of 1, 10, 1, and 10 ppm exhibited 90, 24, 97, and 28 theoretical %BOD, respectively, over incubation periods of 5, 5, 10, and 10 days, respectively, in an aerobic screening study using sewage inoculum(3). A 68 theoretical %BOD (initial concn of 100 ppm) was measured under aerobic conditions over a period of 5 days in a screening test at 20 deg C using sewage inoculum(4). A 39 theoretical %BOD for oleic acid (initial concn not given) was measured under aerobic conditions over a period of 5 days in a screening test at 20 deg C using sewage inoculum(6). [R52] *After a 16 day acclimation time, a 63.5 theoretical %BOD was measured for oleic acid (initial concn not given) over a period of 5 days in an aerobic screening test at 20 deg C using activated sludge inocula(1). A 47.7 and 52.9 theoretical %BOD for oleic acid (initial concn not given) was measured under aerobic conditions over a period of 5 days in screening tests at 20 deg C using sewage inoculum(2). A 57.2 theoretical %BOD was measured for oleic acid (initial concn of 500 ppm) over a period of 5 days in an aerobic screening test at 20 deg C using activated sludge inoculum(3). [R53] ABIO: *The rate constant for the vapor-phase reaction of oleic acid with photochemically produced hydroxyl radicals can be estimated to be 7.5X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 5 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R54] BIOC: *Based on an estimated log octanol/water partition coefficient of 7.73(2) and a regression derived equation(1), the BCF for undissociated oleic acid can be estimated to be approximately 44,000(SRC). This estimated BCF suggets that oleic acid may bioconcentrate in aquatic organisms(SRC). [R55] KOC: *Based on an estimated log octanol/water partition coefficient of 7.73(2) and a regression derived equation(1), the Koc for undissociated oleic acid can be estimated to be approximately 38,000(SRC). According to a suggested classification scheme(3), this Koc value indicates that oleic acid will be immobile in soil(3); therefore, adsorption to soil and sediment may be an important fate process(SRC). Based on a pKa value of 5.02(4), oleic acid will be 99% dissociated at pH 7(SRC). No experimental data are available to determine whether the oleate ion will adsorb to sediment or soil less strongly than its estimated Koc value indicates(SRC). [R56] VWS: *The Henry's Law constant for oleic acid can be estimated to be 4.5X10-5 atm-cu m/mole at 25 deg C using a structure estimation method(1,SRC). According to a suggested classification scheme(2), this value of Henry's Law constant suggests that volatilization may be important in shallow rapidly moving water(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 1.6 days(2,SRC). The volatilization half-life from a model lake (1 m deep) can be estimated to be about 17 days(2,SRC). [R57] WATC: *SURFACE WATER: Oleic acid was qualitatively identified in the lower Fox River, Wisconsin(1). Oleic acid was detected at concns of 1-114 ug/l at distances 0.1-6 km from a kraft pulp mill sewer in the southern part of Lake Saimaa, Finland(2). During summer and fall of 1990, oleic acid was detected at a maximum concn of 12 ug/L from 13 water samples taken in northern Alberta(3). Oleic acid was qualitatively identified in 5 of 15 water samples taken from Thunder Bay, Lake Superior, during the summer of 1983(4). [R58] *DRINKING WATER: Oleic acid was qualitatively detected in drinking water concentrate from New Orleans, LA on January 14, 1976, Cincinnati, OH on January 14, 1980, and Seattle, WA on November 5, 1976(1). Oleic acid was qualitatively identified in water from a British drinking water supply(2). [R59] *GROUNDWATER: Oleic acid was found at a maximum concn of 142 ng/L in groundwater near Barcelona, Spain(1). [R60] EFFL: *Wastewater from olive oil production contains oleic acid(1). Oleic acid was qualitatively identified in advanced waste treatment concentrates from Orange County on January 27, 1976 and February 3, 1976 and from Blue Plains, Washington DC(2). Frying of extra-lean and regular hamburger was found to emit 10.1 mg oleic acid/kg meat(3). Char-broiling of extra-lean and regular hamburger was found to emit 82.4-568 mg oleic acid/kg meat(3); it was suggested that meat cooking operations may be an important source of organic aerosol emissions in Los Angeles, CA(3). Oleic acid is present in kraft paper mill wastewaters(4). Oleic acid was found at a concn of 60-891 ug/L in wastewater at the Iona treatment plant in Vancouver, British Columbia(5). Oleic acid was qualitatively identified in wheat and rye straw pulp mill effluents(6). [R61] *Oleic acid was detected at a concn range of 6-11 ppb in publically owned treatment work (POTW) effluents from three New Jersey facilities(1). [R62] SEDS: *During summer and fall of 1990, Oleic acid was detected at a maximum concn of 4.3 ug/g from 21 sediment samples taken in northern Alberta(1). [R63] ATMC: *URBAN/SUBURBAN: Oleic acid was qualitatively detected in airborne particulate matter in a suburban area in Japan(1). Oleic acid was qualitatively found in the gas phase in air from an unknown urban area and it was quantitatively identified in particulate samples at concns of 1.31-2.68 ug/1000 cu-m(2). [R64] *RURAL/REMOTE: Oleic acid was found at concns of 190 ng/cu-m in January of 1981, 3.6 ng/cu-m in July of 1981, and 2.1 ng/cu-m in August of 1981 from aerosol samples taken 1 m above ground level in a heavily vegetated area of American Samoa(1). Oleic acid was detected at a concn of 0.043 ng/cu-m on an aerosol sample taken above the North Pacific Ocean During May of 1986(1). The mean concn of oleic acid on aerosols over the North Atlantic Ocean was 1.6 ng/cu-m in 1978(2). [R65] FOOD: *Hydrogenated coconut oil, regular hard margarine, and hard butter contain 3.6, 59, and 83 grams oleic acid per 100 grams of fat, respectively(1). Oleic acid is a natural constituent of peanut oil (36-72 wt%), palm kernel oil (9-16 wt%), coconut oil (6-8 wt%), olive oil (65-85 wt%), corn oil (19-50 wt%), palm oil (38-44 wt%), rapeseed oil (11-60 wt%), soybean oil (20-30 wt%), sunflower oil (14-65 wt %), herring oil (8-15 wt%), sardine oil (15-25 wt%), and beef tallow (20-50 wt%)(2). Oleic acid's composition in brown rice ranges from 37.9-51.6 wt% of total acids(3). [R66] PFAC: PLANT CONCENTRATIONS: *Oleic acid is a natural constituent of cotton seed oil (13-44 wt%) and linseed oil (15-25 wt%)(1). [R67] FISH/SEAFOOD CONCENTRATIONS: *Oleic acid is a natural constituent of whale oil (22-35 wt%), sardine oil (15-25 wt%), and herring oil (8-15 wt%)(1). During summer and fall of 1990, oleic acid was detected at a maximum concn of 690 ug/g from 11 fish bile samples taken in northern Alberta(2). Oleic acid was qualitatively identified in lake trout and walleye collected from Lake Michigan and Lake Erie 3). [R68] OEVC: *Oleic acid was found at concns of 1115.5, 10.7, and 130.9 ug/g in tire wear particles, brake lining particles, and road dust particles(1). [R69] RTEX: *During its production and use, workers may be exposed to oleic acid via dermal contact(SRC). The general population is exposed to oleic acid through consumption of food (since it occurs in various foods(2-4)), consumption of drinking water(5,SRC), and through dermal contact during its use in cosmetics and ointments(1,SRC). [R70] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 818,506 workers are potentially exposed to oleic acid in the USA(1). [R71] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of oleic acid are exempted from the requirement of a tolerance when used as a diluent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R72] *Oleic acid is exempted from the requirement of a tolerance when used as a defoaming agent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R73] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Oleic acid is found on List D. Case No: 4083; Pesticide type: insecticide, fungicide, herbicide, rodenticide, antimicrobial; Case Status: RED Approved 09/92; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Oleic acid; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R8] *Residues of oleic acid are exempted from the requirement of a tolerance when used as a diluent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R72] *Oleic acid is exempted from the requirement of a tolerance when used as a defoaming agent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R73] FDA: */Oleic acid derived from tall oil fatty acids/ is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. [R74] */Oleic acid, sulfated/ is an indirect food additive for use only as a component of adhesives. [R75] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *OLEIC ACID DETERMINATION IN OILS AND FATS BY UV SPECTROPHOTOMETRY. [R76] CLAB: *LIPIDS WERE EXTRACTED WITH CHLOROFORM-METHANOL (1:1), METHYLATED, AND FATTY ACIDS WERE DETECTED BY GAS CHROMATOGRAPHY. [R77] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: Budavari, S. (ed.). 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Willoughby, Ohio: Meister, 1980.,p. B-62 R10: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 398 R11: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 711 R12: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 295 R13: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.175 R14: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-86 R15: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 71st ed. Boca Raton, FL: CRC Press Inc., 1990-1991. R16: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 379 R17: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 928 R18: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R19: Dean, J.A. Handbook of Organic Chemistry. New York, NY: McGraw-Hill Book Co., 1987.,p. 4-71 R20: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-76 R21: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R22: Cralley, L.J., L.V. Cralley (eds.). Patty's Industrial Hygiene and Toxicology 2 nd ed. Volume 3B: Theory and Rationale of Industrial Hygiene Practice-Biological Responses. New York, NY: John Wiley Sons, 1985.385 R23: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 R24: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 385 R25: The Merck Index. 9th ed. 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London: The Chemical Society, 1972. 417 R42: RENAUD G ET AL; BIOCHEM BIOPHYS RES COMMUN 95 (1): 220 (1980) R43: LITTLETON JM ET AL; ADV EXP MED BIOL 126 (BIOL EFF ALCOHOL): 7 (1980) R44: NEMOTO EM ET AL; INTRACRANIAL PRESSURE 4: 307 (1980) R45: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-134 R46: (1) Brockmann R et al; Ullmann's Encycl Indust Chem A10: 255 (1987) (2) Taira H et al; J Agric Food Chem 36: 45-7 (1988) (3) Bomboi MT et al; Sci Tot Environ 93: 523-36 (1990) (4) Graedel TE et al; Atmospheric Chemical Compounds NY: Academic Press p. 352 (1986) R47: VERSCHUEREN. HDBK ENVIRON DATA ORG CHEM 936 (983) R48: (1) Bomboi MT et al; Sci Tot Environ 93: 523-36 (1990) (2) Graedel TE et al (eds); Atmospheric Chemical Compounds NY: Academic Press p. 352 (1986) (3) Junk GA, Ford CS; Chemosphere 9: 187-230 (1980) (3) Keith LH; Environ Sci Technol 10: 555-64 (1976) (4) Rogers H et al; Water Poll Res J Canada 21: 187-204 (1986) (5) Folke J, Lindguard-Joergensen P; Toxicol Environ Chem 10: 1-24 (1985) (6) Rogge WF et al; Environ Sci Technol 25: 1112-25 (1991) R49: (1) Novak JT, Kraus DL; Water Res 7: 843-51 (1973) (2) Urano K, Saito M; Chemosphere 14: 1333-42 (1985) (3) Riddick JA et al; Organic Solvents 4th ed; NY: Wiley p. 379 (1986) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-15 to 15-29 (1990) (5) Swann RL et al; Res Rev 85: 17-28 (1983) R50: (1) Gellman I, Heukelekian H; Sew Indust Wastes 23: 1267-81 (1951) (2) Novak JT, Kraus DL; Water Res 7: 843-51 (1973) (3) Read AD, Manser RM; Water Res 10: 243-51 (1976) (4) Stafford W, Northup HJ; Amer Dyestuff Reporter 44: 355-9 (1955) (5) Urano K, Saito M; Chemosphere 14: 1333-42 (1985) (6) Bogan RH, Sawyer CN; Sew Ind Wastes 27: 917-28 (1955) (7) Riddick JA et al; Organic Solvents 4th ed; NY: Wiley p. 379 (1986) (8) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5- 4, 5-10, 15-15 to 15-29 (1990) R51: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals 4 NY: Hemisphere Pub Corp (1989) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; Environ Toxicol Chem 7: 435-42 (1988) (4) Cautreels W, Cauwenberghe K; Atmos Environ 12: 1133-41 (1978) (5) Yokouchi Y, Ambe Y; Atmos Environ 20: 1727-35 (1986) (6) Kawanura K, Gagosian RB; Nature 325: 330-2 (1987) R52: (1) Gellman I, Heukelekian H; Sew Indust Wastes 23: 1267-81 (1951) (2) Novak JT, Kraus DL; Water Res 7: 843-51 (1973) (3) Read AD, Manser RM; Water Res 10: 243-51 (1976) (4) Stafford W, Northup HJ; Amer Dyestuff Reporter 44: 355-9 (1955) (5) Urano K, Saito M; Chemosphere 14: 1333-42 (1985) (6) Bogan RH, Sawyer CN; Sew Ind Wastes 27: 917-28 (1955) R53: (1) Bogan RH, Sawyer CN; Sew Ind Wastes 27: 917-28 (1955) (2) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 27: 1040-53 (1955) (3) Saito T et al; Fresenius' Z Anal Chem 319: 433-4 (1984) R54: (1) Atkinson R; Environ Toxicol Chem 7: 435-42 (1988) R55: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) Meylan WM, Howard PH; Group Contribution Method for Estimating Octanol-Water Partition Coefficients SETAC Meeting Cincinnati,OH Nov 8-12 (1992) R56: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) Meylan WM, Howard PH; Group Contribution Method for Estimating Octanol-Water Partition Coefficients SETAC Meeting Cincinnati,OH Nov 8-12 (1992) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Riddick JA et al; Organic Solvents 4th ed; NY: Wiley p. 379 (1986) R57: (1) Meylan W, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-15 to 15-29 (1990) R58: (1) Peterman PH et al; Hydrocarbons and Halogenated Hydrocarbons in the Aquatic Environment. Afghan, BK, Mackay, D eds. NY: Plenum Press pp. 145-60 (1980) (2) Oikari A et al; Pap Puu 62: 193-6, 199-202 (1980) (3) Morales A et al; Water Environ Res 64: 660-8 (1992) (4) Great Lakes Water Quality Board; A Review of Lake Superior Water Quality with Emphasis on the 1983 Intensive Survey (1990) R59: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. USEPA-600/1-84-020A Columbus,Ohio: Columbus Labs. Health eff res lab pp. 45,134 (1984) (2) Crathorne B et al; Environ Sci Technol 18: 797-802 (1984) R60: (1) Guardiola J et al; Water Supply 7: 11-6 (1989) R61: (1) Sanchezcrespo R, Pradaalvarezbuylla J; Org Micropollut Aquat Environ. Proc Eur Supp 6th pp. 511-7 (1990) (2) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. USEPA-600/1-84-020A Columbus,Ohio: Columbus Labs. Health Eff Res Lab pp. 46,166 (1984) (3) Rogge WF et al; Environ Sci Technol 25: 1112-25 (1991) (4) Keith LH; Environ Sci Technol 10: 555-64 (1976) (5) Rogers H et al; Water Poll Res J Canada 21: 187-204 (1986) (6) Folke J, Lindguard-Joergensen P; Toxicol Environ Chem 10: 1-24 (1985) R62: (1) Clark LB et al; Res J WPCF 63: 104-13 (1991) R63: (1) Morales A et al; Water Environ Res 64: 660-8 (1992) R64: (1) Yokouchi Y, Ambe Y; Atmos Environ 20: 1727-35 (1986) (2) Cautreels W, Vancauwenberghe K; Atmos Environ 12: 1133-41 (1978) R65: (1) Kawanura K, Gagosian RB; Nature 325: 330-2 (1987) (2) Duce RA et al; Rev Geophys Space Phys 21: 921-52 (1983) R66: (1) Noznick PP; Ullmann's Encycl Indust Chem A8: 240 (1987) (2) Brockmann R et al; Ullmann's Encycl Indust Chem A10: 255 (1987) (3) Taira H et al; J Agric Food Chem 36: 45-7 (1988) R67: (1) Brockmann R et al; Ullmann's Encycl Indust Chem A10: 255 (1987) R68: (1) Brockmann R et al; Ullmann's Encycl Indust Chem A10: 255 (1987) (2) Morales A et al; Water Environ Res 64: 660-8 (1992) (3) Hesselberg RJ, Seelye JG; Admen Rep No 82-1 Ann Arbor, MI: US Fish Wildlife soc Great Lakes Fishery Lab (1982) R69: (1) Rogge W et al; Environ Sci Technol 27: 1892-904 (1993) R70: (1) Sax NI, Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 11th ed. NY: Van Nostrand Reinhold Co p. 854 (1987) (2) Noznick PP; Ullmann's Encycl Indust Chem A8: 240 (1987) (3) Brockmann R et al; Ullmann's Encycl Indust Chem A10: 255 (1987) (4) Taira H et al; J Agric Food Chem 36: 45-7 (1988) (5) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. USEPA-600/1-84-020A Columbus, OH: Columbus Labs. Health Effl Res Lab pp. 45,134 (1984) R71: (1) NIOSH National Occupational Exposure Survey (NOES) (1983) R72: 40 CFR 180.1001(c) (7/1/92) R73: 40 CFR 180.1001(e) (7/1/92) R74: 21 CFR 172.862 (4/1/93) R75: 21 CFR 175.105 (4/1/93) R76: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/444 28.045 R77: BAUR C ET AL; BEITR GERICHTL MED 37: 319 (1979) RS: 46 Record 119 of 1119 in HSDB (through 2003/06) AN: 1258 UD: 200302 RD: Reviewed by SRP on 9/23/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MYRCENE- SY: *3-METHYLENE-7-METHYL-1,6-OCTADIENE-; *2-METHYL-6-METHYLENE-2,7-OCTADIENE-; *7-METHYL-3-METHYLENE-1,6-OCTADIENE-; *BETA-MYRCENE-; *1,6-OCTADIENE,-7-METHYL-3-METHYLENE- RN: 123-35-3 MF: *C10-H16 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Obtained by pyrolysis of beta-pinene ... [R1, 1085] *FROM LINALOOL ... [R2] MFS: *Millennium Specialty Chemicals Inc., PO Box 389, Jacksonville, FL 32201 (904) 768-5800; Production Site: Jacksonville, FL 32208 [R3] OMIN: *Intermediate in mfr of perfume chemicals /alpha-Myrcene/ [R1, 1085] *NON-ALCOHOLIC BEVERAGES: 4.4 PPM; ICE CREAM, ICES, ETC: 6.4 PPM; CANDY: 0.50-13 PPM; BAKED GOODS: 4.9 PPM. [R2] *FLAVORS USEFUL IN CITRUS IMITATIONS, FRUIT BLENDS. [R4] *REPELLENCY OF MONOTERPENE AND RESIN VAPORS FOR THE FIR ENGRAVER BEETLE, SCOLYTUS VENTRALIS, DECREASED IN THE FOLLOWING ORDER: LIMONENE, DELTA3-CARENE, ALPHA-PINENE, MYRCENE, BETA-PINENE, PREFORMED RESIN, CAMPHENE, AND TRICYCLENE. [R5] *ADDITION OF MYRCENE TO MIXTURE OF FRASS COMPONENTS ISOLATED FROM THE FEMALE BOLL WEEVIL IMPROVED THE ATTRACTION RESPONSE BY MALES. [R6] *WESTERN PINE BEETLES (DENDROCOTONUS BREVICOMIS) WERE CAUGHT ON UNBAITED STICKY TRAPS PLACED NEAR A SOURCE OF EXO-BREVICOMIN, FRONTALIN, AND MYRCENE. [R7] *FEMA NUMBER 2762 [R8] *Derivatives: geraniol-nerol, mixed; myrcenol; 1-methyl-4-(4-methyl-3-penten-1-yl)-3-cyclohexenecarboxaldehyde; 3/4-(4-methyl-3-penten-1-yl)-3-cyclohexenecarboxaldehyde [R9] USE: *Perfume chemicals and flavoring [R10] *INSECT REPELLENT [R5] *Detergents [R11] *In the production of 7-hydroxygeranyl-neryl dialkylamine. [R12] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Yellow, oily liquid [R10] ODOR: *Pleasant [R1, 1085]; *Terpene odor [R9] TAST: *SWEET, CITRUS [R4] BP: *167 deg C @ 760 mm Hg [R10] MP: *< -10 deg C [R13] MW: *136.23 [R9] DEN: *0.794 @ 20 deg C/4 deg C [R1, 1085] OWPC: *log Kow= 4.17 [R14] SOL: *Practically insol in water; sol in alcohol, chloroform, ether, sol in glacial acetic acid. [R1, 1085]; *Insoluble in water; soluble in ethanol, ethyl ether, and benzene. [R15]; *Soluble in oxygenated and chlorinated solvents. [R9]; *In water, 5.60 mg/l [R16] SPEC: *Index of refraction: 1.4709 @ 20 deg C; max absorption (ethanol): 226 nm (E= 16,100) [R1, 1085]; *MAX ABSORPTION (ALCOHOL): 225 NM (LOG E= 4.30) [R17]; *IR: 4971 (Coblentz Society Spectral Collection) [R18, p. V1 929]; *UV: 5-241 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R18, p. V1 929]; *MASS: 704 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R18, p. V1 929]; *MASS: 710 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R18, p. V1 858] VAP: *2.01 mm Hg [R19] OCPP: *BP: 44 deg C @ 10 mm Hg; Index of refraction: 1.4661 @ 25 deg C /alpha-Myrcene/ [R1, 10815] *Density: 0.7959 @ 25 deg C/25 deg C; max absorption (isooctane): 224.5 nm /alpha-Myrcene/ [R1, 1085] *Triply unsaturated aliphatic hydrocarbon; Index of refraction: 1.471 @ 20 deg C (81% Myrcene) [R10] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *A flammable liquid. [R20] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R20] SERI: *A moderate skin and eye irritant. [R20] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *A 28-YR OLD MAN EMPLOYED AS A BREWERY INSPECTOR IS PRESENTED WITH RESP HYPERSENSITIVITY REACTION TO BETA-MYRCENE COMPONENT OF HUMULUS LUPULUS (HOPS). DERMATITIS, SNEEZING, ITCHING AND INCREASED NASAL CONGESTION ARE REPORTED 6 MONTHS PRIOR TO THE PRESENTING SYMPTOM COMPLEX. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Myrcene's production and use in detergents, perfumes, and flavorings may result in its release to the environment through various waste streams. Myrcene has been detected in water effluent and air emissions from pulp and timber mill processes. Myrcene has been detected as a natural gaseous emission from various plant species and in various fruits and vegetables. If released to air, a vapor pressure of 2.01 mm Hg at 25 deg C indicates myrcene will exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase myrcene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, ozone radicals and nitrate; the half-lives for these reactions in air are estimated to be 1.79 hrs, 37 mins, and 1.1 hrs, respectively. If released to soil, myrcene is expected to have low mobility based upon an estimated Koc of 1300. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 0.0643 atm-cu m/mole. Myrcene may potentially volatilize from dry soil surfaces based upon its vapor pressure. However, adsorption to soil is expected to attenuate volatilization. Biodegradation in soil may be an important fate process based upon considerable biodegradation in the Japanese MITI test. If released into water, myrcene is expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Myrcene, present at 100 mg/l, reached 82-92% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3.43 and 111 hrs, respectively. However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. An estimated BCF of 324 suggests the potential for bioconcentration in aquatic organisms is high. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to myrcene may occur through inhalation and dermal contact with this compound at workplaces where myrcene is produced or used. The general population may be exposed to myrcene via inhalation of ambient air, ingestion of food and drinking water and products containing myrcene. (SRC) NATS: *Found in oil of bay, verbena, hop, and others. [R1, 1085] *REPORTED FOUND IN MIRCIA ACRIS DC; IN DISTILLATES FROM LEAVES OF RHUS COTINUS AND BAROSMA VENUSTUM (52% and 43%, RESPECTIVELY); IN LEMON GRASS, CYPRESS, ARTEMISIA, ORANGE, AND LEMON; IN FRUITS OF PHELLODENDRON AMURENSE (92%) AND PHELLODENDRON JAPONICUM ... IN OILS OF PICEA BALSAMEA, TSUGA CANADENSIS, ABIES BALSAMEA, CLARY SAGE, AND OTHERS. [R2] *Myrcene has been detected as a natural gaseous emission from various plant species(1-8). It has also been detected in various fruits and vegetables(9-19). [R22] ARTS: *Myrcene's production and use as a detergent(1), flavoring(2), and in perfumes(2) may result in its release to the environment through various waste streams(SRC). Myrcene has also been detected in water effluents(3) and air emissions(4) from pulp and timber mill processes. [R23] FATE: *THE INFLUENCE OF LIGHT AND TEMP ON MONOTERPENE EMISSIONS FROM SLASH PINE WERE ASSESSED. QUANT PRESENT IN VAPOR PHASE WERE SUFFICIENT TO MEASURE RELIABLY. [R24] *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1300(SRC), determined from a structure estimation method(2), indicates that myrcene is expected to have low mobility in soil(SRC). Volatilization of myrcene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 0.0643 atm-cu m/mole(SRC), using a fragment constant estimation method(3). The potential for volatilization of myrcene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 2.01 mm Hg(4). However, adsorption to soil is expected to attenuate volatilization(SRC). Biodegradation in soil may be an important fate process based upon considerable biodegradation in the Japanese MITI test(5). [R25] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1300(SRC), determined from a structure estimation method(2), indicates that myrcene is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 0.0643 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Volatilization half-lives for a model river and model lake are 3.43 and 111 hrs, respectively(SRC), using an estimation method(3). However, the volatilization half-life does not take into account the effects of adsorption. This is apparent from the results of two EXAMS model runs, one in which the effect of adsorption was considered, yielding an estimated half-life of 36 days in a model pond 2 m deep, and one in which the effect of adsorption was ignored, yielding an estimated half-life of 40 hrs in a model pond 2 m deep(5). Myrcene, present at 100 mg/l, reached 82-92% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test suggesting rapid degradation(6). According to a classification scheme(7), an estimated BCF of 324(SRC), from a log Kow(6) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is high. [R26] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), myrcene, which has a vapor pressure of 2.01 mm Hg at 25 deg C(2), is expected to exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase myrcene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is 1.79 hrs(SRC), calculated from its rate constant of 2.15X10-10 cu cm/molecule-sec at 25 deg C(3). Vapor-phase myrcene is degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is 37 mins(SRC), calculated from its estimated rate constant of 4.44X10-16 cu cm/molecule-sec at 25 deg C(4). Myrcene reportedly has a half-life of 1.1 hrs in the presence of nitrate radicals in the ambient atmosphere, respectively(5). [R27] BIOD: *Myrcene has been observed to undergo biodegradation in aerated lagoons, rate constant not specified(1). Myrcene, present at 100 mg/l, reached 82-92% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(2). [R28] ABIO: *The rate constant for the vapor-phase reaction of myrcene with photochemically-produced hydroxyl radicals is 2.15X10-10 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 1.79 hrs(SRC) at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(2). The rate constant for the vapor-phase reaction of myrcene with ozone is estimated to be 4.44X10-16 cu cm/molecule-sec(3). This corresponds to an atmospheric half-life of about 37 mins at an atmospheric concn of 7X1011 mol/cu cm(3). Myrcene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(4) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum. Myrcene reportedly has a half-life of 1.1 hrs in the presence of nitrate radicals in the ambient atmosphere, respectively(5). [R29] BIOC: *An estimated BCF of 324 was calculated for myrcene(SRC), using a log Kow of 4.17(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high. [R30] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for myrcene was estimated to be about 1300(SRC). According to a classification scheme(2), this estimated Koc value suggests that myrcene is expected to have low mobility in soil. [R31] VWS: *The Henry's Law constant for myrcene is estimated as 0.0643 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 2.01 mm Hg(1), and water solubility, 5.60 mg/l(2). This Henry's Law constant indicates that myrcene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 3.43 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 111 hrs(SRC). However, the volatilization half-life does not take into account the effects of adsorption. This is apparent from the results of two EXAMS model runs, one in which the effect of adsorption was considered, yielding an estimated half-life of 36 days in a model pond 2 m deep, and one in which the effect of adsorption was ignored, yielding an estimated half-life of 40 hrs in a model pond 2 m deep(4). Myrcene's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of myrcene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 2.01 mm Hg(1). [R32] WATC: *SURFACE WATER: Myrcene has been detected in the Schussen River, Germany presumably due to wood processing industries(pulp mill, timber mills, etc.), concns not specified(1). Myrcene was detected in water samples taken from Resurrection Bay, Alaska on June 17, 1986 at 0.74 ng/l. Presumably, this was caused from conifer rain forest emissions from south of Port Valdez, Alaska(2). [R33] EFFL: *Myrcene has been detected in Kraft mill waste waters ranging from trace to 160 ppb concns(1). Percent composition of myrcene released to air during Kraft processing of softwood Scots pine ranged from 1-1.6% on Feb 22, 1989(2). Percent composition (ug/cu m) of total concn of myrcene in atmospheric emission plumes from kraft pulp industries, processing Scots pine on June 20, 1989 was 1.2%, 0.9%, and 1.3% at 0 m, 20 m and 40 m heights, respectively(2). Kraft processing plant is located on the Swedish coast, 50 km south of Goteborg(2). Myrcene was detected in the headspace and waste exudate of waste trucks, concns not specified(3). Myrcene was detected in 4 of 4 air samples from biodegradable waste and 2 of 7 air samples from mixed waste containing biodegradable and plastics/printed paper wastes, concns not specified(4). Myrcene was detected in air samples from dry log debarking of Scots pine (Pinus sylvestris) and Norway spruce at 1.1 and 2.0%, respectively, of total volatile compounds at a saw-mill plant in Anneberg, Sweden from May 30, 1991 to June 6, 1991(5). Myrcene was detected in air samples from pulp wood dry drum baking and wood chips from Norway spruce at 4.7 and 1.0%, respectively, of total volatile compounds at Bravikus Pappersbuk near Norrkoping, Sweden from March 14, 1990 to June 19, 1990(5). [R34] SEDS: *SOIL: Myrcene was detected in soil samples at a depth of 10-15 cm 20 cm away from a 15 year old Picea abics tree, concn not specified(1). [R35] ATMC: *RURAL/REMOTE: Myrcene was detected in air samples from Lost Mt., Marietta, GA taken Aug 9, 1992 at 4:00 p.m., concn not specified(1). Myrcene has been detected in Smokey Mountain air samples at a concn of 1.76 ppb, presumably from coniferous forests(2). [R36] FOOD: *Myrcene has been detected as an emission from apricots, carrots, cotton, Valencia oranges, pistachios, walnuts and whitehorn at 0.1, 0.6, 0.4, 0.5, 0.5, 0.2, and 1.9 ug/g respectively(1). Volatiles from fresh guava fruit pulp obtained by vacuum distillation revealed that myrcene is 0.001 ug/g of pineapple guava. Myrcene has been reportedly found in common guava and in strawberry and yellow guava, concns not specified(2). Myrcene comprises 22.41% of volatile hydrocarbons identified in extract of Korean Chamchwi(3). The concn of myrcene in relation to ethyl acetate, defined as 1, in Idaho Russet Burbank potatoes is 0.08(4). Myrcene has been detected in emissions from the roasting of filberts, thick shelled sweet flavored tree nuts, concns not specified(5). Volatile components of mango stored at -15 deg C for 1 year contained 2.7 ug/g, while fresh mangos from Florida contained 1.0 ug/g(6). Concentrated natural orange essence used in orange juice concentrate, contains myrcene, concn not specified(7). Myrcene has been detected in freshly squeezed unpasteurized orange juice at concns ranging from 0.34-4.1 ppm(8). Myrcene is found within clove essential oil ranging from 0.30-0.45% of total volatile compounds(9). Myrcene was detected at 0.51% of total volatile constituents in headspace samples of fresh, tree-ripened nectarines(10). [R37] PFAC: PLANT CONCENTRATIONS: *Myrcene has been detected in emissions from Norway spruce, fir, Scots pine (Pinus sylvestris), and larch trees in the country of Switzerland, concns not specified. Highest emission rates take place during the summer month of July(1). Myrcene has been detected in emissions from Scots Pine at 2.3-6.3% of total terpenes(2). Myrcene has been detected in emissions from Siberian pine, silver fir, common juniper, zeravskar juniper, pencil cedar, evergreen cypress, northern white cedar, Chinese arbor vitae and deciduous moss, concns not specified. These plants are characteristic of northern Europe and Asia(2). Myrcene has been detected in emissions from the oak species Quercus ilex L. at Castel Porziano, Rome, Italy on June 1993 at 2.25% of total plant emissions between the hours of 11 a.m. to 1 p.m.(3). Myrcene has been detected in dynamic headspace samples of mushrooms C. carcharias, A. ovoidea, and M. rosea at 0.2, < 0.1, and < 0.1 percent relative to all identified volatile compounds(4). Through solvent extraction, myrcene was detected at 3 and 2 percent relative to all identified volatile compounds in G. glutinosus mushrooms(4). Average emission rate of myrcene for an 18 yr old Norway spruce tree was 3 ug/sq m-h with highest concns at noon and lowest concns at night(5). Myrcene has been detected ranging from 100-1,750 parts per trillion at 13 m height inside the canopy of maple forests in Quebec from July 28-30, 1989(6). Myrcene was detected ranging from 3.1-58 ng/cu m at 1 m above ground Aug 30-Dec 16, 1985 in Kalbelescherer in the Southern Black Forest, Germany. The suspected sources of emission were Picea abies and Abies alba tree species(7). Myrcene was detected at 0.04% of total volatile constituents in headspace samples of kiwi fruit flowers(8). [R38] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,583 workers (302 of these are female) are potentially exposed to myrcene in the US(1). Occupational exposure to myrcene may occur through inhalation and dermal contact with this compound at workplaces where myrcene is produced or used(SRC). The general population may be exposed to myrcene via inhalation of ambient air in forests and other natural environments containing plants that emit myrcene(2), ingestion of food(3-13) and drinking water(14,15) and other products(16) containing myrcene. Since myrcene is an approved food additive, the greatest potential for exposure lies in the consumption of those foods with myrcene additives(16). [R39] BODY: *Myrcene has been detected in pre-diabetic, diabetic and normal subjects in expired air samples, concns not specified(1). [R40] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Myrcene is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and 2) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. [R41] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *MYRCENE WAS DETERMINED IN AMBIENT AIR; MINIMUM DETECTABLE CONCENTRATION WAS 0.03 PPB. [R42] *THE COMPOSITION OF A USSR PEPPERMINT OIL CONTAINING 0.1% MYRCENE WAS CONFIRMED BY A COMBINATION GAS CHROMATOGRAPHY-MASS SPECTROSCOPIC METHOD. [R43] *MYRCENE WAS DETERMINED IN PINE OILS. [R44] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for beta-myrcene. Route: gavage; Species: rats and mice. [R45] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 421 R3: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 639 R4: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 292 R5: BORDASCH RP, BERRYMAN AA; CAN ENTOMOL 109 (1): 95 (1977) R6: HEDIN PA ET AL; J CHEM ECOL 5 (4): 617 (1979) R7: TILDEN PE ET AL; J CHEM ECOL 5 (4): 519 (1979) R8: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 901 R9: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 612 R10: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 802 R11: Otson R et al; pp. 335-421 in Gas Pollut Charact Cycl Nriagu Jo Ed. NY,NY: John Wiley and Sons, Inc (1992) R12: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. V11 (88) 161 R13: Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-121 (1992) R14: Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; p. 2-121 (1992) R15: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-229 R16: Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-380 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R19: Perry RH, Green D; Perry's Chemical Handbook. Physical and Chemical data. NY, NY: McGraw-Hill 6th ed (1984) R20: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2365 R21: FM NEWMARK; ANN ALLERGY 41 (5): 311 (1978) R22: (1) Andreani-Aksoyoglu S et al; J Atmos Chem 20: 71-87 (1995) (2) Isidorov VA et al; Atmos Environ 19: 1-8 (1985) (3) Kesselmeier J et al; Atmos Environ 30: 1841-1850 (1996) (4) Breheret S et al; J Agric Food Chem 45: 831-6 (1997) (5) Bufalini JJ; Impact of Natural Hydrocarbons on Air Quality. USEPA-600/2-80-086 Environ Sci Res Lab pp. 70 (1980) (6) Bufler U et al; Atmos Environ 25A: 251-6 (1991) (7) Clement B et al; Atmos Environ 9: 2513-6 (1990) (8) Juttner F; Chemosphere 17: 309-17 (1988) (9) Arey J et al; J Geophys Res 96D: 9329-36 (1991) (10) Binder RG et al; J Agric Food Chem 37: 734-6 (1989) (11) Chung TY et al; J Agric Food Chem 41: 1693-97 (1993) (12) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (13) Kinlin TE et al; J Agric Food chem 20: 1021 (1972) (14) Macleod AJ et al; J Agric Food Chem 36: 137-9 (1988) (15) Moshonas MG et al; J Agric Food Chem 38: 2181-4 (1990) (16) Moshonas MG et al; J Agric Food Chem 42: 1525-8 (1994) (17) Muchalal M et al; Agric Biol Chem 49: 1583-9 (1985) (18) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) (19) Tatsuka K et al; J Agric Food Chem 38: 2176-80 (1990) R23: (1) Otson R et al; pp. 335-421 in Gas Pollut: Charact Cycl, Nriagu, Jo ed., NY,NY: John Wiley and Sons, Inc (1992) (2) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary. 12th Ed. NY,NY: Van Nostrand Reinhold Company p. 802 (1993) (3) Juettner F; Wat Sci Tech 25: 155-64 (1992) (4) Stroemvall AM et al; Environ Pollut 79: 215-18 (1993) R24: BURNS WF ET AL; TAMPA BAY PHOTOCHEMICAL OXIDANT STUDY. MONOTERPENE EMISSION RATES FROM SLASH PINE p. 26 (1978) EPA/904/9-78/013 R25: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Perry RH, Green D; Perry's Chemical Engineer's Handbook. Physical and Chemical Data. NY, NY: McGraw-Hill 6th Ed p. 3-50 (1984) (5) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-121 (1992) R26: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) USEPA; EXAMS II Computer Simulation (1987) (6) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-121 (1992) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) R27: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Perry RH, Green D; Perry's Chemical Engineer's Handbook. Physical and Chemical Data. NY,NY: McGraw-Hill 6th ed p. 3-50 (1984) (3) Atkinson R; Journal of Physical And Chemical Reference Data. Monograph 1 (1989) (4) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (5) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold p. 1345 (1996) R28: (1) Wilson D et al; Pulp Pap Can 76: 91-3 (1975) (2) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-121 (1992) R29: (1) Atkinson R; Journal of Physical And Chemical Reference Data. Monograph 1 (1989) (2) Atkinson R et al; Atmos Env 24: 2647-54 (1990) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (5) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd Ed. NY,NY: Van Nostrand Reinhold p. 1345 (1996) R30: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-121 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R31: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R32: (1) Perry RH, Green D; Perry's Chemical Engineer's Handbook. Physical and Chemical Data. NY, NY: McGraw-Hill 6th ed p. 3-50 (1984) (2) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan; Published by Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-121 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) USEPA; EXAMS II Computer Simulation (1987) R33: (1) Juettner F; Wat Sci Tech 25: 155-64 (1992) (2) Button DK et al; Mar Chem 26: 57-66 (1989) R34: (1) Wilson D et al; Pulp Pap Can 76: 91-3 (1975) (2) Stroemvall AM et al; Environ Pollut 79: 215-18 (1993) (3) Wilkins K et al; Chemosphere 32: 2049-2055 (1996) (4) Wilkins K; Chemosphere 29: 47-53 (1994) (5) Stroemvall AM et al; Environ Pollut 79: 215-9 (1993) R35: (1) Juettner F; Environ Pollut 68: 377-82 (1990) R36: (1) Riemer DD et al; Chemosphere 28: 837-50 (1994) (2) Bufalini JJ; Impact of Natural Hydrocarbons on Air Quality. USEPA-600/2-80-086 Environ Sci Res Lab pp. 70 (1980) R37: (1) Arey J et al; J Geophys Res 96D: 9329-36 (1991) (2) Binder RG et al; J Agric Food Chem 37: 734-6 (1989) (3) Chung TY et al; J Agric Food Chem 41: 1693-97 (1993) (4) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (5) Kinlin TE et al; J Agric Food chem 20: 1021 (1972) (6) Macleod AJ et al; J Agric Food Chem 36: 137-9 (1988) (7) Moshonas MG et al; J Agric Food Chem 38: 2181-4 (1990) (8) Moshonas MG et al; J Agric Food Chem 42: 1525-8 (1994) (9) Muchalal M et al; Agric Biol Chem 49: 1583-9 (1985) (10) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) R38: (1) Andreani-Aksoyoglu S et al; J Atmos Chem 20: 71-87 (1995) (2) Isidorov VA et al; Atmos Environ 19: 1-8 (1985) (3) Kesselmeier J et al; Atmos Environ 30: 1841-1850 (1996) (4) Breheret S et al; J Agric Food Chem 45: 831-6 (1997) (5) Bufler U et al; Atmos Environ 25A: 251-6(1991) (6) Clement B et al; Atmos Environ 9: 2513-6 (1990) (7) Juttner F; Chemosphere 17: 309-17 (1988) (8) Tatsuka K et al; J Agric Food Chem 38: 2176-80 (1990) R39: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Riemer DD et al; Chemosphere 28: 837-50 (1994) (3) Arey J et al; J Geophys Res 96D: 9329-36 (1991) (4) Binder RG et al; J Agric Food Chem 37: 734-6 (1989) (5) Chung TY et al; J Agric Food Chem 41: 1693-97 (1993) (6) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) (7) Kinlin TE et al; J Agric Food chem 20: 1021 (1972) (8) Macleod AJ et al; J Agric Food Chem 36:137-9 (1988) (9) Moshonas MG et al; J Agric Food Chem 38: 2181-4 (1990) (10) Moshonas M G et al; J Agric Food Chem 42: 1525-8 (1994) (11) Muchalal M et al; Agric Biol Chem 49: 1583-9 (1985) (12) Takeoka GR et al; J Agric Food Chem 36: 553-60 (1988) (13) Tatsuka K et al; J Agric Food Chem 38: 2176-80 (1990) (14) Juettner F; Wat Sci Tech 25: 155-64 (1992) (15) Button DK et al; Mar Chem 26: 57-66 (1989) (16) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary. 12th Ed. NY,NY: Van Nostrand Reinhold Company p. 802 (1993) R40: (1) Krotoszynski BK et al; J Environ Sci Health Part A-Environ Sci Eng 17: 855-83 (1982) R41: 21 CFR 172.515 (4/1/98) R42: SEILA RL; GC-CHEMILUMINESCENCE METHOD FOR ANALYSIS OF AMBIENT TERPENES; INT CONF PHOTOCHEM OXID POLLUT CONTROL PROC 1: 41-50 (1977) EPA-600/3-77-001A R43: ZAMUREENKO VA; IZV TIMIRYAZEVSK S-KH AKAD (1): 169 (1980) R44: GLASL H; DTSCH APOTH-ZTG 120 (2): 64 (1980) R45: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.20 RS: 33 Record 120 of 1119 in HSDB (through 2003/06) AN: 1315 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-LAURYL-SULFATE- SY: *AQUAREX-ME-; *AQUAREX-METHYL-; *CARSONOL-SLS-; *DEHYDRAG-SULFATE-GL-EMULSION-; *DODECYL-ALCOHOL,-HYDROGEN-SULFATE,-SODIUM-SALT-; *DODECYL-SODIUM-SULFATE-; *DODECYL-SULFATE,-SODIUM-SALT-; *DREFT-; *DUPONAL-; *DUPONAL-WAQE-; *DUPONOL-C-; *DUPONOL-ME-; *DUPONOL-METHYL-; *DUPONOL-WA-; *DUPONOL-WAQ-; *EMAL-10-; *IRIUM-; *LANETTE-WAX-S-; *LAURYL-SODIUM-SULFATE-; *LAURYL-SULFATE-SODIUM-SALT-; *MAPROFIX-563-; *MAPROFIX-NEU-; *MAPROFIX-WAC-; *MAPROFIX-WAC-LA-; *MONAGEN-Y-100-; *NCI-C50191-; *NEUTRAZYME-; *ORVUS-WA-PASTE-; *PERKLANKROL-ESD-60-; *PERLANKROL-L-; *QUOLAC-EX-UB-; *SDS-; *SIPEX-OP-; *SIPON-PD-; *SIPON-WD-; *SODIUM-DODECYLSULFATE-; *SODIUM-N-DODECYL-SULFATE-; *SODIUM-DODECYL-SULPHATE-; *SODIUM-LAURYL-SULPHATE-; *SOLSOL-NEEDLES-; *STEPANOL-T-28-; *STEPANOL-ME-; *STEPANOL-ME-DRY-AW-; *STEPANOL-METHYL-; *STEPANOL-METHYL-DRY-AW-; *SULFURIC-ACID,-MONODODECYL-ESTER,-SODIUM-SALT-; *TARAPON-K-12-; *TEXAPON-K12-; *TREPENOL-WA- RN: 151-21-3 MF: *C12-H26-O4-S.Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *SULFATION OF LAURYL ALCOHOL, FOLLOWED BY NEUTRALIZATION WITH SODIUM HYDROXIDE [R1] *Sulfation of lauryl alcohol, followed by neutralization with sodium carbonate [R2] FORM: *SODIUM LAURYL SULFATE USP: SOLUTION 20%; SOLUTION 20%, WITH COAL TAR SOLUTION 10%; SOLUTION 20%, WITH RESORCINOL 10%. [R3] *SODIUM MONODODECYL SULFATE...MIXT OF SODIUM ALKYL SULFATES CONSISTING CHIEFLY OF SODIUM LAURYL SULFATE. COMBINED CONTENT OF SODIUM CHLORIDE AND SODIUM SULFATE IS NOT MORE THAN 8%. [R4] *THE ARTICLE OF COMMERCE IS A MIXTURE OF ANALOGOUS SODIUM ALKYL SULFATES WIH SODIUM LAURYL SULFATE PREDOMINATING. [R5] *Grades: USP; Technical; FCC. [R6] MFS: *Albright and Wilson Americas Inc., Hq, 4851 Lake Brook Drive, Glen Allen, VA 23060, (804) 968-6300; Production site: Blue Island, IL 60406 [R7] *Emkay Chemical Company, 319 Second St., Elizabeth, NJ 07206, (908) 352-7053; Production site: Elizabeth, NJ 07206 [R7] *Henkel Corp., The Triad, Suite 200, 2200 Renaissance Blvd., Gulph Mills, PA 19406, (610) 270-8100; Production site: Hoboken, NJ 07030 [R7] *Rhodia Inc., CN 7500 Prospect Plains Road, Cranbury, NJ 08512-7500, (609) 860-4000; Production site: Baltimore, MD 21226 [R7] *Stepan Co., 22 West Frontage Rd., Northfield, Il 60093, (847) 446- 7500; Production site not specified [R7] *Witco Corp., One American Way, Greenwich, CT 06831, (203) 552-2000; Subsidiary: Oleochemicals and Derivatives Group, One American Way, Greenwich, CT 06831; Production site: Sante Fe Springs, CA 90670 [R7] OMIN: *MEDICAMENTS SUCH AS COAL TAR SOLN OR RESORCINOL MAY BE ADDED TO SOLN OF SODIUM LAURYL SULFATE TO PRODUCE STIMULATING ANTISEPTIC SHAMPOO. RESORCIN GIVES GREENISH TINT TO LIGHT OR GREY HAIR BUT COAL TAR SOLN DOES NOT. [R3] *INCOMPATIBILITIES: REACTS WITH CATIONIC SURFACE-ACTIVE AGENTS WITH LOSS OF ACTIVITY, EVEN IN CONCN TOO LOW TO CAUSE PPTN. UNLIKE SOAPS, IT IS COMPATIBLE WITH DILUTE ACIDS, AND CALCIUM AND MAGNESIUM IONS. [R4] *VET: FOOT AND MOUTH DISEASE VIRUS IS HIGHLY RESISTANT TO.../SODIUM LAURYL SULFATE/, YET TGE VIRUS IS SENSITIVE... FUNGISTATIC (INCL CANDIDA AND TRICHOPHYTON SPP) AND CONCN OF 2% AND OVER ELIMINATED DRUG RESISTANCE AND SEX TRANSFER FACTORS IN E COLI. INHIBITS GROWTH OF MANY G-POS BACTERIA...INEFFECTIVE AGAINST G-NEG TYPES. [R8] *...ANIONIC WETTING AGENT WHICH IS USED AS DETERGENT, ALONE OR IN MEDICATED SHAMPOOS, AND AS SKIN CLEANSER. IT IS BACTERIOSTATIC TOWARD GRAM POSITIVE BUT NOT GRAM NEGATIVE ORGANISMS. ...USED AS SOAP SUBSTITUTE. [R3] *...SODIUM LAURYL SULFATE...DISPERSING AGENTS COMMONLY PRESENT IN LOTIONS, CREAMS, AND OINTMENTS CONTAINING OILY INGREDIENTS AND WATER. [R9] *EMULSIFYING, DETERGENT, AND WETTING AGENT IN OINTMENTS, TOOTH POWDERS, AND OTHER PHARMACEUTICAL PREPN, AND IN METAL, PAPER, AND PIGMENT INDUSTRIES. [R4] *VET: AS WETTING AGENT FOR SOME ANTIBIOTICS AND ANTIMICROBIALS (TYLOSIN, SULFAQUINOXALINE, TYROTHRICIN, ETC) FOR ORAL AND TOPICAL USE. WIDELY USED IN OINTMENT BASES AND AS WETTING AGENT FOR SOME INSECTICIDES AND ANTHELMINTICS. ALSO USEFUL IN PRODUCING CLEAR GEL SHAMPOOS. [R8] USE: *SURFACE-ACTIVE AGENT FOR EMULSION POLYMERIZATION, IN METAL PROCESSING, DETERGENTS AND SHAMPOO; EMULSIFYING, FOAMING, WETTING, DISPERSING AGENT IN CREAMS, LOTION AND MEDICAL PREPARATIONS; FOAMING, WETTING AND DISPERSING AGENT IN TOOTHPASTE; EMULSIFIER, WHIPPING AGENT AND SURFACTANT IN FOODS [R1] *MEDICATION *Used in shampoos, hairdyes, toothpastes, hand dishwashing detergents; used in many cleaning compounds because of cleaning ability, mildness and foaming capability. [R10] *Used in the preparation of blood samples for red blood cell counts [R11] *Used in electrophoretic separation and molecular weight estimation of proteins; wetting agent, detergent, especially in the textile industry [R2] *Used as a cleansing agent in cosmetics [R12, 582] *Used as a whipping aid in dried egg products [R12, 900] *Used in the preparation of samples for dietary fiber content [R12, 142] *Used in the characterization of quaternary ammonium compounds [R13] *Food additive (emulsifier and thickener) [R6] *Used in the electroplating industry, particularly nickel and zinc; as an emulsifier, wetting agent and adjuvant in insecticides; as an emulsifier and penetrant in varnish and paint remover; in the formulation of injection-molded explosives; anti-foaming agent in solid rocket propellants; as a model surfactant and reference toxicant in aquatic and mammalian toxicological testing. [R14] PRIE: U.S. PRODUCTION: *(1972) 1.22X10+10 GRAMS [R1] *(1975) 7.66X10+9 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White or cream-colored crystals, flakes, or powder [R2] ODOR: *Faint odor of fatty substances [R2] MW: *288.38 [R2] OWPC: *log Kow = 1.60 [R15] SOL: *1 g dissolves in 10 ml water, an opalescent solution [R2]; *In water, 1.00X10+5 mg/l (temp not specified) [R14] SPEC: *INDEX OF REFRACTION: 1.461 (ALPHA), 1.491 (GAMMA) [R16] SURF: *39.5 dyn/cm at 25 deg C [R12, 936] OCPP: *Lowers the surface tension of aq solutions; emulsifies fats [R2] *Smooth feel, neutral reaction [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of (sulfur oxides and sodium oxides). [R17] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *...SODIUM LAURYL SULFATE CAN PRODUCE ALLERGIC SENSITIVITY REACTIONS. [R9] */SODIUM LAURYL SULFATE/...MAY PRODUCE DRYING EFFECT ON SKIN. [R3] *SODIUM LAURYL SULFATE IS SAID TO HAVE BEEN COMMONEST CAUSE OF EYE IRRITATION BY COMMERCIAL SHAMPOOS. [R18] *AMONG 242 PATIENTS SUFFERING FROM ECZEMATOUS DERMATITIS, THE PERCENTAGE OF ALLERGIC REACTIONS REACHED 54.6%. GREAT NUMBER OF ALLERGIC REACTIONS TO SODIUM LAURYL SULFATE (6.4%) WAS OBSERVED. [R19] *WIDELY USED ANIONIC DETERGENTS OF LOW ACUTE AND CHRONIC TOXICITY. /ALKYL SODIUM SULFATES/ [R20] *Poison by intravernous and intraperitoneal routes. Moderately toxic by ingestion and a human skin irritant. [R17] NTOX: *IN SUBACUTE AND CHRONIC FEEDING TESTS, EVEN FATALLY POISONED ANIMALS SHOW ONLY DIARRHEA AND INTESTINAL BLOATING, WITH NO GROSS LESIONS OUTSIDE OF THE GASTROINTESTINAL TRACT. [R20] *ACUTE ORAL TOXICITY IN RATS: LOW ORAL TOXICITY. ACUTE EFFECTS ON SKIN: NOT IRRITATING IN LOW CONCENTRATIONS. METABOLIC FATE AND REMARKS: RATS TOLERATE 1% IN DIET; DECREASED GROWTH AT 4%. /FROM TABLE/ [R21] *TAKEN BY MOUTH, SODIUM LAURYL SULFATE STIMULATES GASTRIC MUCUS PRODUCTION AND SOMETIMES INACTIVATES PEPSIN IN TEST ANIMALS. [R20] *.../SODIUM LAURYL SULFATE USP/ TESTED @ CONCN OF 0.5% TO 1% IN WATER AND...FOUND SIGNIFICANTLY IRRITATING OR INJURIOUS TO RABBIT EYE... RABBIT'S EYE APPARENTLY ARE MORE IRRITATED THAN HUMAN'S OR MONKEYS'. ...INJECTED INTO EYE (INTO VITREOUS HUMOR) IN RABBITS HAS CAUSED SEVERE INFLAMMATION. [R22] *SODIUM LAURYL SULFATE ADMIN TO VAGINAL MUCOSA OF GUINEA PIG FOR 7 DAYS IN SLOW RELEASE FASHION; RESPONSE PREDICTED FROM KNOWLEDGE OF SKIN IRRITANCY WAS CONFIRMED. [R23] *Sodium dodecyl sulfate was found to be negative when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Sodium dodecyl sulfate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.003, 0.010, 0.033, 0.100, 0.333, and 1.000 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 1.000 mg/plate. [R24] NTXV: *LD50 Rat oral 1288 mg/kg; [R17] *LD50 Rat ip 210 mg/kg; [R17] *LD50 Rat iv 118 mg/kg; [R17] *LD50 Mouse ip 250 mg/kg; [R17] *LD50 Mouse iv 118 mg/kg; [R17] ADE: *UPTAKE, TISSUE DISTRIBUTION, AND ELIMINATION OF NA N-LAURYL SULFATE WERE INVESTIGATED IN CARP. CONCN FACTORS FOR HEPATOPANCREAS AND GALLBLADDER WERE 50 and 700 RESPECTIVELY. MAX WHOLE-BODY LEVELS WERE REACHED DURING 24-72 HR. SURVIVAL TIME DECR WITH INCR WATER HARDNESS. [R25] INTC: *MAY COMPLEX CATIONIC AGENTS INCL COMMONLY USED QUATERNARY AMMONIUM COMPD. THIS CAN BE BENEFICIAL AS SUCH REACTION DECR SKIN SENSITIZING PROPERTIES OF BACITRACIN. [R8] *SODIUM LAURYL SULFATE INCREASES THE PERMEABILITY OF THE STRATUM CORNEUM NOT ONLY TO MEDICAMENTS BUT ALSO TO NOXIOUS AGENTS AND THUS MAY DIRECTLY OR INDIRECTLY PRODUCE IRRITATION. [R26] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3. 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB). /ALKYL SODIUM SULFATES/ [R20] THER: *SODIUM LAURYL SULFATE MAY BE USED AS SHAMPOO FOR CLEANSING OF SCALP AND IN TREATMENT OF DANDRUFF, SEBORRHEA, SEBORRHEIC DERMATITIS, AND PSORIASIS. [R3] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Sodium lauryl sulfate's production and use as a surfactant may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.7X10-13 mm Hg at 25 deg C indicates sodium lauryl sulfate will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase sodium lauryl sulfate will be removed from the atmosphere by wet and dry deposition. If released to soil, sodium lauryl sulfate is expected to have no mobility based upon an estimated Koc of 1.0X10+4. Volatilization from moist soil surfaces is not expected to be an important fate process based upon a water solubility of 1.00X10+5 mg/l and that it is a salt. Sodium lauryl sulfate is not expected to volatilize from dry soil surfaces based upon its estimated vapor pressure. Approximately 60% of sodium lauryl sulfate, present at 10 mg/kg, was mineralized in a creosote-contaminated sandy loam soil in 10 days. If released into water, sodium lauryl sulfate is expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Approximately 80% of the initial concentration (approximately 25 ppm) of sodium lauryl sulfate was biodegraded in four samples of surface water in 50-140 hours, depending upon the season in which the samples were collected and inoculum source. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's water solubility and that it is a salt. An estimated BCF of 71 suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis of sodium lauryl sulfate is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to sodium lauryl sulfate may occur through inhalation of dust particles and dermal contact with this compound at workplaces where sodium lauryl sulfate is produced or used. The general population may be exposed through the use of food additives and other consumer products such as detergents, shampoos, and toothpaste products containing this compound. (SRC) ARTS: *Sodium lauryl sulfate's production and use as a surfactant(1) may result in its release to the environment through various waste streams(SRC). [R27] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+4(SRC), determined from a structure estimation method(2), indicates that sodium lauryl sulfate is expected to be immobile in soil(SRC). Volatilization of sodium lauryl sulfate from moist soil surfaces is not expected to be an important fate process(SRC) as it is a salt and has a water solubility of 1.0X10+5 mg/l(4). Sodium lauryl sulfate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.7X10-13 mm Hg(3). [R28] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.0X10+4(SRC), determined from an estimation method(2), indicates that sodium lauryl sulfate is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon a water solubility, 1.0X10+5 mg/l(4) and that it is a salt. According to a classification scheme(5), an estimated BCF of 71(SRC), from its log Kow of 1.6(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is moderate. [R29] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sodium lauryl sulfate, which has an estimated vapor pressure of 4.7X10-13 mm Hg at 25 deg C(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase sodium lauryl sulfate may be removed from the air by wet and dry deposition(SRC). [R30] BIOD: *AEROBIC: Sodium lauryl sulfate, present at 100 mg/l, reached 85% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). In 10 days, approximately 60% of sodium lauryl sulfate, present at 10 mg/kg, was mineralized in a creosote-contaminated sandy loam soil; the rate of biodegradation decreased slightly at higher concentrations(2). The biodegradation of sodium lauryl sulfate varied considerably in river water samples collected from four locations of a polluted river at two times(3). The time to removal of approximately 80% of the initial concentration (approximately 25 ppm) of sodium lauryl sulfate ranged from 50-140 hours depending upon the season in which the samples were collected and the inoculum source(3). [R31] *ANAEROBIC: Anaerobic degradation of sodium lauryl sulfate, using anoxic sludge from a wastewater treatment plant and a polluted river as the inoculum, has been observed but was not quantified(1). [R32] ABIO: *Sodium lauryl sulfate is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1). [R33] BIOC: *An estimated BCF of 71 was calculated for sodium lauryl sulfate(SRC), using a log Kow of 1.6(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate. [R34] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for sodium lauryl sulfate can be estimated to be 1.0X10+4(SRC). According to a classification scheme(2), this estimated Koc value suggests that sodium lauryl sulfate is expected to be immobile in soil. [R35] VWS: *Sodium lauryl sulfate is a salt and has a water solubility of 1.0X10+5 mg/l(2) which indicates that sodium lauryl sulfate is expected to be essentially nonvolatile from water and moist surfaces(3). Sodium lauryl sulfate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.7X10-13 mm Hg(1). [R36] WATC: *SURFACE WATER: Sodium lauryl sulfate was detected in 96 of 96 surface water samples collected from 12 locations in Lake Kojima in Japan between May-December, 1993 at concentrations ranging from 71 to 472 ug/l, with an average concentration of 170 ug/l(1). [R37] RTEX: *Occupational exposure to sodium lauryl sulfate may occur through inhalation of dust particles and dermal contact with this compound at workplaces where sodium lauryl sulfate is produced or used(1). The general population may be exposed through the use of food additives and other consumer products such as detergents, shampoos, and toothpaste products containing this compound(SRC). [R38] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Coatings may be applied to fresh citrus fruit for protection of the fruit in accordance with the following conditions: (a) the coating is applied in the minimum amount required to accomplish the intended effect and (b) the coating may be formulated from /sodium lauryl sulfate/ ... used in the minimum quantity required to accomplish the intended effect. Limitation: complying with 172.822. As a film former. [R39] *The food additive sodium lauryl sulfate may be safely used in food in accordance with the following conditions: (a)the additive meets the following specifications: 1. It is a mixture of sodium alkyl sulfates consisting chiefly of sodium lauryl sulfate and 2. it has a minimum content of 90% sodium alkyl sulfates. It is used or intended for use: 1. As an emulsifier in or with egg whites whereby the additive does not exceed the following limits: egg white solids, 1000 ppm; frozen egg whites, 125 ppm; and liquid egg whites, 125 ppm. 2. As a whipping agent at a level not to exceed 0.5% by weight of gelatine used in the preparation of marshmallows. 3. As a surfactant in fumaric acid-acidulated dry beverage base whereby the additive does not exceed 25 ppm of the finished beverage and such beverage base in not for use in a food for which a standard of identity established under section 401 of the Act precludes such use. As a surfactant in fumaric acid-acidulated fruit juice drinks whereby the additive does not exceed 25 ppm of the finished fruit juice drink and it is not used in a fruit juice drink for which a standard of identity established under section 401 of the Act precludes such use. 4. As a wetting agent at a level not to exceed 10 ppm in the partition of high and low melting fractions of crude vegetable oils and animal fats, provided that the partition step is followed by a conventional refining process that includes alkali neutralization and deodorization of the fats and oils. [R40] *Sodium lauryl sulfate is an indirect food additive for use as a component of resinous and polymeric coatings. [R41] *Sodium lauryl sulfate is an indirect food additive for use as a component of resinous and polymeric coatings for polyolefin films. [R42] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC Method 968.18. Sodium lauryl sulfate in egg white. Colorimetric method [R43] *A method is described for determining the concentration of total alkyl sulfates in surface water and wastewater samples. The detection limit is reported as < 5 ug/l. [R44] CLAB: *ANALYTICAL PROCEDURES ARE DESCRIBED FOR DETERMINING RESIDUES OF SODIUM DODECYL SULFATE IN WHOLE BLOOD FROM GUINEA PIGS. METHODS ARE BASED ON HYDROLYSIS AND ANALYSIS BY ELECTRON-CAPTURE GAS-CHROMATOGRAPHY. [R45] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1478 R3: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 84:20 R4: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1245 R5: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1116 R6: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1020 R7: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 908 R8: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 542 R9: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 896 R10: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V1 (92) 886 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V3 (92) 779 R12: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V7 (92) R13: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V20 (92) 749 R14: Singer MM, Tjeerdema RS; Rev Environ Contam Toxicol 133: 95-149 (1993) R15: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 107 R16: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 323 R17: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2974 R18: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 964 R19: BLONDEEL A ET AL; CONTACT DERMATITIS 4(5) 270 (1978) R20: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-178 R21: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1844 R22: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 874 R23: WAGNER GS ET AL; A TEST PROCEDURE FOR EVALUATING IRRITANCY IN THE RODENT VAGINA, AND EFFECTS OF MODEL IRRITANTS; PROCTER AND GAMBLE CO, CINCINNATI, OH R24: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R25: WAKABAYASHI M ET AL; CHEMOSPHERE 7(11) 917 (1978) R26: American Medical Association, Council on Drugs. AMA Drug Evaluations. 2nd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1973. 658 R27: (1) Wagner JD et al; Kirk-Othmer Encycl Chem Technol. 4th. NY, NY: Wiley 1: 886 (1992) R28: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol I Boca Raton, Fl, CRC Press (1985) (4) Singer MM, Tjeerdema RS; Rev Environ Contam Toxicol 133: 95-149 (1993) R29: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 2-1 to 2-52 (1990) (4) Singer MM, Tjeerdema RS; Rev Environ Contam Toxicol 133: 95-149 (1993) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 107 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R30: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol I Boca Raton, FL: CRC Press (1985) R31: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Deschenes L et al; Hydrol Sci J 40: 471-484 (1995) (3) Anderson DJ et al; Appl Environ Microbiol 56: 758-63 (1990) R32: (1) Wagener S, Schink B; Wat Res 21: 615-622 (1987) R33: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R34: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 76 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R35: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R36: (1) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol I Boca Raton, FL: CRC Press (1985) (2) Singer MM, Tjeerdema RS; Rev Environ Contam Toxicol 133: 95-149 (1993) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 2-1 to 2-52 (1990) R37: (1) Muramoto S et al; J Environ Sci Health A31: 721-729 (1996) R38: (1) Painter HA; pp. 1-88 in The Handbook of Environmental Chemistry, Vol 3, Part F, Anthropogenic Compounds, Detergents; Hutzinger O, ed, Heidelberg, Berlin: Springer Verlag (1992) R39: 21 CFR 172.210 (4/1/99) R40: 21 CFR 172.822 (4/1/99) R41: 21 CFR 175.300 (4/1/99) R42: 21 CFR 175.320 (4/1/99) R43: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. V2 1163 R44: Fendinger NJ et al; Environ Sci Technol 26: 2493-2498 (1992) R45: BLAKEMORE WM ET AL; TOXICOL LETT (AMST) 3 (3): 127 (1979) RS: 26 Record 121 of 1119 in HSDB (through 2003/06) AN: 1316 UD: 200302 RD: Reviewed by SRP on 2/28/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BIS(4-AMINOPHENYL) ETHER SY: *ANILINE,-4,4'-OXYDI-; *BENZENAMINE,-4,4'-OXYBIS-; *BIS(P-AMINOPHENYL) ETHER; *DADPE-; *4,4-DADPE-; *DIAMINODIPHENYL-ETHER-; *P,P'-DIAMINODIPHENYL-ETHER-; *4,4'-DIAMINODIPHENYL-ETHER-; *4,4'-DIAMINODIPHENYL-OXIDE-; *NCI-C50146-; *OXYBIS(4-AMINOBENZENE); *4,4'-Oxybisaniline-; *P,P'-OXYDIANILINE-; *OXYDI-P-PHENYLENEDIAMINE- RN: 101-80-4 MF: *C12-H12-N2-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 4,4'-DIAMINODIPHENYL ETHER WITH TIN AND HYDROCHLORIC ACID IN THE PRESENCE OF ETHANOL [R1] FORM: *Minimal purity: 98% [R2] USE: *CHEM INT FOR POLYIMIDE AND POLY(ESTER-IMIDE) RESINS [R2] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] *(1978) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] U.S. IMPORTS: *(1973) 9.01X10+5 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless crystals [R3] BP: *> 300 deg C [R3] MP: *186-187 deg C [R4] MW: *200.26 [R5] OWPC: *log Kow= 2.06 (est) [R6] SOL: *Insoluble in water, benzene, carbon tetrachloride and ethanol; soluble in acetone [R2] VAP: *3.07X10-7 mm Hg at 25 deg C (est) [R7] OCPP: *Henry's Law constant= 1.5X10-11 atm-cu m/mole at 25 deg C (est) [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R9, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R9, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R9, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R9, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R9, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R9, 1979.15] DISP: *Incineration: Incineration with provision for NO(x) removal from flue gases by scrubber, catalytic or thermal device. [R10] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R9, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R9, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R9, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans. [R11] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R9, 1979.23] NTOX: *FISCHER 344 RATS AND B6C3F1 MICE FED DIETS THAT CONTAINED 4,4'-OXYDIANILINE FOR 13 WK. A 0.1 TO 0.2% DIET CAUSED 40-70% MORTALITY IN FEMALE RATS. ALTHOUGH MICE ATE APPROX 3.5 TIMES MORE THAN RATS, NO MICE DIED. [R12] *FISCHER 344 RATS AND B6C3F1 MICE FED DIETS THAT CONTAINED 4-4'-OXYDIANILINE FOR 13 WK. ALOPECIA, DYSPNEA AND CYANOSIS IN RATS, AND LETHARGY IN BOTH SPECIES @ 0.1-0.2% DIET. DIFFUSE PARENCHYMATOUS GOITER WAS SEEN IN MOST RATS @ 0.2% AND IN ALL ANIMALS @ 0.06%. [R12] *FISCHER 344 RATS AND B6C3F1 MICE FED DIETS THAT CONTAINED 4,4'-OXYDIANILINE FOR 13 WK. IN RATS, THYROIDS HAD INTERSTITIAL FIBROSIS AND VASCULAR DEGENERATION, THERE WAS HYPERPLASIA OF PITUITARY BASOPHILS IN BOTH SPECIES, BUT INCR CELLS THAT SECRETE THYROTROPIN IN RATS. [R12] *Twenty-seven chemicals (including 4,4'-diaminophenyl ether) previously tested in rodent carcinogenicity assays were tested for induction of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells as part of a larger analysis of the correlation between results of in vitro genetic toxicity assays and carcinogenicity bioassays. Chemicals were tested up to toxic doses with and without exogenous metabolic activation. 4,4'-Diaminophenyl ether was found to induce a significant increase in the incidence of sister chromatid exchanges as well as chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of S9. [R13] *4,4'-Diaminodiphenyl ether was tested in mice and rats by oral administration and by subcutaneous injection. In two studies in rats, it produced benign and malignant liver cell tumours following oral or subcutaneous administration; and following its oral administration in one study, benign and malignant follicular cell tumors of the thyroid were produced. Other studies in rats by oral and sc administration were not adequate for evaluation. In a study in mice by oral administration it produced benign and malignant liver cell tumors in females given the high dose and in males given the low dose and adenomas of the Harderian gland in animals of both sexes. [R14] *4,4'-Diaminodiphenyl ether is mutagenic to Salmonella typhimurium with metabolic activation. [R14] *Three groups of 50 male and 50 female five wk old Fischer 344 rats were given diets containing 200, 400 or 500 mg/kg (ppm) 4,4'-diaminodiphenyl ether (minimum purity, 98.9%, with three trace impurities) for 103 weeks. The controls consisted of 50 male and 50 female untreated rats. Surviving animals were killed at 105-106 weeks. Significant increases in the incidences of hepatocellular carcinomas were seen in treated rats: males: 0/50, 4/50, 23/50 and 22/50 in the control, low, mid and high dose groups (positive trend: p < 0.001); females 0/50, 0/49, 4/50 and 6/50 (positive trend: p= 0.002), respectively. Neoplastic nodules of the liver occurred in males: 1/50, 9/50, 18/50 and 17/50 (positive trend: p < 0.001); females: 3/50, 0/49 and 6/50 (positive trend: p= 0.002), respectively. Neoplastic nodules of the liver occurred in males: 1/50, 9/50, 18/50 and 17/50 (positive trend: p < 0.001); females: 3/50, 0/49, 20/50 and 11/50 (positive trend: p < 0.001). An increase of thyroid follicular cell adenomas or carcinomas also occurred: males: 1/46, 6/47, 17/46 and 28/50 (positive trend: p < 0.001); females: 0/49, 4/48, 29/48 and 23/50 (positive trend; p < 0.001). The incidences of tumors at other sites were not increased. [R15] *A group of 15 male and 18 female CC57W mice received sc injections of 5 mg/animal 4,4'-diaminodiphenyl ether in 0.2 ml sunflower oil weekly (total dose, 175 mg/animal); animals were observed for up to 316 days. Of 9 mice alive at the appearance of the first tumor (271 days), 3 developed 3 tumors (2 lymphomas and 1 lung adenoma). The incidence of lymphomas in untreated mice of this strain was 6.8%. [R15] *A group of 30 male and 32 female, white, colony-bred rats received sc injections of 25 mg/animal 4,4'-diaminodiphenyl ether in 0.5 ml sunflower oil weekly (total dose, 2 g/animal); animals were observed for up to 949 days. Among 39 rats alive at the appearance of the first tumor (529 days), 7 developed 7 tumors (2 lymphomas, 1 reticulum-cell sarcoma, 1 liver fibrosarcoma, 1 carcinoma of the kidney and 2 mammary gland fibroadenomas). (The Working Group noted that no controls were used). [R15] *Three groups of 50 male and 50 female B6C3F1, mice, 6 weeks of age, were fed diets containing 150, 300 or 800 mg/kg (ppm) 4,4'-diaminodiphenyl ether (minimum purity, 98.9%, with three trace impurities) for 103 weeks. An equal number of untreated mice of both sexes were used as controls. All serviving animals (70% or more) were killed at 104 to 105 weeks. Tumors that appeared statistically to be related to treatment were adenomas of the Harderian gland in animals of both sexes: females, 2/50 controls, and 15/50, 14/50 and 12/50 given the low, mid and high doses, respectively; males, 1/50 controls and 17/50, 13/49 and 17/50 given the low, mid and high doses, respectively (p < 0.001). Hepatocellular adenomas or carcinomas occurred in 40/50 low dose males (29/50 controls) (p= 0.015) and in 29/50 high dose female mice (8/50 controls; p < 0.001). Follicular cell adenomas of the thyroid occurred in 7/48 of the high dose females (p= 0.007). Other tumors, including adenomas of the pituitary and hemangiomas of the circulatory system, occurred more frequently in high dose males than in controls, but the increased incidences were not statistically significant. [R16] *16 male and 24 female CC57W mice (age unspecified) received diets containing 5 mg/animal 4,4'-diaminodiphenyl ether in 0.2 ml sunflower oil on five days per week for six weeks, and later by oral gavage (total dose, 440 mg/animal); animals were observed up to 472 days. Among 14 mice still alive at the appearance of the first tumor (212 days), 8 had developed 10 tumors (6 lymphomas, 2 hemangiomas of the ovaries and 2 lung adenomas). The historical incidence of lymphomas in untreated mice of that strain was 6.8%. [R16] *Rat: 4,4'-Diaminodiphenyl ether (purity and impurities uspecified) was administered by stomach tube to 20 female 40 day old Sprague-Dawley rats; 10 equal doses of 40 mg/rat, which was the maximum tolerated dose, were given at three day intervals. The experiment was terminated at nine months. No increase in tumor incidence was observed in the 11 animals that were autopsied. [R16] *The in vivo/in vitro hepatocyte DNA repair assay has been shown to be useful for studying genotoxic hepatocarcinogens. In addition, measurement of S-phase synthesis provides an indirect indicator of hepatocellular proliferation, which may be an important mechanism in rodent carcinogenesis. This assay was used to examine 24 chemicals for their ability to induce unscheduled DNA synthesis or S-phase synthesis in Fischer 344 rats or B6C3F1 mice following in vivo treatment. Hepatocytes were isolated by liver perfusion and incubated with (3)H-thymidine following in vivo treatment by gavage. Unscheduled DNA synthesis was measured by quantitative autoradiography as net grains/nucleus. Controls from both sexes of both species yielded less than 0.0 net grains/nucleus. Chemicals chosen for testing were from the National Toxicology Program genetic toxicology testing program and most were also evaluated in long-term animal studies conducted by the NTP. 11-Aminoundecanoic acid, benzyl acetate, bis(2-chloro-1-methylethyl)ether CI Solvent Yellow 14, cinnamaldehyde, cinnamyl anthranilate, dichloromethane, dichlorvos, glutaraldehyde, 4,4'-methylenedianiline, 4-nitrotoluene, 4,4'-oxydianiline, a polybrominated biphenyl mixture, reserpine, 1,1,2,2-tetrachloroethane, 1,1,2-trichloroethane, trichloroethylene, and 2,6-xylidine all failed to induce unscheduled DNA synthesis in rats and/or mice. Dinitrotoluene and Michler's Ketone induced positive unscheduled DNA synthesis response in rat, while N-nitrosodiethanolamine and selenium sulfide induced equivocal unscheduled DNA synthesis results in mouse and rat, respectively. bis(2-chloro-1-methylethyl)ether, bromoform, chloroform, PBB, 1,1,2-trichloroethane, and trichloroethylene were all potent inducers of S-phase synthesis in mouse liver, while CI Solvent Yellow 14, and 1,1,2,2-tetrachloroethane yielded equivocal S-phase synthesis results in rat and mouse, respectively. These results indicate that most of the test compounds do not induce unscheduled DNA synthesis in the liver; however, the significant S-phase responses induced by many of these compounds, especially the halogenated solvents, may be an important mechanism in their hepatocarcinogenicity. [R17] *F344 rats of both sexes were fed one of three concentrations (0.02, 0.04, 0.05%) of 4,4'-oxydianiline, an intermediate in the manufacture of polyimide resins, mixed in the diet for 2 years. The incidence of hepatocellular neoplasms was increased in all the 3 groups of male rats and in female rats of the middle and high dose groups. The incidence of hyperplastic and neoplastic changes in the follicular cells of the thyroid gland was increased in male and female rats of the middle and high dose groups. The population of thyrotrophs (thyrotropin producing cells) was increased in the pituitary glands of rats with neoplasms of the thyroid gland. These cells were distinct from prolactin cells. The increase in the number of thyrotrophs suggested insufficient hormone production by the induced thyroid tumors. [R18] NTXV: *LD50 Mouse ip 300 (+ or - 20) mg/kg; [R19] *LD50 Rat ip 365 (+ or - 25) mg/kg; [R20] *LD50 Mouse intragastric 685 (+ or - 42) mg/kg; [R20] *LD50 Rat intragastric 725 (+ or - 50) mg/kg; [R19] NTP: *A bioassay of /4,4'-oxydianiline/ for possible carcinogenicity was conducted by feeding diets containing 200, 400, or 500 ppm test chemical to groups of 50 male or female F344 rats and 150, 300, or 800 ppm to groups of 50 male or female B6C3F1 mice for 104 weeks. Matched controls consisted of 50 untreated rats and 50 untreated mice of each sex. All surviving animals were killed at 104 to 105 weeks. ... In male and female rats, hepatocellular carcinomas or neoplastic nodules occurred at incidences that were dose related, and the incidences in all dosed groups (except low dose females) were higher than those in the controls. The occurence of follicular cell adenomas and carcinomas of the thyroid was dose related. Among groups of male and female rats, the incidences in the mid and high dose groups of either sex were significantly higher than those in the corresponding controls. In male and female mice, adenomas in the harderian glands occurred in all dosed groups at incidences that were significantly higher than the incidence in the matched controls. In low dose male mice and high dose female mice, hepatocellular adenomas and carcinomas occured at incidences significantly higher than those in the matched controls. In female mice follicular cell adenomas in the thyroid occurred with a positive linear trend, and in a direct comparison the incidence in the high dose group was also significantly higher than that in controls. ... Under the conditions of this bioassay, 4,4'-oxydianiline was carcinogenic for male and female F344 rats, including hepatocellular carcinomas or neoplastic nodules and follicular cell adenomas or carcinomas of the thyroid. 4,4-Oxydianiline was also carcinogenic for male and female B6C3F1 mice, inducing adenomas in the harderian glands, hepatocellular adenomas or carcinomas in both sexes, and follicular cell adenomas in the thyroid of females. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4,4'-Diaminodiphenyl ether could be released to the environment in waste streams from its production and use in formulating polymides If released to the atmosphere, vapor-phase 4,4'-diaminodiphenyl ether is expected to degrade rapidly (estimated half-life of 1.8 hr) by reaction with photochemically produced hydroxyl radicals. Particulate phase 4,4'-diaminodiphenyl ether may be removed from the atmosphere via dry deposition. If released to soil, 4,4'-diaminodiphenyl ether may undergo a covalent chemical bonding with humic materials which can result in its chemical alteration to a latent form and prevent leaching. In the absence of covalent bonding, moderate leaching may be possible. If released to water, hydrolysis, volatilization and bioconcentration in aquatic organisms are not expected to be important aquatic fate processes. Covalent bonding with humic materials in the water column and sediments may result in partitioning from the water column to sediments. By analogy to the aromatic amine chemical class, 4,4'-diaminodiphenyl ether in the water column may be susceptible to photooxidation via hydroxyl and peroxy radicals. Insufficient data are available to assess the relative importance of biodegradation of 4,4'-diaminodiphenyl ether in soil or water. In occupational settings, workers may be exposed to 4,4'-diaminodiphenyl ether through inhalation of dust and through eye and skin contact. (SRC) NATS: *4,4'-Diaminophenyl ether is not known to occur as such in nature. [R22] ARTS: *4,4'-Diaminodiphenyl ether is used in formulating polyimides(1) which suggests that it may be released to the environment in waste streams from its production and use(SRC). [R23] FATE: *TERRESTRIAL FATE: When released to soil, 4,4'-diaminodiphenyl ether, by analogy to the aromatic amine chemical class, may undergo covalent chemical bonding with humic materials which can result in its chemical alteration to a latent form and tight adsorption(1). When covalently bound in this latent form, leaching in soil systems is not generally expected to occur. This covalent bonding proceeds in two steps; a rapid and reversible bonding followed by a slower and much less reversible reaction(1). Leaching in soil may be possible prior to the occurrence of the slower bonding reaction. In the absence of covalent bonding, moderate leaching may be possible (Koc value of 315)(2-3). Insufficient data are available to assess the relative importance of biodegradation of 4,4'-diaminodiphenyl ether in soil(SRC). [R24] *AQUATIC FATE: By analogy to other aromatic amines(1), 4,4'-diaminodiphenyl ether may undergo covalent bonding with humic materials in the water column and in sediment; partitioning from the water column to sediment and suspended material may therefore be an important removal process from water. 4,4'-Diaminodiphenyl ether in the water column may be susceptible to photooxidation via hydroxyl and peroxy radicals based on analogy to other aromatic amines(2). Insufficient data are available to assess the relative importance of biodegradation of 4,4'-diaminodiphenyl ether in water. A BCF value of 22(3) suggests that 4,4'-diaminodiphenyl ether will not bioconcentrate in aquatic organisms. Furthermore, aquatic hydrolysis and volatilization do not appear to be environmentally important removal processes of 4,4'-diaminodiphenyl ether in water(SRC). [R25] *ATMOSPHERIC FATE: Based upon an estimated vapor pressure of 3.07X10-7 mm Hg at 25 deg C(1), 4,4'-diaminodiphenyl ether is expected to exist in both the vapor and particulate phases in the ambient atmosphere(2). Vapor phase 4,4'-diaminodiphenyl ether is degraded rapidly in an average ambient atmosphere by reaction with photochemically produced hydroxyl radicals at an estimated half-life of about 1.8 hr(3). Particulate phase 4,4'-diaminodiphenyl ether may be removed from the atmosphere via dry deposition(SRC). [R26] ABIO: *The rate constant for the vapor-phase reaction of 4,4'-diaminodiphenyl ether with photochemically produced hydroxyl radicals has been estimated to be 2.1X10-10 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 1.8 hr at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Aromatic amines and ethers are generally resistant to aqueous environmental hydrolysis(2); therefore, 4,4'-diaminodiphenyl ether is not expected to hydrolyze in water. As a class, aromatic amines react relatively rapidly in sunlit natural water via reaction with photochemically produced hydroxyl radicals and peroxy radicals(3); typical half-lives for hydroxyl radical and peroxy radical reaction are on the order of 19-30 sunlight hours(3); however, rate data specific to 4,4'-diaminodiphenyl ether were not located(SRC). [R27] BIOC: *Based on an estimated log Kow of 2.06(2) and a regression derived equation(1), the BCF for 4,4'-diaminodiphenyl ether can be estimated to be approximately 22. This BCF value suggests that bioconcentration in aquatic organisms may not be an important aquatic fate process(SRC). [R28] KOC: *Aromatic amines have been observed to undergo rapid and reversible covalent bonding with humic materials in aqueous solution; the initial bonding reaction is followed by a slower and much less reversible reaction believed to represent the addition of the amine to quinoidal structures followed by oxidation of the product to give an amino-substituted quinone; these processes represent pathways by which aromatic amines may be converted to latent forms in the biosphere(4). In the absence of covalent bonding, the Koc for 4,4'-diaminodiphenyl ether can be estimated to be 315 based on an estimated log Kow of 2.06(2) and a regression derived equation(1) suggesting that 4,4'-diaminodiphenyl ether has medium soil mobility(3,SRC). [R29] VWS: *The Henry's Law constant for 4,4'-diaminodiphenyl ether can be estimated to be approximately 1.5X10-11 atm-cu m/mole at 25 deg C using a chemical structure estimation method(1,SRC). This value of Henry's Law constant suggests that 4,4'-diaminodiphenyl ether is essentially nonvolatile from water(2). [R30] RTEX: *Often N-substituted aryl compounds are present in the solid state, and thus are subject to dusting(1). Due to low vapor pressures, respiratory exposure to vapors of most aryl amines should be low(1). Direct skin contact is probably the major route of absorption of the aromatic amines(1). Therefore, in occupational settings, workers may be exposed to 4,4'-diaminodiphenyl ether through inhalation of dust and through eye and skin contact(SRC). [R31] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 45 workers were potentially exposed to 4,4'-diaminodiphenyl ether in the USA(1). [R32] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of 4,4'-Oxydianiline for Possible Carcinogenicity (1980) Technical Rpt Series No. 205 DHEW Pub No. (NIH) 80-1761 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 204 (1982) R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 203 (1982) R4: DHEW/NCI; Bioassay of 4,4'-Oxydianiline for Possible Carcinogenicity p.109 (1980) Technical Rpt Series No. 205 DNEW Pub No. (NIH) 80-1761 R5: U.S. Department of Health, Education and Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances. 1977 edition. Washington, D. C.: U.S. Government Printing Office, 1977.99 R6: GEMS; Graphical Exposure Modeling System. PCGEMS. (1987) R7: GEMS; Graphical Exposure Modeling System. PCCHEM. USEPA (1987) R8: SRC; Meylan WM, Howard PH; Environmental Toxicology and Chemistry 10: 1283-93 (1991) R9: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R10: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 86 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 61 (1987) R12: HAYDEN DW ET AL; VET PATHOL 15 (5): 649-62 (1978) R13: Gulati DK et al; Environ Mol Mutagen 13 (2): 133-93 (1989) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 209 (1982) R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 207 (1982) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 206 (1982) R17: Mirsalis JC et al; Environ Mol Mutagen 14 (3): 155-64 (1989) R18: Murthy AS et al; J Natl Cancer Inst 74 (1): 203-8 (1985) R19: DHEW/NCI; Bioassay of 4,4'-Oxydianiline for Possible Carcinogenicity p.1 (1980) Technical Rpt Series No. 205 DHEW Pub No. (NIH) 80-1761 R20: DHEW/NCI; Bioassay of 4,4-Oxydianiline for Possible Carcinogenicity p.1 (1980) Technical Rpt Series No. 205 DHEW Pub No. (NIH) 80-1761 R21: DHEW/NCI; Bioassay of 4,4-Oxydianiline for Possible Carcinogenicity p.v (1980) Technical Rpt Series No. 205 DHEW Pub No. (NIH) 80-1761 R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 205 (1982) R23: (1) Kuney JH; Chemcyclopedia 92 American Chemical Society Washington, DC pp. 94, 291 (1991) R24: (1) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (3) Swann RL et al; Residue Reviews 85: 17-28 (1983) R25: (1) Parris GE; Environ Sci Technol 14: 1099-106 (1980) (2) Mill T, Mabey W; p. 208-11 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) R26: (1) GEMS; Graphical Exposure Modeling System. PCCHEM. USEPA (1987) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; J Inter Chem Kinet 19: 799-828 (1987) R27: (1) Atkinson R; J Inter Chem Kinet 19: 799-828 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (3) Mill T, Mabey W; p. 208-11 in Environmental Exposure from Chemicals Vol I. Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) R28: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) GEMS; Graphical Exposure Modeling System. PCGEMS. (1987) R29: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) GEMS; Graphical Exposure Modeling System. PCGEMS. (1987) (3) Swann RL et al; Residue Reviews 85: 17-28 (1983) (4) Parris GE; Environ Sci Technol 14: 1099-106 (1980) R30: (1) Meylan WM, Howard PH; Environmental Toxicology and Chemistry 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) R31: (1) Schulte PA et al; Proc Int Conf Carcinog Mutagen N-Substituted Aryl Compd 3: 23-85 (1988) R32: (1) NIOSH National Occupational Hazard Survey (NOHS) (1974) RS: 41 Record 122 of 1119 in HSDB (through 2003/06) AN: 1320 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N,N-DIMETHYL-P-NITROSOANILINE- SY: *ACCELERINE-; *ANILINE,-N,N-DIMETHYL-P-NITROSO-; *BENZENAMINE,-N,N-DIMETHYL-4-NITROSO-; *P-(DIMETHYLAMINO)NITROSOBENZENE; *P-(N,N-DIMETHYLAMINO)NITROSOBENZENE; *4-(DIMETHYLAMINO)NITROSOBENZENE; *N,N-DIMETHYL-4-NITROSOBENZENAMINE-; *DIMETHYL(P-NITROSOPHENYL)AMINE; *NCI-C01821-; *NDMA-; *4-NITROSO-N,N-DIMETHYLANILINE-; *P-NITROSO-N,N-DIMETHYLANILINE-; *4-NITROSODIMETHYLANILINE-; *PARANITROSODIMETHYLANILIDE-; *ULTRA-BRILLIANT-BLUE-P- RN: 138-89-6 MF: *C8-H10-N2-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF NITROUS ACID WITH DIMETHYLANILINE [R1] *PREPD IN COLD FROM NANO2 AND SOLN OF DIMETHYLANILINE IN HCL. [R2] MFS: *AMERICAN CYANAMID CO, ORGANIC CHEMS DIV, BOUND BROOK, NJ 08805 [R1] OMIN: *P-NITROSODIMETHYLANILINE (I) IS A SEED-DRESSING FUNGICIDE. THUS, TREATMENT OF WHEAT SEEDS WITH 5% (I) COMPLETELY CONTROLLED TILLETIA CARIES. [R3] USE: *IN PRINTING FABRICS [R2] *AS DYESTUFFS INTERMEDIATE [R4, 96] *CHEM INT FOR ORG COMPOUNDS (N,N-DIMETHYL-P-PHENYLENEDIAMINE); ACCELERATOR FOR RUBBER VULCANIZATION [R1] *5% BY WT WAS USED WITH OTHER CHEMICALS FOR DISINFECTING SEEDS [R5] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 G [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 G [R1] U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *GREEN PLATES OR LEAFLETS [R2]; *GREENISH-YELLOW SOLID [R4, 95] MP: *92.5-93.5 DEG C [R2] MW: *150.18 [R2] DEN: *1.145 @ 20 DEG C [R6] SOL: *INSOL IN WATER; SOL IN ALC, ETHER [R2]; *SOL IN FORMAMIDE [R6] SPEC: +MAX ABSORPTION (ALCOHOL): 234 NM (LOG E= 3.67); 273 NM (LOG E= 3.82); 305 NM (LOG E= 3.18); 314 NM (LOG E= 3.14) [R6]; *MAX ABSORPTION (95% ETHANOL): 271.6 NM (E= 388, 1%, 1 CM) [R7]; +IR: 5891 (Sadtler Research Laboratories Prism Collection) [R8]; +UV: 2908 (Sadtler Research Laboratories Spectral Collection) [R8]; +NMR: 6829 (Sadtler Research Laboratories Spectral Collection) [R8]; +MASS: 104 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME [R9] OPRM: *...CARE MUST ALWAYS BE TAKEN TO PREVENT ESCAPE OF VAPOR OR PARTICLES INTO ATMOSPHERE AND TO PREVENT CONTAMINATION OF SKIN OR CLOTHING OF OPERATOR BY DIRECT CONTACT WITH CHEMICAL. /AROMATIC AMINES/ [R4, 93] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R10] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R11] STRG: *...KEEP ALL FLAMMABLES AWAY FROM AREA WHERE OXIDIZING AGENTS ARE STORED. STORAGE AREA SHOULD BE KEPT COOL AND VENTILATED, AND SHOULD BE FIREPROOF. [R9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *...APPARENTLY NOT METHEMOGLOBIN FORMER, BUT IS HIGHLY IRRITATING TO SKIN BOTH AS PRIMARY IRRITANT AND SENSITIZING AGENT. [R12] NTOX: *P-NITROSODIMETHYLANILINE ADMIN TO NZR RATS AND NZO MICE @ 300 MG/L DRINKING WATER OVER 1ST HALVES OF LIFESPAN, AVG AMT ACTUALLY CONSUMED 1.2 G/RAT AND 262 MG/MOUSE. SIGNIFICANT INCREASES OCCURRED IN TUMORS OF LUNGS, KIDNEY AND MALIGNANT LYMPHOMA IN RATS, AND IN TUMORS OF LUNGS, DUODENUM AND MALIGNANT LYMPHOMA IN MICE. [R13] *THE EFFECTS OF A SINGLE SC INJECTION OF P-NITROSODIMETHYLANILINE (I) ON MALE RATS WERE STUDIED BY THE USE OF URINARY ENZYME MEASUREMENTS. ALKALINE PHOSPHATASE IN URINE WAS ELEVATED 48 HOURS AFTER I. ACID PHOSPHATASE AND MURAMIDASE ACTIVITIES IN URINE WERE SIGNIFICANTLY ELEVATED SOON AFTER THE ADMIN OF I AND REMAINED ABOVE THE NORMAL LEVELS LESS THAN OR EQUAL TO 120 HOURS AFTER I. URINE VOLUME AND PROTEIN LEVELS WERE MARKEDLY REDUCED. PROTEIN IN SERUM WAS REDUCED WHILE KIDNEY AND LIVER PROTEINS WERE RAISED. THE SIGNIFICANCE OF INTERACTION OF THE BIOTRANSFORMATION PRODUCTS OF I WITH THE RENAL SYSTEM IS DISCUSSED. [R14] *AFTER THE APPLICATION OF 25 GAMMA P-NITROSODIMETHYLANILINE (I) TO EPILATED GUINEA PIG SKIN, THE ANIMAL INITIALLY BECAME MILDLY SENSITIVE TO THE COMPOUND, BUT 1-2 WEEKS LATER THE GUINEA PIG BECAME INSENSITIVE TO SC INJECTED I 500 GAMMA IN COMPLETE ADJUVANT. THE SHORTER THE INTERVAL BETWEEN THE TOPICAL APPLICATION OF I AND ITS INJECTION IN ADJUVANT, THE GREATER THE SENSITIVE REACTION, INDICATED BY THE DEGREE OF ERYTHEMA. ONE DAY AFTER A SENSITIZING INJECTION, SOME MEASURE OF INSENSITIVITY WAS INDUCED BY TOPICAL APPLICATION OF THE SENSITIZER. THEREFORE, UNRESPONSIVENESS AND SENSITIZATION DEVELOPED OVER THE SAME PERIOD OF TIME AFTER THE INITIAL TOPICAL APPLICATION OF SENSITIZER. [R15] +N,N-Dimethyl-p-nitrosoaniline was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). N,N-Dimethyl-p-nitrosoaniline was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 1.000, 3.300, 5.000, 8.000,l 10.000, 33.000, 50.000, 100.000, 200.000, and 333.000 ug/plate. The compound was positive in strains TA100 and TA98 with and without activation. The lowest positive dose tested was 8.000 ug/plate in strain TA100 without activation. [R16] ADE: *MOST AROMATIC AMINES ARE LIPID-SOL TO VARIABLE EXTENT AND ARE READILY ABSORBED THROUGH SKIN. /AROMATIC AMINES/ [R4, 93] METB: *THE NITROSOARENES STUDIED REACTED WITH THE THIOLS IN A 2ND-ORDER REACTION. THE REACTION VELOCITIES WITH GLUTATHIONE INCREASED WITH INCREASING HAMMET CONSTANT OF THE SUBSTITUENT. THIOLYTIC CLEAVAGE OF THE LABILE INTERMEDIATE WAS FAVORED BY INCREASING THE THIOL CONCENTRATION AT THE EXPENSE OF SULFINAMIDE ISOMERIZATION. LOWERING THE PH FAVORED SULFINAMIDE ISOMERIZATION AND DECREASED PHENYLHYDROXYLAMINE FORMATION. THE GLUTATHIONE CONCENTRATION IN THE RED BLOOD CELLS RESULTED IN THE ALTERATION OF FERRIHEMOGLOBINEMIA AND COVALENT BINDING OF NITROSOARENES WITH NEGATIVE HAMMET CONSTANTS. THE EFFLUX OF GLUTATHIONE DISULFIDE INCREASED MARKEDLY IN THE BILE AND VENOUS EFFUSATE. [R17] *PARTIALLY PURIFIED, UNTREATED RAT LIVER CYTOSOL CONTAINS AT LEAST 2 ENZYMES WHICH RAPIDLY REDUCE THE C-NITROSO CARCINOGEN P-NITROSO-N,N-DIMETHYLANILINE (I) IN THE PRESENCE OF NADPH OR NADH AT PH 6-7. TWO MOLES OF NADPH ARE REQUIRED FOR EACH MOLE OF I, CORRESPONDING TO THE REDUCTION OF THE NITROSO GROUP TO THE AMINE. I WAS NOT REDUCED BY RAT KIDNEY OR BRAIN CYTOSOL, PLASMA, OR HEMOGLOBIN. [R18] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SATISFACTORY THIN-LAYER CHROMATOGRAPHY RESOLUTION WAS ACHIEVED. [R19] *N,N-DIMETHYL-4-NITROSOANILINE WAS DETERMINED BY POLAROGRAPHY ON A DROPPING MERCURY ELECTRODE IN BRITTON-ROBINSON BUFFERS AND IN A NITROGEN ATMOSPHERE. [R20] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 862 R3: LEHMANN H ET AL; P-NITROSODIMETHYLANILINE-CONTAINING SEED DISINFECTION COMPOSITION; GER (EAST) PATENT NUMBER 100144 09/12/73 R4: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R5: DIETZ HJ ET AL; SEED DISINFECTING MEANS, BRIT PATENT NO 1395449 05/29/75 (VEB FALLBERG-LIST) R6: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-115 R7: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 2156 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 77 R9: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 973 R10: 49 CFR 171.2 (7/1/96) R11: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.4093 (1988) R12: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2476 R13: GOODALL CM, LIJINSKY W; ONCOGENICITY TESTS OF P-NITROSO-N,N-DIMETHYLANILINE AND P-NITROSO-N,N-DIETHYLANILINE IN NZR RATS AND NZO MICE; PATHOLOGY 8(2) 143 (1976) R14: NGAHA EO; RENAL EFFECTS OF DIMETHYLNITROSOANILINE (P-NITROSODIMETHYLANILINE) IN THE RAT AS REVEALED BY CHANGES IN THE URINARY ENZYME LEVELS; NIGER J PHARM 12(3) 437 (1971) R15: LOWNEY ED; SIMULTANEOUS DEVELOPMENT OF UNRESPONSIVENESS AND OF SENSITIVITY FOLLOWING TOPICAL EXPOSURE TO CONTACT SENSITIZERS; J INVEST DERMATOL 48(4) 391 (1967) R16: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R17: DIEPOLD C ET AL; REACTIONS OF AROMATIC NITROSO COMPOUNDS WITH THIOLS; ADV EXP MED BIOL 136B(BIOL REACT INTERMED- 2) CHEM MECH BIOL EFF PT B: 1173 (1982) R18: BERNHEIM ML C; REDUCTION OF CERTAIN C-NITROSO COMPOUNDS BY RAT LIVER CYTOSOL; RES COMMUN CHEM PATHOL PHARMACOL 6(1) 151 (1973) R19: RAO GS, BEJNAROWICZ EA; THIN-LAYER CHROMATOGRAPHY OF SARCOSINE AND ITS N-LAUROYL AND N-NITROSO DERIVATIVES; J CHROMATOGR 123(2) 486 (1976) R20: MEJSTRIK V ET AL; ANALYSIS OF SMALL QUANTITIES OF CARCINOGENIC N-NITROSO COMPOUNDS; CESK HYG 27(3) 145 (1982) RS: 10 Record 123 of 1119 in HSDB (through 2003/06) AN: 1322 UD: 200302 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-CHLORO-2-NITROBENZENE- SY: *BENZENE,-1-CHLORO-2-NITRO-; *O-CHLORONITROBENZENE-; *2-CHLORO-1-NITROBENZENE-; *O-NITROCHLOROBENZENE-; *ONCB- RN: 88-73-3 MF: *C6-H4-Cl-N-O2 SHPN: UN 1578; Nitrochlorobenzene, solid or liquid IMO 6.1; Nitrochlorobenzene, solid or liquid STCC: 49 214 57; Nitrochlorobenzene, ortho, liquid MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...BY DIAZOTIZING O-NITROANILINE AND TREATING DIAZONIUM CMPD WITH CU AND HCL... [R1] *BY NITRATING CHLOROBENZENE AND PURIFYING BY RECTIFICATION. [R2] *NITRATION OF CHLOROBENZENE AND PURIFICATION BY FRACTIONAL DISTILLATION [R3] MFS: *E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Deepwater, NJ 08023 [R4] *Monsanto Co, Hq, 800 N Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Monsanto Chemical Co, Production site: Sauget, IL 62201 [R4] USE: *CHEM INT FOR CARBOFURAN, A PESTICIDE, OTHER INTS, EG, O-NITROPHENOL, 2-CHLOROANILINE, DYES (FORMER USE) [R3] *o-Chloronitrobenzene is used as an intermediate in the manufacture of o-aminophenol (used as a developer in the photography industry). [R5] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 4.99X10+9 G [R3] *(1981) 4.80X10+10 G (ALL ISOMERS-EST) [R3] U.S. IMPORTS: *(1978) 2.32X10+9 G (PRINCPL CUSTMS DISTS) [R3] *(1982) 7.30X10+8 G (PRINCPL CUSTMS DISTS) [R3] U.S. EXPORTS: *(1978) ND [R3] *(1982) ND [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW CRYSTALS [R2]; *MONOCLINIC NEEDLES [R6] BP: *245.5 DEG C [R2] MP: *32 DEG C [R2] MW: *157.56 [R7] CTP: *Critical temperature = 757 deg K; Critical pressure = 3.98X10+6 Pa. [R8] DEN: *1.368 g/l at 242 deg C [R9] HTV: *6.59X10+7 J/kmol @ 306.14 deg K [R8] OWPC: *Log Kow = 2.52 [R10] SOL: *INSOL IN WATER; SOL IN ALCOHOL, BENZENE, ETHER [R11]; *VERY SOL IN ACETONE, PYRIDINE; SOL IN TOLUENE, METHANOL, CARBON TETRACHLORIDE [R6]; *Water solubility = 1.26X10-3 mol/l (198 mg/l) [R12]; *Water solubility = 2800 uM (440 mg/l) at 20 deg C [R13] SPEC: *MAX ABSORPTION (METHANOL): 252 NM (LOG E= 3.51) [R6]; *IR: 3231 (Sadtler Research Laboratories Prism Collection) [R14]; *UV: 5-47 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R14]; *NMR: 10548 (Sadtler Research Laboratories Spectral Collection) [R14] SURF: *4.37X10-2 N/m @ 317.65 deg K [R8] VISC: *2.09X10-3 Pa-s @ 317.65 deg K [R8] OCPP: *Log Kow = 2.24 [R10] *The liquid molar volume is 0.116 cu m/kmol. The ideal gas Heat of Formation is 3.72X10+7 J/kmol. [R8] *Henry's Law constant = 4.45X10-5 atm cu m/mole. [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Nitrobenzenes, liquid or solid/ [R16] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Nitrobenzenes, liquid or solid/ [R16] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Nitrobenzenes, liquid or solid/ [R16] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitrobenzenes, liquid or solid/ [R16] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitrobenzenes, liquid or solid/ [R16] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Nitrobenzenes, liquid or solid/ [R16] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Nitrobenzenes, liquid or solid/ [R16] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitrochlorobenzenes, liquid or solid/ [R16] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, incl self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms and waist should be provided. No skin surface should be exposed. [R17] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R17] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R17] FLPT: *127 deg C [R18] FIRP: +Water may cause foaming or frothing. Use water spray, dry chemical, foam, or carbon dioxide. [R17] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. /Nitrochlorobenzene, ortho, liquid/ [R19, 1992.690] REAC: +Reacts with alkalies, oxidizing materials. [R17] SERI: *Irritation of eyes, nose and throat. [R18] EQUP: *JOB ANALYSIS TO ENSURE PROPER HANDLING PROCEDURES, ADEQUATE EQUIPMENT DESIGN FOR BOTH OPERATING AND MAINTENANCE, AND APPROPRIATE VENTILATION WITH AIR-POLLUTION CONTROL ARE MINIMUM REQUIREMENTS. ... THE NECESSARY PROTECTIVE MEASURES IN ASCENDING ORDER OF EFFECTIVENESS ARE RESPIRATORY PROTECTION, JOB ROTATION, LIMITATION OF EXPOSURE TIME, USE OF PROTECTIVE CLOTHING AND WHOLE-BODY PROTECTION. /NITRO-CMPD, AROMATIC/ [R20, 1453] +WEAR SPECIAL PROTECTIVE CLOTHING AND POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. [R17] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *AN EFFECTIVE HEALTH PROGRAM TO PREVENT HEALTH IMPAIRMENT DUE TO EXPOSURE TO AROMATIC NITRO-COMPOUNDS REQUIRES EXPOSURE CONTROL AND MEDICAL SUPERVISION MEASURES. [R20, 1453] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without hazard. Use water spray to knock-down vapors. /Nitrochlorobenzene, ortho, liquid/ [R19, 1992.691] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. /Nitrochlorobenzene, ortho, liquid/ [R19, 1992.691] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Nitrochlorobenzene, ortho, liquid/ [R19, 1992.691] *Immediately take off contaminated clothing and dispose in an incinerator. [R18] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R22] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R23] STRG: +STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM ALKALIES AND OXIDIZING MATERIALS. [R17] *Containers should be tightly sealed, and is preferably stored in a cool and dark place. [R18] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of chloronitrobenzenes. There is inadequate evidence in experimental animals for the carcinogenicity of chloronitrobenzenes. Overall evaluation: Chloronitrobenzenes are not classifiable as to their carcinogenicity to humans (Group 3). /Chloronitrobenzenes/ [R24] MEDS: *MEDICAL SURVEILLANCE IS BASED FIRST OF ALL ON PRE-EMPLOYMENT EXAMINATIONS AIMED AT DETECTING SUSCEPTIBLE PERSONS WITH RED CELL GLUCOSE-6-PHOSPHATE-DEHYDROGENASE DEFECT AND/OR SICKLE-CELL TRAIT... PERIODICAL EXAMINATIONS SHOULD INCLUDE HISTORY, MEDICAL OBSERVATION, BLOOD PRESSURE, PULSE, WEIGHT, BLOOD AND URINE ANALYSIS AND LIVER FUNCTION TESTS AS APPROPRIATE. ADDITIONAL BLOOD AND URINE SPECIMENS ARE COLLECTED WHENEVER UNUSUALLY HAZARDOUS CONDITIONS OR KNOWN EXPOSURES HAVE BEEN ENCOUNTERED. [R20, 1453] HTOX: *THREE OUT OF 4 CASES OF CYANOSIS WILL EXHIBIT CLASSICAL BLUE OR ASHEN-GREY APPEARANCE BUT ONLY 1/3 OF THE VICTIMS WILL COMPLAIN OF ANOXIA SYMPTOMS (HEADACHE, FATIGUE, NAUSEA, VERTIGO, CHEST PAIN, NUMBNESS, ABDOMINAL PAIN, ACHING, PALPITATION, APHONIA, NERVOUSNESS, AIR HUNGER AND IRRITATIONAL BEHAVIOR). /NITRO-CMPD, AROMATIC/ [R20, 1452] *FORMS METHEMOGLOBIN, SKIN SENSITIZATION, IRRITATION, KIDNEY AND LIVER DAMAGE, CNS DEPRESSION, HYPERTHERMIA. /CHLORONITROBENZENES/ [R25] +Corrosive. Causes severe eye and skin burns. Irritating to skin, eyes, and respiratory system. May cause cyanosis and pulmonary edema. [R17] NTOX: *WHEN ADMIN TO MALE CHARLES RIVER RATS AND MALE AND FEMALE HAM/1CR MICE BY DIET, 1-CHLORO-2-NITROBENZENE PRODUCED TUMORS IN ONE OR MORE TISSUES. [R26] *NONE OF THE 22 NITROBENZENE DERIVATIVES, INCLUDING 1-CHLORO-2-NITROBENZENE, WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM IN THE ABSENCE OF NORHARMAN. HOWEVER, IN THE PRESENCE OF NORHARMAN, NITROBENZENE, NITROTOLUENE, NITROANISOLE, NITROCHLOROBENZENE, AND NITROBENZALDEHYDE WERE MUTAGENIC TO SALMONELLA TYPHIMURIUM WITH S9 MIX. THE MUTAGENESIS INDUCTION BY NORHARMAN WAS STRONG WITH ORTHO ISOMERS, WEAK WITH PARA ISOMERS, AND NOT OBSERVED WITH META ISOMERS. [R27] *THE MUTAGENICITY OF 21 CHLORO- OR FLUORONITROBENZENE COMPOUNDS AND 9 CHLORO- OR FLUOROBENZENE COMPOUNDS IN SALMONELLA TYPHIMURIUM WAS EXAMINED. CHLORONITROBENZENE COMPOUNDS, INCLUDING 1-CHLORO-2-NITROBENZENE, WERE MUTAGENIC FOR BASE-PAIR SUBSTITUTION STRAINS ONLY. MUTAGENIC ACTIVITY WAS EXHIBITED BY ALL COMPOUNDS HAVING A CHLORO OR FLUORO SUBSTITUENT AT THE PARA AND ORTHO POSITION IN THE NITROBENZENE NUCLEUS. [R28] *Twenty-one-day Daphnia reproduction tests were conducted in line with the provisional procedure proposed by the Federal Environmental Agency (Umweltbundesamt, FRG), as of Jan 1, 1984. Groups of 20, 24-hr old Daphnia magna Straus were exposed to 0.125 to 16 mg/l 1-chloro-2-nitrobenzene in semi-static test vessels. Parent animals in the test and control vessels had to be pipetted 3 times/wk in freshly prepared test and control media at the corresponding concn level. The no observed effect concn (NOEC) was determined from the parameters of mortality of the parent animals, reproduction rate and appearance of the first offspring during the test period. In preliminary acute Daphnia tests, the 24 hr EC50 was 12 mg/l for 1-chloro-2-nitrobenzene, the EC0 was 5.0 mg/l. The nominal 21-day no observed effect concn was 4.0 mg/l. [R29] *... Sprague-Dawley rats were exposed to an atmosphere of o-nitrochlorobenzene vapor at target concn of 10, 30 and 60 mg/cu m for 6 hr/day, 5 days/wk for 4 wk. At the end of the study, blood was sampled for clinical analysis, animals were killed, and tissues were examined. All animals survived the duration of the study. There was no evidence of dose related lacrimation, mucoid nasal discharge or ocular disorders. A dose related, statistically significant incr in blood methemoglobin levels was observed after 2 wk of exposure in mid and high concn groups. At 4 wk, incr in methemoglobin in animals exposed to 30 and 60 mg/cu m vapor of o-nitrochlorobenzene were to 3.2 and 5.7% among males, and to 3.1 and 4.8% among females, respectively. The 60 mg/cu m vapor also produced statistically significant incr in reticulocytes at the probability level less than 0.01. Erythrocytes of female rats exhibited polychromia and anisocytosis. No cmpd related gross postmortem changes were observed. [R30] NTP: +2-Chloronitrobenzene (2CNB) ... decreased sperm motility in B6C3F1 mice during inhalation exposure. Based on this preliminary suggestion of effect, 2CNB was tested for its effects on fertility and reproduction in Swiss CD-l mice according to the Continuous Breeding Protocol. Because inhalation Continuous Breeding studies are currently prohibitively expensive, 2CNB was administered via gavage. In Task 1, dose levels of 20, 40, 80, 160, and 320 mg/kg/day were used. All animals in the high dose group died or were moribund and sacrificed. Animals in the 160 mg/kg/day group acclimated to the effects of 2CNB, and no animals died. The following dose levels were chosen for Task 2: 0, 40, 80 and 160 mg/kg bw. Male and female mice (F0) were continuously exposed for a 7-day pre cohabitation and a 98-day cohabitation period. In the final litter of the holding period following the continuous breeding phase, pup weight gain during suckling was lower in the treated groups. At weaning, pups in the 160 mg/kg group weighed 12% less than controls. All other fertility and reproductive parameters were not affected. F0 animals in the 160 mg/kg group had increased body and spleen weights and were methemoglobinemic. F1 animals (160 mg/kg) had significantly lower body weights at weaning but were significantly heavier than controls at mating and terminal necropsy. Spleen and liver weights were also increased in the treated F1 animals at necropsy, and blood analysis showed significant methemoglobinemia. Seminal vesicle-to-body weight ratio was significantly decreased in the F1 males. None of the fertility and reproductive parameters examined were affected by 2CNB treatment in F1 animals. Overall, 2-chloronitrobenzene is not a reproductive toxicant, even in the presence of systemic toxicity, in Swiss CD-l mice. [R31] ADE: *The effect of dose on the dermal absorption of 2-chloronitrobenzene and 4-chloronitrobenzene was studied in rats. (14)C labeled 2-chloronitrobenzene or 4-chloronitrobenzene was applied to the shaved backs of male Fischer 344 rats at an application rates equivalent to doses of 0, 0.65, 6.5 or 65 mg/kg. Urine and feces samples were collected for 24, 48 or 72 hr and assayed for (14)C activity. Exhaled volatiles were collected in ethanol traps and analyzed. After 72 hr, the rats were /sacrificed/ and their skin removed and analyzed for (14)C activity. Approx 21-27% and 43 to 45% of the 2-chloronitrobenzene and 4-chloronitrobenzene doses, respectively, were eliminated in the urine over 72 hr. Approx 11 to 15% of the 2-chloronitrobenzene dose and 5 to 12% of the 4-chloronitrobenzene dose were excreted over 72 hr. Fecal excretion of 4-chloronitrobenzene showed a dose related incr which was statistically significant only when comparing the 65 mg/kg dose with the 0.65 mg/kg dose. Approx 27 to 32% of 2-chloronitrobenzene derived radioactivity and 13 to 15% of the 4-chloronitrobenzene derived (14)C activity were recovered in the ethanol traps. The amt of collected radioactivity did not depend on dose and consisted of unchanged 2-chloronitrobenzene or 4-chloronitrobenzene. ... An analysis of all (14)C data indicated that the dermal absorption of 2-chloronitrobenzene ... was linear over the entire dose range. Dermal absorption of 4-chloronitrobenzene was linear only after application of 0.65 and 6.5 mg/kg. /Results indicate/ that under the experimental conditions used at least 33 to 40% and 51 to 62% of the applied 2-chloronitrobenzene and 4-chloronitrobenzene doses, respectively, are absorbed from the skin of rats. ... Dermal absorption of 2-chloronitrobenzene is linear over the dose range 0.65 mg/kg to 65 mg/kg. Dermal absorption of 4-chloronitrobenzene is essentially unaffected by dose. [R32] METB: *YIELDS N-ACETYL-S-(O-NITROPHENYL)-L-CYSTEINE, O-CHLOROANILINE, 2-CHLORO-3-NITROPHENOL, 3-CHLORO-2-NITROPHENOL, 3-CHLORO-4-NITROPHENOL, 4-CHLORO-3-NITROPHENOL IN RABBIT: BRAY HG BIOCHEM J 64: 38 (1956). /FROM TABLE/ [R33] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *The major sources of environmental release of nitroaromatic compounds, such as 1-chloro-2-nitrobenzene, appears to be production and use plants and by-product manufacturing plants. Minor sources of release to the environment may be loss during transport, storage or land burial, formation in the environment by oxidation of man-made aromatic amines or by reaction of nitrogen oxides in highly polluted air with chlorinated aromatic hydrocarbons. If released to soil, 1-chloro-2-nitrobenzene should be resistant to oxidation and hydrolysis. Leaching may be significant since 1-chloro-2-nitrobenzene is predicted to be moderately mobile in soil. Volatilization from wet soils may be possible; (estimated Henry's Law constant 10-5 atm cu m/mol) however, leaching would lessen the significance of volatilization as a removal mechanism. Volatilization from dry soil surfaces is probably not rapid (estimated VP = 10-2 mmHg), although it may be a significant removal mechanism under some circumstances. If released to water, 1-chloro-2-nitrobenzene should be resistant to oxidation, hydrolysis and biodegradation. 1-Chloro-2-nitrobenzene has the potential to photolyze in water since it absorbs sunlight. Bioconcentration in aquatic organisms and sorption to sediments should not be significant. The volatilization half-life from 1 meter deep in surface water with a current velocity of 1 m/sec and a wind speed of 3 m/sec has been estimated to be 33.5 hours. Volatilization from surface waters with slower current speeds is expected to be less rapid. 1-Chloro-2-nitrobenzene has an estimated half-life in river water of 3.2 days based on monitoring data from the Rhine River. In contrast, 1-chloro-2-nitrobenzene was not altered or physically removed during the time period required for transport down 900 miles of the Mississippi River. If released to the atmosphere, 1-chloro-2-nitrobenzene in the vapor phase is predicted to react with photochemically generated hydroxyl radicals with an estimated reaction half-life of 1.97 days at 25 deg C. 1-Chloro-2-nitrobenzene has the potential to directly photolyze in the atmosphere since it absorbs sunlight. Chloronitrophenols may form as a result of photochemical reaction of 1-chloro-2-nitrobenzene in air. Exposure to 1-chloro-2-nitrobenzene is probably due mainly to occupational exposure during production or use in dye manufacturing. A small segment of the general public may be exposed through ingestion of contaminated drinking water or fish. (SRC) ARTS: *The major source of environmental release of nitroaromatic compounds, such as 1-chloro-2-nitrobenzene, appears to be from production plants and from by- product manufacturing plants(1). 1-Chloro-2-nitrobenzene is used as a chemical intermediate predominantly in dye manufacturing and is known to be inadvertently formed as a by-product of 1-chloro-4-nitrobenzene manufacture(1). Some loss to the environment may occur during transport, storage or land burial in cases where an improper burial site has been chosen(1). Potential minor sources of 1-chloro-2-nitrobenzene are formation in the environment by oxidation of man-made aromatic amines and by reaction of nitrogen oxides in highly polluted air with chlorinated aromatic hydrocarbons(1). [R34] FATE: *TERRESTRIAL FATE: If released to soil, 1-chloro-2-nitrobenzene should be resistant to oxidation and hydrolysis. Leaching should be significant since 1-chloro-2-nitrobenzene is predicted to be moderately mobile in soil. Volatilization from wet soil may be significant (estimated Henry's Law constant = 10-5 atm cu m/mol); however, leaching would lessen the importance of volatilization as a removal mechanism. Volatilization from dry soil surfaces is probably not rapid, although it may be a significant removal mechanism under some circumstances. (SRC) *AQUATIC FATE: If released to water, 1-chloro-2-nitrobenzene should be resistant to oxidation, hydrolysis and biodegradation. 1-Chloro-2-nitrobenzene could potentially photolyze in water since it absorbs sunlight. Bioconcentration in aquatic organisms and adsorption to suspended solids and sediments should not be significant. The volatilization half-life from 1 m deep in surface water with a current velocity of 1 m/sec and a wind speed of 3 m/sec has been estimated to be 33.5 hours. Volatilization from surface waters with slower current speeds should be less rapid(SRC). 1-Chloro-2-nitrobenzene has an estimated half-life in river water of 3.2 days based on monitoring data from the Rhine River(1). However, this compound has been found to travel long distances in surface waters (900 miles in the Mississippi River) at concentrations that could be explained by simple dilution(2). This observation indicates that 1-chloro-2-nitrobenzene was not altered or physically removed at least during the time period required for transport down this river(2). [R35] *ATMOSPHERIC FATE: If released to the atmosphere, 1-chloro-2-nitrobenzene in the vapor phase is predicted to react with photochemically generated hydroxyl radicals with an estimated reaction half-life of 1.97 days at 25 deg C. 1-Chloro-2-nitrobenzene has the potential to photolyze in the atmosphere. Chloronitrophenols may form as a result of the Photochemical reaction of 1-chloro-2-nitrobenzene in air. (SRC) BIOD: *21.1 ppm 1-Chloro-2-nitrobenzene in Ohio River water inoculated weekly with settled sewage underwent no degradation in 175 days(1). 100 ppm 1-Chloro-2-nitrobenzene inoculated with 30 ppm activated sludge at 25 deg C was less than 30% degraded after 2 weeks(2,3). [R36] ABIO: *Based on the molecular structure of 1-chloro-2-nitrobenzene, this compound should be resistant to oxidation and hydrolysis(1,SRC). Weak adsorption of UV light greater than 290 nm by 1-chloro-2-nitrobenzene in methanol indicates potential for photolysis by sunlight of 1-chloro-2-nitrobenzene in water and air. In air, 1-chloro-2-nitrobenzene in the vapor phase is predicted to react with photochemically generated hydroxyl radicals with an estimated reaction rate constant of 5.1X10-12 cu cm/mole.sec at 25 deg C(3). Assuming an ambient hydroxyl radical concentration of 8.0X10+5 mole/cu cm, the reaction half-life has been calculated to be 1.97 days(3). Chloronitrophenols may form as the result of the photochemical reaction of 1-chloro-2-nitrobenzene in air(4). [R37] BIOC: *Results of the Ministry of International Trade and Industry (MITI) test for bioaccumulation indicate that 1-chloro-2-nitrobenzene has a bioconcentration factor(BCF) of less than 100(1). Using a recommended value for the log octanol-water partition coefficient of 2.24(2) and a measured water solubility of 440 mg/L at 20 deg C(3), the BCF for 1-chloro-2-nitrobenzene has been estimated to be 30 and 20, respectively(4,SRC). Based on these BCF values, 1-chloro-2-nitrobenzene should not significantly bioconcentrate in aquatic organisms(SRC). [R38] KOC: *1-Chloro-2-nitrobenzene has been found to travel long distances in surface waters (900 miles in the Mississippi River) at concentrations that could be explained by simple dilution(1). This observation suggests only minimal adsorption to river sediment and fairly high mobility of this compound in the aqueous environment(1). Based on a recommended value for the log octanol-water partition coefficient of 2.24(2) and a measured water solubility of 440 mg/L at 20 deg C(3), the soil adsorption coefficient (Koc) for 1-chloro-2-nitrobenzene has been estimated to be 398 and 155, respectively (4,SRC). These Koc values suggest that this compound should be moderately mobile in water and soil(5,SRC). [R39] VWS: *Henry's Law constant for 1-chloro-2-nitrobenzene has been estimated to be 3.6X10-5 atm cu m/mol using a method of group contributions based on molecular structure(1,SRC). Using this value for Henry's Law Constant, the volatilization half-life from 1 m deep in surface water with a current velocity of 1 m/sec and wind speed of 3 m/sec has been estimated to be 33.5 hours(2,SRC). Volatilization from surface waters with slower current speed should be less rapid(SRC). Based on the soil adsorption coefficient for 1-chloro-2-nitrobenzene of 155-398 (see also KOC(1)), water solubility of 440 mg/L at 20 deg C(3) and estimated vapor pressure of 3.0X10-2 mmHg at 20 deg C(4,SRC), volatilization from wet soil surfaces may be significant. Based on the vapor pressure of this compound volatilization from dry soil surfaces is probably not rapid; although it may be a significant removal process in some situations(SRC). [R40] WATC: *SURFACE WATER: 1-Chloro-2-nitrobenzene was monitored from Sept. 1957 - April 1959 in Mississippi River water samples from Cape Girardeau, MO and New Orleans, LA at concentrations of 0.004-0.037 ppm and 0.001-0.002 ppm, respectively(1). 1-Chloro-2-nitrobenzene has been detected at levels ranging from less than 0.1 ug/L to 1.0 ug/L in the Rhine River during 1978 to 1982(2,3). [R41] *DRINKING WATER: 1-Chloro-2-nitrobenzene has been identified in drinking water from New Orleans LA(1). [R42] EFFL: *1-Chloro-2-nitrobenzene has been identified in advanced waste treatment water in Orange County, CA(1). 1,2-, 1,3- and 1,4-chloronitrobenzene have been identified in the effluent from 1-chloro-3-nitrobenzene production at a concentration of 1,500-1,800 mg/L(2). [R43] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Less than 0.005-0.24 ppm 1-chloro-2-nitrobenzene was found in the edible portion of various species of fish taken from the Mississippi River 0.60 and 150 miles south of St. Louis, MO. 1-Chloro-2-nitrobenzene was not detected in fish taken from the Mississippi River 100 miles north of St. Louis (2 samples) or 260-400 miles south of St. Louis (3 samples) or taken from the Missouri River (6 samples)(1). [R44] RTEX: *Exposure to 1-chloro-2-nitrobenzene is probably due mainly to occupational exposure during manufacture or use as a dye intermediate. A small segment of the general public may be exposed through ingestion of contaminated drinking water or fish. (SRC) *A National Occupational Exposure Survey estimates that 2,215 workers are exposed to 1-chloro-2-nitrobenzene(1). [R45] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *MONITORING METHOD: GAS CHROMATOGRAPHY WAS USED TO DETERMINE O-NITROCHLOROBENZENE IN AIR. [R46] *NIOSH method No. 2005. Nitrobenzenes. Describes the analysis of nitrobenzenes using gas chromatography with a flame ionization detector. The working range for this method is 0.03 to 6.0 ppm./p-Chloronitrobenzene/ [R47] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of 2-Chloronitrobenzene and 4-Chloronitrobenzene Administered by Inhalation to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No.33 NIH Publication No. 93-3382 (1993) WHO; Chemical Safety Card: 2-Chloro-1-nitrobenzene (1992) SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 273 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 269 R3: SRI R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 521 R5: Jarvis W et al; Health and environmental effects document on chloronitrobenzenes. Syracuse Res Corp, Syracuse NY, SRC# TR-92-009. p. 1-4 (1992) R6: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-155 R7: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 84/8302 R8: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-35 R10: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R11: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 332 R12: Mueller M, Klein W; Chemosphere 25: 769-82 (1992) R13: Eckert JW; Phytopathol 52: 642-9 (1962) R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 164 R15: Hellman H; Fresenius' Z Anal Chem 328: 475-9 (1987) R16: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-152 R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 49-40 R18: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 124 R19: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives R20: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R21: 49 CFR 171.2 (7/1/96) R22: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 123 R23: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6100 (1988) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 65 290 (1996) R25: Dreisbach, R. H. Handbook of Poisoning. 9th ed. Los Altos, California: Lange Medical Publications, 1977. 134 R26: WEISBURGER EK ET AL; TESTING OF TWENTY-ONE ENVIRONMENTAL AROMATIC AMINES OR DERIVATIVES FOR LONG-TERM TOXICITY OR CARCINOGENICITY; J ENVIRON PATHOL TOXICOL 2(2) 325 (1978) R27: SUZUKI J ET AL; MUTAGENICITIES OF MONONITROBENZENE DERIVATIVES IN THE PRESENCE OF NORHARMAN; MUTAT RES 120 (2-3): 105-10 (1983) R28: SHIMIZU M ET AL; STRUCTURAL SPECIFICITY OF AROMATIC COMPOUNDS WITH SPECIAL REFERENCE TO MUTAGENIC ACTIVITY IN SALMONELLA TYPHIMURIUM - A SERIES OF CHLORO- OR FLUORONITROBENZENE DERIVATIVES; MUTAT RES 116 (3-4): 217 (1983) R29: Kuhn R et al; Water Res 23 (4): 501-10 (1989) R30: Nair RS et al; Fund Appl Toxicol 7 (4): 609-14 (1986) R31: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of 2-Chloronitrobenzene (CAS No. 88-73-3) in CD-1 Swiss Mice, NTP Study No. RACB90011 (April 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R32: Nomeir AA et al; Drug Metab Dispos 20 (3): 436-9 (1992) R33: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. C-33 R34: (1) Howard PH et al; Investigation of Selected Environmental Contaminants : Nitroaromatics USEPA 560/2-76-010 Research Triangle Park NC (1976) R35: (1) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) (2) Howard PH et al; Investigation of Selected Environmental Contaminants : Nitroaromatics USEPA 560/2-76-010 Research Triangle Park NC (1976) R36: (1) Ludzack FJ, Ettinger MB; Eng Bull Ext Ser No 115: 278-82 (1963) (2) Sasaki S; pp 283-98 in Aquatic Pollutants Transformation and Biological Effects Hutzinger O et al eds; Oxford Pergamon Press (1978) (3) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances OECD Tokyo Meeting Reference Book TSU-NO 3 (1978) R37: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill p 7-4 (1982) (2) Sadtler; Sadtler Standard Spectra Philadelphia PA (3) GEMS; Graphical Exposure Modeling System. Fate of Atmospheric Pollutants Office of Toxic Substances. USEPA (1986) (4) Kanno S, Nojima K; Chemosphere 8: 225-32 (1979) R38: (1) Sasaki S; pp 283-98 in Aquatic Pollutants Transformation and Biological Effects Hutzinger O et al eds; Oxford Pergamon Press (1978) (2) Hansch C, Leo AJ; Medchem Project Issue No. 26 Pomona College Claremont CA (1985) (3) Eckert JW; Phytopathol 52: 642-9 (1962) (4) Lyman WJ et al; Handbook of Chemical Property Extimation Methods. Environ Behavior of Organic Compounds. McGraw-Hill NY p 5-5 (1982) R39: (1) Howard PH et al; Investigation of Selected Env Contaminants Nitroaromatics USEPA 560/2-76-010 Research Triangle Park NC (1976) (2) Hansch C, Leo AJ; Medchem Project Issue No.26 Pomona College Clarmont CA (1985) (3) Eckert JW; Phytopathol 52: 642-9(1962) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environ Behavior of Organic Compounds. McGraw-Hill NY p 4-9 (1982) (5) Swann RL et al; Res Rev 85: 17-28 (1983) R40: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environ Behavior of Organic Compounds. McGraw-Hill Chpt 15 (1982) (3) Eckert JW; Phytopathol 52: 642-9 (1962) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environ Behavior of Organic Compounds. McGraw-Hill p 4-9 (1982) R41: (1) Middleton FM, Lichtenberg JJ; Ind Eng Chem 52: 99A-102A (1960) (2) Malle KG; Z Wasser-Abwasser Forsch 17: 75-81 (1984) (3) Piet GJ, Zoetman BCJ; J Am Water Works Assoc 72: 400-4 (1980) R42: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates 2: Computer-Printed Tabulations of Compound Identification Results from Large Volume Concentrates Columbus OH Health Eff Res Lab (1984) R43: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates 2: Computer Printed Tabulations of Compound Identification Results from Large Volume Concentrates Columbus OH Health Eff Res Lab(1984) (2) Howard PH et al; Investigation of Selected Env Contaminants Nitroaromatics USEPA 560/2-76-010 Research Traingle Park NC (1976) R44: (1) Yurawecz MP, Puma BJ; J Assoc Off Anal Chem 66: 1345-52 (1983) R45: (1) NIOSH National Occupational Exposure Survey (NOES) Sept 20(1985) R46: KOLIEVSKAYA YA, IVANYUK EG; DETERMINATION OF NITROCHLOROBENZENE IN THE WORK AREA AIR BY GAS CHROMATOGRAPHY; GIG TR PROF ZABOL (12) 54 (1975) R47: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. RS: 40 Record 124 of 1119 in HSDB (through 2003/06) AN: 1324 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-BIPHENYLAMINE- SY: *O-AMINOBIPHENYL-; *2-AMINOBIPHENYL-; *O-AMINODIPHENYL-; *2-AMINODIPHENYL-; *O-BIPHENYLAMINE-; *(1,1'-BIPHENYL)-2-AMINE; *O-PHENYLANILINE-; *2-PHENYLANILINE- RN: 90-41-5 MF: *C12-H11-N ASCH: Biphenyl, 3-amino; 2243-47-2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF ORTHO-NITROBIPHENYL [R1] MFS: *MACKENZIE CHEM WORKS, INC, CENTRAL ISLIP, NY 11722 [R2] USE: *CHEM INT FOR CARBAZOLE, RESINS, AND SYNTHETIC RUBBERS [R2] CPAT: *ESSENTIALLY 100% AS A CHEMICAL INTERMEDIATE [R2] PRIE: U.S. PRODUCTION: *(1971) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R2] *(1975) ND [R2] U.S. IMPORTS: *(1972) ND [R2] *(1975) ND [R2] U.S. EXPORTS: *(1972) ND [R2] *(1975) ND [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LEAVES FROM DIL ALCOHOL [R3]; *COLORLESS OR PURPLISH CRYSTALS [R1] BP: *299 DEG C @ 760 MM HG [R3] MP: *51-53 DEG C [R3] MW: *169.23 [R3] SOL: *INSOL IN WATER; SOL IN ALCOHOL, ETHER, BENZENE; MISCIBLE IN PETROLEUM ETHER [R3] SPEC: *MAX ABSORPTION (ALCOHOL): 300 NM (LOG E= 3.5) [R3]; +IR: 3831 (Coblentz Society Spectral Collection) [R4]; +UV: 384 (Sadtler Research Laboratories Spectral Collection) [R4]; +NMR: 9421 (Sadtler Research Laboratories Spectral Collection) [R4]; +MASS: 748 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R4] VAPD: *5.8 (AIR= 1) [R5] OCPP: +IR: 18844 (Sadtler Research Laboratories Prism Collection) /Biphenyl, 3-amino/ [R4] +UV: 6162 (Sadtler Research Laboratories Spectral Collection) /Biphenyl, 3-amino/ [R4] +MASS: 749 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /Biphenyl, 3-amino/ [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: *FLAMMABILITY 1. 1= MATERIALS THAT MUST BE PREHEATED BEFORE IGNITION CAN OCCUR. WATER MAY CAUSE FROTHING IF IT GETS BELOW SURFACE OF LIQ AND TURNS TO STEAM. HOWEVER, WATER FOG GENTLY APPLIED TO SURFACE WILL CAUSE FROTHING WHICH WILL EXTINGUISH FIRE. [R5] *HEALTH 2. 2= MATERIALS HAZARDOUS TO HEALTH, BUT AREAS MAY BE ENTERED FREELY WITH FULL-FACED MASK SELF-CONTAINED BREATHING APPARATUS WHICH PROVIDES EYE PROTECTION. [R5] *REACTIVITY 0. 0= MATERIALS WHICH (IN THEMSELVES) ARE NORMALLY STABLE EVEN UNDER FIRE EXPOSURE CONDITIONS AND WHICH ARE NOT REACTIVE WITH WATER. NORMAL FIRE FIGHTING PROCEDURES MAY BE USED. [R5] AUTO: *842 DEG F [R5] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *CHEM-INDUCED SISTER CHROMATID EXCHANGE WAS MEASURED IN VIVO IN BONE MARROW OF CHINESE HAMSTERS. ADMIN EITHER IP OR ORALLY AND INCR SISTER CHROMATID EXCHANGE FREQUENCIES WERE NOTED WITH 6 OF 6 DIRECT-ACTING GENOTOXINS AND WITH 9 OF 14 ACTIVATION-DEPENDENT GENOTOXINS. [R6] *IN THE PRESENCE OF A RAT LIVER 9000 G SUPERNATANT, SEVERAL AMINOBIPHENYLS WERE ASSAYED FOR MUTAGENICITY TO SALMONELLA TYPHIMURIUM. AMONG THE 3 POSSIBLE AMINOBIPHENYLS ISOMERS, ONLY 4-AMINOBIPHENYL WAS A POTENT MUTAGEN. [R7] +... Under the conditions of the bioassay, 2-biphenylamine hydrochloride was not carcinogenic for F344/N rats of either sex. 2-Biphenylamine hydrochloride was carcinogenic for B6C3F1 female mice, inducing hemangiosarcomas at various sites. The evidence for an association between the admin of 2-biphenylamine hydrochloride and the incr incidence of hemangiosarcomas in male mice was equivocal. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Equivocal; Female Mice: Positive. /2-Biphenylamine hydrochloride/ [R8] NTP: +... The chronic study was conducted with the purified 2-biphenylamine hydrochloride by feeding diets containing 1,000 or 3,000 ppm 2-biphenylamine hydrochloride to groups of 49 or 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 wk. Groups of 50 rats and 50 mice of each sex served as controls. ... Under the conditions of the bioassay, 2-biphenylamine hydrochloride was not carcinogenic for F344/N rats of either sex. 2-Biphenylamine hydrochloride was carcinogenic for B6C3F1 female mice, inducing hemangiosarcomas at various sites. The evidence for an association between the admin of 2-biphenylamine hydrochloride and the incr incidence of hemangiosarcomas in male mice was equivocal. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Equivocal; Female Mice: Positive. /2-Biphenylamine hydrochloride/ [R8] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GAS CHROMATOGRAPHY METHOD IS DESCRIBED FOR DETECTING TRACES OF CARCINOGENS AND RELATED COMPD IN WASTEWATER. [R9] *DETECTION OF 2-BIPHENYLAMINE IN WASTEWATER AND ENVIRONMENTAL SURVEILLANCE SAMPLES (SWABS, AIR FILTERS, ETC) BASED ON ELECTRON CAPTURE GAS CHROMATOGRAPHY OF THEIR PENTAFLUOROPROPIONYL DERIVATIVES. [R10] *THIN LAYER CHROMATOGRAPHY AND FLUOROMETRY USED TO DETERMINE 2-AMINOBIPHENYL. [R11] *HIGH PRESSURE LIQ CHROMATOGRAPHY USED TO DETERMINE A SERIES OF BIPHENYLS. [R12] *CHEMICAL IONIZATION MASS SPECTROMETRY USING AMMONIA AND AMMONIA-D3 AS REAGENT GASES IS USED TO DIFFERENTIATE NITROGEN-CONTAINING COMPD. [R13] CLAB: *GAS CHROMATOGRAPHIC METHOD IS DESCRIBED FOR DETECTING TRACES OF CARCINOGENS AND RELATED COMPD IN HUMAN URINE. [R9] *DETECTION OF 2-BIPHENYLAMINE IN HUMAN URINE BASED ON ELECTRON CAPTURE GAS CHROMATOGRAPHY OF THEIR PENTAFLUOROPROPIONYL DERIVATIVES. [R10] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of 2-Biphenylamine Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 233 (1982) NIH Publication No. 83-1789 SO: R1: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 41 R2: SRI R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-209 R4: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 290 R5: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 325M-35 R6: NEAL SB, PROBST GS; CHEMICALLY-INDUCED SISTER CHROMATID EXCHANGE IN VIVO IN BONE MARROW OF CHINESE HAMSTERS. AN EVALUATION OF 24 COMPOUNDS; MUTAT RES 133(1) 33 (1983) R7: EL-BAYOUMY K ET AL; EFFECTS OF ORTHO-METHYL SUBSTITUENTS ON THE MUTAGENICITY OF AMINOBIPHENYL AND AMINONAPHTHALENES; MUTAT RES 90(4) 345 (1981) R8: Carcinogenesis Bioassay of 2-Biphenylamine Hydrochloride in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 233 (1982) NTIS Publication No. PB83-138842 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R9: NONY CR, BOWMAN MC; CARCINOGENS AND ANALOGS: TRACE ANALYSIS OF THIRTEEN COMPOUNDS IN ADMIXTURE IN WASTEWATER AND HUMAN URINE; INT J ENVIRON ANAL CHEM 5(3) 203 (1978) R10: BORMAN MC; TRACE ANALYSIS: A REQUIREMENT FOR TOXICOLOGICAL RESEARCH WITH CARCINOGENS AND HAZARDOUS SUBSTANCES; J ASSOC OFF ANAL CHEM 61(5) 1253 (1978) R11: JAKOVLJEVIC IN ET AL; THIN LAYER CHROMATOGRAPHIC SEPARATION AND FLUOROMETRIC DETERMINATION OF 4-AMINOBIPHENYL IN 2-AMINOBIPHENYL; ANAL CHEM 47(12) 2045 (1975) R12: JOHNSON H J JR ET AL; HIGH-PRESSURE LIQUID CHROMATOGRAPHY OF SOME SUBSTITUTED BIPHENYLS; J CHROMATOGR 161: 259 (1978) R13: BUCHANAN MV; MASS SPECTRAL CHARACTERIZATION OF NITROGEN-CONTAINING COMPOUNDS WITH AMMONIA CHEMICAL IONIZATION; ANAL CHEM 54(3) 570 (1982) RS: 8 Record 125 of 1119 in HSDB (through 2003/06) AN: 1336 UD: 200302 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-IODIDE- SY: *HALON-10001-; *IODOMETANO- (ITALIAN); *Iodomethane-; *IODURE-DE-METHYLE- (FRENCH); *JOD-METHAN- (GERMAN); *JOODMETHAAN- (DUTCH); *METHANE,-IODO-; *METHYLJODIDE- (DUTCH); *METHYLJODID- (GERMAN); *METYLU-JODEK- (POLISH); *MONOIODOMETHANE-; *MONOIODURO-DI-METILE- (ITALIAN) RN: 74-88-4 MF: *C-H3-I SHPN: UN 2644; Methyl iodide IMO 6.1; Methyl iodide HAZN: U138; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepd from methyl alcohol, iodine and red phosphorus; from potassium iodide and methyl sulfate. [R1, 1039] *From potassium iodide and methyl p-toluenesulfonate; by reaction of dimethyl sulfate with an aqueous iodine slurry containing a reducing agent such as iron or sodium bisulfite; by reaction of methanol and hydrogen iodide; and by reaction of methanol, iodine, and diborane. [R2] IMP: *IODINE MAY BE PRESENT AS AN IMPURITY. [R3] FORM: *... AVAIL IN USA AND JAPAN IN GRADE CONTAINING @ LEAST 99% OF PURE CHEM. [R3] MFS: *Ajay North America, LLC, P.O. 127, 1400 Industry Road, Powder Springs, GA 30127-0127, (770) 943-6202 [R4] *Deepwater Chemicals, Inc., 1210 Airpark Road, Woodward, OK 73801, (508) 256-0500 [R4] *Eagle Pitcher Industries, Inc., Eagle Pitcher Technologies, LLC, ChemSyn Laboratories, Hq, 250 East 5th Street, Suite 500, Cincinnati, OH 45202, (513) 721-7010; Production site: Lenexa, KS 66215 /[3H] Methyl Iodide and [14C] Methyl Iodide/ [R4] *R.S.A. Corporation, 39 Old Sherman Turnpike, Danbury CT 06810, (203) 790-8100 [R4] OMIN: *... COMMERCIAL PRODN ... IN USA WAS FIRST REPORTED IN 1943, WHEN ABOUT 1400 KG WERE MANUFACTURED ... [R3] *Methyl iodide has been investigated in India for use as a fumigant to control internal fungi of grain sorghum. [R5] USE: *Methylating agent; in microscopy because of its high refractive index; as imbedding material for examining diatoms; in testing for pyridine. Light sensitive etching agent for electronic circuits; component in fire extinguishers. [R1, 1039] PRIE: U.S. PRODUCTION: *(1971) 9,000 lb sold [R6, 1971] *(1972) 18,000 lb [R6, 1972] *(1977) Iodinated hydrocarbons: 58,000 lb [R6, 1977] *(1977) AT LEAST 4.99X10+6 G [R7] *(1982) PROBABLY GREATER THAN 6.81X10+6 G [R7] *(1978) Iodinated hydrocarbons: 50,000 lb [R6, 1978] *(1982) 82,000 lb [R6, 1982] *(1983) 103,000 lb [R6, 1983] *(1988) NO DATA PROVIDED [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, transparent liquid (turns brown on exposure to light) [R1, 1039] ODOR: *Pungent, ether-like odor. [R9, 210] BP: *42.5 deg C [R1, 1039] MP: *-66.5 deg C [R1, 1039] MW: *141.94 [R1, 1038] CTP: *Critical temperature: 254.8 deg C; Critical pressure: 72.7 atm [R10, p. F-63] DEN: *2.28 @ 20 deg C/4 deg C [R1, 1038] HTC: +194.7 kg cal/g mole [R10, p. D-275] HTV: *27.97 kJ/mol @ 25 deg C [R11, p. 6-104] OWPC: *log Kow= 1.51 [R12] SOL: *Miscible with alcohol, ether. [R1, 1039]; *Sol in acetone [R11, p. 3-207]; *SOL IN CARBON TETRACHLORIDE [R13]; *1.39X10+4 mg/l at 20 deg C in water [R14] SPEC: *Index of refraction: 1.5293 @ 21 deg C/D [R1, 1039]; *Index of refraction: 1.5380 @ 20 deg C. [R11, p. 3-207]; *SADTLER REFERENCE NUMBER: 59 (IR, PRISM) [R15]; *IR: 1310 (Coblentz Society Spectral Collection) [R16]; *NMR: 7872 (Sadtler Research Laboratories Spectral Collection) [R16]; *MASS: 755 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R16] SURF: *25.8 dynes/cm at 43.5 deg C in contact with air [R10, p. F-34] VAPD: *4.9 (AIR= 1) [R17] VAP: *4.05X10+2 mm Hg @ 25 deg C [R18] VISC: *0.606 cP at 0 deg C, 0.424 cP at 40 deg C. [R10, p. F-40] OCPP: *% IN SATURATED AIR: 53 @ 25 DEG C; CONVERSION FACTORS: 1 MG/L IS EQUIVALENT (EQUIV) TO 172 PPM AND 1 PPM IS EQUIV TO 5.8 MG/CU M @ 25 DEG C, 760 TORR [R19, p. 4030-1] *Decomp @ 270 deg C [R1, 1079] *DENSITY OF SATURATED AIR: 3.04 (AIR= 1) [R17] *Henry's constant of 0.00526 atm-cu m/mole at 25 deg C [R20] *Hydroxyl radical rate constant = 7.20X10-14 cu cm/molecule-sec at 25 deg C [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R22, p. G-151] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R22, p. G-151] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R22, p. G-151] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R22, p. G-151] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R22, p. G-151] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R22, p. G-151] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R22, p. G-151] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R22, p. G-151] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.3 kilometers (0.2 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 60 meters (200 feet); then, PROTECT persons Downwind during DAY 0.3 kilometers (0.2 miles) and NIGHT 1.0 kilometers (0.6 miles). [R22, p. TABLE] FPOT: *Iodomethane is not flammable. [R23] FIRP: *Self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive-pressure mode. [R24, 1981.4] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself dose not burn or burns with difficulty.) Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Keep run-off water out of sewers and water sources. [R25] REAC: *Strong oxidizers [Note: Decomposes at 518 degrees F]. [R9, 210] *Attempts to react silver chlorite with methyl or ethyl iodides caused explosions, immediately in the absence of solvents, or delayed in the presence of solvents. [R26] *... Turns brown on exposure to light. [R27] *Violent reaction with oxygen (at 300 deg C); sodium. [R27] *Explosive reaction with trialkylphosphines; silver chlorite. [R27] DCMP: *IODIDE AND HYDROGEN IODIDE MAY BE RELEASED WHEN METHYL IODIDE UNDERGOES THERMAL DECOMPOSITION (270 DEG C). [R28, 1991.1013] SERI: *Contact with the liquid may cause irritation ... of the skin. [R24, 1981.1] EQUP: *EMPLOYEES SHOULD BE PROVIDED WITH AND REQUIRED TO USE IMPERVIOUS CLOTHING, GLOVES, FACE SHIELDS (EIGHT-INCH MIN), AND OTHER APPROPRIATE PROTECTIVE CLOTHING NECESSARY TO PREVENT REPEATED OR PROLONGED SKIN CONTACT WITH LIQ ... . [R24, 1981.2] *Respiratory protection for methyl iodide at 50 ppm or less: Any supplied-air respirator or any self-contained breathing apparatus; At 250 ppm or less: Any supplied-air respirator with a full facepiece, helmet, or hood or any self-contained breathing apparatus with a full facepiece; At 800 ppm or less: A Type C supplied-air respirator operated in pressure-demand or other positive pressure or continuous-flow mode; At greater than 800 ppm or entry and escape from unknown concn: Self-contained breathing apparatus operated in pressure-demand or other positive pressure mode or a combination respirator which includes a Type C supplied-air respirator with a full facepiece operated in pressure-demand or other positive pressure or continuous-flow mode and an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode; Escape: Any gas mask providing protection against organic vapors, or any escape self-contained breathing apparatus. [R24, 1981.4] *Employees should be provided with, and required to use splash-proof safety goggles where liquid methyl iodide may contact the eyes. [R24, 1981.2] *Wear appropriate personal protective clothing to prevent skin contact. [R9, 211] *Wear appropriate eye protection to prevent eye contact. [R9, 211] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R9, 211] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R9, 211] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R9, 211] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R9, 211] OPRM: *Contact lenses should not be worn when working with this chemical. [R9, 211] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Proper ventilation and protective devices /should be used/. Periodic determination of gas concentration in work place /should be made/. [R23] *Good industrial hygiene practices recommend that engineering controls be used to reduce environmental concentrations to the permissible exposure level. However, there are some exceptions where respirators may be used to control exposure. Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. [R24, 1981.2] *The following list includes some common operations in which exposure to methyl iodide may occur and control methods which may be effective in each case: Operation (1) Use as a methylating agent in organic synthesis; use as a laboratory reagent; use in academic laboratory courses in organic chemistry. Control (1) Process enclosure; local exhaust ventilation; general dilution ventilation; personal protective equipment. Operation (2) Use as an insecticidal fumigant on scale insects and beetles. Control (2) Process enclosure; general dilution ventilation; personal protective equipment. Operation (3) Use in analytical chemistry laboratories (test for pyridine, evaluating type of sulfur linkage in vulcanized rubber). Control (3) Local exhaust ventilation; general dilution ventilation; personal protective equipment. [R24, 1981.3] *Clothing contaminated with methyl iodide should be removed immediately. [R19, 4031] *Skin that becomes wet with liquid methyl iodide should be immediately washed or showered with soap or mild detergent and water to remove any methyl iodide. Employees who handle liquid methyl iodide should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. Eating and smoking should not be permitted in areas where liquid methyl iodide is handled, processed, or stored. [R24, 1981.2] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *The worker should immediately wash the skin when it becomes contaminated. [R9, 211] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R9, 211] *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. [R25] *Personnel protection: Keep upwind. Avoid breathing vapors. ... Avoid bodily contact with the material. [R25] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R25] SSL: *COLORLESS LIQUID THAT TURNS YELLOW, RED OR BROWN WHEN EXPOSED TO LIGHT AND MOISTURE. [R28, 1991.1013] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R29] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R30] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R31] STRG: *Keep containers closed and store in a dark place. [R23] *... MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMPOSE INTO TOXIC COMPONENTS DUE TO CONTACT WITH HEAT, MOISTURE, ACID, OR ACID FUMES, SHOULD BE STORED IN COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD AND SHOULD BE PERIODICALLY INSPECTED AND MONITORED. [R32] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. COLLECT FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR SIMILAR MATERIAL. [R24, 1981.3] */In laboratory/ absorb the spills with paper towels, or like materials. Place in hood to evaporate. Dispose by burning the towel. [R23] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U138, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R33] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R34] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of methyl iodide were available. There is limited evidence in experimental animals for the carcinogenicity of methyl iodide. Overall evaluation: Methyl iodide is not classifiable as to its carcinogenicity to humans (Group 3). [R35] ANTR: *Flush eyes thoroughly with water and wash contaminated areas of body with soap and water. Treat skin burns as usual. [R36] MEDS: *Physical examination of workers for placement in operations involving possible exposure to these alkylating agents should include consideration of increased personal risk due to cigarette smoking, pregnancy, or treatment with steroids or cytotoxic agents. /Alkylating agents/ [R37] *IN HUMANS EXPOSED TO METHYL IODIDE, SERUM LIPID CONTENT, ESP THE TRIGLYCERIDE CONTENT WAS SHARPLY INCR, WITH NO APPARENT NERVOUS DISORDER. THUS, BLOOD EXAM, ESP SERUM LIPID, AND FUNCTIONAL EXAM OF LIVER AND KIDNEY, MAY BE USED FOR EARLY DETECTION OF METHYL IODIDE POISONING. [R38] *Initial Medical Examination: A complete history and physical examination: The purpose is to detect pre-existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the central nervous system should be stressed. The skin should be examined for evidence of chronic disorders. Periodic Medical Examination: The aforementioned medical examinations should be repeated on an annual basis. [R24, 1981.1] HTOX: *MAY PRODUCE SEVERE ... /SRP: CNS DEPRESSION/; LUNG IRRITATION FROM ACUTE EXPOSURE. PROLONGED CONTACT WITH SKIN CAN CAUSE VESICANT BURNS. [R39] *APPLICATION OF 1 ML ... UNDER GAUZE DRESSING TO SKIN OF VOLUNTEER FOR 1/2 HR PRODUCED ERYTHEMATOUS REACTION WITH VESICLES 19 HR AFTER APPLICATION ... . [R40] *A 41 YR OLD CHEMIST DEVELOPED METHYL IODIDE INTOXICATION. CHARACTERISTICS OF METHYL IODIDE POISONING INCLUDE DELAY BETWEEN EXPOSURE AND ONSET OF SYMPTOMS, EARLY SYSTEMIC TOXICITY WITH CONGESTIVE CHANGES IN LUNGS AND OLIGURIC RENAL FAILURE, PROMINENT CEREBELLAR AND PARKINSONIAN NEUROLOGIC SYMPTOMS AS WELL AS SEIZURES AND COMA IN SEVERE CASES, AND PSYCHIATRIC DISTURBANCES THAT LAST FROM MONTHS TO YEARS. [R41] *... FROM INHALATION OF VAPOR ... ONE PATIENT FELT WEAK AND DIZZY, WALKING AS THOUGH DRUNK. ... /SRP: DIPLOPIA DEVELOPED HORIZONTALLY AND VERTICALLY/ AND HE STUMBLED OVER OBSTACLES ... INTERMITTENTLY HE THOUGHT HE COULD NOT SEE. ... 8 DAYS LATER EYES WERE ... FOUND NORMAL, AND HE ... HAD NO FURTHER VISUAL TROUBLES. [R42] */IN FATAL POISONING/ ONLY DESCRIPTION CONCERNING EYES WAS OF NYSTAGMOID MOVEMENTS AND SLIGHT RIGHT INTERNAL STRABISMUS ... FUNDI ... SAID TO BE NORMAL. VISION WAS NOT EVALUATED. [R42] *Methyl iodide may cause nausea and vomiting, diarrhea, dizziness, slurred speech, visual disturbances, staggering, shaking, irritability, drowsiness, coma, and death. It may irritate the eyes and lungs. Contact with the liquid may cause irritation and blistering of the skin. [R24, 1981.1] *THERE ARE INDICATIONS OF LUNG IRRITATION AND KIDNEY INVOLVEMENT FROM ACUTE EXPOSURES. [R19, 4031] *Iodomethane acts as a poison attacking the skin, eyes and the CNS via inhalation, ingestion, eye and skin contact. [R43] *A CNS depressant. [R19, 4031] *Methyl iodide induced DNA repair synthesis in cultured human lymphoblastoid cells, as measured by caesium chloride-gradient centrifugation. [R44] */In/ a fatal case of poisoning in a worker exposed to methyl iodide fumes during its manufacture: severe neurological symptoms preceded death; all organs showed congestion at autopsy. [R45] *Non-fatal poisonings affecting workers in methyl iodide manufacture were characterized by the onset of neurological symptoms (such as vertigo, visual disturbances and weakness); these were followed by psychological disturbances and intellectual impairment, which had not been resolved entirely even after several months or years. [R45] *Massive exposure has led to pulmonary edema; prolonged or repeated exposure may cause CNS effects; prolonged contact may cause skin burns. [R46] */Researchers/ reported a fatal case of poisoning from methyl iodide in a chemical plant worker. The signs and symptoms included nausea, vomiting, diarrhea and oliguria, vertigo, slurred speech, visual disturbances, ataxia, tremor, irritability, drowsiness, and coma. [R28, 1991.1013] NTOX: *... /AFTER/ 15 MIN EXPOSURE TO 22 MG/L IN AIR (3790 PPM). RATS DIED WITHIN ... 11 DAYS. LUNG IRRITATION AND PULMONARY EDEMA /WERE NOTED AT NECROPSY/. [R19, 4031] *EXPOSURE OF MICE TO ... LETHAL CNCN OF VAPOR (25-85 MG/L OF AIR) ... CAUSED IMMEDIATE IRRITATION OF EYES ... EXPOSURE TO ... 5 MG/L OF AIR FOR 10 MIN CAUSED NO SIGNS OF IRRITATION OF EYES IN MOST ANIMALS, ALTHOUGH ALL DIED WITHIN NEXT DAY. [R42] *... METHYL IODIDE IS MUTAGENIC TO SALMONELLA TYPHIMURIUM TA100 WHEN PLATES ARE EXPOSED TO VAPORS ... [R41] *THE EFFECT OF METHYL IODIDE ON NERVOUS SYSTEM OF POISONED RABBITS WAS MANIFESTED BY INCREASE SUSCEPTIBILITY TO D-TUBOCURARINE. METABOLIC DISTURBANCES OF ATP, CREATININE PHOSPHATE, LACTATE, PHOSPHATIDYLSERINE AND PHOSPHATIDYLCHOLINE WERE OBSERVED IN BRAIN TISSUES. MOST SERIOUS EFFECT ON BLOOD SYSTEM WAS MARKED INCR OF SERUM TRIGLYCERIDE. [R38] */Iodomethane/ (57 mg/kg/day) was administered sc to male rabbits on two successive days ... induced a marked hyperlipidemia ... /with an/ 11-fold incr in very low density lipoproteins and a three-fold incr in low-density lipoproteins ... /along with an/ enhancement of triglyceride production ... /and an/ incr insulin resistance, and hyperinsulinemia were also observed ... [R47] */Iodomethane/ had little influence on the productivity /of adults of Trogoderma granarium following fumigation of the larvae/. [R48] *... Iodomethane is generally regarded to be carcinogenic in animals. [R49] *The relative toxicity of 7 fumigants to the 4 life cycle stages of Callosobruchus chinensis (a pest of stored cowpeas) was determined in the laboratory. Their relative toxicities to all stages of the insect were phosphine > methyl iodide > acrylonitrile > methyl bromide > ethylene dibromide > methyl formate > ethyl formate. [R50] *A simple rapid determination of glutathione (GSH) and cytoplasmic protein bound SH groups (PBSH), appropriate to study their relationship in tissues, in rat liver, kidney, and testis was developed. Hepatic glutathione and protein bound SH were measured after treatment with methyl iodide (400, 800 mg/kg, after 0.5 hr). ... Methyl iodide ... showed a decrease of glutathione and protein bound SH. [R51] *Blood and liver glutathione levels were measured under the effect of an acute exposure to high doses of glutathione-depleting substances. Among direct-acting glutathione-depleting substances, diethyl maleate (0.3, 0.7, and 1.4 ml/kg) caused a marked reduction of both blood and liver glutathione, whereas methyl iodide (320 mg/kg) led to a decrease in liver glutathione stores immediately and in blood stores with a longer latency. [R52] *The monohalomethanes are alkylating agents and thus have generated concern as to their potential for inducing mutations and cancer. All compounds tested were found to be direct acting mutagens in the Ames test. They also demonstrated the ability to produce cancer in mice and rats. ... On the basis of these data, NIOSH recommends that ... methyl iodide be considered as a potential occupational carcinogen. [R53] *Depigmentation was produced in mice intradermally injected with nitrogen mustard. The effect in C57 black mice was greater than in CBA brown mice, the females being more sensitive than males. Other alkylating agents which caused depigmentation were ... methyl iodide (50 ug). ... Depigmentation was also seen after intradermal injection of known tumor promoters and phenols; however, it was not caused by carcinogens which required metabolic activation even following pretreatment with phenobarbitone or methylcholanthrene to enhance such activation. [R54] *The quantitation of newly induced trifluorothymidine resistant and 6-thioguanine resistant mutants in TK + or - -3.7.2(C) mouse lymphoma cells was analyzed using conventional soft agar cloning and a newly developed technique that allowed for the sequestering, expression, and selection of mutants in Linbro wells. The conventional method of cloning in semi-soft agar supplemented nutrient medium provided maximum mutant frequencies at 1-3 days posttreatment for trifluorothymidine resistance and 5-8 days for 6-thioguanine resistance. The length of time required to reach maximum expression was mutagen- and dose-dependent. Following complete expression, TK-deficient mutants induced by iodomethane declined in frequency. [R55] *Chemical mutagens including iodomethane have been classified as chromosomal mutagens in a L5178Y/thymidine kinase gene mutation assay. ... /The researchers/ observed mutagen-dependent increases in small thymidine kinase-deficient mutant colonies with detectable damage to the chromosome that carries the thymidine kinase locus. In this study, /the authors/ tested these ... chemicals for the induction of gene mutations at the ouabain-resistance (ouares) locus of 3.7.2(C) L5178Y cells to determine if presumptive chromosomal mutagens would go undetected at a gene locus that is unresponsive to chromosomal damage. A final concentration of 375 micrograms/ml ouabain in soft-agar medium selected against the ouabain-sensitive phenotype without loss of the mutagen-induced ouabain-resistant phenotype. Verification of the mutant phenotype was completed for six individual soft-agar ouares colonies derived from mutagen-treated cultures via growth for 10-11 days in nonselective medium followed by retesting for colony formation in selective soft-agar medium. Dose-related reproducible increases in the frequency of ouabain-resistant mutants were observed for 3.7.2(C) L5178Y cells that had been exposed for 3 hr to 1.9-3.6 ug/ml iodomehtane. [R56] *Groups of BD rats (substrain and sex unspecified), about 100 days old, received weekly subcutaneous injections of 10 (16 animals) or 20 mg/kg body weight (eight animals) methyl iodide (purity unspecified) in arachis oil for about one year (total dose, 500 or 900 mg/kg body weight), or a single subcutaneous injection of 50 mg/kg body weight (14 animals), and were observed for life. Four and two animals in the first two groups, respectively, died of pneumonia. Subcutaneous sarcomas occurred in 9/12 rats injected with 10 mg/kg body weight, in 6/6 rats injected with 20 mg/kg body weight and in 4/14 rats given a single injection of 50 mg/kg body weight. No subcutaneous tumor was reported to have occurred in control rats ... injected with arachis oil alone. Local tumors occurred more than one year after the first injection; histologically, these were fibrosarcomas and spindle-cell and round-cell sarcomas. In most cases ... pulmonary and lymph-node metastases were observed. [R57] *Groups of 10 male and 10 female A/He mice, six to eight weeks old, were injected intraperitoneally thrice weekly with three dose levels (the highest being the maximum tolerated dose) of methyl iodide (> 98% pure) in tricapyrylin for a total of 24 injections (total doses, 8.5, 21.3 and 44.0 mg/kg body weight). A group of 30 untreated mice and a group of 160 tricaprylin-treated mice were used as controls. All survivors were killed 24 weeks after the first injection. Survival was 29/30 and 154/160 in the untreated and vehicle-treated control groups and 19/20 in the low-dose, 20/20 in the mid-dose and 11/20 in the higher dose groups. Proportions of mice with lung tumors were 6/29, 34/154, 4/19, 6/20 and 5/11 in the five groups, respectively (p= 0.048; one sided Cochran-Armitage trend test using vehicle controls only). Average numbers of lung tumors per mouse were 0.21, 0.22, 0.21, 0.30 and 0.55. In positive-control groups receiving a single intraperitoneal injection of 10 or 20 mg urethane, all animals developed lung tumors; the average number of lung tumors per animal was 8.1 in the low-dose and 17.8 in the high-dose group. [R58] *Toxic effects ... observed after exposure to methyl iodide include /SRP: CNS depression/, congestion of the lungs, and liver and kidney damage. No death was observed after daily administration of oral doses of 30-50 mg/kg body weight methyl iodide to rats on five days per week for a month. [R59] *Oral administration to rats of methyl iodide reduced nonprotein thiol concentrations in liver and kidney. [R59] *Methyl iodide induces DNA damage and is mutagenic to bacteria in the presence or absence of an exogenous metabolic system. It induces mitotic recombination in yeast. It induces transformation in Syrian hamster embryo cells but not in C3H 10T1/2 cells. [R60] *Iodomethane injected sc into rabbits elevated the basal levels of glucagon and insulin, decreased the response of plasma glucose to injected insulin, and produced abnormal responses in a glucose-tolerance test. With regard to the latter, an iv injection of glucose into the treated animals produced a biphasic increase in plasma glucose, an increase in plasma insulin greater than that of controls, and an increase in glucagon not seen in controls. Thus, iodomethane resulted in disturbances in the mechanisms regulating carbohydrate metabolism. [R61] *Male rabbits were injected sc with 57 mg/kg of methyl iodide for 2 days and their lipid metabolism was examined 48 hr after the last injection. The plasma triglyceride levels increased from the preinjection average of 56.1 mg/dl to 246.0 mg/dl. Analysis of the lipoprotein profile of plasma showed a significant increase of very-low-density lipoproteins. The rate of triglyceride secretion into plasma, measured by Triton WR 1339 injection method, was significantly higher in the animals treated with methyl iodide than in the controls. Histological examination of the liver showed diffuse fat deposits in the hepatocytes without any destructive and inflammatory changes. Thus, hyperlipidemia and fatty liver of rabbits induced by methyl iodide was related to the elevation of triglyceride synthesis and its secretion in the liver. [R62] *Methyl iodide induces ... mutations in cultured mammalian cells. [R60] *... Methyl iodide /is/ about six times as acutely toxic as methyl bromide to mice; the minimal fatal dose with 24 hr exposure being about 75 ppm. ... Ten times as acutely toxic as carbon tetrachloride. [R28, 1991.1013] HTXV: *LD50 Mouse sc 0.78 mmoles/kg [R1, 1039] NTXV: *LCLO Mouse inhalation 78,693 ppm/10 min; [R63] *LCLO Mouse inhalation 18,109 ppm/30 min; [R63] *LD50 RAT ORAL 76 MG/KG; [R64] *LC50 Mouse inhalation 5 mg/l/57 min; [R19, 4031] *LC50 Rat ihl 1300 mg/cu m/4 hr; [R27] *LD50 Rat ip 101 mg/kg; [R27] *LD50 Rat sc 110 mg/kg; [R27] *LD50 Mouse ip 172 mg/kg; [R27] *LD50 Mouse sc 110 mg/kg; [R27] *LD50 Guinea pig ip 51 mg/kg; [R27] ADE: *RETENTION OF INHALED (132)I-METHYL IODIDE IN 18 VOLUNTEERS RANGED FROM 43-92%, WITH MEAN OF 72% OF AMT INHALED; LEVEL WAS HIGHLY DEPENDENT ON RESP RATE, LOW RATES ... ASSOC WITH HIGH RETENTION AND VICE VERSA ... INHALED (132)I-METHYL IODIDE WAS RAPIDLY CLEARED FROM LUNGS OF 4 VOLUNTEERS AND BROKEN DOWN TO RELEASE IODIDE ION. [R40] *ORALLY ADMIN METHYL IODIDE WAS ... EXCRETED IN BILE OF RAT (22-28% OF 50 MG/KG BODY WT DOSE) ... [R41] *IN POISONED RABBITS METHYL IODIDE WAS FOUND IN BRAIN, LIVER AND KIDNEYS. [R38] *Approximately 1% of an oral dose of 76 mg/kg body weight methyl iodide given to rats was expired unchanged within 30 min of administration. [R59] METB: *ORAL DOSES OF IODOMETHANE TO RATS WERE RAPIDLY CONVERTED INTO S-METHYLGLUTATHIONE IN LIVER AND EXCRETED IN BILE. IT WAS DEGRADED TO S-METHYLCYSTEINE BY KIDNEY HOMOGENATES. ONLY A SMALL PROPORTION OF THE DOSE OF IODOMETHANE OR ITS METABOLITE, S-METHYLCYSTEINE, WAS EXCRETED AS A CMPD RELATED TO METHYLMERCAPTURIC ACID. [R64] *Urinary metabolites (2 percent of the total dose) detected after subcutaneous injection of rats with 50 mg/kg body weight methyl iodide were S-methylcysteine, N-acetyl-S-methylcysteine, S-methylthio-acetic acid and N-(methylthioacetyl)glycine. ... S-Methylglutathione was isolated from livers of rats treated orally with 90 mg/kg body weight methyl iodide; approximately 25% of an oral dose of 50 mg/kg body weight was excreted into the bile as S-methylglutathione. ... Liver and kidney homogenates catalyzed the disappearance of methyl iodide in the presence of glutathione ... . S-Methylglutathione was converted to S-methylcysteine by kidney homogenate. [R59] *Methyl iodide reacted in vitro with 4-(para-nitrobenzyl)pyridine and N-7-deoxy- guanosine. [R59] *After inhalation of trace amounts of I-methyl iodide, the disappearance of radioactivity from the plasma, uptake in the thyroid and excretion in the urine resembled that of orally administered inorganic iodide. [R45] ACTN: *Toxicologic and metabolic similarities among the monohalomethanes (chloride, bromide, iodide substituted) suggest a common mechanism of toxic action, probably methylation and disturbance or inactivation of essential proteins (rather than presence of the parent compound or free halide per se). [R65] INTC: *... SYNERGIZES TOXICITY OF FENITROTHION ELEVEN FOLD AND DICHLOROVOS TWO FOLD /IN MOUSE LIVER/. [R66] *S-Methyl-N-acetylpenicillamine, S-methylthiol, and S-methylcysteine, as well as iodomethane decreased biliary excretion of methylmercury markedly. Excretion of sulfhydryl in bile was not influenced by S-methylcysteine, S-methylthiol, S-methyl-N-acetylpenicillamine or a low dose of iodomethane (0.5 mmol/kg). This indicated that coupling of methylmercury to glutathione in the liver before biliary excretion was glutathione S-transferase-dependent reaction and the methylthiols tested, or metabolites of these compounds were likely to be inhibitors of S-transferase. The effect of S-methylcysteine and low doses of iodomethane (1 mmol/kg) seem to deplete the liver of reduced glutathione through S-methylation as illustrated by decreased biliary excretion of sulfhydryl. [R67] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl iodide is produced by marine macroalgae and the ocean is thought to be a major source of methyl iodide. Anthropogenic sources of methyl iodide resulting from its use as a methylating agent are minor compared with biogenic ones. If released to air, a vapor pressure of 405 mm Hg at 25 deg C indicates methyl iodide will exist solely as a vapor in the ambient atmosphere. Methyl iodide will degrade in the atmosphere primarily as a result of photolysis. Its photolytic half-life is 2.8 to 5.5 days. By comparison, its half-life as a result of reaction with photochemically-produced hydroxyl radicals is about is about 220 days. If released to soil, methyl iodide is expected to have very high mobility based upon an estimated Koc of 14. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 0.00526 atm-cu m/mole. Methyl iodide should volatilize from dry soil surfaces based upon its vapor pressure. Ninety-four percent of methyl iodide applied 30 cm below the surface of a soil column was lost through volatilization. Abiotic degradation will occur as a result of hydrolysis and reaction with nucleophilic ions such as chloride ions. The half-life of methyl iodide in soils that were rich in organic matter was 9-13 days, while in a sandy loam soil it was 42-63 days. If released into water, methyl iodide is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.3 hours and 4.8 days, respectively. Methyl iodide hydrolyzes slowly in water with a half-life of 110-251 days at 20-25 deg C in fresh water. In seawater, it reacts with chloride ions and has a half-life of 20 and 58 days at 19.2 and 10.8 deg C, respectively. An estimated BCF of 2.9 suggests that the potential for bioconcentration in aquatic organisms is low. Monitoring data indicate that the general population may be exposed to methyl iodide from the ambient air and from ingesting seafood from the ocean. (SRC) NATS: *Methyl iodide is formed in the sea as a natural product of marine algae; its estimated annual world production is 4X10+10 kg(1). Methyl iodide production rates of varieties of brown (both kelps and nonkelps), red and green marine microalgae have been measured in the laboratory and estimates of oceanic production of methyl iodide made from these production rates(3). As with previous extrapolations, methyl iodide production rates fail to account for estimated oceanic strengths of the chemical. It is suggested that indirect production of methyl iodide via microbial decay of seaweed iodocarbons may fill this gap(3). However, another investigator pointed out that this additional source is much too small(4). Another explanation is that the results of halocarbon production by algae in the laboratory cannot be extended to natural mixed populations. In addition to oceanic emissions, biomass burning has been identified as a minor secondary source of methyl iodide(2). [R68] ARTS: *Methyl iodide's production and use as a methylating agent and in organic synthesis(1) may result in its release to the environment through various waste streams. Methyl iodide can be formed in the environment of nuclear reactors and vented in exhaust gases(1). Anthropogenic sources have not been identified as major contributors of methyl iodide emissions(2). However, methyl iodide has been suggested as a replacement for methyl bromide as a soil fumigant(3). [R69] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 14(SRC), determined from a structure estimation method(2), indicates that methyl iodide should have very high mobility in soil(SRC). Volatilization of methyl iodide from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 0.00526 atm-cu m/mole at 25 deg C(3). The potential for volatilization of methyl iodide from dry soil surfaces may exist based upon a vapor pressure of 405 mm Hg(4). Cumulative volatilization losses of methyl iodide, applied at 30 cm, from 60-cm soil columns packed with a sandy loam soil ranged from 94% when the soil was untarped to 75% with a high-barrier tarp(5). Volatilization losses were significantly lower, 38% and 53%, from soils high in organic matter and capable of rapidly degrading the chemical. Ten days after methyl iodide was applied to field plots (30 cm depth) covered with a polyethylene film, methyl iodide was detected at most depths(5). It was concluded that should the water table be shallow and the degradation rate in soil low, methyl iodide may leach into ground water(5). Methyl iodide abiotically degrades in soil by hydrolysis and reaction with chloride ions, HS- and other nucleophiles(6). The half-life of methyl iodide in soils that were rich in organic matter was 9-13 days, while in a sandy loam soil it was 42-63 days. The organic-rich soils were thought to contain more nucleophiles with which methyl iodide could react(6). [R70] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 14(SRC), determined from an estimation method(2), indicates that methyl iodide is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 0.00526 atm-cu m/mole at 25 deg C(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.3 hours and 4.8 days, respectively(SRC). Methyl iodide hydrolyses slowly in water with a half-life of 110-251 days at 20-25 deg C(8,9). It reacts with chloride ions in seawater in which its half-life is 20 and 58 days at 19.2 and 10.8 deg C, respectively(8). According to a classification scheme(5), an estimated BCF of 2.9(SRC), from its log Kow of 1.51(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. [R71] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methyl iodide, which has a vapor pressure of 405 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase methyl iodide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 220 days(SRC), from its rate constant of 7.20X10-14 cu cm/molecule-sec at 25 deg C(3). However the major loss process for methyl iodide in the atmosphere is direct photolysis. The half-life of this reaction is 2.8-5.5 days(3,4). Physical removal of methyl iodide from air may occur via wet deposition since methyl iodide is relatively soluble in water(SRC). [R72] ABIO: *Methyl iodide hydrolyses slowly in water yielding methanol(2). The half-life under neutral conditions is 110-251 days at 20-25 deg C(1,2), increasing to 4 yr and 23 yr at 10 and 0 deg C respectively(1). More recent measurements yielded a unimolecular hydrolysis rate constant of 7.1X10-8 1/sec at 25 deg C(6). This is equivalent to a half-life of 110 days(SRC). A base-catalyzed reaction is only important at higher pH's than are observed in the environment(2). However, methyl iodide is unstable in seawater, reacting primarily with the chloride ion to form methyl chloride(1). The half-life in seawater of 19.8 parts/thousand chlorinity is 20 and 58 days at 19.2 and 10.8 deg C, respectively(1). More recent studies of the reaction of chloride with methyl iodide reports rate constants for both seawater (33.3 parts/thousand chlorinity) and 0.5 M NaCl in distilled water of 1.0X10-6 L/mol-sec(7). The rate in NaCl corresponds to a half-life of 16 days. Methyl iodide absorbs UV radiation up to approximately 340 nm and photolyses(3). Photolysis occurs in both the gas phase and in solution. In water photohydrolysis occurs forming methanol and iodide ions; in air, iodine is formed(8). When irradiated in pure air (relative humidity 50%), methyl iodide's half-life was 7 hr(4); with added NO2 its half-life was a little over 3 hr(5). The dissipation half-life of methyl iodide from open surface water (30 cm-deep tank) with sunlight irradiation was 26 hours compared with 29 hours indoors. At the end of 6 days, 3.1% of the methyl iodide was recovered as I-; no iodine was detected(8). It was concluded that photodegradation was a minor loss mechanism compared with volatilization. [R73] *The rate constant for the vapor-phase reaction of methyl iodide with photochemically-produced hydroxyl radicals is 7.20X10-14 cu cm/molecule-sec at 25 deg C(1,2). This corresponds to an atmospheric half-life of about 220 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The major reaction pathway should give rise to CH2I radicals and water(2). A pathway leading to the formation of CH3 radicals and HOI is expected to occur, but to a lesser extent(2). The reaction of methyl iodide with hydroxyl radicals is low compared with the photolysis of methyl iodide, whose half-life of 2.8-5.5 days(2,3). Therefore reaction with hydroxyl radicals is a minor tropospheric process compared with photolysis. The rate constant for the vapor-phase reaction of methyl iodide with nitrate radicals is 1.92X10-17 cu cm/molecule-sec at room temperature(4). This corresponds to an atmospheric half-life of about 4.8 yrs(SRC) at an atmospheric concentration of 2.4X10+8 nitrate radicals per cu cm(5). [R74] *Based upon an experimentally determined rate constant of 7.6X10-4/hr, the half-life for the reaction with hydrated electrons (produced by photochemical reaction with dissolved organic matter in water) is about 38 days(2). The hydrolysis rate of methyl iodide in water can be increased by the presence of sulfur nucleophiles(3); the increase is dependent on the nucleophile concn(3). Reaction with HS- has been suggested as an important removal pathway of methyl iodide from a salt marsh(5). The reaction of methyl iodide with dissolved or metal-bound sulfide represents a potential source of environmental dimethyl sulfide(4). Photolysis studies showed that direct photolysis is not as fast in seawater as the SN2 reaction with chloride ion(1); at 29 deg C, the half-life in dark seawater control tubes was 7.8 days while in tubes exposed to Miami sunlight, the half-life was 6.2 days(1); the SN reaction half-life with chloride ion varies dramatically with ocean latitude and depth with half-lives ranging from 6 days in the warmest water to thousands of days in the coldest waters(1). The degradation of methyl iodide in soils was not markedly affected by sterilization implying that degradation occurred by chemical mechanisms(5). The fact that degradation was considerably faster in organic matter-rich soils suggests that other reactions, probably with nucleophilic functional groups, are involved. The half-life in soils that were rich in organic matter was 9-13 days, while in a sandy loam soil it was 42-63 days. [R75] BIOC: *An estimated BCF of 2.9 was calculated for methyl iodide(SRC), using a log Kow of 1.51(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. While methyl iodide has been detected in various fish and shellfish, it is thought that the chemical may have been formed biogenically(4). [R76] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for methyl iodide can be estimated to be 14(SRC). According to a classification scheme(2), this estimated Koc value suggests that methyl iodide should have very high mobility in soil. The soil/water distribution coefficient of methyl iodide in various soils were (soil, Kd): Greenfield sandy loam, 0.09; Linne clay loam, 0.15; Carsetas loamy sand, 0.16; and potting mix, 0.55(3). [R77] VWS: *The Henry's Law constant for methyl iodide is 0.00526 atm-cu m/mole at 25 deg C(1). This Henry's Law constant indicates that methyl iodide should volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.3 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4.8 days(SRC). The Henry's Law constant in seawater of salinity 30.4 g dissolved inorganic matter/kg seawater was 0.00354 atm-cu m/mole at 20 deg C(4) indicating a lower volatization rate for methyl iodide in seawater(SRC). Dissipation of methyl iodide from open surface water was found to be primarily a result of volatilization(4). Experiments conducted under indoor conditions resulted in a first-order half-life of 29 hours under static conditions and 6.5 hours when stirred at low speed with a magnetic stirrer(5). After 6 days, less that 1% of the methyl iodide was detected as iodide ion. Methyl iodide's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). Methyl iodide is expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 405 mm Hg at 25 deg C(3). [R78] *Experiments were conducted to assess the volatilization loss of methyl iodide, applied at 30 cm, from 60-cm packed soil columns with different soils and under various soil surface conditions(1). In Greenfield sandy loam, the greatest cumulative loss occurred in nontarp applications, 94%, and the least in a high-barrier plastic tarp treatment, 75%. Volatilization losses with a polyethylene film was 90% and therefore this treatment was ineffective at preventing volatilization loss. Volatilization losses using a polyethylene film were significantly lower, 38% and 53%, from two soils high in organic matter and capable of rapidly degrading the chemical. [R79] WATC: *SURFACE WATER: Point Reyes, CA - nearshore 37 parts/trillion(1). Atlantic Ocean surface water 135 parts/trillion(2). The avg methyl iodide concn of seawater sampled in the eastern Pacific Ocean in 1981 was 1.6 ng/l(3). Methyl iodide concns were measured in water samples at 58 stations in the northwest Atlantic in April-May 1991(4). Offshore in the upper 50 m, concns ranged from < 0.1 ng/l to 1 ng/l. Levels were relatively high near the Greenland coast, 2.2 ng/l but were relatively low off of Labrador. The highest concns (up to 8.7 ng/l) were seen in the shallow waters of the Grand Banks. Concns decreased sharply with depth, frequently with undetectable levels by 500 m. [R80] EFFL: *Methyl iodide was detected (conc not reported) in air samples collected above a hazardous waste site in NJ(1); its presence is likely the result of volatile emissions from the site(1). [R81] ATMC: *RURAL/REMOTE: US - 286 samples 0-9.2 parts/trillion, 6.7 parts/trillion median(1). Global background 1-3 parts/trillion(2). USEPA Volatile Organics Data Base: Mean concns (parts/trillion): 3 (remote), 7 (rural)(5). Concns of methyl iodide (parts/trillion) recorded during cruises (location/date, mean, range of concn): Western Pacific (n=48) - Sept-Oct. 1992, 0.87, 0.05-5.0; Eastern and southeast Asian seas (n=73) - Jan-Mar, 1994, 0.63, 0.24-2.0(6). 1994 winter measurements and 1991 summer measurements of methyl iodide were taken over the western Pacific basin. At latitudes > 25 deg N, concns were typically between 0.4 and 0.8 parts/trillion(7). By contrast, concns were significantly lower in winter, remaining between 0.2 and 0.4 parts/trillion. Maximum concns in both seasons were below 3 km altitude. URBAN/SUBURBAN: US - 561 samples 3.5 parts/trillion median, 80 part/trillion max(1). USEPA Volatile Organics Data Base: Mean concns (parts/trillion): 7 (suburban), 2 (urban)(5). The following mean (range) concns (parts/trillion) of methyl iodide were monitored in the air of various US cities between 1983 and 1985(2): Philadelphia, PA, 3; Staten Island, NY, 5; Houston, TX, 12 (11-48); Downey, CA, 3 (< 1-10); Denver, CO, 2 (1-8); San Jose, CA, 3-9 (< 1-51)(2,4). Except for some measurements at Houston and under stagnant conditions in San Jose, methyl iodide concns were indistinguishable from natural background levels(2). Levels most frequently measurable in close proximity to the ocean were consistent with the suggestion that its origins are in the ocean(3). No significant man-made sources are known to exist(2). [R82] *Worldwide measurements show that methyl iodide is almost uniformly distributed over the oceans, with avg mixing ratios ranging between 0.002 and 0.003 ppb in the planetary boundary layer(1); in regions of high marine biomass production, avgs are roughly between 0.007 and 0.022 ppb(1); mixing ratios over the continents are generally lower than over the ocean(1). [R83] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Irish Sea - 3 species of mollusks 3-188 ppb methyliodide, 10 ppb median(1). Irish Sea - 5 species of fish 4-166 ppb, 17 ppb median(1). [R84] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2182 workers (439 of these are female) are potentially exposed to methyl iodide in the US(1). Occupational exposure to methyl iodide may occur through inhalation and dermal contact with this compound at workplaces where it is produced or used(SRC). The general population may be exposed to methyl iodide via inhalation of ambient air or ingestion of food, primarily marine seafood(SRC). [R85] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers methyl iodide to be a potential occupational carcinogen. [R9, 210] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (28 mg/cu m). Skin Designation. [R86] *Vacated 1989 OSHA PEL TWA 2 ppm (10 mg/cu m), skin designation, is still enforced in some states. [R9, 368] NREC: *NIOSH considers methyl iodide to be a potential occupational carcinogen. [R9, 210] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R9, 210] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2 ppm (10 mg/cu m), skin. [R9, 210] TLV: +8 hr Time Weighted Avg (TWA) 2 ppm, skin [R87, 49] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R87, 6] OOPL: *Emergency Response Planning Guidelines (ERPG): ERPG(1) 25 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 50 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 125 ppm (not life threatening) up to 1 hr exposure. [R88] *Australia: 2 ppm, Category 3, suspected human carcinogen, skin (1990); Federal Republic of Germany: no numerical limit, Group III A2, unmistakably carcinogenic in animal experimentation only (1992); Sweden: 1 ppm, short-term value 5 ppm, 15 min, skin, carcinogenic (1991); United Kingdom: 5 ppm, 10-min STEL 10 ppm, skin (1991). [R28, 1991.1014] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Methyl iodide is included on this list. [R89] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Halomethanes/ [R90] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R91] RCRA: *U138; As stipulated in 40 CFR 261.33, when methyl iodide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R92] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *On the interaction of iodomethane over silver-exchanged molecular sieves /in its removal from radioactive gaseous wastes/. [R93] *(13)C NMR analysis of charcoal adsorbents: reaction of methyl iodide /from nuclear reactor waste gases/ with the impregnated tris(ethylene diamine). [R94] *A filter for monitoring radioiodine /including iodomethane/ in air. [R95] *NIOSH Method 1014. Analyte: Methyl iodide. Matrix: Air. Sampler: solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 1 l/min: Sample Size: 50 liters. Shipment: routine. Sample Stability: unknown. [R96] ALAB: *Determination of some iodo-alkanes by molecular emission cavity analysis after gas chromatographic separation. [R97] *A selective photometric method is described for determining /iodomethane/ traces in gas filling of halide incandescent lamps based on the formation of iodide(-1) as a result of complete degradation of /iodomethane/ in an iso-propyl alcohol medium in the presence of alkali. ... The relative error is 5%. The method is suitable for iodomethane detection in air, water, and other iodine containing organic media. [R98] *Analytical methods for halogenated C1-C2 halo hydrocarbons include gas chromatography, mass spectrometry, and multiple ion detection. [R99] *AIR; ELECTRON CAPTURE GAS CHROMATOGRAPHY. [R100] *EXHAUST GASES; FLAME IONIZATION GAS CHROMATOGRAPHY. [R100] *NIOSH Method 1014. Methyl iodide by GC/FID. Analyte: Methyl iodide. Matrix: Air. Procedure: Gas chromatography flame ionization detection. For iodomethane this method has an estimated detection limit of 0.01 mg/sample or 0.200 mg/cu m. The precision/RSD is 0.045 at 0.7 to 2.8 mg/sample. Applicability: The working range of this method is 10 to 100 mg/cu m (1.7 to 17 ppm) for a 50 liter air sample. Interferences: None identified. [R101] *EPA OSW Method 8240B. Determination of Volatile Organics by Purge and Trap Gas Chromatography/ Mass Spectroscopy. Estimated quatitation limit 5 ug/l. [R102] *EPA OSW Method 8260A. Determination of Volatile Organics by Purge and Trap, Capillary Column Gas Chromatography/ Mass Spectroscopy. Detection limit not reported. [R102] *EPA EAD Method 1624. Determination of Volatile Toxic Organic Pollutants and Additional Compounds Amenable to Purge and Trap GC/MS. Gas chromatography/mass spectroscopy. Minimum detection level 10 ug/l. 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Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Hunter-Smith RJ et al; Tellus Ser B B35: 170-6 (1983) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Zafiriou OC; J Mar Res 33: 75-81 (1975) (9) Mabey W, Mill T; J Chem Ref Data 7: 383-415 (1978) R72: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Boublik T et al; The Vapour Pressures of Purse Substances. 2nd Rev Ed, Amsterdam: Elsevier (1984) (3) Brown AC et al; Atmos Environ 24A: 361-7 (1990) (4) Zafirious OC; J Geophys Res 79: 2730-2 (1974) R73: (1) Zafiriou OC; J Mar Res 33: 75-81 (1975) (2) Mabey W, Mill T; J Chem Ref Data 7: 383-415 (1978) (3) Calvert JG, Pitts JM Jr; Photochemistry. 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Brookhaven Natl Lab, Upton, NY (1984) (2) Zepp RG et al; Environ Sci Technol 21: 485-90 (1987) (3) Haag WR, Mill T; Environ Toxicol Chem 7: 917-24 (1988) (4) Thayer JS et al; Environ Sci Technol 18: 726-9 (1984) (5) Gan J, Yates SR; J Agric Food Chem 44: 4001-8 (1996) R76: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 3 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Dickson AG, Riley JP; Mar Pollut Bull 7: 167-9 (1976) R77: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Gan J, Yates SR; J Agric Food Chem 44: 4001-8 (1996) (4) Gan J et al; J Environ Qual 26: 1107-15 (1997) R78: (1) Hunter-Smith RJ et al; Tellus Ser B B35: 170-6 (1983) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. 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USEPA/600/3-88/010(a) (1988) (6) Yokouchi Y et al; J Geophys Res 102: 8805-9 (1997) (7) Blake NJ et al. J Geophys Res 102: 28315-31 (1997) R83: (1) Fabian P; pp 23-51 in The Handbook of Environ Chem Vol 4 Part A Berlin: Springer-Verlag, Hutzinger, O ed (1986) R84: (1) Dickson AG, Riley JP; Mar Pollut Bull 7: 167-9 (1976) R85: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R86: 29 CFR 1910.1000 (7/1/99) R87: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R88: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.26 R89: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R90: 40 CFR 401.15 (7/1/99) R91: 40 CFR 302.4 (7/1/99) R92: 40 CFR 261.33 (7/1/99) R93: Belapurkar AD et al; Surf Technol 21 (3): 263-72 (1984) R94: Resing HA et al; Ext Abstr Program-Bienn Conf Carbon 16: 319-20 (1983) R95: Schwarzback R, Hladik O; Kernenergie 27 (1): 25-7 (1984) R96: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1014-1 R97: Burguera M, Burguera JL; Aval Chim Acta 153: 53-60 (1983) R98: Kochetkova TM; Zavod Lab 47 (8): 19-20 (1981) R99: Naka K et al; Mie-ken Kankyo Kagaku Senta Kenkyu Hokoku 3: 14-24 (1982) R100: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V15 248 (1977) R101: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R102: USEPA; Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September 1994 (1997) R103: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1 PC# 4082. Rockville, MD: Goverment Institutes (1997) RS: 78 Record 126 of 1119 in HSDB (through 2003/06) AN: 1340 UD: 200303 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2,3-TRICHLOROPROPANE- SY: *ALLYL-TRICHLORIDE-; *GLYCEROL-TRICHLOROHYDRIN-; *GLYCERYL-TRICHLOROHYDRIN-; *NCI-C60220-; *PROPANE,-1,2,3-TRICHLORO-; *TRICHLOROHYDRIN- RN: 96-18-4 MF: *C3-H5-Cl3 ASCH: Propane, 1,1,1-trichloro; 7789-89-1; Propane, 1,1,2-trichloro; 598-77-6; Propane, 1,2,2-trichloro; 3175-23-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CHLORINATION OF PROPYLENE [R1] *Addition of chlorine to allyl chloride. [R2] MFS: *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 [R3] *Shell Chemical Company, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Production site: Deer Park, TX 77536 (Houston Plant) [R3] OMIN: *As a method of manufacturing, the selectivity of the chlorination of 1,2-dichloropropane to 1,2,3-trichloropropane is not good. [R2] *The reaction with water at high temperature to give glycerol is not employed commercially. [R2] USE: *Paint and varnish remover, solvent, degreasing agent [R1] *In the synthesis of hexafluoropropylene. [R4] *Solvent for oils, fats, waxes, chlorinated rubber, and resins. Synthesis of thiokol polysulfide elastomers if some branching of the polymer structure is required. [R2] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R5] *(1975) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to straw-colored liquid [R6]; +Colorless liquid. [R7] ODOR: *ODOR DESCRIBED AS BEING QUITE SIMILAR TO THAT OF TRICHLOROETHYLENE OR CHLOROFORM [R6]; *Strong acid odor [R8, 887]; +Chloroform-like odor. [R7] BP: *156.85 DEG C [R9] MP: *-14.7 DEG C [R9] MW: *147.43 [R9] CTP: *Critical temp: 652 deg K; critical pressure: 3.87X10+6 Pa [R9] DEN: *1.3889 @ 20 DEG C/4 DEG C [R10] HTC: *-1.5536X10+9 J/kmol [R9] HTV: *4.7998X10+7 J/kmole [R9] OWPC: *log Kow = 2.27 [R11] SOL: *SOL IN ALCOHOL AND ETHER; SLIGHTLY SOLUBLE IN CHLOROFORM [R10]; *Water solubility: 1750 mg/l at 25 deg C [R12] SPEC: *INDEX OF REFRACTION: 1.4852 @ 20 DEG C/D [R10]; *IR: 5859 (Coblentz Society Spectral Collection) [R13]; *NMR: 6769 (Sadtler Research Laboratories Spectral Collection) [R13]; *MASS: 814 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R13] SURF: *3.77X10-2 N/m @ 20 deg C [R2] VAPD: +5.1 (AIR= 1) [R14] VAP: *3.69 @ 25 deg C /calculated from experimentally derived coefficient/ [R9] VISC: *2.5X10-4 Pa s @ 20 deg C [R2] OCPP: *1 mg/cu m= 0.16 ppm; 1 ppm= 6.13 mg/cu m [R15] *Forms azeotropes with camphene, alpha-pinene, and 2,7-dimethyloctane [R16] *Critical molar volume = 0.334 um/kg [R9] *Enthalpy of vaporization (@ bp)= 8.87 kcal/mol; enthalpy of sublimation (@ 298 deg K)= 11.22 kcal/mol [R17] *MASS: 97 (Aldermaston, Eight Peak Index of Mass Spectra, UK) /Propane, 1,1,1-trichloro/ [R13] *IR: 10638 (Sadtler Research Laboratories IR Grating Collection) /Propane, 1,1,2-trichloro/ [R13] *NMR: 3652 (Sadtler Research Laboratories Prism Collection) /Propane, 1,1,2-trichloro/ [R13] *MASS: 815 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Propane, 1,1,2-trichloro/ [R13] *IR: 23715 (Sadtler Research Laboratories Prism Collection) /Propane, 1,2,2-trichloro/ [R13] *NMR: 383 (Varian Associates NMR Spectra Catalogue) /Propane, 1,2,2-trichloro/ [R13] *MASS: 815 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Propane, 1,2,2-trichloro/ [R13] *Henry's Law constant = 3.43E-4 atm-cu m/mole [R18] *Viscosity = 2.505 cP @ 20 deg C; surface tension 37.80 dyne/cm @ 20 deg C; standard heat of combustion -414.77 kcal/mol; heat of vaporization 11.22 kcal/mol @ 25 deg C [R19] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 1,2,3-trichloropropane stem from its toxicologic properties. Toxic by inhalation and dermal contact, exposure to this colorless to straw colored acid smelling liquid may occur from its use as a crosslinking agent in the synthesis of polysulfides, in the synthesis of hexafluoropropylene, as a paint and varnish remover, solvent and degreasing agent. Effects from exposure may include eye and throat irritation. The ACGIH TLV has been set at a TWA of 10 ppm. OSHA has set a PEL of 10 ppm (TWA) to become effective December 31, 1992. Local exhaust ventilation should be used to control exposure. However, in activities where over exposure may occur, wear a self-contained breathing apparatus and personal protective clothing, including gloves, boots and bands around the legs and arms, so that no skin surface is exposed. If contact should occur, wash immediately with soap and remove nonimpervious clothing if contaminated. 1,2,3-Trichloropropane must be moderately heated before ignition will occur (flashpoint: 180 deg F open cup). For fires involving 1,2,3-trichloropropane, extinguish with dry chemical, or water (as a blanket, spray, or mist). 1,2,3-Trichloropropane should be stored in a cool, well ventilated place, out of direct rays of the sun, and away from flames, sparks, active metals, strong caustics, and strong oxidizers. For spills of 1,2,3-trichloropropane, first ventilate the area, then absorb the spill with vermiculite, dry sand, or earth, and collect for reclamation disposal, or incineration. Before implementing land disposal of waste 1,2,3-trichloropropane, consult with environmental regulatory agencies for guidance. FPOT: *Moderate, when exposed to heat, flames (sparks) or powerful oxidizers. [R20] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, incl self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms and waist should be provided. No skin surface should be exposed. [R14] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R14] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R14] FLMT: *Lower, 3.2%; upper 12.6% [R6] FLPT: *180 DEG F (OPEN CUP) [R21] *160-164 deg F (Closed cup) [R6] AUTO: *304 deg C [R22] FIRP: *Water (as a blanket), spray, mist, dry chemical [R20] REAC: *Active metals, strong caustics, strong oxidizers [R8, 887] +Chemically-active metals, strong caustics and oxidizers. [R23, 316] DCMP: *When heated to decomp it emits highly toxic /hydrogen chloride./ [R24] SERI: *Vapors of 1,2,3-trichloropropane were objectionable to all subjects exposed to a concn of 100 ppm because of eye and throat irritation. [R6] EQUP: *Rubber gloves, self contained breathing apparatus and overalls. [R22] +Wear appropriate personal protective clothing to prevent skin contact. [R23, 317] +Wear appropriate eye protection to prevent eye contact. [R23, 317] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R23, 317] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R23, 317] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R23, 317] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R23, 317] OPRM: +Contact lenses should not be worn when working with this chemical. [R23, 317] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Employees should wash immediately with soap when skin is wet or contaminated. Remove nonimpervious clothing immediately if wet or contaminated. Provide emergency showers and eyewash. [R8, 888] *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any possibility of eye contact. [R8, 888] +The worker should immediately wash the skin when it becomes contaminated. [R23, 317] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R23, 317] STRG: *IN GENERAL, MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL, WELL VENTILATED PLACE, OUT OF DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED ... INCOMPATIBLE MATERIALS SHOULD BE ISOLATED FROM EACH OTHER. [R25] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN A SAFE PLACE (SUCH AS A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR THE HOOD DUCTWORK. BURN THE PAPER IN A SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE RECLAIMED OR COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R26] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *1. BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR A SIMILAR MATERIAL AND DISPOSING IN A SECURED SANITARY LANDFILL. 2. BY ATOMIZING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R26] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R8, 888] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1,2,3-trichloropropane. There is sufficient evidence in experimental animals for the carcinogenicity of 1,2,3-trichloropropane. Overall evaluation: 1,2,3-Trichloropropane is probably carcinogenic to humans (Group 2A). In making the overall evaluation, the working group took into account the following evidence: (1) 1,2,3-Trichloropropane causes tumors at multiple sites and at high incidence in mice and rats. (2) The metabolism of 1,2,3-trichloropropane is qualitatively similar in human and rodent microsomes. (3) 1,2,3-Trichloropropane is mutagenic to bacteria and to cultured mammalian cells and binds to the DNA of animals treated in vivo. [R27] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R28, 2002.58] HTOX: *... found that vapors of 1,2,3-trichloropropane were objectionable to all subjects exposed at a concn of 100 ppm because of eye and throat irritation and unpleasant odor. A borderline majority found that a concn of 50 ppm was acceptable for an 8-hr day ... noted that vapors of 1,2,3-trichloropropane were acrid at 50 ppm. [R29, 1991.1628] *Acute/Subchronic neurotoxic effects of 1,2,3-trichloropropane include CNS damage in humans /from table/ [R30] NTOX: *STRUCTURAL AND ENZYMIC CHANGES WERE OBSERVED IN RAT LIVER FOLLOWING INHALATION OF 1,2,3-TRICHLOROPROPANE. SIGNIFICANT MORPHOLOGICAL AND FUNCTIONAL CHANGES WERE OBSERVED IN CENTRAL LOBULAR SECTIONS OF THE LIVER. [R31] *DOMINANT LETHAL STUDIES WERE CONDUCTED IN SPRAGUE-DAWLEY MALE RATS WITH 5 HALOGENATED 3-CARBON COMPOUNDS THAT ARE STRUCTURALLY SIMILAR TO A KNOWN MUTAGEN 1,2-DIBROMO-3-CHLOROPROPANE (DBCP). 15 MALES IN EACH GROUP WERE ADMINISTERED 1,2,3-TRICHLOROPROPANE BY GASTRIC INTUBATION ONCE A DAY FOR 5 SUCCESSIVE DAYS AT 80 MG/KG/DAY. 1,2,3-TRICHLOROPROPANE PRODUCED NEGATIVE RESPONSES FOR INDUCTION OF DOMINANT LETHALS. [R32] *THE PRESENCE OF A DOUBLE BOND IN THE CASE OF 1,2,3-TRICHLOROPROPENE RESULTED IN A HIGHER LEVEL OF DIRECT MUTAGENIC ACTIVITY THAN 1,2,3-TRICHLOROPROPANE, BUT ACTIVATION WITH S-9 RESULTED IN A FURTHER INCREASE IN MUTAGENIC ACTIVITY OF SALMONELLA TYPHIMURIUM STRAIN TA100 WITH THE FORMER CMPD. [R33] *1,2,3-TRICHLOROPROPANE DID NOT PRODUCE PEROXIDATION OF MICROSOMAL LIPIDS AFTER MALE SPRAGUE-DAWLEY RATS RECEIVED A SINGLE INTRAGASTRIC DOSE OF 180 MG/KG. HEPATIC MICROSOMES SHOWED SIGNIFICANT DECREASE IN CYTOCHROME P-450 (AND TO A LESSER EXTENT IN CYTOCHROME B5), AND A SHIFT IN THE COMPOSITION OF MICROSOMAL FATTY ACID, PRIMARILY CHARACTERIZED BY A DECREASE IN ARACHIDONIC ACID AND AN INCREASE IN LINOLEIC ACID. [R34] *INHALATION OF 0.002-2.2 MG 1,2,3-TRICHLOROPROPANE/L BY RATS FOR 1 DAY TO 3 MONTHS CAUSED MORE POLYPLOIDY OF THE HEPATOCYTE NUCLEI THAN DID 1,2-DICHLOROPROPANE. WITH DECREASING CONCN LONGER INHALATION PERIODS WERE REQUIRED FOR OBTAINING SIMILAR EFFECTS. [R35] *CONTINUOUS INHALATION OF 0.4 and 0.8 MG/CU M OF 1,2,3-TRICHLOROPROPANE FOR 7 DAYS CAUSED HEMORRHAGES IN RAT LUNGS WITH DESQUAMATION AND DESTRUCTION OF BRONCHIAL, BRONCHIOLAR AND ALVEOLAR EPITHELIUM. SYMPTOMS WERE MILDER IN COMPARISON WITH 1,2-DICHLOROPROPANE. [R36] *FOLLOWING INCUBATION OF 1,2,3-TRICHLOROPROPANE, NADPH, EDTA, AND HEPATIC MICROSOMES FROM PHENOBARBITAL-INDUCED RATS, DECREASES IN THE LEVELS OF CYTOCHROME P450, BUT NOT CYTOCHROME B5 OR NADPH-CYTOCHROME C REDUCTASE WERE NOTED. MICROSOMAL HEME DECREASED BY 60-100% OF THE DECREASE IN THE LEVELS OF CYTOCHROME P450, INDICATING THAT 1,2,3-TRICHLOROPROPANE DEGRADED THE HEME MOIETY OF CYTOCHROME P450. [R37] *1,2,3-Trichloropropane was the most toxic of 18 chlorinated alkyl hydrocarbons tested in dogs. Three dogs were fasted for 12 hr prior to intragastric admin. One dog received 0.2 ml/kg, one received 0.3 ml/kg, and one received 0.5 ml/kg. All three ... /had CNS depression/ within 1-2 hr and died within 1-2 days. Microscopic examination of the livers revealed fatty vacuolization and centrilobular necrosis. Cloudy swelling, desquamation of the tubular epithelium, and nuclear changes indicative of beginning necrosis were observed in the kidneys. [R38] *Spectrograde (99% pure) 1,2,3-trichloropropane produced liver damage in male CD1 rats. Rats that inhaled 500 ppm concn of the chemical for 4 hr exhibited increased levels of SGOT, SGPT, and ornithine carbamyl transferase 24 and 48 hr after exposure. [R38] *... found 1,2,3-trichloropropane nonirritating to intact and uncovered skin, but highly irritating to rabbit eyes. [R29, 1991.1626] *... demonstrated that the vapors of 1,2,3-trichloropropane were more toxic than those of 1,1,1-trichloropropane. Exposure @ 1000 ppm 1,2,3-trichloropropane killed 5/6 rats after 4 hr, whereas inhalation of 1,1,1-trichloropropane @ 8000 ppm was required to produce similar mortality. [R29, 1991.1626] *EXPOSURE OF RATS AND GUINEA PIGS (5 OF EACH SEX) TO 800, 2100, OR 5000 PPM 1,2,3-TRICHLOROPROPANE FOR 30 MIN RESULTED IN CNS DEPRESSION, WHICH WAS MINIMAL @ 800 PPM BUT PROGRESSED TO ... /FURTHER CNS DEPRESSION/ AND CONVULSIONS @ THE HIGHER CONCN. 2 OF 10 RATS AND 6 OF 10 GUINEA PIGS DIED FOLLOWING EXPOSURE @ 5000 PPM; THE ONLY HISTOPATHOLOGIC LESION OBSERVED @ 14 DAYS POST-EXPOSURE WAS ADRENAL CORTICO-MEDULLARY NECROSIS. MORTALITY IN THE OTHER TWO EXPOSURE GROUPS WAS LIMITED TO 1 MALE RAT EXPOSED @ 2100 PPM; NO IRREVERSIBLE ORGAN LESIONS WERE REPORTED. [R29, 1991.1626] *... Exposure @ 5000 ppm for 20 min killed mice; delayed deaths were attributed to 1,2,3-trichloropropane-induced hepatic damage ... reported elevated liver enzymes following a single 4-hr exposure @ 500 ppm of the vapor. Groups of 6 rats and mice subjected to single 4-hr exposure @ 0, 125, 340, 700, or 2150 ppm showed concn-dependent mortality. All rats and mice exposed @ 700 or 2150 ppm died, as did mice exposed @ 340 ppm. There were signs of dyspnea, lethargy, and ocular and upper respiratory tract irritation; these signs were also observed @ 125 ppm, but to a lesser degree. Except for a 10% reduction in body weight, there was little evidence for specific injury at necropsy. Daily 10-min exposures @ 2500 ppm 1,2,3-trichloropropane for 10 days killed 7/10 mice. [R29, 1991.1626] *ANESTHETIZED DOGS, RATS, MICE, MONKEYS, HAMSTERS AND RABBITS EXPOSED TO CONCN RANGING FROM 5,000-150,000 PPM HAVE SHOWN VARIOUS CARDIOVASCULAR AND CIRCULATORY ABNORMALITIES. [R39] *Rats given 113 or 149 mg/kg 1,2,3-trichloropropane in drinking water for 13 wk developed renal pyknosis, glomerular adhesions, and accumulated protein in the tubular lumen. [R29, 1991.1626] *In a 120-day study, Fischer 344 rats received daily oral intubations with corn oil soln of 1,2,3-trichloropropane @ 0, 8, 16, 32, 63, 125, or 250 mg/kg. Both sexes had 100% survival at 63 mg/kg. At 125 mg/kg, survival was also very high: males, 18/19 at 60 days and 9/9 at 120 days; females, 18/20 at 60 days and 7/9 at 120 days. All rats of both sexes fed 250 mg/kg/day died, and reductions in body weight occurred at 63 mg/kg/day but not at lower doses. These changes were consistent with the hunched appearance, depression, and abnormal eye secretions and urine stains at 125 and 250 mg/kg/day in both sexes and at 63 mg/kg/day in only the female rats. There was remarkably little gross pathology in animals at termination of the study. One fourth of the rats exposed at 250 mg/kg/day and sacrificed in extremis had mottled livers, irritation of the glandular portion of the stomach, and darkening and reddening of the renal medulla. Liver and liver-to-body weight ratios were increased in the 32, 63, and 125 mg/kg males and in the 16, 32, 63, and 125 mg/kg females; kidney and kidney-to-body-weight ratios were increased in both sexes at 63 and 125 mg/kg/day. Statistically significant increased inflammation in nasal mucosa occurred at 63 and 125 mg/kg. Hematological changes, depressed erythrocyte count, and hematocrit were consistent with the hepatic and renal injury; the lowest-observed-adverse-effect level (LOAEL) in this regard was 16 mg/kg. [R29, 1991.1626] *Groups of B6C3F1 mice given oral 1,2,3-trichloropropane showed that 19/20 survived 63 mg/kg/day for 60 days and 10/10 survived for 120 days. Animals exposed at 32 mg/kg/day appear to be unaffected; however, the liver, kidneys, gastric mucosa, and nasal passages developed histologically detectable damage at higher doses. [R29, 1991.1627] *Groups of 5 rats of each sex were exposed 6 hr/day, 5 days/wk @ 0, 100, 300, 600, or 900 ppm 1,2,3-trichloropropane for 4 wk. After a single exposure, 9 rats died in the 900 ppm groups, 3 died in the 600 ppm group, and 1 died in the 300 ppm group. Spleen weights for females exposed @ 300 ppm and ovarian weights for those that inhaled 300 or 600 ppm were reduced compared to those of the concurrent controls. Liver weights were increased in rats exposed @ 100 ppm or higher. [R29, 1991.1627] *In a 13-wk study, 15 rats of each sex inhaled 1,2,3-trichloropropane @ 5, 15, or 50 ppm for 6 hr/day, 5 days/wk; no treatment-related deaths occurred. Liver weights increased at all concn. Hepatocellular hypertrophy was present in males and splenic hematopoiesis occurred in females at all exposure levels. Lung hyperplasia occurred in rats exposed @ 5 or 15 ppm. No gross or microscopic treatment-related findings could be detected in rats that had inhaled 0, 0.5, or 1.5 ppm 1,2,3-trichloropropane for 13 wk. [R29, 1991.1627] *... Intermittent 4-hr exposures for 11 days @ 3 ppm of 1,2,3-trichloropropane caused a decreased thickness of olfactory epithelium in rats. A degeneration of the olfactory epithelium was found in rats @ 10 ppm or higher concn, and inflammation and decreased thickness of the olfactory epithelium were found in mice @ 10 to 13 ppm with degeneration at higher concn. [R29, 1991.1627] *... Report morphologic and metabolic changes in liver, kidney, and lung of mice and rats exposed continuously @ concn as low as 0.007 and 0.3 ppm. [R29, 1991.1627] *... Groups of F344 rats and B6C3F1 mice were administered 1,2,3-trichloropropane in corn oil by gavage 5 days/wk. Rats received 0, 3, or 10 mg/kg for 103 wk (males) or for 104 wk (females), or they received 30 mg/kg for 76 wk (males) or for 65 wk (females). Mice received 0 or 6 mg/kg for 103 wk (males) or for 104 wk (females), 20 mg/kg for 89 wk (males and females), at 60 mg/kg for 79 wk (males) or for 73 wk (females). At termination of the study, increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas of the pancreas and kidney, and adenoma or carcinoma of the preputial gland in treated male rats were recorded. In the treated female rats, there were increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenoma or carcinoma of the clitoral gland, and increased numbers of mammary adenocarcinomas. In treated male mice, there were increased incidences of squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas, and harderian gland adenomas. In treated female mice, there were increased incidences of squamous cell carcinomas of the oral mucosa, squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas, harderian gland adenomas, and uterine adenomas, adenocarcinomas, and stromal polyps. [R29, 1991.1627] *... 15 Daily doses of 37 mg/kg were given by ip injection to pregnant Sprague-Dawley rats throughout implantation and organogenesis; there were no fetotoxic or teratogenic effects in the offspring, but maternal toxicity was evident ... male Sprague-Dawley rats given 5 oral doses of 80 mg/kg/day showed no evidence of testicular toxicity. In a one-generation reproduction study, progeny indices were unaffected by treatment with 1,2,3-trichloropropane. [R29, 1991.1627] *1,2,3-Trichloropropane induced mutations in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535 only in the presence of a rodent hepatic activation (S9) system ... the substance was mutagenic in strains TA97, TA100, TA1535, and TA97 only in the presence of S9; for strain TA1537, there was no increase in revertants either in the presence of absence of hepatic activation. 1,2,3-Trichloropropane was positive in the mouse lymphoma assay. The substance was positive in cultured Chinese hamster ovary (CHO) cells for the induction of chromosomal aberrations and sister-chromatid exchanges. Repeated oral intubation @ 80 mg/kg/day failed to induce dominant lethal mutations in rats. Covalent binding of [14C]1,2,3-trichloropropane equivalents to rat hepatic protein, RNA, and DNA occurs in conjunction with DNA clastogenesis in the same organ. [R29, 1991.1627] *...Have been tested externally on the eyes of rabbits, and according the degree of injury observed after 24 hours, have been rated on a scale of 1 to 10. The most severly injurious have been rated 10. 1,2,3-Trichloropropane rated 4 on rabbit eyes. [R40] *... The systemic toxicology of 1,2,3-trichloropropane was evaluated after subacute or subchronic exposure in male and female Sprague-Dawley rats. Animals were treated with 0.01, 0.05, 0.20 and 0.80 mmol/kg/day for 10 days and 0.01, 0.05, 0.10 and 0.40 mmol/kg/day for 90 days. Chemical exposure was by oral gavage in corn oil. Lethality did not occur in either study. Toxicity was observed primarily in the high dose group of subacute and subchronically treated rats of both sexes. Weight gain suppression occurred at a dose of 0.8 mmol/kg/ (118 mg/kg) after 10 days. After 90 days of exposure to 0.40 mmol/kg, the final body weights were 81 and 86% of control values for males and females, respectively. When major organ weights were normalized by body weight, liver and kidney values were generally increased relative to control in the two highest dose groups after 10 and 90 day chemical exposure. Serum chemistries and histopathology indicated a mild hepatotoxic response to 1,2,3-trichloropropane in the high dose group of each study but did not support any renal toxicity. Thymic weight reduction due to atrophy occurred at 10 days of exposure in high dose groups but was normal in all groups after the 90 day treatment. The primary histological finding in this study was an inflammation associated cardiopathy produced by 1,2,3-trichloropropane. Myocardial necrosis and degeneration occurred in a diffuse pattern with marked eosinophilia of affected cells. Male and female animals showed a cardiopathic response only at a dose of 0.8 mmol/kg 1,2,3-trichloropropane after the 10 day exposure. [R41] NTXV: *LD50 Rat, oral, 505 mg/kg; [R29, 1991.1626] *LD50 Rabbit, oral, 380 mg/kg; [R29, 1991.1626] *LD50 Guinea pigs, oral, 340 mg/kg; [R29, 1991.1626] *LD50 Mouse, oral, 369 mg/kg; [R29, 1991.1626] *LD50 Rat oral 450 mg/kg (0.32 ml/kg); [R29, 1991.1626] *LD50 Rabbit percutaneous 2500 mg/kg (1.77 ml/kg); [R29, 1991.1626] ETXV: *LD50 Poecilia reticulata (guppies) 42 ppm 7 day exposure /Conditions of bioassay not specified/; [R15] NTP: *... Groups of 60 male and 60 female F344/N rats received 0, 3, 10 or 30 mg/kg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days/wk for up to 104 wk. Groups of 60 male and 60 female B6C3F1 mice received 0, 6, 20 or 60 mg/kg body weight 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days/wk for up to 104 wk. ... Under the conditions of these two yr gavage studies, there was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male F344/N rats based on incr incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas of the pancreas and kidney, adenomas and carcinomas of the preputial gland, and carcinomas of the Zymbal's gland. Adenomatous polyps and adenocarcinomas of the intestine may have been related to chemical admin. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female F344/N rats based on incr incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas or carcinomas of the clitoral gland, adenocarcinomas of the mammary gland, and carcinomas of the Zymbal's gland. Adenocarcinomas of the intestine may have been related to chemical admin. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male B6C3F1 mice based on incr incidences of squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, and harderian gland adenomas. Squamous cell papillomas of the oral mucosa may have been related to chemical admin. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female B63CF1 mice based on incr incidences of squamous cell carcinomas of the oral mucosa, squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, Harderian gland adenomas, and uterine adenomas, adenocarcinomas, and stromal polyps. [R42] +1,2,3-Trichloropropane (TCP) administered via gavage in corn oil, was tested for its effects on fertility and reproduction in Swiss CD-l mice according to the Continuous Breeding Protocol. Based on results of a dose-finding study (Task 1), 30, 60, and 120 mg/kg bw were chosen to investigate effects on fertility and reproduction. Male and female mice were continuously exposed for a 7-day precohabitation and a 98-day cohabitation period (Task 2). Subsequently, the control and 120 mg/kg groups were used in a cross-over mating trial (Task 3) to determine the sex affected by chemical treatment. The F1 generation from control, 30 and 60 as well as 120 mg/kg groups were also evaluated (Task 4). TCP treatment caused a dose-related impairment of fertility. In the high dose group, fewer pairs delivered third, fourth, and fifth litters and the litters had fewer live pups. Parental body weights were not decreased during Task 2 and 3. During Task 3, treated females mated to control males produced fewer live pups. In both male and female F0 mice, liver weights were increased; female kidney and ovary weights were reduced, and epididymal weight was slightly reduced in the high dose group. Sperm parameters were unchanged. The fertility index in the second generation pups fed TCP was also significantly reduced. The number of pups trended lower at the high dose, while other fertility endpoints remained unchanged. Some of the interesting findings of the present study included (1) clear demonstration of a progressive effect on fertility and reproduction by TCP treatment (2) a significant reduction in the proportion of male pups born alive in the 120 mg/kg group in the 5th litter. In summary, there is clear evidence that TCP at 120 mg/kg is a reproductive toxicant in Swiss mice in the presence of mild systemic toxicity. [R43] TCAT: ?Toxicity of 1,2,3-trichloropropane (TCP) with respect to testicular changes was evaluated in male albino Wistar rats (10/treated group, 20 in arachis oil vehicle control group) exposed orally to TCP by gavage at dosage levels of 15 or 60 mg/kg/day for 14 days. On day 15, the animals were sent for pathological examination. Significant differences between treated and control animals were observed only in reduced body weights (high-dose level). No significant differences between treated and control animals were observed in the following: testes weights, morphology, or detailed macroscopic and microscopic examination of the kidneys, testes, epididymides, ductuli efferentes, and vasa deferentes. [R44] ADE: */Following oral or parenteral admin of 1,2,3-trichloropropane (TCP) in Fischer 344 rats/ ... Excretion was nearly complete (90% of the dose) in 24 hr and was predominantly via the urine (47% of the dose). Expiration was the only route by which unchanged TCP (5% of the dose) was excreted. In addition, 25% of the dose was excreted as carbon dioxide. Some 50% of the radioactivity of 13C-labeled 1,2,3-trichloropropane was excreted in urine within 48 hr of a single 30 mg/kg ip dose, but no single metabolite accounted for more than 10% of the dose, suggesting that the cmpd had entered into normal metabolic routes. [R29, 1991.1628] *... Following acute oral exposure of male and female F344 rats (30 mg/kg) and male B6C3F1 mice (30 and 60 mg/kg), 1,2,3-trichloropropane was rapidly absorbed, metabolized, and excreted. The major route of excretion of 1,2,3-trichloropropane was in the urine. By 60 hr postdosing, rats had excreted 50% and mice 65% of the admin dose by this route. Exhalation as (14)C02 and excretion in the feces each accounted for 20% of the total dose in 60 hr rats and 20 and 15%, respectively, in mice. No apparent sex-related differences were observed in the ability of the rats to excrete 1,2,3-trichloropropane derived radioactivity. At 60 hr, 1,2,3-trichloropropane derived radioactivity was most concentrated in the liver, kidney, and forestomach in both rats and male mice. Male mice eliminated 1,2,3-trichloropropane derived radioactivity more rapidly than rats and lower concentrations of radioactivity were found in tissues 60 hr after dosing in mice. ... [R45] METB: */Following oral or parenteral admin of 1,2,3-trichloropropane (TCP) in Fischer 344 rats/ ... No parent 1,2,3-trichloropropane could be detected in urine, but metabolites included S-(3-chloro-2-hydroxypropyl)cysteine, 2,3-dichloropropionic acid, and N-acetyl-S-(3-chloro-2-hydroxypropyl)cysteine. [R29, 1991.1638] *Rat and human hepatic microsomes metabolized 1,2,3-trichloropropane in vitro to the direct-acting genotoxin, 1,3-dichloroacetone, at 0.268 and 0.026 nmol/min/mg protein, respectively. 1,2,3-Trichloropropane was reduced to 1,3-dichloro-2-propanol and 2,3-dichloropropanol was produced in vitro; reactive metabolites were covalently bound in a linear, time-dependent fashion to microsomal protein. The reactive, intermediate metabolites have been held responsible for depletion of reduced cellular glutathione (GSH), hepatotoxicity, and carcinogenicity. The interaction of the metabolites of 1,2,3-trichloropropane with GSH is complex in that GSH conjugation appears to underlie covalent biding with hepatic DNA, but it prevents the reactions with hepatic protein. [R29, 1991.1628] *The metabolism of 1,2,3-trichloropropane was investigated in vitro in rat and human liver microsomes and rat liver cytosols. Male F344 rats were pretreated with phenobarbital in drinking water for 6 days at a 0.1% concn followed by the ip admin of beta-naphthoflavone and dexamethasone for 3 days at 80 and l00 mg/kg, respectively. Microsomes were prepared from rat livers and human liver samples from organ donors or patients at surgery by differential centrifugation. Livers from untreated rats were used for the preparation of cytosols. Microsomes or cytosols were incubated with radiolabeled 1,2,3-trichloropropane, and metabolites were identified. The /results/ suggested that microsomal metabolism of 1,2,3-trichloropropane to 1,3-dichloropropane was catalyzed via cytochrome p450. This metabolism was dependent on NADPH. The rate of formation of 1,3-dichloropropane was incr by the induction of rat hepatic cytochromes p450 through the pretreatment of rats with phenobarbital or dexamethasone. Pretreatment with beta-naphthoflavone caused a 50% decr, possibly due to a preferential induction of isozymes of cytochrome p450 not involved in 1,2,3-trichloropropane metabolism but suppressing those isozymes which were involved. Two 1,2,3-trichloropropane related alcohols, 1,3-dichloro-2-propanol and 2,3-dichloropropanol, were formed when alcohol dehydrogenase and NADH were added to microsomal incubations. The binding of 1,2,3-trichloropropane equivalents to rat hepatic microsomal protein was incr eight times when hepatic microsomes from phenobarbital pretreated animals were used. This binding was inhibited by the addition of either glutathione or N-acetylcysteine to the incubations. The only N-acetylcysteine conjugate detected in the presence of N-acetylcysteine was 1,3-(2-propanone)-bis-S-(N-acetylcysteine) which represented 87% of the 1,2,3-trichloropropane microsomal metabolism. [R46] BHL: *Metabolism was extensive with elimination half-times of 20 and 120 min for kidney and fat, respectively, following iv administration. A subsequent slower elimination phase, with half-times of 87 to 182 hr, was required, suggesting slower excretion of metabolites as compared with parent cmpd. [R29, 1991.1628] INTC: *CONTINUOUS INHALATION OF TRIPLE MIXTURES OF 4.5-680 MG 1,2-DICHLOROPROPYLENE PLUS 2.0-270 MG 1,2,3-TRICHLOROPROPANE PLUS 3.5-1200 MG PERCHLOROETHYLENE/CU M FOR 7-86 DAYS EXERTED AN ADDITIVE PATHOLOGIC EFFECT ON RATS. HIGH CONCN OF THE MIXTURES AND THEIR SINGLE COMPONENTS STIMULATED DESQUAMATION AND PROLIFERATION IN THE LUNGS, AND STIMULATED THE MACROPHAGAL SYSTEM. HEPATOCYTE DYSTROPHY, ASSOCIATED WITH A DECREASE IN THE RNA LEVEL AND INHIBITION OF SUCCINATE DEHYDROGENASE, NAD DIAPHORASE, AND NADP DIAPHORASE, OCCURRED IN THE CENTRAL PORTIONS OF THE LOBES. [R47] *Concurrent 4 hr inhalation exposure of male CD1 rats to 1,2,3-trichloropropane @ 500 ppm and 1,2-dichloropropane @ 1,000 ppm resulted in additive increases in SGOT and ornithine carbamyl transferase. By 48 hr after exposure, the increases were significantly less than additive. [R38] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2,3-Trichloropropane may be released to the environment in emissions and wastewater as a result of its manufacture, transport, storage, and use as a solvent for oils, fats, waxes, chlorinated rubber, and resins and in the synthesis of some thiokol polysulfide elastomers. If released to soil, 1,2,3-trichloropropane would be expected to leach and volatilize from both dry and moist soil. In one study, its volatilization half-life from soil was 2.7 days. 1,2,3-Trichloropropane has a high Henry's Law constant and should readily volatilize from water. Its estimated half-life in a model river and model lake are 6.7 hr and 5.7 days, respectively. Due to its low adsorptivity, it would not adsorb to sediment or particulate matter in the water column. 1,2,3-Trichloropropane is resistant to biodegradation and hydrolysis and therefore these fate processes should not be important in soil or the aquatic environment. It would not be expected to bioconcentrate in aquatic organisms. In the atmosphere, 1,2,3-trichloropropane will react with photochemically-produced hydroxyl radicals resulting in an estimated half-life of 46 days. Due to its high water solubility, 1,2,3-trichloropropane will be subject to washout by rain. The combination of volatilization, washout, and resistance to degradation should result in a recycling of 1,2,3-trichloropropane among the environmental compartments. Exposure to 1,2,3-trichloropropane will be primarily occupational via inhalation of vapors and dermal contact. (SRC) NATS: *1,2,3-Trichloropropane is an anthropogenic compound, and is not known to exist as a natural product. (SRC) ARTS: *1,2,3-Trichloropropane may be released to the environment in emissions and wastewater(SRC) as a result of its manufacture, transport, storage, and use as a solvent for oils, fats, waxes, chlorinated rubber, and resins and in the synthesis of some thiokol polysulfide elastomers(3). It is also found as an impurity in nematicides and soil fumigants and will be released when these products are used(1,2). [R48] FATE: *TERRESTRIAL FATE: 1,2,3-Trichloropropane has low adsorptivity to soil (Koc 77-95(2)) and would readily leach. It has an appreciable vapor pressure, 3.1 mm Hg at 25 deg C(3,SRC), and Henry's Law constant, 3.43X10-4 atm cu-m/mol at 25 deg C(3) and should readily volatilize from dry and moist soil. When 1,2,3-trichloropropane was incubated in Captina silt loam and McLaurin sandy loam soils in the dark at 20 deg C for 7 days, its disappearance half-life from the soils was 2.7 days, a value that was independent of soil type and whether the soil was active or sterile(5). It is possible that 1,2,3-trichloropropane was lost when the incubation jars were flushed with air that passed through a charcoal filled tube fastened to the jar(SRC). The resistance of 1,2,3-trichloropropane to both biodegradation(4) and hydrolysis(6) indicate that they will not be important fate processes. [R49] *AQUATIC FATE: If released to water, 1,2,3-trichloropropane should be readily removed by volatilization. Using the Henry's Law constant for 1,2,3-trichloropropane, 3.43X10-4 atm-cu m/mol at 25 deg C(2), its estimated volatilization half-life from a model river and model lake are 6.7 hr and 5.7 days, respectively(1,SRC). The Koc values for 1,2,3-trichloropropane are of the order of 77-95(3) and therefore adsorption to sediment would not be expected to be an important transport process. Similarly, with a BCF of 5-13(4), 1,2,3-trichloropropane should not bioconcentrate in fish. 1,2,3-Trichloropropane is resistant to both biodegradation(4) and hydrolysis(5). [R50] *ATMOSPHERIC FATE: If released to the atmosphere, 1,2,3-trichloropropane would exist as a vapor due to its high vapor pressure, 3.69 mm Hg at 25 deg C(2) and react with photochemically-produced hydroxyl radicals resulting in an estimated half-life of 46 days(1,SRC). The water solubility of 1,2,3-trichloropropane, 1750 mg/L at 25 deg C(3) suggests that washout by rain may be an important pathway for atmospheric removal(SRC). [R51] BIOD: *1,2,3-Trichloropropane (100 ppm) was found to be resistant to microbial degradation using the standard biodegradability test of the Japanese Ministry International Trade and Industry (MITI), a BOD test utilizing a mixed inoculum of activated sludge, sewage and surface water(1). No degradation occurred over the 4-week test period. 1,2,3-Trichloropropane showed little degradation in an anaerobic serum bottle test over a 60 day period(2). It was one of 12 chlorinated aliphatic compounds (1-3 carbons) in the test mixture. Almost complete removal was obtained in a 7-day aerobic bottle test with methanogenic cultures, but not with phenol-adapted cultures(2). [R52] ABIO: *The experimental neutral and basic hydrolysis rate constants for 1,2,3-trichloropropane at 25 deg C are 1.8X10-6 1/hr and 9.9X10-4 1/M-hr, respectively(1). This translates to a half-life of about 44 years in water at pH 7(SRC). Because of its high vapor pressure, 3.69 mm Hg at 25 deg C(3), 1,2,3-trichloropropane will exist as the vapor in the atmosphere(4). It will react with photochemically-produced hydroxyl radicals with an estimated rate constant of 5.89X10-13 cu cm/molecule-s(2). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of 1,2,3-trichloropropane in the atmosphere would be 46 days(SRC). [R53] BIOC: *In an 8-week test performed at two concn levels, the BCF of 1,2,3-trichloropropane in carp was 5.4 - 12 (0.2 ppm) and 5.3 - 13 (0.02 ppm)(2). A bioconcentration factor of 31 can be estimated for 1,2,3-trichloropropane from its log Kow, 2.27(2) using a recommended regression equation(1,SRC). Therefore, 1,2,3-trichloropropane would not be expected to bioconcentrate in aquatic organisms(SRC). [R54] KOC: *The partition coefficient of 1,2,3-trichloropropane to captina silt loam (pH 4.97, 1.49% OC) and McLaurin sandy loam (pH 4.43, 0.66% OC) soils were 1.41 and 0.508, respectively(3). The respective calculated Koc values are 95 and 77(SRC). A Koc of 72 can be estimated for 1,2,3-trichloropropane from its water solubility, 1750 mg/L(4) using a recommended regression equation(1). According to a suggested classification scheme(2), these Koc values indicate that 1,2,3-trichloropropane would be highly mobile in soil(SRC). [R55] VWS: *Experimental half-lives for volatilization of 1,2,3- trichloropropane from fresh water lakes and sea water obtained in the laboratory are 92 and 93 minutes, respectively (theoretical values 106 and 114 minutes, respectively); (initial conditions 1 mg/l in a cylinder 106 mm diameter x 148 mm deep)(1). The Henry's Law constant for 1,2,3-trichloropropane is 3.43X10-4 atm-cu m/mol at 25 deg C(1). Using this value of the Henry's Law constant, one can estimate a volatilization half-life for 1,2,3-trichloropropane in a model river 1 m deep flowing at 1 m/s with a wind speed of 3 m/s(3) of 6.7 hr(SRC). Similarly, the volatilization half-life of 1,2,3-trichloropropane from a model lake 1 m deep, with a 0.05 m/s current and a 0.5 m/s wind(3) is estimated to be 5.7 days(SRC). Another estimation of its volatilization half-life from a model pond(4) is 88 hours(SRC). The experimental half-life for volatilization from a rapidly stirred solution in the laboratory (initial concn 1 ppm, 25 deg C, average depth - 6.5 cm) was measured to be 56.1 minutes(5). The combination of a high Henry's Law constant, high vapor pressure, 3.69 mm Hg at 25 deg C(2) and low soil adsorptivity indicates that volatilization from moist and dry soil should be an important fate process(3). [R56] WATC: *SURFACE WATER: 1,2,3-Trichloropropane was qualitatively found in 4 samples (2 in summer and 2 in winter in Narragansett Bay, RI(1) in 1979-81(1). In 1989, 1,2,3-trichloropropane was found at 1 station of the main stream Rhine delta, 0.066 and 0.027 ug/L in May and Sept, respectively; no 1,2,3-trichloropropane was detected at 2 other stations on the main stream Rhine delta and 2 stations on branches of the Rhine(2). [R57] *GROUNDWATER: Detected in groundwater samples in CA and HI at a concn ranging 0.1-5.0 ug/L(1,2). 1,2,3-Trichloropropane has been found in small-scale and large-scale retrospective studies of Californian and Hawaiian groundwater, including wells in Oahu and the Central Valley of California. Typical positive values were 0.2 and 2 ppb, respectively(2,3). In 1983-84, it was found in all nine wells sampled on Oahu, HI(4). The maximum detected concns were 300-2800 ng/L(4). 1,2,3-Trichloropropane was not detected in groundwater samples at 25 municipal and industrial landfills in Wisconsin (detection limit not reported)(5). The concn range of 1,2,3-trichloropropane in 52 samples of bore water (7-68 m) in Drenthe, The Netherlands was < 0.05 to 9.1 ug/L with a mean of 1.0 ug/L(6). [R58] *DRINKING WATER: 1,2,3-Trichloropropane was listed as being qualitatively identified in drinking water(2). It has been detected at a concn of 0.2 ug/L in drinking water taken from the Carrollton Water Plant in New Orleans, LA, 1974(1). It was also qualitatively determined in drinking water samples in Cincinnati, OH(3) and Ames, IA(4). [R59] EFFL: *1,2,3-Trichloropropane was qualitatively determined at an advanced wastewater treatment plant in Lake Tahoe, CA, 1974(1). [R60] SEDS: *1,2,3-Trichloropropane has been qualitatively identified in small-scale and large-scale retrospective studies in Californian and Hawaiian soil samples(1,2). [R61] RTEX: *Exposure to 1,2,3-trichloropropane will be primarily occupational via inhalation of vapors and dermal contact. The general population may be exposed to 1,2,3-trichloropropane in drinking water. (SRC) *NIOSH (NOES Survey 1981-1983) has statistically estimated that 492 workers are exposed to 1,2,3-trichloropropane in the USA(1). [R62] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers 1,2,3-trichloropropane to be a potential occupational carcinogen. [R23, 316] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 50 ppm (300 mg/cu m). [R63] +Vacated 1989 OSHA PEL TWA 10 ppm (60 mg/cu m) is still enforced in some states. [R23, 372] NREC: +NIOSH considers 1,2,3-trichloropropane to be a potential occupational carcinogen. [R23, 316] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R23, 316] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (60 mg/cu m), skin. [R23, 316] TLV: +8 hr Time Weighted Avg (TWA): 10 ppm, skin. [R28, 2002.58] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R28, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R28, 2002.58] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. 1,2,3-Trichloropropane is produced, as an intermediate or final product, by process units covered under this subpart. [R64] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 40 ug/l [R65] STATE DRINKING WATER STANDARDS: +(HI) HAWAII 0.8 ug/l [R65] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 42 ug/l [R65] +(CT) CONNECTICUT 0.05 ug/l [R65] +(FL) FLORIDA 42 ug/l [R65] +(ME) MAINE 40 ug/l [R65] +(MN) MINNESOTA 40 ug/l [R65] +(WA) WASHINGTON 21 ug/l [R65] +(WI) WISCONSIN 60 ug/l [R65] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2,3-trichloropropane is included on this list. [R66] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 1003: Sampler: solid sorbent tube (coconut shell charcoal); flow rate: 0.01-0.2 l/min; minimum air sample volume: 0.6 l @ 50 ppm; maximum air sample volume: 60 l; sample stability: not determined; field blanks: 10% of samples. High humidity during sampling will prevent organic vapors from being trapped efficiently on the sorbent and greatly decreases breakthrough volume. [R67] ALAB: *NIOSH 1003: Technique: gas chromatography, flame ionization detector; analyte: 1,2,3-trichloropropane; desorption: 1 ml carbon disulfide; injection volume: 5 ul; column temp: 160 deg C; injector temp: 180 deg C; detector temp: 230 deg C; carrier gas: nitrogen or helium, 30 ml/min; column: 3m x 3mm od stainless steel, 10% free fatty acid phase on 80/100 mesh chromosorb whp; calibration: standard solutions of analyte in carbon disulfide; range (mg/sample): 0.3-9.0; estimated limit of detection: 0.01 mg/sample; overall precision (sr): 0.068; measurement precision (sr): 0.027, range 163-629 mg/cu m (10L samples) [R67] *OSHA Method 07, Issued Nov 1979, Last update Nov 1989, Organic vapors.Gas chromatography. Detection limit not reported. [R68] *EPA Method IP-1B Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbent Tubes, capillary gas chromatography/mass spectroscopy, detection limit 4.7 ng/sample [R69] *EPA Method 1624 Volatile Organic Compounds by Isotope Dilution GCMS. gas chromatography/mass spectroscopy. Detection limit 10 ug/L in water, not reported for soil. [R70] *EPA Method 502.1 Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography, gas chromatography with electrolytic conductivity detector. Detection limit not reported. [R71] *EPA Method 502.2 Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography with Photoionization and Electrolytic conductivity Detectors in Series. gas chromatography with electrolytic conductivity detector. Method detection limit 0.40 ug/L. [R71] *EPA Method 524.2 Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry, capillary gas chromatography/mass spectrometry, Method detection limit 0.32 ug/L [R71] *EPA Method 524.1 Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography/Mass Spectrometry, gas chromatography/mass spectrometry, detection limit not reported. [R71] *EPA Method 8010A Halogenated Volatile Organics, gas chromatography/electron capture detection. Detection limit not reported. [R72] *EPA Method 8021 Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Technique, capillary gas chromatography/electrolytic conductivity detector. Method detection limit 0.40 ug/L [R72] *EPA Method 8240A Volatile Organics by Gas Chromatography/Mass Spectrometry (GC/MS): Packed Column Technique, gas chromatography/mass spectrometry, quantitation limits: 5.0 ug/kg in solids, 5.0 ug/L in water. [R72] *EPA Method 8260 Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique, capillary gas chromatography/mass spectrometry, method detection limit 0.32 ug/L. [R72] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/ATSDR; Toxicological Profile for 1,2,3-Trichloropropane TP-91/28 (1992) DHHS/NTP; Toxicology and Carcinogenesis Studies of 1,2,3-Trichloropropane in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 384 (1993) NIH Publication No. 94-2839 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for 1,2,3-trichloropropane is in progress. Route: aqueous exposure; Species: fish project 1, fish. [R73] SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1172 R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 311 R3: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 974 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 24-35 R5: SRI R6: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.601 R7: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 316 R8: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R9: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R10: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-278 R11: Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R12: Albanese V et al; Env Tech Lett 59: 1419-56 (1987) R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 149 R14: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-88 R15: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 1146 R16: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 145 R17: McEvoy, G.K. (ed.). American Hospital Formulary Service--Drug Information 94. Bethesda, MD: American Society of Hospital Pharmacists, Inc. 1994 (Plus Supplements). 90171 R18: Leighton DTJr, Calo JM; J Chem Eng 26: 382-5 (1981) R19: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 504 R20: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 173 R21: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1178 R22: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 539 R23: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R24: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3242 R25: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 262 R26: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.3 R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 63 240 (1995) R28: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R29: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R30: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985. 137 R31: BONASHEVSKAYA TI ET AL; DEPOSITED DOC (VINITI): 3169-76 (1976) R32: SAITO-SUZUKI R ET AL; MUTAT RES 101 (4): 321-8 (1982) R33: STOLZENBERG SJ, HINE CH; ENVIRON MUTAGEN 2 (1): 59-66 (1980) R34: MOODY DE ET AL; MOL PHARMACOL 20 (3): 685-93 (1981) R35: BELYAEVA NN ET AL; BYULL EKSP BIOL MED 83 (3): 345-8 (1977) R36: BONASHEVSKAYA TI ET AL; DEPOSITED DOC (VINITI): 1733-78 (1978) R37: IVANETICH KM ET AL; DRUG METAB DISPOS 6 (3): 218-25 (1978) R38: National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986. 330 R39: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values, 4th ed., 1980. Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.410 R40: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1061 R41: Merrick BA et al; J Appl Toxicol 11 (3): 179-87 (1991) R42: Toxicology and Carcinogenesis Studies of 1,2,3-Trichloropropane in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.6-7 Report #384 (1993) NIH Pub# 94-2839 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R43: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of 1,2,3-Trichloropropane (CAS No. 96-18-4) Administered by Gavage in CD-1 Swiss Mice, NTP Study No. RACB91039 (October 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R44: Tunstall Lab, Shell Oil Co.; Toxicity of Fine chemicals: Preliminary Studies for the Detection of Testicular Changes in Rats. (1979), EPA Document No. 878216424, Fiche No. OTS0510352 R45: Mahmood NA et al; Drug Metab Dispos Biol Fate Chem 19 (2): 411-18 (1991) R46: Weber GL, Sipes IG; 113 (1): 152-58 (1992) R47: TSULAYA VR ET AL; GIG SANIT (8): 20-2 (1979) R48: (1) Aharonson N et al; Pure Appl Chem 59: 1419-46 (1987) (2) Oki DS, Giambelluca TW; Ground Wat 25: 693-702 (1987) (3) Langer E; Ullmann's Encycl of Indust Chem Vol A6, p. 311 NY: VCH Publishers (1986) R49: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill NY pp. 4-1 to 4-33 (1982) (2) Walton DJ et al; J Environ Qual 21: 552-8 (1992) (3) Leighton DT Jr, Calo JM; J Chem Eng 26: 382-5 (1981) (4) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074- 101-1 (1992) (5) Anderson TA; J Environ Qual 20: 420-4 (1991) (6) Ellington JJ et al; Measurement of Hydrolysis Rate Constants for Evaluation of Hazardous Waste Land Disposal Vol I. USEPA/600/3-86/043 (PB87-140349/GAR) (1987) R50: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-15 to 15-29, 5-1 to 5-30 (1982) (2) Leighton DT Jr, Calo JM; J Chem Eng 26: 382-5 (1981) (3) Walton DJ et al; J Environ Qual 21: 552-8 (1992) (4) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (5) Ellington JJ et al; Measurement of Hydrolysis Rate Constants for Evaluation of Hazardous Waste Land Disposal Vol 1. USEPA/600/3-86/043 (NTIS PB87-140349/GAR) (1987) R51: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (3) Albanese V et al; Env Tech Lett 59: 1419-56 (1987) R52: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 3-31 (1992) (2) Long JL et al; J Environ Eng 119: 300-20 (1993) R53: (1) Ellington JJ et al; Measurement of Hydrolysis Rate Constants for Evaluation of Hazardous Waste Land Disposal Vol I. USEPA/600/3-86/043 (PB87-140349/GAR) (1987) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (3) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (4) Bidleman TF Environ Sci Technol 22: 361-7 (1988) R54: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill NY pp. 5-1 to 5-30 (1982) (2) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R55: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill NY pp. 4-1 to 4-33 (1982) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Walton DJ et al; J Environ Qual 21: 552-8 (1992) (4) Albanese W et al; Environ Tech Lett 59: 1419-56 (1987) R56: (1) Leighton DT Jr, Calo JM; J Chem Eng 26: 382-5 (1981) (2) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 15, 16 (1982) (4) USEPA; Exams II Computer Simulation (1987) (5) Dilling WL; Env Sci Tech 4: 405-9 (1977) R57: (1) Wakeham SG et al; Can J Fish Aq Sci 40: 304-21 (1983) (2) Hendriks AJ et al; Water Res 28: 581-98 (1994) R58: (1) Aharonson N et al; Pure Appl Chem 59: 1419-46 (1987) (2) Cohen SZ et al; pp. 170-96 in Monitoring Groundwater for Pesticides. ACS Symp Ser, Garner WY et al Ed. Washington DC (1986) (3) Cohen SZ et al; pp. 256-94 in Schriftenr Ver Wasser, Bodenlufthyg 68, Grundwasserbeeinflussung Plfanzenschutzm (1987) (4) Oki DS, Giambelluca TW; Ground Wat 25: 693-702 (1987) (5) Battista J, Connelly JP; VOC contamination at selected Wisconsin landfills - sampling results and policy implications. PUBL SW- 094-89 Wisconsin Dept Nat Resources, Madison, WI (1989) (6) Leistra M, Boesten JJTI; Agric Ecosys Environ 26: 369-89 (1989) R59: (1) Keith LH et al; pp. 327-73 in Ident Anal Org Pollut Water, Keith LH Ed Ann Arbor Press, Ann Arbor MI (1976) (2) Kool HJ et al; CRC Crit Rev Env Control 12: 307-57 (1982) (3) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 3 USEPA-600/1-84-020 (NTIS PB85-128247) (1984) (4) USEPA; Health and Environmental Effects Profile for Trichloropropane Isomers (External Review Draft) EACO-CIN-P010 p. 11 (1983) R60: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 3. USEPA-600/1-84-020 (NTIS PB85-128247) (1984) R61: (1) Cohen SZ et al; pp. 170-96 in ACS Symp Ser, 315. Garner WY et al Ed, Washington DC (1986) (2) Cohen SZ et al; pp. 256-9 in Schriftenr Ver Wasser, Bodenlufthyg 68, Grundwasserbeeinflussung Plfanzenschutzm (1987) R62: (1) NIOSH; National Occupational Exposure Survey (NOHS) (1989) R63: 29 CFR 1910.1000 (7/1/98) R64: 40 CFR 60.489 (7/1/94) R65: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R66: 40 CFR 716.120 (7/1/94) R67: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 1003-1 R68: OSHA R69: USEPA/Atmospheric Research and Exposure Laboratory (AREAL); Compendium of Methods for the Determination of Toxic Organic Compounds in Ambient Air (1988) EPA/600/4-89/017 R70: USEPA; EMMI. Environmental Monitoring Methods Index. Version 1.02. EPA-821-B-92-001 (NTIS PB-92-503093), August 1992 R71: USEPA; Methods for the Determination of Organic Compounds in Drinking Water, Environmental Monitoring Systems Laboratory - Cincinnati, Office of Research and Development, USEPA, Cincinnati, OH 45268, EPA/600/4-88/039 (NTIS PB-89-220461/AS), December 1988. R72: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R73: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 67 Record 127 of 1119 in HSDB (through 2003/06) AN: 1341 UD: 200303 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-PROPANOL,-1-CHLORO- SY: *CHLOROISOPROPYL-ALCOHOL-; *1-CHLOROISOPROPYL-ALCOHOL-; *1-CHLORO-2-PROPANOL-; *SEC-PROPYLENE-CHLOROHYDRIN- RN: 127-00-4 MF: *C3-H7-Cl-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ACID-CATALYZED REACTION OF ALLYL CHLORIDE WITH WATER; CHLOROHYDRINATION OF PROPYLENE (PRODUCING THE 2-CHLORO-1-PROPANOL ISOMER ALSO) [R1] USE: *Chemical intermediate [R2] *CHEM INT FOR PROPYLENE OXIDE AND OTHER ORG COMPDS [R1] CPAT: *ESSENTIALLY 100% AS CHEMICAL INTERMEDIATE [R1] PRIE: U.S. IMPORTS: *(1976) 1.76X10+5 G (INCL 2-CHLORO-1-PROPANOL) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R3] BP: *126-127 DEG C [R3] MW: *94.54 [R3] DEN: *1.115 @ 20 DEG C [R3] SOL: *SOL IN WATER, ALC [R3]; *SOL IN ETHANOL, ETHER, CARBON TETRACHLORIDE [R4] SPEC: *INDEX OF REFRACTION: 1.4392 @ 20 DEG C/D [R3]; *SADTLER REF NUMBER: 2249 (IR, PRISM); 310 (IR, GRATING) [R4]; *IR: 3:108E (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R5, p. V2 182]; *NMR: 1:127A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R5, p. V2 182]; *MASS: 59 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R5, p. V2 182]; *IR: 310 (Sadtler Research Laboratories IR Grating Collection) [R5, p. V2 156]; *NMR: 6711 (Sadtler Research Laboratories Spectral Collection) [R5, p. V2 156]; *MASS: 198 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R5, p. V2 156] VAPD: *3.3 (air=1) [R6] VAP: *4.9 mm Hg @ 20 deg C [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME. [R6] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R8, p. 325-27] +Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R8, p. 325-8] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R8, p. 325-27] FLPT: *125 DEG F [R6] FIRP: *ALC FOAM, SPRAY, MIST, DRY CHEM. [R6] DCMP: *WHEN HEATED TO DECOMP, IT EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. [R9] STRG: *SHOULD BE STORED IN COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, and ...PERIODICALLY INSPECTED AND MONITORED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED FROM EACH OTHER. [R6] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Higher alcohols (> 3 carbons) and related compounds/ [R10, p. 200-01] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or has severe pulmonary edema. Positive-pressure ventilation techniques, with a bag-valve-mask device, may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Monitor for signs of hypoglycemia (decreased LOC, tachycardia, pallor, dilated pupils, diaphoresis, and/or dextrose strip or glucometer readings below 50 mg) and administer 50% dextrose if necessary ... . Treat seizures with diazepam (Valium) ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Higher alcohols (> 3 carbons) and related compounds/ [R10, 201] NTOX: *PROPYLENE CHLOROHYDRIN RATED 7 ON RABBIT EYES, ...TESTED EXTERNALLY ON EYES OF RABBITS AND...RATED NUMERICALLY ON SCALE OF 1-10 ACCORDING TO DEGREE OF INJURY... AFTER 24 HR /OBSERVATION/, PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA. MOST SEVERE INJURIES HAVE BEEN RATED 10. /PROPYLENE CHLOROHYDRIN/ [R11] *MUTAGENICITY FOR SALMONELLA OF SOME MONO- AND DI-HALOPROPANOLS STUDIED REVEALED THAT 1-CHLORO-2-PROPANOL WAS AMONG THOSE MUTAGENIC FOR SALMONELLA TYPHIMURIUM. TA1535 BUT NOT FOR TA1538. /SRP: AMES TEST/ [R12] *Rats given 15 exposures by inhalation (6 hr each) of 250 ppm 1-chloro-2-propanol displayed lethargy, irregular weight gains, congestion, and perivascular edema in the lungs. At 100 ppm, the lungs were observed congested with perivascular edema; no effects were observed at 30 ppm. In a 21 day oral study, rats were dosed with either 7.6, 25.4, or 76 mg/kg/day propylene chlorohydrin ... . No systemic toxicity was observed. [R13, 2736] *In a 13 week study, Sprague-Dawley rats were dosed by oral gavage with 1, 7, and 50 mg/kg/day propylene chlorohydrin (75:25 1-chloro-2-propanol and 2-chloro-1-propanol). ... No findings of note except for histopathological changes in the acinar cells of the pancreas. [R13, 2737] *In a 13 week study, dogs were dosed by oral gavage with 1, 7, and 50 mg/kg/day propylene chlorohydrin (75:25 1-chloro-2-propanol and 2-chloro-1-propanol). The only effect noted was decreased body weights in the high-dose animals. [R13, 2737] *One out of six rats died when exposed to 500 ppm propylene chlorohydrin for 4 hr. No deaths were observed when rats were exposed to saturated vapors for 15 min. [R13, 2736] *Low toxicity by inhalation. [R9] +... CONCLUSIONS: Under the conclusions of these 2 yr drinking water studies, there was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female F344/N rats exposed to 150, 325 or 650 ppm. There was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female B6C3F1 mice exposed to 250, 500 or 1,000 ppm. [R14] NTXV: *LC50 Rat inhalation 1000 ppm/4 hr; [R9] *LD50 Rat oral 100 to 300 mg/kg, 381 mg/kg, and 0.22 mL/kg; [R13, 2736] *LD50 Rabbit dermal is 480 mg/kg, 0.48 mL/kg, and 0.5 g/kg; [R13, 2736] NTP: +... Groups of 50 male and 50 female F344/N rats were admin drinking water containing 0, 150, 325 or 650 ppm 1-chloro-2-propanol (equivalent to average daily doses of approx 15, 30 or 65 mg/kg during the first several months of the study and 8, 17 or 34 mg/kg for the remainder of the 2 yr study) for up to 105 wk. ... Groups of 50 male and 50 female B6C3F1 mice were admin drinking water containing 0, 250, 500 or 1,000 ppm 1-chloro-2-propanol (equivalent to average daily doses of approx 45, 75 or 150 mg/kg for the males and 60, 105 or 210 mg/kg to females during the first several months of the study and 25, 50 or 100 mg/kg for the remainder of the 2 yr study for up to 105 wk). CONCLUSIONS: Under the conclusions of these 2 yr drinking water studies, there was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female F344/N rats exposed to 150, 325 or 650 ppm. There was no evidence of carcinogenic activity of technical grade 1-chloro-2-propanol in male or female B6C3F1 mice exposed to 250, 500 or 1,000 ppm. [R14] +1-Chloro-2-propanol (1CP) ... was tested for its effects on reproduction and fertility in Sprague-Dawley rats using the RACB protocol. This was stimulated by preliminary reproductive data that showed a decr in epididymal weight, an incr in sperm abnormalities, and a change in estrous cycle in rats dose for 90 days with 1CP. Data from a 2 wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation study at 0.0, 0.03, 0.065, and 0.13% in drinking water. These concns produced estimated exposures of nearly equal to 30, 65, and 100 mg/kg/d. In the F0 animals in Task 2, 1 control, 1 low dose, and 1 high dose female died; 2 from kidney problems, and the remaining cause of death was undetermined. There was no change in the number of litters/pair, or the number or weight of live pups/litter. The high dose females took 2 days longer than controls to deliver their last litter; the biological significance of 116 days (control) vs. 118 days is questionable. Post-partum dam weights were reduced for the middle dose (by nearly =7%) and high dose females (by nearly =15%); low dose females were reduced, but not significantly so. Sire weights were reduced only at the high dose (by nearly =7%). This is consistent with the 10% and 30% reduction in water consumption measured for the middle and high dose animals, respectively. The last litter from all groups was reared by the dams until weaning at pnd 21. While pup viability was unaffected by 1CP consumption, pup weight was reduced by nearly =9% and nearly =20% at the middle and high dose levels, respectively. No F0 crossover test was conducted since no reproductive changes were observed for the first generation rats. Task 4 was conducted with the control and high dose rats. At the time of mating, body weights were reduced by 14% for males and 11% for females. Despite this difference, there were no differences between the 2 groups in reproductive parameters: both groups delivered equivalent number of litters, numbers of live pups/litter, and the viability and weight of those pups was unchanged by 1CP exposure. After the F2 pups were evaluated and removed, the F1 control and high dose adults were killed and necropsied. For males, body weight was reduced (see above), relative kidney weights increased by 7% in males. Absolute testis weight was 8% lower in 1CP-treated males while relative epididymis weight was increased by 8%. The proportion of abnormal sperm in control rats was 0.78% and the exposed value was 2.4%, a significant incr, but within the historical range. Female body weight was reduced by nearly =11%, relative kidney weight was increased by nearly =8%, and estrous cycle length was unchanged. These data show that even in the presence of 1CP sufficient to limit water consumption by approx 30% and to produce significant differences in body weight, 1CP caused no adverse effects on fertility in either generation. The statistically significant effects on testis weights and sperm abnormalities may indicate very slight reproductive toxicity. No effects were observed in females. [R15] ADE: *Propylene chlorohydrin is absorbed, widely distributed, and rapidly metabolized and eliminated. [R13, 2736] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1-Chloro-2-propanol's production and use as a chemical intermediate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 4.9 mm Hg at 25 deg C indicates 1-chloro-2-propanol will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1-chloro-2-propanol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 5 days. If released to soil, 1-chloro-2-propanol is expected to have very high mobility based upon an estimated Koc of 2. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.7X10-6 atm-cu m/mole. 1-Chloro-2-propanol may potentially volatilize from dry soil surfaces based upon its vapor pressure. The importance of biodegradation of 1-chloro-2-propanol in soil and water is unknown. 1-Chloro-2-propanol is not expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. The half-life for hydrolysis of 1-chloro-2-propanol at pH7 is approximately 2 years; the half-life at pH 8 is expecteed to be about 1 month by analogy to 1,3-dichloro-2-propanol. Occupational exposure to 1-chloro-2-propanol may occur through inhalation and dermal contact with this compound at workplaces where 1-chloro-2-propanol is produced or used. The general population may be exposed to 1-chloro-2-propanol by the ingestion of food fumigated with propylene oxide. (SRC) ARTS: *1-Chloro-2-propanol's production and use as a chemical intermediate(1) may result in its release to the environment through various waste streams. [R16] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2(SRC), determined from a structure estimation method(2), indicates that 1-chloro-2-propanol is expected to have very high mobility in soil(SRC). Volatilization of 1-chloro-2-propanol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.7X10-6 atm-cu m/mole(SRC), obtained using a fragment constant estimation method(3). The potential for volatilization of 1-chloro-2-propanol from dry soil surfaces may exist(SRC) based upon a vapor pressure of 4.9 mm Hg(4). The importance of biodegradation of 1-chloro-2-propanol in soil is unknown(SRC). [R17] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2(SRC), determined from a structure estimation method(2), indicates that 1-chloro-2-propanol is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.7X10-6 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Volatilization half-lives for a model river and model lake are 150 days and 3 years, respectively(SRC), using an estimation method(3). According to a classification scheme(5), an estimated BCF of 3(3,SRC), from an estimated log Kow(6,SRC), suggests the potential for bioconcentration in aquatic organisms is low(SRC). A neutral first-order hydrolysis rate constant of 1.1X10-8 1/s for 1-chloro-2-propanol corresponds to a half-life of 2 years a pH 7(7), the half-life for hydrolysis at pH 8 is expected to be approximately 1 month by analogy to 1,3-dichloro-2-propanol(SRC). The importance of biodegradation of 1-chloro-2-propanol in water is unknown(SRC). [R18] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1-chloro-2-propanol, which has a vapor pressure of 4.9 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1-chloro-2-propanol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5 days(SRC) from its estimated rate constant of 3.19X10-12 cu cm/molecule-sec at 25 deg C(3). [R19] ABIO: *The rate constant for the vapor-phase reaction of 1-chloro-2-propanol with photochemically-produced hydroxyl radicals has been estimated as 3.19X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 5 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). A neutral first-order hydrolysis rate constant of 1.1X10-8 1/s corresponds to a half-life of 2 years a pH 7(2). By analogy to 1,3-dichloro-2-propanol which has a base-catalyzed second-order hydrolysis rate constant of 850 L/mole-hour(3), 1-chloro-2-propanol is expected to have a half-live of approximately 1 month at pH 8(4,SRC). 1-Chloro-2-propanol is not expected to directly photolyze due to the lack of absorption in the environmental spectrum(5). [R20] BIOC: *An estimated BCF of 3 was calculated for 1-chloro-2-propanol(SRC), using an estimated log Kow of 0.53(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R21] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 1-chloro-2-propanol can be estimated to be about 2(SRC). According to a classification scheme(2), this estimated Koc value suggests that 1-chloro-2-propanol is expected to have very high mobility in soil. [R22] VWS: *The Henry's Law constant for 1-chloro-2-propanol is estimated as 1.7X10-6 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 1-chloro-2-propanol is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as approximately 150 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as approximately 3 years(SRC). 1-Chloro-2-propanol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1-chloro-2-propanol from dry soil surfaces may exist(SRC) based upon a vapor pressure of 4.9 mm Hg(3). [R23] FOOD: *1-chloro-2-propanol was qualitatively detected as a volatile component of meat(1). 1-Chloro-2-propanol may be formed in foods (e.g., flour, pepper, cocoa, walnut meat, tapioca starch, glazed cherries, glazed citron, and dehydrated potato granules) fumigated with propylene oxide(2). [R24] RTEX: *Occupational exposure to 1-chloro-2-propanol may occur through inhalation and dermal contact with this compound at workplaces where 1-chloro-2-propanol is produced or used(SRC). The general population may be exposed to 1-chloro-2-propanol via food fumigated with propylene oxide(1). [R25] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *METHOD INVOLVING GAS CHROMATOGRAPHY AND FLAME IONIZATION DETECTION FOR DETERMINATION OF...PROPYLENE /CHLOROHYDRIN/...DESCRIBED BY GRIFFITH LAB. LATTER...APPLIED VOLHARD METHOD FOR CHLORINE TO STEAM DISTILLATE OF SLURRY OF TREATED FOOD. [R26] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology and Carcinogenesis Studies of 1-Chloro-2-propanol (Technical Grade) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies) p.6 Technical Report Series No. 477 (1998) NIH Publication No. 98-3967 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 TEST: *The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The mid-1998 issue indicates that 1-chloro-2-propanol, technical is on the list of post peer review technical reports in progress. Route: dosed-water; Species: rats and mice. NTP TR No 477. [R27] SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 970 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1349 R4: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-283 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R6: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 1063 R7: Yang RSH; Rev Environ Contam Toxicol 99: 46-81 (1987) R8: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 825 R10: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R11: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1008 R12: CARR HS ET AL; MUTAT RES 57(3) 381-4 (1978) R13: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R14: Toxicology and Carcinogenesis Studies of 1-Chloro-2-propanol (Technical Grade) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies) p.6 Technical Report Series No. 477 (1998) NIH Publication No. 98-3967 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; 1-Chloro-2-propanol (CAS No. 127-00-4): Reproduction and Fertility Assessment In CD Sprague-Dawley Rats Via Drinking Water, NTP Study No. RACB88075 (December 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R16: (1) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary 12th ed NY,NY: Van Nostrand Reinhold Co (1993) R17: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Yang RSH; Rev Environ Contam Toxicol 99: 46-81 (1987) R18: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Radding SB et al; Review of the Environmental Fate of Selected Chemicals. NTIS 68-01-2681 (1977) R19: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yang RSH; Rev Environ Contam Toxicol 99: 46-81 (1987) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R20: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Radding SB et al; Review of the Environmental Fate of Selected Chemicals. NTIS 68-01-2681 (1977) (3) Ellington JJ; Hydrolysis Rate Constants for Enhancing Property-Reactivity Relationships USEPA/600/3-89/063, NTIS PB89-220479 (1989) (4) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park,CA: SRI International (1987) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R21: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R22: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) R23: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Yang RSH; Rev Environ Contam Toxicol 99: 46-81 (1987) R24: (1) Shahidi F et al; 24: 141-243 in CRC Crit Food Sci Nature (1986) (2) Yang RSH; Rev Environ Contam Toxicol 99: 46-81 (1987) R25: (1) Yang RSH; Rev Environ Contam Toxicol 99: 46-81 (1987) R26: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 160 R27: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/10/98; p.22 RS: 26 Record 128 of 1119 in HSDB (through 2003/06) AN: 1406 UD: 200302 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MALACHITE-GREEN- SY: *ACRYL-BRILLIANT-GREEN-B-; *ADC-MALACHITE-GREEN-CRYSTALS-; *AI3-18509-; *AIZEN-MALACHITE-GREEN-CRYSTALS-; *AMMONIUM, (4-(P-(DIMETHYLAMINO)-ALPHA-PHENYLBENZYLIDENE)-2,5-CYCLOHEXADIEN-1-YLIDENE)- DIMETHYL-, CHLORIDE; *ANILINE-GREEN-; *ASTRA-MALACHITE-GREEN-; *ASTRA-MALACHITE-GREEN-B-; *ASTRA-MALACHITE-GREEN-BXX-; *BASIC-GREEN-4-; *BENZALDEHYDE-GREEN-; *BENZAL-GREEN-; *BRONZE-GREEN-TONER-A-8002-; *BURMA-GREEN-B-; *CALCOZINE-GREEN-V-; *CASWELL-NO.-534C-; *CHINA-GREEN- (BIOLOGICALSTAIN); *CI-BASIC-GREEN-4-; *CI-42000-; *DIABASIC-MALACHITE-GREEN-; *DIAMOND-GREEN-BX-; *DIAMOND-GREEN-B-EXTRA-; *DIAMOND-GREEN-P-EXTRA-; *(4-(4-Dimethylaminobenzhydriylidene)cyclohexa-2,5-dienylidene)dimethylammonium chloride; *(4-(ALPHA-(4-DIMETHYLAMINO)PHENYL)BENZYLIDENE)CYCLOHEXA-2,5-DIEN-1-YLIDENE DIMETHYLAMMONIUM CHLORIDE; *EPA-PESTICIDE-CHEMICAL-CODE-039504-; *FAST-GREEN-O-; *GREEN-MX-; *GRENOBLE-GREEN-; *HIDACO-MALACHITE-GREEN-BASE-; *HIDACO-MALACHITE-GREEN-LC-; *HIDACO-MALACHITE-GREEN-SC-; *LIGHT-GREEN-N-; *LINCOLN-GREEN-TONER-B-15-2900-; *MALACHITE-GREEN-A-; *MALACHITE-GREEN-B-; *MALACHITE-GREEN-AN-; *MALACHITE-GREEN-CHLORIDE-; *MALACHITE-GREEN-CHLORIDE-SALT-; *MALACHITE-GREEN-CP-; *MALACHITE-GREEN-CRYSTALS-; *MALACHITE-GREEN-CRYSTALS-BPC-; *MALACHITE-GREEN-HYDROCHLORIDE-; *MALACHITE-GREEN-J3E-; *MALACHITE-GREEN-POWDER-; *MALACHITE-GREEN-WS-; *MALACHITE-LAKE-GREEN-A-; *MALACHIT-GRUN- (GERMAN); *METHANAMINIUM, N-(4-((4-(DIMETHYLAMINO)PHENYL)PHENYLMETHYLENE)-2,5-CYCLOHEXADIEN-1-YLIDENE)-N-METHYL-, CHLORIDE; *METHYLENE-GREEN-; *MITSUI-MALACHITE-GREEN-; *NEW-VICTORIA-GREEN-EXTRA-I-; *NEW-VICTORIA-GREEN-EXTRA-O-; *NEW-VICTORIA-GREEN-EXTRA-II-; *OJI-MALACHITE-GREEN-; *SOLID-GREEN-O-; *SOLID-GREEN-CRYSTALS-O-; *TERTROPHENE-GREEN-M-; *TETRAMETHYL-DIAPARA-AMIDO-TRIPHENYL-CARBINOL-; *TOKYO-ANILINE-MALACHITE-GREEN-; *VICTORIA-GREEN-; *VICTORIA-GREEN-B-; *VICTORIA-GREEN-S-; *VICTORIA-GREEN-WB-; *VICTORIA-GREEN-WPB-; *Viride-Malachitum-; *ZELEN-MALACHITOVA- (CZECH); *ZELEN-ZASADITA-4- (CZECH) RN: 569-64-2 MF: *C23-H25-Cl-N2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CONDENSATION OF BENZALDEHYDE WITH N,N-DIMETHYLANILINE IN THE PRESENCE OF AN ACID, FOLLOWED BY OXIDATION OF THE RESULTING PRODUCT WITH LEAD PEROXIDE AND AN ACID; HEATING N,N-DIMETHYLANILINE WITH BENZOTRICHLORIDE [R1] *FOR DYEING IT IS PREPD AS A DOUBLE SALT WITH ZINC CHLORIDE. [R2, 894] MFS: *ALLIED CHEM CORP, SPECIALTY CHEMS DIV, MORRISTOWN, NJ 07960 [R1] *AMERICAN ANILINE PRODUCTS, INC, PATERSON, NJ 07509 [R1] *AMERICAN CYANAMID CO, ORGANIC CHEMS DIV, DYES AND TEXTILE CHEMS DEPT, BOUND BROOK, NJ 08805 [R1] *CIBA-GEIGY CORP, DYESTUFFS AND CHEMS DIV, ARDSLEY, NY 10502 [R1] *CROMPTON AND KNOWLES CORP, DYES AND CHEMS DIV, FAIR LAWN, NJ 07410 [R1] *E I DU PONT DE NEMOURS AND CO, INC, WILMINGTON, DE 19898 [R1] *DYE SPECIALTIES INC, JERSEY CITY, NJ 07306 [R1] *L AND R DYESTUFFS CORP, NEW YORK, NY 10013 [R1] *STERLING DRUG CO, HILTON-DAVIS CHEM CO, DIV, CINCINNATI, OH 45237 [R1] *SYNALLOY CORP, BLACKMAN-UHLER DIV, SPARTANBURG, SC 29301 [R1] *C Lever Company Inc Hq, The Lever Building, 736 Dunks Ferry Road, Bensalem, PA 19020-6575, (215) 639-8640; Production site: Philadelphia, PA 19133 [R3] *Uhlich Color Company Inc, Hq, 1 Railroad Avenue, Hastings-on-Hudson, NY 10706, (914) 478-2000; Production site: Hastings-on-Hudson, NY 10706 [R3] OMIN: *IT HAS ALSO FOUND USE AS AN AGRICULTURAL FUNGICIDE. CHEMICALLY RELATED TO GENTIAN VIOLET ... . [R4] USE: *For directly dyeing silk, wool, jute and leather; dyeing cotton after mordanting. Biological stain, clinical reagent (inorganic phosphate assay). As spot test reagent for detecting sulfurous acid and cerium. [R2, 895] *Effective for control of protozoa. [R5] *MEDICATION (VET) CPAT: *100% AS A DYE (1976) [R1] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 4.54X10+5 G [R1] *(1975) 1.45X10+8 G [R1] U.S. IMPORTS: *(1972) 9.6X10+7 G (PRINCPL CUSTOMS DISTS) [R1] *(1975) 3.03X10+7 G (PRINCPL CUSTOMS DISTS) [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *GREEN CRYSTALS WITH METALLIC LUSTER [R2, 894] MW: *364.95 [R6] PH: *1% sol in water has a pH of 1.4 [R7] SOL: *VERY SOL IN WATER; SOL IN ALCOHOL, METHANOL, AMYL ALCOHOL [R2, 894]; *Sol 1 /part/ in 15 /parts/ of water and 1 /part/ in 15 /parts/ of alcohol. [R7] SPEC: *MAX ABSORPTION: 616.9 NM [R2, 894] OCPP: *WATER SOLN ARE BLUE-GREEN; YELLOW BELOW PH 2; AS ACID-BASE INDICATOR; PH: 0.0 YELLOW; 2.0 GREEN; 11.6 BLUE-GREEN; 14 COLORLESS. [R2, 894] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- CLUP: *COAGULATION WITH FERROUS SULFATE, FERRIC SULFATE, AND FERRIC CHLORIDE AND TREATMENT WITH OZONE WERE TESTED FOR CI BASIC GREEN 4 IN WASTE WATER. EFFECT OF COAGULATION DEPENDED LARGELY ON PH OF SOLN. [R8] DISP: *A study was designed to (1) determine the type of filter and kind of carbon that was most efficient for removal of malachite green and (2) demonstrate that carbon filters can be used to remove malachite green from water used for egg incubation or to hold adult salmon before spawning. Minicolumn simulation studies showed that removing malachite green from water for 230 days at a flow rate of 500 gal/min for only 62 days at a flow rate of 1,000 gal/min. The removal capacity at the slower flow rate was 1.1 oz of malachite green per pound of carbon. A filter system that contained 20,000 lb of activated carbon in each of two chambers was effective for removal of malachite green from treated water in adult salmon holding ponds at flows of 500 gal/min (6.4 gal/min per sq ft) and greater. The removal efficiency was 99.8% after 105 hr of operation, and the adsorption capacity of the system was projected to be sufficient for 20 or more years of routine hatchery operation. A filter system that contained 2,000 lb of activated carbon in each of two chambers was effective for removal of malachite green from treated water in salmon egg incubation units at the designated flow rate of 50 gal/min (4.0 gal/min per sq ft) and also at faster flow rates. Removal efficiency decreased only slightly for faster flows in both filter systems, and the efficiency improved when treated water was passed through two filter chambers in series. [R9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *In treatment of eyes contaminated with cationic dyes, first aid measures are aimed at getting rid of dye which has not reacted with the tissues. This includes copious irrigation, mechanical removal of particles, and in the case of imbedded colored pencil may necessitate surgical exploration and careful removal of the particles. Solutions of tannin or tannic acid precipitate cationic dyes and render them essentially noninjurious, but this disposes of only that portion of the dye which has not already reacted with the tissues. /It was/ determined experimentally that a 5% to 10% solution of tannin was effective essentially in a prophylactic sense if applied within three minutes following application of powdered basic dyes to the eyes of rabbits, but that the effectiveness of this treatment rapidly diminished after three minutes. Other forms of chemical treatment have been aimed at removing both combined and excess dye. However, studies of the reaction of cationic dyes with cornea in vitro have shown these dyes to bind very tenaciously and to be very difficult to remove from combination with the tissue. ... /Cationic dyes/ [R10, 384] HTOX: *INGESTION CAUSES DIARRHEA AND ABDOMINAL PAIN. [R4] *... INJURIOUS TO ... EYE. IN ONE PATIENT AN ATTEMPT TO TREAT CONJUNCTIVITIS WITH 1% SOLN OF THIS DYE RESULTED IN DESTRUCTIVE KERATITIS WITH HYPOPYON AND TERMINATED IN BILATERAL BLINDNESS DUE TO CORNEAL OPACIFICATION. [R11] *Toxic by ingestion. [R12] *... Injurious to ... human eye. [R10, 379] NTOX: *PRIMARY LESIONS IN EXPERIMENTAL ANIMALS SEEM TO BE RENAL. [R4] *... CATIONIC; INJURIOUS TO RABBIT EYE. ... CAUSED INJURY RANGING IN SEVERITY FROM CONJUNCTIVAL EDEMA, HYPEREMIA, AND PURULENT DISCHARGE TO TOTAL OPACIFICATION AND EVEN NECROSIS AND SLOUGHING OF CORNEAL STROMA. [R11] *FINGERLING CHANNEL CATFISH WERE EXPOSED TO 0.1 MG/L, NEUTROPHILIA @ 1 and 3 DAYS AFTER TREATMENT WAS OBSERVED. INCR IN ERYTHROCYTE COUNTS, HEMOGLOBIN CONCN AND HEMOBLAST PERCENTAGES 3 DAYS AFTER TREATMENT; ERYTHROCYTOSIS AFTER 7 DAYS; HEMATOCRIT INCR, 14 DAYS; AND LEUKOPENIA AFTER 21 DAYS. [R13] *2-8 MIN TREATMENT WITH 10 PPM RETARDS EPIBIOTIC INFESTATION AND GIVE A 2 FOLD INCR OF SURVIVAL TO MASS REARED DUNGENESS CRAB LARVAE. SURVIVAL IS ADVERSELY AFFECTED WITH TREATMENT ABOVE 8 PPM FOR 16 MIN AND ABOVE 20 PPM FOR 8 MIN. DEVELOPMENT IS RETARDED ALSO. [R14] *MALACHITE GREEN STUDIED IN MUTANT STRAINS R 79 OF FUSARIUM SPECIES IN AGAR MEDIUM. AFTER TREATMENT OF MUTANT R79 WITH 10 UG/ML THE PERCENT OF SURVIVAL WAS 0. WITH TREATMENT OF SPORES WITH 5 UG/ML 2% SURVIVED AND 10% SURVIVED FROM 2 UG/ML. MALACHITE GREEN IS HIGHLY TOXIC RATHER THAN MUTAGENIC. [R15] *IN EMBRYONATED CHICKEN EGGS TREATED WITH MALACHITE GREEN DEVELOPMENTAL ABNORMALITIES COULD BE DETECTED VISCERAL HYPOPLASIA AND HEMATOPOIETIC METAPLASIA. [R16] *MALACHITE GREEN IS CAPABLE OF INTERACTING WITH DNA OF LIVING CELLS. EXPOSED CELLS COUNTER THIS LETHAL EFFECT BY EXCISING AND REPLACING PORTIONS OF THEIR DNA. DNA POLYMERASE IS CRUCIAL IN REPAIR. THE DYE REACTS WITH CELLULAR DNA AND INDUCES CHANGES. [R17] *For systemic therapy against trophozoites of the skin inhabiting stage of Ichthyophthirius multifiliis in ornamental fish, the latter were fed medicated food flakes containing malachite green once daily for 1-11 days ad libitum. Naturally or artificially infected cardinal tetras (Paracheirodon axelrodi), blue gouramis (Trichogaster trichopterus), or clown loach (Botia macracantha) were used in the trials. The fish were maintained in aerated 12.5 l or 60 l aquaria at 23 deg C. Ultrastructural investigations (scanning and transmission electron microscopy) revealed clear deleterious effects of malachite green on the parasitic stages. Following the initial application, the inner membrane of the mitochondria was destroyed. In fish fed for 2 days, aggregation of the mucocysts and polymerization the microtubules within the macronucleus occurred. Finally, the trophozoite's membrane was completely destroyed. In fish fed for 4 days, the medicated food killed all trophozoites of Ichthyophthirius multifiliis. Sensitive ornamental fish (eg, Paracheirodon axelrodi) showed no adverse effects after they had been fed with only the medicated food flakes for 2 months. Therefore, the oral administration of malachite green using this newly developed medicated food considerably reduces the risk of toxic effects on the fish hosts, which are sometimes caused by malachite green following its application by immersion therapy. The feeding of flakes medicated with malachite green provides an easy to /use/ and highly effective treatment of Ichthyophthirius multifiliis in ornamental fish. [R18] *Prophylactic dip treatments using formalin and malachite green were applied to 4-day old larvae and 12- and 20-day old juveniles of the European common carp, Cyprinus carpio and the African sharptooth catfish, Clarias gariepinus. Treatments consisted of 100 mg/l malachite green for exposure periods of 10, 30 or 90 s and 200 mg/l formalin administered for 30, 60 or 90 min. Larvae and juveniles of Clarias gariepinus could be treated with 100 mg/l malachite green for 10 s, or with 200 mg/l formalin for 30 min, with minimum mortalities. Both chemicals affected the survival of the Clarias gariepinus juveniles, especially the 90 min exposure to formalin. Juveniles of both species were sensitive to 100 mg/l malachite green concentrations. [R19] NTXV: *LD50 Mouse oral 80 mg/kg; [R2, 894] *LD50 Mouse ip 4.2 mg/kg; [R2, 894] ETXV: *LC50 BLUEGILL 0.0305 MG/L/96 HR. THE CHEMICAL IS READILY ABSORBED FROM AQ SOLUTIONS (PH 7.5, TOTAL HARDNESS OF 44 mg/l) BY FILTRATION THROUGH ACTIVATED CARBON; [R20] *LC50 SALMON 0.338 MG/L/96 HR. THE CHEMICAL IS READILY ABSORBED FROM AQ SOLUTIONS (PH 7.5, TOTAL HARDNESS OF 44 mg/l) BY FILTRATION THROUGH ACTIVATED CARBON; [R20] *LC50 RAINBOW TROUT 0.0998 MG/L/96 HR. (LETHAL CONCN PRODUCING 50% MORTALITY INDEPENDENT OF TIME). THE CHEMICAL IS READILY ABSORBED FROM AQ SOLUTIONS (PH 7.5, TOTAL HARDNESS OF 44 mg/l) BY FILTRATION THROUGH ACTIVATED CARBON; [R20] *LC50 FROG 0.173 MG/L/96 HR. THE CHEMICAL IS READILY ABSORBED FROM AQ SOLUTIONS (PH 7.5, TOTAL HARDNESS OF 44 mg/l) BY FILTRATION THROUGH ACTIVATED CARBON; [R20] *LC50 ASIATIC CLAM 122 MG/L/96 HR. THE CHEMICAL IS READILY ABSORBED FROM AQ SOLUTIONS (PH 7.5, TOTAL HARDNESS OF 44 mg/l) BY FILTRATION THROUGH ACTIVATED CARBON; [R20] *LC50 MAYFLY NAIAD 0.0790 MG/L/96 HR; [R20] *LC50 EEL 0.25 PPM/96 HR (95% CONFIDENCE LIMIT 0.20-0.29 PPM); [R21] *LC50 Fingerling channel catfish 0.14 ppm/24 hr. /Conditions of bioassay not specified/; [R5] INTC: *THALIDOMIDE @ 5 MG/KG/DAY FOR 2 MO APPLIED BY STOMACH TUBE TO NORMAL RATS AND RATS OF SAME STRAIN DEVELOPED BY TREATMENT OF PARENT GENERATION WITH MALACHITE GREEN, OR GIVEN IN SINGLE DOSE OF 50 OR 500 MG/KG DURING CRITICAL PERIOD OF PREGNANCY PRODUCED NO EFFECT ON RATE OF MALFORMATIONS. [R22] *The effects of malachite green and phenobarbitone were compared on the development of pre-neoplastic lesions during N-nitrosodiethylamine induced hepatocarcinogenesis in male Wistar rats. Rats were administered 200 ppm N-nitrosodiethylamine in drinking water for a period of 1 month. After an interval of 2 weeks the animals were given either malachite green (25 ppm) or phenobarbitone (500 ppm) in drinking water for 2.5 months. The effects were monitored on the basis of the morphological appearance of the liver, histological pattern, gamma-glutamyltranspeptidase-positive foci, total gamma-glutamyltranspeptidase activity and the induction of glycogen deficient islands. Both malachite green and phenobarbitone were found to enhance liver carcinogenesis to a significant extent when compared with either their corresponding controls or animals given N-nitrosodiethylamine alone. The enhancing effect of malachite green at 25 ppm is comparable with phenobarbitone at 500 ppm. An enhancing effect of malachite green on N-nitrosodiethylamine induced hepatocarcinogenesis in the rats was demonstrated. [R23] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Local; Fungicides, Industrial [R24] *A HIGHLY COLORED SUBSTANCE WHICH HAS BEEN EMPLOYED MEDICINALLY AS AN INTESTINAL ANTHELMINTIC, A WOUND ANTISEPTIC ... . [R4] *MEDICATION (VET): ANTISEPTIC. INTERNALLY, IN CALF SCOURS AND CANINE DYSENTERY (ESCHERICHIA COLI). EXTERNALLY (0.5-10%), ON INFECTED WOUNDS AND ABRASIONS- OFTEN AS TRIPLE DYE, CONTAINING BRILLIANT GREEN, GENTIAN VIOLET, AND RIVANOL. BACTERIOSTATIC EFFECTIVENESS DECR BY INCR CONCN OF BILE SALTS. [R25] *MEDICATION (VET): APPROXIMATELY 10 TIMES MORE EFFECTIVE AGAINST GRAM-POSITIVE THAN GRAM-NEGATIVE ORGANISMS. [R25] *MEDICATION (VET): ... (medical grade, zinc-free) has been used for treatment of mycotic infect in fish. [R26] *MEDICATION (VET): Fungicide and parasiticide in fish [R2, 894] *MEDICATION (VET): The arylmethane dye malachite green oxalate is used as an antimycotic and antiparasitic substance for treatment of fish diseases. ... [R27] *MEDICATION (VET): The results of a series of experiments to investigate the use of the arylmethane dye, malachite green, for the control of proliferative kidney disease in rainbow trout (Salmo gairdneri) are described. Under field conditions using the bath application method the dye gave good control of the disease with treatments at 1.6 ppm for 40 minutes repeated at seven, 14 and 21 day intervals. Flush treatments were also successful using the same treatment intervals and beginning with 3.2 ppm malachite green. [R28] WARN: *The chemical is toxic for many species of aquarium fish and must be used with extreme caution. Malachite green should be used as a short dip or bath at levels from 0.1 to 5 ppm aquarium water for 1 hr or less. [R26] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: *Product registrations which once contained active ingredients /incl malachite green/ have previously been amended to remove the ingredient from the formula or have been cancelled for other reasons. ... These ingredients will be removed from Reregistration List D effective 90 days after publication of this notice ... and will not be considered further for reregistration. [R29] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EPA Method 1625. Isotope Dilution Capillary Column Gas Chromatography/Mass Spectrometry for the determination of semivolatile organic compounds in municipal and industrial discharges. By adding a known amount of an isotopically labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If isotopically labeled compounds are not available, an internal standard method is used. Under the prescribed conditions for malachite green, the method has an estimated detection limit of 330 ug/l in combined solids at high level and 10 ug/kg in base/neutral water with no interferences present as defined by EPA. [R30] *Photocatalytic destruction of organic dyes in aqueous titanium oxide suspensions using concentrated simulated and natural solar energy. [R31] CLAB: *Quantification of malachite green in fish using high performance liquid chromatography with visible spectroscopy at 618 nm. The detection limit is 1 ug/kg and the precision is 67-72%. [R32] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for malachite green is in progress. Route: dosed-feed; Species: rats and mice. [R33] SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R3: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 860 R4: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-384 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 203 (1978) R6: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 85/8209 R7: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 568 R8: SHIMIZU Y, KISHIBE H; SHIGA-KENRI SU TANKI DAIGAKU GAKUJUTSU ZASSHI 18: 1-3 (1977) R9: Marking LL et al; Prog Fish-Cult 52 (2): 92-99 (1990) R10: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R11: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 431 R12: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 724 R13: GRIZZLE JM; PROG FISH-CULT 39 (2): 90-3 (1977) R14: FISHER WS ET AL; AQUACULTURE 8: 151-6 (1978) R15: SINGH UP; Z ALLG MICROBIOL 11: 347-51 (1971) R16: BRAUN S; ACTA MORPHOL ACAD SCI HUNG 4: 61-83 (1954) R17: ROSENKRANZ HS, CARR HS; BR MED J 3: 702-3 (1971) R18: Schmahl G et al; Parasitol Res 78 (3): 183-92 (1992) R19: Theron J et al; Onderstepoort J Vet Res 58 (4): 245-51 (1991) R20: BILLS TD ET AL; INVEST FISH CONTROL 73, 74, 75, 76, PAPER NO 75, 6 (1977) R21: LOYACANO HA JR; PROC ANNU MEET-WORLD MARIC SOC 8: 605-10 (1977) R22: WERTH G, HIRTH R; ARCH TOXICOL 23 (2): 104-11 (1968) R23: Fernandes C et al; Carcinogenesis (Eynsham) 12 (5): 839-46 (1991) R24: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R25: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 51 R26: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 670 R27: Kietzmann M et al; DTW Dtsch Tierarztl Wochenschr 97 (7): 290-3 (1990) R28: Alderman DJ, Clifton-Hadley RS; Vet Rec 122 (5): 103-6 (1988) R29: 56 FR 50423 (10/4/91) R30: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.307 (1991) OST Pub 21W-4005 R31: Reeves P et al; Sol Energy 48 (6): 413-20 (1992) R32: Dafflon O et al; Mitt Geb Labensmittelunters Hyg 83 (3): 215-23 (1992) R33: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 20 Record 129 of 1119 in HSDB (through 2003/06) AN: 1428 UD: 200302 RD: Reviewed by SRP on 9/18/1997 NT: This record contains information specific to the title compound. For general information on the toxicity and environmental fate of antimony ions and antimony compounds, refer to the ANTIMONY COMPOUNDS record; for information on the metal itself, refer to the ANTIMONY, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ANTIMONY-POTASSIUM-TARTRATE- SY: *ANTIMONYL-POTASSIUM-TARTRATE-; *EMETIQUE- (FRENCH); *ENT-50,434-; *EPA-pesticide-chemical-code-006201-; *Potassium-antimonyltartrate-; *POTASSIUM-ANTIMONYL-D-TARTRATE-; *Potassium-antimony-tartrate-; *TARTAR-EMETIC-; *TARTARIC-ACID,-ANTIMONY-POTASSIUM-SALT-; *TARTARIZED-ANTIMONY-; *TARTOX-; *Tartrate-antimonio-potassique- (French); *TARTRATED-ANTIMONY- RN: 28300-74-5 RELT: 6903 [ANTIMONY COMPOUNDS] MF: *C4-H4-K-O7-Sb SHPN: UN 1551; Antimony potassium tartrate, solid IMO 6.1; Antimony potassium tartrate, solid STCC: 49 411 14; Antimony potassium tartrate, solid MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *MANUFACTURED FROM POTASSIUM BITARTRATE AND METALLIC ANTIMONY IN THE PRESENCE OF NITRIC ACID OR SOLID ANTIMONY OXIDE. [R1, 118] FORM: *ANTIMONY TARTRATE, USP, (TARTAR EMETIC), IS AVAILABLE IN CRYSTALLINE FORM OR IN STERILE SOLN IN AMPULS. [R2] *GRADES: TECHNICAL; CRYSTALS; POWDERED; CHEMICALLY PURE; USP. [R3] *... As a poison in baits ... Insect baits usually are applied as sprays containing 0.36 to 0.48% of cmpd in liq formulation. Rodents baits are pastes or solids containing 0.3 to 3% of cmpd, specifically 0.30% with thallium sulfate and zinc phosphide, 1.12% with arsenic trioxide, and 3.00% with ANTU. [R4] USE: *AS MORDANT IN THE TEXTILE AND LEATHER INDUSTRY [R1, 118] *AS PESTICIDE TO CONTROL SNAILS [R5] *Used as an emetic to combine with certain rodenticides to make them less harmful if they are accidentally consumed by people or pets. [R4] *INSECTICIDE APPLIED AS SPRAY ON GLADIOLUS AND CITRUS FOR CONTROL OF THRIPS AND IN ANT BAITS. IT IS ALSO AN ACTIVE INGREDIENT IN LIQUID BAITS FOR MOTHS, WASPS, AND YELLOW JACKETS. [R6] *MEDICATION *MEDICATION (VET) CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- ODOR: *Odorless [R3] TAST: *Sweetish metallic [R1, 110] MW: *667.88 [R1, 118] DEN: *2.6 [R1, 118] PH: *Aq soln is slightly acid [R1, 119] SOL: *1 gram dissolves in 15 ml glycerol; insoluble in alcohol. [R1, 119]; *In water, 83,000 mg/l at 20 deg C [R7] OCPP: *At 100 deg C loses 0.5 mole of water [R8] *Transparent crystals (effloresce on exposure to air) or powder /Trihydrate/ [R1, 118] *Solubility: 8.3 g/100 cc cold water, 33.3 g/100 cc hot water, 6.7 g/100 cc glycerol; insoluble in alcohol /Hemihydrate/ [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R9] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R9] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R9] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R9] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R9] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R9] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R9] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R9] FIRP: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty). /Antimony potassium tartrate solid/ [R10] REAC: */INCOMPATIBLE WITH/ MINERAL ACIDS, TANNIC ACID, GALLIC ACIDS, ALKALI HYDROXIDES AND CARBONATES, LEAD AND SILVER SALTS, MERCURY BICHLORIDE, LIME WATER, ALBUMIN, AND SOAP. [R1, 118] +TRIVALENT ANTIMONY CMPD TEND TO FORM EXPLOSIVE MIXTURES WITH PERCHLORIC ACID WHEN HOT. /TRIVALENT ANTIMONY CMPD/ [R11] +Strong oxidizers, acids, halogenated acids [Note: Stibine is formed when antimony is exposed to nascent (freshly formed) hydrogen.] /Antimony/ [R12, 18] DCMP: *When heated to decomposition it emits toxic fumes of Sb and K2O. [R13] EQUP: *Personnel protection: ... Wear appropriate chemical protective gloves, boots and goggles. /Antimony potassium tartrate solid/ [R10] +Wear appropriate personal protective clothing to prevent skin contact. /Antimony/ [R12, 19] +Wear appropriate eye protection to prevent eye contact. /Antimony/ [R12, 19] +Recommendations for respirator selection. Max. concn for use: 5 mg/cu m. Respirator Class(es): Any dust and mist respirator except single-use and quarter-mask respirators. If not present as a fume. Any supplied-air respirator. /Antimony/ [R12, 19] +Recommendations for respirator selection. Max. concn for use: 12.5 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous-flow mode. Any powered, air-purifying respirator with a dust and mist filter. If not present as a fume. /Antimony/ [R12, 19] +Recommendations for respirator selection. Max. concn for use: 25 mg/cu m. Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. /Antimony/ [R12, 19] +Recommendations for respirator selection. Max. concn for use: 50 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a pressure-demand or other positive-pressure mode. /Antimony/ [R12, 19] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concentrations or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Antimony/ [R12, 19] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Antimony/ [R12, 19] OPRM: *If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. /Antimony potassium tartrate solid/ [R10] *Personnel protection: Keep upwind. ... Avoid breathing vapors or dusts. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Antimony potassium tartrate solid/ [R10] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +Contact lenses should not be worn when working with this chemical. /Antimony/ [R12, 19] +The worker should immediately wash the skin when it becomes contaminated. /Antimony/ [R12, 19] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Antimony/ [R12, 19] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Antimony/ [R12, 19] SSL: *SOLUTIONS (1:12 IN WATER) ARE STABLE [R2] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R15] STRG: *Storage temp: ambient; venting: open [R16] CLUP: *Environmental considerations- land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. /Antimony potassium tartrate solid/ [R10] *Environmental considerations- water spill: Add dilute caustic soda (NaOH); If dissolved, apply sodium sulfide (Na2S) solution to precipitate heavy metals. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. Adjust pH to neutral (pH= 7); allow to aerate. /Antimony potassium tartrate solid/ [R10] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Dissolve wastes in water, acidify and precipitate the sulfide using hydrogen sulfide as the reactant. The antimony sulfide precipitate should be returned to suppliers or manufacturers for reprocessing or be placed into long-term storage. [R16] *Dissolve in minimum quantity of hydrochloric acid concentrated reagent. Filter if necessary. Dilute with water until white precipitates form ... Add just enough 6 M HCl to redissolve. Saturate with hydrogen sulfide. Filter, wash the precipitate, dry, package, and ship to the supplier. [R17, 189] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Call for medical aid. ... If breathing has stopped, give artificial respiration. If breathing is difficult, give oxygen. ... Remove contaminated clothing and shoes. Flush affected areas with plenty of water. If in eyes, hold eyelids open, and flush with plenty of water. If swallowed and victim is conscious, have victim drink water or milk and have victim induce vomiting. If swallowed and victim is unconscious or having convulsions, do nothing except keep victim warm. [R17, 189] *BAL is effective in treating poisoning by antimony potassium tartrate, but this is not true of all organic antimony compounds. [R18, 545] HTOX: *... THE MORTALITY FROM CARDIAC ARRHYTHMIA IN A SERIES OF CASES BETWEEN 1952 AND 1954 WAS 50%. IN SOME CASES THE IV INJECTION ... HAS BEEN FOLLOWED BY IMMEDIATE DEATH. IN OTHERS, SUDDEN DEATH HAS OCCURRED AFTER AN INTERVAL OF SOME HR, WITH NO PRECEEDING SYMPTOMS. [R19, 27] *PAROXYSMS OF COUGHING AND VOMITING MAY OCCUR DURING INJECTION /SRP: FOR THERAPEUTIC PURPOSES/ ... AND NAUSEA AND VOMITING MAY PERSIST AFTER INJECTION. IF INJECTION IS TOO RAPID, ACUTE CIRCULATORY FAILURE MAY OCCUR. REVERSIBLE ELECTROCARDIOGRAPHIC CHANGES ARE COMMON DURING THERAPY ... OTHER ADVERSE AFFECTS ARE PRURITUS, RASHES, COLIC, HEADACHE, FACIAL EDEMA, DIARRHEA, DIZZINESS, DYSPNEA, HYPOTENSION, SYNCOPE, SHOCK, BRADYCARDIA, MYALGIA, SEVERE ARTHRALGIA, WEAKNESS, RENAL DAMAGE, OCCASIONALLY JAUNDICE (SECONDARY TO HEPATITIS OR HEMOLYTIC ANEMIA), AND ANAPHYLACTOID REACTIONS. [R20, 1834] *ONE 5 YR OLD BOY WHO HAD RECEIVED 23 INJECTIONS OF THIS DRUG IN TREATMENT OF KALA-AZAR SUDDENLY DEVELOPED BILATERAL BLINDNESS WITH DILATED UNREACTIVE PUPILS. PAPILLEDEMA WAS OBSERVED ASSOCIATED WITH ACUTE HYDROCEPHALUS AND GLOMERULONEPHRITIS. [R21] *When antimony potassium tartrate is rubbed on the skin in the form of ointment, it produces little irritation at first but produces a pustular eruption if applied for long periods. This is due to decomposition of the double salt by the acid secretions of the follicles leading to formation of the more irritant antimonious oxide and other compounds. [R18, 544] *Analysis of 315 electrocardiograms taken on 100 patients during various stages of treatment with tartar emetic and Fuadin for schistosomiasis revealed ... abnormality in 11 to 99% of patients. Abnormalities in 1 or more leads included increased amplitude of P waves, a fusion of ST segment and T wave, decreased amplitude of T wave, and prolongation of the Q-T interval. The duration of these changes was variable but was noted up to 2 months after treatment stopped. [R18, 545] *At autopsy of persons who ... died following ingestion of a large dose, ulcerations usually are found in the esophagus and stomach but not in the intestine. ... Persons who died, perhaps as result of individual susceptibility, following the usual, intravenous, therapeutic dose ... showed marked degeneration of liver, some necrosis of renal tubular epithelium, and varying degrees of hemorrhage. [R18, 545] *ANTIMONY POTASSIUM TARTRATE IS THE MOST POTENT AND MOST TOXIC OF THE TRIVALENT ANTIMONY COMPOUNDS. [R20, 1833] *Human peripheral blood lymphocytes cultured with or without phytohemagglutinin stimulation from patients treated with potassium antimony tartrate (injected dose= 2 mg/kg, twice each week for 6 weeks) were studied. In peripheral blood lymphocyte cultures of treated patients, 4.0 + or - 0.59% of peripheral blood lymphocytes were transformed into lymphoblasts. Phytohemagglutinin stimulated cultures had a mitotic index significantly lower than that in cultures from nonantimony treated patients. There was also an increase in chromosome breaks and fragmentation in the antimony treated group. Cultures without phytohemagglutinin stimulation did not have a lower mitotic index or increased chromosomal damage between groups. [R22] *The role of occupational factors in the development of heart disease is reviewed. Evidence has been presented to link antimony ... with heart disease. [R23] *General sensation includes eczematous eruption of skin, inflammation of mucous membrances of throat, and nose; vomiting, diarrhea, nervous complaints. Sweet metallic taste. GI disturbances, headache, hepatitis may occur. Therapeutic dose is close to toxic dose. May leave skin rash or damage to liver. [R17, 188] *... SURVEY OF 11 CASES OF ADAMS-STOKES SYNDROME WITH SEVERE VENTRICULAR ARRHYTHMIA IN COURSE OF TARTAR EMETIC TREATMENT FOR SCHISTOSOMIASIS ... LED TO /CONCLUSION/ ... THAT CARDIAC DISTURBANCE IS A COMBINED EFFECT OF FUNCTIONAL DISORDER OF AUTONOMIC SYSTEM CAUSED BY INHIBITORY EFFECT OF ANTIMONY ON THE CEREBRAL CORTEX AND HYPEREXCITABILITY OF THE MYOCARDIUM INDUCED BY ANTIMONY. [R19, 27] NTOX: *... A SINGLE ORAL DOSE OF 125 MG OF POTASSIUM ANTIMONY TARTRATE/KG OF BODY WT OF RABBIT WAS FATAL IN ALL CASES; 120 MG/KG WAS ALMOST CERTAINLY FATAL WITHIN 24-36 HR, AND 115 MG TO 50% OF THE ANIMALS. [R19, 28] *ANIMALS (SPECIES NOT STATED) WHICH HAD DIED FROM ORAL ... SUBCUTANEOUS AND IV ADMINISTRATION OF TARTAR EMETIC /SHOWED AT/ POST MORTEM THAT THE ORGAN CHIEFLY AFFECTED WAS THE LIVER. WITH ORAL ADMINISTRATION FATTY DEGENERATION BEGAN AT THE CENTER OF LOBES, WITH INJECTION AT THE PERIPHERY. KIDNEYS ALSO SHOWED DEGENERATIVE CHANGES AND AT EARLIER STAGE THAN LIVER. [R19, 28] *CHRONIC INCORPORATION OF POTASSIUM ANTIMONY TARTRATE (5 PPM) INTO DRINKING WATER INCREASED MORTALITY RATE AND DECREASED SERUM GLUCOSE LEVELS IN RATS. INCIDENCE OF TUMORS WAS NOT INCREASED. [R24] *MIN LETHAL IP DOSE ... FOR RATS WAS ... 1.1 MG/100 G BODY WEIGHT ... ANIMALS DYING A FEW DAYS AFTER INJECTION SHOWED DYSPNEA, LOSS OF WT, GENERAL WEAKNESS, LOSS OF HAIR AND EVIDENCE OF MYOCARDIAL INSUFFICIENCY. MOST MARKED POST-MORTEM FINDINGS WERE CARDIAC LESIONS MYOCARDIAL CONGESTION AND DILATATION OF RIGHT HEART. THERE WAS LITTLE CHANGE IN LUNG. DEATH WAS ATTRIBUTED TO MYOCARDIAL EDEMA WITH MARKED HYPEREMIA AND CAPILLARY ENGORGEMENT. LIVERS SHOWED CONGESTION WITH SOME DEGENERATION AND POLYMORPHONUCLEAR INFILTRATION. TOXIC GLOMERULAR NEPHRITIS WAS PRESENT ... MARKEDLY. [R19, 29] *SUBACUTE POISONING OF RABBITS BY FEEDING WITH 15 MG OF /ANTIMONY POTASSIUM/ TARTRATE/KG OF BODY WT WAS FOUND ... TO BE ACCOMPANIED BY AN INCREASE IN THE NON-PROTEIN NITROGEN IN BLOOD AND URINE. JAUNDICE WAS NOTICED DURING LAST 2 DAYS OF POISONING AND LIVERS OF SOME ... ANIMALS SHOWED FATTY DEGENERATION AND PARENCHYMAL NECROSIS. [R19, 29] *CHRONIC POISONING, IN EXPERIMENTS ... ON VARIOUS SPECIES OF ANIMALS WITH VARIOUS ANTIMONY CMPD, /SHOWED/ TARTAR EMETIC ... TO BE THE MOST TOXIC, AND DOGS WERE MORE SENSITIVE THAN SMALL RODENTS; 10 MG CAUSED VOMITING IN CATS AND ONLY 4 MG IN DOGS. ... THE EFFECT OF TARTAR EMETIC ON THE HEART OF GUINEA-PIGS HAS ... BEEN ... /SHOWN/ TO BE ONLY SLIGHTLY DEPRESSANT ON CONTRACTILE FORCE OR CARDIAC RATE UNTIL EXTREMELY HIGH CONCN (64 MG/KG) ARE REACHED WHEN DISTINCT SLOWING IS OBSERVED. [R19, 29] *... 76 MICE GIVEN 5 UG OF ANTIMONY POTASSIUM TARTRATE PER ML OF DRINKING WATER THROUGHOUT LIFETIMES SHOWED NO INCR IN INCIDENCE OF TUMORS. [R25] *TARTAR EMETIC WAS RESPONSIBLE FOR A NUMBER OF DEATHS IN CATTLE WHEN USED AS A TRYPANOCIDE. FATALITIES OCCURRED MAINLY IN UNDERNOURISHED ANIMALS, WHICH APPEARED TO BE PARTICULARLY PRONE TO LIVER DAMAGE INDUCED BY ANTIMONY. ... PHLEGMONOUS GASTRITIS /HAS BEEN OBSERVED/ IN CATTLE AFTER ADMIN ... FOR TREATMENT OF RUMINAL ATONY ... ALTHOUGH VERY LARGE DOSES OF ANTIMONY (UP TO 285 G OF TARTAR EMETIC) MAY BE NEEDED TO PRODUCE ANY NOTICEABLE PHYSIOLOGICAL EFFECT ... CASES OF ANTIMONIAL POISONING /IN HORSES/ ARE ON RECORD. [R26] *... 2 MG/KG OF ANTIMONY POTASSIUM TARTRATE /WERE GIVEN/ TO 4 SHEEP DURING MAJOR PORTION OF GESTATION AND ... NO FETAL CHANGES /WERE FOUND/. ... NO DEFECTS /WERE OBSERVED/ IN CHICKS GIVEN 0.10 MG ON THE 4TH DAY /OF INCUBATION/. [R27] *DAILY ADMIN (2 OR 20 MG/KG, IP) TO SCHISTOSOMA MANSONI-INFECTED MICE INCR ACETYLCHOLINE AND DECR GAMMA-AMINOBUTYRIC ACID OF CEREBRAL HEMISPHERES WITH SMALLER EFFECTS IN NONINFECTED MICE. AFTER TREATMENT STOPPED, LEVELS OF TRANSMITTERS TENDED TO RETURN TO NORMAL. [R28] *Antimony potassium tartrate markedly inhibited respiration in Schistomsoma japonicum, but had only a slight effect on glycolysis. [R29] *The effects of praziquantel on cellular and humoral immune responses were studied in Swiss Albino mice and compared with the effects of antimony tartrate. The experimental animals were antigenically primed by iv injection of Schistosoma mansoni eggs; the test drugs were given 1 day before egg injection and their effects monitored 16 days later. ... Tartar emetic was more effective as an immunosuppressant drug in these tests than praziquantel. [R30] *A concentration of 4 ppm antimony in culture solution has been shown to produce a toxic response in cabbage (Brassica oleracea) plants. [R31] *Rat cardiac myocytes were exposed to concentrations of potassium antimonyl tartrate (PAT) ranging from 1 to 1000 um for 1 to 24 hours. Toxicity was assessed measuring lactate dehydrogenase (LDH) release and by monitoring chronotropic depression. Lipid peroxidation was assessed by measuring the release of thiobarbituric acid reactive substances (TBARS). PAT produced a concentration- and time-dependent depression in chronotropy and an increase in the release of LDH and TBARS. A 4 hour exposure to 100 um PAT stopped beating and induced significant increases in TBARS and LDH release in the myocyte cultures. The lipid peroxidation and LDH release induced by 100-200 um PAT at 4 hours could be prevented by pretreatment of the cardiac myocytes with vitamin E or by the simultaneous addition of other antioxidants. Vitamin E continued to protect against lipid peroxidation up to 18 hours after the addition of 100 um PAT, but failed to provide significant protection against LDH release at this time-point. Both 50 and 100 um PAT decreased cardiac myocyte glutathione (GSH) levels after a 4 hour exposure. A series of thiol-containing compounds was evaluated for their effects on PAT toxicity. These results suggest that PAT induces lipid peroxidation in cultured cardiac myocytes but that other mechanisms may contribute to cell death with long-term exposures to PAT. Our results also suggest that PAT interacts with thiol-containing compounds. [R32] *... FOCAL PULMONARY HEMORRHAGE, FATTY DEGENERATION OF LIVER ... CHANGES IN PERIPHERAL BLOOD ... /REPORTED/ ... IN DIFFERENT SPECIES OF ANIMALS ... . /TRIVALENT ANTIMONY CMPD/ [R33] *... INJECTING TRIVALENT ANTIMONY CMPD SLOWLY INTO VEINS OF RABBITS, NOTED ... THE APPEARANCE OF NORMOBLASTS, STIPPLED CELLS, INCREASED NUMBER OF RETICULOCYTES AND MYELOCYTES IN CIRCULATION WITHIN 24 HOURS. /TRIVALENT ANTIMONY CMPD/ [R19, 30] *Chronic inhalation of subtoxic doses of antimony salts causes interstitial pneumonitis, intraalveolar lipoid deposits, and liver and cardiac damage. /Antimony salts/ [R34] NTXV: *LD50 Mouse oral 600 mg/kg; [R18, 543] *LD50 Mouse ip 46-50 mg/kg /for the different isomers/; [R18, 543] *LD50 Mouse sc 55 mg/kg; [R18, 543] *LD50 Mouse iv 65 mg/kg; [R18, 543] *LD50 Rat ip 30 mg/kg; [R18, 544] *LD50 Guinea pig ip 25 mg/kg; [R18, 544] ETXV: *TLm Pimephales promelas (fathead minnows) 12 ppm as antimony/96 hr /Conditions of bioassay not specified/; [R16] ADE: *Ingestion ... usually leads to repeated vomiting. Thus, removal ... from GI tract and inherently poor absorption combine to limit the amount ... reaching the tissues. ... Following single or repeated doses of tartar emetic, there was no ... marked accumulation of antimony in any organ, but concn was always greatest in liver ... . [R18, 544] *... /FOLLOWING THE ADMIN OF/ (124)ANTIMONY LABELLED TARTAR EMETIC TO RATS, AND /THE MEASUREMENT OF/ EXCRETION IN URINE AND FECES IN MICE AND MONKEYS ... /IT WAS CONCLUDED/ THAT SINCE EXCRETION WAS GREATER IN FECES THAN URINE, THIS INDICATED POOR ABSORPTION FROM INTESTINAL TRACT, AND THE FACT THAT ANTIMONY LEVELS IN BLOOD, LIVER, URINE AND FECES REMAINED FAIRLY CONSTANT WITH REPEATED DOSAGE ... SUGGESTED NO PERSISTENT ACCUMULATION OF ANTIMONY IN BODY. [R19, 26] *FOLLOWING IV ADMIN OF (124)ANTIMONY-TARTAR EMETIC TO MONKEYS, MORE THAN 50% OF RADIOACTIVITY WAS DETECTED IN LIVER. RADIOACTIVITY WAS ALSO FOUND IN HEART, KIDNEY, THIGH AND THYROID. MAX CONCN IN BLOOD WAS REACHED AT 8 HR AFTER ADMIN OF DRUG. [R35] *Rats were fed potassium antimony tartrate (8 mg antimony/kg/day) or antimony metal (40 mg/antimony/kg/day) for 7-1/2 months ad libitum. In a third test, potassium antimony tartrate was fed to rats for 6 months in doses increasing to 100 mg antimony/kg/day and then maintained at that level for an additional 6 months. Antimony metal was fed similarly to another group of rats by increasing the dose to 1 g antimony/kg/day. Antimony content of body tissues was measured semiquantitatively by chemical and spectrographic methods. An average of 1 mg of antimony was found in the carcasses of antimony exposed rats, regardless of the daily dose, while control animals contained an average of 0.1 mg antimony. [R36] *Beagle dogs exposed by nose only to aerosol of (224)antimony from an antimony tartrate complex. Aerosol formation at three different temperatures, 100, 500 and 1000 deg C, resulted in production of particles with activity median aerodynamic diameters of 1.3, 1.0 and 0.3 um, respectively. Regional body counting immediately after exposure indicated that the 100 deg C aerosol had deposited in the nasopharynx and the lung and that the smaller particles found at higher temperatures had deposited mainly in the lung. The detection of radioactivity in the pelt and several internal organs on sacrifice at 32-128 days postexposure indicated that absorption from the pulmonary tract did occur. It was not possible to estimate the properties of the inhaled dose that was absorbed or the contribution to radioactivity in the tissues resulting from gastrointestinal absorption of antimony cleared from the pulmonary tract by mucocilliary action. [R37] *Distribution of antimony in the tissue of rats was determined after repeated oral administration of antimony tartrate in drinking water for 1000 days at a concentration of 13.7 mg/l (5 mg/1 as antimony) with an average daily dose of 1.07 mg/kg body weight, assuming rats consumed the equivalent of 7.8% of their body weight in water/day (0.36 mg/kg as antimony with a cumulative dose of 360 mg/kg of antimony). The levels of antimony in the organs were 12.10 ug/g in the heart, 10.14 ug/g in the kidney, 11.57 ug/g in the liver, 17.67 ug/g in the lung, and 5.97 ug/g in the spleen. /From table/ [R38] *Part of the intravenously admin antimony salts are absorbed by erythrocytes, and the rest is distributed to other tissues, predominantly the liver, adrenals, spleen, and thyroid. In rats, trivalent antimony is absorbed by erythrocytes, distributed to other tissues, and retained in the liver for a short time before it is gradually excreted in feces; pentavalent antimony remains in the plasma for a short time, and most of it is excreted in the urine, while a part is retained in the hair. In the livers of mice and humans, pentavalent antimony is reduced to the trivalent form. /Antimony salts/ [R39] INTC: *CYSTEINE PRODUCED A DECR IN TOXICITY OF ANTIMONYL POTASSIUM TARTRATE (APT) WHEN 2 SUBSTANCES INJECTED INTO MICE AND RABBITS IN RATIOS OF APT TO CYSTEINE RANGING FROM 1:1 TO 1:3. HOWEVER, THE COMBINATION (1:3) REDUCED THE ANTISCHISTOSOMAL ACTIVITY OF APT BOTH IN VITRO AND IN VIVO. [R40] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *IN MAN IS 130 MG (ALTHOUGH A 15,000 MG DOSE HAS BEEN SURVIVED). [R42] THER: +Schistosomicides [R41] *Antimony potassium tartrate was once used as an emetic for treating patients poisoned by a wide variety of compounds. ... It has been used for treating a number of tropical diseases, and /was/ the drug of choice for treating infection by Schistosoma japonicum. It is not used to treat S. mansoni or S. haematobium infections because less toxic agents are effective ... . [R18, 544] *MEDICATION (VET): HAS BEEN USED AS PARASITICIDE (GI AND BLOOD PARASITES); AS EXPECTORANT, AND AS RUMINATORIC. [R1, 119] WARN: *TARTAR EMETIC MUST BE GIVEN SLOWLY BY MEANS OF NEEDLE, AND CARE SHOULD BE TAKEN TO AVOID LEAKAGE INTO PERIVASCULAR TISSUE. TOO RAPID INJECTION MAY PRODUCE HACKING COUGH, VOMITING, AND SEVERE OR EVEN FATAL REACTIONS. /ITS/ USE ... IS CONTRAINDICATED IN PRESENCE OF SEVERE HEPATIC, RENAL, OR CARDIAC INSUFFICIENCY. [R2] *ANEMIA OR POOR NUTRITIONAL STATUS SHOULD BE CORRECTED PRIOR TO TREATMENT. ... ANTIEMETICS SHOULD NOT BE USED IN CONJUNCTION WITH ANTIMONY POTASSIUM TARTRATE BECAUSE THEY MASK NAUSEA AND VOMITING, WHICH MAY BE SIGNS OF PROGRESSIVE HEPATIC NECROSIS CAUSED BY TOXIC DOSES OF DRUG. TREATMENT SHOULD BE DISCONTINUED IF VOMITING IS SEVERE OR PERSISTENT OR IF A BLOOD DYSCRASIA (EG, THROMBOCYTOPENIA), ALBUMINURIA, PURPURA, FEVER, OR SEVERE DERMATITIS DEVELOPS. [R20, 1833] *THE MEDICINAL USE OF ANTIMONY CMPD OFTEN CAUSES SYMPTOMS OF OVERDOSE, SINCE THE MARGIN OF THERAPEUTIC SAFETY IS NARROW. THE ESTIMATED FATAL DOSE OF TARTAR EMETIC (ANTIMONY AND POTASSIUM TARTRATE) IS 150 MG. [R43] *... CONSIDERABLE ELECTROCARDIOGRAPHIC ABNORMALITIES /WERE OBSERVED/ IN 7 OUT OF 12 PATIENTS UNDERGOING A COURSE OF TARTAR EMETIC THERAPY. THESE CHANGES WERE ATTRIBUTED TO INTOXICATION OF HEART MUSCLE, WHICH IN EXCEPTIONAL CASES MIGHT RESULT IN DEATH FROM AURICULAR FIBRILLATION. [R19, 27] *Tartar emetic occurs as a white crystalline powder and accidents have occurred through its mistaken use as tartaric acid or sodium bicarbonate. ... Poisoning is likely to occur /in animals/ ... through the injudicious (and largely outmoded) use of "condition powders". [R26] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +50 mg/cu m (as Sb) [R12, 18] ATOL: *A tolerance of 3.5 ppm is established for residues of the insecticide tartar emetic, calculated as combined antimony trioxide, in or on ... the following raw agricultural commodities: citrus fruits, grapes, onions. [R44] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.5 mg/cu m). /Antimony and compounds, as Sb/ [R45] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.5 mg/cu m. /Antimony/ [R12, 18] TLV: +8 hr Time Weighted Avg (TWA): 0.5 mg/cu m. /Antimony and compounds as Sb/ [R46, 2002.15] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Antimony and compounds as Sb/ [R46, 2002.6] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Antimony potassium tartrate is included on this list. [R47] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 6 ug/l /Antimony/ [R48] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 14 ug/l /Antimony/ [R48] +(MN) MINNESOTA 6 ug/l /Antimony/ [R48] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R49] +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Antimony and compounds/ [R50] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R51] FIFR: *A tolerance is established for residues of the insecticide tartar emetic, calculated as combined antimony trioxide, in or on ... the following raw agricultural commodities: citrus fruits, grapes onions. [R44] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Report on the Toxicity Studies of Antimony Potassium Tartrate in F344/N Rats and B6C3F1 Mice (Drinking Water and Intraperitoneal Injection Studies NTP Tox 11 (1992) SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1029 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 89 R4: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 40 R5: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 125 R6: Farm Chemicals Handbook 1997. Willoughby, OH: Meister Publishing Co., 1997.,p. C-355 R7: Shiu WV et al; Rev. Environ Contam Toxicol 116: 15-187 (1990) R8: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 4-41 R9: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-151 R10: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 92 R11: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-23 R12: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R13: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 256 R14: 49 CFR 171.2 (7/1/96) R15: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 102 R16: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R17: Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995. R18: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. R19: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. R20: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 5th ed. Chicago: American Medical Association, 1983. R21: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 113 R22: Hashem N, Shawki R; Afr J Med Sci 5: 155-63 (1976) as cited in Drinking Water Criteria Document for Antimony, EPA Contract No 68-03-3417 p.V-13 (1988) R23: Rosenman KD; Archives of Environ Health 39 (3): 218-24 (1984) R24: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 436 R25: National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980. 79 R26: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 28 R27: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 46 R28: SAMAAN SS ET AL; J PHARM PHARMACOL 28 (5): 465-6 (1976) R29: Huang Z, Li Z; Yaoxue Xuebao 19 (9): 651-5 (1984) R30: Botros SS et al; Trans R Soc Trop Med Hyg 78 (5): 569-72 (1984) R31: Brown, K.W., G. B. Evans, Jr., B.D. Frentrup (eds.). Hazardous Waste Land Treatment. Boston, MA: Butterworth Publishers, 1983. 237 R32: Tirmenstein MA et al; Toxicol Appl Pharmacol 130 (1): 41-7 (1995) R33: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 29 R34: Luckey, T.D. and B. Venugopal. Metal Toxicity in Mammals, 1. New York: Plenum Press, 1977. 179 R35: ABDEL-WAHAB MF ET AL; EGYPT J BILHARZIASIS 1 (1): 101-6 (1974) R36: USEPA; Drinking Water Criteria Document for Antimony, EPA Contract No 68-03-3417 p. III-16 (1988) R37: USEPA; Health Effects Assessment for Antimony and Compounds p.6 (1987) EPA 600/8-88/018 R38: USEPA; Health and Environmental Effects Profile for Antimony Oxides p.43 (1985) EPA 600/x-85/271 R39: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. 214 R40: SALEH S, KHAYYAL MT; BULL WHO 53 (4): 379-84 (1976) R41: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R42: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-133 R43: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 171 R44: 40 CFR 180.179 (7/1/96) R45: 29 CFR 1910.1000 (7/1/98) R46: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R47: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R48: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R49: 40 CFR 116.4 (7/1/88) R50: 40 CFR 401.15 (7/1/88) R51: 40 CFR 302.4 (7/1/96) RS: 40 Record 130 of 1119 in HSDB (through 2003/06) AN: 1432 UD: 200303 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BORIC-ACID- SY: *BORACIC-ACID-; *BORIC-ACID- (H3BO3); *BOROFAX-; *BORON-TRIHYDROXIDE-; *Borsaure- (German); +NCI-C56417-; *ORTHOBORIC-ACID-; *EPA-pesticide-code-011001-; +Three-elephant- RN: 10043-35-3 MF: *B-H3-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +BORIC ACID IS PRODUCED FROM NATIVE BORAX, OR FROM OTHER BORATES, BY REACTING WITH HYDROCHLORIC OR SULFURIC ACID. [R1, 1257] *From weak borax brines, by extraction with a kerosine solution of chelating agent such as 2-ethyl-1,3-hexanediol, or other polyols. Borates are stripped from the chelate by sulfuric acid [R2] IMP: *The principal impurities in technical grade boric acid are the by-product sulfate (0.1%) and various minor metallic impurities present in the borate ore /technical grade/ [R3, p. 4(78) 76] FORM: *Technical, 99.9%; Chemically pure; USP [R2] *Three grades of granular and powdered boric acid are manufactured in the United States. ... technical grade, NF grade ... /and/ special quality grade [R3, p. 4(78) 76] *Saturated solutions at 0 deg C contain 2.6% acid; at 100 deg C, 28% boric acid is soluble [R2] MFS: +Kerr-McGhee Corporation, Hq, Kerr-Mcbee Center, PO Box 25861, Oklahoma City, OK 73125, (405) 270-1313; Subsidiary: Kerr-McGhee Chemical Corporation (address same as Hq), Production sites: Argus-Trona-Westend Complex, Trona, CA 93562; Westend, CA 93562 [R4, 488] +US Borax and Chemical Corporation, Hq, 3075 Wilshire Boulevard, Los Angeles, CA 90010, (213) 251-5400; Production site: Boron, CA 93516 [R4, 489] +In-Cide Technologies, Inc, Hq, 50 North 41st Ave, Phoenix, AZ 85009, (602) 233-0756; Production site: Phoenix, AZ 85000 [R4, 488] +Mountain States Mineral Enterprises, Inc, Hq, 4370 South Fremont Ave, Tucson, AZ 85714, (602) 792-2800; Production site: Newberry Springs, CA 92365 [R4, 489] OMIN: +ITS USE AS PRESERVATIVE IN BEVERAGES AND FOODS IS PROHIBITED BY NATIONAL AND STATE LEGISLATION. [R1, 1258] *Method of purification: Recrystallization [R2] USE: +WEATHERPROOFING WOOD; NICKLING BATHS, FOR PRINTING AND DYEING, AND FOR IMPREGNATING WICKS; MFR CEMENTS, CROCKERY, PORCELAIN, ENAMELS, GLASS, BORATES, LEATHER, CARPETS, HATS, SOAPS, ARTIFICIAL GEMS; IN PAINTING; PHOTOGRAPHY; ELECTRIC CONDENSERS, HARDENING STEEL [R5] *Boric acid is used in the manufacture of paper and paperboard products used in food packaging for use in adhesives, sizes, and coatings. [R6] *FLAME RETARDANT IN WOOD AND TEXTILES; CATALYST; ADDITIVE FOR GLASS FIBERS [R7] *Porcelain enamels; heat-resistant glass [R2] +Flux in soldering and brazing [R8] *Nuclear-reactor cooling water additive [R3, p. 19(85) 177] *Manufacturing synthetic inorganic borate salts, boron phosphate, fluoborate, borate esters, and metal alloys such as ferroboron; catalyst for alcohol production from air oxidation of hydrocarbons [R3, p. 4(78) 76] *Component in high contrast lith-type film developer formula, such as Kodak D-85 Developer [R3, p. 19(85) 118] *HAS FLY REPELLANT INSECTICIDAL QUALITIES. [R9] *Sequestrant [R10] *HAS BEEN INCL IN COCKROACH BAITS AND ANT POISONS, ... USED TO KILL LARVAE HARBORING IN MANURES. [R11] +/USED AS/ BUFFER, AND IT IS THIS USE THAT IS OFFICIALLY RECOGNIZED. [R1, 1257] +MEDICATION +MEDICATION (VET) CPAT: *Textile-grade glass fibers, 35%; borosilicate glasses, 20%; fire retardants, 15%; enamels, fruits and glazes, 7%; metallurgy, 5%; adhesives, 3%; miscellaneous, 15% (1984) [R12] *Principal uses for boron compounds consumed in the United States in 1988 were estimated to be glass products, 56%; soaps and detergents, 6%; agriculture, 4%; and other, 34% /Boron compounds/ [R13] PRIE: U.S. PRODUCTION: +(1972) 6.17X10+10 G [R7] +(1975) 6.81X10+10 G [R7] *(1984) 1.26X10+11 g (est) [R12] U.S. IMPORTS: *(1984) 7.03x10+9 g [R14] *(1986) 12.28x10+6 lb [R15] *(1985) 10 short tons [R13] *(1986) 6 short tons [R13] *(1987) 2 short tons [R13] U.S. EXPORTS: +(1972) 1.72X10+11 G (PLUS SODIUM BORATES) [R7] +(1975) 1.91X10+10 G [R7] *(1984) 3.63X10+10 g [R16] *(1987) 5.95X10+4 content ton [R17] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +COLORLESS, TRANSPARENT CRYSTALS OR WHITE GRANULES OR POWDER [R5] ODOR: +ODORLESS [R5] TAST: *Faintly bitter [R18] BP: *300 DEG C (LOSES 1 1/2 WATER) [R19] MP: *169 + or - 1 Deg C in transition to boric acid [R19] MW: +61.84 [R5] DEN: *1.435 AT 15 DEG C [R19] PH: +5.1 (0.1 MOLAR) [R5] SOL: *20 G/100 CC METHANOL AT 25 DEG C [R19]; *1 G/18 ML COLD WATER [R5]; *1.92 G/100 CC LIQ AMMONIA @ 25 DEG C [R19]; *SLIGHTLY SOL IN ACETONE [R19]; *1 G/4 ML BOILING WATER [R19]; *1 G/6 ML ALCOHOL [R19]; *1 G/4 ML GLYCEROL [R19] SPEC: *INDEX OF REFRACTION: 1.337, 1.461, 1.462 [R19] OCPP: +SLIGHTLY UNCTUOUS TO TOUCH [R5] *SOLUBILITY IN WATER INCR BY HYDROCHLORIC, CITRIC OR TARTARIC ACIDS [R19] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Not flammable [R20] REAC: +During an attempt to make triacetyl borate, a mixture of boric acid and acetic anhydride exploded when heated to 58-60 deg C. [R21, p. 491-31] +A mixture of potassium and /boric acid/ ... may explode on impact ... [R21, p. 491-154] SERI: *Irritant to skin in dry form. [R2] *... May produce irritation of the nasal mucous membranes, the respiratory tract, and eyes. /Boron compounds/ [R22, 138] EQUP: */Wear/ chemical goggles [R20] OPRM: +Containers of boric acid should bear an autoclavable poison label. [R23] *Contact lenses should not be worn when working with this chemical. /Boron oxide/ [R24] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: +STABLE IN AIR [R1, 1257] *... stable up to 100 deg C [R18] STRG: *Preserve in well-closed containers. [R25] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *TREATMENT IS PURELY SYMPTOMATIC. PLASMA VOL SHOULD BE MAINTAINED BY INFUSION OF COPIOUS AMT OF APPROPRIATE FLUID. [R26, 994] MEDS: *No specific considerations are needed for boric acid or borates except for general health and liver and kidney function. /Boric acid and borates/ [R22, 139] HTOX: *WITH REPEATED APPLICATIONS OF THE POWDER TO ABRADED OR INFLAMED SKIN, SUFFICIENT AMT ... IS OR /MAY BE/ ABSORBED TO CAUSE ACUTE POISONING, ESP IN INFANTS. LETHAL AMT CAN BE ABSORBED FROM WOUND CAVITIES IRRIGATED WITH BORIC ACID SOLN. [R23] *CHRONIC INTOXICATION GIVES RISE TO ANOREXIA, ASTHENIA, CONFUSION, MENSTRUAL DISORDERS, AND ALOPECIA. IT HAS OCCURRED FROM USE OF BORATE CONTAINING MOUTHWASHES. [R26, 994] *BORIC ACID POISONING BEGINS WITH NAUSEA, VOMITING AND DIARRHEA, REGARDLESS OF ROUTE OF ADMIN. THE BODY TEMP FALLS, AND ERYTHEMATOUS RASH ... DEVELOPS. THIS IS FOLLOWED BY DESQUAMATION, NOT ONLY IN AREAS OF RASH BUT ALSO OF MUCOUS MEMBRANES. ... HEADACHE, RESTLESSNESS, AND WEAKNESS ... RENAL INJURY ... DEATH RESULTS FROM CIRCULATORY COLLAPSE AND SHOCK USUALLY WITHIN 5 DAYS. [R26, 994] *... BORIC ACID MAY PRODUCE ... CYANOSIS, DELIRIUM, CONVULSIONS, AND COMA. [R27] *VITAMIN B12 DETERMINED IN 14 PT, CHILDREN AND ADULT AFTER BORIC ACID INGESTION. URINARY RIBOFLAVIN GREATLY INCR IN APPROX 2/3 OF PT. EVIDENCE OF INGESTION HAZARD IS PROVIDED. [R28] *LETHAL DOSE ... EST TO BE 15-20 G IN ADULTS AND 5-6 G IN INFANTS. [R26, 994] *Borax and boric acid used in powders and ointments have resulted in serious poisonings and death. [R29, 135] *The fatal dose of boric acid, sodium borate, or sodium perborate is 0.1-0.5 g/kg. [R30, 360] *Chronic boron poisoning ... syndrome usually is seen in children who have been treated in the past with a boric acid preparation for diaper rash. Cutaneous findings develop regardless of the route of poisoning. Renal toxicity includes oliguria, anuria, and renal tubular necrosis, which may supervene after several days. Hypothermia and hyperthermia may occur. Death is more common in infants than adults. [R31] *Four cases of nonfatal ingestion of boric acid were reported after two subjects (adult females) ingested 298 g of a 99% boric acid containing insecticide and 80 g of boric acid in a fungicide, respectively (presumably 1.0 and 0.28 g B/kg, respectively, for a 50 kg body weight). Ingested doses for the two other subjects were not fully specified. All four subjects recovered, and the two adults presented no systemic symptoms following release from the hospital. [R32] *Six male volunteers aged 30-58 years received single oral doses of boric acid. Three volunteers ingested 750 mg boric acid dissolved in 100 ml of water. Three other volunteers swallowed 24.95 g to 49.6 g of commercial water-emulsifing ointment containing 2.97% (wt/wt) boric acid. The accumulated mean 96 hour excretion was 93.9% of the dose after ingestion of the solution and 92.4% after ingestion of the ointment. The initial urinary excretion rate was generally lower after ingestion of the ointment than after ingestion of solution. More than 50% of the ingested dose was excreted within the first 24 hours post ingestion. No adverse health effects were reported for any of the individuals following a single ingestion of about 1.8 mg boron/kg during the 96 hour observation period. [R33] *Application of boric acid powder for diaper rash /produced/ severe erythema of the skin, gastrointestinal symptoms and deaths in infants. [R34] *Eleven infants accidentally ingested boric acid in their formula; from 2-4.5 g of the compound was ingested by six of the survivors, who developed serum borate levels of 20-150 mg/l, while the five infants who ingested larger amounts (4.5 - 14 g) exhibited levels of 200-1600 mg/l and died within 3 days. [R35] *A transplacental distribution of boric acid in a human was reported when a 34-week pregnant female accidentally swallowed 70 g of boric acid (approximately 245 mg B/kg, 50 kg body weight). A fetus delivered 2 hours later by cesarean section died shortly afterward from cardiovascular failure. [R36] *A mixture containing 3 g of boric acid and 300 mg of cinchocaine chloride prescribed due to painful dental protrusion was accidentally ingested by a 12 month old girl. She developed violent vomiting and coughing. Irritability, tremor, seizures and a delirious reaction. She was treated with diazepam, intubated, sedated and ventilated. Her diuresis was stimulated with furosemide and fluid. Within the first 24 hr she was treated with hemodialysis twice on femoral catheters. Her renal function was unaffected. In two days she fully recovered. The maximum measured levels of boric acid and cinchocaine chloride approximately 6 hr after ingestion were 26 ug/ml and 71 ng/ml respectively. The plasma half-life of boric acid was 7.0 hr and decreased to 3.6 and 4.4 hr during the two hemodialyses. The total body clearance of boric acid increased correspondingly from 21 ml/min to 41 and 34 ml/min. The in vitro clearance of boric acid of the dialyser was later determined to be 18 ml/min. It is concluded that hemodialysis is valuable in the treatment of boric acid intoxication because it increases the elimination of the drug even in patients without any sign of renal toxicity. [R37] *113 workers exposed to these dusts and 214 unexposed workers were interviewed regarding symptoms. Statistically significant associations were found between eye irritation, dryness of the mouth or throat, sore throat and productive cough, on the one hand, and mean exposures of 4.1 mg/cu m, on the other. The study indicates that exposures to boric acid at concentrations < 10 mg/cu m are associated with irritation of the eyes and upper respiratory tract. [R38] *A retrospective chart review was conducted at two regional poison centers to determine the clinical outcome of boric acid ingestions and to assess the relationship between serum boric acid levels and clinical presentation. A total of 784 cases were studied; all but 2 were acute ingestions. No patients developed severe manifestations of toxicity, and 88.3% were entirely asymptomatic. The most common symptoms were vomiting, abdominal pain, and diarrhea. Lethargy, headache, lightheadedness, and atypical rash were seen less frequently. Boric acid levels were obtained in 51 patients and ranged from 0 to 340 ug/ml. Blood levels were 70 ug/ml or more in 7 patients; 4 remained asymptomatic, whereas the other 3 had nausea or vomiting. Dialysis was performed in 4 of these patients, only 1 of whom had symptoms (vomiting). On the basis of data from 9 patients, the mean half-life of boric acid was determined to be 13.4 hours (range, 4.0 to 27.8). Hemodialysis in 3 patients significantly shortened the half-life compared with pre- and postdialysis half-lives. Results suggest that acute boric acid ingestions produce minimal or no toxicity and that aggressive treatment is not necessary in most patients. [R39] *Boric acid and its derivatives have been shown to promote riboflavinuria in both animals and man. Boric acid complexes with the polyhydroxyl ribitol side chain of riboflavin and greatly increases its water solubility. Individuals who have accidentally consumed boric acid or one of its derivatives excrete high levels of riboflavin within the first 24 to 48 hours following ingestion. The administration of certain agents, either therapeutic or toxic, which enhance urinary ribovlavin excretion may be of particular concern for high-risk patients who are already nutritionally compromised because of illness or disease. [R40] *Symptomatology: 1. Nausea, vomiting, diarrhea, epigastric pain. ... Vomitus and feces may contain blood, hemorrhagic gastroenteritis may develop ... 2. Weakness, lethargy, headache, restlessness, tremors, and ... convulsions with ... CNS depression. 3. Erythematous skin eruptions ... followed by extensive exfoliation. 4. Shock syndrome, cold clammy skin, cyanosis, thready pulse, and low blood pressure. 5. Occasionally kidney injury (oligura, albuminuria, anuria) and rarely liver damage (hepatomegaly, jaundice) ... reported; former may be cause of death. ... 6. Metabolic acidosis and signs of intravascular coagulation ... 7. ... Fever ... described in absence of recognized intercurrent infection. 8. Death is due to vascular collapse in the early stages or to CNS depression later in the course ... Bronchopneumonia, meningitis, and other terminal infections have been described. /Borate/ [R41, p. III-67] *INFANTS AND YOUNG CHILDREN ARE THOUGHT TO BE MORE SUSCEPTIBLE TO BORATE INTOXICATION THAN ARE ADULTS. ... IN STUDY OF OVER 100 CASES OF ACCIDENTAL POISONING, OVERALL FATALITY RATE WAS 55%, BUT IN INFANTS UNDER 1 YR OF AGE, 70% OF CASES ENDED FATALLY. DEATH MAY OCCUR IN FEW HR BUT IS USUALLY DELAYED SEVERAL DAYS. /BORATE/ [R41, p. III-67] *ACUTE POISONING HAVE FOLLOWED INGESTION, PARENTERAL INJECTION, ENEMAS, LAVAGE OF SEROUS CAVITIES, AND APPLICATION OF POWDERS AND OINTMENTS TO BURNED AND ABRADED SKIN. /BORATE/ [R41, p. III-67] *ONCE A TETRA-, DI-, META-, ORTHO-, OR PYROBORATE SALT DISSOLVES IN A BUFFERED SOLN, ONE BORATE CANNOT BE DISTINGUISHED ON CHEMICAL OR TOXICOLOGICAL GROUNDS, FROM ANY ONE OF THE OTHERS. /BORATE/ [R41, p. II-118] *In chronic poisoning with low levels of ingestion, there may be little more than dry skin and mucous membranes, followed by appearance of a red tongue, patchy alopecia, cracked lips, conjunctivitis, and sometimes periorbital edema and irritability. /Borates/ [R42] *Chronic poisoning: (From ingestion, skin absorption, or absorption from body cavities or mucous membranes) prolonged absorption causes anorexia, weight loss, vomiting, mild diarrhea, skin rash, alopecia, convulsions and anemia. /Boric acid and boron derivatives/ [R30, 361] *BECAUSE HIGHEST CONCN ARE REACHED DURING EXCRETION, THE KIDNEYS ARE MORE SERIOUSLY DAMAGED THAN OTHER ORGANS. /BORIC ACID AND BORON DERIVATIVES/ [R30, 360] NTOX: *... MANY INSTANCES ... OF ACCIDENTAL POISONING ... MOST OF THE FATALITIES HAVE OCCURRED IN YOUNG ANIMALS. ... SIGNS OF BORIC ACID POISONING ARE NAUSEA, VOMITING, DIARRHEA ... INCLUDE SHOCK AND ULTIMATELY COLLAPSE. MUSCULAR AND NERVOUS DISTURBANCES LEADING TO CONVULSIONS AND GENERAL PARALYSIS ... THE USUAL POST-MORTEM FINDINGS ARE INFLAMMATION OF THE ALIMENTARY TRACT, TOXIC DEGENERATIVE CHANGES IN THE LIVER AND KIDNEYS, AND CEREBRAL EDEMA. [R43] *IN ANIMALS CHRONIC POISONING HAS SHOWN ITSELF ONLY IN INHIBITION OF GROWTH WHEN BORIC ACID WAS GIVEN IN AMT OF 0.25% IN DRINKING WATER. THERE WERE NO ... LESIONS AT AUTOPSY AND NO CHANGES IN PERIPHERAL BLOOD. [R44] *BORIC ACID CAUSED HYPERTHERMIA IN LAB ANIMALS. [R45] *... rumplessness, curled toe and facial palate defects /were observed/ in chicks /after/ injections of 2.5 mg. Rumplessness was common following treatment at 24 hr incubation while the facial and palate defects appear after treatment at 4 days. ... boric acid is metabolized differently when the rat becomes pregnant. The chemical begins to appear first in the spinal fluid. ... Boric acid or borax /given/ to pregnant rats at 350 ppm ... during pregnancy /produced no reduction in liveborn nor physical defects/. [R46] *Chronic, 2 yr dietary feeding in dogs and rats showed that boric acid was tolerated at 2000 ppm (350 ppm boron equivalent). Rats fed 1170 ppm levels (boron equivalent) showed growth depression, decreased food utilization efficiency, degeneration of gonads, and skin desquamation. ... Testicular degeneration occurred in both dogs and rats at this level, and rats became sterile ... but at 2000 ppm, there was no adverse effect on fertility, lactation, litter size, weight, and appearance. [R47] *A 2 year toxicology and carcinogenesis study was conducted by feeding diets containing boric acid at concentrations of 0, 2,500, or 5,000 ppm to groups of 50 male and 50 female mice. ... Body weight gain was reduced in each sex after week 30; mean final body weights were 7% and 13% below control values for exposed male mice and 7% and 20% below those of controls for exposed female mice. No chemically related clinical signs were reported. At top dose, boric acid caused an increased incidence of testicular atrophy (control, 3/49; low dose, 6/50; high dose, 27/47) and interstitial cell hyperplasia (0/49; 0/50; 7/47) in male mice. The testicular atrophy was characterized by variable loss of spermatogonia, primary and secondary spermatocytes, spermatids, and spermatozoa from the seminiferous tubules. The seminiferous tubules contained primarily Sertoli cells and variable numbers of spermatogonia. In some mice, there were accumulations of interstitial cells, indicating hyperplasia. Under the conditions of these 2-year feed studies, there was no evidence of carcinogenicity of boric acid at doses of 2,500 or 5,000 ppm for male or female B6C3F1 mice. Testicular atrophy and interstitial cell hyperplasia were observed in high dose male mice. The decrease in survival of dosed male mice may have reduced the sensitivity of this study. [R48] *In rats, high boron levels at 1750 and 5250 ppm of borax and boric acid administered orally caused growth suppression, decreased food utilization efficiency, degeneration of gonads, and skin desquamation on the paws and tails. Both cmpd could be tolerated by rats and dogs at 350 ppm for two years. Rats fed either borax or boric acid at 1170 ppm were sterile, and testicular degeneration was observed in both rats and dogs fed this dosage. Both cmpd at 350 ppm had no adverse effect on fertility, lactation, litter size, weight, and appearance. [R49] *Adult male German cockroaches were exposed to surface deposits of insecticides for 5 min in the central compartment of a three-compartment choice chamber illuminated at one end. They were then allowed access to the escape compartments and their distribution recorded over the subsequent 60 min. ... Boric acid deposits inhibited the movement of the cockroaches away form the light source. [R50] *Twenty-six cows died after accidental exposure to boron fertilizer. Cows developed diarrhea, weakness, ataxia, signs of depression, and died, usually within a few hours. Seizure-like behavior was noticed in two cows, and two were suspected of aborting. High boron concentrations in tissues from affected cows confirmed ingestion of an appreciable amount of boron fertilier. In an attempt to confirm the diagnosis of boron poisoning, boron fertilizer was administered to goats. A kid goat given 3.6 g of fertilizer/kg of body weight developed clinical signs similar to those seen in the cattle. Boron compounds such as sodium borate and boric acid have been considered generally nontoxic, and reports of livestock toxicosis are uncommon. This case report suggests that these compounds may be palatable under certain circumstances leading to ingestion of toxic quantities. [R51] *The mutagenicity of borax and boric acid was examined in Salmonella typhimurium strains TA98 and TA100 by the preincubation method. No mutagenic activity of borax or boric acid was observed with or without S-9 rat liver enzymes. Experiments also were conducted to investigate the enhancement or inhibition of benzo(a)pyrene mutagenicity by the 2 compounds. Neither borax nor boric acid had any effect on the response of Salmonella typhimurium test to benzo(a)pyrene. [R52] *... BORATES INDUCE RIBOFLAVIN DEPLETION IN SEVERAL ANIMAL SPECIES ... /BORATE/ [R53] *IN LAMBS, GI AND PULMONARY DISORDERS HAVE BEEN REPORTED TO RESULT FROM GRAZING WHERE PASTURE SOILS ARE HIGH IN BORON CONTENT. /BORON AND ITS COMPOUNDS/ [R54] *Chronic feeding to rats and dogs leads to accumulation in the testes, germ cell depletion and testicular atrophy. /Borate/ [R41, p. III-67] +[DHHS/NTP; Toxicology and Carcinogenesis Studies of Boric Acid in B6C3F1 Mice (Feed Studies) p.3 Technical Report Series No. 324 (1987) NIH Publication No. 88-2580] ... Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenicity of boric acid at doses of 2,500 or 5,000 ppm for male or female B6C3F1 mice. ... The decrease in survival of dosed male mice may have reduced the sensitivity of this study. [R55] HTXV: *LD 37 mg boron/Kg as boric acid (ingestion); 210 mg boron/Kg as boric acid (dermal: infant) [R56] NTXV: *LD Guinea pig 175 mg boron/Kg as boric acid (ingestion); [R57] *LD50 Rat 900 mg B/kg; [R58] *LD50 Mouse 466 mg B/kg; [R58] ETXV: *LC50 TROUT 100 PPM (SOFT WATER; EXPOSURE WAS INITIATED SUBSEQUENT TO FERTILIZATION AND MAINTAINED THROUGH 4 DAYS POSTHATCHING) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R59] *LC50 TROUT 79 PPM (HARD WATER; EXPOSURE WAS INITIATED SUBSEQUENT TO FERTILIZATION AND MAINTAINED THROUGH 4 DAYS POSTHATCHING) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R59] *LC50 CATFISH 155 PPM (SOFT WATER; EXPOSURE WAS INITIATED SUBSEQUENT TO FERTILIZATION AND MAINTAINED THROUGH 4 DAYS POSTHATCHING) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R59] *LC50 CATFISH 22 PPM (HARD WATER; EXPOSURE WAS INITIATED SUBSEQUENT TO FERTILIZATION AND MAINTAINED THROUGH 4 DAYS POSTHATCHING) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R59] *LC50 GOLDFISH 46 PPM (SOFT WATER; EXPOSURE WAS INITIATED SUBSEQUENT TO FERTILIZATION AND MAINTAINED THROUGH 4 DAYS POSTHATCHING) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R59] *LC50 GOLDFISH 75 PPM (HARD WATER; EXPOSURE WAS INITIATED SUBSEQUENT TO FERTILIZATION AND MAINTAINED THROUGH 4 DAYS POSTHATCHING) /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R59] *LC50 Daphnia magna 133 (115-153) mg/l/48 hr /Static bioassay/; [R60] NTP: +[DHHS/NTP; Toxicology and Carcinogenesis Studies of Boric Acid in B6C3F1 Mice (Feed Studies) p.3 Technical Report Series No. 324 (1987) NIH Publication No. 88-2580] Toxicology and carcinogenesis studies were conducted by feeding technical grade boric acid (99.7% pure) to groups of male and female B6C3F1 mice for 2 yr. ... Diets containing boric acid /was fed/ at concentrations of 0, 2,500, or 5,000 ppm to groups of 50 male or 50 female mice. ... Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenicity of boric acid at doses of 2,500 or 5,000 ppm for male or female B6C3F1 mice. ... The decrease in survival of dosed male mice may have reduced the sensitivity of this study. [R55] +The potential reproductive toxicity of boric acid (BA) in CD- l (Swiss) mice was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) Protocol. Male and female Swiss (CD-l) mice were exposed to BA at concns of 0, 1000, 4500, or 9000 ppm in the feed; this produced estimated consumption levels of approx 152, 636, and 1262 mg/kg bw. During 14 wks of cohabitation with continuous access to a BA-containing diet, no litters of dead or live pups were produced by 9000 ppm cohabited pairs. Among the litters born to pairs fed BA at 4500 ppm, live litter size and pup body weight were significantly reduced in comparison to controls. All aspects of fertility were unaffected at 1000 ppm BA. A crossover mating trial (Task 3) at the end of the continuous cohabitation phase, using the middle dose group, confirmed the male as the affected sex, with observed fertility rates of: 0 ppm male x 0 ppm female, 74%; 4500 ppm male x 0 ppm female, 5%; and 0 ppm male x 4500 ppm female, 65%. The mating index was 79%, 30% and 70% for the same groups. Additionally, adjusted body weights, for pups born from the mating of control male x 4500 ppm female, were significantly decreased from controls (P < O.Ol), indicating that the female and/or pup are also affected by BA. At sacrifice, after 27 wks of BA exposure, the F0 males fed 9000 ppm BA had significantly lower body weight and reproductive organ weights (testes, combined caput and corpus epididymis and cauda epididymis) and significantly fewer spermatozoa in the cauda epididymis. Males fed 4500 ppm BA also had significantly lower testes, epididymis, prostate weight and fewer spermatozoa in the cauda epididymis. Organ weights were unaffected at 1000 ppm BA for the F0 males. The germinal epithelium of F0 males in the 9000 ppm group was atrophied and consisted mostly of Sertoli cells with occasional spermatogonia. The 4500 ppm group had fewer spermatids than in the controls; multinucleate giant cells were observed. Sperm concn/mg cauda was dramatically reduced in 9000 ppm males (2.8±1.7 x 103) compared to controls (519±36 x 103). Motility was difficult to quantify due to extremely low sperm concns. In 4500 ppm males, both sperm concn (146.9±26.5 x 103) and sperm motility (53.3± 8.2%) were lower than in controls (519±36 x 103 sperm with 78.1±3.0% motility). Males fed 1000 ppm BA had normal sperm concns with reduced motility (69.0±4.5%). At necropsy, F0 female body weight was significantly decreased in the high dose group. The F0 females in the 4500 ppm group had significantly decreased kidney/adrenals and liver weights. The F1 mice exposed to dietary BA (0 and 1000 ppm), beginning at conception, had normal fertility. The adjusted mean body weight of F2 pups was decreased. However, the number of live pups/litter, the proportion of pups born alive, sex of pups born alive, and unadjusted weights of pups born alive, were not significantly changed by BA exposure. At necropsy, F1 males had normal reproductive organ weights and sperm motility. However. BA treatment decreased sperm concns in F1 males (585.6±32.5 x 103 in controls vs. 442.6±51.2 x 103). Female F1 mice had significantly greater uterus and kidney/adrenal weights than controls. This study confirms that BA is a reproductive toxicant in mice, primarily through an effect in the male. The 1000 ppm dose approached a No Observed Adverse Effects Level (NOAEL) for the adult reproductive system, as well as for the developing reproductive system. [R61] +... In this study, developmental toxicity was evaluated in timed-mated Sprague-Dawley-derived (CD(R)) rats exposed to boric acid in feed at concentrations of 0.1%, 0.2% or 0.4% on gestational days (gd) 0 to 20 (n=29/group); exposure to 0.8% dietary boric acid (n=14) was restricted to the period of major organogenesis (gd 6 to 15) in order to limit early embryolethality. Average daily intake of boric acid was 78, 163, 330 and 539 mg/kg/day , respectively. Exposure to 0.2% and 0.4% resulted in increased maternal food intake for gd 12 to 20; water intake was increased on gd 18, to 20 at 0.4%. Food intake was decreased during treatment at 0.8% with a rebound increase on gd 15 to 18; water intake was decreased on gd 6 to 9. Other effects summarized across all dose levels included increased relative maternal liver and kidney wts. at greater than or equal to 0.2%, decreased gravid uterine weight at greater than or equal to 0.4%, decreased wt. gain during treatment and gestation at greater than or equal to 0.4%, and increased corrected body wt. gain only at 0.4%. Microscopic evaluation of maternal kidneys (10 dams/group) did not provide any definitive evidence for treatment-related renal pathology. Average fetal body wt./litter was reduced at all doses. Prenatal mortality was increased only at 0.8%. The incidence of fetal malformations was significantly increased at greater than or equal to 0.2% dietary boric acid (2, 3, 8, 50 and 73% malformed fetuses/litter in the control through high-dose groups). The most frequently observed malformations were enlarged lateral ventricles of the brain, and agenesis or shortening of rib XIII. As an associated finding, the incidence of Lumbar I rib(s), a common variation in the CD(R) rat, was reduced following boric acid treatment. In conclusion, the NOAEL for maternal toxicity was 0.1% dietary boric acid and the LOAEL was 0.2%. Embryo/fetal toxicity occurred in all treatment groups (greater than or equal to 0.1%). [R62] +Exposure of Sprague-Dawley-derived (CD(R) ) rats to boric acid (BORA) at 0.1. 0.2. or 0.4% in the diet (w/w) on gd 0-20, or 0.8% on gd 6-15 resulted in fetal body weight deficits ( greater than or equal to O.1% boric acid), increased incidence of malformations ( greater than or equal to O.2% boric acid), and increased prenatal mortality (0.8% boric acid) ... . Among the anatomical anomalies observed enlarged lateral ventricle(s) of the brain (ELV) occurred with an increased incidence in the 0.4% and 0.8% boric acid groups. These findings were accompanied by severe reductions in fetal body weights (63% and 46% of control weights, respectively). The present study was conducted to determine whether induction of ELV could be separated from fetal body weight deficits by focusing the exposure around a known sensitive period for induction of hydrocephaly in rat fetuses. The potential contribution of decreased maternal food intake to the developmental toxicity at 2.4% boric acid was also examined. In the present study, boric acid (0, 0.8, 1.6 or 2.4% in the diet) was provided to timed-mated female rats from gd 14 to 17. During the treatment period, the vehicle control group was fed undosed diet ad libitum, and a pair-fed control group was provided with the median amount of food consumed (g of food/kg of body wt/day) by the 2.4% boric acid group. During the remainder of the study, dams and pups had ad libitum access to undosed diet, except during the second week of lactation (Phase I) when food consumption exceeded the available supply of food during one measurement period. Thus, dam and pup data collected on pnd 14, 21 and 26 may have been compromised due to this temporary shortage of food. Mated females (n=16-17/group/study phase) were assigned to either Phase I (postnatal study) or Phase II (teratology study). In Phase I, dams were allowed to deliver and the offspring were evaluated for body weight, viability and major morphological defects (specifically, external craniofacial defects, palatal defects and CNS defects observed in free-hand sections) through postnatal day (pnd) 21. Pups were terminated on pnd 21, except that the median weight male in each litter was terminated on pnd 26 for evaluation of regional and total brain weights. In Phase II, dams were necropsied on gestational day (gd) 20 and the uterine contents were evaluated to determine prenatal viability. Live fetuses were weighed and examined for morphological defects as in Phase 1. During the treatment period (gd 14 to 17), maternal body weight gain and food consumption were depressed in all boric acid groups. Actual weight loss was experienced by the 2.4% boric acid and pair-fed control groups, with pair-fed animals experiencing the most severe weight loss. Rebound increases in maternal weight gain and food consumption were observed following cessation of boric acid exposure or pair feeding. Maternal water consumption was depressed during the first 24 hours of exposure (all boric acid groups and pair-fed controls), but returned to control levels by the last day of exposure or pair feeding; thus, increased water intake after the treatment period was probably secondary to rebound increases in food consumption. Maternal body weight on gd 20 (both phases), maternal weight gain for the gestational period as a whole (gd 0 to 20, both phases), gravid uterine weight (Phase II) and corrected maternal weight gain on gd 20 (Phase II) were not affected by boric acid exposure or by pair feeding. Maternal relative liver weight was increased on gd 20 (Phase II) by 1.6 and 2.4% boric acid, but not by pair feeding. This effect on relative liver weight was not present on pnd 21. No changes were noted for maternal relative kidney weight on gd 20 or pnd 21 in either the boric acid or pair-fed groups relative to the vehicle (ad libitum) control group. The pair-fed control group did not differ significantly from the ad libitum vehicle control group for any parameter related to offspring development in either phase of this study. In contrast, adverse effects were observed in all BORA-exposed groups. Fetal body weight was significantly reduced in the low, mid, and high dose boric acid groups on gd 20 (82%, 68% and 69% of control weight, respectively). By pnd 21, recovery from body weight deficits was complete for the low dose group (104% of control weight). Persistent body weight deficits were observed at the mid dose (83% of control weight; biologically relevant but not statistically significant) and at the high dose (75% of control weight: statistically significantly). Prenatal mortality was not affected on gd 20 (Phase II), but cumulative post-implantation mortality through pnd 21 was increased at the high dose (34%, 44%, 33% and 72% for the vehicle control through high-dose boric acid groups, respectively). The incidence of treatment-related mortality was most pronounced during the early postnatal period (pnd 0 to 4) as follows: 2%, 8%, 27% and 44% of pups per litter in the vehicle control through high-dose boric acid groups, respectively. No treatment-related effects were noted for the incidence of craniofacial, palatal or CNS structural defects. Changes in absolute brain weights (regional or total) observed in the mid- and high-dose groups were proportional to alterations in body weight on pnd-26, except that the relative weight of the medulla/pons was increased at the high dose. Analysis of brain regions (telencephalon, diencephalon, medulla oblongata/pons and cerebellum) as a percentage of total brain weight indicated that the relative weight of the telencephalon was decreased, while the relative weight of the medulla/pons was increased. No effects on regional or total brain weights were observed at 0.8% boric acid. In summary, gd 14 to 17 was not a sensitive period for boric acid-induced ventricular enlargement. However, fetal body weight was reduced at all doses. Low-dose offspring recovered completely from growth deficits by pnd 21, but body weight effects persisted in the mid- and high-dose groups. These results indicate that boric acid can reduce fetal body weight to 69% of control weight on gd 20 without a concomitant increase in the incidence of ventricular enlargement. However, this study did not answer the question of whether boric acid could induce more severe weight reductions without concomitant ventricular enlargement, or whether there is a sensitive period earlier in gestation for induction of ventricular enlargement in the absence of fetal body weight effects. Preliminary evidence is provided that exposure to boric acid (1.6% or 2.4% on gd 14 to 17) may alter brain weights (total and/or regional), but such effects were not found at 0.8% boric acid. Boric acid-induced developmental toxicity in this study occurred independently of maternal food intake and body weight deficits, since the pair-fed control group did not differ from the ad libitum control group for any developmental measure in this study. [R63] +In a previous study, Sprague-Dawley (CD(R) ) rats were exposed to boric acid (BORA) in the diet (0.1%, 0.2% or 0.4% on gestational days (gestational days) 0 to 20, or 0.8% on gestational days 6 to 15) resulting in average intakes of 78,163, 330 and 539 mg boric acid/kg/day. Evaluation on gestational day 20 revealed fetal body weight reduction at greater than or equal to 0.1 % boric acid, increased malformation incidence at greater than or equal to O.2% boric acid, and increased prenatal mortality at 0.8% boric acid ... . Among the anomalies observed, enlarged lateral ventricle(s) of the brain (ELV) occurred in 0% of control fetuses, but in 11 % and 35% of fetuses examined in the 0.4% and 0.8% boric acid groups, accompanied by severe reductions in fetal body weight (63% and 46% of control weight, respectively). Hydrocephaly was found in only one fetus (0.7%) in the 0.8% boric acid group, and in no fetuses from the other groups. ... The present study was designed to determine (1) whether the induction of ventricular enlargement could be experimentally repeated following exposure to boric acid on gestational days 6 to 15, (2) whether the incidence would exhibit a dose-response relationship at exposure concentrations of 0.4% to 0.8% boric acid in the diet, and (3) whether the incidence and severity of ventricular enlargement would change during postnatal life. Thus, in the present study, BORA (0.4%, 0.5%, 0.6% or 0.8% in the diet) was provided to timed-mated CD(R) rats (42-76/group) from gestational days 6 to 15. All dams were monitored at regular intervals throughout gestation for body weight, clinical condition, food intake and water intake. In Phase I (teratology evaluation), dams were terminated and the uterine contents evaluated on gestational day 20. In Phase II, dams were allowed to deliver and rear their litters until postnatal day (pnd) 21. ... Phase I (and Phase II) dams ingested average doses of 299 (283), 361 (368), 432 (434), or 549 (562) mg boric acid/kg/day in the low- through high-dose groups, respectively. Maternal effects were generally consistent with the results of the earlier study. No maternal deaths occurred, but all boric acid-exposed groups exhibited decreased body weight gain during the treatment period as a whole (gestational days 6 to 15) and at the end of gestation (gestational days 18 to 20). Reduced gravid uterine weight contributed to maternal weight gain deficits, so that neither corrected maternal weight gain (Phase I), nor maternal body weight on postnatal day 0 (Phase II) differed among groups. Maternal body weight deficits observed in the 0.5%-0.8% boric acid group were indicative of residual maternal effects during lactation, especially at the high dose. Food intake decreased across groups during treatment. In Phase I, only the high dose was significantly below controls, but all groups were below controls in Phase II (the high dose reduction in Phase II did not reach statistical significance, apparently due to the smaller number of dams, but did appear to be biologically relevant). After treatment ended, maternal food and water intake increased in all boric acid-exposed groups (gestational days 15 to 20). Maternal relative liver weight was increased at 0.8% boric acid on gestational days 20, and decreased at greater than or equal to 0.6% boric acid on postnatal day 21. Relative kidney weight was increased at greater than or equal to 0.5% boric acid on gestational day 20, with no treatment- related effects on postnatal day 21. Post implantation mortality (i.e., resorption, late fetal death and postnatal death) was increased at greater than or equal to 0.6% BORA on gestational days 20 (4%, 4%, 5%, 9% and 25% for control through high-dose groups), and at all BORA exposures by postnatal day 21 (9%,17%, 30%, 64% and 97%). The 0.8% BORA group was eliminated from Phase 11 (postnatal evaluation) in the second study replicate due to excessive offspring mortality. It is noteworthy that approximately 1%, 5%,17%, 45% and 67% of live bom pups in the control through high-dose groups were missing between postnatal day 0 and 14, presumably due to cannibalism by their own dams. This substantially reduced the numbers of boric acid-exposed pups available for examination of internal head structures, and may have biased the incidence of related findings. Offspring body weight was decreased in all boric acid-exposed groups on gestational day 20 (79%, 70%, 62% and 51 % of control weight for the low- to high-dose groups) and on postnatal day 0 (94%, 87%, 76% and 66% of control weight). On postnatal day 14 and 21, the average weight of offspring in the 0.4-0.6% boric acid groups was comparable to controls (96-107% of control weight per group). Posthoc analysis of body weight (postnatal day 4, 7, 14 and 21) for the subset of pups surviving to postnatal day 21 supported the interpretation that pups actually recovered from intrauterine growth retardation, that is, recovery was not due simply to attrition of low weight offspring. However, persistent weight deficits were still noted on postnatal day 21 (76% of control weight) at 0.8% boric acid. Craniofacial (external) malformations were observed in 28% of high-dose fetuses on gestational day 20 and 17% of high-dose pups on postnatal day 21, as compared to 0% for controls at both ages. As in the earlier study, anophthalmia and microphthalmia were the most frequently observed craniofacial malformations. Examination of head sections revealed a high background incidence of minimal ventricular enlargement (ELV) on gestational day 20 (77% of control fetuses), with a dramatic decrease in ELV by postnatal day 21 (2% of control pups). On gestational day 20, ELV incidence was increased at 0.4%-0.6% boric acid (92-95%), but not in the 0.8% group (80%), and no treatment-related effects were observed on postnatal day 21. Furthermore, covariate analysis in this study indicated that lower fetal body weight was associated with higher incidence and greater severity of ELV. After adjusting for body weight effects, there were no significant dose-related effects of boric acid on ELV incidence or severity, and incidence of ELV was elevated only at 0.5% boric acid ELV incidence and severity did not covary with pup body weight on postnatal day 21. Since the incidence of this finding has increased in control CD(R) rat fetuses in our laboratory in recent years, the high incidence observed in this study is most likely due to a shift in incidence for the experimental population as a whole. Based upon the high control incidence of ELV on gestational day 20, and the low incidence on postnatal day 21, ELV on gestational day 20 (e.g., minimal separation of the lateral ventricular walls) appears to represent a normal stage of CNS development for the population of rats examined in this study. In contrast to ELV, hydrocephaly, which is characterized by more extensive separation of the ventricular walls and generally accompanied by loss or compression of CNS tissue, was not observed in any control fetuses or pups from this study, but was found in 2%, 1 %, 5% and 15% of boric acid-exposed fetuses (low to high dose) on gestational days 20, in 5 and 9% of the premature postnatal deaths examined in the 0.6% and 0.8% boric acid groups, and in 0.3% of pups at 0.4% boric acid and 2% of pups at 0.6% boric acid on postnatal day 21. Covariate analysis in this study indicated that lower fetal body weight was associated with higher incidence and greater severity of hydrocephaly. After adjusting for fetal body weight effects, there remained a significant dose-related effect of treatment upon hydrocephaly incidence and severity for all boric acid groups. Covariate analysis indicated that hydrocephaly severity, but not incidence, covaried with pup body weight on postnatal day 21. There were dose-related increasing trends, and increased incidence and severity of hydrocephaly at 0.4% and 0.6% boric acid on postnatal day 21 relative to the control group. In the earlier study, 0. 1 % boric acid (gestational days 0 to 20) was the LOAEL for reduced fetal body weight. Exposure to 0.4-0.8% boric acid (gestational days 6 to 15) in this study was also associated with dose-related intrauterine growth retardation. Complete recovery from growth deficits was observed prior to the end of lactation at 0.4-0.6% boric acid, but not at 0.8% boric acid. The LOAEL for post implantation mortality was 0.8% boric acid. In the earlier study ..., but was 0.4% boric acid in this study when postnatal mortality was taken into consideration. After adjusting for fetal body weight by covariate analysis, the incidence of ELV showed no significant dose-response relationship, but the incidence of hydrocephaly was increased at all doses. These results support the interpretation that boric acid exposure during organogenesis adversely affects CNS development in the rat independent of its effect upon fetal growth. The LOAEL for adverse CNS effects in this study was 0.4% boric acid in the diet, consistent with the outcome of the prior investigation in which CNS findings were observed at 0.4% (gestational days 0 to 20) and 0.8% (gestational days 6 to 15), but not at less than or equal to 0.2% boric acid (gestational days 0 to 20). [R64] +Boric acid (BORA), ... was tested for developmental toxicity in timed-mated CD-1(R) mice. BORA (0, 0.1, 0.2 or 0.4% in feed) was administered from gestational day 0 to 17 with average intakes of 248, 452 or 1003 mg/kg/day . Dams exposed to 0.4% BORA exhibited decreased weight gain during treatment (gestation) compared to controls, even though food and water consumption were not reduced. Gestational weight gain corrected for gravid uterine weight was not affected. High-dose BORA caused increased water consumption during late gestation (gd 15-17) and increased relative kidney weight. A dose-related incidence of renal tubule dilatation/regeneration was observed in 0/10, 2/10, 8/10 and 10/10 randomly selected dams in the control through high-dose groups. Reduction of fetal body weight was dose-dependent (94%, 89% and 66% of controls), but statistically significant only at 0.2 and 0.4% BORA. The high-dose group had an increased percentage of resorptions (19% vs. 6% for controls) and malformed fetuses/litter (9% vs. 3% for controls). The most apparent treatment-related morphological changes involved deficient rib development at the thoracic-lumbar junction, i.e., an increased incidence of short rib XIII (a malformation) and a decreased incidence of rudimentary or full rib(s) at Lumbar I (an anatomical variation). In summary, maternal renal toxicity was observed at all BORA exposures. The low exposure (0.1%) approached the maternal no-observed adverse effect level (NOAEL) with mild renal lesions in only 2 of 10 females. The NOAEL for developmental toxicity of BORA was 0.1%. [R65] +Artificially-inseminated New Zealand White (NZW) rabbits (30 per group) were exposed to 0, 62.5, 125 or 250 mg/kg/day boric acid. Aqueous solutions were delivered by gavage in a volume of 5 ml/kg on gestational days (gd) 6-19. At study termination (gestational days 30), the uterus was examined to determine pregnancy status (18-23 pregnancies/group), and to evaluate the number of resorptions, and dead or live fetuses. ... Pregnant does exhibited no overt symptoms attributable to boric acid toxicity, except that vaginal bleeding was noted at 250 mg/kg/day (2-11 does/day on gestational days 19-30). All high-dose does with this symptom had no live fetuses on gestational days 30. Vaginal bleeding was not observed in any control females, and in only one female/group at 62.5 or 125 mg/kg/day (day 20 or 22, respectively; each female had 5-7 live fetuses at term). Maternal deaths (one each in the 62.5 or 125 mg/kg/day groups on gestational days 25 and 22, respectively) were not clearly related to boric acid treatment. Maternal food consumption was decreased during most of the treatment period (gestational days 6-15) at 250 mg/kg/day , and was increased at 125 and 250 mg/kg/day after treatment (gestational days 25-30). Maternal body weight (gestational days 9-30), weight gain during treatment (gestational days 6-19), gravid uterine weight and number of corpora lutea per dam were each decreased at 250 mg/kg/day . Corrected maternal weight gain was increased at both 125 and 250 mg/kg/day . Maternal liver weight (absolute or relative) was not affected by boric acid exposure. Relative maternal kidney weight was increased at 250 mg/kg/day , but absolute kidney weight was not affected. Microscopic evaluation of maternal kidney sections did not indicate any pathology associated with boric acid exposure. Thus, 250 mg/kg/day was the "Lowest Observed Adverse Effect Level" (LOAEL) for pregnant does, and 125 mg/kg/day was the maternal "No Observed Adverse Effect Leve1" (NOAEL). No definitive evidence of developmental toxicity was observed following exposure of pregnant does to either 62.5 or 125 mg/kg/day boric acid during the period of major organogenesis (gestational days 6-19). At 250 mg/kg/day , developmental toxicity included a high rate of prenatal mortality (90% of implants/litter were resorbed vs. 6% for controls). Prenatal mortality was also expressed as an increased proportion of pregnant females with no live fetuses (73% vs 0% of controls) and as a reduction in the number of live fetuses/live litter on gestational days 30 (2.3/litter vs. 8.8 for controls). The incidence of malformed live fetuses/litter was also increased at 250 mg/kg/day (81% vs. 26% for controls), primarily due to the incidence of fetuses with cardiovascular defects (72% vs. 3% for controls). The most prevalent cardiovascular malformation was interventricular septal defect which was observed in 57% (8/14) of high dose fetuses as compared to 0.6% (1/159) of fetuses in the control group. At 250 mg/kg/day , the average fetal body weight/litter was 92% of the average control weight, but this difference did not reach statistical significance. Thus, 250 mg/kg/day was the LOAEL for developmental toxicity and 125 mg/kg/day was the NOAEL. In summary, decreased food intake and vaginal bleeding associated with pregnancy loss were the only clear manifestations of toxicity in does exposed to 250 mg/kg/day boric acid on gestational days 6-19. The same dose was associated with severe developmental toxicity, i.e. 90% prenatal mortality/litter and 81% malformed fetuses/litter. No definitive maternal or developmental effects were observed at 62.5 or 125 mg/kg/day. [R66] ADE: *BORIC ACID IS READILY ABSORBED FROM GI TRACT, SEROUS CAVITIES, AND ABRADED OR INFLAMED SKIN. IT DOES NOT PENETRATE INTACT SKIN. APPROX 50% OF GIVEN DOSE IS EXCRETED WITHIN 24 HR. DURING CHRONIC ADMIN, PLATEAU IN URINARY EXCRETION IS REACHED ONLY AFTER 2 WK. ... LARGE AMT OF BORIC ACID ARE LOCALIZED IN BRAIN, LIVER, AND KIDNEY. ... INTRACYTOPLASMIC INCLUSIONS IN PANCREAS /HAVE BEEN NOTED/ IN FATAL CASES. [R26, 995] *SLOW EXCRETION ... CONTRIBUTES TO CUMULATION ... [R26, 994] *By studies in adult volunteers who were heavily exposed to 5% solution or to 10% boric acid ointment, they showed by analysis of the urine that no detectable boron was absorbed from the intact skin. [R18] *A single oral dose of 750 mg of boric acid was administered to each of six human volunteers. At least 93.9% of the dose was absorbed from the gatrointestinal tract, as measured by the recovery of boric acid in urine after 96 hours. [R67] *Eight male volunteers aged 22-28 years were infused intravenously with boric acid in sterile water (21 mg/ml) over 20 minutes. Urinary excretion of boron was 98.7% of the dose in 120 hours after treatment. This indicated nearly complete excretion of boron with no tendency for tissue accumulation. None of the volunteers registered any discomfort following iv infusion of boric acid solution. [R68] *Using an in vitro technique it has been demonstrated that water emulsifying and hydrophobic ointments containing boric acid liberate only minute amounts (1-6%) within 24 hr compared with the nearly total liberation from a jelly. When an amount of boric acid containing ointment is swallowed, the absorption is only slightly delayed compared with a similar intake when dissolved in water, and in both cases nearly total excretion is found in the urine within 96 hr. The half-life is 21 hr (mean 7 adult men). The pharmacokinetics rule out the risk of cumulative poisoning with topical preparations containing low amounts of boric acid. The use of water emulsifying ointments containing up to 3% boric acid should be safe, even for repeated daily use in the napkin region. [R69] *Six male volunteers aged 30-58 years received single oral doses of boric acid. Three volunteers ingested 750 mg boric acid dissolved in 100 ml of water. Three other volunteers swallowed 24.95 g to 49.6 g of commercial water-emulsifing ointment containing 2.97% (wt/wt) boric acid The accumulated mean 96 hour excretion was 93.9% of the dose after ingestion of the solution and 92.4% after ingestion of the ointment. The initial urinary excretion rate was generally lower after ingestion of the ointment than after ingestion of solution. More than 50% of the ingested dose was excreted within the first 24 hr post-ingestion. No adverse health effects were reported for any of the individuals following a single ingestion of about 1.8 mg boron/kg during the 96 hour observation period. [R33] *VAPORS /OF BORON HYDRIDES/ ARE ABSORBED BY LUNG, LIQUIDS OR DISSOLVED BORANES BY SKIN AND IN ANY FORM FROM DIGESTIVE TRACT. /BORON HYDRIDES/ [R70] *BORATES ARE RAPIDLY ABSORBED FROM MUCOUS MEMBRANES AND ABRADED SKIN, BUT NOT FROM INTACT OR UNBROKEN SKIN. ... BORATE EXCRETION OCCURS MAINLY THROUGH KIDNEYS; ABOUT HALF IS EXCRETED IN 1ST 12 HR, AND REMAINDER IS ELIMINATED OVER PERIOD OF 5 TO 7 DAYS. /BORATE/ [R41, p. III-67] METB: +Boric acid is excreted unchanged in the urine. [R18] INTC: *BORIC ACID ENHANCED ACTION OF HYPNOTICS, BUT DEVOID OF ACTIVITY ITSELF. [R45] *The usefulness of N-acetylcysteine (NAC) as a chelating agent was studied for ... boric acid. Mature Sprague-Dawley rats were intoxicated; urinary excretion rates of intoxicant and total urine volume were determined during treatment. N-acetylcysteine proved to be the most effective agent at increasing the excretion of boron and was also able to reverse the oliguria associated with this chemical. [R71] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: */Former use:/ The substance is included in rectal suppositories for hemorrhoids ... [R23] *Aqueous solutions of boric acid are used topically for ophthalmic irrigation to relieve tired or irritated eyes. [R72] *Boric acid, borates and perborates have been used as mild antiseptics or bacteriostats in eyewashes, mouthwashes, burn dressings, and diaper rash powders; however, the effectiveness of boric acid has largely been discredited. [R29, 131] +MEDICATION (VET): ANTIBACTERIAL, ANTIFUNGAL AGENT; USED CHIEFLY IN AQUEOUS SOLN OR POWDERS FOR EXTERNAL USE. [R5] *Boric acid ... /has been used/ medically as eye washes and as lotions and dressing on the skin without inducing local injury. ... Disturbances of vision ... observed in patients who had been poisoned by boric acid used as a wash or dressing for wounds. These disturbances were ... decrease of visual acuity to half normal, plus diplopia lasting for more than two weeks. [R73] *Astringent, antiseptic [R5] +AS PRESERVATIVE IN OPHTHALMIC SOLN ... RETARDS GROWTH OF FUNGI BUT IS NOT BACTERICIDAL. ... 2% SOLN (PH 4.6) IS USEFUL VEHICLE FOR ALKALOIDAL DRUGS ... [R72] +IT IS NOW USUALLY COLORED TO PREVENT ERROR. ... MOST HOSPITALS LIMIT USE ... TO OPHTHALMIC OINTMENT. ... FEW COMMERCIAL DERMATOLOGICAL PREPN CONTAIN ... BORIC ACID TODAY. [R23] WARN: *... The chronic use of boric acid in rectal suppositories and in vaginal deodorants carries the risk of intoxication. [R23] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: +OCCURS IN NATURE AS THE MINERAL SASSOLITE. [R5] *Boron is widely distributed in the environment. ... Borax, kernite, and tourmaline are three of the more commonly mined boron minerals. /Boron/ [R29, 130] *High levels of boron are most likely to occur in soil derived from marine sediments and arid soils. /Total boron/ [R74] KOC: *Some boron is adsorbed by iron and aluminum hydroxy compounds and clay minerals. Finer textured soils retain added boron longer than do coarse, sandy soils. ... Boron sorption by clay minerals and iron and aluminum oxides is pH dependent, with maximum sorption in the range 7-9. The amount of boron adsorbed depends on the surface area of the clay or oxide and this sorption is only partially reversible ... /Boron/ [R74] WATC: *Sea water: Boron is widely distributed in the environment ... 4.5 ug/g in ocean waters ... /Total boron/ [R29, 130] *Surface water: Boron is widely distributed in the environment ... about 0.01 ug/g in freshwater. /Total boron/ [R29, 130] SEDS: *Boron is widely distributed in the environment ... concn average 3-10 ug/g in soil ... /Total boron/ [R29, 130] FOOD: *Most foods contain less the 6 ug boron/g, with many ... less than 0.5 ug B/g. Individual foods may contain more than 20 ug B/g. [R29, 130] AVDI: *Total daily boron intake in normal human diets ranges from 2.1-4.3 mg boron/kg body weight (bw)/day. /Total boron/ [R75] BODY: *In serum (children): Conventional reference range: < 7 mg/l; international recommended reference range: < 119 umol/l /From table, borate/ [R76] *In serum (male adult): Conventional reference range: < 2 mg/l; international recommended reference range: < 34 umol/l /From table, borate/ [R76] *In serum (toxic concn): Conventional reference range: > 20 mg/l; international recommended reference range: > 340 umol/l /From table, borate/ [R76] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Boric acid is exempted from the requirement of a tolerance when used as a sequestrant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R77] *Tolerances for total boron, calculated as elemental boron, are established as follows: 8 ppm in or on citrus fruits to cover residues from postharvest application of the fungicides borax and boric acid .... [R78] OOPL: *1-5 mg/cu m (USSR) /Borates/ [R29, 136] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 600 ug/l /Boron/ [R79] STATE DRINKING WATER GUIDELINES: +(CA) CALIFORNIA 1000 ug/l /Boron/ [R79] +(FL) FLORIDA 630 ug/l /Boron/ [R79] +(ME) MAINE 620 ug/l /Boron/ [R79] +(MN) MINNESOTA 600 ug/l /Boron/ [R79] +(NH) NEW HAMPSHIRE 630 ug/l /Boron/ [R79] +(WI) WISCONSIN 960 ug/l /Boron/ [R79] FIFR: *Boric acid is exempted from the requirement of a tolerance when used as a sequestrant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R77] *Tolerances for total boron are established in or on citrus fruits to cover residues from postharvest application of the fungicides borax and boric acid .... [R78] FDA: *Boric acid is an indirect food additive for use only as a component of adhesives. [R80] *Boric acid is used in the manufacture of paper and paperboard products used in food packaging for use in adhesives, sizes, and coatings. [R6] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Boric acid in deodorants and anti-perspirants is determined by titration with sodium hydroxide in presence of mannitol. [R81, p. 12/648 35.019] *Boric acid in face powder is determined by titration with sodium hydroxide in presence of mannitol. [R81, p. 12/651 35.036] *Boric acid in foods is determined by titration with sodium hydroxide in presence of mannitol. [R81, p. 12/354 20.036] *Boric acid in foods is determined by spectrophotometric method at 555 nm. [R81, p. 12/355 20.037] *Boric acid in food is determined by atomic absorption spectrophotometric method. [R81, p. 12/355 20.042] *Boric acid in mineral waters is determined by titration in presence of manitol. [R81, p. 12/625 33.130] *Characteristic flame test ... can identify boron at levels as low as 0.2 ug in material adhering to a platinum wire loop. At least 26 colorimetric and 4 fluorescent reagents are known for qualitative identification ... with sensitivities of < 1 ug/ml and 0.04 ug (absolute), respectively. /Boron/ [R29, 137] *Spectrophotometric methods include atomic absorption, flame emission, spark or arc emission, and ICAPES. ... Are capable of determining microgram or submicrogram quantities. A neutron activation technique using solid-state tract detectors ... to determine boron in biological material at levels below 0.1 ug/ml in 0.5 ul aliquots. /Boron/ [R29, 137] *DETERMINATION OF BORON IN PLANTS BY EMISSION SPECTROGRAPHIC METHOD. /BORON/ [R81, p. 13/871 49.001] *DETERMINATION OF ACID-SOLUBLE BORON IN FERTILIZERS BY TITRATION. /BORON/ [R81, p. 13/21 2.114] *DETERMINATION OF BORON IN PLANTS BY COLORIMETRY. /BORON/ [R81, p. 13/46 3.102] *EPA Method 200.7: An Inductively Coupled Plasma - Atomic Emission Spectrophotmetric method for the determination of dissolved, suspended, or total elements in drinking water, surface water, and domestic and industrial wastewaters, is described. Boron is analyzed at a wavelength of 249.773 nanometers and has an estimated detection limit of 5.0 ug/l. /Total boron/ [R82] *The curcumin method is applicable for the determination of boron concentrations in the 0.10 to 1.0 mg/l range. When a sample of water containing boron is acidified and evaporated in the presence of circumin, a red colored product called rosocyanine is formed. The rosocyanin is taken up in a suitable solvent and the red color is compared with standards visually or photometrically. A synthetic sample contaning 240 ug boron/l, 40 ug arsenic/l, 250 mg beryllium/l, 20 ug selenium/l, and 6 ug vanadium/l in distilled water was analyzed in 30 laboratories by the curcumin method with a relative standard deviation of 22.8% and a relative error of 0%. /Total boron/ [R83] *The carmine method is suitable for the determination of boron concn in the 1 to 10 mg/l range. In the presence of boron, a soln of carmine or carminic acid in concn sulfuric acid changes from a bright red to a bluish red or blue, depending on the concn of boron present. The ions commonly found in water and wastewater do not interfere with this method. A synthetic sample containing 180 ug boron/l, 50 ug arsenic/l, 400 ug beryllium/l, and 50 ug selenium/l in distilled water was analyzed in nine laboratories by the carmine method with a relative standard deviation of 35.5% and a relative error of 0.6%. /Total boron/ [R84] *Method 305: Emission spectroscopy for the determination of boron in water and wastewater samples using an inductively coupled plasma source. The exact choice of emission line is related to sample matrix and instrumentation. A typically used emission line for boron in water is a wavelength of 249.8 nm, with an expected detection limit of 5.0 ug/l. /Total boron (from table)/ [R85] CLAB: *Boric acid is determined by ashing tissues in an alkaline medium at 600 deg C, dissolving in hydrochloric acid, centrifuging, mixing part of the supernatant with carminic acid in sulfuric acid and measuring the color at 575 nm after 1 hr. [R86] *Spectrophotometric methods include atomic absorption, flame emission, spark or arc emission, and ICAPES. ... Are capable of determining microgram or submicrogram quantities. A neutron activation technique using solid-state tract detectors ... to determine boron in biological material at levels below 0.1 ug/ml in 0.5 ul aliquots. /Boron/ [R29, 137] *Biological fluids may often be analyzed directly by inductively coupled plasma-atomic emission spectrometry. Many products require ashing with a fixative to remove organic material and to convert boron compounds to the borate form. ... The most frequently used extractant for both original or ashed materials is 2-ethyl-1,3-hexanediol in methylisobutyl ketone solvent. /Boron cmpd/ [R29, 137] *Boron is detectable in urine and sometimes in cerebrospinal fluid by the turmeric paper test (Boggs and Anrode, 1955), but quantitative techniques have been used to measure boron in blood. /Borate/ [R41, p. III-68] *Plasma atomic emission spectrometry detection limit 0.001 mg boron/l; 0.012 mg boron/l (in urine). /Boron/ [R57] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Siegel E, Wason S; Pediatr Clin North Am 33 (2): 363-67 (1986) Nat'l Research Council Canada; Data Sheets on Selected Toxic Elements (1982) NRCC No. 19252 USEPA; Health Advisory for Boron (Draft) (1988) USEPA/OWRS; Quality Criteria for Water 1986 Boron (1986) EPA 440/5-86-001 DHHS/ATSDR; Toxicological Profile for Boron (1992) ATSDR/TP-91/05 DHHS/NTP; Toxicology and Carcinogenesis Studies of Boric Acid in B6C3F1 Mice (Feed Studies) Technical Report Series No. 324 (1987) NIH Publication No. 88-2580 SO: R1: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. 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U.S. EXPORTS, SCHEDULE E, 1984 p.2-88 R17: BUREAU OF THE CENSUS. U. S. EXPORTS, SCHEDULE E, DECEMBER 1987, P.2-93 R18: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 62 R19: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-77 R20: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R22: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R23: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 971 R24: NIOSH. Pocket Guide to Chemical Hazards. 2nd Printing. 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New York, NY: Elsevier Science Publishing Co., Inc. 1988. 922 R32: Linden CH et al; Clin Toxicol 24: 269-79 (1986) as cited in USEPA; Health Advisory for Boron (Draft) p.6 (1988) R33: Jansen JA et al; Food Chem Toxicol 22: 49-53 (1984) as cited in USEPA; Health Advisory for Boron (Draft) p.6 (1988) R34: Goldbloom RB, Goldbloom A; J Pediat 43: 631-43 (1953) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 50 (1980) R35: Wong LC et al; Can Med Assoc J 90: 1018-23 (1964) as cited in Baselt RC; Biological Monitoring Methods for Industrial Chemicals p. 50-1 (1980) R36: Grella PB et al; Acta Anaesthesiol 27: 745-8 (1976) as cited in USEPA; Health Advisory for Boron (Draft) p.5 (1988) R37: Egfjord M et al; Hum Toxicol 7 (2): 175-8 (1988) R38: Garabrant DH; J Occup Med 26 (8): 584-86 (1984) R39: Litovity TL et al; Am J Emerg Med 6 (3): 209-13 (1988) R40: Pinto JT, Rivlin S; Drug Nutr Interact 5 (3): 143-51 (1987) R41: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R42: Haddad, L.M. and Winchester, J.F. Clinical Management of Poisoning and Drug Overdosage. Philadelphia, PA: W.B. Saunders Co., 1983. 931 R43: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 36 R44: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. 92 R45: PHAM HUU CHANH ET AL; AGRESSOLOGIE 15 (1): 61-72 (1974) R46: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 75 R47: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2985 R48: NTP; Toxicology and Carcinogenesis Studies of Boric Acid p.3 Report# 324 (1987) NIH Pub# 88-2580 R49: Weir RJ, Fisher RS; Toxicol Appl Pharmacol 23 (3): 351-64 (1972) R50: Miall SM, Le Patourel GNJ; Pestic Sci 25 (1): 43-52 (1989) R51: Sisk DB et al; J Am Vet Med Assoc 193 (8): 943-5 (1988) R52: Benson WH et al; Environ Toxicol Chem 3 (2): 209-14 (1984) R53: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-82 R54: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 440 R55: Toxicology and Carcinogenesis Studies of Boric Acid in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 324 (1987) NIH Publication No. 88-2580 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R56: Nat'l Research Council Canada; Data Sheets On Selected Toxic Elements, p. 24 (1982) NRCC No. 19252 R57: Nat'l Research Council Canada; Data Sheets On Selected Toxic Elements, p. 23 (1982) NRCC No. 19252 R58: USEPA; Health Advisory for Boron (Draft) p.7 (1988) R59: BIRGE WJ, BLACK JA; SENSITIVITY OF VERTEBRATE EMBRYOS TO BORON COMPOUNDS p. 1-77 (1977) NTIS# PB-267085 R60: Gersich FM; Environ Toxicol Chem 3 (1): 89-94 (1984) R61: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Boric Acid (CAS No. 10043-35-3) in CD-1 Swiss Mice, NTP Study No. RACB88034 (April 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R62: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of Boric Acid (CAS No. 10043-35-3) in Sprague-Dawley Rats, NTP Study No. TER89027 (May 1, 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R63: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Boric Acid (CAS No. 10043-35-3) CNS Developmental Toxicity Studies in Sprague-Dawley CD(R) Rats Exposed on Gestation Days 14-17, NTP Study No. TER90123 (October, 1994) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R64: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; CNS Developmental Toxicity of Boric Acid (CAS No. 10043-35-3) in Sprague-Dawley CD(R) Rats Exposed on Gestation Days 6-15, NTP Study No. TER93138 (October, 1994) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R65: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Final Report on the Developmental Toxicity of Boric Acid (CAS No. 10043-35-3) in CD-1(R) Swiss Mice, NTP Study No. TER89028 (August 11, 1989) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R66: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of Boric Acid (CAS No. 10043-35-3) in New Zealand White Rabbits, NTP Study No. TER90003 (November 1991) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 14, 2002 R67: USEPA; Health Advisory for Boron (Draft) p.3 (1988) R68: Jansen JA et al; Arch Toxicol 55: 64-7 (1984) as cited in USEPA; Health Advisory for Boron (Draft) p.6 (1988) R69: Schou JS et al; Arch Toxicol Suppl 7: 232-5 (1984) R70: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 202 R71: Banner W JR et al; Toxicol Appl Pharmacol 83 (1): 142-47 (1986) R72: American Hospital Formulary Service-Drug Information 88. Bethesda, MD: American Society of Hospital Pharmacists, 1988 (Plus supplements). 1527 R73: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 150 R74: Brown, K.W., G. B. Evans, Jr., B.D. Frentrup (eds.). Hazardous Waste Land Treatment. Boston, MA: Butterworth Publishers, 1983. 211 R75: Zook EG, Lehman J; J Assoc Off Agric Chem 48: 850-5 (1965) R76: Tietz, N.W. (ed.). Clinical Guide to Laboratory Tests. Philadelphia, PA: W.B. Saunders Co., 1983. 88 R77: 40 CFR 180.1001(d) (7/1/88) R78: 40 CFR 180.271 (7/1/88) R79: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R80: 21 CFR 175.105 (4/1/88) R81: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982. R82: 40 CFR 136 (7/1/88) R83: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.274-6 (1985) R84: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.276-7 (1985) R85: Franson MA (Ed): Standard Methods for the Examination of Water and Wastewater p.181 (1985) R86: Kobylecka K, Sadlik J; Krim Forensisch Wiss 41: 77-9 (1980) RS: 77 Record 131 of 1119 in HSDB (through 2003/06) AN: 1504 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRANS-1,3-DICHLOROPROPENE- SY: *(E)-1,3-DICHLOROPROPENE; *TRANS-1,3-DICHLORO-1-PROPENE-; *TRANS-1,3-DICHLOROPROPYLENE-; *DI-TRAPEX-; *1-PROPENE, 1,3-DICHLORO-, (E)-; *PROPENE, 1,3-DICHLORO-, (E)-; *Propylene, 1,3-dichloro-(trans); *Telone-II- RN: 10061-02-6 RELT: 1109 [1,3-DICHLOROPROPENE] (MIXTURE); 6293 [DICHLOROPROPENE] (MIXTURE); 6298 [DICHLOROPROPANE-DICHLOROPROPENE MIXTURE] (MIXTURE) MF: *C3-H4-Cl2 SHPN: UN 2047; Dichloropropenes IMO 3.2; Dichloropropenes MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *Mixture of equal quantities of (E)- and (Z)-isomers /1,3-Dichloropropene/ [R1] *1,3-DICHLOROPROPENE TRANS-ISOMER, 45.9%; CIS-ISOMER, 41.6%; 1,2-DICHLOROPROPANE, 2.5%; TRICHLOROPROPENE ISOMER, 1.5%; EPICHLOROHYDRIN, 1.0%; OTHER IMPURITIES 7.5% /TELONE II/ [R2] MFS: *Dow AgroSciences LLC, 9300 Zionsville Rd., Indianapolis, IN 46268 (317) 335-3000; Production site: Freeport, TX 77541 [R3] USE: *Used primarily in soil fumigants for nematodes or as component of soil fumigant mixtures /for nematodes/. [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to amber liquid /1,3-Dichloropropene/ [R1] ODOR: *CHLOROFORM-LIKE ODOR [R4]; *Sharp, sweet, penetrating odor /1,3-Dichloropropene/ [R5, p. V1 810] BP: *112 deg C [R6] MW: *110.97 [R6] DEN: *1.224 @ 20 deg C/4 deg C [R6] OWPC: *log Kow= 2.03 [R1] SOL: *Sol in ether, benzene, chloroform [R6]; *In water, 2,800 mg/l @ 25 deg C. [R5, 810] SPEC: *Index of refraction: 1.4682 @ 20 deg C [R6]; *IR: 2560 (Coblentz Society Spectral Collection) [R7]; *NMR: 14414 (Sadtler Research Laboratories Spectral Collection) [R7]; *MASS: 347 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R8] VAPD: *1.4 AT 37.8 DEG C (AIR= 1) [R4] VAP: *34 mm Hg @ 25 deg C [R5, 810] OCPP: *Henry's Law constant = 8.7X10-4 atm-cu m/mole @ 20 deg C [R9] *Hydroxyl radical reaction rate constant = 1.4X10-11 cu cm/molecule-sec @ 25 deg C [R10] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Dichloropropenes/ [R11] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Dichloropropenes/ [R11] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Dichloropropenes/ [R11] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. /Dichloropropenes/ [R11] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Dichloropropenes/ [R11] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Dichloropropenes/ [R11] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Dichloropropenes/ [R11] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Dichloropropenes/ [R11] FPOT: *A dangerous fire hazard when exposed to heat, flame, or oxidizers. [R12] EXPL: *5% and 14.5% by vol in air /46% cis and 53% trans with 1% other materials, primarily epichlorohydrin/ [R13] REAC: *... /CIS-TRANS MIXTURE/ REACTS READILY WITH ALUMINUM, ALUMINUM ALLOYS, OTHER ACTIVE METALS AND SOME METAL SALTS AND HALOGENS. [R13] DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen chloride/. [R12] SERI: *... SEVERE SKIN IRRITATION WITH MARKED INFLAMMATORY RESPONSE OF EPIDERMIS AND UNDERLYING TISSUES /FROM DERMAL EXPOSURES/. /DICHLOROPROPENES/ [R14] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R15, 1979.8] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R15, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R15, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R15, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R15, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R15, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R15, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R15, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R15, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R15, 1979.11] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R16] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R17] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R18] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R15, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R15, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R15, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R15, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R15, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R15, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R15, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R15, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R15, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *IDENTIFICATION: 1,3-Dichloropropene is a colorless to amber colored liquid with a penetrating, irritating, chloroform-like odor. It has been widely used in agriculture as a pre-plant soil fumigant for the control of nematodes in vegetables, potatoes, and tobacco. It often appears as part of a mixture also including 1,2-dichloropropane. Application is primarily by soil injection. In water, 1-3-dichloropropene is likely to disappear rapidly, because of its relatively low water solubility and high volatility. HUMAN EXPOSURE: The exposure of the general population through air, water, or food is unlikely. Occupational exposure is likely to be through inhalation and via the skin. Irritation of the eyes and the upper respiratory mucosa appears promptly after exposure. Dermal exposure caused severe skin irritations. Inhalation may result in serious signs and symptoms of poisoning with lower exposures resulting in depression of the central nervous system and irritation of the respiratory system. Some poisoning incidents have occurred in which persons were hospitalized with signs and symptoms of irritation of the mucous membrane, chest discomfort, headache, nausea, vomiting, dizziness and, occasionally, loss of consciousness and decreased libido The fertility status of workers employed in the production of chlorinated three-carbon compounds was compared with a control group. There was no indication of an assocation between decreased fertility and exposure. ANIMAL STUDIES: The acute oral toxicity of 1,3-dichloropropene in animals is moderate to high. Acute dermal exposure is moderately toxic. Acute intoxication showed central nervous and respiratory system involvement. Severe reactions were seen in rabbit skin and eye irritation tests. Degeneration of the olfactory epithelium and hyperplasia were seen in inhalation studies with mice and rats. Cis- and trans-1,3-dichloropropene and mixtures were mutagenic in bacteria with, and without, metabolic activation. In mice, increased incidences of hyperplasia of the urinary bladder, the forestomach, and the nasal mucosa were observed. There was an increase in the incidence of benign lung tumors. Some toxic changes in the olfactory mucosa of the nasal cavity were also seen in rats, but no increase in tumor incidence. The major metabolic route of elimination of 1,3-dichloropropene is via conjugation with glutathione. [R19] CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of 1,3-dichloropropene were available. There is sufficient evidence in experimental animals for the carcinogenicity of mixed isomers of 1,3-dichloropropene (technical grade). Overall evaluation: 1,3-Dichloropropene (technical grade) is possibly carcinogenic to humans (Group 2B). /1,3-Dichloropropene (technical grade)/ [R20] ANTR: *1. FLUSH contaminating fumigants from the skin and eyes with copious amounts of water or saline for at least 15 minutes. Some fumigants are corrosive to the cornea and may cause BLINDNESS. Specialized medical treatment should be obtained promptly following removal of toxicant by copious flushing with clean water. Skin contamination may cause BLISTERING and deep chemical burns. Absorption of some fumigants across the skin may be sufficient to cause systemic poisoning in the absence of fumigant inhalation. For all these reasons, decontamination of eyes and skin must be IMMEDIATE and THOROUGH. 2. REMOVE victims of fumigant inhalation to FRESH AIR immediately. Even though initial symptoms and signs are mild, keep the victim quiet, in a semi-reclining position. Minimum pohysical activity limits the likelihood of pulmonary edema. 3. If victim is not breathing, clear the airway of secretions and RESUSCITATE with positive pressure oxygen apparatus. If this is not available, use chest compression to sustain respiration. If victim is pulseless, employ cardiac resuscitation. 4. If PULMONARY EDEMA is evident, there are several measures available to sustain life. Medical judgement must be relied upon, however, in the management of each case. The following procedures are generally recommended: A. Put the victim in a SITTING position with a backrest. B. Use intermittent and/or continuous positive pressure OXYGEN to relieve hypoxemia. ... C. Slowly administer FUROSEMIDE, 40 mg, or SODIUM ETHACRYNATE, 50 mg, to reduce venous load by inducing diuresis. ... D. Morphine in small doses (5-10 mg), slowly, iv to allay anxiety and promote deeper respiratory excursions. E. Administer AMINOPHYLLINE (0.25-0.50 gm) slowly, iv. ... F. Digitalization may be considered, but there is a serious risk of arrhythmias in an anoxic and toxic myocardium. G. TRACHEOSTOMY may be necessary in some cases to facilitate aspiration of large amounts of pulmonary edema fluid. H. Epinephrine, atropine, and expectorants are generally not helpful, and may complicate treatment. I. Watch for RECURRENT PULMONARY EDEMA, even up to 2 weeks after the initial episode. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. 5. Combat SHOCK by placing victim in the Trendelenburg position and administering plasma, whole blood, and/or electrolyte and glucose solutions intravenously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continuously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. 6. Control CONVULSIONS. Seizures are most likely to occur in poisonings by methyl bromide, hydrogen cyanide, acrylonitrile, phosphine, and carbon disulfide. ... /Fumigant poisoning/ [R21] *7. If a FUMIGANT LIQUID OR SOLID has been INGESTED less than several hours prior to treatment, quantities remaining in the stomach must be removed as effectively as possible by gastric intubation, aspiration, and lavage, after all possible precautions have been taken to protect the respiratory tract from aspirated gasric contents. A. Put in place a cuffed ENDOTRACHEAL TUBE prior to gastric intubation. Administer OXYGEN, using a mechanical ventilator if respiration is depressed. B. Lavage the stomach with a slurry of ACTIVATED CHARCOAL in saline or water. Leave a volume of the slurry in the stomach with an appropriate dose of sorbitol as cathartic ... . C. If treatment is delayed and if the patient remains fully alert, administer activated charcoal and sorbitol orally. ... Repeated administration of charcoal at half or more the initial dosage every 2-4 hours may be beneficial. D. Do not give vegetable or animal fats or oils, which enhance gastrointestinal absorption of many of the fumigant compounds. 8. Intravenous infusions of GLUCOSE are valuable in limiting the heptotoxicity of many substances. Monitor central venous pressure to avoid precipitating, or aggravating, pulmonary edema by fluid overload. The victim should be watched closely for indications of delayed or recurrent pulmonary edema, and for bronchopneumonia. Fluid balance should be monitored, and urine sediment should be checked regularly for indications of tubular injury. Measure serum alkaline phosphatase, LDH, ALT, AST, and bilirubin to assess liver injury. 9. HEMOPERFUSION OVER ACTIVATED CHARCOAL has been used in managing a case of carbon tetrachloride poisoning with apparent success. ... 10. EXTRACORPOREAL HEMODIALYSIS may be needed to regulate extracellular fluid composition if renal failure supervenes. It is probably not very effective in removing lipophilic fumigant compounds from blood, but is, of course, effective in controlling extracellular fluid composition if renal failure occurs. /Fumigant poisoning/ [R21] *Stabilization: Treatment is largely supportive. Watch for respiratory depression and arrhythmias. Obtain arterial blood gases. Administer oxygen if there is evidence of altered mental status or dyspnea. Treat hypotension with volume expansion and vasopression. Use lidocaine or beta-blockers for ventricular arrhythmias. Skin: Remove contaminated clothing. Wash affected area with soap and copious amounts or water. Eye: Irrigate the eye for 15-20 min. Obtain a consultation if symptoms persist. Oral: Most of the halogenated solvents ingested in quantities of 1-2 swallows may be partially removed by ipecac-induced emesis if admin within a few hr to a patient who has not lost the gag reflex, is not seizing, is not markedly lethargic, or is not in coma. Observe the patient in the upright position to lessen the possibility of aspiration. Activated charcoal is probably ineffective. Inhalation: Move from the contaminated area. Provide a source of oxygen and prepare for mechanical ventilation. If the patient is unconscious and the pulse is absent, initiate CPR measures. Enhancement of Elimination: Maintain good ventilation. Hemodialysis or hemoperfusion are not likely to be useful because of the high lipophilic properties of these solvents. Antidote: N-acetylcysteine may restore depleted glutathione stores, but no adequate clinical studies are available to validate this possible treatment. Supportive Care: Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encephalopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, EKG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. /Halogenated hydrocarbons/ [R22] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R15, 1979.23] HTOX: *AFTER EXPOSURE TO CONCN VAPORS. LACRIMATION IS PROMINENT. ... SEVERE SKIN IRRITATION WITH MARKED INFLAMMATORY RESPONSE OF EPIDERMIS AND UNDERLYING TISSUES /FROM DERMAL EXPOSURES/. /DICHLOROPROPENES/ [R14] *Thirteen allylic compounds, mostly with close structural relationship were tested for their ability to induce unscheduled DNA synthesis (UDS) in HeLa cells and mutations in the Ames test; 11 induced unscheduled DNA synthesis in a dose dependent fashion. In general, positive qualitative and quantitative correlation between unscheduled DNA synthesis, Ames test and alkylating properties (as measured in the 4-nitrobenzyl-pyridine test, NBP) were found. Among structural analogs and typical allylic compounds with various leaving groups, the amount of induced DNA repair at equimolar concentrations decreased in the same order as the mutagenic and alkylating activities in the other 2 test systems: 1,3-dichloropropene (cis) > 1,3-dichloropropene (trans) > 2-3-dichloro-1-propene; 1-chloro-2-butene > 3-chloro-1-butene > 3-chloro-2-methyl-1-propene > allyl chloride; allyl methane sulfonate > -iodide > -bromide > -chloride. [R23] *A 27 year old previously healthy male worker who accidentally drank a solution containing 1,3-dichloropropene (mixture of cis- and trans-isomers) developed gastrointestinal distress, adult respiratory distress syndrome, hematological and hepatorenal functional impairment, and died 40 hours after ingestion. [R24] *Symptomatology: 1A) Inhalation, high vapor concn: gasping, refusal to breathe, coughing, substernal pain, and extreme respiratory distress at vapor concn over 1500 ppm. Irritation of eyes and upper respiratory mucosa appears promptly after exposure to concentrated vapors. Lacrimation and headache are prominent. Coma may occur rapidly. B) Inhalation, low vapor concn: central nervous depression and moderate irritation of respiratory system. Headache is frequent. 2) Dermal: severe skin irritation with marked inflammatory response of epidermis and underlying tissues. 3) Oral: acute gastrointestinal distress with pulmonary congestion and edema. Central nervous depression, perhaps even in the absence of impaired oxygen uptake. 4) By any route, possible late injuries to liver, kidneys and heart. 5) After inhalation exposures, malaise, headache, chest and abdominal discomfort and irritability have been reported to persist for several weeks and perhaps for several years. [R14] NTOX: *Both the cis and trans isomers of 1,3-dichloropropene and a mixture of the two are mutagenic to bacteria in the presence and absence of an exogenous metabolic system. It was found ... that purification of 1,3-dichloropropene resulted in loss of mutagenic activity, although samples of higher purity were mutagenic in other studies. 1,3-Dichloropropene induces sex-linked recessive lethal mutations, but not reciprocal translocations, in Drosophila melanogaster. [R25] *CIS AND TRANS /1,3-DICHLOROPROPENE WERE/ TESTED USING SALMONELLA TYPHIMURIUM TA1535. ALL ASSAYS GAVE ESSENTIALLY SIMILAR RESULTS. BOTH ISOMERS WERE MUTAGENIC, CIS BEING ABOUT 2 FOLD MORE ACTIVE THAN THE TRANS-ISOMER. CONCN GREATER THAN OR EQUAL TO 2 UMOL/ML CAUSED DROP IN SURVIVAL RATE TO LESS THAN 1%. [R26] *THE ACTIVE PRINCIPAL OF D-D SOIL FUMIGANT AND TELONE IS MIXT OF CIS AND TRANS ISOMERS OF THE CARCINOGEN 1,3-DICHLOROPROPENE. BOTH ISOMERS ARE MUTAGENIC IN SALMONELLA STRAINS TA1535 AND TA100 INDICATING BASE-PAIR SUBSTITUTION. [R27] *THE (Z)-ISOMER IS MORE TOXIC THAN THE (E)-ISOMER TO NEMATODES. [R28] *MALE RATS EXPOSED TO MIXED ISOMERS OF 1,3-DICHLOROPROPENE AT CONCN OF 3 PPM FOR 7 HR/DAY, 5 DAYS/WK FOR 6 MO SHOWED SLIGHT, REVERSIBLE CHANGE IN KIDNEYS. NO CHANGE WAS DETECTED IN RATS KILLED 3 MO AFTER LAST EXPOSURE. FEMALE RATS, MALE AND FEMALE RABBITS, MALE AND FEMALE GUINEA PIGS, AND FEMALE DOGS SHOWED NO ADVERSE EFFECT ... AT 1 PPM (4.5 MG/CU M). [R29] *Subchronic inhalation toxicity data on 1,3-dichloropropene are contradictory. Older data indicate commercial product studied ... (1958-1975) was quite irritating and hepatotoxic, but data developed on currently produced fumigants indicate considerably less hepatotoxicity. ... In early subacute study ... considerable liver and kidney injury /were/ evident grossly in small groups of rats exposed 19 times to 50 ppm, 7 hr/day in a 28-day period. Studies with more recently produced product, Telone II soil fumigants (47% cis, 45% trans, the balance related cmpd), indicate considerably lower toxicity /in/ Fischer 344 rats and CD-1 mice ... exposed 7 hr/day, 5 days/wk for 13 wk to 0, 93, 32, or 12 ppm. Exposures resulted only in failure to gain wt (high dose rats and female mice) and focal histomorphological changes of epithelium of nasal septums and turbinates in high dose rats of both sexes as well as female rats exposed to 32 ppm. Female, but not male mice, exposed to 93 ppm showed similar effects. [R30, 4226] *THE TOXICITY OF MIXED ISOMERS OF 1,3-DICHLOROPROPENE, WHEN REPEATEDLY INHALED AT LOW CONCN (1 OR 3 PPM) FOR SIX MO WAS INVESTIGATED. RATS, GUINEA PIGS, RABBITS, AND DOGS RECEIVED 7 HR DAILY EXPOSURES 5 DAYS PER WK TO 1 PPM FOR 6 MO WITH NO ADVERSE EFFECT. THE ONLY EFFECT IN ANY GROUP EXPOSED TO 3 PPM WAS SLIGHT, APPARENTLY REVERSIBLE CHANGE SEEN MICROSCOPICALLY IN KIDNEYS OF MALE RATS EXPOSED 7 OR 4 HR/DAY. [R31] ADE: *Following oral admin of 8.3-13.5 mg/kg body weight cis- or trans-2-(14)carbon-1,3-dichloropropene to rats, 80% of the radioactivity of the cis-isomer and 57% of the radioactivity of the trans-isomer was excreted in the urine within 24 hr. Little further urinary excretion occurred over the next 72 hr. After 96 hr, 2-5% of the cis-isomer and 23-24% of the trans-isomer were expired as (14)carbon carbondioxide; exhalation of other radioactive compounds was minor. Little fecal excretion was observed. Recovery of both isomers was about 90%. [R32] *... Rats were fed (14)carbon-labeled ... isomers of 1,3-dichloropropene and showed differences in their metabolism. With all compounds, 80-90% was eliminated in the first 24 hr. Major route of excretion was in the urine, where ... 56.5% of trans was found. The amount of (14)carbon dioxide excreted was 23.6%, with correspondingly less ... in the urine. [R30, 4231] *Tomato plants absorbed labeled cis- and trans-1,3-dichloropropene through their roots with max 1,3-dichloropropene absorbed and translocated after 2-4 hr and no 1,3-dichloropropene detected by 48 hr. 1,3-Dichloropropene was metabolized to trans-3-chloroallyl alcohol, part of which was converted to trans-3-chloroacrylic acid and 3-chloropropanol. At 12 and 24 hr after treatment both cis-1,3-dichloropropene and trans-1,3-dichloropropene disrupted the organellar structure of the chloroplasts and the rough endoplasmic reticulum of some plants. However, despite the disruption of normal cellular structure, cis-1,3-dichloropropene and trans-1,3-dichloropropene do not present residue problems and cause concern about their residue fate. [R33] *Following the oral administration to rats of (14)C labeled 1,2-dichloropropane, cis-1,3-dichloropropene, or trans-1,3-dichloropropene, 80-90% of the radioactivity was eliminated in the feces, urine and expired air within the first 24 hr. The urine was the major route of excretion in all three cases. [R34] *... Significant differences are apparent in the elimination rates of the cis and trans /isomers/ of 1,3-dichloropropene. /cis- and trans-1,3-Dichloropropene/ [R35] *The fate of 14C-cis and 14C-trans-1,3-dichloropropene (97%; 62% cis and 38% trans) was studied after oral dosing of male B6C3F1 mice with 1 or 100 mg/kg bw (3 animals/dose level). Urine, feces expired air, tissues, and remaining carcasses were analyzed after 48 hr. Urine was the major route of excretion, with 63 and 79%, respectively, of the admin doses (1 and 100 mg/kg bw) being excreted over 48 hr. Half-lives for urinary excretion raged from 5-6 hr. Feces and expired /carbon dioxide/ accounted for 15 and 14% of the 14C-radioactivity, respectively. In the carcass, 2% was found. The tissue concns of 14C-activity were highest in the stomach wall, followed in decreasing order by kidneys, liver, bladder, fat, and skin ... . [R36] *A biological monitoring study was carried out in the Dutch flower bulb culture to determine the relationship between respiratory occupational exposure to Z and E-1,3-dichloropropene (Z and E DCP) and urinary excretion of two mercapturic acid metabolites, N-acetyl-S-(Z ans E-3-chloropropenyl-2)-L-cysteine. Urinary excretion of N-acetyl-S-(Z and E-3-chloropropenyl-2)-L-cysteine, eitherbased on excretion rates or on creatinine excretion, followed first order elimination kinetics after exposure. Urinary half lives or elimination were 5.0 + or - 1.2 hr for Z-1,3-dichloropropene and 4.7 + or - 1.3 hr for E-DCP-MA and were not statistically significantllydifferent. Calculated coefficient of variation indicated that the half lives of elimination of Z and E-DCP-MA were quite consistent inter and intra-individually. Strong correlations (r=0.93) were observed between respiratory 8 hr time weighted average exposure to Z and E-DCP and complete cumulative urinary excretion of Z and E-DCP-MA. Z-DCP yielded three times more mercapturic acid than E-DCP, probably due to differences in metabolism. Z and E-DCP were excreted 45 and 14% as their respective mercapturic acid metabolites. [R37] METB: *Groups of 3-9 male Fischer 344 rats (200-260g) were admin 50 mg cis-1,3-dichloropropene (94.1% cis- and 2.5% trans-) or 50 mg trans-1,3-dichloropropene (97.3% trans- and 0.8 cis-)/kg bw, by gavage. The rats were sacrificed at various intervals after dosing, to determine the tissue non-protein sulfhydryls (NPS) in the liver, kidneys, forestomach, glandular, stomach, and bladder. Blood samples were also taken to determine the presence of unchanged 1,3-dichloropropene. Cis-1,3-dichloropropene was only detected in the blood (6.58 ug/liter) 15 min after dosing, the blood levels of trans-1,3-dichloropropene were 11.72 and 8.38 ug/liter, respectively, 15 and 45 min after dosing. A statistically significant decr in the non-protein sulfhydryl contents of the liver, kidneys, forestomach, and glandular stomach was found. This depletion reached a max, approx 2 hr after dosing. No depletion was noted in the bladder. It is not possible to distinguish the effects of cis- and trans-1,3-dichloropropene on NPS, as the results for the individual isomers were not reported. The results indicated that orally admin 1,3-dichloropropene produces a rapid and significant depletion of tissue non-protein sulfhydryls in the rat. [R38] *The metabolism of cysteine S-conjugates of both cis and trans-1,3-dichloropropene in the presence of rat kidney microsomes and purified flavin containing monooxygenase from hog liver was investigated in vitro. Putative S-oxide metabolites of cysteine S-conjugates were chemically synthesized, and diastereomers were separated and identified by spectroscopic means. The metabolic products of cysteine S-conjugates were identified by comparing the chemical properties of the metabolites with authentic synthetic cysteine S-conjugate S-oxides. S-conjugate S-oxygenase activity was not observed with rat kidney microsomes but was present when cysteine S-conjugates were incubated with the highly purified flavin containing monooxygenase from hog liver. The kinetic parameters indicated that considerable S-oxygenase stereoselectivity and structural selectivity was observed: cis cysteine S-conjugates were preferred substrates and N-acetylation of cysteine S-conjugates decreased substrate activity. S-Oxygenation was considerably diastereoselective and diastereoselectivity was much greater for cysteine S-conjugates with higher Vmax values. Cysteine S-conjugate S-oxides were not indefinitely stable, and under certain conditions, the S-oxides under- went a (2,3)-sigmatropic rearrangement to acrolein. Formation of acrolein or other electrophilic products from S-(chloropropenyl)cysteine conjugate S-oxides may contribute to the renal effects observed for S-(chloropropenyl)cysteine conjugates. Thus, cytotoxicity studies with isolated rat proximal tubular cells or LLC-PK1 cells treated with cysteine S-conjugates showed a time and dose dependent decrease in cell viability. Reduction of renal cytotoxicity of cysteine S-conjugates in the presence of methimazole, an alternate substrate competitive inhibitor of the flavin-containing monooxygenase, suggested that this enzyme may contribute to the renal effects of 1,3-dichloropropene. [R39] *The biotransformation to sulfur containing products of the Z-isomers and E-isomers of 1,3-dichloropropene administered ip in combination to male Wistar-rats was investigated. The presence of mercapturic acids in the urine of the animals was determined using GC with nitrogen and sulfur selective detection (GC-NDP AND GC-FDP, respectively) AND GC/MS with negative chemical ionization and single ion detection. Quantification of mercapturic acids in the urine of animals treated with the dichloropropene isomers in doses of 5 ug each, was achieved with the use of GC-NDP AND GC-FPD, while GC/negative chemical ionization/MS detected only the mercapturic acids generated by doses = 25 ug or higher, due to the interference of endogenous products. Both products tested are metabolized via glutathione conjugation, with the generation of 2 major mercapturic acid conjugates, and that all three analytical procedures tested are useful for the determination of human exposure to low levels of 1,3-dichloropropene. [R40] ACTN: *Molecular orbital calculations were used to clarify the mechanism of mutagenic action of various substituted allyl chlorides. Computed molecular properties were compared with experimental mutagenic potentials of these allylic cmpd. In agreement with the experiment, the computational results suggest that the primary mechanism of action involves the SN1 formation of allylic cations whih then react with nucleophilic centers of nucleic acid bases. The usefulness of computed propertiee in estimating the degree of alkylating activity and mutagenicity was evaluated. In general, stability of the allylic carbocation intermediate and the degree of charge delocalization in the allyl system correlate well with observed mutagenic potentials. [R41] INTC: *The cis- and trans- isomers of 1,3-dichloropropene, in confirmation of previous reports, caused dose dependent increases in the numbers of reverse mutations in Salmonella typhimurium TA100 in the presence and absence of an S9 fraction in the livers of Aroclor treated rats. cis-1,3-Dichloropropene is efficiently detoxified in mammals by the operation of a glutathione dependent S-alkyl transferase. It is possible that such detoxification could proceed only very slowly in the microbial assays because the concn of glutathione could be severely rate limiting even in those assays fortified by the addition of S9. A dramatic reduction in the microbial mutagenicity in both cis- and trans-1,3-dichloropropene was observed when the concn of glutathione in the microbial mutagenicity assays was adjusted to a normal physiological concn (5 mM). This protective action of glutathione was at least as effective in the absence of S9 as in its presence, suggesting that it was not mediated by mammalian glutathione transferase. There appears to be little or no glutathione alkyl or aryl transferase in the cytosol of Salmonella typhimurium, however intracellular glutathioine is present at a concn similar to that found in mammalian cells. Since the uncatalyzed reaction between the 1,3-dichloropropene and glutathione is relatively slow the effect is not due simply to their destruction by glutathione. A physiological concn of extracellular glutathione could maintain the intracellular glutathione in a reduced form in which its nucleophillic thiol group competes with the nucleophillic centers in the bacterial DNA for the haloalkenes. [R42] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *trans-1,3-Dichloropropene's production and use as a soil fumigant for the control of nematodes, has resulted in its direct release to the environment. If released to air, a vapor pressure of 34 mm Hg at 25 deg C indicates trans-1,3-dichloropropene will exist solely as a vapor in the ambient atmosphere. Vapor-phase trans-1,3-dichloropropene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone molecules. The half-life for this reaction in air with hydroxyl radicals is estimated to be 1.5 days and the half-life for this reaction in air with ozone is estimated to be 76 days. If released to soil, trans-1,3-dichloropropene is expected to have very high mobility based upon an average Koc of 28 calculated from data obtained from 3 soils. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 8.7X10-4 atm-cu m/mole. trans-1,3-dichloropropene may volatilize from dry soil surfaces based upon its vapor pressure. The half-life of 1,3-dichloropropene (cis and trans isomers) in 13 aerobic soils at 20 deg C ranged from 6-17 days and the average half-life in anaerobic soils was reported as 8.4 days at 15 deg C and 2.4 days at 25 deg C. Hydrolysis in moist soils and water is expected based upon hydrolysis half-lives of 51, 11 and 3.1 days at 10 deg C, 20 deg C and 30 deg C, respectively. If released into water, trans-1,3-dichloropropene is not expected to adsorb to suspended solids and sediment based upon the Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 2 hours and 4.5 days, respectively. The volatilization half-life of 1,3-dichloropropene (mixture of cis- and trans-isomers) from a stirred beaker of water 6.5 cm deep was 31 min. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to trans-1,3-dichloropropene may occur through inhalation and dermal contact with this compound at workplaces where 1,3-dichloropropene is produced or used. (SRC) ARTS: *trans-1,3-Dichloropropene's production and use as a soil fumigant for the control of nematodes(1), has resulted in its direct release to the environment(SRC). [R43] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an average Koc value of 28 determined from data on 3 soils(2) indicates that trans 1,3-dichloropropene is expected to have very high mobility in soil(SRC). Volatilization of trans-1,3-dichloropropene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 8.7X10-4 atm-cu m/mole(4). The potential for volatilization of trans-1,3-dichloropropene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 34 mm Hg(5). The neutral hydrolysis half-life of trans-1,3-dichloropropene was reported as 51, 11 and 3.1 days at 10 deg C, 20 deg C and 30 deg C, respectively(5). This data suggests that hydrolysis may be an important fate process in moist soils(SRC). The half-life of 1,3-dichloropropene (cis and trans isomers) in 13 aerobic soils at 20 deg C ranged from 6-17 days(6). The average half-life in anaerobic soils was reported as 8.4 days at 15 deg C and 2.4 days at 25 deg C(6). [R44] *AQUATIC FATE: Based on a classification scheme(1), an average soil Koc value of 28(2), indicates that trans-1,3-dichloropropene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 8.7X10-4 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 2 hours and 4.5 days, respectively(SRC). The volatilization half-life of 1,3-dichloropropene (mixture of cis- and trans-isomers) from a stirred beaker of water 6.5 cm deep was 31 min(5). According to a classification scheme(6), an estimated BCF of 7(SRC), from a log Kow of 2.03(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation data in soils under aerobic and anaerobic conditions(7) suggest that trans-1,3-dichloropropene will also biodegrade in water(SRC). [R45] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trans-1,3-dichloropropene, which has a vapor pressure of 34 mm Hg at 25 deg(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase trans-1,3-dichloropropene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone molecules. The half-life for this reaction in air with hydroxyl radicals is estimated to be 1.5 days(SRC), calculated from its rate constant of 1.4X10-11 cu cm/molecule-sec at 25 deg(3). The half-life for this reaction in air with ozone is estimated to be 76 days(SRC), calculated from its rate constant of 1.5X10-19 cu cm/molecule-sec at 25 deg(3). The degradation products observed from the reaction of trans-1,3-dichloropropene with hydroxide radicals were formyl chloride and chloroacetaldehyde(4). [R46] BIOD: *trans-1,3-Dichloropropene can be chemically hydrolyzed in moist soils to the corresponding 3-chloroalkyl alcohols, which is capable of ... /being biodegraded/ to carbon dioxide and water by a bacterium (Pseudomonas sp). [R47] *The cis and trans isomers of 1,3-dichloropropene have undergone biodehalogenation by a Pseudomonas species isolated from ... soil. [R48] *Cis- and trans-1,3-dichloropropene disappeared in sandy soils (15-20 deg C, closed containers) at a rate of 2.5-3%/day (with an avg half-life of 24 days)(1). In clay containing soils, the disappearance rate was higher than or equal to 25% per day at 20 deg C(1). Twelve weeks after radiolabeled trans-1,3-dichloropropene was added to soil and stored in sealed containers, 18% remained in sandy loam and 22% remained in medium loam (2). After 20 weeks, 4% remained in sandy loam and 14% remained in the medium loam. The primary degradation product was trans-3-chloroallyl alcohol. It was possible that some of the parent compound was lost by volatilization(2). The half-life of 1,3-dichloropropene (cis and trans isomers) in 13 aerobic soils at 20 deg C ranged from 6-17 days(3). The average half-life in anaerobic soils was reported as 8.4 days at 15 deg C and 2.4 days at 25 deg C(3). trans-1,3-Dichloropropene was biodegraded in soil samples obtained from a farm in northern Florida(4). The half-lives ranged from about 4-14 days depending upon the depth of the soil and whether the soil had previously been treated with 1,3-dichloropropene(4). In general, it was determined that soils previously treated had enhanced degradation rates in comparison to soil that had never been treated with 1,3-dichloropropene. [R49] ABIO: *cis-1,3-Dichloropropene and trans-1,3-dichloropropene were chemically hydrolyzed in moist soil to the corresponding biocidal 3-chloroallyl alcohol. [R50] *The rate constant for the vapor-phase reaction of trans-1,3-dichloropropene with photochemically-produced hydroxyl radicals has been measured as 1.4X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 1.5 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The degradation products observed from the reaction of trans-1,3-dichloropropene withhydroxide radicals were formyl chloride and chloroacetaldehyde(6). The rate constant for the vapor-phase reaction of trans-1,3-dichloropropene with ozone has been estimated as 1.5X10-19 cu cm/molecule-sec(1). This corresponds to an atmospheric half-life of about 76 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). The neutral hydrolysis half-life of trans-1,3-dichloropropene was reported as 51, 11 and 3.1 days at 10 deg C, 20 deg C and 30 deg C, respectively(3). Results of another laboratory study and a field study indicate that the hydrolysis half-life for the cis- and trans-isomers in sandy and peat soil is > 69 days(4). It is additionally reported that disappearance is more rapid in clay soils than sandy ones, but no rates were given(5). [R51] BIOC: *An estimated BCF of 7 was calculated for trans-1,3-dichloropropene(SRC), using a log Kow of 2.03(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R52] KOC: *An investigation was carried out on the distribution of cis- and trans-1,3-dichloropropene over the phases in soil with the purpose of obtaining data for mathematical models describing the movement of these fumigants in soil. The measurements included three types and were taken at 2, 11, and 20 deg C. Concn in the vapor and water phases were measured with a gas chromatograph and the amount adsorbed was calculated. The adsorption isotherms appeared to be linear in the important concn range, with the trans isomer being adsorbed considerably stronger than the cis isomer. The value of the adsorption coefficient was proportional to the organic matter content in the soils. The amount adsorbed at a certain concn in the vapor at 2 deg C was approximately 3 times higher than the amount adsorbed at 20 deg C. [R53] *The measured Koc of trans-1,3-dichloropropene in soil was 26(1). The average Koc for 3 soils with % organic carbon of 3.19, 10.4, and 55.1% was 28 for trans-1,3-dichloropropene(2). According to a classification scheme(3), these data suggest that trans-1,3-dichloropropene is expected to have very high mobility in soil. [R54] VWS: *The Henry's Law constant for trans-1,3-dichloropropene is 8.7X10-4 atm-cu m/mole(1). This Henry's Law constant indicates that trans 1,3-dichloropropene is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 2 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4.5 days(SRC). trans-1,3-Dichloropropene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of trans-1,3-dichloropropene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 34 mm Hg(3). The volatilization half-life of 1,3-dichloropropene (mixture of cis- and trans-isomers) from a stirred beaker of water 6.5 cm deep was 31 min(4). [R55] WATC: *SURFACE WATER: trans-1,3-Dichloropropene was detected in the Lake Ontario Basin (Genesee River and Wine Creek)(1). Ohio River System (1978-79) 6 stations, 991 samples on Ohio River; 2 stations, 359 samples on tributaries: 3.9% of samples from the Ohio River had detectable levels of trans-1,3-dichloropropene < 1 ppb and 0.6% between 1 and 10 ppb, whereas it was not detected in tributaries(2). trans-1,3-Dichloropropene was detected in surface water samples from Big Creek, Ontario at concns of 0.18-2.59 ug/l(3). [R56] *DRINKING WATER: trans-1,3-Dichloropropene was detected in drinking water in Kaohsiung, Taiwan at 0.22 ug/l(1). [R57] *RAIN/SNOW: In October 1982, trans-1,3-dichloropropene was detected in the aqueous phase of rain water collected in Portland, OR at a concentration of 2 ng/l(1). [R58] EFFL: *trans-1,3-Dichloropropene was detected in 2 out of 3 samples from a sewage treatment plant, at concns of 3-8 ug/l(1). trans-1,3-Dichloropropene was detected in treated effluent from seven petroleum refineries at concns of < 0.7-1 ug/l(2). [R59] ATMC: *Since it is generally injected into the soil at depths of 15 to 30 cm airborne concn are generally well below 0.5 ppm even when measured in the middle of a fumigated field. [R30, 4225] FOOD: *1,3-Dichloropropene was analyzed for but not detected in bean sprouts, cola, butter, margarine, milk, cake, juice, rice, lactic beverages, ice cream yogurt and tofu(1). [R60] MILK: *Dichloropropene was detected in one of 8 samples of mother's milk from 4 urban areas in the USA but the isomer was not specified(1). /Dichloropropane/ [R61] RTEX: *EXPOSURE OCCURS PRINCIPALLY DURING MFR OR BULK HANDLING ... [R30, 4225] *Occupational exposure to trans-1,3-dichloropropene may occur through inhalation and dermal contact with this compound at workplaces where trans 1,3-dichloropropene is produced or used(SRC). The respiratory 8-hour TWA of trans-1,3-dichloropropene for applicators employed in a flower shop in the Netherlands ranged from 0.34-8.07 ug/cu m(1). [R62] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: *8 hr Time Weighted Avg (TWA) 1 ppm, skin /1,3-Dichloropropene/ [R63] *Excursion Limit Recommendation: Short-term exposures should exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /1,3-Dichloropropene/ [R63] *A3: Confirmed animal carcinogen with unknown relevance to humans. /1,3-Dichloropropene/ [R63] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GC/MS analysis of volatiles including trans-1,3-dichloropropene in solids at low level. The Contract Required Quantitation Limit is 5.0 ug/kg in low solids, 500 ug/kg in medium solids, and 5 ug/l in water as used in EPA Contract Laboratory Program. [R64] *OSW Method 8010. Determination of Halogenated Volatile Organics by Gas Chromatography. Detection limit = 0.340 ug/l. [R65] *OSW Method 8240. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit = 5.000 ug/kg. [R65] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. Detection limit = 0.200 ug/l. [R65] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. Detection limit not specified. [R65] *EPA Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. Detection limit = 10.0 ug/l. [R65] *USGS Method 03115. Total Recoverable Purgeable Organic Compounds in Water by Purge and Trap Gas Chromatography with a Mass Spectrometer. Range = 3.0 ug/l. [R65] CLAB: *A rapid, simple and specific GC and GC/MS methods are described for determining trans-1,3-dichloropropene in rat blood at 5.35 ng/ml with GC, and 47.1 ng/ml with the GC/MS method. The GC column was 20% Carbowax 20M on Chromasorb WAW (80-100 mesh). MS with selected ion (m/z 77) monitoring was used. The chromatographic column combined with MS was a glass column containing HNU Synerg C-1H. The mean recovery of the trans-isomers from blood (GC method) was 90.5%. [R66] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; TOXICOLOGY AND CARCINOGENESIS STUDIES OF TELONE II P.24 (1985) REPORT # 269, NIH PUB # 85-2525. WHO: Environmental Health Criteria 146: 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures (1993) SO: R1: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 366 R2: NTP; TOXICOLOGY AND CARCINOGENESIS STUDIES OF TELONE II P.24 (1985) REPORT # 269, NIH PUB # 85-2525 R3: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 785 R4: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 49-40 R5: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley and Sons. New York, NY. 2001 R6: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-288 R7: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V5 4517 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 183 R9: Leistra M; J Agric Food Chem 18: 1124-26 (1970) R10: Kwok ESC et al; Environ Sci Technol 30: 329-34 (1996) R11: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-132 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1126 R13: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.438 R14: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-142 R15: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R16: 49 CFR 171.2 (7/1/2000) R17: IATA. Dangerous Goods Regulations. 42nd Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2001. 149 R18: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3330 (1998) R19: World Health Organization/International Programme on Chemical Safety. Environmental Health Criteria 146. 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures. pp. 15-23, 26 (1993) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 71 942 (1999) R21: Morgan DP; Recognition and Management of Pesticide Poisonings. 4th ed. p.138 EPA 540/9-88-001. Washington, DC: U.S. Government Printing Office, March 1989 R22: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1439 R23: Schiffman D et al; Cancer Lett 20 (3): 263-70 (1983) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 936 (1999) R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 124 (1986) R26: NEUDECKER T ET AL; EXPERIENTIA 33 (8): 1084-85 (1977) R27: DE LORENZO F ET AL; CANCER RES 37 (6): 1915-17 (1977) R28: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 265 R29: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 162 R30: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R31: TORKELSON TR, OYEN F; AMER IND HYG ASSOC J 38 (5): 217-23 (1977) R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 121 (1986) R33: Berry DL et al; J Amer Hortic Sci 100 (6): 607-13 (1975) R34: Hutson DH et al; Food Cosmet Toxicol 9 (5): 677-80 (1971) R35: USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.C-27 (1980) R36: WHO; Environ Health Criteria 146: 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures p.60 (1993) R37: Van Welie R TH et al; Arch Environ Contam Toxicol 20 (1): 6-12 (1991) R38: WHO; Environ Health Criteria 146: 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures p.66 (1993) R39: Park SB et al; Chem Res Toxicol 5 (2): 193-201 (1992) R40: Onkenhout W et al; Archives of Toxicol 59 (4): 235-241 (1986) R41: Boerth DW et al; Chem Res Toxicol 4 (3): 368-72 (1991) R42: Creedy CL et al; Chem-Biol Interact 50 (1): 39-48 (1984) R43: (1) Tomlin CDS; The Pesticide Manual, 11th ed. Farnham, UK: British Crop Protection Council p. 366 (1997) R44: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hamaker JW, Thompson JM; pp. 49-144 in Organic Chem in the Soil Environ. Goring CAI, Hamaker JN, eds., Vol.I (1972) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Leistra M; J Agric Food Chem 18: 1124-26 (1970) (5) Verschueren K; Handbook on Environmental Data on Organic Chemicals. 4th ed Vol 1 NY, NY: John Wiley and Sons p.810 (2001) (6) Tomlin CDS; The Pesticide Manual, 11th ed. Farnham, UK: British Crop Protection Council p. 366 (1997) R45: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hamaker JW, Thompson JM; pp. 49-144 in Organic Chem in the Soil Environ, Goring CAI, Hamaker JN, eds., Vol.I (1972) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Leistra M; J Agric Food Chem 18: 1124-26 (1970) (5) Dilling WL et al; Environ Sci Technol 9: 833-8 (1975) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Tomlin CDS; The Pesticide Manual, 11th ed. Farnham, UK: British Crop Protection Council p. 366 (1997) (8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R46: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Verschueren K; Handbook on Environmental Data on Organic Chemicals. 4th ed Vol 1 NY, NY: John Wiley and Sons p. 810 (2001) (3) Kwok ESC et al; Environ Sci Technol 30: 329-34 (1996) (4) Tuazon EC et al; Arch Environ Contam Toxicol 13: 691-700 (1984) R47: USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-3 (1980) R48: USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-1 (1980) R49: (1) Van Dijk H; Agro-Ecosystems 1: 193-204 (1974) (2) Roberts TR, Stoydin G; Pestic Sci 7: 325-35 (1976) (3) Tomlin CDS; The Pesticide Manual, 11th ed. Farnham, UK: British Crop Protection Council p. 366 (1997) (4) Chung KY et al; J Environ Sci Health B34: 749-68 (1999) R50: Belser NO, Castro CE; J Agri Food Chem 19 (1): 23-3 (1971) R51: (1) Kwok ESC et al; Environ Sci Technol 30: 329-34 (1996) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (3) Verschueren K; Handbook on Environmental Data on Organic Chemicals. 4th ed NY, NY: John Wiley and Sons 1: 810 (2001) (4) Leistra M; J Agric Food Chem 18: 1124-6 (1970) (5) Callahan MA et al; Water-Related Environ Fate of 129 Priority Pollut. Vol. II. Washington, DC: USEPA-440/4-79-029B (1979) (6) Tuazon EC et al; Arch Environ Contam Toxicol 13: 691-700 (1984) R52: (1) Tomlin CDS; The Pesticide Manual, 11th ed. Farnham, UK: British Crop Protection Council p. 366 (1997) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R53: Leistra M; J Agri Food Chem 18 (6): 1124-26 (1970) R54: (1) Kenaga EE; Ecotoxicol Environ Safety 4: 26-38 (1980) (2) Hamaker JW, Thompson JM; pp. 49-144 in Organic Chem in the Soil Environ, Goring CAI, Hamaker JN, eds., Vol.I (1972) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R55: (1) Leistra M; J Agric Food Chem 18: 1124-26 (1970) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Verschueren K; Handbook on Environmental Data on Organic Chemicals. 4th ed Vol 1 NY, NY: John Wiley and Sons p. 810 (2001) (4) Dilling WL et al; Environ Sci Technol 9: 833-8 (1975) R56: (1) Great Lakes Water Quality Board; An Inventory of Chem Substances Identified in the Great Lakes Ecosystem Vol.I pp 195 (1983) (2) Ohio River Valley Water Sanit Comm; Assessment of Water Quality Conditions, Ohio River Mainstream 1979-80 (1981) (3) Merriman JC et al; Bull Environ Contam Toxicol 47: 572-79 (1991) R57: (1) Kuo HW et al; Bull Environ Contam Toxicol 59: 708-14 (1997) R58: (1) Mazurek MA, Simoneit BRT; Critical Rev in Environ Control Vol. 16; Boca Raton, FL: CRC Press p. 27 (1986) R59: (1) Lao RC et al; Analytical Techniques in Environmental Chemistry II; Albaiges J ed NY: Pergamon Press pp. 107-18 (1982) (2) Snider EH, Manning FS; Environ Internat 7: 237-58 (1982) R60: (1) Miyahara M et al; J Agric Food Chem 43: 320-26 (1995) R61: (1) Pellizzari ED et al; Environ Contam Toxicol 28: 322-8 (1982) R62: (1) van Weile RTH et al; Arch Environ Contam Toxicol 20: 6-12 (1991) R63: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. 2001.27 R64: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.192 (1991) OST Pub 21W-4005 R65: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R66: Kastl PE, Hermann EA; J Chromat 265 (2): 277-83 (1983) RS: 76 Record 132 of 1119 in HSDB (through 2003/06) AN: 1529 UD: 200211 RD: Reviewed by SRP on 03/16/1990 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ARAMITE- SY: *88-R-; +88R-; +ARACIDE-; *ARAMIT-; +Aramite-15W-; +Aramiteararamite-15W-; +ARATRON-; +Butylphenoxyisopropyl-chloroethyl-sulfite-; +2-(P-TERT-BUTYLPHENOXY)ISOPROPYL 2-CHLOROETHYL SULFITE; +2-(P-BUTYLPHENOXY)ISOPROPYL-2-CHLOROETHYL SULFITE; *2-(4-t-butylphenoxy)isopropyl-2-chloroethyl sulfite; +2-(p-t-butylphenoxy)isopropyl-2'-chloroethyl sulphite; *2-(p-t-butylphenoxy)-1-methylethyl 2-chloroethyl ester of sulphurous acid; +2-(p-tert-Butylphenoxy)-1-methylethyl 2-chloroethyl sulfite; *2-(p-butylphenoxy)-1-methylethyl 2-chloroethyl sulfite; *2-(4-tert-Butylphenoxy)-1-methylethyl 2-chloroethyl sulfite; +2-(p-t-butylphenoxy)-1-methylethyl 2'-chloroethyl sulphite; +2-(P-T-BUTYLPHENOXY)-1-METHYLETHYL SULPHITE OF 2-CHLOROETHANOL; *CES-; +BETA-CHLOROETHYL-BETA'-(P-T-BUTYLPHENOXY)-ALPHA'-METHYLETHYL SULFITE; +Beta-chloroethyl-beta-(p-t-butylphenoxy)-alpha-methylethyl sulphite; +Beta-chloroethyl-beta-(p-tert-butylphenoxy)-alpha-methylethyl sulphite; +2-CHLOROETHYL 1-METHYL-2-(P-T-BUTYLPHENOXY)ETHYL SULPHATE; *2-CHLOROETHYL SULPHITE OF 1-(P-T-BUTYLPHENOXY)-2-PROPANOL; *2-Chloroethyl sulphite of 1-(p-tert-butylphenoxy)-2-propanol; +COMPOUND-88R-; +ENT-16,519-; *Ester of 2-chloroethanol with 2-(p-tert-butylphenoxy)-methyl sulphite; *ETHANOL, 2-CHLORO-, 2-(P-T-BUTYLPHENOXY)-1-METHYLETHYL SULFITE; *ETHANOL, 2-CHLORO-, ESTER WITH 2-(P-TERT-BUTYLPHENOXY)-1-METHYLETHYL SULFITE; *ORTHO-MITE-; *NIAGARAMITE-; *2-PROPANOL, 1-(P-T-BUTYLPHENOXY)-, 2-CHLOROETHYL SULFITE; *SULFUROUS ACID, 2-(P-T-BUTYLPHENOXY)-1-METHYLETHYL-2-CHLOROETHYL ESTER; *SULFUROUS ACID, 2-(P-TERT-BUTYLPHENOXY)-1-METHYLETHYL 2-CHLOROETHYL ESTER; *SULFUROUS ACID, 2-CHLOROETHYL 2-(4-(1,1-DIMETHYLETHYL)PHENOXY)-1-METHYLETHYL ESTER RN: 140-57-8 MF: *C15-H23-CL-O4-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... MADE BY REACTION OF 2-CHLOROETHYL CHLOROSULFINATE (MADE FROM 2-CHLOROETHANOL AND THIONYL CHLORIDE) WITH 1-(P-TERT-BUTYLPHENOXY)PROPANOL-2. [R1] IMP: *IT MAY CONTAIN 5-10% OF BIS-2(4-TERT-BUTYLPHENOXY)-1-METHYLETHYL SULFITE. /TECHNICAL PRODUCT/ [R1] FORM: *LIQ CONCENTRATE (90%), FOR PAINTING HOT WATER PIPES; EMULSIFIABLE LIQ (204 LB/US GALLON); DISPERSIBLE POWDERS (USUALLY 15%); DUSTS (USUALLY 3%). [R2] *ARAMITE WAS FORMERLY AVAILABLE IN US AS A TECHNICAL GRADE PRODUCT CONTAINING 90% ACTIVE INGREDIENT. IT WAS ALSO OFFERED FOR SALE AS AN 85% EMULSIFIABLE CONCENTRATE, AS A 15% WETTABLE POWDER ... . [R1] *TECHNICAL: ... AT LEAST 90% PURITY. [R2] OMIN: *INCOMPATIBLE WITH ALKALINE MATERIALS SUCH AS LIME OR BORDEAUX MIXTURE. [R2] *ARAMITE /PRODUCTION/ DISCONTINUED BY UNIROYAL. [R3] *ARAMITE RESISTANCE INDUCED IN /TETRANYCHUS/ PACIFICUS BY LAB SELECTION CARRIED LITTLE OR NO CROSS-RESISTANCE TO DICOFOL OR CHLOROBENZILATE. RESISTANCE TO ... ARAMITE 1ST APPEARED IN TETRANYCHUS TELARIUS IN ... 1955 ... ARAMITE RESISTANCE HAS NOT YET APPEARED IN P ULMI, EVEN IN AREAS SUCH AS OHIO AND INDIANA WHERE THE RED MITE IS RESISTANT TO ALL CHLORINATED ACARICIDES. ARAMITE HAS ... BEEN EMPLOYED FOR MANY YEARS AGAINST P CITRI WITHOUT DEVELOPMENT OF RESISTANCE, AND ITS ADDITION TO DEMETON DELAYS ONSET OF DEMETON RESISTANCE TO WHICH THIS SPECIES IS NORMALLY LIABLE. [R4] *RESIDUAL ACTION EFFECTIVE FOR SOME 7 DAYS. [R2] *PREPN: HARRIS ET AL, US PATENT 2,529,494 (1950 TO US RUBBER). [R5] *STABILIZED BY ADDITION OF POLYPROPYLENE GLYCOL (US PATENT 2,644,008). [R2] USE: *ANTIMICROBICIDE AGENT (FORMER USE) [R6, 96] *MITICIDE (FORMER USE) [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +COLORLESS LIQUID [R7]; *Clear light-colored oil [R6, 96] BP: +175 DEG C AT 0.1 MM HG [R5] MP: +-31.7 DEG C [R5] MW: +334.87 [R5] CORR: *Noncorrosive [R6, 96] DEN: *1.145 @ 20 deg C/20 deg C [R8] SOL: *PRACTICALLY INSOL IN WATER; MISCIBLE WITH MANY ORGANIC SOLVENTS; SOLUBILITY IN PETROLEUM OILS DECR RAPIDLY WITH DECR TEMPERATURES [R5]; *> 10% in ethanol [R8]; *SOL IN DIMETHYL KETONE [R9, 498]; *> 10% in benzene [R8]; *> 10% in acetone [R8]; *> 10% in ether [R8]; *Water solubility of 0.1 ppm. [R10] SPEC: +INDEX OF REFRACTION: 1.5100-1.5118 AT 20 DEG C/D; 1.5075 @ 27 DEG C/D [R5]; +Intense mass spectral peaks: 191 M/z (100%), 57 M/z (89%), 185 M/z (88%), 63 M/z (84%) [R11]; +MASS: 4937 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R8] VAP: *< 10 MM HG AT 25 DEG C [R1] OCPP: +DENSITY: 1.145-1.162 /TECHNICAL PRODUCT/ [R7] *DARK AMBER LIQUID /TECHNICAL PRODUCT/ [R2] *INCOMPATIBLE WITH ALKALINE MATERIALS SUCH AS LIME OR BORDEAUX MIXTURE. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *WHEN HEATED TO DECOMPOSITION, EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE AND SULFUR OXIDES/. [R12] SERI: *Irritant to eyes and skin ... . [R6, 97] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R13, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R13, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R13, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R13, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *STABILITY IN SOLN DECREASES IN STRONG ACID OR ALKALI [R9, 499] *TECHNICAL MATERIAL IS DECOMPOSED BY SUNLIGHT AND DEVELOPS ODOR OF SULFUR DIOXIDE. /TECHNICAL MATERIAL/ [R2] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R13, 1979.15] DISP: *Mix aramite with excess CaO /calcium oxide/ or NaOH /sodium hydroxide/ and sand or other adsorbent in a pit or trench at least 0.5 m deep in a clay soil. NaOH (or Na2CO3) /sodium carbonate/ can also be added to the mixture to help speed the reactions when calcium oxide is used as the main alkali. The amt of calcium oxide or sodium hydroxide to use depends on the amt of pesticide to be disposed of and, to some extent, the concn of active ingredient in the pesticide and the actual chemical nature of the active ingredient. A practical guideline, in the absence of specific directions, is to use an approx vol or wt of alkali from one-half of to the same as that of the pesticide. For dilute formulations, such as a 1% soln or dust, the amt of calcium oxide or sodium hydroxide can be reduced by one-half. For very concn pesticides (over 80% active ingredient) the amt of calcium oxide or sodium hydroxide can be doubled, but the concn should be mixed first with water (or soapy water) before reaction with the alkali. For safety, a preliminary test should be made in which very small amt of the pesticide and alkali are mixed and observed briefly to make sure it does not react too vigorously. Sizeable quantities of pesticides can be disposed of in several smaller batches, rather than all at once, for added safety. Recommendable methods: Incineration, hydrolysis, landfill, and discharge to sewer. Peer review: Small amt when hydrolized can be flushed to sewer or landfilled. Large amt should be incinerated in a unit with effluent gas scrubbing. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R14] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R13, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R13, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R13, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R13, 1979.16] *Acid or alkaline hydrolysis followed by flushing to sewer. [R15, 818] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R16] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on no human data and sufficient data from animal bioassays including increased incidence of liver tumors and/or neoplastic nodules in three strains of male and female rats and males of one strain of mice, and extrahepatic biliary system tumors in dogs following chronic oral exposure. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Sufficient. [R18] +No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans. [R19] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R13, 1979.23] HTOX: *IN UNDILUTED FORM /IT/ MAY CAUSE SKIN IRRITATION. [R5] NTOX: *NO EVIDENCE OF CHRONIC TOXICITY TO DOGS FED 20 WK WITH DIET CONTAINING 500 PPM. [R2] *STUDIES OF ACUTE TOXICITY IN LAB MAMMALS PLACE THIS ACARICIDE NEAR THE BODERLINE BETWEEN TOXICITY CLASSES 2 and 3 (RAT ORAL LD50 3.9 G/KG). A LARGE ORAL DOSE CAUSES CENTRAL NERVOUS DEPRESSION OF LONG DURATION. PRINCIPAL AUTOPSY FINDING IN ANIMALS WAS HEMORRHAGIC SYNDROME INVOLVING PARTICULARLY THE LUNG. [R20] *IN BOTH C57BL AND C3H STRAINS OF MICE, GROUPS OF 50 MALES AND 50 FEMALES WERE FED DIETS CONTAINING 100, 200 OR 400 PPM ARAMITE CONTINUOUSLY OVER 2 YEARS. CONTROLS (100 MALE AND 100 FEMALE MICE OF EACH STRAIN) RECEIVED A STD DIET. THE MEDIAN SURVIVAL TIME WAS LOW (48-67 WK) IN C3H MICE AND HIGHER IN C57BL MICE (65-74 WK); HOWEVER, TREATED C3H MICE SHOWED NO HIGHER INCIDENCE OF MAMMARY OR OTHER TUMORS THAN DID TREATED C57BL MICE. NO HIGHER INCIDENCE OF HEPATIC OR OTHER LESIONS WAS REPORTED FOR TEST GROUPS AS COMPARED WITH CONTROLS IN BOTH STRAINS OF MICE. [R21] *IN A STUDY WHICH WAS REPORTED AS A PRELIMINARY NOTE, EIGHTEEN (C57BL/6XC3H/ANF)F1 MICE OF EACH SEX AND EIGHTEEN (C57BL/6XAKR)F1 MICE OF EACH SEX WERE GIVEN SINGLE DOSES OF 464 MG/KG BODY WT ARAMITE BY STOMACH TUBE AT 7 DAYS OF AGE. THE SAME ABSOLUTE DOSE WAS THEN GIVEN DAILY UNTIL ANIMALS WERE 28 DAYS OF AGE. SUBSEQUENTLY, ANIMALS WERE FED AD LIBITUM, A DIET CONTAINING 1112 PPM ARAMITE. MICE WERE KILLED AT 78-81 WK. HEPATOMAS WERE FOUND IN EXCESS OVER THE CONTROLS AMONG MALES OF (C57BL/6XC3H/ANF)F1 STRAIN, THE INCIDENCE 6/16 VERSUS 8/79 IN THE CONTROLS. THE TOTAL TUMOR INCIDENCE IN FEMALES OF THE STRAIN WAS ALSO INCREASED. [R22] *ARAMITE WAS ADMINISTERED AT LEVELS OF 500, 1580 AND 5000 PPM IN THE DIET OF GROUPS OF 10 MALE AND 10 FEMALE FDRL WISTAR RATS FOR UP TO 2 YEARS. TREATMENT RESULTED IN DEVELOPMENT OF LIVER LESIONS RANGING FROM A SINGLE FOCUS OF NODULAR HYPERPLASIA IN 1/20 RATS RECEIVING 500 PPM, TO MALIGNANT LIVER CHANGES IN 2/21 RATS RECEVING 1580 PPM, AND TO LIVER TUMORS (DIAGNOSED AS HEPATOMAS OR CHOLANGIOMAS) IN 6/20 RATS RECEIVING 5000 PPM. IN A LATER STUDY, LEVELS OF 100, 200, OR 400 PPM ARAMITE WERE ADMIN IN DIET TO GROUPS OF 50 MALE AND 50 FEMALE (WISTAR) FDRL, SPRAGUE-DAWLEY (SD) OR CARWORTH FARM-NELSON (CFN) RATS FOR 2 YR. THE FOLLOWING LIVER CHANGES WERE NOTED: 2 LIVER CARCINOMAS AND 5 BILE DUCT ADENOMAS IN 7/90 FDRL RATS FED 400 PPM, WITH NO SIMILAR LESIONS IN 193 CONTROLS; BILE DUCT ADENOMAS IN 2/93, 1/90 AND 2/96 CFN RATS RECEIVING 3 DOSE LEVELS, RESPECTIVELY, AS COMPARED WITH 0/180 IN CONTROLS. LIVER LESIONS WERE NOT FOUND IN THE GROUPS OF 41-92 SD RATS EXAMINED; HOWEVER, THEY SUFFERED FROM RESP INFECTION AND THE MEDIAL SURVIVAL TIMES RANGED FROM 36-55 WK. THE INCIDENCE OF HYPERPLASIA NODULES WAS INCREASED IN LIVERS OF FDRL RATS FED 400 PPM AND CFN RATS FED 200 and 400 PPM: THE RESPECTIVE INCIDENCES WERE 20/90, 10/90 and 22/96 COMPARED WITH 2/193 IN FDRL AND 5/180 IN CFN CONTROLS. [R22] *GROUPS OF 30 MALE AND 30 FEMALE OSBORNE-MENDEL RATS WERE ADMINISTERED /ORALLY/ 200 PPM ARAMITE FOR 27 MONTHS. ONE HEMANGIOMA OF LIVER WAS FOUND; NO LIVER TUMORS OCCURRED IN CONTROLS. [R23] *TWO GROUPS OF 50 MALE AND 50 FEMALE C34/ANF MICE RECEIVED WEEKLY SKIN APPLICATIONS OF EITHER 0.1 OR 10 MG ARAMITE IN 0.2 ML ACETONE. THE MEAN SURVIVAL TIMES EXCEEDED 400 DAYS, EXCEPT IN FEMALES GIVEN THE LOWEST DOSE, FOR WHICH IT WAS 328 DAYS. THE TOTAL DOSES RANGED FROM 0.3-9.0 MG/MOUSE AT THE LOWER DOSE LEVEL AND 20-1040 MG/MOUSE AT HIGHER LEVEL. GROSS EXAMINATION REVEALED NO SKIN TUMORS; HISTOLOGICAL EXAMINATION OF SKIN WAS LIMITED TO 5-24 MICE/GROUP OF 50. [R23] *IN STUDY LASTING 3.5 YR, 17 MALE AND 23 FEMALE MONGREL DOGS WERE DIVIDED INTO 3 GROUPS OF 12, 12 and 16 ANIMALS, WHICH RECEIVED DIETS CONTAINING 0, 500 OR 828-1420 PPM ARAMITE, RESPECTIVELY. A TOTAL OF 19 TREATED DOGS DIED OR WERE KILLED BETWEEN 462 AND 1,200 DAYS. OF THE 5 DOGS DYING BEFORE 811 DAYS, ONE HAD NEOPLASTIC NODULES IN LIVER. CANCER OF BILIARY SYSTEM WAS FOUND IN ALL OF THE 14 REMAINING DOGS DYING AFTER THIS TIME. OF THESE, ADENOCARCINOMAS OF BOTH THE GALL BLADDER AND EXTRAHEPATIC BILIARY DUCTS OCCURRED IN 7 DOGS, MAINLY IN THOSE ON THE HIGHER AVG DIETARY CONCN OF ARAMITE FOR THE LONGEST PERIODS; 1 DOG HAD CARCINOMAS OF THE EXTRA- AND INTRAHEPATIC BILIARY DUCTS; 2 DOGS HAD ADENOCARCINOMAS OF EXTRAHEPATIC BILIARY DUCTS; and 1 DOG HAD A SINGLE ADENOCARCINOMA OF GALL BLADDER. THERE WERE NO CALCULI PRESENT IN GALL BLADDER OR BILIARY DUCTS. FIVE OF THE 14 DOGS HAD NEOPLASTIC LIVER NODULES AS WELL, BUT NO MALIGNANT CHANGES WERE SEEN IN THESE NODULES. CONTROLS REMAINED ESSENTIALLY NORMAL, AND TUMORS DID NOT OCCUR IN THESE ANIMALS. [R23] *ARAMITE IN TRIOCTANOIN WAS INJECTED SC INTO A GROUP OF 50 MALE AND 50 FEMALE YOUNG ADULT C3H/ANF MICE AS SINGLE DOSES OF 10 MG. MEAN SURVIVAL TIMES WERE 533 DAYS IN MALES AND 401 DAYS IN FEMALES. GROSS EXAMINATION REVEALED NO LOCAL TUMORS; HISTOLOGICAL EXAM OF THE SKIN WAS LIMITED TO 5 FEMALE AND TO 22 MALE MICE. [R24] +UNDILUTED ARAMITE (AN OIL) AND ITS CONCENTRATED SOLN ARE IRRITATING TO SKIN AND CONJUNCTIVA /OF EXPERIMENTAL ANIMALS/. [R20] *APPARENTLY /ARAMITE WAS/ OF LOW PHYTOTOXICITY, EXCEPT PERHAPS TO SOME VARIETIES OF PEAR. [R2] *Aramite ... has been found to give electroretinographic indications of intoxication of retinal photoreceptors when injected into mice, and when applied to the eyeball. [R25] NTXV: *LD50 Rat oral 3900 mg/kg; [R26, 122] *LD50 GUINEA PIG ORAL 3.9 G/KG; [R2] *LD50 MOUSE ORAL 2.0 G/KG; [R2] ETXV: *LC50 Coturnix japonica (Japanese quail, 14-day old) oral > 5000 ppm (5 day ad libitum diet); [R27] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Aramite can be released directly into the environment through its use as an acaricide (miticide); however, this use has apparently been discontinued. If released to soil, aramite is not expected to leach. If released to water, aramite may partition significantly from the water column to sediment and suspended material in water. The estimated BCF value of 2265 suggests a potential for significant bioconcentration in aquatic organisms. Insufficient data are available to predict the relative importance or occurrence of chemical or biological degradation processes in soil or water. If released to air, aramite is expected to exist primarily in the aerosol-phase where it can be physically removed by wet and dry deposition processes. Occupational exposure is possible through dermal contact and inhalation of dusts and sprays during application of aramite as an acaricide. (SRC) ARTS: *Aramite has been used as an acaricide, such as in the control of mites in citrus fruits(2); however, its use has been discontinued and it currently has little commercial interest(1). Use of aramite as an acaricide will release the compound directly into the environment through applications of sprays and dusts(SRC). [R28] FATE: *TERRESTRIAL FATE: Based on an estimated Koc value of 15500(1,SRC), aramite is not expected to leach in soil. Insufficient data are available to predict the relative importance or occurrence of chemical or biological degradation processes in soil(SRC). [R29] *AQUATIC FATE: Based on an estimated Koc value of 15500(1,SRC), aramite may partition significantly from the water column to sediment and suspended material in water. The estimated BCF value of 2265(1,SRC) suggests a potential for significant bioconcentration in aquatic organisms. Insufficient data are available to predict the relative importance or occurrence of chemical or biological degradation processes in water. Aquatic volatilization or direct photolysis do not appear to be important(SRC). [R30] *ATMOSPHERIC FATE: Based on a reported vapor pressure of 0.1 mm Hg at 175 deg C(1), the vapor pressure of aramite can be estimated to be roughly 1X10-8 mm Hg at 25 deg C using the Clausius-Clapeyron relationship(SRC). This vapor pressure suggests that aramite will exist primarily in the particulate-phase in the ambient atmosphere(2,SRC) where physical removal can occur by dry deposition and/or by wet deposition such as rainfall(SRC). [R31] ABIO: *In hexane solution, aramite does not absorb uv irradiation above 290 nm(1); this suggests that aramite does not directly photolyze in the environment(SRC). [R32] BIOC: *Based on a reported water solubility of 0.1 ppm(1), the BCF for aramite can be estimated to be 2265 from a recommended regression-derived equation(2,SRC). This BCF value suggests a potential for significant bioconcentration in aquatic organisms(SRC). [R33] KOC: *Based on a reported water solubility of 0.1 ppm(1), the Koc for aramite can be estimated to be 15500 from an appropriate regression-derived equation(2,SRC). This Koc value indicates soil immobility(3). [R34] VWS: *Based on a reported vapor pressure of 0.1 mm Hg at 175 deg C(1), the vapor pressure of aramite can be estimated to be roughly 1X10-8 mm Hg at 25 deg C using the Clausius-Clapeyron relationship(SRC). Using the reported water solubility of 0.1 ppm(2) and the estimated vapor pressure, the Henry's Law Constant for aramite can be estimated to be 4.4X10-8 atm cu m/mole(SRC). A Henry's Law Constant of this magnitude indicates that a compound is essentially non-volatile from water(3). [R35] RTEX: *Aramite has been used as an acaricide, such as in the control of mites in citrus fruits(2); however, its use has been discontinued and it currently has little commercial interest(1). Although exposure through oral consumption of contaminated fruits is possible, it should no longer be occurring since the use of aramite as an acaricide has been discontinued. During application of aramite as an acaricide, occupational exposure is possible through dermal contact and inhalation of aerosols and dusts(SRC). [R28] *No data are available on the number of workers who were actually or potentially exposed to aramite during its manufacture and formulation. [R15, 817] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: *This product was voluntarily cancelled on the basis of oncogenicity according to US EPA in a notice dated April 12, 1977. [R26, 123] *This rule revokes the tolerances established for residues of 20 pesticide chemicals /including aramite/ in or on certain raw agricultural commodities. This regulatory action is being taken by EPA to revoke tolerances for those pesticides which have no registered food uses or if they were registered the registrations were subsequently cancelled. 40 CFR Part 180 is amended: Section 180.107 is removed. [R36] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *DDT-type compounds may be present in the air in vapor form or adsorbed on particulate matter. Glass fiber filters are suitable for trapping the particulate matter, and DDT in the vapor form may be trapped using impingers of the Greenburg-Smith type and a suitable nonvolatile solvent using ethylene glycol. /DDT type compounds/ [R37] ALAB: *Aramite is stripped from sample /of food/ with benzene, soln is concentrated and Aramite is hydrolyzed with potassium hydroxide-isopropanol to form ethylene oxide. Evolved ethylene oxide is converted to formaldehyde with potassium iodate, and formaldehyde is reacted with acetylacetone to form colored cmpd which is determined colorimetrically. See 29.067-29.071, 12th edition. [R38] *GAS-LIQ CHROMATOGRAPHY METHOD FOR DETERMINING ARAMITE IN PRESENCE OF DDT, TOXAPHENE AND ENDRIN IN CROP RESIDUES. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology review: Oncology 1970, Proceedings of the Tenth International Cancer Congress, Chicago, Year Book Medical Publishers, 1971 5,250,70 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting Aramite (140-57-8); Reason: No U.S. residents exposed. SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 40 (1974) R2: Spencer, E.Y. Guide to the Chemicals Used in Crop Protection. 6th ed. Publication 1093, Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1973. 20 R3: Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989.,p. C-25 R4: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 474 R5: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 112 R6: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 39 (1974) R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 114 R9: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R10: Naishtein SY; Vopr Gigieny Naselen Mest, Kiev, SB 5: 34-7 (1964) R11: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 267 R12: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2491 R13: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R14: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 287 R15: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R16: 40 CFR 165.9(a) (7/1/88) R17: 40 CFR 165.9(b) (7/1/88) R18: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Aramite (140-57-8) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 57 (1987) R20: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-289 R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 41 (1974) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 42 (1974) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 43 (1974) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 44 (1974) R25: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 113 R26: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. R27: Hill, E.F. and Camardese, M.B. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix. Fish and Wildlife Technical Report 2. Washington, DC: United States Department of Interior Fish and Wildlife Service, 1986.27 R28: (1) Worthing CR, Walker SB; The Pesticide Manual. Seventh Ed. The British Crop Protection Council, p. 573 (1983) (2) Jeppson LR, Gunther FE; Res Rev 33: 101-36 (1970) R29: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw-Hill p. 4-9 (1982) R30: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw-Hill p. 4-9, 5-10 (1982) R31: (1) Windholz RC; The Merck Index. Tenth Ed. p. 112 (1983) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) R32: (1) Gore RC et al; J Assoc Off Anal Chem 54: 1040-82 (1971) R33: (1) Naishtein SY; Vopr Gigieny Naselen Mest, Kiev, SB 5: 34-7 (1964) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw- Hill p. 5-10 (1982) R34: (1) Naishtein SY; Vopr Gigieny Naselen Mest, Kiev, SB 5: 34-7 (1964) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (3) Swann RL et al; Res Rev 85: 16-28 (1983) R35: (1) Windholz RC; The Merck Index. Tenth Ed. p. 112 (1983) (2) Naishtein SY; Vopr Gigieny Naselen Mest, Kiev, SB 5: 34-7 (1964) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw-Hill p. 15-15 (1982) R36: 53 FR 15824 (5/4/88) R37: Beyermann K, Eckrich W; Z Analyt Chem 269 (4): 279-84 (1974) as cited in WHO; Environ Health Criteria: DDE p.29 (1979) R38: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/483 29.075 RS: 37 Record 133 of 1119 in HSDB (through 2003/06) AN: 1538 UD: 200304 RD: Reviewed by SRP on 12/10/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SULFALLATE- SY: *CARBAMIC-ACID,-DIETHYLDITHIO-,-2-CHLOROALLYL-ESTER-; *CARBAMODITHIOIC-ACID,-DIETHYL-,-2-CHLORO-2-PROPENYL-ESTER-; *CDEC-; *CHLORALLYL-DIETHYLDITHIOCARBAMATE-; *2-CHLORALLYL-DIETHYLDITHIOCARBAMATE-; *2-CHLOROALLYL-N,N-DIETHYLDITHIOCARBAMATE-; *2-CHLOROALLYL-DIETHYLDITHIOCARBAMATE-; *2-CHLORO-2-PROPENYL-DIETHYLCARBAMODITHIOATE-; *CP-4,742-; *CP-4572-; *CP-4742-; *Diethylcarbamodithioic-acid-2-chloro-2-propenyl-ester-; *DIETHYLDITHIOCARBAMIC-ACID-2-CHLOROALLYL-ESTER-; *NCI-C00453-; *2-PROPENE-1-THIOL,-2-CHLORO-,-DIETHYLDITHIOCARBAMATE-; *THIOALLATE-; *VEGADEX-; *VEGADEX-SUPER-; *VEGEDEX- RN: 95-06-7 MF: *C8-H14-Cl-N-S2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *It is made by the reaction of 2,3-dichloropropene-1 with sodium diethyldithiocarbamate. [R1] FORM: *Formulated into emulsifiable concentrates, liquids, and granules. [R2] OMIN: *WILL NOT CONTROL ESTABLISHED OR VEGETATIVELY-PROPAGATED PLANTS. [R3] *Discontinued by Monsanto Agricultural Co. [R4] USE: *The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R5] *Herbicide [R6] *HERBICIDE FOR VEGETABLE CROPS. [R7] *Used for preemergent control of the growth of grasses and weeds in fruit and vegetable crops. [R8, 312] *Herbicide to control certain annual grasses and broadleaf weeds around vegetable and fruit crops. Sulfallate has also been used for weed control among shrubbery and ornamental plants. [R2] CPAT: *AS AN HERBICIDE, ESSENTIALLY 100% FOR VEGETABLES (1978) [R7] PRIE: U.S. PRODUCTION: *(1975) 4.54X10+7 G (CONSUMPTION) [R7] *(1978) 4.54X10+7 G (CONSUMPTION) [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Amber oil [R9]; *Amber liquid [R6] BP: *128-130 deg C [R6] MW: *223.79 [R6] DEN: *1.088 @ 25 deg C [R6] SOL: *In water, 100 mg/l @ 25 deg C [R6]; *SOL IN ACETONE, BENZENE, CHLOROFORM, ETHYL ACETATE, ETHYL ALCOHOL, KEROSENE AT 25 DEG C [R10, 96]; *Soluble in most organic solvents. [R1] SPEC: *Index of Refraction: 1.5822 @ 25 deg C/D [R6]; *Intense mass spectral peaks: 188 m/z (100%), 72 m/z (33%), 44 m/z (30%), 88 m/z (28%) [R11]; *UV AND IR spectrum [R12] VAP: *2.2X10-3 MM HG @ 20 DEG C [R1] OCPP: *DECOMP TEMP: 150 DEC C; NONCORROSIVE TO METALS [R10, 95] *HYDROLYZED IN AQ SOLN, HALF-LIFE @ PH 5, 47 DAYS, @ PH 8, 30 DAYS [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FIRP: */Wear/ self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode /when fighting fire/. /Carbaryl/ [R13, 1981.5] *Extinguish fire using agent suitable for type of surrounding fire. Material itself does not burn or burns with difficulty. /Carbaryl (agricultural insecticides, nec, liquid); Carbaryl (agricultural insecticides, nec, other than liquid); Carbaryl (insecticides, other than agricultural, nec/ [R14, 1987.134] *If material /is/ on fire or involved in /a/ fire do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical or carbon dioxide. /Carbamate pesticide, liquid, nos, (compounds and preparations) (agricultural insecticides, nec, liquid); Carbamate pesticide, liquid, nos (compounds and preparations) (agricultural insecticides, nec, liquid); Carbamate pesticide, liquid, nos (compounds and preparations) (insecticides, other than agricultural, nec/ [R14, 1987.133] *Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Solid streams of water may be ineffective. Use foam, dry chemical, or carbon dioxide. /Carbamate pesticide, liquid nos (compounds and preparations) (insecticides, other than agricultural, nec)/ [R14, 1987.133] *Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use "alcohol" foam, dry chemical or carbon dioxide. /Carbamate pesticide, solid, nos (compounds and preparations) (insecticides, other than agricultural, nec)/ [R14, 1987.134] *Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam, dry chemical, or carbon dioxide. /Carbamate pesticide, solid, nos (compounds and preparations) (agricultural insecticides, nec, other than liquid)/ [R14, 1987.134] DCMP: *When heated to decomposition it emits very toxic fumes of hydrogen chloride, oxides of nitrogen and oxides of sulfur. [R15] SERI: *PROLONGED CONTACT WITH SKIN AND EYES CAUSES MODERATE IRRITATION. [R16] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R17, 1979.8] *Respirator selection, upper limit devices recommended by NIOSH. For concn up to 50 mg/cu m, use any supplied air respirator; or any self-contained breathing apparatus. For concn up to 125 mg/cu m, use any supplied-air respirator operated in a continuous flow mode. For concn up to 250 mg/cu m, use any self-contained breathing apparatus with a full facepiece; or any supplied-air respirator with a full facepiece. For concn up to 600 mg/cu m, use any supplied-air respirator with a half-mask and operated in a pressure-demand or other positive pressure mode. For emergency or planned entry into unknown concentration or IDLH conditions, use any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode; or any supplied-air respirator with a full facepiece and operated in a pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. Escape conditions use, any air-purifying full facepiece respirator (gas mask) with a chin-style or front- or back-mounted organic vapor canister having a high-efficiency particulate filter; or any appropriate escape-type self-contained breathing apparatus. /Carbaryl/ [R18] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with carbaryl or liquids containing carbaryl. /Carbaryl/ [R13, 1981.3] *Wear appropriate chemical protective gloves, boots and goggles. /Carbaryl (agricultural insecticides, nec, liquid); Carbaryl (agricultural insecticides, nec, other than liquid); Carbaryl (insecticides, other than agricultural, nec)/ [R14, 1987.134] *Wear positive pressure self-contained breathing apparatus. ... Wear appropriate chemical protective clothing. /Carbamate pesticide, liquid, not otherwise specified (compounds and preparations) (agricultural insecticides, nec, liquid)/ [R14, 1987.133] *Wear appropriate chemical protective gloves, boots and goggles. ... Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. /Carbamate pesticide, liquid, nos (compounds and preparations) (agricultural insecticides, nec, liquid); carbamate pesticide, liquid, nos (compounds and preparations) (insecticides, other than agricultural, nec)/ [R14, 1987.133] *Wear positive pressure self-contained breathing apparatus. ... Wear appropriate chemical protective clothing. /Carbamate pesticide, liquid, nos (compounds and preparations) (insecticides, other than agricultural, nec)/ [R14, 1987.133] *Wear appropriate chemical protective gloves, boots and goggles. ... Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. /Carbamate pesticide, solid, nos (compounds and preparations) (insecticides, other than agricultural, nec); Carbamate pesticide, solid, nos (compounds and preparations) (agricultural insecticides, nec, other than liquid)/ [R14, 1987.134] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R17, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R17, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R17, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *INDEFINITE SHELF LIFE AS LONG AS CONTAINER REMAINS SEALED AND NOT EXPOSED TO HIGH TEMP [R10, 96] *Sulfallate is hydrolyzed very slowly in either very weak acid, pH 5, or very weak base, pH 8. It is hydrolyzed rapidly in boiling caustic and is completely decomposed by strong oxidizing agents. [R19] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R17, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R17, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R17, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R17, 1979.15] *1. VENTILATE AREA OF SPILL. 2. ... LARGE QUANTITIES MAY BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN FLAMMABLE SOLVENT (SUCH AS ALCOHOL) AND ATOMIZE IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. /CARBARYL/ [R13, 1981.] *A system for removing pesticides from the wash water produced by pesticide applicators as they clean their equipment has been developed. The first step is the flocculation/coagulation and sedimentation of the pesticide-contaminated wash water. The supernatant from the first step is then passed through activated carbon columns. /Pesticides/ [R20] *Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. /Carbaryl (agricultural insecticides, nec, liquid)/ [R14, 1987.134] *Water spill: If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Carbaryl (agricultural insecticides, nec, liquid)/ [R14, 1987.134] *Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. /Carbaryl (agricultural insecticides, nec, other than liquid); Carbaryl (insecticides, other than agricultural, nec/ [R14, 1987.134] *Water spill: If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Carbaryl (agricultural insecticides, nec, other than liquid); Carbaryl (insecticides, other than agricultural, nec)/ [R14, 1987.134] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Hydrolysis: Sulfallate is hydrolyzed very slowly in either very weak acid, pH 5, or very weak base, pH 8. It is hydrolyzed rapidly in boiling caustic and is completely decomposed by strong oxidizing agents. Recommendable method: Incineration. Peer-review: Large amt should be incinerated in a unit with effluent gas scrubbing. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R21, 123] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R17, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R17, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R17, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R17, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R17, 1979.17] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R22] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R22] *Hydrolysis and landfill: For each 2.265 kg of actual carbaryl, add 0.906 kg of flake caustic (sodium hydroxide) (this amt was stated to be a 50% excess over the minimum required) and allow about 24 hr for completion of the reaction. The first step of the degradation would be: aryl-O-CO-NHR + H2O --- NaOH --- > aryl-OH- + (HO-CO-NHR). The carbamic acid at the right would decompose to the amine and carbon dioxide in neutral soln, or to sodium carbonate in excess base. In excess base the phenol would be converted to the salt, that is, NaO-aryl. Phenolic decomposition products of some carbamate pesticides may, under some circumstances, persist in the environment and harm specific ecosystems. ... Hence, the hydrolysis should be followed by soil burial of the products in disposal. /Carbaryl/ [R21, 128] *The heavy residue solid wastes are burned. One shutdown for cleaning is made peryear, but numerous maintenance cleanups are made and the washings go to the process waste treatment system. Carbaryl may be disposed of: 1) By making packages of carbaryl in paper or other flammable material and burning in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. 2) By dissolving carbaryl in a flammable solvent (such as alcohol) and atomizing in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. Recommendable methods: Alkaline hydrolysis, landfill and incineration. Peer-review: Use 1 part by weight NaOH /sodium hydroxide/ (as a 10% wt/vol soln in 50% ethanol:water) per 4 parts of carbaryl plus 50% excess of NaOH. Leave for 24 hr. Dissolve carbaryl in flammable solvent such as ethanol, then spray the soln in an incinerator with effluent gas scrubbing. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) /Carbaryl/ [R21, 129] *Hydrolysis and landfill: Under the influence of sunlight, the reversal reaction ofcarbaryl to 1-naphthol and methylisocyanate (CH3NCO) has been found to take place. Methylisocyanate is a poisonous and highly reactive substance. Accordingly, carbaryl should always be submitted to alkaline hydrolysis before disposal. For the decontamination of carbaryl containers triple rinse and use of a rinse soln containing caustic soda and detergent may be considered. "Triple rinse" means the flushing of containers three times, each time using a volume of the normal diluent equal to approx ten percent of the container's capacity, and adding the rinse liquid to the spray mixture or disposing of it by a method prescribed for disposing of the pesticide. /Carbaryl/ [R21, 129] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: No adequate data. 2) evidence in animals: Sufficient evidence. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/ [R23] *Based on the evaluation conducted by the National Toxicology Program (NTP), the chemical compound sulfallate is listed as "substances or groups of substances, and medical treatments which may reasonably be anticipated to be carcinogens." [R24] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R17, 1979.23] NTOX: *... NO DEATHS RESULTED IN RATS FED CDEC DAILY @ LEVEL OF 0.085 ML/KG OVER PERIOD OF 30 DAYS. ALL LESIONS OBSERVED IN PATHOLOGICAL EXAMINATIONS WERE REVERSIBLE. [R10, 97] *CHRONIC TOXICITY: BEAGLE DOGS AND RATS FED FOR 90 DAYS @ DOSAGE LEVELS OF 20, 62, and 200 PPM WERE UNAFFECTED DURING STUDY OF 8 PARAMETERS, WITH EXCEPTION THAT DOG LIVER/BODY WT RATIOS WERE SOMEWHAT ELEVATED @ 200 PPM. ... INHALATION: RATS SURVIVED 6 HR EXPOSURE TO SATURATED ATMOSPHERE OF CDEC. [R10, 97] *... PARALYSIS OF NECK HAS BEEN NOTED IN ANIMALS ORALLY ADMIN 550 MG/KG. IF ALLOWED TO REMAIN ON SKIN, CDEC MAY CAUSE TEMPORARY LOSS OF LOCAL SENSATION. [R10, 97] *GROUPS OF 50 MALE AND 50 FEMALE B6C3F1 MICE, SIX WK OLD, WERE FED DIETS CONTAINING TECHNICAL GRADE SULFALLATE. MALES WERE FED 950 PPM (LOW DOSE) OR 1900 PPM (HIGH DOSE), AND FEMALES 900 PPM (LOW DOSE) OR 1800 PPM (HIGH DOSE) FOR 78 WK. ALVEOLAR AND BRONCHIOLAR CARCINOMAS OR ADENOMAS WERE FOUND IN THE LOW AND HIGH DOSE MALE GROUPS. ADENOCARCINOMAS OF THE MAMMARY GLAND WERE FOUND IN THE LOW AND HIGH DOSE FEMALE GROUPS. DOSE-RELATED MORTALITY OCCURRED ONLY IN THE FEMALE GROUP. GROUPS OF 50 MALE AND 50 FEMALE OSBORNE-MENDEL RATS, SIX WK OLD, WERE FED DIETS CONTAINING TECHNICAL GRADE SULFALLATE FOR 78 WK. MALES WERE FED 205 PPM (LOW DOSE) and 410 (HIGH DOSE). FEMALES WERE FED 207 PPM (LOW DOSE) and 414 PPM (HIGH DOSE). SQUAMOUS CELL CARCINOMAS OR PAPILLOMAS OF THE FORESTOMACH WERE FOUND IN THE HIGH DOSE MALE GROUP. ADENOCARCINOMAS OF THE MAMMARY GLAND WERE FOUND IN THE LOW AND HIGH DOSE FEMALE GROUPS. DOSE-RELATED MORTALITY OCCURRED IN BOTH MALE AND FEMALE GROUPS. [R25] *2-CHLOROACROLEIN, THE ULTIMATE MUTAGEN FORMED ON METABOLISM OF THE CARCINOGEN, SULFALLATE, IS MUCH MORE POTENT IN AMES SALMONELLA TYPHIMURIUM STRAIN TA100 ASSAY THAN OTHER ALDEHYDES EXAMINED PREVIOUSLY OR IN THIS STUDY. [R26] *SULFALLATE WAS TESTED FOR ABILITY TO INDUCE REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM AND FORWARD MUTATIONS IN STREPTOMYCES COELICOLOR AND ASPERGILLUS NIDULANS. IT GAVE A POSITIVE RESPONSE, TO DIFFERENT DEGREES, IN ALL MICROORGANISMS. [R27] *2-HALOACROLEINS AS POTENT MUTAGENS AND INTERMEDIARY METABOLITES MAY CONTRIBUTE TO THE ADVERSE TOXICOLOGICAL PROPERTIES OF SULFALLATE. [R28] *Chronic feeding studies have demonstrated that rats fed 250 ppm concentrations of sulfallate in feed for 6 months develop eye irritation, tubular nephropathy, and hyperkeratosis of the forestomach. [R8, 313] *Sulfallate was mutagenic to Salmonella typhimurium in the presence of exogenous metabolic activation and to Aspergillus and Streptomyces but not to Saccharomyces cerevisiae with or without metabolic activation. There is sufficient evidence for the mutagenicity of sulfallate in bacterial systems but insufficient for its mutagenicity in mammalian cells or in mammals. [R29] *Groups of 50 male and 50 female Oborne Mendel rats, six weeks old, were fed diets containing 250 mg/kg technical grade sulfallate (purity, > 90%; analysis not performed) for a total of 78 weeks (low-dose groups) or 500 mg/kg for the first seven (females) and eleven wk (males) (high-dose groups) over a total of 53-56 wk. ... Animals were observed for 25-26 wk after dosing. ... Controls wereobserved for 111 wk. A distinct dose-related depression in mean body wt was observed throughout the study. A dose-related trend was observed ... among females ... with adenocarcinomas of the mammary gland. ... statistically significantly different ... incidences of squamous cell carcinomas and papillomas of the forestomach in males. [R30] *CDEC @ 1X10-4 M SHOWED COMPLETE INHIBITION OF ROOT GROWTH AND APPROX 75% REDN IN PROTEOLYTIC ACTIVITY. ... CDEC @ 2X10-4 MOLAR INHIBITED DEVELOPMENT OF ALPHA-AMYLASE ACTIVITY OF GERMINATING BARLEY SEEDS ... INHIBITION OF ENZYMIC ACTIVITY DURING GERMINATION OF SEEDLINGS IS GENERALLY LINKED TO INHIBITION OF ENZYME SYNTHESIS. [R31] *Sulfallate gave negative results in both the Escherichia coli pol and Bacillus subtilis rec differential killing tests in bacteria, in the absence of metabolic activation. [R32] *CDEC WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM TA100 AND TA1535 ONLY IN PRESENCE OF LIVER MICROSOMAL PREPN INDICATING THE NEED FOR METABOLIC ACTIVATION FOR CONVERSION INTO ACTIVE MUTAGEN. [R33] NTXV: *LD50 Rat oral 850 mg/kg body wt; [R32] NTP: *A bioassay for possible carcinogenicity of sulfallate was conducted using B6C3Fl mice. Sulfallate was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female mice. Twenty mice each sex were placed on test as controls for the bioassay. The time-weighted average high and low dietary concentrations of sulfallate were, respectively, 1897 and 949 ppm for male mice, and 1815 and 908 ppm for female mice. After the 78 week period of chemical administration, there was an additional observation period of 12 to 13 weeks for dosed and control mice. There were significant positive associations between increased sulfallate concentration and accelerated mortality in ... female mice. However, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Statistical analyses of the ... combined alveolar/bronchiolar carcinomas and alveolar/ bronchiolar adenomas in male mice, and adenocarcinomas of the mammary gland in female mice revealed a significant positive association between dosage and incidence. These associations were all supported by at least one significant Fisher exact comparison. The incidence of toxic tubular nephropathy observed in ... mice (both sexes)increased with the concentration of the compound administered. This nonneoplastic lesion was not observed in control animals. Under the conditions of this bioassay dietary administration of sulfallate was carcinogenic to B6C3Fl mice, inducing mammary gland tumors in females, ... and lung tumors in male mice. [R34] *A bioassay for possible carcinogenicity of sulfallate was conducted using Osborne-Mendel rats. Sulfallate was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female rats. Fifty rats of each sex were placed on test as controls for the bioassay. The time-weighted average high and low dietary concentrations of sulfallate were, respectively, 410 and 250 ppm for male rats, 404 and 250 ppm for female rats. After the 78 week period of chemical administration, there was an additional observation period of 25 to 26 weeks for dosed rats, 33 weeks for control rats. There were significant positive associations between increased sulfallate concentration and accelerated mortality in both sexes of rats. However, adequate numbers of animals in all groups survived sufficiently long to be at risk from late developing tumors. Statistical analyses of the incidences of mammary adenocarcinomas in female rats, stomach neoplasms (i.e., combination of papillomas NOS, squamous cell papillomas, and squamous-cell carcinomas) in male rats ... revealed a significant positive association between dosage and incidence. These associations were all supported by at least one significant Fisher exact comparison. The incidence of toxic tubular nephropathy observed in male rats and in mice of both sexes increased with the concentration of the compound administered. This nonneoplastic lesion was not observed in control animals. Under the conditions of this bioassay dietary administration of sulfallate was carcinogenic to Osborne-Mendel rats ... inducing ... tumors of the forestomach in male rats. [R34] METB: *2-CHLOROACROLEIN IS FORMED FROM SULFALLATE WHEN IT IS INCUBATED WITH RAT LIVER MICROSOMES. [R32] *TOLERANT CROP SPECIES COMPLETELY DEGRADE CDEC OR ITS INTERMEDIATE, DIETHYLAMINE. [R10, 97] *The proposed metabolites of diallate, triallate, and sulfallate were identified and quantitated by HPLC and GLC headspace analysis as chloroacroleins and chloroallylthiols. The quantitative relationships indicate that the thiocarbamates yield chloroacroleins on metabolic activation with the mixed function oxidase system alone, while the intermediate S-oxidation products were detoxified on diversion to chloroallylthiols when the glutathione/glutathione-S-transferase system was also present. The major mouse microsomal mixed function oxidase metabolites of three cmpd were identified by HPLC cochromatography as the corresponding sulfoxides. It was concluded that the formation of mutagenic chloroacroleins involves primarily sulfoxidation of diallate followed by sigmatropic rearrangement-1,2-elimination reactions and S-methylene hydroxylation of triallate and sulfallate and then decomposition of their alpha-hydroxy intermediates. Competing glutathione-S-transferase catalyzed conjugations with glutathione divert the sulfoxidized intermediates from activation involving chloroacrolein formation to detoxification on chloroallylthiol liberation. [R35] INTC: *N,N-DIALLYL-ALPHA,ALPHA-DICHLOROACETAMIDE REDUCED TOXICITY OF SULFALLATE TO CORN (ZEA MAYS). [R36] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Sulfallate's past production and use as a herbicide resulted in its direct release to the environment through various waste streams. If released to air, a vapor pressure of 0.0022 mm Hg at 20 deg C indicates sulfallate will exist solely as a vapor. Vapor-phase sulfallate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 4 hours. Sulfallate absorbs light greater than 290 nm in wavelength, suggesting that photolysis may be an important fate process. If released to soil, sulfallate is expected to have moderate mobility based upon an estimated Koc of 350. Volatilization from moist soil surfaces is expected to occur slowly based upon an estimated Henry's Law constant of 6.5X10-6 atm-cu m/mole. Sulfallate is not expected to volatilize from dry soil surfaces based on the vapor pressure. Sulfallate has a reported persistence of 6 weeks in soil surfaces. If released into water, sulfallate is expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 9 and 67 days, respectively. An estimated BCF of 46 suggests the potential for bioconcentration in aquatic organisms is moderate. Occupational exposure to sulfallate may occur through inhalation and dermal contact with this compound at workplaces where sulfallate is produced or used. The general population may be exposed to sulfallate via ingestion of vegatables that have had sulfallate applied to control certain annual grasses and broadleaf weeds. (SRC) NATS: *Sulfallate is not known to occur as a natural product. [R1] ARTS: *Sulfallate's past production and use as a herbicide(1) resulted in its direct release to the environment(SRC). [R37] FATE: *TERRESTRIAL FATE: RESULTANT AVG PERSISTENCE @ RECOMMENDED RATES: GENERALLY 3-6 WK, ON SANDY SOILS WITH HEAVY RAINFALL, CDEC WILL PERSIST 3-4 WK, and 5-6 WK ON LOAMS OR CLAY SOILS WITH MODERATE PRECIPITATION. [R10, 97] *Terrestrial Fate: At commercially recommended rates of 4 lb/gal, the average persistence of sulfallate in soil is 3 to 6 weeks. [R2] *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 350(SRC), determined from a water solubility of 100 mg/l at 25 deg C(2) and a regression-derived equation(3), indicates that sulfallate is expected to have moderate mobility in soil(SRC). Volatilization of sulfallate from moist soil surfaces is expected to occur slowly(SRC) given an estimated Henry's Law constant of 6.5X10-6 atm-cu m/mole(SRC), from its vapor pressure of 0.0022 mm Hg at 20 deg C(4) and water solubility(2). Sulfallate is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure. Sulfallate has a reported persistence of 6 weeks in soil surfaces(5). [R38] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 350(SRC), determined from a water solubility of 100 mg/l(2) and a regression-derived equation(3), indicates that sulfallate is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 6.5X10-6 atm-cu m/mole(SRC), from it vapor pressure of 0.0022 mm Hg at 20 deg C(4) and its water solubility(2). Volatilization half-lives for a model river and model lake are 9 and 67 days, respectively(SRC), using an estimation method(3). According to a classification scheme(5), an estimated BCF of 46(3,SRC), from its water solubility(2) suggests the potential for bioconcentration in aquatic organisms is moderate. [R39] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), sulfallate, which has a vapor pressure of 0.0022 mm Hg at 20 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase sulfallate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hours(SRC) from its estimated rate constant of 1.03X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(3). Sulfallate absorbs light greater than 290 nm(4), suggesting that photolysis may be an important fate process, although the kinetics of this potential reaction are unknown(SRC). [R40] ABIO: *The rate constant for the vapor-phase reaction of sulfallate with photochemically-produced hydroxyl radicals has been estimated as 1.03X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Sulfallate absorbs light greater than 290 nm(2), suggesting that photolysis may be an important fate process, although the kinetics of this potential reaction are unknown(SRC). [R41] BIOC: *An estimated BCF of 36 was calculated for sulfallate(SRC), using water solubility of 100 mg/l at 25 deg C(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate. [R42] KOC: *The Koc of sulfallate is estimated as approximately 350(SRC), using a water solubility of 100 mg/l at 25 deg C(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that sulfallate is expected to have moderate mobility in soil. [R43] VWS: *The Henry's Law constant for sulfallate is estimated as 6.5X10-6 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.0022 mm Hg(1), and water solubility, 100 mg/l(2). This Henry's Law constant indicates that sulfallate is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as approximately 9 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as approximately 67 days(SRC). Sulfallate is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R44] WATC: *Sulfallate was detected in surface water from the Comunitat Valenciana, Spain at a concn of 2.247 ug/ml(1). [R45] EFFL: *SULFALLATE HAS BEEN REPORTED TO BE PRESENT IN THE AIR EMISSIONS FROM SULFALLATE MANUFACTURE AT A LEVEL OF 0.5 KG/1000 KG PESTICIDE PRODUCED. [R46] FOOD: *Sulfallate was identified, not quantified, in vegatables during the 1978-1982 pesticide monitoring program by the US FDA(1) and in the 1988-1989 monitoring program(2). Sulfalate was identified, not quantified in domestic and imported tomatoes(3). [R47] RTEX: *A potential for exposure exists during the manufacture and application of the herbicide. Agricultural workers have the greatest risk of sulfallate exposure, and rural residents of agricultural communities may be exposed to airborne residues of sulfallate after spraying operations. ... The general population may be exposed through ingestion of residues in food crops. [R2] *Occupational exposure to sulfallate may occur through inhalation and dermal contact with this compound at workplaces where sulfallate is produced or used. The general population may be exposed to sulfallate via ingestion of vegatables that have had sulfallate applied to control certain annual grasses and broadleaf weeds. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Tolerances are established for residues of the herbicide 2-chloroallyl diethyldithiocarbamate in or on the following raw agricultural commodities: 0.2 ppm (negligible residues) for beans (snap); bean vines; broccoli; brussels sprouts; cabbage; cantaloupes; cauliflower; celery; chicory; collards; corn (K+CWHR, fodder, forage, and grain); cucumbers; endive (escarole); kale; lettuce; lima beans; mustard greens; okra; potatoes; radishes; soybeans (including forage and hay); spinach; tomatoes; turnip greens; turnips; upland cress; and watermelons. [R48] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Chloroallyl diethyldithiocarbamate is found on List D. Case No: 4084; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Chloroallyl diethyldithiocarbamate; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R5] *Tolerances are established for residues of the herbicide 2-chloroallyl diethyldithiocarbamate in or on the following raw agricultural commodities: beans (snap); bean vines; broccoli; brussels sprouts; cabbage; cantaloupes; cauliflower; celery; chicory; collards; corn (K+CWHR, fodder, forage, and grain); cucumbers; endive (escarole); kale; lettuce; lima beans; mustard greens; okra; potatoes; radishes; soybeans (including forage and hay); spinach; tomatoes; turnip greens; turnips; upland cress; and watermelons. [R48] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *PRODUCT ANALYSIS: MACRO: BY TOTAL CHLORINE (SODIUM-ISOBUTYL ALCOHOL). [R49] *RESIDUE ANALYSIS OF VEGADEX BY GC METHOD APPLICABLE TO BEET TURNIPS, LETTUCE, CABBAGE, BROCCOLI AND CHINESE CABBAGE, SENSITIVITY 0.01 PPM. [R50] *TECHNICAL SAMPLE DILUTED WITH METHANOL MAY BE DETERMINED WITH UV SPECTROSCOPY. [R46] *EPA Method 632. Determination of carbamate and urea pesticides in industrial and municipal wastewater using high performance liquid chromatography with ultraviolet detector. Approximately 1 l is solvent extracted with methylene chloride, dried and concentrated to a volume of 10 ml or less. Under the prescribed conditions, for sulfallate the method detection limit is not determined as defined by EPA. [R51] *EPA Method 3540. Soxhlet Extraction. A solid sample is mixed with anhydrous sodium sulfate and extracted using an appropriate solvent in a Soxhlet extractor. The sample is then dried and concentrated using a Kuderna-Danish apparatus. This is a procedure for extracting nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. [R52] *EPA Method 3550. Sonication Extraction. A 2- to 3-g solid sample is mixed with anhydrous sodium sulfate to form a free-flowing powder, then solvent extracted using a horn-type sonicator, followed by vacuum filtration or centrifugation for organic components of equal or less than 20 mg/kg. This method is applicable to the extraction of nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. Interferences include chlorofluorocarbons and methylene chloride. [R52] *EPA Method 8270B. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique [R53] *EPA Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass Spectrometry (GC/MS): Capillary Column Technique. [R54] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of Sulfallate for Possible Carcinogenicity (1978) Technical Rpt Series No. 115 DHEW Pub No. (NIH) 78-1370 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 284 (1983) R2: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 809 R3: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 527 R4: Farm Chemicals Handbook 1998. Willoughby, OH: Meister Publishing Co., 1998.,p. C-408 R5: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.337 (Spring, 1998) EPA 738-R-98-002 R6: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1522 R7: SRI R8: National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986. R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 283 (1983) R10: Weed Science Society of America. Herbicide Handbook. 4th ed. Champaign, IL: Weed Science Society of America, 1979. of America, 1979. R11: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 234 R12: Gore RC et al; J AOAC 54: 1040-84 (1971) R13: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R14: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE) R15: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 667 R16: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-313 R17: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R18: NIOSH. Pocket Guide to Chemical Hazards. 2nd Printing. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, February 1987.71 R19: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. 688 R20: Nye JC; ACS Symp Ser 259 (Treat Disposal Pestic Wastes): 153-60 (1984) R21: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. R22: 40 CFR 165 (7/1/88) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 72 (1987) R24: DHHS/NTP; Sixth Annual Report on Carcinogens (Summary) p.vii (1991) R25: ROBENS JF; VET HUM TOXICOL 22 (5): 328 (1980) R26: ROSEN JD ET AL; MUTAT RES 78 (2): 113 (1980) R27: PRINCIPE P ET AL; J SCI FOOD AGRIC 32 (8): 826 (1981) R28: MARSDEN PJ, CASIDA JE; J AGRIC FOOD CHEM 30 (4): 627 (1982) R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 289 (1983) R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 286 (1983) R31: Kearney, P.C., and D. D. Kaufman (eds.) Herbicides: Chemistry, Degredation and Mode of Action. Volumes 1 and 2. 2nd ed. New York: Marcel Dekker, Inc., 1975. 342 R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 287 (1983) R33: SIKKA HC, FLORCZYK P; J AGRIC FOOD CHEM 26 (1): 146 (1978) R34: DHEW/NCI; Bioassay of Sulfallate for Possible Carcinogenicity. P.vii (1978) Technical Rpt Series No. 115 DHEW Pub No. (NIH) 78-1370 R35: Mair P, Casida JE; J Agr Food Chem 39 (8): 1504-8 (1991) R36: CHANG FY ET AL; WEED RES 13 (4): 399 (1973) R37: (1) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p 1522 (1996) R38: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p 1522 (1996)) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-10 (1990) (4) IARC Monographs; Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC, Lyon France 30: 284 (1983) (5) Kearney PC et al; pp. 54-67 in Chemical Fallout: Current Research on Persistent Pesticides. Miller MW, Berg CG eds. Springfield,IL: Charles C Thomas (1969) R39: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p 1522 (1996) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-10, 5-4, 5-10, 15-1 to 15-29 (1990) (4) IARC Monographs; Evaluation of the Carcinogenic Risk of Chemicals to Humans.IARC, Lyon France 30: 284 (1983) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R40: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) IARC Monographs; Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC, Lyon France 30: 284 (1983) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Gore RC et al; J AOAC 54: 1040-1084 (1971) R41: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Gore RC et al; J AOAC 54: 1040-1084 (1971) R42: (1) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p 1522 (1996) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R43: (1) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p 1522 (1996) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R44: (1) IARC Monographs; Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC, Lyon France 30: 284 (1983) (2) Budvari S; Merck Index, 12th ed, Whitehouse Station,NJ: Merck and Co. p 1522 (1996) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R45: (1) Pico Y et al; Bull Environ Contam Toxicol 53: 230-37(1994) R46: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 285 (1983) R47: (1) Yess NJ et al; J Assoc Off Anal Chem 74: 265-272 (1991) (2) Minyard JP, Roberts WE; J Assoc Off Anal Chem 74: 438-452 (1991) (3) Roy RR et al; J AOAC Int 78: 930-940 (1995) R48: 40 CFR 180.247 (7/1/91) R49: Spencer, E.Y. Guide to the Chemicals Used in Crop Protection. 6th ed. Publication 1093, Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1973. 470 R50: ZWEIG G, SHERMA J; ACADEMIC PRESS NY, 704 (1972) R51: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.474 (1991) OST Pub 21W-4005 R52: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R53: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R54: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 61 Record 134 of 1119 in HSDB (through 2003/06) AN: 1541 UD: 200303 RD: Reviewed by SRP on 3/2/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CYCOCEL- SY: *AC-38555-; *AMMONIUM, (2-CHLOROETHYL)TRIMETHYL-, CHLORIDE; *ANTYWYLEGACZ-; *Arotex-Extra-; *Barleyquat-; *Bettaquat-; *CCC-; *CCC-PLANT-GROWTH-REGULANT-; *CeCeCe-; *CHLORCHOLINCHLORID- (CZECH); *Chlorcholinchloride-; *CHLORCHOLINE-CHLORIDE-; *Chlormequat-; *CHLORMEQUAT-CHLORIDE-; *CHLOROCHOLINE-CHLORIDE-; *BETA-CHLOROETHYLTRIMETHYLAMMONIUM-CHLORIDE-; *2-Chloroethyltrimethylammonium-chloride-; *2-chloro-N,N,N-trimethylethanaminium-chloride-; *Choline-dichloride-; *60-CS-16-; *Cyclocel-; *Cycocel-C-5-; *Cycocel-460-; *5C-Cycocel-; *Cycocel-extra-; *CYCOGAN-; *CYCOGAN-EXTRA-; *CYOCEL-; *EI-38,555-; *ETHANAMINIUM,-2-CHLORO-N,N,N-TRIMETHYL-,-CHLORIDE-; *Farmacel-; *Halloween-; *Helstone-; *Hico-CCC-; *Hormocel-2CCC-; *Hyquat-; *Increcel-; *Lihocin-; *Mirbel-5-; *NCI-C02960-; *RETACEL-; *STABILAN-; *Titan-; *TRIMETHYL-BETA-CHLORETHYLAMMONIUMCHLORID-; *TRIMETHYL-BETA-CHLOROETHYLAMMONIUM-CHLORIDE-; *TUR-; *WR62-; *Zar- RN: 999-81-5 MF: *C5-H13-Cl2-N MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CONDENSATION OF TRIETHYLAMINE AND ETHYLENE DICHLORIDE [R1] *PREPD FROM CHOLINE CHLORIDE AND BENZENESULFONYL CHLORIDE; FROM CHOLINE CHLORIDE AND THIONYL CHLORIDE. [R2] FORM: *10%, 40% WT/VOL AQ SOLN; 50% WT/VOL AQ SOLN; 11.8% WT/VOL AQ SOLN. [R3] *... Powder liquids [R4, p. C-77 3] *Combinations: Terpal C (with ethephon) [R4, p. C-77] *(Chlormequat chloride +) ... di-1-p-menthene. [R5] *'Titan', soluble concentrate (chlormequat chloride); dustable powder (650 g/kg).Mixtures include: 'Arotex Extra', '5C Cycocel', 'Cycocel 460', 'Cycocel C 5', 'Mirbel 5', 'WR62', soluble concentrate (chlormequat chloride + choline chloride); 'Halloween', 'Helstone', (chlormequat chloride + 9-(10-nor-p-menth-1-en-8-yl)-p-menth-1-ene); 'Mastiff' (chlormequat chloride + carbendazim). [R6, 159] MFS: *American Cyanamid Co, One Cyanamid Plaza, Wayne, NJ 07470, (201) 831-2000 [R4, p. C-77] *BASF Aktiengesellschaft Crop Protection, Postfach 220, Carl-Bosch-Str 64, 6703 Limburger Germany, 49-6236-680 [R4, p. F 81] OMIN: *CYCOCEL IS A PLANT GROWTH REGULANT PREVENTING LODGING OF CEREALS IN CEREAL CROPS ... TREATED PLANTS ARE GENERALLY COMPACT AND STURDY AND HAVE TYPICALLY SHORTENED INTERNODES, DARK GREEN LEAVES AND SHORTENED PETIOLES. PLANTS USUALLY REMAIN DWARFED UNDER OPTIMAL WATERING AND FERTILIZATION. [R3] *Mixtures with other growth regulator herbicides and with urea are possible, but should be applied immediately after mixing. [R7] *... Effective in ... crops such as vegetables (tomatoes, capsicum, cabbage, cauliflower, radishes, cucurbits, peas), grape vines, mango, tobacco, etc. [R8] USE: *Plant growth regulator. [R9] *... Effective for cereal grains. [R10] *Used to increase resistance to lodging ... and to increase yields in wheat, rye, oats, and triticale; to promote lateral branching and flowering in azaleas, fuchsias, begonias, poinsettias, geraniums, pelargoniums, and other ornamental plants; to promote flower formation and improve fruit setting in pears, almonds, vines, olives, and tomatoes; to prevent premature fruit drop in pears, apricots, and plums. Also used on cotton, vegetables, tobacco, sugar cane, mangoes, and other crops. [R5] */For/ wheat, rye, and oats in Europe. For green house use as plant growth regulator on ... geraniums, and hibiscus in US. Lihocin for cotton, various vegetables, grape vines, mango, tobacco and ornamentals. [R4, p. C-77] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 2.27X10+6 G [R1] *(1978) PROBABLY GREATER THAN 2.27X10+6 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE CRYSTALLINE SOLID [R3]; *Colorless [R5] ODOR: *TYPICAL AMINE ODOR [R3]; *Fish-like odor [R9] MP: *245 deg C (decomposes) [R9] MW: *158.07 [R9] CORR: *Corrosive to unprotected metals [R5] OWPC: *log Kow= 3.8 (measured) [R11] SOL: *SOL IN LOWER ALC SUCH AS METHANOL; INSOL IN ETHER AND HYDROCARBONS; WATER SOLUBILITY 74% @ 20 DEG C [R3]; *At 20 deg C in ... ethanol 32 g ai/100 g solvent [R4, p. C-77]; *Acetone 0.3 g/kg at 20 deg C [R5]; *At 20 deg C: > 1 kg/kg water; < 1 g/kg chloroform; insoluble in cyclohexane [R6, 158]; *Water solubility = 996,000 mg/l at 20-25 deg C [R11] SPEC: *MASS: 4202 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R12] VAP: *Vapor pressure= 7.5X10-8 mm Hg at 20 deg C (measured). [R13] OCPP: *VERY HYGROSCOPIC [R9] *Solid, yellowish crystals /Technical chlormequat-chloride/ [R4, p. C-76] *Begins to decompose at 245 deg C [R6, 158] *The technical grade is 97-98% pure. [R6, 158] *Less than 0.01 mPa at 20 deg C [R5] *Henry's Law constant= 1.6X10-14 atm-cu m/mole at 20-25 deg C (est). [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Should not be combined with dinoseb, cyanazine, or other contact herbicides. [R5] EQUP: *Wear protective clothing and impermeable gloves. [R4, p. C-77] OPRM: *Avoid inhalation of spray /and/ prolonged or repeated contact with skin. Clothing should be removed and washed thoroughly after handling chemical. [R4, p. C-77] SSL: *Stable up to 50 deg C for at least 2 years. [R7] *AQ SOLN ARE CHEMICALLY STABLE AND RETAIN BIOLOGICAL EFFECTIVENESS. [R3] STRG: *It may be stored in containers of glass or high density plastics, or of metal lined with rubber or epoxyresin. [R6, 158] DISP: *This crystalline, water-soluble solid melts at 245 deg C with decomp. Incineration is a highly effective disposal method. Heating the product with strong aqueous alkali would result in decomp with the evolution of trimethylamine and other gaseous products. Recommendable method: Incineration. Peer-review: Incinerate in a unit with effluent gas scrubbing. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R15] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *Discussion of a case of acute contact dermatitis caused by occupational exposure to the growth inhibitor cycocel. [R16] *A case was provided of accidental ingestion of Cycocel which manifested as a cholinergic crisis that led to sudden death. The patient was a 59 yr old male nursery worker who accidentally drank a mouthful of plant growth chemical Cycocel, containing the active ingredient (2-chloroethyl)trimethylammonium chloride (chlormequat). Initially he was seen by his family physician and indicated he had not swallowed any of the liquid. He later realized that he must have swallowed some of the liquid. An electrocardiogram revealed-T wave inversion and flat AVF. Following transfer to the hospital, the patient suffered a seizure, demonstrated bradycardia, experienced severe dysrhythmia followed by ventricular fibrillation which eventually resulted in asystole. Autopsy results indicated marked pulmonary edema, coronary atherosclerosis, atheromata of aorta, and localized adenocarcinoma of the prostate. Chlormequat was detected in the stomach contents and urine. The Cycocel the patient ingested apparently was kept in a refrigerator at the nursery along with bottled drinking water. The appearance of these solutions is similar; however, the cycocel has a fishy smell. [R17] NTOX: *RATS OF EACH SEX WERE ADMIN EITHER 1500 OR 3000 PPM IN FEED FOR 108 WK, AND MICE WERE ADMIN 500 OR 2000 PPM IN FEED FOR 102 WK. NO TUMORS OCCURRED IN RATS OR MICE OF EITHER SEX. [R18] */In mallards/ signs of intoxication: Ataxia, miosis, falling, sitting, using wings for pedestrian locomotion, tremors, tetanic seizures, immobility, opisthotonos, and frequent spasms. Signs appeared as soon as 5 min and mortalities usually occurred between 15 and 40 min after /oral/ treatment. Remission took up to 3 days. [R19] *Non-toxic to fish. Not toxic to bees. [R5] *Researchers investigated the effects of CCC on the ability of deer mice (Peromyscus maniculatus) to resist challenge with a sublethal dose of Venezuelan equine encephalitis virus. CCC was continuously delivered in low doses in the feed at 1, 10, 20 or 40 mg/kg body wt/day. CCC had no effect on viremia duration or titer except when given in doses of 1 mg/kg body wt/day when it significantly (P less than or equal to 0.05) decr mean viremia titers compared to controls. Early antibody responses were incr by CCC treatment except in the 10 mg/kg body wt/day treatment group in which titers were decreased. By 30 days post inoculation antibody titers of CCC-treated mice were no different from controls. [R20] *Acutely toxic doses of CCC cause lacrimation, salivation, and intestinal motility, and although these signs of toxicity of CCC in mammals resemble those of anticholinesterase agents, the chemical does not inhibit cholinesterase. These effects are produced by stimulation at muscarinic receptors and are partially antagonized by low doses of atropine, a cholinergic blocking agent which specifically blocks muscarinic receptors. Lethal doses cause respiratory failure that is due to neuromuscular blockage and that is unaffected by atropine treatment. [R21] *500 mg/kg of (2-Chloroethyl)trimethylammonium chloride given orally killed 21/40 male mice. [R22] *... Plant growth regulator which influences the habit of certain plants by shortening and strengthening the stem ... . It can also influence the developmental cycle resulting in increased flowering and harvest. [R6, 158] *Cycocel was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay. This reference reports on the testing of 270 chemicals, including cycocel, using the standard protocol approved by the National Toxicology Program (NTP). The tests were performed by one or more of 3 different laboratories under contract to NTP. This test procedure includes testing of the chemical using a wide range of doses in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9. Cycocel was tested at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any S.typhimurium strain was 10.000 mg/plate. [R23] NTXV: *LD50 Rat oral 330-750 mg/kg; [R22] *LD50 Mouse oral 215-1020 mg/kg; [R22] *LD50 Rat percutaneous > 4000 mg/kg; [R5] *LD50 Rabbit male percutaneous 440 mg/kg; [R5] *LC50 Rat inhalation > 5.2 mg/l/4 hr; [R5] ETXV: *LD50 Anas platyrhynchos (Mallard) male oral 265 mg/kg (95% confidence limit 211-334 mg/kg) 3 mo old /sample purity 98%/; [R19] *LC50 Trout about 4500 mg/l/96 hr /400 g/l formulated product/ /Conditions of bioassay not specified/; [R5] *LD50 Quail oral 555 mg/kg; [R5] *LD50 Pheasant oral 261 mg/kg; [R5] NTP: *A bioassay of (2-chloroethyl)trimethylammonium chloride for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats. Groups of 50 rats of each sex were administered either 1500 or 3000 ppm of the compound for 108 weeks. Matched controls consisted of 20 untreated rats. Mean body weights of dosed rats were lower than those of corresponding controls for part or all of the bioassay. Survival was not affected significantly in any of the dosed groups of rats, and was at least 64% in dosed or control groups at the end of the bioassay. Sufficient numbers of dosed and control rats of each sex were at risk for the development of late-appearing tumors. No tumors occurred in the rats of either sex at incidences that could be associated with administration of the test chemical. It is concluded that under the conditions of this bioassay, (2-chloroethyl)trimethylammonium chloride was not carcinogenic for F344 rats of either sex. [R24] *A bioassay of (2-chloroethyl)trimethylammonium chloride for possible carcinogenicity was conducted by administering the test chemical in feed to B6C3Fl mice. Groups of 50 mice of each sex were administered 500 or 2000 ppm for 102 weeks. Matched controls consisted of and 20 untreated mice of each sex. Mean body weights of dosed female mice were lower than those of corresponding controls for part or all of the bioassay. For the dosed male mice mean body weights were essentially the same as those of the corresponding controls. Survival was not affected significantly in any of the dosed groups of mice and was at least 64% in every dosed or control group at the end of the bioassay. Sufficient numbers of dosed and control mice of each sex were at risk for the development of late appearing tumors. Since there was virtually no decrease in mean body weight in dosed male mice and only a slight decrease in female mice, and since there were no other toxic signs and no dose related mortality, the animals may have been able to tolerate higher doses. No tumors occurred in the mice of either sex at incidences that could be associated with administration of the test chemical. It is concluded that under the conditions of this bioassay, (2-chloroethyl)trimethylammonium chloride was not carcinogenic for B6C3Fl mice of either sex. [R25] ADE: *In mammals, following oral administration, 97% is eliminated within 24 hr, principally as the unchanged substance. [R5] METB: *When (14)C-labeled CCC was applied to kohlrabi, cauliflower, or tomatoes, degradation of CCC was very small. The first product was probably choline which entered the plant pool. Small amounts of labeled methyl groups from choline were found as S-methyl methionine. CCC was not degraded when applied to sugarcane. Inalfalfa, CCC was slowly metabolized and was primarily incorporated into choline of phosphatidylcholine. [R26] *Almond seedlings were treated with labeled CCC. Translocation to leaves and to the roots was observed. (14)CO2 was formed within 2 h after application. Radioactivity was observed in 17 known amino acids, an unidentified ninhydrin positive compound, malic acid, citric acid, choline and 2-chloroethylamine. [R26] *When CCC was incubated in rumen contents or juice under anaerobic conditions, microbial degradation of CCC did not occur. [R26] *(14)CH3 CCC was metabolized to choline in barley, wheat, tobacco and maize. Choline isolated from these plants containea 10-20% of the applied radioactivity. A small part of the radioactivity was also found in the betaine fraction. In Nicotiana rustica, methyl groups of (14)CH3 CCC were incorporated into the alkaloid nicotine; in Hordeum vulgare, into the alkaloid gramine. Radioactivity from l,2-(14)C CCC was also found in the choline moiety of phosphatidyl choline in winter barley (Hordeum vulgare variety Dover). [R27] *When applied to coastal bermudagrass, l,2-(14)C CCC was metabolized; and, within24 to 48 hr after application, about 25% of the label was found distributed among choline, betaine hydrochloride, serine, ethanolamine, glucose and CO2. [R27] *Wheat seedlings were root-treated with 1,2-(14)C chlormequat. Translocation was rapid and choline was formed. The latter was metabolized via betaine, which was demethylated, to glycine and serine. These were then incorporated into the plant protein fractions. Some (14)CO2 was also formed. [R27] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Cycocel is released to the environment during its use as a plant growth regulator. If released to the atmosphere, cycocel will exist in the vapor and particulate phases. Vapor phase cycocel will degrade slowly by reaction with photochemically produced hydroxyl radicals (half-life of about 12 days). Particulate phase cycocel will be physically removed from air by dry deposition. In soil and water, adsorption and biodegradation will be the primary removal processes. Cycocel is a quaternary ammonium compound which exists as a cation in water and moist soils; it is expected to strongly adsorb to various materials, including suspended solids in wastewater treatment facilities, sediments in rivers and lakes, suspended organics and minerals in natural water systems, clays, proteins, and microorganisms. Acclimation enhances biodegradation of quaternary ammonium compounds like the cycocel cation and the reduction of biomass or other nutrient materials in natural water may reduce the biodegradation rate of the cycocel cation. However, no specific adsorption data were located for the cycocel cation and limited biodegradation data are available. Occupational exposure to cycocel occurs through dermal contact and inhalation of dust and sprays. (SRC) ARTS: *During its use as a plant growth regulator(1), cycocel is released to the environment. [R28] FATE: *TERRESTRIAL FATE: Based on analogy to other quaternary ammonium compounds(1), cycocel will exist as a cation in moist soils and the primary fate processes will be biodegradation and adsorption. Cycocel is rapidly degraded in soil by enzyme activity(2). Although no experimental Koc value was located for cycocel chloride, some quaternary ammonium compounds have experimental Koc values of 10,000-200,000(3). Strong adsorption is expected in clays and soils with high organic or mineral content(1,SRC). [R29] *AQUATIC FATE: Based on analogy to other quaternary ammonium compounds(1), cycocel will exist as a cation in water and the primary fate processes will be biodegradation and adsorption. The cycocel cation is expected to rapidly and strongly adsorb to sediments and suspended matter, clay minerals, and other materials with negative surface charges(1,SRC). Adsorption to sediments does not appear to reduce biodegradability of some quaternary ammonium compounds; adsorption to certain clay minerals may retard biodegradation(1). Acclimation enhances biodegradation of quaternary ammonium compounds like the cycocel cation(1). Furthermore, based on analogy to other quaternary ammonium compounds(1), the reduction of biomass or other nutrient materials in natural water may reduce the biodegradation rate of the cycocel cation. Although, no biodegradation rate data were located for the cycocel cation in water; cycocel does appear to rapidly biodegrade in soil(2) which would suggest rapid biodegradation in water. Bioconcentration in aquatic organisms and volatilization are not expected to be important removal processes from water(SRC). [R30] *ATMOSPHERIC FATE: Based upon a measured vapor pressure of 7.5X10-8 mm Hg at 20 deg C(1), cycocel can exist in both the vapor and particulate phases in the ambient atmosphere(2,SRC). It will degrade slowly in the vapor phase by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 12 days(3,SRC). Particulate phase cycocel released to air during spray applications will be physically removed from air by dry deposition(SRC). [R31] BIOD: *Chlormequat chloride is rapidly degraded in soil by enzyme activity and there is no influence on soil microflora or fauna. [R6, 158] *Studies with soil microorganisms indicated that CCC breakdown occurred through oxidative processes. [R26] *Cycocel is rapidly degraded in soil by enzyme activity(2). Cycocel chloride, initial concn of 282 ppm, biodegraded 18 percent after running a compost operation consisting of poultry and pig manure for 56 days; the high concentration may have retarded degradation(1). Based on analogy to other quaternary ammonium compounds(3), the reduction of biomass or other nutrient materials in natural water may reduce the biodegradation rate of the cycocel cation and acclimation enhances biodegradation of quaternary ammonium compounds. [R32] ABIO: *The rate constant for the vapor phase reaction of cycocel with photochemically produced hydroxyl radicals has been estimated to be 1.32X10-12 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 12 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R33] BIOC: *Based upon a measured log Kow of -3.8(1) and a water solubility of 996,000 mg/l at 20-25 deg C(1), the BCF of cycocel can be estimated to be 7.6X10-4 and 0.26, respectively, from regression-derived equations(2,SRC). These BCF values would suggest that cycocel will not bioconcentrate in aquatic organisms(SRC). [R34] KOC: *Based upon a measured Log Kow of -3.8(1) and a water solubility of 996,000 mg/l at 20-25 deg C(1), the Koc of cycocel can be estimated to be 0.2 and 2.2, respectively, from regression-derived equations(2,SRC). According to a suggested classification scheme(3), these estimated Koc values suggest that cycocel is very highly mobile in soil(SRC). However, cycocel is a quaternary ammonium compound and, therefore, would be expected to adsorb more strongly than its estimated Kocs indicate(SRC). [R35] *Cycocel is a quaternary ammonium compound which exists as a cation in water and is expected to strongly adsorb to various materials, including suspended solids in wastewater treatment facilities, sediments in rivers and lakes, suspended organics and minerals in natural water systems, clays, proteins, and microorganisms(1-3). Although no experimental Koc value was located for cycocel chloride, some quaternary ammonium compounds have experimental Koc values of 10,000- 200,000(3). Furthermore, adsorption of quaternary ammonium compounds to river sediment occurs primarily by an ion-exchange mechanism(2). Monitoring studies of river water samples from Germany reported that 50% of an alkyltrimethyl quaternary ammonium compound detectable in the water column was associated with suspended solids in the water; the suspended solids in the water comprise a small fraction of the water(4). [R36] VWS: *Based on the measured vapor pressure of 7.5X10-8 mm Hg at 20 deg C(2) and a measured water solubility of 996,000 mg/l at 20-25 deg C(1), the Henry's Law constant for cycocel can be estimated to be 1.6X10-14 atm-cu m/mole at 20-25 deg C(SRC). According to a suggested classification scheme(3), this Henry's Law constant indicates that cycocel is less volatile than water. In addition, cycocel exists in the water column in the ionic state and this prevents its removal by evaporation(SRC). [R37] RTEX: *During cycocel chloride's use as a growth regulator(1), workers may be exposed to cycocel through dermal contact and inhalation of dust and sprays, especially during application(SRC). [R28] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 106 workers are potentially exposed to cycocel in the USA(1). [R38] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Chlormequat chloride is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100/10,000 lbs. [R39] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Chloroethyl trimethyl ammonium chloride is found on List C. Case No: 3003; Pesticide type: Fungicide, Herbicide, Antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Chloroethyl trimethyl ammonium chloride; Data Call-in (DCI) Date(s): 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R40] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *CYCOCEL WAS DETERMINED IN PLANTS BY COLORIMETRIC AND SPECTROPHOTOMETRIC PROCEDURES. [R41] *Product analysis is by potentiometric titration with silver nitrate (chlormequat chloride and choline chloride can thus be determined separately) or by colorimetry. Residues may be determined by GLC after reaction with sodium phenylsulphide or by colorimetry. [R6, 158] *Quantitative TLC determination of the plant-growth regulator chlorocholine chloride in grain and grain products. [R42] *A simple and sensitive method to detn chlormequat (chlorocholine chloride) residues in plant tissue has been devised. The technique is based on an in vitro multi-step reaction where chlormequat is initially N-demethylated with potassium pentafluorothiophenolate followed by a further reaction with excess reagent to produce a pentafluorothiophenyl deriv. ECD and MS were used for quant detn and identification. The method was applied to the analysis of cotton seed harvested from cotton plants treated with various concn of chlormequat. [R43] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of (2-Chloroethyl)trimethylammonium chloride for Possible Carcinogenicity (1979) Technical Rpt Series No. 158 DHEW Pub No. (NIH) 79-1714 SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 272 R3: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 110 R4: Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993. R5: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A082/Aug 87 R6: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. R7: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. Old Woking, Surrey, United Kingdom: Royal Society of Chemistry/Unwin Brothers Ltd., 1983.,p. A082/Oct 83 R8: Farm Chemicals Handbook 1984. Willoughby, Ohio: Meister Publishing Co., 1984.,p. C-52 R9: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 325 R10: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 342 R11: Baker EA et al; Pestic Sci 34: 167-82 (1992) R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 421 R13: Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk, England: Lavenham Press Ltd p. 158 (1987) R14: SRC; Baker EA et al; Pestic Sci 34: 167-82 (1992) R15: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 84 R16: Fischer T; Contact Dermatitis 10 (5): 316-7 (1984) R17: Winek CL et al; J Anal Toxicol 14 (4): 257-8 (1990) R18: CARCINOG TEST PROGRAM, BETHESDA; BIOASSAY OF (2-CHLOROETHYL) TRIMETHYLAMMONIUM CHLORIDE (CCC) FOR POSSIBLE CARCINOGENICITY; REPORT: 103 PAGES (1979) DHEW/PUB/NIH-79-1714, NCI-CG-TR-158; ORDER NO PB-293627 R19: U.S. Department of the Interior, Fish and Wildlife Service. Handbook of Toxicity of Pesticides to Wildlife. Resource Publication 153. Washington, DC: U.S. Government Printing Office, 1984. 22 R20: Fairbrother A et al; Toxicology 31 (1): 67-71 (1984) R21: DHEW/NCI; Bioassay of (2-Chloroethyl) Trimethylammonium chloride (CCC) for Possible Carcinogenicity p.2 (1979) Technical Rpt Series No. 158 DHEW Pub No. (NIH)79-1714 R22: DHEW/NCI; Bioassay of (2-Chloroethyl)trimethylammonium chloride for Possible Carcinogenicity p. 1 (1979) Technical Rpt Series No. 158 NIH Pub No. 79-1714 R23: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R24: DHEW/NCI; Bioassay of (2-Chloroethyl) Timethylammonium Chloride (CCC) for Possible Carcinogenicity p.v (1979) Technical Rpt Series No. 158 DHEW Pub No. (NIH)79-1714 R25: DHEW/NCI; Bioassay of (2-Chloroethyl) Trimethylammonium chloride (CCC) for Possible Carcinogenicity p.v (1979) Technical Rpt Series No. 158 DHEW Pub No. (NIH)79-1714 R26: Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 115 R27: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.75 R28: (1) Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk, England: Lavenham Press Ltd p. 158 (1987) R29: (1) Boethling RS; Water Res 18: 1061-76 (1984) (2) Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk,England: Lavenham Press Ltd p. 158 (1987) (3) Larson RJ; Res Rev 85: 159-71 (1983) R30: (1) Boethling RS; Water Res 18: 1061-76 (1984) (2) Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk,England: Lavenham Press Ltd p. 158 (1987) R31: (1) Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk, England: Lavenham Press Ltd p. 158 (1987) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R32: (1) Vogtmann H et al; Proc 2nd, Internl Symp Bet Degan, Israel pp. 357-78 (1983) (2) Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk, England: Lavenham Press Ltd p. 158 (1987) (3) Boethling RS; Water Res 18: 1061-76 (1984) R33: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R34: (1) Baker EA et al; Pestic Sci 34: 167-82 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4,5-5 (1990) R35: (1) Baker EA et al; Pestic Sci 34: 167-82 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc p. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R36: (1) Boethling RS; Water Res 18: 1061-76 (1984) (2) Hand C et al; Environ Toxicol Chem 9: 467-71 (1990) (3) Larson RJ; Res Rev 85: 159-71 (1983) (4) Matthijs E, Dehenau H; Vom Wasser 69: 73-83 (1987) R37: (1) Baker EA et al; Pestic Sci 34: 167-82 (1992) (2) Worthing CR, Walker SB; The Pesticide Manual 8th ed; Lavenham Suffolk,England: Lavenham Press Ltd p. 158 (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc Chpt 15 (1990) R38: (1) NIOSH National Occupational Hazard Survey (NOHS) (1974) R39: 40 CFR 355 (7/1/97) R40: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.223 (Spring, 1998) EPA 738-R-98-002 R41: PASARELA NR, ORLOSKI EJ; J SHERMA AND G ZWEIG, EDS, ACADEMIC PRESS, NY, 523-44 (1973) R42: Brueggemann J, Ocker HD; Chem Mikrobiol Technol Lebensm 10 (3-4): 113-9 (1986) R43: Allender WJ; Pestic Sci 35 (3): 265-9 (1992) RS: 31 Record 135 of 1119 in HSDB (through 2003/06) AN: 1613 UD: 200211 RD: Reviewed by SRP on 9/23/1999 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged also to retrieve the record named CADMIUM COMPOUNDS, which has additional information relevant to the toxicity and environmental fate of cadmium ions and cadmium compounds. For information on the metal itself, refer to the CADMIUM, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CADMIUM-OXIDE- SY: *Aska-Rid-; *CADMIUM-FUME-; *CADMIUM-MONOXIDE-; *Caswell-No-136AA-; *KADMU-TLENEK- (POLISH) RN: 1306-19-0 RELT: 282 [CADMIUM, ELEMENTAL]; 6922 [CADMIUM COMPOUNDS] MF: *Cd-O HAZN: D006; A waste containing cadmium (such as cadmium oxide) may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *In commercial process pure Cd metal is melted and then vaporized whereupon air is blown through the hot vapor, oxidizing the cadmium and carrying the product to a baghouse. Oxide is calcined at 550 deg C to ensure uniform properties. [R1] IMP: *Cadmium oxide, powder reagent grade has the following impurities: chloride: 0.002%; nitrate (NO3); 0.01%; sulfate (SO4); 0.20%; copper: 0.005%; iron: 0.002%; lead: 0.01%. [R2] FORM: *Reagent grade: 99.0% assay [R2] *Commercial grade cadmium oxide typically contains 99.7% active ingredient. ... [R3] MFS: *Big River Zinc Corporation, Route 3 and Monsanto Avenue, Sauget, IL 62201 (618) 274-5000; Production site: Sauget, IL 62201 [R4] USE: *High purity cadmium oxide is used as a second polarizer (in addition to silver oxide) in silver-zinc storage batteries. [R1] *Cadmium oxide is used in nitrile rubbers and plastics such as Teflon to improve their high-temperature properties and heat resistence. [R1] *In phosphors, semiconductors; manuf of silver alloys, glass; in storage battery electrodes; as nematocide; as catalyst for organic reactions, in cadmium electroplating; in ceramic glazes. [R5, 266] *Has been used as an ascaricide in swine. [R5, 266] *Starting material for PVC heat stabilizers and other Cd compounds and as the cadmium source in cyanide electroplating baths. [R1] CPAT: *2.04X10+9 GRAMS USED FOR ELECTROPLATING (1971) [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Dark-brown, infusible powder or cubic crystals. [R5, 266]; *... Yellow-brown, finely divided particulate dispersed in air. /fume/ [R7, 44] ODOR: *Odorless [R8] BP: *1559 deg C (sublimes) [R9, p. 4-47] MW: *128.41 [R5, 226] DEN: *8.15 g/cu cm [R5, 226] SOL: *Practically insol in water. [R5, 226]; *Sol in dil acids; slowly sol in ammonium salts. [R5, 226]; *Insoluble in water and alkalies [R1] SPEC: *INDEX OF REFRACTION: 2.49 (LITHIUM) [R10] VAP: *1 Pa @ 770 deg C [R9, p. 6-62] OCPP: *Cadmium oxide decomposes at 950 deg C. [R11] *Cadmium oxide is an n-type semiconductor with an energy gap of 222 kJ/mol (53 kcal/mol). [R1] *Vapor pressure: 10 mm Hg at 1149 deg C; 40 mm Hg at 1257 deg C; 100 mm Hg at 1341 deg C; 400 mm Hg at 1484 deg C. [R12] *Forms a variety of complexes, the most important of which is with cyanide ions. [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of cadmium oxide stem from its toxicologic properties. Toxic primarily by ingestion and inhalation, exposure to this odorless, brown crystalline substance may occur from the smelting and refining of ore, and from the smelting and refining of zinc, lead, and copper ores, spraying cadmium-containing pigments, and from its use in electroplating, as a chemical intermediate or catalyst and in ceramic glazes, silver-zinc storage batteries, and plastics. Effects from exposure may include headache, shortness of breath, chest pain, fever, kidney damage, emphysema, chronic bronchitis, and pulmonary edema (possibly resulting in death). NIOSH has recommended that cadmium (dust and fumes) be treated as a potential human carcinogen. The OSHA PEL for cadmium fume is 0.1 mg Cd/cu m, and for cadmium dust is 0.2 mg Cd/cu m. Processes and operations which may release cadmium fumes or dust should be enclosed and fitted with exhaust ventilation to maintain exposure at or below recommended levels. In activities where over-exposure is possible workers should wear a high efficiency particulate filter respirator or self-contained breathing apparatus. Protective clothing also should be worn. Preferably this should include disposable one-piece suits (close-fitting at the ankles and wrists, gloves, hair covering, and overshoes.These should be removed before leaving work. If contact should occur, immediately wash contaminated skin with large amounts of water. Do not eat, smoke, or drink in work areas. Cadmium oxide presents only a moderate fire hazard(when in the form of dust) if exposed to heat, flame, or by chemical reaction with oxidizing agents, metals, hydrogen azide, zinc, selenium, or tellurium. Wear a self-contained breathing apparatus when fighting such fires. Cadmium oxide should be stored in cool, well-ventilated areas, out of direct rays of the sun, and away from fire hazards. If hazardous concentrations of cadmium oxide are accidentally released, remove all ignition sources, ventilate the area, and collect the released material in closed containers for disposal. Before implementing land disposal of waste cadmium oxide, consult environmental regulatory agencies for guidance. FPOT: *Noncombustible [R13, 96] FLMT: *Not flammable [R8] REAC: *OXIDES OF ... CADMIUM ... CAN REACT EXPLOSIVELY WITH MAGNESIUM WHEN HEATED. [R14] *Mixtures with magnesium explode when heated. [R15, 620] DCMP: *When heated to decomposition it emits toxic fumes of /cadmium/. [R15, 620] EQUP: *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Cadmium fume (as Cd)/ [R7, 45] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Cadmium fume (as Cd)/ [R7, 45] OPRM: *Provide adequate ventilation [R13, 97] */If cadmium oxide is involved in a spill on water/: Notify local health and wildlife officials and operators of nearby water intakes. [R8] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *An eye wash fountain should be provided within the immediate work area where cadmium chloride is being used. /Cadmium oxide dust/ [R16, 1981.4] *The worker should wash daily at the end of each work shift. [R7, 45] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R7, 45] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *The worker should wash daily at the end of each work shift. /Cadmium fume (as Cd)/ [R7, 45] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Cadmium fume (as Cd)/ [R7, 45] STRG: *Storage temperature: Ambient with open venting [R8] CLUP: *1) REMOVE ALL IGNITION SOURCES. 2) VENTILATE AREA OF RELEASE. 3) COLLECT RELEASED MATERIAL IN THE MOST CONVENIENT AND SAFE MANNER FOR RECLAMATION OR FOR DISPOSAL. ... /CADMIUM DUST/ [R16, 1981.1] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D006, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R17] *CADMIUM DUST MAY BE DISPOSED OF IN SEALED CONTAINERS IN SECURED SANITARY /SRP: HAZARDOUS WASTE/ LANDFILL. [R16, 1981.] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is sufficient evidence in humans for the carcinogenicity of cadmium and cadmium compounds. There is sufficient evidence in experimental animals for the carcinogenicity of cadmium compounds. There is limited evidence in experimental animals for the carcinogenicity of cadmium metal. In making the overall evaluation, the Working Group took into consideration the evidence that ionic cadmium causes genotoxic effects in a variety of types of eukaryotic cells, including human cells. Overall evaluation: Cadmium and cadmium compounds are carcinogenic to humans (Group 1). /Cadmium and cadmium compounds/ [R18] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Cadmium and related compounds/ [R19, p. 344-5] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe pulmonary edema. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Cadmium and related compounds/ [R19, 345] HTOX: */AMONG WORKERS EXPOSED TO CADMIUM FUME/ ATROPHIC RHINITIS WITH EPISTAXIS, RHINORRHEA AND GLYCOSURIA WERE ... REPORTED. [R20] *SYSTEMIC CHANGES INCLUDE DAMAGE TO KIDNEYS WITH PROTEINURIA, ANEMIA AND ELEVATED SEDIMENTATION RATE. LUNG DAMAGE OCCURS IN FORM OF EMPHYSEMA ... FOLLOWING EXPOSURE TO CADMIUM OXIDE FUMES. [R21, 233] *IN ... ADVANCED STAGE /FANCONI SYNDROME/ ... ADDITIONAL FINDINGS MAY BE INCREASED URINARY EXCRETION OF AMINO ACIDS, GLUCOSE, CALCIUM AND PHOSPHATES, GLOMERULAR FUNCTION IS OFTEN NORMAL OR SLIGHTLY IMPAIRED. CHANGES MENTIONED MAY LEAD TO FORMATION OF RENAL CALCULI. [R21, 234] *... EVIDENCE OF GONADAL EFFECTS FROM CADMIUM; MICROSCOPIC CHANGES CONSISTING OF DEPRESSION AND MATURATION OF SPERMATOCYTES, ASSOC WITH HIGH LEVELS OF CADMIUM WERE FOUND IN TESTES OF MEN EXPOSED TO CADMIUM FUME. [R22, 1569] *IN 6/9 WORKERS EXPOSED TO CADMIUM SULFIDE DUST 28 TO 45 YR AND TO CADIMUM OXIDE FUME AND DUST FOR SHORTER PERIODS, TUBULAR PROTEINURIA WAS FOUND. ALL HAD HYPERCALCIURIA; 2 BECAME RECURRENT STONE FORMERS, AND SOME SHOWED PROGRESSIVE DETERIORATION OF GLOMERULAR FUNCTION. [R23] *Twelve-sixteen hours after inhalation of /cadmium oxide/ fumes, /symptoms may include the following/: headache, vertigo, gastrointestinal lesions, severe pleurodynia, cough with hemoptysis, dyspnea, high temperature, severe perspiration, collapse, pneumonia. Chronic symptoms by inhalation include the following: rhinopharyngitis, malaise, ... mucosal ulceration, mucous membrane atrophy, ... insomnia, depressed appetite, nausea, and loss of weight. ... In 15-30 hours /after ingestion/, symptoms may include the following: increased salivation, nausea and vomiting, abdominal pains, diarrhea, vertigo, or unconsciousness. [R13, 97] *Women in the USSR occupationally exposed to cadmium oxide ... had normal courses of pregnancy and deliveries, but their children had lower birth weights when compared with unexposed controls. [R24] *An examination of 100 workers exposed to cadmium oxide fumes and 104 controls with similar age distribution in two British copper-cadmium alloy factories, found that 19 of the 100 exposed workers had emphysema, proteinuria, or both, while 3 of the control group had either emphysema or proteinuria. All 19 men with signs and symptoms had been exposed to cadmium for more than 5 years and 13 of them more than 15 years. Four additional workers required hospitalization because of shortness of breath. Significant differences in results from certain respiratory function tests were observed between the exposed and control groups in these same factories, particularly in the time constant of the expiratory forced vital capacity curve. ... The same two factories were re-examined four years later in 1957 and 83 of the original 100 men were still working. An additional 24 workers with emphysema or proteinuria, or both, were found, making a total of 43 (43%). [R25] *Workers, who had been exposed to cadmium oxide fumes, engaged in welding work with cadmium containing silver solder in an automobile parts manufacturing factory, were examined in 1975. Twenty-two male welders aged 22 to 55 years old were exposed to cadmium for periods ranging from 7 mo to 23 yr. The urinary cadmium levels varied from 5.7 ug to 184.9 ug per day, and these values were useful indices of most recent exposures in the workshop environment. The examinees were divided into three groups according to excreted urinary cadmium levels: five of them in high, eleven in middle, and six in low group, respectively. Workers in the high excretion group complained of considerable subjective symptoms and their urinary protein showed a remarkable increase, compared to middle- and low excretion groups, and the electrophoretic pattern of urinary proteins showed preponderance of globulins. Urinary calcium and beta(2)-microglobulin in the high-excretion group showed a remarkable increase. In all examinees, urinary phosphate, calcium, and beta(2)-microglobulin were significantly correlated with urinary excreted cadmium. Furthermore, the high excretion group showed a considerable increase of serum creatinine values and reduction of creatinine clearance, and percent tubular reabsorption of phosphate, calcium and beta (2)-microglobulin decreased. In all examinees, creatinine clearance and percent tubular reabsorption of both phosphate and calcium were significantly negatively correlated with urinary cadmium excretion. /It was concluded that the/ five high excretion workers showed evidence of chronic renal tubular dysfunction and one of these was recognized as having remarkable renal damage. The possibility to affirm the effects of exposure to cadmium was suggested on hematological findings related to anemia. Liver function abnormalities were not recognized. A slight reduction of the respiratory function was found in one worker of the high excretion group, but radiological examination of the chest showed no abnormalities in all examinees. [R26] *... /IN/ COHORT OF 292 SMELTER WORKERS WITH AT LEAST 2 YR EXPOSURE TO ... OXIDE DUST AND FUMES, 4 DEATHS FROM PROSTATE CANCER ... OBSERVED ... 1.15 ... EXPECTED ... IN TOTAL COHORT. ... AUTHORS ALSO REPORTED SIGNIFICANT EXCESS OF RESP TRACT CANCER: THEY OBSERVED 12 DEATHS WHERE ONLY 5.11 WERE EXPECTED (SMOKING HABITS ... NOT GIVEN). [R27] *SYMPTOMS OF BACK AND EXTREMITY PAIN WITH DIFFICULTY IN WALKING ... REPORTED IN STORAGE BATTERY WORKERS IN FRANCE EXPOSED TO ... DUST AND BONE CHANGES IN ISOLATED CASES ARE FOUND IN 2 BRITISH REPORTS. PSEUDOFRACTURES OF SCAPULA, PELVIS, FEMUR AND TIBIA WERE SEEN ON X-RAY ... MOST PROBABLY, CADMIUM-ALTERED TUBULAR FUNCTION ... RESPONSIBLE ... [R22, 1569] *... AMINOACIDURIA (THREONINE AND SERINE) /WAS FOUND/ IN WORKERS EXPOSED TO CADMIUM OXIDE DUST. SWEDISH WORKERS SIMILARLY EXPOSED ... HAVE LOW INSULIN CLEARANCE ... AND INABILITY TO CONCN URINE. THESE ABNORMALITIES ... INCREASE WITH ... TIME AND LEVEL OF CADMIUM EXPOSURE. [R22, 1569] *... POSSIBLE RELATIONSHIP BETWEEN ... EXPOSURE ... AND PROSTATE CANCER REPORTED /IN/ SURVEY OF 70 MEN EXPOSED FOR 10 OR MORE YR TO CADMIUM OXIDE DUST IN PRODUCTION OF ALKALINE BATTERIES. OF 8 DEATHS IN THIS GROUP, 3 WERE FROM PROSTRATE CANCER AND 2 FROM OTHER FORMS OF CANCER. [R28] *... CALCULATED LETHAL INHALATION DOSE OF CADMIUM OXIDE IN MAN TO BE 2500 MG/CU M FOR 1 MIN EXPOSURE. [R29] *LETHAL EXPOSURE HAS BEEN EST @ 50 MG CD/CU M FOR 1 HR ... /FOR/ CADMIUM OXIDE DUST AND ABOUT 1/2 THAT FOR THE FUME ... [R30] *Inhalation of /cadmium oxide/ fumes can cause metal fume fever. [R31] *... Lung impairment is possible at cadmium oxide fume levels below 100 ug/cu m of work place air, depending upon exposure time. [R32] *MOST SERIOUS ACUTE EFFECTS FROM CADMIUM OCCUR FROM EXPOSURE TO CADMIUM (OXIDE) FUME DURING INDUSTRIAL OPERATIONS. ... SILVER-BRAZING ... /HAS/ GIVEN RISE TO CHARACTERISTIC ... FUME SYMPTOMS, BECAUSE OF SILVER SOLDERS'S CADMIUM CONTENT (24%), EXPOSURES, EST ... ABOVE 1 MG/CU M, CAUSED DEATH ... IN 3 DAYS. [R22, 1567] *High inhalation exposure to cadmium oxide fume results in acute pneumonitis with pulmonary edema, which may be lethal. [R33] *... Three out of eight deaths in a small cohort of nickel-cadmium battery workers in the U.K. with at least 10 yr of exposure to cadmium oxide dust were from carcinoma of the prostate. [R34, p. 157 (1992)] *Food and Environmental Agents: Effect on Breast-Feeding: Reported Sign or Symptom in Infant or Effect on Lactation: Cadmium: None Reported. /from Table 7/ [R35] *The consequence of excessive inhalation of cadmium fumes and dusts is loss of ventilatory capacity, with a corresponding increase in residual lung volume. Dyspnea is the most frequent complaint of patients with cadmium induced lung disease. The pathogenesis of cadmium-induced emphysema and pulmonary fibrosis is not well understood; however, cadmium specifically inhibits the synthesis of plasma alpha 1-antitrypsin, and there is an association between severe alpha 1-antitrypsin deficiency of genetic origin and emphysema in human beings. /Cadmium fumes and dusts/ [R36] *The chief chronic pulmonary effects of cadmium are ... centrilobular emphysema and bronchitis resulting from several years of occupational exposure to cadmium oxide fumes, cadmium oxide dust, and cadmium pigment dust. [R37] *SYMPTOMS /FROM INHALATION EXPOSURE/ MAY NOT APPEAR UNTIL 24 HOURS AFTER EXPOSURE HAS TERMINATED, WHICH MAY CAUSE DIFFICULTIES IN OBTAINING THE PROPER DIAGNOSIS. THE PREDOMINANT SYMPTOMS AND SIGNS ARE SHORTNESS OF BREATH, GENERAL WEAKNESS, FEVER AND IN SEVERE CASES RESP INSUFFICIENCY WITH SHOCK AND DEATH. THE CADMIUM INDUCED ACUTE PULMONARY DISORDER IS A CHEM PNEUMONITIS AND SOMETIMES A PULMONARY EDEMA. THIS TYPE OF EFFECT MAY MOST FREQUENTLY RESULT FROM INHALATION OF FUMES GENERATED BY WELDING CADMIUM CONTAINING MATERIALS OR BY SMELTING OR SOLDERING SUCH MATERIALS, BOTH UNDER CONDITIONS OF POOR VENTILATION. /CADMIUM FUMES/ [R38] *ACUTE INHALATION EXPOSURE MAY RESULT DURING FIRST 3 DAYS IN ... DEATH CAUSED BY ANOXIA. SECOND STAGE OF ACUTE INTOXICATION CONSISTS OF CELLULAR PROLIFERATION IN ALVEOLI AND HYPERPLASIA OF THE LINING CELLS WITH OCCASIONAL INTRA-AVEOLAR HEMORRHAGE. /CADMIUM OXIDE/ [R30] NTOX: *... 1 YR, INHALATION OF CADMIUM OXIDE ... BY DOGS @ LEVELS OF 3-7 MG/CU M DAILY RESULTED IN NO DAMAGE ... [R39] *AS ANTIHELMINTHIC /IN PIGS/, THE OXIDE IS MIXED WITH WET OR DRY FOOD IN CONCN OF 150 PPM AND FED FOR 3 DAYS. TWICE THIS CONCN WAS FOUND TO REDUCE FOOD INTAKE AND ... CAUSE DIARRHEA AND VOMITING. [R40] *INTENSE INFLAMMATORY REACTION WITH ULCERATION OF UNDERLYING SKIN FOLLOWED SINGLE SC INJECTION OF 25 MG CADMIUM OXIDE INTO 10 FEMALE RATS, and 8/10 ... DEVELOPED LOCAL TUMORS WITHIN 1 YR POST-INJECTION. NO LOCAL TUMORS DEVELOPED IN 10 CONTROLS GIVEN SC INJECTION OF SALINE ALONE. [R41] *... 450 PPM CAUSED DEATH OF 6 PIGS. CHIEF CLINICAL SIGN WAS INCOORDINATION. POST MORTEM LESIONS WERE ANEMIA, ENLARGED SPLEEN, ICTERUS, ULCERATION OF STOMACH AND FATTY DEGENERATION OF LIVER AND KIDNEYS. [R40] *... CATS UNDERGO FATAL PULMONARY IRRITATION FOLLOWING INHALATION OF CADMIUM OXIDE FUME. [R22, 1566] *RATS EXPOSED DAILY TO FUMES AT 0.1 and 1.0 MG/CU M FOR 4 WK SHOWED USUAL NEUTROPHILIA AND LYMPHOPENIA AND SIGNIFICANT CYTOLOGICAL SHIFT OF LYMPHOCYTES TO LARGE LYMPHOCYTES OBSERVED EARLIER THAN ANEMIA AND OTHER RESPONSES. DECR SMALL LYMPHOCYTE COUNTS AND INCR SPLEEN WT WERE OBSERVED. [R42] *RATS WERE EXPOSED TO AEROSOL (60 UG/L FOR 30 MIN) AND OBSERVED FOR 1 YR. INCR IN BLOOD PRESSURE, BLOOD GLUCOSE LEVELS, URINARY PROTEIN AND IN INCIDENCE OF SEMINIFEROUS TUBULE DEGENERATION OBSERVED. EFFECTS OF INHALATION MAY MANIFEST IN ORGANS OTHER THAN LUNG. [R43] *AFTER 66-DAY INHALATION BY RATS TO 7 UG/CU M, ALVEOLAR MACROPHAGES APPEARED TO BE IN ACTIVATED STATE WITH RESPECT TO PHAGOCYTIC AND INTRACELLULAR ACID PHOSPHATASE ACTIVITY. CELLS IN LUNG LAVAGE IS GOOD INDICATOR IN INHALATION TOXICOLOGY. [R44] *Prolonged exposure of female rats to cadmium oxide aerosols (0.02 and 0.16 mg Cd/cu m in air) had no effect on fertility. Viability and postnatal growth of the offspring of dams that were exposed to 0.16 mg Cd/cu m before and during gestation, however, were depressed. Forepaw muscular strength and endurance of pups in all groups were similar. Maternal cadmium exposure resulted in reduction of exploratory motor activity in 3 month old pups from the 0.16 mg Cd/cu m group and male offspring from the 0.02 mg Cd/cu m group. Dose dependent decreases of avoidance acquisition were seen in female offspring but not in males. In the open-field test, the ambulation of 5 month old males from the 0.16 mg Cd/cu m was lowered, whereas in females from the 0.02 mg Cd/cu m group it was enhanced. The results indicate central nervous system dysfunction in offspring of female rats exposed to low concentrations of cadmium oxide by inhalation. [R45] *Cadmium oxide was not mutagenic in Salmonella typhimurium with/without Arochlor 1254 induced Sprague-Dawley rat or Syrian hamster liver microsome activation. [R46] *The arterial blood pressure, lipid content in serum and some organs, cadmium level in blood, aorta wall, lung, and liver have been examined in rats repeatedly exposed to cadmium oxide fume 5 hr daily, 5 days a wk, during 6 mo. The blood pressure in rats exposed to cadmium oxide at concentration 0.02 mg Cd/cu m and 0.16 mg Cd/cu m was not changed, but it was slightly lowered at concentration 1.0 mg Cd/cu m, which has been found lethal for rats. The concentration of total cholesterol, phospholipids and cholesterol esters in serum of female rats exposed at a concentration of 0.16 mg Cd/cu m for 3 mo was decreased, but was not affected after 6 mo of exposure. The content of cholesterol and triglycerides in the aorta wall, heart, and liver was unchanged, although the content of cholesterol was decreased in adrenals of rats exposed for 3 mo at concentration of 0.16 mg Cd/cu m. Inhalation of cadmium oxide brought about a marked increase of cadmium content in the lung and kidney of rats exposed at all concentration levels, and an increase of cadmium blood level in rats exposed at concentrations of 0.16 mg Cd/cu m and 1.0 mg Cd/cu m. There was no increase of cadmium content in the aorta wall. [R47] *The carcinogenic effects of single or multiple exposures to intratracheally instilled cadmium oxide resulting in total doses of 0, 25, 50, and 75 ug, were studied in groups of 41 to 48 male Fischer rats. Pulmonary deposit of cadmium oxide did not result in increased numbers of tumors, except in the mammary gland, or in rats that had three or more types of tumors. Cadmium oxide was not carcinogenic to the lung, liver, kidneys, or prostate gland of rats. [R48] *THE ULTRASTRUCTURE OF THE CARDIAC MUSCLE OF RATS EXPOSED 5 HR DAILY, 5 DAYS A WK TO CADMIUM OXIDE FUMES AT A CONCN OF 0.16 MG CADMIUM/CU M FOR 3 and 6 MONTHS AND AT A CONCN OF 1 MG CADMIUM/CU M FOR 3 and 4 MONTHS WAS EVALUATED. THE STRUCTURE OF MUSCLE CELLS, ARTERIOLES AND CAPILLARIES REMAINED UNCHANGED. THERE WERE DISTINCT ALTERATIONS OF THE INTERCALATED DISC STRUCTURE DEPENDENT UPON THE LEVEL AND TIME OF EXPOSURE. THE DAMAGE TO INTERCALATED DISCS VARIED FROM THE ENLARGEMENT OF THE FISSURE BETWEEN MEMBRANES (WITHIN UNSPECIALIZED SEGMENTS) TO DISRUPTION OF THE COMPLEX JUNCTIONS. [R49] *A STUDY OF THE EFFECT OF INHALED CADMIUM MICROPARTICLES (CADMIUM OXIDE) ON THE MOUSE DEATH RATE FROM INFLUENZA PNEUMONIA WAS PERFORMED ON 936 FEMALE SPECIFIC PATHOGEN-FREE (SPF) SWISS MICE. THE TEST ANIMALS RECEIVED A SINGLE (ACUTE) 15 MIN EXPOSURE TO 9 MG CADMIUM/CU M OF AIR, OR RENEWED SHORT EXPOSURES TO 1 MG/CU M ONCE A DAY, 5 DAYS/WK/4 WK (SUBCHRONIC). THE CADMIUM FOUND IN THE TRACHEA-BRONCHUS-LUNG AREA WAS ABOUT 5 UG/G OF FRESH TISSUE AT THE END OF ACUTE EXPOSURE, and 4 UG/G AT THE END OF SUBCHRONIC EXPOSURE. THE VIRAL CHALLENGE WAS PERFORMED 48 HR AFTER ACUTE EXPOSURE, OR ON THE 14TH DAY AFTER THE BEGINNING OF SUBCHRONIC EXPOSURE, THE MICE BEING REEXPOSED TO CADMIUM FOR AN ADDITIONAL 14 DAYS IN THE LATTER CASE. SURPRISINGLY, THE INFECTIOUS DEATH RATE OF TEST MICE WAS SIGNIFICANTLY LOWER THAN THAT OF CONTROLS, BOTH FOR ACUTE AND SUBCHRONIC EXPOSURE TO CADMIUM OXIDE. [R50] *Cadmium oxide was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Cadmium oxide was tested at doses of 0.0033, 0.01, 0.033, 1.0, and 3.3 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Cadmium oxide was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 3.3 mg/plate. [R51] *In a long term inhalation study, cadmium aerosols consisting of cadmium chloride and cadmium oxide as dusts and fumes, cadmium sulfate, cadmium sulfide, and a combination of cadmium oxide-zinc oxide were used. Wistar rats were continuously exposed in inhalation chambers for 18 mo 22 hr/day or for 40 hr/wk. The particles of the cadmium aerosols had an average mass medium diameters in the range from 0.2 to 0.5 um. [R52] *There is evidence that cadmium chloride, sulfate, sulfide, and oxide give rise to injection site sarcomata in the rat ... Long-term inhalation studies in rats exposed to aerosols of cadmium chloride, sulfate, and oxide fume and dust at low concentrations demonstrated a high incidence of primary lung cancer with evidence of a dose-response relationship. [R34, p. 199 (1992)] *Female Wistar WU/Kisslegg rats ..., 12 wk of age, each received a single intraperitoneal injection of 50 mg cadmium as cadmium sulfide (81 rats examined) or two weekly intraperitoneal injections of 0.125 mg cadmium as cadmium oxide (47 rats examined) dissolved in saline. Animals were observed for up to 123 weeks. ... Fifty-four of eighty-one given cadmium sulfide had peritoneal cavity tumors, described as sarcomas, mesotheliomas and carcinomas of the abdominal cavity ... [R53] HTXV: *... CALCULATED LETHAL INHALATION DOSE OF CADMIUM OXIDE IN MAN TO BE 2500 MG/CU M FOR 1 MIN EXPOSURE. [R29] NTXV: *LD50 Rat oral 72 mg/kg; [R15, 619] *LC50 Rat ihl 780 mg/cu m/10 mos; [R15, 619] *LD50 Rat ip 12 mg/kg; [R15, 619] *LD50 Mouse oral 72 mg/kg; [R15, 619] *LC50 Mouse ihl 340 mg/cu m/10 mos; [R15, 619] *LC50 Dog ihl 400 mg/cu m/10 mos; [R15, 619] *LC50 Monkey ihl 15 g/cu m/10 mos; [R15, 619] *LC50 Rabbit ihl 3 g/cu m/15 mos; [R15, 619] *LC50 Guinea pig ihl 3 g/cu m/15 mos; [R15, 619] TCAT: ?Cadmium oxide was evaluated for clastogenicity in groups of 20 male Long-Evans rats injected intraperitoneally with total dose levels of 0 or 5 mg/kg bw, in three equal increments at 2 day intervals. Blood and bone marrow samples were obtained from each rat at 1 and 30 days after treatment, for determination of chromosomal abnormalities. The treatment increased the frequency of 1 type of chromosomal aberration (gap/break) in bone marrow cells obtained on day 1, indicating that the test compound was positive for clastogenicity in rats under the conditions of this assay. Positive control treatment with a single intraperitoneal injection of 0.3 mg/kg triethylenemelamine produced a significant increase in the frequency of chromosomal aberrations in bone marrow cells collected on day 1; bone marrow cells collected from positive control rats on day 30 and blood cells collected on day 1 or 30 were similar to negative controls in frequency of chromosomal aberrations. [R54] POPL: */Protect/ from exposure those individuals with diseases of the ... liver, kidneys, or blood. [R13, 97] ADE: *1 YR INHALATION OF CADMIUM OXIDE ... BY DOGS @ LEVELS OF 3-7 MG/CU M DAILY RESULTED IN ... BLOOD CADMIUM CONCN AVG 0.22 MG% AND URINE ... WERE 0.36 MG/L. MOST ... CADMIUM ... RETAINED IN LUNGS, CONSIDERABLE AMT IN KIDNEY AND LIVER ... LESSER AMT IN BONE AND TEETH. LACK OF EFFECT ... ATTRIBUTED TO LOW RATE OF SOLUBILITY ... [R39] *... ARC-PRODUCED CD FUME PARTICLE DEPOSITION IN LARGE NUMBER OF 5 ANIMAL SPECIES AT LD50 DOSES ... /WITH/ PARTICULATE DIAMETER ... FROM 0.3 TO 0.5 MU ... /SHOWED/ AVG FUME DEPOSITION IN LUNG ... ABOUT SAME FOR ALL SPECIES, 11%, WITH RANGE BETWEEN 4.3 and 21.7% ... [R22, 1573] *RATS WHICH DIED WITHIN 3 DAYS OF EXPOSURE TO AEROSOL OF CADMIUM OXIDE (60 M UG/L FOR 30 MIN) SHOWED LUNG LEVEL OF 26.9 UG. [R43] *IN RATS, INTRATRACHEALLY ADMIN CADMIUM OXIDE TAGGED WITH (109)CADMIUM, HALF-LIFE IN LUNG WAS 4 HR AT WHICH TIME NEARLY 40% OF BODY BURDEN WAS IN LIVER. LESS THAN 10% WAS EXCRETED DURING 1ST 2 WK. CADMIUM IS HIGHLY SOL IN LUNG, BUT CADMIUM IS SLOWLY EXCRETED FROM BODY. [R55] *The absorption of an aerosol of cadmium chloride is higher than that of cadmium oxide, and alveolar absorption is higher after intratracheal instillation than after inhalation of an aerosol. [R56] *IN A THIRTY DAY INHALATION STUDY MALE RATS WERE CONTINUOUSLY EXPOSED TO SUBMICRON AEROSOLS OF 3 DIFFERENT CADMIUM CMPD. THE CADMIUM CHLORIDE AND CADMIUM OXIDE AEROSOL CONCN WERE 0.1 MG/CU M CADMIUM. BECAUSE OF ITS LOWER SOL THE CADMIUM SULFIDE LEVEL WAS 1 MG/CU M CADMIUM. FOR CADMIUM CHLORIDE AND CADMIUM OXIDE, MOST OF THE CADMIUM WAS FOUND IN THE LUNG CYTOSOLIC COMPARTMENT, BUT FOR CADMIUM SULFIDE ONLY 30% OF THE CADMIUM WAS RETRIEVED FROM THE LUNG CYTOSOLS. THIS WAS OBSERVED BOTH AT THE END OF THE INHALATION AND ALSO AFTER AN ADDITIONAL TWO MO RECOVERY PERIOD IN FRESH AIR. THE CADMIUM CONTENTS OF THE LUNG HOMOGENATES, CYTOSOLS, AND THE LUNG CYTOSOLIC METALLOTHIONEIN WERE TWICE AS MUCH FOR EXPOSURE TO CADMIUM OXIDE THAN FOR EXPOSURE TO CADMIUM CHLORIDE. FOR EXPOSURE TO CADMIUM SULFIDE AT CADMIUM CONCN 10 TIMES HIGHER, THE SAME CADMIUM LEVELS WERE FOUND AS FOR CADMIUM OXIDE. THESE RESULTS WERE CONFIRMED BY RESULTS FROM ALVEOLAR LAVAGE ANALYSIS INDICATING THAT IN THE LUNG INHALED CADMIUM OXIDE IS EVEN MORE AVAILABLE TO LUNG TISSUE THAN THE VERY SOL CADMIUM CHLORIDE, AND CADMIUM OXIDE HAS AN AVAILABILITY 10 TIMES AS MUCH AS CADMIUM SULFIDE. [R57] BHL: *IN RATS, INTRATRACHEALLY ADMIN CADMIUM OXIDE TAGGED WITH (109)CD, HALF-LIFE IN LUNG WAS 4 HR ... [R55] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): AS AN ASCARICIDE IN SWINE [R5, 266] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ARTS: *Liberation during smelting and refining of ores where it is a by-product of zinc, lead and copper bearing ores. Liberation during recovery of metal by processing scrap; during melting and pouring of cadmium metal; during casting of alloys for cadmium-copper, cadmium-lead, cadmium-bismuth, cadmium-silver, cadmium-nickel, cadmium-lead-silver, cadmium-lead-silver-nickel, cadmium-lead-bismuth-tin, and cadmium-gold products used for coating telephone cables, trolley wires, welding, electrodes, automatic sprinkling systems, steam boilers, fire alarms, high pressure/temperature bearings, starting switches, aircraft relays, light duty circuit breakers, low temperature solder, and jewlery. Liberation during fabrication of metal, alloys, or plated steel. Liberation during casting and use of solders; during melting of cadmium ingots for paint and pigment manufacture used for coloring of plastics and ceramic glazes, electroplating, and in chemical synthesis. Liberation during coating of metals by hot dipping or spraying. Liberation during manufacture of nickel-cadmium batteries for use in radio portable telephones, convenience appliances, and vented cells used in airplanes, helicopters, and stand-by power and lighting. /Cadmium, cadmium oxide/ [R16, 1981.3] RTEX: *The concentrations of cadmium oxide in the pre-mould department of a smelter ranged from 0.074-0.09 mg/cu m, and 1.1 mg/cu m were found in the retort department. [R58] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers cadmium oxide to be a potential occupational carcinogen. [R7, 44] OSHA: *Permissible Exposure Limit: The employer shall assure that no employee is exposed to an airborne concentration of cadmium in excess of 5 ug/cu m, calculated as an 8-hr TWA. /Cadmium, as Cd/ [R59] *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 0.1 mg/cu m. This standard applies to any operations or sectors for which the Cadmium standard, 1910.1027, is stayed or otherwise not in effect. /Cadmium fume/ [R60] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 0.3 mg/cu m. This standard applies to any operations or sectors for which the Cadmium standard, 1910.1027, is stayed or otherwise not in effect. /Cadmium fume/ [R60] *Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 0.2 mg/cu m. This standard applies to any operations or sectors for which the Cadmium standard, 1910.1027, is stayed or otherwise not in effect. /Cadmium dust/ [R60] *Permissible Exposure Limit: Table Z-2 Acceptable Ceiling Concentration: 0.6 mg/cu m. This standard applies to any operations or sectors for which the Cadmium standard, 1910.1027, is stayed or otherwise not in effect. /Cadmium dust/ [R60] NREC: *NIOSH considers cadmium oxide to be a potential occupational carcinogen. [R7, 44] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R7, 44] TLV: *8 hr Time Weighted Avg (TWA) 0.01 mg/cu m; 8 hr Time Weighted Avg (TWA) 0.002 mg/cu m respirable fraction. /Cadmium, elemental and cmpd, as Cd/ [R61, 22] *A2. A2= Suspected human carcinogen. /Cadmium, elemental and compounds, as Cd/ [R61, 22] *BEI (Biological Exposure Index): Cadmium in urine (timing is not critical) is 5 ug/g creatinine. The determinant is usually present in a significant amt in biological specimens collected from subjects who have not been occupationally exposed. Such background levels are incl in the BEI value. (1993 adoption) /Cadmium and inorganic cmpd/ [R61, 96] *BEI (Biological Exposure Index): Cadmium in blood (timing is not critical) is 5 ug/l. The determinant is usually present in a significant amt in biological specimens collected from subjects who have not been occupationally exposed. Such background levels are incl in the BEI value. (1993 adoption) /Cadmium and inorganic cmpd/ [R61, 96] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Cadmium, elemental and cmpd, as Cd/ [R61, 6] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Cadmium oxide is included on this list. [R62] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 5 ug/l /Cadmium/ [R63] FEDERAL DRINKING WATER GUIDELINES: +EPA 5 ug/l /Cadmium/ [R63] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 5 ug/l /Cadmium/ [R63] +(ME) MAINE 5 ug/l /Cadmium/ [R63] +(MN) MINNESOTA 4 ug/l /Cadmium/ [R63] CERC: *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Cadmium oxide is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100/10,000 lbs. [R64] RCRA: *D006; A solid waste containing cadmium (such as cadmium oxide) may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R65] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Toxicity Studies of Cadmium Oxide Administered by Inhalation to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 39 NIH Publication No. 95-3388 (1995) U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 770 R2: JT Baker Chemical Co; Reagents and Laboratory Products Catalog #840C p.27 (1984) R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V2 77 (1973) R4: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 503 R5: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R6: SRI R7: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R8: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999. R10: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. B-78 R11: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 669 R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 65th ed. Boca Raton, FL: CRC Press, Inc. 1984-85.,p. D-95 R13: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. R14: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-112 R15: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R16: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R17: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 58 210 (1993) R19: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R20: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.292 R21: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R22: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R23: KAZANTZIS G; ENVIRON HEALTH PERSPECT 28: 155 (1979) R24: Cvetkova RP; Gig Tr Prof Zabol 14: 31 (1970) as cited in USEPA; Health Assessment Document: Cadmium p.4-72 (1981) EPA 600/8-81-023 R25: Bonnell JA; Br Ind Med 12: 181-97 (1955) as cited in NIOSH; Criteria Document: Cadmium p.19 (1976) DHEW Pub. NIOSH 76-192 R26: Toda K et al; Sangyo Igaku 26 (3): 212-23 (1984) R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 64 (1976) R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 63 (1976) R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V2 91 (1973) R30: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. 469 R31: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 224 R32: USEPA; Health Assessment Document: Cadmium p.1-11 (1981) EPA 600/8-81-023 R33: WHO; Environmental Health Criteria 134: Cadmium p.21 (1992) R34: WHO; Environmental Health Criteria 134: Cadmium R35: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 142 (1994) R36: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 1663 R37: USEPA; Health Assessment Document: Cadmium p.1-11 (1981) EPA-600/8-81-023 R38: Friberg, L., G.R. Nordberg, and V.B. Vouk. Handbook on the Toxicology of Metals. New York: Elsevier North Holland, 1979. 367 R39: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1014 R40: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 37 R41: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 56 (1976) R42: OHSAWA M ET AL; ENVIRON RES 24 (1): 192 (1981) R43: HADLEY JG ET AL; TOXICOL LETT 4 (2): 107 (1979) R44: MUHLE H ET AL; AEROSOLS SCI MED TECHNOL, BIOMED INFLUENCE AEROSOL, CONF 7TH: 144 (1980) R45: Baranski B; Toxicol Lett 22 (1): 53-61 (1984) R46: NTP Bulletin; 7: 7 (1982) R47: Baranski B et al; Med Pr 34 (1): 11-19 (1983) R48: Sanders CL, Mahaffey JA; Environ Res 33 (1): 227-33 (1984) R49: KOLAKOWSKI J ET AL; TOXICOL LETT 19 (3): 273-8 (1983) R50: CHAUMARD C ET AL; ENVIRON RES 31 (2): 428-39 (1983) R51: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R52: Oldiges H, Glaser U; Toxicol Environ Chem 11 (4): 351-7 (1986) R53: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V58 175 (1993) R54: Toxicology Research Laboratory; Estimation of the Carcinogenicity and Mutagenicity of Some Arsenic Compounds Utilizing Somatic Mutations in Rats (Final Report), (1978), EPA Document No. 8EHQ-0579-0150, Fiche No. OTS0200532 R55: HADLEY JG ET AL; TOXICOL APPL PHARMACOL 54 (1): 156 (1980) R56: WHO; Environmental Health Criteria 134: Cadmium p.67 (1992) R57: GLASER U ET AL; ETOXICOL ENVIRON SAF 11 (3): 261-71 (1986) R58: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 11: 49 R59: 29 CFR 1910.1027(c) (7/1/98) R60: 29 CFR 1910.1000 (7/1/98) R61: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R62: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R63: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R64: 40 CFR 355 (7/1/98) R65: 40 CFR 261.24 (7/1/98) RS: 46 Record 136 of 1119 in HSDB (through 2003/06) AN: 1617 UD: 200302 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLOROBENZILATE- SY: *G-338-; *Acar-; *ACARABEN-; *Acaraben-4E-; *Acarben-4E-; *AKAR-; *Akar-50-; *AKAR-338-; *BENZ-O-CHLOR-; *BENZENEACETIC ACID, 4-CHLORO-ALPHA-(4-CHLOROPHENYL)-ALPHA-HYDROXY-, ETHYL ESTER; *BENZILAN-; *BENZILIC-ACID,-4,4'-DICHLORO-,-ETHYL-ESTER-; *CHLORBENZILAT-; *CHLORBENZILATE-; *CHLORBENZYLATE-; *4-Chloro-alpha-(4-chlorophenyl)-alpha-hydroxybenzeneacetic acid ethyl ester; *4,4'-DICHLORBENZILSAEUREAETHYLESTER- (GERMAN); *4,4'-DICHLOROBENZILIC-ACID-ETHYL-ESTER-; *ENT-18,596-; *Ethyl 4-chloro-alpha-(4-chlorophenyl)-alpha-hydroxybenzeneacetate; *Ethyldichlorobenzilate-; *ETHYL-P,P'-DICHLOROBENZILATE-; *ETHYL-4,4'-DICHLOROBENZILATE-; *ETHYL-4,4'-DICHLORODIPHENYL-GLYCOLLATE-; *ETHYL DI(P-CHLOROPHENYL)GLYCOLLATE; *Ethyl-4,4'-dichlorophenyl-glycollate-; *ETHYL-4,4'-DIPHENYLGLYCOLLATE-; *Ethyl-ester-of-4,4'-dichlorobenzilic-acid-; *ETHYL 2-HYDROXY-2,2-BIS(4-CHLOROPHENYL)ACETATE; *Ethyl 2-hydroxy-2,2-di(p-chlorophenyl)acetate; *FOLBEX-; *G23992-; *GEIGY-338-; *KOP-MITE-; *NCI-C00408-; *NCI-C60413-; *Caswell-No.-434-; *EPA-pesticide-code-028801- RN: 510-15-6 MF: *C16-H14-Cl2-O3 SHPN: UN 2762; Organochlorine pesticides, liquid, flammable, toxic, flash point less than 23 deg C UN 2761; Organochlorine pesticides, solid, toxic. UN 2995; Organochlorine pesticides, liquid, flammable, toxic, flash point 23 deg C or more; Organochlorine pesticides, liquid, flammable, toxic, flash point between 23 deg C and 61 deg C. UN 2996; Organochlorine pesticides, liquid, toxic. IMO 3.2; Organochlorine pesticides, liquid, flammable, toxic, flash point less than 23 deg C IMO 6.1; Organochlorine pesticides, liquid, flammable, toxic, flash point 23 deg C or more HAZN: U038; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 4,4'-DICHLOROBENZILIC ACID WITH ETHANOL IN THE PRESENCE OF A CATALYST; REACTION OF 4,4'-DICHLOROBENZILIC ACID WITH DIETHYL SULFATE. [R1] *Hafliger, US patent 2,745,780 (1956 to Geigy); British patent 831,421 (1960 to Metal and Thermit). [R2] IMP: *Chlorobenzilate is suspected to be contaminated by DDT and/or its analogs at or near the limit of detection. ... The Agency is requesting registrants to do further analyses with more sensitive analytical techniques to search for these impurities. [R3] *In 1972, the following components were reported in 13 batches of technical chlorobenzilate: chlorobenzilate 93.8 to 97.3%; ethyl 4-chlorobenzoate 0.23 to 0.47%; 4,4'-dichlorobenzophenone 0.04 to 0.23%; chloropropylate not detected (0.05%); 2,4'-chlorobenzilate less than 0.01%; ethyl ether of chlorobenzilate 0.14 to 0.59%; 2,2'- and 4,4'-dichlorobenzil less than 0.01 to 0.11% combined; and six unknown components 0.38% or less for each. [R4] FORM: *Chlorobenzilate has been avail as an emulsifiable concentrate and as a 25% water-dispersible powder. The emulsifiable concentrate contains 45.5% ethyl 4,4'-dichlorobenzilate, 43.5% xylene and 11% inert ingredients. [R4] *The technical material contains approx 90% of the active cmpd. [R5] *'Akar 338' EC (250 g active ingredient/l); WP (250 g/kg); 'akar 50', EC (500 g/l) [R6] *Emulsifiable concentrate; Tech, wettable powder. [R7, p. C 87] *Rospin [R8] *Types of formulations: Four pound per gallon emulsifiable concentration. ... Aerial and foliar sprays (restricted use). Application rates: 0.75 lb/acre, carrier being water. [R3] MFS: *Ciba-Geigy Corporation, Hq, Saw Mill River Road, Ardsley, NY 10502, (914) 478-3131; Agricultural Division, PO Box 18300, Swing Road at I-40, Greensboro, NC 27419; Production site: Off Highway 43, McIntosh, AL 36553 /Former/ [R9] OMIN: */IT WAS INTRODUCED, IN 1952/ BY JR GEIGY SA ... AS CODE NUMBER 'G 23992'; TRADE MARKS 'AKAR', 'FOLBEX' AND IN USA 'ACARABEN'. [R6] *IT IS A NONSYSTEMIC ACARICIDE WITH LITTLE INSECTICIDAL ACTION. IT IS RECOMMENDED FOR USE AGAINST PHYTOPHAGOUS MITES ON CITRUS, COTTON, GRAPES, SOYBEANS, TEA, AND VEGETABLES AT 30-60 G AI/100 L OR 1.0-1.5 KG/HA. /SRP: FORMER USE IN USA/ [R6] */Chlorobenzilate is a/ material believed to be no longer manufactured, or marketed for crop protection use. [R10] *THE TETRANYCHID MITES HAVE ... DEVELOPED AT LEAST 5 TYPES OF RESISTANCES TO THE CHLORINATED ACARICIDES. THE DATES OF THEIR FIRST REPORTED APPEARANCE IN TWO SPOTTED MITES AND EUROPEAN RED MITES ARE AS FOLLOWS ... CHLOROBENZILATE AND CHLORBENSIDE. [R11] *It is not produced commercially in western Europe. Commercial production of chlorobenzilate was begun in Japan in 1977. Production by the sole Japanese producer in 1980 is est to have been 44,000 kg, down from 102,000 kg produced in 1978. There have been no imports of chlorobenzilate into Japan in recent years, and exports have been negligible. [R12] *US: Some or all applications may be classified as RUP (restricted use pesticide). [R7, p. C 87] *Folbex Acaricide (chlorobenzilate) - Discontinued by Ciba-Geigy Ltd. [R7, p. C 192] *Only one USA company presently produces it and ... the company is estimated to have an annual production capacity of approx 900,000 kg. [R12] *In countries other than the US, chlorobenzilate is believed to be used on crops other than citrus ... . [R12] USE: *For Chlorobenzilate (USEPA/OPP PC Code: 028801) there are 0 label matches. /SRP: Not registered for current use in the U.S./ [R13] *Acaricide in spider-mite control; used as a synergist for DDT /Former use/ [R2] *Pesticide, acaricide /Former use/ [R14] *Used on citrus to control many mite species. [R7, p. C 87] *ON PREMISE AND FOR PLANT MITE CONTROL. POOR EFFECTIVENESS VERSUS D GALLINAE ON POULTRY. /SRP: FORMER USE IN USA/ [R15] *Controls mites on citrus, cotton, and vegetables. [R16] *CHLOROBENZILATE WAS ONE OF THE SEVERAL COMPOUNDS WHICH WERE EFFECTIVE AGAINST THE CITRUS RUST MITE PHYLLOCOPTRUTA OLEIVORA. (FORMER USE) [R17] *ACARICIDE FOR CITRUS CROPS, ORNAMENTALS, COTTON, (NON-CITRUS) FRUITS AND NUTS /SRP: FORMER USE IN USA/ [R1] CPAT: *ACARICIDE FOR CITRUS, 100% (1982) [R1] *Estimates of the national annual usage of individual active ingredients in US agriculture for the years 1966, 1971, 1976, 1982, 1989 were reported to be 465,000 lbs, 812,000 lbs, 839,000 lbs, 1,648,000 lbs, 350,000 lbs of active ingredient per year, respectively. [R18] PRIE: U.S. PRODUCTION: *(1978) 3.63X10+8 G (CONSUMPTION-INCL IMPORTS) [R1] *(1982) 1.36X10+8 G (CONSUMPTION-INCL IMPORTS) [R1] U.S. IMPORTS: *(1978) 6.41X10+7 G (PRINCPL CUSTMS DISTS) [R1] *(1982) 1.21X10+8 G (PRINCPL CUSTMS DISTS) [R1] *(1983) 2.97X10+4 lb [R19] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless solid (pure) [R20]; *Viscous liquid. The commercial product /was/ yellow. [R2]; *Tech: Brownish liquid, approx. 90% pure. Pale yellow solid. [R7, p. C 87]; *Yellowish liquid. [R5] BP: *146-148 deg C @ 0.04 mm Hg [R2] MP: *36 to 37.5 deg C [R7, p. C 87] MW: *325.19 [R2] DEN: *(technical 90%) 12,816 at 20/4 deg C [R14] OWPC: *log Kow= 4.74 [R21] SOL: *Solubility at 20 deg C: 10 mg/l water; 1 kg/kg acetone, dichloromethane, methanol, and toluene; 600 g/kg hexane; 700 g/kg 1-octanol [R6]; *Sol in most organic solvents. [R2]; *Soluble in acetone, benzene, methanol. [R14]; *Tech: Soluble in most organic solvents, including petroleum oils. [R7, p. C 87]; *Soluble to more than 40% in deodorized kerosene, benzene, and methyl alcohol. [R5]; *In water, 13 mg/l at 20 deg C. [R22] SPEC: *Index of refraction 1.5727 @ 20 deg C/D [R2]; *Intensity of mass spectral peaks: 251 M/z (100%), 139 M/z (97%), 253 M/z (65%), 111 M/z (35%) [R23] VAP: *2.2X10-6 mm Hg @ 20 deg C [R24] OCPP: *TECHNICAL PRODUCT IS BROWNISH LIQUID; DENSITY, 1.2816 AT 20 DEG C/D (ABOUT 93% PURE) /TECHNICAL GRADE/ [R20] *Chlorobenzilate is hydrolyzed by alkali and by strong acids to the inactive p,p'-dichlorobenzilic acid and ethanol [R5] *Incompatible with lime [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of chlorobenzilate stem from its toxicologic properties as an organochlorine pesticide. Its acute effects ranging from vomiting and diarrhea to convulsions, and respiratory failure, may be exerted from all routes of exposure (ie, dermal, inhalation, or ingestion). Also, the use of chlorobenzilate has been restricted because of its possible oncogenic and adverse testicular effects. For those uses that are not restricted (ie, certain pesticidal applications) precautions should be taken that include wearing one-piece overalls made of finely woven fabric (eg, jersey), a wide-brimmed hat, heavy duty fabric work gloves, and a facepiece respirator suitable for pesticide spray applications. (Alternatively, the applicator may employ an enclosed tractor cab provided with a filtered air supply.) In addition, heavy duty rubber or neoprene gloves and apron should be worn during loading, unloading, and equipment clean-up. Strict adherence to personal hygiene should be maintained, including the daily cleaning of protective equipment and clothing, and washing of exposed skin with soap and water before eating and at the end of the work day. Chlorobenzilate will not ignite easily, but it will burn with the possible evolution of irritating or poisonous gases. For small fires involving chlorobenzilate, extinguish with dry chemical, CO2, water spray, or foam, and for large fires, use water spray, fog, or foam. Runoff from fire control water may give off poisonous gases or cause water pollution and should therefore, be controlled (eg, diked for later disposal). Chlorobenzilate should be stored in a dry place, away from alkali or strong acids. Small spills of chlorobenzilate should be transferred with a shovel to a clean, dry container such as a vapor-tight plastic bag (liquid spills are absorbed by non-combustible material, like sand), where as dry spills are first dampened with alcohol). Contaminated surfaces are then washed well with soap and water. For large spills, first dike to prevent runoff. Before land disposal of chlorobenzilate, consult with environmental regulatory agencies. Alternatively, chlorobenzilate is a good candidate for liquid injection or rotary kiln incineration. DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Organochlorine pesticide, liquid, flammable, poisonous; Organochlorine pesticide, liquid, flammable, toxic; Organochlorine pesticide, liquid, poisonous, flammable; Organochlorine pesticide, liquid, toxic, flammable/ [R25, p. G-131] +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Organochlorine pesticide, liquid, poisonous; Organochlorine pesticide, liquid, toxic; Organochlorine pesticide, solid, poisonous; Organochlorine pesticide, solid, toxic/ [R25, p. G-151] DCMP: *Emits toxic fumes of /hydrogen chloride/ when heated to decomposition. [R26] SERI: *Irritation of eyes and skin. [R26] EQUP: *It is particularly important to protect the skin from contamination through the proper use of protective clothing and gloves. Where indicated respiratory protective equipment or ... /NIOSH approved breathing apparatus/ or combined respirators, should be used. /Pesticides, halogenated/ [R27] *Required clothing and equipment for application: A) Fine weave cotton fabric (jersey), one-piece jumpsuit, long sleeves; B) Wide brimmed hat; and C) Heavy duty fabric work gloves. Also, instead of the above specified clothing and equipment, the applicator can use an enclosed tractor cab which provides positive-pressure and a filtered air supply. [R28] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering, and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R29, 1979.8] OPRM: *Wash hands with soap and water each time before eating, drinking, or smoking. At the end of each work day, bathe entire body with soap and plenty of water. Wear clean clothes each day, and launder before reusing. [R28] *Avoid breathing vapors or spray mist; Take special care to avoid getting chlorobenzilate in the eyes, on skin, or on clothing. If chlorobenzilate gets on clothing, remove contaminated clothing and wash affected parts of body with soap and water. If the extent of contamination is unknown, bathe the entire body thoroughly, and change to new clothing. [R28] *... A thorough daily cleansing of the clothes and the personal protective equipment should be organized. ... Personal hygiene should include regular hand washing before meals and washing of the body at the end of the working day. /Pesticides, halogenated/ [R27] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R29, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R29, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R29, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used. ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R29, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs. ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R29, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R29, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R29, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing, and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R29, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R29, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *Acaraben 4E shelf life of at least 3 to 5 years when stored in a dry place and minimum storage temperatures (above 32 deg F) are observed. [R30] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R31] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R32] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R33] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R29, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R29, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R29, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms. ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal. ... The plastic bag should be sealed immediately. ... The sealed bag should be labelled properly. ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated. ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R29, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U038, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R34] *Incineration in a unit equipped with an effluent gas scrubber to absorb hydrogen chloride. Incineration temp above 1200 deg C for 1-2 sec. Recommendable method: Incineration. [R35] *Chlorobenzilate is easily hydrolyzed in strong alkali or acid. The dichlorobenzilic acid is unstable and readily decarboxylates. (ClC6H4)2COH COOC2H5 + NaOH --- > (ClC6H4)2COHCOONa + C2H5OH; (ClC6H4)2COHCOOC2H5 + H+ --- > (ClC6H4)2CO + CO2 + H2O + C2H5OH. Chlorobenzilate is dehalogenated by sodium in isopropyl alcohol. The organic products have not been identified. Incineration is the best method to dispose of chlorobenzilate. The incinerator must be equipped with an effluent gas scrubber to absorb hydrogen chloride. Incineration temp above 1000 deg C for 1-2 sec. Recommendable method: Incineration. Not recommendable method: Hydrolysis. Peer-review: Hydrolysis yields p,p'-dichlorobenophenone which is more toxic than chlorobenzilate. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R35] *Good candidate for liquid injection incineration process at 650 to 1,600 deg C with a residence time of 0.1 to 2 seconds. Good candidate for rotary kiln incineration at 820 to 1,600 deg C with a residence time of seconds for liquids and gases, and hours for solids. [R36] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R37] *Group II Containers: Noncombustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal, or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R37] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R29, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R29, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R29, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R29, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R29, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *The Carcinogen Assessment Group in EPA's Research and Development Office has evaluated ethyl 4,4-dichlorobenzilate for carcinogenicity. According to their analysis, the weight of evidence for ethyl 4,4-dichlorobenzilate is group B2, which is based on inadequate evidence in humans and sufficient evidence in animals. As a group B2 chemical, ethyl 4,4-dichlorobenzilate is considered a probable human carcinogen. [R38] *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R39] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Lindane and related compounds/ [R40] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's to maintain hydration and adequate urine flow. Watch for signs of fluid overload and pulmonary edema. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Lindane and related compounds/ [R40] *Skin decontamination. Wash skin with soap and water ... . Eye contamination should be removed by prolonged flushing of the eye with copious amounts of clean water or saline. If irritation persists, specialized medical treatment should be obtained. [R41] *Gastrointestinal decontamination. If a large amount of chlorobenzilate was ingested within a few hours prior to treatment, consider gastrointestinal decontamination ... . If the absorbed dose of chlorobenzilate was small, if treatment is delayed, and if the patient is asymptomatic, oral administration of activated charcoal and sorbitol may be indicated. Do not give fats or oils. [R41] MEDS: *Chlorobenzilate and its metabolites, present in the urine of exposed workers, can be oxidized to p,p'-dichlorobenzophenone, and this can be used to monitor human exposure. [R42] *Medical supervisory preemployment and periodical medical examination should be designed to ... /protect persons/ who should not work with organochlorine pesticides, because of illness of nervous system, liver, blood ... . /Organochlorine pesticides/ [R27] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R29, 1979.23] HTOX: *One case of systemic poisoning due to exposure to chlorobenzilate was reported in a worker involved in mixing and spraying the compound on trees; he developed muscle pains, ataxia, mild delirium and fever. [R42] *ABNORMAL EEG RECORDS OBTAINED IN 16 CASES (21.9%) OF 73 WORKMEN CONTINUOUSLY EXPOSED TO CHLORINATED INSECTICIDES. MOST SEVERE CHANGES WERE OBSERVED IN GROUP EXPOSED FOR 1-2 YR. CHLOROBENZILATE WAS ONE OF THE COMPOUNDS INVOLVED. [R43] *Organochlorine pesticides cause liver and kidney damage. Microsomal enzyme induction has been observed and increased alkaline phosphatase and aldolase activity have also been reported. Protein synthesis, lipid synthesis, detoxification, excretion, and liver functions are all affected. /Organochlorine pesticides/ [R27] *There has been one case in humans of toxic encephalopathy following spraying in a field for 14 days at 10 hours per day. The patient did not wear a mask while spraying. His symptoms included muscle pain, weakness, fever, and mental status changes progressing to a tonic-clonic seizure. He recovered without sequelae within 6 days. [R41] NTOX: *IN 2 YR FEEDING TRIALS NO EFFECT LEVEL WAS: RATS 40 MG/KG DIET (ABOUT 2.7 MG/KG DAILY); DOGS 500 MG/KG DIET (ABOUT 16.0 MG/KG DAILY). [R6] */FOR/ ... RATS ... THE MAX TOLERATED CONCN /OF TECHNICAL CHLOROBENZILATE/ IN THE DIET FOR CONTINUOUS EXPOSURE IS 540 PPM. SIGNS OF POISONING INCL DEPRESSION WITH SALIVATION, LACRIMATION, AND DIARRHEA, ACCOMPANIED BY DEEP RAPID RESPIRATION. AUTOPSY REVEALS ... INTESTINAL IRRITATION AND HEMORRHAGE IN THE LUNG. [R44] *Dogs tolerated daily oral doses of 64 mg/kg body wt for 35 wk, and rats, 500 mg/kg in the diet for 2 yr. In female Wistar rats 100 mg/kg chlorobenzilate in the diet for 4 wk produced liver enlargement. In the chronic feeding studies ... /of male and female C57BL/6 and B6C3F1 mice and Osborne-Mendel rats/ there was a dose related depression in mean body wt in both species, and testicular atrophy was observed in male Osborne-Mendel rats fed 1600 or 3200 mg/kg in the diet (time weighted avg concn over 78 wk for the high dose: 2995 mg/kg). [R45] *... GROUPS OF 20 CF RATS OF EACH SEX WERE FED DIETS CONTAINING ... 0, 50 (MALES ONLY), OR 500 PPM TECHNICAL CHLOROBENZILATE FOR 2 YR. SOME 13-14 RATS/TREATMENT GROUP AND 12-16 MALE AND FEMALE CONTROLS WERE ALIVE AT END OF EXPT. TUMORS OCCURRED SPORADICALLY IN TREATED AND CONTROL ANIMALS. /THUS CHLOROBENZILATE WAS NOT TUMORIGENIC IN THIS STUDY/. [R46] *Groups of 18 male and 18 female (C57BL/6XC3H/Anf)F1 and the same numbers of (C57BL/6XAKR)F1 mice were treated with chlorobenzilate (purity, 99.3%) as follows: At the age of 7 days they received by gavage a single dose of 215 mg/kg body wt in 0.5% gelatin. Not taking into account subsequent wt gains, this treatment was repeated daily until the animals were weaned, at the age of 4 weeks. Then chlorobenzilate, mixed into the diet to give a final concn of 603 mg/kg, was fed until the animals were 83 weeks. (The dose was the maximum tolerated dose for infant and young mice but not necessarily that for adults). Appropriate negative (vehicle or untreated) and positive (using 7 known carcinogens) controls were also included in the study. Hepatomas were found in mice of both strains, but only in males, the incidence being 9/17 in (C57BL/6XC3H/Anf)F1 mice compared with 8/79 in male controls and 7/17 in C57BL/6XAKR)F1 mice compared with 5/90 in male controls. The incidences of other neoplasms (ie, pulmonary tumors and lymphomas) were similar in both treated and control animals. (The Working Group noted that the slides of this study were reviewed and reinterpreted. Apart from differences concerning the terminology of hepatic and pulmonary tumors, gastric lesions were also reported. Of female (C57BL/6XC3H/Anf)F1 mice receiving chlorobenzilate, 10/18 animals developed carcinomas of the forestomach, while in controls papillomas of the forestomach (6/17) but no carcinomas were detected.) [R47] *CHLOROBENZILATE IS CARCINOGENIC IN RATS AND MICE. MALIGNANT NEOPLASMS AT ALL SITES WERE INCREASED IN TREATED MICE AND RATS. ENDOCRINE NEOPLASMS, ESPECIALLY OF THE THYROID GLAND IN MALES AND THE PITUITARY GLAND IN FEMALES, WERE INCREASED. NEOPLASMS OTHER THAN THOSE IN THE STOMACH WERE ADENOCARCINOMAS OF THE LUNG AND RETICULUM CELL SARCOMAS. ATROPHY OF TESTES WAS MARKEDLY INCREASED IN MICE AND RATS AND THROMBOSIS WAS ALSO NOTED. DOGS DEVELOPED CARDIAC CHANGES, SUCH AS VENTRICULAR HYPERTROPHY, HEART BLOCK, OR EXTRAVENTRICULAR SYSTOLES, AS WELL AS ARTERIOSCLEROSIS OF THE PULMONARY ARTERY WHEN TREATED OVER A 2-YEAR PERIOD. [R48] *Groups of 50 male and 50 female B6C3F1 mice, approx 6 weeks old, were fed chlorobenzilate (technical-grade, purity at least 90%; impurities not specified) dissolved in corn oil and mixed into a powdered diet. Preliminary experiments failed to establish chlorobenzilate levels in feed that were well tolerated during the entire course of the study; hence, in order to ascertain adequate survival rates, treatment had to be interrupted repeatedly. There were several exposure levels: Males were maintained on feed containing chlorobenzilate at concn of 6000 mg/kg of diet for 9 wk and 4000 mg/kg of diet for the subsequent 69 wk (referred to as 'low dose'), for a time weighted avg concn of 4231 mg/kg of diet; 'high dose' males received 12,000 mg/kg for 9 wk and 8000 mg/kg continuously for the subsequent 43 weeks and with interruptions for the following 26 weeks (ie, 1 wk on control diet alternated with 4 wk of chlorobenzilate feeding), to give a time weighted avg concn of 7846 mg/kg of diet. Low dose females received feed containing chlorobenzilate at a concn of 3200 mg/kg continuously for 78 wk; high dose females received 6400 mg/kg for the same period and with the same schedule of interruptions as ... for the high dose males, to give a time weighted avg concn of 5908 mg/kg. For the remaining 12 (males) or 13 (females) wk of the study, control diet (powdered chow supplemented with 2% corn oil) was fed. Twenty addnl mice of each sex, serving as controls, received this feed for the entire duration of the 90-wk bioassay. A significantly increased incidence of hepatocellular carcinoma was found in animals of both sexes at all levels of chlorobenzilate exposure: males, 4/19 controls, 32/48 low dose (p= 0.001), 22/45 high dose (p= 0.034); females, 0/20 controls, 11/49 low dose (p= 0.016), 13/50 high dose (p= 0.007) (p values calculated by the Fisher exact test). [R47] *Groups of 18 male and 18 female(C57BL/6 X C3H/Anf)F1 mice and 18 male and 18 female (C57BL/6 X AKR)F1 mice were given single sc injections of 1000 mg/kg body wt chlorobenzilate (93% pure) in dimethyl sulfoxide on the 28th day of life and were observed until they were 78 wk of age, at which time 16, 16, 16 and 18 mice were still alive in the 4 groups, respectively. Several control groups comprised untreated animals and animals treated with gelatine, corn oil or dimethyl sulfoxide. No significant increase in the incidence of tumors was observed in treated animals compared with controls. (The Working Group noted that a negative result following a single sc injection of a compound is not an adequate basis for discounting carcinogenicity.) [R49] *MUTAGENICITY ASSAYS WITH CHLOROBENZILATE GAVE NEGATIVE RESULTS. THE FOLLOWING TESTS WERE USED: 1. LIQUID HOLDING TEST- MITOTIC GENE CONVERSION IN SACCHAROMYCES CEREVISIAE; 2. LIQUID HOLDING TEST- FORWARD MUTATION TO STREPTOMYCIN RESISTANCE IN ESCHERICHIA COLI; and 3. SPOT TEST- BACK MUTATION IN SERRATIA MARCESCENS AND FORWARD MUTATION IN ESCHERICHIA COLI. [R50] *CHLOROBENZILATE CAUSED MARGINAL AND/OR INTERVEINAL BROWNING OF LEAVES ON MOST CROPS SPRAYED WITH 200, 1000, and 5000 PPM IN EMULSIONS OR SUSPENSIONS. [R51] *The use of chlorobenzilate has been restricted in the United States because the compound is oncogenic in rats and mice and causes adverse testicular effects in male rats after repeated exposures. [R52] *A 25% water dispersible powder of chlorobenzilate was mixed into a diet to give concn of 25 or 50 mg/kg chlorobenzilate, and the diet was fed to male and female rats for 3 generations (two matings per generation). The numbers of pups at birth and weaning from 2 litters of each generation, the number of uterine implants and the body wt of the progeny showed no significant deviation from control values. No teratogenic change was observed in the offspring. [R45] *Chlorobenzilate (purity not specified), without exogenous metabolic activation, did not induce reverse mutation in the two autotrophic strains a21 and a742 of Serratia marcescens or induce forward mutations to galactose protrophy (details not given) or to streptomycin resistance in Escherichia coli. Chlorobenzilate (equal to or less than 97% pure) did not induce reverse mutations in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 or TA100 with or without an Aroclor-induced rat liver microsomal preparation. Chlorobenzilate did not induce mitotic gene conversion at the ade 2 or trp 5 loci of Saccharomyces cerevisiae (details not given). [R45] *Chlorobenzilate was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Chlorobenzilate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.001, 0.003, 0.0033, 0.010, 0.033, 0.100, 0.333, 0.3333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any S typhimurium strain was 10.000 mg/plate. Precipitate was observed in some cultures at the high dose. [R53] *Based on observation of dosed animals, extreme absorbed doses may cause tremors, ataxia, and muscle weakness. [R41] *The organochlorine pesticide 1,1'-(2,2,2-trichloroethylidene) bis(4-chlorobenzene) (DDT) and four structural analogues (bromopropylate, chlorobenzilate, dicofol and fenarimol) were investigated for their ability to inhibit gap junctional intercellular communication both in the Chinese hamster V79 metabolic co-operation assay and in the scrape-loading/dye-transfer assay in WB-F344 rat liver epithelial cells. The pesticides were also studied for their ability to enhance the development of gamma-glutamyltranspeptidase-positive altered hepatic foci and induce cytochrome p450 monooxygenase isoenzymes in nitrosamine-initiated male Sprague-Dawley rats. The in vitro studies showed all organohalogens except fenarimol to be potent inhibitors of cell-cell communication in both test systems used. Concomitant results were recorded in the vivo study. Thus, all potent inhibitors of intercellular communication were found to enhance significantly foci development and fenarimol was again without any significant effect. All pesticides studied were shown to be potent inducers of the phenobarbital-inducible cytochrome p450 isoenzyme and to cause hepatomegaly. Thus, no strict correlation between cytochrome p450b induction/liver growth and tumor promotion-related effect in vivo and in vitro was apparent for these organhalogen pesticides in the present study. [R54] NTXV: *LD50 Rat oral 2784-3880 mg/kg; [R55] *LD50 Rabbit percutaneous > 10,000 mg/kg; [R55] *LD50 Rat male oral 1040 mg/kg; [R56] *LD50 Rat female oral 1220 mg/kg; [R56] *LD50 RAT 40 MG/KG DIET; [R6] *LD50 DOG 500 MG/KG DIET; [R6] *LD50 Rat oral 2,784-3,880 mg/kg; [R26] ETXV: *LC50 SALMO GAIRDNERI (RAINBOW TROUT) 0.7 MG/L/96 HR AT 13 DEG C, WT 0.8 G, STATIC BIOASSAY; [R57] *LC50 Colinus virginianus (bobwhite quail) 3375 ppm/7 days /From table/; [R58] *LC50 Anas platyrhynchos (mallard duck) > 8000 ppm/5 days /From table/; [R58] *LC50 Cyprinodon variegatus (sheephead minnow) 1.0 mg/l/48 hr /From table/ /Conditions of bioassay not specified/; [R58] *LC50 Rainbow trout oral 0.6 mg/l/96 hr; [R26] *LC50 Bluegill sunfish oral 1.8 mg/l; [R26] NTP: *A bioassay of technical grade chlorobenzilate for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Chlorobenzilate was administered in the feed, at either two concentrations, to groups of male and 50 female animals of each species. Chlorobenzilate was administered for 78 wk followed by an observation period of 12 or 13 wk in mice and 32 or 33 additional wk in rats. The time weighted average dietary concentrations of chlorobenzilate were 2,995 and 1,600 ppm for high and low dose male rats, respectively, and 2,229 and 1175 ppm for high and low dose female rats. Mice received time weighted average high and low dietary concentrations of 7,846 and 4,231 ppm, respectively, for males and 5,908 and 3,200 ppm, respectively, for females. ... Under the conditions of this bioassay, orally administered chlorobenzilate was carcinogenic in male and female B6C3F1 mice, causing an increased incidence of hepatocellular carcinomas. ... Chlorobenzilate /was not carcinogenic/ in Osborne-Mendel rats. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal; Female Rats: Equivocal; Male Mice: Positive; Female Mice: Positive. [R59] POPL: *... Individuals with /diseases/ of the nervous system, liver, or blood /should be protected from exposure to/ organochlorine pesticides. /Organochlorine pesticides/ [R27] ADE: *WHEN DAILY DOSES OF 12.8 MG/KG BODY WT WERE GIVEN ORALLY TO MALE MONGREL DOGS 5 DAYS A WK FOR 35 WEEKS, APPROX 40% OF THE TOTAL DOSE WAS EXCRETED UNCHANGED OR AS METABOLITES IN THE URINE. NO SIGNIFICANT STORAGE OF CHLOROBENZILATE WAS REPORTED IN THE DEPOT FAT OF RATS OR DOGS. [R45] *BENZILATE ACARICIDES APPLIED TOPICALLY TO SOYBEAN LEAVES. ANALYSIS OF TREATED LEAVES REVEALED THAT COMPOUNDS WERE QUITE STABLE AND ... TRANSLOCATED TO OTHER PLANT TISSUE TO LIMITED EXTENT. /BENZILATE ACARICIDES/ [R60] *ADULT MALE RATS FED LABELED CHLOROBENZILATE EXCRETED 42.78% OF THE TOTAL RECOVERED RADIOACTIVITY IN THE FECES AND 25.63% IN THE URINE, AND 15.47% WAS FOUND IN THE GI TRACT AND 3.31% IN THE LIVER. [R61] *Residues of the acaricide chlorobenzilate were determined in 35 urinary collections obtained from 5 male citrus grove field workers over a period of 23 days. During spray operations, the workers rode in tractors covered only by a canopy, and wore no protective gear (respirators, or face masks). Chlorobenzilate was analyzed as p,p'-dichlorobenzophenone (DPB) by a gas chromatographic method (limit of detection 2 ppb; avg recovery 97%). Urinary values obtained from workers ranged from 0.07 to 6.2 ppm, with an overall avg value of 1.3 ppm. By comparison, non-exposed humans averaged < 0.01 ppm urinary p,p'-dichlorobenzophenone. [R62] *Although structurally similar to DDT, chlorobenzilate is much more rapidly excreted following absorption, chiefly in the urine as the benzophenone and benzoic acid derivatives. [R41] *WHEN DISSOLVED IN OIL OR OTHER LIPID, THEY ARE ALL READILY ABSORBED BY THE SKIN AND ALIMENTARY CANAL. /CHLORINATED HYDROCARBON INSECTICIDES/ [R63] METB: *Chlorobenzilate is metabolized by rat liver homogenates to para,para'-dichlorobenzilic acid; para, para'-dichlorobenzyhydrol; para-chlorobenzoic acid, and para, para'-dichlorobenzophenone. [R45] *CHLOROBENZILATE WAS ACTIVELY METABOLIZED BY /RAT/ LIVER FRACTIONS. MAJOR METABOLITES WERE DICHLOROBENZOPHENONE AND CHLOROBENZOIC ACID. DICHLOROBENZILIC ACID, DICHLOROBENZHYDROL, AND THREE UNIDENTIFIED COMPOUNDS WERE ALSO FOUND. [R60] *YEAST RHODOTORULA GRACILIS METABOLIZED CHLOROBENZILATE ... ARISING ... WERE 4,4'-DICHLOROBENZILIC ACID AND 4,4'-DICHLOROBENZOPHENONE. USING (14)C-CHLOROBENZILATE ... LABELED AT CARBOXYL GROUP, (14)CO2 WAS OBTAINED. THE MAJOR STEPS APPEAR TO BE HYDROLYSIS FOLLOWED BY DECARBOXYLATION. [R60] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Chlorobenzilate's former production and use as an acaricide has resulted in its direct release to the environment. If released to air, a vapor pressure of 2.20X10-6 mm Hg at 20 deg C indicates chlorobenzilate will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase chlorobenzilate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3.2 days. Particulate-phase chlorobenzilate will be removed from the atmosphere by wet and dry deposition. If released to soil, chlorobenzilate is expected to have low mobility based upon an estimated Koc of 1100. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 7.2X10-8 atm-cu m/mole. The half-life of chlorobenzilate in two fine sandy soils was estimated to be 1.5-5 weeks following application of 0.5-1.0 ppm; removal was probably microbial. If released into water, chlorobenzilate is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Chlorobenzilate was reported to mineralized to 14-CO2 in water only if soil or sediment was added to the samples. Measured BCF values for carp (Cyprinus carpio) range from 224 to 586 and 256 to 709 at concentrations of 20 ug/l and 2 ug/l, respectively. These BCF values suggest bioconcentration in aquatic organisms is high. Estimated hydrolysis half-lives are 820 and 82 years at pH values of 7 and 8, respectively. Occupational exposure to chlorobenzilate may have occurred via inhalation and also through dermal contact with this compound at workplaces where chlorobenzilate was formerly produced or used. Monitoring data indicate that the general population may have been exposed to chlorobenzilate via ingestion of contaminated. (SRC) NATS: *Chlorobenzilate is not known to occur as a natural product(1). [R64] ARTS: *Chlorobenzilate's former production(3) and use as an acaricide on crops(1,2) resulted in its direct release to the environment(SRC). [R65] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1100(SRC), determined from a measured water solubility of 13 mg/l(2) and a regression-derived equation(3), indicates that chlorobenzilate is expected to have low mobility in soil(SRC). Volatilization of chlorobenzilate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.2X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 2.20X10-6 mm Hg(4), and water solubility, 13 mg/l(2). Chlorobenzilate is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). The half-life of chlorobenzilate in two fine sandy soils was estimated to be 1.5-5 weeks following application of 0.5-1.0 ppm; removal was probably microbial(5). Half-lives for chlorobenzilate in Lukang silty clay loam and Pincheng clay ranged from 15.1 days at 10 deg C to 10.8 days at 25 deg C; and 169.1 days at 10 deg C to 29.5 days at 25 deg C, respectively(6). [R66] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1100(SRC), determined from a measured water solubility of 13 mg/l(2) and a regression-derived equation(3), indicates that chlorobenzilate is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 7.2X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 2.20X10-6 mm Hg(4), and water solubility, 13 mg/l(2). In 22 days, 40, 29, and 39% of the (14)C-ring-labeled chlorobenzilate added to sediment free water samples from 3 fresh water lakes was converted to organic products; no (14)CO2 evolution was detected(5). Addition of sediment to the water samples from the three lakes gave (14)CO2 yields 3.6, 0.0, and 18.3%(5). Chlorobenzilate was metabolized in water from another freshwater lake only when glucose and inorganic nutrients were added; and mineralized to (14)CO2 only when sediment was added to the water(5). According to a classification scheme(6), measured BCF values for carp (Cyprinus carpio) ranging from 224 to 586, and 256 to 709 at concentrations of 20 ug/l and 2 ug/l(7), respectively, suggest bioconcentration in aquatic organisms is high. [R67] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), chlorobenzilate, which has a vapor pressure of 2.20X10-6 mm Hg at 20 deg C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase chlorobenzilate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3.2 days(SRC), calculated from its rate constant of 5.1X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Particulate-phase chlorobenzilate may be removed from the air by wet and dry deposition(SRC). [R68] BIOD: *AEROBIC: The half-life of chlorobenzilate in two fine sandy soils was estimated to be 1.5-5 weeks following application of 0.5-1.0 ppm; removal was probably microbial(1). It is decarboxylated to 4,4'-dichlorobenzophenone by a yeast isolated from insecticide treated soil under anaerobic conditions(2,3). In 22 days, 40, 29, and 39% of the (14)C-ring-labeled chlorobenzilate added to sediment-free water samples from 3 fresh water lakes was converted to organic products; no (14)CO2 evolution was detected(4). Addition of sediment to the water samples from the three lakes gave (14)CO2 yields 3.6, 0.0, and 18.3%(4). Chlorobenzilate was metabolized in water from another freshwater lake only when glucose and inorganic nutrients were added and mineralized to (14)CO2 only when sediment was also added to the water(4). Chlorobenzilate, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(5). Half-lives for chlorobenzilate in Lukang silty clay loam and Pincheng clay ranged from 15.1 days at 10 deg C to 10.8 days at 25 deg C; and 169.1 days at 10 deg C to 29.5 days at 25 deg C, respectively(6). [R69] ABIO: *The rate constant for the vapor-phase reaction of chlorobenzilate with photochemically-produced hydroxyl radicals has been estimated as 5.1X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of approximately 3.2 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). A base-catalyzed second-order hydrolysis rate constant of 2.7X10-4 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 820 and 82 years at pH values of 7 and 8, respectively(2). The half-life for chlorobenzilate in distilled water, and also from a glass surface in winter, has been reported to be 1,000 days in both cases(3). Chlorobenzilate is hydrolyzed by alkali and by strong acids to the inactive p,p'-dichlorobenzilic acid and ethanol(4). Aqueous solutions of chlorobenzilate at pH 8 irradiated in the laboratory with a sunlamp for 24 to 137 hr decomposed to 4,4'-dichlorobenzophenone and other unidentified polar products(5). The same solutions were exposed to sunlight for 10 to 60 days; no decomposition was shown under these milder conditions(5). This is understandable since the tail of the UV absorption curve extends to about 290 nm(6), the longest wavelength UV radiation in sunlight. [R70] BIOC: *Measured BCF values for carp (Cyprinus carpio) ranged from 224 to 586 and 256 to 709 at concentrations of 20 ug/l and 2 ug/l, respectively(1). According to a classification scheme(2), these BCFs suggest the potential for bioconcentration in aquatic organisms is high. [R71] KOC: *The Koc of chlorobenzilate is estimated as 1100(SRC), determined using a measured water solubility of 13(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that chlorobenzilate is expected to have low mobility in soil. [R72] VWS: *The Henry's Law constant for chlorobenzilate is estimated as 7.2X10-8 atm-cu m/mole(SRC) derived from its vapor pressure, 2.20X10-6 mm Hg(1), and water solubility, 13 mg/l(2). This Henry's Law constant indicates that chlorobenzilate is expected to be essentially nonvolatile from water surfaces(3). Chlorobenzilate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 2.20X10-6 mm Hg(1). [R73] WATC: *GROUNDWATER: According to the STORET database, chlorobenzilate was detected at 260 unspecified stations in the US (323 samples) at a concentration of 0-66.0 ug/l, 0.44 ug/l avg(1). Chlorobenzilate rapidly dissipated at pH 9.0, but only less than 20% dissipated at pH 5.0; using a groundwater pollution potential model, these results suggest that chlorobenzilate could not lead to contamination of groundwater under normal conditions(2). [R74] SEDS: *SOIL: Chlorobenzilate was detected, not quantified, in soil in citrus orchards in Korea(1). SEDIMENT: According to the STORET database, chlorobenzilate was detected in 63 unspecified mud samples in US at a concentration range of 17-530 ppb, with an average of 39.2 ppb(2); it was detected in 3 unspecified sediment samples in the US at 80-200 ppb, with an average of 127 ppb(2). [R75] FOOD: *The U.S. Total Diet Study has analyzed food composite samples for chlorobenzilate residues(1-4). In adult total diet samples, chlorobenzilate was detected in one of 20 composites of fruits collected from 20 cities between Oct 1979-Sept 1980 at a concn of 4 ppb(1) and in 4 of 27 composites of fruits collected from 27 cities between Oct 1980-March 1982 at a concn range of 2-6 ppb(2). In infant and toddler total diet samples, chlorobenzilate was detected in one of 10 composites of fruits collected from 10 cities between Oct 1979-Sept 1980 at a concn of 2 ppb(3) and in one of 13 composites of fruits collected from 13 cities between Oct 1980-March 1982 at a concn of 2 ppb(4). Chlorobenzilate was not detected in composites of food groups other than fruit/fruit juices(1-4). Chlorobenzilate was detected, not quantified, in 2% of the samples of total diet foods collected from April 1982-April 1984 in 8 collections representing the diets of 8 populations(5). Chlorobenzilate was detected in 2 of 6391 domestic agricultural commodities in a survey conducted by surveillance sampling, Oct 1981-Sept 1986; the concn of the positive samples fell into the > 0.50 to 1.0 ppm and the > 1.0 to 2.0 ranges(6). [R76] *Chlorobenzilate residue was detected at a maximum residue concentration of 3.2 ppm in 2 of 862 orange surveillance samples collected for the FDA regulatory monitoring of domestic foods which may be eaten by infants/children between 1985 and 1991(1). Chlorobenzilate was detected at an average concn of 0.0045 ug/g in 7 of 234 ready-to-eat foods tested repeatedly for 10 years through the U.S. Food and Drug Administrations's Revised Market Basket Study from 1982 to 1991(2). Data contributed from 10 state food laboratories (CA, FL, IN, MA, MI, NC, NY, OR, VA, WI) for the FOODCONTAM database indicated that chlorobenzilate was detected, not quantified, in 10 (0.071%) of 13,980 food samples in fiscal year 1988; and in 20 (0.152%) of 13,980 food samples in fiscal year 1989(3). Chlorobenzilate has been found in pears at concn ranging from 0.2 to 1.5 ppm(4). The concn in apples treated once with a 62 g/100 ml solution of chlorobenzilate after 1,8, and 39 days were 4.98, 4.33 and 0.9 ppm, respectively(4). The residues in apples and citrus fruits was found exclusively in the peel where its concn decreased slowly(4). Chlorobenzilate was detected (number of positive samples not identified) in a surveillance study conducted in 1992, consisting of 16,428 (7,777 domestic and 8,651 imported) samples analyzed under regulatory monitoring(5). [R77] MILK: *Chlorobenzilate was not detected in milk in US(1). [R78] OEVC: *Residues of this insecticide have been measured in some samples of animal feeds in the US: in silage, 0.51-1.50 mg/kg; in processed animal feed (fruit by products), 0.11-2.01 mg/kg; and in animal feed made from Florida citrus pulp, 0.39-2.02 mg/kg. [R79] RTEX: *... Dermal and inhalation routes. [R3] *The greatest potential for exposure to chlorobenzilate appears to be among persons associated with its production, formulation, and agricultural application. [R80] *Occupational exposure to chlorobenzilate may have occurred through inhalation and dermal contact with this compound at workplaces where chlorobenzilate was formerly produced or used as an acaricide(SRC). Approximately 650-1250 spray applicators and 25-400 citrus fruit pickers in Florida were exposed to chlorobenzilate in 1978(1,2). Monitoring data indicate that the general population may have been exposed to chlorobenzilate via ingestion of contaminated food, ingestion of contaminated groundwater at locations dependent on drinking water from wells, and dermal contact with this compound(SRC). [R81] AVDI: *Based on data on exposure to ground applicators and citrus pickers during application of other pesticides, the daily dose to such workers exposed to chlorobenzilate has been estimated to be 12-40 mg dermal, and 1 mg inhalation(1,2). Pesticide intakes found in FOA/WHO and also EPA total diet study analyses: 20 (0.005% of ADI) ug/kg body wt/day(3). Specific ADI values for 8 age/sex groups estimated from 1986 to 1991 are as follows: 6-11 mo old, 0.0030; 2 yr old, 0.0044; 14-16 yr old female, 0.0008; 14-16 yr old male, 0.0010; 25-30 yr old female, 0.0008; 25-30 yr old male, 0.0007; 60-65 yr old female, 0.0008; 60-65 yr old male, 0.0005 ug/kg body wt/day(3). [R82] BODY: *Citrus grove spray applicators - urine (35 samples from 5 workers over 23 days of spray application) 0.07-6.2 ppm, 1.3 ppm avg whereas nonexposed humans average < 0.01 ppm(1). The estimated total body accumulation rates of chlorobenzilate for 11 harvesters of oranges from orange trees which had been treated with chlorobenzilate with air blast equipment ranged from 227 to 2085 ug/hr over a period of 6 days with an avg of 952 ug/hr(2). [R83] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *Because all uses of chlorobenzilate are cancelled except citrus, a recalculation of the Theoretical Maximum Residue Concentration (TMRC), Acceptable Daily Intake (ADI), and Maximum Permissible Intake (MPI) was undertaken. These values are 0.2859 mg/day/1.5 kg (3.81% of the ADI), 0.125 mg/kg/day, and 7.50 mg/day/60 kg, respectively. These values are considered provisional, since a data gap exists for a chronic feeding study. Another reassessment and recalculation of the ADI/MPI will be made when the toxicology data gaps are filled. [R3] *The Joint meeting of the FAO Working party of Experts and the WHO Expert Committee on Pesticide Residues established in December 1968 an acceptable daily intake of chlorobenzilate for human of 0 to 0.02 mg/kg body wt. [R12] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Chlorobenzilate is included on this list. [R84] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 0.13 ug/l [R85] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R86] RCRA: *U038; As stipulated in 40 CFR 261.33, when chlorobenzilate, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R87] FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Chlorobenzilate is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0072; Pesticide type: insecticide (acaricide); Registration Standard Date: 12/30/83; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Chlorobenzilate; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R88] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *DDT-type compounds may be present in the air in vapor form or adsorbed on particulate matter. Glass fiber filters are suitable for trapping the particulate matter, and DDT in the vapor form may be trapped using impingers of the Greenburg-Smith type and a suitable nonvolatile solvent using ethylene glycol. /DDT type compounds/ [R89] ALAB: *A GAS LIQUID CHROMATOGRAPHY METHOD FOR THE DETERMINATION OF CHLOROBENZILATE AND CHLOROPROPYLATE IN LIQUID FORMULATIONS CONTAINING ABOUT 46% and 26% ACTIVE INGREDIENT, RESPECTIVELY, WAS COLLABORATIVELY STUDIED, USING A MATCHED PAIR SCHEME. THE SAMPLES WERE DISSOLVED IN ACETONE CONTAINING DIBENZYL SUCCINATE AS AN INTERNAL STD AND CHROMATOGRAPHED ON CARBOWAX 20M, USING FLAME IONIZATION DETECTOR. ANALYSES OF 4 SAMPLES BY 13 COLLABORATORS USING PEAK HEIGHT INSTRUMENTS SHOWED CHLOROBENZILATE AT 2.5% OVERALL COEFFICIENT OF VARIATION WITH 1.0% COEFFICIENT OF VARIATION FOR THE RANDOM ERROR, and 0.7% SYSTEMIC ERROR. THE METHOD HAS BEEN ADOPTED AS OFFICAL 1ST ACTION. [R90] *A SPECTROPHOTOMETRIC METHOD FOR DETERMINATIONS OF CHLOROBENZILATE ON CITRUS FRUITS. A GAS CHROMATOGRAPHIC METHOD FOR THE ANALYSES OF CHLOROBENZILATE IN GRAPES AND COTTON SEED. [R91] *Colorimetric method for the analysis of chlorobenzilate in surface of fruits. Extract; saponify; nitrate. Limit of detection 2 ug Chlorobenzilate. [R79] *Gas chromatography with electron capture detection method for the determination of chlorobenzilate in sediment. Dry; chromatograph; extract; chromatograph (Florisil). The limit of detection is not given. [R79] *AOAC Method 971.08. Triazines in Pesticide Formulations by Gas Chromatographic Method. [R92] *ANALYTICAL METHODS FOR ORGANOCHLORINE PESTICIDES ARE PRESENTED AND RECOMMENDATIONS ARE MADE FOR IMPROVING CLEANUP PROCEDURES FOR ORGANOCHLORINE PESTICIDES SUCH AS CHLOROBENZILATE IN FRUITS AND NUTS. A MINIATURIZED EXTRACTION AND CLEAN-UP PROCEDURE IS RECOMMENDED FOR STUDYING ORGANOCHLORINE PESTICIDES IN FISH. IMPROVEMENT OF A SAPONIFICATION CLEAN-UP METHOD IS DESCRIBED. [R93] *FDA Method 211.1. Organochlorine Residues (Nonionic) General Method for Fatty Foods Including Extraction of Fat, Acetonitrile Partition, Florisil Column Cleanup, Partition Chromatography Cleanup, and Supplemental Cleanup. [R94] *SFSAS Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. Capillary gas chromatography with low resolution mass spectrometry. Limit of quantitation = 2 mg/kg. [R94] *OSW Method 8270. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Estimated quantitation limit= 10 ug/l. [R94] *OSW Method 8081. Organochlorine Pesticides and PCBs. Capillary gas chromatography with electron capture detector. [R94] *EMSLC Method 608.1. The Determination of Organochlorine Pesticides in Industrial and Municipal Wastewater by Gas Chromatography with Electron Capture Detection. Estimated method detection limit= 0.2 ug/l. [R94] *EMSLC Method 508. Determination of Chlorinated Pesticides in Water by Gas Chromatography with an Electron Capture Detector. Revision 3.0. Estimated detection limit= 5 ug/l. [R94] CLAB: *A METHOD FOR DETERMINATION OF 4,4'-DICHLOROBENZOPHENONE AS AN INDICATOR OF CHLOROBENZILATE RESIDUES IN URINE OF WARM BLOODED ANIMALS AND HUMANS BY GAS CHROMATOGRAPHY IS DESCRIBED. AFTER SAMPLE PREPARATION AND CLEANUP, AN ALIQUOT IS INJECTED INTO A GAS CHROM Q GAS CHROMATOGRAPH EQUIPPED WITH AN 63 NICKEL DETECTOR. AVERAGE RECOVERIES FROM FORTIFIED URINE WERE 97% WITH STD DEVIATIONS OF 9%. THE METHOD HAS BEEN USEFUL IN A CHLOROBENZILATE MONITORING STUDY. [R95] *Gas chromatography with electron capture detection method for chlorobenzilate in human or animal adipose tissue. Macerate; a sequence of extraction; chromatograph (Florisil). Limit of detection is not given. [R79] *Chlorobenzilate residues were determined in 35 urinary collections obtained from 5 male citrus grove field workers over a period of 23 days. Chlorobenzilate was analyzed as p,p'-dichlorobenzophenone (DPB) by a gas chromatographic method (limit of detection 2 ppb; average recovery 97%). [R62] *Organochlorine pesticide residues in human liver samples were determined by gas chromatography with electron capture detection on a fused silica SE-52 capillary column or by gas chromatography/mass spectrometry on a silica SE-30 wall coated capillary column with selected ion monitoring detection. /Organochlorine pesticides/ [R96] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Chlorobenzilate: Position Document 3, Office of Pesticide Programs, USEPA (1979) BARTSCH E ET AL; RESIDUE REVIEWS 39: 93 PAGES (1971). REVIEW OF CHLOROBENZILATE AND CHLOROPROPYLATE. SPEC PESTIC REVIEW DIV, ARLINGTON; CHLOROBENZILATE: POSITION DOCUMENT 4; REPORT EPA/SPRD-80/36; ORDER NO PB80-213929, 88 PAGES (1979). THE USES, ENVIRONMENTAL RESIDUES, AND HEALTH HAZARD OF CHLOROBENZILATE ARE REPORTED. Bioassay of Chlorobenzilate for Possible Carcinogenicity (1978) Technical Rpt Series No. 75 DHEW Pub No. (NIH) 78-1325, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 354 R3: Purdue University; National Pesticide Information Retrieval System (1987) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 74 (1983) R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V14 (95) 572 R6: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 162 R7: Farm Chemicals Handbook 1999. Willoughby, OH: Meister Publishing Co., 1999. R8: USEPA/OPP; Chlorobenzilate: Position Document No 3 p.1 (1979) R9: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 829 R10: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 1298 R11: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 3. New York: Marcel Dekker, Inc., 1977. 473 R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 75 (1983) R13: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Chlorobenzilate (510-15-6). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of June 14, 2000. R14: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 253 R15: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 104 R16: USEPA; National Pesticide Survey: Survey Analytes. NTIS PB 93-116010 p. 7 (1990) R17: MARICONI FAM ET AL; SOLO 71 (2): 23-8 (1979) R18: Gianessi LP; U.S. Pesticide Use Trends: 1966-1989. January 1992. Washington, DC; USEPA, Off Policy Analysis. Qual Environ Div. Resources for the Future (1992) R19: USTIC. IMPORTS OF BENZENOID CHEM AND PROD 1983 P.98 R20: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 111 R21: Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R22: Furer R, Geiger M; Pesticide Sci 8: 337-344 (1977) R23: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 110 R24: Martin H, Worthing CR; Pesticide Manual. 5th ed, British Crop Protection Council, 563 pp. (1977) R25: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000 R26: Montgomery, J.H.; Agrochemicals Desk Reference 2nd ed. Lewis Publishers, Boca Raton, FL 1997 98 R27: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1636 R28: USEPA/OPP; Chlorobenzilate: Position Document No 3 Appendix D p.1 (1979) R29: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R30: Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989.,p. C-69 R31: 49 CFR 171.2 (7/1/96) R32: IATA. Dangerous Goods Regulations. 41st Ed.Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2000. 197 R33: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3270, 6219, 6220, 6221 (1988) R34: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R35: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 108 R36: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-2 (1981) EPA 68-03-3025 R37: 40 CFR 165 (7/1/88) R38: USEPA; Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to Cercla Section 102 (Draft) p.A-54 (1986) OHEA-C-073 R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 60 (1987) R40: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 284 R41: U.S. Environmental Protection Agency/Office of Prevention, Pesticides, and Toxic Substances. Reigart, J.R., Roberts, J.R. Recognition and Management of Pesticide Poisonings. 5th ed. 1999. EPA Document No. EPA 735-R-98-003, and available in electronic format at: http://www.epa.gov/pesticides/safety/healthcare79 R42: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 81 (1983) R43: MAYERSDORF A, ISRAELI R; ARCH ENVIRON HEALTH 28 (3): 159-63 (1974) R44: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 130 R45: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 80 (1983) R46: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 78 (1974) R47: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 78 (1983) R48: REUBER MD; CLIN TOXICOL 16 (1): 67-98 (1980) R49: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 79 (1983) R50: FAHRIG R; IARC SCI PUBL 10 (CHEM CARCINOG ESSAYS, PROC WORKSHOP): 161-81 (1973, 1974) R51: ISHITANI A ET AL; NOYAKU KENSASHO HOKOKU (20): 46-50 (1980) R52: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-238 R53: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R54: Flodstorm S et al; Carcinigenesis (Eynsham) 11 (8): 1413-1418 (1990) R55: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A020/Aug 87 R56: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 298 R57: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office, 1980.82 R58: USEPA/OPP; Chlorobenzilate: Position Document No 3 Appendix B p.3 (1979) R59: Bioassay of Chlorobenzilate for Possible Carcinogenicity (1978) Technical Rpt Series No. 75 DHEW Pub No. (NIH) 78-1325, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R60: Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974.102 R61: BOURKE JB ET AL; BULL ENVIRON CONTAM TOXICOL 5 (6): 509-14 (1970) R62: Levy KA et al; Bull Environ Contam Toxicol 27 (2): 235-8 (1981) R63: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 27 R64: (1) IARC; Miscellaneous Pesticides 30: 73-85 (1983) R65: (1) IARC; Miscellaneous Pesticides 30: 73-85 (1983) (2) US EPA; National Pesticide Survey: Survey Analytes. NTIS PB 93-116010 p. 7 (1990) (3) USEPA; Status of Pesticides in Registration, Reregistration, and Special Review. Washington, DC: USEPA, Off Prev Pest Toxic Sub USEPA 738-R-98-002 p. 98 (1998) R66: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Furer R, Geiger M; Pesticide Sci 8: 337 (1977) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Martin H, Worthing CR; Pesticide Manual. 5th ed, British Crop Protection Council, 563 pp. (1977) (5) Wheeler WB et al; J Environ Qual 2: 115-8 (1973) (6) Wang YS et al; Ecotoxicol Environ Safety 28: 193-200 (1994) R67: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Furer R, Geiger M; Pest Sci 8: 337 (1977) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Martin H, Worthing CR; Pesticide Manual. 5th ed, British Crop Protection Council, 563 pp. (1977) (5) Wang YS et al; J Agric Food Chem 33: 495-9 (1985) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R68: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Martin H, Worthing CR; Pesticide Manual. 5th ed, British Crop Protection Council, pp. 563 (1977) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R69: (1) Wheeler WB et al; J Environ Qual 2: 115-8 (1973) (2) Miyazaki S et al; Appl Microbiol 18: 972-6 (1969) (3) Miyazaki S et al; J Agric Food Chem 18: 87-91 (1970) (4) Wang YS et al; J Agric Food Chem 33: 495-9 (1985) (5) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Wang YS et al; Ecotoxicol Environ Safety 28: 193-200 (1994) R70: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Okumura T; Kankyo Kagaku 1: 38-47 (1991) (4) Metcalf RL; Kirk Othmer Encycl Chem Technol. 4th. NY, NY: Wiley 14: 524-602 (1995) (5) Ware GW et al; Arch Environ Contam Tox 9: 135-46 (1980) (6) Gore RC et al; J Assoc Off Anal Chem 54: 1040-82 (1971) R71: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R72: (1) Furer R, Geiger M; Pesticide Sci 8: 337-344 (1977) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R73: (1) Martin H, Worthing CR; Pesticide Manual. 5th ed, British Crop Protection Council, pp. 563 (1977) (2) Furer R, Geiger M; Pesticide Sci 8:337-344 (1977) R74: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Wang YS et al; Ecotoxicol Environ Safety 28: 193-200 (1994) R75: (1) IARC; Miscellaneous Pesticides 30: 73-85 (1983) (2) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R76: (1) Gartrell MJ et al; J Assoc Off Anal Chem 68: 1184-97 (1985) (2) Gartrell MJ et al; J Assoc Off Anal Chem 69: 146-61 (1986) (3) Gartrell MJ et al; J Assoc Off Anal Chem 68: 1163-83 (1985) (4) Gartrell MJ et al; J Assoc Off Anal Chem 69: 123-45 (1986) (5) Gunderson EL; J Assoc Off Anal Chem 71: 1200-9 (1988) (6) Hundley HK et al; J Assoc Off Anal Chem 71: 875-92 (1988) R77: (1) Yess NJ et al; J AOAC Int 76: 492-507 (1993) (2) Rogers WM et al; J AOAC Int 78: 614-31 (1995) (3) Minyard JP Jr, Roberts WE; J Assoc Off Anal Chem 74: 438-52 (1991) (4) IARC; Some organochlorine pesticides 5: 77 (1974) (5) FDA; Pesticide Program: Residue Monitoring 1992. JAOAC Int 76: 127A-48A (1993) R78: (1) IARC; Miscellaneous pesticides 30: 73-84 (1983) R79: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V30 77 (1983) R80: NCI; Bioassay of Chlorobenzilate for Possible Carcinogenicity, Report #75 p.3 (1978) DHEW Pub No (NIH) 78-1325 R81: (1) USEPA; Chlorobenzilate: Position Document 3. NTIS PB80-213887 p. 123 (1978) (2) IARC; Miscellaneous pesticides 30: 73-85 (1983) R82: (1) USEPA; Chlorobenzilate: Position Document 3 p.123 NTIS PB 80-21-3887 (1978) (2) IARC; Miscellaneous pesticides 30: 73-85 (1983) (3) FDA; Pesticide Program: Residue Monitoring 1992. JAOAC Int 76: 127A-48A (1993) R83: (1) Levy KA et al; Bull Environ Contam Toxicol 27: 235-8 (1981) (2) Stampler JH et al; Bull Environ Contam Toxicol 36: 693-700 (1986) R84: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R85: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R86: 40 CFR 302.4 (7/1/99) R87: 40 CFR 261.33 (7/1/99) R88: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.98 (Spring, 1998) EPA 738-R-98-002 R89: Beyermann K, Eckrich W; Z Analyt Chem 269 (4): 279-84 (1974) as cited in WHO; Environ Health Criteria: DDT and its Derivatives p.29 (1979) R90: HOFBERG AH JR ET AL; J ASSOC OFF ANAL CHEM 58 (3): 516-9 (1975) R91: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 77 (1974) R92: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R93: BURKE JA; J ASSOC OFF ANAL CHEM 63 (2): 277-82 (1980) R94: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R95: BRADY SS ET AL; BULL ENVIRON CONTAM TOXICOL 24 (5): 813-5 (1980) R96: Kline WF et al; NBS Spec Publ (US) 656: 91-7 (1983) RS: 99 Record 137 of 1119 in HSDB (through 2003/06) AN: 1618 UD: 200302 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-CHLORO-1,3-BUTADIENE- SY: *1,3-BUTADIENE,-2-CHLORO-; *2-CHLOOR-1,3-BUTADIEEN- (DUTCH); *2-CHLOR-1,3-BUTADIEN- (GERMAN); *CHLOROBUTADIENE-; *2-CHLOROBUTADIENE-; *2-Chlorobutadiene-1,3-; *CHLOROPREEN- (DUTCH); *CHLOROPRENE-; *BETA-CHLOROPRENE-; *CHLOROPREN- (GERMAN,POLISH); *2-CLORO-1,3-BUTADIENE- (ITALIAN); *CLOROPRENE- (ITALIAN) RN: 126-99-8 MF: *C4-H5-CL SHPN: UN 1991; CHLOROPRENE, INHIBITED IMO 3.2; Chloroprene, inhibited STCC: 49 072 23; Chloroprene, inhibited MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Addition of cold hydrochloric acid to vinylacetylene; chlorination of butadiene. [R1] IMP: *INHIBITORS SUCH AS HYDROQUINONE OR PHENOTHIAZINE ARE GENERALLY ADDED WHEN IT IS TO BE STORED. [R2] FORM: *Grade: Pure, 95% min. [R1] MFS: *DuPont Dow Elastomers LLC, Bellevue Parl Corp. Center, 300 Bellevue Pkwy., Wilmington, DE 19809, (302)792-4000; Production site: La Place, LA 70068 [R3] OMIN: *... ISOLATION OF 3,4-DICHLORO-1-BUTENE ISOMER (INCL SOME FROM ISOMERIZATION OF 1,4-1SOMER) AND REACTION WITH SODIUM HYDROXIDE; DIMERIZATION OF ACETYLENE AND ADDITION OF HYDROGEN CHLORIDE (FORMER METHOD; NON USA METHOD). [R4] USE: *... Used as a chemical intermediate in the manufacture of artificial rubber. [R5, p. 104.240] *... AS COMPONENT OF ADHESIVES THAT ARE INTENDED FOR USE IN FOOD PACKAGING. [R6] *Manufacture of neoprene. [R1] CPAT: *ESSENTIALLY 100% AS A MONOMER FOR NEOPRENE ELASTOMERS. [R4] PRIE: U.S. PRODUCTION: *(1978) 1.46X10+11 G (EST) [R4] *(1981) 1.29X10+11 G (EST) [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R7, 68] ODOR: *Pungent, ether-like odor [R7, 68] BP: *59.4 deg C [R8] MP: *-130 deg C [R8] MW: *88.54 [R8] DEN: *0.956 @ 20 deg C/4 deg C [R8] SOL: *Miscible in ethyl ether, acetone, and benzene; slightly soluble in water. [R8]; *Soluble in alcohol, diethyl ether [R9, 4234] SPEC: *MAX ABSORPTION (HEXANE): 223 NM (LOG E= 4.15) [R10]; *MASS: 153 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R11]; *Index of refraction: 1.4583 @ 20 deg C/D [R8] VAPD: *3.0 (AIR= 1) [R12] VAP: *215 mm Hg @ 25 deg C [R13] OCPP: *Polymerizes at room temperature unless inhibited with antioxidants. [R7, 68] *Per cent in saturated air: 28 @ 25 deg C; conversion factors: 1 mg/l approximates 276.5 ppm and 1 ppm approximates 3.62 mg/cu m @ 25 deg C, 760 torr. [R9, 4234] *Density of saturated air: 1.57 (air= 1) [R9, 4234] *RAPIDLY OXIDIZES TO FORM PEROXIDES AND ACIDIC MATERIALS. [R5, p. 104.246] *VAPOR PRESSURE: 300 MM HG @ 32.8 DEG C [R12] *Brittle point: -35 deg F; softens: @ approx 80 deg F [R14, 2392] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Chloroprene, inhibited/ [R15] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Chloroprene, inhibited/ [R15] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R15] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R15] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R15] *Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Chloroprene, inhibited/ [R16, G-131P] *Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Some may polymerize (P) explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Chloroprene, inhibited/ [R16, G-131P] *Public safety: Call Emergency Response Telephone Number ... . Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Chloroprene, inhibited/ [R16, G-131P] *Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. /Chloroprene, inhibited/ [R16, G-131P] *Evacuation: Spill: Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chloroprene, inhibited/ [R16, G-131P] *Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from the ends of tanks. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Chloroprene, inhibited/ [R16, G-131P] *Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Chloroprene, inhibited/ [R16, G-131P] *First aid: Move victim to fresh air. Call emergency medical care. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chloroprene, inhibited/ [R16, G-131] FPOT: *A very dangerous fire hazard when exposed to heat or flame. [R14, 2392] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R17] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R17] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R17] FLMT: *LOWER FLAMMABLE LIMIT 4.0%; UPPER FLAMMABLE LIMIT 20.0%. [R17] FLPT: *-20 DEG C (OPEN CUP) [R5, p. 104.264] FIRP: *DANGEROUS CHLOROPRENE FIRES ARE BEST EXTINGUISHED BY SHUTTING OFF THE SOURCE OF FUEL. CARBON DIOXIDE, DRY CHEMICALS, AND WATER SPRAY (FOG NOZZLE) MAY BE USED AS CONTROL MEASURES. [R18, 468] *To fight fire use alcohol foam. [R14, 2392] TOXC: *IT PRODUCES HYDROGEN CHLORIDE ON BURNING. [R18, 467] EXPL: *Explosive in the form of vapor when exposed to heat or flame. [R14, 2392] REAC: *Peroxides and other oxidizers [Note: Polymerizes at room temperature unless inhibited with antioxidants]. [R7, 68] *Incompatible with liquid or gaseous fluorine. [R14, 2392] *Autooxidizes in air to form an unstable peroxide that catalyzes exothermic polymerization of the monomer. [R14, 2392] DCMP: *When heated to decomposition it emits toxic fumes of chlorine (Cl-). [R14, 2393] SERI: *Beta-chloroprene ... is a lacrimator. [R9, 4239] *Exposure to the vapor can cause respiratory tract irritation leading to asphyxia. [R14, 2392] EQUP: *IN THE EVENT OF POTENTIAL EXPOSURE TO LIQUID OR HIGH VAPOR LEVELS, THE EMPLOYEE SHOULD WEAR PROTECTIVE GARMENTS, CHEMICAL SAFETY GOGGLES, AN AIR SUPPLIED RESPIRATOR OR SELF CONTAINED OXYGEN MASK. [R18, 468] *Wear appropriate personal protective clothing to prevent skin contact. [R7, 69] *Wear appropriate eye protection to prevent eye contact. [R7, 69] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R7, 69] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R7, 69] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R7, 69] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R7, 69] OPRM: *Contact lenses should not be worn when working with this chemical. [R7, 69] *Skin contact should be prevented. [R9, 4239] *The worker should immediately wash the skin when it becomes contaminated. [R7, 69] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R7, 69] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R19, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R19, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R19, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R19, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R19, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R19, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R19, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R19, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R19, 1979.11] SSL: *POLYMERIZES ON STANDING [R2] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R20] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R21] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R22] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R19, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R19, 1979.13] STRG: */OXIDATION/...INHIBITED BY STORAGE AT LESS THAN -15 DEG C AND/OR BY THE ADDN OF ANTIOXIDANTS TO THE FRESH DISTILLATE. [R18, 467] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R19, 1979.13] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN A SAFE PLACE (SUCH AS A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR THE HOOD DUCTWORK. BURN THE PAPER IN A SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. [R23] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R19, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Due to their high reactivity and volatility chloroprene and chloroprene containing wastes cannot be dumped. Therefore, if the chloroprene cannot be distilled, the wastes have to be destroyed in special waste incinerators. Because of the large quantities of chlorine present in exhaust gases during incineration, the flue gases have to be scrubbed. Recommendable method: Incineration. Non recommendable method: Landfill. Peer-review: Potentially polymerized and then landfilled. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R24, 115] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R24, 116] *LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. CHLOROPRENE SHOULD NOT BE ALLOWED TO ENTER A CONFINED SPACE, SUCH AS A SEWER, BECAUSE OF THE POSSIBILITY OF AN EXPLOSION. SEWERS DESIGNED TO PRECLUDE THE FORMATION OF EXPLOSIVE CONCENTRATIONS OF CHLOROPRENE VAPORS ARE PERMITTED. [R25] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R19, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R19, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R19, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R19, 1979.16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate in humans for the carcinogenicity of chloroprene. There is sufficient evidence in experimental animals for the carcinogenicity of chloroprene. Overall evaluation: Chloroprene is possibly carcinogenic to humans (Group 2B). [R26] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aliphatic hydrocarbons and related compounds/ [R27, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory rest. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aliphatic hydrocarbons and related compounds/ [R27, 207] MEDS: *PERIODIC EXAMINATION. RENAL AND HEPATIC FUNCTION. [R28] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R19, 1979.23] HTOX: *SYMPTOMS OF CHRONIC ... EXPOSURE ... HEPATOMEGALY, WITH DECR IN LIVER FUNCTION TESTS, TOXIC HEPATITIS, DYSTROPHY OF MYOCARDIUM AND CHANGES IN NERVOUS SYSTEM, CIRCULATORY CHANGES, ... ALTERED ENZYME ACTIVITIES AND DYSFUNCTION OF BOTH CENTRAL AND PERIPHERAL NERVOUS SYSTEMS, PARTICULARLY CHOLINERGIC BRANCH HAVE ... BEEN REPORTED. [R29] *PRIMARY EFFECTS OF ACUTE EXPOSURE TO HIGH CONCN OF CHLOROPRENE IN AIR ARE CNS DEPRESSION, INJURY TO LUNGS, LIVER AND KIDNEYS, IRRITATION OF SKIN AND MUCOUS MEMBRANES AND RESP DIFFICULTIES. [R29] *INHALATION ... CAUSES PATHOMORPHOLOGICAL CHANGES IN PERIODONTIUM: PERIODONTITIS (49%), GINGIVITIS (22%), EROSION OF TEETH (17%) AND CARIES (5%). [R30] *FUNCTIONAL DISTURBANCES IN SPERMATOGENESIS AND MORPHOLOGICAL ABNORMALITIES OF SPERM WERE OBSERVED AMONG WORKERS OCCUPATIONALLY EXPOSED TO CHLOROPRENE. 3 FOLD EXCESS OF SPONTANEOUS ABORTIONS HAS BEEN REPORTED IN WIVES OF CHLOROPRENE WORKERS. [R30] *SIGNIFICANT RISE IN NUMBER OF CHROMOSOME ABERRATIONS ... IN BLOOD CELLS FROM 18 WORKERS EXPOSED TO AVG ... CONCN OF 18 MG/CU M (5 PPM) FOR 2 TO MORE THAN 10 YR. FREQUENCY OF 4.7% ... ABERRATIONS AND 3.7% GAPS ... IN ... /EXPOSED/ GROUP, AS COMPARED WITH 0.65 and 1.14%, RESPECTIVELY, IN CONTROL GROUP ... AMONG 56 WORKERS EXPOSED TO CHLOROPRENE ... (THE CONCN ... IN AIR BEING ABOUT 6 MG/CU M (1.6 PPM)) THE INCIDENCE OF CHROMOSOMAL ABERRATIONS (MAINLY SINGLE BREAKS AND DOUBLE FRAGMENTS) IN CULTURED PERIPHERAL BLOOD LYMPHOCYTES WAS 2.78%, COMPARED WITH 0.53 AND 1.14% CHROMOSOME ABERRATIONS IN TWO GROUPS OF CONTROLS. [R30] *... CASES OF CHILDREN BORN WITH PHYSICAL AND MENTAL DEFECTS TO FEMALE WORKERS IN POLYMERIZATION AREA OF CHLOROPRENE RUBBER FACTORY /REPORTED/. [R30] *... AN INCR FREQUENCY OF CHROMOSOME ABERRATIONS IN LYMPHOCYTE CULTURES FROM 28 FEMALE WORKERS WHO WERE EXPOSED FOR 1-20 YR TO 1-7 MG/KG ... . [R30] *Swedish and Russian investigators reported a variety of biochemical and hematological alterations in chloroprene-exposed workers. An evaluation of the biochemical and hematological status of active chloroprene workers at a DuPont Company (USA) plant was undertaken. Distributions of biochemical and hematological values of 336 currently exposed and 227 previously exposed chloroprene workers were compared to those of 283 workers never exposed to chloroprene. Comparative analysis did not indicate or suggest that chloroprene workers had biochemical or hematological alterations (or both) of medical significance. [R31] *REPORT FROM SOVIET UNION IN 1972 OF EPIDEMIOLOGIC SURVEY OF WORKERS HAVING ... CONTACT WITH CHLOROPRENE PRODUCTS SHOWED SIGNIFICANTLY INCR INCIDENCE OF SKIN CANCER (1.6-3% VERSUS 0.12-0.66% FOR OTHER WORKERS NOT ... EXPOSED). LUNG CANCER INCIDENCE INCR WAS ALSO CLAIMED BY SAME AUTHOR. /IN ANOTHER STUDY, INVESTIGATOR/ ... FOUND NO INCR OF LUNG CANCER ATTRIBUTABLE TO CHLOROPRENE AMONG 1946 WORKERS WHO HAD BEEN EXPOSED TO ITS VAPOR BETWEEN 1931 and 1957. EARLY EXPOSURES APPARENTLY EXCEEDED THE 25 PPM LIMIT BY WIDE MARGIN. IN CONTRASTS TO REPORTS OF SWEDISH AND RUSSIAN, /INVESTIGATORS/ FAILED TO FIND ABNORMAL BIOCHEMICAL OR HEMATOLOGICAL VALUE DISTRIBUTIONS AMONG 533 WORKERS CURRENTLY OR PREVIOUSLY EXPOSED TO CHLOROPRENE. [R32] *Beta-chloroprene is a very unstable cmpd, which, unless handled with extreme care, epoxidizes and polymerizes to toxic compounds. ... Alleged effects in humans may be due to this same cause or to the use of different chem processes which produce different types of impurities. [R9, p. 4234-5] *Both case control and cohort studies were undertaken from July 1, 1969 to June 30, 1983 to ascertain whether exposure to chloroprene increases the risk of cancer. Fifty-five cases of cancer deaths were verified, 16 of which had histories of exposure to chloroprene ranging from 3 to 23 years (median 11 years) with a latent period of 8-27 years, except for one case of 3 years (median 12.5 years). Fifty-four pairs were obtained by matching the cancer deaths to noncancer deaths in accordance with strict requirements. The odds ratio for the paired data was 13, X2= 8.64, P < 0.005. The average at death from cancer workers exposed to chloroprene was 12.7 years younger than that of unexposed workers, t'= 2.98, P < 0.001. The total cohort consisted of 1213 persons, among whom 149 (11.6%) had histories of exposure for over 25 years, 381 (31.5%) for over 20 years, and 852 (70.2%) for over 15 years. The SMR for the total cohort was 2.38 (P < 0.01), and all SMRs for the high-exposure occupations were of significance (P < 0.05 or P < 0.01), in contrast to those of the low exposure groups whose SMRs were low or zero. Thus, a dose response relationship existed. Among the high exposure occupations, maintenance mechanics seem to have the highest risk of cancers, and SMRs for liver, lung, and lymphatic cancers were significant in this group. These results suggested that chloroprene exposure increases the risk of developing cancer. [R33] NTOX: *... RATS ... TOLERATE A DAILY EXPOSURE OF 8 HR TO CONCN OF 0.3 MG/L ... FOR 13 WEEKS. A CONCN OF 1.2 MG/L WAS FATAL AFTER DAILY EXPOSURES FOR 6, 9, and 13 WEEKS. ... SOME SYSTEMIC TOXICITY FROM REPEATED TOPICAL APPLICATION ... TO THE SKIN OF RATS ... SYSTEMIC POISONING /REPORTED/ FROM TOPICAL APPLICATION ... TO GUINEA PIGS. [R34] *THE DOSE THAT KILLED ABOUT 100% OF ANIMALS AFTER 8 HR INHALATION EXPOSURE WAS APPROX 7.5 G/CU M IN RABBITS AND FROM 15-20 G/CU M IN RATS. SYMPTOMS INCL INFLAMMATION OF MUCOUS MEMBRANES OF EYES AND NOSE, FOLLOWED BY DEPRESSION OF CNS, /AND/ DEATH ... FROM RESP FAILURE. [R35] *IN RATS, REPEATED EXPOSURE TO CHLOROPRENE BY INHALATION FOR 6 HR/DAY ON 5 DAYS/WK FOR 4 WK RESULTED IN SLIGHT GROWTH DEPRESSION AND BEHAVIORAL EFFECTS WITH 1.4 G/CU M ... AND LOSS OF HAIR, GROWTH RETARDATION AND MORPHOLOGICAL LIVER DAMAGE WITH 5.8 G/CU M ... and 22.5 G/CU M ... IN HAMSTERS, THIS EXPOSURE RESULTED IN SLIGHT IRRITATION AND RESTLESSNESS WITH 1.4 G/CU M ... GROWTH RETARDATION, IRRITATION AND LIVER DAMAGE WITH 5.8 G/CU M AND DEATH WITH 22.5 G/CU M ... . [R36] *EMBRYOTOXIC EFFECT ... IN ... RATS THAT INHALED ... CONCN ... RANGING FROM 0.13-53.4 MG/CU M. HIGHEST EMBRYOTOXIC EFFECT ... OBSERVED WHEN 4 MG/CU M (1.1 PPM) ... INHALED DURING THE ENTIRE PREGNANCY, OR INTERMITTENTLY ON DAYS 1-2, 3-4 OR 11-12, OR ... ORALLY ... 0.5 MG/KG ... /DAY FOR 14 DAYS OR ON DAYS 3-4 OR 11-12. [R36] *... REPRODUCTION OF MALE MICE AND RATS WAS AFFECTED AFTER INHALATION OF CHLOROPRENE @ CONCN OF 42-540 MG/CU M FOR MICE AND 430-22,400 MG/CU M FOR RATS. TESTICULAR ATROPHY, OR REDN IN NUMBERS AND MOTILITY OF SPERM IN RATS WITH NON-ATROPHIED TESTES, OCCURRED @ EXPOSURE LEVEL OF 0.15 MG/CU M ... . [R29] *CHLOROPRENE INDUCED DOMINANT LETHAL MUTATIONS AND CHROMOSOME ABERRATIONS IN BONE MARROW CELLS OF RATS EXPOSED TO 0.14-3.6 MG/CU M IN AIR AND DOMINANT LETHAL MUTATIONS IN MICE EXPOSED TO 1.85-3.5 MG/CU M IN AIR ... . [R29] *GROUP OF 110 RANDOM BRED ALBINO RATS RECEIVED 10 SC INJECTIONS OF 400 MG/KG BODY WT CHLOROPRENE IN SUNFLOWER OIL; 88 ... SURVIVED 6 MO OR MORE. ANOTHER GROUP OF 100 ... RECEIVED 50 INJECTIONS OF 200 MG/KG ... 46 SURVIVED 6 MO OR MORE. NO LOCAL SARCOMAS ... IN EITHER GROUP WITHIN 2 YR. [R35] *PREGNANT RATS WERE EXPOSED TO 0, 1, 10 and 25 PPM 4 HR DAILY. DAMS IN ONE STUDY WERE EXPOSED ON DAYS 1-12 AND KILLED ON DAY 17 TO EVALUATE EMBRYOTOXICITY. DAMS IN A TERATOLOGY STUDY WERE EXPOSED ON DAYS 3-20 AND SACRIFICED ON 21ST DAY OF GESTATION. NO MATERNAL, EMBRYONAL OR FETAL TOXICITY WAS OBSERVED IN THESE STUDIES. [R37] *3 GROUPS OF ... MICE RECEIVED EITHER (A) 50 TWICE WEEKLY SKIN APPLICATIONS OF 50% SOLN ... IN BENZENE FOR 25 WK OR (B) 50 TWICE WEEKLY ... APPLICATIONS OF 0.1% 9,10-DIMETHYL-1,2-BENZANTHRACENE ... IN BENZENE, OR (C) 50 ... APPLICATIONS OF 50% CHLOROPRENE SOLN IN BENZENE AND 5 ... OF 0.01% DMBA SOLN IN BENZENE. NO TUMORS WERE REPORTED IN MICE TREATED WITH CHLOROPRENE. [R38] *VARIETY OF IMMUNOLOGICAL EFFECTS HAVE RESULTED FROM CHLOROPRENE EXPOSURE, INCL DECR IN NUMBER OF ANTIBODY FORMING CELLS IN SPLEEN AND ENHANCEMENT OF TRANSPLANTED TUMOR GROWTH. [R36] *CHLOROPRENE VAPORS INDUCED REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA100 AND TA1530. ADDN OF A 9000XG SUPERNATANT OF LIVER FROM MICE OR ONE HUMAN SURGICAL SPECIMEN ENHANCED MUTAGENICITY. IN DROSOPHILA MELANOGASTER, RECESSIVE LETHAL MUTATIONS WERE INDUCED BY FEEDING MALE FLIES 5.7 and 11.4 MMOLE CHLOROPRENE FOR 3 DAYS. [R36] *ENZYMES OF KREBS CYCLE STUDIED FOLLOWING IP ADMIN OF CHLOROPRENE TO RATS. AFTER 15 DAY PERIOD, CITRATE SYNTHASE ACTIVITY SHARPLY INCR AND RETURNED TO NORMAL AT 30 DAYS. [R39] *APPLICATION OF CHLOROPRENE IN MICE BY SKIN SMEARS, SC INJECTIONS, INTRAGASTRIC AND INTRATRACHEAL ADMIN FAILED TO INDUCE TUMORS. NO TUMORS WERE OBSERVED AFTER USING COMBINATION OF CHLOROPRENE AND SMALL DOSES OF DIMETHYLBENZ(A)ANTHRACENE. [R40] *CHLOROPRENE DISSOLVED IN OLIVE OIL WAS ADMIN ORALLY (150 MG/KG) TO RATS ON 17TH DAY OF GESTATION AND THEIR OFFSPRINGS WERE TREATED WEEKLY WITH 50 MG/KG BY STOMACH TUBE FROM TIME OF WEANING FOR LIFE SPAN. TOTAL INCIDENCE OF TUMORS WAS SIMILAR IN TREATED AND UNTREATED ANIMALS. [R41] *AFTER 20 DAYS OF DAILY ORAL ADMIN OF 0.5 MG, BETA-GALACTOSIDASE ACTIVITY INCR IN RAT SERUM AND LACTATE DEHYDROGENASE ISOENZYME SPECTRUM WAS ALTERED IN SEMINAL FLUID. 0.05 MG/KG DAILY FOR 6 MO ORALLY TO RATS DECR WT GAIN AND INCR WT OF LIVER, SPLEEN AND TESTIS. SPERMATOZOID OSMOTIC RESISTANCE DECR AND MOTILITY WAS ALTERED. HEPATIC AND GONADAL BETA-GALACTOSIDASE WAS STIMULATED AND INHIBITED RESPECTIVELY. [R42] *Normal Hamster lung cells from an established line were treated with 1-500 ug/ml 2-chlorobutadiene. those treated with 1 ug/ml of the compound showed malignant transformations 14 weeks after treatment. The treatment with higher concentrations did not accelerate the transformation process. [R43] *MUTAGENICITY OF CHLOROPRENE WAS TESTED IN V79 CHINESE HAMSTER CELLS IN PRESENCE OF LIVER SUPERNATANT FROM PHENOBARBITONE PRETREATED RATS AND MICE. VAPOR INDUCED DOSE RELATED TOXICITY, BUT WAS NOT MUTAGENIC IN V79 CHINESE HAMSTER CELLS. [R44] *FASTED RATS WERE EXPOSED TO 100, 150, 225 and 300 PPM FOR 4 HR AND KILLED AT 24 HR. NONPROTEIN SULFHYDRYL CONCN IN LIVER WAS INCR AFTER ALL EXPOSURES. LUNG NONPROTEIN SULFHYDRYL CONCN DECR AFTER 100-300 PPM. SERUM LACTATE DEHYDROGENASE ACTIVITY WAS INCR AFTER EXPOSURE TO 300 PPM. [R45] *Chloroprene was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using a standard protocol approved by NTP. Chloroprene was tested at doses of 0, 3, 10, 33, 100, 333, 1000, and 3333 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Chloroprene was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 1000 ug/plate. The 3333 ug/plate dose level induced slight or total clearing of the background lawn in all strains tested. [R46] *Pathomorphological changes in rat organs after chronic exposure to chloroprene are described. Many of these changes were dystrophic and the liver was most affected. Protein deficiency aggravated these toxic changes and protein rich diet had a favorable effect. [R47] *Studies of the induction of genotoxic and cytotoxic damage induced in bone marrow cells of mice after inhaling chloroprene showed that chloroprene did not induce genotoxic damage in bone marrow, suggesting that if it has any carcinogenic activity, the tumors would be very site specific. [R48] *Chloroprene treatments involved 6 hr/day exposures on 12 exposure days at concentrations of 0, 12, 32, 80, and 200 ppm for chloroprene in B6C3F1 mice. Chloroprene gave negative results for all cytogenetic end points assessed in bone marrow cells. [R49] *Kunming albino mice weaned at 2 weeks were subjected to inhaling 0, 2.0 + or - 0.3, 19.2 + or - 1.9, and 189.0 + or - 13.3 mg/cu m chloroprene (GC purity, 99.8%) 4 hr daily (except Sunday) for 7 months. All survivors were killed at the end of the 8th month or when moribund. No lung tumors were found before the 6th month. Thus, survivors at the 6th month were counted as effective animals. Most lung tumors observed were papilloadenomas (50/57), and a few were adenomas (7/57). The tumor incidence in the 2.9 mg/cu m group was 8.1% in comparison to 1.3% in the control group, with the significance level at P < 0.05. The higher the concentration, the higher the incidence. Examination of the multiplicity of tumor induction also demonstrated a dose response relationship, and the number of tumors per mouse in the 189 mg/cu m group was significant at P < 0.01. [R50] *CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of chloroprene in male F344/N rats based on incr incidences of neoplasms in the oral cavity; incr incidences of neoplasms of the thyroid gland, lung and kidney were also attributed to chloroprene exposure. There was clear evidence of carcinogenic activity of chloroprene in female F344/N rats based on incr incidences of neoplasms of the thyroid gland, mammary gland and kidney were also attributed to exposure to chloroprene. ... There was clear evidence of carcinogenic activity of chloroprene in male B6C3F1 mice based on incr incidences of neoplasms of the lung, circulatory system (hemangiomas and hemangiosarcomas) and harderian gland; incr incidences of neoplasms of the forestomach and kidney were also attributed to exposure to chloroprene. There was clear evidence of carcinogenic activity of chloroprene in female B6C3F1 mice based on incr incidences of neoplasms of the lung, circulatory system (hemangiomas and hemangiosarcomas), harderian gland, mammary land, liver, skin and mesentery; incr incidences of neoplasms of the forestomach and Zymbal's gland were also attributed exposure to chloroprene. [R51] NTXV: *LD50 Rat oral 450 mg/kg; [R14, 2392] *LC50 Rat inhalation 11,800 mg/cu m/4 hr; [R14, 2392] *LD50 Mouse oral 146 mg/kg; [R14, 2392] *LC50 Mouse inhalation 2300 mg/cu m; [R14, 2392] NTP: *... Groups of 50 male and 50 female F344/N rats were exposed to chloroprene at concn of 0, 12.8, 32 or 80 ppm by inhalation 6 hr/day, 5 days/wk for 2 yr. Groups of 50 male and 50 female B6C3F1 mice were exposed to chloroprene at concn of 0, 12.8, 32 or 80 ppm by inhalation 6 hr/day, 5 days/wk for 2 yr. ... CONCLUSIONS: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of chloroprene in male F344/N rats based on incr incidences of neoplasms in the oral cavity; incr incidences of neoplasms of the thyroid gland, lung and kidney were also attributed to chloroprene exposure. There was clear evidence of carcinogenic activity of chloroprene in female F344/N rats based on incr incidences of neoplasms of the thyroid gland, mammary gland and kidney were also attributed to exposure to chloroprene. ... There was clear evidence of carcinogenic activity of chloroprene in male B6C3F1 mice based on incr incidences of neoplasms of the lung, circulatory system (hemangiomas and hemangiosarcomas) and harderian gland; incr incidences of neoplasms of the forestomach and kidney were also attributed to exposure to chloroprene. There was clear evidence of carcinogenic activity of chloroprene in female B6C3F1 mice based on incr incidences of neoplasms of the lung, circulatory system (hemangiomas and hemangiosarcomas), harderian gland, mammary land, liver, skin and mesentery; incr incidences of neoplasms of the forestomach and Zymbal's gland were also attributed exposure to chloroprene. [R51] ADE: *... RAPIDLY ABSORBED BY SKIN ... . [R52] METB: *WHEN MIXT OF CHLOROPRENE IN AIR WAS PASSED THROUGH A MOUSE LIVER MICROSOMAL PREPN, A VOLATILE ALKYLATING METABOLITE WAS FORMED, AS DEMONSTRATED BY TRAPPING WITH 4-(4-NITROBENZYL)PYRIDINE. [R36] INTC: *PRETREATMENT WITH AROCLOR PREVENTED LIVER INJURY FOLLOWING EXPOSURE TO 100 and 300 PPM OF CHLOROPRENE. LUNG NONPROTEIN SULFHYDRYL CONCN WAS NOT DECR BY CHLOROPRENE EXPOSURE OF POLYCHLORINATED BIPHENYL PRETREATED RATS. [R45] *The brain ATP levels in rats were decreased at 7-30 days after the ip injection of chloroprene (600 umol/100 g body weight). However, the simultaneous administration of alpha-tocopherol acetate (0.1 mg/100 g body weight) counteracted this effect of chloroprene. The toxicity of chloroprene depletes the endogenous alpha-tocopherol supply. Administration of exogenous alpha-tocopherol can then counteract this toxic effect of chloroprene. [R53] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Chloro-1,3-butadiene's manufacture and use in the production of polychloroprene elastomers, such as neoprene, may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 215 mm Hg at 25 deg C indicates 2-chloro-1,3-butadiene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 2-chloro-1,3-butadiene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone molecules. The half-life for this reaction in air with hydroxyl radicals is estimated to be 18 hours. The half-life for the reaction in air with ozone is estimated to be 10 days. The gas-phase reaction of 2-chloro-1,3-butadiene with nitrate radicals may also be an important atmospheric removal process in urban areas at night, but the rate of this reaction is not known. If released to soil, 2-chloro-1,3-butadiene is expected to have high mobility based upon an estimated Koc of 68. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 0.056 atm-cu m/mole. 2-Chloro-1,3-butadiene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 2-chloro-1,3-butadiene is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3 hours and 4 days, respectively. An estimated BCF of 18 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to 2-chloro-1,3-butadiene may occur through inhalation of this compound at workplaces where 2-chloro-1,3-butadiene is produced or used. (SRC) NATS: *2-Chloro-1,3-butadiene is not known to occur as a natural product(1). [R54] ARTS: *2-Chloro-1,3-butadiene's manufacture and use in the production of polychloroprene elastomers, such as neoprene(1), may result in its release to the environment through various waste streams(SRC). [R55] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 68(SRC), determined from a structure estimation method(2), indicates that 2-chloro-1,3-butadiene is expected to have high mobility in soil(SRC). Volatilization of 2-chloro-1,3-butadiene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 0.056 atm-cu m/mole (SRC), using a fragment constant estimation method(3). The potential for volatilization of 2-chloro-1,3-butadiene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 215 mm Hg(4). 2-Chloro-1,3-butadiene will not be susceptible to chemical hydrolysis(SRC). [R56] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 68(SRC), determined from a structure estimation method(2), indicates that 2-chloro-1,3-butadiene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 0.056 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3 hours and 4 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 18(SRC), from an estimated log Kow of 2.53(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. 2-Chloro-1,3-butadiene is not expected to undergo chemical hydrolysis(SRC) because of the lack of hydrolyzable functional groups(3). [R57] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2-chloro-1,3-butadiene, which has a vapor pressure of 2.15X10+2 mm Hg at 25 deg C, is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 2-chloro-1,3-butadiene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals, ozone molecules and nitrate radicals(SRC). The half-life for the reaction in air with hydroxyl radicals is estimated to be 18 hours(SRC), calculated from its rate constant of 22X10-12 cu cm/molecule-sec at 25 deg C(SRC), determined using a structure estimation method(2). The rate constant for the vapor-phase reaction of 2-chloro-1,3-butadiene with ozone has been estimated as 0.12X10-17 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(2). This corresponds to an atmospheric half-life of about 10 days(SRC) at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). The gas phase reaction of 2-chloro-1,3-butadiene with nitrate radicals may be an important atmospheric removal process in urban areas at night(4), but the rate of this reaction is not known. [R58] ABIO: *The rate constant for the vapor-phase reaction of 2-chloro-1,3-butadiene with photochemically-produced hydroxyl radicals has been estimated as 22X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 18 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of 2-chloro-1,3-butadiene with ozone has been estimated as 0.12X10-17 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 10 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). In general, the night time degradation of conjugated diolefins by the gas-phase reaction with nitrate radicals may be important in urban areas or in heavily polluted atmospheres(3); this may be an important removal process for 2-chloro-1,3-butadiene, but the rate of this reaction is not known(SRC). 2-Chloro-1,3-butadiene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(4). [R59] BIOC: *An estimated BCF of 18 was calculated for 2-chloro-1,3-butadiene(SRC), using an estimated log Kow of 2.53(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low (SRC). [R60] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 2-chloro-1,3-butadiene can be estimated to be 68(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2-chloro-1,3-butadiene is expected to have high mobility in soil. [R61] VWS: *The Henry's Law constant for 2-chloro-1,3-butadiene is estimated as 0.056 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2-chloro-1,3-butadiene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 3 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). 2-Chloro-1,3-butadiene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 2-chloro-1,3-butadiene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 215 mm Hg at 25 deg C(3). [R62] WATC: *SURFACE WATER: 2-Chloro-1,3-butadiene was detected in 1 out of 204 samples of surface water collected from sites near heavily industrialized areas across the US during 1975/76(1). [R63] EFFL: *2-Chloro-1,3-butadiene was identified in 1 out of 33 industrial effluents at a concentration greater than 100 ug/l, detection limit of 10 ug/l(1). [R64] ATMC: *URBAN/SUBURBAN: 2-Chloro-1,3-butadiene was detected in the ambient air in 6 of 6 NJ cities at an avg concn of 0.097 ppb and a max concn of 4.0 ppb(1). 2-Chloro-1,3-butadiene was detected in 2 of 2 samples of ambient air in Houston, TX during July 1976, at an average concentration of 0.59 ppb(2). 2-Chloro-1,3-butadiene was not detected in 17 samples of ambient air in Baton Rouge, LA during March 1977 at an unreported detection limit(2). [R65] *SOURCE DOMINATED: The compound was not detected in air above 6 abandoned hazardous wastes sites and one active sanitary landfill in NJ during 1983/84, at a detection limit of 0.01 ppb(1). [R66] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 17,750 workers (654 of these are female) are potentially exposed to 2-chloro-1,3-butadiene in the US(1). During 1977, airborne concentrations of 2-chloro-1,3-butadiene of up to 0.2 ppm were reported in a roll building area in a metal fabricating plant where polychloroprene was applied extensively to metal cylinders prior to vulcanization(2). During 1973, at a US 2-chloro-1,3-butadiene polymerization plant, airborne concentrations of 2-chloro-1,3-butadiene were found to range from 14-1,420 ppm in the make-up area, from 130-6,760 ppm in the reactor area, from 6-440 in the monomer recovery area and from 113-252 ppm in the latex area(2). Occupational exposure to 2-chloro-1,3-butadiene may occur through inhalation of this compound at workplaces where 2-chloro-1,3-butadiene is produced or used(SRC). [R67] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers beta-chloroprene to be a potential occupational carcinogen. /SRP: No IDLH value specified/. [R7, 68] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 25 ppm (90 mg/cu m). Skin Designation. [R68] *Vacated 1989 OSHA PEL TWA 10 ppm (35 mg/cu m), skin designation, is still enforced in some states. [R7, 361] NREC: *Recommended Exposure Limit: 15 Min Ceiling Value: 1 ppm (3.6 mg/cu m). [R7, 68] *NIOSH considers beta-chloroprene to be a potential occupational carcinogen. [R7, 68] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R7, 68] TLV: *8 hr Time Weighted Avg (TWA) 10 ppm, skin [R69, 26] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R69, 6] OOPL: *West Germany: 10 ppm; Sweden: 25 ppm; Romania: 8 ppm; East Germany: 3 ppm; USSR: 0.6 ppm. [R32] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Chloroprene is produced, as an intermediate or a final product, by process units covered under this subpart. [R70] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 2-Chloro-1,3-butadiene is included on this list. [R71] *... Substances for which a Federal Register notice has been published that included consideration of the serious health effects, including cancer, from ambient air exposure to the substance. Chloroprene is included on this list. [R72] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R73] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Chloroprene is included on this list. [R74] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R75] FDA: *Chloroprene is an indirect food additive for use only as a component of adhesives. [R76] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1002. Analyte: Chloroprene. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal 100 mg/50 mg). Flow Rate: 0.01 to 0.05 L/min. Sample Size: 3 liters. Shipment: No special precautions. Sample Stability: At least 8 days at 25 deg C. [R77] ALAB: *OSW Method 0031. Sampling Method for Volatile Organic Compounds. Target detection limit= 0.100 ug/cu m [R78] *OSW Method 8240B. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Estimated qunatitation limit= 5.0 ug/l. [R78] *OSW Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R78] *EAD Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. [R78] *NIOSH Method 1002. Analyte: Chloroprene. Matrix: Air. Procedure: Gas chromatography flame ionization detector. For chloroprene this method has an estimated detection limit of 0.03 mg/sample. The overall precision/RSD is 0.021. Applicability: The working range is 10 to 60 ppm (40 to 200 mg/cu m) for a 3-liter air sample. Interferences: None known. [R77] CLAB: *SFSAS Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. [R78] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology and Carcinogenesis Studies of Chloroprene in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 467 (1998) NIH Publication No. 98-3957 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 261 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 132 (1979) R3: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 524 R4: SRI R5: International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998. R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 133 (1979) R7: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R8: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-88 R9: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-216 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 425 R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 131 (1979) R13: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. 229 R14: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-131 R16: U.S. Department of Transportation. 1996 North American Emergency Response Guidebook. A Guidebook for First Responders During the Initial Phase of a Hazardous Materials/Dangerous Goods Incident. U.S. Department of Transportation (U.S. DOT) Research and Special Programs Administration, Office of Hazardous Materials Initiatives and Training (DHM-50), Washington, D.C. (1996).. R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-26 R18: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R19: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R20: 49 CFR 171.2 (7/1/2000) R21: IATA. Dangerous Goods Regulations. 41st Ed.Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2000. 135 R22: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3110 (1998) R23: Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995. 337 R24: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. R25: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R26: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 245 (1999) R27: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R28: Fuscaldo, A., B. J. Erlick, and B. Hindman. (eds.). Laboratory Safety-Theory and Practice. New York: Academic Press, 1980. 257 R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 138 (1979) R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 139 (1979) R31: Gooch JJ et al; J Occup Med 23 (4): 268-72 (1981) R32: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.135 R33: Li SQ et al; Biomed Environ Sci 2 (2): 141-9 (1989) R34: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1320 R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 136 (1979) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 137 (1979) R37: CULIK R ET AL; TOXICOL APPL PHARMACOL 44 (1): 81-8 (1978) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 135 (1979) R39: MKHITARYAN LV, MKHITARYAN VG; ZH EKSP KLIN MED 18 (1): 3-12 (1978) R40: ZILFYAN VN ET AL; VOPR ONKOL (LENINGR) 23 (4): 61-5 (1977) R41: PONOMARKOV V, TOMATIS ET; ONCOLOGY (BASEL) 37 (3): 136-41 (1980) R42: KRASOVSKII GN ET AL; GIG SANIT 2: 17-9 (1980) R43: Menezes S et al; CR Seances Acad Sci D; 288 (10): 923-6 (1979) R44: DREVON C, KUROKI T; MUTAT RES 67 (2): 173-82 (1979) R45: PLUGGE H, JAEGER RJ; TOXICOL APPL PHARMACOL 50 (3): 565-72 (1979) R46: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R47: Aznauryan AV et al; Zh Eksp Klin Med 21 (2): 136-40 (1981) R48: Tice RR; Cell Biol Toxicol 4 (4): 475-86 (1988) R49: Shelby MD; Environ Health Perspect 86: 71-3 (1990) R50: Dong QA et al; Biomed Environ Sci 2 (2): 150-3 (1989) R51: Toxicology and Carcinogenesis Studies of Chloroprene in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.7 Technical Report Series No. 467 (1998) NIH Publication No. 98-3957 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R52: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 70 R53: Mkhitaryan LV; Biol Zh Arm 35 (4): 315-7 (1982) R54: (1) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some monomers, plastics and synthetic elastomers, and acrolein. Lyon, France: IARC 19: 131-5 (1979) R55: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons, Inc. p. 261 (1997) R56: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Boublik T et al; The Vapor Pressure of Pure Substances. Amsterdam, The Netherlands: Elsevier Sci Pub. p. 229 (1984) R57: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. Boca Raton, FL: Lewis p. 252 (1997) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R58: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (4) Atkinson R et al; J Phys Chem 88: 1210-5 (1984) R59: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (3) Atkinson R et al; J Phys Chem 88: 1210-5 (1984) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R60: (1) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. Boca Raton, FL: Lewis p. 252 (1997) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R61: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R62: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Boublik T et al; The Vapor Pressure of Pure Substances. Amsterdam, The Netherlands: Elsevier Sci Pub. p. 229 (1984) R63: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters. USEPA 560/6-77-015 (1977) R64: (1) Perry DL et al; Identification of Organic Compounds in Industrial Effluent Discharges. USEPA 600/4-79-016, NTIS PB-294794 p. 50 (1979) R65: (1) Harkov R et al; pp. 104-19 in Proc Int Tech Conf Toxic Air Contam. McGovern JJ, ed. APCA. Pittsburgh, PA (1981) (2) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. Menlo Park, CA: SRI International (1982) R66: (1) Harkov R et al; J Environ Sci Health 20: 491-501 (1985) R67: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) IARC; 2-Chloro-1,3-butadiene and Polychloroprene 19: 131-5 (1979) R68: 29 CFR 1910.1000 (7/1/2000) R69: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R70: 40 CFR 60.489 (7/1/2000) R71: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R72: 40 CFR 61.01 (7/1/2000) R73: 40 CFR 302.4 (7/1/2000) R74: 40 CFR 716.120 (7/1/2000) R75: 40 CFR 712.30 (7/1/2000) R76: 21 CFR 175.105 (4/1/2000) R77: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R78: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 78 Record 138 of 1119 in HSDB (through 2003/06) AN: 1623 UD: 200201 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: COUMARIN- SY: *2H-BENZO(B)PYRAN-2-ONE; *2H-1-BENZOPYRAN-2-ONE-; *2H-1-BENZOPYRAN,-2-OXO-; *BENZO-ALPHA-PYRONE-; *5,6-BENZO-ALPHA-PYRONE-; *1,2-BENZOPYRONE-; *CINNAMIC-ACID,-O-HYDROXY-,-DELTA-LACTONE-; *CIS-O-COUMARIC-ACID-ANHYDRIDE-; *O-COUMARIC-ACID-LACTONE-; *CIS-O-COUMARINIC-ACID-LACTONE-; *COUMARINIC-ANHYDRIDE-; *COUMARINIC-LACTONE-; *CUMARIN-; *O-HYDROXYCINNAMIC-ACID-LACTONE-; *O-HYDROXYCINNAMIC-LACTONE-; *2-OXO-1,2-BENZOPYRAN-; *2-PROPENOIC ACID, 3-(2-HYDROXYPHENYL)-, DELTA-LACTONE; *RATTEX-; *TONKA-BEAN-CAMPHOR- RN: 91-64-5 MF: *C9-H6-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... MADE SYNTHETICALLY BY HEATING SALICYLIC ALDEHYDE, SODIUM ACETATE, AND ACETIC ACID ANHYDRIDE. [R1] *FROM O-CRESOL AND CARBONYL CHLORIDE FOLLOWED BY CHLORINATION OF THE CARBONATE AND FUSION WITH A MIXTURE OF ALKALI ACETATE, ACETIC ANHYDRIDE, AND A CATALYST. [R2] *Currently produced by Perkin (reaction of salicyladehyde and acetic anhydride) and Raschig synthesis (from o-cresol). [R3] MFS: *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Main St, Midland, MI 48667 [R4] *Rhone-Poulenc, Inc, Hqr, 52 Vanderbilt Avenue, New York NY 10017, (201) 297-0100; Rhone-Poulenc, Specialty Chemical Division,Fine Organics Business Group, Prospect Plains Rd, CN-7500, Cranbury, NJ 08512, (609) 860-4000; Production site: New Brunswick, NJ 08901 [R4] *Eastman Kodak Company, Laboratory and Research Products, 343 State Street, Rochester, NY 14650, (800)225-5352 [R4] OMIN: *COUMARIN, CONTAINED IN SWEETCLOVER HAY (MELILOTUS SPP), IS CONVERTED TO DICOUMARIN BY MOLDS UNDER CERTAIN CONDITIONS. THIS COMPD INTERFERS WITH PROTHROMBIN SYNTHESIS AND RESULTS IN HEMORRHAGIC DISEASE WHEN MOLDED SWEETCLOVER HAY IS INGESTED OVER PERIOD OF TIME. [R5] *IT IS SUSPECTED THAT COUMARIN IS PRODRUG AND 7-HYDROXYCOUMARIN THE PHARMACOLOGIC ACTIVE MOIETY. [R6] *COMMERCIALLY, IN DETERGENTS, SOAPS, AND COSMETICS, AND AS FLAVORING AGENT FOR CATTLE MEDICINES. [R7] *USE IN FOODS NOT PERMITTED IN USA. [R2] *... Is widely distributed in the plant kingdom but most of it has been produced synthetically for many years for commercial use. [R8, p. V7 647] USE: *Formerly important as a flavor and perfume in foods and pharmaceuticals. [R9] *AS DEODORIZING AND ODOR ENHANCING AGENT IN SOAPS, TOBACCO AND RUBBER PRODUCTS [R1] *IN MEDICATION AS PHARMACEUTIC AID (FLAVOR) [R10] *... An important raw material in the fragrance industry. It is widely used in hand soaps, detergents, lotions, and perfumes at concentrations extending from 0.01 to 0.8%. ... Herbaceous odors and enters in the formulation of fern (Fougere) and Chypre-type fragrances. [R8, p. V7 654] *Odor enhancer to achieve a long lasting effect when combined with natural essential oils such as lavender, citrus, rosemary, oak moss, etc. ... Used in tobacco to enhance its natural aroma. [R8, p. V7 654] *... Applied in large quantities to give pleasant aromas to household materials and industrial products or to mask unpleasant odors. [R8, p. V7 654] *... Has a significant use in the electroplating industry, mostly in the automotive area, to provide high polished quality to chrome plated steel but this use is presently declining. [R8, p. V7 654] *Formerly, large quantites were used in the food industry mostly associated with vanillin for flavoring chocolates, baked goods, and in the confection of cream soda flavored beverages, but since 1954 its use in food has been suspended in the U.S. [R8, p. V7 654] PRIE: U.S. PRODUCTION: *(1990) > 500 tons [R8, p. V7 653] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORTHORHOMBIC, RECTANGULAR PLATES [R10]; *Colorless, crystals, flakes, or powder [R11] ODOR: *PLEASANT, FRAGRANT ODOR RESEMBLING THAT OF VANILLA BEANS [R10]; *HAY-LIKE BITTERSWEET ODOR [R8, p. V7 647] TAST: *BURNING TASTE WITH BITTER UNDERTONE; NUT-LIKE FLAVOR ON DILUTION [R2]; *Bitter, aromatic, burning taste. [R11] BP: *301.71 AT 760 MM HG [R12] MP: *71 DEG C [R12] MW: *146.14 [R10] DEN: *0.935 AT 20/4 DEG C [R12] OWPC: *Log Kow = 1.39 [R13] SOL: *Soluble in ethanol; very soluble in ether and chloroform [R12]; *1 G DISSOLVES IN 400 ML COLD, 50 ML BOILING WATER; FREELY SOLUBLE IN OILS [R10]; *Water solubility = 0.25 g/100g at 25 deg C [R8, p. V7 648]; *Chloroform 49.4 g/100g at 25 deg C; pyridine 87.7 g/100g at 20-25 deg C [R8, p. V7 648] SPEC: *MAX ABSORPTION (ALCOHOL): 274.5 NM (LOG E= 4.20); 312 NM (LOG E= 3.91) [R14]; *IR: 270 (Sadtler Research Laboratories IR Grating Collection) [R15]; *UV: 492 (Sadtler Research Laboratories Spectral Collection) [R15]; *NMR: 225 (Varian Associates NMR Spectra Catalogue) [R15]; *MASS: 819 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R15] VAP: *1 MM HG AT 106.0 DEG C [R16] OCPP: *The lactone is easly hydrolyzed to the corresponding salts of coumarinic acid or o-hydroxy-cis-cinnamic acid. [R8, p. V7 649] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME. [R17] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *... SUBSTITUTION OF LESS IRRITATING SUBSTANCES ... REDESIGN OF OPERATIONS...PREVENT CONTACT, PROVISION OF A PHYSICAL BARRIER AGAINST CONTACT, PROPER WASHING FACILITIES, WORK CLOTHING AND STORAGE FACILITIES, PROTECTIVE CLOTHING, AND BARRIER CREAMS. MEDICAL CONTROL ... . [R18] SSL: *CONVERTED TO A DIMER ON LONG EXPOSURE TO LIGHT [R19, p. V10 113] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Incineration: Coumarin should be combined with paper or other flammable material. An alternate procedure is to dissolve the solid in a flammable solvent and spray the soln into the fire chamber. [R20] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R21] HTOX: *Protein C (PC) a 62,000 molecular weight vitamin K dependent serine protease zymogen, is a natural anticoagulant that occurs in plasma at 4 mg/L. Activated PC inactivates clotting factors V and VIII and is also proflbrinolytic. Activated PC is enhanced in its anticoagulant activity by protein S (PS) another vitamin K-dependent protein. Protein S is found in platelets and endothelial cells as well as in plasma. Inherited PC deficiency and PS deficiency have been associated with venous thrombosis. ... Coumarin induced skin necrosis a rare complication of oral anticoagulant therapy usually seen within three to five days of initiation of therapy, has also been associated with heterozygous PC deficiency. The short half-life of PC (six to eight hours) compared with most of the vitamin K dependent clotting factors (greater than 30 hours) is the probable reason for this paradoxical response to oral anticoagulants in some PC deficient patients since a transient imbalance of procoagulant and anticoagulant factors may exist during initiation of oral anticoagulant therapy. [R22] NTOX: *FATAL DOSES QUICKLY ELICIT /CNS DEPRESSION/. PROMINENT AUTOPSY FINDINGS IN ACUTELY POISONED ANIMALS INCLUDED HYPEREMIA OF STOMACH AND UPPER INTESTINES. PROLONGED FEEDING REVEALED A POSSIBLE TREND TOWARD LIVER INJURY ... ANTIPROTHROMBIN ACTIVITY IS NOT A PROMINENT FEATURE OF COUMARIN TOXICITY. [R9] *GROUPS OF 12 OSBORNE-MENDEL RATS ... WERE FED ... 1000, 2500 OR 5000 MG ... PER KG OF DIET FOR 2 YR (FOOD GRADE MATERIAL ...) TWO GROUPS OF CONTROLS RECEIVED UNTREATED ... OR BASAL DIET CONTAINING 3% CORN OIL. BILE-DUCT PROLIFERATION, CHOLANGIOFIBROSIS AND FOCAL NECROSIS ... /OBSERVED FROM/ 2 HIGHEST DOSE ... NO TUMORS ... DESCRIBED ... . [R19, p. V10 115] *GROUPS OF 40 ALBINO RATS...WERE FED DIETS CONTAINING 1000, 2500 OR 5000 MG COUMARIN/KG OF DIET FOR 2 YR (FOOD GRADE MATERIAL...) OF 24 RATS FED 5000 MG/KG...AND SURVIVING 18 OR MORE MONTHS, 11 MALES AND 1 FEMALE DEVELOPED BILE-DUCT CARCINOMAS. ... NO BILE-DUCT CARCINOMAS OCCURRED IN 2 SEPARATE GROUPS OF 40 and 50 CONTROLS. [R19, p. V10 115] *COUMARIN AND SOME OF ITS METABOLITES HAVE BEEN SHOWN TO INHIBIT GLUCOSE-6-PHOSPHATASE IN LIVER AND IN LIVER MICROSOMAL PREPN. IT INTERFERS WITH EXCISION REPAIR PROCESSES ON ULTRA-VIOLET-DAMAGED DNA AND WITH HOST CELL REACTIVATION OF ULTRA-VIOLET-IRRADIATED PHAGE T1 IN E COLI WP2. [R19, p. V10 116] *GROUPS OF BABOONS WERE FED 0, 2.5, 7.5 22.5 OR 67.5 MG COUMARIN/KG/DAY FOR 16-24 MO. ULTRASTRUCTURAL EXAM OF LIVER REVEALED DILATATION OF ENDOPLASMIC RETICULUM. 67.5 MG/KG/DAY INCR LIVER WT. [R23] *AFTER 125-750 MG/KG TREATMENT WITH COUMARIN, DOSE-RELATED NECROSIS OF CENTRILOBULAR AREAS OF LIVER LOBULES WAS OBSERVED. [R24] *ACID AND NEUTRAL PROTEASE LEVELS OF SKIN WERE DECR BY THERMAL INJURY, BUT ENHANCED BY BENZOPYRONES ADMIN IP PRIOR TO BURNING. [R25] *The rat hepatic toxicity of coumarin and methyl analogs (3-, 4-methyl coumarin and 3,4-dimethylcoumarin) has been determined in vivo and in vitro (freshly-isolated cells). Coumarin at a dose of histological evidence of centrilobular necrosis while the methyl analogs at an equivalent dose were much less toxic. ... The order of cytotoxicity in vitro was identical to that observed in vivo. In hepatocytes depleted of glutathione the toxicity of all four compounds was increased. This was particularly marked for the 3-methyl analogs such that the order of toxicity was different to that observed in vivo and in hepatocytes not depleted of glutathione. [R26] *The acute hepatic effects of coumarin in male Wistar rats and Mongolian gerbils has been compared. A single dose of coumarin (125 mg/kg ip) was hepatotoxic to rats within 24 hr as assessed by its effects on a variety of hepatic parameters. Coumarin induced hepatotoxicity was associated with significant increases in relative liver weight, plasma alanine and aspartate aminotransferase activities and hepatic non-protein sulfhydryl groups. Cytochrome p450 content and 7-ethoxycoumarin 0-deethylase and glucose 6-phosphatase activities were significantly lower in coumarin treated compared with control rats. Centrilobular necrosis was only observed in two out of six rats at this dose but was present in all four coumarin treated rats when the dose was increased to 150 mg/kg. In contrast to the effects observed in the rat, no evidence was found for coumarin induced hepatotoxicity in gerbils following a single ip dose of 125 mg/kg. These data indicate that the gerbil is less sensitive to the hepatotoxic effects of coumarin than the rat. [R27] *Male Sprague-Dawley rats were pretreated with saline, corn oil, sodium phenobarbitone (PB) (100 mg/kg body weight/day), 20-methylcholanthrene (20 MC) 120 mg/kg body weight/day) or Aroclor 1254 (AR0) (100 mg/kg body weight/day) by daily ip injections for 5 days. Animals were then given single oral doses of either 250 or 500 mg coumarin/kg body weight and hepatotoxicity was assessed after 24 hr. Coumarin produced hepatotoxicity, which comprised hepatocyte necrosis and elevation of plasma alanine aminotransferase and aspartate aminotransferase activities, in all pretreated groups. Hepatic microsomal cytochrome p450 levels were reduced after coumarin administration. In rats pretreated with saline, corn oil or PB, coumarin produced centrilobular hepatic necrosis, whereas in rats pretreated with 20 MC or AR0, coumarin produced periportal hepatic necrosis. ... As coumarin is known to be bioactivated by cytochrome p450-dependent enzymes, the change in the lobular distribution of toxicity after pretreatment with 20 MC or ARO is /probably/ due to the induction of particular p450 enzymes in periportal hepatocytes. [R28] *The mechanism of acute coumarin induced hepatotoxicity in the rat has been investigated by comparing the effects of coumarin with those of a number of methyl substituted coumarin derivatives. Male Sprague-Dawley rats were given single ip doses of corn oil (control), coumarin (0.86 and 1.71 umol/kg body weight), 3,4-dimethylcoumarin (3,4-DMC, 1.71 and 2.57 umol/kg), 3-, 4- and 6-methylcoumarins (3-MC, 4-MC and 6-MC, 1.71 umol/kg/kg) and 3- and 4-methyloctahydrocoumarins (3-MOHC and 4-MOHC, 2.57 umol/kg) and hepatotoxicity assessed after 24 hr. Coumarin administration produced dose related hepatic necrosis and a marked elevation of plasma alanine aminotransferase and aspartate aminotransferase activities. In contrast, none of the coumarin derivatives examined produced either hepatic necrosis or elevated plasma transaminase activities. Treatment with coumarin reduced hepatic microsomal ethyl morphine N-demethylase and 7-ethoxycoumarin O-deethylase activities, whereas one or both mixed function oxidases appeared to be induced by treatment with 3,4-DMC, 4-MC, 3-MOHC and 4-MOHC. ... Acute coumarin induced hepatotoxicity in the rat is due to the formation of a coumarin 3,4-epoxide intermediate. That 3- and/or 4-methyl substitution (ie 3-MC, 4-MC and 3,4-DMC) leads to a reduction ln coumarin induced hepatotoxicity, due to diminished formation of 3,4-epoxide intermediates, was confirmed by the results of molecular orbital calculations. [R29] +... CONCLUSIONS: Under the conditions of these 2 yr gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. [R30] NTXV: *LD50 Rat oral 293 mg/kg; [R17] *LD50 Mouse oral 196 mg/kg; [R17] *LD50 Mouse ip 220 mg/kg; [R17] *LD50 Mouse sc 242 mg/kg; [R17] NTP: +Toxicity and carcinogenicity studies were conducted by administering coumarin (97% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were admin coumarin in corn oil by gavage at doses of 0 25, 50, or 100 mg/kg body weight. ... 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were admin coumarin in corn oil by gavage at doses of 0 50, 100, or 200 mg/kg body weight for up to 2 yr. ... CONCLUSIONS: Under the conditions of these 2 yr gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration. [R30] ADE: *A SPECIES DIFFERENCE HAS BEEN REPORTED FOR THE EXCRETION OF AN ORAL DOSE OF (14)C-COUMARIN. WITHIN 4 DAYS RATS EXCRETED 47% OF THE LABEL IN THE URINE AND 39% IN THE FECES, WHEREAS RABBITS EXCRETED 92% IN THE URINE AND NEGLIGIBLE AMT IN THE FECES. [R31, 87] *EXCRETION OF (14)C WAS RAPID IN THE RABBIT /AFTER ORAL ADMINISTRATION OF (14)C-COUMARIN/, AND 80% WAS ELIMINATED IN THE 24 HR URINE INDICATING ALSO THAT IT IS WELL ABSORBED... [R31, 87] *THE REASON FOR THE CONSIDERABLE FECAL EXCRETION OF (14)C /AFTER ORAL ADMIN OF (14)C-COUMARIN/ IN RAT...MAY REPRESENT UNABSORBED MATERIAL. ... [R31, 87] *TWENTY-FOUR HR AFTER AN IP DOSE TO RATS OF ... (14)C-COUMARIN, 38% HAD BEEN EXCRETED IN THE URINE, 13% IN THE FECES, 30% WAS EXCRETED IN THE AIR AS (14)C-CARBON DIOXIDE AND 9% OF THE REMAINDER WAS MAINLY PRESENT IN THE CECUM. [R32] *... /ORALLY ADMIN 3-(14)C-COUMARIN/ WAS RAPIDLY ABSORBED IN RATS AND WIDELY DISTRIBUTED IN SERUM, LIVER AND KIDNEY WITHIN 5 MIN, SERUM LEVELS REACHING MAXIMUM AFTER ABOUT 30 MIN. [R19, p. V10 116] *IN MAN, 68-92% OF AN ORAL DOSE OF COUMARIN WAS EXCRETED IN URINE AS 7-HYDROXY COUMARIN AND 1-6% AS 2-HYDROXYPHENYLACETIC ACID. [R19, p. V10 116] *IV AND ORAL ADMIN REVEALED THAT ALL OF COUMARIN IS ABSORBED, HOWEVER, ONLY APPROX 2-6% REACHES SYSTEMIC CIRCULATION IN INTACT FORM. FRACTION OF UNCHANGED DRUG REACHING SYSTEMIC CIRCULATION VARIED BETWEEN 0 and 38% ASSUMING LIVER BLOOD FLOW RATE OF 1.53 L/MIN. [R33] *IN BLOOD, BRAIN, HEART, LUNG, MUSCLE, AND SPLEEN, PEAK CONCN WERE OBSERVED 2.5 MIN AFTER RETROORBITAL INJECTION OF (14)C-LABELED COUMARIN. LIVER AND KIDNEY SHOWED GREATEST ACCUM WITH PEAK CONCN BEING REACHED AFTER 10 MIN. BLOOD AND BRAIN CONCN WERE EQUAL. [R34] *UNMETABOLIZED COUMARIN WAS FOUND IN ALL ORGANS STUDIED; 7-HYDROXYCOUMARIN (7-HC) WAS FOUND IN ALL ORGANS BUT BRAIN, and 7-HC GLUCURONIDE WAS FOUND IN ALL ORGANS BUT BRAIN AND SPLEEN. APPARENTLY, COUMARIN CROSSES BLOOD BRAIN BARRIER BUT THE METABOLITES DO NOT. [R34] *THE CHICKEN EXCRETES (14)C-LABELED COUMARIN SIMILAR TO MAN AND SUGGESTS THAT THIS SPECIES IS MOST APPROPRIATE MODEL FOR COUMARIN PHARMACODYNAMIC STUDIES APPLICABLE TO HUMANS. ANALYSIS OF URINE FROM INFUSED AND CONTROL SIDE KIDNEYS INDICATE NEG COUMARIN TUBULAR SECRETION. [R35] METB: */THE RAT CAN/ HYDROXYLATE COUMARIN IN THE 3-POSITION. AS CAN ... THE RABBIT ... [R36] *THE HEPATIC ENZYME SYSTEM, COUMARIN-7-HYDROXYLASE, RESPONSIBLE FOR A HIGH PROPORTION OF THE HYDROXYLATION OF COUMARIN IN CATS, GUINEA PIGS, HAMSTERS, RABBITS, AND ESP IN MAN, IS ABSENT FROM THE LIVERS OF FERRETS, MICE AND RATS. RAT LIVER CONTAINS AN INHIBITOR OF THIS ENZYME. [R31, 399] *IN MAN, 7-HYDROXYCOUMARIN IS THE PRINCIPAL METABOLITE (68-92%), BUT IN RATS AND RABBITS, 3-HYDROXYCOUMARIN AND ITS DEGRADATION PRODUCTS, O-HYDROXYPHENYL-LACTIC ACID AND O-HYDROXYPHENYLACETIC ACID PREDOMINATE 39-49%. [R31, 399] *IN MAN, 68-92% OF AN ORAL DOSE OF COUMARIN WAS EXCRETED IN URINE AS 7-HYDROXY COUMARIN AND 1-6% AS 2-HYDROXYPHENYLACETIC ACID. [R19, p. V10 116] *o-Hydroxyphenylacetaldehyde was the major metabolite of coumarin (1 uM) in rat gerbil and human liver microsomes. Treatment of rats with phenobarbitone (PB) or beta-naphthoflavone increased the o-hydroxyphenylacetaldehyde formed. 3-Hydroxycoumarin was the other main metabolite produced by rat liver microsomes. Liver microsomal metabolism of coumarin in gerbil was extensive with 3-, 5-, 6-, 7- and 8-hydroxycoumarins and 3,7- and 6, 7-dihydroxycoumarins produced in addition to o-hydroxyphenylacetaldehyde. The profile of the hydroxy metabolites was altered by in vivo treatment of gerbils with cytochrome p450 inducers but there was no increase of coumarin metabolism. Coumarin was metabolized by human liver microsomes to o-hydroxyphenylacetaldehyde, 7-hydroxycoumarin, 3-hydroxycoumarin and trace amounts of 5-, 6- and 8-hydroxycoumarins. At low substrate concentratlons (0-10 uM) hepatic microsomal metabolism of coumarin in gerbil resembled that in man with 7-hydroxycoumarin being a major metabolite. However the production of o-hydroxyphenylacetaldehyde was greater in gerbil than human liver microsomes. At higher substrate concentrations (l mM) metabolism of coumarin by liver microsomes from PB treated gerbils most closely resembled that by human liver microsomes. The gerbil would appear to be a more appropriate animal model than rat for studies to assess the toxicological hazard of coumarin in man. [R37] *To investigate the effects that methoxsalen or the dose of coumarin has on the excretion of the major metabolite of coumarin (7-hydroxycoumarin) on healthy male volunteers ages 23 to 35 yr were given 5, 25 or 50 mg of oral coumarin and on different days were given 5 mg of coumarin 30 min after receiving 10 or 30 mg of oral methoxsalen; urine samples were analyzed for 7-hydroxycoumarin. Results indicated that the extent of metabolite formation and velocity of excretion is constant in the range between 5 and 50 mg of coumarin. However simultaneous administration of coumarin and methoxsalen provided a dose dependent diminution of total metabolite excretion. ... Methoxsalen may inhibit phase-1 metabolism. [R38] *The hepatic microsomal metabolism of coumarin was studied in vitro. Liver microsomes prepared from untreated or aroclor-1254 pretreated male Sprague-Dawley rats were incubated with up to 25 uM (14)C labeled coumarin. ... The major metabolite was produced at a much higher rate in microsomes from aroclor-1254 pretreated rats than in microsomes from unpretreated rats; it was identified as o-hydroxyphenylacetaldehyde and is a major metabolite of coumarin in rat hepatic microsomes. [R39] *Coumarin is 7-hydroxylated by the p450 isoform Cyp2a-5 in mice and CYP2A6 in humans. Various chemicals were evaluated as possible inhibitors of coumarin 7-hydroxylase (COH) activities in mouse microsomes. ... Furanocoumarin derivatives methoxsalen and psoralen proved to be the most potent inhibitors of mouse COH activity (IC50 values 1.0 and 3.1 uM respectively). The furanocoumarins, bergapten, isopimpinellin, imperatorin and sphondin also effectively inhibited mouse COH activity (IC50 values 19-40 uM). Methoxsalen, isopimpinellin and metyrapone were also inhibitors in mice in vivo. Methoxsalen was a potent inhibitor of COH activity also in human liver microsomes (IC50 value 5.4 uM) whereas bergapten, isopimpinellin and imperatorin had no effect. The imidazole antimycotic miconazole was a potent but non-specific inhibitor of COH activity. ... The coumarin type compounds in particular interact with the active sites of Cyp2a-5 and CYP2A6 are structurally different since a number of compounds inhibited mouse but not human COH activity. [R40] *The metabolism of 3-(14)C coumarin has been studied in rat hepatic microsomes and with two purified cytochrome p450 isoenzymes. 3-(14)C Coumarin was converted by liver microsomes to several polar products including 3- and/or 5-hydroxycoumarin, omicron-hydroxyphenylacetic acid and a major unidentified coumarin metabolite. 3-(14)C Coumarin was also converted to reactive metabolite(s) as indicated by covalent binding to proteins, and by the depletion of reduced glutathione added to the microsomal incubations. ... [R41] *A test designed to estimate the extent and rate of formation of 7-hydroxycoumarin by measuring the urinary excretion of the metabolite in humans after administering 5 mg coumarin was developed. Coumarin was rapidly metabolized after oral administration and more than 95% of the 7-hydroxycoumarin formed was excreted in 4 hr. The total amount of 7-hydroxycoumarin formed was 64 +/- 15% (mean +l/- SD variation 20-100%) of the dose given. The percentage of 7-hydroxycoumarin excreted in 2 hr as compared with the 7-hydroxycoumarin excretion in 4 hr was found to be constant and stable individual characteristic for the rate of the formation of 7-hydroxycoumarin (2 hr coumarin test). In 110 volunteers there was a great interindividual variability ln the extent and rate of 7-hydroxycoumarin formation. Four individuals had relatively slow coumarin test values (50-60%) but much larger populations would be needed for the demonstration of polymorphism. [R42] *Species differences in coumarin hepatotoxicity appear to be metabolism mediated. The rat in which it is markedly hepatotoxic primarily metabolizes coumarin via 3-hydroxylation and cleavage of the heterocyclic ring. Coumarin is less toxic in the baboon gerbil and certain strains of mice which resemble man in their extensive formation of the 7-hydroxy metabolite. Liver toxicity in patients receiving relatively high daily doses of coumarin is very rare. Recent studies indicate that coumarin 3,4-epoxide is the metabolic intermediate responsible for hepatotoxicity in the rat. [R43] ACTN: *Antibody against purified CYP2Al recognizes two rat liver microsomal P450 enzymes, CYP2Al and CYP2A2, that catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone, respectively. In human liver mlcrosomes~ this antibody recognizes a single protein, namely CYP2A6, which catalyzes the 7-hydroxylation of coumarin. To examine species differences In CYP2A function, liver microsomes from nine mammalian species (rat, mouse, hamster, rabbit, guinea pig, cat, dog, cynomolgus monkey and human were tested for their ability to catalyze the 7 alpha- and 15 alpha-hydroxylation of testosterone and the 7-hydroxylation of coumarin. Antibody against rat CYP2Al recognized one or more proteins In liver mlcrosomes from all mammalian species examined. However, liver mlcrosomes from cat, dog, cynomolgus monkey, and human catalyzed negligible rates of testosterone 7 alpha- and~or 15 alpha-hydroxylation, whereas rat and cat liver mlcrosomes catalyzed negligible rates of coumarin 7-hydroxylation. Formation of 7-hydroxycoumarin accounted for a different proportion of the coumarin metabolites formed by liver mlcrosomes from each of the various species examined. 7-Hydroxycoumarin was the major metabolite (greater than 70%) in human and monkey, but only a minor metabolite (less than 1%) in rat. The 7-hydroxylation of coumarin by human liver mlcrosomes was catalyzed by a single, high-affinity enzyme (Km 0.2-0.6 uM, which was markedly Inhibited (greater than 95%) by antibody against rat CYP2Al. The rate of coumarin 7-hydroxylation varied approximately 17-fold among liver microsomes fromn 22 human subjects. This variation was highly correlated (r2 = 0.956) with interindividual differences In the levels of CYP2A6, as determined by immunoblotting. These results indicate that CYP2A6 is largely or entirely responsible for catalyzing the 7-hydroxylation of coumarin In human liver, microsomes. Treatment of monkeys with phenobarbital or dexamethasone increased coumarin 7-hydroxylase activity, whereas treatment with beta-naphthoflavone caused a slight decrease. In contrast to rats and mice, the expression of CYP2A enzymes In cynomolgus monkeys and humans was not sexually differentiated. Despite their structural similarity to coumarin, the anticoagulants dicumarol and warfarin do not appear to be substrates for CYP2A6. The overall rate of dicumarol metabolism varied approx 5 fold among the human liver microsomal samples, but this variation correlated poorly (r2= 0.126) with the variation observed in CYP2A6 levels and hydroxycoumarin levels. [R44] INTC: *COUMARIN WAS A MODERATE INHIBITOR OF 7,12-DIMETHYLBENZ(A)ANTHRACENE-INDUCED NEOPLASIA OF RAT MAMMARY GLAND. IT ALSO INHIBITED BENZO(A)PYRENE-INDUCED NEOPLASIA OF MOUSE FORESTOMACH. [R45] *The possibility that pretreatment with coumarin would inhibit the genotoxicity of benzo(a)pyrene was investigated in ICR mice. Male and female mice weighing 21 to 24 g were given coumarin in olive oil at doses of 65 g/kg or 139 mg/kg body weight by oral gavage. Controls received only olive oil. The animals were treated daily for 1 week with 1 day of no treatment at midweek. After the six treatments the animals were given benzo(a)pyrene injections (150 mg/kg in olive oil). At various times (12-72 hr) after the BP injection, ... bone marrow smears were examined for the presence of micronuclei in polychromatic erythrocytes. ... Pretreatment with coumarin alone did not cause formation in polychromatic erythrocytes in both males and females. In male animals treated with coumarin prior to benzo(a)pyrene treatment there was a statistically significant reduction in the number of micronucleated polychromatic erythrocytes. To clarify that this reduction was not due to a phase shift in the start of micronuclei production studies were conducted at several time intervals after benzo(a)pyrene injection. Again there was no micronuclei induction by coumarin alone and there was a significant reduction in benzo(a)pyrene induced micronuclei when male mice were pretreated with coumarin. This protective effect of coumarin pretreatment was not seen in female animals. [R46] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Coumarin is a naturally occurring compound found in a large number of plants and may be released as a plant volatile. It is widely used as a fragrance ingredient in soaps, detergents, lotions, perfumes, tobacco and household products. It may be released to the environment during the use of these products. It may also be released to the environment during its production, transport, and disposal. If released on soil, coumarin would be expected to leach and readily biodegrade. Photolysis would be expected to occur in surface layers of soil. If released in water, coumarin would be expected to biodegrade. In addition some volatilization losses may occur, especially in rapidly flowing rivers and streams. Losses resulting from photolysis may occur in surface layers of water. Coumarin is not expected to bioconcentrate in aquatic organisms. In the atmosphere, coumarin is estimated to have a half-life of 9 hr as a result of its reactions with photochemically-produced hydroxyl radicals and ozone. The general population is exposed to low concns of coumarin in the air they breathe. People may be exposed to coumarin by dermal contact and inhalation in using a variety of personal care and household products and tobacco that contain this chemical as a fragrance. (SRC) NATS: *REPORTED IN TONKA BEAN (DIPTERYX ODORATA) SEED, THE FLOWERS OF MELILOTUS OFFICIALIS, THE LEAVES OF MELILOTUS ALBUS, IN LIATRIS ODORATISSIMA, ASPERULA ODOROSA, WILD VANILLA (ACHLYS TRIPHYLLA), LAVENDER OIL, AND SEVERAL VARIETIES OF ORCHID. [R2] *...FOUND IN EDIBLE PLANTS SUCH AS STRAWBERRIES, BLACKCURRENTS, APRICOTS, AND CHERRIES... [R47] *Coumarin is a naturally occurring compound found in a large number of plants belonging to many different families, including tonka beans, woodruff, lavender oil, cassia, meliot and sweet clover(1,2). It may therefore be released as a plant volatile(SRC). [R48] ARTS: *Coumarin is widely used as a fragrance ingredient in soaps, detergents, lotions, perfumes, tobacco and household products(1). It is released to the environment during the use of these products. It may also be released to the environment during its production, transport, and disposal(SRC). [R49] FATE: *TERRESTRIAL FATE: Based on estimates made from molecular structure, coumarin would not adsorb strongly to soil(1). Coumarin is readily biodegrable according to screening tests(2,3). Therfore, if released on soil, coumarin would be expected to leach and readily biodegrade. Photolysis would be expected to occur on surface layers of soil(4,SRC). [R50] *AQUATIC FATE: Based on the results of screeing studies(1,2), if released in water, coumarin would be expected to biodegrade. Losses resulting from photolysis may occur in surface layers(3). In addition some volatilization losses may occur, especially in rapidly flowing rivers and streams. Estimates based on molecular structure indicate that coumarin would not be expected to adsorb to sediment or bioconcentrate in aquatic organisms(5,SRC). [R51] *ATMOSPHERIC FATE: In the atmosphere, coumarin will react with photochemically-produced hydroxyl radicals and ozone. The resulting half-life is estimated to be 9 hr. (SRC) BIOD: *In a 5 day biodegradation screening test using an activated sludge inoculum, 29.5% of coumarin was mineralized(1). In a BOD test using a sludge inoculum, 100% of theoretical degradation occurred in 2 weeks(2). [R52] ABIO: *In a photomineralization test in which coumarin was adsorbed on silica gel and exposed to UV radiation > 290 nm for 17 hr, 59.2% of the test compound was mineralized to CO2(1). A coumarin dimer is formed under prolonged exposure to sunlight or UV radiation(2). While the lactone ring in coumarin is readily hydrolyzed by alkalies(2), no data are available concerning the hydrolysis of coumarin under environmental conditions. In the atmosphere, coumarin reacts with photochemically-produced hydroxyl radicals and ozone with rate constants of 13.2X10-12 and 2.1X10-17 cu cm/molecule-s, respectively(3). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm and an ozone concn of 7X10+11 molecules/cu cm, the overall half-life of coumarin in the atmosphere would be 9.0 hr(SRC). [R53] BIOC: *The BCF of coumarin in green algae (Chlorella sp.) after exposure to 50 ug/L of coumarin for 24 hr was 42(1). The BCF in golden orfe was < 10 after 3 days exposure(1). The log Kow for coumarin is 1.39(2). Using this log Kow, one can estimate a BCF of 6.7 for coumarin using a recommended regression equation(3). The experimental and estimated BCFs indicate that coumarin has a very low potential for bioconcentration in fish and aquatic organisms(SRC). [R54] KOC: *The log Koc for coumarin estimated from molecular structure is 146(1). According to a suggested classification scheme(2), this estimated Koc suggests that coumarin would possess high mobility in soil and leach(SRC). [R55] VWS: *The Henry's Law constant for coumarin estimated from structure activity relationships is 6.95X10-6 atm-cu-m/mol(1). Using this value for the Henry's Law constant, one can estimate a volatilization half-life for coumarin of 6.5 days in a model river 1 m deep flowing at 1 m/s with a wind speed of 3 m/s(2,SRC). Similarly, the volatilization half-life of coumarin from a model lake 1 m deep, with a 0.05 m/s current and a 0.5 m/s wind is estimated to be 51 days(2,SRC). [R56] ATMC: *RURAL/REMOTE: The concn of coumarin over the southern North Atlantic Ocean (20 m high) was 0.10 ng/cu m(1). [R57] RTEX: *People may be exposed to coumarin by dermal contact and inhalation by using a variety of personal care and household products and tobacco that contain this chemical as a fragrance. Coumarin is naturally found in plants which may be responsible for the low concn of coumarin found in the atmosphere in remote areas. Therefore the general population will be exposed to coumarin in the air they breathe. (SRC) BODY: *In 387 expired air samples from 54 normal subjects, 63.1% contained coumarin(1). The geometric mean concentration was 1.0(1). As part of EPA's National Human Adipose Tissue Survey, 46 composite adipose fat samples in FY82 were analyzed(2). One of these samples, from an over 45 yr age group from the northeast, contained coumarin. [R58] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GC METHOD FOR DETERMINATION OF COUMARIN IN FLAVORS. [R59, p. 13/193 11.079] *COUMARIN UV ABSORBANCE IS DETERMINED IN VANILLIN SPECTROPHOTOMETRICALLY AT 325 NM. [R59, p. 13/308 19.023] *CITRUS PEEL OILS WERE EXAMINED BY HIGH-PERFORMANCE LIQ CHROMATOGRAPHY FOR THEIR COUMARIN AND PSORALEN CONTENT. RESOLUTION AND IDENTIFICATION WAS CARRIED OUT ON MICRO CN, C-18, AND PORASIL COLUMNS. COUMARINS AND PSORALENS WERE DETECTED AT 320 and 305 NM. [R60] *AOAC Method 976.12. Coumarin in Wines. Gas chromatography with flame ionization detector (GC/FID) detection limit not reported. [R61, p. V2 750] *AOAC Method 955.31. Vanillin, ethyl vanillin, and coumarin in vanilla extract. Spectrophometer detection limit not reportd. [R61, p. V2 892] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Coumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 422 (1993) NIH Publication No. 93-3153 Schardein JL; Drugs Affecting Blood. Chemically Induced Birth Defects 2: 106-25 (1993). Review of the fetal toxicity of anticoagulants. Cole MS et al; Surgery 103 (3): 271-7 (1988). Coumarin necrosis, a review of the literature. Comp PC; Drug Saf 8 (2): 128-35 (1993). A review of coumarin induced skin necrosis. Pelkonen O et al; J Cancer Res Clin Oncol 120: S30-1 (1994). Review of the regulation of coumarin 7-hydroxylation in man. Pineo GF, Hull RD; Drug Safety 9: 263-71 (1993). A review on the adverse effects of coumarin anticoagulants. SO: R1: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 343 R2: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 109 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 208 R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 622 R5: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 587 R6: RITSCHEL WA ET AL; INT J CLIN PHARMACOL BIOPHARM 17(3) 99 (1979) R7: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 143 R8: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R9: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-257 R10: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 401 R11: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 318 R12: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-77 R13: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R14: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-256 R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 449 R16: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 520 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 813 R18: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 579 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R20: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 145 R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 61 (1987) R22: Gladson CL et al; Arch Dermatol 123 (12): 1701a-6a (1987) R23: EVANS JG ET AL; FOOD COSMET TOXICOL 17 (3): 187 (1979) R24: LAKE BG ET AL; BIOCHEM SOC TRANS 8 (1): 96 (1980) R25: PILLER NB; ARZNEIM FORSCH 27 (5): 1069 (1977) R26: Fernyhough L et al; Toxicol 88 (1-3): 113-25 (1994) R27: Fentem JH et al; Toxicol 71 (1-2): 129-36 (1992) R28: Lake BG, Evans JG; Food Chem Toxicol 31 (12): 963-70 (1993) R29: Lake BG et al; Food Chem Toxicol 32 (4): 357-63 (1994) R30: Toxicology and Carcinogenesis Studies of Coumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 422 (1993) NIH Publication No. 93-3153 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R31: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. R32: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 151 R33: RITSCHEL WA ET AL; INT J CLIN PHARMACOL BIOPHARM 17 (3): 99 (1979) R34: RITSCHEL WA ET AL; ARZNEIM FORSCH 30 (2): 260 (1980) R35: CACINI W ET AL; ARCH INT PHARMACODYN THER 243 (2): 197 (1980) R36: LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971. 191 R37: Fentem JH, Fry JR; Xenobiotica 22 (3): 357-67 (1992) R38: Kraul H et al; Pharmazie 47: 389-90 (1992) R39: Lake BG et al; Food Chem Toxicol 30 (2): 99-104 (1992) R40: Maenpaa J et al; Biochem Pharmacol 45 (5): 1035-42 (1993) R41: Peters MM et al; Xenobiotica 21 (4): 499-514 (1991) R42: Rautio A et al; Pharmacogenetics 2 (5): 227-33 (1992) R43: Fentem JH, Fry JR; Comp Biochem Physiol C 104 (1) 1-8 (1993) R44: Pearce R et al; Arch Biochem Biophys 298 (1): 211-25 (1992) R45: WATTENBERG LW ET AL; CANCER RES 39 (5): 1651 (1979) R46: Morris DL, Ward JB; Environ Mol Mutagen 19 (2): 132-8 (1992) R47: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 722 R48: (1) Budavari D et al; The Merck Index 11th ed p. 401 Rahway, NJ: Merck and Co Inc (1989) (2) Boisde PM, Meuly WC; pp. 647-58 in Kirk-Othmer Encycl Chem Technol 4th ed. New York, NY: Wiley Interscience Vol 7 (1993) R49: (1) Boisde PM, Meuly WC; pp. 647-58 in Kirk-Othmer Encycl Chem Technol 4th ed. New York, NY: Wiley Interscience Vol. 7 (1993) R50: (1) Meylan WM et al; Environ Sci Technol 26:1560-7 (1992) (2) Freitag D et al; Chemosphere 14: 1589-616 (1985) (3) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (4) Freitag D et al; Chemosphere 14: 1589-616 (1985) R51: (1) Freitag D et al; Chemosphere 14: 1589-616 (1985) (2) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (3) Freitag D et al; Chemosphere 14: 1589-616 (1985) (4) Meylan WM et al; Environ Sci Technol 26:1560-7 (1992) (5) Freitag D et al; Ecotox Environ Saf 6: 60-81 (1982) R52: (1) Freitag D et al; Chemosphere 14: 1589-616 (1985) (2) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R53: (1) Freitag D et al; Chemosphere 14: 1589-616 (1985) (2) Boisde PM, Meuly WC; pp. 647-58 in Kirk-Othmer Encycl Chemi Technol New York, NY: Wiley Interscience 4th ed. Vol 7 (1993) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R54: (1) Freitag D et al; Ecotox Environ Saf 6: 60-81 (1982) (2) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5, Eqn 5.2 (1982) R55: (1) Meylan WM et al; Environ Sci Technol 26:1560-7 (1992) (2) Swann RL et al; Res Rev 85:17-28 (1983) R56: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) R57: (1) Duce RA et al; Rev Geophys Space Phys 21: 921-52 (1983) R58: (1) Krotoszynski BK et al; J Analyt Toxicol; 3: 225-34 (1979) (2) Onstot JD, Stanley JS; Identification of SARA Compounds in Adipose Tissue. USEPA-560/5-89-003 (1989) R59: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982. R60: FISHER JF ET AL; J AGRIC FOOD CHEM 27(6) 1334 (1979) R61: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 RS: 45 Record 139 of 1119 in HSDB (through 2003/06) AN: 1627 UD: 200302 RD: Reviewed by SRP on 5/11/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 3,3'-DIMETHOXYBENZIDINE- SY: *ACETAMINE-DIAZO-BLACK-RD-; *ACETAMINE-DIAZO-NAVY-RD-; *AI3-00864-; *AMACEL-DEVELOPED-NAVY-SD-; *AZOENE-FAST-BLUE-BASE-; *AZOGENE-FAST-BLUE-B-; *Benzidene,-3,3'-dimethoxy-; *(1,1'-Biphenyl)-4,4'-diamine, 3,3'-dimethoxy-; *Biphenyl,-4,4'diamino-3,3'dimethoxy-; *BLUE-BASE-IRGA-B-; *BLUE-BASE-NB-; *BLUE-BN-BASE-; *BRENTAMINE-FAST-BLUE-B-BASE-; *CELLITAZOL-B-; *Cellitazol-BN-; *C.I.-DISPERSE-BLACK-6-; *CIBACETE-DIAZO-NAVY-BLUE-2B-; *DIACELLITON-FAST-GREY-G-; *DIACEL-NAVY-DC-; *Di-p-aminodi-m-methoxydiphenyl-; *4,4'-DIAMINO-3,3'-DIMETHOXYDIPHENYL-; *o-Dianisidina- (Italian); *O-DIANISIDIN- (CZECH, GERMAN); *Dianisidine-; *O-DIANISIDINE-; *DIATO-BLUE-BASE-B-; *DIAZO-FAST-BLUE-B-; *3,3'-DIMETHOXYBENZIDIN- (CZECH); *3,3'-Dimethoxybiphenyl-4,4'-diamine-; *3,3'-DIMETHOXY-4,4'-DIAMINOBIPHENYL-; *3,3'-DIMETOSSIBENZODINA- (ITALIAN); *FAST-BLUE-B-BASE-; *FAST-BLUE-DSC-BASE-; *HILTONIL-FAST-BLUE-B-BASE-; *KAYAKU-BLUE-B-BASE-; *LAKE-BLUE-B-BASE-; *MEISEI-TERYL-DIAZO-BLUE-HR-; *MITSUI-BLUE-B-BASE-; *NAPHTHANIL-BLUE-B-BASE-; *NEUTROSEL-NAVY-BN-; *SETACYL-DIAZO-NAVY-R-; *SPECTROLENE-BLUE-B- RN: 119-90-4 MF: *C14-H16-N2-O2 HAZN: U091; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. ASCH: 3,3'-Dimethoxybenzidine dihydrochloride; 20325-40-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The methyl ether of o-nitrophenol is reduced by zinc dust and caustic soda to the hydrazo cmpd which is then rearranged with hydrochloric acid. [R1] FORM: *IT IS AVAILABLE COMMERCIALLY AS FREE BASE (TECHNICAL AND 99% GRADES) AND AS ITS DIHYDROCHLORIDE. [R2] OMIN: *3,3'-Dimethoxybenzidine is apparently not produced in the US any longer but may still be imported into the country. [R3] USE: *CHEMICAL INTERMEDIATE IN PRODN OF O-DIANISIDINE DIISOCYANATE ... ; FOR DETECTION OF PRESENCE OF THIOCYANATES, NITRITES AND A NUMBER OF METALS. [R4] *USED IN DYEING LEATHER, PAPER, PLASTIC, RUBBER, TEXTILES [R5] *CHEM INT FOR PIGMENTS, EG, PIGMENT ORANGE 16; DYE FOR ACETATE RAYON (FORMER USE) [R6] *Azo dye intermediate [R1] *Chemical intermediate in the production of azo dyes [R3] CPAT: *ESSENTIALLY 100% AS A CHEM INT FOR DYES AND PIGMENTS [R6] PRIE: U.S. PRODUCTION: *(1967) 368,000 lbs [R7] U.S. IMPORTS: *(1984) 106,005 lb [R8] *(1983) 655,000 lb [R7] *(1977) 55,500 lb [R7] *(1971) 273,000 lb [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LEAFLETS OR NEEDLES FROM WATER [R9]; +Colorless crystals that turn a violet color on standing. [R10] MP: *137 deg C [R1] MW: *244.29 [R11] OWPC: *log Kow = 1.81 [R12] PH: *WEAK BASE [R2] SOL: *Sol in alc, benzene, ether [R11]; *Sol in chloroform, acetone [R13]; *PROBABLY SOL IN MOST ORG SOLVENTS AND LIPIDS [R2]; *In water, 60 mg/l @ 25 deg C [R14] SPEC: *IR: 717 (Sadtler Research Laboratories IR Grating Collection) [R13]; *UV: 1738 (Sadtler Research Laboratories Spectral Collection) [R13]; *NMR: 3193 (Sadtler Research Laboratories Spectral Collection) [R13]; *MASS: 70844 (NIST/EPA/MSDC Mass Spectral Database, 1990 version) [R13] VAPD: *8.43 (air= 1) [R15] OCPP: *HAS GENERAL CHARACTERISTICS OF PRIMARY AROMATIC AMINES [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat or flame. [R16] NFPA: *Flammability: 1. 1= Materials that must be preheated before ignition can occur. Water may cause frothing if it gets below the surface of the liquid and turns to steam. ... water fog gently applied to the surface will cause a frothing which will extinguish the fire. [R15] *Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R15] FLPT: *206 deg C (403 deg F) (closed cup) [R15] FIRP: *WATER, CARBON DIOXIDE, DRY CHEMICAL. [R17] TOXC: *When heated to decomp it emits toxic fumes of /nitrogen oxides/. [R16] EXPL: *The finely powdered carcinogen is a significant dust explosion hazard. [R18] REAC: *... Can react with oxidizing materials. [R17] *Oxidizers. [R19] DCMP: *When heated to decomp it emits toxic fumes of /nitrogen oxides/. [R16] SERI: *... CAN CAUSE SKIN IRRITATION ... [R20] EQUP: *USE GLOVES AND GOGGLES TO AVOID CONTACT WITH SKIN AND EYES. USE EFFECTIVE FUME REMOVAL DEVICE OR OTHER RESPIRATORY PROTECTION. [R21] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R22, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R19] *Wear appropriate eye protection to prevent eye contact. [R19] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R19] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R19] *Respirator Recommendations: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: (APF = 10,000) Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode/(APF = 10,000) Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained positive-pressure breathing apparatus. [R19] *Respirator Recommendations: Escape: (APF = 50) Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter/Any appropriate escape-type, self-contained breathing apparatus. [R19] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R22, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R19] *The worker should wash daily at the end of each work shift. [R19] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R19] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R19] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R22, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R22, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R22, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R22, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U091, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R23] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R24] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R22, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R22, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R22, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Inadequate evidence of carcinogenicity in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans. [R25] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aniline and related compounds/ [R26, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aniline and related compounds/ [R26, 207] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R22, 1979.23] HTOX: *NO EPIDEMIOLOGICAL DATA ON OCCURRENCE OF CANCER IN WORKERS EXPOSED TO O-DIANISIDINE ALONE APPEAR IN LITERATURE. MOST WORKERS EXPOSED ... HAVE ALSO BEEN EXPOSED TO RELATED AMINES SUCH AS BENZIDINE, WHICH HAS BEEN STRONGLY ASSOCIATED WITH OCCURRENCE OF URINARY BLADDER CANCER IN MAN. [R27] NTOX: *... 30 MG O-DIANISIDINE ... /WAS GIVEN/ BY STOMACH TUBE TO RATS 3 TIMES/WK FOR 13 MO. ... TWO RATS HAD ZYMBAL GLAND TUMORS, ONE AN OVARIAN TUMOR AND ONE A FIBROADENOMA OF MAMMARY GLAND. NONE OF THE 50 RATS IN A CONTROL GROUP DEVELOPED TUMORS AT THESE SITES. /DIAMINE WAS GIVEN/ ... BY STOMACH TUBE TO 30 MALE AND 30 FEMALE FISCHER RATS IN DOSES RANGING FROM 0.1-30 MG/ANIMAL IN A STEROID SUSPENDING VEHICLE (SODIUM CHLORIDE, SODIUM CARBOXYMETHYL CELLULOSE, POLYSORBATE 80, BENZYL ALCOHOL, AND WATER) 5 DAYS/ WK FOR 52 WK. TUMORS APPEARED IN 293 DAYS, BUT MOST WERE FOUND ON AUTOPSY AT 18 MO. SIX RATS GIVEN THE 1 MG DOSES AND 6 ... GIVEN THE 3 MG DOSES HAD A TOTAL OF 8 TUMORS; 29 ANIMALS RECEIVING THE 10 MG DOSES HAD A TOTAL OF 19 TUMORS; AND 6 RATS GIVEN 30 MG DOSES HAD A TOTAL OF 5 TUMORS. TUMORS OCCURRED AT VARIOUS SITES INCLUDING THE BLADDER (2 PAPILLOMAS), INTESTINE (3 CARCINOMAS), SKIN (5 CARCINOMAS) AND ZYMBAL GLAND (3 CARCINOMAS). THESE TUMORS WERE NOT FOUND IN 360 CONTROL ANIMALS GIVEN VEHICLE ALONE. [R28] *... 0.1% AND 1.0% ... /WAS FED TO/ GROUPS OF 30 MALE AND 30 FEMALE SYRIAN GOLDEN HAMSTERS. ONE URINARY BLADDER TUMOR OCCURRED IN GROUP RECEIVING ... /0.1%/. NO PRIMARY BLADDER TUMORS, BUT FORESTOMACH PAPILLOMAS, OCCURRED IN 37% ... FED 1% OF THE AMINE. OF CONTROL GROUP ... 2% DEVELOPED STOMACH PAPILLOMAS ... NONE HAD ... BLADDER TUMORS. [R28] *3,3'-Dimethoxybenzidine test results for heritable genetic effects in Drosophila, tested negative for sex-linked recessive lethal. [R29] *The Ames Salmonella/microsome test was used to compare the mutagenic response of Salmonella typhimurium TA100, TA98, TA1538, and TA1535 to 12 benzidine derivatives, ie, benzidine, 3,3'-dimethoxybenzidine, 3,3'-dimethylbenzidine, 3,3'-dichlorobenzidine, and the corresponding N- and N,N'-diacetylated derivatives. With a few exceptions, the mutagenic response to this series of compounds varied in the order TA98 greater than TA1538 greater than TA100 greater than TA1535 = 0, and the N-monoacetylated derivatives were more mutagenic than either the parent diamines or the N,N'-diacetyl derivatives. The relative mutagenicities of the parent amines for TA98, were 3,3'-dichlorobenzidine much greater than 3,3'-dimethoxybenzidine greater than benzidine greater than 3,3'-dimethylbenzidine. [R30] *The carcinogenicity of 3,3'-dimethyoxybenzidine, a congener of the known human bladder carcinogen benzidine, was evaluated in F344/N rats. Male and female rats were given 0, 80, 170, or 330 ppm of 3,3'-dimethoxybenzidine dihydrochloride in their drinking water for up to 21 months. Animals were sacrificed at 9 and 21 months for detailed necropsies and histopathologic examination. After 9 months of exposure, chemical related neoplastic effects included liver foci, carcinoma of the preputial gland, carcinoma of the clitoral gland, and carcinoma of the Zymbal gland. Chemical related nonneoplastic effects included hematopoietic cell proliferation in the spleen and cystic and centrilobular degeneration and necrosis of the liver. Significantly increased incidences of neoplasms were observed in skin, Zymbal gland, preputial and clitoral glands, oral cavity, small and large intestines, liver, brain, mesothelium, mammary gland, and uterus of treated animals. 3,3'-dimethyoxybenzidine is clearly carcinogenic in male and female F344/N rats. /3,3'-Dimethoxybenzidine dihydrochloride/ [R31] *The benzidine congener 3,3'-dimethoxybenzidine and CI Direct Blue 15 (Blue 15), a prototypical compd. of the 3,3'-dimethoxybenzidine derived class of dyes, were evaluated in 13 week studies to characterize the toxicity. Fischer 344 rats of each sex were administered either 3,3'-dimethoxybenzidine, or Blue 15, at 1 of 5 concentrations in drinking water for 13 weeks. 3,3'-dimethoxybenzidine concentrations were 0, 0.017, 0.033, 0.063, 0.125, and 0.25% for males and females. For Blue 15, the concentrations were 0.063, 0.125, 0.25, 0.50, and 1.0% for females and 0, 0.125, 0.25, 0.50, 1.0, and 3.0% for male rats. Liver and kidney weights were increased in rats treated with both compounds. Target organs for 3,3'-dimethoxybenzidine treated rats were the kidney and thyroid. These lesions were characterized by chronic nephropathy, and increased pigment in the follicular cells of the thyroid. The kidney and liver were identified as target organs for Blue 15 treated rats. In the high dose rats that died before termination of the study, renal effects were characterized by degeneration and focal necrosis of proximal tubular epithelial cells. Liver lesions in this group consisted of degeneration and necrosis of hepatocytes, fatty metamorphosis, and minimal megalocytosis. Mild chronic nephropathy was the principal histological effect in Blue 15 treated rats surviving to study termination. [R32] *The carcinogenicity of 3,3'-dimethoxybenzidine, a congener of the known human bladder carcinogen benzidine, was evaluated in BALB/c mice. Male and female mice were given 0, 20, 40, 80, 160, 315, or 630 ppm of 3,3'-dimethoxybenzidine dihydrochloride in their drinking water. There was no treatment related effect upon mortality or pathology. /It was/ concluded that 3,3'-dimethoxybenzidine is not carcinogenic in BALB/c mice under the described conditions. /3,3'-Dimethoxybenzidine dihydrochloride/ [R33] *Covalent binding of benzidine and some congeners to hemoglobin was studied in female Wistar rats after oral administration. Hemoglobin adducts were hydrolyzed under alkaline conditions, and the arylamines analysed by high performance liquid chromatography. With benzidine, three cleavage products were observed, the major component being monoacetylbenzidine. This indicates that 4-nitroso-4'-N- acetylaminobiphenyl is the major reactive metabolite in erythrocytes. In addition benzidine and 4-aminobiphenyl were identified. With 3,3'-dichlorobenzidine dihydrochloride, 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine two cleavage products were observed, the parent diamines being present in excess to or in amounts comparable to the monoacetyl derivative. With 3,3',5,5'-tetramethylbenzidine a hemoglobin adduct could not be found. When the azo dye direct red 28 was administered to the animals, the three cleavage products typical for benzidine were found, indicating that benzidine became bioavailable after reductive cleavage of the azo compound. In this case the fraction of 4-aminobiphenyl was greater than after benzidine. It is proposed to use the analysis of hemoglobin adducts in human blood to control the exposure of individuals to these carcinogenic chemicals in the course of biochemical effect monitoring. [R34] *The relationship between the structure and mutagenicity of benzidine analogues was examined. The mutagenic activities of benzidine, benzidine dihydrochloride, and their analogues, 3,3'-diaminobenzidine, 3,3'-dichlorobenzidine, 3,3'-dimethoxybenzidine, 3,3'-dimethoxybenzidine dihydrochloride, and N,N,N',N'-tetramethylbenzidine, were evaluated in the Ames assay. Salmonella strains (TA-100) and (TA-98) were used, with or without metabolic activation by liver S9 mix from male Sprague-Dawley rats induced with aroclor-1254. In the absence of S9 mix only 3,3'-dichlorobenzidine in strain TA-98 showed significant mutagenic activity. In the presence of S9 mix all compounds except N,N,N',N'-tetramethylbenzidine were mutagenic in strain TA-100. Bridged diphenyl compounds showed mutagenicity equal to or greater than that of the parent compound, benzidine. In strain TA-98 biphenyl compounds were more mutagenic than the bridged diphenyl compounds. No significant differences in mutagenicity were seen between the free base and dihydrochloride salt forms of benzidine or its dimethoxy analogue. Compounds capable of inducing frame shift mutations must have a planar aromatic moiety and an activated electrophilic side chain, mutagenicity in this series of compounds increases with decreasing basicity of the aniline moiety. [R35] *Dimethoxybenzidine and dimethylbenzidine are used to synthesize dyes such as CI Direct Blue 15 and CI Acid Red 114, respectively. These commercially used dyes are metabolically degraded to dimethoxybenzidine or dimethylbenzidine in the intestinal tract of rodents and subsequently dimethoxybenzidine and dimethylbenzidine are absorbed into the blood stream. Animals were exposed to dimethoxybenzidine, dimethylbenzidine, or the dyes in the drinking water. Tumors obtained from control and chemical treated animals were examined for the presence of activated oncogenes by the NIH 3T3 deoxyribonucleic acid transfection assay. Activated oncogenes were detected in less than 3% (1/38) of the tumors from control animals whereas 68% (34/50) of the tumors from chemical treated animals contained detectable oncogenes. Activated oncogenes were detected in both malignant (25/36) and benign (9/14) tumors from chemically treated animals but only in one of 13 malignant tumors from the control animals. The transforming properties of the chemically induced rat tumor deoxyribonucleic acids were due to the transfer of an activated H-ras (31/34) or N-ras (3/34) gene. One spontaneous rat tumor deoxyribonucleic acid was found to contain an activated H-ras gene. The H-ras oncogenes from chemical associated tumors contained mutations at codons 12, 13, or 61 whereas the spontaneously activated H-ras gene contained a point mutation at codon 61. Activation of cellular ras genes by point mutation is an important step in the induction of tumors, at least in rats, by this class of benzidine derived dyes. Because of common histogenesis of the normal counterparts of many of the chemically induced neoplasms and histological evidence of varied tissue differentiation in some basal cell neoplasms, it is possible that most or all of the chemically induced neoplasms were derived from common epidermal progenitor stem cell population. [R36] *3,3'-Dimethoxybenzidine was mutagenic in Salmonella typhimurium strain TA100 with exogenous metabolic activation and in strain TA98 without activation; a weakly positive response was observed in strain TA1535 with metabolic activation. 3,3'-Dimethoxybenzidine induced sister chromatid exchanges and chromosomal aberrations in CHO cells with and without exogenous metabolic activation. 3,3'-Dimethoxybenzidine did not induce sex-linked recessive lethal mutation in adult male Drosophilla melanogaster exposed via feeding or injection. /3,3'Dimethoxybenzidine dihydrochloride/ [R37] *3,3'-Dimethoxybenzidine (DMB), a congener of benzidine used in the dye industry and previously found to be carcinogenic in rats, was evaluated for its genotoxic activity in primary cultures of rat and human hepatocytes and of cells from human urinary bladder mucosa, as well as in liver and bladder mucosa of intact rats. A similar modest dose-dependent frequency of DNA fragmentation was revealed by the alkaline elution technique in metabolically competent primary cultures of both rat and human hepatocytes exposed for 20 h to subtoxic DMB concentrations ranging from 56 to 180 microM. Replicating rat hepatocytes displayed a modest increase in the frequency of micronucleated cells after a 48-h exposure to 100 and 180 microM concentrations. In primary cultures of human urinary bladder mucosa cells exposed for 20 h to 100 and 180 microM DMB, the Comet assay revealed a clear-cut increase of DNA fragmentation. In rats given one-half LD50 of DMB as a single oral dose, the GSH level was reduced in both the liver and urinary bladder mucosa, whereas DNA fragmentation was detected only in the bladder mucosa. Taken as a whole, these results suggest that DMB should be considered a potentially genotoxic chemical in both rats and humans; the selective effect on the rat urinary bladder might be the consequence of pharmacokinetic behavior. [R38] *In mice and rats, prenatal exposure to the dye Congo red permanently reduces the number of germ cells in male and female offspring. In the current investigation, nine other dyes structurally related to Congo red were examined for developmental testicular toxicity. In this study, the structural component of the dyes responsible for the prenatal induction of germ cell aplasia was identified. We found that only benzidine-based dyes altered testicular development and caused hypospermatogenesis in mice during adulthood. Dimethyl- and dimethoxybenzidine-based dyes were without effect. Pregnant mice were dosed orally on Days 8-12 of gestation with a benzidine-, dimethylbenzidine-, or a dimethoxybenzidine-based dye and the testes of 45- to 50-day-old male offspring were examined. The testes of postpubertal male offspring exposed to the benzidine-based dyes, Congo red, diamine blue, and Chlorazol Black E, were small and contained some tubules completely devoid of germ cells, but the dimethylbenzidine-based dyes, trypan blue, Evans blue, and benzopurpurin 4B, and the dimethoxybenzidine-based dye, Chicago sky blue, did not alter testicular development in this manner. Azoic diazo component 48, a dimethoxybenzidine congener, and two other diazo dyes, naphthol blue black and Sudan III, were also without effect on the germ cells. Experiments with Chlorazol Black E (CBE) indicate that the period of susceptibility in the male fetus is limited to the period of primordial germ cell migration and division. When CBE was administered on Days 8-10 of gestation it reduced testis weight after puberty by 30%, while treatment after Day 13 did not affect testicular function.(ABSTRACT TRUNCATED AT 250 WORDS) [R39] *The benzidine congener 3,3'-dimethoxybenzidine (DMOB), and C.I. Direct Blue 15 (Blue 15), a prototypical compound of the DMOB-derived class of dyes, were evaluated in 13-week studies to characterize the toxicity and establish dose levels for subsequent chronic studies. Groups of 10 Fischer 344 rats of each sex were administered either DMOB, or Blue 15, at 1 of 5 concentrations in drinking water for 13 weeks. DMBO concentrations were 0, 0.017, 0.033, 0.063, 0.125, and 0.25% for males and females. For Blue 15, the concentrations were 0.063, 0.125, 0.25, 0.50, and 1.0% for females and 0, 0.125, 0.25, 0.50, 1.0, and 3.0% for male rats. Rats showed dose-related decreases in water consumption and weight gains. All DMOB-treated rats and their controls survived the 13-week treatment. There were 7 deaths in the 3% level of male rats treated with Blue 15. Liver and kidney weights were increased in rats treated with both compounds. Target organs for DMOB-treated rats were the kidney and thyroid. These lesions were characterized by chronic nephropathy, and increased pigment in the follicular cells of the thyroid. The kidney and liver were identified as target organs for Blue 15-treated rats. In the high-dose rats that died before termination of the study, renal effects were characterized by degeneration and focal necrosis of proximal tubular epithelial cells. Liver lesions in this group consisted of degeneration and necrosis of hepatocytes, fatty metamorphosis, and minimal megalocytosis. Mild chronic nephropathy was the principal histological effect in Blue 15-treated rats surviving to study termination. [R40] *Dimethoxybenzidine (DMO) and dimethylbenzidine (DM) are used to synthesize dyes such as C.I. Direct Blue 15 and C.I. Acid Red 114, respectively. These commercially used dyes are metabolically degraded to DMO or DM in the intestinal tract of rodents and subsequently DMO and DM are absorbed into the blood stream. Animals were exposed to DMO, DM, or the dyes in the drinking water. Tumors obtained from control and chemical-treated animals were examined for the presence of activated oncogenes by the NIH 3T3 DNA transfection assay. Activated oncogenes were detected in less than 3% (1/38) of the tumors from control animals whereas 68% (34/50) of the tumors from chemical-treated animals contained detectable oncogenes. Activated oncogenes were detected in both malignant (25/36) and benign (9/14) tumors from the chemically treated animals but only in one of 13 malignant tumors from the control animals. The presence of oncogenes in the chemically induced benign tumors suggests that oncogene activation was an early event in those tumors. Southern blot analysis of transfectant DNA showed that the transforming properties of the chemically induced rat tumor DNAs were due to the transfer of an activated H-ras (31/34) or N-ras (3/34) gene. One spontaneous rat tumor DNA was found to contain an activated H-ras gene. Oligonucleotide hybridization analysis indicated that the H-ras oncogenes from chemical-associated tumors contained mutations at codons 12, 13, or 61 whereas the spontaneously activated H-ras gene contained a point mutation at codon 61. These data suggest that activation of cellular ras genes by point mutation is an important step in the induction of tumors, at least in rats, by this class of benzidine-derived dyes. Moreover, in light of common histogenesis of the normal counterparts of many of the chemically induced neoplasms and histological evidence of varied tissue differentiation in some basal cell neoplasms, it is possible that most or all of the chemically induced neoplasms were derived from a common epidermal progenitor stem cell population. [R36] *The benzidine congener 3,3'-dimethoxybenzidine (DMOB), and C.I. Direct Blue 15 (Blue 15), a prototypical compound of the DMOB-derived class of dyes, were evaluated in 13-week studies to characterize the toxicity and establish dose levels for subsequent chronic studies. Groups of 10 Fischer 344 rats of each sex were administered either DMOB, or Blue 15, at 1 of 5 concentrations in drinking water for 13 weeks. DMBO concentrations were 0, 0.017, 0.033, 0.063, 0.125, and 0.25% for males and females. For Blue 15, the concentrations were 0.063, 0.125, 0.25, 0.50, and 1.0% for females and 0, 0.125, 0.25, 0.50, 1.0, and 3.0% for male rats. Rats showed dose-related decreases in water consumption and weight gains. All DMOB-treated rats and their controls survived the 13-week treatment. There were 7 deaths in the 3% level of male rats treated with Blue 15. Liver and kidney weights were increased in rats treated with both compounds. Target organs for DMOB-treated rats were the kidney and thyroid. These lesions were characterized by chronic nephropathy, and increased pigment in the follicular cells of the thyroid. The kidney and liver were identified as target organs for Blue 15-treated rats. In the high-dose rats that died before termination of the study, renal effects were characterized by degeneration and focal necrosis of proximal tubular epithelial cells. Liver lesions in this group consisted of degeneration and necrosis of hepatocytes, fatty metamorphosis, and minimal megalocytosis. Mild chronic nephropathy was the principal histological effect in Blue 15-treated rats surviving to study termination. [R40] *Enteric bacterial and hepatic azoreductase enzymes are capable of reducing azo dyes to yield the constituent aromatic amines. Azo dyes based on benzidine and benzidine congeners have received particular attention because of their widespread use and the known carcinogenicity of benzidine to humans. Azo dyes based on beta-diketone coupling components exist preferentially as the tautomeric hydrazones. A series of hydrazone dyes based on benzidine and benzidine congeners was prepared and characterized by NMR and UV-visible spectroscopy. These dyes were tested for mutagenicity using a modified Ames assay and, unlike the true azo dyes, showed no significant mutagenic activity. The hydrazone dyes were resistant to enzymatic reduction by FMN-supplemented hamster-liver post-mitochondrial supernatant (S-9); under identical conditions, azo dyes such as trypan blue were rapidly reduced. [R41] *The Ames Salmonella/microsome test was used to compare the mutagenic response of Salmonella typhimurium TA100, TA98, TA1538, and TA1535 to 12 benzidine derivatives, ie, benzidine, 3,3'-dimethoxybenzidine, 3,3'-dimethylbenzidine, 3,3'-dichlorobenzidine, and the corresponding N- and N,N'-diacetylated derivatives. With a few exceptions, the mutagenic response to this series of compounds varied in the order TA98 greater than TA1538 greater than TA100 greater than TA1535 = 0, and the N-monoacetylated derivatives were more mutagenic than either the parent diamines or the N,N'-diacetyl derivatives. The relative mutagenicities of the parent amines for TA98, were 3,3'-dichlorobenzidine much greater than 3,3'-dimethoxybenzidine greater than benzidine greater than 3,3'-dimethylbenzidine. [R30] *Covalent binding of benzidine and some congeners to hemoglobin was studied in female Wistar rats after oral administration. Hemoglobin adducts were hydrolyzed under alkaline conditions, and the arylamines analyzed by high performance liquid chromatography. With benzidine, three cleavage products were observed, the major component being monoacetylbenzidine. This indicates that 4-nitroso-4'-N- acetylaminobiphenyl is the major reactive metabolite in erythrocytes. In addition benzidine and 4-aminobiphenyl were identified. With 3,3'-dichlorobenzidine dihydrochloride, 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine two cleavage products were observed, the parent diamines being present in excess to or in amounts comparable to the monoacetyl derivative. With 3,3',5,5'-tetramethylbenzidine a hemoglobin adduct could not be found. When the azo dye direct red 28 was administered to the animals, the three cleavage products typical for benzidine were found, indicating that benzidine became bioavailable after reductive cleavage of the azo compound. In this case the fraction of 4-aminobiphenyl was greater than after benzidine. It is proposed to use the analysis of hemoglobin adducts in human blood to control the exposure of individuals to these carcinogenic chemicals in the course of biochemical effect monitoring. [R34] *The relationship between the structure and mutagenicity of benzidine analogues was examined. The mutagenic activities of benzidine, benzidine dihydrochloride, and their analogues, 3,3'-diaminobenzidine, 3,3'-dichlorobenzidine, 3,3'-dimethoxybenzidine, 3,3'-dimethoxybenzidine dihydrochloride, and N,N,N',N'-tetramethylbenzidine, were evaluated in the Ames assay. Salmonella strains (TA-100) and (TA-98) were used, with or without metabolic activation by liver S9 mix from male Sprague-Dawley rats induced wit aroclor-1254. In the absence of S9 mix only 3,3'-dichlorobenzidine in strain TA-98 showed significant mutagenic activity. In the presence of S9 mix all compounds except N,N,N',N'-tetramethylbenzidine were mutagenic in strain TA-100. Bridged diphenyl compounds showed mutagenicity equal to or greater than that of the parent compound, benzidine. In strain TA-98 biphenyl compounds were more mutagenic than the bridged diphenyl compounds. No significant differences in mutagenicity were seen between the free base and dihydrochloride salt forms of benzidine or its dimethoxy analogue. Compounds capable of inducing frame shift mutations must have a planar aromatic moiety and an activated electrophilic side chain, mutagenicity in this series of compounds increases with decreasing basicity of the aniline moiety. [R35] NTXV: *LD50 Rat oral 1920 mg/kg; [R16] NTP: *Carcinogenesis studies were conducted by administering 3,3'-dimethoxybenzidine dihydrochloride (greater than 97.5% pure) in drinking water /@ 0, 80, 170, or 330 ppm/ to groups of F344/N rats of each sex for 21 months. ... Average amount of 3,3'-dimethoxybenzidine dihydrochloride consumed per day was approximately 6, 12, or 21 mg/kg for low, mild, or high dose male rats and 7, 14, or 23 mg/kg for low, mid, or high dose female rats. ... Increased incidences of several nonneoplastic lesions were observed in exposed rats, including hematopoietic cell proliferation in the spleen and cystic and centrilobular degeneration and necrosis of the liver. ... There was clear evidence of carcinogenic activity of 3,3'-dimethoxybenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal gland, preputial gland, oral cavity, intestine, liver, and mesothelium. Increased incidences of astrocytomas of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of 3,3'-dimethoxybenzidine dihydrochloride for female F344/N rats, as indicated by benign and malignant neoplasms of the Zymbal gland, clitoral gland, and mammary gland. Increases in neoplasms of the skin oral cavity, large intestine, liver, and uterus/cervix were also considered to be related to chemical administration of 3,3'-dimethoxybenzidine dihydrochloride. /3,3'-Dimethoxybenzidine dihydrochloride/ [R42] ADE: *O-DIANISIDINE HAS BEEN FOUND IN URINE OF WORKERS EXPOSED TO THIS CMPD. [R27] *(14)C-labeled 3,3'-dimethoxybenzidine was absorbed through rat skin after application of an acetone soln, and only 29% had disappeared from the application site in 24 hr. It was found in the tissues and excreta. [R43] *The carcinogenic aromatic amine 3,3'-dimethoxybenzidine was rapidly metabolized in the rat. Thirty min after iv admin of (14)C-3,3'-dimethoxybenzidine less than 2% of the dose could be recovered from the animal as the parent cmpd. Extensive biliary excretion (70%) resulted in the accumulation of 50% in the intestinal tract. Three days after either oral or iv dosing, 50% of the admin radiolabel had been excreted in the feces and 30-40% excreted in the urine while 45% of the remaining radiolabel was present in the liver in the form of covalently bound metabolites. [R44] *... In 1954 /results from laboratory tests indicated/ that skin is principal portal of entry of benzidines. ... It was considered likely that the hydrochloride salt could be absorbed percutaneously. /Benzidines/ [R45] *The dermal absorption of benzidine derivatives was studied in rats. (14)C-labeled benzidine, 3,3-dichlorobenzidine, or 3,3'-dimethoxybenzidine were applied in doses of 1 mg/kg. The heart, spleen, kidney, fat, urinary bladder, ear, bone marrow, brain, muscle, and stomach had less than 0.1% of the radioactivity of the compounds at all time intervals. Blood levels of 14(C) activity were 0.1 to 0.5% of the dose and were relatively consistent among the compounds. 14(C) activity in the urine and feces was found in trace quantities at 1 or 8 hours, but it increased to 10 to 20 percent of the dose at the 24 hour assay. Radioactivity from benzidine was consistently higher in the urine and feces than from the derivatives. The amount of 14(C) activity disappearing from the site of application was the same for benzidine and 3,3-dichlorobenzidine, reaching about 50% in 24 hours. 3,3'-Dimethoxybenzidine was absorbed less rapidly; only 29% had disappeared from the application site in 24 hours. All 14(C) activity that disappeared from the site of application was found in the tissues and excreta. Benzidine and its derivatives are readily absorbed through intact mammalian skin. [R46] *The dermal absorption of benzidine derivatives was studied in rats. (14)C labeled benzidine, 3,3'-dichlorobenzidine, or 3,3'-dimethoxybenzidine were applied in doses of 1 mg/kg. The heart, spleen, kidney, fat, urinary bladder, ear, bone marrow, brain, muscle, and stomach had < 0.1% of the radioactivity of the compounds at all time intervals. Blood levels of (14)C activity were 0.1-0.5% of the dose and were relatively consistent among the compounds. (14)C activity in the urine and feces was found in trace quantities at 1 or 8 hr, but it increased to 10-20% of the dose at the 24 hr assay. Radioactivity from benzidine was consistently higher in the urine and feces than from the derivatives. The amount of (14)C activity disappearing from the site of application was the same for benzidine and 3,3'-dichlorobenzidine, reaching about 50% in 24 hr. 3,3'-Dimethoxybenzidine was absorbed less rapidly; only 29% had disappeared from the application site in 24 hr. All (14)C activity that disappeared from the site of application was found in the tissues and excreta. Benzidine and its derivatives are readily absorbed through intact mammalian skin. [R46] METB: *BISAZOBIPHENYL DYE DERIVED FROM 3,3'-DIMETHOXYBENZIDINE WAS METABOLIZED TO 3,3'-DIMETHOXYBENZIDINE IN BOTH THE DOG AND RAT. THE N-ACETYL DERIV OF 3,3'-DIMETHOXYBENZIDINE WAS IDENTIFIED IN URINE FROM RATS TREATED WITH DYE DERIVED FROM 3,3'-DIMETHOXYBENZIDINE. [R47] *... AFTER ADMIN OF A DOSE OF 1 G O-DIANISIDINE TO 2 DOGS, 0.4% FREE DIAMINE AND ... 5% OF A METABOLITE WITH PROPERTIES SIMILAR TO ... 3,3'-DIHYDROXYBENZIDINE WERE EXCRETED IN URINE. [R27] *The carcinogenic aromatic amine 3,3'-dimethoxybenzidine was rapidly metabolized in the rat. GC/MS studies of urine and bile demonstrated the presence of 8 previously unidentified metabolites formed via-N-acetylation, hydroxylation, O-demethylation, and glucuronidation. [R44] *The conventional Ames assay metabolising system was confirmed to be deficient in its ability to N-acetylate. This may render the test less sensitive to compounds which normally have an acetylation step during their in vivo activation to carcinogens. The addition of acetyl-coenzyme A to the S9 mix in the Ames assay increased the mutagenicity of benzidine in Salmonella typhimurium strains TA98 and TA1538 4-5-fold. This was consistent with the observation that benzidine is N-acetylated prior to deoxyribonucleic acid binding in vivo in rat liver. Two 3,3'-disubstituted benzidines, o-tolidine and o-dianisidine, were also tested. A smaller increase in o-tolidine mutagenicity, compared to that observed with benzidine, occurred with the addition of acetyl-coenzyme A. However, the production of acetylated metabolites from o-tolidine was only 37% of that from benzidine. The mutagenicity of o-dianisidine was unaffected by acetyl-coenzyme A. Acetylation of o-dianisidine was only 16% of that observed with benzidine, and the N-acetyl derivatives of o-dianisidine showed lower mutagenicity than the parent amine. [R48] *Potential carcinogenic metabolites of benzidine congener based azo dyes were studied. The dyes studies were based on benzidine and its congeners 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine. Dyes were administered to male Fischer-344 rats by a single gavage dose of 2 mg. Samples of urine were collected 0 to 12, 12 to 24, 24 to 48, and 48 to 96 hours after administration. Urine samples were subjected to assays of benzidine congener free amines and their monoacetyl metabolites and alkaline hydrolyzable conjugates or for diacetyl metabolites. Six dyes liberated high amounts of benzidine congener amines when held in rat or human urine at 25 degrees for 96 hours. All dyes metabolized to yield appreciable amounts of the corresponding amine, monoacetyl, diacetyl, and alkaline hydrolyzable products. Only red-39, direct-orange-6, and direct-red-46 showed peak excretion amounts during the 12 to 24 hours post interval. Metabolite amounts for all dyes decreased from 24 to 48 hours post administration and by 48 to 96 hours reached pretreatment amounts. Minimum detectable amounts of all metabolites were 12 parts per billion or less. [R49] *Absorption, metabolism and tissue distribution studies were conducted in the rat with 14(C)-biphenyl ring-labeled Direct Blue 15, a 3,3'-dimethoxybenzidine based azo dye; Direct Red 2, based on 3,3'-dimethylbenzidine and the corresponding benzidine congener amines. Single oral doses of the (14)C-labeled dyes (12 mg/kg, 62 muCi/kg) and molar equivalent doses of the respective amines were administered. And urine and fecal samples collected at intervals up to 192 hr. A comparison of the metabolism of Direct Blue 15 with its base 3,3'-dimethoxybenzidine, indicated that the base was more extensively metabolized and that most of the 14(C) in various extracts was identified in known metabolites. The metabolism of Direct Red 2 compared with its base, 3,3'-dimethylbenzidine, indicated that the base was more extensively metabolized, yet only a small percentage of the 14(C) in extracts was identified as known metabolites. Most of the 14(C) present in the urine could not be extracted with benzene nor chloroform, indicating high polarity. Distribution studies conducted with both dyes showed that liver, kidney, and lung accumulated and retained higher levels of 14(C) than other tissues (at 72 hr). Peak levels of 14(C), which occurred 8-12 hr after dosing, were significantly higher with Direct Red 2 than Direct Blue 15. Tissue distribution data (72 hr) for rats dosed with the free amines compared with the dyes showed a generally lower but similar distribution pattern. [R50] *The metabolism of a benzidine-based dye, Direct Black 38, a 3,3'-dimethylbenzidine-based dye, Direct Red 2 and a 3,3'-dimethoxybenzidine-based dye, Direct Blue 15 has been studied both in pure cultures of anaerobic bacteria and in bacterial suspensions derived from the intestinal contents of the rat. All of the pure cultures and the rat intestinal bacteria were able to reduce the azo linkages of Direct Black 38, Direct Red 2 and Direct Blue 15 with the subsequent formation of benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, respectively. [R51] *The differential mutagen activation of 3,3'-dichlorobenzidine, benzidine, o-tolidine, and o-dianisidine was studied using Salmonella-typhimurium (TA-98). Male Sprague-Dawley-rats were pretreated with 3,3'-dichlorobenzidine, 3-methylcholanthrene, or phenobarital; S9 and microsomal suspensions were prepared. Three rat liver enzyme systems were used: S9, S9 plus acetylcoenzyme-A, and microsomes. Activation of the benzidines to mutagens was performed by preincubating S9 or microsomes containing test amines at optimal mutagenic concentrations. ... The response of o-dianisidine was similar to that of 3,3'-dichlorobenzidine. The addition of acetylcoenzyme-A did not significantly alter the activation of 3,3'-dichlorobenzidine, but increased activation of benzidine after pretreatment with phenobarbital or 3-methylcholanthrene. The microsomes from 3,3'-dichlorobenzidine pretreated rats were the most active in mutagenic activation. Microsome catalyzed activation of o-dianisidine and o-tolidine was inhibited by the pretreatment with all inducers. Benzidine activation was increased only by 3-methylcholanthrene pretreatment. 3,3'-Dichlorobenzidine stimulated its own microsome catalyzed activation ninefold on the basis of cytochrome p450. Dithiothreitol had no effect on the microsome catalyzed activation of 3,3'-dichlorobenzidine and glutathione depletion did not alter the S9 catalyzed activation of 3,3'-dichlorobenzidine. ... 3,3'-Dichlorobenzidine is the most mutagenic of the four benzidines under conditions of cytochrome p450 catalyzed activation. [R52] *Although benzidine (Bz), 4-aminobiphenyl (ABP), 3,3'-dichlorobenzidine HCl (DCBz), 3,3'-dimethylbenzidine (DMBz), 3,3'-dimethoxybenzidine (DMOBz) and the benzidine congener-based dye trypan blue (TB) produce primarily frameshift mutations in Salmonella typhimurium, the base-substitution strain TA100 also responds to these compounds when S9 is present. Performing DNA sequence analysis, other investigators have shown that ABP induces frameshift, base-pair and complex mutations. Also, it was found that an uninduced hamster liver S9 preparation with glucose-6-phosphate dehydrogenase, FMN, NADH and four times glucose 6-phosphate gave a stronger mutagenic response than the conventional plate incorporation with rat S9 activation mixture for all the compounds tested. Using the base-specific tester strains of S. typhimurium (TA7001-TA7006) with the above reductive metabolic activation system, we surveyed these compounds for the ability to produce specific base-pair substitutions after reductive metabolism. Bz was weakly mutagenic in TA7005 (0.04 revertants/microg). ABP was mutagenic in TA7002 (1.4 revertants/microg), TA7004 (0.6 revertants/microg), TA7005 (2.98 revertants/microg) and TA7006 (0.4 revertants/microg). DCBz was weakly mutagenic in TA7004 (0.01 revertants/microg). It was concluded that benzidine induced some CG- > AT transversions in addition to frameshift mutations. ABP induced TA- > AT, CG- > AT, and CG- > GC transversions as well as GC- > AT transitions. DCBz induced only GC- > AT transitions. Because DMBz, DMOBz and TB were not mutagenic in this base-substitution mutagen detection system, their mutagenic activity was attributed strictly to frameshift mechanisms. [R53] *Benzidine and its 3,3'-diamino, 3,3'-dimethyl, 3,3'-dimethoxy, 3,3'-difluoro, 3,3'-dichloro, 3,3'-dibromo, 3,3'-dicarbomethoxy and 3,3'-dinitro derivatives together with 2-nitrobenzidine and 3-nitrobenzidine were compared for their in vitro and in vivo genotoxicity. Relative mutagenicity was established with Salmonella strains TA98, TA98/1,8-DNP6 and TA100 with and without S9 activation. All the derivatives in the presence of S9 were more mutagenic than benzidine with 3,3'-dinitro- and 3-nitro-benzidine having the greatest mutagenicity. Mutagenicity in all 3 strains with S9 activation could be correlated to electron-withdrawing ability of substituent groups, as measured by the basicity of the amines. This correlation was explained on the basis that electron-withdrawing groups could favor the stability of the mutagenic intermediate N-hydroxylamine and also enhance the reactivity of the ultimate mutagenic species, the nitrenium ion. Mutagenicity was also correlated to the energy of the lowest unoccupied molecular orbitals (ELUMO). Hydrophobicity was found to have very limited effect on the relative mutagenicity of our benzidine derivatives. The in vivo endpoint was chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of benzidine and its derivatives. In contrast to the in vitro results, while all the amines were genotoxic in vivo, only the 3-nitro derivative had a significant increase in toxicity over benzidine. [R54] *We have evaluated the mutagenic activity of a series of diazo compounds derived from benzidine and its congeners o-tolidine, o-dianisidine and 3,3'-dichlorobenzidine as well as several monoazo compounds. The test system used was a modification of the standard Ames Salmonella assay in which FMN, hamster liver S9 and a preincubation step are used to facilitate azo reduction and detection of the resulting mutagenic aromatic amines. All of the benzidine and o-tolidine dyes tested were clearly mutagenic. The o-dianisidine dyes except for Direct Blue 218 were also mutagenic. Direct Blue 218 is a copper complex of the mutagenic o-dianisidine dye Direct Blue 15. Pigment Yellow 12, which is derived from 3,3'-dichlorobenzidine, could not be detected as mutagenic, presumably because of its lack of solubility in the test reaction mixture. Of the monoazo dyes tested, methyl orange was clearly mutagenic, while C.I. Acid Red 26 and Acid Dye (C.I. 16155; often referred to as Ponceau 3R) had marginal to weak mutagenic activity. Several commercial dye samples had greater mutagenic activity with the modified test protocol than did equimolar quantities of their mutagenic aromatic amine reduction products. Investigation of this phenomenon for Direct Black 38 and trypan blue showed that it was due to the presence of mutagenic impurities in these samples. The modified method used appears to be suitable for testing the mutagenicity of azo dyes, and it may also be useful for monitoring the presence of mutagenic or potentially carcinogenic impurities in otherwise nonmutagenic azo dyes. [R55] *The metabolism of a benzidine-based dye, Direct Black 38, a 3,3'-dimethylbenzidine-based dye, Direct Red 2 and a 3,3'-dimethoxybenzidine-based dye, Direct Blue 15 has been studied both in pure cultures of anaerobic bacteria and in bacterial suspensions derived from the intestinal contents of the rat. All of the pure cultures and the rat intestinal bacteria were able to reduce the azo linkages of Direct Black 38, Direct Red 2 and Direct Blue 15 with the subsequent formation of benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, respectively. The metabolites of Direct Black 38, Direct Red 2 and Direct Blue 15 were isolated and identified by gas chromatography/mass spectrometry and had similar chromatographic and mass spectral properties with those of authentic standards. Results from this study indicate that in vitro anaerobic incubations of rat intestinal microorganisms were able to reduce and cleave the azo bonds of dyes derived from benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine to form potentially carcinogenic aromatic amines. [R56] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *3,3'-Dimethoxybenzidine's production and use as a chemical intermediate in the production of azo dyes may result in its release to the environment through various waste streams(SRC). Although 3,3'-dimethoxybenzidine is apparently not produced in the United States any longer, it may still be imported into the country. If released to air, an estimated vapor pressure of 1.2X10-7 mm Hg at 25 deg C indicates 3,3'-dimethoxybenzidine will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 3,3'-dimethoxybenzidine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3 hours. 3,3'-Dimethoxybenzidine absorbs light greater than 290 nm, and it may be susceptible to direct photolysis in the environment; however, the rate of this potential reaction is unknown. Particulate-phase 3,3'-dimethoxybenzidine will be removed from the atmosphere by wet and dry deposition. If released to soil, 3,3'-dimethoxybenzidine is expected to have moderate mobility based upon an estimated Koc of 230. The first pKa of 3,3'-dimethoxybenzidine is estimated as 4.2, which indicates that 3,3'-dimethoxybenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to soils than neutral molecules. Furthermore, 3,3'-dimethoxybenzidine is an aromatic amine which may form covalent bonds with humic materials resulting in relatively immobile quinone-like complexes. Volatilization from moist soil surfaces is not expected to be an important fate process for 3,3'-dimethoxybenzidine because cations do not volatilize, and the estimated Henry's Law constant of the neutral species is 4.7X10-11 atm-cu m/mole. 3,3'-Dimethoxybenzidine is not expected to volatilize from dry soil surfaces based upon its estimated vapor pressure. No data regarding the biodegradation of 3,3'-dimethoxybenzidine in soil or natural water were found. However, screening studies using sewage sludge inoculum suggest biodegradation will occur slowly in the environment. Benzidine and its derivatives such as 3,3'-dimethoxybenzidine are known to be to be rapidly oxidized by Fe(III) and other cations which are frequently found in soil and environmental waters. If released into water, 3,3'-dimethoxybenzidine is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process for either the free base or its conjugate acid based upon this compound's estimated Henry's Law constant and the fact that cations are non-volatile. An estimated BCF of 5 suggests the potential for bioconcentration in aquatic organisms is low. 3,3'-Dimethoxybenzidine is not expected to undergo hydrolysis due to a lack of hydrolyzable functional groups. Occupational exposure to 3,3'-dimethoxybenzidine may occur through inhalation and dermal contact with this compound at workplaces where 3,3'-dimethoxybenzidine is used. (SRC) ARTS: *3,3'-Dimethoxybenzidine's production and use as a chemical intermediate in the production of azo dyes(1) may result in its release to the environment through various waste streams(SRC). 3,3'-Dimethoxybenzidine is apparently not produced in the US any longer but may still be imported into the country(1). [R57] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 230(SRC), determined from a log Kow of 1.81(2) and a regression-derived equation(3), indicates that 3,3'-dimethoxybenzidine is expected to have moderate mobility in soil(SRC). The first pKa of 3,3'-dimethoxybenzidine is estimated as 4.2(SRC), using an estimation method based on perturbed molecular orbital theory and linear free energy (LFER) methods(4). This estimated pKa indicates that 3,3'-dimethoxybenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to soils than neutral molecules(SRC). Furthermore, 3,3'-dimethoxybenzidine is an aromatic amine which may form covalent bonds with humic materials resulting in relatively immobile quinone-like complexes(5). Volatilization of the neutral species of 3,3'-dimethoxybenzidine from moist soil surfaces is not expected to be an important fate process(SRC) based upon an estimated Henry's Law constant of 4.7X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(6). The conjugate acid of 3,3-dimethoxybenzidine will not volatilize since cations are non-volatile(SRC). 3,3'-Dimethoxybenzidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg(SRC), determined from a fragment constant method(7). No data were found regarding the biodegradation of 3,3'-dimethoxybenzidine in soils; however, screening studies using sewage sludge inoculum suggest biodegradation will occur slowly in the environment(8,9). Structurally similar compounds such as benzidine are shown to be rapidly oxidized by Fe(III) and other cations which are frequently found in soil(10), which suggest that 3,3'-dimethoxybenzidine may also be degraded by a similar process(SRC). [R58] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 230(SRC), determined from a log Kow of 1.81(2) and a regression-derived equation(3), indicates that 3,3'-dimethoxybenzidine is expected to adsorb to suspended solids and sediment(SRC). The frist pKa of 3,3'-dimethoxybenzidine is estimated as 4.2(SRC), using an estimation method based on perturbed molecular orbital theory and linear free energy (LFER) methods(4). This estimated pKa indicates that 3,3'-dimethoxybenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to suspended solids and sediment than neutral molecules(SRC). Volatilization of the free base from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.7X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). The conjugate acid of 3,3'-dimethoxybenzidine will not volatilize since cations are non-volatile(SRC). According to a classification scheme(6), an estimated BCF of 5(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). No information on the biodegradation of 3,3'-dimethoxybenzidine in natural waters was found(SRC), but this compound was reported to be resistant to biodegradation in the Japanese MITI test(8), suggesting biodegradation in waters will most likely occur slowly(SRC). Structurally similar compounds such as benzidine are shown to be rapidly oxidized by Fe(III) and other cations which are frequently found in environmental waters(9), which suggest that 3,3'-dimethoxybenzidine may also be degraded by a similar process(SRC). [R59] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 3,3'-dimethoxybenzidine, which has an estimated vapor pressure of 1.2X10-7 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 3,3'-dimethoxybenzidine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3 hours(SRC), calculated from its rate constant of 1.3X10-10 cu cm/molecule-sec at 25 deg C (SRC)determined using a structure estimation method(3). Since 3,3'-dimethoxybenzidine absorbs light greater than 290 nm(4), it may be susceptible to direct photolysis in the environment(SRC). Particulate-phase 3,3'-dimethoxybenzidine may be removed from the air by wet and dry deposition(SRC). [R60] BIOD: *3,3'-Dimethoxybenzidine was reported to be resistant to biodegradation in the Japanese MITI test(1). At low levels of yeast extract, 3,3'-dimethyoxybenzidine showed no consistent degradation in an OECD AFNOR sewage die-away test and it was not classified as readily biodegradable; only high levels of yeast extract (100-200 mg/l) enchanced the biodegradation of this compound(2). 3,3'-Dimethyoxybenzidine at 35 deg C and an initial concn of 100 mg/l in the presence of an anaerobic sludge inoculum degraded 100% in 42 days(3). [R61] ABIO: *The rate constant for the vapor-phase reaction of 3,3'-dimethoxybenzidine with photochemically-produced hydroxyl radicals has been estimated as 1.3X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The first pKa of 3,3'-dimethoxybenzidine is estimated as 4.2(SRC), using an estimation method based on perturbed molecular orbital theory and linear free energy (LFER) methods(2). This estimated pKa indicates that 3,3'-dimethoxybenzidine will partially exist in the protonated form under acidic conditions(SRC). 3,3'-Dimethoxybenzidine absorbs light greater than 290 nm(3) and may be susceptible to photolysis in the environment(SRC). Other than the protonation of the 2 amine groups, 3,3'-dimethoxybenzidine is not expected to undergo hydrolysis due to a lack of hydrolyzable functional groups(4). [R62] BIOC: *An estimated BCF of 5 was calculated for 3,3'-dimethoxybenzidine(SRC), using a log Kow of 1.81(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R63] KOC: *The Koc of 3,3'-dimethoxybenzidine is estimated as 230(SRC), using a measured log Kow of 1.81(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 3,3'-dimethoxybenzidine is expected to have moderate mobility in soil(SRC). The first pKa of 3,3'-dimethoxybenzidine is estimated as 4.2(SRC), using an estimation method based on perturbed molecular orbital theory and linear free energy (LFER) methods(4). This estimated pKa indicates that 3,3'-dimethoxybenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to soils than neutral molecules(SRC). Furthermore, 3,3'-dimethoxybenzidine is an aromatic amine which may form covalent bonds with humic materials resulting in relatively immobile quinone-like complexes(5). [R64] VWS: *The first pKa of 3,3'-dimethoxybenzidine is estimated as 4.2(SRC), using an estimation method based on perturbed molecular orbital theory and linear free energy (LFER) methods(1). This estimated pKa indicates that 3,3'-dimethoxybenzidine will partially exist in the protonated form under acidic conditions and cations will not volatilize from water or soil surfaces(SRC). The Henry's Law constant for the neutral species (free base) of 3,3'-dimethoxybenzidine is estimated as 4.7X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that 3,3'-dimethoxybenzidine is expected to be essentially nonvolatile from water surfaces(3). 3,3'-Dimethoxybenzidine's Henry's Law constant(2) indicates that volatilization from moist soil surfaces is not expected(SRC). 3,3'-Dimethoxybenzidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg(SRC), determined from a fragment constant method(4). [R65] RTEX: *Processes in which dried dye is handled have the greatest potential for employee exposure during the manufacture or repackaging of benzidine-based dyes. ... During use of benzidine-based dyes, the greatest potential for exposure would be expected to be among dye-weighers who handle dry powders. /Benzidine-based dyes/ [R66] *Human exposure ... is possible through inhalation of dye particles from equipment, vent systems; and skin absorption from finished dyed product, textile processing, mixing operations, or packaging processes. [R67] *Workers potentially exposed to DMOB /3,3'-dimethoxybenzidine/ are dye makers and o-dianisidine diisocyanate prodn workers. However, current prodn processes for DMOB and dyes made from DMOB are generally closed systems with minimal risk to workers. [R67] *It has been estimated that approximately 1,000 workers are exposed to /3,3'-Dimethoxybenzidine/ during dye manufacturing and that perhaps as many as 15,000 workers are exposed in the various dye application industries. [R68] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,482 workers (866 of these are female) are potentially exposed to 3,3'-dimethoxybenzidine in the US(1). Occupational exposure to 3,3'-dimethoxybenzidine may occur through inhalation and dermal contact with this compound at workplaces where 3,3'-dimethoxybenzidine is used(SRC). [R69] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers o-dianisidine to be a potential occupational carcinogen. [R19] NREC: *NIOSH recommends that o-dianisidine-based dyes be regulated as a potential human carcinogen. /o-Dianisidine-based dyes/ [R70] *NIOSH considers o-dianisidine to be a potential occupational carcinogen. [R19] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R19] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 3,3'-Dimethoxybenzidine is included on this list. [R71] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 250 ug/l [R72] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R73] RCRA: *U091; As stipulated in 40 CFR 261.33, when 3,3'-dimethoxybenzidine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R74] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 325. Analyte: o-Dianisidine. Matrix: Air. Procedure: Filter collection, sodium hydrosulfite reduction. Flow Rate: 1.5-2.0 liters/min. Sample Size: 500 liters. [R75] *NIOSH Method 5013. Analyte: o-Dianisidine. Matrix: Air. Sampler: Filter (5 um polytetrafluoroethylene; polyperfluoroethylene; tetrafluoroethene, homopolymer; Teflon). Flow Rate: 1 to 3 l/min. Sample Size: 250 liters. Shipment: Keep samples dry and cool; protect from light. Sample Stability: greater or equal to 7 days @ 25 deg C in the dark. [R76] ALAB: *THIN-LAYER CHROMATOGRAPHY. [R28] *NIOSH Method 5031. Dyes, Benzidine, o-Toluidine, o-Anisidine. HPLC UV detection. [R77] *OSW Method 8270B. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R78] *EPA Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. [R78] *EPA Method 553. Determination of Benzidines and Nitrogen-Containing Pesticides in Water by Liquid-Liquid Extraction and Reverse Phase High Performance Liquid Chromatography, Particle Beam, and Mass Spectrometry. Revision 1.1. [R78] *OSW Method 8325. Solvent Extractable Non-Volatile Compounds by High Performance Liquid Chromatography/Particle Beam/Mass Spectrometry. [R78] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA/ECAO; Health and Environmental Effects Profile for 3,3'-Dimethoxybenzidine (1987) EPA/600/X-87/101, NTIS No. PB89-119515 DHHS/NTP; Toxicology and Carcinogenesis Studies of 3,3'-Dimethoxybenzidine dihydrochloride in F344/N Rats (Drinking Water Studies) Technical Report Series No. 372 (1990) NIH Publication No. 90-2827 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 350 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 41 (1974) R3: U.S. Department of Health and Human Services; Ninth Report on Carcinogens Revised January 2001. Available at http://ehis.niehs.nih.gov/roc/ as of Feb, 2002. R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 42 (1974) R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 43 (1974) R6: SRI R7: DHHS/NTP; Ninth Annual Report On Carcinogens. NTP 95-622 (2001) R8: USITC. Imports of Benzenoid Chem and Prod 1984 p. 17 R9: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-124 R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 90 R11: O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2001. 527 R12: Debnath AK et al; Environ Mol Mutagen 20: 140-44 (1992) R13: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V2 1689 R14: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Ver 5. Tucson, AZ: Univ AZ, College of Pharmacy (1992) R15: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-32 R16: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1039 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 544 R18: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 874 R19: NIOSH. NIOSH Pocket Guide to Chemical Hazards and Other Databases. U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control and Prevention. DHHS (NIOSH) Publication No. 2001-145 (CD-ROM) August 2001. R20: The Merck Index: An Encyclopedia of Chemicals and Drugs 8th ed. Rahway, New Jersey: Merck and Co., Inc., 1968. 340 R21: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/323 R22: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R23: 40 CFR 240-280, 300-306, 702-799 (7/1/90) R24: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (1981) EPA 68-03-3025 R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 62 (1987) R26: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 45 (1974) R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 44 (1974) R29: NTP; Fiscal Year 1986 Annual Plan p.72 (1986) NTP-86-086 R30: Reid TM et al; Environ Mutagen 6 (2): 145-51 (1984) R31: Morgan DL et al; J of the American College of Toxicol 9 (1): 79-91 (1990) R32: Morgan DL et al; Toxicol 59 (3): 297-309 (1989) R33: Schieferstein GJ et al; J American Coll Toxicol 9 (1): 71-7 (1990) R34: Birner G et al; Arch Toxicol 64 (2): 97-102 (1990) R35: Messerly EA et al; Environ Molecular Mutagenesis 10 (3): 263-74 (1987) R36: Reynolds SH et al; Cancer Res 50 (2): 266-72 (1990) R37: DHHS/NTP; Toxicology and Carcinogenesis Studies of 3,3'-dimethoxybenzidine dihydrochloride (Drinking Water Studies) p.2 (1990) Technical Rpt Series No. 372 NIH Pub No 90-2827 R38: MArtelli A et al; Toxicol Sci 53 (1): 71-6 (2000) R39: Gray LE Jr, Ostby JS; Fundam Appl Toxicol 20 (2): 177-83 (1993) R40: Morgan DL et al; Toxicology 59 (3): 297-309 (1989) R41: De France BF et al; Food Chem Toxicol 24 (2): 165-9 (1986) R42: DHHS/NTP; Toxicology and Carcinogenesis Studies of 3,3'-Dimethoxybenzidine dihydrochloride in F344/N Rats (Drinking Water Studies) p.1-2 (1990) Technical Rpt Series No. 372 NIH Pub No. 90-2827 R43: Shah PV, Guthrie FE; Bull Environ Contam Toxicol 31 (1): 73-8 (1983) R44: Rodgers RM et al; Drug Metab Dispos 11 (4): 293-300 (1983) R45: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.180 R46: Shah PV, Guthrie, FE; Bulletin of Environ Contamination and Toxicol 31 (1): 73-8 (1983) R47: LYNN RK ET AL; TOXICOL APPL PHARMACOL 56 (2): 248-58 (1980) R48: Kennelly JC et al; Mutat Res 137 (1): 39-45 (1984) R49: Bowman MC et al.; J of Anal Toxicol 7 (1): 55-60 (1983) R50: Bowman MC et al; J Anal Toxicol 6 (4): 164-74 (1982) R51: Cerniglia CE et al; Carcinogenesis 3 (11): 1255-60 (1982) R52: Iba MM; Mutation Research 182 (5): 231-41 (1987) R53: Claxton LD et al; Food Chem Toxicol 39 (12): 1253-61 (2001) R54: You Z et al; Mutat Res 319 (1): 19-30 (1993) R55: Prival MJ et al; Mutat Res 136 (1): 33-47 (1984) R56: Cerniglia CE; Carcinogenesis 3 (11): 1255-60 (1982) R57: (1) U.S. Department of Health and Human Services; Ninth Report on Carcinogens Revised January 2001. Available at http://ehis.niehs.nih.gov/roc/ as of Feb, 2002. R58: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Debnath AK et al; Environ Mol Mutagen 20: 140-44 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994) (5) Parris GE; Environ Sci Technol 14: 1099-106 (1980)(6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (7) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (8) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (9) Brown D, Laboureur P; Chemosphere 12: 405-14 (1983) (10) Callahan MA et al; Water-related environmental fate of 129 priority pollutants vol II. USEPA-440/4-79-029b pp.102-1 to 102-7 (1979) R59: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Debnath AK et al; Environ Mol Mutagen 20: 140-44 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994) (5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (9) Callahan MA et al; Water-related environmental fate of 129 priority pollutants vol II. USEPA-440/4-79-029b pp. 102-1 to 102-7 (1979) R60: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Sadtler Res Lab; Sadtler Standard UV Spectra No. 1181 R61: (1) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (2) Brown D, Laboureur P; Chemosphere 12: 405-14 (1983) (3) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) R62: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994) (3) Sadtler Res Lab; Sadtler Standard UV Spectra No. 1181 (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R63: (1) Debnath AK et al; Environ Mol Mutagen 20: 140-44 (1992) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R64: (1) Debnath AK et al; Environ Mol Mutagen 20: 140-44 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994) (5) Parris GE; Environ Sci Technol 14: 1099-106 (1980) R65: (1) Hilal SH et al; pp. 291-353 in Quantitative Treatments of Solute/Solvent Interactions: Theoretical and Computational Chemistry Vol. 1 NY, NY: Elsevier (1994) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R66: NIOSH; Special Occupational Hazard Review for Benzidine-Based Dyes p.27 (1980) R67: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 358 R68: NTP; Fiscal Year 1986 Annual Plan p.128 (1986) NTP-86-086 R69: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R70: NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988.10 R71: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R72: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R73: 40 CFR 302.4 (7/1/2001) R74: 40 CFR 261.33 (7/1/2001) R75: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. 325-1 R76: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5013-1 R77: NIOSH; NIOSH Pocket Guide to Chemical Hazards and Other Databases. CD-ROM. Dept Health Human Srv., Cntrs Disease Control Prevent. DHHS (NIOS) Pub No. 2001-145. Aug, 2001. R78: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 93 Record 140 of 1119 in HSDB (through 2003/06) AN: 1629 UD: 200303 RD: Reviewed by SRP on 1/23/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-DIBROMO-3-CHLOROPROPANE- SY: *AI3-18445-; *BBC-12-; *BBCP-; *Caswell-No-287-; *1-CHLORO-2,3-DIBROMOPROPANE-; *3-CHLORO-1,2-DIBROMOPROPANE-; *DBCP-; *DIBROMCHLORPROPAN- (GERMAN); *1,2-DIBROM-3-CHLOR-PROPAN- (GERMAN); *DIBROMOCHLOROPROPANE-; *1,2-Dibromo-3-chloropropane (DBCP)-EM; *1,2-DIBROMO-3-CLORO-PROPANO- (ITALIAN); *1,2-DIBROOM-3-CHLOORPROPAAN- (DUTCH); *Nematocide-EM-12.1-; *Nematocide-EM-15.1-; *EPA-Pesticide-Chemical-Code-011301-; *FUMAGON-; *Fumazon-86-; *FUMAZONE-; *Fumazone-86E-; *NCI-C00500-; *NEMABROM-; *NEMAFUME-; *NEMAGON-; *NEMAGON-20-; *NEMAGON-90-; *NEMAGON-206-; *NEMAGON-20G-; *NEMAGON-SOIL-FUMIGANT-; *NEMANAX-; *Nemanex-; *NEMAPAZ-; *NEMASET-; *Durham-Nematicode-EM-17.1-; *NEMAZON-; *OS1897-; *OXY-DBCP-; *PROPANE,-1-CHLORO-2,3-DIBROMO-; *PROPANE,-1,2-DIBROMO-3-CHLORO-; *SD-1897-; *Nematocide-Solution-EM-17.1-; *Gro-Tone-Nematode-Granular- RN: 96-12-8 MF: *C3-H5-Br2-Cl SHPN: UN 2872; Dibromochloropropane IMO 6.1; Dibromochloropropane HAZN: U066; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... BY THE LIQUID PHASE ADDITION OF BROMINE TO ALLYL CHLORIDE. [R1, p. VA17 129] IMP: *Technical grade DBCP has been shown to contain up to 10% impurities, incl epichlorohydrin and allyl chloride. ... Epichlorohydrin is added intentionally as a stabilizer. [R2] FORM: *FUMAZONE 86E: 1,2-DIBROMO-3-CHLOROPROPANE AND RELATED HALOGENATED C3 HYDROCARBONS, 84.0%, INERT INGREDIENTS 16.0%, (PETROLEUM SOLVENT 9%). FUMAZONE 86: 1,2-DIBROMO-3-CHLOROPROPANE AND RELATED HALOGENATED C3 ALIPHATICS 85.5%, PETROLEUM SOLVENT 14.5%. [R3, p. V-261] *1,2-DIBROMO-3-CHLOROPROPANE IS AVAIL IN USA AS TECHNICAL GRADE CONTAINING NOT LESS THAN 95% OF PURE CHEM, AS EMULSIFIABLE CONCENTRATES CONTAINING 70.7-87.8%, AS SOLN CONTAINING 47.2%, AS GRANULES CONTAINING 5.25-34%, AND IN FERTILIZER MIXT CONTAINING 0.6-5%. [R4, (1979)] *Gro-Tone Nematode Granular; granular, 17.3% Dibromo-3-chloropropane [R5] *Durham Nematocode EM 17.1, Nematocide Solution 17.1, soluble concn, 97% Dibromo-3-chloropropane [R5] *Nematocide EM 12.1, soluble concn, 85% Dibromo-3-chloropropane [R5] *Nematocide EM 15.1, soluble concn, 94% Dibromo-3-chloropropane [R5] *1,2-Dibromo-3-chloropropane (DBCP)-EC, emulsifiable concn, 80% Dibromo-3-chloropropane [R5] OMIN: *MANY PERENNIAL PLANTS TOLERATE HIGH CONCN BUT OTHERS, EG TOBACCO, POTATO, ARE SENSITIVE AND LONG AERATION PERIOD PRIOR TO PLANTING MAY BE NECESSARY. [R6] *1,2-DIBROMO-3-CHLOROPROPANE IS ... EFFECTIVE AGAINST A WIDE RANGE OF NEMATODES, INCLUDING ROOT-KNOT NEMATODES, AT 10-125 KG/HA. SOIL TEMP AT 15 CM DEPTH SHOULD BE 21-27 DEG C FOR BEST RESULTS. [R7] *1,2-Dibromo-3-chloropropane was first produced commercially in the US in 1955. [R4] *All US usage of 1,2-dibromo-3-chloropropane was cancelled in 1979. [R8] *Manufacturers: Shell (formerly); Dow (formerly); Amvac. [R1, p. VA6 538] USE: *Cancellation of all registrations of end use products except for the use on pineapples in Hawaii /as soil fumigant/ (3/31/81) [R9] *Intermediate in organic synthesis; LV (low in volatiles) commercial preparation for the flame retardant tris(2,3-dibromopropyl)phosphate [R10] *Unclassified nematocide used for soil fumigation of cucumbers, summer squash, cabbage, cauliflower, carrots, snap beans, okra, aster, shasta daisy, ornamental turf (lawns), bermuda grass, centipede grass, St Augustine grass, zoysia grass, ardisia, azalea, camellia, forsythia, gardenia, hibiscus, roses, and arborvitae. /Gro-Tone Nematode Granular/ /Former uses/ [R5] *Fumigation of pineapple in Hawaii. /Nematocide EM 12.1, Nematocide EM 15.1/ [R5] *Restricted use against plant-parasitic nematodes in soil fumigation of pineapple. /Nematocide Solution 17.1/ [R5] *Nematicidal soil sterilant used on berries, citrus, grapes, deciduous fruit, nuts, peanuts, cotton, soya beans, turf, vegetables, and ornamentals. /Former use/ [R11] CPAT: *In 1977, 831,000 pounds of 1,2-dibromo-3-chloropropane (DBCP) was used in CA alone, mainly on grapes and tomatoes. In 1974, USA farmers applied 9.8 million pounds of DBCP on crops. [R12] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 4.54X10+6 G [R13] *(1982) PROBABLY GREATER THAN 2.27X10+6 G [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid when pure [R14] ODOR: *PUNGENT ODOR [R15]; *Pungent odor at high concentrations. [R16] TAST: *The threshold for taste ... was reported to be 0.01 mg/l. [R17] BP: *164.5 deg C at 300 mm Hg [R18, 621] MP: *5 deg C [R19, 3532] MW: *236.36 [R15] CORR: *CORRODES ALUMINUM, MAGNESIUM, TIN AND ALLOYS CONTAINING THESE METALS; ATTACKS RUBBER MATERIAL AND COATINGS [R4, (1979)] *Will not corrode steel or copper alloys unless it contains more than 0.02% of water. [R20] DEN: *2.08 AT 20 DEG C/20 DEG C [R10] OWPC: *log Kow= 2.96 [R21] SOL: *MISCIBLE IN ALIPHATIC AND AROMATIC HYDROCARBONS [R18, 621]; *MISCIBLE WITH OILS, DICHLOROPROPANE, ISOPROPYL ALCOHOL [R15]; *0.1% wt/wt in water [R6]; *Miscible with acetone [R18, 621]; *In water= 1230 mg/l at 20 deg C [R22] SPEC: *INDEX OF REFRACTION: 1.553 AT 14 DEG C/D [R15]; *MASS: 4575 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R23]; *Intense mass spectral peaks: 157 m/z (100%), 75 m/z (88%), 155 m/z (85%), 49 m/z (38%) [R24] VAPD: *2.09 at 14 deg C [R25] VAP: *0.58 mm Hg at 20 deg C [R22] OCPP: *Percent in saturated air: 0.13 @ 25 deg C; 1 mg/l= 103.4 ppm and 1 ppm= 9.71 mg/cu m @ 25 deg C, 760 mm Hg [R19, 3533] *Conversion factors: 1 ppm= 9.67 mg/cu m; 1 mg/cu m= 0.103 ppm [R26] *AMBER TO DARK BROWN LIQUID /TECHNICAL GRADE/ [R10] *Dense yellow liquid; may also appear in granular form /Technical Grade/ [R27] *Stable in neutral and acidic media; hydrolyzed by alkali to 2-bromoallyl alcohol. [R4] *Dense yellow or amber liquid (Note: A solid below 43 degrees F). [R16] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Inhalation of vapors or dust is extremely irritating. May cause burning of eyes and flow of tears. May cause coughing, difficult breathing and nausea. Brief exposure effects last only a few minutes. Exposure in an enclosed area may be very harmful. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may cause pollution. [R28] +Fire or explosion: Some of these materials may burn, but none ignite readily. Containers may explode when heated. [R28] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R28] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R28] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R28] +Fire: Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R28] +Spill or leak: Do not touch or walk through spilled material. Stop leak if you can do it without risk. Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. Small spills: Take up with sand or other noncombustible absorbent material and place into containers for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Prevent entry into waterways, sewers, basements or confined areas. [R28] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects should disappear after individual has been exposed to fresh air for approximately 10 minutes. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R28] FPOT: *1,2-Dibromo-3-chloropropane (DBCP) itself is classified in the USA as a combustible liq in class IIIA; formulations of DBCP incl kerosene or other flammable solvents fall into the flammable range (class IB for formulations made with kerosene). [R18, 622] FLPT: *170 DEG F (OPEN CUP) [R29] REAC: +Chemically-active metals such as aluminum, magnesium and tin alloys [Note: Corrosive to metals]. [R30, 92] DCMP: *195.5 deg C at 760 mm Hg, with decomp [R18, 621] ODRT: *Low odor threshold= 0.0965 mg/cu m; High odor threshold= 0.2895 mg/cu m; Irritating concn= 1.93 mg/cu m [R31] SERI: *MAY BE IRRITATING TO SKIN, MUCOUS MEMBRANES. [R32] EQUP: *Protective clothing shall be resistant to the penetration and to the chemical action of dibromochloropropane. Additional protection, incl gloves, bib-type aprons, boots and overshoes, shall be provided for, and worn by, each employee during any operation that may cause direct contact with liq. ... [R33, 309] *Unless eye protection is afforded by a respirator hood or facepeice, protective goggles (splash-proof safety goggles (cup-cover type dust and splash safety goggles)) ... or a face shield (8-in minimum) shall be worn at operations where there is danger of contact of the eyes with liquid dibromochloropropane because of spills or splashes. [R33, 308] *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R34, 1979.8] *Vendor recommendations concerning the protective qualities of materials to minimize potential exposure to 1,2-dibromo-3-chloropropane are as follows: Nitrile and polyvinyl chloride received fair or poor ratings from three or more vendors; Polyethylene and chlorinated polyethylene received fair or poor ratings from less than three vendors. [R35] +Wear appropriate personal protective clothing to prevent skin contact. [R30, 93] +Wear appropriate eye protection to prevent eye contact. [R30, 93] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R30, 93] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R30, 93] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R30, 93] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R30, 93] OPRM: +Contact lenses should not be worn when working with this chemical. [R30, 93] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Transfers of 1,2-dibromo-3-chloropropane (DBCP) from one container to another should be made through closed systems, with venting back to the original container or through charcoal or other absorptive or destructive arrangement that will prevent escape of DBCP into the occupational environment. No acceptable chem decontamination for DBCP is known; destruction by incineration requires dilution with a flammable solvent and passage of the products of burning through scrubbers to remove the hydrogen chloride and hydrogen bromide produced. [R18, 623] *Protective clothing or gear that becomes contaminated should be washed at once with soap or water or discarded. If the odor of 1,2-dibromo-3-chloropropane persists on clothing or protective gear after washing and aeration, the clothing or gear should not be worn. [R18, 623] *The material must not be allowed to remain on the skin. [R36] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R34, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R34, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R34, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R34, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R34, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R34, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R34, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R34, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R34, 1979.8] +The worker should immediately wash the skin when it becomes contaminated. [R30, 93] +The worker should wash daily at the end of each work shift. [R30, 93] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R30, 93] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R30, 93] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R37] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R38] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R39] +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R34, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R34, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R34, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U066, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R40] *No acceptable chem decontamination for 1,2-dibromo-3-chloropropane is known; destruction by incineration requires dilution with a flammable solvent and passage of the products of burning through scrubbers to remove the hydrogen chloride and hydrogen bromide produced. [R18, 623] *Dibromochloropropane is reported to be stable to neutral and acid media. It is hydrolyzed by alkali to 2-bromoallyl alcohol. Controlled incineration with adequate scrubbing and ash disposal facilities. The Manufacturing Chemists Association suggest the following disposal procedures for bromine-containing compounds: - pour onto vermiculite, sodium bicarbonate or a sand-soda ash mixture (90-10). Mix and shovel into paper boxes. Place in an open incinerator. Cover with scrap wood and paper. Ignite with an excelsior train; stay on upwind side or dump into a closed incinerator with afterburner. - Dissolve in a flammable solvent. Spray into the firebox of an incinerator equipped with afterburner and scrubber (alkali). Recommendable methods: Adsorption and incineration. Peer review: Dilute well with hydrocarbon fuel. Adsorb on vermiculite or sodium carbonate. Incinerate with excess non halogenated waste. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R41, 267] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R34, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R34, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": High-efficiency particulate arrestor filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R34, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R34, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R34, 1979.17] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. [R42] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R43] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R43] *The following wastewater treatment technology have been investigated for 1,2-dibromo-3-chloropropane: Resin absorption. [R44] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1,2-dibromo-3-chloropropane. There is sufficient evidence in experimental animals for the carcinogenicity of 1,2-dibromo-3-chloropropane. Overall evaluation: 1,2-Dibromo-3-chloropropane is possibly carcinogenic to humans (Group 2B). [R45] MEDS: *Medical supervision should incl a pre-exposure physical exam, with an assessment of the employee's ability to wear a respirator for a prolonged period of time, and an assessment of fertility for male workers. The assessment of fertility for all male employees other than those with known azoospermia should be repeated after each period of 30 days of working with 1,2-dibromo-3-chloropropane (DBCP) or as requested by the responsible physician. Detailed records of the dates and hours during which each employee worked with DBCP should be incl in the employee's medical record along with any records of environmental monitoring performed in the employee's work station. [R18, 623] *... Periodic examinations containing the elements of the preplacement or initial examination shall be made available on at least an annual basis. Examination of current employees shall be made available as soon as practicable after the promulgation of a standard for 1,2-dibromo-3-chloropropane (DBCP). Medical surveillance shall be made available to any worker suspected of having been exposed to DBCP. Pertinent medical records shall be maintained for all employees subject to exposure to DBCP in the workplace. Such records shall be maintained for 30 yr and shall be avail to medical representatives of the USA Government, the employer, and the employee. [R33, 308] *Sperm count distributions among exposed and control groups at a 1,2-dibromo-3-chloropropane manufacturing plant were remarkably similar. Yet reproductive histories from 60 exposed men indicated that fertility had been reduced during exposure. Wherever there is concern about the potential for adverse reproductive effects in the workplace, data suitable for fertility analyses should be collected during annual medical exam. [R46] *The YFF sperm assay, which is a quantification of the incidence of sperm with 2 fluorescent bodies (YFF= two fluorescent bodies), was performed on human subjects exposed to 1,2-dibromo-3-chloropropane. They showed a statistically significant incr in the incidence of double Y chromosomes. This test should be considered for inclusion as part of a battery of medical tests for monitoring indust populations. [R47] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R34, 1979.23] HTOX: *Sperm count were determined for 36 workers potentially exposed to 1,2-dibromo-3-chloropropane (DBCP) (the extent of exposure to other pesticides is not clear). Of these, 11 were found to be vasectomized. Of the remaining 25, 3 had sperm counts between 10 and 30 million/ml; 11 who had normal counts (> 40 million/ml) had had a short duration of exposure (< 3 mo); 11 who had significantly decr sperm counts (< 1 million/ml) had been exposed for at least 3 yr. Of the latter, 9 had no detectable sperm cells. In a later report, among 142 non-vasectomized workers (incl the ones mentioned above) providing semen samples, the median sperm count was 46 million/ml for 107 men exposed to ... DBCP AND 79 million/ml for 35 men never exposed. [R48] *ANALYSES OF SEMEN SAMPLES TAKEN FROM EXPOSED AND NON-EXPOSED 1,2-DIBROMO-3-CHLOROPROPANE (DBCP) WORKERS REVEALED THAT AVG YFF (Y-CHROMOSOME NONDISJUNCTION) FREQUENCY WAS 3.8% IN EXPOSED AND 1.2% IN NON-EXPOSED. AVG Y-CHROMOSOME FREQUENCY WAS 41.8% IN EXPOSED AND 41.5% IN NON-EXPOSED. THE AVG LENGTH OF EXPOSURE WAS APPROX 15.2 MO. [R49] *SIX WORKERS IN 1,2-DIBROMO-3-CHLOROPROPANE FACTORY WERE EXAMINED. AZOOSPERMIA DIAGNOSED IN EACH. THE PRESENTING SYMPTOM IN 2 PATIENTS WAS INFERTILITY, AND A DECR LIBIDO OR IMPOTENCE IN THE OTHER PATIENTS. ELEVATED PLASMA FOLLICLE-STIMULATING HORMONE LEVELS WERE DEMONSTRATED. [R50] *A study summarizes a four year follow-up of 20 production workers with 1,2-dibromo-3-chloropropane induced testicular dysfunction. It is suggested that the gonadotoxic effect of 1,2-dibromo-3-chloropropane (DBCP) in human males is reversible, being inversely related to previous exposure time and being most likely to occur in the presence of normal follicle stimulating hormone values. The further incr in plasma follicle stimulating hormone and luteinizing hormone and the moderate decr in the mean testosterone level in non-recovered workers may suggest a delayed toxic effect of DBCP on Sertoli and Leydig cell function during the four yr follow-up period. [R51] *A group of 22 factory workers who were exposed to dibromochloropropane (DBCP) during its production were reassessed 8 years after being diagnosed as azoospermic (15) or oligozoospermic (7) when initially evaluated in 1977. A follow-up study after 4 yr had indicated that the gonadotoxic effects of DBCP might be reversible. The objective of the eight yr reassessment was to confirm this reversible effect as well as to assess the outcome of pregnancies among wives of DBCP exposed workers. It was observed that recovery of spermatogenesis occurred in four oligozoospermic and three azoospermic men whose plasma follicle stimulating hormone concentration was normal during the whole period. A marked increase in this hormone and luteinizing hormone levels above the upper limit of normal was found in azoospermic men who did not recover. No significant changes in follicle stimulating hormone levels were detected in both recovered and non-recovered oligozoospermic workers. It was also concluded that paternal exposure to DBCP was not associated with an increased risk of fetal malformations or spontaneous abortions. There were 44 conceptions; 22 occurred during paternal exposure to DBCP and 22 during the recovery period. These 44 conceptions resulted in 36 live births (and one ongoing uncomplicated pregnancy). The spontaneous abortion rate did not differ from the frequency found in the pre-exposed or non-exposed pregnancies. The three induced abortions were not related to paternal DBCP exposure. [R52] *... Study of 62 agricultural workers in Israel suggests that spontaneous abortions may have been more frequent in wives of 1,2-dibromo-3-chloropropane-exposed workers (19% of 121 pregnancies) than in wives of unexposed workers (6.6% of 76 pregnancies). [R53, 316] *In man ... /it/ produces moderate depression of the CNS and pulmonary congestion after exposure by inhalation, and ... /causes/ acute gastrointestinal distress and pulmonary edema after ingestion. [R54] *BLOOD AND SEMEN SAMPLES WERE ANALYZED FROM 73 AGRICULTURAL WORKERS FROM 6 DIFFERENT STATES. SPERM COUNTS DECR IN ORDER OF RESEARCHERS AND SALESMEN, FARMERS, FORMULATORS AND CUSTOM APPLICATORS. DATA SHOW VARIATION OF EFFECT IN EXPOSURE TO DIFFERENT AMT OF 1,2-DIBROMO-3-CHLOROPROPANE. [R55] *... Twenty-four pesticide applicators who were exposed to 1,2-dibromo-3-chloropropane (DBCP) for 2 mo or more during the yr in which they were studied had a mean sperm count of 22 million/ml. Thirty-one applicators ... exposed for less than 2 mo but more than 2 wk had a mean sperm count of 39 million/ml, while the mean count for 19 men exposed for less than 2 wk was 46 million/ml. Twenty-two applicators who reported no exposure to ... /DBCP/ had a mean count of 62 million/ml. This trend was statistically significant (p= 0.018); however, only the men exposed for 2 mo or more had counts which were significantly lower (p < 0.01) than the rest. Serum levels of follicle stimulating hormone incr with incr period of exposure (p < 0.05). Neither the depression of sperm counts nor the incr follicle-stimulating hormone levels were associated with exposure in prior yr, suggesting that these effects develop quickly after exposure to the chemical and are apparently reversible when exposure to the chemical is removed. [R56] *A historical prospective mortality study was conducted on 3579 white male workers employed between 1935 and 1976 with potential exposures to brominated cmpd incl 1,2-dibromo-3-chloropropane (DBCP). Workers were classified by their work areas or departments in order to estimate their potential exposures. A significant mortality excess due to diseases of the circulatory system was observed among workers potentially exposed to DBCP. [R57] *A group of some 3500 workers classified as having had exposure ... to several cmpd incl 1,3-dibromo-3-chloropropane (DBCP), was studied in 4 facilities in the USA. Among the 1034 workers ever exposed to ... /DBCP/, a slightly incr, statistically nonsignificant mortality rate from cancer was observed. Nine respiratory cancers were observed, whereas 5.0 would have been expected; of these, 7 were due to lung cancer (4.8 expected). Among 238 workers exposed on a routine basis, no cancer death was observed (Wong et al, 1984). In view of the number and the lack of control of confounding factors, the studies were considered to be inadequate /by the working group/. [R58] *SYMPTOMATOLOGY: 1. (A) Inhalation, high vapor concn: gasping, refusal to breathe, coughing, substernal pain, and extreme respiratory distress at vapor concn over 1500 ppm. Irritation of eyes and upper respiratory mucosa appears promptly after exposure to concentrated vapors. Lacrimation and headache are prominent. Coma may occur rapidly. (B) Inhalation, low, vapor concn, central nervous depression and moderate irritation of respiratory system. Headache is frequent. 2. Dermal: severe skin irritation with marked inflammatory response of epidermis and underlying tissues. 3. Oral: acute gastrointestinal distress with pulmonary congestion and edema. Central nervous depression, perhaps even in the absence of impaired oxygen uptake. 4. By any route, possible late injuries to liver, kidneys and heart. 5. After inhalation exposure, malaise, headache, chest and abdominal discomfort and irritability have been reported to persist for several weeks and perhaps for several years. /Dichloropropenes/ [R3, p. III-142] *MARKED IMPAIRMENT OF SPERMATOGENESIS WAS NOTED IN GROUP OF MEN EXPOSED TO 1,2-DIBROMO-3-CHLOROPROPANE IN A PLANT, AS DEMONSTRATED BY SEMEN ANALYSES, TESTICULAR BIOPSIES, AND HORMONE STUDIES. CONSIDERATION IS GIVEN TO POSSIBLE EFFECTS RESIDUAL LEVELS COULD PRODUCE IN CONSUMERS. [R59] *The effects of exposure to 1,2-dibromo-3-chloropropane (DBCP) for 1-7 yr on testicular physiology were evaluated in men by measuring the circulating levels of follicle-stimulating hormone, luteinizing hormone, androstenedione, testosterone, and dihydrotestosterone every 4 hr throughout a 24 hr period, and correlating this data with semen analysis and testicular biopsy. Above-normal concn of plasma follicle-stimulating hormone in 29 of 30 samples and plasma luteinizing hormone in 25 of 30 samples were observed. Androstenedione levels were lower than normal. DBCP caused profound damage of the germinal epithelium. The observed elevated levels of luteinizing hormone in the face of normal testosterone concn suggest damage to the Leydig cells, with the chronic overstimulation of those cells by luteinizing hormone being necessary to maintain essentially normal testosterone concn. Histologic evidence of Leydig cell hyperplasia support this interpretation. [R60] *At this point, DBCP appears to be the chemical agent with the most recognizable effect on the testis of any chemical studied in regard to occupational exposure. The impact dibromocloropropane has upon the testis is gross in character, as manifested by markedly decreased sperm counts. With the discovery of new sensitive laboratory analytical techniques and the use of sophisticated epidemiological methods, new studies will help define the impact of occupational exposures to chemical and physical agents on the reproductive potential of man. [R61] *44 Men whose exposure to dibromochloropropane in a formulation plant was first described in 1977. Five to 8 yr after the initial effects of dibromochloropropane exposure were discovered and all exposures terminated, there appeared to be no major changes in testicular function of most of the exposed men as measured by sperm concn or serum FSH levels. Recovery of sperm production in two of eight originally azoospermic workers was observed, and no increase in sperm production could be detected in men who had low sperm counts in 1977. [R62] *The mortality experience of a cohort of 548 employees at the Michigan Division of Dow Chemical Company who had potential exposure to 1,2-dibromo-3-chloropropane (DBCP) was updated through 1989. There were 68 total deaths in this cohort compared to 72.1 expected. There were 19 deaths from all malignancies compared to 19.0 expected. There were no deaths from stomach, liver, kidney, testes, or nasal cavity cancers. There were seven deaths from cancer of the lung compared to 6.6 expected. The findings do not suggest an incr risk for all malignant neoplasm mortality among 548 DBCP production and formulation male workers. Among the 81 workers who were in an exposure subgroup defined as direct with 1 or more years of experience, there were three lung cancer deaths observed to the 0.9 expected; however, smoking was a confounding factor. /Results indicate/ that even though this ... study nearly doubled the number of person years from the original study performed in 1984, the conclusions remain limited by the size of the cohort and the duration of the follow up period. [R63] NTOX: *1,2-Dibromo-3-chloropropane ... tested on animal eyes both undiluted and as a 1% solution in propylene glycol caused slight pain and signs of irritation that lasted for one to two days, but no damage to the cornea. [R64] *IN 90 DAY FEEDING TRIALS THE LOWEST DOSE LEVEL CAUSING A DECR IN GROWTH RATE WAS: FOR FEMALE RATS 150 MG/KG, FOR MALE RATS 450 MG/KG. [R7] *DAILY ORAL ADMIN OF 70 MG/KG BODY WT (20% OF ACUTE LD50) TO RATS WAS LETHAL AFTER 3 WK OF DOSING. DEGENERATIVE EFFECTS WERE NOTED IN VASCULAR SYSTEM AND IN ALL INTERNAL ORGANS. 1,2-DIBROMO-3-CHLOROPROPANE (97% PURE) WAS GIVEN BY GAVAGE TO 190 RATS EITHER IN A DOSE OF 100 MG/KG BODY WT (SINGLE DOSE), OR IN REPEATED DOSES OF 10 MG/KG BODY WT FOR 5 MO. AFTER THE SINGLE DOSE, THE ANIMALS DEVELOPED ... NERVOUS SYSTEM DEPRESSION AND WT LOSS. FOLLOWING REPEATED TREATMENT, AN EFFECT ON SPERMATOGENESIS WAS OBSERVED IN MALES, AND NUMBER AND VIABILITY OF SPERMATOZOA WERE DECR, ESTRUS WAS INHIBITED IN FEMALES. ... INHALATION OF CONCN OF OVER 600 MG/CU M (60 PPM) IN AIR CAUSED IRRITATION OF ... MUCOUS MEMBRANES AND RESPIRATORY TRACT, HEPATIC DEGENERATION, NEUROTOXICITY, AND NEPHROTOXICITY IN RATS. [R48] *TWO GROUPS OF 50 MALE AND 50 FEMALE B6C3F1 HYBRID MICE 5-6 WK OLD WERE FED TECHNICAL-GRADE 1,2-DIBROMO-3-CHLOROPROPANE (MIN 90% PURITY) IN CORN OIL BY GAVAGE ON 5 CONSECUTIVE DAYS/WK. APPROX TIME-WEIGHTED AVG DOSES WERE 114 and 219 MG/KG FOR MALES AND 110 AND 209 MG/KG FOR FEMALES. TWO GROUPS, EACH OF 20 MALES AND 20 FEMALES, WERE USED AS VEHICLE-TREATED AND UNTREATED CONTROLS. LOW-DOSE ANIMALS AND VEHICLE CONTROLS ... KILLED @ 60 and 78 WK AND HIGH-DOSE ANIMALS AT 47 WK BECAUSE OF HIGH MORTALITY RELATED TO TUMORS. ... IN MALES, 40/50 OF HIGH-DOSE GROUP HAS DIED BY END OF WK 47, and 42/50 OF LOW-DOSE GROUP HAD DIED BY WK 59. IN FEMALES, 30/50 OF HIGH-DOSE GROUP HAD DIED BY END OF WK 47, and 41/50 OF LOW-DOSE GROUP ... BY WK 60. SQUAMOUS CELL CARCINOMAS OF FORESTOMACH OCCURRED IN 43/46 LOW-DOSE MALES, 47/49 HIGH-DOSE MALES, 50/50 LOW-DOSE FEMALES, AND 47/48 HIGH-DOSE FEMALES. THIS LESION OCCURRED WITH FREQUENT METASTASES TO ABDOMINAL VISCERA AND LUNG. NO GASTRIC NEOPLASMS OCCURRED IN EITHER VEHICLE OR UNTREATED CONTROLS (NCI, 1978). [R65] *TWO GROUPS OF 50 MALE AND 50 FEMALE OSBORNE-MENDEL RATS, 6-7 WK OLD WERE FED 1,2-DIBROMO-3-CHLOROPROPANE (MIN 90% PURE) IN CORN OIL BY GAVAGE AT APPROX TIME-WEIGHTED AVG DOSAGES OF 15 and 29 MG/KG BODY WT ON 5 CONSECUTIVE DAYS/WK. TWO GROUPS, EACH OF 20 MALES AND 20 FEMALES, WERE USED AS ... CONTROLS. LOW- AND HIGH-DOSE FEMALES WERE TREATED FOR 73 and 64 WK, RESPECTIVELY, AND THEN KILLED ... HIGH-DOSE MALES ... TREATED FOR 64 WK AND THEN KILLED; LOW-DOSE MALES WERE TREATED FOR 78 WK AND THEN KILLED @ 83 WK. ... SQUAMOUS-CELL CARCINOMAS OF FORESTOMACH OCCURRED IN 47/50 BOTH LOW- AND HIGH-DOSE MALES, 38/50 LOW-DOSE FEMALES, and 29/49 HIGH-DOSE FEMALES. THESE LESIONS OCCURRED WITH FREQUENT METASTASES TO ABDOMINAL VISCERA AND LUNGS. NO GASTRIC CARCINOMAS OCCURRED IN ... CONTROLS. IN FEMALES, ADENOCARCINOMAS OF THE MAMMARY GLAND OCCURRED IN 24/50 OF THE LOW-DOSE GROUP, IN 31/50 OF THE HIGH-DOSE GROUP, IN 2/20 UNTREATED CONTROLS AND IN NONE OF THE VEHICLE CONTROLS (NCI, 1978). [R66] *1,2-DIBROMO-3-CHLOROPROPANE WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM TA100, TA1530 AND TA1535, BUT NOT IN TA1538, BOTH IN PRESENCE AND ABSENCE OF LIVER MICROSOMAL ACTIVATION SYSTEM. [R48] *AFTER CHRONIC ADMIN OF 1,2-DIBROMO-3-CHLOROPROPANE BY 1 OR MORE ROUTES TO HA:ICR SWISS MICE, IT WAS ACTIVE AS SKIN TUMOR INITIATOR IN THE TWO-STAGE CARCINOGENESIS ASSAYS; PHORBOL MYRISTATE ACETATE WAS USED AS A PROMOTER. IT ALSO INDUCED LUNG AND/OR STOMACH TUMORS BY REPEATED SKIN APPLICATION. [R67] *1,2-DIBROMO-3-CHLOROPROPANE WAS MOST ACTIVE OF 4 RELATED 3-CARBON HALOGENATED AND OXYGENATED CMPD WHEN TESTED FOR MUTAGENIC ACTIVITY BY AMES TEST (SALMONELLA TYPHIMURIUM, STRAIN TA-100), BUT REQUIRED ENZYMIC CONVERSION BY S9 MICROSOMAL PREPARATION TO ACTIVE MUTAGEN WHICH WAS DOSE-RELATED. [R68] *1,2-DIBROMO-3-CHLOROPROPANE INDUCED DOMINANT LETHALS IN RATS IN POST-MEIOTIC STAGE OF SPERMATOGENESIS, ESPECIALLY IN EARLY SPERMATID STAGE. IT DID NOT CAUSE DOMINANT LETHALS IN MICE. [R69] *... UP TO 50 MG/KG /1,2-DIBROMO-3-CHLOROPROPANE WAS ADMIN/ DAILY TO RATS BY GAVAGE ON DAYS 6-15 OF GESTATION. SOME MATERNAL TOXICITY, FETAL WT DECR, AND DECREASED FETAL VIABILITY WAS FOUND BUT NO INCREASE IN MALFORMATION. [R70] *... SINGLE INTRAPERITONEAL 100 MG/KG INJECTION OF 1,2-DIBROMO-3-CHLOROPROPANE TO PREPUBERTAL MALE MICE INDUCED SIGNIFICANT UNSCHEDULED DNA SYNTHESIS (DNA REPAIR) IN PREMEIOTIC GERM CELLS BUT NOT IN SPERMATOZOA. [R53, 323] *RABBITS EXPOSED TO 1,2-DIBROMO-3-CHLOROPROPANE (10 PPM) BY INHALATION FOR 14 WK HAD NEARLY COMPLETE TESTICULAR ATROPHY BY 8TH WK. ALL STAGES OF SPERMATOGENESIS WERE ABSENT; LIPIDS WITHIN LEYDIG CELLS WERE INCR. RATS, SIMILARLY EXPOSED SHOWED 50% DECR IN TESTICULAR WT AND PATCHY DECR IN SPERMATOGENESIS. [R71] *MALE RATS (AGE 14 WK) WERE EXPOSED CONTINUOUSLY TO 0.3-10 PPM OF 1,2-DIBROMO-3-CHLOROPROPANE. HYPERTROPHY OF ADRENALS AND MARKED WT REDUCTION OF EPIDIDYMIS, TESTES AND SEMINAL VESICLES WERE OBSERVED. REDUCTION IN NUMBER OF SPERMATOZOA IN EPIDIDYMIS, AND REDUCTION IN WHITE BLOOD CELLS ALSO OCCURRED. [R72] *MALE RABBITS EXPOSED TO 1,2-DIBROMO-3-CHLOROPROPANE (10 PPM) FOR 8 WK BY INHALATION APPEARED INFERTILE WHEN MATED DURING 14TH WK. [R73] *... THE MUTAGENICITY OF DBCP /1,2-DIBROMO-3-CHLOROPROPANE/ BY AMES REVERSE MUTATION ASSAY /IN SALMONELLA TYPHIMURIUM, STRAIN TA1535 WAS INVESTIGATED/. ... /IT/ WAS CONCLUDED THAT IN THE ABSENCE OF S9 ACTIVATION IN RATS PRETREATED WITH AROCLOR, THE MUTAGENIC CAPABILITY OF STD DBCP PREPN (0 TO 1600 UG/PLATE) WAS DUE SOLELY TO EPICHLOROHYDRIN, WHICH WAS INCLUDED AS STABILIZER. HOWEVER, AFTER THE ADDN OF S9, TECHNICAL-GRADE AND HIGHLY PURIFIED DBCP (20 TO 200 UG/PLATE) WERE EQUALLY MUTAGENIC. ON THE BASIC OF THOSE DATA ... /IT/ WAS CONCLUDED THAT DBCP IS A POTENT INDIRECT MUTAGEN IN BACTERIA. THAT CONCLUSION HAS BEEN CONFIRMED BY RECENT WORK ... /BY INVESTIGATORS/ WHO FOUND DBCP TO BE MUTAGENIC TO SALMONELLA TYPHIMURIUM TA1535 AND TA100 AND TO ESCHERICHIA COLI WP2 HCR. [R53, 322] *1,2-DIBROMO-3-CHLOROPROPANE HAS BEEN SHOWN TO INDUCE SISTER-CHROMATID EXCHANGE (SCE) AND CHROMOSOME ABERRATIONS IN CULTURED CHINESE HAMSTER CELLS OVER A RANGE OF APPLIED DOSES. [R53, 322] *MALE AND FEMALE RATS INHALED 0, 0.1, 1, OR 10 PPM 1,2-DIBROMO-3-CHLOROPROPANE (DBCP) VAPOR FOR 6 HR/DAY, 5 DAYS/WK FOR 14 WK FOLLOWED BY RECOVERY PERIODS OF UP TO 32 WK. DBCP DID NOT AFFECT THE ABILITY OF MALES TO IMPREGNATE FEMALES; HOWEVER, A DOMINANT LETHAL EFFECT WAS EVIDENT AT 10 PPM. MODERATE TESTICULAR ATROPHY AND FOCAL AGGREGATES OF ALTERED CELLS IN THE ADRENAL CORTEX WERE OBSERVED IN RATS EXPOSED @ 10 PPM FOR 14 WK. LESIONS WERE OBSERVED IN THE ADRENAL CORTEX OF RECOVERY MALES AND FEMALES FROM THE 10 PPM EXPOSURE LEVEL; FEMALES EXPOSED TO 1 PPM HAD SLIGHT ADRENAL CORTICAL LESIONS AT THE END OF THE RECOVERY PERIOD. INCR NUMBERS OF OVARIAN CYSTS OCCURRED IN FEMALES FROM THE 10 PPM LEVEL. BRAIN EFFECTS, INCL FOCAL OR MULTIFOCAL MINERALIZED DEPOSITS, WERE PRESENT IN MALES AND FEMALES IN THE 10 PPM EXPOSURE GROUP. [R74] *1,2-Dibromo-3-chloropropane (DBCP) was evaluated for genotoxicity in the mouse spot test. Male PW mice, homozygous for 5 coat color mutations, were mated with C57BL/6 females. On day 10 of pregnancy, the females received ip injections of 106 mg/kg DBCP dissolved in soybean oil. The offspring were examined for recessive color spots for 14-30 days following birth. Pups from treated animals showed a significantly higher frequency (2.9%) of recessive color spots compared with solvent treated (0.6%) or untreated (0.9%) controls. Most of the spots induced by DBCP were light brown, which suggest that DBCP induced predominately point mutations in the pigment cells. Thus, DBCP is mutagenic in somatic cells of mice in vivo; however, no teratogenic effects were observed. [R75] *1,2-Dibromo-3-chloropropane (DBCP) was evaluated in a specific-locus test for gene-mutation induction in the germ line of male (101 x C3H)F1 mice. A total of 144 males (3 groups) were injected ip with 80 mg/kg DBCP on 5 consecutive days for a total exposure of 400 mg/kg. One group of 12 males was given DBCP as a single dose of 90 mg/kg and another group of 24 males was given a single dose of 110 mg/kg. For treated spermatogonial stem cells, the finding of 2 mutations among 39519 offspring was not remarkable. From treated post stem-cell stages, no mutants were found among 6240 offspring. The fertility of DBCP-treated males was not altered. Thus, DBCP was negative in these tests and the highest ineffective dose tested was 400 mg/kg. [R76] *... 0.2 mg/ml concn of 1,2-dibromo-3-chloropropane (DBCP) in 0.01% ethanol or ethanol alone /was fed/ to Canton-S male Drosophila melanogaster for 72 hr then to individual males mated with Basc females. DBCP treatment produced sex-linked recessive mutations in 9.5% of the first brood. In Drosophila it also caused loss of X or Y chromosomes and induced increases in heritable translocations. [R53, 322] *Male and female rats and mice were exposed to 0, 1, 5, or 25 ppm concn of 1,2-dibromo-3-chloropropane (DBCP) by inhalation 6 hr/day, 5 days/wk for 13 wk. The severity and incidence of histopathological changes of nasal cavity were dose related. Changes in all dosage groups in the region of the respiratory turbinates included cytomegaly of basal cells, focal hyperplasia, squamous metaplasia and disorientation of basal and ciliated cells, and loss of cilia. Necrosis and squamous metaplasia of olfactory, tracheal, and bronchial epithelium were present in the animals receiving 25 ppm. [R53, 321] *1,2-Dibromo-3-chloropropane test results for mutagenicity in L5178Y mouse lymphoma cells were positive. [R77] *No toxic effects of 1,2-dibromo-3-chloropropane were observed at 5.0 ppm for Salmo gairdnerii (rainbow trout) or Petromyzon marinus (sea lamprey). [R78] *The effects of 1,2-dibromo-3-chloropropane (DBCP) on epididymal sperm carbohydrate metabolism was studied in Fischer 344 rats to identify the specific site of DBCP-induced inhibition of metabolism. Glucose and lactate metabolism were significantly inhibited by 3.0 mM DBCP. At a concentration of 3 mM DBCP, carbon dioxide production from the tricarboxylic acid cycle intermediates, acetyl CoA, succinate, alpha-ketoglutarate, and citrate was inhibited by 81-98%. To determine if the inhibitory effects of DBCP occurred in the mitochondrial electron transport chain, oxygen consumption resulting from metabolism of TCA cycle intermediates in intact sperm was measured. The presence of 3 mM DBCP inhibited oxidation of endogenous substrate plus alpha-ketoglutarate and malate by 95 and 92%, respectively, but did not inhibit the flavine adenine dinucleotide linked oxidation of succinate. The activities of alpha-ketoglutarate, pyruvate, malate, and lactic dehydrogenase were not inhibited by 3 mM DBCP. [R79] *Male Sprague-Dawley rats were treated with 1,2-dibromo-3-chloropropane (DBCP) on alternate days during the first 20 days of life and examined at 76-78 days to study the dose-toxicity relationship of DBCP by assessing alterations in the reproductive system. Four dose levels of DBCP, 1, 5, 10, and 20 mg/kg body weight, were used (5 animals/treatment group). The compound was dissolved in propylene glycol and administered subcutaneously at the back of the neck. In another phase of the study, DBCP (10 mg/kg body weight) was administered to rats on alternate days from either Days 2-10 or Days 12-20 of age. Sexually matured male rats were treated with 5 mg/kg of DBCP on alternate days for a total of 10 doses and all animals were killed at 30 or 75 days after the last injection. A dose-response relationship in testes weights was seen in all 4 dose levels of DBCP with 89-98% reduction in the three highest dose groups when treated the first 20 days. The epididymes and seminal vesicles showed marked reductions (82-90%) at the three highest dose groups but an increase in weight in the lowest dose group. Biochemical studies showed that the androgen production capacity per unit weight of testicular tissue was elevated as a function of the DBCP dose, although when the androgen production rate was expressed on the basis of tests pair weight, it showed a reduction, due to the DBCP-induced loss in testis weight. Histopathological study showed cellular alterations in the 5 mg/kg DBCP-treated group and a total absence of seminiferous tubules in the 10 mg/kg group. The results of the critical period study showed that DBCP treatment on Days 2-10 had more effect than treatment on Days 12-20. The age-related study showed that sexually matured rats were less susceptible to the reproductive toxicity of DBCP than was the developing rat. [R80] *Dibromochloropropane was not teratogenic to rats when given orally on days 6-15 of gestation at levels of 12.5, 25, or 50 mg/kg/day. The two highest levels were toxic, resulting in reduced maternal and fetal weights. Oral doses of DBCP given to rabbits at 15 mg/kg in water and to rats at 15 mg/kg in corn oil did not significantly effect fertility. When male rats were exposed to DBCP vapor at a concentration 10 ppm for 14 wk, they were able to fertilize females, but the proportion of resorptions was increased over control levels, suggesting a dominant lethal effect. Rabbits were more sensitive than rats; male rabbits exposed to 1 or 10 ppm DBCP showed testicular atrophy, loss of spermatogenic cells, and complete infertility at the high exposure level confirmed the reproductive toxicity potential of DBCP at 100 mg/kg/day by gavage in a continuous breeding design in mice. [R41, 703] *The comparative toxicities of 2,3-dichloro-1-propanol (DC1P), 1,3-dichloro-2-propanol (DC2P), alpha-chlorohydrin (ACH), epichlorohydrin (ECH) or 1,2-dibromo-3-chloropropane (DBCP) were investigated in rats. Male Wistar rats were given a single sc injection of 0.34 um/kg body weight DC1P, DC2P, ACH, ECH or DBCP. The rats were /sacrificed/ 6 wk after treatment and the testes and epididymes were removed for analysis. Reproductive system effects were evaluated. Significant reductions in body weight and in testis and epididymis weights were measured for DBCP treated rats. Epididymal weight decr significantly from a control value of 0.0229 g to 0.208 g in the DC1P group. Control sperm count in the body plus tail of the epididymis was 177.4 X 10(6), while counts for DBCP, DC1P and DC2P were 15.5 X 10(6), 138.9 X 10(6), and 153.8 X 10(6), respectively, all of which were significant reductions. Sperm counts were also significantly reduced in the head of the epididymis in the DBCP and ACH groups. The occurrence of sperm without tails incr from a control level of 13.8/1000 sperm to 865.8/1000 sperm in the DBCP treated group. A slight incr in immature sperm from 3.8/1000 to 7.3/1000 was /noted/ in the ACH treated group. Histological examination of the seminiferous tubules of the DBCP group showed reduced diameters and loss of step nine spermatids and pachytene spermatocytes. Only Sertoli cells were seen in some tubules. No pathological changes were observed in other treated groups. /The results indicate/ that DC1P is a more potent testicular toxicant than DC2P, ACH, and ECH, though much weaker than DBCP in the damage studied. [R81] +F344 rats and B6C3F1 mice inhaled 0.6 or 3.0 ppm 1,2-dibromo-3-chloropropane (DBCP) for 6 hr/day, 5 days/wk, for 76-103 wk. ... Untreated chamber controls consisted of 50 rats and 50 mice of each sex. ... Under the conditions of this bioassay, DBCP was carcinogenic for male and female F344/N rats, including incr incidences of nasal cavity tumors of the tongue in both sexes, and cortical adenomas in the adrenal glands of females. DBCP was carcinogenic in male and female B6C3F1 mice, including incr incidences of nasal cavity tumors and lung tumors. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R82] +A bioassay for possible carcinogenicity of technical grade dibromochloropropane (DBCP) was conducted by using Osborne-Mendel Rats and B6C3F1 mice. DBCP in corn oil was admin by gavage 5 days/wk at either two dosages, to groups of 50 male and 50 female animals of each species. ... Under the conditions of this study, DBCP is a stomach carcinogen in rats and mice of both sexes and is carcinogenic to the mammary gland in female rats. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R83] NTXV: *LD50 Rabbit (male) oral 100 mg/kg; [R84] *LC50 Rat (Long-Evans male and female) 1,480 mg/cu m/hr; [R84] *LD50 Rabbit (albino) dermal 1,400 mg/kg /95-8% purity/; [R84] *LD50 Mouse ip 123 mg/kg / > 99% purity/; [R85] *LD50 Mouse (female) oral 260 mg/kg /95-8% purity/; [R86] *LD50 Rat (male) oral 170 mg/kg /95-8% purity/; [R84] *LD50 Guinea pig (male) oral 210 mg/kg /95-8% purity/; [R87] ETXV: *LD50 ANAS PLATYRHYNCHOS (MALLARD) 3-5 MO FEMALES ORAL 66.8 MG/KG (95% CONFIDENCE LIMIT 48.2-92.6 MG/KG) /95% ACTIVE INGREDIENT/; [R88, 58] *LD50 PHASIANUS COLCHICUS (RING-NECKED PHEASANT) 3-4 MO FEMALES ORAL 156 MG/KG (95% CONFIDENCE LIMIT 89.3-271 MG/KG) /95% ACTIVE INGREDIENT/; [R88, 54] NTP: +F344 rats and B6C3F1 mice inhaled 0.6 or 3.0 ppm 1,2-dibromo-3-chloropropane (DBCP) for 6 hr/day, 5 days/wk, for 76-103 wk. Early deaths of high-dose rats and mice were assoc with resp tract tumors. Untreated chamber controls consisted of 50 rats and 50 mice of each sex. ... Under the conditions of this bioassay, DBCP was carcinogenic for male and female F344/N rats, including incr incidences of nasal cavity tumors of the tongue in both sexes, and cortical adenomas in the adrenal glands of females. DBCP was carcinogenic in male and female B6C3F1 mice, including incr incidences of nasal cavity tumors and lung tumors. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R82] +A bioassay for possible carcinogenicity of technical grade dibromochloropropane (DBCP) was conducted by using Osborne-Mendel Rats and B6C3F1 mice. DBCP in corn oil was admin by gavage 5 days/wk at either two dosages, to groups of 50 male and 50 female animals of each species. ... The time weighted avg dosages of DBCP in the chronic study were 29 mg/kg/day for the high dose rats of both sexes, and 15 mg/kg/day for the low dose rats of both sexes. The time weighted avg concn for the high dose male and female mice were 219 and 209 mg/kg/day, respectively. The time weighted avg for the low dose male and female mice were 114 and 110 mg/kg/day, respectively. For each species, 20 animals of each sex were placed on test as controls. These animals were intubated with corn oil at the same time that dosed animals were intubated with DBCP mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals received no gavage treatments. ... Under the conditions of this study, DBCP is a stomach carcinogen in rats and mice of both sexes and is carcinogenic to the mammary gland in female rats. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R83] +Dibromochloropropane (DBCP) ... was tested because of the known toxicity in rats and relative paucity of data in mice. DBCP was an early RACB study using Swiss CD-1 mice. Data on food and water consumption's, body weights, and clinical signs during a 2 wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation study at 25.0, 50.0, and 100.0 mg/kg by gavage in corn oil. In the F0 animals, 4 females, 2 females, 2 females, and 3 females and a male died in the control through high dose groups, respectively. The deaths were not attributed to DBCP exposure. In the low and high dose groups, there was a 10% and 8%, respectively, decr in the number of litters/pair. However, there was no change in the number of pups/litter, pup viability, or pup weight adjusted for litter size. There were no treatment-related reductions in F0 mouse body weight. In the absence of a change in pup parameters, no Task 3 was conducted, and the control and high dose mice were reared for second generation evaluation. Body weights between mice in these 2 groups were not different at weaning or at cohabitation. In the Task 4 F1 mating trial, controls and high dose DBCP mice delivered the same number of litters/group, pups/litter, and proportion viable pups; adjusted pup body weight was not affected by DBCP. After the F2 litters were delivered and evaluated, the F1 adults were killed and necropsied. In the high dose treated males, there was a 16% incr in relative liver weight, and a decr of 8% and 20% in relative epididymis and prostate weights, respectively. There were no differences between the groups in sperm endpoints. DBCP treatment increased female relative liver weight by 6%; vaginal cytology was not performed. This study found that DBCP produced minor effects (fewer litters/F0 pair, and reduced epididymis and prostate weights in F1 mice) concomitant with minor increases in liver weight and no change in body weight. These changes are relatively small, compared to effects seen in rats, and probably represent a significant species difference in response. [R89] TCAT: ?1,2-Dibromo-3-chloropropane (CAS# 96-12-8) was evaluated for carcinogenicity. The test substance was administered in the diet of male and female Charles River CD-1 mice (number of animals not reported) at dose levels of 0, 0.3, 1.6, and 4.8 mg/kg bw (after adjustments in actual feed consumption, fortification, and evaporation) for 78-weeks. Survival rates in the control group were 74% (females) and 60% (males); and in the high dose group 80% (females) and 54% (males). The predominant tumor was squamous cell carcinoma of the non-glandular stomach in males (52%) and females (38%). There was one kidney tumor and stomach tumor in one male; and single cases of lung, liver, and uterine tumors accompanied with a stomach tumor in females. Mammary tumors were present in two females with one female having a stomach tumor also. None of the controls had any tumors. [R90] ?1,2-Dibromo-3-chloropropane (CAS# 96-12-8) was evaluated for carcinogenicity. The test substance was administered in the diet of male and female Charles River and Sprague Dawley rats (50/sex/group) at dose levels of 0.24, 0.80, and 2.39 mg/kg bw (after adjustments for fortification and evaporation) for two-years. There was a dose-related increase in non-neoplastic tissue changes in the liver (peliosis hepatitis), kidney (renal tubule hyperplasia and megalocytic cells lining renal tubules), and stomach (acanthosis, hyperkeratosis, and basal cell activity). Tumor incidence in males at 2.39 mg/kg was 20/48 (stomach), 20/48 (kidney), and 6/48 (stomach). In females at 2.39 mg/kg, tumor incidence was 11/48 (stomach), 13/48 (kidney), and 2/48 (stomach). [R90] ?1,2-Dibromo-3-chloropropane (CAS# 96-12-8) was evaluated for mutagenicity. The test substance was positive in the Ames assay. No further information was provided. [R91] ?1,2-Dibromo-3-chloropropane (CAS# 96-12-8) was evaluated for mutagenicity. The test substance was positive in the mouse lymphoma assay using the TK Locus and L5178Y cells. No further information was provided. [R91] ADE: *CAN BE ABSORBED PERCUTANEOUSLY IN TOXIC AMT. [R3, p. II-268] *MALE WISTAR RATS WERE GIVEN ORALLY 20-400 MG/KG (14)C-LABELED 1,2-DIBROMO-3-CHLOROPROPANE. MAJOR SITES OF RADIOACTIVITY WERE FOUND IN THE LIVER AND KIDNEY. IT IS SUGGESTED THAT THE MACROMOLECULAR BINDING IN VIVO IS CAUSED BY AN ACTIVATED METABOLIC INTERMEDIATE FORMED ON MICROSOME. [R92] *When a dose of 20 mg/kg 1,2-dibromo-3-chloropropane-3-(14)C was given orally ... /to/ male rats ... only traces (0.04%) of the (14)C were excreted in the expired air as unchanged 1,2-dibromo-3-chloropropane. Essentially all (98.8%) was absorbed from the gut and 90% of the activity was excreted in 3 days. During the first 24 hr, 49, 14, and 16.5% ... was excreted in the urine, feces, and expired air ... . [R19, 3536] METB: *Following intraperitoneal admin of 50 mg/kg of 1,2-dibromo-3-chloropropane (DBCP) to rats in propylene glycol, S,S'-(2-hydroxypropane-1,3-diyl)bismercapturic acid and S-(2,3-dihydroxypropyl)mercapturic acid were found as metabolites in urine. The metabolic pathway for DBCP incl oxidation and hydrolysis to a series of epoxide metabolites, and formation of male anti-fertility agents alpha-chlorohydrin and alpha-bromohydrin from epoxides. Subsequent oxidative metabolism of these latter two cmpd to oxalic acid presumably causes liver damage. [R93] *Rats treated orally with 1,2-dibromo-3-chloropropane (DBCP) excrete small amt of 2-bromoacrylic acid. Rabbit liver microsomal oxidases also yield 2-bromoacrylic acid from DBCP. The conversion involves initial enzymic sulfoxidation or hydroxylation at methyl chloride moiety (-CH2Cl) substituents and then facile nonenzymic reactions to liberate 2-haloacroleins which are further oxidized to the 2-haloacrylic acids. 2-Haloacroleins as potent mutagens and intermediary metabolites may contribute to the adverse toxicologic properties of DBCP. [R94] ACTN: *ADMIN OF A SINGLE ORAL DOSE OF 1,2-DIBROMO-3-CHLOROPROPANE (DBCP) TO MALE RATS DECR HEPATIC MICROSOMAL CYTOCHROME P450 AND B5 TO 45 AND 65% OF CONTROLS AFTER 48 HR. INCORPORATION OF DELTA-AMINOLEVULINIC ACID INTO PROTEIN, MICROSOMES AND PROTEASE-TREATED MICROSOMES WAS DECR 88, 65, AND 70% OF RESPECTIVE CONTROL VALUE IN ANIMALS TREATED FOR 12 HR. ACTIVITY OF ALA-DEHYDRATASE ALSO DECR TO 75 AND 90% OF CONTROLS AT 24 AND 48 HR. THESE DATA SUGGEST AN INHIBITION OF HEME SYNTH OR AN ALTERATION IN HEME DEGRADATION MAY PLAY A ROLE IN DECR OF THE MICROSOMAL CYTOCHROMES FOLLOWING TREATMENT WITH DBCP. [R95] *Challenge of male rats with a single dose of 1,2-dibromo-3-chloropropane resulted in significant decr in cytochrome p450 in microsomes isolated from liver, kidney, testis, lung, and small intestine mucosa 48 hr after treatment. Lipid peroxidation was not found in hepatic microsomes. In liver tissue, treatment resulted in a decr in cytochrome p450 in both rough and smooth microsomal fractions and nuclei, but not in mitochondrial fractions. Mixed-function oxidase activities in hepatic microsomes decr in parallel with cytochrome p450 content. Thus, treatment with alkyl halides may preferentially affect isozymes of cytochrome p450. [R96] *The potential for 1,2-dibromo-3-chloropropane (DBCP) to reduce male fertility by acting at a site in the genital tract beyond the testis was evaluated in male rats. Doses of 10, 20, or 40 mg/kg DBCP given sc once daily for 7 days caused a dose-dependent redn in the metab of glucose to carbon dioxide by epididymal sperm, as measured in vitro. Conversion of glucose to lactate was not reduced, indicating inhibition of energy metab at a step postglycolysis. The direct addn of DBCP to epididymal sperm being incubated in vitro also inhibited the metab of glucose to CO2. Thus, DBCP may cause a nearly immediate infertility via a direct effect on posttesticular sperm. A possible mechanism of the infertility is inhibition by DBCP of glucose metab in the ejaculated sperm. [R97] *Subcutaneous administration of the nematocide, 1,2-dibromo-3-chloropropane (DBCP), to adult, male, fischer 344 rats transiently depleted hepatic and caput (head) epididymal nonprotein sulfhydryl contents. NPS concentrations in the testis and kidney were not lowered by DBCP. Liver, kidney and testis all exhibited increases in tissue nonprotein sulfhydryl concentrations 48 hr after treatment; the effects were most prominent in the outer medullary section of the kidney 24 hr after treatment with 80 mg/kg of DBCP. The glutathione depleting agent diethyl maleate transiently lowered hepatic, renal and caput epididymal nonprotein sulfhydryl concentrationsin a dose and time dependent manner. Renal and caput epididymal nonprotein sulfhydryl contents were increased relative to control 24 hr after diethyl maleate treatment. Single sc injections of DBCP produced dose dependent lesions in the kidney, testis, caput epididymis and liver. Diethyl maleate treatment 90 min before DBCP treatment enhanced the nephrotoxic potency of DBCP as indicated by greater elevations of blood urea nitrogen and serum creatinine concentrations and by more severe renal tubular necrosis in diethyl maleate pretreated thanin vehicle controls, as determined 48 hr after DBCP exposure. Seminiferous tubular degeneration, as determined 48 hr post-DBCP treatment, was greater in rats pretreated with 600 mg/kg of diethyl maleate than in nonpretreated controls. When examined 16 days after DBCP treatment, however, the severity of testicular atrophy was virtually the same in rats pretreated with a lower dose of diethyl maleate (400 mg/kg) as in nonpretreated rats. These results indicate that DBCP is a depletor of hepatic and caput epididymal NPS in the acutely toxic dose range. Inasmuch as NPS concentrations were not lowered in two of the major target organs, kidney and testis, acute DBCP injury would not appear to be dependent on local glutathione depletion. However, the greater susceptibility of kidney and testis to DBCP injury after diethyl maleate pretreatment suggests an important role for nonprotein sulfhydryl, particularly those in the liver, in modulating DBCP toxicities. [R98] INTC: *Single subcutaneous injection of 1,2-dibromo-3-chloropropane (DBCP) produced dose-dependent injury to kidney, testis, epididymis, and liver in male rats. Pretreatment with enzyme inducer phenobarbital reduced the nephrotoxicity and hepatotoxicity of DBCP, and resulting serum creatinine and urea nitrogen concn. Cobaltous chloride pretreatment enhanced the necrogenic effect of DBCP on the kidney and potentiated DBCP-induced elevations of serum creatinine and urea nitrogen concn. The gonadotoxicity of DBCP was enhanced by cobaltous chloride and reduced by phenobarbital. The modulating effects of cobaltous chloride and phenobarbital could not be ascribed simply to changes in tissue concn of the protective conjugation substrate glutathione, since cobaltous chloride incr and phenobarbital did not alter renal and hepatic nonprotein sulfhydryl concn. A complex role of metab is indicated in determining dose-dependent toxic response to DBCP admin. [R99] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Due to the restrictions on the use of 1,2-dibromo-3-chloropropane as a nematocide and soil fumigant, little release of 1,2-dibromo-3-chloropropane presently occurs. The use of 1,2-dibromo-3-chloropropane as a laboratory reactant is not expected to result in large quantities being released to the environment. If released to the atmosphere, 1,2-dibromo-3-chloropropane will exist solely in the vapor phase in the ambient atmosphere, based on a measured vapor pressure of 0.58 mm Hg at 20 deg C. Vapor-phase 1,2-dibromo-3-chloropropane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated half-life of about 37 days. Products of 1,2-dibromopropanol, chlorobromopropanol, and 1-bromo-3-chloro-2-propanone are formed during this process. 1,2-Dibromo-3-chloropropane released to soil will likely volatilize or leach. In alkaline, but not neutral or acidic soils, hydrolysis may be significant. Biodegradation is possible but is expected to be slow relative to volatilization and leaching. In water, 1,2-dibromo-3-chloropropane is expected to volatilize. It may also slowly hydrolyze (half-life= 38 years, neutral pH, at 25 deg C). Estimated volatilization half-lives for a model river and model lake are 14 hours and 9 days, respectively. In groundwater, 1,2-dibromo-3-chloropropane is expected to persist due to its low estimated rate of hydrolysis (half-life= 141 years, neutral pH, at 15 deg C). In surface waters, biodegradation may occur, but is expected to be slow relative to the rate of volatilization. Photodegradation is not expected to be an important fate process for this compound. Sorption to sediments and bioconcentration are not expected to be important fate processes based on measured Koc values of 40-149 and measured BCF values of 3.6-19, respectively. Human exposure is expected to result primarily from ingestion of drinking water, particularly from groundwater sources, containing 1,2-dibromo-3-chloropropane. Occupational exposure to 1,2-dibromo-3-chloropropane is likely via inhalation and dermal contact with vapors, water, and products containing 1,2-dibromo-3-chloro-propane. (SRC) NATS: *1,2-Dibromo-3-chloropropane is not known to occur as a natural product. [R100, (1979)] ARTS: *1,2-Dibromo-3-chloropropane's former production and use(1) as a soil fumigant and a nematocide(2) resulted in the direct release of this compound to the environment(SRC). Its production and use as an intermediate in organic synthesis(2) may result in its release to the environment through various waste streams(SRC). [R101] FATE: *TERRESTRIAL FATE: 1,2-Dibromo-3-chloropropane has been applied to various types of agricultural soils in CA by injection, flooding and sprinkling. The chemical was still present 40 wk after application; and its distribution in soil was proportional to size of soil particles, with greatest distribution found in sandy soils and lowest in clay. In field experiments, 1,2-dibromo-3-chloropropane was detected in soil at levels in the mean range of 0.008-1.64 mg/kg from 1 day to 16 wk after application at the rate of 13.75 kg/ha. Volatilization is expected to be the primary fate of DBCP near the soil surface. Leaching to groundwater is also anticipated based on the demonstrated weak adsorption of DBCP to several soils. Hydrolysis in acidic and neutral soils is not expected to be significant, but may be so in alkaline soils. Although biodegradation may also be significant, it is expected to be a slow process relative to leaching and volatilization. [R100, (1987)] *TERRESTRIAL FATE: Based on a recommended classification scheme(1), measured soil Koc values ranging from 40(2)-149(3) indicate that 1,2-dibromo-3-chloropropane will have very high to high mobility in soil(SRC). Clay and silt soils adsorb more 1,2-dibromo-3-chloropropane than sands; however, downward migration of this compound was observed regardless of the soil type(4). 1,2-Dibromo-3-chloropropane has been reported in well water samples(5) indicating that this compound does leach to groundwater. Koc values from 305-355 were measured for aquifer solids(6) suggesting that this compound will have moderate mobility in an aquifer system(6,SRC). Hydrolysis in acidic and neutral soils is not expected to be significant based on an estimated aqueous half-life of 38 years at pH 7(7), but may be so in alkaline soils(8,SRC). 1,2-Dibromo-3-chloropropane volatilized rapidly from soil surfaces where it had been applied in irrigation water; at least 85% of this compound was lost over 42 days in experiments using cyclic water applications meant to mimic citrus irrigation practices(9). However, air levels of this compound above shank injection-treated soil rarely exceeded 1 ppb beyond 1 day post treatment(10). [R102] *TERRESTRIAL FATE: Although biodegradation may be an important fate process in soil, it is expected to be a slow process relative to leaching and volatilization(SRC). Persistence of 1,2-dibromo-3-chloropropane was much greater when injected into soils than when applied to soils in irrigation water(1). The most rapid rate of dehalogenation (20% in 1 week) was obtained with pH 8 soil suspensions; the maximum observed dehalogenation was 63% after 4 weeks under unspecified conditions(2). Biodegradation of 1,2-dibromo-3-chloropropane in aerobic soil columns gave half-lives of 6.6, 13.0, and 1130 days for natural, nutrient-enriched, and sterile conditions, respectively(3). In other experiments however, 1,2-dibromo-3-chloropropane was not aerobically degraded in soil over a period of time ranging up to several months(4,5). Soil samples, maintained under anaerobic conditions, transformed 1,2-dibromo-3-chloropropane, at 10 and 100 mg/kg suspension, with 5.6 and 11.6% conversion, respectively, in 28 days(4) [R103] *AQUATIC FATE: Based on a recommended classification scheme(1), measured Koc values from 40(2)-149(3) indicate that 1,2-dibromo-3- chloropropane should not adsorb to suspended solids and sediment in water(SRC). Due to the low measured hydrolysis rate at neutral pH (estimated half-life= 38 years at 25 deg C and pH 7)(4), volatilization is expected to be the predominant fate of aqueous 1,2-dibromo-3-chloropropane (1,2-dibromo-3-chloropropane) under neutral conditions. In basic solution, however, hydrolysis is expected to compete with volatilization, forming 2-bromoallyl alcohol(5). 1,2-Dibromo-3-chloropropane should volatilize from water surfaces(1,SRC) based on an estimated Henry's Law constant of 1.5X10-4 atm-cu m/mole(SRC), calculated from experimental values for vapor pressure(6) and water solubility(6). Estimated volatilization half-lives for a model river and model lake are 14 hours and 9 days, respectively(1,SRC). Photodegradation is not expected to be a major fate process for this compound in water based on experimental results in natural water(7). [R104] *AQUATIC FATE: According to a classification scheme(1), BCF values ranging from 3.6 to 19(2), measured in carp, suggest that bioconcentration in aquatic organisms is low(SRC). Data suggest that 1,2-dibromo-3-chloropropane may biodegrade under some environmental conditions(SRC). In soil samples, the most rapid rate of dehalogenation (20% in 1 week) was obtained with pH 8 soil suspensions; the maximum observed dehalogenation was 63% after 4 weeks under unspecified conditions(3). Four subsoil materials and groundwater samples, and a sewage sample were aerobically incubated in the presence of 0.05 to 500 mg 1,2-dibromo-3-chloropropane/l water. No transformation was noted, by formation of inorganic halide or organic products or by the production of CO2, over 60 days(4). Groundwater and aquifer samples incubated under anaerobic conditions were unable to convert 1,2-dibromo-3-chloropropane over a 4 month period(4) . However, continuous-flow fixed-film columns, used to mimic anoxic groundwater conditions, were run under methanogenic (acclimation period of 9-12 weeks), sulfate-respiring (acclimation period < 2 weeks), or denitrifying conditions giving > 99%, 82-98%, and 14-23% removal, respectively, of 1,2-dibromo-3-chloropropane(5). [R105] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-dibromo-3-chloropropane, which has a measured vapor pressure of 0.58 mm Hg at 20 deg C(2,SRC), will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dibromo-3-chloropropane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC) giving products of 1,2-dibromopropanol, chlorobromopropanol, and 1-bromo-3-chloro-2-propanone(4); the half-life for this reaction in air is estimated to be about 37 days(3,SRC). An upper limit to the ozone reaction rate constant of < 3X10-20 cu cm/molecule-sec was reported for 1,2-dibromo-3-chloropropane(5). [R106] BIOD: *A mixed culture of soil microorganisms containing primarily Pseudomonas and Flavobacteria dehalogenated 1,2-dibromo-3-chloropropane to n-propanol(1). The most rapid rate of dehalogenation (20% in 1 week) was obtained with pH 8 soil suspensions; the maximum observed dehalogenation was 63% after 4 weeks under unspecified conditions(2). Biodegradation of 1,2-dibromo-3-chloropropane was measured in soil columns; half-lives of 6.6, 13.0, and 1130 days were obtained for natural, nutrient-enriched, and sterile conditions, respectively(3). Two soil samples, four subsoil materials and groundwater samples, and a sewage sample were incubated in the presence of 0.05 to 500 mg 1,2-dibromo-3-chloropropane/kg soil, soil suspension, or water. No transformation was noted, by formation of inorganic halide or organic products or by the production of CO2, over 60 days(4). Soil samples, maintained under anaerobic conditions, transformed 1,2-dibromo-3-chloropropane, at 10 and 100 mg/kg suspension, with 5.6 and 11.6% conversion, respectively, in 28 days(4). Groundwater and aquifer samples incubated under similar, anaerobic conditions were unable to convert 1,2-dibromo-3-chloropropane over a 4 month period(4). Alkyl reductive dehalogenation was reported as a transformation mechanism for the biodegradation of 1,2-dibromo-3-chloropropane in anaerobic soil(5). [R107] *Continuous-flow fixed-film columns, seeded with sewage and run under denitrifying, sulfate respiring, or methanogenic conditions, were used to simulate the biodegradation of 1,2-dibromo-3-chloropropane in anoxic groundwater(1). Under methanogenic conditions and following an acclimation period of 9-12 weeks, > 99% removal of 1,2-dibromo-3-chloropropane at an initial concentration of 17 ug/l was measured(1). 98% of the added 1,2-dibromo-3-chloropropane (at 12 ug/l initially) was removed following a < 2 week acclimation period and using a 2.5 day detention time in sulfate-respiring biofilm columns; with a 1.5 hour detention time and an acclimation period of 6 months, 82% removal was reported for this compound(1). 14% of the added 1,2-dibromo-3-chloropropane (at 37 ug/l initially) was removed (no acclimation period), using a 2.5 day detention time in denitrifying biofilm columns; with a 1.0 hour detention time and no acclimation period, 23% removal was reported for this compound (removal under denitrifying conditions was not conclusively attributed to biological transformation)(1). [R108] *Following 182 days incubation, 0.2 and 0.8% mineralization was reported for 1,2-dibromo-3-chloropropane in uncontaminated soil and soil contaminated with isodrin, dieldrin, and p-chlorophenylmethylsulfoxide, respectively(1). Biodegradation rates were faster in top soils collected from Hawaii than in soils obtained from greater depths; rates of 0.00016, 0.00014, and 0.00006/hour were measured at soil depths of 45 cm, 90 cm, and lower depths, respectively(2). 1,2-Dibromo-3-chloropropane at 1 mg/l was not degraded in soil columns filled with a sandy soil (0.087% organic carbon) and subjected to 14 cm water/day(3). 68% of the added 1,2-dibromo-3-chloropropane was not accounted for by either volatilization or adsorption following addition of municipal wastewater to soil columns filled with a Lincoln fine sand (used to simulate rapid infiltration treatment of municipal wastewater); this loss may have been due to biodegradation(4). [R109] ABIO: *Kinetic data on the hydrolysis of 1,2-dibromo-3-chloropropane in water was collected in the range of 40-97 deg C(1). An Arrhenius plot of these data yielded estimated half-lives of 38 and 141 years at 25 and 15 deg C, respectively, at pH 7(1). Under alkaline conditions, 1,2-dibromo-3-chloropropane is hydrolyzed to 2-bromoallyl alcohol(2). A half-life of 6.1 years, due mainly to hydrolysis, was calculated in a study examining the fate of 1,2-dibromo-3-chloropropane in both groundwater and groundwater/aquifer solids(4). Laboratory studies in phosphate buffer solutions indicate that 1,2-dibromo-3-chloropropane dehydrohalogenation to 2-bromo-3-chloro-1-propene (95%) and 2,3-dibromo-1-propene (5%) occurs followed by hydrolysis to the corresponding allyl alcohols; dehydrohalogenation is relatively slow when compared to the hydrolysis of this compound(4). Irradiation of an aqueous solution of 1,2-dibromo-3-chloropropane in pyrex tubes, using a mercury vapor UV lamp, resulted in negligible photodegradation(5). The addition of hydrogen peroxide to the solution increased the rate of photodegradation noticeably, suggesting that this compound may be degraded in natural waters containing a high concentration of hydroxyl radicals(5). [R110] *The dominant removal process of 1,2-dibromo-3-chloropropane in the atmosphere is hydroxyl abstraction; 1,2-dibromopropanol, chlorobromopropanol, and 1-bromo-3-chloro-2-propanone are formed as products during this process(1). The rate constant for the vapor-phase reaction of 1,2-dibromo-3-chloropropane with photochemically-produced hydroxyl radicals has been measured as 4.4X10-13 cu cm/molecule-sec at 25 deg C(2). This corresponds to an atmospheric half-life of about 37 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2,SRC). An upper limit of < 3X10-20 cu cm/molecule-sec to the ozone reaction rate constant was reported for 1,2-dibromo-3-chloropropane(3). [R111] BIOC: *A bioconcentration factor for 1,2-dibromo-3-chloropropane of 11 was estimated from a measured water solubility of 1,230 ppm(1). [R112] *BCF values of 3.6-17 and 4.0-19 were measured at concentrations of 0.3 and 0.03 mg/l 1,2-dibromo-3-chloropropane, respectively, in carp(1). According to a classification scheme(2), these BCF values indicate that bioconcentration of this compound in aquatic organisms is low(SRC). [R113] KOC: *The Kd for the adsorption of 1,2-dibromo-3-chloropropane onto Panoche clay loam is 0.20 cu cm/g for a 1,2-dibromo-3-chloropropane concentration range of 0.5-95 ug/ml(1). A Kd value of 0.286 L/kg was measured in Hanford sandy loam soil columns(2). Values of 40 (Koc value)(3) and 128 (Kom value)(4) were measured for 1,2-dibromo-3-chloropropane in unspecified soils. Koc values of 129 and 149 were measured in a silt loam and in a fine sand soil, respectively(5). Koc values of 305 and 355 were measured for aquifer solids from the Fresno aquifer (pH 7.3-7.7, mass fraction of organic carbon=0.0002); a calculated Rf value from these results indicates that only about 10% of the 1,2-dibromo-3-chloropropane is sorbed to the aquifer material(6). Koc values for 3 soils ranged from 70 to 126 (pH 7.6-8.1, mass fraction of organic carbon=0.0052-0.0544)(6). According to a recommended classification scheme(7), these measured Koc values suggest that 1,2-dibromo-3-chloropropane has moderate to very high mobility in soil(SRC). [R114] *Modeling predicts that 1,2-dibromo-3-chloropropane will adsorb so weakly that it will co-migrate with water through low organic content soil(1). Clay and silt soils adsorb 1,2-dibromo-3-chloropropane more strongly than sand soils, but downward vertical migration of this compound was observed regardless of soil type(2). The retardation factor (defined as the ratio of the interstitial water velocity to the velocity of the chemical) of 1,2-dibromo-3-chloropropane in Lincoln fine sand columns (organic carbon= 0.87%) was measured as 2.1(3) and < 1.5(4). Soil adsorption retarded the transport of 1,2-dibromo-3-chloropropane 3 to 5 times when compared with the wetting front movement(5). Sorption of 1,2-dibromo-3-chloropropane to aquifer sediments (organic carbon= 0.19%) was very low(6). More than 95% of the initially sorbed 1,2-dibromo-3-chloropropane was desorbed in 4 days; a small fraction, < 1% of this compound, resists desorption for at least 35 days(6). Adsorption of 1,2-dibromo-3-chloropropane to montmorillonite (organic carbon content= 0.18 wt%) was greatest at pH 4(7). [R115] VWS: *The Henry's Law constant for 1,2-dibromo-3-chloropropane is estimated as 1.5X10-4 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.58 mm Hg(1), and water solubility, 1230 mg/l(1). This value indicates that 1,2-dibromo-3-chloropropane will volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 14 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 9 days(2,SRC). 1,2-Dibromo-3-chloropropane's values for vapor pressure(1) and Henry's Law constant(1,SRC) indicate that volatilization from dry and moist soil surfaces may occur(SRC). [R116] *The volatilization half-life of 1,2-dibromo-3-chloropropane was estimated to be 1.2 days in a model soil assumed to contain 1,2-dibromo-3-chloropropane evenly distributed within the first 10 cm(1). Volatilization rates of 1,2-dibromo-3-chloropropane were higher from sand (0.8% organic matter, pH= 7.2) and silt loam(0.5% organic matter, pH= 8.4) than from clay loam(1.6% organic matter, pH= 7.8), possibly due to decreased adsorption processes(2). Volatilization losses to the atmosphere accounted for at least 85% of the 1,2-dibromo-3-chloropropane lost over 42 days during experiments meant to mimic citrus irrigation practices(water applications were performed cyclically)(3). Losses of 1,2-dibromo-3-chloropropane due to volatilization were significantly reduced by the application of water immediately following the introduction of this compound to soil(3). In other experiments, air levels of 1,2-dibromo-3-chloropropane 4 feet above shank-injection-treated soil rarely exceeded 1 ppb beyond 1 day post treatment(4). During water-run treatments, air concentrations 4 feet above the surface did not exceed 300 ppb for more than a few hours during application(4). [R117] WATC: *During 1979-80, 236 water samples were collected from 205 sites in SC. Well water, surface water (lakes, ponds, and rivers), and municipal water were sampled. DBCP levels ranged from non-detectable to 0.05 ug/l in an area of non-use (background). In the area of high use, 37% of the surface water samples exceeded the background level, but none exceeded 0.4 ug/l. Twenty-seven percent of the well water samples from the high-use area exceeded the background level. [R118] *SURFACE WATER: South Carolina - not detected (0.008 ppb) to 3.5 ppb in areas where 1,2-dibromo-3-chloropropane was extensively used, and not detected to 0.05 ppb in non-use areas(1). Detected, but not quantified in Magnolia, AK(2). [R119] *DRINKING WATER: Two drinking water wells in California contained 68 and 95 ppb 1,2-dibromo-3-chloropropane; one well in Arizona contained 137 ppb 1,2-dibromo-3-chloropropane(1). Finished water samples from 280 random sites in the US serving less than 10,000 persons were 0.4% positive (one sample) with a maximum concentration of 5.5 ug/l (detection limit= 5.0 ug/l)(2). South Carolina municipal water- ND(0.008 ppb)-0.05 ppb in areas of non- and high use(3). South Carolina well water- ND(0.008 ppb)- > 1.0 ppb (high use areas); ND-0.05 ppb (non-use areas)(3). [R120] *GROUNDWATER: Groundwater samples from AZ, CA, HI, MD and SC contained 0.02-137 ug/l 1,2-dibromo-3-chloropropane(1). Several CA sites (orchards or vineyards): not detected-22 ug/l (5 ng/l detection limit)(2). South Carolina well water: not detected(0.008 ppb)- > 1.0 ppb (high use areas); not detected-0.05 ppb (non-use areas)(3). Two drinking water wells in California contained 68 and 95 ppb 1,2-dibromo-3-chloropropane and one well in Arizona contained 137 ppb 1,2-dibromo-3-chloropropane(4). Groundwater wells in Mililani, Kunia and Waipahu, Hawaii were contaminated with 1,2-dibromo-3-chloropropane in 1981 at concentrations of 26-97 ng/l(5,6). 1,2-Dibromo-3-chloropropane was monitored in 20,545 wells in AZ, CA, FL, HI, IN, MD, SC, VA, and WA from 1978 to 1991; 1,829 wells were positive for this compound with concentrations ranging from 0.001 to 8000 ug/l(7). [R121] *GROUNDWATER: 94 of 262 domestic, municipal, and irrigation wells monitored in California during 1979 contained 1,2-dibromo-3-chloropropane at concentrations ranging from 0.1 to 39 ppb(1). In the California Department of Pesticide Regulation database (data collected from 1975-1991), 1,2-dibromo-3-chloropropane was present in 2480 California wells at a maximum concentration of 60 ug/l(2). In public drinking water wells alone, 1,2-dibromo-3-chloropropane was detected in 275 wells at a maximum concentration of 7.4 ug/l(2). Although 1,2-dibromo-3-chloropropane was banned in California in 1979, increasing concentrations were being detected in well water as of 1984(3). By 1984, 1,473 wells in California contained 1,2-dibromo-3-chloropropane at concentrations above 1 ppb(3). About half of the well water samples collected in the San Joaquin Valley contained 1,2-dibromo-3-chloropropane at an average concentration of 5 ug/l; wells less than 30 m deep were more likely to be contaminated(4). Groundwater from beneath the Rocky Mountain Arsenal contained 1,2-dibromo-3-chloropropane at unreported concentrations, most likely from a pesticide manufacturer located on site(5). In a random survey of wells serving fewer than 10,000 persons or more than 10,000 persons, 1 well (at a concentration of 5.5 ug/l, quantitation limit= 5.0 ug/l) and 0 wells, respectively, contained 1,2-dibromo-3-chloropropane(6). [R122] EFFL: *Spent chlorination liquor from the bleaching of sulphite pulp contained 1,2-dibromo-3-chloropropane at concentrations of 0.2 to 0.9 g/ton pulp(1). 1,2-Dibromo-3-chloropropane was measured in the emissions of a small-scale combustor burning pulverized coal at a maximum concentration of 4.274X10-7 lb/10+6 Btu(2). [R123] SEDS: *IN FIELD EXPT, 1,2-DIBROMO-3-CHLOROPROPANE WAS DETECTED IN SOIL AT LEVELS IN MEAN RANGE OF 0.008-1.64 MG/KG FROM DAY 1 TO 16 WK AFTER APPLICATION AT RATE OF 13.75 KG/HA. [R100, (1979)] *Detected but not quantified in Arkansas sediments and soil(2). Soil samples taken from 0-18 m in or near orchards and vineyards in which 1,2-dibromo-3-chloropropane had been used were ND-9 ppb in 1,2-dibromo-3-chloropropane with the higher 1,2-dibromo-3-chloropropane levels being found in the upper and middle regions(1). 32 fields in California, treated with 1,2-dibromo-3-chloropropane 2 to 4 years previously, contained this compound in the topsoil at about 2 to 5 ug/kg(3). 1,2-Dibromo-3-chloropropane was measured in topsoil, subsoil, and groundwater; topsoils contained ug/kg amounts of this compound, subsoils contained 1,2-dibromo-3-chloropropane at ug/kg amounts, especially in clay and silt layers, at depths as great as 15 meters(3). Groundwater from the same sites contained 1,2-dibromo-3-chloropropane at 1.2 to 12 ug/l(3). By 1986, 1,2-dibromo-3-chloropropane was detected in California soils at depths > 120 m(3). [R124] *Soil samples collected from a peach orchard near a well containing 1 mg/kg 1,2-dibromo-3-chloropropane (1,2-dibromo-3-chloropropane) (contaminated) and from a peach orchard with a well containing 0.1 mg/kg 1,2-dibromo-3-chloropropane (uncontaminated) contained less than 0.1 and 0.5 mg/kg 1,2-dibromo-3-chloropropane, respectively; both orchards had been fumigated with 1,2-dibromo-3-chloropropane via shank injection methods(1). Soil samples taken at the site of a possible spill contained high concn of 1,2-dibromo-3-chloropropane in the upper 1 m and at 6.1 m where the water table was encountered(1). Soil collected from an orchard in California contained 1,2-dibromo-3-chloropropane in the first meter, then had no detectable concentrations of this compound until 9 m depth where clays and silts were encountered; peak concentrations were reached in the clay and silt soil then decreased with increasing depth until the water table was reached at 16 m. Groundwater at the surface of the water table had 12 ug/l 1,2-dibromo-3-chloropropane(2). In a vineyard soil, 1,2-dibromo-3-chloropropane was detected in the topsoil and again in silt and sand lenses at 2 and 4.5 m before detection in a perched water table at 0.54 ug/l(2). [R125] ATMC: *In a trial in California of shank injection in a vineyard, a concn of 11 ppb was determined at the level of the driver's seat on the tractor moving the injecting rig and of 3 ppb at the middle of the vineyard at 5 ft above the ground. Higher airborne concn were measured in citrus groves and a vineyard treated by irrigation. In another trial, in which 1,2-dibromo-3-chloropropane was applied by shank injection into a fallow field ... the workers at the loading site met airborne concn of 7-131 ppb. [R18, 622] *Magnolia, AK: 1,688 to 6,653 ng/cu m, 7/77 to 8/77; El Dorado, AK: not detected to 1.87 ng/cu m(1). 1,2-Dibromo-3-chloropropane was detected in 3 samples of source-dominated air at an average daily concentration of 0.001 ppbv(2). An unspecified urban location in the US had air concentrations of 0.01 ug 1,2-dibromo-3-chloropropane/cu m (1 positive, 2 negative detections total)(3). [R126] FOOD: */1,2-Dibromo-3-chloropropane (DBCP)/ was detected in carrot peel and pulp in concn of 0.339 and 0.607 mg/kg, respectively. After unpeeled carrots were boiled for 5 min, they still contained 0.251 mg/kg DBCP. [R65] *1,2-Dibromo-3-chloropropane residues were measured in peaches harvested from trees growing in fall-fumigated or nonfumigated soil(1). No 1,2-dibromo-3-chloropropane residues were detected in peaches from trees growing on nonfumigated soil or in soil fumigated at or below the previously recommended rate of 46.8 l/ha. An average application rate of 58 and 115 L/treated ha resulted in residues of 0.19 ppb and 0.43 ppb of 1,2-dibromo-3-chloropropane, respectively(1). Foods sampled from the FDA market basket collection contained a mean concentration of 81 and 85 ng/g 1,2-dibromo-3-chloropropane for fatty and non-fatty foods, respectively (out of 5 determinations)(2). [R127] PFAC: PLANT CONCENTRATIONS: *1,2-Dibromo-3-chloropropane (DBCP) residues were measured in peaches from trees growing in fall-fumigated or nonfumigated soil. No DBCP residue was detected in peaches from trees growing on nonfumigated soil or in soil fumigated at or below the previously recommended rate of 46.8 l/ha. An avg application rate of 58 l/ha resulted in residues of 0.19 ppb of DBCP, whereas 115 l/ha gave residues of 0.43 ppb DBCP. [R128] *... /1,2-DIBROMO-3-CHLOROPROPANE/ WAS DETECTED IN CARROTS IN THE RANGE OF 0.009-1.5 MG/KG AND IN RADISHES IN THE RANGE OF 0.03-0.194 MG/KG AFTER APPLICATION OF 13.75 KG/HA TO SOIL. IN THE SAME STUDY, THE CMPD WAS DETECTED IN CARROT PEEL AND PULP IN CONCN OF 0.339 and 0.607 MG/KG, RESPECTIVELY. AFTER UNPEELED CARROTS WERE BOILED FOR 5 MIN, THEY STILL CONTAINED 0.251 MG/KG DBCP. [R65] OEVC: *IT IS PRESENT AT LEVELS OF 0.002 OR 0.05% IN FLAME RETARDANT TRIS(2,3-DIBROMOPROPYL) PHOSPHATE (1977). [R100, (1979)] *Commercially available sodium humate contained 1,2-dibromo-3-chloropropane in the range of 15 to 25 ppb(1). [R129] RTEX: *OCCUPATIONAL EXPOSURE TO 1,2-DIBROMO-3-CHLOROPROPANE IN PRODUCTION OR FORMULATION PLANTS AT LEVELS WHICH CAUSED PHYSIOLOGICAL CHANGES HAS BEEN REPORTED FOR: 1) 41 EMPLOYEES IN CA; 2) 86 ... IN AR; and 3) TOTAL OF 50 EMPLOYEES IN CO AND AL. 1 USA MANUFACTURER ... EST THAT EMPLOYEES EXPOSURE RANGED FROM LESS THAN 1-6 MG/CU M (100-600 PPB) OVER 3 YR. THE USA OSHA HAS EST THAT 2000-3000 EMPLOYEES HAVE RECENTLY BEEN OR MAY CURRENTLY BE EXPOSED DURING THE MANUFACTURE AND FORMULATION OF 1,2-DIBROMO-3-CHLOROPROPANE. ... AN AVG OF 4 MG/CU M (0.4 PPM) ... OVER AN 8-HR DAY /WAS DETECTED IN AN UNSPECIFIED/ MANUFACTURING PLANT. IN ANOTHER FACTORY, LEVELS OF 1-6 MG/CU M (0.1-0.6 PPM) HAVE BEEN ESTIMATED ... [R65] *1,2-Dibromo-3-chloropropane (DBCP) is used as a nematocide in Hawaii. Occupational exposures of Hawaiian agricultural workers to airborne DBCP are mainly in the range of parts per billion. [R130] *1,2-Dibromo-3-chloropropane has not been used as a pesticide in the US since 1979(3). Occupational exposure to 1,2-dibromo-3-chloropropane would have been mainly due to vapors regardless of the route of entry to air(2). 1,2-Dibromo-3-chloropropane is (was) used as a nematocide in Hawaii. Occupational exposures of Hawaiian agricultural workers to airborne 1,2-dibromo-3-chloropropane were mainly in the range of parts per billion(1). The general population will be exposed to 1,2-dibromo-3-chloropropane via inhalation of contaminated air, ingestion of food and drinking water (particularly well water), and dermal contact with vapors, food, and water containing 1,2-dibromo-3-chloro-propane(SRC). [R131] AVDI: *FOOD: 2.21-61.0X10-6 mg/kg/day (USEPA estimate)(1). WATER INTAKE: (assume 5.5 ug/l, 11 ug per person. Insufficient air and food monitoring data were available to estimate an average daily intake(1). An upper-bound estimate of the lifetime inhalation pathway dose of 1,2-dibromo-3-chloropropane attributable to a unit concentration in water supplies (mg/kg d)/(mg/l) was 0.11(2); this represents the amount of compound inhaled due to exchange between household water and air. [R132] BODY: *PERSONAL AIR: Breath samples collected from subjects in Greensboro, NC and Devils Lake, ND did not contain measurable concentrations of 1,2-dibromo-3-chloropropane (detection limit= 1 ug/cu m)(1). [R133] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers 1,2-dibromo-3-chloropropane to be a potential occupational carcinogen. [R30, 92] OSHA: +Inhalation. The employer shall assure that no employee is exposed to an airborne concentration of DBCP in excess of 1 part DBCP per billion parts of air (ppb) as an 8-hour time-weighted average. [R134] +Dermal and eye exposure. The employer shall assure that no employee is exposed to eye or skin contact with DBCP. [R134] NREC: +NIOSH considers 1,2-dibromo-3-chloro-propane to be a potential occupational carcinogen. [R30, 92] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R30, 92] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,2-Dibromo-3-chloropropane is included on this list. [R135] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 0.2 ug/l [R136] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 0.2 ug/l [R136] +(HI) HAWAII 0.04 ug/l [R136] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.025 ug/l [R136] +(ME) MAINE 0.2 ug/l [R136] +(NC) NORTH CAROLINA 0.025 ug/l [R136] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.6 (section IV. D.3.b). [R137] RCRA: *U066; As stipulated in 40 CFR 261.33, when 1,2-dibromo-3-chloropropane, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R138] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A Varian 3700 gas chromatograph equipped with electron capture detector and CDS-111 integrator was used for quantitative analysis of drinking water samples. The mean % recovery of 1,2-dibromo-3-chloropropane in water samples was 95.9%. [R139] *Retention ratio data compiled by the FDA in its Pesticide Anal Manual using packed gas chromatography columns were examined for usage when capillary gas chromatography was applied for residue anal of materials incl 1,2-dibromo-3-chloropropane. [R140] *Sample: air; detection: polarography; detection limit: 7 mg/cu m. Sample: soil; detection: polarography; detection limit: 0.1 mg/kg. Sample: food; detection: gas chromatography/electron capture detection; limit of detection: 2 ug/kg. [R141] *AOAC Method 993.15. 1,2-Dibromoethane and 1,2-Dibromo-3-chloropropane in Water by Microextraction Gas Chromatographic Method. [R142] *APHA Method 6210-C. Volatile Organics in Water by Gas Chromatograph/Mass Spectrometric Purge and Trap Packed-Column Technique. [R142] *APHA Method 6210-D. Volatile Organics in Water by Gas Chromatograph/Mass Spectrometric Purge and Trap Capillary-Column Technique. [R142] *APHA Method 6230-C. Volatile Halocarbons in Water by Purge and Trap Packed-Column Gas Chromatography. OMDL= 0.050 ug/l. [R142] *APHA Method 6230-D. Volatile Halocarbons in Water by Purge and Trap Capillary Gas Chromatography. [R142] *APHA Method 6231-B. 1,2-Dibromoethane (EDB) and 1,2-Dibromo-3-Chloropropane (DBCP) in Water by Liquid-Liquid Extraction and Gas Chromatography. MDL= 0.010 ug/l. [R142] *CLP Method LC_VOA. Analysis of Water for Low Concentration Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry. CRQL= 1.0 ug/l. [R142] *EAD Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. ML= 10 ug/l. [R142] *EMSLC Method 502.2. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. MDL= 3.0 ug/l. [R142] *EMSLC Method 504. 1,2-Dibromoethane (EDB) and 1,2-Dibromo-3-chloropropane (DBCP) in Water by Microextraction and Gas Chromatography. Revision 2.0. MDL= 0.010 ug/l. [R142] *EMSLC Method 504.1. 1,2-Dibromoethane (EDB), 1,2-Dibromo-3-chloropropane (DBCP) and 1,2,3-Trichloropropane (123TCP) in Water by Microextraction and Gas Chromatography. MDL= 0.010 ug/l. [R142] *EMSLC Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. MDL= 2.0 ug/l. [R142] *EMSLC Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. Revision 4.0. MDL= 0.26 ug/l. [R142] *EMSLC Method 551. Determination of Chlorination Disinfection Byproducts and Chlorinated Solvents in Drinking Water by Liquid-Liquid Extraction and Gas Chromatography with Electron-Capture Detection. MDL= 0.0090 ug/l. [R142] *EMSLC Method 608.1. The Determination of Organochlorine Pesticides in Industrial and Municipal Wastewater by Gas Chromatography with Electron Capture Detection. EMDL= 0.040 ug/l. [R142] *OSW Method 8011. 1,2-Dibromoethane and 1,2-Dibromo-2-chloropropane by Microextraction and Gas Chromatography. MDL= 0.010 ug/l. [R143] *OSW Method 8081. Organochlorine Pesticides and PCBs. Analysis by capillary GC/ECD. [R143] *OSW Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R143] *OSW Method 5021. Volatile Organic Comounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. [R143] *EAD Method 1656. Organo-Halide Pesticides in Municipal and Industrial Wastewater by Gas Chromatography. [R142] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. MDL= 0.030 ug/l. [R143] *OSW Method 8021A. Analysis of Halogenated and Aromatic Volatiles by Gas Chromatography Using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. MDL= 3.0 ug/l. [R143] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. MDL= 0.26 ug/l. [R143] *SFSAS Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. Analysis by capillary GC/MS. LOQ= 0.050 mg/kg. [R142] CLAB: *Recoveries of 1,2-dibromo-3-chloropropane (DBCP) from whole rat blood were 92.6-102.4% and the mean % recovery was 96.7%. A Varian 3700 gas chromatograph equipped with electron capture detector and CDS-111 integrator was used for quantitative analysis. 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Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R117: (1) Bomberger DC et al; ACS Symp Ser 225: 197-214 (1983) (2) Saltzman S, Kliger L; J Environ Sci Health B14: 353-66 (1979) (3) Litton GM, Guymon GL; J Environ Qual 22: 311-25 (1993) (4) Peoples SA et al; Bull Environ Contam Toxicol 24: 611-18 (1980) R118: Carter GE Jr, Riley MB; Pestic Monit J 15 (3): 139-42 (1981) R119: (1) Carter GE, Riley MB; Pest Monit J 15: 138-42 (1981) (2) Pellizzari ED et al; Environmental Monitoring Near Industrial Sites: Brominated Chemicals Part 1 Office of Toxic Substances USEAPA Washington DC (1978) R120: (1) Burmaster DE; Environ 24: 6-13 (1982) (2) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) (3) Carter GE, Riley MB; Pest Monit J 15: 138-42 (1981) R121: (1) Rao PSC et al; Soil Crop Sci Soc Fl Proc 44: 1-8 (1985) (2) Nelson SJ et al; Studies Environ Sci 17: 169-74 (1981) (3) Carter GE, Riley MB; Pest Monit J 15: 138-42 (1981) (4) Burmaster DE; Environ 24: 6-13 (1982) (5) Lau LS, Mink JF; J Am Wat Works Assoc 79: 37-42 (1987) (6) Oki DS, Giambelluca TW; Ground Water 25: 693-702 (1987) (7) USEPA; Pesticides in Groundwater Database. A Compilation of Monitoring Studies: 1971-1991. National Summary. USEPA Off Pest Programs. Prevention Pesticides and Toxic Substances (H7507C) USEPA-734-12-92-001 (1992) (8) Peoples SA et al; Bull Environ Contam Toxicol 24: 611-18 (1980) (9) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) R122: (1) Peoples SA et al; Bull Environ Contam Toxicol 24: 611-18 (1980) (2) Lam RHF et al; pp. 15-44 in Water Contamination and Health, Wang, RGM (ed), NY,NY: Marcel Dekker, Inc (1994) (3) Berteau PE, Spath DP; pp. 423-35 in ACS Symp Ser 315(Evaluation Pestic Groundwater) (1986) (4) Aharonson N et al; Pure Appl Chem 59: 1419-46 (1987) (5) Burrows WD; pp.80-2 in JT Conf Sens Environ Pollut Conf Proc 4th, 1977. ACS, Washington, DC (1978) (6) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) R123: (1) Carlberg GE et al; Sci Total Environ 48: 157-67 (1986) (2) Miller CA et al; Environ Sci Technol 28: 1150-58 (1994) R124: (1) Nelson SJ et al; Studies Environ Sci 17: 169-74 (1981) (2) Pellizzari ED et al; Environmental Monitoring Near Industrial Sites: Brominated Chemicals Part 1 Office of Toxic Substances USEPA Washington DC (1978) (3) Aharonson N et al; Pure Appl Chem 59: 1419-46 (1987) R125: (1) Carter GE Jr et al; Water, Air, Soil Pollut 22: 201-8 (1984) (2) Nelson SJ et al; in Studies in Environ Sci, W Van Dujvenbooden et al (eds). 17(Quality of Groundwater): 169-74 (1981) R126: (1) Pellizzari ED et al; Environmental Monitoring Near Industrial Sites: Brominated Chemicals Part 1 Office of Toxic Substances USEPA Washington DC (1981) (2) Shah JJ, Heyerdahl EK; National Ambient Volatile Organic Compounds (VOCs) Database Update USEPA/600/3-88/010 (1988) (3) Kelly TJ et al; Ambient Concentration Summaries for Clean Air Act. Title III. Hazardous Air Pollutants. USEPA Contract No. 68-D80082, USEPA/600/R-94/090, Final Report Research Triangle Park. July. (1993) R127: (1) Carter GE Jr, Riley MB; J Agric Food Chem 32 (3): 186-7 (1984) (2) Daft JL; J Agric Food Chem 37: 560-64 (1989) R128: Carter GE Jr, Riley MB; J Agric Food Chem 32 (3): 186-7 (1984) R129: (1) Gabbita KV; Toxicol Environ Chem 11: 203-13 (1986) R130: Landrigan PJ et al; Scand J Work Environ Health 9 (2 Spec No): 83-8 (1983) R131: (1) Landrigan PJ et al; Scand J Work Environ Health 9 (2 Spec No): 83-8 (1983) (2) Seiber JN, Woodrow JE; pp. 133-46 in Studies in Environmental Science 24(Determination and Assessment of Pesticide Exposure) Siewierski,M (ed). NY,NY: Elsevier (1984) (3) Metcalf RL; Kirk-Othmer Encycl Chem Technol. NY,NY: John Wiley and Sons 14: 580 (1995) R132: (1) IARC; Some Halogenated Hydrocarbons 20: 83-96 (1979) (2) McKone TE; Environ Sci Technol 21: 1194-1201 (1987) R133: (1) Wallace L et al; pp. 289-315 in Pollutants in a Multimedia Environment. Cohen, Y (ed.) NY,NY: Plenum Press (1986) R134: 29 CFR 1910.1044(c) (7/1/98) R135: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R136: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R137: 40 CFR 302.4 (7/1/95) R138: 40 CFR 261.33 (7/1/95) R139: Kastl PE et al; J Chromatogr 213 (1): 156-61 (1981) R140: Fehringer NV, Walters SM; J Assoc Off Anal Chem 67 (1): 91-5 (1984) R141: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 88 (1979) R142: USEPA; EMMI. Environmental Monitoring Methods Index. Version 2.0. NTIS PB-95-502415 (1995) R143: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) RS: 140 Record 141 of 1119 in HSDB (through 2003/06) AN: 1640 UD: 200302 RD: Reviewed by SRP on 5/11/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 3,3'-DIMETHYLBENZIDINE- SY: *BENZIDINE,-3,3'-DIMETHYL-; *BIANISIDINE-; *(1,1'-BIPHENYL)-4,4'-DIAMINE, 3,3'-DIMETHYL-; *4,4'-BI-O-TOLUIDINE-; *CI-AZOIC-DIAZO-COMPONENT-113-; *CI-37230-; *4,4'-DIAMINO-3,3'-DIMETHYLBIPHENYL-; *4,4'-DIAMINO-3,3'-DIMETHYLDIPHENYL-; *DIAMINODITOLYL-; *Diaminotolyl-; *3,3'-DIMETHYLBENZIDIN-; *3,3'-DIMETHYL-(1,1'-BIPHENYL)-4,4'-DIAMINE; *3,3'-DIMETHYLBIPHENYL-4,4'-DIAMINE-; *3,3'-DIMETHYL-4,4'-DIAMINOBIPHENYL-; *3,3'-DIMETHYLDIPHENYL-4,4'-DIAMINE-; *4,4'-DI-O-TOLUIDINE-; *DMB-; *FAST-DARK-BLUE-BASE-R-; *Orthotolidine-; *O-TOLIDIN-; *2-TOLIDINA- (ITALIAN); *O-TOLIDINE-; *O,O'-TOLIDINE-; *2-TOLIDINE-; *3,3'-TOLIDINE-; *2-TOLIDIN- (GERMAN) RN: 119-93-7 MF: *C14-H16-N2 HAZN: U095; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. ASCH: 3,3'-Dimethylbenzidine dihydrochloride; 612-82-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF ORTHO-NITROTOLUENE TO 1,2-DIORTHOTOLYLHYDRAZINE AND SUBSEQUENT REARRANGEMENT WITH ACID [R1] *Derivation of o-nitrotoluene with zinc dust and caustic soda and conversion of the hydrazotoluene by boiling with hydrochloric acid. [R2] FORM: *Grades: technical, dry or paste [R2] *Available as the dihydrochloride [R2] MFS: *GFS Chemicals, Inc. (also known as G Frederick Smith Chemical Co.), P.O. Box 245, Powell, OH 43065, (740) 881-5501; Production ste: Columbus, OH 43222 [R3] USE: *... very sensitive reagent for detection of gold (1:10 million detectable); and free chlorine in water [R4] *Chem int for azo dyes ... [R4] *... Curing agent for urethane resins. [R2] *o-Tolidine and its salts are widely used in the dye industry and in some analytical chemistry procedures. [R5, 1991.1564] *Many of the hundreds of synthetic organic dyes used in the United States contain benzidine or benzidine congeners such as o-tolidine or o-dianisidine and are used to color textiles, leather, and paper. [R6] CPAT: *Over 75% of DMB is used as a dye and as an intermed in the production of dyestuffs and pigments ... approximately 20% of DMB is used in the production of polyurethane-based high-strength elastomers, coatings, and rigid plastics. [R7, 868] PRIE: U.S. IMPORTS: *(1974) 2.73X10+8 g [R8] *(1983) 75,307 lb [R9] *(1979) 3.5 million lbs. [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +White to reddish crystals or powder [Note: Darkens on exposure to air]. [R11] BP: *300 DEG C [R12] MP: *129-131 deg C [R4] MW: *212.28 [R4] DSC: *pKa1= 4.5; pKa2= 3.3 [R13] HTC: *Liquid: 964.3 kg.cal [R14] OWPC: *log Kow= 2.34 [R15] SOL: *Sol in alc, ether, dil acids [R4]; *In water, 1,300 mg/l @ 25 deg C [R16] SPEC: *SADTLER REFERENCE NUMBER: 6379 (IR, PRISM) MAX ABSORPTION (DIL ALC): 284 NM (LOG E= 4.4) [R17]; *Intense mass spectral peaks: 212 m/z (100%), 106 m/z (83%), 213 m/z (16%), 211 m/z (16%) [R18]; *IR: 8468 (Sadtler Research Laboratories IR Grating Collection) [R19]; *UV: 1760 (Sadtler Research Laboratories Spectral Collection) [R19]; *NMR: 269 (Sadtler Research Laboratories Spectral Collection) [R19] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Strong oxidizers. [R20] DCMP: *When heated to decomposition it emits toxic fumes of /nitrogen oxides./ [R21] SERI: *Skin and eye irritant. [R7, 867] EQUP: *Wear clothing and goggles to prevent skin and eye contact. [R7, 868] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R22, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R20] *Wear appropriate eye protection to prevent eye contact. [R20] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R20] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R20] *Respirator Recommendations: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: (APF = 10,000) Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode/(APF = 10,000) Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained positive-pressure breathing apparatus. [R20] *Respirator Recommendations: Escape: (APF = 50) Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter/Any appropriate escape-type, self-contained breathing apparatus. [R20] OPRM: *SRP: The scientific literature supports the wearing of contact lenses in industrial environments, as part of a program to protect the eye against chemical compounds and minerals causing eye irritation. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases contact lenses should not be worn. [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R22, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R20] *The worker should wash daily at the end of each work shift. [R20] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R20] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R20] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. [R20] SSL: *AFFECTED BY LIGHT [R23] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R22, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R22, 1979.13] STRG: *KEEP WELL CLOSED AND PROTECTED FROM LIGHT [R24] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R22, 1979.13] CLUP: *A new method developed for the removal of carcinogenic aromatic amines from industrial aqueous effluents uses horseradish peroxidase and hydrogen peroxide resulting in a nearly complete precipitation of carcinogenic aromatic amines from water due to enzymatic crosslinking. [R25] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R22, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U095, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R26] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R27] *It is shown that the oxidation of benzidine, o-tolidine, and o-dianisidine with potassium permanganate in a sulfuric acid medium results in a deep destruction of these substances in which more than 99.8% of the original compounds is destroyed. [R28] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R22, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R22, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R22, 1979.17] *A suitable method for destruction of carcinogenic amines (benzidine, o-tolidine and o-dianisidine) in laboratory wastes was developed. The method is based on the oxidation of these substances with permanganate in sulfuric acid medium and affords better than 99.8% decontamination for all 3 substrates tested. [R29] *Nine aromatic amines, ie, benzidine; o-tolidine; o-dianisidine; 3,4'-dichlorobenzidine; 4-aminobiphenyl; 1- and 2-naphthylamine; 4,4'-methylene bis(2-chloroaniline) and m-toluenediamine, were oxidized with potassium permanganate/sulfuric acid. Experimental conditions for complete degradation of these aromatic amines are described. The corresponding degradation products were found to be non-mutagenic to Salmonella typhimurium strains TA100, TA98 and TA97, both in the presence and absence of a rat liver S9 activation system. A collaborative study, involving 11 laboratories, has shown the applicability and the reproducibility of this degradation method. [R30] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +This substance/agent has not undergone a complete evaluation under U.S. EPA's IRIS program for evidence of human carcinogenic potential. [R31] *No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans. [R32] *A3; Confirmed animal carcinogen with unknown relevance to humans. Skin notation. [R33] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aniline and related compounds/ [R34, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aniline and related compounds/ [R34, 207] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R22, 1979.23] HTOX: *... VAPOR TOXICITY WAS MUCH LIKE THAT OF ANILINE (SLIGHT SYMPTOMS AFTER SEVERAL HR @ 6 TO 23 PPM AND 7 TO 53 PPM RESPECTIVELY). [R35] NTOX: *20 FEMALE SPRAGUE-DAWLEY RATS WERE GIVEN, BY STOMACH TUBE, SUSPENSION OF O-TOLIDINE IN SESAME OIL UP TO TOTAL DOSE OF 500 MG/RAT, FRACTIONATED IN 10 DOSES @ 3-DAY INTERVALS. 16 RATS WERE ALIVE @ END OF THE OBSERVATION PERIOD, IE, 9 MO: 3 OF THESE SHOWED TOTAL OF 4 MAMMARY CARCINOMAS. IN COMPARISON, FOUR OUT OF FIVE ANIMALS THAT SURVIVED AFTER BEING GIVEN BENZIDINE (50 MG PER RAT) SHOWED A TOTAL OF 17 MAMMARY CARCINOMAS. AMONG 132 RATS THAT RECEIVED THE SOLVENT ONLY, 5 HAD A TOTAL OF 3 MAMMARY CARCINOMAS, 1 FIBROADENOMA AND 5 HYPERPLASIAS. [R36] *COMMERCIAL O-TOLIDINE @ DIETARY LEVEL OF 0.1% (3.0 G/ANIMAL/YR) FED TO GROUPS OF 30 MALE AND 30 FEMALE HAMSTERS THROUGHOUT THEIR LIFE-SPAN DID NOT INDUCE BLADDER OR OTHER TUMORS. NEGATIVE RESULTS WERE ALSO OBTAINED @ DIETARY LEVEL OF 0.3%, WHICH WAS HIGHEST TOLERATED LEVEL. ... COMMERCIAL O-TOLIDINE IN OLIVE OIL WAS GIVEN AS A WEEKLY SC INJECTION, AT A DOSE LEVEL OF 60 MG/RAT/WK (TOTAL DOSE: 5.5 G), TO 105 SHERMAN RATS. 48 SURVIVED MORE THAN 300 DAYS AND WERE KEPT THROUGHOUT THEIR LIFESPAN. IN CONTRAST TO RATS GIVEN BENZIDINE, NO CIRRHOSIS OR HEPATOMAS WERE OBSERVED AMONG THOSE RECEIVING O-TOLIDINE. 5 RATS DEVELOPED CANCER OF EXTERNAL AUDITORY CANAL, ALL TUMORS APPEARING AFTER 354TH DAY. NO CONTROL GROUP WAS RUN AT THE SAME TIME. OUT OF 56 TUMORS OCCURRING AMONG 578 UNTREATED RATS OF THE SAME COLONY, NONE WAS LOCATED IN THE EXTERNAL AUDITORY CANAL. [R37] *RANDOM BRED RATS RECEIVED WEEKLY SC INJECTIONS OF PURIFIED O-TOLIDINE IN SUNFLOWER OIL FOR 13 MO, @ DOSES OF 20 MG/RAT/WK. AMONG 50 ANIMALS THAT SURVIVED FOR 8 MO (TIME OF OCCURRENCE OF 1ST TUMOR), 30 DEVELOPED TOTAL OF 41 TUMORS. 20 CARCINOMAS OF ZYMBAL'S GLAND, AND TUMORS @ OTHER SITES WERE SEEN. 2 ADDITIONAL GROUPS OF RATS ... RECEIVED WEEKLY SC IMPLANT OF PELLET CONTAINING 20 MG OF PURIFIED O-TOLIDINE AND 10 MG OF GLYCEROL FOR 14 MO. IN 2ND OF THESE GROUPS O-TOLIDINE HAD BEEN SUBJECTED TO UV IRRADIATION PRIOR TO PREPARATION OF THE PELLET. THE DIFFERENCE BETWEEN THE 2 GROUPS WAS MINIMAL. OF THE TOTAL OF 68 ANIMALS THAT WERE ALIVE AT THE TIME OF APPEARANCE OF THE FIRST TUMOR (11-12 MO), 48 DEVELOPED A TOTAL OF 60 TUMORS. AMONG THESE WERE 27 ZYMBAL'S GLAND CARCINOMAS AND TUMORS AT OTHER SITES. NO CONTROL GROUP WAS RUN AT THE SAME TIME AS THESE EXPERIMENTS, BUT IN A PRELIMINARY REPORT ON THESE STUDIES IT WAS STATED THAT RATS FROM THE SAME COLONY DID NOT DEVELOP TUMORS OF ZYMBAL'S GLAND. [R37] *EMPLOYING SALMONELLA/MAMMALIAN MICROSOME TEST O-TOLIDINE WAS SHOWN TO BE MUTAGENIC. [R38] *The mutagenicity of o-tolidine and its metabolites in rat urine was examined using Salmonella typhimurium strains TA98 and TA100 with and without S-9 mix. o-Tolidine was mutagenic to TA98 with S9 mix, while the urinary metabolites exerted a direct mutagenic effect on TA98 and TA100. [R39] *The mutagenicity of o-tolidine was tested in Salmonella typhimurium TA1535. o-Tolidine with and without S-9 mix elicited a very weak and variable mutagenic effect. [R40] *The Ames Salmonella/microsome test was used to compare the mutagenic response of Salmonella typhimurium TA100, TA98, TA1538, and TA1535 to 12 benzidine derivatives, ie, benzidine, 3,3'-dimethoxybenzidine, 3,3'-dimethylbenzidine, 3,3'-dichlorobenzidine, and the corresponding N- and N,N'-diacetylated derivatives. With a few exceptions, the mutagenic response to this series of compounds varied in the order TA98 greater than TA1538 greater than TA100 greater than TA1535 = 0, and the N-monoacetylated derivatives were more mutagenic than either the parent diamines or the N,N'-diacetyl derivatives. The relative mutagenicities of the parent amines for TA98, were 3,3'-dichlorobenzidine much greater than 3,3'-dimethoxybenzidine greater than benzidine greater than 3,3'-dimethylbenzidine. [R41] *Assays using the Salmonella/microsome test revealed that the urine extracts of rats orally administered o-tolidine were more strongly mutagenic than o-tolidine itself. Similarly, Evans Blue dye did not exhibit mutagenicity, but the urine extracts of rats administered Evans Blue were mutagenic. Both 3,3'-dimethyl-N- acetylbenzidine and 3,3'-dimethyl-N,N'-diacetylbenzidine were identified as urinary metabolites of o-tolidine and Evans Blue. [R42] *Covalent binding of benzidine and some congeners to hemoglobin was studied in female Wistar rats after oral administration. Hemoglobin adducts were hydrolyzed under alkaline conditions, and the arylamines analysed by high performance liquid chromatography. With benzidine, three cleavage products were observed, the major component being monoacetylbenzidine. This indicates that 4-nitroso-4'-N- acetylaminobiphenyl is the major reactive metabolite in erythrocytes. In addition benzidine and 4-aminobiphenyl were identified. With 3,3'-dichlorobenzidine dihydrochloride, 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine two cleavage products were observed, the parent diamines being present in excess to or in amounts comparable to the monoacetyl derivative. With 3,3',5,5'-tetramethylbenzidine a hemoglobin adduct could not be found. When the azo dye direct red 28 was administered to the animals, the three cleavage products typical for benzidine were found, indicating that benzidine became bioavailable after reductive cleavage of the azo compound. In this case the fraction of 4-aminobiphenyl was greater than after benzidine. It is proposed to use the analysis of hemoglobin adducts in human blood to control the exposure of individuals to these carcinogenic chemicals in the course of biochemical effect monitoring. [R43] *Dimethoxybenzidine and dimethylbenzidine are used to synthesize dyes such as CI Direct Blue 15 and CI Acid Red 114, respectively. These commercially used dyes are metabolically degraded to dimethoxybenzidine or dimethylbenzidine in the intestinal tract of rodents and subsequently dimethoxybenzidine and dimethylbenzidine are absorbed into the blood stream. Animals were exposed to dimethoxybenzidine, dimethylbenzidine, or the dyes in the drinking water. Tumors obtained from control and chemical treated animals were examined for the presence of activated oncogenes by the NIH 3T3 deoxyribonucleic acid transfection assay. Activated oncogenes were detected in less than 3% (1/38) of the tumors from control animals whereas 68% (34/50) of the tumors from chemical treated animals contained detectable oncogenes. Activated oncogenes were detected in both malignant (25/36) and benign (9/14) tumors from chemically treated animals but only in one of 13 malignant tumors from the control animals. The transforming properties of the chemically induced rat tumor deoxyribonucleic acids were due to the transfer of an activated H-ras (31/34) or N-ras (3/34) gene. One spontaneous rat tumor deoxyribonucleic acid was found to contain an activated H-ras gene. The H-ras oncogenes from chemical associated tumors contained mutations at codons 12, 13, or 61 whereas the spontaneously activated H-ras gene contained a point mutation at codon 61. Activation of cellular ras genes by point mutation is an important step in the induction of tumors, at least in rats, by this class of benzidine derived dyes. Because of common histogenesis of the normal counterparts of many of the chemically induced neoplasms and histological evidence of varied tissue differentiation in some basal cell neoplasms, it is possible that most or all of the chemically induced neoplasms were derived from common epidermal progenitor stem cell population. [R44] *3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in tests with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in Drosophila melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. /3,3'-Dimethylbenzidine dihydrochloride/ [R45] *... Study of the dihydrochloride of 3,3'-dimethylbenzidine given in the drinking water to F344 rats at 30, 70, or 150 ppm /was done/. The study was terminated at 14 months because of the low number of surviving rats. Males had many types of skin tumors, neoplasms of the Zymbal gland, liver, and large intestine, and lower numbers of tumors of the preputial gland, oral cavity, small intestine, and lung. Females had a high incidence of tumors of the Zymbal and clitoral glands, in addition to lower incidences of neoplasms of the skin, liver, intestines, lung, and mammary glands. /Dihydrochloride/ [R46] *BALB/c mice (120/sex/dose) were given 0, 5, 9, 18, 35, 70 or 140 ppm of 3,3'-dimethylbenzidine dihydrochloride in their drinking-water and killed after 13, 26, 39, 52, 78 or 116 wk. Full histopathological evaluations were performed on all animals that were found dead or moribund, or that were killed on schedule. Fatal lung alveolar cell neoplasms began to appear in males receiving 140 ppm at 78 wk and there was a significant dose-related decrease in the time-to-death from this cause. There were no significant dose-related trends for this neoplasm in females, nor were there treatment-related effects on body weight, water consumption or other lesions in either sex. [R47] *The Ames Salmonella/microsome test was used to compare the mutagenic response of Salmonella typhimurium TA100, TA98, TA1538, and TA1535 to 12 benzidine derivatives, ie, benzidine, 3,3'-dimethoxybenzidine, 3,3'-dimethylbenzidine, 3,3'-dichlorobenzidine, and the corresponding N- and N,N'-diacetylated derivatives. With a few exceptions, the mutagenic response to this series of compounds varied in the order TA98 greater than TA1538 greater than TA100 greater than TA1535 = 0, and the N-monoacetylated derivatives were more mutagenic than either the parent diamines or the N,N'-diacetyl derivatives. The relative mutagenicities of the parent amines for TA98, were 3,3'-dichlorobenzidine much greater than 3,3'-dimethoxybenzidine greater than benzidine greater than 3,3'-dimethylbenzidine. [R41] *Covalent binding of benzidine and some congeners to hemoglobin was studied in female Wistar rats after oral administration. Hemoglobin adducts were hydrolyzed under alkaline conditions, and the arylamines analyzed by high performance liquid chromatography. With benzidine, three cleavage products were observed, the major component being monoacetylbenzidine. This indicates that 4-nitroso-4'-N- acetylaminobiphenyl is the major reactive metabolite in erythrocytes. In addition benzidine and 4-aminobiphenyl were identified. With 3,3'-dichlorobenzidine dihydrochloride, 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine two cleavage products were observed, the parent diamines being present in excess to or in amounts comparable to the monoacetyl derivative. With 3,3',5,5'-tetramethylbenzidine a hemoglobin adduct could not be found. When the azo dye direct red 28 was administered to the animals, the three cleavage products typical for benzidine were found, indicating that benzidine became bioavailable after reductive cleavage of the azo compound. In this case the fraction of 4-aminobiphenyl was greater than after benzidine. It is proposed to use the analysis of hemoglobin adducts in human blood to control the exposure of individuals to these carcinogenic chemicals in the course of biochemical effect monitoring. [R43] NTP: *Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for ... 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2 mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. ... Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male; control, 60/60; low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 27/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. ... There was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was /also/ clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. /3,3'-Dimethylbenzidine dihydrochloride/ [R48] ADE: *O-TOLIDINE MAY ENTER THE BODY BY PERCUTANEOUS ABSORPTION, BY INGESTION OR BY INHALATION. [R49] *o-Tolidine is rapidly absorbed through intact human skin. ... Absorption also occurs from the respiratory and GI tract, and excretion of the parent compound and its mutagenic metabolites occurs primarily via the urine. [R5, 1991.1565] METB: *Metabolism studies were conducted in the rat with Direct Red 2, based on 3,3'-dimethylbenzidine. The metabolism of Direct Red 2 compared with its base, dimethylbenzidine, indicated that the base was more extensively metabolized, yet only a small percentage of the (14)C in extracts was identified as known metabolites. [R50] *The conventional Ames assay metabolising system was confirmed to be deficient in its ability to N-acetylate. This may render the test less sensitive to compounds which normally have an acetylation step during their in vivo activation to carcinogens. The addition of acetyl-coenzyme A to the S9 mix in the Ames assay increased the mutagenicity of benzidine in Salmonella typhimurium strains TA98 AND TA1538 4-5-fold. This was consistent with the observation that benzidine is N-acetylated prior to deoxyribonucleic acid binding in vivo in rat liver. Two 3,3'-disubstituted benzidines, o-tolidine and o-dianisidine, were also tested. A smaller incr in o-tolidine mutagenicity, compared to that observed with benzidine, occurred with the addn of acetyl-coenzyme A. However, the production of acetylated metabolites from o-tolidine was only 37% of that from benzidine. The mutagenicity of o-dianisidine was unaffected by acetyl-coenzyme A. Acetylation of o-dianisidine was only 16% of that observed with benzidine, and the N-acetyl derivatives of o-dianisidine showed lower mutagenicity than the parent amine. [R51] *Several studies demonstrated that hamster hepatocytes are more effective than rat hepatocytes in mediating the metabolic activation of certain chemicals to their genotoxic (ie, mutagenic) derivatives. A comparison of the amount of deoxyribonucleic acid repair induced in rat and hamster hepatocytes by 7 azo dyes and 17 aromatic amine azo reduction products of the dyes was performed using the primary hepatocyte culture/deoxyribonucleic acid repair assay. Congo Red and its azo reduction product, benzidine, were more potent inducers of deoxyribonucleic acid repair in hamster than in rat hepatocytes, whereas Trypan Blue and its reduction product, o-tolidine, were equipotent in the 2 hepatocyte systems. Evans Blue, another o-tolidine-based dye, elicited a greater deoxyribonucleic acid repair response in hamster hepatocytes. The absolute potency of these dyes, however, was much less than their reduction products. These findings extend previous observations of the superior metabolic activation capabilities of hamster, relative to rat hepatocytes. [R52] *Direct Red 2 was given as an aqueous soln to rats and hamsters to determine whether the dye is cleaved to potentially carcinogenic aromatic amines. The urine from treated animals revealed appreciable levels of 3,3'-dimethylbenzidine, mono- and di-acetyldimethylbenzidine, and alkaline hydrolyzable conjugates. Peak concns of the metabolites in urine occurred 12-24 hr after admin to rats, and within 12 hr in hamsters. The levels of all metabolites and conjugates diminished rapidly in both species after peak concns were reached, with no residues detected after 96 hr. The results demonstrated in vivo cleavage of the dye in both species. [R53] *(14)C Benzidine is rapidly oxidized by a peroxidase/hydrogen peroxide system to products which bind irreversibly to deoxyribonucleic acid. The peroxidase/hydrogen peroxide system also catalyzed the binding of dichlorobenzidine, o-tolidine and o-dianisidine to deoxyribonucleic acid bind. The binding could be prevented by various biological hydrogen donors, thiols, or phenolic antioxidants. [R54] *Absorption, metabolism and tissue distribution studies were conducted in the rat with (14)C-biphenyl ring-labeled Direct Blue 15, a 3,3'-dimethoxybenzidine based azo dye; Direct Red 2, based on 3,3'-dimethylbenzidine and the corresponding benzidine congener amines. Single oral doses of the (14)C-labeled dyes (12 mg/kg, 62 muCi/kg) and molar equivalent doses of the respective amines were administered, and urine and fecal samples collected at intervals up to 192 hr. A comparison of the metab of Direct Blue 15 with its base 3,3'-dimethoxybenzidine, indicated that the base was more extensively metabolized and that most of the 14(C) in various extracts was identified in known metabolites. The metab of Direct Red 2 compared with its base, 3,3'-dimethylbenzidine, indicated that the base was more extensively metabolized, yet only a small % of the 14(C) in extracts was identified as known metabolites. Most of the 14(C) present in the urine could not be extracted with benzene nor chloroform, indicating high polarity. Distribution studies conducted with both dyes showed that liver, kidney, and lung accumulated and retained higher levels of 14(C) than other tissues (at 72 hr). Peak levels of 14(C), which occurred 8-12 hr after dosing, were significantly higher with Direct Red 2 than Direct Blue 15. Tissue distribution data (72 hr) for rats dosed with the free amines compared with the dyes showed a generally lower but similar distribution pattern. [R55] *The metabolism of a benzidine-based dye, Direct Black 38, a 3,3'-dimethylbenzidine-based dye, Direct Red 2 and a 3,3'-dimethoxybenzidine-based dye, Direct Blue 15 has been studied both in pure cultures of anaerobic bacteria and in bacterial suspensions derived from the intestinal contents of the rat. All of the pure cultures and the rat intestinal bacteria were able to reduce the azo linkages of Direct Black 38, Direct Red 2 AND Direct Blue 15 with the subsequent formation of benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, respectively. [R56] *The differential mutagen activation of 3,3'-dichlorobenzidine, benzidine, o-tolidine, and o-dianisidine was studied using Salmonella typhimurium (TA-98). Male Sprague-Dawley rats were pretreated with 3,3'-dichlorobenzidine, 3-methylcholanthrene, or phenobarital; S9 and microsomal suspensions were prepared. Three rat liver enzyme systems were used: S9, S9 plus acetylcoenzyme-A, and microsomes. Activation of the benzidines to mutagens was performed by preincubating S9 or microsomes containing test amines at optimal mutagenic concns. ... The addn of acetylcoenzyme-A did not significantly alter the activation of 3,3'-dichlorobenzidine, but increased activation of benzidine after pretreatment with phenobarbital or 3-methylcholanthrene. The microsomes from 3,3'-dichlorobenzidine pretreated rats were the most active in mutagenic activation. Microsome catalyzed activation of o-dianisidine and o-tolidine was inhibited by the pretreatment with all inducers. Benzidine activation was increased only by 3-methylcholanthrene pretreatment. 3,3'-Dichlorobenzidine stimulated its own microsome catalyzed activation ninefold on the basis of cytochrome p450. Dithiothreitol had no effect on the microsome catalyzed activation of 3,3'-dichlorobenzidine and glutathione depletion did not alter the S9 catalyzed activation of 3,3'-dichlorobenzidine. ... 3,3'-Dichlorobenzidine is the most mutagenic of the four benzidines under conditions of cytochrome p450 catalyzed activation. [R57] *Benzidine and its 3,3'-diamino, 3,3'-dimethyl, 3,3'-dimethoxy, 3,3'-difluoro, 3,3'-dichloro, 3,3'-dibromo, 3,3'-dicarbomethoxy and 3,3'-dinitro derivatives together with 2-nitrobenzidine and 3-nitrobenzidine were compared for their in vitro and in vivo genotoxicity. Relative mutagenicity was established with Salmonella strains TA98, TA98/1,8-DNP6 and TA100 with and without S9 activation. All the derivatives in the presence of S9 were more mutagenic than benzidine with 3,3'-dinitro- and 3-nitro-benzidine having the greatest mutagenicity. Mutagenicity in all 3 strains with S9 activation could be correlated to electron-withdrawing ability of substituent groups, as measured by the basicity of the amines. This correlation was explained on the basis that electron-withdrawing groups could favor the stability of the mutagenic intermediate N-hydroxylamine and also enhance the reactivity of the ultimate mutagenic species, the nitrenium ion. Mutagenicity was also correlated to the energy of the lowest unoccupied molecular orbitals (ELUMO). Hydrophobicity was found to have very limited effect on the relative mutagenicity of our benzidine derivatives. The in vivo endpoint was chromosomal aberrations in the bone-marrow cells of mice following intraperitoneal administration of benzidine and its derivatives. In contrast to the in vitro results, while all the amines were genotoxic in vivo, only the 3-nitro derivative had a significant increase in toxicity over benzidine. [R58] *Enteric bacterial and hepatic azoreductase enzymes are capable of reducing azo dyes to yield the constituent aromatic amines. Azo dyes based on benzidine and benzidine congeners have received particular attention because of their widespread use and the known carcinogenicity of benzidine to humans. Azo dyes based on beta-diketone coupling components exist preferentially as the tautomeric hydrazones. A series of hydrazone dyes based on benzidine and benzidine congeners was prepared and characterized by NMR and UV-visible spectroscopy. These dyes were tested for mutagenicity using a modified Ames assay and, unlike the true azo dyes, showed no significant mutagenic activity. The hydrazone dyes were resistant to enzymatic reduction by FMN-supplemented hamster-liver post-mitochondrial supernatant (S-9); under identical conditions, azo dyes such as trypan blue were rapidly reduced. [R59] *We have evaluated the mutagenic activity of a series of diazo compounds derived from benzidine and its congeners o-tolidine, o-dianisidine and 3,3'-dichlorobenzidine as well as several monoazo compounds. The test system used was a modification of the standard Ames Salmonella assay in which FMN, hamster liver S9 and a preincubation step are used to facilitate azo reduction and detection of the resulting mutagenic aromatic amines. All of the benzidine and o-tolidine dyes tested were clearly mutagenic. The o-dianisidine dyes except for Direct Blue 218 were also mutagenic. Direct Blue 218 is a copper complex of the mutagenic o-dianisidine dye Direct Blue 15. Pigment Yellow 12, which is derived from 3,3'-dichlorobenzidine, could not be detected as mutagenic, presumably because of its lack of solubility in the test reaction mixture. Of the monoazo dyes tested, methyl orange was clearly mutagenic, while C.I. Acid Red 26 and Acid Dye (C.I. 16155; often referred to as Ponceau 3R) had marginal to weak mutagenic activity. Several commercial dye samples had greater mutagenic activity with the modified test protocol than did equimolar quantities of their mutagenic aromatic amine reduction products. Investigation of this phenomenon for Direct Black 38 and trypan blue showed that it was due to the presence of mutagenic impurities in these samples. The modified method used appears to be suitable for testing the mutagenicity of azo dyes, and it may also be useful for monitoring the presence of mutagenic or potentially carcinogenic impurities in otherwise nonmutagenic azo dyes. [R60] *The metabolism of a benzidine-based dye, Direct Black 38, a 3,3'-dimethylbenzidine-based dye, Direct Red 2 and a 3,3'-dimethoxybenzidine-based dye, Direct Blue 15 has been studied both in pure cultures of anaerobic bacteria and in bacterial suspensions derived from the intestinal contents of the rat. All of the pure cultures and the rat intestinal bacteria were able to reduce the azo linkages of Direct Black 38, Direct Red 2 and Direct Blue 15 with the subsequent formation of benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, respectively. The metabolites of Direct Black 38, Direct Red 2 and Direct Blue 15 were isolated and identified by gas chromatography/mass spectrometry and had similar chromatographic and mass spectral properties with those of authentic standards. Results from this study indicate that in vitro anaerobic incubations of rat intestinal microorganisms were able to reduce and cleave the azo bonds of dyes derived from benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine to form potentially carcinogenic aromatic amines. [R56] *This paper confirms the mutagenicity of 2 carcinogenic chemicals, o-tolidine and 4,4'-tetramethyldiaminodiphenylmethane (TDDM). o-Tolidine and TDDM were both tested in the Salmonella/mammalian-microsome test and in the sister-chromatid exchange (SCE) test with rabbit lymphocytes in vitro. The number of revertants was increased in the presence of S9 mix by o-tolidine in the Salmonella typhimurium strains TA98 and TA1538, and by TDDM in strains TA98 and TA100. Both compounds showed weak SCE-inducing activity in cultured rabbit lymphocytes in the absence, but not in the presence, of an exogenous metabolic system. [R61] *Dimethoxybenzidine and dimethylbenzidine are used to synthesize dyes such as CI Direct Blue 15 and CI Acid Red 114, respectively. These commercially used dyes are metabolically degraded to dimethoxybenzidine or dimethylbenzidine in the intestinal tract of rodents and subsequently dimethoxybenzidine and dimethylbenzidine are absorbed into the blood stream. [R44] *Assays using the Salmonella/microsome test revealed that the urine extracts of rats orally administered o-tolidine were more strongly mutagenic than o-tolidine itself. ... Both 3,3'-dimethyl-N- acetylbenzidine and 3,3'-dimethyl-N,N'-diacetylbenzidine were identified as urinary metabolites of o-tolidine and Evans Blue. [R42] *Urine extracts from rats treated with 3,3'-diemthylbenzidine or Evans Blue, a 3,3'-dimethylbenzidine-derived dye, contained N-acetyl-3,3'-dimethylbenzidine and N,N'-diacetyl-dimethylbenzidine, as well as 3,3'-dimethylbenzidine. [R62] ACTN: *In mice and rats, prenatal exposure to the dye Congo red permanently reduces the number of germ cells in male and female offspring. In the current investigation, nine other dyes structurally related to Congo red were examined for developmental testicular toxicity. In this study, the structural component of the dyes responsible for the prenatal induction of germ cell aplasia was identified. We found that only benzidine-based dyes altered testicular development and caused hypospermatogenesis in mice during adulthood. Dimethyl- and dimethoxybenzidine-based dyes were without effect. Pregnant mice were dosed orally on Days 8-12 of gestation with a benzidine-, dimethylbenzidine-, or a dimethoxybenzidine-based dye and the testes of 45- to 50-day-old male offspring were examined. The testes of postpubertal male offspring exposed to the benzidine-based dyes, Congo red, diamine blue, and Chlorazol Black E, were small and contained some tubules completely devoid of germ cells, but the dimethylbenzidine-based dyes, trypan blue, Evans blue, and benzopurpurin 4B, and the dimethoxybenzidine-based dye, Chicago sky blue, did not alter testicular development in this manner. Azoic diazo component 48, a dimethoxybenzidine congener, and two other diazo dyes, naphthol blue black and Sudan III, were also without effect on the germ cells. Experiments with Chlorazol Black E (CBE) indicate that the period of susceptibility in the male fetus is limited to the period of primordial germ cell migration and division. When CBE was administered on Days 8-10 of gestation it reduced testis weight after puberty by 30%, while treatment after Day 13 did not affect testicular function. [R63] *It was found that intoxication of animals with aminobiphenyls leads to the activation of such glutathione-dependent enzymes as glutathione-S-transferase and glutathione reductase. This is accompanied by the induction of activities of individual isoforms of the multifunctional family of glutathione-S-transferases. There was a decrease in the glutathione peroxidase activity after intoxication with benzidine derivatives. It was found that the GSH content in rat liver decreased after benzidine intoxication and sharply increased after effects of 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine. In all cases studied there was a diminution in the level of diene conjugates. It was supposed that the specificity of the catalytic glutathione redox system reaction is due to structural peculiarities of the aminobiphenyls being injected. Analysis of functional pairs of glutathione-dependent enzymes revealed a certain imbalance in the antioxidant system function after aminobiphenyl poisoning. [R64] *Dimethoxybenzidine (DMO) and dimethylbenzidine (DM) are used to synthesize dyes such as C.I. Direct Blue 15 and C.I. Acid Red 114, respectively. These commercially used dyes are metabolically degraded to DMO or DM in the intestinal tract of rodents and subsequently DMO and DM are absorbed into the blood stream. Animals were exposed to DMO, DM, or the dyes in the drinking water. Tumors obtained from control and chemical-treated animals were examined for the presence of activated oncogenes by the NIH 3T3 DNA transfection assay. Activated oncogenes were detected in less than 3% (1/38) of the tumors from control animals whereas 68% (34/50) of the tumors from chemical-treated animals contained detectable oncogenes. Activated oncogenes were detected in both malignant (25/36) and benign (9/14) tumors from the chemically treated animals but only in one of 13 malignant tumors from the control animals. The presence of oncogenes in the chemically induced benign tumors suggests that oncogene activation was an early event in those tumors. Southern blot analysis of transfectant DNA showed that the transforming properties of the chemically induced rat tumor DNAs were due to the transfer of an activated H-ras (31/34) or N-ras (3/34) gene. One spontaneous rat tumor DNA was found to contain an activated H-ras gene. Oligonucleotide hybridization analysis indicated that the H-ras oncogenes from chemical-associated tumors contained mutations at codons 12, 13, or 61 whereas the spontaneously activated H-ras gene contained a point mutation at codon 61. These data suggest that activation of cellular ras genes by point mutation is an important step in the induction of tumors, at least in rats, by this class of benzidine-derived dyes. Moreover, in light of common histogenesis of the normal counterparts of many of the chemically induced neoplasms and histological evidence of varied tissue differentiation in some basal cell neoplasms, it is possible that most or all of the chemically induced neoplasms were derived from a common epidermal progenitor stem cell population. [R44] *In aqueous solution peroxidase catalyzes the conversion of o-tolidine to tolidine blue by hydrogen peroxide. This reaction of practical significance for analytical tests was studied by optical and ESR spectroscopy. For the blue dye formed in aqueous solution a meriquinoidic structure was proposed which is in equilibrium with an instable radical compound. This equilibrium is shifted to higher radical concentrations by ethylene glycol. Naphthene derivatives stabilize the meriquinoidic structure by means of non-covalent interactions resulting in a decrease of the radical concentration. In crosslinked gelatin the dye formation runs analogously, so that this system is suitable for providing evidence for H2O2-forming reactions. Naphthene derivatives substituted by sufficiently long aliphatic groups are diffusion stable in crosslinked gelatin. By interacting with the dye they prevent its rapid chemical decomposition and diffusion into the sample solution. It was shown, furthermore, that by means of such systems with a suitable structure of the layers both substrates and enzymes participating in the reaction may be determined analytically. This does provide a basis for developing new analytical test variants. [R65] INTC: *There is some evidence that concurrent exposure to o-tolidine decreased the time to appearance of tumors in rats treated with benzidine. [R5, 1991.1564] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *3,3'-Dimethylbenzidine's production and use as a chemical intermediate in the production of azo dyes and as a reagent for the detection of gold may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.9X10-7 mm Hg at 25 deg C indicates 3,3'-dimethylbenzidine will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 3,3'-dimethylbenzidine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3 hours. 3,3'-Dimethylbenzidine absorbs light greater than 290 nm, and it may be susceptible to direct photolysis in the environment; however, the rate of this potential reaction is unknown. Particulate-phase 3,3'-dimethylbenzidine will be removed from the atmosphere by wet and dry deposition. If released to soil, 3,3'-dimethylbenzidine is expected to have moderate mobility based upon an estimated Koc of 450. The first pKa of 3,3'-dimethylbenzidine is 4.5, which indicates that 3,3'-dimethylbenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to soils than neutral molecules. Furthermore, 3,3'-dimethylbenzidine is an aromatic amine which may form covalent bonds with humic materials resulting in relatively immobile quinone-like complexes. Volatilization from moist soil surfaces is not expected to be an important fate process for 3,3'-dimethylbenzidine because cations do not volatilize, and the estimated Henry's Law constant of the neutral species is 6.3X10-11 atm-cu m/mole. 3,3'-Dimethylbenzidine is not expected to volatilize from dry soil surfaces based upon its estimated vapor pressure. No data regarding the biodegradation of 3,3'-dimethylbenzidine in soil or natural water were found; however, a single screening study using sewage sludge inoculum, suggests biodegradation will occur slowly in the environment. Benzidine and its derivatives such as 3,3'-dimethylbenzidine are known to be to be rapidly oxidized by Fe(III) and other cations which are frequently found in soil and environmental waters. If released into water, 3,3'-dimethylbenzidine is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process for either the free base or its conjugate acid based upon this compound's estimated Henry's Law constant and the fact that cations are non-volatile. BCF values in the range of 5 to 83, measured in fish, suggests bioconcentration in aquatic organisms is low to moderate. 3,3'-Dimethylbenzidine is not expected to undergo hydrolysis due to a lack of hydrolyzable functional groups. Occupational exposure to 3,3'-dimethylbenzidine may occur through inhalation and dermal contact with this compound at workplaces where 3,3'-dimethylbenzidine is produced or used. (SRC) ARTS: *3,3'-Dimethylbenzidine's production and use as a chemical intermediate in the production of azo dyes and as a reagent for the detection of gold(1) may result in its release to the environment through various waste streams(SRC). [R66] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 450(SRC), determined from a log Kow of 2.34(2) and a regression-derived equation(3), indicates that 3,3'-dimethylbenzidine is expected to have moderate mobility in soil(SRC). The first pKa of 3,3'-dimethylbenzidine is 4.5(4). This pKa indicates that 3,3'-dimethylbenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to soils than neutral molecules(SRC). Furthermore, 3,3'-dimethylbenzidine is an aromatic amine which may form covalent bonds with humic materials resulting in relatively immobile quinone-like complexes(5). Volatilization of the neutral species of 3,3'-dimethylbenzidine from moist soil surfaces is not expected to be an important fate process(SRC) based upon an estimated Henry's Law constant of 6.3X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(6). The conjugate acid of 3,3-dimethylbenzidine will not volatilize since cations are non-volatile(SRC). 3,3'-Dimethylbenzidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-7 mm Hg(SRC), determined from a fragment constant method(7). 3,3'-Dimethylbenzidine, present at 100 mg/l, achieved 3% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(8), suggesting that biodegradation will occur slowly in soil(SRC). Structurally similar compounds such as benzidine are shown to be oxidized by Fe(III) and other cations which are frequently found in soil or clay(9), which suggest that 3,3'-dimethylbenzidine may also be degraded by a similar process(SRC). [R67] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 450(SRC), determined from a log Kow of 2.34(2) and a regression-derived equation(3), indicates that 3,3'-dimethylbenzidine is expected to adsorb to suspended solids and sediment(SRC). The first pKa of 3,3'-dimethylbenzidine is 4.5(4). This pKa indicates that 3,3'-dimethylbenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to suspended solids and sediment than neutral molecules(SRC). Volatilization of the neutral species from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 6.3X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(6). The conjugate acid of 3,3'-dimethylbenzidine will not volatilize since cations are non-volatile(SRC). According to a classification scheme(7), BCF values in the range of 5 to 83(8), measured in fish, suggest bioconcentration in aquatic organisms is low to moderate(SRC). No information on the biodegradation of 3,3'-dimethylbenzidine in natural waters was found(SRC), but this compound was reported to be resistant to biodegradation in the Japanese MITI test(8), suggesting biodegradation in waters will most likely occur slowly(SRC). Structurally similar compounds such as benzidine are shown to be oxidized by Fe(III) and other cations which are frequently found in environmental waters(9), which suggest that 3,3'-dimethylbenzidine may also be degraded by a similar process(SRC). [R68] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 3,3'-dimethylbenzidine, which has an estimated vapor pressure of 6.9X10-7 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 3,3'-dimethylbenzidine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 hours(SRC), calculated from its rate constant of 1.9X10-10 cu cm/molecule-sec at 25 deg C (SRC)determined using a structure estimation method(3). Since 3,3'-dimethylbenzidine absorbs light greater than 290 nm(4), it may be susceptible to direct photolysis in the environment(SRC). Particulate-phase 3,3'-dimethylbenzidine may be removed from the air by wet and dry deposition(SRC). [R69] BIOD: *In a Warburg respirometer that used activated sludge from both domestic and industrial discharges, 100% of the 3,3'-dimethylbenzidine (initial concn 20 mg/l) was depleted in 6 hours at 25 deg C(1). [R70] *3,3'-Dimethylbenzidine, present at 100 mg/l, reached 3% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1), suggesting that biodegradation will occur slowly in the environment(SRC). [R71] ABIO: *The rate constant for the vapor-phase reaction of 3,3'-dimethylbenzidine with photochemically-produced hydroxyl radicals has been estimated as 1.9X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The pKa of 3,3'-dimethylbenzidine is 4.5(2). This pKa indicates that 3,3'-dimethylbenzidine will partially exist in the protonated form under acidic conditions(SRC). 3,3'-Dimethylbenzidine absorbs light greater than 290 nm(3) and may be susceptible to photolysis in the environment(SRC). 3,3'-Dimethylbenzidine is not expected to undergo hydrolysis due to a lack of hydrolyzable functional groups(4). [R72] BIOC: *BCF values in the range of 5-10 were measured for carp exposed to 0.02 mg/l of dimethylbenzidine for 8 weeks in a continuous flow system(1). BCF values in the range of 34-83 were measured for carp exposed to 0.2 mg/l of dimethylbenzidine for 8 weeks in a continuous flow system(1). According to a classification scheme(2), these BCF values suggest bioconcentration in aquatic organisms is low to moderate(SRC). [R73] KOC: *The Koc of 3,3'-dimethylbenzidine is estimated as 450(SRC), using a measured log Kow of 2.34(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 3,3'-dimethylbenzidine is expected to have moderate mobility in soil(SRC). The first pKa of 3,3'-dimethylbenzidine is 4.5(4). This pKa indicates that 3,3'-dimethylbenzidine will partially exist in the protonated form under acidic conditions and cations have greater adsorption to soils than neutral molecules(SRC). Furthermore, 3,3'-dimethylbenzidine is an aromatic amine which may form covalent bonds with humic materials resulting in relatively immobile quinone-like complexes(5). [R74] VWS: *The first pKa of 3,3'-dimethylbenzidine is 4.5(1), which indicates that 3,3'-dimethylbenzidine will partially exist in the protonated form under acidic conditions and cations will not volatilize from water or soil surfaces(SRC). The Henry's Law constant for the neutral species (free base) of 3,3'-dimethylbenzidine is estimated as 6.3X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(2). This Henry's Law constant indicates that 3,3'-dimethylbenzidine is expected to be essentially nonvolatile from water surfaces(3). 3,3'-Dimethylbenzidine's Henry's Law constant(2) indicates that volatilization from moist soil surfaces is not expected(SRC). 3,3'-Dimethylbenzidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.9X10-7 mm Hg(SRC), determined from a fragment constant method(4). [R75] RTEX: *Processes in which dried dye is handled have the greatest potential for employee exposure during the manufacture or repackaging of benzidine-based dyes. ... During use of benzidine-based dyes, the greatest potential for exposure would be expected to be among dye-weighers who handle dry powders. /Benzidine-based dyes/ [R76] *o-Tolidine may enter the body by percutaneous absorption, by ingestion or by inhalation. [R49] *Most occupational exposures to o-tolidine actually involve a mixture of biphenyl amine compounds. [R5, 1991.1565] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 9,369 workers (6,004 of these are female) are potentially exposed to 3,3'-dimethylbenzidine in the US(1). Occupational exposure to 3,3'-dimethylbenzidine may occur through inhalation and dermal contact with this compound at workplaces where 3,3'-dimethylbenzidine is produced or used(SRC). [R77] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers o-tolidine to be a potential occupational carcinogen. [R20] NREC: *NIOSH considers o-tolidine to be a potential occupational carcinogen. [R20] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R20] *Recommended Exposure Limit: 60 Min Ceiling Value: 0.02 mg/cu m, skin. [R20] TLV: *A3; Confirmed animal carcinogen with unknown relevance to humans. Skin notation. [R33] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 3,3'-Dimethylbenzidine is included on this list. [R78] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 250 ug/l [R79] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R80] RCRA: *U095; As stipulated in 40 CFR 261.33, when 3,3'-dimethylbenzidine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R81] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 5013. Analyte: o-Tolidine. Matrix: Air. Sampler: Filter (5 um polytetrafluoroethylene, polyperfuoroethylene, tetrafluoroethene homopolymer, Teflon membrane). Flow Rate: 1 to 3 l/min. Shipment: Keep samples dry and cool; protect from light. Sample Stability: greater than or equal to 7 days @ 25 deg C in the dark. [R20] ALAB: *NIOSH Method 5013. Analyte: o-Tolidine. Matrix: Air. Procedure: High performance liquid chromatography, ultraviolet detection. For o-tolidine this method has an estimated detection limit of 3 ug/benzidine. The precision/RSD is 0.04 to 0.08. Applicability: The working range is ca. 0.06 to 3 mg/cu m for a 250 liter air sample. Interferences: Aniline, azobenzene, p-aminophenol, p-phenylene diamine or p-nitroaniline do not interfere in the measurement when present in equal molar amounts. [R20] *EPA Method EMSLC 553. Determination of Benzidines and Nitrogen-Containing Pesticides in Water by Liquid-Liquid Extraction and Reverse Phase High Performance Liquid Chromatography, Particle Beam, and Mass Spectrometry. Revision 1.1. Detection limit = 3.3 ug/l. [R82] *EPA Method EMSCL 553-LSE. Determination of Benzidines and Nitrogen-Containing Pesticides in Water by Liquid-Solid Extraction and Reverse Phase High Performance Liquid Chromatography, Particle Beam, and Mass Spectrometry. Revision 1.1. Detection limit = 3.0 ug/l. [R82] *OSW Method 8270B. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit = 10 ug/l. [R82] *OSW Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass Spectrometry (GC/MS): Capillary Column Technique. 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Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 122 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. Butterworth, London, (1965) (5) Parris GE; Environ Sci Technol 14: 1099-106 (1980) (6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (7) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (8) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (9) Callahan MA et al; Water-related environmental fate of 129 priority pollutants Vol II. pp. 102-1 to 102-7 USEPA-440/4-79-029b (1979) R68: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 122 (1995)(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. Butterworth, London, (1965) (5) Parris GE; Environ Sci Technol 14: 1099-106 (1980)(6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (9) Callahan MA et al; Water-related environmental fate of 129 priority pollutants vol II; pp.102-1 to 102-7 USEPA-440/4-79-029b (1979) R69: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Sadtler Res Lab; Sadtler Standard UV Spectra No. 1760 R70: (1) Baird R et al; J Water Pollut Control Fed 49: 1609-15 (1977) R71: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R72: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. Butterworth, London, (1965) (3) Sadtler Res Lab; Sadtler Standard UV Spectra No. 1760(4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R73: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R74: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 122 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. Butterworth, London, (1965) (5) Parris GE; Environ Sci Technol 14: 1099-106 (1980) R75: (1) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. Butterworth, London, (1965) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R76: NIOSH; Special Occupational Hazard Review for Benzidine-Based Dyes p.27 (1980) R77: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R78: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R79: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R80: 40 CFR 302.4 (7/1/2001) R81: 40 CFR 261.33 (7/1/2001) R82: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 88 Record 142 of 1119 in HSDB (through 2003/06) AN: 1641 UD: 200303 RD: Reviewed by SRP on 1/31/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIMETHYLPHTHALATE- SY: *AI3-00262-; *AVOLIN-; *1,2-BENZENEDICARBOXYLIC-ACID,-DIMETHYL-ESTER-; *Caswell-No-380-; *DIMETHYL-1,2-BENZENEDICARBOXYLATE-; *DIMETHYL-BENZENEORTHODICARBOXYLATE-; *DIMETHYL-PHTHALATE-; *o-Dimethyl-phthalate-; *DMF- (INSECTREPELLANT); *DMP-; *ENT-262-; *EPA-Pesticide-Chemical-Code-028002-; *FERMINE-; *METHYL-PHTHALATE-; *MIPAX-; *NTM-; *PALATINOL-M-; *PHTHALIC-ACID,-DIMETHYL-ESTER-; *PHTHALIC-ACID-METHYL-ESTER-; *PHTHALSAEUREDIMETHYLESTER- (GERMAN); *REPEFTAL-; *SOLVANOM-; *SOLVARONE- RN: 131-11-3 MF: *C10-H10-O4 HAZN: U102; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared industrially from phthalic anhydride and methanol: Faith, Keyes, and Clark's Industrial Chemicals, F.A. Lowenheim, M.K. Moran, eds. (Wiley-Interscience, New York, 4th ed, 1975) pp 318-24. [R1, 550] FORM: *APPLIED ALONE OR INCORPORATED INTO CREAMS [R2] *GRADE: TECHNICAL [R3, 420] MFS: *Eastman Chemical Company, Hq, P.O. Box 511, Kingsport, TN 37662, (423)229-2000; Tennessee Eastman Division; Production site: Kingsport, TN 37662. [R4] *Unitex Chemical Corporation, Hq, 520 Broome Road, Greensboro, NC 27406, (910) 378-0965; Production site: Greensboro, NC 27406. [R4] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R5] *SOLVENT AND PLASTICIZER FOR CELLULOSE ACETATE AND CELLULOSE ACETATE-BUTYRATE COMPOSITIONS [R1, 551] *FOR MAKING VARNISHES AND CLEAR WHITE OR SLIGHTLY COLORED CLEAR FILMS WHICH MAY BE EXPOSED TO THE SUN [R6, 135] *... IT IS A PLASTICIZER FOR POLYVINYL ACETATE AND HAS A GELLING ACTION ON POLYVINYL CHLORIDE, VINYL CHLORIDE-VINYL ACETATE COPOLYMERS, POLYVINYL ACETAL, AND POLYSTYRENE. IT IS COMPATIBLE WITH ACRYLIC RESINS AND RUBBERS, IMPROVING THEIR PLASTICITY. ... [R6, 135] *PLASTICIZER FOR CELLULOSE ESTER PLASTICS [R7] *DISPERSING MEDIUM, EG, DYE CARRIER [R7] *PLASTICIZER IN HAIR SPRAY [R7] *Leech repellant. [R8] *Used in fuel matrix of double base rocket propellant, fluidized bed coating in manufacture of poly(vinylidene fluoride); plasticizer in cellulose acetate and nitrocellulose, resins, rubber; constituent of ... rubber. [R9] *... AS REPELLANT FOR FLIES ON HORSES AND COWS. [R10] *MEDICATION (VET) *Plasticizer for nitrocellulose and cellulose acetate, resins, rubber, and in solid rocket propellants; lacquers; plastics; rubber; coating agents; safety glass; molding powders; and insect repellent. [R3, 420] *Insect repellent for personal protection against mosquitoes, fleas, and chiggers. [R11] *Peroxide phlegmatising agent. [R12] CPAT: *USED ALMOST ENTIRELY AS A PLASTICIZER IN CELLULOSE ESTER PLASTICS. [R7] PRIE: U.S. PRODUCTION: *(1985) 3.47X10+9 g [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Pale yellow crystals [R14]; *Colorless, oily liquid [Note: A solid below 42 degrees F]. [R15] ODOR: *SLIGHT AROMATIC ODOR [R1, 550] BP: *283.7 DEG C @ 760 MM HG [R1, 550] MP: *5.5 DEG C [R1, 550] MW: *194.19 [R1, 550] DEN: *1.196 @ 15.6 DEG C/15.6 DEG C; 1.1940 @ 20 deg C/20 deg C; 1.189 @ 25 deg C/25 deg C [R1, 550] HTC: *119.7 KG-CAL/MOLE [R1, 550] HTV: *93.1 G-CAL/G [R1, 550] OWPC: *log Kow = 1.60 [R16] SOL: *MISCIBLE WITH ALCOHOL, ETHER, CHLOROFORM [R1, 550]; *0.34 G/100 G IN MINERAL OIL @ 20 DEG C [R1, 550]; *SOL IN PETROLEUM OILS, DIETHYL ETHER AND MOST ORG SOLVENTS [R2]; *SOL IN BENZENE [R17]; *Practically insoluble in petroleum ether, and other paraffin hydrocarbons. [R1, 550]; *Readily soluble in organic solvents, alcohols, esters, ketones, chlorinated hydrocarbons. Slightly soluble in some types of mineral oil. [R11]; *In water, 4000 mg/l at 25 deg C. [R18] SPEC: *INDEX OF REFRACTION: 1.5168 @ 20 DEG C/D; MAX ABSORPTION (ETHANOL): 277 NM (E= 57.7 @ 1%, 1 CM) [R1, 550]; *IR: 4805 (Coblentz Society Spectral Collection) [R19]; *UV: 378 (Sadtler Research Laboratories Spectral Collection) [R19]; *NMR: 89 (Sadtler Research Laboratories Spectral Collection) [R19]; *MASS: 348 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R19]; *Intense mass spectral peaks: 163 m/z (100%), 77 m/z (31%), 76 m/z (17%), 50 m/z (15%) [R20] VAPD: *6.69 (AIR= 1) [R1, 550] VAP: *3.08X10-3 mm Hg at 25 deg C /from experimentally-derived coefficients/ [R21] EVAP: *Almost zero (methyl acetate= 1) [R22, 1981.1] VISC: *17.2 CENTIPOISES @ 25 DEG C [R1, 550] OCPP: *VOLATILITY: 4.0 MG/CM SQ/HR @ 100 DEG C [R10] *WEIGHT/VOLUME CONVERSION: 7.93 MG/CU M= APPROX 1 PPM [R23, 2345] *The release time of the repellent chemical ... dimethyl phthalate ... from porous propylene slabs was much higher (approx 7 times more) than from porous propylene powders. The release time was a function of the initial concn and was inversely proportional to vapor pressure in case of porous powder. [R24] *The commercial product freezes at approximately 0 deg C. [R1, 550] *VAPOR PRESSURE: LESS THAN 0.01 MM HG @ 20 DEG C [R1, 550] *Bulk density 9.93 lb/gal at 68 deg F. [R3, 419] *Readily hydrolyzed by alkalis, with cleavage of both ester groups. [R11] *One gallon weighs 9.93 lbs. [R1, 550] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of dimethylphthalate stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, dermal contact), exposure to this colorless, oily liquid (or pale-yellow crystals at temperatures below 42 deg F) may occur from its use as a plasticizer or solvent. Effects from exposure may include contact burns to the skin and eyes, confusion, ataxia, clonic jerking, coma, seizures, and possibly death. Both the OSHA PEL and the ACGIH TLV have been set at 5 mg/cu m. While its vapor pressure is low (< 0.01 mm Hg at 20 deg C), levels of aerosolized dimethylphthalate should be maintained below the PEL through ventilation. In activities where over-exposure may occur, wear a self-contained breathing apparatus with a full facepiece, and protective clothing to prevent skin contact. If contact should occur, immediately flush eyes with running water for at least 15 minutes, and wash affected skin with soap and water. While dimethylphthalate does not ignite easily (flashpoint: 295 deg F), it may burn with the production of irritating and poisonous gases. Fire involving dimethylphthalate may be extinguished with dry chemical, CO2, or Halon. Water spray, fog, or standard foam, if used, should be applied with caution, as each may cause violent frothing. Dimethylphthalate should be stored away from nitrates, strong oxidizers, alkalies and acids. Before shipping dimethylphthalate, consult with the regulatory requirements of the US Department of Transportation. Small dry spills of dimethylphthalate should be carefully shovelled into a clean, dry, covered container (liquid spills are first absorbed in sand or other noncombustible material) for later disposal. Large liquid spills should be diked (powder spills covered with plastic sheeting) for later disposal. Before implementing land disposal of waste dimethylphthalate, consult with environmental regulatory agencies for guidance. Also, dimethylphthalate is a good candidate for liquid injection and fluidized bed forms of incineration. NFPA: +Health: 0. 0= Materials that on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R25] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R25] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R25] FLMT: +LOWER: 0.9% BY VOL @ 358 DEG F (180 DEG C) [R25] FLPT: +295 deg F (146 deg C) (closed cup) [R25] AUTO: +915 DEG F (490 DEG C) [R25] FIRP: +WATER OR FOAM MAY CAUSE FROTHING [R25] *Extinguishant: Dry chemical, foam, or carbon dioxide [R22, 1981.2] *Depending upon the concentration of dimethylphthalate, the following respiratory protection information is provided: Fire fighting: Self-contained breathing apparatus with a full facepiece operated in pressure demand or other positive pressure mode. [R22, 1981.4] EXPL: +Lower explosive limit in air: 0.9% by volume (at 358 deg F) [R26, 114] REAC: *Incompatible with nitrates, strong oxidizers, strong alkalies, and strong acids. Fires or explosions may result. [R22, 1981.1] +Nitrates; strong oxidizers, alkalis, and acids. [R26, 114] DCMP: *Hazardous decomposition products: toxic gases and vapors (such as carbon monoxide) may be released in a fire involving dimethylphthalate. [R22, 1981.1] *When heated to decomp it emits acrid smoke and irritating fumes. [R27] SERI: *Irritation of nasal passages and upper respiratory system; eye pain. [R28] *Overexposure to hot vapors or mists of dimethyl phthalate may cause irritation of the nasal passages, mouth and throat. Eye contact with liquid dimethyl phthalate causes pain. [R22, 1981.1] EQUP: *USE WITH VENTILATION THAT IS ADEQUATE TO MAINTAIN ATMOSPHERIC CONCN BELOW TLV OF 5 MG/CU M. [R29] *THERE MAY BE ALSO SOME NEED FOR SKIN PROTECTION. /PHTHALATES/ [R30] +Wear appropriate eye protection to prevent eye contact. [R26, 115] +Recommendations for respirator selection. Max concn for use: 50 mg/cu m. Respirator Class(es): Any dust and mist respirator with a full facepiece. [R26, 115] +Recommendations for respirator selection. Max concn for use: 125 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any powered, air-purifying respirator with a dust and mist filter. Eye protection needed. [R26, 115] +Recommendations for respirator selection. Max concn for use: 250 mg/cu m. Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R26, 115] +Recommendations for respirator selection. Max concn for use: 2000 mg/cu m. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R26, 115] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R26, 115] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R26, 115] OPRM: +Contact lenses should not be worn when working with this chemical. [R26, 115] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SYNTH OF PHTHALATES REQUIRE GOOD VENTILATION IN ORDER TO PREVENT CONTAMINATION OF AIR WITH PHTHALIC ANHYDRIDE OR ALCOHOLS. HANDLING MINERAL ACIDS USED AS CATALYSTS REQUIRES ORDINARY PRECAUTIONS. /PHTHALATES/ [R30] SSL: *STABLE IN AIR BUT SLOWLY AFFECTED BY LIGHT [R31] *Half-life calculated at a pH of 7.0 is 3.2 years [R32, p. 94-6] *Readily hydrolyzed by alkalis, with cleavage of both ester groups. [R11] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. [R22, 1981.3] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U102, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R33] */Small quantities/ absorb with paper, then burn the paper in a suitable location away from other combustible materials. [R22, 1981.3] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R34] *Chemical Treatability of Dimethyl Phthalate; Concentration Process: Resin Adsorption; Chemical Classification: Phthalates; Scale of Study: Batch flow, Laboratory scale; Type of Wastewater Used: Pure compound (one solute in a solvent); Results of Study: 100% reduction; 62% desorbed from resin by elutriation with solvent. (Amberlite XAD-2 used. Solvents included pentane-acetone, diethyl ether, methylene chloride-acetone, chloroform-acetone). [R35] *Chemical Treatability of Dimethyl Phthalate; Concentration Process: Activated carbon; Chemical Classification: Phthalates; Scale of Study: Batch flow, Laboratory scale; Type of Wastewater Used: Pure compound (one solute in a solvent); Results of Study: 100% reduction, 13% desorbed from carbon by elutriation with solvent. (Calgon FS-300 used. Solvents included pentane-acetone, diethyl ether, methylene chloride-acetone, chloroform-acetone, and acetone). [R36] *Chemical Treatability of Dimethyl Phthalate; Concentration Process: Chemical Precipitation; Chemical Classification: Phthalates; Scale of Study: Literature Review; Type of Wastewater Used: Domestic wastewater and Pure compound (one solute in a solvent); Results of Study: 15% reduction with aluminum. (Chemical coagulation was followed by dual media filtration). [R37] *Chemical Treatability of Dimethyl Phthalate; Concentration Process: Biological Treatment; Chemical Classification: Phthalates; Scale of Study: Unknown; Type of Wastewater Used: Synthetic wastewater; Results of Study: 100% reduction. [R38] *Incineration: It should be atomized into an incinerator and combustion may be improved by mixing with a more flammable solvent (acetone or benzene). [R39] *Product residues and sorbent media may be packaged in 17h-epoxy lined drums and disposed of at an approved EPA disposal site. Destroy by high-temp incineration or microwave plasma detoxification, if available. Encapsulate by organic polyester resin or silicate fixation. Confirm disposal procedures with responsible environmental engineer and regulatory officials. [R40, 786] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Pertinent data regarding carcinogenicity data was not located in the available literature. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate. [R41] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Esters and related compounds/ [R42] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R42] *Inhalation: Remove to fresh air. Eyes: Flush with water. Skin: Flush with water, wash well with soap and water. [R40, 788] MEDS: *Routine medical examinations should be provided to each employee who is exposed to dimethyl phthalate at potentially hazardous levels. [R22, 1981.1] *Consider the routes of exposure in preplacement and periodic physical examinations. [R28] HTOX: *CONTACT WITH EYE PRODUCES CONSIDERABLE PAIN, BUT CAUSES EITHER NO DAMAGE OR ONLY SLIGHT REVERSIBLE DISTURBANCE OF THE EPITHELIUM. [R43] *ACCIDENTAL INGESTION IN ONE CASE ... RESULTED IN AN IMMEDIATE BURNING SENSATION OF THE LIPS, TONGUE AND MOUTH FOLLOWED TWO HR LATER BY A DEEP COMA. [R44] *IRRITATING TO MUCOUS MEMBRANES, EYES; CAN CAUSE CNS DEPRESSION WHEN INGESTED. NOT IRRITATING TO OR ABSORBED THROUGH SKIN. [R1, 550] *Ingestion of DMP can cause central nervous system depression. [R45] *In one fatal case of suicidal ingestion of a mixture containing dimethyl phthalate and ketone peroxides, the principal toxic symptoms were marked esophagitis, gastritis, and hemorrhage. [R22, 1981.3] *If swallowed, dimethyl phthalate may cause irritation of the stomach, dizziness, and unconsciousness. [R22, 1981.1] *General sensation - Depression of CNS. If swallowed: causes burning-like irritation of lips, tongue, and mouth; vomiting; diarrhea; coma. If inhaled: irritation of respiratory tract, cough, paralysis, conjunctivitis. Symptoms of chemical exposure to phthalates include conjunctivitis, corneal erosion, dizziness, eczema, nausea, and vomiting. [R40, 785] *COMPARATIVE TOXICITY OF PHTHALATE ESTERS TO HELA-S3 CELLS WAS STUDIED BY DETERMINING THEIR EFFECT ON DOUBLING TIME OF THE CELLS. THE TOXICITY OF THE ESTERS DECREASING IN ORDER: DIETHYL PHTHALATE, BUTYL PHTHALYL BUTYL GLYCOLATE, DI-ISO-BUTYL PHTHALATE, ETHYL PHTHALYL ETHYL GLYCOLATE, BIS(2-ETHYLHEXYL) PHTHALATE, DIMETHYL ISOPHTHALATE, DIBUTYL PHTHALATE, METHYL PHTHALYL ETHYL GLYCOLATE, DIMETHYL PHTHALATE, AND DIOCTYL PHTHALATE. [R46] NTOX: *IN 2 YR FEEDING TRIALS THERE WAS NO EFFECT ON GROWTH RATE OF RATS RECEIVING /CUMMULATIVE TOTAL/ 20,000 MG/KG IN DIET. [R11] *CATS ... EXPOSED TO CURRENT OF AIR CHARGED WITH DIMETHYL PHTHALATE VAPORS. AT DOSAGE OF 250 PPM INTENSE IRRITATION OF MUCOUS MEMBRANES ... FOUND ACCOMPANIED BY SALIVATION AND RESTLESSNESS. AT 1250 PPM ANIMALS APPEARED DEPRESSED AND ONE ... DIED. [R6, 136] *INHALATION TOXICITY: CATS: 9.3 MG/L (1213 PPM), TIME: 6.5 HR, EFFECT: LETHAL, 2 MG/L CAUSED NASAL IRRITATION; DERMAL IRRITATION: GUINEA PIGS: NO SKIN SENSITIZATION; EYE IRRITATION: RABBITS: SLIGHT EYE IRRITATION. [R47, 3051] *TWO YR FEEDING STUDIES IN FEMALE RATS @ LEVELS OF 2 TO 8% IN DIET SHOWED ONLY SLIGHT GROWTH EFFECTS @ 4 and 8%. SOME CHRONIC NEPHRITIC CHANGES ... @ 8% LEVEL. [R23, 2343] *TWELVE PHTHALIC ACID ESTERS, INCLUDING THOSE COMMONLY USED AS PLASTICIZERS FOR BIOMEDICAL DEVICES, WERE SUBJECTED TO VARIOUS BIOLOGICAL TESTS FOR ACUTE, SHORT-TERM, AND CHRONIC TOXICITY. THE ACUTE IP LD50 FOR THESE CMPD INCLUDING DIMETHYLPHTHALATE IN MICE RANGED FROM 3.22 TO GREATER THAN 100 G/KG. MOST OF THESE CMPD WERE 2-4 TIMES MORE TOXIC CHRONICALLY. [R48] *CHICK EMBRYOS EXPOSED TO CHICK RINGERS SOLN SATURATED WITH DIMETHYL PHTHALATE SHOWED GROWTH RETARDATION AND MALFORMATIONS IN CNS. [R49] */IN RATS/ ... INJECTIONS WERE MADE IP ON GESTATIONAL DAYS 5, 10, and 15. DOSES WERE GENERALLY FROM ABOUT 0.2 ML TO 1.0 ML/KG. FEW OR NO DEFECTS OCCURRED IN GROUPS RECEIVING .... DIMETHYL ... /PHTHALATE ESTER/. [R50] *AN IP LD50 IN /MICE/ ... HAS BEEN OBSERVED AS ABOUT 1.58 G/KG OR 18.75 MMOL/KG WITH PULMONARY CONGESTION, TOXICITY TO SPLEEN AND LYMPH NODES, AND RENAL TUBULAR NECROSIS. [R47, 3052] *DI-METHYL PHTHALATE PRODUCED A POSITIVE DOSE RELATED MUTAGENIC RESPONSE WITH SALMONELLA TA100, BUT ONLY IN THE ABSENCE OF S-9 LIVER ENZYMES. EXTRACTS OF 24 HR URINES OF RATS INJECTED IP WITH DIMETHYL PHTHALATE (2 G/KG) WERE NOT MUTAGENIC TO TA100 AT DOSE LEVELS EQUIVALENT TO 8 MILLILITERS OF URINE/PLATE (REPRESENTING 30% OF THEIR DAILY URINARY OUTPUT). S-9 ASSOCIATED ESTERASE HYDROLYZED DIMETHYL PHTHALATE TO THE MONOESTER AND METHANOL AND ELIMINATED ITS MUTAGENICITY. BOTH THE MUTAGENICITY AND BINDING OF DIMETHYL PHTHALATE ARE INVERSELY RELATED TO ITS METABOLISM. [R51] *In the anesthetized rabbit, dimethyl phthalate produced a 66.6% incr in the respiratory rate after the admin of a total dose of 100 mg/kg. [R52] *Seed treatment with 10-3 M dimethylphthalate inhibited the germination of a large number of weed and crop species. At 10-3 M, dimethylphthalate showed good weed control in flax, soybean, and alfalfa, with low phytotoxicity to the crop. [R53] *The insect repellent dimethylphthalate ... /was/ tested against Laelops echidninus, Haemolaelaps casalis, and Cosmolaelaps gurabensis. Strips of white cloth (1.2 X 133 cm) were treated with 2 ml solution for test. The repelling effects were 100% for Laelops echidninus, 92.40% for Haemolaelaps casalis, and 99.60% for Cosmolaelaps gurabensis. [R54] *Single ip injection of dimethyl phthalate (DMP) ... 3.6 ml/kg in rats inhibited the activity of hepatic aminopyrine N-demethylase and aniline hydroxylase but had no effect on glucose 6-phosphatase and reduced nicotinamide adenine dinucleotide cytocrome c reductase. ... However, on repeated ip /doses/ of /DMP/ daily for 7 days, no decr was observed in the activity of the enzymes. Single ip administration of DMP ... did not produce any significant effect on hepatic tyrosine aminotransferase activity. ... [R55] *The repellency to Lasioderma serricorne, Oryzaephilus mercator, Oryzaephilus surinamensis, Rhizopertha dominica, Stegobium paniceum, Tribolium castaneum, and Plodia interpunctella of various compounds, depended upon the insect species and on the developmental stage of the insect. ... Dimethyl phthalate showed 100% repellency to adult Plodia interpunctella, but it had no effect on Oryzaephilus surinamensis. The repelling effect of these chemicals was more intense on the adults than on the larvae. [R56] *Testosterone in testis and in serum and dihydrotestosterone in serum were significantly decreased in rats fed diets containing 2% dimethylphthalate for 1 week. [R57] *Total liver cholesterol decreased by 31% and total liver lipids decreased by 10% in rats maintained on a chow diet containing 2.5 mmol/100 g dimethyl phthalate. [R57] *Hexobarbital (60 mg/kg injected ip) sleep time of white mice administered dimethyl phthalate at 500 mg/kg was not significantly different than controls. [R58] *An evaluation of standard and experimental repellents was made against the chigger mite Leptotrombidium fletcheri using dose-response methods. ... Dimethyl phthalate was significantly more effective than the other repellents (ranked by ED50). [R59] *Dimethyl phthalate (DMP) ... was administered by gavage for 8 consecutive days to female CD-1 mice. Wt loss was insensitive as an index of sublethal adult toxicity and was inadequate for determining a max tolerated dose. ... Dimethyl phthalate had no effect on maternal or fetal survival at the doses administered. ... [R60] *The mutagenic activities of several phthalate esters were evaluated in an 8-azaguanine-resistance assay in Salmonella typhimurium. ... Dimethyl phthalate was mutagenic. ... The mutagenic activity in this series was dose dependent but weak. No dose response curve exceeded > 3.5 times background at maximally testable concn. A liq suspension histidine reversion assay of dimethyl phthalate showed levels of mutagenic activity similar to that observed in the azaguanine resistance assay. [R61] *Dimethylphthalate (DMP), dibutylphthalate (DBP) and di(2-ethylhexyl)phthalate were given ip (3.8 mM/kg) to Sprague-Dawley rats for 5 days. DBP increased significantly the liver concentration of cytochrome p450, but decreased the lung concn of cytochrome b5 and reduced nicotinamide adenine dinucleotide-cytochrome-c- reductase activity bytment with DMP and Di(2-ethylhexyl)phthalate. ... All phthalate esters decreased the lung metabolism of benzo(a)pyrene. ... No relationship was found between the C chain length of the investigated chemicals and effects on microsomal enzymatic activities. [R62] *Forty-nine pregnant CD-1 mice were given 3,500 mg/kg/day of dimethyl phthalate (DMP) in corn oil by gavage on days 6-13 of gestation and allowed to deliver. DMP showed no toxic effects in the treated mothers or in their offspring. [R63] *Compounds that have been suggested as solvents or suspending agents in tests of dermal toxicity are ... dimethylphthalate ... . [R64] *Lecithin/cholesterol acyltransferase was weakly inhibited (24.2%) by 5mM dimethyl phthalate. [R65] *The respiration rate of rat liver mitochondria was inhibited (approx 60%) by dimethylphthalate (0.8 M) in the presence of succinate and adenosine diphosphate (ADP). In the absence of ADP, there was no inhibition. [R66] *FIVE PHTHALATE ESTERS, DIMETHYL PHTHALATE, DIETHYL PHTHALATE, DIBUTYL PHTHALATE, DIHEXYL PHTHALATE, AND DIOCTYL PHTHALATE, WERE TESTED FOR THE HATCHING OF BRINE SHRIMP (ARTEMIA SALINA) EGGS. DIBUTYL PHTHLATE ESTER WAS THE MOST TOXIC OF THE PHTHALATES TESTED. THE TOXIC ORDER OF 3 OF THE ESTERS WAS DIBUTYL PHTHALATE GREATER THAN DIETHYL PHTHALATE GREATER THAN DIMETHYL PHTHALATE. CONCN WERE 10, 20, and 50 PPM. [R67] *The effects of phthalic acid esters on concentrations of testosterone and zinc in testicular tissues were studied. Young male Wistar rats were fed diets containing 2% dimethyl, diethyl, di-n-butyl, di-iso-butyl (DIBP), di-n-octyl (DOP), di-2-ethylhexyl phthalate, or o-phthalic acid for one week. The animals were then killed, samples of blood were collected, and the fresh weights of the testes, liver, and kidneys were obtained. ... Testicular weights were decreased in rats fed di-n-butyl, di-iso-butyl and di-2-ethylhexyl phthalates. Rats treated with di-n-butyl, di-iso-butyl or di-2-ethylhexyl phthalate had decreased zinc concentrations in the testes and liver, while di-n-octyl-treated rats had decreased zinc concentrations ... were found in the serum and tested of dimethyl, and diethyl, treated rats, while testosterone levels were significantly increased in the testes of rats fed di-n-butyl, di-iso-butyl and di-2-ethlyhexyl phthalate. [R68] *Eight phthalic acid esters were studied in a rat teratogenicity study. The esters included dimethyl, dimethoxyethyl, diethyl, dibutyl, diisobutyl, butyl carbobutoxymethyl, dioctyl and di-(2-ethylhexyl) phthalates. For all the esters, except two, the dose administered intraperitoneally to pregnant female rats was 1/10, 1/5, or 1/3 the acute LD50. For these esters, the doses /administered undiluted/ ranged from a low of 0.305 ml/kg for dibutyl phthalate to a high of 2.296 ml/kg for butyl carbobutoxymethyl phthalate. Di-(2-ethylhexyl) phthalate and dioctyl phthalate were given at doses of 5 and 10 ml/kg because of their very low acute toxicity. Control groups included: untreated rats, treated with 10 mg/kg of distilled water, rats treated with 10 ml/kg of normal saline and rats treated with 10 ml/kg and 5 ml/kg of cottonseed oil. All treatments took place on days 5, 10, and 15 of gestation. On the 20th day, all rats were sacrificed and the uterine horns and ovaries were surgically exposed to permit counting and recording of the number of corpora lutea, resorption sites, and viable and dead fetuses. Additionally, both viable and nonviable fetuses were excised, weighed, and examined for gross malformation. Thirty to fifty percent of the fetuses (using those which showed no gross malformation when possible) were prepared as transparent specimens to permit visualization of skeletal deformities. All of the esters produced gross or skeletal abnormalities which were dose related. The most common gross abnormalities in the treated animals were absence of tail, anophthalmia, twisted hands and legs, and hematomas. Skeletal abnormalities included elongated and fused ribs (bilateral and unilateral), absence of tail bones, abnormal or incomplete skull bones, and incomplete or missing leg bones. Dead fetuses were found in the groups treated with dimethyl, dimethoxyethyl, and diisobutyl phthalates. The most embryotoxic agent in the series was dimethoxyethyl phthalate. Each of the esters also reduced the weight of the fetuses when compared to the controls. Even at the high dose levels (5 and 10 ml/kg), di-2-ethylhexyl and dioctyl phthalates had the least adverse effects on embryo/fetus development. [R69] *Eight phthalic acid esters were included in a rat teratogenicity study. The esters included dimethyl, dimethoxyethyl, diethyl, dibutyl, diisobutyl, butyl carbobutoxymethyl, dioctyl and di-(2-ethylhexyl) phthalates. For all the esters, except two, the dose administered intraperitoneally to pregnant female rats was 1/10, 1/5, or 1/3 the acute LD50. For these esters, the doses ranged from a low of 0.305 ml/kg for dibutyl phthlate to a high of 2.296 ml/kg for butyl carbobutoxymethyl phthalate. Di-(2-ethylhexyl) phthalate and dioctyl phthalate were given at doses of 5 and 10 ml/kg because of their very low acute toxicity. Control groups included: untreated rats, rats treated with 10 ml/kg of distilled water, rats treated with 10 ml/kg of normal saline, and rats treated with 10 ml/kg and 5 ml/kg of cottonseed oil. All treatments took place on days 5, 10, and 15 of gestation. On the 20th day, all rats were sacrificed and the uterine horns and ovaries were surgically exposed to permit counting and recording of the number of corpora lutea, resorption sites, and viable and dead fetuses. Additionally, both viable and nonviable fetuses were excised, weighed, and examined for gross malformation. 30-50% of the fetuses (using those which showed no gross malformation when possible) were prepared as transparent specimens to permit visualization of skeletal deformities. All of the esters produced gross of skeletal abnormalities which were dose related. The most common gross abnormalities in the treated animals were absence of tail, anophthalmia, twisted hands and legs, and hematomas. Skeletal abnormalities included elongated and fused ribs (bilateral and unilateral), absence of tail bones, abnormal or incomplete skull bones, and incomplete or missing leg bones. [R70] NTXV: *LD50 Mouse oral 7.2 g/kg; [R71] *LD50 Mouse intraperitoneal 1.58 g/kg; [R71] *LD50 Rat oral 2.4 g/kg; [R71] *LD50 Rat intraperitoneal 3.38 ml/kg; [R71] *LD50 Guinea pig oral 2.4 g/kg; [R71] *LD50 Rabbit dermal 10.0 ml/kg; [R71] *LD50 Rat oral > 4800 mg/kg; [R11] *LD50 Rat oral 8,200 mg/kg; [R72] ETXV: *EC50 Selenastrum capricornutum (alga) 42,700 ug/l/96 hr effect: Chlorophyll a /Conditions of bioassay not specified/; [R73] *EC50 Selenastrum capricornutum (alga) 39,800 ug/l/96 hr effect: Cell number /Conditions of bioassay not specified/; [R73] *EC50 Skeletonema costatum (alga) 26,100 ug/l/96 hr effect: Chlorophyll a /Conditions of bioassay not specified/; [R73] *EC50 Skeletonema costatum (alga) 29,800 ug/l/96 hr effect: Cell number /Conditions of bioassay not specified/; [R74] *96-HR MEDIAN TOLERANCE LIMIT OF GYMNODINIUM BREVE TO DIMETHYLPHTHALATE WAS 0.6 PPM. /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R75] *EC50 Gymnodinium breve (alga) 54,000 ug/l/96 hr effect: Chlorophyll a /Conditions of bioassay not specified/; [R74] *EC50 Gymnodinium breve (alga) 125,000 ug/l/96 hr effect: Cell number /Conditions of bioassay not specified/; [R74] *LC50 dinoflagellate Gymnodinium breve 125-185 mg/L/96 hr /Conditions of bioassay not specified/; [R76, 836] *LC50 dinoflagellate Gymnodinium breve 75; 155 mg/L/96 hr /Conditions of bioassay(s) not specified/; [R76, 836] *LC50 Selenastrum capricornutum (algae) 40 mg/L/96 hr /Conditions of bioassay not specified/; [R76, 836] *LC50 Skeletonema costatus (algae) 65 mg/L/96 hr /Conditions of bioassay not specified/; [R76, 836] *LC50 larvae of grass shrimp (Palaemonetes pugio Holthius) 100 mg/L/8 d /Conditions of bioassay not specified/; [R76, 837] *LC50 brine shrimp (Palaemonetes pugio) > 100 mg/L/96 hr /Conditions of bioassay not specified/; [R76, 837] *LC50 mysid shrimp (Mysidopsis bahia) 74 mg/L/96 hr /Conditions of bioassay not specified/; [R76, 837] *LC50 Daphnia magna 33 mg/L/48 hr /Conditions of bioassay not specified/; [R76, 837] *LC50 bluegill (Lepomis macrochirus) 50 mg/L/96 hr /Conditions of bioassay not specified/; [R76, 837] *LC50 Cyprinodon variegatus 21; 58 mg/L/96 hr /Conditions of bioassay(s) not specified/; [R76, 837] NTP: +Dimethyl phthalate (DMP)... was evaluated for developmental toxicity in timed-pregnant Sprague-Dawley (CD) rats. On gestational days (gd) 6 through 15, dietary concentrations of 0. 0.25. 1.0 and 5% dimethyl phthalate were administered resulting in an estimated average dimethyl phthalate intake of 0. 0.2, 0.8 and 3.6 g/kg/day. Females (25-28 confirmed pregnancies/group) were observed daily during and after treatment for clinical signs. Maternal body weight and food and water consumption were measured throughout gestation. At necropsy (gestational day 20), maternal body, liver, kidney and gravid uterus were weighed. The number and status of uterine implantation sites were recorded. ... Neither 0.25% nor 1.0% imethyl phthalate treatment had significant maternal effects, with the exception of reduced water consumption during early treatment and increased food and water consumption following treatment (1.0% only). These results suggest that the apparent toxic effects of high-dose dimethyl phthalate on body weight may reflect the unpalatability of dimethyl phthalate in feed. The no-observed-adverse- effect level (NOAEL) for maternal toxicity was 1.0% dimethyl phthalate . There was no effect of treatment on embryo/fetal viability, average litter size, fetal body weight, or the incidence of external, skeletal or visceral malformations, even at doses producing significant maternal effects. Therefore, the NOAEL for developmental toxicity was 5.0% dimethyl phthalate . In summary, in this study in CD rats, maternal toxicity was observed at a dietary treatment level of 5.0% dimethyl phthalate . No developmental endpoints were affected under the conditions of this study. [R77] TCAT: ?The toxicity of dimethyl phthalate was evaluated in the mouse lymphoma L5178Y cell line in the presence and absence of rat liver S9 metabolic activation. All cultures were treated in duplicate with concentrations of 9.77, 19.50, 39.10, 78.10, 156.00, 313.00, 625.00, 1250.00, 2500.00 or 5000.00nl/ml, and growth was determined at 24 and 48 hours after initiation of the treatment. Under nonactivated conditions, dimethyl phthalate was soluble up to 5000nl/ml, and treatments at 625nl/ml were weakly toxic (69.9% of average solvent (acetone) control suspension growth). Treatments at 1250nl/ml were lethal to nonactivated cultures. Assays with metabolic activation were soluble up to 5000nl/ml, and treatments at 625nl/ml were weakly toxic (75.5% average relative suspension growth). One treatment at 1250nl/ml was lethal and a duplicate treatment at the same concentration was highly toxic (22.9% average relative suspension growth). [R78] ?The ability of dimethyl phthalate to induce morphological transformation was evaluated in the Balb/c3T3 A-31 mouse cell line (Cell Transformation Assay). Based on preliminary toxicity determinations (exposure time = 72hrs), dimethyl phthalate was tested at concentrations of 62.1, 248.5, 469.9, 745.3 or 931.6nl/ml resulting in a range of 91% to 20% relative survival. None of the treatments produced significantly greater transformation frequencies (95% confidence level) relative to the negative control (culture medium). [R79] ?The ability of dimethyl phthalate to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Dimethyl phthalate, diluted with acetone, was incompletely soluble at concentrations above 700nl/ml without activation and above 500nl/ml in the presence of metabolic activation. Nonactivated cultures treated in duplicate with 200, 300, 400, 500 and 600nl/ml produced a range of 101.7 - 52.5% relative growth. Since highly toxic treatments were not achieved, a second trial with 8 nonactivated cultures were treated in duplicate with 400, 500, 650 and 700nl/ml, producing a range of 98.1 - 26.9% relative growth. S9 activated cultures treated in duplicate with 100, 200, 400, 500 and 600nl/ml produced a range of 80.3 - 14.0% relative growth. Nonactivated cultures at 500nl/ml and 650nl/ml produced mutant frequencies significantly greater than the solvent control (acetone), however, a dose-dependent response was not observed. All of the activated cultures produced mutant frequencies significantly greater than the solvent control. [R80] ADE: *After oral administration phthalates are quickly absorbed in the gastrointestinal tract. ... /Phthalates/ [R81] */After/ oral admin of (14)C dimethyl phthalate to rats or mice, radioactivity was found in the blood and various tissues. Maximum values for radioactivity were observed within 1 hr. Tissue radioactivity was highest in the kidneys, followed in decreasing order by the liver, fat, and spleen. After 24 hr, 91% of the admin dose had been excreted in the urine and 4.1% in the feces. [R82] *The phthalic acid esters and/or their metabolites are readily absorbed from the intestinal tract, the intraperitoneal cavity, and the lungs. There is also evidence indicating that these esters can be absorbed through the skin. /Phthalate esters/ [R83] *The percutaneous absorption of a series of phthalate esters, dimethylphthalate, diethylphthalate, dibutyl phthalate, and di-(2-ethylhexyl) phthalate, was measured through human and rat epidermal membranes mounted in glass diffusion cells. The esters were applied directly to the epidermal membranes. Following application to the membranes, a lag phase followed by a linear phase of absorption was detected for each phthalate diester. Human skin was less permeable than rat skin for all four diesters. There appeared to be a trend to an increasing lag time with increasing molecular weight, but this relationship did not always hold true. The phthalate diesters were determined to have a 300 fold range of aqueous solubility and a wide range of lipophilicity. Once the diesters had contacted the human epidermal membrane, a slight increase in the permeability of the skin was detected. Relatively large changes in permeability were detected in the membrane following exposure. [R84] *Dimethyl phthalate when applied to human skin, was absorbed and appeared in the blood. [R65] *This study examined the extent of dermal absorption of a series of phthalate diesters in the rat. Those tested were dimethyl, diethyl, dibutyl, diisobutyl, dihexyl, di(2-ethylhexyl), diisodecyl, and benzyl butyl phthalate. Hair from a skin area (1.3 cm in diameter) on the back of male F344 rats was clipped, the 14(C)phthalate diester was applied in a dose of 157 mumol/kg, and the area of application was covered with a perforated cap. The rat was restrained and housed for 7 days in a metabolic cage that allowed separate collection of urine and feces. Urine and feces were collected every 24 hr, and the amount of (14)C excreted was taken as an index of the percutaneous absorption. At 24 hr, diethyl phthalate showed the greatest excretion (26%). As the length of the alkyl side chain increased, the amount of (14)C excreted in the first 24 hr decreased signficantly. The cumulative percentage dose excreted in 7 days was greatest for diethyl, dibutyl, and diisobutyl phthalate, about 50-60% of the applied (14)C; and intermediate (20-40%) for dimethyl, benzyl butyl, and dihexyl phthalate. Urine was the major route of excretion of all phthalate diesters except for diisodecyl phthalate. This compound was poorly absorbed and showed almost no urinary excretion. After 7 days, the percentage dose for each phthalate that remained in the body was minimal showed no specific tissue distribution. Most of the unexcreted dose remained in the area of application. These data show that the structure of the phthalate diester determines the degree of dermal absorption. Absorption maximized with diethyl phthalate and then decreased significantly as the alkyl side chain length increased. [R85] METB: *INVESTIGATIONS IN HEPATIC AND IN SMALL INTESTINAL MUCOSAL PREPN FROM THE RAT, FERRET, AND BABOON OF A SERIES OF DIALKYL PHTHALATES REVEALS THAT ALL ARE CONVERTED INTO CORRESPONDING MONOALKYL PHTHALATE. DIMETHYL, DIETHYL, DI-N-BUTYL, DI-N-OCTYL, DI-(2-ETHYLHEXYL), AND DICYCLOHEXYL PHTHALATES WERE STUDIED, AND THE RATES FOR THE GENERATION OF THESE METABOLITES WERE: BABOON GREATER THAN RAT GREATER THAN FERRET. THE SMALLER PHTHALATES UNDERWENT MORE EXTENSIVE HYDROLYSIS. IN RATS, THE RATES OF HYDROLYSIS WERE HIGHEST IN PRESENCE OF SMALL-INTESTINE CONTENTS, BUT MUCH LOWER WITH CECAL OR STOMACH CONTENTS. [R86] *IN VITRO STUDIES ON METABOLISM OF DIMETHYLPHTHALATE, DIBUTYL PHATHALATE, DI-N-OCTYL PHTHALATE ... AND DIETHYLHEXYL PHTHALATE BY RAT LIVER AND KIDNEY LIVER HOMOGENATES HAVE DEMONSTRATED THAT THE LOWER THE MOLECULAR WEIGHT OF PHTHALATE ESTER THE FASTER THE RATE OF METABOLISM. RATE OF DEGRADATION OF ESTERS BY RAT KIDNEY HOMOGENATES WAS RELATIVELY SLOW WHEN COMPARED WITH THAT BY LIVER HOMOGENATES. [R87] *... /DIMETHYL PHTHALATE IS/ BIOTRANSFORMED IN RATS INTO MONOMETHYL PHTHALATE (77.5%) AND PHTHALIC ACID (14.4%). [R88] *THE IN VITRO ABSORPTION OF DIMETHYL PHTHALATE WAS STUDIED USING AN EVERTED GUT SAC PREPN FROM THE RAT SMALL INTESTINE. MONOESTERS WERE ABSORBED IN SIGNIFICANTLY GREATER QUANTITY THAN THEIR CORRESPONDING DIESTERS. ESTERASES WITHIN THE MUCOSAL EPITHELIUM ACTIVELY HYDROLYZED 81.2% OF DIMETHYL PHTHALATE TO THE MONOESTER. [R89] *The compound /dimethyl phthalate/ was metabolized and excreted in the urine as monomethyl phthalate and phthalic acid. [R65] *A strain of Enterobacter aerogenes was able to utilize dimethylphthalate (1000 ppm) as the sole source of carbon. [R32, p. 94-12] */When/ dimethyl phthalate (1 mg/ml) was incubated for 16 hr at 37 deg C under an N2 atmosphere, in 20% (v/v) suspensions of rat intestinal contents (gut contents), in a phosphate-buffered Ringer's solution containing 1% (w/v) d-glucose, 60% of the dimethyl phthalate was metabolized. [R90] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): /FORMER USE:/ MITICIDAL AGENT FOR /CONTROL/ OF RICKETTSIAL INFECTIONS [R7] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dimethyl phthalate's production and use as a plasticizer and as an insect repellent may result in its release to the environment through various waste streams. If released to air, a measured vapor pressure of 3.08X10-3 mm Hg indicates this compound will exist solely as a vapor in the ambient atmosphere. Vapor-phase dimethyl phthalate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 28 days. Dimethyl phthalate absorbs light in the environmental spectrum indicating a potential for direct photolysis. If released to soil, measured Koc values ranging from 80 to 360 indicate dimethyl phthalate is expected to have moderate to high mobility. Volatilization from wet and dry soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.0X10-7 atm-cu m/mole and this compound's measured vapor pressure. Biodegradation is expected to be an important fate process in both soil and water. Dimethyl phthalate was readily biodegradable in unacclimated soil cultures. 15% of the 1 hour aqueous dimethyl phthalate concentration remained after 120 hours incubation in soil from Broome County, NY. Complete loss of dimethyl phthalate was observed within 3 days in Rhine river water at 20 deg C; at 4 deg C, biodegradation was negligible. In a river die-away test using Ogawa River water, 100% degradation occurred in 8 to 11 days; in clean and polluted seawater, 33% degradation in 14 days and 100% in 5 days was observed, respectively. Under anaerobic conditions, 0 to 30% of dimethyl phthalate's theoretical mineralization was reached after 96 days in marine sediment. If released into water, measured Koc values ranging from < 5.0X10+4 to 1.6X10+5 indicate this compound is expected to adsorb to suspended solids and sediment in the water column. Volatilization from water surfaces is not expected to occur based upon dimethyl phthalate's estimated Henry's Law constant. Measured BCFs ranging from 4.7 to 57 indicate that bioconcentration in aquatic organisms is low to moderate, not high. Depuration half-lives in bluegill sunfish were between 1 and 2 days. An estimated neutral hydrolysis half-life of 3.2 years at 30 deg C indicates that hydrolysis is not expected to be an important process. Occupational exposure to dimethyl phthalate may occur through inhalation and dermal contact with this compound at workplaces where dimethyl phthalate is produced or used. The general population may be exposed to dimethyl phthalate via inhalation of ambient air, ingestion of contaminated drinking water, and dermal contact with plastic products or insect repellants containing dimethyl phthalate. (SRC) NATS: *Dimethyl phthalate is a metabolite of Gibberella fujikuroi(1). [R91] ARTS: *Dimethyl phthalate's production and use as a plasticizer for nitrocellulose and cellulose acetate, resins, rubber, and in solid rocket propellants; in lacquers; plastics; rubber; coating agents; safety glass; molding powders; and as an insect repellent(1) may result in its release to the environment through various waste streams(SRC). [R92] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), measured Koc values ranging from 80 to 360(2) indicate that dimethyl phthalate is expected to have moderate to high mobility in soil(SRC). Volatilization of dimethyl phthalate from moist soil surfaces is not expected to be important(SRC) given an estimated Henry's Law constant of 2.0X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 3.08X10-3 mm Hg(3), and water solubility, 4.0X10+3 mg/l(4). Dimethyl phthalate is not expected to volatilize from dry soil surfaces based on its measured vapor pressure(3). Biodegradation studies using unacclimated soil cultures indicated that dimethyl phthalate was readily biodegradable(5). In soil-water systems, dimethyl phthalate was completely degraded after 72 hours in leachate sprayed soil; 15% of the 1 hour aqueous dimethyl phthalate concn remained after 120 hours incubation in Broome County, NY soil(6). In biological soil reactor studies, removal half-lives of 15, 51, 19.1, 72.2, and 123.5 days were measured for dimethyl phthalate in derby soil with sludge, derby soil with 66 g/kg slop oil sludge, Masham soil with 33 g/kg slop oil sludge, 86 g/kg wood preserving sludge, and 172 g/kg wood preserving sludge, respectively(7). [R93] *AQUATIC FATE: Based on a recommended classification scheme(1), measured suspended solids Koc values ranging from < 5.0X10+4 to 1.6X10+5(2,3), indicate that dimethyl phthalate is expected to adsorb to suspended solids and sediment in water(SRC). Dimethyl phthalate is not expected to volatilize from water surfaces(4,SRC) based on an estimated Henry's Law constant of 2.0X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 3.08X10-3 mm Hg(5), and water solubility, 4.0X10+3 mg/l(6). According to a classification scheme(7), measured BCFs of 4.7 to 5.4 in brown shrimp and sheepshead minnows(8) and 57 in bluegill sunfish(9), suggest that bioconcentration in aquatic organisms is low to moderate, not high(SRC). The depuration half-life in bluegill sunfish was between one and two days(9). The hydrolysis half-life of dimethyl phthalate is estimated to be 3.2 yr under neutral conditions at 30 deg C(10). In a river die-away test using Ogawa River water, Japan, 100% degradation occurred in 8 to 11 days; in clean and polluted seawater, 33% degradation in 14 days and 100% in 5 days was observed, respectively(11). 50% of the dimethyl phthalate biodegraded in 1 to 5 days and complete disappearance was obtained in 2 to 13 days in sediment-water systems obtained from 6 geographically different estuarine and freshwater sites bordering on the Gulf of Mexico(12). Biodegradation half-lives in the water alone ranged from 2 to 12 days, with complete disappearance occurring in 2 to 17 days with rapid degradation occurring after a lag period that varied from site to site(12). Complete loss of dimethyl phthalate was observed within 3 days in Rhine river water at 20 deg C; at 4 deg C, biodegradation was negligible(13). 0 to 30% of dimethyl phthalate's theoretical mineralization was reached after 96 days in marine sediment under anaerobic conditions(14). When dimethyl phthalate in pure water was irradiated with a UV lamp through a Pyrex filter (> 290 nm), its half-life was 12.7 hr(15). This was reduced to 2.8 hr in the presence of nitrogen dioxide(15). [R94] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dimethyl phthalate, which has a measured vapor pressure of 3.08X10-3 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase dimethyl phthalate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 28 days(3,SRC). Dimethyl phthalate absorbs light in the environmental spectrum(4) indicating a potential for direct photolysis(SRC). [R95] BIOD: *Microorganisms isolated from soil(1) and natural waters(2) are capable of utilizing dimethyl phthalate. After a 2.7 day lag, dimethyl phthalate was degraded in a shake-flask biodegradation test utilizing a soil/sewage inoculum with a half-life of 1.90 days(3). After 28 days, > 99% of the dimethyl phthalate had disappeared and 86% mineralization had occurred(3). It was completely degraded within 7 days in a static flask screening test with a wastewater inoculum(4). In two operating plants, 88 and 58% of the dimethyl phthalate was mineralized by the digested municipal sludge(5). In a river die-away test using Ogawa River water (Japan), 100% degradation occurred in 8 to 11 days in two samples(6). Degradation in ocean water was much slower with 20 and 32% degradation occurring in 2 weeks in ocean water and ocean water near a coastal factory, respectively(6). In waste water treatment plants, essentially 100% removal resulting from biodegradation was reported(7-9). [R96] *In a survey of publicly owned treatment works, an average removal of 97% was attributed to biodegradation(1). 50% of the dimethyl phthalate biodegraded in 1 to 5 days and complete disappearance was obtained in 2 to 13 days in sediment-water systems obtained from 6 geographically different estuarine and freshwater sites bordering on the Gulf of Mexico(2). Biodegradation in the water alone proceeded somewhat slower (half-life 2 to 12 days, complete disappearance in 2 to 17 days) with rapid degradation occurring after a lag period that varied from site to site(2). Dimethyl phthalate, 100 mg/l, reached 90 to 98% of its theoretical BOD after 4 weeks using an activated sludge inoculum(3). Biodegradation studies using unacclimated soil cultures indicated that dimethyl phthalate was readily biodegradable(4). 66% of the initial dimethyl phthalate concn, 1,032.6 ug/l, was removed in a microbial filter system after 24 hours; 81% removal was observed after 24 hours in a microbial filter system supporting the growth of the common reed(5). In soil-water systems, dimethyl phthalate was completely degraded after 72 hours in leachate sprayed soil; 15% of the 1 hour aqueous dimethyl phthalate concn remained after 120 hours incubation in Broome County, NY soil(6). In activated sludge die-away tests, > 90% degradation was achieved in 1 day; in a semi-continuous activated sludge test, > 81.0% degradation was observed after 24 hours(7). In biological soil reactor studies, removal half-lives of 15, 51, 19.1, 72.2, and 123.5 days were measured for dimethyl phthalate in derby soil with DAF sludge, derby soil with 66 g/kg slop oil sludge, Masham soil with 33 g/kg slop oil sludge, 86 g/kg wood preserving sludge, and 172 g/kg wood preserving sludge, respectively(8). > 96 to > 99% removal of dimethyl phthalate was observed at the Cedar Creek Wastewater Reclamation - Recharge Facilities, Nassau County, NY(9). [R97] *Aerobic degradation studies indicated primary degradation for the lower molecular weight phthalate esters (including dimethyl phthalate) occurred rapidly, typically exceeding 90% degradation within a week, even if unacclimated inocula were used(1). Complete loss of dimethyl phthalate was observed within 3 days in Rhine river water at 20 deg C; at 4 deg C, biodegradation was negligible(2). [R98] *ANAEROBIC: In an anaerobic gas production test, dimethyl phthalate reached 0 to 30% and 30 to 75% of its theoretical mineralization after 56 days incubation in anaerobic sewage sludge and a freshwater swamp, respectively; 0 to 30% of its theoretical mineralization was reached after 96 days in marine sediment under anaerobic conditions(1). Following a lag period of 1 week, dimethyl phthalate reached 88 and 58% of its theoretical methane production after 8 weeks incubation in 10% Adrian and Jackson sewage sludge, respectively(2). In anaerobic bioassays, dimethyl phthalate, at a concn of 20 mg/l, achieved 75 to 100% of its theoretical methane production over an extended incubation period of 50 to 100 days; at higher concns, 100 to 200 mg/l, dimethyl phthalate achieved 25 to 50% of its theoretical methane production over the same time period(3). During batch anaerobic digestion of sewage sludge, dimethyl phthalate, at concns of 0.5 to 10 mg/l, had a half-life of 78 hours(4). Under methanogenic conditions, dimethyl phthalate reached 41% of its theoretical gas production following a lag period of 16 days in an anaerobic digesting sludge from the UK(5). Dimethyl phthalate was also completely degraded when digested anaerobically in undiluted and 10% municipal sludge in 1 and 10 days, respectively, with 82% mineralization occurring in the 10% sludge(6). [R99] ABIO: *The rate constant for the vapor-phase reaction of dimethyl phthalate with photochemically-produced hydroxyl radicals has been estimated as 5.7X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 28 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The hydrolysis half-life of dimethyl phthalate is estimated to be 3.2 yr under neutral conditions at 30 deg C(2). The hydrolysis rate under acidic environmental conditions is estimated to be very low compared to neutral conditions(3). At pH 9, the estimated half-lives are 11.6 days and 25 days at 30 deg and 18 deg C, respectively(4). The rate of oxidation by alkoxy radicals in natural waters is negligible(5). Dimethyl phthalate absorbs light in the environmental spectrum(5) indicating a potential for direct photolysis(SRC). The half-life for direct photolysis in surface waters estimated from unpublished work is 3500 hr(3). When dimethyl phthalate in pure water was irradiated with a UV lamp through a Pyrex filter (> 290 nm), its half-life was 12.7 hr(6). This was reduced to 2.8 hr in the presence of nitrogen dioxide(6). Following 300 min irradiation (> 290 nm) in a 30% aqueous hydrogen peroxide solution, 7.4% of the initial 2.87 mg/200 ml dimethyl phthalate disappeared(7). [R100] BIOC: *Mean bioconcentration factors for dimethyl phthalate in brown shrimp and sheepshead minnows were 4.7 and 5.4 after 24 hr(1). Bluegill sunfish showed a bioconcentration factor of 57(2) which may be elevated because only carbon-14 was measured in the experiment and metabolites may be included with the parent compound(SRC). The depuration half-life was between one and two days(2). According to a classification scheme(3), these measured BCFs suggest that bioconcentration in aquatic organisms is low to moderate, not high(SRC). Bioaccumulation factors of 3.1 and 6.3 were measured in shrimp, Peneaus aztecus, following 1 day of exposure(4). [R101] KOC: *A suspended solids Koc of < 50,000 was calculated from the Kd assuming a 0.10 organic carbon fraction(1). Koc values ranging from 80 to 360 were calculated for dimethyl phthalate from its low carbon subsurface core sorption isotherms at different depths(3). A mean sediment log Koc value of > 5.2 was calculated from the mean dimethyl phthalate concentration in water and suspended particulate matter from Lake Yssel, The Netherlands(4). Adsorption of dimethyl phthalate is enhanced in the presence of salt: at a dimethyl phthalate concentration of 700 ug/l, 0.9 ug/g was adsorbed on suspended particulates in seawater, 0.6 ug/g was adsorbed on suspended particulates in 50% sea water, and < 0.2 ug/g was adsorbed on suspended particulates in distilled water(5). An average dimethyl phthalate removal of 79% was observed on a 14 m experimental overland flow slope(6). Relative to the average linear groundwater velocity 18% retardation was calculated for dimethyl phthalate in a natural gradient tracer test using an unconfined sandy aquifer, assuming an organic carbon content of 0.05%(7). According to a recommended classification scheme(8), these Koc values suggest that dimethyl phthalate is expected to have no to high mobility in soil(SRC). [R102] VWS: *The Henry's Law constant for dimethyl phthalate is estimated as 2.0X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 3.08X10-3 mm Hg(1), and water solubility, 4.0X10+3 mg/l(2). This value indicates that dimethyl phthalate is expected to be essentially nonvolatile from water surfaces(3,SRC). Dimethyl phthalate's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Dimethyl phthalate is not expected to volatilize from dry soil surfaces(SRC) based on a measured vapor pressure of 3.08X10-3 mm Hg(1). Less than 1% of dimethyl phthalate was lost in a sewage treatment plant by air stripping(4). [R103] WATC: *DRINKING WATER: Dimethyl phthalate was detected in three New Orleans drinking water plants 0.13 to 0.27 ppb(1). It was detected, but not quantified, in Philadelphia drinking water(2) and Kitakyushu, Japan tap water(3). Dimethyl phthalate was detected in treated drinking water from 6 of 14 sites tested in England, 5 drinking water sites were from rivers and 1 was from a groundwater source(4). Dimethyl phthalate was detected, not quantified, in finished drinking water from 1 of 3 treatment plants in Philadelphia, PA between 1975 and 1976; it was not detected in tap water from 1 hotel(5). Dimethyl phthalate was qualitatively detected in drinking water from Cincinnati, OH in Oct 1978(6). Dimethyl phthalate was detected in tap water from the Kitakyushu Municipal Institute of Environmental Health Sciences, Japan, at a concn of 8.8 parts per thousand million(7). [R104] *GROUNDWATER: Dimethyl phthalate was detected in water samples from two monitoring wells surrounding the Fort Devens, MA municipal wastewater infiltration system at an average concn of 0.10 ug/l(1). [R105] *SURFACE WATER: Dimethyl phthalate was detected, but not quantified, in the Merrimack River(1). Dimethyl phthalate was detected at 0.3 ppb in the Rhine River at Lobith, The Netherlands(2). Dimethyl phthalate was detected in Mississippi River water at concentrations of 2 and 5 parts per trillion at Cairo, IL 25 miles below the inflow of the Ohio River and 20 miles below Memphis, TN, respectively(3). Dimethyl phthalate was detected in 14 of 16 water samples from the River Mersey Estuary, UK; it was detected in the dissolved fraction in 81% of the samples at concentrations ranging from 48 to 973 ng/l and in the particulate fraction in 63% of the samples at concentrations ranging from 14.6 to 39 ng/g(4). Median dimethyl phthalate concentrations in 0.6% of U.S. ambient water STORET stations were < 10.0 ug/l(5). Dimethyl phthalate was detected in water samples collected near the Humber, Mersey, Tamar, Tees, and Tyne estuaries in May to June 1988 and Nov to Dec 1989 at concentrations of < 1 ng/cu dm(6). Water collected from the drum storage area in the "Valley of the Drums" near Louisville, KY contained dimethyl phthalate at a concentration of 18 ug/l(7). Dimethyl phthalate was detected in water samples collected from the River Mersey estuary, UK in Oct 1986 at concentrations ranging from 0.084 to 0.695 ug/l(8). [R106] *RAIN/SNOW/FOG: Dimethyl phthalate was detected, not quantified in the water phase of rain and snow in Norway(1). [R107] EFFL: *Mean effluent levels greater than 100 ppb occur from foundries (280 ppb), metal finishing (200 ppb), and the organic chemicals manufacturing/plastics (510 ppb) industries(1). Industries whose maximum effluent levels exceeded 1000 ppb were: Metal finishing (1200 ppb), foundries (3200 ppb), and nonferrous metals manufacturing (1300 ppb)(1). Dimethyl phthalate was not detected in urban runoff in the Nationwide Urban Runoff Program which included 86 samples from 19 cities across the USA(2). Fort Polk, La (secondary effluent) 0.77 ppb(3). Lake Superior, effluent from pulp and paper mill, detected as minor component(4). 75% of the groundwater samples from four U.S. rapid infiltration sites for primary and secondary municipal effluents contained dimethyl phthalate at concns ranging from 0.01 to 0.19 ppb, average 0.10 ppb(5). Median concns of dimethyl phthalate detected in 2.8% of U.S. industrial effluents were < 10.0 ug/l from all STORET stations(6). Dimethyl phthalate was identified as a component of Iona Island, Vancouver, British Columbia municipal wastewater and sludge, concn was not reported(7). Dimethyl phthalate was identified in a fly ash (municipal incinerator) water extract at 0.16 ng/g at pH 7(8). Dimethyl phthalate was identified in emissions from a waste incinerator plant in Germany at a concn of 0.32 ug/cu m(9). [R108] *Dimethyl phthalate was identified in raw wastewater collected from a dye manufacturing plant at 38 to 130 ppb; it was not detected in the final effluent(1). In a survey of publicly owned treatment works, dimethyl phthalate was detected at average concns of 576, 560, 13, 484, and 41 ug/l in the wastewater feed, primary effluent, secondary effluent, primary sludge, and secondary sludge, respectively(2). In a survey of 28 municipal water pollution control plants, dimethyl phthalate was detected in the secondary effluent of 1 plant at a concn of 2.60 ug/l(3). Dimethyl phthalate was detected in aqueous industrial effluent extracts collected between Nov 1979-81 in the following industrial categories (concentration in one effluent extract, ng/ul): paint and ink (786); and organics and plastics (156)(4). It was identified in effluent from a publicly owned treatment work located in an industrialized area of NJ at an estimated concn of 0.5 ppb(5). Dimethyl phthalate was detected in fly ash from 3 out of 5 municipal refuse incinerators in the U.S. at concns of 1, 2, and 12 ug/kg; it was also detected in a sample of fly ash/bottom ash at a concn of 430 ug/kg(6). Dimethyl phthalate was identified in leachate from a sanitary landfill in Barcelona, Spain(7). Dimethyl phthalate was detected in spent chlorination liquor from the bleaching of sulfite pulp at 0.3, 0.5, and 0.5 g/ton pulp for high lignin content pulp and low lignin content pulp after oxygen treatment, and after alkali treatment, respectively(8). [R109] SEDS: *Chester River (downstream from plasticizer manufacturer) near where it joins Chesapeake Bay (12 sites), not detected(1). Raccoon Creek (tributary of Delaware River) at Bridgeport, NJ (surficial bed material), trace(2). A sediment sample collected from the River Mersey, UK contained 140 ng/g dimethyl phthalate(3). Sediment samples from the Inner Harbor Navigation Canal and the Chef Menteur Pass, Lake Pontchartrain, LA contained 0.2 and 2.0 ng/g dry weight dimethyl phthalate, respectively(4). Dimethyl phthalate was detected in surface sediment samples collected from Speke and Runcorn in the River Mersey estuary, UK in Oct 1986 at concns of 0.130 and 0.150 ug/g dry weight, respectively(5). Sediment samples collected from Klang River water, Malaysia between Jan 1992 to Feb 1993 contained dimethyl phthalate at average concns ranging from not detected to 10.1 ng/g dry weight(6). [R110] ATMC: *URBAN/SUBURBAN: The average concn of dimethyl phthalate in air from Belgium was 101 ug/1000 cu m associated with particulates and 353 ug/1000 cu m in the gas phase(1). [R111] *INDOOR: Dimethyl phthalate was detected in indoor air at telephone office buildings and switching sites in Neenah, WI in 1985-86 and Newark, NJ in 1987 at concns ranging from 0.43 to 0.60 ug/cu m and 1.54 to 1.74 ug/cu m, respectively(1). It was also detected on the second floor of a telephone switching office in Neenah, WI in Mar, May, Dec 1987, Feb, April, and May 1988 at mean concns of 0.7, 1.0, 1.0, 0.9, 1.0, and 1.2 ug/cu m, respectively(2). [R112] PFAC: FISH/SEAFOOD CONCENTRATIONS: *A mean dimethyl phthalate concn of 8.4 ng/g wet weight was detected in oysters collected from the mouth of the Inner Harbor Navigation Canal, Lake Pontchartrain, LA in May to June 1980; clams collected from the mouth of the Rigolets, Lake Pontchartrain, LA during the same time period contained a mean dimethyl phthalate concn of 44 ng/g wet weight(1). [R113] OEVC: *Dimethyl phthalate was identified in limestone weathering crusts collected from a major cathedral in Sevilla, in southwestern Spain(1). [R114] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 42,188 workers (11,879 of these are female) are potentially exposed to dimethyl phthalate in the US(1). Occupational exposure to dimethyl phthalate may occur through inhalation and dermal contact with this compound at workplaces where dimethyl phthalate is produced or used(SRC). The general population may be exposed to dimethyl phthalate via inhalation of ambient air, ingestion of contaminated drinking water, and dermal contact with plastic products or insect repellants containing dimethyl phthalate(SRC). [R115] BODY: *Dimethyl phthalate was identified in a human atherosclerotic aorta at a concn of 40 ppb(1). [R116] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +2000 mg/cu m [R26, 114] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 5 mg/cu m. [R117] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 mg/cu m. [R26, 114] TLV: +8 hr Time Weighted Avg (TWA): 5 mg/cu m. [R118, 2002.29] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R118, 2002.6] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Dimethyl phthalate is included on this list. [R119] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 70,000 ug/l [R120] +(MN) MINNESOTA 70,000 ug/l [R120] CWA: +For the protection of human health from the toxic properties of dimethyl phthalate ingested through water and contaminated aquatic organisms, the ambient water criterion is determined to be 313 mg/l. [R121] +For the protection of human health from the toxic properties of dimethyl phthalate ingested through contaminated aquatic organisms alone, the ambient water criterion is determined to be 2.9 g/l. [R121] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R122] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2-Benzenedicarboxylic acid, dimethyl ester is included on this list. [R123] *A testing consent order is in effect for dimethyl phthalate for environmental effects testing. FR citation: 1/9/89. [R124] RCRA: *U102; As stipulated in 40 CFR 261.33, when dimethyl phthalate, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R125] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Dimethyl phthalate is found on List C. Case No: 3112; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Dimethyl phthalate; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R5] FDA: *Dimethyl phthalate is an indirect food additive for use only as a component of adhesives. [R126] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Collection in air by charcoal tube ... [R28] ALAB: *PRODUCT ANALYSIS IS BY GLC OR BY ALKALINE HYDROLYSIS AND ESTIMATION OF THE RESULTING PHTHALIC ACID BY STANDARD METHODS, OR BY ESTIMATION OF METHOXY GROUPS BY STANDARD METHODS. [R2] *AN EXTRACT IN ETHYL ETHER IS DISSOLVED IN ETHANOL AND THE SOLN WAS SHAKEN WITH ZINC AMALGAM REDUCING NITROGLYCERINE; FILTERED; AFTER PRECIPITATION OF DISSOLVED ZINC, A POLAROGRAM IS RECORDED. TETRAMETHYLAMMONIUM BROMIDE SOLN IS USED AS BASE ELECTROLYTE. [R10] *A RAPID LIQUID-LIQUID EXTRACTION PROCEDURE WAS DEVELOPED FOR ISOLATING POLYCYCLIC ORGANIC MATTER FROM COMPLEX MIXTURES OF ORGANIC COMPOUNDS PRESENT IN AN ALIPHATIC HYDROCARBON SOLVENT. PROCEDURE ENABLES ISOLATION OF DIMETHYLPHTHALATE. [R127] *RECOVERY EFFICIENCIES OF XAD RESINS AND RESIN MIXTURES WERE MEASURED USING DISTILLED WATER SAMPLES CONTAINING 13 ORGANIC POLLUTANTS, INCLUDING DIMETHYLPHTHALATE. HALOMETHANES, N-HYDROCARBONS, POLYNUCLEAR AROMATIC CMPD AND DIBENZOFURAN IN THE ORDER OF NG/L WERE IDENTIFIED USING A GAS CHROMATOGRAPH-MASS SPECTROMETER-COMPUTER SYSTEM. [R128] *Saponification with alcoholic potassium hydroxide and titration of the excess hydroxide. Alternatively, precipitation as lead phthalate with lead acetate solution, and determination of lead with dithizone, or condensation of the phthalic acid with resorcinol to give fluorescein, which is determined photometrically at 488 nm. [R129] *EPA Method 8060: Phthalate Esters This method provides gas chromatographic conditions for the detection of ppb levels. A 2-5 ug aliquot of the extract is injected into a gas chromatograph (GC) using the solvent flush technique, and compounds in the GC effluent are detected by an electron capture detector (ECD) or a flame ionization detector (FID). Ground water samples should be determined by ECD. For dimethyl phathalate, the method detection limit for ECD is 0.29 ug/l and for FID is 19 ug/l, the average recovery range for four measurements is 1.3-35.5 ug/l, and the limit for the standard deviation is 9.5 ug/l. [R130] *EPA Method 8250: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Packed Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water samples. Under the prescribed conditions, dimethyl phthalate has a detection limit of 1.6 ug/l, a range for the average recovery of four measurements of D-100.0 ug/l, and a limit for the standard deviation of 26.5 ug/l. [R130] *EPA Method 8270: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Capillary Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water. Under the prescribed conditions, dimethyl phthalate has a retention time of 14.48 min, a range for the average recovery of four measurements of D-100.0 ug/l, and a limit for the standard deviation of 23.2 ug/l. [R130] *EPA Method 606 A gas chromatography method for the analysis of dimethyl phthalate in municipal and industrial discharges, consists of a glass column. This method has a detection limit of 0.29 ug/l and an overall precision of 0.44 times the average recovery + 0.31 ug/l, over a working range of 0.7 to 106 ug/l. [R131] *EPA Method 625. A gas chromatography/mass spectrometry method for the analysis of dimethyl phthalate in municipal and industrial discharges. This method has a detection limit of 1.6 ug/l and an overall precision of 1.05 times the average recovery + 0.92 ug/l, over a working range of 5 to 1300 ug/l. [R131] *EPA Method 1625: An isotope dilution gas chromatography/ mass spectrometry method for the determination of semivolatile organic compounds in municipal and industrial discharges, this method is designed to meet the survey requirements of Effluent Guidelines Division (EGD) and the National Pollution Discharge Elimination System (NPDES). Under the prescribed conditions, unlabeled dimethyl phthalate has a minimum level of 10 ug/l and a mean retention time of 1273 sec. This method has an initial precision of 76-165 ug/l and an accuracy of 74-169 ug/l for the unlabeled compound. [R131] *EMSLC Method 506. Determination of Phthalate and Adipate Esters in Drinking Water by Liquid-liquid Extraction or Liquid-solid Extraction and Gas Chromatography with Photoionization Detection, CGCPID, drinking water, method detection limit 1.1 ug/l. [R132] *EMSLC Method 525.1. Determination of Organic Compounds in Drinking Water by Liquid-Solid Extraction and Capillary Column Gas Chromatography and Mass Spectrometry. Revision 2.2, CGCMS, drinking water, method detection limit 0.040 ug/l. [R132] *OSW Method 8061. Determination of Phthalate Esters by Gas Chromatography using a Capillary Column and Electron Capture Detector (GC/ECD), CGCECD, various, method detection limit 640 ng/l. [R133] *OSW Method 8410. Determination of Semivolatile Organics by using the Gas Chromatography/ Fourier Transform Infrared (GC/FTIR) with a Capillary Column - Base/Neutral Extractables, GCFTIR, various, identification limit 10 ug/l. [R133] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: AUTIAN J; TOXICITY AND HEALTH THREATS OF PHTHALATE ESTERS: REVIEW OF THE LITERATURE; ENVIRON HEALTH PERSPECT 4: 3-26 (1973). TOPICS DISCUSSED INCLUDE: CHEMISTRY AND PROPERTIES; GENERAL APPLICATIONS, BOTH INDUSTRIAL AND CONSUMER; INDUSTRIAL HEALTH PROBLEMS, OCCUPATIONAL TOXICITY; ACUTE, SUBACUTE AND CHRONIC TOXICITY OF DIMETHYL PHTHALATE; ABSORPTION, DISTRIBUTION, EXCRETION AND METABOLISM; TERATOGENIC, MUTAGENIC, AND CARCINOGENIC EFFECTS; CELLULAR TOXICITY (EFFECT ON MOUSE FIBROBLASTS AND HUMAN BLOOD FORMED ELEMENTS); USE IN CONSTRUCTION OF MEDICAL DEVICES; ENVIRONMENTAL PROBLEMS AND HUMAN HEALTH THREATS. IN GENERAL THE PHTHALATE ESTERS HAVE A VERY LOW DEGREE OF ACUTE TOXICITY TO ANIMALS AND MAN. 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USEPA, Risk Reduction Eng Lab, Cincinnati, OH USEPA/600/S2-89/026 (1990) (3) Canviro Consultants; Thirty Seven Municipal Water Pollution Control Plants, Pilot Monitoring Study Vol 1. Interim Report, Ontario Ministry of the Environment Water Resources Branch ISBN 0-7/29- 4900-X (1988) (4) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey, Contract No. 68-03-2867, Athens, GA: USEPA Environ Res Lab (1982) (5) Clark LB et al; Res J WPCF 63: 104-13 (1991) (6) Shane BS et al; Arch Environ Contam Toxicol 19: 665-73 (1990) (7) Albaiges J et al; Water Res 20: 1153-9 (1986) (8) Carlberg GE et al; Sci Total Environ 48: 157-67 (1986) R110: (1) Peterson JC, Freeman DH; Int J Environ Analyt Chem 18: 237-52 (1984) (2) Hochreiter JJ Jr; Chemical-quality reconnaissance of the water and surficial bed material in the Delaware River Estuary and adjacent New Jersey tributaries, 1980-81. 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R119: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R120: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R121: USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters p.vi (1980) EPA 440/5-80-067 R122: 40 CFR 302.4 (7/1/96) R123: 40 CFR 716.120 (7/1/96) R124: 40 CFR 799.5000 (7/1/96) R125: 40 CFR 261.33 (7/1/96) R126: 21 CFR 175.105 (4/1/96) R127: NATUSCH D FS, TOMKINS BA; ANAL CHEM 50 (11): 1429-34 (1978) R128: VAN ROSSUM P, WEBB RG; J CHROMATOGR 150 (2): 381-92 (1978) R129: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. Old Woking, Surrey, United Kingdom: Royal Society of Chemistry/Unwin Brothers Ltd., 1983.,p. A154/Oct 83 R130: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R131: 40 CFR 136 (7/1/87) R132: USEPA; EMMI. Environmental Monitoring Methods Index. Version 2.0 NTIS PB-95-502415 (1995) R133: USEPA; Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September 1994. Office of Solid Waste and Emergency Response, 401 M St., SW, Washington, DC 20460 (1994) RS: 103 Record 143 of 1119 in HSDB (through 2003/06) AN: 1643 UD: 200303 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLENE-THIOUREA- SY: *AI3-16292-; *Aperochem-ETU-22-; *4,5-DIHYDROIMIDAZOLE-2(3H)-THIONE; *4,5-DIHYDRO-2-MERCAPTOIMIDAZOLE-; *ETHYLENETHIOUREA-; *N,N-Ethylene-thiourea-; *1,3-ETHYLENETHIOUREA-; *1,3-ETHYLENE-2-THIOUREA-; *L'ETHYLENE-THIOUREE- (FRENCH); *ETU-; *IMIDAZOLE-2(3H)-THIONE, 4,5-DIHYDRO-; *IMIDAZOLIDINETHIONE-; *2-Imidazolidine-thione-; *IMIDAZOLINE-2-THIOL-; *2-IMIDAZOLINE-2-THIOL-; *IMIDAZOLINE-2(3H)-THIONE; *MERCAPTOIMIDAZOLINE-; *2-MERCAPTOIMIDAZOLINE-; *2-MERCAPTO-2-IMIDAZOLINE-; *MERCAZIN-I-; *NA-22-D-; *NA-22-; *NCI-C03372-; *Nocceler-22-; *PENNAC-CRA-; *RHENOGRAN-ETU-; *RHODANIN-S-62-; *Robac-22-; *Rodanin-S-62-; *Sanceller-22-; *SODIUM-22-NEOPRENE-ACCELERATOR-; *SOXINOL-22-; *Tetrahydro-2H-imidazole-2-thione-; *2-Thioldihydroglyoxaline-; *THIOUREA, N,N'-(1,2-ETHANEDIYL)-; *UREA,-1,3-ETHYLENE-2-THIO-; *USAF-EL-62-; *VULKACIT-NPV/C-; *WARECURE-C- RN: 96-45-7 RELT: 1170 [NABAM] (Metabolic Precursor); 1787 [ZINEB] (Metabolic Precursor); 4063 [MANEB] (Metabolic Precursor); 6792 [MANCOZEB] (Metabolic Precursor); 6705 [METIRAM] (Metabolic Precursor); 6060 [ETHYLENEBISDITHIOCARBAMIC ACID] (Metabolic Precursor) MF: *C3-H6-N2-S HAZN: U116; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by the action of ethylenediamine upon carbon disulfide in aqueous alcohol. [R1] *Prepn: C.F.H. Allen et al., Org. Syn. coll vol III, 394 (1955); G. Matolcsy, Ber. 101, 522 (1968). [R2, p. 647-8] FORM: *Commercial ethylene thiourea is available as a solid powder, as a dispersion in oil ... and "encapsulated" in a matrix of compatible elastomers. [R3, 435] MFS: *FIKE CHEMS, INC, NITRO, WV 25143 [R4] *Akron Chemical Co, 225 Fountain St, Akron, OH 44304, (216) 535-2108 [R5, p. V20 345] *Mobay Chem Corp, Mobay Road, Pittsburgh, PA 15205, (412) 777-2000 [R5, p. V20 345] OMIN: *MOST STUDIES HAVE BEEN ON MANGANESE SALT (MANEB), SODIUM SALT (NABAM) AND ZINC SALT (ZINEB) [R6] *Degradation product of ethylenebisdithiocarbamate fungicides such as mancozeb, maneb, zineb... [R2, p. 647-8] USE: *... IT WAS FOUND THAT ETU ... WAS PRESENT IN 28 DIFFERENT ETHYLENEBISDITHIOCARBAMATE COMMERCIAL PRODUCTS. [R6] *ACCELERATOR FOR NEOPRENE RUBBERS-EG, FOR COATED FABRICS, FOR EPICHLOROHYDRIN RUBBERS AND FOR CHLOROSULFONATED POLYETHYLENE RUBBERS. [R4] *Accelerator in synthetic rubber production. [R2, p. 647-8] *... Extensively used as an accelerator in the curing of polychloroprene (Neoprene) and other elastomers; may be present as a contaminant in the ethylene-bis-dithiocarbamate fungicides and can also be formed when food containing the fungicides is cooked. [R7] *Electroplating baths; intermediate for antioxidants, insecticides, fungicides, vulcanization accelerators, dyes, pharmaceuticals, synthetic resins. [R8] *The most commonly used vulcanizing agent for the polyethers not containing AGE /allyl glycidyl ether/, that is ECH /polyepichlorohydrin/ and ECH-EO /ethylene oxide coploymer/... [R9] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 4.54X10+7 G [R4] *(1980) PROBABLY GREATER THAN 4.54X10+5 G [R4] U.S. IMPORTS: *(1977) AT LEAST 4.5X10+6 G [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Needles, prisms from alcohol or amyl alcohol [R2, p. 647-8]; *White to pale-green crystals [R8] ODOR: *Faint, amine odor. [R10, 138] MP: *199-204 deg C [R8] MW: *102.16 [R2, p. 647-8] OWPC: *log Kow= -0.66 [R11] SOL: *Moderately sol in methanol, ethanol, ethylene glycol, pyridine, insol in acetone, ether, chloroform, benzene, ligroin [R2, p. 647-8]; *Soluble in ethanol; insoluble in ethyl ether and benzene. [R12]; *Slightly soluble at room temperature in methanol, ethanol, acetic acid, naphtha. [R8]; *2 g/100 ml water at 30 deg C; 9 g/100 ml water at 60 deg C; 44 g/100 ml water at 90 deg C [R2, p. 647-8] SPEC: *MAX ABSORPTION (ALCOHOL SOLVENT): 235 NM (LOG E= 4.18); SADTLER REF NUMBER: 5619 (IR, PRISM) [R13]; *IR: 18092 (Sadtler Research Laboratories IR Grating Collection) [R14]; *UV: 4571 (Sadtler Research Laboratories Spectral Collection) [R14]; *NMR: 7058 (Sadtler Research Laboratories Spectral Collection) [R14]; *MASS: 4011 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R14] OCPP: *ETHYLENE THIOUREA (ETU) IS AVAILABLE IN USA AS WHITE CRYSTALS OR FINELY-GROUND POWDER WITH A MELTING POINT OF 192 DEG C. IT IS ALSO AVAILABLE IN USA AND JAPAN AS A WHITE POWDER WITH A MELTING POINT ABOVE 195 DEG C. IT IS AVAILABLE IN USA AS WHITE POWDER CONSISTING OF 80% DISPERSION OF ETU IN OIL. [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Acrolein [R10, 138] DCMP: *When heated to decomposition it emits very toxic fumes of nitroxides and sulfoxides. [R16] SERI: *An eye irritant. [R16] EQUP: *The least preferred method /of personal protection/ is the use of personal protective equipment. This equipment, which may include respirators, goggles, gloves, and related items, should not be used as the only means to prevent or minimize exposure during routine operations. Exposure to ethylene thiourea should not be controlled with the use of respirators except: 1) during the time necessary to install or implement engineering or work practice controls; or 2) in work situations in which engineering and work practice controls are technically not feasible; or 3) for maintenance; or 4) for operations which require entry into tanks or closed vessels; or 5) in emergencies. [R3, 436] *Respirator selection: Only respirators approved by the NIOSH should be used. Refer to NIOSH Certified Equipment, December 15, 1975, NIOSH Pub #76-145 AND Cumulative Supplement June 1977, NIOSH Certified Equipment, NIOSH Pub #77-195. The use of faceseal coverlets or socks with any respirator voids NIOSH approvals. Quantitative faceseal fit test equipment (such as sodium chloride, dioctyl phthalate, or equivalent) should be used. Refer to "A Guide to Industrial Respiratory Protection", NIOSH Pub #76-189 for guidelines on appropriate respiratory protection programs. [R3, 437] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R17, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. [R10, 139] *Wear appropriate eye protection to prevent eye contact. [R10, 139] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R10, 139] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R10, 139] OPRM: *The most effective control of ethylene thiourea, where feasible, is at the source of contamination by enclosure of the operation and/or local exhaust ventilation. ... The process or operation should be enclosed with a slight vacuum so that any leakage will result in the flow of air into the enclosure. The next most effective means of control would be a well designed local exhaust ventilation system that physically encloses the process as much as possible, with sufficient capture velocity to keep the contaminant from entering the work atmosphere. To ensure that ventilation equipment is working properly, effectiveness (eg, air velocity, static pressure, or air volume) should be checked at least every 3 mo. System effectiveness should be checked soon after any change in production, process or control. ... A 3rd alternative is the isolation of employees ... by use of automated equipment operated by personnel observing from a closed control booth or room. [R3, 436] *Employees working in areas where ETU is manufactured, processed, handled, or stored should wash their hands before eating, drinking, smoking, or using rest room facilities during the work shift. No food or beverages should be stored, prepared, or consumed in areas where ETU is manufactured, processed, handled, or stored. Contaminated clothing should be removed before entering areas where food or beverages are consumed. Smoking should be prohibited in areas where ETU is manufactured, processed, handled, or stored in unsealed containers. Employees should shower or bathe and change clothing after the workday if any possible dermal exposure could have occurred. In many secondary uses of ETU, the dust hazard may be eliminated by the substitution of sheets or pellets of ETU (dispersed in a plastic material) for powdered ETU when it is used as a direct additive. [R18] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R17, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R17, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R17, 1979.11] *The worker should immediately wash the skin when it becomes contaminated. [R10, 139] *The worker should wash daily at the end of each work shift. [R10, 139] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R10, 139] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R10, 139] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. [R10, 139] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R17, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R17, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R17, 1979.13] CLUP: *Work areas, fixtures, equipment, etc, contaminated by ETU spills should be cleaned promptly. ETU powder on floors should be blotted with absorbing clay which, in turn, may be removed with a sweeping compound. An alkaline solution of hypochlorite will oxidize ETU into ethylene urea. Thus, a one to ten dilution of commercially available 5% hypochlorite solutions may be used to mop up areas contaminated with ETU. [R18] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R17, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U116, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R19] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R20] *Incineration: Proper incineration in a furnace with afterburner and scrubber. [R21] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R17, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R17, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R17, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R17, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R17, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated ethylene thiourea for carcinogenicity. According to their analysis, the weight-of-evidence for ethylene thiourea is group B2, which is based on (no data) evidence in humans and sufficient evidence in animals. As a group B2 chemical, ethylene thiourea is considered to be probably carcinogenic to humans. [R22] +Evaluation: There is inadequate evidence in humans for the carcinogenicity of ethylenethiourea. There is sufficient evidence in experimental animals for the carcinogenicity of ethylenethiourea. Overall evaluation: Ethylenethiourea is not classifiable as to its carcinogenicity to humans (Group 3). In making its evaluation, the Working Group concluded that ethylenethiourea produces thyroid tumors in mice and rats by a non-genotoxic mechanism, which involves interference with the functioning of the thyroid peroxidase, resulting in a reduction in circulating thyroid hormone concn and incr secretion of thyroid stimulating hormone. Consequently, ethylenethiourea would not be expected to produce thyroid cancer in humans exposed to concn that do not alter thyroid hormone homeostasis. An additional consideration of the Working Group, based on lack of genotoxicity of ethylenethiourea, was that the liver tumors in mice and benign tumors in rats were also produced by a non-genotoxic mechanism. Evidence from epidemiological studies and from toxicological studies in experimental animals provide compelling evidence that rodents are substantially more sensitive than humans to the development of thyroid tumors in response to thyroid hormone imbalance. [R23] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R17, 1979.23] *Workers to be informed of carcinogenic and teratogenic hazards; special attention to be given to thyroid function tests. /From table/ [R24] HTOX: *Exposed male workers in a rubber factory and an ethylene thiourea (ETU) manufacturing facility participated in a survey. Workers ranged in age from 26 to 62 years. Comparison subjects were obtained from workers who were not exposed to ethylene thiourea or related compounds. Thyroid function tests included measurement of total thyroxine, thyroid stimulating hormone, and thyroid binding globulin. Geometric means for thyroxine were 80.5 nanomoles per liter for mixers, 96.4 nanomoles per liter for process workers, and 105.7 nanomoles per liter for comparisons. Thyroid stimulating hormone concentration were within normal limits for all process workers and comparisons, with a range from 2.1 to 5.4 nanomoles per liter. Values for thyroxine in exposed workers were generally lower than in comparisons, particularly for mixers. Concentrations of thyroid binding globulin and the ratio between thyroxine and thyroid binding globulin were not different between exposed workers and comparisons and were within normal limits for all subjects. There was no evidence that thyroid function is severely affected by exposure to ethylene thiourea in the work place and no clinical evidence of any effect. [R25] NTOX: *Administration of a diet containing 5 ppm for 2 years produced thyroid hyperplasia in 28% of exposed rats, while a diet containing 125 ppm or more produced a high incidence of thyroid carcinoma. [R26] */215 MG/KG ORALLY FROM 7 TO 28 DAYS OF LIFE THEN 646 PPM; EXPT TERMINATED AT 82-83 WK/. INCIDENCE OF HEPATOMAS ... 14/16 (MALE) and 18/18 (FEMALE) IN (C57BL/6XC3H/ANF)F1 MICE AND 18/18 (MALE) and 9/16 (FEMALE) IN (C57BL/6XAKR)F1 MICE, COMPARED WITH 8/79 MALE AND 0/87 FEMALE AND 5/90 MALE AND 1/82 FEMALE NEG CONTROLS OF EACH STRAIN ... LYMPHOMAS WERE ALSO OBSERVED IN 3/18 MALE AND 4/16 FEMALE (C57BL/6XAKR)F1 MICE, COMPARED WITH 1/90 IN MALE AND 4/82 IN FEMALE CONTROLS. [R27] *ADMIN OF 175 OR 350 PPM TECHNICAL GRADE ETU (97%) IN DIET OF GROUPS OF 26 MALE AND 26 FEMALE CHARLES RIVER CD RATS FOR 18 MO, FOLLOWED BY ADMIN OF CONTROL DIET FOR 6 MO, PRODUCED HYPERPLASTIC GOITRE IN 17 MALES AND 13 FEMALES @ HIGH DOSE LEVEL AND IN 9 MALES AND 6 FEMALES AT LOW DOSE LEVEL. IN ADDN, THYROID CARCINOMAS ... IN 17 MALES (2 WITH PULMONARY METASTASES) and 8 FEMALES AT HIGH DOSE LEVEL AND ... 3 MALES AND 3 FEMALES AT LOW DOSE ... NONE IN ... CONTROLS. ... 1 FEMALE AT HIGH DOSE ... and 2 FEMALES AT LOW DOSE ... HAD SOLID-CELL ADENOMAS OF THYROID ... AND TOTAL OF 3 MALES AND 1 FEMALE HAD HYPERPLASTIC LIVER NODULES. [R28] *ETU FED TO RATS AT ... 50-750 PPM IN DIET ... 30-120 DAYS PRODUCED DECREASES IN BODY WT, INCREASES IN THYROID:BODY WT RATIO AND DECREASES IN UPTAKE OF (131)IODINE; EXTENT OF EFFECTS ... RELATED TO DOSAGE AND TIME. AT ... 500 and 750 PPM, MODERATE TO MARKED HYPERPLASIA OCCURRED IN THYROIDS, BUT NO EFFECT ... AT 50 PPM. [R28] *ETU WAS TERATOGENIC IN RATS AT DOSES THAT PRODUCED NO APPARENT MATERNAL TOXICITY OR FETAL DEATHS, SUGGESTING THAT TRANSPLACENTAL TRANSFER OF THE SUBSTANCE MAY TAKE PLACE. [R28] *... /INVESTIGATORS/ STUDIED /ETU/ ... IN RATS DURING SEVERAL PERIODS OF ORGANOGENESIS AT 10-80 MG/DAY. ABOVE 10 MG/KG, NEURAL TUBE CLOSURE DEFECTS, HYDROCEPHALUS AND OTHER MALFORMATIONS OF BRAIN WERE FOUND ALONG WITH KINKY TAILS AND LIMBS DEFECTS. [R29] *MICROBIAL STUDIES REVEALED WEAK MUTAGENIC ACTIVITY OF ETHYLENETHIOUREA (ETU) FOR SALMONELLA STRAIN TA1535. HOWEVER, CYTOGENETIC STUDIES IN CHINESE HAMSTER DON CELLS IN VITRO AND BONE MARROW CELLS OF RATS IN VIVO AND THE DOMINANT LETHAL STUDIES IN MICE FAILED TO REVEAL ANY MUTAGENIC EFFECT. [R30] *ETU INDUCED MUTATIONS OF BASE-PAIR SUBSTITUTION TYPE IN SALMONELLA TYPHIMURIUM TA1530 IN VITRO. [R31] *ETU WAS ADMIN TO RATS BY IP INJECTION, BY NASOGASTRIC TUBE AND IN DIET AND RATES OF HEPATIC RNA SYNTH DETERMINED. HIGH DOSES BY ANY ROUTES FAILED TO INHIBIT SYNTH OF NUCLEAR OR CYTOPLASMIC RNA. [R32] *PREGNANT CATS ADMIN ORALLY 0, 5, 10, 30, 60, OR 120 MG/KG STARTING ON DAY 16 OF GESTATION. 11/35 FETUSES FROM 6 DEAD CATS (4 FROM 30 MG/KG AND 1 EACH FROM 60 and 120 MG/KG GROUPS) WERE MALFORMED, WITH COLOBOMA, CLEFT PALATE, SPINA BIFIDA AND UMBILICAL HERNIA. [R33] *ETU AFFECTS RAT FETAL NERVOUS SYSTEM TRANSPLACENTALLY, CAUSING BRAIN TUMORS POSTNATALLY. RAT FETUSES TREATED WITH 80 MG/KG SHOWED DEFICIENCY OF NERVOUS TISSUE. PORTIONS OF BRAIN WERE EXENCEPHALIC AND CEREBELLUM WAS ABSENT WITH POOR DIFFERENTIATION OF CEREBRAL LOBES. [R34] *ADMIN OF ETHYLENE THIOUREA TO PREGNANT RATS @ 30 and 50 MG/KG ON DAYS 18-20 OF GESTATION GREATLY INCR THE NUMBER OF STILLBORN RATS. HIGHEST INCIDENCE OF DEAD PUPS AT BIRTH FROM DAMS ADMIN ETU ON 20TH DAY. PROGENY VIABILITY IMPAIRED. HIGH MORTALITY IN PUPS WAS ATTRIBUTABLE TO HYDROCEPHALUS. [R35] *THE EFFECT OF ETU ON MICROSOMAL ENZYMES WAS STUDIED BY MEASURING THE HEXOBARBITAL SLEEPING TIME OF MALE AND FEMALE RATS AFTER ADMIN IN SINGLE ORAL DOSES OF 20, 50, 100, AND 200 MG/KG OR IN THE DIET AT LEVELS OF 200 AND 300 PPM AND BY DETERMINING THE AMINOPYRINE-N-DEMETHYLASE AND ANILINE HYDROXYLASE ACTIVITIES IN LIVERS OF MALE RATS GIVEN SINGLE ORAL DOSES OF 20, 50, 100, AND 200 MG/KG. ETU INCR THE SLEEPING TIME AT ALL DOSE LEVELS 1 DAY AFTER SINGLE EXPOSURE, BUT THE INCR WAS SIGNIFICANT ONLY WITH 50, 100, AND 200 MG/KG IN MALES AND 200 MG/KG IN FEMALES. ALL DOSES CAUSED AN INITIAL INHIBITION OF AMINOPYRINE-N-DEMETHYLASE AND ANILINE HYDROXYLASE ACTIVITIES IN LIVERS OF MALE RATS, FOLLOWED BY A DOSE-RELATED INCR. [R36] *IN LAB ANIMALS ETU CAN CAUSE MYXEDEMA (THE DRYING AND THICKENING OF SKIN, TOGETHER WITH SLOWING DOWN OF PHYSICAL AND MENTAL ACTIVITY), GOITER AND OTHER EFFECTS RELATED TO DECR OUTPUT OF THYROID HORMONE. [R37] *Of 20 cmpd evaluated for their ability to induce sister chromatid exchanges in bone marrow and liver of male mice, the known mutagens 4-nitroquinoline 1-oxide, benzo(a)pyrene, benzidine, hexamethyl phosphoramide, and epichlorohydrin were positive. Ethylenethiourea was negative in the system. [R38] *Groups of 50 male and 50 female Sprague Dawley rats were fed diets containing 0, 75, 100, or 150 ppm ethylene thiourea (ETU) for 7 wk, at which time subgroups of 10 animals from each group were killed. Subsequent subgroups of 10, 10, and 20 animals were killed after an additional 2, 3, and 4 wk, respectively, on the control diet in order to examine whether the toxicological effects induced by ethylene thiourea were reversible. In both sexes, the mean body weight and feed consumption were significantly decreased in all treated groups, while the mean thyroid weight appeared to increase linearly with dose. Mean T4 (thyroxine) blood levels in animals fed 150 ppm ETU were significantly below those in controls. The magnitude of the changes in body weight, thyroid weight, and thyroxine blood levels observed during the first 7 wk of the study decreased after ETU was removed from the diet. [R39] *Ethylene thiourea suppressed primary and secondary immune responses in vivo /in mice/ at 460 mg/kg, and also weakly suppressed in vitro primary immune response and proliferation of /mouse/ lymphocytes by mitogens. [R40] *Ethylene thiourea (ETU) was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton S wild type males were treated with concentrations of ETU that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of ETU tested by injection (4900 ppm) and feeding (12,500 ppm) were negative in this assay. [R41] *Ethylene thiourea (ETU) was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Pregnant CD-1 mice (fifty per each dose group) were given 100, 200, 300, or 600 mg/kg/day ETU in water by gavage on days 6-13 of gestation and were allowed to deliver. Pup birth weight and litter size were reduced at 300 mg/kg/day ETU. At 600 mg/kg/day, the number of viable litters was reduced. [R42] *ETU is a mfr, processing, and metabolic product of the ethylene bisdithiocarbamate fungicides, incl nabam, manozeb, metiram, maneb, and zineb. ETU became an environmental issue when toxicological studies indicated that it may be goiterogenic, tumorigenic, and teratogenic to laboratory animals. ETU residues appeared on certain agricultural commodities sprayed with ethylene bisdithiocarbamate fungicides. These residues may result from the presence of ETU in the pesticide formulation or from the subsequent transformation either as a plant metabolite or as a by-product formed during processing of the crop. [R5, p. V21 289] *Sprague Dawley rat embryos were explanted on gestation day 10 and cultured for 48 hr in the presence of 40-200 mg/ml ethylene thiourea. This resulted in a dose related inhibition of growth and differentiation as assessed by crown rump length, protein and DNA content, and somite number and in an increase in the frequency of abnormalities. A variety of anomalies was produced, including fluid accumulation in the brain (hydrocephalus), decreased mandibular size, decreased telencephalon size, abnormal dorsiflexion, as well as subectodermal blisters on the tail and limb buds and maxilla. Frank malformations have been observed at these same sites, hydrocephalus, brachygnathia, kyphosis, limb and tail defects, cleft palate, in the term fetus in vivo. ... Osmolality of the exocoelomic fluid surrounding the embryo was measured after 48 hr of exposure to a concentration of ETU that caused nearly a 100% incidence of subectodermal blisters. Exocoelomic fluid was found to be significantly lower than that of control embryos. [R43] *Time-mated Swiss Webster mice were pretreated in separate experiments with phenobarbital (60 mg/kg/day sc on day 7-10 of pregnancy), SKF-525A (40 mg/kg ip on day 12 of pregnancy) or 3-methylchloanthrene (20 mg/kg/day on day 10-12 of pregnancy). On the day 12 of pregnancy (1 hr after SKF-525A or 3-methylchloanthrene treatment), one group each of pretreated mice was given a single oral dose of 1600, 2000, or 2400 mg/kg of ethylene thiourea (ETU) as a 5% concentrate in a 1.5% aqueous gelatin solution, which as a vehicle was given to other pretreated groups. The respective vol doses were 3.2, 4.0, or 4.8 ml/100 g body weight of vehicle alone. Maternal toxicity was observed in all groups given ETU, whether pretreated with metabolic modifiers or not. In the three experiments, treatment with ETU alone reduced fetal weight by 15% at 2400 mg/kg and 8% with the remaining 2 doses, and increased the incidence of resorptions (19-62% with the 2400 mg/kg dose, 8-59% at 2000 mg/kg, and 7-32% at the 1600 mg/kg dose). The significant defects with incidences ranges in three experiments were: hindpaw ectrodactyly, 2-6% at 1600 mg/kg, 4-20% at 2000 and 20-29% at 2400 mg/kg; and hindpaw syndactyle, 3% at 16 mg/kg, 6-14% at 2000, and 2-12% at 2400 mg/kg doses. Minor incidences of cleft palate and hindpaw polydactyly were observed. ... The 3-methylchloanthrene pretreatment reduced the ETU induced incidences of hindpaw ectodactyly, hindpaw syndactyle, and cleft palate at the 2000 and 2400 mg/kg doses. [R44] *Male Wistar rats and male A mice were given oral doses of 0, 50, or 75 mg/kg and 0, 50, 75, 100, 500, or 1,000 mg/kg ethylenethiourea (ETU), respectively, for 3 days. One, 3, or 8 days after the last dose, the animals were killed, and the livers were removed and homogenized. The homogenates were assayed for cytochrome p450 content and aniline hydroxylase and aminopyrine-N-demethylase activities. In rats, the activity aminopyrine-N-demethylase was reduced to 60 to 70% of the control values 24 hr after treatment. A decrease in aniline hydroxylase activity and cytochrome p450 content occurred on the third day after treatment. In mice, ETU caused an increase in cytochrome p450 content. The activity of aniline hydroxylase was significantly increased in animals receiving doses of 100 mg/kg or higher. [R45] *Oral administration to mice of ethylene thiourea (ETU) at single doses from 50 to 600 mg/kg caused a dose-dependent increase (up to 200 mg/kg) in hepatic microsomal aniline hydroxylase without affecting aminopyrine-N-demethylase activity or total microsomal cytochrome p450 content. Maximal (2.4 fold) enzyme increase was observed 24 hr after treatment by an ETU dose of 200 mg/kg and was followed by a return to control levels within 4 days. Pretreatment of mice with actinomycin-D completely prevented the increase of aniline hydroxylase. [R46] *Ethylene thiourea (ETU) was administered to Sprague Dawley rats ad libitum in drinking water at concentrations of 1, 5, 50, and 500 ppm for time intervals of 1, 2, and 5 days, 1 and 2 weeks, 1, 2, 4, and 8 months. Two additional groups of control rats received ETU free drinking water or a diet supplemented with 0.06% 3-methyl-4'-(dimethylamino)azobenzene. Electron microscopic evaluation of tissue samples could detect no changes in liver cell morphology of rats receiving 1, 5, or 50 ppm ETU for up to 8 months. By contrast, rats receiving 500 ppm ETU exhibited alterations in hepatic cell morphology after 4 months of exposure. These alterations included a dramatic increase in the amount of smooth endoplasmic reticulum with a concomitant reduction in rough endoplasmic reticulum, and a relocation of microbodies and mitochondria to the periphery of the smooth endoplasmic reticulum. [R47] *Sprague-Dawley rats were fed 75 or 100 ppm of ethylene thiourea in the diet for 90 days. On days 46 and 91, selected animals were killed and the thyroids were removed and weighed. Parameters of thyroid function, serum thyroxine, triiodothyronine, thyroid stimulating hormone, triiodothyronine uptake and (131)iodine uptake into the thyroid, were determined. Relative thyroid weights were slightly elevated in treated rats at both sampling times; however, the increase was significant only in females on day 46. Serum thyroxine was reduced in treated animals, the reduction being significant for males on both sampling dates. Serum triiodothyronine was significantly elevated in both sexes on day 91. Serum TSH was significantly elevated only in males. Triiodothyronine was significantly reduced in animals given the 100 ppm dose. There was no significant difference in uptake of 131(I) between treated and control animals. [R48] *The genotoxic behavior of false negative carcinogens was studied in Aspergillus nidulans. The purpose of the study was to investigate the ability of ethylene thiourea ... to induce chromosome malsegregation (mitotic segregation) in Aspergillus nidulans because the compound was regarded as false negative due to being ineffective or barely detectable in bacterial mutagenicity tests. The compound was tested for mitotic segregation either by treating germinating conidia with a liquid medium containing the compounds or growing the mold on an agarized medium supplemented with the compounds. An increase in the frequency of abnormal aneuploid colonies producing yellow euploid segregants showing whole chromosome segregation was regarded as a positive response. The compound was also assayed for induction of forward mutations and mitotic crossing over. Ethylenethiourea showed positive results in the mitotic segregation induction test, and did not increase the frequency of forward mutations or mitotic crossing over. [R49] *Ethylene thiourea (ETU) (1200 ppm in food for 15 days) protected rats against hepatic peroxidation of lipids. The effect was dose- and time-dependent, and appeared to be due to the presence of the SH group in ETU, since ethylene urea did not affect lipid peroxidation. Maneb, a fungicide, was not as effective as ETU, even though Maneb is metabolized to ETU. [R50] *Xenopus laevis embryos at yolk plug stage (Nieuoop and Faber stages 10-12) were exposed to various concn of fresh and 1-7 wk old nabam solns, ethylene thiourea, ethylene diamine, methyl isothiocyanate, thiocyanate, and combinations of some of these substances. thiocyanate, ethylene thiourea, and ethylene diamine (100-10,000 ug/l) were neither toxic nor teratogenic. [R51] *Ethylene thiourea, a degradation product of a widely used group of bisdithiocarbamate fungicides, is a potent teratogen in frog (Microhyla ornata) embryos. Embryos treated from the gastrula stage onwards for 24 hr (10-40 ppm) developed edema, an abnormal and wavy notochord, and other defects such as incomplete pigmentation. [R52] *In rabbits orally administered 37 or 74 mg ethylene thiourea (ETU)/kg or 100 or 200 mg zineb/kg, the changes in liver metabolism, the activities of alkaline phosphatase, leucine aminopeptidase, and p-glutamyltransferase, and the concentrations of iron, copper, and zinc in blood plasma and liver, followed a similar pattern but the changes were faster after ETU than after zineb administration. [R53] *Ethylenethiourea (ETU) is a degradation product from ethylenebisdithiocarbamates such as zineb and maneb which have been extensively used in food crops and ornamental plants. Administration of ETU to pregnant rats could induce anomalies in the visceral organs and the central nervous system. In an attempt to better understand the pathomechanism of teratogenesis in the central nervous system, we have studied the effects of ETU on the central nervous system, of rat fetuses. Pregnant Sprague Dawley (SD) rats were used and subjected to ETU. Various types of congenital malformations of the central nervous system are presented in rat fetuses including spinal dysraphism associated with hindbrain crowding, exencephaly, meningoencephalocele, microencephaly, hydraencephaly, and hydrocephalus. Each malformation depended on the gestation days of the ETU administration and dosages. [R54] *Nitrofen and ethylenethiourea (ETU), agents known to prenatally induce hydronephrosis in rats, were assessed for their effects on postnatal renal functional maturation. Both were given by gavage to pregnant Sprague Dawley rats on gestation day 11. Nitrofen was given at concentrations of 50 or 100 mg/kg, and ETU at 20, 40, or 60 mg/kg. Renal function was examined in the offspring from birth until after weaning, the period of renal functional maturation in the rat. Maximal urine concentrating ability was measured after desmopressin acetate (a vasopressin analog) challenge or water deprivation. Proximal tubule transport was measured in renal cortical slices. Various urinary parameters were measured. Both prenatal nitrofen and ETU exposure caused a large number of neonatal deaths at the high dose, and hydronephrosis was observed. The severity of the lesion increased with age. Hydronephrotic animals were deficient in urine concentrating ability, which became more pronounced after weaning. A few other urinary parameters were altered, but cortical function appeared to be unaffected. Rats prenatally exposed to nitrofen, but with apparently normal kidneys, were significantly compromised in their ability to produce a concentrated urine in response to desmopressin acetate challenge, on postnatal days 6 and 14. By postnatal day 30, they were not different from controls in urine concentrating response. Rats prenatally exposed to the higher doses of ETU, but with grossly normal kidneys, had significantly decreased plasma clearances of certain electrolytes early in life, but by postnatal day 27, they were not different from controls. Proximal tubule transport of PAH was increased on postnatal day 7 in ETU-exposed pups, but this effect did not persist. [R55] *Pregnant Sprague Dawley rats were utilized in this study. They were separated into two groups. In the control group, a single intragastric dose of distilled water was given on the 11th day of gestation. In the test group, a single intragastric dose of ethylenethiourea (ETU), 240 mg/kg was given on the same day of gestation. Embryos were recovered 12, 24, 36, and 48 hr after ETU and distilled water administration, and were prepared for scanning electron microscopy and light microscopy. The posterior neuropore of rat fetuses in the control group closed completely on gestation day 12.5. However, the closure of posterior neuropore in ETU induced fetuses is shown to have been disrupted 12 hr after ETU administration. Marked neural tissue overgrowth in the posterior neuropore resulted in neural fold eversion and finally produced a picture of lumbosacral myeloschisis on day 13 of gestation. Our observation implies that myeloschisis is induced by non-closure of the neural fold, not by reopening after its proper closure. [R56] *Applying the rat liver S9 fraction in rat whole embryo culture system, we studied teratogenicity of ethylenethiourea (ETU). Wistar Imamichi rat embryos were explanted at gestation day 11.5 and cultured for 48 hr including 2 hr pre-culture. ETU was added to the culture media at the concentration of 10 or 30 ug/ml with or without S9 for 17 hr. Embryos were removed from culture, yolk sacs opened, and then recultured for additional 29 hr drug-free media. Cyclophosphamide of 30 ug/ml was used for positive control, and Tyrode's solution for negative. Observations of embryos were carried out after 19 hr and 48 hr in culture. No anomalies were observed in the negative control group and in the cyclophosphamide group without S9 after 48 hr in culture. But, cyclophosphamide induced various anomalies in all embryos with S9 after 19 hr in culture. On the other hand, anomalies of the tail were observed dose-relatedly in embryos exposed to ETU without S9 from 19 hr in culture. All embryos exposed to ETU of 30 ug/ml showed anomalies of tail and limbs after 48 hr in culture. But, in the presence of S9, no anomalies were observed in embryos exposed to ETU at each concentration after 19 hr in culture and at 10 ug/ml after 48 hr in culture. But, the incidence of anomalies rose to 50% in embryos exposed to S9 at 30 ug/ml of ETU. However, the incidence of anomalies induced in ETU was significantly lower within S9 than without. Therefore, it is suggested that ETU is a more potent teratogen than its metabolites. [R57] *Embryos were studied either after direct exposure to ethylenethiourea (ETU) during incubation of embryo cultures or after maternal ETU dosing and subsequent embryonic development in utero with a view to assess the similarity of these two systems to produce hydrocephalus. Ten day old rat embryos were incubated with nutrient media containing 0-2.0 mM of ETU in a constant gaseous environment following a newly modified method. The cultured embryos showed hydrocephalus in the form of dilated rhombencephalon and other anomalies at the 1.5 and 2.0 mM of ETU after 26 hours of incubation. No anomalies were seen in the control group. In vivo studies, dilated rhombencephalon or hydrocephalus was not observed when dams, orally dosed with ETU on gestation day 10, were either killed daily for three postdosing days to examine embryos or killed at term to evaluate fetuses. This discrepancy in dilation that was incidental to the rhombencephalon in the two systems pointed out that the fourth ventricle of the cranial neural tube responded by dilation in vitro but remained unaffected in vivo following ETU exposure. ETU dosing of dams on the 12th day of pregnancy, when embryos are known to be sensitive to ETU-induced hydrocephalus, followed by serial gross examination of embryos, suggested that edema occurred in a generalized form but only after the appearance of both hydrocephalus (dilation primarily in mesencephalon) and, the previously reported, neuroblastic necrosis. [R58] *Teratogenic effect of ethylenethiourea (ETU) was examined in rat embryos developing in vitro and in vivo. In the in vitro experiment, rat embryos explanted at day 9.5 of gestation were cultured in rat serum together with ETU (0, 12.5, 25 and 50 ug/ml) for 48 hr. In the in vivo experiment, ETU (0, 25, 50 and 100 mg/kg) was administered orally to pregnant rats for 3 days from days 9 to 11 of gestation, and embryos were removed from the uterus 3 hr after the last administration. In both the in vitro and in vivo experiments ETU caused a retardation of the embryonic development as measured by yolk sac diameter, crown-rump length, number of somites and protein content. A variety of malformations such as stunted brain, open neural tube and small and irregular somites were produced. The incidence of malformations increased with an increased concentration or dose of ETU. The malformations produced in the in vitro experiment were comparable to those in vivo. In the in vitro experiment, ETU induced different type of malformations from those induced by sodium salicylate. These results suggest that the in vitro rat embryo culture method is useful for in vitro teratogenicity testing, and further, this system has the potential to provide much useful information about teratogenic mechanisms. [R59] *Pregnant Wistar rats were given a single ip injection of 30 mg/kg ethylenethiourea (ETU) on one of gestational days 8.5 to 20.5. After rearing to postnatal day 20, the offspring were sacrificed and their brains were excised. Numerous brains removed from the pups prenatally treated with ETU on any day from gestational days 12.5 to 20.5 showed dilation of lateral ventricle in various degrees. Histological examination revealed forking and stenosis of third ventricle in these brains. Since the degree of the third ventricular stenosis roughly corresponded to the degree of dilation of lateral ventricle, this anomaly is considered to be the main cause of congenital hydrocephalus induced in rats by prenatal ETU treatment. The embryological study showed that the ependymal lining of the third ventricle was partially denuded in the fetuses 24-48 hr after ETU treatment, and also that the denuded ependymal lining was never repaired during the following gestational days; instead, the ventricular walls fused laterally in the area where the ependymal lining had been denuded. [R60] NTOX: *In vivo/in vitro studies on rats showed that ethylenethiourea inhibited the differentiation of midbrain cells more severely than that of limb bud cells. In vitro studies using midbrain cell cultures, ethylenethiourea concentrations inhibited the production of differentiated foci by 50% in mouse cells, a rate 11 fold higher than that in rat cells. Differentiation of rat midbrain cells was also inhibited by the serum samples prepared from rats or mice dosed with up to 200 mg/kg of ethylenethiourea. However, differentiation of mouse cells was not inhibited by these animal serum samples. The concentration of ethylenethiourea in rat sera was only 2 fold higher than that in mice sera at 2 hr after dosing with 200 mg/kg. Therefore, the different sensitivity of the midbrains of these two species may be one reason that ethylenethiourea is teratogenic in rats but not in mice. [R61] NTXV: *LD50 Rat oral 1832 mg/kg; [R2, 648] *LD50 Mouse oral 3000 mg/kg; [R16] *LD50 Mouse ip 200 mg/kg; [R16] NTP: +... Ethylene thiourea (ETU) /was selected for study/ to determine its sensitizing potential when applied to mouse skin. Design ethylene thiourea ... greater than 99% pure, ... was prepared in ethylene glycol, which also served as the vehicle. Primary irritancy studies indicated that all concentrations of ethylene thiourea tested (up to 30%) were non-irritating when applied to the prepared dorsal surface of female B6C3F1 mice although concentrations greater than 10% were not soluble in the vehicle. A 0.5% solution of 1-fluoro-2,4-dinitrobenzene ... was used as a positive control. For the hypersensitivity test, groups of female B6C3F1 mice were sensitized to ethylene thiourea by application of 1.0%, 3.0%, or 10.0% ethylene thiourea for 5 consecutive days to a prepared dorsal surface site. Seven days after the last application, mice were challenged with a 10% concentration of ethylene thiourea on the dorsal and ventral sides of the left ear. Site preparation included intradermal injection of Freund's complete adjuvant in some mice. Mice were divided into 10 treatment groups of 8 mice per group ... . The irritancy response was determined by monitoring the extravasation of 125I- bovine serum albumin into the treated area. The contact hypersensitivity response was determined by monitoring the infiltration of 125I-iododeoxyuridine labeled cells into the challenge site in addition to the mouse ear swelling test. ... There were no treatment-related effects on survival or body weights. There was no evidence of skin irritation in the form of erythema or edema in any of the treatment groups. No statistically significant or dose-related hypersensitivity response was observed in mice sensitized with 1%, 3%, or 10% ethylene thiourea and challenged with 10% ethylene thiourea by either the radioisotopic method (data not shown) or the mouse ear swelling test ... . The positive response with 0.5% 1-fluoro-2,4-dinitrobenzene is shown for comparison ... . Under these experimental conditions, no statistically significant or dose-dependent contact hypersensitivity responses to ethylene thiourea were observed in mice following dermal exposure. [R62] TCAT: ?Ethylene thiourea (CAS # 96-45-7) was evaluated for subacute inhalation toxicity in groups of 20 male Swiss albino mice administered average daily whole-body exposures to dust atmospheres of 0 (negative control) or 13 (+/- 8) mg/cu m, 6 hours/day for 10 days over 2 weeks. Urine was collected from treated and control mice after the treatment phase of study and after a 13-day post-exposure recovery period for analysis of ethylene thiourea levels. Additionally, 5 mice of each group were sacrificed immediately after a 10th exposure and after the recovery phase for thyroid function and histopathological evaluations. Treated mice demonstrated no untoward clinical effects and no gross or microscopic pathology relative to controls throughout treatment and recovery phases of study. Likewise, thyroid function tests did not demonstrate an effect on thyroxine (T4) levels associated with treatment. An average 61 ppm residual ethylene thiourea was detected in the urine of test animals compared to 0.17 ppm in control mice after 9 exposures. The average urine level had returned to near that of control mice by the end of 13-day recovery. [R63] ?Ethylene thiourea (CAS # 96-45-7) was evaluated for subacute inhalation toxicity in groups of 10 male ChR-CD rats administered average daily whole-body exposures to dust atmospheres of 0 (negative control) or 13 (+/- 8) mg/cu m, 6 hours/day for 10 days over 2 weeks. Urine was collected from treated and control rats after the treatment phase of study and after a 13-day post-exposure recovery period for analysis of ethylene thiourea levels. Additionally, 5 rats of each group were sacrificed immediately after a 10th exposure and after the recovery phase for thyroid function and histopathological evaluations. Other than initial mild to moderate weight loss, treated rats demonstrated no untoward clinical effects and no gross or microscopic pathology relative to controls. Thyroid function tests indicated that treatment was associated with reduced thyroxine (T4) levels after a 10th exposure. Average values did not deviate significantly from those in untreated rats following 13-day recovery, although depressed thyroxine levels were noted to persist in 2/5 treated rats during post-exposure recovery. An average 125 ppm residual ethylene thiourea was detected in the urine of test animals compared to 0.22 ppm in the controls after 9 exposures. By the end of 13-day recovery, urine levels were comparable to controls. [R63] ?Ethylene thiourea (CAS# 96-45-7) was studied for reproductive effects in 50 CD-1 mice when administered by oral gavage for 8 days at 300 mg/kg/day on gestation days 7 through 14. Observations continued through day 3 postpartum. The dose was selected based on the results of a preliminary maximum tolerated dose test on groups of 10 nonpregnant, female CD-1 mice using doses of 75, 150, 300, 600 and 1200 mg/kg/day administered by oral gavage for 8 days. Compared to the water (vehicle) control, there were significantly fewer live pups per litter both at 12 hours postpartum (p=0.02) and at 3 days postpartum (p=0.03) in the test group as determined by ANOVA testing. Other reproductive effects,including the reproductive index (number of females bearing viable litters per number of pregnant females), maternal weight changes, and litter weights or litter weight changes were not statistically significant as determined by ANOVA testing or chi-square testing. [R64] ?Ethylene thiourea (CAS # 96-45-7) was evaluated for developmental toxicity in primigravida ChR-CD albino rats exposed dermally during organogenesis. An initial dermal approximate lethal dose (ALD) test for pregnant rats established that one dermal application of 1500 mg/kg in DMSO on gestational day 11 produced no increased embryomortality, but was associated with extensive skeletal malformation. In the current study, pregnant rats (number unspecified) were administered a total dose of 100 mg/kg (1/22 dermal ALD) upon clipped backs on each of gestational days 12 and 13. On gestation day 20 or 21, all rats were sacrificed for evaluation of uteri and fetuses, 2/3 of the fetuses evaluated for skeletal and 1/3 for visceral abnormalities. Treatment was not associated with effects on maternal weight gain or increased embryomortality; however, all 73 fetuses demonstrated marked skeletal malformation. A total dose of 100 mg/kg on gestational days 10 and 11 produced slight (5/83, short tail or fused ribs) skeletal malformations in the progeny of respective groups of treated dams. No effects were observed after a total dose of 50 mg/kg on gestation days 10 and 11. A data table for ethylene thiourea developmental toxicity study was omitted from this document, and no further protocol or results were provided. [R65] ?Clastogenic activity was evaluated in 3 cultures of RL1 rat liver cells per dose, exposed for 22 hours to ethylenethiourea at concentrations of 0, 50.0, 100, or 200.0 ug/ml of culture medium. Both positive (7,12-dimethylbenzanthracene) and solvent (dimethylsulfoxide) controls were used. No metabolic activation system was used. Cell division was arrested, and at least 310 metaphases from each test concentration were examined. Neither chromatid aberrations nor chromosome aberrations were increased significantly. The proportions of cells with chromatid aberrations were 0.0%, 0.6%, 0.0%, and 0.3% at 0.0, 50.0, 100.0, and 200.0 ug/ml, respectively. The proportions of cells at each treatment level with chromosome aberrations were the same, except the negative control showed 0.3% chromosomal aberrations. Although the positive control compound induced chromatid aberrations in 6.3% of cells, no chromosomal aberrations were induced. [R66] ?The mutagenicity of ethylene thiourea was evaluated in Salmonella tester strains TA98, TA100, TA1535, and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Ethylene thiourea was tested for mutagenicity at doses of 0, 0.01, 0.1, 0.5, 2, and 10 mg/plate using the preincubation method. The material caused a reproducible positive response (> 2.5 times the frequency of mutations in the controls) in bacterial tester strains TA100 and TA1535 (with and without activation) at a dose of 10 mg/plate. Ethylene thiourea did not cause a positive response in tester strains TA98 or TA1535, either with or without added metabolic activation. [R67] ADE: *Rapidly absorbed when ingested and disseminated throughout the body. Placental transfer is rapid. Strongly accumulated by thyroid tissue and slowly released. [R26] *Absorption, distribution, excretion, and metabolism of ethylenethiourea (ETU), a well known vulcanization accelerator of neoprene rubber and a thyroid carcinogen in rats, were studied in guinea pigs. Percutaneous absorption of ETU from intact skin was slow; uptake from abraded skin was rapid. Studies on tissue and organ distribution of radioactive ETU indicated that this compound was accumulated in the thyroid at the highest concentration, independent of the route of administration. Most absorbed ETU was excreted unchanged in the urine of guinea pigs. [R68] *... A DOSE OF 100 MG/KG WAS ADMIN ON DAY 12 OF GESTATION, AND PARENT CMPD AND UNKNOWN METABOLITE ... FOUND IN FETUSES; THEIR CONCN WERE MAXIMAL 2 HR AFTER DOSING. /ANOTHER/ ... GROUP /CLAIMED/ ON BASIS OF TISSUE AND FETAL ANALYSIS FOLLOWING ... /ADMIN OF/240 MG/KG ... ON DAY 11, 12, OR 15 OF GESTATION, THAT NEGLIGIBLE METABOLISM OBSERVED POINTS TO ETU BEING TERATOGEN PER SE. [R69] */AFTER ORAL ADMINISTRATION TO ADULT MALE MICE/ ... MAIN URINARY EXCRETION PRODUCT WAS UNCHANGED ETHYLENETHIOUREA. ETHYLENETHIOUREA IS A URINARY METABOLITE OF ZINEB, MANEB AND ETHYLENEBISDIISOTHIOCYANATO SULFIDE. [R70] *(14)C ETU WAS ADMIN BY STOMACH TUBE TO RHESUS MONKEYS AND SPRAGUE DAWLEY RATS. MAJOR ROUTE OF ELIMINATION WAS BY URINE WITH 47 and 64% OF TOTAL (14)C IN MONKEY URINE AND AVG OF 82% IN RAT URINE. FECES ACCOUNTED FOR LESS THAN 1.5%. TISSUE DISTRIBUTION ACCOUNTED FOR 21 and 28% OF ADMIN (14)C IN MONKEY, WHILE LESS THAN 1% IN RAT TISSUES. SKIN AND MUSCULATURE CONTAINED LARGEST AMT OF RADIOACTIVITY IN BOTH SPECIES. [R71] *Urinary and fecal excretion of ethylene thiourea (ETU), a metabolite of ethylene-bis-dithiocarbamic fungicides, was monitored in rats for 16 days after they were administered a single dose of zineb. After 48 hr, 86% of the excreted ETU was in the urine, 14% in the feces. Urinary excretion peaked at 24 hr after ingestion, at which time 52% of the total urinary ETU had been excreted. Low levels of ETU excretion continued in urine for the length of the study, by which time 51% of the zineb received was excreted as urinary ETU. Fecal ETU disappeared after 3 days. [R72] METB: *ADMIN OF (14)C ETU AT 4.0 MG/KG ORALLY PRODUCED METABOLITES IN 24 HR URINE OF MALE RATS. CMPD TENTATIVELY IDENTIFIED WERE IMIDAZOLINE, ETHYLENE UREA AND 4-IMIDAZOLIN-2-ONE. AFTER IV ADMIN OF ETU TO CATS AT 4 MG/KG, S-METHYL ETHYLTHIOUREA WAS ALSO PRESENT IN THE 24 HR URINE; IT COMPRISED 64% OF TOTAL URINARY METABOLITES. [R73] *DEGRADATION OF ETU IN MICE INVOLVED OXIDATION AT THE S ATOM, GIVING 2-IMIDAZOLIN-2-YL SULFENATE AS THE MAJOR PRODUCT. [R74] *DEHYDROGENATION OF ETHYLENEUREA, ETU METABOLITE, YIELDS 4-IMIDAZOLIN-2-ONE (IMIDAZOLONE) WHICH INDICATES MAJOR METABOLITES OF ETU ARISE AFTER OXIDATIVE DESULFURATION. HPLC ANALYSIS REVEALS PRESENCE OF THIOIMIDAZOLE INDICATING THAT DEHYDROGENATION CAN TAKE PLACE WITHOUT FORMING ETHYLENEUREA HIGH PERFORMANCE LIQUID CHROMATOGRAPHY REVEALED PRESENCE OF MINOR SULFUR CONTAINING METABOLITES, NAMELY THIOHYDANTOIN, N-METHYL ETU AND N-METHYL THIOIMIDAZOLE. THESE RESULTS INDICATE A COMPLEX PATTERN OF METABOLISM FOR ETHYLENETHIOUREA. [R75] *ANALYSIS OF URINE BY TLC AND RADIOCHROMATOGRAPHY REVEALED THAT THE MOUSE AND RAT METABOLIZED ETU BY DIFFERENT PATHWAYS. FURTHERMORE, THE MOUSE IS ABLE TO METABOLIZE ETU TO GREATER EXTENT THAN THE RAT. [R76] BHL: *240 MG/KG WERE ADMIN TO PREGNANT RATS AND MICE BY STOMACH TUBE. MATERNAL AND FETAL TISSUE LEVELS WERE SIMILAR AT 3 HR POST TREATMENT; THEREAFTER MOUSE (MATERNAL AND FETUS) SHOWED LESS ETU THAN RAT. /HALF-LIFE/ OF ELIMINATION FROM MATERNAL BLOOD WAS 9.4 FOR RAT AND 5.5 HR FOR MOUSE. [R76] INTC: *Joint administration of ETU and sodium nitrite produced dominant lethal mutations in mice, presumably by formation of N-nitroso-ethylenethiourea. ETU alone was ineffective. [R26] *Administered alone /in rats/, sodium nitrite did not produce any teratogenic response in full-term fetuses, whereas ethylene thiourea produced a high incidence of various anomalies. However, the combined dosing resulted in the elimination of almost all the anomalies. [R77] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethylene thiourea's production and use as vulcanizing agent and chemical intermediate may result in its release to the environment through various waste streams. It is also a degradation product of ethylenebisdithiocarbamate fungicides such as mancozeb, maneb, zineb and, therefore, use of these pesticides will result in ethylene thiourea's direct release to the environment. If released to air, an estimated vapor pressure of 5.01X10-3 mm Hg at 25 deg C indicates ethylene thiourea will exist solely as a vapor in the ambient atmosphere. Vapor-phase ethylene thiourea will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2 hrs. If released to soil, ethylene thiourea is expected to have very high mobility based upon an estimated Koc of 6.5. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.4X10-7 atm-cu m/mole. Biodegradation in soil may be an important environmental fate process however initial conversion of the compound to ethyleneurea is accomplished chemically. If released into water, ethylene thiourea is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3.1 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to ethylene thiourea may occur through inhalation and dermal contact with this compound at workplaces where ethylene thiourea and products containing this compound are produced or used. Pesticide food monitoring data show that the general population may be exposed to ethylene thiourea by the ingestion of some food products. (SRC) ARTS: *Ethylene thiourea's production and use as a vulcanizing agent and chemical intermediate(1) may result in its release to the environment through various waste streams(SRC). It is also an impurity and degradation product of ethylenebisdithiocarbamate fungicides such as mancozeb, maneb, zineb(2,3) and, therefore, use of these pesticides will result in ethylene thiourea's direct release to the environment(SRC). [R78] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 6.5(SRC), determined from a structure estimation method(2), indicates that ethylene thiourea is expected to have very high mobility in soil(SRC). Volatilization of ethylene thiourea from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.4X10-7 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Ethylene thiourea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.01X10-3 mm Hg(4). Biodegradation in soil may be an important environmental fate process(5), however initial conversion of the compound to ethyleneurea is accomplished chemically(6). [R79] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 6.5(SRC), determined from a structure estimation method(2), indicates that ethylene thiourea is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.4X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 73 days and 804 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 3.1(SRC), from its log Kow of -0.66(8) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation in suspended sediments may be an important environmental fate process based on soil results(9), however initial conversion of the compound in soil to ethyleneurea is accomplished chemically(10). [R80] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethylene thiourea, which has an estimated vapor pressure of 5.01X10-3 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase ethylene thiourea is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 hrs(SRC), calculated from its rate constant of 1.4X10-10 cu cm/molecule-sec at 25 deg C determined using a structure estimation method(3). [R81] BIOD: *AEROBIC: Ethylene thiourea was found to be readily degraded by soil microorganisms(1). Ethylene thiourea degraded rapidly in soil to ethyleneurea and then CO2; however, studies with autoclaved soil indicated that initial conversion was accomplished chemically(2) while further degradation to CO2 was accomplished microbially(6). Ethylene thiourea was shown to be biodegradable in oxic soil samples from a sandy locality in western Jylland, Denmark at a concn 125 ug/l, incubated in the dark at 23 deg C for 120 days(4). Oxic decay rates were 11.4 to 13.3 ug/kg soil-day(4). Degradation of 0.07 mg/kg 14C-labelled ethylene thiourea was determined in surface (19% in 24 hrs) coarse sandy field soil from Denmark(6). Subsurface rates were affected by soil depth; 16% and 23% at 100 and 60 cm depth, respectively, after 109 days. Following a 5 day incubation of 0.05 mg/l ethylene thiourea in activated sludge, 2.9% of applied amount was degraded(3). Ethylene thiourea, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(5). [R82] *ANAEROBIC: Ethylene thiourea was shown to be biodegradable in anoxic soil samples from a sandy locality in western Jylland, Denmark at a concn 125 ug/l, incubated in the dark at 23 deg C for 120 days(1). Anoxic decay rates were 2.41 to 3.80 ug/kg soil-day(1). [R83] ABIO: *The rate constant for the vapor-phase reaction of ethylene thiourea with photochemically-produced hydroxyl radicals has been estimated as 1.4X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Ethylene thiourea is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). Ethylene thiourea was found to be extremely stable to hydrolysis over the pH range 5-9 at 90 deg C for a 3 month period(2). Exposure of solutions of ethylene thiourea in deionized water to summer sunlight resulted in no photolysis(3). In the presence of dissolved oxygen and photosensitizers such as acetone or riboflavin, aqueous solutions of ethylene thiourea were rapidly photooxidized in sunlight to glycine sulfate and ethyleneurea products(3). Ethylene thiourea decomposed in sterilized drainage ditch waters when exposed to sunlight, but not in the dark, indicating that natural photosensitizers may be important in its environmental transformation(3). Ethylene thiourea was found to oxidize in 6 of 7 natural waters when exposed to light, but not in the dark(4). Initial conversion of ethylene thiourea in soil to ethyleneurea is accomplished chemically, perhaps by reaction with free radicals(5). [R84] *The rate constant for the vapor-phase reaction of ethylene thiourea with photochemically-produced hydroxyl radicals has been estimated as 1.4X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Ethylene thiourea is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R85] BIOC: *An estimated BCF of 0.500 was calculated for ethylene thiourea(SRC), using a log Kow of -0.66(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. BCF's of 0.7-2.8 and < 2.9 were measured for ethylene thiourea at concns of 0.5 and 0.05 mg/l, respectively(4). [R86] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for ethylene thiourea can be estimated to be 6.5(SRC). According to a classification scheme(2), this estimated Koc value suggests that ethylene thiourea is expected to have very high mobility in soil. Average Rf values of 0.96 (Norfolk sandy loam), 1.00 (Lakeland sandy loam), 0.96 (Hagerstown silty clay loam), 0.83 (Barnes clay loam) and 0.61 (Celeryville muck) were measured using soil TLC plates which is indicative of high mobility in all the soils except the muck which has intermediate mobility(3). [R87] VWS: *The Henry's Law constant for ethylene thiourea is estimated as 3.4X10-7 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that ethylene thiourea is expected to be essentially nonvolatile from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 73 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 804 days(SRC). Ethylene thiourea's estimated Henry's Law constant(1) indicates that volatilization from moist soil surfaces may not occur(SRC). Ethylene thiourea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.01X10-3 mm Hg(3). However, data collected from a microagroecosystem chamber indicate that small amounts of ethylene thiourea may volatilize from soil and plant surfaces(4). [R88] WATC: *GROUNDWATER: Ethylene thiourea was detected, not quantified in an unspecified percentage of 2,893 well samples collected from California in 1984(1). In a US study, only one of 183 wells tested positive for ethylene thiourea at a concn of 0.7 mg/l, location not specified(2). It has been estimated that 8470 (0.1%) rural wells in the US are contaminated with ethylene thiourea(3). Groundwater monitoring in the Netherlands resulted in 8 positive samples with a maximum concn of 1.5 ug/l(3). [R89] *DRINKING WATER: It has been found that 8470 (0.1%) rural wells in the US are contaminated with ethylene thiourea(1). [R90] ATMC: *URBAN/SUBURBAN: Ethylene thiourea was not detected in a US ambient air monitoring study of the USEPA designated 189 Hazardous Air Pollutants(1). [R91] FOOD: *Of 167 food samples analyzed (fruits, vegetables, grain products), which are produced in or imported by Canada, 56 contained detectable levels of ethylenethiourea with concentrations ranging from 0.01-0.150 ppm and a mean concn of about 0.02 ppm(1). Commercial tomato products (whole pack, paste, juice, soup, ketchup) contained residues ranging from < 0.01-0.03 ppm(2). Of 11 commercial grape products (jelly, jam, concentrates, drink, wine), 8 contained detectable levels of ethylene thiourea with positive concn ranging from < 0.01-0.06 ppm(3). Commercial tomatoe products purchased at random from grocery stores in Wilmington, DE contained no ethylenethiourea above the detection limit of 0.05 ppm(4). Commercial apples from a 1974 crop contained residues of less than or equal to 0.01 ppm(5). Levels of 0.01-0.21 ppm were detected in 282 samples of commercial food commodities in Japan(6). Ethylene thiourea was present in 13 of 55 samples of fresh fruit and vegetables collected in Sassari, Italy with concn ranging from 0.007 to 0.43 ppm(7). [R92] *30% of samples of fruits and vegetables from a Sydney, Australia wholesale market which tested positive for residues of ethylenebisdithiocarbamate were tested for ethylene thiourea; residues were below the detection limit of < 0.02 mg/kg(1). Some ethylene thiourea traces have been found in wine but at levels lower than 0.05 ppm(2). Ethylene thiourea was detected at a range of 0.02 to 0.01 mg/kg over 21 days in Bartlett pears after spraying with the fungicide zineb(3). Boiling treated pears resulted in a 3-6% conversion of ethylenebisdithiocarbamate to ethylene thiourea. It was not detected in commercially canned pears but was present in four of six samples of baby food pear puree(3). [R93] PFAC: PLANT CONCENTRATIONS: *... TREATMENT OF KALE AND LETTUCE WITH MANEB (WHICH CONTAINED ... ETU) AT RATE OF 1.09 KG AI/ACRE RESULTED IN INITIAL RESIDUES OF 0.6 MG/KG ETU, WHICH DECR TO UNDETECTABLE LEVELS WITHIN 7 DAYS AFTER APPLICATION. [R6] *RESIDUES OF ETU MONITORED IN TOMATOES AFTER APPLICATION OF SEVERAL EBDC FORMULATIONS FROM 1973-1977. AFTER SPRAYING WITH EBDC AT RECOMMENDED RATES, ETU WAS DETECTED AT LEVELS LESS THAN 0.05 PPM ON TOMATOES. BOILING OF SOME PRODUCTS DEMONSTRATED ADDITIONAL ETU FORMATION. RESIDUES IN TOMATO JUICE AND WHOLE PACK PRODUCTS, PREPD FROM TREATED TOMATOES IN 1ST 3 DAYS AFTER APPLICATION, RANGED FROM LESS THAN 0.01-0.17 PPM. [R94] OEVC: *ETHYLENETHIOUREA (14-15.75 MG/KG) WAS PRESENT IN SMOKE FROM TOBACCO CONTAINING 31.5-32 MG ETHYLENEBIS(DITHIOCARBAMATES)/KG (AS EXPRESSED IN CS2). NO ETHYLENETHIOUREA WAS DETECTED IN THE SMOKE FROM TOBACCO CONTAINING 1.3-4.5 MG ETHYLENEBIS(DITHIOCARBAMATE)/KG. [R95] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 10,749 workers (1,804 of these are female) are potentially exposed to ethylene thiourea in the US(1). The NOES Survey does not include farm workers. Workers preparing commercial formulations of mancozeb and dimethoate risk the potential for inhalation and dermal exposure to ethylene thiourea as the latter is an impurity of these two fungicides(2). Occupational exposure to ethylene thiourea may occur through inhalation and dermal contact with this compound at workplaces where ethylene thiourea is produced or used(SRC). The general population may be exposed to ethylene thiourea via inhalation of ambient air, ingestion of drinking water, and dermal contact with this compound and other consumer products containing ethylene thiourea. Pesticide food monitoring data show that the general population may be exposed to ethylene thiourea by the ingestion of some food products(SRC). [R96] BODY: *The mean levels of ethylene thiourea in urine were 1.5 and 0.9 ug/l for potato and pine nursery workers after the end of the exposure, respectively. The levels of ethylene thiourea in urine declined very slowly during the observation period. The range of ethylene thiourea levels in urine of potato field inspectors was 0-4.5 ug/l (mean 0.12 and SEM (standard error of the mean) 0.13 ug/l). [R97] *Workers preparing commercial formulations of mancozeb and dimethoate risk the potential for inhalation and dermal exposure to ethylene thiourea as the latter is an impurity of these two fungicides(1). Average ethylene thiourea concns in urine of factory workers who prepared these two fungicides ranged from 4.4 to 174.8 ug/g creatine(1). Personal air sample concns ranged from 0.2 to 0.5 ug/cu m for those workers preparing pesticide powder(1). [R98] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers ethylene thiourea to be a potential occupational carcinogen. [R10, 138] ADI: *FAO/WHO ADI: 0.002 mg/kg [R99] NREC: *NIOSH considers ethylene thiourea to be a potential occupational carcinogen. [R10, 138] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R10, 138] *Use encapsulated form. [R10, 138] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Ethylene thiourea is included on this list. [R100] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 15 ug/l [R101] +(ME) MAINE 3 ug/l [R101] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R102] RCRA: *U116; As stipulated in 40 CFR 261.33, when ethylenethiourea, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R103] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 5011. Analyte: Ethylene thiourea. Matrix: Air. Sampler: Filter (5-um PVC or mixed cellulose ester membrane). Flow Rate: 1 to 3 l/min: Sample Size: 200 liters. Shipment: Routine. Sample Stability: Unknown. [R104] *Air samples were collected with a portable pump on a membrane filter in the breathing zone of workers exposed to the pesticide. [R97] ALAB: *THE ETU CONTENTS OF ETHYLENEBISDITHIOCARBAMATE FORMULATIONS WERE DETERMINED BY REVERSED-PHASE CHROMATOGRAPHY. SAMPLES STORED UNDER NORMAL CONDITIONS HAVE SHOWN AN ETU INCR OF 30-80% AFTER 2 YR. [R105] *GAS-LIQUID CHROMATOGRAPHY AND LIQUID CHROMATOGRAPHY OF ETHYLENETHIOUREA IN FRESH VEGETABLE CROPS, FRUITS, MILK, AND COOKED FOODS. [R106] *AOAC Method 978.16. Ethylenethiourea pesticide residues. Gas chromatographic method. Applicable to potatoes, spinach, applesauce, and milk. [R107, 300] *AOAC Method 992.31. Ethylene Thiourea (ETU) in Water by Gas Chromatographic Method using Nitrogen-Phosphorus Detector. [R107, p. SUPP] *A reversed-phase high-pressure liquid chromatographic method was developed for the quantitative determination of ethylene thiourea, ... in wines. The results of analyses of Italian wines are presented. The method involves extraction of ethylene thiourea residues from wine with methylene chloride in the presence of sodium sulfate. The extracts are purified on alumina, and determined chromatographically at 244 nm without derivatization. The detection limit is 2 ng. [R108] *NIOSH Method 5011. Visible absorption spectrophotometry. Matrix: Air. For ethylene thiourea this method has an estimated detection limit of 0.75 ug/sample. The overall precision/RSD is 0.03%. Applicability: The working range is 0.05 to 0.75 mg/cu m for a 200 liter air sample. Interferences: Compounds containing a thiourea group will complex with the pentacyanoamineferrate reagent and may interfere with the ethylene absorbance band at 590 nm. [R109] *Ethylene thiourea on filter samples was dissolved in water and analyzed with high performance liquid chromatography and ultraviolet detection. [R97] *Paper and thin- layer chromatography ... Gas-liquid chromatography ... High performance liquid chromatography. [R110] *EMSLC Method 509. Determination of Ethylene Thiourea (ETU) in Water Using Gas Chromatography with a Nitrogen-Phosphorus Detector. Minimum detection limit= 2.7 ug/l. [R111] *EMSLC Method 533. Determination of Benzidines and Nitrogen-Containing Pesticides in Water by Liquid-Liquid Extraction and Reverse Phase High Performance Liquid Chromatography, Particle Beam, and Mass Spectrometry. Revision 1.1. [R111] *EPA-B Method PMD-MAU. Determination of Ethylenethiourea (ETU) in Ethylene bis(dithiocarbamate) Fungicides by Gas Chromatography with Thermal Conductivity Detector. [R111] *FDA Method 232.4. Determination of Ethylenethiourea (ETU) in Ethylene bis(dithiocarbamate) Fungicides by Gas Chromatography with Thermal Conductivity Detector. [R111] *FDA Method 242.1. Organonitrogen Residues General Method for Nonfatty Foods Including Acetone Extraction and Isolation in Organic Phase. [R111] CLAB: *A METHOD IS DESCRIBED FOR ISOLATION, IDENTIFICATION, AND DETERMINATION OF THIOUREAS IN RAT PLASMA BY HIGH-PERFORMANCE LIQ CHROMATOGRAPHY WITHOUT DERIVATIZATION. [R112] *Urine samples were evaporated, and pretreated with silica gel and aluminum. Ethylene thiourea in the purified urine samples was analyzed with high pressure liquid chromatography (HPLC) and UV detection. [R97] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Ethylene thiourea in F344/N Rats and B6C3F1 Mice Technical Report Series No. 388 (1992) NIH Publication No. 92-2843 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 715 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R3: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R4: SRI R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 47 (1974) R7: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 978 R8: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 472 R9: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V8 (93) 1087 R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R11: Govers H et al; Chemosphere 15: 383-93 (1986) R12: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-198 R13: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-347 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 765 R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 45 (1974) R16: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1910 R17: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R18: Nat'l Research Council Canada; Ethylene Thiourea: Criteria for the Assessment of Its Effects on Man p.110 (1980) NRCC No. 18469 R19: 40 CFR 240-280, 300-306, 702-799 (7/1/90) R20: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (1981) EPA 68-03-3025 R21: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 192 R22: USEPA; Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to Cercla Section 102 (Final) p.40 (1988) EPA/600/8-89/053 R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 79 403 (2001) R24: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 1390 R25: Smith DM; Brit J Indus Med 41 (3): 362-66 (1984) R26: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-314 R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 48 (1974) R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 49 (1974) R29: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 638 R30: TERAMOTO S ET AL; MUTAT RES 56 (2): 121-39 (1977) R31: SCHUEPBACH M, HUMMLER H; MUTAT RES 56 (2): 111-20 (1977) R32: AUSTIN GE, MOYER GH; RES COMMUN CHEM PATHOL PHARMACOL 23 (3): 639 (1979) R33: KHERA KS, IVERSON F; TERATOLOGY 18 (3): 311-14 (1978) R34: MORRISSEY RE, MOTTET NK; NEUROTOXICOL 2 (1): 125-62 (1981) R35: LEWERENZ HJ, BLEYL DW R; ARCH TOXICOL (SUPPL 4): 292-5 (1980) R36: LEWERENZ HJ, PLASS R; ARCH TOXIKOL (SUPPL 1, TOXICOL ASPECTS FOOD SAF): 189-92 (1978) R37: STEIN HP ET AL; AM IND HYG ASSOC J 39 (6): A34-36 (1978) R38: Paika IJ et al; Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep Int Collab Program): 673-81 (1981) R39: Arnold DL et al; Toxicol Appl Pharmacol 67 (2): 264-73 (1983) R40: Teshima R et al; Eisei Shikensho Hokoku (100): 44-8 (1982) R41: Woodruff RC et al; Environ Mutagen 7: 677-702 (1985) R42: Hardin BD et al; Teratog Carcinog Mutagen 7: 29-48 (1987) R43: Daston GP et al; Teratol 35 (2): 239-45 (1987) R44: Khera KS; J Toxicol Environ Health 13 (4-6): 747-56 (1984) R45: Lewerenz HJ, Plass R; Arch Toxicol 56 (2): 92-5 (1984) R46: Meneguz A, Michalek H; Arch Toxicol 9: 346-50 (1986) R47: Moller PC et al; J Environ Pathol Toxicol 6 (5-6): 127-42 (1986) R48: O'Neil WM, Marshall WD; Pest Biochem Physiol 21 (1): 92-101 (1984) R49: Crebelli R et al; Mutat Research 172 (2): 139-49 (1986) R50: Amaral JD et al; Rev Farm Bioquim 21 (2): 183-87 (1985) R51: Birch WX, Prahlad KV; Arch Environ Contam Toxicol 15 (6): 637-45 (1986) R52: Ghale HV; Geobios 13 (2-3): 2-5 (1986) R53: Villa P et al; Acta Med Rom 22 (3): 292-310 (1984) R54: Hung CF et al; Proc Natl Sci Counc Repub China Part B Life Sci 10 (2): 127-136 (1986) R55: Daston GP et al; Fundam Appl Toxicol 11 (3): 401-15 (1988) R56: Hung CF; Proc Natl Sci Counc Repub China (B) 12 (3): 124-8 (1988) R57: Iwase T et al; Teratol 40 (6): 661 (1989) R58: Khera KS; Teratol 39 (3): 277-85 (1989) R59: Nakaura S et al; Teratol 40 (6): 684 (1989) R60: Takeuchi IK, Takeuchi YK; Senten Ijo 30: 121-32 (1990) R61: Tsuchiya T et al; Toxicol Appl Pharmacol 109 (1): 1-6 (1991) R62: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of Ethylene Thiourea (CAS No. 96-45-7) Contact Hypersensitivity Studies in Female B6C3F1 Mice, NTP Study No. IMM90009 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 19, 2002 R63: E I Dupont De Nemours and Co; Subacute Inhalation Toxicity Study (Final Report); 11/26/91; EPA Document No. 88-920000410; Fiche No. OTS0534861 R64: Bioassay Systems Corporation; Determination of the Reproductive Effects in Mice of Nine Selected Chemicals (1983), EPA Document No. 40-8336210, Fiche No. OTS0506158 R65: E I Dupont De Nemours and Co; 01/01/84; Embryotoxicity in Rats and Rabbits from Application of Chemicals to Skin During Organogenesis; EPA Document No. 878213803; Fiche No. OTS0206452 R66: Shell Chem. Co.; The Activity of 27 Coded Compounds in the RL1 Chromosome Assay (1989), EPA Document No. 86-890000950, Fiche No. OTS0520388 R67: Imperial Chemical Industries Ltd.; Mutagenicity Testing with Salmonella Typhimurium Strains on Plates, of Gases, Liquids and Solids for Imperial Chemical Industries Limited with Attachments. (1976), EPA Document No. 86-890000437, Fiche No. OTS0520485 R68: Teshima R et al; Eisei Kagaku 27 (2): 85-90 (1981) R69: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 488 R70: JORDAN LW, NEAL RA; BULL ENVIRON CONTAM TOXICOL 22 (1-2): 271-77 (1979) R71: ALLEN JR ET AL; RES COMMUN CHEM PATHOL PHARMACOL 20 (1): 109-16 (1978) R72: Camoni I et al; Med Lav 75 (3): 207-14 (1984) R73: IVERSON F ET AL; TOXICOL APPL PHARMACOL 52 (1): 16-21 (1980) R74: SAVOLAINEN K, PYYSALO H; J AGRIC FOOD CHEM 27 (6): 1177-81 (1979) R75: LAWRENCE J, MARSHALL W; TOXICOL APPL PHARM 48 (1): A11 (1979) R76: RUDDICK JA ET AL; TERATOL 16 (2): 159-62 (1977) R77: Khera KS; Food Chem Toxicol 20 (3): 273-78 (1982) R78: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons, p. 472 (1997) (2) IARC; Some anti-thyroid and related substances, nitrofurans and industrial chemicals. Lyon, France: Inter Agency Res Cancer 7: 47 (1974) (3) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co., Inc. pp. 647-8 (1996) R79: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Neely WB, Blau GE; Environmental Exposure from Chemicals Boca Raton, FL: CRC Press pp. 31 (1985) (5) Johannesen H et al; Sci Total Environ 191: 271-6 (1996) (6) Kaufman DD, Fletcher DL; Abstr Am Chem Soc 165th Natl Mtg Dallas, TX (1973) R80: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Govers H et al; Chemosphere 15: 383-93 (1986) (9) Johannesen H et al; Sci Total Environ 191: 271-6 (1996) (10) Kaufman DD, Fletcher DL; Abstr Am Chem Soc 165th Natl Mtg Dallas, TX (1973) R81: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Neely WB, Blau GE; Environmental Exposure from Chemicals Boca Raton, FL: CRC Press pp. 31 (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R82: (1) Lyman WR, Lacoste RJ; Environ Qual Saf Suppl p. 67 (1975) (2) Kaufman DD, Fletcher DL; Abstr Am Chem Soc 165th Natl Meeting Dallas TX (1973) (3) Freitag D et al; Chemosphere 14: 1589-1616 (1985) (4) Jacobsen OS, Bossi, R; FEMS Microbiol Rev 20: 539-44 (1997) (5) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Johannesen H et al; Sci Total Environ 191: 271-6 (1996) R83: (1) Jacobsen OS, Bossi R; FEMS Microbiol Rev 20: 539-44 (1997) R84: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Cruickshank PA, Jarrow HC; J Agric Food Chem 21: 333 (1973) (3) Ross RD, Crosby DG; J Agric Food Chem 21: 335 (1973) (4) Ross RD, Crosby DG; Environ Toxicol Chem 4: 773 (1985) (5) Kaufman DD, Fletcher DL; Abstr Am Chem Soc 165th Natl Meeting Dallas TX (1973) R85: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R86: (1) Govers H et al; Chemosphere 15: 383-93 (1986) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R87: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Helling CS, Thompson SM; Soil Sci Soc Am Proc 38: 80-5 (1974) R88: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Neely WB, Blau GE; Environmental Exposure from Chemicals. Boca Raton, FL: CRC Press pp. 31 (1985) (4) Nash RG, Beall LM; J Agric Food Chem 28: 322 (1980) R89: (1) Berteau PE, Spath PP; ACS Symp Ser 315(Evaluation Pestic groundwater): 423-35 (1986) (2) Barrett MR; ACS Symp Ser 630(Herbicide Metabolism in Surface water and Groundwater): 200-225 (1996) (3) Beitz H et al; in Chem Plant Prot. Borner H, ed. Germany: Springer-Verlag. 9(Pest Surf Ground Water): 2-56 (1994) R90: (1) Briskin JS; pp. 143-54 in Mech Pestic Mov Groundwater. CRC Press (1994) R91: (1) Kelly TJ et al; Environ Sci Technol 28: 378-87 (1994) R92: (1) Pecka Z et al; Pestic Monit J 8: 232 (1975) (2) Ripley BD, Cox DF; J Agric Food Chem 26: 1137 (1978) (3) Ripley BD et al; J Agric Food Chem 26: 134 (1978) (4) Pease HL, Holt RF; J Agric Food Chem 25: 561 (1977) (5) Onley JH et al; J Assoc Off Anal Chem 60: 1105 (1977) (6) Uno M et al; Shokuhin Eiseigaku Zasshi 21: 392 (1980) (7) Alamanni U et al; Boll Chim Unione Ital Lab Prov Parte Sci 33(S1): 43 (1982) R93: (1) Ahmad, N et al; J AOAC Inter 78: 1238-43 (1995) (2) Cabras P et al; Rev Environ Contam Toxicol 99: 84-117 (1987) (3) Ripley BD, Simpson CM; Pesti Sci 8: 487-91 (1977) R94: RIPLEY BD, COX DF; J AGRIC FOOD CHEM 26 (5): 1137-43 (1978) R95: MESTRES R ET AL; TRAV SOC PHARM MONTPELLIER 40 (1): 9-14 (1980) R96: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Aprea C et al; J Toxicol Environ Health A 53: 101-19 (1998) R97: Savolainen K et al; Arch Toxicol (Suppl) 13: 120-23 (1989) R98: (1) Aprea C et al; J Toxicol Environ Health A 53: 101-19 (1998) R99: FAO/WHO; Pesticide Residues in Food - 1988 Evaluations Part 1 - Residues p.240 Plant Prod Protect Paper 93/1 (1988) R100: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R101: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R102: 40 CFR 302.4 (7/1/99) R103: 40 CFR 261.33 (7/1/99) R104: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5011-1 R105: VAN DAMME JC ET AL; J CHROMATOGR 206 (1): 125-31 (1981) R106: ONLEY JH ET AL; J ASSOC OFF ANAL CHEM 60 (5): 1105-10 (1977) R107: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R108: Lazzarini C et al; Chim Ind 62 (12): 923-26 (1980) R109: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R110: Bottomley P et al; Res Rev 95: 45-89 (1985) R111: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R112: KOBAYASHI H ET AL; J CHROMATOGR 207 (2): 281-85 (1981) RS: 104 Record 144 of 1119 in HSDB (through 2003/06) AN: 1646 UD: 200302 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: FORMIC-ACID- SY: *ACIDE-FORMIQUE- (FRENCH); *ACIDO-FORMICO- (ITALIAN); *ADD-F-; *AI3-24237-; *AMEISENSAEURE- (GERMAN); *AMINIC-ACID-; *BILORIN-; *COLLO-BUEGLATT-; *COLLO-DIDAX-; *FEMA-No-2487-; *FORMIRA-; *FORMISOTON-; *FORMYLIC-ACID-; *HYDROGEN-CARBOXYLIC-ACID-; *KWAS-METANIOWY- (POLISH); *Kyselina-mravenci- (Czech); *METHANOIC-ACID-; *MIERENZUUR- (DUTCH); *MYRMICYL- RN: 64-18-6 MF: *C-H2-O2 SHPN: UN 1779; FORMIC ACID IMO 8.0; FORMIC ACID STCC: 49 313 20; Formic acid HAZN: U123; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *(A) By treatment of sodium formate and sodium acid formate with sulfuric acid @ low temperatures and distilling in vacuo, (b) by acid hydrolysis of methyl formate, (c) as a by-product in manufacturing of acetaldehyde and formaldehyde. [R1] *DIRECT SYNTHESIS OF FORMIC ACID FROM WATER AND CARBON MONOXIDE ... CAN BE IMPROVED BY OPERATING AT HIGH PRESSURE AND IN THE PRESENCE OF COPPER HALIDES OR MINERAL ACID CATALYSTS. [R2] *FORMIC ACID IS MAINLY PRODUCED AS A BY-PRODUCT OF LIQUID-PHASE OXIDATION OF HYDROCARBONS TO ACETIC ACID. [R3] *... /A/ ... PROCESS, DESIGNED AT THE RCA LABORATORIES IN PRINCETON, NJ, CARBON DIOXIDE IN WATER IS ELECTROCHEMICALLY REDUCED TO FORMIC ACID LIBERATING OXYGEN AT THE ANODE. [R4] IMP: *Specifications of technical grade of formic acid (max): < 0.8 wt% acetic acid; < 20 ppm chlorides; < 5 ppm heavy metals; < 3 ppm iron; and < 10 ppm sulfates. Commercial grade have the same specifications but contain no acetic acid. Pharmaceutical grade: 0.4% acetic acid; 0.5% water; 5% toluene; 5% chlorides; 5% heavy metals; 3% iron; 10% sulfates. /From table/ [R5] FORM: *GRADES: TECHNICAL: 85%; 90%; CP; FCC. [R1] +Usually available as 90% aqueous solutions. [R6, p. 49-73] *Grades: 89-91% for 90% grade; > 98% for technical grade; > 99.5% for pharmaceutical grade. /From table/ [R5] MFS: *Hoechst Celanese Corporation, Hq, Route 202-206 North, Somerville, NJ 08876, (908) 231-2000; Chemical Group, Commodity Chemicals, PO Box 819005, 1601 West KBJ Freeway Dallas, TX 75381-9005; Production site: Pampa, TX 79065 [R7] OMIN: *METHOD OF PURIFICATION: RECTIFICATION. [R1] *... WHEN SUFFICIENTLY DILUTED ... CAN INCREASE THE VITALITY OF YEAST ... [R8] *UNION CARBIDE /DISCONTINUED FORMIC ACID PRODUCTION/ IN 1983. CELANESE ... IS NOW THE ONLY USA FORMIC ACID PRODUCER. [R9, 1984] *The only significant U.S. producer of formic acid is Hoechst-Celanese which operates a butane oxidation process. [R10, p. V11 956] USE: *MFR OF FUMIGANTS [R1] *ACIDULATING AGENT IN TEXTILE DYEING AND FINISHING; LEATHER TANNING; IN PREPARATION OF WIRE STRIPPING COMPOUNDS; NICKEL PLATING BATHS; COAGULANT FOR RUBBER LATEX [R11] *DECALCIFIER; REDUCER IN DYEING WOOL FAST COLORS; DEHAIRING AND PLUMPING HIDES; ... ELECTROPLATING; COAGULATING RUBBER LATEX, AID IN REGENERATING OLD RUBBER; ALSO IN CHEM ANALYSIS [R12, 663] *Animal feed additive, food preservative, flavor adjunct [R13, 4903] *METAL SALTS MADE FROM FORMIC ACID INCLUDE NICKEL, CADMIUM, AND POTASSIUM FORMATES. THE SALT MADE IN LARGEST VOLUME IS NICKEL FORMATE, USED IN THE PREPARATION OF SUPPORTED NICKEL CATALYSTS [R9, 1984] *IN SITU PREPARATION OF PERFORMIC ACID FROM 90% HYDROGEN PEROXIDE AND FORMIC ACID. PERFORMIC ACID IS USED AS THE EPOXIDIZING AGENT IN THE PRODUCTION OF EXPOXIDIZED SOYBEAN OIL PLASTICIZERS [R9, 1984] *REPORTED USES: NON-ALCOHOLIC BEVERAGES: 1.0 PPM; ICE CREAM, ICES: 5.0 PPM; CANDY: 5.0-18 PPM; BAKED GOODS: 5.0-6.1 PPM. [R14] *DYEING AND FINISHING OF TEXTILE; PREPN OF ORG ESTERS; MFR OF INSECTICIDES; REFRIGERANTS; SOLVENT FOR PERFUMES; LACQUERS; BREWING (ANTISEPTIC); SILVERING GLASS; CELLULOSE FORMATE; ORE FLOTATION; VINYL RESIN PLASTICIZERS; [R1] *Several commercial paint strippers contain up to 15% formic acid. [R15] *The largest single use of formic acid is as a silage additive. This market it well developed in Europe but scarcely exists in the United States. If applied to freshly cut grass prior to ensilation, the nutritional value of the ensuing silage is enhanced. [R10, p. V11 957] *... In the synthesis of aspartame and in the manufacture of formate esters for flavor and fragrence applications. [R10, p. V11 957] +MEDICATION (VET) CPAT: *55% USED IN TEXTILE DYEING AND FINISHING; 15% AS AN INT FOR FORMATES; 10% IN LEATHER TANNING; AND 20% IN MISC APPLICATIONS (1965) [R11] *TEXTILE DYEING AND FINISHING, 21 PERCENT; PHARMACEUTICALS, 20 PERCENT; RUBBER INTERMEDIATE, 16 PERCENT; LEATHER AND TANNING TREATMENT, 15 PERCENT; CATALYSTS, 12 PERCENT; MISCELLANEOUS (INCLUDING OIL WELL ACIDIZING), 18 PERCENT (1985) [R9, 1985] PRIE: U.S. PRODUCTION: *(1972) 2.13X10+10 GRAMS [R11] *(1974) 2.84X10+10 GRAMS [R11] *(1983) 1.86X10+10 g (est) [R9, (1984)] *The U.S. market for formic acid is relatively small (ca 30,000 ton/yr) by world standards. [R10, p. V11 956] U.S. IMPORTS: *(1972) 8.59X10+7 GRAMS [R11] *(1975) 2.28X10+6 GRAMS [R11] *(1984) 1.26X10+10 G [R16] *(1986) 13,096,852 LB [R17] U.S. EXPORTS: *(1984) 2.76X10+9 G [R18] *(1987) 196,921 LB [R19] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R1]; +Colorless liquid [Note: Often used in an aqueous solution]. [R20] ODOR: *PUNGENT, PENETRATING ODOR [R21, 44]; +Pungent, penetrating odor. [R20] TAST: *SOUR [R22] BP: *100.5 DEG C [R12, 663] MP: *8.4 DEG C [R12, 663] MW: *46.02 [R12, 662] CORR: *Corrosive to metals [R23] CTP: *Temp 588 K [R24, p. 6-57] DEN: *1.220 @ 20 DEG C/4 DEG C [R12, 662] DSC: *pK = 3.75 @ 20 deg C [R24, p. 8-45] HTC: *254.6 kJ/mol @ 25 deg c (liquid); 300.7 kJ/mol @ 25 deg C (gas) [R24, p. 5-76] HTV: *20.10 kJ/mol @ 25 deg C [R24, p. 6-113] OWPC: *Log Kow= -0.54 [R25] PH: *STRONG ACID IN AQ SOLN (pKa= 3.76, compared with 4.76 for acetic acid) [R26] SOL: *MISCIBLE WITH ALCOHOL ETHER, GLYCEROL [R12, 663]; *Miscible with water [R12, 663]; *Very soluble in acetone [R24, p. 3-166]; *Dissolves to the extent of about 10% in benzene, toluene, and xylenes, and to a lesser extent in aliphatic hydrocarbons. [R10, p. V11 952]; *Miscible with ethyl acetate and methanol. [R10, p. V11 952] SPEC: *MAX ABSORPTION (UNDILUTED): 205 NM (E= 165) [R27]; *Index of refraction: 1.3714 @ 20 deg C/D [R24, p. 3-166]; *IR: 15 (Sadtler Research Laboratories IR Grating Collection) [R28]; *NMR: 6653 (Sadtler Research Laboratories Spectral Collection) [R28]; *MASS: 15 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R28] SURF: *37.13 mN/m @ 25 deg C [R24, p. 6-151] VAPD: *1.59 (AIR= 1) [R29, 1776] VAP: *42.59 mm Hg @ 25 deg C (calculated from experimentally derived coefficients) [R30] EVAP: *2.1 (butyl acetate= 1) [R31, 1981.2] VISC: *1.607 mPas @ 25 deg C [R24, p. 6-241] OCPP: *STRONG REDUCING AGENT [R12, 662] *BULK DENSITY 10.16 LB/GAL @ 20 DEG C [R1] *DENSITY OF SATURATED AIR: 1.03 [R29, 1776] *Heat of Fusion: 12.72 kJ/mol [R24, p. 6-128] *Heat capacity: 99.0 J/mol-K @ 25 deg C [R24, p. 6-142] *Dielectric constant: 57.9 @ 20 deg C [R10, p. V11 952] *May act both as an acid and as an aldehyde because the carboxyl is bound to a hydrogen rather than an alkyl group [R32] *Ionization potential: 11.33 eV [R24, p. 10-215] *Concentration in saturated air: 80 g/cu m @ 20 deg C [R33] *Henry's Law constant = 1.67X10-7 atm cu m/mol @ 25 deg C [R34] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R35] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R35] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R35] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R35] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R35] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R35] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R35] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R35] FPOT: *OPEN FLAMES AND OTHER SOURCES OF IGNITION SHOULD NOT BE ALLOWED IN ... VICINITY OF ACID, PARTICULARLY WHEN IT IS AT TEMP ABOVE 69 DEG C. [R21, 45] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, incl self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms and waist should be provided. No skin surface should be exposed. [R6, p. 325-55] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R6, p. 325-55] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R6, p. 325-55] FLMT: +% BY VOL OF 90% SOLN: LOWER, 18; UPPER, 57 [R6, p. 325-55] FLPT: +156 deg F (69 deg C) (closed cup); 90% soln: 122 deg F (50 deg C) (closed cup) [R6, p. 325-55] *138 deg F, open cup [R36] AUTO: +1004 deg F (539 deg C); 90% soln: 813 deg F (434 deg C) [R6, p. 325-55] FIRP: +Use water spray, dry chemical, "alcohol resistant" foam, or carbon dioxide. Use water spray to keep fire-exposed containers cool. [R6, p. 49-72] *If material on fire or involved in fire: Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, carbon dioxide or dry chemical. Use water spray to knock-down vapors. [R37] TOXC: *Toxic vapor generated in fires. [R36] *Toxic gases and vapors (such as carbon monoxide) may be released in a fire involving formic acid. [R31, 1981.2] REAC: *The slow decomposition in storage of 98-100% formic acid with liberation of carbon monoxide led to rupture of the sealed glass containers. In absence of gas leakage, a full 2.5 l bottle would develop a pressure of over 7 bar during 1 yr at 25 deg C. Explosive decomposition of formic acid on a clean nickel ... surface was studied, using deuteroformic acid. A full 1 l bottle of 96% formic acid burst when the ambient temp fell to -6 deg C overnight and the contents froze and expanded. Gas pressure from previous partial decomposition may also have contributed. [R38, 150] */Aluminium/ ... reduces the acid (itself a reducant) with incandescence. [R38, 24] *During prepn of ... /peroxyformic acid/ by a patented procedure involving interaction of formic acid with hydrogen peroxide in presence of metabolic acid, an explosion occurred which was attributed to spontaneous separation of virtually pure peroxyformic acid. [R38, 152] */REACTS/ ... EXPLOSIVELY WITH OXIDIZING AGENTS ... [R39, p. 13/880 51.024] +DURING AN ATTEMPT TO PREPARE FURFURYL FORMATE FROM FURFURYL ALCOHOL AND CONCN FORMIC ACID, AN EXPLOSION OCCURRED. [R6, p. 491-90] +A CHEMIST WORKING A 50-50 MIXTURE OF FORMIC ACID AND 90% HYDROGEN PEROXIDE, INTRODUCED A SMALL AMT OF ORG MATERIAL INTO SOLN. WHEN REACTION HAD SUBSIDED, CONTAINER WAS REMOVED TO A WORKBENCH. LATER, WHEN FLASK WAS PICKED UP, MATERIAL EXPLODED VIOLENTLY. [R6, p. 491-98] *In the production of formic acid, slurry of calcium formate in approx 50% aq formic acid containing urea is acidified with strong nitric acid to convert the calcium salt to free acid, and interaction of formic acid (reducant) with nitric acid (oxidant) is inhibited by the urea. When only 10% of the required amt of urea had been added ... addition of the nitric acid caused a runaway (redox) reaction to occur which burst the (vented) vessel. [R38, 1163] *Addition of ... acids to nitromethane renders it susceptible to initiation by a detonator. These include ... formic, nitric, sulfuric or phosphoric acids. [R38, 162] *Addition of dry /palladium-carbon/ catalyst to 98% formic acid used as a hydrogenation solvent can be extremely hazardous, because hydrogen is released by decomposition of the acid. [R38, 151] *Removal of formic acid from industrial waste streams with sodium hypochlorite soln becomes explosive at 55 deg C. [R38, 985] +A violent reaction occurred when a small amt of vanillin was added to thallium trinitrate trihydrate (up to 50%) in 90% formic acid. [R6, p. 491-195] +Strong oxidizers, strong caustics, concentrated sulfuric acid [Note: Corrosive to metals]. [R40, 148] ODRT: *Water: 1700 mg/l; air 49 ul/l; Odor safety class E. E= less than 10% of attentive persons can detect TLV concentration in the air. [R41] *Detection threshold: 4.50x10+2 mg/l (liq) and 4.50x10-1 mg/l (gas) /Purity not specified/ [R42] *Detection threshold: 6.25x10-1 ppm, 6.25x10-2 ppm and 8.30x10+1 ppm /Medium water; purity not specified/ [R42] *Detection threshold: 1.50x10+3 ppm /Purity not specified/ [R42] *... 21 ppm. [R31, 1981.2] *Concentration: odor low= 0.0450 mg/cu m; odor high= 37.8 mg/cu m; irritating concentration= 27.0 mg/cu m. [R43] EQUP: *Self-contained breathing apparatus; chem goggles or face shield; rubber suit, gloves, and shoes. [R36] *Breakthrough times greater than one hour reported by two or more testers for natural rubber, neoprene, and polyvinyl chloride. [R44] *Some data suggesting breakthrough times of approximately an hour or more for nitrile rubber. [R44] +Wear appropriate personal protective clothing to prevent skin contact. [R40, 149] +Wear appropriate eye protection to prevent eye contact. [R40, 149] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R40, 149] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R40, 149] +Recommendations for respirator selection. Max concn for use: 30 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R40, 149] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R40, 149] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R40, 149] OPRM: +Contact lenses should not be worn when working with this chemical. [R40, 149] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Clothing contaminated with formic acid should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of formic acid from clothing. If the clothing is to be laundered or otherwise cleaned to remove the formic acid, the person performing the operation should be informed of formic acid's hazardous properties. [R31, 1981.3] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock-down vapors. Neutralize spilled material with crushed limestone, soda ash, or lime. [R37] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective clothing. [R37] *Provide emergency showers and eyewash. [R45] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. +The worker should immediately wash the skin when it becomes contaminated. [R40, 149] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R40, 149] SSL: *MAY DETERIORATE IN NORMAL STORAGE AND CAUSE HAZARD [R46] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R47] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R48] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R49] STRG: +Store in a dry, well-ventilated place. Separate from oxidizing materials and alkaline substances. [R6, p. 49-73] *Protect against physical damage. Store in a cool, dry, well-ventilated location. Outdoors or detached storage is preferred. [R50] CLUP: *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quantities, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quantities can be collected and atomized in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. [R31, 1981.4] *Environmental considerations--land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./. Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash or cement powder. Neutralize with agricultural lime ... crushed limestone (CaCO3) or sodium bicarbonate (NaHCO3). [R37] *Environmental considerations--water spill: Neutralize with agricultural lime (CaO), crushed limestone (CaCO3) or sodium bicarbonate (NaHCO3). Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R37] *Environmental considerations--air spill: Apply water spray or mist to knock down vapors. Vapor knockdown water is corrosive or toxic and should be diked for containment. [R37] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R51] *The following wastewater treatment technologies have been investigated for formic acid: biological treatment. [R52] *Incineration: Burn scrap material in an approved incinerator with afterburner. Flammable solvent may be added to improve burning characteristics. [R53] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *... Hemodialysis accelerates both the elimination of both methanol and formic acid and also assists in correction of metabolic acidosis. Experimental data suggests that the administration of folic acid may be of benefit by hastening the metabolism of formic acid to carbon dioxide. Prompt ... /treatment/ can probably decr the morbidity and mortality /associated with this form/ of poisoning. [R54] MEDS: *The following medical procedures should be made available to each employee who is exposed to formic acid at potentially hazardous levels: 1. Initial medical screening: Employees should be screened for history of certain medical conditions ... /chronic respiratory disease, skin disease, kidney disease, liver diseases and eye disease/ which might place the employee at incr risk from formic acid exposure. ... 2. Periodic medical exam: Any employee developing the above-listed conditions should be referred for further medical exam. [R31, 1981.1] *Consideration should be given to possible irritant effects on skin, eyes, and lung in any placement or periodic examinations. [R45] HTOX: *CHRONIC ABSORPTION HAS BEEN REPORTED TO CAUSE ALBUMINURIA, HEMATURIA. [R55] *PRINCIPAL HAZARD IS THAT OF SEVERE PRIMARY DAMAGE TO SKIN, EYE OR MUCOSAL SURFACE. SENSITIZATION IS RARE, BUT MAY OCCUR IN PERSON PREVIOUSLY SENSITIZED TO FORMALDEHYDE. [R21, 44] *... WORKERS EXPOSED TO FORMIC /ACID/ ... IN A TEXTILE PLANT COMPLAINED OF NAUSEA. AIR TESTS IN THE AREA REVEALED CONCN ... AVERAGING 15 PPM. [R26] *Lacrimation, increased nasal discharge, cough, throat discomfort, erythema, and blistering may occur depending upon soln concentrations. [R45] *Extensive exposure can result in depressive effects to the central nervous system (CNS), like visual and mental disturbances. After oral intake ... severe acidosis ... and nephropathy may occur. [R56] *Swallowing formic acid has caused a number of cases of severe poisoning and death. The symptoms ... include salivation, vomiting, burning sensation in the mouth, bloody vomiting, diarrhea, and pain. In severe poisoning, shock may occur. Later breathing difficulties may develop. Kidney damage may also be present. [R45] *SYMPTOMATOLOGY (AFTER INGESTION OR SKIN CONTACT): 1. CORROSION OF MUCOUS MEMBRANES OF MOUTH, THROAT AND ESOPHAGUS, WITH ... PAIN AND DYSPHAGIA. NECROTIC AREAS ARE AT FIRST GRAYISH WHITE BUT SOON ACQUIRE A BLACKISH DISCOLORATION (YELLOW IN CASE OF NITRIC ACID) AND SOMETIMES SHRUNK OR WRINKLED TEXTURE. 2. EPIGASTRIC PAIN ... MAY BE ASSOC WITH NAUSEA AND VOMITING OF MUCOID AND COFFEE-GROUND MATERIAL. ... INTENSE THIRST. 3. ULCERATION OF ALL MEMBRANES AND TISSUES ... 4. CIRCULATORY COLLAPSE WITH CLAMMY SKIN, WEAK AND RAPID PULSE, SHALLOW RESP AND SCANTY URINE. ... SHOCK IS OFTEN ... CAUSE OF DEATH. 5. ASPHYXIAL DEATH DUE TO GLOTTIC EDEMA. 6. LATE ESOPHAGEAL, GASTRIC AND PYLORIC STRUCTURES AND STENOSIS, WHICH MAY REQUIRE ... SURGICAL REPAIR, SHOULD BE ANTICIPATED. ... PERMANENT SCARS MAY ... APPEAR IN CORNEA, SKIN AND OROPHARYNX. 7. UNCORRECTED CIRCULATORY COLLAPSE OF SEVERAL HR ... MAY LEAD TO RENAL FAILURE AND ISCHEMIC LESIONS IN LIVER AND HEART. /ACIDS/ [R57] *FORMIC ACID PRODUCED BY BEES, WASPS, AND ANTS WILL CAUSE TISSUE IRRITATION UPON CONTACT OR INJECTION. [R58] *... A DROP OF REACTION MIXT COMPOSED OF 0.8 ML 90% FORMIC ACID AND 0.2 ML 30% HYDROGEN PEROXIDE /WAS/ SPLASHED IN ONE EYE /OF A PATIENT/. THE EYE WAS QUICKLY IRRIGATED WITH WATER, BUT AN AREA OF SWELLING OF EPITHELIUM AND ANTERIOR STROMA OF CORNEA AND CELLS AND FLARE IN ANTERIOR CHAMBER WERE OBSERVABLE HALF AN HR LATER. HOWEVER, IN 12 HR THE AQUEOUS AND CORNEA HAD BECOME CLEAR EXCEPT FOR AN AREA OF LOSS OF EPITHELIUM, AND IN 36-60 HR RECOVERY WAS COMPLETE. [R59, 447] *Intentional ingestion (overdoses) are reported to produce salivation, vomiting (which may be bloody), a burning sensation in the mouth and pharynx, diarrhea, and severe pain. Circulatory collapse may follow, causing death. [R60] *A worker who had suffered splashes of hot formic acid to his face developed marked dyspnea with difficulty in swallowing, inability to speak, and died 6 hours later. [R60] *Signs and symptoms from accidental or intentional overdoses (50 g or more) are salivation, vomiting, a burning sensation in the mouth and pharynx, and severe pain. Circulatory collapse may follow, causing death. Ingestion of; or skin contact with, smaller quantities of formic acid may produce ulceration of membranes. Contact with eyes may cause permanent scarring of the cornea. Dilute solutions (eg, 10 percent) appear to be noncorrosive. [R13, 4908] +Causes severe eye and skin burns. May be harmful if inhaled. Inhalation causes damage to nasal and respiratory passages. [R6, p. 49-72] *PRINCIPAL HAZARD IS THAT OF SEVERE ... DAMAGE TO SKIN, EYE OR MUCOSAL SURFACE. [R21, 44] *Methanol toxicity in humans ... is characterized by a latent period of many hours followed by a metabolic acidosis and ocular toxicity. This is not observed in most lower animals. The metabolic acidosis and blindness is apparently due to formic acid accumulation in humans ... a feature not seen in lower animals. The accumulation of formate is due to a deficiency in formate metabolism, which is, in turn, related, in part, to low hepatic tetrahydrofolate (H4 folate). An excellent correlation between hepatic H4 folate and formate oxidation rates has been shown within and across species. Thus, humans ... possess low hepatic H4 folate levels, low rates of formate oxidation and accumulation of formate after methanol. Formate, itself, produces blindness in ... humans also have low hepatic 10-formyl H4 folate dehydrogenase levels, the enzyme which is the ultimate catalyst for conversion of formate to carbon dioxide. [R61] NTOX: *In young rats admin formic acid in the diet (0.5 or 1.0%) or drinking water (0.5 or 1.0%) for 6 wk the body wt gain and the size of most organs were reduced. Rats receiving 8 to 360 mg/kg formic acid in drinking water for 2 to 27 wk showed no adverse effects other than a reduced rate of body wt gain (and feed intake) at the highest dose level. [R13, 4908] *IN A LIVE RABBIT, PURE LIQ FORMIC ACID APPLIED WITH A BRUSH TO PART OF CORNEA ... /CAUSED/ IMMEDIATE LOCAL OPACITY. THIS BEGAN TO CLEAR ... IN 5 DAYS, BUT BY THAT TIME THERE WAS HYPOPYON, POSTERIOR SUBCAPSULAR LENS OPACITY, ABSENCE OF PORTIONS OF CORNEAL ENDOTHELIUM, INFILTRATION, AND GROWTH OF NEW BLOOD VESSELS AT THE LIMBUS. THE IRIS WAS ALSO INFILTRATED AND HYPEREMIC. IN ANOTHER RABBIT A FIVE MINUTE APPLICATION OF FORMIC ACID DILUTED TO 10% ALSO CAUSED DENSE WHITE LOCAL OPACITY, AND AT 5 DAYS THE REACTION IN THE CORNEA WAS SIMILAR TO THAT OF THE EYE EXPOSED TO CONCN ACID, BUT HYPOPYON WAS ABSENT. [R59, 446] *... FORMIC ACID ADMIN IN UNSPECIFIED QUANTITY TO RABBITS AND DOGS PRODUCED THE SAME HISTOPATHOLOGY IN RETINA AND OPTIC NERVE AS DID METHYL ALCOHOL. PRESUMABLY, ACIDOSIS WAS INDUCED BY FORMIC ACID IN THESE EXPT IN WHICH THE EYES WERE FOUND TO BE INJURED, WHEREAS ACIDOSIS WOULD NOT BE PRODUCED BY FEEDING NEUTRAL FORMATES. ... IN ... A SERIES OF STUDIES IN DOGS, /INVESTIGATORS/ ... CONCLUDED THAT METAB OF METHANOL TO FORMIC ACID COULD PRODUCE GENERALIZED ACIDOSIS. FUTHERMORE, THEY POSTULATED THAT AS TISSUE PH WAS LOWERED IN ACIDOSIS, TOXICITY ATTRIBUTABLE TO /FORMIC ACID/ ... INCR, OWING TO GREATER PROPORTION BEING PRESENT AS FORMIC ACID AND SMALLER PROPORTION AS RELATIVELY INNOCUOUS FORMATE ION. [R59, 446] *The same type of toxicity to the optic nerves has been demonstrated by admin of formic acid to monkeys as by admin of methanol and it appears that the accumulation of formic acid and the associated metabolic acidosis is the actual mechanism underlying the blindness notoriously produced by methanol ... . [R59, 447] *EXPOSURE OF 3 MO OLD MALE WISTAR RATS TO 20 PPM FORMIC ACID VAPOR FOR 3 WK (5 DAYS/WK; 6 HR DAILY) RESULTED IN AN INCR IN BRAIN LYSOSOMAL ACID PROTEINASE AND SUCCINATE DEHYDROGENASE AND DECR IN GLUTATHIONE PEROXIDASE AND 2',3'-CYCLIC NUCLEOTIDE 3'-PHOSPHOHYDROLASE. [R62] *MALE WISTAR RATS WERE EXPOSED TO 20 PPM FORMIC ACID VAPOR FOR 3 and 8 DAYS, 6 HR DAILY. ANALYSIS REVEALED AN INCR IN LIVER ETHOXYCOUMARIN DEETHYLASE LEVEL, WHILE HEPATIC GLUTATHIONE AND KIDNEY CYTOCHROME P450 WERE BELOW THE CONTROL LEVEL. [R63] *... Reported ... doses of 0.46 to 1.25 mg/kg iv to rabbits caused central nervous system depression, vasoconstriction and diuresis; larger doses (approx 4 g/kg) produced convulsions and death in rabbits and methemoglobinemia in dogs. In sheep formic acid given orally (150 mg/kg) was without adverse effect, except for some indication of anorexia. [R13, 4908] *Formic acid has been reported to be mutagenic in Escherichia coli and Drosophila germ cells, but did not affect DNA transformation in Bacillus subtilis at concn up to 0.46%. [R13, 4908] *Methanol toxicity in ... monkeys is characterized by a latent period of many hours followed by a metabolic acidosis and ocular toxicity. This is not observed in most lower animals. The metabolic acidosis and blindness is apparently due to formic acid accumulation in ... monkeys, a feature not seen in lower animals. The accumulation of formate is due to a deficiency in formate metabolism, which is, in turn, related, in part, to low hepatic tetrahydrofolate (H4 folate). An excellent correlation between hepatic H4 folate and formate oxidation rates has been shown within and across species. Thus ... monkeys possess low hepatic H4 folate levels, low rates of formate oxidation and accumulation of formate after methanol. Formate, itself, produces blindness in monkeys ... also have low hepatic 10-formyl H4 folate dehydrogenase levels, the enzyme which is the ultimate catalyst for conversion of formate to carbon dioxide. [R61] NTXV: *LD50 Mouse oral 1076 mg/kg; [R13, 4906] *LD50 Mouse iv 142 mg/kg; [R13, 4906] *LD50 Mouse ip 940 mg/kg; [R13, 4906] *LD50 Rat oral 1830 mg/kg; [R13, 4906] ETXV: *TLm Lepomis macrochirus (bluegill) 175 mg/l/24 hr, fresh water /Conditions of bioassay not specified/; [R36] *TLm Daphnia 120 ppm/l/48 hr, fresh water /Conditions of bioassay not specified/; [R36] ADE: *Some formic acid may be excreted unchanged, the amt depending on the species, dose, and route of admin. [R13, 4908] *... READILY ABSORBED THROUGH LUNG. [R29, 1772] *During hemodialysis in a methanol poisoned patient, formate elimination followed first order kinetics with a plasma half-life of 165 min. The mean dialyzer (1.6 at 59 ml) clearance of formate was 148 ml/min at a blood flow of 215 ml/min. Distribution volume was 0.5 l/kg. Formate is more effectively removed by hemodialysis than methanol. /Formate/ [R64] METB: *Formate is a normal constituent of intermediary metabolism ... /of formic acid/. Formate is metabolized in the rat primarily via the one carbon pool, but in some circumstances the catalase-peroxidative pathway may serve as an alternative route of oxidn. Oxidn occurs in a variety of organs and tissues, incl liver, lung, and erythrocytes, the end products being carbon dioxide and water. [R13, 4908] *Formic acid was excreted in the urine of rabbits during inhalation of methyl alcohol ... . [R13, 4535] *Methanol itself has about one third of the intoxicating effect of ethanol, but hepatic metabolism via alcohol dehydrogenase produces (12 to 48 hours later) highly toxic formic acid (formate). Methanol is slowly metabolized to formaldehyde, but the conversion to formic acid follows rapidly, and formic acid concentrations correlate well with acidemia. Thus formic acid appears to be the principal toxic metabolite accounting for the metabolic acidemia and the ocular toxicity. The large anion gap metabolic acidosis is the hallmark of methanol toxicity. [R65] *METHANOL ... CAN RESULT IN BLINDNESS, DUE PROBABLY TO TOXIC ACTION OF ITS METABOLITES, FORMALDEHYDE AND FORMIC ACID. [R66] *The toxic properties of methanol are rooted in the factors that govern both the conversion of methanol to formic acid and the subsequent metabolism of formate to carbon dioxide in the folate pathway. ... The toxic syndrome sets in if the formate generation continues at a rate that exceeds its rate of metabolism. Current evidence indicates that formate accumulation will not challenge the metabolic capacity of the folate pathway at anticipated levels of exposure to automotive methanol vapor. [R67] BHL: *During hemodialysis in a methanol poisoned patient, formate elimination followed first order kinetics with a plasma half-life of 165 min. /Formate/ [R64] ACTN: *THE ROLE OF FORMIC ACID IN METHANOL TOXICITY IN HUMAN SUBJECTS HAS NOT BEEN ESTABLISHED. TWO PT WERE STUDIED WHO PRESENTED WITH METHANOL POISONING. FORMATE ACCUM WAS MARKED WITH INITIAL BLOOD LEVELS RANGING FROM 11.1-26.0 MEQ/L. DECR IN BLOOD BICARBONATE CONCN OF SIMILAR MAGNITUDE COINCIDED WITH THE INCR IN FORMATE ACCUM. ACCUMULATION OF FORMIC ACID THUS PLAYS A MAJOR PART IN THE ACIDOSIS OBSERVED IN HUMAN SUBJECTS POISONED WITH METHANOL. [R68] *Enzyme pathways involved in detoxification of hydrogen peroxide, formaldehyde, and formic acid, which are produced as a consequence of oxidative demethylation by the cytochrome P-450 system, were examined in isolated hepatocytes from phenobarbital-pretreated rats. Formaldehyde produced during oxidative demethylation in isolated hepatocytes is rapidly oxidized to formic acid. Depletion of cellular reduced glutathione by pretreatment of rats with diethylmaleate decreases the rate of formic acid production, and therefore, it appears that formaldehyde produced by oxidative demethylation is oxidized by formaldehyde dehydrogenase, an enzyme which requires but does not consume reduced glutathione. Because of the rapid nonenzymatic reaction of formaldehyde with reduced glutathione, this enzyme system may be viewed as essential to prevent the loss of reduced glutathione due to S-hydroxymethylglutathione formation. reduced glutathione concentration in isolated hepatocytes decreased rapidly following addition of substrates undergoing oxidative demethylation. Addition of other Cytochrome P-450 substrates which do not undergo demethylation did not result in such a dramatic oxidation of reduced glutathione. Formic acid, produced during oxidative demethylation acts as a substrate for the peroxidatic mode of catalase, but also binds to catalase as an anionic ligand. This binding decreases the catalase concentration detectable by cyanide titration and therefore appears to inhibit the catalytic reaction mode. [R69] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +MEDICATION (VET): APPEARS TO PREVENT CANDIDA GROWTH IN PARTRIDGES EXPOSED TO CANDIDA AFTER RECEIVING TREATED FEED (20 ML OF 6% SOLN/100 G FEED FOR 1 WEEK AND THEN 2% SOLN). SIMILARLY, A 15% SOLN CAN BE USED TO CONTROL AN OUTBREAK OF CANDIDA ALBICANS. [R70] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Formic acid occurs naturally in plants and insects. It is also a product of microbial metabolism of organic matter and is produced in the photoxidation of biogenic and anthropogenic compounds. Formic acid will also be released to the environment as emissions and in wastewater in its production and various industrial uses. The fact that formic acid's half-life in air is short and its atmospheric concn in different environments are similar indicates that there are a variety of sources of formic aicd in the environment. Formic acid is the strongest unsubstituted carboxylic acid with a pKa of 3.74(3) and will exist almost entirely as the anion at environmental pHs. If released on land, formic acid should leach into some soils where it would probably biodegrade. In natural water it has been shown to adsorb to sediment and would probably also biodegrade. Bioconcentration in aquatic organisms is not important. In the atmosphere, formic acid would be scavenged by rain and dissolve in cloud water where it reacts with dissolved hydroxyl radicals. It also reacts in the vapor phase with hydroxyl radicals (half-life 36 days). Humans are exposed to formic acid in ambient air, food, as well as occupationally via inhalation and dermal contact. (SRC) NATS: *Formic acid occurs in fruits, vegetables, and leaves and roots of plants, and also in the secretions of numerous insects(1). The secretion of the bombardier beetle is 75% formic acid(1). It is also an intermediate product in the decomposition of organic matter in lake sediment(2) and a photooxidation product of alkanes, alkenes, and biogenic terpenes by hydroxyl radical(3,6) and ozone-olefin reactions(4). An inspection of the diurnal variation of formic acid/CO ratio, acetic acid/CO ratio and ozone during a photochemical smog episode suggests that in-situ production is an important process(9). In-situ formation via olefin-ozone reactions is estimated to be 25.0 metric tons/day during the day and 34.5 metric tons/day at night(10). Formic acid is also produced in clouds by the oxidation of formaldehyde by hydroxyl radicals, oxygen, or hydrogen peroxide(5). Formic acid is an intermediary human metabolite that is immediately transformed to formate(7). Formate can be excreted in human and animal urine(8). [R71] ARTS: *IDENTIFIED AS CILIA TOXIC AND MUCOUS COAGULATING AGENT IN TOBACCO SMOKE. /FROM TABLE/ [R72] *Formic acid is produced in large quantities (48 million lbs in 1984(1)) and may be released to the environment in emissions and in wastewater during its production and uses (% of production) in: textile dyeing and finishing (21%), pharmaceuticals (20%), rubber intermediate (16%), leather and tanning treatment (15%), and catalysts (12%)(1). Formic acid is also a component added to certain paint strippers(3). It is released in photo processing effluents(2) and pulp mill effluents(4). Formic acid is produced in the thermal degradation of polyacetal(polyoxymethylene) (POM) plastics and is released during processing this plastic(6). It is a product of the anaerobic biodegradation of cyanide(5) and therefore may be produced from industrial cyanide effluent. Sources also include automobile exhaust and engine oil(7). Direct emissions of formic acid in the fall and sumnmer in Southern California are estimated to be 5.6 and 9.6 metric tons/day, respectively, at a coastal source-dominated site(8). [R73] FATE: *TERRESTRIAL FATE: If released on land, formic acid should leach into some soils where it would probably biodegrade based upon the results of screening studies. A field study was conducted in which an industrial acid waste that was disposed of by deep well injection, was followed as it traveled a distance of 427-823 meters over a 2-4 yr period(1). The concn of formic acid was not detectable in two observation wells while in a third well it was 0.4% of DOC(1). Before injection the formic acid content was 11.4% of DOC(1). The disappearance of the acid may have been a result of anaerobic degradation, or reaction with the mineral material in the aquifer(1). [R74] *ATMOSPHERIC FATE: In the atmosphere, formic acid will be rapidly scavenged by rain and dissolve in cloud water and aerosols. It may also be removed by dry deposition and is estimated to be 22-52 metric tons/day in a coastal source-dominated area of Southern California depending on season and location (fall > summer and inland > coastal)(2). It participates in reactions in clouds and aerosols involving dissolved hydroxyl radicals. The vapor phase acid also reacts with photochemically produced hydroxyl radicals (half-life 36 days) and possibly with alkenes that may be present in polluted urban air, but these reactions are believed to be too slow to compete wet and dry deposition as removal processes(1). [R75] *AQUATIC FATE: Based on the results of screening studies, formic acid should biodegrade if released in water. It should not adsorb to sediment to any great extent(SRC). BIOD: *It can be degraded biologically ... to innocuous substances in most environments. [R76] *Biological Oxygen Demand (BOD): 2%, 5 days; 40% (theor), 5 days [R36] *Formic acid biodegrades readily in screening tests. Specific results include: 4.3 and 38.8% of theoretical BOD after 5 and 10 days using a sewage seed(1); 43.7-77.6% of theoretical BOD after 5 days with a sewage inoculum(2); 70% of theoretical BOD in 24 hr using activated sludge(3); 66% of theoretical BOD in 12 hours using an activated sludge inoculum(4); 39.9% of theoretical BOD in 24 hr with activated sludge(5); 48 and 51% of theoretical BOD after 5 days with unacclimated and acclimated sewage seed, respectively(6); and 40.5 and 51.7% of theoretical BOD after 5 days with sewage seed in fresh water and synthetic seawater, respectively(7). Formic acid is also amenable to anaerobic biodegradation(8,9). In one study 89% degradation was obtained after a 4 day lag by methane cultures(8). Microorganisms are present in the air that can degrade formate in rainwater(9). In one study, the turnover time of formate was 1.5 days(9). [R77] ABIO: *It can be degraded chemically ... to innocuous substances in most environments. [R76] *Formic acid is the strongest unsubstituted carboxylic acid with a pKa of 3.74(3) and will exist almost entirely as the anion at environmental pHs. The anhydrous material decomposes to carbon monoxide and water(1). Traces of water, including that formed during the decomposition, inhibits the reaction(1). Decomposition rates are measurable at room temperature and storage for more than 6 months is not recommended when the temperature exceeds 30 deg C(1). The anhydrous acid catalyzes its own esterification with alcohols and polyols but often also promotes dehydration to the ether or olefin(1). Dry formic acid readily adds to olefins to form formate esters(1). In the atmosphere, formic acid reacts with photochemically produced hydroxyl radicals with a rate constant of 0.45X10-12 cu cm/molecule- s(2). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half- life of formic acid in the atmosphere would be 36 days (SRC). Hydrogen atoms are a major free radical product of this reaction(2). Reactions between hydroxyl radicals and formic acid also occur in cloud water(4). During daylight hours, aqueous-phase OH radical reactions can both produce and destroy formic acid in cloud drops and may control the formic acid levels in rain(4). [R78] BIOC: *Formic acid has a log octanol/water partition coefficient of -0.54(1) from which one can estimate a BCF of 0.22 using a recommended regression equation(2,SRC). Therefore formic acid should not bioconcentrate in aquatic organisms(SRC). [R79] KOC: *Formic acid is miscible in water(1). Chemicals that are soluble in water do not usually adsorb significantly to soil or sediment due to hydrophobic forces(2). However at ambient pHs, formic acid exists as the ion and may therefore have the potential to bind to clay or humic material by coulombic forces. However, no evidence of such binding has been reported(SRC). [R80] VWS: *The Henry's Law constant for formic acid is 1.67X10-7 atm-cu m/mole(1). Other investigators have obtained Henry's Law constants as high as 2.78X10-7 atm-cum/mole(3). These Henry's Law constants indicate that volatilization from water will not be significant since the half-life in a model river 1 m deep flowing at 1 m/s with a 3 m/s wind is estimated to be 149 and 89 days(2). [R81] WATC: *GROUNDWATER: Groundwater in a sand aquifer at Pensacola, FL, the site of a wood treatment facility contained 0.13 ppb of formic acid at 6 m depth(1). No formic acid was found at 18 m depth(1). [R82] *SURFACE WATER: Concentrations of formic acid in the Ohio River, Little Miami River and Tannes Creek were 12-39 ppb, 18.4-25.2 ppb, and 22.3 ppb, respectively(1). In Lake Kizaki in Japan, surface concentrations of formic acid was 115 ppb(2). Although the concentration varied with depth (0-28 m) between 0 and 115 ppb, the variation was not a smoothly decreasing one(2). [R83] *RAIN/SNOW: Precipitation samples collected at two Wisconsin lakes on the Wisconsin Acid Deposition Monitoring Network contained formic acid ranging from the detection limit (20 ppb) to 2,576 ppb, median 382 ppb(1). In remote areas it may be the major organic acidic component in rain(2). Other results for formic acid in rain include: 18.4 ppb in Ithaca, NY; 0-5.5 ppb in Los Angeles; 20-880 ppb in the South Indian Ocean; 330-980 ppb in remote Venezuela; and 0-1630 ppb in remote Australia(3). The average volume-weighted concn of formic acid in rainwater in a study at Wilmington (154 measurements), NC was 7.4 umol/l and contributed 19% of the rainwater's acidity(4). The formic acid concn was higher during the growing season than in the nongrowing season and higher in continental storms than in maritime ones. The concn was highest, 20.8 umol/l, during a local thunderstorm. The monthly average concn of formate in rain in Charlottesville, VA ranged from 6.23 to 21.8 umol/l during 1984(5). Fogwater in Corvallis, OR had a median and high concn of 61 and 133 umol/l, respectively(6). [R84] EFFL: *Secondary effluents of 4 sewage treatment plants ranged from 51-144 ppb whereas primary effluents from three of the plants ranged from 46-587 ppb(1). With increased treatment long chain fatty acids are broken down to shorter chain acids, thereby increasing the concn of lower acids(1). [R85] SEDS: *The formic acid concn in the 0-1 cm layer of sediment at 2 stations in Lake Biwa in Japan was 437 and 64 ppm (wet weight), while the respective concn in the 9-10 cm layer was 23 and 110 ppm(1). No formic acid was in the interstitial water, indicating that the chemical was adsorbed on the sediment particles(1). [R86] ATMC: *RURAL/REMOTE: Concn of formic acid at various rural and remote sites in Arizona range from a few tenths of a ppb to 3.5 ppb(1). Remote regions of the Southern Hemisphere Pacific and Indian Oceans 0.2 ppb, av(2). Desert areas of the southwest US 0.7 ppb(2). The max concn of formic acid in several forests was 9.8 ppb during a hot, humid summer day in central Pennsylvania(2). [R87] *URBAN/SUBURBAN: Maximum daily formic acid concentrations observed in Claremont, CA during 5 days of an air pollution episode in October 1979 ranged from 5-19 ppb(1). Formic acid concns ranged from 1.9-10.5 ppb during a smog episode in Claremont, CA in September 1985(4). The 75th percentile, median and 25th percentile formic acid concn at 29 sites around Los Angeles sites was 6.0, 4.0, and 2.0 ppb(2). The concn of formic acid in Albuquerque, NM was 6.9, 4.2 and 2.0 ppb in summer, winter, and spring, respectively(3). Oxygenated fuels are required in winter and biogenic emissions may contribute to formic acid production in summer(3). Uniontown, PA (110 samples), a non-industrial town 50 mi SSE of Pittsburg, ND- 44.6 ppb; Boston, MA, 1.8-14.8 ppb(5). [R88] FOOD: *Formic acid is a natural constituent of some fruits, nuts, dairy products. [R13, 4908] *Fruit wine, desert wine and brandies contain formic acid(1). Formic acid concns in these products produced from apples, pears, plums, and apricots ranged from 2.7 to 87 mg/l. Formation of high concn of formic acid depend on mold metabolism(1). Formic acid has been identified as a meat volatile(2). [R89] OEVC: *Several commercial paint strippers contain up to 15% formic acid (1). [R90] *The release of components from PVC bags to infusion liquids was studied by various procedures, for example gas and liquid chromatography. Liquids were autoclaved at 120 deg C for 20 min and analyzed immediately and after storage (for 3, 6, 12 and 24 mo) at 25 deg C. Acid impurities were identified as formic and acetic acids. Release occurred during autoclaving and the first 3 mo of storage. [R91] RTEX: *Formic acid can affect the body if it is inhaled or if it comes in contact with the eyes or skin. It can also affect the body if it is swallowed. [R31, 1981.1] *The general public is exposed to formic acid from ambient air and in some fruits and vegetables. Workers will be occupationally exposed to formic acid via dermal contact and inhalation. (SRC) *The health hazard of exposure to formic acid vapor in silage making is discussed. [R92] *The following list includes some common operations in which exposure to formic acid may occur ... : Use in textile dyeing and finishing industry ... as chemical intermediate ... in leather processing industry ... in rubber industry ... as catalyst in hydrocarbon-formaldehyde resins and phenolic resins and plasticizer for vinyl resins; use in electroplating industry ... as antiseptic in wine and beer brewing, preservative in animal feed additives and cleaning soln cmpd; use in miscellaneous operations as a wire stripping cmpd and preparing bare wires for soldering, laundry sour; and as an oil well acidifying agent. [R31, 1981.3] *Airplane glue makers, cellulose formate workers, and tanning workers are exposed to a 60% soln. [R93] *NIOSH (NOES Survey, 1981-83) has statistically estimated that 145,784 workers are exposed to formic acid in the USA(1). Sixty five percent of the exposures are with trade name mixtures that contain formic acid as a component(1). [R94] AVDI: *AIR INTAKE (assume air concn of 4.0 ppb): 150 ug; WATER INTAKE - Insufficient data; FOOD INTAKE - Insufficient data. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +30 ppm [R40, 148] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 5 ppm (9 mg/cu m). [R95] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 ppm (9 mg/cu m). [R40, 148] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm; 15 min Short Term Exposure Limit (STEL): 10 ppm. [R96] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Formic acid is produced, as an intermediate or final product, by process units covered under this subpart. [R97] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 14,000 ug/l [R98] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R99] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R100] RCRA: *U123; As stipulated in 40 CFR 261.33, when formic acid, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R101] FDA: *Formic acid is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. [R102] *Formic acid may be safely used as a preservative in hay crop silage in an amount not to exceed 2.25% of the silage on a dry weight basis or 0.45% when direct-cut. The top foot of silage stored should not contain formic acid and silage should not be fed to livestock within 4 weeks of treatment. [R103] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *... Air: collection with caustic in an impinger. ... [R45] *A PROCEDURE FOR DETERMINING FORMIC ACID IN FISH AND OTHER MARINE PRODUCTS USING COLUMN CHROMATOGRAPHY IS DESCRIBED. /EXTRACTED BY SULFURIC ACID AND PHOSPHOTUNGSTIC ACID/ [R39, p. 13/292 18.050] ALAB: *ANALYTE: FORMIC ACID; MATRIX: AIR; RANGE: 3.8-75 MG/CU M IN 10 LITER SAMPLE OF AIR; PROCEDURE: IMPINGER COLLECTION; GAS CHROMATOGRAPHY. [R104, p. V1 232-1] *ANALYTE: FORMATE ION; MATRIX: AIR; RANGE: 4.4-21.6 MG/CU M; PROCEDURE: ADSORPTION ON CHROMOSORB 103, DESORPTION WITH DEIONIZED WATER, ION CHROMATOGRAPHY/ELECTROLYTIC CONDUCTIVITY DETECTION. [R104, p. V5 S173-1] *A method for continuous automatic determination of formic acid in industrial emissions is discussed. [R105] *A method is described for the determination of volatile organic acids in the atmosphere, motor exhausts, and engine oils. Atmospheric organic acids were collected on a KOH impregnanted quartz filter and derivatized to p-bromophenacyl esters. The derivatives were analyzed by high-resolution capillary gas chromatography and gas chromatography-mass spectrometry. [R106] CLAB: *A method for analysis of formic acid in concentration of approx 0.2 mg/l in body fluids and tissues is described. Formate dehydrogenase analysis is done in two steps. In the first step, a 0.1 ml sample of blood, urine, or tissue extraction is mixed with 0.1 of 10 mmol/l nicotinamide adenine dinucleotide soln, 0.1 ml of potassium phosphate buffer, and 50 ul of formate dehydrogenase soln. The mixture is incubated for 15 min at 37 deg C then 0.1 ml of diaphorase soln, 50 ul of resazurin soln and 0.5 ml of phosphate buffer (pH 6.00, 200 mmol/l) are added. Fluorescence is measured. [R107] *FORMIC ACID WAS DETERMINED IN EGGS AND EGG PRODUCTS USING A COLUMN CHROMATOGRAPHIC METHOD OR GAS CHROMATOGRAPHIC METHOD. /EXTRACTED BY SULFURIC ACID AND PHOSPHOTUNGSTIC ACID/ [R39, p. 13/281 17.041] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of Formic Acid Administered by Inhalation to F344/N Rats and B6C3F1 Mice NTP Tox 19 (1992) . A review of the metabolism of methanol and formic acid. [R108] Restani P, Galli CL; CRC Crit Rev Toxicol 21 (5): 315-28 (1991). Oral toxicity of formaldehyde and its derivatives are reviewed, /including metabolic products such as formic acid/. Schramm A et al; Anaesthesiol Reanim 16 (4): 259-65 (1991). A review of the methanol metabolites formaldehyde and formic acid concerning central nervous system and ocular symptoms. SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 537 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 252 (1980) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 253 (1980) R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 254 (1980) R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 255 (1980) R6: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R7: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 659 R8: Hayes, W. 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Claremont, CA: Pomona College, 1987. R26: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.279 R27: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-309 R28: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 643 R29: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R30: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. 4904 R31: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R32: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 11(80) 251 R33: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 683 R34: Gaffney JS et al; Environ Sci Technol 21: 519-24 (1987) R35: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R36: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R37: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1992.463 R38: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. 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CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 630 R47: 49 CFR 171.2 (7/1/96) R48: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 154 R49: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.8168 (1988) R50: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 556 R51: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (1981) EPA 68-03-3025 R52: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-14 (1982) R53: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 185 R54: Kruse JA; Intensive Care Med 18 (7): 391-7 (1992) R55: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 605 R56: Seiler, H.G., H. Sigel and A. Sigel (eds.). Handbook on the Toxicity of Inorganic Compounds. New York, NY: Marcel Dekker, Inc. 1988. 200 R57: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-10 R58: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 558 R59: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R60: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. 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New York: Springer Publishing Company, 1974. 228 R71: (1) Wagner FS; Kirk-Other Encycl Chem Technol 3rd ed. 11: 251-8 (1980) (2) Maeda H, Kawai A; Nippon Suisan Gakkaishi 52: 1205-8 (1986) (3) Altshuller AP; Atmos Environ 17: 2131-65 (1983) (4) Chameides WL, Davis DD; Nature 304: 427-9 (1983) (5) Adewuyi YG, et al; Atmos Environ 18: 2413 (1984) (6) Graedel TE; Chemical Compounds In The Atmosphere. New York, NY: Academic Press pp. 50-90 (1978) (7) Malorny G; Z Ernaehrungswiss 9: 340-48 (1969) (8) Van Oettingen WF; Am. Med Assoc Arch Ind Health 20: 517-531 (1959) (9) Grosjean D; Atmos Environ 22: 1637-48 (1988) (10) Grosjean D; Atmos Environ 26A: 3279-86 (1992) R72: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 339 R73: (1) Chemical Marketing Reporter; Chemical Profile: Formic Acid. December 31 (1984) (2) Dagon TJ; J Water Pollut Contr Fed 45: 2123-35 (1973) (3) Hahn WJ, Werschultz PO; Evaluation Alternatives to Toxic Organic Paint Strippers. USEPA-600/52-85/118 (1986) (4) Suntio LR et al; Chemosphere 7: 1249-90 (1988) (5) Fallon RD; Appl Environ Microbiol 58: 3163-4 (1992) (6) Vainiotalo S, Pfaffle P; Am Ind Hyg Assoc J 50: 396-9 (1989) (7) Grosjean D; Atmos Environ 22: 1637-48 (1988) (8) Grosjean D; Atmos Environ 26A: 3279-86 (1992) R74: (1) Leenheer JA, et al; Environ Sci Technol 10: 445-51 (1976) R75: (1) Grosjean D; Atmos Environ 22: 1637-48 (1988) (2) Grosjean D; Atmos Environ 26A: 3279-86 (1992) R76: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V11 251 (1983) R77: (1) Gaffney PE, Ingols RS; Water Sew Works 108: 91 (1961) (2) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) (3) Malaney GW, Gerhold RM; J Water Pollut Control Fed 41: R18-R33 (1969) (4) McKinney RE, et al; Sew Indust Wastes 28: 547-57 (1956) (5) Placak OR, Ruchhoft CC; Sewage Works J 19: 423-40 (1947) (6) Price KS, et al; J Water Pollut Contr Fed 46: 63-77 (1974) (7) Takemoto S, et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) (8) Chou WL, et al; Bioeng Symp 8: 391-414 (1979) (9) Leenheer JA, et al; Environ Sci Technol 10: 445-51 (1976) (9) Herlihy LJ et al; Atmos Environ 21: 2397-2402 (1987) R78: (1) Pryde EH; Kirk-Othmer Encycl Chem Tech 3rd ed 4: 814-34 (1978) (2) Atkinson R; J Chem Phys Ref Data Monograph 1 (1989) (3) Serjeant EP, Dempsey B; Ionization Constants Of Organic Acids In Aqueous Solution IUPAC Chemical Data Series No. 23 New York, NY: Pergamon Press (1979) (4) Chameides WL, Davis DD; Nature 304: 427-9 (1983) R79: (1) Hansch C, Leo AJ; MEDCHEM Project Claremont CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods New York: McGraw-Hill pp. 5-1 to 5-30 (1982) R80: (1) Pryde EH; Kirk-Othmer Encycl Chem Tech 3rd ed 4: 814-34 (1978) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods New York: McGraw-Hill pp. 4-1 to 4-33 (1982) R81: (1) Gaffney JS et al; Environ Sci Technol 21: 519-23 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods New York: McGraw-Hill pp. 15-1 to 15-34 (1982) (3) Betterton EA; pp. 1-50 in Gas Pollut: Character Cycl, Nriagu JO ed John Wiley and Sons, Inc (1992) R82: (1) Goerlitz DF et al; Environ Sci Tech 19: 955-61 (1985) R83: (1) Murtaugh JJ, Bunch RL; J Water Pollut Control Fed 37: 410-5 (1965) (2) Hama T, Handa N; Rikusiugaku Zasshi 42: 8-19 (1981) R84: (1) Chapman EG et al; Atmos Environ 20: 1717-27 (1986) (2) Chameides WL, Davis DD; Nature 304: 427-9 (1983) (3) Mazurek MA, Simoneit BRT; CRC Critical Review Environ Control 16: 140 (1986) (4) Avery GB Jr et al; Environ Sci Technol 25: 1875-80 (1991) (5) Herlihy LJ et al; Atmos Environ 21: 2397-2402 (1987) (6) Muir PS; J Air Waste Manage 41: 32-8 (1991) R85: (1) Murtaugh JJ, Bunch RL; J Water Pollut Control Fed 37: 410-5 (1965) R86: (1) Maeda H, Kawai A; Nippon Suisan Gakkaishi 52: 1205-8 (1986) R87: (1) Altshuller AP; Atmos Environ 17: 2383-427 (1983) (2) Willey JD, Wilson CA; J Atmos Chem 16: 123-33 (1993) R88: (1) Tuazon EC et al; Atmospheric Measurement Of Trace Pollutants: Long Path Fourier Transform Infrared Spectroscopy USEPA-600/S3-81-026 (1981) (2) Shah JJ, Heyerdahl EK; National Ambient VOC Database Update USEPA 600/3-88/010 (1988) (3) Popp CJ et al; Orliminary study of the effects of oxygenated fuel use. Am Chem Soc, Div Environ Chem, Preprint, 205th ACS Nat Meet, vol 33 pp 240-1 (1993) (4) Grosjean D; Atmos Environ 22: 1637-48 (1988) (5) Lawrence JE, Koutrakis P; Environ Sci Technol 28: 957-64 (1994) R89: (1) Sponholz WR et al; Deutche-Lebensmittel-Rundshaw 85: 247-51 (1989) (2) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R90: (1) Hahn WJ, Werschulz PO; Evaluation Of Alternatives To Toxic Organic Paint Strippers USEPA-600/52-85/118 (1986) R91: Arbin A; Sven Farm Tidskr 87 (9-10): 17-18 (1983) R92: Liesivuori J, Kettunen A; Ann Occup Hyg 27 (3): 327-9 (1983) R93: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 925 R94: (1) NIOSH; National Occupational Exposure Survey NOES (1989) R95: 29 CFR 1910.1000 (7/1/98) R96: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.33 R97: 40 CFR 60.489 (7/1/92) R98: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R99: 40 CFR 116.4 (7/1/88) R100: 40 CFR 302.4 (7/1/92) R101: 40 CFR 261.33 (7/1/92) R102: 21 CFR 172.515 (4/1/93) R103: 21 CFR 573.480 (4/1/93) R104: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R105: Beine H; Schriftenr Landesanst Immissionsschutz Landes Nordrhein-Westfalen, Essen 57: 26-30 (1983) R106: Kawamura K et al; Environ Sci Technol 19 (11): 1082-86 (1985) R107: Maker AB et al; Clin Chem 28 (2): 385 (1982) R108: Liesivuori J, Savolainen H; Pharm Toxicol 69 (3): 157-63 (1991) RS: 75 Record 145 of 1119 in HSDB (through 2003/06) AN: 1659 UD: 200211 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MIREX- SY: *Bichlorendo-; *CYCLOPENTADIENE,-HEXACHLORO-,-DIMER-; *1,3-CYCLOPENTADIENE,-1,2,3,4,5,5-HEXACHLORO-,-DIMER-; *Decane,-perchloropentacyclo-; *DECHLORANE-; *DECHLORANE-4070-; *Dechlorane-515-; *Dechlorane-plus-515-; *1,1A,2,2,3,3A,4,5,5A,5B,6-DODECACHLOROOCTAHYDRO-1,3,4- METHENO-1H-CYCLOBUTA(CD)PENTALENE; *1,1a,2,2,3,3a,4,5,5,5a,5b,6-dodecachlorooctahydro-1,3,4-metheno-1- H-cyclobuta(cd)decane; *DODECACHLOROOCTAHYDRO-1,3,4-METHENO-2H-CYCLOBUTA(CD)PENTALENE; *DODECACHLOROOCTAHYDRO-1,3,4-METHENO-2H-CYCLOBUTA(C,D)PENTALENE; *DODECACHLOROPENTACYCLODECANE-; *Dodecachloropentacyclo- (5.2.1.0(2,6).0(3,9).0(5,8))decane; *Dodecachloropentacyclo- (3.2.2.0(sup2,6),0(sup3,9),0(sup5,10))decane; *ENT-25,719-; *Ferriamicide-; *Fire-Ant-Bait-; *GC-1283-; *HEXACHLOROCYCLOPENTADIENE-DIMER-; *1,2,3,4,5,5-hexachloro-1,3-cyclopentadiene-dimer-; *HRS-1276-; *1,3,4-METHENO-1H-CYCLOBUTA(CD)PENTALENE, 1,1A,2,2,3,3A,4,5,5,5A,5B,6-DODECACHLOROOCTAHYDRO-; *NCI-C06428-; *PARAMEX-; *Perchlordecone-; *PERCHLORODIHOMOCUBANE-; *PERCHLOROPENTACYCLODECANE-; *PERCHLOROPENTACYCLO- (5.2.1.0(2,6).0(3,9).0(5,8))DECANE; *Perchloropentacyclo- (5.3.0.0(2,6).0(3,9).0(4,8))decane; *PERCHLOROPENTACYCLO- (5.2.1.0(SUP2,6).0(SUP3,9).0(SUP5,8))DECANE RN: 2385-85-5 RELT: 1558 [CHLORDECONE] MF: *C10-CL12 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *MIREX MAY BE MADE BY THE DIMERIZATION OF HEXACHLOROCYCLOPENTADIENE IN THE PRESENCE OF AN ALUMINUM CHLORIDE CATALYST. [R1] FORM: *It had been formulated mainly as fine granules made from corn cobs impregnated with vegetable oil so that they serve as bait for fire ants. The concentration of oil is about 15% and that of the active ingredient /mirex/ may be 0.075, 0.15, or 0.3%. [R2, 254] *Mirex has been formulated with aliphatic amines and ferrous chloride in an attempt to facilitate its photodegradation and to minimize its environmental contamination. The formulated product was known as ferriamicide. [R3] *Grade or purity: pelleted bait "450"-0.45% mirex [R4] OMIN: +US PATENT 2,671,043, MARCH 1954; US PATENT REISSUE 24,750, MARCH 1959. CODE NUMBER GC-1283 (ALLIED CHEMICAL). [R5] *PREPN: PRINS, REC TRAV CHIM 65, 455 (1946); NEWCOMER, MCBEE, J AM CHEM SOC 71, 952 (1949); GILBERT, US PATENT 2,702,305 (1955 TO ALLIED CHEM); JOHNSON, US PATENT 2,724,730 (1955 TO HOOKER ELECTROCHEM). [R6] *Discontinued by Allied Chem Corp. [R7] USE: +FIRE RETARDANT FOR PLASTICS, RUBBER, PAINT, PAPER, ELECTRICAL GOODS [R6] *INSECTICIDE USED TO CONTROL WESTERN HARVESTER ANTS, YELLOW JACKETS, AND IMPORTED FIRE ANTS (FORMER USE) [R8] *MIREX IS A STOMACH INSECTICIDE WITH LITTLE CONTACT ACTIVITY AND HAS FOUND ITS WIDEST USE AGAINST ANTS; FOR IMPORTED FIRE ANT, BAITS CONTAINING 0.075% ARE USED; FOR HARVESTER ANT BAIT IS 0.15%. [R9] */Former use:/ Mirex is ... marketed under the tradename Dechlorane for use in flame-retardant coatings for various materials. [R10, 879] CPAT: *1.88X10+7 G WERE USED AS BAIT UNDER GOVERNMENT SPONSORED PROGRAMS TO CONTROL THE IMPORTED FIRE ANT, WHICH IS ITS MAJOR USE (1972) [R8] PRIE: U.S. PRODUCTION: *(1972) SLIGHTLY MORE THAN 1.88X10+7 G [R8] *(1975) GREATER THAN 4.5X10+5 G [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +SNOW-WHITE CRYSTALS FROM BENZENE [R6] ODOR: +ODORLESS [R6] MP: +485 deg C [R5] MW: +545.59 [R6] CORR: +PRACTICALLY NON-CORROSIVE TO METALS [R6] OWPC: *log Kow= 5.28 [R11] SOL: *PRACTICALLY INSOL IN WATER [R6]; *15.3% IN DIOXANE AT ROOM TEMP [R6]; *14.3% IN XYLENE AT ROOM TEMP [R6]; *12.2% IN BENZENE AT ROOM TEMP [R6]; *7.2% IN CARBON TETRACHLORIDE AT ROOM TEMP [R6]; *5.6% IN METHYL ETHYL KETONE AT ROOM TEMP [R6] SPEC: *MASS: 6205 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R12]; *Intense mass spectral peaks: 272 m/z (100%), 274 m/z (75%), 270 m/z (54%), 237 m/z (46%) [R13] VAP: *3X10-7 mm Hg at 25 deg C [R14] OCPP: *Vapor specific gravity: 18.8 (calculated) [R4] *0.20 mg/l water at 24 deg C /Practical grade/ [R10, 879] *Highly lipophilic [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Supports combustion [R6] *Nonflammable [R16] REAC: *... On contact with acids or acid fumes they evolve highly toxic chloride fumes. Some organic chlorides decompose to yield phosgene. /Chlorides/ [R17] DCMP: +Decomposes above 500 deg C to give hexachlorobenzene; hexachloropentadiene was found in small amounts in the thermal residue; the products identified from vapor phase were carbon monoxide, carbon dioxide, hydrogen chloride, chlorine, carbon tetrachloride, and phosgene. [R14] ODRT: *Odor low 5.0667 mg/cu m; Odor high 5.0667 mg/cu m. [R18] SERI: *... Moderate skin irritant. [R19] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R20, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R20, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R20, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R20, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R20, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R20, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R20, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R20, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R20, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R20, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SSL: +VERY STABLE AT NORMAL TEMPERATURES. [R14] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R22] +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R20, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R20, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R20, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R20, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R20, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R20, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R20, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R20, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R20, 1979.17] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R23] *Group II Containers: Non-combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple-rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R24] +This highly chlorinated cmpd is unaffected by mineral acids (hydrochloric acid, nitric acid and sulfuric acid). It would be expected to be extremely resistant to oxidation except @ the high temp of an efficient incinerator. Recommendable methods: Incineration and storage. Peer review: Long-term storage may be recommendable for the substance. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R25, 209] +Incineration: Chemical degradation and a combination of chemical degradation and incineration in a standard incinerator were found to be unsatisfactory methods for decontaminating the shipment cartons. Extraction of the mirex from the drums and liners with methylene chloride and hexane respectively were deemed possible but expensive. Alternative solutions to the problem are A) Burn the drums and liners in an incinerator capable of decontaminating mirex, B) Return cartons to the manufacturer for reuse. [R25, 210] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: no data; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/ [R26] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R20, 1979.23] HTOX: *Symptomatalogy (from technical BHC or the gamma isomer): 1. After ingestion a latent period varying from about 1/2 hr to several hr. 2. Hyperirritability and central nervous excitation: notably vomiting, faintness, tremor, restlessness, muscle spasms, ataxia, and clonic and tonic convulsions. 3. Infants and children may experience hyperpyrexia presumably as a consequence of the convulsions. 4. Postictal coma of variable duration, leading eventually (within 24 hr) to respiratory failure and death. 5. A second bout of convulsions may occur after consciousness is regained. Retrograde amnesia is described. 6. Pulmonary edema (with cyanosis and dyspnea) was observed in two fatally poisoned children. 7. From exposure to lindane vapors (and its thermal decomp products), headache, nausea, vomiting, irritation of eyes, nose, and throat. Repeated exposure may lead to agranulocytosis or even fatal aplastic anemia. 8. Dermatitis and urticaria occasionally. /Lindane/ [R27] NTOX: *RATS FED MIREX IN THE DIET FOR 166 DAYS HAD MINIMAL PATHOLOGIC CHANGES IN LIVER WITH 5 PPM AND DEFINITE ENLARGEMENT OF LIVER CELLS, CYTOPLASMIC INCLUSIONS, AND BILIARY STASIS WITH 25 PPM. [R28, 551] *REDUCED LITTER SIZE WAS NOTED IN 2 STRAINS OF MICE FED A DIETARY CONCENTRATION OF 5 MG/KG DIET MIREX BEFORE AND AFTER MATING. PROGENY FROM FEMALE RATS FED A DIET CONTAINING 25 MG/KG DIET BEFORE AND AFTER MATING HAD A REDUCED SURVIVAL RATE AND A HIGH INCIDENCE OF CATARACTS, WHILE PROGENY FROM FEMALES MAINTAINED ON A LEVEL OF 5 MG/KG DIET APPEARED TO BE NORMAL. [R29] *Rats were given daily oral doses of 1.5, 3, 6, and 12.5 mg/kg body wt mirex on days 6-15 of gestation; the highest dose caused maternal toxicity, pregnancy failure, decreased fetal survival, reduced fetal weight and an increased incidence of visceral anomalies. Maternal toxicity and an increased incidence of fetal visceral anomalies were also observed with 6 mg/kg body wt. Lower doses produced minimal or no adverse effects. No perceptible reproductive effects were observed in bobwhite quail fed 40 mg/kg diet mirex or in mallard ducks fed 1 or 10 mg/kg diet. [R29] *Mirex inhibits ovulation induced in immature rats by pregnant mare serum, and the reaction is dosage-related in the range of 5-660 mg/kg. No effect is evident at dosage of 2.8 mg/kg. The number of ova can be increased by admin human chorionic gonadotropin 56 hr after pregnant mare serum, indicating that mirex inhibits pregnant mare serum induced ovulation by means of an effect on the central nervous system controlling the release of luteinizing hormone, rather than a direct effect on the ovary. [R2, 256] *MIREX WAS ADMIN TO PREGNANT RATS BY GAVAGE AT 5-38 MG/KG/DAY ON DAYS 7-16 OF GESTATION. EDEMA RESULTED IN FETUSES AT RATE OF 5.8% FOR 5 MG/KG/DAY GROUP AND UP TO 74% FOR 19 MG/KG/DAY GROUP. CATARACTOGENICITY STUDIES WERE PERFORMED IN RAT AND MOUSE DAMS AND NEONATES FOLLOWING ADMIN BY GAVAGE OF MIREX. 10 MG/KG WAS CATARACTOGENIC IN BOTH ALBINO AND NON-ALBINO RATS. 12 MG/KG WAS CATARACTOGENIC IN MICE. IN RATS, CATARACTS OCCURRED IN 13 DAYS AND IN MICE AFTER 20 DAYS. [R30] *In prenatal study, dams were intubated with 6 mg/kg/day mirex on days 8-15 of gestation and fetal blood samples were obtained on days 18 and 20. In postnatal studies, litters were culled to 8 pups at birth; dams were intubated with 10 mg/kg/day mirex on days 1-4 postpartum, and blood was drawn from pups at 6-14 days. Plasma glucose levels were decr more than 40% in mirex-treated fetuses which developed cataracts. Postnatal exposure did not alter plasma glucose. Hypoproteinemia was a common factor related to cataractogenesis induced by prenatal or postnatal exposure, and may have been a causative factor. Although hypoglycemia may have been a contributing factor in prenatal cataractogenesis, it did not seem to be implicated in postnatal cataractogenesis. [R31] *... /Mirex was admin/ in rats at levels of 6 and 12.5 mg/kg. ... Gavaging the mothers on days 6 through 15 /of gestation produced/ ... an increased incidence of cleft palate ... along with several other types of defects. [R32] *Pregnant rats received an oral dose of 10 mg/kg mirex on day 5 (for day 6 determinations (detn)), days 5-9 (for day 10 detn), days 5-14 (for day 16 detn), or no treatment (controls). On day 6, absolute blood flow (ml/min) to stomach was reduced. On day 10, maternal cardiac output was decr, wt of uterus, ovaries, heart, and spleen were decr, and liver wt were incr. Total conceptus and absolute blood flow to lungs, urinary bladder, kidneys, ovaries, and uterus were decr on day 10. Mean number of viable fetuses/litter was reduced to 5.4 in treated group compared to 11.6 in day 16 and resorption wt and absolute blood flow were incr in treated group. Edema was observed in all live fetuses from treated dams that maternal toxicity may play large role in adverse fetal outcome and that hypoxia during organogenesis may contribute to reduced fetal wt, edema, and death observed on day 16. [R33] *Male and female rats were fed mirex at 5.0, 10, 20, or 40 ppm for 91 days prior to mating, 15 days during mating and through gestation and lactation. The 5.0 ppm dose resulted in fewer positive vaginal smears. Females dosed with 40 ppm had decr wt gain but food consumption was constant. Litter size was decr at all treatment levels but survival of pups was only affected at highest dose levels. Females fed 40 ppm had enlarged livers, elevated cholesterol and total protein levels. Histological changes were apparent in all treatment groups in livers and thyroid of females and pups. [R34] *Prenatal exposure to very low levels of mirex (less than 1% of single LD50 dose) can induce cardiac arrhythmias in neonatal rat pups. These problems can be sufficiently severe to cause death. [R35] *Groups of 18 male and 18 female (C57BL/6xC3H/Anf)F1 mice and 18 male and 18 female (C57BL/6xAKR)F1 mice were given single sc injections of 1000 mg/kg body wt mirex (98% pure) in 0.5% gelatin on the 28th day of life and were observed until they were 78 wk of age, at which time 16, 17, 17, and 15 mice were still alive. A group of negative controls comprised of untreated animals and animals treated with gelatine, corn oil, or dimethylsulfoxide. Proportions of necropsied mice that developed reticulum-cell sarcomas were 6/18, 0/17, 1/17, and 3/18 in the 4 groups, respectively; 2/16 gelatin-treated control males and 8/141 negative control males of the 1st strain developed these tumors (P greater than 0.01 AND P greater than 0.01, respectively). The corresponding proportions of mice with hepatomas were 2/18, 0/17, 4/17 and 1/18; 1/18 gelatin-treated control males and 1/161 negative control males of the 2nd strain developed such tumors (P greater than 0.05 AND P less than 0.01, respectively). Total incidences in the 2 strains (males plus females) of reticulum-cell sarcomas was significantly greater than that in the controls (6/35 versus 9/295 and 4/35 versus 5/318). [R36] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF)F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR)F1 MICE RECEIVED MIREX (98% PURE) ACCORDING TO FOLLOWING SCHEDULE: 10 MG/KG BODY WT IN 0.5% GELATIN AT 7 DAYS OF AGE BY STOMACH TUBE AND THE SAME AMT (NOT ADJUSTED FOR INCR BODY WT) DAILY UP TO 4 WK OF AGE; SUBSEQUENTLY, THE MICE WERE FED 26 MG/KG DIET MIREX. THE DOSE WAS THE MAXIMUM TOLERATED DOSE FOR INFANT AND YOUNG MICE (BUT NOT NECESSARILY THAT FOR ADULTS). THE EXPERIMENT WAS TERMINATED AT 70 WK OF AGE, WHEN ALL ANIMALS HAD DIED. TUMOR INCIDENCES WERE COMPARED WITH THOSE IN 79-90 NECROPSIED MICE OF EACH SEX AND STRAIN, WHICH HAD EITHER BEEN UNTREATED OR HAD RECEIVED GALATINE ONLY. HEPATOMAS WERE FOUND IN 6/18 MALE AND 8/16 FEMALE NECROPSIED MICE OF THE 1ST STRAIN (COMPARED WITH 8/79 and 0/87 IN THE CORRESPONDING CONTROLS) AND IN 5/15 MALE AND 10/16 FEMALE MICE OF THE 2ND STRAIN (COMPARED WITH 5/90 and 1/82 IN THE CORRESPONDING CONTROLS) (FOR EACH OF THE 2 SEXES OF THE 2 STRAINS, P LESS THAN 0.05) (INNES ET AL, 1969). [R37] *In a preliminary report of a study by the NCI, groups of 26 CD rats of each sex, 6 wk old, were fed 50 or 100 mg/kg diet mirex (99% pure) for 18 mo, except during first 10 wk of treatment, when dietary concentrations were 40 and 80 mg/kg diet, respectively. ... 20 Untreated rats of each sex were used as controls. All survivors were killed 24 mo after treatment began; a dose-related effect on survival was noticed after the 1st yr of treatment: at the end of the study 65% of the female and 55% of the male controls were still alive, but survival rates were poorer in the treated group. ... Neoplastic liver nodules ... were observed in 2 males and 4 females given the lowest dose and in 7 males (p less than 0.05) and 4 females given the highest dose. Of the 17 rats with neoplastic nodules, 1 male at lowest dose and 4 males and 1 female at the highest dose also had well-differentiated liver-cell carcinomas. No metastases were observed ... No neoplastic liver nodules were found among controls. Liver megalocytosis was observed in total of 48 treated versus 0 in controls. ... Eight other tumors were found in treated animals: 1 lipoma and 1 squamous-cell carcinoma the ear-duct in males given the lowest dose; 2 fibromas, 1 fibrosarcoma, and 1 squamous-cell carcinoma of the ear-duct in males given the highest dose; 2 fibrosarcomas in females given the highest dose. No such tumors were observed in controls (Ulland et al, 1977). [R36] *Effects of chronic exposure to dietary mirex was investigated in rat livers over 13 mo period. The nodules, such as adenomas and carcinomas, were identified in histologic sections obtained from companion samples, part of which was used for analysis of nuclear ploidy. Mirex disturbed the distribution of nuclei in the ploidy classes, selectively reducing the number of tetraploid cells. The reduction of tetraploid cells corresponds to the nature of the tumor, the most significant effect being noted in hepatocellular carcinomas. [R38] *Mirex induces microsomal enzymes in rats and mice. In both, induction occurs at dietary level of 1 ppm (about 0.05 and 0.12 mg/kg/day in the rat and mouse, respectively), the lowest level tested. At this dosage level, not all enzymes tested may be induced, and there may be no significant increase in liver weight, microsomal protein, or cytochrome p450. ... The induction of microsomal enzymes by mirex is complex. Not all enzymes commonly tested are induced even under circumstances in which microsomal protein and cytochrome p450 are increased. Components of cytochrome p450 induced by mirex and separated by gel electrophoresis show quantitative as well as qualitative differences from controls. In rats, the activities of liver lactic dehydrogenase, and glutamic-oxaloacetic transaminase were reduced by dietary levels of mirex as low as 10 ppm. [R2, 255] *Effect of mirex, 2 monohydrogen and 2 dihydrogen mirex derivatives, and chlordecone on several hepatic parameters were studied 2 days following single oral dose of 100 mg/kg in female rats. All cmpd incr microsomal cytochrome p450 content, reduced nicotinamide adenine dinucleotide cytochrome C reductase activity and hepatic ascorbic acid concn. Microsomal protein concn was generally incr. All cmpd except chlordecone incr relative liver wt and activities of aminopyrine N-demethylase and p-nitroanisole O-demethylase. Hepatic concn of protein and glutathione were unaltered. [R39] *Ip admin of mirex at 50 mg/kg/day for 4 days to male rats resulted in 264% incr in free radical activity in liver microsomes as measured by an in vitro assay for hydroxyl radicals. [R40] *IN RATS INTRAGASTRICALLY ADMIN MIREX, BEHAVIOR CHANGES WERE NOTED AFTER AN AVG PERIOD OF 11, 16, and 33 DAYS @ 25, 12.5 and 5 MG/KG, RESPECTIVELY. [R41] *LIGHT AND ELECTRON (EM) MICROSCOPIC OBSERVATIONS REVEALED HISTOPATHOLOGICAL LESIONS IN LIVERS OF ADULT MALE MAI-WISTAR RATS ADMIN 200 MG/KG VIA STOMACH TUBE. LIPID ACCUMULATIONS OCCURRED AND APPEARED IN DISTINCTIVE PERIPORTAL ZONATION PATTERN. ADDITIONAL LESIONS WERE DETECTED IN CENTRILOBULAR ZONES AND INCLUDED SEVERE GLYCOGEN DEPLETION, CHANGES IN THE ENDOPLASMIC RETICULUM, DILATED ENDOPLASMIC RETICULUM CISTERNAE, FREE RIBOSOMES, AND PROLIFERATION OF SMOOTH ENDOPLASMIC RETICULUM. PERIPORTAL HEPATOCYTES EXHIBITED APPARENT REDUCTION IN CYTOPLASMIC RETICULUM. MYELIN FIGURES WERE SOMETIMES ASSOCIATED WITH DEVELOPING LIPOSOMES. BIOCHEMICAL STUDIES SHOWED GLYCOGEN LEVELS GREATLY DROPPED, LIPID CONTENT GREATLY INCR AND PROTEIN/DNA AND RNA/DNA VALUES DECR. [R42] *THE ACUTE AND SUBCHRONIC (13 WK) TOXICITY OF ORALLY ADMIN MIREX WAS STUDIED IN DOGS, RATS AND RABBITS. NO TOXICITY WAS EVIDENT IN RABBITS EXPOSED PERCUTANEOUSLY TO 3.33 OR 6.67 G OF MIREX BAIT/KG, 6-7 HR EACH DAY, 5 DAYS/WK FOR 9 WK AND NO TOXICITY WAS OBSERVED IN BEAGLE DOGS FED 4 and 20 PPM IN DIETS FOR 13 WK. AT 100 PPM 2 BEAGLE DOGS DIED. CHANGES OBSERVED WERE DECR IN WT GAIN, ABNORMAL BLOOD CHEMISTRY VALUES, INCR LIVER/BODY WT RATIOS, AND DECR SPLEEN/BODY WT RATIOS. NO SIGNIFICANT ADVERSE EFFECTS WERE OBSERVED IN RATS AT LEVELS OF 5, 20, 80 PPM. THE FOLLOWING EFFECTS WERE OBSERVED IN RATS AT 320 and 1280 PPM: DEPRESSED GROWTH, DECREASED HEMOGLOBIN CONCENTRATIONS, ELEVATED WHITE CELL COUNTS, ENLARGED LIVERS, AND DEATHS IN THE 1280 PPM GROUPS. ACUTE ORAL LD50 IN MONGREL DOGS WAS GREATER THAN 1000 MG/KG. [R43] *After daily oral admin of mirex to male mice at 10 mg/kg in corn oil vehicle (10 ml/kg), mortality began at day 10 with LT50 (median cumulative lethal dose) of 132 mg/kg. Symptoms of toxicity incl severe diarrhea, decr food and water consumption, and body wt reduction. Decr in blood glucose levels were due to reduction in liver glycogen levels. [R44] *The adaptive liver growth response was investigated in intact and adrenalectomized rats. When adult male rats were given a single oral dose of mirex (100 mg/kg), there was a 72% incr in relative liver wt in 72 hr. There was also a wave of DNA synthesis which peaked at 48 hr and decr to control values by 96 hr post mirex dose. In mirex-dosed adrenalectomized animals, the relative liver wt was incr by only 38% and there was sustained DNA synthesis. When mirex-dosed adrenalectomized rats were given corticosterone supplements, the relative liver wt response was similar to the relative liver wt response in intact mirex-dosed rats. The 48-hr DNA synthesis peak seen in intact mirex-dosed rats was eliminated. Mirex-induced adaptive liver growth apparently has 2 components: a hypertrophic component which is mediated by corticosterone, and a hyperplastic component which is independent of corticosterone. [R45] *SIGNS OF INTOXICATION /IN MALLARDS AND PHEASANTS FROM ACUTE ORAL ADMIN/: MILD ATAXIA, WITHDRAWAL. SIGNS APPEARED AS SOON AS 40 MIN AFTER TREATMENT. /SAMPLE PURITY 98%/ [R46] *BOBWHITE QUAIL RECEIVED DIETARY CONCENTRATIONS OF 1, 20, and 40 PPM. EGGS FROM F0 GENERATION BREEDERS WERE NOT AFFECTED DELETERIOUSLY BY MIREX AS MEASURED BY EMBRYO SURVIVAL TO 3 WK AND NUMBER OF EGGS FAILING TO HATCH. NO CHICK MORTALITY ATTRIBUTABLE TO STRESS WAS FOUND. [R47] *Mirex fed to captive American kestrels (Falco sparverius) at 8 ppm produced marked decline in sperm concn with a slight compensatory incr in semen vol resulting in a 70% decr in sperm numbers. No effect on sperm motility was observed. [R48] *The survival of Hyalella azteca was reduced relative to that of Crangonyx pseudogracilis during exposure to mirex in water for a 13 day period. This was correlated to greater bioaccumulation of mirex by Hyalella azteca than by Crangonyx pseudogracilis. [R49] *Mirex ... has been shown to produce cataracts in suckling rats when fed to the mother. The mother's milk is the main vehicle. [R50] *Accumulation data suggest that the organochlorine insecticides may alter immune function. ... Chickens exposed to mirex had significantly depressed levels of IgG and IgM, although specific antibody responses were normal. ... Studies ... of chickens exposed to ... mirex revealed a marked reduction in total antibody production and serum IgG level, although serum IgM levels were elevated. The alteration in IgG levels was thought to be related to altered T-cell function. [R28, 273] *Photosynthesis of plankton is inhibited by 16, 10, 33 and 19% after expsoure to 1 ppb after 5, 10, 15 and 20 days, respectively. ... Algae: Tetrahymena pyriformis 0.9 ppb; 16.03% decr in population size; 96 hr growth test. ... [R10, 881] *... Striped hermit crab, Clibanarius vittatus: mortalities in 10 to 70 days using an avg concn of 0.038 ug/l (flow through) ... lab mice: 10 ppm in feed: 100% mortality in 60 days; old field mice (Peromyscus polionutus): at 17.8 ppm in feed: 50% mortality in 105 days, 92% mortality in 450 days. ... [R10, 882] *Procambarus blandingi (crayfish) juveniles were exposed to 1 to 5 ug/l for 6 to 144 hours, transferred to clean water and observed for 10 days. After 5 days in clean water, 95 percent of the animals exposed to 1 ug/l for 14 hours were dead. Exposure to 5 ug/l for 6, 24, and 58 hours resulted in 26, 50 and 98 percent mortality 10 days after transfer to clean water. Crayfish, Procambarus hayi, were exposed to 0.1 and 0.5 ug/l for 48 hours. Four days after transfer to clean water, 65 percent of the animals exposed to 0.1 ug/l were dead. At the 0.5 ug/l concentration, 71 percent of the animals were dead after 4 days in clean water. Tissue residue accumulations (wet weight basis) ranged from 940 to 27,210- fold above water concentrations. [R51] *In three of four 28 day seasonal flow-through experiments, reduced survival of Callinectes sapidus, Penaeus durorarum, and grass shrimp, Palaemonetes pugio /was found/ at levels of 0.12 ug/l in summer, 0.06 ug/l in fall and 0.09 ug/l in winter. [R52] +Conclusions: Under the conditions of these 2-year feed studies of mirex, there is clear evidence of carcinogenic activity for male and female F344/N rats, as primarily indicated by marked increased incidences of benign neoplastic nodules of the liver, as well as by increased incidences of pheochromocytomas of the adrenal gland and transitional cell papillomas of the kidney in males and by incr incidences of mononucleart cell leukemia in females. [R53] NTXV: +LD50 Rat male oral 306 mg/kg; [R7] *LD50 Rabbit subcutaneous 800 mg/kg; [R7] *LD50 Rabbit dermal 800 mg/kg body wt /From table/; [R54] *LD50 Rat dermal 2000 mg/kg body wt /From table/; [R55] *LD50 Dog male oral 1000 mg/kg body wt (in corn oil) /From table/; [R56] *LD50 Hamster female oral 125 mg/kg body wt /From table/; [R57] *LD50 Hamster male oral 250 mg/kg body wt /From table/; [R57] *LD50 Rat male oral 740 mg/kg body wt /From table/; [R55] *LD50 Rat female oral 600 mg/kg body wt (in corn oil) /From table/; [R55] *LD50 Rat female intraperitoneal 365 mg/kg body wt /From table/; [R58] *LD50 Rabbit dermal 800 mg/kg body wt /From table/; [R54] ETXV: *LC50 Colinus virginianus (bobwhite quail) oral 2511 ppm in 5 day diet (95% confidence limit 2160-2908 ppm) /purity, 98%/; [R59] *LC50 Japanese quail oral greater than 5000 ppm in 5 day diet (20% mortality @ 5000 ppm) /purity, 98%/; [R59] *LC50 Phasianus colchicus, (ring-necked pheasants) oral 1540 ppm in 5 day diet (95% confidence limit 1320-1789 ppm) /purity, 98%/; [R59] *LC50 Anas platyrhynchos, (mallard ducks) oral greater than 5000 ppm in 5 day diet (no mortality to 5000 ppm) /purity 98%/; [R59] *LD50 Anas platyrhynchos, (mallard ducks) oral greater than 2400 mg/kg, 3 mo old males /purity 98%/; [R46] *LD50 Phasianus, (pheasants) oral greater than 2000 mg/kg, 3 mo old females /purity 98%/; [R46] *EC50 Daphnid Simocephalus serrulatus, greater than 0.100 mg/l/48 hr at 16 deg C, 1st instar /technical material, 98%; static bioassay without aeration/; [R60] *EC50 Daphnia pulex (daphnid), greater than 0.100 mg/l/48 hr at 16 deg C, 1st instar /technical material, 98%; static of bioassay without aeration/; [R60] *EC50 Daphnia magna (daphnid), greater than 0.100 mg/l/48 hr at 17 deg C, 1st instar /technical material, 98%; static bioassay without aeration/; [R60] *EC50 Chironomus plumosus (midge), greater than 1.0 mg/l/48 hr at 22 deg C, 4th instar /technical material, 98%; static of bioassay without aeration/; [R60] *LC50 Gammarus pseudolimnaeus (scud), greater than 1.0 mg/l/96 hr at 17 deg C, mature /technical material, 98%; static of bioassay without aeration/; [R60] *LC50 Salmo gairdnerii (rainbow trout), greater than 100 mg/l/96 hr at 12 deg C, wt 1 g /technical material, 98%; static of bioassay without aeration/; [R60] *LC50 Perca flavescens (yellow perch), greater than 100 mg/l/96 hr at 15 deg C, wt 2.6 g /technical material, 98%; static of bioassay without aeration/; [R60] *LC50 Pimephales promelas (fathead minnow), greater than 100 mg/l/96 hr at 18 deg C, wt 1.3 g /wettable powder, 50%; static bioassay without aeration/; [R60] *LC50 Lepomis macrochirus (bluegill sunfish), greater than 100 mg/l/96 hr at 18 deg C, wt 1.1 g /wettable powder, 50%; static of bioassay without aeration/; [R60] *LC50 Stizostedion vitreum (walleye), greater than 100 mg/l/96 hr at 18 deg C, wt 1.4 g /wettable powder, 50%; static of bioassay without aeration/; [R60] *LD50 Shrimp 1.01 ppm/72 hr /Conditions of bioassay not specified/; [R4] *A concentration of 0.1 ug/l technical grade mirex in flowing seawater was lethal to juvenile pink shrimp, Panaeus durorarum, in a 3 wk exposure; [R61] *In static tests with larval stages (megalopal) of the mud crab, Rhithropanopeus harrisii, reduced survival was observed in 0.1 ug/l mirex; [R61] NTP: +Mirex (95% pure) ... was studied for toxicologic and carcinogenic effects by administering diets containing 0, 0.1, 1.0, 10, 25, or 50 ppm mirex to groups of 52 F344/N rats of each sex for 104 wk. ... During the first 6 months of the 2 yr study, because of good survival and the absence of observable toxic effects in female rats, additional groups (termed second study) of 52 F344/N female rats were started at higher dietary concn of 0, 50, and 100 ppm mirex. Based on feed consumption data, the estimated average intake per day was 0, 0.007, 0.075, 0.75, 1.95, and 3.85 mg mirex/kg body weight for male rats and female rats in the first study, and 0, 3.9, and 7.7 mg/kg for female rats in the additional study. Conclusions: Under the conditions of these 2-year feed studies of mirex, there is clear evidence of carcinogenic activity for male and female F344/N rats, as primarily indicated by marked increased incidences of benign neoplastic nodules of the liver, as well as by increased incidences of pheochromocytomas of the adrenal gland and transitional cell papillomas of the kidney in males and by incr incidences of mononucleart cell leukemia in females. [R53] ADE: *Mirex is poorly absorbed from the GI tract. [R2, 254] *IN TWO STUDIES OF THE FATE OF MIREX IN RATS, NO METABOLITES WERE DETECTED. ALTHOUGH THERE WAS CONSIDERABLE EXCRETION OF MIREX, MAINLY IN FECES (58%) QUITE EXTENSIVE STORAGE IN TISSUES WAS OBSERVED (FAT, 27.8%; MUSCLE, 3.2%; LIVER, 1.75%; KIDNEY, 0.76%). [R62] *WHEN SINGLE DOSE OF MIREX WAS ORALLY ADMINISTERED TO RATS, 58.5% OF MIREX-(14)C WAS EXCRETED IN FECES AND 0.69% IN URINE AFTER 7 DAYS. TISSUE STORAGE REACHED 27.8 PPM IN FAT IN THE SAME TIME. ... PEA AND BEAN PLANT ROOTS CONCENTRATED MIREX; AND SMALL AMT WERE TRANSLOCATED TO AERIAL PARTS WHEN PLANTS GREW FOR 2 DAYS IN WATER CONTAINING 1-10 PPM MIREX. [R63] *RATS GIVEN SINGLE ORAL DOSES OF 0.2 MG/KG BODY WT (14)C-MIREX EXCRETED 15.2% IN FECES WITHIN 2 DAYS AND 3% OVER THE SUBSEQUENT 5 DAYS; ONLY TRACES WERE FOUND IN URINE. ABOUT 1 UG/G WAS FOUND IN ADIPOSE TISSUE THROUGHOUT THE 28 DAYS OF THE EXPERIMENT. OTHER TISSUE CONCENTRATIONS WERE LOWER AND DECLINED WITHIN THE FIRST 7 DAYS AFTER DOSING. [R29] *IN A REPRODUCTION STUDY IN RATS, MIREX WAS TRANSFERRED THROUGH THE PLACENTA AND EXCRETED IN THEIR MILK. RATS FED 25 PPM MIREX (2.3 MG/KG BODY WT/DAY) IN THEIR DIET FOR 78 DAYS EXCRETED AN ARITHMETIC MEAN OF 11.3 PPM IN THEIR MILK. A MEAN OF 0.23 PPM MIREX WAS FOUND IN FETUSES REMOVED ON 19TH DAY OF GESTATION FROM DAMS WHICH HAD BEEN FED 25 PPM MIREX. [R64] *MIREX RESIDUES ... PRESENT IN 10/12 STARLINGS EXAM RANGED FROM 0.01-1.66 PPM. HIGHEST CONCN WERE FOUND IN FATTY TISSUE OF FISH (0-11.2 PPM), OF BIRDS (TRACES-104.4 PPM), OF DEER (0-0.3 PPM) AND OF BEEF (0-0.1 PPM). CONCN IN LIVER RANGED FROM 0-0.7 PPM FOR FISH AND 0-7.5 PPM FOR BIRDS; AND SMALL QUANTITIES HAVE ALSO BEEN DETECTED IN BRAIN, HEART, AND EGGS OF BIRDS. [R65] *MIREX WAS ABSORBED MORE RAPIDLY FROM DIGESTIVE TRACT OF FEMALE QUAIL THAN OF MALES AND RAPIDLY EXCRETED. MALE QUAIL EXCRETED MORE VIA FECES THAN DID FEMALE QUAIL. NO METABOLISM OF MIREX WAS OBSERVED. ... COWS WERE FED RATIONS CONTAINING MIREX. ANALYSES OF FAT AND MILK WERE THEN CONDUCTED. RESIDUE LEVELS OVER 31 WK FEEDING PERIOD DID NOT EXCEED 0.08 PPM IN MILK AND 1.87 IN OMENTAL FAT WHEN MIREX WAS FED @ 1.00 PPM. IN EGGS OF HENS FED 1.06 PPM MIREX, RESIDUE LEVEL REACHED 2.03 PPM @ 28 WK AND THEN BEGAN DECLINING. [R66, 1978.155] *PRELIMINARY DISCLOSURE THAT MIREX YIELDS NO MAMMALIAN METABOLITES HAS ... BEEN CONFIRMED BY A FULL REPORT OF LONG-TERM FEEDING TRIALS IN RAT. IN FAT OF FEMALE RATS, CONCN OF MIREX HAD DECLINED BY ONLY 40% SOME 10 MO AFTER CESSATION OF DAILY DOSING. THIS RANKS THIS POLYCHLORINATED CAGE CMPD ... AS ONE OF MOST PERSISTENT XENOBIOTICS YET ENCOUNTERED. [R67] *EXPERIMENTS WERE CONDUCTED TO DETERMINE THE LEVELS OF MIREX IN EGGS AND LIVERS OF SLIDER TURTLES AND TERRESTRIAL BOX TURTLES. LIVER VALUES FOR SLIDER TURTLES WERE 0.01 TO 2.1 PPM AND 0.04 TO 2.2 PPM FOR EGGS. LEVELS FOR BOX TURTLE RANGED FROM 0.68 TO 4.1 PPM IN LIVER AND 1.4 TO 2.5 PPM IN EGGS. [R68] *BOBWHITE QUAIL WERE GIVEN 1, 20, and 40 PPM MIREX IN DIET. MALE ADIPOSE TISSUE CONTAINED APPROX 10 TIMES THE AMT IN DIET. BOTH SEXES CONCENTRATED MIREX IN FAT AND BREAST TISSUES IN DIRECT PROPORTION TO INTAKE. [R47] *Oral and iv pharmacokinetics of mirex in albino rats were examined with 10 mg/kg (14)C-mirex (1.45 mCi/nmol). Cumulative urinary elimination 3 wk after treatment was less than 1% for either route. Cumulative fecal elimination 3 wk after treatment was less than 7% following iv exposure but was 18 to 45% for oral-dosed animals. In oral dosed animals most of fecal mirex was recovered within 48 hr of treatment and was attributed to elimination of nonabsorbed mirex. [R69] *Most organochlorines are metabolized slowly and are excreted primarily in the feces. Excretion /of mirex/ occurs in ... months to years. ... [R70] *(14)C-Mirex was given to female Rhesus monkeys. Excretion and tissue distribution was essentially the same when given either orally or iv. Less than 0.6% of the dose appeared in urine and only 7% of the (14)C appeared in feces after slightly more than one yr. [R71, 362] METB: *WHEN SINGLE DOSE OF MIREX WAS ORALLY ADMIN TO RATS, 58.5% OF MIREX-(14)C WAS EXCRETED IN FECES AND 0.69% IN URINE AFTER 7 DAYS. ... NO METABOLITES WERE DETECTED NOR WERE ANY DETECTED AFTER MIREX INCUBATION WITH PREPARATIONS FROM RAT, MOUSE, AND RABBIT LIVERS AND PLANT ROOTS. [R63] +Metabolites of mirex identified in the rat include 2,8-dihydromirex and 5,10-dihydromirex. [R2, 254] *Mirex is probably oxidized to chlordecone. The main metabolite of chlordecone is chlordecone alcohol, which appears in human bile as glucuronic acid conjugates. [R72] BHL: *... IN RATS ... HALF LIVES FOR BIPHASIC EXCRETION OF MIREX WERE 38 HR AND 100 DAYS, RESPECTIVELY. [R62] *In female goats, mirex levels decrease to one half their original concentration 34-52 wk after discontinuance of exposure. ... [R73] ACTN: *PRETREATMENT OF MALE RATS WITH MIREX (50 MG/KG ORALLY FOR 3 DAYS) CAUSED A 91% SUPPRESSION OF BILIARY EXCRETION OF ENDOGENOUS METABOLITES OF IMIPRAMINE. BILIARY EXCRETION OF SULFOBROMOPHTHALEIN WAS ALSO SUPPRESSED BY 90%. RESULTS SUGGEST THAT MIREX-INDUCED IMPAIRMENT OF HEPATOBILIARY FUNCTION IS NOT SPECIFIC TO SUBSTRATES. THE MECHANISM OF MIREX-INDUCED IMPAIRMENT IS LOCATED AT THE SITE OF THE TRANSFER OF OTHERWISE READILY EXCRETABLE SUBSTANCES SUCH AS METABOLITES OF IMIPRAMINE AND SULFOBROMOPHTHALEIN. [R74] *Reduced biliary excretion rates were observed for exogenous taurocholic acid (3 or 10 umol/kg) after 15 day dietary pretreatment of cannulated rats with 100 ppm mirex in feed. Hepatobiliary dysfunction was dose-dependent. Maximal redn in excretory rate on a per g of liver basis (50%) followed treatment with 100 ppm. Bile-to-plasma concn ratios for sucrose incr in parallel with mirex-impaired biliary excretion. Bile flow (on a per g of liver basis) and biliary clearance of erythritol were reduced by 100 ppm. These effects occurred in absence of substantial hepatocellular necrosis, whereas liver enlargement incr in a dose-dependent manner. Hepatobiliary dysfunction induced by mirex is at least partially due to increased permeability of the biliary tree. [R75] *Toxicity and neurotoxic effects of mirex were evaluated in the American cockroach. Severity of symptoms correlated with ability of mirex to increase spontaneous activity and prolong synaptic activity after-discharge in ganglia of ventral nerve cord. After-discharge across the metathoracic ganglion was consistent with a characteristic wing splaying symptom in poisoned cockroaches. The actions of hemicholinium-3 and nicotine on nerve cords from mirex-poisoned cockroaches are described and are consistent with a hypothesis that the increased spontaneous activity and after-discharge are the result of enhanced transmitter release in ganglia of poisoned animals. [R76] *Mirex and its photoderivatives are effective inhibitors of ATPase system. [R77] *Mirex stimulates hepatic microsomal cytochrome p450 oxidative metabolism and causes proliferation of the smooth endoplasmic reticulum of the liver. [R28, 551] INTC: *The excretion of mirex was reduced when fed to captive American kestrels (Falco sparverius) at 8 ppm in combination with 33 ppm Aroclor 1254, and the combination diet reduced the relative concn of Aroclor in the testes. Testicular mass of the PCBs plus mirex group was increased. Apparently, migratory flesh-eating birds feeding on a PCB- or mirex-contaminated food chain could consume enough toxicant to alter their semen quality in that breeding season, which, when coupled with altered courtship, could reduce fertility of eggs and reproductive fitness. [R78] *Ring doves (Streptopelia risoria) with breeding experience were fed a control diet or 1 of 2 dosages of a mixture of DDE, PCBs, mirex, and photomirex throughout an isolated period of 90 days and 1 reproductive cycle. The mixture altered the nature and duration of courtship behavior, incubation and brooding behavior, and androgen levels of males, and estrogen and progesterone levels of females in a dose-related fashion. Thyroxine levels were incr in both sexes in dose-related fashion and there was an alteration of prolactin levels. Correlations were obtained between behavior and some hormones. There was marked dose-related decr of 15 and 50% in the number of squabs fledged/nesting attempt. Squabs of pairs receiving high dosage were of lower wt. [R79] *Treatment of gerbils with mirex at 10 mg/kg/day for 5 days protects them from carbon tetrachloride hepatotoxicity based on elevations of serum glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase and decreases in hepatic microsomal enzymes. [R80] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Mirex is a highly stable insecticide /formerly/ used for fire ant control in the southeastern US. Mirex was also employed as a flame-retardant. Release into the environment has occurred via effluents from manufacturing plants and sites where mirex was utilized as a fire resistant additive to polymers, and at points of application where it was used as a insecticide. Mirex is expected to persist in the environment despite the 1978 ban on its use in the US. For the most part mirex is resistant to biological and chemical degradation. Photolysis of mirex may occur. However, sorption is likely to be a more important fate process. Persistent compounds such as kepone, and monohydro- and dihydro- derivatives of mirex have been identified as products of extremely slow transformation of mirex. Mirex has been shown to bioconcentrate in aquatic organisms. A Koc value of 2.4X10+7 indicates mirex will strongly adsorb to organic materials in soils and sediments. Therefore mirex is expected to be immobile in soil and partition from the water column to sediments and suspended material. A Henry's Law Constant for mirex of 5.16X10-4 atm-cu m/mole at 22 deg C suggests rapid volatilization may occur from environmental waters and moist soils where absorption does not dominate. Based on this Henry's Law Constant, the volatilization half-life from a model river (22 deg C; 1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 10.7 hr; however, this estimation neglects the potentially important effect of adsorption. The volatilization half-life from an environmental pond, which considers the effect of adsorption, can be estimated to be about 1143 years. (SRC) ARTS: *Mirex is a highly stable insecticide formerly used for fire ant control in the southeastern USA(1). Mirex is also formely employed as a fire-retardant additive in thermoplastic, thermosetting and elastomeric resin systems, paper, paint, rubber, electrical, adhesive and textile products(1). Mirex is produced by the dimerization of hexachlorocyclopentadiene in the presence of aluminum chloride or by reacting chlordecone with phosphorus pentachloride(3). About 226 thousand kg of mirex was applied to 132 million acres (53 hectares) in ten states from 1962 to 1976(2). Mirex was manufactured as the technical grade and as an ant bait whose production ceased in 1967 and 1975, respectively(2). With a limited number of legal exceptions the use of mirex has been banned in the USA since 1978(1). Hence present release into the environment may occurred via effluents from manufacturing plants and sites where mirex was utilized as a fire-retardant, and at points of application where it was used as a insecticide(SRC). [R81] FATE: *There is evidence for degradation of mirex to chlordecone (Kepone) in the environment. [R28, 551] *AQUATIC FATE: Sediment-natural water and Daphnia magna-bluegill (Lepomis macrochirus) models were used to study the fate of mirex in aquatic systems. Mirex was shown to move through the food chain when daphnids were used as prey organisms. [R82] *TERRESTRIAL FATE: Mirex does not leach into the soil profile and is predicted to volatilize only slowly. There is no evidence for any rapid transformation so it should be considered persistent. Because it is so strongly adsorbed to the soil and stays on the surface, a major loss from terrestrial systems would probably be erosion and /particle bound/ into surface waters. [R83] *TERRESTRIAL FATE: Mirex did not degrade (rate constant equal to zero) at a concn of 0.5 g/100g dry weight in nine aerobic soils after six mo incubation(4). For the most part mirex is resistant to biological and chemical degradation. Adsorption and volatilization are likely to be important environmental fate processes. Persistent compounds such as kepone, and monohydro- and dihydro- derivatives of mirex have been identified as products of extremely slow transformation of mirex. A Koc value of 2.4X10+7(1) indicates mirex will strongly adsorb to soil organic matter and therefore be immobile in most soils(2 A Henry's Law constant for mirex of 5.16X10-4 atm-cu m/mole at 22 deg C(3) suggest that rapid volatilization of mirex from moist soils may occur where adsorption does not dominate(1). [R84] *AQUATIC FATE: Mirex is expected to be extremely persistent in environmental waters. For the most part mirex is resistant to biological and chemical degradation. Adsorption and volatilization are likely to be more important environmental fate processes. Persistent compounds such as kepone, and monohydro- and dihydro- derivatives of mirex have been identified as products of extremely slow transformation of mirex. Mirex has been shown to bioconcentrate in aquatic organisms. A Koc value of 2.4X10+7(1) indicates mirex will strongly absorb to organic matter and may partition from the water column to sediments and suspended materials. A Henry's Law constant for mirex of 5.16X10-4 atm-cu m/mole at 22 deg C(2) suggests rapid volatilization of mirex from natural waters(3). Based on this Henry's Law constant, the volatilization half-life from a model river (22 deg C; 1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 10.7 hr(3,SRC); however, this estimation neglects the potentially important effect of adsorption(SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, can be estimated to be about 1100 years(4,SRC); if parameters are introduced into the pond model to exclude adsorption effects, the volatilization half-life is reduced to 5.1 days(SRC). [R85] *ATMOSPHERIC FATE: Based upon a vapor pressure of 3.0X10-7 mm Hg at 25 deg C(1) mirex is expected to exist mainly in the particulate phase with a lesser proportion of mirex in the vapor phase in the ambient atmosphere(2). Mirex is expected to be stable against photogenerated hydroxyl radicals in the atmosphere. [R86] BIOD: *Mirex did not degrade when 1 x 10+6 cpm of C(14) mirex was added to 100 ml of medium containing 0.5 g yeast extract/l with 13 bacterial isolates obtained from mirex bait incubated for 2 mo on moist soil(1). Generally mirex is resistant to attack by bacteria and fungi, and can inhibit the growth of actinomyctes(1). Although mirex is taken up by micro-organisms(1), plants(2,4) and higher animals including fish(5) and rats(2), it is not metabolized(2). Yet analysis of soils from spill sites 5 and 12 years after the accidents, suggests that dechlorination takes place very slowly and kepone is a biotransformation product of mirex(3). Kepone was also identified as a transformation product of mirex in estuaries(4). Neither C(14) labeled mirex or kepone degraded in aerobic or anaerobic hydrosoils from the Little Dixie Reservoir and James River tributary, Richmond VA(5). In addition mirex did not degrade at a concn of 0.5 g/100 g dry weight in four anaerobic lake sediments after 6 mo incubation(1). However a loss of mirex was attributed to sludge worms under anaerobic conditions(6). [R87] *When mirex was incubated with sewage sludge, 1% of the mirex was metabolized in 2.5 months. [R71, 363] ABIO: *MIREX WAS EXPOSED ON SILICA GEL THIN-LAYER CHROMATOPLATES TO SUNLIGHT OR UV LIGHT. SLOW DEGRADATION OCCURRED. MAJOR PHOTO-PRODUCT WAS IDENTIFIED AS MONOHYDRO DERIVATIVE ... ANOTHER COMPOUND ... WAS ... KEPONE HYDRATE. A COMPOUND APPEARING IN SMALL AMOUNTS WAS IDENTIFIED AS MONOHYDROKEPONE HYDRATE. [R66, 1978.157] *Exposure to sunlight and UV light have indicated slow degradation; resulting cmpd incl ... undecachloropentacyclodecane, and nonachloropentacyclodecan-5-one hydrate. [R10, 879] *Mirex absorbs very little UV light in the environmentally significant range (wavelength > 290 nm)(1). However mirex transformed to kepone hydrate and small amounts of monohydrokepone at an extremely slow rate when exposed to sun or UV light on silica gel chromatography plates(2). A pure water solution of 1% acetonitrile with 33 ng/ml mirex, placed outdoors for 6 mo, showed loss of mirex with a first order rate constant of 3.7X10-3/day which corresponds to a half-life of about 1 yr(1). Kepone and several isomers of monohydromirex were identified as the phototransformation products(1). An initial mirex concn of 62 ng/l was exposed to summer sunlight for six weeks in Syracuse, NY (42 deg N). At the end of the study period the ratio of monohydromirex (photomirex) to mirex was 3.70(4). The ratio for an identical solution with an added 2 mg DOC/l of humic acid was 5.43(3). [R88] *Mirex at a concn of 33 ng/ml did not hydrolyze after 1 mo at 100 deg C in a pure water soln of 1% acetonitrile with a pH of 7. Hydrolysis of halides by hydroxyl substitution is not important below a pH of 10(2). A first ordered rate constant of 1X10-10/sec at 25 deg C was calculated based on the assumption that the experimental error was indeed a loss of mirex, which corresponds to a half life of over 250 yr(1). [R89] *Mirex underwent slow degradation in the field. Soil samples were taken 12 yr after mirex application for fire ant control and 5 yr after an aircraft crashed with mirex. About 50% of the original mirex was recovered unchanged. Other degradation products incl 8- and 10- monohydro, two dihydro, two trihydro, and one tetrahydro derivatives of mirex in addition to kepone. [R71, 363] BIOC: *THERE IS EVIDENCE FOR DEGRADATION OF MIREX TO CHLORDECONE (KEPONE) IN THE ENVIRONMENT. BOTH MIREX AND KEPONE ARE HIGHLY PERSISTENT AND HAVE HIGH LIPID:WATER PARTITION COEFFICIENTS AND HAVE BEEN SHOWN TO BIOCONCENTRATE SEVERAL THOUSANDFOLD IN FOOD CHAINS. [R28, 551] *Data obtained from the terrestrial aquatic laboratory model ecosystem show that mirex predominated in all the organisms (alga, snail, mosquito and fish), with 98.6% of radiolabel in fish and 99.4% of radiolabel in snails attributable to mirex. Despite high light and temp levels, no mirex metabolites, other than small amounts of radioactivity in polar fraction, were seen. The ecological magnification (EM) values were 219 in fish and 1597 in snails (EM= concn of parent cmpd in organism/concn of parent cmpd in water). [R90] *A log BCF of 7.26 was determined for mirex by taking the average concn in the tissues of Lake Ontario rainbow trout (Salmo gairdneri) captured while spawning in the Ganaraska River over the average concn of mirex in Lake Ontario water(1). However, this field BCF value would also include mirex accumulated via dietary uptake(SRC). Experimental log BCF values of 2.30, 4.26, 4.34 and 5.75 have been reported for mirex in Gambusia affinis (mosquito fish)(2), Pimephales promelas (Fathead minnow)(3), Pimephales promelas (Fathead minnow)(4) and Lepomis machrochirus (Bluegill)(5), respectively. [R91] *PEA AND BEAN PLANT ROOTS CONCENTRATED MIREX; AND SMALL AMT WERE TRANSLOCATED TO AERIAL PARTS WHEN PLANTS GREW FOR 2 DAYS IN WATER CONTAINING 1-10 PPM MIREX. [R63] *Bioaccumulation: BCF: algae: 12200; fish 2580; snails: 4900; crayfish: 16860-71400; daphnids: 14650 [R10, 879] *Bioaccumulation factors after 70 days exposure to 0.038 ug/l: grass shrimp: 13100-17400; sheephead minnows: 28900-50000; mud crabs: 15000-18700; hermit crabs: 44800-71100; ribbed mussels (soft tissue): 42000-52600; American oysters (soft tissue): 34200-73700 [R10, 880] *Bioaccumulation: blue crab (Callinectes sapidus): concn in water: 0.22 ug/l; in crab hepatopancreas after 6 hr: 31 ug/kg; blue crabs: concn in water: 0.03-0.16 ug/l; whole body residue: 20-590 ug/kg after 28 days exposure; grass shrimp: concn in water: 0.03-1.16 ug/l; whole body residue: 90-2400 ug/kg after 28 days exposure. [R10, 880] *... Accumulation in the food chain after 6 applications of mirex (1.25 lb of bait per acre) over a 4 year period: aquatic plants: contained negligible amt; snails, crawfish, fish: 0.01-0.75 ppm; softshell turtle fat: 24.82 ppm; birds: 1.2 to 1.91 ppm; fat of vertebrates: up to 73.94 ppm; marine unicellular algae species: no observable effect on population growth following a 7 day exposure to 10-50 parts per trillion. [R10, 880] *... American oysters (Crassostrea virginica Gmelin): bioconcentration factor after 43 days of exposure: 5100-5500 (based on oven dry wt) ... bioconcentration factors after 4 seasonal experiments, each lasting 28 days, at approx 0.5 ppb: minnows: 40800 (approx 20.4 ppm); pink and grass shrimp: 10000 (approx 5 ppm); blue crabs: 2300 (approx 1.5 ppm) [R10, 880] *Juvenile pinfish exposed to 25-46 ug/l/3 days exhibited a BCF of 3800 /From table/ [R92] KOC: *The average Koc value for 4 samples of Coyote Creek (CA) sediment was determined to be 2.4X10+7(1). This Koc values indicates mirex will be immobile in most soils(2). [R93] VWS: *A Henry's Law Constant for mirex of 5.16X10-4 atm-cu m/mole at 22 deg C(2) indicates rapid volatilization of mirex from environmental waters(1). Based on this Henry's Law Constant, the volatilization half-life from a model river (22 deg C; 1 meter deep flowing 1 m/sec with a wind speed of 3 m/sec) has been estimated to be 10.7 hr(1,SRC); however, this estimation neglects the potentially important effect of adsorption(SRC). The volatilization half-life from an environmental pond, which considers the effect of adsorption, can be estimated to be about 1110 years(3,SRC); if parameters are introduced into the pond model to exclude adsorption effects, the volatilization half-life is reduced to 5.1 days(SRC). [R94] WATC: *SURFACE WATER: Mirex was detected in Niagara River water with a 12% occurrence at concn up to 2.6 ng/l(1). Settling traps were used to determine the mirex concn on particulate matter entering Lake Ontario from the Niagara River(2). Mirex concn ranged from 3.9 to 18 ng/g(2). [R95] *DRINKING WATER: Mirex was detected in 12.5% of the wells tested with an average concn of 2 ng/l and at cocn up to 30 ng/l for rural Chesterfield County in northern SC(1) Mirex was detected in 72.7% of the wells tested with an average cocn of 83 ng/l and at concn up to 437 ng/l for rural Hampton County in southern SC(1). Finished drinking water supplies for the city of Niagara Falls which were drawn from the Niagara River were found to contain mirex at concn (mo/yr) of 0.01(9/77), 0.2(8/78), 0.3(9/78), 0.9(10/78), 0.01(4/79) and 0.01(6/79) ug/l(2). [R96] SEDS: *Mirex was detected at levels ranging from trace concn to 62 ppb in 8 of 13 Lake Ontario sediments collected at distances up to 100 km from the identified source, a dump site along the Niagara River(1). Mirex was detected in 76% of the sediments from the Niagara River at an average concn of 12 ng/g(2). Mirex was detected in the sediments of the Rockaway River NJ at concn ranging from 0.1 to 80 ug/kg(3). Mirex was measured at a concn of 133 mg/kg in sediment dregged from Bailey Creek (a tributary of the James River) VA(4). A survey of the surface soils of 5 counties in western Alabama showed that mirex was detected in 1 of 47 samples at a concn less than 0.1 ppm(5). [R97] ATMC: *Mirex was reported at a rural atmosphere(1). [R98] FOOD: *A survey of items in human food chain showed that detectable residues of mirex were still present 1 yr after a single aerial application of mirex bait, at levels of 1.7 g/acre (4.2 g/ha). The levels observed in various species were: quail, 36 ug/kg; bluegill fish, 18 ug/kg; domestic chickens, 14 ug/kg; and chicken eggs, 1 ug/kg. /Louisiana l971-72/ [R99] *Between 1972 and 1976 mirex tested positive in 4 samples or 0.1% of the 15,200 red meats evaluated with an average conc of 0.0003 ppm(1). Between 1972 and 1976 Mirex tested positive in 1 chicken or 0.02% of the 11,340 poultry samples evaluated with an average concn of 0.0001 ppm(1). [R100] PFAC: FISH/SEAFOOD CONCENTRATIONS: *... MIREX RESIDUES /WERE FOUND/ RANGING FROM 0.008-2.59 PPM IN WILD CATFISH FROM AREAS WHICH HAD RECEIVED A BLANKET APPLICATION OF MIREX BAIT. IN A CONTROL EXPT IN WHICH 1.25 LB/ACRE MIREX BAIT WERE SPRAYED ON A FISH POND AND ITS SURROUNDING DRAINAGE AREA, 0.65 PPM MIREX HAD ACCUMULATED IN UNCAGED FISH AFTER 6 MO. [R101] *Juvenile rainbow trout were reared for 24 wk on practical-type diets formulated with fish meals derived from coho salmon (Oncorhynchus kisutch) taken from Lake Michigan (USA), Lake Ontario (USA, Canada) and the Pacific Ocean. Levels of contaminants (DDT, chlordane, dieldrin, mirex and PCB) incr 10-fold from control and Pacific Ocean salmon-based diets to Lake Ontario salmon-based diets. Rainbow trout accum contaminants in direct proportion to dietary levels. Final concn of mirex and PCB in Lake Ontario-fed fish exceeded the allowed limits to protect human health. Fish meals produced from Lake Ontario salmon were unsuitable as source of feed for aquaculture of rainbow trout intended for human consumption. [R102] *Only mirex concn in fish collected from Lake Ontario exceeded a FDA action level. [R103] *Eels were collected from May to Nov, 1982, in Lake Ontario, Lake St Francois, Lake Champlain, Richelieu River, Lake St Pierre, Quebec City, Kamouraska, Grande Trinite River (St Lawrence North Shore) and the Atlantic region (Canada). All eels sampled from Lake Ontario and in the Kingston-Cornwall area were contaminated with mirex (mean concn 0.18 ug/g). Mean concn was 0.126 ug/g in Lake St. Pierre, 0.157 ug/g in Quebec and 0.223 ug/g in Kamouraska. [R104] *Mirex was detected in 1 of 5 spotted gars at a concn of 0.08 ppm with a geometric mean of 0.03 ppm at Lake Bruin, LA and at a concn of 0.03 ppm in the only spotted gar sampled at Lake Providence, LA(1). Mirex was detected in the non-migratory fish (Carp: Cyprinus carpio, Goldfish: Carassius auratus, Catfish: Ictalurus sp, Sucker: Catostomus commersoni) at 21 of 21 NY tributaries to Lake Ontario at concn ranging from 12 to 1,400 ng/g of lipid, with an overall average of 365 ng/g(2). Photomirex was also detected in the fish at 11 of the 21 sites at concn ranging from 230 to 400 ng/g(2). The average mirex concn in whole fish samples of Lake Ontario rainbow smelt for the years 1977-1983 are 0.11, 0.05, 0.05, 0.04, 0.04, 0.02 and 0.05, respectively(3). The average mirex concn in whole fish samples of Lake Ontario lake trout for the years 1977-1983 are 0.49, 0.15, 0.25, 0.14, 0.15, 0.16 and 0.21, respectively(3). [R105] *Different fish species from Abu Qir Bay, Idku Lake and Maryut Lake in Alexandria, Egypt, were assayed for residues of organochlorine insecticides and polychlorinated biphenyls (PCBs). The fish were obtained from commercial fishermen in 1985: Pagellus erythrinus, Sargus vulgarius, Siganus rivulatus, Sphyraena sphyraena, and Trigla hirundo from Abu Qir Bay; and Tilapia fish from Idku and Maryut Lakes. Twenty grams of dorsal fish muscle were extracted and the residues analyzed by GLC; reagent blanks and spike samples were included with each sample. The waters from which the fish were obtained receive drainage from industrial, agricultural and urban activities. Water samples were not assayed for specific components. Mirex was detected in all fish studied at levels equal to or less than 0.9 ug/kg. The only exception was Sargus vulgarius which had no detectable level of mirex. From a health standpoint, all samples were well below permissible levels for toxic substances. [R106] ANIMAL CONCENTRATIONS: *Levels of mirex were measured in sc fat, breast muscle, liver, and brain of waterfowl collected in New York State during 1979 and 1980. The FDA tolerance level is 3.0 ug/g in fat on a wet wt basis. Mean mirex levels were 0.10 ug/g in fat and 0.07 ug/g in breast muscle on a wet wt basis. [R107] *Mirex was detected in 7 of 10 Green-backed herons, 2 of 13 Yellow crowned night herons and 2 of 10 cottonmouths at maximum concn with geometric means of 0.27, 0.06; 0.07, 0.03 and 0.11, 0.03 ppm, respectively, at Lake Providence, LA(1). Mirex was detected in 3 of 10 Green-backed herons, 4 of 10 little blue herons, 9 of 10 cottonmouths, and 3 of 10 water snakes at maximum concn with geometric means of 0.45, 0.05; 0.51, 0.05; 0.22, 0.10 and 0.10, 0.04 ppm, respectively, at Lake Bruin, LA(1). The geometric means and extreme concn of mirex in the wings of 125 woodcock ranged from 0.26 (0.12-0.60) in ME to 6.97 (5.12-10.11) ppm in LA for 17 eastern states(2). Mirex was detected in the muscle tissue of otter, mink, fox, skunk, raccoon, opossum and bobcat at concn ranging from 0.04-3.69, 0.14-0.53, 0.04-0.95, 0.19-3.50, 0.23-0.98, 0.30-1.51 and 0.01-0.60, respectively, for a 2 yr period after application of mirex in areas of Georgia and Alabama(3). Mirex was also detected in the livers of otter, mink, fox, skunk, raccoon, opossum and bobcat at concn ranging from 0.07-1.05, 0.10-0.41, 0.06-3.06, 0.13-0.61, 0.11-0.74, 0.10-0.68 and 0.04-0.39, respectively, for a 2 yr period after application of mirex in areas of Georgia and Alabama(3). [R108] *The average mirex levels in the subcutaneous fat and breast muscle for 55 waterfowl collected in Columbia and Ulster Co along the Hudson River and in Suffolk Co, Long Island, NY were 0.56 and 0.004 ug/g respectively, on a dry weight basis(1). The mirex concn averaged 0.06 ppm for the eggs of 49 Merganser (Mergus serrator) nests on the islands of NW Lake Michigan(2). Mirex was detected in the eggs of eastern cooper hawks from CT, MD, PA, MI and WI and common loons from Canada and herring gulls from the Detriot and Niagara Rivers and Saginaw Bay at concn up to 0.42 ppm(3), 0.65 ug/g(4) and 0.98 ppm(5), respectively. From 1978 to 1981 mirex was detected in bald eagles from 32 states with a max median concn of 0.48 ppm in 1980(6). [R109] MILK: *IN 2 OUT OF 3 SAMPLES OF COW'S MILK, /MIREX RESIDUES OF/ 0.007 and 0.016 PPM (FAT BASIS) HAVE BEEN FOUND. /Mississippi l970/ [R65] *Only traces of mirex have been found in human breast milk in Canada(1). Mirex was detected in the human milk of 6, 16 and 6 maternity patients from Albany, Oswego and Rochester, NY at average concn of 0.070, 0.120 and 0.162 ng/g wet weight, respectively(2). [R110] RTEX: *Poisonous if swallowed, inhaled, or if skin is exposed. [R4] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 932 workers are exposed to mirex in the USA(1). [R111] *Those involved in the manufacture, formulation and application of the insecticide. ... Because insecticidal use of mirex has been discontinued, direct human exposure is small. ... Residues have been detected in water, soil, food and beverages, and human tissues for as long as 12 yr after exposure. These residues result in potential routes for general population exposure. [R112] BODY: *Mirex has been detected in adipose tissue from 6 human subjects at levels of 0.16-5.94 mg/kg. Avg residues of mirex in the fat of residents of states where mirex is applied were 1.32 mg/kg fat. Traces of mirex have been detected in some human milk samples at 0.1-0.6 ug/kg (wet-weight basis) and 2.3-21.5 ug/kg (fat basis). [R37] *Mirex tested positive in 0.1% of the human blood serum sampled from the general population with maximum concn of 1.70 ppb(1). Mirex tested positive in 0.29% of the human adipose tissues sampled from the general population in 1976 with a respective maximum and geometric average concn of 1.73 and 0.02 ppb(1). Mirex in human adipose tissue ranged in concn from 0.03 to 0.79 ppm for 8 of 8 samples in 1980 and from 0.12 to 0.17 ppm for 2 of 10 samples in 1984 at the St Francis Hospital, Monroe LA(2). The average concn of mirex found in human adipose tissue for 91 samples in Kingston and 84 samples in Ottawa, Canada were 27 and 11 ng/g, respectively(3). Only traces of mirex have been found in human breast milk in Canada(4). Mirex was detected in the human milk of 6, 16 and 6 maternity patients from Albany, Oswego and Rochester, NY at average concn of 0.070, 0.120 and 0.162 ng/g wet weight, respectively(5). [R113] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 0.1 ug/l [R114] FIFR: *All registered products containing Mirex were effectively cancelled on December 1, 1977. (A technical Mirex product made by Hooker Chemical Company is unaffected by this Settlement Agreement. However since Mirex produced under this registration may be used only in the formulation of other pesticide products the registration was useless after December 1, 1977). All existing stocks of Mirex within the continental USA were not to be sold, distributed, or used after June 30, 1978. [R115, 16] *Harvester Bait 300, Reg No 38962-5, may not be used for the control of the pheidole ant, Argentine ant, and fire ant on pineapples in Hawaii. The effective date of cancellation for these uses was December 1, 1977; existing stocks as of December 1, 1977 may not be applied aerially, but may be sold and used (other than aerially) indefinely. [R115, 16] *The application of Harvester Bait 300 is subject to the following restrictions: 1. Aerial Application: No longer permitted. 2. Ground Application a. Permissible in all areas of infestation provided that there is no ground application to aquatic and heavily forested areas or areas where run-off or flooding will contaminate such areas. b. Treatment shall be confined to areas where the imported fire ants are causing significant problems. Note: the following definition is incl in order to clarify the ground application restrictions: Aquatic areas: encompasses without limitation estuaries, rivers, streams, wetlands (those land and water areas subject to inundation by tidal, riverine, or lacustrine flowage), lakes, ponds, and other bodies of water. [R115, 17] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Sample: Air; Procedure: Trap on polyurethane foam, extract (hexane-ether) in Soxhlet, wash; Detection Gas-liq chromatography/electron capture detector; Limit of detection: 0.1 ng/cu m; Lewis RG et al; Anal Chem 49: 1668-72 (1976). Sample: Water; Detection Gas-liq chromatography/electron capture detector; Limit of detection 10 ng/l: Sandhu SS et al; J Am Water Works Assoc 70: 41-5 (1978). Sample: Fatty products and fish; Detection Gas-liq chromatography/electron capture detector; Bong Rl; J Assoc Anal Chem 60: 229-32 (1977). [R116] *MIREX AND PHOTOMIREX WERE SEPARATED FROM PCBS AND OTHER AROMATIC CMPD BY NITRATION AND REMOVAL OF NITRO-PCBS ON ALUMINA MICROCOLUMN. RECOVERIES OF MIREX AND PHOTOMIREX WERE 102 plus or minus 8% and 104 plus or minus 5%, RESPECTIVELY. MIREX WAS ALSO DETECTED IN SAMPLES OF SEDIMENT, FISH, AND EGGS. [R117] *A method using gel permeation and Florisil column chromatographic cleanup techniques is described for determination of residues of nonpolar organohalogen pesticides, incl mirex, and pesticide alteration products in vegetable oils and their refinery by-products. Limit of detection is 0.04 ppm based on response of heptachlor epoxide. [R118] *Methane chemical ionization (CI)-selected ion monitoring (SIM) mass spectrometry was used to identify and to distinguish organochlorine pesticides, incl mirex, from PCBs at parts per thousand to ppb levels in environmental water sample extracts with minimal sample cleanup. [R119] *Two-dimensional gas chromatography on two capillary columns is used for pesticide, incl mirex, residue analysis in food samples. [R120] *A gas chromatographic electron capture detector method was described for quantitative determination of organochlorine pesticide, incl mirex, residues in poultry fat. Avg recovery from fortified samples were 91.9%. [R121] CLAB: *Glass-capillary gas chromatography method was developed to give a detection limit of 0.05 ng/g for mirex in human milk samples. Procedures for sample collection and preparation are given. [R122] *Gas chromatograph-mass spectrometer was used to determine mirex in human adipose tissue. Quantitation limit was 10 ng/g. In samples from Kingston, Canada area 38 ng/g (mean value) for males and 12 ng/g (mean value) for females were detected. In samples from Ottawa, Canada area 12 ng/g (mean value) for males and 9 ng/g (mean value) for females were detected. [R123] *MIREX CAN BE DETERMINED IN PLASMA, LIVER AND FAT FROM MICE AND MONKEYS AFTER EXTRACTION AND CLEAN-UP USING FLORISIL AND SODIUM SULFATE COLUMNS BY GAS-LIQUID CHROMATOGRAPHY. THE METHOD IS SENSITIVE TO 0.01 PPM FOR PLASMA, 0.03 PPM FOR LIVER, and 0.017 PPM FOR FAT. [R124] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Waters EM et al; Mirex I. An Overview. II. An Abstracted Literature Collection, 1947-1976, Toxicology Information Program, National Library of Medicine, ORNL/TIRC-76-4, Oak Ridge, TN, Oak Ridge National Laboratory, 93 pp (1976). An overview of the physical and chemical properties, metabolism, degradation, persistence, and bioaccumulation, and toxicology of mirex is presented. DHHS/NTP; Toxicology and Carcinogenesis Studies of Mirex in F344/N Rats (Feed Studies) Technical Report Series No. 313 (1990) NIH Publication No. 90-2569 U.S. Dept Health and Human Services/Agency for Toxic Substances Disease Registry; Toxicological Profile for Mirex and Chlordecone (1995) NTIS# PB/95/264354 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. 533 R2: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. R3: Francis BM, Metcalf RL; Environ Health Perspect 54: 341-46 (1984) R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R5: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 401 R6: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 889 R7: Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989.,p. C-198 R8: SRI R9: Martin, H. and C.R. Worthing (eds.). Pesticide Manual. 4th ed. Worcestershire, England: British Crop Protection Council, 1974. 360 R10: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R11: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. 341 R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 855 R13: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 99 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 284 (1979) R15: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 13(81) 435 R16: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 886 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 672 R18: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R19: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 697 R20: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R21: 49 CFR 171.2 (7/1/96) R22: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3097-1, 6193, 6194, 6195 (1988) R23: 40 CFR 165.9 (a) (7/1/88) R24: 40 CFR 165.9 (b) (7/1/88) R25: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. R26: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 66 (1987) R27: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-240 R28: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 293 (1979) R30: CHERNOFF N ET AL; ENVIRON RES 18 (2): 257-69 (1979) R31: Rogers JM et al; Environ Res 34 (1): 155-61 (1984) R32: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 1013 R33: Buelke-Sam J et al; Teratology 27 (3): 401-10 (1983) R34: Chu I et al; Toxicol Appl Pharmacol 60: 549-56 (1981) R35: Grabowski CT; Dev Toxicol Environ Sci 11 (Dev Sci Pract Toxicol): 537-40 (1983) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 291 (1979) R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 289 (1979) R38: Abraham R et al; Exp Mol Pathol 38 (2): 271-82 (1983) R39: Chambers JE, Trevathan CA; Toxicol Lett (Amst) 16 (1-2): 109-16 (1983) R40: Havkin-Frenkel D et al; Toxicol Lett 15 (2-3): 219-23 (1983) R41: DIETZ DD, MCMILLAN DE; NEUROTOXICOLOGY 1 (2): 369-85 (1979) R42: KENDALL MW; ARCH ENVIRON TOXICOL 8 (1): 25-41 (1979) R43: LARSON PS ET AL; TOXICOL APPL PHARMACOL 42 (2): 271-7 (1979) R44: Fujimori K et al; Environ Toxicol Chem 2 (1): 49-60 (1983) R45: Yarbrough JD et al; Cell Tissue Kinet 17 (5): 465-73 (1984) R46: U.S. Department of the Interior, Fish and Wildlife Service. Handbook of Toxicity of Pesticides to Wildlife. Resource Publication 153. Washington, DC: U.S. Government Printing Office, 1984. 55 R47: KENDALL RJ ET AL; POULT SCI 57 (6): 1539-45 (1978) R48: Bird DM et al; Arch Environ Contam Toxicol 12 (6): 633-9 (1983) R49: Jessiman BJ, Qadri SU; Ecotoxicol Environ Saf 7 (3): 295-305 (1983) R50: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 638 R51: Ludke JL et at; Bull Environ Contam Toxicol 6: 89 (1971) as cited in USEPA/OWRS; Quality Criteria for Water 1986 Mirex (1986) EPA 440/5-86-001 R52: Tagatz ME et al; Arch Environ Contam Toxicol 3: 371 (1975) as cited in USEPA/OWRS; Quality Criteria for Water 1986 Mirex (1986) EPA 440/5-86-001 R53: Toxicology and Carcinogenesis Studies of Mirex in F344/N Rats (Feed Studies). Technical Report Series No. 313 (1990) NIH Publication No. 90-2569 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R54: WHO; Environ Health Criteria: Mirex p.26 (1984) R55: Gaines TB; Toxicol Appl Pharmacol 14: 5-534 (1969) as cited in WHO; Environ Health Criteria: Mirex p.26 (1984) R56: Larson PS et al; Toxicol Appl Pharmacol 49: 271-7 (1979) as cited in WHO; Environ Health Criteria: Mirex p.26 (1984) R57: Cabral JRP et al; Toxicol Appl Pharmacol 48: A192 (1979) as cited in WHO; Environ Health Criteria: Mirex p.26 (1984) R58: Kendall MW, Bull Environ Contam Toxicol 12: 617-21 (1974) as cited in WHO; Environ Health Criteria: Mirex p.26 (1984) R59: U.S. Department of the Interior, Fish and Wildlife Service, Bureau of Sports Fisheries and Wildlife. Lethal Dietary Toxicities of Environmental Pollutants to Birds. Special Scientific Report - Wildlife No. 191. Washington, DC: U.S. Government Printing Office, 1975.27 R60: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office, 1980.53 R61: Brookhout CG et al; Water, Air, and Soil Pollut 1: 165 (1972) as cited in USEPA/OWRS; Quality Criteria for Water 1986 Mirex (1986) EPA 440/5-86-001 R62: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 409 R63: Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974.263 R64: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 207 (1974) R65: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 205 (1974) R66: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office R67: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. 210 R68: HOLCOMB CM, PARKER WS; BULL ENVIRON CONTAM TOXICOL 23 (3): 369-71 (1979) R69: Byrd RA et al; Toxicol Appl Pharmacol 66 (2): 182-92 (1982) R70: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 1078 R71: Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. R72: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. 1641 R73: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 1093 R74: MEHENDAL HM; DRUG METAB DISPOS 5 (1): 56-62 (1977) R75: Curtis LR, Hoyt D; J Pharmacol Exp Ther 231 (3): 495-501 (1984) R76: Bloomquist JR, Shankland DL; Pest Biochem Physiol 119 (3): 235-42 (1983) R77: Chetty CS et al; Indian J Comp Anim Physiol 1 (1): 107-13 (1983) R78: Bird DM et al; Arch Environ Contam Toxicol 12 (6): 633-39 (1983) R79: McArthur MLB et al; Arch Environ Contam Toxicol 12 (3): 343-53 (1983) R80: Ebel RE, McGrath EA; Toxicol Lett 22 (2): 205-10 (1984) R81: (1) IARC; Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 20: 283-301 (1979) (2) Holden C; Science 194: 301-3 (1976) (3) Sanborn JR et al; Degradation of Selected Pesticides in Soil USEPA-600/9-77-022 pp. 616 (1977) R82: Buikema AL Jr et al; J Water Pollut Control Fed 55 (6): 829-33 (1983) R83: Bomberger DC et al; ACS Symp Ser 225 (Fate Chem Environ): 197-214 (1983) R84: (1) Smith JH et al; Environ Pathways of Selected Chemicals in Freshwater Systems. Part II. Lab Studies USEPA-600/7-78-074 p. 294-315 (1978) (2) Swann RL et al; Res Rev 85: 16-28 (1983) (3) Yin C, Hassett JP; Environ Sci Technol 20: 1213-7 (1986) (4) Jones AS, Hodges CS; J Agric Food Chem 22: 435-9 (1974) R85: (1) Smith JH et al; Environ Pathways of Selected Chemicals in Freshwater Systems. Part II Lab Studies USEPA-600/7-78-074 p 294-315 (1978) (2) Yin C, Hassett JP; Environ Sci Technol 20: 1213-7 (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-15 to 15-29 (1982) (4) USEPA; EXAMS II Computer Simulation (1987) R86: (1) IARC; Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. 20: 283-301 (1979) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) R87: (1) Jones AS, Hodges CS; J Agr Food Chem 22: 435-9 (1974) (2) Mehendale HM et al; Bull Environ Contam Toxicol 8: 200 (1972) (3) Carlson DA et al; Science 194: 939-41 (1976) (4) Brown LR et al; Effect of Mirex and Carbofuran on Estuarine Microorganisms USEPA-600/3-75-024 (NTIS PB-247147) p. 57 (1975) (5) Huckins JN et al; J Agr Food Chem 30: 1020-7 (1982) (6) Andrade PSL, Wheeler WB; Bull Environ Contam Toxicol 11: 415-6 (1974) R88: (1) Smith JH et al; Environ Pathways of Selected Chemicals in Freshwater Systems. Part II Lab Studies USEPA-600/7-78-074 p. 294-315 (1978) (2) Ivie GW et al; J Agric Food Chem 22: 933-5 (1974) (3) Mudambi AR, Hassett JP; Chemosphere 17: 1133-46 (1988) R89: (1) Smith JH et al; Environ Pathways of Selected Chemicals in Freshwater Systems. Part II Lab Studies USEPA-600/7-78-074 p 294-315 (1978) (2) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) R90: Francis BM, Metcalf RL; Environ Health Perspect 54 (6): 341-46 (1984) R91: (1) Oliver BG, Nimi AJ; Environ Sci Technol 19: 842-48 (1985) (2) Francis BM, Metcalf RL; Environ Health Perspec 54: 341-46 (1984) (3) Veith GD et al; J Fish Res Board Can 36: 1040-48 (1979) (4) Buckler DR et al; Trans Amer Fish Soc 110: 270 (1981) (5) Van Valin CC et al; Trans Amer Fish Soc 97: 185 (1968) R92: Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986.,p. V1 70 R93: (1) Smith JH et al; Environ Pathways of Selected Chemicals in Freshwater Systems. Part II Lab Studies USEPA-600/7-78-074 p 294-315 (1978) (2) Swann RL et al; Res Rev 85: 16-28 (1983) R94: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw-Hill p. 15-15 to 15-29 (1982) (2) Yin C, Hassett JP; Environ Sci Technol 20: 1213-7 (1986) (3) USEPA; EXAMS II Computer Simulation (1987) R95: (1) Oliver BG, Nicol KD; Sci Tot Environ 39: 57-70 (1984) (2) Oliver BG, Charlton MN; Environ Sci Technol 18: 903-8 (1984) R96: (1) Sandhu SS et al; J AWWA Jan p. 41-5 (1978) (2) Kim NK, Stone DW; Organic Chemicals in Drinking Water, NYS Dept Health p. 131 (NA__) R97: (1) Kaminsky R et al; J Great Lakes Res 9: 183-9 (1983) (2) Kuntz KW, Warry ND; J Great Lakes Res 9: 241-8 (1983) (3) Smith JA et al; Bull Environ Contam Toxicol 39: 465-73 (1987) (4) Saleh FY et al; J Environ Sci Health 913: 261-94 (1978) (5) Albright R et al; Bull Environ Contam Toxicol 12: 378-84 (1974) R98: (1) Miller JM; The Potential Atmospheric Impact of Chemicals Released to the Environment. USEPA 560/5-80-001 p. 230 (1981) R99: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 287 (1979) R100: (1) Duggan RE et al; Pesticide Residue Levels in Foods in the US from July 1 1969 to June 30 1976, Food Drug Admin Div Chem Technol p. 240 (1983) R101: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V5 206 (1974) R102: Hilton JW et al; Can J Fish Aquat Sci 40 (11): 1987-94 (1983) R103: Clark JR et al; J Great Lakes Res 10 (1): 38-47 (1984) R104: Desjardins C et al; Can Ind Rep Fish Aquat Sci 0 (141): 1-51 (1983) R105: (1) Niethammer KR et al; Arch Environ Contam Toxicol 13: 63-74 (1984) (2) Jaffe R, Hites RA; J Great Lakes Res 12: 63-71 (1986) (3) Great Lakes Water Quality Board; Report on Great Lakes Water Quality p 212 (1985) R106: El Nabawi A et al; Arch Environ Contam Toxicol 16 (6): 689-96 (1987) R107: Kim KS et al; Arch Environ Contam Toxicol 13 (3): 373-81 (1984) R108: (1) Niethammer KR et al; Arch Environ Contam Toxicol 13: 63-74 (1984) (2) McLane MAR et al; Environ Monit Assess 4: 105-11 (1984) (3) Hill EP, Dent DM; Arch Environ Contam Toxicol 14: 7-12 (1985) R109: (1) Kim HT et al; Arch Environ Contam Toxicol 14: 13-18 (1985) (2) Heinz GH et al; Environ Pollut Ser 32: 211-32 (1983) (3) Pattee OH et al; J Wildl Manage 49: 1040-4 (1985) (4) Frank R et al; Arch Environ Contam Toxicol 12: 641-54 (1983A) (5) Struger J et al; J Great Lakes Res 11: 223-30 (1985) (6) Reichel WL et al; Envion Monit Assess 4: 395-403 (1983) R110: (1) Broomhall J, Kovar IZ; Rev Environ Health 6: 311-37 (1986) (2) Bush B et al; Arch Environ Contam Toxicol 12: 739-46 (1983) R111: (1) NIOSH; National Occupational Hazard Survey (NOHS) (1974) R112: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 621 R113: (1) Kutz FW; Res Rev 85: 277-92 (1983) (2) Holt RL et al; Bull Environ Contam Toxicol 36: 651-5 (1986) (3) LeBel GL, Williams DT; J Assoc Off Anal Chem 69: 451-8 (1986) (4) Broomhall J, Kovar IZ; Rev Environ Health 6: 311-37 (1986) (5) Bush B et al; Arch Environ Contam Toxicol 12: 739-46 (1983) R114: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R115: Environmental Protection Agency/OPTS. Suspended, Cancelled and Restricted Pesticides. 3rd Revision. Washington, D.C.: Environmental Protection Agency, January 1985. R116: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 290 (1979) R117: NORSTROM RJ ET AL; J ASSOC OFF ANAL CHEM 63 (1): 37-42 (1980) R118: Young S et al; J Assoc Off Anal Chem 67 (1): 95-106 (1984) R119: Hargesheimer EE; J Assoc Off Anal Chem 67 (6): 1067-75 (1984) R120: Stan HJ, Mrowetz D; J Chromatogr 279: 173-87 (1983) R121: Ault JA, Spurgeon TE; J Assoc Off Anal Chem 67 (2): 284-89 (1984) R122: Bush B et al; Arch Environ Contam Toxicol 12 (6): 739-46 (1983) R123: Williams DT et al; J Toxicol Environ Health 13 (1): 19-30 (1984) R124: STEIN VB, PITTMAN KA; BULL ENVIRON CONTAM TOXICOL 23 (3): 300-5 (1979) RS: 100 Record 146 of 1119 in HSDB (through 2003/06) AN: 1664 UD: 200302 RD: Reviewed by SRP on 5/6/2000 NT: This record contains information specific to the title compound. Those with an interest in this record are strongly encouraged also to retrieve the record on NICKEL COMPOUNDS which has additional, general information relevant to the toxicity and environmental fate of nickel ions and nickel compounds. For information on the metal itself, refer to the NICKEL, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NICKEL-OXIDE- SY: *BUNSENITE-; *CI-77777-; *GREEN-NICKEL-OXIDE-; *MONONICKEL-OXIDE-; *NICKEL- (II)-OXIDE; *NICKELOUS-OXIDE-; *NICKEL- (2+)-OXIDE; *Nickel-oxide- (NiO); *NICKEL-PROTOXIDE- RN: 1313-99-1 RELT: 6933 [NICKEL COMPOUNDS]; 1096 [NICKEL, ELEMENTAL] MF: *Ni-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ROASTING OF REFINED NICKEL ORES [R1] *By heating nickel above 400 deg C in presence of oxygen. [R2] *Green nickel oxide is prepared by firing a mixture of water and pure nickel powder in air at 1000 deg C or by firing a mixture of high purity nickel powder, nickel oxide, and water in air. The latter provides a more rapid reaction than the former method. Single whiskers of green nickel oxide have been made by the closed-tube transport method from oxide powder formed by the decomposition of nickel sulfate using hydrochloric acid as the transport gas. Green nickel oxide also is formed by thermal decomposition of nickel carbonate or nickel nitrate at 1000 deg C. /Green nickel oxide/ [R3, p. V17 18] *Black nickel oxide /is made by/ the calcination of /nickel/ carbonate and nitrate at 600 deg C. /Black nickel oxide/ [R3, p. V17 18] IMP: *Typical impurities, present at levels of 1% or less, include cobalt, copper, iron, and sulfur. [R4] FORM: *A commercial grade of nickel oxide powder contains 78% minimum nickel plus cobalt while nickel oxide sinters (partially reduced commercial forms) are available in grades containing 75%, 77%, and 96% nickel. [R4] *Plasma spray grade; -100 mesh; -150, +325 mesh; -325 mesh, 99 and 99.995% purity grades; high-purity grades; powder grade [R5] MFS: *The Hall Chemical Co., 28960 Lakeland Boulevard, Wickliffe, OH 44092-2321, (440)944-8500; Production Site: Arab, AL 35016-0508 [R6] *Mallinckrodt Baker Inc., 675 McDonnell Blvd., PO Box 5840, St. Louis, MO 63134, (314)654-2000; Production site: Phillipsburg, NJ 08865 [R6] OMIN: *CANADA IS THE LARGEST SINGLE PRODUCING COUNTRY. IN 1972, PRELIMINARY ESTIMATE OF CANADIAN EXPORTS OF NICKEL OXIDE WERE 33 MILLION KG. [R7] *TWO PARTIALLY REDUCED NICKEL OXIDE PRODUCTS, KNOWN AS 'NICKEL OXIDE SINTERS' ARE PRODUCED COMMERCIALLY ON A LARGE SCALE; ONE CONTAINS 75% NICKEL AND THE OTHER, 90% AVAIL DATA ON NICKEL OXIDE PRODUCTS FREQUENTLY COMBINE INFORMATION ON NICKEL OXIDE POWDER AND NICKEL OXIDE SINTERS. [R7] *Theoretical content of nickel oxide is 78.6% nickel and 21.4% oxygen. [R4] USE: *Painting on porcelain [R8] *In fuel cell electrodes [R2] *Miscellaneous applications of nickel oxide include its use in: (a) the manufacture of ferrites (eg NiOFe2O3) which find use in the electronics field because of their magnetic properties; (b) the manufacture of nickel salts (eg chloride, nitrate, and sulfate) which can be used to make refined nickel oxide; (c) the production of active nickel catalysts; (d) electroplating and (e) coloring and decolorizing glass. [R9] *Secondary (rechargeable) cells with zinc anodes ... are alkaline zinc, nickel oxide, and zinc chloride. [R10, p. 24(84) 807-51] *Nonmetallic resistance thermometers or thermistors are generally temperature sensitive semiconducting ceramics. The thermister material is usually a metal oxide, eg, nickel oxide. [R3, p. 2V17 20] *Used in ceramic matrices [R3, p. V17 19] *Brown ceramic colorant [R10, p. 6(79) 555] *Gray ceramic colorant [R10, p. 6(79) 556] *The sinter oxide form is used as charge nickel in the manufacture of alloy steel and stainless steels. [R3, p. V17 19] *Used in the refining of nickel. [R3, p. V17 19] *Used for nickel catalysts manufacture by admixing, usually when wet, with a powdered ceramic support material. [R3, p. V17 19] *Used in a mixture with other high purity metal oxides in varistors or voltage surge arrestors in lightning strike devices or as in-line varistors in electronics. [R3, p. V17 20] *Used along with aluminum azide as the propellent for automotive air bags. [R3, p. V17 20] *Used commercially to make nickel fibers in a process whereby a water slurry containing nickel oxide and a cellulose type binder is forced through tiny orifices to form green fibers. [R3, p. V17 20] CPAT: *(EXCLUDING SINTERS) 72% IS USED IN THE PRODUCTION OF NICKEL SULFATE; 13% FOR THE PRODUCTION OF CATALYSTS; 15% FOR ENAMEL FRITS AND ELECTRONIC DEVICES (1970) [R1] *In 1976, the USA consumption pattern for nickel oxide (representing 2.0x10+10 g contained nickel) is estimated to have been as follows: 60% for stainless and heat resisting steels, 27% for other steel alloys, 8% for other nickel alloys, 2% for cast irons, and 3% for other uses. [R9] *(1975) 1.35X10+10 GRAMS (CONSUMPTION) [R1] PRIE: U.S. PRODUCTION: *(1970) LESS THAN 4.54X10+8 GRAMS [R1] U.S. IMPORTS: *(1972) 5.41X10+9 GRAMS [R1] *USA IMPORTS OF NICKEL OXIDE IN 1973 (MOSTLY FROM CANADA) WERE 5.84 MILLION KG. [R7] *(1975) 4.02X10+9 GRAMS (GROSS WT) [R1] *(1974) 5.8x10+9 grams [R4] *(1976) 5.4x10+9 grams [R4] *(1977) 4.2x10+9 grams [R4] *(1986) 1.57X10+6 lb [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Green powder [R8]; *Greenish-black cubic crystals [R12]; *Yellow when hot [R8] MP: *1955 deg C [R12] MW: *74.69 [R8] DEN: *6.72 [R12] SOL: *0.11 MG/100 ML @ 20 DEG C [R13]; *SOL IN ACIDS; AMMONIUM HYDROXIDE [R14]; *Insol in caustic solutions [R2]; *SOL IN POTASSIUM CYANIDE [R15]; *Insoluble in water; soluble in acids [R8] SPEC: *INDEX OF REFRACTION: 2.1818 (RED) [R14] OCPP: *Absorbs oxygen @ 400 deg C forming nickelic oxide which is reduced to nickel oxide @ 600 deg C [R2] *Reacts with acids to form nickel salts and soaps. [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- TOXC: *Toxic gases and vapors (such as nickel carbonyl) may be released in a fire involving nickel ... /Nickel and sol nickel cmpd/ [R16] REAC: *REACTS VIOLENTLY WITH IODINE, HYDROGEN SULFIDE, (BARIUM OXIDE + AIR). [R17] +Nickel monoxide becomes incandescent in fluorine gas. [R18, p. 491-87] *The effect of metal oxides in sensitizing the thermal decomp and explosion of ... /anilinium perchlorate/ is in the order: manganese dioxide > copper oxide > nickel oxide. [R19] +Mixtures of barium oxide with ... nickel oxide ... react vigorously with hydrogen sulfide in air and vivid incandescence or explosion may result. [R18, p. 491-99] *In the presence of air, contact with mixtures of calcium oxide ... with ... nickel oxide may cause vivid incandescence or explosion. [R20] DCMP: *Toxic gases and vapors (such as nickel carbonyl) may be released ... in the decomp of nickel cmpd. /Nickel and sol nickel cmpd/ [R16] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R21, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R21, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R21, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R21, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R21, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under a fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R21, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R21, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors, benches, ... interior of fume hoods and airducts. As well as regular monitoring, a check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres for chem such as nitrosamines. Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R21, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R21, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R21, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R21, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R21, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R21, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R21, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R21, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R21, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R21, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R21, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R21, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *...Nickel oxide is insoluble in water. ... In polluted air one of the predominant nickel cmpd ... is nickel oxide(s). ... Nickel carbonyl is unstable in air and decomposes to form nickel oxide. ... Respiratory absorption with secondary GI absorption (insoluble and soluble cmpd) is a major route of entry during occupational exposure. A significant quantity of inhaled material is swallowed following mucocillary clearance from the respiratory tract. Poor personal hygiene *and work practices can contribute to GI exposure. Percutaneous absorption is negligible, quantitatively, but is important in the pathogenesis of contact hypersensitivity. Absorption is related to the solubility of the cmpd, following the general relationships nickel carbonyl > soluble nickel cmpd > insoluble nickel cmpd. ... Studies on hamsters and rats with insoluble nickel oxide showed poor absorption, with retention of much of the material in the lung after several weeks. ... Long term inhalation exposure to ... nickel oxide caused mucosal damage and inflammatory reaction in the respiratory tract of rats, mice and guinea pigs. Epithelial hyperplasia was observed in rats after inhalation exposure to aerosols of ... nickel oxide. High level long term exposure to nickel oxide led to gradually progressive pneumoconiosis in rats. ... Inhalation exposure to black nickel oxide did not induce lung tumors in Syrian golden hamsters (a species resistant to lung carcinogenesis). ... Unidentified /nickel/ oxide preparations ... induced local mesenchymal tumors in a variety of experimental animals after im, sc, ip, intrapleural, intraocular, intraosseous, intrarenal, intra-articular, intratesticular, or intra-adipose admin. No local carcinogenic response was seen in single dose studies ... with two specimens of nickel oxide, especially prepared for carcinogenicity testing ... . ... In studies using repeated intratracheal instillation, ... nickel oxide caused pulmonary tumors. ... Nickel oxide was present in almost all circumstances in which cancer risks were elevated, together with one or more other forms of nickel (nickel subsulfide, soluble nickel, metallic nickel). [R22] CARC: *CLASSIFICATION: A; human carcinogen. BASIS FOR CLASSIFICATION: Human data in which exposure to nickel refinery dust caused lung and nasal tumors in sulfide nickel matte refinery workers in several epidemiologic studies in different countries and on animal data in which carcinomas were produced in rats by inhalation and injection. HUMAN CARCINOGENICITY DATA: Sufficient. /Nickel refinery dust/ [R23] *Evaluation: There is sufficient evidence in humans for the carcinogenicity of nickel sulfate, and of the combinations of nickel sulfides and oxides encountered in the nickel refining industry. There is inadequate evidence in humans for the carcinogenicity of metallic nickel and nickel alloys. There is sufficient evidence in experimental animals for the carcinogenicity of metallic nickel, nickel monoxides, nickel hydroxides and crystalline nickel sulfides. There is limited evidence in experimental animals for the carcinogenicity of nickel alloys, nickelocene, nickel carbonyl, nickel salts, nickel arsenides, nickel antimonide, nickel selenides and nickel telluride. There is inadequate evidence in experimental animals for the carcinogenicity of nickel trioxide, amorphous nickel sulfide and nickel titanate. The Working Group made the overall evaluation on nickel compounds as a group on the basis of the combined results of epidemiological studies, carcinogenicity studies in experimental animals, and several types of other relevant data, supported by the underlying concept that nickel compounds can generate nickel ions at critical sites in their target cells. Overall evaluation: Nickel compounds are carcinogenic to humans (Group 1). Metallic nickel is possibly carcinogenic to humans (Group 2B). /Nickel compounds/ [R24] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 t0 15 L/min. Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Nickel and related compounds/ [R25, p. 371-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Consider drug therapy for pulmonary edema ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Nickel and related compounds/ [R25, 372] MEDS: *PRECAUTIONS FOR "CARCINOGENS": ... in relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may preclude them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical Carcinogens/ [R21, 1979.23] *Biological monitoring and hygienic monitoring complement each other in assessing occupational exposure to nickel. Biological monitoring is mainly directed to following the exposure of individual workers. In order to estimate exposure from data on biological monitoring, the exposing agent, ie, the chemical species of nickel involved must be known. Comparisons between exposures are most reliable when made under similar exposure conditions. In particular, when urine is monitored, contamination of the sample from the dust in the air, workers' clothes, and hands, is a major porblem. The sampling time must be standardized. At present, no clear cut preference can be given to plasma rather than urine or vice versa. With the exception of nickel carbonyl poisoning, no health risk estimation can be performed based on the results of biological monitoring. [R26] HTOX: *... SERIOUS HEALTH PROBLEMS OF SINUS AND LUNG CANCER WERE FOUND TO BE ASSOC WITH EXPOSURE TO HIGH LEVELS OF DUST AND FUMES GENERATED DURING HIGH TEMP CALCINATION OR SINTERING OF IMPURE NICKEL SULFIDE TO NICKEL OXIDE. [R27] *Chromosomal aberrations and sister chromatid exchanges were analyzed in the peripheral lymphocytes of nine retired nickel refinery workers 4-15 years after retirement and were compared with 11 matched non-nickel exposed controls. None of the controls had previous occupations with known relation to the induction of chromosomal aberrations or sister chromatid exchanges. The groups were equal as to socioeconomic status and environmental factors other than the occupational ones. The nickel workers' previous occupational employment involved exposure to inhalation of furnace dust of ... nickel oxide. ... The concentration of nickel in the working atmospheres has been higher than 1.0 mg/cu m air and the exposure time more than 25 years. The retired nickel workers showed an increased incidence of breaks (p < 0.001) and gaps (p < 0.05) but no difference in the incidence of sister chromatid exchanges when compared with the controls. [R28] *INTOXICATION FOLLOWING INHALATION OF NICKEL CMPD VARIES ACCORDING TO THE NATURE OF THE CMPD; NICKEL CARBONYL IS THE MOST TOXIC, WHILE DUSTS OF NICKEL OXIDE, CHLORIDE, AND SULFATE ARE LESS TOXIC. [R29, 295] *Carcinogenic hazards in nickel refineries have been associated primarily with exposures to nickel cmpd with low aq solubilities, such as nickel subsulfide and nickel oxide. [R30] *Peripheral lymphocytes were isolated from blood of retired nickel refinery workers after 4 to 15 years of retirement and examined for chromosome aberrations. Selected retirees had nasal dysplasia, but no overt nasal disease. Chromosomal aberrations and sister chromatid exchanges were scored in cells after 48 hr of culture and compared with those of males with no known exposure to agents inducing chromosomal changes. Groups were matched for age, retirement length, and socioeconomic status; subjects did not smoke or consume alcohol. Occupational exposures to nickel sulfide, nickel oxide or aerosols of nickel chloride or nickel sulfate were verified. Exposed workers had more than 25 years of exposure in the refinery where concentrations of nickel in the air were known to exceed 1.0 milligram per cubic meter of air. Nickel workers showed a statistically significant increase in chromosomal breaks and gaps of the chromatid and isochromatid type. Gaps average about 7.6 percent for the exposed and 5.3 percent for the nonexposed. Chromatid breaks averaged 4.1 percent among exposed and 0.5 percent in controls. The difference in plasma concentration of nickel was small (average of 2 micrograms per liter for exposed individuals and 1 microgram per liter for controls). [R28] *Nickel, nickel subsulfide, and nickel oxide are generated in relatively large particle sizes during the production and miniing of nickel and are, thus, associated with damage to the nasal mucosa. [R31] *Nickel oxide cause immunomodulation and hypersensitivity reactions. [R32] *Suspected carcinogen. Poison by subcutaneous route. Mutation data reported. [R33] *Nickel oxide ore has been mined on the South Pacific Island of New Caledonia since 1866 and smelted there since 1885 ... /studies/ identified 92 cases of lung cancer that had occurred in this area between 1970 and 1974. The observed rate was 3-7 times higher than rates in other Central or South Pacific areas, but similar to those seen in industrialized countries. A significant increase in lung cancer rates was observed with decreasing distance from the refinery. The authors found that, in New Caledonia, there was a 3-fold risk of lung cancer among workers compared with nonworkers, independent of age and tobacco smoking, and considered that these results supported the etiological role of nickel in lung cancer. [R34] *In the Soviet Union ... reported an increase in lung and gastric cancer in workers in a nickel refinery plant in the Urals. The refinery was engaged in the preparation of nickel oxide ore, roasting, and smelting. They stated that the lung cancer death rate from 1955 to 1967 exceeded that of the nearby urban population by 180% and that the death rate from sarcomas and stomach cancer was also increased. [R35] NTOX: */25 MALE AND FEMALE HAMSTERS GIVEN 30 WEEKLY INTRATRACHEAL INJECTIONS OF 0.2 ML OF SUSPENSION OF 2 G OF NIO/. ... A CONTROL GROUP ... /SUBSTITUTED/ CARBON DUST FOR NICKEL OXIDE. ONLY 1 TUMOR OF RESP TRACT DEVELOPED IN NICKEL OXIDE TREATED HAMSTERS, COMPARED WITH 4 ... IN CHARCOAL TREATED HAMSTERS; ONLY 3 ... IN EACH GROUP SURVIVED 12 OR MORE MO ... (FARRELL AND DAVIS, 1974). [R36] */SINGLE 5 MG DOSES INJECTED INTO THIGH MUSCLES OF SWISS OR C3H MICE/. % OF SITES WITH SARCOMAS ... 35% IN SWISS ... and 23% IN C3H MICE. /NONE/ ... INDUCED IN SWISS MICE SIMILARLY TREATED WITH COBALT OXIDE; NO UNTREATED CONTROLS USED. [R37] */20 MG NIO INJECTED IM INTO ONE OR BOTH THIGHS OF WISTAR RATS RESULTED IN/ ... 26 LOCAL TUMORS; THE MEAN LATENT /PERIOD/ OF TUMOR INDUCTION ... 302 DAYS ... /THIS IS PROBABLY RESULT OF SOLID STATE CARCINOGENESIS AND NOT SPECIFIC EFFECT OF NICKEL OXIDE/. [R37] *... 5 RHABDOMYOSARCOMAS AND 16 FIBROSARCOMAS WERE SEEN IN 50 SWISS MICE ... /GIVEN A SINGLE IM IMPLANT OF 5 MG NICKEL OXIDE/. NO CONTROLS WERE USED. /THIS IS PROBABLY RESULT OF SOLID-STATE CARCINOGENESIS AND NOT SPECIFIC EFFECT OF NICKEL OXIDE/ [R38] */SURGICAL IMPLANTATION OF NICKEL OXIDE, FORMED INTO PELLETS WITH SHEEP FAT, INTO MUSCLE OF 35 NIH BLACK RATS/ ... 4/35 DEVELOPED SARCOMAS @ SITE OF IMPLANTATION /AFTER 18 MO/. ... NO TUMORS WERE OBSERVED @ IMPLANTATION SITES ... IN CONTROLS /SIMILARLY IMPLANTED WITH PELLETS OF SHEEP FAT ALONE/ [R39] *... 51 MALE SYRIAN GOLDEN HAMSTERS, 2 MO OF AGE /WERE EXPOSED/ TO CHRONIC INHALATION OF NICKEL OXIDE ... /PARTICLE DIAMETER OF 0.3 UM @ MEAN ATMOSPHERIC CONCN OF 52 UG/L/ FOUR MALIGNANT TUMORS ... DETECTED @ VARIOUS SITES IN NICKEL OXIDE TREATED HAMSTERS, COMPARED WITH 1 IN 51 SHAM TREATED CONTROLS. AUTHORS CONCLUDED ... NO CARCINOGENIC EFFECT. [R40] *A total of 18 nickel compound were tested for carcinogenicity in male Fischer rats by a single im injection at equivalent dosages (14 mg nickel/rat). Within two years, the following incidences of sarcomas occurred at the injection site: ... nickel oxide 93%. ... [R41] *The effect of various nickel salts on cultured rhabdomyosarcoma cells was studied. Certain of these compounds, eg nickel subsulfide and nickel itself, induce tumors in muscle, while others have no effect, eg nickel monoxide (NiO). It has been suggested that the carcinogenicity of nickel is related to its penetrating power (phagocytosis) in transformed cells. Electron microscopy and microanalysis have been used to study the ultrastructure and intracellular localization of nickel in ultra-thin sections. Nickel subsulfide and nickel monoxide penetrate into cells and are concentrated in vacuoles, exhibiting a particular affinity for membrane structures. They subsequently appear to be eliminated in the extracellular medium. ... Various tumoral and normal cell lines were compared for their ability to phagocytose nickel subsulfide and it was found that the compound penetrated only macrophages and impregnated the membranes of polynuclear cells. These results suggest that the phagocytosis of nickel compounds is not directly related to the eventual induction of a tumor. [R42] *40 FEMALE SWISS MICE RECEIVED SINGLE IM INJECTION INTO EACH THIGH MUSCLE OF 10 MG OF METALLIC DUST ... TAKEN FROM A FLUE AT A NICKEL (NI) REFINERY. THE DUST CONTAINED 20% NI SULFATE, 57% NI SUBSULFIDE AND 6.3% NI OXIDE AND WAS ADMIN AS SUSPENSION IN PENICILLIN G PROCAINE. THERE WERE 36 SURVIVORS @ 90 DAYS; 23 SARCOMAS ... IN STRIATED MUSCLE WERE FORMED @ APPROX 1/3 OF INJECTION SITES. CONTROLS INJECTED WITH PENICILLIN G PROCAINE DEVELOPED NO SARCOMAS. (GILMAN AND RUCKERBAUER, 1962) [R40] *Wistar male rats were exposed by inhalation to aerosolized nickel oxide (NiO) (1.2 um + or - 2.2) for 1 mo. Tissues examined following exposure and at 12 and 20 mo. Electron microscopy showed that localization of NiO particles was restricted to the lung and that each particle had been engulfed by alveolar macrophages. Type II pneumocytes and nonciliated bronchiolar epithelial cells (Clara cells), as well as numerous tubular myelin (surfactant) in the alveoli, were prominent. After 12 mo, clusters of NiO particles were still present within the terminal bronchioli, alveolar walls, and lysosomes of the alveolar macrophages. Pools of tubular myelin were observed in the peribronchial lymphatics. The Clara cells, which project into the lumen of bronchioli, showed active secretion and were filled with smooth endoplasmic reticulum in the apical cytoplasm. After 20 mo, 1 rat had papillary adenocarcinoma and 2 rats showed adenomatosis in the peripheral portion of the lung, but not in the upper respiratory tract. [R43] *A survey of the epidemiological and experimental evidence for nickel compound carcinogenesis suggests that nickel and nickel oxide should not be considered carcinogens for risk assessment purposes. A rationalization of the observed experimental results from animal models using all exposure routes and based on differential solubilities in water and lipid has been proposed and explored in vitro with C3H10T1/2 cell transfromation studies. The results generated did not support this theory, but did support the argument that nickel and its oxide are noncarcinogenic. It is proposed that the IARC risk classification for nickel and nickel oxide be modified accordingly. [R44] *The effect of intrarenal injection of nickel compounds was investigated in Fischer 344 rats. A total of 17 nickel compounds, 7 milligrams per rat, were injected intrarenally into the right kidney of each rat. Blood hematocrit was measured and histological examinations were performed. Nine of the nickel compounds caused significant erythrocytosis as defined by peak hematocrit values greater than 55 percent 1 to 4 months postinjection. The nine compounds were nickel dust, nickelous oxide, nickel monosulfide, nickel subsulfide, nickel monoselenide, nickel subselenide, nickel sulfarsenide, nickel disulfide, and nickel ferrosulfide. Cancers were found in the injected kidneys exposed to all of the compounds but nickel dust and nickelous oxide. Cancers were also found in kidneys exposed to nickel monoarsenide and an iron/nickel alloy. The incidences of renal cancer in the 17 groups of rats were significantly correlated with the incidences of erythrocytosis and the mean peak hematocrit values. [R45] *Male Wistar rats were continuously exposed to nickel oxide aerosols for 4 weeks and 4 months, respectively, to study the effects on alveolar macrophages and the humoral immune system. Fractions of alveolar macrophages, granulocytes, and lymphocytes in lung lavages, number of polynucleated macrophages, size of macrophages, and phagocytic activity were determined. To test the effects on the humoral immune response sheep erythrocytes were injected, and the antiserum titer in blood and the portion of antibody forming cells in spleen were measured. Significant alterations were found in both systems at 100 and 200 micrograms nickel/cu m after 4 weeks of exposure and at 25 and 150 micrograms nickel/cu m after 4 months of exposure. [R46] *Nickel compounds were tested for carcinogenicity in male Fischer rats following a single im injection of equivalent dosages of 18 compounds (14 mg nickel/rat). Within two years, the following incidence of sarcomas occurred at the injection site: ... nickel oxide (NiO), 93%. ... Distant metastases were found in 109 of 180 sarcoma-bearing rats (61%). The nickel induced sarcomas included rhabdomyosarcomas, 52%, fibrosarcomas, 18%, undifferentiated sarcomas, 13%, osteosarcomas, 8%, and miscellaneous and unclassified sarcomas, 9%. Kendall's rank-correlation test showed that the carcinogenic activities of the compounds were correlated (p= 0.02) with their nickel mass fractions, but not with dissolution half-times in rat serum, renal cytosol, or with phagocytic indices of rat peritoneal macrophages in vitro. Rank correlation (p < 0.0001) was found between the carcinogenic activities and the potencies of the compound to induce erythrocytosis in rats. [R47] *The pathogenicity of nickel oxide (NiO) in hamsters receiving life time exposures to NiO approx 0.55 mg/cu m, 7 hr/day 5 days/wk) was studied. Heavy pulmonary NiO burdens resulted in pneumoconiosis, but no significant carcinogenicity, toxicity, or mortality. Two month exposures to nickel-enriched fly ash or fly ash aerosols (approx 185 mg/cu m) resulted in a lung burden (approx 5.7 mg), dark discoloration of lung, heavily dust laden macrophages, and significantly higher lung wt but only minimal inflammatory reactions and no deaths. The nickel enriched fly ash contained 9% nickel; fly ash contained 0.03% nickel; exposure to aerosols of nickel enriched fly ash (70 mg/cu m; 6% nickel) or fly ash (70 mg/cu m; 0.3% nickel) for 20 months had no effect on body wt or animal mortality. No significant nickel specific toxicity/carcinogenicity was found, but exposure to high concn of NiO resulted in nonspecific dust pneumoconiosis. [R48] *In vitro studies comparing cytotoxicity of different forms of nickel oxide (NiO) and nickel copper oxides calcined at different temperatures and measured in pulmonary macrophages were reported. Batches of NiO, prepared at temperatures ranging from 650 to 1045 deg C, and four types of nickel copper oxides, containing 6.9 to 28 % copper, were tested for their cytotoxic effects against alveolar macrophages from F344/N rats. The most toxic compounds were further tested with macrophages from B6C3F1 mice and Beagle dogs at four different concentrations. Cytotoxicity was highest for NiO calcined at temperatures below 650 deg C and was directly related to the copper content of nickel copper oxide compounds. The most toxic nickel copper oxide compounds were those with the highest copper content. The median lethal concentrations of all NiO and nickel copper oxide compounds for rat pulmonary macrophages were equally sensitive, while dog pulmonary macrophages were considerably more sensitive to nickel copper oxides. [R49] *Nickel subsulfide, nickel sulfate, nickel chloride, and nickel oxide were tested for relative toxicity to beagle dogs and F344/Cr1 rat alveolar macrophages in vitro. Dog alveolar macrophages were at least 10 times more sensitive to the 4 nickel compounds than rat alveolar macrophages. Toxicity ranking of the four nickel compounds to macrophages from both species was nickel subsulfide > nickel chloride approximately nickel sulfate > nickel oxide. [R50] *F344/CR1 rats were administered a single dose of nickel subsulfide, nickel chloride, nickel sulfate, and nickel oxide containing 0.0, 0.01, 0.10, or 1.0 umol nickel by intratrachael instillation. Rats were sacrificed at 1 or 7 days after compound administration; nickel lung burden was determined in half of the animals in each exposure group of the remaining animals were used to evaluate biochemical, cytological, and histological changes. In the latter group, lavage fluid from the right lung was analyzed for lactate dehydrogenase, beta-glucuronidase, total protein, glutathione reductase, glutathione peroxidase, and sialic acid; total and differential cell counts were also determined. The left lobe was examined for morphological changes. Clearance of nickel from the lung was most rapid for nickel chloride and nickel sulfate, followed by nickel subsulfide and NiO. Minimal changes in all parameters were observed at 1 day after exposure. No significant changes occurred in rats exposed to NiO, while nickel subsulfide, nickel sulfate, and nickel chloride caused increases in lactate dehydrogenase, beta-glucuronidase, total protein, glutathione reductase, sialic acid, and total nucleated cells at 7 days. Alveolitis was observed histologically in nickel subsulfide, nickel sulfate, and nickel chloride exposed animals. The following toxicity ranking was assigned: nickel sulfide, nickel sulfate, nickel chloride, nickel oxide. [R51] *The effect of various nickel salts on cultured rhabdomyosarcoma cells was studied. Nickel subsulfide and nickel induced tumors in muscle, whereas others had no effect, eg, nickel oxide (NiO). [R42] *Male rats were exposed to an aerosol concentrations of nickel oxide (NiO) ranging from 0.6 to 8.0 mg/cu m; total exposure time was 140-216 hr. Rats were sacrificed immediatly after exposure; other groups were exposed for 1 mo and allowed a 1 yr clearance period before sacrifice. There were no differences in body wt gain between NiO exposure groups and controls. No apparent deposition of nickel was observed in liver, kidney, spleen, heart, brain, and blood, but lung burdens of up to approx 2.35 mg of NiO were found. The apparent deposition fractions were 19.8 and 14.5% in groups exposed to avg concn of 1.4 and 6.4-7.0 mg/cu m, respectively suggesting that the clearance rate of NiO deposited in lungs may be small. [R52] *Carcinogenicity studies were conducted on rats administered 50 dusts either by injection or intratracheal instillation. Nickel powder, nickel oxide, nickel subsulfide, and cadmium sulfide were all found to be carcinogenic by both routes. The ip test in rats is very sensitive for detecting the carcinogenic potency of natural and man made mineral dusts as well as metal compounds of low acute toxicity. Therefore, if a high ip dose of these materials does not induce tumors, evidence for carcinogenic potency can not be substantiated. [R53] *Under controlled metallurgical conditions, a series of ten nickel-oxides and nickel-copper-oxides were prepared to determine whether these compounds differ in their biological effects. Test animals included 130 male Fischer-344 rats. All compounds, which contained nickel-oxide as the predominant crystalline phase, differed substantially in their biological effects in both in-vitro and in-vivo. A strong rank correlation was noted between results of the cell transformation and erythropoiesis stimulation assays. Biological activities of nickel-oxides were apparently affected by specific physicochemical properties, including the presence of high surface area and demonstrable nickel-II. Dissolution half times in rat serum and renal cytosol, phagocytosis by C3H-10T1/2 cells, morphological transformation of SHE cells, erythropoiesis stimulation in rats, induction of tubular hyperplasia in rat kidneys, and induction of arteriosclerosis in rat kidneys were six colligative biological attributes identified for the compounds. [R54] *Lifetime exposure of hamsters to nickelous oxide and cobaltous oxide caused pneumoconiosis. Concurrent exposure to cigarette smoke caused decreased body weight and increased incidence of tumors and epithelial lesions of the larynx. Increased life spans were seen in the smoke exposed hamsters due to a delayed onset of amyloidosis. Exposure of hamsters to 70 mg/cu m of fly ash or nickel enriched fly ash resulted in increased lung weights and volumes with severe pulmonary dust burdens, interstitial reaction and bronchiolization; there was no statistically significant carcinogenesis observed. [R55] *40 FEMALE SWISS MICE RECEIVED SINGLE IM INJECTION OF 10 MG OF METALLIC DUST ... TAKEN FROM A FLUE AT A NICKEL REFINERY. THE DUST CONTAINED 20% NICKEL SULFATE, 57% NI SUBSULFIDE AND 6.3% NICKEL OXIDE AND WAS ADMIN AS SUSPENSION IN PENICILLIN G PROCAINE. THERE WERE 36 SURVIVORS @ 90 DAYS; 23 SARCOMAS ... IN STRIATED MUSCLE WERE FORMED @ APPROX 1/3 OF INJECTION SITES. CONTROLS INJECTED WITH PENICILLIN G PROCAINE DEVELOPED NO SARCOMAS. (GILMAN AND RUCKERBAUER, 1962) [R40] *Long term exposure to arsenic trioxide aerosols (60 and 200 ug/cu m) did not cause toxic or carcinogenic effects in rats exposed for 1.5 yr or after conventional housing for an additional yr in clean air. A parallel study with nickel oxide aerosols showed lung toxicity. Severe proteinosis was observed in all animals; the survival times were too short to evaluate carcinogenicity. Cytotoxic effects on alveolar macrophages and depressed alveolar clearance mechanisms possibly initiated long term effects of nickel oxide aerosols. [R56] *Nickel compounds that possess similar elemental compositions but vary in physicochemical properties can elicit markedly different biological effects. The crystalline nickel sulfides and oxides that slowly dissolve in body fluids and readily enter cells by phagocytosis tend to be most active in producing morphological transformation of SHE cells in vitro and stimulating erythrocytosis and carcinogenesis following ir administration in rats. The capacities of particulate nickel compounds to induce erythropoietin-mediated erythrocytosis in rats are closely correlated with their carcinogenic activities; hence erythrocytosis stimulation can serve as a screening test for carcinogenicity. [R57] *The relative transformation potency of nickel metal and a number of nickel cmpd was determined in vitro using BHK-21 cells. These included, as relatively insol particulate, a known carcinogen, nickel subsulfide and several oxides either of common interest or found in the work place. Although a wide range of transformation potency was found as a function of the dose of nickel/area of culture, all substances produced the same number of transformed colonies at the same level of toxicity (eg, 50% survival). Toxicity may arise from membrane bound, nickel phagocytized particles, or nickel available from soln. If toxicity is a direct measure of net available nickel, then nickel or nickel ions may be the ultimate transforming agent, independent of source or uptake mechanism. [R58] *... CONCLUSIONS: Under the conditions of these 2 year inhalation studies, there was some evidence of carcinogenic activity of nickel oxide in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of benign or malignant pheochromocytoma (combined) of the adrenal medulla. There was some evidence of carcinogenic activity of nickel oxide in female F344/N rats based on increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of benign pheochromocytoma of the adrenal medulla. There was no evidence of carcinogenic activity of nickel oxide in male B6C3Fl mice exposed to 1.25, 2.5, or 5 mg/cu m. There was equivocal evidence of carcinogenic activity of nickel oxide in female B6C3Fl mice based on marginally increased incidences of alveolar/bronchiolar adenoma in 2.5 mg/cu m females and of alveolar/bronchiolar adenoma or carcinoma (combined) in 1.25 mg/cu m females. [R59] NTP: *... Male and female F344/N rats and B6C3F1 mice were exposed to nickel oxide (high temperature, green nickel oxide, mass median diameter 2.2 +/- 2.6 um; at least 99% pure) by inhalation for ... 2 yr. ... 2 YEAR STUDY IN RATS: ... Groups of 65 male and 65 female F344/N rats were exposed to 0, 0.62, 1.25, or 2.5 mg nickel oxide/cu m (equivalent to 0, 0.5, 1.0, or 2.0 mg nickel/cu m) by inhalation for 6 hr/day, 5 days/wk for 104 wk. ... 2 YEAR STUDY IN MICE: ... Groups of 74 to 79 B6C3F1 mice were exposed to 0, 1.25, 2.5, or 5 mg nickel oxide/cu m by inhalation for 6 hr/day, 5 days/wk for 104 wk. CONCLUSIONS: Under the conditions of these 2 year inhalation studies, there was some evidence of carcinogenic activity of nickel oxide in male F344/N rats based on increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of benign or malignant pheochromocytoma (combined) of the adrenal medulla. There was some evidence of carcinogenic activity of nickel oxide in female F344/N rats based on increased incidences of alveolar/bronchiolar adenoma or carcinoma (combined) and increased incidences of benign pheochromocytoma of the adrenal medulla. There was no evidence of carcinogenic activity of nickel oxide in male B6C3Fl mice exposed to 1.25, 2.5, or 5 mg/cu m. There was equivocal evidence of carcinogenic activity of nickel oxide in female B6C3Fl mice based on marginally increased incidences of alveolar/bronchiolar adenoma in 2.5 mg/cu m females and of alveolar/bronchiolar adenoma or carcinoma (combined) in 1.25 mg/cu m females. [R59] TCAT: ?Nickel oxide (CAS # 1313-99-1) was evaluated for cross-over dermal sensitization (nickel sulfate induction) in the Guinea Pig Maximization Test. Ten female Hartley-derived albino guinea pigs were inducted with propylene glycol (vehicle control) or 0.1 mL intradermal injections of 1.0% (w/v) nickel sulfate in distilled water and 1.0% (w/v) nickel sulfate in Freund's Complete Adjuvant, followed 7 days later with 48-hour topical applications of 0.3 mL of 5.0% (w/v) aqueous nickel sulfate. Challenge 2 weeks later, consisting of 0.2 mL dermal applications of 1.0% aqueous nickel oxide (the maximal non-irritating dose in range-finding study) at virgin sites under occluded binder for 24 hours, induced no erythema in the nickel sulfate-induced pigs. Relative to vehicle control (mean erythema score of 0.1 at 24 hours only) and based on an extension of a Mantel-Haenszel Procedure of analysis, the authors concluded that nickel sulfate did not cause dermal sensitization to nickel oxide challenge in the Guinea Pig Maximization Test. [R60] ?Nickel oxide (CAS # 1313-99-1) was evaluated in the BALB/3T3 cell transformation assay in the absence of exogenous metabolic activation using an exposure intended to produce a 50% minimum toxicity (diminished cloning efficiency). In preliminary tests for cytotoxicity, cell cultures exposed for 24 hours to concentrations of 1, 10, 100, and 1000 ug/mL culture medium, respectively, demonstrated cloning efficiencies of 0, 9, 86, and 93% relative to solvent control. Based on these preliminary cytotoxicity tests, doses of 60 ug/mL in triplicate cultures of 250 cells yielded 40% survival and a significant (p < /= 0.05) increase in transformation frequency in 15 replicate cultures of 100,000 cells relative to solvent (acetone) control: Six (6) Type III foci were observed as compared to 5 and 0, respectively, for nickel subsulfide at 6 ug/mL (62% survival) and the solvent control. A transformation frequency was 2.52 x 10(-4), based on a special application of a Poisson distribution. [R61] ?Nickel oxide (CAS # 1313-99-1) was evaluated for repeated-dose toxicity in F344/N rats (5/sex/group) administered daily whole-body exposures to target aerosol (MMAD 3.9 um) concentrations of 0, 1.2, 2.5, 5.0, 10, and 30 mg/cu m in air, 6 hours/day for a total of 12 exposures in 2 weeks. The 2-week study established exposure limits to be used in 90-day and chronic exposure studies. Treatment produced no clinical signs of toxicity and no increased mortality throughout the course of study. Relative and absolute lung weights were significantly increased in both 10 and 30 mg/cu m exposure groups. Upon terminal necropsy, gross lesions were limited to enlargement of bronchial lymph nodes in 4/10 high-dose rats; however, histological investigation revealed lesions of the lungs (all exposure levels), bronchial lymph nodes (10, 30 mg/cu m), mediastinal lymph nodes (30 mg/cu m), thymus (10, 30 mg/cu m), and nasal epithelium (30 mg/cu m). In the lung, lesions were widespread in high-dose rats and characterized by hyperplasia, vacuolation, or vesiculation of alveolar macrophages, pigmented particles in alveoli and alveolar macrophages, focal purulent inflammation of alveoli and alveolar septa, hyperplasia and focal interstitial cellular infiltrates of peribronchial lymphoid tissue. Macrophage numbers were increased in many areas of the lungs. Lymphocytic hypertrophy was identified in mediastinal lymph nodes and, in the paracortical regions of the bronchial lymph nodes, accounted for gross enlargement noted on necropsy. Rats of a high exposures also exhibited degenerative changes of the cortical thymus (10, 30 mg/cu m) and atrophy of the olfactory epithelium (30 mg/cu m). Changes in the lungs, bronchial lymph nodes, and thymus were similar, but of lesser intensity and seen in fewer animals of lower level nickel oxide aerosol exposures. [R62] ?Nickel oxide (CAS # 1313-99-1) was evaluated for repeated-dose toxicity in B6C3F1 mice (5/sex/group) administered daily whole-body exposures to target aerosol (MMAD 3.9 um) concentrations of 0, 1.2, 2.5, 5.0, 10, and 30, mg/cu m in air, 6 hours/day for a total of 12 days in 2 weeks. The 2-week study established exposure limits to be used in 90-day and chronic exposure studies. One male (5 mg/cu m) of the main study and 2/12 females (5 mg/cu m), from satellite study of effects on natural killer cell activity, died. No significant treatment-related clinical signs of toxicity or bodyweight changes were noted. Upon terminal necropsy, the gross lesions were limited to enlarged bronchial lymph nodes in 4/10 high-exposure mice and atrophied and grayed right intermediate lobes on the lung of a solitary male mouse of a 30 mg/cu m exposure. Histological investigation of the bronchial nodes revealed hyperplasia of lymphocytes in the paracortical regions of the highest exposure group only. Lungs of this group exhibited focal mixed inflammatory cell infiltrate in the interstitium near the vessels, bronchial epithelial hyperplasia (non-ciliated cells), and diffuse alveolar macrophage hyperplasia. These changes were severe only in the 30 mg/cu m male mouse exhibiting gross lesions of the right intermediate lobe. The alveoli of this bronchial lobe contained many particles and macrophages, often vacuolated or necrotic with multiple neutrophils, and showed degenerative changes of the epithelium. Alveolar macrophages were often enlarged and their numbers were moderately increased. Bronchial lesions were also noted in mice of exposures below 30 mg/cu m; however, they were characterized primarily by alveolar macrophage hyperplasia (10 - 30 mg/cu m) and pigmented particles within the alveolar macrophages (2.5 - 30 mg/cu m); these exposure-related changes were of lesser intensity than that seen in association with the high-level exposure to nickel oxide aerosol. [R63] ?Nickel (II) oxide (CAS # 1313-99-1) was evaluated for repeated-dose inhalation toxicity in B6C3F1 mice (5/sex/group) administered daily whole-body exposures to target aerosol (MMAD 2.8 um) concentrations of 0, 1.2, 2.5, 5.0, 10, and 30, mg/cu m in air, 6 hours/day on 5 days per week for a total of 12 exposures in 16 days. The core 16-day study established exposure limits to be used in 90-day and chronic exposure studies, and additional groups (5/sex/group) were exposed to all but the 2 highest levels for body burden analyses. Treatment induced no distinct clinical signs of toxicity, no bodyweight anomalies, and no increased mortality relative to controls. Upon terminal necropsy, pigmented particles were observed in the lungs of mice exposed to levels of 2.5 mg/cu m and above, while both male and female mice of 10 and 30 mg/cu m exposures also exhibited accumulation of macrophages in the alveolar spaces. Pigmented particles and lymphoid hyperplasia were also identified in the bronchial lymph nodes. The lungs of exposed mice contained significantly (p < /= 0.05, Williams' or Dunnett's test) higher concentrations of nickel (32-84 ug nickel/g lung, males; 31-71 ug/g, females) than the lungs of controls. Study Materials and Methods, and Results sections were omitted from this submission; no further information was provided. [R64] ?Nickel (II) oxide (CAS # 1313-99-1) was evaluated for subchronic inhalation toxicity in B6C3F1 mice (10/sex/group) administered daily whole-body exposures to target aerosol (MMAD 2.8 um) concentrations of 0, 0.6, 1.2, 2.5, 5.0, and 10 mg/cu m in air, 6 hours/day on 5 days in each of 13 weeks. Additional groups (5/sex/group) similarly exposed to 0, 0.6, 2.5, and 10.0 mg/cu m in air participated in concurrent tissue burden studies. Among groups of the core study, treatment produced no distinct clinical signs of toxicity, bodyweight anomalies, or increased mortality relative to control. The hemoglobin concentration was minimally increased in females of 5 mg/cu m exposure, while hematocrit values and erythrocyte counts were slightly increased in 5 and 10 mg/cu m females. Upon gross necropsy, absolute and relative lung weights were significantly (p < /= 0.05, Williams' or Dunnett's test) increased in 10 mg/m males and females, and absolute and relative liver weights were significantly less in 10 mg/cu m males than in controls. Histologic examination identified accumulations of alveolar macrophages, often pigmented, in all exposed mice and increased incidence of inflammation (chronic perivascular infiltrates or granulomas) in groups of 2.5 mg/cu m exposures and above. Lymphoid hyperplasia and pigmentation of bronchial lymph nodes also occurred in association with exposures of 2.5 mg/cu m and above. Tissue burden study documented significantly increased concentrations of nickel in the lung at exposures to 0.6, 2.5, and 10 mg/cu m at 13 weeks (42-736 ug nickel/g lung). Neither a NOEL nor a saturation point was established in the core or tissue-burden legs of the study. Study Materials and Methods, and Results sections were omitted from this submission; no further information was provided. [R64] ?Nickel (II) oxide (CAS # 1313-99-1) was evaluated for repeated-dose inhalation toxicity in F344/N rats (5/sex/group) administered daily whole-body exposures to target aerosol (MMAD 2.8 um) concentrations of 0, 1.2, 2.5, 5.0, 10, and 30, mg/cu m in air, 6 hours/day on 5 days per week for a total of 12 exposures in 16 days. The core 16-day study established exposure limits to be used in 90-day and chronic exposure studies, and additional groups (5/sex/group) were exposed to all but the 2 highest levels for body burden analyses. Treatment induced no distinct clinical signs of toxicity, no bodyweight anomalies, and no increased mortality relative to controls. Relative and absolute lung weights were significantly (p < /= 0.05, Williams' or Dunnett's test) increased in both 10 and 30 mg/cu m exposure groups. Upon terminal necropsy, pigmented particles were observed in the lungs of all exposed male and female rats, while inflammation with accumulation of macrophages in the alveolar spaces and lymphoid hyperplasia in respiratory lymph nodes was most marked in the males and females of 10 and 30 mg/cu m exposures. Hyperplasia of the bronchial lymph nodes occurred solely in the 30 mg/cu m rats. The lungs of exposed rats contained significantly higher concentrations of nickel (42-257 ug nickel/g lung, males; 54-340 ug/g, females) than the lungs of controls. Study Materials and Methods, and Results sections were omitted from this submission; no further information was provided. [R64] ?Nickel (II) oxide (CAS # 1313-99-1) was evaluated for subchronic inhalation toxicity in F344/N rats (10/sex/group) administered daily whole-body exposures to target aerosol (MMAD 2.8 um) concentrations of 0, 0.6, 1.2, 2.5, 5.0, and 10 mg/cu m in air, 6 hours/day on 5 days in each of 13 weeks. Additional groups (18/sex/group) similarly exposed at 0, 0.6, 2.5, and 10.0 mg/cu m in air participated in concurrent tissue burden studies. Among groups of the core study, treatment produced no distinct clinical signs of toxicity, bodyweight anomalies, or increased mortality relative to control. Particularly in the females, exposures were associated with slightly increased hemoglobin and mean cell hemoglobin concentrations, hematocrit values, and lymphocyte, neutrophil, monocyte and erythrocyte counts; mean cell volumes were lower than those in controls. Gross necropsy revealed significantly (p < /= 0.05, Williams' or Dunnett's test) increased absolute and relative lung weights, with nonneoplastic lesions of dose-related severity in the lungs of rats exposed to concentrations of 2.5 mg/cu m and above. Histologic examination identified accumulations of alveolar macrophages, often pigmented, in all exposed rats and increased incidence of inflammation in groups of 2.5 mg/cu m exposures and above. Lymphoid hyperplasia and pigmentation of bronchial and mediastinal lymph nodes also occurred in association with exposures of 2.5 mg/cu m and above. Tissue burden study documented significantly increased concentrations of nickel in the lungs with all but the 1.2 mg/cu m exposures at 4 (33-263 ug nickel/g lung), 9 (53-400 ug/g), and 13 (80-524 ug/g) weeks. Neither a NOEL nor a saturation point was established in the core or tissue-burden legs of the study. Study Materials and Methods, and Results sections were omitted from this submission; no further information was provided. [R64] ?Nickel (II) oxide (CAS # 1313-99-1) was evaluated for chronic inhalation toxicity and carcinogenicity in B6C3F1 mice (75-79/group) administered daily whole-body exposures to target aerosol (MMAD 2.8 um) concentrations of 0, 1.25, 2.5, and 5.0 mg/cu m in air, 6 hours/day on 5 days in each of 104 weeks. Treatment produced no distinct clinical signs of toxicity, hematology anomalies (15-month interim evaluation), or increased mortality relative to control; however, mean bodyweights of exposed 5.0 mg/cu m females were minimally reduced in the second year of study relative to controls. Incidence of chronic respiratory tract inflammation and pigmentation generally increased in a dose-dependent manner at 7 and 15 months in both males and females, and a minimal bronchialization (alveolar epithelial hyperplasia) and proteinosis were first noted at 15 months. At 2 years, chronic inflammation, bronchialization, and proteinosis were significantly (p < /= 0.05, Williams' or Dunnett's test) more prevalent in exposed groups than in controls. Pigmentation of the lungs was universal throughout treatment groups. Upon histologic review after 2 years, females of 1.25 mg/cu m exposures exhibited significantly increased incidence of alveolar/bronchiolar adenomas and carcinomas (combined) and 2.5 mg/cu m females showed increased incidence of alveolar/bronchiolar adenomas relative to controls. Lymphoid hyperplasia first occurred in one each of 1.25 mg/cu m females and 2.5 mg/cu m males at 7 months, in males of 2.5 and 5.0 mg/cu m exposures and all females at 15 months. At the 2-year assessment, a dose-dependent relationship for lymphoid hyperplasia was apparent and bronchial lymph node pigmentation was nearly universal in all treatment groups. Tissue burden analysis documented significantly increased concentrations of nickel in the lungs of exposed mice at 7 and 15 months (7 months, 162-1034 ug nickel/g lung; 15 months, 331-2,258 ug/g), these levels rising in both a dose- and time- dependent manner. Study Materials and Methods, and Results sections were omitted from this submission; no further information was provided. [R64] ?Nickel (II) oxide (CAS # 1313-99-1) was evaluated for chronic inhalation toxicity and carcinogenicity in F344/N rats (65/sex/group) administered daily whole-body exposures to target aerosol (MMAD 2.8 um) concentrations of 0, 0.62, 1.25, and 2.5 mg/cu m in air, 6 hours/day on 5 days in each of 104 weeks. Treatment produced no distinct clinical signs of toxicity, hematology anomalies (15-month interim evaluation), or increased mortality relative to control. Mean bodyweights during the second year of 1.25 and 2.5 mg/cu m exposures in both males and females, however, were minimally reduced relative to controls. On interim sacrifice at 7 and 15 weeks, absolute and relative lung weights were significantly (p < /= 0.05, Williams' or Dunnett's test) higher in these groups. Most exposed rats exhibited chronic inflammation of the lung at 7 and 15 months, the dose-dependent increased incidence of statistical significance relative to controls in both males and females at 2 years' assessment. Atypical bronchialization (alveolar epithelial hyperplasia) was also generally enhanced with increasing exposure level in males and females at 2 years. Increased alveolar pigmentation in exposed rats relative to controls reached statistical significance at 7 months and persisted in all treatment groups throughout the study. Upon 2-year terminal sacrifice, alveolar/bronchiolar carcinomas in 1.25 mg/cu m females and alveolar/bronchiolar adenomas and carcinomas (combined) in 1.25 and 2.5 mg/cu m males were significantly increased relative to controls. Bronchiolar lymphoid hyperplasia first observed in 1.25 and 2.5 mg/cu m males and females at 7 months, was generally increased with exposure level at 2 years. Pigmentation of the bronchial lymph nodes appeared in all exposure groups except 0.62 mg/cu m males and females at 7 months. Additionally, increases in pheochromocytoma and adrenal medulla hyperplasia were statistically significant at 2 years in 2.5 mg/cu m females, as benign or malignant pheochromocytoma (combined) was in the 2.5 mg/cu m male rats. Tissue burden analysis documented significantly increased concentrations of nickel in the lungs of exposed rats at 7 and 15 months (7 months, 173-713 ug nickel/g lung; 15 months, 262-1,116 ug/g), these levels rising in both a dose- and time-dependent manner. Study Materials and Methods, and Results sections were omitted from this submission; no further information was provided. [R64] ADE: *Ten days after the inhalation of a nickel oxide aerosol, ... 80% of the deposited dose was still retained in the lung of hamsters. [R65] *Wistar male rats were exposed to green nickel oxide aerosols (mass media aerodynamic diameter, 0.6 um) for 7 hr/day, 5 days/wk for less than or equal to 12 mo. The avg exposure concn was controlled at 0.3 mg/cu m and 1.2 mg/cu m. Rats were sacrificed following a 3-6 or 12 mo exposure. There were no differences in body wt gain between exposure groups and controls. Lung wt in exposed rats were heavier than those in the control groups. Nickel concn in lung of exposure groups were much higher than those of controls. The nickel concn in liver, kidney, spleen, and blood increased slightly with increased exposure times. The nickel content in lung during the 12 mo exposure was estimated theoretically. The estimated values agreed with the experimental data. [R66] *SIGNIFICANT UPTAKE AND ACCUM OCCURRED IN 20, 40, and 80 MG NI/L IN 96 HR EXPT. MUSSELS SECRETED BYSSAL THREADS IN CONCN OF 20 MG NI/L, BUT NOT IN HIGHER CONCN. [R67] *AFTER ACUTE OR CHRONIC EXPOSURE OF RATS ... BY INHALATION, INCR IN NI OCCUR PREDOMINANTLY IN MICROSOMAL AND SUPERNATANT FRACTIONS OF LUNG AND LIVER. AFTER CHRONIC EXPOSURE, INCR AMT OF NI ARE ALSO OBSERVED IN NUCLEAR AND MITOCHONDRIAL FRACTION OF THE LUNG. [R68] *... Exposed Syrian golden hamsters to nickel oxide ... particles with a mass mean aerodynamic diameter (MMAD) of 1.0-2.5 um, and observed that inhalation of 2 days (7 hr/day) at a concn of 10-190 mg/m3 air resulted in deposition of 20% of the inhaled amt. On the 10th day of exposure, more than 75% of the nickel oxide was still present in the lungs, and, even after 45 days, approx 50% of the total amt inhaled still remained. As no significant quantities of nickel oxide were found in the liver and kidney at any time after exposure, absorption seemed to be negligible during this period. [R69] *When rats were exposed through inhalation to nickel oxide aerosol (0.4-70 mg/cu m) for 6-7 hr, 5 days/wk, for a max of 3 mo, the fraction deposited in the lung significantly decr with incr mass median diameter and slightly decr with incr exposure concn ... . [R70] *Following inhalation of high concn of nickel oxide (10-1290 mg/cu m) by hamsters (7 hr daily, repeated exposures for up to 3 mo), 20% of the inhaled amt of nickel oxide was still present in the lungs 3-4 days after exposure. Complete clearance of this oxide was estimated to take weeks to months; 75% of the nickel oxide was still present in the lungs 10 days after exposure and 40% was till present 100 days after exposure ... The lungs retained more than 99% of the nickel oxide deposited there. The liver and kidney retained small amt of 0.21 and 0.04%, respectively. [R71] *The toxicokinetics of inhaled nickel oxide and nickel subsulfide in Fischer-344/N-rats were investigated. Male rats were exposed nose only to 9.9mg/m3 nickel oxide or 5.7 mg/cu m nickel subsulfide for 70 or 120 minutes, respectively. Toxicokinetic parameters used were total and regional respiratory tract deposition of aerosols, lung clearance of deposits, distribution of the solubilized substances to other tissues, and nickel excretion pathways. Results showed that the fractions of inhaled nickel oxide and nickel subsulfide deposited in the respiratory tract were 0.11 and 0.13, respectively. For both aerosols, the fractions deposited in the lungs were 0.05. Clearance of nickel oxide from the lungs was slow, with a half time of about 120 days, and nickel oxide was excreted only in the feces during the first days after exposure. In contrast, nickel subsulfide was cleared rapidly from the lungs, with a half time of only about 4 days. In the case of nickel subsulfide, several other tissues (turbinates, skull, kidneys) showed its presence within the first few hours of exposure, and it was detectable in the lungs and kidneys up to 16 days postexposure. It was concluded that these two nickel compounds have different lung retention and tissue distribution patterns that appear related to the relative insolubility of nickel oxide and the solubility of nickel subsulfide. [R72] BHL: *Male rats were exposed to nickel oxide (NiO) aerosols (mass median aerodynamic diameter, 1.2 and 4.0 um). The average exposure concn was controlled from a low level of 0.6 mg/cu m to a high level of 70 mg/cu m and total exposure time was 140 hr. Some rats were sacrificed just after the exposure, whereas others were exposed for 1 mo and kept for 12 and 20 mo clearance periods before sacrifice. There were no differences in body wt grain between NiO exposure groups and controls. Nickel concn in lung of exposure groups were much higher than those of controls and decreased with increased clearance time. No apparent deposition of nickel was observed in the liver, kidney, spleen, and blood immediately after the exposure, but in the high exposure groups, nickel concn in the liver, spleen, and blood increased slightly with increasing clearance time. The biological half-time of NiO deposited in the lung, assuming that the amt of the clearance is proportional to the amt of the NiO deposited, was 11.5 and 21 mo for 1.2 and 4.0 um, respectively. [R73] *... Half-life for the clearance of nickel /oxide/ from the deep tract /of the lungs/ of 36 days. The half-life for clearance from the tracheobronchiolar compartment was less than 1 day. [R70] ACTN: *Carcinogenic nickel compounds are known to induce promutagenic DNA lesions such as DNA strand breaks and DNA adducts in cultured mammalian cells. In standard mutation assays, in contrast, they were found to be either inactive or weakly active. In our in vitro mutation studies in a lacI transgenic embryonic fibroblast cell line, nickel subsulfide (Ni3S2) increased mutation frequency up to 4. 5-fold. We subsequently applied the comet assay and transgenic rodent mutation assays to investigate the DNA damaging effect and mutagenic potential of nickel subsulfide in target cells of carcinogenesis. A 2-h in vitro treatment of freshly isolated mouse nasal mucosa and lung cells with nickel subsulfide clearly induced DNA fragmentation in a concentration dependent manner. The strong effect was not seen in the same cell types following inhalative treatment of mice and rats, leading only in the mouse nasal mucosa to high DNA damage. When the same inhalative treatment was applied to lacZ and lacI transgenic mice and rats, the spontaneous mutation frequency of these target genes in the respiratory tissues was not increased. These results support a recently proposed non-genotoxic model of nickel carcinogenesis, which acts through gene silencing via DNA methylation and chromatin condensation. This model may also explain our in vitro mutation data in the lacI transgenic cell line, in which nickel subsulfide increased mutation frequency, but in about one-third of the mutants, molecular analysis did not reveal any DNA sequence change in the coding region of the lacI gene despite of the phenotypic loss of its function. [R74] INTC: *The effects of carcinogenic nickel compounds on natural killer cell function were studied in rats. The protective effects of manganese were also investigated. Male WAG-rats were injected intramuscularly with 20 mg metallic nickel powder, 5 mg nickel subsulfide, 20 mg nickel oxide, and 0 or 20 mg mananese with or without rat fibroblast interferon. Rats given nickel subsulfide had a tumor incidence of 2 percent, whereas 46.7 percent of the rats given nickel powder developed tumors. All tumors developed at the injection site. More than 70 percent of the tumor bearing rats died with lung or lymph node metastases within 3 months after the primary tumors were detected. Interferon had little effect on tumor incidence or time to tumor development. Nickel oxide did not induce any tumors. Manganese protected against tumor induction. Only 20 percent of rats given nickel powder plus manganese developed tumors. Rats that developed tumors showed persistent decreases in natural killer cell activity. The lower the natural killer cell activity, the earlier the tumors developed. Manganese almost completely prevented the decrease in PBMC natural killer cell activity when given along with powdered nickel. [R75] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Occurs as the mineral bunsenite. [R8] *THE PRINCIPAL NATURAL FORM OF NICKEL OXIDE OCCURS IN ADMIXTURE WITH NICKEL SULFIDES IN VARYING PROPORTIONS IN WEATHERED ORE. IT IS FORMED BY THE DECOMP OF NICKEL CARBONYL IN DRY AIR. [R76] ARTS: *Nickel oxide has been identified in residual fuel oil and in atmospheric emissions from nickel refineries. [R9] RTEX: *NICKEL POISONING CAN OCCUR INDUSTRIALLY FOLLOWING INHALATION OF ... NICKEL OXIDE DUSTS. [R29, 290] *THE INDUSTRIAL MOND PROCESS WAS DEVELOPED IN WALES FOR PRODUCTION OF PURE NICKEL AND REQUIRED MIXTURE OF NICKEL OXIDE AND CARBON MONOXIDE TO MAKE NICKEL CARBONYL. IT IS THIS PROCESS WHICH HAS BEEN THE GREATEST CAUSE OF INDUSTRIAL ILLNESS ASSOCIATED WITH NICKEL EXPOSURE. [R77] *The National Occupational Hazards Survey estimates that some 1.4 million workers are exposed to nickel in an oxide phase. Such exposures can range up to 1000 ug/cu m. [R9] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers nickel metal and other compounds (as Ni) to be a potential occupational carcinogen. /Nickel metal and other compounds (as Ni)/ [R78, 224] OSHA: *Vacated 1989 OSHA PEL TWA 0.1 mg/cu m is still enforced in some states. /Nickel soluble compounds, as Ni/ [R78, 368] *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1 mg/cu m. /Nickel, metal and insoluble cmpd, as Ni/ [R79] NREC: *NIOSH considers nickel metal and other compounds (as Ni) to be a potential occupational carcinogen. /Nickel metal and other compounds (as Ni)/ [R78, 224] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Nickel metal and other compounds (as Ni)/ [R78, 224] *Recommended Exposure Limit: 10 Hr TWA 0.015 mg/cu m. /Nickel metal and other compounds (as Ni)/ [R78, 224] TLV: *8 hr Time Weighted Avg (TWA) 0.2 mg/cu m, inhalable fraction. A1. A1= Confirmed human carcinogen. /Nickel, insoluble compounds, as Ni/ [R80, 51] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R80, 6] OOPL: *Max allowable concn (MAC) USSR 0.5 mg/cu m /Nickel, nickel oxide and nickel sulfides as dust/ [R81] *Max allowable concn (MAX) USSR 0.005 mg/cu m as Ni /Nickel salts and aerosols/ [R81] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Nickel oxide is included on this list. [R82] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 100 ug/l /Nickel/ [R83] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 150 ug/l /Nickel/ [R83] +(MA) MASSACHUSETTS 100 ug/l /Nickel/ [R83] +(ME) MAINE 150 ug/l /Nickel/ [R83] +(MN) MINNESOTA 100 ug/l /Nickel/ [R83] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Nickel and compounds/ [R84] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NIOSH Method 7300. Determination of Elements by Inductively Coupled Argon Plasma - Atomic Emission Spectroscopy (ICP-AES). [R85] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; Chemical Selection Working Group Profile: Nickel Oxide (1979) SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 788 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: NTP; Chemical Selection Working Group Profile: Nickel Oxide p.1 (1979) R5: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 198 R6: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 760 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 84 (1976) R8: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1117 R9: NTP; Chemical Selection Working Group Profile: Nickel Oxide p.2 (1979) R10: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R11: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-516 R12: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 4-73 R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 79 (1976) R14: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. B-110 R15: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 2161 R16: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.3 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1994 R18: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R19: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 630 R20: Bretherick, L. Handbook of Reactive Chemical Hazards. 3rd ed. Boston, MA: Butterworths, 1985. 1172 R21: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R22: WHO; Environ Health Criteria 108: Nickel p.17-22 (1991) R23: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Nickel refinery dust (NO CAS RN) from the National Library of Medicine's TOXNET System, March 1, 1995 R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V49 410 (1990) R25: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R26: Aitio A; IARC Sci Publ 53: 497-505 (1984) R27: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.425 R28: Waksvik H et al; Carcinogenesis 5 (11): 1525-7 (1984) R29: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. R30: Seiler, H.G., H. Sigel and A. Sigel (eds.). Handbook on the Toxicity of Inorganic Compounds. New York, NY: Marcel Dekker, Inc. 1988. 454 R31: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 352 R32: Chang, L.W. (ed.). Toxicology of Metals. Boca Raton, FL: Lewis Publishers, 1996 789 R33: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2406 R34: WHO; Environ Health Criteria 108: Nickel p.276 (1991) R35: WHO; Environ Health Criteria 108: Nickel p.277 (1991) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 89 (1976) R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 91 (1976) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 98 (1976) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 99 (1976) R40: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 90 (1976) R41: Sunderman FW Jr; IARC Sci Publ 53: 127-42 (1984) R42: Berry JP et al; IARC Sci Publ 53: 153-64 (1984) R43: Hori A et al; Biol Trace Elem Res 7 (4): 223-39 (1985) R44: Longstaff E et al; IARC Sci Publ 53: 235-43 (1984) R45: Sunderman FW et al; Carcinogenesis 5 (11): 1511-7 (1984) R46: Spiegelberg T et al; Ecotoxicol Environ Safety 8 (6): 516-25 (1984) R47: Sunderman FW; IARC Sci Publ 53: 127-42 (1984) R48: Wehner AP et al; IARC Sci Publ 53: 143-51 (1984) R49: Benson JM et al; Inhalation Toxicology Research Institute Annual Report 1985-1986 p. 279-82 (1986) R50: Benson JM et al; J Toxicol Environ Health 19 (1): 105-10 (1986) R51: Benson JM et al; Fundam Appl Toxicol 7 (2): 340-7 (1986) R52: Kodama Y et al; Bio Trace Elem Res 7 (1): 1-9 (1985) R53: Pott F et al; Exp Pathol (JENA) 32 (3): 129-52 (1987) R54: Sunderman FW et al; Carcinogenesis 8 (2): 305-13 (1987) R55: Wehner AP; J Aerosol Science 17 (3): 305-15 (1986) R56: Glaser U et al; Int Congr Ser Excerpta Med 676: 325-8 (1986) R57: Sunderman FW; Sangyo Ika Daegaku Zasshi 9 (Suppl): 84-94 (1987) R58: Hansen K, Stern RM; IARC Sci Publ 53: 193-200 (1984) R59: Toxicology and Carcinogenesis Studies of Nickel Oxide in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 451 (1996) NIH Publication No. 96-3367 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R60: Amer Cyanamid Co; Dermal Contact Sensitization Study of Nickel Sulfate, Nickel Oxide, CT-243-85C and CT-243-85F - Guinea Pig Maximization Test (GPMT); 04/07/86; EPA Document No. FYI-OTS-1086-0516; Fiche No. OTS0000516-0 R61: Amer Cyanamid Co; Morphological Transformation of BALB/3T3 Mouse Embryo Cells in the Absence of Exogenous Metabolic Activation; 00/000/00; EPA Document No. FYI-OTS-1086-0516; Fiche No. OTS0000516-0 R62: Shell Oil Co; Two-Week Repeated Dose Inhalation Study in F344/N Rats with Nickel Oxide (Final Report); 04/01/86; EPA Document No. 88-920002001; Fiche No. OTS0536195 R63: Shell Oil Co; Two-Week Repeated Dose Inhalation Study in B6C3F1 Mice with Nickel Oxide (Final Report); 04/01/86; EPA Document No. 88-920002615; Fiche No. OTS0536515 R64: NIEHS; Draft NTP Technical Reports on the Toxicology and Carcinogenesis of Nickel Oxide, Nickel Subsulfide and Nickel Sulfate Hexahydrate; 12/06/94; EPA Document No. 89-950000154; Fiche No. OTS0556394 R65: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986.,p. V2 467 R66: Tanaka I et al; Biol Trace Elem Res 9 (3): 187-95 (1986) R67: FRIEDRICH AR ET AL; BULL ENVIRON CONTAM TOXICOL 16 (6): 750 (1976) R68: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 100 (1976) R69: WHO; Environ Health Criteria 108: Nickel p.104 (1991) R70: WHO; Environ Health Criteria 108: Nickel p.106 (1991) R71: WHO; Environ Health Criteria 108: Nickel p.133 (1991) R72: Benson JM et al; Inhalation Toxicology 6 (2): 167-83 (1994) R73: Tanaka I et al; Biol Trace Elem Res 8 (3): 203-10 (1985) R74: Mayer C et al; Mutat Res 420 (1-3): 85-98 (1998) R75: Judde JG et al; J Nat Cancer Inst 78 (6): 1185-90 (1987) R76: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 86 (1976) R77: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 151 R78: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R79: 29 CFR 1910.1000 (7/1/99) R80: American Conference of Governmental Industrial Hygienists. Guide to Occupational Exposure Values - 1999. Cincinnati, OH: 1999. R81: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1438 R82: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R83: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R84: 40 CFR 401.15 (7/1/99) R85: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 93 Record 147 of 1119 in HSDB (through 2003/06) AN: 1666 UD: 200304 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-CHLORO-4-NITROBENZENE- SY: *BENZENE,-1-CHLORO-4-NITRO-; *1-CHLOOR-4-NITROBENZEEN- (DUTCH); *1-CHLOR-4-NITROBENZOL- (GERMAN); *P-CHLORONITROBENZENE-; *4-CHLORONITROBENZENE-; *4-CHLORO-1-NITROBENZENE-; *1-CLORO-4-NITROBENZENE- (ITALIAN); *P-NITROCHLOORBENZEEN- (DUTCH); *P-NITROCHLOROBENZENE-; *1-NITRO-4-CHLOROBENZENE-; *4-NITROCHLOROBENZENE-; *4-NITRO-1-CHLOROBENZENE-; *NITROCHLOROBENZENE,-PARA-,-SOLID- (DOT); *P-NITROCHLOROBENZOL- (GERMAN); *P-NITROCLOROBENZENE- (ITALIAN); *P-NITROPHENYL-CHLORIDE-; *PNCB-; *UN-1578- (DOT) RN: 100-00-5 RELT: 2047 [4-CHLOROANILINE] (METABOLITE) MF: *C6-H4-CL-N-O2 SHPN: UN 1578; Nitrochlorobenzene, solid or liquid IMO 6.1; Nitrochlorobenzene, solid or liquid STCC: 49 214 59; Nitrochlorobenzene, para, solid MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *NITRATION OF CHLOROBENZENE AND PURIFICATION BY RECRYSTALLIZATION [R1] *Chloronitrobenzenes are produced by nitration of chlorobenzene. The crude chloronitrobenzene obtained from the nitration process contains about 34% o-chloronitrobenzene, 65% p-chloronitrobenzene, and 1% m-chloronitrobenzene. The isomers are separated by a combination of crystallization and distillation. [R2] FORM: *Product sold is 99% pure. [R3] MFS: *E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Deepwater, NJ 08023 [R4] *Monsanto Co, Hq, 800 N Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Monsanto Chemical Co, Production site: Sauget, IL 62201 [R4] USE: *p-Chloronitrobenzene is used to manufacture p-nitrophenol, p-nitroaniline, p-aminophenol, phenacetin, acetominophen, parathion and other agricultural chemicals, rubber chemicals, antioxidants, oil additives and Dapsone (an antimalarial drug). [R5] *CHEM INT FOR ETHYL AND METHYL PARATHION, ACETAMINOPHEN, TRICLOCARBAN, A BACTERIOSTAT, RUBBER-PROCESSING CHEMICALS, AND OTHER INTS, EG, P-CHLOROANILINE [R1] PRIE: U.S. PRODUCTION: *(1994) < 145 million pounds total produced by both Monsanto Co. and E I du Pont de Nemours and Company. [R4] *(1981) 4.80X10+10 G (ALL ISOMERS-EST) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MONOCLINIC PRISMS [R6]; *YELLOW CRYSTALS [R7]; *Yellow, crystalline solid. [R8] ODOR: *Sweet odor. [R8] BP: *242 DEG C @ 760 MM HG [R9] MP: *82-84 DEG C [R7] MW: *157.56 [R10] CTP: *Critical temperature = 751 deg K; Critical pressure = 398X10+6 Pa. [R11] DEN: *1.520 [R7] HTV: *6.21X10+7 J/Kmol @ 356.65 deg K [R11] OWPC: *Log Kow = 2.39 [R12] SOL: *The water solubility for p-chloronitrobenzene is 1.43X10-3 mol/l(225 mg/l). [R13]; *Water solubility is 2877 uM (453 mg/l) at 20 deg C. [R14]; *SPARINGLY SOL IN COLD ALC AND FREELY IN BOILING ALCOHOL, ETHER, CARBON DISULFIDE. [R7] SPEC: *MAX ABSORPTION (METHANOL): 270.5 NM (LOG E= 4.03); SADTLER REF NUMBER: 4683 (IR, PRISM); 435 (IR, GRATING); INDEX OF REFRACTION: 1.5376 AT 100 DEG C/ALPHA [R6]; *IR: 1409 (Coblentz Society Spectral Collection) [R15]; *UV: 1290 (Sadtler Research Laboratories Spectral Collection) [R15]; *NMR: 122 (Varian Associates NMR Spectra Catalogue) [R15]; *MASS: 114 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R15] SURF: *3.71X10-2 N/m @ 356.65 deg K [R11] VAPD: *5.44 (AIR= 1) [R16] VAP: *0.094 mm Hg at 20 deg C [R17] VISC: *1.07X10-3 Pa-s @ 356.65 deg K [R11] OCPP: *The liquid molar volume is 0.121 cu m/kmol. The IG heat of formation is 3.72X10+7 J/kmol. The heat fusion at the melting point is 1.41X10+7 J/kmol. [R11] *Henry's Law constant = 5.44X10-5 atm cu m/mol [R18] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: *Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] *First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chloronitrobenzenes; Chloronitrobenzenes, solid or liquid/ [R19] FPOT: *FIRE HAZARD SLIGHT WHEN EXPOSED TO HEAT OR FLAME. [R20, 858] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R21, p. 325-74] *Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R21, p. 325-74] *Reactivity: 3. 3= Includes materials that, in themselves, are capable of detonation, explosive decomposition, or explosive reaction, but which require a strong initiating source or heating under confinement. This includes materials that are sensitive to thermal and mechanical shock at elevated temperatures and pressures and materials that react explosively with water. Fires involving these materials should be fought from a protected location. [R21, p. 325-74] FLPT: *261 DEG F (closed cup) [R20, 859] *261 deg F (127 deg C) (closed cup) [R21, p. 325-74] FIRP: *WATER MAY CAUSE FOAMING OR FROTHING. USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. [R21, p. 49-40] *CARBON DIOXIDE, DRY CHEMICAL [R20, 858] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam, dry chemical, or carbon dioxide. /Nitrochlorobenzene, para, solid/ [R22] REAC: *Reacts with alkalies, oxidizing materials. [R21, p. 49-40] *Strong oxidizers, alkalis. [R23, 226] *A steam-heated still used to top the crude material exploded after heating on total reflux for an hour. [R24, 577] *Addition of the chloro compound to a solution of sodium methoxide in methanol caused an unusually exothermic reaction to occur The lid of the 450 l vessel as blown off, and a fire and explosion followed. No cause for the unusual vigor of the reaction was found. [R24, 578] *Mixtures with potassium hydroxide (1:1.5 mol) deflagrate readily at a rate of 1.3 cm/min. [R24, 578] DCMP: *...WHEN HEATED TO DECOMPOSITION IT EMITS VERYY TOXIC FUMES OF /NITROGEN OXIDES AND HYDROGEN CHLORIDE./ [R25] EQUP: *WEAR SPECIAL PROTECTIVE CLOTHING AND POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. [R21, p. 49-40] *PROTECTIVE MEASURES IN ASCENDING ORDER OF EFFECTIVENESS ARE RESPIRATORY PROTECTION, JOB ROTATION, LIMITATION OF EXPOSURE TIME...PROTECTIVE CLOTHING AND WHOLE-BODY PROTECTION. ...USE OF BUTYL RUBBER PROTECTIVE CLOTHING...CAN REDUCE EXPOSURE TO WITHIN TOLERABLE LIMITS. NO OTHER COMMERCIALLY AVAILABLE ELASTOMER APPROACHES BUTYL RUBBER FOR RESISTANCE TO...AROMATIC NITRO COMPD. COMPLETE BODY PROTECTION FOR SEVERE EXPOSURE CONDITIONS CAN BE PROVIDED BY EITHER AN UNVENTILATED CHEM HAZARD SUIT ("ACID SUIT") OR AN AIR-CONDITIONED "CHEM-PROOF AIR SUIT"... /NITRO-COMPD, AROMATIC/ [R26] *Wear appropriate personal protective clothing to prevent skin contact. [R23, 227] *Wear appropriate eye protection to prevent eye contact. [R23, 227] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R23, 227] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R23, 227] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R23, 227] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R23, 227] OPRM: *Contact lenses should not be worn when working with this chemical. [R23, 227] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protectionequipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimizepersonnel exposure to airborne contaminants. *TOTALLY ENCLOSED SYSTEMS ARE PREFERRED. WHERE APPROPRIATE, AIR ANALYSIS CAN BE HELPFUL... A HIGH STD OF PERSONAL HYGIENE.../SUCH AS/ WARM SHOWER WITH PLENTY OF SOAP AND WATER VIGOROUSLY APPLIED AT END OF SHIFT, WILL MINIMIZE CHRONIC EXPOSURE... /NITRO-CMPD, AROMATIC/ [R26] *The worker should immediately wash the skin when it becomes contaminated. [R23, 227] *The worker should wash daily at the end of each work shift. [R23, 227] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R23, 227] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R23, 227] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. /Nitrochlorobenzene, para, solid/ [R22] *Personnel protection: Avoid breathing dusts, and fumes from burning material. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. ... /Nitrochlorobenzene, para, solid/ [R22] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] STRG: *STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM ALKALIES AND OXIDIZING MATERIALS. [R21, p. 49-40] *...MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS...SHOULD BE STORED IN COOL, WELL-VENTILATED PLACE, OUT OF...DIRECT RAYS OF...SUN, AWAY FROM...HIGH FIRE HAZARD...SHOULD BE PERIODICALLY INSPECTED... INCOMPATIBLE MATERIALS SHOULD BE ISOLATED. [R30] CLUP: *1. VENTILATE AREA OF SPILL. 2. FOR SMALL QUANTITIES, SWEEP ONTO PAPER OR OTHER SUITABLE MATERIAL, PLACE IN AN APPROPRIATE CONTAINER AND BURN IN A SAFE PLACE (SUCH AS A FUME HOOD). LARGE QUANTITIES MAY BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN A FLAMMABLE SOLVENT (SUCH AS ALC) AND ATOMIZE IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATED EFFLUENT GAS CLEANING DEVICE. [R31] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *1. BY MAKING PACKAGES OF P-NITROCHLOROBENZENE IN PAPER OR OTHER FLAMMABLE MATERIAL AND BURNING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. 2. BY DISSOLVING P-NITROCHLOROBENZENE IN A FLAMMABLE SOLVENT AND ATOMIZING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. [R31] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of chloronitrobenzenes. There is inadequate evidence in experimental animals for the carcinogenicity of chloronitrobenzenes. Overall evaluation: Chloronitrobenzenes are not classifiable as to their carcinogenicity to humans (Group 3). /Chloronitrobenzenes/ [R32] *A3; Confirmed animal carcinogen with unknown relevance to humans. [R33, 2002.44] MEDS: *PERIODICAL EXAM SHOULD INCLUDED HISTORY, MEDICAL OBSERVATION, BLOOD PRESSURE, PULSE, WT, AND BLOOD AND URINE ANAL. .../RESULTS/ REPORTED TO SUPERVISION RESPONSIBLE FOR CORRECTIVE EXPOSURE-CONTROL ACTION. /NITRO-CMPD, AROMATIC/ [R26] HTOX: *Corrosive. Causes severe eye and skin burns. Irritating to skin, eyes, and respiratory system. May cause cyanosis and pulmonary edema. [R21, p. 49-40] *NITROCHLOROBENZENE...HAS BEEN OBSERVED TO CAUSE METHEMOGLOBINEMIA, WITH DISCOLORATION OF CONJUNCTIVA REFLECTING CHANGE IN COLOR OF BLOOD. /NITROCHLOROBENZENE/ [R34] *...THE EFFECTS ON WORKMEN EXPOSED AT AVERAGE CONCN OF P-NCB OF 8.8, 19.6 AND 22.3 MG/CU M @ A MIXED EXPOSURE OF 3.6 MG/CU M P-NCB AND NITROPHENETOLE /WERE/...STUDIED OVER PERIOD OF TIME. ...NO CHRONIC INTOXICATION OCCURRED WITH THE 3.6 MG/CU M EXPOSURE, ALTHOUGH CHANGES SUCH AS INCR METHEMOGLOBIN, APPEARANCE OF HEINZ BODIES, HEADACHE, VERTIGO AND FEW CASES OF ECZEMA OCCURRED. [R35] *SEVERE ALLERGIC DERMATITIS FREQUENT AFTER SKIN CONTACT. LESS TOXIC THAN DINITROCHLOROBENZENE. SYSTEMIC EFFECTS ARE LIKE ANILINE (METHEMOGLOBINEMIA) BUT PERHAPS CARDIAC DISORDERS ARE MORE SEVERE. /NITROCHLOROBENZENE/ [R36] *In humans, PNCB may be absorbed through the lungs and skin giving rise to methemoglobinemia. ... A workman who cleaned a spill of approximately 50 kg ... was cyanotic and complained of a headache /the /next morning/. ... Four workmen were hospitalized as the result of exposure to PNCB while nitrating chlorobenzene. These cases resulted from 2 to 4 days exposure and all were cyanotic; headache and weakness accompanied the cyanoses. [R37, 1991.1101] *The effects on workmen exposed at average concentrations of 55, 125, and 143 ppm PCNB and at a mixed exposure of 23 ppm PNCB and nitrophenol /were investigated/. These exposure data were compared with physiologic effects studied over a period of time. They found that no chronic intoxication occurred with the 23 ppm exposure, although such changes as increased methemoglobin, the appearance of Heinz bodies, headache, vertigo, and a few cases of eczema were identified. Because skin absorption could not be determined with any degree of precision /in was concluded/ ... that it was impossible to determine precisely whether an air concentration of 23 ppm of PNCB or skin absorption caused the symptoms. The exposures at higher concentrations were apparently intermittent. [R37, 1991.1101] *Eight longshoremen at Osaka South Port were poisoned with p-chloronitrobenzene in July 1994, and all were admitted to a hospital for 5 to 31 days. Headache, faintness and anemia due to methemoglobinemia were observed as characteristic of p-chloronitrobenzene /intoxication/. During hospitalization, daily urinary excretion of diazo positive substances were measured for all patients. Urinary metabolites exponentially decreased with time, fitting a model of two compartment pharmacodynamics. Half-lives of the fast and slow phases were 2.7 +/-0.4 and 14.7+/8.2 days, respectively. estimated total metabolites excreted in urine ranged from 0.17 to 1.0 g. Estimated total absorbed p-chloronitrobenzene of each patient, based on an excretion rate of 26.8% obtained in rats, was 11.9-75.9 mg/kg. These figures correlated well with methemoglobin levels in the blood one day after the accident, the severity of symptoms and the duration of hospitalization. [R38] NTOX: *...THE EFFECTS OF P-NCB BY SC INJECTION OF 1.5 G SUSPENSION IN OLIVE OIL AND BY APPLICATION ON THE SKIN OF RABBITS /SHOWED/...METHEMOGLOBIN INCR IN SEVERAL HR, DECR AFTER ABOUT 12 HR, THEN INCR AGAIN 18-24 HR FOLLOWING EXPOSURE. HEINZ BODIES...FORMED DURING 2ND PERIOD OF INCR METHEMOGLOBIN. CLINICAL SYMPTOMS, SUCH AS ANEMIA, HEMATURIA AND HEMOGLOBINURIA WERE NOTED. [R35] *...SUBCUTANEOUS INJECTION OF 500 TO 600 MG/KG OF P-NCB IN WHITE MALE AND FEMALE RATS PRODUCED A DECREASE IN /EPINEPHRINE/. [R35] *PRODUCED SENSITIZATION IN RATS AND GUINEA PIGS WHEN ADMIN TOPICALLY OR BY PROLONGED INHALATION (0.008 MG/CU M). ALLERGY WAS PASSIVELY TRANSFERRED FROM RATS SENSITIZED TO INTACT GUINEA PIGS BY MEANS OF LEUKOCYTIC MASS OR (LESS EFFECTIVELY) BY SERUM. [R39] *P-CHLORONITROBENZENE REDUCED BLOOD PRESSURE AND MYOCARDIAL GLYCOGEN LEVEL WHEN ADMIN IP TO RABBITS ONCE AT 0.5 G/KG. [R40] *DNA DAMAGE WAS RECOGNIZABLE 4 HR AFTER 1-CHLORO-4-NITROBENZENE WAS INJECTED IP INTO MICE. THE EFFECTS WERE EVALUATED IN BRAIN, LIVER AND KIDNEY AS SINGLE-STRAND DNA BREAKS. [R41] *THE MUTAGENICITY OF 21 CHLORO- OR FLUORONITROBENZENE COMPOUNDS AND 9 CHLORO- OR FLUOROBENZENE COMPOUNDS IN SALMONELLA TYPHIMURIUM WAS EXAMINED. CHLORONITROBENZENE COMPOUNDS, INCLUDING 1-CHLORO-4-NITROBENZENE, WERE MUTAGENIC FOR BASE-PAIR SUBSTITUTION STRAINS ONLY. MUTAGENIC ACTIVITY WAS EXHIBITED BY ALL COMPOUNDS HAVING A CHLORO OR FLUORO SUBSTITUENT AT THE PARA AND ORTHO POSITION IN THE NITROBENZENE NUCLEUS. [R42] *NONE OF THE 22 NITROBENZENE DERIVATIVES, INCLUDING 1-CHLORO-4-NITROBENZENE, WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM IN THE ABSENCE OF NORHARMAN. HOWEVER, IN THE PRESENCE OF NORHARMAN, NITROBENZENE, NITROTOLUENE, NITROANISOLE, NITROCHLOROBENZENE, AND NITROBENZALDEHYDE WERE MUTAGENIC TO SALMONELLA TYPHIMURIUM WITH S9 MIX. THE MUTAGENESIS INDUCTION BY NORHARMAN WAS STRONG WITH ORTHO ISOMERS, WEAK WITH PARA ISOMERS, AND NOT OBSERVED WITH META ISOMERS. [R43] *USING THE COIL PLANET CENTRIFUGE SYSTEM, THE EFFECTS OF SINGLE AND REPEATED SC INJECTIONS OF 1-CHLORO-4-NITROBENZENE ON THE OSMOTIC FRAGILITY OF RBC MEMBRANES IN RABBITS WAS DETERMINED. OSMOTIC FRAGILITY INCREASED IMMEDIATELY AFTER SC INJECTION OF 50, 100, and 200 MG/KG. AN INCREASED METHEMOGLOBIN LEVEL WAS OBSERVED FIRST, AND SECONDLY THE MAX CHANGES IN OSMOTIC FRAGILITY AND APPEARANCE OF HEINZ BODIES WERE OBSERVED NEARLY SIMULTANEOUSLY AFTER INJECTION. IN THE REPEATED INJECTION EXPERIMENT, THE HEMOLYSIS STARTING POINT WAS SHIFTED TOWARD HIGHER OSMOTIC PRESSURE IMMEDIATELY AFTER INJECTIONS OF 5 and 10 MG/KG/DAY, WHILE IT SHIFTED TOWARD LOWER OSMOTIC PRESSURE AFTER THE LAST DOSES ADMIN. THE HEMOLYSIS ENDING POINT WAS SHIFTED TOWARD HIGHER OSMOTIC PRESSURE AFTER INJECTIONS OF 10 MG/KG/DAY, WHILE IT WAS SHIFTED TOWARD LOWER OSMOTIC PRESSURE AFTER INJECTIONS OF 5 MG/KG/DAY. THE INJECTION OF 1-CHLORO-4-NITROBENZENE INDUCED CONTINUOUSLY INCREASED METHEMOGLOBIN LEVELS AND APPEARANCE OF HEINZ BODIES. [R44] *Twenty-one-day Daphnia reproduction tests were conducted in line with the provisional procedure proposed by the Federal Environmental Agency (Umweltbundesamt, FRG), as of Jan 1, 1984. Groups of 20, 24-hr old Daphnia magna Straus were exposed to 0.08 to 20 mg/l 1-chloro-4-nitrobenzene in semi-static test vessels. Parent animals in the test and control vessels had to be pipetted 3 times/wk in freshly prepared test and control media at the corresponding concn level. The no observed effect concn (NOEC) was determined from the parameters of mortality of the parent animals, reproduction rate and appearance of the first offspring during the test period. In preliminary acute Daphnia tests, the 24 hr EC50 was 15 mg/l for 1-chloro-4-nitrobenzene, the EC0 was 3.3 mg/l. The nominal 21 day no observed effect concn was 0.32 mg/l, with the most sensitive parameter being the reproductive rate. [R45] *In a 2-week subchronic inhalation study, groups of 16 rats were exposed head-only for 6 hours/day, 5 days/week at 0.05, 0.29, or 0.64 mg/l (8.2, 45, or 99 ppm) of PNCB. Methemoglobinemia and increased spleen weight were observed at all exposure levels. Decreased testes weight was seen in the 0.29 and 0.64 mg/l groups, and a slight increase in relative liver weight was seen in the 0.64 mg/l group. Pathological examination revealed seminiferous tubule degeneration and abnormal spermatic contents of epididymides and microscopic changes in the spleen, bone marrow, and kidneys in the 0.29 and 0.64 mg/l groups. [R37, 1991.1100] *In a 4 week inhalation study, rats were exposed (whole body) to PNCB at atmospheric concentrations of 0, 0.005, 0.015, or 0.45 mg/l (approximately 0, 0.82, 2.5, or 7.5 ppm) for 6 hours/day, 5 days/week. Increases in blood methemoglobin levels and decreases in hemoglobin, hematocrit, and red blood cell count values were observed in a dose related fashion. The changes were statistically significant in the mid- and high-exposure groups after 2 and 4 weeks. In the low concentration group, only a slight but statistically significant increase in methemoglobin levels was observed at the 4 week interval. Spleen and liver weights were elevated in the 0.045 mg/l group. Microscopic changes in the spleen, including congestion, increased extramedullary hematopoiesis, and hemosiderosis, were noted at all dosage levels, the severity being dose related. [R37, 1991.1100] *Male and female rats were given PNCB by gavage at daily dosages of O, 3, 10, or 30 mg/kg/day for 90 days. Increased methemoglobin levels and decreased hemoglobin, hematocrit, red blood cell count, and urinary urobilinogen values were observed at all dosage levels. Absolute spleen weights were elevated in the mid- and high-dosage groups, while relative spleen weights were elevated in all treated groups. Gross and microscopic changes were observed in the spleen at all treatment levels. Microscopic changes observed in the kidneys and liver of mid- and high-dosage level rats included hemosiderosis and occasional extramedullary hematopoiesis in the liver. Hyperplasia of bone marrow and testicular atrophy were evident at the highest dose. [R37, 1991.1100] *PNCB was administered to groups of 60 male and 60 female rats by stomach tube at daily dosages of 0, 0.1, 0.7, or 5 mg/kg/day for 2 years. Blood methemoglobin levels were elevated at the 0.7 and 5.0 mg/kg/day dosage levels. Slight anemia was observed in the high dose group, and some marginal indications of anemia were apparent in the mid-dose group. The only treatment related microscopic change was accumulation of brown pigment (possibly hemosiderin) in the reticuloendothelial cells of the spleen in high dose group rats. No treatment related increase in tumors was observed. [R37, 1991.1100] *... Groups of rats and mice /were fed/ PNCB for up to 2 years; the oncogenic results were equivocal. No tumors were seen in male rats. However, male and female mice showed an increase in vascular tumors at the highest feeding level, and male mice showed an increase in liver tumors at the lowest feeding level tested. [R37, 1991.1101] *PNCB was administered to pregnant rats by gavage at dosages of 0, 5, 15, and 45 mg/kg/day on days 6 through 19 of gestation. Maternal toxicity, as indicated by decreased body weights and increased spleen weights, embryotoxicity, and fetal skeletal malformations were observed at the 45 mg/kg level. At 15 mg/kg, similar maternal toxicity was recorded, but no fetotoxic or teratogenic responses were observed. At 5 mg/kg, only a slight increase in spleen weight was observed in maternal animals. ... PNCB produced teratogenic effects only at dosages that produced significant maternal toxicity. [R37, 1991.1101] *No teratogenic or fetotoxic effects were observed in the offspring of rabbits administered PNCB by gavage at dosage levels of 0, 5, or 15 mg/kg/day on days 7 through 19 of gestation. High maternal mortality prevented evaluation of fetuses in the group dosed at 40 mg/kg/day. No maternally toxic effects were observed at or below 15 mg/kg/day. [R37, 1991.1101] *In a reproduction study, male and female rats were given PNCB by gavage at dosages of 0, 0.1,0.7, or 5 mg/kg/day throughout premating, mating, gestation, and lactation periods for two generations. The mating index was slightly reduced at the mid- and high-dosage levels. [R37, 1991.1101] *... PNCB caused DNA damage in liver, kidney, and brain cells of rats after a single intraperitoneal dosage of 30 to 1000 mg/kg. [R37, 1991.1101] *PNCB was evaluated for mutagenic or genotoxic potential in the following systems: microbial assays with four Salmonella strains; in vitro L5178y TK mouse lymphoma cell/point mutation assay; in vitro Chinese hamster ovary (CHO) cell/point mutation assay; in vitro rat hepatocyte primary culture/DNA repair assay; and in vivo rat bone marrow cell clastogenesis assay. A positive response was observed in the mouse lymphoma cells both in the presence and absence of metabolic activation and in Salmonella strain TA1535 in the absence of metabolic activation. No evidence of mutagenicity was observed in any of the other assays. [R37, 1991.1101] *4-Chloronitrobenzene ... was tested for its effects on fertility and reproduction in Swiss CD-1 mice. ... It was admin via gavage. ... All animals in the 640 mg/kg dose group died and animals in the 320 mg/kg group became cyanotic. ... Levels for task 2 were 62.5, 125 and 250 mg/kg bw/day. Male and female mice were continuously exposed for 7 day precohabitation and a 98 day cohabitation period (task 2). At terminal sacrifice, liver weight, and liver to body weight ratios were both incr in both F1 sexes, and spleens were enlarged while body weights were unchanged. ... Presence of cyanosis and incr liver weights, 4-chloronitrobenzene decr pup birth weights as well as postnatal survival and weight gain. [R46] *Nephrotoxicity of some aromatic nitro-amino compounds were evaluated by urinary enzymes activities and renal histopathological changes. Male Fischer 344 rats were intraperitoneally Injected with aniline p-aminophenol acetyl-p-aminophenol p-chloroaniline p-chloronitrobenzene p-anisidine or p-nitroaniline at 1.0 uM/kg. In the rats injected with p-aminophenol necrosis of renal tubular epithelial cells and remarkable elevation of urinary N-acetyl-beta-D-glucosaminidase (NAG) and gamma-glutamyltranspeptidase (gamma-GTP) activities were observed. Injection with p-chloroaniline caused significant elevation of the urinary NAG and gama-GTP activities. p-Anisidine and p-niroaniline induced swelling of the tubular epithel?al cells and a significant elevation in urinary NAG activities In rats which was also caused by p-chloronitrobenzene. However administration of aniline or acetyl-p-aminophenol did not change either the urinary enzymes or renal histopathology. These result indicate that p-aminophenol is a highly nephrotoxic substance and that nephrotoxicity of p-chloroaniline, p-chloronitrobenzene, p-anisidine and p-nitroaniline exceed that of acetyl-p-aminophenol which has been known to casue a renal damage. [R47] *Mono-, di- and trinitrochlorobenzenes (1-chloro-4-nitrobenzene, 1-chloro-2,4-dinitrobenzene, 1-chloro-2,4,6-trinitrochlorobenzene) were injected ip into albino Swiss CD1 mice. Their effects were evaluated, in brain, liver and kidney, as single-strand DNA breaks. DNA damage was recognizable 4 hr after admin in vivo, and its increment seemed to be related to the number of nitro groups contained ln the chlorobenzene molecule. ... [R48] *The induction of DNA damage on 1.5 and 24 hr cultured hepatocytes was tested after a 3 hr exposure to 5 and 50 uM mono-, di-, and trinitrochlorobenzene. DNA repair synthesis, elicited by nitrobenzene treatment, was also estimated at 24 and 48 hr after the withdrawal of the nitro-aryl halides. DNA damage was obtained by exposure of 1.5 hr cultured hepatocytes to 5 and 50 uM nitrochlorobenzenes. DNA of 24 hr cultured cells was not affected by nitrochlorobenzene treatment. [R49] *Pregnant Sprague-Dawley rats were admin 25 to 250 mg/kg/day para-nitroaniline or 5 to 45 mg/kg/day para-nitrochlorobenzene on days 6 through 19 of gestation. All animals were observed for clinical signs of toxicity. Surviving rats /were sacrificed/ on days 20 or 30, respectively. Maternal spleen weights were recorded. The uterine horns were examined for the number and location of viable and non viable fetuses and resorptions. Fetuses were removed and examined for abnormalities. Rats given 250 mg/kg/day para-nitroaniline showed decr body weight gain, urogenital staining, and incr spleen weights. An incr number of resorptions and decreased fetal body weights were observed. Fetal skeletal and soft tissue abnormalities were seen. The lower dose caused no teratogenic effects but caused signs of maternal toxicity. In rabbits, the 125 mg/kg/day dose of para-nitroaniline caused a high degree of maternal mortality. No fetotoxic or teratogenic effects were observed. para-Nitrochlorobenzene produced in pregnant rats changes that were similar to para-nitroaniline. The 45 mg/kg/day dose caused maternal toxicity (decr body wt and incr spleen wt), an incr number of resorptions, decr fetal body wt, and an incr in skeletal malformations. The lower doses caused some signs of maternal toxicity, but no adverse effects on fetal development. In rabbits, 45 mg/kg/day para-nitrochlorobenzene caused considerable mortality. No mortality occurred at lower doses. para-Nitrochlorobenzene caused no fetotoxicity or teratogenic effects. ... Fetal effects were observed with para-nitroaniline and para-nitrochlorobenzene only at doses that caused severe maternal toxicity. [R50] *The subchronic inhalation toxicity of p-nitroaniline and p-nitrochlorobenzene was studied in rats. Sprague-Dawley rats were exposed to 0, 10, 30, or 90 mg/cu m p-nitroaniline or 0, 5, 15 or 45 mg/cu m for 6 hr/day, 5 days/wk for 4 wk. The animals were observed for clinical signs of toxicity. Ophthalmoscopic examinations were performed. Hematologic and clinical chemistry parameters were determined. The animals were /sacrificed/ at the end of the study and necropsied. Neither p-nitroaniline or p-nitrochlorobenzene caused any mortality. p-Nitrochlorbenzene caused apparent cyanosis, the degree of which concn dependent. No ocular abnormalities were caused by either cmpd. Mean weekly body weights of all treated animals were comparable to those of controls. p-Nitroaniline and p-nitrochlorobenzene caused dose related incr in methemoglobin concn. p-Nitrochlorobenzene at 15 and 45 mg/cu m significantly decr mean red cell counts, hematocrit, and hemoglobin. The highest doses of p-nitrochlorobenzene and p-nitroaniline reduced absolute and relative spleen weights. p-Nitroaniline at 10 mg/cu m slightly incr absolute and relative liver weights. Extramedullary hematopoiesis and hemosiderosis were the major histologic changes observed in the spleens of p-nitrochlorobenzene or p-nitroaniline treated rats. Spleens of p-nitrochlorobenzene treated animals were also congested. Livers of females exposed to 90 mg/cu m p-nitroaniline also had a higher degree of extramedullary hematopoiesis, compared to controls. No other gross or histopathological effects were noted. ... The 5 mg/cu m p-nitrochlorobenzene caused a slight incr in methemoglobin concn. ... [R51] NTXV: *LD50 Rat oral 530 mg/kg; [R37, 1991.1100] *LD50 Rabbit dermal > 3040 mg/kg; [R37, 1991.1100] NTP: *4-Chloronitrobenzene (4CNB) ... was tested for its effects on fertility and reproduction in Swiss CD-l mice according to the Continuous Breeding protocol. It was administered via gavage. In the dose-range-finding study, all animals in the 640 mg/kg dose group died and animals in the 320 mg/kg group became cyanotic. Dose levels for Task 2 were set at 62.5, 125 and 250 mg/kg bw/day. Male and female mice were continuously exposed for a 7-day pre cohabitation and a 98-day cohabitation period (Task 2). Weights of pups delivered during the 98-day continuous breeding phase to dams in the 125 and 250 mg/kg groups were lower than controls. In the final litter of the continuous breeding phase, the proportion of pups born alive and the pup survival and weight gain during lactation were adversely affected at 250 mg/kg. Most of the 250 mg/kg bw group animals were cyanotic at the time of F1 mating. In the F1 mating, the proportion of F2 pups born alive and live F2 pup weights were significantly reduced in the 250 mg/kg 4CNB group. The average estrous cycle length in the F1 females was significantly increased. At terminal sacrifice, liver weight, and liver-to-body weight ratios were increased in both F1 sexes, and spleens were enlarged while body weights were unchanged. Thus, in the presence of cyanosis and increased liver weights, 4CNB decreased pup birth weights as well as postnatal survival and weight gain. [R52] ADE: *Elimination of PNCB or its metabolites was essentially complete (95.5%) within 72 hours after a single oral dose of approximately 200 mg/kg to male rats. [R37, 1991.1101] *In humans, PNCB may be absorbed through the lungs and skin ... . [R37, 1991.1101] *The effect of dose on the dermal absorption of 2-chloronitrobenzene and 4-chloronitrobenzene was studied in rats. (14)C labeled 2-chloronitrobenzene or 4-chloronitrobenzene was applied to the shaved backs of male Fischer 344 rats at an application rates equivalent to doses of 0, 0.65, 6.5 or 65 mg/kg. Urine and feces samples were collected for 24, 48 or 72 hr and assayed for (14)C activity. Exhaled volatiles were collected in ethanol traps and analyzed. After 72 hr, the rats were /sacrificed/ and their skin removed and analyzed for (14)C activity. Approx 21-27% and 43 to 45% of the 2-chloronitrobenzene and 4-chloronitrobenzene doses, respectively, were eliminated in the urine over 72 hr. Approx 11 to 15% of the 2-chloronitrobenzene dose and 5 to 12% of the 4-chloronitrobenzene dose were excreted over 72 hr. Fecal excretion of 4-chloronitrobenzene showed a dose related incr which was statistically significant only when comparing the 65 mg/kg dose with the 0.65 mg/kg dose. Approx 27 to 32% of 2-chloronitrobenzene derived radioactivity and 13 to 15% of the 4-chloronitrobenzene derived (14)C activity were recovered in the ethanol traps. The amt of collected radioactivity did not depend on dose and consisted of unchanged 2-chloronitrobenzene or 4-chloronitrobenzene. ... An analysis of all (14)C data indicated that the dermal absorption of 2-chloronitrobenzene ... was linear over the entire dose range. Dermal absorption of 4-chloronitrobenzene was linear only after application of 0.65 and 6.5 mg/kg. /Results indicate/ that under the experimental conditions used at least 33 to 40% and 51 to 62% of the applied 2-chloronitrobenzene and 4-chloronitrobenzene doses, respectively, are absorbed from the skin of rats. ... Dermal absorption of 2-chloronitrobenzene is linear over the dose range 0.65 mg/kg to 65 mg/kg. Dermal absorption of 4-chloronitrobenzene is essentially unaffected by dose. [R53] *p-chloronitrobenzene was studied in male Sprague-Dawley rats injected ip with 0, 30, 100, or 333 mg/kg p-nitrochlorobenzene. Blood and urine samples were collected periodically from 1 to 169 hr after dosing. Plasma p-nitrochlorobenzene concn were determined at these times. The urine samples were analyzed for p-nitrochlorobenzene metabolites. The plasma concentrations of p-chloronitrobenzene following injection with the 30 and lOO mg/kg doses decreased linearly with time. The decrease following 333 mg/kg p-chloronitrobenzene was nonlinear. The mean residence time of p-chloronitrobenzene, determined from the first normal moment, increased with increasing dose. Systemic p-chloronitrobenzene clearance, defined as the ratio of the dose to the area under the plasma concn time curve, decreased with increasing p-chlorobenzene dose. The observations indicated that clearance of p-chloronitrobenzene from the plasma was nonlinear. N-acetyl-5-(4-nitrophenyl)-L-cysteine was the major urinary metabolite accounting for approx 30% of each administered p-chloronitrobenzene dose and 50% of the total metabolite concn. The rate constants for estimation of each p-chloronitrobenzene metabolite decr with increasing dose and were larger than those for production of the metabolites. The elimination rate of N-acetyl-S-(4-nitrophenyl)-L-cysteine, however, was proportional to p-chloronitrobenzene. ... [R54] METB: *The major urinary metabolites were conjugated (glucuronide or sulfate) forms of nitrochlorophenol and N-acetylcysteine conjugate of nitrobenzene. Minor metabolites included aminochlorophenol and n-acetylated aminochlorophenol. Para-chloroaniline has also been identified as a metabolite in the urine of rabbits following oral administration of PNCB. [R37, 1991.1101] *P-NITROCHLOROBENZENE YIELDS N-ACETYL-S-(P-NITROPHENYL)-L-CYSTEINE, P-CHLOROANILINE AND 2-CHLORO-5-NITROPHENOL IN RABBITS [R55] *Urinary metabolites from human subjects acutely poisoned with p-chloro-nitrobenzene were identified with glc-mass spectrometry. Eight substances /were identified/, namely, a very large amount of N-acetyl-S-(4-nitrophenyl)-cysteine, relatively large quantities of p-chloroaniline, 2-chloro-5-nitrophenol and p-chloroformanilide produced by pyrolysis of a substance originating from p-chloro-nitrobenzene, small amounts of 2-amino-5-chlorophenol and 2,4-dichloroaniline, and traces of p-chloroacetanilide and 4-chloro-2-hydroxyacetanilide, were detected in urine samples. All of the absorbed p-chloro-nitrobenzene was metabolized prior to excretion, as the parent cmpd was not found in the urine. ... [R56] *Urinary metabolites in rats treated with p-chloronitrobenzene were identified by GC-MS. A single dose of 100 mg/kg bw was admin ip to male Sprague-Dawley rats and urine samples were collected from the 8 to 24 hr after the admin. ... Nine substances were identified: p-chloroaniline, 2,4-dichloroaniline, p-nitrophenol, 2-chloro-5-nitrophenol, 2-amino-5-chlorophenol, p-chloroformanilide, 4-chloro-2-hydroxyacetanilide, a small amt of p-chloroacetanilide and traces of unchanged p-chloronitrobenzene. [R57] INTC: *... INGESTION OF ETHYL ALCOHOL ... AGGRAVATES THE INTOXICATION. /NITROCHLOROBENZENE/ [R36] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *The major source of environmental release of nitroaromatic compounds, such as p-chloronitrobenzene, appears to be from production and use plants and by-product manufacturing plants. Minor sources of release to the environment may occur during transport or storage. If released to soil, p-chloronitrobenzene should be resistant to hydrolysis, oxidation and biodegradation. Biological reduction of p-chloronitrobenzene under aerobic conditions may result in p-chloroaniline, 4-chloroacetaniline and 4-chloro-2-hydroxyaniline as well as other metabolites. Leaching may be significant as moderate mobility in soil is predicted. Volatilization from wet soil surfaces may be significant, but should be considerably slower from dry soil surfaces. If released to water, p-chloronitrobenzene should be resistant to hydrolysis, oxidation and biodegradation. Potential biodegradation products in water are the same as for soil. p-Nitrochlorobenzene could potentially photolyze, although in air-saturated water this compound has been shown to be fairly stable to photolysis (5% degradation in 84 hours). Bioconcentration in aquatic organisms and adsorption to suspended solids and sediments should not be significant. The volatilization half-life from 1 m deep in surface water with a wind speed of 3 m/sec has been estimated to be 33.5 hours. Volatilization from surface waters with slower current speeds is expected to be less rapid. Based on monitoring data, p-chloronitrobenzene has an estimated half-life of 0.3-3 days in rivers and 3-30 days in ground water. If released to the atmosphere, p-chloronitrobenzene vapor is predicted to react with photochemically generated hydroxyl radicals (half-life = 1.97 days). Reaction with ozone is not significant. p-Chloronitrobenzene has the potential to directly photolyze in the atmosphere and 4-chloro-2-nitrophenol may be produced although no experimental evidence is available. Exposure to p-chloronitrobenzene is probably due mainly to occupational exposure during production or use as an intermediate. A small segment of the general population may be exposed through ingestion of contaminated drinking water or fish. (SRC) ARTS: *The major source of environmental release of nitroaromatic compounds, such as p-chloronitrobenzene, appears to be from production and use plants and from by-product manufacturing plants (1,SRC). [R58] FATE: *TERRESTRIAL FATE: If released to soil, p-chloronitrobenzene should be resistant to oxidation, hydrolysis and biodegradation. Reduction of p-chloronitrobenzene by microorganisms under aerobic conditions may result in p-chloroaniline, 4-chloroacetanilide and 4-chloro-2-hydroxyacetanilde as well as other metabolites. Leaching may be significant since p-chloronitrobenzene is predicted to be moderately mobile in soil. Volatilization from wet soil surfaces may be significant, and should be considerably slower from dry soil surfaces. p-Chloronitrobenzene at 0.3 ug/L was detected in Rhine River water before infiltration and less than 0.01 ug/L was detected after bank infiltration (infiltration time = 1-12 months) and after dune infiltration (infiltration time = 2-3 months)(1). [R59] *AQUATIC FATE: If released to water, p-chloronitrobenzene should be resistant to oxidation, hydrolysis and biodegradation . Reduction of p-chloronitrobenzene by microorganisms under aerobic conditions may result in p-chloroaniline, 4-chloroacetanilide and 4-chloro-2-hydroxyacetanilide as well as other metabolites. p-Chloronitrobenzene could potentially photolyze; although, in air-saturated waters this compound may be stable to photolysis. Bioconcentration in aquatic organisms and absorption to suspended solids and sediments should not be significant. The volatilization half-life from 1m deep in surface water with a current velocity of 1m/sec and a wind speed of 3m/sec has been estimated to be 33.5 hours. Volatilization from surface waters with slower current speeds should be less rapid(SRC). Based on monitoring data, p-nitrochlorobenzene has an estimated half-life of 0.3 - 3 days in rivers and 3 - 30 days in groundwater(1). [R59] *ATMOSPHERIC FATE: If released to the atmosphere, p-chloronitrobenzene in the vapor phase is predicted to react with photochemically generated hydroxyl radicals with an estimated half-life of 1.97 days at 25 deg C. Reaction with ozone is not likely. p-Chloronitrobenzene has the potential to photolyze in the atmosphere. 4-Chloro-2-nitrophenol may be produced by the photochemical reaction of p-chloronitrobenzene in air. (SRC) BIOD: *100 ppm p-chloronitrobenzene inoculated with 30 ppm activated sludge at 25 degC was less than 30% degraded after 2 weeks(1,2). 10 ug/ml p-chloronitrobenzene inoculated with a mixed culture of microorganisms in soil was observed to be resistant to biodegradation (significant ring cleavage, as measured by UV absorbance, was not detected after 64 days)(3). 61-70% reduction of p-chloronitrobenzene after 8 - 13 days was observed when a mixture of p-chloronitrobenzene and 2,4-dinitrochlorobenzene under continuous flow conditions involving feeding, aeration, settling and reflux was inoculated with a species of Arthrobacter simplex isolated from industrial waste. When two aeration columns were used, one with A. simplex and the other with A. simplex, Streptomyces coelicolor, Fusarium sp. and Trichoderma Viridis isolated from soil, a 90% reduction of the nitro compounds was observed after 10 days. The reduction of p-chloronitrobenzene produced p-chloroaniline and some undefined products(4). The yeast Rhodosporidiam sp. reduced p-chloronitrobenzene under aerobic conditions to give 4-chloroacetanilide and 4-chloro-2-hydroxyacetanilide as final major metabolites(5). Whether these reductions in pure culture would occur in waste water treatment plants is unknown(SRC). [R60] ABIO: *Based on the molecular structure of p-chloronitrobenzene, this compound should be resistant to oxidation and hydrolysis(1,SRC). When an aqueous solution of p-chloronitrobenzene (1.45X10-6 M) was irradiated with light wave lengths greater than 290nm for 84 hours, less than 5% of the starting material was degraded. The stability of p-chloronitrobenzene under the oxygenated conditions of this experiment was probably due to the lack of available hydrogen atoms for reduction(2). However, p-chloronitrobenzene does absorb uv light in the environmentally significant range, (greater than 290nm)(3), which indicates that potential exists for photolysis in water and air. In air, vapor phase p-chloronitrobenzene is predicted to react with a hydroxyl radical with an estimated rate constant of 5.0X10-12 cu m/molecule-sec at 25 deg C(4). Assuming an ambient hydroxyl radical concentration of 8.0X10+5 molecules/cu m, the reaction half-life has been calculated to be 1.97 days. 4-Chloro-2-nitrophenol may be produced by the photochemical reaction of p-chloronitrobenzene in air(5). [R61] BIOC: *Results of the MITI test for bioaccumulation indicate p-chloronitrobenzene has a bioconcentration factor (BCF) of less than 100(1). Using a recommended value for the log octanol-water partition coefficient of 2.39(2) and a measured water solubility of 453 mg/L at 20 deg C(3), the BCF for p-chloronitrobenzene has been estimated to be 39 and 20, respectively(4,SRC). Based on these BCF values, p-chloronitrobenzene should not significantly bioconcentrate in aquatic organisms(SRC). [R62] KOC: *Based on a recommended value for the log octanol-water partition coefficient of 2.39(1) and a water solubility of 453 mg/L at 20 deg C(2), the soil absorption coefficient (Koc) for p-chloronitrobenzene has been estimated to be 476 and 151, respectively (3,SRC). These Koc values suggest that this compound should be moderately mobile in soil(4). [R63] VWS: *Henry's Law Constant for p-chloronitrobenzene has been estimated to be 3.6X10-5 atm cu m/mole using a method of group contributions based on molecular structure(1,SRC). Using this value for Henry's Law Constant, the volatilization half-life from 1 m deep in surface water with a current velocity of 1 m/sec and wind speed of 3 m/sec has been estimated to be 33.5 hours(2,SRC). Volatilization from surface waters with slower current speed should be less rapid(SRC). Based on a soil absorption coefficient for p-chloronitrobenzene of 151 - 476 (see also KOC), and an estimated Henry's Law Constant of 3.6X10-5 atm cu m/mole, volatilization from wet soil surfaces may be significant. Based on the estimated vapor pressure of 1.04X10-2 mmHg at 20 deg C, volatilization from dry soil surfaces should be considerably slower than from wet soil surfaces(SRC). [R64] WATC: *SURFACE WATER: From 1977 to 1982, p-chloronitrobenzene was detected in the Rhine River at levels ranging from less than 0.1 ug/L to 0.11 ug/L. p-Chloronitrobenzene was monitored in the Rhine River at a concentration of 1 ug/L, but was not detected in related tapwater(2). 0.3 ug/L p-chloronitrobenzene was detected in Rhine River water before bank infiltration and < 0.01 ug/L was detected after bank infiltration (infiltration time = 1-12 months) and after dune infiltration (infiltration time = 2-3 months)(3). [R65] *DRINKING WATER: p-Chloronitrobenzene was positively identified in drinking water from New Orleans, LA(1). [R66] EFFL: *o-, m- and p-Chloronitrobenzene were identified in m-chloronitrobenzene waste water at a concentration of 1.5-1.8 g/L(1). [R67] PFAC: FISH/SEAFOOD CONCENTRATIONS: *p-Chloronitrobenzene was found in the edible portion of various species of fish taken from the Mississippi River 0, 60 and 150 miles south of St. Louis, MO at concentrations ranging from 0.008 to 0.63 ppm(1). [R68] RTEX: *Exposure to p-chloronitrobenzene is probably due mainly to occupational exposure during production or use as an intermediate. A small segment of the general population may be exposed through ingestion of contaminated drinking water or fish. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers p-nitrochlorobenzene to be a potential occupational carcinogen. [R23, 226] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 1 mg/cu m. Skin Designation. [R69] NREC: *NIOSH considers p-nitrochlorobenzene to be a potential occupational carcinogen. [R23, 226] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R23, 226] TLV: *8 hr Time Weighted Avg (TWA): 0.1 ppm, skin. [R33, 2002.44] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R33, 2002.6] *A3; Confirmed animal carcinogen with unknown relevance to humans. [R33, 2002.44] *Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R33, 2002.91] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R70] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Nitrochlorobenzene is included on this list. [R71] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *ANALYTE: P-NITROCHLOROBENZENE; MATRIX: AIR; RANGE: 0.428-2.75 MG/CU M; PROCEDURE: ADSORPTION ON SILICA GEL, DESORPTION WITH METHANOL, GAS CHROMATOGRAPHY. [R72] *ORGANIC CMPD, INCL P-NITROCHLOROBENZENE, DETERMINED IN THE ATMOSPHERE BY GAS CHROMATOGRAPHY. [R73] *THE PROPOSED GAS CHROMATOGRAPHY METHOD FOR THE DETERMINATION OF O-, M-, AND P-NITROCHLOROBENZENE SIMULTANEOUSLY IN AIR IS INTENDED AS AN AIR POLLUTION CONTROL METHOD FOR ANILINE DYE INDUSTRY. [R74] *A QUANTITATIVE PAPER CHROMATOGRAPHIC METHOD OF SEPARATION OF NITROBENZENE AND 1-CHLORO-4-NITROBENZENE IN AIR SAMPLES. THE SEPARATED CMPD WERE EXTRACTED WITH CARBON TETRACHLORIDE AND DETERMINED AT 450 NM. THE METHOD IS APPLICABLE TO TOTAL AMOUNTS OF THE COMPOUNDS IN THE 25-200 UG RANGE. THE RECOVERY AND PRECISIONS OF THE METHOD FOR NITROBENZENE AND 1-CHLORO-4-NITROBENZENE WERE 93 and 99.8% and 10.5 and 11.9%, RESPECTIVELY. [R75] *SPECTROPHOTOMETRIC DETERMINATION OF NITROBENZENE AND 1-CHLORO-4-NITROBENZENE IN AIR. [R76] *NIOSH method No.2005. Nitrobenzenes. Describes the analysis of nitrobenzenes using gas chromatography with a flame ionization detector. The working range for this method is 0.03 to 6.0 ppm. /Nitrobenzenes/ [R77] CLAB: *SPECTROPHOTOMETRIC DETERMINATION OF NITROBENZENE AND 1-CHLORO-4-NITROBENZENE IN URINE. [R76] *Determination of p-chloronitrobenzene and its metabolites in urine by high performance liquid chromatography. [R78] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NIOSH; Extent of Exposure Survey of Monochlorobenzene (1981). A survey was conducted to determine the extent of exposure to workers using or producing monochlorobenzene. USEPA; Chemical Hazard Information Profile: 4-Chloronitrobenzene (1983). Information concerning the hazards of 4-chloronitrobenzene is provided. DHHS/NTP; NTP Technical Report on Toxicity Studies of 2-Chloronitrobenzene and 4-Chloronitrobenzene Administered by Inhalation to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No.33 NIH Publication No. 93-3382 (1993) SO: R1: SRI R2: Howard PH et al; Investigation of Selected Environmental Contaminants: Nitroaromatics USEPA-560/2-76-010 (1976) R3: Aldrich; Catalog Handbook of Fine Chemicals. Milwaukee, WI, Aldrich Chemical Co., p. 299 (1992) R4: SRI. 1994 Directory of Chemical Producers -United States of America. 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C-33 R56: Yoshida T et al; Xenobiotica 22 (12): 1459-70 (1992) R57: Yoshida T et al; Arch Toxicol; 65 (1): 52-8 (1991) R58: (1) Howard PH et al; Investigation of Selected Environmental Contaminants: Nitroaromatics USEPA-560/2-76-010 (1976) R59: (1) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) R60: (1) Sasaki S; p 283-98 in Aquatic Pollutants: Transformation and Biological Effects Oxford Pergammon Press (1978) (2) Kitano M; Biodegradation and Bioaccumulation Test on Chemical Substances OECD Tokyo Meeting Reference Book TSU-No 3 (1978) (3) Alexander M; Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (4) Bielaszczyk E et al; Acta Microbiol Pol 16: 243-8(1967) (5) Corbett MD, Corbett BR; Appl Env Microbiol 41: 942-9 (1981) R61: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY pp 7-4 (1982) (2) Miller GC, Crosby DG; Chemosphere 12: 1217-27(1983) (3) Sadtler; Sadtler Standard Spectra Phil PA UV (No.) 1290 (4) GEMS; Graphical Exposure Modeling System. Fate of Atmospheric Pollutants (FAP) Data Base. Office of Toxic Substances. USEPA (1986) (5) Kanno S, Nojimak; Chemosphere 8: 225-32 (1979) R62: (1) Sasaki S; p 283-98 in Aquatic Pollutants: Transformation and Biological Effects Oxford Pergammon Press (1978) (2) Hansch C, Leo AJ; Medchem Project Issue #26: Pomona College, Claremont, CA: (1985) (3) Eckert JW; Phytopathol 52: 642-9 (1962) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY p 5-5 (1982) R63: (1) Hansch C, Leo AJ; Medchem Project Issue No. 26: Pomona College, Claremont, CA: (1985) (2) Eckert JW; Phytopathol 52: 642-9 (1962) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Orgnaic Compounds. McGraw-Hill NY 4-9 (1982) (4) Swann RL IN et al; Res Rev 85: 17-28 (1983) R64: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY Chpt 15 (1982) (3) Eckert JW; Phytopathol 52: 642-9 (1962) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill NY pp 4-9 (1982) R65: (1) Malle KG; Z Wasser-Abwasser Forsch 17: 75-81 (1984) (2) Piet GJ, Morra CF; p 31-42 in Artificial Groundwater Recharge (Water Resources Eng. Series) Pitman Pub (1983) (3) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) R66: (1) Lucas SV; GC/MS Analysis of Orgnaics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol.2. Computer Printed Tabulations of Compound Identification Results from Large Volume Concentrates. Columbus, OH: Health Eff. Res. Lab (1984) R67: (1) Howard et al; Investigation of Selected Environmental Contaminants: Nitroaromatics USEPA-560/2-76-010 (1976) R68: (1) Yurawecz MP, Puma BJ; J Assoc Off Anal Chem 66: 1345-52 (1983) R69: 29 CFR 1910.1000 (7/1/98) R70: 40 CFR 712.30 (7/1/94) R71: 40 CFR 716.120 (7/1/94) R72: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V3 S218-1 R73: MITCHELL JJ ET AL; DETERMINATION OF TRACES OF ORGANIC CMPD IN THE ATMOSPHERE: ROLE OF DETECTORS IN GAS CHROMATOGRAPHY; ANAL CHIM ACTA 100: 45 (1978) R74: KOLIEVSKAYA YA, IVANYUK EG; DETERMINATION OF NITROCHLOROBENZENE IN THE WORK AREA AIR BY GAS CHROMATOGRAPHY; GIG TR PROF ZABOL: (12) 54 (1975) R75: DANGWAL SK; A QUANTITATIVE PAPER CHROMATOGRAPHIC METHOD OF SEPARATION OF NITROBENZENE AND P-NITROCHLOROBENZENE IN AIR SAMPLES; AM IND HYG ASSOC J 42 (7): 557 (1981) R76: DANGWAL SK, JETHANI BM; A SIMPLE METHOD OF DETERMINATION OF NITROBENZENE AND NITROCHLOROBENZENE IN AIR AND URINE; AM IND HYG ASSOC J 41 (11): 847-50 (1980) R77: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R78: Yoshida T; J Chromatog 613 (1): 79-88 (1993) RS: 70 Record 148 of 1119 in HSDB (through 2003/06) AN: 1753 UD: 200304 RD: Reviewed by SRP on 9/23/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: O-PHENYLPHENOL- SY: *Anthrapole-73-; *Biphenyl-2-o1-; *biphenyl,-2-hydroxy-; *O-BIPHENYLOL-; *(1,1'-BIPHENYL)-2-OL; *2-BIPHENYLOL-; *o-diphenylol-; *'DOWICIDE-A'-; *DOWICIDE-1-; *dowicide-1-antimicrobial-; *2-hydroxybifenyl- (Czech); *O-HYDROXYBIPHENYL-; *2-HYDROXYBIPHENYL-; *o-hydroxydiphenyl-; *2-HYDROXYDIPHENYL-; *KIWI-LUSTR-277-; *NCI-C50351-; *Nectryl-; *OPP-; *Orthohydroxydiphenyl-; *ORTHOPHENYLPHENOL-; *ORTHOXENOL-; *phenol,-o-phenyl-; *phenylphenol-; *Phenyl-2-phenol-; *PREVENTOL-O-EXTRA-; *remol-TRF-; *tetrosin-OE-; *TOPANE-; *TORSITE-; *tumescal-0PE-; *USAF-EK-2219-; *O-XENOL- RN: 90-43-7 MF: *C12-H10-O ASCH: ortho-phenylphenol, sodium; 132-27-4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *By hydrogenation of 2-cyclohexylidenecyclohexanone produced by the base catalyzed dimerization of cyclohexanone. [R1] *From the reaction of chlorobenzene and caustic soda solution at elevated temperatures and pressures. [R2] *Either synthesized directly or isolated as a byproduct in the production of phenol by the hydrolysis of monochlorobenzene. [R3] *Prepared from phenyl ether. [R4] *Biphenyl (sulphonation/alkali fusion; coproduced with p-phenylphenol). Chlorobenzene (arylation/base-catalyzed hydrolysis; coproduced with p-phenylphenol). Xylenol, mixed (fractionation/alkali extraction; coproduced with biphenyl) [R5] *Produced as a by-product in the manufacture of diphenyloxide or by aldol condensation of hexazinone. [R6, p. V4 509] FORM: *USEPA/OPP Pesticide Code 064103; Trade Names: Dowicide 1, NCI-C50351, Preventol O extra, Remol TRF, Torsite, Tumescal OPE, USAF EK-219. [R7] *LIQUID 5-18% ACTIVE INGREDIENT; WETTABLE POWD- 98% ACTIVE INGREDIENT; WAS 0.87, 1.8 and 2.5% ACTIVE INGREDIENT. [R8, 4526] *Coating agent [R9, 956] *Use levels /in cosmetics/ are product dependent but generally do not exceed 0.25%. [R10] MFS: *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 832-1150; Production site: Midland, MI 48667 [R11] OMIN: *THE TENDENCY TO SCALD CITRUS FRUITS IS REDUCED BY ADDITION OF HEXAMINE. [R12] *Water sol sodium salt of o-phenylphenol is used for protecting water extendable paints against decomposition prior to use and is employed as a preservative for proteins and other types of decomposable adhesives. In dish washing formulations, vegetable wax, and in paper dipping for food storage. /o-Phenylphenol sodium/ [R13, 1617] *CANADIAN TOLERANCE ON APPLES AND PEARS: 5 PPM. [R8, 452] *ORTHOPHENYLPHENOL IS CONTAINED IN SEVERAL DERMATOLOGICAL PREPN AND IN HOSPITAL DISINFECTANTS. [R14] *Should not be used on growing plants. [R9, 956] *Most widely used phenol and is used in many countries for treating citrus fruit. [R15] *Produced as /a/ by-product from the hydrolysis of chlorobenzene ... with aqueous sodium hydroxide. [R16] USE: *For 2-Phenylphenol (USEPA/OPP Pesticide Code: 064103) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R7] *Fungicide, germicide, household disinfectant, preservative in water-oil emulsions. [R13, 1617] *Rubber industry [R4] *FUNGICIDE FOR CITRUS (POSTHARVEST USE); DISINFECTANT (EG, FOR CUTTING OILS, TIMBER, + PAPER); DYESTUFF CARRIER FOR POLYESTER FIBERS [R17] *Post-harvest treatment of fruits and vegetables to protect against microbial damage. [R18] *Applications include metal working fluids, leather, paint. [R19] *Plasticizer [R20] *Intermediate for dyes; germicide; fumicide; rubber chemicals; food packaging. [R21] *Fungicide [R22] *Antimicrobial preservative useful in cosmetics. [R16] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 4.54X10+5 G [R17] *(1978) PROBABLY GREATER THAN 4.54X10+5 G [R17] *Current global production is estimated to be less than 10 million pounds per year. [R6, p. V4 509] U.S. IMPORTS: *(1976) 6.01X10+6 G (PRINCPL CUSTMS DISTS) [R17] *(1978) 3.00X10+7 G (PRINCPL CUSTMS DISTS) [R17] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEEDLES FROM PETROLEUM ETHER [R23]; *Colorless to pinkish crystals [R9, 955]; *White, flaky crystals [R4] ODOR: *MILD ODOR [R12]; *Sweetish odor [R5] BP: *286 deg C [R24] MP: *59 deg C [R24] MW: *170.21 [R4] DEN: *1.213 @ 25 deg C/4 deg C [R24] DSC: *pKa= 9.55 @ 22.5 deg C [R25] OWPC: *log Kow= 3.09 [R26] PH: *pH of 1% solution = 11.2-11.6 [R6, p. V4 608] SOL: *Soluble in fixed alkali hydroxide solutions and most organic solvents. [R4]; *Soluble in ethanol, acetone, benzene, chloroform, and ligroin; very soluble in ethyl ether and pyridine. [R27]; *Sol in most organic solvents, including ethanol, ethylene glycol, isopropanol, glycolethers, and polyglycols. [R9, 955]; *In water, 700 mg/l @ 25 deg C [R9, 955] SPEC: *MAX ABSORPTION (METHANOL): 247 NM (LOG E= 4.1); 286 NM (LOG E= 3.7); SADTLER REFERENCE NUMBER: 1192 (IR, PRISM, KBR); 341 (UV) [R28]; *Intense mass spectral peaks: 170 m/z (100%), 169 m/z (69%), 141 m/z (35%), 115 m/z (26%) [R29]; *IR: 6183 (Coblentz Society Spectral Collection) [R27]; *UV: 341 (Sadtler Research Laboratories Spectral Collection) [R27]; *NMR: 6528 (Sadtler Research Laboratories Spectral Collection) [R27]; *MASS: NIST 52386 (NIST/EPA/MSDC Mass Spectral Database, 1990 Version); WILEY 1127 (Atlas of Mass Spectral Data. John Wiley and Sons, New York) [R27] VAP: *2.0X10-3 mm Hg @ 25 deg C [R30] OCPP: *FORMS SALTS OF WHICH THOSE OF THE ALKALI METALS ARE WATER-SOLUBLE; THE SODIUM SALT CRYSTALLIZES AS A TETRAHYDRATE, SOLUBILITY CIRCA 1.1 KG/KG WATER (35 DEG C), GIVING A SOLUTION OF PH 12.0-13.5. [R12] *IR: 5832 (Sadtler Research Laboratories Prism Collection) /Biphenyl, 3-hydroxy/ [R31] *UV: 1629 (Sadtler Research Laboratories Spectral Collection) /Biphenyl, 3-hydroxy/ [R31] *NMR: 262 (Sadtler Research Laboratories Spectral Collection) /Biphenyl, 3-hydroxy/ [R31] *MASS: 1127 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Biphenyl, 3-hydroxy/ [R31] *VAPOR PRESSURE: 1 MM HG @ 100.0 DEG C [R32] *Vapor Pressure: 20 mm Hg @ 163 deg C; 100 mm Hg @ 206 deg C [R21] *Henry's Law constant = 4.3X10-5 atm-cu m/mole @ 25 deg C [R25] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: +SLIGHT, WHEN EXPOSED TO HEAT OR FLAME; CAN REACT WITH OXIDIZING MATERIALS. [R33] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. lll [R34, 410] SERI: *IRRITATING IN THE EYE ... DUSTS ARE ALSO IRRITANTS WHEN INHALED. [R35] *... Moderate skin irritant. [R34, 410] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: The scientific literature supports the wearing of contact lenses in industrial environments, as part of a program to protect the eye against chemical compounds and minerals causing eye irritation. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases contact lenses should not be worn. [R36, 176] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of ortho-phenylphenol and sodium ortho-phenylphenate. Overall evaluation: ortho-Phenylphenol is not classifiable as to its carcinogenicity to humans (Group 3). Sodium ortho-phenylphenate is possibly carcinogenic to humans (Group 2B). [R37] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Administer activated charcoal ... . Dilution may be contraindicated because it may increase absorption. Do not use emetics ... . Cover skin burns with dry, sterile dressings after decontamination ... . Maintain body temperature. /Phenols and related compounds/ [R38, p. 243-4] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Phenols and related compounds/ [R38, 244] HTOX: *WHEN TESTED ON 200 ... SUBJECTS AS A 5.0% SOLN IN SESAME OIL AND AS A 0.1% AQ SOLN OF THE SODIUM SALT, O-PHENYLPHENOL FAILED TO CAUSE EITHER PRIMARY SKIN IRRITATION OR SKIN SENSITIZATION. [R13, 1617] *MAY CAUSE CORNEAL INJURY (NECROSIS), ESP THE SODIUM SALT. /O-PHENYLPHENOL SODIUM SALT/ [R35] *A POSITIVE MUTAGENIC DOSE RESPONSE RELATION WAS PROVED BETWEEN THE NUMBER OF ABERRATIONS OF HUMAN DIPLOID FIBROBLASTS CULTIVATED WITH OPP FOR 24 HR AND THE CONCENTRATION OF OPP IN CULTURE MEDIUM RANGING FROM 0.1 TO 1.0 UG/ML WITH SIGNIFICANCE ABOVE 0.2 UG/ML. [R39] *A fatal oral dose of 10 g was reported, and toxic effects on the urothelium of the bladder were observed in two humans exposed to o-phenylphenol. [R40] *The usual symptoms include headache, giddiness, nervousness, blurred vision, weakness, nausea, cramps, diarrhea, and discomfort in the chest. Signs include sweating, miosis, tearing, salivation and other excessive respiratory tract secretion, vomiting, cyanosis, papilledema, uncontrollable muscle twitches followed by muscular weakness, convulsions, coma, loss of reflexes, and loss of sphincter control. The last four signs are seen only in severe cases but do not preclude a favorable outcome if treatment is prompt and energetic. Cardiac arrhythmias, various degrees of heart block, and cardiac arrest may occur ... /Organic phosphorus pesticides/ [R41] *0-Phenylphenol causes immunosuppression. /from table/ [R42] NTOX: *MALE AND FEMALE RATS ... MAINTAINED FOR 2 YR ON DIETS CONTAINING 0.02 OR O.2% ... SHOWED NO ADVERSE EFFECTS AS JUDGED BY GROSS APPEARANCE, GROWTH, HEMATOLOGY, RATE OF MORTALITY, ORGAN WT AND HISTOPATHOLOGICAL CHANGES IN ... TISSUES. SIMILAR GROUPS /MALE AND FEMALE/ RATS MAINTAINED FOR 2 YR ON DIET CONTAINING 2% ... DEVIATED FROM CONTROLS BY EXHIBITING SLIGHT RETARDATION OF GROWTH, HISTOPATHOLOGICAL KIDNEY CHANGES (MARKED TUBULAR DILATION) AND PRESENCE OF SMALL AMT OF O-PHENYLPHENOL IN TISSUES OF KIDNEY. DOGS THAT RECEIVED ORAL DOSES OF 0.02, 0.2 and 0.5 G/KG/DAY ... FOR ... 1 YR SHOWED NO ADVERSE EFFECTS AS JUDGED BY BODY WT, HEMATOLOGICAL VALUES, ORGAN WT AND HISTOPATHOLOGICAL CHANGES IN VARIOUS TISSUES. [R13, 1618] *IN RATS INGESTION CAUSES DEATH FROM NERVOUS DEPRESSION, AS DOES PHENOL. ... IN CATS ORAL LETHAL DOSES ... IN AQ SUSPENSIONS CAUSE HEMORRHAGIC GASTROENTERITIS AND HEMORRHAGES IN LIVER, LUNG AND MYOCARDIUM. [R35] *NONTUMORIGENIC WHEN ADMIN ORALLY TO MICE @ 35-100 MG/KG/DAY. /FROM TABLE/ [R43] *IN DOMINANT LETHAL STUDIES, OPP INDUCED NO DOMINANT LETHAL MUTATIONS @ ANY STAGE OF SPERMATOGENESIS IN C3H MALE MICE AFTER ORAL ADMIN OF DAILY DOSES OF 100 OR 500 MG/KG FOR 5 DAYS. IN CYTOGENETIC STUDIES, OPP PRODUCED NO STRUCTURAL AND NUMERICAL ABERRATIONS @ ANY DOSE TESTED IN 4 WK OLD WISTAR MALE RATS AFTER ORAL ADMIN OF DAILY DOSES OF 50, 100, 200, 400 and 800 MG/KG FOR 5 DAYS OR SINGLE DOSES OF 250, 500, 1000, 2000 and 4000 MG/KG. NEG RESULTS OBTAINED IN ALL MICTOBIOL STUDIES USING RECOMBINATION ASSAY FOR BACILLUS SUBTILIS, REVERSION ASSAYS WITH AND WITHOUT METABOLIC ACTIVATION IN ESCHERICHIA COLI AND HOST MEDIATED ASSAY WITH SALMONELLA TYPHIMURIUM AND 7 WK OLD MALE MICE. [R44] *O-Phenylphenol was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild type males were treated with concentrations of OPP that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of OPP tested by injection (500 ppm) or feeding (250 ppm) were negative in this assay. [R45] *o-Phenylphenol was weakly mutagenic in strain Ta1535 of Salmonella typhimurium only in the absence of rat liver S9; it was not mutagenic in strains TA1537, TA98, or TA100. It was mutagenic in the mouse lymphoma L5178Y/TK+/- assasy in the presence or absence of Aroclor 1254 induced male F344 rat liver S9. o-Phenylphenol did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. o-Phenylphenol induced sister chromatid exchanges in Chinese hamster ovary (CHO) cells only in the absence of Aroclor 1254 induced male Sprague-Dawley rat liver S9. [R46] *o-Phenylphenol, administered orally to 9 pregnant mice at doses ranging from 1.45 to 2.0 g/kg, produced maternal toxicity and delayed fetal development but not teratogenicity. ... In another study, o-phenylphenol was found to be fetotoxic but not teratogenic when administered to pregnant rats in daily doses of 600 mg/kg, on days 6 through 15 gestation ... . o-Phenylphenol was not embryotoxic or teratogenic to Sprague-Dawley rats at doses up to 700 mg/kg per day administered on gestation days 6 through 15. [R47] *o-Phenylphenol does not induce changes in immune function in mice following short term oral administration. This finding was confirmed ... in studies in which B6C3F1 mice were administered oral doses of o-phenylphenol (up to 200 mg/kg day) for 10 days and then examined for a variety of immune functions. [R48] *An increased incidence of neoplasms of the urinary bladder in F344/DuCrj rats administered sodium o-phenylphenate in the diet. In a 13 week study, urinary bladder papillomas or transitional cell carcinomas developed in 1/10 male rats fed 1% sodium o-phenylphenate, 9/10 male rats fed 2%, 1/10 male rats fed 4%, and 2/10 female rats fed 4%. In a 91-week study, transitional cell carcinomas of the urinary bladder, renal pelvis, or renal papilla developed in 1/21, 7/21, 20/21, and 17/21 male rats fed sodium o-phenylphenate in the diet at concentrations of 0.5%, 1%, 2%, or 4%, respectively. /Sodium o-phenylphenate/ [R40] *Dogs that received oral doses 0.02, 0.2, and 0.5 g/kg/day of o- phenylphenol for a period of 1 year showed no adverse effects as judged by body weughts, hematologic values, organ weights, and histopathological changes in various tissues. [R13, 1618] *Toxic to fish. [R49, 795] *Groups of 20-24 male F344/DuCrj rats, 38-39 days of age, were given ortho-phenylphenol (purity > 98%) in the diet at concns of 0 (control), 0.625, 1.25, or 2.5% for 91 wk. Rats at the high dose consumed significantly less food and had a 17-24% lower weight gain compared to controls. The numbers of rats with bladder tumors were reported as: 0/24, 0/20, 23/24 (p < 0.001) and 4/23 in the controls and rats at the 3 doses, respectively. The 23 bladder tumors in rats at 1.25% were described as 3 papillomas, 15 non-invasive carcinomas, and 5 invasive carcinomas. [R50] *Studies on the ability of ortho-phenylphenol to induce sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells provided contradictory results. In one study performed in the absence of metabolic activation, dose-dependent increases in the incidence of both chromosomal aberrations and sister chromatid exchange were detected after a 27 hr post-treatment incubation; the presence of only chromosomal aberrations after 42 hr suggested that DNA damage resulting in sister chromatid exchange can be repaired during the longer incubation time. In a second study, a borderline incr in the frequency of chromosomal aberrations occurred in both the presence and absence of exogenous metabolic activation from rat liver, but no sister chromatid exchange was seen. In a third study in the presence of metabolic activation, an increased frequency of sister chromatid exchange occurred, which was not inhibited by several scavengers of oxygen reactive species. Finally, in the presence of 15% metabolic activation, ortho-phenylphenol increased the incidence of both chromosomal aberrations and sister chromatid exchange; both these cytogenetic effects were inhibited by cysteine and glutathione, and the frequency of sister chromatid exchange was found to correlate with the formation of the reactive metabolite phenylhydroquinone. [R51] *Ortho-phenylphenol (OPP) and sodium ortho-phenylphenate (NaOPP) are pesticides used commercially in the food industry that have been shown to be carcinogenic to rat urothelium. Dietary administration of 1.25% OPP or 2.0% NaOPP caused increased incidences of urothelial hyperplasia and eventually caused tumors in male F344 rats, with NaOPP apparently having a more potent effect. In other studies, various sodium salts such as saccharin and ascorbate enhanced bladder carcinogenesis, although the acid forms of these salts did not. In studies with high dietary doses of these sodium salts, an amorphous precipitate was produced in the urine; precipitate formation was pH dependent. In previous experiments in which high doses of OPP were fed for up to 17 weeks, severe hyperplasia of the urothelium was produced, but without the formation of an urinary amorphous precipitate, calculi, or abnormal microcrystalluria. In addition, we found no evidence of OPP-DNA adduct formation in the urothelium. The present study was conducted to determine if feeding NaOPP * 4 H(2)0 to male F344 rats as 2.0% of the diet resulted in the formation of an amorphous precipitate in the urine, and if NaOPP caused an increased mineral concentration in the urine and/or kidneys. NaOPP administration produced a higher urinary pH than did OPP fed as 1.25% of the diet. Neither amorphous precipitate nor other solids were observed in the urine of the OPP or NaOPP-treated rats, and urinary calcium concentrations in the treated groups were similar to control. OPP and NaOPP had similar proliferative effects on rat urothelium after 10 weeks of treatment by light microscopy, scanning electron microscopy (SEM), and bromodeoxyuridine (BrdU) labeling indices. The results of this study indicate that formation of abnormal urinary solids is not part of the mechanism by which OPP or NaOPP exert their effects on the rat bladder epithelium. [R52] *The biocides ortho-phenylphenol and its sodium salt (OPP and SOPP) are widely used as fungicides and antibacterial agents for commercial and consumer purposes. The carcinogenicity of OPP/SOPP toward the urinary bladder was demonstrated when rats were chronically fed concentrations of 0.5%-4% in their diet. Other species tested so far did not develop tumours. Understanding the mechanisms underlying OPP/SOPP-induced bladder carcinogenesis is critical to determine whether risks observed at high doses in rats are of relevance to humans exposed at much lower levels. This overview details experimental studies of carcinogenicity, genotoxicity as well as metabolism/toxicokinetics and other mechanistic studies which bear on cancer hazard and risk evaluation of exposure to humans. Based on the presently available knowledge, it is concluded that reactive quinoid metabolites exhibiting redox cycling activities are the crucial factors. At certain concentration levels, these metabolites are able to produce cytotoxic events with concomitant enhanced cell proliferation of the target tissue. Further important risk factors are probably promutagenic lesions induced by oxidative stress and a higher urinary pH. Supposed that these mechanisms are the basis for the tumourigenicity observed, then suitable low doses of OPP/SOPP will practically pose no cancer risk. [R53] *ortho-Phenylphenol (OPP) is a widely used fungicide and antibacterial agent that is also known to be highly effective in inducing bladder tumors in male F344 rats. At present, neither the role of the urinary bladder in the bioactivation of OPP metabolites nor the nature of the molecular target is understood. To address these issues, we investigated the relationship between OPP dosage and macromolecular adduct formation in the urinary bladder of male F344 rats. Male F344 rats were treated with 0, 15, 50, 125, 250, 500, 1000 mg/kg of OPP and its radiocarbon analogue via oral gavage. The dosed rats were euthanized after 24 h, and the proteins were extracted from the liver, kidney, and bladder. The amount of radioactivity associated with the extracted protein was quantified using highly sensitive accelerator mass spectrometry. Protein binding in liver and kidney exhibited a linear or modest curvilinear relationship over the dose range studied. In the urinary bladder, however, a pronounced nonlinear relationship between protein adduct levels and administered dose was observed. The measured protein adduct levels were in agreement with the predicted concentrations of phenylbenzoquinone based on a proposed mechanism involving free phenylhydroquinone autoxidation in the urine. Unlike protein binding, DNA adducts measured from the same bladder samples did not show a significant difference from the control group. These data are consistent with the hypothesis that OPP is an indirect acting carcinogen, and that regenerative hyperplasia due to OPP-metabolite cytotoxicity and/or binding of OPP metabolites to protein targets may play an important role in OPP-induced bladder carcinogenesis. Copyright 1999 Academic Press. [R54] *Phenylhydroquinone (PHQ), a metabolite of o-phenylphenol (OPP), is easily autoxidized to phenylbenzoquinone (PBQ) via the semiquinone (phenylsemiquinone, PSQ) with concomitant production of superoxide anion radicals (O2-.). We have used scavengers of active oxygen species to examine whether or not O2-. produced during oxidation of PHQ is related to cell damage in CHO-K1 cells. PHQ at 10 micrograms/ml (3-h treatment) induced sister-chromatid exchange (SCE), endoreduplication (ERD) and cell-cycle delay in CHO-K1 cells. These effects were inhibited by catalase (280 U/ml), a scavenger of hydrogen peroxide (H2O2), as well as by the reductants, ascorbate (3 mM) and GSH (1 mM). Mannitol (50 mM), a scavenger of hydroxyl radical (OH.), was ineffective and superoxide dismutase (SOD, 150 U/ml), a scavenger of O2-., or SOD plus catalase rather intensified the toxicity as did aminotriazole (20 mM), an inhibitor of catalase. Analyses of incubation solutions by HPLC showed that the extent of cell damage is correlated with PHQ loss; catalase suppressed PHQ loss, whereas SOD promoted it. The correlation was more clearly seen in the time courses of cell death and PHQ loss during incubation of PHQ with each of the scavengers of active oxygen species. These results show that neither O2-. nor OH. participates in the cell damage, but rather H2O2 generated via dismutation of O2-. may participate, probably by accelerating the autoxidation of PHQ and thus causing an increase in the production of toxic intermediates. In fact, conversion of PHQ to PBQ, a reactive product, was demonstrated during incubation with PHQ in phosphate-buffered saline by following the changes in UV-visible spectra of PHQ. Inclusion of H2O2 (0.2 or 1 mM) in the incubation mixture accelerated the PHQ loss. The present results can be explained in terms of the autoxidation mechanism of hydroquinone proposed by O'Brien (1991). Different from the results in the absence of S9 mix, the cell damage induced by 50 micrograms/ml OPP in the presence of S9 mix was not influenced by any of the scavengers of active oxygen species used. We conclude that PHQ causes cytotoxic and genotoxic effects through its autoxidation, both enzymatic and nonenzymatic, and that reactive intermediate(s) such as PSQ and/or PBQ may be ultimately responsible for the effects. H2O2 formed during the oxidation process participates in the damaging effects caused in the absence of S9 mix, probably by accelerating the autoxidation. [R55] *ortho-Phenylphenol (OPP), a fungicide and antibacterial agent with food residues, is carcinogenic to rat bladder. The present studies provide information on changes in urinary composition and urinary metabolites, urothelial cytotoxicity and regenerative hyperplasia, and DNA adducts in male F344 rats fed OPP. An initial experiment evaluated dietary doses of 0, 1,000, 4,000, and 12,500 ppm OPP fed for 13 weeks. There was no evidence of urinary calculi, microcrystalluria, or calcium phosphate-containing precipitate, but urothelial cytotoxicity and hyperplasia occurred at the highest dose only. In a second experiment, rats were fed dietary OPP levels of 0, 800, 4,000, 8,000, and 12,500 ppm. Urinary pH was > 7 in all groups. Urinary volume was increased at the 2 highest doses with consequent decreases in osmolality, creatinine, and other solutes. Total urinary OPP metabolite excretions were increased, mostly excreted as conjugates of OPP and of phenylhydroquinone. Free OPP or free metabolites accounted for less than 2% excreted in the urine without a dose response. Urothelial toxicity and hyperplasia occurred only at doses of 8,000 and 12,500 ppm. OPP-DNA adducts were not detected in the urothelium at any dose. In summary, OPP produces cytotoxicity and proliferation of the urothelium at dietary doses > or = 8,000 ppm without formation of urinary solids. The paucity of unconjugated metabolites and the lack of OPP-DNA adducts suggests that OPP is acting as a bladder carcinogen in male rats by inducing cytotoxicity and hyperplasia without it or its metabolites directly binding to DNA. [R56] *The effects of sodium o-phenylphenate (Na-OPP) treatment on urinary bladder epithelium were examined in male F344 rats, B6C3F1 mice, Syrian golden hamsters and Hartley guinea pigs. Na-OPP was incorporated into diet at a dose of 2% and administered for 4, 8, 12, 24, 36 or 48 weeks. Simple and papillary or nodular (PN) hyperplasias were evident on light microscopy and pleomorphic microvilli demonstrated by scanning electron microscopy were only observed in rats, the lesions becoming more advanced with continued chemical feeding. In mice, hamsters and guinea pigs, proliferative lesions relating to Na-OPP administration were not observed. No significant differences in urinary pH, osmolality or crystal formation were apparent between the various animal species. Since carcinogenicity has been demonstrated for Na-OPP in rats but not in mice, the present findings suggest that Na-OPP might not exert urinary bladder carcinogenic potential in hamsters and guinea pigs. [R57] *A 13-week subchronic oral toxicity study of sodium o-phenylphenate (SOPP) was conducted in B6C3F1 mice. Body weight gain was significantly depressed in 1.0 and 2.0% SOPP-treated males and in both sexes treated with 4.0%. Urinalysis showed an increase in pH and a decrease of specific gravity in the 4.0% group of both sexes. Relative liver weights of both sexes receiving 1.0, 2.0 and 4.0% SOPP were significantly greater than those of the controls. No treatment-related histopathologic findings were noted. On scanning electron microscopic (SEM) examination, the bladder epithelium of mice given 2.0% SOPP appeared normal at any time periods investigated. This study showed that while 4.0% SOPP was very toxic to both sexes, 2.0% SOPP did not cause statistically significant changes in organ weights. [R58] *Sodium o-phenylphenate (OPP-Na) was given at dietary levels of O (control), 0.5, 1.0 and 2.0% to groups of 50 male and 50 female mice for 96 wk, and all the animals were maintained without OPP-Na for a further 8 wk. Both sexes given 2% OPP-Na and females given 0.5% and 1% OPP-Na showed growth retardation. Serum alkaline phosphatase activity in OPP-Na treated females was significantly increased in a dose-related manner. There were no treatment-related effects on clinical signs, mortality, urinalyses, haematology or organ weights. The incidences of several non-neoplastic and neoplastic lesions achieved statistical significance but none was considered to be related to treatment. There were increased incidences of haemangiosarcomas of the liver in males given 1% and of hepatocellular carcinomas in 1 and 2% males, and haemangiomas and leiomyomas of the uterus, present in the controls, were absent or decreased in all treated females. Therefore, this study did not demonstrate any clear carcinogenic effect of OPP-Na on mice at dietary levels of up to 2%. [R59] *o-Phenylphenol (OPP), a fungicide approved as a food additive in Japan, was given in pelleted diets at dietary levels of 0.156, 0.313, 0.625, 1.25 or 2.5% to groups of 11 or 12 F344/DuCrj rats of each sex for 13 wk, and 0.625, 1.25 or 2.5% to groups of 20-24 male F344/DuCrj rats for 91 wk. In the 13-wk study, transitional cell papillomas of the urinary bladder occurred in 6/12 (50%) of the male 1.25% group. In the 91-wk study, urinary bladder tumours appeared in 23/24 (96%) of the 1.25% and 4/23 (17%) of the 2.5% group. Among these tumours, transitional cell carcinomas were found in 20/23 (87%) of 1.25% and 2/4 (50%) of the 2.5% groups. A dose-related increase in the incidence of nephritic lesions was also observed in dosed rats in both the 13- and 91-wk study. [R60] *The role of urinary pH and Na+ concentration on the bladder carcinogenesis of o-phenylphenol (OPP) was examined in male F344 rats. The rats were given powered diet containing 2% sodium o-phenylphenate (OPP-Na, group 1), 1.25% OPP plus 0.64% NaHCO3 (group 2), 1.25% OPP plus 0.32% NaHCO3 (group 3), 1.25% OPP plus 0.16% NaHCO3 (group 4), 1.25% OPP (group 5), 0.64% NaHCO3 (group 6) or no test chemical (group 7) for 104 weeks respectively. Incidences of bladder carcinoma induced were significantly higher in groups 1 (12 of 29 rats, 41.4%) and 2 (9 of 29 rats, 31.0%) than in group 7 (0 of 27 rats, 0%). Groups 3 and 4 induced bladder carcinomas in 4 of 29 rats (13.8%) and 4 of 26 rats (15.4%) respectively, whereas no tumors occurred in group 5 (0 of 27, 0%). The incidence in group 6 was 3.6% (1 of 28 rats). Groups 1 and 2 induced significant increases in urinary pH and Na+ concentrations, whereas group 5 did not. Groups 3 and 4 showed the same tendency as groups 1 and 2. Examination with a scanning electron microscope showed the appearance of pleomorphic microvilli, short, uniform microvilli, and ropy or leafy microridges on the luminal surface of the bladder in groups 1-5 of rats treated with OPP or OPP-Na for 8 weeks. The appearance and severity were the same in groups 1 and 2, followed by the groups with decreasing doses of NaHCO3. The results indicated that OPP-Na is carcinogenic for the rat bladder, but OPP is not. However, increased urinary pH and Na+ concentration play important roles in OPP-Na rat bladder carcinogenesis. [R61] *A single oral administration of orthophenyl-phenol (OPP, 1400 mg/kg; about half the LD50) to male Fischer 344 rats produced an elevation of serum transaminase activity 24 h later. Pretreatment with L-buthionine-S,R-sulfoximine (BSO, 900 mg/kg) in the OPP-treated rats potentiated the hepatic and renal damage which was accompanied by necrosis. Six hours after the administration of OPP (700 or 1400 mg/kg), hepatic and renal glutathione (GSH) levels decreased with increasing dosage. Hepatic GSH depletion with OPP was enhanced with BSO pretreatment and the recovery of GSH in both organs was slow in the high-dose OPP group. These results suggest that hepatic and renal damage is associated with a serious and prolonged GSH depletion. When either phenyl-p-benzoquinone (PBQ) or phenylhydroquinone (PHQ), which are intermediates of OPP, was administered orally to rats at 700 or 1400 mg/kg, the mortality with the high dose of PBQ was 75% at 24 h. The serum transaminase activity and UN level increased with the low dose of PBQ, accompanied by necrotic hepatocytes. The toxic effects of PHQ on kidney or liver were less than those on PBQ. These observations suggest that the liver and kidney may be target organs for toxic actions of a large dose of OPP and its intermediate, PBQ. [R62] *The urinary metabolites from repeated oral doses of 3.7 mg o-phenyl phenol (OPP) to mature and immature dogs and cats were studied. At both age levels, dogs excreted significantly more OPP as sulfate and glucuronide than did cats. Puppies produced 4 times the level of glucuronides than mature dogs. No such age differences were seen with glucuronide formation by cats, nor were there any age differences in either group of animals for sulfate formation. Some sex differences were observed in conjugation of OPP in cats and dogs. The dominant urinary excretion product of oral OPP administration was the unchanged OPP. [R63] NTXV: *LD50 Cat oral 500 mg/kg; [R48] *LD50 Rat single oral dose > 1 g/kg; [R35] *LD50 Rat oral 2.7 g/kg; [R64] *LD50 Guinea pig single oral 3500 mg/kg; [R64] *LD50 White rat single oral 2480 mg/kg; [R64] *LD50 Mouse oral 2000 mg/kg; [R49, 795] *LD50 Mouse ip 50 mg/kg; [R34, 409] *LD50 Cat oral 500 mg/kg; [R36, 177] *LD50 Rat single oral dose 1 g/kg; [R36, 177] *LD50 Rat oral 2.7 g/kg; [R36, 177] *LD50 Guinea pig single oral 3,500 mg/kg; [R36, 177] *LD50 White rat single oral 2,480 mg/kg; [R36, 177] *LD50 Mouse ip 50 mg/kg; [R36, 177] *LD50 Mouse oral 2,000 mg/kg; [R36, 177] ETXV: *EC50 Daphnia magna (6-24 hr old) 2.1 mg/l/24 hr. Lost ability to swim. /Conditions of bioassay not specified/; [R65] *EC0 Daphnia magna (6-24 hr old) 0.75 mg/l/24 hr. Lost ability to swim. /Conditions of bioassay not specified/; [R65] *EC100 Daphnia magna (6-24 hr old) 4.0 mg/l/24 hr. Lost ability to swim. /Conditions of bioassay not specified/; [R65] *EC50 Daphnia magna (6-24 hr old) 15 mg/l/48 hr. Lost ability to swim. /Conditions of bioassay not specified/; [R65] *EC0 Daphnia magna (6-24 hr old) 0.38 mg/l/48 hr. Lost ability to swim. /Conditions of bioassay not specified/; [R65] *EC100 Daphnia magna (6-24 hr old) 29 mg/l/48 hr. Lost ability to swim. /Conditions of bioassay not specified/; [R65] *LC50 Pimephales promelas (fathead minnow) 6.24 (6.03-6.46) mg/l 24 hr, wt 110 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 99%+; [R66] *LC50 Pimephales promelas (fathead minnow) 6.11 (5.85-6.38) mg/l 48 hr, wt 110 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 99%+; [R66] *LC50 Pimephales promelas (fathead minnow) 14.3 (13.2-15.5) mg/l 72 hr, wt 110 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 99%+; [R66] *LC50 Pimephales promelas (fathead minnow) 13.2 (12.1-14.4) mg/l 96 hr, wt 110 mg, flow-through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/l, water hardness 44.9 (42.4-46.6) mg/l as CaCO3, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/l CaCO3, temp: 26.4 +/- 1.4 deg C, Purity 99%+; [R66] *EC50 Daphnia magna (6-24 hr old) 2.1 mg/L/24 hr, Lost ability to Swim (conditions of bioassay not specified); [R36, 177] *EC50 Daphnia Magna (6-24 hr old) 0.75 mg/L/24 hr. Lost ability to Swim (conditions of bioassay not specified); [R36, 177] *EC50 Daphnia magna (6-24 hr old) 15 mg/L/48 hr. Lost ability to swim (conditions of bioassay not specified); [R36, 177] *EC50 Daphnia Magna (6-24 hr old) 0.38 mg/L/48 hr. Lost ability to swim (conditions of bioassay not specified); [R36, 177] *LC50 Pimephales promelas (fathead minnow) 6.24 (6.03-6.46) mg/L 24 hr, wt 110 mg, flow through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/L, water hardness 44.9 (42.4-46.6) mg/L as CaC03, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/L CaC03, temp: 26 4 + or - 1.4 deg C, purity 99%; [R36, 177] *LC50 Pimephales promelas (fathead minnow) 6.11 (5.85-6.38) mg/L 48 hr, wt 110 mg, flow through bioassay, dissolved oxygen 7.4 (4 6-8.8) mg/L, water hardness 44.9 (42.4-46.6) mg/L as CaC03, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/L CaCO3 temp: 26.4 ± 1.4 deg C, Purity 99%; [R36, 177] *LC50 Pimephales promelas (fathead minnow) 14.3(13.2-15.5) mg/L 72 hr, wt 110 mg, flow through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/L, water hardness 44.9 (42.4-46.6) mg/L as CaC03, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/L CaC03, temp: 26 4 + or - 1.4 deg C, purity 99%; [R36, 177] *LC50 Pimephales promelas (fathead minnow) 13.2 (12.1-14.4) mg/L 96 hr, wt 110 mg, flow through bioassay, dissolved oxygen 7.4 (4.6-8.8) mg/L, water hardness 44.9 (42.4-46.6) mg/L as CaC03, pH 6.9-7.7, alkalinity 42.9 (39.6-61.4) mg/L CaC03, temp: 26 4 + or - 1.4 deg C, purity 99%; [R36, 177] NTP: *Carcinogenesis studies were conducted to determine whether o-phenylphenol was a complete carcinogen for skin or a promoter in a two stage initiation/promotion skin paint model. Groups of 50 Swiss CD-1 mice of each sex were used for up to 102 wk. Five dose groups were used: an acetone vehicle control group; a positive control group initiated with 7,12-dimethylbenz(a)anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate; an initiator control group that received DMBA plus acetone; a group that received repeated applications of o-phenylphenol; and a promotion group that was initiated with 7,12-dimethylbenz(a)anthracene and received repeated applications of o-phenylphenol. The following doses were applied dermally to a clipped area on the dorsal interscapular region 3 days/wk: o-phenylphenol 55.0 mg/0.1 ml acetone; or 12-O-tetradecanoylphorbol-13-acetate 0.005 mg/0.1 ml acetone. 7,12-Dimethylbenz(a)anthracene was administered as a single dose at a concn of 0.05 mg/0.1 ml acetone. 7,12-Dimethylbenz(a)anthracene was administered as a single dose at a concn of 0.05 mg/0.1 ml acetone to the dorsal interscapular region. ... Under the conditions of these 2 yr dermal application studies, there was no evidence of carcinogenicity in male or female Swiss CD-1 mice administered o-phenylphenol alone or as a promoter following initiation with 7,12-dimethylbenz(a)anthracene. ... [R67] TCAT: ?Orthophenylphenol (90-43-7) was evaluated for its effects on embryonal and fetal development of rats by administration of the test substance to groups of 25 to 27 pregnant Sprague-Dawley rats at dose levels of 100, 300, or 700 mg/kg/day on days 6-15 of gestation. A control group consisted of 35 rats. Rats were sacrificed on day 21 of gestation. A single death occurred at 700 mg/kg/day which was attributed to a dosing error. Maternal animals in the 700 mg/kg/day group showed a significant decrease in mean body weight and food and water consumption. Animals given 300 mg/kg/day showed increased water consumption. Number of pregnancies, resorptions, litter size, fetal body measurements and fetal alterations were unaffected by treatment with orthophenylphenol. The incidence of major malformations among treated groups was not significantly greater than that of controls. Litters from rats at 700 mg/kg/day showed an increased incidence of delayed ossification of sternebrae and the occurrence of foramina in the bones of the skull (considered to be minor skeletal variants). The authors concluded that orthophenylphenol was not embryotoxic or teratogenic at dose levels up to 700 mg/kg. [R68] ?Orthophenylphenol was administered to groups of 35 Sprague-Dawley rats in the diet at dose levels of 0, 40, 140, and 490 mg/kg/day for two generations (actual doses were 36, 125, and 457 mg/kg/day bases on mean analytical concentrations in the diet). Treatment had no effect on gestation body weight gain, lactation body weight gain, or reproductive parameters. There were no clinical signs of toxicity in adults or pups. mg/kg/day group showed a treatment related decrease in body weight and statistically elevated adult relative kidney weight. Male rats in the 140 and 490 mg/kg/day groups showed an increased incidence of urinary calculi in the kidney and bladder. F0 and F1 males and F0 females at 490 mg/kg/day and F0 males and F0 females showed elevated incidence of transitional cell hyperplasia/papillomatosis in the urinary bladder. Authors conclude that the reproductive NOEL was 490 mg/kg/day. [R69] ?Ortho-Phenylphenol (90-43-7) was evaluated for teratogenicity in groups of 16 to 24 pregnant New Zealand White Rabbits administered the test substance by gavage at dose levels of 0, 25, 100, or 250 mg/kg/day on days 7-19 of gestation. All surviving rabbits were sacrificed on day 28 of gestation. Animals receiving 250 mg/kg/day showed increased mortality (13%). Rabbits at 25 and 100 mg/kg/day showed no significant maternal effects. The test substance did not produce adverse embryonal or fetal effects at any dose level. The NOEL for maternal toxicity was 100 mg/kg/day, while the embryonal/fetal NOEL was 250 mg/kg/day. Tables with further data are referred to in the text but missing from the end document. [R70] ?Ortho-Phenylphenol (90-43-7) was evaluated for potential teratogenicity in groups of 7 pregnant New Zealand white rabbits administered the test substance by gavage at dose levels of 0, 250, 500, or 750 mg/kg/day on days 7-19 of gestation. All surviving animals were sacrificed on day 20 of gestation. Mortalities included one at 250 mg/kg/day, two at 500 mg/kg/day, and six at 750 mg/kg/day. Dose-related signs of toxicity were seen at all dose levels. There was a dose-related decrease in body weight and body weight gain at all levels (the decreases were statistically significant only at 500 and 750 mg/kg/day). Rabbits at 250 and 500 mg/kg/day showed increased absolute and relative kidney weights (kidney and liver weights were not measured at 750 mg/kg/day due to high mortality). A dose-related increase in the incidence of renal tubular degeneration was seen in rabbits at 250, 500, and 750 mg/kg/day. Rabbits at 250 and 500 mg/kg/day showed no treatment related effects on reproductive or embryonal and fetal parameters. The high mortality rate at 750 mg/kg/day prevented adequate evaluation of reproductive parameters. [R71] ADE: *Excreted in mammals principally as the parent compound and as the glucuronide and sulfate conjugates. [R49, 795] *[14C]ortho-Phenylphenol was applied onto the skin of the forearm of 6 volunteers for 8 hr at a dose of 0.4 mg/person (0.006 mg/kg bw). Urine was collected 24 and 48 hr after exposure. By 48 hr, 99% of the dose had been recovered in urine. Sulfation was the major metabolic pathway, accounting for 69% of the metabolites, while conjugates of 2-phenylhydroquinone accounted for 15%. Little or no free ortho-phenylphenol was present in the urine, and no free 2-phenylhydroquinone or 2-phenyl-1,4-benzoquinone was detected. [R72] *[14C]ortho-Phenylphenol was admin by gavage to 10 male B6C3F1 mice at a dose of 15 or 800 mg/kg bw in 0.5% aqueous Methocel and to 2 male and 2 female Fischer 344 rats at a dose of 28 or 27 mg/kg bw. Urine was collected at 12 hr intervals for 24 hr (rats) and 48 hr (mice) after exposure. After admin of 15 or 800 mg/kg bw, 84 and 98% of the admin ortho-phenylphenol was recovered in the urine of mice and 86 and 89% in that of male and female rats. Sulfation of ortho-phenylphenol was the major metabolic pathway at low doses, accounting for 57 and 82% of the urinary metabolites in male mice dosed with 15 mg/kg bw and rats dosed with 28 mg/kg bw, respectively. Conjugates of 2-phenylhydroquinone accounted for 12 and 5%, respectively. Little or no free ortho-phenylphenol was present in the urine, and no free 2-phenylhydroquinone or 2-phenyl-1,4-benzoquinone was detected in either species. Dose-dependent shifts in metabolism were observed in mice for conjugation of ortho-phenylphenol, suggesting saturation of the sulfation pathway. Dose-dependent shifts in metab were observed in mice. the authors noted that their findings did not provide a metabolic explanation for the difference in carcinogenicity in rats and in mice. [R72] METB: *Dogs and cats also excrete urinary sulfonic acid and glucuronic acid metabolites of o-phenyl, although the parent compound predominates. [R47] *(14)C-ortho-Phenylphenol was applied onto the skin of the forearm of 6 volunteers for 8 hr at a dose of 0.4 mg/person (0.006 mg/kg bw). ... Sulfation was the major metabolic pathway, accounting for 69% of the metabolites, while conjugates of 2-phenylhydroquinone accounted for 15%. Little or no free ortho-phenylphenol was present in the urine, and no free 2-phenylhydroquinone or 2-phenyl-1,4-benzoquinone was detected. [R72] *ortho-Phenylphenol was converted to phenylhydroquinone by microsomal cytochrome P450 in vitro. Phenylhydroquinone was oxidized to phenylquinone by cumene hydroperoxide-supported microsomal cytochrome P450, and phenylquinone was reduced back to phenylhydroquinone by cytochrome P450 reductase, providing direct evidence of redox cycling or ortho-phenylphenol. [R73] *Incubation of the o-phenylphenol (OPP) metabolites, o-phenylhydroquinone (PHQ) and o-phenylbenzoquinone (PBQ) with V 79 Chinese hamster cells led to a significant enhancement of the amount of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in nuclear DNA. With OPP no distinct induction of this lesion could be observed. In addition, PHQ and PBQ were able to generate DNA single-strand breaks (DNA SSB), while OPP failed to induce this lesion. All incubations were performed for 1 h without exogenous metabolic activations and the lowest effective concentration tested was 20 microM. It is concluded that these metabolites may contribute to the carcinogenicity of OPP and sodium o-phenylphenolate (SOPP) observed in rats, by generating reactive oxygen species (ROS) through their redox cycling properties. [R74] *Chronic administration of o-phenylphenol (OPP) is known to induce urinary bladder tumours in the Fischer rat. The underlying toxic mechanism is poorly understood. Recently, arachidonic acid (ARA)-dependent, prostaglandin-H-synthase (PHS)-catalysed metabolic activation of the OPP metabolite phenylhydroquinone (PHQ) to a genotoxic species was suggested to be involved in OPP toxicity. To investigate this hypothesis in more detail, we have studied the effects of OPP and its metabolites on PHS. When microsomal PHS from ovine seminal vesicles (OSV) was used as enzyme source, both OPP, PHQ, and 2-phenyl-1,4-benzoquinone (PBQ) inhibited PHS-cyclooxygenase. The inhibitory potency was inversely related to the ARA concentration in the assay; at 7 microM ARA IC50-values were: 13 microM (OPP), 17 microM (PHQ), and 190 microM (PBQ). In cells cultured from OSV, which express high PHS activity, 40 microM OPP almost completely suppressed prostaglandin formation. Studies with microsomal PHS demonstrated that PHQ was an excellent substrate for PHS-peroxidase; both ARA and hydrogen peroxide supported oxidation to PBQ. OPP was only a poor substrate for PHS, but inhibited the ARA-mediated and to a lesser extent also the hydrogen peroxide-mediated in vitro oxidation of PHQ. Moreover, PHQ at up to moderately cytotoxic concentrations (50 microM) did not induce micronuclei in OSV cell cultures. Taken together, our findings do not provide evidence for an ARA-dependent, PHS-catalysed formation of genotoxic species from PHQ. Moreover, it seems to be questionable whether such activation can effectively occur in vivo, since OPP and PHQ turned out to be efficient cyclooxygenase inhibitors, and high levels of OPP and PHQ were found at least in the urine of OPP-treated rats. On the other hand, inhibition of the formation of cytoprotective prostaglandins in the urogenital tract may play a crucial role in OPP-induced bladder carcinogenesis. [R75] *The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (OPP) were followed in six human male volunteers given a single 8 h dermal dose of 6 microg OPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 h post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only). 2. Following dermal application, peak plasma levels of radioactivity were obtained within 4 h post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 h post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of OPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 h. Once absorbed the renal clearance of OPP was rapid with an average half-life of 0.8 h. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of OPP in humans was described by a 'flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data. 3. Approximately 73% of the total urinary radioactivity was accounted for as free OPP, OPP-sulfate and OPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (approximately 69%). Therefore, total urinary OPP equivalents (acid-labile conjugates+free OPP) can be used to estimate the systemically absorbed dose of OPP. 4. The rapid excretion of OPP and metabolites into the urine following dermal exposure indicates that OPP is unlikely to accumulate in humans upon repeated exposure. Based on these data, blood and/or urinary OPP concentration (acid-labile conjugates) could be utilized to quantify the amount of OPP absorbed by humans under actual use conditions. [R76] *1. Ortho-phenylphenol (OPP) was well absorbed in the male B6C3F1 mouse, with 84 and 98% of the administered radioactivity recovered in the 0-48-h urine of animals administered a single oral dose of 15 or 800 mg/kg respectively. High absorption and rapid elimination were also seen in the female and male F344 rat with 86 and 89% respectively of a single oral dose (27-28 mg/kg) found in the urine in 24 h. OPP was also rapidly eliminated from human volunteers following dermal exposure for 8 h (0.006 mg/kg), with 99% of the absorbed dose in the urine in 48 h. 2. Sulphation of OPP was found to be the major metabolic pathway at low doses in all three species, accounting for 57, 82 and 69% of the urinary radioactivity in the male mouse (15 mg/kg, p.o.), male rat (28 mg/kg, p.o.) and male human volunteers (0.006 mg/kg, dermal). OPP-glucuronide was also present in all species, representing 29, 7 and 4% of the total urinary metabolites in the low dose groups of mouse, rat and human volunteers respectively. 3. Conjugates of 2-phenylhydroquinone (PHQ) in these single-dose studies accounted for 12, 5 and 15% of the dose in mouse, rat and human, respectively. Little or no free OPP was found in any species. No free PHQ or PBQ was found in the mouse, rat or human (LOD = 0.1-0.6%). 4. A novel metabolite, the sulphate conjugate of 2,4'-dihydroxybiphenyl, was identified in rat and man, comprising 3 and 13% of the low dose respectively. 5. Dose-dependent shifts in metabolism were seen in the mouse for conjugation of parent OPP, indicating saturation of the sulphation pathway. Dose-dependent increases in total PHQ were also observed in mouse. 6. This study was initiated to elucidate a mechanistic basis for the difference in carcinogenic potential for OPP between rat and mouse. However, the minor differences seen in the metabolism of OPP in these two species do not appear to account for the differences in urinary bladder toxicity and tumour response between mouse and rat. [R77] *ortho-Phenylphenol (OPP), a fungicide and antibacterial agent with food residues, is carcinogenic to rat bladder. The present studies provide information on changes in urinary composition and urinary metabolites, urothelial cytotoxicity and regenerative hyperplasia, and DNA adducts in male F344 rats fed OPP. An initial experiment evaluated dietary doses of 0, 1,000, 4,000, and 12,500 ppm OPP fed for 13 weeks. There was no evidence of urinary calculi, microcrystalluria, or calcium phosphate-containing precipitate, but urothelial cytotoxicity and hyperplasia occurred at the highest dose only. In a second experiment, rats were fed dietary OPP levels of 0, 800, 4,000, 8,000, and 12,500 ppm. Urinary pH was > 7 in all groups. Urinary volume was increased at the 2 highest doses with consequent decreases in osmolality, creatinine, and other solutes. Total urinary OPP metabolite excretions were increased, mostly excreted as conjugates of OPP and of phenylhydroquinone. Free OPP or free metabolites accounted for less than 2% excreted in the urine without a dose response. Urothelial toxicity and hyperplasia occurred only at doses of 8,000 and 12,500 ppm. OPP-DNA adducts were not detected in the urothelium at any dose. In summary, OPP produces cytotoxicity and proliferation of the urothelium at dietary doses > or = 8,000 ppm without formation of urinary solids. The paucity of unconjugated metabolites and the lack of OPP-DNA adducts suggests that OPP is acting as a bladder carcinogen in male rats by inducing cytotoxicity and hyperplasia without it or its metabolites directly binding to DNA. [R56] *The generation of 8-hydroxydeoxyguanosine (8OHdG) in calf thymus DNA treated with O-phenylphenol (OPP) or its major metabolites, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), was studied. The content of 8OHdG residues was increased in DNA treated with PHQ, and the generation of 8OHdG was highly dependent on PHQ concentration. PBQ had little effect on the formation of 8OHdG, and OPP had no effect. The formation of 8OHdG by PHQ was reduced by oxygen radical scavengers such as catalase, sodium benzoate and sodium azide. The PHQ-induced 8OHdG formation was accelerated by the addition of CuCl or CuCl2 to the reaction mixture, but was decreased by the addition of chelating agents such as EDTA, bathocuproinedisulfonic acid disodium salt (bathocuproine disulfonate) and O-phenanthroline. These results demonstrate that hydroxyl radicals generated in the process of oxidation of PHQ contribute to the formation of 8OHdG in DNA, and copper ions facilitate the oxidative DNA damage. Copper ions greatly accelerated the PHQ-induced DNA cleavage in vitro, although they had no effect on cleavage without PHQ. On the other hand, DNA cleavage occurred by the addition of FeCl2 in the absence and presence of PHQ. FeCl2 stimulates 8OHdG formation only slightly with or without PHQ. Furthermore, the stimulatory effect of FeCl2 on 8OHdG formation was observed even in the presence of EDTA. The formation of 8OHdG in bladder DNA is likely to be one of a series of events leading to bladder tumors seen in rats fed OPP-containing diet. [R78] *Because of the expense involved in conducting chronic studies, limited numbers of animals and dose groups are used. This has given rise to the practice of including as one of the dose groups the "Maximum Tolerated Dose" (MTD). This dose is operationally defined as the highest dose which can be administered to animals without adversely affecting their survival through effects other than cancer. Since many detoxification systems in animals are capacity-limited, they frequently become saturated in MTD studies. This may lead to difficulties in interpreting the results of MTD studies, particularly when it is necessary to estimate the hazard for human populations whose exposure is typically much lower than the MTD. For this reason, it is important to characterize the dose-dependency of absorption, distribution, metabolism, and elimination (pharmacokinetics) of test substances prior to the initiation of a chronic study. This provides a basis for determining the number and spacing of doses to be used in a chronic study. If the appropriate information is collected it may also be possible to develop a physiologically based pharmacokinetic model which facilitates extrapolation of the toxicity results between different species and routes of administration as well as between high and low doses. For instance, methylene chloride and vinyl chloride are predominantly metabolized by saturable oxidative pathway(s) at low exposure concentrations. In each case, the oxidative pathway saturates at exposures much lower than the MTD. Knowledge of the pharmacokinetic behavior of these substances provided a basis for appropriately interpreting the chronic studies which have been conducted with these materials. [R79] *The relationship between the metabolism and the cytotoxicity of ortho-phenylphenol (OPP) was investigated using isolated rat hepatocytes. Addition of OPP (0.5-1.0 mM) to the hepatocytes caused a dose-dependent toxicity; 1.0 mM OPP caused acute cell death. Pretreatment of hepatocytes with SKF-525A (50 microM, a non-toxic level) enhanced the cytotoxicity of OPP (0.5-1.0 mM). This was accompanied by inhibition of OPP metabolism. Conversely, OPP at low concentrations (0.5 or 0.75 mM) was converted sequentially to phenyl-hydroquinol (PHQ) and then to glutathione (GSH) conjugate in the cells. The concentrations of both metabolites, especially PHQ-GSH conjugate, were very low in hepatocytes exposed to 1.0 mM OPP alone as well as with SKF-525A. The cytotoxicity induced by 0.5 mM OPP was enhanced by the addition of diethylmaleate (1.25 mM) which continuously depletes cellular GSH. In contrast, additions to hepatocytes of 5 mM of dithiothreitol, cysteine, N-acetyl-L-cysteine or ascorbic acid significantly inhibited the cytotoxicity induced by 0.5 mM PHQ; GSH, protein thiols and ATP losses were also prevented. Further, these compounds depressed the rate of PHQ loss in hepatocyte suspensions. These results indicate that the acute cytotoxicity caused by the high dose (1.0 mM) of OPP is associated with direct action by the parent compound; at low doses (0.5-0.75 mM) of OPP, the prolonged depletion of GSH in hepatocytes enhances the cytotoxicity induced by PHQ. [R80] *1. Ortho-phenylphenol (OPP) was well absorbed in the male B6C3F1 mouse, with 84 and 98% of the administered radioactivity recovered in the 0-48-h urine of animals administered a single oral dose of 15 or 800 mg/kg respectively. High absorption and rapid elimination were also seen in the female and male F344 rat with 86 and 89% respectively of a single oral dose (27-28 mg/kg) found in the urine in 24 h. OPP was also rapidly eliminated from human volunteers following dermal exposure for 8 h (0.006 mg/kg), with 99% of the absorbed dose in the urine in 48 h. 2. Sulphation of OPP was found to be the major metabolic pathway at low doses in all three species, accounting for 57, 82 and 69% of the urinary radioactivity in the male mouse (15 mg/kg, p.o.), male rat (28 mg/kg, p.o.) and male human volunteers (0.006 mg/kg, dermal). OPP-glucuronide was also present in all species, representing 29, 7 and 4% of the total urinary metabolites in the low dose groups of mouse, rat and human volunteers respectively. 3. Conjugates of 2-phenylhydroquinone (PHQ) in these single-dose studies accounted for 12, 5 and 15% of the dose in mouse, rat and human, respectively. Little or no free OPP was found in any species. No free PHQ or PBQ was found in the mouse, rat or human (LOD = 0.1-0.6%). 4. A novel metabolite, the sulphate conjugate of 2,4'-dihydroxybiphenyl, was identified in rat and man, comprising 3 and 13% of the low dose respectively. 5. Dose-dependent shifts in metabolism were seen in the mouse for conjugation of parent OPP, indicating saturation of the sulphation pathway. Dose-dependent increases in total PHQ were also observed in mouse. 6. This study was initiated to elucidate a mechanistic basis for the difference in carcinogenic potential for OPP between rat and mouse. However, the minor differences seen in the metabolism of OPP in these two species do not appear to account for the differences in urinary bladder toxicity and tumour response between mouse and rat. [R77] *(14)C-o-Phenylphenol (OPP) was found to bind covalently to calf thymus DNA during a 60 min incubation in the presence of microsomes, but not in their absence, indicating that metabolic conversion of the parent compound, OPP, to an activated form is essential. Postlabeling analysis with bladder DNA of rats fed a diet containing 2% OPP for 13 weeks revealed one major adduct on TLC. In an in vitro postlabeling experiment with calf thymus DNA, both of the major metabolites of OPP, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), formed adducts, but no adducts were observed with OPP. The chemical structure responsible for adduct formation is thought to be the PHQ semiquinone radical intermediate formed during interconversion between PHQ and PBQ. When the oligonucleotides, pd(A)12-18, pd(C)12-18, pd(G)12-18 and pd(T)12-18, were used in vitro, only pd(G)12-18 gave TLC-detectable adducts on treatment with PHQ and PBQ. The covalent binding appears to be rather specific to guanine residues. These results suggest that covalent binding of the OPP metabolite is one of the underlying events in OPP-induced carcinogenesis in rats. [R81] *The relationship between the metabolism and the cytotoxicity of ortho-phenylphenol (OPP) was investigated using isolated rat hepatocytes. Addition of OPP (0.5-1.0 mM) to the hepatocytes caused a dose-dependent toxicity; 1.0 mM OPP caused acute cell death. Pretreatment of hepatocytes with SKF-525A (50 microM, a non-toxic level) enhanced the cytotoxicity of OPP (0.5-1.0 mM). This was accompanied by inhibition of OPP metabolism. Conversely, OPP at low concentrations (0.5 or 0.75 mM) was converted sequentially to phenyl-hydroquinol (PHQ) and then to glutathione (GSH) conjugate in the cells. The concentrations of both metabolites, especially PHQ-GSH conjugate, were very low in hepatocytes exposed to 1.0 mM OPP alone as well as with SKF-525A. The cytotoxicity induced by 0.5 mM OPP was enhanced by the addition of diethylmaleate (1.25 mM) which continuously depletes cellular GSH. In contrast, additions to hepatocytes of 5 mM of dithiothreitol, cysteine, N-acetyl-L-cysteine or ascorbic acid significantly inhibited the cytotoxicity induced by 0.5 mM PHQ; GSH, protein thiols and ATP losses were also prevented. Further, these compounds depressed the rate of PHQ loss in hepatocyte suspensions. These results indicate that the acute cytotoxicity caused by the high dose (1.0 mM) of OPP is associated with direct action by the parent compound; at low doses (0.5-0.75 mM) of OPP, the prolonged depletion of GSH in hepatocytes enhances the cytotoxicity induced by PHQ., Tayama S, Moore GA, Moldeus P. Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan. The relationship between the metabolism and the cytotoxicity of ortho-phenylphenol (OPP) was investigated using isolated rat hepatocytes. Addition of OPP (0.5-1.0 mM) to the hepatocytes caused a dose-dependent toxicity; 1.0 mM OPP caused acute cell death. Pretreatment of hepatocytes with SKF-525A (50 microM, a non-toxic level) enhanced the cytotoxicity of OPP (0.5-1.0 mM). This was accompanied by inhibition of OPP metabolism. Conversely, OPP at low concentrations (0.5 or 0.75 mM) was converted sequentially to phenyl-hydroquinol (PHQ) and then to glutathione (GSH) conjugate in the cells. The concentrations of both metabolites, especially PHQ-GSH conjugate, were very low in hepatocytes exposed to 1.0 mM OPP alone as well as with SKF-525A. The cytotoxicity induced by 0.5 mM OPP was enhanced by the addition of diethylmaleate (1.25 mM) which continuously depletes cellular GSH. In contrast, additions to hepatocytes of 5 mM of dithiothreitol, cysteine, N-acetyl-L-cysteine or ascorbic acid significantly inhibited the cytotoxicity induced by 0.5 mM PHQ; GSH, protein thiols and ATP losses were also prevented. Further, these compounds depressed the rate of PHQ loss in hepatocyte suspensions. These results indicate that the acute cytotoxicity caused by the high dose (1.0 mM) of OPP is associated with direct action by the parent compound; at low doses (0.5-0.75 mM) of OPP, the prolonged depletion of GSH in hepatocytes enhances the cytotoxicity induced by PHQ. [R80] *o-Phenylphenol (OPP) and its sodium salt (SOPP) are broad spectrum fungicides and antibacterials to which humans are frequently exposed. Both OPP and SOPP have been found to cause cancer in the urinary bladder of male F344 rats at high doses, and the metabolite phenylhydroquinone (PHQ) is believed to play a key role in the carcinogenicity of these compounds. Tumor formation in the treated animals has also been shown to be significantly influenced by urinary pH. To provide additional insights into the mechanisms of OPP carcinogenesis, we have investigated the autoxidation of PHQ over the pH range commonly found in the urine of OPP- and SOPP-treated rats. Over the pH range studied (6.3-7.6), a curvilinear relationship between rate of PHQ oxidation and pH was observed. Phenylbenzoquinone (PBQ) was formed during the autoxidation of PHQ, with a formation yield of 0.92 +/- 0.02. In addition, the effects of PBQ and oxygen concentrations on PHQ autoxidation and the nonenzymatic conversion of PBQ to PHQ were also studied. Our data indicate that the production of reactive metabolites from PHQ involves a pH-independent (i.e., oxygen-dependent) and a pH-dependent pathway and that the rate of pH-dependent PHQ autoxidation was found to be enhanced by the presence of PBQ. A reaction mechanism has been formulated to explain the experimental data observed, with ionization of PHQ semiquinone being identified as a key step in reactive species production for the pH-dependent pathway. By combining data from OPP animal carcinogenicity studies with the proposed reaction pathway, a good correlation between the proposed formation of reactive species and bladder lesions was observed. These results indicate that the pH-dependent autoxidation of free PHQ metabolite in the urine may potentially be responsible for the tumorigenic effects of OPP and SOPP observed in the rat bladder. [R82] *We have previously demonstrated microsomal cytochromes P450-dependent redox cycling of o-phenylphenol and in vitro genotoxicity of o-phenylphenol. In the present work, we have investigated in vivo covalent modification in skin DNA by Na-o-phenylphenol using the 32P-postlabeling method in an attempt to understand the biochemical mechanism of promotion of chemical-induced skin carcinogenesis by Na-o-phenylphenol. Topical application of Na-o-phenylphenol or phenylhydroquinone, a hydroxylated metabolite of o-phenylphenol, to female CD-1 mice skin produced 4 distinct major and several minor adducts in skin DNA. The total covalent bindings in skin DNA produced by treatment of mice with 10 mg and 20 mg Na-o-phenylphenol (doses shown to be effective for tumor promotion) were 0.31 fmoles/microgram DNA and 0.62 fmoles/microgram DNA, respectively. The adducts were not observed in untreated animal skin DNA. Pretreatment of mice with alpha-naphthylisothiocyanate, an inhibitor of cytochromes P450, or indomethacin, an inhibitor of prostaglandin synthase, resulted in lower levels of DNA adducts produced by Na-OPP. The in vitro incubation of DNA with o-phenylphenol or phenylhydroquinone in the presence of cytochromes P450 activation or prostaglandin synthase activation system produced 4 major adducts. The adduct pattern observed in the presence of in vitro enzymatic activation systems appears to be similar in chromatographic mobility to the in vivo adduct pattern. The chemical reaction of DNA or deoxyguanosine monophosphate with pure phenylbenzoquinone, an electrophilic metabolite of o-phenylphenol, also produced 4 major and several minor adducts. The 4 major adducts obtained in chemical reaction of phenylbenzoquinone with deoxyguanosine monophosphate are identical in chromatographic mobility to those of in vivo or in vitro DNA adducts. The results of this study demonstrated that o-phenylphenol or phenylhydroquinone, a hydroxylated metabolite of o-phenylphenol, is able to covalently bind to DNA. DNA binding can be inhibited by the inhibitor of cytochromes, P450 alpha-naphthylisothiocyanate or prostaglandin synthase, indomethacin. One of the DNA-binding metabolite(s) of o-phenylphenol both in vivo and in vitro may be phenylbenzoquinone. We conclude that Na-OPP is genotoxic. Genotoxicity caused by Na-o-phenylphenol treatment in CD-1 mice may play a role in the promotion of dimethylbenz[a]anthracene-induced skin neoplasm. [R83] *The effects of cysteine and reduced glutathione (GSH) on the genotoxicity of o-phenylphenol (OPP) and its metabolites, phenylhydroquinone (PHQ) and phenylbenzoquinone (PBQ), were examined using the frequency of sister-chromatid exchanges (SCEs) and chromosome aberrations in CHO-K1 cells as parameters. Cytotoxic (cell-progression delay) and cytogenetic effects induced by a 3-h treatment with OPP, PHQ (100 micrograms/ml) or PBQ (50 micrograms/ml) with S9 mix after a 27-h expression time were inhibited by cysteine or GSH (3-10 mM). Materials corresponding to the cysteine or GSH adducts were found by HPLC in each incubation mixture. In the culture without S9 mix, PHQ and PBQ showed severe cytotoxicity since no metaphases could be obtained at doses over 25 and 5 micrograms/ml, respectively, and the sulfhydryl compounds inhibited the toxicity by the formation of adducts with PBQ and by inhibiting the formation of PBQ in the case of PHQ. With PHQ, the sulfhydryl compounds appeared to inhibit autooxidation. However, the sulfhydryl compounds did not inhibit the cytotoxic and cytogenetic effects caused by OPP in the cell mixture without S9 mix, but on the contrary intensified them. No adduct formation was detected in the incubation solution. On the basis of these results, it is considered that electrophilic quinone (PBQ) and/or semiquinone (phenylsemiquinone, PSQ) radicals, capable of binding to nucleophilic small molecules (such as cysteine and GSH) or (biological) macromolecules, are produced from metabolite PHQ in metabolic oxidation of OPP, and induce cyto- and geno-toxic effects in the cells. The cyto- and geno-toxic effects of OPP itself to the cells are clearly independent of any electrophilic radical reaction. [R84] *F344 male and female rats were administered 1.25% o-phenylphenol (OPP) or 2% sodium o-phenylphenate (Na-OPP) in combination with 3% NaHCO3 or 1% NH4Cl for 8 weeks and changes in the urinary bladder histopathology and the urinary components were examined. Administration of OPP with NaHCO3 resulted in marked urothelial hyperplasia in the urinary bladder of male rats, the response being less pronounced in females. OPP alone exerted no proliferative effect and NaHCO3 induced only slight hyperplasia in males. Na-OPP alone induced mild hyperplastic lesions only in males, this being completely prevented by concomitant administration of NH4Cl. The findings thus demonstrated a clear correlation between hyperplastic response and reported carcinogenic potential of these treatments. Of the urinary factors examined, increases in levels of pH and sodium ion concentration were positively associated with proliferative lesions especially in males, although the findings failed to explain the sex difference. Urinary concentrations of non-conjugated forms of OPP metabolites were also not directly correlated with the development of hyperplasias. Thus, changes in individual urinary factors presumably affect urothelial proliferation in combination rather than separately. The presence of OPP metabolites, including 2-phenyl-1,4-benzoquinone, in the urine may be unimportant in the OPP urinary carcinogenesis even under conditions of alkalinuria and high sodium ion concentration. [R85] *The role of urinary pH and Na+ concentration on the bladder carcinogenesis of o-phenylphenol (OPP) was examined in male F344 rats. The rats were given powered diet containing 2% sodium o-phenylphenate (OPP-Na, group 1), 1.25% OPP plus 0.64% NaHCO3 (group 2), 1.25% OPP plus 0.32% NaHCO3 (group 3), 1.25% OPP plus 0.16% NaHCO3 (group 4), 1.25% OPP (group 5), 0.64% NaHCO3 (group 6) or no test chemical (group 7) for 104 weeks respectively. Incidences of bladder carcinoma induced were significantly higher in groups 1 (12 of 29 rats, 41.4%) and 2 (9 of 29 rats, 31.0%) than in group 7 (0 of 27 rats, 0%). Groups 3 and 4 induced bladder carcinomas in 4 of 29 rats (13.8%) and 4 of 26 rats (15.4%) respectively, whereas no tumors occurred in group 5 (0 of 27, 0%). The incidence in group 6 was 3.6% (1 of 28 rats). Groups 1 and 2 induced significant increases in urinary pH and Na+ concentrations, whereas group 5 did not. Groups 3 and 4 showed the same tendency as groups 1 and 2. Examination with a scanning electron microscope showed the appearance of pleomorphic microvilli, short, uniform microvilli, and ropy or leafy microridges on the luminal surface of the bladder in groups 1-5 of rats treated with OPP or OPP-Na for 8 weeks. The appearance and severity were the same in groups 1 and 2, followed by the groups with decreasing doses of NaHCO3. The results indicated that OPP-Na is carcinogenic for the rat bladder, but OPP is not. However, increased urinary pH and Na+ concentration play important roles in OPP-Na rat bladder carcinogenesis. [R86] *Carbon-14 labeled sodium orthophenylphenate (SOPP) was incubated with purified microsomes isolated from rat liver. During this incubation, macromolecular binding of radioactivity (MMB) was observed. MMB was dependent upon the presence of both active microsomes and NADP. In vivo studies of MMB were also conducted. MMB was measured in the liver, kidney, and bladder of male F344 rats administered SOPP (0.19 to 1.88 mM/kg) or orthophenylphenol (OPP) (0.29 to 2.97 mM/kg). The levels of MMB were not linearly related to administered dose. Disproportionate increases in MMB were observed in each tissue after administration of 0.75 to 1.88 mM/kg of SOPP. Disproportionate increases in MMB in liver and bladder tissue were also observed with OPP at somewhat higher doses. These studies indicate that the intermediate(s) produced by the oxidative pathway for metabolism of SOPP and OPP are capable of binding to biological macromolecules. The disproportionate increases in MMB observed in vivo after high doses are probably associated with saturation of the primary (conjugative) metabolic pathway for SOPP and OPP metabolism. [R87] *We examined the metabolites of o-phenylphenol (OPP) in the urine of male and female rats dosed with 2% sodium o-phenylphenate (OPP-Na) in food from the age of 5 wk for 136 days. The urinary metabolites of OPP-Na produced during the 24 hr after OPP-Na feeding accounted for 55% of the dose in male rats and 40% in females. The main metabolites were OPP-glucuronide and 2,5-dihydroxybiphenyl (2,5-DHBP)-glucuronide. OPP metabolites in the free form accounted for only 1% of the total phenolic metabolites excreted. 2,5-DHBP was rapidly converted to the corresponding quinone in aqueous solvents but not in organic solvents. There was a clear sex difference in the proportions of urinary metabolites; the amount of 2,5-DHBP excreted by male rats in 24-hr urine was more than seven times that excreted by females. This result may be related to the finding that bladder tumours occur in male but not female rats fed OPP-Na in the diet. [R88] ACTN: *Coadministration of biphenyl and KHCO3 in the diet of male rats for 13 weeks produced urine crystals, which, by means of LC-MS/MS analyses, were determined to be composed of the potassium salt of 4-hydroxy-biphenyl-O-sulfate (4-HBPOSK). Biphenyl alone or biphenyl with KCl or NaHCO3 in the diet did not produce urine crystals. It was found that the higher concentration of potassium in the urine and the alkaline pH induced by feeding KHCO3 to rats resulted in the formation of urine crystals of 4-HBPOSK due to 4-HBPOSK solubility being lower in urine than in plasma. Urine crystals of 4-HBPOSK produced hyperplasia of the transitional epithelium of the ureter, ureteral obstruction, and hydronephrosis in the urinary tract. Copyright 2001 Academic Press. [R89] *Coadministration of biphenyl and KHCO3 in the diet of male rats for 13 weeks produced urine crystals, which, by means of LC-MS/MS analyses, were determined to be composed of the potassium salt of 4-hydroxy-biphenyl-O-sulfate (4-HBPOSK). Biphenyl alone or biphenyl with KCl or NaHCO3 in the diet did not produce urine crystals. It was found that the higher concentration of potassium in the urine and the alkaline pH induced by feeding KHCO3 to rats resulted in the formation of urine crystals of 4-HBPOSK due to 4-HBPOSK solubility being lower in urine than in plasma. Urine crystals of 4-HBPOSK produced hyperplasia of the transitional epithelium of the ureter, ureteral obstruction, and hydronephrosis in the urinary tract. [R90] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *o-Phenylphenol's production and use as a pesticide, household disinfectant, and food preservative may result in its direct release to the environment. o-Phenylphenol may be formed in the environment as a microbial metabolite of biphenyl. If released to air, a vapor pressure of 0.002 mm Hg at 25 deg C indicates o-phenylphenol will exist solely as a vapor in the ambient atmosphere. Vapor-phase o-phenylphenol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 14 hrs. o-Phenylphenol absorbs light in the environmental UV spectrum and may undergo direct photolysis. If released to soil, o-phenylphenol is expected to be immobile based upon an estimated Koc of 10,000. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 4.3X10-5 atm-cu m/mole. o-Phenylphenol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation is expected to occur based on the results of the Japanese MITI test where o-phenylphenol reached 47-86% of its theoretical BOD in 2 weeks. If released into water, o-phenylphenol is expected to adsorb to sediment and suspended solids in water based upon the estimated Koc. Biodegradation in water is expected based on a 50% reduction of o-phenylphenol concentration within 1 week in river water from Midland, MI. Volatilization from water surfaces may occur based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 19 hrs and 13 days, respectively. However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is 16 months if adsorption is considered. An estimated BCF of 48 suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to o-phenylphenol may occur through inhalation and dermal contact with this compound at workplaces where o-phenylphenol is produced or used. The general population may be exposed to o-phenylphenol via inhalation of indoor and outdoor air, ingestion of food and drinking water, and dermal contact with this compound and household disinfectant products, such as "Lysol", containing o-phenylphenol. o-Phenylphenol is widely detected in foods based on its use as a food preservative. (SRC) NATS: *o-Phenylphenol may be formed in the environment as a microbial metabolite of biphenyl(1). [R91] ARTS: *o-Phenylphenol's production and use as a pesticide and household disinfectant(1)is expected to result in its direct release to the environment(SRC). Other uses which may result in its release to the environment include its use in rubber chemicals, in food packaging, as an intermediate for dyes(2), and as a food preservative(3). [R92] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 10,000(SRC), determined from a structure estimation method(2), indicates that o-phenylphenol is expected to be immobile in soil(SRC). Volatilization of o-phenylphenol from moist soil surfaces may be an important fate process(SRC) given a Henry's Law constant of 4.3X10-5 atm-cu m/mole(3). However, adsorption to soil is expected to attenuate volatilization(SRC). Biodegradation is expected to occur based on the results of the Japanese MITI test where o-Phenylphenol, present at 30 mg/l, reached 47-86% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 100 mg/l(4). o-Phenylphenol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.002 mm Hg(5). [R93] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 10,000(SRC), determined from an estimation method(2), indicates that o-phenylphenol is expected to adsorb to sediment and suspended solids in water(SRC). Volatilization from water surfaces is expected to occur(3) based upon a Henry's Law constant of 4.3X10-5 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 19 hrs and 13 days, respectively(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is 16 months if adsorption is considered(5). Biodegradation in water is expected to occur based on an experiment using carbon-14 labeled o-phenylphenol, where 50% reduction was observed in approximately 1 week in river water from Midland, MI(6). According to a classification scheme(7), estimated BCF of 48(SRC) from a log Kow of 3.09(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is moderate. [R94] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), o-phenylphenol, which has a vapor pressure of 0.002 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase o-phenylphenol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 14 hrs(SRC), determined using a structure estimation method(3). Reaction to nitrate radical may be important based on o-phenylphenol structural similarity to phenol. Phenol has a half-life of 12 minutes in night-time air based on its reaction with nitrate radical; the rate constant for this reaction is 3.8X10-12 cu cm/molecule sec(4). By analogy to phenol, o-phenylphenol may degrade very rapidly in night-time air(4). o-Phenylphenol oxidizes in contact with air to form phenylbenzoquinone(5). [R95] BIOD: *Persistence of 50 ppm o-phenylphenol in an activated sludge screening test was less than 9 days(1); an initial concn of 50 ppm was reduced 30% in 7 days in an anaerobic digestion test(1); an initial concn of 100 ppm was reduced 43% in 54 hr in an aerated lagoon simulation(1); an initial concn of 100 ppm was reduced 20% in 168 hr in retention pond simulation(1). Acclimated treatment plant cultures completely degraded 50 ppm o-phenylphenol within 30 hr in a BOD study(2). In an aerobic BOD dilution study using an activated sludge inocula, 100-150 ppm were completely degraded in 8-16 days, although lag periods of 5-13 days were observed(3). Five-day theoretical BODs of 1.2-29.7% were measured using 1-50 ppm o-phenylphenol with the theoretical BOD generally decreasing with an increase in concn(4). In Sapromat respirometer studies using industrial activated sludge, inoculum from a communal clarification plant, or a sewage inocula, 5-day theoretical BODs ranged from 50-100%(5). [R96] *Incubation of 10-40 ppm o-phenylphenol for 21 days in mineral salts solutions containing synthetic sewage, resulted in 100% degradation under both aerobic and anaerobic conditions(1). Using the EEC manometric respirometer method, o-phenylphenol was observed to undergo mean theoretical BODs of 76 and 85% after 10 and 28 respective days of incubation(2). Using carbon-14 labeled o-phenylphenol, a 50% reduction was observed in approximately 1 week in river water from Midland, MI, 24 hr in non-acclimated sludge, and 3 hr in acclimated sludge(3); conversion of o-phenylphenol to 14-CO2 was about 50-65% after 16 days in the river water and 48 hr in the activated sludge(3). [R97] *AEROBIC: After 3 weeks of adaption of o-phenylphenol at 10-40 mg/l and 22 deg C, 100% degradation occurred under aerobic and anaerobic conditions, with o-phenylphenol being used as the sole carbon source(1). o-Phenylphenol, present at 30 mg/l, reached 47-86% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 100 mg/l and the Japanese MITI test(2). [R98] *ANAEROBIC: After 3 weeks of adaption of o-phenylphenol at 10-40 mg/l and 22 deg C, 100% degradation occurred under aerobic and anaerobic conditions, with o-phenylphenol being used as the sole carbon source(1). The degradation potential of o-phenylphenol under methanogenic conditions was examined with an anaerobic digesting sludge from the United Kingdom(2). It was found that o-phenylphenol inhibited anaerobic degradation(2). However, high concentrations of o-phenylphenol were used in the experiment which could have inhibited microbial degradation(2). In a closed bottle test, o-phenylphenol reached 84% of its theoretical oxygen demand(3). At 16 mg/l, o-phenylphenol was found to inhibit biodegradation(3). The metabolic fate of o-phenylphenol under different anaerobic conditions was tested with sediment slurries and enrichment cultures obtained from a shallow anoxic aquifer(4). In a sulfate-reducing slurry, o-phenylphenol degraded at a rate of 2.12 uM/day with 97% degradation after 22 days incubation(4). In a methanogenic slurry, o-phenylphenol was degraded at a rate of 1.65uM/day with 70% degradation after 22 days(4). [R99] ABIO: *The rate constant for the vapor-phase reaction of o-phenylphenol with photochemically-produced hydroxyl radicals has been estimated as 2.7X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 14 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). At 50 deg C, the vapor-phase reaction of o-phenylphenol with photochemically-produced hydroxyl radicals is 1.8X10-11 cu cm/molecule-sec(2). o-Phenylphenol coated on filter paper was found to react with nitrogen oxides in urban air and in a reaction chamber to yield 3-nitro-, 5-nitro, and 3,5-dinitrophenylphenol(3); the reaction occurred in the dark, although the presence of light accelerated the reaction rate(3). Reaction to nitrate radical in night-time air may be important based on o-phenylphenol's structural similarity to phenol. Phenol has a half-life of 12 minutes in night-time air based on its reaction with nitrate radical; the rate constant for this reaction is 3.8X10-12 cu cm/molecule sec(4). By analogy to phenol, o-phenylphenol may degrade very rapidly in night-time air(4). o-Phenylphenol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(5). In both dilute aqueous and hexane solutions, o-phenylphenol exhibits a UV absorption max at 282 nm with decreasing absorption extending into the environmental spectrum to slightly above 310 nm(6,7). This absorption suggests a potential for direct photolysis in the environment(SRC). When o-phenylphenol was exposed to sunlight in a neutral aqueous nitrate solution, it completely degraded in 14 days(8). However, when it was kept in the dark, only 20% of the initial concentration of o-phenylphenol degraded after 56 days(8). When o-phenylphenol was irradiated at 253.7 nm in acidic solution, three main degradation products were formed(9). These included phenylhydroquinone, phenylbenzoquinone, and 2-hydroxydibenzofuran(9). o-Phenylphenol oxidizes in contact with air to form phenylbenzoquinone(10). [R100] BIOC: *An estimated BCF of 48 was calculated for o-phenylphenol(SRC), using a log Kow of 3.09(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate. However, bioconcentration studies on compounds which are structurally similar suggest that bioconcentration may be lower than that indicated by the regression-derived equations due to the ability of aquatic organisms to readily metabolize this class of compounds. Animals excrete o-phenylphenol as the parent compound and as the glucuronide and sulfate conjugates(4). [R101] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for o-phenylphenol can be estimated to be 10,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that o-phenylphenol is expected to be immobile in soil. In laboratory aqueous sorption studies using two types of bentonite clay, between 47 and 96.4 percent of added o-phenylphenol was sorbed after 24 hr(3). [R102] VWS: *The Henry's Law constant for o-phenylphenol is 4.3X10-5 atm-cu m/mole(1). This Henry's Law constant indicates that o-phenylphenol is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 19 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 13 days(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is 16 months if adsorption is considered(4). Laboratory tests involving both aerated and non-aerated aqueous solutions of o-phenylphenol found only slight volatilization(5). o-Phenylphenol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). o-Phenylphenol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.002 mm Hg(6). [R103] WATC: *DRINKING WATER: o-Phenylphenol was qualitatively detected in drinking water sampled from Ames, IA in 1972(1). o-Phenylphenol has been found in West German drinking water at a concn of 0.02 ppb(2). [R104] *GROUNDWATER: o-Phenylphenol was qualitatively detected in groundwater in Australia apparently polluted from wastes being dumped in quarry holes(1). [R105] *SURFACE WATER: o-Phenylphenol was detected at concns generally below 0.1 ppb in the River Lee in England(1). Qualitative detections have been reported for Japanese river water(2). An unspecified isomer of phenylphenol was detected at a concn of 0.3 ppb in the Delaware River in Mar 1977(3). o-Phenylphenol was detected in Delaware River water samples at 0.3 ppb in winter but was not detected in summer time(4). o-Phenylphenol has been detected in rivers, lakes, drinking water supplies, and marine sediments in Europe, the United States, and China(5). In monthly intervals, water samples collected from the Halls Brook Holding Area (a small artificial lake) in Woburn, MA from Sept 1995-Sept 1996 and analyzed for o-phenylphenol(5). Concns of o-phenylphenol ranged from < 0.1-100 ug/l in the upper 3.3 meters of the lake(5). o-Phenylphenol was detected at concns generally below 0.1 ppb in the River Lee in England(6). Qualitative detections have been reported for Japanese river water(7). An unspecified isomer of phenylphenol was detected at a concn of 0.3 ppb in the Delaware River in March 1977(8). [R106] EFFL: *o-Phenylphenol was detected in raw wastewater from a textile finishing plant, probably from use as a dye carrier(1). Wastewater sampled from publicly owned treatment works in Decatur, IL and Bensenville, IL in 1980 contained o-phenylphenol(2). Levels of less than 0.008 ppm were found in sewage samples taken from Phoenix, AZ, but no detections were made in groundwater samples following a rapid infiltration method of sewage disposal(3). o-Phenylphenol was detected in discharges from two of five US leather tanning plants in 1978 and in effluent and sludge from a water treatment plant in Putnam, CT(4). In a four year study carried out in West Germany, o-phenylphenol was found at levels of 0.1-10 ppb in samples from a water filtration plant, at levels of < 1-95 ppb in sanatoria wastewater, and at levels 0.1-1.0 ppb in Ruhr River water(4). Composite five to seven day samples of chlorinated and unchlorinated primary-treated municipal wastewater were collected at the Iona Island treatment plant in Vancouver, Canada during a 62 day exposure of juvenile chinook salmon from June-August 1983(5). o-Phenylphenol was detected, concn not specified, in the base/neutral fraction of Iona Island wastewater and sludge(5). [R107] ATMC: *URBAN/SUBURBAN: The mean concn of o-phenylphenol in outdoor air samples in summer(1986) and winter(1988) at 1.2 and 0.1 ng/cu m, respectively; and in personal air samples in summer(1986), spring(1987) and winter(1988) at 79.7, 55.6 and 39.7 ng/cu m, respectively(1). Overall, an annual average daily concn of o-phenylphenol in Jacksonville, Florida air was determined to be 57.7 ng/ cu m(1). o-Phenylphenol was also detected in outdoor air samples in spring(1987) at 1.6 ng/cu m; and in personal air samples in spring(1987) and winter(1987) at 16.2 and 11.3 ng/cu m, respectively(1). The annual average daily concn of o-phenylphenol in Springfield, Massachusetts air was 39.4 ng/cu m(1). o-Phenylphenol was detected, concn not specified, in ambient air samples taken from Lake Charles, LA(2). [R108] *INDOOR: o-Phenylphenol was detected in 5 indoor air and 4 outdoor air samples collected at 9 residential sites in the southeastern US in Aug 1985(1); presence of the o-phenylphenol in these air samples was attributed to household use of disinfectants and fungicides(1). The mean concn of o-phenylphenol in indoor air samples taken in Jacksonville, Florida for summer(1986), spring(1987) and winter(1988) were 96.0, 70.4, and 59.0 ng/cu m, respectively(2). o-Phenylphenol was also detected in indoor air samples taken from Springfield, Massachusetts in spring and winter(1987) at 44.5 and 22.8 ng/cu m, respectively(2). o-Phenylphenol has a typical indoor concn of 60 ng/cu m(3). Eight weeks after applying o-phenylphenol at an average concn of 63.0 ng/cu m to seven New Jersey homes in mid-September, it was detected in indoor air samples at an average conc of 35.8 ng/cu m(4). [R109] FOOD: *In a compilation of various data from US Food and Drug Administration studies for fiscal years 1970-1976, o-phenylphenol was positively detected in 101 of 448 large domestic fruit samples at an avg concn of 0.293 ppm(1); it was infrequently detected in fish and shellfish (1 positive sample), in leaf and stem vegetables (10 positive samples), and in vine and ear vegetables (5 positive samples)(1). In an analysis of imported fruits and bananas in Kyoto, Japan, o-phenylphenol residues of 0.1-3.2 ppm were found in all citrus fruits, but no residues were found in bananas(2). o-Phenylphenol concns of 2.3 ppm were found in whole lemons used for making marmalade(3). [R110] *Analysis of 324 food composites collected from 27 US cities between Oct 1980 and Mar 1982 (as part of the US FDA Total Diet Studies) detected o-phenylphenol in 2 cereal and grain products at an avg concn of 0.007 ppm(1). Analysis of 240 food composites collected from 20 US cities between Oct 1979 and Sept 1980 (as part of the US FDA Total Diet Studies) detected o-phenylphenol in 1 fruit product at a concn of 0.005 ppm(2). Analysis of 2250 food composites collected from US cities between Jun 1969 and July 1976 (as part of the US FDA Total Diet Studies for fiscal years 1970-1976) detected o-phenylphenol in 27 composites (primarily fruits) at levels ranging from a trace (0.001 ppm) to 0.40 ppm(3). [R111] *The concn of o-phenylphenol found in foods as a preservative range from 10-12 ppm(1). Fourteen kinds of fruits, 22 kinds of vegetables, and 7 other food items were selected to represent the average Belgian diet from April 1991-March 1993 and analyzed for pesticide content(2). o-Phenylphenol was detected in 27.3% of orange and lemon samples with a mean concn of 0.153 ppm for oranges and 0.133 ppm for lemons(2). The pesticide content of 27,065 food samples from CA, FL, IN, MA, MI, NC, NY, OR, VA and WI were analyzed for fiscal years 1988-89(3). o-Phenylphenol was not detected in fiscal year 1988 but was detected in fiscal year 1989 in 0.053% of the samples with 2 samples having significantly high levels (concn exceeded state or federal tolerance level)(3). In 1990, 15,919 food samples acquired from 18 states (AR, CA, CT, DE, FL, GA, IN, ME, MI, MN, NY, OR, PA, RI, VA, WA, WI, WY) were analyzed and found to have detectable amounts of o-phenylphenol (concn not specified)(4). [R112] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Biliary levels of 2-phenylphenol in trout taken from five remote European lakes were as follows (ng/ml): Ovre Neadalsvatn (Norwegian Mountains), 55.7; Bedoichov (Czech Jizera Mountains, Black Triangle), 70.4; Gossenkoelless (Austrian Alps), 25.2; Aube (French Pyrenees), 20.6; Redo (Spanish Pyreness), 28.6(1). [R113] OEVC: *House dust collected from four houses in two residential areas of Seattle, WA contained o-phenylphenol at a concn of 0.49 ppm(1). In a study of the chemicals present in household dust taken from homes of more than 250 children with acute lymphocytic leukemia and 250 control children in nine states, o-phenylphenol was detected in 96% of all samples at a median concn of 0.48 ug/g(2). o-Phenylphenol was not detected (detection limit = 75 ng/g) in dust samples from seven New Jersey homes from mid-September and mid-November 1991(3). House dust samples from residences in the Research Triangle area of North Carolina ranged from 0.07 ug/g in course dust samples (< 2mm) to 1.20 ug/g in fine dust samples (< 4 um)(4). [R114] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 617,394 workers (379,044 of these are female) are potentially exposed to o-phenylphenol in the US(1). The NOES Survey does not include farm workers. Occupational exposure to o-phenylphenol may occur through inhalation and dermal contact with this compound at workplaces where o-phenylphenol is produced or used(SRC). The general population may be exposed to o-phenylphenol via inhalation of indoor and outdoor air(2,3), ingestion of food(4) and drinking water(5), and dermal contact with this compound and household disinfectant products, such as "Lysol"(6), containing o-phenylphenol(SRC). [R115] AVDI: *FOOD INTAKE: The 1971-1976 US dietary intake of o-phenylphenol has been calculated to be 0.03 ug/kg body wt/day(1). Based on results from the USFDA's Total Diet Studies, the US dietary intake for fiscal years 1978, 1979, 1980, and 1981/82 has been estimated to be 0.038, 0.046, 0.015, and 0.047 ug/kg body wt/day(2). [R116] BODY: *Adipose specimens collected in the United States in fiscal year 1982 were analyzed for general volatile and semivolatile organic compounds. Of 46 samples collected, o-phenylphenol was detected in 22 samples (5 samples from people between the ages of 0-14 yrs, 6 samples from people between the ages of 15-44 and 11 samples from people aged 45 or greater)(1). In an analysis of serum from 10 infants exposed to germicidal solutions containing o-phenylphenol, o-phenylphenol was found in the serum of 7 infants at levels of 500-1900 ng/ml(2). In a study comparing semen samples from Danish farmers consuming organically grown commodities as opposed to traditional farmers, the acceptable daily intake of o-phenylphenol among organic farmers was 0.02 mg/kg/day, 1.1% above the acceptable daily intake(3). [R117] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *FAO/WHO ADI: 0.02 mg/kg [R118] ATOL: *Tolerances are established for combined residues of the fungicide o-phenylphenol and sodium o-phenylphenate, each expressed as o-phenylphenol, from postharvest application of either in or on the following raw agricultural commodities (expressed in ppm): apples 25; cantaloupes (not more than 10 ppm in edible portion) 125; carrots 20; cherries 5; citrus 10; citron 10; cucumbers 10; grapefruit 10; kiwifruit 20; kumquats 10; lemons 10; limes 10; nectarines 5; oranges 10; peas 25; peppers (bell) 10; peaches 20; pineapples 10; plums (fresh prunes) 20; sweet potatoes 15; tangerines 10; tomatoes 10. [R119] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 18 ug/l [R120] FIFR: *Tolerances are established for combined residues of the fungicide o-phenylphenol and sodium o-phenylphenate, each expressed as o-phenylphenol, from postharvest application of either in or on the following raw agricultural commodities: apples; cantaloupes; carrots; cherries; citrus; citron; cucumbers; grapefruit; kiwifruit; kumquats; lemons; limes; nectarines; oranges; peas; peppers (bell); peaches; pineapples; plums (fresh prunes); sweet potatoes; tangerines; tomatoes. [R119] *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. o-Phenylphenol is found on List B. Case No: 2575; Pesticide type: fungicide, antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): o-Phenylphenol; Data Call-in (DCI) Date(s): 08/02/91, 05/12/95, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R121] FDA: *ortho-Phenylphenol (for use as a preservative only) is an indirect food additive for use only as a component of adhesives. [R122] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *(IN CONCN ORANGE JUICE) DILUTED SAMPLE IS DISTD. GAS CHROMATOGRAPHIC ANALYSIS ... PERFORMED. FREE FROM BULK OF FRUIT BY STEAM DISTN BEFORE SEPN ... BY SOLN IN ALKALI; DETERMINE COLORIMETRICALLY ... . [R8, 452] *SEPARATION AND ASSAY BY HIGH PRESSURE LIQUID CHROMATOGRAPHY, OF BIPHENYL AND ITS HYDROXYLATED DERIVATIVES. [R123] *ANALYSIS OF AIR SAMPLES BY GAS CHROMATOGRAPHY. [R124] *Residues in fruit wrappers or citrus peel /are/ determined by colorimetry of derivatives, by hplc, or by glc. [R49, 794] *EPA-B Method PMD-PFH.l Determination of Phenols and Chlorophenols by Gas Chromatography (TCD-IS-BSA Derivatization). [R125] *FDA Method 232.4. Organophosphorous Residues General Methods for Nonfatty Foods Using Acetone Extraction and Isolation in Organic Phase [R125] CLAB: *Standard method for the analysis of orthophenylphenyl in urine by using liquid chromatography/ultraviolet detection. The limit of detection is 1-2 mg/l. [R126] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of ortho-Phenylphenol Alone and With 7,12-Dimethylbenz(a)anthracene in Swiss CD-1 Mice (Dermal Studies) Technical Report Series No. 301 (1986) NIH Publication No. 86-2557 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 87 (1978) R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 869 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA16 (1990) 564 R4: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1257 R5: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 690 R6: Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley and Sons. New York, N.Y. (2001). R7: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on 2-Phenylphenol (90-43-7). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of February 6, 2002. R8: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. R9: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 R10: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (1992) 233 R11: SRI International. 2001 Directory of Chemical Producers. SRI Consulting, Menlo Park, CA. 2001. 792 R12: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 660 R13: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R14: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 969 R15: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA8 (1987) 557 R16: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V8 (1993) 249 R17: SRI R18: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. 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V30 334 (1983) RS: 127 Record 149 of 1119 in HSDB (through 2003/06) AN: 1762 UD: 200211 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ROTENONE- SY: *BARBASCO-; *(1)BENZOPYRANO(3,4-B)FURO(2,3-H)(1)BENZOPYRAN-6(6AH)-ONE, 1,2,12,12A-TETRAHYDRO-8,9-DIMETHOXY-2-(1-METHYLETHENYL)-, (2R-(2ALPHA,6AALPHA, 12AALPHA))-; *(1)BENZOPYRANO(3,4-B)FURO(2,3-H)(1)BENZOPYRAN-6(6AH)-ONE, 1,2,12,12A-TETRAHYDRO-2-ALPHA-ISOPROPENYL-8,9-DIMETHOXY-; *(1)BENZOPYRANO(3,4-B)FURO(2,3-H)(1)BENZOPYRAN-6(6ALPHAH)-ONE, 1,2,12,12AALPHA-TETRAHYDRO-2ALPHA-ISOPROPENYL-8,9-DIMETHOXY-; *CENOL-GARDEN-DUST-; *Chem-Fish-Synergized-; *CHEM-MITE-; *Cube-; *CUBE-EXTRACT-; *CUBE-PULVER-; *CUBE-ROOT-; *CUBOR-; *CUREX-FLEA-DUSTER-; *DACTINOL-; *DERIL-; *DERRIN-; *DERRIS-; *Dri-kil-; *ENT-133-; *EXTRAX-; *FISH-TOX-; *Foliafume-E.C.-; *GREEN-CROSS-WARBLE-POWDER-; *HAIARI-; *LIQUID-DERRIS-; *MEXIDE-; *NCI-C55210-; *NICOULINE-; *Noxfire-; *NOXFISH-; *Nusyn-Noxfish-; *Paraderil-; *PB-Nox-; *POWDER-AND-ROOT-; *Prenfish-; *PRENTOX-; *Prentox-Synpren-Fish-; *PRO-NOX-FISH-; *RO-KO-; *RONONE-; *Rotacide-E.C.-; *ROTEFIVE-; *ROTEFOUR-; *ROTENON-; *Rotenona-; *(-)-ROTENONE; *5'BETA-ROTENONE-; *ROTESSENOL-; *ROTOCIDE-; *1,2,12,12a-Tetrahydro-8,9-dimethoxy-2-(1-methylethenyl)-[1]benzopyrano[3,4-b] furo[2,3-h][1]benzopyran-6(6aH)-on; *[2R-(2ALPHA,6AALPHA,12AALPHA)]-1,2,12,12A-TETRAHYDRO-8,9-DIMETHOXY- 2-(1-METHYLETHENYL)[1]BENZOPYRANO[3,4-B]FURO[2,3-H]BENZOPYRAN-6(6AH)-ON; *1,2,12,12AALPHA-TETRAHYDRO-2A-ISOPROPENYL-8,9-DIMETHOXY[1] BENZOPYRANO[3,4-B]FURO[2,3-H][1]BENZOPYRAN-6(6AH)-ON; *TUBATOXIN-; *TUBOTOXINE- RN: 83-79-4 MF: *C23-H22-O6 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The current methods of extraction of rotenone and other natural insecticides from their plant sources are enhanced by mixing the known solvents such as dialkyl phthalates, dichloromethane, or trichlormethane at 10-70% with 30-90% of (C)8-20 aliphatic acid esters with (C)1-16 alkyls or alkenyls. Thus, agitation of 100 g dichloromethane at 45 deg for 0.5 hr, followed by removal of dichloromethane by distillation gave an extraction containing 14% rotenone plus 64% octyl stearate. The extraction was diluted to 7% rotenone and emulsified by a surfactant for spraying plants. [R1] *Pure crystalline rotenone is prepared by extracting powdered rotenone containing roots with a solvent, eg ether or carbon tetrachloride, and concentrating the solution to produce crystallization. [R2] *Produced in Malaysia from Derris elipitica roots and in South America from Lonchocarpus roots; white crystalline solid separated from the root by solvent extraction followed by crystallization. [R3] FORM: *Prentox Prenfish toxicant (5% rotenone); Prentox Synpren-Fish toxicant (2.5% rotenone and 2.5% piperonyl butoxide technical); Prentox, Rotenone Powder and Resins. Chem-Fish Synergized is 2.5% rotenone and 2.5% piperonyl butoxide; Chem-Fish Regular is 5%; Rotenone Resin (Blue Spruce) 45%; Rotenone Powder (Blue Spruce) at 5 to 7.5% pure. Rotenone Soln FK-11 (piperonyl butoxide 2.5% and rotenone 1.5%) (Fairfield American). [R4, p. C-200] *Formulations incl dusts of 0.75 to 1.5% concn, emulsifiable concentrates of 2 to 3% concn, wettable powder of 5% concn, soln of up to 5% concn, and resins of 30% concn intended for manufacture. [R5] *Grades: CP crystals; technical; also as extracts of derris and cube root. [R6] *Formulations include dusts of 0.75-5% concentration, crystalline preparations of 97% purity, and emulsified solution of up to 50% and resins of 42-45% concentration intended for manufacture. [R7, 600] *... Noxfire (5% rotenone) tank mixed with Roussel Bio Corp piperonyl butoxide EC92% for insects which have become resistant to pyrethroid-based insecticides. Nusyn-Noxfish (2.5% rotenone/2.5% piperonyl butoxide technical). Foliafume E.C. (pyrethrins) ... PB-Nox (4.3% rotenone/8.6% piperonyl butoxide). [R8, p. C-314] *Dust, emulsifiable concentrate, wettable powder [R9] MFS: *Prentiss Inc, CB 2000, Floral Park, NY 11002-2000 (516) 326-2312 [R8, p. C-313] *Roussel Uclaf Corp, 95 Chestnit Ridge Rd, Montvale, NJ 07645 (201) 307-3281 [R8, p. C-313] *Tifa Ltd, 50 Division Ave, Millington, NJ 07946 (908) 647-4570 [R8, p. C-313] OMIN: *USEFUL...TO ELIMINATE UNDESIRABLE FISH SPECIES WHICH MAY DOMINATE FARM PONDS, ENABLING DESIRABLE SPECIES TO BE REESTABLISHED. [R10] *IT HAS...BEEN EMPLOYED CLINICALLY FOR EXTERNAL TREATMENT OF CHIGGERS (2% LOTION) AND SCABIES (10% EMULSION). [R11, p. III-366] *ITS USE FOR LOUSE CONTROL ON HUMANS IS NOT RECOMMENDED SINCE IRRITATION IS OFTEN PRODUCED, ESP IN GROIN REGION. ...WIDELY USED TO CONTROL PESTS SUCH AS MEXICAN BEAN BEETLE, CABBAGE WORMS, LEAF HOPPERS AND OTHER INSECTS...IT IS ESP USEFUL FOR APPLICATION TO VEGETABLES NEAR TIME FOR HARVEST WHEN CERTAIN...EFFECTIVE NEWER INSECTICIDES CANNOT BE USED BECAUSE OF POTENTIALLY EXCESSIVE RESIDUES. ...USED FOR CONTROLLING INSECT PARASITES OF ANIMALS. IT IS EFFECTIVE FOR CONTROLLING CATTLE GRUBS, AND IS EMPLOYED ALSO FOR LICE, FLEAS, AND TICKS ON PETS AND LIVESTOCK. [R12] *SELECTIVE CONTACT INSECTICIDE WITH SOME ACARICIDAL PROPERTIES. CUBE (GENUS LONCHOCARPUS) IS NOW THE ONLY COMMERCIAL SOURCE IN USA OF ROTENONE FOR INSECTICIDE PRODUCTION... PERU IS MAJOR SOURCE OF ROOT OF PLANT... ROOTS ARE PREPARED FOR USE IN INSECTICIDES BY...EXTRACTING INSECTICIDAL PRINCIPLES WITH ACETONE, CARBON TETRACHLORIDE, BENZENE, OR OTHER SOLVENTS... FORMULATIONS LOSE THEIR EFFECTIVENESS WITHIN A WK AFTER APPLICATION. [R8, p. C-313] */Rotenone/ is of low persistence in spray or dust residues. [R13, 741] *The (13)C NMR spectra of epimers of rotenone and 4 12a-hydroxy-analogs were examined to determine the stereochemical effect of B/C ring fusion involving the 6a- and 12a-C centers. Chemical shift differences between the epimeric carbon resonances of cis- and trans-6a, 12a-cmpd were notably larger than those of diastereoisomers derived from the same B/C ring junction stereochemically. Results of the spectral analysis are useful for the quantification of mixtures of epimers and for the measurement of rates of epimerization and oxygenation. [R14] USE: *Control of aphids, thrips, psyllids, moths, beetles, spider mites, etc in fruit and vegetable cultivation. Insecticidal control of premises. Control of fire ants. Control of lice, ticks, and warble flies on animals. Also used to control fish populations in fish management. [R15] *Flea powders, fly sprays, moth-proofing agents; insecticide. [R6] *In the form of ground derris root, rotenone has been used as a nonpersistent insecticide to control pests on plants and animals and as a fish poison to manage or to eliminate undesirable species in reservoirs, lakes, and streams. [R16] *Acaricide; insecticide [R3] *MEDICATION *MEDICATION (VET) *Rotenone is very toxic to fish, and one of its main uses by native people over the centuries was to paralyze fish for capture and consumption. [R17, 669] CPAT: *21% USED ON CROPS; 78% USED ON LIVESTOCK; 1% FOR OTHER APPLICATIONS (1975) [R18] PRIE: U.S. PRODUCTION: *(1971) 1.4X10+7 GRAMS (CONSUMPTION) [R18] *(1974) 2.27X10+7 GRAMS (CONSUMPTION) [R18] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORTHORHOMBIC, SIX-SIDED PLATES FROM TRICHLOROETHYLENE [R19, 8429]; *NEEDLES OR LEAVES (ALCOHOL, AQ ACETONE) [R20]; *COLORLESS CRYSTALS [R13, 740]; *White crystals [R6]; *Colorless to red, crystalline solid. [R21] ODOR: *Odorless. [R21] BP: *210-220 DEG C @ 0.5 MM HG [R22] MP: *165-166 DEG C [R19, 8429] MW: *394.41 [R19, 8429] CORR: *Non-corrosive [R15] DEN: *1.27 @ 20 DEG C [R6] OWPC: *Log P = 4.10 [R23] SOL: *Sol in alcohol, acetone, carbon tetrachloride, chloroform, ether [R19, 8429]; *Sol in acetic acid, acetone; sl sol in ethanol [R22]; *15 PPM IN WATER AT 100 DEG C; SLIGHTLY SOL IN PETROLEUM OILS [R24]; *SOL IN LIPIDS [R25]; *Water solubility = 0.2 mg/l at 20 deg C [R26]; *Soluble in ether, alcohol, acetone, and other organic solvents [R6] SPEC: *MAX ABSORPTION (ALCOHOL): 237 NM (LOG E= 4.15), 293.5 NM (LOG E= 4.25), 330.5 NM (LOG E= 3.80); SADTLER REFERENCE NUMBER: 373 (IR, PRISM) [R27]; *Specific optical rotation: -228 deg at 20 deg C/D (concn by vol= 2.22 g in 100 ml benzene) [R19, 8429]; *Specific optical rotation: -225.2 deg at 29.5 deg C/D (benzene) [R20]; *Intense mass spectral peaks: 192 m/z (100%), 191 m/z (31%), 394 m/z (20%), 177 m/z (18%) [R28]; *IR: 21008 (Sadtler Research Laboratories IR Grating Collection) [R29]; *UV: 149 (Sadtler Research Laboratories Spectral Collection) [R29]; *NMR: 16340 (Sadtler Research Laboratories Spectral Collection) [R29]; *MASS: 5060 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R29]; *Strongly levorotatory in solution; specific rotation for D line 230 deg in benzene, 62 deg in ethylene dichloride. [R6] VAP: *8X10-4 mm Hg at 20 deg C [R26] OCPP: *MP: 185-186 DEG C /DIMORPHIC ROTENONE/ [R19, 8429] *SHOWS RAPID RACEMIZATION ON ALKALI TREATMENT; CRYSTALLIZES WITH SOLVENT OF CRYSTALLIZATION; CIS CONFIGURATION IS GENERALLY ACCEPTED [R24] *Dec upon exposure to light and air; colorless solns in organic solvents oxidize upon exposure and become yellow, orange, and then deep red and may deposit crystals of dehydrorotenone and rotenone. [R19, 8429] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flammable if preheated. [R30] REAC: +Strong oxidizers, alkalis. [R31, 274] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R32, 2886] *Decomposes on exposure to light and air. [R32, 2885] SERI: *Direct contact may cause irritation of the skin or conjunctiva. [R16, 64] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R31, 275] +Wear appropriate eye protection to prevent eye contact. [R31, 275] +Recommendations for respirator selection. Max concn for use: 50 mg/cu m. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust, mist, and fume filter. Any supplied-air respirator. [R31, 275] +Recommendations for respirator selection. Max concn for use: 125 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust, mist, and fume filter. [R31, 275] +Recommendations for respirator selection. Max concn for use: 250 mg/cu m. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R31, 275] +Recommendations for respirator selection. Max concn for use: 2500 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a pressure-demand or other positive-pressure mode. [R31, 275] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full facepiece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R31, 275] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R31, 275] *Wear rubber gloves for all handling ... Wear canister-type mask /if combustion occurs/. ... Self-contained breathing apparatus, rubber gloves, hats, suits, and boots must be worn /if extinguishing/. [R30] OPRM: *DO NOT REUSE EMPTY CONTAINER. DESTROY IT BY PERFORATING AND CRUSHING. BURY OR DISCARD IN SAFE PLACE AWAY FROM WATER SUPPLIES. [R4, p. C-199] *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any reasonable probability of eye contact. Employees should wash promptly when skin is wet or contaminated. Work clothing should be changed daily if it is possible that clothing is contaminated. Remove nonimpervious clothing promptly if wet or contaminated. [R33] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +Contact lenses should not be worn when working with this chemical. [R31, 275] +The worker should immediately wash the skin when it becomes contaminated. [R31, 275] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R31, 275] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R31, 275] SSL: *DECOMP UPON EXPOSURE TO LIGHT AND AIR; COLORLESS SOLN IN ORG SOLVENTS OXIDIZE UPON EXPOSURE AND BECOME YELLOW, ORANGE AND THEN DEEP RED [R19, 1423] *DRY CRYSTALLINE POWDER IS RELATIVELY STABLE. [R12] *DUSTS PREPARED FROM EXTRACTS DETERIORATE RAPIDLY, ESP IN PRESENCE OF SMALL AMT OF ANY VOLATILE INERT SOLVENT, BUT ARE STABILIZED BY INCORPORATION OF SMALL AMT OF STRONG ACID ... . [R24] *The dusts /of rotenone/ are stabilized with phosphoric acid to reduce oxidation. [R7, 600] *... Detoxified by heating; 2 hr at 100 deg C results in 76% decomposition. [R34] *Racemized by alkalis to less insecticidal compounds, more rapidly in certain solvents. [R35] STRG: *Containers: Fiber drums; tins; multiwall paper sacks; keep in well-ventilated area. [R30] CLUP: *AQ SOLN OF ROTENONE WERE PERCOLATED THROUGH GLASS COLUMNS CONTAINING GRANULAR ACTIVATED CARBON. THE ABSORPTIVE CAPACITY OF THE ACTIVATED CARBON WAS 0.1 MG/G FOR ROTENONE. [R36] *1. Ventilate area of spill. 2. For small quantities, sweep onto paper or other suitable material, place in an appropriate container and burn in a safe place (such as a fume hood). Large quantities can be reclaimed; however, if this is not practical, dissolve in a flammable solvent (such as alc) and atomize in a suitable combustion chamber. [R37] DISP: *1. By making packages of rotenone in paper or other flammable material and burning in a suitable combustion chamber. 2. By dissolving rotenone in a flammable solvent (such as alcohol) and atomizing in a suitable combustion chamber. [R37] *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. /Rotenone (commercial)/ [R38, 2002.51] ANTR: *In symptomatic overdose treatment is appropriate supportive therapy. [R39] *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Rotenone and related compounds/ [R40] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... /Rotenone and related compounds/ [R40] MEDS: *Consider the points of attack /CNS, eyes, respiratory system/ in preplacement and periodic physical examinations. [R33] HTOX: *Local effects incl conjunctivitis, dermatitis, pharyngitis, and rhinitis. Oral ingestion of rotenone produces GI irritation, nausea, and vomiting. Inhalation of the dust is more hazardous; it can cause resp stimulation followed by depression and convulsions. [R41] *No unscheduled DNA synthesis (UDS) was observed in human fibroblast cultures (VA4) in the presence or absence of a rat S9 liver enzyme activation system when rotenone was tested at 1, 10, and 1000 mM concn. [R16, 67] *CHRONIC POISONING MAY PRODUCE FATTY CHANGES IN LIVER, KIDNEY. [R19, 1423] *MORE TOXIC WHEN INHALED THAN WHEN INGESTED. [R19, 1423] *ROTENONE IS RELATIVELY FREE OF HAZARDS IN NORMAL USE, BECAUSE OF 1) THE LOW PERCENTAGE (1 TO 5%) COMMONLY USED IN FORMULATIONS; 2) THE UNSTABLE NATURE OF ROTENONE ... 3) ITS IRRITANT ACTIONS WHEN INGESTED ... 4) ITS LOW SOLUBILITY IN WATER. NO HUMAN FATALITIES HAVE BEEN REPORTED. ... ALTHOUGH THE MEAN LETHAL DOSE BY MOUTH VARIES WIDELY AMONG COMMON SPECIES OF LAB MAMMALS, A REASONABLE ESTIMATE FOR MAN IS 0.3 TO 0.5 G/KG. ... BECAUSE OF POOR /GI/ ABSORPTION, COARSE PARTICLES OF SOLID ROTENONE ARE MUCH LESS TOXIC THAN FINE POWDERS. FATS AND OILS PROMOTE ABSORPTION AND SO ENHANCE TOXICITY. [R11, p. III-366] *In massive overdose, principal effects include protracted vomiting, respiratory depression, and hypoglycemia and its symptoms. [R39] *When derris powder was applied to the armpits of four persons twice daily for 30 days, one developed a mild rash at the site of application; the rash disappeared within 24 hr. The others experienced no inconvenience, except that one person noted a very mild smarting. When applied to the forearms as a 10% ointment in anhydrous lanolin, no local irritation or anesthesia was observed. About 10 min after derris or a water extract of it was taken into the mouth of volunteers, all experienced a sensation of numbness, as well as a metallic taste; these effects lasted 3 or 4 hr ... . [R7, 602] *A previously healthy 3.5-yr old girl died after drinking about 10 mL of an insecticidal preparation of rotenone ... Symptoms were initial vomiting and drowsiness leading rapidly to coma, depressed respiration, and apnea. Despite artificial ventilation begun within 2-2.5 hr of ingestion, the girl died at 8-8.5 hr. Postmortem showed anoxic damage in the cerebrum, lungs, and heart and serohemorrhagic pleural effusion. There was also evidence of an acute renal tubular necrosis, but the authors suggested that this could have been due to various etherial oils present in the insecticide. HPLC analysis of postmortem tissues showed rotenone concentration of 6 x 10-6 to 1 x 10-5 mol/kg and the estimated oral dose was 40 mg/kg. [R7, 602] *Ingestion of rotenone was a common means of suicide by native of New Ireland ... When such persons were brought to medical attention while still alive, they were found to be in a state of collapse with feeble pulse and dilated pupils. Some, especially those suspected of having taken a very small dose, recovered following gastric lavage and stimulants. The only finding in numerous autopsies was that of acute congestive heart failure. The root was not generally found in the stomach, as vomiting before death was the rule. [R7, 602] *... mentioned the primitive industrial conditions for processing rotenone-bearing plants in the Amazon valley. Physicians observed some cases of severe irritation of the throat with partial destruction of the soft palate as well as of the anterior pillars and, very frequently, an irritation of the conjunctiva followed by ulcerative keratitis. Inflammation of the skin was notable in skin folds or where perspiration led to accumulation of the powder. [R7, 603] *All workers in Lyon who encountered the fine powder developed in 2 or 3 days a violent dermatitis of the genital region. It was characterized by a red-violet color, slight edema, and some itching. In 24 hr, if exposure was topped, the irritated skin underwent desquamation in plaques of different sizes. If contact persisted, the dermatitis became worse; itching, erythema, and the leatherlike texture increased. The skin became covered with large, flat, excoriated, oozing papules in patches 0.5 cm in diameter. The dermatitis recurred with each new exposure. Workers also experienced ulcerative rhinitis and temporary but complete loss of the sense of smell. In some instances there was irritation of the lips and tongue. [R7, 603] *Derris powder or ointment produces only a mild rash or no irritation of human ... skin. ... No anesthetic effect, such as is seen in the human mouth following application of either rotenone or derris, can be observed in the eye. Complete recovery can be expected in several days ... . [R7, 600] NTOX: *RESP DEPRESSION AND FALL IN ARTERIAL BLOOD PRESSURE IN RABBITS /IS/ PRODUCED BY IV ROTENONE ... . [R11, p. III-367] *GIVEN IV TO TEST ANIMALS, IT PRODUCES VOMITING, INCOORDINATION, MUSCLE TREMORS, CLONIC CONVULSIONS AND RESP FAILURE. [R11, p. III-366] *HIGHLY TOXIC TO FISH (LETHAL LESS THAN 50 PPB). [R24] *60 MG/KG WILL KILL GUINEA PIGS. ... POISONING RESULTS IN RESP STIMULATION AND CONVULSIONS, RESP DEPRESSION, COMA AND RESP FAILURE. CHRONIC POISONING OF ANIMALS FED DIET CONTAINING 75 PPM OF DERRIS ROOT CAUSES CENTRAL LOBULAR HEPATIC NECROSIS. [R25] *SIGNS OF INTOXICATION: ATAXIA, NUTATION/ACT OF NODDING ESPECIALLY INVOLUNTARY NODDING/, DYSPNEA, POLYURIA, FEATHERS FLUFFED OR HELD TIGHTLY TO BODY, WING DROP, NECK PULLED IN, IMMOBILITY. REGURGITATION OCCURRED @ LEVELS ABOVE 1500 MG/KG. SIGNS WERE OBSERVED LESS THAN AN HOUR AFTER SINGLE ORAL ADMIN, AND MORTALITIES OCCURRED UP TO 5 DAYS AFTER TREATMENT. REMISSION TOOK UP TO 1 WK. /MALLARDS AND/OR PHEASANTS/ [R42] *ROTENONE WAS ADMIN BY INJECTION TO WISTAR RATS FOR 2-3 MO AT DOSES OF 0.1 TO 0.2 MG/RAT/DAY, 5 DAYS/WK. EARLY MAMMARY TUMORS APPEARED 6 MO AFTER THE END OF TREATMENT AND THE NUMBER OF TUMORS INCR UP TO 24 MO. [R43] *Short term admin of rotenone in sunflower oil, injected ip in doses of 0.1 mg/kg/day for 5 days into female rats, produced a marked elevation in serum growth hormone concn and a decr in serum prolactin. These alterations and transient elevations in concn of estrogens, progesterone, and corticosterone suggested that rotenone was stimulating the hypophysis and that the physiopathogeny of rotenone-induced mammary tumors is indirect and hormonal. [R16, 65] *The colony forming ability of continuously cultivated bovine cells (T4) derived from normal ovarian tissue was reduced to 50% in the presence of 3.5X10-7 M concn of rotenone. Alkali-labile single strand DNA breakage was observed when mouse L1210 leukemia cells were exposed to 1X10-7 M rotenone. ... No sister chromatid exchanges /were observed/ in Chinese hamster ovary cells in the presence or absence of a rat liver S9 metabolic activation system. The max dose level used was the dose that reduced the proportion of dividing cells to 50%. Rotenone added to Chinese hamster cells in vitro incr the mitotic index, and mitotic cells contained monopolar spindles with chromosomes grouped around centriole pairs near the cell center. The cmpd was also found to arrest mitosis in cultured mammalian cells by inhibition of the spindle microtubule assembly. [R16, 67] *... Histological exams were conducted on 30 tissue/organ samples from approx 30 ... /Syrian golden hamsters/ of each sex and exptl group that had received /98%/ rotenone at doses of 0, 125, 250, 500, or 1000 ppm in the diet for as long as 18 mo. There was no evidence /of carcinogenicity/ ... in Sprague Dawley rat study, rotenone in corn oil was admin daily by ip injection to 25 animals of each sex at doses of 0, 1.7, or 3.0 mg/kg body wt for 42 days. Fifteen animals of each sex were used as vehicle controls. The animals were observed for an addnl 18 mo... In the Wistar rat study, rotenone in corn oil was admin by gavage to 25 animals of each sex at doses of 0, 1.7, or 3.0 mg/kg body wt for 42 days. Fifteen animals of each sex were used as vehicle controls. The Wistar rats were observed for an addnl 12 mo... There was no evidence /of carcinogenicity in either study/. [R16, 68] *A 90% mortality of the 4th instar larvae of Aedes aegypti occurred after exposure for 24 hr to 1 day-aged rotenone (4 ppm) extracted from Derris elliptica roots. The mortality percentage was dose-dependent and decreased by aging rotenone extracts. The toxicity of rotenone to mosquitoes was completely lost within 14-15 days after extraction. The content of rotenone in roots was higher (2.27%) in winter than in summer (1.6%). [R44] *Technical grades of rotenone at 0, 2.5, 5 or 10 mg/kg doses, suspended in corn oil, were administered orally in single doses on days 6-15 of pregnancy to Wistar rats. The dams were killed on the last day of pregnancy and all fetuses were evaluated following routine teratologic methods. Rotenone was associated with an increased number of non-pregnant rats and resorptions at 10 mg/kg dose; reductions in maternal body wt gain, fetal wt and skeletal ossification; and increased incidence of extra ribs at 5-10 mg/kg; no significant effects were noted at 2.5 mg/kg. [R45] *Applications of 2 or 5 ul/l concn of synergized rotenone (2.5%) in the Pro-Noxfish formulation to 2 shallow, 0.05 hectare ponds caused a temporary reduction in both total number and diversity of benthic invertebrates, a total mortality of caged Asiatic clams (Corbicula manilensis) in both ponds, and a partial mortality of a resident population of larval leopard frogs (Rana pipiens) in the 5 ul/l treatment. At day 7 after treatment, benthic organisms were reduced 67% by the 2 ul/l concn and 96% by the 5 ul/l application. The diversity index declined sharply in both ponds between days 3 and 7 after treatment, the lowest values being recorded on day 7 and day 37 in the 2 and 5 ul/l treatments, respectively. The equitability index declined from day 3 to day 37 in both ponds. By day 69, however, total numbers of benthic organisms had more than doubled over those originally present in the 2 ul/l treatment, had more than tripled in the 5 ul/l treatment, and were virtually unchanged in the control pond. Pretreatment zooplankton populations were low; no significant deleterious effects from the treatments were observed. [R46] *Rotenone was tested for mutagenicity in the Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. Rotenone was tested over a wide range of doses (0, 100, 333, 1000, 3333, and 10,000 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Rotenone was negative in these tests and the highest ineffective dose level tested (not causing the formation of a precipitate) in any Salmonella tester strain was 333 ug/plate. [R47] *Rotenone was not mutagenic when tested according to a preincubation protocol with Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 with or without metabolic activation by rat or hamster liver S9. Rotenone induced forward mutations in the mouse L5178K/TK + or - lymphoma assay without activation; it was not tested in the presence of S9. Results of tests with rotenone in Chinese hamster oveary cells were negative for induction of sister chromatid exchanges in the absence of exogenous metabolic activation (at concentrations at which the chemical was very toxic), equivocal for sister chromatid exchanges in the presence of rat liver S9 (due to a nonrepeatable positive response when tests were conducted up to toxic concentrations), and negative for chromosomal aberratons in both the presence and absence of metabolic activation. [R48] *It is about one half as toxic as pyrethrum. Rotenone dust affects the nervous system and causes convulsions in animals. Animals repeatedly fed derris powder (the botanical source containing 9.6% rotenone) at levels from 312 to 4,000 ppm developed focal liver necrosis and mild kidney damage. Of 40 female rats given daily intraperitoneal injections of rotenone in sunflower oil of 1.7 mg/kg for 42 days, more than 60% developed mammary tumors 6-11 months after the end of treatment; most of the tumors were mammary adenomas and one was a differentiated adenocarcinoma; none of the control animals had tumors when examined 19 months after treatment. [R49] *Early chick embryo explants /were exposed/ for 15 minutes to 1 ug/ml and observed after explantation various degrees of growth inhibition and neural tube defect. [R50] *Rats /were gavaged/ on days 6 through 15 with 2.5, 5 or 10 mg per kg. Maternal and fetal weights were reduced at 5 and 10 mg. Minor skeletal defects were found in the 5 mg group and resorptions were 46% in the 10 mg group. [R50] *Rotenone is nonphytotoxic, moderately toxic to most animals, and very toxic to swine, but produces no harmful residues on vegetable crops. [R51] *Signs of serious poisoning in animals include initial respiratory stimulation followed by respiratory depression, incoordination, clonic or tonic convulsions, muscle tremors, and death from respiratory failure ... The heart continues to beat and the blood pressure is maintained for a relatively long time after respiration has stopped. [R7, 600] *Dogs fed rotenone at the rate of 5 mg/kg/day for a month appeared well but showed fatty changes of the liver and kidneys. A dosage of 10 mg/kg/day killed 3/5 dogs, and one that was killed showed severe toxic injury of the liver, with possibly 1/3 of the bulk occupied by fat. [R7, 601] *Dietary levels of 75 and 150 ppm of rotenone were tolerated by pregnant guinea pigs but injured the young, which were either born dead or failed to thrive after birth, suggesting that rotenone or a toxic metabolite is excreted in the milk ... . [R7, 601] *... daily oral admin of rotenone to female rats at 5 mg/kg on days 6-15 of pregnancy resulted in reduced maternal weight gain and that 10 mg/kg/day killed 60% of the dams. ... the high dose increased the number of resorptions, but without producing significant fetal abnormalities. Some skeletal malformations such as extra ribs were seen at 5 mg/kg/day although this dose rate did not increase resorptions. Dosing at 2.5 mg/kg/day had no effects. [R7, 601] *There is some disagreement in the literature regarding the carcinogenic potential of rotenone ... rotenone may cause tumors only in vitamin-deficient animals. Rotenone suppresses weight gain at or above 50 ppm in the diet of rats ... or hamsters ... and so suppression of cell division may limit carcinogenic potential ... increased serum growth hormone, progesterone, and estrogen levels may be involved in rotenone carcinogenesis and showed a parallel between tumor incidence and low-level rotenone-induced obesity in rats. [R7, 601] *Rotenone is a potential spindle poison. At concn ranging from 1 x 10-7 to 1 x 10-5 M, the compound causes an increase in the mitotic index of cultured hamster cells within 15 min. The index reaches a peak, the height of which is proportional to the concn of the compound. [R7, 602] *... Under the conditions of these 2 year feed studies ... there was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 600 or 1200 ppm rotenone for 2 years. The decreased incidence of liver neoplasms in male mice may have been related to the administration of rotenone. [R52] *... Under the conditions of these 2 year feed studies, there was equivocal evidence of carcinogenic activity of rotenone for male F344/N rats, as indicated by an increased incidence of parathyroid gland adenomas (uncommon tumors). There was no evidence of carcinogenic activity in female F344/N rats fed diets containing 38 or 75 ppm rotenone. [R53] *Rotenone ... reduced the background incidence of hepatocellular carcinoma in male B6C3Fl mice. In the present studies, rotenone reduced the basal hepatic labeling index of male B6C3Fl mice in a dose dependent fashion and inhibited hepatocellular proliferation, but not peroxisome proliferation, induced by the peroxisome proliferator Wy-14,643. These results indicate that reduction of hepatic tumors by rotenone may have been due to decr liver cell replication, that peroxisome proliferation can be induced in the absence of hepatocellular proliferation and suggest rotenone as a potential tool in studies of relationships cell proliferation, peroxisomal proliferation and hepatocarcinogenesis. [R54] HTXV: *Lethal dose Human 0.3-0.5 g/kg (est) [R49] NTXV: *LD50 Rat oral 132-1500 mg/kg; [R55] *LD50 White mouse oral 350 mg/kg; [R35] *LD50 Mouse ip 2.8 mg/kg; [R19, 1423] *LD50 Rat oral 132 mg/kg; [R19, 1423] *Iv LD50 rat = 6 mg/kg; [R19, 1423] *Oral LD50 Rat oral 64 mg/kg /Calculated from original mortality fractions/; [R7, 600] *LD50 Rat oral 25 mg/kg /Calculated from original mortality fractions; oil solution/; [R7, 600] *LD50 Rat oral 60 mg/kg; [R7, 600] *LD50 rat ip 2.2 mg/kg /Calculated from original mortality fractions/; [R7, 600] *LD50 Rat ip 1.6 mg/kg; [R7, 600] *LD50 Rat iv 0.2-0.3 mg/kg; [R7, 600] *LD50 Mouse ip 5.4 mg/kg /Calculated from original mortality fractions/; [R7, 600] *LD50 Guinea pig oral 13 mg/kg /Calculated from original mortality fractions; oil solution/; [R7, 600] *LD50 Guinea pig oral 130 mg/kg /Calculated from original mortality fractions/; [R7, 600] *LD50 Guinea pig oral 75 mg/kg /Oil solution; minimal lethal dose/; [R7, 600] *LD50 Guinea pig ip 13 mg/kg /Calculated from original mortality fractions/; [R7, 600] *LD50 Guinea pig ip 2 mg/kg /Minimal lethal dose/; [R7, 600] *LD50 Rabbit oral 1,500 mg/kg /Minimal lethal dose/; [R7, 600] *LD50 Rabbit dermal 100-200 mg/kg; [R7, 600] *LD50 Rabbit iv 0.35-0.65 mg/kg /Minimal lethal dose/; [R7, 600] *LD50 Cat iv 0.65 mg/kg /Oil solution/; [R7, 600] ETXV: *LD50 ANAS PLATYRHYNCHOS (MALLARD) ORAL FEMALE GREATER THAN OR EQUAL TO 2200 MG/KG, 3 MO OLD; [R42] *LD50 PHASIANUS COLCHICUS PHEASANT) ORAL FEMALE 1680 MG/KG (95% CONFIDENCE LIMIT 1410-2000 MG/KG), 3 MO OLD; [R42] *LC50 Japanese quail oral 1882 ppm (95% confidence limits 1418-2497 ppm), 14 days old; [R56] *LC50 Ring-necked pheasant oral 1608 ppm (95% confidence limit 1365-1875 ppm), 10 days old; [R56] *LC50 Mallard oral approx 2600 ppm, 10 days old; [R56] *EC50 Simocephalus 310 ug/l/48 hr @ 15 deg C (95% confidence interval 239-402 ug/l), first instar. Static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l. /Technical, 44%/; [R57] *EC50 Daphnia pulex 100000 ug/l/48 hr @ 15 deg C (95% confidence interval 74000-134000 ug/l), first instar. Static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l. /Technical, 44%/; [R57] *LC50 Gammarus fasciatus 2600 ug/l/96 hr @ 21 deg C (95% confidence interval 2100-3200 ug/l), mature. Static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l. /Technical, 44%/; [R57] *LC50 Salmo gairdneri (Rainbow trout) 31 ug/l/96 hr @ 12 deg C (95% confidence interval 27-36 ug/l), wt 0.3 g. Static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l. /Technical, 44%/; [R57] *LC50 Ictaluras punctatus (Channel catfish) 2.6 ug/l/96 hr @ 24 deg C (95% confidence interval 2.1-3.2 ug/l), wt 0.5 g. Static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l. /Technical, 44%/; [R57] *LC50 Lepomis macrochirus (Bluegill) 23 ug/l/96 hr @ 24 deg C (95% confidence interval 20-25 ug/l), wt 0.6 g. Static bioassay without aeration, pH 7.2-7.5, water hardness 40-50 mg/l as calcium carbonate and alkalinity of 30-35 mg/l. /Technical, 44%/; [R57] *LC50 Pimephales promelas (fathead minnow) 6.0 mg/l/96 hr (confidence interval not reliable), flow-through bioassay with measured concentrations, 17.3 deg C, dissolved oxygen 9.2 mg/l, hardness 44.7 mg/l calcium carbonate, alkalinity 42.5 mg/l calcium carbonate, and pH 7.5. Effect: Loss of equilibrium; [R58] *LC50 Coturnix oral 5,608 ppm (95% confidence interval 4459-7053 ppm) for 5 day diet, slope: 5.78, standard error: 1.57; [R59] *LC50 Esox lucius (Northern pike) 33.0 ug/L/96 hr, Static bioassay; [R60] *LC50 Micropterus salmoides (Largemouth bass) 142 ug/L/96 hr, Static bioassay; [R60] *LC50 Stizostedion vitreum (Walleye) 16 ug/L/24 hr, Static bioassay; [R60] *LC50 Amia calva (bowfin) 30 ug/L/96 hr, Static bioassay; [R60] *LC50 Coho salmon 62 ug/L/96 hr, Static bioassay; [R60] *LC50 Chinook salmon 37 ug/L/96 hr, Static bioassay; [R60] *LC50 rainbow trout 46 ug/L/96 hr, Static bioassay; [R60] *LC50 Atlantic salmon 21 ug/L/96 hr, Static bioassay; [R60] *LC50 brook trout 44 ug/L/96 hr, Static bioassay; [R60] *LC50 lake trout 27 ug/L/96 hr, Static bioassay; [R60] *LC50 goldfish 497 ug/L/96 hr, Static bioassay; [R60] *LC50 carp 50 ug/L/96 hr, Static bioassay; [R60] *LC50 fathead minnow 142 ug/L/96 hr, Static bioassay; [R60] *LC50 Catostomus catostomus (longnose sucker) 57 ug/L/96 hr, Static bioassay; [R60] *LC50 white sucker 68 ug/L/96 hr, Static bioassay; [R60] *LC50 black bullhead 389 ug/L/96 hr, Static bioassay; [R60] *LC50 channel catfish 164 ug/L/96 hr, Static bioassay; [R60] *LC50 green sunfish 141 ug/L/96 hr, Static bioassay; [R60] *LC50 bluegill sunfish 141 ug/L/96 hr, Static bioassay; [R60] *LC50 smallmouth bass 142 ug/L/96 hr, Static bioassay; [R60] *LC50 yellow perch 70 ug/L/96 hr, Static bioassay; [R60] *32-Day LC50 Salmo gairdneri 2.1 ug/L /Conditions of bioassay not specified/; [R60] NTP: *Groups of 50 B6C3F1 mice of each sex were administered diets containing 0, 600, or 1,200 ppm rotenone on the same schedule. The estimated average amount of rotenone consumed per day was ... 115 mg/kg or 250 mg/kg for low dose and high dose mice. ... Survival of high dose male mice was significantly greater than that of the controls (male: 29/50; 36/50; 47/50; female: 37/50; 42/50; 45/50). Final mean body weights of dosed mice were lower than those of the controls by 8%-13% for males and 17%-24% for females. ... Hepatocellular adenomas or carcinomas (combined) ... in the high dose group /were/ lower than that in the controls (12/47; 12/49; 1/50). Because this low rate of combined liver tumors is unusual, this decrease may have been related to rotenone administration. ... Subcutaneous tissue fibromas, sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) in male mice occurred with a significant (P < 0.05) negative trend (8/49; 4/50; 2/50). The incidence in the high dose group was significantly lower than that in the controls by the life table test (p=0.01). ... Under the conditions of these 2 year feed studies ... there was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 600 or 1200 ppm rotenone for 2 years. The decreased incidence of liver neoplasms in male mice may have been related to the administration of rotenone. [R52] *Two-year studies of rotenone were conducted by administering diets containing 0, 38, or 75 ppm rotenone to groups of 50 F344/N rats of each sex for 103 weeks. ... The estimated average amount of rotenone consumed per day was 1.7 mg/kg or 3.5 mg/kg for low dose or high dose rats. ... Survival of control and dosed rats was similar (male: control, 22/50; low dose, 31/50; high dose, 30/50; female: control, 27/50; low dose, 32/50; high dose, 31/50). Mean body weights of dosed and control male rats were comparable. Mean body weights of high dose female rats were 5%-9% lower than those of the controls between weeks 58 and 88. ... Parathyroid gland adenomas were observed in 1/41 control, 0/44 low dose, and 4/44 high dose male rats. The historical incidence of this uncommon tumor in untreated control male rats in NTP studies is 4/1,314 (0.3%). Because these tumors are rare and because the highest incidence ever seen in a control group is 1/50, the increase in these tumors may have been related to rotenone administration. The incidence of subcutaneous tissue fibromas, fibrosarcomas, sarcomas, myxosarcomas, or neurofibrosarcomas (combined) in low dose female rats was greater (P < 0.05) than that in the controls (0/50; 5/50; 3/50). These tumors were combined because of their possible common histiogenic origin from fibroblasts or undifferentiated mesenchymal cells. The incidence of those tumors in the low dose females was greater than the historical rate at this laboratory (9/337, 3% + or - 1%) and throughout the Program (50/2,021, 2% + or - 2%). Because of the lack of a significant dose-related trend and because statistical significance was attained only by combining tumors of differing morphology, the subcutaneous tissue tumors in female rats were not considered to be chemically related. The incidences of these tumors in dosed male rats were not significantly different from that in the controls. ... Under the conditions of these 2 year feed studies, there was equivocal evidence of carcinogenic activity of rotenone for male F344/N rats, as indicated by an increased incidence of parathyroid gland adenomas (uncommon tumors). There was no evidence of carcinogenic activity in female F344/N rats fed diets containing 38 or 75 ppm rotenone. [R53] ADE: *EXHALATION OF (14)CO2 WITHIN 50 HR AFTER ORAL OR IP DOSING OF 5'BETA-[3-METHOXY-(14)C]ROTENONE TO MICE AND RATS RESPECTIVELY WAS 27 and 12.5%. /5'BETA-[3-METHOXY-(14)C]ROTENONE/ [R61] *GI ABSORPTION IS PRESUMABLY SLOW AND INCOMPLETE. ... FATS AND OILS PROMOTE ABSORPTION. [R11, p. III-366] *One mechanism of detoxication of natural rotenone ... or one of its metabolites was found to be 3-O-demethylation, as indicated by recovery of 27 and 13% of the admin radiocarbon as 14C-labeled carbon dioxide within 50 hr after admin to mice and rats, respectively. Within the same period, the animals excreted 7-17% of the radioactivity in their urine ... In another study, 19.5 and 20.0% of the dose were recovered in the urine of mice and rats, respectively, within 24 hr after oral admin ... . [R7, 601] METB: *5'BETA-(3-METHOXY-14C)ROTENONE UNDERWENT EXTENSIVE DEMETHYLATION IN RODENTS. /5' BETA-(3-METHOXY-14C)ROTENONE/ [R61] *BIOTRANSFORMATION...IN RATS LEADS TO HYDROXYLATION OF POSITION 12A AT B/C RING JUNCTION TO GIVE ROTENOLONES...TO OXIDATION OF ISOPROPENYL SIDE-CHAIN TO AFFORD 6',7'-DIHYDRO-6',7'-DIHYDROXY-ROTENONE AND 8'-HYDROXYROTENONE, AND TO FORMATION OF UNIDENTIFIED WATER-SOL METABOLITES. [R62] *MICROSOME FRACTIONS FROM HOUSEFLY ABDOMENS, MOUSE LIVERS, AND RAT LIVERS WERE USED TO STUDY ROTENONE DEGRADATION. METABOLITES SO PRODUCED WERE... /ROTENOLONE I AND II, 8'-HYDROXYROTENONE, 8'-HYDROXYROTENOLONE I AND II, 6',7'-DIHYDRO-6',7'-DIHYDROXYROTENONE, 6',7'-DIHYDRO-6',7'-DIHYDROXYROTENOLONE I AND II/ [R63] *In rat liver and in insects, the furan ring is enzymatically opened and cleaved, leaving behind a methoxy group. The principal metabolite is rotenonone. An alcohol has been found as a further metabolite, this being formed via oxidation of a methyl group of the isopropenyl residue. [R35] *Rotenone is metabolized rather efficiently by the liver. In order to produce the same clinical effect, the compound must be injected into a mesenteric vein at about 10 times the dose required for injection into a femoral vein ... . [R7, 601] *Rat and mouse liver enzymes and intact mice hydroxylate rotenone at carbons 7 and 24. In vitro, the change is produced by microsomes in the presence of nicotinamide-adenine dinucleotide phosphate. The products include rotenolone I, rotenolone II, 8'-hydroxyrotenone, 6',7'-dihydro-'6',7'-dihydroxyrotenone, two rotenolones of each of the latter compounds, and uncharacterized polar materials. [R7, 601] *One mechanism of detoxication of natural rotenone ... or one of its metabolites was found to be 3-O-demethylation ... [R7, 601] ACTN: *Rotenone functions as an inhibitor of the mitochondrial oxidative phosphorylation-electron transport system, but the chemical was found to be a potent in vitro antagonist of slow-reacting substance of anaphylaxis. [R16, 64] *Rotenone inhibits the oxidn of NADH to NAD. Consequently, it blocks the oxidn by NAD of substrates such as glutamate, alpha-ketoglutarate, and pyruvate. [R41] *Rotenone is a highly potent mitochondrial poison, blocking NADH oxidation, and this property dominates its actions in animals. [R7, 600] *Rotenone is one of the most potent known inhibitors of the NADH dehydrogenase system. ... 20 pmol/mg protein produces 50% inhibition of mitochondrial pyruvate oxidation. Radiolabel studies showed this to be equivalent to 2 moles rotenone per "mole" of NADH dehydrogenase. The site at which rotenone acts involves Fe-S proteins and is the same as the site at which amytal produces its inhibition, although rotenone is more selective and shows less affinity for other proteins. [R7, 600] *The block of NADH oxidation can lead to increased incorporation of acetate into long-chain fatty acids by isolated mitochondria ... This may be a link with the fatty changes seen in the liver after long-term feeding. [R7, 601] *It is thought that rotenone acts on the spindle by preferential binding at sulfhydryl and disulfide bonds in its protein structure ... Detailed study of cultured mammalian cells by both light and electron microscopy confirmed that rotenone reversibly inhibits spindle microtubule assembly ... However, rotenone delayed cell progression in all phases of the cell cycle. This was thought to be a direct result of respiratory inhibition, even though amytal, which blocks electron transport at the same site as that blocked by rotenone, does not arrest cell progression at mitosis. Thus, the total effect of rotenone was thought to depend on inhibition of respiration and, separately and more importantly, on inhibition of microtubule assembly ... although the relevance of the microtubule effect in cells not unusually resistant to metabolic inhibition is unclear. [R7, 602] *Rotenone is an inhibitor which blocks electron transfer between NADH and coenzyme Q. [R17, 497] INTC: *WHEN APPLIED @ LOW CONCN TO PLANT FOLIAGE, ROTENONE CATALYZES PHOTOISOMERIZATION OF DIELDRIN AND OTHER CYCLODIENE INSECTICIDE RESIDUES. ... HOWEVER PHOTODECOMPOSITION WAS PREDOMINANT EFFECT WHEN RESIDUES OF ROTENONE WERE COMBINED WITH THOSE OF METHYLCARBAMATE AND PHOSPHOTHIONATE INSECTICIDES. [R64] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Vet: acaricide, ectoparasiticide [R19, 1423] *MEDICATION: ANTIPROTOZOAL; MEDICATION (VET): GRUBICIDE; HAS BEEN USED FOR DEMODECTIC MANGE [R65] */Former use/: Rotenone has been used topically for treatment of head lice, scabies, and other ectoparasites, but the dust is highly irritating to the eyes (potentially causing conjunctivitis), the skin (causing contact dermatitis), and to the upper respiratory tract (causing rhinitis) and throat (linked with pharyngitis). [R17, 669] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Rotenone's production and use in insecticides, flea powders, fly sprays, and moth-proofing agents will result in its release to the environment from its use. If released into the atmosphere, rotenone will exist solely in the vapor phase in the ambient atmosphere, based on a measured vapor pressure of 8X10-4 mm Hg at 25 deg C. Vapor-phase rotenone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with a half-life of about 0.05 days. An estimated Koc value of 4,000 suggests that rotenone will have slight mobility in soil. Volatilization from moist soil is not expected based upon an estimated Henry's Law constant of 1.12X10-13 atm-cu m/mole. Volatilization from dry soil surfaces should not be important given the vapor pressure of this compound. The field half-life for rotenone in anaerobic and aerobic soils is 3 days. Rotenone is listed as one of the organic substances which may be degraded during aerobic and anaerobic sewage treatment if adequate acclimatization can be achieved; much depends on the concentration to be treated and possibly on the temperature during treatment. In water, rotenone is expected to adsorb to sediment or particulate matter based on its Koc value. This compound is not expected to volatilize from water surfaces given its estimated Henry's Law constant. Bioconcentration in aquatic organisms should be high based upon an estimated BCF value of 770. Given the commercial uses of rotenone, human exposure appears to be likely from occupational situations through dermal and inhalation routes. The general population may be exposed to rotenone via ingestion of food, and dermal contact with vapors, food and other products containing rotenone. (SRC) NATS: *Many plant sources of rotenone are known, particularly Derris grown in Malaya and the East Indies, and Lonchocarpus (familiarly known as cube) grown in Central and South America. [R11, p. III-366] ARTS: *Rotenone's production and use in insecticides, flea powders, fly sprays, and moth-proofing agents(1) will result in its release to the environment from its use(SRC). [R66] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 4,000(SRC), determined from an experimental log Kow(2,SRC) and a regression-derived equation(3), indicates that rotenone is expected to have slight mobility in soil(SRC). Volatilization of rotenone from moist soil surfaces is not expected(SRC) given an estimated Henry's Law constant of 1.12X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Rotenone is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 8X10-4 mm Hg(SRC), determined from a fragment constant method(5). The field half-life for rotenone in anaerobic and aerobic soils is 3 days(6). [R67] *TERRESTRIAL FATE: A cold water pond (0 to 5 deg C, November 1983) at the Geona National Fish Hatchery, Wisconson and a warm water pond (23 to 27 deg C, July 1984) at the La Crosse National Fisheries Research Center was treated with Noxfish (0.25 mg/l rotenone) and analyzed. Residues of rotenone in bottom sediments in the cold water pond peaked at 0.10 ug/g after 14 days and then declined to < 0.025 ug/g (limit of detection) after 64 days. Accumulation and elimination were much faster in the warm water pond: concentration in bottom sediments peaked at 0.075 ug/g after 6 hours and dropped to < 0.025 ug/g after 24 hours(1). [R68] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 4,000(SRC), determined from an experimental log Kow(2,SRC) and a regression-derived equation(3), indicates that rotenone is expected to adsorb to suspended solids and sediment in water(SRC). Rotenone is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 1.12X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF value of 770(3,SRC), from an experimental log Kow(2,SRC), suggests that bioconcentration in aquatic organisms is high(SRC). Decomposition of rotenone in water followed a first-order decay curve; half-life was 10.3 days in cold water and 0.94 days in warm water. In freshwater mussels and crayfish, rotenone residues gradually increased for 1 week in cold water and 1 day in warm water and then slowly decreased. Rotenone residues in fish varied with species and water temperatures(6). [R69] *AQUATIC FATE: A cold water pond (0 to 5 deg C, November 1983) at the Geona National Fish Hatchery, Wisconsin and a warm water pond (23 to 27 deg C, July 1984) at the La Crosse National Fisheries Research Center was treated with Noxfish (0.25 mg/l rotenone) and analyzed. In the cold water pond, the mean concentration of rotenone in samples taken 3 hours after treatment was 0.229 mg/l; concentration of rotenone declined gradually but steadily to 0.002 mg/l (limit of detection) after 57 days. In the warm water pond the mean concentration of rotenone in samples taken after 3 hours was 0.180 mg/l; concentration of rotenone declined by more than 50 percent in the first 12 hours and then fell to 0.002 mg/l within four days(1). [R68] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), rotenone, which has an experimental vapor pressure of 8X10-4 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase rotenone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 0.05 days(3,SRC). Particulate-phase rotenone may be physically removed from the air by wet and dry deposition(SRC). [R70] BIOD: *ROTENONE IS BIODEGRADABLE. [R71] *Rotenone is listed as one of the organic substances which may be degraded during aerobic and anaerobic sewage treatment if adequate acclimatization can be achieved; much depends on the concentration to be treated and possibly on the temperature during treatment(1). [R72] ABIO: *PHOTODECOMPOSITION PRODUCTS FORMED BY IRRADIATION OF ROTENONE...EXPOSED TO LIGHT ON GLASS SURFACES OR ON BEAN LEAVES: O-DEMETHYL ROTENONE; 6ALPHABETA, 12ALPHAALPHA-ROTENOLONE; DEHYDRO-ROTENONE; 6ALPHABETA, 12ALPHABETA-ROTENOLONE; ROTENONONE; 6',7'-EPOXYROTENONE; 6',7'-EPOXY-6ALPHABETA, 12ALPHABETA-ROTENOLONE. [R73] *The material deteriorates rapidly in sun, air, and water. Formulations lose their effectiveness within a week after application. [R4, p. C-199] *Rotenone is stable in the solid state but degradation is accelerated by the presence of organic solvents. Air and light are required. The rate of decomposition produced the yellow crystalline dehydrorotenone and rotenonone and a complex mixture of other oxidation products of rotenone. [R74] *The rate constant for the vapor-phase reaction of rotenone with photochemically-produced hydroxyl radicals has been estimated as 318X10-12 cu cm/molecule-sec at 25 deg(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 0.05 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). When exposed to light and air, rotenone undergoes hydroxylation at C-7, followed by dehydration to form dehydrorotenone. These reactions inactivate rotenone after 5 to 10 days of exposure to sunlight. In a study of photosensitizers, rotenone was found to be the most effective compound for enhancing the photochemical alteration of dieldrin to photodieldrin when applied to bean plants at levels as low as 0.3 ppm(4). In another study, irradiation of rotenone in oxygenated methanol solution with UV light yielded the following crystalline products: O-demethylrotenone, 6ab,-12ab-rotenolone, rotenonone, 4,5-dimethoxysalicylic acid, rissic acid, and tubaic acid(5). [R75] BIOC: *An estimated BCF value of 770 was calculated for rotenone(SRC), using an experimental log Kow of 4.10(1,SRC) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is high(SRC). A study showed that when yearling bluegills (L. macrohirus) were exposed to 5.2 ug/l of rotenone for 30 days in a continuous flow system, bioconcentration factors for the head, viscera, and carcass were 165, 3,500, and 125, respectively(4). [R76] KOC: *The Koc of rotenone is estimated as approximately 4,000(SRC), using a measured log Kow of 4.10(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that rotenone is expected to have slight mobility in soil(SRC). The field half-life for rotenone in anaerobic and aerobic soils is 3 days(4). [R77] VWS: *The Henry's Law constant for rotenone is estimated as 1.12X10-13 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 8X10-4 mm Hg(1), and water solubility, 0.2 mg/l(1). This value indicates that rotenone will be essentially nonvolatile from water surfaces(2,SRC). Rotenone's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is not expected(SRC). Rotenone is not expected to volatilize from dry soil surfaces based on a measured vapor pressure of 8X10-4 mm Hg(1). [R78] WATC: *Rotenone enters surface waters through direct application in fishery management. [R16, 70] *GROUNDWATER: Groundwater sampling for pesticides in the United States was conducted by the EPA from 1971 to 1991. Results showed that out of 12 wells sampled in California from 1987 to 1988, no concentration of rotenone was detected(1). [R79] FOOD: *Pesticide residues were reported in foods for the 4-year period 1982 to 1986. Rotenone was found as a residue in FY83-86 regulatory monitoring of approximately 11,500 samples(1). [R80] PFAC: FISH/SEAFOOD CONCENTRATIONS: *A cold water pond (0 to 5 deg C, November 1983) at the Geona National Fish Hatchery, Wisconson and a warm water pond (23 to 27 deg C, July 1984) at the La Crosse National Fisheries Research Center was treated with Noxfish (0.25 mg/l rotenone) and analyzed. Channel catfish (Ictalurus punctatus) and largemouth bass (Micropterus salmoides) were used as representative fish for analysis in cold water; black bullheads (Ictalurus melas) and bluegills (Lepomis macrochirus) were used as representative fish for analysis in warm water. Concentrations of rotenone in catfish ranged from 0.123 ug/g after 1 day to 0.178 ug/g after 20 days; no further sampling was possible after this because all the fish had died. Concentrations of rotenone in largemouth bass ranged from 0.082 ug/g after 1 day to 0.502 ug/g after 6 days; no further sampling was possible after this because all the fish had died. Concentrations of rotenone in black bullheads ranged from 0.0.005 ug/g (limit of detection) after 1 day to 0.083 ug/g after 21 days, declining to < 0.005 ug/g after 35 days. Concentrations of rotenone in bluegills ranged from 0.064 ug/g after 1 day to < 0.005 ug/g after 21 days(1). [R68] *A cold water pond (0 to 5 deg C, November 1983) at the Geona National Fish Hatchery, Wisconsin and a warm water pond (23 to 27 deg C, July 1984) at the La Crosse National Fisheries Research Center was treated with Noxfish (0.25 mg/l rotenone) and analyzed. Fresh water crayfish (Orconectes sp.) and mussels (Lampsilis sp. were used as representative invertebrates. Crayfish in the cold water pond had rotenone concentrations ranging from 0.0.395 ug/g after 1 day of treatment to < 0.057 ug/g after 21 days; rotenone concentrations did not reach the limit of detection because all the fish had died by day 21. Crayfish in the warm water pond had rotenone concentrations ranging from 0.058 ug/g after 1 day of treatment to < 0.005 ug/g (limit of detection) after 7 days. Mussels in the cold water pond had rotenone concentrations peak at 0.723 ug/g on day 7 and decline to 0.230 ug/g on day 28. In the warm water pond, rotenone concentrations reached 1.060 ug/g after 1 day of treatment; no further sampling was possible after this because all the mussels had died(1). [R68] RTEX: *Inhalation, ingestion, skin and eye contact. [R33] *... Extraction of derris root, formulation or application of /rotenone/. [R33] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 8,099 workers (2,470 of these are female) are potentially exposed to rotenone in the US(1). Occupational exposure may be through inhalation of dusts and dermal contact with this compound at workplaces where rotenone is produced or used(SRC). The general population may be exposed to rotenone ingestion of food(2) and drinking water, and dermal contact with vapors, food and other products containing rotenone(SRC). Limited monitoring data indicate that non-occupatioal exposures can occur from the ingestion of contaminated drinking water. The most probable human exposure would be occupational exposure, which may occur through dermal contact or inhalation at workplaces where it is produced or used(SRC). [R81] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +2500 mg/cu m [R31, 275] ATOL: *When applied to growing crops, in accordance with good agricultural practice, the following pesticide chemicals are exempt from the requirement of a tolerance: Rotenone or derris or cube roots. [R82] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 5 mg/cu m. [R83] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 mg/cu m. [R31, 275] TLV: +8 hr Time Weighted Avg (TWA): 5 mg/cu m. /Rotenone (commercial)/ [R38, 2002.51] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Rotenone (commercial)/ [R38, 2002.6] +A4; Not classifiable as a human carcinogen. /Rotenone (commercial)/ [R38, 2002.51] WSTD: STATE DRINKING WATER GUIDELINES: +(ME) MAINE 4 ug/l [R84] +(FL) FLORIDA 28 ug/l [R84] FIFR: *When applied to growing crops, in accordance with good agricultural practice, the following pesticide chemicals are exempt from the requirement of a tolerance: Rotenone or derris or cube roots. [R82] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Rotenone is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0255; Pesticide type: Insecticide (acaricide,piscicide); Registration Standard Date: 10/88; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Rotenone; Data Call-in (DCI) Date(s): 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R85] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 5007. Analyte: Rotenone. Matrix: Air. Sampler: Filter (1 um polytetrafluoroethylene membrane). Flow Rate: 1 to 3 liters/min. Sample Size: 100 liters. Shipment: Routine. Sample Stability: At least 7 days at 25 deg C in dark. [R86] ALAB: *A rapid, specific, and sensitive HPLC procedure (limit of detection less than 0.005 mg/l) was developed for monitoring application and degradation rates of rotenone. For analysis, a water sample is buffered to pH 5 and injected through a Sep Pak (C)18 disposable cartridge. The cartridge adsorbs and retains the rotenone which then can be eluted quantitatively from the cartridge with a small volume of methanol. This step effectively concentrates the sample and provides sample cleanup. The methanol extraction is analyzed directly by HPLC on an MCH 10 reverse-phase column. Methanol:water (75:25, vol:vol) is the mobile phase and flow rate is 1.5 ml/min. Rotenone is detected by UV spectrophotometry at a wavelength of 295 nm. [R87] *Determination of rotenone in Derris and Cube powder using crystalization method; an infrared spectroscopic method (not applicable to derris products). [R88, p. V1 168] *Rotenone in pesticide formulations is determined by reverse phase liquid chromatographic method with UV detection at 280 nm. [R88, p. V1 169] *Analysis of products: by infrared spectrophotometry; by HPLC. Analysis of residues: by GLC and TLC; by HPLC. [R15] *NIOSH Method: 5007. Analyte: Rotenone. Matrix: Air. Procedure: HPLC, UV detection For rotenone this method has an estimated detection limit of 4 ug/sample. The precision/RSD is 0.024 and the recovery is not determined. Applicability: The working range is 0.4 to 10 mg/cu m for a 100 liter air sample and the method is applicable to commercial formulations. Interferences: None known. [R86] *EPA Method 635. Determination of rotenone in industrial and municipal wastewaters by high performance liquid chromatography coupled with ultra violet detector. Approximately 1 liter is solvent extracted with methylene chloride using a separately funnel. The method detection limit is 1.60 ug/l as defined by EPA. [R89] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rotenone in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 320 (1988) NIH Publication No. 88-2576 SO: R1: Grinda F, Gueyne J; Extraction of rotenone and other insecticides from source plants; PCT Int Appl PATENT NO 83 03951 11/24/83 (Saphyr Sarl) R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V14 531 R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 792 R4: Farm Chemicals Handbook 1984. Willoughby, Ohio: Meister Publishing Co., 1984. R5: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 82 R6: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1012 R7: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. R8: Farm Chemicals Handbook 1994. Willoughby, OH: Meister, 1994. R9: Augustijn-Beckers PWM et al; Rev Environ Contam Toxicol 137: 1-82 (1994) R10: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 2. New York: Marcel Dekker, Inc., 1976. 302 R11: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R12: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1199 R13: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. R14: Abidi SL, Abidi MS; J Heterocycl Chem 20 (6): 1687-92 (1983) R15: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A363/Aug 87 R16: National Research Council. Drinking Water and Health. Volume 5. Washington, D.C.: National Academy Press, 1983. R17: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. R18: SRI R19: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R20: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-453 R21: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 274 R22: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-77 R23: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 180 R24: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 506 R25: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 30 R26: Augustijn-Beckers PWM et al; Rev Environ Contam Toxicol 137:1-82 (1994) R27: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-493 R28: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 394 R29: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 270 R30: Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. 9:2/1989 R31: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R32: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R33: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 773 R34: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. 665 R35: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium. 10th ed. Surrey, UK: The British Crop Protection Council, 1994. 906 R36: DAWSON VK ET AL; TRANS AM FISH SOC 105 (1): 119-23 (1976) R37: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R38: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R39: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. 1086 R40: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 272 R41: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 1687 R42: U.S. Department of the Interior, Fish and Wildlife Service. Handbook of Toxicity of Pesticides to Wildlife. Resource Publication 153. Washington, DC: U.S. Government Printing Office, 1984. 69 R43: MERCHAN J ET AL; REV ESP ONCOL 25 (1): 107-20 (1978) R44: Ameen M et al; J Bangladesh Acad Sci 7 (1-2): 39-47 (1983) R45: Khera KR et al; Teratology 23 (2): 45A-6A (1981) R46: Burress RM; Invest Fish Control 90-91 (Paper no 2): 1-7 (1982) R47: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R48: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rotenone in F344/N Rats and B6C3F1 Mice (Feed Studies) p.4 (1988) Technical Rpt Series No. 320 NIH Pub No. 88-2576 R49: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 641 R50: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 504 R51: Farm Chemicals Handbook 1997. Willoughby, OH: Meister Publishing Co., 1997.,p. C323 R52: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rotenone in F344/N Rats and B6C3F1 Mice (Feed Studies) p. 3 (1988) Technical Report Series No. 320 NIH Pub No. 88-2576 R53: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rotenone in F344/N Rats and B6C3F1 Mice (Feed Studies) p.3 (1988) Technical Rpt Series No. 320 NIH Pub No. 88-2576 R54: Cunningham ML, et al; Cancer Lett 95 (1-2): 93-7 (1995) R55: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.515 R56: U.S. Department of the Interior, Fish and Wildlife Service, Bureau of Sports Fisheries and Wildlife. Lethal Dietary Toxicities of Environmental Pollutants to Birds. Special Scientific Report - Wildlife No. 191. Washington, DC: U.S. Government Printing Office, 1975.32 R57: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office, 1980.71 R58: Geiger D.L., D.J. Call, L.T. Brooke. (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales- Promelas). Vol. V. Superior WI: University of Wisconsin-Superior, 1990.269 R59: Hill, E.F. and Camardese, M.B. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix. Fish and Wildlife Technical Report 2. Washington, DC: United States Department of Interior Fish and Wildlife Service, 1986.123 R60: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1617 R61: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 410 R62: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 301 R63: Menzie, C.M. Metabolism of Pesticides. U.S. Department of the Interior, Bureau of Sport Fisheries and Wildlife, Publication 127. Washington, DC: U.S. Government Printing Office, 1969. 283 R64: Hayes, W. J., Jr. Toxicology of Pesticides Baltimore: Williams and Wilkins, 1975. 271 R65: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1192 R66: (1) Lewis RJSR; Hawley's Condensed Chemical Dictionary, 12th ed. NY, NY: Van Nostrand Reinhold Company (1993) R67: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Washingtion,DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) (6) Augustijn-Beckers PWM et al; Rev Environ Contam Toxicol 137: 1-82 (1994) R68: (1) Gilderhus PA et al; Investigations in fish control: deposition and persistence of rotenone in shallow ponds during cold and warm seasons. Washington,DC: Fish Wildlife Svc. NTIS PB89-110753 (1988) R69: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Washingtion,DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Gilderhus PA et al; Investigations in fish control: deposition and persistence of rotenone in shallow ponds during cold and warm seasons. Washington,DC: Fish Wildlife Svc. NTIS PB89-110753 (1988) R70: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Augustijn-Beckers PWM et al; Rev Environ Contam Toxicol 137: 1-82 (1994) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R71: Farm Chemicals Handbook 1992. Willoughby, OH: Meister Publishing Co., 1992.,p. C-294 R72: (1) Thom NS, Agg AR; Proc R Soc Lond B 189: 347-57 (1975) R73: Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974.319 R74: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.249 R75: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Metcalf RL; Ullmann's Encyclopedia of Industrial Chemistry. 5th ed. Deerfield Beach, FL: VCH Publ Vol A14: 271-2 (1989) (4) Ivie GW, Casida JE; J Agr Food Chem 19: 405-09 (1971) (5) Cheng HM et al; J Agr Food Chem 20: 850-56 (1972) R76: (1) Hansch C et al; Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Washingtion,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Gingerich WH, Rach JJ; Aquat Toxicol 6: 179-96 (1985) R77: (1) Hansch C et al; Exploring QSAR: Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Washingtion,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Augustijn-Beckers PWM et al; Rev Environ Contam Toxicol 137: 1-82 (1994) R78: (1) Augustijn-Beckers PWM et al; Rev Environ Contam Toxicol 137: 1-82 (1994) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R79: (1) USEPA; USEPA Off Pest Programs: Prevention Pesticides and Toxic Substances. H7507C USEPA-734-12-92-001 (1992) R80: (1) Yess NJ et al; J Off Anal Chem 74: 273-80 (1991) R81: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Gilderhus PA et al; Investigations in fish control: deposition and persistence of rotenone in shallow ponds during cold and warm seasons. Washington,DC: Fish Wildlife Svc. NTIS PB89-110753 (1988) R82: 40 CFR 180.1001(b)(8) (7/1/96) R83: 29 CFR 1910.1000 (7/1/98) R84: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R85: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.147 (Spring, 1998) EPA 738-R-98-002 R86: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5007-1 R87: Dawson VK et al; Trans Am Fish Soc 112 (5): 725-7 (1983) R88: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R89: USEPA/SCC; Environmental Monitoring Methods Index p.242 (1992) RS: 80 Record 150 of 1119 in HSDB (through 2003/06) AN: 1765 UD: 200301 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SIMAZINE- SY: *A-2079-; *G-27692-; *H-1803-; *W-6658-; *AKTINIT-S-; *BATAZINA-; *2,4-BIS(ETHYLAMINO)-6-CHLORO-S-TRIAZINE; *BITEMOL-; *BITEMOL-S-50-; *CAT- (HERBICIDE); *CDT-; *CEKUZINA-S-; *CET-; *2-CHLORO-4,6-BIS(ETHYLAMINO)-S-TRIAZINE; *1-CHLORO,-3,5-BISETHYLAMINO-2,4,6-TRIAZINE-; *2-CHLORO-4,6-BIS(ETHYLAMINO)-1,3,5-TRIAZINE; *6-Chloro-N,N'-diethyl-1,3,5-triazine-2,4-diamine-; *GEIGY-27,692-; *GESARAN-; *GESATOP-; *GESATOP-50-; *HERBAZIN-; *HERBAZIN-50-; *HERBEX-; *HERBOXY-; *HUNGAZIN-DT-; *Caswell-No-740-; *EPA-Pesticide-Code-No-080807-; *PREMAZINE-; *PRIMATOL-S-; *PRINCEP-; *PRINTOP-; *RADOCON-; *SIMADEX-; *SIMANEX-; *SIMAZIN-; *SIMAZINE-80W-; *SYMAZINE-; *TAFAZINE-; *TAFAZINE-50-W-; *TAPHAZINE-; *TRIAZINE-A-384-; *S-TRIAZINE, 2-CHLORO-4,6-BIS(ETHYLAMINO)-; *1,3,5-TRIAZINE-2,4-DIAMINE,-6-CHLORO-N,N'-DIETHYL-; *ZEAPUR- RN: 122-34-9 RELT: 413 [ATRAZINE] (Analog) MF: *C7-H12-Cl-N5 SHPN: UN 2997; Triazine pesticide, liquid, flammable, toxic, not otherwise specified, flashpoint between 23 deg C and 61 deg C UN 2764; Triazine pesticide, liquid, flammable, toxic, not otherwise specified, flashpoint less than 23 deg C UN 2998; Triazine pesticide, liquid, not otherwise specified UN 2763; Triazine pesticide, solid, not otherwise specified IMO 6.1; Triazine pesticide, liquid, flammable, toxic, not otherwise specified, flashpoint between 23 deg C and 61 deg C; Triazine pesticide, liquid, toxic, not otherwise specified; Triazine pesticide, solid, toxic, not otherwise specified IMO 3.2; Triazine pesticide, liquid, flammable, toxic, not otherwise specified, flashpoint less than 23 deg C STCC: 49 216 66; Triazine pesticide, solid, not otherwise specified (compounds and preparations), (agricultural insecticides, not elsewhere classified, other than liquid) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Simazine is made by the reaction of cyanuric chloride with two equivalents of ethylamine in presence of an acid acceptor. [R1] *Prepn: Hofmann, Ber 18, 2776 (1885); Pearlman, Banks, J Am Chem Soc 70, 3726 (1948); Thurston et al, J Am Chem Soc 73, 2981 (1951). [R2] FORM: *Granule, suspension concentrate, wettable powder, water dispersible granules. Mixtures (simazine +) ametryne; 2,4-DES; metoxuron; trietazine; dichlobenil; propyzamide; and many others. [R3, 1106] *Wettable powder, water dispersible granule, liquid, and granule. Premixes: Topanex (+diuron+glyphosate); Derby (+metolachlor); Simazat (+atrazine); Herbimix (+atrazine), Tropazin (+glyphosate); Ametrex Extra (+ametryn), Simazol (+amitrole), Terbutrex Combi (+terbutryn); Simatrol 55 (+atrazine+amitrole); Linusim SA (+linuron); Pathclear (+diquat dibromide+paraquat); Terraklene (+paraquat). [R4] MFS: *Drexel Chemical Company, Hq, 1700 Channel Ave., Memphis, TN 38106-1412, (901) 774-4370; Production site: Tunica, MS 38676 [R5] *Novartis Corporation, Hq, 556 Morris Avenue, Summit, NJ 07901, (908) 277-5000; Novartis Crop Protection, Hq, 410 Swing Road, Greensboro, NC 27409, (910) 632-6000; Production site: River Road, PO Box 11, St. Gabriel, LA 70776 [R5] OMIN: *COMPATIBLE WITH MOST OTHER PESTICIDES AND FERTILIZERS WHEN USED @ NORMAL RATES. [R6] *LIMITED STUDIES HAVE SHOWN SOME MINOR FUNGICIDAL AND NEMATOCIDAL ACTIVITY BUT NO INSECTICIDAL ACTIVITY. [R7, 436] *Applications of either sprays or granules should be made on bare soil prior to weed emergence. It also may be applied prior to planting for many crops. Simazine has little or no foliar activity and must be absorbed by plant roots. Under dry conditions, a shallow incorporation may increase the degree of weed control. For aquatic use such as in recreational or farm ponds, application may be made from several points in the pond. Natural water movement will disperse simazine. [R6] USE: *Selective systemic herbicide. Control of most germinating annual grasses and broad-leaved weeds. [R3, 1106] *Simazine is also used for selective control of algae and submerged weeds in ponds. It is approved for algae control in swimming pools, large aquaria, ornamental fish ponds, fountains, and recirculating water cooling towers. [R6] CPAT: *HERBICIDE, OF WHICH APPROXIMATELY 49% IS USED ON CORN, 8% ON CITRUS, 6% ON DECIDUOUS FRUITS, 5% ON FIELD CROPS, 3% ON VEGETABLES, 17% FOR INDUSTRIAL/COMMERCIAL USES, and 13% FOR AQUATIC USES (1975) [R8] *Estimated noncropland use of simazine: 1.925 to 3.300 million lbs AI/yr. National use of simazine by crop in 1987/89, lbs AI/yr: alfalfa, 420,348; almonds, 85,537; apples, 140,515; artichokes, 5,878; asparagus, 93,709; avocados, 43,355; blueberries, 30,767; cherries, 20,538; corn, 1,552,755; cranberries, 1,488; filberts, 3,447; grapes, 290,296; nectarines, 4,374; olives, 6,653; peaches, 66,846; pears, 12,051; pecans, 60,207; plums, 1,039; pomegranates, 1,380; raspberries, 4,409; seed crops, 186,535; strawberries, 8,165; and walnuts, 63,149. [R9] *In 1993, 91% of the total 1,129,947 pounds was applied to grape, citrus, fruit and nut crops, and right-of-ways. [R10] *In 1989, 1982, 1976, 1971, and 1966, approx. 3.964X10+6, 3.975X10+6, 3.253X10+6, 1.738X10+6, and 1.93X10+5 lbs. AI/yr, respectively, were used in U.S. agriculture. [R11] *Agricultural use of simazine from May 1991 to March 1992 was, metric tonnes: 0.96, 9.5, 67, 4.6, 52, 220, 3.9, 170, and 460 in the Minnesota River Basin, the White River Basin, the Illinois River Basin, the Platte River Basin, the Missouri River Basin, the Ohio River Basin, and the Mississippi River Basin at Clinton, IA, Thebes, IL, and Baton Rouge, LA, respectively. [R12] PRIE: U.S. PRODUCTION: *(1975) 3.54X10+9 G (CONSUMPTION) [R8] *(1976) PROBABLY GREATER THAN 2.27X10+6 G [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE SOLID [R13]; *Colorless powder [R3, 1106]; *Crystals from ethanol or methyl Cellosolve [R2] MP: *225 to 227 deg C (decomp) [R3, 1106] MW: *201.66 [R2] DEN: *1.33 at 22 deg C /as per source/ [R3, 1106] DSC: *pKa = 1.62 at 20 deg C [R3, 1106746] OWPC: *log Kow= 2.18 [R14] SOL: *400 PPM IN METHANOL @ 20 DEG C [R15]; *3.0 PPM IN N-PENTANE @ 25 DEG C [R16]; *Slightly sol in ethyl cellosolve, dioxane [R2]; *In water, 6.2 mg/l (pH 7, 20 deg C) [R3, 1106]; *In ethanol 570, acetone 1500,, toluene 130, n-octanol 390, n-hexane 3.1 (all in mg/l, 25 deg C). [R3, 1106] SPEC: *Intense mass spectral peaks: 44 m/z (100%), 201 m/z (78%), 186 m/z (51%), 43 m/z (51%) [R17]; *Intense mass spectral peaks: 72 m/z, 84 m/z, 173 m/z [R18] VAP: *2.2X10-8 mm Hg @ 25 deg C [R3, 1106] OCPP: *Relatively stable in neutral, weakly acidic and weakly alkaline media. Rapidly hydrolyzed by stronger acids and bases; calculated half-lives: 8.8 days at pH 1, 3.7 days at pH 13 (20 deg C). Decomposed by U.V. irradiation (approx. 90% in 96 h). [R3, 1106] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of simazine stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, dermal contact), exposure to this colorless to white powder may occur from its manufacture, formulation, and use as an herbicide. Effects from exposure may include eye and dermal irritation, shortness of breath, muscle spasms, ataxia, and anorexia. In activities and situations where over exposure may occur, wear a self-contained breathing apparatus and personal protective clothing. If contact should occur, immediately flush affected skin or eyes with running water for at least 15 minutes. Remove contaminated clothing and shoes at the site. While simazine does not ignite easily, it may burn with the production of irritating and poisonous gases. For fires involving simazine, extinguish with dry chemical, CO2, Halon, water spray, fog, or standard foam. Simazine may be shipped domestically via air, rail, road, and water, in containers bearing the label "Poison". Simazine should be stored in its original container, in dark, well-ventilated areas, away from heat, sparks, and other sources of ignition. Small dry spills of simazine may be placed into a clean, dry, covered container for later disposal (liquid solutions are first absorbed in sand or other noncombustible absorbent). Large liquid spills should be diked far ahead to prevent simazine from entering water sources and sewers. Before implementing land disposal of simazine, consult with regulatory agencies for guidance. DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Triazine pesticide, liquid, flammable, poisonous; Triazine pesticide, liquid, flammable, toxic; Triazine pesticide, liquid, poisonous, flammable; Triazine pesticide, liquid, toxic, flammable/ [R19, p. G-131] +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Triazine pesticide, liquid, poisonous; Triazine pesticide, liquid, toxic; Triazine pesticide, solid, poisonous; Triazine pesticide, solid, toxic/ [R19, p. G-151] FPOT: *Combustible. [R20] FIRP: *Extinguish fire using agent suitable for type of surrounding fire. ... Use water in flooding quantities as fog. Use "alcohol foam", dry chemical or carbon dioxide. Wear positive pressure self contained breathing apparatus when fighting fires involving this material. /Triazine pesticide, solid, not otherwise specified (compounds and preparations), (agricultural insecticides, not elsewhere classified, other than liquid)/ [R21] *Avoid breathing dusts and fumes from burning material. Keep upwind. /Triazine pesticide, solid, not otherwise specified (compounds and preparations), (agricultural insecticides, not elsewhere classified, other than liquid)/ [R21] DCMP: *When heated to decomposition it emits very toxic fumes of /hydrogen chloride/ and nitrous oxides. [R22] SERI: *Simazine is a moderate eye and dermal irritant. [R23] EQUP: *The use of personal protective equipment such as glasses, synthetic gloves and /NIOSH/ approved breathing apparatus/ ... is important. /Herbicides/ [R24] OPRM: *Contact lenses should not be worn when working with this chemical. /Ethylamine/ [R25] *AVOID INHALATION OF DUST. [R7, 435] *Avoid contact with skin, eyes and clothing. [R26] *Only clean clothing ... should be worn and clothing should be changed daily ... Adequate sanitary facilites and washing water should be provided for workers to wash before meals. Smoking and consumption of alcoholic drinks before and during the handling of herbicides should be forbidden. Contaminated clothing should be removed immediately and a hot bath taken if possible. Personal hygiene should be encouraged. /Herbicides/ [R24] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. /Triazine pesticide, solid, not otherwise specified (compounds and preparations), (agricultural insecticides, not elsewhere classified, other than liquid)/ [R21] *Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Triazine pesticide, solid, not otherwise specified (compounds and preparations), (agricultural insecticides, not elsewhere classified, other than liquid)/ [R21] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SSL: *VERY STABLE OVER SEVERAL YR OF SHELF LIFE, AND ONLY SLIGHTLY SENSITIVE TO NATURAL LIGHT AND EXTREME TEMPERATURES WHICH WOULD OCCUR NORMALLY. [R7, 435] *Aquazine, Princep 4G, Princep 4L, Princep 80W, Princep Caliber 90 /have a/ half life of at least 3 to 5 yr when stored in a dry place. [R26] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] STRG: *Product must be stored in its sealed original containers, in well aired, fresh and dry storehouses or in shaded and possibly well aired places. It is recommended that the product be kept away from sources of heat, free flames or spark generating equipment. [R26] *Storage stability is three years at room temperature under dry conditions. [R23] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Noncombustible containers should be crushed and buried under more than 40 cm of soil. /Herbicides/ [R24] *Group I Containers: Combustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) should be disposed of in pesticide incinerators or in specified landfill sites. /Organic or metallo-organic pesticides/ [R30] *Group II Containers: Noncombustible containers from organic or metallo-organic pesticides (except organic mercury, lead, cadmium, or arsenic compounds) must first be triple rinsed. Containers that are in good condition may be returned to the manufacturer or formulator of the pesticide product, or to a drum reconditioner for reuse with the same type of pesticide product, if such reuse is legal under Department of Transportation regulations (eg 49 CFR 173.28). Containers that are not to be reused should be punctured ... and transported to a scrap metal facility for recycling, disposal or burial in a designated landfill. /Organic or metallo-organic pesticides/ [R31] *Treatment technologies which will remove simazine from water include activated carbon adsorption; ion exchange, and chlorine, chlorine dioxide, ozone, hydrogen peroxide and potassium permaganate oxidation. [R32] *Large quantities of simazine should be incinerated in unit operating at 850 deg C equipped with off gas scrubbing equipment. Recommendable method: Incineration. [R33] *Strong acid or alkaline hydrolysis leads to complete degradation, hydroxysimazine is not herbicidally active. Recommendable methods: Hydrolysis, ... and landfill. Peer review: Hydrolyze with hot 10% NaOH, dilute well before discharge or landfill. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R33] *... Atrazine, alachlor, metolachlor, cyanazine, metribuzin, carbofuran, linuron, and simazine were found in the influent to three water treatment plants in stormwater runoff. Studies at these plants, together with bench-scale studies, demonstrated poor control by conventional treatment processes. The relatively high adsorption capacities of these agrichemicals indicate that granular activated carbon can be cost effective for their control. Powdered activated carbon applied at dosages used for the control of tastes and odors can also be effective if moderate percent removal is required. [R34] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of simazine. There is limited evidence in experimental animals for the carcinogenicity of simazine. Overall evaluation: Simazine is not classifiable as to its carcinogenicity to humans (Group 3). [R35] MEDS: *Preliminary medical exam to detect chronic diseases of CNS, liver, heart, kidneys, lung and skin, as well as endocrinological or immunological disturbances, should ... /protect/ susceptible individuals. ... Periodical medical exam of internal organs, skin and eyes is important to avoid chronic occupational intoxications. It should include lab tests and patch tests if necessary. /Herbicides/ [R24] HTOX: *NO CASE OF POISONING IN MAN REPORTED, ALTHOUGH EXPOSURE TO SIMAZINE HAS CAUSED ACUTE AND SUBACUTE DERMATITIS IN USSR, CHARACTERIZED BY ERYTHEMA, SLIGHT EDEMA, MODERATE PRURITUS, AND BURNING LASTING 4-5 DAYS. [R36, 535] *EPA MONITORING SYSTEMS HAVE IDENTIFIED 699 BIOREFRACTORIES IN US WATER SUPPLIES. FROM AN ORIGINAL LIST OF 309 BIOREFRACTORIES IN 1977, THE NCI HAS IDENTIFIED AND CLASSIFIED 23 CARCINOGENS. ... THE CARCINOGENS INCL ... SIMAZINE. ... RESULTS OF 12 REPORTED EPIDEMIOLOGIC STUDIES ON DRINKING WATER INDICATE THAT RISK OF CANCER MAY BE GREATER ... IN SURFACE WATER THAN GROUND WATER, CHLORINATED WATER GREATER THAN NONCHLORINATED WATER, HIGH LEVELS OF TRIHALOMETHANES GREATER THAN LOW LEVELS OF TRIHALOMETHANES AND WATER FROM HIGHLY POLLUTED SURFACE WATER SUCH AS THE MISSISSIPPI GREATER THAN SURFACE WATER FROM LESS POLLUTED WATERS. ... [R37] *The possible role of a class of herbicides, triazines, in ovarian carcinogenesis has been evaluated in a population-based case-referent study. Women previously exposed to triazines showed a significant relative risk of 2.7 for ovarian neoplasms. Although none of the doses could be quantified for the study subjects, 2 risk trends in favor of the plausibility of the association were found: the first by duration and the second by probability of exposure. The population representativity of the study and the comparability of information between the cases and referents suggest the lack of any major bias in the results. Triazine-related risk remain consistent when the analysis was restricted to farmers and when the exposure to other herbicides and to other types of cultivation were considered. Unexposed farmers had the same risk as unexposed non-farmers. [R38] *... Implicated as a cause of occupational contact dermatitis. [R39] *Greenhouses are essentially microcosms aimed at providing physical environments suitable for the survival and growth of plants. Crops grown intensively in greenhouses in Great Britain include cut flowers, pot plants and edible crops such as tomato, lettuce, cucumber and celery. The enclosed conditions mean that greenhouse workers are more likely to be exposed conditions mean that greenhouse workers are more likely to be exposed to higher levels of plant material, plant pests and plant protection products than general horticulture workers. The potential for ill-health in greenhouse workers is examined with particular reference to Great Britain. The principal potential effects expected include irritancy, asthma, allergic alveolitis and dermatitis. Although biological control agents are widely used, there were no reports of their having caused ill-health in greenhouse workers. About two people per year are found to have suffered ill-health as a consequence of greenhouse exposure to chemical pesticides in reported pesticides incidents in Great Britain. [R40] NTOX: *SIMAZINE HAS BEEN FED TO RATS FOR 2 YEARS AT DIETARY CONCENTRATIONS OF 1, 10, and 100 PPM AND TO DOGS AT 12, 120, and 1200 PPM. THERE WERE NO EFFECTS IN RATS. DOGS WERE NOT AFFECTED AT 12 and 120 PPM AND SHOWED ONLY SLIGHT SIGNS OF TOXICITY AT 1200 PPM. [R41] *ACUTELY POISONED SHEEP AND CATTLE EXHIBITED MUSCULAR SPASMS, FASCICULATIONS, STIFF GAIT AND INCR RESP RATES. [R42] *... A SINGLE DOSE /ADMIN TO SHEEP/ AT A RATE AS LOW AS 500 MG/KG COULD BE FATAL, BUT THERE WAS CONSIDERABLE DELAY IN ONSET. DEATH OCCURRED WITHIN 5 TO 16 DAYS. THOSE THAT RECOVERED WERE SICK FOR 2-4 WK. SIGNS INCL INTAKE OF LESS FOOD BUT MORE WATER THAN USUAL, INCOORDINATION, TREMOR, AND WEAKNESS OF HIND QUARTERS. CYANOSIS AND CLONIC CONVULSIONS WERE SEEN IN SOME SHEEP. [R15] *PREGNANT RATS WERE EXPOSED TO AEROSOLS OF SIMAZINE DURING DAYS 7 THROUGH 14 OF GESTATION. HIGHEST CONCN WAS 317 + or - 89 MG/CU M. SIMAZINE DID NOT PRODUCE ANY PRENATAL CHANGES. [R43] *MALE ADULT ALBINO MICE, WHEN INJECTED IP WITH 5 MG/KG OF SIMAZINE, SHOWED DECR LEVELS OF GLUTAMATE OXALOACETATE TRANSAMINASE AND INCR LEVELS OF GLUTAMATE PYRUVATE TRANSAMINASE IN THE LIVER. SIGNIFICANT INCR IN HEPATIC PEROXIDATION AND EVIDENCE OF HEPATIC MEMBRANE DAMAGE AND RELEASE OF ENZYMES INTO SERUM WERE ALSO OBSERVED. [R44] *HORSES DIED AFTER INGESTION OF VEGETATION SPRAYED WITH SIMAZINE-AMINOTRIAZOLE MIXTURE. SYMPTOMS OBSERVED WERE COLIC AND INFLAMMATION OF GI TRACT. [R45] *CHRONIC EXPOSURE OF SHEEP TO 1.4 and 3.0 MG/KG OF SIMAZIN CAUSED HYPOFUNCTION OF THYROID; DOSES @ 6.0 and 25 MG/KG CAUSED COLLOID STROMA AND 250 MG/KG CAUSED PARENCHYMAL STROMA. DROP IN LIVER GLYCOGEN AND DEGRANULATION OF MASTOCYTES OF MESENTERY WERE ALSO OBSERVED. [R46] *HERBAZIN 50 ADMIN ORALLY AT 1.4 MG/KG/DAY FOR 150 DAYS DECR SHEEP'S WT BY 5.42%, INHIBITED SERUM CHOLINESTERASE, AND DECR BLOOD CAROTENE, MAGNESIUM AND PHOSPHATE LEVELS, WHEREAS SERUM GLUTAMIC OXALACETIC TRANSAMINASE AND ACID PHOSPHATASE WERE STIMULATED, AND THE BLOOD SUGAR AND LEUKOCYTES NUMBER ROSE. [R47] *HISTOLOGICAL CHANGES IN ORGANS OF 21 SHEEP WITH CHRONIC SIMAZINE POISONING FOLLOWING VARIOUS ORAL DOSES WERE AT DIFFERENT INTERVALS FATTY AND GRANULAR LIVER DEGENERATION, DIFFUSE GRANULAR KIDNEY DEGENERATION, NEURONOPHAGIA, DIFFUSE GLIAL PROLIFERATION AND DEGENERATION OF GANGLION CELLS IN CEREBRUM AND MEDULLA. REPEATED ADMIN OF 6.0 MG/KG FOR 142 DAYS AND 25 MG/KG FOR 37-111 DAYS CAUSED NECROBIOTIC AND DYSTROPHIC CHANGES IN GERMINAL EPITHELIUM OF TESTIS AND DISTURBANCE OF SPERMATOGENESIS. THYROID SHOWED HYPOFUNCTION AFTER REPEATED DOSES AT 1.4 MG/KG FOR 90-129 DAYS, 3.0 MG/KG FOR 63-65 DAYS AND 6.0 MG/KG FOR 142 DAYS. DOSE OF 25 MG/KG FOR 37-111 DAYS PRODUCED MARKED HYPOFUNCTION AND COLLOID GOITER. GREATEST ANTITHYROID EFFECT FOLLOWED 1 OR 2 DOSES OF 250 MG/KG, WHICH IN 1 SHEEP PRODUCED PARENCHYMATOUS GOITER AND PAPILLARY ADENOMA. PARENCHYMATOUS GOITER WAS ALSO PRODUCED IN SHEEP WHICH RECEIVED 50 OR 100 MG/KG EVERY 7 DAYS FOR 153 DAYS. [R48] *RECENT STUDIES THAT DEMONSTRATE THE ACTIVATION OF CHEMICALS, PARTICULARLY PESTICIDES, INTO MUTAGENS BY GREEN PLANTS ARE REVIEWED. RESULTS OF VARIOUS ASSAYS INDICATE THAT SIMAZINE INDUCE BOTH MITOTIC AND MEIOTIC CHROMOSOMAL ABERRATIONS AND THAT IT IS ACTIVATED BIOLOGICALLY INTO AGENT(S) THAT INDUCE POINT MUTATIONS. [R49] *A 2 yr chronic feeding study of simazine in dogs with simazine 80W fed at 15, 150, and 1500 ppm showed only a slight thyroid hyperplasia at 1500 ppm and slight increases in serum alkaline phosphatase and serum glutamic oxalacetic transaminase in several of the dogs fed 1500 ppm. [R50] *WHEN RATS WERE GIVEN SIMAZINE ORALLY AT RATE OF 15 MG/KG/DAY, A FEW HEPATOCYTES DEGENERATED DURING THE FIRST 3 DAYS BUT THE CONDITION DID NOT PROGRESS; INSTEAD, THE LIVER ADAPTED AND THE CMPD WAS METABOLIZED. [R15] *THE SACCHAROMYCES CEREVISIAE D3 AND D7 MUTAGENIC ASSAYS IN ABSENCE AND PRESENCE OF RAT METABOLIC ACTIVATION SYSTEMS WERE COMPARED USING 11 PESTICIDES. TESTS WITH SIMAZINE WERE NEGATIVE. [R51] *ASSAYS FOR DOMINANT LETHAL MUTATIONS, SEX LINKED RECESSIVE LETHAL MUTATIONS, AND CHROMOSOME BREAKAGE, NONDISJUNCTION, AND LOSS WERE PERFORMED ON MALE DROSOPHILA MELANOGASTER TREATED BY INJECTION OR BY LARVAL FEEDING OF SIMAZINE. IT SIGNIFICANTLY INCR RATE OF APPARENT DOMINANT LETHALS. HOWEVER, A REDUCTION IN EGG HATCH WAS PROBABLY DUE TO PHYSIOLOGIC TOXICITY TO SPERM. INJECTION ELEVATED X LINKED LETHALS, BUT LARVAL FEEDING DID NOT. SIMAZINE DID NOT SIGNIFICANTLY INCR PARTIAL LOSS OF Y CHROMOSOMES OR SEX CHROMOSOME NONDISJUNCTION. [R52] *THREE SPECIES OF FRESHWATER FISH, TILAPIA MOSSAMBICA, PUNCTIUS TICTO AND HETEROPNEUSTES FOSSILIS, WERE EXPOSED TO SIMAZINE AT 1, 5 OR 10 PPM. AT 10 PPM, IT CAUSED DEATH IN P TICTO IN ABOUT 10 DAYS AND IN ABOUT 19 DAYS IN H FOSSILIS. PROPOSED SAFE CONCN LIMITS ARE 0.1 PPM FOR T MOSSAMBICA AND P TICTO AND 1 PPM FOR H FOSSILIS. [R53] *THE MEDIAN LETHAL CONCN FOR SIMAZINE, EXPRESSED AS 80% WP FORMULATION, TO FINGERLING STRIPED BASS (MORONE SAXATILIS) WAS > 180 MG/L IN HARD AND SOFT WATER. [R54] *MALLARD DUCKS WERE EXPOSED TO DIETARY LEVELS OF SIMAZINE OF 2.0 and 20.0 PPM FROM PRIOR TO THE ONSET OF EGG LAYING THROUGH THE NORMAL EGG PRODUCTION CYCLE. REPRODUCTIVE PARAMETERS ANALYZED WERE: EGGS LAID, EGGSHELL CRACKS, VIABLE EMBRYOS, LIVE 3-WK EMBRYOS, NORMAL HATCHLINGS, 14 DAY OLD SURVIVORS, AND EGGSHELL THINNING. NO REPRODUCTIVE IMPAIRMENT WAS FOUND. [R55] */Treated/ rats exhibit drowsiness and irregular respiration. [R42] *... Nonirritant to skin and eyes of rabbits. [R56] *In 2 yr feeding trials no effect level was: for rats 100 mg/kg diet (7 mg/kg daily); for dogs 150 mg/kg diet (5 mg/kg daily). ... It is practically nontoxic to birds and honeybees. [R56] *Formation of carcinogenic compounds was observed after the in vitro nitrosation of such pesticides as atrazine and simazine. The carcinogen formed was the N-nitrosotriazine. [R57] *Simazine was negative in the reverse mutation assay using Salmonella typhimurium as the indicator organism, both in the absence and presence of external mammalian metabolic activation. (concentration or dose= 10 ug/plate; application=spot test) /From table/ [R58] *Negative results were obtained in reverse mutation assays. The addition of a mammalian metabolic activation system had no effect on the negative results. (Concentration dose= 6 concentrations, < 10 mg/plate) /From table/ [R59] *CYPRAZINE, ATRAZINE AND SIMAZINE WERE NOT MUTAGENIC IN 4 SALMONELLA TESTER STRAINS (TA98, TA100, TA1535, AND TA1538) AT UP 100 UG/PLATE IN PRESENCE OF AROCHLOR INDUCED S9. [R60] *At concentrations of 25 and 5 muM, simazine inhibited nitrate reductase activity in wheat (Triticum aestivum) and cucumber (Cucumis sativus) roots, respectively. It also lowered the content of soluble sugars and decreased the activities of NADH malate dehydrogenase and NADP+ glucose-6-phosphate dehydrogenase. The inclusion of 50 mM glucose into the medium partially reversed the inhibitor effect of simazine on the activity of nitrate reductase in cucumber roots and slightly increased the activity of this enzyme in wheat roots. These results suggest a complex influence of the herbicide on the activity of nitrate reductase: simazine lowers the level of soluble sugars in roots and decreases the activity of the dehydrogenase supplying the reduced nucleotides indispensable for reduction of nitrates. [R61] *A water-soluble extract from maize plants exposed to 3 s-triazine herbicides (atrazine, simazine and cyanazine) has been shown to be mutagenic in strain TA100 of Salmonella. No mutagenic activity was observed in any control plant extracts using either water or a variety of organic solvents. Gel permeation studies of the extracts suggest that the mutagen(s) are small molecules (less than 1000 MW). HPLC fractionation suggests that the mutagens formed from each of the 3 herbicides are similar in polarity and water solubility, eluting in a 50/50 water:methanol fraction. Approximately 89% of (14)C-labeled HPLC chromatographable metabolites of atrazine were also associated with this fraction, suggesting a close chemical link between a labeled but unidentified metabolite and the mutagenic activity. [R62] *The influence of some s-triazine herbicides on acid phosphatase and phosphodiesterase from corn (Zea mays) roots were investigated. Terbutryn stimulated both phosphatases, whereas prometryn stimulated only the phosphodiesterase. Atrazine, desmetryn, prometon, and simazine inhibited acid phosphatase. No effect was exerted by ametryn. The enzyme assays and the kinetic parameters demonstrated that the interferences observed were due to an action on the synthesis of one or both enzymes rather than on the enzyme reaction. The types of the N-alkyl and the chlorine-substituent groups in the structures of the s-triazines tested appear important in determining the degree if the interference. [R63] *The effects of s-triazine derived herbicides and a number of polycyclic chlorinated hydrocarbon pesticides on soya seed and bovine heart lactate-dehydrogenase activity were investigated in vitro. Dialyzed and lyophilized preparations of the two enzymes were used for the inhibition experiments. Enzyme activity was measured spectrophotometrically as the rate of loss of nicotinamide adenine dinucleotide from a reaction mixture containing sodium-pyruvate, phosphate buffer and an nicotinamide adenine dinucleotide solution. The reaction was started by adding an enzyme solution. Pesticides were added at various concentrations. From measurement of the dependence of the reaction rate on the nicotinamide adenine dinucleotide concentration at a constant saturation concentration of pyruvate, the inhibition constant was calculated for each pesticide. Eight chlorotriazines were used at concentrations of 0.16 or 0.33 mmol: atrazine, trietazine, terbutylazine, norazine, ipazine, chlorazine, propazine, and simazine. All but propazine and simazine inhibited bovine heart lactate-dehydrogenase, producing inhibition contants from 1.5 mmol for atrazine to 2.3 mmol for ipazine. The activity of the plant lactate-dehydrogenase was inhibited by atrazine (inhibition constant 3.7 mmol) and trietazine (inhibition constant 5.4 mmol). The methoxytriazines and methylthiotriazines, ametryne, desmetryne, atratone, and noratrone inhibited the reaction catalyzed by plant or animal enzymes with respect to the nicotinamide adenine dinucleotide coenzyme. Inhibitor concentrations were 0.66, 1.60, 2.50, and 3.30 mmol, respectively. Inhibition constants for bovine heart lactate-dehydrogenase were 6.5, 3.6, 71.0, and 44 mmol; for soya seed lactate-dehydrogenase for the same four compounds, inhibition constants were: 4.1, 7.5, 77.0, and 82.0 mmol. ... The authors conclude that most of these pesticides inhibit the reactions catalyzed by animal and plant lactate-dehydrogenase. Inhibition depends on the direct interaction of the inhibitor with the reduced coenzyme. [R64] *Triazine chloro derivatives, atrazine /and/ simazine, manifest no mutagenic and recombinogenic properties in yeast; triazine methylthio derivatives prometryne, semeron (desmetryne) generate both genetic events /at/ concentrations of 0.5 and 5 mg/l. ... Prometryne is more able to generate point mutations, while semeron generates mitotic recombinations. ... [R65] *Simazine perturbed development of gonads in ovo and in vitro and reduced fertility in chicks and quail. [R66] *Administration of simazine to rats during the organogenetic period (gestational days 6-15) caused embryolethality at > 312 mg/kg bw, decreased fetal body weight at 2500 mg/kg bw and retarded ossification at > or equal to 78 mg/kg bw. No teratogenic effect was observed. [R67] *When injected into male Drosophila melanogaster, simazine increased the frequency of X-linked lethals, but it failed to do so when fed to larvae. Other tests for mutagenicity in this species were negative [R68] *At the highest tolerated dose,...not tumorigenic in mice. The compound was found to produce sarcoma at the site of subcutaneous injection in both rats and mice, but this is not an appropriate route for testing. Simazine was found to be oncogenic in the rat at the highest feeding level tested, 100 ppm. Tumors were restricted to mammary tumors in female Sprague-Dawley rats. [R68] *The toxic potential of a pesticide mixture and two herbicide mixtures, M-HERB-1 and M-HERB-2, on in vitro fertilization (IVF) in the mouse was evaluated. Mixtures were added to the in vitro fertilization medium at various concentrations (0.1, 1.0 and 10.0 ug/mL). Oocytes contained in cumulus masses collected from superovulated B6D2F1 mice were cultured in media containing either the pesticide mixtures M-HERB-1 or M-HERB-2, to which capacitated sperm were added. Oocytes were assessed for fertilization 20-24 hr after insemination. The pesticide mixture significantly affected the in vitro fertilization rate and caused an increased incidence of abnormal embryos and degenerative oocytes at the 10 ug concentration. Both herbicide mixtures failed to show any significant effect on fertilization but did show a trend towards an increased incidence of degenerative oocytes following culture. [R69] *Pesticides and fertilizers, as used in modern agriculture, contribute to the overall low-level contamination of groundwater sources. In order to determine the potential of pesticide and fertilizer mixtures to produce developmental toxicity at concentrations up to 100x those found in groundwater, we studied a mixture of five pesticides (aldicarb, atrazine, dibromochloropropane, ethylene dibromide, and simazine) and one fertilizer component (ammonium nitrate). These chemicals and their relative concentrations in the stock mixture were selected on the basis of survey data from California (pesticides) and Iowa (fertilizer). The mixture (CALF) was administered in the drinking water to Sprague-Dawley rats (21-23/gp) on gestational days 6 to 20 at three dose levels, i.e., 1x, 10x, and 100x, where 1x was the median concentration of each pesticide component as determined in the surveys. Dams were monitored daily for signs of toxicity. On gd 20 fetuses were removed and examined for effects of CALF on growth, viability, and morphological development. Maternal body weights, food and water consumption and clinical signs were all similar to the control values. No adverse effects of CALF treatment were observed for measures of embryo/fetal toxicity, including resorptions per litter, live litter size, and fetal body weight. CALF did not cause an increased incidence of malformations or variations. In summary, under the conditions of this study, exposure of pregnant rats to a mixture of ammonium nitrate and pesticides at levels up to 100-fold greater than the median human exposure in groundwater supplies did not show any detectable adverse effects on the dam or developing conceptus. [R70] *It should be investigated whether UV-disinfection of natural and contaminated organic substances in surface and drinking water may generate a positive mutagenic effect. Selected organic pesticides (atrazine, simazine, metobromurone, methabenzthiazurone, dichlorprop) and organic compounds naturally present in water (phenylalanine, tyrosine, polysaccharides) were examined in Ames-test (bacterial strains TA 98 and TA 100) and sister chromatid exchange (SCE)-test (V79 cells) before and after UV-irradiation. UV-irradiation with low- and high-pressure mercury vapor lamps was carried out in parallel experiments. Based on results in Ames- and sister chromatid exchange-test a mutagenic activity was not obtained for all samples, neither before nor after UV-irradiation. [R71] *... Chlomethoxyfen and simazine induced sister chromatid exchanges significantly in V79, but the dose dependencies were poor. Simetryn had rec effect and was concluded to have DNA damaging activity. [R72] *... The effect of herbicides and management (application of superphosphate and subterranean clover seed) on regeneration of vulpia in pasture was evaluated over a 2 yr period at 6 sites in central and southern New South Wales (Beckom, Wagga Wagga, Eugowra, Bathurst, Holbrook and Millthorpe) during 1989-91. Four herbicide strategies (nil, spraytopping with paraquat in spring 1989, winter cleaning with simazine in winter 1990, and spraytopping with paraquat in spring 1989 followed by winter cleaning with simazine in 1990) were evaluated at a low (no added superphosphate or subterranean clover seed) and high level (250 kg/ha additional superphosphate applied in autumn 1989 and again in autumn 1990, plus 10 kg/ha subterranean clover seed broadcast in 1989) of management. Herbicides decreased the incidence of vulpia (as assessed from seedling density and pasture composition measurements) at low and high levels of management, with simazine and the combined paraquat plus simazine treatment providing more effective control than paraquat. The population of vulpia, however, increased rapidly on both the simazine and paraquat treatments with time. [R73] *Aquatic plant toxicity tests are frequently conducted in environmental risk assessments to determine the potential impacts of contaminants on primary producers. An examination of published plant toxicity data demonstrates that wide differences in sensitivity can occur across phylogenetic groups of plants. Yet relatively few studies have been conducted with the specific intent to compare the relative sensitivity of various aquatic plant species to contaminants. We compared the relative sensitivity of the algae Selenastrum capricornutum and the floating vascular plant Lemna minor to 16 herbicides (atrazine, metribuzin, simazine, cyanazine, alachlor, metolachlor, chlorsulfuron, metsulfuron, triallate, EPTC, trifluarlin, diquat, paraquat, dicamba, bromoxynil, and 2,4-D). The herbicides studied represented nine chemical classes and several modes of action and were chosen to represent major current uses in the United States. Both plant species were generally sensitive to the triazines (atrazine, metribuzin, simazine, and cyanazine), sulfonureas (metsulfuron and chlorsulfuron), pyridines (diquat and paraquat), dinitroaniline (trifluralin), and acetanilide (alachlor and metolachlor) herbicides. Neither plant species was uniformly more sensitive than the other across the broad range of herbicides tested. Lemna was more sensitive to the sulfonureas (metsulfuron and chlorsulfuron) and the pyridines (diquat and paraquat) than Selenastrum. Selenastrum was more sensitive than Lemna to one of two thiocarbamates (triallate) and one of the triazines (cyanazine). Neither species was sensitive to selective broadleaf herbicides including bromoxynil, EPTC, dicamba, or 2,4-D. Results were not always predictable in spite of obvious differences in herbicide modes of action and plant phylogeny. Major departures in sensitivity of Selenastrum occurred between chemicals within individual classes of the triazine, acetanilide, and thiocarbamate herbicides. Results indicate that neither species is predictively most sensitive, and that a number of species including a dicot species such as Myriophyllum are needed to perform accurate risk assessments of herbicides. [R74] *Field studies were conducted at two sites in Nebraska (NE1 and NE2) and one site in Kansas (KS) in 1994 to determine the influence of selected preemergence herbicides on establishment of seeded "Sharp's Improved" buffalograss (Buchloe dactyloides (Nutt.) Engelm.). Herbicides were applied within 2 days after seeding. Application of imazethapyr at 0.07 kg/ha usually resulted in buffalograss seedling density, vigor, and foliar cover that were superior to buffalograss stands where other herbicides were applied. Buffalograss response to AC 263,222 at 0.07 kg/ha was variable and appeared to be influenced by level of weed interference. Seedling density and vigor of buffalograss on areas treated with AC 263,222 were the same or less than on nontreated areas at KS and NE2, where wee infestations were low and moderate (5% and 45% weed foliar cover 12 weeks after treatment (WAT) on nontreated areas). In contrast, buffalograss establishment was similar in AC 263,222- and imazethapyr-treated plots at NE1 where the weed infestation was high (> 70% weed foliar cover 12 WAT on nontreated areas). At 12 WAT weed foliar cover was delta 25% at NE1 and delta at NE2 where imazethapyr and AC 263,222 were applied. Of all herbicides evaluated, imazethapyr at 0.07 kg/ha was superior for suppressing annual grass and broadleaf weeds with no observable deleterious effects on buffalograss establishment from seed. ... [R75] *The overall pesticide effects on mortality, growth and emergence of two dominant species of Ephemeroptera in Japanese rivers, Epeorus latifolium and Ecdyonurus yoshidae, were assessed using an outdoor channel carrying water from the Kokai River. Young larvae collected from another river were introduced into cages in the channel after their body lengths were measured. The concentrations of 17 pesticides were measured three times a week from April to August 1993. A shrimp mortality test on water samples was conducted concurrently. A relationship between the high mortality of the shrimp in the water samples and of E. latifolium in the channel was recognized. The mortality of E. yoshidae increased only when the shrimp mortality increased drastically in early June, reflecting the difference in insecticide susceptibility between he two mayfly species. Almost all the larvae which had been introduced into the channel in winter and/or early spring, when pesticides had cleared from the river, emerged in spring, although their growth rate during the winter was low. The shrimp mortality in the river water samples was caused by the overall pesticide toxicity. The increase in the mortality of the mayfly larvae in the channel might be due to the overall pesticide toxicity, although their concentrations were low and varied independently. [R76] *Feeding rates of different species of fish exposed to 2,4-D, simazine and urea were determination 96th static tests. At various water temperatures (20, 21, 24, 26, 28, 31, 32 and 36 deg C), feeding rates of Labeo rohita and Oreochromis mossambicus were either comparable to control or significantly reduced. At 36 deg C, feeding rates of L. rohita and O. mossambicus exposed to 2,4-D and simazine were decreased by 16.7 and 23.3% of control fish, respectively. At 32 and 36 deg C, feeding rates of L. rohita exposed to urea were decreased by 33.36% of control values. [R77] *The 96 hr LC50 values showed that the toxicity of diammonium phosphate, rockphosphate and simazine to aquatic life increased along with the increase in temperature of water. Simazine was most toxic followed by diammonium phosphate and rockphosphate. Mixture of chemicals being less toxic than individuals. [R78] *We studied differences in family and guild compositions, seasonal trends of abundance, and mean body length of spiders in Massachusetts commercial apple, Malus pumila (P. Mill), orchards under different pesticide regimes. The 4 guilds were active nocturnal hunters (Anyphaenidae), visual hunters (Oxyopidae and Slaticidae), ambushers and runners (Thomisidae and Philodromidae), and web builders (mostly Araneidae and Therididae). In 11 orchard blocks in 1991 and 1992, we compared spider populations in 1st-level integrated pest management (IPM) plots (where insecticides were applied as needed through August) with those in 2nd-level integrated pest management plots (where insecticides were applied only until early June). In a single orchard block in 1995, we compared spider populations in three 2nd-level integrated pest management plots with those in plots that were not treated with pesticides. In all treatments, spider numbers increased over time. However, by the end of the growing season, spiders were 3 times more abundant in 1991 and 2 times more abundant in 1992 in 2nd-level than in 1st-level integrated pest management plots. After treatment, the mean number of spiders collected in 2nd-level integrated pest management plots in 1995 dropped topsprayed plots. Later in the season, spider numbers increased more rapidly in the unsprayed plots. We found no significant differences in family and guild compositions of spiders between 1st-level and 2nd-level integrated pest management plots in 1992. In 1995, however, we found proportionately more philodromids and less theridids in 2nd-level integrated pest management plots than in the unsprayed plots. The mean body length of spiders did not differ between 1st-level and 2nd-level integrated pest management plots in 1992. Following treatment, in 1995, mean body lengths of visual hunters and web builders were numerically smaller in 2nd-level integrated pest management than in no pesticide plots. These differences were most probably caused by insecticide-caused mortality of resident adults in May in 2nd-level integrated pest management plots. Because body lengths of spiders are related to the sizes and therefore the types of prey they consume, the negative effect of pesticides on mean body lengths of visual hunters and web builders may affect their role as predators of different types of arthropod pests. We conclude that insecticides, even if applied only early in the season, have a marked season-long negative effect on spider populations found on apple trees in commercial orchards in Massachusetts. This effect may differ depending on the spider species. [R79] NTOX: *Poison by intraveous route. Moderately toxic by ingestion. May cause weight loss and reduced red blood cell count. [R22] NTXV: *LD50 Rat oral > 5000 mg/kg /Technical/; [R56] *LD50 Rabbit percutaneous > 3100 mg/kg /Technical/; [R26] *LD50 Rat oral > 15380 mg/kg /Princep 80W/; [R26] *LD50 Rabbit percutaneous > 10200 mg/kg /Princep 80W/; [R26] *LD50 Rabbit percutaneous > 3000 mg/kg /Princep 4L/; [R26] *LD50 Rat oral > 34000 mg/kg /Princep 4L/; [R26] *LD50 Rabbit percutaneous > 2000 mg/kg /Princep Caliber 90/; [R26] ETXV: *LC50 BOBWHITE ORAL > 5000 PPM IN 5 DAY DIET, AGE 10 DAYS OLD /SAMPLE PURITY 99.1%/; [R80] *LC50 JAPANESE QUAIL ORAL > 3720 PPM IN 5 DAY DIET, AGE 12 DAYS OLD /SAMPLE PURITY 99.1%/; [R80] *LC50 PHEASANT ORAL > 5000 PPM IN 5 DAY DIET, AGE 10 DAYS OLD /SAMPLE PURITY 99.1%/; [R80] *LC50 MALLARD ORAL > 5000 PPM IN 5 DAY DIET, AGE 1O DAYS OLD; [R80] *LC50 DAPHNIA MAGNA 1.1 MG/L/48 HR AT 21 DEG C, FIRST INSTAR /TECHNICAL MATERIAL, 98.1%; STATIC BIOASSAY/; [R81] *LC50 CYPRIDOPSIS 3.7 MG/L/48 HR AT 21 DEG C, MATURE (95% CONFIDENCE LIMIT 2.6-5.3 MG/L) /TECHNICAL MATERIAL, 98.1%; STATIC BIOASSAY/; [R81] *LC50 GAMMARUS FASCIATUS (SCUDS) > 100 MG/L/96 HR @ 21 DEG C, MATURE /TECHNICAL MATERIAL, 98.1%; STATIC BIOASSAY/; [R81] *LC50 PTERONARCYS 1.9 MG/L/96 HR @ 15 DEG C, 2ND YR CLASS (95% CONFIDENCE LIMIT 0.9-4.0 MG/L) /TECHNICAL MATERIAL, 98.1%; STATIC BIOASSAY/; [R81] *LC50 SALMO GAIRDNERI (RAINBOW TROUT) > 100 MG/L/96 HR @ 12 DEG C, WT 1.2 G /TECHNICAL MATERIAL, 98.1%; STATIC BIOASSAY/; [R81] *LC50 PIMEPHALES PROMELAS (FATHEAD MINNOWS) > 100 MG/L/96 HR @ 25 DEG C, WT 0.7 G /TECHNICAL MATERIAL, 98.1%; STATIC BIOASSAY/; [R81] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) 100 MG/L/96 HR @ 24 DEG C, WT 1.0 G /WETTABLE POWDER, 80%; STATIC BIOASSAY/; [R81] *LC50 Crucian carp > 100 mg/l/96 hr /Conditions not given for assay/; [R56] *LC50 Salmo gairdneri (rainbow trout) 85 ppm/48 hr /Conditions not given for assay/; [R82] *LC50 Lepomis macrochirus (bluegill) 130 ppm/48 hr /Conditions for assay not given/; [R82] *LC50 Oncorhynchus kisutch (coho salmon) 6600 ug/l/48 hr /Conditions for assay not given/; [R82] ADE: */SIMAZINE IS/ ABSORBED MOSTLY THROUGH PLANT ROOTS WITH LITTLE OR NO FOLIAR PENETRATION. IT HAS LOW ADHERING ABILITY AND IS READILY WASHED FROM FOLIAGE BY RAIN. FOLLOWING ROOT ABSORPTION IT IS TRANSLOCATED ACROPETALLY IN THE XYLEM, ACCUMULATING IN APICAL MERISTEMS AND LEAVES OF PLANTS. [R7, 435] *SIMAZINE WAS READILY ABSORBED AND DISTRIBUTED IN SPRUCE SEEDLINGS. DEGRADATION OF SIMAZINE TOOK PLACE IN ROOTS AND STEM TO THE HYDROXY ANALOG ... METABOLITES, BUT NO SIMAZINE, WERE OBSERVED IN NEEDLES. [R83] *SMALL AMT OF PARENT SIMAZINE AND ATRAZINE WERE REPORTED TO BE EXCRETED IN URINE OF COWS FED THE UNLABELED HERBICIDES FOR 4 DAYS. [R84, 170] *SIMAZINE RESIDUES FROM WATER TREATED @ 2.5 PPM ROSE TO A MAX OF 2.2 PPM IN BLUEGILL AFTER 28 DAYS AND DECLINED TO 0.76 PPM AFTER 60 DAYS; IN BASS, THEY ROSE TO 1.50 PPM AFTER 28 DAYS AND DECLINED TO 0.88 PPM AFTER 60 DAYS. [R36, 533] *TRACES OF HERBAZIN 50 WERE FOUND IN LAMBS BORN BY EWES TREATED WITH HERBAZIN 50 DURING PREGNANCY. [R47] METB: *SIMAZINE IS READILY METABOLIZED BY TOLERANT PLANTS TO HYDROXYSIMAZINE AND AMINO ACID CONJUGATES. HYDROXYSIMAZINE CAN BE FURTHER DEGRADED BY DEALKYLATION OF SIDE CHAINS AND BY HYDROLYSIS OF RESULTING AMINO GROUPS ON RING AND SOME CARBON DIOXIDE PRODUCTION. [R7, 435] *GREEN ALGAE (ANKISTRODESMUS BRAUNIL AND CHLOROSARCINA SPECIES) METABOLIZED SIMAZINE. NO METABOLITES WERE IDENTIFIED. ... SIMAZINE ADDED TO POTS CONTAINING CYMBIDIUM PSEUDOBULBS, WAS CONVERTED TO HYDROXY SIMAZINE AND UNIDENTIFIED MATERIALS. [R83] *STUDIES ON FORMATION OF CARCINOGENIC N-NITROSO COMPOUNDS IN VIVO AND IN HUMAN ENVIRONMENT ARE REVIEWED. FORMATION OF A CARCINOGENIC COMPOUND WAS OBSERVED AFTER IN VITRO NITROSATION OF SIMAZINE TO CARCINOGENIC N-NITROSOTRIAZINE. [R85] *THE SOLUBLE FRACTION (105,000XG) FROM GOOSE, PIG AND SHEEP LIVER HOMOGENATES CONTAINS AN ENZYME WHICH METABOLIZES A MIXTURE OF ATRAZINE AND SIMAZINE IN IN VITRO INCUBATIONS BY COMBINATION OF HYDROLYSIS AND PARTIAL N-DEALKYLATION. COMPLETE DEALKYLATION WAS NOT OBSERVED AS SHOWN BY REMOVAL OF ONLY ONE ALKYL GROUP, BUT NOT BOTH, FROM THE COMPOUNDS CONTAINING CHLORINE OR HYDROXY GROUPS ATTACHED TO THE TRIAZINE RING. [R86] *GLUTATHIONE S-TRANSFERASE PREPN FROM MOUSE LIVER WAS PURIFIED 61 FOLD USING ATRAZINE AS THE SUBSTRATE. WHEN EXPT MEASURING CONJUGATION RATE WITH ATRAZINE, SIMAZINE OR PROPAZINE WERE UNDERTAKEN, ATRAZINE WAS CONJUGATED FASTER THAN EITHER OF THE OTHER CMPD. [R87] *Yellow poplar (Liriodendron tulipifera L) and black walnut (Juglans nigra L) dealkylated simazine. In addition to the monodealkylated simazine, the di-dealkylated 2-chloro-4,6-diamino-s-triazine was observed in yellow poplar and black walnut roots. Hydroxysimazine was also observed in yellow poplar roots but not in black walnut extracts. [R88] *Partial deamination may accompany hydrolysis and dealkylation in certain cases, as 2,4-dihydroxy-6-amino-s-triazine (ammelide) was identified as a product of simazine metabolism in Aspergillus fumigatus. [R89] *Simazine was rapidly metabolized to water sol cmpd in the leaves of corn, sorghum, and sugar cane and more slowly in susceptible barley, by displacement of the 2-chloro group with glutathione or gamma-glutamylcysteine. [R90] *In animals, the chief urinary metabolites of atrazine, simazine and propazine were the corresponding N-dealkyl triazines, 2-chloro-4-amino-6-(ethylamino)-s-triazine and 2-chloro-4-amino-6-(isopropylamino)-s-triazine. A third metabolite, 2-chloro-4,6-diamino-s-triazine, was reported in the urine of rats dosed with the 3 parent cmpd. This cmpd was the major metabolite in rats. [R91] *CHLOROTRIAZINES REACTED /WITH A PLANT ENZYME RESPONSIBLE FOR THEIR CONJUGATION/ IN THE DECREASING ORDER OF GS-13529, ATRAZINE, CYPROZINE, PROPAZINE, AND SIMAZINE WITH NO CORRELATION TO THEIR WATER SOLUBILITY OR PARTITION COEFFICIENTS. APPARENTLY, INTACT ALKYLAMINO SUBSTITUENTS @ BOTH C4 AND C6 POSITIONS ARE PREFERRED STRUCTURES FOR CONJUGATION SINCE MOST OF THE ENZYME ACTIVITY WAS LOST WHEN ONE OF THE SIDE CHAIN ALKYL GROUPS WAS REMOVED. [R84, 157] ACTN: *Various investigations indicate that the ability of triazines to interfere with photosynthesis is responsible for their biological activity. Simazine depletes carbohydrate by inhibiting the formation of sugars. The triazines inhibit the Hill reaction, ie, the formation of oxygen by chloroplasts of certain plants in the presence of light and ferric salts. [R92] *UNALTERED SIMAZINE ACCUMULATES IN SENSITIVE PLANTS, CAUSING CHLOROSIS AND DEATH. [R7, 436] *... Simazine, as well as other triazines, appears to act on metabolism of plant hormones, particularly plant growth regulation hormones. This conclusion results from studies in which triazines (including simazine), when applied at low rates, resulted in more vigorous and healthy plants than controls, yet at higher rates of application, resulted in growth inhibition. [R93] *SINCE CHLOROSIS IS THE FIRST SIGN OF THE EFFECT OF TRIAZINES ON PLANTS, INTERFERENCE WITH CARBON DIOXIDE ASSIMILATION AND SUGAR FORMATION CAN BE EXPECTED. STUDIES SHOWING THAT HILL REACTION IS INHIBITED CONFIRMED THIS. /TRIAZINES/ [R94] *... Their chief mode of action appears to involve carbohydrate metabolism. The chlorinated s-triazines inhibit starch accumulation by blocking the prodn of sugars. Similar behavior has been shown for the methoxy and methylthio-s-triazines. It has been reported that the s-triazines affect the tricarboxylic acid cycle with activation of phospho-phenyl pyruvate-carboxylase causing the disappearance of sucrose and glyceric acid with the formation of aspartic and malic acids. /s-Triazines/ [R95] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Simazine's production and use as a selective systemic herbicide is expected to result in its direct release to the environment. If released to air, a vapor pressure of 2.2X10-8 mm Hg at 25 deg C indicates simazine will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase simazine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 22 hours. Particulate-phase simazine will be removed from the atmosphere by wet and dry deposition. 1,3,5-Triazines, such as simazine, have UV absorption bands whose tail extends beyond 290 nm, suggesting a potential for direct photolysis. If released to soil, simazine is expected to have high to slight mobility based upon Koc values ranging from 78 to 3,559. Sorption was observed to increase with decreasing pH. Volatilization from moist and dry soil surfaces is not expected to occur based upon an estimated Henry's Law constant of 3.4X10-9 atm-cu m/mole and this compound's vapor pressure, respectively. Microbial breakdown in soil results in degradation of simazine at very variable rates, half-lives range from 27 to 102 days (median 49 days); temperature and moisture are the main factors affecting the rates. N-Desethyl simazine and 2-chloro-4,6-bisamino-s-triazine have been identified as metabolites. If released into water, some adsorption of simazine to suspended solids and sediment in the water column is expected based upon the Koc values. Biodegradation in surface water samples from three ponds in Japan, ranged from 0 to 30% and 0 to 24% after four and seven days incubation, respectively. In Po River water, an initial simazine concentration of 5 ug/l was reduced to 3.1 and 2.5 ug/l after 24 and 384 hours incubation, respectively. Volatilization of simazine from water surfaces is not expected to occur based upon its estimated Henry's Law constant. BCFs ranging from < 1 to 55 suggest bioconcentration in aquatic organisms is low to moderate, not high. Hydrolysis is expected to be a slow process; half-lives for simazine in aqueous buffer solutions at 25 deg C at pH 5, 7, and 9 are 70, > 200, and > 200 days, respectively. The product of simazine hydrolysis is 2-hydroxy-4,6-bis(ethylamino)-s-triazine. Estimated soil hydrolysis half-lives in Wongan Hills loamy sand at 9, 20, and 28 deg C were 144, 37, and 21 days, respectively. Humic and fulvic acids have been observed to favor the hydrolysis of triazine molecules. Occupational exposure to simazine may occur through inhalation of dust particles and dermal contact with this herbicide during or after its application or at workplaces where simazine is produced. The general population may be exposed to simazine via ingestion of contaminated drinking water. (SRC) ARTS: *Simazine's production and use as a selective systemic herbicide(1) is expected to result in its direct release to the environment(SRC). The amount of simazine used annually in the USA was estimated to be 4,795 million pounds in 1985(2). [R96] FATE: *AQUATIC FATE: Dissipation of simazine in pond and lake water was variable, with half-lives ranging from 50 to 700 days. The degradation compound G-28279 /1,3,5-triazine-2,4-diamine, 6-chloro-N-ethyl-; CAS Number 1007-28-9/ was identified in lake water samples. [R97] *TERRESTRIAL FATE: It has been reported that simazine and other s-triazines can be utilized by certain soil microorganisms as a source of energy(1). Microbial degradation products of simazine in soil include 2-chloro-4-amino-6-ethylamino-1,3,5-triazine and 2,4-dihydroxy-6-amino-1,3,5-triazine(1). Mineralization of 10.4% of (14)C-labeled simazine in 110 days has been reported in a clay-lime soil; no degradation of simazine was detected in a soil suspension test without the addition of glucose as an energy source suggesting that degradation of simazine in these soil experiments was due to co-metabolism(2). Reported persistence of simazine in soil varies from a half-life of < 1 month(3) to no degradation being observed in 3.5 months(4). The amount of organic matter in the soil may have a significant effect on the persistence of simazine(3). Additions of 1%, 5%, and 10% leaf compost to soil gave simazine half-lives of about 140, 60, and 40 days, respectively(3). [R98] *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values ranging from 78 to 3,559(2,3), indicate that simazine is expected to have high to slight mobility in soil(SRC). Increasing sorption has been observed with decreasing pH(4). Volatilization of simazine from moist soil surfaces is not expected to be important(SRC) given an estimated Henry's Law constant of 3.4X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Simazine is not expected to volatilize from dry soil surfaces based on a vapor pressure of 2.2X10-8 mm Hg(6). The half-lives for degradation (purportedly mainly soil-catalyzed hydrolysis) of simazine in Hatzenbuhl soil at pH 4.8 and Neuhofen soil at pH 6.5 are 45 and 100 days, respectively(7). Estimated soil hydrolysis half-lives in Wongan Hills loamy sand at 9, 20, and 28 deg C were 144, 37, and 21 days, respectively(8). Humic and fulvic acids have been observed to favor the hydrolysis of triazine molecules(9). Microbial breakdown in soil results in degradation of simazine at very variable rates, half-lives range from 27 to 102 days (median 49 days); temperature and moisture are the main factors affecting the rates(6). Complete mineralization of the s-triazine ring to CO2 by microbial degradation of triazine herbicides is typically low, 0.5 to 5%, in soil(2). During 6 months incubation in coarse sandy soils at 15 deg C, approx. 4 to 7% of the applied (14)C-ring-labeled-simazine was evolved as (14)CO2(10). Half-lives of simazine in soil biometer studies ranged from 32 to 91 days(11). N-Desethyl simazine and 2-chloro-4,6-bisamino-s-triazine were identified as metabolites(11). [R99] *AQUATIC FATE: Rate constants of 0.66X10-10, 1.01X10-10, and 0.61X10-10 mol/l sec were calculated for simazine following irradiation (300 nm at 40 deg C) in water (1X10-5 M), methanol (1X10-4 M), and n-butanol (1X10-4 M) solutions, respectively(1); these rate constants correspond to half-lives of 21 hours, 5.7 days, 9.5 days(SRC). However, photolysis of simazine did not occur in methanol, ethanol, butanol and water at wavelengths > 300 nm(2). The photolysis of simazine has been reported to be enhanced by the presence of the photosensitizer riboflavin(3). The overall half-life range for simazine in 4 Missouri ponds was 46 to 174 days(4). [R100] *AQUATIC FATE: Based on a classification scheme(1), Koc values ranging from 78 to 3,559(2,3), indicate that some adsorption of simazine to suspended solids and sediment in the water column is expected(SRC). Increasing sorption has been observed with decreasing pH(15). Simazine is not expected to volatilize from water surfaces(4,SRC) based on an estimated Henry's Law constant of 3.4X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(5). According to a classification scheme(6), BCFs ranging from < 1 to 55(7-9) suggest bioconcentration in aquatic organisms is low to moderate, not high(SRC). Hydrolysis is expected to be a slow process(SRC); half-lives for simazine in aqueous buffer solutions at 25 deg C at pH 5, 7, and 9 are 70, > 200, and > 200 days, respectively(10). The product of simazine hydrolysis is 2-hydroxy-4,6-bis(ethylamino)-1,3,5-triazine(10). Humic and fulvic acids have been observed to favor the hydrolysis of triazine molecules(11). Biodegradation in surface water samples from three ponds in Nagoya City, Japan, ranged from 0 to 30% after four days incubation; after 7 days incubation, biodegradation ranged from 0 to 24%(12). In Po River water, an initial simazine concentration of 5 ug/l was reduced to 3.1 and 2.5 ug/l after 24 and 384 hours incubation, respectively(13). A pKa of 1.62(14) indicates simazine will exist predominantly in the unionized form under environmental pHs(SRC). [R101] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), simazine, which has a vapor pressure of 2.2X10-8 mm Hg at 25 deg C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase simazine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 22 hours(3,SRC. Particulate-phase simazine may be physically removed from the air by wet and dry deposition(SRC). [R102] BIOD: *Simazine has been confirmed to be resistant to biodegradation in the Japanese MITI test which utilizes inoculum composed of sewage, soil and natural waters(1). Removal of simazine during biological sewage treatment has been reported to be unlikely, even after prolonged exposure to the biota(2). The simazine ring structure is neither cleaved nor utilized by anaerobic ecosystems(3). 14(C)-labeled simazine is slowly mineralized in a clay-lime soil as evidenced by the release of 10.4% of the theoretical yield of (14)CO2 after incubation for 110 days; no degradation of simazine was detected in a soil suspension test without the addition of glucose as an energy source suggesting that degradation of simazine in these soil experiments was due to co-metabolism(4). The products of microbial degradation of simazine in soil include 2-chloro-4-amino-6-ethylamino-1,3,5-triazine and 2,4-dihydroxy-6-amino-1,3,5-triazine(5). It has been reported that simazine and other s-triazines can be utilized by certain soil microorganisms as a source of energy(5). The decrease in simazine concn in a soil-solution enrichment culture microbial degradation system was 18% in 10 days(5). After 150 days incubation in soil lysimeters, only 3% of the applied simazine was present in lysimeter cores taken from a meadow soil, while up to 26% of simazine was present in lysimeter cores taken from a gravel track; the greater degradation in the meadow soil was partially attributed to a higher microbial biomass(6). During 6 months incubation in coarse sandy soils at 15 deg C, approx. 4 to 7% of the applied (14)C-ring-labeled-simazine was evolved as (14)CO2(7). Evolution of (14)CO2 during 184 days was 5.8% of the added simazine in fertilized moraine sand soil without previous pesticide treatment and 4.2% in unfertilized(7). In moraine sand previously treated with glyphosate, 6.4% of added simazine was evolved as (14)CO2 in unfertilized soil; 5.5% was evolved as (14)CO2 in fertilized soil(7). 5.1 and 7.1% of applied (14)C-simazine was evolved as (14)CO2 from fertilized and unfertilized sand soils, respectively(7). Complete mineralization of the s-triazine ring to CO2 by microbial degradation of triazine herbicides is typically low, 0.5 to 5%, in soil(8). In a study of bioavailability of simazine, using soil from a 20-year continuous corn field treated annually with simazine, 48% of the added (14)C-simazine was biodegraded during the 34-day incubation period; no biodegradation of the native aged simazine residues was observed(8). [R103] *Simazine, at an initial concn of 100 mg/l, reached 0.7% of its theoretical BOD over 2 weeks in an activated sludge inoculum(1). 4.4, 4.4, and 32.8% biodegradation of simazine was observed following 3, 6, and 9 hours incubation in activated sludge, respectively(2). Using the cultivation method to measure biodegradation in surface water samples from three ponds in Nagoya City, Japan, simazine biodegradation ranged from 0 to 30% after four days incubation; after 7 days incubation, biodegradation ranged from 0 to 24%(3). 90 days after the addition of uniformly ring-labeled (14)C-simazine to Lima silt loam, approx. 7% was mineralized; approx. 17% mineralization was observed after 90 days following a second application of the herbicide to the soil, 90 days after the first(4). Half-lives of simazine in soil biometer systems under standard (simulated outdoor) conditions using a silty loam and a silty sand were 77 (63) and 87 (91) days, respectively; half-lives in outdoor fallow (grown with barley) lysimeters using a silty sand and a silty loam were 32 (35) and 49 (53) days, respectively(5). In the biometer experiments, (14)CO2-evolution in the silty sand under standard (simulated outdoor) conditions was 17 (0.8) and 21 (1.2)% of the initial total radioactivity after 64 and 100 days, respectively; (14)CO2-evolution in the silty loam under standard (simulated outdoor) conditions was (3.6) and 4.9 (4.8)% of the initial total radioactivity after 64 and 100 days, respectively(5). N-Desethyl simazine and 2-chloro-4,6-bisamino-s-triazine were identified as metabolites(5). In Po River water, an initial simazine concn of 5 ug/l was reduced to 3.1 and 2.5 ug/l after 24 and 384 hours incubation, respectively(6). Microbial breakdown in soil results in degradation of simazine at very variable rates, half-lives range from 27 to 102 days (median 49 days); temperature and moisture are the main factors affecting the rates(7). [R104] ABIO: *The half-lives for degradation (purportedly mainly soil-catalyzed hydrolysis) of simazine in Hatzenbuhl soil at pH 4.8 and Neuhofen soil at pH 6.5 are 45 and 100 days, respectively(1). The hydrolysis half-lives for simazine in aqueous buffer solutions at 25 deg C at pH 5, 7, and 9 are 70, > 200, and > 200 days, respectively(1). The product of simazine hydrolysis is 2-hydroxy-4,6-bis(ethylamino)-1,3,5-triazine(1). The rate of hydrolysis may be increased by various catalysts based upon the observed increase in hydrolysis rates for the chemically similar herbicide atrazine in water solutions upon addition of sterilized soil(2) and humic(3) and fulvic acids(4). Humic and fulvic acids have been observed to favor the hydrolysis of triazine molecules(6). Estimated soil half-lives for simazine, applied at 1.50 mg/kg soil at 20 deg C were, days: 70 in Shenton Park sand, 45 in Watheroo sand, 53 in Wongan Hills loamy sand, and 91 in Merredin sandy clay loam; degradation was attributed to chemical hydrolysis since sterilization with gamma radiation had no effect on the rate of degradation(7). Estimated soil hydrolysis half-lives in Wongan Hills loamy sand at 9, 20, and 28 deg C were 144, 37, and 21 days, respectively(7). The rate constant for the reaction of simazine with hydroxyl radicals in aqueous solution at 24 deg C is 2.8X10+9 L/mol s at pH 3.5(8). This corresponds to a half-life of about 290 days(SRC) at an average aqueous hydroxyl radical concentration of 1X10-17 mol/l(9). Simazine has a pKa of 1.62 at 20 deg C(10), indicating it will exist predominantly in the unionized form at environmental pHs(SRC). [R105] *The rate constant for the vapor-phase reaction of simazine with photochemically-produced hydroxyl radicals has been estimated as 1.8X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 22 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Irradiation of simazine in water solution with light at wavelengths 290 nm at 40 deg C for 32 hours resulted in a 13% reduction of the simazine concn(2). Irradiation of simazine in saturated aqueous solution at pH 4 in the presence of riboflavin as a photosensitizer with direct outdoor sunlight or in a laboratory with a daylight lamp for 1 hour produced a 25% yield of N-deethylation products which reacted further; no 2-hydroxy derivatives were detected even after several days exposure(3). Photolysis of simazine did not occur in methanol, ethanol, butanol and water at wavelengths > 300 nm(4). 1,3,5-Triazines, such as simazine, have UV absorption bands whose tail extends beyond 290 nm(5), suggesting a potential for direct photolysis(SRC). [R106] BIOC: *BCFs of 2.3 to 3.2 and 9.7 to 14.6 were measured in carp at 0.1 and 0.01 mg/l, respectively(1). BCFs up to 55 have been reported in the literature(2). BCFs of 0.76 to 0.95 were measured in green sunfish (Lepomas cyanellus)(3), < 1 in bluegill sunfish(4), and 5 and 2, in bluegill sunfish and catfish, respectively(2). According to a classification scheme(5), these BCFs suggest the bioconcentration in aquatic organisms is low to moderate, not high(SRC). [R107] KOC: *Evidence has been reported that indicates that the basicity of s-triazine herbicides, such as simazine, is not the main factor governing adsorption to soil humic acids(1). It has been shown that the ability of s-triazines herbicides to act as electron donors to electron acceptor quinone-like units of humic acids also plays an important role in the adsorption(2). Ferrihydrite does not sorb simazine(3). Freundlich coefficients of 18.2, 4,869, 79.6, and 147.3 were measured on Ca Wyoming smectite, Fe Wyoming smectite, soil humic acid, and Fluka humic acid, respectively(3). Distribution coefficients, Kd, of simazine on Ca Wyoming smectite and Ca Arizona smectite showed increasing sorption with decreasing pH; approx. 0, 13.6, and 48.3% sorption was observed on Ca Arizona smectite at pH values of 5.5, 2.6, and 1.4, respectively, 11.8, 100, and 100% sorption was observed on Ca Wyoming smectite at pH values of 5.5, 2.4, and 1.4, respectively(3). An equilibrium sorption constant of 0.55 was determined in Tampa soil(4). Sorption of simazine onto Candler fine sand increased with increasing ionic strength of the electrolyte; using 1.0 M CaCl2 as an electrolyte for equilibration of soil with herbicides increased simazine sorption 32%, as compared to sorption using 0.01 M CaCl2(5). Simazine sorption onto Candler fine sand increased 27% when the electrolyte KCl concentration was increased from 1.0 to 2.0 M(5). Desorption of simazine in 1.0 M ammonium acetate increased as the electrolyte concentration during sorption was increased(5). In soil column studies, after leaching of 1770 mm of water over a four month period, 87.3, 88,5, and 88.2% of the applied (14)C was recovered in moraine sand, moraine sand, and fine sand, respectively; more than 50% of the applied (14)C was found between 0 and 10 cm(6). In soil lysimeters, after 50 mm rainfall during the first 20 days following simazine application at 2.6 kg/ha, leaching into the deeper soil layers was observed(7). [R108] *Koc: 135, avg of 174 soils(1); 138, avg of 147 soils(2). Based upon soil column, soil thin-layer chromatography, and Koc experiments, the mobility of simazine is expected to vary from slight to high in soil-types ranging from clay soils to sandy loam soils, respectively(3). Adsorption of simazine in soil has been observed to increase as titratable acidity, organic matter and, to a lesser extent, cation exchange capacity, and clay content of the soil increased(3,4,5). Soil structural effects may be more important than adsorption in determining movement of simazine in some soils(6). Simazine has been observed to leach to > 60 cm under field conditions in loam and silty clay loam soils(7). However, in another set of field experiments with a sandy loam soil and a clay soil, very little simazine movement was observed with nearly all of it remaining in the top 3 cm of the soil(7). Simazine exhibited low to intermediate mobility in soil thin-layer chromatography and soil-column leaching experiments with loam, silty clay loam, sandy clay loam, silt loam, silty clay, and clay loam soils in which the Rf range for simazine was 0.16 to 0.51; simazine was mobile to very mobile in sandy loam soil with Rf ranging between 0.80 to 0.96(8,9,10). In Taichung loam soil (0.94% organic matter, 21.8% clay, 46.2% silt, 32.0% sand, pH 6.5) under unsaturated conditions, 0.09% simazine residues reached a soil depth of 4 to 5 cm after 28 days; simazine residues were not detected at soil depths > 4 cm after 56 and 84 days(11). [R109] *Koc values ranging from 330 to 840 were calculated for simazine, in 0.005 M CaCl2, from adsorption isotherms following 1 day equilibration in five soils of the Gnangara Mound, western Australia(1). Koc values ranging from 103 to 277 were determined in 12 soils, median 160(2). A mean Koc of 1054 was determined in two sandy loam soils(3). In one soil Koc values ranged from 247 (depth 0 to 30 cm) to 3,559 (depth 165+ cm); Koc values in the second soil ranged from 361 (depth 0 to 27 cm) to 1,690 (depth 53 to 61 cm)(3). Koc values of 78 and 80 were measured using the sorption isotherms for (14)C-simazine in Capac soil following 24 and 48 hours equilibration, respectively(4). Koc values of 1,340 and 1,182 were measured using the desorption of aged simazine residues in Capac soil, with over 20 continuous years of annual simazine application, following 24 and 48 hours equilibration, respectively(4). According to a classification scheme(5), these Koc values suggest that simazine is expected to have high to slight mobility in soil(SRC). The total release of aged simazine from Capac soil with over 20 continuous years of annual simazine application was 32% of the predicted equilibrium concentration after 16 days; in contrast, desorption of recently added simazine was within 90% of the calculated equilibrium concentration within 1 to 24 hours(4). In soil column studies using Candler fine sand, 82% of applied simazine was leached in five pore volumes (equivalent to 15.2 cm rainfall); > 77% was leached in the first four pore volumes(6). [R110] VWS: *THE EFFECT OF MOISTURE ON VOLATILITIES OF SEVEN S-TRIAZINES WAS DETERMINED AT 45 DEG C ON TIFTON LOAMY SAND. ON WET SOIL THE ORDER OF LOSS OF HERBICIDES WAS TRETAZINE > ATRAZINE > AMETRYN APPROX EQUAL TO PROPAZINE APPROX EQUAL TO PROMETRYN APPROX EQUAL TO PROMETONE > SIMAZINE, WHEREAS ON DRY SOIL THE LOSSES WERE NOT AS EXTENSIVE. THE ORDER WAS TRIETAZINE > PROPAZINE > ATRAZINE APPROX EQUAL TO SIMAZINE APPROX EQUAL TO PROMETONE > AMETRYN APPROX EQUAL TO PROMETRYN. ADSORPTION AND WATER SOLUBILITY WERE SUGGESTED AS FACTORS THAT CAN AFFECT THE RATE OF VAPORIZATION OF THESE HERBICIDES. [R84, 924] *The Henry's Law constant for simazine is estimated as 3.4X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that simazine is expected to be essentially nonvolatile from water and moist soil surfaces(2,SRC). Simazine is not expected to volatilize from dry soil surfaces based on a vapor pressure of 2.2X10-8 mm Hg(3). Simazine has been found to be less volatile from moist soil than from dry soil(4). Virtually no loss of simazine was observed from metal planchet surfaces in 6 hours at 25 deg C(4). [R111] WATC: *DRINKING WATER: Simazine has been identified at trace levels (< 0.1 ppb) in 3 New Orleans LA drinking water supplies sampled in 1974(1). In a nationwide survey of pesticides in drinking water wells, simazine was detected in community water system wells (1.1%) and rural domestic wells (0.2%)(2). Simazine was detected in 2 water samples collected from 240 private wells in rural IL from March 1990 through Feb 1991 at concns of 0.24 and 0.76 ug/l(3). Simazine residues were verified in 142 wells in 9 counties in CA out of 2,203 wells sampled in 42 counties; concns of verified detections ranged from 0.05 to 0.86 ppb(4). Simazine was detected in 45.3% of Belgian drinking water samples collected between 1991 and 1993 at a mean concn of 0.00005 ppm; max concn 0.0002 ppm(5). Simazine was detected in water samples from 5 out of 102 farm wells in Kings County, Nova Scotia, Canada(6). It was detected in 32 water supply wells sampled between 1984 and 1990 in the State of CA at a max concn of 28 ug/l(7). Simazine was detected in drinking water in 1993 by European drinking water companies, number of samples > 0.1 ug/l: 32 Anglian; 1 North West; 7 Severn-Trent; and 3,652 Thames(8). Simazine was detected in 66 of 6,158 water samples from public drinking water sources in CA at concns ranging from 0.06 to 28.0 ug/l; mean 0.75, median 0.50 ug/l(9). Annual avg simazine concn in CA public drinking water sources were, ug/l: 0.0 in 1984, 0.72 in 1985, 0.54 in 1986, 0.42 in 1987, 1.21 in 1988, 0.65 in 1989, 0.67 in 1990, 0.55 in 1991, and 0.35 in 1992(9). [R112] *GROUNDWATER: Simazine has been found in groundwater from new wells in the Northern Italy province of Bergamo at a concn range of 0 to 200 parts/trillion(1). Simazine was detected in 5 of 237 wells in Ontario, Canada during 1969 to 1978 with 3 samples in the concn range of 0.1 to 1.0 ug/l, 1 sample was in the concn range of 1.1 to 10 ug/l, and one sample was in the concn range of greater than 10,000 ug/l(2). Simazine was detected in 4 of 112 wells suspected of contamination due to runoff and spray drift between 1979 and 1984 in rural Ontario, Canada; concn in 3 of the shallow wells were 0.1, 2.8, and 6.0 ug/l, respectively(3). Simazine was detected in groundwater samples from 7 out of 79 wells in New Zealand in 1994 at concns ranging from 0.06 to 1.6 mg/cu m(4). In a groundwater monitoring program carried out from 1985 to 1992 in southwestern Ontario, Canada, simazine was detected in water samples drawn from piezometers (located adjacent to fields in the sand plain areas) at max concns of 6.2, 2.2, 1.5, 15.3, and 3.6 ug/l in 1988, 1989, 1990, 1991, and 1992, respectively(5). Simazine was detected in approx. 22% of groundwater samples collected from alluvial wells in the Denver, CO metropolitan area at a max concn of 0.068 ug/l(6). Simazine has been detected in groundwater samples from various agricultural sites in Germany, ug/l (site, agricultural use): 1.4 (Coswig, decorative plants); 0.31 (Meiben, apple); 0.25 (Weinbohla, field forage); 0.18 and 0.6 (Coswig, cauliflower, strawberries, and kohlrabi); 0.1 (Brockwitz, pasture and strawberries); 0.12 and 2.9 (Weinbohla, strawberries and forage); 1.9 (Sornewitz and cereals)(7). Groundwater samples from 7 out of 9 agricultural sites in Germany, collected in Oct 1990, contained simazine at concns ranging from 0.05 to 5.0 ug/l(7). Simazine was detected in 1.2% of 303 groundwater wells sampled in the U.S. between 1991 and 1992(8). Simazine was detected in groundwater samples collected from the San Joaquin Valley, CA in 1985 to 1987; concns ranged from 0.1 to 1.1 ug/l(9). [R113] *GROUNDWATER: Concns of simazine in water samples taken from groundwater bores and springs in Germany ranged from < 0.01 to 0.2 ug/l(1). Simazine was detected in 287 water wells in California between 1975 to 1991; max concn detected was 19 ug/l(2). Simazine was detected in 2.6% of the 303 midwestern groundwater wells sampled between 1991 and 1994 at a max concn of 0.27 ug/l(3). Simazine was detected in groundwater in seven states (CA, CT, MD, NE, NJ, PA, VT) at a max concn of 9.10 ppb; median concn of positive detections 0.30 ppb(4). It was detected in 14 of 174 well water samples collected throughout NE at a median concn of 0.10 ppb, avg 0.17 ppb(5). [R114] *SURFACE WATER: Simazine was detected in the following numbers of samples out of 708 total samples from Central European streams in spring 1976 to fall 1977 within the indicated concn ranges: 7 samples 1.1 to 10 ppb; 25 samples 0.4 to 1.0 ppb; 86 samples < 0.4 ppb(1). Simazine was found in Swedish stream waters (1985 to 1987) in 3 of 153 samples taken during July to Sept at a max concn of 1.1 ppb and not detected in 106 samples taken during April to May and in Oct(2). Simazine was detected, not quantified, in 37% of creek water samples from the Hillman Creek watershed in southwestern Ontario, Canada(3). The residues were consistently higher at upstream sites than at the mouth(3). Simazine was found in 9.3% of samples of waters collected from 11 agricultural watersheds in Ontario, Canada during 1975 to 1976 at a max concn of 3.4 ng/l(4). The avg concn ranged from not detected to 0.04 ng/l and from not detected to 0.37 ng/l during May 1975 to April 1976 and May 1976 to April 1977, respectively, and he overall avgs were 0.02 and 0.06 ng/l, respectively(4). Simazine was detected in 27 out of 105 samples of river water collected from seven rivers flowing into Lake Biwa, Japan in April 1993 to March 1994(5). Simazine was detected in water samples collected from Lake Erie tributaries draining an agricultural watershed between April 1983 to Dec 1991; max concns were 2.374 ug/l in the Maumee River, 6.006 ug/l in the Snadusky River, 6.493 ug/l in Honey Creek, 3.683 ug/l in Rock Creek, 6.991 ug/l in Lost Creek, 2.530 ug/l in the Cuyahoga River, and 1.033 ug/l in the Raisin River(6). The net avg concn of simazine in water samples collected from a stream flowing through a golf course in Japan from April 1989 to March 1990 was 0.92 ug/l(7). Simazine was detected in 58% of water samples collected from the Susquehanna River fall line at concns ranging from 2 to 91 ng/l, mean 24 ng/l; max concn occurred in May(8). Simazine was detected in 80% of water samples collected from the Potomac River fall line at concns ranging from 6 to 140 ng/l, mean 62 ng/l; max concn occurred in June(8). Simazine was detected in 50% of water samples collected from the James River fall line at concns ranging from 3 to 370 ng/l, mean 6 ng/l; max concn occurred in April(8). In 1993, simazine was detected in 11.8% of the 17 water samples from Hungerford Brook, VT at a mean concn of 0.15 ug/l; range 0.1 to 0.2 ug/l(9). It was detected in 25% of 339 samples collected from 150 midwestern streams between 1989 and 1990, in 30% of 230 samples collected from the Mississippi River at Baton Rouge, LA between 1991 and 1994, and in 17% of 456 water samples collected from 76 reservoirs in 1992 and 1993(10). [R115] *SURFACE WATER: Loadings of simazine at the mouth of the Grand River and entering Lake Erie were 3.27 and 0.62 kg/yr, respectively, with all of the loading in the water and none in suspended solids(2). Simazine was found in samples of water from the mouths of the following rivers in Ontario, Canada from 1981 to 1985: Thames River, 8 of 201 samples positive, avg concn 0.6 ug/l; Saugeen River, 1 of 143 samples positive, avg concn 0.1 ug/l; Grand River, not detected in 85 samples(1). Simazine was detected in water from the mouths of the above rivers at the following concn: Grand River, 1975 to 1976, 20 samples, not detected to 10 ng/l, 5.8 ng/l avg, 1976 to 1977, 30 samples, not detected to 10 ng/l, 0.3 ng/l avg; Saugeen River, not detected in 34 samples from 1975 to 77(2). The U.S. EPA STORET data base has reported the occurrence of simazine in 1243 samples of surface water at an avg concn of 0.03 ug/l with a concn range of not detected to 25 ug/l and in 195 samples of whole water at an avg concn of 0.33 ug/l with a concn range of not detected to 25 ug/l(3). The National surface water monitoring program from 1976 to 1980 reported the detection of simazine in 0.4% of the water samples collected in the US at a max concn of 1.13 ppb(2). Simazine was detected in water samples collected from four sites in the river Windrush in Oxfordshire at concns ranging from 1.5 to 26 ng/l(5). In a study of streams in a small agricultural and a small urban area in CO, conducted between April 1993 and April 1994, simazine was detected in > 40% of the samples collected from the agricultural area and in > 75% of the samples collected from the urban area; median (maximum) concns were < 0.01 (0.033) and 0.022 (0.17) ug/l, respectively(6). Simazine was detected in water samples from streams in the Lower Susquehanna River and Potomac River Basins in June 1994 at concns ranging from < 0.008 to 1.40 ug/l(7). Simazine concns in water samples from small tributaries in the Sacramento Valley, CA in Jan 1994 ranged from 30 to 1,350 ng/l; it was not detected in water samples from two tributaries(8). Simazine was detected in the Rhine River at Karlsruhe (Dusseldorf) in 1986, 1987, and 1988 at 90th percentile concns of 0.40 (0.26), 0.08 (0.12), and 0.07 (0.14) mg/l, respectively(9). Simazine was detected in 8 rural Canadian ponds sampled between 1971 to 1985 at mean concns of 1.0 ug/l; it was also detected in two other ponds contaminated from spills at a mean concn of 1,470 ug/l(10). [R116] *SURFACE WATER: Mean simazine concns in water samples from four locations in the Yakima River Basin collected in Sept 1988, ng/l: 7.5 in Sulfur Creek; 55 in Granger Drain; 1.7 in Moxee Drain; and 1.5 in Yakima River at Kiona(1). Simazine was detected in 2,843 of approx. 3,000 water samples collected at 1,183 sampling sites between 1981 and 1991 in France, 140 sites had simazine concns above 100 ng/l; highest concn 2.7 ug/l(2). Simazine was detected in sub-surface seawater samples collected from estuarine and near-coastal sites of England and Wales in 1990, 1991, and 1992; concns in 1990, 1991, and 1992 ranged from < 0.6 to 34, < 0.6 to 12, and < 0.1 to 36 ng/l, respectively(3). Sub-surface seawater concns from offshore location ranged from < 0.6 to 3 ng/l in 1990 and < 0.1 to 9.6 ng/l in 1992(3). A max concn of 0.36 ug/l was detected in water samples from the Sacramento-San Joaquin Delta(4). Simazine concns in water samples collected from the Sacramento River at Rio Vista and the San Joaquin River Vernalis in Feb 1993 ranged from 65 to 331 and 89 to 844 ng/l, respectively(5). Simazine was detected in water samples from the Rhone river, France collected from seven stations located at the Camargue region in Nov 1990 at concns ranging from 10 to 19 ng/l(6). Median (maximum) simazine concns in rivers and streams of the midwestern U.S. were < 0.05 (8.7), 0.07 (7.0), and < 0.05 (0.21) ug/l in water samples collected prior to planting in March and April, after planting in May and June, and at harvest in Oct and Nov 1989, respectively(7). Simazine was detected in river water samples from an agricultural area in Japan in 1992 at concns ranging from 0.007 to 0.078 ug/l(8). Simazine was detected in 35% of water samples from Maskenthine Lake, NE and 33 to 37% of water samples from Willow Lake, NE at avg (maximum) concns of 0.07 (0.13) and 0.06 (0.11 to 0.13) ug/l, respectively(9). Concn ranges of simazine in water samples from different Mediterranean estuarine waters were, ug/l: 0.087 to 0.440, Ebro Drainage Canal; 0.028 to 0.138, Ebro River; 0.010 to 0.078, Ebro Delta Lagoons; 0.022 to 0.372, Rhone River; 0.018 to 0.227, Rhone Delta; 0.006 to 0.081, Po River; < 0.003 to 0.006, Northern Adriatic; < 0.06 to 0.30, Axios, Loudias, and Aliakmon Rivers; < 0.06, Thermaikos Gulf; < 0.06 to 0.40, Louros and Aracthos Rivers; < 0.06 to 0.10, Amvrakikos Gulf; and < 0.001, Nile Delta(10). [R117] *SURFACE WATER: Simazine concns in different natural water from the Valencia Community, Spain ranged from 0.308 to 0.629 ug/ml(1). Simazine was detected in 21 of 22 water samples from the Mississippi River and its tributaries in May to June 1988 at concns ranging from 6 to 130 ng/l; the highest concn was detected in the Mississippi River at Fulton, TN(2). It was detected in water samples collected from the Lower Mississippi River in May 1990 at concns ranging from 0.10 to 0.62 ug/l; concns in tributaries ranged from < 0.05 to 0.86 ug/l(3). 71 samples of surface water from south FL canals, collected in Nov 1991 to June 1995, contained simazine at a max concn of 2.5 ug/l(4). [R118] *RAIN/SNOW: Simazine was detected, not quantified, in samples of rainwater during spring and summer in the following locations: West Lafayette, IN (5 of 14 pos), Tifin, OH (3 of 24 pos), Parsons, WV (1 of 20 pos), and Potsdam, NY (1 of 21 pos)(1). Concns of 0.1 and 0.2 ug/l have been detected in rainwater(2). Simazine was detected in 2.7% of 1,056 rainwater samples collected in 10 midwestern states in 1990 and 1991(3). Simazine was detected in bulk precipitation samples collected from La Ferte sous Jouarre and Paris from 1992 to 1993 at concns ranging from < 5 to 650 and < 5 to 680 ng/l, respectively(4). Concns of simazine in rainwater collected from Paris, France in 1991 ranged from < 5 to 100 ng/l; the highest concn was found in June(5). Simazine was detected in 7 (2) samples of rain from Schauinsland (Deuselbach), Germany between June 1990 and August 1991 at concns ranging from 0.010 to 0.094 (0.012 to 0.044) ug/l, mean 0.32 (0.028) ug/l(6). It was also detected in 5 samples of rain from Bensheim, Germany between May 1990 and April 1991 at concns ranging from 0.005 to 0.063 ug/l, mean 0.025 ug/l(6). [R119] EFFL: *Simazine was detected in 6 of 48 wells suspected of contamination due to spills between 1979 and 1984 in rural Ontario, Canada(1). Simazine was detected, not quantified, in 1 (oil refinery final effluent) of 10 final effluents from industrial plants and publicly-owned treatment works in the US in 1980(2). Whereas simazine was not detected in a sample of industrial effluent nor in the water of the river into which the effluent was discharged, it was detected at 1,000 and 10 ppm in the sediment of the river 1.5 km downstream from the plant and near a nearby dam, respectively(3). [R120] SEDS: *SOIL: Simazine was detected in Ninigret sandy loam collected at Franklin, CT at concns of 6.9 and 10.2 ppb at soil depths of 0 to 0.9 and 5.9 to 7.5 ft, respectively(1). Simazine was detected in 50 of 822 soil samples collected from 49 agrichemical facilities located throughout IL at a median concn of 73 ug/kg, range 18 to 72,100 ug/kg(2). [R121] *SEDIMENT: The U.S. EPA STORET database has reported the occurrence of simazine in 382 samples of surface water mud at an avg concn of 1.3 ug/kg; range of not detected to 500 ug/kg(1). The National surface water monitoring program from 1976 to 1980 reported the detection of simazine in 0.2% of the sediment samples collected in the USA at a max concn of 0.1 ppb(2). Simazine was detected in sediment collected from the German Wadden Sea in Sept 1993 at concns ranging from 11 to 400 ng/kg wet weight(3). Simazine was detected in sediment samples from 3 of 5 Essex salt marsh sites, UK, max concn: Walton-on-the-Naze, 2.1 ng/g; Tollesbury Wall, 10.1 ng/g; and South Woodham Ferrers, 15.3 ng/g(4). It was also detected in mud flat cores at Walton-on-the-Naze at a concn of 0.1 ng/g dry weight and vegetated marsh creek cores at Tollesbury Wall at a concn of 2.0 ng/g dry weight(4). [R122] ATMC: *URBAN/SUBURBAN: Simazine was detected in samples of ambient air from Kitakyushu City, Japan at concns of 0.14 and 0.58 ng/cu m in July 1991 and April 1992, respectively(1). [R123] *RURAL/REMOTE: Vapor phase concns of simazine at La Ferte sous Jouarre between 1992 and 1993 ranged from < 0.03 to 3 ng/cu m(1). [R124] FOOD: *Simazine was not detected (detection limit 10 ppb) in 25 composite samples of Ontario-grown potatoes analyzed in 1983-1985(1). Simazine was detected in 1 out of 862 samples of domestic oranges in 1985 to 1991 at a concn of 0.10 ppm(2). [R125] OEVC: *Extinguishing water used to fight a chemical fire in an industrial storage complex in a suburb of Antwerp, Belgium contained simazine; concn was not reported(1). [R126] RTEX: *Those involved in manufacture, formulation and application of this ... herbicide. [R50] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 357 workers are potentially exposed to simazine in the US(1). The NOES Survey does not include farmworkers. Occupational exposure to simazine may occur through inhalation of dust particles and dermal contact with this herbicide during or after its application or at workplaces where simazine is produced(SRC). The general population may be exposed to simazine via ingestion of contaminated drinking water(SRC). [R127] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *... 0.215 mg/kg/day. [R1] ATOL: *Tolerances are established for residues of the herbicide simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) in or on the following raw agricultural commodities: alfalfa 15 ppm; alfalfa, forage 15 ppm; alfalfa, hay 15 ppm; almonds 0.25 ppm; almonds, hulls 0.25 ppm; apples 0.25 ppm; artichokes 0.5 ppm; asparagus 10 ppm; avocados 0.25 ppm; bermuda grass 15 ppm; bermuda grass, forage 15 ppm; bermuda grass, hay 15 ppm; blackberries 0.25 ppm; blueberries 0.25 ppm; boysenberries 0.25 ppm; cattle, fat 0.02(N) ppm; cattle, mbyp 0.02(N) ppm; cattle, meat 0.02(N) ppm; cherries 0.25 ppm; corn, fodder 0.25 ppm; corn, forage 0.25 ppm; corn, fresh (inc. sweet K+CWHR) 0.25 ppm; corn, grain 0.25 ppm; cranberries 0.25 ppm; currants 0.25 ppm; dewberries 0.25 ppm; eggs 0.02(N) ppm; filberts 0.25 ppm; goats, fat 0.02(N) ppm; goats, mbyp 0.02(N) ppm; goats, meat 0.02(N) ppm; grapefruit 0.25 ppm; grapes 0.25 ppm; grass 15 ppm; grass, forage 15 ppm; grass, hay 15 ppm; hogs, fat 0.02(N) ppm; hogs, mbyp 0.02(N) ppm; hogs, meat 0.02(N) ppm; Horses, fat 0.02(N) ppm; horses, mbyp 0.02(N) ppm; horses, meat 0.02(N) ppm; lemons 0.25 ppm; loganberries 0.25 ppm; macadamia nuts 0.25 ppm; milk 0.02(N) ppm; olives 0.25 ppm; oranges 0.25 ppm; peaches 0.25 ppm; pears 0.25 ppm; pecans 0.01(N) ppm; plums 0.25 ppm; poultry, fat 0.02(N) ppm; poultry, mbyp 0.02(N) ppm; poultry, meat 0.02(N) ppm; raspberries 0.25 ppm; sheep, fat 0.02(N) ppm; sheep, mbyp 0.02(N) ppm; sheep, meat 0.02(N) ppm; strawberries 0.25 ppm; sugarcane 0.25 ppm; walnuts 0.2 ppm; [R128] *Tolerances are established for combined residues of the herbicide simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) and its metabolites 2-amino-4-chloro-6-ethylamino-s-triazine and 2,4-diamino-6-chloro-s-triazine in or on raw agricultural commodities as follows: bananas 0.2 ppm; fish 12 ppm. [R129] *A tolerance of 1 ppm is established for residues of the herbicide simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) in the sugarcane byproduct molasses intended for animal feed, resulting from application of the herbicide to the growing crop sugarcane. [R130] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 4 ug/l [R131] FEDERAL DRINKING WATER GUIDELINES: +EPA 4 ug/l [R131] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 35 ug/l [R131] +(ME) MAINE 4 ug/l [R131] +(MN) MINNESOTA 30 ug/l [R131] FIFR: *Tolerances are established for residues of the herbicide simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) in or on the following raw agricultural commodities: alfalfa; alfalfa, forage; alfalfa, hay; almonds; almonds, hulls; apples; artichokes; asparagus; avocados; bermuda grass; bermuda grass, forage; bermuda grass, hay; blackberries; blueberries; boysenberries; cattle, fat; cattle, mbyp; cattle, meat; cherries; corn, fodder; corn, forage; corn, fresh (inc. sweet K+CWHR); corn, grain; cranberries; currants; dewberries; eggs; filberts; goats, fat; goats, mbyp; goats, meat; grapefruit; grapes; grass; grass, forage; grass, hay; hogs, fat; hogs, mbyp; hogs, meat; Horses, fat; horses, mbyp; horses, meat; lemons; loganberries; macadamia nuts; milk ; olives; oranges; peaches; pears; pecans; plums; poultry, fat; poultry, mbyp; poultry, meat; raspberries; sheep, fat; sheep, mbyp; sheep, meat; strawberries; sugarcane; walnuts; [R128] *Tolerances are established for combined residues of the herbicide simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) and its metabolites 2-amino-4-chloro-6-ethylamino-s-triazine and 2,4-diamino-6-chloro-s-triazine in or on raw agricultural commodities as follows: bananas 0.2 ppm; fish 12 ppm. [R129] *A tolerance ... is established for residues of the herbicide simazine (2-chloro-4,6-bis(ethylamino)-s-triazine) in the sugarcane byproduct molasses intended for animal feed, resulting from application of the herbicide to the growing crop sugarcane. [R130] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Simazine is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0070; Pesticide type: herbicide; Registration Standard Date: 03/01/84; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Simazine; Data Call-in (DCI) Date(s): 09/11/91, 03/03/95, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R132] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TRIMETHYLSILYL DERIVATIVES OF 6 SUSPECTED METABOLITES OF SIMAZINE WERE PREPARED BY REACTION WITH N,O-BIS(TRIMETHYLSILYL) TRIFLUOROACETAMIDE. THE DERIVATIVES WERE ANALYZED BY GAS CHROMATOGRAPHY MASS SPECTROMETRY WTIH ELECTRON IMPACT IONIZATION AND CHEMICAL IONIZATION. [R133] *A METHOD IS DESCRIBED FOR QUANTITATIVE DETERMINATION OF HYDROXY-S-TRIAZINE RESIDUES IN PLANT TISSUE. HYDROXY METABOLITES OF SIMAZINE WERE SEPARATED BY HIGH-PRESSURE LIQ CHROMATOGRAPHY ON A SILICA GEL COLUMN AND DETECTED AT 240 NM WITH A UV SPECTROPHOTOMETER DETECTOR. THE PROCEDURE INVOLVES EXTRACTION OF SAMPLES WITH METHANOL, CLEANUP WITH CATION-EXCHANGE RESIN, A POLYACRYLAMIDE ADSORPTION RESIN AND STYRENE DIVINYL BENZENE GEL FILTRATION COLUMN. THE RANGE OF RECOVERY WAS 70-113%, WITH DETECTION LIMITS OF 0.05 MG/KG. [R134] *MULTI-COMPONENT MIXTURES OF N-DIALKYLATED DEGRADATION PRODUCTS OF TWENTY NINE S-TRIAZINES AND THEIR PARENT CMPD WERE SEPARATED ON CARBOWAX 20M GLASS CAPILLARY GAS-LIQ CHROMATOGRAPHY COLUMN AT 473 DEG C. SIMAZINE WAS ONE OF THE TRIAZINES. [R135] *A TLC-DENSITOMETRIC METHOD FOR DETERMINATION OF TRIAZINE HERBICIDES, ATRAZINE AND SIMAZINE IN NATURAL AND TAP WATER IS DESCRIBED. [R136] *RESULTS OF THIN LAYER CHROMATOGRAPHIC SEPARATION (NON-REVERSED PHASE) FOR 2 CHROMATOGRAPHIC SYSTEMS FOR S-TRIAZINE HERBICIDES, ONE OF WHICH WAS SIMAZINE, ARE PRESENTED. IN 1 CHROMATOGRAPHIC SYSTEM, THE TLC GLASS PLATES WERE PRECOATED AND COVERED WITH SILANIZED SILICA GEL 60-F-254 AND IMPREGNATED WITH 20% DIETHYLENE GLYCOL SOLN IN ACETONE. IN THE 2ND SYSTEM, THE SAME PRECOATED GLASS PLATES WERE IMPREGNATED WITH 20% FORMAMIDE SOLN IN ACETONE. MOBLE PHASES ARE GIVEN FOR BOTH. [R137] *Product analysis is by gas-liq chromatography (CIPAC Handbook, 1980, 1A, 1343; BG Tweedy and RA Kahrs, Anal Methods Pestic Plant Growth Regul, 1979, 10, 493; AOAC Methods, 1984, 6.590-6.594) or by titration of liberated chloride (AP Bosshardt et al, J Assoc Off Anal Chem, 1971, 54, 749). Residues may be determined by gas liq chromatography with ... flame photometric detection, (K Ramsteiner et al, J Assoc Off Anal Chem, 1974, 57, 192 ... TH Byast et al, Tecn Rep ARC Weed Res Organ, No 15 (2nd ed) page 79) or by high-pressure liq chromatography ... [R56] *Triazine herbicides were determined in water samples following chloroform extraction and concentration, by chromatography on silica gel/diatomite plates with solvent system consisting of liq paraffin/acetic acid/benzyl/cyclohexane. With o-tolidine as spray reagent, blue spots were produced; limits of detection were 0.1-0.3 ug. Silver nitrite reagent produced brown/black spots for chlorine-containing triazines and white spots for sulfur containing cmpd with limits of detection in the range of 0.1-0.3 ug. Simazine was one of the triazines. [R138] *Optimum experimental conditions were found for the determination of simazine and 6 other herbicides by differential pulse polarography. The limits of detection were 3.7-7.1 ug/l in a phosphate buffer (pH 2.9). [R139] */DETERMINATION OF/ SIMAZINE IN PESTICIDES BY GAS CHROMATOGRAPHY. USE INSTRUMENT EQUIPPED WITH FLAME IONIZATION DETECTOR AND 4 MM ID GLASS COLUMN (1.8 M) PACKED WITH 3% CARBOWAX 20M ON 80-100 MESH GAS-CHROM Q. ... CONDITION 24 HR @ 240 DEG C WITH NITROGEN OR HELIUM AT ABOUT 40 ML/MIN. ... OPERATE @ FOLLOWING CONDITIONS: TEMP INLET 240 DEG C, COLUMN 200 +/- 10 DEG C, DETECTOR 240 DEG C ... NITROGEN OR HELIUM GAS, 80-100 ML/MIN; AIR AND HYDROGEN, 80-100 ML/MIN; ATTENUATION VARIED SO THAT PEAK HEIGHTS OF PESTICIDE AND INTERNAL STD /DIELDRIN STD SOLN/ ARE 60-80% FULL SCALE. RETENTION TIME /FOR SIMAZINE/ 5-7 MIN, INTERNAL STANDARD 9-15 MIN. WT OF SAMPLE: 300 MG 80% WETTABLE POWDER. [R140] *Analysis of simazine is by a gas chromatographic (GC) method applicable to the determination of certain nitrogen-phsphorus containing pesticides in water samples . In this method, approximately 1 liter of sample is extracted with methylene chloride. The extract is concentrated and the compounds are separated using capillary column GC. Measurement is made using a nitrogen-phosphorus detector. The method detection limit has not been determined for the analytes in this method, including simazine. The estimated detection limit is 0.075 ug/l. [R141] *Gas Chromatographic Method. [R142] *EMSLC Method 507. Determination of Nitrogen- and Phosphorus-Containing Pesticides in Water by Gas Chromatography with a Nitrogen-Phosphorus Detector. Revision 2.0. CGCNPD, drinking water, estimated detection limit 0.075 ug/l. [R143] *EMSLC Method 619. The Determination of Triazine Pesticides in Municipal and Industrial Wastewater by Gas Chromatography with a Nitrogen-specific Detector, GCNPD, wastewater, method detection limit 0.060 ug/l. [R143] *EAD Method 1656. Organo-halide Pesticides in Municipal and Industrial Wastewater by Gas Chromatography, CGCECD, method detection limit 400.00 ng/l. [R143] CLAB: *Analytical methodology for the separation and characterization of s-triazine residues in urine was developed. In the sample preparation procedure developed, a urine sample at pH 12 was extracted with hexane 3 times, using sodium chloride as an emulsion inhibitor. The combined hexane extract was dried by passing it through a sodium sulfate column and concentrated by rotary evaporation. 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ISBN #4-89074-101-1 p. 5-52 (1992) (2) Reinert KH, Rodgers JH; Rev Environ Contam Toxicol 98: 61-91 (1987) (3) Rogers CA; Weed Sci 18: 134-6 (1970) (4) Mauk WL et al; Bull Environ Contam Toxicol 16: 1-8 (1976) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R108: (1) Senesi N, Testini C; Geoderma 28: 129-46 (1982) (2) Senesi N, Testini C; Chemosphere 13: 461-8 (1984) (3) Celis R et al; Soil Sci Soc Am J 61: 436-43 (1997) (4) Brusseau ML; Environ Toxicol Chem 12: 1835-46 (1993) (5) Alva AK, Singh M; J Environ Sci Health B26: 147-63 (1991) (6) Ahonen U, Heinonen-Tanski H; Acta Agric Scand, Sect B 44: 55-60 (1994) (7) Hassink J et al; Chemosphere 28: 285-95 (1994) R109: (1) Hamaker JW, Thompson JM; pp. 49-144 in Organic Chemicals in the Soil Environment. Goring CAI, Hamaker JW eds (1972) (2) Rao PSC, Davidson JM; Retention and transformation of selected pesticides and phosphorus in soil-water systems. USEPA-600/S3-82-060 (1982) (3) USEPA; pp. 706-8 in Drinking Water Health Advisory: Pesticides. USEPA Off Drink Water Advisories. Chelsea,MI: Lewis Pub (1989) (4) Weber JB; Res Rev 32: 93-130 (1970) (5) Helling CS; Res Rev 32: 175-210 (1970) (6) Hance RJ et al; Weed Res 21: 289-97 (1981) (7) Burnside OC et al; Weeds 11: 209-13 (1963) (8) Helling CS; Soil Sci Soc Amer Proc 35: 737-43 (1971) (9) Helling CS, Dragun J; pp. 43-88 in Test Protocols for Environmental Fate and Movement of Toxicants. Proc Symp AOAC (1981) (10) Helling CS, Turner BC; Science 162: 562-3 (1968) (11) Wang YS et al; Bull Environ Contam Toxicol 55: 351-8 (1996) R110: (1) Gerritse RG et al; Aust J Soil Res 34: 599-607 (1996) (2) Tomlin CDS, ed. The Pesticide Manual, 11th ed. The British Crop Protection Council p. 1106 (1997) (3) Sukop M, Cogge CG; J Environ Sci Health, Part B 27: 565-90 (1992) (4) Scribner SL et al; J Environ Qual 21: 115-20 (1992) (5) Swann RL et al; Res Rev 85: 23 (1983) R111: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Tomlin CDS ed; The Pesticide Manual, 11th ed. The British Crop Protection Council p. 1106 (1997) R112: (1) Keith LH et al; pp. 329-73 in Identification and Analysis of Organic Pollutants in Water, Keith LH ed, Ann Arbor Sci Publ (1976) (2) USEPA; Pesticides in Groundwater Database. A Compilation of Monitoring Studies: 1971-1991. National Summary. USEPA Off Pest Programs Prevention Pesticides and Toxic Substances (H7507C) USEPA-734-12-92-001 (1992) (3) Mehnert E et al; Groundwater Monit Remed 15: 142-9 (1995) (4) California EPA; California EPA, Dept Pesticide Regulation, 10th Annual Report (1995) (5) Dejonckeere W et al; J AOAC Intl 79: 97-110 (1996) (6) Briggins DR, Moerman DE; Water Qual Res J Canada 30: 429-42 (1995) (7) Lam RHF et al; pp. 15-44 in Water Contamination and Health, Wang RGM ed, NY,NY: Marcel Dekker, Inc (1994) (8) White SL, Pinkstone DC; BCPC Monogr 62: 263-8 (1995) (9) Storm DL; pp. 67-124 in Water Contamination and Health, Wang RGM, ed, Marcel Dekker, Inc (1994) R113: (1) Bagnati R et al; Chemosphere 17: 59-65 (1988) (2) Frank R et al; Pestic Monit J 13: 120-7 (1979) (3) Frank R et al; Arch Environ Contam Toxicol 16: 9-22 (1987) (4) Close ME; N Z J Mar Freshwater Res 30: 455-61 (1996) (5) Lampman W; Water Qual Res J Canada 30: 443-68 (1995) (6) Bruce BW, McMahon PB; J Hydrol 186: 129-51 (1996) (7) Beitz H et al; Chemistry of Plant Protection, Borner H, ed. Berlin, Germany: Springer-Verlag 9(Pesticides in Ground and Surface Water): 3-56 (1994) (8) Goolsby DA et al; Preprints of Papers presented at the 209th ACS National Meeting; Anaheim, CA 35: 278-81 (1995) (9) Domagalski JL, Dubrovsky; J Hydrol 130: 299-338 (1992) R114: (1) Leistra M, Boesten JJTI; Agr Ecosyst Environ 26: 369-89 (1989) (2) Lam RHF et al; pp. 15-44 in Water Contamination and Health, Wang RGM, ed, Marcel Dekker, Inc (1994) (3) Kolpin DW et al; Environ Sci Technol 30: 335-40 (1996) (4) Williams WM et al; Pesticides in Groundwater Database: 1988 Interim Report, NTIS PB89 164230 AS (1988) (5) Spalding RF et al; Ground Water Monit Rev 9: 126-33 (1989) R115: (1) Hormann WD et al; Pestic Monit J 13: 128-31 (1979) (2) Kreuger J, Brink N; Vaextskyddsrapp Jordbruk 49: 50-61 (1988) (3) Roberts GC et al; J Great Lakes Res 5: 246-55 (1979) (4) Frank R et al; J Environ Qual 11: 497-505 (1982) (5) Tsuda T et al; Bull Environ Contam Toxicol 57: 442-9 (1996) (6) Richards RP, Baker DB; Environ Toxicol Chem 12: 13-26 (1993) (7) Sudo M, Kunimatsu T; Water Sci Technol 25: 85-92 (1992) (8) Foster GD, Lippa KA; J Agric Food Chem 44: 2447-54 (1996) (9) Gruessner B, Watzin MC; Environ Sci Technol 29: 2806-13 (1995) (10) Goolsby DA et al; Preprints of Papers presented at the 209th ACS Natl Mtg. Anaheim,CA 35: 278-81 (1995) R116: (1) Frank R, Logan L; Arch Environ Contam Toxicol 17: 741-54 (1988) (2) Frank R; J Great Lakes Res 7: 440-54 (1981) (3) USEPA; STORET Data Base (1983) (4) Carey AE, Kutz FW; Environ Mont Assess 5: 155-63 (1985) (5) House WA et al; Brighton Crop Prot Conf, Pests Dis 1992 (2): 865-70 (1992) (6) Kimbrough RA, Litke DW; Environ Sci Technol 30: 908-16 (1996) (7) Hainly RA, Kahn JM; Water Resour Bull 32: 965-84 (1996) (8) Domalgalski J; Water Res Bull 32: 953-64 (1996) (9) Brauch HJ; Acta Hydrochim Hydrobiol 21: 137-44 (1993) (10) Frank R et al; Bull Environ Contam Toxicol 44: 401-9 (1990) R117: (1) Foster GD et al; Environ Sci Technol 27: 1911-7 (1993) (2) Duguet JP et al; Water Supply 12: SS11/1-SS11/5 (1994) (3) Law RJ; Mar Pollut Bull 28: 668-75 (1994) (4) Lam RHF et al; pp. 15-44 Water Contamination and Health, Wang RGM, ed, NY,NY: Marcel Dekker, Inc (1994) (5) Kuivila KM, Foe CG; Environ Toxicol Chem 14: 1141-50 (1995) (6) Tronczynski J et al; Sci Total Environ 132: 327-37 (1993) (7) Thurman EM et al; Environ Sci Technol 26: 2440-7 (1992) (8) Takagi H et al; Water Supply 13(ISWA Internat Spec Conf Adv Treat Integrated Water Syst Manag 21st Century): 119-24 (1995) (9) Spalding RF et al; J Environ Qual 23: 571-8 (1994) (10) Readman JW et al; Mar Pollut Bull 26: 613-9 (1993) R118: (1) Pico Y et al; Bull Environ Contam Toxicol 53: 230-7 (1994) (2) Pereira WE, Rostad CE; Environ Sci Technol 24: 1400-6 (1990) (3) Moody JA, Goolsby DA; Environ Sci Technol 27: 2120-6 (1993) (4) Miles CJ, Pfeuffer RJ; Arch Environ Contam Toxicol 32: 337-45 (1997) R119: (1) Richards RP et al; Nature 327: 129-31 (1987) (2) Beitz H et al; Chemistry of Plant Protection, Borner H, ed. Berlin, Germany: Springer-Verlag 9(Pesticides in Ground and Surface Water): 3-56 (1994) (3) Goolsby DA et al; Preprints of Papers presented at the 209th ACS Natl Mtg. Anaheim, CA 35: 278-81 (1995) (4) Chevreuil M et al; Sci Total Environ 182: 25-37 (1996) (5) Chevreuil M, Garmouma M; Chemosphere 27: 1605-8 (1993) (6) Scharf J et al; Fresenius J Anal Chem 342: 813-6 (1992) R120: (1) Frank R et al; Arch Environ Contam Toxicol 16: 9-22 (1987) (2) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (3) Hites RA, Lopez-Avila in Contaminants and Sediments Vol 1. Baker RA ed. Ann Arbor MI: Ann Arbor Press (1980) R121: (1) Huang LQ, Frink CR; Bull Environ Toxicol 43: 159-64 (1989) (2) Krapac IG et al; J Soil Contam 4: 209-26 (1995) R122: (1) USEPA; STORET Data Base (1983) (2) Carey AE, Kutz FW; Environ Mont Assess 5: 155-63 (1985) (3) Bester K, Huhnerfuss H; Chemosphere 32: 1919-28 (1996) (4) Fletcher CA et al; Sci Total Environ 155: 61-72 (1994) R123: (1) Haraguchi K et al; Atmos Environ 28: 1319-25 (1994) R124: (1) Chevreuil M et al; Sci Total Environ 182: 25-37 (1996) R125: (1) Frank R et al; J Assoc Off Anal Chem 70: 1081-6 (1987) (2) Yess NJ et al; J AOAC Intl 76: 492-507 (1993) R126: (1) Selala MI et al; Bull Environ Contam Toxicol 51: 325-32 (1993) R127: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R128: 40 CFR 180.213 (7-1-97) R129: 40 CFR 180.213a (7-1-97) R130: 40 CFR 186.5350 (7-1-97) R131: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R132: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.148 (Spring, 1998) EPA 738-R-98-002 R133: LUSBY WR, REARNEY PC; J AGRIC FOOD CHEM 26 (3): 635-8 (1978) R134: RAMSTEINER KA, HOERMANN WD; J AGRIC FOOD CHEM 27 (5): 934-8 (1979) R135: MATISOVA, KRUPCIK J; J CHROMATOGR 205 (2): 464 (1981) R136: SHERMA J, MILLER NT; J LIQ CHROMATOGR 3 (6): 901 (1980) R137: OGIERMAN L, SILOWIECKI A; J HIGH RESOLUT CHROMATOGR CHROMATOGR COMMUN 4 (7): 357-8 (1981) R138: Lawerenz A; Acta Hydrochim Hydrobiol 11 (3): 347-50 (1983) R139: Stastny M et al; Sb Vys Sk Chem-Technol Praze, Anal Chem H17: 69-85 (1982) R140: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/121 6.431 R141: USEPA; Health Advisories for 50 Pesticides p.780 (1988) PB88-245931 R142: USEPA; Methods for Benzidine, Chlorinated Organic Cmpds, Pentachlorophenol and Pesticides in Water and Wastewater (1978) as cited in 40 CFR 136.3 (1988) R143: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R144: Erickson M et al; J Agric Food Chem 27 (4): 740-3 (1979) R145: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 143 Record 151 of 1119 in HSDB (through 2003/06) AN: 1766 UD: 200303 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-FLUORIDE- SY: *ALCOA-SODIUM-FLUORIDE-; *ANTIBULIT-; *CAVI-TROL-; *Chemifluor-; *CREDO-; *DISODIUM-DIFLUORIDE-; *FDA-0101-; *FLORIDINE-; *FLOROCID-; *FLOZENGES-; *FLUORADAY-; *FLUORAL-; *T-FLUORIDE-; *FLUORIDENT-; *FLUORID-SODNY- (CZECH); *FLUORIGARD-; *FLUORINEED-; *FLUORINSE-; *FLUORITAB-; *FLUOR-O-KOTE-; *FLUOROCID-; *FLUOROL-; *FLUORURE-DE-SODIUM- (FRENCH); *FLURA-DROPS-; *FLURCARE-; *FLURSOL-; *FUNGOL-B-; *GLEEM-; *IRADICAV-; *KARIDIUM-; *LEMOFLUR-; *LURIDE-; *Luride-SF-; *NAFPAK-; *NATRIUM-FLUORIDE-; *NCI-C55221-; *OSSALIN-; *OSSIN-; *PERGANTENE-; *PHOS-FLUR-; *ROACH-SALT-; *SODIUM-FLUORIDE-CYCLIC-DIMER-; *SODIUM-FLUORURE- (FRENCH); *SODIUM-HYDROFLUORIDE-; *SODIUM-MONOFLUORIDE-; *F1-TABS-; *THERA-FLUR-; *THERA-FLUR-N-; *TRISODIUM-TRIFLUORIDE-; *VILLIAUMITE-; *ZYMAFLUOR- RN: 7681-49-4 MF: *F-Na SHPN: UN 1690; Sodium fluoride IMO 6.1; Sodium fluoride STCC: 49 323 75; Sodium fluoride, solution 49 441 50; Sodium fluoride, solid ASCH: FLUORIDE ION; 16984-48-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPARED BY FUSING CRYOLITE WITH SODIUM HYDROXIDE [R1] *Normally manufactured by the reaction of hydrofluoric acid with soda ash (sodium carbonate) or caustic soda (sodium hydroxide), with control of pH essential and proper agitation necessary to obtain the desired crystal size. [R2, p. 10(80) 797] IMP: *... Sodium and aluminum fluosilicates [R1] *Sulfates and iron [R3] FORM: *Commercial grade (purity 93-99%) is used to prepare baits [R4] *TECHNICAL GRADES ARE 90% and 95% NAF, LIGHT (37 CU IN/LB) AND DENSE (23 CU IN/LB), and 98% [R1] *Sodium fluoride solution contains not less than 95% and not more than 105.0% of the labelled amount of sodium fluoride, USP XXI [R5] *The purity of the commercial material is about 98% [R2, p. 10(80) 797] *Commercially available as tablets or solutions for oral admin and in dentifrices or as oral gels, pastes, or rinsing solutions for topical administration. [R6, 2158] *Prepared by neutral neutralizing aqueous solutions of hydrofluoric acid with sodium carbonate or sodium hydroxide. [R7] MFS: +Chemtech Industries, Inc, Hq, 1655 Des Peres Road, PO Box 31000, St Louis, MO 63131, (314) 966-9900; Fluoride Manufacturing Division; Production site: East Saint Louis, IL 62202 [R8, 952] +The Procter and Gamble Co, Hq, 301 E Sixth St, PO Box 599, Cincinnati, OH 45201, (513) 983-2641; Subsidiaries: Richardson-Vicks, Inc, 10 Westport Rd, Wilton, CT 06897, (203) 762-2222; JT Baker Inc, (201) 859-2151; Production site: 222 Red School Ln, Phillipsburg, NJ 08865 [R8, 953] +Pennwalt Corporation, Hq, Pennwalt Building, Three Parkway, Philadelphia, PA 19102, (215) 587-7000; Chemicals Group; Subsidiary: Ozark-Mahoning Company, 1870 S Boulder Ave, Tulsa, OK 74119, (918) 585-2661 [R8, 953] +Henley Manufacturing Inc, Hq, 11255 N Torrey Pines Road, La Jolla, CA 92037, (619) 455-9494; General Chemical Corporation, 90 E Halsey Road, Parsippany, NJ 07054- 0393; Production site: Route 13, Claymont, DE 19703 (Delaware Valley Works) [R8, 952] +Olin Corporation, Hq, 120 Long Ridge Road, PO Box 1355, Stamford, CT 06904-1355, (203) 356-2000; Olin Chemicals (address same as Hq); Production site: Joliet, IL 60434 [R8, 952] OMIN: *NOT APPROVED FOR /INSECTICIDAL/ USE IN BARNS, GRAIN BINS, POULTRY HOUSES. [R9] *PREPARED ... BY ADDING EQUIV AMT OF SODIUM HYDROXIDE OR SODIUM CARBONATE TO 40% HYDROGEN FLUORIDE (PPTN IS INSTANTANEOUS AND CRYSTAL SIZE DEPENDS ON PH, BUT TOO MUCH HYDROGEN FLUORIDE YIELDS SODIUM BIFLUORIDE, NAHF2): MULLER, CHEM-ZTG 52, 5 (1928) ... [R1] *SODIUM FLUORIDE ... FOR CONTROLLING ROACHES AND SILVERFISH IN HOMES AND INDUSTRIAL ESTABLISHMENTS. IN THE SUSPENDED AND CANCELLED LIST OF THE EPA (MAY 1978), SODIUM FLUORIDE IS CANCELLED FOR HOME USE IF THE PRODUCT CONTAINS MORE THAN 40% OF THIS COMPOUND. [R10, 1199] *Only the powdered grade is authorized by and registered with the EPA for use in pesticide formulations, with the further provison that it must be tinted blue or green, or otherwise discolored. The word poison appears on all labels together with first aid information. [R2, p. 10(80) 797] USE: *IN ELECTROPLATING; IN HEAT TREATING SALT COMPOSITIONS; FOR DISINFECTING FERMENTATION APPARATUS IN BREWERIES AND DISTILLERIES; MFR COATED PAPER; FROSTING GLASS; IN DENTAL LAB; IN REMOVAL OF HYDROGEN FLUORIDE FROM EXHAUST GASES TO REDUCE AIR POLLUTION [R11] *Fungicide, rodenticide, glass manufacture [R12] *FLUORIDATION AGENT IN DRINKING WATER; A FLUX IN THE MANUFACTURE OF RIMMED STEEL, ALUMINUM, AND MAGNESIUM; A FUNGICIDE; A GLASS FROSTING AGENT; A COMPONENT OF GLUES AND ADHESIVES; AN AGENT IN ORE FLOTATION; A STAINLESS STEEL PICKLING AGENT; A TOOTHPASTE INGREDIENT; A COMPONENT OF BITREOUS ENAMELS; AND A COMPONENT OF WOOD PRESERVATIVES. [R11] *Used in chemical cleaning, cryolite manufacture, single crystals used as windows in UV and infrared radiation detecting systems. [R13] *Used as an anti-coagulant in vitro for blood; Sodium fluoride, 2 mg/ml blood. [R2, p. 4(78) 121] *Used in the resmelting of aluminum, pickling of stainless steel, and component of laundry sours. [R2, p. 10(80) 798] *Sodium fluoride is used orally to increase bone density and relieve bone pain in the treatment of various metabolic and neoplastic bone diseases. [R6, 2160] +MEDICATION (VET) *SODIUM FLUORIDE ... FOR CONTROLLING ROACHES AND SILVERFISH IN HOMES AND INDUSTRIAL ESTABLISHMENTS. IN THE SUSPENDED AND CANCELLED LIST OF THE EPA (MAY 1978), SODIUM FLUORIDE IS CANCELLED FOR HOME USE IF THE PRODUCT CONTAINS MORE THAN 40% OF THIS COMPOUND. [R10, 1199] +MEDICATION PRIE: U.S. PRODUCTION: *(1977) AT LEAST 4.60X10+8 G [R14] *(1986) 5.44X10+9 g /estimate/ [R15] U.S. IMPORTS: *(1977) AT LEAST 5.95X10+7 G [R14] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS, CUBIC OR TETRAGONAL CRYSTALS [R16]; *WHITE CRYSTALLINE POWDER [R17]; +White powder or colorless crystals [Note: Pesticide grade is often dyed blue]. [R18] ODOR: +Odorless. [R18] TAST: *SALTY [R17]; *5X10-3 moles/l in water (Taste detection) [R19] BP: *1704 DEG C [R1] MP: *993 DEG C [R1] MW: *42.00 [R1] DEN: *2.78 [R1] PH: *7.4 (Freshly prepared saturated soln) [R1] SOL: *Very slightly sol in alcohol [R16]; *Solubility in water 4.0 g/100 ml water @ 15 deg C [R1]; *Solubility in water 4.3 g/100 ml water @ 25 deg C [R1]; *Solubility in water 5.0 g/100 ml water @ 100 deg C [R1] SPEC: *INDEX OF REFRACTION: 1.336 [R16] VAP: *1 MM HG @ 1077 DEG C [R20] OCPP: *AQ SOLN HAVE ALKALINE REACTION CAUSED BY PARTIAL HYDROLYSIS; AQ SOLN ETCH GLASS [R1] *All alkali fluorides, with the exception of the lithium salt, absorb hydrogen fluoride to form acid fluorides of the type MHF2 where M is the alkali metal. [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC, inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY, it is not effective in spill situations. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Sodium fluoride; Sodium fluoride, solid; Sodium fluoride, solution/ [R22] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R23] +Flammability: 0. 0= Materials that will not burn. [R23] +Reactivity: 0. 0= Materials which are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R23] FIRP: *Extinguish fire using agent suitable for type of surrounding fire (material itself does not burn or burns with difficulty). Use water in flooding quantities as fog; Cool all affected containers with flooding quantities of water; Apply water from as far a distance as possible. /Sodium fluoride solution/ [R24] REAC: +Strong oxidizers. [R25, 282] +Reacts with acids to form hydrogen fluoride. [R23] DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen fluoride and disodium oxide/. [R26] SERI: *Dust inhalation and skin or eye contact may cause irritation of the skin, eyes or respiratory tract ... [R2, p. 10(80) 798] EQUP: +Wear special protective clothing and positive pressure self-contained breathing apparatus. [R23] *Wear appropriate chemical protective gloves, and boots. /Sodium fluoride solution/ [R24] +Wear appropriate personal protective clothing to prevent skin contact. [R25, 283] +Wear appropriate eye protection to prevent eye contact. [R25, 283] +Recommendations for respirator selection. Max concn for use: 12.5 mg/cu m. Respirator Class(es): Any dust and mist respirator. [R25, 283] +Recommendations for respirator selection. Max concn for use: 25 mg/cu m. Respirator Class(es): Any dust and mist respirator except single-use and quarter-mask respirators. May require eye protection. Any supplied-air respirator. May require eye protection. [R25, 282] +Recommendations for respirator selection. Max concn for use: 62.5 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. Any powered, air-purifying respirator with a dust and mist filter. May require eye protection. May need gas acid sorbent. [R25, 283] +Recommendations for respirator selection. Max concn for use: 125 mg/cu m. Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. May need acid gas sorbent. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R25, 283] +Recommendations for respirator selection. Max concn for use: 250 mg/cu m. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R25, 283] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R25, 283] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. May need acid gas sorbent. Any appropriate escape-type, self-contained breathing apparatus. [R25, 283] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away; Keep material out of water sources and sewers; Build dikes to contain flow as necessary; Neutralize spill material with crushed limestone, soda ash, or lime. /Sodium fluoride solution/ [R24] *Avoid breathing vapors; Keep upwind; Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment; ... any material which may have contacted the body /should be removed by washing/ with copious amounts of water or soap and water. /Sodium fluoride solution/ [R24] *Contact lenses should not be worn when working with this chemical. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. [R25, 283] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R25, 283] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R25, 283] +Contact lenses should not be worn when working with this chemical. [R25, 283] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R27] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R28] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R29] STRG: *SOLN /USP TOPICAL FLUORIDE SOLN/ SHOULD BE STORED IN PLAX (PLASTIC), PARAFFIN LINED, OR PYREX BOTTLES. [R10, 1890] +Store in a cool, dry, well-ventilated location. Separate from acids and alkalies. [R23] CLUP: *Environmental considerations-land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material; /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike a surface flow using soil, sand bags, foamed polyurethane, or foamed concrete; Absorb bulk liquid with fly ash or cement powder; Neutralize with agricultural lime , crushed limestone or sodium bicarbonate (NaHCO3). /Sodium fluoride solution/ [R24] *Environmental considerations-water spill: Neutralize with agricultural lime, crushed limestone (CaCO3) or sodium bicarbonate; Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates; Adjust pH to neutral (pH= 7). /Sodium fluoride solution/ [R24] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Group III Containers (both combustible and non-combustible) that previously held organic mercury, lead, cadmium, arsenic, or inorganic pesticides should be triple rinsed, punctured and disposed of in a sanitary landfill. Non-rinsed containers should be encapsulated and buried at a specially designated landfill site. /Organic mercury, lead, cadmium, arsenic, or inorganic pesticides/ [R30] +A suggested disposal method converts the soluble fluoride ions to insoluble calcium fluoride ... a naturally occurring mineral (fluorspar) which can safely be added to a landfill. The method is as follows: add slowly to a large container of water. Stir in slight excess of Na2CO3 /sodium carbonate/. If fluoride is present add Ca(OH)2 /calcium hydroxide/ also. Let stand 24 hr. Decant or siphon into another container and neutralize with 6 m HCl /hydrochloric acid/ before washing down with large cxcess of water. The sludge may be added to landfill. Recommendable methods: Precipitation and landfill. [R31, 279] +Precipitation and landfill: Industry wastes with a high fluoride concn are treated in two phases. By adding CaO /calcium oxide/, the soluble fluorides are precipitated as CaF2 /calcium fluoride/ until the concn has been reduced to 10 mg/l. The compact sludge is disposed of on special waste dumps. [R31, 280] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *The IARC Working Group concluded that sodium fluoride (Group 3) are not classifiable as to their carcinogenicity to humans. /Sodium fluoride was reviewed by the IARC Working Group. Data for it are published in the IARC Monograph on sodium fluoride. No evaluation of the carcinogenicity for sodium fluoride is given; Fluorides (inorganic, used in drinking-water/ [R32] +A4; Not classifiable as a human carcinogen. /Fluorides as F/ [R33, 2002.33] MEDS: *Fluoride levels in urine should be checked periodically and all workers should be subjected to periodical skeletal X-ray exam particularly of the pelvis. /Fluoride and cmpd/ [R34] HTOX: *Symptomatology: A. Ingestion of soluble fluoride salts. 1. Salty or soapy taste, salivation, nausea. Repeated small doses (as in drinking water) may produce no other symptoms, but polyuria and polydipsia have also been reported. 2. Large doses lead promptly to burning or crampy abdominal pain, intense vomiting and diarrhea, often with hematemesis and melena. Dehydration and thirst. 3. Muscle weakness, tremors and rarely transient epileptiform convulsions, preceded or followed by progressive central nervous depression (lethargy, coma, and respiratory arrest, even in the absence of circulatory failure). 4. Shock characterized by pallor, weak and thready pulse (sometimes irregular), shallow unlabored respiration, weak heart sounds, wet cold skin, cyanosis, anuria, dilated pupils, followed almost invariably by death in 2 to 4 hours. 5. Even in the absence of shock, arrhythmias may occur, especially multiple episodes of ventricular fibrillation leading eventually to cardiac arrest. 6. If the victim survives a few hours, paralysis of the muscles of deglutition, carpopedal spasm and painful spasms of the extremities. 7. Occasionally localized or generalized urticaria. 8. The above signs and symptoms are related to a variety of metabolic disorders that may occur in acute fluoride poisoning, including hypocalcemia (which may be the only invariable finding), hypomagnesemia, metabolic and/or respiratory acidosis and sometimes hyperkalemia. /Fluoride/ [R35, p. III-190] *Acute poisoning: Ingestion of neutral fluorides such as sodium fluoride ... causes salivation, nausea and vomiting, diarrhea, and abdominal pain. Later, weakness, tremors, shallow respiration, carpopedal spasm, and convulsions occur. Death is by respiratory paralysis. If death does not occur immediately, jaundice and oliguria may appear. Experience with oral fluoride supplements used to prevent tooth decay has been reassuring; no adverse effects occur unless enormous amounts are ingested. [R36] *... THE MAJOR MANIFESTATIONS OF CHRONIC INGESTION OF EXCESSIVE AMT OF FLUORIDE ARE OSTEOSCLEROSIS AND MOTTLED ENAMEL. CHRONIC EXPOSURE TO EXCESS FLUORIDE CAUSES INCR OSTEOBLASTIC ACTIVITY. ... DENSITY AND CALCIFICATION OF BONE ARE INCREASED; IN THE CASE OF FLUORIDE INTOXICATION, IT IS THOUGHT TO REPRESENT THE REPLACEMENT OF HYDROXYAPATITE BY THE DENSER FLUOROAPATITE. /FLUORIDE SALTS/ [R37] *Sodium fluoride was reported to induce unscheduled DNA synthesis in cultured human cells, and conflicting results were obtained on the induction of chromosome aberrations; it did not induce sister chromatid exchanges. [R38] *Giant cells were discovered in the bone marrow of a woman taking 150 mg of sodium fluoride daily for osteoporosis. After fluoride was discontinued, these cells disappeared. [R39] *CLINICAL SYMPTOMS OBSERVED IN A CASE OF POISONING BY SODIUM FLUORIDE IS DESCRIBED. AUTOPSY REVEALED GASTROINTESTINAL CHEMICAL BURNS, VENOUS PLETHORA, AND BRAIN EDEMA. HISTOLOGICAL EXAMINATION SHOWED SWELLING OF MYOCARDIAL FIBERS. [R40] *A cross sectional study was performed to clarify a possible role of atopy in the occurrence of acute bronchoconstrictive impairment observed in workers in a plant for the electrolytic extraction of aluminum. At the time of examination, mean hydrogen fluoride exposure was 0.56 mg/cu m, mean particulate fluoride exposure was 0.15 mg/cu m, and mean sulfur dioxide concentration was 3.38 mg/cu m. No information on duration of exposure or employment is provided. Of 227 workers examined (mean age 37, 43% current smokers) the percentage of those with a history of atopy and positive skin tests for common allergens was within the expected range. Six had a positive patch test with 2% sodium fluoride. Among 7 workers with paroxysmal wheezing and dyspnea, of whom 3 were light smokers, 3 had positive skin tests with common allergens but only 1 had an increased IgE value. The same worker also had a positive patch test with 2% sodium fluoride. Two had symptoms defined as chronic bronchitis. Forced expiratory volumes, with 2 exceptions, measured at the beginning of the workshift were within normal limtis. In 5 of the 7 workers, nonspecific bronchoprovocative tests with histamine or metacholine indicated objectively the presence of bronchial hyperreactivty. [R41] *Two percent solutions of sodium fluoride may kill intestinal mucosal cells and result in severe hemorrhagic gastroenteritis. ... Fluorosis affecting bone is not detectable until the water concentration exceeds at least 4 ppm. [R42, 531] *Numerous reports of accidental and intentional poisonings with flouride were tabulated and concluded that a dose range of 5 to 10 grams of sodium fluoride can be cited as a reasonable estimate of a "certainly lethal (single) dose" for a 70 kg man. They noted that this corresponds from 70 to 140 mg/kg. [R43] *The toxicity of sodium fluoride in relation to the beneficial effects of fluoride therapy in the treatment of malignant neoplasia was examined. They described the effects of fluoride administered to more than 70 patients for periods of 5 to 6 months. Most of these subjects, suffering from malignant neoplastic disease, were being treated with metabolic inhibitors. Some were leukemic children 3 to 6.5 years old, while others were adults including elderly individuals. Doses for the children were 20 to 50 mg sodium fluoride (9.0 to 22.5 mg fluoride) four times daily. Doses for adults were 80 mg sodium fluoride (36.3 mg fluoride) four times daily. The material was administered orally with an antacid containing 4 percent aluminum oxide or as an enteric coated tablet to avoid gastric irritation. No evidence of systemic toxicity or of parenchymatous damage was seen which could be attributed to fluoride, even though some patients had received more than 27 g of sodium fluoride over a period of 3 months. Criteria evaluated included growth and development in the children, mottled enamel, eruption of permanent teeth, hematopoisis, liver function, albumin-globulin ratio, blood sugar and cholesterol concentrations and kidney function. Postmortem data from 4 cases showed no parenchymatous degeneration attributable to fluoride. In hypertensive patients a tendency was noted for decreased diastolic and systolic blood pressure. In two patients with functioning colostomies there was no apparent effect of the fluoride on the exposed mucosa of the colon. [R44] *33 post-menopausal women with 100 mg sodium fluoride daily for two years and another 23 similar patients with 50 mg sodium fluoride daily for two years were treated. A decrese of cortical bone was evident at both dose levels. However, cancellous bone was increased to some extent in half of those receiving the higher dose. The findings also suggested that two years of treatment at the lower dose or one year at the higer dose avoided new vertebral fractures. Gastrointestinal discomfort sometimes combined with nausea was encountered chiefly at the higher dose, but was of minor clinical importance. Osteoarticular pain was the major side effect of fluoride therapy and was seen in about 60 percent of the patients at both dose levels. The maximum effect was seen after 6 to 12 months of treatment and then gradually disappeared. In 18% of the patients, treatment had to be discontinued. [R45] *Chronic poisoning: Intake of more than 6 mg of fluoride per day results in fluorosis. Symptoms are weight loss, brittleness of bones, anemia, weakness, general ill health, stiffness of joints. ... /Fluoride/ [R46] NTOX: *Experimentally, sodium fluoride has been tested on rabbit eyes in several different ways. Application of a 2% aqueous solution to the eye caused corneal epithelial defects and necrotic areas in the conjunctiva. Injection subconjunctivally or into the anterior chamber caused corneal edema and a severe inflammatory reaction in the eye with hemorrhages in the iris. [R47] */ACUTE POISONING/ IF SUFFICIENT FLUORIDE IS ABSORBED ... FLUORIDE ION INCREASES CAPILLARY PERMEABILITY AND ALSO PRODUCES A COAGULATION DEFECT. THESE ACTIONS LEAD TO HEMORRHAGIC GASTROENTERITIS AND HEMORRHAGES, CONGESTION, AND EDEMA IN VARIOUS ORGANS INCL THE BRAIN. CLINICAL MANIFESTATIONS INCLUDE EXCITABILITY, MUSCLE TREMORS, WEAKNESS, URINATION, DEFECATION, SALIVATION, EMESIS, SUDDEN COLLAPSE, CLONIC CONVULSIONS, COMA, AND DEATH DUE TO RESP AND CARDIAC FAILURE. CYANOSIS AND EARLY RIGOR MORTIS ... /FLUORIDE/ [R48, 1014] *SHEEP RECEIVING WATER CONTAINING 10 PPM OF FLUORINE AS SODIUM FLUORIDE OVER A SEVEN YEAR PERIOD SHOWED A DECREASE IN WOOL PRODUCTION AND CHARACTERISTIC CHANGES IN THE TEETH; THE AVG DAILY INTAKE OF FLUORINE WAS 14 MG. [R49, 51] *FLUOROSIS /CHRONIC POISONING/ CAN OCCUR IN MILD FORM IN CATTLE IF DIET CONTAINS 40 PPM AS SODIUM FLUORIDE. ... THERE IS A 6 MONTH TO 1 YR OR MORE ONSET OF PERIODIC LAMENESS; PAINFUL, STIFF GAIT OR POSTURE; DECREASED FEED INTAKE; ANOREXIA; ROUGH HAIRCOAT; EMACIATION; AND DECR MILK PRODUCTION. BONY EXOSTOSES MAY BE SEEN OR FELT ON THE LEGS, AND THE TEETH HAVE A CHARACTERISTIC MOTTLING AND PATCHY LOSS OF DENTINE. THE TEETH ALSO BECOME STAINED BROWN AROUND ERODED AREAS, AND THEY WEAR UNEVENLY. SPONTANEOUS FRACTURES MAY OCCUR. DENTAL LESIONS ... MOST SEVERE IN DEVELOPING TEETH ... BEGIN BILATERALLY ON THE MEDIAL SIDE OF THE PROXIMAL THIRD OF THE METATARSAL OF CATTLE ... CONSIST OF HYPEROSTOSIS, POROSIS, ENLARGEMENT, CHALKY WHITE APPEARANCE, AND ROUGHENING. LESIONS PROGRESS TO THE MANDIBLE, METACARPALS, RIBS AND SPINE. [R48, 1045] *ADENYLATE CYCLASE ACTIVITY OF HOMOGENATES OF MONKEY FRONTAL CORTEX WAS STIMULATED BY SODIUM FLUORIDE. [R50] *PLASMA POLYPS WERE FOUND AT END OF A NORMAL PREGNANCY IN GUINEA PIGS. FOLLOWING SODIUM FLUORIDE INTOXICATION, THERE WAS AN EXTREME INCR OF PLASMA POLYPS IN PLACENTA. THIS ACCELERATED FORMATION WAS PREVENTED BY INJECTION OF SODIUM PYRUVATE. [R51] *SODIUM FLUORIDE DID NOT INDUCE REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM STRAINS TA1535, TA1537, TA1538, TA98, OR TA100 WHEN TESTED AT UP TO 500 UG/PLATE IN THE ABSENCE, OR AT UP TO 2000 UG/PLATE IN THE PRESENCE, OF A LIVER ACTIVATION SYSTEM FROM AROCLOR 1254 INDUCED RATS. IT DID NOT INDUCE GENE CONVERSION IN SACCHAROMYCES CEREVISIAE STRAIN D4 IN THE SAME STUDY. NO SEX LINKED RECESSIVE LETHALS WERE INDUCED IN DROSOPHILA MELANOGASTER WHEN SODIUM FLUORIDE WAS ADMIN BY INJECTION OF A 1X10-3 MOLAR SOLUTION ... [R52] *Sodium fluoride did not induce DNA strand breaks in testicular cells of rats treated in vivo and did not cause chromosomal aberrations in bone marrow or testicular cells or sister chromatid exchanges in bone marrow cells of mice treated in vivo. [R38, (1987)] *CYTOLOGICAL CHANGES HAVE BEEN OBSERVED IN THE CHROMOSOMES OF COW AND EWE OOCYTES WHEN CULTURED IN THE PRESENCE OF UP TO 0.1 AND 0.2 MG/ML SODIUM FLUORIDE, RESPECTIVELY AND IN CULTURES OF MOUSE OOCYTES AT CONCN BELOW 0.4 MG/ML. THE EFFECTS WERE NOT DOSE RELATED. NO CYTOGENETIC EFFECTS WERE INDUCED IN OOCYTES OF MICE EXPOSED TO SODIUM FLUORIDE AS A SINGLE, ACUTE DOSE (500 UG INTRAVENOUSLY) OR CHRONICALLY (250 UG SUBCUTANEOUSLY DAILY FOR 16 DAYS). [R52] *GROUPS OF 54 MALE AND 54 WEANLING FEMALE SWISS CD1 MICE WERE GIVEN 10 MG/L SODIUM FLUORIDE IN DOUBLY DEIONIZED DRINKING WATER FOR LIFE, TO GIVE A DOSE OF ABOUT 70 UG/DAY FLUORINE. AN EQUAL NUMBER OF ANIMALS SERVED AS MATCHED CONTROLS. NO FLUORINE WAS DETECTED IN THE DIET OF THE ANIMALS. DEAD ANIMALS WERE WEIGHED AND NECROPSIED, GROSS LESIONS WERE RECORDED, AND VISIBLE TUMORS AND TISSUES WERE EXAMINED HISTOLOGICALLY. THE BODY WEIGHT OF MALES WAS NOT AFFECTED, BUT THAT OF FEMALES WAS SOMEWHAT INCREASED WHEN COMPARED WITH THE CORRESPONDING CONTROLS. MALES GIVEN SODIUM FLUORIDE SURVIVED ONE TO TWO MONTHS LONGER THAN CONTROLS; THE LIFE SPANS OF TREATED AND CONTROL FEMALE MICE WERE SIMILAR. TUMORS WERE OBSERVED IN 24/71 CONTROLS AND 22/72 TREATED MICE, IN SIMILAR LOCATIONS AND OF SIMILAR TYPES. [R53] *A GROUP OF FEMALE DBA MICE, 7-10 WK OF AGE, WERE FED 900 MG/KG OF DIET SODIUM FLUORIDE UNTIL THE SURVIVING ANIMALS WERE 97-100 WEEKS OF AGE. /MATCHED CONTROLS USED/. ... MAMMARY GLAND CARCINOMAS OCCURRED IN 37/47 CONTROLS AND IN 20/40 TREATED ANIMALS (TANNENBAUM AND SILVERSTONE, 1949). [R53] *GROUPS OF 94 C3H AND 46 DBA FEMALE MICE, 4-12 MO OF AGE, WERE GIVEN 0.4, 1.0 OR 4.0 MG/L SODIUM FLUORIDE IN DISTILLED DRINKING-WATER FOR 7-12 MONTHS. GROUPS OF 96 C3H AND 45 DBA FEMALES ... AS MATCHED CONTROLS ... ALSO FED DIET CONTAINING 20-38 MG/KG FLUORINE. /OTHER GROUPS OF/ 65 and 36 C3H MICE AND 66 and 66 DBA MICE, 2-9 MONTHS OF AGE, RECEIVED 1.0 and 10.0 MG/L, RESPECTIVELY, SODIUM FLUORIDE IN DISTILLED WATER FOR 10-17 MONTHS. ALL ... FED MIXED GRAIN DIET CONTAINING NEGLIGIBLE AMT OF FLUORINE. ... AMONG MICE THAT RECEIVED 10.0 MG/L FLUORIDE, 63% DIED OF MAMMARY GLAND CARCINOMAS, COMPARED WITH 50% OF CONTROLS (TAYLOR, 1954). [R53] *Sodium fluoride was evaluated for mutagenicity in the Salmonella/microsome assay using strains TA97a, TA98, TA100, TA102, and TA1535. Sodium fluoride was tested at nine concentrations ranging from 0.44 to 4421 ug/plate both in the presence and absence of Aroclor induced rat liver microsomes. Sodium fluoride was negative in these tests and the highest ineffective dose tested was 4421 ug/plate. [R54] *After intraperitoneal administration of a single large dose of fluoride (sodium fluoride, 35 mg/kg body weight), the calcium contents of the renal cortex and medulla of fluoride intoxicated rats were increased by 33 and 10 times, respectively. [R55] *The ionic fluoride levels in plasma following intraperitoneal administration of 15, 20, or 25 mg of fluoride per kg body weight to 200 g rats /was studied/. In animals given 25 mg/kg, the mean ionic fluoride level in plasma was 38 mg/liter after 10 min and the animals invariably died within 1 hr. All animals receiving 15 or 20 mg/kg survived, despite mean ionic fluoride levels in plasma of 22.9 and 29.2 mg/l, respectively. [R56] *Fish exposed to poisonous amounts of sodium fluoride become apathetic, lose weight, have periods of violent movement, and wander aimlessly. Finally, there is a loss of equilibrium accompanied by tetany and death. Mucous secretion increases, accompanied by proliferation of mucous producing cells in the respiratory and integumentary epithelium. [R57] *Typical symptoms of acute toxicity are reduction or loss of appetite, local or general congestion, and sub-mucosal haemorrhages of the gastrointestinal tract. Such acute responses were recognized when chickens were fed for 10 days on a diet containing 6786 mg fluoride/kg (as sodium fluoride). Roosters receiving sodium fluoride at 200 mg/kg body weight, twice in 24 hr, developed gastroenteritis with edema of the mucosa of the stomach and upper bowels, subcutaneous edema, hepatomegaly, and atrophy of the pancreas. [R58] *No effect of sodium fluoride in drinking water on the frequency of sister chromatid exchange in mice /were found/. Twelve week old mice were taken from colonies which had been maintained for at least the seven prior generations on a low fluoride diet (estimated to equal less than 0.1 mg/kg/day) or a high fluoride diet (50 ppm-estimated to equal 10 mg/kg/day). Sodium fluoride was added to the drinking water of the group exposed to 50 ppm fluoride. Sister chromatid exchange status was identified in a separate laboratory with no knowledge of the fluoride status of the animals. No significant differences in sister chromatid exchange status were found between the low and high fluoride groups. [R59] *In a chronic study, mice (female, CSE mice, 3 to 4 weeks old, initially weighing 22.5 to 25.5 grams) were given drinking water containing 1 to 6 mg fluoride (as sodium flouride)/l for six months. No histological effects attributable to fluoride were seen in the heart, stomach, intestines, or bones. [R60] *The mutagenicity of sodium fluoride in Salmonella typhimurium and in Saccharomyces cerevisiae /was evaluated/. Sodium fluoride was added to plates at 0.1, 1, 10, 100 and 500 ug/plate; with and without microsomal enzyme preparatins from rats treated with Aroclor 1254. There was no indication of mutagenic activity in this experiment. On test which gave an elevated result (TA100) was repeated. There was no repetition of the elevated result. [R61] *Holstein calves /were exposed/ to dietary sodium fluoride. At the start of the experiment the calves were 6 to 27 weeks old. Sodium fluoride was added to their diet to supply 1.0, 1.2, 1.4, 1.6, and 2.0 mg fluoride/kg/day. The majority of the cattle were removed from the experiment either during or at the end of the second lactation period. Length of exposure in calendar time was not specified and varied from animal to animal. Severe fluorosis (characterized by rapid weight loss, general deterioration of condition, intermittent lameness and stiffness) was consistently associated with a skeletal fluoride concentration greater than 5,500 ppm. This concentration was reached by the first lactation in cows receiving 2.0 mg fluoride/kg/day and by the second lactation in cows receiving 1.6 mg fluoride/kg/day. The authors stated that a fluoride level in bone in excess of 5,500 ppm is one of the most reliable indices of fluoride toxicosis. [R62] *The effect of sodium flouride on reproductive performance in Hereford heifers was studied. These animals were free from tuberculosis and Bang's disease and were immunized against brucellosis. Sodium fluoride was added to feed so that over the nine year period of exposure, groups of three calves received 0.17, 0.39, 0.59, 0.91, 1.03, 1.24, 1.56 and 1.96 mg fluoride/kg/day. The cows were yearlings at the start of the experiment. They were bred first when two years old, then at yearly intervals for nine years. Breeding records of these animals were kept. ... It is apparent that there was some deficit in reproductive performance associated with exposure to 1.56 and 1.96 mg/kg/day. Exposure to less than 1.56 mg/kg/day did not have an obvious effect on reproductive performance. [R63] *The acute and subacute physiological and pathological effects of fluoride (as sodium fluoride) administered intravenously and orally to male and female dogs /were described/. When fluoride was infused intravenously in four dogs at the rate of 5.4 mg Fluoride/min, the mean acute lethal dose was 36.0 + or - 0.5 mg Fluoride/kg with death occurring after 59 to 64 minutes of infusion. The principal effects observed were a progressive decline in blood pressure, heart rate, central nervous system activity (pupil size, response to light, tendon reflexes) with vomiting and defecation. [R64] *Sodium fluoride test for mutagenicity in mouse lymphoma cells was positive. [R65] *... LAMENESS; PAINFUL, STIFF GAIT OR POSTURE; DECR FEED INTAKE; ANOREXIA; ROUGH HAIRCOAT; EMACIATION; AND DECR MILK PRODUCTION. BONY EXOSTOSES ... TEETH HAVE ... MOTTLING AND PATCHY LOSS OF DENTINE. ... SPONTANEOUS FRACTURES MAY OCCUR. ... LESIONS CONSIST OF HYPEROSTOSIS, POROSIS, ENLARGEMENT ... ROUGHENING. /FLUORIDE/ [R66] +... Conclusions: Under the conditions of these 2 year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. [R67] NTXV: *LD50 Mice oral 44.3 mg/kg (Admin via stomach tube, under light ether anaesthesia); [R68, (1982)] *LD50 Mice intraperitoneal 17.2 mg/kg; [R68, (1982)] *LD50 Mice oral 46.0 mg/kg; [R68, (1982)] *LD50 Mice intravenous 23.0 mg/kg; [R68, (1982)] *LD50 rats oral 51.6 mg/kg (Admin via stomach tube, under light ether anaesthesia); [R68, (1982)] *LD50 Rats oral 32.0 mg/kg; [R68, (19820] *LD50 Rats intravenous 11.8 mg/kg; [R68, (1982)] *LD50 Rats intraperitoneal 24 mg/kg; [R68, (1982)] NTP: +... Toxicology and carcinogenesis studies were conducted with F344/N rats and B6C3F1 mice of each sex by incorporating sodium fluoride into the drinking water in studies lasting ... 2 yr. ... The sodium fluoride concentrations selected for the 2 yr studies in both rats and mice were 0, 25, 100, and 175 ppm in the drinking water. These concn were selected based on the decr weight gain of rats at 300 ppm and of mice at 200 ppm and above, on the incidence of gastric lesions in rats at 300 ppm in the 6 month studies, and on the absence of significant toxic effects at sodium fluoride concentrations as high as 100 ppm in an earlier 2 year study. Conclusions: Under the conditions of these 2 year dosed water studies, there was equivocal evidence of carcinogenic activity of sodium fluoride in male F344/N rats, based on the occurrence of a small number of osteosarcomas in dosed animals. "Equivocal evidence" is a category for uncertain findings defined as studies that are interpreted as showing a marginal increase of neoplasms that may be related to chemical administration. There was no evidence of carcinogenic activity in female F344/N rats receiving sodium fluoride at concentrations of 25, 100, or 175 ppm (11, 45, or 79 ppm fluoride) in drinking water for 2 years. There was no evidence of carcinogenic activity of sodium fluoride in male or female mice receiving sodium fluoride at concentrations of 25, 100, or 175 ppm in drinking water for 2 years. [R67] +... Sodium fluoride (NaF) ... was administered ad libitum in drinking water to mated CD rats (26 per group) on gestation days (gd) 6 through 15 at levels of 0, 50, 150, or 300 ppm. Control water contained less than 0.6 ppm NaF (method detection limit) and food contained an average of 12.4 ppm F (11.6 - 13.4 ppm F). The calculated doses from drinking water were 7, 18 and 27 mg NaF/kg/day (i.e., 3, 8 and 12 mg F/kg/day) for the low- through high-dose groups, respectively. Intake from food added approximately 2 mg NaF/kg/day (i.e., 1 mg F/kg/day) to the intake for each group. Animals were observed daily for clinical signs of toxicity. Food, water, and body weights were recorded for the animals in each group on gd 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20. ... No maternal lethality occurred in this study. No treatment-related clinical signs of toxicity or effects on maternal body weight were observed. However, maternal weight gain was significantly reduced at 300 ppm during the first two days of exposure (gd 6 to 8), and a trend toward decreased weight gain was noted for the treatment period as a whole (gd 6 to 16). Maternal food intake (grams/kg/day) for NaF-exposed dams was generally comparable to controls, except for a significant decrease at 300 ppm from gd 8 to 10. In contrast, maternal water consumption (grams/kg/day) during exposure was significantly decreased in the animals exposed to 300 ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of decreased palatability of the 300 ppm solution. Necropsy of the maternal animals revealed no effects on kidney or liver weights. NaF exposure did not significantly affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations. Determination of serum fluoride levels in the 10 animals per group terminated on gd 16 revealed mean levels of 0.007 and plusmn; 0.002, 0.035 and plusmn; 0.040, 0.039 and plusmn; 0.039, and 0.187 and plusmn; 0.076 ppm F at the end of the exposure period (per data provided by the NTP). The poor palatability of the 300 ppm NaF solution in this study apparently reduced maternal water consumption. Maternal weight gain was significantly reduced from gd 6 to 8, but recovered thereafter. There was no definitive evidence of developmental toxicity at levels of sodium fluoride in drinking water as high as 300 ppm (resulting in an average exposure of 27 mg NaF/kg/day, or 12 mg F/kg/day). When rodent chow was considered as a source of F, the total intake for the high dose group was 13 mg F/kg/day. By comparison, the estimated human intake from a 1 ppm F drinking water source is approximately 0.027 mg F/kg/day, and the estimated range of intake from both food and drinking water sources for an adult human is 0.014-0.080 mg F/kg/day. Thus, the average daily intake of F from drinking water at the developmental NOAEL in this study was approximately 450 times the estimated adult human intake from a fluoridated drinking water source. Total daily intake in this study was approximately 165 times the upper estimate for human intake from food and fluids, including fluoridated water. This study established a NOAEL for maternal toxicity at 150 ppm (18 mg NaF/kg/day) and a NOAEL at 300 ppm for developmental toxicity (27 mg NaF/kg/day) administered in drinking water to pregnant CD(R) rats during organogenesis. [R69] +This study was conducted to assess the potential for orally administered sodium fluoride (NaF) to cause developmental toxicity in rabbits. ... NaF ... was administered ad libitum in drinking water to mated NZW rabbits (26/group) on gestation days (gd) 6-19 at levels of 0, 100, 200, or 400 ppm (0.1, 0.2, or 0.4 mg/ml). Drinking water (vehicle) contained < 0.6 ppm of sodium fluoride (the detectable limit). Animals were observed daily for clinical signs of toxicity. Food, water, and body weights were recorded for the animals in each group on /gestation day/ 0 and every 2 days thereafter through /gestation day/ 30. Blood samples were collected from 5 animals/group/replicate on /gestation day/ 20; serum was delivered to the sponsor for determination of fluoride concn. All animals were killed on /gestation day/ 30 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development. Based on measurement of water intake, animals in the low, mid and high concn groups ingested an avg of 10, 18 or 29 mg NaF/kg bw/day, respectively. However, samples of rabbit chow contained an avg of 15.6 ppm fluoride (range 14.6-16.6 ppm) and therefore feed served as a secondary source of fluoride exposure. The average measured fluoride intake from both sources (food and water) was 3, 21, 34 and 52 mg fluoride/animal/day (or 0.8, 6, 9 and 14 mg fluoride/kg bw/day) for the control through high concn groups. Water intake provided approx 84%, 91% and 95% of the total /fluoride/ consumed for the low through high concn groups in this study. No maternal mortality occurred in this study. Pregnancy rates were 84%, 87%, 78%, and 83% in the control to high exposure groups, respectively. Maternal body weight change for the animals receiving 400 ppm NaF was significantly lower than that of control animals for the period from /gestational day/ 6-8 (14 g avg weight gain for controls vs. 112 g weight loss for the 400 ppm group); this difference probably resulted from significantly decreased food and water consumption during the same period. Maternal body weight change was significantly increased from /gestation day/ 10-12 (22 g avg weight gain for controls vs. 71 g weight gain for the 400 ppm group), but did not differ among groups for the treatment period as a whole, indicating that animals in the 400 ppm group recovered from the weight change effects observed during the first few days of exposure to NaF in the drinking water. Maternal water consumption (g/kg/day) during exposure was significantly decreased in the animals exposed to 400 ppm NaF. Post-exposure water consumption was normal in these animals indicating the probability of dereased palatability of the 400 ppm solution. Maternal food consumption was decreased compared to control during the first four days of treatment (g/day on /gestation day/ 6-8 and 8-10; g/kg/day on /gestation day/ 6-8), but was normal thereafter. No clear clinical signs of toxicity were observed. Determination of serum fluoride levels by the sponsor, in 7-8 pregnant animals/group, revealed levels of 0.06 and plusmn; 0.04, 0.24 and plusmn; 0.10, 0.39 and plusmn; 0.14, and 0.70 and plusmn; 0.33 ppm at the end of the exposure period for the control through high dose groups, respectively. Necropsy of the maternal animals revealed no effects on kidney or liver weights. In utero sodium fluoride exposure did not affect the frequency of post-implantation loss, mean fetal body weight/litter, or external, visceral, or skeletal malformations. In summary, there was evidence of minimal maternal toxicity but no definitive evidence of developmental toxicity with levels of sodium fluoride in drinking water as high as 400 ppm (resulting in an avg exposure of 29 mg/kg/day) although the palatabillity of a 400 ppm sodium fluoride solution apparently reduced water consumption. This study established a NOAEL for maternal toxicity at 200 ppm NaF in drinking water (approximately 18 mg/kg/day) and a NOAEL for developmental toxicity of 400 ppm NaF in drinking water (approximately 29 mg/kg/day) administered to pregnant NZW rabbits during organogenesis. [R70] POPL: *Populations that appear to be at increased risk from the effects of fluoride are individuals that suffer from diabetes insipidus or some forms of renal impairment. These high risk populations represent a relatively small segment of the general populations. /Fluoride/ [R71] ADE: */Studies in man revealed/ peak serum levels are reached within a half hour, and levels fall promptly, with 20% of a given dose being excreted in the urine within 4 hr. [R72] *FLUORIDES ARE ABSORBED FROM GI TRACT, LUNG, AND SKIN. GI TRACT IS MAJOR SITE OF ABSORPTION. THE RELATIVELY SOL CMPD, SUCH AS SODIUM FLUORIDE, ARE ALMOST COMPLETELY ABSORBED. ... FLUORIDE HAS BEEN DETECTED IN ALL ORGANS AND TISSUES EXAMINED. ... THERE IS NO EVIDENCE THAT IT IS CONCENTRATED IN ANY TISSUES EXCEPT BONE, THYROID, AORTA, AND PERHAPS KIDNEY. FLUORIDE IS PREPONDERANTLY DEPOSITED IN THE SKELETON AND TEETH, AND THE DEGREE OF SKELETAL STORAGE IS RELATED TO INTAKE AND AGE. ... MAJOR ROUTE OF ... EXCRETION IS BY WAY OF KIDNEYS; ... ALSO EXCRETED IN SMALL AMT BY SWEAT GLANDS, LACTATING BREAST, AND GI TRACT. ... ABOUT 90% OF FLUORIDE ION FILTERED BY GLOMERULUS IS REABSORBED BY RENAL TUBULES. /FLUORIDE/ [R37] *Sodium fluoride is almost 100% absorbed through the stomach and small intestine. Absorption may be retarded if calcium salts, milk, or antacids are taken simultaneously. ... A 1.5 mg dose produces a peak blood level of 6 ug/dL. [R42, 532] *After sodium fluoride solution (1.5 mg orally) was administered to a mother, plasma fluoride levels increased but there was no corresponding increase in the fluoride concentration in the breast milk; 2 to 8 ng/ml appeared in the breast milk. [R42, 532] */RENAL CLEARANCE/ 1. VIRTUALLY ALL FLUORIDE IN PLASMA ... IS ULTRAFILTERABLE. 2. RENAL EXCRETION OF RADIOFLUORIDE DEPENDS ON GLOMERULAR FILTRATION AND VARIABLE TUBULAR REABSORPTION. 3. PROBABLY, REABSORPTION IS LARGELY PASSIVE ... 4. FLUORIDE EXCRETION INCR WHEN PLASMA CONCN IS INCREASED. 5. PROCEDURES THAT INCREASE URINARY FLOW RATE (EG, ADMIN OF OSMOTIC DIURETICS, HYPERTONIC SALINE, OR DIURETIC DRUGS) INCREASE THE CLEARANCE OF FLUORIDE. /FLUORIDE/ [R73] *IN FEMALE RATS, POISONED BY ORAL ADMIN OF SODIUM FLUORIDE, THE SKELETONS OF YOUNGER RATS APPARENTLY ARE MORE EFFICIENT AT REMOVING FLUORIDE FROM CIRCULATION THAN ARE THOSE OF OLDER RATS. [R74] *RATS GIVEN (18)FLUORIDE ION AS A RADIOTRACER BY CONTINUOUS IV INFUSION OF SODIUM FLUORIDE FOR 3 HR SHOWED AT SUBLETHAL DOSE RATES, BLOOD FLUORIDE CONCN NEARS STEADY STATE PROPORTIONAL TO FLUORIDE INFUSION RATE. BLOOD, KIDNEY, AND LUNG HAD HIGHEST CONCN @ DOSES UP TO 3 MG FLUORIDE/KG/HR, BUT @ 6 MG/KG/HR THE FLUORIDE OF THE LIVER, SPLEEN AND HOLLOW ORGANS INCR SHARPLY. AMT ABOVE THIS WAS NOT WELL PROCESSED BY EXCRETORY MECHANISM. RATS INFUSED 3 HR WITH 6 MG FLUORIDE/KG/HR: DURING INFUSION FLUORIDE CONCN OF BONE AND OTHER TISSUES WAS HIGH, BONE THE HIGHEST. OF SOFT TISSUES, LUNG HAD THE HIGHEST, BRAIN, TESTES, AND FAT PADS THE LEAST CONCN. DURING DEPLETION PHASE, TISSUE FLUORIDE CONCN DECR, BONE FLUORIDE REMAINED CONSTANT, AND SUBSTANTIAL AMOUNT REMAINED IN THE LUNG. [R75] *FOLLOWING ORAL ADMIN OF SODIUM FLUORIDE TO RABBITS, THE FLUORIDE CONCN OF PLASMA ROSE RAPIDLY FROM A RANGE OF 0.01 TO 0.07 PPM TO A MAXIMAL LEVEL USUALLY WITHIN 1 HR AND THEN USUALLY DECLINED WITH A HALF-LIFE OF 4 OR 5 HR. DOSES OF 100 TO 140 MG/KG GAVE 1 HR CONCN OF 12 TO 14 PPM. [R17] *Following ingestion, soluble fluorides are rapidly absorbed from the gastrointestinal tract at least to the extent of 97%. Absorbed fluoride is distributed throughout the tissues of the body by the blood. Fluoride concentrations in soft tissues fall to pre-exposure levels within a few hours of exposure. Fluoride exchange with hydroxyl radicals of hydroxyapatite (the inorganic constituent of bone) to form fluorohydroxyapatite. Fluoride that is not retained is excreted rapidly in urine. In adults under steady state intake conditions, the urinary concentration of fluoride tends to approximate the concentration of fluoride in the drinking water. This reflects the decreasing retention of fluoride (primarily in bone) with increasing age. Under certain conditions perspiration may be an important route of fluoride excretion. The concentration of fluoride retained in bones and teeth is a function of both the concentration of fluoride intake and the duration of exposure. Periods of excessive fluoride exposure will result in increased retention in the bone. However, when the excessive exposure is eliminated, the bone fluoride concentration will decrease to a concentration that is again reflective of intake. /Fluoride/ [R76] BHL: +FOLLOWING ORAL ADMIN OF SODIUM FLUORIDE TO RABBITS, THE FLUORIDE CONCN OF PLASMA ROSE RAPIDLY FROM A RANGE OF 0.01 TO 0.07 PPM TO A MAXIMAL LEVEL USUALLY WITHIN 1 HR AND THEN USUALLY DECLINED WITH A HALF-LIFE OF 4 OR 5 HR. [R17] ACTN: *The mechanism of action of orally and topically administered fluorides in reducing tooth decay are not fully understood. Fluoride ions are incorporated into and stabilize the apatite crystal of teeth and bone. /Fluorides/ [R6, 21580] *Acidification of sodium fluoride solutions increases fluoride uptake by dental enamel ... [R6, 2158] *FLUORIDE IS VERY REACTIVE AND CAPABLE OF INHIBITING A NUMBER OF ENZYMES, INCL PREGLYCOLYTIC ENZYMES, PHOSPHATASES, AND CHOLINESTERASE. THE RESULT IS INHIBITION OF CELLULAR GLUCOSE PHOSPHORYLATION (HENCE SUBSEQUENT GLYCOLYSIS) AND RESPIRATION AND INCR SENSITIVITY OF CHOLINERGIC MECHANISMS TO ACETYLCHOLINESTERASE. [R48, 1014] *INHIBITION OF ONE OR MORE ENZYMES CONTROLLING CELLULAR GLYCOLYSIS (AND PERHAPS RESP) MAY RESULT IN A CRITICAL LESION. ... BINDING OR PRECIPITATION OF CALCIUM AS CALCIUM FLUORIDE ... SUGGESTED AS MECHANISM UNDERLYING MANY DIVERSE SIGNS AND SYMPTOMS IN FLUORIDE POISONING, PARTICULARLY IF DEATH IS DELAYED. ... AT LEAST IN SOME SPECIES FLUORIDE INTERFERES WITH BOTH CONTRACTILE POWER OF HEART AND THE MECHANISM OF BEAT IN A WAY THAT CANNOT BE ASCRIBED TO HYPOCALCEMIA. /FLUORIDE/ [R35, p. II-112] *SODIUM FLUORIDE INHIBITED AEROBIC GLYCOLYSIS AND LACTATE FORMATION. CELLULAR PYRUVATE DECR, AND PHOSPHOENOLPYRUVATE ACCUMULATED. FLUORIDE INHIBITS ENOLASE AND PYRUVATE KINASE. [R77] INTC: *... PRETREATMENT OF RATS WITH FLUORIDE INCR THEIR SENSITIVITY TO SUCCINYLCHOLINE, DEMETON AND PARATHION. /FLUORIDE/ [R35, p. II-112] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Fluorides, Topical [R78] *... A CONCN OF ABOUT 1 PPM OF /SODIUM/ FLUORIDE IN WATER SUPPLY RESULTS IN A 50-66% REDUCTION IN INCIDENCE OF DENTAL CARIES IN PERMANENT TEETH. INGESTED FLUORIDE IS EFFECTIVE ONLY WHILE TEETH ARE BEING FORMED. THE FLUORIDE IS INCORPORATED INTO TOOTH SALTS AS FLUOROAPATITE. [R10, 732] *Sodium fluoride is used orally to increase bone density and relieve bone pain in the treatment of various metabolic and neoplastic bone diseases. [R6, 2160] +MEDICATION (VET): ... USE ... AS AN ANTHELMINTIC AGAINST ROUND WORMS (ASCARIS) AND STOMACH WORMS (HYOSTRONGYLUS) IN PIG. FOR THIS PURPOSE ... USUALLY MIXED WITH DRY FOOD IN CONCENTRATION NOT EXCEEDING 1%. [R49, 49] *EXPTL USE: PRETREATMENT OF MICE WITH ATROPINE (17.4 MG/KG) AND SODIUM FLUORIDE (5 OR 15 MG/KG) HAD A SIGNIFICANT ANTIDOTAL EFFECT OVER ATROPINE ALONE AGAINST THE LETHALITY PRODUCED BY SOMAN AND SARIN. ATROPINE AND SODIUM FLUORIDE (15 MG/KG) WAS EFFECTIVE AGAINST TABUN, WHEREAS THE LOWER DOSE OF NAF WAS NOT. AN EFFECT OF SODIUM FLUORIDE ON ORGANOPHOSPHATE INHIBITED ACETYLCHOLINESTERASE COULD NOT ACCOUNT FOR THE ANTIDOTAL ACTION OF SODIUM FLUORIDE. SODIUM FLUORIDE HAD NO EFFECT ON LIVER SOMANASE ACTIVITY BUT INHIBITED ALIESTERASE ACTIVITY. ALIESTERASE ACTIVITY IN SODIUM FLUORIDE PRETREATED SOMAN POISONED MICE WAS SIGNIFICANTLY HIGHER THAN IN THOSE RECEIVING ATROPINE ALONE. THE ANTIDOTAL EFFECT OF SODIUM FLUORIDE VERSES ORGANOPHOSPHATE POISONING APPEARED TO BE DUE TO ITS ANTIDESENSITIZING ACTION AT NICOTINIC RECEPTORS IN THE NEUROMUSCULAR JUNCTION AND/OR SYMPATHETIC GANGLIA IN ADDITION TO THE PROPOSED INCREASED HYDROLYSIS OF SARIN AND DIRECT DETOXIFICATION OF TABUN. [R79] +MEDICATION (VET): ANTHELMINTIC, PEDICULICIDE, ACARICIDE [R11] WARN: *... Sodium fluoride is used in tablets and drops to supplement intake in children and is also contained in mouth washes at such high levels, 200 to 900 ppm as to represent ... a hazard if large volumes are ingested. [R72] +Food and Environmental Agents: Effect on Breast-Feeding: Reported Sign or Symptom in Infant or Effect on Lactation: Fluorides: None. /from Table 7/ [R80] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *... The natural concentration of fluoride in ground-water depends on such factors as the geological, chemical, and physical characteristics of the water-supplying area, the consistency of the soil, the porosity of rocks, the pH and temperature, the complexing action of other elements, and the depth of wells. ... /Fluoride/ [R81] *At Lake Magadi Kenya, raw trona is dredged from encrustations on the lake, crushed, washed, and calcined to convert the sodium sesquicarbonate to soda ash. The calcined material is crushed and screened to produce a dense product with ... a characteristically high (1.0%) sodium fluoride content. [R2, p. 1(78) 877] *Fluorine ranks 13th among the elements in the order of abundance in the Earth's crust. /Fluorine/ [R81] *Because it is so reactive, fluorine rarely, if ever, occurs naturally in the elementary state, existing instead in the ionic form or as a variety of inorgainc and orgainc fluorides. Rocks, soil, water, air, plants, and animals all contain fluoride in widely-varying concentrations. /Fluoride and fluorine/ [R82] ARTS: *FROM FACTORIES, PROCESSING FLUORINE CONTAINING ORES, DUSTS MAY CONSIST OF SODIUM FLUORIDE VOLATILIZED .../AND/... THEN CONDENSED BY COOLER SURROUNDING AIR. LEAVES OF PLANTS MAY COLLECT SOME OF THE DUST. EXTENT OF CONTAMINATION WILL DEPEND UPON TOPOGRAPHY OF SURROUNDING TERRAIN AND ESPECIALLY DIRECTION OF PREVAILING WIND. [R83] WATC: *...Fluoride concentrations in ground-water fluctuate within wide limits e.g. from < 1 to 25 mg or more per litre. ... In surface fresh fluoride content is usually low, 0.01-0.3 mg/l. ... Fluoride concentrations are higher in sea ... averaging 1.3 mg/l. ... /Fluoride/ [R84] RTEX: *ACUTE FLUORIDE POISONING IS NOT RARE. IT USUALLY RESULTS FROM ACCIDENTAL INGESTION OF INSECTICIDES AND RODENTICIDES CONTAINING FLUORIDE SALTS. /FLUORIDES/ [R37] *Sodium fluoride ... source of toxic fluoride ions which cannot be detoxified. Thus, precautions must be taken to insure that /this/ material does not enter a water supply in large amounts ... [R85] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +250 mg/cu m (as F) [R25, 282] ATOL: *Sodium flouride (not more than 0.25% pesticide formulation) is exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops. [R86] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 2.5 mg/cu m. /Fluorides, as F/ [R87] +Permissible Exposure Limit: Table Z-2 8-hr Time Weighted Avg: 2.5 mg/cu m. /Fluoride as dust/ [R87] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2.5 mg/cu m. [R25, 282] TLV: +8 hr Time Weighted Avg (TWA): 2.5 mg/cu m. /Fluorides as F/ [R33, 2002.33] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Fluorides as F/ [R33, 2002.6] +Biological Exposure Index (BEI): Determinant: fluorides in urine; Sampling Time: prior to shift; BEI: 3 mg/g creatinine. Determinant: fluorides in urine; Sampling Time: end of shift; BEI: 10 mg/g creatinine. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. /Fluorides as F/ [R33, 2002.90] +A4; Not classifiable as a human carcinogen. /Fluorides as F/ [R33, 2002.33] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 4,000 ug/l /Fluoride ion/ [R88] FEDERAL DRINKING WATER GUIDELINES: +EPA 2,000 ug/l /Fluoride ion/ [R88] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 2,000 ug/l /Fluoride/ [R88] +(DE) DELAWARE 1800 ug/l /Fluoride ion/ [R88] +(HI) HAWAII 1,400-2,400 ug/l /Fluoride ion/ [R88] +(NC) NORTH CAROLINA 4,000 ug/l /Fluoride ion/ [R88] +(PA) PENNSYLVANIA 2,000 ug/l /Fluoride ion/ [R88] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 4,000 ug/l /Fluoride ion/ [R88] +(ME) MAINE 2,400 ug/l /Fluoride ion/ [R88] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R89] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R90] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R91] FIFR: *Sodium fluoride (not more than 0.25% pesticide formulation) is exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops. [R86] FDA: *Sodium fluoride is an indirect food additive for use only as a component of adhesives. For use only as a bonding agent for aluminum foil stabilizer, or preservative. Total fluoride for all sources not to exceed 1 percent by weight of the finished adhesive. [R92] *Bottled water packaged in the USA to which no fluoride is added shall not contain fluoride in excess of 1.8 mg/l at 63.9-70.6 deg F. Bottled water packaged in the USA to which fluoride is added shall not contain fluoride in excess of 1.2 mg/l at 63.9-70.6 deg F. Imported bottled water to which no fluoride is added and imported bottled water to which fluoride is added shall not contain fluoride in excess of 1.4 mg/l and 0.8 mg/l, respectively. /Fluoride/ [R93] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 8308: Analyte: fluoride ion (F-); Specimen: urine, pre- and post- shift; Vol: 50 ml in chemically clean polyethylene bottles; Preservative: 0.2 g EDTA added to bottles before collection; Stability: 2 wk @ 4 deg C, longer if frozen; Controls: collect 3 sets of specimens from unexposed workers pre- and post- shift /Fluoride in urine/ [R94, p. V1 8308-1] *NIOSH 7902: Analyte: fluoride ion (F-); Matrix: air; Sampler: filter plus treated filter (0.8-um cellulose ester membrane followed by sodium carbonate treated cellulose pad; Flow rate: 1-2 l/min; Vol: min: 20 l @ 2.5 mg/cu m, max: 800 l @ 2.5 mg/cu m; Stability: stable /Fluorides, aerosol and gas/ [R94, p. V1 7902-1] ALAB: *NIOSH 7902: Analyte: fluoride ion (F-); Matrix: air; Sampler: filter + treated filter (0.8-um cellulose ester membrane followed by sodium carbonate treated cellulose pad; Flow rate: 1-2 l/min; Vol: min: 20 l @ 2.5 mg/cu m, max: 800 l @ 2.5 mg/cu m; Stability: stable; Technique: ion-specific electrode; Range: 0.03-1.2 mg F-/sample; Est LOD (Limit of detection): 3 ug F-/sample; Precision Rel. Std. Dev. (Sr): 0.017; Interferences: hydroxide ion greater than 1/10 fluoride level will interfere positively. Al3+ gives a negative interference. /Fluorides, aerosol and gas/ [R94, p. V1 7902-1] *Matrix: toothpaste; Technique: Dissolve in acid medium; react sodium fluoride with trimethylchlorosilane to form trimethylfluorosilane; extract with benzene; Gas chromatography, flame ionization detector; Limit of detection: not given. [R95] *PRODUCT ANALYSIS IS BY DETERMINATION OF THE FLUORINE CONTENT BY TITRIMETRIC METHODS. (AOAC METHODS, 1984, 6.019-6.024). [R4] *FLUORIDE ANALYSIS IN DIFFERENT SUBSTRATES BY FLUORIDE SPECIFIC ELECTRODE. /FLUORIDE/ [R96] *A DETERMINATION OF FLUORIDE BY SPECIFIC ION ELECTRODE AND REPORT OF A FATAL CASE OF FLUORIDE POISONING. /FLUORIDE/ [R97] *Method 413B: Electrode Method. This method is suitable for fluoride concn from 0.1 to more than 10 mg/l. The fluoride electrode is a selective ion sensor. The key element in the fluoride electrode is the laser-type doped lanthanum fluoride crystal across which a potential is established by fluoride soln of different concn. The crystal contacts the sample soln at one face and an internal reference soln at the other. The fluoride electrode measures the ion activity of fluoride in soln rather than concn. Fluoride ion activity depends on the soln total ionic strength and pH, and on fluoride complexing species. Adding an appropriate buffer provides a uniform ionic strength background, adjusts pH, and breaks up complexes so that, in effect, the electrode measures concn. A synthetic sample containing 0.850 mg fluoride ion/l in distilled water was analyzed in 111 laboratories with relative standard deviation of 3.6% and relative error of 0.7%. /Total fluoride/ [R98] *Method 413C: SPADNS Method. This method is suitable only for concn in the range of 0.05 to 1.4 mg/l. /This is a colorimetric method based on the color developed upon addition of SPADNs solution and Zirconyl-acid reagent to fluoride containing sample/. The reaction rate between fluoride and zirconium ion is influenced greatly by the acidity of the reaction mixture. If the proportion of acid in the reagent is incr, the reaction can be made almost instantaneous. Under such conditions, however, the effect of various ions differs from that in the conventional alizarin method. The selection of dye for this rapid fluoride method is governed largely by the resulting tolerance to these ions. A synthetic sample containing 0.830 mg fluoride ion/l and no interference in distilled water was analyzed in 53 laboratories with a relative standard deviation of 8.0% and a relative error of 1.2%. After direct distillation of the sample, the relative standard deviation was 11.0% and the relative error 2.4%. /Total fluoride/ [R99] *Method 413E: Complexone Method. This method is applicable to potable, surface, and saline waters as well as domestic and industrial wastewaters. The range of the method, which can be modified by using the adjustable colorimeter, is 0.1 to 2.0 mg fluoride/l. The sample is distilled and the distillate is reacted with alizarin fluorine blue-lanthanum reagent to form a blue complex that is measured colorimetrically at 620 nm. In a single laboratory, four samples of natural water containing from 0.40 to 0.82 mg fluoride/l were analyzed in septuplicate. Average precision was + or - 0.03 mg fluoride/l. To two of the samples, additions of 0.20 and 0.80 mg fluoride/l were made. Average recovery of the additions was 98%. /Total fluoride/ [R100] *EPA Method 340.1 is a colorimetric method using sodium 2-(parasulfophenylazo)- 1,8-dihydroxy-3,6-naphthalene disulfonate with Bellack distillation for the measurement of total fluoride in drinking, surface, and saline waters, and domestic and industrial wastes. It covers a range from 0.1 to about 1.4 mg/l fluoride. On samples containing 0.57, 0.68, and 0.83 mg/l fluoride, the mean obtained was 0.60, 0.72, and 0.81, respectively with a standard deviation of + or - 0.103, + or - 0.092, and + or - 0.089 mg/l respectively. /Total fluoride/ [R101] *EPA Method 340.2 is a potentiometric method using an ion selective electrode for the measurement of fluoride in drinking, surface, and saline waters, and domestic and industrial wastes. Concentration of fluoride from 0.1 up to 1000 mg/l may be measured. For total or total dissolved fluoride, the Bellack distillation is required for National Pollutent Discharge Elimination System monitoring, but is not required for Safe Drinking Water Act. A synthetic sample prepared by the Analytical Reference Service containing 0.85 mg/l fluoride and no interferences had a mean of 0.84 mg/l with a standard deviation of + or - 0.03. A synthetic sample containing 0.75 mg/l fluoride, 2.5 mg/l polyphosphate and 300 mg/l alkalinity had a mean of 0.75 mg/l fluoride with a standard deviation of + or - 0.036. /Fluoride/ [R102] *EPA Method 340.3 is an automated complexone colorimetric method for the determination of fluoride in drinking, surface, and saline waters, and domestic and industrial wastes. The applicable range is 0.05 to 1.5 mg/l fluoride. For total or total dissolved fluoride, the Bellack Distillation must be performed on the samples prior to analysis. In a single laboratory using surface water samples concentrations of 0.06, 0.15, and 1.08 mg/l fluoride the standard deviation was + or - 0.018, and at concentrations of 0.14 and 1.25 mg/l fluoride, recoveries were 89% and 102% respectively. /Fluoride/ [R103] CLAB: *CHARGED PARTICLE ACTIVATION TECHNIQUE IS USEFUL IN NONDESTRUCTIVELY DETERMINING CONCN PROFILES OF F- IN EXTRACTED TEETH. /FLUORIDE/ [R104] *NIOSH 8308: Analyte: fluoride ion (F-); Specimen: urine, pre- and post-shift; Vol: 50 ml in chemically clean polyethylene bottles; Preservative: 0.2 g EDTA added to bottles before collection; Stability: 2 wk @ 4 deg C, longer if frozen; Technique: ion selective electrode; Quality control: spike urine pools, correct for creatinine content; Range: 1-100 mg/l urine; Est LOD: 0.1 mg/l urine; Precision(Sr): 0.04; Interferences: Hydroxide, the only positive interference, is eliminated by use of the buffer /Fluoride in urine/ [R94, p. V1 8308-1] *MATRIX: URINE: PROCEDURE: ION SPECIFIC ELECTRODE; RANGE: LOWER LIMIT URINE 0.19 MG/L. /TOTAL FLUORIDE/ [R105] *Analyte: Fluoride ion (F-); Matrix: urine; Procedure: Ion selective electrode; Quality control: spike urine pools, correct for creatinine content; Range: 1-100 mg/l urine; Precision: 0.04 /Fluoride in urine/ [R94, p. V1 8308-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NEWBURN E; J AM DENT ASSOC 94: (2) 301 (1977) A REVIEW OF THE SAFETY OF WATER FLUORIDATION. DHHS/NTP; Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3F1 Mice (Drinking Water Studies) Technical Report Series No. 393 (1990) NIH Publication No. 91-2848 DHHS/ATSDR; Toxicological Profile for Fluorides, Hydrogen Fluoride, and Fluorine (F) TP-91/17 (1993) SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1235 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: CHEMICAL PRODUCTS SYNOPSIS: Sodium Fluoride, (1985) R4: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. 750 R5: USP Convention. The United States Pharmacopeia 21st Revision/The National Formulary 16th ed. Rockville, MD: United States Pharmacopeial Convention, Inc., Jan. 1, 1985 (plus Supplements 1-6).969 R6: American Hospital Formulary Service-Drug Information 88. Bethesda, MD: American Society of Hospital Pharmacists, 1988 (Plus supplements). R7: WHO; Environ Health Criteria: Fluorine and Fluorides p.16 (1984) R8: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. R9: Farm Chemicals Handbook 1989. Willoughby, OH: Meister Publishing Co., 1989.,p. C-264 R10: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 244 (1982) R12: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 477 R13: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1060 R14: SRI R15: CHEMICAL PRODUCTS SYNOPSIS: Sodium Fluoride,(1985) R16: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-130 R17: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 58 R18: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 282 R19: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 150 R20: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2430 R21: Banks RE et al; Handbook of Experimental Pharmacology 20 (1): 608 (1966) as cited in WHO; Environ Health Criteria: Fluorine and Fluorides p. 16 (1984) R22: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-154 R23: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 49-119 R24: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.629 R25: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R26: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2965 R27: 49 CFR 171.2 (7/1/96) R28: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 213 R29: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6228 (1988) R30: 40 CFR 165.9 (c) (7/1/88) R31: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 63 (1987) R33: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R34: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 894 R35: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R36: Dreisbach, R.H. Handbook of Poisoning. 12th ed. Norwalk, CT: Appleton and Lange, 1987. 217 R37: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. 1539 R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 209 R39: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 700 R40: ZINGERMAN MY; UCH ZAP PETROZAVODSK GOS UNIV 21 (4): 230-1 (1974) R41: Saric M et al; Am J Ind Med 9: 239-42 (1986) R42: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R43: Hodge HD et al; Fluorine Chemistry Vol IV: p.3-518 (1965) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.VI-11 (1985) EPA Contract No. 68-03-3279 R44: Black MM et al; NY State J Med 49: 1187-88 (1949) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.VI-9-10 (1985) EPA Contract No. 68-03-3279 R45: Dambacher MA; Centre d'etude des Maladies Osted-Articulaires de Geneve: 238-41 (1978) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.VI-4 (1985) EPA Contract No. 68-03-3279 R46: Dreisbach, R. H. Handbook of Poisoning. 9th ed. Los Altos, California: Lange Medical Publications, 1977. 207 R47: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 435 R48: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. R49: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. R50: AHN HS ET AL; BRAIN RES 116 (3): 437-541 (1976) R51: THORN W ET AL; ARCH GYNAEKOL 221 (3): 203-10 (1976) R52: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 275 (1982) R53: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 271 (1985) R54: Li Y et al; Mutat Res 190: 229-36 (1987) R55: Suketa Y et al; Toxicol Appl Pharmacol 39: 313-19 (1977) as cited in WHO; Environ Health Criteria: Fluorine and Fluorides p.54 (1984) R56: Singer L et al; Proc Soc Exp Biol Med 157: 363-68 (1978) as cited in WHO; Environ Health Criteria: Fluorine and Fluorides p.53 (1984) R57: Neuhold JM et al; Trans Am Fish Soc 89: 358-70 (1960) as cited in WHO; Environ Health Criteria: Fluorine and Fluorides p.49 (1984) R58: Cass JS; J Occup Med 3: 471-77, 527-43 (1966) as cited in WHO; Environ Health Criteria: Fluorine and Fluorides p.49 (1984) R59: Kram D et al; Mutat Res 57: 51-55 (1978) as cited in WHO; Environ Health Criteria: Fluorine and Fluorides p.V-29 (1984) R60: Hansen K; Bios 19: 51-55 (1978) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.V-27 (1985) EPA Contract No. 68-03-3279 R61: Martin GR; Mutat Res 66: 159-67 (1979) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.V-31 (1985) EPA Contract No. 68-03-3279 R62: USEPA; Drinking Water Criteria Document for Fluoride p.VI-4 (1985) EPA Contract No. 68-03-3279 R63: Hobbs CS et al; Tennessee Agricultural Experiment Station Bulletin 235: (1962) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.V-19 (1985) EPA Contract No. 68-03-3279 R64: Leone NC et al; Public Health Rep 71: 459-67 (1956) as cited in USEPA; Drinking Water Criteria Document for Fluoride p.III-9 (1985) EPA Contract No. 68-03-3279 R65: NTP; Fiscal Year 1988 Annual Plan p.84 (1988) NTP-87-200 R66: Jones, L.M., et al. Veterinary Pharmacology and Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. 1275 R67: Toxicology and Carcinogenesis Studies of Sodium Fluoride in F344/N Rats and B6C3F1 Mice (Drinking water Studies). Technical Report Series No. 393 (1990) NIH Publication No. 91-2848 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R68: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 273 R69: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of Sodium Flouride (CAS No. 7681-49-4) in Sprague-Dawley CD Rats, NTP Study No. TER91022 (September, 1994) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R70: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of Sodium Flouride (CAS No. 7681-49-4) in New Zealand White (NZW) Rabbits, NTP Study No. TER91033 (December, 1993) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 19, 2002 R71: USEPA; Drinking Water Criteria Document for Fluoride p.I-5 (1985) EPA Contract No. 68-03-3279 R72: Haddad, L.M. and Winchester, J.F. Clinical Management of Poisoning and Drug Overdosage. Philadelphia, PA: W.B. Saunders Co., 1983. 691 R73: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 376 R74: DE LOPEZ OH ET AL; TOXICOL APPL PHARMACOL 37 (1): 75-83 (1976) R75: KNAUS RM ET AL; TOX APPL PHARM 38 (2): 335-43 (1976) R76: USEPA; Drinking Water Criteria Document for Fluoride p.III-19 (1985) EPA Contract No. 68-03-3279 R77: GUMINSKA M, STERKOWICZ J; ACTA BIOCHEM POL 23 (4): 285-91 (1976) R78: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R79: CLEMENT JG, FILBERT M; LIFE SCI 32 (16): 1803-10 (1983) R80: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 142 (1994) R81: WHO; Environ Health Criteria: Fluorine and Fluorides p.25 (1984) R82: WHO; Environ Health Criteria: Fluorine and Fluorides p.11 (1984) R83: Garner's Veterinary Toxicology. 3rd ed., rev. by E.G.C. Clarke and M.L. Clarke. Baltimore: Williams and Wilkins, 1967. 83 R84: WHO; Environ Health Criteria: Fluorine and Fluorides p.26 (1984) R85: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. 679 R86: 40 CFR 180.1001 (7/11/88) R87: 29 CFR 1910.1000 (7/1/98) R88: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R89: 40 CFR 116.4 (7/1/88) R90: 40 CFR 302.4 (7/1/88) R91: 40 CFR 712.30 (7/1/88) R92: 21 CFR 175.105 (4/1/88) R93: 21 CFR 103.35 (4/1/88) R94: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R95: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 269 (1982) R96: STAHR HM; IN ANAL TOXIC METHODS MANUAL. 65-7 (1977) R97: SPEAKER, JH; J FORENSIC SCI 21: 121-6 (1976) R98: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.357-9 (1985) R99: Franson MA (Ed); Standard Methods for Examination of Water and Wastewater p.359-61 (1985) R100: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.362 (1985) R101: USEPA; Methods of Chemical Analysis or Water and Wastes p.340.1 (1983) R102: USEPA; Methods for Chemical Analysis of Water and Wastes p.340.2 (1983) R103: USEPA; Methods for Chemical Analysis of Water and Wastes p.340.3 (1983) R104: RAJAN KS ET AL; J DENT RES 55 (4): 671 (1976) R105: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V1 114-1 RS: 87 Record 152 of 1119 in HSDB (through 2003/06) AN: 1788 UD: 200302 RD: Reviewed by SRP on 12/10/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ZIRAM- SY: *Antene-; *Pomarsol-Z-; *Z-75-; *AAPROTEC-; *Aaprotent-; *AAVOLEX-; *AAZIRA-; *ACCELERATOR-L-; *ACETO-ZDED-; *ACETO-ZDMD-; *ALCOBAM-ZM-; *BIS-DIMETHYLDITHIOCARBAMATE-DE-ZINC- (FRENCH); *BIS- (DIMETHYLDITHIOCARBAMATO)ZINC; *BIS(N,N-DIMETIL-DITIOCARBAMMATO) DI ZINCO (ITALIAN); *CARBAMODITHIOIC-ACID,-DIMETHYL-,-ZINC-SALT-; *Carbazinc-; *CORONA-COROZATE-; *COROZATE-; *CRITTAM-; *Crittan-; *CUMAN-; *CUMAN-L-; *CYMATE-; *Drupina-90-; *ENT-988-; *EPA-Pesticide-Chemical-Code-034805-; *EPTAC-1-; *FUCLASIN-; *FUCLASIN-ULTRA-; *FUKLASIN-; *Fungostop-; *HERMAT-ZDM-; *HEXAZIR-; *KARBAM-WHITE-; *METHASAN-; *METHAZATE-; *METHYL-ZIMATE-; *METHYL-ZIRAM-; *Mezene-; *Micosin-F30-; *MILBAM-; *MOLURAME-; *MYCRONIL-; *Vancide-MZ-96-; *NCI-C50442-; *NOCCELER-PZ-; *ORCHARD-BRAND-ZIRAM-; *Pomarsol-Z-Forte-; *POMARZOL-Z-FORTE-; *Prodaram-; *Ramedit-; *RHODIACID-; *RODISAN-; *SOXINAL-PZ-; *SOXINOL-PZ-; *Z-C-Spray-; *TSIRAM- (RUSSIAN); *USAF-P-2-; *Vancide-MA-96-; *VULCACURE-ZM-; *VULKACIT-L-; *VULKACITE-L-; *ZARLATE-; *ZERLATE-; *ZIMATE-; *ZINC, BIS(DIMETHYLCARBAMODITHIOATO-S-S')-, (T-4)-; *ZINC-BIS- (DIMETHYLDITHIOCARBAMATE); *ZINC, BIS(DIMETHYLDITHIOCARBAMATO)-; *ZINC-DIMETHYLDITHIOCARBAMATE-; *ZINK-BIS(N,N-DIMETHYL-DITHIOCARBAMAAT) (DUTCH); *ZINK-BIS(N,N-DIMETHYL-DITHIOCARBAMAT) (GERMAN); *Zirame-; *Zirasan-90-; *ZIRBERK-; *Ziride-; *ZIRTHANE- RN: 137-30-4 MF: *C6-H12-N2-S4-ZN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Ziram can be prepared from zinc oxide, dimethylamine and carbon disulfide. [R1] *... OLIN, DEGER, US PATENT 2,492,314 (1949 TO SHARPLES CHEMICALS). [R2] *Reaction of sodium dimethyldithiocarbamate with soluble zinc salt in aqueous soln. [R3] IMP: *In Japan ... technical grade ... /contains/ less than 0.5% water, 0.4-0.5% sodium chloride and 1.0-1.1% other impurities (mostly zinc methyldithiocarbamate). [R1] FORM: *ZIRAM IS AVAILABLE IN THE USA AS DUSTS CONTAINING 3.5 TO 76% OF CHEMICAL, AS WP CONTAINING 30-96% OF THE CHEMICAL, AS AQ SUSPENSIONS CONTAINING 30-40% OF THE CHEMICAL AND AS A 0.1% PASTE. IN JAPAN ... ZIRAM IS AVAILABLE AS A TECHNICAL GRADE CONTAINING 98% OF THE CHEMICAL ... . [R1] *Powder and oil-coated powder forms. [R4] *Wettable powder 76% (Pennwalt) (Farmoplant), 88% and 96%, flowable, 4 lb/gal. Technical 98%, 85% and 90% wettable powder, Drupina 90 (wettable powder 80% active ingredient), Fungostop (EC 27% ai); Pomarsol Z Forte (Bayer AG) ... . [R5] *Crittam (Siapa), wettable powder; Aaprotect, repellent paste (370 g/kg + sticker). Mixtures include: Ramedit (Siapa), wettable powder (570 g ziram + copper(II) oxychloride (125 g copper)/kg). [R6, 850] MFS: *Atomergic Chemetals Corp, Hq, 222 Sherwood Ave, Farmingdale, NY 11735-1718, (516) 694-9000; Production site: Paterson, NJ 07524 [R7] *Textile Rubber and Chemical Co, Hq, Tiarco Chemical Div, 1300 Tiarco Dr, Dalton, GA 30720 (404) 277-1300; Production site: Dalton, GA 30720 [R7] *Uniroyal Chemical Co Inc, Hq, World Headquarters, Middlebury, CT 06749 (203) 573-2000; Production site: Naugatuck, CT 06770 [R7] *RT Vanderbilt Co, Inc, Hq, 30 Winfield St, Norwalk, CT 06855, (203) 853-1400; Subsidiary: Vanderbilt Chemical Corp (address same as Hq); Production site: Murray, KY 42071 [R7] OMIN: *USEFULNESS OF ZIRAM AS FUNGICIDE WAS FIRST OBSERVED IN 1944. IT IS REGISTERED IN USA FOR USE ON 24 FRUIT AND VEGETABLE CROPS AND ON SEVERAL COMMERCIAL AND HOUSEHOLD ORNAMENTAL FLOWERS. [R8] USE: *Ziram is used in the rubber processing industry as an accelerator or promoter ... . Small amounts are used in industrial fungicides, in combination with 2-mercaptobenzothiazole, in adhesives (including those used in food packaging), paper coatings (for non-food contact), industrial cooling water, latex-coated articles, neoprene, paper and paperboard, plastics (polyethylene and polystyrene) and textiles. [R8] *Has been used as repellent to birds and rodents. [R6, 850] *EXTENSIVE USE IN CONTROL OF VEGETABLE DISEASES (CELERY LEAF BLIGHT, DOWNY MILDEWOF CUCURBITS, BEAN ANTHRACNOSE, CABBAGE DOWNY MILDEW, AND SQUASH BLACK ROT). [R9] *Used extensively on almond and peaches to control shot hole, brown rot, and peach leaf curl. [R10] *Control of snails (3-5 ppm in water) [R11] *Ziram is an indirect food additive for use as a component of adhesives. [R12] CPAT: *USE AS A FUNGICIDE, 1.82X10+7 G (1978) [R13] PRIE: U.S. PRODUCTION: *(1976) 8.59X10+8 G [R13] *(1978) 1.01X10+9 G [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM HOT CHLOROFORM + ALCOHOL [R2]; *WHITE WHEN PURE [R3]; *Crystalline white solid [R14] ODOR: *ODORLESS WHEN PURE [R3] MP: *250 deg C (crystals); 148 deg C (dust). [R1] MW: *305.82 [R2] CORR: *NONCORROSIVE EXCEPT TO IRON AND COPPER [R15] DEN: *1.66 AT 25 DEG C/4 DEG C [R2] SOL: *SOL IN CARBON DISULFIDE, AND CONCN HYDROCHLORIC ACID [R3]; *IN ALCOHOL: LESS THAN 0.2 G/100 ML @ 25 DEG C [R2]; *IN ACETONE: LESS THAN 0.5 G/100 ML @ 25 DEG C [R2]; *IN BENZENE: LESS THAN 0.5 G/100 ML @ 25 DEG C [R2]; *IN CARBON TETRACHLORIDE: LESS THAN 0.2 G/100 ML @ 25 DEG C [R2]; *IN ETHER: LESS THAN 0.2 G/100 ML @ 25 DEG C [R2]; *IN NAPHTHA: 0.5 G/100 ML @ 25 DEG C [R2]; *SOL IN DILUTED CAUSTIC SOLN; PRACTICALLY INSOL IN WATER [R2] SPEC: *Intense mass spectral peaks: 88 m/z (100%), 44 m/z (28%), 58 m/z (25%), 43 m/z (22%) [R16] VAP: *Practically 0 [R17] OCPP: *Technical grade: mp 240-244 deg C [R6, 850] *THRESHOLD CONCN OF TASTE FOR ZINC SALTS /IN WATER/ APPROX 15 PPM ... 40 PPM ... /IMPARTS/ A METALLIC TASTE. /ZINC SALTS/ [R18] *Ionization Potential: 7.72 electron volts [R19] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *CAN FORM FLAMMABLE DUST. [R2] REAC: */Incompatability only with those/ preparations ... containing iron, copper, mercury, TEPP, lime, and calcium arsenate. [R17] *Decomposed by acids ... . [R6, 850] DCMP: +When heated to decomp ... emits very toxic fumes of /nitrogen oxides and sulfur oxides/. [R20] SERI: *... VERY IRRITATING TO CONJUNCTIVA AND UPPER AIRWAY MUCOUS MEMBRANES. IT CAN CAUSE EXTREME PAIN IN EYES, / and / SKIN IRRITATION ... . [R21, 399] *... IRRITATING TO SKIN, EYES, AND UPPER RESP TRACT. [R22] OPRM: *In all cases where zinc is heated to the point where fume is produced, it is most important to ensure that adequate ventilation is provided. Individual protection is best ensured by education of the worker concerning metal-fume fever and the provision of local exhaust ventilation, or, in some situations by wearing of supplied-air hood or mask. /Zinc compounds/ [R21, 2342] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *Biological activity of Mezene remains practically unvaried for 2 yr under environmental conditions, provided stored as directed. [R23] STRG: *Mezene must be stored in its sealed original containers, in well-aired, fresh and dry storehouses or in shaded and possibly well-aired places. It is recommended that the product's temp not exceed 25-30 deg C. Container must be stacked in such a way to permit free circulation of air also at bottom and inside of piles. [R5] DISP: *Chemical Treatability of Ziram; Concentration Process: biological treatment; Chemical Classification: pesticide; Scale of Study: respirometer study; Type of Wastewater Used: unknown; Results of Study: slightly degraded. [R24] *Chemical Treatability of Zinc; Concentration Process: Biological Treatment; Chemical Classification: Metals; Scale of Study: Literature review; Type of Wastewater Used: Unknown; Results of Study: 89% reduction; Activated sludge process. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Biological treatment; Chemical Classification: Metals; Scale of Study: full scale; Type of Wastewater Used: domestic wastewater; Results of Study: 20-91% reduction achieved; Survey of municipal wastewater treatment plants. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Biological treatment; Chemical Classification: Metals; Scale of Study: Continuous flow and pilot scale; Type of Wastewater Used: domestic wastewater; Results of Study: 13-14% reduction in primary treatment. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Biological treatment; Chemical Classification: Metals; Scale of Study: Laboratory scale; Type of Wastewater Used: Synthetic wastewater; Results of Study: Biological growth inhibited; Study of Nitrosomonas bacteria. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Biological treatment; Chemical Classification: Metals; Scale of Study: Continuous flow and full scale; Type of Wastewater Used: Domestic wastewater; Results of Study: 60% reduction; Activated sludge process. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Biological treatment; Chemical Classification: Metals; Scale of Study: Laboratory scale; Type of Wastewater Used: Synthetic wastewater; Results of Study: Oxygen uptake inhibited. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Biological treatment; Chemical Classification: Metals; Scale of Study: Literature review; Type of Wastewater Used: Unknown; Results of Study: 57% reduction; Activated sludge process. /Zinc cmpd/ [R25] *Chemical Treatability of Zinc; Concentration Process: Chemical precipitation; Chemical Classification: Metals; Scale of Study: Pilot scale; Type of Wastewater Used: Synthetic wastewater; Results of Study: 1% reduction with alum; 3 coagulants used: 220 ppm of alum at pH= 6.4. 40 ppm of ferric chloride at pH= 6.2; 415 ppm of lime at pH= 11.5; chemical coagulation was followed by dual media filtration. /Zinc cmpd/ [R26] *Chemical Treatability of Zinc; Concentration Process: Chemical precipitation; Chemical Classification: Metals; Scale of Study: Laboratory scale, continuous flow; Type of Wastewater Used: Synthetic wastewater; Results of Study: 100% reduction with lime; Lime dose of 50 ppm added. /Zinc cmpd/ [R26] *Chemical Treatability of Zinc; Concentration Process: Chemical precipitation; Chemical Classification: Metals; Scale of Study: Pilot scale; Type of Wastewater Used: Domestic wastewater and pure compound (one solute in a solvent) Results of Study: Iron system - 63% reduction, low lime system - 85% reduction; High lime system - 76% reduction; 3 coagulant systems were used: Iron system used 45 ppm as Fe of Fe2(SO4)3 at pH= 6.0. Low lime system used 20 ppm as Fe of Fe2 (SO4)3 and 260 ppm of CaO at pH= 10.0. High lime system used 600 ppm of CaO at pH= 11.5. Chemical coagulation was followed by multimedia filtration. /Zinc cmpd/ [R26] *Chemical Treatability of Zinc; Concentration Process: Chemical precipitation; Chemical Classification: Metals; Scale of Study: Full scale, continuous flow; Type of Wastewater Used: Domestic wastewater; Results of Study: 90% reduction with lime (full scale); 37% reduction with lime (continuous flow); Lime dose of 350-400 ppm as calcium oxide at pH= 11.3. /Zinc cmpd/ [R27] *Chemical Treatability of Zinc; Concentration Process: Chemical precipitation; Chemical Classification: Metals; Scale of Study: Literature review; Type of Wastewater Used: Unknown; Results of Study: 10.6% reduction by sedimentation. /Zinc cmpd/ [R27] *Chemical Treatability of Zinc; Concentration Process: Chemical precipitation; Chemical Classification: Metals; Scale of Study: Literature review; Type of Wastewater Used: Unknown; Results of Study: 91.4% reduction with lime; Lime dose of 400 ppm added. /Zinc cmpd/ [R27] *Chemical Treatability of Zinc; Concentration Process: Reverse osmosis; Chemical Classification: Metals; Scale of Study: Batch flow; Type of Wastewater Used: Pure compound (one solute in a solvent); Results of Study: 96.6% reduction with C/PEI membrane at pH= 8.0 100% reduction with C/PEI membrane at pH= 11.0; CA membrane operated at 400 psig and 16-22 deg C. /Zinc cmpd/ [R28] *Chemical Treatability of Zinc; Concentration Process: Reverse osmosis; Chemical Classification: Metals; Scale of Study: Batch flow; Type of Wastewater Used: Pure compound (one solute in a solvent); Results of Study: 96.9%-99.5% reduction with CA membrane; CA membrane operated at 400 psig and 16-22% deg C. /Zinc cmpd/ [R28] *Chemical Treatability of Zinc; Concentration Process: Ultrafiltration; Chemical Classification: Metals; Scale of Study: Continuous flow, pilot scale; Type of Wastewater Used: Industrial wastewater; Results of Study: 0.38 ppm effluent concentration. /Zinc cmpd/ [R29] *Chemical Treatability of Zinc; Concentration Process: Activated carbon; Chemical Classification: Metals; Scale of Study: Full scale continuous flow; Type of Wastewater Used: (not stated); Results of Study: 81% reduction; 124 ppb effluent concentration; Carbon used as advanced treatment of biologically and chemically treated wastewater. Plant capacity 0.66 cu m/sec. Data presented for two time periods. /Zinc cmpd/ [R30] *Chemical Treatability of Zinc; Concentration Process: Activated carbon; Chemical Classification: Metals; Scale of Study: Full scale continuous flow; Type of Wastewater Used: (not stated); Results of Study: 61% reduction; 162 ppb effluent concentration; Carbon used as advanced treatment of biologically and chemically treated wastewater. Plant capacity 0.66 cu m/sec. Data presented for two time periods. /Zinc cmpd/ [R30] *Chemical Treatability of Zinc; Concentration Process: Miscellaneous sorbents; Chemical Classification: Metals; Scale of Study: Literature review; Type of Wastewater Used: Unknown; Results of Study: Final concentration reduced to 0.1 ppb; SiO2 + CaO slags used. /Zinc cmpd/ [R31] *The proprietary Sulfex process (Permutit Co) has been applied to zinc wastes. The process involves addition of ferrous sulfide, which gradually releases sulfide to precipitate the zinc ... . /Zinc/ [R32] *In the case where zinc removal is the only consideration and recovery is not warranted, removal by precipitation can be accomplished by standard pH adjustment through lime addition, precipitation and flocculation, and sedimentation, employing standard waste treatment equipment. Operating data for existing chemical precipitation units indicate that levels of 1 mg/l or less of zinc are readily obtainable with lime precipitation, although assurance of consistent removal of precipitated zinc to lower levels from the effluent stream may require filtration. /Zinc/ [R33] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No data were available from studies in humans. There is limited evidence in experimental animals for the carcinogenicity of ziram. Overall evaluation: Ziram is not classifiable as to its carcinogenicity to humans (Group 3). [R34] ANTR: *1) WASH CONTAMINATING CHEMICAL FROM SKIN AND HAIR WITH SOAP AND WATER. PERSONS SENSITIVE TO THIRAM (RUBBER-SENSITIVE) SHOULD BE PROTECTED FROM CONTACT WITH COMPOUNDS OF THIS NATURE. 2) FLUSH CONTAMINANT FROM EYES WITH FRESH WATER FOR 10-15 MIN. 3) IF THIRAM OR METALLO DITHIOCARBAMATE COMPOUNDS HAVE BEEN INGESTED: A) IF VIGOROUS EMESIS HAS NOT ALREADY OCCURRED AND VICTIM IS FULLY ALERT, GIVE SYRUP OF IPECAC, FOLLOWED BY 1-2 GLASSES OF WATER TO INDUCE VOMITING (ADULTS, 12 YR AND OLDER: 30 ML; CHILDREN UNDER 12: 15 ML). CAUTION: OBSERVE VICTIM CLOSELY AFTER ADMIN IPECAC. IF CONSCIOUSNESS LEVEL DECLINES OR VOMITING HAS NOT OCCURRED IN 15 MIN, EMPTY THE STOMACH BY INTUBATION, ASPIRATION, AND LAVAGE. /DITHIOCARBAMATES AND THIOCARBAMATES/ [R35, 39] *3) IF THIRAM ... HAS BEEN INGESTED: B) IF CONSCIOUSNESS LEVEL OR RESPIRATION IS DEPRESSED, EMPTY THE STOMACH BY INTUBATION, ASPIRATION, AND LAVAGE, USING ALL AVAILABLE MEANS TO AVOID ASPIRATION OF VOMITUS: LEFT LATERAL TRENDELENBURG POSITION, FREQUENT ASPIRATION OF THE PHARYNX AND, IN UNCONSCIOUS VICTIMS, TRACHEAL INTUBATION (USING A CUFFED TUBE) PRIOR TO GASTRIC INTUBATION. AFTER ASPIRATION OF THE STOMACH AND WASHING WITH ... /PRC: ISOTONIC SALINE IN ADULTS, TAP WATER IN CHILDREN; INSTILL 60-100 G ACTIVATED CHARCOAL IN 8-10 OZ WATER FOR ADULTS; 30 G OF CHARCOAL IN 3-4 OZ WATER FOR CHILDREN/ THROUGH THE STOMACH TUBE TO LIMIT ABSORPTION OF REMAINING TOXICANT. C) IF THE IRRITANT PROPERTIES OF THE TOXICANT FAIL TO PRODUCE A BOWEL MOVEMENT IN 4 HR, ADMIN SODIUM OR MAGNESIUM SULFATE AS A CATHARTIC: 0.25 G/KG BODY WT IN 1-6 OZ OF WATER. /DITHIOCARBAMATES AND THIOCARBAMATES/ [R35, 40] *4) MANAGEMENT OF A REACTION TO ETHANOL, FOLLOWING ABSORPTION OF A DITHIOCARBAMATE: A) ADMINISTER 100% OXYGEN AS LONG AS THE REACTION CONTINUES. OXYGEN USUALLY GIVES SUBSTANTIAL RELIEF FROM THE DISTRESSING SYMPTOMS OF VASODILATION AND HYPOTENSION. CAUTION: IF RESPIRATION IS DEPRESSED, ADMINISTER OXYGEN BY AN INTERMITTENT POSITIVE PRESSURE BREATHING DEVICE AND OBSERVE THE VICTIM CLOSELY TO MAINTAIN PULMONARY VENTILATION MECHANICALLY IN CASE OF APNEA. /DITHIOCARBAMATES AND THIOCARBAMATES/ [R35, 40] *Treatment of poisoning by ziram is symptomatic. [R36, 1446] HTOX: *DUST CAUSES BURNING SENSATION IN EYES, NOSE AND THROAT AND MAY PRODUCE EPISTAXIS AND DIFFICULTY IN BREATHING. [R22] *In fatal case of human poisoning, brain edema and hemorrhage, in vivo hemolysis, "dystrophy" of muscle, liver and kidney, emphysema, and local necrosis of intestine were found. Prolonged ... inhalation exposure ... produced neural and visual disturbances, dermatitis, and irritation of upper resp tract. Irritating to skin and mucous membranes, esp in sensitive persons. [R37] *Ingestion of 0.5 l of a solution of ziram of unknown concentration was fatal within a few hr; nonspecific pathology was observed. A case of contact dermatitis has also been reported. [R38] *... APPROX SIX TIMES HIGHER FREQUENCY OF CHROMOSOME AND CHROMATID ABERRATIONS IN METAPHASES OF CULTURED PERIPHERAL LYMPHOCYTES FROM WORKERS HANDLING ZIRAM /HAS BEEN REPORTED/. EXPOSURE OF CULTURED HUMAN PERIPHERAL LYMPHOCYTES TO 0.003 TO 0.06 MG/ML OF ZIRAM RESULTED IN DOSE-DEPENDENT INCR IN NUMBER OF CHROMOSOME AND CHROMATID ABERRATIONS. [R39] *Condoms and other rubber products immobilized sperm, but the mechanism is unknown. Sperm motility and eosin Y exclusion were measured following exposure of samples of semen to latex condoms of various types. Sperm motility was marked reduced by exposure to all latex condoms, but eosin Y exclusion was unchanged. While there appeared to be some variability between semen samples and in time to complete immobilization of all sperm, condoms from one batch were similar. The immobilizing effect was not altered by prewashing the condom with buffer, chelating agent or acid. After immobilization, motility was not recovered by sperm washed in buffer, mixed with normal mid-cycle cervical mucus, or exposed to caffeine or adenosine triphosphate after demembranation with detergent. Studies with components of condoms indicated that raw latex and zinc dimethyl- and dibutyl-dithiocarbamate accelerators immobilized sperm within 30 min. [R40] *... /IT WAS/ CONCLUDED THAT ... ABNORMAL AMT OF ZINC MAY ENTER AND LEAVE THE BODY FOR YEARS WITHOUT CAUSING SYMPTOMS OR EVIDENCE WHICH CAN BE DETECTED CLINICALLY OR BY LABORATORY EXAMINATIONS OF GI, KIDNEY, OR OTHER DAMAGE. /ZINC/ [R41] *ZINC SALTS ARE RELATIVELY NONTOXIC OWING TO EFFICIENT ZINC HOMEOSTATIC MECHANISM ... . /ZINC SALTS/ [R42] *The cytogenetic activity of some substances formed in agricultural plants during metabolism of pesticides of four classes of chemical compounds was studied in the culture of human blood lymphocytes. Metabolites were shown either to have mutagenic properties similar to those of the initial compounds (ziramtetramethylthiourea, both being mutagens; captan phthalimide, both possessing no cytogenetic activity) or to be considerably transformed in comparison with them as a result of deactivation (benomile-MBC) or activation (betanal-MHPC) processes. [R43] *Cytogenetic investigations were conducted in workers who are occupationally exposed to rubber chemicals such as tetramethylthiuram disulfide, zinc dimethyldithiocarbamate, and tetraethylthiuram disulfide using lymphocytes of peripheral blood. A significant increase in the frequency of chromosomal breaks and gaps was recorded. [R44] *Use experience with ziram has been good with certain exceptions in the USSR. Injury /in work place/ consisted of irritation of the skin, nose, throat, and eyes; gastritis; reduced hemoglobin; and vegetodystonia. Similar difficulties were described in several collective farm workers who used a 70% formulation of ziram to treat seed. Several women had to be hospitalized for 2 to 4 days; they were considered recovered in 25 days. Some other workers lost as much as 3 days of work. The method of treating the seed was not stated. ... On the contrary, apparently less severe irritation of the skin and upper respiratory tract was encountered in a factory where the concentration of ziram in the air ranged from 0.77 to 3.7 mg/cu m. [R45, 607] *The critical effects of ziram are sensitization and cross-sensitization with other thiurams. [R46] NTOX: *ZIRAM ADMIN IN DIET OF FEMALE RATS AT 2.5 MG/KG FOR 9 MO RESULTED IN DECR ANTIBODY FORMATION, DECR PHAGOCYTIC ACTIVITY, AND DECR COMPLEMENT ACTIVITY. LYMPHATIC BLASTOGENIC CENTERS IN SPLEEN WERE ALSO REDUCED. [R47, 656] *OF 82 STRAIN A AND 54 C57BL MICE GIVEN WEEKLY DOSES OF 75 MG/KG BODY WT ZIRAM BY STOMACH TUBE FOR 20 WK AND KILLED 6 MO AFTER BEGINNING OF EXPT, 42/82 (51%) and 4/54 (7%) DEVELOPED LUNG ADENOMAS, COMPARED WITH 23/54 (43%) and 0/28 CONTROLS. [R48] *OF 60 RANDOM BRED RATS GIVEN 70 MG/KG BODY WT COMMERCIAL ZIRAM TWICE WEEKLY IN WATER BY STOMACH TUBE FOR UP TO 22 MO, 10 SURVIVED 22 MO, and 4 DEVELOPED TUMORS (2 MALIGNANT HEPATOMAS, 2 FIBROSARCOMAS). AMONG 46 UNTREATED CONTROLS STILL ALIVE AT 22 MO, 1 DEVELOPED FIBROSARCOMA. [R48] *GROUPS OF 25 MALE AND 25 FEMALE 4 WK OLD ROCHESTER (EX-WISTAR) RATS WERE FED DIETSCONTAINING 0, 25, 250 OR 2500 MG ZIRAM ... PER KG OF DIET FOR 2 YR. LIFESPANS OF ... TREATED AND CONTROL RATS WERE BETWEEN 600 and 700 DAYS. OF 11 TUMORS FOUND IN TREATED RATS, 3 MALIGNANT TUMORS OF PITUITARY AND 2 THYROID ADENOMAS OCCURRED IN RATS GIVEN THE HIGHEST DOSE; HYPERPLASTIC THYROID WAS OBSERVED IN RATS GIVEN LOWEST DOSE. SEVEN TUMORS WERE SEEN IN CONTROL RATS, BUT THEIR LOCATIONS WERE NOT INDICATED. [R48] *GLYCOGENOLYTIC RESPONSE WAS ELICITED IN RATS BY IP INJECTION OF 10 MG ZIRAM/KG BODY WT. ... ADMIN OF 50 MG/KG BODY WT/DAY TO MICE FOR 15 DAYS SUBSTANTIALLY REDUCED THE FERTILITY AND FECUNDITY OF FEMALES BUT DID NOT AFFECT FERTILITY OF MALES. [R49] *NO INCR IN NUMBER OF RECESSIVE LETHALS IN DROSOPHILA MELANOGASTER WAS OBTAINED WITH ZIRAM; HOWEVER, ONLY 929 CHROMOSOMES WERE TESTED. ... NO SIGNIFICANT INCR IN GENE CONVERSION IN SACCHAROMYCES CEREVISIAE /WERE OBSERVED/; METABOLIC ACTIVATION SYSTEMS WERE NOT USED IN THESE TESTS. AN INCR IN NUMBER OF CHROMOSOME ABERRATIONS IN METAPHASES OF BONE-MARROW CELLS WAS FOUND IN MICE TREATED WITH 100 MG/KG BODY WT ORALLY. [R39] *AMONG 12 THIURAM AND DITHIOCARBAMATE CMPD USED AS RUBBER ACCELERATORS, ZIRAM WAS ONE OF 4 MOST POTENT DIRECTLY ACTING MUTAGENS ON SALMONELLA TYPHIMURIUM STRAINS TA1535 AND TA100 IN THE PRESENCE OF METABOLIC ACTIVATION (S9 MIX). [R50] *THE MUTAGENICITY OF DIMETHYL DITHIOCARBAMATES AND RELATED FUNGICIDES WAS TESTED USING SALMONELLA TYPHIMURIUM TA1535, TA1537, TA1538, TA98 AND TA100. ZIRAM WAS ONE OF 6 CMPD MUTAGENIC TO SALMONELLA TYPHIMURIUM TA100, BUT NOT FOR STRAINS TA1537, TA1538 AND TA98. THE N-DIMETHYL GROUP IS ESSENTIAL FOR MUTAGENICITY OF THESE CMPD. [R51] *ZIRAM WAS GIVEN ORALLY TO YOUNG AND ADULT DOMESTIC FOWL (CHICKENS). ADVERSE EFFECTS WERE OBSERVED ON BODY WT; IT RETARDED TESTICULAR DEVELOPMENT, AND CAUSED DEGENERATION IN SEMINIFEROUS EPITHELIUM OF MATURE BIRDS. [R52] *ZINC DIMETHYLDITHIOCARBAMATE SHOWED INHIBITORY EFFECT ON OXIDATION OF SUCCINATE, ALPHA-KETOGLUTARATE, GLUTAMATE AND ISOCITRATE AS WELL AS ON OXIDATIVE PHOSPHORYLATION BY ISOLATED LIVER MITOCHONDRIA. SUCCINATE AND ALPHA-KETOGLUTARATE DEHYDROGENASE ACTIVITY WAS INHIBITED AT CONCN OF 7.7X10-4 M. A LOWER CONCN (4.2X10-4 M) INDUCED A SIGNIFICANT SWELLING OF LIVER MITOCHONDRIA. [R53] *Zinc dimethyldithiocarbamate (ziram) was administered to pregnant CD rats by intubation during the first 5 days of pregnancy (preimplantation study, 0, 25, 50, and 100 mg/kg) or during the organogenesis period (teratogenic study, 0, 12.5, 25, 50, and 100 mg/kg). All females were sacrificed on day 21 of gestation. Their reproductive status was recorded and live fetuses were examined for external, visceral, and skeletal malformations. In the preimplantation study, the only observed embryotoxic effect was reduced fetal weight at the 50 and 100 mg/kg dose level. The teratogenic study revealed a slight dismorphogenic effect of ziram at 100 mg/kg; embryofetotoxic effects appeared at the 25 mg/kg dose level and higher. Maternal toxicity was evident at all tested doses. [R54] *The mutagenic activity of a blend of primary zinc dialkyldithiophosphate lubricant additives suspended in process oils and a blend of the process oils alone was investigated in agar layer cultures of Salmonella typhimurium TA1535, TA1537, TA1538, TA98 and TA100, both with and without the incorporation of a rat liver microsomal activation system (S9). Zinc dimethyldithiocarbamate was tested as a structurally related model bacterial mutagen. Zinc dimethyldithiocarbamate increased the reverse mutation frequency in some bacterial tester strains, but did not significantly increase the transformation frequency of BHK cells under the described conditions. [R55] *IT IS NON-PHYTOTOXIC EXCEPT TO ZINC-SENSITIVE PLANTS. [R6, 850] *Rats were given ziram orally at 0.12-4.16 mmol/kg and 5 hr later their livers were removed and the microsomes examined for epoxide hydrolase and glutathione S-transferase activities and the liver cytosol fraction was examined for glutanthione S-transferase activity only; ziram inhibited the enzyme activities in all cases, especially at the higher doses. [R56] *Incubation of Mytilus galloprovincialis with 0.5 mg/l methylene thiocyanate, phelam, tributyltin oxide, salicyltin chloride, and 10-chlorophenoxarsine for 1-3 days almost completely suppressed muscle lactate dehydrogenase; ziram halved its activity. [R57] *Ziram and thiram are wildlife repellents and therefore can be used as agents for agricultural pesticides. Thus, addition of 2% ziram to granular 3% bendiocarb reduced by 50% the mortality caused by the latter to birds in a wildlife park. [R58] *Female SPF Wistar rats were given by gavage 16 umol/kg thiram, tetramethylthiuram monosulfide, cyanamide, ziram, or zineb or 256 umole/kg zineb or cyanamide. After 90 minutes, 2 gm/kg ethanol was injected ip. Blood was collected at intervals to 4 hr after ethanol administration and analyzed for ethanol concentration. Pharmacokinetic parameters were calculated for the third thiram group and controls. Compared to control values, blood ethanol concentration after 4 hr was increased about 70% by 16 umol/kg thiram, ziram, or tetramethylthiuram monosulfide, and 90 percent by 256 umol/kg cyanamide. [R59] *LARGE DOSES OF ZINC SALTS PRODUCE GENERAL SIGNS OF ACUTE METAL POISONING, IE VIOLENT VOMITING, PURGATION, EVIDENCE OF ABDOMINAL PAIN AND COLLAPSE. CATTLE ... SHOW DRAMATIC DROP IN MILK YIELD. SOME ANIMALS BECOME SOMNOLENT AND DEVELOP PARESIS. ... POST MORTEM LESIONS INCLUDE PULMONARY EMPHYSEMA, PALE, FLABBY MYOCARDIUM, PETECHIAE IN KIDNEYS, AND DEGENERATIVE CHANGES IN LIVER. /ZINC CMPD/ [R60] *ATTEMPTS TO PRODUCE ZINC (ZN) TOXICITY ... /WITH/ 0.25% IN DIET OF RATS HAVE NOT BEEN SUCCESSFUL. AT LEVELS ABOVE THIS HOMEOSTATIC MECHANISM BREAKS DOWN; GROWTH RETARDATION, HYPOCHROMIC ANEMIA AND DEFECTIVE MINERALIZATIONS OF BONE OCCUR. DISPLACEMENT OF COPPER AND ALTERED PHOSPHATASE ACTIVITY ARE PERHAPS MECHANISMS OF ACTION. /ZINC CMPD/ [R61] *SYMPTOMS OF ZINC (ZN) TOXICITY ARE LASSITUDE, SLOWER TENDON REFLEXES, BLOODY ENTERITIS, DIARRHEA, LOWERED LEUKOCYTE COUNT AND DEPRESSION OF CNS ... AND PARALYSIS OF EXTREMITIES. /ZN CMPD/ [R42] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF) F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR) F1 MICE RECEIVED COMMERCIAL ZIRAM ... /AT/ 4.6 MG/KG BODY WT IN GELATIN AT 7 DAYS OF AGE BY STOMACH TUBE AND THE SAME AMOUNT (NOT ADJUSTED FOR INCR BODY WT) DAILY UP TO 4 WK OF AGE; SUBSEQUENTLY ... 15 MG ... PER KG OF DIET. DOSE WAS MAX TOLERATED DOSE FOR INFANT AND YOUNG MICE, BUT NOT NECESSARILY SO FOR ADULTS. EXPT WAS TERMINATED WHEN ANIMALS WERE ABOUT 78 WK OF AGE, AT WHICH TIME 15, 18, 17 and 17 MICE IN THE 4 GROUPS, RESPECTIVELY, WERE STILL ALIVE. TUMOR INCIDENCES WERE COMPARED WITH THOSE OBSERVED AMONG 79-90 NECROPSIED MICE OF EACH SEX AND STRAIN, WHICH EITHER HAD BEEN UNTREATED OR HAD RECEIVED GELATIN ONLY; INCIDENCES WERE NOT SIGNIFICANTLY GREATER (P > 0.05) FOR ANY TUMOR TYPE IN ANY SEX-STRAIN SUBGROUP OR IN COMBINED SEXES OF EITHER STRAIN. [R62] *OF 48 RANDOM BRED RATS GIVEN 15 MG/KG BODY WT ZIRAM (90.5% PURE) IN A SC IMPLANTED 250 MG PARAFFIN PELLET, 10 SURVIVED 22 MO, and 3 DEVELOPED TUMORS (1 HEPATOMA, 1 FIBROSARCOMA AND 1 LYMPHOSARCOMA OF INTESTINE). NO TUMORS WERE OBSERVED AT SITE OF IMPLANTATION. OF 46 CONTROLS WHICH DID NOT RECEIVE PARAFFIN PELLETS AND WHICH WERE STILL ALIVE AT 22 MO, 1 DEVELOPED A FIBROSARCOMA. [R49] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF) F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR) F1 MICE WERE GIVEN SINGLE SC INJECTIONS OF 46.4 MG/KG BODY WT COMMERCIAL ZIRAM ... IN 0.5% GELATINE ON 28TH DAY OF LIFE AND WERE OBSERVED UNTIL ... 78 WK OF AGE AT WHICH TIME 16, 17, 17 and 13 MICE IN THE 4 GROUPS, RESPECTIVELY, WERE STILL ALIVE. TUMOR INCIDENCES WERE COMPARED WITH ... 141, 154, 161 and 157 UNTREATED OR VEHICLE-INJECTED CONTROLS THAT WERE NECROPSIED. INCIDENCES WERE NOT INCR (P GREATER THAN 0.05) FOR ANY TUMOR TYPE IN ANY SEX-STRAIN SUBGROUP OR IN COMBINED SEXES OF EITHER STRAIN. [R48] *Following ip injection of ziram at an approximately LD50 rate, animals show no reaction during the 1st hour, later they become stuporous and die in coma. Survivors appear entirely normal within 24 or 48 hours. [R45, 606] *In a 2 yr experiment ... growth was retarded in rats fed 2500 ppm (about 125 mg/kg/day) even though their lifespan was normal. A dietary level of 250 /ppm/ did not interfere with growth. Rats that had received the compound at the rate of 2500 /ppm/ for about 2 mo or more showed an abnormal reflex: when picked up by the tail they did not thrust their hind legs out like normal rats but instead clasped the hind feet or crossed and stiffened the hind legs. Histological study of the rats after 2 yr of feeding showed no significant changes with the possible exception of atrophy of the testis and hypertrophy of the thyroid. However, the intensity of these changes did not correspond with dosage, and both may occur in controls, although they did not in this particular experiment. [R45, 606] *When placed in the conjunctival sac of rabbits, ziram was moderately irritating, whereas DDC, feram, and the corresponding calcium compounds were not. This indicates that the irritation was caused by the zinc and not by the dimethyldithiocarbamate moiety. [R45, 606] *Convulsions occurred in dogs fed ziram at a rate of 25 mg/kg/day, and some died after being dosed for 5 to 9 mo Symptomatology, hematology, urinalysis, organ weights, and histology were normal in dogs fed 5.0 or 0.5 mg/kg/day for 1 yr. [R45, 606] *Rats that received ziram at a dosage of 50 mg/kg/day for 2 months or more became relatively sterile; some fetuses that were conceived were resorbed and some that were born had abnormal tails. ... A dosage level of 10 mg/kg/day produced no significant effect on reproduction. [R45, 607] *A number of immunological changes were reported to appear and disappear at varying intervals in female rats that received oral doses of ziram for 9 mo at a rate of 2.5 mg/kg/day. [R45, 607] *Rats survived dietary levels of 5000 and 2500 ppm for a month, but growth was retarded and there was slight anemia. Growth retardation at 500 ppm was slight but possibly significant. At 100 ppm, growth equaled or surpassed that of controls. There were no significant histological changes in the thyroid or in other organs when the animals were killed for examination. [R45, 606] *Of 45 rubber additivities tested for mutagenicity in the Salmonella/microsome mutagenicity tests, 16 had no mutagenic properties when tested on strains TA 1535, 1537, 1538, 98, and 100 with and without S9. Because of the low solubility and insufficient penetration of bacterial membranes, another 15 cmpd gave a negative response. The thiuram and dithiocarbamate type accelerators were the most mutagenic compounds examined. Under oxygen enriched conditions, the mutagenic response was doubled. No metabolic activation was obtained in an oxygen deficient atmosphere. [R63] *Convulsions occurred in dogs fed ziram at a rate of 25 mg/kg/day, and some died after being dosed for 5-9 mo. [R36, 1445] *In a 24 mo chronic feeding study in rats, epiphyseal abnormalities in the long bones of the hind legs were observed in males and females at the highest dose tested (200 ppm (mg/kg)) in the diet. [R64] *Injection of ziram into the air chamber of eggs prior to incubation was embryo lethal to chicks (LD50; 2.1 ug/egg). [R64] *A commonly used dithiocarbamate fungicide, ziram, was investigated for its mutagenic and carcinogenic potency using sperm shape abnormalities in mice. The fungicide was administered ip in single and cumulative doses. The fungicide was found to induce significant increases in the frequency of abnormal sperm at all the doses, and a linear dose effect was observed. [R65] *Ziram has been assayed in a battery of nine bacterial strains of different genetic specificity. The results obtained suggest the induction of excisable DNA lesion(s), and indicate similar mutability of strains with adenine/thymine or guanine/cytosine base pairs at target sites. This mutagenic profile is clearly distinct from that of oxidative mutagens, and it does not support the proposed role of oxidative stress in the mechanism of dithiocarbamates mutagenicity in bacteria. Furthermore, the bone marrow micronucleus test has been carried out in B6C3F1 mice with ip administration of high grade ziram samples (2.5-10 mg/kg in males, and 5-20 mg/kg in females). Ziram resulted negative in both sexes. [R66] *As conflicting results have been obtained concerning the mutagenicity of ziram in different test systems, an investigation was undertaken of its genotoxicity in four different assays in Drosophila melanogaster. First, second, and third instar larvae, carrying suitable recessive genetic markers on their first and third chromosomes, were exposed to ziram. The results of the wing mosaic assay indicated that the frequency of small single spots with the mwh phenotype was significantly increased in all treated series. The frequency of large single spots increased with the duration of exposure. The results of the eye mosaic assay suggested that genetic alterations of chromosome 3 did not influence the genetic alterations of chromosome 1. The percentage of mosaic spots was significantly higher in all treatment groups compared to controls. The data on female germ line mosaicism indicated that the percentage of mosaic induction was significantly higher in all treatments except for the 48 hr larvae treated with half the median lethal dose for 72 hr. A significant increase was noted in the frequency of sex/linked recessive lethals in the treated series. Poisson distribution calculations followed by a chi square goodness of fit demonstrated no significant difference between the expected and observed values, indicating that the lethal mutations originated from independent events and did not represent clusters. [R67] *Fischer 344 rats were administered 0, 20, 200, or 2000 ppm ziram in their diet for up to 24 mo; animals were sacrificed after 26, 52, 78, or 104 wk for analysis of abnormalities of the femur and tibia. Epiphyseal lesions were observed at 2000 ppm. Of the 80 animals treated with 2000 ppm, three males showed partial paralysis of the hind legs and 11 of 34 males developed marked curvature of the proximal end of the crus. While females showed no clinical signs or gross abnormalities, histopathological examination revealed retarded epiphyseal closure of the proximal end of the tibia and the distal end of the femur. Severely affected aged rats exhibited marked proliferation of epiphyseal cartilaginous tissue and irregular arrangement of chondrocytes. It was concluded that the occurrence of lesions appears to be associated with impaired regulation of epiphyseal closure related to treatment with ziram; there seems to be some differences between male and female rats in the senile changes of the bone or the activity of the epiphyseal cartilage in the epiphysis of the tibia and the femur. [R68] NTXV: *LD50 Rat percutaneous more than 6000 mg/kg; [R17] *LD50 Mice oral 17 mg/kg; [R17] *LD50 Japanese quail (Coturnix japonica) oral 3346 ppm (95% confidence limit 2664-4430 ppm), diluent corn oil; [R69] *LD50 Rat oral 1400 mg/kg; [R17] *LD50 Guinea pig oral 100-150 mg/kg; [R17] *LD50 Rabbit oral 100-300 mg/kg; [R17] *LD50 Rat dermal more than 6000 mg/kg; [R10] ETXV: *LD50 Goldfish (Carassius auratus) (5-10 mg/l/5 hr) /Conditions of bioassay not specified/; [R17] *LC50 Tilapia metanopleura (5-10 mg/l/5 hr) /Conditions of bioassay not specified/; [R70] NTP: *Groups of 50 F344/N rats of each sex received diets containing 300 or 600 ppm of commercial grade ziram /89% pure, with 6.5% thiram/ for 103 weeks; and groups of 50 rats of each sex served as untreated controls. C Cell carcinomas of the thyroid in male rats occurred with a statistically significant positive trend (p < O.OI) and the incidence in the high dose group was significantly higher (p < 0.05) than that in the controls (control, 0/50, 0%; lo dose, 2/49, 4%; high dose, 7/49, 14%) and higher than that previously observed in control male rats at the same laboratory ( 18/584, 3%; range 0% to 8%). The combined incidence of males with either C cell adenoma or carcinoma also showed a statistically significant (p < 0.05) positive trend (control, 4/50, 8%; low dose, 9/49, 18%; high dose, 12/49, 24%). There were no significant histopathologic changes noted in the follicular cells. ... There was a significant decrease in the incidence of mammary fibroadenomas in high dose female rats (control, 16/50, 32%; low dose, 17/50, 34%; high dose, 8/50, 16%). Under the conditions of these studies, ziram was carcinogenic for male F344/N rats, causing increased incidences of C-cell carcinomas of the thyroid gland. Ziram was not carcinogenic for ... female F344/ N rats. [R71] *Groups of 49 or 50 B6C3F1 mice of each sex received diets containing 600 or 1,200 ppm ziram /89% pure, with 6.5% thiram/; and groups of ... 50 mice of each sex served as untreated controls. ... Survival of male and female mice was not adversely affected by ziram in feed. ... Mice probably could not have tolerated higher doses. ...The incidence of alveolar/ bronchiolar adenomas was significantly (p < 0.05) increased in female mice (control, 2/50, 4%; low dose, 5/49, 10%; high dose, 10/50, 20%). The combined incidence of alveolar/ bronchiolar adenomas or carcinomas in female mice showed a statistically significant (p < 0.05) positive trend. The incidence in the high dose group was significantly (p < 0.05) higher than that in the controls (control, 4/50, 8%; low dose, 6/49, 12%; high dose, 11/50, 22%). Pulmonary adenomatous hyperplasia consistent with chronic Sendai virus infection (confirmed by serologic analyses performed on untreated animals from the same animal shipment and present in the same room) was observed in control and dosed male mice (control, 15/49, 31%; low dose, 19/50, 38% high dose, 16/49, 3%,) as well as in control and dosed female mice (control, l8/50, 36%; low-dose, 27/49, 55%; high dose 26/50, 52%). Six of the 26 high dose females with the adenomatous hyperplasia had pulmonary tumors, whereas 4 of the 24 high dose females without pulmonary adenomatous hyperplasia also had pulmonary tumors. Only 1 of 27 low dose females with adenomatous hyperplasia had a pulmonary tumor. Significant dose related decreased incidences of liver carcinomas in male mice (control, 13/49, 27%; low dose, 8/50, 16%; high dose, 1/49, 2%) and of liver adenomas in female mice (control, 7/50, 14%; low dose, 2/50, 4%; highdose, 0/50, 0%) were observed. Under the conditions of these studies, ziram was not carcinogenic for ... male B6C3F1 mice. Increased incidences of alveolar/bronchiolar adenomas and of combined alveolar bronchiolar adenomas or carcinomas occurred in female B6C3F1 mice. However, the interpretation of this increase in lung tumors is complicated by an intercurrent Sendai virus infection. [R71] ADE: *ORAL DOSES POORLY ABSORBED IN ABSENCE OF OILS. MAY BE ABSORBED THROUGH INTACT SKIN. [R37] *Water soluble metabolites were found in the blood, kidneys, liver, ovaries, spleen, and thyroid of female rats 24 hr after oral administration of radiolabelled ziral; unchanged ziram was excreted in the feces. [R38] *In short time static bioaccumulation experiments with 14(C)-labelled zinc ethylenebisdithiocarbamate (zineb) and zinc dimethyldithiocarbamate (ziram) both compounds were rapidly disseminated through the tissues. Whole body accumulation was low, with bioconcentration factors < 100. Whole body elimination was rapid with 45% and 25% of the initial radioactivity from ziram and zineb, respectively, being retained by the end of the 16 day depuration period. Pigmented tissues appeared to be major distribution sites as well. This may be related to the affinity of the compounds and/or their degradation products to melanin or to complexation with phenoloxidase, a copper containing enzyme involved in melanin synthesis. Autoradiography also revealed a high labelling of thyroid follicles. The results show that dithiocarbamates are selectively localized in various tissues, reported to be the target organs for their toxic actions. [R72] *The fact that the ip toxicity is substantially greater suggests that absorption of oral dose is relatively slow or incomplete. [R45, 606] *Rats that received ziram at a dietary level of 2500 ppm for 2 yr had a concentration of about 4 ppm of the compound in the liver. ... Following oral administration of (35)S ziram, rats eliminated a portion in the feces (largely in chloroform soluble form) but by far the majority was excreded in the urine as water soluble metabolites. [R36, p. 1446`] *Rats that had received ziram at a dietary level of 2500 ppm for 2 years had a concentration of about 4 ppm of the compound in the liver. Thus an animal that received about 30 mg/day for 2 years had at most only 0.03 mg of the substance in its liver. On the contrary, the concentration of zinc stored in bone increased in an almost linear fashion corresponding to the logarithm of the concentration of ziram in the diet, the means increasing from 180 to 300 ppm of zinc in bone ash in animals maintained for 2 years on diets containing 0 and 2000 ppm of ziram, respectively. Thus, ziram is not stored but the zinc metabolized from it is stored to a slight degree. [R45, 606] METB: *PRESENCE OF WATER SOL METABOLITES INDICATES GENERATION OF DIMETHYLDITHIOCARBAMATE ION IN STOMACH AFTER INGESTION OF ZIRAM ... . [R49] *Ethylene thiourea is the major metabolite in plants. Ethylene thiuram monosulfide and presumably ethylene thiuram disulfide and sulfur are also formed. [R17] *Following oral administration of (35)S ziram, rats eliminated a portion in the feces (largely in chloroform soluble form) but by far the majority was excreted in the urine as water soluble metabolites. After 24 hours only small concentrations, mainly in water soluble form, remained in the tissues. In addition to ziram, five chloroform soluble metabolites and five water soluble metabolites were distinguished by paper chromatography. In the feces, 57% of the chloroform soluble activity was unchanged ziram. The five chloroform soluble metabolites were found in the gastric contents among other locations, suggesting but certainly not proving, that a part of the breakdown of ziram occurs before absorption. [R45, 606] *In studies of ziram in rats, ... production of dimethyldithiocarbamic acid, dimethylamine, and carbon disulfide /was confirmed, a well as/ two compounds that lacked zinc but contained four methyl groups. [R36, 1446] *Rats were used to study possible effects of ziram on epoxide hydrolase and glutathione S-transferase activities in metabolic inactivation of chemicals with cytotoxic, mutagenic or carcinogenic properties. An in vivo dose of 4.16 mmol/kg ziram decreased epoxide hydrolase activity significantly. Lower doses showed a slight tendency to lower epoxide hydrolase activity. Glutathione S-transferase activity in cytosol was decreased significantly by 2.08 mmol/kg ziram; more effective were 4.16 mmol/kg levels. Microsomal glutathione S-transferase activity was diminished significantly by 4.16 mmol/kg ziram, while doses below exerted a lesser and insignificant effect. In vitro concentrations of 1 to 8 umol/ml ziram caused a steady and significant decrease of epoxide hydrolase and glutathione S-transferase activities. [R56] *Administration of ziram with nitrite in aqueous solution by stomach tube to rats led to the formation of detectable amounts of N-nitrosodimethylamine in the stomach contents after 15 min. [R38] *Absorption, translocation and metabolism of dizinc bis(dimethyldithiocarbamate)-ethylenebis(dithiocarbamate), bisdithane, were studied in kidney bean seedlings with its ethylene-(14)C-labeled and dimethyl-(14)C-labeled compounds. Most of the radioactivity remained at the application sites when labeled bisdithanes were applied on the surface of the first trifoliate leaves of the plants. A small amount of the radioactivity was absorbed through the treated leaves. Translocation of the radioactivity from the leaves treated with the labeled bisdithanes to other parts of the plant was very small. These results were supported by the autoradiographic observations. The radioactive metabolites obtained from ethylene-(14)C bisdithane were identified as ethylenethiourea and ethyleneurea. Tetramethylthiuram monosulfide, tetramethylthiuram disulfide, thiazolidine-2-thione-4-carboxylic acid and 1-(dimethylthiocarbamoylthio)-beta-glucoside were identified when dimethyl-(14)C bisdithane was used. [R73] ACTN: *Fungitoxicity is apparently due to chelation of iron (2+) necessary for action of aconitase. [R37] *The effect of ziram on norepinephrine synthesis by laying hens was investigated. Inhibition experiments with dopamine beta-hydroxylase purified from chicken adrenals indicated that ziram is a potent competitive inhibitor with the substrate ascorbate. Experiments investigating the interaction of ziram with cupric ion suggested that this cmpd probably inhibits the enzyme by complexing the fully oxidized copper at its active site. When tested in vivo, ziram at oral doses of about 2.5 mg/kg reduced the conversion of radioactive dopa given systemically, to brain norepinephrine. Since it did not affect the uptake of radioactive dopa by the brain or its subsequent decarboxylation within the brain to yield dopamine, ziram inhibits cerebral dopamine beta-hydroxylase in vivo. Previously published results demonstrated that ziram has antifertility action in laying hens. The correlation between this action and inhibition of dopamine beta-hydroxylase suggests that the antifertility effects of ziram might result from its antiadrenergic action. [R74] *Ziram was reported to inhibit epoxide hydrolase and glutathione S-transferase in rat liver both in vivo and in vitro. [R64] *The mechanism of action of ziram induced mutagenicity was investigated by in vitro bacterial reversion assays and an in vivo mouse micronucleus test. Bacterial mutagenicity assays were conducted on nine bacterial strains of different genetic specificity. These strains included Salmonella typhimurium strains (TA15355), (TA1537), (TA98), (TA100), (TA102), (TA1950), and (TA1975), and Escherichia coli strains WP2 and WP2 uvrA. Ziram in vivo mutagenicity was evaluated by the mouse bone marrow micronucleus test using male and female B6C3F1 mice. Female mice were administered 5, 10, and 20 mg/kg ziram and male mice were given 2.5, 5, and 10 mg/kg ziram. Ziram exhibited a mutagenic profile in bacterial strains that were deficient in the DNA excision repair system. These strains included Salmonella typhimurium (TA1535) and (TA100), and Escherichia coli WP2 uvrA. The bacterial assay results also indicated that uvr strains with adenine/thymine or guanine/cytosine base pairs at target sites were similarly sensitive to the mutagenic effect of ziram. Ziram was ineffective in the bone marrow micronucleus assay. It was concluded that ziram is directly mutagenic in bacteria. [R75] *The toxicity of seven dithiocarbamates and interactions occurring with copper were studied with the ciliate protozoan Colpidium campylum. No product was toxic at 0.1 mg/l. Ziram was one of the least toxic products. The synergistic toxic effect of copper and ziram seems to be related mainly to the alkyl- or the ethylene bis-dithiocarbamate structure. [R76] *The observed spin-spin relaxation time of intracellular water protons reflects the membrane water permeability. Effects of various types of fungicides on the membrane were investigated by using the spin-spin relaxation time of the water protons in the mycelial cells of Botrytis cinerea. Ziram had no effect on the permeability. [R77] INTC: *LIKE MOST DITHIOCARBAMATES, ZIRAM INDUCES ACCUM OF ACETALDEHYDE IN BLOOD OF RATS RECEIVING ETHANOL AT SAME TIME. ADMIN OF ZIRAM WITH NITRITE IN AQ SOLN TO RATS BY STOMACH TUBE LED TO FORMATION OF DETECTABLE AMT OF N-NITROSO-DIMETHYLAMINE IN STOMACH CONTENTS 15 MIN LATER. [R49] *The retarding effect of dithiocarbamate derivatives on ethyl alcohol elimination was studied in rats. Oral administration of 16 mmol/kg of ziram 90 min before ethyl alcohol increased alcohol concentration in the blood (4 hr). A dose of 256 mmol cyanamide was required for an increase of blood ethyl alcohol concentration. [R78] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ziram (zinc N-dimethyldithiocarbamate) may be released into the environment as a dust or aerosol or in wastewater during its manufacture and use as an agricultural and industrial fungicide and vulcanization accelerator in the rubber-processing industry. Ziram would adsorb moderately to the soil or sediment. No data could be found on its persistence in soil or natural waters. Little bioconcentration would be expected in aquatic organisms. In the atmosphere, ziram would primarily exist as an aerosol or dust and be subject to gravitational settling. It may photolyze; however, no rates for this process could be found in the literature. Human exposure is primarily occupational via inhalation and dermal contact. In agricultural applications, ziram is applied as a spray to fruits and vegetables. (SRC) NATS: *Ziram is not known to occur as a natural product. [R8] ARTS: *Ziram, which was introduced in the early 1930s(3), may be released to the environment in wastewater or dust during its manufacture or use as an agricultural and industrial fungicide(1) and vulcanization accelerator(1) in the rubber-processin industry. In agricultural applications, it may be released when it is applied as a spray to crops such as almonds, apples, apricots, cherries, nectarines, peaches, pears, cucumbers, melons, beans, and tomatoes(2). [R79] FATE: *TERRESTRIAL FATE: If released on land, ziram would adsorb moderately to the soil. While it reportedly ionizes and biodegrades in soil(1), no data could be found concerning its persistence. Since it is fairly toxic to bacteria(2), biodegradation may only occur at very low concentrations. (SRC) [R80] *AQUATIC FATE: No information could be found concerning ziram's fate in natural waters. (SRC) *ATMOSPHERIC FATE: In the atmosphere, ziram would primarily exist as an aerosol or dust and be subject to gravitational settling. It is reportedly degraded by UV light but no photolysis rates could be found in the literature. (SRC) BIOD: *Ziram ionizes to form dimethyldithiocarbamate ions that biodegrade in soil, releasing carbon disulfide and forming dimethylamine(1). However ziram possesses antibacterial properties, particularly for gram positive organisms, and this would hinder biodegradation under many situations(2). [R81] ABIO: *IN STUDIES WITH ... ZINC DIMETHYLDITHIOCARBAMATES, VOLATILE PRODUCTS WERE FORMED FROM RESIDUES ON HIGHER PLANTS. SIGNIFICANT AMT OF CARBON DISULFIDE WERE RELEASED. THIS REACTION COULD OCCUR ON LEAF SURFACES WHERE THE APPROX PH= 5.7 IS PROBABLY DUE IN PART TO DISSOLVED CARBON DIOXIDE. THE OTHER PRODUCT OF ACIDIC DECOMP, TRIMETHYLAMMONIUM BICARBONATE, WOULD BE UNSTABLE. THIS WOULD DECOMP TO TRIMETHYLAMINE. ONLY SMALL AMT OF TRIMETHYLAMINE WERE OBSERVED. NO METHYLISOTHIOCYANATE OR HYDROGEN SULFIDE WAS DETECTED. [R82] *Ziram is decomposed by acids and UV radiation, but is otherwise stable(2). Under acidic conditions, dimethyldithiocarbamates readily decompose to form carbon disulfide and dimethylamine(1). It is likely that ziram also complexes with cupric ions in soil as the fungicide readily forms a copper complex in the presence of copper sulfate(1). [R83] BIOC: *The BCF for Ziram calculated from the water solubility is 59(1) indicating a relatively low tendency to bioconcentrate in fish(1). [R84] KOC: *The Koc for Ziram calculated from the water solubility is 440(1) indicated a moderate adsorption to soil. Ziram showed moderate mobility (Rf=0.33-0.62) in soil thin layer chromatography experiments, but was immobile in other experiments using black clay and a red sandy loam soil(2). [R85] VWS: *The vapor pressure of ziram is "practically zero"(1), so little loss would be expected from dry soil and surfaces. [R86] FOOD: *No ziram residues were reported in tested composite samples of cherries, peaches, and strawberries delivered to farmer's wholesale markets in Leamington and Toronto, Ontario(1). [R87] RTEX: *Human exposure is primarily occupational via inhalation and dermal contact. Agricultural workers would be especially exposed during spraying operations or by coming into contact with recently treated crops or soil. (SRC) *NIOSH (NOHS Survey, 1972-74) has statistically estimated that 27,889 workers are exposed to ziram in the USA(1). NIOSH (NOES Survey, 1981-83) has statistically estimated that 9243 workers are exposed to ziram in the USA(2). Since the NOES survey excludes exposure to trade name chemicals which may contain the chemical, occupational exposure could be higher(SRC). Concentrations of dithiocarbamate fungicides in the workroom air of a pesticide residue laboratory was below the provisional threshold level value of 5 mg/cu m(3). [R88] *Exposure can occur during its production, its use in the rubber industry, and its application as a fungicude, and, at much lower levels, from consumption of foods containing residues. [R89] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *0.0125 MG/KG/DAY [R47, 657] ATOL: *Tolerances for residues of the fungicide ziram (zinc dimethyldithiocarbamate), calculated as zinc ethylenebisdithiocarbamate, in or on raw agricultural commodities are established as follows: 7 ppm in or on apples, apricots, beans, beets (with or without tops) or beet greens alone, blackberries, blueberries (huckleberries), boysenberries, broccoli, brussels sprouts, cabbage, carrots, couliflower, celery, cherries, collards, cranberries, cucumbers, dewberries, eggplants, gooseberries, grapes, kale, kohlrabi, lettuce, loganberries, melons, nectarines, onions, peaches, peanuts, pears, peas, peppers, pumpkins, quinces, radishes (with or without tops) or radish tops, rasberries, rutabagas (with or without tops) or rutabaga tops, spinach, squash, strawberries, summer squash, tomatoes, turnips (with or without tops) or turnip greens, and youngberries; and 0.1 ppm in or on almonds and pecans. [R90] WSTD: STATE DRINKING WATER GUIDELINES: +(ME) MAINE 25 ug/l [R91] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Zinc and compounds/ [R92] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Zinc dimethyldithiocarbamate is found on List B. Case No: 2180; Pesticide type: Fungicide and Antimicrobial; Case Status: OPP is reviewing data from the pesticide's producers regarding its human health and/or environmental effects, or OPP is determining the pesticide's eligibility for reregistration and developing the Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Zinc dimethyldithiocarbamate; Data Call-in (DCI) Date(s): 10/01/91, 10/02/95, 10/13/95; AI Status: The producers of the pesticide has made commitments to conduct the studies and pay the fees required for reregistration, and are meeting those commitments in a timely manner. [R93] *Tolerances for residues of the fungicide ziram (zinc dimethyldithiocarbamate), calculated as zinc ethylenebisdithiocarbamate, in or on raw agricultural commodities are established for the following: almonds, apples, apricots, beans, beets (with or without tops) or beet greens alone, blackberries, blueberries (huckleberries), boysenberries, broccoli, brussels sprouts, cabbage, carrots, couliflower, celery, cherries, collards, cranberries, cucumbers, dewberries, eggplants, gooseberries, grapes, kale, kohlrabi, lettuce, loganberries, melons, nectarines, onions, peaches, peanuts, pears, peas, pecans,peppers, pumpkins, quinces, radishes (with or without tops) or radish tops, rasberries, rutabagas (with or without tops) or rutabaga tops, spinach, squash, strawberries, summer squash, tomatoes, turnips (with or without tops) or turnip greens, youngberries. [R90] FDA: *Ziram is an indirect food additive for use as a component of adhesives. [R12] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Sample volumes required depend upon the number of different digestion procedures necessary for analysis. Samples are collected in either polyethylene or glass containers. Preservation of the sample is maintained by adjusting the pH < 2 with nitric acid. Maximum holding time is 6 months. ... Solid samples must be at least 200 g and usually require no preservation other than storing at 4 deg C until analyzed. /Total metals (except hexavalent chromium and mercury)/ [R94] ALAB: *GC has been used to determine ziram residues in food samples. [R62] *HPLC was used to determine dithiocarbamate fungicides /including ziram/ in food. [R95] *Catalytic thermometric titration was used to determine dithiocarbamate residues. The dithiocarbamates can be determined in the range of 0.5-20 mmol with relative errors of approx 5%. The recoveries of zinc dimethyldithiocarbamate fungicide residues on apples were 97%. [R96] *Product analysis is by acid hydrolysis, the carbon disulfide liberated being converted to potassium O-methyl dithiocarbonate which is estimated by titration with iodine. Residues may be determined by acid hydrolysis followed by colorimetry of liberated carbon disulfide. [R6, 851] *TLC has been described in which the presence of ziram was shown by spraying with a sodium azide-iodine reagent or with cupric chloride hydroxylamine. [R62] *... Ziram was hydrolysed and the products reacted to yield strongly fluorescent derivatives which were separated by TLC and visualized under UV light. [R62] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Chemical Hazard Information Profile: Ziram (Draft) (1983) Borzsonyi M et al; IARC Sci Publ 56: 465-86 (1984). Data on 83 pesticides grouped according to their chem structure as organohalogens, organophosphates, carbamates, and other pesticides were analyzed to elucidate possible modes of action related to genotoxicity (short-term tests) and carcinogenicity. Shirasu Y et al; Environ Sci Res 31: 617-24 (1984). Microbial mutagenicity screening by Ames tests of 228 pesticides showed mutagenicity in 49 cmpd; 5 of them required metabolic activation with S9 mix for their activities. Org phosphates, halogenated alkanes, and dithiocarbamates contained mutagens at a higher ratio than the other pesticides, but mutagenicity of these was less potent than that of other mutagens. Van Leeuwen CJ et al; Aquat Toxicol 9 (2-3): 129-46 (1986). Early life stages ofSalmo gairdneri, from the fertilized egg to the early fry stage, were continuously exposed to various dialkyldithiocarbamates, ethylenebisdithiocarbamates and a number of degradation products. USEPA; Ambient Water Quality Criteria Doc: Zinc (1980) EPA 400/5-80-079 USEPA; Ambient Water Quality Criteria Doc: Zinc (1987) EPA 400/5-87-003 DHHS/NTP; Carcinogenesis Bioassay of Ziram in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 238 (1983) NIH Publication No. 83-1794 SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 260 (1976) R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1602 R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1258 R4: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 123 R5: Farm Chemicals Handbook 87. Willoughby, Ohio: Meister Publishing Co., 1987.,p. C-275 R6: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. R7: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 1059 R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 261 (1976) R9: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1208 R10: Farm Chemicals Handbook 1992. Willoughby, OH: Meister Publishing Co., 1992.,p. C-367 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V18 305 (1982) R12: 21 CFR 175.105 (4/1/91) R13: SRI R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V53 423 (1991) R15: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 591 R16: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 348 R17: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A422/Aug 87 R18: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2039 R19: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS(NIOSH) Publication No. 90-117. Washington, DC: U.S. Government Printing Office, June 1990 114 R20: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 452 R21: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R22: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 1098 R23: Farm Chemicals Handbook 1993. Willoughby, OH: Meister Publishing Co., 1993.,p. C-373 R24: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-57 (1982) R25: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-54 (1982) R26: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-74 (1982) R27: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-75 (1982) R28: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-88 (1982) R29: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-93 (1982) R30: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-166 (1982) R31: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-202 (1982) R32: Patterson JW; Industrial Wastewater Treatment Technolgy 2nd Edition p.444 (1985) R33: Patterson JW: Industrial Wastewater Treatment Technology 2nd Edition p.447 (1985) R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 53 435 (1991) R35: Morgan, D.P. Recognition and Management of Pesticide Poisonings. EPA 540/9-80-005. Washington, DC: U.S. Government Printing Office, Jan. 1982. R36: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 3. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. R37: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-314 R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V53 430 (1991) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 265 (1976) R40: Jones DM et al; Clin Reprod Fertil 4 (6): 367-72 (1986) R41: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 187 R42: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. 72 R43: Pilinskaya MA; Tsitol Genet 20 (2): 143-5 (1986) R44: Hema Prasad M et al; Environ Res 40 (1): 199-201 (1986) R45: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. R46: Savolainen K; Arbetsmiljoinstitutet, Forlagstjanst 171 (84): 1-35 (1990) R47: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R48: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 263 (1976) R49: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 264 (1976) R50: HEDENSTEDT A ET AL; MUTAT RES 68 (4): 313-25 (1979) R51: MORIYA M ET AL; MUTAT RES 54 (2): 221 (1978) R52: RASUL AR, HOWELL JM; TOXICOL APPL PHARMACOL 30 (1): 63-78 (1974) R53: ZANON LB ET AL; ARQ BIOL TECNOL 21 (1): 3-8 (1978) R54: Giavini E et al; Ecotoxicol Environ Safety 7 (6): 531-7 (1983) R55: Brooks TM et al; Mutat Res 124 (2): 129-44 (1983) R56: Schreiner E, Freundt KJ; Bull Environ Contam Toxicol 37 (1): 53-4 (1986) R57: Shapiro AZ, Bobkova AN; Gidrobiol Zh 22 (16): 79-82 (1986) R58: Soyez JL; US Patent No 2552975 (4/12/85) R59: Romer KG et al; Bull Environ Contam Toxicol 32 (5): 537-42 (1984) R60: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 77 R61: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 462 R62: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 262 (1976) R63: Rannug A et al; Prog Clin Biol Res 141: 407-19 (1984) R64: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V53 431 (1991) R65: Hemavathi E, Rahiman MA; J Toxicol Environ Health 38 (4): 393-8 (1993) R66: Crebelli R et al; Teratog Carcinog Mutagen 12 (3): 97-112 (1992) R67: Tripathy NK et al; Mutation Research 224 (2): 161-9 (1989) R68: Enomoto A et al; Toxicol 54 (1): 45-58 (1989) R69: Hill, E.F. and Camardese, M.B. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix. Fish and Wildlife Technical Report 2. Washington, DC: United States Department of Interior Fish and Wildlife Service, 1986.140 R70: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. Old Woking, Surrey, United Kingdom: Royal Society of Chemistry/Unwin Brothers Ltd., 1983.,p. A422/Oct 83 R71: DHEW/NTP; Carcinogenesis Bioassay of Ziram (CAS No. 137-30-4) in F344/N Rats and B6C3F1 Mice (Feed Study) p. 7 (1983) Technical Rpt Series No. 238 NIH Pub No. 83-1794 R72: Van Leeuwen CJ et al; Toxicol 42 (1): 33-46 (1986) R73: Kumagai H et al; J Pestic Sci 16 (4): 641-50 (1991) R74: Serio R et al; Toxicol Appl Pharmacol 72 (2): 333-42 (1984) R75: Crebelli R et al; Teratogen Carcinogen Mutagen 12 (3): 97-112 (1992) R76: Bonnemain H, Dive D; Ecotoxicol Environ Safety 19 (3): 320-6 (1990) R77: Yoshida M et al; Pestic Biochem Physiol 38 (2): 172-7 (1990) R78: Roemer KG et al; Bull Environ Contam Toxicol 32 (5): 537-42 (1984) R79: (1) IARC; Monograph. Some Carbamates, Thiocarbamates and Carbazides 12: 259-70 (1976) (2) Crop Protection Chemicals Reference; 2nd Ed New York: John Wiley pp. 703-4 (1986) (3) Rajagopal BS, et al; Res Rev 93: 1-199 (1984) R80: (1) Rajagopal BS et al; Res Rev 93: 1-199 (1984) (2) Hansen JC; Chemosphere 1: 159-62 (1972) R81: (1) Rajagopal BS, et al; Res Rev 93: 1-199 (1984) (2) Hansen JC; Chemosphere 1: 159-62 (1972) R82: Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974.182 R83: (1) Rajagopal BS et al; Res Rev 93: 1-199 (1984) (2) Hartley D; The Agrochemicals Handbook p. A422 The Royal Society of Chemistry, Nottingham, England (1984) R84: (1) Kenaga EE; Ecotoxicol Environ Safety 4: 26-38 (1980) R85: (1) Kenaga EE; Ecotoxicol Environ Safety 4: 26-38 (1980) (2) Rajagopal BS, et al; Res Rev 93: 1-199 (1984) R86: (1) Hartley D; The Agrochemicals Handbook p. A422 The Royal Society of Chemistry Nottingham England (1984) R87: (1) Frank R et al; Bull Environ Contam Toxicol 39: 272-9 (1987) R88: (1) NIOSH; National Occupational Health Survey (1975) (2) NIOSH; National Occupational Exposure Survey (1985) (3) Maini P, Boni R; Bull Environ Contam Toxicol 37: 931-7 (1986) R89: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V53 434 (1991) R90: 40 CFR 180.116 (7/1/91) R91: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R92: 40 CFR 401.15 (7/1/91) R93: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.174 (Spring, 1998) EPA 738-R-98-002 R94: USEPA; Test Methods for Evaluating Solid Waste. Physical/Chemical Methods 3rd Ed (1986) EPA 955-001-00000-1 R95: Gustafsson KH, Fahlgren CH; J Agric Food Chem 31 (2): 461-3 (1983) R96: Kiba N et al; Talanta 29 (5): 416-8 (1982) RS: 73 Record 153 of 1119 in HSDB (through 2003/06) AN: 1813 UD: 200303 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: o-CRESOL- SY: *2-CRESOL-; *O-CRESYLIC-ACID-; *1-HYDROXY-2-METHYLBENZENE-; *O-HYDROXYTOLUENE-; *2-hydroxytoluene-; *O-KRESOL- (GERMAN); *O-METHYLPHENOL-; *2-METHYLPHENOL-; *O-METHYLPHENYLOL-; *ORTHOCRESOL-; *PHENOL,-2-METHYL- RN: 95-48-7 RELT: 250 [CRESOL]; 131 [TOLUENE] (Metabolic precursor) MF: *C7-H8-O SHPN: UN 2076; Cresols (o-, m-, and p-) IMO 6.1; Cresols (o-, m-, and p-) STCC: 49 314 17; Cresols (o-, m-, and p-) HAZN: F004; A hazardous waste from nonspecific sources when a spent solvent. /Cresols/ U052; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. /Cresol (Cresylic acid)/ D023; A waste containing o-cresol may (or may not) be characterized a hazardous waste following testing for the toxicity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *From m-toluic acid: Toland, US patent 2,766,294 (1956 to California Research Corporation); Barnard, Meyer, US patent 2,852,567 (1958 to Dow). [R1, 436] *BYPRODUCT OF NAPHTHA CRACKING RECOVERED FROM THE SPENT CAUSTIC LIQUOR USED TO WASH PETROLEUM DISTILLATES AND ISOLATED BY FRACTIONAL DISTILLATION AS MIXED CRESOLS OR AS HIGHER PURITY GRADES [R2] *Ortho-cresol is obtained from the fractional distillation of tar acid. [R3] FORM: *Grades: according to freezing point: 25, 29, 30, 30.5 deg C ... [R4] *PURE CRESOL IS A MIXTURE OF ORTHO-, META- AND PARA-ISOMERS. CRUDE CRESOL (COMMERCIAL CRESOL) IS A MIXTURE OF AROMATIC CMPD CONTAINING ABOUT 20% OF O-CRESOL, 40% OF M-CRESOL, and 30% OF P-CRESOL WITH SMALL AMT OF PHENOL AND XYLENOLS. [R5, 2597] MFS: *General Electric Company, 3135 Easton Turnpike, Fairfield, CT 06431 (203) 373-2211. GE Plastics, One Plastics Avenue, Pittsfield MA 01201 (413) 448-7110. Production site: Selkirk, NY 12158 [R6] *Merichem-Sasol LLC, 800 Travis Street, Suite 4800, Houston, TX 77002-3068, (713) 224-3030. Production site: Houston, TX 77015 [R6] *PMC Specialties Group, Inc., 20525 Center Ridge Road, Rocky River, OH 44116 (440) 356-0700. Production site: Chicago, IL 60628 [R6] *Schenectady International, Congress Street and Tenth Avenue, P.O. Box 1046, Schenectady, NY 12301, (518) 370-4200. Production site: Freeport, TX 77541 [R6] OMIN: *Cresylic acids: commercial mixtures of phenolic materials boiling above cresol range. An arbitrary standard in use for cresylic acids is that 50% must boil above 204 deg C. If boiling point is below 204 deg C, material is called cresol ... Cresylic acid varies widely according to its source and boiling range. [R4] USE: *For making synthetic resins; in disinfectants and fumigants; as industrial solvent [R1, 437] *CHEM INT FOR PHENOLIC AND EPOXY CRESOL-NOVOLAC RESINS, 4,6-DINITRO-O-CRESOL (DNOC) AND OTHER HERBICIDES (EG, MCPA, MCPB, AND MCPP), DYES (EG, SULFUR AND CHROMIUM DYES), 2-METHYL-6-T-BUTYLPHENOL, MAGNET WIRE COATINGS (AS CRESYLIC ACID), PHOSPHATE ESTERS (AS CRESOL MIXT), AND FOR PHARMACEUTICALS (EG, MEPHENESIN); SOLVENT; DISINFECTANT (AS MIXED CRESOLS); FIBER TREATMENT AGENT (AS CRESOLS/CRESYLIC ACID); TANNING AGENT (AS CRESOLS/CRESYLIC ACID); METAL DEGREASING AGENT (AS CRESOLS/CRESYLIC ACID) [R2] */Cresols/ have wide applications in synthetic resin, explosive, petroleum, photographic, paint, and agricultural industries. [R7, 1597] PRIE: U.S. PRODUCTION: *(1978) 9.14X10+9 G [R2] *(1982) 1.76X10+10 G [R2] *(1984) 3.49X10+10 g /includes (o,m,p)- cresol from coal tar, m-cresol, p-cresol, cresylic acid refined from petroleum and coal tar, and (m,p)- cresol from petroleum/ [R8] *(1985) 24,014X10+3 lb [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS CRYSTALLINE CMPD [R5, 2598]; *White crystals [R4]; *White crystals (Note: A liquid above 88 degrees F). [R10] ODOR: *Phenolic odor [R1, 436]; *Sweet tarry odor [R11]; *Sweet, tarry odor. [R10] BP: *191-192 deg C [R1, 436] MP: *30 deg C [R1, 436] MW: *108.14 [R1, 436] CTP: *Critical temperature: 424.4 deg C; Critical pressure: 5.01 MPa [R12] DEN: *1.047 @ 20 deg C/4 deg C [R1, 436] DSC: *pKa= 10.287 [R13] HTC: *Crystal: 3693 kJ/mol @ 25 deg C; Gas: 3769.3 kJ/mol @ 25 deg C [R14, p. 5-81] HTV: *45.19 kJ/mol @ 191.04 deg C [R14, p. 6-123] OWPC: *log Kow= 1.95 [R15] SOL: *Sol in about 40 parts water [R1, 436]; *Miscible with ethanol, chloroform and ether [R1, 436]; *Sol in solution of the fixed alkali hydroxides [R1, 436]; *SOL IN CARBON TETRACHLORIDE [R16]; *SOL IN VEGETABLE OILS @ 30 DEG C [R5, 2598]; *In water, 2.59X10+4 mg/l @ 25 deg C [R17] SPEC: *Index of refraction: 1.553 @ 20 deg C/D [R1, 436]; *MAX ABSORPTION (WATER): 219 NM (LOG E= 3.71); 275 NM (LOG E= 3.22) [R18]; *SADTLER REFERENCE NUMBER: 844 (IR, PRISM) [R18]; *MASS: 117 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R19, p. V2 68]; *Intense mass spectral peaks: 108 m/z (100%), 107 m/z (75%), 77 m/z (34%), 79 m/z (33%) [R20]; *IR: 166 (Sadtler Research Laboratories IR Grating Collection) [R19, p. V1 452]; *UV: 259 (Sadtler Research Laboratories Spectral Collection) [R19, p. V1 452]; *NMR: 3153 (Sadtler Research Laboratories Spectral Collection) [R19, p. V1 452]; *MASS: 338 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R19, p. V1 452] VAPD: *3.72 (AIR= 1) [R21] VAP: *0.299 mm Hg @ 25 deg C [R22] VISC: *3.035 cp @ 50 deg C; 1.562 cp @ 75 deg C; 0.961 cp @ 100 deg C [R14, p. 6-248] OCPP: *0.0323% IN SATURATED AIR AT 25 DEG C; DENSITY OF SATURATED AIR AT 25 DEG C= 1.00089 (AIR= 1) [R5, 2598] *Wt/gal= 8.67 lb [R4] *Henry's Law constant = 1.2X10-6 atm-cu m/mol @ 25 deg C [R23] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of o-cresol stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this colorless to white, tar-smelling, crystalline substance may occur from its use in the production of disinfectants, herbicides, dyes, explosives, pharmaceuticals and phenolic resins. Effects from exposure may include nausea, contact burns to skin and eyes, ventricular arrhythmias, pulmonary edema, seizures, coma, and death from cardio-pulmonary failure. Both the OSHA PEL and the ACGIH TLV have been set at a TWA of 5 ppm. In activities or situations where over exposure may occur, wear a self-contained breathing apparatus and full chemical protective clothing which is specifically recommended by the shipper or producer to prevent skin contact with o-cresol. If contact should occur, immediately flush affected skin or eyes with running water for at least 15 minutes, and remove contaminated clothing and shoes at the site. Eyewash and quick drench facilities should be readily available in o-cresol work areas. While o-cresol does not ignite easily, it can burn with the production of irritating and poisonous gases. Also, containers of o-cresol can explode violently in the heat of a fire. Fires involving o-cresol may be extinguished with dry chemical, CO2, Halon, water spray, or standard foam. Fight the fire from a maximum distance and dike runoff from fire control water. o-Cresol should be stored in iron or steel containers, in cool, dark, well-ventilated areas, away from oxidizing materials, and sources of ignition and physical damage. o-Cresol may be shipped via air, rail, road, and water. Small spills of p-cresol may be shovelled into clean, dry, covered containers for later disposal (solutions are first absorbed with sand or other noncombustible material). Large spills on land should be contained in pits or other excavated holding areas that are sealed with an impermeable flexible membrane liner. Any surface flow should be diked with sand bags, foamed concrete, or foamed polyurethane. Once contained, bulk o-cresol solutions can be neutralized with crushed limestone, soda ash, or lime, and absorbed with fly ash, cement powder, or sawdust. For spills in bodies of water, trap the material at the bottom with sand bags, or add activated carbon, then use mechanical dredges to remove the immobilized masses. o-Cresol is a good candidate for fluidized bed and rotary kiln forms of incineration. Prior to implementing land disposal of o-cresol, consult with environmental regulatory agencies for guidance. DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Cresols/ [R24] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Cresols/ [R24] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Cresols/ [R24] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Cresols/ [R24] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Cresols/ [R24] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Cresols/ [R24] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Cresols/ [R24] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Cresols/ [R24] FPOT: *Flammable when exposed to heat, flames, or oxidants. [R25, 930] NFPA: *Health: 3. 3= Materials extremely hazardous to health but areas may be entered with extreme care. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist should be provided. No skin surface should be exposed. [R26, p. 325M-28] *Flammability: 2. 2= Liquids which must be moderately heated before ignition will occur and solids that readily give off flammable vapors. Water spray may be used to extinguish the fire because the material can be cooled below its flash point. [R26, p. 325M-28] *Reactivity: 0. 0= Materials which are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R26, p. 325M-28] FLMT: *LOWER: 1.4% AT 300 DEG F [R26, p. 49-43] FLPT: *81 DEG C CLOSED CUP [R26, p. 325-28] AUTO: *1110 DEG F [R25, 929] FIRP: *USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. /CRESOLS (o-, m-, p-)/ [R26, p. 49-43] *If material on fire or involved in fire: Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Use water spray to knock-down vapors. /Cresol/ [R27] TOXC: *Flammable toxic vapors given off in fire. [R11] EXPL: *LOWER 1.4% @ 300 DEG F [R25, 929] *FLAMMABLE WHEN EXPOSED TO HEAT, FLAME, ... . [R25, 930] REAC: *IT CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. /CRESOL/ [R25, 929] DCMP: *WHEN HEATED TO DECOMPOSITION, IT EMITS HIGHLY TOXIC AND IRRITATING FUMES. /CRESOL/ [R25, 929] ODRT: *5 ppm [R11] *1.4 mg/l [R28] SERI: *Fairly severe skin irritant ... [R11] *A severe eye ... irritant. [R25, 930] EQUP: *Organic vapor canister unit (USBM type B) approved by US Bureau of Mines. Rubber gloves; chemical safety goggles; face shield; coveralls and/or rubber apron; rubber shoes or boots. [R11] *... TO PREVENT ABSORPTION THROUGH SKIN ... WEAR RUBBER HAND PROTECTION AND APRONS. /CRESOLS, CRESOTE AND DERIVATIVES/ [R29] *EYE PROTECTION SHOULD ... BE PROVIDED AGAINST DROPLETS OR SPRAY. /CRESOLS, CRESOTE AND DERIVATIVES/ [R29] *The use of respirators to achieve compliance with the recommended exposure limits is permitted only: (a) during the time necessary to install or test the required engineering controls, and (b) during emergencies or during nonroutine operations, such as maintenance or repair activities, when the concentration of airborne cresol may exceed the permissible environmental limit. /Cresol/ [R30] *Wear appropriate eye protection to prevent eye contact. [R31] *Wear appropriate personal protective clothing to prevent skin contact. [R31] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R31] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities should provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R31] *Recommendations for respirator selection. Max concn for use: 23 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Any supplied-air respirator. [R31] *Recommendations for respirator selection. Max concn for use: 57.5 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. [R31] *Recommendations for respirator selection. Max concn for use: 115 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor and acid gas canister having a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. May require eye protection. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R31] *Recommendations for respirator selection. Max concn for use: 250 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R31] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R31] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor and acid gas canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R31] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Eyewash and quick drench should be available. [R32] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *The worker should immediately wash the skin when it becomes contaminated. [R31] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R31] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R31] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Neutralize spilled material with crushed limestone, soda ash, or lime. /Cresol/ [R27] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective clothing. /Cresol/ [R27] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R33] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R34] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R35] STRG: *STORE IN A COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS. /Cresols (o-, m-, p-)/ [R26, p. 49-43] *PROTECT FROM LIGHT. [R36] *Cresol should be stored in iron or steel containers, properly labelled. /Cresols, cresotes and derivatives/ [R29] *All bulk containers that hold cresol shall carry, in a readily visible location, a label that bears the trade name of the product, if appropriate, and information on the effects of exposure to the compound on human health. /Cresol/ [R37] CLUP: *Environmental considerations - Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Cresol/ [R27] *Environmental considerations - Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. /Cresol/ [R27] *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. Vapor knockdown water is corrosive or toxic and should be diked for containment. /Cresol/ [R27] *Optimum conditions for removing cresol from wastewater with Lewatit MP 500 (a strong-base, large-pore, polystyrene-based anion exchange resin) were pH 6, 30 deg C, and a flow rate of 1 l/hr, and when removing cresol from 10 mg/l solutions, the capacity of the exchanger was 0.46 equiv/l. /Cresol/ [R38] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F004 or U052, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. /Cresols/ [R39] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D023, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R39] *Chemical Treatability of o-Cresol; Concentration Process: Biological Treatment; Chemical Classification: Phenols; Scale of Study: Unknown; Type of Wastewater Used: Pure (one solute in a solvent); Results of Study: 95% reduction based on chemical oxygen demand; rate of biodegradation 54 mg chemical oxygen demand/g hr. (Activated sludge process). [R40] *Chemical Treatability of o-Cresol; Concentration Process: Solvent Extraction; Chemical Classification: Phenols; Scale of Study: Laboratory Scale, continuous flow; Type of Wastewater Used: Industrial wastewater; Results of Study: 90% reduction (Extraction of evaporator condensate from spent caustic processing using isobutylene (S/W= 1.8); spray extractor used). [R41] *Chemical Treatability of o-Cresol; Concentration Process: Solvent Extraction; Chemical Classification: Phenols; Scale of Study: Laboratory Scale, continuous flow; Type of Wastewater Used: Industrial wastewater; Results of Study: 99.9% reduction (Sequential extraction of wastewater from lube-oil refining using butyl acetate (S/W= 0.30) and isobutylene (S/W= 0.101); RDC extractor used). [R41] *Cresols: Potential candidate for rotary kiln incineration, with a temp range of 820 to 1,600 deg C (1,500 to 2,900 deg F) and a residence time of seconds. Also a potential candidate for fluidized bed incineration, with a temp range of 450 to 980 deg C (840 to 1,800 deg F) and a residence time of seconds. /Cresols/ [R42] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. [R43] MEDS: */It is recommended that a/ preplacement medical examination should include at least: ... a urinalysis that includes a microscopic examination. Additional tests, such as complete blood counts and liver and kidney function tests, should be considered by the responsible physican. ... An evaluation of the worker's ability to use positive and negative pressure respirators. ... Periodic examinations shall be made available on at least an annual basis. These examinations should include ... interim medical and work histories. ... Employees complaining of skin abnormalities, such as scaling, crusting, or irritation, that may be attributed to exposure to cresol shall be medically evaluated. ... Pertinent medical records shall be maintained by the employer for all employees occupationally exposed to cresol. Such records shall be retained for at least 30 years after termination of employment. Records of environmental exposures applicable to an employee shall be included in the employee's medical records. These records shall be made available to the designated medical representatives of the /Secretary of Health and Human Services/, the Secretary of Labor, and the employer, employee, or former employee. [R44] *... In cases of splashes, spills, or leaks where significant skin or eye contact with, or inhalation of the material occurs, appropriate medical personnel shall be notified. Medical attendants shall be informed of the possibility of delayed systemic effects, and the persons so exposed shall be observed for a minimum of 72 hours. Medical examinations ... shall be made available as warranted by the results of the 72 hour observation period. [R45] *The assessment of exposure to cresols can be accomplished through measurement of o, m, or p-cresol. However, cresol in urine is often measured to determine exposure to toluene or other aromatic compounds, of which cresol is a metabolite. O-cresol is a frequently used test used as an indicator of toluene exposure. Although o- and m- cresols are not normally detected in urine, p-cresol is excreted daily in the urine as a result of the breakdown of tyrosine. Measurement of cresols in urine for assessing only cresol exposure is useful for identification of exposure only. Measurement of o- or m-cresol are the better choices of tests, since they are not normally present in unexposed people. However since other compounds produce cresols as metabolites, it may be necessary to rule out these exposure prior to evaluation of results. Urine Reference Ranges: Normal - none detected (o-cresol, m-cresol); p-cresol is normally found in the urine, but normal levels have not been established; Exposed - not established; Toxic - not established. /Cresols/ [R46, 895] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society (ATS) and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. /Cresols/ [R46, 899] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. /Cresols/ [R46, 900] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. /Cresols/ [R46, 900] *Sputum Cytology: Sputum cytology along with chest radiographs have been the standard procedures for detecting early lung cancer in asymptomatic patients. Sputum cytology has been found to be useful for detection of central tumors, especially squamous carcinomas. /Cresols/ [R46, 900] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. /Cresols/ [R46, 900] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. /Cresols/ [R46, 901] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell Assessment ... Vision Assessment ... Facial and Trigeminal Nerve Assessment ... Vestibular Assessment ... Hearing Assessment. /Cresols/ [R46, 901] HTOX: *SYMPTOMATOLOGY: 1. Burning pain in mouth and throat. White necrotic lesions in mouth, esophagus and stomach. Abdominal pain, vomiting ... and bloody diarrhea. 2. Pallor, sweating weakness, headache, dizziness, tinnitus. 3. Shock: Weak irregular pulse, hypotension, shallow respirations, cyanosis, pallor, and a profound fall in body temperature. 4. Possibly fleeting excitement and confusion, followed by unconsciousness ... 5. Stentorous breathing, mucous rales, rhonchi, frothing at nose and mouth and other signs of pulmonary edema are sometimes seen. Characteristic odor of phenol on the breath. 6. Scanty, dark-colored ... urine ... moderately severe renal insufficiency may appear. 7. Methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia have been reported ... 8. Death from respiratory, circulatory or cardiac failure. 9. If spilled on skin, pain is followed promptly by numbness. The skin becomes blanched, and a dry opaque eschar forms over the burn. When the eschar sloughs off, a brown stain remains. /Phenol/ [R47, p. II-192] *... CRESOL IS A STRONG DERMAL IRRITANT AND CAUSES FREQUENT DERMATITIS ... /CRESOL, ALL ISOMERS/ [R48, 1991.340] *Ten subjects exposed to o-cresol at 6 mg/cu m by inhalation suffered respiratory tract irritation. [R49] *TUMOR PROMOTER IDENTIFIED IN PARTICULATE PHASE OF TOBACCO SMOKE: 7,200 UG/100 CIGARETTES (QUANTITATIVE VALUE). /FROM TABLE/ [R50] *CRESOL SLIGHTLY MORE CORROSIVE /TO THE SKIN OR EYES/ THAN PHENOL, BUT SYSTEMIC EFFECTS MAY BE A LITTLE MILDER BECAUSE OF SLOWER ABSORPTION. /CRESOL/ [R47, p. II-192] *o-, m- and p-Cresols were evaluated in both an in vitro and in vivo sister chromatid exchange assay. Dose dependent sister chromatid exchange increases were not observed in cultured human fibroblasts with any of the isomers at concentrations up to 8 mM. There was a small but significant increase in sister chromatid exchange frequency compared to control at 8 mM o-cresol. A significant decrease in cell cycle progression as measured by average generation time (AGT), was seen for all isomers at a concentration of 8 mM. [R51] *Skin contact with cresols has resulted in skin peeling on the hands, facial peripheral neuritis, severe facial burns, and damage to internal organs, including loss of kidney function and necrosis of the liver and kidneys. /Cresols/ [R52, 703] *... 8 out of 10 subjects experimentally exposed to o-cresol vapor at a concentration of 6 mg/cu m complained of dryness of the throat and the sensation of an unspecified taste. [R52, 703] *Cresol introduced into the uteri of pregnant women has produced abortion, extensive hemolysis, erosion of blood vessels, damage to the kidney tubules, necrosis of the liver, and death. /Cresol/ [R52, 703] *A 32-year-old man ingested 50 mL of a solution containing 90% cresols (1.035 g/vol). He remained conscious, became dyspneic, and developed a tachycardia, systolic hypotension and respiratory failure, myocardial failure, and pulmonary edema. He died on the fourth day after he had been hemodialyzed and had been given sodium bicarbonate, intravenous potassium, dextrose and insulin, a dopamine drip, and a forced diuresis with furosemide. Total serum phenols were 90 ug/mL. (A total phenol level of 10 ug/mL has been suggested to be of serious prognostic significance.) /Cresols/ [R53, 1210] *Ingestions of 4-120 mL of 25-50% cresol result, immediately or within 10 min, in a feeling of nausea; within 15 min, a burning sensation is felt in the mouth, throat, esophagus, and epigastrium. On the skin, cresol leaves a red burn. Burns and scalding with cresol are potentially lethal. Burns are seen on the lips, gums, tongue, cheeks, pharynx, and tonsils. Blisters may form followed by a painful sloughing of the mucous membrane. Hoarseness or aphonia may develop. Coma comes on quickly and may last for over 12 hr, accompanied by hypothermia. Stricture rarely forms in the gastrointestinal tract. Acute pancreatitis may be seen. /Cresol/ [R53, 1211] *Methemoglobinemia, decrease in red cell glutathione, Heinz body formation, and massive intravascular hemolysis may follow ingestion of 100-250 mL of lysol. /Lysol (50% mixture of cresols)/ [R53, 1211] *META-CRESOL ... SOMEWHAT LESS POISONOUS AND LESS IRRITANT THAN PHENOL, WHILE ORTHO-CRESOL IS MORE TOXIC AND PARA-CRESOL IS MOST TOXIC OF ALL THREE. [R54] NTOX: *PHENOL AND THREE ISOMERIC CRESOLS PRODUCE IDENTICAL SYMPTOMS IN POISONED ANIMALS AND ALL EXHIBIT TOXICITY OF ABOUT THE SAME MAGNITUDE ... [R47, p. III-192] *PHENOL, O- AND P-CRESOL HAVE ABOUT EQUAL TOXICITY TO /CATS/ M-CRESOL BEING SLIGHTLY LESS TOXIC ... SYMPTOMS OF ACUTE POISONING ... MUSCULAR CONVULSIONS, COMA ... WITH DEATH ENSUING FROM RESPIRATORY PARALYSIS. CONCN SOLN OF ... CRESOL HAVE VIOLENT CORROSIVE EFFECTS. PROSTRATION FROM SHOCK MAY FOLLOW INGESTION OF LARGE AMT. [R55] *... Sublethal concentrations of cresols were capable of producing abnormal metaphases and anaphases in onion root tip cells, Allium cepa, undergoing mitosis. [R56] *0.5% o-cresol was given to mice dermally over a 6 week period and resulted in no effect. [R57] *9.0 mg/cu m of o-cresol was given to rats through inhalation over a 4 month period and resulted in CNS effects and blood changes. [R58] *26-76 mg/cu m of o-cresol was given to mice through inhalation over a 1 month period and resulted in vascular congestion, changes in CNS, and inflammation of airways. [R58] *1,000-2,000 mg/kg of o-cresol was given orally to rats in a single dose and resulted in twitching, coma, and death. [R58] *9.0 mg/cu m of o-cresol was given to guinea pigs through inhalation over a 4 month period and resulted in changes in ECG. [R58] *940-1,400 mg/kg of o-cresol was given orally to rats in a single dose and resulted in convulsions, coma and death. [R59] *180-280 mg/kg of o-cresol was given to rabbits intraveneously in a single dose and resulted in convulsions, coma, and death. [R60] *Sarotherodon mossambicus /a teleost/ was exposed to a sublethal concn of o-cresol ... for 30 days was observed to show degenerative changes. LC50 value for 96 hr /exposure/ of 23.5 mg/l. ... Pathological changes ... were: vacuolation, necrosis, interzonal separation, blood capillary dilation, and fibrosis in the optic tectum when compared with control fish brain. [R61] *No increase in sister chromitid exchange frequencies was observed in bone marrow, alveolar macrophages, and regenerating liver cells of male DBA/2 mice treated with a single ip injection of either o-cresol (200 mg/kg), m-cresol (200 mg/kg), or p-cresol (75 mg/kg) 21.5 hr prior to sacrifice. [R51] *GLAUCOMA HAS BEEN INDUCED EXPERIMENTALLY IN RABBITS AND MONKEYS BY INJECTION OF 0.5-1.0% P-CRESOL EMULSION IN PHYSIOLOGIC SALINE INTO THE ANTERIOR CHAMBER. [R62] *Cresols are monomethyl derivatives of phenol ... In 28-day toxicity studies, F344/N rats and B6C3FI mice of both sexes were given o-cresol, m- cresol, p-cresol, or m/p-cresol, (60:40) at concentrations from 300 ppm to 30,000 ppm in the diet. In 13-week studies, o-cresol or m/p-cresol (60:40) were added to the diet in concentrations as high as 30,000 ppm to F344/N rats and 20,000 ppm (o-cresol) or 10,000 ppm (m/p-cresol) to B6C3F1 mice. In the 28-day studies, all rats survived (5/sex/dose), but some mice given o-cresol at 30,000 ppm, or m-cresol or p-cresol at 10,000 ppm or 30,000 ppm died before the end of the studies. Feed consumption was depressed during the first study week in all high-dose groups of animals and weight gains were generally less than controls in groups given 10,000 or 30,000 ppm in the four 28 day studies. Increased relative liver weights and kidney weights were noted in both rats and mice given concentrations of cresols as low as 3,000 ppm. However, there were no consistent microscopic changes associated with these organ weight increases. Bone marrow hypocellularity and uterus, ovary, and occasional mammary gland atrophy were seen primarily at the highest dietary concentration (30,000 ppm), but also at 10,000 ppm with certain cresols. An effect specific to the p-cresol and/or m/p-cresol studies was atrophy and regenerative changes in the nasal epithelia and forestomach, presumably a direct result of the irritant effects of the chemical or its vapors. In the 13-week studies, no deaths of rats (20/sex/dose) or mice (10/sex/dose) could clearly be related to administration of either o-cresol or m/p-cresoL hematology, clinical chemistry, and urinalysis results were generally unremarkable in all studies, although an accumulation of bile acids in the serum of dosed rats (15,000 to 30,000 ppm) was considered evidence of a deficit in hepatocellular function resulting from ingestion of the chemical. Results of microscopic analyses were consistent with findings in the 28 day studies, and revealed evidence of mild bone marrow hypocellularity in rats and forestomach hyperplasia in mice given diets containing the higher concentrations of o-cresol. Evidence of nasal irritation was present in rats and mice receiving feed containing m/p-cresol. Additional lesions in rats receiving m/p-cresol included bone marrow hypocellularity and uterine atrophy. Results of reproductive tissue evaluations and estrus cycle characterizations with o-cresol and m/p-cresol in the 13-week studies gave no indication of adverse effects to the male reproductive system, but the estrus cycle was lengthened in rats and mice receiving the higher concentrations of o-cresol and rats receiving m/p-cresol. When compared to the results of the 28 day studies, there was little evidence of a significant increase in toxic effects with lengthened administration of o-cresol or m/p-cresol in the 13-week studies. The cresol isomers exhibited a generally similar pattern of toxicities in rats and mice. Dietary concentrations of 3,000 ppm appeared to be minimal effect levels for increases in liver and kidney weights and 15,000 ppm for deficits in liver function. Histopathologic changes, including bone marrow hypocellularity, irritation to the gastrointestinaltract and nasal epithelia, and atrophy of female reproductive organs, occasionally occurred at 10,000 ppm, but were more common at the high dose of 30,000 ppm. [R63] NTXV: *LD50 Rat dermal 620 mg/kg; [R64] *LD50 Cat subcutaneous injection 55 mg/kg; [R65] *LD50 Rabbit oral 20% aqueous emulsion 0.94 g/kg; [R66] *LD50 Rabbit iv injection through marginal ear vein 0.18 g/kg; [R66] *LD50 Rabbit oral 10% solution 1.8 g/kg; [R66] *LD50 Mouse iv 1,470 mg/kg; [R59] *LD50 Rabbit single skin penetration 890 (460-1,690) mg/kg with skin corrosion; [R67] *LD50 Rat oral 121 mg/kg; [R25, 929] *LD50 Mouse oral 344 mg/kg; [R25, 929] *LC50 Mouse ihl 179 mg/cu m/2 hr; [R25, 929] *LD50 Mouse skin 620 mg/kg; [R25, 929] *LD50 Rat oral 1.35 g/kg; [R48, 1991.340] NTP: +Ortho-cresol (OCRE) ... was evaluated for reproductive toxicity in CD-1 (Swiss) mice using the Reproductive Assessment by Continuous Breeding Protocol (RACB). Exposure to OCRE at levels ranging from a mean of 66 mg/kg/day in the low-dose group (0.05% in feed) to a mean of 660 mg/kg/day in the high-dose group (0.05% in feed) for 14 wks of cohabitation did not significantly affect measures of reproductive competence, including initial fertility, mean number of litters/pair, live litter size, the proportion of pups born alive, or adjusted live pup weight. A small but significant non-dose-related incr (2-3 days) in cumulative days to litter was observed in the three treated groups. F0 body weight and feed and water consumption, after 16 weeks of OCRE exposure, were not adversely affected by treatment. Treatment had no effect on body or liver, kidney, or testis weight at necropsy, with the exception of a decr in absolute but not relative kidney weight among females in the high-dose group. No treatment-related testicular histopathology was observed. OCRE at a dose level of 0.5% in feed did not adversely affect preweaning growth or survival in the F1 generation, nor was there an effect of this dose level on feed or water consumption in the F1 generation. Calculated exposure averaged 773 and 1128 mg/kg/day for adult F1 males and females, respectively. No treatment-related clinical signs were noted. OCRE at 0.5% in feed had no effect on the reproductive competence of the F1 generation. There was no effect of treatment on male body weight or liver, epididymis, kidney, prostate, seminal vesicle, or testis weight, sperm parameters, or histopathology. Female terminal body weight was slightly reduced, but there was no effect on organ weight, vaginal cytology, or liver, kidney, or ovarian histopathology. In summary, exposure to OCRE in feed at dose levels as high as 0.5% had no significant adverse effect on reproductive competence in F0 or F1 mice. However, the max tolerated dose (MTD) was not reached, because no evidence of generalized toxicity was noted for the F0 generation at 0.5% OCRE, and only minimal evidence of generalized toxicity was noted for F1 females at 0.5% OCRE. Although the MTD was not reached for the F0 generation, data from Task 1 suggested that the animals could not have tolerated higher doses for the length of exposures in Tasks 2 and 3. The 0.2% dose level was the no adverse effects level (NOAEL) for both reproductive and general toxicity in both generations. These data indicate that OCRE is not a reproductive toxicant to either F0 or F1 mice under the conditions of this study (i.e., up to 1230 mg/kg/day). [R68] TCAT: ?The ability of o-cresol to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated in the absence of added metabolic activation. o-Cresol was tested at concentrations of 0, 0.264, 2.64, 10.6, 42.3 and 169.0 ug/ml in 0.5% DMSO, with cell survival ranging from approximately 90-20% relative to solvent control. There were no significant increases in the transformation frequencies at any of the concentrations tested relative to solvent control. [R69] ?The mutagenicity of ortho-cresol was evaluated in Salmonella tester strains TA1535, TA1537, TA1538, TA98 and TA100 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, ortho-cresol, was tested at concentrations up to 50ul/plate using the plate incorporation technique. Ortho-cresol did not cause a positive response in any tester strains with or without metabolic activation. [R70] ?The ability of ortho-cresol to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity tests, five nonactivated cultures exposed from 15.6nl/ml to 250nl/ml were cloned, producing a range of 60.6 - 5.5% relative growth. Five S9 activated cultures exposed from 3.91nl/ml to 62.5nl/ml were cloned, producing a range of 28.7 to 1.4% relative growth. None of the nonactivated or activated cultures produced mutant frequencies significantly greater than the solvent control (DMSO). [R71] ?The ability of ortho-cresol to induce Sister Chromatid Exchange (SCE) in Chinese hamster ovary (CHO) cells was evaluated both in the presence and absence of Aroclor-induced rat liver S9 fraction metabolic activation. Based on preliminary toxicity tests, ortho-cresol, diluted with DMSO, was tested at concentrations of 0, 12.5, 25.0, 50.0, 75.0 or 100.0 nl/ml without activation and at concentrations of 1.56, 3.13, 6.25, 12.5 or 15.0 nl/ml with activation. In repeat tests with activation, ortho-cresol was tested at 45.0, 50.0, 400, 500, 600, 700 or 800 nl/ml. Treatment was for 24 hrs in the nonactivation tests and 2 hrs in the activation tests. Where possible, 50 cells were scored for frequency of SCE (100 nl/ml without activation contained only 1 readable cell in the second division). Concentrations up to 50.0 nl/ml with activation were not scored due to lack of toxicity in test cultures and 800 nl/ml with activation was not scored due to excessive toxicity. Nonactivated cultures treated with 50 and 75 nl/ml exhibited SCE frequencies significantly greater than negative controls and exhibited evidence for a positive dose response. Activated cultures treated with 500 to 700 nl/ml exhibited SCE frequencies significantly greater than negative controls. [R72] ?The effect of ortho-cresol was examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, ortho-cresol was tested at concentrations of 0, 0.5, 1.0, 2.5, 5.0, 10, 25, 50 or 100 nl/ml (highest concentration was completely cytotoxic, and survival ranged from 46-101% for the remaining concentrations tested). None of the concentrations tested produced statistically significant increases in unscheduled DNA synthesis over the solvent control (the medium). [R73] ADE: *CRESOL IS ABSORBED THROUGH SKIN, OPEN WOUNDS, AND MUCOUS MEMBRANES OF GASTROENTERIC AND RESP TRACTS. RATE OF ABSORPTION THROUGH SKIN DEPENDS MORE UPON SIZE OF AREA EXPOSED THAN ON CONCENTRATION OF MATERIAL APPLIED. MAJOR ROUTE OF EXCRETION ... IS URINE, BUT CONSIDERABLE AMOUNTS MAY BE EXCRETED IN BILE AND TRACES IN EXHALED AIR. [R7, 1600] *All 6 hydrocarbons tested were excreted from the gills of Dolly Varden char (Salvelinus malma), although less of the largest and least polar cmpd was excreted. Approx equal amounts of the administered (14)C-labeled cresol (28.9%) was excreted from the gills. A large amt of administered (14)C-labeled cresol (38%) was recovered from the cloacal chamber. [R74] METB: *FROM URINE OF ANIMALS FED /O-CRESOL/ ... 2,5-DIHYDROXYTOLUENE /WAS ISOLATED/ ... [R7, 1600] *O-CRESOL YIELDS O-CRESYL-BETA-D-GLUCURONIDE, O-CRESYL SULFATE, METHYLQUINOL (1), O-METHYLANISOLE (2), and 3-METHYLCATECHOL (3) IN RABBITS. O-CRESOL YIELDS O-CRESOL SULFATE (1) AND O-METHYLANISOLE (2) IN RATS. O-CRESOL YIELDS O-METHYLANISOLE (1) IN GUINEA PIGS AND MICE. /FROM TABLE/ [R75] *Ten healthy men were exposed to approximately 200 ppm toluene for 4 hr. Urinary o-cresol concentration was 1.603 mg/l at the end of the exposure, 1.400 mg/l 4 hr after exposure, and 0.495 mg/l 20 hr after exposure. [R76] *In two workers admitted to hospital because of coma due to accidental occupational exposure to mixture of solvents, the level of toluene was respectively 823-1122 ug/l in blood and 53-38 ug/l in alveolar air on second day (36 hr after exposure). On fifth day (112 hr after exposure) the toluene level was 120-45 ug/l in blood and 3-1 ug/l in alveolar air. Urinary excretion of o-cresol, calculated as a toluene equivalent, was 0.8-0.9 mg on second day and 1.7 to 1.6 mg on third day. Urinary hippuric acid, as a toluene equivalent, was 1.7 to 1.4 g on second day and 1.3 to 0.7 g on third day. [R77] *Urinary excretion of hippuric acid and o-cresol was studied after resp exposure of human volunteers to 80 ppm (306 mg/cu m +/- std deviation 13) of toluene for 2 hr under different work loads (0, 50, 100, 150 W, respectively, during 30 min periods). The correlation between total urinary excretion, excretion rate and concn of hippuric acid, and resp uptake of toluene was poor or nonexistent. The same was true for excretion of o-cresol, which 4 hr after exposure amounted to 0.03 to 0.26% of toluene uptake. After a short-time exposure neither metabolite was a reliable measure of individual toluene uptake at varying work-loads or food intake in combination with low exposure levels. [R78] *Rana and Xenopus excrete 90-95% dose, and metabolize 50-65% dose of ... 2-methylphenol within 24 hr. Kinetic data for the excretion of phenols from both species fit a two compartment model. The elimination constants of Rana and Xenopus are not significantly different. Metabolism is mostly conjugation by glucuronidation and sulfation of the original /compound/. Additionally, oxidations leading to dihydroxyphenols and benzoic acid from 2-methylphenol ... occurs, followed by conjugation. There is an important difference between the metabolite patterns of Rana and Xenopus in that the latter is unable to glucuronidate phenols. As the amount of metabolites produced is similar in both species, Xenopus compensates for its inability to glucuronidate by increasing other metabolites. [R79] *The metabolism of phenols in Brachydanio rerio (zebra fish) was studied after uptake from the medium. The results showed no qualitative differences to other cyprinid fish species, only the oxidation rate seemed to be lower. Identified metabolites of 2-cresol were 2-cresyl glucuronide, 2-cresyl sulfate, and 2-hydroxybenzoic acid in trace amounts. [R80] *A study was conducted to examine the presence of a new metabolic product of toluene (108883), S-p-toluylmercapturic-acid (p-TMA), in the urine of occupationally exposed workers. Urine and blood samples from 33 men who worked in the production of glass and ceramic fibers or in the production of high temperature sealing components and clutch linings were analyzed. The measured ambient toluene air concentrations at the workplaces ranged from 13 to 151 ppm with a median of 63 ppm. The median blood toluene concentration was 804 ug/l which corresponded to a median urinary o-cresol (95487) level of 2.3 mg/l, a median urinary hippuric-acid (495692) level of 2.3 g/l, and a median urinary p-toluylmercapturic acid concentration of 20.4 ug/l. Eighty-seven percent of the urine samples from the exposed workers were found to contain p-toluylmercapturic acid compared with no samples from nonexposed referents. p-Toluylmercapturic acid was the only isomeric toluylmercapturic-acid detectable. The maximum concentration of p-toluylmercapturic acid in urine samples was 188 ug/l. The limit of detection of the analytical method, which was based on the method for the determination of S-phenylmercapturic-acid in urine, was 5 ug/l. Significant correlations were seen between renal excretion of p-toluylmercapturic acid and toluene blood levels and urinary o-cresol and hippuric-acid levels. Benzylmercapturic-acid (19542779) was identified in urine samples of all toluene exposed workers (median concentration 190 ug/l) as well as in samples from nonexposed referents (median concentration 30 ug/l). The authors conclude that p-toluylmercapturic acid may be a new biomarker for toluene exposure. [R81] *... A cross-sectional study on 100 workers indicated that the biological threshold for o-cresol:creatinine ratio reference value of < 1 mg/g could presently be used as a reference for non-industrial human exposure while the < 2 mg/g rate is for worker exposure in an industrial environment at a coal combustion plant. [R82] *Objectives: Widespread exposure to toluene occurs in the printing, painting, automotive, shoemaking, and speaker-manufacturing industries. The relationship between air concentrations and the absorbed dose /of toluene/ is confounded by dermal exposure, personal protective devices, movement throughout the workplace, and interindividual differences in toluene uptake and elimination. Methods: To determine the best biological indicator of exposure /the authors/ examined the blood and alveolar breath concentrations of toluene as well as the urinary excretion rates of hippuric acid and of o-, m-, and p-cresols from 33 controlled human inhalation exposures to 50 ppm for 2 hr. Results: Among the metabolites, o-cresol was least influenced by background contributions, whereas the p-cresol and hippuric acid rates were obscured by endogenous and dietary sources. Toluene levels in alveolar breath proved to be the most accurate and noninvasive indicator of the absorbed dose. ... [R83] *The biological monitoring of toluene (108883) exposure based on hippuric-acid (495692) and o-cresol (95487) concentrations in urine and toluene concentrations in alveolar air was examined. Four adult subjects were exposed for 7 hours to 10 to 100 ppm toluene or 20 to 50 ppm toluene plus 30 to 80 ppm xylene (1330207) in a controlled environment exposure chamber. ... Toluene exposure concentrations were highly correlated with the urinary hippuric acid and o-cresol levels collected during the last 4 hours of exposure, with coefficients of 0.87 and 0.81, respectively. Toluene exposure concentrations were also highly correlated with the o-cresol concentrations in the urine samples collected during the 17 hours following exposure, with a coefficient of 0.88. Exposure to 100 ppm toluene for 7 hours resulted in a urinary hippuric acid concentration of 1.27 mmol/mmol and a urinary o-cresol concentration of 1.27 umol/mmol. Toluene exposure concentrations were highly correlated with the toluene concentration measured in alveolar air at the end or 30 minutes after exposure, with coefficients of 0.99 and 0.97, respectively. The toluene concentration in alveolar air resulting from 7 hours of exposure to 100 ppm toluene equaled 21.4 ppm. Only urinary o-cresol excretion was significantly influenced by concurrent exposure to xylene. ... Toluene levels in alveolar air and o-cresol concentrations in urine are useful biological markers of low level exposure to toluene. [R84] *Occupational exposure to toluene (108883) was examined by air sampling and biological monitoring. Personal diffusion samplers were used to determine ambient toluene exposure in 23 workers. Urine and blood samples were collected at the end of the work shift. ... Both high performance liquid chromatography with ultraviolet detection and gas chromatography mass spectrometry were applied to the analysis of o-cresol (95487) in the urine. The urinary hippuric-acid concentration was also determined. The workers were exposed to a mean ambient toluene level of 65 ppm. The mean blood toluene concentration equaled 911 ug/l. The mean urinary hippuric acid and o-cresol concentrations measured 2.4 g/l and 2.9 mg/l, respectively. Urinary hippuric acid and o-cresol levels were significantly correlated with blood and ambient toluene levels, with coefficients ranging from 0.455 to 0.766. Urinary hippuric acid and o-cresol levels were significantly correlated with each other, with a coefficient of 0.845. Ambient toluene levels were significantly correlated with blood toluene levels, with a coefficient of 0.803. The authors conclude that postshift levels of toluene in the blood and o-cresol in the urine are reliable biomarkers of toluene exposure. A biological tolerance value for o-cresol of 3 mg/l was recommended. [R85] *Cytochrome P450 isoforms responsible for the metabolism of volatile hydrocarbons of low relative molecular mass are reviewed. Rat CYP2E1 catalyzes the metabolism of all hydrocarbons with a low Km, whereas CYP1A1/2, CYP2B1/2 and CYP2C11/6 catalyze the metabolism of many hydrocarbons with a high Km, although the contribution of the first two is minimal. The metabolism of hydrocarbons is affected by physiological and environmental factors, changes in the expression of P450 isoforms and the affinity of the chemicals for the isoforms. Human CYP2E1 also catalyzed all of the hydrocarbons investigated, with the same kinetics as that of rat CYP2E1. Human CYP2B6 and CYP2C8 catalyze the metabolism of some hydrocarbons, but with slightly different catalytic properties for the formation of o- and p-cresol from toluene. Although CYP2B1/2 is poorly expressed in liver microsomes from control rats, CYP2B6 is found immunochemically to be constitutive in human liver microsomes. Human CYP1A2 also catalyzes the metabolism of some organic solvents, with varying kinetic and catalytic features. The contribution of human CYP3A3, CYP3A4 and CYP3A5 to metabolism is very low. In conclusion, CYP2E1 is an essential isoform for the metabolism of hydrocarbons in both rodents and humans, especially at low concentrations. [R86] *The role of human hepatic cytochrome-P450 side chain oxidation and ring oxidation of toluene (108883) was investigated. ... Hepatic microsomes were exposed to 0.2 or 5.0 mM toluene, and toluene metabolism was assessed by measuring formation of benzyl-alcohol (100516) and o-cresol (95487) and p-cresol (106445). At both toluene doses, benzyl-alcohol and o-cresol and p-cresol were formed in all microsomes from the patients. The average ratio was 92% for benzyl-alcohol, 3% for o-cresol, and 5% for p-cresol. Regular consumption of alcohol did not affect the formation of benzyl-alcohol or the cresols. Tobacco use did not affect the formation of benzyl-alcohol or p-cresol, but o-cresol was enhanced in smokers. Of the human cytochrome-P450 forms, five catalyzed the formation of benzyl-alcohol, with 2E1 being most active, followed by 2B6, 2C8, 1A2, and 1A1. The activities of the 2A6, 2C9, 2D6, 3A3, 3A4, and 3A5 forms were not detectable. The differences in product formation when using high and low concentration toluene substrates were only three to five fold for 2E1 and 1A2, but nine fold for 2B6 and 2C8. Mouse 1A1 catalyzed benzyl-alcohol more than 1A2, but not the cresols. Rat 2B1 catalyzed the formation of benzyl-alcohol and the cresols. ... Human cytochrome-P450 forms 1A2, 2B6, 2E1, and 2C8 may play a role in the formation of benzyl-alcohol in the human liver, and forms 1A2, 2B6, and 2E1 may play a role in the formation of o-cresol and/or p-cresol. [R87] ACTN: */Cresol/ is a general protoplasmic poison and is toxic to all cells. /Cresols, cresote and derivatives/ [R29] INTC: *Effect of ethanol, cimetidine, and propranolol on toluene metabolism in man /is discussed/. ... The results indicate that ethanol may prolong the time interval in which toluene is retained in the human body in persons simultaneously exposed to ethanol and toluene. When using o-cresol or hippuric acid in biological monitoring of persons occupationally exposed to toluene, the consumption of ethanol should be considered. [R88] *Cresols cross-react with phenol. /Cresol, from table/ [R52, 537] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The smallest amount of cresol that produced death was 4 ml of a 25% to 50% cresol solution in an 11-month-old child. /Cresol/ [R52, 704] *The lethal dose of Lysol /(50% mixture of cresols)/ is about 60-120 mL, although lesser amounts have been associated with death. /Lysol/ [R53, 1211] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *o-Cresol's production and use as a solvent, disinfectant and chemical intermediate in the production of synthetic resins may result in its release to the environment through various waste streams. o-Cresol is also released to the environment through automobile exhaust, coal tar and petroleum refining and wood pulping. Cresols, including o-cresol, are widespread in nature occurring in many plants and trees. If released to air, a vapor pressure of 0.3 mm Hg at 25 deg C indicates o-cresol will exist solely as a vapor in the ambient atmosphere. Vapor-phase o-cresol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 9 hours. If released to soil, o-cresol is expected to have high mobility based upon a log Koc of 1.34. Volatilization from moist soil surfaces is expected to occur slowly based upon a Henry's Law constant of 1.2X10-6 atm-cu m/mole. o-Cresol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. This compound is expected to biodegrade rapidly based upon half-lives of 1.6 and 5.1 days in 2 agricultural soils. If released into water, o-cresol is not expected to adsorb to suspended solids and sediment in the water column based upon the Koc value. o-Cresol is expected to biodegrade in water based on a reported half-life of 50 days in southern California coastal waters and a half-life of 20 days in gasoline contaminated groundwater. Volatilization from water surfaces is expected to be slow based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 31 and 235 days, respectively. o-Cresol is not exepcted to undergo hydrolysis. An estimated BCF of 20 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to o-cresol may occur through inhalation and dermal contact with this compound at workplaces where o-cresol is produced or used. The general population may be exposed to o-cresol via inhalation of ambient air, ingestion of drinking water, and dermal contact with this compound. (SRC) NATS: *Coal, petroleum, constituent in wood, constituent in natural runoff. [R89, 542] *Cresols, including o-cresol, are widespread in nature occurring in many plants and trees(1). o-Cresol has been identified in the volatile components of smoldering biomass(2). [R90] ARTS: *Automobile exhaust, roadway runoff ... petroleum distillates, fuels, perfumes, oils, lubricants, metal cleaning, and scouring cmpd ... [R89, 543] *o-Cresol's production and use as a solvent, disinfectant and chemical intermediate in the production of synthetic resins(1) may result in its release to the environment through various waste streams(SRC). o-Cresol is also released to the environment through automobile exhaust, coal tar and petroleum refining and wood pulping(2,3). [R91] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a log Koc value of 1.34 reported for soil(2) indicates that o-cresol is expected to have high mobility in soil(SRC). Volatilization of o-cresol from moist soil surfaces is expected to occur slowly(SRC) given a Henry's Law constant of 1.2X10-6 atm-cu m/mole(3). o-Cresol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.3 mm Hg at 25 deg C(4). Biodegradation half-lives of 1.6 and 5.1 days were reported for 2 agricultural soils(5). [R92] *AQUATIC FATE: Based on a classification scheme(1), a log Koc value of 1.7 reported for river sediment(2) indicates that o-cresol is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1.2X10-6 atm-cu m/mole(4). Volatilization half-lives for a model river and model lake are 31 and 235 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 20(3,SRC), from a log Kow of 1.95(6), suggests the potential for bioconcentration in aquatic organisms is low. o-Cresol is expected to biodegrade in water based on a reported half-life of 50 days in southern California coastal waters(7) and a half-life of 20 days in gasoline contaminated groundwater(8). [R93] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), o-cresol, which has a vapor pressure of 0.3 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase o-cresol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 9 hours(SRC) from its rate constant of 4.2X10-11 cu cm/molecule-sec at 25 deg C(3). [R94] BIOD: *Biological oxygen demand: 1.64 lb/lb, 5 days [R11] *o-Cresol biodegrades rapidly in screening studies using soil, sewage, activated sludge, or municipal wastewater inocula(1-8). Acclimation is frequently not necessary(1-3,6-8). It is completely degraded in river water in 2 and 7 days at 20 and 4 deg C, respectively(9). In a field study, water from a down gradient well below a coal distillation plant showed a 76% concn reduction (after corrections for dispersion were made) compared with near surface water(10). o-Cresol is reported to degrade in soil but no rates were given(11). The disproportionate decrease in concn of o-cresol in groundwater down-gradient from a wood preserving facility has been ascribed to biodegradation(12). Groundwater from a gasoline contaminated aquifer completely degraded o-cresol in 20 days under aerobic conditions(13). The half-life of o-cresol in southern California coastal waters was reported as 50 days(14). Pure cultures isolated from reed-sedge peat bogs completely degraded o-cresol during a 48 hour incubation period(15). The first-order aerobic biodegradation rate constant of o-cresol was reported as 0.0023/day(16), corresponding to a half-life of about 305 days(SRC). Biodegradation half-lives of 1.6 and 5.1 days were reported for 2 agricultural soils(17). [R95] *No mineralization was observed when o-cresol was incubated with two digester sludge samples for 8 weeks under anaerobic conditions(1), nor was there any mineralization in 29 weeks when incubated with anaerobic freshwater sediment(1). o-Cresol was not biodegraded in an anaerobic digester sludge over a 10 week incubation period(2). In-situ microcosms installed in landfill leachate plumes under anaerobic conditions resulted in no biodegradation of o-cresol during a 60 day incubation period(3). o-Cresol was completely degraded in creosote contaminated groundwater in 95 days (lag time, 70 days) at 10 deg C and 39 days (lag time, 30 days) at 20 deg C under nitrate reducing conditions(4). [R96] ABIO: *The rate constant for the vapor-phase reaction of o-cresol with photochemically-produced hydroxyl radicals has been measured as 4.2X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 9 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). o-Cresol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). [R97] BIOC: *An estimated BCF of 20 was calculated for o-cresol(SRC), using a log Kow of 1.95(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R98] KOC: *The log Koc of o-cresol in soil was reported as 1.34(1). The log Koc of o-cresol in river sediment and coal sediment was reported as 1.7 and 1.75, respectively(2). According to a classification scheme(3), these Koc values indicate that o-cresol is expected to have high mobility in soil. [R99] VWS: *The Henry's Law constant for o-cresol is 1.2X10-6 atm-cu m/mole(1). This Henry's Law constant indicates that o-cresol is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as approximately 31 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as approximately 235 days(SRC). o-Cresol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). o-Cresol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.3 mm Hg(3). [R100] WATC: *DRINKING WATER: o-Cresol was identified, not quantified, in drinking water in the US(1-4). [R101] *SURFACE WATER: o-Cresol was identified, not quantified, in the Danube River in Germany(1). o-Cresol was detected in stream water near the American Creosote Works facility in Pensacola, FL at 0.0047 mg/l(2). [R102] *GROUNDWATER: o-Cresol was detected in groundwater in a sand aquifer at a wood-preserving facility in Pensacola, FL (5 sites, 5 depths) 0-7.10 mg/l(1) and in 2 aquifers under the Hoe Creek underground coal gasification site in Wyoming 15 months after gasification was complete at 63 and 6,600 ppb(2). o-Cresol was identified, not quantified, in 1 well water in USA(3). o-Cresol was detected in the Biscayne Aquifer, Fl at a concn of 390 ug/l(4). Groundwater near an abandoned pine tar manufacturing plant in Gainesville, FL had concns of o-cresol at less than 0.3 to 5,200 ug/l(5). o-Cresol was detected in 12 % of the samples of groundwater at 5 wood treatment facilities in the US at an avg concn of 1,268 ug/l(6). o-Cresol was detected at concns of 29.9 and 4,057 ug/l in groundwater in Ville Mercier, Quebec, Canada(7). o-Cresol was detected in the groundwater at the Gas Works Park, Seattle, WA at concns of 0.55 and 2.2 mg/l(8). o-Cresol was detected in a groundwater sample from a coal gasification plant in the US at 192 ppb(9). o-Cresol was detected in groundwater at the American Creosote Works facility in Pensacola, FL at 4.2 mg/l(10). o-Cresol was detected in groundwater near coal gasification plants in Denmark at concns of 10-77 ug/l(11). [R103] *RAIN/SNOW: o-Cresol was detected in 7 rainfall events in Portland, OR at concns of 240-2,800 parts per trillion(1) and in rainfall in Los Angeles, CA at concns of less than 2 ug/l(2). o-Cresol was detected in rainfall in Switzerland at a concn of 1.5 mg/cu m(3). o-Cresol was detected in rainfall in Beaverton, OR and Portland, OR at 110-210 ng/l(4). o-Cresol was detected in rainfall in Azusa, CA at 52 ng/l(4). [R104] EFFL: *o-Cresol was identified, not quantified in 20 of 28 samples representing effluents from refineries, petrochemical, and metallurgical industries, municipal wastewater plants and polluted fjords in Norway(1). o-Cresol was identified, not quantified in finished water from advanced waste treatment plants(2). o-Cresol was detected in 10 of 4000 effluent samples in a broad survey covering 46 industrial categories in the US(3). o-Cresol was found in effluents from timber products, iron and steel manufacturing, coal mining, organics and plastics, inorganic chemicals, textile mills, plastics and synthetics, organic chemicals, and publicly owned treatment works(3). o-Cresol was identified, not quantified in leachate from a hazardous waste site in the midwestern US(4). Process water from a coal gasification plant in Gillette, WY contained o-cresol at 8,000 ppm(5). o-Cresol was detected at trace concns in boiler water from a shale oil processing plant in DeBeque, CO(5). o-Cresol was detected in feedwater and permeate water at the American Creosote Works facility in Pensacola, FL at 10.95 and 0.157 mg/l, respectively(6). o-Cresol was detected in condensate retort water (54.3 mg/l) and process retort water (26 mg/l) in an oil shale processing plant in Logan, WA(7). o-Cresol was identified, not quantified, in effluent from a coal power plant (8) and the ash from wood burning stoves(9). o-Cresol was detected in wastewater from a coal gasification plant in North Dakota at a concn of 640 mg/l(10). o-Cresol was detected in wastewater from a coal power plant in India at 483.56 mg/l(11). o-Cresol was identified, not quantified, in landfill leachate in Sweden(12). [R105] SEDS: *o-Cresol was detected at max concns of 12, 21 and 34 ug/g in the soil of an abandoned pine tar manufacturing plant in Gainesville, FL(1). o-Cresol was detected at concns of 0-8.8 ug/kg in soil in Ville Mercier, Quebec, Canada(2). [R106] ATMC: *SOURCE DOMINATED: o-Cresol was detected in 6 of 54 source dominated samples in the US at a median concn of 1.6 ppb and a max concn of 29 ppb(1). o-Cresol was detected near a shale oil wastewater facility at 0.44 ppb(2) and near a phenolic resin factory in Japan at 40 ppb(3). The mean concn of o-cresol was reported as 6 ppb (Upland, CA), 0.1 ppb (Baton Rouge, LA), 3.8 ppb (El Paso, TX), 0.3 ppb (Houston, TX) and 0.3 ppb (Charleston, WV)(4). [R107] *URBAN/SUBURBAN: o-Cresol was detected in the ambient air of Portland, OR at concns of up to 30 parts per trillion(1) and at a mean concn of 0.07 ug/cu m (range, 0-0.13 ug/cu m) in the US(2). o-Cresol was detected in 10 samples at 3 locations in the US at a median concn of 1.5 ug/cu m(3). The ambient outdoor avg concn of o-cresol in the US was reported as 2.221 ppb(4). o-Cresol was detected at a concn of 0.02 ug/cu m in Switzerland(5). o-Cresol was detected at concns of 22-255 ng/cu m during the winter months in Minneapolis, MN and at concns of 36-351 ng/cu m during the winter months in Salt Lake City, UT(6). [R108] FOOD: *o-Cresol has been identified, not quantified, in the volatiles of cooked pork(1). [R109] PFAC: PLANT CONCENTRATIONS: *Cresols, including o-cresol, are widespread in nature occurring in many plants and trees(1). [R110] FISH/SEAFOOD CONCENTRATIONS: *o-Cresol was detected in salt-fermented herring at a concn of 18.6 ng/g(1). [R111] RTEX: *Estimates indicate that between 600,000 and 1.2 million people are exposed to cresols each year via manufacturing, processing, and/or use activities. /Cresol/ [R112] *A partial list of occupations in which exposure may occur includes: Antioxidant makers, chemical disinfectant workers, dye makers, flotation agent makers, foundry workers, insulation enamel workers, paint remover workers, pitch workers, plastic makers, resin makers, stain workers and wool scourers. /Cresol/ [R113] *Based on 1978 emissions data, it has been estimated that the total annual USA dosage (equal number of exposed persons time annual average atmospheric concn to which they were exposed) of o-cresol is 5,820 mg/cu m-persons(1). This is a result of inhalation by occupationally exposed persons(1). Indoor air at oil shale wastewater faculty contained 1.8 ppb o-cresol(2). [R114] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,214 workers (2 of these are female) are potentially exposed to o-cresol in the US(1). Occupational exposure to o-cresol may occur through inhalation and dermal contact with this compound at workplaces where o-cresol is produced or used(SRC). The general population may be exposed to o-cresol via inhalation of ambient air, ingestion of drinking water, and dermal contact with this compound(SRC). [R115] BODY: *Varnish worker exposed to alkyl benzenes including a very low concn of toluene had 0.2 mg/l of o-cresol in urine(1). Urine of 10 men exposed to approx 200 ppm toluene in air for 4 hr: Urinary o-cresol concn was: 0.159 mg/l, (mean concn before exposure); 1,400 mg/l (mean concn 4 hr after exposure)(2). Printing workers exposed to an average of 139.8 ppm toluene had 3.11 mg/l of o-cresol (mean concn) in urine(3). [R116] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *250 ppm [R31] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (22 mg/cu m). Skin Designation. /Cresol, all isomers/ [R117] NREC: *Recommended Exposure Limit: 10 hr Time-Weighted avg: 2.3 ppm (10 mg/cu m). [R31] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm, skin. /Cresol, all isomers/ [R118, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Cresol, all isomers/ [R118, 2002.6] OOPL: *Australia: 5 ppm, skin (1990); Federal Republic of Germany: 5 ppm, short-term level 10 ppm, 5 min, 8 times per shift, skin (1990); United Kingdom: 5 ppm, skin (1991). /Cresol, all isomers/ [R48, 1991.341] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. o-Cresol is produced, as an intermediate or a final product, by process units covered under this subpart. [R119] WSTD: STATE DRINKING WATER GUIDELINES: +(MN) MINNESOTA 30 ug/l [R120] +(NH) NEW HAMPSHIRE 40 ug/l [R120] +(FL) FLORIDA 350 ug/l [R120] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R121] CERC: *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Cresol, o- is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 1,000/10,000 lbs. [R122] *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R123] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. o-Cresol is included on this list. [R124] RCRA: *When cresol is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F004), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. /Cresols/ [R125] *U052; As stipulated in 40 CFR 261.33, when cresol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /Cresol (cresylic acid)/ [R126] *D023; A solid waste containing o-cresol may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. (Note: If o-, m-, and p-cresol concentrations cannot be differentiated, the total cresol (D026) concentration is used. The regulatory level of total cresol is 200 mg/l.) [R127] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A known volume of air is drawn through a silica gel tube consisting of 2, 20/40 mesh silica gel sections, 150 and 75 mg, separated by a 2 mm portion of urethane foam. The collected sample is desorbed with acetone and analyzed by gas chromatography. (This method for sampling and analysis is adapted from NIOSH Method No S167) /Cresols/ [R128] *Traces of phenols (incl o-cresol) in auto exhaust and tobacco smoke were collected using a fritted bubbler with 10 ml 0.12% sodium hydroxide. [R129] ALAB: *AOAC 930.11. Phenol in Hazardous Substances. Colorimetric Method. Applicable to com. cresols, saponified cresol solns, coal tar dips, and disinfectants, and to kerosene solns of phenols in absence of slaicylates of beta-naphthol. [R130] *THE SEPARATION OF 13 ISOMERIC ALKYLPHENOLS WAS STUDIED BY HIGH-PERFORMANCE LIQ (HPLC), GAS-LIQ (GLC) AND HIGH-PERFORMANCE THIN-LAYER CHROMATOGRAPHIC (HPTLC) TECHNIQUES. [R131] *CRESOL WAS DETERMINED IN A 50% SOAP SOLUTION BY DETERMINING ITS UV ABSORPTION AT 239 NM. THE UV METHOD GAVE RELIABLE RESULTS IN LESS TIME THAN THE CONVENTIONAL INDIAN PHARMACOPEIA (IP) METHOD. /CRESOLS/ [R132] *Infrared spectrophotometry was shown to be effective in identifying cresol from other structurally related substances. Identification and quantitative analyses of the cresol isomers, phenol, and xylenols were possible when either cyclohexane or carbon disulfide was used as the solvent. In the direct-reading infrared analyzers, cresol reportedly absorbs at the 8.6 um wavelength, with a sensitivity of 0.3 ppm. /Cresols/ [R133] *Ultraviolet spectrophotometry has been used to determine cresol in air samples. Cresol was measured by detecting particular absorption bands, but interference from other air contaminants with absorption bands in the same range reduced the sensitivity and precision of the ultraviolet spectrophotometric method ... Paper and thin-layer chromatography have been suggested as methods for the separation and analysis of cresol and structurally similar compounds. /Cresols/ [R134] *Acetone desorbed samples are analyzed using gas chromatography equipped with a flame ionization detector. The column is packed with 10% free fatty acid polymer in 80/100 mesh, acid washed DMCS Chromosorb W. The useful range of this method is 5-60 mg/cu m. (This method for sampling and analysis is adapted from NIOSH Method No S167). [R128] *A procedure for determining phenols in coal liquefaction is described. Mixture of phenols (incl o-cresol) was separated with a high-resolution fused-silica capillary column wall-coated with Superox-20M. The compounds were identified by using two identification parameters: cochromatography with authentic standards and matching mass spectra. [R135] *Traces of phenols (incl o-cresol) in auto exhaust and tobacco smoke were collected using a fritted bubbler with 10 ml 0.12% sodium hydroxide, derivatized with p-nitrobenzenediazonium tetrafluoroborate, and determined by reversed-phase high-performance liquid chromatography. The columns (20 cm diameter) were packed with LiChrosorb RP-18 (5 um) and with Polygosil 60-5C18 and mobile phase was 85% methanol/15% water. Detection limit was 0.05 to 2.0 ng. [R129] *NIOSH Method 2546. Analyte: cresol isomers/phenol; Matrix: air; Procedure: absorption on silica gel, desorption with acetone, gas chromatography, FID. [R136] *Method 0020. Source Assessment Sampling System. [R137] *Method 8270B. Determination Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R138] *Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass Spectrometry (GC/MS): Capillary Column Technique. [R138] *Method 3630B. Silica Gel Cleanup Method. [R138] *Method 1311. Toxicity Characteristic Leaching Procedure. [R139] *Method 3640A. Gel Permeation Chromatography (GPC) Cleanup Procedure. [R138] *Method 8041. Phenols by Gas Chromatography: Capillary Column Technique. [R140] *Method 8250A. Determination of Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry. [R138] *Method 8410. Determination of Semivolatile Organics By Gas Chromatography/Fourier Transform Infrared (GC/FT-IR) Spectrometry: Capillary Column. [R138] CLAB: *GAS CHROMATOGRAPHIC DETERMINATION OF O-CRESOL IN URINE IS DISCUSSED. [R141] *The concentrations of phenol and cresol in alkaline solutions were determined quantitatively using a colorimetric procedure. When reacted with Folin-Denis reagent, the compounds yielded distinct colors whose intensities could be measured. The concentration of the cresol isomers was determined as total cresol. This method has been applied to analysis of cresol and phenol in biologic fluids, such as blood and urine. /Cresols/ [R142] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: o-Cresol; Dangerous Prop Ind Mater Rep 5 (3): 30-4 (1985). Review of the safety of cresol, and its toxicology. GORDON P; AIR POLLUTION ASSESSMENT OF CRESOLS; US NTIS, PB REP: 1-76 PP (1976) PB-256737. THE TOXIC EFFECTS AND REMOVAL OF CRESOL FROM WASTE GASES ARE DISCUSSED. NIOSH; Criteria Document: Cresol (1978) DHEW Pub. NIOSH 78-133 USEPA/ECAO; Health and Environmental Effects Profile: Cresols (1985) ECAO-CIN-P138 Santodonato J; Monograph on Human Exposure to Chemicals in the Workplace: Cresols Govt Rpts Announcements and Index 7: (1986). This report presents a summary and evaluation of information relevant to an occupational hazard assessment of cresols. USEPA; Chemical Profiles: Cresylic Acid 4pp (1985). Aspects covered in this data sheet /include the following/: Chemical identity, exposure limits, physiochemical properties, fire and explosion hazards, reactivity, health hazards, uses, and handling of spills or releases. DHHS/NTP; NTP Report on the Toxicity Studies of Cresols in F344/N Rats and B6C3F1 Mice (Feed Studies) NTP TOX 9 (1991) DHHS/ATSDR; Toxicological Profile for Cresols: o-Cresol, p-Cresol, m-Cresol (1992) ATSDR/TP-91/11 USEPA; Health Effects Assessment for Cresols (1984) EPA/540/1-86/050. George JD et al; NTIS; Final Report on the Reproductive Toxicity of ortho-Cresol in CD-1 Swiss Mice II (1992) vol 1 PB92-176890. George JD et al; NTIS; Final Report on the Reproductive Toxicity of ortho-Cresol in CD-1 Swiss Mice (1992) vol 2 PB92-176908. SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: SRI R3: CHEMICAL PRODUCTS SYNOPSIS: Cresols and Creslyic Acids, 1980 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 322 R5: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R6: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 532 R7: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R8: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.25 R9: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.29 R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 78 R11: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R12: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA8 27 R13: Shiu WY et al; Chemosphere 29: 1155-1224 (1994) R14: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996. R15: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. 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NIOSH 78-133 R38: Ozcan E, Benlioglu G; Chim Acta Turc 9 (1): 291-6 (1981) R39: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R40: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-58 (1982) R41: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-120 (1982) R42: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-2, 3-12 (1981) EPA 68-03-3025 R43: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 2-Methylphenol (95-48-7) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R44: NIOSH; Criteria Document: Cresol p.4-5 (1978) DHEW Pub. NIOSH 78-133 R45: NIOSH; Criteria Document: Cresol p.5 (1978) DHEW Pub. NIOSH 78-133 R46: Ryan, R.P., C.E. Terry (eds.). Toxicology Desk Reference 4th ed. Volumes 1-3. Taylor and Francis, washington, D.C. 1997. R47: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. 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(1981), EPA Document No. FYI-OTS-0981-0126, Fiche No. 0126-0 R70: Litton Bionetics Inc.; Mutagenicity Evaluation of Ortho-Cresol in the Ames Salmonella/Microsome Plate Test, Final Report, (1981), EPA Document No. FYI-OTS-0981-0126, Fiche No. OTS0000126-0 R71: Litton Bionetics Inc; mutagenicity Evaluation of Ortho-Cresol in the Mouse Lymphoma Forward Mutation Assay, Final Report, (1981), EPA Document No. FYI-OTS-0981-0126, Fiche No. OTS0000126-0 R72: Litton Bionetics, Inc.; Mutagenicity Evaluation of ortho-Cresol in the Sister Chromatid Exchange Assay with Chinese Hamster Ovary (CHO) Cells, Final Report. (1981), EPA Document No. FYI-OTS-0981-0126, Fiche No. OTS0000126-0 R73: Litton Bionetics, Inc.; Evaluation of ortho-Cresol in the Primary Rat Hepatocyte Unscheduled DNA Synthesis Assay, Final Report. (1981), EPA Document No. FYI-OTS-0981-0126, Fiche No. OTS0000126-0 R74: Thomas RE, Rice SD; Physiol Mech Mar Pollut Toxic, (Proc Symp Pollut Mar Org) 161-76 (1982) R75: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. 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Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. R90: (1) Fiege H; Ullmann's Encycl Indust Chem. Gerhartz W ed. NY,NY: VCH 8: 25 (1987) (2) McKenzie LM et al; Environ Sci Technol 29: 2047-54 (1995) R91: (1) Budavari S; Merck Index, 12th ed, Whitehouse Station, NJ Merck and Co. p 436 (1996) (2) Graedel TE; Chemical Compounds in the Atmosphere. NY, NY: Academic Press p. 256 (1978) (3) Hampton CV; Environ Sci Technol 16: 287-98 (1982) R92: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Shiu WY et al; Chemosphere 29: 1155-1244 (1994) (3) Gaffney JS et al; Environ Sci Technol 21: 519-25 (1987) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (5) Loehr RC; Treatability Potential For EPA Listed Hazardous Wastes In Soil. USEPA Robert S Kerr Environ Res Lab, ADA, OK USEPA/600/2-89/011 (1989) R93: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Kopinke FD et al; Environ Sci Technol 29: 941-50 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Gaffney JS et al; Environ Sci Technol 21: 519-25 (1987) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: Amer Chem Soc (1995) (7) Boyd TJ, Carlucci AF; Aquatic Toxicol 25: 71-82 (1993) (8) Arvin E et al; Int Conf Physiochemical Biol Detox Hazard Wastes 2: 828-47 (1989) R94: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington, DC: Taylor and Francis (1989) (3) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) R95: (1) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (2) Baird RB et al; Arch Environ Contam Toxicol 2: 165-78 (1974) (3) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) (4) Pitter P; Water Res 10: 231-5 (1976) (5) Singer PC et al; Treatability and Assess of Coal Conversion Waste Waters Phase I p 178 USEPA-600/7-79-248 (1979) (6) Takemoto S et al; Suishitsu Odaku Kenkyu 4: 80-90 (1981) (7) Urushigawa Y et al; Kogai Shigen Kenkyusho Iho 12: 37-46 (1983) (8) Young RHF et al; J Water Pollut Contr Fed 40: 354-68 (1968) (9) Ludzack FJ, Ettinger MB; J Water Pollut Contrl Fed 32:1173-200 (1960) (10) Godsy EM et al; Bull Environ Contam Toxicol 30: 261-8 (1983) (11) Medvedev VA, Davidov VD; Pochvovedenie 11: 22-8 (1972) (12) Goerlitz DF et al; Environ Sci Technol 19: 955-61 (1985) (13) Arvin E et al; Int Conf Physiochemical Biol Detox Hazard Wastes 2: 828-47 (1989) (14) Boyd TJ, Carlucci AF; Aquatic Toxicol 25: 71-82 (1993) (15) Dawson TD, Chang FH; Bull Environ Contam Toxicol 49: 10-17 (1992) (16) Desai S et al; Determination of Monod Kinetics of Toxic Compounds by Respirometry for Structure-biodegradability Relationships ACS Symp Ser (Emerging Technol Hazard Waste Manage) 142-156 (1989) (17) Loehr RC; Treatability Potential For EPA Listed Hazardous Wastes In Soil. USEPA Robert S Kerr Environ Res Lab, ADA, OK USEPA/600/2-89/011 (1989) R96: (1) Horowitz A et al; Dev Ind Microbial 23: 435-44 (1982) (2) Battersby NS, Wilson V; Appl Environ Microbial 55: 433-39 (1989) (3) Christensen TH et al; pp. 1/207-1/214 in Proc ISWA Int Congr Exhib 7th Yokohama, Japan (1996) (4) Flyvbjerg J et al; pp. 471-79 in In Situ Bioreclamation. Hinchee RE, Olfenbuttel RF eds. Stoneham,MA: Butterworth-Heinemann (1991) R97: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R98: (1) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R99: (1) Shiu WY et al; Chemosphere 29: 1155-1244 (1994) (2) Kopinke FD et al; Environ Sci Technol 29: 941-50 (1995) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R100: (1) Gaffney JS et al; Environ Sci Technol 21: 519-25 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation Washington,DC: Taylor and Francis (1989) R101: (1) Lucas SV; GC/MS Anal of Org in Drinking Water and Advanced Waste Treatment Concn Vol 2 p. 397 USEPA-600/1-84-020B (1984) (2) Kopfler FC et al; Adv Environ Sci Technol 8(Fate Pollut Air Water Environ): 419-33 (1977) (3) Shackelford WM, Keith LH; Freq of Org Compounds Identified in Water USEPA-600/4-76-062 (1976) (4) Richardson SD et al; Environ Sci Technol 28: 592-99 (1994) R102: (1) Shakelford WM, Keith LH; Freq of Org Compounds Identified in Water USEPA-600/4-76-062 (1976) (2) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) R103: (1) Goerlitz DF et al; Environ Sci Technol 19: 955-61 (1985) (2) Stuermer DH et al; Environ Sci Technol 16: 582-7 (1982) (3) Shackelford WM, Keith LH; Freq of Org Compounds Identified in Water USEPA-600/4-76-062 (1976) (4) Canter LW, Sabatini DA; Intern J Environ Studies 46: 35-57 (1994) (5) McCreary JJ et al; Chemosphere 12: 1619-32 (1983) (6) Rosenfeld JK, Plumb RH; Ground Wat Monit Rev 11: 133-40 (1991) (7) Pakdel H et al; pp. 381-421 in Groundwater Contamination and Analysis at Hazardous Waste Sites, Lesage S, Jackson RE eds. NY,NY: Marcel Dekker, Inc (1994) (8) Turney GL, Goerlitz DF; Ground Wat Monit Rev 10: 187-98 (1990) (9) Pellizzari ED et al; in ASTM Spec Tech Publ. STP 686: 256-74 (1979) (10) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) (11) Johansen SS et al; Ground Water Monit Rev 17: 106-15 (1997) R104: (1) Leuenberger C et al; Environ Sci Technol 19: 1053-8 (1985) (2) Grossjean D; Sci Total Environ 100: 367-414 (1991) (3) Tremp J et al; ACS Div Environ Chem 192nd Natl Mtg 26: 142-43 (1988) (4) Mazurek MA, Simoneit BRT; CRC Crit Rev Environ Control 16: 1-140 (1986) R105: (1) Sporstoel S et al; Int J Environ Anal Chem 21: 129-38 (1985) (2) Lucas SV; GC/MS Anal of Org in Drinking Water Concn and Advanced Waste Treatment Concentrates Vol 2 Computer Printed Tabulation of Compound Identification Results for Large Volume Concn p 397 USEPA-600/1-84-020B (1984) (3) Bursey JT, Pellizzari ED; Anal of Industrial Wastewater for Org Pollut in Consent Decree Survey Athens GA USEPA 68-03-2867 (1982) (4) Puskar MA, Levine SP; Environ Sci Technol 21: 90-96 (1987) (5) Pellizzari ED et al; in ASTM Spec Tech Publ. STP 686: 256-74 (1979) (6) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) (7) Leenheer JA et al; Environ Sci Technol 16: 714-23 (1982) (8) Junk GA et al; ACS Symp Ser 319 (Fossil Fuels Utilization) (1986) (9) Hawthorne SB et al; Environ Sci Technol 22: 1191-96 (1988) (10) Giabbai MF et al; Intern J Environ Anal Chem 20: 113-29 (1985) (11) Pandey RA et al; J Environ Sci Health A24: 603-32 (1989) (12) Oman C, Hynning PA; Environ Pollut 80: 265-71 (1993) R106: (1) McCreary JJ et al; Chemosphere 12: 1619-32 (1983) (2) Pakdel H et al; pp. 381-421 in Groundwater Contamination and Analysis at Hazardous Waste Sites, Lesage S, Jackson RE eds. NY,NY: Marcel Dekker, Inc (1994) R107: (1) Brodzinsky R, Singh HB; Volatile Org Chem The Atmos An Assess Of Avail Data p 198 SRI 68-02-3452 (1982) (2) Hawthorne SB, Sievers RE; Environ Sci Technol 18: 483-90 (1984) (3) Hoshika Y, Muto G; J Chromatogr 157: 277-84 (1978) (4) Grossjean D; Sci Total Environ 100: 367-414 (1991) R108: (1) Grossjean D; Sci Total Environ 100: 367-414 (1991) (2) Kelly TJ et al; Ambient concn Summaries for Clean Air Act Title III Hazardous Air Pollutants. USEPA/600/R-94/090 Final Report Research Triangle Park (1993) (3) Kelly TJ et al; Environ Sci Technol 28:378-387 (1994) (4) Shah JJ, Singh HB; Environ Sci Technol 22: 1381-88 (1988) (5) Tremp J et al; ACS Div Environ Chem 192nd Natl Mtg 26: 142-43 (1988) (6) Hawthorne SB et al; Environ Sci Technol 26: 2251-62 (1992) R109: (1) Ho CT et al; J Agric Food Chem 31; 336-42 (1983) R110: (1) Fiege H; Ullmann's Encycl Indust Chem. Gerhartz W ed. NY,NY: VCH 8: 25 (1987) R111: (1) Cha YJ, Caderwallader KR; J Food Sci 60: 19-24 (1995) R112: 48 FR 31813 (7/11/83) R113: Sittig, M. Handbook of Toxic And Hazardous Chemicals. Park Ridge, NJ: Noyes Data Corporation, 1981. 151 R114: (1) Anderson GE; Human Exposure to Atmos Concentrations of Selected Chemicals Vol 1 (1983) (2) Hawthorne SB; Sievers RE; Environ Sci Technol 18: 483-90 (1984) R115: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R116: (1) Angerer J, Wulf H; Int Arch Occup Environ Health 56: 307-21 (1985) (2) Fatiadi AJ; environ Int 10: 175-205 (1984) (3) Angerer J; Int Arch Occup Environ Health 56: 322-8 (1985) R117: 29 CFR 1910.1000 (7/1/98) R118: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R119: 40 CFR 60.489 (7/1/97) R120: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R121: 40 CFR 116.4 (7/1/88) R122: 40 CFR 355 (7/1/97) R123: 40 CFR 302.4 (7/1/97) R124: 40 CFR 716.120 (7/1/97) R125: 40 CFR 261.31 (7/1/97) R126: 40 CFR 261.33 (7/1/97) R127: 40 CFR 261.24 (7/1/97) R128: NIOSH; Criteria Document: Cresol p.92-103 (1978) DHEW Pub. NIOSH 78-133 R129: Kuwata K et al; Anal Chem 53 (9): 1531-4 (1981) R130: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 236 R131: HUSAIN S ET AL; J CHROMATOGR 137 (1): 53-60 (1977) R132: TALWAR AB ET AL; INDIAN J PHARM SCI 40 (4): 135-6 (1978) R133: NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 R134: NIOSH; Criteria Document: Cresol p.63 (1978) DHEW Pub. NIOSH 78-133 R135: White CM, Li NC; Anal Chem 54 (9): 1570-2 (1982) R136: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R137: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R138: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R139: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd edition, Final Update I, July (1992) R140: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846-III, 3rd Edition, (Proposed) R141: WOIWODE W ET AL; ARCH TOXICOL 43 (2): 93-8 (1979) R142: Chapin RM; J Biol Chem 47: 309-14 (1921) as cited in NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 RS: 110 Record 154 of 1119 in HSDB (through 2003/06) AN: 1814 UD: 200301 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: p-CRESOL- SY: *PARA-CRESOL-; *4-CRESOL-; *PARA-CRESYLIC-ACID-; *FEMA-NUMBER-2337-; *1-HYDROXY-4-METHYLBENZENE-; *p-HYDROXYTOLUENE-; *4-HYDROXYTOLUENE-; *p-KRESOL- (GERMAN); *p-METHYLHYDROXYBENZENE-; *1-METHYL-4-HYDROXYBENZENE-; *p-METHYLPHENOL-; *4-METHYLPHENOL-; *PARACRESOL-; *PARAMETHYL-PHENOL-; *PHENOL,-4-METHYL-; *P-TOLUOL-; *P-TOLYL-ALCOHOL- RN: 106-44-5 RELT: 250 [CRESOL]; 131 [TOLUENE] (Metabolic precursor) MF: *C7-H8-O SHPN: UN 2076; Cresol (o-, m-, and p-) IMO 6.1; Cresol (o-, m-, and p-) STCC: 49 314 17; Cresol (o-, m-, p-) HAZN: F004; A hazardous waste from nonspecific sources when a spent solvent. /Cresols/ U052; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. /Cresol (Cresylic acid)/ D025; A waste containing p-cresol may (or may not) be characterized a hazardous waste following testing for the toxicity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY-PRODUCT OF NAPHTHA-CRACKING PROCESS OF PETROLEUM ACIDS; BY-PRODUCT IN CRUDE COKE-OVEN PROCESS OF COAL TAR ACIDS [R1] *... From benzene by the cumene process; method of purification: crystallization [R2] *... p-Cymene is oxidized and cleaved to produce p-cresol and acetone [R3, p. 1(78) 185] *Para-cresol is prepared synthetically by methylation of phenol using methanol or by fusion hydrolysis of toluenesulfonic acid [R4] *Lab prepn from p-toluenesulfonic acid by fusion with potassium hydroxide: Hartman, Org Syn 3, 37 (1923); from toluene: Braunwarth, US patent 3,046,305 (1962 to Pure Oil). [R5, 437] FORM: *Grades: Technical: 98%, 99.0% Minimum purity ... [R2] *PURE CRESOL IS A MIXTURE OF ORTHO-, META- AND PARA-ISOMERS. CRUDE CRESOL (COMMERCIAL CRESOL) IS A MIXTURE OF AROMATIC CMPD CONTAINING ABOUT 20% OF O-CRESOL, 40% OF M-CRESOL, and 30% OF P-CRESOL WITH SMALL AMT OF PHENOL AND XYLENOLS. [R6, 2597] MFS: *Bell Flavors and Fragrances Inc., 500 Academy Drive, Northbrook, IL 60062, (800) 323-4387. Production sites: Northbrook, IL 60062; Oakland, NJ 07436 [R7] *Merichem-Sasol LLC, 800 Travis Street, Suite 4800, Houston, TX 77002-3068, (713) 224-3030. Production site: Houston, TX 77015 [R7] *PMC Specialties Group, Inc., 20525 Center Ridge Road, Rocky River, OH 44116 (440) 356-0700. Production site: Chicago, IL 60628 [R7] OMIN: *META- AND PARA-CRESOL ARE SEPARATED BY TREATING THE MIXTURE WITH SULFURIC ACID. ... LIQ FRACTION, WHEN HYDROLYZED WITH STEAM AT 130 DEG C, YIELDS META-CRESOL, WHICH MAY BE FURTHER PURIFIED BY DOUBLE DISTILLATION IN VACUO. [R8, 1597] *REPORTED USES: NON-ALCOHOLIC BEVERAGES, 0.67 PPM; ICE CREAM, ICES, ETC, 0.01-1.0 0.01-2.0 PPM; BAKED GOODS, 0.01-2.0 PPM. [R9] *Zeolite absorbants are used to separate p-cresol from m-cresol after coal tar distillation [R3, p. 1(78) 572] *Cresylic acids: commercial mixtures of phenolic materials boiling above cresol range. An arbitrary standard in use for cresylic acids is that 50% must boil above 204 deg C. If boiling point is below 204 deg C, material is called cresol ... Cresylic acid varies widely according to its source and boiling range. [R2] USE: *CHEM INT FOR TRICRESYL PHOSPHATE AND CRESYL DIPHENYL PHOSPHATE; AGENT IN PRODN OF DISINFECTANTS, EXPLOSIVES, AND SYNTHETIC PERFUMERY MATERIALS; METAL CLEANING AGENT; SOLVENT FOR WIRE ENAMELS; AGENT IN ORE FLOTATION; MONOMER FOR PHENOLIC RESINS [R1] *IN SYNTHETIC FLAVOR [R10] *Organic sulfur is removed from coal by extraction with p-cresol. [R3, p. 22(83) 288] *Para-cresol ... is used to produce 2,6-di-tertiary-butyl-para-cresol, also known as butylated hydroxytoluene (BHT). [R11] */Cresols/ have wide applications in synthetic resin, explosive, petroleum, photographic, paint and agricultural industries. [R8, 1597] *For making synthetic resins; in disinfectants and fumigants; as industrial solvent. [R5, 437] PRIE: U.S. IMPORTS: *(1975) 2.15X10+9 GRAMS [R1] *(1983) 9.06X10+8 g [R12] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crystals [R5, 437]; *PRISMS [R13]; *COLORLESS [R14]; *WHITE CRYSTALS [R6, 2598]; *Crystalline mass [R2]; *Crystalline solid [Note: A liquid above 95 degees F]. [R15] ODOR: *Phenolic odor [R5, 437]; *Tarlike odor [R16]; *Sweet, tarry odor. [R15] BP: *201.8 deg C [R5, 437] MP: *35.5 deg C [R5, 437] MW: *108.14 [R5, 436] CTP: *Critical temperature: 431.4 deg C; Critical pressure: 5.15 MPa [R17] DEN: *1.0185 @ 40 deg C/4 deg C [R18, p. 3-257] DSC: *pKa= 10.26 [R19] HTC: *3772.5 kJ/mol @ 25 deg C (gas); 3698.6 kJ/mol @ 25 deg C (crystal) [R18, p. 5-81] HTV: *47.45 kJ/mol @ 201.98 deg C [R18, p. 6-123] OWPC: *log Kow= 1.94 [R20] SOL: *2.5 g in 100 ml water @ 50 deg C [R5, 437]; *5.0 g in 100 ml water @ 100 deg C [R5, 437]; *Sol in aqueous alkali hydroxides [R5, 437]; *Sol in organic solvents [R5, 437]; *Miscible in ethanol, ether, and acetone [R18, p. 3-257]; *SOLUBILITY IN MINERAL OIL: 0.7% [R6, 2598] SPEC: *Index of refraction: 1.5395 @ 20 deg C/D [R5, 437]; *MAX ABSORPTION (CYCLOHEXANE): 280 NM (LOG E= 3.23) [R21]; *SADTLER REFERENCE NUMBER: 33 (IR, PRISM) [R21]; *MASS: 117 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R22, p. V2 69]; *Intense mass spectral peaks: 107 m/z (100%), 108 m/z (91%), 77 m/z (28%), 79 m/z (21%) [R23]; *IR: 8005 (Sadtler Research Laboratories IR Grating Collection) [R22, p. V1 457]; *UV: 15 (Sadtler Research Laboratories Spectral Collection) [R22, p. V1 457]; *NMR: 9491 (Sadtler Research Laboratories Spectral Collection) [R22, p. V1 457]; *MASS: 336 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R22, p. V1 457] SURF: *41.8 dynes/cm [R16] VAPD: *3.72 (air= 1) [R24] VAP: *0.11 mm Hg @ 25 deg C [R25] VISC: *7.0 cp at 40 deg C [R26] OCPP: *PERCENT IN SATURATED AIR @ 25 DEG C: 0.0142; DENSITY OF SATURATED AIR @ 25 DEG C: 1.00039 (AIR= 1) [R6, 2598] *Wt/gal= 8.67 [R2] *Heat of fusion: 26.28 cal/g [R16] *Henry's Law constant= 1X10-6 atm-cu m/mol @ 25 deg C [R27] *Hydroxyl radical rate constant: 4.7X10-11 cu cm/molecule-sec @ 25 deg C [R28] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of p-cresol stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this colorless to white, tar-smelling, crystalline substance may occur from its use in coal desulfurization, and in the production of disinfectants, explosives, perfumery materials, and phenolic resins. Effects from exposure may include nausea, contact burns to the skin and eyes, ventricular arrhythmias, pulmonary edema, seizures, coma, and death. Both the OSHA PEL and the ACGIH TLV have been set at a TWA of 5 ppm. In activities or situations where over exposure may occur, wear a self-contained breathing apparatus and full chemical protective clothing which is specifically recommended by the shipper or producer to prevent skin contact with p-cresol. If contact should occur, immediately flush affected skin or eyes with running water for at least 15 minutes, and remove contaminated clothing and shoes at the site. Eyewash and quick drench facilities should be readily available in p-cresol work areas. While p-cresol does not ignite easily, it can burn with the production of irritating and poisonous gases. Also, containers of p-cresol can explode violently in the heat of a fire. Fires involving p-cresol may be extinguished with dry chemical, CO2, Halon, water spray, or standard foam. Water spray, if used, should be applied with caution because it may cause frothing. Fight the fire from a maximum distance and dike runoff from fire control water. p-Cresol should be stored in iron or steel containers, in cool, dry, well-ventilated areas, away from oxidizing materials, and sources of ignition and physical damage. p-Cresol may be shipped via air, rail, road, and water. Small spills of p-cresol may be shovelled into clean, dry, covered containers for later disposal (solutions are first absorbed with sand or other noncombustible material). Large spills on land should be contained in pits or other excavated holding areas that are sealed with an impermeable flexible membrane liner. Any surface flow should be diked with sand bags, foamed concrete, or foamed polyurethane. Once contained, bulk p-cresol solutions can be neutralized with crushed limestone, soda ash, or lime, and absorbed with fly ash, cement powder, or sawdust. For spills in bodies of water, trap the material at the bottom with sand bags, or add activated carbon, then use mechanical dredges to remove the immobilized masses. p-Cresol is a good candidate for fluidized bed and rotary kiln forms of incineration. Prior to implementing land disposal of p-cresol, consult with environmental regulatory agencies for guidance. DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Cresols/ [R29] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Cresols/ [R29] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Cresols/ [R29] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Cresols/ [R29] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Cresols/ [R29] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Cresols/ [R29] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Cresols/ [R29] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Cresols/ [R29] FPOT: *COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME [R30, 930] NFPA: *Health: 3. 3= Materials extremely hazardous to health but areas may be entered with extreme care. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms, and waist should be provided. No skin surface should be exposed. [R31, p. 325-28] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R31, p. 325-28] *Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R31, p. 325-28] FLMT: *1.1% BY VOL @ 302 DEG C [R32] *Lower: 1.1% at 302 deg F [R31, p. 325-28] FLPT: *86 DEG C CLOSED CUP [R33] AUTO: *1038 DEG F [R30, 930] FIRP: *USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. /CRESOLS (O-, M-, P-)/ [R31, p. 49-43] *If material on fire or involved in fire: Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Use water spray to knock-down vapors. /Cresol/ [R34] EXPL: *MODERATELY EXPLOSIVE IN THE FORM OF VAPOR WHEN EXPOSED TO HEAT OR FLAME. [R30, 930] REAC: *IT CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. /CRESOL/ [R30, 929] *Strong oxidizers, acids. [R35] DCMP: *WHEN HEATED TO DECOMPOSITION, IT EMITS HIGHLY TOXIC AND IRRITATING FUMES /CRESOL/ [R30, 929] ODRT: *0.2 ppm recognition in air; 0.46 ppb detection in air. [R16] SERI: *Fairly severe skin irritant. [R16] *A severe ... eye irritant. [R30, 930] EQUP: *WEAR ... POSITIVE PRESSURE SELF-CONTAINED BREATHING APPARATUS. /CRESOLS (O-, M-, P-)/ [R31, p. 49-43] *... TO PREVENT ABSORPTION THROUGH SKIN ... WEAR RUBBER HAND PROTECTION AND APRONS. /CRESOLS, CRESOTES AND DERIVATIVES/ [R36] *EYE PROTECTION SHOULD ... BE PROVIDED AGAINST DROPLETS OR SPRAY. /CRESOLS, CRESOTES AND DERIVATIVES/ [R36] *The use of respirators to achieve compliance with the recommened exposure limits is permitted only: (a) during the time necessary to install or test the required engineering controls, and (b) during emergencies or during nonroutine operations, such as maintenance or repair activities, when the concentration of airborne cresol may exceed the permissible environmental limit. [R37] *Wear appropriate personal protective clothing to prevent skin contact. [R35] *Wear appropriate eye protection to prevent eye contact. [R35] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R35] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities should provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R35] *Recommendations for respirator selection. Max concn for use: 23 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Any supplied-air respirator. [R35] *Recommendations for respirator selection. Max concn for use: 57.5 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. [R35] *Recommendations for respirator selection. Max concn for use: 115 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor and acid gas canister having a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. May require eye protection. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R35] *Recommendations for respirator selection. Max concn for use: 250 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R35] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R35] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor and acid gas canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R35] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *The worker should immediately wash the skin when it becomes contaminated. [R35] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R35] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R35] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Neutralize spilled material with crushed limestone, soda ash, or lime. /Cresol/ [R34] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective clothing. /Cresol/ [R34] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R38] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R39] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R40] STRG: *STORE IN A COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS. /Cresols (o-, m-, p-)/ [R31, p. 49-43] *Cresol should be stored in iron or steel containers, properly labelled. /Cresols, cresotes and derivatives/ [R36] *All bulk containers that hold cresol shall carry, in a readily visible location, a label that bears the trade name of the product, if appropriate, and information on the effects of exposure to the compound on human health. /Cresol/ [R41] CLUP: *Optimum conditions for removing cresol from wastewater with Lewatit MP 500 (a strong-base, large-pore, polystyrene-based anion exchange resin) were pH 6, 30 deg, and a flow rate of 1 l/hr, and when removing cresol from 10 mg/l solutions, the capacity of the exchanger was 0.46 equiv/l. /Cresol/ [R42] *Environmental considerations - Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Cresol/ [R34] *Environmental considerations - Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. /Cresol/ [R34] *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. Vapor knockdown water is corrosive or toxic and should be diked for containment. /Cresol/ [R34] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F004 or U052, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R43] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D025, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R43] *Chemical Treatability of p-Cresol; Concentration Process: Biological Treatment; Chemical Classification: Phenols; Scale of Study: Unknown; Type of Wastewater Used: Pure (one solute in a solvent); Results of Study: 95.5% reduction based on chemical oxygen demand; rate of biodegradation 55 mg chemical oxygen demand/g hr. (Activated sludge process). [R44] *Chemical Treatability of p-Cresol; Concentration Process: Solvent Extraction; Chemical Classification: Phenols; Scale of Study: Laboratory Scale, Continuous flow; Type of Wastewater Used: Industrial Wastewater; Results of Study: 91% reduction (Extraction of evaporation condensate from spent caustic processing using isobutylene (S/W= 1.8); spray extractor used). [R45] *Cresol: A good candidate for rotary kiln incineration at temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. /Cresols/ [R46] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. [R47] MEDS: */It is recommended that a/ preplacement medical examination should include at least: ... a urinalysis that includes a microscopic examination. Additional tests, such as complete blood counts and liver and kidney function tests, should be considered by the responsible physican. ... An evaluation of the worker's ability to use positive and negative pressure respirators. ... Periodic examinations shall be made available on at least an annual basis. These examinations should include ... interim medical and work histories. ... Employees complaining of skin abnormalities, such as scaling, crusting, or irritation, that may be attributed to exposure to cresol shall be medically evaluated. ... Pertinent medical records shall be maintained by the employer for all employees occupationally exposed to cresol. Such records shall be retained for at least 30 years after termination of employment. Records of environmental exposures applicable to an employee shall be included in the employee's medical records. These records shall be made available to the designated medical representatives of the /Secretary of Health and Human Services/, the Secretary of Labor, and the employer, employee, or former employee. [R48] *... In cases of splashes, spills, or leaks where significant skin or eye contact with, or inhalation of the material occurs, appropriate medical personnel shall be notified. Medical attendants shall be informed of the possibility of delayed systemic effects, and the persons so exposed shall be observed for a minimum of 72 hours. Medical examinations ... shall be made available as warranted by the results of the 72 hour observation period. [R49] *The assessment of exposure to cresols can be accomplished through measurement of o, m, or p-cresol. However, cresol in urine is often measured to determine exposure to toluene or other aromatic compounds, of which cresol is a metabolite. O-cresol is a frequently used test used as an indicator of toluene exposure. Although o- and m- cresols are not normally detected in urine, p-cresol is excreted daily in the urine as a result of the breakdown of tyrosine. Measurement of cresols in urine for assessing only cresol exposure is useful for identification of exposure only. Measurement of o- or m-cresol are the better choices of tests, since they are not normally present in unexposed people. However since other compounds produce cresols as metabolites, it may be necessary to rule out these exposure prior to evaluation of results. Urine Reference Ranges: Normal - none detected (o-cresol, m-cresol); p-cresol is normally found in the urine, but normal levels have not been established; Exposed - not established; Toxic - not established. /Cresols/ [R50, 895] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society (ATS) and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. /Cresols/ [R50, 899] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. /Cresols/ [R50, 900] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. /Cresols/ [R50, 900] *Sputum Cytology: Sputum cytology along with chest radiographs have been the standard procedures for detecting early lung cancer in asymptomatic patients. Sputum cytology has been found to be useful for detection of central tumors, especially squamous carcinomas. /Cresols/ [R50, 900] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. /Cresols/ [R50, 900] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. /Cresols/ [R50, 901] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell Assessment ... Vision Assessment ... Facial and Trigeminal Nerve Assessment ... Vestibular Assessment ... Hearing Assessment. /Cresols/ [R50, 901] HTOX: *... CRESOL IS A STRONG DERMAL IRRITANT AND CAUSES FREQUENT DERMATITIS ... /CRESOL/ [R51, 1991.340] *SYMPTOMATOLOGY: 1. Burning pain in mouth and throat. White necrotic lesions in mouth, esophagus and stomach. Abdominal pain, vomiting ... and bloody diarrhea. 2. Pallor, sweating weakness, headache, dizziness, tinnitus. 3. Shock: Weak irregular pulse, hypotension, shallow respirations, cyanosis, pallor, and a profound fall in body temperature. 4. Possibly fleeting excitement and confusion, followed by unconsciousness ... 5. Stentorous breathing, mucous rales, rhonchi, frothing at nose and mouth and other signs of pulmonary edema are sometimes seen. Characteristic odor of phenol on the breath. 6. Scanty, dark-colored ... urine ... moderately severe renal insufficiency may appear. 7. Methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia have been reported ... 8. Death from respiratory, circulatory or cardiac failure. 9. If spilled on skin, pain is followed promptly by numbness. The skin becomes blanched, and a dry opaque eschar forms over the burn. When the eschar sloughs off, a brown stain remains. /Phenol/ [R52] *TUMOR PROMOTER IDENTIFIED IN PARTICULATE PHASE OF TOBACCO SMOKE: 7,200 UG/100 CIGARETTES (QUANTITATIVE VALUE). /FROM TABLE/ [R53] *CRESOL SLIGHTLY MORE CORROSIVE /TO THE SKIN OR EYES/ THAN PHENOL, BUT SYSTEMIC EFFECTS MAY BE A LITTLE MILDER BECAUSE OF SLOWER ABSORPTION. [R52] *o-, m- and p-Cresols were evaluated in both an in vitro and in vivo SCE assay. Dose dependent sister chromitid exchange increases were not observed in cultured human fibroblasts with any of the isomers at concentrations up to 8 mM. There was a small but significant increase in sister chromitid exchange frequency compared to control at 8 mM o-cresol. A significant decrease in cell cycle progression as measured by average generation time (AGT), was seen for all isomers at a concentration of 8 mM. [R54] *Skin contact with cresols has resulted in skin peeling on the hands, facial peripheral neuritis, severe facial burns, and damage to internal organs, including loss of kidney function and necrosis of the liver and kidneys. /Cresols/ [R55, 703] *Cresol introduced into the uteri of pregnant women has produced abortion, extensive hemolysis, erosion of blood vessels, damage to the kidney tubules, necrosis of the liver, and death. /Cresol/ [R55, 703] *A 32-year-old man ingested 50 mL of a solution containing 90% cresols (1.035 g/vol). He remained conscious, became dyspneic, and developed a tachycardia, systolic hypotension and respiratory failure, myocardial failure, and pulmonary edema. He died on the fourth day after he had been hemodialyzed and had been given sodium bicarbonate, intravenous potassium, dextrose and insulin, a dopamine drip, and a forced diuresis with furosemide. Total serum phenols were 90 ug/mL. (A total phenol level of 10 ug/mL has been suggested to be of serious prognostic significance.) /Cresols/ [R56, 1210] *Ingestions of 4-120 mL of 25-50% cresol result, immediately or within 10 min, in a feeling of nausea; within 15 min, a burning sensation is felt in the mouth, throat, esophagus, and epigastrium. On the skin cresol leaves a red burn. Burns and scalding with cresol are potentially lethal. Burns are seen on the lips, gums, tongue, cheeks, pharynx, and tonsils. Blisters may form followed by a painful sloughing of the mucous membrane. Hoarseness or aphonia may develop. Coma comes on quickly and may last for over 12 hr, accompanied by hypothermia. Stricture rarely forms in the gastrointestinal tract. Acute pancreatitis may be seen. /Cresol/ [R56, 1211] *Methemoglobinemia, decrease in red cell glutathione, Heinz body formation, and massive intravascular hemolysis may follow ingestion of 100-250 mL of lysol. /Lysol (50% mixture of cresols)/ [R56, 1211] *META-CRESOL ... SOMEWHAT LESS POISONOUS AND LESS IRRITANT THAN PHENOL, WHILE ORTHO-CRESOL IS MORE TOXIC AND PARA-CRESOL IS MOST TOXIC OF ALL THREE. [R57] NTOX: *PHENOL, O- AND P-CRESOL HAVE ABOUT EQUAL TOXICITY TO /CATS/ M-CRESOL BEING SLIGHTLY LESS TOXIC ... SIGNS OF ACUTE POISONING ... MUSCULAR CONVULSIONS, COMA ... WITH DEATH ENSUING FROM RESPIRATORY PARALYSIS. CONCN SOLN OF ... CRESOL HAVE VIOLENT CORROSIVE EFFECTS. PROSTRATION FROM SHOCK MAY FOLLOW INGESTION OF LARGE AMT. [R58] *GLAUCOMA HAS BEEN INDUCED EXPERIMENTALLY IN RABBITS AND MONKEYS BY INJECTION OF 0.5-1.0% P-CRESOL EMULSION IN PHYSIOLOGIC SALINE INTO THE ANTERIOR CHAMBER. [R59] *AQ INFUSIONS OF DECAYED PAPER BIRCH, BETULA PAPYRIFERA CONTAINED AN OVIPOSITION ATTRACTANT FOR TREE-HOLE MOSQUITO, AEDES TRISERIATUS, IN LAB EXPT. CONTACT OF OVIPOSITIONING MOSQUITOES WITH P-CRESOL ODOR ALONE SUFFICED TO INDUCE INCREASED OVIPOSITION. [R60] *The effects of p-cresol were examined on benthic macroinvertebrate flora and fauna in an Environmental Protection Agency outdoor experimental stream facility located at Monticello, Minnesota. ... The primary effect of p-cresol was on the photosynthetic and respiration processes of aquatic plants. [R61] *PHENOL AND THREE ISOMERIC CRESOLS PRODUCE IDENTICAL SYMPTOMS IN POISONED ANIMALS AND ALL EXHIBIT TOXICITY OF ABOUT THE SAME MAGNITUDE ... [R52] *0.5% p-Cresol was given dermally to mice over a 6 week period and resulted in skin corrosion and depigmentation. [R62] *1,300-2,700 mg/kg of p-cresol given orally to rats in a single dose, resulted in twitching, coma, and death. [R63] *620-1400 mg/kg of p-cresol given orally to rabbits in a single dose, resulted in convulsions, coma, and death. [R64] *180-280 mg/kg of p-cresol given iv to rabbits in a single dose, resulted in convulsions, coma, and death. [R64] *No increase in sister chromatid exchange frequencies was observed in bone marrow, alveolar macrophages, and regenerating liver cells of male DBA/2 mice treated with a single ip injection of either o-cresol (200 mg/kg), m-cresol (200 mg/kg), or p-cresol (75 mg/kg) 21.5 hr prior to sacrifice. [R54] *Larval fathead minnows (Pimephales pomelas) were exposed for 96 hr to several concentrations of ... p-cresol. The range of safe concentrations determined from 96 hr macromolecular content (RNA, DNA and protein) and growth was within or near the range of safe concentrations determined by concomitant longer term exposure (28-32 day early life stage toxicity test). RNA, DNA and protein content/larva and RNA/DNA ratio were sensitive to toxicant stress and followed a log-linear dose response. Larval RNA content appeared to be the 96 hr measurement most responsive to toxicant exposure. A disruption of nucleic acid and protein metabolism apparently occurred within 96 hr of sublethal toxicant exposure and resulted in decreased rates of mitosis, reduced protein synthesis and reduced growth. Measurement of growth and macromolecular content after a 96 hr larval exposure provided a physiologically relevant measurement of toxicity that was predictive of longer term sublethal toxicity. [R65] *Activities of plasma leucine aminonaphthylamidase were assayed to quantify toxicant stress in rainbow trout (Salmo gairdneri) in a series of experiments. Blood samples were taken from groups of fish weighting 80-100 g following ip and/or waterborne exposure to p-methylphenol. The duration of postinjection holding significantly affected activity in control p-methylphenol dose rainbow trout; the largest increases occurred after 96 hr. There were significant correlations between dose and plasma leucine aminonaphthylamidase activity after p-methylphenol injection. Plasma leucine aminonaphthylamidase activity levels of fish injected with p-methylphenol at 0.075-0.75 of the 96 hr ip LD50 values were elevated by 27-63% relative to controls 96 hr after injection. Exposure of fish to a waterborne concn of 0.028 mM p-methylphenol significantly increased plasma leucine aminonaphthylamidase activity after 48, 96, and 192 hr; activities increased by 38-87-% relative to controls. Elevated plasma leucine aminonaphthylamidase activity was strongly correlated with decreased plasma protein levels. The temp and duration of plasma storage affected the measured plasma leucine aminonaphthylamidase activity of control and p-methylphenol dosed rainbow trout. While diet modified plasma leucine aminonaphthylamidase activity, the gender of immature fish had no effect. Hepatic lesions visible by light microscope were observed with waterborne p-methylphenol exposure; parenchymatous edema was closely associated with increased liver somatic index. ... [R66] *The assay of serum sorbitol dehydrogenase activity to indicate liver damage by toxicants in rainbow trout (Salmo gairdneri) was assessed using p-cresol as a model toxicant. A waterborne concn of 0.028 mM p-cresol resulted in statistically significant increases in serum sorbitol dehydrogenase activities shown by rainbow trout after 96 hr of exposure. Serum sorbitol dehydrogenase activity increased with increasing p-cresol dose in the range 0.25-4.0 mmol/kg. [R67] *... Sublethal concentrations of cresols were capable of producing abnormal metaphases and anaphases in onion root tip cells, Allium cepa, undergoing mitosis. [R68] NTXV: *LD50 Rabbit single skin penetration 300 (130-910) mg/kg with skin corrosion; [R69] *LD50 Rat dermal 750 mg/kg; [R70] *LD50 Cat subcutaneous injection 80 mg/kg; [R71] *LD50 rabbit oral 20% aqueous emulsion 0.62 g/kg; [R72] *LD50 Rabbit iv injection through marginal ear vein 0.18 g/kg; [R72] *LD50 Rabbit oral 10% solution 1.8 g/kg; [R72] *LD50 Mouse intraveneously 1460 mg/kg; [R64] *LD50 Rat oral 207 mg/kg; [R30, 930] *LD50 Mouse oral 344 mg/kg; [R30, 930] *LD50 Mouse ip 25 mg/kg; [R30, 930] *LD50 Rabbit skin 301 mg/kg; [R30, 930] ETXV: *LC100 Tetrahymena pyriformis 3.7 mmole/l/24 hr /Conditions of bioassay not specified/; [R73] *LC50 Crucian Carp 21 mg/l/24 hr /Conditions of bioassay not specified/; [R73] *LC50 Roach 17 mg/l/24 hr; [R73] *LC50 Trout embryos 4 mg/l/24 hr /Conditions of bioassay not specified/; [R73] *LC50 30 mg/l/1 hr, 26 mg/l/24 hr, 21 mg/l/48, 72 hr, 19 mg/l/96 hr in a static bioassay using Lake Superior water at 18-22 deg C; [R73] TCAT: ?The frequency of sister chromatid exchange (SCE) was determined in male DBA mice exposed to p-cresol by intraperitoneal injection. Groups of mice (number not reported) were sacrificed 21 hours after receiving a single injection of test article in sunflower oil at a dose of 75 mg/kg. p-Cresol did not induce significant (statistics not reported) increases in SCE frequencies in bone marrow, alveolar macrophage or regenerating liver cells. The dose level administered was reported to be 1/2 the subcutaneous LD50. [R74, ] ?The frequency of sister chromatid exchange (SCE) was determined in human diploid fibroblasts exposed in vitro to p-cresol without metabolic activation. The test article did not induce significant (statistics not reported) increases in SCE frequency when cells were exposed for 2 hours to concentrations up to 0.01 molar. Significant cell-cycle inhibition was not observed at any dose level. [R74] ADE: *FROM THE URINE OF ANIMALS FED ... PARA-CRESOL, PARA-CRESYLGLUCURONIDE /WAS ISOLATED/. ... IT HAS BEEN REPORTED THAT THE NORMAL HUMAN EXCRETES IN THE URINE FROM 16 TO 39 MG OF PARA-CRESOL PER DAY. [R8, 1601] *CRESOL IS ABSORBED THROUGH SKIN, OPEN WOUNDS, AND MUCOUS MEMBRANES OF GASTROENTERIC AND RESP TRACTS. RATE OF ABSORPTION THROUGH SKIN DEPENDS MORE UPON SIZE OF AREA EXPOSED THAN ON CONCENTRATION OF MATERIAL APPLIED. MAJOR ROUTE OF EXCRETION ... IS URINE, BUT CONSIDERABLE AMOUNTS MAY BE EXCRETED IN BILE AND TRACES IN EXHALED AIR. /CRESOL/ [R8, 1600] *All 6 hydrocarbons tested were excreted from the gills of Dolly Varden (Salvelinus malma), although less of the largest and least polar cmpd was excreted. Approx equal amounts of the administered (14)C-labeled cresol (28.9%) was excreted from the gills. A large amt of administered (14)C-labeled cresol (38%) was recovered from the cloacal chamber. [R75] METB: *P-CRESOL FED TO RABBITS IS EXCRETED IN THE URINE AS THE GLUCURONIDE (60%) AND SULFATE (15%) CONJUGATES, SOME 10% IS OXIDIZED TO P-HYDROXYBENZOIC ACID AND A TRACE IS HYDROXYLATED TO 3,4-DIHYDROXYTOLUENE. [R76] *P-CRESOL YIELDS P-CRESYL-BETA-D-GLUCURONIDE, P-CRESYL SULFATE, P-HYDROXYBENZYL ALCOHOL, (1), 4-METHYLCATECHOL (1,2), AND P-METHYLANISOLE (3) IN RABBITS. [R77] *P-CRESOL YIELDS P-CRESYL SULFATE IN MAN. [R77] *P-CRESOL YIELDS P-CRESYL SULFATE (1) AND P-METHYLANISOLE (2) IN RATS. [R77] *P-CRESOL YIELDS P-HYDROXYBENZYL ALCOHOL (1) AND P-METHYLANISOLE (2) IN MICE. [R77] *P-CRESOL YIELDS P-METHYLANISOLE IN GUINEA PIGS. [R77] *Ten healthy men were exposed to approximately 200 ppm toluene for 4 hr. Urinary p-cresol concentration was 39.590 mg/l at the end of the exposure, 40.968 mg/l 4 hr after exposure, and 39.965 mg/l 20 hr after exposure. [R78] *... CRESOLS ARE EXCRETED BY RABBIT PRIMARILY AS OXYGEN CONJUGATES; 60-72% AS ETHER GLUCURONIDES, 10-15% AS ETHEREAL SULFATES ... [R8, 1600] *Ruminal bacteria can perform biochemical transformations on plant constituents that may affect the health of ruminant animals. ... The deamination and decarboxylation reactions associated with the degradation of tryptophan and tryosine result in the formation of 3-methylindole and p-cresol, which are toxic. [R79] *Objectives: Widespread exposure to toluene occurs in the printing, painting, automotive, shoemaking, and speaker-manufacturing industries. The relationship between air concentrations and the absorbed dose /of toluene/ is confounded by dermal exposure, personal protective devices, movement throughout the workplace, and interindividual differences in toluene uptake and elimination. Methods: To determine the best biological indicator of exposure /the authors/ examined the blood and alveolar breath concentrations of toluene as well as the urinary excretion rates of hippuric acid and of o-, m-, and p-cresols from 33 controlled human inhalation exposures to 50 ppm for 2 hr. Results: Among the metabolites, o-cresol was least influenced by background contributions, whereas the p-cresol and hippuric acid rates were obscured by endogenous and dietary sources. Toluene levels in alveolar breath proved to be the most accurate and noninvasive indicator of the absorbed dose. ... [R80] *The role of human hepatic cytochrome-P450 side chain oxidation and ring oxidation of toluene (108883) was investigated. ... Hepatic microsomes were exposed to 0.2 or 5.0 mM toluene, and toluene metabolism was assessed by measuring formation of benzyl-alcohol (100516) and o-cresol (95487) and p-cresol (106445). At both toluene doses, benzyl-alcohol and o-cresol and p-cresol were formed in all microsomes from the patients. The average ratio was 92% for benzyl-alcohol, 3% for o-cresol, and 5% for p-cresol. Regular consumption of alcohol did not affect the formation of benzyl-alcohol or the cresols. Tobacco use did not affect the formation of benzyl-alcohol or p-cresol, but o-cresol was enhanced in smokers. Of the human cytochrome-P450 forms, five catalyzed the formation of benzyl-alcohol, with 2E1 being most active, followed by 2B6, 2C8, 1A2, and 1A1. The activities of the 2A6, 2C9, 2D6, 3A3, 3A4, and 3A5 forms were not detectable. The differences in product formation when using high and low concentration toluene substrates were only three to five fold for 2E1 and 1A2, but nine fold for 2B6 and 2C8. Mouse 1A1 catalyzed benzyl-alcohol more than 1A2, but not the cresols. Rat 2B1 catalyzed the formation of benzyl-alcohol and the cresols. ... Human cytochrome-P450 forms 1A2, 2B6, 2E1, and 2C8 may play a role in the formation of benzyl-alcohol in the human liver, and forms 1A2, 2B6, and 2E1 may play a role in the formation of o-cresol and/or p-cresol. [R81] ACTN: */Cresol/ is a general protoplasmic poison and is toxic to all cells. /Cresols, cresotes and derivatives/ [R36] INTC: *Cresols cross-react with phenol. /Cresol, from table/ [R55, 537] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The smallest amount of cresol that produced death was 4 ml of a 25% to 50% cresol solution in an 11-month-old child. /Cresol/ [R55, 704] *The lethal dose of Lysol /(50% mixture of cresols)/ is about 60-120 mL, although lesser amounts have been associated with death. /Lysol/ [R56, 1211] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *p-Cresol's production and use as a solvent, disinfectant and chemical intermediate in the production of synthetic resins may result in its release to the environment through various waste streams. p-Cresol is also released to the environment through automobile exhaust and tobacco smoke. Cresols, including p-cresol, are widespread in nature occurring in many plants and trees. If released to air, a vapor pressure of 0.11 mm Hg at 25 deg C indicates p-cresol will exist solely as a vapor in the ambient atmosphere. Vapor-phase p-cresol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 8 hours. If released to soil, p-cresol is expected to have moderate to high mobility based upon log Koc values of 1.69-2.81. Volatilization from moist soil surfaces is expected to occur slowly based upon a Henry's Law constant of 1X10-6 atm-cu m/mole. p-Cresol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. This compound is expected to biodegrade rapidly based upon half-lives of 1 and 0.5 days in 2 agricultural soils. If released into water, p-cresol may adsorb to suspended solids and sediment in the water column based upon the log Koc values. p-Cresol is expected to biodegrade in water based on reported half-lives of 4 and 6 days in Lake Tahoe, CA water. Volatilization from water surfaces is expected to occur based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 38 and 281 days, respectively. Photolysis in surface water may be an important fate process for p-cresol based on a photolysis half-life of 3 days in a water/humic mixture. p-Cresol is not expected to undergo hydrolysis. An estimated BCF of 20 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to p-cresol may occur through inhalation and dermal contact with this compound at workplaces where p-cresol is produced or used. The general population may be exposed to p-cresol via inhalation of ambient air and dermal contact with this compound. (SRC) NATS: *REPORTED IN ACACIA FARNESIANA, YLANG-YLANG OIL (PROBABLY AS P-CRESYL ACETATE), JASMINE ABSOLUTE, ORANGE OIL FROM LEAVES, THE ESSENCE FROM FLOWERS OF LILIUM CANDIDUM, ANISE-SEED OIL, THE ESSENCE OF ARTEMISIA SANTOLINOFLIA, AND SOME SEA ALGAE. [R9] *Cresols, including p-cresol, are widespread in nature occurring in many plants and trees(1). [R82] ARTS: *In sewage effluents [R83, 551] *Constituent of coal tar at 0.27 wt% of dry tar /USA average/. [R3, p. 22(83) 572] *In exhaust of a 1970 gasoline engine: 0.4-0.7 ppm [R83, 550] *p-Cresol's production and use as a solvent, disinfectant and chemical intermediate in the production of synthetic resins(1) may result in its release to the environment through various waste streams(SRC). p-Cresol is also released to the environment through automobile exhaust and tobacco smoke(2,3). [R84] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), log Koc values of 1.69 and 2.7 reported for soil(2) indicates that p-cresol is expected to have moderate to high mobility in soil(SRC). Volatilization of p-cresol from moist soil surfaces is expected to occur slowly(SRC) given a Henry's Law constant of 1X10-6 atm-cu m/mole(3). p-Cresol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.11 mm Hg at 25 deg C(4). Biodegradation half-lives of 1 and 0.5 days were reported for 2 agricultural soils(5), suggesting biodegradation of p-cresol will be rapid in soil. [R85] *AQUATIC FATE: Based on a classification scheme(1), a log Koc value of 2.81 reported for sediment(2) indicates that p-cresol is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1X10-6 atm-cu m/mole(4). Volatilization half-lives for a model river and model lake are 38 and 281 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 20(3,SRC), from a log Kow of 1.94(6), suggests the potential for bioconcentration in aquatic organisms is low. p-Cresol is expected to biodegrade in water based on reported half-lives of 4 and 6 days in Lake Tahoe, CA water(7). Photolysis in surface water may be an important fate process for p-cresol(SRC) based on a photolysis half-life of 3 days in a water/humic mixture(7). [R86] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), p-cresol, which has a vapor pressure of 0.11 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase p-cresol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 8 hours(SRC) from its rate constant of 4.7X10-11 cu cm/molecule-sec at 25 deg C(3). [R87] BIOD: *Complete degradation of p-cresol was obtained in a simulated biological treatment plant in 16-74 hours(1). p-Cresol biodegrades rapidly in environmental waters including oligotrophic lakes, eutrophic ponds, rivers, creeks and bays(2-5). Total degradation occurred in Lake Tahoe, CA water within 6 days and 4 days depending on whether the water contained sediment or not, respectively(2). In a eutrophic pond, degradation was complete in 7-8.5 hr after a 5.5-6 hr lag period(2). The half-life of p-cresol in two fish ponds ranged from 2-7 hr after a 30-56 hr lag(3). In 3 river waters of the Pacific North West, the half-life of p-cresol ranged from 1-10 hr after a 2 day lag period(3). At 3 sites in Pensacola Bay, FL the half-life of p-cresol ranged from 9-43 hr in salt water(4). In marine water/sediment ecocores from 3 Pensacola Bay sites, biodegradation half-lives ranged from 3-16 hr(4). 95% of the p-cresol added to fresh water/sediment ecocores from the Escamba River, FL degraded in 75 hr and 22% was mineralized in that period(5). The disproportionate decrease in the concentration of p-cresol in groundwater down-gradient from a wood preserving facility has been ascribed to biodegradation(6). Biodegradation half-lives of 1 and 0.5 days were reported for p-cresol in 2 agricultural soils(7). The first-order aerobic biodegradation rate constant of p-cresol was reported as 0.0029/day(8), corresponding to a half-life of about 239 days(SRC). Pure cultures isolated from reed-sedge peat bogs resulted in 97.7 % degradation of p-cresol during a 40 hour incubation period(9). [R88] *ANAEROBIC: Under anaerobic conditions, p-cresol was mineralized in 3 and 8 weeks in two screening studies using digester sludge inocula(1,2). However, no mineralization was observed when incubated for 29 weeks in anaerobic lake sediment(3). The half-life of p-cresol in an anaerobic digester sludge was 18.5 days(4). At 3 sites in Pensacola Bay, FL the half-life of p-cresol ranged from 6-11 hr when anaerobic sediment was added to the water(5). [R89] ABIO: *The rate constant for the vapor-phase reaction of p-cresol with photochemically-produced hydroxyl radicals has been measured as 4.7X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 8 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). p-Cresol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). Under photochemical smog conditions a half-life of 3 hr has been reported for p-cresol with the formation of nitrocresols(3,4). p-Cresol in pure water photolyzed in the presence of sunlight (half-life 35 days) in the laboratory(5). The addition of humic acid to the water increases this rate by a factor of 12 (half-life 3 days)(5). The resulting photolysis half-life in a river, eutrophic lake or pond, and oligotrophic lake are 400, 830, and 200 summer days (12 hr of sunlight), respectively(5). The absorptivity of p-cresol increases markedly as the pH increases from 5.1 to 8.9(5) and photolysis may therefore be much more important in alkaline lakes. [R90] BIOC: *An estimated BCF of 20 was calculated for p-cresol(SRC), using a log Kow of 1.94(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF value suggests the potential for bioconcentration in aquatic organisms is low. [R91] KOC: *The log Koc of p-cresol in soil was reported as 1.69 and 2.7(1). The log Koc of p-cresol in sediment was reported as 2.81(1). According to a classification scheme(2), this Koc value indicates that p-cresol is expected to have moderate to high mobility in soil. [R92] VWS: *The Henry's Law constant for p-cresol is 1X10-6 atm-cu m/mole(1). This Henry's Law constant indicates that p-cresol is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as approximately 38 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as approximately 281 days(SRC). p-Cresol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). p-Cresol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.11 mm Hg(3). [R93] WATC: *DRINKING WATER: p-cresol was identified, not quantified, in drinking water in the US(1). [R94] *SURFACE WATER: p-Cresol was detected in stream water near the American Creosote Works facility in Pensacola, FL at 0.0022 mg/l(1). p-Cresol was detected in the Lower Tennessee River below Calvert City, KY at 200 ppb in a water/sediment sample(2) and in the Hayashida River in Tatsumo City, Japan at a concn of 204 ppb(3). [R95] *GROUNDWATER: p-Cresol was detected in groundwater in a sand aquifer at a wood-preserving facility in Pensacola, FL (5 sites, 5 depths) 0-6.17 mg/l(1) and in the Southington, CT landfill site at 1.5 mg/l(2). p-Cresol was detected at an underground coal gasification site in Wyoming at concns of 9.6-16,000 ppb(3). Groundwater near an abandoned pine tar manufacturing plant in Gainesville, FL had concns of combined m,p-cresol isomers at less than 0.3 to 11,100 ug/l(4). p-Cresol was detected in the groundwater at the Gas Works Park, Seattle, WA at a concn of 0.06 and 1.5 mg/l(5). p-Cresol was detected in groundwater at the American Creosote Works facility in Pensacola, FL at 2 mg/l(6). Combined isomers of m,p-cresol were detected in groundwater near coal gasification plants in Denmark at concns of 5-77 ug/l(7). p-Cresol was detected in groundwater at a landfill in Norman, OK at 14.6 ppb(8). [R96] *RAIN/SNOW: p-Cresol was detected in 7 rainfall events in Portland, OR at concns of 380-2,000 parts per trillion(1). Combined m,p-cresol isomers were detected in rainfall in Switzerland at a concn of 4.5 mg/cu m(2). Combined m,p-cresol isomers were detected in the rain in Portland, OR at concns of greater than 1.1 ug/l(3). Combined m,p-cresol isomers were detected in rain in the Vosges Mountains, France at concns of 0.47-2.23 ug/l(4). p-Cresol was detected in rainfall in Portland, OR at a concn of 350 ng/l(5). [R97] EFFL: *p-Cresol was identified, not quantified, in 20 of 28 samples representing effluents from refineries, petrochemical, and metallurgical industries, municipal wastewater plants and polluted fjords in Norway(1). p-Cresol was identified, not quantified, in finished water from advanced waste treatment plants(2). p-Cresol was identified, not quantified, in leachate from a hazardous waste site in the midwestern US(3). Product water from a coal gasification plant in Hanna, WY contained p-cresol at 10,200 ppm, aqueous condensate from low Btu gasification of coal in Morgantown, WV contained p-cresol at 40 ppm and boiler water from a shale oil processing plant in DeBeque, CO contained p-cresol at 779 ppm(4). p-Cresol was detected in feedwater and permeate water at the American Creosote Works facility in Pensacola, FL at 8.5 and 0.75 mg/l, respectively(5). Combined m,p-cresol isomers were detected in condensate retort water (42.6 mg/l) and process retort water (9.6 mg/l) in an oil shale processing plant in Logan, WA(6). p-Cresol was identified, not quantified, in the ash from wood burning stoves(7). Combined isomers of m,p-cresol were detected in wastewater from a coal gasification plant in North Dakota at a concn of 1,840 mg/l(8). p-Cresol was detected in wastewater from a coal power plant in India at 470.8 mg/l(9). Combined isomers of m,p-cresol were detected in landfill leachate in Sweden at 34 ug/l(10). [R98] SEDS: *p-Cresol was identified, not quantified, in the soil of an abandoned pine tar manufacturing plant in Gainesville, FL(1). [R99] ATMC: *SOURCE DOMINATED: Combined isomers of m,p-cresol were detected near a shale oil wastewater facility at 88 ppb(1). [R100] *URBAN/SUBURBAN: Combined m,p-cresol isomers were reported in the ambient air of Portland, OR at a mean concn of 0.03 ppb(1) and at a mean concn of 1.4 ug/cu m (range, 0-4.1 ug/cu m) at unspecified locations in the US(2). p-Cresol was identified, not quantified, in ambient outdoor air in the US(3). Combined m,p-cresol isomers were detected at a concn of 0.04 ug/cu m in Switzerland(4). Combined isomers of m,p-Cresol were reported at concns of 38-411 ng/cu m during the winter months in Minneapolis, MN and at concns of 53-408 ng/cu m during the winter months in Salt Lake City, UT(5). [R101] *INDOOR AIR: Combined m,p-cresol isomers were detected in the indoor air at a shale oil wastewater facility at a concn of 5.1 ppb(1). [R100] FOOD: *p-Cresol has been identified, not quantified, in the volatiles of cooked pork(1) and roasted filberts(2). [R102] PFAC: PLANT CONCENTRATIONS: *Cresols, including p-cresol, are widespread in nature occurring in many plants and trees(1). [R103] RTEX: *Estimates indicate that between 600,000 and 1.2 million people are exposed to cresols each year via manufacturing, processing, and/or use activities. /Cresols/ [R104] *A partial list of occupations in which exposure may occur includes: Antioxidant makers, chemical disinfectant workers, dye makers, flotation agent makers, foundry workers, insulation enamel workers, paint remover workers, pitch workers, plastic makers, resin makers, stain workers and wool scourers. /Cresol/ [R105] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,269 workers (667 of these are female) are potentially exposed to p-cresol in the US(1). Occupational exposure to p-cresol may occur through inhalation and dermal contact with this compound at workplaces where p-cresol is produced or used(SRC). Combined m,p-cresol isomers were detected in the indoor air at a shale oil wastewater facility at a concn of 5.1 ppb(2). The general population may be exposed to p-cresol via inhalation of ambient air and dermal contact with this compound(SRC). [R106] AVDI: *AIR INTAKE: assume typical concn for m- plus p- isomers 28.6 parts per trillion being divided equally between the two isomers, 1.3 ug(1). [R107] BODY: *Urine of 10 men exposed to approx 200 ppm toluene for 4 hr: Urinary p-cresol concn was 31.206 mg/l, (mean concn) before exposure; 40.968 mg/l, (mean concn) 4 hr after exposure(1). [R108] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *250 ppm [R35] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (22 mg/cu m). Skin Designation. /Cresol, all isomers/ [R109] NREC: *Recommended Exposure Limit: 10 hr Time-Weighted avg: 2.3 ppm (10 mg/cu m) [R35] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm, skin. /Cresol, all isomers/ [R110, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Cresol, all isomers/ [R110, 2002.6] OOPL: *Australia: 5 ppm, skin (1990); Federal Republic of Germany: 5 ppm, short-term level 10 ppm, 5 min, 8 times per shift, skin (1990); United Kingdom: 5 ppm, skin (1991). /Cresol, all isomers/ [R51, 1991.341] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. p-Cresol is produced, as an intermediate or a final product, by process units covered under this subpart. [R111] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 35 ug/l [R112] +(MN) MINNESOTA 3 ug/l [R112] +(NH) NEW HAMPSHIRE 40 ug/l [R112] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R113] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R114] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Cresol is included on this list. [R115] RCRA: *When cresol is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F004), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. /Cresols/ [R116] *U052; As stipulated in 40 CFR 261.33, when cresol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /Cresol (cresylic acid)/ [R117] *D025; A solid waste containing o-cresol may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. (Note: If o-, m-, and p-cresol concentrations cannot be differentiated, the total cresol (D026) concentration is used. The regulatory level of total cresol is 200 mg/l.) [R118] FDA: *p-Cresol is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and 2) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. [R119] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A known volume of air is drawn through a silica gel tube consisting of 2, 20/40 mesh silica gel sections, 150 and 75 mg, separated by a 2 mm portion of urethane foam. The collected sample is desorbed with acetone and analyzed by gas chromatography. (This method for sampling and analysis is adapted from NIOSH Method No S167) /Cresols/ [R120] *Traces of phenols (incl p-cresol) in auto exhaust and tobacco smoke were collected using a fritted bubbler with 10 ml 0.12% sodium hydroxide. [R121] ALAB: *AOAC 930.11. Phenol in Hazardous Substances. Colorimetric Method. Applicable to com. cresols, saponified cresol solns, coal tar dips, and disinfectants, and to kerosene solns of phenols in absence of salicylates of beta-naphthol. [R122] *THE SEPARATION OF 13 ISOMERIC ALKYLPHENOLS WAS STUDIED BY HIGH-PERFORMANCE LIQ (HPLC), GAS-LIQ (GLC) AND HIGH-PERFORMANCE THIN-LAYER CHROMATOGRAPHIC (HPTLC) TECHNIQUES. [R123] *CRESOL WAS DETERMINED IN A 50% SOAP SOLUTION BY DETERMINING ITS UV ABSORPTION AT 239 NM. THE UV METHOD GAVE RELIABLE RESULTS IN LESS TIME THAN THE CONVENTIONAL INDIAN PHARMACOPEIA (IP) METHOD. /Cresols/ [R124] *Infrared spectrophotometry was shown to be effective in identifying cresol from other structurally related substances. Identification and quantitative analyses of the cresol isomers, phenol, and xylenols were possible when either cyclohexane or carbon disulfide was used as the solvent. In the direct-reading infrared analyzers, cresol reportedly absorbs at the 8.6 um wavelength, with a sensitivity of 0.3 ppm. /Cresols/ [R125] *Ultraviolet spectrophotometry has been used to determine cresol in air samples. Cresol was measured by detecting particular absorption bands, but interference from other air contaminants with absorption bands in the same range reduced the sensitivity and precision of the ultraviolet spectrophotometric method ... Paper and thin-layer chromatography have been suggested as methods for the separation and analysis of cresol and structurally similar compounds. /Cresols/ [R126] *Acetone desorbed samples are analyzed using gas chromatography equipped with a flame ionization detector. The column is packed with 10% free fatty acid polymer in 80/100 mesh, acid washed DMCS Chromosorb W. The useful range of this method is 5-60 mg/cu m. (This method for sampling and analysis is adapted from NIOSH Method No S167). [R120] *A procedure for determining phenols in coal liquefaction is described. Mixture of phenols (incl p-cresol) was separated with a high-resolution fused-silica capillary column wall-coated with Superox-20M. The compounds were identified by using 2 identification parameters: cochromatography with authentic standards and matching mass spectra. [R127] *Traces of phenols (incl p-cresol) in auto exhaust and tobacco smoke were collected using a fritted bubbler with 10 ml 0.12% sodium hydroxide, derivatized with p-nitrobenzenediazonium tetrafluoroborate, and determined by reversed-phase high-performance liquid chromatography. The columns (20 cm diameter) were packed with LiChrosorb RP-18 (5 um) and with Polygosil 60-5C18 and mobile phase was 85% methanol/15% water. Detection limit was 0.05 to 2.0 ng. [R121] *NIOSH Method 2546. Analyte: cresol isomers/phenol; Matrix: air; Procedure: absorption on silica gel, desorption with acetone, gas chromatography, FID. [R128] *Method 0020. Source Assessment Sampling System. [R129] *Method 8270B. Determination Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R130] *Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass Spectrometry (GC/MS): Capillary Column Technique. [R130] *Method 8275. Screening Semivolatile Organic Compounds Using Thermal Chromatography/Mass Spectrometry (TC/MS). [R130] *Method 1311. Toxicity Characteristic Leaching Procedure. [R131] *Method 3630B. Silica Gel Cleanup Method. [R130] *Method 3640A. Gel Permeation Chromatography (GPC) Cleanup Procedure. [R130] *Method 8041. Phenols by Gas Chromatography: Capillary Column Technique. [R132] *Method 8250. Determination of Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry. [R130] *Method 8410. Determination of Semivolatile Organics By Gas Chromatography/Fourier Transform Infrared (GC/FT-IR) Spectrometry: Capillary Column. [R130] CLAB: *GAS CHROMATOGRAPHIC DETERMINATION OF P-CRESOL IN URINE IS DISCUSSED. [R133] *The concentrations of phenol and cresol in alkaline solutions were determined quantitatively using a colorimetric procedure. When reacted with Folin-Denis reagent, the compounds yielded distinct colors whose intensities could be measured. The concentration of the cresol isomers was determined as total cresol. This method has been applied to analysis of cresol and phenol in biologic fluids, such as blood and urine. [R134] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: GORDON P; AIR POLLUTION ASSESSMENT OF CRESOLS; US NTIS, PB REP: 1-76 PP (1976) PB-256737. THE TOXIC EFFECTS AND REMOVAL OF CRESOL FROM WASTE GASES ARE DISCUSSED. NIOSH; Criteria Document: Cresol (1978) DHEW Pub. 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USEPA/600/R-94/090 Final Report Research Triangle Park (1993) R108: (1) Fatiadi AJ; Environ Int 10: 175-205 (1984) R109: 29 CFR 1910.1000 (7/1/98) R110: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R111: 40 CFR 60.489 (7/1/97) R112: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R113: 40 CFR 116.4 (7/1/88) R114: 40 CFR 302.4 (7/1/97) R115: 40 CFR 716.120 (7/1/97) R116: 40 CFR 261.31 (7/1/97) R117: 40 CFR 261.33 (7/1/97) R118: 40 CFR 261.24 (7/1/97) R119: 21 CFR 172.515 (4/1/97) R120: NIOSH; Criteria Document: Cresol p.92-103 (1978) DHEW Pub. NIOSH 78-133 R121: Kuwata K et al; Anal Chem 53 (9): 1531-4 (1981) R122: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 236 R123: HUSAIN S ET AL; J CHROMATOGR 137 (1): 53-60 (1977) R124: TALWAR AB ET AL; INDIAN J PHARM SCI 40 (4): 135-6 (1978) R125: NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 R126: NIOSH; Criteria Document: Cresol p.63 (1978) DHEW Pub. NIOSH 78-133 R127: White CM, Li NC; Anal Chem 54 (9): 1570-2 (1982) R128: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R129: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R130: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R131: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd edition, Final Update I, July (1992) R132: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846-III, 3rd Edition, (Proposed) R133: WOIWODE W ET AL; ARCH TOXICOL 43 (2): 93-8 (1979) R134: Chapin RM: J Biol Chem 47: 309-14 (1921) as cited in NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 RS: 93 Record 155 of 1119 in HSDB (through 2003/06) AN: 1815 UD: 200301 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: m-CRESOL- SY: *Bacticin-; *Gallex-; *META-CRESOL-; *3-CRESOL-; *M-CRESOLE-; *Franklin-Cresolis-; *META-CRESYLIC-ACID-; *Rover's-Dog-Shampoo-; *Celcure-Dry-Mix- (ChemicalsforWoodPreserving); *FEMA-NUMBER-2337-; *1-HYDROXY-3-METHYLBENZENE-; *M-HYDROXYTOLUENE-; *3-HYDROXYTOLUENE-; *M-KRESOL- (GERMAN); *M-METHYLPHENOL-; *3-METHYLPHENOL-; *PHENOL,-3-METHYL- RN: 108-39-4 RELT: 250 [CRESOL]; 131 [TOLUENE] (Metabolic precursor) MF: *C7-H8-O SHPN: UN 2076; Cresol (o-, m-, and p-) IMO 6.1; Cresol (o-, m-, and p-) STCC: 49 314 17; Cresol (o-, m-, and p-) HAZN: F004; A hazardous waste from nonspecific sources when a spent solvent. /Cresols/ U052; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. /Cresol (Cresylic acid)/ D024; A waste containing m-cresol may (or may not) be characterized a hazardous waste following testing for the toxicity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Maesawa, Kurakano, Japan patent 8929('55) (to Osaka Gas), CA 52, 1231d (1958); Macak, Rehak, Brennstoff Chem 43, 80 (1962). From toluene: Toland, US patent 2,760,991 (1956 to California Research Corp); by oxidation of o- or p-toluic acid: Kaeding et al, Ind Eng Chem 53, 805 (1961). [R1, 436] *BY-PRODUCT OF NAPHTHA CRACKING RECOVERED FROM THE SPENT CAUSTIC LIQUOR USED TO WASH PETROLEUM DISTILLATES AND ISOLATED BY FRACTIONAL DISTILLATION AS MIXED CRESOLS OR AS HIGHER PURITY GRADES [R2] *Meta-cresol is obtained by formation of an addition product with oxalic acid, separated from the para isomers by distillation, and then the cresol is regenerated [R3] *m-Cresol is manufactured from coal tar via fractional distillation ... purified via rectification [R4, 322] *m-Cresol may be prepared by the dealkylation of 5-methyl-2,4-di-tert-butylphenol [R5, p. 2(78) 83] FORM: *Grade: Technical (95-98%) [R4, 322] *Pure cresol is a mixture of ortho-, meta- and para-isomers. Crude cresol (commercial cresol) is a mixture of aromatic cmpd containing about 20% of o-cresol, 40% of m-cresol, and 30% of p-cresol with small amt of phenol and xylenols. [R6, 1597] *Franklin Cresolis, Soluble concentrate, 50% cresol, 31% soap [R7] *Bacticin, Solution-ready to use, 0.4660% cresol, 0.4630% xylenol [R7] *Celcure Dry Mix, Soluble concentrate 5% cresol, 50% copper sulfate, 45% potassium dichromate [R7] *Rover's Dog Shampoo, Solution-ready to use, 0.40.% cresol, 1.0% paradichlorobenzene, 0.1% pine oil, 19.3% soap [R7] *Gallex, Solution-ready to use, 0.4660% cresol, 0.4630% xylenol [R7] MFS: *Merichem-Sasol USA LCC, 600 Travis St., Suite 4800, Houston, TX 77002-3068, (713) 224-3030; Production site: Houston, TX 77015 [R8] *Merisol Antioxidants LLC, RR 1, Box 8 A, Oil City, PA 16301-9702, (814) 677-2028. Production site: Oil City, PA 16301 [R8] OMIN: *META- AND PARA-CRESOL ARE SEPARATED BY TREATING THE MIXTURE WITH SULFURIC ACID. ... LIQ FRACTION, WHEN HYDROLYZED WITH STEAM AT 130 DEG C, YIELDS META-CRESOL, WHICH MAY BE FURTHER PURIFIED BY DOUBLE DISTILLATION IN VACUO. [R9, 2597] *Zeolite absorbants are used to separate p-cresol from m-cresol after coal tar distillation. [R5, p. 1(78) 572] *Cresylic acids: commercial mixtures of phenolic materials boiling above cresol range. An arbitrary standard in use for cresylic acids is that 50% must boil above 204 deg C. If boiling point is below 204 deg C, material is called cresol ... Cresylic acid varies widely according to its source and boiling range. [R4, 323] USE: *For making synthetic resins; in disinfectants and fumigants; as industrial solvent; in photographic developers; in explosives [R1, 437] *CHEM INT FOR THYMOL USED IN COUGH/COLD MEDICINALS, SYNTHETIC PYRETHROID INSECTICIDES, 3-METHYL-6-T-BUTYLPHENOL, TRINITRO-M-CRESOL FOR EXPLOSIVES, AND PHENOLIC RESINS (POSSIBLE USE); DISINFECTANT INGREDIENT (POSSIBLE USE); ORE FLOTATION AGENT (POSSIBLE USE); SOLVENT (EG, FOR WIRE ENAMEL) [R2] */Uses include/ textile scouring agent, manufacture of salicylaldehyde, coumarin, herbicides, and surfactants [R4, 322] *Used as disinfectant/bacteriocide/germicide for animal pathogenic bacteria (G- and G+ vegetative) in households (unspecified), sickrooms (unspecified), hospitals (unspecified), veterinary hospital premises, veterinary clinics, veterinary hospitals, hospital critical premises; on surgical instruments, hospital instruments, diagnostic instruments/equipment and on hospital critical rubber/plastic items. /Franklin Cresolis/ [R7] *Used as an insecticide and miticide on dogs for treatment of lice and fleas. /Rover's Dog Shampoo/ [R7] *Used as a bacteriocide/bacteriostat in treatment of crown gall (Agrobacterium tumefaciens) by bark treatment in grapes, almonds, walnuts, apples, pears, apricots, cherries, peaches, plums, and prunes; also used to treat olive knot (Pseudomonas savastanoi) by bark treatment in olives. /Gallex/ [R7] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 1.45X10+9 G [R2] U.S. IMPORTS: *(1977) AT LEAST 9.13X10+8 G [R2] *(1982) 7.76X10+8 G (PRINCPL CUSTMS DISTS) [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, yellowish, brownish-yellow, or pinkish liquid [R1, 436]; *Colorless to yellow liquid [Note: A solid below 54 degrees F]. [R10] ODOR: *Phenolic odor [R1, 436]; *Odor of coal tar [R11]; *Sweet, tarry odor. [R10] TAST: *Taste threshold: 2.00X10-3 ppm [R12] BP: *202 deg C [R1, 436] MP: *11-12 deg C [R1, 436] MW: *108.14 [R1, 436] CTP: *Critical temperature: 342.6 deg C; Critical pressure: 4.56 MPa [R13] DEN: *1.034 @ 20 deg C/4 deg C [R1, 436] DSC: *pKa= 10.09 [R14] HTC: *3703.9 kJ/mol @ 25 deg C (liquid); 3765.6 kJ/mol @ 25 deg C (gas) [R15, p. 5-81] HTV: *47.40 kJ/mol @ 202.27 deg C; 61.71 kJ/mol @ 25 deg C [R15, p. 6-123] OWPC: *log Kow= 1.96 [R16] SOL: *In solutions of fixed alkali hydroxides; miscible in alcohol; chloroform; ether [R1, 436]; *Sol in about 40 parts water. [R1, 436]; *Miscible in ethanol, ether, and acetone [R15, p. 3-257]; *2.5% IN MINERAL OIL [R9, 2598]; *In water, 2.27X10+4 mg/l @ 25 deg C. [R17] SPEC: *Index of refraction: 1.5398 @ 20 deg C/D [R1, 436]; *MAX ABSORPTION (HEXANE): 214 NM (LOG E= 3.79); 271 NM (LOG E= 3.20); 277 NM (LOG E= 3.27) [R18]; *SADTLER REFERENCE NUMBER: 2338 (IR, PRISM); 322 (IR, GRATING) [R18]; *MASS: 117 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R19, p. V2 69]; *Intense mass spectral peaks: 108 m/z (100%), 107 m/z (85%), 79 m/z (35%), 77 m/z (29%) [R20]; *IR: 4818 (Coblentz Society Spectral Collection) [R19, p. V1 455]; *UV: 622 (Sadtler Research Laboratories Spectral Collection) [R19, p. V1 455]; *NMR: 160 (Varian Associates NMR Spectra Catalogue) [R19, p. V1 455]; *MASS: 335 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R19, p. V1 455] VAPD: *3.72 (air=1) [R13] VAP: *0.14 mm Hg @ 25 deg C [R21] VISC: *12.9 cp @ 25 deg C; 4.417 cp @ 50 deg C; 2.093 cp @ 75 deg C; 1.207 cp @ 100 deg C [R15, p. 6-248] OCPP: *PER CENT IN SATURATED AIR @ 25 DEG C: 0.0201 [R9, 2598] *Wt/gal= 8.66 lb [R4, 322] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of m-cresol stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this colorless to yellowish, tar-smelling, liquid may occur from its use as a chemical intermediate in the production of fumigants, photographic developers, explosives, resins, herbicides, and disinfectants. Effects from exposure may include headache, nausea, dizziness, contact burns to skin and eyes, ventricular arrhythmias, pulmonary edema, seizures, coma, and death. Both the OSHA PEL and the ACGIH TLV have been set at a TWA of 5 ppm. In activities or situations where over exposure may occur, wear a self-contained breathing apparatus and full chemical protective clothing which is specifically recommended by the shipper or producer to prevent skin contact with m-cresol. If contact should occur, immediately flush affected skin or eyes with running water for at least 15 minutes, and remove contaminated clothing and shoes at the site. Eyewash and quick drench facilities should be readily available in m-cresol work areas. While m-cresol does not ignite easily, it can burn with the production of irritating and poisonous gases. Also, containers of m-cresol can explode violently in the heat of a fire. Fires involving m-cresol may be extinguished with dry chemical, CO2, Halon, or standard foam. Water spray, if used, should be applied with caution because it may cause frothing. Fight the fire from a maximum distance and dike runoff from fire control water. m-Cresol should be stored in iron or steel containers, in cool, well-ventilated areas, away from oxidizing materials, and sources of ignition and physical damage. m-Cresol may be shipped via air, rail, road, and water. Small spills of m-cresol may be taken up with sand or other noncombustible absorbent and placed into containers for later disposal. Large spills on land should be contained in excavated pits or other holding areas that are sealed with an impermeable flexible membrane liner. Any surface flow should be diked with sand bags, foamed concrete, or foamed polyurethane to prevent the material from entering water sources of sewers. Once contained, m-cresol can be neutralized with crushed limestone, soda ash, cement powder, or sawdust. For spills in bodies of water, trap the material at the bottom with sand bags, or add activated carbon, then use mechanical dredges to remove the immobilized masses. m-Cresol is a good candidate for fluidized bed and rotary kiln forms of incineration. Prior to implementing land disposal of m-cresol, consult with environmental regulatory agencies for guidance. DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Cresols/ [R22] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Cresols/ [R22] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Cresols/ [R22] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Cresols/ [R22] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Cresols/ [R22] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Cresols/ [R22] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Cresols/ [R22] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Cresols/ [R22] FPOT: *Flammable when exposed to heat or flame. [R23] NFPA: *Health: 3. 3= Materials extremely hazardous to health but areas may be entered with extreme care. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms, and waist should be provided. No skin surface should be exposed. [R24, p. 325-28] *Flammability: 2. 2= This degree includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R24, p. 325-28] *Reactivity: 0. 0= Materials which (in themselves) are normally stable even under fire exposure conditions and which are not reactive with water. Normal fire fighting procedures may be used. [R24, p. 325-28] FLMT: *LOWER: 1.1% BY VOL IN AIR @ 302 DEG C [R25] *Lower: 1.1% at 302 deg F closed cup [R24, p. 325-8] FLPT: *86 DEG C CLOSED CUP [R26] AUTO: *558 DEG C [R27] FIRP: *Wear goggles and self-contained breathing apparatus. [R28] *USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. USE WATER SPRAY TO KEEP FIRE-EXPOSED CONTAINERS COOL. /CRESOLS (O-, M-, P-)/ [R24, p. 49-43] *If material on fire or involved in fire: Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Use water spray to knock-down vapors. /Cresol/ [R29] TOXC: *Poisonous gases may be produced in fire. [R28] EXPL: *MODERATELY EXPLOSIVE IN FORM OF VAPOR WHEN EXPOSED TO HEAT OR FLAME. [R23] REAC: *It can react vigorously with oxidizing materials. /Cresol/ [R23] *Strong oxidizers, acids. [R30] DCMP: *WHEN HEATED TO DECOMP, IT EMITS HIGHLY TOXIC AND IRRITATING FUMES. /CRESOL/ [R23] ODRT: *WATER: 0.037 MG/L; AIR: 0.0028 UL/L; ODOR SAFETY CLASS A; A= MORE THAN 90% OF DISTRACTED PERSONS PERCEIVE WARNING OF TLV CONCN IN AIR. [R31] *Odor detection in water: 6.80X10-1 ppm (chemically pure) [R12] SERI: *Severe eye and skin irritant. [R23] EQUP: *... TO PREVENT ABSORPTION THROUGH SKIN ... WEAR RUBBER HAND PROTECTION AND APRONS. /CRESOLS, CRESOTES AND DERIVATIVES/ [R32] *EYE PROTECTION SHOULD ... BE PROVIDED AGAINST DROPLETS OR SPRAY. /CRESOLS, CRESOTES AND DERIVATIVES/ [R32] *The use of respirators to achieve compliance with the recommended exposure limits is permitted only: (a) during the time necessary to install or test the required engineering controls, and (b) during emergencies or during nonroutine operations, such as maintenance or repair activities, when the concentration of airborne cresol may exceed the permissible environmental limit. /Cresol/ [R33] *There is some data suggesting a breakthrough time for natural rubber of approximately one hour or more for m-cresol. Breakthrough times greater than one hour for neoprene have been reported by two or more tests for m-cresol. There is some data (usually from immersion tests) suggesting that a breakthrough time for neoprene/natural rubber greater than one hour are not likely for m-cresol. A breakthrough time greater than one hour for nitrile have been reported by two or more testers for m-Cresol. Breakthrough times USS (usually significantly USS) than one hour for polyvinyl chloride have reported by (normally) two or more testers for m-cresol. [R34] *Wear appropriate eye protection to prevent eye contact. [R30] *Wear appropriate personal protective clothing to prevent skin contact. [R30] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R30] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities should provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.) [R30] *Recommendations for respirator selection. Max concn for use: 23 ppm. Respirator Class(es): Any chemical cartridge respirator with organic vapor cartridge(s) in combination with a dust and mist filter. Any supplied-air respirator. [R30] *Recommendations for respirator selection. Max concn for use: 57.5 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Any powered, air-purifying respirator with organic vapor cartridge(s) in combination with a dust and mist filter. [R30] *Recommendations for respirator selection. Max concn for use: 115 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s) in combination with a high-efficiency particulate filter. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor and acid gas canister having a high-efficiency particulate filter. Any powered, air-purifying respirator with a tight-fitting facepiece and a high-efficiency particulate filter. May require eye protection. Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R30] *Recommendations for respirator selection. Max concn for use: 250 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R30] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R30] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor and acid gas canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R30] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *The worker should immediately wash the skin when it becomes contaminated. [R30] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R30] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R30] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Neutralize spilled material with crushed limestone, soda ash, or lime. /Cresol/ [R29] *Personnel protection: Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective clothing. /Cresol/ [R29] SSL: *Crystals or liquid darken with exposure to air and light. [R35] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R36] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R37] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R38] STRG: *STORE IN A COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM OXIDIZING MATERIALS. /CRESOLS (O-, M-, P-)/ [R24, p. 49-43] *Avoid loading together with explosives, oxidizing materials and organic peroxides. [R39] *Cresol should be stored in iron or steel containers, properly labelled. /Cresols, cresote and derivatives/ [R32] *All bulk containers that hold cresol shall carry, in a readily visible location, a label that bears the trade name of the product, if appropriate, and information on the effects of exposure to the compound on human health. /Cresol/ [R40] CLUP: *Environmental considerations - Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Cresol/ [R29] *Environmental considerations - Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. /Cresol/ [R29] *Environmental considerations - Air spill: Apply water spray or mist to knock down vapors. Vapor knockdown water is corrosive or toxic and should be diked for containment. /Cresol/ [R29] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number F004 or U052, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. /Cresols/ [R41] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D024, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R41] *Chemical Treatability of m-Cresol; Concentration Process: Biological Treatment; Chemical Classification: Phenols; Scale of Study: Unknown; Type of Wastewater Used: Pure (one solute in a solvent); Results of Study: 96% reduction based on chemical oxygen demand; rate of biodegradation 55 mg chemical oxygen demand/g hr. (Activated sludge process). [R42] *Chemical Treatability of m-Cresol; Concentration Process: Solvent Extraction; Chemical Classification: Phenols; Scale of Study: Laboratory scale; continuous flow. Type of Wastewater Used: Industrial wastewater; Results of Study: 91% reduction (Extraction of evaporator condensate from spent caustic processing using isobutylene (S/W= 1.8); spray extractor used). [R43] *Cresols: Potential candidate for rotary kiln incineration, with a temp range of 820 to 1,600 deg C (1,500 to 2,900 deg F) and a residence time of seconds. Also a potential candidate for fluidized bed incineration, with a temp range of 450 to 980 deg C (840 to 1,800 deg F) and a residence time of seconds. /Cresols/ [R44] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. [R45] MEDS: */It is recommended that a/ preplacement medical examination should include at least: ... a urinalysis that includes a microscopic examination. Additional tests, such as complete blood counts and liver and kidney function tests, should be considered by the responsible physican. ... An evaluation of the worker's ability to use positive and negative pressure respirators. ... Periodic examinations shall be made available on at least an annual basis. These examinations should include ... interim medical and work histories. ... Employees complaining of skin abnormalities, such as scaling, crusting, or irritation, that may be attributed to exposure to cresol shall be medically evaluated. ... Pertinent medical records shall be maintained by the employer for all employees occupationally exposed to cresol. Such records shall be retained for at least 30 years after termination of employment. Records of environmental exposures applicable to an employee shall be included in the employee's medical records. These records shall be made available to the designated medical representatives of the /Secretary of Health and Human Services/, the Secretary of Labor, and the employer, employee, or former employee. [R46] *... In cases of splashes, spills, or leaks where significant skin or eye contact with, or inhalation of the material occurs, appropriate medical personnel shall be notified. Medical attendants shall be informed of the possibility of delayed systemic effects, and the persons so exposed shall be observed for a minimum of 72 hours. Medical examinations ... shall be made available as warranted by the results of the 72 hour observation period. [R47] *The assessment of exposure to cresols can be accomplished through measurement of o, m, or p-cresol. However, cresol in urine is often measured to determine exposure to toluene or other aromatic compounds, of which cresol is a metabolite. O-cresol is a frequently used test used as an indicator of toluene exposure. Although o- and m- cresols are not normally detected in urine, p-cresol is excreted daily in the urine as a result of the breakdown of tyrosine. Measurement of cresols in urine for assessing only cresol exposure is useful for identification of exposure only. Measurement of o- or m-cresol are the better choices of tests, since they are not normally present in unexposed people. However since other compounds produce cresols as metabolites, it may be necessary to rule out these exposure prior to evaluation of results. Urine Reference Ranges: Normal - none detected (o-cresol, m-cresol); p-cresol is normally found in the urine, but normal levels have not been established; Exposed - not established; Toxic - not established. /Cresols/ [R48, 895] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society (ATS) and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. /Cresols/ [R48, 899] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. /Cresols/ [R48, 900] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. /Cresols/ [R48, 900] *Sputum Cytology: Sputum cytology along with chest radiographs have been the standard procedures for detecting early lung cancer in asymptomatic patients. Sputum cytology has been found to be useful for detection of central tumors, especially squamous carcinomas. /Cresols/ [R48, 900] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. /Cresols/ [R48, 900] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. /Cresols/ [R48, 901] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell Assessment ... Vision Assessment ... Facial and Trigeminal Nerve Assessment ... Vestibular Assessment ... Hearing Assessment. /Cresols/ [R48, 901] HTOX: *... CRESOL IS A STRONG DERMAL IRRITANT AND CAUSES FREQUENT DERMATITIS ... /CRESOL, ALL ISOMERS/ [R49, 1991.340] *SYMPTOMATOLOGY: 1. Burning pain in mouth and throat. White necrotic lesions in mouth, esophagus and stomach. Abdominal pain, vomiting ... and bloody diarrhea. 2. Pallor, sweating weakness, headache, dizziness, tinnitus. 3. Shock: Weak irregular pulse, hypotension, shallow respirations, cyanosis, pallor, and a profound fall in body temperature. 4. Possibly fleeting excitement and confusion, followed by unconsciousness ... 5. Stentorous breathing, mucous rales, rhonchi, frothing at nose and mouth and other signs of pulmonary edema are sometimes seen. Characteristic odor of phenol on the breath. 6. Scanty, dark-colored ... urine ... moderately severe renal insufficiency may appear. 7. Methemoglobinemia, Heinz body hemolytic anemia and hyperbilirubinemia have been reported ... 8. Death from respiratory, circulatory or cardiac failure. 9. If spilled on skin, pain is followed promptly by numbness. The skin becomes blanched, and a dry opaque eschar forms over the burn. When the eschar sloughs off, a brown stain remains. /Phenol/ [R50, p. III-346] *META-CRESOL ... SOMEWHAT LESS POISONOUS AND LESS IRRITANT THAN PHENOL, WHILE ORTHO-CRESOL IS MORE TOXIC AND PARA-CRESOL IS MOST TOXIC OF ALL THREE. [R51] *CRESOL SLIGHTLY MORE CORROSIVE /TO THE SKIN OR EYES/ THAN PHENOL, BUT SYSTEMIC EFFECTS MAY BE A LITTLE MILDER BECAUSE OF SLOWER ABSORPTION. [R50, p. II-192] *o-, m- and p-Cresols were evaluated in both an in vitro and in vivo sister chromatid exchange assay. Dose dependent sister chromatid exchange increases were not observed in cultured human fibroblasts with any of the isomers at concentrations up to 8 mM. There was a small but significant increase in sister chromatid exchange frequency compared to control at 8 mM o-cresol. A significant decrease in cell cycle progression as measured by average generation time (AGT), was seen for all isomers at a concentration of 8 mM. [R52] *Skin contact with cresols has resulted in skin peeling on the hands, facial peripheral neuritis, severe facial burns, and damage to internal organs, including loss of kidney function and necrosis of the liver and kidneys. /Cresols/ [R53, 703] *Cresol introduced into the uteri of pregnant women has produced abortion, extensive hemolysis, erosion of blood vessels, damage to the kidney tubules, necrosis of the liver, and death. /Cresol/ [R53, 703] *A 32-year-old man ingested 50 mL of a solution containing 90% cresols (1.035 g/vol). He remained conscious, became dyspneic, and developed a tachycardia, systolic hypotension and respiratory failure, myocardial failure, and pulmonary edema. He died on the fourth day after he had been hemodialyzed and had been given sodium bicarbonate, intravenous potassium, dextrose and insulin, a dopamine drip, and a forced diuresis with furosemide. Total serum phenols were 90 ug/mL. (A total phenol level of 10 ug/mL has been suggested to be of serious prognostic significance.) /Cresols/ [R54, 1210] *Ingestions of 4-120 mL of 25-50% cresol result, immediately or within 10 min, in a feeling of nausea; within 15 min, a burning sensation is felt in the mouth, throat, esophagus, and epigastrium. On the skin, cresol leaves a red burn. Burns and scalding with cresol are potentially lethal. Burns are seen on the lips, gums, tongue, cheeks, pharynx, and tonsils. Blisters may form followed by a painful sloughing of the mucous membrane. Hoarseness or aphonia may develop. Coma comes on quickly and may last for over 12 hr, accompanied by hypothermia. Stricture rarely forms in the gastrointestinal tract. Acute pancreatitis may be seen. /Cresol/ [R54, 1211] *Methemoglobinemia, decrease in red cell glutathione, Heinz body formation, and massive intravascular hemolysis may follow ingestion of 100-250 mL of lysol. /Lysol (50% mixture of cresols)/ [R54, 1211] NTOX: *m-Cresol has stimulant activity on Aedes triseriatus. [R55] *PHENOL AND THREE ISOMERIC CRESOLS PRODUCE IDENTICAL SYMPTOMS IN POISONED ANIMALS ALL EXHIBIT TOXICITY OF ABOUT THE SAME MAGNITUDE ... [R50, p. III-346] *... Sublethal concentrations of cresols were capable of producing abnormal metaphases and anaphases in onion root tip cells, Allium cepa, undergoing mitosis. [R56] *PHENOL, O- AND P-CRESOL HAVE ABOUT EQUAL TOXICITY TO /CATS/ M-CRESOL BEING SLIGHTLY LESS TOXIC ... SIGNS OF ACUTE POISONING ... MUSCULAR CONVULSIONS, COMA ... WITH DEATH ENSUING FROM RESPIRATORY PARALYSIS. CONCN SOLN OF ... CRESOL HAVE VIOLENT CORROSIVE EFFECTS. PROSTRATION FROM SHOCK MAY FOLLOW INGESTION OF LARGE AMT. [R57] *215-464 mg/kg of m-cresol was given orally to rats in a single dose orally and resulted in hypoactivity, convulsions, GI tract inflammation, hyperemia, death. [R58] *1,400-2,100 mg/kg of m-cresol was given to rabbits in a single dose orally and resulted in convulsions, coma, and death. [R59] *0.5% m-Cresol applied dermally to a mouse for 6 weeks resulted in no effects. [R60] *280-420 mg/kg of m-cresol was given to rabbits in a single dose intraveneously and resulted in convulsions, coma and death. [R59] *No increase in sister chromitid exchange frequencies was observed in bone marrow, alveolar macrophages, and regenerating liver cells of male DBA/2 mice treated with a single ip injection of either o-cresol (200 mg/kg), m-cresol (200 mg/kg), or p-cresol (75 mg/kg) 21.5 hr prior to sacrifice. [R52] *GLAUCOMA HAS BEEN INDUCED EXPERIMENTALLY IN RABBITS AND MONKEYS BY INJECTION OF 0.5-1.0% P-CRESOL EMULSION IN PHYSIOLOGIC SALINE INTO THE ANTERIOR CHAMBER. [R61] NTXV: *LD50 Rat dermal 1,100 mg/kg; [R62] *LD50 Cat subcutaneous 0.18 g/kg; [R63] *LD50 Rabbit oral 20% aqueous emulsion 1.4 g/kg; [R64] *LD50 Rabbit iv injection into marginal ear vein 0.28 g/kg; [R64] *LD50 Rabbit oral 10% solution 2.02 g/kg; [R64] *LD50 Mouse intraveneously 2010 mg/kg; [R59] *LD50 Rabbit single skin penetration 2,830 mg/kg with skin corrosion; [R65] *LD50 Rat oral 242 mg/kg; [R23] *LD50 Mouse oral 828 mg/kg; [R23] *LD50 Mouse ip 168 mg/kg; [R23] *LD50 Rabbit skin 2050 mg/kg; [R23] ETXV: *Toxicity threshold (cell multiplication inhibition test): Pseudomonas putida 53 mg/l; [R66, 407] *Toxicity threshold (cell multiplication inhibition test): Microcystis aeruginosa 13 mg/l; [R66, 407] *Toxicity threshold (cell multiplication inhibition test): Scenedesmus quadricauda 15 mg/l; [R66, 407] *Toxicity threshold (cell multiplication inhibition test): Entosiphon sulcatum 31 mg/l; [R66, 407] *LC100 Tetrahymena pyriformis (ciliate) 3.5 mmole/l/24 hr /Conditions of bioassay not specified/; [R66, 408] *TLm Mosquito fish 24 mg/l/24 hr-96 hr /Conditions of bioassay not specified/; [R66, 408] *TLm Crucian carp 25 mg/l/24 hr /Conditions of bioassay not specified/; [R66, 408] *TLm Roach 23 mg/l/24 hr; [R66, 408] *TLm Trout embryos 7 mg/l/24 hr /Conditions of bioassay not specified/; [R66, 408] ADE: *CRESOL IS ABSORBED THROUGH SKIN, OPEN WOUNDS, AND MUCOUS MEMBRANES OF GASTROENTERIC AND RESP TRACTS. RATE OF ABSORPTION THROUGH SKIN DEPENDS MORE UPON SIZE OF AREA EXPOSED THAN ON CONCENTRATION OF MATERIAL APPLIED. MAJOR ROUTE OF EXCRETION ... IS URINE, BUT CONSIDERABLE AMOUNTS MAY BE EXCRETED IN BILE AND TRACES IN EXHALED AIR. [R6, 1600] *All 6 hydrocarbons tested were excreted from the gills of Dolly Varden (Salvelinus malma), although less of the largest and least polar cmpd was excreted. Approx equal amounts of the administered (14)C-labeled cresol (28.9%) was excreted from the gills. A large amt of administered (14)C-labeled cresol (38%) was recovered from the cloacal chamber. [R67] METB: *M-CRESOL YIELDS M-CRESYL-BETA-D-GLUCURONIDE, M-CRESYL SULFATE, 4-METHYLCATECHOL, METHYLQUINOL (1) AND M-METHYLANISOLE (2) IN RABBITS. M-CRESOL YIELDS M-CRESYL SULFATE (1) AND M-METHYLANISOLE (2) IN RATS. M-CRESOL YIELDS M-METHYLANISOLE IN GUINEA PIGS AND MICE. M-CRESOL YIELDS M-CRESYL-BETA-D-GLUCURONIDE IN HENS. [R68] *FROM URINE OF ANIMALS FED /m-CRESOL/ ... 2,5-DIHYDROXYTOLUENE /WAS ISOLATED/ ... [R6, 1600] *Ten healthy men were exposed to approximately 200 ppm toluene for 4 hr. Urinary m-cresol concentration was 0.570 mg/l at the end of the exposure, 0.599 mg/l 4 hr after exposure, and 0.527 mg/l 20 hr after exposure. [R69] *The urinary and biliary excretion of (14)C-labeled m-cresol was investigated in 12 species of freshwater fish when immersed in sublethal concn in the aquarium water for 48 hr. The oxidation product, m-hydroxybenzoic acid and the m-cresol sulfate conjugate were excreted into the aquarium water by all species except the guppy, which did not excrete m-hydroxybenzoic acid. In addition to these two metabolites, the m-cresol glucuronic acid conjugate was found in the bile of all species, except the guppy. [R70] *... Cresols are excreted by rabbit primarily as oxygen conjugates; 60-72% as ether glucuronides, 10-15% as ethereal sulfates. ... meta-cresols are hydroxylated to small extent ... [R6, 1600] ACTN: */Cresol/ is a general protoplasmic poison and is toxic to all cells. /Cresols, cresote and derivatives/ [R32] INTC: *Cresols cross-react with phenol. /Cresol, from table/ [R53, 537] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The smallest amount of cresol that produced death was 4 ml of a 25% to 50% cresol solution in an 11-month-old child. /Cresol/ [R53, 704] *The lethal dose of Lysol /(50% mixture of cresols)/ is about 60-120 mL, although lesser amounts have been associated with death. /Lysol/ [R54, 1211] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *m-Cresol's production and use as a solvent, disinfectant, chemical intermediate in the production of synthetic resins and in photographic developers may result in its release to the environment through various waste streams. m-Cresol is also released to the environment through automobile exhaust and tobacco smoke. Cresols, including m-cresol, are widespread in nature occurring in many plants and trees. If released to air, a vapor pressure of 0.14 mm Hg at 25 deg C indicates m-cresol will exist solely as a vapor in the ambient atmosphere. Vapor-phase m-cresol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 6 hours. If released to soil, m-cresol is expected to have high mobility based upon a log Koc of 1.54. Volatilization from moist soil surfaces is expected to occur slowly based upon an estimated Henry's Law constant of 8.7X10-7 atm-cu m/mole. m-Cresol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. This compound is expected to biodegrade rapidly based upon half-lives of 0.6 and 11.3 days in 2 agricultural soils. If released into water, m-cresol is not expected to adsorb to suspended solids and sediment in the water column based upon the Koc value. m-Cresol is expected to biodegrade in water based on a reported half-life of 2 days in aerobic waters and a half-life of 15 days in anaerobic water. Volatilization from water surfaces is expected to occur slowly based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 54 and 394 days, respectively. m-Cresol is not expected to undergo hydrolysis. Log BCF values of 1.3 and 1.03 reported for m-cresol in fish suggest that bioconcentration in aquatic organisms is low. Occupational exposure to m-cresol may occur through inhalation and dermal contact with this compound at workplaces where m-cresol is produced or used. The general population may be exposed to m-cresol via inhalation of ambient air and dermal contact with this compound. (SRC) NATS: *Cresols, including m-cresol, are widespread in nature occurring in many plants and trees(1). m-Cresol is 1 of 9 major volatile organic compounds secreted from the tail gland of the red deer (Cervus elaphus)(2). Cresols occur in small quantites in petroleum(3). m-Cresol was found in surface water in the blast zone of the Mount St. Helens eruption and is believed to have been formed during the destruction of the plant and soil material by the volcanic action(4). [R71] ARTS: *Found in exhaust of 1970 gasoline engine operated on a chassis dynamometer following the 7-mode California cycle: 0.2 - 0.4 ppm [R72] *Identified as a volatile component of roasted filberts(1). [R73] *m-Cresol's production and use as a solvent, disinfectant, chemical intermediate in the production of synthetic resins and in photographic developers(1) may result in its release to the environment through various waste streams(SRC). m-Cresol is also released to the environment through automobile exhaust(2,3), in smoke from woodstoves and fireplaces(3), and tobacco smoke(2). [R74] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a log Koc value of 1.54 reported for soil(2) indicates that m-cresol is expected to have high mobility in soil(SRC). Volatilization of m-cresol from moist soil surfaces is expected to occur slowly(SRC) given a Henry's Law constant of 8.7X10-7 atm-cu m/mole(SRC), from its vapor pressure of 0.14 mm Hg at 25 deg C(3) and water solubility of 2.27X10+4 mg/l at 25 deg C(4). m-Cresol is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(3). Biodegradation half-lives of 0.6 and 11.3 days were reported for 2 agricultural soils(5). [R75] *AQUATIC FATE: Based on a classification scheme(1), a log Koc value of 1.54(2) indicates that m-cresol is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected to occur slowly(3) based upon a Henry's Law constant of 8.7X10-7 atm-cu m/mole from its vapor pressure of 0.14 mm Hg at 25 deg C(4) and water solubility of 2.27X10+4 mg/l at 25 deg C(5). Volatilization half-lives for a model river and model lake are 54 and 394 days, respectively(SRC). According to a classification scheme(6), log BCF values of 1.3 and 1.03 reported for m-cresol in golden ide and zebrafish, respectively(2), suggest that bioconcentration in aquatic organisms is low. m-Cresol is expected to biodegrade in water based on reported half-lives of 2 days (aerobic water) and 15 days(anaerobic water)(7). [R76] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), m-cresol, which has a vapor pressure of 0.14 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase m-cresol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 6 hours(SRC) from its rate constant of 6.4X10-11 cu cm/molecule-sec at 25 deg C(3). [R77] BIOD: *AEROBIC: m-Cresol was degraded 99-100% in 7 and 2 days at 4 and 20 deg C, respectively in river die-away tests(1). Die-away studies were performed in freshwater, estuarine water, and marine water from sites near Newport, NC throughout the year(2). In estuarine water the half-life ranged from 1-6 days(2). Rates were faster in freshwater and slower in marine water(2). While rates were highest during the summer in fresh and estuarine waters, the rate of degradation in marine water was almost independent of the season(2). m-Cresol was completely degraded in soil in 11 days at an application rate of 500 ppm(3). Low concns (39 ppb) of m-cresol degraded in subsurface materials taken from an uncontaminated aquifer(4). There was a linear increase in biodegradation with time over the 160 day experiment with a 0.07% per day average mineralization rate(4). When the concentration of m-cresol was increased to 788 ppb, no mineralization was observed(4). The disproportionate decrease in concentration of m-cresol in groundwater down-gradient from a wood-preserving facility has been ascribed to biodegradation(5). The biodegradation half-life of m-cresol in aerobic natural waters was reported as 2 days(6). Pure cultures isolated from reed-sedge peat bogs resulted in 99.3 % degradation of m-cresol during a 48 hour incubation period(7). The first-order aerobic biodegradation rate constant of m-cresol was reported as 0.0031/day(8), corresponding to a half-life of about 222 days(SRC). Biodegradation half-lives of 0.6 and 11.3 days were reported for m-cresol in 2 agricultural soils(9). [R78] *ANAEROBIC: When m-cresol was incubated with two digester sludges under anaerobic conditions, 92 and 90% mineralization was reported in 4 and 5 weeks, respectively(1). No mineralization occurred in 29 weeks; however, when it was incubated with anaerobic freshwater sediment(1). m-Cresol was degraded 75% in an anaerobic digester sludge over a 10 week incubation period(2). m-Cresol was completely degraded in creosote contaminated groundwater in 37 days (lag time, 25 days) at 10 deg C and 12 days (lag time, 8 days) at 20 deg C under nitrate reducing conditions(3). No mineralization occurred when m-cresol was incubated anaerobically for 40 days at 37 deg C with a sludge inoculum(4). The biodegradation half-life of m-cresol in anaerobic natural waters was reported as 15 days(5). [R79] ABIO: *The rate constant for the vapor-phase reaction of m-cresol with photochemically-produced hydroxyl radicals has been measured as 6.4X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). m-Cresol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). Under photochemical smog conditions m-cresol is the most reactive cresol isomer and a half-life of 2 hr has been reported with the formation of nitrocresols(3,4). When m-cresol sorbed on silica gel was irradiated for 3 days with light greater than 290 nm, 33.5% of the chemical was degraded to CO2(5). [R80] BIOC: *Log BCF values of 1.3 and 1.03 were reported for m-cresol in golden ide and zebrafish, respectively(1). According to a classification scheme(2), these BCF values suggest bioconcentration in aquatic organisms is low. [R81] KOC: *The log Koc of m-cresol in soil was reported as 1.54(1). According to a classification scheme(2), this Koc value indicates that m-cresol is expected to have high mobility in soil. [R82] VWS: *The Henry's Law constant for m-cresol is estimated as 8.7X10-7 atm-cu m/mole(SRC) from its vapor pressure of 0.14 mm Hg at 25 deg C(1) and water solubility of 2.27X10+4 mg/l at 25 deg C(2). This Henry's Law constant indicates that m-cresol is expected to volatilize slowly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as approximately 54 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as approximately 394 days(SRC). m-Cresol's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces may occur slowly(SRC). m-Cresol is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R83] WATC: *DRINKING WATER: m-Cresol was identified, not quantified, in drinking water in the US(1). [R84] *SURFACE WATER: m-Cresol was identified, not quantified, in the Lake Michigan Basin - St. Joseph River(1). m-Cresol was detected in stream water near the American Creosote Works facility in Pensacola, FL at 0.0031 mg/l(2). [R85] *GROUNDWATER: m-Cresol was detected in groundwater in a sand aquifer at a wood-preserving facility in Pensacola, FL (5 sites, 5 depths) 0-13.73 mg/l(1) and in the Southington, CT landfill site at 0.6 mg/l(2). m-Cresol was detected at a monitoring well under a rapid infiltration site at Fort Devens, MA at 0.02 ug/l(3). Groundwater near an abandoned pine tar manufacturing plant in Gainesville, FL had concns of combined m,p-cresol isomers at less than 0.3 to 11,100 ug/l(4). m-Cresol was detected in the groundwater at the Gas Works Park, Seattle, WA at a concn of 1.5 mg/l(5). m-Cresol was detected in groundwater at the American Creosote Works facility in Pensacola, FL at 2.5 mg/l(6). Combined isomers of m,p-cresol were detected in groundwater near coal gasification plants in Denmark at concns of 5-77 ug/l(7). [R86] *RAIN/SNOW: m-Cresol was detected in 7 rainfall events in Portland, OR at concns of 380-2,000 parts per trillion(1). Combined m,p-cresol isomers were detected in rainfall in Switzerland at a concn of 4.5 mg/cu m(2). Combined m,p-cresol isomers were detected in the rain in Portland, OR at concns of greater than 1.1 ug/l(3). Combined m,p-cresol isomers were detected in rain in the Vosges Mountains, France at concns of 0.47-2.23 ug/l(4). [R87] EFFL: *m-Cresol was identified, not quantified in 20 of 28 samples representing effluents from refineries, petrochemical, and metallurgical industries, municipal wastewater plants and polluted fjords in Norway(1). m-Cresol was identified, not quantified in finished water from advanced waste treatment plants(2). m-Cresol was identified, not quantified in leachate from a hazardous waste site in the midwestern US(3). Product water from a coal gasification plant in Gillette, WY contained m-cresol at 850 ppm and aqueous condensate from low Btu gasification of coal in Morgantown, WV contained m-cresol at 4,490 ppm(4). m-Cresol was detected at 561 ppm in boiler water from a shale oil processing plant in DeBeque, CO(4). m-Cresol was detected in feedwater and permeate water at the American Creosote Works facility in Pensacola, FL at 11.30 and 0.271 mg/l, respectively(5). Combined m,p-cresol isomers were detected in condensate retort water (42.6 mg/l) and process retort water (9.6 mg/l) in an oil shale processing plant in Logan, WA(6). m-Cresol was identified, not quantified, in the ash from wood burning stoves(7). Combined isomers of m,p-cresol were detected in wastewater from a coal gasification plant in North Dakota at a concn of 1,840 mg/l(8). m-Cresol was detected in wastewater from a coal power plant in India at 901.2 mg/l(9). Combined isomers of m,p-cresol were detected in landfill leachate in Sweden at 34 ug/l(10). [R88] SEDS: *m-Cresol was identified, not quantified, in the soil of an abandoned pine tar manufacturing plant in Gainesville, FL(1). [R89] ATMC: *SOURCE DOMINATED: Combined isomers of m,p-cresol were detected near a shale oil wastewater facility at 88 ppb(1). [R90] *URBAN/SUBURBAN: Combined m,p-cresol isomers were detected in the ambient air of Portland, OR at a reported mean concn of 0.03 ppb(1) and at a mean concn of 1.4 ug/cu m (range, 0-4.1 ug/cu m) in the US(2). m-Cresol was identified, not quantified, in the ambient outdoor air in the US(3). Combined m,p-cresol isomers were detected at a concn of 0.04 ug/cu m in Switzerland(4). Combined isomers of m,p-Cresol were detected at concns of 38-411 ng/cu m during the winter months in Minneapolis, MN and at concns of 53-408 ng/cu m during the winter months in Salt Lake City, UT(5). [R91] *RURAL/REMOTE: Not detected in rural sample from western Colorado and Utah(1). [R92] FOOD: *m-cresol has been identified, not quantified, in the volatiles of cooked pork(1). [R93] PFAC: PLANT CONCENTRATIONS: *Cresols, including m-cresol, are widespread in nature occurring in many plants and trees(1). [R94] RTEX: *Estimates indicate that between 600,000 and 1.2 million people are exposed to cresols each year via manufacturing, processing, and/or use activities. /Cresols/ [R95] *A partial list of occupations in which exposure may occur includes: Antioxidant makers, chemical disinfectant workers, dye makers, flotation agent makers, foundry workers, insulation enamel workers, paint remover workers, pitch workers, plastic makers, resin makers, stain workers and wool scourers. /Cresol/ [R96] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 5,573 workers (1,173 of these are female) are potentially exposed to m-cresol in the US(1). Occupational exposure to m-cresol may occur through inhalation and dermal contact with this compound at workplaces where m-cresol is produced or used(SRC). Combined m, p-cresol isomers were detected in the indoor air at a shale oil wastewater facility at a concn of 5.1 ppb(2). The general population may be exposed to m-cresol via inhalation of ambient air and dermal contact with this compound(SRC). [R97] BODY: *Urine of 10 men exposed to approx 200 ppm toluene in the air for 4 hr: /Urinary m-cresol concn was/ < 0.2 mg/l, mean before exposure; 0.599 mg/l, mean 4 hr after exposure(1). [R98] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *250 ppm [R30] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (22 mg/cu m). Skin Designation. /Cresol, all isomers/ [R99] NREC: *Recommended Exposure Limit: 10 hr Time-Weighted avg: 2.3 ppm (10 mg/cu m) [R30] TLV: +8 hr Time Weighted Avg (TWA): 5 ppm, skin. /Cresol, all isomers/ [R100, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Cresol, all isomers/ [R100, 2002.6] OOPL: *Australia: 5 ppm, skin (1990); Federal Republic of Germany: 5 ppm, short-term level 10 ppm, 5 min, 8 times per shift, skin (1990); United Kingdom: 5 ppm, skin (1991). /Cresol, all isomers/ [R49, 1991.341] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. m-Cresol is produced, as an intermediate or a final product, by process units covered under this subpart. [R101] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 350 ug/l [R102] +(MN) MINNESOTA 30 ug/l [R102] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R103] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R104] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. m-Cresol is included on this list. [R105] RCRA: *When cresol is a spent solvent, it is classified as a hazardous waste from a nonspecific source (F004), as stated in 40 CFR 261.31, and must be managed according to State and/or Federal hazardous waste regulations. /Cresols/ [R106] *U052; As stipulated in 40 CFR 261.33, when cresol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /Cresols (cresylic acid)/ [R107] *D024; A solid waste containing o-cresol may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. (Note: If o-, m-, and p-cresol concentrations cannot be differentiated, the total cresol (D026) concentration is used. The regulatory level of total cresol is 200 mg/l.) [R108] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Cresol is found on List D. Case No: 4027; Pesticide type: Fungicide; Case Status: RED Approved 09/94; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Cresol; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R109] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *m-Cresol in water samples was sorbed from aqueous phase on the macroporous polymer sorbent. Desorption was performed by heating the sorbent. [R110] *A known volume of air is drawn through a silica gel tube consisting of 2, 20/40 mesh silica gel sections, 150 and 75 mg, separated by a 2 mm portion of urethane foam. The collected sample is desorbed with acetone and analyzed by gas chromatography. (This method for sampling and analysis is adapted from NIOSH Method No S167) /Cresols/ [R111] *Traces of phenols (incl m-cresol) in auto exhaust and tobacco smoke were collected using a fritted bubbler with 10 ml 0.12% sodium hydroxide. [R112] ALAB: *AOAC 930.11. Phenol in Hazardous Substances. Colorimetric Method. Applicable to com. cresols, saponified cresol solns, coal tar dips, and disinfectants, and to kerosene solns of phenols in absence of slaicylates of beta-naphthol. [R113] *m-Cresol was converted into the corresponding bromophenol by reaction with bromine. The minimum detectable amount of bromophenol by gas chromatography with electron capture detector was about 0.01 ng. [R114] *m-Cresol in water samples was sorbed from aqueous phase on the macroporous polymer sorbent. Desorption was performed by heating the sorbent, and the desorbed components were led directly into the gas chromatograph. Method is suitable for determining phenols in water at concn of 1 to 103 ppb. [R110] *A procedure for determining phenols in coal liquefaction is described. Mixture of phenols (incl m-cresol) was separated with a high-resolution fused-silica capillary column wall-coated with Superox-20M. The compounds were identified by using 2 identification parameters: cochromatography with authentic standards and matching mass spectra. [R115] *m-Cresol in engine exhaust was determined by high-pressure liquid chromatography (HPLC). A sample of the water condensate collected with Grimmer device was extracted with ether. The phenols were isolated by stepwise elution on a Lobar column packed with LiChroprep Si 60. Relative recovery ranged from 90-100%. Quantitative analysis was carried out on a prepacked Zorbax ODS column of 250 30/70 (vol/vol) using a UV photometer of 254 nm wavelength, and 2,4-dichlorophenol as internal standard. Concn of phenols ranged from 1 to 10 ppm or 0.03 to 0.18 mg/cu m of exhaust. [R116] *Traces of phenols (incl m-cresol) in auto exhaust and tobacco smoke were collected using a fritted bubbler with 10 ml 0.12% sodium hydroxide, derivatized with p-nitrobenzenediazonium tetrafluoroborate, and determined by reversed phase high-performance liquid chromatography. The columns (20 cm diameter) were packed with LiChrosorb RP-18 (5 um) and with Polygosil 60-5C18 and mobile phase was 85% methanol/15% water. Detection limit was 0.05 to 2.0 ng. [R112] *THE SEPARATION OF 13 ISOMERIC ALKYLPHENOLS WAS STUDIED BY HIGH-PERFORMANCE LIQ , GAS-LIQ AND HIGH-PERFORMANCE THIN-LAYER CHROMATOGRAPHIC TECHNIQUES. [R117] *CRESOL WAS DETERMINED IN A 50% SOAP SOLUTION BY DETERMINING ITS UV ABSORPTION AT 239 NM. THE UV METHOD GAVE RELIABLE RESULTS IN LESS TIME THAN THE CONVENTIONAL INDIAN PHARMACOPEIA (IP) METHOD. /CRESOLS/ [R118] *Infrared spectrophotometry was shown to be effective in identifying cresol from other structurally related substances. Identification and quantitative analyses of the cresol isomers, phenol, and xylenols were possible when either cyclohexane or carbon disulfide was used as the solvent. In the direct-reading infrared analyzers, cresol reportedly absorbs at the 8.6 um wavelength, with a sensitivity of 0.3 ppm. [R119] *Ultraviolet spectrophotometry has been used to determine cresol in air samples. Cresol was measured by detecting particular absorption bands, but interference from other air contaminants with absorption bands in the same range reduced the sensitivity and precision of the ultraviolet spectrophotometric method ... Paper and thin-layer chromatography have been suggested as methods for the separation and analysis of cresol and structurally similar compounds. [R120] *Acetone desorbed samples are analyzed using gas chromatography equipped with a flame ionization detector. The column is packed with 10% free fatty acid polymer in 80/100 mesh, acid washed DMCS Chromosorb W. The useful range of this method is 5-60 mg/cu m. (This method for sampling and analysis is adapted from NIOSH Method No S167). [R121] *NIOSH Method #2546. Analyte: cresol isomers/phenol; Matrix: air; Procedure: absorption on silica gel, desorption with acetone, gas chromatography, FID. [R122] *Method 8270B. Determination Semivolatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R123] *Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass Spectrometry (GC/MS): Capillary Column Technique. [R123] *Method 3640A. Gel Permeation Chromatography (GPC) Cleanup Procedure. [R123] *Method 8041. Phenols by Gas Chromatography: Capillary Column Technique. [R124] CLAB: *GAS CHROMATOGRAPHIC DETERMINATION OF M-CRESOL IN URINE IS DISCUSSED. [R125] *The concentrations of phenol and cresol in alkaline solutions were determined quantitatively using a colorimetric procedure. When reacted with Folin-Denis reagent, the compounds yielded distinct colors whose intensities could be measured. The concentration of the cresol isomers was determined as total cresol. This method has been applied to analysis of cresol and phenol in biologic fluids, such as blood and urine. /Cresols/ [R126] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: GORDON P; AIR POLLUTION ASSESSMENT OF CRESOLS; US NTIS, PB REP: 1-76 PP (1976) PB-256737. THE TOXIC EFFECTS AND REMOVAL OF CRESOL FROM WASTE GASES ARE DISCUSSED. NIOSH; Criteria Document: Cresol (1978) DHEW Pub. NIOSH 78-133 USEPA/ECAO; Health and Environmental Effects Profile: Cresols (1985) ECAO-CIN-P138 Dangerous Prop Ind Mater Rep 6 (1): 41-6 (1986). Review of m-cresol safety, toxicology, and health hazards. Santodonato J; Monograph on Human Exposure to Chemicals in the Workplace: Cresols Govt Rpts Announcements and Index 7: (1986). This report presents a summary and evaluation of information relevant to an occupational hazard assessment of cresols. USEPA; Chemical Profiles: Cresylic Acid 4pp (1985). Aspects covered in this data sheet /include the following/: Chemical identity, exposure limits, physiochemical properties, fire and explosion hazards, reactivity, health hazards, uses, and handling of spills or releases. DHHS/NTP; NTP Report on the Toxicity Studies of Cresols in F344/N Rats and B6C3F1 Mice (Feed Studies) NTP TOX 9 (1991) DHHS/ATSDR; Toxicological Profile for Cresols: o-Cresol, p-Cresol, m-Cresol (1992) ATSDR/TP-91/11 NTIS; Final report on the reproductive toxicity of meta-/para-cresol in CD-1 Swiss mice (1992) Technical Report # PB92-191741 vol. 1. NTIS; Final report on the reproductive toxicity of meta-/para-cresol in Swiss mice (1992) Technical Report # PB92-191758 vol. 2. WHO; Environmental Health Criteria 168: Cresols p.143 (1995). NTP; Toxicity studies of cresols in F344/N rats and B6C3F1 mice (feed studies) p. 128 TOX 9 (1992). SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: SRI R3: CHEMICAL PRODUCTS SYNOPSIS: Cresols and Cresylic Acids, 1980 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R6: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R7: Purdue University; National Pesticide Information Retrieval System (1987) R8: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 526 R9: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 78 R11: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 122 R12: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 40 R13: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA8 26 R14: Shiu WY et al; Chemosphere 29: 1155-1224 (1994) R15: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996. R16: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. 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NIOSH 78-133 R41: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R42: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-58 (1982) R43: USEPA; Management of Hazardous Waste Leachate, EPA Contract No. 68-03-2766 p.E-120 (1982) R44: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-2, 3-12 (1981) EPA 68-03-3025 R45: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 3-Methylphenol (108-39-4) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R46: NIOSH; Criteria Document: Cresol p.4-5 (1978) DHEW Pub. NIOSH 78-133 R47: NIOSH; Criteria Document: Cresol p.5 (1978) DHEW Pub. NIOSH 78-133 R48: Ryan, R.P., C.E. Terry (eds.). Toxicology Desk Reference 4th ed. Volumes 1-3. Taylor and Francis, washington, D.C. 1997. R49: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. 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USEPA Robert S Kerr Environ Res Lab, ADA, OK, USEPA/600/2-89/011 (1989) R79: (1) Horowitz A et al; Dev Ind Microbial 23: 435-44 (1982) (2) Battersby NS, Wilson V; Appl Environ Microbial 55: 433-39 (1989) (3) Flyvbjerg J et al; pp. 471-9 in In Situ Bioreclamation. Hinchee RE, Olfenbuttel RF eds. Stoneham,MA: Butterworth-Heinemann (1991) (4) Fedorak PM, Hrudey SE; Water Res 18: 361-7 (1984) (5) Capel PD, Larson SJ; Chemosphere 30: 1097-1107 (1995) R80: (1) Atkinson R; J Phys Chem Ref Data Monograph 1 (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. 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Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R84: (1) Richardson SD et al; Environ Sci Technol 28: 592-99 (1994) R85: (1) Great Lakes Water Quality Board; An Inventory of Chem Substances Identified in the Great Lakes Ecosystem Vol 1 Summary Report Windsor Ontario Canada p. 195 (1983) (2) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) R86: (1) Goerlitz DF et al; Environ Sci Technol 19: 955-61 (1985) (2) Sawhney BL, Kozloski RP; J Environ Qual 13: 349-52 (1984) (3) Hutchins SR et al; Water Res 18: 1025-36 (1984) (4) McCreary JJ et al; Chemosphere 12: 1619-32 (1983) (5) Turney GL, Goerlitz DF; Ground Wat Monit Rev 10: 187-98 (1990) (6) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) (7) Johansen SS et al; Ground Water Monit Rev 17: 106-15 (1997) R87: (1) Leuenberger C et al; Environ Sci Technol 19: 1053-8 (1985) (2) Tremp J et al; ACS Div Environ Chem 192nd Natl Mtg 26: 142-43 (1988) Grossjean D; Sci Total Environ 100: 367-414 (1991) (4) Levsen K et al; Int J Environ Anal Chem 52: 87-97 (1993) R88: (1) Sporstoel S et al; Int J Environ Anal Chem 21: 129-38 (1985) (2) Lucas SV; GC/MS Anal of Org in Drinking Water Concn and Advanced Waste Treatment Concentrates Vol 2 Computer Printed Tabulation of Compound Identification Results for Large Volume Concn p 397 USEPA-600/1-84-020B (1984) (3) Puskar MA, Levine SP; Environ Sci Technol 21: 90-96 (1987) (4) Pellizzari ED et al; Identification of Organic Components in Aqueous Effluents From Energy Related Processes. In ASTM Spec Tech Publ; STP 686: 256-74 (1979) (5) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) (6) Leenheer JA et al; Environ Sci Technol 16: 714-23 (1982) (7) Hawthorne SB et al; Environ Sci Technol 22: 1191-96 (1988) (8) Giabbai MF et al; Intern J Environ Anal Chem 20: 113-29 (1985) (9) Pandey RA et al; J Environ Sci Health A24: 603-32 (1989) (10) Oman C, Hynning PA; Environ Pollut 80: 265-71 (1993) R89: (1) McCreary JJ et al; Chemosphere 12: 1619-32 (1983) R90: (1) Hawthorne SB, Sievers RE; Environ Sci Technol 18: 483-90 (1984) R91: (1) Grossjean D; Sci Total Environ 100: 367-414 (1991) (2) Kelly TJ et al; Ambient Concentration Summaries for Clean Air Act Title III Hazardous Air Pollutants. 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TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R101: 40 CFR 60.489 (7/1/97) R102: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R103: 40 CFR 116.4 (7/1/88) R104: 40 CFR 302.4 (7/1/97) R105: 40 CFR 716.120 (7/1/97) R106: 40 CFR 261.31 (7/1/97) R107: 40 CFR 261.33 (7/1/97) R108: 40 CFR 261.24 (7/1/97) R109: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.305 (Spring, 1998) EPA 738-R-98-002 R110: Voznakova A, Popl M; J Chromatogr Sci 17 (12): 682-6 (1979) R111: NIOSH; Criteria Document: Cresol p.92-103 (1978) DHEW Pub. NIOSH 78-133 R112: Kuwata K et al; Anal Chem 53 (9): 1531-4 (1981) R113: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. 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R123: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R124: USEPA/Office of Solid Waste (OSW); Test Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846-III (Proposed) R125: WOIWODE W ET AL; ARCH TOXICOL 43 (2): 93-8 (1979) R126: Chapin RM; J Biol Chem 47: 309-14 (1921) as cited in NIOSH; Criteria Document: Cresol p.64 (1978) DHEW Pub. NIOSH 78-133 RS: 87 Record 156 of 1119 in HSDB (through 2003/06) AN: 1819 UD: 200303 RD: Reviewed by SRP on 08/07/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GLYCIDOL- SY: *ALLYL-ALCOHOL-OXIDE-; *EPIHYDRIN-ALCOHOL-; *1,2-EPOXY-3-HYDROXYPROPANE-; *2,3-EPOXY-1-PROPANOL-; *Epoxypropyl-alcohol-; *GLYCIDE-; *GLYCIDYL-ALCOHOL-; *1-HYDROXY-2,3-EPOXYPROPANE-; *3-HYDROXY-1,2-EPOXYPROPANE-; *Hydroxymethyl-ethylene-oxide-; *2-Hydroxymethyloxiran-; *2-(HYDROXYMETHYL)OXIRANE; *3-HYDROXYPROPYLENE-OXIDE-; *METHANOL,-OXIRANYL-; *NCI-C55549-; *OXIRANEMETHANOL-; *OXIRANYLMETHANOL-; *1-PROPANOL,-2,3-EPOXY- RN: 556-52-5 MF: *C3-H6-O2 ASCH: Glycidol (D); 57044-25-4; Glycidol (DL); 61915-27-3; Glycidol (L); 60456-23-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Treatment of monochlorohydrin with bases; reaction product of allyl alcohol and perbenzoic acid. [R1] MFS: *DIXIE CHEM CO, BAYPORT, TEX 77062 [R2] USE: *ALKYLATING AGENT [R3] *CHEM INT FOR PHARMACEUTICALS, COSMETICS, GLYCERIN, SURFACTANTS AND POLYMERS [R2] *IT IS SUGGESTED FOR USE IN PREPN OF GLYCEROL AND GLYCIDYL ETHERS, ESTERS, AND AMINES, IN PHARMACEUTICAL INDUSTRY, AND SANITARY CHEMICALS. IT HAS BEEN USED FOR STERILIZING MILK OF MAGNESIA. [R4, 2247] *Stabilizer for natural oils, demulsifier, dye-leveling agent, stabilizer for vinyl polymers. [R1] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R2] *(1978) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS, SLIGHTLY VISCOUS LIQUID [R4, 2247]; +Colorless liquid. [R5] BP: *160 DEG C @ 760 MM HG [R4, 2247] MW: *74.08 [R6] DEN: *SP GR: 1.115 @ 20 DEG C/4 DEG C [R4, 2247] SOL: *SOL IN WATER, ALCOHOL AND ETHER [R1] VAPD: *2.15 [R4, 2247] VAP: *0.9 MM HG AT 25 DEG C [R4, 2247] OCPP: *BP: 167 DEG C @ 760 MM HG, DECOMP /DL-ISOMER/ [R4, 582] *INDEX OF REFRACTION: 1.4293 @ 16 DEG C/D; SPECIFIC OPTICAL ROTATION (UNDILUTED): +15 DEG/D /D-ISOMER/ [R7] *SPECIFIC OPTICAL ROTATION (UNDILUTED): -8.6 DEG AT 18 DEG C/D /L-ISOMER/ [R7] *BP: 56.5 DEG C @ 11 MM HG /D-ISOMER/; 56 DEG C @ 11 MM HG /L-ISOMER/ [R7] *DENSITY: 1.117 @ 20 DEG C/4 DEG C /D-ISOMER/; 1.1050 @ 18 DEG C /L-ISOMER/ [R7] *DENSITY: 1.1143 @ 25 DEG C/4 DEG C /DL-ISOMER/ [R6] *SOL IN ACETONE, BENZENE, WATER, ALCOHOL, ETHER, /D-ISOMER; L-ISOMER/ [R7] *IR: 15765 (Sadtler Research Laboratories Prism Collection) /Glycidol (D)/ [R8] *MASS: 80 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Glycidol (D)/ [R8] *IR: 15765 (Sadtler Research Laboratories Prism Collection) /Glycidol (DL)/ [R8] *MASS: 80 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Glycidol (DL)/ [R8] *MASS: 22 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /Glycidol (L)/ [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: +Strong oxidizers, nitrates. [R9, 152] SERI: */Glycidyl ethers/ are primary skin and eye irritants. ... /Glycidyl ethers/ [R10] *HAZARD WARNING: EXPOSURE TO VAPORS HAS BEEN FOUND TO HAVE ADEQUATE WARNING PROPERTIES (EYE AND RESP IRRITATION) ... . [R11] *Glycidol vapor is an irritant to the eyes and upper respiratory tract, and a skin irritant. ... [R12] *Dermal contact is the usual mode of exposure, but droplets in mist can also attack the eyes and respiratory tract. Glycidyl and diglycidyl ethers tend to be irritants and sensitizing agents. /Glycidyl and diglycidyl ethers/ [R13] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing, necessary to prevent repeated or prolonged skin contact with liquid glycidol. [R12] +Wear appropriate personal protective clothing to prevent skin contact. [R9, 153] +Wear appropriate eye protection to prevent eye contact. [R9, 153] +Recommendations for respirator selection. Max concn for use: 150 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. Any self-contained breathing apparatus with a full facepiece. [R9, 153] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R9, 153] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R9, 153] OPRM: +Contact lenses should not be worn when working with this chemical. [R9, 153] *Clothing contaminated with liquid glycidol should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of glycidol from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the glycidol, the person performing the operation should be informed of glycidol's hazardous properties. [R12] *Nonimpervious clothing which becomes contaminated with liquid glycidol should be removed promptly and not reworn until the glycidol is removed from the clothing. [R12] +The worker should immediately wash the skin when it becomes contaminated. [R9, 153] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R9, 153] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ... BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER, OR ABSORBED IN VERMICULITE, DRY SAND, EARTH, OR SIMILAR MATERIAL AND DISPOSED IN A SANITARY LANDFILL. [R12] DISP: *GLYCIDOL MAY BE DISPOSED OF BY DISSOLVING IN PETROLEUM AND ATOMIZING IN SUITABLE COMBUSTION CHAMBER, OR ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL AND DISPOSING IN SANITARY LANDFILL. [R12] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A3; Confirmed animal carcinogen with unknown relevance to humans. [R14, 2002.34] HTOX: *CAUTION: MODERATELY IRRITATING TO SKIN, MUCOUS MEMBRANES. CAN CAUSE STIMULATION OF CNS FOLLOWED BY DEPRESSION. [R6] *SLIGHTLY TOXIC AFTER INGESTION OR PERCUTANEOUS ABSORPTION. MODERATELY TOXIC UPON INHALATION. MODERATELY IRRITATING TO SURFACE TISSUES. STIMULANT AND DEPRESSANT OF NERVOUS SYSTEM. [R15] *Short-term Exposure: Overexposure to glycidol may cause irritation of the eyes, nose, and throat. Long-term Exposure: Prolonged overexposure might produce irritation of the skin. [R12] *The only report of toxic effects in humans is that of irritation of the eyes, nose, and respiratory tract of experimenters working with the compound at room temperature. [R12] *Glycidol vapor is an irritant to the eyes and upper respiratory tract, a skin irritant, and a central nervous system depressant. [R12] *Dermal contact is the usual mode of exposure, but droplets in mist can also attack the eyes and respiratory tract. Glycidyl and diglycidyl ethers tend to be irritants and sensitizing agents. /Glycidyl and diglycidyl ethers/ [R13] NTOX: *DNA REPAIR-DEFICIENT BACTERIAL TESTS: POSITIVE. [R16] *... RATS EXPOSED @ 400 PPM ... 7 HR A DAY FOR 50 DAYS GAVE NO EVIDENCE OF SYSTEMIC TOXICITY. ... SLIGHT IRRITATION OF EYES, WITH SLIGHT LACRIMATION AND ENCRUSTATION OF EYELIDS, and ... RESP DISTRESS...FOLLOWING FIRST FEW EXPOSURES. EXCEPT FOR SLIGHT RETARDATION OF WT GAIN, COMPARED WITH CONTROLS, NO EVIDENCE OF CUMULATIVE TOXICITY ... . [R11] *ORAL LD50 OF 10% SOLN ... IN PROPYLENE GLYCOL IS 850 MG/KG FOR RAT AND 450 FOR MOUSE. SYMPTOMS ... WERE INITIAL DEPRESSION OF CNS, FOLLOWED BY STIMULATION INDUCING HYPERSENSITIVITY TO SOUND WITH MUSCULAR TREMORS AND FACIAL MUSCULAR FIBRILLATION; SOME RATS SHOWED TERMINAL CONVULSIONS. ALL ... HAD DYSPNEA AND SHOWED LACRIMATION. [R4, 2248] *GLYCIDOL IS RATED MODERATE SKIN IRRITANT (DRAIZE SCORE OF 4.5) FOR SINGLE APPLICATION ON COVERED SKIN OF RABBITS BUT IS SEVERELY IRRITANT WHEN APPLIED REPEATEDLY ON THE UNCOVERED SKIN. DEEP SKIN NECROSIS WAS PRESENT. ... NO EXPTL DATA EXIST, BUT GLYCIDOL LIKE MANY OTHER EPOXIDES SHOULD BE CONSIDERED A SENSITIZER. [R4, 2248] *BY INHALATION LC50 (4 HR EXPOSURE) IS 580 PPM FOR RAT AND 450 ... FOR MOUSE. SEVERE DYSPNEA ... SALIVATION AND NASAL DISCHARGE SHOWED THE IRRITATION CAUSED BY VAPOR EXPOSURE. SIGNS OF STIMULATION OF CNS WERE APPARENT. DEATH WAS USUALLY DUE TO PULMONARY EDEMA. AUTOPSY ... SHOWED ... PULMONARY IRRITATION; EMPHYSEMA WAS ALSO DETECTED. SOME DISCOLORATION OF KIDNEYS AND LIVERS ... . [R4, 2248] *... /APPLICATION OF/ DROP TO EYES OF RABBIT HAS CAUSED SEVERE BUT REVERSIBLE CORNEAL INJURY. [R17] *REPEATED IM INJECTIONS FAILED TO AFFECT HEMOPOIESIS IN RATS. [R4, 2248] *NO TUMORS FOUND IN TWENTY ICR/HA SWISS MICE AFTER GLYCIDOL APPLIED TO THE SKIN (5 MG, THREE TIMES WEEKLY). DURATION: 520 DAYS. /FROM TABLE/ [R18] *ORAL ADMINISTRATION OF 15 MG/KG OF 2,3-EPOXYPROPANOL FOR 1 WK REVERSIBLY STERILIZED MALE RATS WITHOUT ADVERSELY AFFECTING SEXUAL LIBIDO OR EJACULATION. 12 DAYS OF TREATMENT DID NOT INDUCE APPARENT HISTOLOGICAL ABNORMALITIES IN THE TESTES, EPIDIDYMIS, PROSTATE, OR SEMINAL VESICLES. [R19] *ORAL ADMIN OF 100 MG/KG/DAY GLYCIDOL FOR 5 DAYS PRODUCED FUNCTIONAL STERILITY IN MALE RATS WITH NO APPARENT EFFECTS ON SPERM MOBILITY OR MATING ACTIVITY; HOWEVER, 200 MG/KG/DAY FOR 5 DAYS INDUCED EPIDIDYMAL SPERMATOCELES. THERE WAS NO EVIDENCE OF DOMINANT LETHAL MUTATIONS. [R20] *THE MUTAGENIC ACTION OF 45 EPOXIDES WAS INVESTIGATED WITH KLEBSIELLA PNEUMONIAE AS TEST ORGANISMS. GLYCIDOL WAS MORE MUTAGENIC TO KLEBSIELLA PNEUMONIAE THAN 1,2-EPOXYPROPANE. [R21] *The 14 day LC50 value of glycidol to the guppy (Poecilia reticulata) was determined, and investigated through the construction of a quantitative structure activity relationship (QSAR). Both hydrophobicity and alkylating potency of the compound were found to be necessary parameters for the satisfactory description of the LC50 data. The log LC50 experimental data for glycidol was 2.83 umol/l as compared to the calculated QSAR value of 3.00 umol/l. The log P (octanol-water partition coefficient) for glycidol was -0.92 while the pseudo first order reaction rate constant towards 4-nitrobenzylpyridine was -0.13/day. [R22] +... Toxicology and carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. [R23] NTXV: *LC50 Mouse inhalation 450 ppm/4 hr; [R11] *LC50 Rat inhalation 580 ppm/4 hr; [R11] NTP: +... Toxicology and carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... Doses selected for the 2 yr studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. [R23] +... Glycidol was ... selected for immunotoxicity studies /using female B6C3F1 mice/. ... Female B6C3F1 mice ... were administered glycidol daily for 14 days at doses of 25, 125 and 250 mg/kg. Glycidol was administered by gavage as a solution in sterile distilled water. ... Mice exposed to glycidol at doses up to and including 250 mg/kg did not have significant decreases in body weight or body weight gain when evaluated over the two-week exposure period. While the brain, thymus, spleen and lungs were unaffected by the glycidol exposure, an increasing trend was observed in liver weights. Additionally, kidney weights were increased (42%) in the glycidol exposure animals dose dependently. No statistically significant effects were observed on leukocyte numbers, leukocyte differentials, reticulocytes, mean corpuscular volume, mean corpuscular hemoglobin or mean corpuscular hemoglobin concentrations. A slight, albeit statistically significant, decrease was observed in the erythroid elements, erythrocytes (4%), hemoglobin (4%), and hematocrit (5%) which was dose related. ... Exposure to glycidol decreased the number of B cells (23%) and decreased the number of CD4+CD8- (15%) in the T cell subsets. Total T cells and the other T cell subsets were not affected. Glycidol produced a dose-dependent decrease (41%) in the antibody-forming cell response to sheep erythrocytes. The proliferative response to mitogens, both Con A and LPS, was not affected. However, a decreasing trend in the proliferative response to F(ab)2+BSF-1 was observed. The proliferative response to allogeneic cells as evaluated in the MLR was not affected and overall the CTL response was not affected. A dose-dependent decrease was observed in the natural killer cell activity (29%) when evaluated at the highest (25:1) effector:target ratio. An increase in cytotoxicity of both resident macrophages alone and resident macrophages stimulated with gamma interferon was observed in animals receiving low dose glycidol exposure. No effect was observed on macrophage cytotoxicity at the middle and high dose groups. The peritoneal cell numbers were not affected at any dose level. In the three host resistance studies conducted, host resistance to Listeria monocytogenes was not affected, while an increase in host resistance to Streptococcus pneumoniae and a decrease in host resistance to the B16F10 Melanoma tumor model was observed. In summary, while most of the immunosuppressive effects resulting from glycidol exposure were observed at the 125 mg/kg and above dose levels, a true no-effect level for glycidol in the female B6C3F1 mouse could not be established since the lowest dose administered significantly altered several parameters including erythrocyte number, hemoglobin, spleen cell number and macrophage cytotoxicity. [R24] TCAT: ?The mutagenicity of 2-hydroxymethyloxirane was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, 2-hydroxymethyloxirane, diluted in DMSO, was tested at concentrations up to 8mg/plate using the plate incorporation technique. 2-Hydroxymethyloxirane caused a positive response in tester strains TA1535 and TA100 with and without metabolic activation. [R25] ADE: *ABSORBED THROUGH SKIN. [R6] METB: *LIVER EPOXIDE HYDRASE CONVERTED GLYCIDOL TO GLYCEROL. GLYCIDOL WAS A SUBSTRATE FOR LUNG AND LIVER CYTOSOLIC GLUTATHIONE S-TRANSFERASES. [R26] *GLYCIDOL WAS METABOLIZED TO BETA-CHLOROACETIC ACID, PRESUMABLY BY FIRST BEING CONVERTED TO ALPHA-CHLOROHYDRIN IN RATS. [R27] ACTN: *REACTION PRODUCTS OF GLYCIDOL WITH DNA BASES ARE CHARACTERIZED BY UV AND NMR SPECTROSCOPY. GLYCIDOL REACTED WITH DEOXYGUANOSINE PRODUCING A MAJOR ADDUCT OF 1,7-(OR 1,9)-DIALKYLGUANINE. ALL EPOXIDES PRODUCE A 7-ALKYLGUANINE ADDUCT. REACTION WITH DEOXYADENOSINE TOOK PLACE AT N-6 AND AT N-3 WITH DEOXYCYTIDINE. [R28] INTC: *IN RATS PRETREATED WITH 278 MG OF 2,3-EPOXYPROPAN-1-OL THE ACUTE LD50 OF 1,2-DICHLOROETHYLENE WAS DECREASED TO LESS THAN 40 MG/KG AND DOSES OF 1,1-DICHLOROETHYLENE AS LOW AS 12.5 MG/KG INCREASED ASPARTATE TRANSAMINASE LEVELS. [R29] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Absorbed through skin. [R6] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +150 ppm [R9, 152] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 50 ppm (150 mg/cu m). [R30] +Vacated 1989 OSHA PEL TWA 25 ppm (75 mg/cu m) is still enforced in some states. [R9, 365] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 25 ppm (75 mg/cu m). [R9, 152] TLV: +8 hr Time Weighted Avg (TWA): 2 ppm. [R14, 2002.34] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R14, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R14, 2002.34] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Glycidol (oxiranemethanol) is included on this list. [R31] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R32] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1608. Analyte: Glycidol. Matrix: Air. Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg). Flow Rate: 0.01 to 1 l/min. Sample Size: 50 liters. Shipment: at 4 deg C. Sample Stability: At least 7 days at 4 deg C. [R33] ALAB: *COLORIMETRIC PROCEDURE FOR DETERMINING GLYCIDOL IN THE AIR OF INDUSTRIAL PREMISES IS PRESENTED. THE EPOXIDE GROUP OF GLYCIDOL REACTS WITH KSCN IN THE PRESENCE OF BROMOTHYMOL BLUE WITH A COLOR EXCHANGE WHICH IS PROPORTIONAL TO THE CONCENTRATION OF GYLCIDOL IN THE REACTION MIXTURE. SENSITIVITY OF THE METHOD IS 3 MG/CU M GLYCIDOL IN THE ATMOSPHERE. [R34] *NIOSH Method 1608. Analyte: Glycidol. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. The overall precision/RSD is 0.080 and the recovery is 0.953. Applicability: The working range is 16 to 450 mg/cu m (5 to 55 ppm) for a 50 liter air sample. Interferences: None identified. [R33] CLAB: *A new internal surface reversed phase silica support was designed for direct injection analysis of drugs in biological fluids by liquid chromatography. The support, prepared by using a new enzyme, polymyxin acylase, has N-octanoylaminopropyl phases bound only to the internal surfaces of the porous silica, AND N-(2,3-dihydroxypropyl)aminopropyl phases on the external surfaces in order to be nonadsorptive of proteins. The average pore diameter of the internal surface reversed phase silica support was 50 angstroms, which is small enough to exclude macromols, such as serum proteins from the pores. The new internal surface reversed phase support can be used for the direct injection analysis of hydrophilic and hydrophobic drugs in serum or plasma without destructive accumulation of proteins over the eluent pH range 3-7. The recovery of drugs from serum was almost 100%, regardless of the difference in their protein binding. [R35] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Glycidol in F344/N Rats and B6C3F1 Mice(Gavage Studies) Technical Report Series No. 374 (1990) NIH Publication No. 90-2829 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for glycidol. Route: gavage; Species: transgenic model evaluation II, mice. [R36] SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 569 R2: SRI R3: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. 76 R4: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R5: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 152 R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 706 R7: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-261 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 670 R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R10: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 787 R11: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.287 R12: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R13: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-411 R14: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R15: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1634 R16: MUTAGENICITY: MUTATION RESEARCH 87: 211 (1981) R17: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 465 R18: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 175 R19: HAHN JD; NATURE (LONDON) 226 (5240): 87 (1970) R20: JACKSON H ET AL; NATURE (LONDON) 226 (5240): 86 (1970) R21: VOOGD CE ET AL; MUT RES 89: 269 (1981) R22: Deneer JW et al; Aquatic Toxicol 13 (3): 195-204 (1988) R23: Toxicology and Carcinogenesis Studies of Glycidol in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 374 (1990) NIH Publication No. 90-2829 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R24: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Immunotoxicity of Glycidol (CAS No. 556-52-5) in Female B6C3F1 Mice, NTP Study No. IMM91019 (October 1993) available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 19, 2002 R25: Inveresk Research International; Testing for Mutagenic Activity in Dehydroacetic Acid, (1977), EPA Document No. 878212445, Fiche No. OTS0206089 R26: PATEL JM ET AL; DRUG METAB DISPOS 8 (5): 305 (1980) R27: JONES AR, O'BRIEN RW; XENOBIOTICA 10 (5): 365 (1980) R28: HEMMINKI K ET AL; CHEM-BIOL INTERACT 30 (3): 259 (1980) R29: ANDERSEN ME ET AL; DRUG CHEM TOXICOL 1 (1): 63 (1978) R30: 29 CFR 1910.1000 (7/1/98) R31: 40 CFR 716.120 (7/1/88) R32: 40 CFR 712.30 (7/1/88) R33: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 1608-1 R34: LARYUKHINA FZ, CHECHKOVA NV; NEFTEPERERAB NEFTEKHIM (MOSCOW) (3): 35 (1978) R35: Haginaka J et al; Anal Chem 61 (21): 2445-8 (1989) R36: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.20 RS: 28 Record 157 of 1119 in HSDB (through 2003/06) AN: 1901 UD: 200205 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: AGAR-AGAR- SY: *AGAR-; *AGAR-AGAR-FLAKE-; *AGAR-AGAR-GUM-; *AGAROPECTIN,-MIXT-WITH-AGAROSE-; *AGAROSE,-MIXT-WITH-AGAROPECTIN-; *BENGAL-; *BENGAL-GELATIN-; *BENGAL-ISINGLASS-; *CEYLON-; *CEYLON-ISINGLASS-; *CHINESE-GELATIN-; *CHINESE-ISINGLASS-; *DIGENEA-SIMPLEX-MUCILAGE-; *GELOSE-; *JAPAN-AGAR-; *JAPANESE-GELATIN-; *JAPAN-ISINGLASS-; *LAYOR-CARANG-; *MACASSAR-GELATIN-; *NCI-C50475-; *VEGETABLE-GELATIN- RN: 9002-18-0 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HARVESTING, EXTRACTION, AND PROCESSING OF VARIOUS RED-PURPLE SPECIES OF ALGAE OF THE CLASS RHODOPHYCEAE [R1] *The agar can be extracted from the seaweed with hot water, followed by freezing and thawing for purification. Commercial extraction procedures involve washing, chemical extraction, filtration, gelation, freezing, bleaching, washing, drying, and milling. [R2] FORM: *Grades: technical; USP; FCC. [R3] MFS: *AMERICAN AGAR AND CHEMICAL CO, SAN DIEGO, CALIF 92101 [R1] OMIN: *Structure believed to be a complex range of polysaccharide chains having alternating alpha-(1,3) and beta-(1,4) linkages and varying in total charge content; three extremes of structure noted, namely neutral agarose, pyruvated agarose having little sulfation, and sulfated galactan... [R4] *SINCE AGAR IS COMPOSED OF AT LEAST TWO POLYMERIC ELECTROLYTES, THE PHOSPHATES SHOULD BE USEFUL IN IMPROVING ITS GELLING CHARACTERISTICS. ...DEMONSTRATED THAT THE GELLING STRENGTH OF THE AGAR GEL WAS SIGNIFICANTLY INCREASED BY...ADDITION OF 0.12-0.3% DSP. [R5, 690] *AGAR WAS ALSO THE FIRST SEAWEED KNOWN TO BE EXTRACTED, PURIFIED, AND DRIED WHEN THE PROCESS WAS ACCIDENTALLY DISCOVERED BY A JAPANESE INNKEEPER ABOUT 1658. IT WAS INTRODUCED TO EUROPE AND THE UNITED STATES FROM CHINA IN THE NINETEENTH CENTURY... [R5, 303] *CHEMICALLY, AGAR IS BELIEVED TO BE COMPOSED OF 3,6-ANHYDRO-L-GALACTOSE AND D-GALACTOPYRANOSE RESIDUES IN VARYING PROPORTIONS. THE TERM AGAR...HAS BEEN USED TO DESIGNATE BOTH THE DRIED EXTRACT AND THE SEAWEED SOURCE, BUT IT HAS BEEN PROPOSED THAT..."AGAROPHYTE" BE USED FOR THE WEED. [R5, 303] *THE WEED GROWS ON ROCKS IN FAST-MOVING WATER, FROM...TIDE LEVEL TO DEPTHS OF 40 TO 50 FT. ...USUALLY HARVESTED FROM MAY TO OCTOBER BY...DIVERS... AFTER GATHERING, THE SEAWEED IS CLEANED, WASHED WITH FRESH WATER...SPREAD...TO DRY...4 TO 20 DAYS...PRESSED...AND SHIPPED TO...PROCESSOR. [R5, 304] *AMERICAN AND JAPANESE AGAR ARE GRADED ACCORDING TO PUBLISHED SPECIFICATIONS. THE HIGH QUALITY AMERICAN AGAR IS DIVIDED INTO BACTERIOLOGICAL, MEDICINAL AND DENTAL GRADES, AND THE JAPANESE AGAR INTO 3 GRADES AND 2 SUBGRADES. [R5, 304] *A polysaccharide complex extracted from agarocytes of algae of Rhodophyceae. Predominant agar-producing genera are Gelidium, Gracilaria, Acanthopeltis, Ceramium, Pterocladia found in Pacific...Indian Oceans and Japan Sea. ...separated into neutral gellingfraction, agarose, and sulfated non-gelling...agaropectin... [R4] *PRESENT COMMERCIAL METHODS OF PRODUCING AGAR ARE STILL BASED ON THE FUNDAMENTAL PRINCIPLES OF HOT WATER EXTRACTION, COOLING TO FORM A GEL, FREEZING, THAWING, AND DRYING. [R5, 304] *THE ORIGINAL PROCESS DEVELOPED DEPENDED ENTIRELY ON NATURAL MEANS FOR FREEZING, THAWING...DRYING, AND THIS TRADITIONAL METHOD IS STILL USED BY MANY SMALL JAPANESE PRODUCERS. [R5, 304] *...MANY JAPANESE PRODUCERS, AND THE AMERICAN PRODUCERS USE MORE MECHANICAL, SCIENTIFIC PROCESSING. CHEMICAL TREATMENT OF THE WEED, PRESSURE EXTRACTION, ARTIFICIAL FREEZING AND DRYING, CHEMICAL BLEACHING, AND MANY MORE ADVANCED METHODS ARE USED... [R5, 304] *FEMA 2012 [R5, 787] *This gum is extracted from certain marine algae belonging to the class Rhodophyceae, red seaweed... [R6] USE: *INGREDIENT OF CULTURE MEDIA IN MICROBIOLOGY; ANTITACKINESS AND ANTISTALLING AGENT IN BAKED GOODS; INGREDIENT IN DESSERTS AND BEVERAGES, LAXATIVES AND HEALTH FOODS, PET FOODS, IMPRESSION MATERIALS; INGREDIENT IN PHARMACEUTICAL PREPARATIONS, WAVESET PREPARATIONS; LABORATORY AGENT IN CHEM AND BIOLOGICAL APPLICATIONS [R1] *In prodn of medicinal encapsulations and ointments; as dental impression mold base; as corrosion inhibitor [R4] *Sizing for silks and paper; dyeing and printing fabric and textiles; in adhesives; vet: laxative for dogs and cats, demulcent [R4] *MEDICATION *MEDICATION (VET) *Substitute for gelatin, isinglass, etc. in making emulsions including photographic, gels in cosmetics, and as thickening agent in foods esp. confectionaries and dairy products; in meat canning; in production of medicinal encapsulations and ointments; as dental impression mold base; as corrosion inhibitor; sizing for solids and paper; in the dyeing and printing of fabrics and textiles; in adhesives. In nutrient media for bacterial cultures. [R4] *Therap Cat: Cathartic [R4] *Therap Cat (Vet): Laxative in dogs, cats. Demulcent. [R4] *Microbiology and bacteriology (culture medium); antistaling agent in bakery products, confectionery, meats, and poultry; gelation agent in desserts and beverages; protective colloid in ice cream, pet foods, health foods, laxatives, pharmaceuticals, dental impressions, laboratory reagents, and photographic emulsions. [R3] */one of the/ most important gelling agents used in food... [R7, 571] *Used in canned meat and fish products as gel filter or gel binder; in baked goods (icings and glazes); and in confectionery, dairy products, processed fruits, sweet sauces, and reconstituted vegetables, among others. Highest average maximum use level usually about 0.4% in baked goods. Agar has been used as a food in the Far East for centuries. [R8] CPAT: *ABOUT 38% AS AN INGREDIENT OF CULTURE MEDIA; 19% IN BAKED GOODS; 10% IN CONFECTIONS; 10% IN MEAT AND POULTRY; 8% IN DESSERTS AND BEVERAGES; 4% IN LAXATIVES AND HEALTH FOODS; 4% IN PET FOODS; 3% IN IMPRESSION MATERIALS; 3% IN MISC APPLICATIONS; 1% IN PHARMACEUTICALS (1968) [R1] PRIE: U.S. PRODUCTION: *(1972) 6.7X10+8 GRAMS (CONSUMPTION) [R1] *(1975) 3.24X10+8 GRAMS [R1] U.S. IMPORTS: *(1972) 5.36X10+8 GRAMS [R1] *(1975) 4.05X10+8 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Transparent strips or coarse or fine powder [R4]; *Thin, translucent, membranous pieces, or pale buff powder [R3]; *...usually in the form of chopped shreds, sheets, flakes, granules, or powder. [R2] ODOR: *Odorless [R4] TAST: *Tasteless [R4] SOL: *Slowly sol in hot water to a viscid soln [R4]; *Insol in cold water [R4]; *Insol in alcohol [R4] VISC: *RELATIVELY LOW VISCOSITIES FOR SEAWEED EXTRACTS; VISCOSITY IS DEPENDENT ON TEMP AND PH, BUT FAIRLY CONSTANT FROM PH 4.5-9.0 [R5, 305] OCPP: *1.5% AQ SOLN FORMS A FIRM, RESILIENT GEL WHEN COOLED TO 32-39 DEG C WHICH DOES NOT MELT BELOW 85 DEG C [R5, 305] *DRIED HYDROPHILIC COLLOIDAL SUBSTANCE; RICH IN INDIGESTIBLE HEMICELLULOSE [R9, 979] *GELS HAVE EXTREME HYSTERESIS LAG; GELS FORM @ 40-50 DEG C AND DO NOT MELT UNLESS REHEATED TO 80-85 DEG C [R5, 301] *GELS ARE EXTREMELY BRITTLE IN TEXTURE [R5, 301] *USUAL CONCN RANGE FOR GEL IS 1-2%; GELS IN THIS RANGE ARE STRONG, SOMEWHAT ELASTIC, THERMALLY REVERSIBLE AND EXHIBIT SYNERESIS [R5, 305] *Strongly hydrophilic, it absorbs 20 times its weight of cold water with swelling [R3] *DEHYDRATED AND PPT FROM SOLN BY ALCOHOL; TANNIC ACID CAUSED PRECIPITATION [R10] *ELECTROLYTES CAUSE PARTIAL DEHYDRATION AND DECR IN VISCOSITY OF SOLUTIONS [R10] *A 1% soln forms a stiff jelly on cooking. [R4] *Structure believed to be a complex range of polysaccaride chains having alternating alpha-(1-3) and beta-(1-4) linkages and varying in total charge content; three exremes of structure noted, namely neutral agarose, pyruvated agarose having little sulfation, and a sulfated galactan. [R4] *Forms extremely strong gels. [R7, 503] *On cooling to about 35 deg C, a firm gel forms that does not melt or liquefy below about 85 deg C. Gels formed at agar concentrations greater than 0.5% are rigid, but gelation can take place at concentrations as low as 0.04%. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition, it emits acrid smoke and fumes. [R11] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *ASIDE FROM AN OCCASIONAL ALLERGIC REACTION, THESE DRUGS CAN BE INGESTED IN LARGE AMT, WITH LITTLE DANGER OR DISTRESS EXCEPT FOR DIARRHEA, FLATULENCE, AND RARELY FECAL IMPACTION. /GUMS, VEGETABLE/ [R12] NTOX: *... Under the conditions of this bioassay, the agar isolated from Pterocladia was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R13] *One study has demonstrated agar to have antipeptic activities in vitro. Another study ... suggested that it may elevate serum or tissue cholesterol levels in rats. When fed to rats at 5 and 15% levels in their diet, agar impaired 16 protein utilization. [R8] *Agar is nontoxic and can be ingested in large doses without much distress. It passes through the intestinal tract mostly unabsorbed. However, a 1981 study found that mice fed agar had significantly more colon tumors per animal (twice as many) than those fed diets without agar, despite the fact that agar fed animals had decreased levels of fecal neutral sterol and bile acid concentrations. [R8] NTXV: *LD50 Rat oral 11 g/kg; [R11] *LD50 Mouse oral 16 g/kg; [R11] *LD50 Rabbit oral 5800 mg/kg; [R11] *LD50 Hamster oral 6100 mg/kg; [R11] NTP: *A carcinogenesis bioassay of agar isolated from Pterocladia ... was conducted on groups of 50 F344 rats and 50 B6C3F1 mice of either sex which were fed diets containing 25,000 or 50,000 ppm of the test substance for 103 wk. Groups of 50 untreated rats and mice of either sex served as controls. ... Under the conditions of this bioassay, the agar isolated from Pterocladia was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R13] ADE: *It passes through the intestinal tract mostly unabsorbed. [R8] ACTN: *THESE SUBSTANCES DISSOLVE OR SWELL IN WATER TO FORM AN EMOLLIENT GEL OR VISCOUS SOLN THAT SERVES TO MAINTAIN THE FECES SOFT AND HYDRATED. THE RESULTING BULK PROMOTES PERISTALSIS, AND TRANSIT TIME IS REDUCED. /BULK-FORMING LAXATIVES/ [R9, 978] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *1(?)= PRACTICALLY NON-TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) ABOVE 15 G/KG, MORE THAN 1 QUART FOR 70 KG PERSON (150 LB). /GUMS, VEGETABLE/ [R12] THER: *IT MAY BE EATEN AS A CEREAL SUBSTITUTE OR ADDED TO OTHER FOODS, OR IT MAY BE DISSOLVED IN HOT WATER AND ALLOWED TO GEL BEFORE BEING TAKEN. HOWEVER, AGAR IS A RELATIVELY INEFFECTIVE BULK-FORMING AGENT IN THE USUAL DOSE OF 4 TO 16 G. [R9, 979] *...ALSO EMPLOYED AS AN EMULSIFYING AGENT IN A VARIETY OF PROPRIETARY NOSTRUMS COMBINED WITH MINERAL OIL AND OTHER CATHARTICS, BUT THE DOSE OF AGAR IN THESE PREPARATIONS IS TOO SMALL TO CONTRIBUTE TO THEIR LAXATIVE EFFECT. [R9, 979] *MEDICATION (VET): LAXATIVE...USED IN CONSTIPATION. [R14] *MECHANISTIC STUDIES REVEALED ANTIPEPTIC EFFECT OF AGAR WAS DUE TO A SUBSTRATE-INHIBITOR INTERACTION WITH HEMOGLOBIN. POSSIBLE SIGNIFICANCE IN THE INHIBITORY EFFECT OF AGAR IN ULCER THERAPY. [R15] *NINE FULL- TERM INFANTS GIVEN A FORMULA SUPPLEMENTED WITH AGAR EXCRETED MORE BILIRUBIN IN FECES WITHIN FIRST 5 DAYS OF LIFE, AND LOST LESS WEIGHT THAN CONTROL INFANTS. RESULTS SUGGEST POSSIBLE USE OF AGAR FOR MGMNT OF CERTAIN TYPES OF HYPERBILIRUBINEMIA. [R16] *As a bulk laxative, particularly in chronic constipation ... . [R8] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R17] *Agar-agar used as a stabilizer in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R18] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R19] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC Method 945.57. Agar in Meat. Qualitative Test. [R20] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Agar in F344 Rats and B6C3F1 Mice Technical Report Series No. 230 (1982) NIH Publication No 82-1786 SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V12 (94) 844 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 26 R4: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 34 R5: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R6: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994.p. V12 (94) 843 R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 (88) R8: Leung, A.Y., Foster, S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. New York, NY. John Wiley and Sons, Inc. 1996. 10 R9: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R10: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1242 R11: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 78 R12: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-6 R13: Carcinogenesis Bioassay of Agar in F344/N Rats and B6C3F1 Mice Technical Report Series No. 230 (1982) NIH Publication No. 82-1786 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R14: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 6 R15: GOUDA MW; JODHKA G; INHIBITORY EFFECT OF AGAR ON PEPSIN ACTIVITY; CAN J PHARM SCI 12 (1): 4 (1977) R16: POLAND RL, ODELL GB; NEW ENGLAND J MEDICINE 284 (1): 1 (1971) R17: 21 CFR 184.1115 (4/1/99) R18: 21 CFR 582.7115 (4/1/99) R19: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R20: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 945 RS: 16 Record 158 of 1119 in HSDB (through 2003/06) AN: 1904 UD: 200205 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GUAR-GUM- SY: *A-20D-; *J-2FP-; *1212A-; *BURTONITE-V-7-E-; *BURTONITE-V-7E-; *CYAMOPSIS-GUM-; *DEALCA-TP1-; *DEALCA-TP2-; *DECORPA-; *GENDRIV-162-; *GUAR-; *GUARAN-; *GUAR-FLOUR-; *GUM-CYAMOPSIS-; *GUM-GUAR-; *INDALCA-AG-; *INDALCA-AG-BV-; *INDALCA-AG-HV-; *JAGUAR-; *JAGUAR-A-20-B-; *JAGUAR-A-20B-; *JAGUAR-A-20D-; *JAGUAR-A-40F-; *JAGUAR-6000-; *JAGUAR-GUM-A-20-D-; *JAGUAR-NO-124-; *JAGUAR-PLUS-; *LYCOID-DR-; *NCI-C50395-; *REGONOL-; *REIN-GUARIN-; *SUPERCOL-GF-; *SUPERCOL-U-POWDER-; *SYNGUM-D-46D-; *UNI-GUAR- RN: 9000-30-0 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *SEPARATED FROM THE SEEDS OF THE GUAR PLANT (CYAMOPSIS TETRAGONOLOBUS) [R1] *IN PROCESSING GUAR...THE SEED MUST BE REMOVED FROM...POD, THE HULL OF... SEED REMOVED...ENDOSPERM SEPARATED FROM GUM. THE HULL IS LOOSENED AND CLEANED BY TREATMENT WITH 55% SULFURIC ACID AND WASHING, OR BY WATER SOAKING AND FLAME-CHARRING. [R2, 320] *ANOTHER METHOD USED IS DIFFERENTIAL GRINDING AND SIFTING, WHICH IS ALSO USED TO SEPARATE THE ENDOSPERM FROM THE GUM. THE ENDOSPERM OBTAINED, CONTAINING APPROX 80% GALACTOMANNAN, IS GROUND TO FINE PARTICLE SIZE. IN THE US BASIC FLOUR MILLING EQUIPMENT IS USED FOR THIS PROCESS. [R2, 320] FORM: *Grades: industrial; technical; FCC [R3] *Prepn in pill form prevents the substance from becoming viscous in the mouth and causing problems swallowing. [R4] MFS: *CELANESE CORP, CELANESE COATINGS AND SPECIALTY CHEMS CO, SUBSID, CELANESE RESINS DIV, VERNON, TEX [R1] *GENERAL MILLS, INC, GENERAL MILLS CHEMS, INC, SUBSID, INDUST CHEMS OPERATIONS, KENEDY, TEX [R1] OMIN: *CF a comparative study of commercially available guar gums by IA Schlakman and AJ Bartilucci, Drug Standards 25, 149-154 (1957). [R5] *INDIA AND PAKISTAN ARE MAJOR SOURCES OF SUPPLY...US IS ALSO A PRODUCER. THE GUAR IS A HARDY AND DROUGHT-RESISTANT PLANT WHICH GROWS 3 TO 6 FT HIGH... THE ENDOSPERM, WHICH COMPRISES 35-42% OF...SEED IS THE SOURCE OF THE GUM. IT IS HARVESTED BEFORE...FIRST RAIN FOLLOWING FIRST FROST... [R2, 319] *Ground endosperms of Cyamopsis tetragonolobus (l) Taub, Leguminosae which is cultivated in India as livestock feed. Water sol fraction (85%) of guar flour is called guaran which consists of linear chains of (1-4)-beta-d-mannopyranosyl units with alpha-d-galactopyranosyl units attached by (1-6) linkages. [R5] *WASTEWATERS ARE COAGULATED WITH GUAR GUM, A WATER SOL CATIONIC POLYMER, AND PEG, POLYETHYLENE GLYCOL. [R6] *ADHESIVES FOR SURGICAL USE (SUCH AS FOR COLOSTOMY) CONTAIN GUAR GUM. [R7] USE: *As protective colloid, stabilizer, thickening and film forming agent for cheese, salad dressing, ice cream, soups; in paper sizing; as binding and disintegrating agent in tablet formulations; in pharmaceutical jelly formulations; in suspensions, emulsions, lotions, creams, toothpastes; in mining industry as flocculant, as filtering agent; in water treatment as a coagulant [R5] *Therap Cat: adjunct to diet, insulin or oral hypoglycemics in control of diabetes [R5] *IN BULK LAXATIVES, APPETITE DEPRESSANTS [R8] *FLOCCULANT IN MINING; HYDRAULIC FRACTURING AID IN OIL WELL RECOVERY; GELLING AND WATERPROOFING AGENT IN EXPLOSIVES [R1] *CHEM INT FOR DERIVATIVES USED IN PAPER AND TEXTILE INDUST, THICKENER AND BINDER OF FREE WATER IN FOOD [R1] *MEDICATION *Used extensively as a thickener, stabilizer, suspending agent, and binder of free water in many food products, including nonalcoholic beverages (e.g. fruit drinks), frozen dairy desserts (especially ice cream and sherbets where it binds free water to prevent ice crystals formation), baked goods, gelatins and puddings, meat and meat products, condiments and relishes, breakfast cereals, cheeses (especially soft cheeses and spreads), milk products, soups. sweet sauces. gravies, snack foods. and processed vegetables, among others. Highest average maximum use level reported is about 1% in breakfast cereals (11,260 ppm), sweet sauces (9,000 ppm), and processed vegetables (10,747 ppm). [R9, 290] *Paper coating, cosmetics, pharmaceuticals, binder in tablet mixtures, interior coating of firehose nozzles, fracturing aid in oil wells, textiles, printing, polishing, thickener and emulsifier in food products (e.g., cheese spreads, ice cream, and frozen desserts) [R3] CPAT: *ABOUT 36% AS A HYDRAULIC FRACTURING AID IN OIL WELL RECOVERY; 64% IN OTHER APPLICATIONS (1969) [R1] PRIE: U.S. PRODUCTION: *(1972) 7.26-9.08X10+9 GRAMS [R1] *(1975) 7.76X10+9 TO 9.08X10+9 GRAMS (EST) [R1] U.S. IMPORTS: *(1972) 1.27X10+10 GRAMS [R1] *(1975) 2.72X10+10 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Yellowish-white free-flowing powder [R3] PH: *A 1% SOLN MAY REACH..., A PH OF 5.5-6.1 AND TEND TO BECOME MORE ACIDIC WHILE STANDING. [R2, 320] SOL: *Completely sol in water; practically insol in oils, greases, hydrocarbons, ketones, and esters [R5] VISC: *A 1% SOLN MAY REACH A VISCOSITY OF 2700 CPS. [R2, 320] OCPP: *Reduces friction drag of water on metals [R3] *Water solutions are tasteless, odorless, of a pale, translucent gray color, and neutral; has 5 to 8 times the thickening power of starch; water solutions may be converted to a gel by small amt of borax; stable to heat [R5] *THE MANNOSE-GALACTOSE RATIO IS ABOUT 2:1 AND MOLECULAR WT APPROX 220,000-250,000; MAX VISCOSITY IS REACHED IN APPROX 2 HR IN COLD WATER; THE RATE OF HYDRATION AND VISCOSITY ARE INCREASED @ HIGHER TEMPERATURES; SOLUTIONS ARE SLIGHTLY CLOUDY DUE TO PRESENCE OF A SMALL AMT OF INSOL FIBER AND CELLULOSE; SOLUTIONS ARE THIXOTROPIC AND VISCOSITY IS RELATIVELY UNAFFECTED BY THE PRESENCE OF ELECTROLYTES; COMPATIBLE WITH STARCH, GELATIN AND OTHER WATER SOL GUMS; GUAR IS COMPOSED OF A STRAIGHT CHAIN OF D-MANNOSE WITH A D-GALACTOSE SIDE CHAIN AT APPROX EVERY MANNOSE UNIT. [R2, 320] *SUGAR UNITS: D-MANNOSE BETA-(1 TO 4), D-GALACTOSE-(1 TO 6) BRANCHES [R2, 299] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition, it emits acrid smoke and irritating fumes. [R10] SSL: *RELATIVELY STABLE OVER THE RANGE OF PH 4-10.5 [R2, 320] *STABLE TO HEAT [R11] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *GUAR GUM WAS INCORPORATED INTO DIETS OF 6 INSULIN DEPENDENT DIABETICS DRAWN FROM ONE GENERAL PRACTICE. AMT BETWEEN 6 AND 59.6 G DAILY WERE USED FOR 4-6 WK AND COMPARED WITH PREVIOUS 2 WK CONTROL. A SMALL REDUCTION IN CHOLESTEROL LEVELS OCCURRED. [R12] *In women, ... ingestion of guar gum led to permanent weight loss, but did not influence serum lipids in hypercholesterolemia. Similar results were noted in male patients and elderly patients. However, positive results are reported in use of guar gum as a long-term dietary supplement in control of hypercholesterolemia in diabetics. [R9, 290] *Longterm administration (21 g/day) produced a sustained improvement in control of Type 2 diabetes, with significantly lower serum total and LDL cholesterol concentrations. An average reduction of 14% total cholesterol levels was observed in doses of 10 g b.i.d. immediately before meals as well as a 16 reduction in postprandial glucose levels. [R9, 290] *Occupational asthma has been reported in subjects working with industrial production of guar gum. [R9, 290] *Guar gum was blamed in causing esophageal obstruction. A death has been attributed to the use of one guar gum tablet product, which apparently swelled in the esophagus, indirectly resulting in complications that caused the fatality. [R9, 290] *Mildly toxic by ingestion. [R10] NTOX: *GUAR GUM INDUCED NO CONSISTANT RESPONSES IN DOMINANT LETHAL GENE TEST TO SUGGEST THAT IT WAS MUTAGENIC TO THE RAT. [R13] *ADDITION OF 5% GUM GUAR TO A DIET CONTAINING 10% CASEIN DID NOT CHANGE THE OVERALL NITROGEN RETENTION OF YOUNG RATS BUT INDUCED SIGNIFICANT SHIFT IN NITROGEN EXCRETION FROM URINE TO FECES, RESULTING IN MARKEDLY DECR APPARENT PROTEIN DIGESTIBILITY. [R14] *Guar gum has been reported to lower the serum and liver cholesterol levels in chickens and rats as well as the serum cholesterol and postprandial (after meal) blood glucose in humans ... . When included at different levels in the diets of chickens, guar gum has been demonstrated to cause growth depression. though with inconsistent results. It also reduced the metabolizable energy of the diets in which it was included. Guar gum does not seem to be digested by animals. [R9, 290] NTXV: *LD50 Rat oral 6770 mg/kg; [R10] *LD50 Mouse oral 8100 mg/kg; [R10] *LD50 Rabbit oral 7000 mg/kg; [R10] *LD50 Hamster oral 6000 mg/kg; [R10] INTC: *EXPTL USE: SODIUM ALGINATE AS WELL AS GUAR GUM INHIBIT THE ABSORPTION OF A (59)FE-LABELED FE BY JEJUNAL SEGMENTS OF EITHER NORMAL OR FE-DEFICIENT RATS. HIGHEST DOSE OF GUAR GUM, 30 MG, INHIBITED THE AMOUNT OF FE ABSORBED BY ABOUT 25%. [R15] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *EXPTL USE: GUAR GUM WAS INVESTIGATED ON POSTPRANDIAL CHYLOMICRONEMIA. RESULTS SUGGEST AN INFLUENCE ON FAT ABSORPTION RATE AND CHYLOMICRON FORMATION. IT WAS CONCLUDED THAT IT MAY BE A USEFUL AGENT FOR THE MGMNT OF HYPERLIPIDEMIA. [R16] *It is used as a binding and disintegrating agent in tablets and as a thickener in lotions and creams, also used as an appetite depressant and in certain antihypercholesterolemic preparations. [R9, 290] *Capsules, tablets, powder, and other product forms have, until recently, been widely used in weight loss formulations. [R9, 291] WARN: *A human study found guar gum consumption in diabetic mellitus patients did not adversely affect mineral balance. Flatulence has frequently been reported as a side effect to guar gum dietary supplementation. [R9, 290] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *SEEDS OF THE GUAR PLANT (CYAMOPSIS TETRAGONOLOBUS) [R1] FOOD: *IT MIGRATES TO FOOD FROM PACKAGING MATERIALS. [R17] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of guar gum are exempted from the requirement of a tolerance when used as a surfactant and related adjuvant of surfactant in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R18] FIFR: *Residues of guar gum are exempted from the requirement of a tolerance when used as a surfactant and related adjuvant of surfactant in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R18] FDA: *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R19] *Guar gum used as a stabilizer in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R20] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R21] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *MICRODETERMINATION OF GUAR IN MINE WATER. [R22] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Guar Gum in F344 Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 229 (1982) NIH Publication No. 82-1785 SO: R1: SRI R2: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 555 R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA3 (85) 7 R5: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 780 R6: COAGULATION OF WASTEWATER; JPN KOKAI TOKKYO KOHO PATENT NUMBER 81 21609 02/28/81 (DAIICHI KOGYO SEIYAKU CO, LTD) R7: USA; JPN KOKAI TOKKYO KOHO PATENT NUMBER 79 03847 01/12/79 (SQUIBB ER, AND SONS, INC R8: The Merck Index: An Encyclopedia of Chemicals and Drugs 8th ed. Rahway, New Jersey: Merck and Co., Inc., 1968. 512 R9: Leung, A.Y., Foster, S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. New York, NY. John Wiley and Sons, Inc. 1996. R10: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1757 R11: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 595 R12: CARROLL DG ET AL; NZ MED J 93(683) 292 (1981) R13: NEWELL GW ET AL; US NAT TECH INFORM SERV PB REP ISS NUMBER 221815/4 102 (1972) R14: HARMUTH-HOENE A-E ET AL; NUTR METAB 22(1) 32 (1978) R15: WOELBLING RH ET AL; DIGESTION 20(6) 403 (1980) R16: NOBORU I ET AL; NUTRITION REPORTS INTERNATIONAL 26(2) 207 (1982) R17: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 796 R18: 40 CFR 180.1001(c) (7/1/99) R19: 21 CFR 184.1339 (4/1/99) R20: 21 CFR 582.7339 (4/1/99) R21: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R22: JUNGREIS E; A SIMPLE MICRODETERMINATION OF POLYMER FLOCCULANTS (POLYACRYLMIDES AND GUAR) IN MINE WATER. ANAL LETT 14(A14) 1177 (1981) RS: 14 Record 159 of 1119 in HSDB (through 2003/06) AN: 1908 UD: 200205 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CAROB-BEAN-GUM- SY: *ALGAROBA-; *AROBON-; *CAROB-FLOUR-; *CAROB-GUM-; *CAROB-SEED-GUM-; *CERATONIA-GUM-; *FRUCTOLINE-; *INDALCA-ABV-; *JOHANNISBROTMEHL-; *LOCUST-BEAN-GUM-; *LOCUST-GUM-; *LUCTIN-; *LUPOGUM-; *NCI-C50419-; *ST-JOHN'S-BREAD-GUM-; *SUPERCOL-; *TRAGACOL-; *TRAGASOL-; *TRAGON-; *TRAGON-AY-; *TRAGON-GUM-; *UNIGUM- RN: 9000-40-2 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REMOVAL AND PROCESSING OF ENDOSPERM FROM SEEDS OF THE CAROB TREE (CERATONIA SILIQUA) [R1] *Extracted from carob seeds, from the tree Ceratonia siliqua [R2] *...produced by milling the seeds from the leguminous evergreen plant, Ceratonia siliqua, or carob tree...pods produced by the carob tree consist of a husk, embryo, and endosperm. The latter, the source of the gum, is separated from the tough outer husk and the yellow embryo issue by a variety of rolling and milling operations...milled into a fine powder [R3] *For removal of the hulls, two different processes exist. In the acid process the hulls are carbonized by treating the kernels with moderately dilute sulfuric acid at elevated temperatures...the remaining hull fragments are then removed by washing and brushing operations...after a drying step the dehulled kernels are cracked and the germs sifted off from the endosperm...commercial products are obtained by milling and screening...in the vanishing roasting process the kernels are roasted in a rotating furnace, where the hulls pop...this process yields products of somewhat darker color...the use of sulfuric acid is avoided. [R4, 55] FORM: *Grades: technical; FCC (as locust-bean gum). [R2] MFS: *NOT PRODUCED COMMERCIALLY IN THE US [R1] OMIN: *...GUM IS REFINED ENDOSPERM OF THE SEED OF CAROB TREE, CERATONIA SILIQUA, A LARGE LEGUMINOUS EVERGREEN WHICH IS WIDELY CULTIVATED IN THE MEDITERRANEAN AREA. [R5, 317] *...CULTIVATION OF THE CAROB TREE DATES BACK MORE THAN 2000 YEARS. THE ANCIENT EGYPTIANS USED...GUM AS AN ADHESIVE IN MUMMY BINDING. ...CAROB POD IS SOMETIMES CALLED ST JOHN'S BREAD AND CAROB SEED GUM IS ANOTHER COMMON NAME FOR LOCUST BEAN GUM. [R5, 318] *...DERIVED FROM FRUIT OF CAROB TREE, OR CERATONIA SILIQUA...FAMILY LEGUMINOSAE...SUBFAMILY CAESALPINIACEAE. CAROB...EVERGREEN TREE...40-50 FT HIGH. FRUIT IS DARK, CHOCOLATE COLORED POD, RICH IN SUGAR AND PROTEIN, ABOUT 4-12 IN LONG...ABOUT 10 SEEDS THE SIZE AND SHAPE OF WATERMELON SEEDS. [R5, 318] *SOURCE OF THE GUM...SEED ENDOSPERM...MAKES UP ABOUT 1/3 OF THE SEED. THE FRUIT IS HARVESTED IN THE FALL BY SHAKING...FROM TREE WITH POLES, AND RAKING... GIANT TREES HAVE...PRODUCED UP TO A TON OF FRUIT. [R5, 318] *THE CAROB IS CULTIVATED...IN CALIFORNIA. CYPRUS, SPAIN, ITALY, GREECE AND SYRIA ARE THE MOST IMPORTANT PRODUCING AREAS, BUT ALGERIA, PORTUGAL, TURKEY AND MOROCCO ARE ALSO SOURCES. [R5, 318] */CAROB SEEDS/...COVERED BY...HUSK, UNDER WHICH IS...WHITE, SEMI-TRANSPARENT ENDOSPERM, WITH THE HARD, YELLOW GERM IN CENTER. PRODUCTION...REMOVAL...SEED FROM POD...DEHUSKING OF THE SEED COAT, AND SEPARATION OF ENDOSPERM FROM GERM. SEED COMPRISES 8-10% WT OF POD...ENDOSPERM...1/3 OF SEED. [R5, 317] */CAROB/ PODS ARE CLEANED...BROKEN INTO PIECES (KIBBLED) AND SEED REMOVED. THE SEEDS.../MECHANICALLY/ DEHUSKED...A PRETREATMENT WITH DILUTE ALKALI... SOMETIMES USED. THE DEHUSKED SEEDS...SPLIT...GERM SEPARATED FROM ENDOSPERM...DIFFERENTIAL GRINDING...ENDOSPERM GROUND INTO FINE FLOUR. [R5, 317] */CAROB/ FLOUR IS GRADED ACCORDING TO ACCEPTED STANDARDS OF COLOR, IMPURITIES, VISCOSITY AND GERM CONTENT. HIGHEST GRADES ARE A NEAR-WHITE, SPECK FREE POWDER. [R5, 318] *AN ALTERNATE PROCEDURE INVOLVES THE FURTHER PURIFICATION OF /CAROB/ ENDOSPERM BY DISPERSING...IN BOILING WATER, FILTERING...TO REMOVE IMPURITIES, THEN RECOVERING GUM BY EVAPORATION OF SOLN AND FINAL TRAY OR ROLL DRYING. [R5, 318] *...CONTAINS D-MANNOSE AND D-GALACTOSE AS STRUCTURAL UNITS WITH MANNOSE CONTENTS OF 73-82%...DEPENDING ON METHODS USED AND GEOGRAPHICAL ORIGIN OF GUM. ...NO URIC ACID OR PENTOSE IS PRESENT. [R5, 318] *...CONSISTS OF PROTEINS SUCH AS ALBUMINS, GLOBULINS, PROLAMINS, GLUTELINE; CARBOHYDRATES SUCH AS REDUCING SUGARS, SUCROSE, DEXTRINS, PENTOSANS; ASH; FAT; CRUDE FIBER; MOISTURE. [R6] *WHEYING OFF TENDENCIES OF LOCUST BEAN GUM ARE PREVENTED BY USING IT IN CONJUNCTION WITH CARRAGEENAN. IMPROVED PERFORMANCE HAS BEEN CLAIMED FOR LOCUST BEAN GUM WHEN USED IN CONJUNCTION WITH A PROTEIN-STABILIZING SALT SUCH AS SODIUM HEXAMETAPHOSPHATE. [R5, 332] *A SUBSTANCE MIGRATING TO FOOD FROM PACKAGING MATERIALS. [R7] *FEMA NUMBER 2648 [R5, 816] *OPHTHALMIC SOLUTIONS OF CHOLINERGIC AGENTS CONTAINING LOCUST BEAN GUM TO ENHANCE THE DRUG THERAPEUTIC ACTIVITY ARE DESCRIBED. [R8] USE: *FIBER BONDING AND BEATER ADDITIVE IN PAPER INDUST (LOCUST BEAN GUM AND DERIVATIVES) [R1] *STOCK FEED BECAUSE OF HIGH PROTEIN COUNT; SOMETIMES SERVES AS HUMAN FOOD /CAROB POD/ [R5, 318] *STABILIZER IN ICE CREAM, SAUCES, SALAD DRESSINGS, PIE FILLINGS, BAKERY PRODUCTS [R5, 318] *TEXTURE MODIFIER IN SOFT CHEESE; AS A BINDING AND LUBRICATING AGENT IN SAUSAGES [R5, 319] *SIZING AGENT FOR COTTON AND STAPLE FIBER YARNS; PRINT-PASTE THICKENER; FINISHING AGENT IN TEXTILES; DRILLING MUD ADDITIVE; AGENT TO IMPROVE CONSISTENCY OF PHARMACEUTICAL TABLETS; THICKENER FOR TOOTHPASTE; THICKENER AND STABILIZER FOR CREAMS AND LOTIONS [R1] */FORMERLY/ AS ADHESIVE IN MUMMY BINDING [R5, 318] *In foods as stabilizer, thickener, emulsifier, and packaging material; cosmetics; sizing and finishes for textiles; pharmaceuticals; paints, bonding agent in paper manufacturer; drilling fluids [R2] *MEDICATION *Feed additive, flavor [R9, 2136] *The primary use...is in dairy applications such as ice cream...often used in conjunction with carrageenan because the chemical structures of the two enable them to cross-link and form a gel. [R10] PRIE: U.S. PRODUCTION: *...Mediterranean Sea, in Spain, Portugal, and Morocco...the annual production is estimated at 10,000 - 12,000 tons [R4, 54] U.S. IMPORTS: *(1972) 4.08X10+9 GRAMS [R1] *(1975) 2.61X10+9 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *SOLN OF GUM IS CLOUDY WITH WHITE OPACITY DUE TO INSOL IMPURITIES SUCH AS PROTEIN AND CELLULOSE [R5, 319]; *In powdered form, nearly pure white [R9, 2135]; *Yellow-green [R9, 2135] ODOR: *Odorless [R9, 2135] TAST: *Tasteless, but acquires leguminous taste when boiled in water [R9, 2135] MW: *Approximately 310,000 [R2] PH: *NORMAL PH OF A 1% SOLN IS 5.3, BUT VISCOSITY IS LITTLE AFFECTED OVER A RANGE OF PH 3-11 [R5, 319] SOL: *Insol in organic solvents [R2] VISC: *1% SOLN CAN ATTAIN A VISCOSITY OF 3000-3500 CPS [R5, 319] OCPP: *SWELLS IN COLD WATER; HEATING IS NECESSARY FOR MAXIMUM SOLUBILITY [R5, 319] *IT IMPARTS EXCELLENT WATER-BINDING, SWELLING, SMOOTH MELT-DOWN QUALITIES AND HEAT-SHOCK RESISTANCE TO FINAL PRODUCT [R5, 332] *GUM NEUTRAL GALACTOMANNAN POLYMER WITH MAIN CHAIN OF 1,4-LINKED D-MANNOSE UNITS WITH D-GALACTOSE CHAINS EVERY 4TH-5TH UNIT [R5, 318] *D-GALACTOSE LINKED TO POLYMANNOSE CHAIN THROUGH 1,6-GLYCOSIDIC LINKAGES [R5, 318] *GUM SOLUTIONS HAVE NO GELLING PROPERTIES, BUT CAN IMPART ELASTIC CHARACTER TO CARRAGEENAN AND AGAR GELS AND RETARD SYNERESIS [R5, 319] *GUM IS COMPATIBLE WITH CARBOHYDRATES, PROTEIN, AND OTHER PLANT GUMS [R5, 319] *GUM SOLN ARE RELATIVELY UNAFFECTED BY NEUTRAL SALTS, BUT CAN BE PRECIPITATED BY LEAD ACETATE AND TANNIC ACID [R5, 319] *MOLECULAR WEIGHT: ABOUT 310,000 [R6] *A SLIGHT INCREASE IN VISCOSITY ON AGING IS EXHIBITED [R5, 319] *Viscosity increases when heated. [R2] *Swells in cold water [R2] *A polysaccharide plant mucilage that is essentially galactomannan (carbohydrate) [R2] *...not completely soluble in cold water...must be heated to 80 deg C and cooled to attain a stable solution that has high viscosity at low concentrations. The gum is compatible with other plant gums and the viscosity of solutions is not appreciably affected by pH or salts. [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition, it emits acrid smoke and irritating fumes. [R11] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *NONTOXIC ON BASIS OF PRESENT DATA... [R12] *Mildly toxic by ingestion. [R11] NTOX: *LOCUST BEAN GUM PRODUCED NO MUTAGENIC RESPONSE OR ALTERATION IN RECOMBINATION FREQUENCY FOR SACCHAROMYCES CEREVISIAE IN THE HOST-MEDIATED ASSAY OR IN IN VITRO TESTS. [R13] *CAROB BEAN GUM HAD NO ADVERSE EFFECT ON EITHER METAPHASE CHROMOSOMES FROM RAT BONE MARROW OR ANAPHASE CHROMOSOMES FROM HUMAN EMBRYONIC LUNG CELL CULTURES, AND DID NOT APPEAR TO BE MUTAGENIC TO RAT ACCORDING TO DOMINANT LETHAL GENE TEST. [R14] *... Locust bean gum does not seem to be digested by animals. Its growth-depressing effects in laboratory animals have been reported, with inconclusive results as in guar gum. [R15] NTXV: *LD50 Rat oral 13 g/kg; [R11] *LD50 Mouse oral 13 g/kg; [R11] *LD50 Rabbit oral 9100 mg/kg; [R11] *LD50 Hamster oral 10 g/kg; [R11] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Antidiarrheals [R16] *ADSORBENT-DEMULCENT IN DIARRHEA [R6] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R17] *Locust bean gum used as a stabilizer in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R18] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R19] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Locust Bean Gum in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 221 (1982) NIH Publication No. 82-1777 SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 217 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V12 (94) 855 R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA25 (94) R5: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R6: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 725 R7: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 473 R8: LIN S; PRAMODA MK; LOCUST BEAN GUM THERAPEUTIC COMPOSITIONS, US PATENT NO 4136178 01/23/79 (AMERICAN HOME PRODUCTS CORP) R9: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. R10: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V11 (94) 827 R11: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2065 R12: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 168 R13: NEWELL GW, MAXWELL WA; US NAT TECH INFORM SERV, PB REP, ISS NO 221819/6 (1972) R14: NEWELL GW, MAXWELL WA; US NAT TECH INFORM SERV, PB REP; ISS NO 221819/6 (1972) R15: Leung, A.Y., Foster, S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. New York, NY. John Wiley and Sons, Inc. 1996. 356 R16: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R17: 21 CFR 184.1343 (4/1/99) R18: 21 CFR 582.7343 (4/1/99) R19: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) RS: 13 Record 160 of 1119 in HSDB (through 2003/06) AN: 1914 UD: 200205 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACACIA- SY: *ACACIA-DEALBATA-GUM-; *ACACIA-GUM-; *ACACIA-SENEGAL-; *ACACIA-SYRUP-; *ARABIC-GUM-; *AUSTRALIAN-GUM-; *GUM-ACACIA-; *GUM-ARABIC-; *GUM-DRAGON-; *GUM-OVALINE-; *GUM-SENEGAL-; *INDIAN-GUM-; *SENEGAL-GUM-; *STARSOL-NO-1-; *WATTLE-GUM- RN: 9000-01-5 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *COLLECTED FROM BREAKS OR WOUNDS IN THE OUTER BARK OF THE ACACIA TREE, MAINLY ACACIA SENEGAL [R1] *...comes from various species of Acacia...the gum exudes through cracks, injuries, and incisions in the bark and is collected by hand as dried tears. [R2] FORM: *ACACIA, USP (GUM ARABIC)... ACACIA SYRUP, NF, IS VANILLA-FLAVORED SYRUP THAT CONTAINS 10% ACACIA. ... IT IS ALSO INCORPORATED IN LOZENGES. [R3] *ACACIA MUCILAGE NF XII [MUCILAGE OF GUM ARABIC]... DEMULCENT AND SUSPENDING AGENT. ...AS EXCIPIENT IN MAKING PILLS AND TROCHES, AND AS EMULSIFYING AGENT FOR COD LIVER OIL AND OTHER SUBSTANCES. CAUTION- ACACIA MUCILAGE MUST BE FREE FROM MOLD OR ANY OTHER INDICATION OF DECOMP. [R4, 1246] *Grades: USP; FCC (Both grades as Acacia). [R5] *Moisture content usually varies from 13-15%; USP limit 15% [R6, 3] MFS: *NOT PRODUCED IN THE US [R1] OMIN: *GUM IS EXUDED THROUGH...WOUNDS IN BARK IN FORM OF TEARS, OR DROPS WHICH RAPIDLY HARDEN DUE TO EVAPORATION. MOST OF GUM...PRODUCTION IS FROM WILD TREES... WILD GUM (CALLED HASHAB WADY) IS COLLECTED ON A PART TIME BASIS IN...DRY SEASON FROM OCTOBER TO MAY OR JUNE... [R7, 311] *...PRIVATELY OWNED CULTIVATED GARDENS...ARE TAPPED AND COLLECTED ON SYSTEMATIC BASIS. THIS GUM, CALLED HASHAB GENEINA (GARDEN GUM), IS CLEANEST AND LIGHTEST GRADE, AND IS MOST PREFERRED FOR US MARKET. [R7, 312] *AFTER GATHERING, IT IS TAKEN TO CENTRAL COLLECTING STATIONS WHERE IT IS AUCTIONED UNDER GOVERNMENT SUPERVISION, GRADED BY HAND AND DRIED, BEFORE EXPORTING TO GUM SUPPLIERS IN ALL PARTS OF WORLD. THERE IT IS RESORTED, GROUND, PROCESSED, AND GRADED TO VARIOUS SPECIFICATIONS. [R7, 312] *PRINCIPAL CONSTITUENTS OF VARIOUS TYPES OF GUM ARABIC, INCL GUMS FROM...BLUE NILE DISTRICT, FROM KORDOFAN, SENNAR, SOMALIA AND ETHIOPIA ARE CALCIUM (WITH TRACES OF MAGNESIUM AND POTASSIUM), SALTS OF ARABIN AND ARABIC ACID...AND WATER. ...ALSO...TANNIN, SUGAR AND ENZYMES AND ITS COMPOSITION IS SIMILAR TO THAT OF PECTINS. [R8] *THE GUMMY EXUDATION LOSES ABOUT 15% OF WATER BY EVAPORATION AND IS EXPORTED IN FORM OF ROUND OR OVAL TEARS HAVING A MATT SURFACE AND WHICH BREAKS WITH A VITREOUS FRACTURE SIMILAR TO GLASS. [R8] *IN WEST AFRICA THE GUM IS ALSO COLLECTED FROM ACACIA SENEGAL AND IS USUALLY CALLED SENEGAL GUM. IT IS MORE YELLOW, OR REDDISH, THAN KORDOFAN OR SUDAN GUM AND IS REGARDED AS BEING LESS ADHESIVE AND MORE VISCOUS. IT IS USED EXTENSIVELY IN EUROPE. [R7, 312] *BESIDES BEING CALLED KORDOFAN, SUDAN, OR SENEGAL GUM, GUM ARABIC HAS A GREAT MANY OTHER NAMES, BASED ON GEOGRAPHICAL OR BOTANICAL ORIGIN, OR PHYSICAL CHARACTERISTIC OF THE GUM ITSELF. [R7, 312] *Incompatibilities: precipitates or jellies result upon addition of soln of ferric salts, borax, basic lead acetate (lead sub-acetate, but not neutral lead acetate), alcohol, sodium silicate, gelatin, ammoniated tincture of guaiac. [R6, 3] *INCOMPATIBILITIES: ALC AND ALCOHOLIC SOLN PRECIPITATE ACACIA AS STRINGY MASS WHEN ALC AMT TO MORE THAN ABOUT 35% OF TOTAL VOL. SOLN IS EFFECTED BY DILUTION WITH WATER. MUCILAGE IS DESTROYED THROUGH PRECIPITATION OF ACACIA BY HEAVY METALS. ... ACACIA CONTAINS CALCIUM AND, THEREFORE, POSSESSES INCOMPATIBILITIES FOR THIS ION. [R4, 1242] *INCOMPATIBILITIES: ACACIA CONTAINS PEROXIDASE WHICH ACTS AS OXIDIZING AGENT AND PRODUCES COLORED DERIVATIVES OF AMINOPYRINE, ANTIPYRINE, CRESOL, GUAIACOL, PHENOL, TANNIN, THYMOL, VANILLIN, AND OTHER SUBSTANCES. [R4, 1242] *INCOMPATIBILITIES: ACACIA CONTAINS PEROXIDASE WHICH ACTS AS OXIDIZING AGENT AND PRODUCES COLORED DERIVATIVES...ALKALOIDS AFFECTED ARE ATROPINE, APOMORPHINE, COCAINE, HOMATROPINE, HYOSCYAMINE, MORPHINE, PHYSOSTIGMINE, AND SCOPOLAMINE. PARTIAL DESTRUCTION OF ALKALOID OCCURS IN REACTION. [R4, 1242] *Acacia was originally thought to be composed only of (-)-arabinose, (+)-galactose, (-)-rhamnose, (+)-glycuronic acid. Revised composition and structural studies: Anderson et al, J Chem Soc (c) 1966, 1959. [R6, 3] *ACACIA IS A CARBOHYDRATE GUM... BECAUSE IT IS A CARBOHYDRATE IT IS NECESSARY TO PRESERVE ACACIA EMULSIONS AGAINST MICROBIAL ATTACK BY USE OF SUITABLE PRESERVATIVE. [R4, 333] *Estimations of mol wt range from about 240,000. [R6, 3] *Grades of kordofan gum which are commercial variety. Grades of kordofan gum which are clear, white (sun bleached) and tasteless are preferred for food prepn and pharmaceuticals. (There is close relationship between color and flavor due to presence of tannins.) [R6, 3] *EXTENSIVELY AS SUSPENDING AGENT FOR INSOL SUBSTANCES IN WATER, IN PREPN OF EMULSIONS, AND FOR MAKING PILLS AND TROCHES. IT IS USED FOR ITS DEMULCENT ACTION IN INFLAMMATIONS OF THROAT OR STOMACH. [R4, 1242] *BESIDES BEING CALLED KORDOFAN, SUDAN, OR SENEGAL GUM, GUM ARABIC HAS A GREAT MANY OTHER NAMES, BASED ON GEOGRAPHICAL OR BOTANICAL ORIGIN, OR PHYSICAL CHARACTERISTIC OF THE GUM ITSELF. [R7, 312] *FEMA NUMBER 2001 [R7, 784] *The dried, water-soluble exudate from the stems of Acacia senegal or related species. [R5] USE: *DEMULCENT IN COUGH MIXTURES AND EMULSIONS; IN PREPN OF LOZENGES; BINDING MEDIUM FOR FLAMMABLE MATERIALS OF MATCHES; IN MFR OF WATER COLORS; HAS BEEN EMPLOYED IN COLOR PRINTING AS ANTI-OFFSET AGENT [R8] *ADHESIVE FOR ICINGS AND TOPPINGS; FOAM STABILIZER IN BEVERAGES [R7, 311] *RETARDER OF SUGAR CRYSTALLIZATION IN CONFECTIONERIES; STABILIZER IN DAIRY AND BAKERY PRODUCTS; FLAVOR FIXATIVE AND EMULSIFIER; PROTECTIVE COLLOID IN PHARMACEUTICALS, COSMETICS, AND INKS; EMULSIFIER IN CONFECTIONERIES [R1] *Mucilage, excipient for tablets, size, emulsifer, thickener, also in candy, other foods; as colloidal stabilizer; demulcent. In the manufacture of spray-dried "fixed" flavors - stable, powdered flavors used in packaged dry-mix products (puddings, desserts, cake mixes) where flavor stability and long shelf life are important. [R6, 4] *MEDICATION *MEDICATION (VET) *Currently, its major use is in foods, where it performs many functions, e.g.,, as a suspending or emulsifying agent. stabilizer. adhesive, and flavor fixative and to prevent crystallization of sugar, among others. It is used in practically all categories of processed foods, including candy, snack foods, alcoholic and nonalcoholic beverages, baked goods, frozen dairy desserts, gelatins and puddings, imitation dairy products. breakfast cereals, and fats and oils, among others. Its use levels range from < 0.004% (40 ppm) in soups and milk products to 0.7-2.9% in nonalcoholic beverages, imitation dairy, and snack foods to as high as 45% in candy products. [R9] *Pharmaceuticals, adhesives, inks, textile printing, cosmetics, thickening agent and colloidal stabilizer in confectionery and food products, binding agent in tablets, emulsifier. [R5] CPAT: *OVER 50% AS AN EMULSIFIER AND RETARDER OF SUGAR CRYSTALLIZATION IN CONFECTIONERIES, AS A STABILIZER IN DAIRY AND BAKERY PRODUCTS AND AS A FLAVOR FIXATIVE AND EMULSIFIER; THE REMAINDER AS A PROTECTIVE COLLOID IN PHARMACEUTICALS AND COSMETICS, AND IN MISC APPLICATIONS (1975) [R1] PRIE: U.S. PRODUCTION: *(1972) NOT PRODUCED IN THE US [R1] *(1975) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1972) 1.45X10+10 G [R1] *(1973) 7.62X10+9 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Spheroidal tears up to 32 mm in diameter; also flakes and powder [R6, 3]; *COLORLESS OR HAS A YELLOWISH-BROWNISH HUE [R8]; *WHEN GROUND, IT IS WHITE POWDER [R3]; *Thin flakes, powder, granules, or angular fragments; color white to yellowish white; mucilaginous consistency [R5] ODOR: *SOLN OF GOOD GRADES ARE PRACTICALLY ODORLESS [R7, 312]; *Almost odorless [R5] TAST: *SOLN OF GOOD GRADES ARE PRACTICALLY TASTELESS [R7, 312]; *POORER QUALITY (DARK) GRADES HAVE UNPLEASANT FLAVOR AND ODOR, PROBABLY DUE TO TANNIC ACID [R7, 312] MW: *240,000 [R10] DEN: *1.35-1.49 (samples dried @ 100 deg C are heavier) [R6, 3] PH: *Aq soln acid to litmus [R6, 3] SOL: *READILY SOL IN WATER [R3]; *Insol in alc. Sol in glycerol and in propylene glycol, but prolonged heating (several days) may be necessary for complete soln (about 5%) [R6, 3]; *Almost completely sol in twice its weight of water. [R6, 3]; *INSOL IN MOST ORGANIC SOLVENTS [R7, 313]; *Completely soluble in hot and cold water; yielding a viscous solution of mucilage; insoluble in alcohol. [R5] SPEC: *Soln of gum from Acacia verek are levorotatory; other Acacia species are dextrorotatory [R6, 3] VISC: *VISCOSITIES OF GUM ARABIC SOLN ARE RELATIVELY LOW WITH A VISCOSITY OF 200 CPS HAVING BEEN REPORTED FOR 30% SOLN; MAX VISCOSITY IS ATTAINED @ PH 6-7 WITH ONLY GRADUAL CHANGE OVER PH RANGE 5-10; VISCOSITY INCR GRADUALLY AS CONCN IS INCR UP TO 20-25%, @ WHICH POINT MORE MARKED INCR TAKES PLACE; VISCOSITY OF GUM ARABIC SOLN DECR WITH TEMP [R7, 313] OCPP: *MIXED WITH TWICE ITS WT IN WATER IT DISSOLVES SLOWLY FORMING A VISCOUS LIQ WHICH IS VERY STICKY [R8] *Material containing less than 12% moisture chips easily and produces dust during transportation. [R6, 3] *THE EQUIVALENT OF 0.002 TO 0.011 G POTASSIUM HYDROXIDE MAY BE NECESSARY TO NEUTRALIZE 1 G OF GUM [R11] *BEST DESCRIBED AS "HETEROPOLYMOLECULAR" IS NOT VERY VISCOUS [R7, 312] *THE MOST RECENT, CAREFUL STUDY OF THE EXUDATE FROM ACACIA SENEGAL HAS SHOWN AVG MOL WT OF ABOUT 600,000 [R7, 312] *PARTIAL HYDROLYSIS MAY OCCUR @ LOW PH [R7, 313] *QUALITATIVE BREAKDOWN OF SUGARS BY %: 30.3 L-ARABINOSE, 11.4 L-RHAMNOSE, 36.8 D-GALACTOSE, 13.8 D-GLUCURONIC ACID [R7, 312] *Combustible...when heated to decomposition it emits acrid smoke [R10] *A carbohydrate polymer, complex and highly branched. The central core or nucleus is D-galactose and D-glucuronic acid (actually the calcium, magnesium, and potassium salts), to which are attached sugars such as L-arabinose and L-rhamnose [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT. [R12] OPRM: *PROVISIONS OF BETTER VENTILATION IN PRINTING SHOPS USING GUM ARABIC HAS NOT GIVEN SATISFACTORY RESULTS. THEREFORE THE USE OF GUM ARABIC ANTI-OFFSET SOLN HAS BEEN ABANDONED IN MOST COUNTRIES IN FAVOR OF POWDERED CHALK. [R8] *SUBSTITUTION OF GUM ARABIC BY LESS HAZARDOUS SUBSTANCES HAS LED TO...TOTAL ELIMINATION OF NEW CASES OF PRINTER'S ASTHMA, AND IN ALL CASES OF ASTHMA, CESSATION OF EXPOSURE HAS LED TO THE DISAPPEARANCE OF SYMPTOMS IN PERSONS SUFFERING FROM THE DISEASE. [R8] SSL: *EMULSIONS PREPD WITH ACACIA ARE STABLE OVER WIDE PH RANGE [R4, 333] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *PRINTING WORKERS EXPOSED TO.../GUM ARABIC/ MIST HAVE BEEN FOUND TO SUFFER FROM ALLERGIC REACTIONS OFTEN KNOWN AS "PRINTER'S ASTHMA", FREQUENCY OF ALLERGIC SYMPTOMS DEPENDING MAINLY ON ATMOSPHERIC GUM ARABIC CONCN. [R8] *STUDY CARRIED OUT IN PRINTING WORKS IN STUTTGART REVEALED SYMPTOMS SUCH AS INCIPIENT OR CLEARLY DEFINED ASTHMA, CATARRH AND...IRRITATION OF NASAL MUCOUS, SINUS, THROAT, RESPIRATORY TRACT AND BRONCHUS. CASES OF FAINTING FITS AMONG WOMEN EXPOSED TO GUM ARABIC HAVE BEEN RECORDED. [R8] *EXAMINATION OF 37 PRINTING WORKERS REVEALED 13 CASES OF MARKED DYSPNEA, SOON AFTER EXERTION. A DISTINGUISHING FEATURE WAS THAT THE TROUBLE APPEARED SHORTLY AFTER ARRIVAL AT WORK AND DID NOT OCCUR ON NON-WORKING DAYS. [R8] *EXAMINATION OF 37 PRINTING WORKERS...SOON AFTER EXERTION. IN 20 OF THE 37 PRINTERS, THERE WERE WELL-DEFINED RADIOLOGICAL FINDINGS IN...LUNGS, WITH OCCASIONAL CHRONIC BRONCHITIS, AND PULMONARY CONGESTION. [R8] *EXAMINATION OF 37 PRINTING WORKERS REVEALED...DYSPNEA SOON AFTER EXERTION. IN 9 CASES VITAL CAPACITY WAS APPRECIABLY REDUCED, EVEN IN WORKERS WHO WERE OTHERWISE APPARENTLY WITHOUT SUBJECTIVE DISTURBANCES. INTRACUTANEOUS INJECTION OF 1% GUM ARABIC SOLN PRODUCED POSITIVE REACTION IN 16 OF 37 WORKERS. [R8] *AN ATTEMPT AT PASSIVE TRANSMISSION USING THE SERUM FROM A PATIENT SUFFERING FROM PRINTER'S ASTHMA HAS PROVED POSITIVE, AND 11 EMPLOYEES OF A PRINTWORKS WHO HAD NEVER HAD ANY ILL EFFECTS ALSO SHOWED POSITIVE REACTIONS. FURTHER STUDIES HAVE SHOWN THAT SENSITIZATION OCCURRED IN ABOUT 50% OF WORKERS. [R8] *PROVED TO BE A SPECIFIC ALLERGEN GIVING RISE TO SKIN LESIONS AND TO SEVERE ASTHMATIC ATTACKS IN PRINTERS EXPOSED TO ACACIA DUST. [R13] *ACACIA SOLN...IV INJECTION... THERE IS VACUOLIZATION OF LIVER, WITH MODERATE REDUCTION OF HEPATIC FUNCTION. [R14] *HYPERSENSITIVITY REACTIONS TO ACACIA USED AS ADHESIVE IN PREDNISONE TABLETS WERE OBSERVED IN KIDNEY TRANSPLANT PT ON LONG TERM THERAPY. [R15] *ORAL TOXICITY LOW. [R13] *...STUDY OF PRINTERS EXPOSED TO GUM... ON THE AVG, 5 YEARS OR MORE PASSED BEFORE ASTHMA OCCURRED...PRINTERS WITH PERSONAL FAMILY HISTORY OF ATOPIC ALLERGY DEVELOPED SYMPTOMS MUCH SOONER. ...ONE FIRM IN WHICH 30%...COMPLAINED OF WHEEZING AND 19%...ASTHMA. [R16] *FURTHER STUDIES HAVE SHOWN...SENSITIZATION OCCURRED IN ABOUT 50% OF WORKERS. COURSE OF ALLERGY IS IN 2 PERIODS...FIRST ANTIGEN-ANTIBODY REACTION SOMETIMES WITHOUT SYMPTOMS (SILENT SENSITIZATION). THIS IS FOLLOWED IN MANY CASES BY CLINICAL DISORDERS DUE TO ANOTHER MECHANISM... [R8] *Ingested orally, acacia is nontoxic. ... Some people are allergic to its dust and develop skin lesions and severe asthmatic attacks when in contact with it. [R9] NTOX: *REPEATED ORAL ADMIN OF GUM ARABIC TO RATS CAUSED UNCOUPLING OF OXIDATIVE PHOSPHORYLATION IN LIVER AND HEART MITOCHONDRIA AND PARTIAL INHIBITION OF MIXED FUNCTION OXIDASES OF LIVER ENDOPLASMIC RETICULUM. [R17] *... Under the conditions of this bioassay, gum arabic was not carcinogenic for F344 rats or B6C3F1 mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R18] *Acacia can be digested by rats to an extent of 71%; guinea pigs and rabbits also seem to use it for energy, as do humans to a certain extent. ... Acacia may actually elevate serum or tissue cholesterol levels in rats. [R9] NTP: *A carcinogenesis bioassay of gum arabic (81 -86% pure) ... was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance to 50 F344 rats and 50 B6C3F1 mice of each sex for 103 wk. Groups of untreated rats and mice of each sex served as controls. ... Under the conditions of this bioassay, gum arabic was not carcinogenic for F344 rats or B6C3F1 mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R18] ADE: *RECENT STUDIES DEMONSTRATED THAT ACACIA IS STORED IN VACUOLES FOR LONG PERIODS BY THE LIVER. [R14] ACTN: *WHEN APPLIED LOCALLY TO IRRITATED OR ABRADED TISSUES, DEMULCENTS TEND TO COAT SURFACE AND, BY MECHANICAL MEANS, PROTECT UNDERLYING CELLS FROM STIMULI THAT RESULT FROM CONTACT WITH AIR OR IRRITANTS IN ENVIRONMENT. /DEMULCENTS/ [R3] *DEMULCENTS /EG ACACIA/ ACT BY COATING IRRITATED PHARYNGEAL MUCOSA AND THEY MAY HAVE BRIEF ANTITUSSIVE EFFECT ON COUGH SECONDARY TO SUCH IRRITATION. /DEMULCENTS/ [R19] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *1. 1= PRACTICALLY NON-TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) ABOVE 15 G/KG, MORE THAN 1 QUART FOR 70 KG PERSON (150 LB). [R13] THER: *Excipients [R20] *EFFICACY OF /ANTITUSSIVE AGENTS/ PERIPHERALLY ACTING GROUP HAS NOT BEEN DEFINITELY ESTABLISHED. THIS CATEGORY INCL DEMULCENTS (EG, GLYCERIN, HONEY, ACACIA, LICORICE)... [R19] *MEDICATION (VET): TREATMENT OF MILD DIARRHEA [R21] *Mainly in the manufacture of emulsions and in making pills and troches (as an excipient); as a demulcent, for inflammations of the throat or stomach and as a masking agent for acrid tasting substances such as capsicum ...; also as a film forming agent in peel off facial masks. [R9] WARN: *ACACIA SOLN SHOULD NOT BE USED AS SUBSTITUTE FOR SERUM PROTEIN IN TREATMENT OF SHOCK AND AS DIURETIC IN HYPOPROTEINEMIC EDEMA, SINCE IT PRODUCES SERIOUS SYNDROMES WHICH MAY RESULT IN DEATH. [R4, 1242] *IN 1930'S.../ACACIA/ WAS USED IV TO RELIEVE EDEMA OF NEPHROSIS; REACTIONS CONSISTED OF NAUSEA, VOMITING, DYSPNEA, AND URTICARIA... [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *GUM ARABIC IS OBTAINED FROM TREES OF THE GENUS ACACIA... GUM ARABIC IS THE RESULT OF AN INFECTION, EITHER BACTERIAL OR FUNGOIDAL. IT IS EXUDED ONLY BY UNHEALTHY TREES; HEAT, POOR NUTRITION, AND DROUGHT STIMULATE ITS PRODUCTION. ...INFECTION TAKES PLACE THROUGH WOUNDS IN THE TREE... [R7, 312] *...USP acacia is dried gummy exudation from stems and branches of Acacia senegal (l) Willd, Leguminosae, or other African species of Acacia. According to CL Mantell, the Water-Sol Gums (NY, 1947), Kordofan gum... from Acacia verek...from Kordofan province (Sudan) is considered best commercial variety. [R6, 3] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of gum arabic are exempted from the requirement of a tolerance when used as a surfactant, suspending agent and dispersing agent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R22] FIFR: *Residues of gum arabic are exempted from the requirement of a tolerance when used as a surfactant, suspending agent and dispersing agent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R22] FDA: *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R23] *Gum arabic used as a stabilizer in animal drugs, feeds, and related products is generally recognized as safe when used in accordance with good manufacturing or feeding practice. [R24] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R25] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DAIRY PRODUCTS; GUMS, INFRARED METHOD- OFFICIAL FINAL ACTION. [R26] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of Gum Arabic in F344 Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 227 (1982) NIH Publication No. 82-1783 SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (92) 943 R3: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 946 R4: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 89 R6: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R7: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R8: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 629 R9: Leung, A.Y., Foster, S. Encyclopedia of Common Natural Ingredients Used in Food, Drugs, and Cosmetics. New York, NY. John Wiley and Sons, Inc. 1996. 5 R10: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 289 R11: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 2 R12: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 331 R13: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-155 R14: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 146 R15: RUBINGER D ET AL; HYPERSENSITIVITY TO TABLET ADDITIVES IN TRANSPLANT RECIPIENTS ON PREDNISONE; LANCET 2(SEPT 23): 689 (1978) R16: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 461 R17: BACHMANN E ET AL; PHARMACOLOGY (BASEL) 17 (1): 39 (1978) R18: Carcinogenesis Bioassay of Gum Arabic in F344 Rats and B6C3F1 Mice. Technical Report Series No. 227 (1982) NIH Publication No. 82-1783 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R19: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 663 R20: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R21: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 1 R22: 40 CFR 180.1001(c) (7/1/99) R23: 21 CFR 184.1330 (4/1/99) R24: 21 CFR 582.7330 (4/1/99) R25: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R26: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/273 16.290 RS: 23 Record 161 of 1119 in HSDB (through 2003/06) AN: 1933 UD: 200211 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CASTOR-OIL- SY: *AROMATIC-CASTOR-OIL-; *CASTOR-OIL-AROMATIC-; *COSMETOL-; *CRYSTAL-O-; *Pesticide-Code:-031608-; *GOLD-BOND-; *NCI-C55163-; *NEOLOID-; *OIL-OF-PALMA-CHRISTI-; *OLIO-DI-RICINO- (ITALIAN); *PHORBYOL-; *RICINUS-OIL-; *RICIRUS-OIL-; *TANGANTANGAN-OIL- RN: 8001-79-4 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OBTAINED FROM CASTOR BEANS (RICINUS COMMUNIS) BY PRESSING AND/OR SOLVENT EXTRACTION, FOLLOWED BY REFINING, DEODORIZING OR DECOLORIZING [R1] *From the seeds of the castor bean, Ricinus communis, ... They are cold-pressed for the first grade of medicinal oil and hot pressed for the common qualities, approximately 40% of the oil content of the bean being obtained. Residual oil in the cake is obtained by solvent extraction. [R2] *Cold pressing of the spotted, oblong seeds yields a light, viscous oil which is used primarily in pharmaceutical products. Subsequent expelling at elevated temperatures and extraction with hexane yields a yellowish-brown oil which is used primarily in technical applications. [R3] FORM: *OFFICIAL PREPN ARE CASTOR OIL, USP, AND AROMATIC CASTOR OIL, NF. ALTHOUGH THE OBJECTIONABLE TASTE OF THE OIL IS PARTIALLY MASKED IN THE LATTER PREPN, FLAVORED CASTOR OIL EMULSIONS ARE SOMEWHAT MORE PALATABLE. [R4] *Grades: USP Number 1; Number 3; Refined; FCC. [R2] *Fatty acid composition is approx ricinoleic 87%, oleic 7%, linoleic 3%, palmitic 2%, stearic 1%, and dihydroxystearic trace amounts. [R5, 311] *Castor oil quality and specifications prescribed by the International Castor Oil Association, Inc.: pale oil, No. 1 oil, No. 2 oil, and No. 3 oil. [R6, 304] MFS: *Castor oil acids (ricinoleic, 12-hydroxystearic), U.S Producers: Caschem, Union Camp [R6, 184] OMIN: *PRESSING REMOVES BETWEEN 70 AND 90% OF...OIL FROM BEAN... [R7] *THE CASTORBEAN (RICINIS COMMUNIS).../YIELDS/ APPROX 50% CASTOR OIL... [R8] *Castor oil, prepared by cold-pressing the seeds is bland and innocuous when applied to the eye. However, both the original seed and the residue after pressing contain a highly toxic substance, ricin, which is not present in the oil. [R9] *FIXED OIL OBTAINED BY COLD-PRESSING THE SEEDS OF RICINUS COMMUNIS L, EUPHORBIACEAE. TRIGLYCERIDE OF FATTY ACIDS. FATTY ACID COMPOSITION IS APPROX RICINOLEIC 87%, OLEIC 7%, LINOLEIC 3%, PALMITIC 2%, STEARIC 1%, AND DIHYDROXYSTEARIC TRACE AMT: BINDER ET AL, J AM OIL CHEM SOC 39, 513 (1962). [R10] *FEMA NUMBER: 2263 [R11] USE: *For Castor oil (USEPA/OPP Pesticide Code: 031608) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R12] *CASTOR OIL HAS BEEN REPORTED USED IN FOLLOWING: NON-ALCOHOLIC BEVERAGES: 1.5-140 PPM, ICE CREAM, ICES, ETC: 3.0-540 PPM; CANDY: 3.0-410 PPM; BAKED GOODS: 210 PPM [R13] *MEDICATION *MEDICATION (VET) *As an industrial raw material for the prepn of chemical derivs used in coatings, urethane derivs, surfactants and dispersants, cosmetics, lubricants; chief raw material for the production of sebacic acid, a basic ingredient in the production of synthetic resins and fibers; as lubricant in metal drawing, machine lubrication and 2-cycle engine fuels, in hydraulic fluids, rubber preservative and mold lubricants; constituent of embalming fluids; in soap manuf; to impart emollient and lubricant properties to cosmetic prepns; as Turkey-red oil (sulfated castor oil) for dyeing and finishing textiles; as dehydrated castor oil in alkyds, resinous copolymers, varnishes, oil-based paints, enamels, caulks and putties; as blown oil (oxidized oil) for plasticizing oilcloth, artificial leather, coated fabrics, and lacquers, to plasticize rosin in the manuf of sticky fly-paper, for nitrocellulose and similar coating systems, hot melts, duplicating and stencil inks, adhesives and laminants; as release and anti-sticking agent in hard candy manuf. [R5, 311] *Prodn of elastomers, fatty acids, electrical insulating compd [R2] *IN MFR OF FUNGICIDES /DEHYDRATED CASTOR OIL/ [R7] *PLASTICIZER IN NITROCELLULOSE LACQUER; CHEM INT FOR HEPTALDEHYDE, UNDECYLENIC ACID AND 2-OCTYL ALCOHOL [R1] *Used as a chemical intermediate for the synthesis of: alkyd resins, non-drying; castor oil, blown; castor oil, dehydrated; castor oil, hydrogenated; castor oil, sulfated; castor oil ethoxylates; factice; glycerol monoricinoleate; methyl ricinoleate; polyurethane, low-resilience elastomers; ricinoleic acid [R14] *Air-blown castor oil is used as a plasticizer for varnishes and polymers. The oil is used in the production of transparent soap, textile processing aids, special lubricants, and toiletries. [R3] *Another cosmetic application of aluminum compounds is as lakes for lipstick manufacture...These lakes are mixed with castor oil, finely ground, and used as lipstick ingredients. [R15] *Castor oil is used as a defoamer in industrial processes. [R16] CPAT: *7% IN RESINS AND PLASTICS; 6% FOR DEHYDRATED CASTOR OIL USED AS A DRYING OIL IN PAINTS AND VARNISHES; 5% IN LUBRICANTS AND SIMILAR OILS; 2.5% AS CHEM INT FOR FATTY ACIDS; and 79.5% FOR AL OTHER USES (1973) [R1] *Paint (includes caulks and sealants), 40%; Lubricants, 30%, Textiles (includes sulfated castor oil), 20%; Plasticizers and Synthetic Lubricants, 5%; Urethanes, 3%; Cosmetics and Pharmaceuticals, 2% (1984) [R17] PRIE: U.S. PRODUCTION: *(1972) 1.36X10+9 GRAMS [R1] *(1975) 4.54X10+8 GRAMS [R1] *(1984) No current US production [R17] U.S. IMPORTS: *(1972) 4.45X10+10 GRAMS [R1] *(1975) 3.12X10+10 GRAMS [R1] *(1984) 3.54X10+10 g [R17] U.S. EXPORTS: *(1972) 1.51X10+9 G-INCL PALM AND PALM KERNEL OIL [R1] *(1975) 2.42X10+9 G-INCL PALM AND PALM KERNEL OIL [R1] *(1984) 1.93X10+9 g /Castor oil, palm, and palm kernel oil, unmixed/ [R18] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Pale-yellowish or almost colorless, transparent, viscous liquid [R2] ODOR: *Slight, somewhat characteristic odor [R5, 312] TAST: *The crude oil tastes slightly acrid with a decidedly nauseating after-taste. [R5, 312] BP: *313 DEG C [R19] DEN: *0.961-0.963 @ 15.5 deg C/15.5 [R5, 312] SOL: *Sol in absolute ethanol, methanol, ether, chloroform, and glacial acetic acid. [R5, 312]; *Sol in benzene, carbon disulfide [R2]; *INSOL IN WATER [R19] SPEC: *Dextrorotatory (undil in sodium light) [R5, 312]; *Index of refraction: 1.473-1.477 @ 25 deg C/D; 1.466-1.473 @ 40 deg C/D [R5, 312] SURF: *At 20 deg C: 39.0 dynes/cm; at 80 deg C: 35.2 dynes/cm [R5, 312] VISC: *At 25 deg C: 6-8 poises, also expressed as U +/- 1/2 (Gardner-Holdt scale) [R5, 312] OCPP: *Weight of technical grades: 8.1 to 8.9 lb/gallon; solidifies: -10 deg C to -18 deg C; acid value: less than 4; saponification number 176-187; iodine number (Wijs'): 81-91; Reichert-Meissl value: less than 5; Polenske value: less than 0.5; acetyl value: 144-150; hydroxyl value: 161-169; dissolves in its own vol of petroleum ether or 95% alcohol; does not dissolve to any extent in mineral oil, unless mixed with another vegetable oil; when heated to 300 deg C for several hours it polymerizes and becomes miscible. [R5, 312] *Non-drying oil [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat. Spontaneous heating may occur. [R20] NFPA: *Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R21] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R21] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R21] FLPT: *445 DEG F (229 DEG C) (CLOSED CUP) [R21] *445 deg F (closed cup) [R20] AUTO: *840 DEG F (449 DEG C) [R21] FIRP: *To fight fire, use /carbon dioxide/, dry chemical, fog, mist. [R20] SERI: *A human skin and eye irritant. [R20] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *HAS EXCELLENT KEEPING QUALITIES, DOES NOT TURN RANCID UNLESS SUBJECTED TO EXCESSIVE HEAT [R10] STRG: *CASTOR OIL EMULSIONS SHOULD BE PROTECTED FROM FREEZING. [R22] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *A PURGATIVE, OFTEN CAUSING GRIPING... PRODUCES PELVIC CONGESTION AND MAY INDUCE ABORTIONS. FATAL DOSE UNKNOWN BUT PRESUMABLY IT IS LARGE. [R23] *An allergen. [R20] NTOX: *HIGH DOSES MAY CAUSE GRIPING IN CATS AND DOGS. [R24] ADE: *THE EXTENT OF GI ABSORPTION...IS UNKNOWN. [R22] *...SOME ABSORPTION OF ITS INTESTINAL METABOLITES OCCURS BEFORE THE INTESTINE IS CLEARED. [R25] *RICINOLEATE, LIKE OTHER ANIONIC SURFACTANTS, REDUCES NET ABSORPTION OF FLUID AND ELECTROLYTES AND STIMULATES INTESTINAL PERISTALSIS. RICINOLEIC ACID ALSO IS ABSORBED IS METABOLIZED LIKE OTHER FATTY ACIDS. [R26, 924] METB: *WITHIN THE SMALL INTESTINE, ... PANCREATIC LIPASES HYDROLYZE THE OIL TO GLYCEROL AND RICINOLEIC ACID. RICINOLEATE, LIKE OTHER ANIONIC SURFACTANTS, REDUCES NET ABSORPTION OF FLUID AND ELECTROLYTES AND STIMULATES INTESTINAL PERISTALSIS. RICINOLEIC ACID ALSO IS ABSORBED IS METABOLIZED LIKE OTHER FATTY ACIDS. [R26, 924] ACTN: *CASTOR OIL HAS BEEN CLASSIFIED AS A STIMULANT BECAUSE LIPOLYSIS IN SMALL INTESTINE LIBERATES RICINOLEIC ACID.../WHICH/ STIMULATES SMOOTH MUSCLE AND INHIBITS ABSORPTION OF WATER AND ELECTROLYTES RESULTING IN FLUID ACCUMULATION IN VITRO, BUT IT IS NOT KNOWN WHETHER THESE CHANGES AFFECT FLUID MOVEMENT OR...LAXATIVE EFFECT IN VIVO. [R27] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *2(?). 2= SLIGHTLY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN): 5-15 G/KG, BETWEEN 1 PINT AND 1 QUART FOR 70 KG PERSON (150 LB). [R23] THER: *Cathartics; Emollients; Pharmaceutic Aids [R28] *...IT IS USUALLY ADMIN ONLY WHEN PROMPT, THOROUGH EVACUATION OF THE BOWEL IS DESIRED, AS IN PREPN FOR CERTAIN RADIOLOGICAL EXAMINATIONS. [R26, 925] *THE USUAL CATHARTIC DOSE /OF CASTOR OIL/ (IN ADULTS, 15-60 ML ON AN EMPTY STOMACH) PRODUCES ONE OR TWO COPIOUS AND SEMIFLUID STOOLS WITHIN 1-6 HR. THUS, CASTOR OIL SHOULD NOT BE TAKEN LATE IN THE DAY WITH THE EXPECTATION OF SLEEPING. [R26, 924] *IF CHILLED CASTOR OIL IS TAKEN WITH FRUIT JUICE OR A CARBONATED BEVERAGE IS CONSUMED IMMEDIATELY THEREAFTER, TOLERANCE IS IMPROVED. NEOLOID, A MINT-FLAVORED EMULSION OF CASTOR OIL, ALSO MAY BE MORE PALATABLE. [R27] *IT IS FREQUENTLY USED TO EMPTY THE GI TRACT OF GAS AND FECES PRIOR TO PROCTOSCOPY OR X-RAY STUDIES OF GI TRACT. ...SOMETIMES EMPLOYED TO INITIATE LABOR AT TERM. HYPEREMIA OF INTESTINAL TRACT CAUSES REFLEX STIMULATION OF UTERUS. [R29] *NO HARM RESULTS IF THIS DOSE (USUALLY 15 ML) IS EXCEEDED INASMUCH AS THE CATHARTIC ACTION OF THE FIRST PORTION OF THE OIL SWEEPS THE REMAINING OIL THROUGH INTESTINAL TRACT. [R29] *MEDICATION (VET): PRIMARILY AS A LAXATIVE OR PURGATIVE IN NON-RUMINANTS OR YOUNG RUMINANTS, WHERE SAPONIFICATION IN SMALL INTESTINE HELPS PRODUCE A SMALL AMT OF AN IRRITANT SODIUM RICINOLEATE SOAP WHICH PRODUCES MOST OF DESIRED EFFECT. THIS OCCURS WITHIN APPROX 4-6 HR IN DOGS AND LONGER...IN LARGE ANIMALS (12 HR IN CALVES AND FOALS). [R24] *MEDICATION (VET): THE BALANCE OF THE OIL PRODUCES BULK ENHANCING AND LUBRICATING EFFECTS. PART OF THIS IS DUE TO FORMATION OF GLYCERINE FROM HYDROLYSIS OF PART OF CASTOR OIL. STILL POPULAR ORAL TREATMENT OF CALVES AND FOALS FOR MECONIUM RETENTION. [R24] *MEDICATION (VET): THE SOAP HAS PROTECTED GUINEA PIGS AGAINST LETHAL DOSES OF TETANUS AND DIPHTHERIA TOXINS. THUS, BILE SAPONIFICATION AND THE FORMATION OF ALKALINE FATTY ACID ESTERS ARE A NORMAL HOST DEFENSE AGAINST EXOTOXINS (PROTEIN IN NATURE) BUT INEFFECTIVE AGAINST ENDOTOXINS (POLYSACCHARIDES). [R24] *MEDICATION (VET): EXTERNALLY, IT IS USED LIKE OTHER BLAND OILS IN ZINC OXIDE-TYPE OINTMENTS, ULCER THERAPY, AND TO AID EPITHELIAZATION OF BURN-LIKE LESIONS WITHOUT DESSICATION AND CORNIFICATION. ALONE OR WITH THUJA BY DAILY APPLICATION FOR THE REMOVAL OF TEAT WARTS ON COWS. [R24] *MEDICATION (VET): TOPICALLY, AS A CORNEAL PROTECTANT AFTER FOREIGN BODY INJURIES, AND AS A VEHICLE FOR PROLONGED ACTION OF ALKALOIDS SUCH AS COCAINE AND ATROPINE ON THE EYE. [R24] WARN: *CASTOR OIL IS CONTRAINDICATED IN PREGNANT OR MENSTRUATING WOMEN. [R22] *... SHOULD NOT BE TAKEN LATE IN THE DAY WITH THE EXPECTATION OF SLEEPING. [R26, 924] *SENSITIVITY TO CASTOR OIL WHEN USED MEDICINALLY IS EXTREMELY RARE, ONLY ONE CASE HAVING BEEN REPORTED IN THE LITERATURE. [R7] *FATAL DOSE UNKNOWN BUT PRESUMABLY IT IS LARGE. [R23] *THE ALTERED INTESTINAL PERMEABILITY CAUSED BY CASTOR OIL MAY REFLECT GROSSER MORPHOLOGICAL DAMAGE TO THE INTESTINAL EPITHELIUM. THE STRONG PURGATIVE ACTION CAN CAUSE COLIC AS WELL AS DEHYDRATION WITH ELECTROLYTE IMBALANCE. FOR THESE REASONS AND BECAUSE OF POSSIBLE REDUCTION OF THE ABSORPTION OF NUTRIENTS, LONG-TERM USE OF CASTOR OIL MUST BE AVOIDED. [R26, 924] *THIS STRONG CATHARTIC SHOULD NOT BE USED TO TREAT COMMON CONSTIPATION. [R27] *VET: CONTRAINDICATED IN CHRONIC CONSTIPATION. [R24] *VET: /SAPONIFICATION OF CASTOR OIL IN SMALL INTESTINE/...PRODUCES A SMALL AMT OF AN IRRITANT SODIUM RICINOLEATE SOAP... THIS SOAP CAN BE ABSORBED AND ELIMINATED IN MILK PRODUCING SECONDARY EFFECTS ON NURSING OFFSPRING. [R24] *THE COLON IS EMPTIED SO COMPLETELY THAT PASSAGE OF NORMAL STOOL MAY BE DELAYED FOR TWO DAYS OR MORE. [R27] *CASTOR OIL CAUSES MORPHOLOGIC CHANGES IN SMALL INTESTINE AND INCR MUCOSAL PERMEABILITY. BECAUSE OF ITS STRONG ACTION, THE PT EXPERIENCES MORE COLIC AND MAY BE MORE VULNERABLE TO DEHYDRATION AND ELECTROLYTE IMBALANCE. [R27] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *SMALL TREES, UP TO 5 M (15 FT) HIGH IN THE TROPICS. THE LEAVES ARE LARGE, ALTERNATE, PELTATE, PALMATELY 5-12 LOBED...SEEDS ARE OVOID... ENDOSPERM...FLESHY AND OILY. THE PLANT THRIVES IN RICH, WELL DRAINED, SANDY OR CLAY LOAM; IT IS GROWN IN INDIA AND US. /RICINUS COMMUNIS L/ [R13] *Fixed oil obtained by cold-pressing seeds of Ricinis communis L., Euphorbiaceae [R5, 311] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *The food additive castor oil may be safely used in accordance with the following conditions: (a) The additive meets the specifications of the United States Pharmacopeia XX (1980). (b) The additive is used or intended for use as follows: Hard candy production - As a release agent and antisticking agent, not to exceed 500 ppm in hard candy. [R30] *Natural flavoring substances natural adjuvants may be safely used in food in accordanace with the following conditions. (a) They are used in the minimum quantity required to produce their intended physical or technical effect and in accordance with all the principles of good manufacturing practice. (b) In the appropriate forms (plant paarts, fluid and solid extracts, concretes, absolutes, oils, gums, balsams, resins, oleoresins, waxes, and distillates) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, previously sanctioned for such use, or regulated in any section of this part. Castor oil in included on this list. [R31] *Certification of this color additive when used as a diluent in color additive mixtures for food use is not necessary for the protection of the public health, and therefore batches thereof are exempt from the certification pursuant to section 721(c) of the act. [R32] *Castor oil is an indirect food additive for use only as a component of adhesives. [R33] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on the Toxicity Studies of Castor Oil in F344/N Rats and B6C3F1 Mice (Dosed Feed Studies). Toxicity Rpt Series No. 12 NIH Publication No. 92-3131 SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 221 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA10 (1987) 233 R4: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 982 R5: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R6: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V5 (1993) R7: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 269 R8: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 2. New York: Marcel Dekker, Inc., 1976. 124 R9: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 193 R10: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 242 R11: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 818 R12: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Castor oil (8001-79-4). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R13: Fenaroli's Handbook of Flavor Ingredients. Volume 1. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 312 R14: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 180 R15: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V2 (1992) 265 R16: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V7 (1993) 929 R17: CHEMICAL PRODUCTS SYNOPSIS: Castor Oil, 1984 R18: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.2-69 R19: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 325M-49 R20: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 681 R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-25 R22: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 56:12 R23: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-152 R24: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 87 R25: Hayes, W. J., Jr. Toxicology of Pesticides Baltimore: Williams and Wilkins, 1975. 397 R26: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R27: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. 982 R28: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R29: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 741 R30: 21 CFR 172.876 (4/1/2000) R31: 21 CFR 172.510 (4/1/2000) R32: 21 CFR 73.1 (4/1/2000) R33: 21 CFR 175.105 (4/1/2000) RS: 21 Record 162 of 1119 in HSDB (through 2003/06) AN: 1935 UD: 200303 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-SALICYLATE- SY: *ANALGIT-; *BENZOIC-ACID,-2-HYDROXY-,-METHYL-ESTER-; *BETULA-; *BETULA-OIL-; *EXAGIEN-; *FEMA-NUMBER-2745-; *FLUCARMIT-; *GAULTHERIA-OIL-; *GAULTHERIA-OIL,-ARTIFICIAL-; *O-HYDROXYBENZOIC-ACID,-METHYL-ESTER-; *2-HYDROXYBENZOIC-ACID-METHYL-ESTER-; *2-(METHOXYCARBONYL)PHENOL; *METHYL-O-HYDROXYBENZOATE-; *METHYL-2-HYDROXYBENZOATE-; *METYLESTER-KYSELINY-SALICYLOVE- (CZECH); *NATURAL-WINTERGREEN-OIL-; *Oil-of-Wintergreen-; *SALICYLIC-ACID,-METHYL-ESTER-; *SWEET-BIRCH-OIL-; *SYNTHETIC-WINTERGREEN-OIL-; *TEABERRY-OIL-; *WINTERGREEN-OIL-; *WINTERGREEN-OIL,-SYNTHETIC- RN: 119-36-8 MF: *C8-H8-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...OIL IS WATER-STEAM DISTILLED FROM LEAVES CHARGED INTO THE STILL AND ALLOWED TO MACERATE FOR SEVERAL HR TO HYDROLYZE GAULTHERIN GLUCOSIDE (METHYL SALICYLATE + GLUCOSE). DISTILLATION FROM 5-6 HR YIELDS APPROXIMATELY 0.7% ESSENTIAL OIL. OFTEN ADULTERATED BY CO-DISTILLING SWEET BIRCH BARK. [R1, 490] *MOSTLY PREPD BY ESTERIFICATION OF SALICYLIC ACID WITH METHANOL. PRODUCT OF COMMERCE IS ABOUT 99% PURE. [R2] FORM: *USP: LINIMENT, COMPOUND: MENTHOL 4.5 G, CAMPHOR OIL RECTIFIED 25 ML, OLIVE OR PEANUT OIL 30 ML, METHYL SALICYLATE TO MAKE 100 ML. OINTMENT, COMPOUND: METHYL SALICYLATE 10 ML, MENTHOL 10 G, WHITE WAX 5 G, HYDROUS WOOL FAT TO MAKE 100 G. [R3] *USP: SPIRIT, PHENOLATED (PODIATRY): LIQUEFIED PHENOL 1 ML, METHYL SALICYLATE 3 ML, COMPOUND MYRCIA SPIRIT 25 ML, ALCOHOL RUBBING COMPOUND TO MAKE 100 ML. [R3] *GRADES: TECHNICAL; USP; FCC. [R4] MFS: *Dow Chemical USA, 2020 Dow Center, Midland, MI 48674, (517) 636-1000 [R5] *Kalama Chemical Inc, Hq, The Bank of California Center, Suite 1110, Seattle, WA 98164, (206) 682-7890; Production site: Garfield, NJ 07026 [R5] *Penta Manufacturing Co, PO Box 1448, Fairfield, NJ 07007, (201) 740-2300 [R5] *Rhone-Poulenc Inc, Hq, CN 5266, Princeton, NJ 08543-5266, (908) 297-0100; Rhone-Poulenc Specialty Chemicals Div, Fine Organics Business Group, Prospect Palins Rd, CN-7500, Cranbury, NJ 08512, (609) 860-4000; Production site: St Louis, MO 63104 [R5] OMIN: *WINTERGREEN: DESCRIPTION OF BOTANICAL SOURCE: EVERGREEN SHRUB WITH SLENDER, CREEPING STEMS, ASSURGENT, FLOWERING BRANCHES WITH LEAVES CLUSTERED AT TOP, WHITE, BELL-SHAPED FLOWERS BLOSSOMING IN JULY-AUGUST, FOLLOWED BY RED BERRIES (CHECKERBERRY). ...IN WOODS OF CANADA AND US. [R1, 489] *VET: NATURAL AND SYNTHETIC GRADES ARE USED INTERCHANGEABLY. [R6] *METHYL SALICYLATE MUST BE LABELED TO INDICATE WHETHER IT WAS MADE SYNTHETICALLY OR DISTILLED FROM...PLANTS... [R7] *IN USP, GAULTHERIA OIL, BETULA OIL, AND METHYL SALICYLATE ARE COMBINED UNDER SAME TITLE...IT IS DIFFICULT TO DISTINGUISH BETWEEN THEM CHEMICALLY AND...SAME TEST APPLY TO ALL. ...SLIGHT DIFFERENCES IN SPECIFIC GRAVITY AND OPTICAL ACTIVITY BUT THESE FACTORS ARE NOT SUFFICIENTLY CHARACTERISTIC TO ENABLE DETECTION OF EITHER IN MIXT. [R7] USE: *OIL: IN FERN AND CYPRESS TYPE PERFUMES AND IN TOOTHPASTE [R1, 490] *MEDICATION (VET) *MEDICATION *UV-absorber in sunburn lotions; flavor in foods, beverages, pharmaceuticals; odorant [R8] *CHEWING GUM; FRAGRANCE IN DETERGENTS; SOLVENT FOR INSECTICIDES, POLISHES, AND INKS [R9] *REPORTED USES: ... NON-ALCOHOLIC BEVERAGES 10 PPM; CANDY 900-5000 PPM. [R1, 490] *In perfumery as a modifier in blossom fragrances and as a mild antiseptic in oral hygiene products [R10] */Medication:/ As a pharmaceutical, it is used in liniments and ointments for the relief of pain in the lumbar and sciatic regions, and for rheumatic conditions ... other misc applications for methyl salicylate are as a dye carrier, UV light stabilizer in acrylic resins, and chem intermed [R11] *AS PHARMACEUTICAL NECESSITY, IT IS USED TO FLAVOR OFFICIAL AROMATIC CASCARA SAGRADA FLUID EXTRACT ... . [R7] PRIE: U.S. PRODUCTION: *(1976) 1.27X10+8 G (MIN CONSUMPTION IN FOODS) [R9] *(1978) 4.09X10+7 G (CONSUMPTION AS FRAGRANCE) [R9] U.S. IMPORTS: *(1977) 8.19X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R9] *(1979) 4.58X10+7 GRAMS [R9] *(1985) 3.43X10+8 g [R12] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS, YELLOWISH OR REDDISH, OILY LIQ [R2] ODOR: *LIQUID HAVING THE CHARACTERISTIC ODOR OF WINTERGREEN [R13] TAST: *LIQUID HAVING THE CHARACTERISTIC TASTE OF WINTERGREEN [R13] BP: *220-224 DEG C [R2] MP: *-8.6 DEG C [R2] MW: *152.14 DEN: *1.184 @ 25 DEG C/25 DEG C [R2] DSC: *pKa = 9.8 [R14] HTC: *-902.2 kcal/mole @ 25 deg C [R15] HTV: *11.155 kcal/mol @ the boiling point [R15] OWPC: *Log Kow = 2.55 [R16] SOL: *SOL IN CHLOROFORM, ETHER; MISCIBLE WITH ALC, GLACIAL ACETIC ACID [R2]; *SOL IN DIETHYL ETHER [R17, 76]; *SOLUBLE IN MOST COMMON ORGANIC SOLVENTS [R18]; *Sol in water: 0.74%w @ 30 deg C [R15] SPEC: *INDEX OF REFRACTION: 1.5369 AT 20 DEG C/D; MAX ABSORPTION: 306 NM (LOG E= 3.64); SADTLER REFERENCE NUMBER: 2238 (IR, PRISM); MAX ABSORPTION (ALC): 238 NM (LOG E= 3.97) [R19]; *Intense mass spectral peaks: 65 m/z, 92 m/z, 120 m/z, 152 m/z [R20] SURF: *44.2 dynes/cm @ -19.8 deg C; 19.8 dynes/cm @ 212.2 deg C [R15] VAPD: *5.2 [R21, 1896] VAP: *Vapor pressure = 0.0343 mm Hg @ 25 deg C [R22] OCPP: *DENSITY OF NATURAL ESTER IS ABOUT 1.180 [R2] *WINTERGREEN ESSENTIAL OIL: ESTER VALUE: 354-356; OPTICAL ROTATION: -0 DEG 25' TO -1 DEG 30' [R1, 490] *1 MM HG @ 54.0 DEG C [R23] *Heat capacity = 59.46 cal/deg K-mol @ 15-30 deg C [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME; CAN REACT WITH OXIDIZING MATERIALS. [R23] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and breathing protection is needed. [R24] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R24] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R24] FLPT: +205 Deg F (96 deg C) (Closed cup) [R24] AUTO: +850 DEG F [R24] FIRP: *WATER, FOAM, CARBON DIOXIDE, DRY CHEMICAL. [R23] REAC: *INCOMPATIBILITIES: DECOMP BY ALKALIES TO FORM METHYL ALC AND SALICYLATE. [R7] SSL: *SENSITIVE TO LIGHT AND HEAT [R17, 77] STRG: *METHYL SALICYLATE SHOULD BE STORED AND DISPENSED IN TIGHT CONTAINERS. [R3] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *THE LETHAL DOSE OF METHYL SALICYLATE IS CONSIDERABLY LESS THAN THAT OF SODIUM SALICYLATE. AS LITTLE AS 4 ML (4.7 G) OF METHYL SALICYLATE MAY BE FATAL IN CHILDREN. /METHYL SALICYLATE/ [R25, 651] *Symptoms of poisoning by methyl salicylate differ little from those described for aspirin. Central excitation, intense hyperpnea, and hyperpyrexia are prominent features. The odor of the drug can easily be detected on the breath and in the urine and vomitus. /Methyl salicylate/ [R25, 651] *In reviews of methyl salicylate poisoning, dimness of vision is mentioned as occurring in about 15% of all cases, but the nature of the impairment has been poorly characterized, and the impression is given that it is a manifestation of disturbance of the CNS. /Methyl salicylate/ [R26] *MILD CHRONIC SALICYLATE INTOXICATION IS TERMED SALICYLISM / and /...SYNDROME INCLUDES HEADACHE, DIZZINESS, RINGING IN EARS, DIFFICULTY IN HEARING, DIMNESS OF VISION, MENTAL CONFUSION, LASSITUDE, DROWSINESS, SWEATING, THIRST, HYPERVENTILATION, NAUSEA, VOMITING, AND OCCASIONALLY DIARRHEA. /SALICYLATES/ [R25, 651] *TOXIC EFFECTS SIMILAR TO OTHER SALICYLATES. HYPERPNEA, FOR WHICH PATIENT SHOULD BE CLOSELY OBSERVED, IS FIRST SIGN. THIS INITIAL HYPERVENTILATION MAY LEAD TO RESPIRATORY ALKALOSIS AND, IN SEVERE CASES FOLLOWED BY A METABOLIC ACIDOSIS. [R3] *Salicylates cross the placental barrier. A 33 week old fetus died in utero 20 hours after 3 g salicylate was ingested by the mother. The salicylate level of the mother was 568 mg/l at admission and 212 mg/l at the time fetal heart tones stopped. Autopsy blood from the fetus, which aborted 8 days later, was 243 mg/l. /Salicylates/ [R27, 564] *Generally, ingestion /of salicylates at/ doses larger than 150 mg/kg (or 70 mg/lb) can produce toxic symptoms such as tinnitus, nausea, and vomiting. Serious toxicity can be seen with ingestions greater than 400 mg/kg (approximately 180 mg/lb), with severe vomiting, hyperventilation, hyperthermia, confusion, coma, convulsions, hyper- or hypoglycemia, and acid-base disturbances such as respiratory alkalosis or metabolic acidosis. In severe cases, the clinical course may progress to pulmonary edema, hemorrhage, acute renal failure, or death. It is important to note that the salicylate-overdose patient can progress to a more serious condition over time as additional drug is absorbed from the gastrointestinal tract. Chronic salicylism presents clinically in a similar fashion to the acute situation, although it is often associated with a higher morbidity and mortality as well as more pronounced hyperventilation, dehydration, coma seizures, and acidosis. /Salicylates/ [R28] *Methyl salicylate (Oil of Wintergreen, Ben Gay) is one infrequent cause of salicylate poisoning but is the most dangerous salicylate formulation by strength. One teaspoon contains 7,000 mg of salicylate, equivalent to 21 aspirin tablets, and childhood fatalities may occur after ingestion of as little as 4 ml of Oil of Wintergreen. A 1 oz tube of external liniment (20% methyl salicylate) is equivalent to the above fatal dose of Oil of Wintergreen. When applied to large areas of skin, topical salicylic acid may cause sufficient dermal absorption to produce toxic serum salicylate levels. [R27, 562] *The ingestion of salicylate may result in epigastric distress, nausea, and vomiting. ... Salicylate may also cause gastric ulceration; exacerbation of peptic ulcer symptoms (heartburn, dyspepsia), gastrointestinal hemorrhage, and erosive gastritis have all been reported in patients on high dose therapy, but may occur rarely with low doses as a hypersensitivity response. Salicylate induced gastric bleeding is painless and may lead to an iron deficiency anemia. /Salicylates/ [R25, 646] *... Salicylates can cause retention of salt and water as well as acute reduction of renal function in patients with congestive heart failure or hypovolemia. /Salicylates/ [R25, 647] *There is no evidence that moderate therapeutic doses of salicylates cause fetal damage in human beings; however, babies born to women who ingest salicylates for long periods may have significantly reduced weights at birth. In addition, there is an increase in perinatal mortality, anemia, antepartum and postpartum hemorrhage, prolonged gestation, and complicated deliveries ... . /Salicylates/ [R25, 649] *The average lethal dose /SRP: 95-98% methyl salicylate/ for children is 10 ml, and for adults, 30 ml or 0.5 g/kg. [R29, 2309] *... One patient complained of dimness of vision and difficulty in hearing on first regaining consciousness after ingestion of 30 ml of methyl salicylate, after going through severe acidosis, coma, and convulsions, which were treated with iv amytal, sodium lactate, and calcium gluconate. Vision and hearing were said to have returned to normal within two weeks, but no actual measurements of visual acuity, visual fields or examination of the fundi were reported. [R26] *... /A/ patient, who took 24 ml of methyl salicylate in the course of 48 hr, complained of xanthopsia and inability to read. This patient was reported to have recovered in about five days after the drug was discontinued, but the reason for the inability to read was not explained. [R26] *A topically applied rubifacient delivered by aerosol (Deep-Heat) was studied. After spray application to the forearms of volunteers, without massage, the erythema produced was measured by thermography and correlated with the concentration of 2 salicylate components of the mixture found in local and systemic venous blood. Maximum erythema occurred at about 30 minutes, while blood salicylate levels were maximal between 20 and 30 minutes after application. Methyl salicylate was absorbed before ethyl salicylate. Over the time period of the erythematous response oxygen levels in local venous blood were raised. Finally, platelets collected from venous blood draining from the sprayed site, when induced to clump by the addition of arachidonic acid in an aggregometer, showed increased resistance to clumping when compared with control cells. [R30] NTOX: *METHYL SALICYLATE, GIVEN ORALLY BY CAPSULE TO DOGS AT RATE OF 1200 MG/KG/DAY, WAS FATAL IN 3-4 DAYS; 500-800 MG/KG/DAY WAS FATAL IN A MONTH; 350 MG/KG/DAY COULD BE FED FOR 2 YEARS CAUSING ONLY LOSS IN WEIGHT AND SOME ENLARGEMENT OF THE LIVER. [R31] *UNLIKE SALICYLATE SALTS, METHYL SALICYLATE DID NOT AFFECT FERTILITY AND FECUNDITY OF DAMS OR GROWTH AND VIABILITY OF PUPS IN 3-GENERATION FEEDING STUDY IN OSBORNE-MENDEL RATS. NO GROSSLY ABNORMAL PUPS WERE FOUND. [R32] *DRUG-INDUCED RENAL ABNORMALITY IS APPARENT HYDRONEPHROSIS IN OFFSPRING OF RATS EXPOSED TO METHYL SALICYLATE ON DAYS 10 and 11 OF GESTATION. IT ALSO CAUSED RETARDED RENAL DEVELOPMENT, PARTICULARLY GROWTH OF RENAL PAPILLA, AND INCR NUMBER OF RENAL ABNORMALITIES IN FETUSES. [R33] *Methyl salicylate was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Methyl salicylate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 1,000, 3,300,10,000, 33,300, 100,000, and 333,300 ug/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 333,000 ug/plate. [R34] *Methyl salicylate (MS) is teratogenic in animals and can be absorbed in toxic quantities by the dermal route. Consequently the dermal absorption and teratogenic potential of a petroleum-based grease (PBG) manufactured using methyl salicylate (3%) was assessed. The test material (petroleum based grease/methyl salicylate) was dermally applied at doses of either 0, 1, 3, or 6 g/kg/day to groups (N greater than or equal to 12) of pregnant rats on gestational days 6-15. Undiluted methyl salicylate was applied to the positive control group at a dose of 2 g/kg/day and was reduced to 1 g/kg/day on gestational days 10-15 due to maternal toxicity (ie, 25% mortality and severe dermal irritation). Positive control animals evidenced a 100% incidence of total resorptions. Urinalysis revealed very high concentrations of salicylic acid in the positive controls and that a significant proportion of the available methyl salicylate was absorbed from the petroleum based grease/methyl salicylate test material. However, the urinary concentrations of salicylic acid in petroleum based grease/methyl salicylate treated animals were far below the toxic levels observed in methyl salicylate treated animals. Despite the high doses of petroleum based grease/methyl salicylate, there were no signs of maternal toxicity (as measured by food consumption and body weight parameters or clinical signs) and no alterations in reproductive parameters. Fetal external and visceral examinations revealed no malformations or variations that were related to petroleum based grease/methyl salicylate treatment. These findings confirm the developmental toxicity of methyl salicylate and indicate that petroleum based grease/methyl salicylate was not a teratogenic hazard under these test conditions. The maternal and developmental No-Observable-Adverse-Effect-Level for petroleum based grease/methyl salicylate was greater than 6 g/kg/day. [R35] *Prenatal exposure to methyl salicylate on kidney function in rats were studied. Pregnant female Sprague Dawley rats were treated with methyl salicylate by intraperitoneal injections between gestational days 10 and 14. Functional assessments of renal toxicity included baseline urinary parameters, urine concentrating ability and in-vitro determination of the transport function of the renal cortex. Methyl salicylate exposure was teratogenic and embryotoxic. Prenatal exposure decreased fetal weight and increased the number of resorptions, fetal mortality, and the incidence of fetal malformations including ectopic kidneys. The primary postnatal renal defect associated with prenatal methyl salicylate treatment was a decreased urine concentrating ability in weanlings. [R36] *Methyl salicylate was administered topically to pregnant hamsters at 7 day 9 hr and the teratogenic results were compared with those obtained following oral treatment with the same compound. Both treatments produced the same defect in embryos recovered at day 9: failure of fusion of the neural tube, especially in the area of the developing brain. Analysis of serum salicylate levels following both treatments produced similar curves and indicated that teratogenic levels of salicylate can reach the maternal circulation after topical exposure. [R37] HTXV: *LDLO Child oral 0.17 g/kg; LD50 Adult oral 0.5 g/kg [R29, 2310] NTXV: *LD50 Rat oral 0.887 g/kg; [R29, 2310] *LD50 Rabbit oral 2.8 g/kg; [R29, 2310] *LD50 Guinea pig oral 1.060 g/kg; [R29, 2310] *LD50 Dog oral 2.1 g/kg; [R29, 2310] *LD50 Guinea pig dermal 0.70 ml/kg; [R29, 2310] NTP: +Methyl salicylate (MS) ... was tested to update and expand the reproductive toxicity database, and used, in part, as a known positive: this is the second of two simultaneous studies conducted at different labs, using the RACB protocol and Swiss mice. Food and water consumptions, clinical signs, and body weights were used in the Task 1 dose-range-finding study to set doses for the continuous cohabitation phase (Task 2) at 25, 50, and 100 mg/kg/day by gavage in corn oil. Deaths occurred at a rate of 2, 1, 5, and 3 mice in the control to high dose groups, respectively. Some of these deaths were apparently due to gavage trauma; the cause of death was not determined in the remaining cases. MS exposure had no effect on parental body weights or clinical signs. There was no adverse effect of MS exposure on the reproductive endpoints measured in Task 2. Since there were no treatment-related changes, no Task 3 was conducted. The last litter in Task 2 from the control and high dose groups was reared by the dams until weaning (/postnatal day/ 21), and then dosed with MS until the Task 4 mating at nearly =/postnatal day/ 74. There were no reductions in pup viability or weight during nursing, and no differences between treated and control mice before and during the wk of mating in Task 4. In the single mating that comprises Task 4, there were no MS-related changes in the number of pups/litter, their viability or sex ratio, or their body weight adjusted for litter size. After the F2 litters were evaluated, all animals were killed, and the F1 adults necropsied. For males and females, there were no effects on body weights or organ weights. The % motile, density, and % morphologically abnormal endpoints were all unchanged for epididymal sperm. No estrous cyclicity evaluation was performed. At the doses used for this study (which were 20% the dose used in the previous positive study), MS caused no adverse effects on body weight or reproductive indices in either the first or second generation. [R38] +Methyl salicylate (MS) ... was tested to update and expand the reproductive toxicity database, and used, in part, as a known positive: it was simultaneously tested by two different labs at different doses, using the RACB protocol and Swiss mice. Food and water consumptions, clinical signs, and body weights were used in the Task 1 dose-range-finding study to set doses for the continuous cohabitation phase (Task 2) at 100, 250, and 500 mg/kg/day by gavage in corn oil. Deaths occurred at a rate of 3, 2, 2, and 4 mice/group in the control to high dose groups, respectively. The causes of death varied, and were ultimately not considered due to MS exposure. There were no effects of MS exposure on body weights during Task 2. There was a 9% reduction in the mean number of litters/pair at the high dose, and a 31% reduction in the number of live pups/litter (from a control value of 11.3, to 7.8 pups/litter). While the viability and sex ratio of these pups was not altered, the pup weight adjusted for litter size in the middle and high dose groups was decreased by 3% and 6%, respectively. MS exposure increased the time to deliver each litter in the high dose group, starting with the second litter, by 2-3 days. These effects led to Task 3 in an attempt to define the affected sex using the control and high dose groups. MS exposure caused no discernible effects on the proportion of pairs mating or delivering pups, nor on the number, viability, or adjusted weight of those pups. Because only 5 of 17 control X control pairs delivered any young, Task 3 was repeated. Though 7 of 17 pairs delivered young, the same lack of MS effects were observed as in the first trial. It was decided that the animals should be killed and discarded. No necropsy was performed, and the second generation was not evaluated. In summary, MS exposure, at dose levels that did not alter body weight or produce adverse clinical signs, adversely affected reproduction (reduced numbers of litters/pair, and number of pups/litter) in Swiss mice. [R39] ADE: *MAY BE ABSORBED RAPIDLY THROUGH INTACT SKIN. BOWEL ABSORPTION IS SOMEWHAT ERRATIC ... ABSORBED AT LEAST IN PART AS THE INTACT ESTER AND SMALL AMT ARE EVEN EXCRETED AS SUCH BY THE KIDNEYS ... . [R40] *HUMAN SUBJECTS WERE GIVEN 7 MG/KG OF METHYL SALICYLATE BY MOUTH. AFTER 0.25 HOURS THE BLOOD CONCN WAS 1.28 MG%. AFTER 1.5 HOURS THE BLOOD CONCN WAS 1.33 MG%. /FROM TABLE/ [R17, 362] *At therapeutic doses, conjugation accounts for most salicylic elimination, whereas renal elimination becomes more important with large or multiple doses. A substantial first-pass effect occurs at therapeutic doses. /Salicylates/ [R27, 563] *Orally ingested salicylates are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. Appreciable conc are found in plasma in less than 30 min; after a single dose, a peak value is reached in about 2 hr and then gradually declines. /Salicylates/ [R25, 649] *After absorption, salicylate is distributed throughout most body tissues and most transcellular fluids, primarily by pH dependent passive processes. Salicylate is actively transported by a low-capacity, saturable system out of the CSF across the choroid plexus. The drug readily crosses the placental barrier. /Salicylates/ [R25, 649] *Salicylates are excreted in the urine as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl (5%) glucuronides, and gentisic acid (less than 1%). However, excretion of free salicylate is extremely variable and depends upon both the dose and the urinary pH. In alkaline urine, more than 30% of the ingested drug may be eliminated as free salicylate, whereas in acidic urine this may be as low as 2%. /Salicylates/ [R25, 650] METB: *...EVIDENCE THAT CONSIDERABLE HYDROLYSIS OF ESTER OCCURS IN INTESTINAL TRACT... IN SOME SPECIES, SUCH AS RABBIT, MAY BE PARTLY EXCRETED AS SULFATE OR GLUCURONIC ACID CONJUGATE ON THE FREE HYDROXYL GROUP. CONJUGATION APPEARS TO TAKE PLACE BEFORE HYDROLYSIS OF THE METHYL ESTER. [R21, 1899] *For small doses 80% of the hepatic metabolism results from conjugation with glycine to form salicyluric acid and with glucuronic acid to form salicyl acyl and phenolic glucuronide. The two parallel pathways (glycine, glucuronide conjugation) have limited capacity and saturate easily above therapeutic doses. /Salicylates/ [R27, 563] *The biotransformation of salicylates takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. The three chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small fraction is oxidized to gentisic acid (2,5-dihydroxybenzoic acid) and to 2,3-dihydroxybenzoic and 2,3,5-trihydroxybenzoic acids; gentisuric acid, the glycine conjugate of gentisic acid, is also formed. /Salicylates/ [R25, 649] BHL: *The plasma half-life for ... salicylate is 2 to 3 hr in low doses and about 12 hr at usual antiinflammatory doses. The half-life of salicylate may be as long as 15 to 30 hr at high therapeutic doses or when there is intoxication. /Salicylates/ [R25, 650] INTC: *... The prolonged and excessive ingestion of analgesic mixtures containing salicylates in combination with acetaminophen or salicylamide can produce papillary necrosis and interstitial nephritis. /Salicylates/ [R25, 647] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *4= VERY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG, BETWEEN 1 TEASPOON AND1 OZ FOR 70 KG PERSON (150 LB). [R40] THER: *OINTMENTS OR LINIMENTS CONTAINING METHYL SALICYLATE ARE APPLIED TOPICALLY AS COUNTERIRRITANTS FOR RELIEF OF PAIN ASSOCIATED WITH LUMBAGO, SCIATICA, AND RHEUMATIC CONDITIONS. FORMERLY USED INTERNALLY IN SMALL DOSES AS A CARMINATIVE. [R3] *MEDICATION (VET): ORALLY, PRIMARILY AS FLAVORING AGENT OR AS CARMINATIVE; TOPICALLY, AS IRRITANT OR COUNTERIRRITANT AIDED BY MASSAGE OR RUBBING AS IN UDDER OINTMENTS (1-3% CONCN), POULTICES AND COUNTERIRRITANT MIXT (@ LEAST 5-10%) OVER SORE JOINT, MUSCLE, AND BONE AREAS. [R6] *LOCAL ANALGESIC FOR HUMAN AND VETERINARY MEDICINE [R9] WARN: *OINTMENTS OR LINIMENTS ... . SHOULD NOT BE APPLIED TO BURNED AREAS OR TO OTHERWISE DAMAGED SKIN...USUALLY IN CONCN FROM 10-25% ... . [R3] *ABSORPTION OF METHYL SALICYLATE CAN OCCUR THROUGH THE SKIN, AND DEATH HAS RESULTED FROM SYSTEMIC POISONING FROM THE LOCAL MISAPPLICATION OF THE DRUG. IT IS A COMMON PEDIATRIC POISON, AND ITS USE SHOULD BE STRONGLY DISCOURAGED. [R25, 653] *Children with fever and dehydration are particularly prone to intoxication from relatively small doses of salicylate. ... The use of aspirin is contraindicated in children and adolescents with febrile viral illnesses because of the risk of Reye's syndrome. /Salicylates/ [R25, 651] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl salicylate is produced in significant quantities and may be released to the environment during its production, transport, disposal, and use in perfumes and sunburn lotions and in foods, beverages and pharmaceuticals. It is also a plant volatile and will be released by some plants. In soil, methyl salicylate is likely to biodegrade. In alkaline soil, chemical hydrolysis may contribute to its disappearance. It may also undergo direct photolysis on the soil surface. Methyl salicylate is expected to be fairly mobile in soil. It should partially volatilize from dry soil. If released in water, methyl salicylate should slowly volatilize (half-life 49 days in a model river), biodegrade, and be lost as a result of direct photolysis and photooxidation in surface waters. In alkaline water, hydrolysis may also be a significant fate process (estimated half-life 14 days at pH 7.5). Methyl salicylate is not likely to bioconcentrate in aquatic organisms. Methyl salicylate will react with photochemically-produced hydroxyl radicals in the atmosphere resulting in as estimated half-life of 1.4 days. It is fairly soluble in water and may be washed out by rain. Exposure to methyl salicylate will be via ingestion of foods and dermal contact with various consumer products. Occupational exposure will probably be via dermal contact and inhalation. (SRC) NATS: *Methyl salicylate occurs in the leaves of Gaulteria procumbens L. Ericacae, in the bark of Betula lenta L. Betulaceae(1) and in the leaves of Burnum dilitatum(2). It was tentatively identified in emissions from agricultural and natural plant species in the San Joaquin and Sacramento Valley in California(3). [R41] ARTS: *Methyl salicylate may be released to the environment in effluent and emission as a result of its production, transport, disposal and use as a flavoring in foods, beverages, pharmaceuticals(1) and dentrifices(2), fragrance agent in cosmetics and perfumes(2), UV-absorber in sunburn lotions(1) counterirritant in some ointments and linaments(3), carrier for fabric dyes and UV stabilizer in acrylic resins(2). [R42] FATE: *TERRESTRIAL FATE: If released on soil, methyl salicylate would readily leach. It would also be expected to partially volatilize from dry soil and photolyze on the soil surface. Based on the results of sceening tests, it would be expected to readily biodregrade. Chemical hydrolysis may be important in alkaline soil. (SRC) *AQUATIC FATE: Methyl salicylate is readily biodegradable in screening tests and may be expected to biodegrade in surface waters. Methyl salicylate is expected to hydrolyze in water, the hydrolysis rate increasing with pH. At pH 7.5, its hydrolysis half-life is estimated to be 14.1 days(1,2,SRC). Methyl salicylate will react with singlet oxygen in natural surface waters resulting in a half-life of about 52 hr(3). Methyl salicylate absorbs UV radiation > 290 nm and therefore may undergo direct photolysis under environmental conditions. Based on an estimated Henry's Law constant of 9.3X10-7 atm-cu-m/mol(4,5,SRC), a volatilization half-life of 49 days would be expected in a model river(SRC). [R43] *ATMOSPHERIC FATE: Methyl salicylate reacts with photochemically-produced hydroxyl radicals in the atmosphere resulting in an estimated half-life of 1.4 days(1,SRC). It is fairly soluble in water, 7400 mg/L(2) and may be washed out by rain. [R44] BIOD: *Methyl salicylate in a five day BOD test exhibited a value of 55-57% of the theoretical BOD(1,2). Another 5-day BOD determination yielded 65% of the theoretical BOD(3). Methyl salicylate was completely degraded by a microbial mixture when incubated for 7 days at 30 deg C(4). Significant biodegradation of methyl salicylate in the environment would be expected from this result; however no data concerning biodegradation in natural waters or soil could be located. [R45] ABIO: *Methyl salicylate hydrolyzes in water by acid and base-catalyzed reaction(3). The base-catalyzed rate constant can be estimated to be 4.0X10-2 L/mole-sec if the ortho consituents to the phenyl ring are ignored(4). The half-life of methyl salicylate calculated from this rate constant is 201 days at pH 8(SRC). A rate constant of 1.59X10(-5) sec(-1) was determined for the hydrolysis of methyl salicylate at pH 9.2 and a temperature of 25 deg C(1). A half-life of 12.1 hours was calculated from this rate constant(SRC). At pH 11.26 the hydrolysis rate constant was 3.62X10(-3) min(-1) at 24 C(2). A half-life value of 3.2 hours was calculated from this rate constant. Another investigator measured a hydrolysis half-life of 57 min at a pH of 9.48 and temperature of 44 deg C(5). Data from these studies indicate a general increase in rate constant with increasing pH as would be expected from abase-catalyzed reaction. Although the two first order rate constants do not lead to identical second order rate constants, an approximate half-life at pH 7.5 of 22 days can be estimated(SRC). [R46] *The UV absorption maximum of a methanol solution of methyl salicylate is 305 nm(1) which indicates that methyl salicylate can undergo direct photolysis. One photolysis study was performed which yielded a half-life of methyl salicylate in solution of about 48 min(2). The exact medium was not identified, but the authors stated that compounds with low water solubilities were dissolved in a 10% ethanol-water mixture. Based on the concentration of methyl salicylate which was used (3.5 g/L), and the water solubility of the ester of 7.4 g/L(3), it is likely that the result above was obtained using an ethanol-water mixture or absolute ethanol. The UV dose used in the study was 0.0077 erg/sq cm/min, and the UV wavelengths ranged from 300 nm to 400 nm with a maximum at 350 nm. Direct photolysis may, therefore, be an important degradative process in the environment; no available data, however, were collected under environmental conditions. [R47] *Methyl salicylate, which has a pKa of 9.8, reacts with singlet oxygen in water which is produced by sunlight absorbed by humic substances in natural surface waters(1). The rate of the ionized phenol is much greater than that of the neutral molecule and therefore the rate increases with pH. Assuming a steady state concentration of singlet oxygen of 4X10-14 moles/L (47 deg N latitude with noon summer sunlight), the half life of methyl salicylate is 52 hr(1). In the atmosphere, methyl salicylate reacts with photochemically-produced hydroxyl radicals with an estimated rate constant of 11.6X10-12 cu cm/molecule-s(2). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of methyl salicylate in the atmosphere would be 1.4 days(SRC). [R48] BIOC: *The log octanol/water partition coefficient for methyl salicylate is 2.55(1). The BCF estimated from this log Kow using a regression equation is 4 which indicates that the ester will not bioconcentrate in fish(SRC). [R49] KOC: *The Koc for methyl salicylate estimated from molecular structure is 128(1) and is 33(3,SRC) estimated from its water solubility, 7400 mg/L(2), using a regression equation. According to a suggested classification scheme(4), these low Koc values suggest that methyl salicylate would be highly or very highly mobile in soil(SRC). [R50] VWS: *The Henry's Law constant for methyl salicylate is 9.3X10-7 atm-cu-m/mol(SRC) calculated from its vapor pressure, 0.0343 mm Hg(1), and water solubility, 7400 mg/L(2). Using this value for the Henry's Law constant, one can estimate a volatilization half-life of 49 days in a model river 1 m deep flowing at 1 m/s with a wind speed of 3 m/s(3). Similarly, the volatilization half-life of methyl salicylate from a model lake 1 m deep, with a 0.05 m/s current and a 0.5 m/s wind is estimated to be 359 days. Methyl salicylate sprayed onto air-dried soil volatilizes rapidly(4). The amount of chemical that is adsorbed to the soil, evaporates more slowly by a diffusion-controlled mechanism(4). [R51] WATC: *SURFACE WATER: Methyl salicylate was identified in 2 surface water within the blast zone of Mount St Helens, WA, 3 months after the volcano erupted(1). In another surface water it was identified 2 months after the volcano erupted but not after 3 months(1). [R52] EFFL: *In a comprehensive survey of wastewater from 4000 industrial and publicly owned treatment works (POTWs) sponsored by the Effluent Guidelines Division of the U.S. EPA, methyl salicylate was identified in discharges of the following industrial category (positive occurrences, median concn in ppb): organics and plastics (2; 419), aluminum (3; 127), electronics (1; 29) and organic chemicals (2; 6.2)(1). The highest effluent concn was 1881 ppb in the organics and plastics industry(1). [R53] FOOD: *Methyl salicylate concentrations of 54 ppm in bakery goods, 840 ppm in candy, 59 ppm in non-alcoholic beverages, 8400 ppm in chewing gum, 27 ppm in ice cream and 200 ppm in syrups. Methyl salicylate has been identified as a volatile component of meat(2). [R54] *FLAVOR INGREDIENT, METHYL SALICYLATE...NON-ALCOHOLIC BEVERAGES 59 PPM; ICE CREAM, ICES, ETC 27 PPM; CANDY 840 PPM; BAKED GOODS 54 PPM; CHEWING GUM 8400 PPM; SYRUPS 200 PPM. [R18] RTEX: *The primary route of human exposure is the consumption of consumer products which contain methyl salicylate as a flavoring agent. Methyl salicylate is used in chewing gum, baked goods, syrups, candy, non-alcoholic beverages and ice cream. Other potential routes of exposure include dermal contact resulting from its use in perfumes. (SRC) *NIOSH (NOES Survey 1981-1983) has statistically estimated that 284,093 workers are exposed to methyl salicylate in the USA(1). Ninety five percent of exposures are with trade name products containing methyl salicylate(1). [R55] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of wintergreen oil are exempted from the requirement of a tolerance when used as a attractant in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R56] FIFR: *Residues of wintergreen oil are exempted from the requirement of a tolerance when used as a attractant in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *QUANTITATIVE FOR METHYL SALICYLATE OFFICIAL FINAL ACTION, GAS CHROMATOGRAPHY. [R57] *NMR PROCEDURE IS DESCRIBED FOR QUANTITATIVE DETERMINATION OF METHYL SALICYLATE AS DRUG ENTITY AND IN WINTERGREEN OIL. [R58] *CONCN OF SALICYLATES OR OTHER COMPLEXING AGENTS IN 26 SAMPLES OF 20 DIFFERENT FLAVORS WAS DETERMINED. COLORIMETRIC METHOD PROVIDING SENSITIVITY TO APPROX 1 PPM WAS USED. [R59] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 1. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 961 R3: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 84:2404 R4: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 578 R5: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 644 R6: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 360 R7: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1232 R8: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 781 R9: SRI R10: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 202 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V20 513 R12: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1985 p.1-564 R13: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 335 R14: Scully FE Jr, Hoigne J; Chemosphere 16: 681-94 (1987) R15: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 715 R16: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R17: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R18: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 406 R19: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-192 R20: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.210 R21: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R22: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R23: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 832 R24: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-72 R25: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R26: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 627 R27: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R28: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. 940 R29: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R30: Collins AJ et al; Ann Rheum Dis 43 (3): 411-5 (1984) R31: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 93 R32: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 649 R33: GIBSON E; ENVIRON HEALTH PERSPECTIVES 15: 121 (1976) R34: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R35: Infurna R et al; Teratology 41 (5): 566 (1990) R36: Daston GP et al; Fundam and Appl Toxicol 11 (3): 381-400 (1988) R37: Overman DO, White JA; Teratology 28 (3): 421-6 (1983) R38: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Methyl Salicylate, CAS #119-36-8): Reproduction and Fertility Assessment in CD-1 Mice When Administered by Gavage, NTP Study No. RACB82104 (August 10, 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R39: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Methyl Salicylate (CAS 119-36-8): Reproduction and Fertility Assessment in CD-1 Mice When Administered by Gavage, NTP Study No. RACB85061 available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R40: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-205 R41: (1) Windholz M et al; Merck Index 9th ed Merck and Co Inc; Rahway NJ pp.798 (1976) (2) Clayton GD, Clayton FE; Patty's Industrial Hygiene and Toxicology 3r ed; Wiley and Sons Inc NY Vol 2a (1981) (3) Winer AM; Atmos Environ 26A; 2647-5 (1992) R42: (1) Hawley GG; Condensed chemical dictionary 10th ed; Van Nostrand Reinhold Co NY (1981) (2) Kirk-Othmer Encycl Chem Tech 3rd ed; John Wiley and Sons Inc NY 20:200-524 (1982) (3) Clayton GD, Clayton FE; Patty's Industrial Hygiene and Toxicology 3rd ed; Wiley and Sons Inc NY Vol 2a (1981) R43: (1) Magid LJ, Larsen JW; J Org Chem 39: 3142-4 (1974) (2) Senent S et al; An Quim; 69:13-23 (1973) (3) Scully FE Jr, Hoigne J; Chemosphere 16: 681-94 (1987) (4) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (5) Riddick JA et al; Organic Solvents 4th ed; NY, NY: Wiley (1986) R44: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Riddick JA et al; Organic Solvents 4th ed; NY, NY: Wiley (1986) R45: (1) Maggio P et al; Ind Carta 14:105-11 (1976) (2) Maggio P et al; Tinctoria 73:15-20 (1976) (3) Crespi-Rosell M, Cegarra-Sanchez J; Bol Inst Invest Text Coop Ind 77: 41-57 (1980) (4) Goulding C et al; J Appl Bact 65: 1-5 (1988) R46: (1) Magid LJ, Larsen JW; J Org Chem 39: 3142-4 (1974) (2) Senent S et al; An Quim; 69: 13-23 (1973) (3) Mill T; Environ Toxicol Chem 1: 135-141 (1982) (4) USEPA; PCGEMS (Graphical Exposure Modeling System) PCHYDRO (1988) (5) Mata F, Mucientes A; Z Phys Chem Leipzig 259: 881-8 (1978) R47: (1) Sadtler S; UV Spectrum Sadtler Res Lab Inc Philadelphia PA Utk6751 (1969) (2) Kondo M; Simulation studies of degradation of chemicals in the water and soil; Office of Health Studies Environment Agency Japan (1978) (3) Riddick JA et al; Organic Solvents 4th ed; NY, NY: Wiley (1986) R48: (1) Scully FE Jr, Hoigne J; Chemosphere 16: 681-94 (1987) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R49: (1) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al (eds); Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5 (1982) R50: (1) Meylan WM et al; Environ Sci Technol 26: 1560-7 (1992) (2) Riddick JA et al; Organic Solvents 4th ed; NY, NY: Wiley (1986) (3) Lyman WJ et al ; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 4 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R51: (1) Daubert TE, Danner RP; Data Compilation Tables of Properties of Pure Compounds NY, NY: Amer Inst for Phys Prop Data (1989) (2) Riddick JA et al; Organic Solvents 4th ed; NY, NY: Wiley (1986) (3) Lyman WJ et al (eds); Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) (4) Reichman R et al; Soil Sci 148: 191-8 (1989) R52: (1) McKnight DM et al; Org Geochem 4: 85-92 (1982) R53: (1) Shackelford WM et al; Analyt Chim Acta 146: 15-27 (supplemental data) (1983) R54: (1) Furia TE, Bellanca N; Fenaroli's Handbook of Flavor Ingredients. CRC Press Cleveland OH (1975) (2) Shahidi F et al; CRC Crit Rev Food Sci Nature 24: 141-243 (1986) R55: (1) NIOSH; National Occupational Exposure Survey (1989) R56: 40 CFR 180.1001(c) (7/1/92) R57: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/197-12.046 R58: EL-OBEID HA, HASSAN MM A; SPECTROSC LETT 12 (7-8): 555 (1979) R59: CATES LA, BRANDINO TF; CAN J HOSP PHARM 32 (NOV-DEC): 169 (1979) RS: 47 Record 163 of 1119 in HSDB (through 2003/06) AN: 1995 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,1-DICHLOROETHYLENE- SY: *as-Dichloroethylene-; *CHLORURE-DE-VINYLIDENE- (FRENCH); *1,1-DCE-; *1,1-DICHLOROETHENE-; *ASYM-DICHLOROETHYLENE-; *Pesticide-Code:-600033.-; *ETHENE,-1,1-DICHLORO-; *ETHYLENE,-1,1-DICHLORO-; *NCI-C54262-; *SCONATEX-; *VDC-; *VINYLIDENE-CHLORIDE- (II); *VINYLIDENE-CHLORIDE- (INHIBITED); *VINYLIDENE-CHLORIDE,-MONOMER-; *VINYLIDENE-DICHLORIDE-; *VINYLIDINE-CHLORIDE- RN: 75-35-4 RELT: 6878 [DICHLOROETHYLENE] (Mixture) MF: *C2-H2-Cl2 SHPN: UN 1303; Vinylidene chloride, inhibited or stabilized IMO 3.1; Vinylidene chloride, inhibited or stabilized STCC: 49 072 80; Vinylidene chloride, inhibited HAZN: U078; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. D029; A waste containing 1,1-dichloroethylene may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Produced commercially by the dehydrochlorination of 1,1,2-trichloroethane by lime or sodium hydroxide and is extracted from the reactor by distillation, with the removal of oxygen to prevent polymerization. An azetropic distillation column is used to dry the monomer. The monomethyl ether of hydroquinone is added to commercial grades of vinylidene chloride as an inhibitor. [R1] *... Vinylidene chloride has been prepared from vinyl chloride by successive chlorination and dehydrochlorination steps ... . [R2, p. 1(78) 246] *Thermal dehydrochlorination of 1,1,1-trichloroethane (former commercial method). [R3] *Prepn from ethylene chloride: Reilly, US pat 2,140,548 (1938 to Dow.). By dechlorination of 1,1,2-trichloroethane: Conrad, Gould, US pat 2,989,570 (1961 to Ethyl Corp). [R4] IMP: *Water content (75 ppm), acetylene (25 ppm), acidity as hydrochloric acid (15 ppm), iron (0.5 ppm), methyl ether hydroquinone (180-220 ppm), trans-dichloroethylene (0.25%), 1,1-dichloroethane (0.25%), trichloroethylene (0.25%), ethylene dichloride (0.25%), peroxides (H2O2) (25 ppm). [R5] *A typical analysis of commercial-grade vinylidene chloride monomer (excluding inhibitors) is as follows: vinylidene chloride 99.8%; trans-1,2-dichloroethylene 900 ppm; vinyl chloride 800 ppm; 1,1,1-trichloroethane 150 ppm; cis-1,2-dichloroethylene 10 ppm; and 1,1-dichloroethane, ethylene chloride, and trichloroethylene, each less than 10 ppm. [R6] *Dichloroacetylene has been reported to be an impurity in some commercial samples of vinylidene chloride. [R7] *Commercial product contains small proportion of inhibitor. [R8] FORM: *Liquid grade [R9] MFS: *Dow Chemical USA, 2030 Dow Center, Midland, MI 48674, (517) 832-1150; Production site: Freeport, TX 77541 [R10] *PPG Industries, Inc., One PPG Place, 36 East, Pittsburgh, PA 15272, (412) 434-3131, Chemicals Group; Production site: Lake Charles, LA 70602 [R10] OMIN: *Vinylidene chloride monomer can be ... prepared in laboratory by reaction of 1,1,2-trichloroethane with aqueous alkali. ... Other /manufacturing/ methods are based on bromochloroethane, trichloroethyl acetate, tetrachloroethane, and catalytic cracking of trichloroethane. [R2, p. 23(83) 764] *Seven manufacturers in western Europe reported a combined capacity for vinylidene production of 352000 tons in 1983; Belgium (160000 tons), Federal Republic of Germany (100000), France (50000), The Netherlands (12000) and the UK (30000). In 1985 western European capacity had decreased to an estimated 130000 tons. [R1] *The monomethyl ether of hydroquinone is added to commercial grades of vinylidene chloride as an inhibitor. [R1] USE: *For 1,1-Dichloroethylene (USEPA/OPP Pesticide Code: 600033) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R11] *Used as comonomer, primarily with vinyl chloride. [R1] *... 1-chloro-1,1-difluoroethane, also known as (refrigerant 142b), is synthesized from 1,1-difluoroethane, vinylidene chloride and 1,1,1-trichloroethane. [R2, p. 11(80) 65] *COMONOMER FOR MODACRYLIC FIBERS; UNISOLATED CHEMICAL INTERMEDIATE FOR 1,1,1-TRICHLOROETHANE. [R12] *Chemical intermediate in production of chloracetyl chloride. [R13] *Copolymerized with vinyl chloride or acrylonitrile to form various kinds of saran. Other copolymers are also made. Adhesives; component of synthetic fibers. [R8] *Intermediate in the production of "vinylidene polymer plastics" such as Saran and Velon. [R4] CPAT: *Virtually all of the vinylidene chloride produced is used in the production of copolymers with vinyl chloride or acrylonitrile. A small percentage (4%) of vinylidene chloride is used as chemical intermediates (1985). [R14, EPA/600/8-83/031A] *U.S. Demand: 68,000 tonnes in 1987; was projected to be 79,000 tonnes in 1992 [R15] *Of all important chloroethanes and -ethylenes, vinylidene chloride has presently the smallest sales volume. Because of its unique applications in polymers for food containers, long-term demand will grow. [R16] *The annual production rate for the Western World amounts to about 150,000-200,000 tonnes, of which ca. 120,000 tonnes are used for poly(vinylidene chloride) and its copolymers. The rest is converted to 1,1,1-trichloroethane. [R16] *(1998) 14.029 billion pounds; (1999) 14.66 billion pounds; (2003) 17.82 billion pounds. [R17] *Polyvinyl chloride (PVC), 98 percent; miscellaneous, including copolymers with vinyl acetate, vinyl stearate and vinylidene chloride, and 1,1,1-trichloroethane, 2 percent. [R17] PRIE: U.S. PRODUCTION: *(1977) 9.1X10+10 G MIN-MAY INCL CAPTIVE PRODN [R3] *(1980) 7.8X10+10 G (EST, EXCL CAPTIVE PRODN) [R3] *(1985) 8.08X10+10 g (capacity) [R14, EPA/600/8-83/031F] *An estimated 90700 tons/yr of the monomer were produced in the USA during the early 1980s. [R1] *> 90,700 metric tons in 1982 [R18] U.S. IMPORTS: *(1977) 1.63X10+7 G [R3] *(1982) 4.60X10+5 G [R3] *(1984) 1.81X10+7 g [R19] *(1986) 2.17X10+8 lb [R20] *(1998) 21 million pounds; (1999) 72 million pounds [R17] U.S. EXPORTS: *(1998) 1.979 billion pounds; (1999) 2.481 billion pounds [R17] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R8]; *Colorless liqid or gas (above 89 degrees F). [R21] ODOR: *Mild, sweet odor resembling that of chloroform [R4]; *Mild, sweet, chloroform-like odor. [R21] BP: *31.7 deg C @ 760 mm Hg [R4] MP: *-122.5 deg C [R4] MW: *96.94 [R22] CORR: *Vinylidene chloride may be corrosive or unstable in the presence of steel. [R23] CTP: *Critical temperature: 220.8 deg C; critical pressure: 5.21 MPa [R24] DEN: *1.2129 @ 20 deg C/4 deg C [R4] HTC: *1095.9 kJ/mole @ 25 deg C [R24] HTV: *26.48 kJ/mole @ 25 deg C [R24] OWPC: *log Kow = 2.13 [R25] SOL: *0.63 g/100 g water at 50 deg C (solubility at saturation vapor pressure) [R26]; *In water: 3.5 g/l at 4 deg C; 3.0 g/l at 16 deg C [R27]; *Soluble in ethanol, acetone, benzene, carbon tetrachloride; very soluble in ethyl ether, chloroform. [R28, p. V3 2764]; *In water, 2,420 mg/l @ 25 deg C [R29] SPEC: *MAX ABSORPTION (VAPOR): LESS THAN 200 NM [R30]; *Index of refraction: 1.4249 @ 20 deg C/D [R22]; *IR: 11632 (Sadtler Research Laboratories Prism Collection) [R28, p. V3 2764]; *NMR: 6385 (Sadtler Research Laboratories Spectral Collection) [R28, p. V3 2764]; *IR GRATING: 29675 (Sadtler Research Laboratories) [R7]; *MASS: NIST 888 (NIST/EPA/MCDC Mass Spectral Database 1990 version); WILEY 203 (Atlas of Mass Spectral Data) [R28, p. V3 2763]; *IR: 2:55F (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R31] SURF: *24 DYNES/CM @ 15 DEG C (INHIBITED) [R32] VAPD: *3.25 (air= 1) [R33, p. 49-38] VAP: *600 mm Hg @ 25 deg C [R34] EVAP: *... The evaporation half-life of a dilute aq soln of vinylidene chloride (1 ppm w/w) in an open container stirred at 200 rpm at 25 deg C /was/ 22 min, 90% of the cmpd was lost in 89 min. [R35] VISC: *0.3302 cP at 20 deg C [R36] OCPP: *HEAT OF POLYMERIZATION: -185 CAL/G; VAPOR SPECIFIC GRAVITY: 3.3 [R32] *The water/air partition coefficient at 20 deg C is 0.16. [R37] *Heat of combustion: -4860 BTU/lb= -2700 cal/g [R32] *Liquid density at 0 deg C: 1.2517 g/cu m [R38] *Latent heat of vaporization at 25 deg C: 6328 cal/mol [R36] *Latent heat of vaporization at boiling point: 6257 cal/mol. [R36] *Latent heat of fusion: 1557 cal/mol. [R36] *Specific heat: 0.275 cal/g. [R36] *Dielectric constant 4.67 at 16 deg C. [R36] *Heat of polymerization: -18.0 Kcal/mol. [R36] *Heat of formation (liquid monomer): -6 kcal/mol; Heat of formation (gaseous monomer): 0.3 kcal/mol [R36] *Heat capacity at 25.15 deg C (liquid monomer): 26.745 cal/mol/deg. [R36] *Heat capacity @ 25 deg C: 111.3 J/mole-K @ 1 atmosphere (liq); 67.4 J/mole-K @ 1 atmosphere (gas) [R39] *Saturated concn in air: 2,640 g/cu m @ 20 deg C, 3,675 g/cu m @ 30 deg C [R40] *Solubility of water in monomer, @ 25 deg C, 0.035 wt%; critical vol: 218 cu m/mole [R24] *Conversion factor: 1 mg/cu m= 0.25 ppm, 1 ppm= 3.97 mg/cu m [R40] *Dipole moment: 1.30 debye @ 25 deg C in benzene [R41, p. 4-55] *Gibbs energy of formation: 5.85 kcal/mole (liq), 5.78 kcal/mole (gas) [R41, p. 5-13] *Enthalpy of melting: 1.557 kcal/mole @ mp; enthalpy of sublimation: 6.328 kcal/mole @ 298 K [R41, p. 5-52] *Henry's Law constant = 2.61X10-2 atm-cu m/mole @ 24 deg C [R42] *Hydroxyl radical rate constant = 1.09X10-11 cu cm/molecule-sec @ 25 deg C [R43] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Vinylidene chloride, inhibited/ [R44] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Vinylidene chloride, inhibited/ [R44] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Vinylidene chloride, inhibited/ [R44] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Vinylidene chloride, inhibited/ [R44] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Vinylidene chloride, inhibited/ [R44] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Vinylidene chloride, inhibited/ [R44] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Vinylidene chloride, inhibited/ [R44] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Vinylidene chloride, inhibited/ [R44] FPOT: *Flammable liquid [R32] *A very dangerous fire hazard when exposed to heat or flame. [R45] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R46, p. 325-93] *Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R46, p. 325-93] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R46, p. 325-93] FLMT: *Lower flammable limit: 6.5% by volume; Upper flammable limit: 15.5% by volume [R46, p. 325-93] FLPT: *3 deg F (Open cup); -2 deg F (Closed cup). [R36] *-19 deg C (Closed cup), -15 deg C (Open cup) [R47] *-17 deg C (Closed cup) [R48] AUTO: *1058 DEG F (570 DEG C) [R46, p. 325-93] FIRP: *Use dry chemical, foam, carbon dioxide, or water spray. Use water spray to keep fire-exposed containers cool. Use flooding quantities of water. Fight fire from protected location or maximum possible distance. /Vinylidene chloride, inhibited/ [R46, p. 49-137] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. /Vinylidene chloride, inhibited/ [R49] *Personnel protection: ... Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. /Vinylidene chloride, inhibited/ [R49] *Evacuation: If fire becomes uncontrollable, or container is exposed to direct flame--consider evacuation of one-half (1/2) mile radius. /Vinylidene chloride, inhibited/ [R49] TOXC: *Combustion by--products may include hydrogen chloride, phosgene. /Vinylidene chloride, inhibited/ [R46, p. 49-137] OFHZ: *VAPORS ARE HEAVIER THAN AIR AND MAY TRAVEL TO SOURCE OF IGNITION AND FLASH BACK. /VINYLIDENE CHLORIDE, INHIBITED/ [R46, p. 49-137] EXPL: *Moderately explosive in the form of gas when exposed to heat or flame. It forms explosive peroxides upon exposure to air. ... Also can explode spontaneously. [R45] REAC: *At ambient temp, perchloryl fluoride is unreactive with 1,1-dichloroethylene, but reaction is explosive at 100-300 deg C, or if the mixture is ignited. [R50, 939] *Condensation of trichlorotrifluoroethylene and 1,1-dichloroethylene at 180 deg C under pressure to give 1,1,2-trichloro-2,3,3-triflurorocyclobutane was effected smoothly several times in a 1 l autoclave. Scaling up to a 3 l preparation led to uncontrolled polymerization which distorted the larger autoclave. [R50, 237] *Mixing vinylidene chloride and chlorosulfonic acid in a closed container caused the temp and pressure to increase. [R46, p. 491-205] *Mixing vinylidene chloride and 70% nitric acid in a closed container caused the temp and pressure to increase. [R46, p. 491-222] *Mixing oleum and vinylidene chloride in a closed container caused the temp and pressure to increase. [R46, p. 491-134] *Aluminum, sunlight, air, copper, heat [Note: Polymerization may occur if exposed to oxidizers, chlorosulfonic acid, nitric acid, or oleum. Inhibitors such as the monomethyl ether of hydroquinone are added to prevent polymerization]. [R21] *Reaction with ozone forms dangerous products. [R45] *Potentially explosive reaction with chlorotrifluoroethylene at 180 deg C. ... Explosive reaction with perchloryl fluoride when heated above 100 deg C. [R45] DCMP: *WHEN NOT STABILIZED, DECOMP IN AIR INTO CHLORINE, HYDROGEN CHLORIDE, PHOSGENE, AND FORMALDEHYDE AND WHITE POLYMERIC POWDER [R51] *When heated to decomposition it emits toxic fumes of /hydrogen chloride/. [R45] POLY: *POLYMERIZATION CAN OCCUR IF EXPOSED TO SUNLIGHT, AIR, COPPER, ALUMINUM, OR HEAT. [R32] *When stored between -40 and +25 deg C in the absence of inhibitor and in presence of air, vinylidene chloride rapidly absorbs oxygen with formation of a violently explosive peroxide. The latter initiates polymerization, producing an insoluble polymer which adsorbs the peroxide. Separation of this polymer in a dry state must be avoided, since if more than 15% of peroxide is present, the polymer may be detonable by slight shock or heat. [R50, 237] *In the presence of polymerization initiators, vinylidene chloride undergoes self-polymerizaton to form homopolymers, or polymerizes with other compounds, /such as/ vinyl chloride, alkylacrylates, and acrylonitrile to form copolymers. [R6] ODRT: *MOST PERSONS CAN DETECT MILD BUT DEFINITE ODOR @ 1000 PPM IN AIR. SOME ... CAN DETECT IT @ 500 PPM. VAPORS CONTAINING DECOMP PRODUCTS HAVE DISAGREEABLE ODOR AND CAN BE DETECTED @ CONCN CONSIDERABLY LESS THAN 500 PPM. NEITHER ODOR NOR IRRITATING PROPERTIES OF VINYLIDENE CHLORIDE IS ADEQUATE TO WARN OF EXCESSIVE EXPOSURE. [R52, 4187] *Odor threshold (air) = 2000-5500 mg/cu m [R53] SERI: *Vapor is irritating to eyes, nose, and throat. [R32] *SKIN CONTACT WITH VINYLIDENE CHLORIDE CAUSES IRRITATION, WHICH MAY PARTLY BE DUE TO HYDROQUINONE MONOMETHYL ETHER INHIBITOR. [R54] EQUP: *APPROVED CANISTER OR AIR-SUPPLIED MASK; GOGGLES OR FACE SHIELD; RUBBER GLOVES AND BOOTS. [R32] *Wear appropriate chemical protective gloves, boots and goggles. [R55] *For 1,1-dichloroethylene some data (usually from immersion tests) suggesting break-through times greater than one hour are not likely for chlorinated polyethylene (CPE). [R56] *Wear appropriate personal protective clothing to prevent skin contact. [R21] *Wear appropriate eye protection to prevent eye contact. [R21] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R21] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R21] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R21] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R21] OPRM: *The primary requirement for reduction of exposure to vinylidene chloride would be to limit emissions through improved housekeeping procedures in the industry. [R57] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personal hazard. Use water spray to knock down vapors. /Vinylidene chloride, inhibited/ [R49] *Evacuation: If material leaking (not on fire) consider evacuation from downwind area based on amt of material spilled, location and weather conditions. /Vinylidene chloride, inhibited/ [R49] *Personnel protection: ... Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Vinylidene chloride, inhibited/ [R49] *Contact lenses should not be worn when working with this chemical. [R21] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R21] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R21] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R58] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R59] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R60] STRG: *PROTECT AGAINST PHYSICAL DAMAGE. OUTSIDE OR DETACHED STORAGE IS PREFERABLE. INSIDE STORAGE SHOULD BE IN STD FLAMMABLE LIQUIDS STORAGE ROOM OR CABINET. SEPARATE FROM OXIDIZING MATERIALS. [R33, p. 49-39] *Vinylidene chloride must be stored in tanks that have nickel, baked phenolic, or glass linings. [R23] *Vinylidene chloride is generally stored at -10 deg C, in the absence of light, air, water, and other polymerization initiators under a nitrogen blanket at 10 psi pressure; the oxygen content of the nitrogen should remain at less than 100 ppm. [R61] CLUP: *Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, sawdust, or commercial sorbents. Apply appropriate foam to diminish vapor and fire hazard. /Vinylidene chloride, inhibited/ [R49] *Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Inject "universal" gelling agent to solidfy encircled spill and increase effectiveness of booms. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Vinylidene chloride, inhibited/ [R49] *Air spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. /Vinylidene chloride, inhibited/ [R49] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers U078 and U029, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R62] *A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. Also a potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. Also a potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R63] *This compound should be susceptible to removal from waste water by air stripping. [R64] *The following wastewater treatment technologies have been investigated for 1,1-dichloroethylene: Concentration Process: Solvent extraction. [R65] *The following wastewater treatment technologies have been investigated for 1,1-dichloroethylene: Concentration Process: Stripping. [R66] *Environment Canada's Wastewater Technology Center operated a pilot plant at a landfill site to treat groundwater contaminated with volatile organic chemicals during the summer of 1986. The treatment system consisted of a packed air stripping column to treat the wastewater and two sequential granular activated carbon adsorbers to treat the off-gases. Among volatile organic chemicals in the wastewater were 1,1-dichloroethane, 1,2-dichloroethane, chloroform, 1,1-dichloroethylene, 1,1,1-trichloroethane, benzene, toluene, and trichloroethylene. Removal efficiencies varied from 27 to 99.9%. Optimal conditions, resulting in 94% removal of all volatile organic chemicals, were met with a 70:1 air-to-water ratio, a liquid flow rate of 4 l/min, and 1.3 cm Intalox saddles. Concentration of all compounds were below the lower detection limit of 2 ug/l in the effluent of the second granular activated carbon absorber. [R67] *An air stripping and incineration process is being used to clean a contaminated aquifer at McClellan Air Force Base. Groundwater is extracted and volatile organics are removed via a high-temperature air stripping system. Water soluble organics and some non-volatile organics are destroyed in a biological treatment unit. Volatile organics removed during air stripping are incinerated. Waste heat is recycled to preheat the air stripper water. Organic chemical concentrations are reduced from as high as 50 ppm to below detection limits. [R68] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of vinylidene chloride. There is limited evidence in experimental animals for the carcinogenicity of vinylidene chloride. Overall evaluation: Vinylidene chloride is not classifiable as to its carcinogenicity to humans (Group 3). [R69] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Tumors observed in one mouse strain after inhalation exposure is the basis for this classification. Other studies were of inadequate design. Vinylidene chloride is mutagenic, and a metabolite is known to alkylate and to bind covalently to DNA. It is structurally related to the known human carcinogen, vinyl chloride. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. [R70] *A4. Not classifiable as a human carcinogen. [R71] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations as needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Minimize physical activity and provide a quiet atmosphere. Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. Rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Treat frostbite with rapid rewarming techniques ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R72] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Chlorinated fluorocarbons (CFCs) and related compounds/ [R72] MEDS: *Physical examination of exposed personnel, including studies of liver and kidney functions. [R73] *Respiratory Symptom Questionnaires: Questionnaires published by the American Thoracic Society (ATS) and the British Medical Research Council have proven useful for identifying people with chronic bronchitis. Certain pulmonary function tests such as the FEV1 have been found to be better predictors of chronic airflow obstruction. [R74, 498] *Chest Radiography: Chest radiographs are widely used to assess pulmonary disease. They are useful for detecting early lung cancer in asymptomatic people, and especially for detecting peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such asbestos, experts' views on the risk-to-benefit ratio in detection of pulmonary disease conflict, so routine annual chest x-rays are not recommended for all people. [R74, 498] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. Spirometry, for the measurement of FVC (forced vital capacity) and FEV1 (forced expiratory volume in 1 sec), has been found to be the most reproducible and least variable test of pulmonary function. [R74, 498] *Liver Function Tests: Biochemical tests - Enzymes that reflect cholestasis: alkaline phosphatase (AP), 5'-nucleotidase (5'-NT) and leucine aminopeptidase (LAP); Enzymes that detect direct hepatic damage: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gammma glutamyl Transpeptidase (GGTP); Clearance tests - indocyanine green, antipyrine test and serum bile acids. [R74, 497] HTOX: *ACUTE EXPOSURE TO HIGH CONCN OF VINYLIDENE CHLORIDE IN AIR RESULTS IN CNS DEPRESSION ... REPEATED EXPOSURES TO LOW CONCN ARE ASSOC WITH LIVER AND RENAL DYSFUNCTION. ... CONTACT WITH THE EYE CAUSES CONJUNCTIVITIS AND TRANSIT CORNEAL INJURY. [R54] *... Acute exposure to VDC vapor at approximately 4,000 ppm (1.58 g/cu m) causes symptoms of drunkenness that may progress to unconsciousness if exposure is continued for longer than a few min and that complete recovery occurs when exposure is of short duration. [R75] *... The cancer risk among cohort of 138 workers exposed to vinylidene chloride /was investigated/, where vinyl chloride was not used as a copolymer. /It was/ reported that no findings were statistically related or individually attributable to vinylidene chloride exposure in this cohort (The Working Group noted that 27 workers were lost to follow-up but considered to be alive in the analyses, and that 55 people had less than 15 yr since first exposure, and only 5 deaths were observed; these factors precluded any judgement on the findings). [R54] *It was weakly mutagenic in the presence of a 9000 X gravity supernatant of liver cells from a human subject who had been receiving long-term phenobarbital /treatment/. [R54] *Vapor concentrations of 4000 ppm are said to induce promptly symptoms of drunkenness progressing to unconsciousness. [R76] *Vinylidene chloride is a central nervous system depressant. Repeated exposure to low concentrations of vinylidene chloride may cause liver and renal dysfunction. Skin contact with vinylidene chloride causes irritation, which may be due partly to the presence of an inhibitor, hydroquinone monomethyl ether. In one study, spirometry, blood clinical chemistry for liver and renal toxicity, hematological parameters and blood pressure measurements did not differ between vinylidene chloride-exposed workers and controls. Measured past time-weighted average vinylidene chloride concentrations ranged from < 5 to 70 ppm (< 20-280 mg/cu m). [R77] NTOX: *Vinylidene chloride is moderately irritating to the eyes of rabbits. It will cause pain, conjuctival irritation, and some transient corneal injury. Permanent damage is not likely. ... Liquid vinylidene chloride is irritating to the skin of rabbits after direct contact of only a few minutes. [R52, 4182] *... After exposure to 48 ppm continuously for 90 days, liver damage was evident in monkeys, dogs and rats, and deaths occurred among monkeys and guinea pigs. In this study only rats showed evidence of renal tubular injury. [R76] *... GROUPS OF 50 MALE AND 50 FEMALE SPRAGUE-DAWLEY RATS WERE ADMIN 5, 10 OR 20 MG/KG BODY WT VINYLIDENE CHLORIDE IN OLIVE OIL BY STOMACH TUBE ONCE DAILY ON 4-5 DAYS/WK FOR 52 WK; 1 CARCINOMA OF ZYMBAL GLAND WAS OBSERVED IN RAT TREATED WITH 10 MG/KG BODY WT. AT TIME OF REPORTING, RATS HAD BEEN OBSERVED FOR 93 WK OF TREATMENT. /NO DATA ON CONTROLS./ [R78] *A GROUP OF 36 MALE AND 36 FEMALE CD RATS WERE EXPOSED TO 220 MG/CU M (55 PPM) VINYLIDENE CHLORIDE IN AIR FOR 6 HR/DAY ON 5 DAYS A WK FOR UP TO 12 MO, @ WHICH TIME THE EXPERIMENT WAS TERMINATED AND ALL SURVIVORS KILLED. 2 RATS DEVELOPED ANGIOSARCOMAS, 1 IN MESENTERIC LYMPH NODE AND 1 IN SC TISSUE. NO SUCH TUMORS OCCURRED IN CONTROLS. (THE WORKING GROUP NOTED THE SHORT DURATION OF THE EXPERIMENT). [R79] *A GROUP OF 16-WK-OLD 60 MALE AND 60 FEMALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO 800 MG/CU M REDUCED TO 600 MG/CU M (200 PPM REDUCED TO 150 PPM), AND 4 FURTHER GROUPS OF 30 FEMALE AND 30 MALE SPRAGUE-DAWLEY RATS OF THE SAME AGE WERE EXPOSED TO 40, 100, 200 OR 400 MG/CU M (10, 25, 50 OR 100 PPM) VINYLIDENE CHLORIDE IN AIR FOR 4 HR/DAY ON 4-5 DAYS A WK FOR 52 WK AND OBSERVED FOR UP TO 82 WK (TIME OF REPORTING). AN INCR INCIDENCE OF MAMMARY FIBROADENOMAS AND CARCINOMAS (40-60%) WAS REPORTED, IN COMPARISON WITH 100 MALE AND 100 FEMALE CONTROLS (32%), ALTHOUGH NO DOSE-RESPONSE RELATIONSHIP WAS FOUND. IN ADDITION, ONE ZYMBAL GLAND CARCINOMA WAS SEEN IN ONE RAT TREATED WITH 100 PPM. [R79] *INHALATION STUDIES USING RATS, GUINEA PIGS, DOGS, RABBITS AND MONKEYS EXPOSED TO MEAN LEVEL OF 189 MG/CU M (48 PPM) FOR 90 DAYS SHOWED SIGNIFICANT MORTALITY AND LIVER DAMAGE BUT NO CHANGES IN HEMATOLOGICAL PARAMETERS. [R80] *INHALATION OF 2000 MG/CU M (500 PPM) VINYLIDENE CHLORIDE DURING 20 6-HR EXPOSURES CAUSED NASAL IRRITATION, REDUCED WT GAIN AND INDUCTION OF HEPATIC HISTOPATHOLOGICAL CHANGES IN RATS. LIVER PARENCHYMAL-CELL INJURY WAS OBSERVED IN FASTED RATS EXPOSED TO 800 MG/CU M (200 PPM) FOR 4 HR. [R80] *RATS WERE GIVEN VINYLIDENE CHLORIDE EITHER AS 200 MG/L IN DRINKING WATER OR AS 80-640 MG/CU M (20-160 PPM) BY INHALATION FOR 7 HR/DAY ON DAYS 6-15 OF GESTATION; RABBITS WERE GIVEN THE SAME DOSE BY INHALATION ON DAYS 6-18 OF GESTATION. NO TERATOGENIC EFFECT WAS SEEN IN EITHER RATS OR RABBITS, ALTHOUGH SOME EVIDENCE OF EMBRYOTOXICITY AND FETOTOXICITY WAS OBSERVED IN BOTH SPECIES EXPOSED BY INHALATION; THESE EFFECTS WERE ASSOCIATED WITH MATERNALLY TOXIC LEVELS OF EXPOSURE. [R81] *CONCN OF 2 and 20% (20000 and 200000 PPM) VINYLIDENE CHLORIDE IN AIR PRODUCED REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA100 AND TA1530 IN PRESENCE OF 9000 X G SUPERNATANTS FROM LIVER, LUNG AND KIDNEYS OF MICE AND RATS ... AT A CONCN OF 5% (50000 PPM) IN AIR, IT IS MUTAGENIC IN S TYPHIMURIUM TA1535 IN PRESENCE OF A 9000 X G SUPERNATANT OF LIVER OR KIDNEY FROM MICE AND RATS PRETREATED WITH AROCLOR 1254. ... REVERSED MUTATIONS WERE INDUCED IN ESCHERICHIA COLI K12 BY VINYLIDENE CHLORIDE SOLN IN THE PRESENCE OF LIVER MICROSOMES FROM MICE PRETREATED WITH PHENOBARBITAL. [R54] *VINYLIDENE CHLORIDE WAS NOT MUTAGENIC IN THE DOMINANT LETHAL TEST IN MALE CD-1 MICE EXPOSED BY INHALATION TO 40, 120 and 200, MG/CU M (10, 30, and 50 PPM) FOR 6 HR/DAY FOR 5 DAYS. [R54] *ACUTE, ORAL NEPHROTOXICITY OF 1,1-DICHLOROETHYLENE AS DEMONSTRATED BY INCR IN KIDNEY WT, PLASMA UREA NITROGEN, PLASMA CREATININE CONCN WERE DETERMINED IN MALE AND FEMALE RATS AFTER ORAL ADMIN. FASTING MALES WERE SUSCEPTIBLE TO 400 MG/KG WITH UREA NITROGEN ELEVATED 24, 48, and 72 HR LATER WHEREAS FED MALES WERE NOT. DOSES OF 200, 400, and 600 MG/KG CAUSED UREA NITROGEN ELEVATIONS, and 400 MG/KG CAUSED ELEVATED CREATININE. BY THESE CRITERIA, MALES WERE MORE SUSCEPTIBLE THAN FEMALES. IN MALE RATS HISTOPATHOLOGIC CHANGES OBSERVED INCLUDED VACUOLIZATION, TUBULAR DILATATION, AND NECROSIS. THE PREVALENCE OF HISTOPATHOLOGIC LESIONS HOWEVER, WAS AS GREAT IN FEMALES AS THE MALES AND MAY HAVE BEEN SLIGHTLY MORE /PRONOUNCED/, BUT THE OTHER INDICATORS OF NEPHROTOXICITY WERE NOT AFFECTED BY 1,1-DICHLOROETHYLENE. [R82] *MALE RATS NORMALLY FED OR PREVIOUSLY FASTED FOR 18 HR WERE EXPOSED TO 10 OR 200 PPM OF (14)C-VDC VAPORS FOR 6 HR. FASTED RATS EXPOSED TO 200 PPM SUSTAINED LIVER AND KIDNEY DAMAGE AND CENTRILOBULAR HEPATIC NECROSIS. [R83] *MUTAGENICITY OF VINYLIDENE CHLORIDE TO CHINESE HAMSTER CELLS WAS TESTED IN PRESENCE OF 15000 X G LIVER SUPERNATANT FROM PHENOBARBITONE PRETREATED RATS AND WAS FOUND NEGATIVE. THE CELLS WERE EXPOSED TO 2.0 and 10.0% OF THE VAPOR IN AIR FOR 5 HR IN REACTION MIXT CONTAINING S15 FRACTION. [R84] *VINYLIDENE CHLORIDE, /WAS ADMINISTERED/ ORALLY, TO FEMALE BD IV RATS, 150 MG/KG BODY WT ON 17TH DAY OF GESTATION. OFFSPRING WERE TREATED WEEKLY, 50 MG/KG BODY WT (WEANING TO LIFE SPAN). THE TOTAL NUMBER OF TUMOR-BEARING ANIMALS WAS NO DIFFERENT FROM CONTROLS, BUT MORE LIVER AND MENINGEAL TUMORS OCCURRED. [R85] *EXPOSURE OF MALE SPRAGUE-DAWLEY RATS AND CD-1 MICE TO 10 and 50 PPM OF VINYLIDENE CHLORIDE FOR 6 HR RESULTED IN MASSIVE TISSUE DAMAGE BUT MINIMAL DNA ALKYLATION OR DNA REPAIR SYNTHESIS. [R86] *ORAL ADMIN OF 1,1-DICHLOROETHYLENE PRODUCES ACUTE INJURY TO THE LUNGS OF C57BL/6 MICE. THE BRONCHIOLAR EPITHELIUM IS MOST SEVERELY AFFECTED WITH DAMAGE SELECTIVE FOR CLARA CELLS. AFTER A 100 MG/KG DOSE, CLARA CELLS SHOW EXTENSIVE DILATATION OF CISTERNAE AND DEGENERATION OF THE ENDOPLASMIC RETICULUM. AT 6 HR AFTER ADMIN OF 200 MG/KG, BOTH CILIATED AND CLARA CELLS ARE NECROTIC, AND BRONCHIOLAR EPITHELIAL LINING EXFOLIATES. [R87] *DOGS WERE ADMIN VDC IN PEANUT OIL IN A GELATIN CAPSULE AT CONCN WHICH PROVIDED 6.25, 12.5, OR 25 MG VDC/KG/DAY FOR 97 DAYS. NO EXPOSURE-RELATED CHANGES WERE PRESENT IN TISSUES TAKEN FROM DOGS AT TERMINATION OF THE STUDY. [R88] *Groups of 47-48 male and 48 female Sprague-Dawley rats, 6 to 7 wk of age, were admin 50, 100 or 200 mg/l vinylidene chloride (99.5% pure, with 1-5 mg/l hydroquinone monomethyl ether) in drinking water ad libitum for 2 yr (avg time-weighted daily doses: males, 7, 10, 20 mg/kg body wt; females, 9, 14 or 30 mg/kg body wt). A group of 80 males and 80 females received drinking water only. Mortality and body-wt gain were similar in the treated and control groups; no statistically significant increase in tumor incidence was found. [R89] *24 HR AFTER THE ADMIN OF 1,1-DICHLOROETHYLENE @ 125 MG/KG IP TO MICE, A REDN OF CYTOCHROME P450 LEVELS AND RELATED MONOOXYGENASES IN LUNG MICROSOMES OCCURRED. EXAMINATION OF THE LUNG TISSUE REVEALED NECROSIS RESTRICTED TO THE CLARA CELLS. [R90] *REVERSE MUTATIONS WERE INDUCED IN ESCHERICHIA COLI K12 BY VINYLIDENE CHLORIDE SOLN IN PRESENCE OF LIVER MICROSOMES FROM MICE PRETREATED WITH PHENOBARBITAL. [R54] *Parenchymal cell injury was apparent in the livers in fasted 250-350 g male Holtzman rats as early as 2 hr after a 4 hr exposure by inhalation of 200 ppm (0.79 g/cu m) vinylidene chloride. Cell damage involved plasma membranes, mitochondria, and chromatin. There was a retraction of cell borders with the formation of pericellular lacunae which may have contained cytoplasm, erythrocytes and fibrin. In cell nuclei there was an aggregation of chromatin, and with time, a loss of chromatin from the organelle; mitochondria appeared swollen and their outer membranes were ruptured. Six hr following exposure of rats, hemorrhagic and necrotic areas were seen in the centrilobular region of the liver. [R91] *Incr in serum alanine-alpha-ketoglutarate transaminase (SAKT) showed a dose-response relationship in /Holtzman rats/ (weighing 150 to 300 g) exposed to 100, 150, or 200 ppm vinylidene chloride (VDC) for 4 hr. ... Increased serum alanine-alpha-ketoglutarate transaminase levels were noted at 150 ppm, and deaths and increased serum alanine-alpha-ketoglutarate transaminase levels occurred at 200 ppm. [R92] *... Rats and rabbits /were exposed/ by inhalation to concentrations of up to 160 ppm for 7 hr period during days 6 through 18 and 6 through 15 of gestation. Maternal toxicity was demonstrated in both species. No increased general malformation rate was found but wavy ribs and delayed ossification were increased in rat fetuses exposed to 80 and 160 ppm. Rats were fed 200 ppm in their drinking water on days 6 through 15 of gestation and no differences from the fetal controls were found. [R93] *Vinylidine chloride was mutagenic with D7 yeast Saccharomyces cerevisiae only in the presence of a mammalian activation system. When a mouse hepatic supernatant was included, vinylidene chloride (above 20 mm) was effective in increasing point mutations in a dose-related response. In an intrasanguinous host-mediated assay, vinylidine chloride was mutagenic to yeast (injected into mice) which were removed from the liver and kidneys after both acute (400 mg/kg by gavage to mice) and subacute exposure (100 mg/kg/day 5 times/wk for 23 admins) to vinylidene chloride. [R94] *In the Tradescantia ... assay system, vinylidene chloride exposure for 24 hr at 22 ppm was sufficient to induce a mutagenic response. /The end point/ was: a mutation (or loss) of a dominant gene (for blue color) resulting in the expression of a recessive pink flower pigmentation. [R95] *Vinylidine chloride was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Vinylidene chloride was tested at doses of 0.033, 0.10, 0.33, 1.0, and 3.3 mg/plate in as many as five Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Vinylidine chloride was negative in these tests and the highest ineffective dose tested in any S typhimurium strain was 3.3 mg/plate. Some clearing of the background lawn was seen in the high dose for all strains tested using hamster liver S-9. [R96] *Chromosomal aberration and sister-chromatid exchange (SCE) tests in vitro on 1,1-dichloroethylene (1,1-DCE), its two isomers, cis- and trans-1,2-dichloroethylene, and two possible metabolites of 1,1-dichloroethylene, chloroacetyl chloride and chloroacetic acid, were carried out using a Chinese hamster cell line. 1,1-Dichloroethylene induced chromosomal aberrations in the presence of S9 mix prepared from the rat liver, but not in the absence of S9 mix. Sister chromatid exchanges were also slightly induced by 1,1-dichloroethylene only in the presence of S9 mix. On the other hand, two isomers and two metabolites of 1,1-dichloroethylene induced neither chromosomal aberrations nor sister chromatid exchange with and without S9 mix. 1,1-Dichloroethylene, however, was negative even at a sublethal dose in the micronucleus test using mouse bone marrow, fetal liver and blood. [R97] *The chronic toxicity and carcinogenicity of vinylidene chloride (VDC) were studied in rats. Sprague-Dawley rats were exposed to 0, 10, or 40 ppm vinylidene chloride by inhalation for 6 hr daily, 5 days/wk for 5 wk, then to 25 or 75 ppm through 18 mo. The animals were observed for clinical signs of toxicity. Urinary, clinical chemistry, and hematologic parameters were evaluated. Rats were exposed to 0, 25, or 75 ppm vinylidene chloride for 6 months. Femoral bone marrow samples were taken and assayed for chromosomal abnormalities. Vinylidene chloride did not cause any clinical signs of toxicity, body weight changes, or deaths. The results of the hematologic, urinalysis, and clinical chemistry studies were normal. No treatment related chromosomal abnormalities were detected. After 12 months, males exposed to 25 or 75 ppm vinylidene chloride had decreased liver weights and females exposed to the same doses had increased kidney weights. Similar changes were not observed at 6 or 24 mo. Fatty changes in the mid zonal region of the hepatic lobule occurred in animals exposed to 25 or 75 ppm vinylidene chloride at 6 and 12 mo. This effect was not seen after 24 mo. No other treatment related histopathologic changes, including tumor induction, were observed. /Conclusions indicate/ that 25 or 75 ppm vinylidene chloride shows a target organ effect in the liver. The liver lesions, however, are reversible, as they disappeared during the last 6 mo of the study after exposures had been discontinued. The effects on liver and kidney weights at 12 mo are of questionable biological significance since they were not observed at any other times. [R98] *The effects of 1,1-dichloroethylene (DCE) on lung injury and repair were studied in male C57Bl/6 mice. Animals were administered 200 mg/kg 1,1-dichloroethylene orally in mineral oil. Control animals received only the vehicle. Mice were sacrificed at 1 hr or 1, 2, 3, 5, 7, and 30 days after exposure to the chemical. For study of DNA synthesis, animals were given 2 microCuries/g tritiated thymidine ip in a volume of 0.01 ml/g. Autoradiography and histopathology examinations were performed. A significant loss of body weight was observed 1 day after treatment with 1,1-dichloroethylene and was sustained throughout the experimental period. Lung weight increased significantly, with peak elevation occurring 3 days after exposure. Necrosis and exfoliation of bronchiolar epithelium Clara cells were observed at day 1 following exposure, and increased in severity by day 2. Repair was noted at day 3 and by day 7 the epithelium was substantially regenerated. No areas devoid of epithelium were evident after 30 days. Activity of tritiated thymidine was markedly inhibited 1 day after injection, but increased until at day 7 after exposure to 1,1-dichlorethylene the values were about the same as control. /Significant differences in labeling indices in parenchymal cells between control and treated lungs were not observed at day 7. In contrast,/ marked increases in bronchiolar labeling indices, returning to control values at day 7 after treatment, were found. Labeling in endothelial cells showed marked decreases while increases in interstitial cell labeling were observed, both returning to control values by day 7. [R99] *The results of 6 mo repeated inhalation studies on rats, rabbits, guinea pigs, and dogs are reported. ... Animals exposed 5 days/wk, 8 hr/day for several mo showed some injury of the liver and kidney even at 25 ppm. Similar exposures to 50 or 100 ppm were injurious to these organs. [R100] *THE LIVER GLUTATHIONE CONTENT WAS MEASURED AFTER ORAL ADMINISTRATION OF VINYLIDENE CHLORIDE DISSOLVED IN OLIVE OIL AND ITS SIGNIFICANCE FOR THE METABOLISM AND HEPATOTOXICITY OF VDC WAS INVESTIGATED. AFTER TREATMENT OF RATS WITH 1000 MG/KG VINYLIDENE CHLORIDE ORALLY, GLUTATHIONE /LEVELS WERE/ DECREASED TO 33% OF THE CONTROL VALUES WITHIN 4 HR BUT RETURNED TO THE CONTROL LEVEL AFTER 24 HR. AN IDENTICAL FALL IN GLUTATHIONE AFTER VDC ADMIN OCCURRED IN ANIMALS WHICH FASTED FOR 18 HR. NO EFFECT ON VIABILITY OR ON METABOLIC RATE WAS NOTED WHEN PERFUSING THE LIVERS OF 18 HR FASTED ANIMALS. THE CONCENTRATIONS OF THE GLUTAMATE-OXALOACETATE TRANSAMINASE AND GLUTAMATE PYRUVATE TRANSAMINASE IN THE PERFUSATE FAILED TO SHOW AN INCREASE. THUS, THERE IS NO CORRELATION BETWEEN THE LIVER GLUTATHIONE LEVEL AND THE INCREASED LETHALITY OF VDC IN FASTED RATS. [R101] *VINYLIDENE CHLORIDE AFFECTS ACTIVITY OF SEVERAL LIVER ENZYMES; NOTABLY, IT DECR HEPATIC GLUCOSE-6-PHOSPHATASE AND INCR SERUM ALANINE ALPHA-KETOGLUTARATE TRANSAMINASE. IT INCR LIVER CONTENT OF TRIGLYCERIDES ... . [R80] *Groups of 50 male and 50 female B6C3F1/N mice, 9 wk old, received 2 or 10 mg/kg body wt vinylidene chloride (99% pure, with < 0.1% of cis- or 0.1% trans-dichloroethylene and stabilizer, hydroquinone monomethyl ether) in corn oil by gavage on 5 days/wk for 104 wk. Groups of 50 males and 50 females received corn oil only and served as vehicle controls. A redn in body wt was observed in male and female mice receiving the lower dose. Survival rates at end of the experiment were: 33/50 (66%) vehicle control, 35/50 (70%) low-dose and 36/50 (72%) high-dose males; and 40/50 (80%) vehicle control, 32/50 (64%) low-dose and 42/50 (84%) high-dose females. A statistically significant increase in the combined incidence of lymphomas and leukemia was observed in low-dose females compared to vehicle controls: 7/48 (15%) control, 15/49 (31%) low-dose (p= 0.05), Fisher exact test) and 7/50 (14%) high-dose females. The increased incidence of lymphomas and leukemias in low-dose females was not considered to be the result of treatment because no significant increased incidence of these malignancies was observed in high-dose females or in low- or high-dose males. [R102] *A group of 24 female BDIV rats (age unspecified) received a single dose of 150 mg/kg body wt vinylidene chloride (99% pure, containing 0.03% 4-methoxyphenol) in olive oil by stomach tube on day 17 of gestation. Their progeny (89 males and 90 females) received weekly doses of 50 mg/kg body wt vinylidene chloride in 0.3 ml olive oil on day 17 of gestation, and their progeny (53 males and 53 females) received 0.3 ml olive oil weekly for life, beginning at weaning. All survivors were killed at 120 wk or when moribund. Litter sizes, preweaning mortality, survival rates and body-wt gain were similar in vinylidene chloride-treated and vehicle-control groups. No statistically significant increase in the incidence of tumors was noted in treated animals, although tumors that were not seen in controls appeared at a variety of sites in treated animals. Hyperplastic liver nodules were found in 2/23 dams treated with vinylidene chloride during pregnancy and in 2/81 male and 6/80 female progeny; no such effect was seen in controls (p= 0.04). [R102] *Groups of 50 male and 50 female Fischer 344/N rats, 9 wk of age, received 1 or 5 mg/kg body wt vinylidene chloride (99% pure, with < 0.1% cis- or trans-dichloroethylene and stabilizer, hydroquinone monomethyl ether) in corn oil by gavage on 5 days/wk for 104 wk. A group of 50 males and 50 females received corn oil only and served as vehicle controls. Survival rates at end of the study period were: 20/50 (40%) vehicle-control, 24/50 (48%) low-dose and 37/50 (74%) high-dose males; and 27/50 (54%) vehicle-control, 28/50 (56%) low-dose and 29/50 (58%) high-dose females. The large number of accidental deaths in control and low-dose males may have influenced the incidence of late-appearing tumors in these groups. The pattern of neoplasms in the treated animals resembled that in controls, and no significant increase in tumor incidence was observed. (The Working Group noted the poor survival.) [R89] *Groups of 36 male and 36 female CD-1 mice, 2 mo of age, were exposed to 0 or 220 mg/cu m (55 ppm) vinylidene chloride (99% pure) (impurities unspecified) in air for 6 hr/day on 5 days/wk for 12 mo, at which time the experiment was terminated. An increase in the incidence of bronchioalveolar adenomas was observed in males (1/26 controls versus 6/35 treated), and increases in the incidence of angiosarcomas of the liver also occurred (0/26 control males versus 2/35 treated; 0/36 female controls versus 1/35 treated). Three hepatomas (in 2 males and 1 female) and two skin keratoacanthomas were also reported to occur in treated mice (sex unspecified). (The Working Group noted the short duration of the experiment.) [R89] *A group of 30 female Ha:ICr Swiss mice, 6 to 8 wk of age, received three-weekly topical applications of 40 or 121 mg vinylidene chloride in 0.2 ml acetone on the dorsal skin for 440-594 days. Controls received no treatment or treatment with acetone only. No skin papillomas were observed in the vinylidene chloride-treated animals; two papillomas of the forestomach were observed in the group treated with the high dose. [R103] *In Sprague-Dawley rats given 200 mg/ml vinylidene chloride in drinking water on gestation days 6-15, no adverse effect was observed. In a three generation study in which Sprague-Dawley rat received 50, 100 or 200 mg/l vinylidene chloride in drinking water, survival was comparable in 6 sets of litters over 3 generations in control and exposed groups. There was no evidence of adverse effects on the reproductive capacity of animals of either sex. [R104] *Groups of male CD-1 mice were exposed for 6 hr to 40 or 200 mg/cu m (10 or 50 ppm) (14)C-vinylidene chloride. DNA purified from kidneys and livers of animals exposed to 50 ppm contained 30 and 6 alkylations per 1X10+6 nucleotide, respectively; and with 10 ppm, kidney DNA contained 11 and liver 0.94 alkylations/1X10+6 nucleotides. DNA binding decreased (with biphasic kinetics) with increasing time after exposure. Unscheduled DNA synthesis, measured by (3)H-thymidine incorporation, was increased by 38% (statistically significant) in the kidneys of mice treated with 50 ppm vinylidene chloride. No treatment-related unscheduled DNA synthesis was seen in livers of mice treated with 50 ppm, or in kidneys or livers of mice treated with 10 ppm. [R105] *Vinylidene chloride is mutagenic to bacteria and this activity is largely dependent on microsomal activation. Vinylidene chloride gave positive results for gene reversion in yeast that was also dependent on metabolic activation, and was positive in Tradescantia. In mammalian systems, vinylidene chloride failed to induce gene mutations in V79 cells at two separate loci, failed to induce chromosomal aberrations in mouse bone marrow in vivo, and failed to induce dominant lethals in either mice or rats. Vinylidene chloride was found to alkylate DNA of mice exposed through inhalation and may have caused unscheduled DNA synthesis in kidneys of similarly exposed mice. [R106] *The metabolism and covalent binding of (14)C labeled 1,1-dichlorethylene to liver, kidney, and lung from control and drug pretreated mice was investigated in vitro. Male C57BL/6N mice were either untreated or were given the inducers phenobarbital, 3-methylcholanthrene, beta-napthoflavone or pregnenolone-16alpha-carbonitrile. Mice were killed 24 hr after the last dose of the inducer. ... Microsomal fractions bound more radioactive label than the other subcellular fractions. Liver and lung microsomes covalently bound radiolabel, and binding was apparently correlated with cytochrome p450 content. Kidney microsomes had twice the cytochrome p450 content as lung microsomes, but only kidney microsomes pretreated with 3-methylcholanthrene and pregnenolone-16alpha-carbonitrile showed binding. Cytochrome p450 inhibitors, reduced covalent binding of radiolabel to liver and lung microsomes. Reduced glutathione also decreased covalent binding. Pretreated mice showed increases in total liver microsomal cytochrome p450 content and corresponding increases in covalent binding. Mouse liver and lung may metabolized and covalently bind 1,1-dichloroethylene, but that in the kidney binding is attributable to reactive intermediates that come from the liver via the blood. [R107] *Canalicular and mitochondrial membranes were investigated as early foci of hepatocyte injury in fed and fasted male Sprague-Dawley rats given 50 mg of 1,1-dichloroethylene/kg. Staining of the bile canaliculi localized enzymes, leucine aminopeptidase, and Mg2+ dependent ATPase, was examined by histochemistry in frozen sections. Mitochondrial membrane enzymes, including succinate dehydrogenase, also were examined by histochemistry. Staining of two monoclonal antibodies, C-1 and 9-B1, whose binding is localized in the bile canalicular region, was examined by immunofluorescence in frozen sections. Fasted rats treated with Mg2+ dependent ATPase developed moderate liver damage by 4 hr as evidenced by increases in serum transaminase and bilirubin, whereas fed rats developed only slight cell damage. Centrolobular loss of immunocytochemical and histochemical canalicular staining, especially for C-1 and 1,1-dichloroethylene, was evident as early as 1 hour after Mg2+ dependent ATPase and was striking by 2 hr in both fed and fasted rats. Decreases in mitochondrial enzymes were not evident histochemically in fed animals at any time after Mg2+ dependent ATPase and were found only at the later times in fasted animals given the toxin. [R108] NTOX: *Cytosolic Ca2+ rapidly rises to supraphysiologic levels in liver cells exposed to the hepatotoxins carbon tetrachloride and 1,1-dichloroethylene in vivo and in vitro. The study examines whether increases in intracellular Ca2+ activates endonucleases could initiate or contribute to the ensuing hepatotoxic events. There was no generalized breakdown of hepatic DNA in intact rats exposed to carbon tetrachloride and 1,1-dichloroethylene as assessed by the appearance of nucleosomal fragments in liver nuclear DNA separated on agarose gels. Nor was generalized fragmentation observed in DNA isolated from primary hepatocyte cultures exposed to halocarbons, except at very late times following loss of plasma membrane integrity. Endonuclease activation was further examined by specifically monitoring hypersensitive sites in serum albumin gene. Actively transcribed genes, such as albumin in liver tissue, are extremely sensitive to attack by exogenous nucleolytic enzymes at discrete sites. ... No cleavage at hypersensitive sites was detected in DNA isolated from rat liver or hepatocyte DNA at early times when elevations of Ca2+ were developing. Thus, endonuclease activation by intracellular Ca2+ and resultant nucleolytic destruction of DNA is not an early event in the hepatotoxicity produced by halocarbons. [R109] *The chlorinated ethylenes 1,1-dichloroethylene (vinylidene chloride), trans-1,2-dichloroethylene, trichloroethylene, and tetrachloroethylene (perchloroethylene) were assayed for their ability to induce mitotic gene conversion and point mutation as well as mitotic aneuploidy in diploid strains of the yeast Saccharomyces cerevisiae. From strain D7 late logarithmic-phase cells containing a high level of cytochrome p450, as well as stationary-phase cells combined with an exogenous metabolic activating sytem (S9) were used, to activate the chlorinated compounds and to produce electrophilic mutagenic intermediates. Only 1,1-dichloroethylene exhibited a dose-dependent genetic activity, while the other ethylenes did not. The two ways of metabolic activation were compared and were found to cause approximately the same effect. In contrast to the findings with strain D7, vinylidene chloride, trans-1,2-dichloroethylene, and trichloroethylene induced, without metabolic activation, mitotic chromosomal malsegregation in strain D61.M The presence of liver homogenate as an activating system did not enhance the respective frequencies of chromosome loss. [R110] *Hepatocytes isolated from male Sprague-Dawley rats were treated with carbon tetrachloride, 1,1-dichloroethylene, or phenylephrine, and the levels of cytosolic calcium were determined by evaluating the activity of glycogen-phosphorylase-a and by monitoring the fluorescence of cell permeant quin2. In 5 minutes, treatment with carbon tetrachloride, 1,1-dichloroethylene, or phenylephrine increased phosphorlase-a activity while in the presence of quin2 the basal Ca levels of 0.25 micromolar increased to 0.83, 0.59, and 0.99 micromolar, respectively. The increased phosphorlase-a activity in liver cells treated with carbon tetrachloride lasted at least 60 minutes, while the increase recorded with phenylephrine returned to basal levels in 20 minutes. The toxic effects of carbon tetrachloride and 1,1-dichloroethylene on the liver cells are manifested a sustained increase in the levels of calcium in the cytosls, while nontoxic phenylephrine induces a transient increase in the cytosolic concentrations of calcium. [R111] *The response of fed, fasted, and hyperthyroid Sprague-Dawley male rats to 50 mg 1,1-dichloroethylene/kg were compared. Hyperthyroid rats received three sc injections of thyroxine (100 micrograms/100 g) at 48 hr intervals. 1,1-Dichloroethylene was given po in mineral oil 24 hr after the last hyperthyroid dose. Animals were killed at 2, 4, and 8 hr. Liver glutathione contents were lowered about 55% by both fasting and hyperthyroid while glutathione transferase activities were lowered about 20% by fasting and 35% by hyperthyroid pretreatment lowered alcohol dehydrogenase activities. Liver injury (ie, serum glutamate pyruvate transaminase, histology) after 1,1-dichloroethylene was minimal in fed rats, moderate in fasted rats, and intermediate in hyperthyroid rats. Fasted rats showed a more pronounced depletion of liver glutathione after 1,1-dichloroethylene than hyperthyroid rats and only in fasted rats did the toxicant decrease activities of the detoxification enzymes. Hypoglycemia after 1,1-dichloroethylene occurred in rats, but more rapidly in hyperthyroid rats. In contrast, fasted rats unexpectedly became hyperglycemic after the toxicant. Patterns of body temperature change were dissimilar. Hypothermia was not observed in fed rats, was only transiently evident in hyperthyroid rats, but occurred rapidly within 1 hr in fasted rats and steadily became more severe. [R112] *In vivo ... pretreatment of rats with phenobarbital protected against the hepatotoxicity of vinylidene chloride. [R113] *Treatment of rats with 3-methylcholanthrene incr the liver microsome-mediated mutagenicity of vinylidene chloride in Salmonella typhimurium TA1530 approx two-fold. [R114] *The administration of 1,1-dichloroethylene (125 mg/kg ip) to CD-1 mice caused bronchiolar necrosis, which was accompanied by substantial covalent binding of radiolabeled compound and/or metabolite to lung. Lung injury and covalent binding were not modified by phenobarbital pretreatment. However, 3-methylcholanthrene provided protective influence but failed to alter covalent binding to lung macromolecules. Prior administration of piperonyl butoxide exacerbated bronchiolar injury by 1,1-dichloroethylene, but covalent binding remained unaltered. In contrast, SKF 525-A protected from lung damage and significantly decreased covalent binding. Hepatic necrosis was relatively mild, and was not observed in all animals treated with 1,1-dichloroethylene. Although the hepatic lesion was not modified by phenobarbital, liver injury was slightly diminished by 3-methylcholanthrene. Piperonyl butoxide and SKF 525-A enhanced liver necrosis, with the latter eliciting more severe effects than the former agent. Covalent binding to liver tissues was not significantly changed by pretreatment with either inducers or inhibitors. These results indicate lack of an unequivocal correlation of cellular injury with covalent binding, but suggest that metabolism may be involved in the pneumotoxicity by 1,1-dichloroethylene. [R115] *Data on mutagenesis and carcinogenesis by chlorinated ethylenes was reviewed, and studies on the relationship between chemical structrue and mutagenic activity in yeast were reported. ... Vinylidene chloride induced point mutations in bacterial test systems with exogenous bioactivtion. It was not mutagenic in V79 cells but induced some tumors in laboratory animals. Vinyldene chloride was mutagenic to Saccharomyces cerevisiae (D-7) in a dose related manner. Point mutations and mitotic gene conversions were induced with exogenous metabolic activation. In an in vivo Intrasanguinous Host Mediated Assay (IHMA), vinylidene induced mutations in Saccharomyces cerevisiae in liver and kidneys but not lung. [R116] *Male and female Sprague-Dawley rats were exposed to 100 ppm vinylidene chloride through inhalation, 4 to 7 hr daily, 5 days a week, for 104 weeks (breeders) or through the transplacental route followed by inhalation exposures (offspring) for 104 or 105 weeks. Vinylidene chloride was not found to affect survival of any of the exposed groups. ... Exposed offspring showed an increase incidence of leukemias, which was related to the length of treatment. The /data suggests/ that vinylidene chloride is carcinogenic in rat. [R117] *A comparative study on the short term toxicity of vinylidene chloride in male Sprague-Dawley rats and in both sexes of Swiss-Webster mice was reported. Animals (minimum of 10 per group) were exposed to an atmosphere containing vinylidene chloride at 40 or 200 mg/cu m (10 or 50 ppm) (mice) or 800 mg/cu m (200 ppm) (rats) for 6 hr, on 1, 3, or 8 days, and killed ane day after the last treatment. The majority of male mice exposed to 200 mg/cu m (50 ppm) for 8 days did not survive. However, female mice survived this treatment as did rats exposed to 800 mg/cu m (200 ppm). Various changes in the activities of monooxygenase, epoxide hydrolase, and glutathione transferase enzymes occurred in animals treated with vinylidene chloride. The enzyme changes could contribute to the relative susceptibility of the animals, according to the balance of activating and detoxifying activity. In particular, cystolic glutathione transferase activity towards the substrate 2,4-dinitrochlorobenzene was decreased in the kidneys of male mice (an organ susceptible to carcinogenicity, but not in the kidney of rats or female mice or in the liver of either of these species (where activity was either unchanged or enhanced). [R118] *Non-ciliated Clara cells of the pulmonary bronchiolar epithelium are preferentially damaged by the admin of 1,1-dichloroethylene to mice. In this study, an in vivo system was utilized to investigate the dose dependent effects of 1,1-dichloroethylene (75, 125, 175 and 225 mg/kg) on covalent binding and on reduced glutathione (GSH) in murine lung. Treatment of mice with each dose level of 1,1-dichloroethylene elicited significant decr in GSH content and resulted in covalent binding of (14)C-1,1-dichloroethylene in a dose dependent manner. Histochemical staining for GSH in lungs of control mice revealed positive cellular sites in alveolar septa and bronchiolar epithelium, with the highest staining intensities in Clara cells. Staining was reduced after exposure to 75 and 125 mg/kg 1,1-dichloroethylene, and at higher doses it was abolished in alveolar septa and retained in bronchiolar epithelium, albeit at considerably reduced intensities. Heterogeneity with respect to staining intensities was consistently observed in Clara cell population in both control and 1,1-dichloroethylene treated mice. Progressive increases in covalent binding and decreases in GSH content correlated with increasing severities of Clara cell injury. These correlated with increasing Clara cell injury. These results /indicate/ a dose dependence in regard to the magnitudes of (14)C-1,1-dichloroethylene binding, the alterations in cellular GSH, and the severities of Clara cell necrosis. [R119] *It was found that 1,1-dichloroethylene has the property of activating phospholipase A2 (PLA2) of isolated hepatocytes in suspension, as determined over a 60 to 120 min time period. PLA2 activation, measured as the appearance of lysophosphatidylethanolamine, preceded the release of lactic dehydrogenase during incubation of the cells at 37 deg C. It is concluded that for /this/ halogenated hydrocarbon phospholipase A2 activation must be part of the chain of causality leading from initial bioactivation to ultimate cell death. [R120] *The toxic effects of 1,1-dichloroethylene and its metabolites were studied in vitro. Hepatocytes isolated from the livers of untreated BALB/c and Swiss mice or mice pretreated with buthionine sulfoximine (BSO) were exposed to 1,1-dichloroethylene in vitro with or without the addition of N-acetylcysteine, octylamine, diethyldithiocarbamate or N,N-dimethylformamide. A concn dependent leakage of lactate dehydrogenase was seen following incubation of the cells with 1,1-dichloroethylene. Maximal toxicity was seen using a concn of 0.5 uM 1,1-dichloroethylene and the effect was similar on hepatocytes obtained from either of the two tested strains. The toxicity of 0.25 uM 1,1-dichloroethylene was increased in hepatocytes obtained from BSO pretreated mice and decreased in normal hepatocytes incubated with N-acetylcysteine. A drastic reduction in LDH release following 1,1-dichloroethylene exposure was seen with the addition of octylamine to the hepatocyte suspension. Hepatocytes obtained from animals pretreated with acetone or ethanol were more sensitive to the effects of 1,1-dichloroethylene than cells obtained from untreated animals or those treated with 3-methylcholanthrene or phenobarbital. A significant reduction in the toxicity of 1,1-dichloroethylene was seen with the addition of diethylenedithiocarbamate or N,N-dimethylformamide. The 1,1-dichloroethylene metabolites, chloroacetic acid and dichloroacetaldehyde demonstrated toxicity at concentrations of 0.75 uM and above. [R121] *A new protocol for testing vapors and gases in L5178Y mouse lymphoma assay is presented. Four chemicals, propylene, 1,2-propylene oxide, 1,3-butadiene and /1,1-dichloroethylene/ were tested for their mutagenic potential. Cultures were exposed to the chemicals, which were delivered as vapors or gases for 4 hr, then cultured for two days before plating in soft agar with or without trifluorothymidine, 3 ug/ml. Each chemical was tested at least twice. Significant responses were obtained with 1,2-propylene oxide and /1,1-dichloroethylene/. ... Rat liver S9 mix was not a requirement for the mutagenic activity of 1,2-propylene oxide, whereas the liver preparation markedly enhanced both the cytotoxicity and mutagenicity of /1,1-dichloroethylene/. [R122] *Under the conditions of this bioassay, vinylidene chloride administered by gavage was not carcinogenic for F344/N rats or B6C3Fl/N mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R123] *Pulmonary toxicity of vinylidene chloride was related to levels of CYP2E1 activity in male and female adult and weanling CD-1 mice following exposure to 50, 75 and 100 mg/kg body weight vinylidene chloride. For a given dose of vinylidene chloride, cytotoxicity was greatest in the lungs of male mice, followed in severity by male and female weanling mice and then female mice. Levels of CYP2E1 also followed this pattern, with adult male mice having the lowest concentrations of CYP2E1 in lung tissue and female adult mice having the greatest amount of the enzyme. Inhibition of CYP2E1 in male CD-1 mice by diallyl sulfone pretreatment resulted in an absence of pulmonary cytotoxicity following intraperitoneal injection of 75 mg/kg body weight vinylidene chloride. [R124] *Hyperthyroidism was noted to increase the hepatotoxicity, covalent binding and biliary clearance of vinylidene chloride in male Sprague-Dawley rats following oral administration of 50 mg/kg. Increased serum levels of markers of liver toxicity and decreases in hepatic glutathione S-transferase and alcohol dehydrogenase levels were noted in hypothyroid rats. Vinylidene chloride administered orally at doses of 50 or 200 mg/kg body weight caused alterations in biliary excretion of insulin and other marker solutes (indocyanine green and phenolphthalein glucuronide). These vinylidene chloride doses were also reported to cause damage to the bile canaliculi, with fasted rats exhibiting greater damage than fed rats. [R125] NTXV: *LC50 Rat (nonfasted) inhalation 10000-15000 ppm/4 hr; [R126] *LC50 Rat (fasted) inhalation 500-2500 ppm/4 hr; [R126] *LD50 Mouse oral approx 200 mg/kg; [R126] *LD50 Rat oral 1500 mg/kg; [R126] *LD50 Rat (adrenalectomized) oral 80 mg/kg body wt; [R126] *LD50 Rat oral 200 mg/kg; [R45] *LC50 Rat inhalation 6350 ppm/4 hr; [R45] *LD50 Mouse oral 194 mg/kg; [R45] ETXV: *LC50 Pimephales promelas (fathead minnow) 169,000 ug/l/96 hr in a static bioassay; 108,000 ug/l/96 hr flow-through bioassay; [R127] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL) 74 MG/L @ 24 HR AND 96 HR, TEMP @ 21-23 DEG C, WATER HARDNESS 32-48 MG/L (CALCIUM CARBONATE), PH 6.7-7.8, DISSOLVED OXYGEN CONCN 7.0-8.8 MG/L (STATIC BIOASSAY); [R128] *LC50 Cyprinodon variegatus (sheepshead minnow) 249 mg/l/24 hr, 48 hr, 72 hr, 96 hr in a static bioassay using sea water; [R129] *LC50 Mysidopsis bahia (mysid shrimp) > 798 mg/l/24 hr, 48 hr, 72 hr; 224 mg/l/96 hr in a static bioassay using seawater; [R129] *LC50 Lepomis macrochirus (bluegill) 220 ppm/96 hr in a static bioassay in fresh water at 23 deg C with mild aeration; [R130] *LC50 Menidia beryllina (inland silverside) 250 ppm/96 hr in a static bioassay in synthetic seawater at 23 deg C with mild aeration; [R130] *EC50 Selenastrum capricornutum (green alga) > 798,000 ug/l/96 hr, Toxic effects: inhibition of chlorophyll synthesis; cell count. /Conditions of bioassay not specified/; [R131] *EC50 Skeletonema costatum (alga) > 712,000 ug/l/96 hr, Toxic effects: Inhibition chlorophyll synthesis; reduced cell counts. /Conditions of bioassay not specified/; [R131] NTP: *A ... chronic carcinogenesis study of vinylidene chloride (99% pure), ... was conducted in F344/N rats and B6C3Fl/N mice. ... In the 104 wk chronic exposure study, conducted primarily to determine possible carcinogenic potential of vinylidene chloride by the oral route, 50 F344/N rats and 50 B6C3Fl/N mice of either sex were gavaged with vinylidene chloride suspended in corn oil at dose levels of 1 or 5 mg/kg (rats) and 2 or 10 mg/kg (mice). Groups of 50 rats and 50 mice of either sex received corn oil alone and served as vehicle controls. Under the conditions of this bioassay, vinylidene chloride administered by gavage was not carcinogenic for F344/N rats or B6C3Fl/N mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R123] TCAT: ?Chronic toxicity and oncogenicity were evaluated in groups of male and female Sprague-Dawley rats (80/sex/dose level) ingesting 1,1-dichloroethylene in drinking water at nominal doses of 50, 100 and 200 ppm (equivalent to 5-12, 18-20 and 16-40 mg/kg/day) every day for 2 years. Statistically significant treatment related differences were limited to the liver in which an increase in hepatic lesions was observed (females at all dose levels and males at 200 ppm) which usually had a minimal amount of hepatocellular fatty change and periportal hepatocellular hypertrophy. Statistically significant differences in pancreatic nodules (decreased in males at 100 ppm) and mammary gland fibroadenomas/adenofibromas (females at 50 ppm) were considered not to be treatment related. There were no statistical differences between treated animals and controls in the following: mortality, body weight, hematology, urinalysis, clinical chemistry, relative and absolute body weights and all pathologic and histopathologic observations except for those of the liver. [R132] ?Chronic toxicity and oncogenicity were evaluated in groups of male and female Sprague-Dawley rats (equally divided by sex) exposed to 1,1-dichloroethylene via inhalation at 0, 10 and 40 ppm for 5 weeks, then 0, 25 or 75 ppm for the remainder of the 18 months of exposure. Some of the animals were allowed to live and were observed for a total of 24 months. There were statistically significant differences between treated animals and controls in the following: incidence of several tumors and/or tumor types (increased or decreased in either sex at all dose levels, not judged to be treatment related), and liver histopathology as evidenced by hepatocellular fatty changes (increased in both sexes at 25 and 75 ppm at 12 months, but at 18 months only significant in females at 75 ppm). There were no statistical differences observed between treated animals and controls in the following: mortality, clinical chemistry, hematology, urinalysis, body weight, relative or absolute organ weights, and chromosomal aberrations in bone marrow preparations. [R133] ?As part of chronic inhalation study, the ability of 1,1-dichloroethylene to cause chromosome aberrations was evaluated in bone marrow cells of Sprague-Dawley rats (4/sex/group) receiving nominal concentrations of test material at 0, 25 or 75ppm in a dynamic air flow chamber for 6hours/day, 5days/week for 6 months. At the end of the six month exposure period, all animals were injected intraperitoneally with colchicine four hours prior to sacrifice. It was attempted to analyze 50 good metaphase spreads per animal, and although this was not always possible, it was considered that sufficient metaphases were available for analysis. No chromosome aberrations were observed in bone marrow cells of treated or control animals. [R134] POPL: *... Individuals with disorders of the central nervous system, liver, and kidney. [R73] ADE: *AS DOSE LEVEL OF RADIOACTIVE VINYLIDENE CHLORIDE IS INCR IN RATS FROM 1-50 MG/KG BODY WT ORALLY, OR FROM 40-800 MG/CU M (10-200 PPM) BY INHALATION, THE METABOLIC PATHWAY BECOMES SATURATED, SO THAT SMALLER PERCENTAGE OF DOSE ADMIN IS METABOLIZED AND MORE IS ELIMINATED VIA LUNG AS VINYLIDENE CHLORIDE. WITH THE 1 MG/KG BODY WT ORAL DOSE AND THE 10 PPM INHALATION DOSE, THERE WAS NO DIFFERENCE IN ELIMINATION BY FED VERSUS FASTED RATS. AT 50 MG/KG BODY WT ORALLY OR 200 PPM BY INHALATION, THERE WAS SIGNIFICANT INCR IN EXCRETION OF VINYLIDENE CHLORIDE VIA LUNG AND DECR IN URINARY EXCRETION OF RADIOACTIVITY IN FED VERSUS FASTED RATS. THE MAIN EXCRETORY ROUTE FOR (14)C-VINYLIDENE CHLORIDE AFTER INTRAGASTRIC, IV, OR IP ADMIN TO RATS IS PULMONARY: BOTH UNCHANGED VINYLIDENE CHLORIDE AND RELATED CARBON DIOXIDE ARE EXCRETED BY THAT ROUTE; OTHER VDC METABOLITES ARE ELIMINATED VIA KIDNEYS. [R81] *SEVENTY-TWO HR AFTER DOSE OF 0.5, 5.0 and 50.0 MG/KG, 1.26, 9.70, 16.47% RESPECTIVELY, ARE EXHALED AS UNCHANGED VINYLIDENE CHLORIDE, and 13.64, 11.35, 6.13% AS (14)C-CARBON DIOXIDE. MAIN PATHWAY OF ELIMINATION IS THROUGH RENAL EXCRETION WITH 43.55, 53.88, 42.11% OF THE ADMIN RADIOACTIVITY. THROUGH THE BILIARY SYSTEM, 15.74, 14.54, 7.65% OF THE ACTIVITY ARE ELIMINATED. [R135] *... Single oral doses of (14)C-VDC /were admin/ by gavage to groups of 4 200 g male Alderley Park rats; excretion of radioactivity was followed for 72 hr: at 0.5 mg/kg, 0.7% was exhaled in the air as unchanged vinylidene chloride, 4.8% as (14)CO2; 80.2% was excreted in the urine. At 350 mg/kg, however, 67.3% was exhaled as unchanged vinylidene chloride and 1.0% as (14)CO2; 29.5% was excreted in the urine. [R136] *The absorption kinetics of 1,1-dichloroethylene (DCE) was studied in male Fischer 344 rats exposed to DCE atmosphere exposure system. Initial concentrations ranged up to 4000 ppm. The atmosphere of the exposure systems was analyzed every 10 minutes by gas/liquid chromatography. Chemical to air and tissue to air coeffiecients were estimated by a vital equilibration method. Tissues utilized in the partition experiments included blood, liver, muscle, and fat. The data were used to investigate metabolism kinetics of the compounds. Uptake was adequately described by a single saturable metabolic pathway, and the metabolism was essentially abolished by pyrazole pretreatment. Maximum velocities of metabolism for the saturable pathways for 1,1-dichloroethylene was 27.2 moles per hour, calculated for a 225 gram rat. [R137] *A study of 1,1-dichloroethylene (1,1-DCE), was undertaken to contrast the kinetics of the chemical following iv injection with that following oral administration. Four dosage-levels of 1,1-dichloroethylene (10, 25, 50, and 100 mg/kg bw) in 50% aqueous polyethylene glycol 400 were given iv and po to fasted and nonfasted male Sprague-Dawley rats. Serial blood samples were taken from the tail artery of the lightly etherized animals for up to 490 min after dosing. The iv data revealed that disappearance of 1,1-dichloroethylene from the systemic circulation followed a triexponential pattern. Light ether anesthesia did not appear to alter the pharmacokinetics of iv injected 1,1-dichloroethylene. There was no difference between nonfasted and fasted iv rats in biological half-life or in any other pharmacokinetic parameter. Total body clearance, half-life, apparent volume of distribution and volume of distribution in the central compartment did show increases with increasing dose in these animals. Oral dosing experiments revealed that 1,1-dichloroethylene was absorbed very rapidly and completely from the gastrointestinal tract. Peak blood levels were reached 2 to 8 min following oral administration of 1,1-dichloroethylene as an aqueous suspension. The half-life of 1,1-dichloroethylene in orally dosed rats was somewhat longer than in their iv counterparts. The half-life values for nonfasted, orally dosed rats were longer than for their fasted counterparts, suggesting delayed absorption due to the presence of food. [R138] *A physiologically based pharmacokinetic model has been developed for vinylidene chloride in the rat based on oxidative metabolism of vinylidene chloride and subsequent glutathione detoxification of metabolite. The model offers insight into the complex interrelationship between the processes of absorption, metabolism, and glutathione conjugation, and simulates the manner in which these factors operate in regulating vinylidene chloride toxicity. The physiologically based pharmacokinetics model successfully predicts blood, tissue, and exhaled air concentrations of vinylidene chloride, and liver glutathione levels as a function of dose and route of administration. The model also explains the complex dose-response mortality curves seen with vinylidene chloride. Because of the low blood:air partition coefficient of vinylidene chloride and its saturable metabolism, the amount of vinylidene chloride dose that is metabolized is sensitive to the rate of absorption. After an intravenous bolus dose, most of the administered vinylidene chloride is exhaled unchanged within a few minutes. Blood vinylidene chloride half-life is not representative of metabolism rates but to reequilibration of vinylidene chloride from fat. Rats with greater fat content, therefore, display longer vinylidene chloride blood half-lives. [R139] METB: *BIOTRANSFORMATION OF VINYLIDENE CHLORIDE GIVES THIODIHYDROXYACETIC ACID AND N-ACETYL-S-CYSTEINYLACETYL DERIV AS MAJOR URINARY METABOLITES, TOGETHER WITH SUBSTANTIAL AMT OF CHLOROACETIC ACID, DITHIOHYDROXYACETIC ACID (DITHIOGLYCOLIC ACID) AND THIOHYDROXYACETIC ACID (THIOGLYCOLIC ACID). [R81] *METABOLIC CONVERSION OF VINYLIDENE CHLORIDE INTO AN EPOXIDE WHICH CAN REARRANGE TO CORRESPONDING ACYL CHLORIDE HAS BEEN PROPOSED. [R81] *Following administration of a single oral dose of (14)C-vinylidene chloride by gavage to 180-to-220 g female Wistar rats, isolated 24 hr urinary metabolites /included/ n-acetyl-S-(2-carboxymethyl)cysteine and n-(hydroxyethyl)-methylthioacetamide. [R140] *Comparative studies in mice and rats have revealed that mice, which are more susceptible to vinylidene chloride than rats, biotransform the chemical to a greater extent than rats. [R141] *A gram- positive, strictly anaerobic, motile, endospore-forming rod, tentatively identified as a proteolytic Clostridium sp, was isolated from the effluent of an anaerobic suspended-growth bioreactor. The organism was able to biotransform 1,1,1-trichloroethane, trichloromethane, and tetrachloromethane. 1,1,1-Trichloroethane was completely transformed (99.5%) by reductive dehalogenation to 1,1-dichloroethane (30 to 40%) and, presumably by other mechanisms, to acetic acid (7%) and unidentified products. ... 1,1-Dichloroethene, and 1,1-dichloroethane, were not biotransformed significantly by the organism. [R142] *In vivo metabolic constants were determined in male Fischer rats for five chemicals: 1,1-dichloroethylene, diethyl ether, bromochloromethane, methyl chloroform, and carbon tetrachloride in a closed recirculated exposure system. Metabolism of both 1,1-dichloroethylene and carbon tetrachloride was represented by a single saturable process while methyl chloroform required only a first-order pathway. Bromochloromethane and diethyl ether exhibited a combination of both a saturable and a first-order process. Pyrazole, which blocks oxidative microsomal metabolism, inhibited the saturable pathways of 1,1-dichloroethylene, bromochloromethane, diethyl ether, and carbon tetrachloride metabolism and abolished the first-order pathway for methyl chloroform. The maximum velocity of metabolism for the saturable pathway with 1,1-dichloroethylene, bromochloromethane, diethyl ether, and carbon tetrachloride for a 225 g rat was 27.2, 19.9, 26.1, and 0.92 mol/hr, respectively. The simulation approach distinguishes between single and multiple metabolic pathways. [R143] *The metabolic activation of 1,1-dichloroethylene by mouse lung and liver microsomes was studied in vitro. Lung and liver microsomes from CD-1-mice were incubated with (14)C-1,1-dichloroethylene. The effects on covalent binding of 1,1-dichloroethylene to microsomal macromolecules were determined. ... Phenobarbital pretreatment had no effect on 1,1-dichloroethylene microsomal binding. Pretreatment with 3-methylcholanthrene had no effect on 1,1-dichloroethylene lung microsomal binding, but increased 1,1-dichloroethylene liver microsome binding. Piperonyl butoxide inhibited binding in both microsome preparations. SKF525A inhibited binding only in liver microsomes. Lung and liver can metabolize 1,1-dichloroethylene as indicated by covalent binding of 1,1-dichloroethylene. [R144] *1,1-Dichloroethylene is hepatotoxic in mice and its cytotoxic effects are associated with cytochrome p450 dependent formation of metabolites that bind covalently to tissue macromolecules. /The effects/ of 1,1-dichloroethylene on p450 in liver microsomes /was investigated/. Specific objectives were to examine inactivation of p450 by 1,1-dichloroethylene and to determine if during this inactivation the heme and/or apoprotein moieties are destroyed and isozyme selective biotransformation of 1,1-dichloroethylene by p450. ... Results showed significant reduction of the p450 content in reactions containing 1,1-dichloroethylene and microsomes from untreated (30%) or phenobarbital treated (20%) mice. Maximal reduction (50%) of p450 was evoked by 1,1-dichloroethylene in reactions catalyzed by microsomes from acetone treated mice. Alterations in heme levels were not detected in any microsomal preparation incubated in the presence of 1,1-dichloroethylene. Significant inhibition of p-nitrophenol hydroxylation was found in microsomes incubated previously with 1,1-dichloroethylene and was most pronounced in acetone treated mice, as compared to control and phenobarbital treated mice. 1,1-Dichloroethylene did not cause inhibition of 7-pentoxyresorufin-O-dealkylation in any microsomal preparation. Immunoinhibition with an anti-2E1 antibody abolished the observed inhibition of p-nitrophenol hydroxylation. Densitometric scanning of protein immunoblots using an anti-2E1 antibody revealed a 40% decr in microsomes reacted with 1,1-dichloroethylene, whereas no change was observed in immunoblots prepared with an anti-2B antibody. These results showed biotransformation of 1,1-dichloroethylene is catalyzed by the 2E1 and not by the 2B enzyme and 1,1-dichloroethylene inactivates p450 by destruction of the apoprotein rather than the heme moieties. [R145] *Vinylidene chloride has been shown to be activated by human liver S9 supernatant in the Ames assay, suggesting the presence of a cytochrome p450 enzyme. Also, the formation of dichloroacetaldehyde was demonstrated in two human liver microsomal preparations; the rate of formation was approximately the same as in rat liver microsomes. [R146] *In rats, metabolism, which probably proceeds via a cytochrome p450 generated epoxide intermediate and subsequent either direct or indirect glutathione conjugation, is saturated between doses of 1-50 mg/kg body weight orally or 10-200 ppm (40-800 mg/cu m) by inhalation, resulting in a dose dependent increased elimination via the lungs as unchanged vinylidene chloride. Mice metabolize vinylidene chloride to a greater extent than rats. Also the alkylation of proteins by vinylidene chloride metabolites is greater in mice than in rats. Metabolic activation via epoxidation was suggested. [R146] BHL: *In male Sprague-Dawley rats, the t1/2 (after dose of 10 to 100 mg/kg) was 46-55 min after iv admin in fasted rats, 62-69 min after oral admin in fasted rats, 42-63 min after iv admin in nonfasted rats, and 78-138 min after oral admin in nonfasted rats. [R138] ACTN: *Effects of pretreatment with metabolic inducers and inhibitors on covalent binding and cellular reactivity in lung and liver of CD-1 mice following intraperitoneal injection of 1,1-dichloroethylene (1,1-DCE) were investigated. Pretreatment with 3-methylcholanthrene produced marked proliferation of membranes of smooth endoplasmic reticulum in Clara cells, while similar pulmonary cellular reactivity was not evoked by administration of phenobarbital. Administration of SKF-525A in conjunction with 1,1-DCE resulted in loss of apical bulges characteristic of Clara cells and, concomitantly, a reduction in smooth endoplasmic reticulum. ... No potentiation in hepatocellular necrosis by pretreatment with phenobarbital was noted. Pretreatment with 3-methylcholanthrene provided a small degree of protection from pulmonary and hepatic injury. Pretreatment with SKF-525A indicates that alkylation reactions in the lung appear to be directed to macromolecules which are not critical to the integrity of Clara cells, or occurred at noncritical sites, while those in the liver may not follow similar patterns of reactivities. Prior treatment of piperonyl-butoxide exacerbated injury in both lung and liver, but elicited no alterations in concentrations of covalently bound 1,1-DCE. These results suggest the lack of an association between pneumotoxicity and metabolism through a p448 dependent pathway. [R147] *The role of calcium ions in halocarbon hepatotoxicity in rats is reviewed. Halogenated hydrocarbons, including 1,1-dichloroethylene, ... are potent hepatotoxins. They cause a wide spectrum of hepatocellular dysfunctions such as surface blebbing, decreased lipid secretion, fatty liver, decreased protein synthesis, loss of glycogen, and cell necrosis. An early consequence of 1,1-dichloroethylene poisoning in rats is destruction of the calcium ion sequestering ability of the endoplasmic reticulum. ... The intracellular calcium content of hepatocytes is decreased. The evidence suggests that calcium released from the endoplasmic reticulum is transported from the cell by the activity of the plasma membrane calcium adenosine triphosphatase. [R148] *Admin of 1,1-dichloroethylene to mice evokes cytotoxicity involving Clara cells in lung and at higher doses centrilobular hepatocytes in liver. /The/ objective is to investigate temporal alterations in nonprotein sulfhydryl glutathione (GSH) content in lung and liver after admin of a dose of 1,1-dichloroethylene 125 /kg. Contribution of GSH from whole blood comprised 54% and of the amounts found in lung and liver, respectively, of 1,1-dichloroethylene treated mice and were taken into account to determine tissue content of GSH. In lung, a significant decrease in GSH (60% of control) was first detected at 6 hr and levels remained low from 8 to 12 hr. In liver, a 50% decrease was initially detected at 1 hr after 1,1-dichloroethylene treatment. Progressive increases were found thereafter with a return to the control level at 24 hr. Histochemical staining for GSH in liver revealed homogeneous labeling in hepatocytes across the lobule; 1,1-dichloroethylene treatment diminished staining uniformly in all hepatocytes. In control lung histochemical reactivity was exhibited in bronchiolar epithelium and alveolar septa. Clara cells were stained to the greatest extent and with considerable variability whereas staining was more uniform in alveolar septa. Staining was markedly diminished by 1,1-dichloroethylene treatment and was initially abolished in the alveolar septa but retained to a limited extent within a small number of Clara cells. These findings suggest that susceptibility of a subpopulation of Clara cells to cytotoxicity may be associated, in part, with low expression of nonprotein sulfhydryl content at the time of 1,1-dichloroethylene treatment. [R149] INTC: *To determine if L-2-oxothiazolidine-4-carboxylate protects rats from the hepatoxicity of 1,1-dichloroethylene, fasted male Sprague-Dawley-rats were treated with 10 mm/kg of L-2-oxothiazolidine-4-carboxylate sc, or an equivalent amount of saline, 1 hour prior to the peritoneal administration of 50 mg/kg 1,1-dichloroethylene. Serum alanine-aminotransferase was used to monitor onset, peak, and extent of liver damage. L-2-oxothiazolidine-4- carboxylate pretreated rats showed consistently lower serum alanine- aminotransferase activities 2 to 24 hr after 1,1-dichloroethylene. Alanine-aminotransferase activities in L-2-oxothiazolidine-4-carboxylate pretreated rats exceeded control levels at about 4 hr after 1,1-dichloroethylene treatment compared to only 2 hr in the saline pretreated group. Peak alanine-aminotransferase values were approximately ten fold lower in the L-2-oxothiazolidine-4-carboxylate treated animals indicating a protective effect of L-2-oxothiazolidine-4-carboxylate on 1,1-dichloroethylene hepatotoxicity. This protection was associated with about 50% less total, acid soluble and acid precipitable 1,1-dichloroethylene in serum, 30% less in urine and at 24 hr 30 to 68% less covalently bound in the liver, kidney and lung. Peak liver injury correlated well with the amount of 1,1-dichloroethylene in serum at early times and with the amount covalently bound to liver at 24 hr. There was only a poor correlation with 1,1-dichloroethylene in the urine. Fasted rats demonstrated a persistent loss of hepatic cytochrome p450 at 3 and 6 hr whereas their hepatic and renal reduced glutathione contents were transiently diminished at 3 hr. The L-2-oxothiazolidine-4-carboxylate induced loss of hepatic cytochrome p450 which converted 1,1-dichloroethylene to reactive intermediates, contributed to the apparent decrease in toxin metabolism and therefore to the L-2-oxothiazolidine-4-carboxylate protection against 1,1-dichloroethylene induced liver injury. [R150] *Pretreatment of rodents with diethyldithiocarbamate, carbon disulfide, ... thiram or disulfiram resulted in different degrees of protection against the acute toxicity of vinylidene chloride. [R104] *The inhibitor of mixed-function oxidase, SKF-525A, had no effect on mortality in immature rats (80-100 g), but markedly exacerbated 1,1-dichloroethylene toxicity in rats weighing 260-270 g. Pretreatment with 3-aminotriazole or carbon tetrachloride protected fasted, male rats of all sizes tested from lethal effects of doses of 1,1-dichloroethylene below 700 mg/kg. [R151] *Pyrrazole, a cytochrome p450 antagonist, was found to inhibit the uptake and toxic effects of vinylidene chloride in a perfused rat liver system. [R152] *Treatment with the glutathione depleting agent ... vinylidene chloride dose dependently inhibited paw edema induced by carrageenan in rats. This effect was accompanied by a decrease in the glutathione concn of the target tissue ... and may result in an inhibition of prostaglandin biosynthesis. ... [R153] *VINYLIDENE CHLORIDE WAS TESTED FOR CARCINOGENICITY BY CHRONIC ADMIN BY ONE OR MORE ROUTES IN HA:ICR SWISS MICE. IT WAS ACTIVE A SKIN TUMOR INITIATOR IN 2 STAGE CARCINOGENESIS ASSAYS; PHORBOL MYRISTATE ACETATE WAS USED AS A PROMOTER. [R154] *Simultaneous admin of vinyl chloride with vinylidene chloride prevented the hepatotoxicity associated with vinylidene chloride inhalation in fasted rats. [R104] *Male Fischer-344 rats were tested to determine kinetic constants for trichloroethylene and 1,1-dichloroethylene and to develop a linked model for examing the pattern of the pharmacokinetic interactions between the two agents, using gas uptake simulation methods. The respective allometrically scaled maximum velocities for trichloroethylene and 1,1-dichloroethylene equalled 11 and 7.5 mg/hr. Mixtures of the two products were used to determine uptake curves described by equations based on pharmacokinetic models in which each product was regarded as the metabolic inhibitor of the other. ... Good correlation between predicted and observed behavior was obtained when inhibition was considered to be competitive for binding contants of 0.25 and 0.10 mg/l of trichloroethylene and 1,1-dichloroethylene, respectively. This model to predict conditions of 1,1-dichloroethylene induced hepatotoxicity during exposure to a constant concentration of the agents tested was compared with the activity of liver enzymes in the plasma of animals exposed to 1,1-dichloroethylene alone or in combination with trichloroethylene. [R155] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,1-Dichloroethylene's production and use as a copolymer in various types of saran, in adhesives, and as a component of synthetic fibers may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 600 mm Hg at 25 deg C indicates 1,1-dichloroethylene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,1-dichloroethylene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 1.5 days. Products which are formed in the photooxidation of 1,1-dichloroethylene in the presence of nitrogen oxides include chloroacetyl chloride, phosgene, formaldehyde, formic acid, hydrochloric acid, carbon monoxide, and nitric acid. If released to soil, 1,1-dichloroethylene is expected to have high mobility based upon a Koc of 64. Volatilization from moist soil surfaces is expected to be an important fate process based upon a estimated Henry's Law constant of 2.61X10-2 atm-cu m/mole. If released into water, 1,1-dichloroethylene is not expected to adsorb to suspended solids and sediment based upon the Koc. Aerobic biodegradation is not expected to be an important fate process, with 1,1-dichloroethylene reaching 0% of its theoretical BOD in 4 weeks using the Closed Bottle Test. However, in anaerobic microcosms designed to simulate a groundwater environment, 50% of the 1,1-dichloroethylene disappeared in 5-6 months. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively. A BCF range of 2.5 to < 13 suggests bioconcentration in aquatic organisms is low. A hydrolysis half-life of 6-9 months has been observed with no significant difference in hydrolysis rate between pH 4.5 and 8.5. Occupational exposure to 1,1-dichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where 1,1-dichloroethylene is produced or used. Monitoring data indicate that the general population may be exposed to 1,1-dichloroethylene via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and other consumer products containing 1,1-dichloroethylene, such as plastic wrap which contains residual monomer. (SRC) NATS: *Vinylidene chloride is not known to occur as a natural product(1). [R156] ARTS: *1,1-Dichloroethylene's production and use as a copolymer in various types of saran, in adhesives, and as a component of synthetic fibers(1) may result in its release to the environment through various waste streams(SRC). 1,1-Dichloroethylene is formed by a minor pathway during the anaerobic biodegradation of trichloroethylene(4) and also by the hydrolysis of 1,1,1-trichloroethane(3). Therefore, there is a potential for it to form in groundwater that has been contaminated by chlorinated solvents. 1,1-Dichloroethylene is also produced by the thermal decomposition of 1,1,1-trichloroethane, a reaction that is catalyzed by copper(2). 1,1,1-Trichloroethane is used as a degreasing agent in welding shops so there is a potential for 1,1-dichloroethylene to be formed in these shops as well as in other industrial environments where 1,1,1-trichloroethane is used near sources of heat(2). [R157] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), a Koc value of 64(2), indicates that 1,1-dichloroethylene is expected to have high mobility in soil(SRC). Volatilization of 1,1-dichloroethylene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 2.61X10-2 atm-cu m/mole(3). The potential for volatilization of 1,1-dichloroethylene from dry soil surfaces may exist(SRC) based upon a estimated vapor pressure of 600 mm Hg(4). Biodegardation in soil is not an important environmental fate process(SRC) based a 0% theoretical BOD(5). However, anaerobic degradation may occur, with degradation occurring in 1-3 weeks under simulated landfill conditions(6). [R158] *AQUATIC FATE: Based on a classification scheme(1), a Koc value of 64(2), indicates that 1,1-dichloroethylene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 2.61X10-2 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 2 hrs and 4 days, respectively(SRC). In water, the photooxidation of 1,1-dichloroethylene is insignificant(5,6). A hydrolysis half-life of 6-9 months has been observed with no significant difference in hydrolysis rate between pH 4.5 and 8.5(7). According to a classification scheme(8), BCF values of 2.5 to < 13(9), suggest bioconcentration in aquatic organisms is low(SRC). Biodegradation in water is not expected to be an important fate process, with 1,1-dichloroethylene reaching 0% of its theoretical BOD in 4 weeks(9). However, in anaerobic microcosms designed to simulate a groundwater environment, 50% of the 1,1-dichloroethylene disappeared in 5-6 months(10). [R159] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,1-dichloroethylene, which has a vapor pressure of 600 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,1-dichloroethylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1.5 days(SRC), calculated from its rate constant of 1.09X10-11 cu cm/molecule-sec at 25 deg C(3). Under photochemical smog situations with nitrogen dioxide present, 1,1-dichloroethylene decomposes rapidly (half-life < 2 hr)(4). [R160] BIOD: *AEROBIC: 1,1-Dichloroethylene, present at 9.7 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 2 mg/l and the Closed Bottle Test(1). In another study, 45-78% of the chemical was lost in 7 days when incubated with a wastewater inoculum; however, a sizeable fraction of the loss was due to volatilization(2). 97% of 1,1-dichloroethylene was reported to be removed in a municipal wastewater plant(3) but again the fraction lost by evaporation is unknown(SRC). 1,1-Dichloroethylene at a concn of 160 ug/l was degraded using continuous mixed, batch-fed reactors at a 20-day operating solids retention time(4). [R161] *ANAEROBIC: Using microcosms designed to simulate the anaerobic conditions in groundwater(1) and landfills(2), 1,1-dichloroethylene underwent reductive dechlorination to vinyl chloride. In the microcosms designed to simulate a groundwater environment, 50% of the 1,1-dichloroethylene disappeared in 5-6 months(1). Under the simulated landfill conditions, degradation occurred in 1-3 weeks(2). In another anaerobic biodegradation study that used materials from an aquifer that receive municipal landfill leachate and is known to support methanogenesis, 1,1-dichloroethylene disappeared in 40 weeks(3). However, no significant degradation occurred for 16 weeks. 1,1-Dichloroethylene was formed from the municipal solid waste as a degradation product(3). An effluent concn of 2 ug/l was measured using continuous mixed, batch-fed reactors at a 53-day operating solids retention time with 1,1-dichloroethylene influent at a concn of 120 ug/l(4). [R162] ABIO: *The rate constant for the vapor-phase reaction of 1,1-dichloroethylene with photochemically-produced hydroxyl radicals is 1.09X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 1.5 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of 1,1-dichloroethylene with ozone has been estimated as 3.6X10-20 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(2). This corresponds to an atmospheric half-life of about 320 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). [R163] *Under photochemical smog situations with nitrogen dioxide present, 1,1-dichloroethylene decomposes rapidly (half-life < 2 hr)(2). Products which are formed in the photooxidation of 1,1-dichloroethylene in the presence of nitrogen oxides include chloroacetyl chloride, phosgene, formaldehyde, formic acid, hydrochloric acid, carbon monoxide, and nitric acid(1,2). When adsorbed on silica gel, 1,1-dichloroethylene undergoes photolysis; approximately 72% of it degrades on exposure to 170 hrs of sunlight(5). In water, the photooxidation of 1,1-dichloroethylene is insignificant(3,4). A hydrolysis half-life of 6-9 months has been observed with no significant difference in hydrolysis rate between pH 4.5 and 8.5(6). This value differs markedly from the estimated hydrolytic half-life of 2 yr at pH 7(7). The environmental base-catalyzed hydrolysis half-life at 25 deg C and pH 7 for 1,1-dichloroethylene was 1.2X10+8 yrs(8). [R164] BIOC: *BCFs of 2.5 to 6.4 and < 13 were measured for 1,1-dichloroethylene at concns of 0.5 and 0.05 mg/l, respectively(1). According to a classification scheme(2), these BCF values suggest bioconcentration in aquatic organisms is low(SRC). [R165] KOC: *The Koc for 1,1-dichloroethylene is 64(1). According to a classification scheme(2), this Koc value suggests that 1,1-dichloroethylene is expected to have high mobility in soil. [R166] VWS: *The Henry's Law constant for 1,1-dichloroethylene is 2.61X10-2 atm-cu m/mole(1). This Henry's Law constant indicates that 1,1-dichloroethylene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 2 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). 1,1-Dichloroethylene's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,1-dichloroethylene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 600 mm Hg(3). [R167] WATC: *GROUNDWATER: Contaminated drinking water wells in New Jersey, Massachusetts and Maine had maximum 1,1-dichloroethylene concentrations of 280, 118, and 70 ppb, respectively(3). A 13-US city survey of raw groundwater supplies resulted in 15.4% pos, and 0.5 ppb avg and max(2). Miami, Florida had 0.1 ppb 1,1-dichloroethylene in their raw drinking water supply(1). 1,1-Dichloroethylene was detected in several domestic and industrial well water samples in Sacramento, CA(4). In a survey of 15 Japanese cities conducted in 1982, 10 of 1,083 shallow wells and 3 of 277 deep wells were found to contain 1,1-dichloroethylene(5). [R168] *DRINKING WATER: In a nationwide survey, 1,1-dichloroethylene was detected in 7.1% of finished supplies from groundwater sources(4). In 1979, the highest reported concn was 0.1 ppb(1,3). Of 103 USA cities sampled, 1.9% pos, 0.36 mean ppb mean, 0.2-0.51 ppb range in finished surface water(5). 13 USA cities sampled, 7.7% pos, 0.2 ppb mean and max, in finished groundwater(2,5). In a screening of 1174 community wells and 617 private wells in Wisconsin, 1 community and 3 private wells had detectable levels of 1,1-dichloroethylene(6). According to the USA Groundwater Supply Survey (945 supplies derived from groundwater chosen both randomly and on the basis that they may contain VOCs) 24 samples were positive for 1,1-dichloroethylene, with a max of 6.3 ppb(7). Mean and max conc of 1,1-dichloroethylene in 2 New Jersey drinking water supplies serving roughly 100,000 persons each ranged from 0.1-0.2 and 0.9-2.5 ppb, respectively(8). 1,1-Dichloroethylene was one of the most frequently detected pollutants in California public drinking water wells, sampled during 1984 and 1990(9). It was present in 72 of 7,712 wells sampled at a max concn of 78 ug/l(9). [R169] *SURFACE WATER: 1,1-Dichloroethylene was detected in 3 tributaries and 7 of 8 sites on the Ohio River (4972 samples, 343 pos): 304 samples 0.1 to 1.0 ppb, 36 samples 1.0 to 10 ppb, and 3 samples > 10 ppb(3). 2 of 4 cities with surface water contaminated with industrial, municipal, agricultural, and natural waste, which also acted as a source of drinking water supply contained 1,1-dichloroethylene in the raw water; of the pos supplies one contained < 0.1 ppb and one was not quantified(1). In a survey of 105 USA cities using surface water supplies, no 1,1-dichloroethylene was detected in the raw water(2). The reported concn of 1,1-dichloroethylene in Quantico Creek water, off the Potomac River, VA collected in the spring of 1986 was < 2 ug/l(4). [R170] EFFL: *1,1-Dichloroethylene was detected, not quantified, in effluent from USA latex and chemical manufacturing plants(1,2). A concn of 32 ppb was detected in wastewater discharged from a chemical manufacturing plant in the Netherlands(1,2). Concns in samples from the 4 largest, publicly owned, treatment plants in Southern Calif were as follows: primary effluent, 3 of 4 pos, < 10 to 20 ppb, secondary effluent, 2 of 3 pos, < 10 ppb, 7 mile sludge and centrate, 2 of 3 pos, < 10 ppb(3). It was detected in 1 of 2 municipal treatment plants(4). Industries with mean 1,1-dichloroethylene effluent concn > 100 ppb were as follows: metal finishing (760 ppb), non-ferrous metal mfg and organic chemicals mfg/plastics(5). 17% of 48 samples of influent to a sewage treatment plant in US tested positive, with 5.0 ppb being the avg concn when found above detection limit(4). [R171] ATMC: *URBAN/SUBURBAN: 1,1-Dichloroethylene was detected in 325 USA samples at 8.0 parts/trillion mean, 5 parts/trillion median, with 25% of samples > 7.5 parts/trillion and a max concn of 2400 parts/trillion(1). It was detected but not quantified in samples from representative cities in New Jersey(4,5). Samples from 3 western USA urban areas contained 4.9 to 28.8 parts/trillion mean concn(6). Samples from 5 unspecified US cities contained concns of 0-31 part/trillion avg, with 34-224 parts/trillion max(7). [R172] *INDOOR AIR: 1,1-Dichloroethylene was found in 4 of 15 samples of indoor air taken during the summer, concn range of 1.8-93.6 ppb, and 4 of 16 samples taken during the winter, concn range of 5.0-9.6 ppb(1). None of the chemical was found in parallel samples taken out of doors(1). No correlation was found between the presence of 1,1-dichloroethylene in indoor air and structural characteristics of the dwelling or activity(1). [R173] *RURAL/REMOTE: 1,1-Dichloroethylene was not detected in 2 unspecifed USA samples(1), but has been reported at < 5 parts/trillion the rural northwest near Pullman, WA(2), and in the Grand Canyon, AR at 0.065 ppb(3). [R174] *SOURCE DOMINATED: 14 samples in the USA, location unspecified, showed a mean 1,1-dichloroethylene concn of 3800 parts/trillion, a median of 3600 parts/trillion, and a max of 6700 parts/trillion(1). Samples from the Kin-Buc Disposal site, Edison, NJ contained a concn of 114-148 parts/trillion; 1,1-dichloroethylene was not detected downwind of several petroleum facilities in Baton Rouge, LA(2). Samples from 5 Dow plant sites, one at Freeport, TX, four at Plaquemine, LA, contained 1,1-dichloroethylene concns ranging from 9 to 249 parts/trillion(3). It was not detected at 7 other Dow sites at Plaquemine, LA(3). 1,1-Dichloroethylene was detected in gas emitted from municipal landfill sanitary sites in the US at an avg concn of 130 ppb volume(4). 1,1-Dichloroethylene represented 0.2% of the total non-methane organic compounds in the gas collection system from the Fresh Kills landfill in New York City, NY(5). [R175] FOOD: *Although no monitoring data could be found, vinylidene chloride is a known contaminant in plastic wrap made from this monomer; the maximum amount possible that could be adsorbed by food from such food wraps has been estimated to be less than or equal to the detection limit (< 10 ppb)(1). [R176] RTEX: *Humans are exposed to vinylidene chloride from ambient air, particularly near industrial sources and contaminated drinking water. Indoor air sometimes contains vinylidene chloride although its source is unknown. Exposure can also occur from ingestion of food wrapped in plastic that contains residue vinylidene chloride monomer(1). [R176] *Number of exposed workers not available; however, the estimated population residing near plants manufacturing monomers and polymers of vinylidene chloride in 1976 is 3,573,385(1,2). Levels of 8 mg/cu m (2 ppm) were reported to occur as contaminants in atmospheres of submarines, and levels of 0-2 ppm have been found in spacecraft(3). [R177] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,679 workers (291 of these are female) are potentially exposed to 1,1-dichloroethylene in the US(1). Occupational exposure to 1,1-dichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where 1,1-dichloroethylene is produced or used(SRC). Monitoring data indicate that the general population may be exposed to 1,1-dichloroethylene via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and consumer containing 1,1-dichloroethylene(SRC). [R178] BODY: *12% of approximately 300 breath samples from residents of Elizabeth and Bayonne New Jersey contained quantifiable levels (0.2-2 ug/cu m) of 1,1-dichloroethylene(1). [R179] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers vinylidene chloride to be a potential occupational carcinogen. [R21] NREC: *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R21] *NIOSH considers vinylidene chloride to be a potential occupational carcinogen. [R21] TLV: *8 hr Time Weighted Avg (TWA) 5 ppm [R180, 2001.59] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R180, 2001.6] *A4: Not classifiable as a human carcinogen. [R180, 2001.59] OOPL: *Occupational exposure limits to vinylidene chloride have been set by ... /the following/ countries ... Belgium (1978) Time weighted (TWA) 40 mg/cu m; Finland (1981) TWA 40 ppm, Short Term Exposure Limit (STEL) 80 mg/cu m for 15 min; Germany Federal Republic of (1984) TWA 40 mg/cu m; The Netherlands (1978) TWA 40 mg/cu m; Poland (1976) ceiling limit 50 mg/cu m; Romania (1975) TWA 500 mg/cu m, ceiling limit 700 mg/cu m; Sweden (1984) TWA 20 mg/cu m, STEL 40 mg/cu m; Switzerland (1978) TWA 40 mg/cu m; UK (1985) TWA 40 mg/cu m, STEL 80 mg/cu m for 10 min; ... USSR (1977) ceiling limit 50 mg/cu m. /From table/ [R181] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. 1,1-Dichloroethylene is produced, as an intermediate or a final product, by process units covered under this subpart. [R182] *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,1-Dichloroethylene is included on this list. [R183] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 7 ug/l [R184] FEDERAL DRINKING WATER GUIDELINES: +EPA 7 ug/l [R184] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 6 ug/l [R184] +(NJ) NEW JERSEY 2 ug/l [R184] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 7 ug/l [R184] +(CT) CONNECTICUT 7 ug/l [R184] +(ME) MAINE 7 ug/l [R184] +(MN) MINNESOTA 6 ug/l [R184] CWA: +Vinylidene chloride is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R185] +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Dichloroethylenes (1,1-, and 1,2-dichloroethylene)/ [R186] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R187] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R188] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Vinylidene chloride is included on this list. [R189] RCRA: *U078; As stipulated in 40 CFR 261.33, when 1,1-dichloroethylene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R190] *D029; A solid waste containing 1,1-dichloroethylene may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R191] FDA: *Vinylidene chloride is an indirect food additive for use only as a component of adhesives. [R192] *Substances used in the manufacture of paper and paperboard products used in food packaging shall include: Vinylidene chlorides (polymerized). [R193] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Sampling techniques using activated carbon adsorbent ... have been evaluated for determining vinylidene chloride in industrial atmospheres. [R194] *VINYLIDENE CHLORIDE HAS BEEN IDENTIFIED IN AIR BY TRAPPING IN PYRIDINE ... /USING AN IMPINGER/. [R194] *NIOSH Method 1015: Matrix: air; Analyte: 1,1-dichloroethylene; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Minimun vol: 2.5 l @ 1 ppm, Max vol: 7 l; Sample stability: 7 days @ 25 deg C; 21 days @ 5 deg C; Field blanks: 10% of samples. [R195] *Method 8010: Halogenated Volatile Organics. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw-cap VOA vial equipped with a Teflon-faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. [R196] ALAB: *NIOSH 1015: Analyte: Vinylidene chloride; Matrix: air; Technique: Gas chromatography, flame ionization detection; Desorption: 1 ml carbon disulfide; stand 30 min; Injection vol: 5 ul; Temp: injection 150 deg C, detector 200 deg C, column: 65 deg C; Carrier gas: Helium or nitrogen, 30 ml/min; Column: Silanized glass, 3 m x 6 mm outer diameter, packed with Durapak OPN 100/120 mesh or equivalent. Calibration: Std soln of vinylidene chloride in carbon disulfide; Range: 0.01 to 0.1 mg/sample; Estimated limit of detection: 0.007 mg/sample; Precision (relative std deviation): 0.048 @ 0.012 to 0.085 mg/sample; Interferences: The gas chromatography column will not separate vinyl chloride and carbon disulfide. Other gas chromatography packings that separate vinyl chloride or carbon disulfide may not separate vinylidene chloride and carbon sulfide. If determination of both of these monomers is to be performed, use two different gas chromatography columns. [R195] *Gas chromatography has been used to determine vinylidene chloride as an impurity in trichloroethylene and in vinyl chloride monomer, with a limit of detection of 5 mg/kg. The same method has been applied to the detection of free vinylidene chloride in latex. [R194] *Vinylidene chloride has been detected in Saran films by gas chromatography, with electron capture detection and mass spectrometry confirmation. The limit of detection of the method was 5 mg/kg. [R78] *The compounds /including vinylidene chloride/ were thermally desorbed and analyzed by gas chromatography using a flame-ionization detection; the limit of detection was 4 ug/cu m (1 ppb). [R78] *Matrix: soil; Sample prepn: Extract with n-hexane; add internal std; Assay procedure: Gas chromatography/electron capture detection. /From table/ [R197] *Sample matrix: foods; Sample prepn: Withdraw vapor sample from headspace at 90 deg C; Assay procedure: Gas chromatography/electron capture detection; Limit of detection: 1 ug/kg (validated at 4-50 ug/kg). [R197] *EMSLC Methods 502.1 and 502.2; Gas Chromatography/Electrolytic conductivity detector, Detection limits of 0.003 and 0.07 ug/L, respectively; EMSLC Methods 524.1 and 524.2; Gas Chromatography/Mass Spectrometry, Detection limits 0.2 ug/L and 0.12 ug/L, respectively. [R198] *OSHA Method 19; Gas Chromatography, Detection limit 0.05 ppm. [R199] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. Method detection limit = 0.130 ug/l. [R200] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. Method detection limit = 2.80 ug/l. [R200] *OSW Method 8240B. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Estimated quantitation limit = 5.000 ug/l. [R200] *AREAL IP-1B. Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbent Tubes. Detection limit = 6.9 ng. [R200] *AREAL TO-14. Determination of Volatile Organic Compounds (VOCs) in Ambient Air using SUMMA Passivated Canister Sampling and Gas Chromatographic Analysis. [R200] *EPA Method CLP OHC. Organics Analysis, Multi-Media, High-Concentration. Detection limit = 2.5 mg/kg. [R200] *EPA Method CLP MC_VOA. Analysis of Water for Low Concentration Volatile Organic Compounds by Gas Chromatography/Mass Spectroscopy. Contract required quantitation limit = 1 ug/l. [R200] *EPA Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. Method detection limit = 10 ug/l. [R200] *EMSLC Method 624-S. Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. Method detection limit = 4.7 ug/l. [R200] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit = 0.120 ug/l. [R200] *OSW Method 8021A. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. Method detection limit = 0.070 ug/l. [R200] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. Method detection limit = 0.003 ug/l. [R200] CLAB: *A method is presented which is suitable for the analysis of certain halocarbons in blood and tissue samples. Among these halocarbons is ... dichloroethylene. ... [R201] *The purge-and-trap gas chromatography/mass spectrometry method has been adapted for analysis of volatile organics, including vinylidene chloride, in fish (limit of detection, 10 ug/kg) and in body tissue (limit of detection, 10 ug/kg). [R202] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Phase I Document: Vinylidene Chloride (1981) EPA No. 68-01-6030. ORNL/TIRC; Vinylidene Chloride (1978) Contract No. W-7405-Eng-26. USEPA; Health Assessment Document: Vinylidene Chloride (1983) EPA 600/8-83-031A. USEPA; Health Advisories for 25 Organics (1987) PB87-235578. USEPA, Office of Drinking Water; Criteria Document (Draft): Dichloroethylenes (1,1-Dichloroethylene, cis-1,2-Dichloroethylene, and trans-1,2-Dichlorethylene) (1984) PB86-117785. DHHS/ATSDR; Toxicological Profile for 1,1-Dichloroethene (Update) (1994) ATSDR/TP-93/07 DHHS/NTP; Carcinogenesis Bioassay of Vinylidene Chloride in F344/N Rats and B6C3F1 Mice (Gavage Study) Technical Report Series No. 228 (1982) NIH Publication No 82-1784 HIST: *A Chessie System freight train derailed in a wooded, rural area near Woodland Park, Michigan in February 1978. Four tank cars were damaged, spilling approx 300,000 lb of vinylidene chloride, 330,000 lb of phenol, and 125,000 lb of ethylene oxide. Most of the phenol, which had solidified on the surface, was removed by a cleanup contractor although residual phenol remained in the soil. The ethylene oxide vaporized, posing no groundwater contamination problems. The vinylidene chloride percolated through the sandy soils into the groundwater about 50 ft below the ground surface. Vinylidene chloride concentrations as high as 300 mg/l were found in monitoring wells near the derailment site. The groundwater cleanup program was completed over a three yr period. ... [R203] SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 197 (1986) R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: SRI R4: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1706 R5: Dow Chem Co; Vinylidene Chloride Methyl Ether Hydroquinone (MEHQ) Inhibited. Quality Assurance Sales Specification Sheet (1970) as cited in USEPA; Phase I Document: Vinylidene Chloride p.5 (1981) EPA No. 68-01-6030 R6: USEPA; Health Assessment Document: Vinylidene Chloride p.3-5 (1983) EPA-600/8-83-031A R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 196 (1986) R8: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1170 R9: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1994. 118 R10: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 962 R11: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on 1,1-Dichloroethylene (75-35-4). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 441 (1979) R13: USEPA; Health Assessment Document: Vinylidene Chloride p.5-15 (1983) EPA-600/8-83-031A R14: USEPA; Health Assessment Document for Vinylidene Chloride p.1-1 (1985) R15: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V5 (1993) 1018 R16: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 (1986) 294 R17: ChemExpo; Chemical Profile Database on Vinyl chloride monomer (75-35-4). August 28, 2000. Available from the Database Query page at http://www.chemexpo.com/news/newsframe.cfm?framebody=/news/profile.cfm as of March 23 2001. R18: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V23 (1983) 787 R19: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-363 R20: BUREAU OF THE CENSUS. US IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1986 P.1-530 R21: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 332 R22: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-163 R23: USEPA; Air Pollution Assessment of Vinylidene Chloride p.1-74 (1978) EPA 68-02-1495 R24: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 23 (1983) 765 R25: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. R26: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 14 (1981) 83 R27: Dow Chem Co; Vinylidene Chloride Monomer: Safe Handling Guide (1980) R28: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. 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Washington, DC: Association of American Railroads, Bureau of Explosives, 1992.952 R56: ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.50 (1983) R57: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 925 R58: 49 CFR 171.2 (7/1/2000) R59: IATA. Dangerous Goods Regulations. 42nd Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2001. 241 R60: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3146 (1998) R61: Dow Chem Co; Vinylidene Chloride Monomer: Safe Handling Guide (1980) as cited in USEPA; Phase I Document: Vinylidene Chloride p.20 (1981) EPA No. 68-01-6030 R62: 40 CFR 240-280, 300-306, 702-799 (7/1/2000) R63: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-12 (1981) EPA 68-03-3025 R64: USEPA/ORD; Innovative and Alternative Technology Assessment Manual pp.3-5, 3-11,12 (1980) EPA 430/9-78-009 R65: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.p.E-115 (1982) R66: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.p.E-100 (1982) R67: Semovic L et al; Second International Conference on New Frontiers for Hazardous Waste Management p.409-18 (1987) R68: Anon; Civil Engineering 57 (6): 16 (1987) R69: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1175 (1999) R70: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 1,1-Dichloroethylene (75-35-4) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R71: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 70 R72: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 192 R73: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 555 R74: Ryan, R.P., C.E. Terry, S.S. Leffingwell (eds.) Toxicology Desk Reference 5th ed. Volumes 1-2. Taylor and Francis Philadelphia, PA. 2000 R75: USEPA; Phase I Document: Vinylidene Chloride p.76 (1981) EPA No. 68-01-6030 R76: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-163 R77: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1167 (1999) R78: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 443 (1979) R79: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 444 (1979) R80: IARC. 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Technical Report Series No. 288 (1982) NIH Publication No. 82-1784 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R124: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1168 (1999) R125: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1170 (1999) R126: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 209 (1986) R127: USEPA; Ambient Water Quality Criteria Doc: 1,1-Dichloroethylene p.B-1 (1980) EPA 440/5-80-41 R128: BUCCAFUSCO RJ ET AL; BULL ENVIRON CONTAM TOXICOL 26: 446-52 (1981) R129: USEPA; Health Assessment Document: Vinylidene Chloride p.9-2 (1983) EPA-600/8-83-031A R130: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 488 R131: USEPA; Ambient Water Quality Criteria Doc: Dichloroethylenes p.B-7 (1980) EPA 440/5-80-041 R132: Dow Chemical U.S.A.; Results of a Two-Year Toxicity and Oncogenicity Study With Vinylidene Chloride Incorporated In the Drinking Water of Rats. (1978), EPA Document No. FYI-AX-0978-0007, Fiche No. 0007-0 R133: Dow Chemical USA; Vinylidene Chloride: A Chronic Inhalation Toxicity and Oncogenicity Study in Rats. (1982), EPA Document No. FYI-AX-1082-0215, Fiche No. 0215-0 R134: Dow Toxicology Research Laboratory; A Chronic Inhalation Toxicity and Oncogenicity Study in Rats, Final Report, (1982), EPA Document No. FYI-AX-1082-0215, Fiche No. OTS0000215-0 R135: REICHERT D ET AL; ARCH TOXICOL 42 (3): 159-69 (1979) R136: USEPA; Phase I Document: Vinylidene Chloride (VDC) p.47 (1981) EPA No. 68-01-6030 R137: Gargas ML et al; Toxicol Appl Pharmacol 86 (3): 341-52 (1986) R138: Putcha L et al; Fundam Appl Toxicol 6 (2): 240-50 (1986) R139: D'Souza RW, Anderson ME; Toxicol Appl Pharmacol 95 (2): 230-40 (1988) R140: USEPA; Phase I Document: Vinylidene Chloride p.50 (1981) EPA No. 68-01-6030 R141: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 211 (1986) R142: Galli R, McCarty PL; Appl Environ Microbiol 55 (4): 837-44 (1989) R143: Gargas ML et al; Toxicol Appl Pham 86 (3): 341-52 (1986) R144: Forhert PG et al; Can J Phys Pharm 65 (7): 1496-99 (1987) R145: Lee RP, Forkert PG; J Pharmacol Exptl Ther 270 (1): 371-6 (1994) R146: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1166 (1999) R147: Forhert PG et al; Exper Molecular Pathol 45 (1): 44-58 (1986) R148: Brattin WJ et al; Environ Health Perspect 57: 321-23 (1984) R149: Forkert PG, Moussa M; Drug Metb Disp 21 (5): 770-6 (1993) R150: Moslen MT et al; J Pharmacol Exp Ther 248 (1): 157-63 (1989) R151: Anderson ME et al; Toxicol Appl Pharmacol 46: 227-34 (1978) R152: Reichert D, Henschler D; Int Arch Occup Envir Health 41: 169-78 (1978) R153: Strubelt O, Youngs M; Agents Actions 14 (5-6): 680-3 (1984) R154: VAN DURREN BL ET AL; JNCI 63 (6): 1433-9 (1979) R155: Andersen ME et al; Toxicol Appl Pharm 89 (2): 149-57 (1987) R156: (1) IARC; Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 39: 195-226 (1986) R157: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons, Inc. p. 1170 (1997) (2) Glisson BT; Am Ind Hyg Assoc J 47: 427-35 (1986) (3) Cline PV, Delfino JJ; Am Chem Soc Div Environ Chem Natl Mtg, New Orleans LA 27: 577-9 (1987) (4) Fiorenza S et al; pp. 277-86 in Bioremediation of chlorinated polycyclic aromatic hydrocarbons. Hinchee RE, ed. Boca Raton, FL: Lewis (1994) R158: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (3) Gossett JM; Environ Sci Tech 21: 202-6 (1987) (4) Boublik T et al; The Vapour Pressures of Pure Substances. 2nd Rev Ed, Amsterdam: Elsevier p. 96 (1984) (5) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-23 (1992) (6) Hallen RT et al; Am Chem Soc Div Environ Chem 26th Natl Mtg 26: 344-6 (1986) R159: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Gossett JM; Environ Sci Tech 21: 202-6 (1987) (5) Mabey WB et al; Aquatic Fate Process Data for Organic Priority Pollutants. USEPA 440/4-81-014 p. 157 (1981) (6) Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants. USEPA 440/4-79-029a p. 50-1 to 50-10 (1979) (7) Cline PV, Delfino JJ; Am Chem Soc Div Environ Chem Preprint New Orleans LA 27: 577-9 (1987) (8) Franke C et al; Chemosphere 29: 1501-14 (1994) (9) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-23 (1992) (10) Barrio-Lage G et al; Environ Sci Technol 20: 96-9 (1986) R160: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Boublik T et al; The Vapour Pressures of Pure Substances. 2nd Rev ed, Amsterdam: Elsevier p. 96 (1984) (3) Kwok ESC, Atkinson R; Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) (4) Edney E et al; Atmospheric Chemistry of Several Toxic Compounds. USEPA-600/53-82-092 (1983) R161: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-23 (1992) (2) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (3) Patterson JW, Kodukala PS; Chem Eng Prog 77: 48-55 (1981) (4) Long JL et al; J Environ Eng 119: 300-20 (1993) R162: (1) Barrio-Lage G et al; Environ Sci Technol 20: 96-9 (1986) (2) Hallen RT et al; Am Chem Soc Div Environ Chem 26th Natl Mtg 26: 344-6 (1986) (3) Wilson BH et al; Environ Sci Technol 20: 997-1002 (1986) (4) Long JL et al; J Environ Eng 119: 300-20 (1993) R163: (1) Kwok ESC, Atkinson R; Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) R164: (1) Edney E et al; Atmospheric Chemistry of Several Toxic Compounds. USEPA-600/53-82-092 (1983) (2) Gay BW et al; Environ Sci Technol 10: 58-67 (1976) (3) Mabey WB et al; Aquatic Fate Process Data for Organic Priority Pollutants. USEPA 440/4-81-014 p. 157 (1981) (4) Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants. USEPA 440/4-79-029a p. 50-1 to 50-10 (1979) (5) Parlar H; Fresenius Z Anal Chem 319: 114-8 (1984) (6) Cline PV, Delfino JJ; Am Chem Soc Div Environ Chem Preprint New Orleans LA 27: 577-9 (1987) (7) Schmidt-Bleek F et al; Chemosphere 11: 383-415 (1982) (8) Jeffers PM et al; Environ Sci Technol 23: 965-9 (1989) R165: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-23 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R166: (1) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R167: (1) Gossett JM; Environ Sci Tech 21: 202-6 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Boublik T et al; The Vapour Pressures of Pure Substances. 2nd Rev Ed, Amsterdam: Elsevier p. 96 (1984) R168: (1) Coleman WE et al; pp. 305-27 in Analysis and Identification of Organic Substances in Water. Keith L, ed. Ann Arbor, MI: Ann Arbor Sci (1976) (2) Coniglio WA et al; The Occurrence of Volatile Organics in Drinking Water Exposure Assessment Project. Criteria and Standards Division, Science and Technology Branch (1980) (3) Burmaster DE; Environ 24: 6-13,33-6 (1982) (4) USEPA; Subst Risk Not, 8(e) 35 USEPA 560/11-80-020 (1980) (5) Tase N; Environ Geol Water 20: 15-20 (1992) R169: (1) IARC; Monograph. Some Monomers, Plastics and Synthetic Elastomers, and Acrolein. 19: 439-59 (1979) (2) Council on Environmental Quality Contamination of Groundwater by Toxic Organic Chemicals (1981) (3) Fishbein L; Sci Total Environ 11: 111-61 (1979) Arbor Sci p 305-27 (1976) (4) Dyksen JE, Hess AF III; J Amer Water Works Assoc 74:394-403 (1982) (5) Coniglio WA et al; The Occurrence of Volatile Organics in Drinking Water Exposure Assessment Project. Criteria and Standards Division, Science and Technology Branch (1980) (6) Krill RM, Sonzogni WC; J Am Water Works Assoc 78: 70-5 (1986) (7) Westrick JJ et al; J Am Water Works Assoc 76: 52-9 (1984) (8) Wallace LA et al; Environ Res 43: 290-307 (1987) (9) Lam RHF et al; pp. 15-44 in Water Contamination and Health. Wang RGM, ed. NY, NY: Marcel Dekker (1994) R170: (1) Coleman WE et al; pp. 305-27 in Analysis and Identification of Organic Substances in Water. Keith L, ed. Ann Arbor, MI: Ann Arbor Sci (1976) (2) Coniglio WA et al; The Occurrence of Volatile Organics in Drinking Water Exposure Assessment Project. Criteria and Standards Division, Science and Technology Branch (1980) (3) Ohio River Valley Water Sanit Comm; Assessment of water quality conditions, Ohio River Mainstream 1980-81 Cincinnati, OH (1982) (4) Hall LW Jr et al; Aquat Tox 10: 73-99 (1987) R171: (1) IARC; Monograph Some Monomers, Plastics and Synthetic Elastomers, and Acrolein 19: 439-59 (1979) (2) Fishbein L; Sci Total Environ 11: 111-61 (1979) (3) Young DR; Ann Rep Southern Calif Coastal Water Res Proj. pp. 103-12 (1978) (4) Callahan MA et al; Proc Natl Conf Munic Sludge Manag. 8th pp. 55-61 (1979) (5) USEPA; Treatability Manual page I.12.24-1 to I.12.24-5 USEPA 600/2-82-001a (1981) R172: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data 198 p SRI Inter Contract 68-02-3452 (1982) (4) Harkov R et al; Toxic and Carcinogenic Air Pollutants in New Jersey - Volatile Organic Substances, Unpublished work Trenton NJ: Office of Toxic Substances Res (1981) (5) Lioy PJ et al; J Water Pollut Control Fed 33: 649-57 (1983) (6) Singh HB et al; Atmos Environ 15: 601-12 (1981) (7) Singh HB et al; Environ Sci Technol 16: 872-80 (1982) R173: (1) Pleil JD; Volatile Organic Compounds in Indoor Air: A Survey of Various Structures USEPA-600/D-85-100 (1985) R174: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. SRI Inter Contract 68-02-3452. pp. 198 (1982) (2) Grimsrud EP, Rasmussen RA; Atmos Environ 9: 1014-7 (1975) (3) Pellizzari ED; Quantification of Chlorinated Hydrocarbons in Previously Collected Air Samples USEPA-450/3-78-112 (1978) R175: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. SRI Inter Contract 68-02-3452. pp. 198 (1982) (2) Pellizzari ED; Quantification of Chlorinated Hydrocarbons in Previously Collected Air Samples USEPA-450/3-78-112 (1978) (3) Basu D et al; Health Assessment Document for Vinylidene Chloride. USEPA External Review Draft page 7-1 to 7-21 (1983) (4) Brosseau J, Heitz M; Atmos Environ 28: 295-93 (1994) (5) Eklund B et al; Environ Sci Technol 32: 2233-7 (1998) R176: (1) Fishbein L; Sci Total Environ 11: 111-61 (1979) R177: (1) Fishbein L; Sci Total Environ 11: 111-61 (1979) (2) Basu D et al; Health Assessment Document for Vinylidene Chloride USEPA External Review Draft p 7-1 to 7-21 (1983) (3) IARC; Monograph Some Monomers, Plastics and Synthetic Elastomers, and Acrolein 19: 439-59 (1979) R178: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R179: (1) Wallace L et al; J Occup Med 28: 603-7 (1986) R180: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R181: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 198 (1986) R182: 40 CFR 60.489 (7/1/2000) R183: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R184: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R185: 40 CFR 116.4 (7/1/2000) R186: 40 CFR 401.15 (7/1/2000) R187: 40 CFR 302.4 (7/1/2000) R188: 40 CFR 712.30 (7/1/2000) R189: 40 CFR 716.120 (7/1/2000) R190: 40 CFR 261.33 (7/1/2000) R191: 40 CFR 261.24 (7/1/2000) R192: 21 CFR 175.105 (4/1/2000) R193: 21 CFR 181.30 (4/1/2000) R194: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V19 442 (1979) R195: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R196: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R197: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 203 (1986) R198: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water 500 Series Methods (1988) EPA/600/4-88/039 R199: OSHA; OSHA Analytical Methods Manual, 2nd Ed, Part 1 Organic Substances, Volume I Methods 1 - 28, Volume II Methods 29 - 54, and Volume III Methods 55 - 80. January 1990, Volume IV Methods 81-102, April 1993. U.S. Department of Labor Occupational Safety and Health, Administration, Directorate of Technical Support, OSHA Technical Center, Salt Lake City, Utah R200: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R201: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 435-44 (1985) R202: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 202 (1986) R203: Posthuma AR et al; 1983 Nat Conf Environ Engin p.775-82 (1983) RS: 163 Record 164 of 1119 in HSDB (through 2003/06) AN: 2034 UD: 200302 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PENTACHLOROETHANE- SY: *EPA-Pesticide-Chemical-Code-598300-; *ETHANE-PENTACHLORIDE-; *ETHANE,-PENTACHLORO-; *NCI-C53894-; *PENTACHLOORETHAAN- (DUTCH); *PENTACHLORAETHAN- (GERMAN); *PENTACHLORETHANE- (FRENCH); *PENTACLOROETANO- (ITALIAN); *PENTALIN- RN: 76-01-7 MF: *C2-H-Cl5 SHPN: UN 1669; Pentachloroethane IMO 6.1; Pentachloroethane STCC: 49 215 96; Pentachloroethane HAZN: U184; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Pentachloroethane can be made by chlorinating 1,1,2,2-tetrachloroethane under ultraviolet light, or trichloroethylene at 70 deg C in the presence of ferric chloride, sulfur, or ultraviolet light. Oxychlorination of ethylene gives pentachloroethane as well as lower chlorinated hydrocarbons. Chlorination of trichloroethylene can also give pentachloroethane in good yield. [R1] MFS: *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48640 (517) 636-1000 [R2] *PPG Industries, Hq, One PPG Place, Pittsburg, PA 15272 (412) 434-3131 [R2] OMIN: *Formation during combustion or incineration of polyvinyl chloride (PVC) waste products is a potential source of pentachloroethane release to the environment. [R3] USE: *SOLVENT FOR OIL AND GREASE IN METAL CLEANING; SEPARATION OF COAL FROM IMPURITIES. /FORMER USE/ [R4] *IN DRY CLEANING, BUT ONLY TO A SMALL EXTENT; IN SOIL STERILIZATION; IN ORG SYNTHESIS. /FORMER USE/ [R5, 261] *Pentachloroethane is used as a solvent for cellulose acetate, certain cellulose ethers, resins and gums. Pentachloroethane is also used as a drying agent for timber /immersed in it/ at temperatures greater than 100 deg C. [R6] PRIE: U.S. PRODUCTION: *(1977) 0.45-2.27X10+10 g /TSCA Inventory (1980) based on 1977 production/ [R2] *Pentachloroethane is not currently produced commerically or imported into the United States. [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R1]; +Colorless liquid. [R8] ODOR: *CHLOROFORM-LIKE [R9]; *CAMPHOR-LIKE [R1]; +Sweetish, chloroform-like odor. [R8] BP: *159.8 DEG C [R10] MP: *-29 DEG C [R10] MW: *202.29 [R10] CORR: *Dry pentachloroethane does not corrode iron at temperatures up to 100 deg C. [R1] DEN: *1.6796 @ 20 deg C/4 deg C [R10] HTV: *9,800.1 gcal/gmole [R11] SOL: *0.05 G/100 ML WATER @ 20 DEG C [R12, 3520]; *MISCIBLE WITH ALCOHOL, ETHER [R9]; *Miscible with common organic solvents [R1] SPEC: *INDEX OF REFRACTION: 1.50250 @ 24 DEG C [R12, 3520]; *INDEX OF REFRACTION: 1.5054 @ 15 DEG C/D [R9]; *IR: 178 (Sadtler Research Laboratories Prism Collection) [R13]; *MASS: 1407 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R13] VAPD: *7.0 (air= 1) [R5, 261] VAP: *3.5 mm Hg at 25 deg C. [R14] EVAP: *0.03 (ETHER= 1) [R5, 261] VISC: *2.45 cP @ 20 deg C [R15] OCPP: *DISTILLATION @ ATMOSPHERIC PRESSURE CAUSES SOME DECOMPOSITION; BOILING WITH ALCOHOLIC POTASH CAUSES FORMATION OF TETRACHLOROETHYLENE. [R5, 261] *% IN "SATURATED" AIR: 0.45 @ 25 DEG C; 1 MG/L= 120.8 PPM, 1 PPM= 8.37 MG/CU M @ 25 DEG C, 760 MM HG [R12, 3520] *(Wt per gallon @ 20 deg C= 14.00 lb) (Latent heat of vaporization @ bp= 43.6 cal/g= 78.4 Btu/lb) (Acidity as HCl= 0.001% by wt, max) (Coefficient of cubical expansion Av/deg C, liquid= 0.0009097; Solubility of water in solvent @ 20 deg C= 0.24 g water/100 g). [R15] *Saturated concentration in air: 37 g/cu m @ 20 deg C, 64 g/cu m @ 30 deg C. [R16] *Hydrolysis of pentachloroethane will produce dichloroacetic acid. [R17, 174] *Density = 1.6712 @ 25 deg C/4 deg C [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R18] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R18] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R18] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R18] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R18] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R18] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R18] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R18] FPOT: *MODERATE, WHEN EXPOSED TO HEAT OR FLAME. [R19] FIRP: *WATER, CARBON DIOXIDE, DRY CHEMICAL. [R19] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Keep run-off water out of sewers and water sources. [R20] EXPL: *MODERATE, BY SPONTANEOUS CHEMICAL REACTION. [R19] REAC: +Mixtures of sodium-potassium alloy and ... pentachloroethane can explode on standing at room temperature. They are especially sensitive to impact. [R21] *Violent reaction with (sodium-potassium alloy + bromoform), potassium. [R19] *... DEHALOGENATION BY REACTION WITH ALKALI, METALS ... WILL PRODUCE SPONTANEOUS EXPLOSIVE CHLOROACETYLENES. [R19] *Mixtures /of potassium or its alloys/ with tetrachloroethane and pentachloroethanewill often explode after a short delay. [R22] *Mixtures of potassium with tetra- and pentachloroethane will often explode spontaneously after a short delay during which a voluminous solid separates out. [R23] +(Sodium-potassium alloy + bromoform), alkalis, metals, water [Note: Hydrolysis produces dichloroacetic acid. Reaction with alkalis and metals produces spontaneously explosive chloroacetylenes]. [R8] DCMP: +... WHEN HEATED TO DECOMP, EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. [R24] *Decomposition of pentachlorethane with aluminum chloride will produce chloroform. [R17, 699] SERI: *Symptoms: Irritation of eyes and respiratory tract ... . [R25] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R8] +Wear appropriate eye protection to prevent eye contact. [R8] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R8] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R8] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Do not use water. [R20] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. [R20] +The worker should immediately wash the skin when it becomes contaminated. [R8] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R8] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R26] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R27] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R28] CLUP: *Absorb the spills with paper towels or the like materials. Place in a hood to evaporate. Dispose by burning he towel. [R25] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R29] *Incineration after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. Recommendable method: Incineration. [R30] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of pentachloroethane were found. There is limited evidence in experimental animals for the carcinogenicity of pentachloroethane. Overall evaluation: Pentachloroethane is not classifiable as to its carcinogenicity to humans (Group 3). [R31] HTOX: *Symptomatology: 1. Prompt nausea, vomiting and abdominal pain. ... After ingestion, hematemesis, and diarrhea. 2. Headaches, dizziness, confusion, drowsiness, and occasionally, convulsions. 3. Visual disturbances. ... 4. ... Coma and death from resp arrest or circulatory collapse. 5. Occasionally sudden death due to ventricular fibrillation. ... 8. Oliguria, albuminuria, anuria, gradual wt gain, edema. 9. Anorexia, jaundice, and rt upper quadrant pain due to an enlarged and tender liver. /Carbon tetrachloride/ [R32, p. III-105] */Produces/ more potent central nervous effects than chloroform or even tetrachloroethane. [R32, p. II-164] *CAUTION: IRRITANT ... /CNS DEPRESSANT/ [R33] *NO STANDARDS HAVE BEEN PROPOSED FOR PENTACHLOROETHANE. IT IS PROBABLY NOT POSSIBLE TO SET A RELIABLE STANDARD BECAUSE OF THE LIMITED TOXICOLOGICAL INFORMATION AND EXPERIENCE REPORTED ... IT IS OBVIOUS THAT A CONCN SAFE FOR REPEATED EXPOSURE WOULD BE WELL BELOW THE 121 PPM THAT WAS SHOWN TO CAUSE PATHOLOGICAL CHANGES. [R12, 3521] NTOX: *PENTACHLOROETHANE, AS REVEALED BY ANIMAL EXPERIMENTS IS A STRONG /SRP: CNS DEPRESSANT/ ... HAS AN ACTION ON LIVER SIMILAR TO THAT OF TETRACHLOROETHANE AND A MORE HIGHLY TOXIC ACTION ON THE HEART, BUT /LESS OF/ A HEMOLYTIC EFFECT. /SRP: CNS DEPRESSANT/ DOSE FOR CATS; LIGHT ... 13 MG/L AFTER 1 HR; 21 MG/L AFTER 23 MIN; 37 MG/L AFTER 5 MIN; DEEP /SRP: CNS DEPRESSANT/, 13 MG/L AFTER 89 MIN; 21 MG/L AFTER 32 MIN; 37 MG/L AFTER 5.5 MIN; ... 25 MG/L FOR LOSS OF REFLEXES. [R5, 262] *WITH ACUTE POISONING, UNCONSCIOUSNESS IS PRECEDED BY INTENSE IRRITATION OF MUCOUS MEMBRANES OF NOSE, THROAT, AND EYE, TREMOR OF LIMBS, MUSCULAR CRAMPS OF AN OPISTHOTONOS-LIKE CHARACTER, AND DIARRHEA. [R5, 262] */IN DOGS/ ... INHALATION OF 10 ML ... INITIAL PERIOD OF RESTLESSNESS AND EXCITEMENT, COMPLETE ... /CNS DEPRESSION/ WITHIN 20 MIN. ... CATS INHALING 146 PPM 8 TO 9 HR DAILY FOR 23 DAYS SHOWED PRACTICALLY NO SYMPTOMS OF POISONING, BUT WITH HIGHER ... /CNS DEPRESSING/ DOSAGE, RECOVERY WAS SLOW--30 TO 140 MIN. [R5, 262] *LIVER: ALL ANIMALS /VIA INHALATION/ ... SHOWED A HIGH DEGREE OF FATTY DEGENERATION. KIDNEYS: INFLAMMATION, WITH ALBUMIN AND BLOOD PIGMENTS IN URINE OF DOGS /REPORTED/ ... LUNG: MARKED HYPEREMIA ... ACUTE PURULENT INFLAMMATION OF TRACHEA AND LARGE BRONCHI. [R5, 263] *2.6 MMOL/KG, INTRAGASTRIC ADMIN OF PENTACHLOROETHANE REDUCED EPOXIDE HYDRATASE ACTIVITY BY 50% IN RATS. [R34] *THE MAJOR CONTAMINANT IN THE PENTACHLOROETHANE (PCE) SAMPLE USED FOR CHRONIC CARCINOGENICITY STUDY IN MALE AND FEMALE RATS AND MICE IS HEXACHLOROETHANE. DURING THE STUDY, DOSE LEVELS OF 75 AND 150 MG/KG FOR RATS AND 250 AND 500 MG/KG FOR MICE WERE ADMIN BY GAVAGE, 5 DAYS/WK (41-103 WK). THE SURVIVAL OF HIGH-DOSED RATS (BOTH SEXES) WAS REDUCED AS COMPARED TO SURVIVAL OF CONTROLS. PENTACHLOROETHANE DID NOT INCR THE INCIDENCE OF PRIMARY TUMORS IN RATS, BUT DID PRODUCE CHRONIC RENAL INFLAMMATION AMONG MALES. THE SURVIVAL TIMES OF MICE WAS SHORTENED BY PENTACHLOROETHANE ADMIN. /INCIDENCE OF/ HEPATOCELLULAR CARCINOMA WAS INCR IN ALL TREATED GROUPS. TECHNICAL GRADE PENTACHLOROETHANE IS AN HEPATOCARCINOGEN IN MICE. [R35] */Fathead minnows, 32 days of age were studied in 25.3 deg C water, in a pentachloroethane concn of 1.55 to 12.0 mg/l. Affected fish lost schooling behavior and equilibrium prior to death. No effect data were recorded. Individual lengths and wt of the test fish were not recorded. ... Measured mean wt was 0.102 g. ... Mean recovery was likely > 90%. ... No samples taken at 96 hr. [R36] *VARIOUS POLYCHLORINATED HYDROCARBONS WERE ADMIN INTRAGASTRICALLY TO RATS TO EXAMINE THEIR EFFECTS ON THE BIOTRANSFORMATION CAPACITY OF THE LIVER. DUE TO HIGH TOXICITY, PENTACHLOROETHANE WAS GIVEN AT A DOSE LEVEL EQUIV TO 1/4 OF THAT OF CCL4 AND THE OTHER CHLOROHYDROCARBONS. EPOXIDE HYDRATASE ACTIVITY IN RAT LIVER DECLINED SIGNIFICANTLY AFTER PENTACHLOROETHANE ADMIN. [R34] *IN A STUDY OF THE EFFECTS OF CHRONIC ACTION OF LOW CONCN OF CHLORINATED HYDROCARBONS ON PRODN OF VARIOUS CLASSES OF IMMUNOGLOBULINS ... RABBITS ... INHALED CHLORINATED HYDROCARBONS @ 2 MG/CU M FOR 3 HR/DAY FOR 8-10 MONTHS. TETRACHLOROETHANE WAS FOUND TO BE MORE HARMFUL TO TOTAL ANTIBODY FORMATION THAN ITS PENTACHLORO- OR DICHLORO- ANALOG. [R37] *Oral administration of 2.6 mmol (525 mg)/kg body weight pentachloroethane (practical grade; 95% pure) to male rats reduced hepatic cytochrome p450 content and microsomal epoxide hydrolase activities. [R38] *Exposure of rabbits for 3 hr per day, six times per week, for eight to ten months to 100 mg/cu m pentachloroethane resulted in decreased total antibody titres, which were more pronounced at the highest dose. [R38] *Pentachloroethane (96% pure) was not mutagenic to Salmonella typhimurium TA1535, TA1537, TA98, or TA100 when tested at up to toxic conetntrations (333 ug/plate) in a preincubation assay either in the presence or absence of an exogenous metabolic system (S9) from the liver of Aroclor-induced rats or hamsters. [R38] *Technical grade pentachloroethane (containing 4.2% hexachloroethane) was tested for carcinogenicity by oral administration by gavage in one experiment in mice and one experiment in rats. Hepatocellular carcinomas were induced in mice of each sex and hepatocellular adenomas in female mice; a marginally increased incidence of kidney tubular-cell adenomas was observed in male rats by not in female rats. [R39] ETXV: *LC50 Daphnia magna (cladoceran) 62,900 ug/l/96 hr in an unmeasured static bioassay; [R40] *LC50 Pimephales promelas (fathead minnow) 7,300 ug/l/96 hr in a measured, flow-through bioassay; [R41] *LC50 Lepomis macrochirus (bluegill) 7,240 ug/l/96 hr in an unmeasured, static bioassay; [R41] *LC50 Mysidopris bahia (Mysid shrimp) 5,060 ug/l/96 hr in an unmeasured, static bioassay; [R42] *LC50 Mysidopsis bahia (mysid shrimp) 390 ug/l/96 hr in a measured, flow-through bioassay; [R42] *LC50 Cyprinodon variegatus (sheepshead minnow) 116,000 ug/l/96 hr in an unmeasured, static bioassay; [R42] *EC50 Selenastrum capricornutum (alga) 121,000 ug/l/96 hr; Toxic effect: Chlorophyll a. /Conditions of bioassay not specified/; [R43] *EC50 Selenastrum capricornutum (alga) 134,000 ug/l/96 hr; Toxic effect: cell numbers. /Conditions of bioassay not specified/; [R43] *EC50 Skeletonema costatum (alga) 58,200 ug/l/96 hr; Toxic effect: Chlorophyll a. /Conditions of bioassay not specified/; [R43] *EC50 Skeletonema costatum (alga) 58,200 ug/l/96 hr; Toxic effect: cell count. /Conditions of bioassay not specified/; [R43] *LC50 Pimephales promelas (fathead minnow) 7.53 mg/l/96 hr (95% confidence limit 7.22- 7.85 mg/l), flow-through bioassay with measured concentrations, 25.3 deg C, dissolved oxygen 8.0 mg/l, hardness 45.5 mg/l calcium carbonate, alkalinity 42.4 mg/l calcium carbonate, and pH 7.45; [R36] NTP: *A carcinogenesis bioassay of technical grade pentachloroethane (95.5% pure, with 4.2% hexachloroethane) was conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 75 or 150 mg/kg body weight ... . Doses were administered for 103 weeks for rats ... . Groups of 50 rats ... of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. ... Survival of high-dose rats of each sex was significantly (p < 0.05 less than that of the controls. Mean body weights of dosed male and female rats were lower than those of the corresponding controls during the second year of the study. Final mean body weights for rats were 4%-5% lower for male rats and 8%-12% lower for female rats when compared to controls. Chronic, diffuse inflammation of the kidney, distinguishable from nephropathy seen in aging F344/N rats, was found in male rats in a significant (p < 0.001) and dose-related incidence (control, 4/50, 8%; low-dose, 14/49, 29%; high-dose, 33/50, 66%). Mineralization of the renal papilla, considered to be secondary to chronic inflammation, was also observed at increase incidences in dosed male rats. Pentachloroethane administration did not cause any increased incidences of tumors in either male or female rats. Statistically significant negative trends were detected for subcutaneous tissue fibromas amoung males and for pituitary adenomas in both sexes. ... Under the conditions of this bioassay, technical grade pentachloroethane containing 4.2% hexachloroethane was not carcinogenic in F344/N rats. ... Pentachloroethane was nephrotoxic to male rats. [R44] *A carcinogenesis bioassay of technical grade pentachloroethane (95.5% pure, with 4.2% hexachloroethane) was conducted by administering the test chemical in corn oil by gavage to groups of ... 50 male and 50 female B6C3F1 mice at doses of 250 or 500 mg/kg. Doses were administered for ... 41-103 weeks for mice. Groups of ... 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. ... Forty-two high-dose male mice died by week 41, and the 8 remaining animals in the group were killed at that time. Twenty-five male control mice were killed at week 44 to serve as controls for the high-dose males. Only 22/50 (44%) of the low-dose male mice survived to the end of the study. All high-dose female mice were dead by week 74, and only 9/50 (18%) low-dose females survived to the end of the study. Mean body weights of mice were lower than those of controls. The incidence of hepatocellular carcinoma was significantly elevated in all groups of dosed mice (male: 4/48, 8%; 26/44, 59%, p < 0.001; 7/45, 16%; female: 1/46, 2% 28/42, 67%, p < 0.001; 13/45, 29% p < 0.001). Early mortalities in the high-dose male mice precluded an evaluation of their lifetime incidence of hepatocellular carcinoma. There was a significant increase in incidence over that observed among 25 controls killed at week 44 (0/25 versus 7/45, p < 0.05). There was also a significant (p < 0.001) dose-related increase in hepatocellular adenoma in female mice (2/46, 4%; 8/42, 19%; 19/45, 42%). ... Technical grade pentachloroethane was carcinogenic for B6C3F1 mice, causing hepatocellular carcinomas in males and females, and adenomas in females. [R44] POPL: */SRP: INDIVIDUALS WITH LIVER DISEASE ARE AT SPECIAL RISK./ METB: *MOST OF ITS METABOLITES ARE GENERATED BY NON-REDUCTIVE DEHALOGENATIONS ... HOWEVER THE METABOLITE TRICHLOROETHYLENE IS EXPLAINED IN TERMS OF A REDUCTIVE DECHLORINATION WITHIN THE PATHWAY. [R45] *... INJECTED (14)C-PENTACHLOROETHANE SC IN MICE @ DOSES OF 1.1 TO 1.8 G/KG ... ABOUT ONE-THIRD OF THE DOSE (12 TO 51 PERCENT) WAS EXPIRED UNCHANGED; 16 TO 32 PERCENT WAS EXCRETED AS 2,2,2-TRICHLOROETHANOL AND 9 TO 18 PERCENT AS TRICHLOROACETIC ACID IN THE URINE. THE EXPIRED AIR ALSO CONTAINED TRICHLOROETHYLENE (3 TO 9 PERCENT OF THE DOSE), INDICATING BOTH DECHLORINATION AND DEHYDROCHLORINATION. [R12, 3521] *UNDER ANAEROBIC CONDITIONS, POLYHALOGENATED ALKANES STIMULATED REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE OXIDN BY RAT LIVER MICROSOMAL FRACTIONS, AND PARTICIPATION OF CYTOCHROME P450 WAS SHOWN BY INDUCERS AND INHIBITORS OF MONOOXYGENASE SYSTEM. PENTACHLOROETHANE WAS METABOLIZED TO TRICHLOROETHENE AND TETRACHLOROETHANE. [R46] *PENTACHLOROETHANE WAS INJECTED SC INTO MICE AND ITS EXCRETION WAS FOLLOWED FOR 3 DAYS. THE METABOLIZED PART WAS EXCRETED AS 2,2,2-TRICHLOROETHANOL AND TRICHLOROACETIC ACID IN THE URINE. THE EXPIRED AIR CONTAINED TRICHLOROETHYLENE AND TETRACHLOROETHYLENE, INDICATING BOTH DECHLORINATION AND DEHYDROCHLORINATION OF PENTACHLOROETHANE. [R47] *In the presence of oxygen, NADPH and rat liver microsomes, 1.7% dechlorination of pentachloroethane was observed. In contrast, in the absence of oxygen, pentachloroethane was metabolized by NADPH-fortified hepatic microsomal fractions to trichloroethylene (96%) and 1,1,2,2-tetrachloroethane (4%). The in-vitro reductive dechlorination of pentachloroethane was catalysed by a purified (rabbit liver) reconstituted cytochrome p450 system. [R38] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Pentachloroethane is not currently produced commercially or imported in the United States. However, this compound may be released to the environment as a combustion product of polyvinyl chloride (PVC). If released to moist soil, pentachloroethane is expected to have moderate to high mobility and it may undergo slow chemical hydrolysis. Pentachloroethane may volatilize slowly from dry soil surfaces. If released to water, volatilization appears to be an important, if not the dominant, removal mechanism (half-life 5 hours from a model river). This compound also has the potential to oxidize in the presence of light and form trichloroacetyl chloride. Moderate to slight adsorption of pentachloroethane to suspended solids and sediments may occur. Chemical hydrolysis is not expected to be environmentally important. If released to the atmosphere, pentachloroethane is expected to exist almost entirely in the vapor phase. It appears that reaction with photochemically generated hydroxyl radicals (half-life 1.2 years) would be the dominant fate process in the atmosphere. Potential products of this reaction include trichloroacetyl chloride and phosgene. Due to its persistence in the atmosphere long-range transport of pentachloroethane is expected to occur. (SRC) NATS: *There is no evidence available which indicates that pentachloroethane is a natural product. (SRC) ARTS: *Pentachloroethane is not currently produced commerically or imported into the United States(1). Formation during combustion or incineration of polyvinyl chloride (PVC) waste products is a potential source of pentachloroethane release to the environment(2). [R48] FATE: *TERRESTRIAL FATE: If released to moist soil, pentachloroethane is expected to have moderate to high mobility. This compound may undergo slow chemical hydrolysis. Pentachloroethane may volatilize slowly from dry soil surfaces. (SRC) *AQUATIC FATE: If released to water, volatilization appears to be an important, if not the dominant, removal mechanism. The half-life for this compound volatilizing from a model river has been estimated to be 5 hours. This compound also has the potential to oxidize in the presence of light and form trichloroacetyl chloride. Moderate to slight adsorption of pentachloroethane to suspended solids and sediments may occur. Chemical hydrolysis probably occurs too slowly to be environmentally important. (SRC) *ATMOSPHERIC FATE: Based on a vapor pressure of 3.5 mm Hg at 25 deg C, pentachloroethane is expected to exist almost entirely in the vapor phase in the atmosphere(1,2,SRC). It appears that reaction with photochemically generated hydroxyl radicals in the atmosphere would be the dominant fate process. The half-life for this reaction has been estimated to be 1.2 years. Potential photooxidation products include trichloroacetyl chloride and phosgene. Due to its persistence in the atmosphere long-range transport of pentachloroethane is expected to occur(SRC). [R49] ABIO: *Pentachloroethane undergoes slow hydrolysis in water at normal temperatures(1). This compound oxides in the presence of light to yield trichloroacetyl chloride(1). The half-life for pentachloroethane vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 1.2 years based on an estimated reaction rate constant of 2.2X10-14 cu cm/molecule-sec at 25 deg C and an average ambient hydroxyl radical concentration of 8.0X10+5 molecules/cu cm(2,3,SRC). Potential photooxidation products include trichloroacetyl chloride and phosgene(4). [R50] *The hydrolysis rate constant of pentachloroethane was measured in dilute aqueous solutions within the temperature ranges of 85 to 190 C (neutral range) and 0 to 80 C (basic range), and at pH values of 2 to 10. The rate constant value was determined by 5 to 20 time-concn points, with each sample analyzed in triplicate. Arrhenius parameters were determined for both neutral and alkaline hydrolysis reactions. The hydrolysis rate constant k (neutral, 25 deg C) was determined to be 4.93X10-8/min, while the basic k (pH 7, 25 deg C) was 1.31X10-4/min. The environmental half life of pentachloroethane (at 25 deg C, pH 7) is 0.010 yr. [R51] BIOC: *A bioconcentration factor of 67 was measured for pentachloroethane in bluegill sunfish (14 day exposure), and this compound was found to have a half-life of < 1 day in tissue(1). These data suggest that pentachloroethane will not bioaccumulate significantly in aquatic organisms(SRC). [R52] KOC: *A soil adsorption coefficient (Koc) of 117 for pentachloroethane was estimated using a molecular topology and quantitative structure activity relationship(1,SRC), and a Koc of 244 was estimated using a linear regression equation based on a water solubility of 500 mg/l at 25 deg C(2,3,SRC). These Koc values suggest that pentachloroethane would be moderately to highly mobile in soil and that adsorption to suspended solids and sediments in water would be moderate to slight(4,SRC). [R53] VWS: *Henry's Law Constant for pentachloroethane has been estimated to be 1.9X10-3 atm-cu m/mole at 25 deg C based on vapor pressure of 3.5 mm Hg at 25 deg C and a water solubility of 500 mg/l at 25 deg C(1,2,SRC). Using this value of Henry's Law Constant the half-life of pentachloroethane volatilizing from a model river 1 m deep, flowing 1 m/sec, with a wind speed of 3 m/sec has been estimated to be 5 hours(3,SRC). The volatilization half-life of a dilute solution of pentachloroethane in a beaker 6.5 cm deep, stirred 200 rpm in still air has been experimentally determined to be 46.5 minutes(4). The relatively high vapor pressure of this compound suggests that it would volatilize slowly from dry soil surfaces(SRC). [R54] WATC: *SURFACE WATER: Detected in water taken from Fields Brook in Ashtabula, OH during 1976 at a concentration of 2 ug/l(1). Identified in 2 out of 204 water samples collected from 14 heavily industrialized river basins located throughout the U.S., detection limit 1 ug/l(2). DRINKING WATER: Detected in finished drinking water collected in the New Orleans/Baton Rouge area, mean concn < 0.03 ug/l, sampling date not reported(3). [R55] EFFL: *Identified in the spent chlorination liquor from the bleaching of sulphite pulp at a concentration corresponding to 0.1 g/ton pulp process(1). During Aug 1972, pentachloroethane was detected in chlorinated effluent from a sewage treatment plant(2). [R56] ATMC: *Monitoring data obtained from samples collected in the Atlantic Ocean between 1982 and 1985 indicate that the average baseline level of pentachloroethane in the Northern hemisphere is 0.1 parts per trillion/volume. In tradewind systems and in the Southern hemisphere the baseline level is below the detection limit (0.02 to 0.04 parts per trillion/volume(1). During 1976-1977 pentachloroethane was detected in 0 out of 2 air samples collected in rural/remote areas, 0 out of 74 samples collected in urban/suburban areas, and 2 out of 54 samples in source dominated areas(2). During Feb 1977 trace levels were found in ambient air of Iberville Parish, LA and 3,984 ng/cu m was detected in ambient air collected from Dow Chemical Property in Freeport, TX during Aug 1986(3). [R57] RTEX: *231 workers are potentially exposed to pentachloroethane based on statistical estimates derived from the NIOSH survey conducted 1981-83 in the USA(1). Since there is currently no commercial production or importation of this compound in the US occupational exposure to pentachloroethane is probably substantially lower than the NIOSH estimate indicates(2,SRC). [R58] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- NREC: +HANDLE WITH CAUTION IN THE WORKPLACE. [R8] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Chlorinated ethanes/ [R59] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R60] RCRA: *U184; As stipulated in 40 CFR 261.33, when pentachloroethane, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R61] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *A known volume of air is drawn through a tube containing Porapak R to trap the pentachloroethane vapor present. The Porapak R in the tube is transferred to a small vial where the pentachloroethane is desorbed with hexane. [R62] ALAB: *Analyte: Pentachloroethane. Matrix: air. Procedure: Adsorption on Porapak R; desorption with hexane; gas chromatography/electron capture detection; range: 14 to 5370 ug/cu m in 3 L of air; Precision: 0.075. [R62] *Method No. 2517. Pentachloroethane. Gas chromatography; detetection limit 0.01-20 mg/cu-m. [R63] *AREAL Method IP-1B. Determination of Volatile Organic Compounds (VOCs) in Indoor Air using Solid Absorbant Tubes. Capillary gas chromatography/ mass spectrometry (CGCMS) detection limit 1.8 ng. [R64] *EAD Method 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. Capillary gas chromatography/mass spectrometry (CGCMS) detection limit 10 ug/L. [R65] *OSW Method 8240A. Volatile Organics by Gas Cromatography/Mass Spectrometry (GC/MS): Packed Column Technique. GCMS detection limit 10 ug/kg. [R66] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes (1980) EPA 440/5-80-0269 DHHS/NTP; Toxicology and Carcinogenesis Studies of Pentachloroethane in F344/N Rats and B6C3F1 Mice (Gavage Study) Technical Report Series No. 232 (1983) NIH Publication No. 83-1788 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 28 R2: USEPA; CHIP (Draft) Pentachloroethane p.2 (1983) R3: Class T, Ballschmiter K; Chemosphere 15: 413-27 (1986) R4: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 782 R5: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R6: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 693 R7: USEPA; The Verification of the Production of 56 Chemicals p.7 Office of Toxic Substances Contract No. 68-02-4209 (1985) R8: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 242 R9: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1126 R10: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-156 R11: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 67th ed. Boca Raton, FL: CRC Press, Inc., 1986-87.,p. C-671 R12: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 606 R14: Boublik T et al; The Vapor Pressure of Pure Substances: Selected Values of the Temperature Dependence of the Vapor Pressures of Some Pure Substances in the Normal and Low Pressure Region. Vol 17 Elsevior Sci Pub Amsterdam, Netherlands p. 89 (1984) R15: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 131 R16: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 950 R17: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R18: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-151 R19: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2126 R20: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1992.729 R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-183 R22: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 1289 R23: Bretherick, L. Handbook of Reactive Chemical Hazards. 3rd ed. Boston, MA: Butterworths, 1985. 1236 R24: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2580 R25: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 398 R26: 49 CFR 171.2 (7/1/96) R27: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 193 R28: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6191 (1988) R29: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-15 (1981) EPA 68-03-3025 R30: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 171 R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1521 (1999) R32: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R33: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1021 R34: VAINIO H ET AL; XENOBIOTICA 6 (10): 599 (1976) R35: MENNEAR JH ET AL; FUNDAM APPL TOXICOL 2 (2): 82 (1982) R36: Geiger D.L., Poirier S.H., Brooke L.T., Call D.J., (eds). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Vol. II. Superior, Wisconsin: University of Wisconsin-Superior, 1985.35 R37: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 768 R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 105 (1986) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 106 (1986) R40: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes p.B-8 (1980) EPA 440/5-80-0269 R41: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes p.B-9 (1980) EPA 440/5-80-0269 R42: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes p.B-10 (1980) EPA 440/5-80-0269 R43: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Ethanes p.B-13 (1980) EPA 440/5-80-0269 R44: NTP; Toxicology and Carcinogenesis Studies of Pentachloroethane p.7 Report# 232 (1983) NIH Pub# 83-1788 R45: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 132 R46: NASTAINCZYK W ET AL; BIOCHEM PHARMACOL 31 (3): 391 (1982) R47: YLLNER S; ACTA PHARMACOL TOXICOL 29 (5-6): 481 (1971) R48: (1) USEPA; The Verification of the Production of 56 Chemicals p. 7 Office of Toxic Substances Contract No. 68-02-4209 (1985) (2) Class T, Ballschmiter K; Chemosphere 15: 413-27 (1986) R49: (1) Boublik T et al; The Vapor Pressure of Pure Substances: Selected Values of the Temperature Dependence of the Vapor Pressures of Some Pure Substances in the Normal and Low Pressure Region. Vol 17 Elsevoir Sci Pub Amsterdam, Netherlands p. 89 (1984) (2) Eisenreich SJ et al; Environ Sci Tech 15: 30-8 (1981) R50: (1) Archer WL; Kirk-Othmer Encycl Chem Tech 3rd ed NY: Wiley 5: 737 (1979) (2) Atkinson R; Chem Rev 85: 69-201 (1985) (3) Gem; Graphical Exposure Modeling System. FAP Fate of Atmos Pollut (1986) (4) Spence JW, Hanst PL; J Air Pollut Control Fed 18: 250-3 (1978) R51: Jeffers PM et al; Environ Sci Technol 23 (8): 965-9 (1989) R52: (1) Barrows ME et al; Dyn, Exposure Hazard Assess Toxic Chem Ann Arbour Science: Ann Arbor, MI pp. 379-92 (1980) R53: (1) Sabljic A; J Agric Food Chem 32: 243-6 (1984) (2) Lyman WJ et al: Handbook of Chem Property Estimation Methods Environ Behavior of Organic Compounds McGraw-Hill NY p. 4-9 (1982) (3) Yalkowsky SH; Arizona Data Base of Aqueous Solubility (1987) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R54: (1) Boublik T et al; The Vapor Pressure of Pure Substances: Selected Values of the Temperature Dependence of the Vapor Pressures of Some Pure Substances in the Normal and Low Pressure Region. Vol 17 Elsevior Sci Pub Amsterdam, Netherlands p. 89 (1984) (2) Yalkowsky SH; Arizona Data Base of Aqueous Solubility (1987) (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Environ Behavior of Organic Compounds McGraw-Hill NY p. 15-12 to 15-32 (1982) (4) Dilling WL; Environ Sci Tech 11: 405-9 (1977) R55: (1) Konasewich D et al; Status Report on Organics and Heavy Metal Contaminants in the Lakes Erie, Michigan, Huron and Superior Basins Great Lakes Water Quality Board p. 26 (1978) (2) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters p. 71 USEPA 560/6-77-015 (1977) (3) Pellizzari ED et al; Formulation of Preliminary Assessment of Halogenated Aromatic Compound in Man and Environmental Media p. 77 USEPA 560/13-79-006 (1979) R56: (1) Carlberg GE et al; Sci Total Environ 48: 157-67 (1986) (2) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Water p. 119 USEPA 600/4- 76-062 (1976) R57: (1) Class T, Ballschmiter K; Chemosphere 15: 413-27 (1986) (2) Brodzinsky R, Singh HB, Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data Menol Park, CA: Atmospheric Science Center pp. 191-21 (1982) (3) Pellizzari ED; Quanitification of Chlorinated Hydrocarbons in Previously Collected Air Samples pp. 41-43 USEPA 450/3-78-112 (1978) R58: (1) NIOSH; National Occupationl Exposure Survey (NOES) (1983) (2) U.S. EPA; The Verification of the Production of 56 Chemicals p. 7 Office of Toxic Substances Contract No. 68-02-4209 (1985) R59: 40 CFR 401.15 (7/1/87) R60: 40 CFR 302.4 (7/1/92) R61: 40 CFR 261.33 (7/1/92) R62: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V6 335-1 R63: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R64: USEPA/Atmospheric Research and Exposure Assessment Laboratory (AREAL); Compendium of Methods for the Determination of Air Pollutants in Indoor Air, Engineering Science, One Harrison Park, Suite 305, 401 Harrison Oaks Blvd, Cary, NC 27513 as cited in USEPA; EMMI. Environmental Monitoring Index Database Version 1.02 (1992) EPA/871-B-92-001 (NTIS Document No. PB92-503093) R65: USEPA; EMMI. Environmental Monitoring Methods Index. Version 1.02. EPA-821-B-92- 001 (NTIS PB-92-503093). August 1992 R66: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) RS: 46 Record 165 of 1119 in HSDB (through 2003/06) AN: 2047 UD: 200302 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-CHLOROANILINE- SY: *P-AMINOCHLOROBENZENE-; *1-AMINO-4-CHLOROBENZENE-; *ANILINE,-P-CHLORO-; *ANILINE,-4-CHLORO-; *BENZENAMINE,-4-CHLORO-; *P-CA-; *4-CHLORANILIN- (CZECH); *P-CHLORANILINE-; *4-CHLORO-1-AMINOBENZENE-; *P-CHLOROANILINE-; *4-CHLOROBENZAMINE-; *4-CHLOROBENZENAMINE-; *P-CHLOROPHENYLAMINE-; *4-CHLOROPHENYLAMINE-; *NCI-C02039- RN: 106-47-8 RELT: 2045 [2-CHLOROANILINE]; 2046 [3-CHLOROANILINE] MF: *C6-H6-Cl-N SHPN: IMO 6.1; Chloroanilines, liquid or solid UN 2019; Chloroanilines, liquid UN 2018; Chloroanilines, solid HAZN: P024; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. ASCH: p-Chloroaniline hydrochloride; 20265-96-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Catalytic hydrogenation of chloronitrobenzene; by reduction of chloronitrobenzene with NaHS. [R1] FORM: *GRADES: 99.0%; TECHNICAL [R2] MFS: *E.I DuPont de Nemours and Co., Inc, DuPont Chemicals, Hqr, 1007 Market Street, Wilmington, DE 19898, (302) 774- 1000; Production site: Deepwater, NJ 08023 [R3] OMIN: *Ozonization of p-aminoazobenzene in water at room temp in the presence of HCl produced phenol, p-chloroaniline, and p-nitroazobenzene. [R4] USE: *DYE INT, PHARMACEUTICALS, AGRICULTURAL CHEMICALS [R5] *CHEM INT FOR DYES, EG, VAT RED 32 [R6] *CHEM INT FOR AZOIC COUPLING AGENTS 5 and 10 [R6] *CHEM INT FOR PIGMENTS, EG, PIGMENT GREEN 10 [R6] *Reacts with anhydrous hydrogen chloride and phosgene at 70-75 deg C in dioxane to produce p-chlorophenyl isocyanate, an intermediate used for the production of urea herbicides. [R7] PRIE: U.S. PRODUCTION: *(1978) PROBABLY GREATER THAN 4.54X10+6 G [R6] *(1982) PROBABLY GREATER THAN 4.54X10+6 G [R6] U.S. IMPORTS: *(1978) 3.66X10+7 G (PRINCPL CUSTMS DISTS) [R6] *(1982) 6.39X10+7 G (PRINCPL CUSTMS DISTS) [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORTHORHOMBIC CRYSTALS FROM ALC OR PETROLEUM ETHER [R1]; *Colorless crystals [R8] ODOR: *SLIGHTLY SWEETISH; CHARACTERISTIC AMINE ODOR [R2] BP: *232 DEG C [R1] MP: *72.5 DEG C [R1] MW: *127.57 [R1] DEN: *1.169 @ 77 DEG C/4 DEG C [R1] DSC: *pKa= 3.982 [R9] HTC: *-11,000 BTU/LB= -6,000 CAL/G= -250X10+5 J/KG [R2] HTV: *12,832.8 gcal/gmole [R10, p. C-672] OWPC: *Log Kow = 1.83 [R11] SOL: *FREELY SOL IN ALCOHOL, ETHER, ACETONE, CARBON DISULFIDE [R1]; *Solubility in water: 3.9 g/l. [R12] SPEC: *INDEX OF REFRACTION: 1.5546 @ 87 DEG C; [R10, p. C-68]; *MAX ABSORPTION (ALCOHOL): 242 NM (LOG E= 3.9); 295 NM (LOG E= 3.2); SADTLER REF NUMBER: 1317 (IR, PRISM); 8140 (IR, GRATING) [R13]; *IR: 5546 (Coblentz Society Spectral Collection) [R14]; *UV: 393 (Sadtler Research Laboratories Spectral Collection) [R14]; *NMR: 123 (Varian Associates NMR Spectra Catalogue) [R14]; *MASS: 234 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R14] VAP: *0.027 mm Hg @ 26 deg C [R15] OCPP: *DISTILLING RANGE 229-233 DEG C [R5] *Vapor pressure = 10 MM HG @ 102.1 DEG C; 40 MM HG @ 135 DEG C; 100 MM HG @ 159.9 DEG C [R10, p. D-201] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chloroanilines, liquid; Chloroanilines, solid/ [R16] FLPT: *GREATER THAN 220 DEG F (OPEN CUP) [R2] FIRP: *WATER, DRY CHEMICAL, FOAM OR CARBON DIOXIDE [R2] TOXC: *IRRITATING AND TOXIC HYDROGEN CHLORIDE AND OXIDES OF NITROGEN MAY FORM IN FIRES. [R2] DCMP: *DISASTER HAZARD: DANGEROUS; WHEN HEATED TO DECOMP, IT EMITS HIGHLY TOXIC FUMES. [R17] SERI: *Irritating to the eyes. [R18, 144] EQUP: *RUBBER GLOVES; CHEMICAL GOGGLES; PROTECTIVE CLOTHING; DUST RESPIRATOR. [R2] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R19, 1979.8] OPRM: *Immediately wash contaminated areas of body with concentrated soap solution. Remove contaminated clothing, dry, then wash with concentrated soap solution or dispose as waste. Contaminated shoes may be disposed of in an incinerator. [R20] *IT IS LESS HAZARDOUS THAN ANILINE OR MONONITROBENZENE IN INDUSTRIAL EXPOSURES. RELATIVELY LOW VAPOR PRESSURE, BUT PRECAUTION SHOULD BE TAKEN TO AVOID INHALATION OF VAPORS. [R21, 2438] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R19, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R19, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R19, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R19, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R19, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R19, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R19, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R19, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R19, 1979.11] SSL: *Stability during transport: stable. [R2] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R22] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R23] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R24] +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R19, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R19, 1979.13] STRG: *Storage temperature: ambient. [R2] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R19, 1979.13] CLUP: *Removal of chloroaniline from wastewater by electrochemical treatment is discussed. [R25] *Cover with the 9:1 mixture of sand and soda ash. After mixing, transfer into a paper carton, stuffed with ruffled paper. Burn in an open furnace with the utmost care or in the furnace with afterburner and scrubber. [R20] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R19, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P024, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R26] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. [R27] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R19, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R19, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R19, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R19, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R19, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicty of para-chloroaniline. There is sufficient evidence in experimental animals for the carcinogenicity of para-chloroaniline. OVERALL EVALUATION: Group 2B: para-Chloroaniline is possibly carcinogenic to humans. [R28] HTOX: *In the United Kingdom between 1961 and 1980, chloroaniline, p-toluidine, nitrobenzene, and nitrochlorobenzene were the most common industrial causes of methemoglobinemia. Dermal exposure was a more frequent route of toxicity than inhalation with these compounds. /Chloroaniline/ [R29] *Symptomatology: 1. Lips, tongue and mucous membranes navy blue to black; skin slate gray, all without signs of cardiac or pulmonary insufficiency. 2. Severe headache, nausea, sometimes vomiting, dryness of throat. 3. Central nervous symptoms: confusion, ataxia, vertigo, tinnitus, weakness, disorientation, lethargy, drowsiness, and finally coma. Convulsions may occur but appear to be uncommon. 4. Cardiac effects: heart blocks, arrhythmias, and shock. 5. Death, although uncommon, is usually due to cardiovascular collapse and not resp paralysis. 6. Urinary signs and symptoms may incl painful micturition, hematuria, hemoglobinuria, and renal insufficiency (usually mild). 7. A late acute hemolytic episode should be anticipated at 6 to 8 days after ingestion. /Aniline/ [R30, p. II-197] *p-Chloroaniline ... may cause methemogloginemia. [R21, 2447] *Aromatic amine concentrations in blood and partition of the aromatic amines in plasma and erythrocytes were measured using gas chromatography after five dialysis steps. The aromatic amine content of erythrocytes was examined after in vitro spiking of stabilized blood samples with aniline, p-chloroaniline, alpha-naphthylamine, and o-toluidine at 500 ug/l. The correlation between urinalysis studies and erythrocyte binding was examined in workers accidentally exposed to aniline and p-chloroaniline. ... Although aromatic amines permeated the erythrocyte membrane, they did not bind with intracellular substrates such as hemoglobin, and could be removed from inside the erythrocytes by consecutive dialysis stages. ... Following accidental exposure, urinary excretion of aniline and p-chloroaniline fell from an initial high peak to below detection limits within 3 days, but hemoglobin conjugation for p-chloroaniline reached a peak after 3 hr and for aniline after approximately 16 hr. Total degradation was not completed until day 12. [R31] *TOXIC BY INHALATION AND INGESTION. [R32] *SAID TO BE MORE TOXIC THAN ANILINE. [R30, p. II-140] *Methemoglobinemia, which is also consistent with the presence of a circulating N-hydroxy-para-chloroaniline metabolite, has been reported in workers exposed to para-chloroaniline and in neonates inadvertently exposed in incubators to chlorhexidine gluconate, which is known to decompose spontaneously to para-chloroaniline ... . [R33] NTOX: *... P-CHLOROANILINE INDUCED METHEMOGLOBINEMIA ... [R34] *ENZYMIC DEPLETION OF GLUTATHIONE INDUCED BY ANILINE ANALOGS WAS MOSTLY DEPENDENT ON THE CYTOCHROME P450 LEVEL IN ISOLATED MOUSE LIVER MICROSOMES. IN MOUSE, RAT, GUINEA PIG, AND RABBIT LIVER MICROSOMES, DEPLETION OCCURRED WITH THE ANILINE ANALOG, P-CHLOROANILINE. [R35] *4-CHLOROANILINE (DEGRADATION PRODUCT OF DIFLUBENZURON) HAD 96-HR MEDIAN LETHAL DOSE OF 2.4 MG/L TO BLUEGILLS AND 48-HR MEDIAN IMMOBILIZATION DOSE LEVEL OF 43 MG/L FOR EARLY 4TH INSTAR MIDGE LARVAE. [R36] *Toxicity of p-chloroaniline was determined by the 14 day Daphnia reproduction test and the 24 hr median effective concn (EC50). EC50 values ranged from 0.008-38 ppm. p-Chloroaniline at concentrations (0.0427-1.35 ppm) which were less than the EC50 showed marked effects on the reproduction rate. [R37] *p-Chloroaniline ... induced DNA repair in hepatocyte cultures from F344 rats. [R38] *P-chloroaniline was nonmutagenic in TA92, TA1535, TA100, TA1537, TA94, AND TA98 strains of Salmonella typhimurium with or without metabolic activation. [R39] *ACUTE TOXICITIES OF ANILINE, 4-FLUOROANILINE, 4-CHLOROANILINE, 4-BROMOANILINE, 4-IODOANILINE, 4-METHYLANILINE, and 4-NITROANILINE WERE DETERMINED IN RATS; LD50 VALUES CORRELATED WELL WITH HAMMETT TAU CONSTANTS USING THE HANSEN EMPIRICAL EQUATION. [R40] *In six carcinogenicity bioassays, male and female F344 rats were fed diets containing aniline hydrochloride, p-chloroaniline, o-toluidine hydrochloride, azobenzene, daspone, (4,4'-sulfonyldianiline), or D AND C red number 9; (5-chloro-2-(2-hydroxy-1-napthalenyl)azo)-4-methylbenzenesulfonic acid, barium salt). The rats, from 6 weeks to 2 years old, were given the cmpd at two dose levels, the estimated maximum tolerated dose and one-half that dose. In all six bioassays, dose dependent incidences of splenic sarcomas and fibrosis were seen, with the highest incidences in male rats. Fatty infiltration also was seen in the spleen. Sarcomas appeared to arise in the splenic red pulp or splenic capsule, usually in association with areas of parenchymal and capsular fibrosis and pigmentation. Larger tumors metastisized to the peritoneal cavity and abdominal organs. [R41] *The nephrotoxicity of aniline and its monochlorophenyl derivatives was studied in vivo and in vitro. Male Fischer 344 rats were injected ip with 0, 0.4, 1.0, or 1.5 mmol/kg aniline, 2-chloroaniline, 3-chloroaniline, or 4-chloroaniline. Food and water intake and body weight were monitored for two days after dosing. Kidney function parameters such as urine volume, blood urea nitrogen, and basal and lactate stimulated p-aminohippurate accumulation by renal cortical slices were evaluated. Kidney slices were examined for histopathological changes. In vitro, kidney slices were taken from untreated rats and incubated with aniline, 2-chloroaniline, 3-chloroaniline, or 4-chloroaniline. ... In vivo, food and water intake and body weight were markedly decreased by aniline and its derivatives the effects being greatest with 2-chloroaniline. 2-Chloroaniline at 1.0 mmol/kg and 3-chloroaniline and 4-chloroaniline at 1.5 mmol/kg decreased urine vol, elevated blood urea nitrogen, and decreased basal and lactate stimulated p-amino-hippurate uptake. Treatment related morphological changes included marked degenerative changes in proximal and distal tibular cells and occlusion of distal tubular segments. In vitro, 0.001 molar concentrations of all four cmpd depressed tetraethylammonium accumulation. [R42] *P-Chloroaniline has a lethal effect on the embryos of Xenopus laevis at 100 ppm and is teratogenic at 1 and 10 ppm. [R43] *Groups of 50 male and 50 female B6C3F1 mice, 6 wk of age, were fed a diet containing 2500 or 5000 mg/kg (ppm) para-chloroaniline [technical grade (purity unspecified), melting-point, 68-71 deg C) for 78 weeks, followed by a 13-week observation period. A group of 20 male and 20 female controls received the diet alone. Decreased body weight gain was observed in both treated males and females relative to that of controls. The numbers of surviving animals at 91 weeks were: males--control, 18/20; low-dose, 44/50; high-dose, 44/50; females--control, 20/20; low-dose, 41/50; high-dose, 39/50. Hemangiosarcomas occurred in different organs (subcutaneous tissue, spleen, liver, kidney) in 2/20 control, 9/50 low-dose and 14/50 high-dose males; one hemangioma was observed in the low-dose group. The increased incidence of all vascular tumors was significant LP < 0.025, Cochran-Armitage trend test]. Among females, hemangiosarcomas occurred at all of the sites in 0/18 control, 3/49 low-dose and 7/42 high-dose animals; one hemangioma was observed in the high-dose group. The increased incidence of combined vascular tumors in females was significant (p = 0.012, Cochran-Armitage trend test) ... . [R44] *Groups of 50 male and 50 female B6C3F1 mice, seven to eight weeks old, were administered 3, 10 or 30 mg/kg bw para-chloroaniline (99.1% pure) in aqueous hydrochloric acid (molar equivalents) by gavage on five days a week for 103 weeks. Controls received deionized water at a volume of 5 ml/kg. Survival at 104 weeks was: males--controls, 43/50; low-dose, 36/50; mid-dose, 29/50 (p = 0.005); high-dose 35/50; females--controls, 39/50; low-dose, 42/50, mid-dose; 44/50, high-dose, 41/50. Hepatocellular adenomas were observed in male mice: controls, 9/50; low-dose, 15/49; mid- dose, 10/50; high-dose, 4/50; and hepatocellular carcinomas occurred with a significantly positive trend: controls, 3/50; low-dose, 7/49; mid-dose, 11/50; high-dose, 17/50 (p < 0.001, logistic regression trend test). The incidence in males of hepatocellular adenomas and carcinomas combined was: controls, 11/50; low-dose, 21/49 (p = 0.019, logistic regression test); mid-dose, 20/50 (p = 0.045, logistic regression test); high- dose, 21/50 (p = 0.027, logistic regression test). The incidence of hemangiosarcomas of liver and spleen combined was 4/50 controls, 4/49 low-dose, 1/50 mid-dose and 10/50 high-dose male mice (p = 0.014, logistic regression trend test). No significant increase in the incidence of such tumors occurred in females ... . [R45] *Groups of 50 male and 50 female Fischer 344 rats, six weeks of age, were fed diets containing 250 or 500 ppm (mg/kg) para-chloroaniline (technical grade, purity unspecified) for 78 weeks. A group of 20 male and 20 female controls received the diet alone. Following a 24-week observation period, the surviving animals were sacrificed. There was no difference in body weight gain in the treated animals compared to the controls. Survival at week 102 was: males controls, 18/20; low-dose, 46/50; high-dose, 38/50; females--controls, 18/20; low- dose, 49/50; high-dose, 45/50. Mesenchymal tumors (fibroma, fibrosarcoma, hemangiosarcoma, osteosarcoma, sarcoma not otherwise specified) of the spleen or splenic capsule occurred in 0/20 control, 0/49 low-dose and 10/49 high-dose male rats (p = 0.001, Cochran-Armitage trend test) and in 0/18 control, 2/49 low- dose and 5/42 high-dose females ... . [R45] *Groups of 50 male and 50 female Fischer 344 rats, 8-9 wk old, were administered 2, 6 or 18 mg/kg bw para-chloroaniline (99.1% pure) in aqueous hydrochloric acid (molar equivalents) by gavage on five days per week for 103 weeks. A group of 50 male and 50 female controls received deionized water at 5 ml/kg. Survival at 105 weeks in low-dose and mid-dose males was significantly greater than that in the control group: controls, 18/50; low-dose, 32/50 (p = 0.007); mid-dose, 32/50 (p = 0.005); high-dose 21/50; as was that of high-dose females: controls, 27/50; low-dose, 39/50; mid-dose, 36/50; high-dose, 37/50 (p = 0.043). The incidences of proliferative mesenchymal lesions and fatty metamorphosis of the spleen were increased in high-dose males and females ... Adrenal pheochromocytomas, including a few malignant pheochromocytomas, were observed in 13/49 controls, 14/48 low-dose, 15/48 mid-dose and 26/49 high-dose male rats (p = 0.001, logistic regression trend test). The incidence of mononuclear cell leukemias was decreased in all treated groups: males--controls, 21/49; low-dose, 3/50; mid-dose, 2/50; high-dose, 3/50; females--controls, 10/50; low-dose, 2/50; mid-dose, 1/50; high-dose, 1/50 ... . [R45] *High levels of methemoglobinemia have been demonstrated after oral treatment of female Wistar rats with para-chloroaniline (purity unspecified) in propylene glycol at 0.6 mmol (77 mg)/kg bw; of male and female Fischer 344 rats with para-chloroaniline hydrochloride (purity, > 99%) in water at 5-80 mg/kg, five days per week for 13 weeks; of male and female B6C3F1 mice with para-chloroaniline hydrochloride (purity, > 99%) in water at 7.5-120 mg/kg, five days per week for 13 weeks; and of cats with para-chloroaniline (purity and vehicle unspecified) at 0.0625 mmol (8 mg)/kg bw ... Fischer rats given 80 mg/kg for a further 13 weeks had lowered body weights; and both rats and mice showed dose-related decreases in erythrocyte hemoglobin and increases in spleen weight. Numerous lesions indicative of hemolytic anemia and methemoglobinemia were observed, including hemosiderosis in the kidney, liver and spleen and increased hematopoiesis in the liver and spleen in mice and rats; bone-marrow hyperplasia was seen only in rats ... Nephrotoxicity was also reported in male Fischer 344 rats given a single intraperitoneal dose of para-chloroaniline (purity unspecified) at 1.5 mmol (191 mg)/kg bw in saline, which induced decreased urine volume, hematuria, elevated blood urea nitrogen and decreased renal cortical uptake of para-aminohippurate ... . [R33] *In a study conducted in Germany, zebrafish (Brachydanio rerio) were kept in tap-water to which 0, 0.04, 0.2 or 1.0 mg/l para-chloroaniline (technical grade; purity, > 99%) had been added. ... The concentrations in the aquaria were analyzed weekly by high-performance liquid chromatography. No adverse effect was noted in the F0 fish or on the numbers and viability of eggs produced. Eggs collected during the 22nd week of exposure were allowed to develop with continuing exposure to 4-chloroaniline. Mortality was not increased, but, at sexual maturity, over 90% of the F1 fish raised in 1.0 mg/l had spinal abnormalities and abnormal abdominal swellings. Significantly fewer eggs were produced by F1 fish in all three exposed groups, and the viability of eggs was reduced in the 1.0 mg/l group. An F2 generation exhibited the same effects: morphological abnormalities, reduced egg counts and reduced viability of eggs at 1.0 mg/l, and reduced egg counts at 0.04 and 0.2 mg/l. [R46] *para-Chloroaniline preferentially killed the pol A- strain in the Escherichia coli pol A-/pol A+ assay, both in the presence and absence of an exogenous metabolic system. It was not mutagenic to Salmonella typhimurium, except to strain TA98, for which conflicting data were obtained. It induced mutations in Aspergillus nidulans and in mouse lymphoma L5178Y cells at the tk locus. It did not induce mitotic recombination in Saccharomyces cerevisiae. para-Chloroaniline transformed primary cultures of Syrian hamster embryo cells, only in the later of two studies from the same laboratory. It induced sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells in vitro. [R46] +... Under the conditions of this bioassay, /there was not/ sufficient evidence ... to establish the carcinogenicity of p-chloroaniline for Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal; Female Rats: Negative; Male Mice: Equivocal; Female Mice: Equivocal. [R47] +... Under the conditions of these 2 yr water gavage studies, there was clear evidence of carcinogenic activity of p-chloroaniline hydrochloride in male F344/N rats as indicated by incr incidences of uncommon sarcomas of the spleen. Pheochromocytomas of the adrenal gland may also have been associated with chemical administration. There was equivocal evidence of carcinogenic activity of p-chloroaniline hydrochloride for female F344/N rats indicated by the presence of uncommon sarcomas of the spleen in one mid and one high dose animal and incr incidence of pheochromocytomas of the adrenal gland. There was some evidence of carcinogenic activity of p-chloroaniline hydrochloride for male B6C3F1 mice as indicated by incr incidences of hepatocellular neoplasms and hemangiosarcomas of the liver or spleen. There was no evidence of carcinogenic activity p-chloroaniline hydrochloride for female B6C3F1 mice admin 3, 10 or 30 mg/kg for 2 yr. /para-Choroaniline hydrochloride/ [R48] NTXV: *LD50 Rat male oral 200-480 mg/kg bw /Purity and vehicle unspecified/; [R33] *LD50 New Zealand Rabbit male dermal 360 mg/kg bw /Purity and vehicle unspecified/; [R33] NTP: +A bioassay for the possible carcinogenicity of p-chloroaniline was conducted using Fischer 344 rats and B6C3F1 mice. p-Chloroaniline was admin in the feed, at either two concn, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of p-chloroaniline were, respectively, 500 and 250 ppm for rats and 5,000 and 2,500 ppm for mice. The cmpd was administered in the diet for 78 wk, followed by an observation period of 24 wk for rats and 13 wk for mice. ... The finding of small numbers of fibromas and sarcomas in the spleens of male rats was strongly suggestive of carcinogenicity because of the rarity of these tumors in the spleens of control rats. Hemangiomatous tumors in dosed mice may also have been associated with the administration of p-chloroaniline. ... Under the conditions of this bioassay, /there was not/ sufficient evidence ... to establish the carcinogenicity of p-chloroaniline for Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal; Female Rats: Negative; Male Mice: Equivocal; Female Mice: Equivocal. [R47] +... Groups of 50 F344/N rats of each sex were admin 2,6 or 18 mg/kg p-chloroaniline hydrochloride in water by gavage, 5 days/wk for 103 wk. Groups of 50 B6C3F1 mice of each sex were admin 3, 10 or 30 mg/kg on the same schedule. ... Under the conditions of these 2 yr water gavage studies, there was clear evidence of carcinogenic activity of p-chloroaniline hydrochloride in male F344/N rats as indicated by incr incidences of uncommon sarcomas of the spleen. Pheochromocytomas of the adrenal gland may also have been associated with chemical administration. There was equivocal evidence of carcinogenic activity of p-chloroaniline hydrochloride for female F344/N rats indicated by the presence of uncommon sarcomas of the spleen in one mid and one high dose animal and incr incidence of pheochromocytomas of the adrenal gland. There was some evidence of carcinogenic activity of p-chloroaniline hydrochloride for male B6C3F1 mice as indicated by incr incidences of hepatocellular neoplasms and hemangiosarcomas of the liver or spleen. There was no evidence of carcinogenic activity p-chloroaniline hydrochloride for female B6C3F1 mice admin 3, 10 or 30 mg/kg for 2 yr. /para-Choroaniline hydrochloride/ [R48] TCAT: ?p-Chloroaniline was examined for mutagenic activity in Salmonella typhimurium tester strains TA98, TA100, TA1535 and TA1537 with and without metabolic activation provided by rat liver S9 fraction. The method used for inducing liver enzyme activities was not reported. The test article was not mutagenic when it was administered in the plate incorporation assay at concentrations of 1, 3, 10, and 30 ug/plate either with or without activation. The investigators reported that p-chloroaniline in a previous assay using an old protocol was toxic to cells at 100 ul/plate, however it was observed to be non-toxic over the concentration range tested in this assay. [R49] ADE: *p-Chloroaniline is absorbed through the intact skin ... . [R21, 2447] *TOMATO UPTAKE OF 4-CHLOROANILINE FROM SOIL INCR IN DIRECT PROPORTION WITH AMT PRESENT IN SOIL. CMPD WAS MOSTLY ROOT-LOCALIZED, BUT TRANSLOCATION TO STEM INCR WITH INCR CONCN. IN CARROTS, ROOTS ACCUM ONLY SLIGHTLY MORE CHLOROANILINE THAN GREEN PARTS. 4-CHLOROANILINE WAS ALSO TAKEN UP BY WHEAT AND BARLEY. [R50] *OATS TOOK UP AND TRANSLOCATED 1.4% OF SOIL-BOUND (14)C-4-CHLOROANILINE WITHIN 6 WK; UPTAKE FROM SOLN WAS 1.7-2.3%. LABELED CMPD WAS ADDED TO SOIL AT 1 PPM. THERE WERE ONLY SLIGHT DIFFERENCES IN RESULTS BETWEEN 2 SOIL TYPES (HUMUS-RICH GLEY AND PARABROWN SOILS) STUDIED. [R51] *In male /Fischer 344/ rats administered (14)C-labelled compound (5 mCi/mmol (0.04 mCi/mg) (radiochemical purity unspecified)) at 0.3-30 mg/kg bw by gavage in 0.01 N hydrochloric acid, 75-85% of the dose was excreted in urine and 8-12% in feces by 24 hr; only 4% was excreted as unchanged amine in urine, 2.5% in bile and 1% in feces. At seven days, appreciable radiolabel was still present in blood cells, accounting for 1-2% of the dose. After an intravenous dose of 3.0 mg/kg bw in ethanol:propylene glycol:water (1:1:8), 60% of the dose was excreted in urine after 4 hr, 25% was excreted in bile after 6 hr, and 90% was eliminated in urine and feces by 8 hr. Initial levels in tissues were highest in muscle > fat > skin > liver > blood ... . [R52] *Additional studies of the metabolism of (l4)C-para-chloroaniline (133 uCi/mg (17 mCi/mmol); radiochemical purity, > 98%) were carried out in male Fischer 344 rats, female C3H mice and male rhesus monkeys. The compound was given by oral intubation at a dose of 20 mg/kg bw in an aqueous solution adjusted to pH 5 with hydrochloric acid. In rats, mice and monkeys, respectively, the urine contained 90, 82 and 67-74%, and the feces contained 8, 5 and 1% of the dose after 48 hr. [R52] *After oral dosing of female Wistar rats with para-chloroaniline (purity unspecified) in propylene glycol at 0.6 mmol (77 mg)/kg bw by gavage, higher levels of hemoglobin binding (569 mmol bound/mol hemoglobin per (mmol cmpd/kg bw)) were observed than with 12 other monocyclic aromatic amines. [R52] METB: *YIELDS PARA-CHLORO-N-HYDROXYANILINE IN RABBIT. YIELDS PARA-AMINOPHENOL IN RABBITS. YIELDS PARA-CHLOROANILINE-N-BETA-DEXTRO-GLUCURONIDE IN RABBIT. YIELDS 2-AMINO-5-CHLOROPHENOL IN RABBITS. YIELDS 3-AMINO-7-CHLOROPHENOXAZIN-2-ONE IN RABBITS. /FROM TABLE/ [R53] *P-CHLOROANILINE IS METABOLIZED COMPLETELY BY CHLORELLA FUSCA RUBRA MOSTLY TO WATER-SOL PRODUCTS. 4 WK AFTER APPLICATION, 28% OF THE RADIOACTIVITY WAS RECOVERED FROM ALGAE AND 35% FROM AQ MEDIUM. METABOLITES ISOLATED WERE P,P'-DICHLOROAZOXYBENZENE AND P,P'-CHLOROAZOBENZENE FROM ALGAE AND P-CHLOROFORM ANILIDE AND P,P'DICHLOROACETANILIDE FROM NUTRIENT MEDIUM. [R54] *Microsomal fraction of germinated pea seeds oxidized 4-chloroaniline (4-CA) primarily to 4-chloronitrosobenzene, although (4-chlorophenyl)hydroxylamine was also a major product at high substrate concn. The enzyme-catalyzed oxidation of (4-chlorophenyl)hydroxylamine was faster than that for 4-chloroaniline. Oxidation of 4-chloroaniline was dependent on hydrogen peroxide and would not proceed when O2 and nicotinamide adenine dinucleotide phosphate reductase were substituted for hydrogen peroxide. Further slow oxidation of 4-chloronitrosobenzene to 4-chloronitrobenzene was an enzymatic process that was also dependent on hydrogen peroxide. [R55] *The amines undergo a process of metabolism within the organism and real active agents are the metabolites, some of which induce methemaglobinemia while others are carcinogenic. These metabolites generally take the form of hydroxylamines, changing to aminophenols as a form of detoxification. /Amines/ [R18, 142] *4-Chloroaniline undergoes N-oxidation in ram seminal vesicle microsomal preparations supplemented with arachidonic acid to yield N-(4-chlorophenyl)-hydroxyamine of the amine substrate to the same organic solvent extractable products, suggesting that the hydroperoxides activity of prostaglandin synthase is responsible for the co-oxidation. Analysis of the reaction mixtures by ESR spectrometry reveals the formation of a radical intermediate bearing the characteristics of a strongly immobilized nitroxide. [R56] *In a patient suffering from acute poisoning by para-chloroaniline, conjugates of the parent cmpd and 2-hydroxy-4-chloroaniline (2-amino-5-chlorophenol) were detected as major urinary metabolites ... . [R57] *Metabolism of para-chloroaniline in vitro by human granulocyte myeloperoxidase has been reported, resulting in at least 10 unknown peroxidation products ... . [R52] *... para- Chloroacetanilide was detected as a metabolite in bile and in blood /of Fischer 344 rats/, but not in urine or feces, indicating further metabolism prior to excretion ... . [R52] *The major urinary metabolite in all three species /male Fischer 344 rats, female C3H mice and male rhesus monkeys/ was 4-chloroaniline-2-sulfate; in rats and monkeys, its N-acetyl derivative was also detected as a minor urinary metabolite. In rats and to a lesser extent in mice, two additional metabolites, para-chloro-oxanilic acid and para-chloroglycolanilide, were observed as major and minor urinary metabolites, respectively. In monkeys, para-chloroacetanilide, which was not detected in urine or feces, and 4-chloroaniline-2-sulfate were the major metabolites found in plasma ... . [R52] *After oral dosing of female Wistar rats with para-chloroaniline (purity unspecified) in propylene glycol at 0.6 mmol (77 mg)/kg bw by gavage. ... The release of free para-chloroaniline after alkaline hydrolysis is consistent with the presence of a circulating N-hydroxy-para-chloroaniline metabolite that enters erythrocytes, is oxidized to para-chloronitrosobenzene and forms a sulfinamide adduct with hemoglobin ... . [R52] BHL: *... The kinetics of elimination /in Fischer 344 rats/ was biphasic, with an initial half-time of 8 min and terminal half-times of 3-4 hr in most tissues, except small intestine and fat (2329 h). [R52] ACTN: *Rabbit hemoglobin effects reduced pyridine nucleotide-dependent N-oxidation of 4-chloroaniline (4-CA) in the presence of NADPH-cytochrome c reductase. The apparent Km value for 4-CA is 5.9 mM. The substrate interacts with hemoglobin in a non-cooperative manner; highly purified alpha- and beta-subunits mediate amine oxidation with kinetic constants close to those of the intact tetramer. Metabolism of 4-chloroaniline is associated with the formation of 421 nm absorbing spectral complex, which might represent a ferryl species or a product adduct. Erythrocyte reductases, such as nicotinamide adenine dinucleotide phosphate-methemoglobin reductase or sol nicotinamide adenine dinucleotide phosphate reductase-cytochrome b5 reductase, also sustain amine oxidation in the presence of an appropriate electron carrier. Similarly, intact rabbit erythrocyes generate low amounts of N-oxy products when incubated with the parent amine. These findings support the idea that the red blood cell might be a site of bioactivation of aromatic amines. [R58] *N-Hydroxylation of para-chloroaniline has been demonstrated in vitro and shown to be catalyzed by hepatic microsomal cytochromes p450 in a wide variety of species, including rats, mice, hamsters, guinea-pigs, rabbits, rainbow trout and red-winged blackbirds. In mammals, multiple isozymes appear to be involved in the catalysis, since enzymes are induced by both phenobarbital- and 3-methylcholanthrene-type inducers. ... Peroxidative metabolism of para-chloroaniline has also been shown to be mediated by horseradish peroxidase, fungal chloroperoxidases, ram seminal vesicle prostaglandin synthase, rabbit liver microsomal lipid peroxides and by rabbit hemoglobin in the presence of erythrocyte reductases. These results indicate that the N-hydroxy derivative may be the initial product but that it is further oxidized enzymatically or non-enzymatically to para-chloronitrosobenzene. Several dimeric or halogen-containing oxidation products have also been detected ... . [R52] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4-Chloroaniline may be released to the environment during its production or use in the manufacture of dye intermediates, agricultural chemicals and pharmaceuticals. It is also a widespread soil contaminant resulting from the use of phenylurea herbicide of which it is a degradation product. If released on soil, it rapidly combines with soil components forming covalent bonds and polymers. As a consequence of these binding reactions, 4-chloroaniline is highly resistant to mineralization. It is partially mineralized by chemical and biological action. A few percent of the 4-chloroaniline will volatilize from the soil. If released into water, 4-chloroaniline will be lost due to volatilization, photooxidation in surface layers (half-life 0.4 hr), and rapid chemical reactions with humic materials and clay in the water column and sediment. Degradation in air will primarily be due to reaction with hydroxyl radicals (half-life 4.6 hr), although direct photolysis is also possible. Human exposure will primarily be in the workplace from inhalation or dermal contact. (SRC) ARTS: *4-Chloroaniline may be released to the environment as fugitive emissions or in wastewater during its production or use as a dye intermediate or in the manufacture of pharmaceuticals and agricultural chemicals(1). As 4-chloroaniline is a photoxidation product of monuron(6) and a degradation product of 4-chlorophenylurea(2) and diflubenzuron(7), release to the environment is possible as a result of the use of these pesticides. It is also a degradation product of chlorhexidine digluconate (a hospital disinfectant) exposed to acclimated activated sludge(3). 11 years after a 2-year application of (14-C)buturon, 4-chloroaniline accounted for 15% of the label(4). 4-Chloroaniliine is a contaminant of chlorhexide, which is used in disinfection of soft contact lenses(5) and therefore 4-chloroaniline may be disposed of by soft contact lens wearers(SRC). [R59] FATE: *The average concn of chemicals, 4-chloroaniline, hexachlorobenzene, and pentachloronitrobenzene, dosed in small experimental ponds in Southern Germany during the application period (4-6 wk) was about 50 ug/l. Residues were determined in water, sediment, and flora and fauna species up to 166 wk later. Decrease of all chemicals in water phase follows exponential functions and can be correlated to some extent with the physicochemical properties such as volatility and vapor pressure. The residual behavior of the model compounds followed a similar pattern resulting in high initial concentrations in biota and a slow buildup and subsequent decline of concentrations in sediment. Radioactivity could be found in some fauna species and sediment 3 yr after application. Anisols and azo compounds were found to be conversion products of pentachloronitrobenzene and 4-chloroaniline. [R60] *(14)C labeled 4-chloroaniline was applied to soil in lysimeter, corresponding to 1.25 ppm to a depth of 10 cm, and barley was sown. After 20 wk, a total of 32.8% of the radiocarbon applied was recovered, in soil 32.4%, in plants 0.3% and in leaching water 0.1%. Radioactivity in soil consisted of 30.8% unextractable residues and 1.6% sol conversion products; that in plants consisted of 0.24% unextractable residues and 0.03% sol metabolites (% of applied (14)C). In the 2nd and 3rd yr after the application potatoes and carrots, respectively, were grown; total recoveries were 32.0% and 31.2% respectively. The soluble radioactive fractions in soil and plants of the first 2 yr contained 4-chloroformanilide, 4-chloroacetanilide, 4-chloronitrobenzene, 4-chloronitrosobenzene, 4,4'-dichloroazoxybenzene, and 4,4'-dichloroazobenzene. The radioactive substances unextractable in soil and those in leaching water were partially hydrolyzable and gave 4-chloroaniline. [R61] *TERRESTRIAL FATE: If released on soil, 4-chloroaniline will bind tightly to soil although in the first few hours after a spill, a small amount should volatilize. It will undergo both biological and chemical transformation(2). When 4-chloroaniline (30 ppm) was incubated in Guelph loam with water added to 60% water-holding capacity, levels declined rapidly for two wk after which time the rate of loss decreased(2). The percent of 4-chloroaniline remaining after 2 and 8 wks were 45 and 25%, respectively. Mineralization occurs most rapidly in the early weeks of incubation with as much as 7.5% degradation to CO2 occurring in 6 weeks and 17% occuring in 16 weeks. Most (70-90%) of the 4- chloroaniline is transformed into inextractable residues and there is no significant leaching out either vertically or horizontally into surrounding layers of soil. A three year field test in which (14)C labeled 4-chloroaniline was applied to 60X60X60 cm box cultivated with barley and later with potatoes and carrots under outdoor conditions resulted in approximately 30% of the applied radioactivity being retained at the application site in the upper layer of soil after the first year and 67% being lost to the atmosphere(1). Uptake by plants, migration into deeper soil layers or into leaching water was low(1). From previous experiments, it is known that the bulk of the atmospheric loss is not volatilized 4-chloroaniline or conversion products, but rather CO2 resulting from mineralization(1). The situation after the second and third year did not alter appreciably(1). No free unchanged 4-chloroaniline could be detected in either soil or plants(1). Conversion products isolated under these environmental conditions included 4-chloroformanilide, 4-chloroacetanilide, 4-chloronitrobenzene, 4-chloronitrosobenzene, and the condensation products 4,4'- dichloroazoxybenzene and 4,4'-dichloroazobenzene(1). It is hypothesized that phenolic and hydroxylamine metabolites were not identified because of their chemical instability although they were found in laboratory experiments(1). In summary, it is clear that free 4-chloroaniline is not persistent in soil; it is subject to various acylation and oxidation reactions and finally to total biodegradation and incorporation into soil and plant constituents(1,SRC). [R62] *TERRESTRIAL FATE: Experiments were conducted in which (14C)4-chloroaniline was incubated under outdoor conditions for 20-25 wk and stepwise extractions conducted in order to establish the binding sites and degradability of the chemical in the different soil fractions(1). The total recovery of 14C was 32.4% of which 95.1% was as bound residues. The concns (ug equivalents to parent compound per g dry soil fraction) of bound 14C in the soil fractions were: humic acids, 30.7 ppm; humin, 6.97 ppm; fulvic acids, 5.95 ppm, and inorganic fractions 0.526 ppm. Aerobic biomineralization over 28 days in the soil ranged from 1.21% (humic acid) to 4.98% (fulvic acids and 2.18% overall, compared with 9.04% for the free chemical(1). Similarly, in a standard photomineralization test in which the test substance is put on silica gel and illuminated for 17 hr, 14CO2 formation ranged from 0.08% (humic acid) to 1.43% (fulvic acid) and 1.39% overall, compared with 26.06% for the free chemical(1). [R63] *AQUATIC FATE: If released into water, 4-chloroaniline will volatilize (half-life 35.7 days in a typical river), photooxidize in surface layers (half-life 0.4 hr), biodegrade (half-life several days in well acclimated water but otherwise of the order of several months), and chemically bind to clay and humus in sediment and particulate matter in the water column. When (14)C labeled 4-chloroaniline was added to an experimental pond (ca. 50 ppb over 6-8 wk), the (14)C label disappeared from the water in two phases with half-lives of about 3 and 11 days(1). It was assumed that the initial loss results from volatilization. After a day, a thin brown film of decomposition products was formed. The reduced loss rate after the first few days is probably a result of lower volatility of the decomposition products(1). The concn in sediment reached a maximum of 3 ppm between 4 and 9 wk after the last dosing and declined to about 0.7 mg/kg after 60 wk(1). No vertical or horizontal leaching into the surrounding soil was observed(1). The concn in the whole body of goldfish was about 3 ppm after the last dose and decreased by about half after 60 wk(1). In estuarine water, photolysis was an important loss process for 4-chloroaniline, but no biodegradation occurred in 3 days(2). The estimated half-lives of 4-chloroaniline in river water and ground water based on monitoring data are 0.3-3 day and 30-300 day, respectively(3). [R64] *ATMOSPHERIC FATE: According to its vapor pressure, 0.027 mm Hg at 26 deg C(2), 4-chloroaniline should exist in the atmosphere as a vapor(4). It will react with photochemically-produced hydroxyl radicals with a half-life 4.6 hr (3,SRC) and possibly also photolyze in the vapor phase or while adsorbed on airborne particulate matter. The rates of vapor-phase photolysis are unknown. A highly soluble chemical (3900 mg/L(1)), 4-chloroaniline should be scavenged by rain(SRC). [R65] BIOD: *THE METABOLISM OF 4-CHLOROANILINE BY ISOLATED CULTURES OF THE SOIL FUNGUS FUSARIUM OXYSPORUM SCHLECHT WAS STUDIED. 2-AMINO-5-CHLOROPHENOL WAS POSITIVELY IDENTIFIED AS METABOLITE OF 4-CHLOROANILINE IN THE ISOLATED SOIL FUNGUS CULTURES. [R66] *A Pseudomonas species, isolated from soil, was grown aerobically on 4-chloroaniline (4-CA) as the only carbon and nitrogen source with generation time of 15 hr. Balance studied with (14)C-ring-labeled 4-CA revealed that 64% of the carbon of 4-CA was released as CO2 and 14% was associated with the biomass. [R67] *The results of biodegradability screening studies for 4-chloroaniline are conflicting with results ranging from no degradation to rapid degradation using soil, sewage, activated sludge and fresh water inocula. The most frequently reported results are that 4-chloroaniline biodegrades rather slowly with acclimation(1-6). The reason for the conflicting results may be due to toxicity of metabolic intermediates(1), differences in concentrations and inocula used, sensitivity of 4-chloroaniline to chemical oxidation, and lack of sufficient acclimation. Some results are: 28% degradation in 5 days(2), 10% and 18% degradation in 28 days(2,5), no degradation in 28-30 days(2,3), 97% degradation in 10 days including an 8 day lag period(3), 97% removal in 5 days after 20 days acclimation(4) and 46 and 100% removal in 8 and 22 days, respectively, after a 14 day acclimation period(5). In the Zahn-Wellens test, 97% DOC was removed in 14 days(8). Biotransformation frequently involves acylation and oxidation to phenols(7). [R68] *In a river die-away test, 4-chloroaniline (10 ppm) degraded slowly in Nile River water over a period of 2 months but on redose increasingly larger concentrations of the chemical were degraded in shorter and shorter times so that on the 8th redose 100 ppm was degraded in a few days(7). No 4-chloroaniline (18.8 and 0.48 mg/L) degraded in 103 days at 15 deg C in a shake flask screening test using natural sea water(6). However, in simulation tests performed at the same temperature and with the same sea water, but at very low concns, 1 and 4 ug/L, first order rate constants (half-lives) of 0.0073/day (95 day) and 0.0076/day (91 day), respectively were obtained(6). Several studies were performed where labeled 4-chloroaniline was incubated with soil(4,5,8). In one study, 12-17% mineralization occurred in 16 weeks with the maximum rate of degradation occurring between 1 and 3 weeks(8). 86% of the labeled residue was present as unextractable material bound to the soil and 1-4% of the residues were extractable(8). In another study 7.5% mineralization occurred in 6 weeks, with 72% and 7% unextractable and extractable residue remaining(5). In comparing fractions with autoclaved controls, it is apparent that part of the extractable fraction is being biologically mineralized(5). Biological transformation of the unextractable residue, however, also occurs(5). In a third study, 8-9%, 69-73%, and 5-7% CO2, unextractable residue, and extractable residue, respectively, resulted after 16 weeks of incubation(4). It has been suggested that the binding of the chloroaniline to soil may extend its life in soil to 10 years(1). During composting with refuse, 14% of the 4-chloroaniline was metabolized in 21 days(2). No mineralization occurred when 4-chloroaniline was incubated under anaerobic conditions with digester sludge for 1 month(3). [R69] *In a 3-day Cultivation test using river water and sea water, none of the 4-chloroaniline (0.2 ppm) was degraded(2). In a study of the removal of 4-chloroaniline and other toxic organic pollutants (0.25 mg/L each) in pilot-scale continuous-flow conventional activated sludge treatment plants (7.5 hr hydraulic retention time and 4 day solids retention time), 87.6% of the 4-chloroaniline was removed during treatment with 78% being ascribed to biodegradation(1). [R70] *4-Chloroaniline was not biotransformed when anaerobically incubated for 8 months with samples from two sites, one methanogenic and one sulfate-reducing, within a shallow unconfined aquifer polluted by leachate from a municipal landfill(1). [R71] ABIO: *4-Chloroaniline absorbs light > 290 nm(1). On irradiation with light > 290 nm in air-saturated water it photolyzes to form 4-chloronitrobenzene and 4-chloronitrosobenzene(2). 4-Chloroaniline completely disappears within 6 hours and dark purple condensation products are subsequently formed(2). The half-life of 4-chloroaniline under illumination conditions typifying those for USA surface waters in summer is 0.4 hr(4). This rate is not increased by the presence of algae in the water(4). 28% of the 4-chloroaniline adsorbed on silica gel was photomineralized to CO2 in 17 hr(3). Photodecomposition is increased by the presence of photosenzitizers. The half-life of 4-chloroaniline in a photoreactor exposed to light > 290 nm was decreased by a factor of 2 (from 5 min) when riboflavin was present(8). After adsorption onto clay surfaces or humus, irreversible chemical reactions occur. 4-Chloroaniline also reacts rapidly with manganese dioxide, which may be present in natural water and soil, resulting in the formation of azo compounds(9). In one experiment (pH 4, concn MnO2 5X10-3 mol/L), the initial rate of reaction at pH 4 was 1.1X10-3 mol/L-min(9). Sunlight did not enhance the rate of reaction(10). 4-Chloroaniline has a vapor pressure of 0.027 mm Hg at 26 degC(6) and therefore in the atmosphere, it will exist primarily as the vapor(7). It reacts with photochemically- produced hydroxyl radicals with a rate constant of 8.3X10-11 cu cm/molecule-s(5). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of 4-chloroaniline in the atmosphere would be 4.6 hr(SRC). [R72] BIOC: *The average BCFs in the whole body of carp exposed to 4-chloroaniline in flow-through experiments (25 deg C, 12 L/hr) for 24 to 336 hr at high (10.4 ug/L) and low (0.30 ug/L) exposure levels were 0.8 and 1.7, respectively(3). Excretion was rapid with depuration rates and half-lives of 0.16/hr and 4.3 hr, respectively(3). Therefore, 4-chloroaniline should not bioconcentrate in fish. Uptake was rapid in static tests (0.20 umol/L, 26 deg C) on zebrafish and a BCF of 8.1 was obtained for 24 hr exposure(4). Elimination was best described by a two compartment first order model(4). After 53 hr of depuration, the concn of 4-chloroaniline in the zebrafish declined to 12.0% of the steady state value. The log BCF in Golden orfe was < 1.30 for 3 day exposure(1). The 24-hr log BCF in green alga was 3.08 (dry wt basis(2)) and 2.42 (wt weight basis(1)). [R73] KOC: *ADSORBED 4-CHLOROANILINE DESORPTION RATES FROM DIFFERENT SOILS INTO WATER WERE 11.9% TO 68.3%; % REPLACEABLE BY 3,4-DICHLOROANILINE WAS 17.9% TO 100%, INDICATING WEAKLY SORBED FRACTION. PROLONGED SOIL RESIDENCE OF 4-CHLOROANILINE GIVES CHEMICAL BONDING, INSEPARABLE FROM SOIL. [R74] *Adsorption of p-chloroaniline by 5 soils was studied in the lab. Adsorption decreased with the depth of the soil sample, due to decreased organic carbon. [R75] *Adsorption coefficients of 4-chloroaniline and 4 other organic compounds for organic and inorganic materials and natural soils were determined. With few exceptions, the organic constituents of the soils were mainly responsible for their adsorption properties. Cellulose appeared to be a well-suited model adsorbent for simulating the relative adsorption behavior of the chemicals. [R76] *The Koc for 5 Belgium soils ranged from 230-469(1). The adsorption isotherm was not linear and the exponent in the Freundlich adsorption isotherm averaged 0.70(1). The Koc for 5 German soils ranged from 96 to 1530 with the Freundlich exponent ranging from 0.92 to 1.23(2). From adsorption studies on three soils with radically different organic carbon and clay contents, it was shown that the percent (14)C labeled 4-choloroaniline that was bound increased with the organic carbon content of the soil and decreased with its clay content(3). Stronger binding at low concns, particularly with the soil of low organic carbon content, suggests that there are a limited number of available binding sites on the soil(3). At the lower concn (5ppm), percent binding ranged from 46-78%(3). The Koc to colloidal organic matter in ground water was high, 5550, suggesting that adsorption onto this microparticulate matter could effectively increase the solubility and leaching of 4-chloroaniline into landfill groundwater(4). However, the bound chemical is chemically altered. [R77] *The pKb of 4-chloroaniline is 10.02(3) so it will be partially ionized at alkaline pH. Binding to clays which may be ionic in character should therefore be stronger at lower pH(SRC). Thus the binding of 4-chloroaniline to bentonite was significant at pH 3, but not at pH 6.5(4). Adsorption and oxidation of aromatic amines can occur on clay surfaces which is dependent on the exchangeable cation in the clay and the presence of oxygen(1,2) as is partially evidenced by the formation of oligomeric or polymeric complexes when 4-chloroaniline is absorbed on montmorillonite clay(2). [R78] *Aromatic amines form covalent bonds with humic materials, adding to model quinoidal structures such as are found in humic materials, followed by slow oxidation to nitrogen-substituted quinoidal rings(1,6). Condensation with hydroquinones to form phenoxazines is another mechanism for incorporating anilines into humic substances(6). The reaction half-life of 4-chloroaniline with one test humic constituent was 13 min(1). Hybrid oligomers were formed between 4-chloroanline and carboxyphenolic humus constituents(2,5). These oxidative coupling reactions are mediated by biotic and abiotic catalysts, such as microbial and plant enzymes, inorganic chemicals, clay and soil extracts with MnO2 and enzymes having the strongest catalytic effect(5,6). This type of crosscoupling product would explain the fast, strong, and irreversible binding of anilines to soil(3). After 1 year, 10-20% of (14)C residues remained in the upper 10 cm of soil(3). Another field experiment using (14)C resulted in 30% of the label remaining where it was applied, while little was found at lower depths or in leachate(4). [R79] VWS: *The Henry's Law constant for 4-chloroaniline calculated from its water solubility (3,900 mg/L(5)) and vapor pressure (0.027 mm Hg at 26 deg C(1)) is 1.16X10-5 atm-cu m/mol(SRC), from which one would estimate a half-life of 35.7 day for a model river 1 m deep with a 1 m/sec current and 3 m/sec wind(2). In an experimental pond, the initial exponential decline in the concn of spiked 4-chloroaniline (half-life 3 days) was ascribed to volatilization(3). When 50 ppm of labeled 4-chloroaniline was put in water in a laboratory test, 0.62% of the radioactivity was lost in the first hour(5). When 50 ppm of (14C)4-chloroaniline was added to a sandy soil (0.51% organic carbon, pH 6.8), loamy soil (1.00% organic carbon, pH 6.1), and humus soil (2.89% organic carbon, pH 6.8) dampened to 40% of their water-holding capacity, 2.53%, 0.70%, and 0.19% of C-14 volatilized, respectively, during the first hour per ml of evaporated water(5). 3.5% of the radioactivity recovered when (14)C labeled 4-chloroaniline was incubated in soil was a volatile trapped in sulfuric acid solution(4) and therefore was probably the volatilized 4-chloroaniline rather than a degradation product(SRC). [R80] WATC: *DRINKING WATER: Germany; (treated Rhine water source) 7 parts/trillion (detection limit not reported), annual average(1). The Netherlands; maximum from bank-filtered Rhine water 1 ppb, including m-isomer(2). [R81] *SURFACE WATER: Not detected in Lakes Ontario (1 location), Erie (2 locations), Michigan (5 locations), and Superior (1 location). Rhine River (Germany) - 80 part/trillion, yearly average(2). Rhine River and two tributaries (The Netherlands) 130-220 part/trillion, average; 240-740 part/trillion maximum with 96-100% frequency of detection(3). Meuse River (The Netherlands) 20-30 part/trillion, average, 80-120 part/trillion maximum, 44-50% frequency of detection(3). While detected in Rhine Delta water, not found in surface waters from agricultural areas in the Netherlands(4). [R82] SEDS: *Release of tightly complexed 4-chloroaniline (4-CA) from treated soil humic acids and whole soils by pyrolysis in atmosphere of helium was studied. Pyrolysis of soil humic acids containing tightly complexed 4-CA resulted in release of approx 54% of the radioactivity with approx 5% detected via radioassay or gas-liq chromatography as intact 4-CA. Three soils of varying organic matter and clay concentrations complexed 10% of applied 4-CA; extractable radioactivity incr and tightly complexed 4-CA decreased as organic matter concn decreased and clay concn increased. The quantity of radioactivity released by pyrolysis was greatest for soils with low organic matter and high clay contents; 22-73% of the radioactivity could be released with 3-16% extractable into benzene from basified pyrolyzate, the amt depending on the nature of the soil, the type of pyrolysis probe, and the concn of the applied 4-CA. [R83] *WITH INCR TEMP, SOIGNES SOIL COLLOIDS HAVE HIGHER AFFINITY FOR P-CHLOROANILINE, IN COMPARISON TO ANILINE. [R84] *Of the 3 compounds, kepone, p-chloroaniline, and aldrin, persistence of kepone residues in soil was highest. Decrease in kepone and p-chloroaniline in soil occurred in about 2 stages, a fast one lasting in the case of p-chloroaniline 0.5 yr and a subsequent slow one. In another experiment, these compounds were detectable in soil, ground waters and plants 3 yr after application. [R85] ATMC: *SOURCE AREAS: 8 Industrial sites in the New Jersey area - 33 ng/cu m of chloroaniline (isomer not specified) near American Cyanamide plant in Bound Brook, not detected in the 7 other areas(1). [R86] FOOD: *4-Chloroaniline has been qualitatively identified as a volatile flavor component of Idaho Russet baked potatoes(1). [R87] RTEX: *Humans will be primarily exposed to p-chloroaniline by dermal contact or inhalation in occupational settings(SRC). 4-Chloroaniliine is a contaminant of chlorhexide, which is used in disinfection of soft contact lenses(1); therefore wearers of soft contact lenses my be exposed to 4-chloroaniline(SRC). [R88] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). These standards implement Section 111 of the Clean Air Act and are based on the Administrator's determination that emissions from the SOCMI cause, or contribute significantly to, air pollution which may reasonably be anticipated to endanger public health or welfare. The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. p-Chloroaniline is produced, as an intermediate or final product, by process units covered under this subpart. These standards of performance become effective upon promulgation but apply to affected facilities for which construction or modification commenced after January 5, 1981. [R89] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 28 ug/l [R90] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R91] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R92] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Benzenamine, 4-chloro is included on this list. [R93] RCRA: *P024; As stipulated in 40 CFR 261.33, when Benzenamine, 4-chloro, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R94] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HPLC METHOD WAS DEVELOPED FOR THE DETECTON OF SUB-NG QUANTITIES OF HALOGENATED ANILINE DERIVATIVES. [R95] *p-Chloroaniline was determined in chlorhexidine gluconate by spectrophotometry. Absorbance was measured at 455 nm. [R96] *Fused silica capillary column/mass spectrometry was used to analyze 28 nonpriority organic pollutants in environmental samples. [R97] *A method is described for determining 4-chloroaniline in the ppm range using ion-pairing, reversed-phase high pressure liquid chromatographic technique and uv detection at 260 nm. [R98] *4-chloroaniline was extracted from soils and plants with acetone and determined by gas chromatography. [R99] *Gas-liq chromatography with electron capture detection was used to quantitate released (14)C-labeled 4-chloroaniline from soil as its heptafluorobutyryl derivative. Alkaline hydrolysis was used to release the complexed 4-chloroaniline. [R100] *Method 8270: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Capillary Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water. [R101] *The oxidation of 4-chloroaniline by horseradish peroxidase resulted in 8 oligomeric products. A reverse phase high performance liquid chromatography method was developed so that substrate disappearence and the corresponding product formations could be quantitatively monitored. The product mixture was isolated from the aqueous reaction solution with solid phase extraction and the extracted components were seperated by thin layer chromatography. The individual thin layer chromatography bands were extracted for mass spectrometric and 1H Nuclear Magnetic Resonance analyses. [R102] *Method 8250, Gas Chromatography/Mass Spectrometry for Semivolatile Organics: Packed Column Technique, detection limit not reported. [R101] *Method 1625, Semivolatile Organic Compounds by Isotope Dilution, capillary gas chromatography/mass spectrometry, estimated detection limit 10 ug/L for water, not reported for solids. [R103] *Method 8270A, Method 8270A, Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique, estimated quanitation limit 1300 ug/kg for solids, 20 ug/L for water. [R101] CLAB: *4-CHLOROANILINE WAS DETERMINED IN URINE BY HPLC WITH ELECTROCHEMICAL DETECTOR. [R104] *A simple gas liquid chromatographic method has been developed which provides sensitivity and specificity for the analysis of complex mixtures of the commonly occurring herbicide metabolites aniline, 3-chloroaniline, 4-chloroaniline, 4-bromoaniline, and 3-chloro-4-methylaniline. All of these anilines react with acetic anhydride directly in basified aqueous solution. Further reaction of the acetylated anilines with trifluoroacetic anhydride gave diacyl derivatives which were readily resolved by gas chromatography. The technique was applied to the determination of anilines added to urine samples. 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V57 313 (1993) R47: Bioassay of p-Chloroaniline for Possible Carcinogenicity (1979) Technical Rpt Series No. 189 DHEW Pub No. (NIH) 79-1745, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R48: Toxicology and Carcinogenesis Studies of para-Chloroaniline hydrochloride in F344/N Rats and B6C3F1 Mice Technical Report Series No. 351 (1989) NIH Publication No. 89-2806 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R49: Monsanto Co.; Mutagenicity Plate Assay: p-Chloroaniline (1977), EPA Document No. 8782211296, Fiche No. OTS0206222 R50: FUCHSBICHLER G ET AL; Z PFLANZENKR PFLANZENSCHUTZ 85 (5): 298-307 (1978) R51: FUCHSBICHLER G ET AL; Z PFLANZENKR PFLANZENSCHUTZ 85 (7): 404-12 (1978) R52: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 311 (1993) R53: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. C-16 R54: ANAGNOSTOPOULOS E ET AL; CHEMOSPHERE 7 (4): 351-7 (1978) R55: Corbett MD, Corbett BR; J Agric Food Chem 31 (6): 1276-82 (1983) R56: Golly I, Hlavica P; Biochem J 226 (3): 803-10 (1985) R57: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 310 (1993) R58: Golly I, Hlavica P; Biochim Biophys Acta 760 (1): 69-76 (1983) R59: (1) Verschueren K; Handbook of Environmental Data on Organic Chemicals 2nd Ed Von Nostrand Reinhold NY p 356 (1983) (2) Nimmo WB et al; Pestic Sci 17: 403-11 (1986) (3) Sakagami Y et al; Eisei Kagaku 32: 427-32 (1986) (4) Scheunert I et al; Schriftenr Ver Wasser-, Boden- Lufthyg 68: 313-22 (1987) (5) Stevens LE et al; J Pharm Sci 75: 83-6 (1986) (6) Crosby DG; pp 260-78 in Degradation Syn Org Mol Biosphere, Proc Conf 1971 Washington, DC: Natl Acad Sci (1972) (7) Mutanen RM et al; Pestic Sci 23: 131-40 (1988) R60: Schauerte W et al; Ecotoxicol Environ Saf 6 (6): 560-9 (1982) R61: Freitag D et al; J Agric Food Chem 32 (2): 203-7 (1984) R62: (1) Freitag D et al; J Agric Food Chem 32: 203-7 (1984) (2) Thompson FR, Corke CT; Can J Microbiol 15: 791-6 (1969) R63: (1) Scheunert I et al; Toxicol Environ Chem 31-32: 107-12 (1991) R64: (1) Schauerte W et al; Ecotox Environ Saf 6: 560-9 (1982) (2) Hwang HM et al; Water Res 21: 309-16 (1978) (3) Zoetman BC et al; Chemosphere 9: 231-49 (1980) R65: (1) Kilzer L et al; Chemosphere 8: 751-61 (1979) (2) Piacente V et al; J Chem Eng Data 30: 372-6 (1985) (3) Wahner A, Zetzsch C; J Phys Chem 87: 4945-51 (1983) (4) Bidleman TF Environ Sci Technol 22: 361-7 (1988) R66: FLETCHER CL, KAUFMANN DD; J AGRIC FD CHEM 27 (5): 1127-30 (1979) R67: Zeyer J, Kearney PC; Pestic Biochem Pestic Biochem Physiol 17 (3): 215-23 (1982) R68: (1) Baird R, et al; J Water Pollut Control Fed 49: 1609-15 (1977) (2) Rott B et al; Chemosphere 11: 531-8 (1982) (3) Janicke W, Hilge G; Gas Wasserfach Wasser Abwasser 121: 131-5 (1980) (4) Pitter P; Water Res 10: 231-5 (1976) (5) Schmidt-Bleek F et al; Chemosphere 11: 383-415 (1982) (6) Torgeson DC; Interaction of Herbicides and Soil Microorganisms p 73 16060 DMP 03/71 (1971) (7) Freitag D et al; J Agric Food Chem 32: 203-7 (1984) (8) Wellens H; Z Wasser Abwassser Forsch 23: 85-98 (1990) R69: (1) Bartha R; J Agric Food Chem 19: 385-7 (1971) (2) Korte F et al; Chemosphere 1: 79-102 (1978) (3) Shelton DR, Tiedje JM; Development of Tests for Determining Anaerobic Biodegradation Potential p 92 USEPA 560/5-81-013 (1981) (4) Fuchsbichler G et al; Z Pflanzenkr Pflanzenschutz 85: 724-34 (1978) (5) Bollag JM et al; J Agric Food Chem 26: 1302-6 (1978) (6) Nyholm N et al; Ecotoxicol Environ Safety 23: 173-90 (1992) (7) El-Dib MA, Aly OA; Water Res 10: 1055-9 (1976) (8) Suess A et al; Z Pflanzezernaehr Bodenkd 141: 57-66 (1978) R70: (1) Bhattacharya SK et al; Removal and fate of RCRA and CERCLA toxic organic pollutants in wastewater treatment. Cincinnati OH: USEPA/600/S2-89/026 (1990) (2) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) R71: (1) Kuhn EP, Suflita JM; Environ Sci Technol 23: 848-52 (1989) R72: (1) Stadler Index; 393 UV (2) Miller GC, Crosby DG; Chemosphere 12: 1217-28 (1983) (3) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) (4) Zepp RG, Schlotzhauer PF; Environ Sci Technol 17: 462-8 (1983) (5) Wahner A, Zetzsch C; J Phys Chem 87: 4945-51 (1983) (6) Piacente V et al; J Chem Eng Data 30: 372-6 (1985) (7) Bidleman TF Environ Sci Technol 22: 361-7 (1988) (8) Larson RA et al; Environ Toxicol Chem 8: 1165-70 (1989) (9) Laha S, Luthy RG; Environ Sci Technol 24: 363-373 (1990) (10) Bertino DJ, Zepp RG: Environ Sci Technol 25: 1267-73 (1991) R73: (1) Korte F et al; Chemosphere 1: 79-102 (1978) (2) Geyer H et al; Chemosphere 13: 269-84 (1984A) (3) Tsuda T et al; Chemosphere 26: 2301-6 (1993) (4) Kalsch W et al; Chemosphere 22: 351-63 (1991) R74: FUCHSBICHLER G, SUESS A; CHEMOSPHERE 7 (4): 345-50 (1978) R75: Mueller-Wegener U; Chem Erde 41 (2): 175-81 (1982) R76: Rippen G et al; Ecotoxicol Environ Saf 6 (3): 236-45 (1982) R77: (1) Van Bladel R, Moreale A; J Soil Sci 28: 93-102 (1977) (2) Rippen G et al; Ecotox Environ Safety 6: 236-45 (1982) (3) Worobey BL, Webster GRB; J Agric Food Chem 30: 164-9 (1982) (4) Means JC; Amer Chem Soc 186th Natl Mtg Washington,DC. Preprints Div Environ Chem 23: 250-1 (1983) R78: (1) Furukawa T, Brindley GW; Clay Clay Minerals 21: 279-88 (1973) (2) Cloos P et al; Chim Organo Minerale Lab Phys Chim Minerale Catalyse Grp Catholic Univ Louvain Belgium 14: 307-21 (1979) (3) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution, IUPAC Chem Data Ser Suppl Buttersworth London (1972) (4) Bengtsson G et al; Water Res 20: 935-7 (1986) R79: (1) Parris GE; Environ Sci Tech 14: 1099-105 (1980) (2) Bollag JM et al; Environ Sci Tech 17: 72-80 (1983) (3) Schauerte W et al; Ecotox Environ Safety 6: 560-9 (1982) (4) Freitag D et al; J Agric Food Chem 32: 203-7 (1984) (5) Bollag JM et al; Sci Tot Environ 123/4: 205-17 (1992) (6) Adrian P et al; Chemosphere 18: 1599-1609 (1989) R80: (1) Piacente V et al; J Chem Eng Data 30: 372-6 (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Environ Behavior of Organic Compounds McGraw-Hill NY pp 15-1 - 15-34 (1982) (3) Schauerte W et al; Ecotox Environ Safety 6: 560-9 (1982) (4) Bollag JM et al; J Agric Food Chem 26: 1302-6 (1978) (5) Kilzer L et al; Chemosphere 8: 751-61 (1979) R81: (1) Kussmaul H; pp 265-75 in Pergamon Ser Environ Sci (1978) (2) Piet GJ, Morra CF; pp 31-42 in Artificial Groundwater Recharge, Water Resources Engineering Series Huisman L, Olsthorn TN eds. Pitman (1983) R82: (1) Great Lakes Water Quality Board; An Inventory of Chemical Sub Identified in the Great Lakes Ecosystem Vol 1 pp 195 (1983) (2) Kussmaul H; pp 265-75 in Pergamon Ser Environ Sci (1978) (3) Wegman RCC, Dekorte GAL; Water Res 15: 391-4 (1981) (4) Greve PA, Wegman RCC; Schriftenr Ver Wasser, Boden, Lufthyg Berlin-Dahlem 46: 59-80 (1975) R83: Worobey BL, Webster GR Ba; J Agric Food Chem 30 (1): 164-9 (1982) R84: MOREALE A, VAN BLADEL R; SOIL SCI 127 (1): 1-9 (1979) R85: Scheunert I; Results of long-term studies on the behavior of foreign substances in plant-soil system; GSF-Ber O (599, Inst Oekol Chem, Kolloq): 85-93 (1981) R86: (1) Pellizzari ED; The Measurement of Carcinogenic Vapors in Ambient Atmospheres USEPA-600/7-77-055 (1977) R87: (1) Coleman EC et al; J Agric Food Chem 29: 42-8 (1981) R88: (1) Stevens LE et al; J Pharm Sci 75: 83-6 (1986) R89: 40 CFR 60.489 (7/1/94) R90: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R91: 40 CFR 302.4 (7/1/94) R92: 40 CFR 712.30 (7/1/94) R93: 40 CFR 716.120 (7/1/94) R94: 40 CFR 261.33 (7/1/94) R95: LORES EM ET AL; J CHROMATOGR SCI 16 (8): 358-62 (1978) R96: Arzamastsev AP et al; Khim-Farm Zh 17 (2): 247-9 (1983) R97: Hunt GT, Hoyt MP; J High Resolut Chromatogr Commun 5 (6): 291-8 (1982) R98: Perez RL; J Chromatogr Sci 19 (11): 570-2 (1981) R99: Sukhoparova VP, Sokolov MS; Agrokhimiya 8: 117-34 (1983) R100: Worobey BL, Webster GR; J Agric Food Chem 30 (1): 161-4 (1982) R101: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R102: Simmons KE et al; Int J Environ Anal Chem 26 (3-4): 209-27 (1986) R103: EPA; EMMI. Environmental Monitoring Methods Index. Verson 1.02. EPA- 821-B-92-001 (NTIS PB-92-503093). August 1992 R104: LORES EM ET AL; J CHROMATOGR 188 (2): 412-16 (1980) R105: Hargesheimer EE et al; J Assoc Off Anal Chem 64 (4): 833-40 (1981) RS: 97 Record 166 of 1119 in HSDB (through 2003/06) AN: 2074 UD: 200201 RD: Reviewed by SRP on 1/31/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ANTHRAQUINONE- SY: *ANTHRACENE,-9,10-DIHYDRO-9,10-DIOXO-; *9,10-ANTHRACENEDIONE-; *ANTHRADIONE-; *9,10-ANTHRAQUINONE-; *CORBIT-; *9,10-DIOXOANTHRACENE-; *HOELITE-; *MORKIT- RN: 84-65-1 MF: *C14-H8-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Through the oxidation of naphthalene to naphthaquinone, which is condensed with butadiene to yield tetrahydroanthraquinone; this is dehydrogenated to produce anthraquinone. [R1] *PRODUCED INDUSTRIALLY FROM PHTHALIC ANHYDRIDE AND BENZENE IN PRESENCE OF ALUMINUM CHLORIDE BY FRIEDEL-CRAFTS REACTION. FROM ANTHRACENE WITH VANADIUM PENTOXIDE, SODIUM CHLORATE, GLACIAL ACETIC AND SULFURIC ACIDS. CONVENIENT LAB PROCEDURE. [R2] *Anthracene + nitric acid, concentrated (nitric acid oxidation process); o-Benzoylbenzoic acid (acid-catalyzed condensation) [R3] FORM: *GRADES: SUBLIMED; 30% PASTE (SOLD ON 100% BASIS); ELECTRICAL 99.5%. [R4] *ANTHRAQUINONE CATHARTICS ALL CONTAIN CHARACTERISTIC DERIV WHICH ARE PRESENT IN THE FREE STATE...OR IN GLYCOSIDIC COMBINATION WITH GLUCOSE, ARABINOSE, OR RHAMNOSE. MAJOR ACTIVE CONSTITUENTS.../INCL/ ANTHRAQUINONE... [R5] *AS SEED DRESSINGS: 25% WP OR IN CONJUNCTION WITH OTHER SEED PROTECTANTS. [R6] MFS: *James River Corp of Virginia. PO Box 2218 Tredegar Street Richmond, VA 23217 (804) 644-5411. James River Specialty Chemicals, 4th and Adams Street, Camas, WA 98607 (360) 834-8278. Production Site: Camas, WA 98607 [R7] OMIN: *BASIC PRODUCERS: BAYER AG (WEST GERMANY) (CORBIT*, MORKIT*) JF HENRY CHEM CO, INC, FINE CHEM DIV. [R8] *ANTHRAQUINONE DYE. A DYE WHOSE MOLECULAR STRUCTURE IS BASED ON ANTHRAQUINONE. ... CI NUMBERS FROM 58000 TO 72999. THESE ARE ACID OR MORDANT DYES WHEN OH OR HSO3 GROUPS RESPECTIVELY ARE PRESENT. THOSE ANTHRAQUINONE DYES THAT CAN BE REDUCED TO ALKALINE SOL LEUCO (VAT) DERIVATIVE THAT HAS AFFINITY FOR FIBERS, AND WHICH CAN BE REOXIDIZED TO THE DYE, ARE KNOWN AS ANTHRAQUINONE VAT DYES. THEY ARE LARGELY USED ON COTTON, RAYON, AND SILK, AND HAVE EXCELLENT PROPERTIES OF COLOR AND FASTNESS, AND RELATIVELY LOW TOXICITY. /ANTHRAQUINONE DYE/ [R4] *...DISPERSE DYES (USED FOR ACETATE, RAYON AND SYNTHETIC FIBERS)... DISPERSE COLORS MAY BE ANTHRAQUINONE...DYES... [R9] *FUNGICIDAL ACTIVITY IS FOUND IN VARIETY OF QUINONES IN GENERAL ORDER 1,4-NAPHTHOQUINONE GREATER THAN PHENANTHROQUINONE GREATER THAN P-BENZOQUINONE GREATER THAN ANTHRAQUINONE. [R10] *AS BIRD REPELLANT TREAT SEEDS OF CEREALS, VEGETABLES AND LEGUMES @ RATE OF ABOUT 1 LB (OF 25% FORMULATION)/500 LB SEED. [R6] USE: *CHEM INT FOR VAT DYES, ACID DYES, MORDANT DYES, DISPERSE DYES, SOLVENT DYES, AND FOR PIGMENTS [R11] *Anthraquinone serves as the basis for the production of a large number of acid and base dyes, vat dyes, disperse dyes, and reactive dyes. [R12, p. VA2 353] *As an additive in the soda and kraft chemical alkaline pulping processes in the paper pulping industry. [R1] *Anthraquinone is used as an intermediate in the manufacture of the laxative Danthron, also as a major dyestuff intermediate, as a catalyst in the isomerization of linseed and other vegetable oils, as an accelerant in nickel electroplating, and has a use in improving adhesion and heat stability of tirecords. [R1] *Intermediate for dyes and organics, organic inhibitor, bird repellent for seeds. [R4] CPAT: *ESSENTIALLY 100% AS A CHEMICAL INTERMEDIATE FOR THE MANUFACTURE OF DYES (1976) [R11] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R11] *(1975) GREATER THAN 4.54X10+5 GRAMS [R11] U.S. IMPORTS: *(1972) 3X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R11] *(1975) 1.03X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R11] *813,322 pounds (in 1983) [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LIGHT YELLOW, SLENDER MONOCLINIC PRISMS BY SUBLIMATION IN VACUO; ALMOST COLORLESS, ORTHORHOMBIC, BIPYRAMIDAL CRYSTALS FROM SULFURIC ACID + WATER [R2]; *YELLOW RHOMBIC NEEDLES FROM ALCOHOL, BENZENE [R14]; *YELLOW-GREEN CRYSTALS [R15] BP: *377 DEG C @ 760 MM HG [R2] MP: *286 DEG C [R2] MW: *208.20 [R2] DEN: *1.42-1.44 AT DEG 20 C/4 DEG C [R2] OWPC: *log Kow = 3.39 [R16] SOL: *INSOL IN WATER; 0.44 G/100 G ALC @ 25 DEG C; 2.25 G/100 G BOILING ALC; 0.11 G/100 G ETHER @ 25 DEG C; 0.61 G/100 G CHLOROFORM @ 20 DEG C; 0.26 G/100 G BENZENE @ 20 DEG C; 0.30 G/100 G TOLUENE @ 25 DEG C [R2]; *SOL IN CONCN SULFURIC ACID [R14]; *SOL IN ACETONE [R4]; *Solubility in water = 1.353 mg/l [R17] SPEC: *MAX ABSORPTION (ALCOHOL): 252 NM (LOG E= 4.7), 278 NM (LOG E= 4.1), 330 NM (LOG E= 3.7); SADTLER REF NUMBER: 1815 (IR, PRISM); 508 (UV) [R14]; *Intense mass spectral peaks: 208 m/z (100%), 180 m/z (96%), 152 m/z (75%), 151 m/z (38%) [R18]; *IR: 279 (Sadtler Research Laboratories IR Grating Collection) [R19]; *UV: 815 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) [R19]; *MASS: 1478 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R19]; *The UV spectrum exhibits four bands - 251 nm (Emax = 54000), 279 (Emax = 17600), 321 nm (Emax = 4800), 377 nm (Emax = 110) [R12, p. VA2 347] VAPD: +7.16 (AIR= 1) [R20] VAP: *1.16X10-7 mm Hg @ 25 deg C [R21] OCPP: *VAPOR PRESSURE = 1 MM HG @ 190.0 DEG C [R22] *Liquid Molar Volume = 0.193625 cu m/kmol; IG Heat of Formation = -9.52X10+7 J/kmol; Heat Fusion at Melting Point = 3.2552X10+7 J/kmol [R23] *Flash point = 185 deg C [R4] *Anthraquinone is sublimed easily without decomposition [R12, p. VA2 348] *Anthraquinone dissolves in 90% sulfuric acid giving a yellow to orange solution, and in oleum (20% SO3), giving a red solution. [R12, p. VA2 348] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME. SPONTANEOUS HEATING: NO [R24] NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R20] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R20] FLPT: +365 DEG F (185 DEG C) (CLOSED CUP) [R20] FIRP: *WATER, FOAM, CARBON DIOXIDE, WATER SPRAY OR MIST, DRY CHEM [R24] SERI: *Irritates .. skin. [R25] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *LOW SYSTEMIC TOXICITY, BUT MAY CAUSE SKIN IRRITATION, SENSITIZATION. [R26] *Chronic neurotoxic effects include vision disturbances. /From table/ /Quinones/ [R27] NTOX: *ANTHRAQUINONE...HAS BEEN NOTED ONLY IN EXPTL ANIMAL EYES TO CAUSE IRRITATION AND INFLAMMATION WHEN APPLIED TO THE EYE. ...IT IS POSSIBLE THAT IRRITATION IS DUE TO MECH ACTION OF POWDER RATHER THAN TO TOXIC EFFECT... [R28] *SODIUM-POTASSIUM-ACTIVATED ATPASE FROM RABBIT RED CELL MEMBRANE WAS INHIBITED BY ANTHRAQUINONE. THE INHIBITORY ACTION OF ANTHRAQUINONE WAS DUE TO THE INHIBITION OF -SH GROUP OR THE CARBOXYL GROUP OF THE ENZYME. [R29] *ANTHRAQUINONE WAS MUTAGENIC FOR STRAINS TA1537, TA1538, AND TA98, IN THE ABSENCE OF RAT LIVER HOMOGENATE, IN THE AMES/SALMONELLA MICROSOME ASSAY. [R30] *ANTHRAQUINONE WAS NONMUTAGENIC, WITH OR WITHOUT METABOLIC ACTIVATION, IN SALMONELLA TYPHIMURIUM STRAINS TA98, TA100, AND TA2637 BY THE PREINCUBATION METHOD. [R31] *Acute neurotoxic effects reported in animals include convulsions; medullary paralysis. /From table/ /Quinones/ [R27] METB: *YIELDS ANTHRONE, 9,10-DIHYDROXYANTHRACENE, and 2-HYDROXYANTHRAQUINONE IN RATS. /FROM TABLE/ [R32] *Quinones (ie, 6,12-dione) have been shown to undergo oxidation-reduction cycles involving quinone, hydroquinone, and molecular oxygen, resulting in the formation of oxygen radicals and semiquinone radicals. /Quinones/ [R33] ACTN: *THE QUINONES ARE ALPHA-BETA-UNSATURATED KETONES AND REACT WITH SULFHYDRYL (-SH) GROUPS. THIS REACTION HAS BEEN SUGGESTED AS THE CRITICAL BIOCHEMICAL LESION INVOLVING THE -SH GROUPS OF ENZYMES SUCH AS AMYLASE AND CARBOXYLASE WHICH ARE INHIBITED BY QUINONES. ... OVERALL /FUNGICIDAL/ MECHANISM MAY INVOLVE BINDING OF ENZYME TO QUINONE NUCLEUS BY SUBSTITUTION OR ADDN @ THE DOUBLE BOND, OXIDATIVE REACTION WITH -SH GROUP, AND CHANGE IN REDOX POTENTIAL. /QUINONES/ [R10] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Anthraquinone's production and subsequent use as an additive in the paper pulping industry,as a bird repellent for seeds, and as the basis for the production of a large number of dyes may result in its release to the environment through various waste streams. Anthraquinone is also produced from anthracene in the environment through photolytic and biodegradation processes. If released to the atmosphere, anthraquinone will exist in both the vapor-phase and the particulate phase based on an experimental vapor pressure of 1.16X10-7 mm Hg. In the vapor-phase, it should react with hydroxyl radicals with an estimated half-life of 11 days. Particulate phase anthraquinone may be physically removed from air by wet and dry deposition. Anthraquinone should have slight to low mobility in soil based on estimated Koc values of 1664 and 3702. This compound is expected to biodegrade fairly rapidly with 68% degradation reported in 12 weeks by a mixed soil population. In water, anthraquinone is expected to adsorb to particulate matter and sediment in the water column based on its Koc values. Biodegradation is a major fate process in water; over a three day period, 82% of the added anthraquinone (at 10 mg/L) was degraded by river water, 91% was degraded by sea water. Anthraquinone is also readily biodegraded by natural bacterial populations in groundwater and by activated sludge. A photolysis half-life of 2.8 hours was measured when anthraquinone was exposed to incident light (295-500 nm). Anthraquinone may bioconcentrate in aquatic organisms based on estimated BCF values of 222 and 522; this compound has been detected in fish. Monitoring data indicate that exposure to anthraquinone by the general population is through the ingestion of drinking water. Exposure to anthraquinone may occur occupationally during its use as a dye intermediate or as a catalytic agent in the paperpulping process. (SRC) ARTS: *Anthraquinone's production and subsequent use as an additive in the soda and kraft chemical alkaline pulping processes in the paper pulping industry(1) and as the basis for the production of a large number of acid and base dyes, vat dyes, disperse dyes, and reactive dyes(2) may result in its release to the environment through various waste streams(SRC). Anthracene, which is frequently detected in the environment probably due to its pyrogenic origin, is known to yield anthraquinone upon direct photooxidation in aqueous media(3). The biodegradation of anthracene by white rot fungi results in anthraquinone as a major degradation intermediate(4). Soil samples contaminated with diesel oil and originally not containing anthraquinone were found to contain anthraquinone following 25 weeks(5). Aqueous chlorination products of standard PAH's include anthraquinone; this process works via oxidation of the PAH using hypochlorite(6). [R34] FATE: *TERRESTRIAL FATE: Estimated Koc values of 1664 and 3702(1,SRC), based on experimental values for log Kow(2) and water solubility(3), indicate that anthraquinone will have low to slight mobility in soil using a soil mobility classification(4). Anthraquinone is not expected to volatilize from dry surfaces based on an experimental vapor pressure of 1.16X10-7 mm Hg(5) or to volatilize from moist soil surfaces given an estimated Henry's Law constant of 3.18X10-9 atm-cu/mole(1,SRC) from the water solubility(3) and vapor pressure(5). Biodegradation of anthraquinone is expected to be a major fate process for this compound in soil; 68% of added anthraquinone was biodegraded by a mixed soil population within 12 weeks(6). A mixed bacterial population, isolated from a coal-tar contaminated soil, biodegraded anthraquinone even faster with only 6.5% of the initial concentration of anthraquinone remaining after 3 days(7). [R35] *AQUATIC FATE: Based on estimated Koc values of 1664 and 3702(1,SRC), determined from experimental values for log Kow(2) and water solubility(3), anthraquinone may adsorb to particulate matter and sediment in the water column(4); this may be a major fate process for this compound(SRC). Photolysis of anthraquinone may occur in water. When exposed to incident light (295-500 nm), a photolysis half-life of 2.8 hours was measured(5). Anthraquinone may bioconcentrate in aquatic organisms based on estimated BCF values of 222 and 522(1,SRC) determined from experimental values of log Kow(2) and water solubility(3), respectively; this compound has been detected in fish(6). [R36] *AQUATIC FATE: Biodegradation of anthraquinone in the water column is expected to be a major fate process. Over a three day period, 82% of the added anthraquinone (at 10 mg/l) was degraded by river water, 91% was degraded by sea water(1). Biodegradation using mixed cultures from seawater degraded anthraquinone 50% over 10 days; metabolite concentration was low but included mainly benzoic and phthalic acids(2). Mixed bacterial populations from groundwater were able to completely degrade anthraquinone within 5 days(3). From 50-100% degradation has been reported using activated sludge as an inoculum and a three week incubation period(4-9). [R37] *ATMOSPHERIC FATE: Based on an experimental vapor pressure of 1.16X10-7 mm Hg at 25 deg C(1), anthraquinone will exist in both the vapor phase and the particulate phase in the ambient atmosphere(2,SRC). Anthraquinone is expected to degrade fairly quickly in the vapor phase by reaction with photochemically produced hydroxyl radicals with an estimated half-life of 11 days(3,SRC). Particulate phase anthraquinone may be removed physically from air by wet and dry deposition(SRC). Anthraquinone absorbed to airborne wood soot particles and exposed to sunlight (3-4 hour period) was stable. Under the same conditions but with 0.1 ppm NOx present a half-life of 2.5 hours was reported indicating that ozone in the presence of sunlight promotes degradation reactions for this compound(4). Anthraquinone has been detected in rain water from several storm events(5). [R38] BIOD: *Anthraquinone (at 10 mg/l organic carbon), inoculated with activated sludge, reached 28% of the theoretical CO2 within 28 days(1). 52.3% of the initial concn of anthraquinone (100 mg/l) was biodegraded by an activated sludge inoculum (time = 3 weeks)(2). Biodegradation of anthraquinone was measured using three standard tests (each using activated sludge inocula)(3). Over a 20 day period, 51-91%, 81-93%, and 70% of the added anthraquinone was biodegraded in the Sturm test, MITI test, and the RDA test, respectively(3). Anthraquinone (at 100 mg/l) was biodegraded by 46% over a 28 day period (UK-MITI test); a lag time of about 7 days was observed(4). From 30-100% BODT was measured in the Japanese-MITI test over 14 days (anthraquinone = 100 mg/l)(5). Varying activated sludge inoculum sizes had little impact on the final oxidation of anthraquinone; 40-60% oxidation at 56 days was seen for all inoculum levels(6). [R39] *A mixed bacterial population (EM4) isolated from sea water foam biodegraded anthraquinone (concentration = 1 g/l); 50% of the added compound was degraded over 10 days(1). Metabolites included benzoic and phthalic acids in low concentrations(1). Over a three day period, 82% of the added anthraquinone (at 10 mg/l) was degraded by river water, 91% was degraded by sea water(2). Anthraquinone was present in groundwater at an initial concentration of 3.3 ug/ml; 1.9 ug/ml remained after 3 days, and an undetectable amount was left following 5 days after inoculation with a mixed population derived from creosote contaminated soil(3). Anthraquinone, using an anaerobic digesting sludge inoculum, inhibited gas production for 4 weeks (lag phase > 75 days) before limited net gas production began; the volume of gas produced during the experiment (60-100 days) was not greater than that produced by the blanks. It was not possible to say whether degradation of this compound occurred as this gas may have been produced either by degradation of anthraquinone or by degradation of substrates in the sludge which were not degraded during the inhibitory phase(4). [R40] *White rot fungi of the genus Trametes degraded anthracene without any accumulation of anthraquinone suggesting that either anthraquinone was not formed as a metabolite of this process or that this genus can rapidly metabolize anthraquinone(1). Lignolytic cultures of Phanerochaete chrysosporium metabolized anthraquinone(1). Anthraquinone, initially present at 48.6 mg/3 kg soil, was biodegraded by the soil bacterial population to 15.3 mg/3 kg soil following 12 weeks incubation(2). Anthraquinone initially present at 1229.7 mg/3 kg sediment was biodegraded by the sediment bacterial population to 1122.9 mg/3 kg sediment following 12 weeks incubation(2). A seven strain bacterial community isolated from a coal-tar contaminated soil biodegraded anthraquinone with only 6.5% of the initial concentration remaining after 3 days(3). [R41] ABIO: *Anthraquinone in aquatic media (ethanol(99%): water (1%)) exposed to incident light from 295-500 nm resulted in a reported photolysis half-life of 2.8 hours(1). Anthraquinone subjected to exhaustive photolysis (16 hr, 253.7 nm irradiation, in ethanol) undergoes photochemical conversion to 9,10-dihydroxyanthracene and secondly to 9-anthranol in the absence of oxygen(2). Anthraquinone deposited on silica gel and exposed in the dark did not react to the presence of ozone at varying concentrations and exposure times(3). Anthraquinone absorbed to airborne wood soot particles and exposed to sunlight (3-4 hour period) was stable; under the same conditions but with 0.1 ppm NOx present, a half-life of 2.5 hours was reported. This indicates that ozone in the presence of sunlight promotes degradation reactions for this compound(4). The rate constant for the vapor-phase reaction of anthraquinone with photochemically produced hydroxyl radicals has been estimated as 1.498X10-12 cu cm/molecule-sec at 25 deg C(5,SRC). This corresponds to an atmospheric half-life of about 11 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(5,SRC). [R42] BIOC: *BCF values of 222 and 522 were calculated for anthraquinone, using an experimental log Kow of 3.39(1) and an experimental water solubility of 1.353 mg/l(2), respectively, and recommended regression-derived equations(3,SRC). This BCF value suggests that anthraquinone may bioconcentrate in aquatic organisms(3). Anthraquinone was detected in brown bullhead catfish from the Black River, Ohio(4) indicating that bioconcentration may occur(SRC). [R43] KOC: *Based on an experimental log Kow of 3.39(1)and an experimental water solubility of 1.353 mg/l(2), Koc values of 1664 and 3702, respectively, for anthraquinone can be calculated using regression-derived equations(3,SRC). According to a suggested classification scheme(4), these Koc values suggest that anthraquinone has low to slight mobility in soil(SRC). [R44] VWS: *The Henry's Law constant for anthraquinone was determined from experimental values of vapor pressure(1) and water solubility(2) as 2.35X10-8 atm-cu/mole(3,SRC). This value indicates that volatilization of anthraquinone from water surfaces will be slow(3). [R45] WATC: *SURFACE WATER: Anthraquinone was detected in 2 of 79 samples of industrial wastewater from either the timber products or organics and plastics industries(1). Surface water from 2 sites and anoxic deep water from a single site in the Baltic Sea contained anthraquinone at unreported concentrations(2). Anthraquinone was detected at unreported concentrations in the Waal River, April 1974(3). [R46] *GROUNDWATER: Anthraquinone was present in groundwater down-gradient from an abandoned wood-preserving plant at concentrations of 3.3 mg/25 ml; at 0.002 mg/l in streamwater that flowed through the plant site(1). [R47] *DRINKING WATER: A tap water sample taken from Kitakyushu, Japan contained 5.2 ng/l anthraquinone(1). Tap water from Tsukuba, Japan contained anthraquinone at unreported concentrations(2). Anthraquinone was detected in Ottawa's drinking water supply, sampled in January and February 1978 (concn = 1.8-2.4 ng/l)(3). Twelve Great Lakes municipal drinking water supplies in Canada contained anthraquinone with concentrations ranging from not detected to 72 ng/l(4). Drinking water taken from 6 unspecified water treatment plants, was analyzed for the presence of anthraquinone in June and October 1978; anthraquinone was detected at all sites in concentrations of 0.6 to 2.1 ng/l(5). Tap water from Athens, GA contained anthraquinone at concentrations of 20-100 ng/l(6). [R48] *RAIN/SNOW: Anthraquinone was detected in eight of nine documented rain storms in Oregon at concentrations of 2.2 to 16 ng/l for spring storms and 18-74 ng/l for fall storms(1). Anthraquinone was detected in 7 of 7 rain storms in Portland, OR from February to April, 1984 (concns = 1.5-3.6 ng/cu-m)(2). Anthraquinone was detected in precipitation in Norway with a possible source of this chemical in Eastern Europe and England(3). [R49] EFFL: *Anthraquinone was emitted at concns of 24.3 and 4.4 ug/km during particulate emission tests (simulating urban driving conditions) of tailpipes of non-catalyst (average of 1965 Mercury Monterey, 1969 Ford Mustang, 1970 Buick Skylark, 1972 Chevrolet Caprice, 1974 Ford Pinto, and 1976 Volkswagen Beetle) and catalyst cars (average of 1977 Chevrolet Vega, 1980 Honda Civic 150, 1980 Honda 1500, 1980 Toyota Corolla, Datsun 200 SX, 1983 Chevrolet Malibu CL, and 1983 Dodge Omni), respectively; at a concn of 23.5 ug/km from tailpipes of heavy-duty diesel trucks (average of a 1987 GMC truck, two-axle, and a 1987 Ford Dump truck, three-axle)(1). Particulate samples obtained from an automobile using a diesel engine contained anthraquinone at unreported concns(2). Diesel emission particulates from a Volkswagen Rabbit contained anthraquinone(3). Particulate emissions from a representative small aircraft gas turbine engine contained detectable quantities of anthraquinone in 5 of 8 different sampling conditions (concns of 0.06-58.49 ng/cu-m; detection limit=0.01 ug)(4). Organic extracts of emissions from burning cereal straw contained anthraquinone at 995 ug/kg fuel(5). Particulate samples from the exhaust of a flame retention head residential oil burner combusting No. 2 fuel oil contained anthraquinone(6). [R50] *Anthraquinone was detected in 2 of 4 extracts of MM5 trains from 4 different municipal waste incinerators (concn = 2.9-9.0 ug/ml)(1). Flyash extracts from municipal incinerators contained anthraquinone in 3 of 5 sites(2). Anthraquinone was identified in the flyash of an Ontario municipal incinerator at unreported concentrations(3). Anthraquinone was not detected in tire wear particles and was present at concentrations of 0.31 and 0.41 ug/g in brake lining particles and road dust particles, respectively(4). [R51] *Anthraquinone was detected in leachate (concentration=0.7 ug/l) from central Texas lignite under conditions meant to replicate rainfall leaching of coal piles(1). Tap water (pH=9) exposed to test panels coated with a commercial coal tar contained anthraquinone(2). Anthraquinone was detected in pulping liquors from processes using this compound as a catalyst for the delignification of wood; in black liquors n=14, concentration=3.0-170 mg/l; in alkaline pulping liquors n=6, concentration=0.5-11.5 mg/l; in wash liquors n=5, concentration=0.13-0.75; in filtrates from bleaching n=5, concentration=0.04-0.66(3). Anthraquinone was detected at concentrations of 49-110 ppb in the raw wastewater of a dye manufacturing plant; it was not detected in the final effluent of the same plant(4). Anthraquinone was detected in 235 samples obtained from superfund sites; data were compiled from CLP Analytical Results Database(5). [R52] SEDS: *Marine sediments from the sewage area of Marseilles, France contained anthraquinone in 9 of 10 sites (concentration=2-400 ng/g)(1). Sediment from Dokai Bay contained anthraquinone(2). [R53] ATMC: *SOURCE DOMINATED: Anthraquinone was detected in one of eight air samples (concn = 44.5 ng/cu m) near a chemical factory in Czechoslovakia(1). Anthraquinone was detected in air samples collected in the potroom of an aluminum reduction plant at a concn of 297 ng/cu m(2). [R54] *URBAN/SUBURBAN: Organic extracts from airborne particulate matter collected in Barcelona City contained anthraquinone at 9, not detected, 26, and 21 pg/cu m during the spring, summer, fall, and winter, respectively(1). Atmospheric aerosol samples were collected in Barcelona; anthraquinone was present in the summer sample at 82 pg/cu m and in the winter sample at 75 pg/cu m(2). Anthraquinone was detected in airborne particulate matter in Duisburg, Germany from February to April, 1982 (concn = 0.22-1.89 ng/cu m(3). Ambient air levels of anthraquinone in Toronto, Ontario were reported as 0.9-1.3 pg/cu m(4). 2 of 7 sites in the US sampled for ambient air particulates (Upland, CA; Lake Charles, LA) contained anthraquinone at unreported concentrations(5). Mean gas and particulate-phase concentrations of anthraquinone were measured in Portland, OR during February and April, 1984 and February and April, 1985 (gas concn = 2.5 ng/cu m; particulate concn = 0.59 ng/cu m)(6). Urban air particles from St. Louis, MO contained anthraquinone at unreported concentrations(7). [R55] *RURAL/REMOTE: Airborne particulate matter sampled near Chacaltaya, Bolivia (remote location) and Antwerp, Belgium (urban location) contained anthraquinone in 6 of 6 samples (Bolivia, n = 2, concn = 0.064-0.065 ug/1000 cu m; Belgium, n = 4, concn = 0.57-1.0 ug/1000 cu m; detection limit = 0.02 ug/1000 cu m)(1). [R56] PFAC: PLANT CONCENTRATIONS: *2 of 6 samples of mosses and 3 of 6 samples of needles contained anthraquinone (mosses = 1756.8 to 4054.1 ng/g; needles = 459.5 to 1918.9 ng/g) near a chemical factory in Czechoslovakia(1). [R57] FISH/SEAFOOD CONCENTRATIONS: *42 ppb anthraquinone was detected in Black River (Ohio) bullhead catfish(1). [R58] ANIMAL CONCENTRATIONS: *2 of 5 earthworm samples contained anthraquinone (concns = 473 to 4715.9 ng/g) near a chemical factory in Czechoslovakia(1). [R57] RTEX: *Anthraquinone was detected in air samples collected in the potroom of an aluminum reduction plant at 297 ng/cu m(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 6188 workers (1603 of these are female) are potentially exposed to anthraquinone in the USA(2). [R59] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R60] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Anthraquinone is included on this list. [R61] *Manufacturers and processors of anthraquinone are required to conduct specific chemical tests as required under TSCA section 4. [R62] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A CONVENIENT PROCEDURE IS DESCRIBED FOR QUANTITATION OF POLYNUCLEAR AROMATIC HYDROCARBONS BY HPLC-GC IN WATER AT THE NANOGRAM TO MICROGRAM PER LITER LEVEL. APPLICATION OF THIS PROCEDURE TO THE STUDY OF AQ CHLORINATION REACTIONS OF SEVERAL POLYNUCLEAR AROMATIC HYDROCARBONS IS DESCRIBED. [R63] *A METHOD WAS DEVELOPED FOR THE DETECTION OF 9,10-ANTHRAQUINONE BIRD REPELLANT IN SEEDS, CROPS, AND SOIL. THE DETECTION WAS BY ELECTRON-CAPTURE DETECTOR. RECOVERIES WERE 94-106% @ 0.5-0.05 PPM, AND THE MAX SENSITIVITY WAS 0.05 PPM. [R64] *ANTHRAQUINONE DETERMINATION IN AIRBONE PARTICULATE MATTER BY CAPILLARY GAS CHROMATOGRAPHY AND GAS CHROMATOGRAPHY/MASS SPECTROMETRY. [R65] *POLAROGRAPHIC DETERMINATION OF ANTHRAQUINONE WITH DMF AS SOLVENT, AMMONIUM ACETATE SOLN AS SUPPORTING ELECTROLYTE, AND GELATIN SOLN AS MAX SUPPRESSOR. RESULTS WERE REPRODUCIBLE AND ERRORS DID NOT EXCEED + OR - 3%. [R66] *Anthraquinone was detected in rainwater using GC/MS (MDL = 0.05-0.10 ng/l). [R67] *Anthraquinone was detected in fish tissue using capillary gas chromatography followed by GC/MS (detection limit = 0.2 ppb, average recovery = 72%). [R68] *Anthraquinone was detected in tap water using GC/MS followed by mass fragmentography. [R69] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: ZWAVING JH; RECENT DEVELOPMENTS IN THE ANALYSIS OF ANTHRAQUINONE DERIVATIVES; PHARMACOLOGY 20(SUPPL 1) 65 (1980). A REVIEW AND DISCUSSION ON RECENT DEVELOPMENTS IN THE ANALYSIS OF ANTHRAQUINONE DERIVATIVES. FRIEDMANN CA; STRUCTURE-ACTIVITY RELATIONSHIPS OF ANTHRAQUINONES IN SOME PATHOLOGICAL CONDITIONS; PHARMACOLOGY 20(SUPPL 1) 113 (1980). A REVIEW ON THE STRUCTURE-ACTIVITY RELATIONSHIPS OF ANTHRAQUINONES IN SOME PATHOLOGICAL CONDITIONS. ANTON R ET AL; PHARMACOLOGY 20 (SUPPL 1): 104 (1980). A REVIEW AND DISCUSSION ON THE THERAPEUTIC USE OF NATURAL ANTHRAQUINONE FOR OTHER THAN LAXATIVE ACTIONS. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that anthraquinone is on the list of post peer review technical reports in progress. Route: dosed-feed; Species: rats and mice. NTP TR No 494. [R70] SO: R1: Appleton HT et al; Technical Support Document 9,10-Anthraquinone. SRC TR-85-105. EPA Fiche # OTS0581336. Syracuse, NY (1985) R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 109 R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 84 R5: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 738 R6: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 19 R7: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 460 R8: Farm Chemicals Handbook 1981. Willoughby, Ohio: Meister, 1981.,p. C-20 R9: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 426 R10: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 9 R11: SRI R12: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R13: Appleton HT et al; Technical Support Document 9,10-Anthraquinone. SRC TR-85-105. Syracuse, NY (1985) R14: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-121 R15: Worthing, C. R. (ed.). Pesticide Manual. 6th ed. Worcestershire, England: British Crop Protection Council, l979. 19 R16: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R17: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona-Tucson, AZ. PC Version (1992) R18: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 44 R19: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 102 R20: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-16 R21: Shimizu T et al; J Soc Dyers Colour 103: 132-7 (1987) R22: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 411 R23: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R24: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 292 R25: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 46 R26: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 94 R27: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985. 129 R28: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 109 R29: KOH IS; TAEHAN SAENGRI HAKHOE CHI 11 (1): 1 (1977) R30: LIBERMAN DF ET AL; APPL ENVIRON MICROBIOL 43 (6): 1354 (1982) R31: TIKKANEN L ET AL; MUTAT RES 116 (3-4): 297 (1983) R32: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. A-62 R33: Dean, J.H., M.I. Luster, A.E. Munson, I. Kimber. Immunotoxicology and Immunopharmacology. 2nd ed. New York, NY: Raven Press, Ltd., 1994. 577 R34: (1) Appleton HT et al; Technical Support Document 9,10-Anthraquinone. SRC TR-85-105. USEPA Doc#: 40-8580018. Syracuse, NY (1985) (2) Vogel A; Ullman's Encyl Indus Chem. Gerhartz W (ed). VCH Publishers, Deerfield Beach, FL VA2: 353 (1985) (3) Rontani JF et al; Chemosphere 14: 1909-912 (1985) (4) Field JA et al; Appl Environ Microbiol 58: 2219-2226 (1992) (5) Langbehn A, Steinhart H; Chemosphere 30: 855-868 (1995) (6) Alben K; Anal Chem 52: 1825-828 (1980) R35: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. Chihara H et al, eds; ACS Prof Ref Book, Washington,DC: Amer Chem Soc p. 118 (1995) (3) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. Coll Pharm, Univ Arizona-Tucson, AZ. PC Version (1992) (4) Swann RL et al; Res Rev 85: 23 (1983) (5) Shimizu T et al; J Soc Dyers Colour 103: 132-7 (1987) (6) Mueller JG et al; Environ Sci Technol 25: 1045-55 (1991) (7) Mueller JG et al; Appl Environ Microbiol 55: 3085-90 (1989) R36: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10 (1990) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. Chihara H et al, eds; ACS Prof Ref Book, Washington,DC: Amer Chem Soc p. 118 (1995) (3) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. Coll Pharm, Univ Arizona-Tucson, AZ. PC Version (1992) (4) Swann RL et al; Res Rev 85: 23 (1983) (5) Svenson A, Bjorndahl H; Chemosphere 17: 2397-2405 (1988) (6) Vassilaros DL et al; Anal Chem 54: 106-112 (1982) R37: (1) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (2) Rontani JF et al; Chemosphere 14: 1909-912 (1985) (3) Mueller JG et al; Appl Environ Microbiol 57: 1277-285 (1991) (4) Struijs J, Stoltenkamp J; Ecotoxicol Environ Safety 19: 204-211 (1990) (5) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) De Morsier A et al; Chemosphere 16: 833-47 (1987) (7) Nyholm N; Chemosphere 21: 1477-87 (1990) (8) Kawasaki M; Ecotoxic Environ Saf 4: 444-54 (1980) (9) Blok J, Booy M; Ecotox Environ Saf 8: 410-22 (1984) R38: (1) Shimizu T et al; J Soc Dyers Colour 103: 132-7 (1987) (2) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-2299 (1993) (4) Kamens RM et al; Environ Sci Technol 23: 801-06 (1989) (5) Ligocki MP et al; Atmos Environ 19: 1609-617 (1985) R39: (1) Struijs J, Stoltenkamp J; Ecotoxicol Environ Safety 19: 204- 211 (1990) (2) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (3) De Morsier A et al; Chemosphere 16: 833-47 (1987) (4) Nyholm N; Chemosphere 21: 1477-87 (1990) (5) Kawasaki M; Ecotoxic Environ Saf 4: 444-54 (1980) (6) Blok J, Booy M; Ecotox Environ Saf 8: 410-22 (1984) R40: (1) Rontani JF et al; Chemosphere 14: 1909-912 (1985) (2) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (3) Mueller JG et al; Appl Environ Microbiol 57: 1277-285 (1991) (4) Battersby NS, Wilson V; Appl Environ Microbiol 55: 433-39 (1989) R41: (1) Field JA et al; Appl Environ Microbiol 58: 2219-2226 (1992) (2) Mueller JG et al; Environ Sci Technol 25: 1045-1055 (1991) (3) Mueller JG et al; Appl Environ Microbiol 55: 3085-3090 (1989) R42: (1) Svenson A, Bjorndahl H; Chemosphere 17: 2397-2405 (1988) (2) Carlson SA, Hercules DM; Anal Chem 45: 1794-99 (1973) (3) Grosjean D et al; Environ Sci Technol 21: 635-43 (1987) (4) Kamens RM et al; Environ Sci Technol 23: 801-06 (1989) (5) Meylan WM, Howard PH; Chemosphere 26: 213-218 (1993) R43: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. Chihara H et al, eds; ACS Prof Ref Book, Washington,DC: Amer Chem Soc p. 118 (1995) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. Coll Pharm, Univ Arizona-Tucson, AZ. PC Version (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (4) Vassilaros DL et al; Anal Chem 54: 106-112 (1982) R44: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. Chihara H et al, eds; ACS Prof Ref Book, Washington,DC: Amer Chem Soc p. 118 (1995) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. Coll Pharm, Univ Arizona-Tucson, AZ. PC Version (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Swann RL et al; Res Rev 85: 23 (1983) R45: (1) Shimizu T et al; J Soc Dyers Colour 103: 132-7 (1987) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. Coll Pharm, Univ Arizona-Tucson, AZ. PC Version (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc p. 15-1 to 15-29 (1990) R46: (1) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey. Contract No. 68- 03-2867. Athens, GA: USEPA Environ Res Lab pp 167 (1982) (2) Ehrhardt M et al; Marine Chem 11: 449-61 (1982) (3) Meijers AP, Van der Leer RC; Water Res 10:697-604 (1976) R47: (1) Middaugh DP et al; Arch Environ Contam Toxicol 21: 233-44 (1991) R48: (1) Akiyama T et al; J UOEH 2: 285-300 (1980) (2) Shiraishi H et al; Environ Sci Technol 19: 585-590 (1985) (3) Benoit FM et al; Intern J Environ Anal Chem 6: 277-87 (1979) (4) Williams DT et al; Chemosphere 11: 263-76 (1982) (5) Benoit FM et al; Bull Environ Contam Toxicol 23: 774-78 (1979) (6) Thruston AD Jr.; J Chrom Sci 16: 254-59 (1978) R49: (1) Pankow JF et al; Environ Sci Technol 18: 310-18 (1984) (2) Ligocki MP et al; Atmos Environ 19: 1609-617 (1985) (3) Lunde G; Ambio 5: 207-8 (1976) R50: (1) Rogge WF et al; Environ Sci Technol 27: 636-651 (1993) (2) Yu ML, Hites RA; Anal Chem 53: 951-54 (1981) (3) Choudhury DR; Environ Sci Technol 16: 102- 06 ((1982) (4) Robertson DJ et al; J Air Pollut Control Assoc 30: 261-66 (1980) (5) Ramdahl T, Becher G; Analytica Chimica Acta 144: 83-91 (1982) (6) Leary JA et al; Environmental Health Perspectives. 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San Francisco, CA Paper 84-18.5 pp. 1-25 (1984) (2) Eiceman GA et al; Anal Chem 51: 2343-350 (1979) (3) Tong HY et al; J Chrom 285: 423-41 (1984) (4) Rogge WF et al; Environ Sci Technol 27: 1892-904 (1993) R52: (1) Stahl RG Jr. et al; Arch Environ Contam Toxicol 13: 179-90 (1984) (2) Alben K; Anal Chem 52: 1825-828 (1980)(3) Nelson KH, Cietek DJ; J Chrom 281: 237-44 (1983) (4) Games LM, Hites RA; Anal Chem 49: 433-40 (1977) (5) Eckel WP; Amer Chem Soc, Div Environ Chem, Preprint Ext Abstr, 208th ACS Nat Meet, 34: 67-9 (1994) R53: (1) Milano JC, Vernet JL; Oceanis 14: 19-27 (1988) (2) Terashi A et al; Bull Environ Contam Toxicol 50: 348-55 (1993) R54: (1) Holoubek I et al; Toxicol Environ Chem 29: 251-260 (1991) (2) Thrane KE, Stray H; Sci Total Environ 53: 111-31 (1986) R55: (1) Bayona JM et al; Chemosphere 29: 441-50 (1994) (2) Galceran MT, Moyano E; Talanta 40: 615-21 (1993) (3) Konig J et al; Anal Chem 55: 599-603 (1983) (4) Harkov R; J Environ Sci Health A21: 409-33 (1986) (5) Kolber A et al; In: Short-term Bioassays in the Analysis of Complex Environmental Mixtures II, pp. 21-43, Mar 82, PB82-233198 (1982) (6) Ligocki MP, Pankow JF; Environ Sci Technol 23: 75-83 (1989) (7) Ramdahl T et al; Environ Sci Technol 16: 861-865 (1982) R56: (1) Cautreels W et al; Sci Total Environ 8: 79-88 (1977) R57: (1) Holoubek I et al; Toxicol Environ Chem 29: 251-260 (1991) R58: (1) Vassilaros DL et al; Anal Chem 54: 106-112 (1982) R59: (1) Thrane KE, Stray H; Sci Total Environ 53: 111-31 (1986) (2) NIOSH; National Occupational Exposure Survey (NOES) (1983) R60: 40 CFR 712.30 (7/1/94) R61: 40 CFR 716.120 (7/1/94) R62: 40 CFR 799.500 (7/1/94) R63: OYLER AR ET AL; ANAL CHEM 50 (7): 837 (1978) R64: MAINI P; J CHROMATOGR 128 (1): 174 (1976) R65: KOENIG J ET AL; ANAL CHEM 55 (4): 599 (1983) R66: POPESCU S; ANAL LETT 12 (B15): 1565 (1979) R67: Pankow JF et al; Environ Sci Technol 18: 310-8 (1984) R68: Vassilaros DL et al; Anal Chem 54: 106-12 (1982) R69: Shinohara R et al; Water Research 15: 535-42 (1981) R70: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 44 Record 167 of 1119 in HSDB (through 2003/06) AN: 2094 UD: 200302 RD: Reviewed by SRP on 1/23/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,6-XYLIDINE- SY: *AI3-52358-; *1-AMINO-2,6-DIMETHYLBENZENE-; *2-AMINO-1,3-DIMETHYLBENZENE-; *2-AMINO-M-XYLENE-; *2-AMINO-1,3-XYLENE-; *ANILINE,-2,6-DIMETHYL-; *BENZENAMINE,-2,6-DIMETHYL-; *BENZENE,-2-AMINO-1,3-DIMETHYL-; *2,6-DIMETHYLANILINE-; *2,6-DIMETHYLBENZENAMINE-; *NCI-C56188-; *O-XYLIDINE-; *2,6-XYLYLAMINE- RN: 87-62-7 RELT: 6464 [XYLIDINE] (Mixture) MF: *C8-H11-N SHPN: UN 1711; Xylidines IMO 6.1; Xylidines MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *NITRATION OF XYLENE AND REDUCTION, FOLLOWED BY THE REMOVAL OF THE 2,4-ISOMER BY FORMATION OF THE ACETATE SALT, REMOVAL OF THE 2,5-ISOMER BY FORMATION OF THE HYDROCHLORIDE, AND RECOVERY OF THE 2,6-ISOMER BY SUBLIMATION [R1] *Aniline + methanol (orthoalkylation); m-xylene (nitration/nitro reduction; coproduced with 2,4-xylidine); 2,6-xylenol + ammonia (ammoniation) [R2] *Catalytic hydrogenation of corresponding nitro derivative. [R3, p. VA2 311] MFS: *Albemarle Corporation, Hq, 451 Florida St, Baton Rouge, LA 70801, (504) 388-8011; Production site: Orangeburg, SC 29115 [R4] *First Chemical Corporation, Hq,1001 Industrial Road, Pascagoula, MS 39581-3237, (601) 762-0870; Production site: Pascagoula, MS 39568. [R4] USE: *CHEM INT FOR DYES [R1] *Pesticide and pharmaceutical intermediate [R5] *2,6-Xylidine is used as a chemical intermediate for the manufacture of pesticides, dyestuffs, antioxidants, pharmaceuticals, synthetic resins, fragrances, and other products. [R6] *Used as a chemical intermediate in the synthesis of: benalaxyl; bupivacaine; denatonium benzoate; dimethaclor; furalaxyl; lidocaine; lidoflazine; mepivacaine; metalaxyl; metazachlor; ofurace; oxadixyl; xipamide. [R2] *Starting material in the production of agrochemicals. [R3, p. VA17 423] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1972) 5.05X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1975) 8.25X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Yellow liquid [R2]; *Colorless to reddish-yellow, clear liquid [R3, p. VA2 311] BP: *216 deg C [R2] MP: *11.2 DEG C [R7] MW: *121.18 [R7] DEN: *0.9842 @ 20 DEG C [R7] OWPC: *log Kow = 1.84 [R8] SOL: *Water solubility of 8240 ppm at 25 deg C [R9]; *Very soluble in ethanol, ether [R7]; *Soluble in oxygenated and aromatic solvents. [R2] SPEC: *Index of refraction: 1.5610 at 20 deg C/D [R7]; *Max absorption (Isooctane): 233 nm (Log E= 3.92); 284 nm (Log E= 3.37) [R10]; *Sadtler Ref Number: 7555 (IR prism); 10785 (IR grating) [R10]; *IR: 4180 (Coblentz Society Spectral Collection) [R11]; *UV: 15776 (Sadtler Research Laboratories Spectral Collection) [R11]; *NMR: 6006 (Sadtler Research Laboratories Spectral Collection) [R11] VAP: *0.125 mm Hg at 25 deg C [R12] OCPP: *Forms more or less sol salts with the strong mineral acids /Xylidine/ [R13] *All /isomers/ except ortho-4-xylidine are liquids above 27 deg C [R13] *BOILING POINT: 214 DEG C @ 739 MM HG [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 2,6-xylidine stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this liquid may occur from its use as a chemical intermediate for the production of dyes, pesticides, and pharmaceuticals. Contact with 2,6-xylidine may cause burns to the skin and eyes. Death is also a possible outcome from exposure. While the OSHA PEL is set at a TWA of 5 ppm, the ACGIH lists xylidine (mixed isomers) on its 1988-1989 Notice of Intended Changes with a proposed TLV of 0.5 ppm, and a designation of "suspected human carcinogen". In activities or situations where over-exposure may occur, wear a self-contained breathing apparatus, and full chemical protective clothing which is specifically recommended by the shipper or manufacturer to prevent skin contact with xylidine. If contact should occur, immediately flush the affected skin or eyes with running water for at least 15 minutes. Remove contaminated clothing and shoes at the site. Do not eat or smoke in xylidine work areas. While xylidine does not ignite easily, it can burn with the production of irritating or poisonous gases. Also, containers may explode violently in the heat of a fire. Fires involving xylidine may be extinguished with dry chemical, CO2, Halon, or standard foam. Water spray if used, should be applied with caution because it may cause frothing. Fight the fire from a maximum distance and dike runoff from fire control water. Xylidine should be stored away from heat, strong oxidizers, and hypochlorite bleaches. Shipping regulations and other DOT regulatory requirements should be consulted before transport. If xylidine should spill, dike far ahead, then take up with sand or other noncombustible absorbent and place into containers for later disposal. Incineration is a possible form of disposal for xylidine. Before implementing land disposal of waste 2,6-xylidine, consult with environmental regulatory agencies for guidance. DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Xylidines/ [R15] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Xylidines/ [R15] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Xylidines/ [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Xylidines/ [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Xylidines/ [R15] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Xylidines/ [R15] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Xylidines/ [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Xylidines/ [R15] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. /Xylidines/ [R16] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. /Xylidines/ [R16] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. /Xylidines/ [R16] FLMT: +1.0% BY VOL (LOWER) [R16] FLPT: +206 deg F (Closed Cup) (97 deg C) [R16] FIRP: +USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CO2. WEAR FULL PROTECTIVE CLOTHING. /XYLIDINES/ [R16] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. /Xylidines/ [R17] EXPL: +FORMS EXPLOSIVE CHLOROAMINES ON EXPOSURE TO HYPOCHLORITES. /XYLIDINES/ [R16] *Lower explosive limit in air: 1.5% by vol /Xylidines/ [R18, 1985.238] REAC: *Strong oxidizers, hypochlorite bleaches /Xylidines/ [R18, 1985.238] DCMP: +WHEN HEATED TO DECOMP, XYLIDINES EMIT HIGHLY TOXIC FUMES. /XYLIDINES/ [R16] ODRT: *Odor threshold in air= 1.00X10+12 molecules/cc /Xylidines/ [R19] *Threshold for xylidine is 0.0240 mg/cu m /Xylidines/ [R20] EQUP: *The following types of respirators should be selected under the prescribed concentrations: 20 ppm: Any chemical cartridge respirator with organic vapor cartridge(s); any supplied air respirator; any self contained breathing apparatus. 50 ppm: Any supplied air respirator operated in a continuous flow mode; any powdered air purifying respirator with organic vapor cartridge(s). 100 ppm: Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s); any powered air purifying respirator with a tight fitting facepiece and organic vapor cartridge(s); any air purifying full facepiece respirator (gas mask) with a chin style or front or back mounted organic vapor canister; any supplied air respirator with a full facepiece; any self contained breathing apparatus with a full facepiece. 150 ppm: Any supplied air respirator with a half mask and operated in a pressure demand or other positive pressure mode. Emergency or planned entry in unknown concentration or IDLH condition: Any self contained breathing apparatus with a full facepiece and operated in a pressure demand or other positive pressure mode; Any supplied air respirator with a full facepiece and operated in a pressure demand or other positive pressure mode in combination with an auxiliary self contained breathing apparatus operated in pressure demand or other positive pressure mode. Escape: Any air purifying full facepiece respirator (gas mask) with a chin style or front or back mounted organic vapor canister; any appropriate escape type self contained breathing apparatus. /Xylidines/ [R18, 1985.239] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with liquid xylidine. /Xylidines/ [R21, 1981.2] *Employees should be provided with and required to use splash proof safety goggles where there is any possibility of liquid xylidine contacting the eyes. /Xylidines/ [R21, 1981.3] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R22, 1979.8] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Non-impervious clothing which becomes contaminated with xylidine should be removed immediately and not reworn until the xylidine is removed from the clothing. /Xylidines/ [R21, 1981.3] *Eating and smoking should not be permitted in areas where liquid xylidine is handled, processed, or stored. /Xylidines/ [R21, 1981.3] *Employees who handle liquid xylidine should wash their hands thoroughly with soap or mild detergent and water before eating, smoking, or using toilet facilities. /Xylidines/ [R21, 1981.3] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Use water spray to knock-down vapors. /Xylidines/ [R17] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. ... /Xylidines/ [R17] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R22, 1979.11] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R23] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R24] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R25] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R22, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R22, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R22, 1979.13] CLUP: *Environmental considerations - land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. /Xylidines/ [R17] *Environmental considerations - water spill: Use natural barriers or oil spill control booms to limit spill travel. Remove trapped material with suction hoses. /Xylidines/ [R17] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R22, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Disposal methods: incineration. A). Dissolve in such combustible solvent as alcohols, benzene, etc. Spray solvent into the furnace with afterburner and scrubber. B). Pour into a mixture of sand and soda ash (9:1). After mixing, put into a paper carton stuffed full with packing paper to serve as fuel. Burn in the furnace. /Xylidines/ [R26] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R22, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R22, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R22, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of 2,6-dimethylaniline. There is sufficient evidence in experimental animals for the carcinogenicity of 2,6-dimethylaniline. Overall evaluation: 2,6-dimethylaniline is possibly carcinogenic to humans (Group 2B). [R27] +A3; Confirmed animal carcinogen with unknown relevance to humans. /Xylidine (mixed isomers)/ [R28, 2002.61] MEDS: *Initial medical examination: a complete history and physical examination. The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Exam of the blood, lungs, liver, kidneys, and cardiovascular system should be stressed. ... Periodic medical exam ... should be repeated on an annual basis. /Xylidine/ [R21, 1981.1] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R22, 1979.23] HTOX: *Methemoglobinemia has been reported following lidocaine treatment of human subjects. Like hemoglobin adduct formation, it can be attributed to a circulating N-hydroxy metabolite. [R29] NTOX: *THE ORAL LD50 VALUES IN RATS FOR DI-SUBSTITUTED ANILINES INCR COMPARED TO MONO-SUBSTITUTED ANILINES. /SUBSTITUTED ANILINES/ [R30] *EFFECT OF REPEATED (4 WK) ORAL ADMIN OF 2,6-XYLIDINE (@ DOSE LEVELS OF 400-500 MG/KG/DAY) ON MICROSOMAL DRUG METABOLIZING ENZYME OF LIVER WAS STUDIED IN RATS. RESULTS INDICATE THAT 2,6-XYLIDINE CAN BE INDUCER OF MICROSOMAL DRUG-METABOLIZING ENZYME ACTIVITY. [R31] *In the Rec-assay using Bacillus subtillis, the 2,3-, 2,5-, 2,6-, 3,4-, and 3,5-isomers were negative; 2,4-xylidine was positive. [R32, 1991.1744] *The oral application of 200 mg/kg bw or the intraperitoneal injection of 100 mg/kg bw inhibited testicular DNA synthesis in male mice by the 2,4-, 2,5-, and 3,4-isomers. No inhibition was found by the 2,3-, 2,6-, and 3,5-xylidines. [R32, 1991.1744] *The isomers, 2,4- and 2,6-xylidine, were given daily by gavage to male F344 rats for 20 days. The daily dose was one-fourth of the acute LD50 (117 or 157 mg/kg bw for the 2,4- and 2,6-isomers, respectively). The 2,4-isomer caused a decrease in bw gain, enlargement of the liver and kidneys, hepatocellular necrosis, and biliary hyperplasia. The only effect produced by the 2,6-isomer was hemosiderosis in the spleen. [R32, 1991.1743] *The daily oral administration by gavage of the 2,4-, 2,5-, and 2,6-isomers in doses of 100 mg/kg bw for 1 week and then of 500 mg/kg bw for an additional 3 weeks to male SD-rats produced increased liver weight, proliferation of the reticular endothelial system, enlargement of hepatocytes, decreased glycogen and glucose-6-phosphatase in the liver, and an increase of p450 microsomal protein and glucuronyltransferase in the liver. [R32, 1991.1743] *In Chinese hamster ovary (CHO) cells, 2,6-xylidine produced chromosomal aberrations and sister chromatid exchanges. [R32, 1991.1744] *Groups of 28 male and 56 female Charles River CD rats, five weeks of age, were administered 1, 300, 1000, or 3000 ppm (mg/kg) of diet 2,6-dimethylaniline (99.06% pure). At 16 weeks of age, they were mated, and the pregnant females were allowed to deliver naturally over a two-week period (F0 generation). F0 females continue to receive treatment or control the diet during pregnancy and lactation. Progeny (F1) were weaned at 21 days of age, and groups of 56 males and 56 females received the same diet as their parents for 102 weeks. Mean body weight gains relative to those of controls were reduced for high-dose male and mid-dose and high-dose female rats (by > 10%). Survival at 105 weeks was: males-controls, 43/56; low-dose 40/56; mid-dose 33/56; high-dose 14/56 (p < 0.001); females-control, 33/56; low-dose 25/56; mid-dose 32/56; high-dose 24/56. In males, papillary adenomas of the nasal cavity occurred in 0/56 control, 0/56 low-dose, 2/56 mid-dose and 10/56 high-dose rats (p= 0.001, incidental tumor test). Carcinomas (not otherwise specified) of the nasal cavity were observed only in high-dose male rats. In females, nasal adenomas occurred in 0/56 control, 0/56 low-dose, 1/56 mid-dose, 6/56 high-dose rats (p= 0.02, incidental tumor test). Carcinomas of the nasal cavity occurred in 0/56 control, 0/56 low-dose, 1/56 mid-dose, and 24/56 high-dose females (p < 0.001, life table test). Unusual tumors of the nasal cavity also occurred among high-dose males and females; one undifferentiated sarcoma was present in a female, rhabdomyosarcomas occurred in two males and two females, and malignant mixed tumors (features of adenocarcinomas the rhabdomyosarcomas) were observed in one male and one female rats. Subcutaneous fibromas and fibrosarcomas combined occurred in 0/56 control, 2/56 low-dose, 2/56 mid-dose and 5/56 high-dose rats (p= 0.001, life table test; p < 0.001 life table trend test); and in 1/56 control, 2/56 low-dose, 2/56 mid-dose and 6/56 high-dose female rats (p= 0.01, life table trend test). Neoplastic nodules of the liver occurred in female rats with a significant positive trend: control, 0/56; low-dose, 1/56, mid-dose, 2/56; high-dose, 4/55 (p+ 0.03, incidental test; p= 0.012, incidental trend test). Hepatocellular carcinomas occurred in 1/56 control, 0/56 low-dose, 1/56 mid-dose and 1/55 high dose female rats. [R33] *Methemoglobinemia has been reported in cats but not dogs following an intravenous dose of 30 mg/kg body weight, 2,6-dimethylaniline (purity unspecified) in a pH 5.5 saline vehicle. Lidocaine also caused methemoglobinemia in cats after intravenous treatment at 47 mg/kg body weight. [R29] *Chronic dosing of male and female beagle dogs with oral doses (in capsules) of 50 mg/kg body weight 2,6-dimethylaniline for four weeks resulted in decreased body weight, hyperbilirubinemia, hypoproteinemia and, in contrast to rats, marked fatty degenerative changes in the liver. [R34] *In rats, only splenic hemosiderosis was observed in male Fischer 344 animals administered 2,6-dimethylaniline (purity unspecified) by gavage without a vehicle at daily doses of 157.5 mg/kg bw for 5-20 days. In male and female Sprague Dawley rats given 400-700 mg/kg by gavage (purity not specified) daily for four weeks, however, decreased weight gain, lowered haemoglobin values and liver enlargement were observed, with increases in the levels of microsomal glucuronyltransferase in males and females and of aniline hydroxylase in females. Similarly, in male and female Fischer 344 rats given the compound ( > 99% pure) by gavage in corn oil at doses up to 310 mg/kg for five days a week for 13 weeks, increased liver weight, decreased body weight and decreases in erythrocyte, haemoglobin and hematocrit levels were observed. In male Osborne-Mendel rats given up to 10 000 ppm 2,6-dimethylaniline in the diet for three to six months, 25% weight retardation, anaemia, liver enlargement (no microscopic change), splenic congestion and kidney damage that included depressed scar formation, tubular atrophy, interstitial fibrosis, chronic inflammation, papillary oedema and necrosis, and cystic dilation of tubular segments were observed, predominantly at the high dose. In the 104-week ... male and female Charles River CD rats developed non-neoplastic changes including dose-related decreases in body weight gain and inflammation, hyperplasia and squamous metaplasia of the nasal mucosa. [R34] *A study was conducted to measure the covalent binding index (CBI) for binding of radiolabeled 2,6-dimethylaniline or a metabolite to DNA of ethmoid turbinate epithelium in rats. Binding to DNA in liver was studied for the purpose of comparison. The CBI of 2-acetylaminofluorene was also measured to serve as a positive control for CBI values in liver. Covalent binding of 2,6-dimethylaniline and 2-acetylaminofluorene was studied in two test groups of Fischer-344 rats for each compound: a 24 hr sacrifice group dosed once with the test cmpd, and a 10 day sacrifice group, dosed for 9 days with the unlabeled test cmpd, admin the labeled cmpd, and sacrificed 24 hr later. In nonpretreated rats the mean CBI of 2,6-dimethylaniline to hepatocyte DNA was only 0.6 and the apparent binding to DNA of ethmoid turbinate epithelium was below the limit of sensitivity of the assay. Following 9 days of pretreatment with 262.5 mg/kg/day of unlabeled 2,6-dimethylaniline, the CBI for binding to liver DNA did not significantly change. However, pretreatment significantly incr binding to DNA in ethmoid turbinate tissues. In nonpretreated rats the CBI in liver for 2-acetylaminofluorene was 271.5 while in rats pretreated with 461 mg/kg/day of unlabeled 2-acetylaminofluorene it decr to 18.3. A significant reduction was also noted in the ethmoid turbinate tissue, with the value decr from 39.3 to below 0.5 in pretreated animals. [R35] +Conclusions: Under the conditions of these 2 yr feed studies, 2,6-xylidine was clearly carcinogenic for male and female Charles River CD rats, causing significant increases in the incidences of adenomas and carcinomas of the nasal cavity. A rhabdomyosarcoma, a rare tumor of the nasal cavity, was observed in dosed rats of each sex. In addition, the increased incidences of subcutaneous fibromas and fibrosarcomas in male and female rats and the increased incidence of neoplastic nodules of the liver in female rats may have been related to the administration of 2,6-xylidine. [R36] NTXV: *LD50 Rat oral 1230 mg/kg bw. /From table/; [R32, 1991.1744] *LD50 Mouse oral 710 mg/kg bw. /From table/; [R32, 1991.1744] NTP: +The 56 male and 56 female Charles River CD rats used in the 104 wk carcinogenesis studies were the offspring of animals fed diets containing 0, 300, 1,000, or 3,000 ppm 2,6-xylidine before breeding during pregnancy, and through the lactation period. The concentrations of 2,6-xylidine offered to animals in the 104 wk studies were the same as those given to their parents. Conclusions: Under the conditions of these 2 yr feed studies, 2,6-xylidine was clearly carcinogenic for male and female Charles River CD rats, causing significant increases in the incidences of adenomas and carcinomas of the nasal cavity. A rhabdomyosarcoma, a rare tumor of the nasal cavity, was observed in dosed rats of each sex. In addition, the increased incidences of subcutaneous fibromas and fibrosarcomas in male and female rats and the increased incidence of neoplastic nodules of the liver in female rats may have been related to the administration of 2,6-xylidine. [R36] TCAT: ?The mutagenicity of 2,6-dimethylaniline (DMA) was evaluated in Salmonella tester strains TA98 and TA100 (Ames Assay), both in the absence and presence of metabolic activation by Aroclor 1254-induced rat liver S9 fraction (varying amounts - 5, 10, 30 and 40%). Based on preliminary toxicity tests, cultures were treated with concentrations of 0.03, 0.1, 0.3, 1.0 and 3.0 mg/plate using the plate incorporation and preincubation techniques. DMA did not induce a positive response in strain TA98 with or without activation, in strain TA100 without activation, or in strain TA100 with 5 and 10% S9 fraction. Weak mutagenic activity (< 2-fold increase in revertants/plate) was observed in strain TA100 with 30 and 40% S9 fraction in both plate incorporation and preincubation assays. [R37] ?2,6-Dimethylaniline (CAS# 87-62-7) was evaluated for carcinogenicity. The test substance was administered in the diet of Charles River F1 generation CD rats (56/sex/group) at dose levels of 0, 300, 1000, and 3000 ppm for 102-weeks. The F0 parents received the test diet at the same doses before breeding, during pregnancy and through the lactation period. The study was terminated at 104 weeks. The high-dose group showed reduced body weight gain. Survival was reduced in the high- and mid-dose groups. The epithelium of the nasal cavity was the primary target organ for both neoplastic and non-neoplastic lesions. The incidence of carcinomas and papillary adenomas of the nasal cavity was significantly increased in the high-dose group. Carcinomas in high-dose males (28/56); in high-dose females (24/56); and in mid-dose females (1/56). Papillary adenomas in high-dose males (10/56); in mid-dose males (2/56); and high-dose females (6/56). Rhabdomyosarcomas in high-dose males (2/56) and high-dose females (2/56). Non-neoplastic lesions in the nasal cavities of dosed rats included acute inflammation, epithelial hyperplasia, and squamous metaplasia. The incidence of subcutaneous fibromas was statistically significant in the high-dose group: 300 ppm (1/56 M, 2/56 F); 1000 ppm (2/56 M, 1/56 F); and 3000 ppm (4/56 M, 4/56 F). There was also a statistically significant increase of neoplastic nodules of the liver in female rats: 300 ppm (1/56), 1000 ppm (2/56), 3000 ppm (4/55). [R38] METB: *METABOLITE OF 2,6-DIMETHYLANILINE IN MAN, GUINEA PIG, RAT AND DOG IS 4-AMINO-3,5-DIMETHYLPHENOL. /FROM TABLE/ [R39] *REPEATED ORAL ADMIN OF 2,6-XYLIDINE TO RATS INDICATE THAT IT MAY BE METABOLIZED BY OXIDATION AND THAT XYLIDINE MOLECULE MAY BE ELIMINATED AS CONJUGATE WITH GLUCURONIC ACID. [R31] *2,6-Xylidine is oxidized mainly to para-amino xylenols, eg, 4-hydroxy-2,6-dimethylaniline. [R40] *Evidence for the metabolism of 2,6-dimethylaniline in humans is derived from studies on cigarette smokers and nonsmokers and on patients receiving the anesthetic and cardiac drug, lidocaine, which is known to be metabolized principally to 2,6-dimethylaniline. Using capillary gas chromatography-mass spectrometry, hemoglobin adducts of 2,6-dimethylaniline were found to be present at high levels in nonsmokers with no known exposure to this compound; moreover, adduct levels were appreciably lower in cigarette smokers. In contrast, 2,6-dimethylaniline-hemoglobin adduct levels were elevated substantially in patients receiving lidocaine treatment. These results are indicative of environmental and iatrogenic exposure to 2,6-dimethylaniline, and of its biotransformation to a circulating N-hydroxy-2,6-dimethylaniline metabolite in humans, which enters erythrocytes, is oxidized to 2,6-dimethyl-nitrosobenzene and forms a sulfinamide adduct with hemoglobin. [R41] *On the basis of the hemoglobin binding index determined in rats, the levels of 2,6-dimethylaniline-hemoglobin adducts found in nonsmokers corresponding to an estimated daily exposure of 23 ug. 2,6-Dimethylaniline has also been found as a human urinary metabolite of two other drugs, etidocaine and lidamidine hydrochloride. [R29] *Since free 2,6-dimethylaniline may be formed by intestinal metabolism of 2,6-dimethylaniline-based azo dyes, its absorption into the circulation from the small intestine was studied. Male Wistar rats were instilled with 10 mg 2,6-dimethylaniline ('pure') in 10 ml phosphate-buffered saline pH 6 into the intestine. Since the absorption half-time was rapid (14.4 min), metabolism of azo dyes by intestinal microflora would be expected to result in complete absorption of the resulting 2,6-dimethylaniline by the body. [R29] *The metabolism of 2,6-dimethylaniline was examined qualitatively in male Osborne Mendel rats given the hydrochloride salt [purity unspecified] by gavage in water at 200 mg/kg bw. 4-Hydroxy-2,6-dimethylaniline and 3-methyl-2-aminobenzoic acid were identified as major and minor urinary metabolites, respectively. The unchanged amine could be detected chromatographically, but only after acidic urine hydrolysis, suggesting the presence of urinary N-conjugates. These data were confirmed by enzymatic hydrolysis in male Fischer 344 rats given 2,6-dimethylaniline ( > 99% pure) by gavage in corn oil at a daily dose of 262.5 mg/kg bw for 10 days. Levels of the 4-hydroxy metabolite were further increased by pretreatment with 3-methylcholanthrene, but not by pretreatment with phenobarbital. Oral administration to male beagle dogs (25 mg/kg bw per day for 10 days) resulted in the same major metabolite; 3-methyl-2-aminobenzoic acid and its glycine conjugate were minor components in the urine. Evidence was also provided for the presence of two potentially reactive metabolites, 2,6-dimethyl-4-nitrosobenzene, which may arise from N-hydroxy-2,6-dimethylaniline, and 2,6- or 3,5-dimethyl-4-iminoquinone, neither of which was detectable in rats. [R29] BHL: *THE HALF-LIFE OF 2,6-XYLIDINE ABSORPTION BY RAT SMALL INTESTINE IN VIVO /WAS/ 14.4 MIN. ... [R42] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,6-Xylidine has been detected in tobacco smoke. 2,6-Xylidine's production and use as a chemical intermediate may result in it release to the environment through various waste streams. If released to the atmosphere, 2,6-xylidine is expected to exist solely in the vapor phase. Vapor-phase 2,6-xylidine is expected to be rapidly degraded by reaction with photochemically-produced hydroxyl radicals (measured half-life 2.4 hours). 2,6-Xylidine absorbs light in the environmental spectrum, which suggests a potential for direct photolysis on the environment. If released to the soil, 2,6-xylidine is expected to be highly mobile based on an estimated Koc of 52. However, anilines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group; therefore, mobility may be much lower in some soils. 2,6-Xylidine is expected to volatilize from wet soil, based on an estimated Henry's Law constant of 2.5X10-6 atm-cu m/mol. If released into water, volatilization of 2,6-xylidine is expected to occur, based on an estimated Henry's law constant of 2.5X10-6 atm-cu m/mol. An estimated BCF of 15 suggests that bioconcentration of 2,6-xylidine in aquatic organisms is low. Based on its structure, aromatic amine, 2,6-xylidine may adsorb strongly to suspended solids and sediment in water. As a class, aromatic amines react relatively rapidly in sunlit natural water via reaction with photochemically produced hydroxyl radicals and peroxy radicals (typical half-lives for peroxy radical and hydroxyl radical reactions are on the order of 19 and 30 sunlight hours, respectively). Hydrolysis is not expected to be an environmentally important removal process in aquatic systems. Limited biodegradation data suggest that 2,6-xylidine is susceptible to biodegradation. Occupational exposure may occur through inhalation and dermal contact with this compound at workplaces where it is produced and used as a chemical intermediate. (SRC) ARTS: *2,6-Xylidine's production and use as a chemical intermediate in the manufacture of pesticides, dyestuffs, antioxidants, pharmaceuticals, synthetic resins, fragrances(1), as a starting material in the production of agrochemicals(2), and as an organic product of the coke industry(3) may result in its release to the environment through various waste streams(SRC). The commercial manufacture of xylidines may result in the release of 2,6-xylidine to the environment through various waste streams(4,SRC). [R43] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 52(SRC), determined from an experimental log Kow of 1.84(2) and a recommended regression- derived equation(3), indicates that 2,6-xylidine will have high mobility in soil(SRC). However, anilines are expected to bind strongly to humus or organic matter in soils due to the high reactivity of the aromatic amino group(4,5); therefore, mobility may be much lower in some soils(SRC). Volatilization of 2,6-xylidine may be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 2.5X10-6 atm-cu m/mole(SRC), estimated from the experimental values for vapor pressure, 0.13 mm Hg(6), and water solubility, 8.2X10+3 mg/l(7). A soil adsorption study observed 66% of applied 2,6-xylidine to become adsorbed within 24 hr(8). In a laboratory soil degradation study, 100% of applied 2,6-xylidine (500 mg/kg soil) degraded within 3 days utilizing 2 kg of a chernozem loam soil contained in a glass vessel(9); the route of degradation in this soil study was not determined(SRC). [R44] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 52(SRC), determined from an experimental log Kow of 1.84(2,SRC) and a recommended regression-derived equation(1), indicates that 2,6-xylidine may not adsorb to suspended solids and sediment in water(SRC). However, aromatic amine groups are recognized as having a strong affinity to organic carbon, suggesting that this compound may bind strongly to suspended organic material in water(3,4). 2,6-Xylidine may volatilize from water surfaces(1,SRC) based on an estimated Henry's Law constant of 2.5X10-6 atm-cu m/mole(SRC), using the experimental values for vapor pressure, 0.13 mm Hg(5), and water solubility, 8.2X10+3 mg/l(6). Estimated volatilization half-lives for a model river and model lake are 16 days and 120 days, respectively (1,SRC). According to a classification scheme(7), an estimated BCF value of 15(1,SRC), from an experimental log Kow of 1.84(2), suggests that bioconcentration in aquatic organisms is low(SRC). 2,6-Xylidine in the water column may be susceptible to significant photooxidation via hydroxyl and peroxy radicals; half-lives for these photooxidations may be on the order of 19-30 sunlight hours(8). [R45] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,6-xylidine, which has an experimental vapor pressure of 0.13 mm Hg at 25 deg C(2), will exist solely as a vapor in the ambient atmosphere. Vapor-phase 2,6-xylidine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2.4 hours(3,SRC). 2,6-Xylidine absorbs UV light in the environmental spectrum(4), which suggests a potential for direct photolysis in the environment(SRC). [R46] BIOD: *A Warburg respirometer study utilizing an activated sludge seed and 6 hr of incubation resulted in a 2,6-xylidine depletion of 33-37% at a concentration of 20 ppm(1). In a 6 week soil degradation study using (14)C-labelled 2,6-xylidine, 8.4% of applied radioactivity was recovered via CO2 evolution in non-autoclaved soil while 0% CO2 evolution occurred in autoclaved soil(2). [R47] ABIO: *The rate constant for the vapor-phase reaction of 2,6-xylidine with photochemically- produced hydroxyl radicals has been estimated as 1.6X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2.4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 2,6-Xylidine is not expected to undergo hydrolysis in the environment due to the lack of functional groups to hydrolyze(2,SRC). As a class, aromatic amines react relatively rapidly in sunlit natural water via reaction with photochemically produced hydroxyl radicals and peroxy radicals(3); typical half-lives for peroxy radical and hydroxyl radical reactions are on the order of 19 and 30 sunlight hours, respectively(3). 2,6-Xylidine absorbs light in the environmental spectrum(4), which suggests a potential for direct photolysis in the environment(SRC). [R48] BIOC: *An estimated BCF value of 15 was calculated for 2,6-xylidine(SRC), using the experimental log Kow of 1.84(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R49] KOC: *The Koc of 2,6-xylidine is estimated as approximately 52(SRC), using the experimental log Kow of 1.84(1,SRC) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that 2,6-xylidine has high mobility in soil(SRC). In a short term soil adsorption study using 14C-labelled 2,6-xylidine, 66% of the applied radioactivity was bound to the soil (3.4% organic matter, 36.6% sand, 28.2% silt, 35.2% clay) after 24 hr(4). [R50] VWS: *The Henry's Law constant for 2,6-xylidine was estimated as 2.5X10-6 atm-cu m/mole(SRC), using the experimental values for vapor pressure, 0.13 mm Hg(1), and water solubility, 8.2X10+3 mg/l (2). This value indicates that 2,6-xylidine will volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 16 days(3,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 120 days(3,SRC). 2,6-Xylidine's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces may occur(SRC). [R51] EFFL: *2,6-Xylidine was detected (no concn reported) in the wastewater effluent from a chemical facility in St. Louis, MO in Dec 1974(1). 2,6-Xylidine was detected in the stack effluents from an incinerator burning hazardous wastes(2). 2,6-Xylidine was identified at unreported concentrations in Latakia tobacco smoke(3). [R52] OEVC: *2,6-Xylidine has been detected in tobacco smoke(1). [R53] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 4400 workers (730 of these are female) are potentially exposed to 2,6-xylidine in the US(1). Occupational exposure to 2,6-xylidine may occur through inhalation and dermal contact with this compound at workplaces where it is produced or used(SRC). The general population may be exposed to 2,6-xylidine through inhalation of tobacco smoke(SRC). [R54] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (25 mg/cu m). Skin Designation. /Xylidine/ [R55] +Vacated 1989 OSHA PEL TWA 2 ppm (10 mg/cu m), skin designation, is still enforced in some states. /Xylidine/ [R56] TLV: +8 hr Time Weighted Avg (TWA): 0.5 ppm, skin. /Xylidine (mixed isomers); inhalable fraction; vapor and aerosol/ [R28, 2002.61] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Xylidine (mixed isomers)/ [R28, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. /Xylidine (mixed isomers)/ [R28, 2002.61] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R28, 2002.91] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Analyte: Xylidine; matrix: air; Procedure: A known vol of air is drawn through a silica gel tube to trap the organic vapors present; desorption with 95% ethanol, gas chromatography. /Xylidine and xylidine cmpd/ [R57, p. V3 S162-1] ALAB: *ANALYTE: AROMATIC AMINES; MATRIX: AIR; RANGE: 0.01-14 MG/SAMPLE; PROCEDURE: ADSORPTION ON SILICA GEL; ELUTION BY ETHANOL; GAS CHROMATOGRAPHY ANALYSIS. /AROMATIC AMINES/ [R57, p. V1 168-1] *ANALYTE: XYLIDINE; MATRIX: AIR; RANGE: 12.5-50.0 MG/CU M; PROCEDURE: ADSORPTION ON SILICA GEL, DESORPTION WITH 95% ETHANOL, GAS CHROMATOGRAPHY. /XYLIDINE/ [R57, p. V3 S162-1] *GAS CHROMATOGRAPHIC METHOD FOR THE ANALYSIS AND SEPARATION OF ISOMERS OF XYLIDINE. /XYLIDINE/ [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Health and Environmental Profile for Xylidines, March 1983, p. D-183-91 DHHS/NTP; Toxicology and Carcinogenesis Studies of 2,6-Xylidine in Charles River CD Rats (Feed Studies) Technical Report Series No.278 (1990) NIH Publication No. 90-2534 SO: R1: SRI R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 958 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R4: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 971 R5: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 123 R6: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1994. 204 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-22 R8: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 3 R9: Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-146 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 444 R12: Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) R13: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1723 R14: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. C-551 R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R16: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 49-138 R17: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 1133 R18: NIOSH. Pocket Guide to Chemical Hazards. 5th Printing/Revision. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, Sept. R19: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 165 R20: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R21: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R22: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R23: 49 CFR 171.2 (7/1/96) R24: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 231 R25: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6248 (1988) R26: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 301 R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 57 332 (1993) R28: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 328 (1993) R30: JACOBSON KH; TOXICOL APPL PHARMACOL 22 (1): 153 (1972) R31: MAGNUSSON G ET AL; TOXICOLOGY 2 (1): 63 (1979) R32: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 326-7 (1993) R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 329 (1993) R35: Short CR et al; J Toxicol and Environ Health 27 (1): 85-94 (1989) R36: Toxicology and Carcinogenesis Studies of 2,6-Xylidine (2,6-Dimethylaniline) in Charles River CD Rats (Feed Studies). Technical Report Series No. 278 (1990) NIH Publication No. 90-2534 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R37: Monsanto Environmental Health Laboratory; Evaluation of the Effects of Varying S-9 and Cofactor Concentrations and Assay Conditions in the Ames/Salmonella Mutagenicity Assay using o-toluidine and 2,6-dimethylaniline. (1987), EPA Document No. 86-880000064, Fiche No. OTS0513954 R38: ROHM AND HAAS CO; Initial Submission: Carcinogenesis Bioassay with 2,6-Xylidine in Charles River CD Rats with Cover Letter Dated 08/03/92; 09/22/82; EPA Doc. No. 88-920005596; Fiche No. OTS0544380 R39: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-87 R40: Health and Environmental Effects Profile, March 1983, p. D-183 R41: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 327 (1993) R42: PLA-DELFINA ET AL; CIENC IND FARM 4 (2): 47 (1972) R43: (1) Kuney JH; Chemcyclopedia 1995, Washington, DC: Amer Chem Soc p. 204 (1994) (2) Booth G; in Ullmann's Encyclopedia of Industrial Chemistry. 5th ed. Gerhartz W (ed). NY, NY: VCH Publishers Vol A17: 423 (1991) (3) Medvedev VA, Davidov VD; p. 245-54 in Decomposition of Toxic and Nontoxic Organic Compounds in Soil. Overcash MR ed Ann Arbor, MI: Ann Arbor Sci Publ(1981) (4) Leipins R et al; Industrial Process Profiles for Environmental Use: Chapter 6. The Industrial Organic Chemicals Industry. USEPA-600/2-77-023f. p. 6-840 (1977) R44: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc p 3(1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, eq 4-9 (1990) (4) Bollag JM et al; J Agric Food Chem 26: 1302-1306 (1978) (5) Adrian P et al; Toxicol Environ Chem 20-21: 109-120 (1989) (6) Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) (7) Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) (8) Bollag JM et al; J Agric Food Chem 26: 1302-6 (1978) (9) Medvedev VA, Davidov VD; p. 245-54 in Decomposition of Toxic and Nontoxic Organic Compounds in Soil. Overcash MR ed Ann Arbor, MI: Ann Arbor Sci Publ(1981) R45: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc p 3(1995) (3) Bollag JM et al; J Agric Food Chem 26: 1302-1306 (1978) (4) Adrian P et al; Toxicol Environ Chem 20-21: 109-120 (1989) (5) Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) (6) Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Mill T, Mabey W; p. 208-11 in Environmental Exposure from Chemicals Vol. I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) R46: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Meallier P; Ann Chim 4: 15-28 (1969) R47: (1) Baird R et al; J Water Pollut Control Fed 49: 1609-15 (1977) (2) Bollag JM et al; J Agric Food Chem 26: 1302-6 (1978) R48: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Mill T, Mabey W; p. 208-11 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (4) Meallier P; Ann Chim 4: 15-28 (1969) R49: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc p 3 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R50: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Bollag JM et al; J Agric Food Chem 26: 1302-6 (1978) R51: (1) Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) (2) Huyskens P et al; Bull Soc Chim Belg 84: 253-62 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R52: (1) Shackelford WM, Keith LM; Frequency of Organic Compounds Identified in Water. USEPA-600/4-76-062 p. 60 (1976) (2) James RH et al; J Air Pollut Control Assoc 35: 959-61 (1985) (3) Irvine WJ, Saxby MJ; Phytochemistry 8: 473-6 (1969) R53: (1) Irvine WJ, Saxby MJ; Phytochemistry 8: 473-6 (1969) R54: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R55: 29 CFR 1910.1000 (7/1/98) R56: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 374 R57: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R58: CHIAVARI G, GIUMANINI AG; J CHROMATOGR 206 (3): 555 (1981) RS: 72 Record 168 of 1119 in HSDB (through 2003/06) AN: 2107 UD: 200303 RD: Reviewed by SRP on 1/31/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BUTYL-BENZYL-PHTHALATE- SY: *BBP-; *1,2-BENZENEDICARBOXYLIC-ACID,-BUTYL-PHENYLMETHYL-ESTER-; *BENZYL-BUTYLPHTHALATE-; *BENZYL-N-BUTYL-PHTHALATE-; *BUTYLBENZYL-PHTHALATE-; *N-BUTYL-BENZYL-PHTHALATE-; *BUTYL-PHENYLMETHYL-1,2-BENZENECARBOXYLATE-; *NCI-C54375-; *PALATINOL-BB-; *PHTHALIC-ACID,-BENZYL-BUTYL-ESTER-; *SANTICIZER-160-; *SICOL-160-; *UNIMOLL-BB- RN: 85-68-7 MF: *C19-H20-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... FIRST SYNTHESIZED BY THE REACTION OF THE MONOBUTYL ESTER OF PHTHALIC ACID WITH BENZYL CHLORIDE IN NEUTRAL AQUEOUS OR ALCOHOLIC SOLUTION. COMMERCIAL PRODUCTION IN THE US BASED ON THE SAME PROCESS WITH THE MONOBUTYL ESTER PRODUCED BY THE REACTION OF PHTHALIC ANHYDRIDE WITH N-BUTYL ALCOHOL IN THE PRESENCE OF AN ACIDIC CATALYST. IN JAPAN, THE MONOBUTYL ESTER IS TREATED WITH BENZYL ALCOHOL IN THE PRESENCE OF AN ACID CATALYST. [R1] FORM: *A NAIL POLISH COMPRISES A MIXTURE OF SUCROSE BENZOATE, SUCROSE ACETATE ISOBUTYRATE, AND 4% BUTYL BENZYL PHTHALATE. [R2] *GRADES: TECHNICAL. [R3, 183] MFS: *Monsanto Co, Hq, 800 N Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Monsanto Chemical Co (address same as Hq); Production site: Bridgeport, NJ 08014 [R4] OMIN: *A GAS-PERMEABLE CONTACT LENS COMPOSITION CONSISTED OF A PARTIALLY ESTERIFIED CELLULOSE POLYMER AND A COMPATIBLE PLASTICIZER /INCLUDING BUTYL BENZYL PHTHALATE/ IN AN AMOUNT SUFFICIENT TO INCR THE OXYGEN PERMEABILITY OF THE CELLULOSE POLYMER GREATER THAN OR EQUAL TO 13% HIGHER THAN THAT OF THE UNPLASTICIZED POLYMER. [R5] USE: *ORGANIC INTERMEDIATE [R3, 183] *PLASTICIZER FOR PVC-BASED FLOORING PRODUCTS, POLYVINYL ACETATE EMULSION ADHESIVES, OTHER PLASTICS, EG, ETHYL CELLULOSE, IN COATINGS, EG, FOR AUTOMOBILES [R6] *Plasticizer for polyvinyl and cellulose resins. [R3, 184] CPAT: *ALL PHTHALATE PLASTICIZERS: 89% IN POLYVINYL CHLORIDE RESINS; 3% IN OTHER VINYL RESINS; 3% IN CELLULOSE ESTER PLASTICS; 3% IN SYNTHETIC ELASTOMERS AND OTHER POLYMERS; 2% IN OTHER APPLICATIONS (1974). /PHTHALATE ESTERS/ [R6] PRIE: U.S. PRODUCTION: *(1977) 6.81X10+10 G [R6] *(1981) 7.47X10+10 G [R6] *Over 100 million pounds of butyl benzyl phthalate (BBP) were produced in 1978. [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CLEAR, OILY LIQUID [R3, 183] ODOR: *SLIGHT ODOR [R3, 183] BP: *370 DEG C (698 DEG F) [R8] MP: *-35 DEG C [R9] MW: *312.39 [R10] DEN: *1.113-1.121 @ 25 DEG C/25 DEG C [R3, 183] HTC: *-14,550 BTU/LB= -8,090 CAL/G= -338X10+5 JOULES/KG [R11] OWPC: *log Kow= 4.91 [R12] SOL: *In water, 0.71 mg/l (temperature not specified) [R13] SPEC: *INDEX OF REFRACTION: 1.535-1.540 @ 25 DEG C/D [R1] VAPD: *10.8 [R10] VAP: *8.6X10-6 mm Hg at 20 deg C [R14] OCPP: *Conversion factor: l ppm= 12.8 mg/cu m [R9] *... Resistance to migration from polymers, low temperature flexibility ... compatibility with polar polymers and additives over a wide range of compositions. /Phthalate esters/ [R15] *MAXIMAL ACIDITY: 0.37 MEQ/100 G [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R16] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R16] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R16] FLPT: *390 DEG F (OPEN CUP) [R11] FIRP: *SPRAY OR MIST, FOAM, CARBON DIOXIDE, DRY CHEMICAL ... [R17] DCMP: *When heated to decomposition, it emits acrid smoke and irritating fumes. [R17] SERI: *PROLONGED CONTACT WITH LIQUID CAUSES SOME IRRITATION OF EYES AND SKIN. [R11] EQUP: *Protective gloves and goggles. [R11] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Incineration: It should be atomized into an incinerator and combustion may be improved by mixing with a more flammable solvent (acetone or benzene). [R18] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: Butyl benzyl phthalate is a clear oily liquid that is used as a plasticizer mainly in the polyvinyl chloride for vinyl floor tile, vinyl foams and carpet backing and in cellulose plastics and polyurethane. HUMAN EXPOSURE: Available data in humans are inadequate to serve a basis for assessment of effects of long term exposure to butyl benzyl phthalate in human populations ANIMAL/ PLANT STUDIES: This compound is readily metabolized by vertebrates and invertebrates. Reported bioconcentration factors (BCFs) are less than 1,000 based on total residues and well under 100 based on intact butyl benzyl phthalate residues. The acute toxicity of this compound is low, with oral LD50 values in rats being greater than 2 g/kg body weight. Target organs following acute exposure include the hematological and central nervous systems. Available data are inadequate to assess the irritant and sensitizing effects of butyl benzyl phthalate in animal species. Repeated dose toxicity studies of this compound has well been investigated in recent tests, primarily in the rat, in which dose response was well characterized. Effects observed consistently have been decreases in body weight gain (often accompanied by decreases in food consumption) and increases in organ to body weight ratios, particularly for the kidney and liver. Histopathological effects on the pancreas and kidney and hematological effects have also been observed. At higher doses, degenerative effects on the testes and, occasionally histopathological effects on the liver have been reported. In specialized investigations, peroximal proliferation in the liver has been noted. The chronic toxicity and carcinogenicity of butyl benzyl phthalate bioassays in rats (including standard and feed restricted protocols) and mice, indicated that there was some evidence of carcinogenicity in male rats, based on an increased incidence of pancreatic tumors, and equivocal evidence in female rats, based on marginal increases in pancreatic and bladder tumors. Dietary restriction prevented full expression of the pancreatic tumors. There was no evidence for the carcinogenicity of butyl benzyl phthalate in mice. The weight of evidence of the genotoxicity of butyl benzyl phthalate is clearly negative. Data are inadequate to conclude unequivocally that butyl benzyl phthalate is not clastogenic, although in identified studies it has induced, at most weak activity of a magnitude consistent with secondary effects on DNA. In a range of studies, including those designed to investigate the reproductive effects of butyl benzyl phthalate on the testes and endocrine hormone in male rats, a modified mating protocol and a one generation study, adverse effects on the testes and, consequently fertility have generally been observed only at doses higher than those that induce effects on other organs (such as the kidney and liver), although decreases in sperm counts have been observed at doses similar to those that induce effects in the kidney and liver. This is consistent with the results of repeated dose toxicity studies. Reduction in testes weight and daily sperm production in the offspring were reported at relatively low level in rats exposed in utero and during lactation in a study in which dose response was not investigated. However, such effects were not observed in another study of a similar, but not identical, design in another strain of rats in which only increases in absolute and relative liver weights were observed at postnatal day 90. Butyl benzyl phthalate is estrogenic in human breast cancer cell lines in vitro; results in yeast cells have been mixed. Neither butyl benzylphthalate nor its principal metabolites have been uteritrophic in vivo in rats or mice, In several well conducted studies in rats and mice, butyl benzyl phthalate induced marked developmental effects, but only at dose levels that induce significant maternal toxicity. Although the potential neurotoxicity of butyl benzyl phthalate has not been well investigated, histopathological effects on the central and peripheral nervous systems have not been observed following short term exposure to relatively high dietary concentrations. Available data are inadequate to assess the potential immunotoxicity of butyl benzyl phthalate. A range of toxicity tests with aquatic organisms has indicated the adverse effects occur at exposure concentrations greater than 100 ug/l. No information about the effects of butyl benzyl phthalate on sediment dwelling organisms, soil invertebrates, terrestrial plants or birds have been identified. [R19] CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on statistically significant increase in mononuclear cell leukemia in female rats; the response in male rats was inconclusive and there was no such response in mice. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R20] *Evaluation: There is inadequate evidence in humans for the carcinogenicity of butyl benzyl phthalate. There is limited evidence in experimental animals for the carcinogenicity of butyl benzyl phthalate. Overall evaluation: Butyl benzyl phthalate is not classifiable as to its carcinogenicity to humans (Group 3). [R21] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Esters and related compounds/ [R22] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R22] *Call for medical aid. ... Remove contaminated clothing and shoes. Flush affected areas with plenty of water. ... flush /eyes/ with water for 15 min ... wash /skin/ well with soap and water. [R23] HTOX: *WOMEN WORKING IN SYNTHETIC LEATHER INDUSTRY SHOWED A HIGHER INCIDENCE OF MISCARRIAGES AND MENSTRUAL DISORDERS THAN DID WOMEN IN CONTROL GROUP, PRESUMABLY BECAUSE OF PROLONGED EXPOSURE TO VOLATILE PHTHALIC ACID DERIVATIVES, INCLUDING BUTYL BENZYLPHTHALATE, USED AS PLASTICIZING AGENTS. [R24] *... BUTYL BENZYL PHTHALATE /REPORTEDLY HAS/ ... CAUSED ... /POLYNEUROPATHY/ IN INDUSTRIAL WORKERS. [R25] *THE TOXICITY TO HELA CELLS OF BUTYL BENZYL PHTHALATE WAS DETERMINED IN THE METABOLIC INHIBITION TEST (MIT)-24 TEST SYSTEM. THE MINIMAL INHIBITORY CONCENTRATIONS WERE 160 MG/ML FOR TOTAL INHIBITION AND 31 MG/ML FOR PARTIAL INHIBITION (24 HR MICROSCOPY). IN 7-DAY TOXICITY TESTING, CYTOTOXICITY IN TESTS WITH 10% SERUM DECREASED BY A FACTOR OF 2.5 COMPARED WITH 5% SERUM. THIS COULD DEPEND ON PROTECTION OF CELLS BY THE SERUM AND/OR A GENERAL ENHANCEMENT OF CELL GROWTH. [R26] *Exposure to phthalic acid esters, mainly di-(2-ethylhexyl), diisodecyl and butylbenzyl phthalates, or workers in a polyvinyl chloride processing industry ranged from 0.02 to 2 mg/cu m in different job categories. The workers excreted slightly but significantly higher levels of phthalic acid ester metabolites in urine than controls. In 54 workers studied clinically, there were no indications of peripheral nerve or respiratory system effects. Some biochemical tests were abnormal which indicates the need for further study. [R27] *... The phthalates represent one of the lowest toxicity classes used in industry. /Phthalates/ [R28] *The acute toxicity of phthalates is very slight and decreases generally with the increasing molecular weight. /Phthalates/ [R29] *An increase in toxic polyneuritis has been reported in workers exposed primarily to dibutyl phthalates. Lesser levels of exposure to dioctyl, diisooctyl, benzylbutyl phthalates, and tricresyl phosphate were also noted. [R30] *An increase in toxic polyneuritis has been reported in workers exposed primarily to dibutyl phthalates. Lesser levels of exposure to dioctyl, diisooctyl, benzylbutyl phthalates, and tricresyl phosphate were also noted. [R30] NTOX: *INTRADERMAL INJECTIONS INTO RABBITS PRODUCED NO INFLAMMATORY RESPONSE AS INDICATED BY DYE EXTRAVASATION AFTER 10 MIN, THERE WAS A MILD RESPONSE AFTER 15 MIN AND MODERATE RESPONSE AFTER 26 MIN. /FROM TABLE/ [R31] *THREE GROUPS OF 50 MALE AND 50 FEMALE B6C3F1 MICE, 5-6 WK OLD AT THE START OF EXPERIMENT, WERE FED DIETS CONTAINING 0, 6000 OR 12000 MG/KG (PPM) BUTYL BENZYL PHTHALATE (MAXIMUM PURITY, 97.2%; WITH AT LEAST 10 UNIDENTIFIED IMPURITIES FOUND BY GLC) FOR 103 WK. THE EXPERIMENT ENDED AT 105-106 WK, AT WHICH TIME 84-88% OF MALES AND 70-72% OF FEMALES WERE STILL ALIVE. THE INCIDENCES AND TYPES OF TUMORS OBSERVED WERE COMPARABLE IN TREATED AND CONTROL ANIMALS. [R32] *TWO GROUPS OF 50 MALE AND 50 FEMALE 5-WK-OLD FISCHER 344 RATS WERE FED DIETS CONTAINING 6000 OR 12000 MG/KG (PPM) BUTYL BENZYL PHTHALATE (... MAXIMUM PURITY, 97.2%; WITH AT LEAST 10 UNIDENTIFIED IMPURITIES FOUND BY GLC) FOR 28 WK (MALES) and 103 WK (FEMALES). ANOTHER GROUP OF 50 ANIMALS PER SEX WERE USED AS MATCHED CONTROLS. MALE RATS IN BOTH DOSED GROUPS BEGAN TO DIE AT 14 WK, AND BY 29-30 WK ALL OF THEM WERE KILLED WITHOUT FURTHER HISTOLOGICAL EXAMINATION. SURVIVING FEMALE RATS (31/50 CONTROLS AND 29/50 and 32/50 TREATED ANIMALS) WERE KILLED AT 105-106 WK. AN INCREASED INCIDENCE OF MYELOMONOCYTIC LEUKEMIA WAS OBSERVED IN HIGH-DOSE FEMALES (7/49 CONTROLS, 7/49 LOW-DOSE AND 18/50 HIGH-DOSE). THE INCIDENCES AND TYPES OF OTHER TUMORS WERE COMPARABLE IN TREATED AND CONTROL GROUPS. THE WORKING GROUP NOTED THAT THE MEAN INCIDENCE OF THESE TUMORS IN HISTORICAL CONTROLS WAS 11% (RANGE 8-15%) IN FEMALES AND 17% (RANGE 9-24%) IN MALES. [R32] *THREE GROUPS OF 20 MALE A/ST MICE, 6-8 WK OLD, WERE GIVEN 24 IP INJECTIONS (THREE TIMES WEEKLY DURING SIX WEEKS) OF 160, 400 OR 800 MG/KG BODY WT BUTYL BENZYL PHTHALATE (REAGENT GRADE, MORE THAN 95% PURE, WITH UNSPECIFIED PURITIES) IN TRICAPRYLIN. AN APPROPRIATE CONTROL GROUP WAS INJECTED WITH TRICAPRYLIN. MICE WERE KILLED 18 WK AFTER THE LAST INJECTION AND ANALYZED FOR THE PRESENCE OF LUNG TUMORS: 0.10 TO 0.25 LUNG TUMORS/MOUSE WERE FOUND IN TREATED ANIMALS AND 0.39 IN VEHICLE CONTROLS. THESE DIFFERENCES WERE NOT SIGNIFICANT, AND NO DOSE-RESPONSE RELATIONSHIP WAS SEEN. THE WORKING GROUP NOTED THAT A NEGATIVE RESULT IN THIS EXPERIMENTAL MODEL CANNOT BE TAKEN AS EVIDENCE OF THE NON-CARCINOGENICITY OF THE COMPOUND. [R32] *... DOGS (SEX AND NUMBER UNSPECIFIED) INGESTING DIETS CONTAINING 1, 2, OR 5% (WT/WT) BUTYL BENZYL PHTHALATE FOR 90 DAYS EXHIBITED NO ALTERATIONS IN URINARY OR HEMATOLOGICAL PARAMETER AND NO GROSS OR HISTOPATHOLOGICAL EFFECTS. [R33] *FISCHER 344 RATS FED DIETS CONTAINING 0-100,000 MG/KG (PPM) AND B6C3F1 MICE FED 0-25,000 MG/KG (PPM) BUTYL BENZYL PHTHALATE FOR 14 DAYS OR 0-25,000 MG/KG FOR 90 DAYS SHOWED NO EVIDENCE OF CMPD-RELATED MORTALITY. IN THE 14-DAY STUDIES, BODY WT GAIN OF MALE AND FEMALE RATS WAS DEPRESSED WITH DOSES OF 25,000 MG/KG AND MORE. TESTICULAR DEGENERATION WAS OBSERVED IN MALE RATS FED 50,000 OR 100,000 MG/KG; AND THYMIC ATROPHY WAS OBSERVED IN ALL RATS GIVEN 100,000 MG/KG. IN THE 90-DAY STUDIES, MALE RATS FED 25,000 MG/KG HAD DEPRESSED BODY WT GAIN AND TESTICULAR DEGENERATION, BUT FEMALE RATS WERE UNAFFECTED. NEITHER GROSS NOR HISTOPATHOLOGICAL EFFECTS WERE OBSERVED IN MICE IN EITHER STUDY. [R33] *... 0.05 ML UNDILUTED BUTYL BENZYL PHTHALATE (0.05 G) PRODUCED NO MALFORMATION IN 17 CHICKS WHEN INJECTED INTO 32 FERTILIZED HENS' EGGS. [R33] *... (30 MG/PLATE) WAS REPORTED TO BE NON-MUTAGENIC IN ESCHERICHIA COLI, AND NEGATIVE IN RECOMBINATION REPAIR ASSAYS WITH ESCHERICHIA COLI AND BACILLUS SUBTILIS. DOSES UP TO 10 UL/PLATE ... WERE NOT MUTAGENIC TO SALMONELLA TYPHIMURIUM STRAINS TA1535, TA1537, TA1538, TA98 OR TA100, NOR TO SACCHAROMYCES CEREVISIAE STRAIN D4, IN THE PRESENCE OR ABSENCE OF A RAT LIVER MICROSOMAL PREPN. ... DID NOT INDUCE FORWARD MUTATIONS AT THE TK LOCUS OF L5178Y MOUSE LYMPHOMA CELLS. [R33] *... BUTYL BENZYL PHTHALATE MAY PRODUCE CENTRAL AND PERIPHERAL NEUROPATHIES IN ANIMALS. [R25] *BUTYL BENZYL PHTHALATE (BBP) IS ACUTELY TOXIC TO A VARIETY OF ALGAE, INVERTEBRATES, AND FISH IN THE 0.5-5 MG/L RANGE AND CHRONICALLY TOXIC TO DAPHNIA AND FATHEAD MINNOWS IN THE 0.1-0.8 MG/L RANGE. [R34] *STATIC ACUTE TOXICITY TESTS CONDUCTED WITH BUTYL BENZYL PHTHALATE AND DAPHNIA MAGNA SHOWED 48-HR EC50 VALUE TO BE 1.0 MG/L. TESTS PERFORMED IN THE PRESENCE OF VARIOUS CONCENTRATIONS OF DAPHNID FOODS (ALGAE OR TROUT CHOW) INDICATE THAT THE 48-HR EC50 VALUES INCREASED PROPORTIONALLY WITH AN INCREASE IN FOOD CONCENTRATIONS. [R35] *SANTICIZER 160 AT 0.5-4.0 ML/KG DID NOT CAUSE ANY DAMAGE TO THE TESTIS OF ALBINO WISTAR RATS WHEN APPLIED DERMALLY. AT 4 ML/KG, HOWEVER, IT CAUSED DEVIATIONS IN SPERM MOBILITY. [R36] *BENZYL BUTYL PHTHALATE DECREASED THE HEART RATE OF GOLDFISH AT 200 PPM. THE EFFECT MAY BE DUE TO DIBUTYL PHTHALATE CONTAMINATION. [R37] *THE 96-HR MEDIAN LETHAL CONCN VALUES OF BUTYL BENZYL PHTHALATE FOR ENGLISH SOLE WERE 0.66 MG/L (STATIC REPLENISH EXPOSURE) AND 0.55 MG/L (FLOW-THROUGH EXPOSURE) WITH LETHAL THRESHOLD CONCENTRATIONS OF 0.45 MG/L AND 0.30 MG/L, RESPECTIVELY. SUBLETHAL EFFECTS WERE NOTED AT ALL EXPOSURES, THE LOWEST OF WHICH WAS 0.1 MG/L. [R38] *SEVERAL CHEMICALS THAT ARE USED FOR MANUFACTURING OF RUBBER WERE TESTED FOR EMBRYOTOXICITY ON 3-DAY CHICKEN EMBRYOS. BUTYL BENZYL PHTHALATE HAD ED50 VALUE OF ABOUT 27 MUMOL/EGG. [R39] *THE INHIBITORY EFFECT OF 18 PHTHALIC ACID ESTERS ON T PYRIFORMIS WAS INVESTIGATED. BENZYL N-BUTYL PHTHALATE SHOWED MODERATE CYTOSTATIC TOXICITY. [R40] *BUTYL BENZYL PHTHALATE MARKEDLY INHIBITED THE OUTGROWTH OF NERVE FIBERS AND GLIAL CELLS FROM CEREBELLAR EXPLANTS OF NEWBORN RAT IN PRIMARY CULTURE AT A CONCENTRATION OF 7.0 MOLAR. [R41] *Butyl benzyl phthalate was administered both orally (1.8 g/kg) and ip (4 g/kg) to groups of rats. Animals died after four to eight days and histopathological studies demonstrated toxic splenitis and degeneration of central nervous system tissue with congestive encephalopathy. Further, myelin degeneration and glial proliferation were reported. [R42] *RINGERS SOLN SATURATED WITH PHTHALATE ESTERS CAUSED GROWTH RETARDATION AND MALFORMATIONS IN CNS OF CHICK EMBRYOS. EFFECTS APPEARED RELATED TO SOLUBILITIES OF ESTERS IN WATER. ESTERS TOXIC TO CULTURED CHICK EMBRYONIC CELLS @ 0.05 MG/ML. UNDILUTED PHTHALATE ESTERS WERE LETHAL TO EMBRYOS. /PHTHALATE ESTERS/ [R43] *TWELVE PHTHALIC ACID ESTERS TESTED: MOST WERE 2-4 TIMES MORE TOXIC CHRONICALLY THAN ACUTELY IN MICE AFTER IP ADMIN. /PHTHALIC ACID ESTERS/ [R44] *A 14 day dietary study was conducted in adult, male, Fischer 344 rats at levels of 0.0, 0.625, 1.25, 2.5, and 5.0% butylbenzylphthalate (BBP) to evaluate potential effects of this plasticizer on the male reproductive and hematopoeitic systems. Total body, thymus, testis, epididymis, prostate and seminal vesicle weight were reduced in the /groups fed/ 2.5% and 5% BBP ... while pituitary weight was unaffected. Histological evaluations revealed dose-dependent atrophy of the testis, prostate, and seminal vesicles at 2.5% and 5%, atrophy of the thymus and epididymis at 5%, and the presence of immature sperm cells in the tubular lumens and necrosis of the testerone concentration was decreased at 5%, while follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations were increased at 2.5% and 5.0% BBP. ... Changes in non-reproductive organs included enlargement of liver and kidneys, thymic atrophy and associated morphological abnormalities in these organs. ... [R45] *Uptake efficiencies of the gills of English sole for four homologous phthalic acid esters were directly measured and compared with octanol-water partition coefficients (Kow). Test compounds were di-ethyl phthalate (DEP), butyl benzyl phthalate (BBP), bis(2-ethylhexyl) phthalate (DEHP), and di-n-octyl phthalate (DOC). Mean uptake efficiencies in a single pass through the gills were 11% for DEP (log Kow= 3.2), 42% for BBP (log Kow= 5.8), 3% for bis(2-ethylhexyl) phthalate (log Kow= 8.7), and 12% for di-n-octyl phthalate (log Kow= 9.2). [R46] *Chronic toxicity and carcinogenicity studies of several phthalic acid esters (PAEs) and compounds containing a 2-ethylhexyl moiety were conducted in Fischer 344 rats and B6C3F1 (hybrid) mice. The compounds studied were phthalic anhydride, bis(2-ethylhexyl) phthalate, butyl benzyl phthalate, diallyl phthalate, di(2-ethylhexyl) adipate, tris(2-ethylhexyl) phosphate, and 2-ethylhexyl sulfate. Estimated maximum tolerable doses and fractionally lower doses of each compound were administered to groups of 50 male and 50 female rats and mice for 2 yr, followed by sacrifice, necropsy, and histopathological examination of major organs and tissues. The low toxic potencies of most of the compounds allowed for relatively high doses to be given during the chronic studies. In general, the toxic manifestations of the phthalic acid esters were closely correlated with their ester substituents. Although many of the phthalic acid esters possessed some carcinogenic activity, target sites for such effects were dissimilar, suggesting the absence of a common mode of action. ... [R47] *Bis(2-ethylhexyl) phthalate and 33 other phthalates /including butyl benzyl phthalate/, ethylhexanol derivatives, and related chemcials were tested for mutagenicity in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 without metabolic activation and in the presence of rat or hamster liver S-9 metabolic activation systems. No mutagenic activity was found with any of the chemicals tested. ... [R48] *COUPLED WITH BEHAVIORAL CHANGES, REDUCED BRAIN LEVELS OF EPINEPHRINE FOUND IN TREATED FISH INDICATED THAT THE MODE OF ACUTE TOXICITY FOR BUTYL BENZYL PHTHALATE MAY BE THROUGH ITS EFFECTS ON THE CATECHOLAMINES OF THE CENTRAL ADRENERGIC NERVOUS SYSTEM. [R49] *Seven phthalate esters of different chain lengths and degrees of branching were evaluated for their ability to induce peroxisomes in the livers of Fischer-344 rats. The esters included di(2-ethylhexyl)phthalate, butyl(benzyl)phthalate di(n-butyl)phthalate, di(isodecyl)phthalate, di(isononyl)phthalate, di(undecyl)phthalate, di(n-hexyl,n-octyl,undecyl) phthalate, and di(heptyl,nonyl,undecyl)phthalate. Each of the compounds was fed to groups of five male and five female rats in the diet at concentrations of 2.5, 1.2, and either 0.6 or 0.3 percent for a period of 21 days. Cyanide insensitive palmitoyl-CoA oxidation, lauric-acid-11-hydroxylase, and lauric-acid-12-hydroxylase were assayed in the liver microsomes. Cholesterol and triglyceride concentrations were measured in the serum. The results indicated that none of the esters was more potent than di(2-ethylhexyl) phthalate. The most sensitive parameters were relative liver weight and cyanide insensitive palmitoyl-CoA oxidation. The latter parameter was assumed to be an indicator of peroxisome proliferation and thereby predictive of liver tumorigenesis. [R50] *The objective of this study was to characterize the developmental toxicity of mono-n-benzyl phthalate (MBeP), which is one of the major metabolites of n-butyl benzyl phthalate. Pregnant rats were given mono-n-benzyl phthalate by gastric intubation at 250, 375, 500 or 625 mg/kg on days 7 to 9, 10 to 12, or 13 to 15 of pregnancy. A significantly increased incidence of postimplantation loss was found at 500 mg/kg and above regardless of the days of administration. While administration of mono-n-benzyl phthalate on days 7 to 9 or 13 to 15 at 375 mg/kg and above was significantly teratogenic, no evidence of teratogenicity was detected when mono-n-benzyl phthalate was given on days 10 to 12. Deformity of the vertebral column and ribs and dilation of the renal pelvis were frequently observed after administration on days 7 to 9. Cleft palate and fused sternebrae were exclusively found after administration on days 13 to 15. These findings indicate that the susceptibility and spectrum of the developmental toxicity of mono-n-benzyl phthalate vary with the developmental stages at the time of administration. [R51] *In our previous studies, butyl benzyl phthalate (BBP) was found to be teratogenic when administered to rats on days 7-9 and days 13-15 of pregnancy but not days 10-12. The present study was conducted to determine the phase specificity of the developmental toxicity of mono-n-benzyl phthalate, which is one of the major metabolites of butyl benzyl phthalate, and to assess the role of mono-n-benzyl phthalate in the developmental toxicity of butyl benzyl phthalate. Pregnant rats were given mono-n-benzyl phthalate by gavage at a dose of 375, 500 or 623 mg/kg on days 7-9, days 10-12 or days 13-15 of pregnancy. A significant increase in embryolethality was noted in pregnant rats given mono-n-benzyl phthalate at 500 mg/kg and above regardless of the days of treatment. No evidence of teratogenicity was found when mono-n-benzyl phthalate was given on days 10-12. A significantly increased incidence of fetuses with external malformations was found after treatment on days 13-15 at 500 mg/kg. A significantly increased incidence of fetuses with skeletal malformations was observed after treatment on days 7-9 at 625 mg/kg and on days 13-15 at 375 mg/kg and above. Deformity of the vertebral column and ribs was predominantly observed after treatment on days 7-9. Cleft palate and fusion of the sternebrae were exclusively found after treatment on days 13-15. The dependence of gestational days of treatment on the manifestation of the developmental toxicity and the spectrum of fetal malformations induced by mono-n-benzyl phthalate were similar to those induced by butyl benzyl phthalate. These findings suggest that mono-n-benzyl phthalate and/or its further metabolites may be responsible for the production of the developmental toxicity of butyl benzyl phthalate. [R52] *n-Butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP) were evaluated and compared for their developmental toxic potential. Pregnant rats were given either butyl benzyl phthalate or di-n-butyl phthalate by gastric intubation at a dose of 0.75, 1.0 and 1.25 g/kg on days 7-9, days 10-12 and days 13-15 of pregnancy. Regardless of the days of treatment, a significantly increased incidence of postimplantation loss was found at all doses of butyl benzyl phthalate and di-n-butyl phthalate. While treatment with butyl benzyl phthalate and di-n-butyl phthalate at doses of 0.75 g/kg and above on days 7-9 or days 13-15 resulted in a significant increase in the incidence of fetuses with malformations, no increase in the incidence of malformed fetuses was found after treatment with butyl benzyl phthalate and di-n-butyl phthalate on days 10-12. The incidences of postimplantation loss and malformed fetuses increased as the doses of butyl benzyl phthalate and di-n-butyl phthalate were increased. Deformity of the vertebral column and ribs commonly occurred after treatment with butyl benzyl phthalate and di-n-butyl phthalate on days 7-9. Cleft palate and fusion of the sternebrae were predominantly observed after treatment with butyl benzyl phthalate and di-n-butyl phthalate on days 13-15. The similarity in dependence of gestational days of treatment on the manifestation of developmental toxicity and on the spectrum of fetal malformations caused by butyl benzyl phthalate and di-n-butyl phthalate suggests that they may act by the same mechanism, possibly via a common metabolite of these two parent compounds. [R53] *This study assessed whether exposure of male rats to two estrogenic, environmental chemicals, 4-octylphenol (OP) and butyl benzyl phthalate (BBP) during gestation or during the first 21 days of postnatal life, affected testicular size or spermatogenesis in adulthood (90-95 days of age). Chemicals were administered via the drinking water or concentrations of 10-1000 ug/l (4-octylphenol) or 1000 ug/l (butyl benzyl phthalate), diethylstilbestrol (DES; 100 ug/l) and an octylphenol polyethoxylate (OPP; 1000 ug/l), which is a weak estrogen or nonestrogenic in vitro, were administered as presumptive positive and negative controls, respectively. Controls received the vehicle (ethanol) in tap water. In study 1, rats were treated from days 1-22 after births in studies 2 and 3, the mothers were treated for approximately 8-9 weeks, spanning a 2-week period before mating throughout gestation and 22 days after giving birth. With the exception of diethylstilbestrol, treatment generally had no major adverse effect or body weight: in most instances, treated animals were heavier than controls at day 22 and at days 90-95. Exposure to 4-octylphenol, octylphenol polyethoxylate, or butyl benzyl phthalate at a concentration of 1000 ug/l resulted in a small (5-13%) but significant (p < 0.01 or P < 0.0001) reduction in mean testicular size in studies 2 and 3, an effect that was still evident when testicular weight was expressed relative to body weight or kidney weight. The effect of octylphenol polyethoxylate is attributed to its metabolism in vivo to 4-octylphenol. Diethylstilbestrol exposure caused similar reductions in testicular size but also caused reductions in body weight, kidney weight, and litter size. Ventral prostate weight was reduced significantly in diethylstilbestrol-treated rats and to a minor extent in 4-octylphenol-treated rats. Comparable but more minor effects of treatment with diethylstilbestrol or 4-octylphenol on testicular size were observed in study 1. None of the treatments had any adverse effect on testicular morphology or on the cross-sectional area of the lumen or seminiferous epithelium at stages VII-VIII of the spermatogenic cycle, but diethylstilbestrol, 4-octylphenol, and butyl benzyl phthalate caused reductions of 10-21% (p < 0.05 to p < 0.001) in daily sperm production. Humans are exposed to phthalates, such as butyl benzyl phthalate, and to alkylphenol polyethoxylates, such as 4-octylphenol, but to what extent is unknown. More detailed studies are warranted to assess the possible risk to the development of the human testis from exposure to these and other environmental estrogens. [R54] *Sewage, a complex mixture of organic and inorganic chemicals, is considered to be a major source of environmental pollution. A random screen of 20 organic man-made chemicals present in liquid effluents revealed that half appeared able to interact with the estradiol receptor. This was demonstrated by their ability to inhibit binding of 17 beta-estradiol to the fish estrogen receptor. Further studies, using mammalian estrogen screens in vitro, revealed that the two phthalate esters butylbenzyl phthalate (BBP) and di-n-butylphthalate (DBP) and a food antioxidant, butylated hydroxyanisole (BHA) were estrogenic; however, they were all less estrogenic than the environmental estrogen octylphenol. Phthalate esters, used in the production of various plastics (including PVC), are among the most common industrial chemicals. Their ubiquity in the environment and tendency to bioconcentrate in animal fat are well known. Neither butylbenzyl phthalate nor di-n-butylphthalate were able to act as antagonists, indicating that, in the presence of endogenous estrogens, their overall effect would be cumulative. Recently, it has been suggested that environmental estrogens may be etiological agents in several human diseases, including disorders of the male reproductive tract and breast and testicular cancers. The current finding that some phthalate compounds and some food additives are weakly estrogenic in vitro, needs to be supported by further studies on their effects in vivo before any conclusions can be made regarding their possible role in the development of these conditions. [R55] *The OECD421 reproductive toxicity screening test protocol was evaluated using the reproductive and developmental toxicant butyl benzyl phthalate (BBP). Female rats were orally exposed from 14 days premating to 6 days postpartum. Male rats were exposed for gain and food consumption, on spermatogenesis, time to conception, pregnancy rate, postimplantation survival, and litter size and weight. Food consumption and pup weight were slightly affected at 500 mg/kg also. Effects occurred at expected dosages on the basis of literature data. These findings support the conclusion that the OECD421 test scores butyl benzyl phthalate correctly as a reproductive toxicant, both in a qualitative and in a quantitative sense. [R56] *Chronic toxicity studies were performed with commercial phthalate esters and Daphnia magna (14 phthalates) and rainbow trout (Oncorhynchus mykiss) (six phthalates). For the lower-molecular-weight phthalate esters - dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), and butylbenzyl phthalate (BBP) - the results of the studies indicated a general trend in which toxicity for both species increased as water solubility decreased. The geometric mean maximum acceptable toxicant concentration (GM-MATC) for D. magna ranged from 0.63 to 34.7 mg/l. For the higher-molecular-weight phthalate esters - dihexyl phthalate (DHP), butyl 2-ethylhexyl phthalate (BOP), di-(n-hexyl, n-octyl, n-decyl) phthalate (610P), di-(2-ethylhexyl) phthalate (DEHP), diisooctyl phthalate (DIOP), diisononyl phthalate (DINP), di-(heptyl, nonyl, undecyl) phthalate (711P), diisodecyl phthalate (DIOP), diundecyl phthalate (DUP), and ditridecyl phthalate (DTDP) - the GM-MATC values ranged from 0.042 to 0.15 mg/l. Survival was equally sensitive and sometimes more sensitive than reproduction. The observed toxicity to daphnids with most of the higher-molecular-weight phthalate esters appeared to be due to surface entrapment or a mode of toxicity that is not due to exposure to dissolved aqueous-phase chemical. Early life-stage toxicity studies with rainbow trout indicated that survival (DMP) and growth (DBP) were affected at 24 and 0.19 mg/lg, respectively. This pattern of observed toxicity with the lower-molecular-weight phthalate esters and not the higher-molecular-weight phthalate esters is consistent with previously reported acute toxicity studies for several aquatic species. [R57] NTXV: *LD50 RAT ORAL 13.5 G/KG; [R58] ETXV: *EC50 Selenastrum capricornutum (alga) 110 ug/l/96 hr, toxic effect: chlorophyll a; 130 ug/l/96 hr, toxic effect: cell number; [R59] *EC50 Skeletonema costatum (alga) 170 ug/l/96 hr, toxic effect: chlorophyll a; 190 ug/l/96 hr, toxic effect: cell number; [R59] *EC50 Microcystis aeruginosa (alga) 1X10+6 ug/l/96 hr, toxic effect: cell number; [R59] *EC50 Navicula pelliculosa (alga) 600 ug/l/96 hr, toxic effect: cell number; [R60] *LC50 Lepomis macrochirus (bluegill) 62 mg/l/24 hr and 43 mg/l/96 hr /Conditions of bioassay not specified/; [R61] *LC50 Microcystis (algae) 1,000 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Dunaliella (algae) 1.0 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Navicula (algae) 0.6 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Skeletonema (algae) 0.6 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Selenastrum (algae) 0.4 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Mysid shrimp 0.9 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Mysid shrimp (Mysidopsis bahia) 9.6 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Daphnia magna 92 mg/L/96 hr /Static bioassay/; [R62, 374] *LC50 Fathead minnow (Pimephales promelas) 2.1; 5.3 mg/L/96 hr /Conditions of bioassay(s) not specified/; [R62, 374] *LC50 Bluegill (Lepomis macrochirus) 43 mg/L/96 hr /Conditions of bioassay not specified/; [R62, 374] *LC50 Rainbow trout (Salmo gairdneri) 3.3 mg/L/96 hr /Conditions of bioassay not specified/; [R62, 375] *LC50 Fathead minnow 2.3 mg/L/4 d /Flow-through bioassay/; [R62, 375] *LC50 Fathead minnow 2.2 mg/L/14 d /Flow-through bioassay/; [R62, 375] NTP: *A carcinogenesis bioassay of butyl benzyl phthalate ... was accomplished by feeding diets containing 6,000 or 12,000 ppm of the phthalate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 28 to 103 wk. ... After wk 14, an increasing number of dosed male rats died as a result of an unexplained internal hemorrhaging, and all surviving male rats were /sacrificed/ at wk 29 to 30. Because of cmpd related mortality, butyl benzyl phthalate was not adequately tested for carcinogenicity in male F344/N rats. ... Under the conditions of this bioassay, butyl benzyl phthalate was probably carcinogenic for female F344/N rats, causing an incr incidence of mononuclear cell leukemias. The male F344/N rat study was considered inadequate for the evaluation due to cmpd related toxicity and early mortality. Butyl benzyl phthalate was not carcinogenic for B6C3Fl mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Inadequate Study; Female Rats: Positive; Male Mice: Negative; Female Mice: Negative. [R63] *... Male and female F344/N rats were given butyl benzyl phthalate (at least 97% pure) in feed for ... 2 yr. ... 2 YEAR STUDY IN RATS: Groups of 60 male F344/N rats were given 0, 3,000, 6,000, or 12,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approx 120, 240 or 500 mg butyl benzyl phthalate/kg body weight), and groups of 60 female F344/N rats were given 0, 6,000, 12,000 or 24,000 ppm butyl benzyl phthalate (equivalent to average daily doses of approx 300, 600 or 1,200 mg/kg) in feed for 2 yr. ... CONCLUSIONS: Under the conditions of this 2 yr feed study, there was some evidence of carcinogenic activity of butyl benzyl phthalate in male F344/N rats based on the increased incidences of pancreatic acinar cell adenoma and of acinar cell adenoma or carcinoma (combined). There was eauivocal evidence of carcinogenic activity of butyl benzyl phthalate in female 344/N rats based on the marginally increased incidences of pancreatic acinar cell adenoma and of transitional epithelial papilloma of the urinary bladder. [R64] +Butyl benzyl phthalate (BBP) ... was evaluated for maternal and developmental toxicity in timed- pregnant Swiss albino (CD-l) mice (n=28-30 per group, except n=14 at 2.0% butyl benzyl phthalate). Butyl benzyl phthalate (0, 0.1, 0.5, 1.25 or 2.0% in feed) was administered between the mornings of gestational day (gd) 6 and 15. At sacrifice (gestational day 17), the status of implantation sites was recorded; each fetus was weighed and examined for external, visceral and skeletal malformations. No maternal or embryo/fetal effects were observed at 0.1% butyl benzyl phthalate (0.182 g/kg/day). At 0.5% butyl benzyl phthalate (0.910 g/kg/day), maternal effects were limited to a 15% reduction in wt. gain during treatment. The percent nonlive implants/litter (i.e., resorptions plus late fetal deaths) was increased at 0.5% butyl benzyl phthalate (15% vs. 8% for controls), as was the percent fetuses malformed/litter (14% vs. 4%). Dams in the 1.25% butyl benzyl phthalate (2.330 g/kg/day) group showed a 71% reduction in gestational wt. gain, a 66% reduction in treatment wt. gain, and a 25% reduction in corrected wt. gain. Absolute liver wt. was decreased, and relative liver and kidney wts. were increased in the absence of treatment-related microscopic lesions. Relative food intake (g/kg/day) was increased by 27% (gestational days 15 to 17) and relative water intake by 35-36% (gestational days 12 to 17). Also at 1.25% butyl benzyl phthalate, the percent nonlive implants/litter was increased (93% vs. 8%), average fetal body wt./litter was reduced by 17%, and the percent malformed fetuses/litter was increased (89% vs. 4%). The 2.0% butyl benzyl phthalate dose (4.121 g/kg/day) was eliminated after evaluation of 14 dams since all implanted conceptuses were resorbed. In summary, 0.1% dietary butyl benzyl phthalate was a no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity. At 0.5%, butyl benzyl phthalate produced minimal evidence of maternal toxicity (reduced wt. gain during treatment) and significant developmental toxicity (increased prenatal mortality and malformations). At 1.25% butyl benzyl phthalate and 2.0%, significant maternal and embryo/fetal effects were observed, including greater than 90% prenatal mortality. [R65] +Butyl benzyl phthalate (BBP), a phthalate ester plasticizer, was evaluated for maternal and developmental toxicity in timed-pregnant Sprague-Dawley derived (CD) rats (27-30/group). Butyl benzyl phthalate (0, 0.5, 1.25 or 2.0%) in feed between the mornings of gestational day (gd) 6 and 15 yielded average doses of 0, 0.42, 1.10 or 1.64 g butyl benzyl phthalate/kg/day, respectively. At sacrifice (gestational day 20), the status of implantation sites was recorded; each fetus was weighed and examined for external, visceral and skeletal malformations. No maternal or embryo/fetal effects were observed at 0.5% butyl benzyl phthalate other than increased relative water intake (g/kg/day) between gestational days 15 and 18. Dams in the 1.25% butyl benzyl phthalate group exhibited a 37% reduction in weight gain during treatment, increased relative liver wt., increased relative food intake (11-25% after gestational day 12), and increased relative water intake (18-41% after gestational day 9). At 1.25% butyl benzyl phthalate, the percent fetuses with variations/litter was increased, and the percent fetuses malformed/litter (5.9% vs. 2% for controls) approached statistical significance. Dams in the 2% butyl benzyl phthalate group showed a 93% reduction in treatment weight gain, and a 17% reduction in corrected weight gain. Relative liver and kidney weights were increased. Relative food intake was initially decreased (14% for gestational days 6 to 9), and later increased (16-44% after gd 12). Relative water intake was increased (25-73% after gd 9). At 2% butyl benzyl phthalate, the resorptions/litter were increased (40% vs. 4% for controls), average fetal body weight/litter was reduced by 20%, and the percent malformed fetuses/litter was increased (53% vs. 2% for controls). In summary, 0.5% dietary butyl benzyl phthalate was a no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity. The mid-dose (1.25% butyl benzyl phthalate) produced significant maternal toxicity and minimal evidence of developmental toxicity. At the high dose (2% butyl benzyl phthalate), significant maternal and developmental toxicity was observed, including an increased incidence of malformations. [R66] TCAT: ?Effects on the liver and liver lipids were evaluated in groups of male and female Fischer 344 rats (5/sex/dose level) fed nominal levels of 0, 1.2 or 2.5% butyl benzyl phthalate in the diet for 21 days. Toxicity was evident by statistical differences between dosed groups and controls for: mean body weights (2.5 and 1.2% group males and 2.5% group females), food consumption values (2.5% group males and females), relative liver and kidney weights (all treated groups) and relative testis weights (2.5% group males). There was a statistically significant decrease in serum triglyceride levels for the 1.2 and 2.5% group males and a significant increase in triglycerides for the 2.5% group females. There was a moderate increase in the amount of peroxisome proliferation for the high dose animals. Liver biochemistry revealed statistically significant differences between treated groups and controls as indicated by cyanide-insensitive palmitoyl-CoA oxidation levels (all treated males and 2.5% group females), lauric acid 11- and 12- hydroxylase activities (all treated males and 2.5% group females) and hepatic microsomal protein levels (2.5% group males). There was no consistent dose response relationship among the treatment groups for lipid content in the liver. Histological changes attributable to butyl benzyl phthalate were reduction in cytoplasmic basophilia in the livers of the high dose rats. Also at the 2.5% dietary level, butyl benzyl phthalate caused severe testicular atrophy. [R67] ?The toxicity of butyl benzyl phthalate was evaluated in the mouse lymphoma L5178Y cell line in the presence and absence of rat liver S9 metabolic activation. All cultures were treated in duplicate with concentrations of 9.77, 19.50, 39.10, 78.10, 156.00, 313.00, 625.00, 1250.00, 2500.00 or 5000.00nl/ml, and growth was determined at 24 and 48 hours after initiation of the treatment. Under nonactivated conditions, butyl benzyl phthalate was soluble up to 313nl/ml, and treatments at 625nl/ml and 1250nl/ml were highly toxic (less than 2% of the relative suspension growth). Treatments at 2500nl/ml were lethal to nonactivated cultures. Assays with metabolic activation were soluble up to 1250 nl/ml and produced moderate toxicity at 1250nl/ml (average percent suspension growth, 25% of the solvent (acetone) control). Treatments at 2500nl/ml and 5000nl/ml were lethal to activated cultures. [R68] ?The ability of butyl benzyl phthalate to induce morphological transformation was evaluated in the Balb/c-3T3 A-31 mouse cell line (Cell Transformation Assay). Based on preliminary toxicity determinations (exposure time = 72hrs), butyl benzyl phthalate, was tested at concentrations of 10.0, 20.0, 40.0, 80.0 or 160.0nl/ml, resulting in a range of 90% to 8% relative survival. None of the treatments produced significantly greater transformation frequencies (95% confidence level) relative to the negative control (culture medium). [R69] ?The ability of butyl benzyl phthalate to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S-9 metabolic activation. Based on preliminary toxicity tests, 16 nonactivated cultures treated from 6.25nl/ml to 40.0nl/ml were cloned, producing a range of 83 - 2.5% relative growth. Twenty S-9 activated cultures treated from 200 to 1400nl/ml were cloned, producing a range of 65.7 - 1.0% relative growth. None of the cultures produced mutant frequencies significantly greater than the solvent control (acetone). [R70] ADE: *Phthalate /esters/ ... are not absorbed through skin ... . /Phthalate esters/ [R28] *After oral administration phthalates are quickly absorbed in the gastrointestinal tract ... (Species not stated). /Phthalates/ [R29] *... It is not clear whether the phthalate esters are biosynthesized or occur as a result of dietary sources and subsequent localization in the heart. These findings are significant because the phthalate esters could influence the bioenergetics of the myocardial cells. /Phthalate esters/ [R71] *... Male Fischer-344 rats were dosed with (14)C-labeled butyl benzyl phthalate (BBP) at 2, 20, 200, or 2000 mg/kg orally or 20 mg/kg iv to detect the effects of dose on rates and routes of excretion. In 24 hr, 61-74% of the dose was excreted in the urine and 13-19% in the feces at 2-200 mg/kg. At 2000-mg/kg, 16% of the (14)C was excreted in the urine and 57% in the feces. Urinary (14)C was composed of monophthalate glucuronides derivatives (MP: 10-42% of the dose) and monophthalate glucuronides (2-21% of the dose). At 4 hr after iv administration of BBP (20 mg/kg), 53-58% of the dose was excreted in the bile of anesthetized rats. BBP was not found in the bile, but monobutyl glucuronide and monobenzyl phthalate glucuronide (26 and 13% of the dose, respectively) and trace amts of free monoesters (2% of the dose) and unidentified metabolites (14% of the dose) were present. ... The half-lives of BBP, MP, and total (14)C in blood (20 mg/kg, iv) were 10 min, 5.9 hr, and 6.3 hr, respectively. ... [R72] *Frequency of detection = 69% and max observed concn = 1700 ng/g /Broad scan analysis of composite specimens of human adipose tissue for the U.S. National Adipose Tissue Registry, Fiscal Year 1982; From table/ [R73] METB: *There seems to be a certain connection between metabolism and toxicity of the phthalates because the phthalates with a short alcohol chain, which have a higher toxicity, are /hydrolyzed quickly/ to monoesters and many of the toxic effects of phthalates are provoked by the monoesters in the animal experiments. /Phthalates/ [R29] *ALL OF THE VARIOUS IN VIVO AND IN VITRO STUDIES CONDUCTED ON ... /PHTHALATES/ REVEAL THAT, IN GENERAL, THERE IS READY LOSS OF ONE ALKYL RESIDUE (POSSIBLY ESTERASE), YIELDING A MONOPHTHALATE, BUT LOSS OF BOTH ALKYL RESIDUES TO YIELD PHTHALIC ACID OCCURS TO ONLY A VERY MINOR EXTENT. INSTEAD, THE MONOPHTHALATE IS PARTLY EXCRETED WITHOUT FURTHER MODIFICATION, AND PARTLY SUFFERS HYDROXYLATION IN THE SIDE-CHAIN, AT ONE OR SEVERAL POSITIONS; NO PRODUCTS OF RING HYDROXYLATION HAVE BEEN IDENTIFIED SO FAR. /PHTHALATES/ [R74] *BBP was not found in the bile, but monobutyl glucuronide and monobenzyl phthalate glucuronide (26 and 13% of the dose, respectively) and trace amounts of free monoesters (2% of the dose) and unidentified metabolites (14% of the dose) were present. Although BBP is an asymetrical diester with the potential of forming equal amounts of monobutyl phthalate and monobenzyl phthalate, larger quantities of monobutyl phthalate were formed (monobutyl phthalate= 44% vs monobenzyl phthalate= 16% of the dose). ... [R72] *Strains of Mycobacterium and Nocardia isolated because of their ability to use di(2-ethylhexyl) phthalate (DEHP) as sole carbon source also grew on diethyl, diisooctyl, and butyl benzyl phthalates. As the two bacteria grew on di(2-ethylhexyl) phthalate, they excreted products that increased the solubility of di(2-ethylhexyl) phthalate and diisooctyl, dihexyl, and diisodecyl but not butyl benzyl or di-n-butyl phthalates. The solubilizer was produced by Mycobacterium sp. even when grown on a water-soluble substrate such as acetate. Addition of the solubilizer to culture media enhanced the degradation of di(2-ethylhexyl) phthalate and diisooctyl phthalate by Mycobacterium sp. and Nocardia sp. but not butyl benzyl phthalate. The extent of di(2-ethylhexyl) phthalate degradation by Mycobacterium sp. in media amended with the solubilizer was reduced and the initiation of degradation was delayed if the slubilizer was first treated with protease. The effect of protease was not a result of its toxicity to Mycobacterium or use of the enzyme preparation for growth of the organism. The results thus show that microbial products increase the solubility of certain phthalates and enhance their degradation. [R75] BHL: *The half-lives of butyl benzyl phthalate (BBP), monophthalate (MP), and total (14)C in blood (20 ng/kg, intravenously) were 10 min, 5.9 hr, and 6.3 hr, respectively. [R72] INTC: *MOST OF 12 PHTHALIC ACID ESTERS TESTED PRODUCED A PROLONGATION OF PENTOBARBITAL SLEEPING TIME IN MICE PRETREATED WITH A PHTHALATE ESTER. /PHTHALIC ACID ESTERS/ [R44] *Studies were undertaken to compare outcomes when four chemicals were evaluated under typical NTP bioassay conditions as well as by protocols employing dietary restriction. Four chemicals, using three different routes of exposure (in utero [accomplished by feeding the dam dosed feed], and gavage) were used to 1) evaluate the effect of diet restriction on the sensitivity of the bioassay toward chemically-induced chronic toxicity and carcinogenicity; and 2) evaluate the effect of weight-matched control groups on the sensitivity of the bioassays. Control and chemical exposed F344 rats and B6C3F1 mice (50-0/group) were fed NIH-07 diet either ad libitum or at restricted levels such that body weights were approximately 80% of ad libitum control weights. The dietary restricted groups were either sacrificed at the end of two or 3-years. Results consistently show that feed restriction decreased the incidence of neoplastic and non-neoplastic lesions at a variety of anatomic sites in both control and chemical exposed animals. Furthermore, the sensitivity of the bioassay to detect chemical carcinogenic response were altered by dietary restriction: three of the four chemicals were found to increase the incidence of neoplastic lesions at four sites when evaluated under standard ad libitum conditions for 104 weeks. When unexposed and exposed groups were both subjected to dietary restriction, none of these 4 sites were detected as a target for carcinogenesis after two or three years. Rather, two different sites of carcinogenesis were detected. When the top dosed ad libitum fed animals were compared against their weight-matched control groups, a total of 10 sites were identified as targets for carcinogenesis. These included all four sites identified under the ad libitum protocol, both sites identified under the feed restricted protocol, and an additional four sites that were not identified under the other two protocols. These studies show that dietary restriction of all animals can be expected of decrease the sensitivity of carcinogenesis bioassays. However, restricting only unexposed groups (weight matching) of control for non-specific weight loss in chemical exposed groups yielded the most sensitivity among our comparisons. [R76] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Butyl benzyl phthalate's production and use as a plasticizer and organic intermediate lead to its release to the environment through various waste streams. Based on a measured vapor pressure of 8.25X10-6 mm Hg at 25 deg C, butyl benzyl phthalate is expected to exist in both the vapor and particulate-phase in the ambient atmosphere. Vapor-phase butyl benzyl phthalate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an atmospheric half-life of about 35 hours. Particulate-phase butyl benzyl phthalate is removed from the atmosphere by wet and dry deposition. Butyl benzyl phthalate is expected to have low mobility in soil based upon a measured log Koc value of greater than 4.7. Volatilization from dry soil surfaces is not expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is expected based upon the estimated Henry's Law constant of 4.78X10-6 atm-cu m/mole. This compound is expected to biodegrade rapidly in the environment with estimated half-lives in the range of 4 to 13 days. In water, butyl benzyl phthalate is expected to adsorb to sediment or particulate matter given its measured Koc value. This compound is expected to volatilize from water surfaces given its experimental Henry's Law constant. Estimated half-lives for a model river and model lake are 14 and 106 days respectively. Hydrolysis may be an important environmental fate for this compound based upon an estimated hydrolysis half-life of 51 days at pH 8. The potential for bioconcentration in aquatic organisms is considered high based upon an experimental BCF value of 772 measured for bluegill sunfish. Occupational exposure may be through inhalation of dusts and dermal contact with this compound at workplaces where butyl benzyl phthalate is produced or used. The general population will be exposed to butyl benzyl phthalate via inhalation of ambient air, ingestion of drinking water, and dermal contact with products containing this compound. (SRC) ARTS: *Butyl benzyl phthalate's production and use as a plasticizer and organic intermediate(1) may result in its release to the environment through various waste streams(SRC). [R77] FATE: *TERRESTRIAL FATE: An experimental log Koc of greater than 4.7 was determined from sediment samples from Lake Yssel, the Netherlands(1). Based on a recommended classification scheme(2), butyl benzyl phthalate is expected to have low mobility in soil(SRC). Volatilization of butyl benzyl phthalate is expected to occur from moist soil surfaces(SRC) given an estimated Henry's Law constant of 4.78X10-6 atm-cu m/mole(SRC), determined from a measured vapor pressure of 8.25X10-6 mm Hg at 25 deg C(3) and water solubility of 0.71 mg/l at 25 deg C(4). Butyl benzyl phthalate is not expected to volatilize from dry soil surfaces based on the vapor pressure of this compound(3,SRC). Butyl benzyl phthalate is expected to biodegrade rapidly in soils, with an estimated half-life of about 4 to 13 days(5,6). [R78] *AQUATIC FATE: An experimental log Koc of greater than 4.7 was determined from sediment samples from Lake Yssel, the Netherlands(1). Based on a recommended classification scheme(2), butyl benzyl phthalate is expected to adsorb to suspended solids and sediment in water(SRC). Butyl benzyl phthalate is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 4.78X10-6 atm-cu m/mole(SRC), determined from a measured vapor pressure of 8.25X10-6 mm Hg at 25 deg C(4) and water solubility of 0.71 mg/l at 25 deg C(5). Estimated half-lives for a model river and model lake are 14 and 106 days, respectively(3,SRC). This compound is expected to hydrolyze in the environment with an estimated half-life of 51 days at pH 8(6,SRC). Butyl benzyl phthalate is expected to biodegrade rapidly with an estimated half-life of about 4 to 13 days(7,8). According to a classification scheme(9), the potential for bioconcentration in aquatic organisms is considered high based upon an experimental BCF value of 772 measured in bluegill sunfish(10). [R79] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), butyl benzyl phthalate, which has a measured vapor pressure of 8.25X10-6 mm Hg at 25 deg C(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase butyl benzyl phthalate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 35 hours(3,SRC). Particulate-phase butyl benzyl phthalate may be physically removed from the air by wet and dry deposition(SRC). [R80] BIOD: *Butyl benzyl phthalate is expected to biodegrade rapidly under aerobic and anaerobic conditions(SRC). Butyl benzyl phthalate samples inoculated with diluted anaerobic digester sludge were 50 percent biodegraded in 4 weeks(1). The half-life of butyl benzyl phthalate in an anaerobic sewage sludge was measured as 107 hours(2). Butyl benzyl phthalate was completely biodegraded in Rhine River water over a 6 day incubation period(3). Butyl benzyl phthalate incubated in a lake water/sediment microcosm had a primary half-life of 5 days and an ultimate biodegradation half-life of about 13 days, while butyl benzyl phthalate incubated in river water had a primary half-life of 2 days(4). [R81] ABIO: *The rate constant for the vapor-phase reaction of butyl benzyl phthalate with photochemically-produced hydroxyl radicals has been estimated as 1.1X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 35 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). A base-catalyzed second-order rate constant of 0.158 L/mol-sec (SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 504 and 51 days at pH values of 7 and 8, respectively(2,SRC). [R82] BIOC: *Bluegill sunfish exposed to 9.73 ug/L of butyl benzyl phthalate for 21 days had a measured BCF value of 772(1). According to a classification scheme(2), this BCF value suggests that bioconcentration in aquatic organisms is high(SRC). [R83] KOC: *An experimental log Koc of greater than 4.7 was determined from sediment samples from Lake Yssel, the Netherlands(1) and a log Koc value of 3.3 was measured from unsaturated soil columns at pH 4.8(2). According to a recommended classification scheme(3), butyl benzyl phthalate is expected to have low mobility in soil(SRC). [R84] VWS: *The Henry's Law constant for butyl benzyl phthalate is estimated as 4.78X10-6 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 8.25X10-6 mm Hg at 25 deg C(1), and water solubility, 0.71 mg/l at 25 deg C(2). This value indicates that butyl benzyl phthalate will volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 14 days(3,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 106 days(3,SRC). The estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). This compound is not expected to volatilize from dry soil surfaces based on its measured vapor pressure(1,SRC). [R85] WATC: *DRINKING WATER: Butyl benzyl phthalate was identified, not quantified, in Cincinnati, OH drinking water(1). The maximum reported concn of butyl benzyl phthalate in drinking water were: 0.1 ppb in Philadelphia(1), 1.8 ug/l in New Orleans(2), and 38 ppb (well water) in New York State(3). Butyl benzyl phthalate was detected at a maximum concn of 20 ug/l in a survey of 49 drinking water sites in the US(4). Butyl benzyl phthalate was detected in 5 out of 39 public water system wells in New York State; the highest concn found was 38 ppb (5). Butyl benzyl phthalate was detected at a maximum concn of 38 ppb in a survey of US drinking water facilities(6). [R86] *GROUNDWATER: Butyl benzyl phthalate was identified, not quantified, in groundwater near a landfill in Oklahoma(1), and at a maximum concn of 2 ug/l in groundwater near a chemical plant in Michigan(2). [R87] *SURFACE WATER: Butyl benzyl phthalate was found in the Delaware River at 0.6 ppb(1) and at 2.4 ug/l in Mississippi River near St. Louis(2). Butyl benzyl phthalate was identified, not quantified, in Lake Michigan water(3). Butyl benzyl phthalate was detected in the Rhine River in the Netherlands at concns of less than 1 ug/l(4) and 0.022-0.060 ug/l(5). Butyl benzyl phthalate was detected in the Mersey Estuary in the UK at concns of 0-0.135 ug/l(6). [R88] EFFL: *Effluent from waste incinerators in West Germany contained butyl benzyl phthalate at concns of 2.8 ug/cu m(1), 19.09 ng/cu m(2) and 17.46 ng/cu m(2). Butyl benzyl phthalate was detected in storm water runoff at concns of 100 ug/l (roofs) and 12 ug/l (parking areas) in Alabama(3). Hazardous waste incinerators in the US released 114 tons of butyl benzyl phthalate in 1990(4). Butyl benzyl phthalate is commonly found in landfill leachate in the US at concns of 5.1-8.0 ug/l(5). Butyl benzyl phthalate was detected in the ashes of a municipal refuse incinerator at concns of 0-1,200 ug/kg(6) and in the sediment of a waste disposal facility in Kansas at a concn of 11,000 ug/kg(7). Leachate from a landfill in Sweden contained less than 5 ug/l to 8.1 ug/l of butyl benzyl phthalate(8). [R89] SEDS: *Butyl benzyl phthalate was identified, not quantified, in sediment from Newark Bay, NJ(1). Average butyl benzyl phthalate sediment concns in the Kanauha River, Lake Erie, the Mississippi River (Memphis) and the Missouri River were 0.13, 0.41, 0.63 and 0.23 ug/g, respectively(2). Butyl benzyl phthalate was detected in sediment from the Rhine River in the Netherlands at concns of 0.01-0.05 mg/kg(3) and at concns of 0.12-0.22 mg/kg in Detroit River sediment(4). Butyl benzyl phthalate was detected in soil at a gravel pit near Utica NY at a concn of 940 ug/kg(5). [R90] ATMC: *Butyl benzyl phthalate was detected in indoor air at 20 ng/cu m(1) and identified, not quantified, in the atmosphere of a forest in Germany(2). [R91] PFAC: PLANT CONCENTRATIONS: *Butyl benzyl phthalate was identified, not quantified, in plants and vegetation near a coal reclamation site in Illinois(1). [R92] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 228,808 workers (45,011 of these are female) are potentially exposed to butyl benzyl phthalate in the US(1). Occupational exposure may be through inhalation of dusts and dermal contact with this compound at workplaces where butyl benzyl phthalate is produced or used(SRC). The general population may be exposed to butyl benzyl phthalate via inhalation of ambient air, ingestion of drinking water, and dermal contact with products containing this compound(SRC). [R93] BODY: *Butyl benzyl phthalate was detected in human adipose tissue in the US at a mean concn of 0.19 ug/g(1). [R94] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Butyl benzyl phthalate is exempted from the requirement of a tolerance for residues in or on cottonseed, when used as an inert plasticizer in the formulation of controlled-release laminated dispensers of the attractant gossyplure ((Z,Z) and (Z,E) 7,11-hexadecadien-1-ol acetate) to disrupt the mating of the pink bollworm. [R95] *Butyl benzyl phthalate is exempt from the requirement of a tolerance for residues in or on the raw agricultural commodity artichokes when used as an inert plasticizer in multi-layered laminated controlled-release dispensers of (Z)-11-hexadecenal to disrupt the mating of the artichoke plume moth. [R96] OOPL: *A MAXIMUM PERMISSIBLE LIMIT OF 0.5 MG/CU M IS RECOMMENDED FOR CONCN OF PHTHALATE ESTERS IN AIR OF FACTORIES. /PHTHALATE ESTERS/ [R24] WSTD: STATE DRINKING WATER GUIDELINES: +(MN) MINNESOTA 100 ug/l [R97] +(FL) FLORIDA 1,400 ug/l [R97] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Phthalate esters/ [R98] +The clean water act of 1977 requires the EPA administrator to publish ambient water quality criteria for the pollutant butyl benzyl phthalate listed under section 307. The criteria are to be used as effluent guidelines as required under Section 301 of the act and will also be used under section 3001 of the Resource Conservation and Recovery Act (RCRA). /Phthalate esters/ [R99] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R100] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulagated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Butyl benzyl phthalate is included on this list. [R101] FDA: *Butyl benzyl phthalate is an indirect food additive for use only as a component of adhesives. [R102] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Because of the ubiquitous presence of phthalate esters in the most common of laboratory materials, the choice of a suitable container has been somewhat limited. ... Precleaned mason glass jars, with capliners of clean aluminum foil, for collection and storage of water, sediment and biota samples. Whole fish samples were wrapped in aluminum foil and stored at or below 0 deg C. The skin or shells of biota samples were removed when possible and discarded before sample analysis. /Phthalate esters/ [R103] *Because attempts to lower the limits of detection necessarily involve large water samples not easily transported to the analytical laboratory, it has become increasingly important to concentrate trace organics on the sites. The concentration of phthalate esters from aqueous samples has been investigated, as part of a larger group of organic compounds, using XAD macrorecticular resins and carbon as adsorbents. Studies specific to phthalate esters have been carried out with XAD resin and polyurethane foam. These on-site concentration techniques may help to simplify phthalate ester analysis if enough water can be sampled to give quantities of phthalate esters well above background levels. /Phthalate esters/ [R104] *Two methods for the collection of ambient organic vapors (potential toxic and carcinogenic compounds) at the ng/cu m to ug/cu m level were utilized in field sampling at a residential site in Portland (Oregon, USA) during the winter and spring of 1984. The methods were adsorption/solvent extraction with polyurethane foam plugs (ASE/PUFP) and adsorption/thermal desorption with Tenax-GC cartridges (ATD/Tenax-GC). ASE/PUFP was used with a single sample flow rate in a single channel of the sampler. ATD/Tenax-GC was used with 2 different sample flow rates in 2 separate channels. Each method was well suited to the analysis of compounds in a specific range of volatility. ... The low sample volumes used with ATD/Tenax-GC for determinations at the ng/cu m level make it an attractive method for many applications. [R105] ALAB: *DETERMINATION OF BUTYL BENZYLPHTHALATE IN WATER, SEDIMENT, AND FOOD SAMPLES BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY. [R106] *A METHOD FOR DETERMINATION OF BUTYL BENZYL PHTHALATE IN WASTEWATER BY GC/MS/COMPUTER SYSTEMS. [R107] *A METHOD FOR DETERMINATION OF POLLUTANTS INCLUDING BUTYL BENZYL PHTHALATE IN WASTEWATER AND SLUDGE SAMPLES BY HIGH-RESOLUTION GC AND SELECTIVE DETECTORS (FID, ECD, NPD AND MS-DS). [R108] *GLC RETENTION INDICES OF TOXIC SUBSTANCES INCLUDING BUTYL BENZYL PHTHALATE. [R109] *THE COMBINED DATA OF HIGH-RESOLUTION CHROMATOGRAPHY (GC/FOURIER TRANSFORM-IR AND GC/MS) WERE USED TO IDENTIFY A STANDARD SOLUTION OF PRIORITY POLLUTANTS INCLUDING BUTYL BENZYL PHTHALATE. [R110] *DETERMINATION OF ORGANICS INCLUDING BUTYL BENZYL PHTHALATE IN WATER BY FUSED SILICA CAPILLARY COLUMN GC/MS AND PACKED COLUMN GC/MS. [R111] *METHOD FOR DETERMINING PHTHALATE ESTERS IN ENVIRONMENTAL SAMPLES USING A SINGLE EXTRACT BY DUAL COLUMN LIQUID CHROMATOGRAPHY FRACTIONATION AND GC/ELECTRON CAPTURE DETECTION. /PHTHALATE ESTERS/ [R112] *GC/MS DETERMINATION OF COMPOUNDS INCLUDING BUTYL BENZYL PHTHALATE IN AQUATIC SEDIMENT. [R113] *FLY ASH SAMPLES EXTRACTED FOR 12 HR IN A SOXHLET APPARATUS; EXTRACT WAS CONCENTRATED TO 100 MUL AND ANALYZED BY GC/MS. [R114] *EPA Method 606: A gas chromatographic method for the analysis of butyl benzyl phthalate in municipal and industrial discharges, consists of a glass column, 1.8 m x 4 mm ID, packed with Supelcoport (100/120 mesh) coated with 1.5% SP-2250/1.95%SP-2401, with electron capture detection, and a mixture of 5% methane/95% argon as the carrier gas at a flow rate of 60 ml/min, is an EPA approved method. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 220 deg C. This method has a detection limit of 0.34 ug/l and an overall precision of 0.25 times the average recovery + 0.07, over a working range of 0.7 to 106 ug/l. [R115] *Method 8060: Phthalate Esters This method provides gas chromatographic conditions for the Phthalate Esters This method provides gas chromatographic conditions for the detection of ppb levels. A 2- to 5-ug aliquot of the extract is injected into a gas chromatograph (GC) using the solvent flush technique, and compounds in the GC effluent are detected by an electron capture detector (ECD) or a flame ionization detector (FID). Ground water samples should be determined by ECD. For Butyl benzyl phthalate, the method detection limit for ECD is 0.34 ug/l and for FID is 15 ug/l, the average recovery range for four measurements is 5.7-11.0 ug/l, and the limit for the standard deviation is 4.2 ug/l. [R116] *Method 8250: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Packed Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water samples. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride, including the title compound, and capable of being eluted without derivatization as sharp peaks from a gas chromatographic packed column. For base/neutral compound detection, a 2-m by 2-mm I.D. stainless or glass column packed with 3% SP-2250-DB on 100/120 mesh Supelcoport or equivalent is used. For acid compound detection, a 2-m by 2-mm I.D. glass column packed with 1% SP-1240-DA on 100/120 mesh Supelcoport or equivalent is used. A representative sample is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Under the prescribed conditions, Butyl benzyl phthalate has a detection limit of 2.5 ug/l, a range for the average recovery of four measurements of > 0-139.9 ug/l, and a limit for the standard deviation of 23.4 ug/l. [R116] *Method 8270: Gas Chromatography/Mass Spectrometry for Semivolatile Organics, Capillary Column Technique. This gas chromatography/mass spectrometry method is used to determine the concentration of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and ground water. The practical quantitation limit for determining an individual compound is approximately 1 mg/kg (wet weight) for soil/sediment samples, 1-200 mg/kg for wastes, and 10 ug/l for ground water. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride, including the title compound, and are capable of being eluted without derivatization as sharp peaks from a gas chromatographic-fused silica capillary column coated with a slightly polar silicone [30-m by 0.25-mm ID (or 0.32-mm ID) 1-um film thickness silicon-coated fused silica capillary column (J and W Scientific DB-5 or equivalent)]. A representative sample is collected in a glass container equipped with a Teflon-lined cap. Care is taken to avoid sample contact with any plastic. Under the prescribed conditions, Butyl benzyl phthalate has a retention time of 26.43 min, a range for the average recovery of four measurements of > 0-139.9 ug/l, and a limit for the standard deviation of 23.4 ug/l. [R116] *Trace analysis of organic priority pollutants by high-resolution gas chromatography and selective detectors (FID, ECD, NPD and MS-DS) on minicipal wastewater and sludge samples. [R117] *Chromatographic separation and analysis of phthalic acid esters including, Butyl benzyl phthalate from ambient air samples. [R118] *A screening procedure was developed for the determination of 49 priority pollutants in soil. An extraction procedure was developed for the ... 49 priorty pollutants in soil. An extraction procedure followed by the capillary gas chromatographic technique was used. Duel pH solutions with methylene chloride were used as extraction solvent system; no sample clean-up procedure was applied. Both base/neutral and acidic fractions were analyzed on the same capillary column (SPB-1). The relative standard deviation for 5.1 ppm (51 mug/10 g) concentration in "zero soil" was less than 25%. [R119] *A method was developed which allowed phthalate esters (PE) to be determined in environmental samples along with PCB (polychlorinated biphenyl) and several organochlorine pesticides, using a single sample extract. The extract was fractionated by dual column liquid chromatography (LC) into 4 fractions prior to analysis by GC/ECD (gas chromatography/electron capture detector). This new LC fractionation scheme for /phthalate esters, including butyl benzyl phthalate/ involved elution from an alumina column with benzene (separation from PCB and pesticides which were eluted with hexane followed by elution from silica gel by an acetone/benzene mixture (separation from interfering moderately polar organics). Selected GC conditions enabled 9 different /phthalate esters, including butyl benzyl phthalate/ to be resolved sufficiently for quantitation. The observation that /phthalate esters, including butyl benzyl phthalate/ exhibited a decrease in ECD response as the detector temperature increased it was investigated, and an optimum temperature was selected. ... [R112] *A gradient, normal-phase high-performance liquid chromatographic (HPLC) separation procedure that effectively provided a compound class separation was applied to the analysis of extracts of fly ash from municipal incinerators in Ontario, Canada and Oslo, Norway. Each fraction collected from the HPLC procedure was analyzed by capillary gas spectrometry. Organic components /including butyl benzyl phthalate/ (> 200) were identified in the Canadian extract. ... [R120] *Occasionally, results from the highly reproducible automated log P (octanol/water (o/w) (ALPM) differ from those determined by shake-flask methods. Several specific examples affording different values are presented. One source of these differences may be curvilinearity in plots of log (t-tO) vs precent methyl alcohol which complicate accurate intercept determinations and, thus, estimates of log P(o/w). Other sources of these differences are presented and discussed, although their cause remains unclear. Equil ALPM log P(o/w) measurements of various phenyl-, methyl-, fluoro-, chloro-, and bromobenzenes, suggest substituent constantsare not strictly additive. Moreover, the higher values indicate that calculated values may not be accurate for those compounds having multiple substituents (eg, butyl benzyl phthalate) or high log P(o/w) values. ALPM gives better predictability of the in vivo concn process of 8 or 12 toxicants in fish than the shake-flask method, another HPLC method, or even calculated log P(o/w) values. ... [R121] *Organic components in sewage sludges were extracted with nonaqueous solvents (hexane and methanol) and characterized by chromatography, infrared spectroscopy and mass spectrometry. On the average, nonaqueous solvent soluble compounds represented 10.6% of sludge dry weight (24.8% of ash-free dry weight), and contained 36% of the total organic carbon in sludge. ... Significant amounts of dibutyl phthalate, di(2-ethylhexyl)phthalate, and butyl benzyl phthalate were present in sludges. The presence of phthalate esters in sludges has apparently not been previously reported. The types of phthalate esters in sludge suggest that they are derived from industrial inputs to the municipal sewage treatment system. ... [R122] CLAB: *A CLEANUP OF BIOLOGICAL SAMPLES IS DESCRIBED: PHTHALATE PLASTICIZERS ARE QUANTITATED BY GAS CHROMATOGRAPHY, CONFIRMED BY MEASUREMENT OF FLUORESCENSE IN CONCN SULFURIC ACID. /PHTHALATE PLASTICIZERS/ [R123] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: PIERCE RC ET AL; NATL RES COUNC CAN ASSOC COMM SCI CRITER ENVIRON QUAL PUBL 0(17583) 1-100 (1980) THE PHYSICAL-CHEMICAL PROPERTIES, ANALYTICAL DETERMINATION AND ENVIRONMENTAL DYNAMICS OF PHTHALATE ESTERS (INDUSTRIAL PLASTICIZERS) ARE REVIEWED. Nat'l Research Council Canada; Phthalate Esters In The Aquatic Environment (1980) NRCC No. 17583 USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters (1980) EPA 440/5-80-067 Health and Welfare Canada; Phthalic Acid Esters (1980) Report # 80-EDH-62 Swartz RC et al; ASTM Spec Tech Publ 865: 152-75 (1985) Staples CA et al; Environ Toxicol Chem 4 (2): 131-42 (1985). 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Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. R63: Carcinogenesis Bioassay of Butyl Benzyl Phthalate in F344/N Rats and B6C3F1 mice (Feed Study) Technical Report Series No. 213 (1982) NIH Publication No. 82-1769 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R64: Toxicology and Carcinogenesis Studies of Butyl Benzyl Phthalate in F344/N Rats (Feed Studies). 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Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979.p. 94-11 R72: Eigenberg DA et al; J Toxicol Environ Health 17 (4): 445-56 (1986) R73: Hayes, W.J., Jr., E.R. Laws Jr., (eds.). Handbook of Pesticide Toxicology Volume 1. General Principles. New York, NY: Academic Press, Inc., 1991. 301 R74: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. 239 R75: Gibbons JA, Alexander M; Environ Toxicol Chem 8 (4): 283-92 (1989) R76: Abdo KM and FW Kari; Exp Toxicol Pathol 48 (2-3): 129-37 (1996) R77: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Reinhold Co., p. 183 (1993) R78: (1) Ritsema R et al; Chemosphere 18: 2161-75 (1989) (2) Swann RL et al; Res Rev 85: 23 (1983) (3) Howard PH et al; Environ Toxicol Chem 4: 653-61(1985) (4) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (5) Ziogou K et al; Water Res 23: 743-48 (1990) (6) Carson DB et al; pp .48-59 in Aquatic Toxicol Risk Assess 13: ASTM STP 1096 (1990) R79: (1) Ritsema R et al; Chemosphere 18: 2161-75 (1989) (2) Swann RL et al; Res Rev 85: 23 (1983) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Howard PH et al; Environ Toxicol Chem 4: 653-61(1985) (5) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (6) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (7) Ziogou K et al; Water Res 23: 743-48 (1990) (8) Carson DB et al; pp. 48-59 in Aquatic Toxicol Risk Assess 13: ASTM STP 1096 (1990) (9) Franke C et al; Chemosphere 29: 1501-14 (1994) (10) Veith GD et al; pp. 116-129 in Aquatic Toxicology. Eaton JG et al eds. Am Soc for Testing and Mat (1980) R80: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Howard PH et al; Environ Toxicol Chem 4: 653-61 (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R81: (1) Painter SE, Jones WJ; Environ Technol 11: 1015-26 (1990) (2) Ziogou K et al; Water Res 23: 743-48 (1990) (3) Ritsema R et al; Chemosphere 18: 2161-75 (1989) (4) Carson DB et al; in Aquatic Toxicol Risk Assess 13: ASTM STP 1096 pp. 48-59 (1990) R82: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) R83: (1) Veith GD et al; pp. 116-129 in Aquatic Toxicology. Eaton JG et al eds. Am Soc Testing Mat (1980)(2) Franke C et al; Chemosphere 29: 1501-14 (1994) R84: (1) Ritsema R et al; Chemosphere 18: 2161-75 (1989) (2) Zurmuehl T et al; J Contam Hydrol 8: 111-33 (1991) (3) Swann RL et al; Res Rev 85: 23 (1983) R85: (1) Howard PH et al; Environ Toxicol Chem 4: 653-61(1985) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona - Tucson, AZ (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R86: (1) Kopfler FC et al; Amer Chem Soc Natl Mtg Div Env Chem Prep 15: 185-7 (1975) (2) Keith LH et al; pp. 329-73 in Identification and analysis of organic pollutants in water. Keith LH ed Ann Arbor,MI: Ann Arbor Press (1976) (3) Burmaster DE; Environ 24: 6-13, 33-6 (1982) (4) Canter LW, Sabatini DA; Int J Environ Stud; 46 35-57 (1994) (5) Kim NK, Stone DW; Organic chemicals and drinking water; Albany,NY: New York State Dept of Health (1980) (6) Steelman BL, Ecker RM; Organics Contamination of Groundwater: An Open Literature Review. Richland,WA: Battele Pacific Northwest Lab, DE-AC06-76RLO (1984) R87: (1) Sawhney BL; in Reactions and Movements of Organic Chemicals in Soils, SSSA Special Publication 22 pp. 447-74 (1989) (2) USEPA; Superfund Record of Decision (EPA Region 5): Ott/Story/Cordova Chemical Site, North, Muskegon, Michigan (First Remedial Action), September 1989. Washington,DC: USEPA, Off Emerg Rem Responce. USEPA/EOD/R05-89/111 (NTIS PB90-138405) pp. 103 (1989) R88: (1) Hites RA; pp. 107-20 in Natl Conf Munic Sludge Manage 8th (1979) (2) Konasewich D et al; Status report on organic and heavy metal contaminants in the Lakes Erie, Michigan, Huron and Superior Basins; Great Lake Water Qual Board (1978) (3) Gledhill WE et al; Env Sci Tech 14: 301-5 (1980) (4) Ritsema R et al; Chemosphere 18: 2161-75 (1989) (5) Hendricks AJ et al; Water Res 28: 591-98 (1994) (6) Preston MR, Al-Omran LA; Environ Pollut 62:183-93 (1989) R89: (1) Jay H, Stieglitz L; Chemosphere 30: 1249-60 (1995) (2) Wienecke J et al; Chemosphere 30: 907-13 (1995) (3) Pitt R et al; Water Environ res 67: 260-75 (1995) (4) Dempsey CR; J Air Waste Manage Assoc 43: 1374-79 (1993) (5) Christensen TH et al; Crit Rev Environ Sci Technol 24: 194-202 (1994) (6) Shane BS et al; Arch Environ contam Toxicol 19: 665-73 (1990) (7) USEPA; Superfund Record of Decision (EPA Region 7): Doepke Disposal (Holliday),KS. (First Remedial Action), September 1989. Washington,DC: USEPA, Off Emerg Rem Responce. USEPA/ROD/R07-89/032 (NTIS PB90-162645) pp. 84 (1989) (8) Oman C, Hynning PA; Environ Pollut 80: 265-71 (1993) R90: (1) Crawford DW et al; Ecotoxicol Environ Safety 30: 85-100 (1995) (2) Michael PR et al; Env Tox Chem 3: 377-89 (1984) (3) Ritsema R et al; Chemosphere 18: 2161-75 (1989) (4) Great Lakes Water Quality Board; Report on the Great Lakes Water Quality. Great Lakes Surveillance, Vol 2 (1989) (5) USEPA; Superfund Record of Decision (EPA Region 2): Ludlow Sand and Gravel Site, Town of Paris, Onieda County, New York (First Remedial Action), Spetember 1989. Washington,DC: USEPA, Off Emerg Rem Response. USEPA/ROD/R02-88/067 (NTIS PB89-182521) pp. 78 (1989) R91: (1) Weschler CJ; Environ Sci Technol 18: 648-52 (1984) (2) Helmig D et al; Atmos Environ 24A: 179-84 (1990) R92: (1) Webber MD et al; J Environ Qual 23: 1019-26 (1994) R93: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R94: (1) USEPA; NHATS Broad Scan Analysis: Population Estiamtes from Fiscal Year 1982 Specimens. Washington,DC: USEPA, Off Tox Sub. USEPA 560/5-90-001 (1989) R95: 40 CFR 180.1062(a) (7/1/96) R96: 40 CFR 180.1062(b) (7/1/96) R97: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R98: 40 CFR 401.15 (7/1/87) R99: 40 CFR 129 (1985) R100: 40 CFR 302.4 (7/1/96) R101: 40 CFR 716.120 (7/1/96) R102: 21 CFR 175.105 (4/1/96) R103: Nat'l Research Council Canada; Phthalate Esters p.39 (1980) NRCC No. 17583 R104: Nat'l Research Council Canada; Phthalate Esters p.40 (1980) NRCC No. 17583 R105: Ligocki MP, Pankow JF; Anal Chem 57 (6): 1138-44 (1985) R106: MESTRES R ET AL; ANN FALSIF EXPERT CHIM 70 (751) 177 (1977) R107: LAO RC ET AL; PERGAMON SER ENVIRON SCI 7 (ANAL TECH ENVIRON CHEM 2): 107-18 (1982) R108: GIABBAI M ET AL; ANAL CHEM SYMP SER 13 (CHROMATOGR BIOCHEM, MED ENVIRON RES 1): 41-52 (1983) R109: ARDREY RE, MOFFAT AC; J CHROMATOGR 220 (3): 195-252 (1982) R110: SHAFER KH ET AL; APPL SPECTROSC 35 (5): 469-72 (1981) R111: EICHELBERGER JW ET AL; ANAL CHEM 55 (9): 1471-9 (1983) R112: RUSSELL DJ, MCDUFFIE B; INT J ENVIRON ANAL CHEM 15 (3): 165-84 (1983) R113: LOPEZ-AVILA V ET AL; ANAL CHEM 55 (6): 881-9 (1983) R114: EICEMAN GA ET AL; ANAL CHEM 51 (14): 2343-50 (1979) R115: 40 CFR 136 (7/1/87) R116: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R117: Giabbai M et al; Anal Chem Symp Ser 13: 41-52 (1983) R118: Chang LW et al; Int J Environ Anal Chem 19 (2): 145-53 (1985) R119: Kiang PH, Grob RL; J Environ Sci Health Part A Environ Sci Eng 21 (1): 15-54 (1986) R120: Tong HY et al; J Chromatogr 285 (3): 423-56 (1984) R121: Garst JE; J Pharm Sci 73 (11): 1623-9 (1984) R122: Strachan SD et al; J Environ Qual 12 (1): 69-74 (1983) R123: ZITKO V; INT J ENVIRON ANAL CHEM 2 (3): 241-52 (1974) RS: 106 Record 169 of 1119 in HSDB (through 2003/06) AN: 2185 UD: 200303 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-BROMATE- SY: *BROMATE-DE-SODIUM-; *BROMIC-ACID,-SODIUM-SALT-; *DYETONE-; *NEUTRALIZER-K-126-; *NEUTRALIZER-K-140-; *NEUTRALIZER-K-938- RN: 7789-38-0 MF: *Br-H-O3.Na SHPN: UN 1494; Sodium bromate IMO 5.1 STCC: 49 187 43; Sodium bromate MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *By passing bromine into a soln of sodium carbonate, sodium bromide and sodium bromate being formed. [R1] *Electrolytic oxidation of sodium bromide [R2] FORM: *Article of commerce contains about 99% nabro3. [R3] */Available as/ BP, Cosmetic, aqueous solution, and technical grades [R4] *Pure, min 99.5%, and Reagent, min 99.7%, grades available [R5] OMIN: *...IN 1940'S AND 1950'S...WAS MARKETED AS "NEUTRALIZER" IN HOME PERMANENT COLD WAVE HAIR KITS... MOST MFR /SRP: IN US/ HAVE NOW SUBSTITUTED LESS TOXIC SUBSTANCES... [R6, p. III-66] *A typical neutralizer composition contains sodium bromate. [R7] *Hair wave-setting oxidant compositions which are resistant to repeated shampooing are prepared comprising sodium bromate. [R8] USE: *As mixt with sodium bromide for dissolving gold from its ores [R3] *Analytical reagent [R1] *Boiler cleaning; and oxidation of sulfur and vat dyes [R4] *Neutralizer or oxidizer in certain hair wave preparations [R5] PRIE: U.S. PRODUCTION: *(1986) ND U.S. IMPORTS: *(1986) ND U.S. EXPORTS: *(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless crystals [R9, 4509]; *White granules or crystalline powder [R3] ODOR: *Odorless [R1] MP: *381 deg C [R9, 4509] MW: *150.89 [R3] CORR: *Neutral in aqueous soln [R3] DEN: *3.339 @ 17.5 deg C [R1] PH: *Aq soln is neutral [R3] SOL: *27.5 g/100g H2O at 0 deg C; 36.4 g/100g H2O at 20 deg C; 48.8 g/100g H2O at 40 deg C; 62.6 g/100g H2O at 60 deg C; 75.8 g/100g H2O at 80 deg C; 90.8 g/100g H2O at 100 deg C [R10] SPEC: *INDEX OF REFRACTION: 1.594 [R11] OCPP: *Decomp @ 381 deg C with liberation of oxygen [R3] *Oxidizer [R12] *May ignite combustible materials [R9, 4511] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: These substances will accelerate burning when involved in a fire. May explode from heat or contamination. Some may burn rapidly. Some will react explosively with hydrocarbons (fuels). May ignite combustibles (wood, paper, oil, clothing, etc.). Containers may explode when heated. Runoff may create fire or explosion hazard. [R13] +Health: Toxic by ingestion. Inhalation of dust is toxic. Fire may produce irritating, corrosive and/or toxic gases. Contact with substance may cause severe burns to skin and eyes. Runoff from fire control or dilution water may cause pollution. [R13] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 10 to 25 meters (30 to 80 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R13] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing will only provide limited protection. [R13] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R13] +Fire: Small fires: Use water. Do not use dry chemicals or foams. CO2, or Halon may provide limited control. Large fires: Flood fire area with water from a distance. Move containers from fire area if you can do it without risk. Do not move cargo or vehicle if cargo has been exposed to heat. Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R13] +Spill or leak: Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Small dry spills: With clean shovel place material into clean, dry container and cover loosely; move containers from spill area. Large spills: Dike far ahead of spill for later disposal. [R13] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R13] FIRP: *If material on fire or involved in fire: Flood with water. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. [R14] *Evacuation: If fire becomes uncontrollable - consider evacuation of one-half (1/2) mile radius. [R14] OFHZ: *Prolonged exposure to fire or heat by the material may result in an exposion. [R14] EXPL: *A combination of finely divided /sodium bromate with aluminum, arsenic, carbon, copper, org matter, metal sulfides, phosphorus, or sulfur/...can be exploded by heat, percussion, and, sometimes, light friction. [R15] *Mixtures with grease are shock-sensitive explosives at 120 deg C. [R16] REAC: *Violent reactions with aluminum, arsenic, carbon, copper, oil, F2, metal sulfides, organic matter, phosphorus, sulfur. [R16] DCMP: *When heated to decomposition it emits toxic fumes of Na2O and /hydrogen bromide/. [R16] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. [R14] *Personnel protection: ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R14] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R17] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R18] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R19] STRG: *KEEP FROM CONTACT WITH ORG MATTER. [R20] *IN GENERAL, MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS...SHOULD BE STORED IN COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD AND SHOULD BE PERIODICALLY INSPECTED AND MONITORED. [R21] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *ACCIDENTAL POISONING FROM BROMATE IN CHILDREN IS REPORTED. BROMATE CONTENTS IN HOME HAIR SETTING FORMULAS ARE HAZARDOUS SOURCE OF POISONING. ACUTE CASES REQUIRED LONG PERIODS OF HOSPITALIZATION. TREATMENT GENERALLY INCL INDUCTION OF VOMITING AND LIFE SUPPORT MEASURES; IN SEVERE CASES HEMODIALYSIS MAY BE REQUIRED. [R22] HTOX: *SEE BROMATE. SYMPTOMATOLOGY: 1. VOMITING, DIARRHEA, GASTRIC PAIN. 2. RESTLESSNESS AND LATER APATHY... 3. METHEMOGLOBIN FORMATION AND HEMOLYSIS, WHICH DEVELOP SLOWLY @ FIRST...MAY OR MAY NOT OCCUR IN BROMATE POISONING... 4. LUMBAR PAIN, OLIGURIA AND ALBUMINURIA, PROGRESSING TO ANURIA AND AZOTEMIA WITHIN FEW HR OR FEW DAYS. 5. DEATH FROM RENAL FAILURE, USUALLY WITHIN 1-2 WK. /BROMATE/ [R6, p. II-77] *ACCIDENTAL POISONING FROM BROMATE IN CHILDREN IS REPORTED. ACUTE CASES REQUIRED LONG PERIODS OF HOSPITALIZATION. /BROMATE/ [R22] NTOX: *RABBITS DIED APPROX 12 HR AFTER ORAL ADMIN OF 0.5 G/KG... [R6, p. III-66] *DEATH IN...ANIMALS...IS APPARENTLY DUE TO ACUTE RENAL FAILURE RESULTING FROM NEPHROTOXIC ACTION OF BROMATE ION. /BROMATE/ [R6, p. III-66] *SODIUM BROMATE (200 MG/KG, SC) DECR VOLTAGE OF ENDOCOCHLEAR POTENTIAL (EP), INCR ELECTRIC RESISTANCE OF COCHLEAR PARTITION AND CAUSED OCCASIONAL DEGENERATION OF STRIA VASCULARIS IN GUINEA PIGS. [R23] *DAILY IP ADMIN OF 10-20 MG/KG OF SODIUM AND POTASSIUM BROMATES FOR 10 DAYS TO GUINEA PIGS CAUSED A HISTOLOGICAL LESION IN OUTER HAIR CELLS OF COCHLEA. [R24] *Sodium bromate was tested in the Ames test, the micronucleus test on mouse bone marrow, and the recessive lethal test using Drosophila. It was negative in the Ames test and in the Drosophila recessive lethal test. However, it showed significant mutagenic effects in a dose-dependent manner in the mouse micronucleus test system. [R25] *Striped bass eggs (12 hr after fertilization) and larvae (4 days after hatching) and juvenile spot were exposed to a series of bromate concn (incl sodium bromate) for 4, 10, and 10 days, resp, using a static replacement bioassay technique. Newly hatched striped bass prolarvae were most sensitive to bromate and had a 96 hr median lethal concn of (LC50) 30.8 mg/L (as bromate). Four-day-old striped bass larvae were less sensitive, with 2- to 10-day LC50s ranging from 605.0 to 92.6 mg/L bromate, resp. Juvenile spot were least sensitive, with 1- to 10-day LC50s ranging from 698.0 to 278.6 mg/L bromate, resp. [R26] NTXV: *LD50 Mouse ip 140 mg/kg; [R16] NTP: +... A dose range-finding study be performed in order to establish the potential effects of sodium bromate on the immune system and to determine the doses that could be used in a full immunotoxicology study. These studies were conducted in female B6C3F1 mice. The animals were exposed to sodium bromate based on the concentration of the test article in the drinking water. Five sodium bromate concentrations of 80, 200, 400, 600 and 800 mg/L for 28 days were utilized. Sodium bromate solutions were prepared fresh every two weeks in tap water and stored refrigerated. ... Sodium bromate was administered in the drinking water from water bottles for 28 days at 80, 200, 400, 600 and 800 mg/L. There was no statistically significant difference in drinking water consumption between animals exposed to sodium bromate and the tap water controls. Exposure to sodium bromate did not produce any signs of overt toxicity. There was no significant difference in body weight and body weight change between the exposed and control animals during the experimental period. No gross pathological lesions were observed in sodium bromate-exposed animals; furthermore, there were no differences observed in the weights of thymus, liver, kidneys or lung. However, animals exposed to 80, 600 and 800 mg/L of sodium bromate had a significant increase in absolute spleen weight of 20%, 28% and 23%, respectively. The increase was also reflected in relative spleen weight with 19%, 26% and 23%, respectively. The erythrocyte count, hemoglobin, hematocrit, MCV, platelet count, total leukocyte count, and counts of leukocyte differentials were unaffected by sodium bromate. MCH and MCHC were significantly decreased (2%) when the animals were exposed to the highest dose of sodium bromate; however, this decrease is not considered to be biologically relevant. A dose-related increase in reticulocytes, significant at the two high dose levels, was observed following exposure to sodium bromate with the greatest increase (78%) observed at the highest dose level. ... As in the toxicological parameters, exposure to sodium bromate produced few changes in various immunological parameters. There were no changes in the absolute number of total T cells, CD4+ T cells, CD8+ T cells, natural killer cells and macrophages. However, an increase was observed in total spleen cells and B cells at the dose of 600 mg/L. The increase in B cell number was not considered to be biologically relevant for several reasons. First, no dose-related response was observed; secondly, there was no significant difference when the number of B cells was expressed as the percentage of total spleen cells; thirdly, the IgM antibody response to T-dependent antigen sheep erythrocytes was not altered after exposure to sodium bromate. The effect of sodium bromate on the activity of spleen T cells and natural killers (NK) cells was evaluated using the one-way mixed leukocyte response (MLR) and cytotoxic assay of YAC-1 cells, respectively. There was no alteration in MLR and NK activity after exposure to sodium bromate. When the activity of peritoneal macrophages was evaluated using the cytotoxic/cytostatic assay of B16F10 tumor cells, the suppressive effect of peritoneal macrophages on the proliferation of B16F10 tumor cells was decreased by sodium bromate at doses of 200, 400 and 800 mg/L. In the absence of macrophage stimulation, macrophages from the vehicle control animals produced a 32% suppression of the B16F10 tumor cell proliferation, which was decreased to 20% and 22% when the animals were exposed to 200 mg/L and 800 mg/L of sodium bromate, respectively. Macrophages, stimulated with gamma interferon and LPS, from the vehicle control animals produced a 65% suppression of the B16F10 cell proliferation, which was decreased to 46%, 46% and 47% when the animals were exposed to 200 mg/L, 400 mg/L and 800 mg/L of sodium bromate, respectively. In conclusion, sodium bromate, when administered in the drinking water at doses from 80 mg/L to 800 mg/L, produced minimal toxicological and immunotoxic effects in female B6C3F1 mice, with biologically significant effects only observed in spleen weights, reticulocyte counts and macrophage activity. Based on the results of this range-finding study, further investigation of the effect of sodium bromate on the immune system may not be warranted. [R27] +The potential toxicity of sodium bromate ... was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to sodium bromate exposure. A dose range-finding study was conducted at concns of 0, 250, 500, 1,000, and 2,000 ppm in order to select concns for the 35-day study. Based on dose-related body weight reductions and decreased feed and water consumption, the concns for the 35-day study were selected to be 0, 25, 80, and 250 ppm. For the main study, Sprague-Dawley rats were administered sodium bromate at these concns in the drinking water over a 35-day period. One group of male rats (10/group) and 2 groups of female rats designated as Group A (peri-conception, 10/group) AND Group B (gestational exposure, 13/group) were used at each dose level. Control animals received deionized water, the vehicle. During the treatment period, all animals survived to the scheduled necropsy and there were no general toxic effects noted at any level. The overall avg calculated consumption of sodium bromate for Groups 2-4 was approx 2.6, 9.0, and 25.6 mg/kg bw/day, respectively. There were no changes observed in the reproductive data for the Group A AND Group B females. The male and female weekly absolute body weights, feed consumption, water consumption, clinical observations, and gross findings were comparable among dose groups. The male organ weights and organ-to-body weight ratios were also comparable across dose groups. Although there was no effect on male fertility, there was a slight decr in epididymal sperm density, which decreased with increasing concn and reached significance in the 250 ppm males (reduced by 18%). Sodium bromate resulted in no treatment-related gross or microscopic changes in the kidney, liver, spleen, testis, or epididymis. Serum ALT was decreased by 14% in the 80 and 250 ppm groups. Because this change was small, and in the absence of changes in other liver enzymes, this was deemed to be biologically insignificant. Results of this study indicate that sodium bromate treatment did not produce any adverse signs of general toxicity in any of the dose levels tested, and based on these findings, a max tolerated dose (MTD) was not reached. Female reproductive function was not adversely affected in this study. Sodium bromate appeared to slightly reduce male epididymal sperm density at 250 ppm. Based on the lack of general toxicity findings at any dose, and the epididymal sperm density decr at 250 ppm , the no-observable-adverse-effect-level (NOAEL) was determined to be 80 ppm. From these data, sodium bromate may be a selective male reproductive toxicant at 250 ppm since male reproductive toxicity was noted in the absence of general toxicity. [R28] ADE: *THEY ARE READILY ABSORBED FROM ALIMENTARY TRACT... /BROMATES/ [R29, 158] *...BROMATES ARE SURPRISINGLY STABLE IN BODY AND ARE EXCRETED AS SUCH BY KIDNEYS. /BROMATES/ [R6, p. III-67] *Skin penetration of sodium bromate is slight as judged by blood bromide levels of somewhat less than 1 mg % from a 7-hr moistened application of the salt to rabbit's skin. [R30] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *5. 5= EXTREMELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 5-50 MG/KG, BETWEEN 7 DROPS AND 1 TEASPOONFUL FOR 70 KG PERSON (150 LB). /BROMATE SALTS/ [R6, p. II-77] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 10 ug/l /Bromate ion/ [R31] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *COLORIMETRIC METHOD FOR DETECTING BROMATE IN COLD WAVE NEUTRALIZERS. TO 1 ML 5% SOLN OF SAMPLE...ADD 2 ML H2SO4 WITH VIGOROUS SHAKING...COOL...CAREFULLY ADD 2 ML CARBON DISULFIDE AND SHAKE. CS2 LAYER BECOMES YELLOW OR RED IF BROMINE IS PRESENT. /BROMATE/ [R32, p. 13/587 35.059] *QUANTITATIVE TITRATIONAL METHOD FOR DETECTING BROMATES IN WHITE AND WHOLE WHEAT FLOUR. /BROMATES/ [R32, p. 13/217 14.040] CLAB: *DETERMINATION OF BROMATE IN BLOOD OR URINE. SENSITIVITY OF TEST IS 10 UG. NITRITE CAN INTERFERE WITH REACTION BUT ADDITION OF UREA WILL REMOVE THE NITRITE: DUNN AND MCINTYRE, J LAB CLIN MED, 34, 425, 1949. /BROMATES/ [R29, 424] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for sodium bromate is completed, and the chemical is in review for further evaluation. Route: dosed water feed; Species: water disinfection model, mice. [R33] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for sodium bromate is completed, and the chemical is in review for further evaluation. Route: topical; Species: water disinfection model, mice. [R33] SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1051 R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 807 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1473 R4: CHEMCYCLOPEDIA 1986 p.200 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V4 249 R6: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976. R7: Shirakura S, Namiki H; Neutralizer for permanent wave; US Patent no 4426376 01/17/84 (Curtis, Helene, Industries, Inc) R8: Matsumoto H; Oxidant composition for permanent waving; French Demande Patent No 2487673 02/05/82 (Yamahatsu Sangyo Kaisha, Ltd R9: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R10: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. A4 (85) 426 R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. B-124 R12: Aldrich; Handbook Catalog of Fine Chemicals 1996-1997. Milwaukee, WI: Aldrich Chem Co. (1996) R13: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-141 R14: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 971 R15: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978.,p. 491M-379 R16: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2951 R17: 49 CFR 171.2 (7/1/96) R18: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 212 R19: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.5071 (1988) R20: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1231 R21: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 592 R22: SAMUELSON G, WESTMAN G; BROMATE POISONING IN CHILDREN; LAEKARTIDNINGEN 75 (10): 954-7 (1978) R23: ASAKUMA S, SNOW JB JR; EFFECTS OF SODIUM BROMATE AND NITROGEN MUSTARD ON ENDOCOCHLEAR DC POTENTIAL AND ELECTRICAL RESISTANCE OF THE COCHLEAR PARTITION IN NORMAL AND KANAMYCIN-TREATED GUINEA PIGS; SURG FORUM 29: 573-5 (1978) R24: MIZUSHIMA N; EXPERIMENTAL STUDY ON THE OTOTOXICITY OF BROMATE; NICHIDAI IGAKU ZASSHI 37 (9): 1057-82 (1978) R25: Eckhardt K et al; Mutagenic activity of chlorate, bromate, and iodate; Mutation Res 97: 185 (1982) R26: Richardson LB et al; Toxicity of bromate to striped bass ichthyoplankton (Morone saxatilis) and juvenile spot (Leiostomus xanthurus); J Toxicol Environ Health 8 (4): 687-95 (1981) R27: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of Sodium Bromate (CAS No. 7789-38-0) Dose Range-Finding Study in Female B6C3F1 Mice, NTP Study No. IMM98004 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 21, 2002 R28: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Sodium Bromate (rats), CAS No. 7789-38-0, NTP Study No. RDGT94007 available at http://ntp-server.niehs.nih.gov/htdocs/pub-RDGT0.html as of August 16, 2002 R29: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. R30: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2971 R31: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R32: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982. R33: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 26 Record 170 of 1119 in HSDB (through 2003/06) AN: 2187 UD: 200302 RD: Reviewed by SRP on 1/20/2001 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged also to retrieve the record named MANGANESE COMPOUNDS, which has additional information relevant to the toxicity and environmental fate of manganese ions and manganese compounds. For information on the metal itself, refer to the MANGANESE, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MANGANESE-SULFATE- SY: *MANGANESE- (II)-SULFATE; *MANGANESE-SULFATE- (MNSO4); *MANGANESE-SULPHATE-; *Sorba-Spray-Manganese-; *SULFURIC-ACID,-MANGANESE- (2+)-SALT- (1:1) RN: 7785-87-7 RELT: 6945 [MANGANESE COMPOUNDS]; 550 [MANGANESE, ELEMENTAL] MF: *Mn-O4-S ASCH: Manganese(II) sulfate tetrahydrate; 10101-68-5; Manganese sulfate monohydrate; 10034-96-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *By-product of hydroquinone production or by the action of sulfuric acid on manganous hydroxide or carbonate. [R1] *Manganous oxide + sulfuric acid (salt formation); manganese ores + sulphuric acid (acid extraction; coproduced with manganese dioxide). [R2] IMP: *TRACE IMPURITIES: Zinc, nitrogen and cobalt [R3] FORM: *32% manganese sulfate monohydrate, maxi-granular, mini-granular and powder /Techmangam/ [R4, p. B 68] *Grades: technical; CP /chemically pure/; fertilizer; feed [R1] *The commercial product is the monohydrate (technical grade). [R5, 132] *Commercial grades contain 29.5-32.0% Mn corresponding to the mono- or dihydrate. [R2] *Several hydrates, mono-, tri-, and tetrahydrate are all used as fertilizers; double salts (2MnSO4-CaSO4 and 2MnSO4-MgSO4), and several grades containing ammonium sulfate are also used as by-products of the photographic supply and chemical manufacture. [R4, p. B 30] *Manganese sulfate, monohydrate 29.5% Mn, mini and maxi prills; Manganese sulfate, monohydrate 31.5% Mn, powder. [R4, p. B 51] *28% Mn, manganese sulfate, granular powder; F-287 G, 28% Mn, manganese oxide- sulfate, granular; 42% Mn, 52% Mn, manganese oxide-sulfate, granular. [R4, p. B 51] MFS: *Jost Chemical Co., Inc., 8130 Lackland Rd., St. Louis, MO 63114, (314) 428-4300; Production site: St. Louis MO 63114 [R6] *The Prince Manufacturing Co., One Prince Plaza, P.O. Box 1009, Quincy, IL 62306, (217) 222-8854; Production sites: Bowmanstown, PA 18030; Qunicy, IL 62306 [R6] *TETRA Micronutrients, Inc., 25025 1-45 North, The Woodlands, TX 77380, (281) 367-1983; Production site: Fairbury, NE 68352-5519 [R6] OMIN: *Article of commerce is usually a mixture of tetra- and pentahydrates. [R7] USE: *In dyeing; for red glazes on porcelain; boiling oils for varnishes; in fertilizers for vines, tobacco; in feeds. [R7] *Starting material for electrolytic manganese metal, electrolytic manganese dioxide, and other manganese compounds such as manganese carbonate, manganese soaps, and certain inorganic pigments; use in textile printing and glass making; fertilizer for manganese-deficient soils; animals feeds [R5, 132] *Therap Cat(Vet): Nutritional factor (essential trace element in all animals); prevention of perois in poultry. [R7] CPAT: *CHEMICAL PROFILE: Manganese Sulfate. Fertilizer, 60%; livestock nutrients, 30%; miscellaneous industrial uses, 10%. [R8] PRIE: U.S. PRODUCTION: *8000 tons/annual [R5, 133] *CHEMICAL PROFILE: Manganese sulfate. Demand: 1986: 14,000 tons; 1987: 14,350 tons; 1991 /projected/: 15,800 tons. [R8] U.S. IMPORTS: *(1984) 1.83X10+8 g [R9] *6000-6500 tons/annual [R5, 133] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White orthorhombic crystals [R10] BP: *Decomp @ 850 deg C [R10] MP: *700 deg C [R10] MW: *151.00 [R10] DEN: *3.25 [R11] SOL: *52 G/100 CC OF WATER @ 5 DEG C [R12]; *70 G/100 CC OF WATER @ 70 DEG C [R12]; *SOL IN ALCOHOL; INSOL IN ETHER [R12]; *Slightly soluble in methanol. [R13] OCPP: *Translucent, pale-rose-red, efflorescent prisms; density 2.107 g/cu cm; MP 30 deg C; decomposes at 850 deg C; soluble in water; insoluble in alcohol. /Tetrahydrate/ [R1] *Mono-, tetra-, penta-, and hepta- hydrates are pink. [R14] *Pale red, slightly efflorescent crystals; sol in about 1 part cold, 0.6 part boiling water; insol in alcohol; loses all water @ 400-450 deg C. /Monohydrate/ [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of /sulfur oxides/. [R15] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Manganese and related compounds/ [R16, 365] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Manganese and related compounds/ [R16, p. 365-6] NTOX: *MANGANESE SULFATE INJECTIONS STIMULATE HEMATOPOIESIS IN ANIMALS ... . [R17] *INTRAHEPATIC CHOLESTASIS CAN ... BE PRODUCED IN RATS BY ADMIN OF IV ... MANGANESE SULFATE ... THIS RESPONSE IS ASSOCIATED WITH DEVELOPMENT OF NECROTIC LESIONS, WHICH VARIES FROM FOCAL NECROSIS TO SUBTOTAL MIDZONAL NECROSIS. WIDESPREAD DILATATION OF BILE CANALICULI WITH LOSS OF MICROVILLI IS OBSERVED 20 HR AFTER TREATMENT. MAX BILIARY EXCRETION OF BILIRUBIN IS MARKEDLY DIMINISHED IN MANGANESE SULFATE-LOADED RATS; THERE IS NO CORRELATION BETWEEN EXTENT OF NECROSIS AND CHOLESTATIC RESPONSE. /THIS/ TREATMENT FOLLOWED BY BILIRUBIN INFUSION CAN CAUSE MORE SEVERE CHOLESTASIS; RECOVERY OF BILE FLOW IS PARTIAL @ 24 HR AND ESSENTIALLY COMPLETE @ 48 HR. [R18] *Manganese sulfate in sodium chloride has been tested for carcinogenic activity in the Strain A mouse lung tumor system. In this study, Strain A/Strong mice of both sexes, 6-8 weeks old, were injected intraperitoneally 3 times/week for a total of 22 injections. Three dose levels (132, 330, or 660 mg/manganese sulfate/kg) were employed that represented the maximum tolerated dose. Twenty mice were used at each dose level (10/sex) including vehicle (saline) and positive (urethan) controls. Mice were sacrificed 30 weeks after the first injection. A slight statistically significant increase (p= 0.068, Fisher Exact Test) in the number of pulmonary adenomas per mouse was associated with administration of the high dose. The response was somewhat elevated at the other doses, but was not statistically significant. [R19] *A comparison of the cytotoxic activity of cationic (MnSO4) and anionic (KMnO4) salts of inorganic manganese in the mouse in vivo indicated that the former was more strongly clastogenic than the latter. Mice were administered different doses of the salt orally over a period of 3 weeks. In general, both the frequencies of chromosomal aberrations in bone marrow cells and micronuclei were increasd significantly by both salts. Sperm-head abnormalities showed a significant enhancement as well. The clastogenic effects were directly related to the concentrations used and were not markedly influenced by the duration of treatment. In view of the known affinity of Mn2+ for chromosomal components, it has been suggested that the effects were mediated by these ions produced directly from MnSO4 and indirectly from KMnO4 following conversion under acidic pH of the gastric juices. [R20] *Male rats were exposed to manganese sulfate ip daily for a period of four weeks to see its effects on tissue levels and urinary excretion of total nicotinamide nucleotides. Increased levels of total nicotinamide nucleotides were observed in blood and brain while the levels were found to be decreased in liver. There was a progressive increase in the excretion of total nicotinamide nucleotides during the experimental period. Total nicotinamide nucleotides levels in blood and urine might serve as useful biological indicators of manganese toxicity. [R21] NTXV: *LD100 Mouse oral 305 mg/kg /From table/; [R22] *LD50 Mouse intraperitoneal 64 mg/kg /From table/; [R23] *LD100 Mouse subcutaneous 146 mg/kg /From table/; [R24] NTP: *... Toxicology and carcinogenesis studies were conducted by administering manganese (II) sulfate monohydrate (97% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. ... 2 YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were fed diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. Based on average daily feed consumption, these doses resulted in the daily ingestion of 60, 200, or 615 mg/kg body weight (males) or 70, 230, or 715 mg/kg (females). ... 2 YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received diets containing 0, 1,500, 5,000, or 15,000 ppm manganese (II) sulfate monohydrate. These levels resulted in an average daily ingestion of 160, 540, or 1,800 mg/kg body weight (males) or 200, 700, or 2,250 mg/kg (females). ... CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male or female F344/N rats receiving 1,500, 5,000, or 15,000 ppm. There was equivocal evidence of carcinogenic activity of manganese (II) sulfate monohydrate in male and female B6C3FI mice, based on the marginally increased incidences of thyroid gland follicular cell adenoma and the significantly increased incidences of follicular cell hyperplasia. /Mangansese sulfate monohydrate/ [R25] ADE: *WHEN LARGE DOSES OF MANGANESE SULFATE ARE INJECTED IV EXCRETION IS ALMOST EXCLUSIVELY IN FECES ... . [R26] */Manganese sulfate/ is poorly absorbed through lung and gut. [R27] INTC: *The present study was designed primarily to investigate the biliary excretion of organic bile constituents following administration of the manganese-bilirubin combination. Experiments in hyperbilirubinemic Gunn rats were also performed to determine whether the unconjugated or the conjugated form of bilirubin is involved in this cholestatic interaction. Male Sprague-Dawley rats and male homozygous Gunn rats were given the following (iv.): (a) manganese (4.5 mg per kg); (b) unconjugated bilirubin (25 mg per kg); (c) bilirubin ditaurate (38 mg per kg); (d) manganese- unconjugated bilirubin, or (e) manganese-bilirubin ditaurate. Bile flow was measured and bile was analyzed for manganese, total bilirubin, bile salts, cholesterol and phospholipid content. The results show that: (i) manganese- unconjugated bilirubin treatment caused about manganese unconjugated bilirubin treatment caused about a 50% reduction in bile flow in Sprague Dawley rats, whereas in Gunn rats the manganese bilirubin ditaurate treatment resulted in about a 75% reduction, and (ii) in both strains, bile salt excretion was not appreciably modified during the cholestatic phase, as biliary bile salt concentration increased. The results suggest that although that although important differences regarding the form of bilirubin apparently exist, unconjugated bilirubin could be implicated in the cholestatic interaction in both strains of rats. Manganese bilirubin induced cholestasis is not related to a defect in bile salt excretion. The latter supports our contention that diminished canalicular membrane permeability to water is likely to be a key factor in this form of experimental cholestasis. [R28] *EFFECTS OF PARENTERAL METAL SUPPLEMENTS ON SALICYLATE TERATOGENICITY WAS STUDIED IN RATS. MANGANOUS SULFATE (10 MG/KG) SIGNIFICANTLY ENHANCED TERATOGENIC EFFECTS OF SODIUM SALICYLATE. [R29] *Manganese-bilirubin (Mn-BR)-induced cholestasis in rats is associated with altered lipid composition of various hepatic subcellular fractions. Increased bile canalicular (BCM) cholesterol content in Mn-BR cholestasis and the intracellular source of the accumulating cholesterol were investigated. To label the total hepatic cholesterol pool, male Sprague-Dawley rats were given ip 3H-cholesterol, followed 18 hr later by 2-14C-mevalonic acid (a precursor of cholesterol synthesis). To induce cholestasis, manganese (Mn, 4.5 mg/kg) and bilirubin (BR, 25 mg/kg) were injected iv; animals were killed 30 min after BR injection; canalicular and sinusoidal membranes, microsomes, mitochondria, and cytosol were isolated. Total cholesterol content of each fraction was determined by spectrophotometric techniques as well as radiolabeled techniques. In Mn-BR cholestasis, the total cholesterol concns of BCM and cytosol were significantly increased. Also, the contribution of 14C-labeled cholesterol (newly synthesized cholesterol) was enhanced in all isolated cellular fractions. The results are consistent with the hypothesis that accumulation of newly synthesized cholesterol in BCM is involved in Mn-BR cholestasis. An enhanced rate of synthesis of cholesterol, however, does not appear to be the causal event, as the activity of HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis), assessed in vitro, was decreased following Mn-BR treatment. Treatment with the Mn-BR combination may affect other aspects of intracellular cholesterol dynamics. [R30] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): To prevent or treat manganese deficiency. [R31] *MEDICATION (VET): NUTRITIONAL FACTOR (ESSENTIAL TRACE ELEMENT IN ALL ANIMALS); PREVENTION OF PEROSIS IN POULTRY. [R32] *MEDICATION: NUTRIENT AND/OR DIETARY SUPPLEMENTAL FOOD ADDITIVE [R33] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *500 mg/cu m /Manganese compounds and fume (as Mn)/ [R34] OSHA: *Permissible Exposure Limit: Table Z-1 Ceiling value: 5 mg/cu m. /Manganese cmpd (as Mn)/ [R35] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 mg/cu m. /Manganese compounds and fume (as Mn)/ [R34] *Recommended Exposure Limit: 15 Min Short-Term Exposure Limit: 3 mg/cu m. /Manganese compounds and fume (as Mn)/ [R34] TLV: *8 hr Time Weighted Avg: 0.2 mg/cu m /Manganese, elemental, and inorganic compounds, as Mn/ [R36] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Manganese sulfate is included on this list. [R37] *... Substances for which a Federal Register notice has been published that included consideration of the serious health effects, including cancer, form ambient air exposure to the substance. Manganese (50 FR 32627; Aug. 13, 1985) is included on this list. /Manganese/ [R38] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 50 ug/l /Manganese/ [R39] STATE DRINKING WATER STANDARDS: +(IL) ILLINOIS 150 ug/l /Manganese/ [R39] +(NC) NORTH CAROLINA 50 ug/l /Manganese/ [R39] +(NY) NEW YORK 300 ug/l /Manganese/ [R39] STATE DRINKING WATER GUIDELINES: +(CT) CONNECTICUT 500 ug/l /Manganese/ [R39] +(ME) MAINE 200 ug/l /Manganese/ [R39] +(MN) MINNESOTA 100 ug/l /Manganese/ [R39] +(MN) MINNESOTA 100 ug/l /Manganese/ [R39] FDA: *Manganese sulfate in nutrients and/or dietary supplements is generally recognized as safe when used in accordance with good manufacturing or feeding practices. [R40] *Substance added directly to human food affirmed as generally recognized as safe (GRAS). [R41] *Trace minerals added to animal feeds. These substances added to animal feeds as nutritional dietary supplements are generally recognized as safe when added at levels consistent with good feeding practice. Element: Manganese; Source compound: manganese sulfate. (All substances listed may be in anhydrous or hydrated form.) [R42] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Locating and Estimating Air Emissions from Sources of Manganese (1985) EPA-450/4-84-007h USEPA; Health Assessment Document: Manganese (1984) EPA-600/8-83-013F WHO; Environ Health Criteria: Manganese (1981) WHO; Environ Health Criteria: Manganese-Executive Summary (1981) DHHS/ATSDR; Toxicological Profile for Manganese (1992) ATSDR/TP-91/19 DHHS/NTP; Toxicology and Carcinogenesis Studies of Manganese (II) Sulfate Monohydrate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 428 (1993) NIH Publication No. 94-3159 SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 701 R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 551 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 14(1980) 878 R4: Farm Chemicals Handbook 2000. Willoughby, Ohio: Meister 2000. R5: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA16 (1990) R6: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 710 R7: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 978 R8: Kavaler AR; Chemical Marketing Reporter 231 (18): 50 (1987) R9: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-349 R10: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 4-72 R11: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 4-70 R12: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. B-106 R13: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V15 (95) 997 R14: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA16 (90) 132 R15: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1732 R16: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R17: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1084 R18: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 298 R19: USEPA; Health Assessment Document: Manganese p.7-1 (1984) EPA-600/8-83-013F R20: Joardar M, Sharma A; Mutat Res 240 (3): 159-164 (1990) R21: Patel AB, Pandya AA; Hum Exp Toxicol 13 (5): 307-9 (1994) R22: Date S; J Kumamoto Med Soc 34: 19-82 (1960) as cited in WHO; Environ Health Criteria: Manganese p.55 (1981) R23: WHO; Environ Health Criteria: Manganese p.55 (1981) R24: Date S; J Kumamoto Med Soc 34: 159-82 (1960) as cited in WHO; Environ Health Criteria: Manganese p.55 (1981) R25: Toxicology and Carcinogenesis Studies of Manganese (II) Sulfate Monohydrate in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 428 (1993) NIH Publication No. 94-3159 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R26: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. 215 R27: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-144 R28: Ayotte P, Plaa GL; Hepatology 8 (5): 1069-78 (1988) R29: KIMMEL CA ET AL; TERATOLOGY 10 (3): 293-300 (1974) R30: Duguay AB et al.; Toxicol Sci 53 (1): 150-155 (2000) R31: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 937 R32: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 818 R33: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 383 R34: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 190 R35: 29 CFR 1910.1000 (7/1/2000) R36: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 45 R37: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R38: 40 CFR 61.01(b) (7/1/2000) R39: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R40: 21 CFR 582.5461 (4/1/2000) R41: 21 CFR 184.1461 (4/1/2000) R42: 21 CFR 582.80 (4/1/2000) RS: 23 Record 171 of 1119 in HSDB (through 2003/06) AN: 2189 UD: 200303 RD: Reviewed by SRP on 05/08/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-NITROTOLUENE- SY: *Benzene,-1-methyl-2-nitro-; *O-METHYLNITROBENZENE-; *1-METHYL-2-NITROBENZENE-; *2-METHYLNITROBENZENE-; *2-METHYL-1-NITROBENZENE-; *o-Nitrotoluene-; *o-Nitrotoluol-; *NSC-9577-; *Toluene,-o-nitro- RN: 88-72-2 RELT: 6301 [NITROTOLUENES] MF: *C7-H7-N-O2 SHPN: UN 1664; Nitrotoluenes IMO 6.1; Nitrotoluenes STCC: 49 631 55; Nitrotoluene MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM TOLUENE BY NITRATION AND SEPARATION BY FRACTIONAL DISTILLATION. [R1] *TREATING 2,4-DINITROTOLUENE WITH AMMONIUM SULFIDE FOLLOWED BY DIAZOTIZATION AND BOILING WITH ETHANOL. [R2, 929] FORM: *TECHNICAL [R3] MFS: +E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Deepwater, NJ 08023 [R4] +First Mississippi Corp, Hq, 700 North St, PO Box 1249, Jackson, MS 39205, (601) 948-7550; Subsidiary: First Chemical Corp, (601) 949-0246; Production site: Pascagoula, MS 39567 [R4] USE: *FOR PRODUCTION OF TOLUIDINE, TOLIDINE, FUCHSINE, AND VARIOUS SYNTHETIC DYES. [R1] *MANUFACTURE OF AZO DYES, SULFUR DYES, RUBBER CHEMICALS, AND AGRICULTURAL CHEMICALS. [R2, 930] *Organic synthesis of a wide variety of compounds including petrochemicals, pesticides and pharmaceuticals. [R5, 1249] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 9.08X10+5 G [R6] *(1975) 9.09X10+9 G (CONSUMPTION) [R6] *(1981) 1.3X10+10 G /CALCULATED/ [R7] *(1983) 2.0X10+10 g /(ORTHO- AND PARA- ISOMERS COMBINED)/ [R2, 929] U.S. IMPORTS: *(1983) 1.63X10+8 g [R8] *(1984) 2.73X10+8 g (NITRATED BENZENE, TOLUENE OR NAPHTHALENE) [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOWISH LIQUID @ ORDINARY TEMP [R10]; +Yellow liquid. [Note: A solid below 25 degrees F.] [R11, 232] ODOR: *Weak aromatic [R12, 670]; *Bitter almond [R13]; +Weak, aromatic odor. [R11, 232] BP: *222 DEG C [R10] MP: *-9.5 deg C (needles); -2.9 deg C (crystals) [R14, p. C-520] MW: *137.13 [R10] DEN: *SP GR: 1.1622 @ 19 DEG C/15 DEG C [R10] HTC: *-11,290 Btu/lb= -6,272 cal/g= -262 x 10+5 J/kg [R13] HTV: *12,239.1 gcal/gmole [R14, p. C-676] OWPC: *log Kow= 2.30 [R15] SOL: *ALMOST INSOL IN WATER; SOL IN ALCOHOL, BENZENE, PETROLEUM ETHER [R10]; *SOL IN CHLOROFORM [R16]; *Sol in acetone [R5, 1248]; *0.06 g/100 g of water @ 20 deg C. [R17, 1981.2]; *Water solubility of 652 mg/l at 30 deg C [R18] SPEC: *INDEX OF REFRACTION: 1.5472 @ 20 DEG C/D [R10]; *MAX ABSORPTION (ALCOHOL): 259 NM (LOG E = 3.72); SADTLER REFERENCE NUMBER: 4692 (IR, PRISM); 437 (IR, GRATING) [R19]; *IR: 7426 (Coblentz Society Spectral Collection) [R20]; *UV: 1292 (Sadtler Research Laboratories Spectral Collection) [R20]; *NMR: 676 (Sadtler Research Laboratories Spectral Collection) [R20]; *MASS: 714 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R20] SURF: *In dynes/cm: 42.29, 41.76, and 40.50 @ 15, 19.5, 20, and 30 deg C respectively. [R13] VAPD: +4.73 (air = 1) [R21, p. 325-74] VAP: *1 MM @ 50 DEG C [R22] OCPP: *% IN SATURATED AIR: 0.21 @ 60 DEG C [R16] *Volatile with steam [R5, 1248] *Heat of fusion: 26.76 cal/g [R13] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 2-nitrotoluene stem from its toxicologic properties and explosivity. Toxic by all routes (inhalation, ingestion, and dermal absorption), exposure to this bitter-almond-smelling, yellowish liquid may occur from its use in the manufacture of toluidine, tolidine, fuchsine, azo dyes, sulfur dyes, rubber chemicals, and agricultural chemicals. Effects from exposure may include contact burns to the skin and eyes, headache, weakness, dizziness, nausea, shortness-of-breath, tachycardia, and methemoglobinemia. The onset of symptoms may be delayed up to 4 hours. OSHA has set a time-weighted-average (TWA) limit of 2 ppm as a final rule to become effective December 31, 1992. Local exhaust ventilation should be applied to control airborne 2-nitrotoluene to permissible limits. In activities and situations where over-exposure may occur,wear a positive pressure self-contained breathing apparatus and chemical protective clothing which is specifically recommended by the shipper or manufacturer. If contact should occur, irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes and wash exposed skin thoroughly with soap and water. Contaminated clothing should be removed and left at the site for cleaning. While 2-nitrotoluene does not ignite easily, it may burn with the production of irritating or poisonous gases. Also, containers of this substance may explode violently in the heat of a fire. For fires involving 2-nitrotoluene, extinguish with dry chemical, CO2, water spray, fog, or standard foam. Fight fire from as far a distance as possible, and if fire is advanced, evacuate the area. Dike fire control water. 2-Nitrotoluene should be stored in a cool, dry, well-ventilated area, away from sources of ignition, strong oxidizers, and sulfuric acid. For small spills of 2-nitrotoluene, take up with vermiculite, dry sand, or earth and place into containers for later disposal. Large spills on land should be diked far ahead of the spill and not allowed to enter water sources or sewers. Spills into bodies of water should be trapped at the bottom with sand bag barriers and removed with suction hoses, or treated with activated carbon and the resulting immobilized masses removed with mechanical dredges or lifts. DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R23] FPOT: *LOW WHEN EXPOSED TO HEAT OR OPEN FLAME. [R22] *... Contact with strong oxidizers or sulfuric acid may cause fires ... . /Nitrotoluene/ [R17, 1981.2] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R21, p. 325-74] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R21, p. 325-74] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R21, p. 325-74] FLPT: +106 deg C; 223 deg F (Closed cup) [R21, p. 325-74] FIRP: *Water spray, fog, foam, CO2. [R22] *Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible, solid streams of water may be ineffective. /Nitrotoluene/ [R24] TOXC: *Toxic gases and vapors (such as oxides of nitrogen and carbon monoxide) may be released in a fire involving nitrotoluene. /Nitrotoluene/ [R17, 1981.2] REAC: *Nitrotoluene will attack some forms of plastics, rubber, and coatings. /Nitrotoluene/ [R17, 1981.2] *... Contact with strong oxidizers or sulfuric acid may cause fires and explosions. /Nitrotoluene/ [R17, 1981.2] +Strong oxidizers, sulfuric acid. [R11, 232] ODRT: *0.05 mg/l [R13] SERI: *Slightly irritating to eyes. [R13] +Irritating to the skin, eyes, and respiratory system. [R21, p. 49-99] EQUP: *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any reasonable probability of eye contact. Employees should wash promptly when skin is wet or contaminated. Remove nonimpervious clothing promptly if wet or contaminated. [R12, 671] *Wear self-contained breathing apparatus, protective shoes. [R25] *Respirators may be used when engineering and work practice controls are not technically feasible. ... Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... Respirators permitted are those that have been approved by the Mine Safety and Health Admin ... or by the NIOSH. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (8-inch min), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with solid or liq nitrotoluene. ... Employees should be provided with and required to use dust- and splash-proof safety goggles where solid or liq nitrotoluene may contact the eyes. /Nitrotoluene/ [R17, 1981.2] +Wear appropriate personal protective clothing to prevent skin contact. [R11, 232] +Wear appropriate eye protection to prevent eye contact. [R11, 232] +Recommendations for respirator selection. Max concn for use: 20 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R11, 232] +Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R11, 232] +Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R11, 232] +Recommendations for respirator selection. Max concn for use: 200 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R11, 232] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R11, 232] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R11, 232] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *... A complete respiratory protection program should be instituted which incl regular training, maintenance, inspection, cleaning, and evaluation. ... Non-impervious clothing which becomes contaminated ... should be removed ... and not reworn until nitrotoluene is removed. Eating and smoking should not be permitted in areas where solid nitrotoluene is handled, processed, or stored. Employees who handle solid or liq nitrotoluene should wash ... hands thoroughly with soap or mild detergent and water before eating or smoking. /Nitrotoluene/ [R17, 1981.2] *Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. /Nitrotoluene/ [R24] +Contact lenses should not be worn when working with this chemical. [R11, 232] +The worker should immediately wash the skin when it becomes contaminated. [R11, 232] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R11, 232] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: */Heat contributes/ ... to instability. /Nitrotoluene/ [R17, 1981.2] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R26] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R27] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R28] STRG: +STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM ACIDS, ALKALIES, OXIDIZING MATERIALS, AND REDUCING AGENTS. [R21, p. 49-99] CLUP: *1) Ventilate area of spill or leak. For small quantities of liq nitrotoluene, absorb on paper towels. For small quantities of solid nitrotoluene, sweep onto paper or other suitable material. Remove to safe place (such as fume hood) and burn. Large quantities of liq nitrotoluene can be collected and atomized in suitable combustion chamber equipped with appropriate effluent gas cleaning device. Large quantities of solid nitrotoluene can be reclaimed; ... If not practical, dissolve in flammable solvent (such as alcohol) and atomize in suitable combustion chamber equipped with appropriate effluent gas cleaning device. /Nitrotoluene/ [R17, 1981.3] *Land Spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. /Nitrotoluene/ [R24] *Water Spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom, remove trapped material with suction hoses. If dissolved, apply activated carbon at ten times the spilled amount in region of 10 ppm or greater concentration. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Nitrotoluene/ [R29] DISP: *1) For liq nitrotoluene, by absorbing it in vermiculite, dry sand, earth or similar material. 2) By atomizing liq nitrotoluene in suitable combustion chamber equipped with appropriate effluent gas cleaning device. 3) By making packages of solid nitrotoluene in paper or other suitable material or by dissolving in a flammable solvent (such as alcohol) and burning in a suitable combustion chamber equipped with appropriate effluent gas cleaning device. /Nitrotoluene/ [R17, 1981.3] *The following wastewater treatment technologies have been investigated for 2-Nitrotoluene: Concentration process: Biological treatment. [R30] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of nitrotoluenes. There is limited evidence in experimental animals for the carcinogenicity of 2-nitrotoluene. Overall evaluation: Nitrotoluenes are not classifiable as to their carcinogenicity to humans (Group 3). [R31] MEDS: *Routine checking of lips, tongue, and nail beds of exposed personnel for signs of cyanosis. /Nitrotoluene/ [R25] *The following medical procedures should be made available to each employee who is exposed to nitrotoluene at potentially hazardous levels. Initial Medical Examination: (1) A complete history and physical examination ... to detect preexisting conditions that might place the exposed employee at increased risk ... . Examination of the blood, nervous system, and cardiovascular system should be stressed. (2) Complete blood count: ... Shown to cause methemeglobinemia. Persons with blood disorders may be at increased risk from exposure. Periodic Medical Examination: The aforementioned medical examination should be repeated on an annual basis. /Nitrotoluene/ [R17, 1981.1] *Initial Medical Exam: A complete history and physical exam: ... Exam of blood, nervous system, GI system, and cardiovascular system should be stressed. Skin should be exam for evidence of chronic disorders. ... A complete blood count should be performed, including red cell count, a white cell count, a differential count of stained smear, as well as hemoglobin and hematocrit. Periodic Medical Exam: The ... /initial med exam/ should be repeated on an annual basis. Methemoglobin determinations should be performed if overexposure is suspected or signs and symptoms of toxicity occur. [R17, 1981.1] HTOX: *... Produces methemoglobin causing hypoxia, but of a low potency. It is also suspected of causing anemia in chronic exposures. [R16] *Symptoms: Headache, flushing of face; dizziness, dyspnea, ... cyanosis, nausea, vomiting, muscular weakness, increased pulse and respiratory rate, irritability and convulsions. [R25] *... Cases of poisoning from nitrotoluene are uncommon. Some authorities considered it only slightly toxic, esp in comparison with nitrobenzene. There is some evidence that the different isomers vary ... in toxicity. ... It is stated that nitrotoluene is a methemoglobin former of apparently low grade. /Nitrotoluene/ [R32] *... The onset of symptoms of methemoglobinemia is insidious and may be delayed up to 4 hours; headache is commonly the first symptom and may become quite intense as the severity of methemoglobinemia progresses. ... Cyanosis develops early in the course of intoxication, first the lips, the nose, and the ear lobes, and is usually recognized by fellow workers ... . Until the methemeglobinemia concentration approaches approximately 40%, the individual usually feels well, has no complaints, and will insist that nothing is wrong. ... Over 40% ... weakness and dizziness; at up to 70% ... there may be ataxia, dyspnea on mild exertion, tachycardia, nausea, vomiting, and drowsiness. /Nitrotoluene/ [R17, 1981.1] NTOX: *MOLAR RATIO OF METHEMOGLOBIN FORMED TO DOSE OF O-NITROTOLUOL IN CATS: 0.05. /FROM TABLE/ [R33, 2109] *WHEN ADMIN ORALLY AT DOSES CORRESPONDING TO 0.1-0.2 LD50 VALUES IN RATS FOR 1-3 MO, THE HEMOTOXICITY OF TOLUENE DERIV DECR IN THE ORDER: TRINITROTOLUENE, DINITROTOLUENE, M-NITROTOLUENE, P-NITROTOLUENE, AND O-NITROTOLUENE. THEY CAUSED ANEMIA ACCOMPANIED BY RETICULOCYTOSIS AND A DECR IN THE LEVEL OF SH-GROUPS AND AN INCR IN THAT OF FIBRINOGEN IN THE BLOOD. [R34] *NITROTOLUENE, A MIXT OF THE 3 ISOMERS ADDED TO THE DIET OF RATS, INCR THE NUMBER OF LEUKOCYTES AND THE METHEMOGLOBIN BLOOD LEVEL, DECR THE NUMBER OF ERYTHROCYTES AND THE HEMOGLOBIN LEVEL, IMPAIRED THE ANTITOXIC FUNCTION OF THE LIVER AS MEASURED BY THE INCR IN URINARY HIPPURIC ACID, SHORTENED THE PROTHROMBIN TIME, AND RAISED THE PROTHROMBIN INDEX. THE CONCN OF NITROTOLUENE IN RESERVOIRS MUST BE LOW ENOUGH TO AVOID POSSIBLE TOXIC EFFECTS IN THE DRINKING WATER. /NITROTOLUENE/ [R35] *To determine whether hepatic macromolecular covalent binding of mononitrotoluene isomers to hepatic DNA in vivo was decreased by inhibitors of sulfotransferase, male Fischer 344 rats were given a single oral dose of ring-U-(14)C-labeled 2-, 3-, or 4-nitrotoluene, and were killed at various times thereafter. Livers were removed and analyzed for total and covalently bound radiolabel. Maximal concentrations of total radiolabel were observed between 3 and 12 hr after the dose, and there were no large differences among the 3 isomers in peak concentrations achieved. Covalent binding to hepatic macromols was maximal 12 hrs after administration for all 3 isomers. Thereafter, concn of administration for all 3 isomers. Thereafter, concn of covalently bound 2-nitrotoluene derived material were always 2-6 times higher than those of 3- or 4-nitrotoluene derived material. When DNA was isolated from livers of rats given mononitrotoluene isomers 12 hrs previously, only 2-nitrotoluene was observed to covalently bind at concns above the limits of detection of the assay. The covalent binding of 2-nitrotoluene, but not that of 3- or 4-nitrotoluene, to both total hepatic macromols and DNA was markedly decreased by prior administration of pentachlorophenol or 2,6-dichloro-4-nitrophenol. Covalent binding to hepatic DNA was decreased by > 96%. Thus, 2-nitrotoluene, but not 3- or 4-nitrotoluene, induces DNA excision repair. Furthermore, 2-nitrotoluene, like the hepatocarcinogen 2,6-dinitrotoluene, may require the action of sulfotransferase for its conversion to a species capable of covalently binding to hepatic DNA. [R36] *The mutagenicities of the o, m, and p-isomers of nitrotoluene ... were tested with or without S9 mix and norharman in the Salmonella assay system. None of the compounds were mutagenic without norharman. ... The induction of mutagenesis with norharman was strong for the o-isomer, weak for p-isomer, and was not observed for the m-isomer. [R37] *Chemical-induced DNA repair, as measured specific genotoxic activity in lab animals ... In rat hepatocytes, 2-nitrotoluene ... induced DNA repair. 2-Nitrotoluene produced a positive response in hepatocytes from Charles River associated flora-inoculated rats, whereas no DNA repair was observed in hepatocytes isolated from germ-free animals. [R38] +... 2-YEAR STUDY IN RATS: ... In the core study, Groups of 60 male and 60 female F344/N rats were fed diets containing 625, 1,250 or 2,000 ppm o-nitrotoluene (equivalent to avg daily doses of approx 25, 50 or 90 mg/kg o-nitrotoluene/kg bw to males and 30, 60 or 100 mg/kg to females for 105 wk. In a 3 month stop exposure study, 70 male rats were fed diets containing 2,000 or 5,000 ppm o-nitrotoluene (equivalent to avg daily doses of approx 125 or 315 mg/kg) for 13 wk followed by undosed feed for the remainder of the study. A group of 70 male rats receiving undosed feed served as control group for both male rat studies, 60 female rats receiving undosed feed were the control group for the female core study. Ten control males and 10 males from each stop exposure group were sacrificed at 3 months. ... 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 1,250, 2,500 or 5,000 ppm o-nitrotoluene (equivalent to avg daily doses of approx 165, 360 or 700 mg/kg to males and 150, 320 or 710 mg/kg to females) for 105 wk. CONCLUSIONS: Under the conditions of these 2-year feed studies there was clear evidence of carcinogenic activity of o-nitrotoluene in male F344/N rats based on incr incidences of malignant mesothelioma, subcutaneous skin neoplams, mammary gland adenofibroma and liver neoplasms. The incr incidences of lung neoplasms in male rats were also considered to be exposure related. There was clear evidence of carcinogenic activity of o-nitrotoluene in female F344/N rats based on incr incidences of subcutaneous skin neoplasms and mammary gland fibroadenoma. The incr incidence of hepatocellular adenoma in female rats was also considered exposure related. There was equivocal evidence of carcinogenic activity of o-nitrotoluene in male and female mice based incr incidences of hemangiosarcoma, carcinoma of the intestine (cecum) and hepatocellular neoplasms (females only). [R39] NTP: +... 2-YEAR STUDY IN RATS: ... In the core study, Groups of 60 male and 60 female F344/N rats were fed diets containing 625, 1,250 or 2,000 ppm o-nitrotoluene (equivalent to avg daily doses of approx 25, 50 or 90 mg/kg o-nitrotoluene/kg bw to males and 30, 60 or 100 mg/kg to females for 105 wk. In a 3 month stop exposure study, 70 male rats were fed diets containing 2,000 or 5,000 ppm o-nitrotoluene (equivalent to avg daily doses of approx 125 or 315 mg/kg) for 13 wk followed by undosed feed for the remainder of the study. A group of 70 male rats receiving undosed feed served as control group for both male rat studies, 60 female rats receiving undosed feed were the control group for the female core study. Ten control males and 10 males from each stop exposure group were sacrificed at 3 months. ... 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 0, 1,250, 2,500 or 5,000 ppm o-nitrotoluene (equivalent to avg daily doses of approx 165, 360 or 700 mg/kg to males and 150, 320 or 710 mg/kg to females) for 105 wk. CONCLUSIONS: Under the conditions of these 2-year feed studies there was clear evidence of carcinogenic activity of o-nitrotoluene in male F344/N rats based on incr incidences of malignant mesothelioma, subcutaneous skin neoplams, mammary gland adenofibroma and liver neoplasms. The incr incidences of lung neoplasms in male rats were also considered to be exposure related. There was clear evidence of carcinogenic activity of o-nitrotoluene in female F344/N rats based on incr incidences of subcutaneous skin neoplasms and mammary gland fibroadenoma. The incr incidence of hepatocellular adenoma in female rats was also considered exposure related. There was equivocal evidence of carcinogenic activity of o-nitrotoluene in male and female mice based incr incidences of hemangiosarcoma, carcinoma of the intestine (cecum) and hepatocellular neoplasms (females only). [R39] POPL: *Preclude from exposure those individuals with anemia, cardiovascular or pulmonary diseases. [R25] *Persons with blood disorders may be at increased risk from exposure. /Nitrotoluene/ [R17, 1981.1] ADE: *IT MAY BE ABSORBED THROUGH THE INTACT SKIN AND THROUGH THE RESP TRACT. [R33, 2148] METB: *... The metabolism /of 2-nitrotoluene/ was compared in hepatocytes isolated from male Fischer 344 rats. ... Hepatocytes were incubated with U-(14)C 2-nitrotoluene, ... at concentrations from 25-1000 uM for up to 60 minutes. ... 2-Nitrotoluene was converted to 2-nitrobenzyl alcohol (52%), 2-nitrobenzyl alcohol glucuronide (28%), and unidentified metabolite (20%) and 2-nitrobenzoic (3%). ... Incubation of 2-nitrotoluene (1mM) with rat hepatic microsomes produced only the respective nitrobenzyl alcohols ... . [R40] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *The major sources of release of 2-nitrotoluene to the environment appears to be production and use facilites and plants which produce this compound as a by-product. If released to soil, 2-nitrotoluene should be resistant to oxidation and chemical hydrolysis. One study on 2-nitrotoluene under aerobic conditions in a mixed culture of soil microorganisms in aqueous mineral salts media resulted in persistence of > 64 days. 2-Nitrotoluene is expected to be moderately to highly mobile in soil and volatilize slowly from dry soil surfaces. If released to water, 2-nitrotoluene would be susceptible to direct photolysis, indirect photolysis (half-life < 1 hour in river water containing a high concn of humic substances), volatilization (estimated half-life 21 hours in water 1 m deep flowing 1 m/sec with a wind speed of 3 m/sec) and possibly aerobic biodegradation provided suitable acclimation has taken place. Oxidation chemical hydrolysis, adsorption to suspended solids and sediments and bioacculmulation in aquatic organisms are not expected to be significant fate processes. Based on monitoring data, the half-life of 2-nitrotoluene in a river 4 to 5 m deep has been estimated to be 3.2 days. If released to the atmosphere, 2-nitrotoluene is expected to exist almost entirely in the vapor phase. The dominat removal mechanism would be direct photolysis (half-life < 5 hours). 2-Methyl-6-nitrophenol and 2-methyl-4-nitrophenol are photoproducts of 2-nitrotoluene. The most probable routes of human exposure to 2-nitrotoluene are inhalation and dermal contact by workers involved in the production and use of this compound, dinitrotoluenes and trinitrotoluenes. (SRC) ARTS: *In general, the major sources of release of nitroaromatic compounds to the environment appears to be production and use facilities and plants which produce these compounds as by-products(1). 2-Nitrotoluene may also enter the environment from the disposal of waste products which contain this compound(SRC). [R41] FATE: *TERRESTRIAL FATE: If released to soil, 2-nitrotoluene may be resistant to oxidation and chemical hydrolysis. One study on 2-nitrotoluene under aerobic conditions in a mixed culture of soil microorganisms in aqueous mineral salts media resulted in persistence of > 64 days. 2-Nitrotoluene is predicted to be moderately to highly mobile in soil and volatilize slowly from dry soil surfaces. (SRC) *AQUATIC FATE: If released to water, 2-nitrotoluene may be susceptible to direct photolysis, indirect photolysis (half-life < 1 hr in river water containing a high concn of humic substances), volatilization (estimated half-life 21 hours in water 1 m deep flowing 1 m/sec with a wind speed of 3 m/sec) and possibly aerobic biodegradation, provided suitable acclimation has taken place. Adsorption to suspended solids and sediments and bioaccumulation in aquatic organisms are not expected to be significant fate processes. Based on monitoring data, the half-life of 2-nitrotoluene in a river 4 to 5 m deep has been estimated to be 3.2 days(1). [R42] *ATMOSPHERIC FATE: If released to the atmosphere 2-nitrotoluene is expected to exist entirely in the vapor phase. The dominant removal mechanisms would be reaction with photochemically generated hydroxyl radicals (estimated half-life 8 hr) and direct photolysis. 2-Methyl-6-nitrophenol and 2-methyl-4-nitrophenol are photoproducts of 2-nitrotoluene. (SRC) BIOD: *100 ppm 2-nitrotoluene inoculated with 30 ppm activated sludge under aerobic conditions at 25 deg C was < 30% degraded after 2 weeks(1,2). 2-Nitrotoluene (200 mg/l COD) inoculated with adapted activated sludge under aerobic conditions at 20 deg C underwent 98% degradation in 5 days as measured by COD removal(3). 2-Nitrotoluene should be degraded by biological sewage treatment provided suitable acclimation can be achieved(4). 10 ug/l 2-nitrotoluene inoculated with a mixed culture of soil microorganisms under aerobic conditions in aqueous mineral salts media persisted > 64 days as measured by UV absorbancy(5). In general, anaerobic biodegradation of nitroaromatic compounds results in the reduction of the nitro group to an amino group(6). [R43] ABIO: *Chemical hydrolysis and oxidation of 2-nitrotoluene are not expected to be important removal processes since this compound contains no functional groups which are susceptible to these types of reactions(1,SRC). Absorption of UV light in the environmentally significant range (> 290 nm) by 2-nitrotoluene in cyclohexane(2), indicates that the potential exists for photolysis in water and air(SRC). Irradiation (at > 300 nm) of 2-nitrotoluene vapor in air for 5 hour resulted in 79% loss of the 2-nitrotoluene initially present and formation of 2-methyl-6-nitrophenol (6.1% yield) and 2-methyl-4-nitrophenol (7.5% yield)(3). 2-Nitrotoluene in triethylamine underwent 100% conversion when irradiated (wavelengths > 290 nm) for 3 hours forming aniline (32%), azoxybenzene (5%), azobenzene (2.5%), and 2-hydroxyazo compound (10%)(4). The mid day half-life of 2-nitrotoluene in Aucilla River water due to indirect photolysis has been calculated to be 45 minutes using an experimentally determined reaction rate constant of 0.92 l/hr (5) (Aucilla River water contains a high concn of humic substances, which appears to act as a photosensitizer(5)). The half-life for 2-nitrotoluene vapor reacting with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 8.0 hr based on a reaction rate constant of 3.0X10-11 cu cm/molecules-sec at 25 deg C and and ambient hydroxyl radical concn of 8.0X10-5 molecules/cu cm(6). [R44] BIOC: *The bioconcentration factor (BCF) for 2-nitrotoluene has been experimentally determined to be less than 100 in carp (Carprinus carpio)(1,2). BCF values of 33 and 16 have been calculated based on a log octanol/water partition coefficient (log Kow) of 2.30 and a measured water solubility of 652 mg/L at 30 deg C(3,4,5,SRC). These BCF values suggest that 2-nitrotoluene will not bioaccumulate significantly in aquatic organisms(SRC). [R45] KOC: *The soil adsorption coefficient for 2-nitrotoluene has been calculated to be 425 and 124 based on a log octanol/water partition coefficient (log Kow) of 2.30 and a measured water solubility of 652 mg/l at 30 deg Crespectively (1,2,3,SRC). These Koc values suggest that 2-nitrotoluene would be moderately to highly mobile in soil and would adsorb slightly to suspended solids and sediments in water(4,SRC). [R46] VWS: *The volatilization half-life of o-nitrotoluene from water 1 m deep, flowing 1 m/sec with a wind speed of 3 m/sec has been calculated to be 21 hr based on a measured Henry's Law constant of 5.6X10-5 atm-cu m/mole at 25 deg C(1,2,SRC). A vapor pressure of 0.1 mm Hg at 20 deg C for 2-nitrotoluene suggests that this compound will volatilize slowly from dry soil surfaces(2,SRC). [R47] WATC: *SURFACE WATER: During 1974, 2- and 4-nitrotoluene were detected in the Waal River (Netherlands), avg concn 4.5 ug/l, max concn 18.1 ug/l, and in the Maas River (Netherlands), max concn 0.3 ug/l(1). 2-Nitrotoluene has been detected in Rhine River water at a concn of 10 ug/l(2). [R48] *DRINKING WATER: 2-Nitrotoluene has been qualitatively identified in German drinking water(1). [R49] EFFL: *2-Nitrotoluene has been detected in the effluent from a plant manufacturing trinitrotoluene in Radford, VA, 0.32-16 mg/l detected(1). 2-Nitrotoluene has been detected in the wastewater resulting from the production and purification of 2,4,6-trinitrotoluene, 0.02-0.14 mg/l detected, 38% samples pos(2). 2-Nitrotoluene has also been detected in raw effluent from a plant manufacturing dinitrotoluene, 7.8 mg/l detected, and in a waste treatment lagoon of a paper mill(1). [R50] ATMC: *2-Nitrotoluene has been detected in the ambient air at the Dupont plant in Deepwater, NJ at a concn of 47 ng/cu m(1). [R51] RTEX: *The most probable route of human exposure to 2-nitrotoluene are inhalation and dermal contact of workers involved in the production and use of this compound, dinitrotoluenes, and trinitrotoluene. (SRC) *A National Occupational Hazard Survey (1973-74) estimates that 285 workers are exposed to 2-nitrotoluene(1). [R52] BODY: *Under controlled experimental conditions 2-nitrotoluene was detected in human expired air, 387 samples from 54 people, 19.1% samples pos, 0.04 ng/l mean concn(1). [R53] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +200 ppm [R11, 232] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (30 mg/cu m). Skin Designation. /Nitrotoluene, all isomers/ [R54] +Vacated 1989 OSHA PEL TWA 2 ppm (11 mg/cu m), skin designation, is still enforced in some states. /Nitrotoluene (o-, m-, p- isomers)/ [R11, 369] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2 ppm (11 mg/cu m), skin. [R11, 232] TLV: +8 hr Time Weighted Avg (TWA): 2 ppm, skin. /Nitrotoluene, all isomers/ [R55, 2002.45] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Nitrotoluene, all isomers/ [R55, 2002.6] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R55, 2002.91] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R56] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R57] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2005. Analyte: o-Nitrotoluene. Matrix: Air. Sampler: Solid sorbent tube (silica gel, 150 mg/75 mg). Flow Rate: 0.01 to 0.21 l/min. Sample Size: 1 to 30 l. Shipment: Routine. Sample Stability: Unknown. [R58] ALAB: *KNOWN MIXT OF O-NITROTOLUENE, M-NITROTOLUENE, AND P-NITROTOLUENE IN AIR OF INDUSTRIAL INSTALLATIONS WERE ANALYZED BY GAS CHROMATOGRAPHY. THE MINIMUM CONCN OF THE ISOMERS WAS 1X10-6 G/ML, TIME FOR EACH DETERMINATION 10 MIN, AND THE ABSOLUTE ERROR 9%. [R59] *A METHOD WAS DEVELOPED FOR DETERMINING O- AND P-NITROTOLUENE IN SOLN AND IN AIR BASED ON REDUCTION TO TOLUIDINE. [R60] *NIOSH Method 2005. Analyte: o-Nitrotoluene. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. For o-nitrotoluene, this method has an estimated detection limit of 0.0008 for a 20 liter sample. The overall precision/RSD is 0.062 and the recovery is not given. Applicability: The working range is 0.25 to 52 mg/cu m for a 25 l air sample. Interferences: None identified. [R61] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of o-, m-, and p-Nitrotoluenes Administered in Dosed Feed to F344/N Rats and B6C3F1 Mice Toxicity Rpt Series No. 23 NIH Publication No. 93-3346 (1992) DHHS/NTP; NTP Technical Report on Comparative Toxicity Studies of o-Nitrotoluene and o-Toluidine Hydrochloride Administered in Feed to Male F344/N Rats. Toxicity Rpt Series No. 44 NIH Publication No. 96-3936 (1996) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that o-nitrotoluene is on the list of post peer review technical reports in progress. Route: dosed-feed; Species: rats and mice. NTP TR No 504. [R62] SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 833 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: CHEMCYCLOPEDIA 1985 p.103 R4: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 809 R5: Keith, L.H., D.B. Walters, (eds.). Compendium of Safety Data Sheets for Research and Industrial Chemicals. Parts I,II,and III. Deerfield Beach, FL: VCH Publishers, 1985. R6: SRI R7: KIRK-OTHMER, ENCYC CHEM TECH 3RD ED 1978-PRESENT V15 p.929 R8: USITC. IMPORTS OF BENZENOID CHEMICALS AND PRODUCTS 1983 p.24 R9: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS, 1984 p.1-329 R10: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1051 R11: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R12: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R13: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R14: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R15: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, June 1984. 76 R16: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2473 R17: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R18: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 865 R19: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-527 R20: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 369 R21: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R22: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1884 R23: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-152 R24: Bureau of Explosives; Emergency Handling of Haz Matl in Surface Trans p.375 (1981) R25: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 381 R26: 49 CFR 171.2 (7/1/96) R27: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 187 R28: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6187 (1988) R29: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.501 R30: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-46 (1982) R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 66 430 (1996) R32: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.444 R33: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R34: KOVALENKO II; FARMAKOL TOKSIKOL (KIEV) 8: 137-40 (1973) R35: KOSACHEVSKAYA PI; VRACH DELO (2): 104-7 (1967) R36: Rickert DE et al; Chem-Biol Interact 52 (2): 131-9 (1984) R37: Susuki J et al; Mutat Res 120 (2-3): 105-110 (1983) R38: Butterworth BE et al; Banbury Rep 13 (Indic Genotoxic Expose): 101-14 (1982) R39: Toxicology and Carcinogenesis Studies of o-Nitrotoluene in F344/N Rats and B6C3F1 Mice p.7-9 Technical Report Series No. 504 (2002) NIH Publication No. 02-4438 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R40: Debethizy JD, Rickert DE; Drug Metab Dispos 12 (1): 45-50 (1984) R41: (1) Howard PH et al; Investigation of Selected Environ Contam, Nitroaromatics USEPA 560/2-76-010 (1976) R42: (1) Zoeteman et al; Chemosphere 9: 231-49 (1980) R43: (1) Kawasaki M Ecotox Env Safety 4: 444-54 (1980) (2) Sasaki S; in Aquatic Pollut, Transformation and Bio Effects, Hutzinger O, Van Leytoeld LH, Zoeteman BCJ eds (1978) (3) Pitter P; Water Res 10: 231-5 (1976) (4) Thom NS, Agg AR; Proc R Soc Lond B 189: 347-57 (5) Alexander M, Lustigman BK; J Agric Food Chem 14: 410-3 (1966) (6) McCormick NG et al; Appl Environ Microb 31: 949-58 (1976) R44: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 7-4 (1982) (2) Sadtler Research Lab; Sadtler Standard UV Specta no 1292 (1961) (3) Nojima K, Kanno S; Chemosphere 6: 371-6 (1977) (4) Barltrop JA, Bunce NJ; J Chem Soc C: 1467-74 (1968) (5) Zepp RG et al; Fresenius Z Anal Chem 319: 119-25 (6) GEMS; Graphical Exposure Modeling System. FAP. Fate of Atmos Pollut (1986) R45: (1) Kawasaki M; Ecotox Env Safety 4: 444-54 (1980) (2) Sasaki S; pp 283-98 in Aquatic Pollut, Transformation and Bio Effects, Hutzinger O, Van Leytoeld LH, Zoeteman BCJ eds (1978) (3) Hansch C, Leo AJ; Medchem Project Issue No 26 Pomona College Claremont CA (1985) (4) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY (1983) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods McGraw-Hill NY pp 5-5 (1982) R46: (1) Hansch C, Leo AJ; Medchem Project Issue No 26 Pomona College Claremont CA (1985) (2) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 2nd ed Van Nostrand Reinhold NY (1983) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. McGraw-Hill NY pp 4-9 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R47: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-7 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. McGraw-Hill NY Chpt.15 (1982) R48: (1) Meijers AP, Van Der Leer CR; Water Res 597-604 (1976) (2) Piet GJ, Morra CF; pp 31-42 in Artificial Groundwater Recharge, Huisman L, Olsthorn Tn eds (1983) R49: (1) Kool HJ et al; Criteria Rev Env Control 12: 307-57 (1982) R50: (1) Howard PH et al; Investigation of Selected Potential Environ Contam, Nitroaromatics USEPA 560/2-76-010 (1976) (2) Spanggord RJ et al; Environ Sci Tech 16: 229-32 (1982) R51: (1) Pellizari ED; Quantification of Chlorinated Hydrocarbons in Previously Collected Air Samples USEPA 450/3-78-112 (1978) R52: (1) NIOSH; National Occupational Hazard Survey (1974) R53: (1) Krotoszynski BW et al; J Anal Tox 3: 225-30 (1979) R54: 29 CFR 1910.1000 (7/1/98) R55: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R56: 40 CFR 116.4 (7/1/90) R57: 40 CFR 302.4 (7/1/90) R58: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.2005 R59: IVANYUK EG, KOLIEVSKAYA YA; ZAVOD LAB 43 (2): 157-8 (1977) R60: KURENKO LT; GIG TR PROF ZABOL 16 (4): 60-1 (1972) R61: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2005-1 R62: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 53 Record 172 of 1119 in HSDB (through 2003/06) AN: 2505 UD: 200303 RD: Reviewed by SRP on 9/9/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 8-METHOXYPSORALEN- SY: *AMMOIDIN-; *5-BENZOFURANACRYLIC-ACID,-6-HYDROXY-7-METHOXY-,-DELTA-LACTONE-; *7H-FURO(3,2-G)(1)BENZOPYRAN-7-ONE, 9-METHOXY-; *6-HYDROXY-7-METHOXY-5-BENZOFURANACRYLIC-ACID-DELTA-LACTONE-; *MELADININ-; *MELADININE-; *MELADOXEN-; *MELOXINE-; *METHOXA-DOME-; *METHOXALEN-; +METHOXSALEN-; *8-METHOXY[FURANO-3',2':6,7-COUMARIN; *9-METHOXY-7H-FURO(3,2-G)(1)BENZOPYRAN-7-ONE; *8-METHOXY-2',3',6,7-FUROCOUMARIN-; *8-METHOXY-4',5':6,7-FUROCOUMARIN; *9-METHOXYPSORALEN-; *8-METHOXYPSORALENE-; *8-MOP-; *8-MOP-Capsules-; *8-MP-; *NCI-C55903-; *OXORALEN-ULTRA-; *Oxsoralan-; *OXSORALEN-; *Oxsoralen-Ultra-; *OXYPSORALEN-; *Psoralon-MOP-; *XANTHOTOXIN-; *XANTHOTOXINE- RN: 298-81-7 MF: *C12-H8-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PROBABLY BY REACTION OF GERANOXYPSORALEN WITH SULFURIC ACID, FOLLOWED BY TREATMENT WITH DIAZOMETHANE. OCCURS NATURALLY IN SEVERAL PLANTS (EG, PSORALES CORYFOLIA). [R1] FORM: *METHOXSALEN IS IN 10 MG CAPSULES (OXORALEN-ULTRA). ... A TOPICAL 1% LOTION OF METHOXSALEN (OXSORALEN) IS ALSO AVAILABLE. [R2] *Capsules, 10 mg. Lotion (to be applied by a physician and not to be dispensed to patients), 1%. [R3] *Topical Lotion 1%, Oxsoralen (with acetone, alcohol 71%, and propylene glycol), ICN [R4, 2270] *Oral Capsules 10 mg, 8-MOP Capsules (with tartrazine), ICN; Capsules, liquid-filled, Oxsoralen-Ultra, ICN [R4, 2270] MFS: *ICN Pharmaceuticals Inc, ICN Plaza, 3300 Hyland Ave, Costa Mesa, CA 92626 (714) 545-0100, (800) 556-1937, (800) 331-2331 (in CA) [R4, 2270] USE: *SUNTAN ACCELERATOR, SUNBURN PROTECTOR [R5] *Photoactive agent [R3] +MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *SILKY NEEDLES FROM HOT WATER OR BENZENE + PETROLEUM ETHER [R6]; *LONG RHOMBIC PRISMS FROM ALCOHOL + ETHER [R6]; *WHITE TO CREAM-COLORED, FLUFFY, NEEDLE-LIKE CRYSTALS [R4, 2266] ODOR: *ODORLESS [R6] TAST: *BITTER TASTE [R6] MP: *148 DEG C [R7] MW: *216.18 [R6] PH: *PH 5.5 [R6] SOL: *PRACTICALLY INSOL IN COLD WATER; SPARINGLY SOL IN BOILING WATER, LIQ PETROLATUM, ETHER; SOL IN BOILING ALC, ACETONE, ACETIC ACID, VEGETABLE FIXED OILS, PROPYLENE GLYCOL, BENZENE; FREELY SOL IN CHLOROFORM [R6]; *Sol in alc [R4, 2266] SPEC: *MAX ABSORPTION (ALCOHOL): 249 NM (LOG E= 4.35); 300 NM (LOG E= 4.06) [R8]; *UV: 8-229 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R9]; *MASS: 4497 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R9] OCPP: *SOL IN AQ ALKALIES WITH RING CLEAVAGE, BUT IS RECONSTITUTED UPON NEUTRALIZATION [R6] *Methoxsalen is a psoralen derivative which is structurally and pharmacologically related to trioxsalen. [R4, 2266] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EXPL: *Combustible [R5] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R10] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R11, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R11, 1979.11] SSL: *Methoxsalen conventional capsules and topical lotion should be protected from light and stored in well-closed, light-resistant containers at 15-30 deg C. [R4, 2266] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R11, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R11, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R11, 1979.13] *Methoxsalen conventional capsules and topical lotion should be protected from light and stored in well-closed, light-resistant containers at 15-30 deg C. [R4, 2266] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R11, 1979.15] DISP: *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R11, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R11, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R11, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. [R12] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R11, 1979.23] HTOX: *HIGH CONCN OF TOPICAL METHOXSALEN AND OVEREXPOSURE UVA RADIATION CAN CAUSE TOXIC REACTIONS (SEVERE ERYTHEMA AND BLISTERING). [R13] *SIDE EFFECTS AFTER ORAL THERAPY ARE USUALLY MILD AND INCL GASTRIC DISCOMFORT, NAUSEA, NERVOUSNESS, INSOMNIA, AND DEPRESSION. TOPICAL APPLICATION FOLLOWED BY OVEREXPOSURE TO UV LIGHT MAY RESULT IN SEVERE BURNS. [R14] *... WHEN EXCESSIVE DOSES ARE TAKEN LIVER IS INJURED. [R15] *A 20 YR OLD MALE PATIENTSTREATED TOPICALLY WITH 8-METHOXYPSORALEN AND LONG WAVE UV LIGHT DEVELOPED CONTACT ALLERGY AFTER 6TH TREATMENT (DAY 17). [R16] *73 YR OLD MAN TREATED WITH SYSTEMIC PSORALEN AND LONG WAVE UV LIGHT DEVELOPED PRELEUKEMIC CONDITION AFTER 1 YEAR. [R17] *ACUTE MYELOID LEUKEMIA DEVELOPED IN PATIENT TREATED WITH 8-METHOXYPSORALEN AND LONG WAVE UV LIGHT 2 YR EARLIER. [R18] *CELL KILLING AND INDUCTION OF MUTATION IN DIVIDING AND NON-DIVIDING HUMAN SKIN FIBROBLASTS RESULTED FROM TREATMENT WITH 8-METHOXYPSORALEN AND LONG WAVE UV IRRADIATION. CYTOTOXIC EFFECT WAS HIGHLY DEPENDENT UPON DURATION OF LONG WAVE UV EXPOSURE. [R19] *OF 52 PATIENTS UNDER CONTINUED TREATMENT WITH METHOXSALEN AND LONG WAVE UV IRRADIATION, 6 SUBJECTS WHO HAD COMPLETED 1 YR AND 6 WHO HAD COMPLETED 2 YR HAD SMALL SUPERFICIAL DERMAL AMYLOID DEPOSITS. [R20] *... The side effects from 41,000 courses of treatment with methoxsalen plus UV light /were summarized/; erythema or burns occurred in about 10%, pruritis in 14% and nausea in 3%; headache and dizziness were also recorded. In a similar study, reactivation of peptic ulcer symptoms was reported in 3 patients who had a history of previous ulceration. [R21] *Damage to the nail beds was induced by methoxsalen and sunlight in 2 patients. Histological examination of the nail beds showed that the photosensitizing effect of the drug induced the generation of many multinucleated epithelial cells and fibroblasts in the dermis. [R22] *Three of 20 healthy volunteers given increasing doses of topically applied 1% methoxsalen in hydrophillic ointment 3 times a week plus UV light developed photoallergy. [R22] *The methoxsalen concentrations and UV irradiation conditions to which human lymphocytes are exposed therapeutically in vivo have been shown to be too low to induce observable numbers of sister chromatid exchanges. However, more point mutations, as indicated by the increased incidence of 6-thioguanine-resistant lymphocytes, were observed in patients treated with psoralen drugs and UV irradiation than in healthy controls. [R23] *Because oral methoxsalen and UV-A radiation therapy is mutagenic, concern exists about the potential for teratogenic effects resulting from the use of this therapy at the time of conception and during pregnancy. After 12.8 yr of prospective study, the pregnancy outcomes among 1380 patients (892 men and 488 women) were documented who received UV-A radiation treatments. Ninety four men reported 167 pregnancies in their partners, and 93 women reported 159 pregnancies. For 34% of pregnancies among partners of male patients, the man received UV-A radiation therapy near the time of conception. Nineteen percent of female patients reported exposure to UV-A radiation at the time of conception or during pregnancy. Induced and spontaneous abortions were reported as the outcome of pregnancy more often by female than by male patients (12% vs 30%). Two congenital malformations and two stillbirths occurred, an incidence not significantly different from that expected for the general population. Although the power of this study to detect an increase in the risk of specific defects is limited, data show no evidence to suggest that UV-A radiation is a potent teratogen. [R24] NTOX: *... GUINEA PIGS ... ADMIN ... 40 TO 100 MG IP ... PLUS EXPOSURE TO LONG UV IRRADIATION ... DIFFERENCE BETWEEN WHITE AND BLACK GUINEA PIGS IN SEVERITY OF RESPONSE WAS OBSERVED. IN BLACK ANIMALS CORNEA AND LENS WERE ... DAMAGED, BUT PIGMENTED SKIN AND IRIS WERE RELATIVELY UNAFFECTED. [R25] *... MICE ... ADMIN ... 40 TO 100 MG IP ... PLUS EXPOSURE TO LONG UV IRRADIATION ... DEVELOPED CATARACTS. THEIR IRISES BECAME DEVASCULARIZED AND PUPILS BECAME ENLARGED. [R25] *SYSTEMIC ADMIN OF 8-METHOXYPSORALEN THROUGH IP INJECTION, FOLLOWED BY ACTIVATION WITH TOPICAL NEAR-ULTRAVIOLET LIGHT RESULTED IN INCR IN SISTER CHROMATID EXCHANGE IN CHINESE HAMSTER CHEEK POUCH MUCOSAL CELLS. [R26] *CELLS EXHIBITED MIXOPLOIDY; SMALL NUMBER OF THESE CELLS CAUSED SPINDEL CELL SARCOMAS IN HAMSTER CHEEK POUCHES, AND PRODUCED TUMORS IN NEWBORN HAMSTERS; AND GENERATION TIMES WERE CHARACTERISTIC OF TRANSFORMED CELLS. [R27] *FEMALE DUTCH BELTED RABBITS GIVEN METHOXSALEN (12 MG/KG) ORALLY AND 1 HR LATER EXPOSED TO LONG WAVE UV RADIATION FOR 2 OR 8 HR 5 DAYS EACH WK FOR 18 MO, SKIN SHOWED SIGNS OF ACUTE AND CHRONIC PHOTOTOXICITY. LIVER, KIDNEY AND HEMATOLOGIC FUNCTIONS WERE NORMAL, NO CATARACTS. [R28] *MICE TREATED WITH VARIOUS REGIMENS OF 8-METHOXYPSORALEN FOLLOWED BY EXPOSURE TO LONG WAVE UV LIGHT ARE RENDERED TUMOR-SUSCEPTIBLE WHEN CHALLENGED WITH SHORTWAVE UV LIGHT INDUCED REGRESSOR TUMORS. [R29] *COMBINED TREATMENT WITH 8-METHOXYPSORALEN AND LONG WAVE ULTRAVIOLET IRRADIATION INDUCED CELL KILLING AND MUTATION. [R30] *A group of 24 female ICR Swiss mice were given applications of a 0.1% solution of methoxsalen in ethanol on the ears and exposed to whole body UV irradiation (280-360 nm) on 5 days a week for 25 weeks, at which time the incidence of ear tumors (epidermal papillomas and carcinomas) was 52% versus 20% in a control group exposed to UV light only. [R31] *No statistically signifiant increase in the incidence of skin tumors or tumors of internal organs was observed in either sex of mice of various strains given methoxsalen orally (0.6-40 mg/kg body weight or 200-1000 mg/kg diet daily) for 4-12 months alone or in combination with UV irradiation (250-400 nm). [R31] *Two groups of 20 SKH: hairless mice were given daily skin applications of 40 ug of a 0.01% solution of methoxsalen in methanol, or of 40 ug of methanol only, 30-60 minutes before a whole body 10 minute exposure to ultra violet light (300-400 nm) on 5 days a week. Skin tumors, most of which developed at the site of application near the midline of the back, were seen in 15/30 and 12/24 animals (i.e., 50%) in the two groups at 14 and 30 weeks, respectively. The number of tumors per mouse was significantly higher in animals given methoxsalen plus ultra violet light. Most of the tumors were squamous cell carcinomas; others were fibrosarcomas, lymphosarcomas, sebaceous adenomas and hemangiomas. [R31] *Chronic toxicity studies in mice revealed that small ip doses (12 mg/kg body weight daily for 1 year) of a suspension (of unspecified particle size) of methoxsalen in saline induced no detectable changes; however, ip injection of 4 mg/kg body weight methoxsalen in saline followed by exposure to long wave ultra violet irradition (320-400 nm) resulted in severe toxic effects including erythema, burns and liver damage. [R32] *Daily ip injections of 0.4 mg methoxsalen to 24 female ICR Swiss mice 1 hour before exposure to ultra violet light (280-360 nm) on 5 days a week for 25 weeks resulted in an increased incidence of ear tumors (epidermal papillomas and carcinomas): 68% of mice developed tumors versus 20% of controls exposed only to ultra violet light. [R33] *Accounts of animal studies indicating danger to the eyes from photosensitizationby methoxsalen began to appear in 1960 when severe reactions were reported in guinea pigs given very large doses, 40 mg of methoxsalen by intraperitoneal injection one hour before they were exposed to long wavelength UV continuously for 24 hours. White guinea pigs developed ulceration of the lids, edema of the corneas, congestion of iris vessels, permanently dilated pupils, and multiple anterior cortical punctate opacities in the lenses. (The retinas were not evaluated.) In black guinea pigs the lids and iris were less damaged. Guinea pigs given 80 to 100 mg of methoxsalen/kg showed no damage to the eyes unless they were also exposed to long wavelength UV. [R34] +... Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity of 8-methoxypsoralen (without ultraviolet radiation) for male F344/N rats, as shown by incr incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney and carcinomas of the Zymbal gland. Subcutaneous tissue fibromas and alveolar/bronchiolar adenomas of the lung in male F344/N rats may have been related to chemical administration. Dose related nonneoplastic lesions in male F344/N rats included increased severity of nephropathy and mineralization of the kidney and forestomach lesions. There was no evidence of carcinogenic activity of 8-methoxypsoralen for female F344/N rats given the chemical at 37.5 or 75 mg/kg/day for 2 yr. [R35] NTP: +... Based on these results, 2 yr studies were conducted by admin 0, 37.5 or 75 mg/kg 8-methoxypsoralen in corn oil by gavage, 5 days/wk for 103 wk, to groups of 50 F344/N rats of each sex. ... Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity of 8-methoxypsoralen (without ultraviolet radiation) for male F344/N rats, as shown by incr incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney and carcinomas of the Zymbal gland. Subcutaneous tissue fibromas and alveolar/bronchiolar adenomas of the lung in male F344/N rats may have been related to chemical administration. Dose related nonneoplastic lesions in male F344/N rats included increased severity of nephropathy and mineralization of the kidney and forestomach lesions. There was no evidence of carcinogenic activity of 8-methoxypsoralen for female F344/N rats given the chemical at 37.5 or 75 mg/kg/day for 2 yr. [R35] +... 8-Methoxypsoralen (0, 40, 80, or 105 mg/kg/day) was administered by gavage to pregnant New Zealand white rabbits during the period of major organogenesis (gestational days 6-19). Maternal clinical signs, body weight, and food consumption were monitored from gestational day 0-30. On gestational day 30, fetuses were removed from the does and examined for evidence of developmental toxicity. There was no maternal mortality during the study and there was no dose-related incr in the incidence of clinical signs of toxicity. Maternal absolute and relative food consumption were suppressed during the dosing period (gestational days 6-19) by all doses of 8-Methoxypsoralen, but returned to control levels after the end of the dosing period. In keeping with the effects on food intake, maternal body weight gain (gestational days 6-19) was reduced in the 80 and 105 mg/kg/day dose groups, but that effect, too, was transient, as weight gain in those two groups was comparable to controls from gestational days 19-30. 8-Methoxypsoralen at 40 mg/kg/day also reduced maternal body weight gain, but the effects was not statistically significant. Although 8-Methoxypsoralen (80 and 105 mg/kg/day) decreased maternal weight gain, maternal body weights remained comparable to controls at all gestational ages because the changes in weight gain represented only 4-5% of total maternal body weight. Maternal relative liver weight displayed a rising trend, but the largest change was a 9% incr at the 105 mg/kg/day dose. These results indicate the LOAEL for 8-Methoxypsoralen-induced maternal toxicity was 80 mg/kg/day. Gravid uterine weight was unaffected by 8-Methoxypsoralen admin. Examination of the uterine contents revealed 8-Methoxypsoralen did not cause developmental toxicity. Avg live litter size, avg fetal body weight (both sexes), and the incidence of external, visceral, and skeletal malformations or variations were comparable to controls at all doses of 8-Methoxypsoralen. The only significant difference observed was a decr in the % male fetuses/litter at 105 mg/kg/day 8-Methoxypsoralen. In the absence of an incr in the number of resorptions or fetal deaths at this dose, this result probably reflects normal variation in sex ratio. Based on the above results, the developmental NOAEL for 8-Methoxypsoralen was > or = 105 mg/kg/day. Thus, 8-Methoxypsoralen, at doses which cause minor maternal toxicity, does not affect fetal growth, viability, or morphological development. [R36] ADE: *AFTER ORAL ADMIN OF (3)H 8-METHOXYPSORALEN TO RATS, IT WAS ABSORBED RAPIDLY AND MAX BLOOD LEVEL WAS OBSERVED @ 10 MIN. MODERATE RADIOACTIVITY WAS FOUND IN LIVER AND KIDNEYS @ 0.5-4 HR, AND LOW LEVELS IN OTHER TISSUES. [R37] *AFTER ORAL ADMIN OF (3)H 8-METHOXYPSORALEN TO RATS, 62.8% OF RADIOACTIVITY WAS EXCRETED IN URINE AND 20.4% IN FECES WITHIN 24 HR AND 65.1% and 21.9% DURING 6 DAYS, RESPECTIVELY. IN BILE, 30.0% WAS ALSO RECOVERED WITHIN 24 HR; THIS PASSED THROUGH ENTEROHEPATIC CIRCULATION. [R37] *AFTER PERCUTANEOUS ADMIN TO RATS OF (3)H 8-METHOXYPSORALEN, 22.0% WAS EXCRETED IN URINE AND 6.1% IN FECES WITHIN 24 HR. AFTER REPEATED ORAL ADMIN FOR 21 DAYS, SCARCELY ANY RADIOACTIVITY ACCUM IN ANY TISSUE. PLACENTAL TRANSFER AND MAMMARY SECRETION WERE DETECTED. [R37] *IMPROVEMENT IN EFFECTIVE BIOAVAILABILITY OF METHOXSALEN WAS ACHIEVED WHEN IT WAS ADMIN TO RATS AND DOGS IN SOLN AS COMPARED TO SUSPENSION. [R38] *(14)C METHOXSALEN ADMIN IVTO DOGS, DISAPPEARED RAPIDLY FROM PLASMA, ALTHOUGH PLASMA LEVELS OF RADIOACTIVITY PERSISTED FOR 5 WK. PERSISTENT PLASMA RADIOACTIVITY WAS DUE TO METABOLITE BOUND TO PLASMA PROTEIN. [R39] *SINGLE DOSES OF (14)C-LABELED METHOXSALEN WERE ADMIN IV TO DOGS. AS MUCH RADIOACTIVITY WAS EXCRETED IN FECES AS IN URINE, SUGGESTING THAT BILIARY SECRETION OF METABOLITES WAS AN IMPORTANT ROUTE OF EXCRETION. [R39] *MAX SERUM CONCN OCCURRED BETWEEN 0.5 and 2 HR AFTER ORAL ADMIN OF 0.6 MG/KG METHOXSALEN. THERE WAS SIGNIFICANT NEG CORRELATION BETWEEN LOGARITHM OF SERUM CONCN AND MIN PHOTOTOXIC DOSE. HENCE DEGREE OF PHOTOSENSITIVITY APPEARS TO BE RELATED TO SERUM LEVEL OF METHOXSALEN. [R40] *Single iv doses of 5 mg/kg body weight (14)C methoxsalen to dogs disappeared rapidly from plasma, although small levels of radioactivity persisted for 5 weeks after administration. Evidence suggested that the persistent plasma radioactivity was due to a metabolite bound to plasma protein. Elimination occurred in both urine and bile; 45% of the dose appeared in the urine and 40% in the feces within 72 hrs of administration. [R41] *The distribution of (3)H Methoxsalen was studied by whole body radiography in albino and pigmented rats after oral and iv treatment. The total radioactivity present in the various organs was estimated semiquantitatively: the higher accumulation of radioactivity (approximately 6 times higher than blood) occurred in the liver, kidneys and adrenal cortices. Skin concentrations of radioactivity were comparable with blood levels and were similar in albino and pigmented rats; ultra violet light 1x10+5 J/sq m) increased the sc concentrations of radioactivity. After oral administration (3 mg/kg body weight), pigmented rats had a very high concentration of (3)H methoxsalen (or its metabolites) in the pigmentary layer of the retina, ciliary body and iris, which were not comparable with those in albino rats. [R32] *Methoxsalen appears to be well, but variably, absorbed from the GI tract following oral administration. The extent to which topically applied methoxsalen is absorbed has not been determined. When oral methoxsalen is administered with food, the extent of absorption and the peak serum concentration appear to be increased. Considerable interindividual variations in peak serum concentrations of methoxsalen have been reported. Following oral administration of a single dose of methoxsalen as conventional capsules or liquid filled capsules with low fat milk, peak serum drug concentrations occur within 3 hr (range: 1.5-6 hr) or 1.8 hr (range: 0.5-4 hr), respectively, and serum concentrations decline to low levels within 8-10 hr. Peak serum methoxsalen concentrations are approximately 2-3 times higher and the area under the serum concentration-time curve is approximately 1.5-2 times greater with the liquid filled capsules than with the conventional capsules. [R4, 2266] *Distribution of methoxsalen into human tissues and fluids has not been fully characterized. The drug appears to be preferentially taken up by epidermal cells. Methoxsalen distributes into the lens of the eye in concentrations proportional to the serum concentrations. It is not known if methoxsalen crosses the placenta or is distributed into milk. The drug is reportedly 75-91% bound to serum proteins, principally albumin. [R4, 2267] *Methoxsalen and 8-hydroxypsoralen and their conjugates are excreted in urine. Following oral administration of methoxsalen, 80-90% of the drug is excreted in urine within 8 hours as hydroxylated, glucuronide, and sulfate metabolites; less than 0.1% of a dose is excreted in urine as unchanged drug. About 95% of the drug is excreted in urine within 24 hours as metabolites. [R4, 2267] METB: *AFTER ORAL ADMIN OF 8-METHOXYPSORALEN TO RATS, METABOLITES IN URINE WERE; 8-HYDROXYPSORALEN, 5-HYDROXY-8-METHOXYPSORALEN, 5,8-DIOXOPSORALEN, 5,8-DIHYDROXYPSORALEN, 4,6,7-TRIHYDROXY-5-COUMARANOYL-BETA-ACRYLIC ACID, 4,6-DIHYDROXY-7-METHOXY-5-COUMARANOYL-BETA-ACRYLIC ACID. [R42] *Although the exact metabolic fate of methoxsalen has not been fully established, the drug is rapidly and apparently almost completely metabolized. Methoxsalen is demethylated to 8-hydroxypsoralen (8-HOP), and methoxsalen and 8-HOP are conjugated with glucuronic acid and sulfate; other unidentified metabolites have also been detected. Methoxsalen and 8-hydroxypsoralen and their conjugates are excreted in urine. Following oral administration of methoxsalen, 80-90% of the drug is excreted in urine within 8 hours as hydroxylated, glucuronide, and sulfate metabolites; less than 0.1% of a dose is excreted in urine as unchanged drug. About 95% of the drug is excreted in urine within 24 hours as metabolites. [R4, 2267] *Methoxsalen is extensively metabolized, and less than 2% of the drug is excreted unchanged in the urine. Four urinary metabolites were isolated; 3 of them resulted from opening of the furan ring: these are 7-hydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid, alpha,7-dihydroxy-8-methoxy-2-oxo-2H-1-benzopyran-6-acetic acid, and an unknown conjugate of the former at the 7-hydroxy position. The fourth metabolite, formed by opening of the pyrone ring, is an unknown conjugate of (Z)-3-(6-hydroxy-7-methoxybenzofuran-5-yl)-2-propenoic acid. [R41] BHL: *The elimination half-life of methoxsalen is reportedly about 0.75-2.4 hours. [R4, 2267] ACTN: *INCR PHOTODYNAMIC PIGMENTATION OF SKIN; IT DOES NOT INDUCE PIGMENTATION IN ABSENCE OF UV LIGHT. [R43] *EXPOSURE OF METHOXSALEN-TREATED PATIENTS TO UV LIGHT THICKENS STRATUM CORNEUM, INDUCES INFLAMMATORY REACTION IN SKIN, AND INCR AMT OF MELANIN IN EXPOSED AREA. [R14] *METHOXSALEN IS POTENT PHOTOSENSITIZER OF SKIN, PARTICULARLY TO LONG-WAVE (320 TO 400 NM) UV LIGHT. PHOTOSENSITIZATION SELECTIVELY INHIBITS EPIDERMAL DNA SYNTHESIS WITHOUT PROPORTIONATE INHIBITION OF EPIDERMAL CELL FUNCTION. [R14] *Methoxsalen, when activated by long wavelength UV light in the range of 320-400 nm, is strongly erythemogenic, melanogenic, and cytotoxic in the epidermis; the maximal erythemogenic activity occurs in the range of 330-360 nm. The mechanisms of action of methoxsalen in inducing repigmentation of vitiliginous skin have not been established. Repigmentation depends on the presence of functioning melanocytes and UV light. Methoxsalen may activate the few functional and dihydroxyphenylalanine-positive melanocytes present in vitiliginous skin. An increase in the activity of tyrosinase, the enzyme that catalyzes the conversion of tyrosine to dihydroxyphenylalanine (a precursor of melanin), has been shown in melanin-producing cells exposed in vitro to trioxsalen and UVA light. In addition, binding of photoactivated psoralens (in triplet states) to pyrimidine bases of nucleic acids, with subsequent inhibitions of DNA synthesis, cell division, and epidermal turnover, has been demonstrated. Following photoactivation, methoxsalen forms covalent bonds with DNA to produce monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking to both strands of DNA). Reactions with other proteins also occur. Psoralens may also increase melanin formation by producing an inflammatory reaction in the skin. Other mechanisms of increased pigmentation may include an increase in the number of functional melanocytes (and possibly activation of dormant melanocytes); enhancement of melanin granule synthesis; stimulation of the movement of melanocytes up hair follicles resulting in melanocytic repopulation of the epidermis; and/or hypertrophy of melanocytes and increased arborization of their dendrites. [R4, 2266] *Since psoriasis is a hyperproliferative disorder and other agents effective in the treatment of psoriasis are known to inhibit DNA synthesis, the therapeutic effect of methoxsalen in the treatment of psoriasis probably involves binding to DNA and inhibition of DNA synthesis resulting in decreased cell proliferation; other vascular, leukocyte, or cell regulatory mechanisms may also be involved. [R4, 2266] INTC: *KINETICS OF 8-METHOXSALEN WERE STUDIED IN 5 HEALTHY SUBJECTS UNDER FASTING AND NONFASTING CONDITIONS, INDICATING HIGHER RELATIVE BIOAVAILABILITY OF DRUG IN PRESENCE OF FOOD. [R44] *Concomitant therapy with methoxsalen and other systemic or topical photosensitizing agents (e.g., anthralin, coal tar or coal tar derivatives, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides [bacteriostatic soaps], sulfonamides, tetracyclines, thiazides, or certain organic staining dyes such as methylene blue, toluidine blue, rose bengal, and methyl orange) may produce additive photosensitizing effects. Particular caution is necessary if methoxsalen is administered concomitantly with any topical or systemic photosensitizing agent. [R4, 2269] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Carcinogens; Photosensitizing Agents [R45] *METHOXSALEN IS USED TO ENHANCE PIGMENTATION, TO PROTECT AGAINST SUNBURN, AND TO REPIGMENT VITILIGINOUS AREAS. [R4, p. 84:50.06] *CLINICAL RESPONSE IN REPIGMENTING VITILIGINOUS SKIN AREAS IS ERRATIC AND UNPREDICTABLE AND IS COSMETICALLY ACCEPTABLE IN ONLY ABOUT 5% OF PATIENT TREATED. [R4, p. 84:50.06] *IN ALBINISM, METHOXSALEN MAY INCR TOLERANCE TO SUNLIGHT BUT HAS NO EFFECT UPON PIGMENTATION. [R4, p. 84:50.06] *ORAL ROUTE IS PREFERRED IF EXTENSIVE REPIGMENTATION IS DESIRED SINCE METHOXSALEN CAN BE APPLIED TOPICALLY TO ONLY SMALL AREA AT TIME AND UNIFORM REPIGMENTATION IS DIFFICULT. [R4, p. 84:50.06] *AFTER ORAL INGESTION, INCR SENSITIVITY APPEARS IN 1 HR, REACHES MAX IN 2 HR, AND DISAPPEARS IN ABOUT 8 HR. TOPICAL APPLICATION IS MORE EFFECTIVE, AND INCR SKIN SENSITIVITY PERSISTS FOR SEVERAL DAYS. ... REPIGMENTATION PERSISTS FOR 8 TO 14 YR WITHOUT FURTHER TREATMENT. [R14] *PHOTOCHEMOTHERAPY FOR PSORIASIS USING FLUORESCENT BLACKLIGHT COMBINED WITH ORAL METHOXSALEN WAS USED IN TREATMENT OF 20 PT SUFFERING FROM LONG STANDING PSORIASIS. 10 OF PATIENT HAD COMPLETE CLEARING OF LESIONS, 2 HAD 75% OR MORE CLEARANCE. SIDE EFFECTS WERE MINIMAL. [R46] *TOPICAL METHOXSALEN PHOTOCHEMOTHERAPY HAS BEEN ASSESSED IN 22 PATIENTS SUFFERING FROM RECALCITRANT PALMOPLANTAR PUSTULOSIS OR PSORIASIS. 20 OUT OF 22 PATIENTS IMPROVED, ONLY 4 PATIENTS WERE CLASSIFIED AS BEING "CLEAR" OR "MINIMALLY INVOLVED" @ END OF 12 WK. [R47] *Photoactive agent indicated with long wave ultraviolet radiation for the repigmentation of idiopathic vitiligo, and with long wave UV radiation for the symptomatic control of severe, recalcitrant disabling psoriasis. [R3] *Methoxsalen is used orally (as conventional capsules) or topically in conjunction with controlled exposure to long wavelength ultraviolet radiation (UVA) or sunlight to repigment vitiliginous skin in patients with idiopathic vitiligo. The liquid-filled capsules currently are not approved by the US Food and Drug Administration for this use. Clinical response to methoxsalen is erratic and unpredictable and is cosmetically acceptable in only a small percentage of patients with vitiligo. Complete cures following psoralen therapy are infrequent; only about one-third of patients with vitiligo have an appreciable amount of pigmentation restored. In one study of 20 patients treated with topical methoxsalen and blacklight, complete repigmentation occurred in only 3 patients. In one study using UVA light and oral methoxsalen or oral trioxsalen for 12-14 mos, 73% of vitiligo patients had some pigmentation restored and, in 23% of patients, pigmentation improved by about 73%. Repigmentation varies among patients in completeness, time of onset, and duration. Methoxsalen-induced repigmentation occurs more rapidly on fleshy areas such as the face, abdomen, and buttocks than on bony areas such as the dorsa of the hands and feet. To retain new pigment, periodic treatment with the drug and some form of UVA light is often required; however, in one study, 90% or more of the new pigment established during oral methoxsalen and conventional UV light therapy remained in 85% of patients 8-14 yrs after methoxsalen treatment was discontinued. [R4, 2267] *Methoxsalen is used orally (as conventional or liquid filled capsules) in conjunction with controlled exposure to long wavelength ultraviolet radiation (UVA) for the symptomatic treatment of severe, recalcitrant, disabling psoriasis that is refractory to other forms of therapy and when the diagnosis has been confirmed by biopsy. In several studies, psoriatic lesions cleared in about 90% of patients treated with a mean of 10-20 exposures to a psoralen and UVA light (PUVA therapy). For extensive or refractory psoriasis, some clinicians consider PUVA therapy to be more acceptable and effective than other therapies (e.g., corticosteroids, hydroxyurea, total body tar application) and safer than methotrexate; however, the role of PUVA therapy in the treatment of psoriasis remains to be clearly established. In one controlled study, PUVA therapy was effective in most patients who had previously required methotrexate to control the disease and in some patients whose disease did not respond to a topical anthralin regimen. Limited data indicate that PUVA with liquid filled methoxsalen capsules is effective in clearing psoriatic lesions in many patients whose disease is refractory to PUVA therapy with conventional methoxsalen capsules. Because of more rapid and extensive absorption and a substantially lower minimum phototoxic dose (MPD) associated with the liquid-filled capsules, use of these capsules may substantially decrease the number of PUVA treatments necessary in many patients compared with use of the conventional capsules. The role of PUVA maintenance therapy to prevent recurrence of psoriatic lesions remains to be determined. [R4, 2267] *Psoralens have been used topically in conjunction with UVA light for the treatment of psoriasis, but the use of topical methoxsalen largely has been abandoned because it produces a greater incidence of adverse effects and is less cosmetically acceptable than oral psoralens. /Use is not currently included in the labeling approved by FDA/ [R4, 2267] *Oral methoxsalen is used in conjunction with photopheresis with the UVAR(R) instrument (Therakos(R), King of Prussia, PA) for the palliative treatment of the skin manifestations of cutaneous T-cell lymphoma (CTCL; e.g., mycosis fungoides, Sezary syndrome). Limited evidence indicates that photopheresis therapy (e.g., administered once daily for 2 consecutive days per month) can produce reductions in the size and/or severity of skin lesions without serious toxicity; sustained responses (2 yrs or longer) have occurred in some patients. [R4, 2267] WARN: *PATIENTS WITH VITILIGO TAKING METHOXSALEN SHOULD HAVE LIVER FUNCTION TESTS PERFORMED MONTHLY FOR FIRST FEW MONTHS AND OCCASIONALLY THEREAFTER. IT SHOULD BE GIVEN IN SMALLER DAILY DOSES OR DISCONTINUED IF IMPAIRMENT OF LIVER FUNCTION IS SUSPECTED. [R48] *WHEN METHOXSALEN IS USED TO INCREASE TOLERANCE TO SUNLIGHT AND ACCELERATE SUNTAN, IT SHOULD NOT BE ADMIN FOR PERIODS EXCEEDING 2 WK. [R48] *THE USE OF THIS DRUG SIMPLY TO PRODUCE A COSMETIC TAN IS UNWISE BECAUSE OF ITS POTENTIAL TOXICITY AND THE EQUIVOCAL RESULTS. [R48] *THE TOPICAL SOLN SHOULD NEVER BE DISPENSED TO THE PATIENTS FOR HOME USE. [R14] *... METHOXSALEN IS CONTRAINDICATED IN HEPATIC INSUFFICIENCY AND DISEASES ASSOCIATED WITH PHOTOSENSITIVITY, SUCH AS PORPHYRIA, ACUTE LUPUS ERYTHEMATOSUS, HYDROA, AND POLYMORPHIC LIGHT ERUPTIONS. [R14] *TOPICAL APPLICATION FOLLOWED BY OVEREXPOSURE TO UV LIGHT MAY RESULT IN SEVERE BURNS. [R49] *WHEN ORAL THERAPY IS COMBINED WITH TOPICAL APPLICATION, IT IS MANDATORY THAT TOPICALLY TREATED AREAS BE PROTECTED FROM DAILY EXPOSURE TO UV LIGHT. [R48] *DRUG SHOULD BE TAKEN AFTER MEALS OR WITH MILK. MILD SEDATIVES MAY COUNTERACT NERVOUS EFFECTS. [R48] *... 1% TOPICAL SOLN IS ... APPLIED @ WEEKLY INTERVALS TO WELL DEFINED VITILIGINOUS LESIONS FOLLOWED WITH 1 MIN EXPOSURE TO UV LIGHT. SUBSEQUENT EXPOSURES SHOULD BE INCR WITH CAUTION. [R14] *POSSIBILITY OF OVEREXPOSURE /TO UV LIGHT AFTER TOPICAL TREATMENT OF SKIN/ CAN BE MINIMIZED BY TOPICAL APPLICATION OF SUNSCREENS CONTAINING BENZOPHENONE DERIVATIVES OR BY WASHING TREATED SITE AFTER EXPOSURE TO SUNLIGHT. [R50] *Methoxsalen conventional capsules and liquid-filled capsules exhibit substantially different rates and extents of absorption, minimum phototoxic doses, and peak photosensitivity times and should not be used interchangeably in the treatment of psoriasis. [R4, 2268] *Since methoxsalen is a strong photosensitizer capable of producing severe burns if used improperly, the drug should be used only under the supervision of a physician with special training and experience in photochemotherapy. Methoxsalen lotion should be applied only by a physician under controlled conditions for light exposure and subsequent light shielding; the lotion should not be dispensed to a patient for home use. Methoxsalen lotion should be applied only to small, well-defined vitiliginous lesions, preferably those lesions that can be protected by clothing or a sunscreen from subsequent exposure to UVA light. Because of the potential for serious adverse effects (eg, ocular damage, aging of the skin, and skin cancer [including melanoma]) resulting from PUVA therapy, the patient should be fully informed by the physician of the risks associated with the treatment. To prevent serious adverse effects, the physician should carefully instruct the patient to adhere to the prescribed methoxsalen dosage regimen and schedules for UVA exposure. When oral methoxsalen is used in the treatment of vitiligo, the dosage should not exceed 0.6 mg/kg. [R4, 2268] *Mild, transient erythema occurring 24-48 hours after PUVA therapy is an expected cutaneous reaction, and indicates that a therapeutic interaction between methoxsalen and UVA has occurred. Areas of skin showing fiery erythema with edema should be shielded during subsequent UVA exposures until the erythema has resolved. Fiery erythema with edema which occurs within 24 hours following UVA exposure may indicate a potentially severe burn, since the peak erythemal reaction usually occurs 48-72 hours following PUVA therapy. If burning or blistering of skin or intractable generalized pruritus occurs, therapy should be discontinued until these effects subside. [R4, 2268] *Prior to methoxsalen administration and UVA exposure, patients should not sunbathe for at least 24 hours, since the presence of sunburn may prevent an accurate evaluation of patient response to photochemotherapy. Following methoxsalen ingestion and controlled exposure to UVA or sunlight, patients must avoid additional, direct or indirect (through window glass or cloud cover) exposure to sunlight for at least 8 hours; following topical treatment with methoxsalen, additional exposure to UV light should be avoided for at least 12-48 hours. If exposure to sunlight cannot be avoided, the patient should wear protective clothing (eg, hat, gloves) and/or apply sunscreens that filter out UVA radiation (eg, sunscreens with a sun protective factor greater than or equal to 15). Sunscreens should be applied to all areas of the body that may be exposed to the sun (including lips). Skin of the abdomen, breasts, genitalia, and other sensitive areas should be protected during PUVA therapy for about one-third of the initial exposure time until sufficient tanning occurs; unless affected by disease, male genitalia should be shielded. Sunscreens should not be applied to areas affected by psoriasis until the patient has been treated with controlled exposure to UVA. Following PUVA therapy, patients should not sunbathe for 48 hours, since erythema and/or burning resulting from photochemotherapy and sunburn are additive. If methoxsalen is used topically to treat vitiligo of the face or hands, the patient must be carefully instructed to keep the treated areas protected from light with the use of clothing or sunscreens; the treated areas may be highly photosensitive for several days and severe burns could result from additional exposure to UVA or sunlight. [R4, 2268] *Following ingestion of methoxsalen and after combined oral methoxsalen and UVA therapy, wrap around sunglasses with UVA absorbing properties should be worn by patients during daylight hours for 24 hours. The protective eyewear must be designed to prevent entry of stray radiation into the eyes, including that which may enter from the sides of eyeglasses. Protective eyewear is used to prevent irreversible binding of methoxsalen to proteins and DNA components of the lens. Total UVA-absorbing/blocking goggles must be worn during PUVA therapy. Failure to do so may increase the risk of cataract formation. A radiometer may be used to verify elimination of UVA transmission through the protective goggles. [R4, 2268] *Exposure of animals to large doses of UVA without eye protection has produced cataracts and this effect is enhanced by methoxsalen; however, in patients receiving PUVA therapy who use appropriate eye protection, there is no evidence to date for an increased risk of cataract formation. Prior to the initiation of PUVA therapy and yearly thereafter, patients should have an ophthalmologic examination because of the cataractogenic potential of psoralens. [R4, 2268] *Before and 6-12 mos after oral methoxsalen therapy is initiated, a complete blood count, antinuclear antibody titer, and hepatic and renal function tests should be performed. If the leukocyte count is abnormal, a differential cell count should be performed. Additional laboratory tests at more extended time periods should be performed as clinically indicated. The manufacturer states that oral methoxsalen should be used with caution in patients with hepatic insufficiency . [R4, 2268] *Exposure to sunlight and/or UVA may result in premature aging of the skin or skin cancer. In patients with multiple basal cell carcinomas or history of basal cell carcinomas, careful observation during treatment with methoxsalen is recommended. Patients with a history of radiation therapy or treatment with arsenic should be carefully observed for signs of carcinoma. The total cumulative dose of UVA that can be given over long periods of time with safety has not been established. [R4, 2268] *Patients with cardiac disease or those unable to tolerate prolonged standing or exposure to heat stress should not be treated in a vertical UVA chamber. [R4, 2268] *8-MOP 10 mg conventional capsules contain the dye tartrazine (FD and C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin. [R4, 2268] *Because psoralens have caused photoallergic contact dermatitis and may precipitate sunlight allergy, methoxsalen should be used with caution in patients with a family history of sunlight allergy. The drug should also be used with caution in patients with GI diseases or chronic infection. Oral or topical methoxsalen should be used with particular caution in patients receiving topical or systemic therapy with known photosensitizing agents. [R4, 2268] *Oral or topical methoxsalen is contraindicated in patients exhibiting idiosyncratic reactions to psoralens or with a history of a sensitivity reaction to the drugs; in patients with diseases associated with photosensitivity (eg, lupus erythematosus, porphyria cutanea tarda, erythropoietic protoprophyria, variegate porphyria, xeroderma pigmentosum, albinism, hydroa vacciniforme, leukoderma of infectious origin, polymorphous light eruptions), except under special circumstances; in patients with melanoma or history of melanoma; and in patients with invasive squamous cell carcinoma. Oral methoxsalen is also contraindicated in patients with aphakia (absence of lenses) because of the increased risk of retinal damage. [R4, 2268] *Safe use of methoxsalen in children younger than 12 yrs of age has not been established, and the drug is contraindicated in this age group. The Committee on Drugs of the American Academy of Pediatrics recommends that under no circumstance should children receive PUVA therapy, except under established investigational new drug (IND) protocols. [R4, 2268] *Since it is not known whether methoxsalen is distributed into milk, the drug should be used with caution in nursing women. [R4, 2269] *When oral methoxsalen is administered with food, the extent of absorption and the peak serum concentration appear to be increased. The mechanism of this interaction is not known but may involve the effect of food on dissolution or hepatic metabolism of methoxsalen. Since the photosensitizing effect may be related to the serum concentration of methoxsalen, it has been suggested that the drug be administered in a consistent manner with regard to food intake. [R4, 2269] TOLR: *Tolerance to the effects of psoralens may occur when pigmentation occurs much more rapidly than does erythema. [R4, 2266] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *METHOXSALEN, DELTA-LACTONE OF E-(6-HYDROXY-7-METHOXYBENZOFURANYL)ACRYLIC ACID, IS THE PURE CRYSTALLINE FORM OF THE ACTIVE PRINCIPLE CONTAINED IN FRUIT OF AMMI MAJUS LINN. [R48] *FOUND IN PSORALEA CORYLIFOLIA L, AMMI MAJUS L, ANGELICA ARCHANGELICA L, FAGARA ZANTHOXYLOIDES LAM, RUTA CHALEPENSIS L, R MONTANA L, R GRAVEOLENS L AND LUVUNGA SCANDENS BUCH -HAM. [R51] *Methoxsalen occurs naturally in several different plants including Ammi majus (Umbelliferae), Psorales coryfolia, and Ruta chalepensis ... . [R4, 2266] *Naturally occurring analog of psoralen ... found in species of Leguminosae, Umbelliferae, and Rutaceae. [R6] *Methoxsalen is a naturally occurring substance, produced by several plants, eg Psoralea corylifolia Leguminosae, Ammi majus Leguminosae, Ruta chalepensis Leguminosae, Ruta graveolens Leguminosae, and others which are found in both temperate and tropical regins. Ammi majus is a white umbellifer related to the wild carrot (Daucus carota); plants of the genus Ruta include rue, a perennial evergreen shrug with bitter, strong-scented leaves, once widely used as a medicine. It is also produced by the fungus Sclerotinia sclerotiorum, which causes 'pink rot' disease in celery. [R52] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R53] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl methoxsalen, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. [R54] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determination of methoxsalen using LC equipped with a 254 nm detector. The flow rate is about 1.5 ml/min. [R55] CLAB: *8-METHOXYPSORALEN WAS DETECTED IN PLASMA BY HPLC ... . [R56] *DETERMINATION OF 8-METHOXYPSORALEN IN HUMAN PLASMA BY EC/GLC. [R57] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) DHHS/NTP; Toxicology and Carcinogenesis Studies of 8-Methoxypsoralen in F344/N Rats (Gavage Studies) Technical Report Series No. 359 (1989) NIH Publication No. 89-2814 SO: R1: SRI R2: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1580 R3: Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 103 R4: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 752 R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 945 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-519 R8: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-545 R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 437 R10: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2738 R11: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 243 (1987) R13: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1046 R14: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 954 R15: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 136 R16: WEISSMANN I ET AL; BR J DERMATOL 102 (1): 113 (1980) R17: WAGNER J ET AL; SCAND J HAEMATOL 21 (4): 299 (1978) R18: HANSEN NE; SCAND J HAEMATOL 22 (1): 57 (1979) R19: BURGER PM, SIMONS JW; MUTAT RES 63 (2): 371 (1979) R20: GREENE I, COX AJ; ARCH DERMATOL 115 (10): 1200 (1979) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 111 (1980) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 112 (1980) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 113 (1980) R24: Stern RS, Lange R; Arch Dermatol 127 (3): 347-50 (1991) R25: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 678 R26: SHULER CF, LATT SA; CANCER RES 39(7 PT 1): 2510 (1979) R27: EVANS DL, MORROW KJ; J INVEST DERMATOL 72 (1): 35 (1979) R28: PARRISH JA ET AL; J INVEST DERMATOL 73 (3): 250 (1979) R29: ROBERTS LK ET AL; J INVEST DERMATOL 72 (6): 306 (1979) R30: BURGER PM, SIMONS JW; MUTAT RES 6 (3): 381 (1979) R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 105 (1980) R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 108 (1980) R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 107 (1980) R34: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 602 R35: Toxicology and Carcinogenesis Studies of 8-Methoxypsoralen in F344/N Rats (Gavage Studies). Technical Report Series No. 359 (1989) NIH Publication No. 89-2814 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R36: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of 8-Methyoxypsoralen (CAS No. 298-81-7) in New Zealand White (NZW) Rabbits, NTP Study No. TER91016 (May, 1994) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R37: NOZU T ET AL; OYO YAKURI 18 (3): 489 (1979) R38: KREUTER J, HIGUCHI T; J PHARM SCI; 68 (4): 451 (1979) R39: KOLIS SJ ET AL; DRUG METAB DISPOS 7 (4): 220 (1979) R40: SWANBECK G ET AL; CLIN PHARMACOL THER 25 (4): 478 (1979) R41: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 109 (1980) R42: NOZU T ET AL; OYO YAKURI 18 (3): 497 (1979) R43: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 726 R44: EHRSSON H ET AL; CLIN PHARMACOL THER 25 (2): 167 (1979) R45: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R46: ROSTEN M; NZ MED J 90 (641): 101 (1979) R47: WILKINSON JD ET AL; ACTA DERM VENEREOL (SUPPL) (STOCKH) 59 (85): 193 (1979) R48: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 84:2412 R49: Goodman, L.S., and A. G. Gilman. (eds.). The Pharmacological Basis of Therapeutics. 4th ed. New York: Macmillan Co., 1970. 996 R50: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 913 R51: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 783 R52: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V24 103 (1980) R53: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91 R54: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-187 (1992) R55: USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990. 858 R56: HENSBY CN; CLIN EXP DERMATOL 3 (4): 355 (1978) R57: VAN BOVEN M, DAENENS P; J PHARM BELG 35 (2): 103 (1980) RS: 66 Record 173 of 1119 in HSDB (through 2003/06) AN: 2517 UD: 200301 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIBROMOMETHANE- SY: *BROMOFORM-; *BROMOFORME- (FRENCH); *BROMOFORMIO- (ITALIAN); *METHANE,-TRIBROMO-; *METHENYL-TRIBROMIDE-; *NCI-C55130-; *TRIBROMMETHAAN- (DUTCH); *TRIBROMMETHAN- (GERMAN); *TRIBROMOMETAN- (ITALIAN) RN: 75-25-2 RELT: 56 [CHLOROFORM]; 2763 [CHLORODIBROMOMETHANE]; 4160 [BROMODICHLOROMETHANE] MF: *C-H-Br3 SHPN: UN 2515; Bromoform IMO 6.1; Bromoform HAZN: U225; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared from acetone and sodium hypobromite: Gunther, Jahresber Fortschr Chem 1887, 741 (Beilstein, vol 1, 68); Kergomard, Bull Soc Chim France 1961, 2360. [R1] *... PRODUCED BY ADDING BROMINE TO HEATED SOLN OF ACETONE AND SODIUM CARBONATE, BY TREATING CHLOROFORM WITH ALUMINUM BROMIDE OR BY ELECTROLYSIS OF POTASSIUM BROMIDE IN ETHYL ALCOHOL. [R2] *By heating acetone or ethanol with bromine and alkali hyroxide and recovery /of tribromomethane/ by distillation [R3] IMP: *Usually sold mixed with 3-4% ethanol as a stabilizer [R4] FORM: *Grades: technical; pharmaceutical; spectrophotometric. [R3] *Usually sold mixed with 3-4% ethanol as a stabilizer [R4] *Liquid grade [R5] MFS: *Aldrich Chemical Company, Inc., 1001 West St. Paul Ave., Milwaukee, WI 53233, (414) 273-3850 [R6] *Geoliquids, Inc., 15 East Palatine Rd., Suite 109, Prospect Heights, IL 60070, (800) 827-2411; Production site: Prospect Heights, IL 60070 [R6] USE: *Used for synth of pharmaceuticals; used in shipbuilding, aircraft, and aerospace industries; used in fire extinguishers. [R7] *CHEM INTERMED FOR ORGANIC SYNTHESIS; SOLVENT FOR WAXES, GREASES, AND OILS; REAGENT FOR GRAPHITE ORE FRACTIONATION [R8] *Used as a heavy liquid floatation agent in mineral separation, sedimentary petrographical surveys, and purification of materials such as quartz; Used as an industrial solvent in liquid-solvent extractions, in nuclear magnetic resonance studies; Used as a catalyst, initiator, or sensitizer in polymer reactions, and in vulcanization of rubber. [R9, 1981.3] *Ingredient in gauge fluids [R4] *Used in organic synthesis, geological assaying, as a solvent for waxes, greases and oils, medicinal (sedative). [R3] *Used to separate minerals; medicinal (sedative, hypnotic, antitussive) [R1] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 4.5X10+5 GRAMS [R8] *(1978) PROBABLY GREATER THAN 4.5X10+5 GRAMS [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Heavy liquid [R1]; *HEXAGONAL SCALES [R10]; *Colorless to yellow liquid [Note: A solid below 47 degrees F]. [R11, 34] ODOR: *Chloroform odor [R1] TAST: *Sweetish taste [R1] BP: *149.1 deg C [R12, p. 3-207] MP: *8.0 deg C [R12, p. 3-207] MW: *252.73 [R12, p. 3-207] CORR: *... Liquid bromoform will attack some forms of plastics, rubber, and coatings. [R9, 1981.2] DEN: *2.8899 g/cu cm @ 15 deg C [R12, p. 3-207] HTV: *39.66 KJ/mol @ 149.1 deg C; 46.05 KJ/mol @ 25 deg C [R12, p. 6-103] OWPC: *log Kow= 2.40 [R13] SOL: *Sol in benzene, ethyl ether, ethanol [R12, p. 3-207]; *Sol in about 800 parts water; miscible with acetone, alc, ether, petroleum ether, oils [R1]; *Sol in solvent naphtha [R3]; *0.3 g/100 ml water at 30 deg C [R14, 4064]; *0.1 g/100 g water at 20 deg C [R9, 1981.2]; *3,100 mg/l water at 25 deg C [R15] SPEC: *MAX ABSORPTION (TERTIARY BUTYL ALCOHOL): 224 NM; SADTLER REFERENCE NUMBER: 10 (IR, PRISM) [R16]; *Index of refraction: 1.6005 @ 15 deg C/D [R12, p. 3-207]; *MASS: 1746 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R17, p. V1 311]; *IR: 8 (Sadtler Research Laboratories IR Grating Collection) [R17, p. V1 842]; *UV: 5-1 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R17, p. V1 842]; *NMR: 6375 (Sadtler Research Laboratories Spectral Collection) [R17, p. V1 842]; *MASS: 1744 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R17, p. V1 842] SURF: *41.53 dynes/cm @ 20 deg C [R3] VAPD: *8.7 (Air= 1) [R18] VAP: *1 KPa @ 30.5 deg C; 10 KPa @ 78.3 deg C; 100 KPa @ 148.8 deg C [R12, p. 6-65] OCPP: *Solidifies @ +7.5 deg C [R1] *Conversion factors: 1 mg/l is equiv to 97 ppm; 1 ppm is equiv to 10.34 mg/cu m @ 25 deg C, 760 mm Hg; % in saturated air: 0.7 @ 25 deg C [R14, 4064] *Percent in saturated air: 0.7 @ 25 deg C [R14, 4064] *Dielectric constant: 4.5 @ 20 deg C [R3] *Weight: 23.72 lb/gal at 25 deg C. [R19] *Hexane/water partition coefficient 1.76 (log) [R20] *Pentane/water partition coefficient 2.09 (log) [R20] *Air/water partition coefficient -1.56 (log) [R20] *Undecane/water partition coefficient 2.10 (log) [R20] *Henry's Law constant= 5.35X10-4 atm-cu m/mol @ 25 deg C [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of tribromomethane stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this heavy, colorless to yellow liquid may occur from its use a chemical intermediate in the synthesis of pharmaceuticals, as a flotation agent in mineral separation. Effects from exposure may include severe irritation of the skin, eyes and respiratory tract, pulmonary edema, headache, vertigo, amnesia, shock, unconsciousness, and convulsions. Both the OSHA PEL and the ACGIH TLV have been set at a TWA of 0.5 ppm. In activities or situations where over exposure may occur, wear a self-contained breathing apparatus, and full chemical protective clothing which is specifically recommended by the shipper or producer to prevent skin contact with tribromomethane. If contact should occur, immediately flush affected skin or eyes with running water for at least 15 minutes, and remove contaminated clothing and shoes at the site. While tribromomethane is not easily ignited, it may burn with the release of toxic gases and vapors. Fires involving tribromomethane may be extinguished with dry chemical, CO2, Halon, water spray, fog, or standard foam. Tribromomethane should be stored in cool, dark areas, away from chemically active metals and strong caustics. Note that this substance will attack some forms of plastics, rubber, and coatings. Tribromomethane may be shipped via air, rail, road, and water, in containers bearing the label, "Keep Away From Food". Small spills of tribromomethane should be taken up with vermiculite, dry sand, earth, and placed into containers for later disposal. Large spills first should be diked far ahead of the spill area. Tribromomethane is a potential candidate for rotary kiln, liquid injection, and fluidized bed forms of incineration. Before implementing land disposal of waste tribromomethane, consult with regulatory agencies for guidance. DOT: +Health: Inhalation of vapors or dust is extremely irritating. May cause burning of eyes and flow of tears. May cause coughing, difficult breathing and nausea. Brief exposure effects last only a few minutes. Exposure in an enclosed area may be very harmful. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may cause pollution. [R22] +Fire or explosion: Some of these materials may burn, but none ignite readily. Containers may explode when heated. [R22] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R22] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R22] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R22] +Fire: Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R22] +Spill or leak: Do not touch or walk through spilled material. Stop leak if you can do it without risk. Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. Small spills: Take up with sand or other noncombustible absorbent material and place into containers for later disposal. Large spills: Dike far ahead of liquid spill for later disposal. Prevent entry into waterways, sewers, basements or confined areas. [R22] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects should disappear after individual has been exposed to fresh air for approximately 10 minutes. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R22] FPOT: *Not flammable by standard tests in air [R14, p. 4064\] *Not combustible [R9, 1981.2] FIRP: */Wear/ self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode. [R9, 1981.5] TOXC: *Toxic gases and vapors (such as hydrogen bromide and bromine) may be released in a fire involving bromoform. [R9, 1981.2] EXPL: *Explosive reaction with crown ethers or potassium hydroxide. [R23] REAC: *Incompatibilities: chemically active metals: sodium, potassium, calcium, powdered aluminum, zinc, magnesium, strong caustics. [R24] *Violent reaction with acetone or bases. Incompatibile with lithium or sodium-potassium alloys. [R23] *LITHIUM MIXED WITH ... /BROMOFORM/ CAN EXPLODE ON IMPACT ... . [R25, p. 491-108] *MIXT OF SODIUM-POTASSIUM ALLOY AND BROMOFORM ... CAN EXPLODE ON STANDING @ ROOM TEMP. ... ESP SENSITIVE TO IMPACT. [R25, p. 491-183] *Lithium, sodium, potassium, calcium, aluminum, zinc, magnesium, strong caustics, acetone [Note: Gradually decomposes, acquiring yellow color; air and light accelerate decomposition.] [R11, 64] DCMP: *GRADUALLY DECOMP, ACQUIRING A YELLOW COLOR; AIR AND LIGHT ACCELERATE THE DECOMPOSITION. [R1] *When heated to decomposition it emits highly toxic fumes of /hydrogen bromide/. [R23] ODRT: *In water: detection: 0.3 mg/kg [R26] *In air: 4.80X10+8 molecules/cu cm [R27] SERI: *EXPOSURE TO BROMOFORM VAPOR ... CAUSED IRRITATION OF THE RESPIRATORY TRACT, PHARYNX, LARYNX ... [R28, 1991.154] *Bromoform can cause irritation of the eyes and nose. [R9, 1981.1] EQUP: *... Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with liquid bromoform. ... Employees should be provided with and required to use splash-proof safety goggles where liquid bromoform may contact the eyes. [R9, 1981.2] *Respiratory protection: 25 ppm or less: A chemical cartridge respirator with a full facepiece and an organic vapor cartridge(s); A gas mask with a chin-style or a front- or back-mounted organic vapor canister; Any supplied-air respirator with a full facepiece, helmet, or hood; Any self-contained breathing apparatus with a full facepiece; 1000 ppm or less: A Type C supplied-air respirator with a full facepiece operated in pressure-demand or other positive pressure mode or with a full facepiece, helmet, or hood operated in continuous-flow mode; Greater than 1000 ppm or entry and escape from unknown concentrations: Self-contained breathing apparatus with a full facepiece operated in pressure-demand or other positive pressure mode; A combination respirator which includes a Type C supplied-air respirator with a full facepiece operated in pressure-demand, or other positive pressure or continuous-flow mode and an auxillary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode; Escape: Any gas mask providing protection against organic vapors, or any self-contained breathing apparatus. [R9, 1981.5] *Wear appropriate personal protective clothing to prevent skin contact. [R11, 35] *Wear appropriate eye protection to prevent eye contact. [R11, 35] *Recommendations for respirator selection. Max concn for use: 12.5 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection needed. [R11, 35] *Recommendations for respirator selection. Max concn for use: 25 ppm. Respirator Class(es): Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with a tight-fitting facepiece and organic vapor cartridge(s). Eye protection needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R11, 35] *Recommendations for respirator selection. Max concn for use: 850 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R11, 35] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R11, 35] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R11, 35] OPRM: *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... Non-impervious clothing which becomes contaminated with bromoform should be removed promptly and not reworn until the bromoform is removed from the clothing. [R9, 1981.2] *Skin that becomes contaminated with liquid bromoform should be promptly washed or showered with soap or mild detergent and water to remove any bromoform. Eating and smoking should not be permitted in areas where bromoform is handled, processed, or stored. Employees who handle bromoform should wash their hands thoroughly with soap or mild detergent before eating or smoking. [R9, 1981.2] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. [R9, 1981.2] *Contact lenses should not be worn when working with this chemical. [R11, 35] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. *The worker should immediately wash the skin when it becomes contaminated. [R11, 35] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R11, 35] SSL: *GRADUALLY DECOMP, ACQUIRING YELLOW COLOR; AIR AND LIGHT ACCELERATE THE DECOMPOSITION. [R1] *Heat /contributes to instability/. [R9, 1981.2] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R29] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R30] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R31] STRG: *KEEP IN WELL-CLOSED CONTAINERS, PROTECTED FROM LIGHT. [R1] CLUP: *1. Ventilate area of spill or leak. 2. Collect for reclamation or absorb in vermiculite, dry sand, earth, or similar material. [R9, 1981.3] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U225, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R32] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. /SRP: If packaged as an aerosol, be careful when releasing in an incinerator or it will blow past the combustion zone./ [R33] *Distillation and recycling: Purify by distillation and return to suppliers. [R34, 206] *Incineration requires dilution with excess fuel. Adsorb on vermiculite before landfill disposal. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R34, 206] *Landfill: Bromoform may be disposed of by adsorbing it in vermiculite, dry sand, earth, or a similar material and disposing in a secured sanitary landfill. [R34, 207] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of bromoform were available. There is limited evidence in experimental animals for the carcinogenicity of bromoform. Overall evaluation: Bromoform is not classifiable as to its carcinogenicity to humans (Group 3). [R35] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on inadequate human carcinogen data and sufficient evidence of carcinogenicity in animals, namely an increased incidence of tumors after oral administration of bromoform in rats and intraperitoneal administration in mice. Bromoform is genotoxic in several assay systems. Also bromoform is structurally related to other trihalomethanes (e.g., chloroform, bromodichloromethane, dibromochloromethane) which have been verified as either probable or possible carcinogens. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R36] +A3. Animal carcinogen with unknown relevance to humans. [R37, 21] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with sterile dressings after decontamination ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R38] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the unconscious patient. Positive pre s sure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of cardiac irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R38] MEDS: *Recommended medical surveillance: The following medical procedures should be made available to each employee who is exposed to bromoform at potentially hazardous levels; Initial Medical Screening: Employees should be screened for history of certain medical conditions which might place the employee at increased risk from bromoform exposure. /Such conditions include/: skin, liver, kidney, and chronic respiratory diseases. ... Periodic Medical Examination: Any employee developing the above conditions should be referred for further medical exam. [R9, 1981.1] HTOX: *... INDICATED AS CAUSING /CNS/ DEPRESSION... . THERE ARE ALSO INDICATIONS OF LIVER INJURY. [R18] *EXPOSURE TO BROMOFORM VAPOR ... CAUSED IRRITATION OF THE RESPIRATORY TRACT, PHARYNX, LARYNX, AS WELL AS LACRIMATION AND SALIVATION. [R28, 1991.154] *SEVERAL CASES OF POISONING HAVE OCCURRED IN CHILDREN; SOME HAVE HAD MAXIMALLY CONSTRICTED PUPILS, BUT OTHERS HAVE HAD MYDRIASIS, PROBABLY RELATED TO DEPTH OF DEPRESSION OF CNS ... . [R39] *Anesthesia incl resp failure has been reported. [R14, 4067] *Irritation of eyes and skin, pulmonary edema, headache, vertigo (dizziness), amnesia (loss of memory), shock, unconsciousness, convulsions (fits). [R40] *Relatively little is known about bromoform, particularly from industrial experience. [R14, 4069] *The in vitro effects of different volatile halocarbons present in drinking water and body fluids were examined on the stimulation of human peripheral blood lymphocytes and on the surface properties of cells of the urinary tract. Proliferation of human lymphocytes was stimulated by phytohemagglutinin, and adhesion of Escherichia coli to uroepithelial cells obtained from human urine was measured. Chloroform, carbon tetrachloride, bromodichloromethane, chlorodibromomethane, and bromoform reduced stimulated lymphocyte proliferation. These inhibiting effects were most noticeable at the highest concentrations (150 to 290 ug/l) of volatile hydrocarbons used, although they were still evident even at the lowest concentrations (0.2 to 0.5 ug/l). Incubation with these compounds also caused a decreased viability of uroepithelial cells. At low concentrations, viability ranged from 40 to 80% of normal levels. At highest concentrations, viability ranged from 10 to 30% of normal levels. No effect on bacterial adhesion was noted. [R41] NTOX: *... /DOG EXPOSED/ TO 10 CC/100 L OF AIR (56,000 PPM). DOG BECAME DEEPLY ANESTHETIZED AFTER 20 MIN AND DIED AFTER 1 HR EXPOSURE. ... 0.41 CC/KG /BY SC INJECTION/ CAUSED DEEP /SRP: CNS DEPRESSION/ AND WAS FATAL TO RABBITS IN 6 HR. [R42] *... MORE TOXIC TO LIVER AND MORE IRRITANT ON INHALATION /THAN CHLOROFORM/, CAUSING TEARING AND SALIVATION. [R39] *... SC DOSE OF 278 MG/KG WAS NEGATIVE /LIVER TOXICITY/ IN MICE, WHEREAS 1,113 MG/KG PRODUCED DECR LIVER FUNCTION AS WELL AS HEPATIC HISTOPATHOLOGY. IN RATS MAXIMAL SINGLE ORAL DOSE SURVIVED WAS 6,578 MG/KG @ 1 HR, 2,099 MG/KG @ 8 HR, [R43] *... INJECTING 100-200 MG/KG/DAY INTO GUINEA PIGS FOR 10 DAYS RESULTED IN PATHOLOGIC CHANGES IN KIDNEY AND LIVER. ... INHALATION BY RATS OF 0.25 MG/L OF AIR FOR 4 HR/DAY FOR 2 MO PRODUCED DISORDERS IN PROTHROMBIN SYNTHESIS AND GLYCOGENESIS IN LIVER AND REDUCED RENAL FILTRATION CAPACITY ... . [R43] *... /CNS DEPRESSANT/ IN 8 MIN AND DEATH IN 1 HR FROM EXPOSURE OF DOGS TO 580 MG/L OF AIR (29,000 PPM). [R18] *FOLLOWING SINGLE ORAL DOSES OF TRIBROMOMETHANE TO RATS CLINICAL SIGNS WERE SEDATION, FLACCID MUSCLE TONE, ATAXIA, PILOERECTION, AND PROSTRATION. PATHOLOGIC EXAM REVEALED LIVER AND KIDNEY CONGESTION. [R44] *FOLLOWING ADMIN OF TRIBROMOMETHANE BY GAVAGE TO MICE, CHANGES INCL FATTY INFILTRATION OF LIVER AND SIGNS OF HEMORRHAGE IN KIDNEYS, ADRENALS, LUNG, AND BRAIN. MALES WERE MORE SENSITIVE THAN FEMALES TO TRIBROMOMETHANE. [R45] *FOLLOWING MULTIPLE IP INJECTIONS IN STRAIN A MICE, BROMOFORM PRODUCED PULMONARY ADENOMAS SIGNIFICANTLY GREATER THAN VEHICLE TREATED CONTROL MICE. [R46] *The undiluted liquid was moderately irritating to rabbit eyes, but healing appeared complete in 1 to 2 days. It was only moderately irritating to rabbit skin even on repeated contact. Single doses of 2000 mg/kg under a cuff on the intact skin of rabbits were survived by two rabbits treated with undiluted bromoform. Lethargy and a slight wt loss were noted from these 24-hr applications. ... Exposure to 2.5 mg/l for 10 days produced functional changes in the CNS, liver, and kidneys. ... Bromoform appears to be mutagenic when tested against three strains of Salmonella typhimurium. [R14, 4065] *Bromoform was tested for the induction of sex linked recessive lethal mutations in Drosophila melanogaster using a standard protocol approved by the National Toxicology Program. Canton-S wild type males were treated with concentrations of bromoform that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce broods for analysis. Bromoform was positive at a dose of 3,000 ppm when administered to males by feeding. [R47] *Byproducts of disinfection were tested for initiating and/or promoting activity in rat liver by using the rat liver foci bioassay. The assay uses an increased incidence of gamma-glutamyltranspeptidase positive foci as an indicator of carcinogenicity. The byproducts of disinfection, including halogenated methanes, did not initiate gamma-glutamyltranspeptidase positive foci, which would indicate that they were not capable of initiating carcinogenesis. [R48] *The effect of trichloromethanes, dichlorobromomethane, dibromochloromethane, and tribromomethane on in vitro lipid metabolism was compared using rat liver slices. The incorporation of (32)P and (3)H glycerol into phospholipid of liver slices was inhibited in the presence of trihalomethanes. The inhibitory effect followed the number of bromine atoms in the trihalomethane molecule in the initial period of incubation. Tribromomethane markedly inhibited the incorporation of (3)H glycerol into triacylglycerol; dibromochloromethane was less effective, and the other two trihalomethanes were without effect. The activities of glycerophosphate acyltransferase, phosphatidate phosphatase, and diacylglycerol acyltransferase were changed by the exposure to trihalomethanes. The effects of dibromochloromethane and tribromomethane were much more severe as compared to those of dichlorobromomethane and trichloromethane. [R49] *Halomethanes were assessed for toxicity using cultured primate cells. Cultures of ... African green monkey kidney cells were used. Cells were incubated for 72 hr in the presence of 30 to 300 ug/ml tribromomethane or dibromochloromethane, 100 to 1000 ug/ml bromodichloromethane, 300 to 3000 ug/ml trichloromethane, or vehicle only. After incubation, viable cells were counted, and concentrations causing 50% inhibition of cell growth (LD50) were determined. Linear dose versus response relationship was obtained for all compounds. LD50s in ... cultures were 70 to 80 ug/ml for tribromomethane, 130 to 140 ug/ml for dibromochloromethane, 405 to ug/ml for trichloromethane. Tribromomethane is the most toxic of the compounds tested, and trichloromethane is the least toxic. [R50] *The effects of alkyl halides on hepatic heme metabolism were studied in rats. Male Sprague-Dawley rats were administered by oral gavage one of 13 alkyl halides. Eighteen hours after dosing, animals were killed, and livers were removed and assayed for microsomal cytochrome p450, 5-aminolevulinate hydrolase, reduced glutathione, and total protein and porphyrins. The most consistent response was a decrease in microsomal cytochrome p450 content, shown by 11 of 13 alkyl halides. 5-Aminolevulinate hydrolase activity was significantly reduced by 10 alkyl halides reduced glutathione showed a variable response; it was significantly elevated by four alkyl halides and significantly decreased by three alkyl halides. Total porphyrins were significantly decreased by five alkyl halides and significantly increased by bromoform. Total hepatic protein was significantly elevated only by chloroform. Alkyl halide intoxication commonly perturbs hepatic heme synthesis. Cytochrome p450 and 5-aminolevulinate hydrolase activity are the most sensitive indices of this perturbation. [R51] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of tribromomethane for male F344/N rats and clear evidence of carcinogenic activity for female F344/N rats, based on incr incidences of uncommon neoplasms of the large intestine. Reduced survival for male rats given 200 mg/kg tribromomethane lowered the sensitivity of this group to detect a carcinogenic response. ... There was no evidence of carcinogenic activity for male B6C3F1 mice given 50 or 100 mg/kg tribromomethane or for female B6C3F1 mice given 100 or 200 mg/kg; male mice might have been able to tolerate a higher dose. Survival of female mice was reduced, partly due to a utero-ovarian infection. [R52] *Bromoform was tested for carcinogenicity in two-year studies by oral gavage in male and female B6C3F1 mice and Fischer 344 rats. It induced a low incidence of adenomatous polyps and adenocarcionmas of the large intestine in male and female rats. [R53] *A single ip dose of 3 mmol/kg bw given to Sprague-Dawley rats has also been shown to produce renal dysfunction, characterized by a reduction in glomerular filtration rate, reduced renal concentrating ability and elevated blood urea nitrogen levels. [R35] *... Bromoform was rated as 38 times less hepatotoxic than tetrabromomethane. [R28, 1991.154] *PHENOBARBITAL TREATMENT INCR BLOOD CARBON MONOXIDE LEVELS AFTER ADMIN OF BROMOFORM IN RATS. SKF 525-A (2-DIETHYLAMINOETHYL 2,2-DIPHENYLVALERATE HYDROCHLORIDE) SIGNIFICANTLY INHIBITED THE IN VIVO METABOLISM OF BROMOFORM TO CARBON MONOXIDE. [R54] NTXV: *LD50 Rat male oral 2500 mg/kg /10% soln in corn oil/; [R55] *LD50 Mouse female oral 1500 mg/kg; [R55] *LD50 Rat male oral 1388 mg/kg; [R56] *LD50 Rat female oral 1147 mg/kg; [R56] *LD50 Rat ip 414 mg/kg; [R23] *LD50 Mouse sc 1820 mg/kg; [R23] ETXV: *LC50 Crassostrea virginica (eastern oyster) larvae 1 mg/l/48 hr static bioassay; after 48 hr, only approx 30% of original concn was still present; [R26] *LC50 Lepomis macrochirus (bluegill sunfish) 29,300 mg/l/96 hr static bioassay; [R57] *LC50 Mysidopsis bahia (mysid shrimp) 24,400 mg/l/96 hr static bioassay; [R57] *LC50 Cyprinodon variegatus (sheepshead minnow) 17,900 mg/l/96 hr static bioassay; [R57] NTP: *Toxicology and carcinogenesis studies were conducted by admin tribromomethane (95-97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. Based on these results, 2 yr studies of tribromomethane were conducted by admin 0, 100, or 200 mg/kg tribromomethane in corn oil by gavage, 5 days/wk for 103 wk, to groups of 50 F344/N rats of each sex and 50 female B6C3F1 mice. Male B6C3F1 mice were admin 0, 50, or 100 mg/kg tribromomethane on the same schedule. Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of tribromomethane for male F344/N rats and clear evidence of carcinogenic activity for female F344/N rats, based on incr incidences of uncommon neoplasms of the large intestine. Reduced survival for male rats given 200 mg/kg tribromomethane lowered the sensitivity of this group to detect a carcinogenic response. ... There was no evidence of carcinogenic activity for male B6C3F1 mice given 50 or 100 mg/kg tribromomethane or for female B6C3F1 mice given 100 or 200 mg/kg; male mice might have been able to tolerate a higher dose. Survival of female mice was reduced, partly due to a utero-ovarian infection. [R52] TCAT: ?The mutagenicity of bromoform was evaluated in Salmonella tester strains TA98, TA1535, TA1537, and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, bromoform was evaluated for mutagenicity at concentrations of 5, 10, 50, 100, 500, and 1000 ug/plate using the direct plate incorporation method. Bromoform did not cause a reproducible positive response in any of the tester strains, either with or without metabolic activation. The mutagenicity of bromoform was also tested for mutagenicity in Salmonella tester strains TA98, TA100 and TA1535, both with and without metabolic activation at dose levels of 0.02, 0.05, 0.1, and 0.2 ml/dessicator. In this study, bromoform caused a reproducible positive response in all three strains. [R58] ?The ability of bromoform to induce mitotic recombination was evaluated in Sacchomyces cerevisiae D3 at levels of 0,0.02, 0.04, and 0.08% concentration (w/v or v/v), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Bromoform did not cause a significant increase in mitotic recombinations, either with or without added metabolic activation. [R58] POPL: *Individuals ... with skin, liver, kidney,or chronic respiratory diseases may be at a increased risk from bromoform exposure. [R9, 1981.1] ADE: *... MAY BE ABSORBED THROUGH THE LUNGs, FROM THE GI TRACT AND, TO A CERTAIN EXTENT, THROUGH THE SKIN. THE BRAIN CONTAINS HIGHER CONCN OF BROMOFORM THAN BLOOD AND LIVER FOLLOWING INHALATION. [R28, 1991.154] *... IN RABBITS ... BROMOFORM ADMIN RECTALLY OR BY INHALATION WAS BIOTRANSFORMED IN LIVER AND ... INORGANIC BROMIDES WERE LATER FOUND IN TISSUES AND URINE. AFTER RECTAL ANESTHESIA WITH BROMOFORM, 0.3-1.2% OF DOSE WAS RECOVERED IN URINE AS SODIUM BROMIDE. [R43] *... Bromoform ... labeled with (14)C was administered by intragastric intubation to male Sprague-Dawley rats and male B6C3F1 mice. After 36 or 48 hr, necropsies were performed. Blood, bladder, brain, kidneys, liver, lung, skeletal muscle, pancreas, stomach, and thymus were studied. The total radioactivity for sampled organs ranged from 3 to 6% of the total dose in the rats versus 5 to 14% for the mice. In both species, the urine contained less than 5% of total radiolabel at 8 hr post intubation and less than 10% of the total radiolabel at 36 to 48 hr. ... (14)C activity was found in the blood following bromoform dosing. Mice metabolize /bromoform/ to a greater extent than rats. [R59] METB: *TRIBROMOMETHANE METABOLIZED TO CARBON MONOXIDE BY HEPATIC MICROSOMAL MIXED FUNCTION OXIDASES. [R60] *ADMIN TO RATS OF (13)CARBON-BROMOFORM LED TO FORMATION OF ENRICHED (13)CARBON MONOXIDE A DOSE-DEPENDENT RELATIONSHIP BETWEEN BROMOFORM DOSE AND CARBON MONOXIDE PRODUCTION WAS OBSERVED. [R54] *TRIBROMOMETHANE FORMS COMPLEXES WITH FERROUS CYTOCHROME P450, CARBON MONOXIDE WAS DETECTED AS METABOLIC PRODUCT OF THE INTERACTION. [R61] *BIOTRANSFORMATION OF BROMOFORM TO CARBON MONOXIDE WAS CHARACTERIZED WITH RESPECT TO TIME COURSE, MICROSOMAL PROTEIN CONCN, PH AND TEMP. [R62] *IT IS METABOLIZED TO CARBON MONOXIDE AND BROMIDE. [R14, 4052] *When hepatocytes isolated from phenobarbital-induced rats were incubated with chloroform and the spin trap phenyl-t-butyl nitrone under anaerobic conditions, a free radical-spin trap adduct was detectable by ESR spectroscopy. A similar incubation of hepatocytes in the presence of air resulted in an ESR signal that was eight times less intense than that seen under anaerobic conditions; incubation mixtures exposed to pure oxygen had non-detectable adduct signal. A significant reduction in the signal intensity was also produced by the addition of cytochrome p450 inhibitors such as SKF-525A, metyrapone and carbon monoxide, indicating that free radical formation depended upon the reductive metablism of chloroform mediated by the mixed oxidase system. Free radical intermediates were also detected during the aerobic and anaerobic incubation of isolated hepatocytes with bromoform and iodoform. The intensity of the ESR signal obtained with the various trihalomethanes increases in the order chloroform < bromodichloromethane < bromoform < iodoform. [R63] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: */Former use:/ Medication: sedative [R64] */Former use:/ Medication: antitussive [R65] */Former use:/ Medication: antiseptic [R14, 4064] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Tribromomethane's production and use in fire extinguishers, in the shipbuilding, aircraft and aerospace industries, in organic synthesis, as a solvent for waxes, greases and oils may result in its release to the environment through various waste streams. Tribromomethane is a byproduct of water chlorination. Marine algae produce significant quantities of tribromomethane. If released to air, an estimated vapor pressure of 5.4 mm Hg at 25 deg C indicates tribromomethane will exist solely as a vapor in the ambient atmosphere. Vapor-phase tribromomethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 330 days. If released to soil, tribromomethane is expected to have very high mobility based upon an estimated Koc of 35. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 5.4X10-4 atm-cu m/mole. Tribromomethane may volatilize from dry soil surfaces based upon its vapor pressure. In simulated anoxic groundwater environments, approximately 20% degradation of tribromomethane has been observed in approximately 6 hours; 99% degradation was observed after approximately 2.5 days. If released into water, tribromomethane is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 7.3 hours and 7.1 days, respectively. In a couple of aqueous aerobic biodegradation tests, tribromomethane exhibited little biodegradation. An estimated BCF of 14 suggests the potential for bioconcentration in aquatic organisms is low. Based upon an estimated half-life of 602 years at pH 8, hydrolysis is not expected to be an important fate process. Occupational exposure to tribromomethane may occur through inhalation and dermal contact with this compound at workplaces where tribromomethane is produced or used. Due to the production of tribromomethane by marine algae, low concentrations of tribromomethane are typically detected in sea water and the surrounding air. (SRC) NATS: *Tribromomethane is produced by macroalgae(1-3) and microalgae(4). An experimentally-determined production rate for coralline algae (Corallinaceae) collected from the Sea of Japan is 83 ng/hour - g of algae (wet weight)(2). Laboratory and in-situ measurements of tribromomethane production by giant kelp (M. Pyrifera) collected from the southern California coastal region ranged from 25-1,126 (median = 171) ng/day/g of fresh weight and 136-304 (median = 256) ng/day/g of fresh weight, respectively(3). [R66] ARTS: *Tribromomethane's production and use in fire extinguishers(1), in the shipbuilding, aircraft and aerospace industries(1), in organic synthesis(2), as a solvent for waxes, greases and oils(2) and in medicinal(3) uses may result in its release to the environment through various waste streams(SRC). Tribromomethane is a byproduct of the chlorination of sea water(4). [R67] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 35(SRC), determined from a structure estimation method(2), indicates that tribromomethane is expected to have very high mobility in soil(SRC). Volatilization of tribromomethane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 5.35X10-4 atm-cu m/mole(3). The potential for volatilization of tribromomethane from dry soil surfaces may exist(SRC) based upon a an estimated vapor pressure of 5.4 mm Hg(4). Anaerobic biodegradation in soil may be an important fate process based on anaerobic sewage studies(5-7). [R68] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 35(SRC), determined from an estimation method(2), indicates that tribromomethane is not expected to adsorb to suspended solids and sediment in water(SRC). However, sorption of tribromomethane has been observed in field studies performed in contaminated groundwater environments(3) and in batch experiments performed in a laboratory(4). Volatilization from water surfaces is expected(5) based upon a Henry's Law constant of 5.35X10-4 atm-cu m/mole(6). Using this Henry's Law constant and an estimation method(5), volatilization half-lives for a model river and model lake are 7.3 hours and 7.1 days, respectively(SRC). In a couple of aqueous aerobic biodegradation tests, tribromomethane exhibited little biodegradation(11,12). According to a classification scheme(7), an estimated BCF of 14(SRC), from a log Kow of 2.40(8) and a regression-derived equation(9), suggests the potential for bioconcentration in aquatic organisms is low. The rate constant for the aqueous-phase reaction of tribromomethane with hydroxyl radicals is 1.3X10+8 L/mole-sec at 24 deg C(10). This corresponds to an half-life of about 1.7 years at an aqueous concentration of 1X10-17 mole/l hydroxyl radicals(SRC). Based upon an estimated half-life of 602 years at pH 8(SRC), hydrolysis is not expected to be an important fate process. [R69] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tribromomethane, which has an estimated vapor pressure of 5.4 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase tribromomethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 330 days(SRC), from its rate constant of 4.9X10-14 cu cm/molecule-sec at 25 deg C, determined using a structure estimation method(3). [R70] BIOD: *Tribromomethane was incubated with sewage seed at 5 and 10 mg/l for 7 days followed by three weekly subcultures at 25 deg C(1). In the 5 and 10 mg/l cultures, tribromomethane had degraded by 11% and 4% respectively, at 7 days and by 48% and 35% respectively at 28 days(1). Tribromomethane was not biodegraded in aerobic batch cultures, but > 99% of the initial tribromomethane was removed by treatment in a methanogenic (anaerobic conditions) biofilm column (2 day retention time in column)(2). Under denitrifying conditions, a 60 ug/l solution of tribromomethane degraded to 59, 37, 35, and 2 ug/l after 2, 3, 4, and 6 weeks, respectively(3). [R71] *AEROBIC: Tribromomethane, present at 100 mg/l, underwent 0% biodegradation in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). [R72] *ANAEROBIC: Transformation of tribromomethane has been observed in laboratory experiments under conditions of denitrification and methanogenesis(1-3). The experiments were conducted in continuous flow columns intended to simulate groundwater environments(1,2). The columns were seeded with mixed cultures of bacteria; acetate was used as the primary substrate(1,2). Approximately 20% of the initial concentration of 57 ug/l underwent biodegradation after 6.25 hours; approximately 30% biodegraded after 25 hours(1). Greater than 99% of the initial concentration of 18 ug/l was removed under methanogenic, denitrification and sulfate reducing conditions after 2.5 days(2). Greater than 99% reduction of tribromomethane, initially present at 132-177 ug/l was observed after 1.5 hours in a continuous flow column that was seeded with primary settled sewage; the above removal rate was attained approximately 1 year after operation of the column began(3). [R73] ABIO: *The rate constant of the hydrolysis of tribromomethane is 3.2X10-11 1/sec and the half-life of the reaction is 686 years(1). Direct photolysis is not expected to be significant in the troposphere, but by analogy to methyl bromide(2), direct photolysis in the stratosphere may be an important fate process(SRC). [R74] *The rate constant for the vapor-phase reaction of tribromomethane with photochemically-produced hydroxyl radicals has been estimated as 4.94X10-14 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 325 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(4). A base-catalyzed second-order hydrolysis rate constant of 3.65X10-5 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 6020 and 602 years at pH values of 7 and 8, respectively(2). Based upon an estimated half-life of 602 years at pH 8(SRC), hydrolysis is not expected to be an important fate process. [R75] BIOC: *An estimated BCF of 14 was calculated for tribromomethane(SRC), using a log Kow of 2.40(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R76] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for tribromomethane can be estimated to be 35.04(SRC). According to a classification scheme(2), this estimated Koc value suggests that tribromomethane is expected to have very high mobility in soil. A Freundlich K value of 1.54 was determined on Keweenaw sandy loam(3). [R77] VWS: *The volatilization half-lives of tribromomethane at 25 deg C at depths of 6.5 cm and 14.5 cm are 29.3 and 65.4 min, respectively(1). Using a measured Henry's Law constant of 6.6X10-4 atm cu-m/mol(2), the estimated half-life for the volatilization of tribromomethane from a model river with a wind velocity of 3 m/s, a current of 1 m/s, and a depth of 1 m is 7.2 hrs(3). [R78] *The Henry's Law constant for tribromomethane was measured as 5.35X10-4 atm-cu m/mole. This Henry's Law constant indicates that tribromomethane is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 7.26 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 7.08 days(SRC). Tribromomethane's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of tribromomethane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 5.40 mm Hg(3). The volatilization half-lives of tribromomethane at 25 deg C at depths of 6.5 cm and 14.5 cm are 29.3 and 65.4 min, respectively(4). [R79] WATC: *SURFACE WATER: Eugene, OR - 1% samples pos, 1 ug/l(1). New Jersey - 604 samples, 32.6% pos, 3.7 ppb maximum(2). New Jersey - 0.6 ug/l mean(3). New Orleans/Baton Rouge - not detected-0.57 ug/l, 0.25 ug/l mean(3). Delaware - 280 ppb maximum(4). Niagara River (lower) - not detected-6 ng/l(5). Lake Ontario - not detected-7 ng/l(5). [R80] *SURFACE WATER: Allegheny River (at Pittsburgh, PA) - 501 samples, 1.4% pos, 2 at 0.1-1.0 ug/l and 5 at 1.0-10.0 ug/l(1). Ohio River (at West View, OH) - 113 samples, 9.7% pos, 10 at 0.1- 1.0 ug/l and 1 at 1.0-10.0 ug/l(1). Ohio River (at Wheeling, WV) - 539 samples, 0.7% pos, 3 at 0.1-1.0 ug/l, 1 at 1.0-10.0 ug/l(1). Ohio River (at Parkersburg, WV) - 264 samples, 1.5% pos, 4 at 1.0-10.0 ug/l(1). Kanawha River (at St. Albans, WV) - 257 samples, 1.5% pos, 4 at 1.0-10.0 ug/l(1). Kanawha River (at St. Albans, WV) - 257 samples, 31.5% pos, 70 at 0.1-1.0 ug/l, 11 at 1.0-10.0 ug/l(1). Ohio River (at Huntington, WV) - 530 samples, 17.4% pos, 84 at 0.1-1.0 ug/l, 8 at 1.0-10.0 ug/l(1). Ohio River (at Portsmouth, OH) - 451 samples, 2.0% pos, 6 at 0.1-1.0 ug/l, 3 at 1.0-10.0 ug/l(1). Ohio River (at Cincinnati, OH) - 717 samples, 0.3% pos, 2 at 0.1-1.0 ug/l(1). Ohio River (at Louisville, KY) - 712 samples, 0.4% pos, 3 at 0.1-1.0 ug/l(1). Ohio River (at Evansville, IN) - 632 samples. 0.9% pos, 5 at 0.1-1.0 ug/l, 1 at 1.0-10.0 ug/l(1). Tribromomethane was detected but not quantified in surface water samples taken in Narragansett Bay, RI(2). [R81] *SURFACE WATER: Tribromomethane was detected in samples collected from the Nansen Basin in Arctic Ocean at 3-7 ng/l at depths less than 200 m below the ice cover; at depths greater than 3000 m concentrations ranged from 0.7-0.9 ng/l(1). Marine algae were suggested as the source of the emissions(1). Tribromomethane was detected at concentrations ranging from 0.6-15.0 ng/l in 58 samples collected from the NW Atlantic between April-May 1991; the highest concentrations were detected in shelf waters(2). [R82] *DRINKING WATER: Various US water treatment plants (80) - not detected-92 ug/L(1). Unspecified US cities - 12 ug/l mean (of positives), < 0.3 ug/l median of all samples(2). Delaware - 20 ppb in drinking water wells(3). Tribromomethane was detected but not qualified in drinking water samples taken in Washington, DC(4), Philadelphia, PA(5), unspecified US drinking water(6), Japan(7), England(8). [R83] *DRINKING WATER: Tribromomethane was detected in 145 of 11,765 samples collected between 1984-1990 from public drinking water sources in California, none of which exceeded the California MCL; the mean, median, maximum and minimum concentrations of the positive samples are 7.63, 3.13, 90.50 and 0.03 ug/l(1). Tribromomethane was detected in 27 of 7,712 samples collected between 1984-1990 from groundwater wells used for potable water supply in California; the maximum concentration detected was 78 ug/l(2). The maximum concentration of tribromomethane detected in treated water samples collected on a monthly basis in 1994 from four locations in the distribution systems of three water treatment plants in Canada, each employing a different disinfection process, was 0.3 ug/l(3). In 1978, tribromomethane was detected in 13 and 26% of U.S. surface water and groundwater supply systems (total=450 systems), respectively.; the mean (median) values in groundwater and surface water systems were 2.1 (< 1) and 11 (< 0.5) ug/l, respectively(4). In 1978-80, tribromomethane was detected in 18% of the drinking water samples collected from 2000 rural households in the U.S. that were serviced by surface water supplies; the mean of the positive samples was 8.7 ug/l and the median of all samples was < 0.5 ug/l(4). Of the 2000 households serviced by groundwater supplies, tribromomethane was detected in 12% of the homes; the mean of the positive samples was 12 ug/l and the median of all samples was < 0.5 ug/l(4). Based on 117 samples collected in February 1984, the population-weighted estimates of the mean (median) concentration of tribromomethane in Los Angeles, CA drinking water were estimated as 0.78 (0.54) ug/l; based on 52 samples collected in May 1984: 8.08 (3.0) ug/l; based on 9 samples collected in February 1987: 3.2 (3.2) ug/l; based on 7 samples collected in February 1987: 25.5 (9.6) ug/l; the population-weighted mean (median) for Antioch-Pittsburgh, CA based on 71 samples collected in June 1984: 0.78 (0.58) ug/l(4). [R84] *GROUNDWATER: New Jersey - 1072 samples, 21.9% pos, 34.3 ppb maximum(1). Delaware - 20 ppb in drinking water wells(2). Unspecified, randomly selected US sites serving < 10,000 persons - 280 samples, 15.7% pos, 2.4 ug/l median (of positives), 54 ug/l maximum(3). Unspecified, randomly selected US sites serving > 10,000 persons - 186 samples, 30.6% pos, 3.8 ug/l median (of positives), 50 ug/l maximum(3). Unspecified, non-randomly selected US sites serving < 10,000 persons - 321 samples, 27.4% pos, 3.7 ug/l median (of positives), 110 ug/l maximum(3). Unspecified, non-randomly selected US sites serving > 10,000 persons - 158 samples, 38.0% pos, 5.1 ug/l median (of positives), 68 ug/l maximum(3). Tribromomethane was detected but not quantified in groundwater samples taken in New Jersey(4). [R85] *RAIN/SNOW: Oregon (SW of Portland, OR) - Rain samples, not detected-0.50 ng/l, 0.3 ng/l mean(1). [R86] *SWIMMING POOLS: The mean concentration of tribromomethane in 5 outdoor pools, 4 indoor pools and four hot tubs were < 0.1 ug/l, 6 and 13 ug/l, respectively(1). [R87] EFFL: *Tribromomethane residues in treated wastewater effluents from several industries were as follows(1). Nonferrous metals manufacturing - 49 samples, 6.1% pos, not detected-44 ug/l, 2.1 ug/l mean; Pulp and Paperboard Mills - 18 samples, 5.5% pos, not detected-62 ug/l, 10 ug/l mean(1). Tribromomethane was detected but not quantified in front and tail brine from bromine industries in El Dorado, AR and Magnolia, AR(2), and in secondary effluents from wastewater treatment plant(3). Tribromomethane has been detected in leachate/contaminated groundwater from industrial landfills from 10-380 ug/l; from municipal landfills at 0.2 ug/l(4). [R88] SEDS: *Tribromomethane was detected but not quantified in sediment samples taken in El Dorado, AR and Magnolia, AR(1). [R89] ATMC: *URBAN/SUBURBAN: El Dorado, AR - not detected-27.9 ng/cu m, 8.37 ng/cu m mean; Lakes Charle, LA - 68.2-734 ng/cu m, 516.9 ng/cu m; Magnolia, AR - not detected-85.8 ng/cu m, 15.5 ng/cu m(1). Tribromomethane was not detected in 355 pairs of ambient air samples/personal breathing zone samples collected in Elizabeth and Bayonne, NJ in the fall of 1981(2). Tribromomethane was not detected in any of the 240 outdoor air samples collected in Los Angeles and Contra Costa, CA in February-June 1984; detection limit was not reported(3). A survey of available information on ambient concentrations of the 189 hazardous air pollutants (HAPs) listed in the 1990 Clean Air Act Amendment found no detectable quantities of tribromomethane reported out of 423 samples collected in 17 locations between 1976-1989(4,5). [R90] *RURAL/REMOTE: Tribromomethane was detected in air samples collected during three sampling efforts: in the western Pacific between January 31 and February 1991 at concentrations ranging from 0.28-2.9 parts per trillion/volume, with a mean of 1.01 (n=23); in the western Pacific between September and October 1992 at concentrations ranging from 0.13-1.91 parts per trillion/volume with a mean of 0.63 parts per trillion/volume (n=48); and in the East China Sea, South China Sea and Bay of Bengal between January and March 1994 at concentrations ranging from 0.32-7.1 parts per trillion/volume, with a mean of 1.2 parts per trillion/volume (n=73)(1). [R91] FOOD: *The range and mean tribromomethane concentration in three meals eaten by 30 housewives in Japan in 1990 were < 0.5-8.1 ppb and 0.5 ppb, respectively; the mean intake of tribromomethane was 0.9 ug/d(1). [R87] PFAC: PLANT CONCENTRATIONS: *Tribromomethane was quantified in several species of algae as follows: Ascophyllum nodosum - 28-520 ng/g, 120 ng/g mean; Fucus vesiculous - 24-62 ng/g, 41 ng/g mean; Gigartina stellata - 3-19 ng/g, 9 ng/g mean(1). All measurements were made on a dry weight basis(1). [R92] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,473 workers (230 of these are female) are potentially exposed to tribromomethane in the US(1). Occupational exposure to tribromomethane may occur through inhalation and dermal contact with this compound at workplaces where tribromomethane is produced or used(SRC). The general population may be exposed to tribromomethane via inhalation of ambient air, ingestion of food and drinking water, consumption of products prepared with chlorinated water and dermal contact with this compound(SRC). [R93] BODY: *The range and mean concentration of tribromomethane in the whole blood of 250 hospital patients, 121 males and 129 females, half of was nd-3.4 ng/ml and 0.6 ng/ml, respectively(1). Tribromomethane was not detected in any of the composite samples analyzed as part of EPA's 1982 National Human Adipose Tissue Survey, although the accuracy of the measurements have been questioned due to sample handling and preparation(2). [R94] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *850 ppm [R11, 34] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 0.5 ppm (5 mg/cu m). Skin Designation. [R95] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.5 ppm (5 mg/cu m), skin. [R11, 34] TLV: +8 hr Time Weighted Avg (TWA) 0.5 ppm, skin [R37, 20] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R37, 6] +A3. A3= Confirmed animal carcinogen with unknown relevance to humans. [R37, 20] OOPL: *Australia: 0.5 ppm, skin (1990); United Kingdom: 0.5 ppm, skin (1990). [R28, 1991.155] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Tribromomethane is included on this list. [R96] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 80 ug/l [R97] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.19 ug/l [R97] +(FL) FLORIDA 4 ug/l [R97] +(MN) MINNESOTA 40 ug/l [R97] +(NH) NEW HAMPSHIRE 4.0 ug/l [R97] +(WI) WISCONSIN 4.4 ug/l [R97] CWA: +For the maximum protection of human health from the potential carcinogenic effects due to exposure of bromoform, the ambient water concentration should be zero based on the non-threshold assumption for this chemical. However, zero level may not be attainable at the present time. Therefore, the levels which may result in incremental increase of cancer risk over the lifetime are estimated at 1X10-5, 1X10-6, and 1X10-7. The corresponding recommended criteria are 1.9 ug/l, 0.19 ug/l, and 0.019 ug/l, respectively. If the above estimates are made for consumption of aquatic organisms only, excluding consumption of water, the levels are 157 ug/l, 15.7 ug/l, and 1.57 ug/l, respectively. [R98] +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Halomethanes/ [R99] +The maximum contaminant level (MCL) set forth by the National Primary Drinking Water Regulations for organic chemicals including total trihalomethanes (the sum of the concentrations of bromodichloromethane, dibromochloromethane, tribromomethane (bromoform) and trichloromethane (chloroform)) is 0.10 mg/l. /Total trihalomethanes/ [R100] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R101] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R102] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Tribromomethane is included on this list. [R103] RCRA: *U225; As stipulated in 40 CFR 261.33, when tribromomethane, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R104] FDA: *Tribromomethane is a chemical derivative of bromal, specified in section 502(d) of the Federal Food, Drug, and Cosmetic Act, and is designated as habit forming. [R105] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Measurements to determine employee exposure are best taken so that the avg 8 hr exposure is based on a single 8 hr sample or on two 4 hr samples. ... Air samples should be taken in the employee's breathing zone. ... Sampling ... may be performed by collection of bromoform vapors using an adsorption tube. [R9, 1981.3] *Air samples containing bromoform are taken with a glass tube, 7 cm x 4 mm ID, containing two sections of activated coconut shell charcoal (front= 100 mg, back= 50 mg) separated by a 2 mm urethane foam plug. A silyated glass wool plug precedes the front section and a 3 mm urethane foam plug follows the back section. A sampling pump is connected to this tube and accurately calibrated at a flow rate of 0.01 to 0.2 l/min for a total sample size of 1.0 to 10 l. Elution is performed with 1.0 ml of carbon disulfide and allowed to stand for 30 min. This technique has an overall precision of 0.047, over a studied range of 3.0 to 10 mg/cu m using 10-liter samples. [R106] ALAB: *NIOSH Method 1003. Hydrocarbons, halogenated. Limit of detection is 0.01 mg/sample. [R107] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. This method is applicable to municipal and industrial discharges as provided under 40 CFR 136.1. The method detection limit is 0.200 ug/l. [R108] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. This method is applicable to the determination of purgeable organics in industrial and municipal discharges. The method detection limit is 4.700 ug/l. [R108] *EPA Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. This method is applicable to the analysis of soils and sludges for VOCs. The method detection limit is 7.000 ug/l. [R108] *EPA Method 502.1. Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography Revision 2.0. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. The method detection limit is 0.050 ug/l. [R108] *EPA Method 502.2. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. The method detection limit is 1.600 ug/l. [R108] *EPA Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. This method is applicable to finished drinking water, raw source water, and drinking water in any treatment stage. The method detection limit is 0.700 ug/l. [R108] *EPA Method 524.2. Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry. Revision 4.0. This method is applicable to surface water, ground water, and drinking water in any treatment stage. The method detection limit is 0.120 ug/l. [R108] *EPA Method OSW 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. The method detection limit is 0.020 ug/l. [R109] *EPA Method OSW 8240B. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). This method is applicable to various types of samples regardless of water content, including ground water, aqueous sludges, caustic liquors, acid liquors, waste solvents, oily waste, mousses, tars, fibrous wastes, polymeric emulsions, filter cakes, spent carbons, spent catalysts, soils, and sediments. The estimated quantitation limit is 5.000 ug/kg. [R109] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Halomethanes (1980) EPA 440/5-80-051 DHHS/ATSDR; Toxicological Profile for Bromoform/Chlorodibromomethane (1990) ATSDR/TP-90/05 DHHS/NTP; Toxicology and Carcinogenesis Studies of Tribromomethane in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 350 (1989) NIH Publication No. 89-2805 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 232 R2: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 328 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 165 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (92) 570 R5: CHEMCYCLOPEDIA 1986 p.59 R6: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 488 R7: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983.,p. V1 (83) 328 R8: SRI R9: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R10: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. C-350 R11: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R12: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999. R13: Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R14: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R15: Horvath AL; Halogenated hydrocarbons: solubility-miscibility with water. NY, NY: Marcel Dekker, Inc pp. 889 (1982) R16: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-375 R17: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R18: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1262 R19: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 160 R20: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. 10 R21: Munz C, Roberts PV; J Am Water Works Assoc 79: 62-9 (1987) R22: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-159 R23: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 519 R24: National Research Council. Drinking Water and Health. Volume 2. Washington, DC: National Academy Press, 1980. 52 R25: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R26: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 333 R27: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 158 R28: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R29: 49 CFR 171.2 (7/1/99) R30: IATA. Dangerous Goods Regulations. 40th Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 1999. 119 R31: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6088 (1998) R32: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R33: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-16 (1981) EPA 68-03-3025 R34: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1311 (1999) R36: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Bromoform (75-25-2) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R37: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R38: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 188 R39: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 203 R40: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 81 R41: Kroneld R; Bull Environ Contam Toxicol 38 (5): 856-61 (1987) R42: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.67 R43: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 696 R44: CHU I ET AL; TOXICOL APPL PHARMACOL 52 (2): 351-3 (1980) R45: BOWMAN F ET AL; TOXICOL APPL PHARMACOL 44 (1): 213-6 (1978) R46: THEISS JC ET AL; CANCER RES 37 (8 PART 1): 2717-20 (1977) R47: Woodruff RC et al; Environ Mutagen 7: 677-702 (1985) R48: Herren-Freund SL, Pereira NA; Environ Heath Perspect 69: 59-65 (1986) R49: Kayama Y, Nakazawa Y; Toxicol Lett 31 (1): 37-44 (1986) R50: Mochida K, Yamasaki M; Bull Environ Contam Toxicol 33 (3): 253-6 (1984) R51: Moody DA, Smuckler EA; Toxicol Lett 32 (3): 209-14 (1986) R52: Toxicology and Carcinogenesis Studies of Tribromomethane (Bromoform) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 350 (1989) NIH Publication No. 89-2805 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R53: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1310 (1999) R54: ANDERS MW ET AL; DRUG METAB DISPOS 6 (5): 556-60 (1978) R55: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3469 R56: Chu I et al; Toxicol Appl Pharmacol 52 (2): 351-53 (1980) R57: USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.B-5 (1980) EPA 440/5-80-051 R58: SRI International; In Vitro Microbiological Mutagenicity Studies of Dow Chemical Company Compounds (Interim Report), EPA Doc. No. 86-870001204, Fiche No. OTS0516107 R59: Mink FL et al; Bull Environ Contam Toxicol 37 (5): 752-8 (1986) R60: STEVENS JL, ANDERS MW; BIOCHEM PHARMACOL 28 (21): 3189-94 (1979) R61: WOLF CR ET AL; MOL PHARMACOL 13 (4): 698-705 (1977) R62: AHMED AE ET AL; DRUG METAB DISPOS 5 (2): 198-204 (1977) R63: Tomasi A et al; Chem Biol Intract 55 (3): 303-16 (1985) R64: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 172 R65: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 4(78) 253 R66: (1) Laturnas F; Chemosphere 31: 3387-95 (1995) (2) Itoh N, Shinya M; Marine Chemistry 45: 95-103 (1994) (3) Goodwin KD et al; Limnol Oceanogr 42: 1725-1734 (1997) (4) Sturges WT et al; Tellus, Ser B 45B: 120-6 (1993) R67: (1) Inter Lab Off; Encycl Occup Health Safety. Geneva, Switzerland: Inter Lab Off 1: 328 (1983) (2) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons p. 165 (1997) (3) Budavari S, ed; The Merck Index. 12th ed Whitehouse Station, NJ: Merck and Co p. 232 (1996) (4) Wakeham SG et al; Can J Fish Aquat Sci 40: 304-21 (1983) R68: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Munz C, Roberts PV; J Am Water Works Assoc 79: 62-9 (1987) (4) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Publ (1984) (5) Wookeun B et al.; J Contam Hydrol 6: 53-68 (1990) (6) Bouwer EJ, Wright JP; J Contam Hydrol 2: 155-169 (1988) (7) Cobb GD, Bouwer EJ; Environ Sci Technol 25: 1068-1074 (1991) R69: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Roberts PV et al; Wat Resources 22: 2047-58 (1986) (4) Curtis GP et al; Wat Resources 22: 2059-67 (1986) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (6) Munz C, Roberts PV; J Am Water Works Assoc 79: 62-9 (1987) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (9) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (10) Haag HR, Yao CCD; Environ Sci Technol 26: 1005-13 (1992) (11) Tabak HH et al; J Water Pollut Cont Fed 53: 1503-18 (1981) (12) Bouwer EJ, McCarthy PL; Ground Water 22: 433-40 (1984) R70: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R71: (1) Tabak HH et al; J Water Pollut Cont Fed 53: 1503-18 (1981) (2) Bouwer EJ, McCarthy PL; Ground Water 22: 433-40 (1984) (3) Bouwer EJ, McCarthy PL; Appl Env Microbiol 45: 1295-9 (1983) R72: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R73: (1) Wookeun B et al.; J Contam Hydrol 6: 53-68 (1990) (2) Bouwer EJ, Wright JP; J Contam Hydrol 2: 155-169 (1988) (3) Cobb GD, Bouwer EJ; Environ Sci Technol 25: 1068-1074 (1991) R74: (1) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (2) Robbins DE; Geophys Res Lett 3: 213-6 (1976) R75: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (4) Atkinson R; Inter J Chem Kinet 19: 799-828 (1987) R76: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R77: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Hutzler NJ et al; Water Resources Res 22: 285-95 (1986) R78: (1) Francois CL et al; Travaux Soc Pharm Montpellier 39: 49-58 (1979) (2) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-21 (1982) R79: (1) Munz C, Roberts PV; J Am Water Works Assoc 79: 62-9 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Boublik T et al; Vapour Press Pure Subst (1984) (4) Francois CL et al; Travaux Soc Pharm Montpellier 39: 49-58 (1979) R80: (1) Cole RH et al; J Water Pollut Cont Fed 56: 898-908 (1984) (2) Page GW; Environ Sci Technol 15: 1475-81 (1981) (3) Pellizzari ED et al; Formulation of a Preliminary Assessment of Halogenated Organic Compounds in Man and Environmental Media USEPA/560-13-79-06 (1979) (4) Council on Environmental Quality; Contamination of Ground Water by Toxic Organic Chemicals (1981) (5) Kaiser KLE et al; J Great Lakes Res 9: 212-23 (1983) R81: (1) Ohio River Valley Water Sanit Comm; Assessment of Water Quality Conditions. Ohio River Mainstream 1980-81 (1982) (2) Wakeham SG et al; Can J Fish Aquatic Sci 40: 304-21 (1983) R82: (1) Krysell M; Mar Chem 33: 187-97 (1991) (2) Moore RM, Tokarczyk R; Global Biogeochem Cycles 7: 195-210 (1993) R83: (1) Symons JM et al; J Amer Water Works Assoc 67: 634-47 (1975) (2) Brass HJ et al; pp. 393-416 in Drinking Water Qual Enhancement Source Prot (1977) (3) Burmaster DE; Environ 24: 6-13, 33-6 (1982) (4) Saunders RA et al; Water Res 9: 1143-5 (1975) (5) Suffet IH et al; pp. 375-97 in Identification and Analysis of Organic Pollutants in Water. Keith LH ed. Ann Arbour Science Publ (1976) (6) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982) (7) Shiraishi H et al; Environ Sci Technol 19: 585-9 (1985) (8) Fielding M et al; Organic Micropollutants in Drinking Water. TR-159 (1981) R84: (1) Storm DL; pp. 67-124 in Water contamination and health, Wang RGM, ed. NY, NY: Marcel Dekker (1994) (2) Lam RHF et al; pp. 15-44 in Water contamination and health, Wang RGM, ed. NY, NY: Marcel Dekker (1994) (3) Lebel GL et al; Chemosphere 34: 2301-17 (1997) (4) Wallace LA; Crit Rev Environ Sci Technol 27: 133-94 (1997) R85: (1) Page GW; Environ Sci Technol 15: 1475-81 (1981) (2) Burmaster DE; Environ 24: 6-13, 33-6 (1982) (3) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) (4) Greenberg M et al; Environ Sci Technol 16: 14-9 (1982) R86: (1) Pankow JF et al; Environ Sci Technol 18: 310-8 (1984) R87: (1) Wallace LA; Crit Rev Environ Sci Technol 27: 133-94 (1997) R88: (1) USEPA; Treatability Manual Vol 1 Treatability Data USEPA-600/2-81-001a (1981) (2) DeCarlo VJ; Ann NY Acad Sci 320: 678-81 (1979) (3) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (4) Brown KW, Donnelly KC; Haz Wast Haz Mater 5: 1-29 (1988) R89: (1) DeCarlo VJ; Ann NY Acad Sci 320: 678-81 (1979) R90: (1) Brodzinsky R, Singh HB; Volatilization Organic Chemicals in the Atmosphere: An Assessment of Available Data. SRI International Menlo Park, CA (1982) (2) Wallace L et al; Atmos Environ 19: 1651-61 (1985) (3) Wallace L et al; Atmos Environ 22: 2141-63 (1988) (4) Kelly JK et al; Environ Sci Technol 28: 378-387 (1994) (5) Kelly TJ et al; Ambient concentration summaries for Clean Air Act Title III Hazardous Air Pollutants Final Report Research Triangle Park USEPA/600/R-94/090 (1993) R91: (1) Yokouchi Y et al; J Geophys Res 102: 8805-9 (1997) R92: (1) Gschwend PM et al; Science 227: 1033-5 (1985) R93: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R94: (1) Antoine SR et al; Bull Environ Contam Toxicol 36:364-71 (1986) (2) Wallace LA; Crit Rev Environ Sci Technol 27:133-94 (1997) R95: 29 CFR 1910.1000 (7/1/99) R96: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R97: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R98: USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.vi (1980) EPA 440/5-80-051 R99: 40 CFR 401.15 (7/1/99) R100: 40 CFR 141.12 (7/1/99) R101: 40 CFR 302.4 (7/1/99) R102: 40 CFR 712.30 (7/1/99) R103: 40 CFR 716.120 (7/1/99) R104: 40 CFR 261.33 (7/1/99) R105: 21 CFR 329.1 (4/1/99) R106: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. 1003-1 R107: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R108: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R109: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) RS: 86 Record 174 of 1119 in HSDB (through 2003/06) AN: 2518 UD: 200301 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,4-BENZENEDIAMINE- SY: *PARA-; *P-AMINOANILINE-; *4-AMINOANILINE-; *BASF-URSOL-D-; *P-BENZENEDIAMINE-; *BENZOFUR-D-; *CI-DEVELOPER-13-; *CI-OXIDATION-BASE-10-; *CI-76060-; *DEVELOPER-13-; *DEVELOPER-PF-; *P-DIAMINOBENZENE-; *1,4-DIAMINOBENZENE-; *DURAFUR-BLACK-R-; *FENYLENODWUAMINA- (POLISH); *FOURAMINE-D-; *FOURRINE-D-; *FOURRINE-1-; *FUR-BLACK-41866-; *FUR-BLACK-41867-; *FURRO-D-; *FUR-YELLOW-; *FUTRAMINE-D-; *NAKO-H-; *ORSIN-; *OXIDATION-BASE-10-; *PARAPHENYLEN-DIAMINE-; *Paraphenylenediamine-; *PELAGOL-D-; *PELAGOL-DR-; *PELAGOL-GREY-D-; *PELTOL-D-; *P-PHENYLENEDIAMINE-; *1,4-PHENYLENEDIAMINE-; *PHENYLENEDIAMINE,-PARA,-SOLID- (DOT); *PPD-; *RENAL-PF-; *SANTOFLEX-LC-; *TERTRAL-D-; *URSOL-D-; *USAF-EK-394-; *Vulkanox-4020-; *ZOBA-BLACK-D- RN: 106-50-3 RELT: 6256 [1,4-BENZENEDIAMINE SULFATE] (Analog); 5384 [1,3-BENZENEDIAMINE] (Isomer); 2893 [O-PHENYLENEDIAMINE] (Isomer); 5436 [1,4-DIAMINOBENZENE DIHYDROCHLORIDE] (Analog) MF: *C6-H8-N2 SHPN: UN 1673; Phenylenediamines IMO 6.1; Phenylenediamines MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF 1-AMINO-4-NITROBENZENE WITH IRON AND HYDROCHLORIC ACID. [R1] *Prepn: A. Rinne, T. Zincke, Ber. 7, 869 (1874); Ger. pat. 202,170 (1907 to BASF), C. A. 3, 382 (1909); A.J. Quick, J. Am. Chem. Soc. 42, 1033 (1920); J.F. Norris, E.O. Cummings, Ind. AND Eng. Chem. 17, 305 (1925). See also: Beilstein XIII, 61 (1930). [R2] IMP: *ORTHO-PHENYLENEDIAMINE (1,2-DIAMINOBENZENE) CONTENT, 0.1% MAXIMUM; AND IRON CONTENT, 50 MG/KG MAXIMUM. [R3] FORM: *ONE TECHNICAL GRADE OF PARA-PHENYLENEDIAMINE AVAILABLE IN THE USA HAS THE FOLLOWING SPECIFICATIONS: PURITY, 99.2% MINIMUM; MOISTURE CONTENT, 0.1% MAXIMUM; ORTHO-PHENYLENEDIAMINE (1,2-DIAMINOBENZENE) CONTENT, 0.1% MAXIMUM; AND IRON CONTENT, 50 MG/KG MAXIMUM. [R3] MFS: *E I du Pont de Nemours and Company, Inc, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000; Chemicals and Pigments Department; Production site: Deepwater, NJ 08023; darrow, LA 70725 [R4] OMIN: *ALL COLORING AGENTS CONTAINING PARA-PHENYLENEDIAMINE OR ONE OF ITS HOMOLOGS MUST INCL STATEMENT ON PACKAGE RELATIVE TO SENSITIZING PROPERTIES ... AND ITS ABILITY TO CAUSE BLINDNESS IF IT CONTACTS EYES. LAW ... REQUIRES THAT PATCH TEST BE CONDUCTED 24 HR BEFORE ... DYE IS APPLIED /TO HAIR/. [R5] *Formerly: as an eyelash dye ... sold under proprietary name Lash Lure. [R6] USE: *Dyeing furs; also in photochemical measurements, accelerating vulcanization; manuf azo dyes. [R7] *CHEM INT FOR DYES (EG, DIRECT BLACK 19, 78 and 80); OXIDN BASE 10 AND DEVELOPER 13 FOR DYES; CHEM INT FOR ARAMID FIBERS (USED IN TIRE CORD); CHEM INT FOR N,N'-DISUBSTITUTED-P-PHENYLENEDIAMINES; COMPONENT OF GASOLINE ANTIOXIDANTS. [R1] *Used as an intermediate for the manufacture of diisocyanates for polyurethane [R8] PRIE: U.S. PRODUCTION: *(1978) PROBABLY GREATER THAN 4.54X10+6 G [R1] *(1982) PROBABLY GREATER THAN 4.54X10+6 G [R1] U.S. IMPORTS: *(1978) 1.50X10+6 G (PRINCPL CUSTMS DISTS) [R1] *(1982) 9.99X10+4 G (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE TO SLIGHTLY RED CRYSTALS [R2]; *WHITE PLATES FROM BENZENE, ETHER [R9] BP: *267 DEG C [R2] MP: *145-147 DEG C [R2] MW: *108.14 [R2] DEN: *Greater than 1 (water= 1) [R10] DSC: *The pKa value of the conjugate acid is 6.2. [R11] OWPC: *log Kow= -0.25 [R12] SOL: *SOL IN 100 PARTS COLD WATER; SOL IN ALCOHOL, CHLOROFORM, ETHER [R2]; *SOL IN HOT BENZENE [R13]; *Water solubility= 38,000 ppm [R14] SPEC: *MAX ABSORPTION (CYCLOHEXANE): 246 NM (LOG E= 3.93), 315 NM (LOG E= 3.30); SADTLER REFERENCE NUMBER: 4111 (IR, PRISM); 1187 (UV) [R13]; *IR: 8322 (Sadtler Research Laboratories IR Grating Collection) [R15]; *UV: 6-80 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R15]; *MASS: 45 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R15] VAPD: *3.72 (AIR= 1) [R16] VAP: *< 1 mm Hg at 21 deg C (technical product) [R3] OCPP: *BLACK COLOR DEVELOPED WITH 3% HYDROGEN PEROXIDE, BROWN WITH 5% IRON CHLORIDE SOLN, DARKENS ON EXPOSURE TO AIR. [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Phenylenediamines/ [R17] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Phenylenediamines/ [R17] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Phenylenediamines/ [R17] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Phenylenediamines/ [R17] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Phenylenediamines/ [R17] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Phenylenediamines/ [R17] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Phenylenediamines/ [R17] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Phenylenediamines/ [R17] FPOT: *COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME. [R18] FIRP: *WATER, CARBON DIOXIDE, DRY CHEM ... . [R18] EXPL: *Minimum explosive concentration: 0.025 g/l [R10] *The finely powdered base is a significant dust explosion hazard. [R19] REAC: *Contact with strong oxidizers may cause fires and explosions. [R10] +Strong oxidizers. [R20] DCMP: *Toxic gases and vapors (such as oxides of nitrogen and carbon monoxide) may be released in a fire involving p-phenylenediamine. [R10] *When heated to decomposition it emits acrid smoke and irritating fumes. [R18] SERI: *... Is a skin and respiratory system sensitizer ... [R10] +Eye irritation. [R20] EQUP: *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other protective clothing necessary to prevent skin contact ... . [R10] +Wear appropriate personal protective clothing to prevent skin contact. [R20] +Wear appropriate eye protection to prevent eye contact. [R20] +Recommendations for respirator selection. Max concn for use: 2.5 mg/cu m. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. [R20] +Recommendations for respirator selection. Max concn for use: 5 mg/cu m. Respirator Class(es): Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R20] +Recommendations for respirator selection. Max concn for use: 25 mg/cu m. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R20] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R20] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern and having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R20] OPRM: +Contact lenses should not be worn when working with this chemical. [R20] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R20] +The worker should wash daily at the end of each work shift. [R20] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R20] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R20] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *ON STANDING IN AIR, OXIDIZES TO PURPLE AND BLACK /COLOR/. [R21] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R22] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R23] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R24] STRG: *Keep well closed and protected from light. [R2] *IN GENERAL MATERIALS ... TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS ... SHOULD BE STORED IN COOL ... VENTILATED PLACE, OUT OF ... SUN, AWAY FROM ... FIRE HAZARD ... /AND/ BE PERIODICALLY INSPECTED AND MONITORED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED. [R25] DISP: *The following wastewater treatment technologies have been investigated for p-phenylenediamine: biological treatment. [R26] *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R27] +A4; Not classifiable as a human carcinogen. [R28, 2002.48] ANTR: *Flush eyes with water. Wash contaminated areas of body with soap and water. [R29, 409] *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Organic bases, amines, and related compounds/ [R30] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... Anticipate seizures and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... Cover skin burns with sterile dressings after decontamination ... . /Organic bases, amines, and related compounds/ [R30] MEDS: */Annual/ physical examinations of exposed personnel, including blood counts and studies of liver function. Those persons with allergy and with diseases of skin, liver, blood, and lungs should avoid exposure. Sensitized persons should avoid re-exposure. [R29, 409] HTOX: *EXPOSED WORKMEN ... SUFFER FROM ALLERGIC ASTHMA AND FREQUENTLY SHOW INFLAMMATORY REACTIONS OF THE LARYNX AND PHARYNX, EVIDENTLY CAUSED BY DIRECT IRRITATION. ... VERY SMALL QUANTITIES ... COULD CAUSE ASTHMA IN PERSONS AFTER 3 MO TO 10 YR OF EXPOSURE. THESE EPISODES WERE CVHARACTERIZED BY THE IMMEDIATE ONSET OF SYMPTOMS WHICH PROMPTLY DISAPPEARED UPON DISCONTINUATION OF THE EXPOSURE. [R31, 1991.1227] *Potential symptoms of overexposure are irritation of pharynx and larynx; bronchial asthma; sensitization dermatitis. [R2] */HYPERSENSITIVITY/ REACTIONS WHICH HAVE FOLLOWED APPLICATION OF DYES CONTAINING P-PHENYLENEDIAMINE TO HAIR ... CHARACTERISTICALLY HAVE CONSISTED OF DERMATITIS OF HEAD, FOREHEAD, AND NECK, ASSOC WITH EDEMA OF LIDS AND CONJUNCTIVA, WITH TEARING AND EXOPHTHALMOS. [R32, 697] *Produces severe local reactions and systemic effects from percutaneous absorption and from ingestion. Local actions incl severe dermatitis and urticaria; in the eye, chemosis, lacrimation, exophthalmos, ophthalmia, and even permanent blindness. Systemic actions incl asthma, gastritis (regardless of portal of entry), rise in blood pressure, transudation into serous cavities, vertigo, tremors, convulsions and coma. ... The ortho isomer (diolene) is less toxic than the para (orsin). [R33] *20 PEOPLE WHO SUFFERED ALLERGIC CONTACT DERMATITIS FROM P-PHENYLENEDIAMINE WERE RETESTED WITH HAIR THAT HAD BEEN DYED 24 HR PREVIOUSLY. NONE SHOWED ANY REACTION TO DYED HAIR AFTER 48 HR OR @ END OF 3 WK. [R34] *TWO PATIENTS DEVELOPED OLIGURIC RENAL FAILURE FOLLOWING PARA-PHENYLENEDIAMINE INTOXICATION. THE ASSOCIATED CLINICAL FEATURES INCLUDED VOMITING, ANGIONEUROTIC EDEMA, CYANOSIS, INTRAVASCULAR HEMOLYSIS AND METHEMOGLOBINEMIA. THERAPEUTIC DIALYSIS AND SYMPTOMATIC MANAGEMENT WAS FOLLOWED BY COMPLETE RECOVERY IN ONE, AND DEATH DUE TO SEPTICEMIA DURING THE OLIGURIC PHASE IN ANOTHER PATIENT. RENAL HISTOLOGY IN BOTH CASES REVEALED ACUTE TUBULAR NECROSIS. [R35] *Poison by ingestion, subcutaneous, intravenous, and intraperitoneal routes. Mildly toxic by skin contact. A human skin irritant. Mutation data reported. Implicated in aplastic anemia. Can cause fatal liver damage. The p-form is more toxic and a stronger irritant than the o- and m-isomers. When used as a hair dye it caused vertigo, anemia, gastritis, exfoliative dermatitis, and death. Has caused asthma and other respiratory symptoms in the fur-dying industry. [R18] *SUSPECTED AS CAUSE OF BLADDER TUMORS IN "ANILINE" WORKERS. [R33] *Para-phenylenediamine poisoning has been known for many years, but few studies have been devoted to the subject. /Reports indicating/ 4 cases, seen in the nephrology department, concerning women aged from 18 to 35 years who had tried to commit suicide by drinking varying amounts of that hair dye. The initial symptom was acute asphyxia which required emergency tracheotomy in 3 cases. Thereafter, the most important visceral damage was acute renal failure, usually with oliguria or anuria, for which hemodialysis was performed in 2 cases. In these patients treated at an early stage the mid- and long-term prognosis was satisfactory. Rhabdomyolysis is the principal mechanism underlying para-phenylenediamine systemic toxicity; it is, in particular, responsible for the renal failure observed. [R36] *An autopsy case of rhabdomyolysis following homicidal intoxication of para-phenylenediamine was reported and the toxicological mechanism of para-phenylenediamine against skeletal muscles was discussed. The case was a 44 year old, previously healthy male, drinking a beverage containing para-phenylenediamine, prepared for a homicidal use. Total intake of paraphenylenediamine was about 3 g (63 mg/kg). Principal clinical manifestation of the patient was muscle rigor with tenderness, initially developed in the lower extremities and subsequently extending to all over the skeletal muscles. Laboratory examinations disclosed high CPK (137,600), LDH (3895), GOT (3400) and GPT (545), and leukocytosis (26600), indicating massive skeletal muscle necrosis. ECG revealed mild depression of ST junction in the II and aVF leads. Urine showed dark brownish discoloration and diminished in volume subsequently. Scattered necrosis of muscular fibers was observed in a biopsy of the femoral muscles. The consciousness was rather clear during the course. The patient collapsed suddenly and soon died in the course of about 30 hours. Clinically, the cause of death was thought to be acute renal failure due to rhabdomyolysis. Afterwards, para-phenylenediamine was detected in the urine obtained in the hospital. Autopsy confirmed the clinical diagnosis: Renal collecting ductules and distal tubules were occluded by dark brownish myoglobin casts and its epithelium massively necrotized. Skeletal muscles showed scattered coagulation necrosis and were partially associated with inflammatory cell infiltration. [R37] *Observations based on clinical and experimental studies of the effect of p-phenylenediamine on the lens showed lenticular changes in 89% of 200 individuals of either sex examined, all of whom had used hair dyes. The lenticular changes seemed related to duration, quantity, and individual sensitivity to the hair dye. In addition, some individuals (7%) were found to develop presbyopia. An experimental study confirmed the cataractogenic effects caused by hair dyes containing p-phenylenediamine. [R31, 1991.1226] *Edema of the upper airways and rhabdomyolysis developed in a young patient as a consequence of para-phenylenediamine /intoxication/. Treatment with adrenaline, steroids and enforced diuresis prevented tracheostomy and renal failure. [R38] *A case of suicidal poisoning with para-phenylenediamine is reported. The patient presented with typical features of severe oropharyngeal edema and rhabdomyolysis. He suffered sudden cardiac death within 4 hr of admission despite full supportive treatment. The diagnosis was only established after his death. Systemic poisoning with para-phenylenediamine is rare in western countries, and therefore a high deg of awareness and circumstantial evidence is required to make an early diagnosis. The classical and other less commonly reported features of this poisoning are discussed. There is no specific antidote available but some guidelines for management of such a case are reviewed. [R39] *Combined sensitizations to different azo dyes, probably based both on true cross-sensitization and on simultaneous positive reactions, have frequently been described. ... Out of 6203 consecutively tested patients, 236 were sensitized to at least 1 of 6 azo compounds employed as textile dyes, included in our standard series. 107 subjects reacted to Disperse Orange 3 (DO3), 104 to Disperse Blue 124 (DB124), 76 to p-aminoazobenzene (PAB), 67 to Disperse Red 1 (DR1), 42 to Disperse Yellow 3 (DY3), and 31 to p-dimethylaminoazobenzene (PDAAB). Co-sensitizations to para-phenylenediamine were present in most subjects sensitized to DO3 (66%) and PAAB (75%), in 27% and 36% of DRl and DY3-sensitive subjects, and only in 16% of subjects sensitized to DB124. Apart from the hands and the face, the neck and the axillae were the most frequently involved skin sites. Whereas the involvement of flexural areas was mainly connected with sensitization to DB 124, in patients with hand dermatitis and in those working as hairdressers, sensitization to DO3 and PAAB was more frequent. Moreover, in the former patient group, a history of textile dye allergy was most frequently obtained. ... [R40] *During the course of evaluating the interaction between allergens and keratinocytes in the pre-immunological phase of contact sensitization, ... the effects of paraphenylenediamine (pPD) on membrane lipid peroxidation and on intracellular antioxidant levels in cultured human keratinocytes /was studied/. pPD is an aromatic amine which undergoes spontaneous oxidation in culture medium, generating short-lived free radical species including oxyradicals. Following exposure to non-toxic concentrations of pPD (0.5-10 micrograms/ml), ... the fatty acid pattern of membrane phospholipids as a target of peroxidative damage, and the intracellular level of reduced glutathione (GSH), the activity of superoxide dismutase (SOD), and that of catalase (CAT) as parameters of the antioxidant system /was evaluated/. Depending on pPD concentration and the period of exposure, peroxidative damage with a significant decr in membrane polyunsaturated fatty acids, was detected. Concentrations between 0.5 and 2 micrograms/ml produced an initial incr and then a decrease in both SOD and CAT activities, and in the oxidation of GSH, up to 12 h. After 24 hr, when all the pPD had decomposed, recovery of the initial levels of the antioxidants was detected. Concentrations over 5 micrograms/ml induced a progressive decrease in both the enzymatic activities and the GSH concentrations. These results are consistent with the view that oxidative stress can be an essential event in the pre-immunological phase of contact sensitization [R41] *TOXIC BY INHALATION... [R42] NTOX: *EXPERIMENTALLY, SYSTEMIC POISONING OF RABBITS, CATS, AND DOGS BY ORAL OR PARENTERAL ADMIN OF P-PHENYLENEDIAMINE HAS NOT BEEN FOUND TO INDUCE OPTIC NEURITIS, BUT HAS CAUSED A PECULIAR SELECTIVE EDEMA OF HEAD AND NECK, IN SOME INSTANCES PRODUCING TEMPORARY PROTRUSION OF EYES, OWING TO EDEMA OF ORBITAL TISSUES AND CONJUNCTIVA ... [R32, 697] *AFTER IV INJECTION INTO DOGS, VARIED BUT DEFINITE SYMPTOMS APPEARED @ 0.017 G/KG. WITH NONFATAL DOSES, RESP RATE BECAME RAPID, ... LOUD WHEEZING /OCCURRED/ ... and ... /THERE WERE/ INCR IN SECRETIONS FROM /THE/ MOUTH, NOSE, AND EYES. WITHIN 1.5 TO 4 HR, CHARACTERISTIC SWELLING OF /THE/ NOSE, LIPS, CONJUNCTIVAE AND NECK BECAME PRONOUNCED. [R43] *PARA-PHENYLENEDIAMINE HAS BEEN REPORTED TO INDUCE REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA1538 IN THE PRESENCE OF A RAT LIVER POSTMITOCHONDRIAL SUPERNATANT FRACTION FROM ANIMALS PRETREATED WITH PHENOBARBITAL. [R44] *P-PHENYLENEDIAMINE WAS MILDLY IRRITATING TO RABBIT SKIN AND ONLY A MILD CONJUNCTIVAL REACTION FOLLOWED ADMIN TO RABBIT EYES. [R45] *THIS COMPOUND DID NOT INDUCE MICRONUCLEATED CELLS IN BONE MARROW WHEN 300 MG/KG BODY WEIGHT WERE ADMINISTERED ORALLY TO TWO GROUPS OF 5 MALE AND 5 FEMALE RATS IN TWO DOSES SEPARATED BY AN INTERVAL OF 24 HOURS. [R46] *PURIFIED P-PHENYLENEDIAMINE HAD NO MUTAGENIC ACTION, ONLY STERILIZING AND TOXIC EFFECTS. [R47] *P-PHENYLENEDIAMINE IN DIETS (SUBACUTE) OF MALE AND FEMALE F344 RATS SHOWED 0.4% TO BE VERY TOXIC TO BOTH SEXES, BUT 0.2, 0.1 AND 0.05% WERE NONTOXIC. 0.1 AND 0.05% ADMINISTERED IN DIETS FOR 80 WEEKS SHOWED NO CARCINOGENIC EFFECTS. [R48] *P-PHENYLENEDIAMINE WAS ADMINISTERED BY GAVAGE TO PREGNANT RATS AT 5, 10, 15, 20, AND 30 MG/KG/DAY ON DAYS 6 THROUGH 15 OF GESTATION; THE RATS WERE KILLED ON DAY 20 OF GESTATION. FETAL EVALUATIONS SHOWED NO BIOLOGICAL OR STATISTICALLY SIGNIFICANT INCREASE IN MALFORMATIONS OR DEVELOPMENTAL VARIATIONS IN ANY GROUP: NO EVIDENCE OF TERATOGENIC OR OTHER EMBRYOTOXIC EFFECTS. [R49] *PARA-PHENYLENEDIAMINE HAS BEEN INADEQUATELY TESTED IN MICE BY SKIN APPLICATION AND IN RATS BY ORAL AND SUBCUTANEOUS ADMINISTRATION. STUDIES IN MICE IN WHICH PARA-PHENYLENEDIAMINE AS A CONSTITUENT OF HAIR-DYE PREPARATIONS WAS TESTED BY SKIN APPLICATION CANNOT BE EVALUATED. NO EVALUATION OF THE CARCINOGENICITY OF THIS COMPOUND CAN BE MADE. [R50] *Two-generation reproduction and chronic toxicity carcinogenicity studies were conducted in Sprague-Dawley rats receiving topical applications of six oxidative hair coloring formulations. These formulations were prepared as prototypes of permanent hair colorings using the base ingredients and primary intermediates and couplers most often used in this kind of product. Among the dyes included in the various formulations were p-phenylenediamine ... . The dye solutions were mixed with an equal volume of 6% hydrogen peroxide prior to application. In the reproduction study the samples were applied topically twice weekly throughout the growth, mating, gestation and lactation phases of the F0 parents to the weaning of the F1a and F2b litters. Fertility, gestation and fetal viability indices and body weights were evaluated for the six treatment groups and these were compared with the values for the three concurrent control groups. Weanlings selected from the F1a litters were the subjects for the lifetime carcinogenesis study. For 24 months they received twice-weekly topical applications of the same dyes as were administered to their parents. Clinical chemistry, hematological and urinalysis studies were performed at months 3, 12, 18 and 24, and five animals/sex/group were killed at month 12 and autopsied for histological examination of the rat tissues. All animals in the chronic study were evaluated for incidence of neoplastic and non-neoplastic lesions. In the reproduction phase the application of hair dyes had no adverse effect on the fertility of the males or females, or on gestation, lactation and weaning indices. The average number weaned per litter and the mean body weights of the weanlings were comparable among the treated and control groups. No treatment related gross lesions were observed in any animals necropsied at month 12 or at study termination, or in any rats that died during the course of the carcinogenicity study. Comparison of the tumor incidences among the six treated and three control groups showed some significant variations among those tumors occurring most frequently in this strain of rats, and pituitary adenomas were also increased significantly (p < 0.05) in the females of one of the treated groups. The incidence of this tumor is known to be high and variable in untreated female Sprague-Dawley rats. [R51] *The three aromatic amines, p-phenylenediamine, 2-nitro-p-phenylenediamine, and 4-nitro-p-phenylenediamine induce mutations in Ames Salmonella test as well as sister chromatid exchanges in Chinese hamster ovary cells. In the absence of S9 mixture, BHA significantly reduces the mutagenicity of 2-nitro-p-phenylenediamine and 4-nitro-p-phenylenediamine, but not p-phenylenediamine, in Ames Salmonella test. In the presence of the S9 mixture, the mutagenicity of p-phenylenediamine and 2-nitro-p-phenylenediamine, were significantly reduced by BHA but that of 4-nitro-p-phenylenediamine is enhanced by BHA. The induction of sister chromatid exchanges by 2-nitro-p-phenylenediamine and p-phenylenediamine, but not by 4-nitro-p-phenylenediamine, were significantly decreased by BHA in the absence of the S9 mixture. In the presence of the S9 mixture, BHA decreased the sister chromatid exchange induction of p-phenylenediamine strongly, but it did not reduce the sister chromatid exchange frequencies of 2-nitro-p-phenylenediamine. [R52] *The modifying effects of p-phenylenediamine on liver carcinogenesis were investigated in male F344/DuCrj rats initially treated with N-nitrosodiethylamine. Two weeks after a single dose of N-nitrosodiethylamine (200 mg/kg, intraperitoneally), rats were given p-phenylenediamine at dietary levels of 1000, 330 and 110 ppm, or 3'-methyl-4-dimethylaminoazobenzene at 600 ppm as a positive control for 6 weeks. At week 3 following N-nitrosodiethylamine administration, all animals were subjected to partial hepatectomy. Slight retardation of body weight was observed in rats treated with p-phenylenediamine at all dietary levels. Significant increases in relative liver weight were found in animals treated with 1000 ppm p-phenylenediamine. Remarkable growth retardation and increased liver weight were found in rats given 3'-methyl-4-dimethylaminoazobenzene. p-Phenylenediamine did not significantly increase the level of gamma-glutamyl transpeptidase positive foci observed after N-nitrosodiethylamine initiation. In contrast, 3'-methyl-4-diethylaminoazobenzene demonstrated marked enhancing activity as evidenced by significantly increased values for gamma-glutamyl transpeptidase positive foci as compared with the controls given N-nitrosodiethylamine alone. The results demonstrate that p-phenylenediamine does not modify liver carcinogenesis in our in-vivo medium-term bioassay system. [R53] *Changes in some of the biochemical parameters of skin and serum, together with histopathological changes in liver, kidney and skin of guinea pigs caused by repeated dermal exposure to para-phenylenediamine were assessed. Guinea pigs were painted with a 1% solution of para-phenylenediamine in 25% ethanol at a dose of 0.1 ml/day over an area of 2x2 cm that was clipped free of fur. Animals were sacrificed on day 1, 3, 5, or 7 after exposure. The contents of para-phenylenediamine in skin and urine on days 1, 3, 5, and 7 revealed an increase which indicated that para-phenylenediamine was absorbed readily after dermal application. Lipid peroxidation was elevated on days 3, 5, and 7 and histamine demonstrated significant increases on days 1, 3, 5, and 7. The glutathione content of the skin did not reveal any significant change. The enzymatic activity of aspartate aminotransferase was increased on day 7. The enzymatic activity of alanine aminotransferase was increased on days 5 and 7. Tyrosinase activity was increased on day 7. The activities of beta-glucuronidase, gamma-glutamyl transpeptidase and alanine aminotransferase enzymes were elevated after 5 and 7 days of para-phenylenediamine painting, but aspartate aminotransferase was increased only after 7 days of exposure. The livers of the exposed animals revealed no signs of toxicity on days 1 and 3 other than a few focal and early degenerative changes in hepatocytes and mild fatty changes. Moderate congestion of lobules and congestion of sinusoids developed by day 5. By day 7 a focal granulomatous reaction with occasional Langerhans type giant cells was noted. No significant histological changes occurred in the kidney. Moderate changes occurred in the skin on the first day which comprised hyperkeratosis of the stratum corneum and focal infiltration of polymorphs and mononuclear leukocyte in the dermis. By day 7 the exposure resulted in marked hyperkeratosis together with infiltration of cells in the dermis. Edema and congestion in the dermis persisted. [R54] *A study of muscle necrosis caused by p-phenylenediamine and some of its methylated derivatives was conducted on female Sprague-Dawley rats. A possible correlation between myotoxicity and the oxidation rates of these p-phenylenediamine derivatives was also investigated. Groups of six rats were dosed with the various compounds at 40 um/kg, twice a day for 3 days. Rates of oxidation were determined from rates of oxygen uptake and intracellular hydrogen peroxide production. On day four, the rats were killed and analyses were performed on the blood, heart, tongue, diaphragm, kidneys, spleen and liver. Tissue samples from the various organs were microscopically analyzed for muscle necrosis. Blood samples were assayed for a variety of enzymes including phosphokinase, aldolase and lactate dehydrogenase. Results from the oxidation studies demonstrated that although p-phenylenediamine oxidized slowly, with larger amounts of methylation the rates of oxidation were much faster. The levels of hydrogen peroxide generated following exposure showed the same trends as observed with oxidation (greater methylation resulted in more hydrogen peroxide production). Histological examinations of tissues from the various organs considered were also consistent with data from oxidation and hydrogen peroxide production tests. Finally, plasma enzyme concentrations were observed to be generally higher for larger amounts of methylation, but there were some inconsistencies between the trimethyl and tetramethyl p-phenylenediamine derivatives. It was concluded that the p-phenylenediamine derivatives cause myotoxic effects which appear to correlate with the rates of oxidation. [R55] *It has been proposed that the cross-reactions seen clinically between hydroquinone and para-phenylenediamine arise from the formation of a common hapten, benzoquinone, in vivo, and that these chemicals therefore represent "prohaptens". A series of 1,4-substituted benzene derivatives has been used to examine this prohapten concept in the guinea pig model. Using both topical and intradermal routes of application, it is demonstrated that in the guinea pig, 1,4-substituted benzene derivatives capable of oxidation to benzoquinone, including hydroquinone and para-phenylenediamine, show only restrictive evidence of cross-reactions. These results support the prohapten concept. However taken in combination with data on cross-reactivity with 1,2- and 1,3-substituted benzenes, rather than giving rise to a single common hapten, they can be more readily interpreted as the formation of a spectrum of antigenic determinants in vivo, some of which are shared in common. [R56] *para-Phenylenediamine was injected subcutaneously into the backs of rats divided in 2 groups, each of 5 animals (strain and sex not specified), at a daily dose of 12.5 or 20 mg/kg body weight. Fibrosarcomas were produced at the site of injection in 2/5 rats that received 12.5 mg/kg body weight after 7 months of administration. No sc tumors were observed in the group that received 20 mg/kg body weight nor in 5 controls. [R57] *para-Phenylenediamine was administered orally in daily doses of 0.06, 0.3 and 10 mg/kg body weight for 8 months to groups: of 10 rats ( 5 males and 5 females) for the 0.06 and 0.3 mg/kg doses and of 5 rats (sex not specified) for the 10 mg/kg body weight dose. Four animals were given daily doses of 30 mg/kg body weight, but three of them died within a 4 month period. The strain of rats, survival times and the solvent used were not mentioned. No tumors were observed in any of the treated animals within the 8 month period nor in 5 controls. [R58] *A group of 30 adult, albino mice were treated twice weekly for 20 weeks with one drop of a 5% solution of para-phenylenediamine in acetone applied to the backs of the animals. None of the 19 which survived at 20 weeks had skin tumors. [R59] *The urine of rats treated ip with aqueous solutions of phenylenediamine at 2, 6, or 20 mg/kg, 3 times/week for 8 weeks were not mutagenic in Salmonella typhimurium strain TA1538. Urine concentrates from rats treated topically with oxidation mixtures of p-phenylenediamine/resorcinol (300 mg/kg) were mutagenic in Salmonella strain TA98 with metabolic activation. The urine of 15 women who had used hair dyes containing 0.46% to 2.55% p-phenylenediamine was no more mutagenic in Salmonella strain TA1538 after hair-dye application than before hair-dye application. [R31, 1991.1226] *. PARA-, META-, AND ORTHO-PHENYLENEDIAMINE IN DECR ORDER OF ACTIVITY INDUCED ALLERGIC REACTIONS IN RATS AND GUINEA PIGS. [R60] *SKELETAL MUSCLE LESIONS INDUCED IN RATS BY P-PHENYLENEDIAMINE. IN DIAPHRAGM, LESIONS CHARACTERIZED BY MYOPATHIES AND NEUROMYOPATHIES. /P-PHENYLENEDIAMINE/ [R61] *Guinea pigs were dermally exposed to the hair dye para-phenylenediamine for 15 and 30 days to assess the effects on selected enzyme activities, lipid peroxidation, and histamine content in the skin. The activities of acid phosphatase, glutathione-s-transferase, and tyrosinase were enhanced after application of para-phenylenediamine. The lipid peroxidation, histamine, and para-phenylenediamine content of skin also showed marked elevation following dermal exposure to /this cmpd/. [R62] *... The need to develop predictive tests which could identify potential allergens has been recognized for many years. There is as yet no accepted in vitro method for the assessment of contact sensitizers. ... The ability of a range of contact allergens to induce in vitro primary sensitization of autologous T cells /have been tested/. ... T-cell proliferation induced by haptens using 2 day cultured human Langerhans cells as antigen presenting cell was assessed by (3)H thymidine incorporation. Antigen specific stimulation was calculated as stimulation indexes. ... Strong allergens induced in vitro a primary T-cell response in all (trinitrophenyl, TNP: 13/13) or in the majority (fluorescein isothiocyanate, FITC: 7/10) of experiments. An irritant, sodium dodecyl sulfate (SDS), failed to generate a significant T-cell proliferation in any of the experiments (0/10). ... A significant lymphoproliferative response to weak sensitizers only in a limited number of experiments: (coumarin: 1/12, citronellal: 0/10, hydroxycitronellal: 2/8) /was obtained/. p-Phenylenediamine (PPDA), a prohapten and highly sensitizing chemical in vivo, generated primary sensitization in vitro in only one of six experiments, while Bandrowski's base (BB), a metabolization product of PPDA induced a significant T-cell response in all six experiments. ... The present in vitro model allows discrimination between two groups of substances: strong contact sensitizers (TNP, FITC, BB) on the one hand and weak sensitizers (coumarin, citronellal and hydroxycitronellal) and irritants (SDS) on the other hand. It could be used as a screening in vitro assay to eliminate strong contact allergens before further predictive animal tests have to be performed. [R63] *Three isomers of the promutagen phenylenediamine at mM concentrations were plant-activated and induced mutation in stamen hairs of Tradescantia clone 4430. The rank order of the mutagenicity of the isomers was: o-phenylenediamine > m-phenylenediamine > p-phenylenediamine with corresponding mutagenic potencies of 5.60, 1.43, and 0.46 mutant stamen hair cells/mumole, respectively. Diethyldithiocarbamate (DEDTC) and ammonium meta-vanadate (vanadate) repressed the mutagenic activity of o-phenylenediamine (o-PDA) in intact plants. Based on inhibition kinetics and reaction rates, the mechanism of DEDTC antimutagenicity was attributed to the inhibition of peroxidases that are required in the plant activation of o-PDA to mutagenic product(s). Spectrophotometric measurements of equimolar concentrations of o-PDA and vanadate demonstrated that the antimutagenic property of vanadate was mainly due to its reactivity with o-PDA. [R64] *... To provide further background data for the somatic mutation and/or recombination tests in Drosophila melanogaster, we have evaluated the response in 3 assays (zeste-white, white-ivory and wing spot) of 5 chemicals classified by the U.S. National Toxicology Program (NTP) as genotoxic non-carcinogens (or ambiguous). The selected compounds were 2-chloromethylpyridine, 1-nitronaphthalene, 4-nitro-o-phenylenediamine, 3-nikopropionic acid and p-phenylenediamine. Our results show that all the compounds tested produce significant increases in the frequency of mutant clones, in at least one of the assays, p-phenylenediamine being the compound which presents a clearer mutagenic activity, and the wing spot test, the assay that detects more genotoxic compounds (4/5). [R65] *... Cross-sensitization between p-phenylenediamine (pPDA) and p-aminophenol (pAP) or m-phenylenediamine (mPDA) by a modified lymphocyte transformation test /was evaluated/. Guinea pigs were sensitized with pPDA using the maximization test procedure. Lymph node cells from the animals were then cultured with pPDA, pAP or mPDA in the presence or absence of epidermal cells (EC). Transformed Iymphocyte counts were evaluated by means of (3)H-thymidine uptake. Non-sensitized guinea pigs were used as controls. Blastogenesis in lymphocytes from sensitized guinea pigs was enhanced when cultured with pPDA, pAP or mPDA in the absence or presence of EC than without the sensitizers, and the extent of response depended on the concentration of pPDA, pAP or mPDA added to the cultures. Blastogenesis in lymphocytes from control animals was not significantly enhanced in response to pPDA, pAP or mPDA in the presence or absence of EC. The extent of the response to pPDA was greater than that to pAP, which in turn was greater than that to mPDA. In contrast, because pPDA, pAP and mPDA are color developing agents, cross-sensitization between pPDA and pAP or mPDA could not be evaluated by the results of an in vivo challenge due to pigmentation in the patch application sites. The results suggested that there is cross-sensitization between pPDA and pAP or mPDA, and that the modified lymphocyte transformation test is a useful predictive means of detecting cross-sensitization among chemicals, especially for color developing agents. [R66] *Paraphenylenediamine (pPDA), which is used frequently in hair dyes, has a high sensitization potential and is also well known to cross react with chemicals of similar structure. pPDA specific lymphocytes from sensitized inbred guinea pigs were prepared and the cross reaction of pPDA was examined using cultured epidermal cells as the target. The cytolytic effect was observed to be highest with pPDA, followed by para-aminophenol, ortho-phenylenediamine, and meta-phenylenediamine. Resorcinol and the control produced no cytolytic reaction. These results showed a good correlation between in vitro and in vivo tests. The recognizing ability of hapten specific lymphocytes is suggested to vary according to the position of the functional group and its type. [R67] *Allergic contact dermatitis from moderate and weak contact sensitizers is generally studied with guinea pigs, since they are readily sensitized to contact allergens. Mice, by contrast, are poor responders to weak contact allergens. However, the variety of in vitro murine systems as well as murine specific reagents make mice the preferable species. With the use of vitamin A supplementation, 2 protocols were developed which sensitized CA/J female mice to paraphenylenediamine. Mice were sensitized by S daily topical applications to shaven dorsal skin. Alternately, mice were sensitized by two ip injections of antigen pulsed spleen cells. Sensitization to para-phenylenediamine was determined by ear swelling following topical application. Vitamin A supplementation was found to be essential for optimum response. Lymph node and spleen cells from sensitized mice were capable of proliferating to para-phenylenediamine in vitro. With the use of vitamin A supplementation and ip injection, CA/J mice were also sensitized to a number of compounds structurally related to para-phenylenediamine, including the ortho- and meta-derivatives of paraphenylenediamine, as well as hydroquinone and resorcinol. ... [R68] *The mutagenicity of o- and m-phenylenediamine (PD) was remarkedly enhanced by oxidation; their major mutagenic oxidation products were 2,3- and 2,7-diaminophenazine, respectively. ... To evaluate the modulation effect of p-PD on the oxidation of m- or o-PD, p-PD and mixtures of m- and p-PD (m-PD/p-PD) and o- and p-PD (o-PD/p-PD) were oxidized with hydrogen peroxide and their mutagenicity was tested in Salmonella typhimurium TA98 in the presence or absence of a mammalian metabolic activation system (S9 mix). The hydrogen peroxide m-PD/p-PD and o-PD/p-PD were potent mutagens with S9 mix, whereas hydrogen peroxide oxidized p-PD was slightly mutagenic. The major mutagenic oxidation products of m-PD/p-PD and o-PD/p-PD were identified as 2,7 and 2,3-diaminophenazine. ... 2.8-Diaminophenazine was also found as a reaction product in oxidized m-PD/p-PD, and it was weakly mutagenic. The mutagenic potency of oxidized m-PD/p-PD or o-PD/p-PD was lower than that of slightly oxidized m-PD or o-PD. The yield of 2,7- and 2,3-diaminophenazine was obviously decr with incr in p-PD, and it was concluded that the declined mutagenic potency of oxidized m-PD/p-PD or o-PD/p-PD was due to decr in diaminophenazines. ... The formation of diaminophenazines was not completely inhibited by the addition of 9 fold molar ratio of p-PD to m-PD or o-PD, 8.6 nmole of 2,7-diaminophenazine and 1882.4 nmole of 2,3-diaminophenazine were formed from 1 mmole of m-PD and o-PD respectively. [R69] *The Ames Salmonella/microsomal assay was employed to test the mutagenicity of some benzamines (aniline, and o- and p-phenylenediamine) and their nitro-derivatives (p-nitroaniline, 2-nitro-p-phenylenediamine, 3- and 4-nitro-o-phenylenediamine), using strains TA98 and TA100 and their nitroreductase deficient mutants, TA98NR and TA100NR, in the presence and absence of rat S9 mix. The addition of the nitro-group to benzamine molecules converted them into direct mutagens. Furthermore, the position of the nitro-group affected their mutagenic activities. Cytotoxicity testing with Chinese hamster ovary cells (CHO-Kl ) showed that the presence of the nitro-group in these compounds had no specific effect on toxicity. The test compounds all showed a dose-related increase in inducing chromosomal aberrations in CHO cells. However, the presence of the nitro-group did not affect potency in inducing chromosomal aberrations. Compounds containing the nitro-group had higher initial oxidation potentials and dipole moments (mu) than their nonnitro-containing counterparts. The mutagenicity and toxicity of these compounds were not related to physico-chemical properties, including oxidation potential, energy difference between the lowest unoccupied molecular orbital and the highest occupied molecular orbital, ionization potential or dipole moments. [R70] NTOX: *The static acute toxicities and degradative rates of the unsubstituted phenylenediamines (pdas) varied significantly among the ortho, para and meta isomers. With fathead minnows, the nominal 96 hr LC50s were 0.06, 44 and 1,600 mg/l for p-pda, o-pda and m-pda, respectively. In daphnid tests, the nominal 48 hr EC50s were 0.28, 0.87 and 5.9 mg/l for p-pda, o-pda and m-pda, respectively. The nominal 96 hr EC50s in algae were 0.28, 0.16, and 2.4 mg/l for p-pda, o-pda and m-pda, respectively. With oxygenation, the times to reach 1/2 initial concn were 4 to 9 hr for p-pda, 650 to 1,100 hr for o-pda and 3,200 to 8,100 hr for m-pda. Results suggest that acute toxicities of pdas are related to their chemical reactivities (degradative rates) and that pdas may degrade rapidly under environmental conditions. [R71] NTXV: *LDLo Rat oral 100 mg/kg; [R29, 408] *LDLo Rat ip 50 mg/kg; [R29, 408] *LDLo Rat sc 170 mg/kg; [R29, 408] *LD50 Dog iv 17 mg/kg; [R29, 408] *LD50 Cat oral 100 mg/kg; [R29, 408] *LDLo Rabbit sc 250 mg/kg; [R29, 408] *LD50 Rat oral 80 mg/kg; [R2] *LD50 Rat ip 37 mg/kg; [R2] ETXV: *LC50 Goldfish 5.75 mg/L/48 hr /Conditions of bioassay not specified/; [R14] TCAT: ?1,4-Benzenediamine was examined for mutagenic activity in Salmonella typhimurium tester strains TA1535, TA1537, TA1538, TA100, and in Saccharomyces cerevisiae strain D3 with and without metabolic activation provided by phenobarbitol-induced rat liver S9 fraction. The test article was not mutagenic at concentrations ranging from 1 to 1000 ug/ml in the Salmonella strains (plate incorporation assay), or at 0.05% in the Saccharomyces D3 strain (mitotic recombination assay), in the presence or absence of metabolic activation. In preliminary experiments, 1,4-benzenediamine was toxic to Saccharomyces D3 cells at a concentration of 0.1%, however, toxicity to Salmonella was not reported. [R72] ?para-Phenylenediamine (CAS # 106-50-3) was evaluated as cause for methemoglobinuria in sets of 2 each beagle dogs fed single gavage doses of 1.0, 3.0, and 10.0 mg/kg bodyweight. All dogs exhibited lacrimation, while 10.0 mg/kg dosed dogs showed red and swollen eyes persisting in one dog at 24-hour post-gavage observation. Slight redness was also noted in the eyes of 3.0 mg/kg dogs, but all such signs were resolved by 24 hours after treatment. Methemoglobinemia was not induced at levels producing pharmacotoxic effects in beagle dogs. [R73] ?1,4-Phenylenediamine (CAS # 106-50-3) was evaluated for neurotoxic effects in groups of Crl:CDBR rats (12/sex/group) administered single gavage doses in sterile water of 0, 20, 40, and 80 mg/kg bodyweight. Neurotoxicity was assessed by functional operational battery and motor activity tests performed prior to treatment (baseline assessment) and at approximately 1.5 hours (time of maximal clinical signs), 24 hours, and 4 days post-gavage. Both females of all dose levels and males of 40 and 80 mg/kg dosage groups exhibited signs of a systemic toxicity with significantly reduced weight gain. These deviations from control were echoed in significantly reduced food consumption in all except 20 mg/kg females after Day 1 and in males of 80 mg/kg doses. No other clinical signs of toxicity were significantly dose-related. Upon the functional observation batteries through post-treatment Day 4, females only demonstrated significant dose-related malaise, postural changes, palpebral closure, and diminished arousal. Males showed similar functional aberrations which were not statistically significant relative to controls. Treatment was not significantly reflected in fore- or hind-limb grip strength or foot splay. Measurements of decreased motor activity in treated rats were significantly dose-related, except after Day 1 in both 20 mg/kg groups. [R74] POPL: *P-PHENYLENEDIAMINE OR ITS INTERMEDIARY OXIDN PRODUCTS APPEAR NOT TO BE PARTICULARLY CAUSTIC OR INJURIOUS, EXCEPT WHEN THERE IS HYPERSENSITIVITY TO THEM. APPARENTLY HYPERSENSITIVITY IS SPONTANEOUSLY PRESENT IN SOME INDIVIDUALS AND IS READILY DEVELOPED IN MANY OTHERS. [R32, 696] ADE: *PARAPHENYLENEDIAMINE HYDROCHLORIDE WAS APPLIED TO THE SKIN OF DOGS IN GELS AND FLUIDS, AS THEY ARE USED IN HAIR DYEING; ABSORPTION WAS DETERMINED BY COMPARING BLOOD CONCENTRATIONS WITH THAT OBTAINED AFTER IV INJECTION OF THE DIAMINE OVER A COMPARABLE PERIOD OF TIME. IT WAS CALCULATED THAT 16 MG WERE ABSORBED WHEN 50 ML OF A LAURYL SULFATE-BASED GEL CONTAINING 1.5 G PARAPHENYLENEDIAMINE WAS APPLIED FOR 3 HOURS AND FREE ACCESS TO AIR WAS ALLOWED (THE MAXIMAL BLOOD CONCENTRATION WAS 0.15 UG/ML). THIS AMOUNT ROSE TO 110 MG IF THE TREATED AREA WAS IMMEDIATELY COVERED WITH ALUMINUM FOIL (THE MAXIMAL BLOOD CONCENTRATION WAS 0.5 UG/ML). /P-PHENYLENEDIAMINE HYDROCHLORIDE/ [R75] *THE DISTRIBUTION KINETICS OF THE (3)H-LABELED P-PHENYLENEDIAMINE HYDROCHLORIDE WAS STUDIED WHEN ADMINISTERED IV AND WHEN APPLIED PERCUTANEOUSLY IN MICE AND RABBITS. IN RABBITS, IV ADMINISTRATION LED TO A BIPHASIC BLOOD CLEARANCE WITH T/2 VALUES OF 24 MINUTES AND 43.5 HOURS AND QUICK PERCUTANEOUS ABSORPTION. THE TISSUE DISTRIBUTION PATTERN INVESTIGATED AFTER IV AND PERCUTANEOUS ADMINISTRATION IN 16 DIFFERENT TISSUES AND ALSO IN BLOOD DID NOT DEMONSTRATE ANY TARGET ORGAN FOR SELECTIVE LOCALIZATION OF THE DYE. NO GREATER THAN 0.06% OF THE IV ADMINISTERED RADIOACTIVITY WAS MEASURED PER 10 G OF ANY TISSUE AT THE 12TH DAY. /P-PHENYENEDIAMINE HYDROCHLORIDE/ [R76] *After the /dog abdominal/ skin was washed, m-phenylenediamine concentration in the blood was observed to decline more rapidly than was the case with p-phenylenediamine and 2,5-diaminotoluene. [R77] *A homologous series of hair dyes was selected for percutaneous absorption studies with excised human skin. The permeability constants obtained for the dyes were compared with octanol/water and skin membrane/water partition coefficients. The compounds examined were: p-phenylenediamine, o-phenylenediamine, 2-nitro-p-phenylenediamine, 2-amino-4-nitrophenol, 4-chloro-m-phenylenediamine, and 4-amino-2-nitrophenol. Skin absorption of the dyes was observed when they were applied in an aqueous solution. With one exception, the octanol/water partition coefficients were in the same rank order as the permeability constants. The determination of the partitioning of the hair dyes between water and either stratum corneum or epidermis was more complex. Preliminary stratum corneum/water partition studies resulted in values that were in the reverse order of skin permeation. When binding of the compounds to components of the membrane was saturated, the partition values more closely duplicated the rank order of permeability of the dyes. Prediction of percutaneous absorption of substances based on their partition coefficients may be confounded if these compounds are capable of binding to skin. [R78] METB: *P-PHENYLENEDIAMINE YIELDS P-QUINONE PROBABLY IN MAN, MONKEY, PIG, HORSE, SHEEP, GOAT, CAT, RABBIT, GUINEA PIG, RAT, MOUSE, AND HEN. /FROM TABLE/ [R79] *P-PHENYLENEDIAMINE YIELDS P-QUINONE PROBABLY IN HORSERADISH ... WITH CERULOPLASMIN AND LACCASE. /FROM TABLE/ [R79] *P-PHENYLENEDIAMINE YIELDS P-QUINONE PROBABLY IN PERIPLANETA, ... IN CITRUS, ... IN TEA. /FROM TABLE/ [R79] *N,N'-DIACETYL-PARA-PHENYLENEDIAMINE WAS IDENTIFIED AS A URINARY METABOLITE OF PARA-PHENYLENEDIAMINE IN DOGS. [R75] ACTN: *FROM STUDIES OF THE INTRACUTANEOUS SENSITIZATION OF GUINEA-PIGS USING PARA-PHENYLENEDIAMINE, HYDROQUINONE, QUINHYDRONE AND BENZOQUINONE, IT HAS BEEN SUGGESTED THAT BENZOQUINONE FORMATION PLAYS AN IMPORTANT ROLE IN THE ALLERGIC ACTION OF PARA-PHENYLENEDIAMINE. [R57] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,4-Benzenediamine's production and use as an intermediate in the manufacture of diisocyanates for polyurethane; antioxidants and accelerators for rubber, and its use in dye mixtures for hair, fur and photographic developing chemicals may result in its release to the environment through a variety of waste streams. Based on an extrapolated vapor pressure of 0.005 mm Hg at 25 deg C, 1,4-benzenediamine is expected to exist primarily as a vapor in the ambient atmosphere. Vapor-phase 1,4-benzenediamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of about 2 hours. If released to soil, 1,4-benzenediamine is expected to have high mobility based on an estimated Koc value of 16; however it may form covalent bonds to humic material which would limit its movement through soil. Volatilization from dry soil surfaces is not expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is not expected based on an estimated Henry's Law constant of 6.7X10-10 atm-cu m/mol. Biodegradation is expected to occur slowly in moist and dry soils. In water, 1,4-benzenediamine is not expected to adsorb to sediment or particulate matter based on its estimated Koc value. Volatilization from water surfaces is not expected based upon the estimated Henry's Law constant for this compound. Abiotic degradation of 1,4-benzenediamine by photochemically produced peroxy radicals is an important environmental fate process in surface waters. The half-life of this reaction has been estimated as about 1 day. The potential for bioconcentration in aquatic organisms is low based on an estimated BCF value of 0.3. A measured pKb value of 6.2 indicates that the protonated form of 1,4-benzenediamine will exist at environmentally significant pH and this may affect the environmental fate of this compound in aquatic environments. Occupational exposure may occur through inhalation and dermal contact with this compound at workplaces where 1,4-benzenediamine is produced or used. The general population may be exposed to this compound by dermal contact, primarily through the use of hair dyes containing 1,4-benzenediamine. (SRC) NATS: *1,4-Benzenediamine is not known to occur as a natural product(1). [R80] ARTS: *1,4-Benzenediamine may be released in emissions and wastewater during its production and use in the manufacture of diisocyanates for polyurethanes (largest volume use) such as Kevlar(1) and as an intermediate in manufacture of antioxidants and accelerators for rubber. It is used in manufacture of azo dyes and as a component of dye mixtures for hair and fur(2). Its derivatives are also used as developers for black-and-white and color photographs(3). [R81] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 16(SRC), determined from a measured log Kow of -0.30(2), and a recommended regression-derived equation(3), indicates that 1,4-benzenediamine is expected to have high mobility in soil(SRC); however it may form covalent bonds to humic material which would limit movement through soil(4). Volatilization of 1,4-benzenediamine is not expected from moist soil surfaces(SRC) given an estimated Henry's Law constant of 6.7X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Volatilization of 1,4-benzenediamine from dry soil surfaces is not expected(SRC) based on an extrapolated vapor pressure of 0.005 mm Hg(SRC) at 25 deg C(6). Biodegradation is expected to occur slowly in soils based on standard biodegradability tests conducted with activated sludge(7-11). [R82] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 16(SRC), determined from a measured log Kow of -0.30(2), and a recommended regression-derived equation(3), indicates that 1,4-benzenediamine is not expected to adsorb to suspended solids and sediment in water(SRC). 1,4-benzenediamine is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 6.7X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Degradation of 1,4-benzenediamine by photochemically produced peroxy radicals will be an important environmental fate process in surface waters(5,SRC). The half-life of this reaction is estimated as 1 day for a solution concentration of 1X10-9 M of peroxy radicals and an estimated rate constant of 1X10+4 L/mol-s(5). According to a classification scheme(6), an estimated BCF value of 0.3(3,SRC), from a measured log Kow of -0.3(2,SRC), suggests that bioconcentration in aquatic organisms is low(SRC). Biodegradation in aquatic environments is not expected to be an important environmental fate process(SRC). A 0% theoretical oxygen demand was observed for 1,4-benzenediamine in a Warburg apparatus during a 5 day incubation period(7). A measured pKb value of 6.2 indicates that the protonated form of 1,4-benzenediamine will exist at environmentally significant pH and this may affect the environmental fate of this compound in aquatic environments(8). [R83] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,4-benzenediamine, which has an extrapolated vapor pressure of 0.005 mm Hg at 25 deg C(2,SRC), is expected to exist primarily as a vapor in the ambient atmosphere. Vapor-phase 1,4-benzenediamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2 hours(3,SRC). [R84] BIOD: *Biodegradation of 1,4-benzenediamine (60 ng/l) with an adapted mixed culture from soil, compost or mud from a waste lagoon capable of rapid degradation of phenol led to a 9% theoretical BOD in 3hr at 30 deg C (phenol reference - 70% theoretical BOD)(1). An 80% degradation of 1,4-benzenediamine (25-30 mg/l) with acclimated activated sludge in 120 hr at 20 deg C has been reported(2). Aniline-acclimated activated sludge led to 8% theoretical BOD in 190 hr at 20 deg C(3). No degradation of 500 mg/l 1,4-benzenediamine was observed with 3 activated sludges in 24 hr at 20 deg C, the test compound was toxic to the 3 sludges(4). A 0% theoretical BOD was observed for 1,4-benzenediamine in a Warburg apparatus during a 5 day incubation period(5). 3.8% Biodegradation was observed when 1,4-diaminobenzene dihydrochloride (initial concentration unspecified) was incubated with an activated sludge inoculum obtained from a municipal sewage treatment facility over a 5 day incubation period(6). [R85] ABIO: *The rate constant for the vapor-phase reaction of 1,4-benzenediamine with photochemically-produced hydroxyl radicals has been estimated as 2.3X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). A measured pKb value of 6.2 indicates that 1,4-benzenediamine is expected to exist in the protonated form at environmentally significant pH values(2,SRC). Abiotic degradation of 1,4-benzenediamine by photochemically produced peroxy radicals is an important environmental fate process in surface waters(3,SRC). The rate constant for this reaction has been estimated as 1X10+4 L/mol-s at 25 deg C(3). This corresponds to a half-life of about 1 day for a solution concentration of 1X10-9 M of peroxy radicals(3). 1,4-Benzenediamine adsorbs UV light above 290 nm (UV maximum 308 nm(4)) and therefore may undergo direct photolysis in the environment by sunlight. 53.7% Photooxidation of a 1,4-diaminobenzene dihydrochloride sample (initial concentration unspecified) on a silica gel substrate was observed when irradiated with light above 290 nm for 17 hours(5). [R86] BIOC: *An estimated BCF value of 0.3 was calculated for 1,4-benzenediamine(SRC), using a measured log Kow of -0.3(1,SRC) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). An experimental BCF value of 450 was measured for algae exposed to 1,4-diaminobenzene dihydrochloride for 24 hours(4). An experimental BCF value of 6 was measured for fish (golden ide) exposed to 1,4-diaminobenzene dihydrochloride for 3 days(4). [R87] KOC: *Based on a recommended classification scheme(1), an estimated Koc value of 16(SRC), determined from a measured log Kow of -0.3(2) and a recommended regression-derived equation(3), indicates that 1,4-benzenediamine is expected to have high mobility in soil(SRC); however it may form covalent bonds to humic material which would limit movement through soil(4). [R88] VWS: *The Henry's Law constant for 1,4-benzenediamine is estimated as 6.7X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that 1,4-benzenediamine will be essentially nonvolatile from water surfaces(2,SRC). 1,4-Benzenediamine is not expected to volatilize from dry soil surfaces based on an extrapolated vapor pressure of 0.005 mm Hg at 25 deg C(3). [R89] RTEX: *Occupational exposure to 1,4-benzenediamine may occur through inhalation and dermal contact with this compound at workplaces where 1,4-benzenediamine is produced or used(1,SRC). NIOSH (NOES Survey 1981-83) has statistically estimated that 104 workers are potentially exposed to 1,4-benzenediamine in the USA(2). The general population may be exposed to this compound by dermal contact, primarily through the use of hair dyes containing 1,4-benzenediamine(1,3). [R90] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +25 mg/cu m [R20] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 0.1 mg/cu m. Skin Designation. [R91] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.1 mg/cu m, skin. [R20] TLV: +8 hr Time Weighted Avg (TWA): 0.1 mg/cu m. [R28, 2002.48] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R28, 2002.6] +A4; Not classifiable as a human carcinogen. [R28, 2002.48] OOPL: *Australia: 0.1 mg/cu m, skin designation (1900); Federal Republic of Germany: 0.1 mg/cu m (total dust), short term level 0.2 mg/cu m, 30 min TWA, 4 times per work shift (1991); Sweden: 0.1 mg/cu m, short term limit, 0.3 mg/cu m, skin, sensitizer (1990); United Kingdom: 0.1 mg/cu m, skin (1991). [R31, 1991.1228] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1,4-Benzenediamine is included on this list. [R92] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 1,330 ug/l [R93] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R94] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. p-Phenylenediamine is included on this list. [R95] *Manufacturers and processors of para-phenylenedimine are required to conduct health efffects, chemical fate and environmental effects testing under TSCA section 4. [R96] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *ELECTROCHEMICAL DETECTION AND HPLC ANALYSIS OF NONVOLATILE POLLUTANTS. /NONVOLATILE POLLUTANTS/ [R97] *ION-EXCHANGE THIN LAYER CHROMATOGRAPHY ANALYSIS OF HAIR DYES. /HAIR DYES/ [R98] *AROMATIC AMINES (INCLUDING 1,4-BENZENEDIAMINE) ARE DETECTED IN WATER BY ELECTROCHEMICAL DETECTION. [R99] *SEPARATION AND DETERMINATION OF PHENYLENEDIAMINE DERIVATIVES IN HAIR DYE PRODUCTS BY HPLC. /PHENYLENEDIAMINE DERIVATIVES/ [R100] *Method No. 87; m-, o- and p-Phenylenediamine, HPLC, quantitation limit 2.1 ug/cu-m (based on a 100-L air volume). [R101] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: TSCA CHIPs present a preliminary assessment of 1,4-Benzenediamine's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404. Waters MD et al; The Genetic Toxicology of Gene-Tox Non-Carcinogens; Mutat Res 205(1-4): 139-82 (1988). USEPA; PHENYLENEDIAMINES; RESPONSE TO INTERAGENCY TESTING COMMITTEE; FED REGIST 47(5) 973 (1982). EVIDENCE IS GIVEN SUPPORTING TESTING OF THE CLASS OF COMPOUNDS PHENYLENEDIAMINES FOR THEIR TOXIC EFFECTS ON HUMAN HEALTH AND THE ENVIRONMENT. THE RESULTS OF TOXICITY TESTING OF 22 COMPOUNDS ARE TABULATED AS ARE THE EFFECTS FOR WHICH TESTING IS BEING CONSIDERED FOR 13 COMPOUNDS, AND THE USES OR POTENTIAL USES OF 47 PHENYLENEDIAMINES. Fukunaga T, et al; Contact Dermat 35 (3): 185-6 (1996). Contact anaphylaxis due to para-phenylenediamine. Yagi H et al; Hum Exp Toxicol 15 (8): 617-18 (1996). Paraphenylenediamine induced optic atrophy following hair dye poisoning. SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1255 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 126 (1978) R4: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 798 R5: Arena, J.M. Poisoning: Toxicology-Symptoms Treatments. Third Edition. Springfield, Illinois: Charles C. Thomas, 1974. 488 R6: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. 528 R7: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1157 R8: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 348 R9: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-392 R10: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R11: Perrin DD; Dissociation constants of organic bases in aqueous solution. IUPAC Chem Data Ser, Buttersworth, London (1965) R12: USEPA; Fed Reg 47: 937-83 (1982) R13: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-156 R14: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1531 R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 166 R16: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2184 R17: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R18: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2654 R19: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 631 R20: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. 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S7 70 (1987) R28: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R29: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. R30: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 168 R31: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R32: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R33: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. 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Du Pont De Nemours and Co. Chemicals, EPA Document No. 878213782, Fiche No. OTS0206445 R73: CLAIROL RESEARCH LABS; Methemoglobin Levels in Beagle Dogs Following Oral Administration of p-Phenylenediamine; 7/22/80; EPA Doc No. 408036147; Fiche No. OTS0506089 R74: E I DUPONT DE NEMOURS AND CO; Acute Oral Neurotoxicity Study of p-PDA in Rats; 09/14/90; EPA Doc No. 40-9036454; Fiche # OTS0528739 R75: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 134 (1978) R76: REHANI MM ET AL; INDIAN J MED RES 74 (JULY): 129-34 (1981) R77: Kiese M et al; Toxicol Appl Pharm 12: 495-507 (1968) R78: Bronaugh RL, Congdon ER; J Invest Dermatol 83 (2): 124-27 (1984) R79: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-23 R80: (1) IARC; Some Aromatic Amines and Related Nitro Compounds - Hair Dyes, Colouring Agents and Miscellaneous Industrial Chemicals 16: 125-42 (1978) R81: (1) Layer RW; Kirk-Othmer Encycl Chem Technol 3rd ed 2: 348-54 (1978) (2) Hawley GG; The Condensed Chemical Dictionary 12th ed. NY,NY: Van Nostrand Reinhold Co Inc, p. 899 (1993) (3) IARC; Some Aromatic Amines and Related Nitro Compounds - Hair Dyes, Coloring Agents and Miscellaneous Industrial Chemicals 16: 125-42 (1978) R82: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C, Leo A; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Adrian P et al; Chemosphere 18: 1599-1609 (1989) (5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (6) Yaws CL; Handbook of Vapor Pressure. Vol 2 C5-C7 Compounds. 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Butterworth, London (1965) (3) Gray DA et al; Health Hazard Profile on Phenylenediamines SRC TR85-004 (1985) (4) Sadtler Standard References Spectra UV 1187 (1960) (5) Freitag D et al; Chemosphere 14: 1589-1616 (1985) R87: (1) Hansch C, Leo A; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: American Chemical Society (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Freitag D et al; Chemosphere 14: 1589-1616 (1985) R88: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C, Leo A; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington, DC: Amer Chem Soc (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (4) Adrian P et al; Chemosphere 18: 1599-1609 (1989) R89: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Yaws CL; Handbook of Vapor Pressure. Vol 2 C5-C7 Compounds. Houston, TX: Gulf Publ Co (1994) R90: (1) Gagliardi L et al; Int J Cosmet Sci 14: 19-31 (1992) (2) NIOSH; National Occupational Exposure Survey (NOES) (1983) (3) IARC; Some Aromatic Amines and Related Nitro Compounds - Hair Dyes, Coloring Agents and Miscellaneous Industrial Chemicals 16: 125-42 (1978) R91: 29 CFR 1910.1000 (7/1/98) R92: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R93: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R94: 40 CFR 302.4 (7/1/96) R95: 40 CFR 716.120 (7/1/96) R96: 40 CFR 799.3300 (7/1/96) R97: GRAFFEO AP, RIGGIN RM; JT CONF SENS ENVIRON POLLUT, (CONF PROC), 4TH, 637: (1978) R98: LEPRI ET AL; ANN CHIM (ROME) 66 (7-8): 451 (1976) R99: CONCIALINI V ET AL; J CHROMATOGR 258: 244-51 (1983) R100: HOOGEWIJS G, MASSART DL; J PHARM BELG 30 (2): 76-80 (1983) R101: OSHA Analytical Methods Manual. 2nd ed., Part 1 Organic Substances, Vol IV Meth 81-102, Apr 1993. US Dept Labor Occupational Safety and Health, Admin, Direct Tech Supp, OSHA Technical Center, Salt Lake City, Utah RS: 85 Record 175 of 1119 in HSDB (through 2003/06) AN: 2555 UD: 200302 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYL-CARBAMATE- SY: *AETHYLCARBAMAT- (GERMAN); *AETHYLURETHAN- (GERMAN); *AI3-00553-; *CARBAMIC-ACID,-ETHYL-ESTER-; *CARBAMIDSAEURE-AETHYLESTER- (GERMAN); *Ethylester-Kyseliny-Karbaminove- (Czech); *ETHYLURETHAN-; *ETHYL-URETHANE-; *O-ETHYLURETHANE-; *LEUCETHANE-; *LEUCOTHANE-; *NSC-746-; *PRACARBAMIN-; *PRACARBAMINE-; *Uretan-Etylowy- (Polish); *Uretano-; *URETHAN-; *URETHANE-; *Urethanum- (INN-Latin) RN: 51-79-6 MF: *C3-H7-N-O2 HAZN: U238; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *(A) BY HEATING ETHANOL AND UREA NITRATE AT 120-130 DEG C; (B) BY ACTION OF AMMONIA ON ETHYL CARBONATE OR ETHYL CHLOROFORMATE. [R1] *Prepared by the reaction of carbamic acid with ethyl alcohol. [R2] FORM: *GRADES: TECHNICAL; NF. [R1] OMIN: *URETHANE HAS BEEN REPORTED TO OCCUR AS RESULT OF REACTION OF AMMONIA AND DIETHYLPYROCARBONATE ADDED AT LEVELS OF 10 UG/L IN CERTAIN BEVERAGES AT PH BELOW 4.0 ... ALSO ... IN DIETHYLPYROCARBONATE TREATED WINES AT LEVELS UP TO 50 UG/L; IT WAS CONSIDERED POSSIBLE THAT SOME OF THIS WAS OF NATURAL ORIGIN ... . [R3] *... Urethane can occur as a contaminant in two anticonvulsant drugs (trimethadione and paramethadione), with an allowable limit of 1 ppm; these anticonvulsant drugs may be used only to treat epilepsy. ... [R4] USE: *MOLTEN URETHAN IS GOOD SOLVENT FOR VARIOUS ORG MATERIALS; PREPN AND MODIFICATION OF AMINO RESINS; AS SOLUBILIZER AND CO-SOLVENT FOR PESTICIDES, FUMIGANTS. [R5] *SOLUBILIZER AND CO-SOLVENT FOR COSMETICS. [R6] *AS CHEMICAL INTERMEDIATE, PRIMARILY FOR REACTION WITH FORMALDEHYDE TO PRODUCE N-HYDROXYMETHYL DERIVATIVES, WHICH ARE USEFUL AS CROSS LINKING AGENTS IN TEXTILE TREATMENTS DESIGNED TO IMPART WASH AND WEAR PROPERTIES TO FABRICS. [R3] *Intermediate for pharmaceuticals; biochemical research. [R1] *THERAP CAT (VET): ANESTHETIC [R5] *THERAP CAT: ANTINEOPLASTIC [R5] PRIE: U.S. PRODUCTION: *(1972) 4.5X10+7 G (EST) [R6] *(1975) GREATER THAN 4.54X10+5 G (EST) [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS, COLUMNAR CRYSTALS OR WHITE, GRANULAR POWDER [R7]; *PRISMS FROM BENZENE AND TOLUENE [R8] ODOR: *ALMOST ODORLESS [R7] TAST: *COOLING, SALINE, BITTER TASTE [R9, 230] BP: *182-184 DEG C [R5] MP: *48-50 DEG C [R5] MW: *89.09 [R5] DEN: *0.9862 g/cu cm at 21 deg C [R10] HTC: *397.2 kcal/g mol wt at 25 deg C [R11, p. D-280] HTV: *13,078.6 gcal/gmole [R11, p. C-673] OWPC: *log Kow= -0.15 [R12] PH: *AQ SOLN IS NEUTRAL [R5] SOL: *1 G DISSOLVES IN 0.5 ML WATER [R5]; *SOL IN BENZENE [R10]; *1 g in 0.8 ml alcohol [R5]; *1 g in 1.5 ml ether [R5]; *1 G IN 0.9 ML CHLOROFORM [R5]; *1 G in 2.5 ml glycerol [R5]; *1 g in 32 ml olive oil [R5] SPEC: *INDEX OF REFRACTION: 1.4144 AT 51 DEG C/D [R10]; *IR: 5961 (Coblentz Society Spectral Collection) [R8]; *NMR: 245 (Sadtler Research Laboratories Spectral Collection) [R8]; *MASS: 172 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R8] VAPD: *3.07 [R13] VAP: *0.36 torr at 25 deg C [R14] OCPP: *SUBLIMES READILY AT 103 DEG C AND 54 MM PRESSURE [R5] *Heat of fusion: 40.85 cal/g [R11, p. C-666] *VOLATILE AT ROOM TEMP [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *COMBUSTIBLE [R1] TOXC: *WHEN HEATED, IT EMITS TOXIC FUMES OF NOx. [R15] REAC: *This intermediate /N-carbomethoxymethylimino phosphoryl chloride/ (or its ethyl homologue), produced during prepn of phosphoryl dichloride isocyanate from interaction of phosphorus pentachloride and methyl (or ethyl) carbamate, is unstable. Its decomposition to the required product may be violent or explosive unless moderated by the presence of a halogenated solvent. [R16] *INCOMPATIBILITIES: ALKALIES, ACIDS, ANTIPYRINE, CHLORAL HYDRATE, CAMPHOR, MENTHOL, SALOL, OR THYMOL [R17] DCMP: *Hot aqueous acids or alkalies decompose urethane to ethanol, carbon dioxide, and ammonia. [R15] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R18, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R18, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R18, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R18, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R18, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R18, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R18, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R18, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R18, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R18, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R18, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R18, 1979.13] STRG: *... SHOULD BE STORED IN COOL, WELL VENTILATED PLACE, OUT OF DIRECT RAYS OF SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED AND MONITORED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED FROM EACH OTHER. [R19] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R18, 1979.13] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U238, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R20] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R18, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R18, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R18, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R18, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R18, 1979.17] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R21] *The following wastewater treatment technologies have been investigated for urethane: Biological treatment. [R22] *These compounds are all hydrolyzed using 5 M sodium hydroxide solution, although the reaction times vary. Methyl carbamate is hydrolyzed to methanol and carbamic acid and urethane /ethyl carbamate/ is hydrolyzed to ethanol and carbamic acid. ... Carbamic acid decomposes to carbon dioxide and ammonia ... In all cases destruction is greater than 99% and good accountances are obtained for the products ... . [R23] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: no data; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table/ [R24] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Esters and related compounds/ [R25] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R25] HTOX: *CLINICAL FINDINGS: VOMITING, COMA, HEMORRHAGES; KIDNEY AND LIVER INJURY. /FROM TABLE/ [R26] *TWO ADULT MALE PATIENTS WITH ACUTE LEUKEMIA DEVELOPED A FATAL BUDD-CHIARI-LIKE ILLNESS WHILE RECEIVING 6-THIOGUANINE. BOTH HAD PREVIOUSLY RECEIVED CYTOSINE ARABINOSIDE. POSTMORTEM SPECIMENS OF LIVER SHOWED CHANGES CHARACTERISTIC OF TOXIC VENOOCCLUSIVE DISEASE. SIMILAR FINDING HAVE BEEN REPORTED AFTER TREATMENT WITH URETHANE. [R27] *A retrospective cohort study was performed on a group of 664 male workers employed for at least one month during the period 1942-1979 in a chemical factory. Both established and suspected carcinogens had been handled in the plant, primarily piperazine, but also urethane, ethylene oxide, formaldehyde, and organic solvents. A significantly increased mortality, compared with the regional death rate, was observed in the cohort. The increase was mainly due to violent deaths and cardiovascular diseases. No rise in death rates was observed for asthma, bronchitis or emphysema, in spite of other evidence of a high risk of occupational asthma, due to exposure to piperazine. A statistically significant increase in cancer morbidity was observed for malignant lymphoma/myelomatosis when an induction latency time of at least 10 years was used. Furthermore, an increase in bronchial cancer was noted, but it was statistically significant only when an induction latency time of at least 15 years was used. [R28] *Exposure to urethane produces severe myelotoxicity resulting in suppression of NK cell activity and antibody responses to SRBC. [R29] NTOX: *URETHANE IS ONE OF THE PROCARCINOGENS LISTED REQUIRING BIOCHEMICAL ACTIVATION. /FROM TABLE/ [R30, 3] */One investigator/ ... produced neural tube closure defects in the mouse fetus by injecting 15 mg on the 7th day of gestation. /Others/ ... gave 1.5 g/kg daily to mice from the 9th through 12th day of gestation and found skeletal and palate defects. [R31] *... Eye developmental defects /have been demonstrated/ in rats treated with this substance. ... 1 g/kg /admin/ to rats on days 6 through 11 ... produced a high incidence of skeletal defects. Gross defects were uncommon. [R31] *... Defects /were produced/ in hamsters by injecting 25 to 100 mg iv on days 9, 10 or 11. Neural tube defects and cardiac malformations were found. [R31] *URETHANE CAUSES CHROMOSOME DAMAGE IN RATS BUT NOT IN CULTURED ANIMAL CELLS NOR IN PLANT CELLS. [R32] *THREE STRAINS OF MICE (BLH, NMRI AND C57BL) WERE EXPOSED TO TWO TYPES OF AEROSOL SPRAYS (PRESSURE AND ULTRASONIC) CONTAINING URETHANE. THE BHL AND C57BL MICE WERE 4-8 WK OF AGE AT THE START OF THE EXPERIMENT, AND NMRI MICE WERE LESS THAN 6 MO OLD. GROUPS OF MICE WERE KEPT FOR 20-60 MIN/DAY IN ATMOSPHERES SATURATED WITH AEROSOLS AT URETHANE CONCN OF 5, 10, 15 OR 20%. MAX PERIOD OF TREATMENT AT A CONCN OF 20% VARIED FROM 14.5 WK FOR BLH MICE TO 3.5 WK FOR C57BL MICE. TREATMENT OF MICE WITH PRESSURE SPRAY YIELDED THE FIRST LUNG TUMORS AFTER 10-22 WK, AND WITH THE ULTRASONIC SPRAY AFTER A PERIOD OF 7-15 WK. AN INCR IN SURVIVAL TIME RESULTED IN AN INCR IN BOTH TUMOR SIZE AND NUMBER, AS WELL AS IN EXTENT OF DEDIFFERENTIATION. WHEREAS BLH AND NMRI MICE SHOWED ONLY ADENOMAS, C57BL MICE EXPOSED TO 5% URETHANE FOR 22 WK MOSTLY HAD SOLID TUMORS OF SQUAMOUS TYPE. NO CASES WERE METASTASES (OTTO AND PLOTZ, 1966). /NO DATA ON CONTROLS GIVEN./ [R33] *URETHANE IS NOT CARCINOGENIC FOR MOUSE SKIN BUT HAS BEEN USED WIDELY IN TWO STAGE CARCINOGENESIS AS INITIATOR EITHER WHEN APPLIED TOPICALLY OR WHEN GIVEN BY SC OR IP INJECTION IN HIGH DOSES ... . [R30, 28] *SINGLE ORAL DOSE OF 1, 4, 16 OR 64 MG URETHANE GIVEN AS 5% SOLN IN WATER BY STOMACH TUBE TO GROUPS OF MALE AND FEMALE SWISS MICE FOLLOWED BY TWICE WEEKLY SKIN APPLICATION OF CROTON OIL FOR 26 WK PRODUCED DOSAGE RELATED INCR IN SKIN PAPILLOMAS AND LUNG ADENOMAS. OF CONTROLS, 2/20 MICE HAD SKIN PAPILLOMAS AND 1/20 LUNG ADENOMAS, WHEREAS AT THE HIGHEST DOSE LEVEL 24/24 MICE HAD AN AVG OF 5 and 7 TUMORS/MOUSE, RESPECTIVELY (BERENBLUM AND HARAN-GHERA, 1957). /NO DATA ON CONTROLS./ [R34] *A GROUP OF 31 MALE AND 30 FEMALE SYRIAN GOLDEN HAMSTERS WAS GIVEN 0.2% URETHANE IN DRINKING WATER FOR 20 WK. CONCN WAS THEN INCR TO 0.4% FOR FURTHER 20 WK, AT WHICH TIME TREATMENT WAS DISCONTINUED FOR 8 WK ... TREATMENT WAS RESUMED FOR A FURTHER 2 WK, WHEN THE ANIMALS WERE LEFT UNTREATED AND OBSERVED UP TO 80 WK. TUMORS WERE FOUND IN 22/27 MALE AND 21/25 FEMALE SURVIVORS, COMPARED WITH 9/54 IN MALE AND 3/47 IN FEMALE CONTROLS. TUMORS IN TREATED ANIMALS INCL: MELANOTIC TUMORS OF SKIN (23 ANIMALS), PAPILLOMAS AND SQUAMOUS CELL CARCINOMAS OF FORESTOMACH (40 ANIMALS), MALIGNANT LYMPHOMAS (5 ANIMALS), MAMMARY TUMORS (3 ANIMALS), HEPATOMAS (3 MALES), HEMANGIOMAS (6 ANIMALS), HEMANGIOSARCOMAS (2 ANIMALS), PULMONARY ADENOMATOSIS (8 ANIMALS) AND ADENOMATOUS POLYPS OF CECUM (6 ANIMALS). VERY FEW OF THESE TUMORS OCCURRED IN THE 12 TUMOR BEARING CONTROLS (TOTH ET AL, 1969B). SIMILAR RESULTS WERE OBTAINED IN A GROUP OF 52 MALE AND 48 FEMALE 5 WK OLD SYRIAN GOLDEN HAMSTERS ADMIN 0.1% URETHANE IN DRINKING WATER FOR LIFE (TOTH AND BOREISHA, 1969). [R34] *IN A GROUP OF 100 MALE AND 100 FEMALE FEMALE SWISS ALBINO MICE ADMIN 0.4% URETHANE IN DRINKING WATER FOR TWO 10 DAY TREATMENT PERIODS COMMENCING WHEN THE ANIMALS WERE 10 WK OF AGE, NEARLY 100% INCIDENCE OF MULTIPLE LUNG ADENOMAS WAS OBSERVED. ALL ANIMALS HAD DIED OR WERE KILLED AFTER 42 WK (IE WHEN THE ANIMALS WERE 1 YR OF AGE). LUNG ADENOMAS OCCURRED IN 9 MALE AND IN 23 FEMALE CONTROLS. ... LYMPHOMAS (MAINLY LYMPHOSARCOMAS) OCCURRED IN 28 FEMALES AND 15 MALES OFTEN BEFORE 40 WK OF AGE COMPARED WITH 16 and 4 IN FEMALE AND MALE CONTROLS, IN WHICH THE TUMORS MOSTLY OCCURRED AFTER 60 WK OF AGE. MULTIPLE SMALL HEMANGIOMAS OF LIVER OCCURRED IN SEVERAL URETHANE TREATED ANIMALS OF BOTH SEXES WHICH HAD DIED OR WERE KILLED AFTER 40TH WK OF AGE. IN 3 TREATED MALES AND 2 FEMALES A TOTAL OF NINE PAPILLOMAS AND ONE SEBACEOUS CARCINOMAS OF SKIN WERE ALSO OBSERVED (TOTH ET AL, 1961A). [R35] *50% SOLN /OF URETHANE/ IN ACETONE WAS APPLIED TO SKIN OF 40 MALE AND 40 FEMALE HAMSTERS 2 OR 3 TIMES/WK; TOTAL NUMBER OF TREATMENTS VARIED FROM 50-105 AND EACH APPLICATION CONSISTED OF APPROX 125 MG URETHANE. ANIMALS WERE KILLED BETWEEN 8-18 MO FROM BEGINNING OF TREATMENT, AND MAMMARY TUMORS OCCURRED IN 4/40 FEMALES. IN ADDITION, A LARGE NUMBER OF MELANOTIC TUMORS WHICH GREW UPON TRANSPLANTATION, OCCURRED IN BOTH SEXES, AND IN TWO ANIMALS BEARING MELANOTIC TUMORS METASTASES TO LUNG WERE PRESENT. TUMORS DID NOT OCCUR IN CONTROL ANIMALS (REVIERE ET AL, 1964A,B,C; 1965). [R33] *GROUPS OF APPROX 100 MALE AND 100 FEMALE 5 WK OLD OUTBRED ALBINO CTM MICE WERE ADMIN 0.4% URETHANE IN DRINKING WATER FOR 1 OR 10 DAY PERIODS, OR ONE, TWO OR THREE 5 DAY PERIODS WITH AN INTERVAL OF 10 DAYS BETWEEN EACH TREATMENT PERIOD. ALL ANIMALS DIED OR WERE KILLED WITHIN 60-80 WK. THE HIGHEST INCIDENCE OF TUMORS OCCURRED IN ANIMALS GIVEN TWO 10 DAY TREATMENTS. IN THIS GROUP THE INCIDENCE OF LUNG ADENOMAS WAS 80-84% IN TREATED ANIMALS COMPARED WITH 2-7% IN CONTROLS. LYMPHOSARCOMA OCCURRED IN 33% OF MALES AND 27% OF FEMALES COMPARED WITH 4.5 and 5.0% IN CONTROLS. OF ALL THE LYMPHOSARCOMAS OBSERVED IN TREATED ANIMALS, 75% WERE OF THYMIC ORIGIN. A SLIGHT INCR IN THE INCIDENCE OF LIVER ANGIOMAS AND OF HARDERIAN GLAND TUMORS WAS ALSO OBSERVED IN TREATED ANIMALS (DELLA PORTA ET AL, 1963). [R36] *IN 2 GROUPS OF 36 5-WK OLD C3H FEMALE MICE ADMIN 0 OR 0.1% URETHANE IN DRINKING WATER FOR 13 WK AND OBSERVED UP TO 76 WK, THE INCIDENCE OF PULMONARY ADENOMAS INCR FROM 2/36 IN CONTROLS TO 15/32 IN TREATED ANIMALS. IN GROUPS OF 54-62 MALE OR FEMALE 53 WK OLD DBA MICE ADMIN 0.1% URETHANE IN DRINKING WATER FOR 31 WK AND OBSERVED UP TO 45 WK, PULMONARY ADENOMATOSIS WAS OBSERVED IN 20/54 MALES AND 20/52 FEMALES, COMPARED WITH 1/59 and 2/56 CONTROLS. PULMONARY ADENOMAS ALSO OCCURRED IN 10 OF THE TREATED MALES AND IN 11 TREATED FEMALES, COMPARED WITH 0 IN CONTROLS. SQUAMOUS-CELL TUMORS OCCURRED IN 11 TREATED MALES AND IN 6 TREATED FEMALES; AGAIN THIS TUMOR WAS FOUND IN CONTROLS. INCIDENCE OF LEUKEMIA WAS INCR ONLY IN C3H FEMALES, FROM 0/36 IN CONTROLS TO 8/36 IN TREATED ANIMALS, AS WAS INCIDENCE OF MAMMARY CARCINOMAS IN DBA FEMALES, FROM 13/57 IN CONTROLS TO 34/54 IN TREATED ANIMALS; THE HIGH SPONTANEOUS INCIDENCE IN C3H CONTROLS WAS NOT INCR, POSSIBLY DUE TO THE EARLIER DEATH OF TREATED FEMALES. MALIGNANT MESENCHYMAL TUMORS OF FAT PADS WERE ALSO OBSERVED IN 3 TREATED DBA MALES AND IN 3 TREATED C3H FEMALES. TUMORS OF THIS TYPE WERE NOT FOUND IN CONTROLS (TANNENBAUM AND MALTONI, 1962). [R36] *URETHANE HAS BEEN SHOWN TO BE CARCINOGENIC IN MICE, RATS, AND HAMSTERS FOLLOWING ADMINISTRATION BY THE ORAL, INHALATION, SUBCUTANEOUS OR INTRAPERITONEAL ROUTES, PRODUCING, AMONG OTHERS, LUNG TUMORS, LYMPHOMAS, HEPATOMAS, MELANOMAS, AND VASCULAR TUMORS. IT IS AN INITIATOR FOR SKIN CARCINOGENESIS IN MICE BOTH WHEN GIVEN ORALLY AND TOPICALLY. IT WAS ALSO SHOWN TO ENHANCE THE LEUKEMOGENIC EFFECT OF X-IRRADIATION. IT IS CARCINOGENIC IN SINGLE DOSE EXPERIMENTS AND FOLLOWING PRENATAL EXPOSURE. NEONATAL AND INFANT MICE ARE MORE SUSCEPTIBLE TO CANCER INDUCTION BY URETHANE THAN ARE ADULT MICE. [R37] *URETHANE (1 MG/G BODY WT) ADMIN 8 TIMES AT WEEKLY INTERVALS BY SC ROUTE TO C57BL MICE, FIRST WITHIN 24 HR OF BIRTH, PRODUCED THYMIC LYMPHOMAS BETWEEN 12TH AND 27TH WK OF LIFE (DOELL AND CARNES, 1962). /NO DATA ON CONTROLS GIVEN./ [R38] *WHEN MRC (WISTAR) RATS WERE ADMIN 0.5 MG/G BODY WT URETHANE ONCE 4 DAYS BEFORE PARTURITION, A SMALL NUMBER (4.5%) OF HEPATOMAS AND SARCOMAS OF THE HEART WERE OBSERVED IN OFFSPRING (KOMMINENI ET AL, 1970). /NO DATA FOR CONTROLS./ [R39] *WHEN 7 DAY OLD SYRIAN HAMSTERS WERE INJECTED SC WITH 1 MG/G BODY WT URETHANE ONCE WEEKLY FOR 6 WK AND OBSERVED FOR THEIR LIFESPAN, 6 (30%) FEMALES AND 2 (25%) MALES SURVIVING AT 52 WK DEVELOPED ADRENAL CORTICAL TUMORS. IN ADDN, BETA CELL TUMOR OF PANCREATIC ISLET CELLS WAS FOUND IN 1 MALE DYING AT 112 WK OF AGE (MATSUYAMA AND SUZUKI, 1970). /NO DATA FOR CONTROLS GIVEN./ [R40] *IN A GROUP OF 50 FEMALE SPRAGUE-DAWLEY RATS ADMIN URETHANE (1 PART IN 1000) IN DRINKING WATER FOR LIFE, AVG SURVIVAL TIME 12.5 (8-19) MO. OF 40 ANIMALS ON WHICH AUTOPSIES WERE PERFORMED, 33 HAD TUMORS, INCL 7 MALIGNANT LYMPHOMAS; 11 HEMANGIOMAS OR HEMANGIOSARCOMAS OF LIVER, SPLEEN, OR UTERUS; 7 HEPATOMAS; 10 ADRENAL CORTEX ADENOMAS AND 4 FIBROSARCOMAS OF MESENTERY OR UTERUS. NO CONCOMITANT CONTROLS WERE USED (ADENIS ET AL, 1968). [R34] *FEMALE A MICE WERE ADMIN SINGLE IP OR IV INJECTION OF 25 MG URETHANE, 1, 2, 3, 4 OR 5 DAYS BEFORE PARTURITION AND OFFSPRING WERE OBSERVED FOR 6 MO AFTER BIRTH. THE INCIDENCE OF LUNG TUMORS WAS 100% IN OFFSPRING EXPOSED IN UTERO 1 DAY BEFORE BIRTH, WITH AN AVG OF 8.9-10 LUNG TUMORS/MOUSE. URETHANE ADMIN ON DAYS 2-5 BEFORE PARTURITION PRODUCED A 60-80% INCIDENCE OF LUNG TUMORS, WITH 1-2 LUNG TUMORS/MOUSE (LARSEN, 1947). [R41] *WHEN URETHANE WAS ADMIN TO /MRC (WISTAR)/ ... RATS, BEGINNING ON DAY 1, 28 OR 46 OF LIFE AS 6 IP /0.5 MILLIGRAMS PER GRAM/ INJECTIONS AT 3 DAY INTERVALS, A BROAD SPECTRUM OF TUMORS WERE PRODUCED WITHIN 146 WK. OF 150 RATS TREATED AT 24 HR AFTER BIRTH, 18% HAD LIVER TUMORS, 2% ANTISCHKOW SARCOMAS OF HEART, 15.3% NEUROGENIC TUMORS AND 6% EMBRYONAL KIDNEY TUMORS. IN MOST CASES NONE OF THE 118 CONTROLS DEVELOPED SUCH TUMORS. ADULT RATS WERE LESS SENSITIVE TO INDUCTION OF THESE TUMORS; HOWEVER, THYROID TUMORS OCCURRED IN UP TO 6.8% OF THE TREATED ANIMALS, COMPARED WITH 0.8% IN CONTROLS (KOMMINENI ET AL, 1970). [R41] *SPRAGUE-DAWLEY RATS AND NMRI MICE WERE GIVEN DAILY DOSES OF 100, 500, 2,500 and 12,500 MG/KG URETHANE IN DRINKING WATER FOR 2 YR. THE FREQUENCY OF ANIMALS WITH MALIGNANCIES INCR WITH INCR DOSES, BEGINNING FROM 500 MG/KG/DAY FOR RATS, AND FROM 100 MG/KG/DAY FOR MICE. [R42] *Study of the ciliary processes in rabbits ... showed that when animals were killed by an overdose of either urethane or pentobarbital, this caused edema of the ciliary epithelium and stroma. [R43] *Groups of (C3HxC57) F1 mice (usually five groups of three mice each) were given urethane daily by subacute injection for 5 days. Bone marrow cell suspensions were then prepared. ... /Using this protocol,/ urethane tested positive in the micronucleus assay for chromosomal breakage. [R44] *In vitro mutagenesis/genetic toxicity studies in Chinese hamster ovary cells tested were negative for chromosome aberrations and positive for sister chromatid exchanges. [R45] *The chemical tests on urethane for heritable genetic effects on Drosophila melanogaster were positive for both sex linked recessive lethal and reciprocal translation. [R46] *Ethyl carbamate and vinyl carbamate, a suspect metabolic intermediate in carcinogenesis, were tested for tumorigenesis and genotoxicity in mouse lung, and transformation in hamster embryo cells. Induction of adenomas and sister chromatid exchange were studied in lungs of ip exposed A/J, C3H, and C57BL mice. Ethyl carbamate doses ranged from 30 to 1000 mg/kg, vinyl carbamate doses ranged from 1 to 60 mg/kg in tumorigenesis experiments. For sister chromatid exchange induction studies, ethyl carbamate (300 or 1000 mg/kg) and vinyl carbamate (10 to 60 mg/kg) were administered as a single injection. Enhancement of SA7 virus transformation was tested in primary Syrian hamster embryo cells using vinyl carbamate at 31 to 1000 ug/ml. Both ethyl carbamate and vinyl carbamate induced a dose related increase in the percentage of mice with lung tumors. Vinyl carbamate was much more potent than ethyl carbamate. Vinyl carbamate was also more potent for sister chromatid exchange induction. Dose related increases in sister chromatid exchange frequency were observed, but no strain specificity. There was no difference between A/J and C57BL mice in the persistence of sister chromatid exchange in a time course study. Vinyl carbamate induced significant enhancement of adenovirus transformation and an increase in transformation frequency at 125 to 500 ug/ml. Within this concn range, vinyl carbamate was moderately cytotoxic, while at 1000 ug/ml vinyl carbamate was completely cytotoxic. [R47] *High levels of sister chromatid exchanges can be induced in murine bone marrow, alveolar macrophages and regenerating liver cells by carcinogenic carbamate esters; however, the frequencies observed in the latter two tissues, which are also common tissues for carbamate induced tumors, are relatively enhanced compared to the frequency in bone marrow. Sister chromatid exchanges were apparent in lymphocytes of BDF1 mice eight weeks after a series of 12 multiple injections (2.2 mmol/kg; 3 times weekly) of ethyl carbamate. Long-term persistence of genetic damage produced by ethyl carbamate in murine lymphocytes is in agreement with previous findings of highly persistent sister chromatid exchanges inducing damage in murine bone marrow and alveolar macrophage cells. [R48] *During chemical carcinogenesis, Langerhans cells are depleted from the epidermis, disrupting the normal immunological functions of the skin. Tumor promotors but not initiators, have been shown to deplete adenosine triphosphatase positive Langerhans cells from the skin and therefore the cutaneous immune system may be impaired during tumor promotion but not initiation. The present study shows that the tumor promotor 12-O-tetradecanoylphorbol 13-acetate but not the initiator urethane depletes Ia-positive Langerhans cells from BALB/c murine ear epidermis, and beta-glucuronidase-positive Langerhans cells from C57BL mouse tail skin. Sensitization with 2,4-dinitrofluorobenzene through urethane treated skin resulted in a normal contact sensitivity response when the mice were challenged 5 days later. In contrast, tolerance resulted from sensitization through 12-O-tetradecanoylphorbol 13-acetate treated skin as a result of the generation of suppressor cells. In addition 12-O-tetradecanoylphorbol 13-acetate but not urethane treated C57BL mouse tail skin survived for an extended time when grafted onto histoincompatible BALB/c mice. [R49] *One physiological role for endogenous opioid peptides is to attenuate the release of oxytocin from the hypothalamo-neurohypophysial system during dehydration and hemorrhage when vasopressin maintains fluid balance and blood pressure. During lactation oxytocin, which stimulates milk ejection, is released without vasopressin. The influence of endogenous opioid peptides on oxytocin release during suckling has been studied primarily in animals anesthetized with urethane. In addition, anesthesia, urethane dehydrates the animal by elevating plasma osmolality and reducing cardiovascular volume. ... In lactating rats, the response of the magnocellular neuroendocrine system to dehydration and the role of endogenous opioid peptides in regulating oxytocin release during suckling under conditions of altered fluid balance in conscious and urethane anesthetized rats /was examined/. Release of oxytocin in response to plasma osmolality or a decrease in blood volume was attenuated during lactation in both conscious and anesthetized rats. Blockade of opiate receptors with naloxone (5 mg/kg) did not alter suckling induced release of immunoreactive oxytocin in conscious, normally hydrated rats, but did augment hormone release after urethane (1.1 g/kg, ip) or after osmotic stimulation with hypertonic sodium chloride (2.5%; 20 ml/kg, ip). During dehydration, the combination of decreased responsiveness of oxytocinergic neurons to osmotic stimulation and inhibition of oxytocin release by opioid peptides may be important in the lactating rat for conserving pituitary stores of oxytocin needed for milk ejection. [R50] *Nucleotoxic and cytotoxic effects of urethane on chick embryo primitive erythrocytes included swollen nuclei at interphase, fragmentation, clumping, stickiness and misdistribution of chromosomes as well as inhibition of cytokinesis. These effects were alleviated by simultaneous treatment with thymidine and folic acid but not with uridine. Observed effects of urethane are due to its antifolate action which may have resulted into abnormal nucleic acid metabolism. [R51] *The induction of micronuclei in mice exposed to aerosols of the following 6 genotoxic chemicals by inhalation was examined: cyclophosphamide, methyl methanesulfonate, mitomycin C, dimethylnitrosamine, ethylcarbamate and colchicine. Exposure of mice to cyclophosphamide aerosols at a theoretical concentration of 2426 mg/cu m for 29, 81 and 139 min induced 0.6, 1.0 and 2.3% micronucleated polychromatic erythrocytes in bone marrow 24 hr after the termination of exposure. The other chemicals except for dimethylnitrosamine showed a similar exposure response relationship following in vivo exposures to their aerosols. The results obtained in this study suggest that the cytogenetic effect of inhaled aerosols can be detected by the micronucleus test, and the method described in the present report is useful as a rapid in vivo test for atmospheric aerosols. [R52] *To determine whether the administration of urethane also decreases the associated cleft palate in CL/Fr mice, pregnant CL/Fr mice (30% of their offspring have spontaneous cleft lip with associated cleft palate) were treated with various doses of urethane on different days of pregnancy. In the groups treated with 250, 500, and 750 mg/kg urethane on day 9 of pregnancy, the frequency of associated cleft palate decreased with the dose to 18%, 14%, and 11% of term fetuses, respectively. In the group treated with 1000 mg/kg on day 9, the frequency of cleft palate decreased to 6.1%, but isolated cleft palate was observed in 23% of term fetuses. Most fetuses in the same group had severe tail anomaly (absence of tail or stub tail), and showed marked loss in weight. The isolated cleft palate observed in the group treated with 1,000 mg/kg urethane on day 9 might possibly be due to the teratogenicity of the drug. [R53] *The effects of exposure to selenium and nickel on the frequency of pulmonary adenomas induced by urethane in mice were investigated. Groups of female Swiss cross mice were exposed every other day for 15 weeks to either 3 ug/ml sodium selenite or to 100 ug/ml nickelous chloride in drinking water. Other groups were exposed on successive days to both metals. After 3 weeks of treatment, the mice were administered 1.5 mg/kg of urethane ip. The mice were killed at the end of the 15 week period. Mice exposed to nickel or selenium showed no clinical toxicity and no difference in wt gain compared to controls. Sleep time induced by urethane (a measure of urethane metabolism and excretion) was significantly reduced by selenium exposure but not nickel exposure. Exposure to selenium alone did not significantly affect the size or number of urethane induced adenomas. Exposure to nickel alone increased adenoma size but had no effect on tumor number. Combined selenium and nickel exposure appeared to produce more tumors than the corresponding single metal exposure treatments. Interactions associated with tumor size and tumor number following combined selenium and nickel exposure, suggests that the immunological and carcinogenic or anticarcinogenic actions of nickel and selenium differ considerably from the corresponding mechanism controlling urethane induced carcinogenesis. [R54] *Administration of urethane to mice results in the development of a variety of tumors, and, in certain strains of mice, marked suppression of the immune response. Perinatal exposure of mice to urethane has been found to result in increased tumor induction compared to exposure of adult animals. In the present study, the effects of perinatal exposure to urethane on the development of immunocompetence was investigated. Pregnant mice were injected with total doses of either 0.5 or 1.0 mg urethane/g of body weight over days 7-16 of gestation or pups of nontreated dams were administered a total dose of 2.0 mg urethane/g of body weight over postpartum days 5-14. Postnatal exposure to urethane suppressed natural killer cell activity but left intact other measured parameters of the host defense system. Prenatal exposure, on the other hand, resulted in elevated leukocyte counts and a trend toward increased spleen and thymus size in offspring of treated mothers. Humoral immune function, as measured by the IgM response to sheep erythrocytes, was suppressed in pups from dams injected with a total of 1.0 mg/g urethane. These results indicate that marked differences in immunopharmacologic effects may be observed if chemical exposure occurs at different times during the ontogeny of the immune system. [R55] *The immunotoxic potentials of the two relatively weak carcinogens, methyl methanesulfonate and urethane were studied in mice. Cyclophosphamide, a potent immunosuppressive carcinogen, was used as a positive control. Female C57BL/6J mice were administered 0, 10, 40 or 80 mg/kg methyl methanesulfonate over 5 days, or 0, 1, 2, or 4 ug/kg urethane over 12 days, or 180 mg/kg cyclophosphamide over 4 days. Mice were sacrificed 2 days after the last chemical administration. Marked suppression of the humoral response to sheep erythrocytes and suppression of T-cell responses to foreign antigens were observed in mice treated with methyl methanesulfonate. No changes in body weight, absolute or relative spleen or thymus weights, nor any hematologic parameters were observed in animals treated with methyl methanesulfonate. Urethane treatment resulted in dose dependent decreases in relative and absolute spleen weights, and a significant decrease in relative and absolute thymus weight was observed in the group treated with 4 ug/kg urethane. A dose related suppression in the number of circulating leukocytes and decrease in the number and viability of spleen cells were observed in animals treated with urethane. T-cell mitogen responsiveness was significantly suppressed at all dose levels of urethane, and B-cell mitogen responsiveness and delayed hypersensitivity responses were decreased at the highest urethane dose. Treatment with cyclophosphamide resulted in significant decreases in absolute and relative thymus weights, and suppression of lymphoproliferative responses of T-cells and B-cells, antibody production, and delayed hypersensitivity responses. Methyl methanesulfonate, urethane, and cyclophosphamide produce contrasting effects on host immunocompetence, suggesting different modes of biological activity. [R56] *The role of germ line mutations in carcinogenesis and teratogenesis was explored using virgin male or female mice exposed to x-rays or chemicals prior to mating with untreated mice at different time intervals after exposure. An almost linear increase in dominant lethals was induced by treatment of postmeiotic sperm, while treatment of spermatogonia showed no significant increases. Parental x-rays exposure also induced significant numbers of anomalies in offspring. In general, higher rates of anomalies were detected prenatally than postnatally since many were lethal shortly after birth. Tumors were also induced in offspring by parental exposure to x-irradiation. A fractionated dose of x-rays caused a lower incidence of anomalies and tumors when mature oocytes were treated. Parental treatment with urethane or 4-nitroquinoline-1-oxide induced significant yields of tumors and anomalies in offspring. Dominant lethals were not induced, and maternal treatment produced more tumorigenic and teratogenic effects in offspring than did paternal treatment. The incidence of prenatal anomalies per rad of x-rays per gamete was about three to four times higher than that of dominant skeletal mutations. While parental x-ray exposure induced a high incidence of translocations in F1 offspring which were detected in meiotic configurations of primary spermatocytes, tumor incidence was not associated with translocation incidence. In further analysis using C-Q banding in bone marrow cells, no visible chromosome alterations were detected. For anomalies, one inversion was found in one malformed offspring, while no changes were detected in 23 other malformed offspring or in 82 nonmalformed offspring. [R57] NTOX: *Male CF-1 mice were treated with urethane (0, 0.5, 1.0, 1.5, and 2 g/kg; ip) and 18 hr later hepatic metallothionein concentrations were determined with the cadmium hemoglobin radioassay. Urethane (1 g/kg and higher) significantly increase hepatic metallothionein levels, resulting in a 14-fold increase after 2 g/kg. Time course experiments indicated that metallothionein levels were increased significantly at 6 hr after administration of urethane (1.5 g/kg) and reached a maximum between 12 and 24 hr. Gel filtration, anion exchange chromatography, and UV spectral analysis were used to characterize the protein induced by urethane. Pretreatment with actinomycin-D prevented induction of metallothionein by urethane. Administration of equimolar dosages (20 mmol/kg) of urethane, N-hydroxyurethane, and methyl carbamate indicated that urethane and N-hydroxyurethane induce metallothionein but that methyl carbamate does not. Metallothionein induction was also not observed with (pentobarbital and phenobarbital). Urethane induces hepatic metallothionein but this effect is not related to its anesthetic action, nor is it a common property of all carbamates. [R58] *The studies reported investigated whether gene mutations scorable in specific locus tests are induced by urethane in any germ cell stage of male mice, and whether urethane reaches the testis. For toxicity tests, urethane was administered to male (10xC3H)F1 mice at 1750 to 2500 mg/kg by ip injection, and mice were observed for 4 weeks. There were no deaths in the 1750 mg/kg group. Based on the preliminary toxicity tests, the 1750 mg/kg dose of urethane was chosen for the specific locus test. Males were mated with multiple recessive T-stock females at various time periods following treatment. For studies on germ cell histology, intraperitoneal injections of urethane solution (900, 1500, 1750, or 2000 mg/kg) were administered to male (10xC3H)F1 mice. Animals from the 900 mg/kg dose group were killed 12, 24, 48, 72, 120, 207 hours or 12 days after treatment. The other three dose groups were killed 8 days after treatment. Spermatogonia and preleptotene spermatocytes were counted from histological preparations. Changes in litter sizes indicated no dominant lethality from successive matings in any of the first 7 weeks. No significant evidence of mutations were found in offspring derived from treated spermatogonial stem cells or treated poststem cell stages. Reduction for A1 spematogonia was consistent ... indicating urethane affects A-single, A-paired and A-aligned spermatogonia. The data indicated that spermatogonia underwent cytotoxic effects due to urethane. [R59] *The mouse specific locus method was used to study 11 chemicals for which there has been considerable human exposure and for which other test systems have shown positive mutagenicity results. The study was carried out to determine the relationship of specific locus test results to those of other assays. The chemicals studied included ... urethane. All 11 were positive in the Drosophila sex linked recessive lethal test and the ten tested in mammalian somatic cells were mutagenic. In mouse stem cell spermatogonia, none of these chemicals has given a specific locus mutation frequency higher than control levels. The lack of mutation induction cannot be attributed to failure of the chemicals to reach the testis, small sample size, or insensitivity of the test. The inconsistency of this test system with others in due to that fact that mammalian stem cell spermatogonia have an effective repair capability. This conclusion is supported by the dose response and dose fractionation results obtained with ethylnitrosourea. Positive genetic hazard predictions from short term tests of chemicals may therefore often give false predictions of expected results in mammalian spermatogonia, which are considered to be of major concern for genetic risk in men. [R60] *The genetic effects of the H-2 histocompatibility gene complex on the frequencies of urethane and ethylnitrosourea induced malformations in prenatal fetuses of mice were examined, and a new functional gene linked to the H-2 complex on chromosome 17 was mapped. The H-2 congenic pair strains of mouse, B-10.A and C57BL/10, were tested for susceptibility to urethane induced external malformations in fetuses. The B10.A strain expressing the H-2a haplotype characteristically showed a high susceptibility to urethane induced polydactyly and kinky tail. However, the C57BL/10 strain expressing the H-b haplotype was resistant to urethane induced malformation. The same tendency was observed for ethylnitrosourea induced malformations. Thus, susceptibilities to urethane and ethylnitrosourea induced external malformation must be affected by a gene linked to the H-2 complex. In a mapping study using B10.A recombinant mouse strains, B10.A (5R) was sensitive, while B10.A (2R) and B10.A (4R) was resistant to urethane induced external malformations. Variations in the susceptibility to teratogenicity of urethane in B10.A recombinant strains indicated that a new functional gene located between the H-25 region and the Upg-1 susceptibility. [R61] *The distribution of radiolabelled urethane administered in water or ethanolic solution, was compared in mice by whole-body autoradiography. Two fasted male A/JAX mice were administered 6 uCi (ethyl-1-(14)C)urethane by oral intubation. One mouse received urethane in 1 ml of an aqueous solution, the other in a 12% ethanol solution. One hour after treatment, the mice were frozen and processed for whole body autoradiography. When urethane was administered in water, the radioactivity localized in the salivary, seromucous, and Harderian glands, medullary bone, liver, bile, and epithelia of the stomach and intestine. Lower levels were seen in brown fat, and in the thymus and esophagus. When urethane was administered in ethanol, localization of urethane at each of these sites was almost completely inhibited; high concentrations were still found in the lumen of the stomach and intestine. No evidence was found of transesterification at pH 1.5 in 12% ethanol. [R62] *Urethane exposure leads to increased frequency of spontaneous lung adenomas in susceptible mouse strains and impaired resistance to B16F10 melanoma cells and metastatic tumor growth in the lungs. [R29] NTXV: *MLD Mouse ip 2.1-2.2 mg/kg; [R5] ADE: *IN MICE, URETHANE IS ACTIVE BY TRANSPLACENTAL ROUTE AND IS PASSED TO OFFSPRING IN MILK. [R63] *Ethyl-1-(14)C-urethane in water or in 12% ethanol was administered orally to male A/JAX mice and 1 hr later the mice were frozen and processed for whole body autoradiography to identify sites of localization of radioactivity. When the (14)C urethane was administered in water, radioactivity was localized in the liver and bile, the salivary, seromucous and Harderian glands, the bone marrow and pancreas and the stomach and intestinal epithelia. When the labelled urethane was administered in 12% ethanol, localization of radioactivity in each of these sites was almost completely inhibited; radioactivity was still seen within the lumen of the stomach and intestine. Using a defined chemical system, no transesterification was observed between urethane and 12% aqueous (2)H6-ethanol at pH 1.5 in 80 min. [R64] *In an attempt to understand route of administration dependency, (3)H-benzo(a)pyrene, (14)C-urethane and (14)C-acrylamide were administered as single doses orally or topically to male Sencar mice. Distribution in skin, stomach, liver, and lung was determined for time periods up to 48 hr. The binding of these compounds to DNA, RNA, and protein in these tissues was determined 6 and 48 hr after administration. For all three compounds, high concentrations were found in the skin following topical application, but very little material reached this target organ following oral administration. The internal organs generally contained more material after oral administration compared to topical application, whereas the opposite was true for the skin. Differences in distribution to the skin and binding to macromolecules following oral or topical administration cannot explain the greater tumorigenicity of urethane and acrylamide after oral administration in the Sencar mouse. [R65] METB: *IN RATS, RABBITS AND HUMANS (PATIENTS WITH MULTIPLE MYELOMA TREATED WITH URETHANE IN CONJUNCTION WITH ALKYLATING AGENT), URINARY METABOLITES ARE: URETHANE (0.5-1.7% OF ADMIN DOSE), N-HYDROXY URETHANE (0.02-0.15%), ACETYL-N-HYDROXY URETHANE (0.1-0.6%), ETHYL MERCAPTURIC ACID (0.1-0.2%) AND N-ACETYL-S-ETHOXY CARBONYLCYSTEINE (0.9-2.1%). [R66] *REACTIVITY OF ... /N-HYDROXYURETHANE/ IN VITRO AND IN VIVO FAVORS ITS CONSIDERATION AS BEING A PROXIMAL CARCINOGENIC METABOLITE OF ... /URETHANE/ ... [R67, 263] *IT IS METABOLIZED TO ETHYL ALCOHOL AND CARBAMIC ACID, AND THE LATTER ACTS AS A WEAK DIURETIC. [R68] *... BASIC AMINES ... ARE N-OXIDIZED BY NON-CYTOCHROME P450 DEPENDENT SYSTEM, WHEREAS NONBASIC NITROGEN CONTAINING CMPD, EG, URETHANE ... UTILIZE CYTOCHROME P450 DEPENDENT SYSTEM. [R69] *BIOTRANSFORMATION OF URETHANE IN RATS AND RABBITS AND IN MAN AFFORDS N-HYDROXYURETHANE, N-ACETYL-S-CARBOXYETHYLCYSTEINE, AND ETHYLMERCAPTURIC ACID AS URINARY METABOLITES, AND THUS URETHANE IS CONVERTED INTO AN ALKYLATING AGENT THROUGH N-HYDROXYLATION. [R67, 262] *The modification of liver DNA of mice and rats by ethyl carbamate and its putative proximate metabolite, vinyl carbamate, has been investigated. Following treatment with ethyl-1-(14)C-ethyl carbamate, the main radioactive DNA adduct was identified as 7-(2-oxoethyl)guanine by cochromatography with the authentic marker in several separation systems. After reduction by sodium borohydride to 7-(2-hydroxyethyl)guanine, the radioactive material again cochromatographed with the respective marker. Reduction of modified liver DNA by (3)H-sodium borohydride, following administration of unlabelled ethyl carbamate or vinyl carbamate, allowed the quantitation of 7-(2-oxoethyl)guanine (as 7-(2-hydroxy-2-(3)H-ethyl)guanine). Vinyl carbamate led to about 100 times as much 7-(2-oxoethyl)guanine (on a molar basis) as did ethyl carbamate. Both the formation of 7-(2-oxoethyl)guanine by ethyl carbamate and vinyl carbamate, and the much higher activity of the latter compound, strongly support the existence of the /proposed/ metabolic activation pathway, ethyl carbamate, vinyl carbamate to epoxyethyl carbamate. ... The possible role of 7-(2-oxoethyl)guanine in the initiation of the carcinogenic process is discussed in view of the structural equilibrium with its hemiacetal conformation, O6, 7-(1'-hydroxyethano)guanine. In the latter conformation, it is assumed to represent a promutagenic lesion. In addition, cytosine or adenine seem possible and may have promutagenic consequences. Replication of DNA containing such lesions may lead to the induction of mutations. This may be a critical event in the initiation, and eventually progression, of the carcinogenic process as determined by ethyl carbamate and other carcinogens, such as vinyl chloride, which lead to the same DNA modification. [R70] ACTN: *The clonal origin of pulmonary tumors by treatment with the chemical carcinogens, urethane and 4-nitroquinoline-1-oxide, were verified by PGK-isozyme mosaicism in DS strain mice. Six pulmonary tumors (12.5%) in 48 mice treated with urethane, and one (3.4%) in 23 mice treated with 4-nitroquinoline 1-oxide, were observed respectively. A single band, either PGK-la or PGK-lb occurred in two out of 7 tumors; and 5 remaining tumors showed either band la and lb associated with a trace band of the other isozyme. Though traces of stromal element and/or blood cells seem to be mixed among the neoplastic tissue, the pulmonary tumor could have originated from a single cell, when one takes into account the significantly higher expression in one band. [R71] *The ability of a number of metals and organic chemicals to induce metallothionein synthesis in primary cultures of rat hepatocytes was tested to determine whether metallothionein induction in vivo results from a direct effect of the agent on the liver or as a result of an indirect, physiological response to the agent. Hepatocytes were exposed to metals (zinc, cadmium, mercury, mangasese, lead, cobalt, nickel, and vanadium) or org compd. Ethanol, urethane, L-2-oxothiazolidine-4-carboxylate, or dexamethasone and were assayed for metallothionein by the cadmium/mercury radioassay. Cell viability was monitored by protein synthesis activity and cellular potassiumion concn. Increases in metallothionein concn were noted for zinc (22 fold), mercury (6.4 fold), cadmium (4.8 fold), cobalt (2.4 fold), nickel (22 fold), and dexamethasone (4.5 fold). However, even at max tolerated concn, manganese, lead, vanadium, ethanol, urethane, and L-2-oxothiazolidine-4-carboxylate did not increase metallothionein. Thus, zinc, cadmium, mercury, cobalt, nickel, and dexamethasone induce metallothionein in vitro and are direct inducers of metallothionein synthesis in hepatic tissue. In contrast, manganese, lead, ethanol, urethane, and L-2-oxothiazolidine-4-carboxylate, which did not increase the metallothionein content of hepatocytes, apparently do so in vivo by an indirect mechanism. [R72] *A single injection of urethane (ethyl carbamate) induces lung tumors in 80% of male and 10% of female NMRI mice, respectively. In time the initially benign adenomatous tumors can develop into malignant adenomatosis of the lung (alveolar cell carcinoma). For an analysis of the mechanisms of tumor development and the possible interactions involved, low doses of X-rays (5-100 cGy) were administered 6 hours after urethane treatment. A significant anticarcinogenic and, also, anti-teratogenic action was observed. This implies that in both cases similar mechanisms are involved. Single injections of vitamin C or chloroquine counteract the urethane effects in the same manner as do the low doses of X-rays, but probably by different mechanisms. [R73] *The suitability of urethane anesthesia for physiopharmacological investigations is reviewed. Total dose administered and route of administration are recognized as factors having a great influence on both resting parameters and biological responses to drugs. A peculiar characteristic of urethane is represented by its ability to induce a surgical plane of anesthesia without affecting neurotransmission in various subcortical areas and the peripheral nervous system. This makes urethane a suitable general anesthetic nervous systems and accounts for the preservation of a number of reflex responses in urethane anesthetized animals. [R74] *Previous results obtained in the laboratory suggested that natural antibodies reactive with L5178Y lymphoma cells play a role in the induction of lung tumors by the chemical carcinogen urethane. In order to characterize some of the naturally occurring L5178Y reactive antibodies, hybridomas were prepared that secreted natural monoclonal IgM antibodies reactive with L5178Y lymphoma cells. In the present study we characterized some of these antibodies and provided further proof as to their role in urethane carcinogenesis. One hybridoma secreted a cytotoxic antibody that reacted only with mouse lymphoma cell lines. Other non-cytotoxic monoclonal L5178Y reactive antibodies showed various degrees of cross reactivity with syngeneic, allogeneic and xenogeneic cells of normal or malignant origin. One of these antibodies reacted much better with activated T cells than with resting ones. Four groups of mice were treated with urethane. Three groups were injected twice a week during 5 months with different IgM preparations of natural monoclonal antibodies. The mice in the fourth group were not treated with IgM and served as controls. Five months after the urethane treatment the mice were sacrificed and the number of tumor foci in the lung of each mouse was determined. The results show that the group treated with the determined. The results show that the group treated with the cytotoxic monoclonal antibody 1.80 had a significant decrease, while the group treated with the IgM myeloma protein 104E had a significant increase in the number of tumor foci compared to urethane treated mice that did not receive any IgM treatment. The tumor incidence in the group treated with the 104E IgM was significantly higher than that in the control group. [R75] INTC: *IT WAS ... SHOWN TO ENHANCE LEUKEMOGENIC EFFECTS OF X-IRRADIATION. [R37] *TWO WEEKLY DOSES OF 120 MG OF URETHANE FOLLOWED AFTER INTERVAL OF 3 WK BY 18 WEEKLY APPLICATIONS OF 0.3 ML OF 0.5% CROTON OIL SOLN IN ACETONE PRODUCED 115 SKIN TUMORS IN 22 SURVIVING 'S' MICE. ALTERNATE APPLICATIONS OF 60 MG URETHANE AND 0.5% CROTON OIL AT 3 TO 4 DAY INTERVALS DURING 18 WK PRODUCED 138 SKIN TUMORS IN 17 SURVIVING MICE. WHEN URETHANE WAS APPLIED ALONE, EITHER AS 2 WEEKLY APPLICATIONS OF 120 MG OR AS 18 WEEKLY APPLICATIONS OF 60 MG, NO TUMORS WERE PRODUCED IN 19 and 17 MICE, RESPECTIVELY. A SIMILAR RESULT WAS OBSERVED WHEN URETHANE WAS ADMIN IN CONJUNCTION WITH DMBA. URETHANE PRODUCED NO RECOGNIZABLE HISTOLOGICAL CHANGES IN MOUSE SKIN, EVEN AFTER PROLONGED APPLICATION; AND TUMORS PRODUCED WHEN IT WAS GIVEN IN CONJUNCTION WITH CROTON OIL HAD THE APPEARANCE OF BENIGN PAPILLOMAS. ONE SQUAMOUS EPITHELIOMA OCCURRED 8 WK AFTER THE END OF TREATMENT IN THE GROUP GIVEN ALTERNATE TREATMENTS OF URETHANE AND CROTON OIL (SALAMAN AND ROE, 1953). [R76] *The antipellagratic vitamin, nicotinamide, significantly suppressed urethane induced malformations, when it was given intraperitoneally to pregnant JCL:ICR mice immediately after a single subcutaneous injection of urethane (1.0 mg/g) on the 9th day of gestation. The level of inhibition increased with the doses of nicotinamide: 33.0, 55.8, and 70.0% at doses of 0.2, 0.3, and 0.5 mg/g, respectively. Polydactyly and tail anomalies were markedly suppressed by the post treatment with nicotinamide, while cleft palates were less effectively suppressed. Nicotinamide was still effective, when it was given during the period of 24-48 hr after urethane treatment. The level of inhibition was 39.4 and 61.1% at 0.5 and 1.0% of nicotinamide in the diet, respectively. Higher doses of nicotinamide (3 and 5% in diet) also inhibited urethane induced malformations, but not so effectively as lower doses. The inhibiting effects of nicotinamide on the spontaneous incidence of cleft lips and palates in CL/Fr mice were significant at a low dose (0.5% in diet), but not at a higher dose (1.0%). [R77] *The progression of papillomas to squamous cell carcinomas (malignant conversion) was studied in the skin of Sencar and Charles River CD-1 mice, using a three stage treatment protocol. After initiation with 7,12-dimethylbenz(a)anthracene (stage 1) and limited promotion by 12-O-tetradecanoylphorbol-13-acetate (stage II), papilloma bearing mice were treated (stage III) with either tumor initiators, such as urethane, N-methyl-N'-nitro-N-nitrosoguanidine or 4-nitroquinoline-n-oxide; the promoter 12-O-tetradecanoylphorbol-13-acetate, or solvent (acetone). Treatment with tumor initiators in stage III increased both the rate of appearance and the final yield of carcinomas. Similar results were obtained in both Sencar and CD-1 mice. A papilloma stage appears to be necessary for carcinoma development since elimination of 12-O-tetradecanoylphorbol-13-acetate treatment in stage II greatly reduced the incidence of both papillomas and carcinomas in both stocks of mice. The carcinomas that develop using the three stage regimen vary in metastatic potential. In CD-1 mice, the frequency of metastases to lymph nodes were similar in groups treated in stage III with N-methyl-N'-nitro-N-nitrosoguanidine, urethane, 4-nitroquinoline-n-oxide, 12-O-tetradecanoylphorbol-13-guanidine or acetone, but treatment with urethane substantially increased metastases to the lung. [R78] *N-homocysteine thiolactonyl retinamide was synthesized from trans-retinoic acid and the free base of homocysteine thiolactone. In doses of 90-1800 mg/kg given ip in mixed lipid vehicle over nine weeks, the compound decreased to 60% of controls the number of lung tumors which was induced in A/J mice by 20 mg of ethyl carbamate. The highest dose also decreased the mean volume of lung tumors to 505 of controls, resulting in a total tumor volume of 30% of controls. Retinoic acid itself of 450 mg/kg was toxic, and no chemopreventive activity was observed. The free base and the lipophilic perchlorate salt of homocysteine thiolactone both increased the number of lung tumors to 114-117% of controls, indicating a co-carcinogenic effect. In C57BL/6N mice with transplanted MUO4 rhabdomyosarcoma, N-homocysteine thiolactonyl retinamide in a dose of 1000 mg/kg given over 11-21 days decreased the weight of the tumors to 30-70% of controls. Therefore, N-homocysteine thiolactonyl retinamide has chemopreventive activity against chemical carcinogenesis and antineoplastic activity against a transplanted neoplasm. [R79] *The thiol N-acetylcysteine, a precursor of intracellular glutathione, efficiently prevented the induction of lung tumors in Swiss albino mice, when supplemented to the diet (0.2%) both before and after an ip injection of the carcinogen urethane (ethyl carbamate). Irrespective of urethane administration, N-acetylcysteine also significantly enhanced glutathione S-transferase activity in liver preparations of the same animals. These data show that, under certain conditions, it is possible to prevent chemically induced cancer by increasing the levels of physiological trapping agents. [R80] *The effect of urethane anesthesia on cigarette smoke induced airway responsiveness and permeability was studied in the guinea pig. Airway responsiveness was determined by measuring changes to airway resistance to graded doses of aerosolized histamine, and mucosal permeability was determined by measuring the appearance of fluorescein isothiocyanate dextran in the blood and examining its distribution in lung tissue after it had been delivered to the lung and in an aerosol. The results confirm previous studies that smoke exposure increased airway responsivenes and mucosal permeability. They also show that urethane anesthesia administered before smoke exposure prevented the smoke related changes in airway reactivity and mucosal permeability. In animals that remained conscious during the smoke exposure, there was increased deposition of the dextran in the regions of the bronchioloalveolar junctions with a more rapid uptake of fluorescein isothiocyanate dextran into the blood. [R81] *Female Swiss mice were exposed to sodium arsenite or sodium arsenate in the drinking water for 15 weeks at concentrations ranging from 0 to 100 ug/ml arsenic content. After three weeks of the 15 week exposure period, the mice were administered urethane (1.5 mg/g) intraperitoneally. Pulmonary adenoma formation was evaluated 12 weeks later. Arsenic exposure produced a protective effect with respect to tumor development. Both forms of arsenic reduced the size and number of pulmonary adenomas observed per mouse. In addition, urethane induced sleeping times which reflect the rate of urethane metabolism or excretion remained unchanged. This suggests that arsenic exposure does not alter urethane excretion and is not a factor influencing subsequent adenoma formation of these levels of exposure. [R82] *Female Swiss mice were exposed to cadmium in the drinking water at concentrations ranging from 0 to 50 ppm for 105 or 280 day time periods. In the 105 day study, the effect of cadmium on urethane induced pulmonary adenoma formation was evaluated. Urethane induced sleeping times observed following ip injection of urethan after 3 weeks of cadmium exposure were not affected by cadmium indicating that chronic cadmium exposure did not alter the elimination of urethane. Pulmonary adenoma formation which was evaluated 84 days later was not affected by cadmium. The size and number of tumors remained unchanged. This suggests that the immunosuppressive actions of cadmium do not influence urethane induced adenoma formation. In the 280 day study, the effects of cadmium on the incidence of spontaneous murine lymphocytic leukemia was evaluated. Mortality from the leukemia virus was greater in the cadmium exposed mice. Mice exposed to 10 or 50 ppm cadmium experienced 33% more deaths from the virus. The average time till death was unaffected. It appears that the immunosuppresive effects of cadmium impair immunosurveillance mechanisms that control expression of the murine lymphocytic leukemia virus. [R83] *Female mice were exposed to sodium selenite (3 ug/m selenium content) and nickel chloride (100 ug/ml nickel content) in the drinking water on alternate days for 15 wk. After 3 wk of metal exposure, the mice were administered urethane (1.5 mg/g) ip. Pulmonary adenoma formation was evaluated 12 wk later. Selenium exposure did not alter the tumor incidence or the tumor size. Nickel exposure did not affect the tumor incidence, but increased the average tumor size. Combined selenium and nickel exposure resulted in significant interactions assoc with tumor size and tumor number. Urethane induced sleeping times were reduced by selenium exposure, but were unaffected by nickel exposure. Combined metal exposure did not influence urethane induced sleeping times. [R54] *A study examined the effects of lead acetate on the incidences of spontaneous murine lymphocytic leukemia and urethane induced adenomas. Female albino Swiss mice (3 weeks old) were exposed to lead acetate in the drinking water (0 to 1000 ppm) for 15 weeks. Three weeks into the administration period, some of the mice received urethane, 1.5 mg/g ip. At the end of the 15 week period, the tissue concentration of lead in the exposed animals had increased in a dose related fashion. As indicated by unchanged urethane induced sleeping times, lead did not change urethane metabolism or excretion rate. The number of lung adenomas was not affected by lead. In contrast, the incidence of spontaneous lymphocytic leukemia increased. Mice exposed to 50 and 1000 ppm lead had 41.6 and 58.3 percent more deaths from leukemia, respectively, than did the nonexposed mice. Lead induced the murine lymphocytic leukemia virus, while it has no effect on the urethane induced adenoma formation. [R84] *Effects of ozone on the modification of lung cancer in mice was studied. Male A/J and Swiss-Webster mice were injected ip with 1000 mg/kg of urethane dissolved in 0.9% sodium chloride. Animals were exposed to 0.40 and 0.80 ppm ozone for 8 hours per night, 7 days per week, for 18 weeks. Four weeks after treatment with urethane, mice were killed and lung examined microscopically. Incidence of spontaneous tumors in sodium chloride treated Swiss-Webster mice was 3%. Exposure to ozone had no effect. Tumor incidence in urethane treated animals was 61%. Ozone seemed to reduce the average number of tumors found per lung, but the difference was not statistically significant. Incidence of spontaneous tumors in A/J mice exposed to filtered air was 12%. The low dose of ozone had no effect, while the high dose produced a significant increase in lung tumor incidence. The average number of tumors per lung was higher in animals that received sodium chloride and were exposed to 0.8 ppm ozone. Urethane elicited 100% tumor incidence in A/J mice, and exposure to ozone significantly reduced the number of tumors. Most of the tumors in mice given urethane were Clara cell tumors. Exposure to 0.4 ppm ozone decreased type II tumors from 42 to 12% in Swiss-Webster mice. In A/J mice given urethane, 51% of tumors could be classified as alveolar type II cell tumors. Exposure to ozone reduced this tupe of tumor in a concentration dependent manner. Lungs from mice treated with urethane had mild bronchiolar hyperplasia, while mice exposed to 0.4 ppm ozone had diffuse mild to moderate bornchiolar epithelial hyperplasia. [R85] *The effects of selenium and arsenic on tumor size and tumor number were examined in mice using the urethane pulmonary adenoma model. Female Swiss cross mice were administered the metals in drinking water at levels of 3 ug/ml selenium and 80 ug/ml arsenic on alternate days for 15 weeks. The urethane was administered after 3 weeks of the metal treatment, and the incidence and size of pulmonary adenomas were determined 12 weeks later. Weight gain was diminished in mice exposed to arsenic but not selenium. No other clinical signs were pesent due to metal exposure. Urethane induced sleeping times were significantly reduced in animals given both metals relative to those administered either arsenic or selenium. Both arsenic and selenium administered alone reduced tumor size; the efect of arsenic was greater than that of selenium and arsenic treatment also resulted in a decreased number of tumors per animal. No interactive effects between the metals were determined with regard to tumor production. Both arsenic and selenium alter urethane induced adenoma formation. [R86] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anesthetics, Intravenous; Antineoplastic Agents; Carcinogens [R87] */IT WAS/ ... REPORTED IN 1968 THAT URETHANE HAD FOUND USE IN HUMAN MEDICINE AS AN ANTI-NEOPLASTIC AGENT AND FORMERLY WAS USED AS A HYPNOTIC, AN ADJUNCT TO SULFONAMIDE THERAPY, A COMPONENT (WITH QUININE) OF SCLEROSING SOLN FOR VARICOSE VEINS, AND AS A TOPICAL BACTERIOCIDE. [R88] *A MORE RECENT SOURCE STATES THAT LARGE DOSES OF URETHANE PRODUCE BONE MARROW DEPRESSION, AND THAT FOR A TIME IT WAS USED IN TREATMENT OF CHRONIC LEUKEMIA AND MULTIPLE MYELOMA. NO EVIDENCE WAS FOUND THAT URETHANE PRESENTLY FINDS USE IN USA IN HUMAN MEDICINE. [R88] *MEDICATION (VET): REPORTED ... APPLICATIONS OF URETHANE INCL ITS INFREQUENT USE AS A HYPNOTIC AND ITS MORE FREQUENT USE AS AN ANESTHETIC FOR LAB ANIMALS. [R3] *MEDICATION (VET): HAS OCCASIONALLY BEEN USED WITH OTHER DRUGS, SINCE IT NOT ONLY AUGMENTS THEIR ACTION, BUT INCR THEIR AQ SOLUBILITY. WIDE MARGIN OF SAFETY IN FISH ANESTHESIA, BUT NOT POPULAR SINCE IT MAY BE CARCINOGENIC TO USER. [R68] *A combination of urethane (95.2 g) and chloralose (9.25 g) in 150 ml normal saline has been used iv (1 mg/kg) for anesthesia in the dog. Urethane is not used clincially because there are safer anesthetics available. [R89] *MEDICATION (VET): ANESTHETIC, HYPNOTIC, SEDATIVE, DIURETIC [R68] *ANTI-NEOPLASTIC AGENT; HYPNOTIC; AS ADJUNCT TO SULFONAMIDE THERAPY; AS COMPONENT (WITH QUININE) OF SCLEROSING SOLN FOR VARICOSE VEINS, AND AS TOPICAL BACTERICIDE. /FORMER USES/ [R88] WARN: *OVERDOSAGE WITH ANY /ANTICANCER AGENTS WHICH INCL URETHANE/ CAUSES LEUKOPENIA, GRANULOCYTOPENIA, THROMBOCYTOPENIA, HYPOPLASIA OF ALL ELEMENTS OF BONE MARROW, NAUSEA ... AND ANOREXIA. /FROM TABLE/ [R90] *MEDICATION(VET): ... HEPATOTOXIC. CONTRAINDICATED IN NEPHRITIS OR HEPATITIS. HEMATOPOIETIC DEPRESSANT. MAY BE TERATOGENIC (HAMSTERS) AND CARCINOGENIC (RATS AND MICE). CONTINUED USE MAY DEPRESS WHITE CELL COUNTS. MAY INCR BLOOD GLUCOSE LEVELS. ... USUALLY RESERVED FOR TERMINAL EXPERIMENTS, AS PULMONARY EDEMA MAY OCCUR DURING LONG LASTING ANESTHESIA AND RECOVERY PERIODS. [R68] *Although positive evidence of teratogenicity in humans is not available for all antineoplastic agents, it is considered that they are best avoided during pregnancy, especially during the first trimester, and should not be used in mothers who are breast feeding. /Anti-neoplastic agents/ [R9, 175] *... Urethane can occur as a contaminant in two anticonvulsant drugs (trimethadione and paramethadione), with an allowable limit of 1 ppm; these anticonvulsant drugs may be used only to treat epilepsy ... . [R4] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethyl carbamate may be released to the environment in various waste streams from its production and use in the preparation and modification of amino resins, as a solubilizer and co-solvent for pesticides and fumigants, as an intermediate in the production of pharmaceuticals, as an antineoplastic agent, and as a reagent in biochemical research. If released to the atmosphere, ethyl carbamate is expected to exist solely as a vapor in the ambient atmosphere based on an extrapolated vapor pressure of 0.26 mm Hg at 25 deg C. Vapor-phase ethyl carbamate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated half-life of 2.2 days. If released to soil, an estimated Koc of 20 suggests that ethyl carbamate is expected to have very high mobility. Volatilization from moist soil surfaces is not expected to occur based on an estimated Henry's Law constant of 6.4X10-8 atm-cu m/mole. Biodegradation of ethyl carbamate in soil may be important. If released into water, ethyl carbamate is not expected to adsorb to suspended solids and sediment in the water column based on its estimated Koc. Volatilization from water surfaces is not expected given this compound's estimated Henry's Law constant. The potential for bioconcentration in aquatic organisms is low based on an estimated BCF of 0.45. Purely aliphatic carbamates are expected to be resistant to hydrolysis under environmental conditions; hydrolysis half-lives of 3300 and 330 years at pHs 7 and 8, respectively, were estimated for ethyl carbamate. Ethyl carbamate was judged easy to biodegrade in river die-away tests. Other biodegradation studies using activated sludge indicate ethyl carbamate may biodegrade slowly. Occupational exposure to ethyl carbamate may occur through inhalation of dust particles and dermal contact with this compound at workplaces where ethyl carbamate is produced or used. The general population may be exposed to ethyl carbamate via ingestion of fermented foods and alcoholic beverages. (SRC) NATS: *It was ... reported to be present in diethylpyrocarbonate treated wines at levels up to 50 ug/l; it was considered possible that some of this was of natural origin. [R3] *Ethyl carbamate occurs as a natural by-product in fermented products such as wine, liquors, yogurt, beer, bread, olives, cheeses, and soy sauces(1). [R91] ARTS: *Ethyl carbamate's production and use in the preparation and modification of amino resins, as a solubilizer and co-solvent for pesticides and fumigants(1), as an intermediate in the production of pharmaceuticals, as an antineoplastic agent, and as a reagent in biochemical research(2) may result in its release to the environment through various waste streams(SRC). [R92] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 20(SRC), determined from a measured log Kow of -0.15(2) and a recommended regression-derived equation(3), indicates that ethyl carbamate is expected to have very high mobility in soil(SRC). Volatilization of ethyl carbamate from moist soil surfaces is not expected to occur(SRC) given an estimated Henry's Law constant of 6.4X10-8 atm-cu m/mole(SRC) from its extrapolated vapor pressure, 0.26 mm Hg(4), and measured water solubility, 4.8X10+5 mg/l(5). Ethyl carbamate is converted to nitrate in fresh soils after a lengthy lag period(6). The initial step in this process is the hydrolysis of the ethyl carbamate to ethanol, ammonia, and CO2 by soil microorganisms(6). [R93] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 20(SRC), determined from a measured log Kow of -0.15(2) and a recommended regression-derived equation(3), indicates that ethyl carbamate is not expected to adsorb to suspended solids and sediment in water(SRC). Ethyl carbamate is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 6.4X10-8 atm-cu m/mole(SRC) from its extrapolated vapor pressure, 0.26 mm Hg(4), and measured water solubility, 4.8X10+5 mg/l(5). According to a classification scheme(6), an estimated BCF of 0.45(3,SRC), from a measured log Kow(2), suggests that bioconcentration in aquatic organisms is low(SRC). Purely aliphatic carbamates are expected to be resistant to hydrolysis under environmental conditions(7); hydrolysis half-lives of 3300 and 330 years at pH values of 7 and 8, respectively, were estimated for ethyl carbamate(8,SRC). Ethyl carbamate was judged easy to biodegrade in river die-away tests(9). Ethyl carbamate, present at a concn of 500 mg/l, was not degraded when incubated with shaking for 144 hr with activated sludge at 20 deg C(10). When exposed to activated sludges from several USA cities, trace to 1.6% of theoretical BOD was observed(11). [R94] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethyl carbamate, which has an extrapolated vapor pressure of 0.26 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase ethyl carbamate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2.2 days(3,SRC). [R95] BIOD: *Ethyl carbamate, present at a concn of 49 ppm, was judged easy to biodegrade in river die-away tests based on TOC measurements(1). Ethyl carbamate, present at a concn of 500 mg/l, was not degraded when incubated with shaking for 144 hr with activated sludge at 20 deg C(2). When exposed to activated sludges from several USA cities, trace to 1.6% of theoretical BOD was observed(3). Ethyl carbamate is converted to nitrate in fresh soils after a lengthy lag period(4). The initial step in this process is the hydrolysis of the ethyl carbamate to ethanol, ammonia, and CO2 by soil microorganisms(4). [R96] ABIO: *The rate constant for the vapor-phase reaction of ethyl carbamate with photochemically-produced hydroxyl radicals has been estimated as 7.4X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2.2 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Purely aliphatic carbamates are expected to be resistant to hydrolysis under environmental conditions(2). A base-catalyzed second-order rate constant of 6.6X10-5 L/mol-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 3300 and 330 years at pH values of 7 and 8, respectively(3,SRC). A neutral hydrolysis rate constant of < 2.6X10-7 /hr was measured for ethyl carbamate(4); this corresponds to a half-life of greater than 300 years at pH 7(4). [R97] BIOC: *An estimated BCF of 0.45 was calculated for ethyl carbamate(SRC), using a measured log Kow of -0.15(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF suggests that bioconcentration in aquatic organisms is low(SRC). [R98] KOC: *The Koc of ethyl carbamate was estimated as approximately 20(SRC), using a measured log Kow of -0.15(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that ethyl carbamate is expected to have moderate mobility in soil(SRC). [R99] VWS: *The Henry's Law constant for ethyl carbamate is estimated as 6.4X10-8 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.26 mm Hg(1), and water solubility, 4.8X10+5 mg/l(2). This value indicates that ethyl carbamate will be essentially nonvolatile from water surfaces(3,SRC). Ethyl carbamate's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). [R100] WATC: *DRINKING WATER: Ethyl carbamate was detected in drinking water from Cincinnati, OH and Ottuma, IA(1). [R101] *GROUNDWATER: Ethyl carbamate was detected but not quantified in groundwater samples taken near a landfill in Norman, Oklahoma(1,2). [R102] EFFL: *Raw wastewater from two kraft paper mills in Georgia sampled in March 1972 were found to contain an average of 0.018 and 0.037 mg/l ethyl carbamate(1). The wastewater treatment in the first kraft mill consisted of a trickling biofilter and aerated lagoon, while that in the second consisted of lime treatment and holding in a storage basin(1). Ethyl carbamate was identified, but not quantified, in groundwater samples from the saturated zone of a landfill well, near Norman, OK(2). [R103] FOOD: *Monitoring data have revealed ethyl carbamate in beverages with pH's lower than 4.0 at 10 ug/l and in diethylpyrocarbonate-treated wines at up to 50 ug/l(1). It has been demonstrated that ethyl carbamate is formed in acid beverages as a result of the reaction of ammonia and diethylpyrocarbonate(1). However the use of the fermentation inhibitor, diethylpyrocarbonate, in food products is no longer allowed by the U.S. FDA(2). [R104] *Ethyl carbamate was detected in (concentration range in ppb): whiskey (60.0 to 389), sherry (32 to 242), port (13.6 to 60), and wine(3 to 9)(1). Ethyl carbamate was detected in a variety of fermented foods and beverages (concentration range in ppb): 15 cheeses (0 to 3); 6 teas (0 to 3); 12 yogurts (0 to 3); 8 ciders (0 to 3); 30 breads (0 to 13); 69 malt beverages (0 to 13); and in 12 soy sauces (0 to 84)(2). Ethyl carbamate was detected in 56 out of 19,851 domestic and imported food and feed samples between Oct 1981 and Sept 1986; 39 of the positive detections were between 0 and 0.05 ppm, 8 were between 0.06 and 0.1 ppm, and 9 were between 0.20 and 0.50 ppm(3). Ethyl carbamate was detected in alcoholic beverages from various countries(number of samples; concn range, ug/kg): white wines(15; 0 to 24); red wines (7; 1.8 to 14); Sake (2; 3 to 29); sherry (4; 28 to 58); whiskey (6; 26 to 247); rye (1; 8); bourbon (4; 44 to 208); gin (1; 0.5); rum (1; 19) fruit brandy (3; 104 to 2,344); apricot brandy (1; 11); Armagnac (2; 410 to 432); other brandies (3; 25 to 28)(4). Various breads and toasts were found to contain ethyl carbamate: 10 bread varieties had an average ethyl carbamate concn of 3.1 ug/kg; light toast and dark toast made from these breads contained ethyl carbamate at mean concns of 4.3 and 15.7 ug/kg, respectively(4). Soy sauce contained ethyl carbamate at concns ranging from 0 to 59 ug/kg(4). Plain natural yogurt contained ethyl carbamate at concns ranging from 0.1 to 0.4 ug/kg(4). [R105] RTEX: *Urethane ... has been found to occur in foods ... made by a fermentation process, including ale, beer, bread, wine, soy sauce, yogurt, and olives. [R106] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 8,005 workers (5,050 of these are female) are potentially exposed to ethyl carbamate in the US(1). Occupational exposure to ethyl carbamate may occur through inhalation of dust particles and dermal contact with this compound at workplaces where ethyl carbamate is produced or used(SRC). The general population may be exposed to ethyl carbamate via ingestion of fermented foods and alcoholic beverages(SRC). [R107] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Ethyl carbamate is included on this list. [R108] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R109] RCRA: *U238; As stipulated in 40 CFR 261.33, when carbamic acid, ethyl ester, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R110] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TWO SOLVENT PARTITION STEPS, COLUMN CHROMATOGRAPHY, AND GC/MS CONSTITUTE THE METHOD USED TO IDENTIFY AND QUANTITATE ETHYL CARBAMATE IN TOBACCO SMOKE. [R111] *IDENTIFICATION OF URETHANE IN MIXT OF CARBAMATES USING GAS CHROMATOGRAPHIC ANALYSIS ON CARBOWAX 20 M, VERSAMID 900 OR SE-30 COLUMN HAS BEEN DESCRIBED BY ZIELINSKI AND FISHBEIN (1965), J GAS CHROMAT, 3, 142-4; IBID, 3, 260-2. USING TLC /INVESTIGATOR/ WAS ABLE TO DISTINGUISH 13 CARBAMATES WITH 3 CHROMATOGRAPHIC SYSTEMS AND 3 SPRAY REAGENTS /MCCONNELL DAVIS; J CHROMAT 29: 283-7 (1967)/. SIMILAR IDENTIFICATION TESTS USING PAPER CHROMATOGRAPHY ... /WERE/ DESCRIBED BY FISHBEIN AND CAVANAUGH; J CHROMAT 20: 283-94 (1965). [R3] *MICROGRAM QUANTITIES OF URETHANE MAY BE ANALYZED AS TRIMETHYLSILYL DERIV BY GAS CHROMATOGRAPHY ON SE-30 COLUMNS, BUT INTERFERENCE FROM BIOLOGICAL MATERIALS WAS FOUND WHEN ATTEMPTS WERE MADE TO ANALYZE URETHANE IN TISSUES OF EXPERIMENTAL ANIMALS (NERY, R, ANALYST, 94, 130-135, 1969). ISOTOPE DILUTION METHODS ... IN BEVERAGES ... (LOFROTH AND GEJVALL, SCIENCE, 174, 1248-1250, 1971). [R3] CLAB: *TITRATION METHOD FOR EST OF URETHANE @ CONCN GREATER THAN 3-5 MG/100 ML BLOOD FROM PATIENTS TREATED FOR LEUKEMIA WITH THIS CMPD WAS DESCRIBED BY ARCHER ET AL, BIOCHEM J, 42, 58-59, 1948. [R3] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Services, Research Triangle Park, NC. (2000) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for urethane is in progress. Route: dosed-water feed; Species: mice. [R112] SO: R1: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. 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NY,NY: Van Nostrand Reinhold p. 350 (1981) R105: (1) Brumley WC et al; Anal Chem 60: 975-8 (1988) (2) Canas BJ et al; J Assoc Off Anal Chem 72: 873-6 (1989) (3) Luke MA et al; J Assoc Off Anal Chem 71: 415-20 (1988) (4) Sen NP et al; Food Chem 48: 359-66 (1993) R106: DHHS/NTP; Fourth Annual Report On Carcinogens p.199 (1985) NTP 85-002 R107: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R108: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R109: 40 CFR 302.4 (7/1/96) R110: 40 CFR 261.33 (7/1/96) R111: SCHMELTZ ET AL; J ANAL TOXICOL 2 (6): 265-8 (1978) R112: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 109 Record 176 of 1119 in HSDB (through 2003/06) AN: 2562 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIOCTYL-PHOSPHATE- SY: *DISFLAMOLL-TOF-; *2-ETHYL-1-HEXANOL-PHOSPHATE-; *2-Ethylhexanol,-phosphate-triester-; *FLEXOL-TOF-; *1-HEXANOL,-2-ETHYL-,-PHOSPHATE-; *KRONITEX-TOF-; *NCI-C54751-; *PHOSPHORIC ACID, TRIS(2-ETHYLHEXYL) ESTER; *TEHP-; *TOF-; *TRIETHYLHEXYL-PHOSPHATE-; *TRI(2-ETHYLHEXYL)PHOSPHATE; *Tris-2(2-ethylhexyl)fosfat (Czech); *TRIS(2-ETHYLHEXYL)PHOSPHATE RN: 78-42-2 MF: *C24-H51-O4-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PROBABLY BY REACTION OF PHOSPHORUS OXYCHLORIDE AND OCTANOL [R1] *2-Ethylhexanol + phosphorous oxychloride (dehydrochlorination) [R2] MFS: *Akzo Nobel Chemicals Inc., 300 South Riverside Plaza, Suite 2200, Chicago, IL 60606, (312) 906-7680; Production site: Gallipolis Ferry, WV 25515-1721 [R3] *Rhodia Inc., CN 7500 Prospect Plains Road, Cranbury, NJ 08512-7500, (609) 860-4000; Production site: Charleston, SC 29405 [R3] OMIN: *... /TRI-2-ETHYLHEXYL PHOSPHATE/ IS COMPATIBLE WITH POLYVINYLBUTYRALS AND VINYL ACETATE COPOLYMERS, AND ALSO WITH NITROCELLULOSE, ETHYLCELLULOSE; AND CHLORINATED RUBBER. TRIOCTYL PHOSPHATE ... COMPATIBLE WITH POLYVINYL CHLORIDE AND MAKES IT POSSIBLE TO USE LATTER @ LOW TEMP. PLASTIC STAYS FLEXIBLE AND RESISTS VERY LOW TEMP (-70 DEG C) ... USED EXTENSIVELY AS DISPERSING AGENT IN PLASTISOLS ... GOOD FLAMEPROOFER FOR POLYVINYL CHLORIDE COMPD. [R4] USE: *FLAME RETARDANT PLASTICIZER FOR POLYVINYL CHLORIDE RESINS [R1] *Solvent, antifoaming agent, plasticizer [R5] *Hydrogen peroxide production cosolvent; fire-resistant polyvinyl chloride/cellulose nitrate plasticizer. [R2] PRIE: U.S. PRODUCTION: *(1972) 1.13X10+9 GRAMS [R1] *(1974) 1.36X10+9 GRAMS (EST) [R1] U.S. IMPORTS: *(1972) NEGLIGIBLE [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *VISCOUS LIQUID [R6]; *Liquid [R5] BP: *215 deg C at 4 mm Hg [R7] MP: *-74 deg C [R8] MW: *434.72 [R9] DEN: *0.924 @ 26 deg C [R5] SOL: *Soluble in alcohol, acetone, and ether. [R5]; *Water solubility: 0.6 mg/l at 24 deg C [R10] SPEC: *INDEX OF REFRACTION: 1.441 @ 25 DEG C [R11, 1186] VAPD: *14.95 (Air= 1) [R12] VAP: *8.25X10-8 mm Hg at 25 deg C [R13] VISC: *15 mPa sec at 20 deg C. [R11, 1189] OCPP: *POUR POINT: -74 DEG C; MID-BOILING POINT: 216 DEG C @ 4 MM HG [R11, 1186] *BELOW -90 DEG C (SETS TO GLASS) [R11, 1186] *VAPOR PRESSURE: 0.23 MM HG AT 150 DEG C [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *COMBUSTIBLE WHEN EXPOSED TO HEAT OR FLAME. [R12] FIRP: *FOAM, CARBON DIOXIDE, DRY CHEMICAL. [R12] REAC: *... CAN REACT WITH OXIDIZING MATERIALS. [R12] DCMP: *When heated to decomposition it emits toxic fumes of /phosphorous oxides/. [R12] SERI: *A skin and eye irritant. [R12] STRG: *IN GENERAL, MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMP INTO TOXIC COMPONENTS...SHOULD BE STORED IN A COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED ... . INCOMPATIBLE MATERIALS SHOULD BE ISOLATED FROM EACH OTHER. [R15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *TEHP /Tris(2-ethylhexyl phosphate/ has a low acute toxicity for mammals ... TEHP is a skin irritant but not an eye irritant. ... Gavage studies in rats and mice revealed no significant toxic effects. ... In a 3 month inhalation study ... the lungs of dogs showed mild chronic inflammatory changes ... No studies on reproductive toxicity were available. TEHP gave negative results in several in vivo and in vitro tests for mutagenicity. ... There was some evidence of carcinogenicity based on an increased incidence of hepatocellular carcinomas in female mice ... and equivocal evidence of carcinogenicity based on the increased incidence of adrenal pheochromocytomas in male rats ... Considering the low incidence of this tumor /hepatocellular carcinoma/, its occurrence in only one sex of one species, the lack of evidence of genetic toxicity, and the low exposure of humans to TEHP, it is unlikely that TEHP poses a significant carcinogenic risk to humans. Neurotoxicity studies have been conducted in several species. TEHP causes no alteration in activity of plasma or red blood cell cholinesterase. No studies on delayed neurotoxicity have been reported. In a study on human volunteers, no skin irritation was reported. ... Occupational exposure to TEHP is likely to be by the dermal route during manufacture (accidental exposure) and from the use of some products. The compound is absorbed dermally in experimental animals but no information is available on its kinetics or metabolism via this route. Dermal exposure cannot, therefore, be quantified but is expected to be low. ... Exposure of the general population is principally via food and drinking water. [R16] ANTR: */SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R17] */SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R17] HTOX: *No irritant effects were seen after 24 hr of exposure to a TEHP saturated cotton swab placed on the skin of the forearm of 6 volunteers. A piece (2 sq cm) of PVC plastic containing 40% TEHP was placed on the arm of 8 volunteers for 72 hr. Slight redness but no irritation was observed. [R18] *A skin and eye irritant. [R12] NTOX: *Acute inhalation toxicity of TEHP has been investigated in Wistar rats and Hartley guinea-pigs. Groups of 10 animals of each species (sex not stated) were used. Rats were exposed to air concns of 287-460 mg/cu m for 30-210 min without any mortality in any group. Guinea pigs were exposed to air concn of 287-460 mg/cu m for 30-180 min, with some mortality in each group, varying from 30% (at 450 mg/cu m for 30 min, 298 mg/cu m for 60 min, and 460 mg/cu m for 60 min) to 80% (at 287 mg/cu m for 120 min). The mass median diameter for the TEHP aerosol was 1.5 um ... . [R19] *TRI(2-ETHYLHEXYL)PHOSPHATE RATED 1 ON RABBIT EYES /RATED NUMERICALLY ON SCALE OF 1 TO 10 ACCORDING TO DEGREE OF INJURY OBSERVED AFTER 24 HR, PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA, MOST SEVERE INJURY RATED 10/. [R20] *ORAL TOXICITY: ... TRIOCTYL PHOSPHATE APPEARS TO HAVE ONLY VERY SLIGHT ACUTE TOXICITY ... THERE IS NO INFORMATION ABOUT LONG-TERM TOXICITY. [R4] *SUBACUTE DAILY FEEDING OF 0.43 G/KG IN THE DIET OF RATS PRESENTED A NO-EFFECT LEVEL, WHEREAS AT 1.55 G/KG/DAY SOME WEIGHT LOSS OCCURRED. A DOSE OF 250 MG APPLIED TO THE SHAVED RABBIT SKIN PRODUCED, WITHIN 24 HOURS, SIGNS OF MODERATE ERYTHEMA, WHICH PERSISTED FOR ABOUT A WEEK. NO EVIDENCE OF SYSTEMIC INTOXICATION WAS OBSERVED IN THE EYE AND SKIN. NO DEMYELINATING ACTION WAS FOUND IN A STUDY WITH CHICKENS, USING TRI-ORTHO-CRESYL PHOSPHATE AS A POSITIVE CONTROL. [R6] *Tris(2-ethylhexyl)phosphate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of S9 fractions from Aroclor 1254 induced Sprague Dawley rat or Syrian hamster liver. [R21] *Placed in the eyes of rabbits at doses of 0.1-0.5 ml, tris(2-ethylhexyl)phosphate produced moderate conjunctivitis that cleared up in 24 hours. [R22] *Tris(2-ethylhexyl)phosphate was ... nontoxic when administered to rats and rabbits iv, intratracheally, or by inhalation. [R22] *Tris(2-ethylhexyl)phosphate applied to clipped skin of rabbits produced moderate erythema that persisted for approximately 1 week. [R22] *Tris(2-ethylhexyl)phospahte, unlike some other organophosphates, does not produce neuropathologic effects on chickens or inhibit cholinesterase. Tris(2-ethylhexyl)phosphate did not have a significant effect on the trained behavior of monkeys but did have a dose-related effect on the trained behavior of dogs. [R22] *Feeding doses of 110-1550 mg TEHP/kg bw/day to rats in their diet for 30 days revealed a NOEL of 430 mg/kg bw. At 1550 mg/kg bw, weight loss was observed. [R19] *... TEHP was admin in corn oil (10 ml/kg bw) by gavage 5 days/wk for 103 wk to groups of 50 male and 50 female F-344/N rats and B6C3F1 mice. the doses admin were: /Fischer-344 rats (male)- 2000 and 4000 mg/kg, (female)- 1000 and 2000 mg/kg; B6C3F1 mice (male and female)- 500 and 1000 mg/kg./ The animals were observed twice daily and body weight was measured weekly for the first 13 weeks and once every 4 weeks thereafter. Clinical exams were performed once every 4 weeks. ... Decr in body weight, compared with controls, was limited to male rats at the low dose (11.5%) and the high dose (15.8%). The decreased body weight did not affect survival. In male rats the incidence of phaeochromocytomas of the adrenal gland increased with dose and two (4%) were malignant in the high-dose group. The incidence of adrenal phaeochromocytomas in male rats was: control 2/50 (4%), low-dose 9/50 (18%) and high-dose 12/50 (24%). In two previous gavage studies in the same lab, the incidence of phaeochromocytomas in control male rats was 24 and 26%. In female mice the incidence of hepatocellular carcinomas was: control 0/48 (0%), low dose 4/50 (8%), and high dose 7/50 (14%). The incidence of hepatocellular carcinomas showed a dose-related incr and the incidence at the high-dose level was statistically significant. The results of these 2-yr gavage studies in rats and mice were interpreted by NTP as showing some evidence of carcinogenicity in male rats based on the increased incidence of phaeochromocytomas ... . In this same study ..., TEHP caused a dose-related incr in the incidence of follicular cell hyperplasia of the thyroid in male and female B6C3F1 mice. The incidence of hyperplasia was: in males, control 0/49 (0%), low dose 12/48 (25%), and high dose 24/47 (51%); in females, control 1/44 (2%), low dose 13/47 (28%), and high dose 12/46 (26%). There was no dose-related incr in thyroid tumors. The LOAEL for thyroid hyperplasia was 357 mg/kg bw/day ... . [R23] NTXV: *LD50 Rat oral > 36.8 g/kg; [R22] *LD50 Rabbit oral approx 46.0 g/kg; [R22] *LD50 Rabbit skin 20 g/kg; [R12] *LC50 Guinea pig inhalation 450 mg/cu m/30 min; [R12] NTP: *Two year toxicology and carcinogenesis studies of tris(2-ethylhexyl)phosphate were conducted by administering the test chemical in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female F344/N rats. Male rats received doses of 2000 or 4000 mg/kg body weight female rats received 1,000 or 2000 mg/kg. Fifty vehicle control animals of each sex received 10 ml/kg body wt corn oil by gavage on the same schedule. ... In the 2 year studies, survival rates and mean body weight gains of dosed female rats were comparable to those of their respective vehicle controls. Survival rates of dosed male rats were comparable to that of the vehicle controls, but body weight gains were depressed. In male rats, the incidence of pheochromocytoma of adrenal glands increased with dose (2/50, 4%; 9/50, 18%; 12/50, 24%). There were also two additional malignant pheochromocytomas in the high dose group. However, the incidence of adrenal pheochromocytoma in vehicle controls of this study (2/50, 4%) was low compared with the 25% incidence observed in two previous studies or the overall historical incidence of 18% observed throughout the Program, and thus the evidence of carcinogenicity was considered to be equivocal. ... Decreased incidences were observed for acinar cell adenomas of the pancreas in dosed male rats (14/50, 28%; 5/48, 10%; 2/49, 4%) and for fibroadenomas of the mammary glands in low dose female rats (11/50, 22%; 2/50, 4%; 7/50, 14%). Increased incidences of liver carcinomas and decreased incidences of mammary fibroadenomas were observed also in female rats in the di(2-ethylhexyl)phthalate studies. A possible common link among three chemicals may be metabolic conversion to 2-ethylhexanol. ... A comparison of concurrent and historical controls indicated that there was equivocal evidence of carcinogenicity in male F344/N rats receiving 2000 and 4000 mg/kg tris(2-ethylhexyl)phosphate, as evidenced by increased incidences of pheochromocytomas of the adrenal glands. There was no evidence of carcinogenicity in female F344/N rats ... receiving tris(2-ethylhexyl)phosphate. [R21] *Two year toxicology and carcinogenesis studies of tris(2-ethylhexyl)phosphate were conducted by administering the test chemical in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female B6C3F1 mice. Male and female mice received 500 or 1000 mg/kg. Fifty vehicle control animals of each sex ... received 3.3 ml/kg corn oil by gavage on the same schedule. Survival rates and mean body weight gains of dosed dosed mice were comparable to those of their respective vehicle controls. One nonneoplastic lesion, follicular cell hyperplasia of the thyroid, was observed at increased incidences in dosed male and female mice. In female mice, the incidence of hepatocellular carcinoma (0/48; 4/50; 7/50) in high dose animals (1000 mg/kg) was significantly increased relative to that of the vehicle controls. Hemangiosarcomas of the ciculatory system in male mice (7/50, 14%; 0.50; 1/49, 2%) and lymphomas of the hematopoietic system in female mice (14/49, 29%; 10/50, 20%; 6/50, 12%) were decreased compared with vehicle controls. A decrease in the incidence of lymphomas and an increased incidence of carcinomas of the liver in female mice (both seen in this study) were observed in studies of di(2-ethylhexyl)adipate. ... There was no evidence of carcinogenicity in male B6C3F1 mice receiving tris(2-ethylhexyl)phosphate. There was some evidence of carcinogenicity in female B6C3F1 mice that received 1000 mg/kg tris(2-ethylhexyl)phosphate, as shown by an increased incidence of hepatocellular carcinoma. Tris(2-ethylhexyl)phosphate was associated with increased incidences of follicular cell hyperplasias of the thyroid gland in male and female B6C3F1 mice. [R21] TCAT: ?Tri-2-ethylhexyl phosphate (CAS # 78-42-2) was evaluated for clastogenic effects in groups of 10 male rats (strain unreported) exposed to nominal concentrations of 0, 0.25 and 0.50 mg/l, 6 hours per day, for 5 and 4 weekdays, respectively, for 2 successive weeks. Treatment was concluded with harvest of both mature and immature, normochromatic (NCE) and polychromatic (PCE) red blood cells of the bone marrow for assessment of cytotoxicity and micronucleus formation. A PCE/NCE ratio of a total 1000 harvested erythrocytes per animal indicated no treatment-related cytotoxicity. Likewise, there was no statistically significant increased incidence of either micronucleated PCE's or NCE's in any treated group relative to control. [R24] ?The mutagenicity of tris(2-ethylhexyl)phosphate was evaluated in Salmonella tester strains TA98, TA100, TA1535, and TA1537, both in the presence and absence of added metabolic activation by Aroclor-induced rat or hamster liver S9 fraction. The material was tested for mutagenicity at concentrations of 0, 100, 333, 1000, 3333, and 10000 ug/plate using the preincubation method. Tris(2-ethylhexyl)phosphate was not mutagenic in any of the bacterial tester strains, either in the presence or absence of added metabolic activation. [R25] ADE: *In an inhalation study, 9 male rats received a single, head-only exposure of 20 min to an aerosol of [32P]-TEHP. The animals were killed after the following post-exposure intervals: 5 min, 30 min; 1, 4, 17, 18, 24, 48, and 70 hr. Exposure concns were 0.72 and 0.91 mg/l. TEHP AND/or its metabolites were distributed into the lungs (13% of total radioactivity after 5 min), stomach contents (64% after 1st hr), brain and liver (9 and 16%, respectively, after 30 min). Spleen, kidney, bone, muscle and fat retained < 2% of the radioactivity at any time. Fecal excretion was high but urinary excretion was relatively low. Chromatographic analysis of urine and feces showed TEHP was partly biotransformed but the nature of the metabolites was not mentioned. [R26] METB: *... one of the suggested metabolites, 2-ethylhexanol. [R27] *It is reported to be transformed to at least one other compound in rats. The nature of this transformation was not reported. [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Trioctyl phosphate's production and use as a hydrogen peroxide production cosolvent and as a low-temperature plasticizer for PVC resins may result in its release to the environment. If released to the atmosphere, trioctyl phosphate is expected to exist almost entirely in the particulate phase in the ambient atmosphere based on a measured vapor pressure of 8.2X10-8 mm Hg at 25 deg C. Particulate-phase trioctyl phosphate may be physically removed from the atmosphere by wet or dry deposition. If released to soil, an estimated Koc of 3.5X10+6 suggests that trioctyl phosphate is expected to be immobile. Volatilization from wet and dry soil surfaces is not expected to occur based on an estimated Henry's Law constant of 7.9X10-8 atm-cu m/mole at 25 deg C and the measured vapor pressure, respectively. The biodegradation of trioctyl phosphate in water suggests that biodegradation in soil may be important. If released into water, the estimated Koc for trioctyl phosphate suggests that this compound will adsorb strongly to suspended solids and sediment in the water column. Bioconcentration in aquatic organisms is expected to be low based on measured BCF values ranging from 2.4 to 22 in carp. Volatilization from water surfaces is not expected to be an important fate process given this compound's Henry's Law constant. Trioctyl phosphate biodegrades in river water with a rate of 26 to 75% over 30 days. Occupational exposure may occur through inhalation of dust particles and dermal contact with trioctyl phosphate at workplaces where it is produced or used. The general population may be exposed to trioctyl phosphate via inhalation of ambient air and ingestion of contaminated food and drinking water. (SRC) ARTS: *Trioctyl phosphate's production and use as a hydrogen peroxide production cosolvent(1) and as a low-temperature plasticizer for PVC resins, imparting flame and fungus resistance(2) may result in its release to the environment(SRC). [R28] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 3.5X10+6(SRC), determined from an estimated log Kow of 9.5(2) and a recommended equation(3), indicates that trioctyl phosphate is expected to have no mobility in soil(SRC). Volatilization of trioctyl phosphate from moist soil surfaces is not expected (SRC) given an estimated Henry's Law constant of 7.9X10-8 atm-cu m/mole(SRC), determined from its experimental values for vapor pressure, 8.2X10-8 mm Hg(4), and water solubility, 0.6 mg/l(5). Trioctyl phosphate is not expected to volatilize from dry soil surfaces based on a measured vapor pressure of 8.2X10-8 mm Hg(4). The biodegradation of trioctyl phosphate in water(6,7) suggests that biodegradation in soil may be important(SRC). [R29] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 3.5X10+6(SRC), determined from an estimated log Kow of 9.5(2) and a recommended regression-derived equation(3), indicates that trioctyl phosphate is expected to adsorb to suspended solids and sediment in water(SRC). Trioctyl phosphate is not expected to volatilize from water surfaces(3) based on an estimated Henry's Law constant of 7.9X10-8 atm-cu m/mole(SRC), determined from its experimental values for vapor pressure, 8.2X10-8 mm Hg(4), and water solubility, 0.6 mg/l(5). According to a classification scheme(6), BCF values of 2.5 to 6.5 and 9.2 to 22 measured for trioctyl phosphate in carp at 2 and 0.2 mg/l, respectively(7), suggest that bioconcentration in aquatic organisms is low(SRC). Trioctyl phosphate, concentration of 5 ppm, was degraded 26% after 3 days incubation in Mino River water and 24% after 3 days incubation in seawater(8). Trioctyl phosphate was moderately degraded in river die-away tests; 75%, 53%, and 60% was degraded after 30 days incubation in Ebisubashi, Kemabashi, and Tokueibashi river water, respectively(9). [R30] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trioctyl phosphate, which has a measured vapor pressure of 8.2X10-8 mm Hg at 25 deg C(2), is expected to exist almost entirely in the particulate phase in the ambient atmosphere. Particulate-phase trioctyl phosphate may be physically removed from the air by wet and dry deposition(SRC). [R31] BIOD: *In a semi-continuous activated sludge study, using a trioctyl phosphate feed level of 3 mg/l per 24 hours, 20% degradation occurred after 34 weeks(1). Trioctyl phosphate, concentration of 5 ppm, was degraded 26% after 3 days incubation in Mino River water (Japan) and 24% after 3 days incubation in seawater(2). Trioctyl phosphate was moderately degraded in river die-away tests; 75%, 53%, and 60% was degraded after 30 days incubation in Ebisubashi, Kemabashi, and Tokueibashi river water (Japan), respectively(3). A biodegradation study on trioctyl phosphate, based on BOD measurements, using an activated sludge seed, and an initial chemical concentration of 100 mg/l indicated 0% biodegradation after 4 weeks(4). In a screening test, using an activated sludge seed trioctyl phosphate was degraded 40-60% after 48 hours(5). [R32] ABIO: *Phosphoric acid esters are susceptible to hydrolysis(1). Trioctyl phosphate underwent hydrolysis in sodium hydroxide(2). Trioctyl phosphate was moderately decomposed by UV irradiation(2). The measured neutral hydrolysis half-lives of trimethyl phosphate and triethyl phosphate at 25 deg C are 1.2 and 5.5 years, respectively(3). Based on the structural similarities to trimethyl and triethyl phosphate, trioctyl phosphate is expected to have a similar hydrolysis rate(SRC). [R33] BIOC: *BCF values of 2.4 to 6.5 and 9.2 to 22 were determined in carp using flow-through conditions and trioctyl phosphate concentrations of 2 and 0.2 mg/l, respectively(1). According to a classification scheme(2), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R34] KOC: *The Koc of trioctyl phosphate is estimated as approximately 3.5X10+6(SRC), using an estimated log Kow of 9.5(1) and a regression-derived equation(2). According to a recommended classification scheme(3), this estimated Koc value suggests that trioctyl phosphate is expected to be immobile in soil(SRC). Trioctyl phosphate was adsorbed by activated carbon(4). [R35] VWS: *The Henry's Law constant for trioctyl phosphate is estimated as 7.9X10-8 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 8.2X10-8 mm Hg(1), and water solubility, 0.6 mg/l(2). This value indicates that trioctyl phosphate will be essentially nonvolatile from water surfaces(3). Trioctyl phosphate's Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Trioctyl phosphate is not expected to volatilize from dry soil surfaces(SRC) based on a measured vapor pressure of 8.2X10-8 mm Hg(1). [R36] WATC: *DRINKING WATER: Trioctyl phosphate was detected in drinking water from the Lemieux Island, Ontario water treatment plant in Oct 1978 at a concentration of 0.3 ng/l(1). [R37] *SURFACE WATER: Trioctyl phosphate was detected in river water samples from the Ebisubashi R, Japan at a concentration of 0.048 and 0.060 ug/l, Kemabashi R, Japan at a concentration of 0.042 and 0.015 ug/l, and the Tokueibashi R, Japan at a concentration of 0.073 and 0.084 ug/l in Nov 1985 and Jan 1986, respectively(1). [R38] ATMC: *INDOOR AIR: Trioctyl phosphate was detected in association with indoor air particles at a telephone office site at a concentration of 5.0 ng/cu m(1). The average concentration of trioctyl phosphate detected in association with airborne particles from a Wichita, KS office was 6 ng/cu m(2). [R39] FOOD: *Trioctyl phosphate was detected in the following ready-to-eat food items (times found, average concentration ug/g): roasted beef chuck roast (1,0.2370); cooked beef loin or sirloin (1,0.1030); rye bread (1,0.0360); whole wheat bread (1,0.0170); caramel candy (1,0.0740); milk chocolate candy (1,0.3500); American cheese (1,0.2600); sweet raw cherries (1,0.5050); coffee (1,0.0550); frozen fried chicken dinner (1,0.1590); honey (1,0.0800); vanilla ice milk (1,0.4590); lemonade (1,0.0550); raw lettuce (1,0.0940); blueberry or plain muffins (1,0.2580); canned pineapple (1,0.0400); dried prunes (2,0.0990); Italian salad dressing (1,0.3800); beef and vegetable stew (1, 0.4330); white sugar (1,0.1020); and cane syrup (1,0.0900)(1). Trioctyl phosphate was detected in unspecified grain products (flours, bread, cereals) at unreported concentrations(2). [R40] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,209 workers (725 of these are female) are potentially exposed to trioctyl phosphate in the US(1). Trioctyl phosphate has been detected in association with indoor airborne particles(2,3). Occupational exposure may occur through inhalation of dust particles and dermal contact with trioctyl phosphate at workplaces(SRC). The general population may be exposed to trioctyl phosphate via ingestion of contaminated food(4) and drinking water(5). [R41] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R42] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Phosphoric acid, tris(2-ethylhexyl) ester is included on this list. [R43] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GC DETERMINATION OF TRIALKYL PHOSPHATES AND TRIARYL PHOSPHATES IN DRINKING WATER, FOLLOWING ISOLATION USING MACRORETICULAR RESIN. [R44] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tris(2-ethylhexyl)phosphate in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 274 (1984) NIH Publication No. 84-2530 SO: R1: SRI R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 913 R3: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 823 R4: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 337 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1140 R6: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2380 R7: Aldrich; Handbook Catalog of Fine Chemicals. Milwaukee, WI: Aldrich Chem Co. p. 1702 (2000) R8: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 3423 R9: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8307 R10: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Ver (1992) R11: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3327 R13: Hinckley DA et al; J Chem Eng Data 35: 232-7 (1990) R14: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 3067 R15: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 1210 R16: Environmental Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl) Phosphate and Tetrakis(hydroxymethyl) Phosphonium Salts pp. 33-36 (2000) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labor Organisation and the World Health Organization. R17: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R18: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.59 (2000) R19: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate p.50 (2000) R20: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1008 R21: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tris(2-Ethylhexyl)Phosphate in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.11 (1984) Technical Rpt Series No. 274 NIH Pub No. 83-027 R22: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tris(2-Ethylhexyl)Phosphate in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.18 (1984) Technical Rpt Series No. 274 NIH Pub No. 83-027 R23: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate p.55-56 (2000) R24: MOBIL OIL CORP; Micronucleus Assay of Bone Marrow Cells from Rats Treated via Inhalation of Aerosolized (Tri-2-ethylhexyl phosphate); 10/11/91; EPA Doc No. 86-920000464S; Fiche No. OTS0533753 R25: DEPT HEALTH AND HUMAN SERVICES; Toxicology and Carcinogenesis Studies of Tris(2-ethylhexyl)phosphate (CAS #78-42-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies) with Attachments, (1984), EPA Doc. No. 40-8440572, Fiche No. OTS0522515 R26: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.49 (2000) R27: Environmental Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl) Phosphate and Tetrakis(hydroxymethyl) Phosphonium Salts pp. 36 (2000) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labor Organisation and the World Health Organization. R28: (1) Ashford RD; Ashford's Dictionary of Industrial Chemicals: Properties, Production, Uses. London, England: Wavelength Publ, Ltd. p.913 (1994) (2) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY, NY: Van Nostrand Reinhold Co p. 1189 (1993) R29: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Hinckley DA et al; J Chem Eng Data 35: 232-7 (1990) (5) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Ver (1992) (6) Kondo M et al; Eisei Kagaku 34: 175-83 (1985) (7) Kawai S et al; Annu Rep Osaka City Inst Public Health Environ 48: 175-83 (1985) R30: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Hinckley DA et al; J Chem Eng Data 35: 232-7 (1990) (5) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Ver (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Chemicals Inspection Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center, ISBN 4-89074-101-1 (1992) (8) Kondo M et al; Eisei Kagaku 34: 175-83 (1985) (9) Kawai S et al; Annu Rep Osaka City Inst Public Health Environ 48: 175-83 (1985) R31: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Hinckley DA et al; J Chem Eng Data 35: 232-7 (1990) R32: (1) Saeger VW et al; Environ Sci Technol 13: 840-4 (1979) (2) Kondo M et al; Eisei Kagaku 34: 175-83 (1985) (3) Kawai S et al; Annu Rep Osaka City Inst Public Health Environ 48: 175-83 (1985) (4) Chemicals Inspection Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center, ISBN 4-89074-101-1 p 2-112 (1992) (5) Ishikawa S et al; Suishitsu Odaku Kenkyu 8: 799-807 (1985) R33: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (2) Ishikawa S et al; Suishitsu Odaku Kenkyu 8: 799-807 (1985) (3) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants. USEPA 440/4-81-014 (1981) R34: (1) Chemicals Inspection Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology - Toxicology and Information Center, ISBN 4-89074-101-1 p. 2-112 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R35: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Ishikawa S et al; Suishitsu Odaku Kenkyu 8: 799-807 (1985) R36: (1) Hinckley DA et al; J Chem Eng Data 35: 232-7 (1990) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Ver 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Ver (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R37: (1) Lebel GL et al; J Assoc Off Anal Chem 64: 991-8 (1981) R38: (1) Kawai S et al; Annu Rep Osaka City Inst Public Health Environ 48: 175-83 (1985) R39: (1) Weschler CJ, Shields HC; in APCA Annu Meet, 79th (Vol 4), 86/52.2 (1986) (2) Weschler CJ; Environ Sci Technol 18: 648-52 (1984) R40: (1) Paul TG, Woodson BL; Chem Contam Monit 78: 614-31 (1995) (2) Daft GL; Bull Environ Contam Toxicol 29: 221-7 (1982) R41: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Weschler CJ, Shields HC; The Accumulation of "Additives" in Office Air. in Proc - APCA Annu Meet. 79th (Vol 4), 86/52.2 (1986) (3) Weschler CJ; Environ Sci Technol 18: 648-52 (1984) (4) Paul TG, Woodson BL; Chem Contam Monit 78: 614-31 (1995) (5) Lebel GL et al; J Assoc Off Anal Chem 64: 991-8 (1981) R42: 40 CFR 712.30 (7/1/2000) R43: 40 CFR 716.120 (7/1/2000) R44: LEBEL GL ET AL; J ASSOC OFF ANAL CHEM 64 (4): 991 (1981) RS: 37 Record 177 of 1119 in HSDB (through 2003/06) AN: 2577 UD: 200303 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIS(2-CHLOROETHYL) PHOSPHATE SY: *3CF-; *AI3-15023-; *Amgard-TCEP-; *Antiblaze-TCEP-; *Celanese-Celluflex-CEF-; *CELLUFLEX-; *CELLUFLEX-CEF-; *2-CHLOROETHANOL-PHOSPHATE-; *DISFLAMOLL-TCA-; *ETHANOL,-2-CHLORO-,-PHOSPHATE- (3:1); *FYROL-CEF-; *Fyrol-CF-; *Genomoll-P-; *Hostaflam-UP810-; *Levagard-EP-; *NCI-C60128-; *NIAX-3CF-; *NIAX-FLAME-RETARDANT-3CF-; *Nuogard-TCEP-; *PHOSPHORIC ACID, TRIS(2-CHLOROETHYL)ESTER; *TCEP-; *Tolgard-TCEP-; *TRICHLOROETHYL-PHOSPHATE-; *TRI(BETA-CHLOROETHYL) PHOSPHATE; *TRI(2-CHLOROETHYL) PHOSPHATE; *TRIS(2-CHLOROETHYL)ESTER PHOSPHORIC ACID; *Tris-(2-chloroethyl)fosfat (Czech); *TRIS(2-CHLOROETHYL) ORTHOPHOSPHATE; *TRIS- (CHLOROETHYL)-PHOSPHATE; *TRIS(BETA-CHLOROETHYL) PHOSPHATE RN: 115-96-8 MF: *C6-H12-Cl3-O4-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Made from a three-to-one mole ratio of ethylene oxide (qv) and phosphorus oxychloride. [R1] FORM: */Tri(2-chloroethyl) phosphate/ is a liquid containing 10.8 wt % phosphorus and 36.7 wt % chloride. [R1] MFS: *Akzo Nobel Chemicals Inc., 300 South Riverside Plaza, Suite 2200, Chicago, IL 60606, (312) 906-7500; Production site: Gallipolis Ferry, WV 25515-1721 [R2] OMIN: *IT IS PLASTICIZER FOR CELLULOSE CMPD AND IN THEM IT ACTS AS FLAMEPROOFER, BECAUSE OF ITS CHLORINE CONTENT AND ITS PHOSPHORIC RADICAL. ... PARTICULARLY SUITABLE FOR MANUFACTURE OF NONINFLAMMABLE VARNISHES AND PLASTICS, PARTICULARLY MATERIALS BASED ON ETHYLCELLULOSE, NITROCELLULOSE, AND CELLULOSE ACETATE. /TRICHLOROETHYL PHOSPHATE/ [R3] *EXCELLENT FLAMEPROOFER FOR POLYESTER RESINS, POLYACRYLATES, AND POLYURETHANES. IT IS COMPATIBLE TO SOME EXTENT WITH POLYVINYL CHLORIDE, BUT PLASTICIZING EFFICIENCY IS LOW AND THERE IS TENDENCY TO EXUDATION. PRIMARY PLASTICIZER MUST BE USED TOGETHER WITH IT. /TRICHLOROETHYL PHOSPHATE/ [R3] *Compatible with essentially all polymers containing polar groups. [R1] USE: *Flame-retardant plasticizer. [R4, 1143] *Used in rigid polyurethane and polyisocyanurate foams, carpet backing, flame-laminated and rebonded flexible foam, flame-retardant coatings, most classes of thermosets, adhesives (gv), cast acrylic sheet, and wood-resin composites such as particle board. [R1] *Emulsions of tris(2-chloroethyl) phosphate, blended with a binder such as a vinyl or acrylic emulsion, can be used for applications such as the backcoating of upholstery. It can be used as a secondary plasticizer in polyvinyl chloride to suppress the flammability resulting from plasticizers such as phthalates. Where a particularly high degree of flame retardancy is required, it can be used in combination with the aromatic phosphate plasticizers. Such formulations can serve as an alternative to the use of antimony oxide in plasticized vinyl polymers. [R5] *Used with melamine in flexible urethane foam cushions and institutional mattresses. [R1] *Tris(beta-chloroethyl) phosphate is used as versatile flame retardant for flexible as well as rigid polyurethane foams. Even though tris(beta-chloroethyl) phosphate is an additive type of flame retardant, that is, not incorporated as a part of the substrate by chemical bonding, it still offers good retention except under very hot and humid conditions. [R6] *Flame retardant in plastics, especially in flexible foams used in automobiles and furniture, and in rigid foams used for building insulation. [R7] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R8] *(1975) GREATER THAN 9.08X10+5 GRAMS (EST) [R8] U.S. IMPORTS: *(1972) NEGLIGIBLE [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear, transparent liquid [R4, 1194]; *Low viscosity liquid [R1] ODOR: *SLIGHT ODOR [R3] BP: *330 deg C @ 1 atm [R9] MP: *-55 deg C [R7] MW: *285.5 [R10] DEN: *1.425 @ 20 deg C/20 deg C [R4, 1143] OWPC: *log Kow = 1.44 [R11] SOL: *Insoluble in benzene. Soluble in most organic solvents. [R10]; *Soluble in carbon tetrachloride. [R9]; *Very slightly soluble in aliphatic hydrocarbons; soluble in alcohols, esters, ketones and aromatic hydrocarbons. [R12]; *In water, 7,000 mg/l, temp not specified. [R13] SPEC: *Index of refraction: 1.4721 @ 20 deg C/D [R4, 1143]; *IR: 2:493D (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R14]; *NMR: 10:67D (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R14]; *IR: 6850 (Sadtler Research Laboratories Prism Collection) [R15]; *NMR: 10547 (Sadtler Research Laboratories Spectral Collection) [R15]; *MS: NIST 53926 (NIST/EPA/MCDC Mass Spectral Database 1990 version) [R15] VAP: *6.125X10-2 mm Hg at 25 deg C [R16] VISC: *45 cP @ 20 deg C [R12] OCPP: *11.65 mg/cu m equivalent to 1 ppm (w/v conversion factor) [R17, 2363] *Phosphoric acid esters slowly hydrolyze in water at pH of 7 and 25 deg C. [R18] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat or flame. [R19, 761] FLPT: *216 deg C (open cup) [R20] AUTO: *1115 deg F [R19, 760] TOXC: *When heated to decomposition it emits very toxic fumes of /phosphorous oxides/ and /hydrogen chloride/. [R19, 761] DCMP: *When heated to decomposition it emits very toxic fumes of POx /phosphorous oxides/ and Cl- /chlorides/. [R19, 761] *Rapid decomposition occurs above 220 deg C. [R21] SERI: *Does not appear to be absorbed through the skin nor is it a dermal irritant. [R22, 3085] *A skin and eye irritant. [R19, 761] EQUP: *Some data suggesting breakthrough times for /butyl rubber and nitrile rubber/ of approximately an hour or more. /Organo-phosphorus cmpd/ [R23] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Usually, all skin contact and inhalation of vapors or dusts should be avoided. [R17, 2374] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: */Tris(2-chloroethyl) phosphate is not readily biogradable. Bioconcentration factors are low ... In rats, oral doses ... are absorbed and distributed around the body to various organs, particularly the liver and kidney, but also the brain. Metabolites in rats and mice include bis(2-chloroethyl)carboxymethyl phosphate; bis(2-chloroethyl) hydrogen phosphate; and bis(2-chloroethyl)-2-hydroxyethyl phosphate glucuronide. Excretion is rapid, nearly complete and mainly via the urine. ... In repeat dose studies /Tris(2-chloroethyl) phosphate/ caused adverse effects on the brain (hippocampal lesions in rats), liver and kidneys. ... Non-irritant to skin and eyes but has not been tested for sensitization potential. /SRP: conflicting reports in the literature on skin irritation./ ... Not teratogenic. It adversely affects the fertility of male rats and mice. ... In vitro /mutagenicity/ test resilts were inconsistent and an in vivo ... micronucleus test gave equivocal results. /Tris(2-chloroethyl) phosphate/ causes benign and malignant tumors at various organ sites in rats and mice. A very high oral dose ... caused some inhibition of plasma cholinesterase and brain neuropathy target esterase... but did not cause delayed neurotoxicity. In rats, a high dose ... caused convulsions, brain lesions and impaired performance ... [R24] CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of tris(2-chloroethyl)phosphate were available. There is limited evidence for the carcinogenicity of tris(2-chloroethyl)phosphate in experimental animals. Overall evaluation: Tris(2-chloroethyl)phosphate is not classifiable as to its carcinogenicity to humans (Group 3). [R25] MEDS: *All persons ... should undergo regular medical examinations, with special /attention to/ the central nervous system. [R17, 2374] NTOX: *Tri(2-chloroethyl) phosphate produces prolonged epileptiform convulsions in the rat intraperitoneally at levels of 0.28 g/kg. At higher doses, convulsions occur, but only weak cholinesterase inhibition. The material does not appear to be absorbed through the skin nor is it a dermal irritant. A subacute study ... showed a definite hemorrhagic tendency by trichloroethyl phosphate. [R22, 3085] *GENERAL TOXICITY OF TRICHLOROETHYLPHOSPHATE IS COMPARABLE WITH THAT OF TRIBUTYL PHOSPHATE AND TRIPHENYL PHOSPHATE. [R3] *No paralysis /in rats/ at 80-125 mg/kg, ip X 37 days; hemorrhagic effect at high dose level. No irritant effect on guinea pigs. /From table/ [R22, 3075] */TRI(2-CHLOROETHYL) PHOSPHATE PRESENTS/ ... INTERESTING CONTRAST WITH TRIETHYL PHOSPHATE, PRODUCING ANESTHETIC-LIKE PICTURE WITH CONSIDERABLE MUSCLE RELAXATION AT RELATIVELY HIGH DOSAGES. [R26, 1923] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats receiving TRCP as shown by incr incidences of renal tubule adenomas. Thyroid follicular cell neoplasms and mononuclear cell leukemia in male and female rats may have been related to chemical administration. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice as shown by a marginally incr incidence of renal tubule cell neoplasms. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice as shown by a marginally incr incidence of harderian gland adenomas. [R27] *An oral LD50 of 0.5 g/kg bw was found in a ... study within male rats. Treated rats died with 24 hr and showed spasmodic contractions and acute depressions. [R28] *In a study ... groups of 5 male and 5 female Sprague-Dawley rats received 800, 1000 or 1260 mg/kg bw by oral gavage. One female receiving 1000 mg/kg died on day 2 and 4/5 males and 4/5 females receiving 1260 mg/kg bw died by day 4. ... Clinical signs of toxicity included piloerection and incr salivation amongst all animals; hunched posture, abnormal gait, lethargy, labored respiration, ptosis and pale extremities were observed amongst all animals receiving 1000 and 1260 mg/kg bw. No clinical signs of toxicity were observed in surviving animals from day 4 onwards. No microscopic pathology abnormalities were seen amongst decedent animals or those killed on completion of the 14 day observation period. [R29] *Groups of 5 rats of each sex of the strain F-344/N were admin by gavage 0, 22, 44, 88, 175 or 350 mg TCEP/kg bw 5 days/wk for 2 wk. No difference in body weight gain was found in the treated animals versus controls. The mean absolute and relative kidney weights of the males given 175 and 350 mg/kg bw were incr (10% and 12% respectively). Liver weights of the high-dose females were also significantly incr (17%). Serum cholinesterase activity was not reduced in males, but was decr by 18% and 20% in female at 175 and 350 mg/kg bw. No gross or histopathological abnormalities were found. [R30] *In a study conducted according to modern protocol standards, 0.5 ml TCEP was applied to the skin of 3 New Zealand white rabbits under a semi-occlusive dressing for 4 hr. Slight erythema (grade 1) was observed in each animal on day 1 only. Thereafter there were no signs of skin irritation. [R31] *In a study conducted according to modern protocol standards, 0.1 ml TCEP was instilled into the eye of each of 3 New Zealand white rabbits. Slight conjunctival redness (grade 1) was observed in each animal on day 1 and in one animal on day 2. Thereafter, there were no signs of eye irritation. [R31] *Wistar rats were given by gavage 50, 100, or 200 mg TCEP/kg bw suspended in olive oil on days 7-15 of gestation. No change in maternal body weight gain, food consumption or general appearance was found in the low and mid-dose groups. In the highest dose group, maternal food consumption was markedly suppressed; piloerection and general weakness occurred and 7/30 dams died. On day 20 of gestation, no incr in fetal death or malformations attributable to treatment were observed in any group. There was some incr (not statistically significant) in the incidence of supernumerary cervical and lumbar ribs in the high-dose group (this end-point is considered a variation not a malformation). Postnatal exam revealed normal development in the offspring of all groups; no abnormalities on morphological exam or in functional behavior tests (open field, water maze, rota rod, inclined plane test, pain reflex or Preyer's reflex) were found. [R32] *TCEP was tested for its effect on fertility and reproduction in Swiss CD-1 mice according to a continuous breeding protocol. Animals were exposed via gavage to doses of 175, 350 and 700 mg/kg bw. Males and females (F0 generation) were exposed daily for 7 days pre-cohabitation and 98 days cohabitation periods. In the F0 generation, TCEP decr the number of litters/pair and the number of pups/litter. Both sexes were affected, but the males relatively more sensitive. All sperm end-points (concn, motility, and % of abnormal sperm) were adversely affected. Due to poor fertility in the 700 mg/kg bw/day group, only one F0 pair delivered a litter. None of these pups survived to postnatal day 4. The data indicated reduced fertility due to TCEP exposure at doses of 175 mg/kg bw or more. [R32] *In an inhalation study using whole body exposure, male rats (strain and group size not specified) were continuously exposed to 0.5 or 1.5 mg TCEP/cu m for 4 months. Testicular toxicity was seen at both dose levels, with most severe effects at the highest dose. There were decr sperm counts, decr sperm motility and abnormal sperm morphology. Histology of the testes showed an incr number of spermatogonia but decr numbers of sperm in the later stages of development. When the treated males were mated, there was decr fertility at the 1.5 mg/cu m dose, with incr pre- and post- implantation loss, and litter sizes were decr. [R33] *Groups of 50 male and 50 female Slc:ddy mice received approx 0, 12, 60, 300 or 1500 mg/kg bw/day by dietary admin (assuming 30 g bw and 3 g/day food consumption) for 18 months. Distention of the abdomen was noted in males receiving 1500 mg/kg/day from wk 65. Reduced survival was noted in males and females receiving 1500 mg/kg/day (approx 40% survival compared to around 65% in controls). A marked reduction in body weight gain was noted in males and females receiving 1500 mg/kg/day (approx 60% lower than the control value). Other groups were not adversely affected, and there were no changes in food consumption. There were no significant changes in hematological parameters recorded at termination. Histologically, hyperplasia hypertrophy and karyomegaly were observed in the kidney of all treated animals although the incidence and severity of effects in the kidneys was unclear. In addn, cysts of the kidneys, necrosis and interstitial fibrosis were reported only amongst animals given 1500 mg/kg/day, although no further details were available. An incr incidence of renal adenomas was noted in males (0/50, 0/49, 0/49, 2/49, 9/50,) and females (0/49, 0/49, 0/50, 0/49, 2/50). In addn, there was an incr incidence of renal carcinomas in males (2/50, 0/49, 2/49, 3,47, 32/50) and females (1/50, at 1500 mg/kg/day and zero in all other groups). In the liver, there was an incr incidence of adenomas in males and females (3/50, 4/49, 3/49, 10/47, 16/50 in males, and 2/50 in females at 1500 mg/kg/day with zero in all other groups). In addn, there was a slight, but not dose-related, incr in the incidence of liver carcinomas in males (1/50, 1/49, 4/49, 2/47, 3/50). A slight incr in the incidence of forestomach papillomas and carcinomas was reported in treated males and females. [R34] *Groups of 60 males and 60 females B6C3F1 mice received 0, 175 or 350 mg/kg 5 days/wk by gavage for 103 wk. An interim sacrifice was performed on groups of 10 males and 10 females. At 66 wk, there were no effects seen on body weight gain, hematology or clinical chemistry. At 103 wk there were no adverse effects on survival or body weight gain. Non-neoplastic lesions were seen in the kidney; karyomegaly in the proximal convoluted tubules (2/50, 16/50, and 39/50 in males and 0/50, 5/49, and 44/50 in females). In the liver, an incr incidence of eosinophilic foci was observed in males (0/50, 3/50, 8/50). Neoplastic lesions in the kidney were observed: adenoma, 1/50, 0/50 and 1/50 in males and 0/50, 1/49 and 0/50 in females; adenocarcinoma, 0/50, 0/50 and 1/50 in males. In the liver of males an incr incidence of adenomas was seen: 20/50, 18/50 and 28/50. In addn, there was a slight incr in the incidence of Harderian gland adenomas in females. [R35] *Groups of 60 males and 60 females F-344 rats received 0, 44 or 88 mg/kg 5 day/wk by gavage for 103 wk. An interim sacrifice was performed on groups of 10 males and 10 females. At 66 wk, there were no adverse effects seen on body weight gain or hematology. There were unquantified decr in serum alkaline phosphatase and alanine aminotransferase in females receiving 88 mg/kg/day. Slight incr in liver and kidney weights were recorded in males at 88 mg/kg/day (14% and 20%, respectively, > controls). Also observed at this time point were renal tubule adenomas in one male receiving 88 mg/kg/day and local necrosis and accumulation of inflammatory cells in the cerebrum and thalamus of the brains of 3/10 females given 88 mg/kg/day. At 103 wk there were no adverse effects on body weight gain and no clinical signs of toxicity. Reduced survival was noted in males and females at 88 mg/kg/day (males 51% survival compared to 78% controls; females 37% compared to 66% in controls). No organ weight data were presented for this time point. Non-neoplastic findings in the kidneys were hyperplasia: 0/50, 2/50 and 24/50 in males and 0/50, 3/50, 16/50 in females. A marked incr in the incidence of degenerative lesions of the brain stem and cerebrum (thalamus, hypothalamus and basal ganglia) (such as gliosis, hemorrhage, necrosis and mineralization) was noted at 88 mg/kg/day (occurring in approx 40% of females at 88 mg/kg/day compared to 2% of controls). Neoplastic lesions were observed in the kidney; the frequency of adenomas was 1/50, 5/50 and 24/50 in males and 0/50, 2/50, 5/50 in females. In the brain, benign granular cell tumors were observed in 3/50 males at 88 mg/kg/day only. There were no treatment-related incr in the incidence of tumors in the brain of females. A slight incr in the incidence of thyroid follicular adenomas was noted in males (1/50, 2/48, 3/50), and of carcinomas in males and females (0/50, 0/48, 2/50 in males; 0/50, 2/50, 3/50 in females). There were incr occurrences of mononuclear cell leukemia in males (5/50, 14/50, 13/50) and in females (14/50, 16/50, 20/50). These occurrences, however, were within the range of historical controls (2-44%). [R35] *Female Fischer-344 rats gavaged with 275 mg TCEP/kg bw convulsed within 60-90 min and had extensive loss of CA1 hippocampal pyramidal cells when examined after 7 days. When convulsions were controlled, the histological lesions were diminished, indicating possibly that the lesions were due to convulsions and not directly due to TCEP. In a second study, rats gavaged with 275 mg TCEP/kg bw had impaired acquisition of a reference memory task in a water maze when trained and tested starting 3 wk following exposure, suggesting long-term impairment of some brain functions. [R35] *Mild inhibition of serum cholinesterase activity was seen in female rats receiving 175 and 350 mg/kg body weight for either 16 days or 16 weeks, but not in male rats or in male or female mice. Clinical signs of toxicity in female rats included ataxia, excessive salivation, gasping and convulsions, which may have been related to the cholinesterase inhibition. Alternatively, some of the clinical signs may be attributed to the observed neuronal necrosis in the hippocampus and thalamus. [R36] *Tris(2-chloroethyl) phosphate was not mutagenic to bacteria in the absence of an exogenous metabolic system but gave equivocal results in the presence of an exogenous metabolic system. It caused cell transformation and, in single studies, sister chromatid exchanges but not chromosomal aberrations or mutations in rodent cells in vitro. It single studies, it gave equivocal results in a micronucleus test in Chinese hamsters and caused dominant lethal mutations in rats in vivo. [R25] NTXV: *LD50 Rat oral 1230 mg/kg; [R19, 761] *LD50 Mouse oral 1866 mg/kg; [R19, 761] NTP: *... Toxicology and carcinogenesis studies were conducted by administering Tris(2-chloroethyl) phosphate (TRCP) (approximately 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... The 2 yr studies in rats were conducted by admin 0, 44, or 88 mg/kg TRCP to groups of 60 males and females, 5 days/wk for up to 104 wk. ... The 2 yr studies in mice were conducted by admin 0, 175, or 350 mg/kg TRCP to groups of 60 males and females, 5 days/wk for up to 104 wk. ... Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats receiving TRCP as shown by incr incidences of renal tubule adenomas. Thyroid follicular cell neoplasms and mononuclear cell leukemia in male and female rats may have been related to chemical administration. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice as shown by a marginally incr incidence of renal tubule cell neoplasms. There was equivocal evidence of carcinogenic activitv for female B6C3F1 mice as shown by a marginally incr incidence of harderian gland adenomas. [R27] +Tris(2-chloroethyl)phosphate (TCEP) ... was tested for its effects on fertility and reproduction in Swiss CD-1 mice according to the Continuous Breeding Protocol. It was administered via gavage. Based on results of previous data and a dose-finding study, 175, 350, and 700 mg/kg bw where chosen to investigate effects on fertility and reproduction. Male and female mice (F0) were continuously exposed for a 7-day precohabitation and a 98-day cohabitation period (Task 2). Male and female body weights in Task 2 were within 10% of the control body weights. The water consumption values in all three treated groups were similar to the control values. In the F0 generation, TCEP decreased the number of litters/pair and the number of live pups/litter. Task 3, designed to determine the affected sex, showed that both sexes were adversely affected but the males were relatively more sensitive. All sperm endpoints (concn, motility and % abnormal) were adversely affected. The F1 pups from the last litter in the control and all three treated groups were weaned. Due to poor fertility in the 700 mg/kg/day dose group, only one F0 pair delivered a litter in the holding period (after the cohabitation phase). None of these pups survived to postnatal day 4. Although the pregnancy index for F1 mice in the 350 mg/kg dose group was not significantly decreased, in Task 4 that group delivered fewer pups/litter and both groups of TCEP-exposed mice had fewer males/litter than did controls. These data document changes in fertility in the presence of altered kidney weights, indicating that TCEP is not a selective reproductive toxicant. Nonetheless, this study clearly shows that TCEP is a reproductive toxicant in both generations of Swiss CD-1 mice and produces changes at doses as low as 175 mg/kg/day. [R37] ADE: *MATERIAL DOES NOT APPEAR TO BE ABSORBED THROUGH SKIN ... . [R26, 1924] *The distribution and excretion of C14-labelled TCEP in 5 wk old male Wistar rats orally dosed with 50 umol/kg bw /was studied/. The label was concn by various tissues, especially the liver and kidney, during the first 6 hr following admin and then rapidly decr. Most of the label was excreted by 24 hr and by 168 hr < 1% remained in tissues. Urine accounted for 96%, feces for 6%, and expired air for 2% of the label. [R28] *In a study on male B6C3F1 mice, more than 70% of an oral dose of 175 mg C14-labelled TCEP/kg bw was excreted in urine within 8 hr. [R28] *Male and female Fischer-344 rats were gavaged with C14-labelled TCEP at 0, 175, 350 or 700 mg/kg bw. Plasma concn of TCEP and its metabolites in rats dosed at 175 mg/kg peaked by 30 min. Concn were higher in females at the peak but by 4 hr there were no sex differences. TCEP concn in the hippocampus, the site of the major lesions, were no higher than in other brain tissues and there was no sex differences. [R28] *Urinary elimination of TCEP in rats was not incr by 9 daily doses of 175 mg/kg, indicating that TCEP is not capable of inducing its own metabolism. [R38] *To investigate the pharmacokinetics of tris(2-chloroethyl) phosphate, awake male and female and anesthetized male rats received 20 mg drug; blood samples were taken frequently and analyzed using conventional sampling/detection methods and in vivo microdialysis coupled with tandem MS technique. No differences in the pharmacokinetics of tris(2-chloroethyl) phosphate in male and female rats was demonstrated; however, the free drug in plasma at early time points differed between the 2 methods. [R39] METB: *The hepatic microsomal fraction from male rats, but not female rats, metabolized TCEP. Liver slices and blood plasma, however, of both sexes metabolized the cmpd, demonstrating that at least part of the metabolism is extramicrosomal. Liver slices and microsomes from both male and female humans metabolized TCEP, but plasma and whole blood did not. [R28] *Identified urinary metabolites of TCEP in mice were bis(2-chloroethyl)carboxymethyl phosphate, bis(2-chloroethyl)hydrogen phosphate and bis(2-chloroethyl)2-hydroxyethyl phosphate glucuronide. [R28] ACTN: *The present study was conducted to clarify the acute effect of tris(2-chloroethyl)phosphate, an organophosphate flame-retardant, on spontaneous ambulatory activity in male ICR mice and to examine the neurochemical mechanism of this effect. Single dose administration of 200 mg/kg ip of tris(2-chloroethyl)phosphate increased ambulatory activity in ICR mice. Neither the nicotinic cholinergic antagonist mecamylamine nor the muscarinic cholinergic antagonist scopolamine affected the ambulatory activity response to tris(2-chloroethyl)phosphate. On the other hand, the benzodiazepine agonist diazepam, the GABAA agonist muscimol and the GABAB agonist baclofen all attenuated the effect of tris(2-chloroethyl)phosphate. Diazepam and muscimol blocked the increase of ambulatory activity within the first 10 min after administration of tris(2-chloroethyl)phosphate. These drugs did not attenuate the ambulatory activity-increasing effect of scopolamine, suggesting that the mechanism of tris(2-chloroethyl)phosphate action is distinct from that of scopolamine. Muscimol and baclofen did, but diazepam did not, inhibit the ambulatory activity increasing effect of the dopaminergic agonist apomorphine, suggesting that dopamine is involved in the control of ambulatory activity, and that GABA can affect ambulatory activity through interaction with dopaminergic neurons. These results suggest that tris(2-chloroethyl)phosphate acts as a GABA antagonist and not as a cholinergic agonist, and that tris(2-chloroethyl)phosphate increases ambulatory activity in ICR mice through a GABAergic mechanism. [R40] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Tris(2-chloroethyl) phosphate's production and use as a flame retardant and fire-resistant cellulose ester plasticizer may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 6.125X10-2 mm Hg at 25 deg C indicates tris(2-chloroethyl) phosphate will exist solely as a vapor in the ambient atmosphere. Vapor-phase tris(2-chloroethyl) phosphate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 17 hrs. If released to soil, tris(2-chloroethyl) phosphate is expected to have high mobility based upon an estimated Koc of 140. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 3.3X10-6 atm-cu m/mole. If released into water, tris(2-chloroethyl) phosphate is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Biodegradation is not expected to be an important environmental fate process in soil or aquatic ecosystems based on a 5% BOD using the Japanese MITI test. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 19 and 143 days, respectively. Generally, phosphate esters are resistant to hydrolysis in acid or neutral waters. The estimated base-catalyzed hydrolysis half-life of tris(2-chloroethyl) phosphate is 100 days at environmental pH. A BCF range of 0.3 to 3.3 suggests that bioconcentration in aquatic organisms is low. Occupational exposure to tris(2-chloroethyl) phosphate may occur through inhalation and dermal contact at workplaces where tris(2-chloroethyl) phosphate is produced or used. Monitoring data indicate that the general population may be exposed to tris(2-chloroethyl) phosphate via ingestion of food and drinking water contaminated with this compound and other products containing tris(2-chloroethyl) phosphate. (SRC) ARTS: *Tris(2-chloroethyl) phosphate's production and use as a flame retardant and fire-resistant cellulose ester plasticizer(1) may result in its release to the environment through various waste streams(SRC). [R41] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a log Kow of 1.44(6) and a regression-derived equation(3), indicates that tris(2-chloroethyl) phosphate is expected to have high mobility in soil(SRC). Volatilization of tris(2-chloroethyl) phosphate from moist soil surfaces may be an important fate process(SRC) given an estimated Henry's Law constant of 3.3X10-6 atm-cu m/mole(SRC), derived from its vapor pressure, 6.125X10-2 mm Hg(4), and water solubility, 7,000 mg/l(2). Tris(2-chloroethyl) phosphate is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). Biodegradation is not expected to be an important environmental fate process in soil based on a 5% BOD using the Japanese MITI test(5). [R42] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 140(SRC), determined from a log Kow of 1.44(7) and a regression-derived equation(3), indicates that tris(2-chloroethyl) phosphate is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 2.55X10-8 atm-cu m/mole(SRC), derived from its vapor pressure, 6.125X10-2 mm Hg(4), and water solubility, 7,000 mg/l(2). Generally, phosphate esters are resistant to hydrolysis in acid or neutral waters(6). The estimated base-catalyzed hydrolysis half-life of tris(2-chloroethyl) phosphate is 100 days at environmental pH(8). According to a classification scheme(5), a BCF range of 0.3-3.3(7), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation is not expected to be an important environmental fate process in aquatic ecosystems based on a 5% BOD using the Japanese MITI test(7). [R43] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), tris(2-chloroethyl) phosphate, which has a vapor pressure of 6.125X10-2 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase tris(2-chloroethyl)phosphate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 17 hrs(SRC), calculated from its rate constant of 2.2X10-11 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). [R44] BIOD: *AEROBIC: Tris(2-chloroethyl) phosphate, present at 100 mg/l, reached 4% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). Tris(2-chloroethyl) phosphate was for the most part resistant to biodegradation by activated sludge(2). Therefore this compound is not expected to biodegrade rapidly. [R45] ABIO: *The rate constant for the vapor-phase reaction of tris(2-chloroethyl) phosphate with photochemically-produced hydroxyl radicals has been estimated as 2.2X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 17 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Phosphoric acid esters slowly hydrolyze in water at pH of 7 and 25 deg C(2). For example triethylphosphate ((EtO)3PO) has a hydrolysis half-life of 5.5 yr(2). The half-life of tris(2-chloroethyl) phosphate has been estimated to be 100 days and the chlorine may hydrolyze moderately rapid with a half-life of 38 days based on the half-life of ethyl chloride(3). Generally, phosphate esters are resistant to hydrolysis in acid or neutral waters(4). [R46] BIOC: *A BCF of 2.2 was determined for tris(2-chloroethyl) phosphate using killifish (Oryzias latipes) exposed to the chemical in static water for 72 hr(1). A BCF of 0.9 was obtained for goldfish (Carassius auratus) under identical conditions(1). BCF's of 1.1 and 1.3 were determined using killifish exposed to 12.7 ppm of tris(2-chloroethyl) phosphate for 5 days and 2.3 ppm for 11 days, respectively, in a continuous flow water system(2). A BCF range of 0.30 to 3.3 was observed using killifish exposed to 20 ug/l test compound(3). According to a classification scheme(4), these BCF values suggest the potential for bioconcentration in aquatic organisms is low(SRC). [R47] KOC: *The Koc of tris(2-chloroethyl) phosphate is estimated as 140(SRC), using a log Kow of 1.44(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that tris(2-chloroethyl) phosphate is expected to have high mobility in soil. [R48] VWS: *The Henry's Law constant for tris(2-chloroethyl)phosphate is estimated as 3.3X10-6 atm-cu m/mole(SRC) derived from its vapor pressure, 6.125X10-2 mm Hg(1), and water solubility, 7000 mg/l(2). This Henry's Law constant indicates that tris(2-chloroethyl) phosphate is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 19 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 143 days(SRC). Tris(2-chloroethyl) phosphate's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). Tris(2-chloroethyl) phosphate is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R49] WATC: *GROUNDWATER: A study identified the effects of dune soil on the removal and modification of organic compounds present in the water of the river Rhine (Netherlands)(1). Tris(2-chloroethyl) phosphate increased in concn 400% which was attributed to a zone formation phenomenon during passage through the soil(1). A chemical analysis of tap water from three municipal water plants using bank-filtrated Rhine (Netherlands) water reported tris(2-chloroethyl) phosphate at maximum concns of 100 ng/l(2). [R50] *DRINKING WATER: In a 1980 analysis of drinking water supplies from 12 Great Lakes municipalities in Canada, tris(2-chloroethyl) phosphate was detected in all but one water supply at concns ranging from 0.4 to 8.3 ng/l during the mo of January and from 0.3 to 13.8 ng/l for August(1). A 1978 analysis of the water from six eastern Ontario municipal water treatment plants showed drinking water concns of tris(2-chloroethyl) phosphate between 0.3 and 9.2 ng/l(2). Tris(2-chloroethyl) phosphate was detected at levels between 0.3 and 52.0 ng/l for 22 of 29 municipal water supplies representing the major urban centers across Canada(3). The mean concn of tris(2-chloroethyl) phosphate of water supplies among drainage basins ranged from 0.2 ng/l at the Atlantic and Pacific Sea Boards to 11 ng/l for St. Lawrence River(3). Whereas the average level according to source measured 8.7, 1.7, and 0.1 ng/l for rivers, lakes and wells, respectively(3). A chemical analysis of tap water from three municipal water plants using bank-filtrated Rhine (Netherlands) water reported tris(2-chloroethyl) phosphate at maximum concns of 100 ng/l(4). Tris(2-chloroethyl) phosphate was detected in all of the Italian water samples collected from the River Po at Turin and Ferrara and Lake Como at Como between September 1986 and February 1987 at concns ranging from < 10 to 40 ng/l(5). [R51] *SURFACE WATER: Tris(2-chloroethyl) phosphate was detected in 14 of 16 water samples taken from several rivers in Kitakyushu City, Japan during Aug 1980 at levels ranging from 17 to 347 ng/l(1). River waters in Japan were found to contain small amounts of tris(2-chloroethyl) phosphate(2,3). Tris(2-chloroethyl) phosphate was detected in all of the water samples collected from the River Po at Pontelagoscuro, Italy and Adriatic Seac at Lido delle Nazioni, Italy, and Marina di Ravenna, Italy between April and August 1988 at concns ranging from < 10 to 293 ng/l(4). [R52] *RAIN/SNOW/FOG: Tris(2-chloroethyl) phosphate was detected in rain sample collected from Mace Head, Republic of Ireland in March 1996; in all snow samples collected from the city of Gdansk, Poland in January 1996, lakes Jarlunden, Stora Rangen, and Ovre Follingen, Sweden and Queen Maud's Land, Antarctica in December 1996 to February 1997 and in ice sample collected from the Marna Glacier in northern Sweden(1). The amount of tris(2-chloroethyl) phosphate detected ranged from 1 - 21 ng/l(1). [R53] EFFL: *Ground water testwells down-gradient from the land application of primary wastewater effluent at Fort Devens, MA showed 0.28 and 0.81 ug/l of tris(2-chloroethyl) phosphate(1). Sewage sludge in Japan was found to contain small amounts of tris(2-chloroethyl) phosphate(2). Tris(2-chloroethyl) phosphate was in the leachate from the Osaka North Port Sea-Based Solid Waste Disposal Site at concns ranging from 0.4 to 300 ug/l(1). [R54] SEDS: *SEDIMENTS: Tris(2-chloroethyl) phosphate was detected in 5 of 6 samples taken from river and sea sediments in the vicinity of Kitakyushu City, Japan during Aug 1980 at levels ranging from 13 to 28 ng/l(1). [R55] ATMC: *URBAN/SUBURBAN: Atmospheric aerosols in Japan were found to contain minute amounts of tris(2-chloroethyl) phosphate(1). The compound was detected at concns of 2-5 ng/cu m in ambient air samples from Kitakyusu, Japan(2). [R56] *INDOOR: Tris(2-chloroethyl) phosphate was found in the house dust in almost all of the 59 rooms investigated in a pilot study in Germany, with a median concn of 0.1 ug/g(1). [R57] FOOD: *Tris(2-chloroethyl) phosphate was found in fruit and fruit juice samples for infants at an average concns of 0.0002 ppm, with a range from 0 to 0.002 ppm(1) at 10 different U.S. cities during the 1979 fiscal year(1). In a ten-year study of ready to eat foods (1982-1991) tris(2-chloroethyl) phosphate was found in peaches and purple plums at concns 113 to 7 ng/g(2). [R58] PFAC: PLANT CONCENTRATIONS: *Tris(2-chloroethyl) phosphate was found in the needles of Pinus ponderosa in the samples collected from the foothills of Sierra Nevada in 1993-94 at concns ranging from < 2.5 to 1950 ng/g(1). [R59] FISH/SEAFOOD CONCENTRATIONS: *Fish and shellfish captured in Okayama Prefecture (Japan) contained less than 0.005-0.019 ug/g of tris(chloroethyl) phosphate(1). [R60] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 5,073 workers (578 of these estimated to be female) are potentially exposed to tris(chloroethyl) phosphate in the US(1). Occupational exposure to tris(chloroethyl) phosphate may occur through inhalation and dermal contact with this compound at workplaces where tris(chloroethyl) phosphate is produced or used(SRC). Monitoring data indicate that the general population may be exposed to tris(chloroethyl) phosphate ingestion of food and drinking water contaminated with this compound and other products containing tris(chloroethyl) phosphate(SRC). [R61] AVDI: *The average daily intake for infants of tris(2-chloroethyl)phosphate was found to be 0.0287 ug through fruit and fruit juice(1). The average daily intake for toddlers of tris(2-chloroethyl)phosphate was found to be 0.385 ug through oils and fats(2). The daily intake per unit of body weight for infants and toddlers of tris(2-chloroethyl)phosphate in 1979 was found to be 0.016 and 0.009 ug/kg, respectively; and for infants in 1980 was 0.004 ug/kg(1); and for toddlers in 1981-82 was 0.028 ug/kg(2). The average daily intake for adults of tris(2-chloroethyl)phosphate was found to be 1.73 ug through meat, fish and poultry(3). The daily intake per unit of body weight for adults of tris(2-chloroethyl)phosphate in both 1979 and 1981-82 was found to be 0.003 ug/kg(3). [R62] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Ethanol-, 2-chlorophosphate is included on this list. [R63] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) phosphate in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.5 Technical Report Series No. 391 (1991) NIH Publication No. 91-2846 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V10 (1993) 981 R2: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 956 R3: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 335 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 10(80) 401 R6: Toy ADF, Walsh EN; Phosphorus Chemistry in Everyday Living 2nd ed p.155 (1987) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 (1999) 1543 R8: SRI R9: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-158 R10: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 926 R11: Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-109 (1992) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 (1990) 110 R13: Muir DCG; in Handbook of Environmental Chemistry. Germany: Springer-Verlag 3: 41-66 (1984) R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 421 R15: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V3 2678 R16: Dobry A, Keller R; J Phys Chem 61: 1448-9 (1957) R17: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R18: Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) R19: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R20: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1194 R21: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.55(1998) R22: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R23: ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.79 (1983) R24: Environmental Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl) Phosphate pp. 52-53 (1998) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labor Organisation and the World Health Organization. R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1546 (1999) R26: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R27: Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) Phosphate in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 391 (1991) NIH Publication No. 91-2846 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R28: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.65 (1998) R29: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.67 (1998) R30: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.68 (1998) R31: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.70 (1998) R32: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.71 (1998) R33: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.72 (1998) R34: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.74 (1998) R35: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.75 (1998) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1545 (1999) R37: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Tris(2-chloroethyl)phosphate (CAS No. 115-96-8) in CD-1 Swiss Mice, NTP Study No. RACB92040 (June 1991) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R38: WHO; Environ Health Criteria 209: Flame Retardants: Tris(chloropropyl) Phosphate and Tris(2-chloroethyl)Phosphate p.66 (1998) R39: Dix K et al; J Pharm Sci 83 (Nov): 1622-9 (1994) R40: Umezu T et al; Toxicol Appl Pharmacol 148 (1): 109-16 (1998) R41: (1) Weil ED; Kirk-Othmer Encycl Chem Tech 4th ed. NY, NY: Wiley 10: 981 (1993) R42: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Muir DCG; in Handbook of Environmental Chemistry. Germany: Springer-Verlag 3: 41-66 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-5 (1990) (4) Dobry A, Keller R; J Phys Chem 62: 1448-9 (1957) (5) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-109 (1992) R43: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Muir DCG; in Handbook of Environmental Chemistry. Germany: Springer-Verlag 3: 41-66 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-5, 15-1 to 15-29 (1990) (4) Dobry A, Keller R; J Phys Chem 62: 1448-9 (1957) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Muir DCG; The Handbook of Environmental Chemistry; Berlin, Germany: Springer-Berlag 3: 41-66 (1984) (7) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-109 (1992) (8) Brown SL et al; Research Program on Hazard Priority Ranking of Manufactured Chemicals (Chemicals 61-79) NTIS PB 263-164. Menlo Park CA, Stanford Res Inst (1975) R44: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Dobry A, Keller R; J Phys Chem 62: 1448-9 (1957) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R45: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-109 (1992) (2) Ishikawa S et al; Suishitsu Odaku Kenkyu 8: 799-807 (1985) R46: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (3) Brown SL et al; Research Program on Hazard Priority Ranking of Manufactured Chemicals (Chemicals 61-79) NTIS PB 263-164. Menlo Park CA, Stanford Res Inst (1975) (4) Muir DCG; The Handbook of Environmental Chemistry; Berlin, Germany: Springer-Berlag 3: 41-66 (1984) R47: (1) Sasaki K et al; Bull Environ Contam Toxicol 27: 775-82 (1981) (2) Sasaki K et al; Bull Environ Contam Toxicol 28: 752-9 (1982) (3) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-109 (1992) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) R48: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 p. 2-109 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R49: (1) Dobry A, Keller R; J Phys Chem 62: 1448-9 (1957) (2) Muir DCG; in Handbook of Environmental Chemistry. Germany: Springer-Verlag 3: 41-66 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R50: (1) Piet GJ et al; Studies Environ Sci 17: 557-64 (1981) (2) Piet GJ, Morra CF; Artificial Ground Water Recharge (Water Resources Engineering Series) pp. 31-42 (1983) R51: (1) Williams DT et al; Chemosphere 11: 263-76 (1982) (2) LeBell GL et al; J Assoc Off Anal Chem 64: 991-8 (1981) (3) Williams DT, LeBell GL; Bull Environ Contam Toxicol 27: 450-7 (1981) (4) Piet GJ, Morra CF; Artificial Ground Water Recharge (Water Resources Engineering Series) pp. 31-42 (1983) (5) Galassi S et al; Enivon Toxic Chem 8: 109-116 (1989) R52: (1) Ishikawa S et al; Water Res 19: 119-25 (1985) (2) Kenmochi U et al; Okayama-Ken Kankyo Hoken Senta Nenpo 5: 167-75 (1981) (3) Kenmotsu K et al; Okayama-Ken Kankyo Hoken Senta Nenpo 9: 160-9 (1985) (4) Galassi S ; Toxic Environ Chem 31-32: 291-296 (1991) R53: (1) Laniewski K et al; Environ Sci Technol 32: 3935-3940 (1998) R54: (1) Hutchins SR et al; Water Res 18: 1025-36 (1984) (2) Kenmochi U et al; Okayama-Ken Kankyo Hoken Senta Nenpo 5: 167-75 (1981) (3) Kawagoshi Y, Fukunaga I; Kankyo Kagaku 4: 797-804 (1994) R55: (1) Ishikawa S et al; Water Res 19: 119-25 (1985) R56: (1) Kenmochi U et al; Okayama-Ken Kankyo Hoken Senta Nenpo 5: 167-75 (1981) (2) IARC; Some flame retardants and textile chemicals and exposures in the textile manufacturing industry. Lyon, France: Inter Agency Res Cancer 48: 111 (1990) R57: (1) Sagunski H et al; Unweltmed Forsch Prax 2: 185-192 (1997) R58: (1) Gartrell MJ et al; J Assoc Off Anal Chem 68: 1163-83 (1985) (2) Rogers WM et al; J AOAC Intern 78: 185-192 (1995) R59: (1) Aston LS et al; Bull Environ Contam Toxicol 57: 859-866 (1996) R60: (1) Kenmochi U et al; Okayama-Ken Kankyo Hoken Senta Nenpo 5: 167-75 (1981) R61: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R62: (1) Gartrell MJ et al; J Assoc Off Anal Chem 68: 1163-83 (1985) (2) Gartrell MJ et al; J Assoc Off Anal Chem 69: 123-45 (1986) (3) Gartrell MJ et al; J Assoc Off Anal Chem 69: 146-61 (1986) R63: 40 CFR 716.120 (7/1/2000) RS: 54 Record 178 of 1119 in HSDB (through 2003/06) AN: 2587 UD: 200302 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-CARBAMATE- SY: *CARBAMIC-ACID,-METHYL-ESTER-; *METHYLURETHAN-; *METHYLURETHANE-; *NCI-C55594-; *URETHYLANE- RN: 598-55-0 MF: *C2-H5-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM SILVER OR MERCURICYANATE WITH H2S AND METHANOL: BIRKENBACH, KOLB, BER 68, 901 (1953). FROM UREA AND METHANOL: GERMAN PATENT 753,127 (1940 TO IG FARBENIND). [R1] *IT CAN...BE PREPD BY REACTION OF AMMONIA WITH METHYL CHLOROFORMATE ... AND THIS METHOD IS BELIEVED TO HAVE BEEN USED COMMERCIALLY. [R2] MFS: *KEWANEE INDUST, INC, MILLMASTER ONYX CORP, SUBSID, MILLMASTER CHEM CO, DIV, BERKELEY CHEM DIV, BERKELEY HEIGHTS, NJ [R3] *Aldrich Chemical Company, Inc., Hq, 1001 West Saint Paul, Milwaukee, WI 53233, (414) 273-3850 [R4] USE: *USED IN EUROPE AS PHARMACEUTICAL INTERMEDIATE [R2] *An intermediate in the manufacture of dimethylol methyl carbamate-based resins, which are used in the textile industry as durable-press fabric finishes for polyester/cotton blends. [R2] CPAT: *PROBABLY 100% AS A CHEM INT FOR DIMETHYLOL METHYL CARBAMATE-BASED RESINS AS A DURABLE-PRESS FABRIC FINISH (1976) [R3] PRIE: U.S. PRODUCTION: *(1972) 3.5X10+8 GRAMS (EST) [R3] *(1975) PROBABLY GREATER THAN 9.1X10+5 GRAMS [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE CRYSTALS [R1]; *NEEDLES [R5] BP: *177 DEG C [R1] MP: *52-54 DEG C [R1] MW: *75.07 [R1] DEN: *1.1361 g/cu cm at 56 deg C [R6] OWPC: *log Kow = -0.66 [R7] SOL: *SOL IN WATER: 217 PARTS IN 100 @ 11 DEG C [R5]; *SOL IN ETHANOL: 73 PARTS IN 100 @ 15 DEG C; SOL IN ETHER [R5]; *In water, 6.91X10+5 mg/l at 15.5 deg C [R8] SPEC: *INDEX OF REFRACTION: 1.4125 @ 56 DEG C/D [R5]; *SADTLER REF NUMBER: 12994 (IR, PRISM) [R9]; *IR: 607 (Sadtler Research Laboratories IR Grating Collection) [R10, p. V1 396]; *NMR: 5240 (Sadtler Research Laboratories Spectral Collection) [R10, p. V1 396]; *MASS: 88 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R10, p. V1 396]; *MASS: 53 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R10, p. V1 848] OCPP: *Freely sublimes at room temperature [R1] *These compounds are all hydrolyzed using 5 M sodium hydroxide solution, although the reaction times vary. Methyl carbamate is hydrolyzed to methanol and carbamic acid and urethane /ethyl carbamate/ is hydrolyzed to ethanol and carbamic acid. ... Carbamic acid decomposes to carbon dioxide and ammonia ... In all cases destruction is greater than 99% and good accountances are obtained for the products ... . [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *This intermediate /N-carbomethoxymethylimino phosphoryl chloride/ (or its ethyl homolog), produced during prepn of phosphoryl dichloride isocyanate from interaction of phosphorus pentachloride and methyl (or ethyl) carbamate, is unstable. Its decomposition to the required product may be violent or explosive unless moderated by the presence of a halogenated solvent. [R12] DCMP: *When heated to decomposition it emits toxic fumes of NOx. [R13] SSL: *Freely sublimes even at room temperature. [R1] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R14] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Esters and related compounds/ [R15] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R15] NTOX: *TWO GROUPS OF 27 AND 30 7-WK-OLD MALE HALL MICE WERE GIVEN SINGLE INJECTION...OF 27 MEQ/KG BODY WT METHYL CARBAMATE. 18 HR BEFORE TREATMENT...2ND GROUP RECEIVED AN APPLICATION OF 0.25 ML OF A 0.075% CROTON OIL SOLN IN ACETONE OVER THE WHOLE AREA OF THE SKIN OF THE BACK. 3 WK LATER, BOTH GROUPS WERE GIVEN A COURSE OF 32 WEEKLY TREATMENTS WITH CROTON OIL, EACH APPLICATION CONSISTING OF 0.24 ML OF AN ACETONE SOLN, THE CONCN OF WHICH WAS 0.075% DURING THE FIRST 18 WK AND WAS THEN INCR TO 0.15% FOR A FURTHER 14 WK. A CONTROL GROUP OF 90 MICE RECEIVED CROTON OIL ALONE. ...INCIDENCES OF SKIN TUMORS, HEPATOMAS, LIVER HEMANGIOMAS, LUNG ADENOMAS AND LEUKEMIAS WERE SIMILAR IN 2 EXPTL GROUPS AND CONTROLS RECEIVING CROTON OIL ALONE. [R16] *...RANDOM-BRED MALE MICE RECEIVED 3 SC INJECTIONS OF 1 MG/KG BODY WT METHYL CARBAMATE @ 2-DAY INTERVALS, AND WERE OBSERVED FOR 3 MO...3/29 MICE KILLED HAD LUNG ADENOMAS, COMPARED WITH 3/22 CONTROLS AND WITH 23/27 MICE GIVEN 1 MG/KG BODY WT URETHANE PLUS 1 MG/KG BODY WT METHYL CARBAMATE. [R17] *...RANDOM-BRED MALE MICE RECEIVED...3 SC INJECTIONS OF 0.1 MG/KG BODY WT METHYL CARBAMATE /@ 2-DAY INTERVALS/ AND WERE OBSERVED FOR 6 MO. ...2/26 MICE KILLED HAD LUNG ADENOMAS, COMPARED WITH 0/26 CONTROLS AND WITH 6/28 MICE GIVEN URETHANE PLUS METHYL CARBAMATE. [R17] *...46 10-12-WK OLD STRAIN A MICE...RECEIVED 13 WEEKLY IP INJECTIONS OF 0.5 MG/G RECRYSTALLIZED METHYL CARBAMATE IN WATER... LUNG ADENOMAS...IN 16%..WHEREAS 17% OF 141 UNTREATED CONTROLS...DEVELOPED...TUMORS. [R17] *...20 7-9 WK-OLD MALE 'S' MICE RECEIVED 15 WEEKLY CUTANEOUS APPLICATIONS OF 25% SOLN OF METHYL CARBAMATE IN ACETONE (TOTAL DOSE, 1.12 G). 3 DAYS AFTER START OF...TREATMENT, 18 WEEKLY APPLICATIONS OF CROTON OIL (0.3 ML OF A 0.5% SOLN IN ACETONE) WERE GIVEN. ...1/18 DEVELOPED SKIN TUMOR, COMPARED WITH 1/20 CONTROLS GIVEN CROTON OIL ONLY. IN ADDN, 7 /TREATED/ MICE...HAD TOTAL OF 12 LUNG ADENOMAS. NO CONTROL GROUP KILLED AT THE SAME TIME IS REPORTED. [R16] *METHYL CARBAMATE DID NOT INDUCE INCR IN NUMBER OF STREPTOMYCIN-INDEPENDENT MUTATIONS IN ESCHERICHIA COLI...AND NO REVERSE MUTATIONS WERE RECORDED IN BACILLUS SUBTILIS...METABOLIC ACTIVATION SYSTEMS WERE NOT USED... [R18] *IP DOSE OF 200 OR 1000 MG/KG CAUSED NO INCR OF DOMINANT LETHALS IN MICE. IN PRESENCE OF AROCLOR-INDUCED RAT LIVER MICROSOMES, NO REVERSE MUTATIONS OCCURRED IN SALMONELLA TYPHIMURIUM STRAINS TA100, TA98, TA1535 OR TA1537. [R18] *METHYL CARBAMATE WAS NOT MUTAGENIC IN SALMONELLA TYPHIMURIUM STRAINS TA1535, TA1536, TA1537, TA1538, TA98, AND TA100 WITH OR WITHOUT S9 LIVER MICROSOMAL MIXTURE FROM AROCLOR 1254 TREATED MALE SPRAGUE-DAWLEY RATS. [R19] *THE METHYL ESTER OF CARBAMIC ACID WAS EXAMINED FOR ITS ABILITY TO INDUCE SISTER CHROMATID EXCHANGES (SCES) IN ALVEOLAR MACROPHAGES, BONE MARROW, AND REGENERATING LIVER CELLS OF C57BL/6JXDBA/2JF1 MICE. THE NONCARCINOGENIC METHYL CARBAMATE WAS INACTIVE IN THE SCE ASSAY. [R20] *FEMALE B6C3F1 HYBRID MICE (5-7 WK OF AGE) WERE GIVEN METHYL CARBAMATE OVER A 2 WEEK PERIOD AND EXAMINED FOR ALTERATIONS IN VARIOUS IMMUNOLOGICAL PARAMETERS. EXPOSURE TO THE NONCARCINOGEN DID NOT CAUSE ANY ALTERATIONS IN THESE PARAMETERS. [R21] *... Conclusions: Under the conditions of these ... 2 yr gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats given methyl carbamate as indicated by incr incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas. There was no evidence of carcinogenic activity for male and female B6C3F1 mice given methyl carbamate at doses of 500 or 1,000 mg/kg. ... [R22] NTXV: *LD50 MICE ORAL 6200 MG/KG; [R18] NTP: *... 2 yr studies of methyl carbamate were conducted by administering 0, 100, or 200 mg/kg methyl carbamate in distilled water by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex for 103 weeks. Groups of 50 B6C3F1 mice of each sex were administered 0, 500, or 1,000 mg/kg methyl carbamate on the same schedule. Additional groups of 30 rats of each sex were administered 0 or 400 mg/kg methyl carbamate, and additional groups of 30 mice of each sex were administered 0 or 1,000 mg/kg methyl carbamate in distilled water by gavage, 5 days per week. ... Conclusions: Under the conditions of these ... 2 yr gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats given methyl carbamate as indicated by incr incidences of hepatocellular neoplastic nodules and hepatocellular carcinomas. There was no evidence of carcinogenic activity for male and female B6C3F1 mice given methyl carbamate at doses of 500 or 1,000 mg/kg. ... [R22] ADE: *RATS INJECTED IP WITH METHYL CARBAMATE...EXCRETED...CARBAMATE...IN URINE... [R18] *DNA BINDING OF...(14)C-METHYL CARBAMATE LABELED IN METHYL GROUP HAS BEEN INVESTIGATED IN MOUSE LIVER AND KIDNEY. ... INCORP OF (3)H-METHYL CARBAMATE INTO LIVER-CELL RNA HAS BEEN EXAMINED IN MICE... [R18] INTC: *Male CF-1 mice were treated with urethane (0, 0.5, 1.0, 1.5, and 2 g/kg; ip) and 18 hr later hepatic metallothionein concentrations were determined with the cadmium hemoglobin radioassay. Urethane (1 g/kg and higher) significantly increase hepatic metallothionein levels, resulting in a 14 fold increase after 2 g/kg. Time course experiments indicated that metallothionein levels were increased significantly at 6 hr after administration of urethane (1.5 g/kg) and reached a maximum between 12 and 24 hr. Gel filtration, anion exchange chromatography, and UV spectral analysis were used to characterize the protein induced by urethane. Pretreatment with actinomycin-D prevented induction of metallothionein by urethane. Administration of equimolar dosages (20 mmol/kg) of urethane, N-hydroxyurethane, and methyl carbamate indicated that urethane and N-hydroxyurethane induce metallothionein but that methyl carbamate does not. Metallothionein induction was also not observed with (pentobarbital and phenobarbital). Urethane induces hepatic metallothionein but this effect is not related to its anesthetic action, nor is it a common property of all carbamates. [R23] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl carbamate may be released to the environment in various waste streams from its production and use as an intermediate in the manufacture of dimethylol methyl carbamate-based resins. If released to the atmosphere, methyl carbamate is expected to exist solely as a vapor in the ambient atmosphere based on an estimated vapor pressure of 0.56 mm Hg at 25 deg C. Vapor-phase methyl carbamate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 4.8 days. If released to soil, an estimated Koc of 10 suggests that methyl carbamate is expected to have very high mobility. However, methyl carbamate was observed to adsorb onto the clay mineral montmorillonite. Exchangeable cations associated with montmorillonite may catalyze the hydrolysis of methyl carbamate in moist soils. Volatilization from moist soil surfaces is not expected to be an important fate process based on an estimated Henry's Law constant of 4.0X10-8 atm-cu m/mole. Biodegradation of methyl carbamate in soil may be important, based upon its biodegradation in river and sea water; methyl carbamate was degraded 19 and 18% in river and seawater, respectively, over a three day period. If released into water, methyl carbamate is not expected to adsorb to suspended solids and sediment in the water column based on its estimated Koc. Volatilization from water surfaces is not expected to occur based on the estimated Henry's Law constant of this compound. The potential for bioconcentration in aquatic organisms is low based on an estimated BCF of 0.19. Purely aliphatic carbamates are expected to be resistant to hydrolysis under environmental conditions; hydrolysis half-lives of 3300 and 330 years at pHs 7 and 8, respectively, were estimated for methyl carbamate. Occupational exposure to methyl carbamate may occur through inhalation and dermal contact with this compound at workplaces where methyl carbamate is produced or used. Limited monitoring data indicate the general population may be exposed to methyl carbamate via inhalation of ambient air and ingestion of foods. (SRC) NATS: *METHYL CARBAMATE HAS BEEN ISOLATED FROM 4 SALSOLA SPECIES... [R2] ARTS: *Methyl carbamate's production and use as an intermediate in the manufacture of dimethylol methyl carbamate-based resins(1) may result in its release to the environment through various waste streams(SRC). [R24] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 10(SRC), determined from a measured log Kow of -0.66(2) and a recommended regression-derived equation(3), indicates that methyl carbamate is expected to have very high mobility in soil(SRC). However, methyl carbamate was determined to adsorb onto the clay mineral montmorillonite(4). Volatilization of methyl carbamate will not be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 4.0X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Hydrolysis of methyl carbamate in moist soils may be catalyzed by adsorption to Na+, Mg2+, Al3+, and Cu2+ montmorillonites(4,SRC). Biodegradation of methyl carbamate in soil may be important(SRC), based on its biodegradation in river and seawater(6). [R25] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 10(SRC), determined from a measured log Kow of -0.66(2) and a recommended regression-derived equation(3), indicates that methyl carbamate is not expected to adsorb to suspended solids and sediment in water(SRC). Methyl carbamate is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 4.0X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF value of 0.19(3,SRC), from a measured log Kow(2), suggests that bioconcentration in aquatic organisms is low(SRC). Methyl carbamate was degraded 19 and 18% in river and seawater, respectively, over a three day period(6). Purely aliphatic carbamates are expected to be resistant to hydrolysis under environmental conditions(7); hydrolysis half-lives of 3300 and 330 years at pH values of 7 and 8, respectively, were estimated for methyl carbamate(8,SRC). [R26] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methyl carbamate, which has an estimated vapor pressure of 0.56 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase methyl carbamate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 4.8 days(3,SRC). [R27] BIOD: *Methyl carbamate, present at a concentration of 100 ppm, was degraded 19 and 18% after three days cultivation in water from the Mino River and Akashi Beach, Japan, respectively(1). [R28] ABIO: *The rate constant for the vapor-phase reaction of methyl carbamate with photochemically-produced hydroxyl radicals has been estimated as 3.4X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 4.8 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Purely aliphatic carbamates are expected to be resistant to hydrolysis under environmental conditions(2). A base-catalyzed second-order rate constant of 6.6X10-5 L/mol-sec(SRC) was estimated using a structure estimation method(3); this corresponds to half-lives of 3300 and 330 years at pH values of 7 and 8, respectively(3,SRC). Hydrolysis in moist soils may be catalyzed by adsorption to Na+, Mg2+, Al3+, and Cu2+ montmorillonites(4,SRC). [R29] BIOC: *An estimated BCF value of 0.19 was calculated for methyl carbamate(SRC), using a measured log Kow of -0.66(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R30] KOC: *The Koc of methyl carbamate is estimated as approximately 10(SRC), using a measured log Kow of -0.66(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that methyl carbamate is expected to have very high mobility in soil(SRC). Methyl carbamate adsorbs on Na+, Mg2+, Al3+, and Cu2+ montmorillonites which catalyze the hydrolysis of methyl carbamate when equilibrated at room temperature and 100% relative humidity(4). [R31] VWS: *The Henry's Law constant for methyl carbamate is estimated as 4.0X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that methyl carbamate will be essentially nonvolatile from water surfaces(2,SRC). Methyl carbamate's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). [R32] FOOD: *Methyl carbamate was detected in trace amounts in red and white wines, sherry, whisky, and Armagnac(1). Methyl carbamate was detected in fruit brandy from France and Austria at an average concentration of 28 and 9 ug/kg, respectively(1). Methyl carbamate was detected in various breads, light toast, and dark toast at an average concentration of 3.0, 2.2, and 2.7 ug/kg, respectively(1). Trace levels, 1 to 4 ug/kg, of methyl carbamate were detected in various yogurt samples(1). Soy sauce samples contained minute amounts, 0.1 to 1.1 ug/kg, of methyl carbamate(1). [R33] RTEX: *Occupational exposure to methyl carbamate may occur through inhalation and dermal contact with this compound at workplaces where methyl carbamate is produced or used. Limited monitoring data indicate the general population may be exposed to methyl carbamate via inhalation of ambient air and ingestion of food. (SRC) MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *COLORIMETRIC METHODS HAVE BEEN USED TO DETERMINE METHYL CARBAMATE IN AIR @ SENSITIVITY OF 20 UG/L (BABINA, 1975, GIG I SANIT, 7, 76-77). THIN-LAYER AND CHROMATOGRAPHIC METHODS...ALSO USED FOR ITS DETERMINATION (KARAWYA ET AL, 1972, PHYTOCHEMISTRY, 11, 441-442; KNAPPE AND ROHDEWALD, 1966, Z ANALYT CHEM, 217, 110-113). [R17] *METHODS FOR CHROMATOGRAPHIC ANALYSIS OF CARBAMATES, INCL ALKYL CARBAMATES HAVE BEEN REVIEWED (FISHBEIN AND ZIELINSKI, CHROMAT REV, 9, 37-101, 1967). GAS CHROMATOGRAPHIC METHOD...FOR DETECTION OF UG AMT OF METHYL CARBAMATE IN MIXT OF ALKYL CARBAMATES...(NERY R, ANALYST, 94, 130-135 (1969)). [R2] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Methyl Carbamate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 328 (1987) NIH Publication No. 88-2584 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1032 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 152 (1976) R3: SRI R4: Aldrich Catalog of Fine Chemicals, 1996-1997, p. 974 (1996) R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 151 (1976) R6: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-109 R7: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 4 R8: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, Univ of Ariz - Tucson, AZ. PC Version (1992) R9: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-237 R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R11: Lunn, G., E.B. Sansone. Destruction of Hazardous Chemicals in the Laboratory. New York, NY: John Wiley and Sons, Inc. 1994. 96 R12: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 247 R13: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2202 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 66 (1987) R15: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 221 R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 154 (1976) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 153 (1976) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 155 (1976) R19: SIMMON VF; J NATL CANCER INST 62 (4): 893 (1979) R20: CHENG M ET AL; CANCER RES 41 (11, PART 1): 4489 (1981) R21: LUSTER MI ET AL; CLIN EXP IMMUNOL 50 (1): 223 (1982) R22: Toxicology and Carcinogenesis Studies of Methyl Carbamate in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 328 (1987) NIH Publication No. 88-2584 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R23: Brzeznicka EA et al; Toxicol Appl Pharmacol 87 (3): 457-63 (1987) R24: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency for Research on Cancer. Vol 12 p. 152 (1976) R25: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Kowalska M et al; Sci Total Environ 141: 223-40 (1994)(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (6) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) R26: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (7) Mabey WR et al; J Phys Chem Ref Data Vol 7, No. 2 p. 413 (1978) (8) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) R27: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R28: (1) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) R29: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mabey WR et al; J Phys Chem Ref Data Vol 7, No. 2 p. 413 (1978) (3) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (4) Kowalska M et al; Sci Total Environ 141: 223-40 (1994) R30: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R31: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc p 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Kowalska M et al; Sci Total Environ 141: 223-40 (1994) R32: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R33: (1) Sen NP et al; Food Chem 48: 359-66 (1993) RS: 27 Record 179 of 1119 in HSDB (through 2003/06) AN: 2590 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIMETHYL-METHYLPHOSPHONATE- SY: *DIMETHOXYMETHYLPHOSPHINE-OXIDE-; *DIMETHYL-METHANEPHOSPHONATE-; *DMMP-; *METHANEPHOSPHONIC-ACID-DIMETHYL-ESTER-; *PHOSPHONIC-ACID,-METHYL-,DIMETHYL-ESTER-; *PYROL-DMMP- RN: 756-79-6 MF: *C3-H9-O3-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF TRIMETHYL PHOSPHITE OR THE SODIUM SALT OF DIMETHYL HYDROGEN PHOSPHITE AND METHYL CHLORIDE [R1] MFS: +Akzo America, Inc, Akzo Chemicals Inc, Hq, 111 W 40th St, New York, NY 10018, (212) 382-5500; Akzo Chemical Division, 300 S Riverside Plaza, Chicago, IL 60606; Production site: Gallipolis Ferry, WV 25515 [R2] +Tenneco Inc, Hq, Tenneco Bldg, PO Box 2511, Houston, TX 77001, (713) 757-2131; Albright and Wilson Americas, PO Box 26229, Richmond, VA 23260; Production site: Charleston, SC 29400 [R2] USE: *IN HEAVY METAL EXTRACTION AND SOLVENT SEPARATION; PRE-IGNITION ADDITIVE FOR GASOLINE; ANTIFOAM AGENT; PLASTICIZER AND STABILIZER; TEXTILE CONDITIONER AND ANTISTATIC AGENT; ADDITIVE IN SOLVENTS AND LOW TEMP HYDRAULIC FLUIDS [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: *181 DEG C @ 754 MM HG [R3] MW: *124.08 [R3] DEN: *1.150 AT 20 DEG C/4 DEG C [R3] SOL: *SOL IN WATER, ALCOHOL, ETHER [R3] SPEC: *INDEX OF REFRACTION: 1.4099 @ 30 DEG C/D; MAX ABSORPTION (ALCOHOL): 217 NM (LOG E= 1.12) [R3]; +IR: 10468 (Documentation of Molecular Spectroscopy Collection) [R4]; +NMR: 42 (Johnson and Jankowski, Carbon-13 NMR Spectra, John Wiley and Sons, New York) [R4] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: +Dimethyl methylphosphonate was found to be negative when tested for mutagenicity in the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Dimethyl methylphosphonate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.1, 0.333, 1.0, 3.333, and 10 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 10 mg/plate. [R5] +Dimethyl methylphosphonate (DMP) was evaluated for developmental toxicity in a proposed new short-term in vivo animal bioassay. In this assay, pregnant mice are dosed with the test agent in mid-pregnancy and allowed to go to term. Observations are then made on litter size as well as the birth weight, neonatal growth, and survival of pups as indicators of developmental toxicity. Fifty pregnant CD-1 mice were given 4175 mg/kg/day DMP in corn oil by gavage on days 6-13 of gestation and were allowed to deliver. DMP caused a reduction in the birth weight of the offspring of treated mice, but had no effect on maternal weight or the viability of the pups. [R6] +... Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of dimethyl methylphosphonate for male F344/N rats as shown by incr incidences of tubular cell hyperplasia, tubular cell adenocarcinomas, hyperplasia of the transitional cell epithelium, and transitional cell papillomas of the kidney. There was an increased incidence of mononuclear cell leukemia in male rats at 1,000 mg/kg. Renal toxicity and decreased survival occurred in dosed male rats. There was no evidence of carcinogenic activity of dimethyl methylphosphonate for female F344/N rats given doses of 500 or 1,000 mg/kg. The study in male B6C3F1 mice was an inadequate study of carcinogenic activity because of decreased survival in both dosed groups. There was no evidence of carcinogenic activity for female B6C3FI mice receiving dimethyl methylphosphonate at 1,000 mg/kg; decreased survival of female mice at 2,000 mg/kg made this group inadequate for determination of carcinogenic activity. [R7] NTP: +In the 2 yr studies, dimethyl methylphosphonate was admin in corn oil by gavage at doses of 0; 500, or 1,000 mg/kg per day to groups of 50 F344/N rats of each sex and at 0, 1,000, or 2,000 mg/kg per day to groups of 50 B6C3F1 mice of each sex. All animals were dosed S days per week for 103 weeks. Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of dimethyl methylphosphonate for male F344/N rats as shown by incr incidences of tubular cell hyperplasia, tubular cell adenocarcinomas, hyperplasia of the transitional cell epithelium, and transitional cell papillomas of the kidney. There was an increased incidence of mononuclear cell leukemia in male rats at 1,000 mg/kg. Renal toxicity and decreased survival occurred in dosed male rats. There was no evidence of carcinogenic activity of dimethyl methylphosphonate for female F344/N rats given doses of 500 or 1,000 mg/kg. The study in male B6C3F1 mice was an inadequate study of carcinogenic activity because of decreased survival in both dosed groups. There was no evidence of carcinogenic activity for female B6C3FI mice receiving dimethyl methylphosphonate at 1,000 mg/kg; decreased survival of female mice at 2,000 mg/kg made this group inadequate for determination of carcinogenic activity. [R7] TCAT: ?Teratogenicity was evaluated in fertilized female Sprague Dawley rats (25/group) exposed orally by gavage to dimethyl methylphosphonate (in 2% sodium carboxymethylcellulose vehicle) at dose levels of 0, 100, 1000 or 2000 mg/kg on gestation days (GD) 6-15. Dams were sacrificed on GD 21. Significant differences were observed between treated and control animals in the following: decreased maternal body weight gain and feed consumption (high-dose group), and retarded fetal physiological growth (including decreased body weight and delay in skeletal maturation, mid- and high-dose group). No significant differences were observed between treated and control animals with respect to fetal malformations. In a supplementary study, fertilized female Sprague Dawley rats (25/group) exposed orally by gavage to dimethyl methylphosphonate (in 2% sodium carboxymethylcellulose vehicle) at dose levels of 0 or 2000 mg/kg on gestation days (GD) 6-15 and 2500 mg/kg on GD 6-10. Dams were sacrificed on GD 21. Significant differences were observed between treated and control animals in the following: decreased maternal body weight gain and feed consumption and retarded fetal physiological growth (including decreased body weight and delay in skeletal maturation) (both treatment levels). No significant differences were observed between treated and control animals in the following: gross malformations, visceral or skeletal anomalies. [R8] ?The mutagenicity of dimethyl methylphosphonate was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Dimethyl methylphosphonate, diluted in DMSO, was tested at concentrations up to 2025ug/plate using the plate incorporation technique. Dimethyl methylphosphonate did not cause a positive response in any tester strain with or without metabolic activation. [R9] ?The mutagenicity of dimethyl methylphosphonate was evaluated in Salmonella tester strains TA1535 and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by rat liver S9 fraction. Based on preliminary toxicity determinations, dimethyl methylphosphonate, diluted in DMSO, was tested at concentrations up to 50mg/plate using the plate incorporation technique. Dimethyl methylphosphonate did not cause a positive response in any tester strain with or without metabolic activation. [R10] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: +Between 0.2 and 2 million pounds of dimethyl methylphosphonate are manufactured annually in the United States. It is used as a flame retardant and as a viscosity depressant in polyester and epoxy resins. It is not known how much dimethyl methylphosphonate enters the environment, but it may be released during its manufacture and use. Dimethyl methylphosphonate will hydrolyze to the half ester and methanol with an estimated half-life of 13.2 years at 20 deg C. Half-lives in muddy water range from 7-210 days, depending on the initial dimethyl methylphosphonate concentration and temperature. Dimethyl methylphosphonate half-lives in soil range from 0.2-60 days with an average half-life of 12.4 days. No information was found on volatilization rates, photolysis, or biodegradation. (SRC) ARTS: +A total of 200,000 to 2 million pounds of dimethyl methylphosphonate were manufactured in 1977 by Mobile Oil Corporation and Stauffer Chemical Company(2). These two companies continue to be the sole producers of dimethyl methylphosphonate in the United States(3). Dimethyl methylphosphonate is used as a flame retardant, as an intermediate in the manufacture of several other flame retardants (e.g., Fyrol 76, Antiblaze 19), and as a viscosity depressant in polyester and epoxy resins(1). In the latter use, dimethyl methylphosphonate may be used as both a viscosity depressant and flame retardant in the manufacture of bathtubs and shower stalls(1). [R11] FATE: +TERRESTRIAL FATE: Dimethyl methylphosphonate will hydrolyze in moist soils. Although no infromation was found, hydrolysis rates in moist soil will probably be similiar to those in water. In environmental chamber studies, dimethyl methylphosphonate at initial concentrations in soil from 100-1000 ppm had half-lives from 0.2-60 days(1). The average half-life was 12.4 days. Temperatures ranged from 10-40 deg C, wind speed from 0-4 mph, and the soil moisture content from 1-5%. The transport and/or degradation process responsible for the loss of dimethyl methylphosphonate was not determined. [R12] +AQUATIC FATE: Dimethyl methylphosphonate in water will hydrolyze to form the half ester and methanol(1). Hydrolysis half-lives, extrapolated from data at higher temperatures (80, 90 and 98 deg C) (2) and unspecified pH, are estimated to be 13.2 years at 20 deg C and 43.3 years at 10 deg C. In a study performed by the U.S. Army(3), dimethyl methylphosphonate half-lives in muddy water ranged from 7-210 days. The 7 day and 210 day half-lives corresponded to initial dimethyl methylphosphonate concentrations of 500 and 1000 ppm and temperatures of 40 and 10 deg C, respectively. The removal mechanism for dimethyl methylphosphonate, however, was not specified. Removal may have been due to one or more mechanisms such as volatilization, adsorption, hydrolysis, biodegradation, and photolysis. [R13] +ATMOSPHERIC FATE: The atmospheric vapor phase half-life for dimethyl methylphosphonate is estimated to be 1.6 months(1). [R14] ABIO: +dimethyl methylphosphonate will hydrolyze to the half ester and methanol(1). Half-lives for dimethyl methylphosphonate are calculated to be 13.2 years and 43.3 years at 20 deg C and 10 deg C, respectively. These two half-lives were calculated from kinetic data collected at 98, 90 and 80 deg C(2). The corresponding rate constants (k x 10(+6)sec(-1)) for these three temperatures were 1.92, 1.15 and 0.50. Activation energy was 19.7 kcal/mole and the log A factor was 5.87. The pH, however, was unspecified. No information was found on dimethyl methylphosphonate photolysis. Information is, however, available on a similiar compound, diisopropyl methylphosphonate (DIMP). DIMP, in both distilled and Rocky Mountain Arsenal water, did not photolyze when exposed to light (> 290 nm) for 232 hours (9.7 days)(3). Thus, photolysis of dimethyl methylphosphonate may also be insignificant. [R15] BIOC: +The high water solubility of dimethyl methylphosphonate suggests that it will not bioconcentrate in aquatic organisms. (SRC) KOC: +The high water solubility of dimethyl methylphosphonate suggests that it will not sorb to soils or sediments. Therefore, dimethyl methylphosphonate would be expected to leach through soil and possibly enter groundwater. (SRC) VWS: +The low vapor pressure (0.61 mm Hg, 25 degC)(1) and high water solubility of dimethyl methylphosphonate suggests that it will not readily volatilize from water or soils. However, dimethyl methylphosphonate has been detected in the air near a liquid waste pond at concentrations as high as 109,000 ng/cubic meter(2). [R16] ATMC: +Dimethyl methylphosphonate ambient air concentrations at three different locations near the edge of a hazardous liquid waste lagoon were 109,000, 10,600 and 2450 ng/cubic meter(1). Concentrations at two sites approximately 1 mile from this lagoon were 31 and 20 ng/cubic meter(1). [R17] RTEX: +Human exposure to dimethyl methylphosphonate probably will occur primarily in occupational settings. Specifically, exposure may occur at dimethyl methylphosphonate production sites and where dimethyl methylphosphonate is used as a flame retardant and as a viscosity depressant in polyester and epoxy resins. EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 100 ug/l [R18] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Dimethyl Methylphosphonate in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 323 (1987) NIH Publication No. 88-2579 SO: R1: SRI R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 578 R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-376 R4: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 843 R5: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R6: Hardin BD et al; Teratog Carcinog Mutagen 7:29-48 (1987) R7: Toxicology and Carcinogenesis Studies of Dimethyl Methylphosphonate in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 323 (1987) NIH Publication No. 88-2579 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R8: CIBA-GEIGY Ltd.; Reproduction Study - FAT80 021/Methyl Methylphosphonate) (Test For Teratogenic or Embryotoxic Effects). (1978), EPA Document No. OTS-0784-0242-2, Fiche No. OTS0000242-2 R9: Ciba-Geigy LTD.; Salmonella/Mammalian-Microsome Mutagenicity Test, (1978), EPA Document No. FYI-OTS-0784-0242, Fiche No. OTS0000242-2 R10: Inveresk Research International; Testing for Mutagenic Activity in Dimethyl Methylphosphonate, (1976), EPA Document No. FYI-OTS-0784-0242, Fiche No. OTS0000242-2 R11: (1) Weil ED; Kirk-Othmer Encycl Chem Tech 3rd Wiley and Sons NY 10:401 (1980) (2) TSCA; TSCA Inventory of Chemicals in Commerce Public 1977 USEPA (1982) (3) SRI Inter; Directory of Chemical Producers Menlo Park CA (1985) R12: (1) Dynamac Corp; Chemical Hazard Information Profile dimethyl methylphosphonate Rockville Md (1983) R13: (1) Christol H et al; J Organometal Chem 12:459-70 (1968) (2) Belskii VE et al; Izv Akad Nauk SSSR Ser Khim 12:2813-4 (1969) (3) Dynamac Corp; Chemical Hazard Information Profile dimethyl methylphosphonate Rockville Md 1983) R14: (1) GEMS; Graphical Exposure Modeling System. Fate of atmospheric pollutants (FAP) data base. Office of Toxic Substances USEPA R15: (1) Christol H et al; J Organometal Chem 12:459-70 (1968) (2) Belskii VE et al; Izv Akad Nauk SSSR Ser Khim 12:2813-4 (1969) (3) Spanggord RJ et al; Studies of environental fates of DIMP and DCPD USNTIS AD-A078236 (1979) R16: (1) Simulant Data Base; Chemical Research and Development Aberdeen Proving Ground MD US Army (2) Guzewich DC et al; Air sampling around a hazardous liquid surface impoundment; Air Pollut Control Assoc Proc 76 Ann Mtg 2:83-24.1 p.14 (1983) R17: (1) Guzewich DC et al; Air sampling around a hazardous liquid surface impoundment; Air Pollut Control Assoc Proc 76 Ann Mtg 2:83-24.1 p.14 (1983) R18: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) RS: 17 Record 180 of 1119 in HSDB (through 2003/06) AN: 2593 UD: 200211 RD: Reviewed by SRP on 6/15/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIMETHYL-HYDROGEN-PHOSPHITE- SY: *DIMETHOXYPHOSPHINE-OXIDE-; *DIMETHYLACID-PHOSPHITE-; *DIMETHYLESTER-KYSELINI-FOSFORITE- (CZECH); *DIMETHYLHYDROGENPHOSPHITE-; *DIMETHYL-PHOSPHITE-; *DIMETHYL-PHOSPHONATE-; *DMHP-; *METHYL-PHOSPHONATE- ((MEO)2HPO); *NCI-C54773-; *PHOSPHONIC-ACID,-DIMETHYL-ESTER- RN: 868-85-9 MF: *C2-H7-O3-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF PHOSPHORUS TRICHLORIDE AND METHANOL OR SODIUM METHOXIDE [R1] MFS: *Tenneco Inc, Hq, Tenneco Bldg, PO Box 2511, Houston, TX 77001, (713) 757-2131; Albright and Wilson Americas, PO Box 26229, Richmond, VA 23260; Production site: Charleston, SC 29400 [R2] USE: *LUBRICANT ADDITIVES; INTERMEDIATE; ADHESIVE [R3] *Nylon-6 fibers can be fire-proofed by grafting with a caprolactam copolymer followed by treatment with dimethylphosphite. [R4] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.5X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MOBILE, COLORLESS LIQUID [R3] ODOR: *MILD ODOR [R3] BP: *72-73 DEG C @ 25 MM HG [R3] MW: *110.05 [R5] DEN: *1.200 @ 20 DEG C/4 DEG C [R3] SOL: *SOL IN WATER; MISCIBLE WITH MOST ORGANIC SOLVENTS [R3]; *Soluble in pyrimidine [R5] SPEC: *INDEX OF REFRACTION: 1.400 @ 25 DEG C/D [R3]; *IR: 634 (Coblentz Society Spectral Collection) [R6]; *NMR: 6652 (Sadtler Research Laboratories Spectral Collection) [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *WHEN HEATED TO DECOMP, CAN EMIT HIGHLY TOXIC FUMES OF /PHOSPHORUS OXIDES/. [R7] EQUP: *Respiratory protection (supplied-air respirator with full facepiece or self-contained breathing apparatus) should be available where these compounds are manufactured or used and should be worn in case of emergency and overexposure. /Phosphorus compounds/ [R8] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of dimethyl hydrogen phosphite were available. There is limited evidence for the carcinogenicity of dimethyl hydrogen phosphite in experimental animals. Overall evaluation: Dimethyl hydrogen phosphite is not classifiable as to its carcinogenicity to humans (Group 3). [R9] HTOX: *THE TOXICITY OF PHOSPHITES APPEARED TO BE RELATED TO THEIR LIPOPHILIC AND ELECTRONIC PROPERTIES. /PHOSPHITES/ [R10] NTOX: *Dimethyl hydrogen phosphite was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. The test procedures used include the treatment of Canton-S wild-type males with concentrations of the test chemical that result in approximately 30% mortality after 72 hr of feeding or 24 hr after injection. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of dimethyl hydrogen phosphite tested by injection (1500 ppm) or feeding (650 ppm) were negative in this assay. [R11] NTP: */A carcinogenicity bioassay of dimethyl hydrogen phosphite was conducted by administering the test cmpd (greater than 97% pure)/ in corn oil for 103 wk by gavage to groups of 50 male F344/N rats and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to groups of 50 female F344/N rats at doses of 0, 50, or 100 mg/kg. ... Under the conditions of these gavage studies, there was clear evidence of carcinogenicity in male F344/N rats receiving dimethyl hydrogen phosphite, as shown by increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and squamous cell carcinomas of the lung and of neoplasms of the forestomach. There was equivocal evidence of carcinogenicity in female F344/N rats receiving dimethyl hydrogen phosphite, as shown by marginally increased incidences of alveolar/bronchiolar carcinomas of the lung and neoplasms of the forestomach. There was no evidence of carcinogenicity in male or female B6C3F1 mice receiving dimethyl hydrogen phosphite at doses of 100 or 200 mg/kg for 103 wk. [R12] TCAT: ?The mutagenicity of dimethyl hydrogen phosphite was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test), and in Saccharomyces cerevisiae strain D4, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, dimethyl hydrogen phosphite, diluted in DMSO, was tested at concentrations up to 5ul/plate using the plate incorporation technique. Dimethyl hydrogen phosphite did not cause a positive response in any tester strain with or without metabolic activation. [R13] ?The mutagenicity of dimethyl hydrogen phosphite was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, dimethyl hydrogen phosphite, diluted in DMSO, was tested at concentrations up to 15ul/plate using the preincubation method. Dimethyl hydrogen phosphite did not cause a positive response in any tester strain with or without metabolic activation. [R14] ?The ability of dimethyl hydrogen phosphite to induce specific locus mutations at the TK locus of cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity determinations, nonactivated cultures were treated with 1.3, 1.0, 0.75, 0.56, 0.42, 0.32, 0.24, 0.18 and 0.13ul/ml, producing a range of 13 - 107% total growth. S9 activated cultures treated with 1.8, 1.3, 1.0, 0.75, 0.56, 0.42, 0.32, 0.24, 0.18 and 0.13ul/ml produced a range of 8 - 61% total growth. The nonactivated culture at highest dose level produced a mutant frequency which was two fold of the solvent control (DMSO). Activated cultures at the four highest concentrations produced mutant frequencies significantly greater than the solvent control, and a dose-response relationship was observed. [R15] ?The mutagenic potential of dimethyl hydrogen phosphite was evaluated in the germ cells of Drosophila melanogaster males employing the following: somatic reversion of white-ivory test, Y chromosome loss test, Dominant lethal test and Bithorax test, sex-linked lethal test and timing of crosses test. Male flies were exposed to 0.07ml of test article delivered as an aerosol in an 25ml flask, after 5 minutes of exposure flies experienced a 20% mortality with about 20% of the survivors being sterile. Dimethyl hydrogen phosphite did cause a significant increase in the mutant frequencies in male Drosophila germ cells employing the dominant lethal and sex-linked lethal assays. All other tests were negative. [R16] ?The effect of dimethyl hydrogen phosphite (DMHP) was evaluated in the bacterial DNA repair assay using E. coli tester strains WP2uvrA+recA+ and WP100uvrA-recA- and Salmonella tester strains TA1978uvrB+ and TA1538uvrB-, both with and without metabolic activation by Aroclor-induced rat liver S9 fraction. (strains designated with a "+" are repair proficient and strains designated with a "-" are repair deficient). DMHP was tested at a concentrations of 0, 0.3, 3.0, 30.0 or 50.0 ug/plate. DMHP caused significant preferential killing of the repair deficient strain WP100, at 30.0 mg/plate with activation and at 50.0 ug/plate without activation (survival indices = , 0.01 and 0.38, respectively). DMHP caused significant preferential killing of the repair deficient strain TA1538, at 30.0 and 50.0 mg/plate without activation (survival indices = < 0.01). A clear dose-response was not observed in any of the tests. DMHP did not cause significant preferential killing of the repair deficient strain TA1538 with activation. [R17] ADE: *Phosphate is absorbed from, and to a limited extent secreted into, the gastrointestinal tract. The transport of phosphate from the lumen of the gut is an active, energy-dependent process, and there are factors that appear to modify the degree of its intestinal absorption. ... Vitamin D stimulates phosphate absorption, and this effect has been reported to precede the action of the vitamin on transport of calcium ion. In general, in adults, about two thirds of the ingested phosphate is absorbed from the bowel, and that which is absorbed from the gut is almost entirely excreted into the urine. In growing children, there is a positive balance of phosphate. Concentrations of phosphate in plasma are higher in children than in adults. This "hyperphosphatemia" decreases the affinity of hemoglobin for oxygen and is hypothesized to explain the physiological "anemia" of childhood. /Phosphates/ [R18] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dimethyl hydrogen phosphite (DMHP) is produced in significant quantities and is used as a flame retardant and chemical intermediate, and in lubricant additives and adhesives. It is not known how much is released into the environment. In soil, DMHP will probably hydrolyze and leach to groundwater (where it will completely hydrolyze); it will not volatilize significantly. In water, DMHP wil hydrolyze but will not evaporate readily nor sorb to sediments or biota. It is not known if DMHP biodegrades, although it may photodegrade since diethyl hydrogen phosphonate appears to be photosensitive. The fate of DMHP in air is not known, although photolysis may occur. (SRC) ARTS: *DMHP is used as a flame retardant in textiles which may result in environmental release(1). [R19] FATE: *TERRESTRIAL FATE: DMHP will hydrolyze in moist soils. Although no half-life can be estimated for the soil matrix, the hydrolysis should be at least as fast as in water in saturated soil. DMHP will leach extensively, possibly reaching groundwater where it will hydrolyze completely. (SRC) *AQUATIC FATE: DMHP released to water will hydrolyze with a half-life of 10 days at 25 deg C and 19 days at 20 deg C(1). Basic conditions speed the hydrolysis(2). The ethyl homologue of DMHP has been reported to photolyze(3) indicating that DMHP may also photolyze; however, no rates can be estimated for either compound(3). DMHP will not sorb to sediments or biota and little or no volatilization will occur. [R20] *ATMOSPHERIC FATE: One study reports that DMHP will photolyze in moist air(1); however, no photolysis rates can be estimated from their data(SRC). [R21] ABIO: *DMHP will hydrolyze in water (pH unspecified) with a half-life of 10 days at 25 deg C and 19 days at 20 deg C(1) This is based on kinetic data obtained at higher temperature (50-90 deg C) to determine an activation energy (E) of 22.1 (Kcal/mole) and a preexponential coefficient (A) of 1.26X10(+10) 1/sec where k=Aexp(-E/RT). Hydrolysis appears tobe faster in base, although reports conflict as to how much faster hydrolysis will be. A French study(2) presented data for base hydrolysis that predicted a half-life on the order of several days for DMHP under environmental conditions (pH 7)(3) while another study(4) presented data that predicted a half-life of 9 min under environmental conditions. The diethyl homologue of DMHP has been reported to photolyze indicating that DMHP may also, although no rates were determined(5). [R22] BIOC: *No experimental data for the octanol/water partition coefficients of DMHP is available. Estimation of Kow from molecular structure is not possible because of missing fragments. However, the low log Kow of dimethyl methyl phosphate, -0.61(1) and dimethyl ethyl phosphate, 0.66(1) suggests that the log Kow for DMHP is very low(SRC). A low octanol/water partition coefficient suggests that DMHP will not bioconcentrate in aquatic organisms(SRC). [R23] KOC: *No experimental data for the octanol/water partition coefficients of DMHP is available. Estimation of Kow from molecular structure is not possible because of missing fragments. However, the low log Kow of dimethyl methyl phosphate, -0.61(1) and dimethyl ethyl phosphate, 0.66(1) suggest that the log Kow for DMHP is very low. A low octanol/water partition coefficient suggests that DMHP will not sorb to soils of sediments and therefore, would be expected to leach through soil, possibly reaching groundwater if complete hydrolysis did not occur first(SRC). [R23] VWS: *The vapor pressure (1.5 mm Hg at 20 deg C(1)), ability to hydrogen bond, and the high water solubility suggest that DMHP will not volatilize from water or soils(SRC). [R24] RTEX: +Primary human exposure appears to be from its use as a flame retardant in textiles. (SRC) MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *If phosphorus forms are to be differentiated, filter sample immediately after collection. Preserve by freezing at or below -10 deg C. Add 40 mg mercury chloride/l to the samples. ... Do not add either acid or chloroform as a preservative when phosphorus forms are to be determined. /Phosphorus forms/ [R25] *NIOSH Method 7905. Analyte: Phosphorus. Matrix: Air. Sampler: Solid sorbent tube (Tenax Gas chromatography, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min: Sample Size: 12 liters. Shipment: Routine. Sample Stability; 94% recovery after 7 days at 25 deg C. /Phosphorus/ [R26, p. 7905-1] *NIOSH Method 7300. Analyte: Phosphorus. Matrix: Air. Sampler: Filter (0.8 um cellulose ester membrane) Flow Rate: 1 to 4 l/min: Sample Size: 500 liters. Shipment: Routine. Sample Stability; Stable. /Phosphorus/ [R26, p. 7300-1] ALAB: *Phosphorus was determined by a continuous flow method using fluorescence quenching of Rhodamine 6G with molybdophosphate. /Phosphorus/ [R27] *Phosphorus and organic carbon were simultaneously determined in wastewater using flame ionization and photometric detectors. /Phosphorus/ [R28] *Phosphorus was determined in natural waters by direct current plasma atomic emission spectrometry. /Phosphorus/ [R29] *Proton-induced x-ray emission analysis constitutes a method for trace element analysis characterized by multielement capability, detection limits in the low ppm-range, and size resolution approximating a millimicron. /Phosphorus/ [R30] *Microamounts of phosphorus in wastewater were determined by high-speed liquid chromatography. /Phosphorus/ [R31] *The sample is collected and extracted. A 1 ml aliquot of the decant from the first or second 10 ml portion is placed in a beaker. A 5 ml volume of concentrated nitric acid is added and the mixture evaporated to 1 ml in a fume hood. A 2 ml volume of water is added and the mixture transferred to a test tube. A 1 ml volume of 1M ammonium nitrate and 2 ml of 0.5M ammonium molybdate are added. The solution is heated to boiling and the formation of a yellow precipitate of ammonium phosphomolybdate indicates phosphate. /Phosphate/ [R32] *NIOSH Method 7905. Analyte: Phosphorus. Matrix: Air. Procedure: Gas chromatography, phosphorus flame photometric detector. For phosphorus this method has an estimated detection limit of 0.005 ug/sample. The precision/RSD is 0.024 at 0.6 to 2.4 ug/sample and the recovery is not given. Applicability: The working range is 0.04 to 0.18 mg/cu m (0.008 to 0.16 ppm) for a 12 l air sample. Interferences: None identified. /Phosphorus/ [R26, p. 7905-1] *NIOSH Method 7300. Analyte: Phosphorus. Matrix: Air. Procedure: Inductively coupled argon plasma. For phosphorus this method has an estimated detection limit of 1 ug/sample. The precision/RSD and the recovery are not given. Applicability: The working range of this method is 0.005 to 2.0 mg/cu m in a 500 l air sample. Interferences: Spectral interferences. /Phosphorus/ [R26, p. 7300-1] *Method 4500-Phosphorus C. Vanadomolybdophosphoric Acid Colorimetric Method. This method determines the total phosphorus in natural waters and wastewaters following a digestion procedure to release phosphorus as orthophosphate. The method is based on the formation of yellow vanadomolybdo- phosphoric acid upon the addition of ammonium molybdate and vanadium to ortho- phosphate solution. This method is most useful for routine analysis in the range of 1 to 20 mg phosphorus/l. Minimum detectable concentration is 200 ug phosphorus/l in 1 cm spectrometer cells. Positive interference is caused by silica and arsenate. Negative interference is caused by arsenate, fluoride, thorium, bismuth, sulfide, thiosulfate, thiocyanate or excess molybdate. /Phosphorus/ [R33, p. 4-173 (1989)] *Method 4500-Phosphorus D. Stannous Chloride Method. This method determines total phosphorus in natural waters and wastewaters following a digestion procedure to release phosphorus as orthophosphate. The method is based upon the reduction of molybdophosphoric acid by stannous chloride to intensely colored molybdenum blue. This method is most suited for the concentration range of 0.01-6 mg phosphorus/l. The minimum detectable concentration is 3 ug phosphorus/l. The sensitivity at 0.3010 absorbance is 10 ug phosphorus/l for an absorbance change of 0.009. Positive interference is caused by silica and arsenate. Negative interference is caused by arsenate, fluoride, thorium, bismuth, sulfide, thiosulfate, thiocyanate, or excess molybdate. /Phosphorus/ [R33, p. 4-175 (1989)] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: WHO; Diseases Caused by Phosphorus and Its Toxic Compounds; Early Detection of Occupational Diseases pg 53-62 (1986). Review of diseases and health related effects resulting from exposure to phosphorus or phosphorus cmpd. /Phosphorus or phosphorus cmpd/ DHHS/NTP; Toxicology and Carcinogenesis Studies of Dimethyl Hydrogen Phosphite in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 287 (1985) NIH Publication No. 86-2543 SO: R1: SRI R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 565 R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 417 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V1 286 (1978) R5: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-399 R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 110 R7: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2120 R8: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1684 R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1440 (1999) R10: RUMYANTSEV GI ET AL; TR KHAR'K MED INST 124: 50-4 (1976) R11: Woodruff RC et al; Environ Mutagen 7:677-702 (1985) R12: DHHS/NTP; Toxicology and Carcinogenesis Studies of Dimethyl hydrogen phosphite in F344/N Rats and B6C3F1 Mice p.11 (1985) Technical Rpt Series No. 287 NIH Pub No. 86-2543 R13: Litton Bionetics Inc.; Mutagenicity of Dimethyl Hydrogen Phosphite, Final Report, (1977), EPA Document No. 88-8100187, Fiche No. OTS0204866 R14: EG and G Manson Research Institute; Salmonella/Mammalian-Microsome Preincubation Mutagenesis Assay, (1979), EPA Document No. 88-8100187, Fiche No. OTS0204866 R15: EG and G Manson Research Institute; Evaluation of Dimethyl Hydrogen Phosphite for Mutagenic Potential Employing the L5178Y TK +/- Mutagenesis Assay, (1979), EPA Document No. 88-8100187, Fiche No. OTS0204866 R16: EG and G Manson Research Institute; Drosophila Mutagenicity Assays of Dimethyl Hydrogen Phosphite, (1980), EPA Document No. 88-8100187, Fiche No. OTS0204866 R17: EG and G Mason Research Institute; Bacterial DNA Damage/Repair Suspension Assay, Dimethyl Hydrogen Phosphite. (1981), EPA Document No. 88-8100187, Fiche No. OTS0204866 R18: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1501 R19: (1) Drake GL Jr; Kirk Othmer Encyclopedia of Chemical Technology; 3rd ed. 10: 420-444 (1980) R20: (1) Bel'skii VE et al; Izv Akad Nauk SSSR Ser Khim No.6 pp.1297-1300 (1969) (2) Vilceanu R, Schulz P; Rev Roum Chim 17: 361-366 (1972) (3) Knoevenagel K, Himmelreich R; Arch Environ Contam Toxicol 4: 324-333 (1976) R21: (1) Knoevenagel K, Himmelreich R; Arch Environ Contam Toxicol 4: 324-333 (1976) R22: (1) Bel'skii VE et al; Izv Adad Nauk SSSR Ser Khim No. 6 pp.1297-1300 (1969) (2) Francina A et al; Compt Rendez Acad Sci Paris, Ser.C 266: 1050-1052 (1968) (3) Mabey LW, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (4) Vilceanu R, Schulz P; Rev Roum Chim 17: 361-366 (1972) (5) Knoevenagel K, Himmelreich R; Arch Environ Contam Toxicol 4: 324-333 (1976) R23: (1) Krikorian SE et al; Quant Struct Act Relat 6: 65-9 (1987) R24: (1) Page FM, Purnell JH; J Chem Soc 1958: 621-3 (1958) R25: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater 16th edition p.441 (1985) R26: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R27: Motomizu S et al; Bunseki Kagaku 33 (2): 116-9 (1984) R28: Nakajima K; Water Res 18 (5): 555-9 (1984) R29: Urasa IT; Anal Chem 56 (6): 904-8 (1984) R30: Malmquist KG et al; Scanning Electron Microsc (4): 1815-26 (1983) R31: Sakurai N et al; Fresenius' Z Anal Chem 314 (7): 634-7 (1983) R32: Welcher FJ, Hahn RB; Semimicro Qual Anal 458 pp (1955) as cited in Environment Canada; Tech Info for Problem Spills: Phosphoric acid (Draft) p.82 (1981) R33: Franson MA, ed; Standard Methods for the Examination of Water and Wastewater, 17th ed RS: 23 Record 181 of 1119 in HSDB (through 2003/06) AN: 2658 UD: 200303 RD: Reviewed by SRP on 05/08/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIPROPYLENE-GLYCOL- SY: *PROPANOL,-OXYBIS- RN: 25265-71-8 RELT: 2854 [1,1'-OXYDI-2-PROPANOL] MF: *C6-H14-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared commercially as a by-product of propylene glycol production. [R1, 3864] FORM: *GRADE: TECHNICAL [R2] *MIXTURE OF ISOMERS: % 2,2'-DIHYDROXDIISOPROPYL ETHER; 43% 2,2'-DIHYDROXYDIPROPYL ETHER; 53% 2-HYDROXYPROPYL 2'-HYDROXYISOPROPYL ETHER [R3] MFS: +ARCO Chemical Co, Hq, 3801 W Chester Pike, Newtown Square, PA 19073; Production site: Bayport, TX 77062 [R4] +Olin Corp, Hq, 120 Long Ridge Rd, PO Box 1355, Stamford, CT 06904-1355, (203) 356-2000; Olin Chemicals (address same as Hq); Production site: Brandenburg, KY 40108 (Doe Run Works) [R4] +Texaco Inc, Hq, 2000 Westchester Ave, White Plains, NY 10650, (914) 253-4000; Subsidiary: Texaco Chemical Company, 4800 Fournace Place, PO Box 430, Bellaire, TX 77401, (713) 666-8000; Production site: Port Neches, TX 77651 [R4] +Union Carbide Corporation, Hq, Old Ridgeway Road, Danbury, CT 06817, (203) 794-2000; Chemicals and Plastics Business Group; Specialty Chemicals Division; Production site: South Charleston, WV 25303 [R4] OMIN: *THERE ARE 3 LINEAR ISOMERS POSSIBLE BUT THESE HAVE NOT BEEN SEPARATED AND STUDIED AND EXACT COMPOSITION OF COMMERCIAL PRODUCT IS NOT KNOWN. [R1, 3864] *IT IS NOT USED IN DRUGS, PHARMACEUTICALS, OR FOOD APPLICATIONS BECAUSE ITS TOXICOLOGICAL CHARACTERISTICS HAVE NOT BEEN CLEARLY DEFINED. [R1, 3864] USE: *ANTIFREEZE AGENT; AIR SANITATION [R5, 653] *STABILIZER IN COSMETIC PREPN *Polyester and alkyd resins, reinforced plastics, plasticizers, solvent. [R2] +MEDICATION CPAT: *60% FOR POLYESTER RESINS; 30% FOR PLASTICIZERS; 10% FOR ALKYD RESINS, HYDROCARBON EXTRACTION, URETHANE POLYOLS, AND OTHER (1985) [R6] *CHEMICAL PROFILE: Dipropylene glycol. Demand: 1986: 55 million lb; 1987: 56.5 million lb; 1991 /projected/: 62 million lb. [R7] *CHEMICAL PROFILE: Dipropylene glycol. Demand: 1989: 84 million lb.; 1990 /projected/: 86 million lb; 1994 /projected/: 95 million lb. (Includes exports; imports are minimal.) [R8] PRIE: U.S. PRODUCTION: *(1972) 2.35X10+10 GRAMS [R9] *(1975) 1.77X10+10 GRAMS [R9] *(1984) 2.19X10+10 g [R10] U.S. IMPORTS: *(1972) NEGLIGIBLE [R9] *(1975) NEGLIGIBLE [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQ [R1, 3818] ODOR: *ODORLESS [R1, 3818] BP: *231.9 DEG C @ 760 MM HG [R1, 3819] MW: *134.18 DEN: *SP GR: 1.0252 @ 20 DEG C/20 DEG C [R1, 3819] HTV: *53.64 kJ/mol @ 101.3 kPa /=760 mm Hg/ [R11, 934] SOL: *MISCIBLE WITH WATER, METHANOL, AND ETHER [R1, 3819] SPEC: *INDEX OF REFRACTION: 1.439 @ 25 DEG C [R1, 3819]; *IR: 5888 (Coblentz Society Spectral Collection) [R12]; *MASS: 659 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R12] VAP: *LESS THAN 0.01 MM HG @ 20 DEG C [R1, 3819] VISC: *107 mPa.s (=cP) @ 20 deg C [R11, 934] OCPP: *VISCOUS; MP: SUPERCOOLS; % IN "SATURATED" AIR: LESS THAN 0.0013 @ 20 DEG C [R1, 3819] *1 PPM EQUIV 5.49 MG/CU M @ 25 DEG C, 760 MM HG AND 1 MG/L EQUIV 182 PPM @ 25 DEG C, 760 MM HG [R13] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *SLIGHT, WHEN EXPOSED TO HEAT OR FLAME; CAN REACT WITH OXIDIZING MATERIALS. [R14] NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R15] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R15] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R15] FLPT: +250 DEG F (121 DEG C) (OPEN CUP) [R15] FIRP: *TO FIGHT FIRE /USE/ ALCOHOL FOAM, CO2, DRY CHEM. [R14] DISP: *The following wastewater treatment technologies have been investigated for dipropylene glycol: Concentration process: Activated carbon. [R16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: *Propylene glycol and other hydroalcoholic gels augment the keratolytic action of salicylic acid; this combination may be effective in ichthyosis. If the formulation contains 6% salicylic acid, no more than 20% of the body surface should be covered at any one time to prevent excessive absorption of salicylate. Initially the preparation is applied nightly to wet skin (an occlusive dressing may be applied at bedtime) and the preparation is washed off in the morning. The frequency of application is reduced when improvment is noted. Subjective irritation (burning and stinging) occurs, particularly if the skin is damaged. Patients who cannot tolerate propylene glycol probably experience a special form of irritation but only rarely develop allergic contact dermatitis. /Propylene glycol/ [R17] HTOX: *... MORE ACUTELY DEPRESSANT TO CNS THAN ETHYLENE, DIETHYLENE OR PROPYLENE GLYCOL ... . [R5, 654] */VAPOR TOXICITY/ ... IS NOT LIKELY TO PRODUCE INJURY BECAUSE OF ITS LOW VAPOR PRESSURE AND LOW SYSTEMIC TOXICITY. ... NO UNTOWARD EFFECTS HAVE BEEN REPORTED FROM USE OF DIPROPYLENE GLYCOL NOR WOULD ANY BE EXPECTED. [R1, 3865] *... DIPROPYLENE GLYCOL IS MORE ACTIVE PHYSIOLOGICALLY THAN PROPYLENE GLYCOL, IT IS STILL VERY LOW IN TOXICITY. [R1, 3864] *SUMMARY TOXICITY STATEMENT: LOW BY /ACUTE/ ORAL ROUTE. CAUSES READILY REVERSIBLE TISSUE CHANGES WHICH DISAPPEAR AFTER EXPOSURE STOPS; CAUSES SOME DISCOMFORT. [R14] *INDUSTRIAL HANDLING AND USE OF DIPROPYLENE GLYCOL SHOULD PRESENT NO SIGNIFICANT PROBLEMS FROM INGESTION, SKIN CONTACT, OR VAPOR INHALATION. [R1, 3864] *An evaluation was made of worker exposure to hydraulic fluid used on the longwall mining operations at Consolidated Coal Company's Humphrey Number 7 Mine, Pentress, West Virginia. Employees were complaining of headache, eye and throat irritation, congestion, and cough. A particular emulsion oil, Solcenic-3A, was used with water in the mine's hydraulic roof support system. An analysis of the oil indicated the presence of methyl isobutyl carbinol, dipropylene glycol and paraffin hydrocarbons. Personal breathing zone samples for methyl isobutyl carbinol were collected from all workers on the longwall mining operation during the two days of the visit. All the analysis indicated concentrations of methyl isobutyl carbinol below the limit of quantification, which was 0.6 ppm for an 8 hr sample. These levels were well below the exposure recommendations of the Mine Safety and Health Administration. Exposure to methyl isobutyl carbinol may be occurring through skin contact with oil through hydraulic line leaks, accidents, and maintenance activity on the hydraulic machines. The report concludes that Solcenic-3A oil constituents in air did not pose a health hazard at the time of the survey. [R18] *Study was made of possible worker exposure to two hydraulic fluids at the Old Ben Coal Company located in Benton, Illinois. Employees using Solcenic-3A hydraulic fluid or working near its area of use had reported eye, skin, or respiratory irritation. Solcenic-2 fluid produced no symptoms. Chemical analysis revealed that Solcenic-3A contained dipropylene glycol isomers and a small amount of ethanolamine which were not present in Solcenic-2. /It was suggested/ that these components may lower the Solcenic-3A odor threshold. Area air evaluations indicated no harmful exposures to the component methyl isobutyl carbinol, with exposures of 1.4 and 3.4 mg/cu m determined for two of 11 samples. No excessive exposure to the component naphthenic mineral oil was found; it was considered that workers were exposed to it only during hydraulic line ruptures or fluid spills. Of 13 workers reporting symptoms, nine of 11 interviewed had symptoms possibly due to skin or inhalation exposure to Solcenic-3A. /It was/ suggested that inhalation symptoms are a reaction to its strong vapor. /It was/ concluded that there is no health hazard, but they recommend use of protective equipment, proper disposal of waste, and use of nonirritating Solcenic-2. [R19] NTOX: *DOGS ... AFTER SURVIVAL OF REPEATED GASTRIC DOSAGE OF DIPROPYLENE GLYCOL SHOWED ONLY MODERATE DEGENERATIVE CHANGES IN KIDNEYS AND ONLY MINIMAL EVIDENCE OF LIVER DAMAGE /CHRONIC/. [R5, 655] *RATS WERE NOT AFFECTED BY 5% DIPROPYLENE GLYCOL IN THEIR DRINKING WATER FOR 77 DAYS. ... ADMIN LEVEL OF 10%, SOME DIED WITH HYDROPIC DEGENERATION OF KIDNEY TUBULAR EPITHELIUM AND LIVER PARENCHYMA. ... EFFECTS WERE SIMILAR TO THOSE OF DIETHYLENE GLYCOL BUT LESS SEVERE AND LESS UNIFORMLY PRODUCED. [R1, 3865] */CNS DEPRESSION/ WAS PRODUCED IN DOG BY IV INJECTION OF 5.9 ML/KG /ACUTE/. [R5, 655] *DEPRESSION OF RUNNING ACTIVITY OCCURRED IN RATS GIVEN 12% IN DIET FOR 15 WK ... [R5, 655] *DIPROPYLENE GLYCOL RATED 1 ON RABBIT EYES. /TESTED EXTERNALLY ON EYES, RATED NUMERICALLY ON SCALE OF 1 TO 10 ACCORDING TO DEGREE OF INJURY OBSERVED AFTER 24 HR, PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA. MOST SEVERE INJURIES HAVE BEEN RATED 10./ [R20] *WHEN DIPROPYLENE GLYCOL WAS APPLIED REPEATEDLY FOR PROLONGED PERIODS (10 APPLICATIONS IN 12 DAYS) TO SKIN OF RABBITS IT HAD NEGLIGIBLE IRRITATING ACTION AND THERE WAS NO INDICATION THAT TOXIC QUANTITIES WERE ABSORBED THROUGH INTACT SKIN. [R1, 3865] *DIPROPYLENE GLYCOL MARKEDLY STIMULATED CHOLERESIS WHEN INJECTED INTRADUODENALLY @ 1 ML/KG INTO RATS. [R21] NTXV: *LD50 Rat ip 10.3 ml/kg (10.56 g/kg); [R1, 3865] *LD50 Dog iv 11.5 ml/kg (11.79 g/kg); [R1, 3865] *LD50 Rat oral 14.8 ml/kg; [R11, 936] *LD50 Rabbit dermal 20 ml/kg (24 hr covered skin contact with liquid chemical); [R11, 936] NTP: +... This study was conducted to assess the potential for Dipropylene glycol (DPG) to cause developmental toxicity and to compare its toxicity to other glycols. Dipropylene glycol (CAS No. 25265-71-8) was administered by gavage to timed-pregnant CD(R) rats (20-25/group) on gestational days (gd) 6-15 at dose levels of 0, 800, 2,000, or 5,000 mg/kg body weight/day. Animals were observed daily for clinical signs of toxicity. Food and water weights and body weights were reported on gestational days 0, 3, 6, 9, 12, 15, 18, and 20. All animals were killed on gd 20 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development. The mid-dose (2,000 mg/kg/day dipropylene glycol) produced maternal lethality in 1 out of 25 pregnant animals while the high dose (5,000 mg/kg/day) caused the death of 2 out of 22 pregnant animals. Maternal body weights were significantly decreased in the 5,000 mg/kg/day group from gestational days 9 through gd 20. Maternal body weight gain of the animals exposed to 5,000 mg/kg/day was significantly reduced across the treatment period and across gestation. Corrected maternal weight gain (gestation gain minus gravid uterine weight) was also significantly reduced in the 5,000 mg/kg/day group. Absolute (g/day) and relative (grams/kg body weight/day) food consumption of animals in the 5,000 mg/kg/day group were significantly decreased from control for the intervals from gestational days 6 to 9 and gestational days 9 to 12. As a result, the absolute and relative food consumption was decreased during treatment (gestational days 6 to 15) and across gestation (gestational days 0 to 20). Absolute food consumption was decreased in the animals from the 2000 mg/kg/day group from gestational days 6 to 9. Relative water consumption by the animals in the 5,000 mg/kg/day group was increased for all measurement periods between gestational days 9 and gd 18. Relative liver weight of the maternal animals was significantly increased in the animals exposed to 2,000 and 5,000 mg/kg/day of dipropylene glycol. No effects of dipropylene glycol were observed on pre- or post-implantation loss. The mean male and female body weights per litter were associated with a significant decreasing linear trend, but mean male and female body weights were not significantly different from control in the exposed groups. Examination of the fetuses for external, visceral and skeletal malformations and variations did not reveal any significant effects among dose groups. In summary, there was no maternal or developmental toxicity at 800 mg/kg/day of dipropylene glycol. Maternal toxicity and lethality were observed at 2,000 and 5,000 mg/kg/day, but developmental toxicity was not observed even at these maternally lethal exposures. [R22] +... Dipropylene glycol was administered by gavage to artificially inseminated NZW rabbits (24 per group) on gestation days (GD) 6-19 at dose levels of 0, 200, 400, 800, or 1200 mg/kg body weight/day. Animals were observed daily for clinical signs of toxicity. Mean food and body weights were calculated for each group on gestation days 0, 6, 9, 12, 15, 19, 25, and 30. All animals were killed on gestation days 30 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development. No maternal lethality occurred in this study. Pregnancy rates were 95%, 83%, 91%, 92%, and 82% in the control to high dose groups, respectively. No effect that could be attributed to exposure to dipropylene glycol was noted on maternal body weight, food consumption, or clinical signs. Necropsy of the maternal animals revealed no effects on kidney and liver weights. In utero ipropylene glycol exposure did not affect the frequency of post-implantation loss, mean fetal body weight per litter, or external, visceral, or skeletal malformations. In summary, no maternal toxicity was observed in animals exposed to 1200 mg/kg/day of ipropylene glycol from gestation day 6 through gestation days 19, although preliminary study data indicated that this exposure would be in the maternally toxic range for this species. No developmental toxicity was noted in the offspring of the animals from any group exposed to ipropylene glycol during this study. The study established a NOAEL of at least 1200 mg/kg/day for both maternal and developmental toxicity of dipropylene glycol administered orally in rabbits. [R23] ADE: *... GIVEN TO DOGS BY GASTRIC ADMIN IN DOSES OF 5 ML/KG ... DIPROPYLENE GLYCOL DISAPPEARED FROM BLOOD IN APPROX 24 HR ... . [R5, 654] *IT IS ... NOT ABSORBED IN TOXIC AMT THROUGH INTACT SKIN. [R5, 654] *... ONCE ABSORBED INTO BODY, ESTERS ARE SAPONIFIED AND SYSTEMIC EFFECT IS QUITE TYPICAL OF PARENT GLYCOL OR GLYCOL ETHER. /ETHER-ESTERS OF GLYCOLS/ [R1, 4010] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Commercially, propylene glycol is a diluent for injectable drugs (eg, vitamins, anthihistamines, barbiturates) and a component of topical and cosmetic preparations. /Propylene glycol/ [R24] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dipropylene glycol may be released to the environment via effluents at sites where it is produced or used as a solvent, and a plasticizer in polyester and alkyd resins, and in reinforced plastics. Dipropylene glycol is not expected to undergo hydrolysis or direct photolysis in the environment. The miscibility of dipropylene glycol in water suggests that volatilization, adsorption and bioconcentration are not important fate processes. This is supported by an estimated Henry's Law constant of 3.58X10-9 atm-cu m/mole at 25 deg C which indicates that volatilization of dipropylene glycol from natural waters and moist soil should be extremely slow. A low estimated log BCF suggests dipropylene glycol should not bioconcentrate among aquatic organisms. A low Koc indicates dipropylene glycol should not partition from the water column to organic matter contained in sediments and suspended solids, and it should be highly mobile in soil. Although aerobic biodegradation screening test data suggests that the rate should be slow, biodegradation may still be an important removal mechanism of dipropylene glycol from aerobic soil and water. In the atmosphere, dipropylene glycol is expected to exist almost entirely in the vapor phase and reactions with photochemically produced hydroxyl radicals should be important (estimated half-life of 13 hrs). Physical removal of dipropylene glycol from air by precipation and dissolution in clouds may occur; however, its short atmospheric residence time suggests that wet deposition is of limited importance. The most probable human exposure would be occupational exposure, which may occur through dermal contact or inhalation at workplaces where it is produced or used. Limited monitoring data indicates that non-occupational exposures can occur from the ingestion contaminated drinking water supplies. (SRC) ARTS: *Dipropylene glycol may be released to the environment via effluents at sites where it is produced or used as a solvent, and a plasticizer in polyester and alkyd resins, and in reinforced plastics(1). [R25] FATE: *TERRESTRIAL FATE: Alcohols and ethers are generally resistant to hydrolysis(2). They do not absorb UV light in the environmentally significant range (> 290 nm) and are commonly used as solvents for obtaining UV spectra(6). Therefore, dipropylene glycol should not undergo hydrolysis in moist terrestrial environments, or direct photolysis on sunlit soil surfaces. An estimated Henry's Law constant of 3.58X10-9 atm-cu m/mole at 25 deg C(1) indicates that volatilization of dipropylene glycol from moist soil should not be an important fate process(2). An estimated Koc of 6(2) indicates dipropylene glycol should be highly mobile in soil(3). Although aerobic screening test data suggests that the rate should be slow(4,5), biodegradation may still be an important removal mechanism of dipropylene glycol from aerobic soil(SRC). [R26] *AQUATIC FATE: Alcohols and ethers are generally resistant to hydrolysis(3). They do not absorb UV light in the environmentally significant range (> 290 nm) and are commonly used as solvents for obtaining UV spectra(6). Therefore, dipropylene glycol should not undergo hydrolysis or direct photolysis in aquatic environments. The complete miscibility of dipropylene glycol in water(1) suggests that volatilization, adsorption and bioconcentration are not important fate processes. This is supported by an estimated Henry's Law constant of 3.58X10-9 atm-cu m/mole at 25 deg C(2) which indicates that volatilization of dipropylene glycol from natural waters should be extremely slow(3). An estimated Koc of 6(3) indicates dipropylene glycol should not partition from the water column to organic matter contained in sediments and suspended solids; and an estimated bioconcentration factor (log BCF) of -1.04(3) indicates dipropylene glycol should not bioconcentrate among aquatic organisms. Although aerobic screening test data suggests that the rate should be slow(4,5), biodegradation may still be an important removal mechanism of dipropylene glycol from aquatic systems(SRC). [R27] *ATMOSPHERIC FATE: Alcohols and ethers do not absorb UV light in the environmentally significant range (> 290 nm) and are commonly used as solvents for obtaining UV spectra(5). Therefore, dipropylene glycol should not undergo direct photolysis in the atmosphere. Based on a vapor pressure of 3.19X10-2 mm Hg at 25 deg C(1), dipropylene glycol is expected to exist almost entirely in the vapor phase in ambient air(2) where vapor phase reactions with photochemically produced hydroxyl radicals may be important(SRC). The rate constant for dipropylene glycol has been estimated to be 2.97X10-11 cu cm/molecule-sec at 25 deg C, which corresponds to an atmospheric half-life of about 13 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(3). The miscibility of dipropylene glycol in water(4) indicates that physical removal from air by precipitation and dissolution in clouds may occur; however, its short atmospheric residence time suggests that wet deposition is of limited importance(SRC). [R28] BIOD: *Soil grab sample and river die-away test data pertaining to the biodegradation of dipropylene glycol in soil and natural waters were not located in the available literature. Yet, a few aerobic biological screening studies, which utilized settled waste water, sewage, or activated sludge for inocula, indicate that dipropylene glycol should biodegrade slowly in the environment(1-2). [R29] ABIO: *Alcohols and ethers are generally resistant to hydrolysis(1). They do not absorb UV light in the environmentally significant range (> 290 nm) and are commonly used as solvents for obtaining UV spectra(2). Therefore, dipropylene glycol should not undergo hydrolysis or direct photolysis in the environment(SRC). The rate constant for the vapor-phase reaction of dipropylene glycol with photochemically produced hydroxyl radicals in air has been estimated to be 2.97X10-11 cu cm/molecule-sec at 25 deg C, which corresponds to an atmospheric half-life of about 13 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(3). [R30] BIOC: *Because dipropylene glycol is miscible in water(1); bioconcentration in aquatic systems is not expected to be an important fate process. Based upon an estimated log Kow of -1.07(2), a bioconcentration factor (log BCF) of -1.04 for dipropylene glycol has been calculated using a recommended regression-derived equation(3,SRC). This BCF value also indicates dipropylene glycol should not bioconcentrate in aquatic organisms(SRC). [R31] KOC: *Because dipropylene glycol is miscible in water(1), soil adsorption is not expected to be an important fate process. Based on an estimated log Kow of -1.07(2), a Koc of 6 for dipropylene glycol has been calculated using a recommended regression-derived equation(3,SRC). This Koc value indicates dipropylene glycol will be highly mobile in soil(4), and it should not partition from the water column to organic matter contained in sediments and suspended solids(SRC). [R32] VWS: *Because dipropylene glycol is miscible in water(1); and based upon an estimated Henry's Law constant of 3.58X10-9 atm-cu m/mole at 25 deg C, which has been calculated using a bond contribution method(2), the volatilization of dipropylene glycol from natural bodies of water and moist soils is not expected to be an important fate process(3,SRC). [R33] WATC: *DRINKING WATER: Dipropylene glycol was listed as a contaminant found in drinking water for a survey of US cities including Pomona, Escondido, Lake Tahoe and Orange Co, CA and Dallas, Washington, DC, Cincinnati, Philadelphia, Miami, New Orleans, Ottumwa, IA, and Seattle(1). [R34] RTEX: *The most probable route of human exposure to dipropylene glycol is by inhalation, dermal contact and ingestion. Drinking water supplies have been shown to contain dipropylene glycol(1). [R34] *INDUSTRIAL EXPOSURE IS MOST LIKELY TO BE FROM DIRECT CONTACT AND POSSIBLE INHALATION OF MIST FROM HEATED OR VIOLENTLY AGITATED MATERIAL. [R1, 3864] *The most probable human exposure to dipropylene glycol would be occupational exposure, which may occur through dermal contact or inhalation at places where it is produced or used as a solvent, plasticizer and humectant(SRC). NIOSH (NOES Survey as of 3/28/89) has estimated that 218,354 workers are potentially exposed to dipropylene glycol in the USA(1). Non-occupational exposures may occur among populations with contaminated drinking water supplies(2). [R35] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Residues of dipropylene glycol are exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R36] NREC: *NIOSH recommends reducing exposure to lowest feasible concn and preventing contact with the skin. /Glycol ethers/ [R37] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Dipropylene glycol is produced, as an intermediate or final product, by process units covered under this subpart. [R38] FIFR: *Residues of dipropylene glycol are exempted from the requirement of a tolerance when used as a solvent or cosolvent in accordance with good agricultural practices as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops or to raw agricultural commodities after harvest. [R36] FDA: *Dipropylene glycol is an indirect food additive for use only as a component of adhesives. [R39] *Cross-linked polyester resins may be safely used as articles or components of articles intended for repeated use in contact with food. The cross-linked polyester resins are produced by the condensation of acids with one or more alcohols or epoxides incl dipropylene glycol. [R40] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *In instances where materials are very soluble in water, samples of air can be taken effectively by scrubbing through water. /Glycol ethers/ [R1, 3910] *NIOSH Method 5500. Analyte: Ethylene glycol. Matrix: Air. Sampler: Filter and Sorbent (glass fiber filter and silica gel, 520 mg/260 mg). Flow Rate: 0.2 l/min. Sample Size: 0.3 to 60 liters. Shipment: Filter in glass vial with 1 ml 2:98 2-propanol:water directly after sampling; silica gel tube sealed with plastic caps. Sample Stability: 15 days at 25 deg C. /Ethylene glycol/ [R41] ALAB: *NIOSH Method 5500. Analyte: Ethylene glycol. Matrix: Air. Procedure: Gas Chromatography, flame ionization detection. For Ethylene glycol this method has an estimated detection limit of 4 ug/6 l sample. The overall precision/RSD is 0.060 (filters); 0.080 (gel). Applicability: The working range is 7 to 330 mg/cu m for a 3 liter air sample. Interferences: None known. /Ethylene glycol/ [R41] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study on dipropylene glycol is scheduled for peer review. Route: dosed-water feed; Species: rats and mice. NTP TR No 511. [R42] SO: R1: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 430 R3: KIRK-OTHMER. CONCISE ENCYC CHEM TECH p.567 1985 R4: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 586 R5: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. R6: KIRK-OTHMER. CONCISE ENCYC CHEM TECH 1985 p.567 R7: Kavaler AR; Chemical Marketing Reporter 231 (7): 50 (1987) R8: Kavaler AR; Chemical Marketing Reporter 237 (3): 50 (1990) R9: SRI R10: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 11 (1980) R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 578 R13: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1520 R14: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 627 R15: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-45 R16: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-132 (1982) R17: American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986. 1029 R18: Kullman GJ; Health Hazard Evaluation Report GRA and I 10: 1-12 (1990) R19: Cornwell RJ, Stark G; Health Hazard Evaluation Report MHETA 87-039-1837 GRA and I 10: 1-14 (1990) R20: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1032 R21: CROCE G, FERRINI R; BOLL SOC ITAL BIOL SPER 49 (11): 653-9 (1973) R22: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Final Report on the Developmental Toxicity of Dipropylene Glycol (CAS No. 25265-71-8)in Sprague-Dawley CD(R) Rats, NTP Study No. TER91013 (May, 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R23: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of Dipropylene glycol (CAS No. 25265-71-8) in New Zealand White Rabbits, NTP Study No. TER90014 (September 1992 ) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R24: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 809 R25: (1) Hawley GG; Condensed Chemical Dictionary 10th ed Van Nostrand Reinhold NY p. 375 (1981) R26: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-9, 5-4, 6-3, 15-16 (1982) (3) Swann RL et al; Res Rev 85: 16-28 (1983) (4) Bridie AL et al; Water Res 13: 627-30 (1979) (5) Niemi, GJ et al; Environ Toxicol Chem 6: 515-27 (1987) (6) Silverstein RM, Bassler GC; Spectrometric Id Org Cmpd NY: J Wiley and Sons Inc p. 148-69 (1963) R27: (1) Hann RW, Jensen PA; Water Quality Characteristics of Hazardous Materials. NTIS-PB-285946 Texas A AND M Univ pp. 1751 (1977) (2) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-9, 5-4, 6-3, 15-16 (1982) (4) Bridie AL et al; Water Res 13: 627-30 (1979) (5) Niemi, GJ et al; Environ Toxicol Chem 6: 515-27 (1987) (6) Silverstein RM, Bassler GC; Spectrometric Id Org Cmpd NY: J Wiley and Sons Inc p. 148-69 (1963) R28: (1) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Cmpds, Design Inst for Phys Prop Data, Am Inst for Phys Prop Data, NY,NY (1989) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; Intern J Chem Kin 19: 799-828 (1987) (4) Hann RW, Jensen PA; Water Quality Characteristics of Hazardous Materials. NTIS-PB-285946 Texas A AND M Univ pp. 1751 (1977) (5) Silverstein RM, Bassler GC; Spectrometric Id of Org Cmpd NY: J Wiley and Sons Inc p. 148-69 (1963) R29: (1) Bridie AL et al; Water Res 13: 627-30 (1979) (2) Niemi, GJ et al; Environ Toxicol Chem 6: 515-27 (1987) R30: (1) Silverstein RM, Bassler GC; Spectrometric Id Org Cmpd NY: J Wiley and Sons Inc p. 148-69 (1963) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 7-4 (1982) (3) Atkinson R; Intern J Chem Kin 19: 799-828 (1987) R31: (1) Hann RW, Jensen PA; Water Quality Characteristics of Hazardous Materials. NTIS-PB-285946 Texas A AND M Univ pp. 1751 (1977) (2) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-4 (1982) R32: (1) Hann RW, Jensen PA; Water Quality Characteristics of Hazardous Materials. NTIS-PB-285946 Texas A AND M Univ pp. 1751 (1977) (2) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (4) Swann RL et al; Res Rev 85: 16-28 (1983) R33: (1) Hann RW, Jensen PA; Water Quality Characteristics of Hazardous Materials. NTIS-PB-285946 Texas A AND M Univ pp. 1751 (1977) (2) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-15 to 15-29 (1982) R34: (1) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p. 397 (1984) R35: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) (2) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p. 397 (1984) R36: 40 CFR 180.1001(c) (7/1/90) R37: NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988.16 R38: 40 CFR 60.489 (7/1/90) R39: 21 CFR 175.105 (4/1/90) R40: 21 CFR 177.2420 (4/1/90) R41: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5500-1 R42: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 35 Record 182 of 1119 in HSDB (through 2003/06) AN: 2697 UD: 200303 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACETIC-ACID,-ALLYL-ESTER- SY: *ACETIC-ACID,-2-PROPENYL-ESTER-; *3-ACETOXYPROPENE-; *3-ACETOXY-1-PROPENE-; *ALLYL-ACETATE-; *ALLYL-ACETIC-ACID-; *2-PROPENYL-METHANOATE- RN: 591-87-7 MF: *C5-H8-O2 SHPN: UN 2333; Allyl acetate IMO 3.2; Allyl acetate MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY DECARBOXYLATION BY HEATING ALLYLMALONIC ACID; OR FROM THE CORRESPONDING ETHYL ESTER PREPARED BY BOILING ETHYL 4-CHLORO-N-VALERATE IN QUINOLINE. [R1] *By acetoxylation of propylene. [R2, p. V2 156] OMIN: *IT IS USED IN NON-ALCOHOLIC BEVERAGES AT 1.0 PPM; ICE CREAM, ICES AT 2.0 PPM; CANDY AT 5.0 PPM; BAKED GOODS AT 5.0 PPM; MARGARINE AT 2.0 PPM. [R1] *FEMA NUMBER 2843 [R1] *ACYLOXY, SUBSTITUTED OR UNSUBSTITUTED ALKENYL ARE EFFECTIVE COCKROACH REPELLENTS. [R3] USE: *SYNTHETIC FLAVOR USEFUL IN CHEESE, BUTTER, FRUIT [R4] *Allyl acetate is produced mostly for manufacturing allyl alcohol. [R2, p. V2 156] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R1] ODOR: *ACRID AT HIGH LEVELS [R1] TAST: *SOUR, CARAMELLIC, WITH SWEET AFTERTASTE, ACRID AT HIGH LEVELS [R1] BP: *103.5 deg C [R5] MP: *Freezing point: -96 deg C [R2, p. V2 155] MW: *100.12 [R5] DEN: *0.9275 g/cu cm at 20 deg C [R5] OWPC: *log Kow = 0.97 [R6] SOL: *Soluble in acetone; miscible in ethanol and ethyl ether. [R5]; *2.8% in water at 20 deg C [R2, p. V2 155] SPEC: *SADTLER REFERENCE NUMBER: 6476 (IR, PRISM) [R7]; *IR: 5686 (Coblentz Society Spectral Collection) [R8]; *NMR: 18713 (Sadtler Research Laboratories Spectral Collection) [R8]; *MASS: 246 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R8]; *INDEX OF REFRACTION: 1.4049 AT 20 DEG C/D [R7]; *1.4049 at 20 deg C/D [R5] VAPD: *3.45 (AIR= 1) [R9, 2979] VAP: *27.2 mm Hg at 20 deg C /from experimentally-derived coefficients/ [R10] VISC: *0.52 cP at 20 deg C [R2, p. V2 155] OCPP: *CONVERSION FACTORS: 1 MG/L IS EQUIVALENT TO 245 PPM [R11, 1876] *CONVERSION FACTORS (WT/VOL): 4.14 MG/CU M IS EQUIVALENT TO 1 PPM [R9, 2979] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R12] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R12] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R12] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R12] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R12] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R12] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R12] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R12] FPOT: *...EVOLVE FLAMMABLE...VAPORS. [R13, 85] *Dangerous fire hazard. [R14] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R14] SERI: *ALLYL ACETATE...IS HIGHLY IRRITANT AND TOXIC BY INHALATION, INGESTION, EYE, AND DERMAL CONTACT. [R9, 2988] EQUP: *WORKERS WHO...HANDLE ALLYL ALCOHOL, OR WHO MAY BE LIABLE TO...EXPOSURE...SHOULD WEAR...PROTECTIVE EQUIPMENT APPROPRIATE TO EXTENT OF... EXPOSURE. ...EYE PROTECTION SHOULD BE PROVIDED /WHEN NECESSARY/. /ALLYL ALCOHOL/ [R13, 85] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *...VAPOR SHOULD BE PREVENTED FROM ESCAPING...INTO WORKROOM BY...EXHAUST VENTILATION. WHEN PROCESSES CANNOT BE ENCLOSED, EXHAUST...HOODS SHOULD BE FITTED TO TRAP AND EXTRACT ESCAPING VAPOR BEFORE IT CAN DIFFUSE INTO WORKROOM ATMOSPHERE. /ALLYL ALCOHOL/ [R13, 85] *PRECAUTIONS MUST BE ADOPTED...TO EXCLUDE OPEN LIGHTS OR ANY AGENCIES CAPABLE OF IGNITING VAPOR WHEN LIQUID IS BEING HANDLED IN A WARM WORKROOM. /ALLYL ALCOHOL/ [R13, 85] *TO PREVENT THE LIQUID OR VAPOR FROM COMING INTO CONTACT WITH THE WORKERS, PROCESSES IN WHICH ALLYL ALCOHOL IS PRESENT SHOULD...BE CONDUCTED IN ENCLOSED PLANT. /ALLYL ALCOHOL/ [R13, 85] *BEFORE HEAT IS APPLIED FOR PURPOSE OF WELDING OR CUTTING A VESSEL WHICH HAS CONTAINED ALLYL ALCOHOL, VESSEL SHOULD BE EMPTIED AND PURGED WITH STEAM AND AIR TO REMOVE EVERY TRACE OF FLAMMABLE LIQUID AND VAPOR. /ALLYL ALCOHOL/ [R13, 85] *PROCESS BUILDINGS SHOULD BE SO CONSTRUCTED AND PROCESS VESSELS SHOULD BE SO SITED AS TO PREVENT SPREAD OF ESCAPING LIQUID THROUGHOUT BUILDING. /ALLYL ALCOHOL/ [R13, 85] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R15] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R16] STRG: *STORAGE TANKS OUTSIDE BUILDING SHOULD BE BUNDED /SRP: DIKED/ TO PREVENT SPREAD OF ACCIDENTALLY ESCAPING LIQUID, AND A RAMPED SILL SHOULD BE CONSTRUCTED AT DOORWAYS OF STOREROOMS TO RETAIN FLAMMABLE LIQUID THAT MAY ESCAPE FROM STORAGE VESSELS INSIDE. /ALLYL ALCOHOL/ [R13, 85] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *VAPOR AND LIQ...IRRITATING TO SKIN AND MUCOUS MEMBRANE. PRODUCES LACRIMATION AND CORNEAL BURNS. LIQ MAY PRODUCE FIRST OR SECOND DEGREE BURNS WITH BLISTERING AND SUPERFICIAL NECROSIS. ... INHALED VAPOR MAY LEAD TO PULMONARY EDEMA... /ALLYL ALCOHOL/ [R17] *ALLYL ACETATE...IS HIGHLY IRRITANT AND TOXIC BY INHALATION, INGESTION, EYE, AND DERMAL CONTACT. [R9, 2988] NTOX: *IT HAS BEEN OBSERVED THAT UNSATURATED ALIPHATIC ESTERS /WHICH INCLUDE THE ALLYL ESTER OF ACETIC ACID/ EXHIBIT IRRITANT AND LACRIMATORY PROPERTIES... [R13, 84] *ALLYL ACETATE CAUSES SLIGHT SKIN IRRITATION AND MODERATE EYE EFFECT IN RABBITS. /FROM TABLE/ [R11, 1880] *ENZYMATIC HYDROLYSIS IS A NECESSARY STEP IN ACTIVATION OF ALLYL ACETATE TO HEPATOTOXINS FROM ORAL ADMIN OF 60-150 MG/KG TO RATS. [R18] NTXV: *LD50 Rat oral 0.142 g/kg; [R9, 2980] ADE: *IT IS...ABSORBED THROUGH INTACT SKIN. [R9, 2988] METB: *A MERCAPTURIC ACID WAS ISOLATED FROM URINE OF RATS TREATED SC WITH ALLYL ACETATE AND IDENTIFIED AS 3-HYDROXYPROPYLMERCAPTURIC ACID N-ACETYL-S-3-HYDROXYPROPYL-L-CYSTEINE. [R19] *MERCAPTURIC ACIDS WERE DETECTED IN URINE OF RATS FOLLOWING ADMIN OF VARIOUS ALLYL ESTERS WHICH COULD BE METAB BY ACYL-OXYGEN FISSION OR ALKYL-OXYGEN FISSION TO YIELD 3-HYDROXYMERCAPTURIC ACID OR ALLYLMERCAPTURIC ACID. LATTER OCCURRED ONLY WHEN THE ESTER WAS FORMED FROM A STRONG ACID. [R20] INTC: *125 MG/KG TRIORTHOTOLYL PHOSPHATE PRETREATMENT SIGNIFICANTLY INHIBITED RISE IN PLASMA ALANINE-ALPHA-KETOGLUTARATE TRANSAMINASE ACTIVITY AND PREVENTED CHANGES IN LIVER MORPHOLOGY PRODUCED BY 60-150 MG/KG ALLYL ACETATE ADMIN ORALLY TO RATS 18 HR AFTER PRETREATMENT. [R18] *O.5 TO 10 MG/KG PRETREATMENT WITH THE DEFOLIANT, S,S,S-TRIBUTYLPHOSPHOROTRITHIOATE (DEF) PROTECTED AGAINST HEPATOTOXICITY OF 60 MG/KG ALLYL ACETATE ADMIN ORALLY TO RATS 18 HR LATER. [R18] *PRETREATMENT OF RATS WITH 375 MG/KG PYRAZOLE, AN INHIBITOR OF ALCOHOL DEHYDROGENASE, COMPLETELY PREVENTED THE ELEVATION OF PLASMA ALANINE-ALPHA-KETOGLUTARATE TRANSAMINASE (AKT) ACTIVITY AFTER 90 MG/KG ALLYL ACETATE ADMIN. [R18] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Allyl acetate's use in the production of allyl alcohol may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 27.2 mm Hg at 20 deg C indicates allyl acetate will exist solely as a vapor in the ambient atmosphere. Vapor-phase allyl acetate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 14 hours. If released to soil, allyl acetate is expected to have high mobility based upon an estimated Koc of 80. Volatilization from moist soil surfaces is expected to occur based upon an estimated Henry's Law constant of 1.3X10-4 atm-cu m/mole. Allyl acetate's vapor pressure of 27.2 mm Hg at 20 deg C indicates a potential for volatilization from dry soil surfaces. If released into water, allyl acetate is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon the estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 9.8 hours and 6.0 days, respectively. An estimated BCF of 3.2 suggests the potential for bioconcentration in aquatic organisms is low. Estimated hydrolysis half-lives of 1.1 years and 41 days at pH values of 7 and 8, respectively, indicate hydrolysis is expected to be a slow process. In general, acetates are expected to be readily biodegradable. Occupational exposure to allyl acetate may occur through inhalation and dermal contact with this compound at workplaces where allyl acetate is used. (SRC) ARTS: *Allyl acetate's use in the production of allyl alcohol(1) may result in its release to the environment through various waste streams(SRC). [R21] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 80(SRC), determined from a log Kow of 0.97(2) and a regression-derived equation(3), indicates that allyl acetate is expected to have high mobility in soil(SRC). Volatilization of allyl acetate from moist soil surfaces may be important(SRC) given an estimated Henry's Law constant of 1.3X10-4 atm-cu m/mole(SRC) derived from its vapor pressure, 27.2 mm Hg(4), and water solubility, 2.8X10+4 mg/l(5). The potential for volatilization of allyl acetate from dry soil surfaces may exist(SRC) based on this compound's vapor pressure(4). In general, acetates are expected to be readily biodegradable(SRC). [R22] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 80(SRC), determined from a log Kow of 0.97(2) and a regression-derived equation(3), indicates that allyl acetate is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based on an estimated Henry's Law constant of 1.3X10-4 atm-cu m/mole(SRC), derived from its vapor pressure, 27.2 mm Hg(4), and water solubility, 2.8X10+4 mg/l(5). Estimated volatilization half-lives for a model river and model lake are 9.8 hours and 6.0 days, respectively(3). According to a classification scheme(5), an estimated BCF of 3.2(3,SRC), from a log Kow(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Estimated hydrolysis half-lives of 1.1 years and 41 days at pH values of 7 and 8, respectively(7), indicate hydrolysis is expected to be a slow process(SRC). In general, acetates are expected to be readily biodegradable(SRC). [R23] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), allyl acetate, which has a vapor pressure of 27.2 mm Hg at 20 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase allyl acetate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 14 hours(SRC) from the estimated rate constant(3). [R24] ABIO: *The rate constant for the vapor-phase reaction of allyl acetate with photochemically-produced hydroxyl radicals has been estimated as 2.8X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 14 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). An average alkaline second-order hydrolysis rate constant of 0.194 L/mol-sec was determined for allyl acetate at 30 deg C(2); this rate constant corresponds to half-lives of 1.1 years and 41 days at pH values of 7 and 8, respectively(SRC). [R25] BIOC: *An estimated BCF of 3.2 was calculated for allyl acetate(SRC), using a log Kow of 0.97(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R26] KOC: *The Koc of allyl acetate is estimated as approximately 80(SRC), using a log Kow of 0.97(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that allyl acetate is expected to have high mobility in soil. [R27] VWS: +The Henry's Law constant for allyl acetate is estimated as 1.3X10-4 atm-cu m/mole at 20 deg C(SRC) from its vapor pressure, 27.2 mm Hg(1), and water solubility, 2.8X10+4 mg/l(2). This Henry's Law constant indicates that allyl acetate is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is approximately 9.8 hours(SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is approximately 6.0 days(SRC). Allyl acetate's Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of allyl acetate from dry soil surfaces may exist(SRC) based on a vapor pressure of 27.2 mm Hg(1). [R28] ATMC: *SOURCE DOMINATED: Allyl acetate was identified in ambient air samples collected near the Kin-Buc chemical waste disposal site in Edison, NJ in 1976 at an estimated concentration of 31 ug/cu m(1). [R29] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 4,280 workers (1,700 of these are female) are potentially exposed to allyl acetate in the US(1). Occupational exposure to allyl acetate may occur through inhalation and dermal contact with this compound at workplaces where allyl acetate is used(SRC). [R30] BODY: *Allyl acetate was identified in approx 40% of the expired air samples collected from an urban population of 28 normal, healthy, non-smoking human subjects(1). It was detected in 36.9% of 387 expired air samples collected from 54 normal, healthy, non-smoking human subjects at a geometric mean concentration of 0.296 ng/l(2). [R31] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Cometto-Muniz JE, Cain Ws; Pharmacol Biochem Behav 39 (4): 983-990. Nasal pungency, odor, and eye irritation thresholds for homologous acetates. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on Allyl acetate is scheduled for peer review. Route: gavage; Species: rats and mice. NTP TR No 48. [R32] SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 456 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R3: TANAKA I ET AL; ALLYL DERIVATIVES AS COCKROACH REPELLENTS; JAPAN KOKAI PATNET 75105821 08/20/75 (TAISHO PHARMACEUTICAL CO, LTD) R4: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 295 R5: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-9 R6: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 14 R7: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-82 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 16 R9: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R10: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R11: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R12: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-131 R13: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R14: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 92 R15: 49 CFR 171.2 (7/1/96) R16: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3054-3 (1988) R17: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-69 R18: SILVER EH ET AL; TOXICOL APPL PHARMACOL 45(2) 377 (1978) R19: CLAPP JJ ET AL; BIOCHEM J 114(1) 6 (1969) R20: KAYE CM; BIOCHEM J 134(4) 1093 (1973) R21: (1) Nagato N; Kirk-Othmer Encycl Chem Technol 4th ed, NY,NY: John Wiley and Sons 2: 144-60 (1992) R22: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp, Vol 2 (1996) (5) Nagato N; Kirk-Othmer Encycl Chem Technol 4th ed, NY,NY: John Wiley and Sons, 2: 144-60 (1992) R23: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p. 14 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp, Vol 2 (1996) (5) Nagato N; Kirk-Othmer Encycl Chem Tech 4th ed, NY,NY: John Wiley and Sons, 2: 144-60 (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Roy RS; Anal Chem 44: 2096-8 (1972) R24: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp, Vol 2 (1996) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R25: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Roy RS; Anal Chem 44: 2096-8 (1972) R26: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p 14 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R27: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p. 14 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R28: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp, Vol 2 (1996) (2) Nagato N; Kirk-Othmer Encycl Chem Tech 4th ed, NY,NY: John Wiley and Sons,2: 144-60 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R29: (1) Pellizzari ED; Environ Sci Technol 16: 781-5 (1982) R30: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R31: (1) Krotoszynski B et al; J Chromatog Sci 15: 239-44 (1977) (2) Krotoszynski BK et al; J Anal Toxicol 3: 225-34 (1979) R32: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 26 Record 183 of 1119 in HSDB (through 2003/06) AN: 2733 UD: 200303 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2,4,5-TETRACHLOROBENZENE- SY: *BENZENE-TETRACHLORIDE-; *BENZENE,-1,2,4,5-TETRACHLORO-; *S-TETRACHLOROBENZENE- RN: 95-94-3 RELT: 4269 [1,2,3,5-TETRACHLOROBENZENE] (Isomer); 4268 [1,2,3,4-TETRACHLOROBENZENE] (Isomer) MF: *C6-H2-Cl4 SHPN: UN 1134; Chlorobenzene IMO 3.3; Chlorobenzene HAZN: U207; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... MANUFACTURED ... /BY/ THE CHLORINATION OF BENZENE WITH 4 MOLES OF CHLORINE ... [R1, p. VA6 338] *Iodine plus antimony trichloride is effective in selectively chlorinating 1,2,4-trichlorobenzene to 1,2,4,5-tetrachlorobenzene. [R2, p. V6 91] FORM: *TECHNICAL GRADE /HEXACHLOROBENZENE/ USED IN AGRIC CONTAINS 98% HEXACHLOROBENZENE, 1.8% PENTACHLOROBENZENE, and 0.2% 1,2,4,5-TETRACHLOROBENZENE. /HEXACHLOROBENZENE/ [R3, 1477] OMIN: *Distillation range: 240-246 deg C [R4] USE: *IN SYNTH OF 2,4,5-TRICHLOROPHENATE SODIUM [R5] *Int for herbicides and defoliants /former use/; insecticide /former use/; impregnant for moisture resistance; electrical insulation [R4] *USED IN THE PRODUCTION OF 2,4,5-TRICHLOROPHENOL /FORMER USE/ [R1, p. VA6 340] PRIE: U.S. IMPORTS: *(1983) 1.60X10+6 g [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS SUBLIMABLE NEEDLES [R1, p. VA6 332] ODOR: *STRONG, UNPLEASANT ODOR [R1, p. VA6 332] BP: *244.5 DEG C [R7] MP: *139.5 DEG C [R7] MW: *215.89 [R7] CTP: *Critical temp: 489.8 deg C; critical pressure: 3380 kPa [R2, p. V6 89] DEN: *1.833 kg/l [R2, p. V6 89] HTV: *221.8 J/g [R2, p. V6 89] OWPC: *Log Kow= 4.60 [R8] SOL: *Slightly soluble in ethanol; soluble in ether and benzene [R7]; *In water, 0.595 mg/l at 25 deg C. [R9] SPEC: *MAX ABSORPTION (ALCOHOL): 276 NM (LOG E= 2.81); 285 NM (LOG E= 3.02); and 294 NM (LOG E= 3.02); SADTLER REFERENCE NUMBER: 2976 (IR, PRISM) [R10]; *IR: 360 (Sadtler Research Laboratories IR Grating Collection) [R11]; *UV: 856 (Sadtler Research Laboratories Spectral Collection) [R11]; *NMR: 1179 (Sadtler Research Laboratories Spectral Collection) [R11]; *MASS: 1520 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R11] VAPD: *7.4 (air=1) [R12] VAP: *0.0054 mm Hg at 25 deg C [R13] OCPP: *NEEDLES, MONOCLINIC PRISMS FROM ETHER, ALCOHOL OR BENZENE [R11] *Heat of fusion: 112.2 J/g; heat capacity for liquid: 1.142 J/g; critical density: 0.475 kg/l [R2, p. V6 89] *Henry's Law constant = 1.0X10-3 atm-cu m/mol at 20 deg C [R13] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Chlorobenzene/ [R14] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Chlorobenzene/ [R14] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Chlorobenzene/ [R14] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Chlorobenzene/ [R14] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chlorobenzene/ [R14] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Chlorobenzene/ [R14] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Chlorobenzene/ [R14] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chlorobenzene/ [R14] FPOT: *Combustible when exposed to heat or flame. [R12] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R15] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R15] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R15] FLPT: +311 deg F (155 deg C) (closed cup) [R15] FIRP: */USE/ CARBON DIOXIDE / and / DRY CHEMICAL. [R12] REAC: *... Serious accidents have occurred during the commercial preparation of 2,4,5-trichlorophenol by alkaline partial hydrolysis of 1,2,4,5-tetrachlorobenzene during the period 1949 to 1976 ... The earlier process used methanolic alkali under autogenous pressure to effect the hydrolysis, and on 2 occasions around 1949 the reaction at 125 deg C went out of control, one attaining 400 deg C. ... In a further incidents in 1953, the explosion was associated with the post reaction stage during distillation of methanol from the reaction mixture. The later process used ethylene glycol as solvent to effect hydrolysis with sodium hydroxide and operated essentially at or near atmosphere pressure. ... Violent decomposition could ... occur during the subsequent solvent distillation phase in the absence of effective temp control. A laboratory residue from vacuum stripping using electric heating (without knowledge of the liquid temp) exploded when the vapor temp had reached 160 deg C. In the Coalite plant incident in 1968, where the hydrolysis was run at about 180 deg C in a reaction vessel heated by circulating oil at 300 deg C, failure of the manually regulated oil heating system led to an uncontrollable temp incr during 50 min to above 250 deg C, when a violent explosion occurred. [R16] *... CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. [R12] DCMP: *WHEN HEATED TO DECOMPOSITION IT EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. [R12] EQUP: *... Wear appropriate chemical protective gloves, boots and goggles. /Chlorobenzene/ [R17] OPRM: *If material /is/ not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock down vapors. /Chlorobenzene/ [R17] *Avoid breathing vapors. Keep upwind. /Chlorobenzene/ [R17] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R18] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R19] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R20] CLUP: *Environmental considerations: Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, or commercial sorbents. Apply universal gelling agent to immobilize spill. Apply appropriate foam to diminish vapor and fire hazard. /Chlorobenzene/ [R17] *Environmental considerations: Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. If dissolved, in region of 10 ppm or greater concn, apply activated carbon at ten times the spilled amount. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Chlorobenzene/ [R17] *Environmental considerations: Air spill: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. /Chlorobenzene/ [R17] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U207, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R21] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R22] *The following wastewater treatment technologies have been investigated for 1,2,4,5-tetrachlorobenzene: Biological treatment. [R23] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R24, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's to maintain hydration and adequate urine flow. Watch for signs of fluid overload and pulmonary edema. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatic hydrocarbons and related compounds/ [R24, 182] HTOX: *WORKERS PRODUCING 1,2,4,5-TETRACHLOROBENZENE SHOWED A CLUSTER OF CHROMOSOMAL ABERRATIONS. NO APPRECIABLE INCREASE WAS FOUND IN THE LINDANE WORKERS; CHROMATID-TYPE ABERATIONS WERE MODERATELY INCREASED IN WORKERS IN THE BASUDIN E (DIAZINON) AND THE SAFIDON 40 WP (PHOSMET) GROUPS; STABLE CHROMOSOME-TYPE ABERRATIONS WERE OBSERVED IN THE DITRIFON 50 (TRICHLOROFON) AND THE BASUDIN E GROUPS. [R25] NTOX: *OF 12 CHLORINATED BENZENES GIVEN ORALLY TO RATS, THE ONES WITH HIGHEST CHLORINE NUMBER, SUCH AS 1,2,3,4-TETRACHLOROBENZENE, HAD THE MOST DELTA-AMINOLEVULINIC ACID SYNTHETASE (DELTA-ALA), CYTOCHROME P450 AND DRUG METABOLIZING ENZYME INCREASING ACTIVITY. [R26] *PURE HEXACHLOROBENZENE AND DIFFERENT MIXT WERE FED TO RATS. 20% OF HEXACHLOROBENZENE WAS REPLACED BY 1,2,4,5-TETRACHLOROBENZENE. DETERMINATION OF PORPHYRINS AT DIFFERENT INTERVALS ONCE FEEDING HAD STARTED DID NOT GIVE RISE TO AN INCR IN PORPHYRIA. [R27] *1,2,4,5-TETRACHLOROBENZENE WAS ADMIN IN DIET TO DOGS AT 5 MG/KG/DAY FOR 2 YR, FOLLOWED BY A 20 MONTH RECOVERY PHASE. AFTER 18 MO OF EXPOSURE, ALL CLINICAL CHEM PARAMETERS WERE NORMAL. AFTER 24 MO, SERUM ALKALINE PHOSPHATASE ACTIVITY AND TOTAL BILIRUBIN LEVELS WERE SLIGHTLY ELEVATED. [R28] *Groups of 10 male and 10 female rats were dosed orally with 1,2,3,4-, 1,2,4,5- and 1,2,3,5-tetrachlorobenzene at levels that ranged from 200-4000 mg/kg, and were observed clinically for 14 days. ... Clinical signs of toxicity included depression, flaccid muscle tone, prostration, piloerection, loose stool, hypothermia, dacryorrhea, coma, and death. [R29] *Groups of 15 male and 15 female rats were fed diets containing 0, 0.5, 5.0, 50 or 500 ppm of each of 1,2,3,4- 1,2,3,5- and 1,2,4,5-tetrachlorobenzene (TCB) for 13 weeks. Rats fed 500 ppm 1,2,4,5-TCB exhibited significant increases in liver and kidney weight. Moderate to severe histological changes occurred in the liver and kidney of rats fed the three isomers, but the 1,2,4,5-isomer caused more severe lesions. 1,2,4,5-TCB accumulated in fat and liver in a dose dependent manner. Results indicate that 1,2,4,5-TCB is the most toxic isomer of the three. [R30] *The effective concentrations of benzene and twelve chlorobenzenes that reduced 50% of the primary productivity ... of a freshwater green algae, Ankistrodemus falcatus, were determined. Benzene was the least toxic chemical and the toxicity increased as the degree of chlorine substitution in the aromatic ring increased. /Chlorobenzenes/ [R31] *RESORPTION OF ORG TRACE IMPURITIES IN WATERS IN BODY WAS INVESTIGATED. TIME AND DOSE-DEPENDENCE OF ACCUM OF HEXACHLOROBENZENE AND TETRACHLOROBENZENE DERIV IN RAT WAS STUDIED. RESULTS ARE DISCUSSED WITH REGARD TO NEW CONSIDERATIONS ON HOW DRINKING WATER STD FOR ORG CMPD CAN BE ESTABLISHED. [R32] *Three tetrachlorobenzene (TCB) congeners (1,2,3,4-, 1,2,3,5-, and 1,2,4,5-) were administered daily by gavage to pregnant Sprague-Dawley rats at levels of 50, 100, or 200 mg/kg from day 6 through 15 of gestation. Mothers were sacrificed on day 21 of gestation and the pups removed by cesarean section for teratological evaluation. Administration of 1,2,3,4- and 1,2,3,5-TCB failed to alter maternal body weight, organ weights, hematological, or biochemical parameters. The highest dose level of 1,2,4,5-TCB caused maternal death in 9 of 10 animals. In addition, it induced mixed function oxidases and increased serum cholesterol values at 50 and 100 mg/kg. There was a decrease in the number of fetuses at the highest dose levels of 1,2,3,4- and 1,2,3,5-TCB and at the lowest dose level of the 1,2,4,5- congener. None of the congeners produced any anomalies. There were no treatment-related histopatholgical changes in either the mothers or fetuses. Residues of all three congeners were found in maternal and fetal tissues but generally the amounts of the 1,2,4,5- isomer were about 100 times higher than the other two. [R33] *1,2,4,5-Tetrachlorobenzene at 30, 100, 300, and 1000 mg/kg/day was orally administered to rats on days 9, 10, 11, 12, and 13 of gestation and the animals were sacrificed on day 14 of pregnancy. ... The maternal hepatic microsomal enzyme induction observed after TCB administration to pregnant rats suggests the presence of both cytochrome p450 and p448 inducers in the sample of TCB used. [R34] *... THE CONTENTS OF CYTOCHROMES AND HEPATIC CONSTITUENTS IN ADDITION TO THE ACTIVITIES OF DRUG-METABOLIZING ENZYMES AND DELTA-AMINOLEVULINIC ACID (DELTA-ALA) SYNTHETASE WERE EXAMINED IN RATS TREATED WITH ... 1,2,4,5-TETRACHLOROBENZENE ... THE CONTENT OF CYTOCHROME P450 AND ACTIVITIES OF AMINOPYRINE DEMETHYLASE AND ANILINE HYDROXYLASE WERE INCR BY ORAL ADMINISTRATION /OF 1,2,4,5-TETRACHLOROBENZENE/ ... AS A DAILY DOSE OF 250 MG/KG, ONCE DAILY, FOR 3 DAYS. ... THE ACTIVITY OF DELTA-ALA SYNTHETASE WAS INCREASED ... [R3, 1488] *All 11 chlorobenzenes studied stimulated Bacillus hydrogenase activity as measured by the resazurin method, implying the perturbation of bacterial cellular components or functions by chlorobenzenes. /Chlorobenzenes/ [R35] *Control and phenobarbital or polychlorinated biphenyl pretreated rats were given single oral doses of (14)C-1,2,4,5-tetrachlorobenzene at 30 or 300 mg/kg body weight. ... Both phenobarbital and polychlorinated biphenyl increased the rate of (14)C-1,2,4,5-tetrachlorobenzene excretion and decreased the levels of radioactivity in most tissues examined at 7 days after dosing. It was concluded that, at the dose ranges studied, pretreatment with phenobarbital or polychlorinated biphenyl did not significantly alter the toxic effects produced by (14)C-1,2,4,5-tetrachlorobenzene. [R36] *These studies were designed to investigate the relationship between the initial uptake of a model toxicant, 1,2,4,5-tetrachlorobenzene (TCB), and the rate of oxygen consumption in trout during exercise. There was no effect of environmental TCB concentrations ((TCB)) on the rate of oxygen consumption of resting or exercising adult rainbow trout, and body accumulations of the toxicant did not affect the maximal aerobic swimming velocity attained by juvenile rainbow trout. Rainbow trout were exposed to TCB for 1 hr while swimming at different velocities and the (TCB) was measured in plasma and 11 other tissues. Tissue TCB concentrations were found to be extremely variable despite similar exposure conditions, likely due to differences in tissue lipid content. No one tissue was representative of body burden, but tissue TCB delivery appears to be directly related to the (TCB) in the plasma because at different swimming velocities the plasma: tissue TCB ratios remained constant despite regional changes in blood flow. After 2 hr of TCB exposure, (TCB) in the plasma was equal to whole-body (TCB); however, this relationship broke down after 6 h. Thus, whole-body TCB concentrations can only be obtained through direct measurement. There was a highly significant relationship (r2 = 0.79) between the rate of oxygen consumption and TCB uptake rate during initial toxicant exposure in adult rainbow trout forced to swim over a large proportion of its aerobic potential. Thus, toxicant uptake in fish may be estimated based upon the rate of oxygen consumption, which can be measured or can be obtained from the literature [R37] ETXV: *LC50 Bluegill (sunfish) 5.69 mg/l/24 hr; 4.35 mg/l/48 hr; 1.55 mg/l/96 hr /Conditions of bioassay not specified/; [R38] *LC50 Sheepshead minnow > 1.80 mg/l/24 hr; 0.90 mg/l/48 hr /Conditions of bioassay not specified/; [R38] *LC50 Guppy (Poecilia reticulata) 0.30 ppm/14 days /Conditions of bioassay not specified/; [R39] NTP: +1,2,4,5-Tetrachlorobenzene (TCB) was tested for its effects on fertility and reproduction in Swiss CD-1 mice using the continuous breeding protocol. Male and female mice (F0) were continuously exposed for a 7 day precohabitation and a 98 day cohabitation period (Task 2) to TCB at levels of 0.028, 0.072, and 0.18% /weight/volume/ in the diet. TCB treatment at 0.18% was significantly more toxic than anticipated. Nineteen of the 20 high-dose females died (or were humanely sacrificed) and almost all of these deaths occurred at parturition. None of the males died. In the 0.072% group, a 9% (significant) decr in the number of live pups/litter was noted; no changes were observed in pup weights, proportion of male pups, or days to deliver each litter. Task 3, the determination of the affected sex, was not conducted, given the small change in litter size. At terminal sacrifice, the avg liver weight and the liver-to-body weight ratio in F0 males exposed to 0.18% TCB were almost twice the control values. In the F1 generation, liver and kidneys were enlarged in both sexes exposed to 0.072% TCB. Sperm abnormalities were greater in the 0.18% TCB group by 40%, compared to controls. Seminal vesicle weight was increased in the high-dose-treated males. The second generation was reared consuming control diet, or diet with 0.072% TCB. At sexual maturity, there was no difference in mating, litter size, pup weight (absolute or adjusted), or dam weight. At F1 necropsy, there was an incr in the absolute and relative weights of liver, kidneys, and testis in the 0.072% TCB group, with similar increases in female liver and kidneys weights. There was no change in F1 female estrual cycle parameters. TCB, under the present experimental conditions, exerted mild reproductive toxicity in the presence of considerable systemic toxicity. Thus, TCB is a reproductive toxicant in the presence of significant systemic toxicity. [R40] TCAT: ?The skin absorption of 1,2,4,5-tetrachlorobenzene (TCB) was studied in male New Zealand rabbits (number of animals not reported) exposed to TCB by skin painting at concentrations of 0, 1 or 2 g/kg. The animals were placed on their backs and were denied access to food or water. Blood samples were taken at 3, 6, 12, and 24 hrs, the samples were extracted with isooctane, and the extracts analyzed for the presence of TCB. No TCB was detected in blood plasma up to 24 hrs after skin application. The TCB animals exhibited symptoms of hyperemia and slight edema of the skin. [R41] POPL: *... Certain medical conditions /skin, liver, kidney, and chronic respiratory disease/ ... might place the employee at increased risk from chlorobenzene exposure. /Chlorobenzene/ [R42] ADE: *1,2,4,5-TETRACHLOROBENZENE ACCUM IN ADIPOSE TISSUE FOLLOWING CONTINUOUS ADMIN WITH FOOD TO RATS. [R43] *AT END OF 2 YR EXPOSURE AT 5 MG/KG/DAY IN DIET OF DOGS, 1,2,4,5-TETRACHLOROBENZENE REACHED 98 and 97% OF CALCULATED STEADY STATE CONCN IN FAT AND PLASMA. IT WAS ELIMINATED FROM FAT AND PLASMA WITH HALF-LIFE OF 111 and 104 DAYS. RATE OF ELIMINATION RESULTED IN DRAMATIC CHANGES IN FAT/PLASMA RATIO. [R28] *Three tetrachlorobenzene (TCB) congeners (1,2,3,4-, 1,2,3,5-, and 1,2,4,5-tetrachlorobenzene) were administered daily by gavage to pregnant Sprague-Dawley rats at levels of 50, 100, or 200 mg/kg from day 6-15 of gestation. Residues of all three congeners were found in maternal and fetal tissues but generally the amounts of the 1,2,4,5- isomer were about 100 times higher than the other two. [R33] *... This study was designed to determine the subchronic toxicity of the tetrachlorobenzenes. Results indicated that 1,2,4,5-tetrachlorobenzene accumulated in fat and liver in a dose dependent manner. [R44] *THE MEAN LEVELS OF CHLOROBENZENES (INCLUDING 1,2,4,5-TETRACHLOROBENZENE) IN HUMAN MILK AND ADIPOSE TISSUE WERE DETERMINED AND RANGED FROM TRACES TO 25 UG/KG FOR HUMAN MILK AND FROM NOT DETECTED TO 146 UG/KG FOR ADIPOSE TISSUE. THE DISTRIBUTION OF DIFFERENT CHLOROBENZENE ISOMERS IN ADIPOSE TISSUE AND MILK WAS DIFFERENT. [R45] METB: *... /IN URINE FROM RATS DOSED/ WITH TOTAL OF 300 MG/KG OF HEXACHLOROBENZENE FOR 10 MONTHS ... 1,2,4,5-TETRACHLOROBENZENE AND CERTAIN OTHER CHLOROBENZENES WERE DETECTED, BUT NOT COMPLETELY IDENTIFIED. [R3, 1487] *ORAL ADMIN OF 100 MG/KG HEXACHLOROBENZENE TO RATS TWICE/WK PRODUCED 1,2,3,4-TETRACHLOROBENZENE IN URINE AND 1,2,4,5-TETRACHLOROBENZENE IN FECES. [R46] *1,2,4,5-TETRACHLOROBENZENE IS METABOLIZED TO 2,3,5,6-TETRACHLOROPHENOL IN RABBITS. /FROM TABLE/ [R47] *Lindane administered to hen pheasants resulted in tetrachlorobenzene being identified ... as part of the array of metabolites found in eggs and chicks as well as in the body tissues of hens. /Tetrachlorobenzenes/ [R48] *Tetrachlorobenzenes have ... been identified as metabolites of gamma-pentachlorocyclohexane in corn and pea seedlings. /Tetrachlorobenzenes/ [R49] *The metabolism of both 1,2,3,4-tetrachlorobenzene and 1,2,3,5-tetrachlorobenzene yielded two common metabolites 2,3,4,5- and 2,3,4,6-tetrachlorophenol. Another metabolite of 1,2,3,5-tetrachlorobenzene was 2,3,5,6-tetrachlorophenol which was the only metabolite identified following the administration of 1,2,4,5-tetrachlorobenzene. [R50] *Adult male rats were given orally single doses of (14)C-labeled ... 1,2,4,5-tetrachlorobenzene (TCB) at 10 mg/kg body weight, and were housed in individual metabolism cages to collect urine and feces for radioassay. ... Analysis of urine indicated that the tetrachlorobenzene was biotransformed to a number of polar compounds. [R51] *WHEN PENTACHLOROBENZENE WAS ADDED TO CULTURE OF MOLD, DEGRADATION PRODUCED FOLLOWING METABOLITES: PENTACHLOROPHENOL, 2,3,4,5- and 2,3,4,6-TETRACHLOROPHENOL; 1,2,3,4-TETRACHLOROBENZENE; 1,2,4,5- and /OR 1,2,3,5-TETRACHLOROBENZENE; 2,3,4-, 2,4,6- and 3,4,5-TRICHLOROPHENOL; and 1,3,5-TRICHLOROBENZENE. [R52] BHL: *AT END OF 2 YR EXPOSURE AT 5 MG/KG/DAY IN DIET OF DOGS, 1,2,4,5-TETRACHLOROBENZENE WAS ELIMINATED FROM FAT AND PLASMA WITH HALF-LIFE OF 111 and 104 DAYS. [R28] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2,4,5-Tetrachlorobenzene's former production and use as an insecticide and intermediate in the production of herbicides and defoliants will have resulted in its release to the environment through various waste streams. It is a degradation byproduct of pentachlorobenzene and hexachlorobenzene and therefore may enter the environment as a result of the microbial degradation of these compounds. Based on a vapor pressure of 0.005 mm Hg at 25 deg C, 1,2,4,5-tetrachlorobenzene is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2,4,5-tetrachlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of 200 days. 1,2,4,5-Tetrachlorobenzene is expected to have low mobility in soils based upon log Koc values in the range of 3.2-3.9. Volatilization of 1,2,4,5-tetrachlorobenzene from dry soil surfaces is not expected to be important based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is expected based on the Henry's Law constant of 1.0X10-3 atm-cu m/mole at 20 deg C, but adsorption may attenuate this process. Biodegradation of 1,2,4,5-tetrachlorobenzene is expected to occur slowly based on a half-life of 47 days in a sewage sludge amended soil and a half-life of 29 days in anaerobic river sediment. In water, 1,2,4,5-tetrachlorobenzene is expected to adsorb to sediment or particulate matter based on its measured Koc values. This compound is expected to volatilize from water surfaces given its Henry's Law constant, but adsorption may attenuate this process. Estimated volatilization half-lives for a model river and model lake are 6 and 150 hours, respectively if adsorption is neglected. The volatilization half-life from a model pond is about 34 days when adsorption is considered. When irradiated with light greater than 285 nm, this compound was 61 percent degraded in a water solution in 16 hrs, suggesting that photolysis in surface waters may be important. Bioconcentration in aquatic organisms is considered high based on BCF values in the range of 1,600 to 4,800 measured in carp and log BCF values of 3.7-4.1 measured in trout. The general population may be exposed to 1,2,4,5-tetrachlorobenzene via inhalation of ambient air, ingestion of food and drinking water. (SRC) ARTS: *The Interagency Testing Committee (ITC) cited several possible sources of contamination /of air, water, soil, and food chains by chlorinated benzenes/ which include the use of chlorinated benzenes as chemical intermediates, as solvents in the manufacture of dyes, as lubricants and pesticides, and as transformer oils. /Chlorinated benzenes/ [R53] *1,2,4,5-Tetrachlorobenzene's /former/ production and use as an insecticide and intermediate in the production of herbicides and defoliants may have resulted in its release to the environment through various waste streams(1,SRC). [R54] *1,2,4,5-Tetrachlorobenzene is a degradation byproduct of pentachlorobenzene and hexachlorobenzene and therefore may enter the environment as a result of the microbial degradation of these compounds(1,SRC). [R55] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), and log Koc values in the range of 3.2-3.9(2-4), 1,2,4,5-tetrachlorobenzene is expected to have low mobility in soil(SRC). Volatilization of 1,2,4,5-tetrachlorobenzene is expected from moist soil surfaces(SRC) given its Henry's Law constant of 1.0X10-3 atm-cu m/mole at 20 deg C(5), but adsorption may attenuate this process(SRC). Volatilization of 1,2,4,5-tetrachlorobenzene from dry soil surfaces is not expected(SRC) based on a vapor pressure of 0.005 mm Hg at 25 deg C(5). Biodegradation is expected to occur slowly based on a half-life of 47 days in a sewage sludge ammended soil(6). [R56] *AQUATIC FATE: Based on a recommended classification scheme(1), and log Koc values in the range of 3.2-3.9(2-4), 1,2,4,5-tetrachlorobenzene is expected to adsorb to suspended solids and sediments in water(SRC). 1,2,4,5-Tetrachlorobenzene is expected to volatilize from water surfaces(5,SRC) given its Henry's Law constant of 1.0X10-3 atm-cu m/mole at 20 deg C(6), but adsorption may attenuate this process(SRC). Estimated volatilization half-lives for a model river and model lake are 6 and 150 hours, respectively when neglecting adsorption(5,SRC). The volatilization half-life in a model pond is approximately 34 days when adsorption is considered(7). According to a classification scheme(8), BCF values in the range of 1,600 to 4,800, measured in carp(9) and log BCF values of 3.7-4.1 measured in trout(10), suggest that bioconcentration in aquatic organisms is high(SRC). Biodegradation is expected to occur slowly based on a half-life of 29 days measured in anaerobic river sediment(11). When irradiated with light greater than 285 nm, this compound was degraded 61 percent in a water solution in 16 hrs(12), suggesting that photolysis in surface waters may be important(SRC). [R57] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2,4,5-tetrachlorobenzene, which has a vapor pressure of 0.005 mm Hg at 25 deg C(2), is expected to exist in the vapor phase in the ambient atmosphere. Vapor-phase 1,2,4,5-tetrachlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 200 days(SRC) from its estimated rate constant of 8.2X10-14 cu cm/mole-sec(3). [R58] BIOD: *Using the Warburg technique, 1,2,4,5-tetrachlorobenzene was not biologically-oxidized by benzene-acclimated activated sludge at a concn of 500 ppm over 192 hr of incubation(1). Microbial decomposition of 1,2,4,5-tetrachlorobenzene by a Pseudomonas sp. or by a mixed culture of soil bacteria yielded 2,3,5,6-tetrachlorophenol(2,3). An analysis of monitoring data from sediment cores indicated insufficient evidence to show occurrence of anaerobic dehalogenation of tetrachlorobenzene in Lake Ontario sediments(4). Anaerobic incubation of 1,2,4,5-tetrachlorobenzene with mixed primary sewage sludge for 32 days reduced its concn by 61%(5). [R59] *A 0% theoretical BOD in sludge over a 4 week incubation period suggests that biodegradation of 1,2,4,5-tetrachlorobenzene will be slow(1). 1,2,4,5-Tetrachlorobenzene was biodegraded by an acclimated anaerobic sediment slurry obtained from the Tsurumi River, Japan(2). The first-order biodegradation rate constant was 0.024 days-1, corresponding to a half-life of about 29 days(2). The half-life of 1,2,4,5-tetrachlorobenzene in sewage sludge amended soil was 47 days(3). An enriched microbial culture derived from sediment of the Rhine River reductively dechlorinated 1,2,4,5-tetrachlorobenzene to 1,2,4-trichlorobenzene in 280 days after a lag period of 47 days(4). [R60] ABIO: *The rate constant for the vapor-phase reaction of 1,2,4,5-tetrachlorobenzene with photochemically-produced hydroxyl radicals has been estimated as 8.2X10-14 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 200 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 1,2,4,5-Tetrachlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(SRC). 1,2,4,5-Tetrachlorobenzene in a water solution irradiated at wavelengths greater than 285 nm was 61 percent degraded in 16 hours(2). [R61] BIOC: *Bioconcentration factor predicted from water solubility= 225 (calculated). /From table/ [R62] *BCF values of 2,700 to 4,800 were calculated in carp exposed to 10 ug/l of 1,2,4,5-tetrachlorobenzene during a 6 week incubation period and BCF values of 1,600 to 3,900 were measured in carp exposed to 1 ug/l of 1,2,4,5-tetrachlorobenzene during a 6 week incubation period(1). Mean log BCF values of 3.7-4.1 were calculated for rainbow trout exposed to 1,2,4,5-tetrachlorobenzene(2). Mean BCF values of 4,500 and 4,900 were calculated in fish exposed to 1,2,4,5-tetrachlorobenzene in flowing water and static aquaria(3). According to a classification scheme(4), these BCF values suggest that bioconcentration in aquatic organisms is high(SRC). [R63] KOC: *Koc= 1600 (calculated). /From table/ [R62] *Log Koc values of 3.9(1) and 3.2(2) were observed for 1,2,4,5-tetrachlorobenzene. A log Koc value of 3.9 was measured for 1,2,4,5-tetrachlorobenzene in sediment obtained from Ise Bay, Japan(3). According to a recommended classification scheme(4), these Koc values suggest that 1,2,4,5-tetrachlorobenzene has low mobility in soil(SRC). [R64] VWS: *The Henry's Law constant for 1,2,4,5-tetrachlorobenzene is 1.0X10-3 atm-cu m/mole at 20 deg C(1). This value indicates that 1,2,4,5-tetrachlorobenzene will volatilize from water(2,SRC), but adsorption may attenuate this process(SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as approximately 6 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as approximately 150 hours(SRC). The volatilization half-life in a model pond is approximately 34 days when adsorption is considered(3). 1,2,4,5-Tetrachlorobenzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is expected, but adsorption may attenuate(SRC). 1,2,4,5-Tetrachlorobenzene is not expected to volatilize from dry soil surfaces(SRC) based on a vapor pressure of 0.005 mm Hg at 25 deg C(1). [R65] WATC: *DRINKING WATER: Combined isomers of tetrachlorobenzene were detected in the drinking water of homes near Love Canal, NY at concns of 120-2,000 ng/l(1). 1,2,4,5-Tetrachlorobenzene was detected in drinking water from 3 Canadian cities near Lake Ontario, with a mean concn of 0.2 ng/l (2). [R66] *SURFACE WATER: A mean concentration of 0.1 ng/l was reported at 5 stations on Lake Ontario, but 1,2,4,5-tetrachlorobenzene was not detected in Lake Huron or the Grand River(1). Concentrations of 0.63-6.9 ng/l (mean concn 1.6 ng/l) were detected in Niagara River water between Sept. 1981 and March 1983(2). Levels of 0.39-9.3 ng/l (mean concn 2.0 ng/l) were found in the Niagara River at Niagara-on-the Lake(3). Unidentified isomers of tetrachlorobenzene were detected at levels of 25-200 ppm in water samples taken from sites near two hazardous waste disposal areas in Niagara Falls, NY(4). 1,2,4,5-Tetrachlorobenzene was identified, not quantified, in water/sediment samples from Love Canal, NY(5). Concn of 25 ng/l found in the Rhine River in Germany in 1977(6). Concentrations ranging from approximately 1 to 100 ng/l were detected in the Rhine River in July 1976(7). [R67] *SURFACE WATER: Tetrachlorobenzenes (1,2,4,5- and/or 1,2,3,5-tetrachlorobenzene) have been found in water from 9 of 14 stations in Lake Ontario sampled in Oct 1983. The concn found at positive stations ranged from 0.009-0.322 ng/l and the avg of positives was 0.064 ng/l(1). [R68] *SURFACE WATER: 1,2,4,5-Tetrachlorobenzene was reported at a mean concn of 0.1 parts per trillion in Lake Ontario(1). 1,2,4,5-Tetrachlorobenzene was detected at concns of 0.39-9.3 ng/l in the Niagara River(2). Water collected in the vicinity of an industrial outfall in the Calacasieu River, LA contained 1,2,3,5- and 1,2,4,5-tetrachlorobenzene at a concn of 42 ng/l(3). Combined isomers of tri- and tetrachlorobenzene were reported in rivers from Slovenia at a mean concn of 80 ng/l(4) and combined isomers of 1,2,3,5- and 1,2,4,5-tetrachlorobenzene were detected at 0.04 ug/l in the Forth Estuary, England(5). 1,2,4,5-Tetrachlorobenzene was detected at concns of 0.048, 0.053 and 0.057 ng/l in Lake Ontario(6). 1,2,4,5-Tetrachlorobenzene was reported at an avg concn of 73 pg/l in Lake Ontario(7). 1,2,4,5-Tetrachlorobenzene was detected in the Elbe River, Germany at concns of 0.2-1.6 ng/l(8). 1,2,4,5-Tetrachlorobenzene was reported at mean concns of 0.02 ng/l (Edwards Point) and 0.04 ng/l (Port Lambton) in Ontario, Canada(9). [R69] EFFL: *Concentrations of 0.3 to 2 ng/l (mean concentration 1.2 ng/l) were reported in waste water effluents from 4 treatment plants discharging into Lake Ontario and the Grand River(1). An unidentified isomer of tetrachlorobenzene was qualitatively identified in an effluent from a sewage treatment plant(2). 1,2,4,5-Tetrachlorobenzene was identified, not quantified, in effluent from the organic chemical industry in the US from 1979 to 1982(3). 1,2,4,5-Tetrachlorobenzene was found at concn of 81, 80, and 550 ng/cu m in the raw flue gas (up-stream from the electrostatic precipitator) from three runs under different conditions of a Swedish hazardous waste incinerator which was burning chlorinated waste, mostly solvents(4). [R70] *Combined tetrachlorobenzene isomers were detected at concns of 38-1,800,000 ng/cu m in the effluent of a waste gasification and combustion pilot plant(1) and detected at concns of 74.7 and 48 ng/cu m in the effluent of a hazardous waste incinerator in Biebesheim, Germany(2). 1,2,4,5-Tetrachlorobenzene was identified, not quantified, in pulp mill effluents in Canada(3). Combined tetrachlorobenzene isomers were detected at concns of 29 and 57 ug/cu m in the effluent of municipal refuse incinerators located in Virginia and Ohio, respectively(4). 1,2,4,5-Tetrachlorobenzene was detected at concns of 450 and 100 ppb in the ash of municipal waste incinerators in the US(5). [R71] SEDS: *1,2,4,5-Tetrachlorobenzene was detected in the sediment of Lake Ketelmeer, Netherlands at concns of 45 and 20 ng/kg(1). Mean 1,2,4,5-tetrachlorobenzene concns of 0.3, 1, 1 and 52 ppb were reported in the surficial sediments from Lakes Superior, Huron, Erie, and Ontario, respectively(2). Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene was detected at concns of 0-0.4 ng/g in sediment from Ise Bay, Japan(3). 1,2,4,5-Tetrachlorobenzene was detected at a max concn of 21 ng/g in sediment taken from the Scheldt estuary, Netherlands(4). Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene was detected in soil samples in Niagara Falls, NY at mean concns of 910, 4,620, 2,000, 1,300 and 290 pg/g(5). Sediment from the St Lawrence River contained 1,2,4,5-tetrachlorobenzene at concns of 0.18-2.1 ng/g(6). 1,2,4,5-Tetrachlorobenzene was detected in sediment(42 ng/g) and suspended particulate matter (14 ng/g) in Lake Ontario(7). Combined isomers of 1,2,3,5- and 1,2,4,5-tetrachlorobenzne were detected in sediment off the coast of Taiwan at concns of 1-12 ng/g(8). [R72] *Mean concentrations of 0.3, 1, 1, and 52 ppb were detected in surficial sediments from Lake Superior, Lake Huron, Lake Erie and Lake Ontario, respectively(1). Concentrations of 0.6 to 210 ppb found in a Lake Ontario sediment core (0 to 8 cm in depth) with the higher concentration in the upper 2 cm(1). Concentration of 17 ng/g detected in the settling particulates at a station on Lake Ontario(2). Concentrations ranging from 7 to 24 ng/g detected in suspended sediments collected at 6 locations of the Niagara River in 1982(3). Concentrations ranging from 13 to 21 ng/g detected in suspended sediment of Lake Ontario at depths from 20 to 68 meters with an average concentration of 68 ng/g found on bottom sediment(3). Unidentified isomers of tetrachlorobenzene identified at levels from not detected to 70 ng/g in the suspended sediment of the Niagara River in 1981(4). Qualitative detection reported for sediments collected in a canal in Berlin, Germany(5). Qualitative detection reported for both soil and sediment collected near the Love Canal(6). The ranges and mean concn (dry wt basis) of 1,2,4,5-tetrachlorobenzene detected in sediments taken from the following Great Lakes area in 1980 and 1982 were: southern Lake Huron, 0.3-1.7 ppb, 1.1 ppb avg; Lake St. Clair, 3.3-7.8 ppb, 5.6 ppb avg; western Lake Erie; 0.6-5.3 ppb, 1.7 ppb avg; central Lake Erie, 0.2-0.9 ppb, 0.6 ppb avg; and eastern Lake Erie, 0.2-1.0 ppb, 0.6 ppb avg(7). [R73] *SEDIMENT SAMPLES FROM THE WESTERN PORTION OF LAKE ONTARIO WERE COLLECTED IN OCTOBER 1980. THE SAMPLES WERE ANALYZED FOR CHLORINATED ORGANIC COMPOUNDS USING GC/MS. MANY OF THE CHLORINATED COMPOUNDS PREVIOUSLY FOUND TO BE LEAKING INTO THE NIAGARA RIVER FROM WASTE DISPOSAL SITES IN THE CITY OF NIAGARA FALLS WERE IDENTIFIED IN THE SEDIMENTS OF LAKE ONTARIO. THE COMPOUNDS (INCLUDING PENTACHLOROBENZENE) SHOWED A TENDENCY TO ACCUMULATE IN THE ZONES OF HIGH SEDIMENTATION IN BOTH THE NIAGARA AND MISSISSAUGA BASINS. THE AVERAGE RELATIVE CONCENTRATIONS OF TRI, TETRA, PENTA, AND HEXACHLOROBENZENES OBSERVED AT THE NIAGARA RIVER DUMP SITES WERE 25%, 100%, 45%, AND 25%, RESPECTIVELY. IN THE NIAGARA BASIN OF LAKE ONTARIO, THE CORRESPONDING PROPORTIONS WERE 72%, 100%, 48%, AND 126% (NORMALIZED TO TETRACHLOROBENZENE FOR COMPARISON). /TETRACHLOROBENZENE/ [R74] ATMC: *URBAN/SUBURBAN: 1,2,4,5-Tetrachlorobenzene was detected in the air of Hamburg, Germany at concns of 0.5-20.9 ng/cu m(1). Combined tetrachlorobenzene isomers were detected at mean concns of 690 parts per trillion in the urban air of the US and 95 parts per trillion in source dominated air(2). 1,2,4,5-Tetrachlorobenzene was detected in suburban air in MI at concns of 22-30 pg/cu m(3). The overall mean concn of tetrachlorobenzene isomers in 3 US locations was 3,502 ng/cu m with mean concns of 198 ng/cu m in urban-remote areas, 6,196 ng/cu m in urban areas and 853 ng/cu m in source dominated areas(4). Combined tetrachlorobenzene isomers were detected at concns of trace levels to 300 ng/cu m in the air of Love Canal, NY(5). [R75] FOOD: *1,2,4,5-Tetrachlorobenzene was detected in potatoes (0.486 and 2.19 mg/kg) and lettuce (0.012 mg/kg)(1). Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene were detected in the following oils: corn (0.04 mg/kg), rape (0.005 mg/kg), sunflower (0.001 mg/kg), peanut (0.001 mg/kg), sesame (0.005 mg/kg) walnut (0.005 mg/kg), hazelnut (0.01 mg/kg) and poppy (0.005 mg/kg)(2). 1,2,4,5-Tetrachlorobenzene was detected in meat from Yugoslavia at a concn of 1.8 ng/g(3). [R76] PFAC: PLANT CONCENTRATIONS: *Combined isomers of tri- and tetrachlorobenzene were detected in pine needles at concns of 3-30 ng/g and grass at 15 ng/g(1). [R77] FISH/SEAFOOD CONCENTRATIONS: *A mean concentration of 0.5 ng/g was detected in rainbow trout taken from Lake Ontario(1). Concentrations of 0.3, 1, 0.2 and 2-5 ppb detected in trout from Lake Superior, Lake Huron, Lake Erie and Lake Ontario, respectively(2). Concentrations of 2-81 ng/g (fat basis) found in Yugoslavian fish(3). Tetrachlorobenzene (1,2,4,5- and/or 1,2,3,5-tetrachlorobenzene) have been found in concn of 0.08-1.5 ppm on a fat basis in fish from Norwegian coastal waters polluted by industrial effluents(4). 1,2,4,5-Tetrachlorobenzene was detected in composite samples of sedentary fish from 3 of 16 Lake Superior and Lake Huron tributaries sampled in the fall of 1983(5). The concn on a fat basis of chemical found in the composite samples of carp from the Flint River, MI was not detected/8.6 ppb (duplicate analysis results of the same sample), 150 ppb in the composite sample of carp from Saginaw Bay, MI, and 66/74 ppm in the composite sample of carp from the Saginaw River, MI(5). [R78] *Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene isomers were detected in aquatic organisms collected in the vicinity of an industrial outfall in the Calacasieu River estuary, LA (ug/g of lipids): 4.7 ug/g - Atlantic croaker; 7.5 ug/g - blue crabs; 0.79 ug/g - spotted sea trout; and 3.4 ug/g - blue catfish(1). 1,2,4,5-Tetrachlorobenzene was detected in trout from the Great Lakes at concns of 0.3-5.0 ng/g(2). Combined isomers of tri- and tetrachlorobenzene were detected in fish from Slovenia at concns of 40 and 180 ug/g(3). 1,2,4,5-Tetrachlorobenzene was detected at a mean concn of 0.3 ng/g in fish from 400 sites in the US(4). [R79] ANIMAL CONCENTRATIONS: *Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene isomers were reported in herring gull eggs from the Detroit River at mean concns of 0.01-0.45 ppm(1). Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene isomers were reported in herring gull eggs near Lake Huron at median concns of 0.5-201 ng/g(2) and near Lake Superior at concns of 0.004-0.01 ug/g(3). Combined 1,2,3,5- and 1,2,4,5-tetrachlorobenzene isomers were detected in eggs of terns (0.002 and 0.005 mg/kg), double-crested cormorant (0.003 mg/kg) and black-crowned night herons (0.005 and 0.002 mg/kg)(4). [R80] MILK: *1,2,4,5-Tetrachlorobenzene was detected in human milk at a concn of 2 ug/kg(1). [R81] RTEX: *Occupational exposure to 1,2,4,5-tetrachlorobenzene may be through inhalation and dermal contact with this compound at workplaces where this compound is produced or used. The general population may be exposed to 1,2,4,5-tetrachlorobenzene via inhalation of ambient air, ingestion of food and drinking water. (SRC) AVDI: *The World Health Organization (WHO) estimates the AVDI of all tetrachlorobenzene isomers for humans is less than 0.1 ng/kg body weight(1). [R82] BODY: *Unidentified tetrachlorobenzene isomer(s) were found in human blood samples taken from a resident in the area of the Love Canal at a concentration of 2.6 ng/ml(1). Concentrations of 0.008 to 0.039 ug/g 1,2,4,5-tetrachlorobenzene were detected in human adipose tissue in Japan(2). Mean concentrations of 0.016 ug/g were detected in Yugoslavian human adipose tissue and 2 ug/kg in human milk, respectively(3). [R83] *Combined trichlorobenzene and tetrachlorobenzene isomers were detected in human adipose tissue in Slovenia at a concn of 60 ng/g and in human hair samples at 40 ng/g(1). 1,2,4,5-Tetrachlorobenzene was identified, not quantified, in the adipose tissue of non-occupationally exposed individuals in Germany(2). [R84] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 2 ug/l [R85] +(FL) FLORIDA 4 ug/l [R85] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Chlorinated benzenes/ [R86] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R87] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2,4,5-Tetrachlorobenzene is included on this list. [R88] RCRA: *U207; As stipulated in 40 CFR 261.33, when 1,2,4,5-tetrachlorobenzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R89] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 5517: Analyte: 1,2,4,5-tetrachlorobenzene; Matrix (or specimen): air; Sampler: filter and solid sorbent tube (PTFE fiber mat + Amberlite XAD-2, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Vol: min: 3 l, max: 12 l; Sample stability: no significant losses after 13 days at room temp [R90] *Air Samples ... an air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. The adsorbent is desorbed with carbon tetrachloride and analyzed by gas chromatography using a photoionization detector. /Chlorobenzenes/ [R91] ALAB: *NIOSH 5517-2: Analyte: 1,2,4,5-tetrachlorobenzene; Matrix: air; Technique: gas chromatography, (63)-Ni electron capture detector; Desorption: 2 ml hexane; 30 min ultrasonic agitation; Injection vol: 2 ul; Temp: injection: 220 deg C; detector: 300 deg C; column: 160 deg C; Gases carrier: nitrogen, 30 ml/min, purge: nitrogen, 90 ml/min; Column: 2.0 m X 2 mm ID nickel, 10% Carbowax 20M-TPA on 80/100 mesh Chromosorb W AW; Calibration: standard soln of analytes in hexane; Range: 0.02 to 500 ug/sample; Precision (relative standard deviation): 0.042; Estimated limit of detection: 0.001 ug/ml in hexane; Interferences: Using chromatographic conditions given above, 1,2,3,5-tetrachlorobenzene coelutes with 1,2,4,5-tetrachlorobenzene. [R92] *Air Samples ... an air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. The adsorbent is desorbed with carbon tetrachloride and analyzed by gas chromatography using a photoionization detector. When using this method the minimum detection limits for mono, di, tri, tetra and pentachlorobenzenes is 15, 20, 30, 35, and 45 ppb (v/v), respectively. /Chlorobenzenes/ [R91] *HIGH RESOLUTION GAS CHROMATOGRAPHY OF CHLORINATED BENZENES WAS STUDIED. SATISFACTORY RESOLUTION OF 12 BENZENES, INCLUDING 1,2,4,5-TETRACHLOROBENZENE, WAS OBTAINED. [R93] *Negative ion chemical ionization mass spectrometry is evaluated as a method for qualitative and quantitative determination of polyhalogenated aromatic hydrocarbons, including 1,2,4,5-tetrachlorobenzene. Each cmpd or mixture of cmpd is analyzed by glass capillary gas chromatography-mass spectrometry by using different modes of chemical ionization in the mass spectrometer. [R94] *OSW Method 8270B. Determination of semivolatile organic compounds by gas chromatography/mass spectrometry (GC:MS). Capillary column technique. [R95] *OSW Method 8270C. Semivolatile organic compounds by gas chromatography/mass spectrometry (GC:MS). Capillary column technique. [R96] *EPA Method 8121. Determination of chlorinated hydrocarbons by gas chromatography: capillary column technique. [R95] *EPA Method 8250A. Determination of semi-volatile organic compounds by gas chromatography/mass spectrometry. [R95] *EPA Method 1625. Semivolatile organic compounds by isotope dilution GCMS. [R97] CLAB: *CHLOROBENZENES (INDUSTRIAL PRODUCTS), MONOCHLOROBENZENE THROUGH HEXACHLOROBENZENE, @ PPB LEVELS IN HUMAN URINE AND BLOOD SAMPLES WERE DETERMINED BY GAS CHROMATOGRAPHY WITH PHOTOIONIZATION DETECTION. [R98] *THE MEAN LEVELS OF CHLOROBENZENES (INCLUDING 1,2,4,5-TETRACHLOROBENZENE) IN HUMAN MILK AND ADIPOSE TISSUE WERE DETERMINED BY GLASS CAPILLARY GAS CHROMATOGRAPHY AND RANGED FROM TRACES TO 25 UG/KG FOR HUMAN MILK AND FROM NOT DETECTED TO 146 UG/KG FOR ADIPOSE TISSUE. [R45] *RESIDUES OF POLYCHLORINATED COMPOUNDS INCLUDING 1,2,4,5-TETRACHLOROBENZENE HAVE BEEN QUANTITATED BY MULTIPLE-ION-DETECTION GAS CHROMATOGRAPHY-MASS SPECTROMETRY IN GREAT LAKES FISH COLLECTED BETWEEN 1974 AND 1980. [R99] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes (1980) EPA 440/5-80-028 USEPA; Health Assessment Document: Chlorinated Benzenes (1985) EPA 600/8-84-015 51 FR 24657-67 (1986) Chlorinated benzenes; final test rule DHHS/NTP; NTP Report on the Toxicity Studies of 1,2,4,5-Tetrachlorobenzene in F344/N Rats and B6C3F1 Mice (Feed Studies) NTP TOX 7 (1991) NIH Pub No. 91-3126 SO: R1: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R3: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1127 R5: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 554 R6: USITC. IMPORTS OF BENZENOID CHEM AND PROD 1983 p.28 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-63 R8: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 16 R9: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-170 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 183 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3086 R13: Shiu WY, Mackay D; J Chem Eng Data 42: 27-30 (1997) R14: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-130 R15: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-85 R16: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990,p. 562-3 R17: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 239 R18: 49 CFR 171.2 (7/1/96) R19: IATA. Dangerous Goods Regulations. 39th Ed. Montreal, Canada and Geneva, Switzerland : International Air Transport Association, Dangerous Goods Regulations, 1998. 116 R20: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3123 (1988) R21: 40 CFR 240-280, 300-306, 702-799 (7/1/97) R22: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-15 (1981) EPA 68-03-3025 R23: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-47 (1982) R24: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R25: KIRALY J ET AL, ARCH ENVIRON CONTAM TOXICOL 8 (3): 309-19 (1979) R26: ARIYOSHI T ET AL, PROC SYMP DRUG METAB ACTION 5: 187-94 (1974) R27: SIKLOSI C ET AL, DERM BERUF UMWELT 29 (2): 40-2 (1981) R28: BRAUN WH ET AL, J ENVIRON PATHOL TOXICOL 2 (2): 225-34 (1978) R29: Chu I et al; J Toxicol Environ Health II (4-6): 663-77 (1983) R30: Chu I et al; Drug Chem Toxicol 7 (2): 113-27 (1984) R31: Wong PTS et al; Chemosphere 13 (9): 991-6 (1984) R32: JACOBS A ET AL; VOM WASSER 48: 255-72 (1977) R33: Kacew S et al; Teratology 29 (1): 7-21 (1984) R34: Kitchin KT, Ebron MT; Environ Res 32 (1): 134-44 (1983) R35: Liu D, Thomson K; Bull Environ Contam Toxicol 31 (1): 105-11 (1983) R36: Chu I et al; J Environ Sci Health 21 (3): 229-42 (1986) R37: Brauner CJ et al; 13 (11): 1813-20 (1994) R38: USEPA; Health Assessment Document: Chlorinated Benzenes p.6-6 (1985) EPA 600/8-84-015 R39: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 1069 R40: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of 1,2,4,5-Tetrachlorobenzene (CAS No. 95-94-3) in CD-1 Swiss Mice, NTP Study No. RACB89010 (October 1991) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R41: Dow Chemical Biochemical Research Laboratory; Progress Report on Tetrachlorobenzene: Skin Absorption in the Rabbit, and Metabolism in the Rat. (1969), EPA Document No. 878211085, Fiche No. OTS0206149 R42: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.1 R43: JACOBS A ET AL, VOM WASSER 48: 255-72 (1977) R44: Chu I et al; Drug Chem Toxicol Vol 7 (2): 113-27 (1984) R45: JAN J; BULL ENVIRON CONTAM TOXICOL 30 (5): 595-9 (1983) R46: RENNER G ET AL, CHEMOSPHERE 7 (12): 943-7 (1978) R47: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. T-2 R48: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes p.C-52 (1980) EPA 440/5-80-028 R49: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes p.C-51 (1980) EPA 440/5-80-028 R50: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes p.C-56 (1980) EPA 440/5-80-028 R51: Chu I et al; J Toxicol Environ Health 13 (4-6): 777-86 (1984) R52: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.148 R53: 51 FR 11729 (4/7/88) R54: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Reinhold Co., p. 1127 (1993) R55: (1) Masunga S et al; Wat Sci Technol 33: 173-80 (1996) R56: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Sacan MT, Balcioglu IA; Chemosphere 32: 1993-2001 (1996) (3) Gao C et al; Environ Toxicol Chem 15: 1089-96 (1996) (4) Masunga S et al; J Environ Sci Health A31: 887-903 (1996) (5) Shiu WY, Mackay D; J Chem Eng Data 24: 27-30 (1997) (6) Wang MJ, Jones KC; Environ Sci Technol 28: 1843-52 (1994) R57: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Sacan MT, Balcioglu IA; Chemosphere 32: 1993-2001 (1996) (3) Gao C et al; Environ Toxicol Chem 15: 1089-96 (1996) (4) Masunga S et al; J Environ Sci Health A31: 887-903 (1996) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (6) Shiu WY, Mackay D; J Chem Eng Data 24: 27-30 (1997) (7) US EPA; EXAMS II Computer Simulation (1987)(8) Franke C et al; Chemosphere 29: 1501-14 (1994) (9) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (10) Axelman J et al; Environ Sci Pollut Res 2: 33-36 (1995) (11) Masunga S et al; Wat Sci Technol 33: 173-80 (1996) (12) Choudhry CG et al; Tox Environ Chem 14: 43-61 (1987) R58: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Shiu WY, Mackay D; J Chem Eng Data 24: 27-30 (1997) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R59: (1) Malaney GW, McKinney RE; Water Sewage Works 113: 302 (1966) (2) Ballschmiter K, Scholz C; Chemosphere 9: 457 (1980) (3) Ballschmiter K et al; Angew Chem Int Ed English 16: 645 (1977) (4) Oliver BG, Nicol KD; Environ Sci Technol 17: 505 (1983) (5) Kirk FWW et al; Chemosphere 18: 1771-84 (1981) R60: (1) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center. 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Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) R66: (1) Barkley J et al; Biomed Mass Spect 7: 139-47 (1980) (2) Oliver BG, Nicol KD; Environ Sci Tech 16: 532-6 (1982) R67: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532 (1982) (2) Oliver BG; in Symp Amer Soc, Div Environ Chem 186th Natl Mtg 23: 421-2 (1983) (3) Oliver BG, Nicol KD; Sci Tot Env 16: 532 (1984) (4) Elder VA et al; Environ Sci Technol 15: 1237 (1981) (5) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249 (1982) (6) Malle KG; Z Wasser-Abwasser Fursch 17: 75 (1984) (7) Fischer A, Slemrova J; Von Nasser 51: 33 (1978) R68: (1) Biberhofer J, Stevens RJJ; Sci Ser - Inland Waters/Lands Dir (Can) No. 159 pp.11 (1987) R69: (1) Oliver BG, Nicol KD; Environ Sci Tech 16: 532-6 (1982) (2) Oliver BG, Nicol KD; Sci Tot Env 39: 57-70 (1984) (3) Pereira WE et al; Environ Sci Technol 22: 772-8 (1988) (4) Zupancic-Kralj L, Jan J; Acta Chim Slov 41: 447-56 (1994) (5) Rogers HR et al; Mar Pollut Bull 20: 276-81 (1989) (6) Halfon E, Poulton D; Water Poll Res J Canada 27: 751-72 (1992) (7) Oliver BG, Niimi AJ; Environ Sci Technol 22: 388-97 (1988) (8) Gotz R et al; Chemosphere 36: 2085-2101 (1998) (9) Chan CH; Wat Pollut Res J Canada 28: 451-71 (1993) R70: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532 (1982) (2) Shackelford WM, Keith LH; Frequency of Organic Compounds Identified in Water USEPA 600/4-76-062 (1976) (3) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey. Contract No. 68-03-2867. Athens, GA: USEPA Environ Res Lab (1982) (4) Oberg T et al; Chemosphere 16: 2451-65 (1987) R71: (1) Wienecke J; et al; Chemosphere 25: 437-47 (1992) (2) Wienecke J; et al; Chemosphere 30: 907-13 (1995) (3) Suntio LR et al; Chemosphere 17: 1249-90 (1988) (4) Tiernan TO et al; Environ Health Pers 59: 145-58(1985) (5) Shane BS et al; Arch Environ Contam Toxicol 19: 665-73 (1990) R72: (1) Beurskens JEM et al; Water Sci Technol 29: 77-85 (1994) (2) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-36 (1982) (3) Masunga S et al; Wat Res 25: 275-88 (1991) (4) van Zoest R, van Eck GTM; Sci Total Environ 103: 57-71 (1991) (5) Ding WH et al; Chemosphere 25: 675-90 (1992) (6) Kaiser KLE et al; Sci Total Environ 97/98: 496-506 (1990) (7) Oliver BG, Niimi AJ; Environ Sci Technol 22: 388-97 (1988) (8) Lee CL, Fang MD; Chemosphere 35: 2039-50 (1997) R73: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532 (1982) (2) Oliver BG; in Symp Amer Soc, Div Environ Chem 186th Natl Mtg 23: 421-2 (1983) (3) Oliver BF, Charlton MN; Environ Sci Technol 18: 903 (1984) (4) Kuntz KW; Toxic Contaminants in the Niagara River, 1975-1982 Tech Bull No. 134, Burlington, Ontario (1984) (5) Buchert H et al; Chemosphere 10: 945 (1981) (6) Hauser TR, Bromberg Sm; Env Monit Assess 2: 249 (1982) (7) Oliver BG, Bourbonniere RA; J Great Lakes Res 11: 366-72 (1985) R74: KAMINSKY R ET AL; J GREAT LAKES RE 9 (2): 183-9 (1983) R75: (1) Bruckmann P et al; 17: Chemosphere 17: 2363-80 (1988) (2) Grosjean D; Sci Total Environ 100: 367-414 (1991) (3) Hermanson MH et al; Atmos Environ 31: 567-73 (1997) (4) USEPA; Health Assessment document For Chlorinated Benzenes. USEPA-600/8-84-015A (1984) (5) Barkley J et al; Biomed Mass Spect 7: 139-47 (1980) R76: (1) Wang MJ, Jones KC; J Agric Food Chem 42: 2322-28 (1994) (2) Peattie ME et al; Sci Total Environ 34: 73-86 (1984) (3) Jan J; Mitt Geb Lebensmittelunter Hyg 74: 420-26 (1983) R77: (1) Jan J et al; Chemosphere 29:1603-10 (1994) R78: (1) Oliver BG, Niimi AJ; Environ Sci Technol 17: 287 (1983) (2) Oliver BG, Nicol KD; Environ Sci Technol 16: 532 (1982) (3) Jan J, Malnersic S; Bull Toxicol 24: 824 (1980) (4) Peatte ME et al; Sci Tot Environ 34: 73-86 (1984) (5) Jaffe R et al; J Great Lakes Res 11: 156-62 (1985) R79: (1) Pereira WE et al; Environ Sci Tech 22: 772-8 (1988) (2) Oliver BG, Nicol KD; Environ Sci Tech 16: 532-6 (1982) (3) Zupancic-Kralj L, Jan J; Acta Chim Slov 41: 447-56 (1994) (4) Kuehl DW et al; Chemosphere 29: 523-35 (1994) R80: (1) Struger J et al; J Great Lakes Res 11: 223-30 (1985) (2) Ewins PJ et al; J Great Lakes Res 18: 316-30 (1992) (3) Great Lakes Water Quality Board; A Review of Lake Superior Water Quality With Emphasis on the 1983 Intensive Survey. Report to the Surveillance Subcommittee of the Great Lakes Water quality Board, Windsor, Ontario (1990) (4) Weseloh DV et al; J Great Lakes Res 21: 121-37 (1995) R81: (1) Jan J; Bull Environ Contam Toxicol 30: 595-99 (1983) R82: (1) Gunderson EL; J Assoc Off Anal Chem 71: 1200-1209 (1988) R83: (1) Barkely J et al; Biomed Mass Spect 7: 143 (1980) (2) Morita M et al; Environ Pollut 9: 175 (1975) (3) Jan J; Bull Environ Contam Toxicol 30: 595 (1983) R84: (1) Zupancic-Kralj L, Jan J; Acta Chim Slov 41: 447-56 (1994) (2) Geyer H et al; Reg Toxicol Pharmacol 6: 313-47 (1986) R85: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R86: 40 CFR 401.15 (7/1/88) R87: 40 CFR 302.4 (7/1/97) R88: 40 CFR 716.120 (7/1/97) R89: 40 CFR 261.33 (7/1/96) R90: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 5517-1 R91: Langhorst ML, Nestrick TJ; Anal Chem 51 (12): 2018-25 (1979) as cited in USEPA Health Assessment Document: Chlorinated Benzenes p.3-17 (1985) EPA 600/8-84-015 R92: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R93: MILLER LJ ET AL; J ASSOC OFF ANAL CHEM 66 (3): 677-83 (1983) R94: Crow FW et al; Anal Chem 53 (4): 619-25 (1981) R95: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R96: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, Proposed. as cited in USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R97: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R98: LANGHORST ML ET AL; ANAL CHEM 51 (12): 2018-25 (1979) R99: KUEHL DW; GOVT REPORTS ANNOUNCEMENTS AND INDEX (GRA and I) 15 (1983) RS: 72 Record 184 of 1119 in HSDB (through 2003/06) AN: 2745 UD: 200211 RD: Reviewed by SRP on 12/01/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORNAPHAZINE- SY: *R-48-; *ALEUKON-; *2-BIS(2-CHLOROETHYL)AMINONAPHTHALENE; *BIS(2-CHLOROETHYL)-BETA-NAPHTHYLAMINE; *N,N-BIS(2-CHLOROETHYL)-2-NAPHTHYLAMINE; *CB-1048-; *CHLORNAFTINA-; *CHLORNAPHAZIN-; *CHLORNAPHTHIN-; *CHLORONAPHTHINA-; *CHLORONAPHTHINE-; *CLORONAFTINA-; *DICHLOROETHYL-BETA-NAPHTHYLAMINE-; *DI(2-CHLOROETHYL)-BETA-NAPHTHYLAMINE; *2-N,N-DI(2-CHLOROETHYL)NAPHTHYLAMINE; *ERYSAN-; *NAFTICLORINA-; *2-NAPHTHALENAMINE, N,N-BIS(2-CHLOROETHYL)-; *2-NAPHTHYLAMINE, N,N-BIS(2-CHLOROETHYL)-; *NAPHTHYLAMINE-MUSTARD-; *BETA-NAPHTHYLBIS(BETA-CHLOROETHYL)AMINE; *2-NAPHTHYLBIS(2-CHLOROETHYL)AMINE; *BETA-NAPHTHYLDI(2-CHLOROETHYL)AMINE; *NSC-62209-; *R48- RN: 494-03-1 MF: *C14-H15-Cl2-N HAZN: U026; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD FROM 2-C10H7N(C2H4OH)2 BY TREATMENT WITH PHOSPHORUS OXYCHLORIDE: ROSS, J CHEM SOC 1949, 183. [R1] OMIN: *Not produced or used commercially in the United States ... Currently, this drug does not have wide therapeutic usage. [R2] *Chlornaphazine has reportedly been withdrawn from use in Denmark because of detected instances of cancer of the bladder following its administration. [R3] USE: +MEDICATION *Not produced or used commercially in the United States ... Currently, this drug does not have wide therapeutic usage. [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PLATELETS FROM PETROLEUM ETHER [R1] BP: *210 DEG C @ 5 MM HG [R1] MP: *54-56 DEG C [R1] MW: *268.20 [R1] OWPC: *log Kow = 4.535 (est) [R4] SOL: *VERY SPARINGLY SOL IN WATER, GLYCEROL; MORE SOL (IN ASCENDING DEGREE) IN PETROLEUM ETHER, ETHANOL, OLIVE OIL, ETHER, ACETONE, BENZENE [R1] VAP: *2X10-6 mm Hg at 25 deg C (est) [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of chlornaphazine stem from its toxicologic properties. The primary effect from exposure to this crystalline substance is cancer. Chlornaphazine has been indicated as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC). Exposure should be controlled by mechanical ventilation with high-effici ency particulate arrestors (HEPA) or charcoal filters to minimize the amount of the substance in exhausted air. In activities or situations where over-exposure may occur, wear full protective clothing and a carefully fitted respirator. If contact should occur, immediately irrigate affected eyes with copious amounts of tepid water for at least 15 minutes and wash affected skin extremely thoroughly with soap and water. Contaminated clothing should be removed and discarded or left at the work site for cleaning before reuse. Smoking, eating, and drinking should be prohibited in chlornaphazine work areas. Chlornaphazine should be stored and transported in securely sealed glass bottles or ampoules, which are in turn placed inside strong screw-cap or snap-top containers. This substance is a good candidate for disposal by rotary kiln or fluidized bed forms of incineration. EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R6, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R6, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R6, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R6, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R6, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R6, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R6, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R6, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U026, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R7] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R6, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R6, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R6, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R6, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R6, 1979.17] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R8] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: limited. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. /From table/ [R9] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R6, 1979.23] HTOX: *ELEVEN SEPARATE CASES OF BLADDER CANCER ASSOC WITH USE OF CHLORNAPHAZINE WERE REPORTED. THREE FURTHER CASES HAVE BEEN IDENTIFIED. [R10] *A COMMON FACTOR AMONG 10 PT IN WHOM BLADDER TUMORS HAVE BEEN DIAGNOSED IS THAT 9 OF THE PATIENTS WERE ALSO TREATED WITH (32)P AS SODIUM PHOSPHATE INJECTIONS. HOWEVER, ... /IT HAS BEEN REPORTED/ THAT OUT OF 46 PATIENTS TREATED WITH (32)P AS SODIUM PHOSPHATE ALONE WITHOUT CHLORNAPHAZINE, NO CASES OF BLADDER TUMORS WERE REPORTED. [R11] *CHLORNAPHAZINE, FORMERLY USED IN THE TREATMENT OF POLYCYTHEMIA, HAS BEEN PROVEN TO INDUCE BLADDER CANCER IN 30% OF THE PATIENTS TREATED. [R12] *TWO CASES OF BLADDER CARCINOMA FOLLOWING TREATMENT WITH CHLORNAPHAZINE FOR HODGKIN'S DISEASE ARE PRESENTED. BLADDER CANCER DEVELOPED 5 and 6 YR AFTER THERAPY, WHEN THE DRUG WAS STOPPED. [R13] *Among 61 patients with polycythemia vera treated with chlornaphazine in 1954-1962 and followed until 1974, eight developed invasive carcinoma of the bladder, five developed papillary carcinomas of the bladder and eight had abnormal urinary cytology. The invasive carcinomas were seen in four of five patients given 50-99 g and in one of 31 patients given less than 50 g. No noncausal explanation can be suggested. [R14] NTOX: *IN 4 GROUPS OF 30 A/J MICE GIVEN TOTAL DOSES OF 280, 1119, 4477 and 17,900 UMOL/KG BODY WT (EQUIVALENT TO 75, 300, 1200, and 4800 MG/KG BODY WT) IN AQUEOUS SOLUTION BY IP INJECTION 3 TIMES WEEKLY FOR 4 WK, DOSE RELATED INCR IN INCIDENCE OF PULMONARY ADENOMAS, AND IN NUMBER OF LUNG TUMORS PER MOUSE, WAS OBSERVED. THE MICE WERE FIRST INJECTED WHEN 4 TO 6 WEEKS OLD AND WERE KILLED AT 39 WK AFTER THE FIRST INJECTION. THE RESPECTIVE INCIDENCES OF LUNG TUMORS PER MOUSE IN THE TREATED GROUPS WERE 0.5, 0.9, 2.0 and 3.6, and 0.48 IN THE VEHICLE CONTROL GROUP (SHIMKIN ET AL, 1966). [R10] *REPEATED SC INJECTIONS OF 40 MG N,N-BIS(2-CHLOROETHYL)-2-NAPHTHYLAMINE INDUCED LOCAL SC SARCOMAS IN 7 RATS (KOLLER, 1953). [R10] *CHLORNAPHAZIN, A CARCINOGEN, WAS POS IN SALMONELLA/MICROSOME TEST. THERE WAS HIGH CORRELATION (AMONG AGENTS TESTED) BETWEEN MUTAGENICITY AND CARCINOGENICITY. [R15] *... Nitrogen mustard chlornaphazine (CN) has been confirmed to be mutagenic to Salmonella and, unexpectedly, the more so when evaluated in the presence of liver S9 mix. It also has been established as clastogenic to Chinese hamster lung cells exposed in vitro to dose levels > 2.5 ug/ml. Chlornaphazine subdued mice at doses of 5 g/kg, but only the occasional death occurred during the 4 days following oral administration of this dose in corn oil. Consequently, a median lethal dose level was not established. Nonetheless, dose levels of 500 mg/kg or greater gave a clear positive response in both the mouse and the rat bone marrow micronucleus assay. Although depression of erythropoiesis was observed in mice, a clastogenic response still was observed in the bone marrow 24 hr after dosing. The positive response in the rat was greater than that observed in the mouse. The present data provide a further instance of an established human carcinogen being readily detected by standard in vitro and in vivo mutagenicity assays. [R16] METB: *RATS INJECTED WITH N,N-BIS(2-CHLOROETHYL)-2-NAPHTHYLAMINE EXCRETED 2-AMINO-1-NAPHTHYL HYDROGEN SULFATE AND 2-ACETAMIDO-6-NAPHTHYL HYDROGEN SULFATE. [R10] ACTN: *QUANTITATIVE STRUCTURE-ACTIVITY RELATIONS FORMULATED FOR HYDROLYSIS OF SEVERAL ANILINE MUSTARDS AND THEIR ANTITUMOR ACTIVITY AGAINST WALKER 256 TUMOR AND L1210 AND P388 LEUKEMIA. THE ANTITUMOR ACTIVITY PARALLELS HYDROLYSIS; TOXICITY PARALLELS ANTITUMOR EFFICACY. [R17] INTC: *CHLORNAPHAZINE NONCOMPETITIVELY BLOCKED THE ACTIVATION OF RAT HEPATIC GUANYLATE CYCLASE BY N'-NITRO-N-NITROSO-N-PROPYLGUANIDINE AND HYDRAZINE. [R18] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *THIS CMPD HAS BEEN USED IN A NUMBER OF COUNTRIES AS A CHEMOTHERAPEUTIC AGENT FOR THE TREATMENT OF LEUKEMIA AND OF HODGKIN'S DISEASE AS WELL AS FOR THE CONTROL OF POLYCYTHEMIA VERA. [R3] *ALTHOUGH IT STILL APPEARS IN SOME DRUG DIRECTORIES, N,N-BIS(2-CHLOROETHYL)-2-NAPHTHYLAMINE PROBABLY DOES NOT HAVE WIDE THERAPEUTIC USAGE. [R3] WARN: *IT HAS REPORTEDLY BEEN WITHDRAWN FROM USE IN DENMARK BECAUSE OF DETECTED INSTANCES OF CANCER OF BLADDER FOLLOWING ITS ADMIN. [R3] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Chlornaphazine is not believed to have been produced or used commercially in the United States. No data are available to indicate that it is currently manufactured or imported into the United States. If released to the atmosphere, vapor-phase chlornaphazine is expected to degrade rapidly by reaction with photochemically produced hydroxyl radicals (estimated half-life of 1.4 hrs in typical air). If released to water, hydrolysis is expected to be the major degradation process. Chlornaphazine has a measured aqueous hydrolysis half-life of 216 hrs at 25 deg C and pH 7. If released to moist soil, chlornaphazine can be expected to hydrolyze. An estimated Koc value of 21000 indicates that chlornaphazine should be immobile in soil. No data are available to predict the biodegradability of chlornaphazine in soil or water. (SRC) NATS: *Chlornaphthazine has not been reported to occur as such in nature. [R3] FATE: *TERRESTRIAL FATE: Chlornaphazine has a measured aqueous hydrolysis half-life of 216 hrs at 25 deg C and pH 7(1) which indicates that the compound will hydrolyze in moist soil(SRC). An estimated Koc value of 21000, which was derived from an estimated log Kow of 4.535, suggests that chlornaphazine will be essentially immobile in soil and not expected to leach(2,3,4,SRC). No data are available to predict the biodegradability of chlornaphazine in soil(SRC). [R19] *AQUATIC FATE: Chlornaphazine has a measured aqueous hydrolysis half-life of 216 hrs at 25 deg C and pH 7(1) indicating that hydrolysis will be a major environmental fate process in water. An estimated Koc value of 21000, which was derived from an estimated log Kow of 4.535(2,3,SRC), suggests that chlornaphazine may partition from the water column to sediment and suspended material; however, concurrent hydrolysis may greatly diminish the potential importance of adsorption to sediment(SRC). Chlornaphazine is not expected to volatilize from water based upon an estimated Henry's Law Constant of 1X10-7(3,4,SRC). No data are available to predict the biodegradability of chlornaphazine in water(SRC). [R20] *ATMOSPHERIC FATE: Based upon a reported boiling point of 210 deg C at 5 mm Hg(1), the vapor pressure of chlornaphazine at 25 deg C can be estimated to be roughly 2X10-6 mm Hg using a Clausius-Clapeyron relationship(2,SRC). This estimated vapor pressure suggests that chlornaphazine may exist in both the vapor-phase and particulate-phase in the ambient atmosphere(3,SRC). Vapor-phase chlornaphazine is expected to degrade rapidly in the ambient atmosphere by reaction with photochemically formed hydroxyl radicals; the half-life for this reaction in typical air can be estimated to be about 1.4 hrs(4,SRC). Chlornaphazine associated with atmospheric particulate material will be subject to physical removal by wet (rainfall, etc) and dry deposition(SRC). [R21] ABIO: *At 25 deg C, the neutral aqueous hydrolysis rate constant for chlornaphazine has been experimentally determined to be 0.0032/hr which corresponds to a half-life of 216 hrs at pH 7(1). The rate constant for the vapor-phase reaction of chlornaphazine with photochemically produced hydroxyl radicals has been estimated to be 270.4X10-12 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 1.4 hrs at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(2,SRC). [R22] BIOC: *Based upon an estimated Log Kow of 4.535(1), the BCF for chlornaphazine can be estimated to be about 1650 from a recommended regression-derived equation(2,SRC). This BCF value suggests that bioconcentration in aquatic organisms may be important(SRC). [R23] KOC: *Based upon an estimated log Kow of 4.535(1), the Koc for chlornaphazine can be estimated to be about 21000 from a regression-derived equation developed for aromatic and polyaromatic compounds(2,SRC). This Koc value suggests that chlornaphazine may be essentially immobile in soil(3). [R24] VWS: *The Henry's Law constant for chlornaphazine can be estimated to be about 1.7X10-7 atm cu m-mole at 25 deg C using a chemical structure estimation method(1,SRC). The value of this Henry's Law constant suggests that chlornaphazine is essentially nonvolatile from water(2). [R25] RTEX: *No data are available to suggest that the general population of the US is exposed to chlornaphazine(SRC). EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R26] RCRA: *As stipulated in 40 CFR 261.33, when chlornaphazine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R27] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *INFLUENCE OF SUBSTITUENTS AND OF SOLVENTS ON UV SPECTROPHOTOMETRIC BEHAVIOR OF 12 MEDICINALS (INCL CHLORNAPHAZINE) WAS STUDIED. DISPLACEMENT OF ABSORPTION BANDS E, K, AND B OF ABSORPTION MAX AND MIN ARE DISCUSSED. RESULTING DATA CAN BE APPLIED TO THE QUANTITATIVE DETERMINATION OF PURE SUBSTANCES OR OF THEIR PREPARATIONS. [R28] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: CLEMMESEN J, HJALGRIM-JENSEN S; ARCH TOXICOL (SUPPL) (3): 19-25 (1980). IN A RECENT REVIEW OF CHEMICALS ASSOCIATED WITH CANCER PRODUCTION IN MAN FROM US NATIONAL CANCER INSTITUTE AND TWO FEDERAL AGENCIES, SEVEN DRUGS WERE LISTED. THE EVIDENCE FOR THE CARCINOGENICITY OF CHLORNAPHAZINE WILL BE REVIEWED. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting Chlornaphazine (494-03-1); Reason: No U.S. residents exposed. SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 296 R2: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 221 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 120 (1974) R4: Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) R5: Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants. USEPA-440/4-81-014 p. 412-4 (1981) R6: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R7: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R8: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-11 (1981) EPA 68-03-3025 R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 67 (1987) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 121 (1974) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 122 (1974) R12: SCHMAHL D; J CANCER RES CLIN ONCOL 99 (1-2): 71-5 (1981) R13: LAURSEN B; BRIT MED J 3 (SEPT): 684-5 (1970) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. Supp 7 (1987) R15: BENEDICT WF ET AL; CANCER RES 37 (7): 2209 (1977) R16: Ashly J et al; Environ Mol Mutagen 12 (4): 365-74 (1988) R17: PANTHANANICKAL A ET AL; J MED CHEM 21 (1): 16 (1977) R18: VESELY DL, LEVEY GS; ONCOLOGY 36 (3): 122-6 (1979) R19: (1) Ellington JJ et al; Measurement of Hydrolysis Rate Constants for the Evaluation of Hazardous Waste Land Disposal: Vol 3. USEPA-600/3-88-028. p. 16 (1988) (2) GEMS; Graphical Exposure Modeling System. CLOGP (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (4) Swann RL et al; Res Rev 85: 23 (1983) R20: (1) Ellington JJ et al; Measurement of Hydrolysis Rate Constants for the Evaluation of Hazardous Waste Land Disposal: Vol 3. USEPA-600/3-88-028. p. 16 (1988) (2) GEMS; Graphical Exposure Modeling System. CLOGP. (1989) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9, 15-16 (1982) (4) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) R21: (1) Windholz M; The Merck Index. Tenth Edition. p. 297 (1983) (2) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants. USEPA-440/4-81-014 p. 412-4 (1981) (3) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (4) Atkinson R; Intern J Chem Kinet 19: 799-828 (1987) R22: (1) Ellington JJ et al; Measurement of Hydrolysis Rate Constants for the Evaluation of Hazardous Waste Land Disposal: Vol 3. USEPA-600/3-88-028 p. 16 (1988) (2) Atkinson R; Intern J Chem Kinet 19: 799-828 (1987) R23: (1) GEMS; Graphical Exposure Modeling System. CLOGP. (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-4 (1982) R24: (1) GEMS; Graphical Exposure Modeling System. CLOGP. (1989) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (3) Swann RL et al; Res Rev 85: 23 (1983) R25: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-15 to 15-16 (1982) R26: 54 FR 33418 (8/14/89) R27: 40 CFR 261.33 (7/1/88) R28: KRACMAR J, KRACMAROVA J; PHARMAZIE 29 (7): 462 (1974) RS: 34 Record 185 of 1119 in HSDB (through 2003/06) AN: 2746 UD: 200302 RD: Reviewed by SRP on 9/24/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,5-DITHIOBIUREA- SY: *BISTHIOCARBAMYL-HYDRAZINE-; *BIS- (THIOUREA); *BITHIOUREA-; *BIUREA,-2,5-DITHIO-; *DITHIOBIUREA-; *DITHIOCARBAMOYLHYDRAZINE-; *2,5-DITHIODIUREA-; *DITHIOUREA-; *1,2-HYDRAZINEDICARBOTHIOAMIDE-; *NCI-C03009-; *USAF-B-44-; *USAF-EK-P-6281- RN: 142-46-1 MF: *C2-H6-N4-S2 CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *150.24 TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *In the manufacture of rubber, irritant contact dermatitis may occur from a variety of acids, alkalies, detergents, and solvents used in the process. Allergic contact dermatitis occurs not infrequently and is almost always due to an organic accelerator or antioxidant. While the list of potential sensitizing accelerators and antioxidants is enormous, common allergens include ... thioureas. /Thioureas/ [R1] NTOX: *ADMIN TO MALE AND FEMALE MICE IN FEED FOR 78 WK @ CONCN OF 1 and 2%. AMONG FEMALE MICE HIGH INCIDENCE OF HEPATOCELLULAR CARCINOMA, WHILE THERE WAS NO INCREASE IN CARCINOGENICITY IN MALE MICE AND CONTROLS. [R2] *INCR WT OF ADRENAL GLANDS AND OVARIES IF FED DURING ESTRUS CYCLE TO GILTS. LOWER FOLLICLE STIMULATING HORMONE INDICATED INHIBITION OF SYNTHESIS. RELEASE OF LUTEINIZING HORMONE WAS SUPPRESSED, THIS SUPPRESSION WAS SUPPORTED BY LACK OF OVULATION AND ESTRUS. [R3] *ADMIN TO MALE AND FEMALE RATS IN FEED FOR 78 WK AT CONCN OF 0.6 OR 1.2%. THERE WAS NO CARCINOGENICITY FOR EITHER MALE OR FEMALE RATS. [R4] *2,5-Dithiobiurea was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 2,5-Dithiobiurea was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S9, at doses of 0.001, 0.0033, 0.010, 0.033, 0.100, 0.333, and 1.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 1.000 mg/plate. [R5] NTP: *A bioassay of 2,5-dithiobiurea for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 2,5-Dithiobiurea was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species, with the exception of high dose male rats, of which there were only 49. The dietary concentrations used in the chronic bioassay were 0.6% for the low dose rats and 1.2% for the high dose rats. The dietary concentrations used for low and high dose mice were 1.0 and 2.0%, respectively. After a 78 week dosing period, observation of the rats continued for an additional 31 weeks and observation of the mice continued for an additional 16 weeks. For each species, 50 animals of each sex were placed on test as controls. Among female mice, the Cochran-Armitage test indicated a significant positive association between the incidence of hepatocellular carcinoma and dietary concentration of 2,5-dithiobiurea. According to results of the Fisher exact test, the incidence of hepatocellular carcinoma was significantly higher in the high dose female mouse group when compared to the corresponding control group but not when compared to the laboratory historical control data. No neoplasms occurred at a significantly higher incidence in dosed male mice than in their controls. Under the conditions of this bioassay, the evidence suggested, but was insufficient to establish the carcinogenicity of 2,5-dithiobiurea for female B6C3F1 mice. The compound was not carcinogenic to male B6C3F1 mice or to male or female Fischer 344 rats. [R6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of 2,5-Dithiobiurea for Possible Carcinogenicity (1979) Technical Rpt Series No. 132 DHEW Pub No. (NIH) 79-1387 SO: R1: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 145 R2: REPORT; ISS DHEW/PUB/NIH-79-1387, NCI-CG-TR-132; ORDER NO PB-291535, P.96 (1978) R3: STRATMAN FW ET AL; J ANIM SCI 35 (2): 370 (1972) R4: REPORT; ISS DHEW/PUB/NIH-79-1387, NCI-CR-TR-132; ORDER NO PB-291535, P.96 (1978) R5: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R6: DHEW/NCI; Bioassay of 2,5-Dithiobiurea for Possible Carcinogenicity p.vii (1979) Technical Rpt Series No. 132 DHEW Pub No. (NIH) 79-1387 RS: 5 Record 186 of 1119 in HSDB (through 2003/06) AN: 2763 UD: 200303 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORODIBROMOMETHANE- SY: *DIBROMOCHLOROMETHANE-; *METHANE,-CHLORODIBROMO-; *METHANE,-DIBROMOCHLORO-; *NCI-C55254- RN: 124-48-1 MF: *C-H-Br2-Cl MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *98% grade; 99% purity grade [R1] OMIN: *Trihalomethane contaminant found in chlorinated water. [R2] USE: *LAB CHEM [R3] *Organic synthesis [R4] PRIE: U.S. PRODUCTION: *(1976) NOT PRODUCED COMMERCIALLY IN USA [R3] *(1978) NOT PRODUCED COMMERCIALLY IN USA [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to pale yellow liquid [R5]; *Clear, colorless, heavy liquid [R4] BP: *120 deg C [R6] MP: *-20 deg C [R6] MW: *208.28 [R6] DEN: *Specific Gravity: 2.38 [R4] OWPC: *log Kow= 2.16 [R7] SOL: *> 10% in acetone; > 10% in benzene; > 10% in ethyl ether; > 10% in ethanol [R5]; *Soluble in ethanol, ethyl ether, and acetone [R6]; *Miscible in organic solvents. [R8]; *In water, 2.70X10+3 mg/l @ 20 deg C [R9] SPEC: *Index of refraction: 1.5482 @ 20 deg C/D [R6]; *IR: 284 (Sadtler Research Laboratories IR Grating Collection) [R10]; *NMR: 6708 (Sadtler Research Laboratories Spectral Collection) [R10]; *MASS: 1458 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R10] OCPP: *Enthalpy of formation @ 25 deg C: -5.0 kcal/mole (gas); Gibbs (free) energy of formation @ 25 deg C: -4.50 kcal/mole (gas); entropy @ 25 deg C: 78.31 cal/deg.mole (gas) [R5] *Water solubility: 4400 ppm at 22 deg C [R11] *Henry's Law constant= 7.83X10-4 atm-cu m/mol @ 20 deg C [R12] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *NONFLAMMABLE. WILL BURN ON PROLONGED EXPOSURE TO FLAME OR HIGH TEMPERATURE. /CHLOROFORM/ [R13] DCMP: *WHEN HEATED TO DECOMP, EMITS TOXIC FUMES OF /HYDROGEN CHLORIDE AND HYDROGEN BROMIDE/. [R14] EQUP: *When handling /chloroform/, use safety glasses, self-contained breathing apparatus, protective clothing. Note: PVC and rubber are unsuitable materials for protective clothing. /Chloroform/ [R15, p. 7-1] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Chloroform/ [R16] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. /Chloroform/ [R16] OPRM: *Skin that becomes wet with liquid chloroform should be promptly washed or showered with soap or mild detergent and water to remove any chloroform. Employees who handle chloroform should wash their hands thoroughly with soap and mild detergent and water before eating, or smoking. /Chloroform/ [R17, 1981.3] *Where there is any possibility that employees' eyes may be exposed to chloroform, an eye-wash fountain should be provided within the immediate work area for emergency use. /Chloroform/ [R17, 1981.3] *Good industrial hygiene practices recommend that engineering controls be used to reduce environmental concentrations to the permissible level. However, there are some exceptions where respirators may be used to control exposure. Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. /Chloroform/ [R17, 1981.3] *Clothing wet with liquid chloroform should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of chloroform from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the chloroform, the person preforming the operation should be informed of chloroform's hazardous properties. /Chloroform/ [R17, 1981.3] *Non-impervious clothing which becomes wet with liquid chloroform should be removed promptly and not worn until the chloroform is removed ... /Chloroform/ [R17, 1981.3] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. COLLECT FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR MATERIAL. /CHLOROFORM/ [R17, 1981.5] *Do not touch spilled material. Use water spray to reduce vapors. For small spills, take up with absorbent material then flush area with water. For large spills, dike far ahead. /Chloroform/ [R15, p. 8-1] */SRP: In laboratory setting only:/ Absorb on paper and evaporate on a glass dish in hood. Burn the paper. Purify /liquids/ by distillation, then return to supplier. /Chloroform/ [R18] *Oxidation processes are responsible for the removal of organic compounds and precursors of trihalomethanes. Substitution reactions are the source of chlorine incorporation into the organic matter. Disinfectants differ in their abilities to carry out oxidation and substitution reactions, but studies show that chloramines also add chlorine to organic materials by substitution. Before a decision is made to change disinfectants, operating parameters and chemical functions must be taken into account to achieve the best quality drinking water. [R19] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Chloroform is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration, preferably after mixing with another combustible fuel; care must be exercised to assure complete combustion to prevent the formation of phosgene; an acid scrubber is necessary to remove the halo acids produced. /Chloroform/ [R20] *Potential candidate for liquid injection incineration, with a temperature range of 650 to 1600 deg C and a residence time of 0.1 to 2 seconds; for rotary kiln incineration with a temperature of of 820 to 1600 deg C and a residence time of seconds for liquids and gases, hours for solids; and for fluidized bed incineration, with a temperature range of 450 to 980 deg C and a residence time of seconds for liquids and gases, longer for solids. /Chloroform/ [R21] *The following wastewater treatment technologies have been investigated for bromochloromethane: Concentration process: Stripping. /Bromochloromethane/ [R22] *The following wastewater treatment technologies have been investigated for bromochloroemethane: Concentration process: Solvent extraction. /Bromochloromethane/ [R23] *The following wastewater treatment technologies have been investigated for bromochloromethane: Concentration process: Activated carbon. /Bromochloromethane/ [R24] *The following wastewater treatment technologies have been investigated for bromochloromethane: Concentration process: Resin adsorption. /Bromochloromethane/ [R25] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of chlorodibromomethane. There is limited evidence in experimental animals for the carcinogenicity of chlorodibromomethane. Overall evaluation: Chlorodibromomethane is not classifiable as to its carcinogenicity to humans (Group 3). [R26] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on inadequate human data and limited evidence of carcinogenicity in animals; namely, positive carcinogenic evidence in B6C3F1 mice (males and females), together with positive mutagenicity data, and structural similarity to other trihalomethanes, which are known animal carcinogens. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. [R27] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with sterile dressings after decontamination ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R28] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the unconscious patient. Positive pre s sure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of cardiac irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R28] HTOX: *Cultures of human oral carcinoma cells ... were incubated for 72 hr in the presence of 30 to 300 ug/ml dibromochloromethane. After incubation, viable cells were counted, and concentrations causing 50% inhibition of cell growth (ID50) were determined. Linear dose versus response relationship was obtained. ID50 /was/ 130 ug/ml for dibromochloromethane. The ... /study/ concluded that human oral carcinoma cells ... are ... sensitive to halomethane compounds. [R29] *Both di- and tri-halogenated methane derivatives have been found to produce increased blood levels of methemoglobin; the greatest increase caused by iodo-, followed by bromo- and chloro- compounds. CNS functional disturbances are reported, including depression of rapid eyemovement sleep, as seen in carbon monoxide exposures. /Di- and tri-halogenated methane derivatives/ [R30] NTOX: *THE ORAL LD50'S FOR FEMALE AND MALE SWISS ICR MICE ARE 1200 (945-1524) MG/KG AND 800 (667-960) MG/KG /DIBROMOCHLOROMETHANE/, RESPECTIVELY. ... DEATHS OCCURRED FROM 1 TO 5 DAYS AFTER EXPOSURE. ORAL ADMIN OF 500 MG/KG PRODUCED SEDATION AND ANESTHESIA THAT LASTED APPROX 4 HR. ... FATTY INFILTRATION OF THE LIVER, PALE KIDNEYS, AND HEMORRHAGING OF THE ADRENALS /WERE FOUND/ BUT ... NO GROSS CHANGES IN OTHER TISSUES. [R31] *FOLLOWING SINGLE ORAL DOSES OF CHLORODIBROMOMETHANE IN RATS, CLINICAL SIGNS OBSERVED WERE SEDATION, FLACCID MUSCLE TONE, ATAXIA, PILOERECTION, AND PROSTRATION. EXAM REVEALED LIVER AND KIDNEY CONGESTION. FEMALES WERE MORE SENSITIVE THAN MALES TO THE LETHAL EFFECT (LD50: MALE, 1186 MG/KG; FEMALE, 848 MG/KG). [R32] *GROUPS OF 10 MALE AND 10 FEMALE RATS WERE GIVEN SINGLE ORAL DOSES OF CHLORODIBROMOMETHANE (CDBM) AND WERE OBSERVED FOR CLINICAL SYMPTOMS FOR THE FOLLOWING 14 DAYS. ELEVATED SERUM CHOLESTEROL LEVELS WERE OBSERVED IN THE SURVIVING MALE RATS TREATED WITH CDBM. [R33] *GROUPS OF 20 MALE AND 20 FEMALE RATS WERE FED 0, 5, 50, 500, OR 2500 PPM CHLORODIBROMOMETHANE IN THEIR DRINKING WATER FOR 90 DAYS. TEN RATS FROM EACH GROUP WERE KILLED AND THE REMAINING ANIMALS WERE FED TAP WATER FOR A FURTHER 90 DAYS BEFORE THEY WERE SACRIFICED. FOOD CONSUMPTION WAS DEPRESSED IN MALES AND FEMALES RECEIVING 2500 PPM CHLORODIBROMOMETHANE FOR 90 DAYS AND DURING THE RECOVERY PERIOD. DECR LYMPHOCYTE COUNTS WERE ONLY OBSERVED IN THE RECOVERY GROUPS FED CHLORODIBROMOMETHANE (2500 PPM, FEMALE). TRIHALOMETHANES PRODUCED BIOCHEMICAL, HEMATOLOGICAL AND HISTOLOGICAL CHANGES, BUT MOST WERE REVERSIBLE WHEN EXPOSURE HAD TERMINATED. [R34] *Chlorodibromomethane was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using a standard protocol approved by National Toxicology Program. Chlorodibromomethane was tested at doses of 0, 10, 33, 100, 333, 1000, 3333, and 10,000 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Chlorodibromomethane was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 3333 ug/plate. Only one data point for the 10,000 ug/plate dose level was shown for strain TA1535 without activation. [R35] *Chlorodibromomethane tested positive for sister chromatid exchanges and negative for chromosome aberrations in a cytogenetic effects test on Chinese Hamster ovary cells. [R36] *Chlorodibromomethane tested positive for mutagenicity in L5178Y mouse lymphoma cells. [R37] *Cultures of ... African green monkey kidney cells were incubated for 72 hr in the presence of 30 to 300 ug/ml dibromochloromethane. After incubation, viable cells were counted, and concentrations causing 50% inhibition of cell growth (ID50) were determined. Linear dose versus response relationship was obtained. ID50 /was/ 140 ug/ml for dibromochloromethane. The ... /study/ concluded that ... African green monkey kidney cells are ... sensitive to halomethane compounds. [R29] *Fischer-344 rats and B6C3F1 mice were administered 0, 15, 30, 60, 125, or 250 mg/kg chlorodibromomethane for 13 weeks or 0 to 100 mg/kg for 2 years by gavage. Males receiving 125 mg/kg showed a significantly reduced body weight gain. The 250 mg/kg dose produced lesions in the kidneys, liver and salivary glands. In mice receiving chlorodibromomethane for 13 weeks, no compound related mortality was observed. The 250 mg/kg produced fatty changes in the liver and toxic nephropathy in male mice, but not in females. No mortality occurred in rats treated with chlorodibromomethane for 2 years. Male rats receiving 80 mg/kg had reduced body weight gain. Dose-related non-neoplastic liver lesions were observed. No statistically significant increases in tumor incidence were observed. Male mice given 100 mg/kg chlorodibromomethane for 2 years had reduced survival. All males and females given 100 mg/kg chlorodibromomethane had reduced body weight gain. Non-neoplastic liver lesions occurred in mice of both sexes. The incidence of hepatocellular adenomas and carcinomas was significantly increased in treated female mice. A marginally significant increase in hepatocellular adenoma plus carcinoma occurred in treated male mice. [R38] *Chlorodibromomethane was tested for carcinogenicity in two-year studies by oral gavage in male and female B6C3F1 and Fischer 344 rats and in a lifetime study in CBA x C57Bl/6 hybrid mice by administration in the drinking water. In B6C3F1 mice, it produced a significant increase in the incidence of hepatocellular neoplasms in females and a marginal increase in males. Chlorodibromomethane did not increase the proportion of rats with tumors at any site relative to that in controls. There was no increase in tumor incidence in CBA x C57BL/6 hybrid mice given chlorodibromomethane in the drinking water. [R39] *Chlorodibromomethane can cause maternal toxicity in the absence of fetal or embryo toxicity in orally dosed rats. [R26] NTXV: *LD50 RAT (MALE) ORAL DOSE 1186 MG/KG; AND (FEMALE) ORAL DOSE 848 MG/KG; [R32] *LD50 Mice (female) oral 1200 (945-1524) mg/kg; (male) oral 800 (667-960) mg/kg; [R31] *LD50 Rat oral 370 mg/kg; [R14] NTP: *... There was no evidence of carcinogenicity in male or female F344/N rats receiving chlorodibromomethane at doses of 40 or 80 mg/kg 5 times per wk for 104 wk. Fatty metamorphosis and ground-glass cytoplasmic changes of the liver in male and female F344/N rats were related to admin of chlorodibromomethane. There was equivocal evidence of carcinogenicity for male B6C3F1 mice; chlorodibromomethane caused an incr incidence of hepatocellular carcinomas, whereas the combined incidence of hepatocellular adenomas or carcinomas was only marginally incr. Some evidence of carcinogenicity was observed for female B6C3F1 mice, since chlorodibromomethane caused an incr incidence of hepatocellular adenomas and an incr combined incidence of hepatocellular adenomas or carcinomas. [R40] +The potential toxicity of chlorodibromomethane ... (CDBM) was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to chlorodibromomethane exposure. A dose-range finding study was conducted at concns of 0, 5, 50, 150, and 450 ppm in drinking water in order to select concns for the 35-day study. Based on dose-related body weight gain reductions and decreased water consumption, the concns for the 35-day study were selected to be 0, 50, 150, and 450 ppm. One group of male rats (10/group) and two groups of female rats, designated as Group A (peri-conception, 10/group) AND Group B (gestational exposure, 13/group), were used at each dose level. Control animals received deionized water, the vehicle. During the treatment period, all animals survived to the scheduled necropsy and there were no clinical signs of general toxicity noted at any dose level. The male and female mean absolute body weights, feed consumption, clinical observations, and gross findings were comparable across dose groups. Water consumption was decreased by 13-44% at most of the intervals in all treated groups. The overall avg calculated consumption of CDBM for Groups 2-4 was 5.7, 16.3, and 40.3 mg/kg/day, respectively. The male organ weights and organ-to-body weight ratios were also comparable across dose groups. There were no treatment-related reproductive findings in the males or females. There were biologically significant changes noted in male clinical chemistry endpoints: all treated males showed increases (although not always significant) in alkaline phosphatase (22-41%) and 5 nucleotidase (11-24%) and a decr in total serum protein (5%) which may indicate mild liver damage. Results of this study indicate that CDBM treatment did produce possible mild liver dysfunction in the 50, 150, and 450 ppm dose levels in males. A max tolerated dose (MTD) in both males and females was achieved at 450 ppm based on a > 40% reduction in water consumption at that concn of CDBM. Male and female reproductive function was not adversely affected in this study. From these data, CDBM may be a general toxicant at 50, 150, or 450 ppm in male rats and 450 ppm in female rats, but is not a reproductive toxicant in males or females at dose levels up to 450 ppm. [R41] ADE: *A study was performed to determine the absorption, distribution and excretion characteristics of dibromochloromethane in mice and rats. The total radioactivity for sampled organs ranged from 3 to 6% of the total dose in the rats versus 5 to 14% for the mice. The stomach (without contents), nonperfused liver, and kidneys in both rodent species were the organs of highest residual radioactivity levels. In both species the urine contained less than 5% of total radiolabel at 8 hr post-intubation and less than 10% of the total radiolabel at 36 to 48 hr. The majority of dibromochloromethane in both rats and mice was eliminated through the lungs in the expired air within 8 hr. Dibromochloromethane exhibits limited metabolic activation, which was shown by recovery of a higher percentage of the dose as parent compound. [R42] METB: *TRIHALOMETHANES WERE METABOLIZED TO CARBON MONOXIDE BY RAT LIVER MICROSOMAL FRACTION REQUIRING BOTH NADPH AND MOLECULAR OXYGEN FOR MAX ACTIVITY. /TRIHALOMETHANES/ [R43] *HALOFORMS ARE METABOLIZED TO CARBON MONOXIDE BY HEPATIC MIXED FUNCTION OXIDASES AND THIS REACTION IS MARKEDLY STIMULATED BY SULFHYDRYL CMPD. MAX STIMULATION OCCURRED AT 0.5 MMOLAR GLUTATHIONE. A MECHANISM FOR CONVERSION OF HALOFORMS TO CARBON MONOXIDE IS PROPOSED. /HALOFORMS/ [R44] *ADMIN OF HALOFORMS (TRIHALOMETHANES) TO RATS LED TO SUBSTANTIAL ELEVATIONS IN BLOOD CARBON MONOXIDE LEVELS. NA-PHENOBARBITAL TREATMENT INCR BLOOD CARBON MONOXIDE LEVELS. SKF 525-A SIGNIFICANTLY INHIBITED IN VIVO METAB. THE IN VIVO METAB FOLLOWED THE HALIDE ORDER; THUS, ADMIN OF TRIIODOMETHANE YIELDED THE HIGHEST BLOOD CARBON MONOXIDE LEVELS, WHEREAS TRICHLOROMETHANE YIELDED THE LOWEST LEVELS. /HALOFORMS/ [R45] INTC: *Acetone potentiates the responses /hepatotoxicity/ to ... chlorodibromomethane. ... Chlordecone (Kepone) ... exhibits remarkable potentiating properties /hepatotoxicity/ with ... chlorodibromomethane ... [R46] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Chlorodibromomethane's production and use as a chemical intermediate, and its inadvertent formation during chlorination treatment processes of drinking, waste, and cooling waters may result in its release to the environment through various waste streams. Chlorodibromomethane is also produced naturally via bio-synthesis and emitted to seawater (and eventually to the atmosphere) by various species of marine macroalgae which are abundant in the various locations of the world's oceans. If released to air, an estimated vapor pressure of 5.54 mm Hg at 25 deg C indicates chlorodibromomethane will exist solely as a vapor. Vapor-phase chlorodibromomethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 278 days. Direct photolysis is not an environmentally relevant fate process with respect to chlorodibromomethane. If released to soil, chlorodibromomethane is expected to have very high mobility based upon an estimated Koc of 35. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 7.83X10-4 atm-cu m/mole. Chlorodibromomethane may volatilize from dry soil surfaces based upon its vapor pressure. Chlorodibromomethane is resistant to aerobic biodegradation, but degrades anaerobically within 2 weeks to 8 weeks. If released into water, chlorodibromomethane is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 2.6 hr and 6 days, respectively. An estimated BCF of 9 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to chlorodibromomethane may occur through inhalation and dermal contact with this compound at workplaces where chlorodibromomethane is produced or used. The general population may be exposed to chlorodibromomethane via inhalation of ambient air, ingestion of this drinking water disinfection by-product, and dermal contact with this compound and other products containing chlorodibromomethane. (SRC) NATS: *Chlorodibromomethane is biosynthesized and emitted to seawater (and eventually to the atmosphere) by various species of marine macroalgae which are abundant in the various locations of the world's oceans(1,2). [R47] ARTS: *Chlorodibromomethane's production and use as a chemical intermediate(1), and its inadvertent formation during chlorination treatment processes of drinking, waste, and cooling waters(2,3) may result in its release to the environment through various waste streams. [R48] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 35(SRC), determined from a structure estimation method(2), indicates that chlorodibromomethane is expected to have very high mobility in soil(SRC). Volatilization of chlorodibromomethane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 7.83X10-4 atm-cu m/mole(3). The potential for volatilization of chlorodibromomethane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 5.54 mm Hg(SRC), determined from a fragment constant method(4). Chlorodibromomethane is resistant to aerobic biodegradation(5), but degrades anaerobically within 2 weeks(6) to 8 weeks(7). [R49] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 35(SRC), determined from an estimation method(2), indicates that chlorodibromomethane is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 7.83X10-4 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 2.6 hr and 6 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 9(SRC), from an estimated log Kow of 2.16(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Volatilization of chlorodibromomethane is the dominant removal mechanism from environmental surface waters. The volatilization half-life from rivers and streams has been estimated to range from 43 min to 16.6 days with a typical half-life being 46 hours(8). Chlorodibromomethane is resistant to aerobic biodegradation(9), but degrades anaerobically within 2 weeks(10) to 8 weeks(11). [R50] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), chlorodibromomethane, which has an estimated vapor pressure of 5.54 mm Hg at 25 deg C(SRC), using a fragment constant estimation method(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase chlorodibromomethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 278 days(SRC), calculated from its rate constant of 5.78X10-14 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Direct photolysis does not occur below the ozone layer(4). [R51] BIOD: *AEROBIC: Loss of chlorodibromomethane was observed to be 25-39% utilizing a static flask screening procedure and 28 days of incubation, which was interpreted as relative resistance to biodegradation under aerobic conditions(1). [R52] *ANAEROBIC: In anaerobic tests using mixed methanogenic bacterial cultures from sewage effluents, chlorodibromomethane was totally degraded within 2 weeks while only 43-50% was lost in sterile controls after 6 weeks; no degradation was noted in aerobic tests in either sterile or seeded conditions(1). Studies conducted under anoxic conditions with denitrifying bacteria found > 50% degradation in bacterial cultures after 8 weeks but no degradation in sterile controls(2). Rapid degradation was observed in a continuous-flow methanogenic fixed-film laboratory-scale column using seeded cultures, but only slow degradation was noted in sterile controls(3). [R53] ABIO: *The rate constant for the vapor-phase reaction of chlorodibromomethane with photochemically-produced hydroxyl radicals has been estimated as 5.78X10-14 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 278 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). A base-catalyzed second-order hydrolysis rate constant of 3.14X10-4 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 700 and 70 years at pH values of 7 and 8, respectively(2). Direct photolysis or aquatic oxidation (via peroxy radicals or singlet oxygen) are not environmentally relevant processes with respect to chlorodibromomethane(3). [R54] BIOC: *An estimated BCF of 9 was calculated for chlorodibromomethane(1), using a log Kow of 2.16(4) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R55] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for chlorodibromomethane can be estimated to be 35(SRC). According to a classification scheme(2), this estimated Koc value suggests that chlorodibromomethane is expected to have very high mobility in soil. Bromodichloromethane, which is similar in structure to chlorodibromomethane, has been observed to have significant mobility in laboratory soil column experiments utilizing a sandy soil(3). Relatively high soil mobility was noted for chlorodibromomethane during a water infiltration study conducted in the Netherlands along the Rhine River(4). A soil retardation factor of 6 (indicating significant mobility) was estimated during a groundwater recharge project(5). [R56] VWS: *The Henry's Law constant for chlorodibromomethane is 7.83X10-4 atm-cu m/mole(1). This Henry's Law constant indicates that chlorodibromomethane is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 2.6 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 6 days(SRC). Chlorodibromomethane's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of chlorodibromomethane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 5.54 mm Hg(SRC), determined from a fragment constant method(3). Volatilization (half-life of about one hour) was observed from laboratory tanks(4). In another soil column study, 15.3-20.4% was volatilized at 12-21 deg C after 168 hr which was considered to be 10-100 times slower than volatilization from water(5). [R57] WATC: *DRINKING WATER: As part of the USEPA Groundwater Supply Survey, chlorodibromomethane was positively detected in 405 of 945 USA finished water supplies that use groundwater sources at a median level of about 3.3 ppb(1). Median levels of 7.5-17 ppb were detected in the water supplies of over 40% of the 113 USA cities monitored during the three phases (1976-7) of USEPA National Organic Monitoring Survey(2). A Canadian national survey of 70 drinking water supplies found chlorodibromomethane levels of 0-33 ppb with an overall median level of 1.4 ppb(2). In a survey of drinking waters from 12 areas of the world (China, Taiwan, north and south Philippines, Egypt, Indonesia, Australia, England, Brazil, Nicaragua, Venezuela, Peru), chlorodibromomethane was found in 7 of the 12 waters at levels ranging from 1.1-13 ppb(3). Positive detections were made in 30 of 40 Michigan drinking water supplies at a median concn of 2.2 ppb(4). Drinking water samples collected from Los Angeles and Contra Coast, CA in 1984 contained mean concns of 8-28 ug/l(5). In New England, tap water was found to have a chlorodibromomethane concn ranging from < 0.01 to 3 ppb in 1974(6). Muscat, Oman was found to have concns ranging 1.42-2.79, 1.36-2.15, 1.23-1.92, and 1.28-1.85 ug/l in the Main, Al Qurum, Wattayah, and Muscat reservoirs, respectively(7). [R58] *GROUNDWATER: Chlorodibromomethane was one of 27 organic compounds identified in groundwater collected from 315 wells in the area of the Potomac-Raritan-Magothy aquifer system adjacent to the Delaware River(1). Levels of 0.3 ppb have been detected in groundwater from the Netherlands(2). Muscat, Oman was found to have concns ranging 11.7-16.2, 10.4-16.2, 13.9-16.2, and 22.0-23.0 ug/l in the wells 1, 2, 3, and 4, respectively(3). Chlorodibromomethane was detected in Delaware and New York in groundwater at a concn range of 20-55 ug/l(4). [R59] *SURFACE WATER: An analysis of the USEPA STORET Data Base found that chlorodibromomethane had been positively detected in 8.0% of 8515 water observation stations at a median concn below 0.1 ug/l(1). Chlorodibromomethane was detected in 9.8% of 4972 samples collected from 11 stations on the Ohio River during 1980-1 with most concn between 0.1-1.0 ppb(2). Concns ranging from a trace-15 ng/l and not detected-630 ng/l were reported for 16 stations on the Niagara River and 95 stations on Lake Ontario, respectively, for 1981 monitoring(3). Chlorodibromomethane minimum, maximum, and median concns in the river Elbe in 1992/1993 at Zollenspieker and Seemannshoft were found to be 2.6-17 ng/l, median 4 ng/l and 2-12.1 ng/l, median 2.3 ng/l, respectively(4). [R60] *SEAWATER: Chlorodibromomethane concentrations of 0.1-2.2 ng/l have been detected in the North Atlantic while a concn of 0.12 ng/l was detected in the South Atlantic during 1985 monitoring(1). Qualitative detection has been reported for the Narragansett Bay off RI in 1979-80(2). [R61] *RAIN/SNOW: Chlorodibromomethane was detected at a concn of 0.4 ng/l in rain collected in southern Germany in 1985(1). [R62] *OTHER WATER: A chlorodibromomethane concn of 2 ppb was detected in stormwater runoff from Eugene, OR as part of the USEPA Nationwide Urban Runoff Program(1). Chlorodibromomethane has been detected in swimming pool water at levels of 6-10 ppb(2), and ranging from 0.2-0.8 ug/dm cu in the swimming pool of the Technical University of Gdansk(3). [R63] EFFL: *An analysis of the USEPA STORET Data Base found that chlorodibromomethane had been positively detected in 6.5% of 1298 effluent observation stations at a median concn below 2.4 ug/l(1). Chlorodibromomethane was detected in 8 of 63 industrial wastewater discharges in the USA at levels ranging from < 10-100 ppb(2). Three municipal wastewater treatment facilities in Cincinnati, OH were found to be discharging levels as high as 25 ppb in 1982(3). Chlorodibromomethane was not detected in a septic tank effluent in a Regina Saskatachewan study (detection limit not specified)(4). Effluent water from a paper and pulp mill released into Idefjorden contained 4 ng/l of chlorodibromomethane annually(5). [R64] SEDS: *Chlorodibromomethane has been qualitatively detected in soil/sediment/water samples collected from the Love Canal near Niagara Falls, NY(1). [R65] ATMC: *URBAN/SUBURBAN: Mean chlorodibromomethane levels of 0.0, 0.48, 14, 14 and 19 parts per trillion have been detected in the ambient air of Magnolia (AR), El Dorado (AR), Chapel Hill (NC), Beaumont (TX), and Lake Charles (LA), respectively(1). An analysis of ambient air of several German cities found chlorodibromomethane concn generally ranging from not detectable to 0.1 ug/cu m, although one industrial city had a level of 0.9 ug/cu m(2). Monitoring of four CA sites between 1982-3 found mean composite concns of 10-50 parts per trillion in ambient air(3). Chlorodibromomethane was qualitatively detected in air samples collected at two unidentified hazardous waste sites in NJ(4). [R66] *RURAL/REMOTE: Atmospheric chlorodibromomethane levels ranging from 0.06-10 parts per trillion (median of about 0.4) were found in ambient air samples collected from the north and south Atlantic Ocean, the beaches of the Azore Islands and Bermuda, and southern Germany between 1982-5(1). [R62] FOOD: *An analysis of 12 samples of various German milk products (ice cream, yogurt, curds, buttermilk) found chlorodibromomethane levels ranging from not detectable to 0.3 ug/kg with an overall mean concn of 0.1 ug/kg(1). [R67] PFAC: PLANT CONCENTRATIONS: *Mean chlorodibromomethane levels of 150-590 ng/g (dry wt) have been detected in various species of marine algae(1). [R68] MILK: *An analysis of 12 samples of various German milk products (ice cream, yogurt, curds, buttermilk) found chlorodibromomethane levels ranging from not detectable to 0.3 ug/kg with an overall mean concn of 0.1 ug/kg(1). [R67] OEVC: *Chlorodibromomethane has been identified in various German cosmetic products at maximum levels of 0.2 ug/l(1). [R67] RTEX: *Occupational exposure to chlorodibromomethane may occur through inhalation and dermal contact with this compound at workplaces where chlorodibromomethane is produced or used. The general population may be exposed to chlorodibromomethane via inhalation of ambient air, ingestion of this drinking water disinfection by-product, and dermal contact with this compound and other products containing chlorodibromomethane. (SRC) BODY: *Chlorodibromomethane was identified in one of 12 human milk samples collected from volunteers from four USA cities (Bridgeville, PA; Bayonne, NJ; Jersey City, NJ; and Baton Rouge, LA) (1). Chlorodibromomethane was not detected in any sample from the USEPA National Human Adipose Tissue Survey for fiscal year 1982(2). 12% of 1035 blood samples tested positive for chlorodibromomethane exposure in a non-occupationally exposed U.S. population(3). [R69] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 80 ug/l [R70] FEDERAL DRINKING WATER GUIDELINES: +EPA 60 ug/l [R70] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.19 ug/l [R70] +(FL) FLORIDA 1 ug/l [R70] +(MN) MINNESOTA 10 ug/l [R70] +(WI) WISCONSIN 60 ug/l [R70] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Halomethanes/ [R71] +The maximum contaminant level (MCL) set forth by the National Primary Drinking Water Regulations for organic chemicals including total trihalomethanes (the sum of the concentrations of bromodichloromethane, dibromochloromethane, tribromomethane (bromoform) and trichloromethane (chloroform)) is 0.10 mg/l. /Total trihalomethanes/ [R72] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R73] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Chlorodibromomethane is included on this list. [R74] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 1003: Analyte: Chlorobromomethane; Matrix: Air; Sampler: Solid sorbent tube (coconut shell charcoal, 100 mg/50 mg); Flow rate: 0.01-0.2 l/min; Vol: min 0.5 l @ 200 ppm, max 8 l; Stability: not determined /Hydrocarbons, halogenated/ [R75] *The hydropunch: an in situ sampling tool for collecting ground water from unconsolidated sediments. [R76] ALAB: *DETERMINATION OF CHLORODIBROMOMETHANE IN WATER BY GLASS CAPILLARY GAS CHROMATOGRAPHY AND ELECTRON CAPTURE DETECTION. [R77] *SEVERAL METHODS WERE PUBLISHED FOR ANALYSIS OF VOLATILE ORGANOHALIDES IN WATER BY LIQ-LIQ EXTRACTION. THESE METHODS ARE COMPARED TO ONE ANOTHER AND TO THE PURGE- and -TRAP METHOD WITH REGARD TO QUALITATIVE AND QUANTITATIVE ACCURACY. /ORGANOHALIDES/ [R78] *AN ATMOSPHERIC PRESSURE HELIUM MICROWAVE EMISSION DETECTION SYSTEM FOR GAS CHROMATOGRAPHY WAS EVALUATED FOR ANALYSIS OF TRIHALOMETHANES IN DRINKING WATER. THE DETECTION LIMITS FOR THE TRIHALOMETHANES AND OTHER PURGABLE ORGANOHALIDES ARE BELOW 1 PPB. /TRIHALOMETHANES/ [R79] *Determination of halocarbons in drinking water by gas chromatography mass spectrometry using negative ion chemical ionization. /Halocarbons/ [R80] *Determination of halogenated hydrocarbons in water by gas chromatography with time-delayed injection of calibration standard. /Halogenated hydrocarbons/ [R81] *Determination of trihalomethane in drinking water by spectrophotometric method. /Trihalomethane/ [R82] *NIOSH Method 1003. Analyte: chlorobromomethane; Matrix: air; Technique: gas chromatography, flame ionization detector; Desorption: 1 ml carbon disulfide, stand 30 min; Range: 0.5 to 15 mg/sample; Precision (relative standard deviation): 0.61; Est limit of detection: 0.01 mg/sample; Interferences: none /Hydrocarbons, halogenated/ [R83] *EPA Method 601: Purgeable Halocarbons. A purge-and-trap gas chromatography method for the analysis of Dibromochloromethane in municipal and industrial discharges, consists of a stainless steel column, 8 ft x 0.1 in ID, packed with Carbopack B (60/80 mesh) coated with SP-1000, with electrolytic conductivity detection, and helium as the carrier gas at a flow rate of 40 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 45 deg C for 3 min then programmed at 8 deg C/min to final temperature of 220 deg C. This method has a detection limit of 0.09 ug/l and an overall precision of 0.24 times the average recovery + 1.68, over a working range of 8.0 to 500 ug/l. [R84] *EPA Method 624: Purgeables. A purge-and-trap gas chromatography/mass spectrometry method for the analysis of Dibromochloromethane in municipal and industrial discharges, consists of a glass column, 6 ft x 0.1 in, packed with Carbopack B (60/80 mesh) coated with 1% SP-1000, with the detection performed by the mass spectrometer, and helium as the carrier gas at a flow rate of 30 ml/min. A sample injection volume of 2 to 5 ul is suggested, the column temperature is held isothermal at 45 deg C for 3 min and then programmed at 8 deg C/min to a final temperature of 220 deg C. This method has a detection limit of 3.1 ug/l and an overall precision of 0.17 times the average recovery + 0.49, over a working range of 5 to 600 ug/l. [R84] *EPA Method 1624: Volatile Organic Compounds. An isotope dilution gas chromatography/mass spectrometry method for the determination of volatile organic compounds in municipal and industrial discharges is described. This method is designed to meet the survey requirements of Effluent Guidelines Division (EGD) and the National Pollution Discharge Elimination System (NPDES). Under the prescribed conditions, unlabeled Chlorodibromomethane has a minimum level of 10 ug/l and a mean retention time of 251 sec. This method has an initial precision of 7.9 ug/l, an accuracy of 11.2-29.1 ug/l, and a labeled compound recovery of 16-185%. [R84] *AOB Method VA-001-1. Volatile Organic Compounds (VOCs) in Air Sampled by Sorbent Tubes and Analyzed by Purge and Trap GC. [R85] *AOB Method VG-001-1. Volatile Organics in Soil Gas - Adsorbent Tube Method. [R85] *AOB Method VG-007-1. Halogenated and Aromatic Volatile Organic Compounds (VOCs) in Air and Soil Gas Sampled by Sorbent Tubes and Analyzed by Purge and Trap GC/ELCD/PID. [R85] *AOB Method VG-008-1. Volatile Organic Compounds (VOCs) in Soil Gas sampled by Tenax Tubes and Analyzed by Thermal Desorption GC/PID/ELCD. [R85] *AOB Method VG-011-1. Halogenated and Aromatic Volatile Organic Compounds (VOCs) in Whole Gas Analyzed by Purge and Trap GC/ELCD/PID. [R85] *OSW Method 0031. Sampling Method for Volatile Organic Compounds. [R85] *AOB Method VW-001-1. Volatile Organic Compounds (VOCs) in Water by Purge and Trap GC/PID/ELCD. [R85] *AOB Method VW-002-1. Volatile Organic Compounds (VOCs) in Water by Automated Headspace GC/PID/ELCD. [R85] *AOB Method VW-003-1. Volatile Organic Compounds (VOCs) in Water by Automated Headspace GC/PID/ELCD (Internal Standard). [R85] *OSW Method 8240B. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). [R85] *OSW Method 5021. Volatile Organic Compounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. [R85] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. [R85] *OSW Method 8021A. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. [R85] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R85] CLAB: *CHLORODIBROMOMETHANE WAS DETERMINED IN HUMAN TISSUES BY GAS CHROMATOGRAPHY (OV-101 CAPILLARY WITH TEMP PROGRAMMING AND ELECTRON CAPTURE DETECTION). MEAN RECOVERIES WERE 87%, AND LIMITS OF DETECTION WERE IN THE NG/KG RANGE. [R86] *GAS CHROMATOGRAPHY-MASS SPECTROMETRY-COMPUTER ANALYSIS WAS USED TO DETERMINE LEVELS OF VOLATILE HALOGENATED HYDROCARBONS INCL BROMODICHLOROMETHANE IN BREATH, BLOOD AND URINE OF THE POPULATION OF OLD LOVE CANAL AREA, NIAGARA, NY. [R87] *A method is presented for the analysis of bromodichloromethane, and chlorodibromomethane. Blood samples are warmed and an inert gas is passed through the sample to extract the volatile halocarbons. Tissue samples are macerated in water, then treated the same as for blood samples. A Tenax gas chromatography cartridge is used to trap the vapors which are then recovered by thermal desorption and analyzed on gas chromatography /mass spectrometry. Caution should be exercised in handling the volatile components due to their suspected and proven carcinogenicity. The limits of detection of this method are approximately 3 nanograms/milliliter for a 10 milliliter blood sample and 6 nanograms/gram for 5 gram tissue samples. [R88] *Breath samples are collected on Tenax gas chromatography cartridges, dried over calcium sulfate and analyzed using thermal desorption of volatiles into a gas chromatography /mass spectrometer. Halocarbons for which the method is suitable include bromodichloromethane, and chlorodibromomethane. [R89] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/ATSDR; Toxicological Profile for Bromoform/Chlorodibromomethane (1990) ATSDR/TP-90/05 DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorodibromomethane in F344/N Rats and B6C3F1 Mice (Gavage) Technical Report Series No. 282 (1985) NIH Publication No. 85-2538 SO: R1: Kuney, J.H. (ed.). CHEMCYCLOPEDIA 90. Washington, DC: American Chemical Society, 1990. 288 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 356 R3: SRI R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 354 R5: Prager, J.C. Environmental Contaminant Reference Databook Volume 1. New York, NY: Van Nostrand Reinhold, 1995. 819 R6: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-206 R7: Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) R8: Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991. 247 R9: Heikes DL; J Assoc Off Anal Chem 70: 215-226 (1987) R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 839 R11: Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants USEPA 440/4-81-014 (1981) R12: Warner HP et al; Determination of Henry's Law Constants of Selected Priority Pollutants. USEPA/600/D-87/229, NTIS PB87-212684 (1987) R13: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 267 R14: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 745 R15: Kayser, R., D. Sterling, D. 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NY, NY: John Wiley and Sons, p. 354 (1997) (2) Perwak J et al; Exposure and Risk Assessment for Trihalomethanes (Chloroform, Bromoform, Bromodichloromethane, Dibromochloromethane) USEPA-440/8-81-018 p.13 (1980) (3) USEPA; Health and Environmental Effects Profile for Bromochloromethanes ECAO-CIN-P122 (Final Draft) p.12, 21 (1985) R49: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Warner HP et al, Determination of Henry's Law Constants of Selected Priority Pollutants. 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Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (4) Francois C et al; Trav Soc Pharm Montpellier 39: 49-50 (1979) (5) Park KS et al; Hazard Waste Hazard Mater 5: 219-29 (1988) R58: (1) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) (2) USEPA; Ambient Water Quality Criteria for Halomethanes USEPA-440/5-80-051 p.C-7 (1980) (3) Trussel AR et al; Water Chlorination Environ. Impact Health Effects 3: 39-53 (1980) (4) Furlong EAN, Ditri FM; Ecol Modeling 32: 215-25 (1986) (5) Wallace LA et al; Atmos Environ 22: 2141-63 (1988) (6) Verschueren K; Handbook of Environmental Data on Organic Chemicals. 3rd ed. NY, NY: Van Nostrand Reinhold Co. p. 630 (1996) (7) Badawy MI; Bull Environ Contam Toxicol 48:157-62 (1992) R59: (1) Fusillo TV et al; Groundwater 23: 354-60 (1985) (2) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) (3) Badawy MI; Bull Environ Contam Toxicol 48: 157-62 (1992) (4) Jury WA et al; Ecosystem 99: 119-64 (1987) R60: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Ohio River Valley Sanit Comm; Assessment of Water Quality Conditions. Ohio River Mainstream, Cincinnati, OH (1982) (3) Kaiser KLE et al; J Great Lakes Res 9: 212-23 (1983) (4) Gotz R et al; Chemosphere 36: 2085-101 (1998) R61: (1) Class T et al; Chemosphere 15: 429-36 (1986) (2) Wakeham SG et al; Can J Fish Aquatic Sci 40: 304-21 (1983) R62: (1) Class T et al; Chemosphere 15: 429-36 (1986) R63: (1) Cole RH et al; J Wat Pollut Control Fed 56: 898-908 (1984) (2) Aggazzotti G, Predieri G; Wat Res 20: 959-63 (1986) (3) Biziuk M et al; Intern J Environ Anal Chem 50: 109-15 (1993) R64: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Perry DL et al; p. 42-3 in Identification of Organic Compounds in Industrial Effluent Discharges USEPA-600/4-79-016 (1979) (3) Dunovant VS et al; J Water Pollut Control Fed 58: 886-95 (1986) (4) Virarghavan T, Hasen S; Water Air Soil Pollut 28: 299-308 (1986) (5) Abrahamsson K, Klick S; Chemosphere 18: 2247-56 (1989) R65: (1) Hauser TR, Bromberg SM; Environ Monitor Assess 2: 249-72 (1982) R66: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data, Menlo Park, CA: SRI International (1982) (2) Bauer U; Zentralbl Bakteriol Mikrobiol Hyg ABT 1 Orig B Hyg Umwelthyg Krankenhaushyg Arbeitshyg Praev Med 174: 200-37 (1981) (3) Shikiya J et al; Proc-APCA 77th Annual Mtg Vol 1, 84-1.1 (1984) (4) LaRegina J et al; Environ Prog 5: 18-27 (1986) R67: (1) Bauer U; Zentralbl Bakteriol Mikrobiol Hyg ABT 1 Orig B Hyg Umwelthyg Krankenhaushyg Arbeitshyg Praev Med 174: 200-37 (1981) R68: (1) Gschwend PM et al; Science 227: 1033-5 (1985) R69: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 322-8 (1982) (2) Stanley JS; Broad Scan Analysis of Human Adipose Tissue: Volume II: Volatile Organic Compounds USEPA-560/5-86-036 p.74 (1986) (3) Ashley DL et al; Clin Chem 40: 1401-4 (1994) R70: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R71: 40 CFR 401.15 (7/1/99) R72: 40 CFR 141.12 (7/1/99) R73: 40 CFR 302.4 (7/1/99) R74: 40 CFR 716.120 (7/1/99) R75: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 1003-1 R76: Edge RN, Cordry K; Ground Water Monit. Rev. 9 (3): 177-183 (1989) R77: EKLUND G ET AL; HRC CC, J HIGH RESOLUT CHROMATOGR CHROMATOGR COMMUN 1 (1): 34-40 (1978) R78: DRESSMAN RC ET AL; AM WATER WORKS ASSOC J 71 (7): 392-6 (1979) R79: QUIMBY BD ET AL; ANAL CHEM 51 (7): 875-80 (1979) R80: Daishima S et al; Nippon Kagaku Kaishi 7: 1146-50 (1984) R81: Gruber H; GIT Fachz Lab 28 (3): 161-2 165 (1984) R82: Huang JY C, Smith GC; J Am Water Works Assoc 76 (4): 168-71 (1984) R83: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R84: 40 CFR 136 (7/1/88) R85: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC#4082. Rockville, MD: Government Institutes (1997) R86: ALLES G ET AL; ZENTRALBL BAKTERIOL, MIKROBIOL HYG, ABT 1, ORIG B 174 (3): 238-48 (1981) R87: BARKLEY J ET AL; BIOMED MASS SPECTROM 7 (4): 139-47 (1980) R88: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 435-44 (1985) R89: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 413-31 (1985) RS: 61 Record 187 of 1119 in HSDB (through 2003/06) AN: 2798 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BUTYRALDEHYDE- SY: *ALDEHYDE-BUTYRIQUE- (FRENCH); *ALDEIDE-BUTIRRICA- (ITALIAN); *BUTAL-; *BUTALDEHYDE-; *BUTALYDE-; *BUTANAL-; *N-BUTANAL-; *1-butanal-; *N-BUTANAL- (CZECH); *BUTANALDEHYDE-; *Butylaldehyde-; *N-BUTYL-ALDEHYDE-; *BUTYRAL-; *N-BUTYRALDEHYDE-; *BUTYRALDEHYDE- (CZECH); *BUTYRALDEHYD- (GERMAN); *BUTYRIC-ALDEHYDE-; *BUTYRYLALDEHYDE-; *Pesticide-Code:-202500-; *FEMA-NUMBER-2219-; *NCI-C56291- RN: 123-72-8 MF: *C4-H8-O SHPN: UN 1129; Butyraldehyde IMO 3.2; Butyraldehyde MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *From butyryl chloride; by redn of corresponding nitrile; by alkali aluminum hydride redn of methyl butyrate. Usually mfr by catalytic dehydrogenation of butanol, catalytic hydrogenation of crotonaldehyde, or by the oxo process from propene. [R1] *BY DRY DISTILLATION OF CALCIUM BUTYRATE AND CALCIUM FORMATE. [R2] *The most widely used manufacturing technique for butyraldehyde is the oxo process, in which propylene, carbon monoxide, and hydrogen are combined with a suitable catalyst, usually a cobalt compound, at about 130-160 deg C and 100-200 atm pressure. Butyraldehyde can also be produced from 2-butenal (crotonaldehyde) formed by the Aldol condensation of acetaldehyde. This process was a major source of butyraldehyde until about 1970. [R3, 741] *Propylene + synthesis gas (hydroformylation; coproduced with isobutylaldehyde) [R4] IMP: *DRY BUTYRALDEHYDE WILL UNDERGO SOME POLYERMIZATION DURING STORAGE TO FORM PARABUTYRALDEHYDE. [R5] FORM: *USEPA/OPP Pesticide Code 202500; Trade Names: Butanal. [R6] *Grades: technical (93% minimum). [R7] *98% LIQUID GRADE ... [R8] *Available commercially as a 55% aqueous solution [R4] MFS: *Aristech Chemical Corp., 210 Sixth Ave., Pittsburgh, PA 15222-2611, (412) 316-2747; Production site: Pasadena, TX 77501 [R9] *BASF Corp., 3000 Continental Drive - North, Mount Olive, NJ 07828-1234, (973) 426-2600. Chemicals Division, Industrial Organics; Production site: Freeport, TX 77541 [R9] *Celanese Ltd., Celanese Chemicals-Americas, 86 Morris Ave., Summit, NJ 07901, (972) 443-4000; Production sites: Bay City, TX 77414 [R9] *Eastman Chemical Co., P.O. Box 511, Kingsport, TN 37662, (423) 224-0323. Texas Eastman Division; Production site: Longview, TX 75607 [R9] *Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817-001, (203) 794-2000; Production sites: Taft, LA 70057; Texas City, TX 77590 [R9] OMIN: *BUTYRALDEHYDE BECAME A COMMERCIAL CHEMICAL IN THE DECADE FOLLOWING WORLD WAR II [R10] USE: *For Butyraldehyde (USEPA/OPP Pesticide Code: 202500) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R6] *Chiefly in mfr of rubber accelerators, synthetic resins, solvents, plasticizers. [R1] *SYNTHETIC FLAVORING IN FOODS [R2] *Use to manufacture 1-butanol, 2-ethylhexanol, poly(vinyl butyral), 2-ethylhexanal, trimethylolpropane, methyl amyl ketone, and butyric acid. [R3, 740] */Mfr of/ high polymers [R7] CPAT: *(1988) 1-butanol and 2-ethylhexanol (92%); poly(vinyl butyral), 2-ethylhexanal, trimethylolpropane, methyl amyl ketone, and butyric acid (8%). [R3, 740] *USED CHIEFLY AS AN INTERMEDIATE (1978 DATA) [R10] PRIE: U.S. PRODUCTION: *(1984) 5.64X10+11 g [R11] *(1991) 2.19X10+9 lbs [R12] *(1989) Capacity, 9.63X10+5 tons [R3, 740] U.S. EXPORTS: *(1984) 3.77X10+7 g [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R14, p. 49-44]; *Water-white liquid [R7] ODOR: *Characteristic, pungent, aldehyde odor [R7] BP: *74.8 deg C [R1] MP: *-99 deg C [R1] MW: *72.11 [R1] CTP: *Critical temperature: 263.95 deg C; Critical pressure: 30,003 mm Hg (4000 kPa) [R3, 740] DEN: *0.8016 @ 20 deg C/4 deg C [R1] HTC: *2479.34 kJ/mol @ 25 deg C (liquid) [R15, 330] HTV: *33.68 kJ/mol @ 25 deg C [R15, 3309] OWPC: *log Kow = 0.88 [R16] SOL: *Sol in ethanol, ether, ethyl acetate, acetone, toluene; sol in oils [R1]; *SOL IN BENZENE [R17]; *In water, 7.10X10+4 mg/l @ 25 deg C [R18] SPEC: *Index of refraction: 1.379 @ 20 deg C/D [R1]; *MAX ABSORPTION (WATER): 225 NM (LOG E= 1.07); 282 NM (LOG E= 1.13) [R19]; *IR: 333 (Sadtler Research Laboratories Prism Collection) [R20]; *UV: 1-33 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R20]; *NMR: 78 (Varian Associates NMR Spectra Catalogue) [R20]; *MASS: NIST 61771 (NIST/EPA/MCDC Mass Spectral Database 1990 version) [R20]; *13C NMR: JJ 74 (Johnson and Jankowski; Carbon-13 NMR for Organic Chemists, John Wiley and Sons, NY) [R20] SURF: *29.9 dyn/cm @ 24 deg C [R15, 330] VAPD: *2.5 (AIR= 1) [R14, p. 325M-25] VAP: *111 mm Hg @ 25 deg C [R21] VISC: *0.0043 Poise @ 20 deg C [R7] OCPP: *Wt/gal: 6.7 lb @ 20 deg C; Coefficient of expansion: 0.00114 @ 20 deg C [R7] *Henry's Law constant = 1.15X10-4 atm-cu m/mole @ 25 deg C [R22] */BUTYRALDEHYDE IS/ ... OXIDIZED VERY POORLY OR NOT AT ALL. [R23] *Hydroxyl radical reaction rate constant = 2.35X10-11 cu cm/molecule-sec @ 25 deg C [R24] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances labeled "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R25] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R25] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to lOO meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R25] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R25] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R25] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Do not use dry chemical extinguishers to control fires involving nitromethane or nitroethane. Large fires: Water spray, fog or alcohol-resistant foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R25] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R25] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R25] FPOT: *Highly flammable liquid. [R26] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R27, p. 325-24] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R27, p. 325-24] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R27, p. 325-24] FLMT: *Lower: 1.9% by volume; Upper: 12.5% by volume. [R28, 357] FLPT: *-8 DEG F (-22 DEG C) (CLOSED CUP) [R27, p. 325-24] AUTO: *425 DEG F [R27, p. 325-24] FIRP: *Use dry chemical, foam, or carbon dioxide. Water may be ineffective but should be used to keep fire-exposed containers cool. Fight fire from protected location or maximum possible distance. [R28, 357] *Fight fire from protected location or maximum possible distance. Use dry chemical, foam, carbon dioxide. Water may be ineffective. Use water spray to keep fire-exposed containers cool. [R27, p. 49-32] OFHZ: *Flammable liquid. Forms explosive peroxides. Vapors are heavier than air and may travel to a source of ignition and flash back. Combustion may produce irritants and toxic gases. Closed containers may rupture violently when heated. [R27, p. 49-32] EXPL: *LOWER: 1.9%; UPPER: 12.5%; EXPLOSIVE PEROXIDES MAY BE FORMED IN THE AIR. [R27, p. 49-32] REAC: *Incompatible with oxidizing materials. [R26] *Reacts vigorously with chlorosulfonic acid, /nitric acid/, oleum, /sulfuric acid/. [R26] *Butyraldehyde mixed with chlorosulfonic acid, 70% nitric acid, oleum, or 96% sulfuric acid in closed containers causes the temperature, and pressure to increase. [R28, 357] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R26] POLY: *Hazardous polymerization may occur. [R27, p. 49-32] SERI: *Eye, nose, skin, and throat irritant. [R14, p. 49-43] EQUP: *Wear special protective clothing and positive-pressure self-contained breathing apparatus. [R28, 357] OPRM: *THE BASIC VENTILATION METHODS ARE LOCAL AND EXHAUST VENTILATION AND DILUTION OR GENERAL VENTILATION. [R29] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R30] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R31] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R32] STRG: *MATERIALS WHICH ARE TOXIC AS STORED OR WHICH CAN DECOMPOSE INTO TOXIC COMPONENTS ... SHOULD BE STORED IN A COOL WELL VENTILATED PLACE, OUT OF THE DIRECT RAYS OF THE SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, AND SHOULD BE PERIODICALLY INSPECTED. INCOMPATIBLE MATERIALS SHOULD BE ISOLATED ... . [R29] *Store in cool, dry, well ventilated location. Separate from oxidizing materials, amines, strong alkalies, acids, and other reactive hazards. Inside storage should be in a standard flammable liquids storage warehouse, room, or cabinet. Bulk storage should be blanketed with inert gas. [R27, p. 49-32] CLUP: *Contaminated wastewaters containing butyraldehyde are produced during the MFR of poly(vinyl butyral) and poly(vinyl formal ethylal). On tha basis of lab tests, a scheme for treating wastewater is recommended. After neutralization with sodium hydroxide or calcium oxide, the organic fraction is distilled from the wastewater and incinerated. [R28, p. 357-8] *Eliminate all ignition sources. Stop or control the leak, if this can be done without undue risk. Use water spray to cool and disperse vapors and protect personnel. Control runoff and isolate discharged material for proper disposal. [R27, p. 49-32] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *The following wastewater treatment technology has been investigated for butyraldehyde: Concentration process: Activated carbon. [R28, 358] *Butyraldehyde is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R33] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Aggressive airway management may be necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Anticipate seizures and treat if necessary ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aldehydes and related compounds/ [R34, p. 234-35] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Intubation should be considered at the first sign of upper airway obstruction caused by edema. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Treat seizures with diazepam ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aldehydes and related compounds/ [R34, 235] HTOX: *MAY ACT AS IRRITANT, /SRP: CNS DEPRESSANT/ ... [R35] *MAY PRODUCE SKIN AND EYE BURNS AFTER CONTACT. [R14, p. 49-44] *BUTANAL HAD NO EFFECT ON THE RATE OF SISTER CHROMATID EXCHANGE IN HUMAN LYMPHOCYTES IN VITRO. [R36] *LOW INHALATION TOXICITY. GOOD WARNING PROPERTIES DUE TO PUNGENT ODOR. [R37] *BUTYRALDEHYDE HAS BEEN TESTED FOR IRRITANT EFFECT ON HUMAN EYES @ VAPOR CONCN IN AIR SUCH AS MIGHT OCCUR IN SMOG, AND HAS BEEN FOUND NONIRRITANT. ... IN SIX INSTANCES OF INDUSTRIAL CORNEAL INJURY FROM BUTYRALDEHYDE RECOVERY IS SAID TO HAVE BEEN PROMPT AND COMPLETE. [R38] *Human immunological effects by inhalation: delayed hypersensitivity. [R26] NTOX: *... Anesthesia /noted/ in rats at high levels of inhalation for propionaldehyde and butyraldehyde. The survivors recovered promptly. Autopsies showed principally evidence of bronchial and alveolar inflammation. ... Rats tolerated inhalation of 90 ppm of propionaldehyde, for 20 days, 6 hr/day, with no obvious pathology, although 1300 ppm for 6 days produced hepatic damage. [R39] *... Acute toxicity of aldehydes in mice, guinea pigs, and rabbits /have been studied/. all animals exposed to high levels by inhalation developed fatal pulmonary edema. /Higher aliphatic aldehydes/ [R39] *THE LIQUID APPLIED AS A DROP TO RABBIT EYES PROVED ... DAMAGING, GRADED 8 ON A SCALE OF 1 TO 10 AFTER TWENTY-FOUR HOURS. [R38] *RESPIRATION AND HEART BEAT WERE INCR IN MALE RABBITS EXPOSED TO 10-20 PPM BUTYLALDEHYDE. [R40] *THE CHANGES IN EXCITABILITY AND CONDUCTION PROPERTIES OF FROG SCIATIC NERVE UNDER THE INFLUENCE OF BUTYRALDEHYDE WERE EXAMINED IN THE CONCN RANGE 0.01-1.00% (WT/VOL) AND AT 20, 25, 30, AND 35 DEG. IT IRREVERSIBLY REDUCED THE AMPLITUDE OF THE CMPD ACTION POTENTIAL OF THE NERVE AND DECR THE CONDUCTION VELOCITY UP TO THE COMPLETE BLOCK. [R41] *Butyraldehyde was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Butyraldehyde was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. [R42] NTXV: *LD50 Rat oral 5.89 g/kg; [R35] *LC50 Rat inhalation 60,000 ppm/0.5 hr; [R43] *LD50 Rat oral 2,490 mg/kg; [R5] *LD50 Rat ip 800 mg/kg; [R26] *LC50 Mouse inhalation 44,610 mg/cu m/2 hr; [R26] *LD50 Mouse ip 1140 mg/kg; [R26] *LD50 Mouse sc 2700 mg/kg; [R26] *LD50 Rabbit skin 3560 mg/kg; [R26] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Butyraldehyde's production and use in the manufacture of rubber accelerators, synthetic resins, solvents, and plasticizers may result in its release to the environment through various waste streams. Butyraldehyde has been detected in emissions from fireplaces burning wood, and has been detected in gasoline and diesel vehicle emissions. Butyraldehyde can also occur in trace amounts in tea leaves, certain oils, coffee aroma, and tobacco smoke. If released to air, a vapor pressure of 111 mm Hg at 25 deg C indicates butyraldehyde will exist solely as a vapor in the ambient atmosphere. Vapor-phase butyraldehyde will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 16.4 hrs. Butyraldehyde absorbs light in the environmental UV spectrum and has the potential for direct photolysis. If released to soil, butyraldehyde is expected to have high mobility based upon an estimated Koc of 72. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 1.2X10-4 atm-cu m/mole. Butyraldehyde may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, butyraldehyde is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Butyraldehyde is expected to biodegrade rapidly under both aerobic and anaerobic conditions. Under aerobic conditions, butyraldehyde, present at 100 mg/l, reached > 100% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test. Under anaerobic conditions, butyraldehyde underwent 99% degradation using a serum bottle technique. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 5.2 hrs and 5.3 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Butyraldehyde is not expected to chemically hydrolyze in the environment due to the lack of hydrolyzable functional groups. Occupational exposure to butyraldehyde may occur through inhalation and dermal contact with this compound at workplaces where butyraldehyde is produced or used. Monitoring data indicate that the general population may be exposed to butyraldehyde via inhalation of ambient air containing butyraldehyde. (SRC) NATS: *REPORTED FOUND IN THE ESSENTIAL OILS FROM FLOWERS, FRUITS, LEAVES, OR BARK OF: MONARDA FISTULOSA, LITSEA CUBEBA, BULGARIAN CLARY SAGE, CAJEPUT, EUCALYPTUS CINEREA, EUCALYPTUS GLOBULUS, AND OTHERS, AS WELL AS IN APPLE AND STRAWBERRY AROMAS. [R2] *Carbonyl compounds, such as butyraldehyde, are formed in the atmosphere by photochemical oxidation of emitted hydrocarbons and other reactive organic gases(1); during smog pollution episodes that occur in the Los Angeles, CA area, the primary source of butyraldehyde that exists in the atmosphere may result from this photochemical generation(1). Microbial degradation processes and plant volatiles can emit butyraldehyde to the atmosphere(2). Butyraldehyde can also occur in trace amounts in tea leaves, certain oils, coffee aroma, and tobacco smoke(3). [R44] ARTS: *Butyraldehyde's production and use as in the manufacture of rubber accelerators, synthetic resins, solvents, and plasticizers(1) may result in its release to the environment through various waste streams(SRC). Butyraldehyde has been detected in emissions from fireplaces burning wood(2), and has been detected in gasoline and diesel vehicle emissions(3-5). Volatile emissions from poultry manure contain butyraldehyde(6). Butyraldehyde can be released to the atmosphere in emissions from animal waste, coffee mfg, fish meal mfg, petroleum processing, and tobacco smoke(5). [R45] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 72(SRC), determined from a log Kow of 0.88(2) and a regression-derived equation(3), indicates that butyraldehyde is expected to have high mobility in soil(SRC). Volatilization of butyraldehyde from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 1.2X10-4 atm-cu m/mole(4). The potential for volatilization of butyraldehyde from dry soil surfaces may exist(SRC) based upon a vapor pressure of 111 mm Hg(5). Butyraldehyde is expected to biodegrade rapidly under both aerobic(6) and anaerobic(7) conditions. Under aerobic conditions, butyraldehyde, present at 100 mg/l, reached > 100% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(6). Under anaerobic conditions, butyraldehyde underwent 99% degradation (7 day lag period) using the Hungate serum bottle technique(8). [R46] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 72(SRC), determined from a log Kow of 0.88(2) and a regression-derived equation(3), indicates that butyraldehyde is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 1.2X10-4 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 5.2 hrs and 5.3 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Butyraldehyde is expected to biodegrade rapidly under both aerobic(7) and anaerobic(8) conditions. Under aerobic conditions, butyraldehyde, present at 100 mg/l, reached > 100% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(7). Under anaerobic conditions, butyraldehyde underwent 99% degradation (7 day lag period) using the Hungate serum bottle technique(9). [R47] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), butyraldehyde, which has a vapor pressure of 111 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase butyraldehyde is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is 16.4 hrs(SRC), calculated from its rate constant of 2.4X10-11 cu cm/molecule-sec at 25 deg C(3). Based upon analogy to acetaldehyde and propionaldehyde, the direct photolysis rate constant for butyraldehyde in air is about 4X10-5 sec-1(4), which corresponds to a half-life of about 4.8 hours(SRC). [R48] BIOD: *AEROBIC: Butyraldehyde, present at 100 mg/l, reached > 100% of its theoretical BOD in 2 weeks using an activated sludge inoculum at 30 mg/l and the Japanese MITI test(1). Butyraldehyde had a 5-day theoretical BOD of 28% using the AFNOR T test and an inoculum from 3 polluted surface waters(2). Using a sewage inocula and standard dilution water, butyraldehyde had a 5-day theoretical BOD of 43%(3). Theoretical BODs of 43.4, 59.8, and 68% were measured after 5, 10, and 50 days, respectively, using a sewage seed(4). A 5-day theoretical BOD of 106% was reported for a sewage inocula(5). Using an electrolytic respirometer and an activated sludge inocula, theoretical BODs of 46-57% were observed after 90-135 hr of incubation(6). Butyraldehyde is expected to biodegrade rapidly under aerobic conditions(SRC). [R49] *ANAEROBIC: Butyraldehyde underwent 99% degradation (7 day lag period) under anaerobic conditions using the Hungate serum bottle technique(1). Degradation in anaerobic reactor (after 52 days of acclimation) was 82%(1). Butyraldehyde is considered amendable to anaerobic biodegradation(2). [R50] ABIO: *The rate constant for the vapor-phase reaction of butyraldehyde with photochemically-produced hydroxyl radicals is 2.4X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 16.4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). The rate constant for the reaction between photochemically produced hydroxyl radicals in water and butyraldehyde is 3.9X10+9 L/mole-sec(2); assuming that the concn of hydroxyl radicals in brightly sunlit natural water is 1X10-17 M, the half-life would be about 206 days(SRC). Butyraldehyde is not expected to chemically hydrolyze in the environment due to the lack of hydrolyzable functional groups(3). Based upon analogy to acetaldehyde and propionaldehyde, the direct photolysis rate constant for butyraldehyde in air is about 4X10-5 sec-1(4), which corresponds to a half-life of about 4.8 hours(SRC). [R51] BIOC: *An estimated BCF of 3 was calculated for butyraldehyde(SRC), using a log Kow of 0.88(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R52] KOC: *The Koc of butyraldehyde is estimated as 72(SRC), using a log Kow of 0.88(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that butyraldehyde is expected to have high mobility in soil(SRC). [R53] VWS: *The Henry's Law constant for butyraldehyde is 1.2X10-4 atm-cu m/mole(1). This Henry's Law constant indicates that butyraldehyde is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 5.2 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5.3 days(SRC). Butyraldehyde's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of butyraldehyde from dry soil surfaces may exist(SRC) based upon a vapor pressure of 111 mm Hg(3). [R54] WATC: *DRINKING WATER: Butyraldehyde has reportedly been detected in drinking water samples collected in the US (concn or locations not reported)(1). [R55] *SURFACE WATER: Butyraldehyde was qualitatively detected in Niagara River water flowing into Lake Ontario(1). [R56] *SEAWATER: Seawater samples collected from the Straits of Florida on Feb 27, 1968 contained butyraldehyde levels ranging from a trace (0.005 mg/L) to 0.048 mg/L(1). [R57] *RAIN/SNOW: Butyraldehyde levels of 0-0.52 ug/mL (mean 0.07 ug/mL) have been detected in cloud water collected from Henninger Flats, CA(1); levels of 0-0.052 ug/mL have been detected in fog water collected from Pasadena, CA(1). [R58] EFFL: *A butyraldehyde concn of 42 ppb was detected in an aqueous effluent from a coal gasification facility in Morgantown, WV(1). Butyraldehyde emission rates of 0.01-0.90 g/kg wood have been detected in emissions from fireplaces burning jack pine and red oak wood(2). Butyraldehyde was detected in 2 of 63 effluents (concn < 100 ppb) collected from chemical manufacturing plants across the US(3). The emission rate of butyraldehyde in the gas-phase from medium duty diesel trucks and from particle board/carpet degassing are 1,300 ug per km driven(4) and 0.047 mg/sq m-hr(5), respectively. [R59] ATMC: *URBAN/SUBURBAN: The gas-phase concn of butyraldehyde in ambient Los Angeles, CA air during photochemical pollution episodes (July-Oct 1980) ranged from 0 to 7 ppb with a median conc of about 1.5 ppb(1); particulate-phase conc during the same pollution episodes was 0 to 0.098 ug/cu m which was less than one percent total airborn conc(1). Air sample collected from Claremont, CA in Sept 1985 contained butyraldehyde levels of 0.2 to 0.8 ppb(2); sampling was not conducted during any smog/pollution episodes, therefore, airborn levels were smaller than reported above(1,2). Butyraldehyde levels in Los Angeles, CA air in the fall of 1981 were 0-5 ppb(3). A field monitoring study along a highway in Raleigh, NC in May 1983 detected butyraldehyde levels of 2.88-7.29 ppb(4); the primary source of the butyraldehyde was considered to be exhaust from cars and trucks(4). The concn of butyraldehyde in outdoor air near 4 residences during the winter of 1993 and 9 residences during the summer of 1993 from greater Boston, MA area were 0.26 ppb (range, 0.0-0.51 ppb) and 0.13 ppb (range, 0.0-0.58 ppb), respectively(5). [R60] *INDOOR: The concn of butyraldehyde in indoor air of 4 residences during the winter of 1993 and 9 residences during the summer of 1993 from greater Boston, MA area were 0.62 ppb (range, 0.37-0.98 ppb) and 0.56 ppb (range, 0.15-1.5 ppb), respectively(1). [R61] FOOD: *Butyraldehyde has been qualitatively detected as a volatile component of raw chicken breast muscle(1) and fried chicken(2). [R62] MILK: *Butyraldehyde was qualitatively detected in 6 of 12 samples of human milk collected from volunteers in Bayonne, NJ, Jersey City, NJ, Bridgeville, PA, and Baton Rouge, LA(1). [R63] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 5,392 workers (950 of these are female) are potentially exposed to butyraldehyde in the US(1). Occupational exposure to butyraldehyde may occur through inhalation and dermal contact with this compound at workplaces where butyraldehyde is produced or used(SRC). Monitoring data indicate that the general population may be exposed to butyraldehyde via inhalation of ambient air containing butyraldehyde(SRC). [R64] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 25 ppm. [R65] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Butyraldehyde is produced, as an intermediate or a final product, by process units covered under this subpart. [R66] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Butanal is included on this list. [R67] FDA: *Butyraldehyde is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: a) they are used in the minimum quantity required to produce their intended effect, and otherwise in accordance with all the principles of good manufacturing practice, and 2) they consist of one or more of the following, used alone or in combination with flavoring substances and adjuvants generally recognized as safe in food, prior-sanctioned for such use, or regulated by an appropriate section in this part. [R68] *Butyraldehyde is an indirect food additive for use only as a component of adhesives. [R69] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *OSW Method 0100. Sampling for Formaldehyde and Other Carbonyl Compounds in Indoor Air. This method provides procedures for the sampling of various carbonyl compounds in indoor air by derivatization with 2,4-dinitrophenylhydrazine (DNPH) in a silica gel cartridge. [R70] ALAB: *A REVERSED-PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY SYSTEM WITH A LICHROSORB RP 18 COLUMN AND ACETONITRILE-WATER MOBILE PHASE HAS BEEN APPLIED TO THE DETERMINATION OF C1-C6 ALIPHATICS IN POLLUTED AIR. [R71] *LOWER ALIPHATIC CARBONYL CMPD WERE DETERMINED BY GAS-LIQUID-SOLID CHROMATOGRAPHY IN THE EXHAUST GASES FROM SOME ODOR SOURCES USING THE COLD-TRAPPING METHOD WITH LIQ ARGON. THE DETECTION LIMIT WAS APPROX 10 PPB. [R72] *CARBONYL CMPD INCL BUTYRALDEHYDE WERE IDENTIFIED BY GAS CHROMATOGRAPHY AND GAS CHROMATOGRAPHY-MASS SPECTROMETRY IN THE VAPOR GENERATED BY THERMAL DECOMP OF POLY(BUTYL METHACRYLATE), A SYNTHETIC RESIN. THE ALDEHYDES STARTED TO BE GENERATED @ ABOUT 100 DEG, AND 90% OF THE AMT WAS GENERATED FROM 200 TO 280 DEG. [R73] *NIOSH Method 2539. Screening of Aldehydes by Gas Chromatography. This method is applicable to air samples. Detection limit = 0.4 mg/cu m. [R74] *EPA Method 554. Determination of Carbonyl Compounds in Drinking Water by Dinitrophenylhydrazine Derivatization and High Performance Liquid Chromatography. This method is used for the determination of selected carbonyl compounds in finished drinking water or raw source water. Detection limit = 8.6 ug/l. [R70] *OSW Method 8315. Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC). This method is applicable to various matrices by derivatization with 2,4-dinitrophenylhydrazine (DNPH). Detection limit not specified. [R70] *OSW Method 8315A-LLE. Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC) Using Liquid-Liquid Extraction. This method is applicable to the determination of free carbonyl compounds in various matrices by derivatization with 2,4-dinitrophenylhydrazine (DNPH). Detection limit = 7.8 ug/l. [R70] *OSW Method 8315A-LS: Determination of Carbonyl Compounds by High Performance Liquid Chromatography (HPLC) using Liquid-Solid Extraction. This method is applicable to the determination of free carbonyl compounds in various matrices by derivatization with 2,4-dinitrophenylhydrazine (DNPH). Detection limit = 6.3 ug/l. [R70] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: ENVIRONMENTAL HEALTH PERSPECTIVES; DHEW PUBLICATION NO 11,163,75. TOXICOLOGY REVIEW. SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 261 R2: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 77 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (1992) R4: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 162 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V4 384 (1978) R6: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Butyraldehyde (123-72-8). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R7: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 185 R8: CHEMCYCLOPEDIA 1986 p.64 R9: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 500 R10: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V4 376 (1978) R11: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 p.255 R12: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 509 R13: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1984 p.277 R14: National Fire Protection Guide. Fire Protection Guide on Hazardous Materials. 10 th ed. Quincy, MA: National Fire Protection Association, 1991. R15: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. R16: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 9 R17: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-149 R18: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson,AZ: Univ Az, College of Pharmacy (1992) R19: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. 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Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (6) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. Butyraldehyde (123-72-8). Available from the Database Query page at http://www.citi.or.jp/data/searchidx.htm as May 8, 2001. (7) Speece RE; Environ Sci Technol 17: 416A-27A (1983) (8) Chou WL et al; Biotechnol Bioeng Symp 8: 391-414 (1979) R47: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 9 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Buttery RG et al; J Agric Food Chem 17: 385-9 (1969) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. 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(2) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (3) Heukelekian H, Rand MC; J Water Pollut Control Assoc 27: 1040-53 (1955) (4) Ettinger MB; Ind Eng Chem 48: 256-9 (1956) (5) Stafford W, Northrup HJ; Amer Dyestuff Reporter 44: 355-9 (1955) (6) Urano K, Kato Z; J Hazardous Mater 13: 135-45 (1986) R50: (1) Chou WL et al; Biotechnol Bioeng Symp 8: 391-414 (1979) (2) Speece RE; Environ Sci Technol 17: 416A-27A (1983) R51: (1) Atkinson R; Chem Rev 85: 69-201 (1985) (2) Buxton GV et al; J Phys Chem Ref Data 17: 706 (1988) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 7-4 (1990) (4) Grosjean D, Swanson RD; Sci Total Environ 29: 65-85 (1983) R52: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 9 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R53: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 9 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R54: (1) Buttery RG et al; J Agric Food Chem 17: 385-9 (1969) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. 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AIHA Press, Fairfax, VA. 2001. 37 R66: 40 CFR 60.489 (7/1/2000) R67: 40 CFR 716.120 (7/1/2000) R68: 21 CFR 172.515 (4/1/2000) R69: 21 CFR 175.105 (4/1/2000) R70: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R71: KUWATA K ET AL; J CHROMATOGR SCI 17 (5): 264 (1979) R72: HOSHIKA Y; ANALYST (LONDON) 106 (1263): 686 (1981) R73: OHNO K ET AL; TAIKI OSEN GAKKAISHI 14 (9): 382 (1979) R74: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 50 Record 188 of 1119 in HSDB (through 2003/06) AN: 2851 UD: 200302 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZYL-ACETATE- SY: *Acetic-acid-benzyl-ester-; *Acetic-acid-phenylmethyl-ester-; *ALPHA-ACETOXYTOLUENE-; *BENZYL-ETHANOATE-; *NCI-C06508-; *Phenylmethyl-acetate- RN: 140-11-4 MF: *C9-H10-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY INTERACTION OF BENZYL CHLORIDE AND SODIUM ACETATE; BY ACETYLATION OF BENZYL ALCOHOL; OR FROM BENZALDEHYDE AND ACETIC ACID WITH ZINC DUST. [R1] *METHOD OF PURIFICATION: DISTILLATION. [R2] *Prepared from benzyl chloride, acetic acid or sodium acetate and triethylamine: Merker, Scott, J Org Chem 26, 5180 (1961); Hennis et al, Ind Eng Chem Prod Res Develop 6, 193 (1967). [R3] FORM: *FREE FROM CHLORINE GRADE WHICH SHOULD HAVE ESTER CONTENT OF 97% BUT FOR WHICH LOWER GRADE MATERIAL IS SOMETIMES SUBSTITUTED; TECHNICAL GRADE WHICH IS NOT FREE FROM CHLORINE AND FOR WHICH ESTER CONTENT VARIES CONSIDERABLY; "FOOD CHEMICALS CODEX". [R2] MFS: *H AND R Florasynth, 300 North St., Teterboro, NJ 07608 (201)288-0843; Production site: Bushy Park, SC 29411. [R4] *International Flavors and Fragrances, Inc., Hq, 521 West 57th Street, New York, NY 10019, (212) 765-5500; Production site: Keyport, NJ 07735. [R4] *Kalama Chemical Inc., Hq, The Bank of California Center, Suite 1110, Seattle, WA 98164, (206) 682-7890; Production site: 1296 Northwest 3rd Avenue, Kalama, WA 98625. [R4] *Penta Manufacturing Company, 50 Okner Parkway, Livingston, NJ 07039 (201)740-1939; Production site: Fairfield, NJ 07006. [R4] *Quest International, Hq, 400 International Drive, Mount Olive, NJ 07828, (201) 691-7100; Production site: Mount Olive, NJ 07828 [R4] *Schweizerhall Inc., Hq, 10 Corporate Place South, Piscataway, NJ 08854, (908) 981-8200; Production site: Piscataway, NJ 08854. [R4] OMIN: *FEMA NUMBER 2135. NON-ALCOHOLIC BEVERAGES, 7.8 PPM; ICE CREAM, ICES ... 14 PPM; CANDY, 34 PPM; BAKED GOODS, 22 PPM; GELATINS AND PUDDINGS, 23 PPM; CHEWING GUM, 760 PPM. [R1] USE: *In perfumery, solvent for cellulose acetate and nitrate. [R3] *Artificial jasmine and other perfumes; soap perfume; flavoring; solvent and high boiler for cellulose acetate and nitrate, natural and synthetic resins; oils; lacquers; polishes; printing inks; varnish removers. [R2] CPAT: *The bulk of benzyl acetate is used in soap odors, but it is also popular for other perfumes and is used to a minor extent in flavors (1980). [R5] PRIE: U.S. PRODUCTION: *(1972) 6.42X10+8 GRAMS [R6] *(1975) 5.87X10+8 GRAMS [R6] U.S. IMPORTS: *(1972) 6.61X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R6] *(1975) 1.60X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R6] *(1984) 4.83X10+9 g [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WATER-WHITE LIQUID [R2] ODOR: *PEAR-LIKE ODOR [R3]; *CHARACTERISTIC FLOWERY (JASMINE) ODOR [R1]; *Powerful but thin, sweet floral fresh, fresh and light, fruity odor reminiscent of Jasmin, Gardenia, Muguet, Lily and other flowers. [R8] TAST: *BITTER, PUNGENT TASTE [R1] BP: *213 DEG C [R3] MP: *-51 DEG C [R3] MW: *150.18 [R3] DEN: *1.050 @ 25 DEG C/4 DEG C [R3] OWPC: *log Kow = 1.96 [R9] SOL: *PRACTICALLY INSOL IN WATER; MISCIBLE WITH ALCOHOL, ETHER [R3]; *SOL IN BENZENE, CHLOROFORM [R10]; *Miscible in ethanol, soluble in ethyl ether and acetone. [R11]; *In water, 3.1 g/l. [R12] SPEC: *INDICES OF REFRACTION: 1.5232 @ 20 DEG C/D; 1.4998 @ 25 DEG C/D [R13]; *IR: 3715 (Coblentz Society Spectral Collection) [R14, p. V1 16]; *UV: 260 (Sadtler Research Laboratories Spectral Collection) [R14, p. V1 16]; *NMR: 53 (Varian Associates NMR Spectra Catalogue) [R14, p. V1 16]; *MASS: 879 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R14, p. V1 16]; *IR: 2:892C (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R14, p. V1 268]; *NMR: 7:21A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R14, p. V1 268]; *MASS: 4147 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R14, p. V1 268] VAPD: *5.1 (AIR= 1) [R15, 2979] VAP: *0.177 mm Hg at 25 deg C /from experimentally-derived coefficients/ [R16] OCPP: *Bp: 134 deg C at 102 mm Hg [R3] *VAPOR PRESURE = 1.0 MM HG @ 45 DEG C [R15, 2979] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible liquid. [R17] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R18] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R18] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R18] FLPT: +90 deg C (closed cup) [R18] AUTO: +460 deg C [R18] FIRP: *ALCOHOL FOAM, CARBON DIOXIDE. [R17] DCMP: *When heated to decomposition it emits irritating fumes. [R17] SERI: *... Irritating to skin, eyes, respiratory tract. [R13] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of benzyl acetate were available. There is limited evidence in experimental animals for the carcinogenicity of benzyl acetate. Overall evaluation: Benzyl acetate is not classifiable as to its carcinogenicity in humans (Group 3). [R19] +A4. A4= Not Classifiable as a Human Carcinogen. [R20, 19] HTOX: *IF INGESTED CAN CAUSE GI IRRITATION WITH VOMITING AND DIARRHEA. [R13] *... BENZYL ACETATES ... ARE OF LOW VOLATILITY ... AND EXCEPT FOR LOCAL IRRITATION, NO EFFECTS HAVE BEEN REPORTED IN MAN. [R21] *SUMMARY TOXICITY STATEMENT: ACUTE= HIGH VIA INHALATION ROUTE. HIGH= CAPABLE OF CAUSING DEATH OR PERMANENT INJURY DUE TO EXPOSURES OF NORMAL USE; INCAPACITATING AND POISONOUS; REQUIRES SPECIAL HANDLING. [R22] *SUMMARY TOXICITY STATEMENT; ACUTE= MODERATE VIA ORAL ROUTE. AN IRRITANT. MODERATE= MAY CAUSE REVERSIBLE OR IRREVERSIBLE CHANGES TO EXPOSED TISSUE, NOT PERMANENT INJURY OR DEATH; CAN CAUSE CONSIDERABLE DISCOMFORT. [R22] *Benzyl acetate produces respiratory tract irritation and /CNS depressant/ effects in humans, and continued exposure to benzyl acetate at an ambient concentration of 50 ppm results in kidney damage. When ingested, benzyl acetate can cause general intestinal irritation. [R23] NTOX: *MICE EXPOSED TO 212 PPM FOR 7-13 HR: RESULTS INCL DYSPNEA; /SRP: CNS DEPRESSION/; DEATH. /FROM TABLE/ [R15, 2983] *CATS EXPOSED TO 180 PPM 8-9 HR FOR 7 DAYS: RESULTS INCL IRRITATION; GRADUAL WEAKNESS; LOSS OF APPETITE AND WEIGHT; DROWSINESS; DEATH. /FROM TABLE/ [R15, 2983] *... IN MODERATE CONCN VAPOR IS RATHER IRRITATING TO EYES. DISCOMFORT TENDS TO DIMINISH DURING CONTINUED EXPOSURE. TESTING BY APPLICATION OF DROP OF LIQUID TO EYES OF RABBITS CAUSED IMMEDIATE BLEPHAROSPASM FOR ... MINUTE DESPITE PREVIOUS APPLICATION OF LOCAL ANESTHETIC. CORNEAS WERE FOUND NOT TO BE DAMAGED. [R24] *ORAL, SC AND IP ADMIN HAS CAUSED CENTRAL NERVOUS PARALYSIS IN RABBITS, AND ORAL ADMIN DIURESIS. REPEATED EXPOSURE TO ITS VAPOR HAS CAUSED ALBUMINURIA ... CONSIDERED TO BE INDICATION OF KIDNEY INJURY. [R25] *ANIMALS SUBJECTED TO LETHAL ORAL DOSAGE SHOWED SLIGHT EDEMA OF LUNGS. ANIMALS KILLED AFTER REPEATED INHALATION SHOWED SLIGHT TRACHEITIS AND BRONCHITIS. KIDNEYS SOME HYPEREMIA. [R25] *Benzyl acetate was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Benzyl acetate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S9, at doses of 0.033, 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. [R26] *Benzyl acetate gave negative results in an assay for differential killing of repair proficient and deficient strains of Bacillus subtilus H17 and M45, and it was not mutagenic in strains TA1535, TA1537, TA98, or TA100 of Salmonella in the presence or absence of Aroclor 1254-induced rat liver S9. In tests performed by the NTP, neither benzyl acetate not benzyl alcohol was mutaganic in Salmonella in the presence or absence of Aroclor 1254-induced Sprague Dawley rat or Syrian hamster liver S9. In cultured Chinese hamster ovary cells, benzyl acetate did not induce sister chromatid exchanges or chromosomal aberrations. Benzyl acetate was mutagenic in the L5178Y/TK + or - mouse lymphoma assay in the presence, but not in the absence, of Aroclor 1254-induced rat liver S9. Benzyl acetate did not induce unscheduled DNA synthesis in Fischer 344 rat hepatocytes following in vivo and in vitro treatment. [R23] *Urine flow in dogs and rabbits increased approximately 180% two hours after they received an ip injection of 0.4 ml/kg body weight. [R27] *Benzyl acetate / > 99% pure was administered/ in corn oil by gavage to groups of 50 male 50 female F344/N rats at doses of 0, 250, or 500 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 500, or 1000 mg/kg once daily five of days per week for 103 weeks. ... Under the conditions of these gavage studies, benzyl acetate incr the incidence of acinar cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenicity for female F344/N rats. For male and female B6C3F1 mice there was some evidence of carcinogenicity in that benzyl acetate caused an incr incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. [R28] *Benzyl acetate is used as a flavoring agent in foods, as a fragrance in soaps and perfumes, as a solvent for cellulose acetate and nitrate, and as a component of printing inks and varnish removers. The NTP previously studied the toxicology and carcinogenicity of this chemical in F344/N rats and B6C3F1 mice using the gavage route of administration and corn oil as a vehicle. Benzyl acetate increased the incidences of pancreatic acinar cell adenomas in male rats and the incidences of hepatocellular adenomas and forestomach neoplasms in male and female mice. Because of the confounding effect of corn oil on the incidences of pancreatic neoplasms and because of controversy over the use of the gavage route of administration, the NTP decided to restudy benzyl acetate using the dosed feed route of administration . In these repeat studies, male and female F344/N rats and B6C3F1 mice received benzyl acetate (at least 98% pure) in feed for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella Typhimurium, cultured Chinese hamster ovary cells, L5178Y mouse lymphoma cells, Drosophila melanogaster, and mouse bone marrow and peripheral blood cells. [R29] *13-week study in rats: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm (0, 230, 460, 900, 1,750, or 3,900 mg/kg body weight for males and 0, 240, 480, 930, 1,870, or 4,500 mg/kg for females) benzyl acetate for 13 weeks. Nine male and nine female rats receiving 50,000 ppm benzyl acetate died or were killed moribund between weeks 2 and 8 of the study. The mean body weight gain and the final mean body weight of 25,000 ppm males were significantly lower (P < 0.01) than those of the control group. Feed consumption by exposed rats, except the 25,000 and 50,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females, was similar to that by the controls. The reduced feed consumption by 25,000 and 50,000 ppm males and 50,000 ppm females may have been due to toxicity or decreased palatability. Tremors and ataxia occurred only in the 50,000 ppm rats. These findings were first observed on day 15 in nine males and six females and continued until the end of the study. Cholesterol levels in 12,500 and 25,000 ppm females and triglyceride levels in 25,000 ppm females were lower than those in the controls. Chemical-related lesions occurred in the brain, kidney, tongue, and skeletal muscles of the thigh. Necrosis of the brain involving the cerebellum and/or hippocampus, degeneration and regeneration of the renal tubule epithelium, and degeneration and sarcolemma nuclear hyperplasia of the tongue and skeletal muscles occurred in most male and female 50,000 ppm rats. This effect was observed in the 1,000 mg/kg group in the previous gavage study. 13-week study in Mice: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3,130, 6,250, 12,500, 25,000, or 50,000 ppm (0, 425, 1,000, 2,000, 3,700, or 7,900 mg/kg body weight for males and 0, 650, 1,280, 2,980, 4,300, or 9,400 mg/kg for females) benzyl acetate. One 50,000 ppm male mouse died and one 50,000 ppm female mouse was killed moribund before the end of the study. Mean body wight gains and final mean body weights of all exposed male and female mice were significantly lower than those of the controls and the mean body weight gains decreased with increased exposure level. Feed consumption by 3,130 ppm males and all exposed females was lower than that by the controls. Tremors occurred only in females and were first observed on day 16 in three females receiving 50,000 ppm, day 94 in one female receiving 25,000 ppm, and day 93 in one female receiving 12,500 ppm. The tremors continued until the end of the study. Necrosis of the brain involving the hippocampus occurred in four 50,000 ppm mice, one male and three females. Hepatocellular necrosis also occurred in the male with brain lesions. On reexamination of the previous 13-week gavage study, a similar lesion was seen in the brain of one mice. The lesion was less sever than that described in the present doses feed study. The highest dose used in the gavage study was 1,000 mg/kg compared to an estimated high dose of 7,200 mg/kg for the feed study. [R30] *Genetic Toxicology: Benzyl acetate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). However, a positive response was observed for benzyl acetate, with and without S9, in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178T cells. No significant increases in the frequencies of sister chromatid exchanges or chromosomal aberrations occurred in in vitro, with or without S9, and no increases in either sister chromatid exchanges or chromosomal aberrations occurred in bone marrow cells of male mice treated in vivo by intraperitoneal injection. No increase in sex-linked recessive lethal germ cell mutations occurred in male Drosophila melanogaster administered benzyl acetate in feed or by injection. Tests of benzyl acetate for induction of micronucleated erythrocytes in some bone marrow and peripheral blood of mice were also negative. [R29] NTXV: *Rat (Osborne-Mendel) oral 2.49 g/kg; [R31] NTP: *Benzyl acetate / > 99% pure was administered/ in corn oil by gavage to groups of 50 male 50 female F344/N rats at doses of 0, 250, or 500 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 0, 500, or 1000 mg/kg once daily five of days per week for 103 weeks. ... Under the conditions of these gavage studies, benzyl acetate incr the incidence of acinar cell adenomas of the exocrine pancreas in male F344/N rats; the gavage vehicle may have been a contributing factor. There was no evidence of carcinogenicity for female F344/N rats. For male and female B6C3F1 mice there was some evidence of carcinogenicity in that benzyl acetate caused an incr incidences of hepatocellular adenomas and squamous cell neoplasms of the forestomach. [R28] ADE: *Benzyl acetate was absorbed from the gastrointestinal tract of rats and mice, with approximately 90% of the administered dose recovered as various metabolites in the urine within 24 hr. ... This capacity for absorption, metabolism, and disposition was unaffected by the amount or number of doses administered. [R32] *The effect of vehicle and occlusion on the in vitro percutaneous absorption of [methylene-14C]-benzyl acetate (1.7-16.6 mg/sq cm) has been studied in diffusion cells using full thickness skin from male Fischer 344 rats. Absorption of neat benzyl acetate through rat skin occluded with parafilm was 49.3 +/- 2.0% (mean +/- SD, n=4) after 48 hr. When benzyl acetate in ethanol was applied to the skin and the skin was occluded with parafilm, the extent of absorption at 48 hr was not significantly different from that after neat application. However at 6 hr, as the ethanol content of the application mixture was increased, the absorption of benzyl acetate through occluded skin was enhanced proportionally. When phenylethanol was used as a vehicle, the extent of the benzyl acetate absorption through occluded skin at 48 hr was enhanced (P less than 0.05) compared with that after application neat; with 50% (v/v) phenyl-ethanol, absorption at 48 hr was 56.3 +/- 4.9%. However, this enhanced absorption did not correlate with the proportion of phenylethanol in the application mixture. When dimethylsulphoxide was used as a vehicle, the extent of absorption of benzyl acetate through occluded skin at 48 hr was enhanced (P less than 0.05) compared with that after application neat (absorption was 59.3 +/- 3.7% of the applied dose when 50% (v/v) dimethylsulphoxide was used). As the dimethylsulphoxide content of the application mixture was increased, the absorption of benzyl acetate was enhanced proportionally. Occlusion of the skin surface with parafilm often significantly enhanced absorption (P less than 0.05), although the effect varied with time and vehicle. In general, the degree of any enhanced absorption caused by the use of a vehicle or occlusion of the skin was small, and, in most cases, would be unlikely to be toxicologically significant. [R33] *The comparative absorption of ... benzyl acetate has been studied in rat and human skin, using shaved, full-thickness dorsal skin of male Fischer 344 rats and full-thickness human skin obtained from patients undergoing surgical resection. Penetration of the compound through rat and human skin was evaluated in vitro in flow-through diffusion cells following topical application of neat [methylene-14C] benzyl acetate (33.1 mg/sq cm) to the epidermal surface and occlusion with a teflon cap, 2.9 cm above the skin surface. The absorption of benzyl acetate across rat skin was rapid and extensive, reaching 34.3 +/- 3.9% of the applied dose (11.3 +/- 1.3 mg/sq cm) (mean +/-SD, n=12) at 24 hr and 55.8 +/- 5.0% of the applied dose (18.5 +/- 1.7 mg/sq cm)at 72 hr. The penetration of benzyl acetate was significantly (P < 0.05) less rapid and extensive through human skin, reaching 5.5 +/- 0.1% of the applied dose (1.8 +/- 0.0 mg/sq cm) (mean +/- SD, n=12) at 24 hr and 17.8 +/- 3.3% of the applied dose (5.9 +/-1.1 mg sq cm) at 72 hr. The rate of penetration of benzyl acetate was greater through rat skin than through human tissue at all time points studied up to 72 hr. The maximum rate of skin penetration was 0.6 +/- mg/sq cm/hr and 0.1 +/_- 0.0 mg/sq cm/hr through rat and human skin, respectively. These data indicate that systemic exposure to benzyl acetate may occur after skin contact in humans. They also support the evidence from the literature that human skin is generally less permeable to xenobiotics than rat skin. [R34] METB: *... BENZYL ACETATE IS RAPIDLY HYDROLYZED TO ACETIC ACID AND BENZYL ALCOHOL, AND THE LATTER OXIDIZED TO BENZOIC ACID AND ... EXCRETED AS HIPPURIC ACID. [R15, 2989] *In rats, benzyl acetate is hydrolyzed to benzyl alcohol, which is oxidized to benzoic acid and excreted as hippuric acid and benzyl mercapturic acid. [R31] *In a chemical disposition study conducted by the NTP, male Fischer 344 rats and male B6C3F1 mice were shown to efficiently absorb and rapidly metabolize and excrete orally administered benzyl acetate. The doses used in this study were 5, 50, or 500 mg/kg for rats and 10, 100, or 1000 mg/kg for mice in single dose corn oil gavage administrations and 500 mg/kg for rats and 1000 mg/kg for mice daily five times per week for two weeks, also administered by gavage in corn oil. Most (90%) of the benzyl acetate-derived radioactivity was recovered in the urine and none was detected in the liver, blood, muscle, adipose tissue skin, lung, kidney, or stomach of treated rats or mice. The major metabolite isolated in the urine was hippuric acid (94%-99% of the dose). Other metabolites found were mercapturic acid and benzyl alcohol. Benzyl acetate was not detected in the urine of treated animals. Neither the size of the dose nor the frequency of dosing had any effect on the absorption, metabolism, or excretion of this compound. There was no evidence to indicate any saturation of this metabolizing capacity in either species over the range of doses studied. [R23] *Effects of gavage versus dosed feed administration on the toxicokinetics of benzyl acetate were studied in male F344 rats and B6C3F1 mice. Benzyl acetate was rapidly hydrolyzed to benzyl alcohol and then oxidized to benzoic acid. After gavage administration of benzyl acetate in corn oil at 500 mg/kg (rats) and 1000 mg/kg(mice), high benzoic acid plasma concentrations were observed. In contrast, much lower benzoic acid plasma concentrations were found after dosed feed administration at about 615 mg/kg/day for rats and about 850 mg/kg/day for mice. Results show that although the daily doses of benzyl acetate are comparable, bolus gavage administration effectively saturated the benzoic acid elimination pathway whereas dosed feed administration did not. In contrast, hippuric acid plasma concentrations were similar after both gavage and dosed feed administration due to the depletion of the glycine supply pool. ... [R35] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Benzyl acetate occurs in a number of plants, particularly jasmine. Benzyl acetate's production and use in artificial jasmine and other perfumes, as a flavoring, as a solvent may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.18 mm Hg at 25 deg C indicates benzyl acetate is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase benzyl acetate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the estimated half-life for this reaction in air is 2.5 days. If released to soil, an estimated Koc of 280 suggests that benzyl acetate is expected to have moderate mobility. Volatilization from wet soil surfaces may be important based upon this compound's estimated Henry's Law constant of 1.1X10-5 atm-cu m/mole. Biodegradation is expected to be an important process in both soil and water. Benzyl acetate reached 92 to 96% of its theoretical BOD over a period of 4 weeks. If released into water, the estimated Koc suggests that some adsorption of benzyl acetate to suspended solids and sediment in the water column is expected. Volatilization from water surfaces may be an important fate process given this compound's estimated Henry's Law constant. The potential for bioconcentration in aquatic organisms is low based on this compound's estimated BCF of 18. An estimated hydrolysis half-life of 38 days at pH 7 suggests that hydrolysis is not expected to be an important process. Occupational exposure to benzyl acetate may occur through inhalation and dermal contact with this compound at workplaces where benzyl acetate is produced or used. The general population may be exposed to benzyl acetate via ingestion of food, and inhalation and dermal contact with consumer products containing benzyl acetate. (SRC) NATS: *PRESENT AS MAIN CONSTITUENT IN SEVERAL OILS AND FLOWER ABSOLUTES: YLANG-YLANG, CANANGA, NEROLI, JASMINE, HYACINTH, GARDENIA, TUBEROSE. IT HAS BEEN ISOLATED FROM FLOWERS OF ... /AZALEA/ ... CAN BE ISOLATED FROM NATURAL SOURCES (IN WHICH IT MAY OCCUR AT LEVELS UP TO 65%). [R1] *Benzyl acetate occurs in a number of plants, particularly jasmine(1). Benzyl acetate was identified as a volatile component of roasted filberts(2) and in the juice of Japanese Kogyoku apples(3). [R36] ARTS: *Benzyl acetate's production and use in artificial jasmine and other perfumes; in soap perfume; as a flavoring; a solvent and high boiler for cellulose acetate and nitrate, natural and synthetic resins; in oils; lacquers; polishes; printing inks; and in varnish removers(1) may result in its release to the environment through various waste streams(SRC). [R37] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 280(SRC), determined from a log Kow of 1.96(2) and a regression-derived equation(3), indicates that benzyl acetate is expected to have moderate mobility in soil(SRC). Volatilization of benzyl acetate from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.1X10-5 atm-cu m/mole(SRC) derived from its experimental values for vapor pressure, 0.18 mm Hg(4), and water solubility, 3.1X10+3 mg/l(5). Biodegradation of benzyl acetate in soil may be important(SRC), based upon its biodegradation in water(5). [R38] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 280(SRC), determined from a log Kow of 1.96(2) and a regression-derived equation(3), indicates some adsorption of benzyl acetate to suspended solids and sediment in the water column is expected(SRC). Benzyl acetate is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 1.1X10-5 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.18 mm Hg(4), and water solubility, 3.1X10+3 mg/l(5). Estimated volatilization half-lives for a model river and model lake are 4.1 and 34 days, respectively(3,SRC). According to a classification scheme(6), an estimated BCF of 18(3,SRC), from a log Kow(2), suggests that bioconcentration in aquatic organisms is low(SRC). Benzyl acetate is expected to biodegrade in aquatic systems(SRC); benzyl acetate reached 92 to 96% of its theoretical BOD over a period of 4 weeks(5). An estimated hydrolysis half-life of 38 days at pH 7(7), indicates hydrolysis may be an important process(SRC). [R39] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), benzyl acetate, which has a vapor pressure of 0.18 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase benzyl acetate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2.5 days(3,SRC). [R40] BIOD: *Benzyl acetate reached 92 to 96% of its theoretical BOD over a period of 4 weeks using an activated sludge seed and an initial chemical concentration of 100 mg/l(1). [R41] ABIO: *The rate constant for the vapor-phase reaction of benzyl acetate with photochemically-produced hydroxyl radicals has been estimated as 6.4X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2.5 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). A hydrolysis half-life of 38 days at 25 deg C and pH 7 was calculated for benzyl acetate from an estimated pseudo-first-order hydrolysis rate constant of 2.1X10-7/s(2). The UV spectrum of benzyl acetate in methanol indicates no absorption above 290 nm, suggesting this compound is not expected to directly photolyze(3). Photolysis of benzyl acetate in t-butanol with 1.3 mol/l acetone added as a sensitizer at 300 nm produced (quantum yields) t-butyl benzyl ether (< 0.01) and bibenzyl (< 0.01)(4). The rate constant for the reaction of benzyl acetate with peroxy radicals in water at 30 deg C was determined to be 2.3 L/mol s(5). This value corresponds to an estimated half-life of 9.6 years(SRC) at an aqueous peroxy radical concentration of 1X10-9 mol/l(6). [R42] BIOC: *An estimated BCF of 18 was calculated for benzyl acetate(SRC), using a log Kow of 1.96(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests that bioconcentration in aquatic organisms is low(SRC). [R43] KOC: *The Koc of benzyl acetate is estimated as approximately 180(SRC), using a log Kow of 1.96(1) and a regression-derived equation(2,SRC). According to a classification scheme(3), this estimated Koc value suggests that benzyl acetate is expected to have moderate mobility in soil(SRC). [R44] VWS: *The Henry's Law constant for benzyl acetate is estimated as 1.1X10-5 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 0.18 mm Hg(1), and water solubility, 3.1X10+3 mg/l(2). This value indicates that benzyl acetate is expected to volatilize from water surfaces(3,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 4.1 days(3,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 34 days(3,SRC). Benzyl acetate's Henry's Law constant(1,2,SRC) indicates that volatilization from moist soil surfaces may be important(SRC). [R45] EFFL: *Benzyl acetate was detected in an aqueous industrial effluent extract collected between Nov 1979-81 in the organics and plastics industrial category at a concentration of 40 ng/ul extract(1). [R46] FOOD: *Benzyl acetate was identified as a volatile component of roasted filberts(1). Benzyl acetate was identified as a volatile flavor compound in the juice of Japanese Kogyoku apples(2). [R47] OEVC: *Benzyl acetate was identified as a volatile component in 15 out of 31 consumer fragrance products, including perfume, shampoo, and fabric softener(1). Benzyl acetate was identified as a volatile component emitted from a sample of rubberized jute carpet cushion during chemical screening experiments(2). Benzyl acetate was identified as a volatile organic compound emitted by a household detergent(3). Benzyl acetate was identified as a volatile compound in two colognes, a perfume and a soap(4). [R48] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 128,306 workers (52,480 of these are female) are potentially exposed to benzyl acetate in the US(1). Occupational exposure to benzyl acetate may occur through inhalation and dermal contact with this compound at workplaces where benzyl acetate is produced or used(SRC). The general population may be exposed to benzyl acetate via ingestion of food, and inhalation and dermal contact with consumer products containing benzyl acetate(SRC). [R49] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: +8 hr Time Weighted Avg (TWA): 10 ppm [R20, 19] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R20, 6] +A4. A4= Not classifiable as a human carcinogen. [R20, 19] FDA: *Benzyl acetate is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. Synthetic flavoring substances and adjuvants incl benzyl acetate may be safely used in foods. [R50] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GC with FID or MS has been used to analyze for benzyl acetate in volatile mixtures. [R51] CLAB: *Combined GC/MS has been used to detect benzyl acetate at trace levels in mouse urine. [R51] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzyl Acetate in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 250 (1986) NIH Publication No. 86-2506 WHO/IPCS; Toxicological Evaluation of Certain Food Additives and Contaminants WHO Food Additives Series 32 (1993) SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 44 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 134 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 189 R4: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 612 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V9 334 (1987) R6: SRI R7: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-344 R8: Arctander S; Perfume and Flavor Chemicals (Aroma Chemicals) I (1969) R9: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 57 R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-86 R11: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-9 R12: Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN #4-89074-101-1 p. 3-84 (1992) R13: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 176 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R15: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R16: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R17: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 371 R18: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-17 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1263 (1999) R20: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R21: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1864 R22: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 409 R23: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzyl acetate in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.19 (1986) Technical Rpt Series No. 250 NIH Pub No. 86-2506 R24: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 183 R25: Browning, E. Toxicity and Metabolism of Industrial Solvents. New York: American Elsevier, 1965. 544 R26: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R27: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzyl Acetate in F344/N Fats and B6C3F1 Mice (Gavage Studies) p. 18 (1986) Technical Rpt Series No. 250 NIH Pub No. 86-2506 R28: Toxicology and Carcinogenesis Studies of Benzyl Acetate in F344/N Rats and B6C3F1 (Gavage Studies). Technical Report Series No. (1986) NIH Publication No.86-2506 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R29: National Toxicology Program Technical Report Series 431: 288 (1993) R30: National Toxicology Program Technical Report Series 431 : 288 (1993) R31: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzyl Acetate in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.18 (1986) Technical Rpt Series No. 250 NIH Pub No. 86-2506 R32: DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzyl Acetate in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.8 (1986) Technical Rpt Series No. 250 NIH Pub No. 86-2506 R33: Hotchkiss SA et al; Food Chem Toxicol 30: 145-53 (1992) R34: Garnett A et al; Food Chem Toxicol 32: 1061-65 (1994) R35: Yuan JH et al; Food Chem Toxicol; 33: 151-8 (1995) R36: (1) Budavari S; The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 12th ed. Whitehouse Station, NJ: Merck and Co Inc p.189 (1996) (2) Kinlin TE et al; J Agric Food Chem 20: 1021-8 (1972) (3) Yajima I et al; Agric Biol Chem 48: 849-55 (1984) R37: (1) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY, NY: Van Nostrand Reinhold Co p. 134 (1993) R38: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p 57 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp (1989) (5) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN #4-89074-101-1 p. 3-84 (1992) R39: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p 57 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp (1989) (5) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN #4-89074-101-1 p. 3-84 (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants, USEPA 440/4-81-014 p. 411 (1981) R40: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY,NY: Hemisphere Pub Corp (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R41: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN #4-89074-101-1 p. 3-84 (1992) R42: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants, USEPA 440/4-81-014 p. 411 (1981) (3) Sadtler NA; Sadtler Standard Spectra. Philadelphia, PA: Sadtler Research Lab UV (4) Appleton DC et al; J Chem Soc Perkin Trans II 1980: 87-90 (1980) (5) Hendry DG et al; J Phys Chem Ref Data 3: 944-78 (1974) (6) Mill T et al; Science 207: 886-7 (1980) R43: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p 57 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R44: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR (consult ed) Washington,DC: Amer Chem Soc p. 57 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R45: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng., NY, NY: Hemisphere Pub Corp (1989) (2) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN #4-89074-101-1 p. 3-84 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R46: (1) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey, Contract No. 68-03-2867, Athens, GA: USEPA Environ Res Lab (1982) R47: (1) Kinlin TE et al; J Agric Food Chem 20: 1021-8 (1972) (2) Yajima I et al; Agric Biol Chem 48: 849-55 (1984) R48: (1) Wallace LA et al; Identification of Polar Volatile Organic Compounds in Consumer Products and Common Microenvironments. Res Triangle Inst, Research Triangle Park, NC. Report 1991, USEPA/600/D-91/074; (NTIS PB-91-182865) (1991) (2) Schaeffer VH et al; J Air Waste Manage Assoc 46: 813-20 (1996) (3) Knoppel H, Schauenburg H; Environ Int 15: 413-8 (1989) (4) Cooper SD et al; J Exposure Anal Environ Epidemiol 5: 57-75 (1995) R49: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R50: 21 CFR 172.515 (4/1/97) R51: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V40 113 (1986) RS: 44 Record 189 of 1119 in HSDB (through 2003/06) AN: 2855 UD: 200301 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-BUTENE-OXIDE- SY: *BUTANE,-1,2-EPOXY-; *N-BUTENE-1,2-OXIDE-; *1,2-BUTENE-OXIDE-; *BUTYLENE-OXIDE-; *ALPHA-BUTYLENE-OXIDE-; *1-BUTYLENE-OXIDE-; *1,2-BUTYLENE-OXIDE-; *EPOXYBUTANE-; *1,2-EPOXYBUTANE-; *ETHYLETHYLENE-OXIDE-; *ETHYLOXIRANE-; *2-ETHYLOXIRANE-; *NCI-C55527-; *OXIRANE,-ETHYL-; *PROPYL-OXIRANE- RN: 106-88-7 MF: *C4-H8-O SHPN: UN 3022; 1,2-Butylene oxide, stabilized IMO 3.2; 1,2-Butylene oxide, stabilized ASCH: Butane, 2,3-epoxy (cis isomer); 1758-33-4; Butane, 2,3-epoxy (trans isomer); 21490-63-1 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *EPOXIDATION OF 1-BUTENE WITH PEROXYACETIC ACID [R1] *Prepared on a small scale by chlorohydrin technology [R2] FORM: *Approximately 97.5% purity [R3] MFS: *Dow Chemical USA, 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Midland, MI 48667 [R4] USE: *Intermediate, for various polymers; stabilizer for chlorinated solvents [R3] *Acid scavenger for chlorine-containing materials such as trichloroethylene [R2] *Corrosion inhibitor. [R5] *React with ammonia to produce alkanolamines. [R6] PRIE: U.S. PRODUCTION: *(1972) MORE THAN 4.54X10+5 G (BUTYLENE OXIDE) [R1] *(1974) 4.54X10+9 G (ESTIMATE) [R1] U.S. IMPORTS: *(1973) 1.68X10+6 G (BUTYLENE OXIDE) [R1] *(1975) 2.43X10+6 G (BUTYLENE OXIDE) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R3] ODOR: *DISAGREEABLE ODOR [R7, p. 49-23] BP: *63.3 deg C [R8] MP: *-150 deg C [R8] MW: *72.12 [R8] DEN: *0.8297 @ 20 deg C [R8] HTC: *-15,200 btu/lb (-8,470 cal/g or -3.54X10+7 J/kg) [R9] HTV: *180 btu/lb (est; 100 cal/g or 4.2X10+5 J/kg) [R9] SOL: *Sol in alcohol, ether, acetone, organic solvents [R8]; *Miscible with common aliphatic and aromatic solvents [R10, 2163]; *In water, 95,000 ppm at 25 deg C [R11] SPEC: *Index of refraction: 1.3851 @ 20 deg C [R8]; *IR: SAD 15718 (Sadtler Research Laboratories Prism Collection) [R12, p. V4 3799]; *NMR: SAD 18401 (Sadtler Research Laboratories Spectral Collection) [R12, p. V4 3799]; *MS: WILEY 72 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R12, p. V4 3799] VAPD: *2.2 (AIR= 1) [R7, p. 325M-22] VAP: *180 mm Hg @ 25 deg C [R13] OCPP: *Liquid is lighter than water, vapor is heavier than air [R7, p. 49-23] *MS: NIST 46213 (NIST/EPA/MSDC. Mass Spectral Database, 1990 Version); WILEY 72 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Butane, 2,3-epoxy (cis)/ [R12, p. V4 3797] *IR: u COB 1758 (Coblentz Society Spectral Collection) /Butane, 2,3-epoxy (trans)/ [R12, p. V4 3797] *MS: NIST 296 (NIST/EPA/MSDC. Mass Spectral Database, 1990 Version) /Butane, 2,3-epoxy (trans)/ [R12, p. V4 3797] *Hydroxyl radical rate constant = 1.91X10-12 cu-cm/mol-sec @ 25 deg C [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /1,2-Butylene oxide, stabilized/ [R15] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. /1,2-Butylene oxide, stabilized/ [R15] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /1,2-Butylene oxide, stabilized/ [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /1,2-Butylene oxide, stabilized/ [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /1,2-Butylene oxide, stabilized/ [R15] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /1,2-Butylene oxide, stabilized/ [R15] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /1,2-Butylene oxide, stabilized/ [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /1,2-Butylene oxide, stabilized/ [R15] FPOT: *DANGEROUS FIRE HAZARD WHEN EXPOSED TO HEAT, FLAME OR POWERFUL OXIDIZERS. [R16] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R17, p. 325-22] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R17, p. 325-22] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R17, p. 325-22] FLMT: *LOWER FLAMMABLE LIMIT: 1.7% BY VOLUME AND UPPER FLAMMABLE LIMIT: 19% BY VOLUME [R17, p. 49-31] FLPT: *-7 DEG F (-22 DEG C) (CLOSED CUP) [R17, p. 49-31] AUTO: *822 deg F (439 deg C) [R17, p. 49-31] FIRP: *Use water spray, dry chemical, foam, or carbon dioxide. Water may be ineffective. Fight fire from protected location or maximum possible distance. Use water spray to keep fire exposed containers cool. [R17, p. 49-31] *To fight fire, use dry chemical, water spray, mist or fog, alcohol foam. [R16] OFHZ: *... MAY TRAVEL CONSIDERABLE DISTANCE TO SOURCE OF IGNITION AND FLASH BACK. [R7, p. 49-23] EXPL: *VAPOR FORMS EXPLOSIVE MIXTURES WITH AIR. ... IF POLYMERIZATION TAKES PLACE IN CONTAINER, THERE IS POSSIBILITY OF VIOLENT RUPTURE OF CONTAINER. [R7, p. 49-23] *Lower explosive limit: 1.5%; Upper explosive limit: 18.3% [R16] REAC: *LIQ ARE USUALLY STABLE BUT THEY MAY REACT VIOLENTLY WITH MATERIALS HAVING A LABILE HYDROGEN, PARTICULARLY IN THE PRESENCE OF CATALYSTS SUCH AS ACIDS, ALKALIES, AND CERTAIN SALTS. /BUTYLENE OXIDES/ [R18] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R16] POLY: *Hazardous polymerization may occur. Usually contains inhibitors to prevent polymerization. Uninhibited monomer vapor may form polymer in vents and other confined spaces. [R17, p. 49-31] EQUP: *CLEAN PROTECTIVE CLOTHING; RUBBER GLOVES; CHEMICAL WORKER'S GOGGLES; SELF-CONTAINED BREATHING APPARATUS. [R19] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R20, 1979.8] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R20, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R20, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R20, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R20, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R20, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R20, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R20, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R20, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R20, 1979.11] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R22] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R23] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R20, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R20, 1979.13] STRG: *Store in a cool, dry, well-ventilated location. Store away from heat, oxidizing materials, and sunlight. [R17, p. 49-31] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R20, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R20, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R20, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R20, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R20, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R20, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R20, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of 1,2-epoxybutane were available. There is limited evidence in experimental animals for the carcinogenicity of 1,2-epoxybutane. Overall evaluation: 1,2-Epoxybutane is possibly carcinogenic to humans (Group 2B). In making the overall evaluation, the Working Group took into consideration that 1,2-epoxybutane is a direct acting alkylating agent which is mutagenic in a range of test systems. [R24] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aliphatic hydrocarbons and related compounds/ [R25, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory rest. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aliphatic hydrocarbons and related compounds/ [R25, 207] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R20, 1979.23] HTOX: *... DIFUNCTIONAL EPOXIDES ARE IN GENERAL MORE POTENT CARCINOGENS THAN MONOFUNCTIONAL. ... MONOFUNCTIONAL AGENTS WITH ADJACENT CENTERS OF UNSATURATION MAY BE CONVERTED IN VIVO TO DIFUNCTIONAL AGENTS. ... MONOFUNCTIONAL AGENTS ALKYLATE TO INSUFFICIENT EXTENT ... OR TYPES OF REACTIONS UNDERGONE DO NOT LEAD TO ... EFFECT. [R26] *Moderately toxic by ingestion and skin contact. Mildly toxic by inhalation. [R16] NTOX: *... RATED 4 ON RABBIT EYES. ... TESTED EXTERNALLY ON EYES OF RABBITS ... PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA. MOST SEVERE INJURIES HAVE BEEN RATED 10. [R27] *REPRESENTATIVE ONCOGENESIS TESTS- EPOXIDES (MONOFUNCTIONAL) REPORTED TO BE INACTIVE. CMPD- 1,2-EPOXYBUTANE. TEST SYSTEM- MOUSE SKIN. /FROM TABLE/ [R26] *WHEN MIXED BUTYLENE OXIDES WERE FED TO RATS BY INTUBATION AS A 30% SOLN IN CORN OIL, THE LD50 WAS FOUND TO BE ABOUT 0.5 G/KG. DEATH OCCURRED WITHIN A DAY OR NOT AT ALL. /BUTYLENE OXIDES/ [R10, 2164] *THE LIQ IS MARKEDLY IRRITATING TO THE SKIN OF RABBITS WHEN CONFINED BENEATH A COVERING. WHEN FREE TO EVAPORATE, IT DOES NOT CAUSE APPRECIABLE IRRITATION. A SHORT CONTACT WOULD NOT BE EXPECTED TO CAUSE MORE THAN MILD IRRITATION, BUT PROLONGED OR REPEATED EXPOSURE WOULD BE EXPECTED TO CAUSE BLISTERING AND NECROSIS. [R10, 2164] *BUTYLENE OXIDE HAS NOT BEEN SHOWN TO BE CARCINOGENIC AND IS ONLY WEAKLY MUTAGENIC BY THE AMES TEST. [R10, 2164] *RATS EXPOSED TO AN ATMOSPHERE SATURATED WITH BUTYLENE OXIDES AT ROOM TEMP SHOWED ANESTHETIC EFFECTS WITHIN MIN. EXPOSURES LASTING 12 MIN WERE LETHAL WHEREAS THOSE LASTING 6 MIN CAUSED SOME DELAYED DEATHS, ALL OF WHICH WERE DUE TO SECONDARY PNEUMONIA. IT APPEARS THAT THE PRINCIPAL HAZARD FROM ACUTE VAPOR EXPOSURE IS IRRITATION OF THE LUNG FOLLOWED BY EDEMA AND PNEUMONITIS. /BUTYLENE OXIDES/ [R10, 2164] *EXPOSURE OF MALE AND FEMALE FISCHER 344 RATS AND B6C3F1 MICE TO 0, 400, 800, OR 1600 PPM 1,2-BUTYLENE OXIDE VAPORS 6 HR/DAY, 5 DAYS/WK, FOR 9 DAYS DURING A 2-WK INTERVAL REVEALED A DEFINITE SPECIES DIFFERENCE IN SENSITIVITY TO HIGH CONCENTRATIONS. ALL MICE IN THE 1600 PPM GROUP WERE DEAD PRIOR TO THE 3RD DAY OF EXPOSURE, WHILE ALL RATS EXPOSED TO 1600 PPM SURVIVED UNTIL SCHEDULED SACRIFICE WITH NO OBVIOUS SIGNS OF DISTRESS EXCEPT FOR A PRONOUNCED RETARDATION OF GROWTH. INFLAMMATORY AND DEGENERATIVE CHANGES IN THE NASAL MUCOSA WERE DETECTED IN RATS IN THE 1600 PPM GROUP. MYELOID HYPERPLASIA IN BONE MARROW, AND ELEVATED MEAN WHITE BLOOD CELL COUNTS FOR MALE AND FEMALE RATS IN THE 1600 PPM GROUP MAY POSSIBLY HAVE BEEN RELATED TO THE INFLAMMATORY NASAL LESIONS OR TO GENERALIZED STRESS. [R28] *MUTAGENICITY ASSAYS WERE PERFORMED ON TWO STABILIZERS, EPICHLOROHYDRIN AND 1,2-EPOXYBUTANE, CONTAINED IN TECHNICAL GRADE SAMPLE OF TRICHLOROETHYLENE. BOTH STABILIZERS WERE FOUND TO BE MUTAGENIC IN THE IN VITRO ASSAY IN SCHIZOSACCHAROMYCES POMBE USING METABOLIC ACTIVATION SYSTEMS SUPPLIED BY LIVER HOMOGENATES (S9) FROM MICE AND RATS UNTREATED AND PRETREATED WITH PHENOBARBITAL AND/OR BETA-NAPHTHOFLAVONE. [R29] *1,2-Epoxybutane was evaluated for the induction of sex-linked recessive mutations in Drosophila melanogaster using a standard protocol approved by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of 1,2-epoxybutane that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. 1,2-Epoxybutane was positive in this assay at a dietary level of 50,000 ppm. [R30] *1,2-Epoxybutane was evaluated for its mutagenic potential in the L5178Y TK+/TK- mouse lymphoma forward mutation assay using established procedures. Four experiments were conducted, two with metabolic activation and two without metabolic activation. The dose levels tested in these experiments ranged from 0-800 ug/ml. Significant mutagenic responses were obtained in all four experiments. Thus, 1,2-epoxybutane was positive in these tests and the lowest effective dose tested was 200 ug/ml. [R31] *Epoxybutane (10% in acetone) applied three times per week for 540 days to the clipped skin of ICR/Ha Swiss mice did not have a toxic effect. [R32] *Artificially inseminated rabbits were exposed to epoxybutane at 0, 250, or 1,000 ppm 7 hours per day from gestation day 0 to 24; animals were examined at gestation day 30. Some maternal deaths occurred at both exposure concentrations, but no teratogenic effects were seen. The pregnancy rate was reduced in the high dose group. [R33] *Female rats were exposed by inhalation to epoxybutane 7 hours per day, 5 days per week for 3 weeks prior to mating, and from day 0 to 19 of gestation at, 0, 250, or 1,000 ppm. Animals were evaluated at gestation day 21. The only maternal toxicity observed in the high dose group was slight decrease in body weight relative to that of the controls; no teratogenic effects were seen in any exposed group. [R33] *1,2-Epoxybutane caused inflammatory and degenerative changes in the nasal mucosa and myeloid hyperplasia in the bone marrow in rats and mice. [R34] *1,2-Epoxybutane has been shown to induce SOS repair activity in Salmonella typhimurium TA1525/pSK1002 and to produce differential killing zones in various pol- and rec-proficient and -deficient strains of Escherichia coli. It induced streptomycin-resistant mutants in Klebsiella pneumonia. It was shown to be mutagenic to E. coli WP2 uvrA- ... . In S. typhimurium, it induced base-pair substitutions (strains TA100 and TA1535) but not frameshift mutations in the presence or absence of exogenous metabolic activation. 1,2-Epoxybutane induced forward mutation in Schizosaccharomyces pombe P1 and mitotic recombination in Saccharomyces cerevisiae D3. It was weakly mutagenic at the adenine locus in Neurospora crassa. It induced sex-linked recessive lethal mutations and translocations in Drosophila melanogaster after either feeding or injection. [R35] *It /1,2-epoxybutane/ did not induce unscheduled DNA synthesis in rat primary hepatocytes but did induce mutation in L5178Y TK+/- mouse lymphoma cells in the absence or presence of an exogenous metabolic system. ... 1,2-epoxybutane gave marginally positive results for induction of 6-thioguanine-resistant mutations in L5178Y cells. It increased the frequency of sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary CHO cells with or without exogenous metabolic activation. It induced morphological transformation in Syrian hamster embryo cells and virally enhanced Fischer 344 rat embryo cells but not in BALB/c 3T3 cells. [R36] *TOXICITY SUMMARY STATEMENT: (ACUTE): MODERATE IRRITANT VIA DERMAL, INHALATION AND ORAL ROUTES. MODERATE: MAY CAUSE REVERSIBLE OR IRREVERSIBLE CHANGES TO EXPOSED TISSUE, NOT PERMANENT INJURY OR DEATH; CAN CAUSE CONSIDERABLE DISCOMFORT. [R37] NTXV: *LD50 Rat oral 1,170 mg/kg; [R32] *LC100 Rat inhalation 8000 ppm/4 hr; [R32] *LD50 Rat oral 500 mg/kg; [R16] *LD50 Rabbit skin 2100 mg/kg; [R16] NTP: *Two year toxicology and carcinogenesis studies of 1,2-epoxybutane were conducted by exposing groups of 50 animals per species and sex to the chemical by inhalation, 6 hours per day, 5 days per week. Rats were exposed at concentrations of 0, 200, or 400 ppm for 103 weeks and mice at 0, 50, or 100 ppm for 102 weeks. Dosed rats had nonneoplastic lesions of the nasal cavity including inflammation, epithelial hyperplasia, squamous metaplsias, hyperostosis of the nasal turbinate bone, and atrophy of the olfactory epithelium. Seven papillary adenomas of the nasal cavity were seen in high dose male rats and two in high dose female rats. The historical incidences of nasal cavity adenomas in untreated male and untreated female F344/N rats are less than 0.1%. The incidences of alveolar/bronchiolar carcinomas (0/50; 1/50; 4/49) and adenomas or carcinomas (combined) (0/50; 2/50; 5/49) were increased in high dose male rats; no increased incidences of these tumors were observed in dosed female rats. Dosed mice had increased incidences of nonneoplastic lesions of the nasal cavity. The nonneoplatic lesions included suppurative inflammation empyema, epithelial hyperplasia, erosion, regeneration, and squamous metaplasia in the nasal cavity; atrophy of the olfactory sensory epithelium; hyperplasia of the nasal gland (Bowman's glands); and inflammation and hyperplasia of the nasolacrimal duct. A single squamous cell papilloma was seen in the incisive duct of one high dose male mouse. [R38] TCAT: Dermal sensitization was evaluated in 10 male Hartley guinea pigs receiving dermal applications of 1,2-epoxybutane (purity not reported). The test material was applied as an occluded dose 4 times at 48 hour intervals over a 7 day treatment period; 0.2 ml of Freunds Adjuvant was injected intradermally adjacent to the treatment site at the time of the third application. Following a 2 week rest period, animals were challenged with an unspecified amount of test material to their shaved flanks. The investigators observed no sensitization reaction in any of the 10 animals when compared to controls. [R39] ?Subchronic inhalation toxicity was evaluated in a range finding study using 1,2 epoxybutane (purity not reported) to determine the exposure concentrations for chronic study. Groups of 20 Fischer-344 rats (10 male, 10 female) and 20 B6C3F1 mice (10 male, 10 female) were exposed to 0,50,100,200,400 or 800 ppm 1,2 epoxybutane for 13 weeks. The number of hours/day and days/week of exposure were not reported. The investigators observed severe inflammation of the nasal cavity, hemorrhage of the tracheobronchial lymph nodes, and statistically significantly decreased body weight gain in rats exposed at 800 ppm; the incidence and severity of lesions in rats exposed at other levels were not considered to be different from controls. Observations in mice exposed to 800 ppm included inflammation of the nasal cavity, red discoloration of the lungs, paleness of the spleen, distension of the G.I. tract, thymic necrosis, thymic atrophy, splenic atrophy, splenic necrosis, along with renal tubular necrosis and inflammation. At 200 and 400 ppm mice exhibited a reduction in the number of cell layers in the olfactory epithelium and an increase in amount of serous fluid, especially in the recesses of the turbinate area; but no effects on the thymus, spleen or kidneys. [R40] ?The effect of butylene oxide was examined in the Drosophila sex-linked recessive lethal assay. Male flies were exposed to 1000 ppm test article for 7 hours and then mated. Butylene oxide did not substantially increase the incidence of lethals in the F1, F2 or F3 generations compared to controls. A survival rate of 70% was observed after 7 hours of exposure indicating that butylene oxide was being tested at toxic levels. [R41] ?The effect of butylene oxide (dissolved in DMSO) was examined in the DNA repair assay with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. Human embryonic intestinal cells were exposed for 3 hours to concentrations of test article ranging from 11 to 525 ug/ml in activated assays, and from 57 to 7300 ug/ml in nonactivated assays. Butylene oxide did not induce an increase in the number of grain counts at any concentration. Toxicity to cells was observed at concentrations greater than 525 ug/ml in assays with activation, while toxicity in assays without activation was not reported. [R42] ?The fate of 1-butene oxide (BO) was studied in male CDF Fischer rats (4/group) exposed by inhalation to 50 or 1000 ppm of 1-14C-labeled BO for 6 hrs. The animals were then placed for 66 hrs into new chambers through which room air was drawn and then passed over activated charcoal (to trap BO) and bubbled through a CO2 trap. Samples of traps, urine and feces were taken during various intervals. The animals were sacrificed at 66 hrs and samples of various tissues were analyzed for radioactivity. Also, three male rats were exposed by inhalation as above to 50 ppm uniformly labeled BO (UL-BO) for 6 hrs or by gavage (2 rats) at 20 mg/kg UL-BO. These rats were placed for 32 hrs following exposure into new cages as above. BO administered either by inhalation or gavage was rapidly metabolized and eliminated primarily as non-volatile urinary metabolites and expired as CO2. Most of the material recovered in the traps or urine was excreted within 36 hrs postexposure. Small amounts of radioactivity were retained in the carcass after 32 hrs or were absorbed in the charcoal. The amounts of radioactivity recovered respectively in the urine of C1-BO and UL-BO exposed animals were 40-46% and 12%, and that recovered as CO2 was 27-33% and 60%, respectively. Only minor changes in the disposition of BO were observed over the 50-1000 ppm range. Recovery of radioactivity from rats exposed by gavage was 93.2% and the routes of elimination were very similar to those of rats exposed by inhalation. [R43] ?The steady state uptake of 1-butene oxide (BO) was studied in male Fischer CDF 344 rats (3/concentration) exposed to nominal concentrations of 50 or 100 ppm BO using a plethesmograph/head-only exposure device. BO vapor of the appropriate concentration was pumped into the conical-shaped exposure chamber at 300 ml/min and the tidal volume, respiratory rate, and concentration of BO in the supply and exit lines were monitored after the animals were in the chambers for 45, 75, and 105 min. The rate of uptake of BO (as measured by the supply/exit concentrations of BO) for the high- and low-dose rats were 0.0433 and 0.720 mg/kg/min, respectively (resp). Since steady state is rapidly established during BO exposure, these rates may be used to estimate the total uptake during a 6 hr exposure as 15.6 and 252 mg/kg, resp. High-dose rats breathe more slowly and more shallowly than low- dose animals which appears to be associated with a slightly higher relative retention of BO at the higher dose. The ratio of expired BO to inspired BO concentrations for the high- and low-dose rats were 0.586 and 0.647, resp. [R43, ] ADE: */When/ 1,2-epoxybutane was administered as a single dose to rats (1.9 mmol/kg), 11% of the original dose was excreted in the urine as 2-hydroxybutyl mercapturic acid. [R33] METB: *Epoxides are detoxified in vivo by conjugation with glutathione. /Epoxides/ [R33] *Metabolism of isobutene (2-methylpropene) in rats (Sprague Dawley) and mice (B6C3F1) follows kinetics according to Michaelis-Menten. The maximal metabolic elimination rates are 340 umol/kg/hr for rats and 560 umol/kg/hr for mice. The atmospheric concentration at which Vmax/2 is reached is 1200 ppm for rats and 1800 ppm for mice. At steady state, below atmospheric concentrations of about 500 ppm the rate of metabolism of isobutene is directly proportional to its cooncentration. 1,1-Dimethyloxirane is formed as a primary reactive intermediate during metabolism of isobutene in rats and can be detected in the exhaled air of the animals. Under conditions of saturation of isobutene metabolism the concentration fo 1,1-dimethyloxirane in the atmosphere of a closed exposure system is only about 1/15 of that observed for ethene oxide and about 1/100 of that observed for 1,2-epoxy-3-butene as intermediates in the metabolism of ethene or 1,3-butadiene. [R44] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Epoxybutane's production and use as an intermediate for various polymers and use as a stabilizer for chlorinated solvents may result in its release to the environment through various waste streams. Evaporation of 1,2-epoxybutane into the atmosphere is likely to occur as stabilized chlorinated solvents evaporate with their use in metal cleaning and degreasing operations. If released to air, a vapor pressure of 180 mm Hg at 25 deg C indicates 1,2-epoxybutane will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-epoxybutane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 8.4 days If released to soil, 1,2-epoxybutane is expected to have very high mobility based upon an estimated Koc of 8. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 1.80X10-4 atm-cu m/mole. 1,2-Epoxybutane may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 1,2-epoxybutane is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Aerobic aqueous biodegradation screening studies indicate that 1,2-epoxybutane will biodegrade, although the rate of degradation may be slow. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3.6 hours and 4.6 days, respectively. An estimated BCF of 0.96 suggests the potential for bioconcentration in aquatic organisms is low. The hydrolysis rate of 1,2-epoxybutane in water is probably similar to that of 1-propene oxide; at 25 deg C, propene oxide has a hydrolysis half-life of 11.6 days at pH 7. Occupational exposure to 1,2-epoxybutane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-epoxybutane is produced or used. Occupational and consumer exposure are likely where chlorinated solvents are used. (SRC) ARTS: *1,2-Epoxybutane's production and use as an intermediate for various polymers and use as a stabilizer for chlorinated solvents(1) may result in its release to the environment through various waste streams(SRC). Evaporation of 1,2-epoxybutane into the atmosphere is likely to occur as stabilized solvents evaporate with their use in metal cleaning and degreasing operations(2). [R45] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 8(SRC), determined from a water solubility of 95,000 mg/l(2) and a regression-derived equation(3), indicates that 1,2-epoxybutane is expected to have very high mobility in soil(SRC). Volatilization of 1,2-epoxybutane from moist soil surfaces is expected to be an important fate process(SRC), given an estimated Henry's Law constant of 1.80X10-4 atm-cu m/mole(SRC), based upon its vapor pressure, 180 mm Hg(4), and its water solubility(2). The potential for volatilization of 1,2-epoxybutane from dry soil surfaces may exist(SRC) based upon a its vapor pressure(4). [R46] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 8(SRC), determined from a water solubility of 95,000 mg/l(2) and a regression-derived equation(3), indicates that 1,2-epoxybutane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a estimated Henry's Law constant of 1.8X10-4 atm-cu m/mole(SRC) derived from its vapor pressure, 180 mm Hg(4), and water solubility(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3.6 hours and 4.6 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 0.96(SRC), from its water solubility(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Aerobic aqueous biodegradation screening studies indicate that 1,2-epoxybutane will biodegrade in the environment(7), although the rate of degradation may be slow(SRC). The rate constant for the reaction of 1,2-epoxybutane with hydroxyl radicals in aqueous solution is approximately 7.5X10+8 L/mol-sec(8); if the hydroxyl radical concn of sunlit natural water is assumed to be 1X10-17 moles/l(9), the half-life would be approximately 2.9 years(SRC). The epoxides (eg, butene oxide) degrade in water by hydrolysis and related ionic reactions to glycols(2); hydrolysis of 1,2-epoxybutane will yield butene glycol(2). The hydrolysis rate of 1,2-epoxybutane in water is probably similar to that of the similar structure 1-propene oxide(SRC); at 25 deg C, propene oxide has hydrolysis half-lives of 6.6, 11.6, and 11.6 days at respective pHs of 5, 7, and 9(2); in seawater, the hydrolysis rate of propene oxide is accelerated by at least 30% due to chloride ion reaction(2). [R47] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-epoxybutane, which has a vapor pressure of 180 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase 1,2-epoxybutane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is 8.4 days(SRC), calculated from its rate constant of 1.91X10-12 cu cm/molecule-sec at 25 deg C(3). [R48] BIOD: *AEROBIC: 1,2-Epoxybutane failed the ready biodegradability test (sewage sludge test; 17% degradation after 30 d) and passed the inherent biodegradability test (sewage sludge test; 100% degradation with added dissolved organic matter)(1). These screening studies indicate that 1,2-epoxybutane will biodegrade in the environment(1), although the rate of degradation may be slow(SRC). [R49] ABIO: *The rate constant for the vapor-phase reaction of 1,2-epoxybutane with photochemically-produced hydroxyl radicals is 1.91X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of 8.4 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). The rate constant for the reaction of 1,2-epoxybutane with hydroxyl radicals in aqueous solution is approximately 7.5X10+8 L/mol-sec(2); if the hydroxyl radical concn of sunlit natural water is assumed to be 1X10-17 moles/l(3), the half-life would be approximately 2.9 years(SRC). The epoxides (eg, butene oxide) degrade in water by hydrolysis and related ionic reactions to glycols(4); hydrolysis of 1,2-epoxybutane will yield butene glycol(4). The hydrolysis rate of 1,2-epoxybutane in water is probably similar to that of the similar structure 1-propene oxide(SRC); at 25 deg C, propene oxide has hydrolysis half-lives of 6.6, 11.6, and 11.6 days at respective pHs of 5, 7, and 9(4); in seawater, the hydrolysis rate of propene oxide is accelerated by at least 30% due to chloride ion reaction(4). [R50] BIOC: *An estimated BCF of 0.96 was calculated for 1,2-epoxybutane(SRC), using a water solubility of 95,000 mg/l(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R51] KOC: *The Koc of 1,2-epoxybutane is estimated as 8(SRC), using a water solubility of 95,000 mg/l(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1,2-epoxybutane is expected to have very high mobility in soil(SRC). [R52] VWS: *The Henry's Law constant for 1,2-epoxybutane is estimated as 1.8X10-4 atm-cu m/mole(SRC), based upon its vapor pressure, 180 mm Hg(1), and water solubility, 95,000 mg/l(2). This Henry's Law constant indicates that 1,2-epoxybutane is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 3.6 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4.6 days(SRC). 1,2-Epoxybutane's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1,2-epoxybutane from dry soil surfaces may exist based upon its vapor pressure(1). [R53] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 261,650 workers (42,961 of these are female) are potentially exposed to 1,2-epoxybutane in the US(1). Occupational exposure to 1,2-epoxybutane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-epoxybutane is produced or used(SRC). [R54] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 2 ppm. [R55] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 1-Butene oxide is included on this list. [R56] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R57] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Oxirane, ethyl is included on this list. [R58] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EPOXIDES, INCLUDING 1-BUTENE OXIDE, WERE REACTED WITH AN EXCESS AMOUNT OF 4-(P-NITROBENZYL)PYRIDINE, AND ABSORBANCE OF THE PRODUCT WAS MEASURED FOR CONCN OF EPOXIDES. THE METHOD WAS SENSITIVE, AND AS LOW AS 0.01 UMOL/SAMPLE CAN BE DETECTED. [R59] CLAB: *A quantitative method for analysis of low levels of 1,2-butylene oxide in whole rat blood was proposed using gas chromatography/mass spectrometry with multiple ion detection. Using spiked blood samples resulted in individual recovery determinations of butylene-oxide ranging from 82 to 107.6%. For the concentration range of 0.335 to 100 ug butylene-oxide/ml whole blood was 93%. At a concentration of 13.4 ug/ml the coefficient of variation for three individual determinations was 2.3%. The corresponding figure at 0.33 ug/ml was 10.4%. No interference peaks were noted. Retention time was approximately 1 minute. In studies designed to simulate the procedure used to collect blood samples from rodents, less than 5% of the butylene oxide was lost when blood was transferred via a syringe and venous cannula. Stability of the spiked blood samples was demonstrated over an 8 hour period using dry ice. As little as 250 microliters of blood were needed for the analysis and detectable concentrations of butylene oxide ranged from 0.335 to 100 ug/ml whole rat blood. [R60] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 1,2-Epoxybutane in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 329 (1988) NIH Publication No. 88-2585 SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (92) 727 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 179 R4: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 586 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V17 (96) 1073 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V2 (92) 1 R7: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986. R8: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-237 R9: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R10: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R11: Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4 (1980) R12: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994. R13: Osborn AG, Scott DW; J Chem Thermodynamic 12: 429-38 (1980) R14: Kwok ESC, Atkinson R; Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-127 R16: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 547 R17: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R18: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 353 R19: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R20: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R21: 49 CFR 171.2 (7/1/2000) R22: IATA. Dangerous Goods Regulations. 41st Ed.Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2000. 125 R23: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3192 (1998) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 637 (1991) R25: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R26: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 177 R27: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 1152 R28: MILLER RR ET AL; FUNDAM APPL TOXICOL 1 (4): 319 (1981) R29: ROSSI AM ET AL; TETRATOGENESIS CARCINOG MUTAGEN 3 (1): 75 (1983) R30: Yoon JS et al; Environ Mutagen 7:349-367 (1985) R31: McGregor DB et al; Environ Mutagen 9: 143-60 (1987) R32: NTP; Toxicology and Carcinogenesis Studies of 1,2-Epoxybutane in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.14 Report #329 (1988) NIH Pub # 88-2585 R33: NTP; Toxicology and Carcinogenesis Studies of 1,2-Epoxybutane in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.15 Report #329 (1988) NIH Pub # 88-2585 R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 631 (1999) R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 631-2 (1999) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 636 (1999) R37: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 551 R38: NTP; Toxicology and Carcinogenesis Studies of 1,2-Epoxybutane in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.4 Report #329 (1988) NIH Pub # 88-2585 R39: Dow Chemical; 1,2-Butylene oxide: Skin sensitization potential in the guinea pig. (1984), EPA Document No. 40- 8475031, Fiche No. OTS0507304 R40: Battelle Pacific Northwest Labs; Prechronic test phase review, (1981), EPA Document No. 40-8275009, Fiche No. OTS0509932 R41: Inveresk Research International Limited; Tier II Mutagenic Screening of 13 NIOSH Priority Compounds (1981), EPA Document No. 40-8175007, Fiche No. OTS0509930 R42: Inveresk Research Intl. Lmtd.; Tier II Mutagenic Screening of 13 NIOSH Priority Compounds: Individual Compound Report Butylene Oxide (1981), EPA Document No. 40-8175007, Fiche No. OTS0509930 R43: Dow Chemical Co.; Fate of 1,2-Butylene Oxide in Male Rats Following Inhalation Exposure. (1983), EPA Document No. 878213688, Fiche No. OTS0206355 R44: Csanady GA et al; Arch Toxicol 65 (2): 100-5 (1991) R45: (1) Lewis RJ, Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons Inc. p. 179 (1997) (2) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4-79 (1980) R46: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4-79 (1980) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Osborn AG, Scott DW; J Chem Thermodynamic 12: 429-38 (1980) R47: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4-79 (1980) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Osborn AG, Scott DW; J Chem Thermodynamic 12: 429-38 (1980) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) Kaiser KLE; Water Qual Res J Canada 33: 185-211 (8) Guesten H et al; Atmos Environ 15: 1763-5 (1981) (9) Mill T et al; Science 207: 886-7 (1980) R48: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Osborn AG, Scott DW; J Chem Thermodynamic 12: 429-38 (1980) (3) Kwok ESC, Atkinson R; Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) R49: (1) Kaiser KLE; Water Qual Res J Canada 33: 185-211 (1998) R50: (1) Kwok ESC, Atkinson R; Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) (2) Guesten H et al; Atmos Environ 15: 1763-5 (1981) (3) Mill T et al; Science 207: 886-7 (1980) (4) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4-79 (1980) R51: (1) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4 (1980) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R52: (1) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4-79 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R53: (1) Osborn AG, Scott DW; J Chem Thermodynamic 12: 429-38 (1980) (2) Bogyo DA et al; Investigation of Selected Potential Environmental Contaminants: Epoxides. USEPA-560/11-80-005 p. 4 (1980) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R54: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R55: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R56: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R57: 40 CFR 302.4 (7/1/2000) R58: 40 CFR 716.120 (7/1/2000) R59: AGARWAL SC ET AL; BULL ENVIRON CONTAM TOXICOL 23 (6): 825 (1979) R60: Kastl PE et al; J Chromatogr 398: 347-50 (1987) RS: 65 Record 190 of 1119 in HSDB (through 2003/06) AN: 2863 UD: 200302 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PENTACHLOROBENZENE- SY: *BENZENE,-PENTACHLORO-; *1,2,3,4,5-PENTACHLOROBENZENE-; *QCB- RN: 608-93-5 MF: *C6-H-Cl5 SHPN: UN 1334; Chlorobenzene IMO 3.3; Chlorobenzene HAZN: U183; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *When BHC /benzene hexachloride/ is chlorinated in carbon tetrachloride, various substitution derivatives are formed. By use of liquid chlorine, higher substituted derivatives can be obtained. BHC vapor in a mixture with oxygen (air) and chlorine at 470 deg C in the presence of a catalyst containing alumina, copper chloride, and potassium chloride yields a mixture of hexachlorobenzene and pentachlorobenzene. [R1] MFS: *Chemical Dynamics Corporation, PO Box 395, South Plainfield, NJ 07080, (201) 753-5000 [R2] OMIN: *TECHNICAL GRADE PCNB /PENTACHLORONITROBENZENE/ CONTAINS ... LESS THAN 0.1% PENTACHLOROBENZENE ... [R3, 673] USE: *Chem int for pentachloronitrobenzene [R4, p. VA17 431] CPAT: *ESSENTIALLY 100% AS A CHEM INT FOR PENTACHLORONITROBENZENE [R5] PRIE: U.S. PRODUCTION: *(1977) AT LEAST 4.54X10+8 G [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless needles [R4, p. VA6 332] ODOR: *Pleasant aroma [R6] BP: *277 DEG C [R7, p. 3-58] MP: *86 DEG C [R7, p. 3-38] MW: *250.34 [R7, p. 3-58] DEN: *1.8342 @ 16.5 DEG C [R7, p. 3-58] HTV: *15,124.2 gcal/gmole [R8] OWPC: *Log Kow= 5.18 [R9] SOL: *Insoluble in ethanol; slightly soluble in ether and benzene [R7, p. 3-58]; *In water, 1.33 mg/l at 25 deg C. [R10] SPEC: *MAX ABSORPTION (ALCOHOL): 288 NM (LOG E= 2.56); 298 NM (LOG E= 2.54) [R11]; *IR: 1091 (Coblentz Society Spectral Collection) [R12, p. V1 181]; *UV: 5-44 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R12, p. V1 181]; *NMR: 3044 (Sadtler Research Laboratories Spectral Collection) [R12, p. V1 181]; *MASS: 4635 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R12, p. V1 181] VAP: *0.0065 mm Hg @ 25 deg C [R13] OCPP: *Vapor Pressure: 1 mm Hg at 98.6 deg C; 40 mm Hg at 178.5 deg C. [R12, p. VI 181] *Henry's Law constant = 7.1X10-4 atm-cu m/mol @ 20 deg C [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *... ON CONTACT WITH ACIDS OR ACID FUMES ... /CHLORIDES/ EVOLVE HIGHLY TOXIC /HYDROGEN CHLORIDE/ FUMES. /CHLORIDES/ [R15, 715] DCMP: *When heated to decomp it emits ... fumes of /hydrogen chloride/. [R15, 2579] *Some organic chlorides decompose to yield phosgene. /Chlorides/ [R15, 715] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U183, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R16] *Potential candidate for rotary kiln incineration, with temperature range of 820 to 1,600 deg C, and a residence time of hours. [R17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: No human data and no animal data available. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: None. [R18] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R19, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who unconscious or in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's to maintain hydration and adequate urine flow. Watch for signs of fluid overload and pulmonary edema. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatic hydrocarbons and related compounds/ [R19, 182] NTOX: *FEMALE ADULT WISTAR RATS WERE FED WITH A DIET CONTAINING 0.05% HEXACHLOROBENZENE OR ITS METABOLITES, PENTACHLOROBENZENE AND PENTACHLOROPHENOL. NO ALTERATION WAS OBSERVED IN URINARY PORPHYRIN EXCRETION IN PENTACHLOROBENZENE AND PENTACHLOROPHENOL TREATED ANIMALS. IT SEEMS UNLIKELY THAT PENTACHLOROBENZENE AND PENTACHLOROPHENOL ARE PORPHYROGENIC AGENTS, ALTHOUGH BOTH INDUCE INCREASED LIVER CYTOCHROME P450. [R20] *ACUTE AND SUBCHRONIC TOXICITY OF PENTACHLOROBENZENE WERE REPORTED. CLINICAL SIGNS OF ORAL TOXICITY IN RATS AND MICE INCLUDED TREMORS AND CENTRAL NERVOUS DEPRESSION. DERMAL APPLICATION OF 2500 MG/KG DID NOT PRODUCE CLINICAL SIGNS IN RATS. [R21] *PENTACHLOROBENZENE, A METABOLITE OF HEXACHLOROBENZENE IN CHICK EMBRYO LIVER CELL PRIMARY CULTURE, DID NOT INDUCE A PATHOLOGICAL PORPHYRIN PATTERN. [R22] *CD-1 mice showed no teratogenic effects at 100 mg/kg/day (NOEL). [R23] *(Quintochlorobenzene) QCB at 50, 100 or 200 mg/kg in corn oil was administered by stomach tube to pregnant rats on days 6 through 15 of gestation. The high dose of QCB produced an increased incidence of uni or bilateral extra ribs, as well as sternal defects consisting of unossified or nonaligned sternbrae with cartilagenous precursors present. ... The sternal defects suggested a retarded sternal development and that these were related to a decreased mean fetal weight. At lower doses the sternal defects were not noted, /however/ there was an increased incidence ... /in the number of fetuses with extra ribs/. The number of litters with one or more litter mates showing an anomalous rib number (14th and 15th combined), versus numbers of litters examined for each dose group, was 3/19 for 0 mg/kg, 14/19 for 50 mg/kg, 11/19 for 100 mg/kg and 15/19 for 200 mg/kg /manifesting/ an apparent dose-related incidence. [R24] *Suckling /rat/ pups whose mothers were fed > 250 ppm pentachlorobenzene developed tremors. At 1000 ppm, most died before weaning. Though no clinical signs of tremors were observed in parents ... this result was presumptive evidence ... for excretion of a toxic agent via the milk. Because pentachlorobenzene accumulates in the fetus, prenatal exposure of the pups may also have contributed to the observed effects. [R25] *Oral feeding of pentachlorobenzene to pregnant rats has produced developmental effects and decr body wt in fetuses. No adverse reproductive or developmental effects were seen in mice following maternal admin of the cmpd orally. ... A single study has alluded to carcinogenic effects of pentachlorobenzene in mice and lack of carcinogenic effects in dogs and rats. [R6] *... Pentachlorobenzene ... incr the activity of NADPH-cytochrome p450 dependent enzyme systems in rats. Induction of the cytochrome p450 monoxygenase-catalyzed metabolism could result in an increase or decr in the toxicity of the compound. Therefore, exposure to pentachlorobenzene could result in the biotransformation, and toxicity of drugs, and other chemicals. [R26] *The growth rate reduction of mosquito fish (Gambusia affinis) fry was investigated with a range of sublethal exposure levels of four halobenzenes for 42 days. These compounds were found to produce growth rate reduction in mosquito fish fry at concentrations as low as 0.30, 0.18, 0.025, and 0.010 mumol liter-1 for 1,4-dibromobenzene, 1,2,3-trichlorobenzene, 1,2,4-tribromobenzene, and pentachlorobenzene, respectively. The aqueous exposure concentrations causing growth rate reduction of 50 and 10% (EC50 and EC10, respectively) for the halobenzenes were 0.067-3.4 and 0.0042-0.32 mumol liter-1, respectively. The EC50 and LC10 values are within the ranges of 5 to 8% and 0.1 to 3.9% of the LC50 values, respectively. The percentage of growth rate reduction relative to the LC, could possibly be used to describe chronic toxicity effects of organic compounds with the aquatic organisms. The internal concentrations obtained from the analysis for the halobenzenes were generally consistent with the calculated internal concentrations. The lipid-based internal concentrations that gave 50 and 10% growth rate reductions were 8.3-27 and 0.5-1.6 mmol kg-1, respectively. These values have a more limited range than the corresponding external aqueous concentrations. The quantitative structure-activity relationships between the internal concentrations at 50 and 10% growth rate reduction and physicochemical parameters were found to be less satisfactory than those based on external aqueous concentrations. SS 2 /C? [R27] *... THE CONTENTS OF CYTOCHROMES AND HEPATIC CONSTITUENTS IN ADDITION TO THE ACTIVITIES OF DRUG-METABOLIZING ENZYMES AND DELTA-AMINOLEVULINIC ACID (DELTA-ALA) SYNTHETASE WERE EXAMINED IN RATS TREATED WITH ... PENTACHLOROBENZENE ... THE CONTENT OF CYTOCHROME P450 AND ACTIVITIES OF AMINOPYRINE DEMETHYLASE AND ANILINE HYDROXYLASE WERE INCR BY ORAL ADMINISTRATION /OF PENTACHLOROBENZENE/ ... AS A DAILY DOSE OF 250 MG/KG, ONCE DAILY, FOR 3 DAYS. ... THE ACTIVITY OF DELTA-ALA SYNTHETASE WAS INCREASED. [R28] NTXV: *LD50 RAT MALE ADULT ORAL 1125 MG/KG; [R21] *LD50 RAT FEMALE ADULT ORAL 1080 MG/KG; [R21] *LD50 RAT FEMALE WEANLING ORAL 940 MG/KG; [R21] *LD50 MOUSE MALE ORAL 1175 MG/KG; [R21] *LD50 MOUSE FEMALE ORAL 1370 MG/KG; [R21] ETXV: *LC50 Bluegill sunfish 2.27 mg/l/24 hr; 0.55 mg/l/48 hr; 0.25 mg/l/96 hr /Conditions of bioassay not specified/; [R29] *LC50 Sheepshead minnow > 32.0 mg/l/24 hr; 9.55 mg/l/48 hr; 0.83 mg/l/96 hr /Conditions of bioassay not specified/; [R29] *LC50 Poecilia reticulata (guppy) 0.178 ppm/14 days /Conditions of bioassay not specified/; [R30] POPL: *... Certain medical conditions /skin, liver, kidney and chronic respiratory disease/ ... might place the employee at increased risk from chlorobenzene exposure. /Chlorobenzene/ [R31] ADE: *... PENTACHLOROBENZENE ... ACCUMULATED TO APPRECIABLE EXTENT IN BOTH MATERNAL AND FETAL TISSUES /AFTER DAILY ORAL ADMINISTRATION OF 50, 100 and 200 MG/KG TO RATS ON DAYS 6-15 OF GESTATION OR 22-DAY-OLD FETUSES/. [R3, 675] *THE MEAN LEVELS OF CHLOROBENZENES (INCLUDING PENTACHLOROBENZENE) IN HUMAN MILK AND ADIPOSE TISSUE WERE DETERMINED AND RANGED FROM TRACES TO 25 UG/KG FOR HUMAN MILK AND FROM NOT DETECTED TO 146 UG/KG FOR ADIPOSE TISSUE. THE DISTRIBUTION OF DIFFERENT CHLOROBENZENE ISOMERS IN ADIPOSE TISSUE AND MILK WAS DIFFERENT. [R32] *SINGLE ORAL DOSES OF 0.5 MG/KG OF (14)C-PENTACHLOROBENZENE WERE GIVEN TO MALE AND FEMALE RHESUS MONKEYS. THE CHEMICAL WAS READILY ABSORBED AND EVIDENCE INDICATES THAT THE LYMPHATIC SYSTEM WAS INVOLVED IN THE ABSORPTION PROCESS. THE MAJOR EXCRETORY PATHWAY WAS VIA THE FECES. IT IS SUGGESTED THAT THE METABOLIC SYSTEM INVOLVED SOME MECHANISM OTHER THAN THE HEPATIC CYTOCHROME P450. IT IS SUGGESTED THAT TWO DIFFERENT HYDROXYLATION PATHWAYS COULD BE INVOLVED. THE FIRST CALLS FOR OXIDATION OF THE PENTACHLOROBENZENE TO PENTACHLOROPHENOL, AND THE 2ND CALLS FOR NUCLEOPHILIC DISPLACEMENT REACTIONS OF PENTACHLOROBENZENE TO TETRACHLOROPHENOLS IN SITES WHICH ARE METABOLICALLY ACTIVE, OTHER THAN THE LIVER. [R33] *THE REPORTED DATA ARE PART OF A CONTINUING MONITORING PROGRAM OF CHLORINATED HYDROCARBONS IN ADIPOSE TISSUE OF CANADIANS IN ORDER TO MONITOR DISAPPEARANCE OF RESTRICTED ORGANOCHLORINE PESTICIDES AS WELL AS THE APPEARANCE OF NEW ENVIRONMENTAL CONTAMINANTS. HUMAN ADIPOSE TISSUES WERE OBTAINED DURING AUTOPSIES ON ACCIDENT VICTIMS. PENTACHLOROBENZENE WAS FOUND IN ALL TISSUES SAMPLED, REGARDLESS OF GEOGRAPHIC REGION, AGE, OR SEX OF THE SUBJECT. AMOUNTS RECOVERED WERE ERRATIC, HOWEVER, MAKING QUANTITATIVE DETERMINATIONS INVALID. [R34] *Pentachlorobenzene is stored in the fat, kidney, liver, and skeletal muscle in the rat, dog, and cow. [R35] *Tissues of monkeys given a single dose of (14)C-labeled pentachlorobenzene (0.5 mg/kg) by gavage were analyzed after 40 days. ... The highest concn /of (14)C/ was found in the fat and bone marrow, followed by the thymus, lymph nodes, and adrenal cortex. [R25] *... The distribution of pentachlorobenzene in rabbits /revealed/ that the compound was readily isolated from the feces and gut contents 3-4 days following administration by gavage at 0.5 g/kg. Subcutaneous injections of 0.5 g/kg (10% w/v solutions in arachis oil) resulted in concentrations of 47% in the pelt (mostly at the site of injection), 22% in the fat, a total of 2% in the gut and feces, and 10% in the rest of the body. [R36] *The distribution of pentachlorobenzene /was studied/ in dams and fetuses after daily administration by gavage of pentachlorobenzene prepared in corn oil at levels of 40, 100, and 200 mg/kg to pregnant rats on days 6 through 15 of gestation. On day 22, the dams were killed, fetuses removed and tissues analyzed by gas-liquid chromatography for organo-halogen residues. Recovery of pentachlorobenzene was greater than 80% for all tissues. In the tissues of the maternal animals, fat had the greatest accumulation of pentachlorobenzene, followed by the liver, brain, heart, kidneys and spleen. In the fetuses, the levels detected in the brain were equal to those measured in the whole fetus, while the levels in the liver were double the whole fetus concentration. ... Both the maternal tissues and the whole fetuses appeared to accumulate pentachlorobenzene in a dose-related manner. [R37] METB: *PENTACHLOROBENZENE AND PENTACHLOROPHENOL /ARE/ METABOLITES OF LINDANE IN THE RABBIT. [R3, 586] *THE BILIARY EXCRETION OF METABOLITES OF HEXACHLOROBENZENE WAS STUDIED IN RATS DOSED INTRAGASTRICALLY WITH (14)C-HEXACHLOROBENZENE. BY GLC-MASS SPECTROMETRY, 1.8% OF THE (14)C EXCRETED IN THE 24 HOUR BILE WAS SHOWN TO BE DUE TO PENTACHLOROBENZENE. [R38] *PENTACHLOROBENZENE IS A METABOLITE OF HEXACHLOROBENZENE IN CHICK EMBRYO LIVER CELL PRIMARY CULTURE. [R22] *PENTACHLOROBENZENE YIELDS CHLOROBENZENE IN RABBIT. /FROM TABLE/ [R39] *WHEN PENTACHLOROBENZENE WAS ADDED TO CULTURE OF MOLD, DEGRADATION PRODUCED FOLLOWING METABOLITES: PENTACHLOROPHENOL, 2,3,4,5- and 2,3,4,6-TETRACHLOROPHENOL; 1,2,3,4-TETRACHLOROBENZENE; 1,2,4,5- and /OR 1,2,3,5-TETRACHLOROBENZENE; 2,3,4-, 2,4,6- and 3,4,5-TRICHLOROPHENOL; and 1,3,5-TRICHLOROBENZENE. [R40] *PENTACHLOROBENZENE WAS METABOLIZED TO GIVE BOTH PENTACHLOROPHENOL AND A DECHLORINATION-HYDROXYLATION PRODUCT WHICH WAS IDENTIFIED AS 2,3,4,5-TETRACHLOROPHENOL IN RABBITS. [R41] *TWO MALE AND 2 FEMALE RHESUS MONKEYS ADMIN SINGLE DOSE OF 1 MG/KG BODY WT OF (14)C-PENTACHLOROBENZENE. PENTACHLOROBENZENE IS METABOLIZED MORE RAPIDLY THAN HEXACHLOROBENZENE. [R42] *... Pentachlorophenol, 2,3,4,5-tetrachlorophenol, tetrachloro-hydroquinone, and a hydroxylated chlorothio-compound /were reported/ as metabolites of pentachlorobenzene in the urine and feces of three female rats collected for 4 days, after administering a single intraperitoneal dose of 403 ug/kg. [R43] *The major metabolite /of pentachloronitrobenzene/ after single oral dosages of 2 or 91 mg/kg or chronic dosing (2 ppm in the diet for 71 days) was pentachloroaniline (... 50-60%). Lesser amt (9-12%) of pentachlorobenzene, formed presumably by reductive removal of nitro-group ... were identified. [R44] *Organochlorine compounds are widely used as pesticides and are substantial environmental pollutants and carcinogens due to their extensive environmental release. In the present study biotransformation of these pesticides was observed in the microsomal fractions and whole cells of Saccharomyces cerevisiae expressing human cytochrome P450 3A4. In both in vitro and in vivo studies, hexachlorobenzene and pentachlorobenzene were metabolised into pentachlorophenol which was further transformed into tetrachlorohydroquinone. Metabolites were identified by thin layer chromatography and 13C-NMR spectroscopy. The formation of products was observed only in the presence NADPH in microsomal fractions and no activity was observed in control microsomal fractions, or in whole cells. [R45] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Pentachlorobenzene's production and use as a starting reagent in the manufacture of the fungicide quintozene (pentachloronitrobenzene) may result in its release to the environment through various waste streams. It is a technical impurity of this pesticide and therefore, may also enter the environment as a result of the use of quintozene. Based upon a vapor pressure of 6.5X10-3 mm Hg at 25 deg C, pentachlorobenzene is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase pentachlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated atmospheric half-life of about 277 days. Pentachlorobenzene is expected to be immobile in soils based upon log Koc values in the range of 3.5-5.1 measured in soils and sediment. Volatilization of pentachlorobenzene from dry soil surfaces is not expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is expected based on the Henry's Law constant of 7.1X10-4 atm-cu m/mole at 20 deg C, but this process may be attenuated due to adsorption. Pentachlorobenzene was shown to be resistant to degradation in laboratory soil tests with half-lives of 194 and 345 days reported in duplicate experiments. In water, pentachlorobenzene is expected to adsorb to sediment or particulate matter based on its measured Koc values. This compound is expected to volatilize from water surfaces given its Henry's Law constant, but adsorption may attenuate this process. Estimated volatilization half-lives for a model river and model lake are 7 and 160 hours, respectively, when neglecting adsorption. The volatilization half-life from a model pond is about 11 months when adsorption is considered. Pentachlorobenzene may undergo photolysis in surface waters based on 41 percent photodegradation when irradiated with light greater than 290 nm in water solution after 24 hrs. Bioconcentration in aquatic organisms is very high based on BCF values in the range of 1,100 to 6,800 measured in fish. Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where pentachlorobenzene is produced or used. Exposure may also arise in occupations where the pesticide quintozene is produced and used. The general population may be exposed to pentachlorobenzene via inhalation of ambient air, ingestion of food and drinking water. (SRC) ARTS: *PHOTOLYSIS /OF HEXACHLOROBENZENE/ IN METHANOL OR HEXANE WITH LIGHT OF WAVELENGTHS GREATER THAN 260 OR 220 NM, RESPECTIVELY, WAS RAPID, AND THE ANTICIPATED PRODUCTS OF REDUCTIVE DECHLORINATION (PENTACHLOROBENZENE AND TETRACHLOROBENZENE) WERE OBTAINED IN EACH CASE. [R46] *Pentachlorobenzene has been identified in the effluent from a wastewater treatment plant in southern California. Access to water can occur by industrial discharge or from the degradation of other organochlorine compounds, such as lindane. [R6] *It has been suggested that pentachlorobenzene is a contaminant of hexachlorobenzene. It /may/ enter the food chain as a result from the use of hexachlorobenzene as a fungicide. [R47] *The Interagency Testing Committee (ITC) cited several possible sources of contamination /of air, water, soil, and food chains by chlorinated benzenes/ which include the use of chlorinated benzenes as chemical intermediates, as solvents in the manufacture of dyes, as lubricants and pesticides, and as transformer oils. /Chlorinated benzenes/ [R48] *Pentachlorobenzene's production and use as a starting reagent in the manufacture of the fungicide quintozene (pentachloronitrobenzene) may result in its release to the environment through various waste streams(1,SRC). It is a technical impurity of this pesticide and therefore, may also enter the environment as a result of the use of quintozene(SRC). [R49] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), and a log Koc value of 3.5(2) measured in soil, pentachlorobenzene is expected to be immobile in soil(SRC). Volatilization of pentachlorobenzene is expected from moist soil surfaces given its Henry's Law constant of 7.1X10-4 atm-cu m/mole(3) at 20 deg C, but adsorption may attenuate this process(SRC). Volatilization of pentachlorobenzene from dry soil surfaces is not expected based on a vapor pressure of 6.5X10-3 mm Hg at 25 deg C(4). Pentachlorobenzene was shown to be resistant to degradation in laboratory soil tests with half-lives of 194 and 345 days reported in duplicate experiments(5). [R50] *AQUATIC FATE: Based on a recommended classification scheme(1), and log Koc values in the range of 4.4-5.1(2,3) measured in sediment, pentachlorobenzene is expected to adsorb to suspended solids and sediment in water(SRC). Pentachlorobenzene is expected to volatilize from water surfaces(4,SRC) given its Henry's Law constant of 7.1X10-4 atm-cu m/mole(5) at 20 deg C, but adsorption may attenuate this process(SRC). Estimated volatilization half-lives for a model river and model lake are 7 and 180 hours, respectively when adsorption is ignored(4,SRC). The volatilization half-life from a model pond is about 11 months when adsorption is considered(6). According to a classification scheme(7), BCF values in the range of 1,100 to 6,800(8), measured in carp, suggest that bioconcentration in aquatic organisms is very high(SRC). This compound may photolyze from surface waters(SRC). Pentachlorobenzene irradiated with light greater than 290 nm in water solution resulted in 41% photodegradation after 24 hrs(9). Pentachlorobenzene was biodegraded by an acclimated anaerobic sediment slurry obtained from the Tsurumi River, Japan with a biodegradation half-life of 17 days and the following biodegradation products were detected: 1,2,3,4-tetrachlorobenzene; > 1,3,5-trichlorobenzene; > 1,2,4-trichlorobenzene; > 1,2,3-trichlorobenzene; > 1,3-dichlorobenzene; > 1,2-dichlorobenzene; > monochlorobenzene(10). [R51] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), pentachlorobenzene, which has a vapor pressure of 6.5X10-3 mm Hg at 25 deg C(2,SRC), is expected to exist in the vapor phase in the ambient atmosphere. Vapor-phase pentachlorobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 277 days(SRC) from its estimated rate constant of 5.9X10-14 cu cm/mole-sec(3). [R52] BIOD: *CHLORINATED BENZENES (INCLUDING PENTACHLOROBENZENE) WERE STABLE UNDER BOTH AEROBIC AND ANAEROBIC CONDITIONS. (36)C-LABELED CHLORINATED HYDROCARBONS WERE PREPARED AND INCUBATED WITH MIXED MICROBIAL CULTURES OBTAINED AEROBICALLY OR ANAEROBICALLY FROM ARABLE SOIL OR SEWAGE SLUDGE. PENTACHLOROBENZENE SHOWED SLIGHT DECHLORINATION (3-4%) DURING ANAEROBIC INCUBATION WITH CLOSTRIDIA AND WITH AEROBIC PSEUDOMONAS SPECIES. [R53] *A 0% theoretical BOD in sludge over a 4 week incubation period(1) suggests that biodegradation of pentachlorobenzene will be slow(SRC). Pentachlorobenzene was shown to be resistant to degradation in laboratory soil tests with half-lives of 194 and 345 days reported in duplicate experiments(2). Reductive dechlorination of pentachlorobenzene to lower chlorinated benzenes may be possible under anaerobic conditions(3,4), but there is conflicting data regarding the rates of biodegradation. A culturally enriched anaerobic microbial consortium was shown to biodegrade pentachlorobenzene with a half-life of several days, but the native anaerobic microbial population (from Lake Ketelmeer sediment) was shown to biodegrade polychlorinated benzenes only after a period of a few years(3). Pentachlorobenzene was biodegraded by an acclimated anaerobic sediment slurry obtained from the Tsurumi River, Japan with a biodegradation half-life of 17 days and the following biodegradation products were detected: 1,2,3,4-tetrachlorobenzene; > 1,3,5-trichlorobenzene; > 1,2,4-trichlorobenzene; > 1,2,3-trichlorobenzene; > 1,3-dichlorobenzene; > 1,2-dichlorobenzene; > monochlorobenzene(4). [R54] ABIO: *The rate constant for the vapor-phase reaction of pentachlorobenzene with photochemically-produced hydroxyl radicals has been estimated as 5.9X10-14 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 277 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Pentachlorobenzene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzaboe functional groups(SRC). Pentachlorobenzene absorbs light greater than 290 nm(2), therefore it has the potential to photolyze directly(SRC). Pentachlorobenzene irradiated with light greater than 290 nm in an acetonitrile-water solution resulted in 41% photodegradation(3). [R55] BIOC: *Bioconcentration factor predicted from water solubility= 1900 (calculated); Predicted from soil adsorption coefficient= 280 (calculated). Bioconcentration factor= 5000 approx (experimental). /From table/ [R56] *Bioconcentration factor in bacteria (Siderocapsa treubii): approx 16,000 [R57] *Bioconcentration factor in guppies (Poecilia reticulata): approx 260,000 (on lipid content) [R57] *BCF values of 1,400 to 6,800 were measured in carp exposed to 10 ug/l of pentachlorobenzene during an 8 week incubation period and BCF values of 1,100 to 5,100 were measured in carp exposed to 1 ug/l of pentachlorobenzene during an 8 week incubation period(1). BCF values in trout were reported as 13,000-20,000(2). According to a classification scheme(3), these BCF values suggest that bioconcentration in aquatic organisms is very high. [R58] KOC: *A Koc of 40,000 was determined for adsorption onto whole bottom sediments from a stream(1). Estimated Koc values from the literature range from 3,160(2) to 5,450(3,4). Using a recommended log Kow of 5.17(5) a Koc of 15,500 was estimated(4,SRC). Based on these Koc values, significant adsorption to soil and sediments will be expected(SRC). A Kom of 3162 has been reported(1) which corresponds to a Koc of 5,450 using a reported conversion factor of 1.724(6,SRC). [R59] *A log Koc value of 5.1 was reported for pentachlorobenzene in freshwater river sediment(1). A log Koc value of 4.6 was reported for pentachlorobenzene in sediment obtained from the Ise Bay, Japan(2). A measured log Koc value of 3.5(3) was reported in soils. According to a recommended classification scheme(4), these Koc values suggest that pentachlorobenzene is immobile in soil(SRC). [R60] *KOC= 13,000 (Calculated) /From table/ [R61] VWS: *The Henry's Law constant for pentachlorobenzene is 7.1X10-4 atm-cu m/mole(1). This value indicates that pentachlorobenzene will volatilize from water surfaces(2,SRC), but adsorption may attenuate this process(SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 7 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 160 hours(2,SRC). The volatilization half-life from a model pond is about 11 months when adsorption is considered(3). Pentachlorobenzene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is expected, but adsorption may attenuate this process(SRC). Pentachlorobenzene is not expected to volatilize from dry soil surfaces based on a vapor pressure of 6.5X10-3 mm Hg at 25 deg C(4). [R62] WATC: *A STUDY WAS CONDUCTED TO DETERMINE THE DISTRIBUTION OF SEVERAL ORGANOCHLORINES IN THE REGION OF THE RHINE-MEUSE ESTUARY. A SERIES OF SAMPLING STATIONS WAS ESTABLISHED. BOTTOM SEDIMENT, INTERSTITIAL AND SURFACE WATER, AND SESTON SAMPLES WERE COLLECTED. DISSOLVED PENTACHLOROBENZENE WAS LOWER IN THE ESTUARINE REGION. IT WAS PRIMARILY IN SOLUTION AND WAS A MAIN COMPOUND OBSERVED IN THE RIVERS. CONCENTRATIONS OF ALL COMPOUNDS WERE SALINITY DEPENDENT. THE CONCENTRATION OF PENTACHLOROBENZENE WAS 0.1 NG/L IN THE ESTUARY. [R63] *DRINKING WATER: "Old Love Canal" area, Niagara, NY, July 1978: 9 samples, 1 pos - 240 ppb(1). Three cities in the Lake Ontario vicinity, 1980 - 0.03-0.05 parts per trillion(2). [R64] *SURFACE WATER: Pentachlorobenzene was detected in 3 of 24 samples collected in 1981 from the Niagara River, at a max concn of 1 part per trillion(1). Pentachlorobenzene was detected in 104 of 104 samples collected from 1981-1983 in the Niagara River, at concns of 0.34-6.4 parts per trillion and an avg concn of 1.1 parts per trillion(2). Pentachlorobenzene was detected in Lake Huron at concns of 0.03-0.04 and Grand River, Ontario at 0-0.1 parts per trillion(3). Pentachlorobenzene was identified, not quantified, in all 5 Great Lakes(6). Pentachlorobenzene was detected in the Waal and Oude Maas Rivers, Holland at concns of 1-34 parts per trillion(4). Pentachlorobenzene was detected in the Lek River, Holland at 0-3 parts per trillion and the Meuse River, Holland at 2-4 parts per trillion(4). Pentachlorobenzene was detected in the the Rhine River, Germany at 1-200 parts per trillion in 1976(5). [R65] *SEAWATER: Pentachlorobenzene was detected in the surface water of the Rhine-Meuse estuaries, Holland at concns of less than 0.1 parts per trillion to 18 parts per trillion from 1974-1979(1). [R66] *SURFACE WATER: Pentachlorobenzene has been found in water from 100% of the 14 stations in Lake Ontario sampled in Oct 1983. The concn ranged from 0.009-0.220 ng/1 and avg concn of 0.055 ng/1(1). [R67] *DRINKING WATER: Pentachlorobenzene was detected in the drinking water of 3 Canadian cities at concns of 0.03-0.05 parts per trillion(1) and in Niagara, NY at a concn of 240 ppb(2). SURFACE WATER: Pentachlorobenzene was detected at concns of 0.031-0.036 ng/l in Lake Ontario(3). Pentachlorobenzene was detected in the Rhine River at concns of 1-200 parts per trillion(4) and identified, not quantified in all 5 great lakes(5). Pentachlorobenzene was detected in Lake Ontario at concns of 0.009-0.220 ng/l(6) and in the St. Lawrence river at a concn of 0.01 ng/l(7). RAIN/SNOW: Polychlorinated benzenes, including pentachlorobenzene, were detected at a combined concn of 60 pg/l in melted snow of the Canadian Arctic(8). [R68] EFFL: *Effluent from activated sludge waste-water treatment plants, 2 discharges into Lake Ontario and 2 into Grand River, Ontario, April to Nov 1980 - 0.5 to 1 parts per trillion, avg 0.9 parts per trillion(1). Niagara Falls, NY, dumpsites, June and November, 1979, 102nd street - 100 ppm; Bloody Run Creek (drainage ditch for Hyde Park landfill) - 10 ppm; Gill Creek (runs through industrial park with dumpsites) - not detected(2). Virginia, municipal refuse - fired steam boiler - 39 ug/cu m; Ohio, refuse-derived fuel fired power plant - not detected(3). Pentachlorobenzene was found at concn of 790, 1300, and 4800 ng/cu m in the raw gas (up-stream from the electrostatic precipitator) from three runs under different conditions of a Swedish hazardous waste incinerator which was burning chlorinated waste, mostly solvents(4). [R69] *Pentachlorobenzene was detected in the soot of combusted plastics at a concn of 218 ug/g(1). Pentachlorobenzene was detected in the leachate of a municipal waste incinerator in Germany at concns of 944.3 ng/l and 80.5 ng/l (unsolidified fly ash) and 1,096.2 ng/l and 134.5 ng/l (solidified fly ash)(2). Pentachlorobenzene was detected at concns of 0.2-0.9 ug/cu m in the flue gas of pulp and paper mills located in Finland(3) and at a concn of 0.42 ug/cu m in the effluent of a municipal waste incinerator in Germany(4). Pentachlorobenzene was detected at concns of 95 and 300 ppb in the ash of municipal waste incinerators in the US(5). Pentachlorobenzene was detected at concns of 290-800,000 ng/cu m in the effluent of a waste gasification and combustion pilot plant(6) and detected at concns of 3.66 and 6.44 ng/cu m in the effluent of a hazardous waste incinerator in Germany(7). [R70] SEDS: *SEDIMENT SAMPLES FROM THE WESTERN PORTION OF LAKE ONTARIO WERE COLLECTED IN OCTOBER 1980. THE SAMPLES WERE ANALYZED FOR CHLORINATED ORGANIC COMPOUNDS USING GC/MS. MANY OF THE CHLORINATED COMPOUNDS PREVIOUSLY FOUND TO BE LEAKING INTO THE NIAGARA RIVER FROM WASTE DISPOSAL SITES IN THE CITY OF NIAGARA FALLS WERE IDENTIFIED IN THE SEDIMENTS OF LAKE ONTARIO. THE COMPOUNDS (INCLUDING PENTACHLOROBENZENE) SHOWED A TENDENCY TO ACCUMULATE IN THE ZONES OF HIGH SEDIMENTATION IN BOTH THE NIAGARA AND MISSISSAUGA BASINS. THE AVERAGE RELATIVE CONCENTRATIONS OF TRI, TETRA, PENTA, AND HEXACHLOROBENZENES OBSERVED AT THE NIAGARA RIVER DUMP SITES WERE 25%, 100%, 45%, AND 25%, RESPECTIVELY. IN THE NIAGARA BASIN OF LAKE ONTARIO, THE CORRESPONDING PROPORTIONS WERE 72%, 100%, 48%, AND 126% (NORMALIZED TO TETRACHLOROBENZENE FOR COMPARISON). [R71] *SEDIMENTS: Pentachlorobenzene was detected in 92 % of the samples from Lake Superior (0-0.3 ppb, 0.1 ppb avg); 100 % of the samples from Lake Huron (0.2-3.0 ppb, 1 ppb avg); 100% of the samples from Lake Erie (0.3-3 ppb, 1 ppb avg); 100 % of the samples from Lake Ontario (9-320 ppb, 97 ppb avg)(1). Pentachlorobenzene was detected in sediment from Frierfjord, Norway at avg concns of 37 ppm (0-5 cm) and 23 ppm (5-10 cm)(2). Surficial sediment from the Niagara River Basin contained pentachlorobenzene at concns of 5.3-42 ppb(3). Pentachlorobenzene was detected in 92 % of the samples from Lake Ontario and the Mississuaga basins at concns of trace levels to 32 ppb(4). Pentachlorobenzene was detected in 96 % of suspended sediment samples from the Niagara River at an avg concn of 58 ppb(5). Pentachlorobenzene was detected in suspended sediement from the Rhine-Meuse estuary, Holland at concns of 3-500 ppb(6). Pentachlorobenzene was detected at a concn of 1.22 ppm in soil in Japan that had previously been treated with pentachlorobenzene(7). Pentachlorobenzene was detected at concns of 1-94 ppb in soils in Finland that had previously been treated with pentachlorobenzene(8). [R72] *The ranges and mean concn (dry wt basis) of pentachlorobenzene detected in sediments taken from the following Great Lakes areas in 1980 and 1982 were: southern Lake Huron, 0.4-0.9 ppb, 0.6 ppb avg; Lake St. Clair, 4.9-6.7 ppb, 5.8 ppb avg; western Lake Erie, 1.4-4.2 ppb, 2.9 ppb avg; central Lake Erie, 0.7-1.4 ppb, 1.0 ppb avg; and eastern Lake Erie, 0.5-1.3 ppb, 0.9 ppb avg(1). [R73] *Pentachlorobenzene was detected in the sediment of Lake Ketelmeer, Netherlands at concns of 10 and 15 ng/kg(1). Pentachlorobenzene was detected at concns of 0.3 ug/kg in the Danube and Traun Rivers in Austria(2) and at concns of 1-13 ng/g in the Scheldt estuary in the Netherlands(3). Pentachlorobenzene was identified, not quantified, in soil from Niagra, NY(4) and detected at concns of 0.3-3.1 ng/g in sediment from the St Lawrence River in Ontario, Canada(5). Pentachlorobenzene was detected at a concn of 1.22 ppm(6) and 1-94 ppb(7) in soil for which quintozene had previously been used. [R74] ATMC: *URBAN/SUBURBAN: Pentachlorobenzene was detected in 1 of 15 samples in Niagara Falls, NY at a concn of 17 ng/cu m(3). Pentachlorobenzene was detected at 4 sites in Michigan at concns of 35-69 pg/cu m(4). Pentachlorobenzene was detected at concns of 31-135 pg/cu m at Ellesmere Island, Canada(5) and concns of 100-190 pg/cu m in Bavaria, Germany(6). Pentachlorobenzene was detected in southern Ontario air at mean concns of greater than 8 pg/cu m(7). RURAL/REMOTE: Pentachlorobenzene was detected in in the Arctic at concns of 3.3-6.2 pg/cu m (4.5 pg/cu m, avg) in Sept 1980 and 7-31 ppb (18 ppb, avg) in Feb 1981(1). Pentachlorobenzene was detected in Spitzenbergen, Norway at concns of 5.1-37 pg/cu m in 1980-1981 and Lellestrom, Norway at concns of 30-78 pg/cu m in 1981(1). Pentachlorobenzene was detected in Enewetak atoll (27-39 pg/cu m, 1979), American Samoa (9 pg/cu m, 1981), New Zealand (16 pg/cu m, 1983) and the Peruvian coast (24 pg/cu m)(2). [R75] FOOD: *Pentachlorobenzene was detected in 20 of 1,500 composite foods in the US with a daily intake of of 0.3 ug in 1975 and in 12 of 1,500 composite food samples in the US with a daily intake of 0.03 ug in 1976(1). In 1976-1977 pentachlorobenzene was detected in 15 of 300 composite food samples in the US at trace concns to 0.003 ppm(2) and in 1977-1978 was detected in 22 of 240 composite food samples at concns of trace amounts to 0.005 ppm(3). Pentachlorobenzene was detected in 3 of 117 infant food samples at concns of trace amounts to 0.005 ppm and in 10 of 132 toddler food composites at concns of trace amounts to 0.010 ppm(4). Pentachlorobenzene was detected in 4 of 98 infant food samples at concns of 0.002-0.012 ppm and in 13 of 110 toddler food composites at concns of trace amounts to 0.008 ppm(5). Pentachlorobenzene has been found in the following crude seed oils: Yugoslavian corn oil (0.010 ppm), rape seed oil (0.001 ppm), sunflower oil (0.005 ppm), walnut oil (0.005 ppm), and poppy oil (0.005 ppm); US soybean oil (trace concn); Chinese peanut oil (0.005 ppm) and sesame seed oil (trace concn); Turkish hazelnut oil (0.001 ppm)(6). [R76] *Pentachlorobenzene was detected in 2 percent of all food products sampled in the US between 1982-1984 and 1 percent of food products sampled between 1984-1986(1). Pentachlorobenzene was detected in 15 of 230 ready to eat foods in the US at an avg concn of 0.0012 ug/g(2). [R77] *... in peanut butter samples: avg: 16 ppb, range: 1.8-62 ppb ... [R57] *Pentachlorobenzene was detected in 15 of 20 composite samples of fats and oils at a range of trace levels to 0.003 ppm(1), 1 of 20 composite samples of meat, fish and poultry at trace levels, 1 of 20 composite samples of grain and cereal at a concn of 0.002 ppm and in 1 of 20 composite samples of potatoes at 0.008 ppm obtained from 20 US cities(1). Pentachlorobenzene was detected in 9 of 20 composite samples of fats and oils at a concn range of trace levels to 0.019 ppm and in 2 of 20 composite samples of sugars and sugar adjuncts at trace levels and 0.001 ppm in 20 US cities(2). Pentachlorobenzene was detected in 21 of 27 composite samples of fats and oils at a range of trace levels to 0.004 ppm, in 1 of 27 composite samples of root vegetables at trace levels and in 2 of 27 composite samples of sugars and sugar adjuncts at trace levels collected in 27 US cities(3). [R78] PFAC: FISH/SEAFOOD CONCENTRATIONS: *THE AMOUNTS OF FIVE ORGANOCHLORINE COMPOUNDS IN THE BODIES AND BODY FAT OF COD, SHRIMP, FLOUNDER, MUSSEL, SNAIL, SAITHE, BARNACLE, BRISTLE WORM, BRITTLE STAR, COMMON GOBY, HERMIT CRAB, SEA STAR, WERE DETERMINED IN AT LEAST ONE OF TWO DIFFERENT FJORDS IN NORWAY. THE LEVELS OF PENTACHLOROBENZENE IN THE FAT OF DIFFERENT SPECIES WAS ABOUT 10 TIMES AS HIGH AS IN SEDIMENTS. RESULTS WITH PENTACHLOROBENZENE SUPPORT THE IDEA THAT DIRECT UPTAKE FROM WATER VIA RESPIRATORY ORGANS IS DUE TO BODY CONTACT WITH CONTAMINANTS AND IS THE MOST IMPORTANT ROUTE OF ENTRY. [R79] *Pentachlorobenzene was detected in trout from Lake Superior (0.7 ppb), Lake Huron (2 ppb), Lake Ontario (8 and 16 ppb) and Lake Erie (0.6 ppb)(1). Pentachlorobenzene was detected in 78 of 300 fish from the Lahn River, Germany at trace levels(2). Fish caught in Slovenia, Yugoslavia in 1978 had the following pentachlorobenzene concns: trout, 6 ppb; nase, 10-75 ppb; whiting, 90 ppb; pilchard, 9 ppb(3). Various invertabrates from the Dutch Waden Sea had avg pentachlorobenzene concns of 0.1-10 ppb(4). Pentachlorobenzene was detected in fish and crustaceans from Frierfjord, Norway at avg concns of: 6 ppb (cod); 9 ppb (saithe), 9 ppb (sea star); 45 ppb (hermit crab)(5). Pentachlorobenzene was identified not quantified in 5 of 28 fish caught in major watersheds near the Great Lakes in 1979(6) and 4 of 10 rivers in the US in 1976(7). [R80] *Pentachlorobenzene was detected in composite samples of sedentary fish from 8 of 16 sites at Lake Superior and Lake Huron tributaries sampled in the fall of 1983(5). The concn on a fat basis of chemical found in the composite sample of carp from the Flint River, MI was 8.8/8.9 ppb (duplicate analysis results for the same sample), 110 ppb in the composite sample from Saginaw Bay, MI, 11 ppb in the sample from the Ausable River, 21 and 16 ppb in the samples from two Chippewa River sites, 73 ppb in one of the samples from Saginaw Bay, and 48/49 ppb and 120 in the samples from two Saginaw River sites, MI(5). [R81] *... In fat phase of the following fish from the Frierfjord (Norway), April 1975-Sept 1976: cod, whiting, plaice, eel, sprot: avg: 3.87 parts per million , range: 0.4-10 parts per million. [R57] *Fish accumulated ... /pentachlorobenzene/ in an area polluted by industrial effluents. [R82] *Pentachlorobenzene residues were identified, not quantified, in fish and mussels caught in the coastal waters of Norway(1). Pentachlorobenzene was detected in trout from Lake Superior (0.7 ppb), Lake Huron (2 ppb), Lake Ontario (16 ppb) and Lake Erie (0.6 ppb)(2). Cod and hermit crabs caught in Norwegian coastal waters had pentachlorobenzene residues at concns of 6 ppb and 13 ppb respectively(3). [R83] ANIMAL CONCENTRATIONS: *PENTACHLOROBENZENE WAS FOUND IN MOST SAMPLES TAKEN FROM EGGS OF HERRING GULLS (LARUS ARGENTATUS) AND DOUBLE-CRESTED CORMORANTS (PHALACROCORAX AURITUS). THE EGGS FROM THE MARITIME PROVINCES HAD LESS CHLORINATED BENZENES THAN SIMILAR SAMPLES FROM LAKE ONTARIO. [R84] *Pentachlorobenzene was detected at mean concns of 2 ng/g (males) and 3 ng/g (females) in the blubber of beluga whales in the St Lawrence River estuary(1). Pentachlorobenzene was detected in the eggs of seabirds in Canada at concns of 0.011 and 0.007 mg/kg(2) and the eggs of robins at concns of 0-0.9 ug/g(3). Pentachlorobenzene was detected in the eggs of herring gulls in Ontario, Canada at concns of 6-95 ng/g(4) and various bird eggs in Hamilton Harbor, Canada at concns of 0.002-0.02 mg/kg(5). Pentachlorobenzene was detected in 37 percent of the pheasants sampled from Kansas at concns of trace levels to 6 ppb(6). [R85] MILK: *A survey of human milk from the general population of Canada found pentachlorobenzene residues in 17 percent of the samples at an avg concn of 2 ppb(1). Chlorobenzenes (including pentachlorobenzene) were detected in human milk at trace concns to 25 ug/kg(2). Pentachlorobenzene was detected in whole milk (0.05 ng/g) and milk fat (1.5 ng/g) in Canada(3). [R86] *THE MEAN LEVELS OF CHLOROBENZENES (INCLUDING PENTACHLOROBENZENE) IN HUMAN MILK AND ADIPOSE TISSUE WERE DETERMINED AND RANGED FROM TRACES TO 25 UG/KG FOR HUMAN MILK AND FROM NOT DETECTED TO 146 UG/KG FOR ADIPOSE TISSUE. THE DISTRIBUTION OF DIFFERENT CHLOROBENZENE ISOMERS IN ADIPOSE TISSUE AND MILK WAS DIFFERENT. [R32] RTEX: *Occupational exposure to pentachlorobenzene may be through inhalation and dermal contact with this compound at workplaces where pentachlorobenzene is produced or used. Exposure may also arise in occupations where the pesticide quintozene is produced and used. The general population may be exposed to pentachlorobenzene via inhalation of ambient air, ingestion of food and drinking water. (SRC) AVDI: *AIR INTAKE: (Assume 17 ng/cu m(1) 340 ng. WATER INTAKE: (Assume 0.03-0.05 parts per trillion(2) 0.06-0.10 ng. FOOD INTAKE: not found. [R87] *The AVDI of pentachlorobenzene in the US from 1984-1986 was 0.003 ug/kg (6-11 months old), 0.0014 ug/kg (2 years old), 0.0003 ug/kg (14-16 years old, female), 0.0005 ug/kg (14-16 years old, male), 0.0002 ug/kg (25-30 years old, female), 0.0004 ug/kg (25-30 years old, male), 0.0002 ug/kg (60-65 years old, female) and 0.0002 ug/kg (60-65 years old, male)(1). [R88] BODY: *Slovenia Province, Yugoslavia: human adipose tissue, 1979-80, 15 samples, not detected to 3 ppb, 1.2 ppb avg (fat basis), human milk, 1981, 12 samples, 18 ppb (fat basis)(1); Human milk, 6 samples, 0-3.4 ppb, 2.0 ppb avg, 2 whole milk(2). Human adipose autopsy samples from six Ontario, Canada, municipalities were analyzed for the presence of pentachlorobenzene(3). The chemical was detected (1.9 ppb detection limit), not quantified, in the adipose tissue of 4% of 21 autopsy patients from Cornwall, 3% of 37 patients in London, 12% of 17 patients from St. Catherines, and 14% of 36 patients from Windsor(3). Pentachlorobenzene was not detected in the tissue of 7 patients from Toronto or 23 patients from Welland(4). [R89] *Pentachlorobenzene /was found/ at /a concentration of/ 0.009 ppm in samples of human adipose tissue in Japan. [R90] *A survey of human milk from the general and indigenous (Canadian Indian and Inuit mothers) population of Canada found pentachlorobenzene residues in 17% of the 18 indigenous population samples at an avg concn of positive samples of 2 ppb (milkfat basis) and trace levels (whole milk basis) and in 97% of the general population samples (number of samples not reported) at an avg concn of positive samples of 3 ppb (milkfat basis) and 0.1 ppb (whole milk basis)(1). [R91] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 6 ug/l [R92] +(FL) FLORIDA 5.6 ug/l [R92] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Chlorinated benzenes/ [R93] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R94] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Pentachlorobenzene is included on this list. [R95] RCRA: *U183; As stipulated in 40 CFR 261.33, when pentachlorobenzene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R96] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 5517: Analyte: pentachlorobenzene; Matrix: air; Sampler: filter and solid sorbent tube (PTFE fiber mat + Amberlite XAD-2, 100 mg/50 mg); Flow rate: 0.01 to 0.2 l/min; Vol: min: 3 l, max: 12 l; Sample stability: no significant losses after 13 days at room temp. /Polychlorobenzenes/ [R97] *THE DEVELOPMENT OF A PERSONAL SAMPLING AND ANALYTICAL METHOD FOR DETERMINATION OF PENTACHLOROBENZENE IN AIR IS DESCRIBED. THE PERSONAL AIR SAMPLER CONSISTED OF A TEFLON FILTER IN A STAINLESS STEEL HOLDER AND A SOLID SORBENT TUBE CONTAINING AMBERLITE XAD-2. THE POOLED RELATIVE STANDARD DEVIATION FOR THE DETERMINATION OF THE COMPOUND BY THE OVERALL SAMPLING AND ANALYTICAL METHOD WAS 9.8% FOR PENTACHLOROBENZENE. [R98] *Air Samples; ... An air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. The absorbent is desorbed with carbon tetrachloride and analyzed by GC using a photoionization detector. /Chlorobenzenes/ [R99] ALAB: *NIOSH 5517-2: Analyte: pentachlorobenzene; Matrix: air; Technique: gas chromatography, (63)Ni electron capture detector; Desorption: 2 ml hexane; 30 min ultrasonic agitation; Injection vol: 2 ul; Temp: injection: 220 deg C; detector: 300 deg C; column: 160 deg C; Gases carrier: nitrogen, 30 ml/min, purge: nitrogen, 90 ml/min; Column: 2.0 m X 2 mm ID nickel, 10% Carbowax 20M-TPA on 80/100 mesh Chromosorb W AW; Calibration: standard soln of analytes in hexane; Range: 0.02 to 500 ug/sample; Precision (relative standard deviation): 0.057; Estimated limit of detection: 0.001 ug/ml in hexane; Interferences: Using chromatographic conditions given above, 1,2,3,5-tetrachlorobenzene coelutes with 1,2,4,5-tetrachlorobenzene. /Polychlorobenzenes/ [R100] *HIGH RESOLUTION GAS CHROMATOGRAPHY OF CHLORINATED BENZENES WAS STUDIED. SATISFACTORY RESOLUTION OF 12 BENZENES, INCLUDING PENTACHLOROBENZENE, WAS OBTAINED. [R101] *VAPOR-PHASE ORGANICS (INCLUDING PENTACHLOROBENZENE) IN AMBIENT AIR NEAR INDUSTRIAL COMPLEXES AND CHEMICAL WASTE DISPOSAL SITES WERE CHARACTERIZED BY CAPILLARY GAS CHROMATOGRAPHY/MASS SPECTROMETRY/COMPUTER. [R102] *ORGANIC COMPOUNDS PRESENT AT TRACE LEVELS (INCLUDING PENTACHLOROBENZENE) WERE EXTRACTED FROM FLY ASH SAMPLES COLLECTED FROM MUNICIPAL INCINERATORS IN JAPAN, CANADA, AND THE NETHERLANDS. SAMPLES WERE EXTRACTED FOR 12 HOURS IN A SOXHLET APPARATUS WITH 200 ML OF BENZENE. THE EXTRACT WAS CONCENTRATED TO 100 UL AND ANALYZED BY GC/MS. [R103] *RESIDUES OF POLYCHLORINATED COMPOUNDS INCLUDING PENTACHLOROBENZENE HAVE BEEN QUANTITATED BY MULTIPLE-ION-DETECTION GAS CHROMATOGRAPHY-MASS SPECTROMETRY IN GREAT LAKES FISH COLLECTED BETWEEN 1974 AND 1980. [R104] *Air Samples: ... An air sampling tube packed with two sections of Amberlite XAD-2 resin separated by a silanized glass wool plug, to collect the chlorobenzenes /is used/. The adsorbent is desorbed with carbon tetrachloride and analyzed by GC using a photoionization detector. When using this method the minimum detection limits for mono, di, tri, tetra and pentachlorobenzenes is 15, 20, 30, 35 and 45 ppb (v/v), respectively. [R99] *Negative ion chemical ionization MS is evaluated as a method for qualitative and quantitative determination of polyhalogenated aromatic hydrocarbons, including pentachlorobenzene. Each cmpd or mixture of cmpd is analyzed by glass capillary gas chromatography-mass spectrometry by using different modes of chemical ionization in the mass spectrometer. [R105] CLAB: *THE MEAN LEVELS OF CHLOROBENZENES (INCLUDING PENTACHLOROBENZENE) IN HUMAN MILK AND ADIPOSE TISSUE WERE DETERMINED BY GLASS CAPILLARY GAS CHROMATOGRAPHY AND RANGED FROM TRACES TO 25 MUG/KG FOR HUMAN MILK AND FROM NOT DETECTED TO 146 MUG/KG FOR ADIPOSE TISSUE. THE DISTRIBUTION OF DIFFERENT CHLOROBENZENE ISOMERS IN ADIPOSE TISSUE AND MILK WAS DIFFERENT. [R32] *CHLOROBENZENES (INDUSTRIAL PRODUCTS), MONOCHLOROBENZENE THROUGH HEXACHLOROBENZENE, @ PPB LEVELS IN HUMAN URINE AND BLOOD SAMPLES WERE DETERMINED BY GAS CHROMATOGRAPHY WITH PHOTOIONIZATION DETECTION. /CHLOROBENZENES/ [R106] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Dichlorobenzenes (1980) EPA 440/5-80-039 USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes (1980) EPA 440/5-80-028 USEPA; Health Assessment Document: Chlorinated Benzenes (1985) EPA-600/8-84-015 DHHS/NTP; NTP Report on the Toxicity Studies of Pentachlorobenzene in F344/N Rats and B6C3F1 Mice (Feed Studies) NTP TOX 6 (1991) NIH Pub No. 91-3125 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 812 (1979) R2: Van, H. (ed.). OPD Chyemical Buyer's Directory 1989. 76th ed, New York, NY: Schnell Publishing Co., Inc. 1989. 460 R3: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R5: SRI R6: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 692 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996. R8: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-674 R9: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 16 R10: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-170 R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R13: Resendes J et al; Environ Sci Technol 26: 2381-87 (1988) R14: Oliver BG; Chemosphere 14: 1086-1106 (1985) R15: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R16: 40 CFR 240-280, 300-306, 702-799 (7/1/97) R17: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-15 (1981) EPA 68-03-3025 R18: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Pentachlorobenzene (608-93-5) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R19: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R20: GOERZ G ET AL; ARCH DERMATOL RES 263 (2): 189-96 (1978) R21: LINDER R ET AL; GOVT REPORTS ANNOUNCEMENTS AND INDEX (GRA and I) 8 (1983) R22: DEBETS F MH ET AL; TOXICOLOGY 19 (3): 185-96 (1981) R23: Courtney KD et al; Teratology Study of Pentachlorobenzene in Mice. (1977) EPA-600/J-77-123 R24: USEPA; Ambient Water Quality Criteria Doc: Chlorinated Benzenes p.C-81-82 (1980) EPA 440/5-80-028 R25: USEPA; Health Assessment Document: Chlorinated Benzenes p.11-5 (1985) EPA 600/8-84-015 R26: USEPA; Health Assessment Document: Chlorinated Benzenes p.11-26 (1985) EPA 600/8-84-015 R27: Chaisuksant Y et al; Ecotoxicology and Environmental Safety 39 (2): 120-30 (1998) R28: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 1488 R29: USEPA; Health Assessment Document: Chlorinated Benzenes p.6-6 (1985) EPA 600/8-84-015 R30: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 948 R31: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.1 R32: JAN J; BULL ENVIRON CONTAM TOXICOL 30 (5): 595-9 (1983) R33: ROZMAN K ET AL; BULL ENVIRON CONTAM TOXICOL 22 (1-2): 190-5 (1979) R34: MES J ET AL; BULL ENVIRON CONTAM TOXICOL 28 (1): 97-104 (1982) R35: Borzelleca JF et al; Toxicol Appl Pharmacol 18: 522-34 (1971) R36: USEPA; Health Assessment Document: Chlorinated Benzenes p.11-5-7 (1985) EPA 600/8-84-015 R37: USEPA; Health Assessment Document: Chlorinated Benzenes p.11-2 (1985) EPA 600/8-84-015 R38: INGEBRIGTSEN K ET AL; XENOBIOTICA 11 (11): 795-800 (1981) R39: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-2 R40: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.148 R41: KOHLI J ET AL; CAN J BIOCHEM 54 (3): 203-8 (1976) R42: ROZMAN K ET AL; TOXICOL APPL PHARMACOL 45 (1): 283 (1978) R43: USEPA; Health Assessment Document: Chlorinated Benzenes p.11-7 (1985) EPA 600/8-84-015 R44: The Royal Society of Chemistry. Foreign Compound Metabolism in Mammals. Volume 6: A Review of the Literature Published during 1978 and 1979. London: The Royal Society of Chemistry, 1981. 328 R45: Mehmood Z et al; Chemosphere 33 (4): 759-69 (1996) R46: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3642 R47: Greve PA; Meded Fac Landbouwaret Rijksuniv Gent 38: 775-84 (1973) R48: 51 FR 11729 (4/7/88) R49: (1) Booth G; Ullmann's Encycl Indust Chem 5th ed Deerfield,FL: VCH Publ A17: 393 (1991) R50: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Sabljic A et al; Chemosphere 31: 4489-4514 (1995) (3) Oliver BG; Chemosphere 14: 1087-1106 (1985) (4) Resendes J et al; Environ Sci Technol 26: 2381-87 (1988) (5) Beck J, Hansen KE; Pestic Sci 5: 41-48 (1974) R51: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Cornelissen G et al; Environ Toxicol Chem 16: 1351-57 (1997) (3) Masunga S et al; J Environ Sci Health A31: 887-903 (1996) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (5) Oliver BG; Chemosphere 14: 1087-1106 (1985) (6) USEPA; EXAMS II Computer Simulation (1987) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (9) Choudry GG, Hutzinger O; Environ Sci Technol 18: 235-41 (1984) (10) Masunga S et al; Wat Sci Technol 33: 173-80 (1996) R52: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Resendes J et al; Environ Sci Technol 26: 2381-87 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R53: HAIDER K; COMM EUR COMMUNITIES (REP) EUR(EUR 6388) ENVIRON RES PROGRAMME 200 (1980) R54: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Beck J, Hansen KE; Pestic Sci 5: 41-48 (1974)(3) Beurskens JEM et al; Environ Sci Technol 28: 701-706 (1994) (4) Masunga S et al; Wat Sci Technol 33: 173-80 (1996) R55: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Choudry GG et al; Chemosphere 12: 487-92 (1983) (3) Choudry GG, Hutzinger O; Environ Sci Technol 18: 235-41 (1984) R56: Kenaga EE; Ecotoxicol Environ Safety 4: 30 (1980) R57: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1457 R58: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Oliver BG, Niimi AJ; Environ Sci Technol 17: 287-91 (1983) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R59: (1) Karickhoff SW, Morris KR; Environ Sci Technol 19: 51-6 (1985) (2) Sabljic A; J Agric Food Chem 32: 243-6 (1984) (3) Kenaga EE; Ecotoxicol Environ Safety 4: 26-38 (1980) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-3, 4-9 (1982) (5) Hansch C, Leo AJ; Medchem Project Pomona College Claremont CA Issue No. 26 (1985) (6) Sabljic A; J Agric Food Chem 32: 243-6 (1984) R60: (1) Cornelissen G et al; Environ Toxicol Chem 16: 1351-57 (1997) (2) Masunga S et al; J Environ Sci Health A31: 887-903 (1996) (3) Sabljic A et al; Chemosphere 31: 4489-4514 (1995) (4) Swann RL et al; Res Rev 85: 23 (1983) R61: Kenaga EE; Ecotoxicology and Environmental Safety 4: 30 (1980) R62: (1) Oliver BG; Chemosphere 14: 1087-1106 (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) (4) Resendes J et al; Environ Sci Technol 26: 2381-87 (1988) R63: DUINKER JC, HILLEBRAND MTJ; NETH J SEA RES 13 (2): 256-81 (1979) R64: (1) Barkley J et al; Biomed Mass Spect 7: 139-47 (180) (2) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-6 (1982) R65: (1) Kuntz KW; Toxic Contaminants in the Niagara River, 1975-1982. Environment Canada Tech Bull No.134 (1984) (2) Oliver BG, Nicol KD; Sci Total Environ 39: 57-70 (1984) (3) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-6 (1982) (4) Duinker JC, Hillebrand MTJ; Neth J Sea Res 13: 256-81 (1979) (5) Fisher A, Slemrova J; Vom Wasser 51: 33-46 (1978) (6) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem. Volume I - Summary: Report to the Great Lakes Water Quality Board, Windsor Ontario, Canada pp. 195 (1983) R66: (1) Kuntz KW; Toxic Contaminants in the Niagara River, 1975-1982. Environment Canada Tech Bull no 134 (1984) R67: (1) Biberhofer J, Stevens RJJ; Sci Ser - Inland Waters/Lands Dir 159: pp. 11 (1987) R68: (1) Oliver BG, Nico KD; Environ Sci Technol 16: 532-36 (1982) (2) Barkley J et al; Biomed Mass Spect 7: 139-47 (1980) (3) Halfon E, Poulton D; Water Poll Res J Canada 27: 751-72 (1992) (4) Fisher A, Slemrova J; Vom Wasser 51: 33-46 (1978) (5) Great Lakes Water Quality Board, Inventory of Chemical Substance Identified in Great Lakes Ecosystem Vol 1:Report to the Great Lakes Water Quality Board. Windsor, Ontario (1983) (6) Biberhofer J, Stevens RJJ; Sci Ser Inland/WatersLands Dir 159 pp. 11 (1987) (7) Germain A, Langlois C; Water Pollut Res J Can 23: 602-14 (1988) (8) Welch HE et al; Environ Sci Technol 25: 280-86 (1991) R69: (1) Oliver BG, Nicol KP; Environ Sci Technol 16: 532-6 (1982) (2) Elder VA et al; Environ Sci Technol 15: 1237-43 (1981) (3) Tiernan TO et al; Environ Health Perspec 59: 145-58 (1985) (4) Oberg T et al; Chemosphere 16: 2451-65 (1987) R70: (1) Blankenship A et al; Chemosphere 28: 183-96 (1994) (2) Fischer J et al; Chemosphere 25: 543-52 (1992) (3) Halonen I et al; Chemosphere 27: 1253-68 (1993) (4) Jay K, Stieglitz L; Chemosphere 30:1249-60 (1995) (5) Shane BS et al; Arch Environ Contam Toxicol 19: 665-73 (1990) (6) Wienecke J et al; Chemosphere 25: 437-47 (1992) (7) Wienecke J et al; Chemosphere 30: 907-13 (1995) R71: KAMINSKY R ET AL; J GREAT LAKES RE 9 (2): 183-9 (1983) R72: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-6 (1982) (2) Bjeih JE, Brevick EM; Arch Environ Contam Toxicol 9: 743-50 (1980) (3) Oliver BG, Charlton MN; Environ Sci technol 18: 903-8 (1984) (4) Kaminsky R et al; J Great Lakes 9: 183-9 (1983) (5) Kuntz KW; Toxic contaminants in the Niagara River, 1975-1982. Environment Canada Tech Bull no 134 (1984) (6) Duinker JC, Hillebrand MTJ; Netherlands J Sea Res 13: 256-81 (1979) (7) Ohsawa K et al; J Pestic Sci 9: 339-45 (1984) (8) Rautapaa J et al; Am Agric Fenn 16: 277-82 (1977) R73: (1) Oliver BG, Bourbonniere RA; J Great Lakes Res 11: 366-72 (1985) R74: (1) Beurskens JEM et al; Water Sci Technol 29: 77-85 (1994) (2) Chovanec A et al; Chemosphere 29: 2117-33 (1997) (3) Vanzoest R, Vaneck GTM; Sci Total Environ 103: 57-71 (1991) (4) Ding WH et al; Chemosphere 25: 675-90 (1992) (5) Kaiser KLE et al; Sci Total Environ 97/98: 495-506 (1990) (6) Ohsawa K et al; J Pestic Sci 9: 339-45 (1984) (7) Rautappa J et al; Am Agric Fenn 16: 277-82 (1977) R75: (1) Oehme M, Mano S; Fresenius Z Anal Chem 319: 141-6 (1984) (2) Giam CS, Atlas E; Amer Chem Soc 25: 5-7 (1985) (3) Pellizzari ED et al; Formulation of preliminary assessment of halogenated organic compounds in man and environmental media p. 469 USEPA-560/13-79-006 (1979) (4) Hermanson MH et al; Atom Environ 31: 567-73 (1997) (5) Patton GW et al; J Geophys Res 96: 10867-77 (1991) (6) Kaupp H, Umlauf G; Atmos Environ 26A: 2259-67 (1992) (7) Hoff RM et al; Environ Sci Technol 26: 266-75 (1992) R76: (1) Duggan RE et al; Pesticide Residue levels in foods in the United States from July 1, 1969 to June 30, 1976. FDA and AOAC (1983) (2) Johnson RD et al; J Assoc Off Anal Chem 67: 154-66 (1984) (3) Podrebarac DS; J Assoc Off Anal Chem 67: 176-85 (1984) (4) Johnson RD et al; J Assoc Off Anal Chem 67: 145-54 (1984) (5) Podrebarac DS; J Assoc Off Anal Chem 67: 166-75 (1984) (6) Peattie ME et al; Sci Tot Environ 34: 73-86 (1984) R77: (1) Gunderson EL; J AOAC Int 78: 910-921 (1995) (2) Paul TG, Woodson BL; J AOAC Int 78: 614-31 (1995) R78: (1) Gartrell MJ et al; J Assoc Off Anal Chem 68: 862-73 (1985) (2) Gartrell MJ et al; J Assoc Off Anal Chem 68: 1184-97 (1985) (3) Gartrell MJ et al; J Assoc Off Anal Chem 69: 146-61 (1986) R79: BJERK JE, BREVIK EM; ARCH ENVIRON CONTAM TOXICOL 9 (6): 743-50 (1980) R80: (1) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-6 (1982) (2) Schuler W et al; Bull Environ Contam Toxicol 34: 608-16 (1985) (3) Jan J, Malnersic S; Bull Environ Contam Toxicol 24: 824-7 (1980) (4) Eder G et al; Netherlands J Sea Res 15: 78-87 (1981) (5) Bjerk JE, Brevik EM; Arch Environ Contam Toxicol 9: 743-50 (1980) (6) Kuehl DW et al; Environ Internat 9: 293-9 (1983) (7) Veith GD et al; Pest Monit J 13: 1-11 (1979) R81: (1) Jaffe R et al; J Great Lakes Res 11: 156-62 (1985) R82: Murty, A.S. Toxicity of Pesticides to Fish. Volumes I, II. Boca Raton, FL: CRC Press Inc., 1986.,p. V1 45 R83: (1) Knutzen J, Oehme M; 19: Chemosphere 1897-1909 (1989) (2) Oliver BG, Nico KD; Environ Sci Technol 16: 532-36 (1982) (3) Bjerk JE, Brevik EM; Arch Environ Contam Toxicol 9: 743-50 (1980) R84: MATHESON RA F ET AL; SURVEILL REP EPS (CAN ENVIRON PROT SERV) 37 PAGES (1980) ISS EPS-5-AR-80-1 R85: (1) Muir DCG et al; Environ Pollut 93: 1219-34 (1996) (2) Elliot JE et al; I Persistent Pollut Mar Ecosystem. Walker CH, Livingstone DR Eds. Pergamon Press Oxford, UK (1992) (3) Herbert CE et al; Arch Environ Contam Toxicol 26: 356-66 (1994) (4) Ewins PJ et al; J Great Lakes Res 18: 316-30 (1992) (5) Weseloh DV et al; J Great Lakes Res 21:121-37 (1995) (6) Layher WG et al; Bull Environ Contam Toxicol 34: 317-22 (1985) R86: (1) Davies D, Mes J; Bull Environ Contam Toxicol 39: 743-50 (1987) (2) Jan J Bull Environ Contam Toxicol 30: 595-99 (1983) (3) Newsome WH et al; Chemosphere 30: 2143-53 (1995) R87: (1) Pellizzari ED et al; Formulation of Preliminary Assessment of Halogenated Organic Compounds in Man and Environmental Media p. 469 USEPA-560/13-79-006 (1979) (2) Oliver BG, Nicol KD; Environ Sci Technol 16: 532-6 (1982) R88: (1) Gunderson EL; J AOAC Int 78: 910-921 (1995) R89: (1) Jan J; Bull Environ Contam Toxicol 30: 595-9 (1983) (2) Cone MV et al; Chemicals Identified in Human Breast Milk: A Literature Search USEPA-560/583009 (1983) (3) Williams DT et al; J Assoc Off Anal Chem 71: 410-4 (1988) (4) Davies D, Mes J; Bull Environ Contam Toxicol 39: 743-50 (1987) R90: Morita, M; Ecotox Env Saf 1: 1-6 (1977) R91: (1) Davies D, Mes J; Bull Environ Contam Toxicol 39: 743-50 (1987) R92: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R93: 40 CFR 401.15 (7/1/88) R94: 40 CFR 302.4 (7/1/97) R95: 40 CFR 716.120 (7/1/97) R96: 40 CFR 261.33 (7/1/97) R97: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. V2 5517 R98: GRAHAM MM, DILLON HK; GOVT REPORTS ANNOUNCEMENTS AND INDEX (GRA and I) 6 (1983) R99: USEPA; Health Assessment Document: Chlorinated Benzenes p.3-17 (1985) EPA 600/8-84-015 R100: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R101: MILLER LJ ET AL; J ASSOC OFF ANAL CHEM 66 (3): 677-83 (1983) R102: PELLIZZARI ED; ENVIRON SCI TECHNOL 16 (11): 781-5 (1982) R103: EICEMAN GA ET AL; ANAL CHEM 51 (14): 2343-50 (1979) R104: KUEHL DW; GOVT REPORTS ANNOUNCEMENTS AND INDEX (GRA and I) 15 (1983) R105: Crow FW et al; Anal Chem 53 (4): 619-25 (1981) R106: LANGHORST ML ET AL; ANAL CHEM 51 (12): 2018-25 (1979) RS: 69 Record 191 of 1119 in HSDB (through 2003/06) AN: 2870 UD: 200302 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HEXACHLORO-1,3-BUTADIENE- SY: *C-46-; *1,3-BUTADIENE,-HEXACHLORO-; *1,3-BUTADIENE,-1,1,2,3,4,4-HEXACHLORO-; *DOLEN-PUR-; *GP-40-66:120; *HCBD-; *HEXACHLOR-1,3-BUTADIEN- (CZECH); *HEXACHLOROBUTADIENE-; *1,1,2,3,4,4-HEXACHLORO-1,3-BUTADIENE-; *1,3-HEXACHLOROBUTADIENE-; *PERCHLOROBUTADIENE- RN: 87-68-3 MF: *C4-Cl6 SHPN: UN 2279; Hexachlorobutadiene IMO 6.1; Hexachlorobutadiene HAZN: U128; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. D003; A waste containing hexachlorobutadiene may (or may not) be characterized a hazardous waste following testing for the reactivity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY-PRODUCT OF TETRACHLOROETHYLENE, TRICHLOROETHYLENE, AND CARBON TETRACHLORIDE MANUFACTURING PROCESSES. [R1] *Hexachlorobutadiene is produced chiefly as a by-product in the manufacture of chlorinated solvents and related products, in which it occurs in the heavy fractions. [R2] OMIN: *Hexachlorobutadiene was first prepared in 1877 by chlorination of hexyl iodide. ... Until about 1974, it was recovered as a by-product in the production of tetrachloroethylene. ... Since 1974, all hexachlorobutadiene used commercially in the USA has been imported from the Federal Republic of Germany. ... It is believed that all hexachlorobutadiene now produced as a by-product in the USA is disposed of. ... No data on its production in Europe were available; and no evidence has been found that hexachlorobutadiene has ever been produced or imported in Japan. [R3] *Information available in 1994 indicated that hexachlorobutadiene was produced only in Austria. [R4] USE: *Solvent for elastomers; heat-transfer liq; transformer and hydraulic fluid; wash liquor for removing C4 and higher hydrocarbons. [R5] *CHEM INT FOR FLUORINATED LUBRICANTS, RUBBER COMPOUNDS; FLUID FOR GYROSCOPES [R1] */Used in/ the USSR ... as a fumigant against Phylloxera on grapes. It is also used as a fumigant in vineyards in France, Italy, Greece, Spain and Argentina. [R6] *Ultraviolet irradiation on hexachlorobutadiene monomer has been used to photopolymerize the pin-hole free film. [R7] *The largest use of hexachlorobutadiene in USA in 1975 was for recovery of 'snift' (chlorine-containing) gas in chlorine plants. /Former use/ [R6] CPAT: *No information was available on the quantities used in USA. [R3] PRIE: U.S. PRODUCTION: *In 1975, total USA production of hexachlorobutadiene (HCBD) was reported as 8.0 million pounds (3.6 million kg)/year. [R8] *(1978) AT LEAST 4.54X10+7 G [R1] *(1982) PROBABLY GREATER THAN 2.27X10+6 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear, colorless liquid [R5] ODOR: *Mild, turpentine-like odor. [R9, 158] BP: *215 deg C @ 760 mm Hg [R10] MP: *-21 deg C [R10] MW: *260.76 [R10] DEN: *1.556 @ 25 deg C [R10] OWPC: *log Kow = 4.78 [R11] SOL: *Sol in alc, ether [R10]; *In water, 3.20 mg/l @ 25 deg C [R12] SPEC: *Index of refraction: 1.5542 @ 20 deg C/D [R10]; *MAX ABSORPTION (HEPTANE): 253 NM (LOG E= 3.7) [R13]; *IR: u SAD 3229 (Sadtler Research Laboratories Prism Collection) [R14]; *UV: SAD 956 (Sadtler Research Laboratories Spectral Collection) [R14]; *MS: NIST 12582 (NIST/EPA/MSDC Mass Spectral Database 1990 version) [R14]; *13C NMR: JJ 43 (Johnson and Jankowski, Carbon-13 NMR Spectra, John Wiley and Sons, New York) [R14]; *Raman: SAD 314 (Sadtler Research Laboratories Spectral Collection) [R14] VAPD: *8.99 (AIR= 1) [R15] VAP: *0.22 mm Hg @ 25 deg C [R16] VISC: *2.447 centipoise at 37.7 deg C, 1.479 centistokes; 1.131 centipoise at 98.8 deg C, 0.724 centistokes. [R5] OCPP: *Compatible with numerous resins. [R5] *Percent in saturated air: 0.037 at 25 deg C; 1 mg/l is equiv to 936 ppm and 1 ppm is equiv to 10.7 mg/cu m at 25 deg C, 760 torr. [R17, 4240] *Henry's Law constant = 1.03X10-2 atm-cu m/mole @ 20 deg C [R18] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R19] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R19] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R19] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R19] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R19] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R19] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R19] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R19] FPOT: *Combustible when exposed to heat or flame; can react vigorously with oxidizing materials. [R20] NFPA: *Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R21] *Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R21] *Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R21] AUTO: *1130 DEG F (610 DEG C) [R21] FIRP: *To fight fire, use dry chemical, CO2, alcohol foam, water spray, fog, mist. [R20] EXPL: *Reacts with bromine perchlorate to form an explosive product. [R20] REAC: *Oxidizers. [R9, 158] *Can react vigorously with with oxidizing materials. ... Reacts with bromine perchlorate to form an explosive product. [R20] DCMP: *When heated to decomposition it emits very toxic fumes of /chlorine/ Cl-. [R20] ODRT: *12 mg/cu m (odor low) 12 mg/cu m (odor high) [R22] SERI: *A skin and eye irritant. [R20] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R9, 159] *Wear appropriate eye protection to prevent eye contact. [R9, 159] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R9, 159] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R9, 159] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R9, 159] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R9, 159] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. [R9, 159] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R9, 159] *Contact lenses should not be worn when working with this chemical. [R9, 159] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R23] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R24] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R25] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U128, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R26, (7/1/89)] *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R26, (7/1/2000)] *Incineration: Spray into a furnace with afterburner and alkali scrubber. Incineration will become easier by mixing with a more flammable solvent. [R27] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. Hexachlorobutadiene is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R28] *The following wastewater treatment technologies have been investigated for hexachlorobutadiene: Concentration process: Resin adsorption. [R29] *The following wastewater treatment technologies have been investigated for hexachlorobutadiene: Concentration process: stripping. [R30] *The following wastewater treatment technologies have been investigated for hexachlorobutadiene: Concentration process: Solvent extraction. [R31] *The following wastewater treatment technologies have been investigated for hexachlorobutadiene: Concentration process: Activated carbon. [R32] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Observation of renal neoplasms in male and female rats in one study. HUMAN CARCINOGENICITY DATA: None. [R33] *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R34] *A2. A2= Suspected human carcinogen, skin (1982) [R35] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with sterile dressings after decontamination ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R36] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of myocardial irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R36] MEDS: *Renal Function Tests /include/ ... Urine Albumin ... Urinary Beta-2-Microglobulin and/or Retinal Binding Protein (RBP) ... Urinary Alpha and Pi Isoenzymes of Glutathione S-Transferase ... Urinary Enzyme N-Acetylglucosaminidase ... /and/ Routine Urinalysis. /Hexachlorobutadiene/ [R37, 748] *Liver Function Tests: Biochemical tests - Enzymes that reflect cholestasis: alkaline phosphatase (AP), 5'-nucleotidase (5'-NT) and leucine aminopeptidase (LAP); Enzymes that detect direct hepatic damage: aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGTP). Clearance tests - indocyanine green, antipyrine test and serum bile acids. /Hexachlorobutadiene/ [R37, 749] *... Suggested that urinary excretion of copropophyrims be incl as part of a medical surveillance program on employees. [R17, 4246] *Studies on the mechanisms by which organohalogenated chemicals can be activated by renal tissue and cause toxicity were reviewed and discussed. Two major pathways of metabolism have been suggested which call for mediation either by cytochrome p450 or by glutathione conjugation. As an example of cytochrome p450 mediated activation, chloroform was discussed. As examples of glutathione conjugation followed by activation, the dihaloethanes and hexachloro-1,3-butadiene were discussed. Several biological tests have been developed which can be used to detect chronic nephrotoxicity as chronic low level exposures can occur in the work place. Many case histories existed in the literature of accidental or deliberate exposure to chlorinated compounds, resulting in acute toxicity. Screening tests for chronic renal injury included urine analysis, blood analyses, and functional tests. Studies which have been conducted of workers exposed chronically to organohalogenated solvents have indicated central nervous system depression, liver injury and, occasionally, acute renal failure. Owing mainly to the marked functional compensatory ability of the kidney, chronic exposure at the work place may be difficult to detect. The following combination of tests may be useful for detecting such dysfunction in occupationally exposed workers: examination of urine with reagent strips for the presence of glucosuria and proteinuria, and quantitative determination of at least two proteins, one of the high molecular weight for glomerular function and one of the low molecular weight for tubular function. Some value has also come from the determination of the lysosomal enzyme N-acetyl-beta-D-glucosaminidase in urine. [R38] HTOX: *A GROUP OF 205 VINEYARD WORKERS WHO WERE EXPOSED SEASONALLY TO HEXACHLOROBUTADIENE AND POLYCHLOROBUTANE-80 (0.8-30 MG/CU M AND 0.12-6.7 MG/CU M, RESPECTIVELY, IN AIR OVER THE FUMIGATED ZONES) SHOWED MULTIPLE TOXIC EFFECTS CONTRIBUTING TO THE DEVELOPMENT OF HYPOTENSION, CARDIAC DISEASE, CHRONIC BRONCHITIS, DISTURBANCES OF NERVOUS FUNCTION AND CHRONIC HEPATITIS. [R39] *In two cytogenetic studies of occupationally exposed workers form the same plant engaged in the production of hexachlorobutadiene, an incr in the frequency of chromosomal aberrations in peripheral blood lymphocytes was observed. The workers were exposed to hexachlorobutadiene concn that ranged form 1.6 to 16.9 mg/cu m. The Task Group noted that exposure concn were determined by the factory and that the frequency of chromosome aberrations was not assoc with the /srp: length/ of employment. [R40] NTOX: *LETHALITY OF HCBD FOLLOWING SINGLE ORAL DOSES INDICATED THAT YOUNG RATS ARE MORE SENSITIVE THAN ADULTS. [R41, 1991.736] *GROUPS OF 39 OR 40 MALE AND FEMALE SPF SPRAGUE-DAWLEY RATS, 8-WK OLD ... WERE FED DIETS CONTAINING HEXACHLOROBUTADIENE (99% PURE) AT CONCN PROVIDING INTAKES OF 0.2, 2.0 OR 20 MG/KG BODY WT/DAY. NINETY MALES AND 90 FEMALES SERVED AS UNTREATED CONTROLS. ALL MALE SURVIVORS WERE KILLED AFTER 22 MO, ALL FEMALES AFTER 24 MO OF TEST DIETS ... IN MALES, TUMOR INCIDENCES WERE 39/90 CONTROLS, 24/40 LOW-DOSE, 13/40 MID-DOSE AND 15/39 HIGH-DOSE. IN FEMALES, TUMOR INCIDENCES WERE 82/90 CONTROLS, 35/40 LOW-DOSE, 37/40 MID-DOSE AND 39/40 HIGH-DOSE. A STATISTICALLY SIGNIFICANT INCR (P < 0.05) OF KIDNEY TUMORS WAS OBSERVED IN MALE AND FEMALE RATS FED THE HIGHEST DOSE LEVEL ... SIX OF 39 HIGH-DOSE MALES HAD ADENOCARCINOMAS (SOME BILATERAL); 2 DEVELOPED ADENOMAS ONLY (ANOTHER HAD AN ADENOMA AS WELL AS ADENOCARCINOMAS); and 1 MALE HAD AN UNDIFFERENTIATED CARCINOMA IN ONE KIDNEY AND AN ADENOCARCINOMA WITH METASTASES TO THE LUNG IN THE OTHER KIDNEY. ONE CONTROL MALE HAD AN ADENOMA; 3 FEMALES HAD KIDNEY ADENOMAS (UNI- AND BILATERAL), 1 DEVELOPED AN ADENOCARCINOMA, 1 HAD AN ADENOCARCINOMA WITH METASTASES TO LUNG AND 1 DEVELOPED AN UNDIFFERENTIATED UNILATERAL CARCINOMA. [R42] *IN A 30 DAY PRELIMINARY DIETARY STUDY /IN RATS/, 30, 65, and 100 MG HCBD/KG/DAY RESULTED IN RENAL TOXICITY ... INCR KIDNEY TO BODY WT RATIO AND RENAL TUBULAR DEGENERATION, NECROSIS AND REGENERATION. OTHER ADVERSE EFFECTS OBSERVED INCL DECR FOOD CONSUMPTION AND BODY WT GAIN AT 10, 30, 65, and 100 MG/KG/DAY, MINIMAL HEPATOCELLULAR SWELLING AT 100 MG/KG/DAY AND HEMOCONCENTRATION AT 10, 30, 65 and 100 MG/KG/DAY. [R41, 1991.736] *... SHORT-TERM REPEATED INHALATION STUDIES USING GROUPS OF 4 MALE AND 4 FEMALE RATS /WERE CONDUCTED/ ... 250 PPM: TWO 4-HR EXPOSURES: EYE AND NOSE IRRITATION, RESP DIFFICULTY, FEMALES AFFECTED MORE THAN MALES ... DEGENERATION OF MIDDLE RENAL PROXIMAL TUBULES AND OF ADRENAL CORTEX. 100 PPM: TWELVE 6-HR EXPOSURES: EYE AND NOSE IRRITATION, RESPIRATORY DIFFICULTY, POOR CONDITION, WT LOSS, SLIGHT ANEMIA IN FEMALES ... KIDNEYS PALE AND ENLARGED, ADRENALS ENLARGED, DEGENERATION OF RENAL CORTICAL TUBULES WITH EPITHELIAL REGENERATION. 25 PPM: FIFTEEN 6-HR EXPOSURES: POOR CONDITION, DIMINISHED WT GAIN IN FEMALES, RESP DIFFICULTY ... DAMAGE TO RENAL PROXIMAL TUBULES. [R41, 1991.736] *THE DOSAGE CAUSING DEATH BY DERMAL ABSORPTION IS IN THE SAME RANGE AS BY ORAL ADMIN. ... FOUR TO 7 HR EXPOSURES TO 133-500 PPM CAUSED DEATH OF SOME OR ALL OF RATS SO EXPOSED. ALL RATS SURVIVED 161 PPM FOR 0.88 HR OR 34 PPM FOR 3.3 HR. MOST GUINEA PIGS AND CATS DIED SUBSEQUENT TO INHALATION EXPOSURE OF 161 PPM FOR 0.88 HR OR 34 PPM FOR 7.5 HR. [R41, 1991.736] *RABBITS WERE DERMALLY EXPOSED TO PURE HEXACHLOROBUTADIENE (0.25, 0.50, 0.75 and 1.00 ML/KG) DURING 8 HR; SOME DIED WITHIN 24 HR. HEXACHLOROBUTADIENE INDUCED IN SITU CUTANEOUS NECROSIS AND SYSTEMIC DAMAGE (FATTY LIVER DEGENERATION AND EPITHELIAL NECROTIZING NEPHRITIS). [R43] *TWO GROUPS OF MALE A/ST MICE, 6-8 WK OF AGE, WERE GIVEN THRICE WEEKLY IP INJECTIONS OF 4 OR 8 MG/KG BODY WT HEXACHLOROBUTADIENE IN TRICAPRYLIN FOR A TOTAL OF 12-13 INJECTIONS (TOTAL DOSES, 52 and 96 MG/KG BODY WT). ALL SURVIVING MICE (19 and 14 ANIMALS) WERE KILLED 24 WK AFTER THE FIRST INJECTION AND EXAMINED FOR LUNG TUMORS. THE INCIDENCE OF LUNG TUMORS PER MOUSE WAS NOT INCR COMPARED WITH THAT IN THE TRICAPRYLIN INJECTED CONTROLS. [R42] *ALL NEWBORN RATS FROM MOTHERS THAT RECEIVED A SINGLE SC DOSE OF 20 MG/KG BODY WT HEXACHLOROBUTADIENE BEFORE MATING DIED DURING THE NEXT 3 MO, COMPARED WITH ONLY 21.3% IN A CONTROL GROUP. [R44] *ADULT MALE AND FEMALE JAPANESE QUAILS WERE FED DIETS CONTAINING 0.3, 3, 10 OR 30 MG/KG DIET HEXACHLOROBUTADIENE FOR 90 DAYS. THESE DOSE LEVELS HAD NO EFFECT ON BODY WT, DEMEANOR, FOOD CONSUMPTION, EGG PRODUCTION, PERCENT FERTILITY AND HATCHABILITY OF EGGS, SURVIVAL OF HATCHED CHICKS OR EGGSHELL THICKNESS. [R44] *IN RATS GIVEN DAILY DOSES OF 0, 0.4, 1.0, 2.5, 6.3 and 15.6 MG OF HEXACHLORO-1,3-BUTADIENE PER KG BY GAVAGE FOR 13 WK, NO EFFECT LEVELS OF 1.0 and 2.5 MG/KG WERE ESTABLISHED FOR FEMALES AND MALES, RESPECTIVELY. INHIBITION OF GROWTH OCCURRED IN BOTH SEXES AT THE 2 HIGHEST DOSES AND DEGENERATION OF PROXIMAL RENAL TUBULES OCCURRED AT DOSES OF 2.5 and 6.3 MG/KG OR MORE IN FEMALES AND MALES, RESPECTIVELY. URINE-CONCENTRATING ABILITY WAS SIGNIFICANTLY REDUCED IN FEMALES AT DOSES OF 2.5 MG/KG OR MORE AND IN MALES AT 15 MG/KG. EXCEPT FOR DECREASED BODY WEIGHTS AT BIRTH AND WEANING, NO EFFECTS ON FERTILITY OR PROGENY WERE FOUND. [R45] *THE ADMIN OF HEXACHLORO-1,3-BUTADIENE (HCBD) IP AT 200 MG/KG IN RATS CAUSED NECROSIS OF PARS RECTA OF PROXIMAL TUBULES SITUATED IN THE OUTER STRIP OF OUTER MEDULLA OF THE RAT KIDNEY. ULTRASTRUCTURAL CHANGES WERE SEEN AS EARLY AS 1 HR AFTER HCBD (300 MG/KG, IP) ALTHOUGH NECROSIS WAS NOT MARKED UNTIL 8 HR. MITOCHONDRIAL SWELLING WAS SEEN 1-4 HR AFTER DOSING IN THE S1 AND S2 SEGMENTS OF THE PROXIMAL TUBULE. BY 8 HR, THE MAJOR PATHOLOGICAL CHANGES WERE LARGELY CONFINED TO THE S3 SEGMENT AND CONSISTED OF LOSS OF BRUSH BORDER, MITOCHONDRIAL SWELLING, AND CELLULAR NECROSIS. [R46] *A SINGLE DOSE OF 50 MG/KG HEXACHLORO-1,3-BUTADIENE (HCBD) IP IN ADULT ALDERLEY PARK FEMALE RATS PRODUCED MARKED RENAL TUBULAR NECROSIS AND INCREASED PLASMA UREA BY 24 HR. YOUNG MALE RATS WERE ALSO MORE SUSCEPTIBLE TO HCBD-INDUCED NEPHROTOXICITY; A DOSE OF 25 MG/KG PRODUCED MARKED TUBULAR NECROSIS AND INCREASED PLASMA UREA IN 21-DAY OLD RATS, WHILE A DOSE OF 200 MG/KG WAS REQUIRED TO PRODUCE A SIMILAR RESPONSE IN ADULT MALES. HCBD WAS MORE TOXIC TO YOUNG MALE RATS (21 and 29 DAYS OLD, LD50 57 and 96 MG/KG, RESPECTIVELY) THAN TO ADULT MALES (7 WK OLD, LD50 360 MG/KG). RENAL NONPROTEIN SULFHYDRYL CONTENT WAS DECREASED IN FEMALE BUT NOT IN MALE RATS 4 HR AFTER HCBD ADMIN. FISCHER 344 RATS WERE SLIGHTLY MORE SUSCEPTIBLE AND LONG EVANS RATS SLIGHTLY LESS SUSCEPTIBLE THAN THE ALDERLEY PARK STRAIN TO HCBD-INDUCED NEPHROTOXICITY, ALTHOUGH THE DIFFERENCES WERE NOT AS MARKED AS THOSE SEEN WITH AGE AND SEX. [R47] *AFTER SINGLE IP DOSE /200 OR 300 MG/ OF HEXACHLORO-1,3-BUTADIENE (HCBD) IN RATS, THERE WAS A RAPID, DOSE-RELATED INCREASE IN LIVER WATER WHICH REACHED A MAXIMUM BETWEEN 16 and 24 HR AFTER HCBD ADMIN AND THEN RETURNED TO CONTROL VALUES BY DAY 4. AN INCREASE IN SODIUM AND POTASSIUM IONS WAS NOTED WHEN RELATED TO DRY WEIGHT OF THE LIVER; HOWEVER, ACTUAL CONCN OF BOTH CATIONS IN TOTAL LIVER WATER DID NOT ALTER. THE TOTAL LIVER DNA, PROTEIN, OR CYTOCHROME P450 CONCN, DID NOT CHANGE, AT A TIME WHEN THERE WAS A MAXIMAL INCREASE IN LIVER WATER. THERE WAS A RAPID DECREASE IN LIVER NP-SH (NONPROTEIN-SULFHYDRYL), WHICH REACHED A NADIR (50% OF CONTROL) 8 HR AFTER HCBD ADMIN, THEN INCREASED TO 150% OF NORMAL ON DAY 5, AND RETURNED TO NORMAL BY DAY 10. THE LIVER APPEARED ESSENTIALLY NORMAL, APART FROM A SLIGHT FATTY CHANGE. ULTRASTRUCTURAL CHANGES WERE, HOWEVER, OBSERVED 8 HR AFTER DOSING, WHEN PERIPORTAL HEPATOCYTES CONTAINED OCCASIONAL SWOLLEN MITOCHONDRIA, WHEREAS CENTRILOBULAR HEPATOCYTES APPEARED NORMAL. [R48] *MALE RATS TREATED WITH HEXACHLORO-1,3-BUTADIENE (HCBD) (200-400 MG/KG, IP) SHOWED A TIME-DEPENDENT LOSS OF RENAL CYTOCHROME P450 WHICH WAS ASSOCIATED WITH NECROSIS OF THE S3 SEGMENT OF PROXIMAL TUBULE. IN MICE AN ALMOST COMPLETE LOSS OF RENAL CYTOCHROME P450 WAS OBSERVED 24 HR AFTER HCBD ADMIN (50 MG/KG, IP) WHICH WAS PARALLELED BY A LOSS OF MONOOXYGENASE ACTIVITY. THIS IS ASSOCIATED WITH THE MORE EXTENSIVE LESION IN THIS SPECIES. [R49] *THE ESTIMATED MAXIMUM ACCEPTABLE TOXICANT CONCENTRATION (MATC) FOR FATHEAD MINNOWS EXPOSED TO HEXACHLORO-1,3-BUTADIENE WAS BETWEEN 6.5 and 13 UG/L. TOXIC EFFECTS ON EARLY DEVELOPMENTAL STAGES DEMONSTRATED THAT LARVAL GROWTH AND SURVIVAL WERE THE MOST SENSITIVE INDICATORS OF TOXIC STRESS. [R50] */IN RATS/ ... DATA INDICATE CLEAR-CUT DOSE-RESPONSE RELATIONSHIP FOR HCBD-INDUCED TOXICITY AFFECTING PRIMARILY KIDNEY. HCBD-INDUCED RENAL NEOPLASMS OCCURRED ONLY AT A DOSE LEVEL HIGHER THAN THAT CAUSING DISCERNIBLE RENAL INJURY. ... SINCE A SIGNIFICANT CARCINOGENIC RESPONSE RESULTED FROM INGESTION OF LESS THAN 50 MG/KG/DAY, HCBD CAN BE CONSIDERED A RODENT CARCINOGEN OF INTERMEDIATE POTENCY. ACCORDINGLY, HCBD HAS BEEN GIVEN THE A2 DESIGNATION, SUSPECTED HUMAN CARCINOGEN. [R41, 1991.737] *Hexachloro-1,3-butadiene was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of HCB that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of hexachloro-1,3-butadiene tested by injection (15 ppm) or feeding (15 ppm) were negative in this assay. [R51] *The nephrotoxicity of hexachloro-1,3-butadiene (HCBD), its GSH conjugate, and its N-acetylcysteine conjugate (HCBD-NAC) were compared in male and female Alderley Park rats. Rats, 6-8 wk of age, were given a single ip injection of HCBD or its conjugates and killed 24 hr later. Nephrotoxicity was assessed by histologic examination and plasma urea. All 3 conjugates produced an elevation of plasma urea and proximal renal tubular necrosis with a similar localization in the pars recta as seen with HCBD. All the conjugates were more nephrotoxic than HCBD itself. HCBD was approx 4 times more toxic to female rats than to males. This sex difference is also shown by all the HCBD metabolites. [R52] *Administration of a single ip dose of hexachloro-1,3-butadiene (HCBD) to adult male or female Alderley Park mice at 96 umol/kg produced renal tubular necrosis of the pars convoluta and pars recta of the proximal tubule by 24 hr. Renal damage was also observed biochemically by the reduced accumulation of the organic anion (p-aminohippurate) and organic cation (tetraethylammonium) by renal slices and by an elevated plasma urea. The toxicity of HCBD to adult Alderley Park mice was similiar for males and females. Young male mice (21 and 28 days old) were slightly more susceptible to HCBD-induced nephrotoxicity than adult (7-wk-old) males. A strain difference in susceptibility to HCBD-induced renal damage was observed, the BALB/c strain being slightly more sensitive than C57BL/10J, C3H, DBA/2J, and Aderley Park strains. This strain difference was reflected in the lethality of HCBD to mice. Prior administration of the monooxygenase inducers, phenobarbital or beta-napthoflavone, or the monooxygenase inhibitor, piperonyl butoxide, did not alter the extent of renal damage produced by HCBD in male Aderley Park mice. However, HCBD produced a marked decrease in kidney but not liver nonprotein sulfhydryl content in this strain of mouse, suggesting the formation of glutathione conjugates in the kidney. Administration of the glutathione or N-acetylcysteine conjugates of HCBD produced a marked renal tubular necrosis similar to that seen with HCBD. The mechanism of HCBD-induced nephrotoxicity in the mouse may involve nonoxidative metabolism of HCBD in the kidney and the cysteine conjugates formed are further metabolized to a nephrotoxic agent. [R53] *Hexachloro-1,3-butadiene (HCBD), its glutathione conjugate (HCBD-GSH), cysteine conjugate produce (HCBD-CYS), and mercapturic acid derivative (HCBD-NAC) all produce acute necrosis of the pars recta of the proximal renal tubule in the rat. Previous studies have shown that radiolabel from administered HCBD appears to concentrate in the pars recta region. Renal uptake of radioactivity from mercapturic acid derivative was studied in rats by giving a single ip injection of the chemical and measuring its concentration in plasma and renal cortex 4 hr and later. Cortex/plasma ratios (C/P) or mercapturic acid derivative were 4.35 (+ or -) 0.21 (8 animals) at a dose of 64 mmol/kg and 10.4 (+ or -) 0.55 (5) at a dose of 16 mmol/kg. These ratios were greater than that of inulin (C/P inulin = 1.5 (+ or - ) 0.2 (4)). Thus cortical mercapturic acid derivative content was filtration alone. Prior administration of probenecid (500 mmol/kg), a competitive inhibitor of organic acid transport, to animals receiving 16 or 64 mmol/kg of mercapturic acid derivative reduced the C/P to 1.03 (+ or -) 0.09 (5) and 0.81 (+ or -) 0.05(80), respectively. Administration of probenecid in increasing doses (100, 200, 300 and 400 mmol/kg) to animals receiving 64 mmol/kg mercapturic acid derivative resulted in decreases of C/P (2.59, 2.29, 1.35, and 0.84, respectively), suggesting a competitive inhibition of cortical mercapturic acid derivative uptake. The extent of covalently bound radioactivity from 64 mmol/kg mercapturic acid derivative was significantly greater in the renal cortex (1.11 (+ or -) 0.2 nmol eq/mg protein) than in the liver (0.19 < 0.01 nmol eq/mg protein). Prior administration of probenecid (500 mmol/kg) reduced the renal cortical concentration of mercapturic acid derivative to 0.25 (+ or -) 0.02 nmol eq/mg protein. Increasing doses of probenecid resulted in a progressive decrease in renal cortical covalent binding. When treatment with probenecid led to renal cortical concentrations of less than 120 nmol eq mercapturic acid derivative/g and an amount of covalently bound material less than 0.4 nmol eq/mg protein the animals were completely protected against the nephrotoxicity, as assessed by plasma urea and histopathological examination 24 hr after dosing. Prior administration of probenecid (500 mmol/kg) also protected rats against the nephrotoxicity by HCBD (192 mmol/kg), glutathione conjugate (47 mmol/kg), and cysteine conjugate (36 mmol/kg). It is suggested that the renal cortical accumulation and selective proximal tubular toxicity to HCBD and its conjugates is related to a carrier-mediated transport system. [R54] *The cysteine conjugates of the nephrotoxins hexachlorobutadiene (HCBD), tetrafluoroethylene (TFE) and hexafluoropropene (HFP), together with those of trichloroethylene and perchloroethylene, were prepd and a relation determine between their structures and their nephrotoxicity and mutagenicity in vitro. All of the conjugates had a marked effect on the uptake of both the organic anion p-aminohippuric acid and the cation tetraethylammonium bromide (TEA) into rat kidney slices to a toxic species which interferes with ion transport. This observation in consistent with the known nephrotoxicity of HCBD, tetrafluoroethylene, and hexafluoropropene in vivo. Each of the conjugates was metabolized by rat kidney slices and by semipurified rat kidney beta-lyase to pyruvate NH3, and an unidentified reactive metabolite. When semipurified beta-lyase was used stoichiometric amounts of pyruvate and NH3 were produced. Although all of the conjugates were activated by beta-lyase and had a similar effect on ion transport their mutagenicity differed markedly. The conjugates of HCBD, trichloroethylene, and perchloroethylene were mutagenic in the Ames bacterial mutation assay when activated by rat kidney S9. Metabolic cofactors were not required suggesting that activation was due to the enzyme beta-lyase. ... With a limited number of cysteine conjugates a clear distinction was identified between the conjugates of chloroalkenes which were both nephrotoxic and mutagenic and the conjugates of fluoroalkenes which were not mutagenic. The mutagenicity of the cysteine conjugates of HCBD is consistent with the known renal carcinogenicity of this chemical. [R55] *SINGLE IP INJECTION OF HEXACHLORO-1,3-BUTADIENE (HCBD) DECREASED HEPATIC AND RENAL NON-PROTEIN SH (NPS) CONCENTRATIONS IN MICE IN A DOSE-RELATED MANNER. SMALL NON-PROTEIN SH LOSSES WERE PRODUCED IN LUNG, TESTIS AND STOMACH BUT ONLY AT HIGH DOSES. HEXACHLORO-1,3-BUTADIENE DEPLETED RENAL NON-PROTEIN SH IN MICE ONLY (NOT RATS), ALTHOUGH HCBD WAS NEPHROTOXIC IN RATS AND MICE. [R56] *Urine was collected for up to 48 hr after dosing and was analyzed by (1)H NMR spectroscopy (400 MHz) and conventional biochemical methods to provide biochemical fingerprints of urine in various site-specific nephrotoxic states. Hexachlorobutadiene and HgCl2 produced severe glycosuria and transient enzymuria. (1)H NMR urinalysis revealed aminoaciduria, glycosuria, and lactic aciduria after exposure to all proximal tubular toxins except cisplatin, whereas papillary insult resulted in early elevations in urinary trimethylamine N-oxide and dimethylamine, together with later elevations in urinary acetate succinate, and N,N-dimethylglycine (after propyleneimine). Trimethylamine N-oxide and dimethylamine are suggested as novel markers of site-specific renal papillary injury in the rat. [R57] *Cysteine conjugate beta-lyase (beta-lyase) was purified to electrophoretic homogeneity from the kidney cytosol of male Wistar rats. The highly purified enzyme exhibited amonomeric molecular weight of 50,000 Da and was active in the alpha-beta elimination of cysteine conjugates including S-(1,2-dichlorovinyl)-L-cysteine, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, and S-(2-benzothiazolyl)-L-cysteine, particularly toward S-(1,2,-dichlorovinyl)-L-cysteine and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine. The purified enzyme also exhibited glutamine transaminase K activity with phenylalanine and alpha-keto-gamma-methiolbutyrate as substrates. An antibody was raised to the purified rat protein in sheep and the crude immune serum affinity purified, yielding a specific antibody that recognized only the beta-lyase protein in whole kidney homogenates. Immunocytochemical studies on rat kidney sections stained with the purified antibody revealed that the cytosolic beta-lyase enzyme was mainly localized in the pars recta of the proximal tubule in untreated rats. This localization is coincident with the site-specific kidney necrosis produced by hexachloro-1,3-butadiene. These results indicate that the tissue localization of beta-lyase in the proximal tubule plays an important role in determining the specific nephrotoxicity produced by halogenated alkenes such as hexachloro-1,3-butadiene. [R58] *The teratogenic potential of hexachloro-1,3-butadiene was studied in rats. Pregnant Sprague-Dawley rats inhaled 0, 2, 5, 10, or 15 ppm hexachloro-1,3-butadiene 6 hr/day from day six to 20 of gestation. The dams were monitored for clinical signs of toxicity. Body weight was monitored. The dams were killed on gestational day 21. The uterine horns were removed and opened and the numbers of implantations and resorption sites and live and dead fetuses were determined. The live fetuses were weighed, sexed, and examined for malformations. Hexachloro-1,3-butadiene at 5 and 15 ppm significantly reduced maternal weight gain. The 2 and 10 ppm exposures caused slight, nonsignificant reductions of maternal body weight gain. No other signs of toxicity were seen. The 15 ppm exposure caused a significant reduction in fetal body weight. The incidence of fetal, external, viceral, and skeletal changes was similar in fetuses from hexachloro-1,3-butadiene treated and control dams. The authors conclude that exposing pregnant rats at concentrations high enough to cause maternal toxicity is neither embryotoxic nor teratogenic, but is slightly fetotoxic. [R59] *S-(1,2,3,4,4-Pentachloro-1,3-butadienyl)-L-cysteine has been identified as the penultimate cmpd responsible for hexachlorobutadiene-induced nephrotoxicity. The primary goal of these studies was to determine the mechanism of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine induced toxicity in rabbit renal proximal tubules by examining the early changes in tubular physiology. S-(1,2,3,4,4-Pentachloro-1,3-butadienyl)-L-cysteine (2-500 uM) induced a specific sequence of toxic events. Following 15 min of exposure, 200 uM S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine increased basal (25%) and ouabain-insensitive (78%) respiration. This was followed by a decrease in basal (46%), nystatin-stimulated (54%), and ouabain-insensitive (21%) respiration and a decrease in glutathione content (79%). Finally, there was a decrease in cell viability as measured by a decrease in LDH retention at 60 min. Direct probing of mitochondrial function revealed that the initial increase in respiration resulted from the uncoupling of oxidative phosphorylation, while the late changes in respiration appeared to result from gross mitochondrial damage characterized by inhibited state 3 respiration, inhibited cytochrome c-cytochrome oxidae, and inhibited electron transport. Studies utilizing tubules with decreased glutathione content revealed that glutathione plays little if any role in the early events of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine induced toxicity. These results suggest that S-(1,2,3,4,4-pentachloro-1,3- butadienyl)-L-cysteine induced mitochondrial dysfunction may initiate the renal proximal tubule injury. [R60] *The covalent binding of hexachlorobutdiene to nuclear DNA and mitochondrial DNA was studied in an attempt to elucidate a possible mechanism of hexachlorobutadiene nephrocarcinogenesis in mice. Female NMRI-mice were exposed to 30 mg/kg hexachlorobutadiene 12 hr prior to their death via stomach tube. Livers and kidneys were pooled from 12 mice. A low level of binding of hexachlorobutadiene metabolites to nuclear DNA was noted from kidney with a covalent binding index of 27. From the liver, nuclear DNA did not retain any significant binding. Higher binding of metabolites occurred to mitochondrial DNA with the covalent binding index with liver mitochondrial DNA being 500 and for kidney mitochondrial DNA, 7500. The presence of three compounds, which may represent DNA bases altered by hexachlorobutadiene metabolites, was demonstrated on enzymatic hydrolysis followed by high pressure liquid chromatographic fractionation of mitochondrial DNA from mouse kidney. The authors conclude that the binding of hexachlorobutadiene metabolites to DNA constituents in-vivo suggest that genotoxic mechanisms are operative in initiating hexachlorobutadiene nephrocarcinogenesis. [R61] *Proximal tubular damage caused by hexachlorobutadiene and papillary damage caused by BEA were distinguished both by conventional urinalysis (volume and specific gravity) and by measurement of the two urinary enzymes. Alkaline phosphatase and glucose were markedly and transiently elevated in proximal tubular damage and N-acetyl-beta- glucosaminidase showed a sustained elevation in papillary damage. It is concluded that both selective urinary enzymes and the molecular weight pattern of urinary proteins can be used to provide diagnostic information about the possible site of renal damage. [R62] *... Following single exposures to HCBD vapors ... some or all of the rats exposed for 4 to 7 hr at 133 to 500 ppm died. All rats survived 161 ppm for 0.88 hr or 34 ppm for 3.3 hr. Most guinea pigs and cats died subsequent to inhalation of 161 ppm for 0.88 hr or 34 ppm for 7.5 hr. [R41, 1991.736] *Rats were exposed to 250 ppm for 4 hr and 100, 25, 10, or 5 ppm for 6 hr. Fifteen exposures to 5 or 10 ppm resulted in no observed toxic effect except for retarded weight gain at 10 ppm. Fifteen exposures to 25 ppm, two exposures to 100 ppm, and two exposures to 250 ppm resulted in respiratory irritation and injury as well as rather pronounced affects on the renal tubules. The adrenals showed injury at 100 and 250 ppm. [R17, 4242] *Groups of 21 male Wistar rats, six weeks of age, were given 0.1% N-nitrosoethylhydroxyethylamine (NEHEA) in the drinking water for two weeks and then 0.1% hexachlorobutadiene (purity, > 99%) in the diet for 30 weeks. Three other groups received either hexachlorobutadiene or NEHEA according to the same regimen or basal diet for 32 weeks. The rate of survival was 100%. The incidence of renal tubular tumors in the group given NEHEA plus hexachlorobutadiene (15/21) was greater than that in rats given NEHEA alone (5/10), and the incidence of preneoplastic renal tubular hyperplasia was also increased (21/21 versus 4/10). [R63] NTOX: *Following oral administration of a nephrotoxic dose (200 mg/kg) of hexachloro-1,3-butadiene (HCBD) to male rats, the principal route of excretion was biliary, 17-20% of the dose being eliminated on each of the first 2 days. Fecal excretion was < 5% of the dose/day, suggesting enterohepatic recirculation of biliary metabolites. Urinary excretion was small, not exceeding 3.5% of the dose during any 24 hr period. The major biliary metabolite was a direct conjugate between glutathione and HCBD itself. The cysteinylglycine conjugate of HCBD was also found in bile. Biliary metabolites of HCBD were reabsorbed and excreted via the kidneys. The glutathione conjugate, its mercapturic acid derivative and bile containing HCBD metabolites were all nephrotoxic when dosed orally to rats. In common with HCBD, these metabolites caused localized damage to the kidney with minimal effects in the liver. Rats fitted with a biliary cannula were completely protected from kidney damage when dosed with HCBD, demonstrating that hepatic metabolites were solely responsible for the nephrotoxicity of this compound. The hepatic glutathione conjugate of HCBD was degraded to its equivalent cysteine conjugate which was cleaved by the renal cytosolic enzyme beta-lyase to give a toxic thiol which caused localized kidney damage. A urinary sulfenic acid metabolite of HCBD was identified which was consistent with this hypothesis. The mode of activation of HCBD conjugates in the kidney was probably analogous to that proposed for S-(1,2-dichlorovinyl)-L-cysteine. [R64] *S-1, 2-dichlorovinylcysteine, S-1, 2,2-trichlorovinylcysteine, and S-1, 1,2,3,4,4-pentachloropropenylcysteine were mutagenic in three strains of Salmonella typhimurium (TA100, TA2638 and TA98) in the Ames-test without addition of mammalian subcellular fractions; their mutagenicity was decreased by the addition of AOAA to preincubation mixture. S-3-chloropropenylcysteine was not mutagenic in any of the strains of bacteria tested. These results indicate that beta-lyase plays a key role in the metabolism and mutagenicity of haloalkenylcysteines when tested in S. typhimurium systems. The demonstrated formation in mammals of the mutagen S-1, 2-dichlorovinylcysteine, S-1, 2,2-trichlorovinylcysteine, and S-1, 1,2,3,4,4-pentachloropropenylcysteine biotransformation of trichloroethylene, tetrachloroethylene and hexachlorobutadiene may provide a molecular explanation for the nephrocarcinogenicity of these compounds. [R65] NTXV: *LD50 Guinea pig single oral 90 mg/kg; [R66] *LD50 Mouse single oral 87-116 mg/kg; [R66] *LD50 Rat single oral 200-350 mg/kg; [R66] *LD50 21-day-old male and female mice oral 64 and 46 mg/kg, respectively; [R41, 1991.736] *LD50 Rat oral 90 mg/kg; [R20] *LD50 Rat ip 175 mg/kg; [R20] *LD50 Mouse ip 76 mg/kg; [R20] *LD50 Rabbit skin 1211 mg/kg; [R20] *LD50 Hamster oral 960 mg/kg; [R20] ETXV: *LC50 Fathead minnow 0.09 mg/l/96 hr (confidence limit, 0.09-0.10 mg/l), age 31 days, 24.9 deg C, 8.0 mg/l dissolved oxygen, 45.0 mg/l CaCO3 as water hardness, pH 7.42 /Sample 98% pure/ /Conditions of bioassay not specified/; [R67] *TLm Carassius quratus (goldfish): 0.09 mg/l at 17.5 deg C (Renewal bioassay); [R66] *LC50 Poecilia reticulata (guppy) 0.4 ppm/14 days /Conditions of bioassay not specified/; [R66] TCAT: ?The concentration of hexachlorobutadiene in the eggs of Japanese quail fed hexachlorobutadiene in a diet of poultry feed at concentrations of 0, 0.3, 3, 10 or 30 ppm was determined (treatment schedule or duration was not reported). Five eggs/concentration tested and 8 eggs from the control group were analyzed. The following levels (concentration, range (average) in ng/g) were detected in the eggs (including shells): 0 ppm, < 70; 0.3 ppm, 25-37 (30); 3 ppm, 200-330 (248), 10 ppm, 1500-2300 (1960); and 30 ppm, 2300-3900 (2980). In two eggs from birds exposed to 30 ppm the levels in the egg and shell ranged from 2300-2600 and 78-92 ng/g, respectively. Four control eggs were reported to contain < 50 and < 20 ng/g in the egg portion and shell, respectively (apparently below detection limits). [R68] ADE: *... /HEXACHLOROBUTADIENE/ IS ABSORBED THROUGH SKIN OF RABBITS. ... [R41, 1991.736] *IN RATS, HEXACHLOROBUTADIENE WAS FOUND IN LUNG, BLOOD, LIVER, BRAIN, KIDNEY, SPLEEN AND MESENTERY AFTER A SINGLE INJECTION (UNSPECIFIED) AND WAS EXCRETED WITH THE URINE FOR 7 DAYS. IN THE KIDNEY, THE HIGHEST CONCN WAS OBSERVED IN THE PROXIMAL SECTION OF THE NEPHRON. [R39] *Hexachlorobutadiene has been detected in post-mortem human tissue samples, at levels of 0.8 to 13.7 ug/kg (wet tissue). ... [R69] *Chronic daily administration of hexachlorobutadiene /in rats/ /SRP: results in tissue concn in the order/ adipose tissue > small and large intestine > stomach > skeleton > liver > kidney > brain > lung > spleen. [R70] METB: *(14)C-hexachlorobutadiene (HCBD), a mutagenic and nephrocarcinogenic pollutant, was administered by oral gavage /at a dose/ of 100 mg/kg to female rats, and the radioactivity in 24 hr urine pooled. The average amount of radioactivity recovered in urine was 5.4% of the total (14)C-activity ingested. Solvent extraction, high performance liquid chromatography (HPLC), radio gas chromatography and gas chromatography/mass spectrometry were used for separation and identification of metabolites. After solvent extraction and high performance liquid chromatography, four fractions were separated containing 1%, 5%, 15% and 80% of radioactivity. In the 80% fraction one metabolite was identified after derivatization and comparison with the authentic compound as the mercapturic acid of HCBD (N-acetyl-S-1,1,2,3,4-pentachlorobutadienyl-L-cysteine). The mercapturic acid accounts for 10% of the urinary (14)C-activity. ... The results identify the formation of the intermediary step in the metabolism of hexachlorobutadiene. [R71] *The genotoxic properties of hexachloro-1,3-butadiene (HCBD) and its monooxidation product pentachloro-3-butenoic acid (PCBA) were investigated by comparative induction of unscheduled DNA synthesis (UDS) and morphological transformation in the same cell system (Syrian hamster embryo fibroblasts). Hexachloro-1,3-butadiene and pentachloro-3-butenoic acid induce unscheduled DNA synthesis both in the presence and absence of an exogenous metabolizing system. The lowest ED (ED) for unscheduled DNA synthesis induction is smaller for pentachloro-3-butenoic acid (1 ug/ml) than for hexachloro-1,3-butadiene (2 ug/ ml). The intensity of unscheduled DNA synthesis induction is increased approx 3-fold for both cmpd after metabolic activation. Hexachloro-1,3-butadiene and pentachloro-3-butenoic acid induce morphologic transformation. The lowest ED for transformation differs considerably between pentachloro-3-butenoic acid (0.8 ug/ml) and HCBD (10 ug/ml). [R72] *The major metabolite was S-(pentachlorobutadienyl)glutathione, and the major urinary metabolites included S-(pentachlorobutadienyl)-L-cyteine, N-acetyl-S-(pentachlorobutadienyl)- L-cysteine, and 1,1,2,3-tetrachlorobutenoic acid. The /data suggests/ that relevant metabolic pathway for hexachloro-1,3-butadiene renal toxicity in mice is conjugation of hexachloro-1,3-butadiene with glutathione, renal procesing of the glutathione-S-conjugate and formation of reactive intermediates by beta-lyase. [R73] *An early event in the nephrotoxicity of haloalkene cysteine conjugates is their metab by cysteine conjugate beta-lyase to generate a reactive thiol moiety which binds to protein. This reactive metabolite(s) has been reported to cause mitochondrial dysfunction. ... The effect of 3 haloalkene cysteine conjugate on the activity of rat renal cortical cytosolic glutathione reductase and mitochondrial lipoyl dehydrogenase, 2 enzyme which have been reported to be inhibited by S-(1,2-dichlorovinyl)-L-cyteine in the liver /have been examined/. N-acetyl-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine produced a time- and concn-dependent inhibition of glutathione reductase and kinetic studies showed that the inhibition was noncompetitive with a Ki of 215 microM. The enzyme activity from male rat kidney was more sensitive to N-acetyl-S-(1,2,3,4, 4-pentachloro-1,3-butadienyl)-L-cysteine than that from female rat kidney. Amino-oxyacetic acid, an inhibitor of cysteine conjugate beta-lyase, and bis-p-nitrophenyl phosphate, an amidase inhibitor, blocked the effect of N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine on glutathion reductase, indicating that metab by the cytosol is required to produce enzyme inhibition. S-(1,1,2,2-tetrafluoroethyl)-L-cysteine and -(1,2-dichlorovinyl)-L-cysteine are also noncompetitive inhibitors of glutathione reductase but are less active than N-acetyl-S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine with Ki's of 2.6 and 6.2 mM for S-(1,2-dichlorovinyl)-L-cysteine and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, respectively, S-(1,2-dichlorovinyl)-L-cysteine produced a time- and concn-dependent inhibition of lipoyl dehydrogense and kinetic studies showed that the inhibition was noncompetitive with Ki of 762 umol. S-(1,1,2,2-tetrafluoroethyl)-L-cysteine and S-(1,2,3,4,4-pentachloro-1,3- butadienyl)-L-cysteine also inhibit lipoyl dehydrogenase. Aminooxyacetic acid blocked the effect of S-(1,2-dichlorovinyl)-L-cysteine, S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, AND S-(1,2,3,4,4-pentachloro-1,3- butadienyl)-L-cysteine on lipoyl dehydrogenase, indicating that metab by the mitochondrial fraction is required to produce enzyme inhibition. Glutathione reductase activity in the renal cortex of male rats treated with 200 mg/kg hexachloro-1,3-butadiene was inhibited as early as 1 hr after dosing, before signs of marked morphological damage. The activity of lipoyl dehydrogenase was also reduced but was only statistically significant 8 hr after dosing when there was marked renal dysfunction. These findings indicate that reactive thiol moiety formed by cysteine conjugate beta-lyase cleavage of S-(1,2,3,4,4-pentachloro-1,3-butadienyl)-L-cysteine can inhibit both glutathione reductase and lipoyl dehydrogenase activities in vivo following hexachloro-1,3- butadiene admin. We suggest that such inhibition is a general phenomenon, occurring with diverse and as yet unidentified renal proteins. [R74] *The mutagenicity of hexachloro-1,3-butadiene and its S-conjugates 1-(glutathione-S-yl)1,2,3,4,4- penttachloro-1,3-butadiene, 1,4-(bis-glutathione-S-yl-1,2,3,4-tetrachloro-1,3- butadiene and 1,4-(bis-cystein-S-yl)-1,2,3,4-tetrachloro-1,3-butadiene was investigated in Salmonella typhimurium TA100 using a modified preincubation assay. 1-(glutathione-S-yl)-1,2,3,4,4-pentachloro-1,3-butadiene was a direct-acting mutagen; the mutagenic potency of 1-(glutathione-S-yl)-1,2,3,4,4- pentachloro-1,3-butadiene was markedly enhanced by rat kidney microsomes or mitochondria and less so by cytosol. The bis-conjugates 1,4-(bis-glutathione-S- yl-1,2,3,4-tetrachloro-1,3-butadiene and 1,4-(bis-cystein-S-yl)-1,2,3,4- tetrachloro-1,3-butadiene were not mutagenic in the strains TA100, TA2638 and TA98. Purified hexachloro-1,3-butadiene was not mutagenic either with exogenous metabolic activation or with rat liver microsomes fortified with NADPH. Preincubation with rat liver microsomes and glutathione resulted in an unequivocal mutagenic activity of hexachloro-1,3-butadiene which was increased by additional inclusion of rat kidney microsomes. The cysteine conjugate beta- lyase inhibitor aminooxyacetic acid decreased the mutagenicity of hexachloro-1,3-butadiene and its S-conjugates. These results provide strong evidence that formation of the corresponding monoglutathione S-conjugate from hexachloro-1,3-butadiene and subsequent cleavage of this conjugate by gamma-glutamylltranspeptidase and beta-lyase may be responsible for the nephrocarcinogenicity of the parent compound in vivo, whereas formation of the bis-glutathione S-conjugate probably plays no role in the organ specific effects of hexachloro-1,3-butadiene. [R75] INTC: *The effects of piperonyl butoxide were measured. The time course and severity of toxicity were affected. Glomerular filtration rate was decreased 5 hr after piperonyl butoxide or hexachloro-1,3-butadiene administration; at 24 hr, glomerular filtration rate had recovered for the piperonyl butoxide group but continued to fall in the hexachloro-1,3-butadiene group. The group treated with piperonyl butoxide and hexachloro-1,3-butadiene had the same glomerular filtration rate as the group treated not different from the oil-pretreated controls. At 48 hr after hexachloro-1,3-butadiene, reabsorption of water and glucose was more severely impaired in the group pretreated with piperonyl butoxide. These results support the hypothesis that hexachloro-1,3-butadiene metabolites are involved in renal tubular dysfunction. [R76] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Hexachloro-1,3-butadiene's production and use as a solvent for elastomers, heat transfer liquid, transformer and hydraulic fluid may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.22 mm Hg at 25 deg C indicates hexachloro-1,3-butadiene will exist solely as a vapor in the ambient atmosphere. Vapor-phase hexachloro-1,3-butadiene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 534 days. Direct photolysis of hexachloro-1,3-butadiene is expected to occur due to absorption of light in the environmental UV spectrum (> 290 nm). If released to soil, hexachloro-1,3-butadiene is expected to have low to no mobility based upon a range of Koc values from 5.02X10+3 to 2.75X10+5. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 1.03X10-2 atm-cu m/mole. However, adsorption to soil is expected to attenuate volatilization. Hexachloro-1,3-butadiene vaporization from light (silty) soils is more rapid than from heavy (clayey) soils. If released into water, hexachloro-1,3-butadiene is expected to adsorb to suspended solids and sediment based upon the range of Kocs. Hexachloro-1,3-butadiene biodegrades in aqueous aerobic and anaerobic batch tests. Estimated disappearance half-lives for hexachloro-1,3-butadiene, which are based upon monitoring data, are 3-30 days in river water and 30-300 days in lake and ground waters. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.7 hours and 6.4 days, respectively. However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. BCF values for hexachloro-1,3-butadiene from 5800 to 17000 suggest bioconcentration in aquatic organisms is very high. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to hexachloro-1,3-butadiene may occur through inhalation and dermal contact with this compound at workplaces where hexachloro-1,3-butadiene and tetrachloroethylene are produced. Hexachloro-1,3-butadiene is produced as a by-product of tetrachloroethylene manufacture. Monitoring data indicate that the general population may be exposed to hexachloro-1,3-butadiene via inhalation of ambient air, and ingestion of food and drinking water contaminated with this compound. (SRC) NATS: *Hexachloro-1,3-butadiene is not known to occur as a natural product(1). [R77] ARTS: *Hexachloro-1,3-butadiene's production and use as a solvent for elastomers, heat transfer liquid, transformer and hydraulic fluid(1,2) may result in its release to the environment through various waste streams(SRC). A survey of six industries, found that higher concns of hexachloro-1,3-butadiene were associated with the production of perchloroethylene and trichloroethylene than with plants producing chlorine and triazine herbicides(3). Hexachloro-1,3-butadiene is also released during refuse combustion and is found in fly ash(4). [R78] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), Koc values ranging from 5.02X10+3 to 2.75X10+5(2-4), indicate that hexachloro-1,3-butadiene is expected to have low to no mobility in soil(SRC). Volatilization of hexachloro-1,3-butadiene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 1.03X10-2 atm-cu m/mole(5). However, volatilization from moist soil surfaces is expected to be attenuated by adsorption to soil(SRC). One day and 1 month after a spring application of 250 kg hexachloro-1,3-butadiene/ha in a vineyard, the air contained 0.08 and 0.003 mg hexachloro-1,3-butadiene/cu m, respectively(4). After an application of 150 kg, corresponding values were 0.06 and 0.001 mg/ha, respectively(6). Hexachloro-1,3-butadiene vaporization from light (silty) soils was more rapid than from heavy (clayey) soils(6). Raising temperatures from 13 to 18 deg hastened hexachloro-1,3-butadiene vaporization 5-fold in static conditions, and its application on granulated superphosphate decreased vaporization in comparison with liquid application(6). In aerobic and anaerobic batch tests in aqueous systems, hexachloro-1,3-butadiene biodegrades(7-9); thus, hexachloro-1,3-butadiene may biodegrade in soil(SRC). [R79] *AQUATIC FATE: Based on a classification scheme(1), a range of Koc values from 5.02X10+3 to 2.75X10+5(2-4), indicate that hexachloro-1,3-butadiene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(5) based upon a Henry's Law constant of 1.03X10-2 atm-cu m/mole(6). Using this Henry's Law constant and an estimation method(5), volatilization half-lives for a model river and model lake are 1.7 hours and 6.4 days, respectively(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column(SRC). The estimated volatilization half-life from a model pond is 201 days if adsorption is considered(7). According to a classification scheme(8), BCF values for hexachloro-1,3-butadiene from 5,800 to 17,000 suggest bioconcentration in aquatic organisms is very high(9-10). Hexachloro-1,3-butadiene may biodegrade in natural waters(11). Estimated half-lives for hexachloro-1,3-butadiene disappearance based on monitoring data are 3-30 days in river water and 30-300 days in lake and ground waters(12). Hexachloro-1,3-butadiene biodegrades under methanogenic conditions(13,14). [R80] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), hexachloro-1,3-butadiene, which has a vapor pressure of 0.22 mm Hg at 25 deg C(2) is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase hexachloro-1,3-butadiene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 534 days(SRC), calculated from its rate constant of 3.0X10-14 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Hexachloro-1,3-butadiene absorbs light in the environmental spectrum and has the potential for direct photolysis(4). [R81] BIOD: *AEROBIC: Hexachloro-1,3-butadiene may biodegrade in natural waters since 100% degradation occurred in 7 days in an aerobic batch culture incubated at 25 deg C and inoculated with settled domestic sewage(1). Estimated half-lives for hexachloro-1,3-butadiene disappearance based on monitoring data are 3-30 days in river water and 30-300 days in lake and ground waters(2). ANAEROBIC: Greater than 99% of hexachloro-1,3-butadiene transformed to (E,E)-1,2,3,4-tetrachlorobutadiene by reductive dechlorination in columns with Rhine sediment (Germany) operated at 20 deg C with methanogenic electron acceptors(3). Hexachloro-1,3-butadiene was only removed under methanogenic conditions using these sediments and not when oxygen or nitrate were present in the column experiments(4). Reductive dechlorination in the column was ascribed to the activity of anaerobic microorganisms(4). [R82] ABIO: *The rate constant for the vapor-phase reaction of hexachloro-1,3-butadiene with photochemically-produced hydroxyl radicals has been estimated as 3.0X10-14 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 534 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). An estimate of tropospheric half-life obtained from monitoring data at remote sites is 1.6 yr in the northern hemisphere and 0.6 yr in the southern hemisphere(2). Hexachloro-1,3-butadiene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). In the laboratory, hexachloro-1,3-butadiene was adsorbed on silica gel, placed in a pure oxygen atmosphere, and exposed to an artificial light source through quartz or pyrex glass(4). After a 3 day exposure through the quartz filter, 10-50% of the theoretical HCl and/or Cl2 and 50-90% of the CO2 were formed; after 6 days exposure through the pyrex filter (> 290 nm wavelength), 50-90% of the theoretical HCl and/or CO2 and 50-90% of the CO2 were formed(4). [R83] BIOC: *The mean bioconcentration factor (BCF) for rainbow trout exposed to 0.10 ng/l and 3.4 ng/l of hexachloro-1,3-butadiene was 5,800 and 17,000, respectively(1). The BCF for fathead minnow exposed to hexachloro-1,3-butadiene was 6,918(2). According to a classification scheme(3), these BCF values suggest bioconcentration in aquatic organisms is very high. The mean bioconcentration factor for hexachloro-1,3-butadiene between oligocheate worms and sediment in Lake Ontario near the Niagara River was 0.43(4). The concn of the chemical in the sediment pore water was the main factor affecting bioconcentration(4). [R84] KOC: *The Koc of hexachloro-1,3-butadiene ranges from 5.02X10+3 to 2.75X10+5(1-3). According to a classification scheme(4), these Koc values suggest that hexachloro-1,3-butadiene has slight to no mobility in soil(SRC). [R85] VWS: *The Henry's Law constant for hexachloro-1,3-butadiene is 1.03X10-2 atm-cu m/mole(1). This Henry's Law constant indicates that hexachloro-1,3-butadiene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.7 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 6.4 days(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column(SRC). The estimated volatilization half-life from a model pond is 201 days if adsorption is considered(3). Hexachloro-1,3-butadiene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). One day and 1 month after a spring application of 250 kg hexachloro-1,3-butadiene/ha in a vineyard, the air contained 0.08 and 0.003 mg hexachloro-1,3-butadiene/cu m, respectively(4). After an application of 150 kg, corresponding values were 0.06 and 0.001 mg/ha, respectively(4). Hexachloro-1,3-butadiene vaporization from light (silty) soils was more rapid than from heavy (clayey) soils(4). Raising temperatures from 13 to 18 deg hastened hexachloro-1,3-butadiene vaporization 5-fold in static conditions, and its application on granulated superphosphate decreased vaporization in comparison with liquid application(4). [R86] WATC: *SURFACE WATER: Hexachloro-1,3-butadiene was detected in surface water at 4 of 522 stations in the United States at an average concn and range of concns of 51.8 ug/l and 2.1 to 180 ug/l, respectively(1). Hexachloro-1,3-butadiene was found at concns of 10 and 23 ug/l in water sampled beyond the boundaries of two chemical plants(2). Hexachloro-1,3-butadiene concn in an open waste treatment pond was 244 ug/l(2). Mississippi River water at Baton Rouge, LA contained 1.9 ppb of hexachloro-1,3-butadiene(3). Hexachloro-1,3-butadiene was found in the Ashtabula River (Ohio) at an unspecified concn(4). Hexachloro-1,3-butadiene has also been detected in Lake Erie water(5). Grab samples of water from Lake Ontario, the Niagara River, and the Detroit River contained mean hexachloro-1,3-butadiene concns of 0.01, 0.2, and 0.1 parts per trillion, respectively(6). Between 1982 and 1985 the average concn of hexachloro-1,3-butadiene in the Rhine River ranged from 0.01-0.1 ppb(7). The concn of hexachloro-1,3-butadiene in the North Sea off the coast of the Netherlands during 1983-1984 ranged from < 0.02-1.30 parts per trillion, median 0.23 parts per trillion(8). Since the concn in the Rhine River was 15 parts per trillion, it was concluded that the river was a source of this contaminant(8). The range of concns of hexachloro-1,3-butadiene in the River Elbe upstream (at Zollenspieker) and downstream (at Seemannshoft) of Hamburg, Germany was 2-4.23 ng/l and 2.3-2.6 ng/l, respectively(9). [R87] *GROUNDWATER: Hexachloro- 1,3-butadiene was detected in groundwater at 3 of 3802 stations in the United States at an average concn and range of concns of 45.4 ug/l and 0.2 to 890 ug/l, respectively(1). In Lombardia, Italy, groundwater contaminated by industrial wastes contained hexachloro-1,3-butadiene ranging from 0.1 to 266.2 ng/l(2). In wells near Limbiate and Senago, Italy, goundwater contaminated by industrial wastes contained hexachloro-1,3-butadiene at max concns of approximately 3 ng/ml and 0.9 ng/ml, respectively(3). [R88] *DRINKING WATER: At public water systems (PWS) in the United States, the mean concn of hexachloro-1,3-butadiene in water was 1.32 ug/l (range, 0.0005-10 ug/l; 33 of 2,913 stations with detections), 0.1 ug/l (1 of 125 stations with detections), and 0.36 ug/l (range, 0.0005-8 ug/l; 81 of 17,038 stations with detections) for surface water, ground water under the direct influence of surface water, and ground water sources, respectively(1). PWS water quality testing is performed at many points in the system, including the intake and at various points in the treatment and distribution systems, as well as at the point where the drinking water can be labeled as finished drinking water(1). Hexachloro-1,3-butadiene concn ranged from 0.04 to 0.70 ug/l in New Orleans drinking water from the Carrollton water plant(2). The highest hexachloro-1,3-butadiene concn found in tap water from houses near Love Canal (Niagara Falls, NY) was 170 ng/l(3). [R89] EFFL: *Effluent from the Diamond Shamrock Corp in Deerpark, TX contained 2 ug/l hexachloro-1,3-butadiene(1). Hexachloro-1,3-butadiene was found to be discharged from the Niagara Falls Sewage treatment plant (concns were not indicated)(2). Surficial sediments near the Tso-yin (Taiwan) ocean outfall sewage pipe had a high concn of hexachloro-1,3-butadiene, ranging from 7-7500 ng/cu m(3). [R90] SEDS: *VINEYARDS INFECTED WITH PHYLLOXERA WERE TREATED WITH HEXACHLOROBUTADIENE (HCBD) AT 250 KG/HA. THE MAXIMUM LEVEL OF HCBD WAS DETECTED 8 MONTHS AFTER THE LAST APPLICATION (4.36 MG/KG IN THE 75-100 CM LAYER AND 7.3 MG/KG IN THE 50-75 CM LAYER); HCBD LEVELS 32 MONTHS AFTER APPLICATION IN THE 50-75 CM AND 75-100 CM LAYERS WERE 0.65 AND 2.99 MG/KG, RESPECTIVELY. [R91] *SOILS: Hexachloro-1,3-butadiene concn in soil near a chemical plant was 0.11 ug/g(1). Hexachloro-1,3-butadiene levels of 0.15 and 0.34 ug/g were found at the boundaries of the two other plants(1). Hexachloro-1,3-butadiene was found in soil near the Mississippi River at 433.0 ppb (dry basis)(2). Sediment from Lake Ontario near the Niagara River contained 3-11 ppb hexachloro-1,3-butadiene(3,4). Levee soil in Louisiana contained levels ranging from undetectable to 800 ug/kg, ditch mud levels ranged from undetectable to 500 ug/kg and soil samples collected from sites removed from a transect of the levees contained levels ranging from < 0.7 to 321.5 ug/kg (433.0 ug/kg corrected to dry wt)(5). In a US study in 1975 and 1976, highest levels were detected in soil around factories associated with the production of tetrachloroethylene and trichloroethylene (highest reported concn, 980 ug/g)(5). [R92] *SEDIMENTS: Hexachloro-1,3-butadiene has also been detected in Lake Michigan sediment(1) and from suspended matter of the Hylebos Waterway in Tacoma, WA(2). Hexachloro-1,3-butadiene was found in Ohio River sediment near Louisville, KY at 2 and 17 ng/g(3). Sediments in southern Lake Huron, Lake St. Clair, Western Lake Huron, Central Lake Erie, and Eastern Lake Erie contained mean hexachloro-1,3-butadiene concns of 0.08, 7.3, 1.6, 0.2, and 0.2 ppb (dry/wt), respectively(4). Concn of hexachloro-1,3-butadiene in sediments from Liverpool Bay, England ranged from < 0.02 to > 8 mg/kg(5). The mean concn of hexachloro-1,3-butadiene in Lake Charles, LA sediments was 49.5 ug/g (wet wt)(6). The mean concn of hexachloro-1,3-butadiene in sediments from Bayou d'Inde near Lake Charles, LA were 95.1 mg/kg, 2.8 mg/kg, and 1.9 mg/kg (dry wt) for the 106-1400 um, 53-106 um, and < 53 um sediment size fractions, respectively(7). Surficial sediments near the Tso-yin (Taiwan) ocean outfall sewage pipe had a high concn of hexachloro-1,3-butadiene; sediments in this area had a hexachloro-1,3-butadiene concn of 47.4 ng/g(8). [R93] ATMC: *ONE DAY AND 1 MONTH AFTER A SPRING APPLICATION OF 250 KG HEXACHLOROBUTADIENE (HCBD)/HA VINEYARD, THE AIR CONTAINED 0.08 AND 0.003 MG HCBD/CU M, RESPECTIVELY. AFTER AN APPLICATION OF 150 KG HCBD/HA, CORRESPONDING VALUES WERE 0.06 AND 0.001. [R94] *SOURCE DOMINATED: The max hexachloro-1,3-butadiene concn was 460 ug/cu m in the air at a plant that produced perchloroethylene, carbon tetrachloride, and chlorine(1). Max hexachloro-1,3-butadiene air concn off plant property was 0.22 ug/cu m(1). At another plant, hexachloro-1,3-butadiene concn was 10 ug/cu m at the plant boundary(1). The normalized concn of hexachloro-1,3-butadiene in emissions from a pilot plant for waste gasification and combustion ranged from 7-7500 ng/cu m(2). Hexachloro-1,3-butadiene was found at 0.41 ug/cu m in the ambient air of a household basement in Niagara Falls, NY(3). [R95] *URBAN/SUBURBAN: In Houston, hexachloro-1,3-butadiene ambient air concn was 117 ng/cu m(1). Hexachloro-1,3-butadiene was found at 0.39 ug/cu m in the ambient air of Niagara Falls, NY(3). In the United States from 1981-1984, the average daily concn of hexachloro-1,3-butadiene in outdoor air was 0.036 ppbv (ppb by volume)(2). [R96] *RURAL/REMOTE: The mean concn (standard deviation) of hexachloro-1,3-butadiene in remote sites in the northern and southern hemisphere selected for being influenced by long range transport only is 0.17 (0.05) and 0.07 (0.03) parts per trillion/volume, respectively(1). [R97] FOOD: *... FOUR MONTHS AFTER FUMIGATION, GRAPE BERRIES CONTAINED 0.006 MG HCBD/KG FRESH WT. [R94] *Hexachloro-1,3-butadiene concns (ug/kg) in United Kingdom foodstuffs were: Butter (2.0), vegetable cooking oil (0.2), ale (0.2), tomatoes (0.8), and black grapes (3.7)(1). Hexachloro-1,3-butadiene was also found in the following foodstuffs and feeds (country not specified) (ug/kg): evaporated milk (4.0), egg yolk (42), vegetable-oil margarine (33), chicken grain feed (39), and chicken laying rations (20)(2). Hexachloro-1,3-butadiene residues have been detected in must wine (< 0.01 to 0.45 ug/l) and grape juice in the USSR(3); however, no residues were detected in fermented wine or in pasteurized grape juices(3). In a study of foods collected within 25-mile (40-km) radius of factories producing tetrachloroethylene or trichloroethylene, no hexachloro-1,3-butadiene residues were found in any of 15 egg samples or 20 samples of a variety of vegetables(3); of 20 milk samples collected, only one contained residues (1.32 mg/kg on a fat basis)(3); in a later follow-up sample, no residues were detected(3). [R98] PFAC: PLANT CONCENTRATIONS: *In a United Kingdom study, 5 species of marine algae were found to contain hexachloro-1,3-butadiene residues at levels ranging from 0 to 8.9 ug/kg(1). [R77] FISH/SEAFOOD CONCENTRATIONS: *Mosquito fish taken from the Mississippi River near Baton Rouge, LA contained an average of 827.3 ppb hexachloro-1,3-butadiene(1). Crayfish from a ditch near Baton Rouge, LA contained 70.1 ppb hexachloro-1,3-butadiene(1). Hexachloro-1,3-butadiene was found, but not quantified, in fish from the Ashtabula River, Ohio(2) and the Wabash River, Indiana(3). Mean hexachloro-1,3-butadiene concn in Lake Ontario rainbow trout was 0.2 ng/g(4). Hexachloro-1,3-butadiene has also been detected in fish from Lakes Erie, Huron, and Superior(5). A study of 9 Great Lakes harbors and tributaries in Ohio and Wisconsin, between 1980 and 1981, found no hexachloro-1,3-butadiene in composite fish samples(6). A study of the distribution of hexachloro-1,3-butadiene in the St. Clair and Detroit Rivers using clams (E. complanatus) suspended in cages, found that none of the sites in the Detroit R. and 55% of the sites in the St. Clair River contained levels of hexachloro-1,3-butadiene above the detection limit, 1 ppb, wet wt(7). The highest mean concn was 83 ppb and results indicated that sources of pollutants were present in the Sarnia area(7). Residues of hexachloro-1,3-butadiene were found in 10 samples from fish collected from within 25 miles (40 km) of tetrachloroethylene or trichloroethylene production plant sites, at levels ranging from 0.01 to 1.2 mg/kg(8) In a United Kingdom study, various organs of 15 species of fish contained hexachloro-1,3-butadiene residues ranging from 0 to 2.6 ug/kg(8). [R99] ANIMAL CONCENTRATIONS: *In a United Kingdom study, 14 species of invertebrates were found to contain hexachloro-1,3-butadiene residues at levels ranging from 0 to 7 ug/kg by wt of wet tissue(1). Eggs or organs of 8 species of sea and freshwater birds were found to contain hexachloro-1,3-butadiene residues at levels ranging from, 0 to 9.9 ug/kg; and organs of 2 species of mammals, 0 to 3.6 ug/kg(1). Oligochaete worms from Lake Ontario sediment near the Niagara River 2.0 - 8.6 ppb dry weight(2). [R100] MILK: *Hexachlorobutadiene was found in fresh milk at a concentration of 0.08 ug/kg(1). [R101] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1010 workers (26 of these are female) are potentially exposed to hexachloro-1,3-butadiene in the US(1). Occupational exposure to hexachloro- 1,3-butadiene may occur through inhalation and dermal contact with this compound at workplaces where hexachloro-1,3-butadiene and tetrachloroethylene are produced(SRC). Hexachloro-1,3-butadiene is produced as a by-product of tetrachloroethylene manufacture(2). The max hexachloro-1,3-butadiene concn at nine manufacturing plants was 460 ug/cu m(3). In another study, the max observed concn of hexachloro-1,3-butadiene in workplace air from municipal solid waste composting facilities was 4 ug/cu m(4). Semiconductor plasma etching process workers may potentially be exposed to high levels of by- products, such as hexachloro-1,3-butadiene, in the workplace through accidents, maintenance procedures, or insufficient protection(5). Monitoring data indicate that the general population may be exposed to hexachloro-1,3- butadiene via inhalation of ambient air, ingestion of food and drinking water containing hexachloro-1,3-butadiene(SRC). [R102] AVDI: *WATER INTAKE: Assume 0.04 to 1.3 ug/l(1,2): 0.08-2.6 ug(SRC). [R103] BODY: *Average hexachloro-1,3-butadiene concn in Canadian adipose tissue (human) was 0.004 ug/g(1). Hexachloro-1,3-butadiene was found at a concn of 13.7 ug/kg (wet tissue) in the liver of a 75 year old male and at 1.8 ug/kg in the body fat of a 48 year old male(2). [R104] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers hexachlorobutadiene to be a potential occupational carcinogen. [R9, 158] OSHA: *Vacated 1989 OSHA PEL TWA 0.02 ppm (0.24 mg/cu m) is still enforced in some states. [R9, 365] NREC: *NIOSH considers hexachlorobutadiene to be a potential occupational carcinogen. [R9, 158] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R9, 158] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.02 ppm (0.24 mg/cu m), skin. [R9, 158] TLV: *8 hr Time Weighted Avg (TWA) 0.02 ppm, skin [R105, 41] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R105, 6] *A3: Confirmed animal carcinogen with unknown relevance to humans. [R105, 41] OOPL: *Emergency Response Planning Guidelines (ERPG): ERPG(1) 3 ppm (no more than mild, transient effects) for up to 1 hr exposure; ERPG(2) 10 ppm (without serious, adverse effects) for up to 1 hr exposure; ERPG(3) 30 ppm (not life threatening) up to 1 hr exposure. [R106] *Australia: 0.02 ppm, skin, Category 3, suspected of having carcinogenic potential; Federal Republic of Germany: no MAK, skin, Group B, justifiably suspected of having carcinogenic potential. [R41, 1991.737] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Hexachloro-1,3-butadiene is included on this list. [R107] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 1 ug/l [R108] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 15 ug/l [R108] +(ME) MAINE 1 ug/l [R108] +(MN) MINNESOTA 1 ug/l [R108] +(NH) NEW HAMPSHIRE 0.50 ug/l [R108] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R109] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R110] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Hexachloro-1,3-butadiene is included on this list. [R111] RCRA: *U128; As stipulated in 40 CFR 261.33, when 1,3-butadiene, 1,1,2,3,4,4-hexachloro-, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R112] *D003; A solid waste containing hexachlorobutadiene may become characterized as a hazardous waste when subjected to testing for reactivity as stipulated in 40 CFR 261.23, and if so characterized, must be managed as a hazardous waste. [R113] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2543. Analyte: hexachlorobutadiene. Matrix: air. Range: 0.06 ug to 6 ug per sample. Procedure: adsorption on amberlite XAD-2, desorption with hexane, GC-ECD. Precision: 0.03. [R114] *... HCBD IS SORBED FROM AIR ONTO SILICA GEL ... . [R115] ALAB: *Gas chromatography with electron capture detection is described for the analysis of hexachlorobutadiene in air samples. Colorimetric method is described for detection of HCBD in air with a detection limit of 5 mg/cu m. Ultraviolet analytical method is described for the analysis of HCBD in air with a detection limit of 0.2 mg/cu m. [R116] *Gas chromatography with electron capture detection is described for the analysis of hexachlorobutadiene in grab water. Colorimetric method is described for detection of HCBD in grab water with a detection limit of 0.2 mg/l. [R116] *Gas chromatography with electron capture detection is described for the analysis of hexachlorobutadiene in (a) fish, (b) vegetable, (c) fish and eggs, and (d) milk extracts with limit of detection of (a) not given, (b and c) 5 ug/kg and (d) 40 ug/kg (b,c, and d). Ultraviolet detection is used for the analysis in wine. [R116] *Gas chromatography with electron capture detection is described for the analysis of hexachlorobutadiene in soil. [R117] *NIOSH Method 2543. Extraction with hexane. Analysis by GC-ECD. Accuracy: +/- 18.1%. Detection limit = 0.002 ug/cu m. [R114] *OSW Method 8270B. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit = 660 ug/kg. [R118] *OSW Method 8120A. Determination of Chlorinated Hydrocarbons by Gas Chromatography. Detection limit = 0.340 ug/l. [R118] *OSW Method 8410-BN. Determination Of Semivolatile Organics By Using The Gas Chromatography/ Fourier Transform Infrared (GC/FT-IR) With a Capillary Column - Base/Neutral Extractables. Detection limit = 60 ug/l. [R118] *EPA Method 625. Protocol for the Analysis of Base/Neutral and Acid Extractable (BNA) Organic Priority Pollutants in Industrial and Municipal Wastewater. Detection limit = 0.9 ug/l. [R118] *OSW Method 5021. Volatile Organic Compounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. Detection limit not specified. [R118] *EPA Method 612. Chlorinated Hydrocarbons in Wastewater by Gas Chromatography with Electron Capture Detection. Detection limit = 0.34 ug/l. [R118] *APHA Method 6410B. Liquid-liquid extraction gas chromatographic/mass spectrometric method. Detection limit = 0.9 ug/l. [R119] *APHA Method 6200B. Purge and Trap Capillary-Column Gas Chromatography/Mass Spectrometric Method. [R119] CLAB: *Colorimetric method is described for the analysis of hexachlorobutadiene in blood with a detection limit of 5 mg/l; and ultraviolet analytical method is described for the analysis of HCBD in urine with a detection limit of 0.05 mg/l. [R117] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Lock EA, Studies on the Mechanism of Nephrotoxicity and Nephrocarcinogenicity of Halogenated Alkenes, CRC Critical Reviews in Toxicol 1988. DHHS/ATSDR; Toxicological Profile for Hexachlorobutadiene (Update) (1994) ATSDR/TP-93/08 NTP TR No 001; Route: oral in feed; Species: mice. NTIS No PB91185884. [R120] SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V73 (99) 277 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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(Multivolume work).p. V20 185 (1979) R118: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R119: American Public Health Association, American Water Works Association, Warer Environment Federation. M.A.H. Franson (ed.); Standard Methods for the Examination of Water and Wastewater 20th ed., Washington, D.C. 1998.p. 6-59 R120: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.21 RS: 110 Record 192 of 1119 in HSDB (through 2003/06) AN: 2872 UD: 200303 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-VINYL-1-CYCLOHEXENE- SY: *BUTADIENE-DIMER-; *CYCLOHEXENE,-4-ETHENYL-; *CYCLOHEXENE,-4-VINYL-; *CYCLOHEXENYLETHYLENE-; *ETHENYL-1-CYCLOHEXENE-; *4-Ethenylcyclohexene-; *NCI-C54999-; *1,2,3,4-TETRAHYDROSTYRENE-; *VCH-; *Vinylcyclohexene-; *1-VINYLCYCLOHEXENE-3-; *4-VINYLCYCLOHEXENE-; *4-Vinylcyclohex-1-ene- RN: 100-40-3 MF: *C8-H12 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DIMERIZATION OF BUTADIENE UNDER PRESSURE AND HIGH TEMPERATURE USING A SILICON CARBIDE CATALYST, OR COPPER OR CHROMIUM SALTS OF NAPHTHENIC OR RESIN ACIDS. [R1] *DIMERIZATION OF BUTADIENE WITH LOW- OR ZERO-VALENT NICKEL AS A CATALYST IN THE PRESENCE OF ELECTRON DONOR LIGANDS, SUCH AS CERTAIN PHOSPHITES AND PHOSPHINES. [R2] *BYPRODUCT FROM THE VAPOR PHASE CHLORINATION OF BUTADIENE AT HIGH TEMPERATURE. [R3] *Dimerization of butadiene by Diels-Alder reaction [R4] FORM: *Grades: Technical, 95%; Pure, 99%; Research. [R5] MFS: *Dupont, 1007 Market St., Wilmington, DE 19898, (800) 441-7515; Production site: Victoria, TX 77901 [R6] *Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817-0001, (203) 794-3170; Production site: Institute, WV 25103 [R6] USE: *Polymers; organic synthesis [R5] *Used as an intermediate for the production of vinylcyclohexene dioxide, which is used as a reactive diluent in epoxy resins. Previous uses of 4-vinyl-1- cyclohexene include comonomer in the polymerization of other monomers and for halogenation to polyhalogenated derivatives which are used as flame retardants. [R7] *Precursor for ethyl cyclohexyl carbinol plasticizers, as an intermediate for thiocyamate insecticides and as an antioxidant. [R8] PRIE: U.S. PRODUCTION: *(1974) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Liquid [R5] BP: *128 deg C @ 760 mm Hg [R9] MP: *-108.9 deg C [R9] MW: *108.18 [R9] DEN: *0.8299 @ 20 deg C [R9] OWPC: *log Kow = 3.93 [R10] SOL: *Miscible with methanol [R11]; *Soluble in ether, benzene, petroleum ether. [R9]; *In water, 50 mg/l @ 25 deg C [R12] SPEC: *Index of refraction: 1.4639 @ 20 deg C [R9]; *MAX ABSORPTION (ETHANOL): 230 NM (E= 1935) [R13, p. V11 277]; *IR: u API 146 (American Petroleum Institute spectral collection) [R14]; *1H NMR: VAR 210 (Varian Associates NMR Spectra Catalogue) [R14]; *MS: NIST 1402 (NIST/EPA/MSDC Mass Spectral database 1990 version); NBS 4444 [R14] VAPD: *3.76 (Air= 1) [R15] VAP: *15.7 mm Hg @ 25 deg C [R16] OCPP: *Conversion factor: 4.43 mg/cu m = 1 ppm [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *FLAMMABLE, DANGEROUS FIRE RISK. [R17] *DANGEROUS FIRE HAZARD WHEN EXPOSED TO HEAT OR FLAME [R18] NFPA: *Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R19] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R19] *Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R19] FLPT: *61 DEG F (Closed cup), 16 DEG C [R19] AUTO: *517 DEG F (269 DEG C). [R19] FIRP: *To fight fire, use foam, CO2, dry chemical. [R18] REAC: *Can react with oxidizers. [R18] *Upon contact with oxygen, VCH undergoes auto-oxidation to produce vinylcyclohexene hydroperoxide. The hydroperoxide can be formed during prolonged storage of butadiene, and further autocondensation leads to 1,2,3,6,1',2',3',6'-octahydrobiphenyl. [R20, 1991.1703] SERI: *It is an irritant, and it defats the skin on direct contact. [R21] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R22, 1979.8] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R22, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R22, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R22, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R22, 1979.11] SSL: *OXIDIZES IN AIR TO FORM HYDROPEROXIDE [R23] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R22, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R22, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R22, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R22, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R22, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R22, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R22, 1979.16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of 4-vinyl-1-cyclohexene. There is sufficient evidence in experimental animals for the carcinogenicity of 4-vinyl-1-cyclohexene. Overall evaluation: 4-Vinyl-1-cyclohexene is possibly carcinogenic to humans (Group 2B). [R24] *A2. A2= Suspected human carcinogen. [R25] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aliphatic hydrocarbons and related compounds/ [R26, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory rest. Positive pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aliphatic hydrocarbons and related compounds/ [R26, 207] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R22, 1979.23] HTOX: *It is an irritant, and it defats the skin on direct contact. It is a anesthetic and CNS depressant. When ingested, it represents a low to moderate pulmonary aspiration hazard. [R21] *Russian rubber workers inhaling mean VCH concn of 271 to 542 ppm (with peak VCH concn to 677 ppm) were reported to suffer from keratitis, rhinitis, headache, hypotonia, leukopenia, neutrophilia, lymphocytosis, and "impairment of pigment and carbohydrate metabolism." [R20, 1991.1705] NTOX: *4-VINYLCYCLOHEX-1-ENE AND ITS EPOXIDE METABOLITES WERE NONMUTAGENIC TOWARD SALMONELLA TYPHIMURIUM IN PRESENCE AND ABSENCE OF POLYCHLORINATED BIPHENYL-INDUCED RAT LIVER 9000 G SUPERNATANT FRACTION FORTIFIED WITH NADPH-GENERATING SYSTEM. [R27] *4-Vinylcyclohexene was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 in the presence or absence of Aroclor 1254 induced male Sprague Dawley rat or male Syrian hamster liver S9 when tested according to the preincubation protocol. Several recognized metabolites of 4-vinylcyclohexene, including 4-vinylcyclohexene diepoxide, 4-vinyl-1,2-epoxycyclohexane, and 4-epoxy-ethyl-1,2-dihydroxycyclohexane, were mutagenic in Salmonella and/or produced chromosomal damage in vitro. [R28] *A group of 30 male Swiss ICR/HA mice, eight weeks old, received thrice weekly topical applications of 45 mg 4-vinylcyclohexene (purified by removing auto oxidaton products with ferrous sulfate) in 0.1 ml of a 50% solution in benzene on the clipped dorsal skin for life. Median survival time was 375 days. Skin tumors were found in six males (one with a squamous cell carcinoma and five with squamous papillomas) (p= 0.04). In a vehicle control group of 150 mice, ten developed skin papillomas and one a carcinoma. Because the 4-vinylcyclohexene used in ... this study may have been contaminated with a minute amount of the hydrogen peroxide formed by autooxidation, a further study was carried out using 'oxygen-free material'. In this experiment, one-fifth of the dose used in the previous study (9 mg in 0.1 ml of a 10% solution in benzene) was applied thrice weekly for life to 30 male Swiss ICR/Ha mice. The median survival time was 565 days; no carcinogenic effect was observed. [R29] *Exposure of rats and mice to 1000 mg/cu m (226 ppm) 4-vinycyclohexene by inhalation for 6 hr per day over four months was reported to inhibit weight gain and to cause leucocytosis, leucopenia and impairment of haemodynamics. [R30] *IP administration to Swiss mice of two doses of 500 m/kg body weight 4-vinyl-cyclohexene in corn oil at 24 hr intervals induced liver microsomal NADPH cytochrome c reductase and aminopyrine N-dimethylase. The same treatment with 4-vinyl-1,2-epoxycyclohexane induced the same enzymes plus epoxide hydrolase and increased the concentration of cytochrome p450. Liver glutathione depletion was also observed following treatment with either compound or with 4-epoxyethyl-1,2-epoxycyclohexane, most probably as a result of conjugation of 4-vinylcyclohexene and/or its metabolites. [R31] *Like other vinylalicyclic compounds, 4-vinylcyclohexene destroys hepatic cytochrome p450 when incubated in vitro in the presence of liver microsomes from phenobarbital-treated mice. [R32] *4-Epoxyethyl-1,2-epoxycyclohexane, but not 4-vinyl-1,2-epoxycyclohexane or 4-epoxyethycyclohexane-1,2-diol, induce 6-thioguanine-resistant mutants in cultured Chinese hamster V79 cells when tested at 0.3-20 mM. 4-Vinyl-1,2-epoxycyclohexane and 4-epoxyethylcyclohexane-1,2-diol, tested at 2.0 mM, induced micronuclei, but 4-epoxyethyl-1,2-epoxycyclohexane did not; all three metabolites induced chromosomal damage (bridges and lagging chromosomes in analphase) in V79 cells. [R32] *Rats could tolerate exposure to a concn /4-Vinylcyclohexene/ VCH vapor for up to 15 min without death; inhalation of 8000 ppm VCH for 4 hr killed 4 of 6 rats. [R20, 1991.1703] *Skin irritation after application of undiluted VCH to shaved rabbit skin was rated moderate. [R20, 1991.1703] *A small necrotic area on the cornea resulted from instillation of 0.5 ml undiluted VCH into a rabbit eye. [R20, 1991.1703] *Admin of VCH (stock soln containing 0.01% butylated hydroxytoluene) by gavage in corn oil at 0, 300, 600, 1250, 2500, or 5000 mg/kg/day for 14 days to groups of five male and five female F344 rats and B6C3F1 mice killed all rats dosed with 1250 mg/kg or more VCH and killed all mice dosed with 2500 or 5000 mg/kg. Prior to death, rats showed CNS depression, tremors, and gastrointestinal distress. No compound-related gross or histologic changes were observed. Tremors and inactivity were observed in the mice that died. [R20, 1991.1703] *Application of 45 mg VCH in 50% benzene to the shaved dorsal skin of 30 Swiss mice, 3 days/wk for 54 wk resulted in extensive skin damage and produced one squamous cell carcinoma, a result attributed ... to trace concn of VCH hydroperoxide, a known animal carcinogen. ... Similar skin-painting bioassay or ip injection with the VCH metabolite VCH-1,2-diepoxide produced squamous cell carcinomas and sarcomas or peritoneal sarcomas, respectively, confirming earlier dermal and parenteral VCH-1,2-diepoxide studies in rodents. [R20, 1991.1704] *... 15 female B6C3F1 mice /were given/ daily ip injections of 6 mmol/kg bw of VCH in sesame seed oil and an equal number of control mice equivalent injections of the vehicle alone for 30 days. Daily vaginal smears were used to determine estrus. On day 31, all mice were sacrificed and the numbers of primary (22 + or - 10) and secondary (26 + or - 7) ovarian follicles were found to be reduced in the VCH-treated mice compared to the controls (298 + or - 63 and 115 + or - 32, respectively). The number of estrous cycles per 30 days was also reduced significantly in the VCH-treated mice (3.2 + or - 1.0) compared to the control (4.8 + or - 1.5). [R20, 1991.1704] *A group of 30 male Swiss ICR/HA mice (age unspecified) received skin applications of 9 mg 4-vinylcyclohexene (purity not specified but stated to be "oxygen-free) in 0.1 ml of a 50% solution of benzene, three times a week for life. The median survival was 565 days; no skin tumors occurred. [R33] *OF 30 8 WK OLD SWISS ICR/HA MALE MICE TREATED WITH 45 MG 4-VINYLCYCLOHEXENE IN 0.1 ML OF 50% SOLN IN BENZENE ON CLIPPED DORSAL SKIN THRICE WEEKLY FOR LIFE, 6 DEVELOPED SKIN TUMORS; 1 ... HAD SQUAMOUS CELL CARCINOMA; MEDIAN SURVIVAL TIME WAS 375 DAYS. OF 150 CONTROL ... PAINTED WITH BENZENE ... 10 DEVELOPED SKIN PAPILLOMAS AND 1 A CARCINOMA. ... WHEN 'OXYGEN-FREE MATERIAL' (0.1 ML OF A 10% SOLN IN BENZENE) WAS APPLIED THRICE WEEKLY FOR LIFE TO 30 MALE SWISS ICR/HA MICE, THE MEDIAN SURVIVAL TIME WAS 565 DAYS, AND NO CARCINOGENIC EFFECT WAS OBSERVED. [R23] *DOSES OF 500 MG/KG 4-VINYLCYCLOHEXENE, 4-VINYLCYCLOHEXENE MONOXIDE AND 4-VINYLCYCLOHEXENE DIEPOXIDE DEPLETED HEPATIC REDUCED GLUTATHIONE LEVELS SUGGESTING THAT GLUTATHIONE WAS PROBABLY INVOLVED IN METABOLISM OF 4-VINYLCYCLOHEXENE. [R34] *4-VINYL-1-CYCLOHEXENE DIOXIDE INCREASED (APPROX 10 TIMES) THE FORWARD MUTATION RATE OF V79 CHINESE HAMSTER CELLS. [R35] NTXV: *LD50 Rat (Carworth-Wistar) oral 1.6 g/kg; [R29] *LD50 Rat oral 2563 mg/kg; [R18] *LD50 Rabbit skin 16,640 mg/kg; [R18] NTP: *Toxicology and carcinogenesis studies of 4-vinylcyclohexene (greater than 98% pure), a dimer of 1,3-butadiene present in the off-gases from tire curing, were conducted by administering the chemical in corn oil by gavage 5 days per week at doses of 0, 200, or 400 mg/kg body weight to groups of 50 F344/N rats for 103 weeks. ... Many dosed rats died early in the 2 year studies (male: vehicle control, 17/50; low dose, 37/50; high dose, 45/50; female: vehicle control, 10/50; low dose, 22/55; high dose, 36/50; P < 0.001 for all groups except low dose female rats, for which p= 0.022). The poor survival of dosed male and female rats reduced the sensitivity of the studies for detecting the possible carcinogenic effects of 4-vinylcyiclohexene. Mean body weights of dosed rats were comparable to those of their respective vehicle controls, except for high dose males late in the study. Administration of 4-vinycyclohexene ... was associated with a slightly increased incidence of epithelial hyperplasia of the forestomach (1/50; 3/50; 5/47) and squamous cell papillomas or carcinomas (combined) of the skin in high dose males (0/50; 1/50; 4/50). Low dose female rats whose survival was more similar to that of the vehicle controls, had a marginally increased incidence of adenomas was more similar to that of the vehicle controls, had a marginally increased incidence of adenomas or squamous cell carcinomas (combined) of the clitoral gland (1/50; 5/50; 0/49). ... Under these conditions, the 2 year gavage studies of 4-vinylcyclohexene in male and female rats ... were considered inadequate studies of carcinogenicity because of extensive and early mortality at the high dose or at body doses and the lack of conclusive evidence of a carcinogenic effect. [R36] *Toxicology and carcinogenesis studies of 4-vinylcyclohexene (greater than 99% pure), a dimer of 1,3-butadiene present in the off-gases from tire curing, were conducted by administering the chemical in corn oil by gavage 5 days per week at doses of 0, 200, or 400 mg/kg body weight to groups of 50 B63F1 mice of each sex for 103 weeks. ... Survival of high dose mice of each sex was lower (p < 0.001) than that of the vehicle controls, whereas survival of low dose mice of each sex was comparable to that of the vehicle controls. Mean body weights of high dose mice of each sex were generally lower than those of the vehicle controls throughout most of the 2 year studies. ... In B6C3F1 mice, administration of 4-vinylcyclohexene ... was associated with mild, acute inflammatory lesions and epithelial hyperplasia of the forestomach, especially in males (0/47; 7/50; 7/46), and with an increased incidence of a number of other nonneoplastic lesions including lung congestion in high dose males and females, splenic red pulp atrophy in high dose males, congestion of the adrenal gland in high dose females and cytologic alteration of the adrenal cortex in low dose and high dose females. ... The incidences of uncommon ovarian neoplasms were markedly increased (p < 0.01) in both groups of dosed female mice (mixed tumor, benign: 0/49; 25/48, 52%; 11/47, 23%; granulosa cell tumor: 1/49, 2%; 9/48, 19%; 11/47, 23%; granulosa cell tumor or carcinoma [combined]: 1/49, 2%; 10/48, 21%; 13/47, 28%). In addition, a slight increase in the incidence of adrenal gland adenomas in high dose females was observed (0/50; 3/39, 6%; 4/48, 8%). The extensive mortality seen in the high dose male mice confounded interpretation of the increased incidences of malignant lymphomas and alveolar/bronchiolar adenomas or carcinomas (combined) of the lung seen in these animals surviving to the end of the study (malignant lymphomas: 3/37, 8%; 5/39, 13%; 4/7, 57%; alveolar/bronchiolar adenomas or carcinomas [combined]: 3/37, 8%; 9/39, 23%; 3/7, 43%). ... Under these conditions, the 2 year gavage studies of 4-vinylcyclohexene in ... male mice were considered inadequate studies of carcinogenicity because of extensive and early mortality at the high dose or at both doses and the lack of conclusive evidence of a carcinogenic effect. There was clear evidence of carcinogenicity of 4-vinylcyclohexene for female mice, as shown by markedly increased incidences of uncommon ovarian neoplasms at both doses. In addition, the increased incidence of adrenal gland adenomas in high dose female mice may have been related to the administration of 4-vinylcyclohexene. [R36] +4-Vinylcyclohexene (VCH) was evaluated for reproductive toxicity in CD-1 mice using a continuous breeding protocol. VCH was administered to the animals by gavage in corn oil at doses of 0, 100, 250, or 500 mg/kg/day. Exposure to VCH for 14 wks did not significantly affect measures of reproductive competence. including initial fertility, mean number of litters/pair, live litter size, the proportion of pups born alive, or adjusted live pup weight. Absolute live pup weight was decreased (males and sexes combined) at the high dose. F0 feed and water consumption were not adversely affected by treatment. At necropsy, the F0 females in the high-dose group had slightly decreased body weight. VCH did not adversely affect preweaning growth or survival in the F1 generation. High-dose (500 mg/kg/day VCH) males, selected on postnatal day 21 for inclusion in Task 4, had decreased body weight throughout Task 4 to scheduled necropsy. F1 females selected from the high-dose group for inclusion in Task 4 had decreased body weight beginning at 74±10 days of age through Task 4 to necropsy. There was no effect of VCH treatment on feed or water consumption. VCH had no effect on the reproductive competence of the F1 generation; adjusted live pup weight for females and the sexes combined was slightly but significantly depressed in the VCH-treated litters. At necropsy, relative, but not absolute, liver weight (males and females) and sperm motility were increased in the VCH-treated group; testicular spermatid count was decreased by VCH treatment. The number of primordial, growing, and antral oocytes was significantly reduced in VCH-treated females. VCH at doses up to 500 mg/kg/day had no significant adverse effect on reproductive competence in either the F0 or F1 generation. For the F1 males and females, this was in spite of a slight but significant reduction in spermatid head count (83% of control) and ovarian follicles (46-67% of control), respectively. F0 females receiving 500 mg/kg/day exhibited slight general toxicity manifested as an 8% decr in body weight after 18 wks treatment. F1 males and females receiving 500 mg/kg/day VCH exhibited generalized toxicity manifested as an 8-10% decr in body weight throughout Task 4. These data indicate that VCH did not cause a detectable decr in reproductive competence in the F0 generation, nor was reproductive function adversely affected in F1 mice at doses that caused decreased body weight and ovarian and testicular toxicity. [R37] ADE: *A single oral dose of 400 mg/kg 4-[ethylene-C]VCH (99%, containing tert-butylcatechol as antioxidant) in corn oil was given to fasted female B6C3F1 mice and female F344 rats. The mice excreted 95% of the admin dose within 24 hr, and the rats excreted 95% of the dose within 48 hr via urine (50-60%) and expired air (30-40%). Negligible amounts of VCH appeared as CO2; fecal elimination accounted for 3% to 9% of the dose. Total tissue radioactivity in mice at 24 hr constituted < 1% of the dose; in rats 3.4%, 1.1%, and 1.1% of the dose was retained in adipose tissue, skeletal muscle, and skin, respectively. Neither parent VCH nor its metabolites accumulated in the ovaries of either species [accounting for 0.05% of the admin dose], and there were no species-specific differences in ovarian distribution. [R20, 1991.1705] *A single dose of 400 mg/kg body weight (14)C-4-vinylcyclohexene given by oral gavage in corn oil to fasted female B6C3F1 mice and Fischer 344 rats resulted in peak blood levels of about 100 nmol/ml between 1 and 2 hours after administration. Mice eliminated 95% of the radioactivity within 24 hours, whereas rats required 48 hours. The main routes of excretion of the radioactivity were the urine (50-60%) and expired air (30-40%). The concentration of 4-vinylcyclohexene was highest in adipose tissue (about 5 umol/g), which was about 10 times higher than that in tissues such as liver, skin and ovary. [R38] METB: *WHEN 4-VINYLCYCLOHEXENE AND 4-VINYLCYCLOHEXANE MONOXIDE WERE ADMIN TO MICE AT 500 MG/KG, CYTOCHROME p450, CYTOCHROME B5, NADPH-CYTOCHROME C REDUCTASE, AMINOPYRINE-N-DEMETHYLASE AND EPOXIDE HYDROLASE WERE INDUCED. DOSES OF 500 MG/KG 4-VINYLCYCLOHEXENE, 4-VINYLCYCLOHEXENE MONOXIDE AND 4-VINYLCYCLOHEXENE DIEPOXIDE DEPLETED HEPATIC REDUCED GLUTATHIONE LEVELS SUGGESTING THAT GLUTATHIONE WAS PROBABLY INVOLVED IN METABOLISM OF 4-VINYLCYCLOHEXENE. [R34] *THE MAIN 4-VINYL-1-CYCLOHEXENE METABOLITE FORMED IN MICE LIVER MICROSOMES AFTER INCUBATION WAS 4-VINYLCYCLOHEXANE-1,2-DIOL. OTHER METABOLITES WERE 4-VINYL-1,2-EPOXYCYCLOHEXANE AND 4-VINYL-1-CYCLOHEXENE DIOXIDE. 4-VINYL-1-CYCLOHEXENE DIOXIDE INCREASED (APPROX 10 TIMES) THE FORWARD MUTATION RATE OF V79 CHINESE HAMSTER CELLS. [R35] *4-Vinylcyclohexene is metabolized in vitro by liver microsomal enzymes. The major metabolic products are 4-vinyl-1,2-epoxycyclohexane and 4-epoxyethyl-1,2-dihydroxycyclohexane, with trace amounts (less than 0.001%) of vinylcyclohexene diepoxide also being produced. [R39] *Wistar rat and Swiss mouse liver microsomal mixed function oxidase metabolize 4-vinylcyclohexene ... to 4-vinyl-1,2-epoxycyclohexane ..., 4-epoxyethylcyclohexene and traces of 4-epoxyethyl-1,2-epoxycyclohexane. These are further hydrolysed by epoxide hydrolase to the corresponding diols: 4-vinylcyclohexane-1,2-diol, 4-dihydroxyethylcyclohexene ... and possibly 4-epoxyethylcyclohexane-1,2-diol. The last two metabolites may be further metabolized to 4-dihydroxyethyl-1,2-epoxycyclohexane and the tetrol 4-dihydroxyethylcyclohexane-1,2-diol. [R40] *Human microsomes prepared from 12 cadavers or from liver resected at surgery metabolized VCH to VCH-1,2- or 7,8-epoxides in vitro even in the absence of glucose-6-phosphate (required for NADPH production). The 7,8-epoxide was formed 6 times slower than the 1,2-epoxide; there was no substantial difference in the rates measured for males and females. [R20, 1991.1705] *Liver microsomes from B6C3F1 mice formed 4-vinyl-1,2-epoxycyclohexane 13 times faster than microsomes from humans and six times faster than those from Fischer 344 rats. The rate of 4-vinylcyclohexene epoxidation by hepatic microsomes derived from men and women was similar. The rate of formation of 4-epoxyethylcyclohexene was about six times lower than that of 4-vinyl-1,2-epoxycyclohexane in humans. [R38] ACTN: *VINYLALICYCLIC OLEFINS DESTROYED HEPATIC CYTOCHROME P450 FROM PHENOBARBITAL-PRETREATED MALE MICE, IN PRESENCE OF NADPH; THE LOSS OF THE ENZYME WAS ALWAYS ACCOMPANIED BY A QUANTITATIVELY CORRELATED LOSS OF MICROSOMAL HEME. THE COMPOUNDS (INCL 4-VINYL-1-CYCLOHEXENE) CAUSED MUCH SMALLER LOSSES OF CYTOCHROME P450 AND HEME IN 3-METHYLCHOLANTHRENE-MICROSOMES THAN WITH PHENOBARBITAL ONES. THE EFFECT HAS BEEN SHOWN TO BE SPECIFIC FOR CYTOCHROME P450, IT IS NOT STIMULATED BY NADH, IT IS INHIBITED BY CARBON MONOXIDE, METYRAPONE, AND IT SHOWS PSEUDO FIRST-ORDER KINETICS. THE EPOXIDES OF THE PARENT ACTIVE OLEFINS DID NOT INTERVENE IN THE DESTRUCTION OF THE ENZYME. THE INABILITY OF THE EPOXIDES RELATED TO THESE OLEFINS TO DESTROY CYTOCHROME P450 AND THEIR STABILITY STRENGTHENS THE HYPOTHESIS THAT AN INTERMEDIATE ZWITTERION SPECIES IS RESPONSABLE FOR THE DESTRUCTIVE PROCESS BEFORE THE OXIRANE RING FORMATION. [R41] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4-Vinylcyclohexene's production and use in polymers and organic synthesis may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 15.7 mm Hg at 25 deg C indicates 4-vinylcyclohexene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-vinylcyclohexene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone. The half-life for reaction with hydroxyl radicals in air is estimated to be 4.3 hours; and the half-life for reaction with ozone in air is estimated to be 1.3 hours. If released to soil, 4-vinylcyclohexene is expected to have slight mobility based upon an estimated Koc of 3300. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 4.5X10-2 atm-cu m/mole. 4-Vinylcyclohexene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 4-vinylcyclohexene is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Based upon aerobic aqueous screening tests, 4-vinylcyclohexene is not expected to biodegrade rapidly. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.1 hours and 4.1 days, respectively. An estimated BCF of 571 suggests the potential for bioconcentration in aquatic organisms is high. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to 4-vinylcyclohexene may occur through inhalation and dermal contact with this compound at workplaces where 4-vinylcyclohexene, acrylonitrile-butadiene-styrene, or rubber compounds are produced or used. Consumers may be exposed to 4-vinylcyclohexene from volatiles from carpets based on monitoring data. (SRC) ARTS: *IT IS FORMED ON PROLONGED STORAGE OF BUTADIENE ... . [R13, p. V11 278] *4-Vinylcyclohexene's production and use in polymers and organic synthesis(1) may result in its release to the environment through various waste streams(SRC). [R42] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3300(SRC), determined from an measured log Kow of 3.93(2) and a regression-derived equation(3), indicates that 4-vinylcyclohexene is expected to have slight mobility in soil(SRC). Volatilization of 4-vinylcyclohexene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.5X10-2 atm-cu m/mole(SRC), derived from its vapor pressure, 15.7 mm Hg(4), and water solubility, 50 mg/l(5). The potential for volatilization of 4-vinylcyclohexene from dry soil surfaces may exist(SRC) based upon its vapor pressure(4). 4-Vinylcyclohexene, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the modified Japanese MITI test(2). Therefore, this compound should not biodegrade rapidly in soil(SRC). [R43] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3300(SRC), determined from a measured log Kow of 3.93(2) and a regression-derived equation(3), indicates that 4-vinylcyclohexene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 4.5X10-2 atm-cu m/mole(SRC), derived from its vapor pressure, 15.7 mm Hg(4), and water solubility, 50 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.1 hours and 4.1 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 571(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is high(SRC). 4-Vinylcyclohexene, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the modified Japanese MITI test(2). Therefore, this compound is not expected to biodegrade rapidly in aqueous systems(SRC). [R44] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-vinylcyclohexene, which has a vapor pressure of 15.7 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase 4-vinylcyclohexene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC). The half-life for reaction in air with hydroxyl radicals is estimated to be 4.3 hours(SRC), calculated from its rate constant of 8.93X10-11 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). The half-life for reaction in air with ozone is estimated to be 1.3 hours(SRC), calculated from its rate constant of 2.12X10-16 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). [R45] BIOD: *AEROBIC: 4-Vinylcyclohexene, present at 100 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum at 30 mg/l and the modified Japanese MITI test(1). Therefore, this compound is not expected to biodegrade rapidly in the environment(SRC). [R46] ABIO: *The rate constant for the vapor-phase reaction of 4-vinylcyclohexene with photochemically-produced hydroxyl radicals has been estimated as 8.93X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of 4-vinylcyclohexene with photochemically-produced ozone has been estimated as 2.12X10-16 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1.3 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(1). 4-Vinylcyclohexene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm)(SRC). [R47] BIOC: *An estimated BCF of 571 was calculated for 4-vinylcyclohexene(SRC), using a log Kow of 3.93(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC). [R48] KOC: *The Koc of 4-vinylcyclohexene is estimated as 3300(SRC), using a measured log Kow of 3.93(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 4-vinylcyclohexene is expected to have slight mobility in soil(SRC). [R49] VWS: *The Henry's Law constant for 4-vinylcyclohexene is estimated as 4.5X10-2 atm-cu m/mole(SRC), derived from its vapor pressure, 15.7 mm Hg(1), and water solubility, 50 mg/l(2). This Henry's Law constant indicates that 4-vinylcyclohexene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 1.1 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4.1 days(SRC). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The estimated volatilization half-life from a model pond is 19 days if adsorption is considered(4). 4-Vinylcyclohexene's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 4- vinylcyclohexene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 15.7 mm Hg(1). [R50] EFFL: *The concn of 4-vinylcyclohexene in air emissions from extruded ABS composite resins was between 0.26-6.50 ug/l(1). The quasi steady-state emission rate of 4-vinylcyclohexene from new carpets (measured in an environmental chamber) ranged 7.3-24.2 and 0.6-2.7 ug/sq m per hr after 24 and 168 hours of equilibration, respectively(2). [R51] ATMC: *INDOOR AIR: The indoor air concn of 4-vinylcyclohexene was 0.27 ppb in a freshly carpeted 20 cu m stainless-steel room after a 168 hours equilibration period(1). [R52] RTEX: *Occupational exposure to 4-vinylcyclohexene may occur through inhalation and dermal contact with this compound at workplaces where 4-vinylcyclohexene, acrylonitrile-butadiene-styrene, or rubber compounds are produced or used(SRC). Concn of 4-vinylcyclohexene in workplace air averaged between 1.2-2.4 g/cu m and occasionally reached 3 g/cu m(1). The concn of 4-vinylcyclohexene was between 30-210 ug/cu m in the workplace air of shoe-sole factories that use polyisoprene, styrene-butadiene, and cis-polybutadiene polymers(2). The mean concn of 4-vinylcyclohexene in workplace air during rubber vulcanization at a tire manufacturing facility was between 71-92 ppb(3). Consumers may be exposed to 4-vinylcyclohexene from volatiles from carpets based on monitoring data(SRC). [R53] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: *8 hr Time Weighted Avg (TWA) 0.1 ppm [R54, 71] *A3: Confirmed animal carcinogen with unknown relevance to humans. [R54, 71] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R54, 6] OOPL: *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 5 ppm. [R55] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R56] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 4-Vinylcyclohexene is included on this list. [R57] *A testing consent order is in effect for 4-Vinylcyclohexene for health effects and chemical fate testing. FR publication date: 9/23/91. [R58] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GC was used to determine the quantity of 4-vinylcyclohexene formed from butadiene by its dimerization in the GC. [R59] *Quick simple method using GC with flame ionization for determination of 4-vinyl-1-cyclohexane in air. Sensitive to 1 ppm using 1 ml of air. [R60] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinylcyclohexene in F344/N Rats (Gavage Studies) Technical Report Series No. 303 (1986) NIH Publication No 86-2559 SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V4 316 (1978) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 777 (1979) R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 (1992) 670 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1170 R6: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 962 R7: Sittig, M. 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V60 351 (1994) R34: GIANNARINI C ET AL; TOXICOL LETT (AMST) 8 (1-2): 115 (1981) R35: GERVASI PG ET AL; IND ENVIRON XENOBIOTICS PROC INT CONF: 205 (1981) R36: DHHS/NTP; Toxicology and Carcinogenesis of 4-Vinylchlohexene in F344/N Rats andB6C3F1 Mice (Gavage Studies) p.9 (1986) Technical Rpt Series No. 303 NIH Pub No. 86-2559 R37: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of 4-Vinylcyclohexene (CAS No. 100-40-3) in CD-1 Swiss Mice, NTP Study No. RACB90035 (May 6, 1991) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 352 (1994) R39: DHHS/NTP; Toxicology and Carcinogenesis of 4-Vinylchlohexene in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.17 (1986) Technical Rpt Series No. 303 NIH Pub No. 86-2559 R40: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V32 186 (1986) R41: TESTAI E ET AL; BIOCHEM BIOPHYS RES COMMUN 107 (2): 633 (1982) R42: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary 13th ed NY, NY: John Wiley and Sons Inc. p. 1170 (1997) (2) Schaeffer VH et al; J Air Waste Management Assoc 46: 813-20 (1996) R43: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. 5th Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R44: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. 5th Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R45: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R46: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R47: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R48: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R49: (1) Chem Inspect Test Inst; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R50: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. 5th ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (4) US EPA; EXAMS II Computer Simulation (1987) R51: (1) Contos DA et al; J Air Waste Manage Assoc 45: 686-94 (1995) (2) Hodgson et al; in Proc Annu Meet-Air Waste Manage Assoc 85th, 92-79.15, p. 19 (1992) R52: (1) Weschler CJ et al; Environ Sci Technol 26: 2371-7 (1992) R53: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, International Agency For Research on Cancer Occupational. 11: 278 (1975) (2) Cocheo V et al; Am Ind Hyg Assoc J 44: 521-527 (1983) (3) Rappaport SM; pp. 185-216 in Proc Environ Aspects of Chem Use in Rubber Processing Operations Mar 12-14. USEPA 560/1 75-002 (1975) R54: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R55: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.41 R56: 40 CFR 712.30 (7/1/2000) R57: 40 CFR 716.120 (7/1/2000) R58: 40 CFR 799.5000 (7/1/2000) R59: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. P:V11 278 (1975) R60: Bianchi A, Muccioli G; ICP 9: 77 (1980) RS: 63 Record 193 of 1119 in HSDB (through 2003/06) AN: 2876 UD: 200302 RD: Reviewed by the SRP on 3/11/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-NITROSODIPHENYLAMINE- SY: *AMINE,-DIPHENYL,-4-NITROSO-; *BENZENAMINE,-4-NITROSO-N-PHENYL-; *DIPHENYLAMINE,-4-NITROSO-; *DIPHENYLNITROSAMINE-; *NAUGARD-TKB-; *NCI-C02244-; *P-NITROSODIFENYLAMIN- (CZECH); *P-NITROSODIPHENYLAMINE-; *4-NITROSO-N-PHENYLANILINE-; *PARA-NITROSO-N-PHENYLANILINE-; *4-NITROSO-N-PHENYLBENZENAMINE-; *NITROUS-DIPHENYLAMIDE-; *N-PHENYL-PARA-NITROSOANILINE-; *TKB- RN: 156-10-5 MF: *C12-H10-N2-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PROBABLY BY REACTION OF AN ALKYL ETHER OF 4-NITROSOPHENOL WITH ANILINE. [R1] *PARA-NITROSODIPHENYLAMINE CAN BE PREPARED BY THE FISCHER-HEPP REARRANGEMENT OF N-NITROSODIPHENYLAMINE; THIS IS BELIEVED TO BE THE METHOD USED FOR ITS COMMERCIAL PRODUCTION. [R2] FORM: *PARA-NITROSODIPHENYLAMINE IS AVAILABLE IN THE USA AS A PURPLE SOLID, TYPICALLY CONTAINING 95% ACTIVE INGREDIENT, 0.25% ASH, AND WITH A MELTING RANGE OF 140 TO 145 DEG C. [R2] MFS: *Uniroyal Chemical Company, Inc, Hq. World Headquarters, Middlebury, CT, 06749, (203) 573-2000; Production site: Geismar, LA 70734 [R3] OMIN: *USE OF PARA-NITROSODIPHENYLAMINE AS A CHEMICAL INTERMEDIATE IS BELIEVED TO BE LIMITED PRIMARILY TO THE PRODUCTION OF N-PHENYL-PARA-PHENYLENEDIAMINE AND ITS DERIVATIVES. THIS DIAMINE SERVES AS AN AZOIC DIAZO COMPONENT, AS AN OXIDATION BASE, AS A DEVELOPER OF DIAZOTIZED DIRECT DYES, AND AS AN INTERMEDIATE IN THE MANUFACTURE OF OTHER DYES. IT IS ALSO BELIEVED TO BE USED AS AN ANTIOXIDANT IN RUBBER AND AS AN INTERMEDIATE IN THE SYNTHESIS OF OTHER ANTIOXIDANTS. [R2] USE: *ACCELERATOR FOR RUBBER VULCANIZATION [R1] *USED AS A CHEMICAL INTERMEDIATE FOR DYES AND PHARMACEUTICALS AND AS A POLYMERIZATION INHIBITOR DURING THE MANUFACTURE OF VINYL MONOMERS SUCH AS STYRENE. [R2] CPAT: *ESSENTIALLY 100% AS ACCELERATOR FOR RUBBER VULCANIZATION [R1] PRIE: U.S. PRODUCTION: *(1975) PROBABLY GREATER THAN 9.08X10+5 G [R1] *(1977) PROBABLY GREATER THAN 9.08X10+5 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *GREEN PLATES WITH BLUISH LUSTER (FROM BENZENE) OR STEEL-BLUE PRISMS OR PLATES (FROM ETHER + WATER) [R4]; *YELLOW LIQUID PLATES [R5]; *Greenish crystals [R6] MP: *144-145 DEG C [R4] MW: *198.24 [R7] SOL: *SLIGHTLY SOL IN WATER OR PETROLEUM ETHER; FREELY SOL IN ALCOHOL, ETHER, CHLOROFORM, BENZENE [R4] SPEC: *MAX ABSORPTION (ALCOHOL-HYDROCHLORIC ACID): 259 NM (LOG E= 3.62); 406 NM (LOG E= 4.31) [R8]; *IR: 9744 (Sadtler Research Laboratories Prism Collection) [R9]; *UV: 17154 (Sadtler Research Laboratories Spectral Collection) [R9]; *MASS: 1156 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R9] OCPP: *UNDERGOES REDUCTION, ALKYLATION AND NITROSATION; FORMS SALTS WITH STRONG ACIDS AND BASES; THE BASIC SALTS REARRANGE TO A QUINOID STRUCTURE. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *WHEN HEATED TO DECOMPOSITION, IT EMITS TOXIC FUMES OF NITROGEN OXIDES. [R10] EQUP: *Wear nitrile rubber gloves, protective laboratory coat, self-contained breathing apparatus, eye protection and protective shoes. /Nitrosamines/ [R11] SSL: *AN UNUSUALLY STABLE NITROSO COMPOUND [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R12] NTOX: *TWO GROUPS OF 50 MALE AND 50 FEMALE B6C3F1 MICE, SIX WEEKS OF AGE, WERE FED DIETS CONTAINING PARA-NITROSODIPHENYLAMINE (TECHNICAL GRADE, 73% ACTIVE MATERIAL, 25% WATER, WITH UNSPECIFIED IMPURITIES). THE LOW DOSE GROUP RECEIVED 5000 MG/KG OF DIET FOR 40 WEEKS, THEN 2500 MG/KG FOR 17 WEEKS; THE HIGH DOSE GROUP RECEIVED 10000 MG/KG OF DIET FOR 40 WEEKS, THEN, AFTER A SEVEN WEEK INTERVAL, 5000 MG/KG FOR 10 WEEKS. BOTH GROUPS WERE OBSERVED FOR AN ADDITIONAL 35 WEEKS. A GROUP OF 20 ANIMALS OF EACH SEX SERVED AS MATCHED CONTROLS AND WERE KEPT UNDER OBSERVATION FOR 92 WEEKS. OF THE HIGH DOSE GROUP, 19 MALES AND 21 FEMALES DIED BEFORE 52 WEEKS DUE TO TOXICITY. BY THE END OF THE STUDY, 85, 88, AND 60% OF MALES AND 90, 84 AND 52% OF THE FEMALES WERE STILL ALIVE IN THE CONTROL, LOW DOSE AND HIGH DOSE GROUPS, RESPECTIVELY. A STATISTICALLY SIGNIFICANT INCREASE IN INCIDENCE OF LIVER TUMORS WAS OBSERVED IN TREATED MALE MICE ONLY: HEPATOCELLULAR CARCINOMA OR ADENOMA- 2/18 IN CONTROLS, 22/42 IN LOW DOSE ANIMALS (P= 0.002) AND 12/13 IN THE HIGH DOSE ANIMALS (P= 0.038); INCIDENCES OF HEPATOCELLULAR CARCINOMAS ALONE WERE 0/18, 10/42 (P= 0.02) AND 1/31 IN THE THREE GROUPS, RESPECTIVELY. [R13] *IN A FOUR WEEK SUBCHRONIC STUDY, FISCHER 344 RATS AND B6C3F1 MICE WERE FED DIETS CONTAINING UP TO 3.2% AND 2.6% PARA-NITROSODIPHENYLAMINE, RESPECTIVELY. THERE WAS DOSE RELATED MORTALITY IN MALE AND FEMALE MICE, BUT NOT IN RATS. THE RATS SHOWED A DOSE DEPENDENT DEPRESSION OF MEAN BODY WEIGHT GAIN OF UP TO 53%. [R14] *PARA-NITROSODIPHENYLAMINE DID NOT TRANSFORM CELLS OF EMBRYOS EXCISED FROM PREGNANT HAMSTERS TREATED INTRAPERITONEALLY WITH UP TO 20 MG/KG BODY WEIGHT. [R14] *A bioassay of N-nitrosodiphenylamine for possible carcinogenicity was /administered in/ feed to mice and rats. Rats of each sex received either 1000 or 4000 ppm for 100 weeks. Male mice received 10,000 or 20,000 ppm for 101 weeks. Female mice received either 2315 or 5741 ppm (Time-weighted average). Carcinogenesis occurred in both sexes of rats, with transitional cell carcinomas of the urinary bladder, but not in the mice. /N-Nitrosodiphenylamine/ [R15] *p-Nitrosodiphenylamine showed no evidence of potential carcinogenicity in an in vivo-in vitro combination bioassay. Pregnant Syrian golden hamsters were given an intraperitoneal injection of 0.5 ml of a solution containing 0.5 to 2 mg of the chemical per 100 gm maternal weight on day 10 or 11 of gestation. Embryos were excised at day 13, and cells from these embryos were cultured and scored for transformation. No transformed cells were observed. Subcutaneous injection of the cultured cells into weanling, male hamsters produced no tumors. [R16] NTP: *A bioassay for the possible carcinogenicity of p-nitrosodiphenylamine was conducted using Fischer 344 rats and B6C3F1 mice. p-Nitrosodiphenylamine was administered in the feed ... /to/ 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of p-nitrosodiphenylamine were, respectively, 5000 and 2500 ppm for rats. The high and low time-weighted average concentrations for mice were 9000 and 4254 ppm, respectively. The compound was administered for 78 weeks to rats, for 50 weeks to high dose mice and for 57 weeks to low dose mice. The period of compound administration was followed by an observation period of 27 weeks for rats and 35 weeks for mice. There were significant positive associations between the concentrations of p-nitrosodiphenylamine administered and mortality among male and female mice, but not for rats of either sex. ... Under the conditions of this bioassay, p-nitrosodiphylamine was carcinogenic when administered in the diet to male B6C3F1 mice, causing hepatocellular carcinomas. The chemical was also carcinogenic in male Fischer 344 rats, causing liver neoplasms. No evidence was provided for the carcinogenicity of p-nitrosodiphenylamine in female B6C3F1 mice or in female Fischer 344 rats. [R17] METB: *THE INTESTINES OF RATS TREATED IP WITH 1 G N-NITROSODIPHENYLAMINE WERE STAINED AND DILATED AFTER 24 HOURS. N-NITROSODIPHENYLAMINE WAS RAPIDLY REMOVED FROM THE LIVER AND KIDNEY WITH DIPHENYLAMINE AS AN IMPORTANT DEGRADATION PRODUCT. /N-NITROSODIPHENYLAMINE/ [R18] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *PARA-NITROSODIPHENYLAMINE HAS BEEN PRODUCED COMMERCIALLY SINCE AT LEAST 1970. ITS USE AS A CHEMICAL INTERMEDIATE COULD RESULT IN OCCUPATIONAL EXPOSURE. [R19] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *COLORIMETRIC DETERMINATION OF P-NITROSODIPHENYLAMINE IN WASTE WATER. [R20] *HIGH PERFORMANCE LIQUID CHROMATOGRAPHY METHOD IS USED FOR ANALYSIS OF PARA-NITROSODIPHENYLAMINE IN AMINE MIXTURES; ... HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY OF COMPOUNDS OBTAINED DURING THE PRODUCTION OF N-NITROSODIPHENYLAMINE. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of p-Nitrosodiphenylamine for Possible Carcinogenicity (1979) Technical Rpt Series No. 190 DHEW Pub No. (NIH) 79-1746 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting p-Nitrosodiphenylamine(156-10-5); Reason: Insufficient evidence of carcinogenicity. SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 227 (1982) R3: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 811 R4: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1049 R5: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-320 R6: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 832 R7: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8209 R8: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-108 R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 571 R10: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2048 R11: Armour, M.A. Hazardous Laboratory Chemicals Disposal Guide. Boca Raton, FL: CRC Press Inc., 1991. 256 R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 68 (1987) R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 230 (1982) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 231 (1982) R15: DHEW/NCI; Bioassay of N-Nitrosodiphenylamine for Possible Carcinogenicity p.V 1979 Technical Rpt Series No. 164 DHEW Pub No. (NIH) 79-720 R16: DHEW/NCI; Bioassay of p-Nitrosodiphenylamine for Possible Carcinogenicity p.3 (DATE) Technical Rpt Series No. 190 DHEW Pub No. (NIH) 79-1746 R17: DHEW/NCI; Bioassay of p-Nitrosodiphenylamine for Possible Carcinogenicity p.VIII (1979) Technical Rpt Series No. 190 DHEW Pub No. (NIH) 79-1746 R18: ROSENBERG C ET AL; BIOCHEM PHARMACOL 32 (6): 1119 (1983) R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 232 (1982) R20: LEVITAN VD, ZELENEVA OA; METODY ANAL KONTROLYA KACH PROD KHIM PROM-STI 3: 62 (1978) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 229 (1982) RS: 12 Record 194 of 1119 in HSDB (through 2003/06) AN: 2879 UD: 200302 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,3-DIBROMOPROPANOL- SY: *1,2-DIBROMOPROPAN-3-OL-; *2,3-DIBROMO-1-PROPANOL-; *2,3-DIBROMOPROPYL-ALCOHOL-; *NCI-C55436-; *1-PROPANOL,-2,3-DIBROMO-; *USAF-DO-42- RN: 96-13-9 MF: *C3-H6-Br2-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ALLYL ALCOHOL WITH BROMINE IN CARBON TETRACHLORIDE [R1] MFS: +Great Lakes Chemical Corporation, Hq, Highway 52, North West, West Lafayette, IN 47906, (317) 497-6100; Production sites: El Dorado, AR 71730 [R2] USE: *Intermediate in the preparation of flame retardants, insecticides, and pharmaceuticals. [R3] *Main use is in the production of tris(1,2,3-dibromopropyl) phosphate, commonly called Tris. [R4] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R3] BP: *219 DEG C [R3] MW: *217.91 [R5] DEN: *2.120 @ 20 DEG C/4 DEG C [R3] SOL: *SOL IN ACETONE, ALCOHOL, ETHER, BENZENE [R3]; *In water, 5.20X10+4 mg/l @ 25 deg C. [R4] VAP: *0.09 mm Hg @ 25 deg C [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes. [R7] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *A SINGLE IP INJECTION OF THE CARCINOGENIC FLAME RETARDANT, TRIS(2,3-DIBROMOPROPYL)PHOSPHATE (TRIS-BP) (154 MG/KG), WHEN ADMIN TO MALE SPRAGUE-DAWLEY RATS, CAUSED POLYURIC ACUTE RENAL FAILURE WITH TUBULAR NECROSIS INVOLVING THE LATE PROXIMAL TUBULE. GLOMERULAR FILTRATION RATE AND IN VITRO TRANSPORT OF THE ORGANIC ACID, PARA-AMINOHIPPURATE AND THE ORGANIC BASE, METHYLNICOTINAMIDE, WERE DEPRESSED. IN CONSTRAST, AN APPROX EQUIMOLAR DOSE OF THE METABOLITE 2,3-DIBROMOPROPANOL (BP) (61 MG/KG) WAS NONNEPHROTOXIC. [R8] *... CONCLUSIONS Under the conditions of these long term dermal studies, there was clear evidence of carcinogenic activity of 2,3-dibromo-1 -propanol in male F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, tunica vaginalis, and spleen. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, clitoral gland, and mammary gland. There was clear evidence of carcinogenic activity of 2,3-dibromo-1- propanol in male B6C3F1 mice based on increased incidences of neoplasms of the skin, forestomach, liver, and lung. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female B6C3F1 mice based on increased incidences of neoplasms of the skin and the forestomach. The increased incidences of alveolar/bronchiolar adenomas in female mice may have been related to chemical administration. [R9] *2,3-Dibromo-1-propanol is a metabolite of the flame retardant tris(2,3-dibromopropyl) phosphate, previously shown to be a mutagen and carcinogen in experimental animals. Toxicology and carcinogenesis studies of 2,3-dibromo-1-propanol were conducted by applying the chemical in 95% ethanol to the interscapular skin of male and female F344/N rats and B6C3F1 mice 5 days a week for 13 weeks in the prechronic study and 48-55 weeks (rats) or 36-42 weeks (mice) in the carcinogenicity study. In the 13-week study, 10 rats and 10 mice of each sex received doses of 0, 44, 88, 177, 375, or 750 mg/kg. Deaths associated with chemical application occurred only in the high-dose (750 mg/kg) male mice. Chemical-related lesions were seen in the kidney of male rats, liver of female rats, and liver and lung of both sexes of mice. Based on the toxicity observed in the 13-week study, 50 rats of each sex received doses of 0, 188, or 375 mg/kg and 50 mice of each sex received 0, 88, or 177 mg/kg in the carcinogenicity study. The planned 2-year study was terminated early because of reduced survival of rats related to chemical-induced neoplasia and because of the appearance of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Nearly all dosed rats had malignant neoplasms at one or more sites, while only one control male and one control female had malignant neoplasms. In rats, neoplasms induced by 2,3-dibromo-1-propanol occurred in the skin, nasal mucosa, Zymbal's gland, oral mucosa, esophagus, forestomach, intestines, liver, kidney, mammary gland (females), clitoral gland (females), spleen (males), and mesothelium (males). In mice, chemical-induced neoplasms occurred in the skin, forestomach, liver (males), and lung (males). [R10] *Drosophila mutagenicity tests of 45 chemical compounds were assayed for the National Toxicology Program. Each chemical was tested blind for the induction of sex linked recessive lethals. The nine positive compounds that induced recessive lethals included 1,2-dibromo-3-chloropropane and 2,3-dibromo-1-propanol. 1,2-Dibromo-3-chloropropane was found to be strongly mutagenic. [R11] NTP: *... Toxicology and carcinogenicity studies were conducted by applying 2,3-dibromo-1-propanol (approximately 98% pure) in ethanol to the subscapular area of the skin of male and female F344/N rats and B6C3F1 mice 5 days/wk for ... 48 to 51 weeks (male rats), 52 to 55 weeks (female rats), 36 to 39 weeks (male mice), or 39 to 42 weeks (female mice). ... LONG-TERM STUDY IN RATS: Originally planned to last for 2 years, the chronic study in rats was terminated early because of reduced survival in the high-dose groups related to chemical induced neoplasms and because of the detection of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female rats received dermal applications of 0, 188 or 375 mg/kg 2,3-dibromo-1-propanol 5 days/wk for 48 to 51 wk (males) or 52 to 55 (females). LONG-TERM STUDY IN MICE: Originally planned to last for 2 yr, the chronic study in mice was terminated early because of the detection of antibodies to lymphocytic choriomeningitis virus in sentinel mice. Groups of 50 male and 50 female mice received dermal applications of 0, 88, or 177 mg/kg 2,3-dibromo-1-propanol 5 days/wk for 36 to 39 wk (males) or 39 to 42 wk (females). CONCLUSIONS Under the conditions of these long term dermal studies, there was clear evidence of carcinogenic activity of 2,3-dibromo-1 -propanol in male F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, tunica vaginalis, and spleen. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female F344/N rats based on increased incidences of neoplasms of the skin, nose, oral mucosa, esophagus, forestomach, small and large intestine, Zymbal's gland, liver, kidney, clitoral gland, and mammary gland. There was clear evidence of carcinogenic activity of 2,3-dibromo-1- propanol in male B6C3F1 mice based on increased incidences of neoplasms of the skin, forestomach, liver, and lung. There was clear evidence of carcinogenic activity of 2,3-dibromo-1-propanol in female B6C3F1 mice based on increased incidences of neoplasms of the skin and the forestomach. The increased incidences of alveolar/bronchiolar adenomas in female mice may have been related to chemical administration. [R9] METB: *2,3-DIBROMOPROPANOL, A METABOLITE OF TRIS-BP AND A MUTAGEN ITSELF, WAS FOUND IN THE URINE SAMPLES OF 10 CHILDREN WHO WERE WEARING OR WHO WORE TRIS-BP-TREATED SLEEPWEAR. [R12] *WHEN TRIS(2,3-DIBROMOPROPYL) PHOSPHATE WAS APPLIED TO THE SKIN OF A RAT, ITS HYDROLYSIS PRODUCT, 2,3-DIBROMOPROPANOL, WAS DETECTED IN THE URINE. [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,3-Dibromopropanol's production and use as a chemical intermediate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 0.09 mm Hg at 25 deg C indicates 2,3-dibromopropanol will exist solely as a vapor in the ambient atmosphere. Vapor-phase 2,3-dibromopropanol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 8 days. If released to soil, 2,3-dibromopropanol is expected to have very high mobility based upon an estimated Koc of 4. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 6.3X10-8 atm-cu m/mole. Limited data indicate that 2,3-dibronopropanol may biodegrade under aerobic conditions. If released into water, 2,3-dibromopropanol is not expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. 2,3-Dibromopropanol may slowly hydrolyze in basic waters although the rate of this process is expected to be slower than for biodegradation. Occupational exposure to 2,3-dibromopropanol may occur through inhalation and dermal contact with this compound at workplaces where 2,3-dibromopropanol is produced or used. (SRC) ARTS: *2,3-Dibromopropanol's production and use as a chemical intermediate for flame retardants, insecticides, and pharmaceuticals(1) may result in its release to the environment through various waste streams(SRC). [R14] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 4(SRC), determined from a structure estimation method(2), indicates that 2,3-dibromopropanol is expected to have very high mobility in soil(SRC). Volatilization of 2,3-dibromopropanol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.3X10-8 atm-cu m/mole(SRC), obtained using a fragment constant estimation method(3). 2,3-Dibromopropanol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.09 mm Hg(4). Limited data indicate that 2,3-dibromopropanol may biodegrade under aerobic conditions(5). [R15] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 4(SRC), determined from a structure estimation method(2), indicates that 2,3-dibromopropanol is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 6.3X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3(3,SRC), from an estimated log Kow(6,SRC), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Limited data indicate that 2,3-dibromopropanol may biodegrade under aerobic conditions(7). [R16] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,3-dibromopropanol, which has a vapor pressure of 0.092 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 2,3-dibromopropanol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half- life for this reaction in air is estimated to be 8 days(SRC) from its estimated rate constant of 2.07X10-12 atm cu m/mol(3). [R17] BIOD: *Cell-free extracts of Flavobacterium sp isolated from soil degraded 2,3-dibromopropanol to epibromohydrin, dihydroxybromopropane, glycidol, and ultimately glycerin(1,2). [R18] ABIO: *The rate constant for the vapor-phase reaction of 2,3-dibromopropanol with photochemically-produced hydroxyl radicals has been estimated as 2.1X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 8 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 2,3-Dibromopropanol is not expected to directly photolyze due to the lack of absorption in the environmental spectrum(2). [R19] BIOC: *An estimated BCF of 3 was calculated for 2,3-dibromopropanol(SRC), using an estimated log Kow of 0.96(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R20] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 2,3-dibromopropanol can be estimated to be about 4(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2,3-dibromopropanol is expected to have very high mobility in soil. [R21] VWS: *The Henry's Law constant for 2,3-dibromopropanol is estimated as 6.3X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2,3-dibromopropanol is expected to be essentially nonvolatile(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 107 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 780 days(SRC). 2,3-Dibromopropanol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). 2,3-Dibromopropanol is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.092 mm Hg(3). [R22] RTEX: *Occupational exposure to 2,3-dibromopropanol may occur through inhalation and dermal contact with this compound at workplaces where 2,3-dibromopropanol is produced or used. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R23] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2,3-Dibromopropanol is included on this list. [R24] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2,3-Dibromo-1-propanol in F344/N Rats and B6C3F1 Mice (Dermal Studies) Technical Report Series No. 400 (1993) NIH Publication No. 94-2855 SO: R1: SRI R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 555 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 370 R4: Lande SS; Investigation of selected potential environmental contaminants: haloalcohols. USEPA-560/11-80-004 (1980) R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8212 R6: Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. NY,NY: Lewis Pub (1997) R7: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1068 R8: ELLIOTT WC ET AL; TOXICOL APPL PHARMACOL 62 (1): 179 (1982) R9: Toxicology and Carcinogenesis Studies of 2,3-Dibromo-1-Propanol in F344/N Rats and B6C3F1 Mice (Dermal Studies). Technical Report Series No. 400 (1993) NIH Publication No. 94-2855 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R10: Eustis SL et al; Fundam Appl Toxicol 26 (1): 41-50 (1995) R11: Yoon JS et al; Environ Mutagenesis 7 (5): 349-67 (1985) R12: BLUM A ET AL; SCIENCE (WASH DC) 201 (4360): 1020 (1978) R13: ST JOHN LE JR ET AL; BULL ENVIRON CONTAM TOXICOL 15 (2): 192 (1976) R14: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th Ed. NY,NY: Van Nostrand Reinhold Company (1993) R15: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. NY,NY: Lewis Pub (1997) (5) Castro CE; Environ Health Perspec 21: 279-83 (1977) R16: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Castro CE; Environ Health Perspec 21: 279-83 (1977) R17: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. NY,NY: Lewis Pub (1997) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R18: (1) Castro CE, Bartnicki EW; Biochem 7: 3213-8 (1968) (2) Castro CE; Environ Health Perspec 21: 279-83 (1977) R19: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R20: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R21: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) R22: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Howard PH, Meylan WM; Handbook of Physical Properties of Organic Chemicals. NY,NY: Lewis Pub (1997) R23: 40 CFR 712.30 (7/1/97) R24: 40 CFR 716.120 (7/1/97) RS: 19 Record 195 of 1119 in HSDB (through 2003/06) AN: 2884 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N-PHENYLHYDROXYLAMINE- SY: *ANILINE,-N-HYDROXY-; *BENZENAMINE,-N-HYDROXY-; *BENZENE,-HYDROXYLAMINO-; *N-HYDROXYANILINE-; *N-HYDROXYBENZENAMINE-; *HYDROXYLAMINE,-N-PHENYL-; *NCI-C60093-; *PHENYLHYDROXYAMINE-; *PHENYLHYDROXYLAMINE-; *BETA-PHENYLHYDROXYLAMINE- RN: 100-65-2 MF: *C6-H7-N-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF AN ALCOHOLIC SOLUTION OF NITROBENZENE WITH ZINC DUST AND A SMALL QUANTITY OF CALCIUM CHLORIDE [R1] +PREPD BY ZINC REDUCTION OF NITROBENZENE IN AMMONIUM CHLORIDE SOLN: KAMM, ORG SYNTH 4, 57 (1925). [R2] MFS: *NOT PRODUCED COMMERCIALLY IN US [R1] USE: +CHEMICAL INTERMEDIATE FOR CUPFERRON (A REAGENT) AND P-AMINOPHENOL [R1] CPAT: *ESSENTIALLY 100% AS CHEMICAL INTERMEDIATE [R1] PRIE: U.S. PRODUCTION: *(1972) NOT PRODUCED COMMERCIALLY IN US [R1] *(1975) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEEDLES FROM SATURATED SODIUM CHLORIDE SOLN [R2]; *NEEDLES FROM WATER, BENZENE OR PETROLEUM ETHER SOLN [R3] MP: *82 DEG C [R2] MW: *109.14 [R4] SOL: *VERY SOL IN CHLOROFORM; INSOL IN PETROLEUM ETHER; FREELY SOL IN ALCOHOL, CARBON DISULFIDE, DIL MINERAL ACID, ETHER, HOT BENZENE, ACETIC ACID [R3] SPEC: *MAX ABSORPTION (ALCOHOL): 236 NM (LOG E= 3.8); 279 NM (LOG E= 3.0) [R3]; +UV: 1-94 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R5]; +MASS: 119 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *DETERIORATES ON STORAGE [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *.../THERE HAVE BEEN/ RATHER SEVERE POISONINGS FROM PHENYLHYDROXYLAMINE /IN INDUSTRIAL PLANTS/, AND STILL HAVE NOT OBSERVED IN MAN CONCN BEYOND APPROX 75% METHEMOGLOBIN. [R6, 2115] *METHEMOGLOBIN LEVELS TO 40% MAY EXIST WITHOUT SYMPTOMS OTHER THAN SENSE OF WELL-BEING. @ HIGHER CONCN HEADACHE MAY BECOME SEVERE; WEAKNESS, ATAXIA AND LIGHTHEADEDNESS OCCUR. WITH INCREASING CONCN...DYSPNEA, TACHYCARDIA AND ALARMING CYANOSIS ARE NOTED. EVEN @...LEVELS APPROXIMATING 75%, HOWEVER, RECOVERY WITHOUT SPECIFIC THERAPY HAS BEEN THE RULE. /AROMATIC AMINO COMPD/ [R7] *HUMAN FIBROBLASTS WERE ALLOWED TO ATTACH TO PLASTIC PETRI DISHES FOR 4 HOURS AND EXPOSED IN SERUM-FREE MEDIUM FOR 2 HOURS TO N-PHENYLHYDROXYLAMINE (0.001-0.5 MMOL). THE TREATMENT MEDIUM WAS REPLACED WITH COMPLETE MEDIUM CONTAINING 5-BROMODEOXYURIDINE (10 MUMOL), AND CELLS WERE ALLOWED TO GROW FOR 48 HOURS WITH COLCEMIDE PRESENT FOR THE FINAL 4.5 HOURS. CELL CYCLE ANALYSES (PERCENTAGE OF CELLS IN 1ST, 2ND, OR 3RD DIVISION) REVEALED THAT N-PHENYLHYDROXYLAMINE INHIBITED CELL PROLIFERATION. CELL DEATH WAS SEEN AT DOSES OF 0.5 MMOL. SIGNIFICANT INCREASES IN SISTER CHROMATID EXCHANGE WERE FOUND. N-PHENYLHYDROXYLAMINE INDUCED A DOSE-RELATED INCREASE IN SISTER CHROMATID EXCHANGE FREQUENCY WITH A 1.4-FOLD ELEVATION. [R8] NTOX: *...RATS /DIED WHEN DOSED WITH/...BETA-PHENYLHYDROXYLAMINE...BUT LEVELS OF METHEMOGLOBIN WERE INSUFFICIENT TO CAUSE DEATH BY ANOXIA. .../IT WAS/ CONCLUDED THAT METHEMOGLOBINEMIA PLAYS NO IMPORTANT PART IN ACUTE TOXICITY OF /THIS COMPD/... [R6, 217] *AS TESTED IN MICE, PHENYLHYDROXYLAMINE, N-HYDROXY-P-AMINOTOLUENE AND N-HYDROXY-P-ACETOPHENONE WERE ALL ABOUT EQUIPOTENT, IE GENERATED EQUIVALENT PEAK CONCENTRATIONS OF METHEMOGLOBIN AT EQUAL DOSES. AT SAME TIME THEY WERE 10 OR MORE TIMES MORE POTENT THAN NITRITE, HYDROXYLAMINE, OR SIMPLE AMINOPHENOLS. [R9] *AROMATIC NITRO AND AMINO COMPOUNDS PROBABLY ARE NOT, IN THEMSELVES, CYANOSIS PRODUCERS, BUT BIOCHEMICAL REDOX PROCESSES CREATE DERIVATIVES WHICH HINDER OXYGEN TRANSPORT TO TISSUES BY FORMING HB-COMPLEXES. ENZYME SYSTEMS CATALYZE OXIDATION OF AMINE GROUP...TO KNOWN CYANOPATHIC NITROSO-...DERIVATIVES. PHENYLHYDROXYLAMINES ARE PROBABLY MOST POTENT CYANOSIS PRODUCERS IN REDOX SERIES. /AROMATIC NITRO AND AMINO COMPOUNDS/ [R10, 2416] *A MECHANISM IS PROPOSED IN WHICH CYCLIC CONVERSION OF PHNO TO PHENYLHYDROXYLAMINE WITHIN ERYTHROCYTE LEADS TO ACCUM OF H2O2 WHICH REACTS WITH FERRO-HB, INITIATING OXIDATIVE DEGRADATION OF HEME. [R11] *PHENYLHYDROXYLAMINE (I) 10, 20, OR 50 MG/KG, IP INJECTION INTO ADULT JAPANESE QUAIL GAVE SYMPTOMS NORMALLY OBSERVED AFTER ANILINE. FERRIC HEMOGLOBIN FORMATION 5 MINUTES AFTER INJECTION WAS 70% OF TOTAL HEMOGLOBIN. I BLOOD CONCENTRATION WAS HIGHEST (0.2 MUMOL/ML, LESS THAN 4% DOSE) 5 MINUTES AFTER ADMINISTRATION, WHEREAS ANILINE CONCENTRATION WAS 4-FOLD GREATER, SUGGESTING THAT I WAS REDUCED TO ANILINE WITHIN 5 MINUTES. THUS, THE ANILINE-TYPE SYMPTOMS ARE MOST PROBABLY DUE TO OXYGEN SHORTAGE CAUSED BY THE FERRIC HEMOGLOBIN FORMATION. [R12] +N-phenylhydroxylamine was found to be positive when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). N-phenylhydroxylamine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.001, 0.0033, 0.010, 0.033, 0.050, 0.067, 0.100, 0.200, and 0.333 mg/plate. The lowest positive dose tested in any S. typhimurium strain was 0.033 mg/plate in strain TA100 with hamster liver S-9 and also with rat liver S-9. [R13] METB: *PHENYLHYDROXYLAMINE IS BIOSYNTHESIZED FROM ANILINE AND N-ETHYLANILINE IN PIG AND RABBIT: HEINZE E, HLAVICA P, KIESE M AND LIPOWSKY G; BIOCHEM PHARMAC 19: 641 (1970). HLAVICA P, KIESE M; BIOCHEM PHARMAC 18: 1501 (1969) /FROM TABLE/ [R14] *PHENYLHYDROXYLAMINE IS METABOLIZED TO ANILINE IN PIG: KADLUBAR FF, MCKEE EM, ZIEGLER DM; ARCHS BIOCHEM BIOPHYS 156: 46 (1973) /FROM TABLE/ [R14] *CYTOCHROME P-450 COMPLEX WAS FORMED BY DIRECT INTERACTION OF NITROSOBENZENE WITH NADPH-REDUCED RAT LIVER MICROSOMES IN ANAEROBIC CONDITIONS, AND BY REACTION OF PHENYLHYDROXYLAMINE WITH AEROBIC MICROSOMES. [R15] *DETOXIFICATION BY REARRANGEMENT OF THE PHENYLHYDROXYLAMINE TO ORTHO- AND PARA-AMINOPHENOLS OF LOWER POTENTIAL FOR EXCRETION THROUGH THE KIDNEYS PROBABLY IS RESPONSIBLE FOR RESTORATION OF THE OXYGEN TRANSPORT BALANCE /FOLLOWING CYANOSIS/. [R10, 2417] +N-PHENYLHYDROXYLAMINE IS OXIDIZED IN AQUEOUS PHOSPHATE BUFFER TO NITROSOBENZENE, NITROBENZENE AND AZOXYBENZENE. DEGRADATION IS OXYGEN DEPENDENT AND SHOWS GENERAL CATALYSIS BY H2PO4- (K1= 2.3 M-2 SEC-1) AND PO4-3 (K2= 2.3 M-2 SEC-1). EVIDENCE SUGGESTS THE INTERMEDIACY OF A HIGHLY REACTIVE SPECIES LEADING TO THESE PRODUCTS. (METABOLIC N-HYDROXYLATION IS POSTULATED TO BE PREREQUISITE FOR THE CARCINOGENIC ACTIVITY OF PRIMARY ARYL AMINES.) [R16] *IN THE HUMAN RED CELL NITROSOBENZENE FORMED GLUTATHIONE-SULFINANILIDE FROM REDUCED GLUTATHIONE, AND THE CORRESPONDING SULFINANILIDE WITH THE REACTIVE CTSTEINE RESIDUES OF HEMOGLOBIN. GLUTATHIONESULFINANILIDE WAS REDUCTIVELY CLEAVED BY AN NADPH-LINKED REDUCTASE WITH FORMATION OF FREE ANILINE, HALF AN EQUIVALENT OF REDUCED GLUTATHIONE AND HALF OF GLUTATHIONE SULFINIC ACID. ABOUT 3/4 OF THE ANILINE PRODUCED FROM PHENYLHYDROXYLAMINE WAS FORMED VIA THIS PATHWAY WITHIN THE RED CELL. [R17] *HEMOGLOBIN-FREE SINGLE-PASS PERFUSION OF ISOLATED RAT LIVER WITH (14)C-PHENYLHYDROXYLAMINE WAS CARRIED OUT. A METABOLIC PATTERN SIMILAR TO ANILINE WAS DISPLAYED, WITH APPARENT PHENYLHYDROXYLAMINE REDUCTION KINETICS OF KM= 260 MUMOL AND VMAX= 600 NMOL/MINUTE/G. AN ACID-LABILE PHENYLHYDROXYLAMINE GLUCURONIDE WAS FORMED. [R18] ACTN: *...INTRAERYTHROCYTIC RECYCLING ACCOUNTS FOR THE HIGH POTENCY /AS METHEMOGLOBIN FORMER/ OF PHENYLHYDROXYLAMINE RELATIVE TO OTHER COMPOUNDS. ...PHENYLHYDROXYLAMINE AND HEMOGLOBIN REACT TO FORM METHEMOGLOBIN AND NITROSOBENZENE. IN INTACT NORMAL RED CELL PROVIDED WITH SUBSTRATE, MECHANISMS EXIST FOR REDUCTION OF NITROSOBENZENE TO REGENERATE PHENYLHYDROXYLAMINE. [R9] *UNDER ANAEROBIC CONDITIONS, PHENYLHYDROXYLAMINE REACTS WITH THE MODEL NUCLEOPHILE BISULFITE TO FORM ANILINE, O-AMINOPHENOL, 0-AMINOBENZENESULFONIC ACID, AND P-AMINOBENZENESULFONIC ACID. ALL PRODUCTS RESULT FROM IMTERMEDIATES FORMED FROM NUCLEOPHILIC ATTACK OF BOTH BISULFITE AND SULFITE ON THE ARYLHYDROXYLAMINE WITH SUBSEQUENT COVALENT ADDITION-ELIMINATION PROCESSES LEADING TO PRODUCTS. THIS SCHEME IS A POSSIBLE ALTERNATIVE PATHWAY FOR DESCRIBING THE MECHANISM FOR CARCINOGENIC ARYLATION OF NUCLEIC ACID RESIDUES BY ARYLHYDROXYLAMINES NOT REQUIRING THE INTERMEDIACY OF SHORT-LIVED FREE RADICALS OR NITRENIUM IONS. [R19] *THE MECHANISM OF SULFHEMOGLOBIN FORMATION AND SPECIES DIFFERENCES IN THE FORMATION OF SULFHEMOGLOBIN AND METHEMOGLOBIN WERE INVESTIGATED. ERYTHROCYTES OR HEMOLYZATES WERE INCUBATED WITH PHENYLHYDROXYLAMINE, ANILINE-HCL OR ITS MONOCHLORO DERIVATIVES IN THE PRESENCE OR ABSENCE OF LIVER MICROSOMES FROM MICE, RATS, GUINEA PIGS, RABBITS, CATS, DOGS, AND MONKEYS. SULFHEMOGLOBIN WAS NOT INDUCED VIA METHEMOGLOBIN. SPECIES DIFFERENCES IN THE PRODUCTION RATES OF N-HYDROXY METABOLITES FROM ANILINE AND ITS DERIVATIVES BY LIVER MICROSOMES (AS WELL AS THE SUSCEPTIBILITY OF ERYTHROCYTES TO N-HYDROXY COMPOUNDS) IN VITRO WERE NOT REFLECTED IN SPECIES DIFFERENCES IN METHEMOBGLOBIN AND SULFHEMOGLOBIN FORMATION IN VIVO. [R20] INTC: *NORHARMAN WAS COMUTAGENIC WITH PHENYLHYDROXYLAMINE WHEN TESTED WITH SALMONELLA TYPHIMURIUM TA98 IN THE PRESENCE OF S-9 MIX. THE COMUTAGENIC EFFECTS WERE FOUND ONLY WITH THE FRAMESHIFT-TYPE MUTANTS OF S TYPHIMURIUM. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ARTS: *THE NONENZYMATIC REDUCTION OF NITROSOBENZENE BY NADPH AND NADH IN AQUEOUS BUFFER SOLUTION AT 25 DEG C IS DESCRIBED. BOTH REACTANTS QUANTITATIVELY CONVERT NITROSOBENZENE TO PHENYLHYDROXYLAMINE. THE OXIDATION OF PHENYLHYDROXYLAMINE BY NAD(P) TO NITROSOBENZENE IS ONLY STIMULATED BY A FACTOR OF 1.2 OVER OXIDATION IN ITS ABSENCE (WHEN THE RATIO OF NADP:PHENYLHYDROXYLAMINE WAS 8:1). [R22] EFFL: +AGMENELLUM QUADRUPLICATUM STRAIN PR-6 AND OSCILLATORIA SP STRAIN JCM WERE GROWN PHOTOAUTOTROPHICALLY IN THE PRESENCE OF ANILINE. CYANOBACTERIUM WAS EXTREMELY SENSITIVE TO THE ANILINE DERIVATIVE PHENYLHYDROXYLAMINE. ANILINE AND DERIVATIVES HAVE BEEN FOUND IN THE EFFLUENT FROM DYE MANUFACTURING PLANTS. [R23] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A METHOD IS GIVEN FOR DETERMINATION OF ANILINE AND ITS DEGRADATION PRODUCTS IN TISSUES BY HPLC. THE DETECTION LIMIT FOR ANILINE ALONE IS 5 MUMOL/L AND ITS RETENTION VOLUME IS 13.0 ML, WITH ITS METABOLITES (INCLUDING N-PHENYLHYDROXYLAMINE) HAVING THE SAME VALUES. THIS METHOD IS WELL-SUITED FOR MONITORING IN AQUEOUS SOLUTION, ALSO. [R24] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 949 R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-166 R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8207 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 96 R6: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R7: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 307 R8: WILMER JL ET AL; SISTER CHROMATID EXCHANGE INDUCTION AND CELL CYCLE INHIBITION BY ANILINE AND ITS METABOLITES IN HUMAN FIBROBLASTS; ENVIRON MUTAGEN 3(6) 627 (1981) R9: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 320 R10: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R11: HIROTA K ET AL; OXIDATIVE DEGRADATION OF HEMOGLOBIN BY NITROSOBENZENE IN THE ERYTHROCYTE; BIOCHEM J 174(3) 693 (1978) R12: BLAAUBOER B ET AL; EFFECTS OF PHENYLHYDROXYLAMINE AND AMINOPHENOLS IN JAPANESE QUAIL IN VIVO; XENOBIOTICA 10(7-8) 495 (1980) R13: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R14: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-27 R15: MANSUY D ET AL; FORMATION OF COMPLEXES BETWEEN MICROSOMAL CYTOCHROME P-450-IRON(II) AND NITROSOARENES OBTAINED BY OXIDATION OF ARYLHYDROXYLAMINES OR REDUCTION OF NITROARENES IN SITU; EUR J BIOCHEM 86(2) 573 (1978) R16: KALHORN T; EVIDENCE FOR GENERAL CATALYSIS AND FORMATION OF NITROBENZENE IN THE OXIDATION OF PHENYLHYDROXYLAMINE IN AQUEOUS PHOSPHATE BUFFER; BIOORG CHEM 10(2) 144 (1982) R17: EYER P, LIERHEIMER E; BIOTRANSFORMATION OF NITROSOBENZENE IN THE RED CELL AND THE ROLE OF GLUTATHIONE; XENOBIOTICA 10(7-8) 517 (1980) R18: EYER P ET AL; BIOTRANSFORMATION OF NITROSOBENZENE, PHENYLHYDROXYLAMINE AND ANILINE IN THE ISOLATED PERFUSED RAT LIVER; XENOBIOTICA 10(7-8) 499 (1980) R19: STERNSON LA ET AL; REACTION OF PHENYLHYDROXYLAMINE WITH BISULFITE. A POSSIBLE MODEL FOR AMINE-MEDIATED CARCINOGENESIS; J ORG CHEM 48(1) 57 (1983) R20: NOMURA A, FUJIMURA H; STUDIES ON SULFHEMOGLOBIN FORMATION BY VARIOUS DRUGS. (5) THE MECHANISM OF SULFHEMOGLOBIN FORMATION AND SPECIES DIFFERENCES IN METHEMOGLOBIN AND SULFHEMOGLOBIN FORMATION; JPN J PHARMACOL 31(4) 601 (1981) R21: SUGIMURA T ET AL; METABOLIC ASPECTS OF THE COMUTAGENIC ACTION OF NORHARMAN; ADV EXP MED BIOL 136B(BIOL REACT INTERMED-2, CHEM MECH BIOL EFF, B) 1011 (1982) R22: BECKER AR, STERNSON LA; NONENZYMATIC REDUCTION OF NITROSOBENZENE TO PHENYLHYDROXYLAMINE BY NAD(P)H; BIOORG CHEM 9(3) 305 (1980) R23: CERNIGLIA CE ET AL; BIOTRANSFORMATION AND TOXICITY OF ANILINE AND ANILINE DERIVATIVES IN CYANOBACTERIA; ARCH MICROBIOL 130(4) 272 (1981) R24: STERNSON LA; METHOD 10. DETERMINATION OF ANILINE AND ITS DEGRADATION PRODUCTS BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; IARC SCI PUBL 40: 219 (1981) RS: 15 Record 196 of 1119 in HSDB (through 2003/06) AN: 2888 UD: 200302 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-NAPHTHYLAMINE,-N-PHENYL- SY: *ACETO-PBN-; *AGERITE-POWDER-; *2-ANILINONAPHTHALENE-; *ANTIOXIDANT-116-; *ANTIOXIDANT-PBN-; *2-NAPHTHALENAMINE,-N-PHENYL-; *N-(2-NAPHTHYL)ANILINE; *BETA-NAPHTHYLPHENYLAMINE-; *2-NAPHTHYLPHENYLAMINE-; *NEOSONE-D-; *NEOZON-D-; *NEOZONE-; *NEOZONE-D-; *NILOX-PBNA-; *NONOX-D-; *NONOX-DN-; *PBNA-; *2-PHENYLAMINONAPHTHALENE-; *PHENYL-BETA-NAPHTHYLAMINE-; *N-PHENYL-BETA-NAPHTHYLAMINE-; *PHENYL-2-NAPHTHYLAMINE-; *STABILIZATOR-AR-; *VULKANOX-PBN- RN: 135-88-6 RELT: 1131 [2-NAPHTHYLAMINE] (METABOLITE) MF: *C16-H13-N MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...WAS PREPARED BY GRAEBE IN 1880 BY HEATING 2-NAPHTHOL WITH ANILINE HYDROCHLORIDE (PRAGER ET AL, 1929). METHOD...CURRENTLY...USED IN JAPAN (THE CHEM DAILY CO LTD, 1976) AND IN US (KEHE AND KOURIS, 1965) IS CONDENSATION OF 2-NAPHTHOL AND ANILINE IN PRESENCE OF A CATALYST. [R1] IMP: +Commercial product may contain 20-30 ppm beta-naphthylamine [R2] FORM: *UNTIL RECENTLY...WAS AVAILABLE IN US AS COMMERCIAL GRADE...PURITY, 97.0% MIN; SET-POINT, 106.0 DEG C MIN; ASH CONTENT, 0.5% MAX; 2-NAPHTHOL CONTENT, 0.5% MAX. [R3] */IT IS/...AVAILABLE IN US IN VARIETY OF FORMULATIONS, COMPOUNDED WITH OTHER ANTIOXIDANTS, EG, PARA-ISOPROPOXYDIPHENYLAMINE AND DIPHENYL-PARA-PHENYLENEDIAMINE... [R1] MFS: *UNIROYAL, INC, UNIROYAL CHEM, DIV, NAUGATUCK, CONN 06770 [R4] OMIN: *...DETECTED IN EXTRACTS FROM WIDE VARIETY OF ANIMAL, PLANT AND MICROBIAL LIPIDS. IT HAS BEEN SHOWN, HOWEVER, THAT IT WAS CONTAMINANT OF SOLVENTS USED TO EXTRACT THEM, WHICH HAD COME INTO CONTACT WITH RUBBER CONTAINING THE ANTIOXIDANT... [R5] *IT IS BELIEVED THAT NO US COMPANIES ARE CURRENTLY PRODUCING THIS COMPD COMMERCIALLY [R6] *...IS USED PRIMARILY AS ANTIOXIDANT (GENERALLY @ LEVELS OF 1-2%) IN RUBBER PROCESSING...TO IMPART HEAT, OXIDN AND FLEX-CRACKING RESISTANCE IN NATURAL RUBBER, SYNTHETIC RUBBERS AND LATEXES... [R6] *.../IT/ HAS BEEN USED AS CHEM INTERMEDIATE IN PRODN OF RUBBER ANTIOXIDANT, N-PHENYL-2-NAPHTHYLAMINE-ACETONE CONDENSATE, AND IN PRODN OF 7 DYES...OF WHICH...CI ACID BLUE 98.../IS/ OF COMMERCIAL WORLD SIGNIFICANCE... [R5] *N-Phenyl-2-naphthylamine, an antioxidant in rubber processing, is gradually being displaced by improved products. [R7] USE: *RUBBER ANTIOXIDANT; LUBRICANT; INHIBITOR (BUTADIENE) [R8] *STABILIZER IN ELECTRICAL-INSULATING SILICONE ENAMELS; HEAT AND LIGHT STABILIZER; VULCANIZATION ACCELERATOR; COMPONENT OF ROCKET FUELS; IN SURGICAL PLASTERS; IN TIN-ELECTROPLATING BATHS; CHEM INTERMEDIATE; IN DYES; CATALYST AND POLYMERIZATION INHIBITOR [R6] PRIE: U.S. PRODUCTION: *(1972) 2.05X10+9 GRAMS [R4] *(1975) 7.09X10+8 GRAMS [R4] U.S. IMPORTS: *(1972) 4.00X10+5 GRAMS [R4] *(1975) 7.58X10+7 GRAMS [R4] *Imports through the principal U.S. customs districts totaled 18,166 pounds in 1983. [R9] U.S. EXPORTS: *(1972) ND [R4] *(1975) ND [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEEDLES FROM METHANOL [R10]; *WHITE TO YELLOWISH CRYSTALS [R11]; *GRAY TO TAN FLAKES OR POWDER [R12]; +White to yellow crystals or gray tan flakes or powder [Note: Commercial product may contain 20-30 ppm of beta naphthylamine]. [R2] BP: *395.5 DEG C [R13] MP: *108 DEG C [R13] MW: *219.29 [R13] DEN: *1.24 [R14] OWPC: *log Kow = 4.38 [R15] SOL: *SOLUBILITY IN ETHANOL 50 G/L, IN BENZENE 27 G/L, IN ACETONE 640 G/L [R1]; *INSOL IN WATER; SOL IN ALC, ETHER, ACETIC ACID (BLUISH FLUORESCENCE) [R10] SPEC: *MAX ABSORPTION (ALC): 220 NM (LOG E= 4.7); 275 NM (LOG E= 4.4); 312 NM (LOG E= 4.3); SADTLER REFERENCE NUMBER: 155 (IR, PRISM); 48 (IR, GRATING); 61 (UV) [R10]; *IR: 2:657D (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R16, p. V1 904]; *NMR: 5:88D (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R16, p. V1 904]; *IR: 7366 (Sadtler Research Laboratories Prism Collection) [R16, p. V2 98] OCPP: *MAY BE OXIDIZED TO 7-PHENYL-7H-DIBENZO[C,G]CARBAZOLE [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *FIRE HAZARD: MODERATE, WHEN EXPOSED TO HEAT OR FLAME... CAN REACT WITH OXIDIZING MATERIALS. [R17] REAC: +Oxidizers. [R2] DCMP: *WHEN HEATED TO DECOMP, IT EMITS TOXIC FUMES OF /NITROGEN OXIDES/. [R18] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R2] +Wear appropriate eye protection to prevent eye contact. [R2] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R2] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R2] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R2] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R2] OPRM: +The worker should immediately wash the skin when it becomes contaminated. [R2] +The worker should wash daily at the end of each work shift. [R2] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R2] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R2] STRG: *...MATERIALS WHICH ARE TOXIC AS STORED OR WHICH...DECOMP INTO TOXIC COMPONENTS DUE TO CONTACT WITH HEAT...SHOULD BE STORED IN COOL, WELL-VENTILATED PLACE, OUT OF DIRECT RAYS OF SUN, AWAY FROM AREAS OF HIGH FIRE HAZARD, and ...PERIODICALLY INSPECTED AND MONITORED. [R17] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Inadequate evidence of carcinogenicity in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R19] +A4; Not classifiable as a human carcinogen. [R20] ANTR: *TREATMENT: SYMPTOMATIC AND SUPPORTIVE. HTOX: *LEUCOPLAKIA, ACNE AND HYPERSENSITIVITY TO SUNLIGHT...OBSERVED IN 36 WORKERS EXPOSED FOR PROLONGED PERIODS TO N-PHENYL-2-NAPHTHYLAMINE... [R21] *OUT OF 57 CU-SMELTING WORKERS SUFFERING FROM INFLAMMATORY LESIONS OF MUCOUS MEMBRANE AND SKIN OF LIPS, 22 HAD INCR SENSITIVITY TO RUBBER AS MAIN CAUSE OF CHEILITIS. [R22] *OCCUPATIONAL ALLERGIC DERMATOSIS WAS OBSERVED IN RUBBER WORKERS DUE TO ADDITIVES SUCH AS NEOZON D. [R23] *IT HAS BEEN REPORTED THAT COMMERCIAL N-PHENYL-2-NAPHTHYLAMINE IS CONTAMINATED WITH 20-30 MG/KG OF CARCINOGEN 2-NAPHTHYLAMINE... [R1] *Experimental evidence from human volunteers ingesting PBNA at a single 10-50 mg dose and from workers inhaling PBNA dust show that BNA is eliminated in the urine as a metabolite of PBNA. [R24, 1991.1212] *Acne and leukoderma have been reported as well as dermatitis. The carcinogenic potential of phenylnaphthylamines is questionable because of the presence of naphthylamine as a contaminant. /Phenylnaphthylamines/ [R25] NTOX: *...GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF)F1 MICE.../ and / (C57BL/6XAKR)F1 MICE...GIVEN SINGLE SC.../DOSE/ OF 464 MG/KG... N-PHENYL-2-NAPHTHYLAMINE IN DIMETHYL SULFOXIDE...ON 28TH DAY OF LIFE... OBSERVED UP TO 80 WK OF AGE, @ WHICH TIME 16, 17, 16 and 18 MICE IN 4 GROUPS, RESPECTIVELY, WERE STILL ALIVE. [R26] *IN FEMALES OF.../(C57BL/6XC3H/ANF)F1 STRAIN OF MICE/, FREQUENCY OF TUMOR-BEARING ANIMALS WAS SIGNIFICANTLY GREATER.../THAN/ WITH CONTROL ANIMALS (UNTREATED OR GIVEN DMSO BY INJECTION: 5/18 VERSUS 9/154, P LESS THAN 0.01... ). /TREATED MICE GIVEN SINGLE DOSE 464 MG/KG SC ON DAY 28 OF LIFE AND OBSERVED UP TO 80 WK OF AGE./ [R26] *...THERE WAS...A STATISTICALLY SIGNIFICANT INCR IN FREQUENCY OF HEPATOMAS IN MALES OF...STRAIN /(C57BL/6XAKR)F1 MICE GIVEN SINGLE SC DOSE OF 464 MG/KG N-PHENYL-2-NAPHTHYLAMINE IN DIMETHYL SULFOXIDE ON DAY 28 OF LIFE AND OBSERVED UP TO 80 WK OF AGE/ (2/18 VERSUS 1/16, P LESS THAN 0.05)... /SEE TABLES/ [R26] *DAILY INHALATION BY RATS OF...AEROSOL (900 MG/CU M) FOR 14 DAYS CAUSED WT LOSS, SLIGHT ERYTHROCYTOPENIA AND PULMONARY EMPHYSEMA... MICE EXPOSED DAILY FOR 4 HR DURING 1 MO TO...12 MG/CU M N-PHENYL-2-NAPHTHYLAMINE /IN AIR/ and 339 MG/CU M 1,3-BUTADIENE SHOWED SLIGHT LEUCOPENIA AND IRRITATION OF RESP TRACT... [R26] *DAILY INTRAGASTRIC ADMIN OF 100 MG/KG...TO RATS... LUNG AND LIVER WT INCR WITHIN 1 and 12 MO, RESPECTIVELY; CHANGES...OBSERVED IN GI TRACT AFTER 6 MO, AND REPRODUCTIVE FUNCTION...IMPAIRED. DOSES OF 20 MG/KG...CAUSED NO SIGNIFICANT TOXIC EFFECTS. [R26] *REPEATED INTRAGASTRIC ADMIN...TO RATS CAUSED FALL IN BODY WT, DEPRESSION OF NERVOUS SYSTEM AND DISTURBANCE OF LIVER FUNCTION... DAILY INTRAGASTRIC ADMIN OF 100 MG/KG...TO RATS CAUSED DECR IN URINARY HIPPURIC ACID AND ADRENAL ASCORBIC ACID AFTER 6 MO AND DROP IN URINARY FUNCTION AFTER 18 MO; URINARY PROTEIN...HIGHER AFTER 1 MO. [R26] *...THREE DOGS WERE FED N-PHENYL-2-NAPHTHYLAMINE IN DAILY DOSES OF 540 MG ON 5 DAYS A WK FOR...4.5 YR. NO BLADDER TUMORS..OBSERVED... [R27] *NO DATA ON EMBRYOTOXICITY, TERATOGENICITY OR MUTAGENICITY OF N-PHENYL-2-NAPHTHYLAMINE WERE AVAILABLE TO THE WORKING GROUP. [R21] *NEOZONE D SHOWED SIGNIFICANT CUMULATIVE PROPERTIES WHEN ADMIN ORALLY TO RATS @ DOSES OF 20-200 MG/KG/DAY FOR 6-12 MO. [R28] *NEOZONE D ADMIN IP FOR 4 MO IN CHRONIC EXPT AS 20 and 2% SUSPENSIONS IN 3% STARCH SOLN IN DOSES OF 1.0 and 0.1 G/KG- 24 HR CAUSED RED BLOOD CELL DAMAGE, LIVER AND KIDNEY DAMAGE AND LESS DAMAGE ON BLOOD ENZYMES. [R29] *When groups of five male and five female F344/N rats were fed 0 to 50,000 ppm PBNA for 14 days, almost all of the animals fed 50,000 ppm died; rats fed 12,500 ppm or more developed diarrhea and rough coats. When groups of five male and five female B6C3F1 mice were fed 0 to 20,000 ppm PBNA for 14 days, no clinical signs of intoxication were recorded; however, the mice lost up to 12% of their body weight. [R24, 1991.1211] *Rats given 100 mg/kg/day PBNA by oral intubation showed a decrease in normal acid content of urine in 6 months and a decrease in urinary function after 18 months. Additionally, lung and liver weights increased within 1 and 12 months, respectively, and changes were observed in the GI tract after 6 months. [R24, 1991.1211] *Dose dependent nephropathy with epithelial regeneration in the cortex tubules and increased liver-to-body-weight ratios were observed in B6C3F1 mice fed up to 40,000 ppm PBNA for 13 weeks. Dose dependent degeneration of the renal tubules also occurred in F344/N rats fed 10,000, 20,000, or 40,000 ppm PBNA for 13 weeKs. Nearly all (13/20) rats fed 40,000 ppm PBNA died. [R24, 1991.1211] *Rats inhaling 900 mg/cu m PBNA for 14 days experienced weight loss, slight erythrocytopenia, and pulmonary emphysema. Mice exposed 4 hours daily during 1 month at a concentration of 12 mg/cu m PBNA and 339 mg/cu m 1,3-butadiene showed slight leukopenia and irritation of the respiratory tract. [R24, 1991.1211] *Male and female mice were given PBNA by oral intubation for 21 days and then fed the compound for 18 months. The males developed a statistically significant increase in the incidence of hepatomas, a common liver tumor in mice having debatable significance to man. Other mice also showed an increased number of hepatomas from a single subcutaneous injection of 464 mg/kg PBNA, but the site specific tumor incidences did not differ from the controls. [R24, 1991.1211] *... There was no evidence of carcinogenic activity of PBNA in F344/N male or female rats and B6C3F1 male mice fed up to 5000 ppm PBNA for 103 weeks. There was equivocal evidence of carcinogenic activity in female mice as indicated by the occurrence of two rare kidney tumors. [R24, 1991.1211] *PBNA was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1538 either in the presence or absence of a rat or hamster hepatic microsomal activating system. [R24, 1991.1212] *The compound was not clastogenic in rat bone marrow, and it failed to induce chromosomal aberrations in cultured hamster fibroblasts. [R24, 1991.1212] *FOR DOGS TO FORM BNA TUMORS THROUGH HIGH LEVEL EXPOSURE TO PBNA, PERIOD OF DAILY DOSING WOULD EQUAL OR EXCEED NORMAL LIFE SPAN. [R30] *The effect of N-phenyl-2-naphthylamine (PNA) exposure by various routes of admin were investigated in rats and mice. Wistar rats, male albino rats and male C57BL mice were exposed in situ at three suspect locations inside a rubber factory for 2 yr. The animals were intubated with 8% soln of PNA for 18 to 24 mo, inhaled PNA aerosol at 180 to 230 mg/cu m 5 days/wk for 1 yr, consuming incr concn in the diet for 18 to 24 mo, or received repeated injections of PNA for 12 mo. ... Rats exposed in situ developed significantly more carcinomas but not sarcomas. Carcinomas included those of the digestive tract, lungs, kidneys, adrenals, prostrate gland and seminal vesicles. Liver and bladder cancer was /not noted/. Intubation resulted in high incidence of gastrocecal ulcers in male Wistar rats and carcinomas of the lung, prostate, pancreas and kidney. Chronic feeding induced significant incidence of carcinomas and hemangiosarcomas of the liver and lung carcinomas in male mice, along with carcinomas of the pancreas, salivary glands, and kidneys. Chronic inhalation induced lung carcinomas in 27% of the animals. The mice showed a dose related response to PNA. ... [R31] NTXV: *LD50 Rat oral 8730 mg/kg; [R24, 1991.1211] *LD50 Mouse oral 1450 mg/kg; [R24, 1991.1211] NTP: *Under the conditions of these 2 year studies, there was no evidence of carcinogenic activity for male or female F344/N rats fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. Decreased incidence of several neoplasms were observed in dosed rats: thyroid gland C-cell neoplasms in males and females and mononuclear cell leukemia, pituitary gland adenomas, and mammary gland fibroadenomas in females. There was no evidence of carcinogenic activity for male B6C3Fl mice fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. There was equivocal evidence of carcinogenic activity of N-phenyl-2-naphthylamine for male B6C3F1 mice as indicated by the occurrence of two rare kidney neoplasms. [R32] ADE: *IN DOGS GIVEN SINGLE ORAL DOSES OF 5 MG/KG...(1,4,5 ,8-(14)C)-N-PHENYL-2-NAPHTHYLAMINE ALONE OR FOLLOWING REPEATED DOSES OF 400 MG/ANIMAL...N-PHENYL-2-NAPHTHYLAMINE ON 5 DAYS A WK FOR 4 WK, MORE THAN 90% OF RADIOACTIVITY...EXCRETED OVER 3 DAYS, MAINLY IN FECES. ONLY 2.8% OF RADIOACTIVITY WAS EXCRETED IN URINE. [R21] *NO INCR EXCRETION OF LABELED 2-NAPHTHYLAMINE...OBSERVED FOLLOWING 4 WK PRETREATMENT WITH 400 MG/ANIMAL UNLABELED N-PHENYL-2-NAPHTHYLAMINE... [R21] *2-NAPHTHYLAMINE WAS FOUND @ LEVEL OF 3-4 UG IN 24-HR SAMPLES OF URINE FROM 2 VOLUNTEERS WHO INGESTED 50 MG N-PHENYL-2-NAPHTHYLAMINE CONTAINING 0.7 UG 2-NAPHTHYLAMINE AND FROM WORKERS (UNSPECIFIED NUMBER) EST TO HAVE INHALED 30 MG N-PHENYL-2-NAPHTHYLAMINE... [R21] *IN 4 WORKERS EXPOSED TO N-PHENYL-2-NAPHTHYLAMINE DUSTS (EST INTAKE, 40 MG)... EST TO CONTAIN 32 NG 2-NAPHTHYLAMINE, 3-8 UG 2-NAPHTHYLAMINE...FOUND IN 24-HR URINE SAMPLES... [R21] *IN 19 VOLUNTEERS GIVEN 10 MG N-PHENYL-2-NAPHTHYLAMINE CONTAINING 8 NG 2-NAPHTHYLAMINE (0.8 MG/KG), FROM 0.4-3 UG 2-NAPHTHYLAMINE WERE FOUND IN 24-HR URINE SAMPLES FROM 7 SUBJECTS, 6 OF WHICH WERE NON-SMOKERS. [R21] METB: *AMT RANGING FROM 0-10 UG 2-NAPHTHYLAMINE WAS DETECTED IN URINE OF DOGS GIVEN SINGLE DOSE OF 5 MG/KG...N-PHENYL-2-NAPHTHYLAMINE... [R21] *Hepatic microsomal preparations from rat, hamster, dog, monkey, and humans catalyze PBNA biotransformation in vitro to 6-hydroxy-N-phenyl-2-naphthylamine and 4'-hydroxy-N-phenyl-2-naphthylamine. [R24, 1991.1212] *A dose dependent relationship between the concn of parent compound and its BNA metabolite in rat urine was observed after oral doses of 50 or 100 mg PBNA/kg/day for 4 days. Some 34 ug BNA was recovered in rat urine after a total PBNA dose of 400 mg. [R24, 1991.1212] *Experimental evidence from human volunteers ingesting PBNA at a single 10-50 mg dose and from workers inhaling PBNA dust show that BNA is eliminated in the urine as a metabolite of PBNA. [R24, 1991.1212] *The carcinogenic antioxidants, N-phenyl-1-naphthylamine (P1NA) and phenyl-2-naphthylamine (P2NA) were examined in vitro for biotransformation by rat hepatic microsomes and in freshly isolated hepatocytes. HLPC analysis of hepatocyte incubations revealed that phenols were the major metabolites in both cases. P1NA formed one phenolic metabolite only, while incubation with P2NA yielded two phenols identified as 6-hydroxy-P2NA and 4'-hydroxy-P2NA by chromatography with authentic samples. beta-Naphthylamine, a metabolite indicating dephenylation of P2NA was not detectable. Metabolism studies with microsomes revealed that the phenols were formed by cytochrome p450 dependent monooxygenases. Pretreatment of animals with phenobarbital and 3-methylcholanthrene both incr the rate of microsomal metabolism of P1NA and P2NA, indicating that more than one p450 enzyme mediate the oxygenation reaction. Animal pretreatment with single and repeated doses of P1NA and P2NA did not markedly stimulate metabolism, but induced ethylmorphine demethylation in males and females and benzo(a)pyrene hydroxylation in females. [R33] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *N-Phenyl-2-naphthylamine is probably released to the environment in waste streams from its production and use. In the atmosphere, it should exist in the vapor and particulate phases. Vapor phase N-phenyl-2-naphthylamine is expected to degrade rapidly (estimated half-life of 55 minutes) by reaction with photochemically produced hydroxyl radicals. Particulate-phase N-phenyl-2-naphthylamine may be removed via dry deposition. If released to soil, N-phenyl-2-naphthylamine may undergo a covalent chemical bonding with humic materials which can result in its chemical alteration to a latent form and prevent leaching. In the absence of covalent bonding, N-phenyl-2-naphthylamine will be immobile in soil. Photolysis may be important on soil surfaces. N-Phenyl-2-naphthylamine should rapidly biodegrade to beta-naphthylamine at concns < 5 ppm in soil and water; however, the apparent covalent bonding and adsorption may reduce biodegradation. In water, covalent bonding with humic materials in the water column and sediments may result in partitioning from the water column to sediments. By analogy to the aromatic amine chemical class, N-phenyl-2-naphthylamine may be susceptible to photolysis and photooxidation via hydroxyl and peroxy radicals in water. Experimental data suggest that bioconcentration in aquatic organisms will not be an important fate process. Hydrolysis and volatilization from water should not be important. In occupational settings, workers may be exposed to N-phenyl-2-naphthylamine through inhalation and through eye and skin contact. (SRC) ARTS: *N-Phenyl-2-naphthylamine is used as an antioxidant, lubricant, and inhibitor(1) and, therefore, it may be released to the environment during its production and use(SRC). [R34] FATE: *TERRESTRIAL FATE: One screening study observed that N-phenyl-2-naphthylamine is readily biodegradable to beta-naphthylamine at concns < 5 ppm(2). Higher concns appear to be toxic to microorganisms(2,SRC). Because N-phenyl-2-naphthylamine absorbs UV light > 290 nm(3), photolysis may be important if N-phenyl-2-naphthylamine is spilled on terrestrial surfaces(SRC). By analogy to other aromatic amines(1), when released to soil, N-phenyl-2-naphthylamine may undergo covalent chemical bonding with humic materials which can result in its chemical alteration to a latent form and result in tight adsorption. When covalently bound in this latent form, leaching in soil systems is not expected to occur. This covalent bonding proceeds in two steps: a rapid and reversible bonding followed by a slower and much less reversible reaction(1,SRC). In the absence of covalent bonding, leaching would not be possible based on an estimated Koc of 12,500(4-6). [R35] *AQUATIC FATE: Based on analogy to other aromatic amines(1), N-phenyl-2-naphthylamine may undergo covalent bonding with humic materials in the water column and in sediment; therefore, partitioning from the water column to sediment and suspended material may be important. N-Phenyl-2-naphthylamine may be susceptible to photooxidation via hydroxyl and peroxy radicals based on analogy to other aromatic amines(2,SRC). Because N-phenyl-2-naphthylamine abosorbs UV light > 290 nm(4), photolysis may be important in near-surface water. A BCF value of 147(3,SRC) suggests that N-phenyl-2-naphthylamine will have low potential to bioconcentrate in aquatic organisms(SRC). Aquatic hydrolysis and volatilization do not appear to be environmentally important removal processes of N-phenyl-2-naphthylamine in water(SRC). It appears that N-phenyl-2-naphthylamine is readily biodegradable to beta-naphthylamine at concns < 5 ppm(5). [R36] *ATMOSPHERIC FATE: Based on a modified regression-derived equation(1,SRC), the vapor pressure for N-phenyl-2-naphthylamine can be estimated to be 8.3X10-6 mm Hg at 25 deg C(SRC). According to a suggested classification scheme(2), this vapor pressure value suggests that N-phenyl-2-naphthylamine will exist in both the vapor and particulate phases in the ambient atmosphere. Particulate-phase N-phenyl-2-naphthylamine will probably be removed from air via dry deposition. Vapor-phase N- phenyl-2-naphthylamine is degraded rapidly in an average ambient atmosphere by reaction with photochemically produced hydroxyl radicals at an estimated half-life of about 55 minutes(3,SRC). [R37] BIOD: *Using an initial concn of 100 mg/L N-phenyl-2-naphthylamine, 0 %BOD was observed after a 2 week period in a biodegradation screening test using 30 mg/L sludge(1). N-Phenyl-2-naphthylamine, initial concn of 100 ppm, exhibited a 0-29 % Theoretical BOD in a Japanese MITI test after 14 days of incubation at 25 deg C(2). N-phenyl-2-naphthylamine was shown to degrade to beta-naphthylamine in a screening study using activated sludge inoculum at 21 deg C(3). In this study, 44.2 and 9.3 %CO2 production was observed in 1 day at initial concns of 2 and 5 ppm, respectively(3). At an initial concn of 8 ppm, N-phenyl-2-naphthylamine was observed to be inhibitory to microorganisms under the same test conditions(3). Furthermore, adsorption to solids was found to occur and, hence, reduce biodegradation(3). [R38] ABIO: *The rate constant for the vapor-phase reaction of N-phenyl-2-naphthylamine with photochemically produced hydroxyl radicals has been estimated to be 4.18X10-10 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 55 min at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Aromatic amines are generally resistant to aqueous environmental hydrolysis(2); therefore, N-phenyl-2-naphthylamine is not expected to hydrolyze in water(SRC). As a class, aromatic amines react relatively rapidly in sunlit natural water via reaction with photochemically produced hydroxyl radicals and peroxy radicals(3); typical half-lives for hydroxyl radical and peroxy radical reaction are on the order of 19-30 sunlight hours(3); however, rate data specific to N-phenyl-2-naphthylamine were not located(SRC). Photolysis may be important(SRC), since N-phenyl-2-naphthylamine absorbs UV radiation > 290 nm(4). [R39] BIOC: *The BCF value for N-phenyl-2-naphthylamine was determined to be 147 with the fathead minnow (Pimephales promelas) in a 32 day exposure flow-through test of Lake Superior water at 25 deg C(1). [R40] KOC: *Aromatic amines have been observed to undergo rapid and reversible covalent bonding with humic materials in aqueous solution; the initial bonding reaction is followed by a slower and much less reversible reaction believed to represent the addition of the amine to quinoidal structures followed by oxidation of the product to give an amino-substituted quinone; these processes represent pathways by which aromatic amines may be converted to latent forms in the biosphere(4). In the absence of covalent bonding, one can estimate the adsorption potential based on the Koc value. Based on an experimental log octanol-water partition coefficient of 4.38(2) and a recommended regression-derived equation(1), the Koc value for N-phenyl-2-naphthylamine can be estimated to be 12,500(SRC). According to a suggested classification scheme(3), this Koc value indicates that N-phenyl-2-naphthylamine will be immobile in soil. [R41] VWS: *The Henry's Law constant for N-phenyl-2-naphthylamine can be estimated to be 1.03X10-7 from a chemical structure estimation method(1). According to a suggested classification scheme(2), this Henry's Law constant indicates that N-phenyl-2-naphthylamine is essentially nonvolatile from water. [R42] RTEX: *Human exposure to 2-naphthylamines in the past was primarily via inhalation and dermal routes(1). [R43] *IT SHOULD BE POSSIBLE TO DESIGNATE A TLV FOR PBNA WHICH WOULD ENSURE SAFETY OF WORKERS IF ADHERED TO, PROVIDED ABSORPTION FROM OTHER SOURCES WAS ALSO PREVENTED. ...EXTREME PRECAUTIONS NEEDED IN HANDLING BNA, WHOSE MFR AND USE HAVE BEEN PROHIBITED IN SEVERAL JURISDICTIONS, APPEAR UNNECESSARY FOR PBNA. [R11] *WHEN SAMPLES OF 1,3-BUTADIENE RUBBER WERE HEATED TO 220 DEG C, EVOLVED FUMES CONTAINED 0.012 MG/G (12 MG/KG) OF AIR N-PHENYL-2-NAPHTHYLAMINE... STUDIES CONDUCTED IN SEVERAL SYNTHETIC RUBBER PLANTS IN USSR DETECTED.../THIS COMPD/ IN AIR... [R44] *IN US...NIOSH...RECOMMENDED...EMERGENCY TEMPORARY STD TO REGULATE...EXPOSURE TO N-PHENYL-2-NAPHTHYLAMINE BE ISSUED, IN LIGHT OF...FINDINGS INDICATING...IT IS METABOLIZED IN HUMAN BODY TO FORM CARCINOGEN, 2-NAPHTHYLAMINE... NIOSH EST THAT 15,000 WORKERS IN US...POTENTIALLY EXPOSED...DURING ITS MFR AND USE (NIOSH, 1976). [R5] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 368 workers are potentially exposed to N-phenyl-2-naphthylamine in the USA(1). [R45] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers N-phenyl-beta-naphthylamine to be a potential occupational carcinogen. [Note: Since metabolized to beta-Naphthylamine]. [R2] NREC: +NIOSH considers N-phenyl-beta-naphthylamine to be a potential occupational carcinogen. [Note: Since metabolized to beta-Naphthylamine]. [R2] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R2] TLV: +A4; Not classifiable as a human carcinogen. [R20] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GAS CHROMATOGRAPHY...USED TO DETERMINE...N-PHENYL-2-NAPHTHYLAMINE, IN VULCANIZED RUBBERS...COULSON CONDUCTIMETRIC DETECTOR...PREFERRED METHOD OF DETECTION... [R27] *TLC...USED FOR SEPARATION AND IDENTIFICATION...IN VULCANIZED RUBBER FOLLOWING THERMAL EXTRACTION...IN PLASTICS USED AS FOOD WRAPS...IN LIQ WHICH HAD COME INTO CONTACT WITH STABILIZED RUBBERS, WITH SENSITIVITY OF 2-5 UG N-PHENYL-2-NAPHTHYLAMINE...IN RUBBER (LESS THAN 10% ERROR)...AND IN TRANSFORMER OILS... [R44] *HIGH-PRESSURE LIQ CHROMATOGRAPHY...USED TO SEPARATE MIXT OF AROMATIC AMINE-TYPE ANTIOXIDANTS, INCL N-PHENYL-2-NAPHTHYLAMINE; AS LITTLE AS 5 UG... DETECTED... GEL PERMEATION CHROMATOGRAPHY IN COMBINATION WITH TLC...USED TO SEPARATE AND IDENTIFY...IN EXTRACTS OF VULCANIZED RUBBER SAMPLES AND IN MIXT OF VULCANIZATION INGREDIENTS... [R44] *...UV, FLUORESCENT AND PHOSPHORESCENT SPECTRA HAVE BEEN STUDIED... SELISKAR, CJ AND BRAND, L, "ELECTRONIC SPECTRA OF 2-AMINONAPHTHALENE-6-SULFONATE AND RELATED MOLECULES. GENERAL PROPERTIES AND EXCITED-STATE REACTIONS," J AMER CHEM SOC, 93, 5405-5414 (1971). [R12] *UV SPECTROPHOTOMETRY HAS BEEN USED TO DETECT N-PHENYL-2-NAPHTHYLAMINE IN FOOD MATERIALS... [R44] *MONITORING IN WASTEWATER. [R46] *PHOTOMETRIC DETERMINATION OF NEOZONE D IN WATER. [R47] *Method No. 96, N-Phenyl-1-Naphthylamine (N-Phenyl-Alpha-Naphthylamine), N-Phenyl-2-Naphthylamine (N-Phenyl-Beta-Naphthylamine); HPLC, quantitation limit = 3 parts/trillion. [R48] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of N-Phenyl-2-naphthylamine in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 333 (1988) NIH Publication No. 88-2589 DISCUSSES CARCINOGENIC RISK OF PBNA TO HUMAN SUBJECTS. [R49] Scmidt E et al; Zeitschr Gesamte Hyg 29 (8): 452-6 (1983). Toxicological evaluation of vulcanization vapors with special reference to nitrogen containing aging preventative agents. SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 326 (1978) R2: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 250 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 326 (1978) R4: SRI R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 328 (1978) R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 327 (1978) R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA17 18 R8: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 903 R9: USITC; U.S. International Trade Commission, publication 1548, Imports of Benzenoid Chemicals and Products (1983) R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-109 R11: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)452 R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 325 (1978) R13: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-213 R14: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 675 R15: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R16: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R17: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 1018 R18: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2669 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 70 (1987) R20: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.47 R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 334 (1978) R22: ANTONEV AA, GERASIMENKO IV; VESTN DERMATOL VENEROL 1: 56-60 (1976) R23: SOMOV BA ET AL; VESTN DERMATOL VENEROL 5: 68-70 (1976) R24: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R25: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 708 R26: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 333 (1978) R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 330 (1978) R28: SHUMSKAYA NI, STASENKOVA KP; GIG SANIT 8: 28-30 (1973) R29: TARADIN YI, KUCHMINA NY; PROM-ST SINT KAUCH 12: 14-17 (1977) R30: BATTEN PL, HATHWAY DE; BR J CANCER 35 (3): 342-6 (1977) R31: Wang HW et al; Cancer Res 44 (7): 3101-5 (1984) R32: DHHS/NTP; Toxicology and Carcinogenesis Studies of N-Phenyl-2-naphthylamine in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 333 (1988) NIH Publication No. 88-2589 R33: Xue X, Wolff T; J Environ Sci 4 (1): 19-21 (1992) R34: (1) Sax NI, Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 11th ed NY, NY: Van Nostrand Reinhold Co p.905 (1987) R35: (1) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) (2) Ku Y, Alverez GH; Chemosphere 11: 41-6 (1982) (3) Sadtler Res Lab; Sadtler Standard UV Spectra No 460 (1966) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (5) Swann RL et al; Res Rev 85: 17-28 (1983) (6) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) R36: (1) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) (2) Mill T, Mabey W; p. 208-11 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (4) Sadtler Res Lab; Sadtler Standard UV Spectra No 460 (1966) (5) Ku Y, Alverez GH; Chemosphere 11: 41-6 (1982) R37: (1) Lyman WJ; pp. 13-48 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R38: (1) Chemicals Inspection and Testing Institute; Japan Chemical Industry Ecology - Toxicology and Information Center ISBN 4-89074- 101-1 (1992) (2) Sasaki S; pp. 283-98 in Aquatic Pollutants Hutzinger O et al, eds Oxford: Pergamon Press (1978) (3) Ku Y, Alverez GH; Chemosphere 11: 41-6 (1982) R39: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Mill T, Mabey W; p. 208-11 in Environmental Exposure from Chemicals Vol I, Neely WR, Blau GE eds Boca Raton, FL: CRC Press (1985) (4) Sadtler Res Lab; Sadtler Standard UV Spectra No 61 (1966) R40: (1) Veith GD et al; J Fish Res Board Can 36: 1040-8 (1979) R41: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc p. 4-9 (1990) (2) Hansch C, Leo AJ; Medchem Project Issue No 26 Claremont, CA: Pomona College (1985) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) R42: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-15 to 15-32 (1990) R43: (1) Fishbein L; Aromatic Amines In: The Handbook of Environmental Chemistry; Anthropogenic Substances Germany: Springer-Verlag Berlin Heidelberg 3: 1-40 (1984) R44: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 329 (1978) R45: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R46: KROTOVA ZA, ZATKOVETSKII VM; USE OF THIN-LAYER CHROMATOGRAPHY FOR SEPARATING MIXT OF ISOPROPYLBENZENE HYDROPEROXIDE, DIMETHYLPHENYLCARBINOL, ACETOPHENONE, AND RUBBER STABILIZER, NEOZON-D; SB TR- MOSK INZH- STROIT INST 108: 86-89 (1977) R47: KROTOVA ZA; PHOTOMETRIC DETERMINATION OF ISOPRENE AND NEOZONE D IN WATER; GIG SANIT 4: 61-63 (1975) R48: OSHA; Analytical Methods Manual. 2nd ed., Part 1 Organic Substances, Vol IV Meth 81-102, Apr 1993. US Dept Labor Occupational Safety and Health, Admin, Direct Tech Supp, OSHA Technical Center, Salt Lake City, Utah R49: BATTEN PL, HATHWAY DE; BR J CANCER 35 (3): 342-346 (1977) RS: 39 Record 197 of 1119 in HSDB (through 2003/06) AN: 2891 UD: 200211 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PEROXYBENZOIC-ACID,-T-BUTYL-ESTER- SY: *BENZENECARBOPEROXOIC-ACID,-1,1-DIMETHYLETHYL-ESTER-; *BENZOYL-TERT-BUTYL-PEROXIDE-; *T-BUTYL-PERBENZOATE-; *T-BUTYL-PEROXY-BENZOATE-; *CHALOXYD-TBPB-; *ESPEROX-10-; *PERBENZOATE-DE-BUTYLE-TERTIAIRE- (FRENCH); *PERBUTYL-Z-; *PEROXYBENZOIC-ACID,-TERT-BUTYL-ESTER-; *TERC-BUTYLPERBENZOAN- (CZECH) RN: 614-45-9 MF: *C11-H14-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF T-BUTYL HYDROPEROXIDE WITH BENZOYL CHLORIDE (OR ANHYDRIDE) IN THE PRESENCE OF A BASE [R1] *t-Butyl hydroperoxide + benzoyl chloride (dehydrochlorination). [R2] FORM: *GRADE: 98% MIN. [R3] MFS: *Akzo Nobel Chemicals Inc., Hq, 300 South Riverside Plaza, Chicago, IL 60606, (312) 906-7500; Production site: Pasadena, TX 77507 [R4] *Aztec Peroxides, Inc., Hq, One Northwind Plaza, 7600 West Tidwell, Suite 500, Houston, TX 77040, (713) 895-2015; Production sites: Bayport, TX 77507; Elyria, OH 44035 [R4] *Elf Atochem North America, Inc, Hq, 2000 Market Street, 21st Floor, Philadelphia, PA 19103-3222, (215) 419-7000; Organic Peroxides Division; Production sites: Crosby, TX 77532; Geneseo, NY 14454 [R4] *The Norac Company, Inc, 405 South Motor Avenue, Azusa, CA 91702, (818) 334-2908; Production site: Azusa, CA 91702. [R4] *Witco Corporation, 1 American Lane, Greenwich, CT 06831, (203) 552-2000; Polymer Additives Group; Production site: Marshall, TX 75761 [R4] USE: *Polymerization initiator for polyethylene, polystyrene, polyacrylates, and polyesters; chemical intermediate. [R3] *POLYMERIZATION INITIATOR FOR POLYESTER AND OTHER RESINS; CURING AGENT FOR UNSATURATED POLYESTERS [R1] *Silicon rubber curing agent; polyester crosslinking agent. [R2] PRIE: U.S. PRODUCTION: *(1972) 7.00X10+8 GRAMS [R1] *(1975) 1.00X10+9 GRAMS [R1] *(1993) 1,963,000 kg [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS TO SLIGHT YELLOW LIQ [R6]; *Liquid [R2] ODOR: *MILD AROMATIC ODOR [R3] BP: *75-76 deg C at 0.2 mm Hg [R7] MP: *8 deg C [R7] MW: *194.25 [R8] DEN: *1.021 g/cu cm at 25 deg C [R9] SOL: *SOL IN ALC, ESTERS, ETHERS, KETONES; INSOL IN WATER [R3] SPEC: *IR: 2:899H (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R10]; *NMR: 7:28C (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R10]; *Index of Refraction = 1.4990 at 20 deg C/D [R9] VAP: *0.33 MM HG @ 50 DEG C [R3] OCPP: *Half-life of ten hours at 104 deg C [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Dangerous fire hazard by chemical reaction with reducing agents or exposure to heat. /Organic peroxides/ [R11, 2611] FLPT: *200 DEG F [R12] EXPL: *Potentially explosive when heated above 115 deg C. [R11, 595] *Severe explosion hazard when shocked, exposed to heat, or by spontaneous chemical reaction. /Organic peroxides/ [R11, 2611] REAC: *Explosive reaction on contact with organic matter or copper (I) bromide plus limonene. [R11, 595] *Upon contact with reducing materials, such as organic matter or thiocyanates, an explosion can occur. /Organic peroxides/ [R11, 2611] DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R11, 595] STRG: *OXIDIZING MATERIAL; DO NOT STORE NEAR COMBUSTIBLE MATERIALS. [R12] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Organic peroxides/ [R13, 134] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... Anticipate seizures and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Do not attempt to neutralize because of exothermic reaction. Cover skin burns with dry, sterile dressings after decontamination ... . /Organic peroxides/ [R13, 135] HTOX: *...MAIN RECOGNIZED EFFECT IS IRRITATION TO SKIN, MUCOUS MEMBRANES AND EYES. PROLONGED INHALATION OF VAPORS RESULTS IN HEADACHE AND THROAT IRRITATION, AND SPLASHES IN EYE CAN BE DAMAGING. PROLONGED SKIN CONTACT WITH CLOTHING CONTAMINATED WITH PEROXIDES MAY CAUSE IRRITATION AND BLISTERING. /PEROXIDES, ORG/ [R14] NTOX: *T-BUTYL PERBENZOATE TESTED AS 50% SOLN IN DIMETHYL PHTHALATE BY APPLICATION OF 2 DROPS TO RABBIT EYES CAUSED SLIGHT INJURY, GRADED 1 ON SCALE OF 0 TO 7. [R15] *Butyl perbenzoate was tested for embryotoxicity in 3-day chicken embryos using the air-chamber method. It caused malformations at a rate of 16%. [R16] *T-butyl perbenzoate was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). T-butyl perbenzoate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.3, 1.0, 3.3, 10, 16, 16.7, 33, 33.3 66.7, 67, 100, and 333 ug/plate. A positive response was observed in both strain TA98 and TA1537 with and without activation and in strain TA100 with activation. Total clearing of the background bacterial lawn occurred at the highest dose (33 ug/plate) tested using TA100 without metabolic activation. However, a dose dependent increase was observed at the lower doses. The lowest positive dose tested in any S. typhimurium strain was 10 ug/plate in strain TA98 with metabolic activation. [R17] *1992 Studies were conducted on the toxicity, stability, dermal absorption, and tissue distribution of t-butyl-perbenzoate (BP). Fourteen day and 13 week oral toxicity studies were conducted using F344/N rats and B6C3Fl mice. BP was mutagenic in Salmonella typhimurium strains (TA-100), (TA-1537), and (TA-98) with or without metabolic activation. In vitro sister chromatid exchange and chromosomal aberrations were noted in Chinese hamster ovary cells. BP was rapidly degraded in blood, stomach contents and liver homogenates, or in the presence of glutathione. In 14 day studies, BP administered by gavage in corn oil in doses ranging from 70 to 1112 mg/kg caused no systemic toxicity. Toxicity in the stomach was demonstrated by the presence of forestomach epithelial hyperplasia, ulceration, and acute inflammation. In studies lasting for 13 weeks, the animals demonstrated hyperplasia of the forestomach mucosa, particularly in dosed rats. BP toxicity in mice was limited to incr forestomach weight in most dose level groups and incr severity with dose. The ... no observed effect level for BP was approximately 30 mg/kg and that systemic toxicity was not observed with oral doses as high as 1112 mg/kg. [R18] *Electron paramagnetic resonance spin trapping has been used to study the production of free radicals from tert-butyl hydroperoxide, tert-butyl peroxybenzoate, cumene hydroperoxide and ethyl hydroperoxide in isolated murine keratinocytes. Free radical species could be trapped from keratiocytes treated with all peroxides, with radicals produced from 60th one electron oxidative and reductive pathways. The hindered phenolic antioxidants butylated hydroxyanisole (BRA) and butylated hydroxytoluene (BHT), which are known to inhibit peroxide induced tumor promotion in vivo, decr the amount of radical adduct production at a concn of 10 mM, with BHA being significantly more effective than BHT. That all the peroxides in this study produced free radicals in keratinocytes, and that BHA and BHT decreased the amounts of radicals trapped, suggests that free radical production by organic peroxide cmpd is involved in their in vivo tumor promoting activity. [R19] TCAT: ?The mutagenicity of tert-butyl peroxybenzoate was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, tert-butyl peroxybenzoate, diluted in DMSO, was tested at concentrations up to 500 ug/plate using the plate incorporation technique. Tert-butyl peroxybenzoate did not cause a positive response in any tester strain with or without metabolic activation. [R20] ?The ability of tert-butyl peroxybenzoate to induce specific locus mutations at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of metabolic (source not specified) activation. Based on preliminary toxicity determinations, nonactivated cultures were treated in duplicate with 3, 5, 7, 10 and 15 ug/ml, producing a range of 100.2 - 14.6% total survival. Activated cultures treated in duplicate with 5, 7, 10, 15 and 22 ug/ml produced a range of 125.4 - 22.7% total survival. Nonactivated cultures at the three highest doses levels produced better than a two-fold increase in the mutant frequency relative to the solvent control (DMSO), and a dose-response relationship was observed. Activated cultures at the high dose level produced greater than two-fold increase in the mutant frequency relative to the solvent control. [R21] ?The ability of t-butylperoxybenzoate (BPB) to induce Sister Chromatid Exchange (SCE) in Chinese hamster ovary (CHO) cells was evaluated both in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity tests, BPB, diluted with DMSO, was tested at concentrations of 0, 0.52, 1.8, 5.2, 18 or 52 ug/ml without activation and at concentrations of 0, 0.18, 0.52, 1.8, 5.2 or 18 ug/ml with activation. Fifty cells and 981-993 chromosomes were analyzed per concentration. Concentrations of 1.8 to 52 ug/ml without activation and concentrations of 5.2 and 18 ug/ml with activation induced statistically significant increases in the frequency of SCE relative to solvent controls (p < 0.005, one-tailed student's t-test). [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Peroxybenzoic acid, t-butyl ester may be released to the environment in various waste streams from its production and use as a polymerization initiator, chemical intermediate, and silicon rubber curing agent. If released to the atmosphere, peroxybenzoic acid, t-butyl ester is expected to exist solely as a vapor in the ambient atmosphere based on a measured vapor pressure of 0.33 mm Hg at 50 deg C. Vapor-phase peroxybenzoic acid, t-butyl ester will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with and estimated half-life of 7.0 days. If released to soil, an estimated Koc of 750 suggests that peroxybenzoic acid, t-butyl ester is expected to have low mobility. Volatilization from moist soil surfaces may occur based on an estimated Henry's Law constant of 2.1X10-4 atm-cu m/mole. If released into water, peroxybenzoic acid, t-butyl ester is expected to adsorb to suspended solids and sediment in the water column based on its estimated Koc. Volatilization of peroxybenzoic acid, t-butyl ester from water surfaces is expected based on this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 10 hours and 7.3 days, respectively. The potential for bioconcentration of peroxybenzoic acid, t-butyl ester in aquatic organisms is moderate, not high based on an estimated BCF of 93. No data were available concerning the biodegradation of peroxybenzoic acid, t-butyl ester. Occupational exposure to peroxybenzoic acid, t-butyl ester may occur through dermal contact with this compound at workplaces where peroxybenzoic acid, t-butyl ester is produced or used. (SRC) ARTS: *Peroxybenzoic acid, t-butyl ester's production and use as a polymerization initiator, chemical intermediate(1), and as a silicon rubber curing agent(2) may result in its release to the environment through various waste streams(SRC). [R23] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 750(SRC), determined from a structure estimation method(2), indicates that peroxybenzoic acid, t-butyl ester is expected to have low mobility in soil(SRC). Volatilization of peroxybenzoic acid, t-butyl ester is expected to be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 2.1X10-6 atm-cu m/mole(SRC), using a fragment constant estimation method(3). No data was available concerning the biodegradation of peroxybenzoic acid, t-butyl ester(SRC). [R24] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 750(SRC), determined from a structure estimation method(2), indicates that peroxybenzoic acid, t-butyl ester is expected to adsorb to suspended solids and sediment in water(SRC). Peroxybenzoic acid, t-butyl ester is expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 2.1X10-4 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Estimated volatilization half-lives for a model river and model lake are 10 hours and 7.3 days, respectively(3,SRC). According to a classification scheme(5), an estimated BCF value of 93(3,SRC), from an estimated log Kow(6,SRC), suggests that bioconcentration in aquatic organisms is moderate, not high(SRC). No data was available concerning the biodegradation of peroxybenzoic acid, t-butyl ester(SRC). [R25] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), peroxybenzoic acid, t-butyl ester, which has a measured vapor pressure of 0.33 mm Hg at 50 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase peroxybenzoic acid, t-butyl ester is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 7.0 days(3,SRC). [R26] ABIO: *The rate constant for the vapor-phase reaction of peroxybenzoic acid, t-butyl ester with photochemically-produced hydroxyl radicals has been estimated as 2.3X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 7.0 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Peroxybenzoic acid, t-butyl ester has a half-life of ten hours at 104 deg C(2). [R27] BIOC: *An estimated BCF value of 93 was calculated for peroxybenzoic acid, t-butyl ester(SRC), using an estimated log Kow of 2.89(1,SRC) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF suggests that bioconcentration in aquatic organisms is moderate, not high(SRC). [R28] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for peroxybenzoic acid, t-butyl ester can be estimated to be about 750(SRC). According to a recommended classification scheme(2), this estimated Koc value suggests that peroxybenzoic acid, t-butyl ester is expected to have low mobility in soil(SRC). [R29] VWS: *The Henry's Law constant for peroxybenzoic acid, t-butyl ester is estimated as 2.1X10-4 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that peroxybenzoic acid, t-butyl ester will volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 10 hours(2,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 7.3 days(2,SRC). The volatilization half-life from an environmental pond 2 m deep is estimated to be about 9.2 days when considering adsorption to suspended solids and sediment(3). Peroxybenzoic acid, t-butyl ester's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is expected to occur(SRC). [R30] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 21,377 workers (8,213 of these are female) are potentially exposed to peroxybenzoic acid, t-butyl ester in the US(1). Occupational exposure to peroxybenzoic acid, t-butyl ester may occur through dermal contact with this compound at workplaces where peroxybenzoic acid, t-butyl ester is produced or used(SRC). [R31] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Report on the Toxicity Studies of t-Butyl Perbenzoate Administered by Gavage to F344/N Rats and B6C3F1 Mice NTP Tox 15 (1991) Watts P; Food Chem Toxicol 23: 957-60 (1985). Peroxides, genes and cancer is reviewed. Lai DY, et al; J Environ Sci Hlth 14 (1, Pt C): 63-80 (1996). Carcinogenic potential of organic peroxides prediction based on structure activity relationships and mechanism based short term test. SO: R1: SRI R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 158 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 189 R4: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 486 R5: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-93 R6: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 450 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V18 286 R8: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8307 R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-33 R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 353 R11: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R12: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 140 R13: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R14: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 1013 R15: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 164 R16: Korhonen A et al; Environ Res 33 (1): 54-61 (1984) R17: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R18: DHHS/NTP; NTP Technical Report on Toxicity Studies of t-Butyl Perbenzoate (CAS Number: 614-45-9) Administered by Gavage to F344/N Rats and B6C3Fl Mice. National Toxicology Program, U.S. Department of Health and Human Services, Research Triangle Park, North Carolina, Toxicity Report Series No. 15, NIH Publication No. 92-3134 (1992) R19: Timmins GS, Davis M; Carcinogenesis 14 (8): 1615-20 (1993) R20: Hazleton Laboratories American Inc.; Salmonella/Mammalian Microsome Plate Incorporation Assay with Tert-Butyl Peroxybenzoate, Final Report, (1984), EPA Document No. FYI-OTS-0585-0401, Fiche No. OTS0000401-0 R21: Hazleton Biotechnologies Corporation; Mouse Lymphoma Forward Mutation Assay, Final Report, (1984), EPA Document No. FYI-OTS-0585-0401, Fiche No. OTS0000401-0 R22: Hazelton Biotechnologies Corp.; In Vitro Sister Chromatid Exchange in Chinese Hamster Ovary Cells, t-Butyl Peroxybenzoate, Final Report. (1984), EPA Document No. FYI-OTS-0585-0401, Fiche No. OTS0000401-0 R23: (1) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY, NY: Van Nostrand Reinhold Co p. 189 (1993) (2) Ashford RD; Ashford's Dictionary of Industrial Chemicals: Properties, Production, Uses. London, England: Wavelength Publ, Ltd. p.158 (1994) R24: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) R25: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) R26: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY, NY: Van Nostrand Reinhold Co p. 189 (1993) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R27: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Ashford RD; Ashford's Dictionary of Industrial Chemicals: Properties, Production, Uses. London, England: Wavelength Publ, Ltd. p. 158 (1994) R28: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R29: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) R30: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) U.S. EPA; EXAMS II Computer Simulation (1987) R31: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) RS: 23 Record 198 of 1119 in HSDB (through 2003/06) AN: 2892 UD: 200301 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PETROLEUM-ETHER- SY: *AROMATIC-SOLVENT-; *BENZIN-; *BENZINE-; *BENZOLINE-; *CANADOL-; *HERBITOX-; *HI-FLASH-NAPHTHAYETHYLEN-; *HYDROFINING-; *HYDROREFINING-; *LIGHT-LIGROIN-; *LIGROIN-; *MINERAL-SPIRITS-; *MINERAL-SPIRITS-NO-10-; *MINERAL-THINNER-; *MINERAL-TURPENTINE-; *NAPHTHA-; *NAPHTHA,-PETROLEUM-; *NAPTHA,-VM-AND-P-; *PAINTERS'-NAPHTHA-; *PETROLEUM-BENZIN-; *PETROLEUM-DISTILLATES- (NAPHTHA); *REFINED-SOLVENT-NAPHTHA-; *Rubber-solvent-; *SKELLY-SOLVE-F-; *SKELLY-SOLVE-H-; *SKELLY-SOLVE-R-; *SKELLY-SOLVE-S-; *SKELLY-SOLVE-S-66-; *SOLVENT-NAPHTHA-; *STODDARD-SOLVENT-; *VARNISH-MAKERS'-AND-PAINTERS'-NAPHTHA-; *VARNISH-MAKERS'-NAPHTHA-; *VARSOL-; *VM-AND-P-NAPHTHA-; *WHITE-SPIRIT-; *WHITE-SPIRITS- RN: 8030-30-6 MF: *UNKNOWN SHPN: UN 1271; Petroleum ether IMO 3.1; Petroleum ether MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FRACTIONAL DISTILLATION OF PETROLEUM (BENZIN IS THE LOW BOILING FRACTION OF PETROLEUM WHICH CONSISTS MOSTLY OF PENTANES AND HEXANES) [R1] *Source (by various cracking processes) of gasoline, special naphthas, petroleum chemicals, especially ethylene. Cracking for ethylene also produces propylene, butadiene, pyrolysis gasoline, and fuel oil, source of synthetic natural gas. [R2] FORM: *Available with less than 8% aromatic content [R3, p. V2 39] MFS: *AMOCO OIL CO (NAPHTHA SOLVENTS), CHICAGO, IL 60601 [R1] *APCO OIL CORP (NAPHTHA SOLVENTS), OKLAHOMA CITY, OK 73101 [R1] *CPS CHEM CO (NAPHTHA SOLVENTS), OLD BRIDGE, NJ 08857 [R1] *CHARTER INTERNAT'L OIL CO (NAPHTHA SOLVENTS), CHARTER CHEMS, HOUSTON, TX 77012 [R1] *CITIES SERVICE OIL CO (NAPHTHA SOLVENTS), TULSA, OK 74102 [R1] *CROWLEY CHEM CO (NAPHTHA SOLVENTS), NEW YORK, NY 10016 [R1] *CROWLEY TAR PRODUCTS CO, INC (NAPHTHA SOLVENTS), NEW YORK, NY 10016 [R1] *EXXON CO USA (NAPHTHA SOLVENTS), HOUSTON, TX 77001 [R1] *GETTY REFINING AND MARKETING CO (NAPHTHA SOLVENTS), TULSA, OK 74102 [R1] *PIERCE AND STEVENS CHEM CORP (NAPHTHA SOLVENTS), BUFFALO, NY 14240 [R1] *SUN PETROLEUM PROD CO (NAPHTHA SOLVENTS), PHILADELPHIA, PA 19103 [R1] *UNION OIL CO OF CALIF (NAPHTHA SOLVENTS), UNION CHEM DIV, SHAUMBERG, IL 60196 [R1] *WITCO CHEM CORP (NAPHTHA SOLVENTS), KENDELL/AMALIE DIV, BRADFORD, PA 16701 [R1] *Atlantic Richfield Co, ARCO Chem CO Div, 260 Broad St, Philadelphia, PA 19101 [R4] *Skelly Oil Co, Kansas City, MO 64141 [R4] *Union Oil Co of California, Amsco Div, 3100 S Meacham Rd, Palatine Rd, IL 60067 [R4] USE: *SOLVENT IN PAINT AND VARNISH INDUSTRY; MEDICINAL AGENT-COUNTERIRRITANT [R1] *Used in the manufacture of Pearl glue as an extractant [R3, p. V11 916] *As a solvent for varnishing or sealing wood/furniture, automotive brake and rotor cleaning, fuel oil tank cleaning, and painting. [R5] PRIE: U.S. EXPORTS: *(1972) 9.75X10+8 GRAMS (NAPHTHA SOLVENT) [R1] *(1975) 7.60X10+9 GRAMS (NAPHTHA SOLVENT) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear, colorless liquid [R6]; +Reddish-brown mobile liquid. [R7] ODOR: *Gasoline odor [R4]; +Aromatic odor. [R7] BP: *38-93 deg C [R8] DEN: *0.6 (water= 1) [R9] SOL: *Miscible with absolute alcohol, benzene, chloroform, ether, carbon disulfide, carbon tetrachloride, and oils except castor oil [R6] VAPD: *2.5 (air= 1) [R9] OCPP: *Does not solidify in the cold [R6] *Boiling Point: 95-140 deg F (35-60 deg C) [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. Substances may be transported hot. [R10] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R10] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R10] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R10] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R10] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R10] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R10] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R10] FPOT: *Highly flammable [R11] NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R12] +Flammability: 4. 4= This degree includes flammable gases, pyrophoric liquids, and Class IA flammable liquids. The preferred method of fire attack is to stop the flow of material or to protect exposures while allowing the fire to burn itself out. [R12] +Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R12] FLMT: *Lower: 1.1%; upper: 5.9% [R13] FLPT: +Less than 0 deg F (less than -18 deg C) (Closed cup) [R12] AUTO: +550 deg F (288 deg C) [R12] FIRP: *Foam, carbon dioxide, or dry chemical [R4] EXPL: *The vapors mixed with air explode if ignited. [R11] REAC: +Strong oxidizers. [R7] SERI: *Petroleum naphtha vapor is an irritant of the mucous membranes and respiratory tract. /Petroleum naptha/ [R14] EQUP: *Goggles or face shield. [R4] +Recommendations for respirator selection. Max concn for use: 1000 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. Eye protection is needed. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any powered, air-purifying respirator with organic vapor cartridge(s). Eye protection is needed. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R7] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full face piece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R7] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R7] +Wear appropriate personal protective clothing to prevent skin contact. [R7] +Wear appropriate eye protection to prevent eye contact. [R7] OPRM: +The worker should immediately wash the skin when it becomes contaminated. [R7] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R7] SSL: *Volatile [R11] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R15] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R16] STRG: *Keep tightly closed in a cool place and away from fire. [R11] CLUP: *1. Remove all ignition sources. 2. Ventilate area of spill or leak. 3. For small quant, absorb on paper towels. Evaporate in a safe place (such as a fume hood). Allow sufficient time for evaporating vapors to completely clear the hood ductwork. Burn the paper in a suitable location away from combustible materials. Large quant can be collected and atomized in a suitable combustion chamber. Petroleum distillates should not be allowed to enter a confined space, such as a sewer, because of the possibility of an explosion. [R17] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Petroleum distillates may be disposed of by atomizing in a suitable combustion chamber. [R17] *Incineration: Dispose of the adsorbed material or free waste liquid by incineration or via a licensed solvent disposal company. [R18] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Much controversy surrounds different aspects of treatment: the induction of vomiting, nasogastric lavage, administration of oils to thicken the petroleum distillate, administration of prophylactic steroids, and the use of antibiotics. /Petroleum distillates/ [R19, 1182] HTOX: *... Petroleum ether applied to the skin may ... induce severe irritation ... . [R20] *Subjective symptoms originating from the central nervous system, such as headache, fatigue, poor concentration, emotional instability, impaired memory and other intellectual functions, and impaired psychomotor performance have been reported in a series of cross-sectional studies of paint industry workers, house painters, car painters, shipyard painters and floorlayers, all of whom had been exposed to a mixture of solvents, including petroleum solvents ... Some of these are short- or mid-term effects, others are potentially persistent. In some studies, dose-response relationships were observed between symptoms and lifetime exposure (duration and intensity) to solvents. /Petroleum solvents/ [R20] *A rubber solvent /SRP: C5-C7 aliphatic and alicyclic hydrocarbons/ induced chromosomal aberrations but not sister chromatid exchange in human whole-blood cultures ... . /Rubber solvent/ [R21] *In workers exposed to a glue solvent (rubber solvent; C5-C7 aliphatic and alicyclic hydrocarbons), indications of slight renal tubular effects were reported ... . /Rubber solvent/ [R20] *A case-control study of cancer at many sites was performed in Montreal, Canada, to generate hypotheses on potential occupational carcinogens ... About 20 types of cancer were included, and, for each cancer site analyzed, controls were selected from among cases of cancer at other sites. Job histories and information on possible confounders were obtained by interview from 3726 men aged 35-70 years with cancer diagnosed at one of 19 participating hospitals between 1979 and 1985. The response rate was 82%. Each job was translated into a series of potential exposures by a team of chemists and hygienists using a check-list of 300 of the most common occupational exposures in Montreal. Cumulative indices of exposure were estimated for a number of occupational exposures: exposure below the median was considered to be 'nonsubstantial' and that above the median to be 'substantial'. Risks associated with exposure to petroleum-derived liquids were analyzed separately. A total of 739 men were classified as having been potentially exposed to 'mineral spirits'. The term 'mineral spirits' included white spirits, Stoddard solvent, VM AND P naphtha, rubber solvent, benzine and ligroin (30-90% aliphatics, 1-20% aromatics). Those with long (> 20 years), substantial potential exposure were found to have a RR for squamous-cell cancer of the lung of 1.7 (90% CI, 1.2-2.3), based on 44 cases, and a RR for prostatic cancer of 1.8 (90% CI, 1.3-2.6), based on 43 cases. Men with 'substantial' exposure also had a RR for Hodgkin's lymphoma of 2.0 (90% CI, 1.0-4.1), based on 12 cases. There was no increased risk for cancers of the bladder (1.0; 0.8-1.2; 91 cases) or kidney (1.1; 0.8-1.4; 39 cases) or for non-Hodgkin's lymphoma (0.8; 0.6-1.1; 35 cases). The risks were adjusted for age, socioeconomic status, ethnic group, cigarette smoking and blue-/white-collar job history, and for all potential confounders on which information was available. Of the 739 exposed men, 21% had been employed in the construction trade, mostly as painters. [R22] *Acute neurotoxic effects of petroleum ether include anesthesia, euphoria, abuse, vertigo, and limb numbness. Chronic neurotoxic effects include motor polyneuropathy /From table/ [R23] *... Patch-tested petroleum solvents of various boiling ranges on the skin of human volunteers. They found a correlation between the boiling ranges of the petroleum products of paraffinic origin and their irritant and defatting action on the skin. Both effects decreased, the higher the boiling range. Petroleum solvents with boiling ranges up to and including that of kerosene (approx 230 deg C) were found to be primary irritants. Petroleum solvents of naphthenic origin or with a high aromatic content were more irritant than solvents of paraffinic origin of the same boiling range. The skin of Negroes showed a higher tolerance than that of Caucasians. /Petroleum solvents/ [R24] *The effects of various solvents on the horny layer of the skin were examined ... They found that petroleum ether (SBP 40/65) caused serious irritation of human forearm skin, when applied for periods of 10-30 min. When applied for 15 min on 6 successive days, injury occurred in the horny layer. Recovery - as measured by water vapor loss - could take up to 6 wk. The skin irritation and the changes in the composition of the horny layer were independent phenomena. [R25] *... Studied the gynecological disease rate in more than 5000 female operators in plants producing rubber articles (petroleum solvent vapor concn in the air of 250-350 mg/cu m). They observed disturbances in the menstrual cycle in workers with more than 5 years' service and a high frequency of metrorrhagia. As the period of service increased, a reduction in the frequency of miscarriages was noticed, which was interpreted by the authors as possible adaptation. A disturbance of the ovarian function was noted in 24.4% of the workers examined, mostly in the form of a functional deficiency of corpus luteum. /Petroleum solvent vapor/ [R26] *Women who had been in contact with petroleum solvents were found to have a reduced estrogen level in the blood. ... Essentially, no changes were observed in the excretion of the follicle-stimulating and luteinizing hormone pregnanediol. /Petroleum solvents/ [R27] *... Studied lactation in 332 nursing mothers 288 of whom worked in the rubber industry (vulcanizers, pressers, gluers). The concn of petroleum solvents (the physicochemical properties of which are not described) in the air of the operating premises was predominantly 300 mg/cu m. Hypolactation, found in 23.8% of the women compared with 6.7% in the control group was related to length of service. Hydrocarbon solvents were found in the milk of all the persons examined (71) in concn of 0.50 + or - 0.05 mg to 0.60 + or - 0.09 mg/l. The serotonin content of the blood of these women was significantly lower than in the control group. It is assumed that hypolactation was the result of the effect of solvents on the lactation control mechanism via the hypothalamus and the serotoninergic system. /Petroleum solvents/ [R28] *Most cases, however, /of accidental ingestion of petroleum solvents/ are caused by gasoline and kerosene and fewer by petroleum solvents. The symptomatology is the same in all cases. Coughing, choking, and gagging are often noted at the time of ingestion of these substances. Respiratory embarrassment may be present early, indicating the aspiration has taken place. Epigastric discomfort may develop, followed by vomiting with a further risk of aspiration. ... In cases where aspiration does not take place, and especially with the lower-boiling solvents, CNS symptoms may develop such as lethargy, convulsions, and coma. With smaller doses, the symptoms include vertigo, headache, and signs of drunkenness. Nausea, vomiting, and diarrhea may occur and the stools may be blood-tainted. In uncomplicated cases, the GI symptoms will disappear within 48 hr. Pulmonary symptomatology will not develop, if aspiration has not occurred and if there was no massive exposure to vapors ... Chemical pneumonitis with pulmonary oedema and hemorrhagic frothy sputum may develop extremely rapidly following aspiration of petroleum solvents. Roentgenographic changes may be seen within a few hours, especially at the lung bases. Later, bacterial pneumonia can complicate the situation. [R29] *In 1971, ... examined employees working in a furniture factory who were exposed to n-hexane. Air samples of hexane were found to average 2286 mg/cu m and peaked at 4573 mg/cu m. The patients complained of one or more of the following symptoms: abdominal cramps, burning sensations, numbness and weakness of the distal extremities, and paresthesia. The peripheral neuropathy (sensory and motor) caused by n-hexane is due to the metabolite 2,5-hexanedione. /n-Hexane/ [R30] *Petroleum naphtha vapor is a CNS depressant as well as an irritant of the mucous membranes and respiratory tract. Exposure to high concn of the vapor can produce headache, dizziness, nausea, and shortness of breath. Dermal contact to vapor or liquid can produce dermatitis. [R14] *A petroleum distillate with a viscosity below 45 SSU (Sable universal seconds, petroleum ether) petroleum naphtha, gasoline, mineral spirits, kerosene, lamp oil, and mineral seal oil) is highly toxic by aspiration. [R19, 1178] *Aspiration of a petroleum distillate results in chemical pneumonitis. Bronchospasm, hyperemia, edema, and atelectasis are noted. Diffuse hemorrhagic alveolitis with granulocytic infiltrates occurs soon after aspiration and peaks at about 3 days. Frank necrosis of bronchial, bronchiolar, and alveolar tissues can occur, along with vascular thrombosis and micro abscess formation. A late proliferative process with alveolar thickening may occur later and peaks at about 10 days. Late complications may include bacterial pneumonia, residual small airway abnormalities, and pneumatoceles. /Petroleum distillates/ [R19, 1180] *Upper airway pathology may occur with or without aspiration and includes hyperemia, mucosal irritation, and inflammation of the oropharynx. /Petroleum distillates/ [R19, 1180] *Although petroleum distillates are poorly absorbed from the GI tract, some systemic absorption does occur. The GI pathology of petroleum distillate ingestion is generally mild and self limited. Mucosal inflammation and superficial ulceration is common, and although fatty infiltration of the liver may occur, frank necrosis is uncommon. Petroleum distillate ingestion may cause myocarditis and mild degenerative changes of myofibrils. At least one case of petroleum distillate ingestion resulted in electrocardiographic and vectorcardiographic evidence of myocardial infarction. Petroleum distillates are said to sensitize the myocardium to catecholamines. Petroleum distillates have also been reported to cause intravascular hemolysis and renal damage, which usually consists of mild degenerative changes of the renal tubules but may rarely result in acute tubular necrosis. /Petroleum distillates/ [R19, 1180] *... A wide range of presentations occurs, from the asymptomatic patient to the patient with significant pulmonary or neurologic manifestations. ... Presenting symptoms and signs, however, are usually related to three main organ systems: pulmonary, central nervous, and GI. /Petroleum distillates/ [R19, 1181] *Complaints relating to pulmonary involvement include coughing paroxysms, choking, or gagging, and these are indicative of a high likelihood of aspiration. Symptoms of CNS involvement include light-headedness, headache, visual changes, impaired memory, or unusual behavior. Physical exam may reveal fever, tachypnea, and tachycardia. Stridor may be present and is an indication to consider upper respiratory obstruction as an immediate concern. ... Dyspnea, tachypnea, tachycardia, intercostal retractions, and nasal flaring are often noted within 30 min of aspiration, but may not manifest for up to 2 days. Auscultation may reveal rales, wheezes, or coarse or decreased breath sounds, specially in the lower lobes. /Petroleum distillates/ [R19, 1181] *... The general effects of intoxication are peripheral nerve disorders, CNS depression, and skin and respiratory irritation ... . [R31] *Ingestion of furniture polish or lighter fluid which may contain ligroin has caused chemical pneumonia and pneumatoceles in children. [R31] *On human skin, it has caused erythema, edema, disruption of the horny layer, and peeling. [R31] *Acute inhalation of petroleum ether, when mistakenly used as an anesthetic agent, caused reversible cerebral edema. [R31] *Numerous reports point to the neurotoxic effects on prolonged inhalation of petroleum ether in inadequately ventilated business establishments where employees experienced polyneuropathy. Signs and symptoms included loss of appetite, muscle weakness, impairment of motor action, and paresthesia ... . [R31] *The association between recent and long term naphtha exposure and urinary markers of renal dysfunction was studied among workers at a facility that made fuel injectors for motor vehicles. Renal function was assessed at two time points separated by a 1 year interval with relatively high exposure to naphtha and a comparison group with low exposure. In June of 1988 248 subjects participated of whom 181 participated again in June of 1989. Urine samples were collected and a self administered questionnaire concerning confounding variables was provided. Naphtha air concentrations ranged from 9 to 590 mg/cu m in June of 1988 and from 4 to 790 mg/cu m in June of 1989. Naphtha levels were significantly higher inside calibration rooms than outside calibration rooms . Fluctuations in measures of renal function among 17 individuals over one work week period indicated no changes associated with naphtha exposure. In longitudinal analyses there was a change in beta-N-acetyl-D-glucosaminidase which was positively associated with the change in recent naphtha exposure. The /results suggest/ that this study does not provide strong evidence of an association between either cumulative or recent exposure to naphtha and adverse renal effects on this group of naphtha exposed workers. [R32] *The neuropsychological effects of exposure to naphtha in automotive factory workers were investigated. A total of 248 workers (119 from calibration rooms and 129 from outside) participated in June 1988 and 185 workers (87 from inside and 98 from outside the calibration rooms) did so again in June 1989. The naphtha blend used was 50% paraffins, 25% monocyclic naphthenes, 18% benzenes and less than 5% each of dicyclic naphthenes, indans or teralins, naphthalenes, and olefins. Mean naphtha air levels were calculated from 514 personal air samples. Behavioral functions were measured through questionnaires and psychological tests on mood states (MS), trails (Tr), delayed recognition (DR), visual reproduction (VR), pattern memory (PM), symbol/digit substitution (SD), vocabulary (VO), the Wisconsin card sorting test (WCST), and the Rey Osterreith complex figure test (ROT). Results showed that mean naphtha levels were significantly higher in calibration rooms than outside and higher in June 1988 than in June 1989. Of the subjective symptoms, fatigue was the most intensely endorsed at all threshold values. Nausea and inflamed gums were significantly associated with cumulative exposures in 1988. Of the behavioral tests, Tr, WCST, and VR were marginally associated with cumulative exposure in 1988. Threshold models showed that for 1988, the strongest association was with Tr; a significant association with SD was evident in the 90th percentile threshold model. For 1989, the only test with significant association in the no threshold model was SD. It showed a significant increase in the 90th percentile threshold model and showed a significant association for VR. Longitudinal multiple regression models showed significant associations with acute exposure for SD and MS, with marginal significance for Tr. The /results suggest that/ that the effects of naphtha exposure are mild and transitory and recommend factory ventilation systems to limit exposure to less than 90 ppm/hr. [R33] NTOX: *Acute neurotoxic effects of petroleum ether include restlessness and ataxia. Chronic effects include motor polyneuropathy and CNS depression. /From table/ [R23] *... Examined various aspects of the acute toxicity of 10 samples of petroleum solvents that contained components representative of the range of hydrocarbons found in commercial petroleum solvents /described in table/ ... findings ... showed that all the solvents tested could be considered of low hazard to health unless aspirated or inhaled in extremely high concentrations. Aromatic solvents were more toxic than non-aromatic materials, the dose of solvent required to kill 50% of rats, when administered orally or percutaneously, being lower for aromatic than for non-aromatic solvents. Skin and eye irritancy were also greater with aromatic solvents. The toxicity of the vapors could not be compared, because the volatility of samples varied greatly. All solvents induced similar toxic effects, whatever the route of administration, including CNS depression (characterized by incoordination, prostration, and coma) followed by death. Convulsions sometimes occurred. All solvents caused skin and eye irritation though, in general, as the chain length of the non-aromatic solvents increased their irritant properties decreased. Repeated skin exposure led to skin irritation and necrosis with all solvents. /Petroleum solvents/ [R34] *Mature female Wistar rats were exposed to petroleum solvents vapor properties not given) at a concn of 300 + or - 8.2 mg/m3 for 30-45 days, for 4 hr/day. The serotonin content of the myometrium in exposed rats equalled 75.7 + or - 2.6 ug/kg compared with 68.47 + or - 2.5 ug/kg in the control group. Uterine contractions were more numerous and stronger in exposed animals. The level of solvent in the venous blood was 2.0 + or - 0.4 mg/l. In the uterine tissues it was almost twice as high (3.8 + or - 0.6 mg/kg). The increase in serotonin content in the organism could cause disturbances in the transport of the fertilized egg cell and the nidation, and subsequently, early abortion ... . /Petroleum solvents/ [R35] *Tests for teratogenicity induced by inhalation of high and low doses of ... rubber solvent ... were all negative /Rats; rubber solvent/ [R36] *...VARIOUS LIQUID HYDROCARBONS OF PETROLEUM CAUSE LITTLE OR NO INJURY ON DIRECT EXTERNAL CONTACT WITH THE EYE. /PETROLEUM PRODUCTS/ [R37] *A white spirit/naphtha, three kerosines, two gas oils and a catalytically cracked light cycle oil (LCO) were applied topically to mice three times a week for up to 6 weeks and skin changes were examined histopathologically at intervals. The changes within 1 week of treatment appeared to depend on the effect that the physicochemical properties of each type of product had on their penetration through the skin surface or via hair follicles. With white spirit the most prominent change was widespread epidermal necrosis occurring after the second treatment implying that the lowest boiling point materials penetrate mainly through the surface epidermis. The earliest effects with kerosines were within and around hair follicles with epidermal degeneration developing later suggesting a predominance of follicular entry. Gas oils and LCO produced similar changes to kerosines within 1 week, gas oils producing a slower and less severe response and LCO a more severe response. In skin examined after 1-6 weeks of treatment with all middle distillates repeated cycles of necrosis and healing responses were evident; this implied that once the epidermal barrier layer had been damaged follicular entry became less important. The severity of the skin changes observed with these middle distillates was probably sufficient for skin tumors to arise by a non-genotoxic mechanism if a similar treatment regime was used in a long-term skin painting study. A method of avoiding excessive skin irritation is therefore essential if such a study in order to obtain a reliable prediction of the human hazard of such materials. [R38] NTXV: *LD50 Rat oral > 25 ml/kg bw /Special boiling range 65-75 deg C solvents, from table/; [R39] *LC50 Rat inhalation 73,680 ppm for 4 hr /Special boiling range 65-75 deg C solvents, from table/; [R39] *LD50 Rabbit percutaneous 4 hr > 5.0 mg/kg bw /Special boiling range 65-75 deg C solvents, from table/; [R40] POPL: *Pre-existing skin disease may increase the susceptibility of the skin to the effects of contact with petroleum solvents and will also facilitate uptake by this route ... . /Petroleum solvents/ [R41] ADE: *The highly volatile C-5, C-6, and C-7 paraffins, cycloparaffins, and aromatic hydrocarbons readily pass across the alveolar membrane /of rats/ into the bloodstream and are transported within minutes to the CNS. Longer-chain homologues can, to a certain extent, also pass the alveolar membrane, but their principal effects is local. /Petroleum solvents/ [R42] *The elimination of the lower-boiling solvents (SBP type) in both animals and man is usually /rapid/ and mainly occurs via the respiratory tract. /Petroleum solvents/ [R43] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Petroleum ether is a mixture of hydrocarbons having carbon numbers predominately in the range of C5 through C6, which have boiling point ranges of 38 to 93 degrees C. The hydrocarbons used for the estimation of petroleum ether's chemical properties were cyclopentane, pentane, cyclohexane, isohexane, and 1,1-dimethylcyclopentane. Petroleum ether's use as a solvent and pharmaceutic aid may result in its release to the environment through various waste streams. If released to water, volatilization of petroleum ether will be rapid with estimated half-lives of 2.5 to 2.7 hours and 3.3 to 3.7 days from a model environmental river and a model lake, respectively. Adsorption to sediment will vary based on estimated Koc values of 81 to 650. Bioconcentration of petroleum ether in aquatic organisms may not be an important fate process. Petroleum ether is expected to biodegrade quickly in soil and aquatic conditions. If released to the atmosphere, petroleum ether will exist primarily in the vapor phase. Vapor-phase petroleum ether will degrade in the atmosphere by reaction with photochemically produced hydroxyl radicals with estimated half-lives of approximately 4 to 8 days. Removal of atmospheric petroleum ether may occur through wet deposition. If released to soil, petroleum ether is expected to have low to high mobility based on estimated Koc values of 81 to 650. Volatilization of petroleum ether is expected from both moist and dry soils. Occupational exposure to petroleum ether can occur through inhalation, dermal contact, and ingestion. (SRC) ARTS: *Petroleum ether is a mixture of hydrocarbons having carbon numbers predominately in the range of C5 through C6, which have boiling point ranges of 38 to 93 degrees C(1). Petroleum ether's use as a pharmaceutic aid(2) and solvent for varnishing or sealing wood/furniture, automotive brake and rotor cleaning, fuel oil tank cleaning, and painting(3) may result in its release to the environment through various waste streams(SRC). [R44] FATE: *TERRESTRIAL FATE: Petroleum ether will have low to high mobility(1) in soil based on estimated Koc values of 81 to 650(2,SRC). Volatilization of petroleum ether is expected from both moist and dry soils based on estimated Henry's Law constants of 0.19 to 1.7 atm-cu m/mol(3,SRC) and an estimated vapor pressure of 35 mm Hg(4,SRC). Petroleum ether will biodegrade in soil conditions based on a variety of biodegradation studies(5,6,SRC). [R45] *AQUATIC FATE: Volatilization of petroleum ether from water is rapid based upon estimated Henry's Law constants of 0.19 to 1.7 atm-cu m/mol, using cyclopentane and isohexane(1,2,SRC). Volatilization half-lives from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) and a model lake (1 meter deep) can be estimated to be 2.5 to 2.7 hours(2,SRC) and 3.3 to 3.7 days(2,SRC), respectively. Adsorption to sediment will vary based on a wide range of estimated Koc values from 81 to 650(3,SRC). Bioconcentration of petroleum ether in aquatic organisms is not expected to be an important fate process because of the expected moderate water solubility of petroleum ether fractions(SRC). Petroleum ether will biodegrade in natural waters based on a variety of biodegradation studies(4,5,SRC). [R46] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of approximately 35 mm Hg at 25 deg C(1), and a suggested classification scheme(2), petroleum ether will exist primarily in the vapor phase in the atmosphere(SRC). It will degrade in the ambient atmosphere by reaction with photochemically produced hydroxyl radicals with estimated half-lives of 4 to 8 days based on cyclohexane and pentane(1,SRC). Removal of atmospheric petroleum ether may occur through wet deposition(SRC). [R47] BIOD: *Oxidation of petroleum ether in a normal town sewage, active silt (6 mg/L) and prepurified petroleum containing sewage mixture was 82 and 93 percent after 24 and 48 hours, respectively(1). However, poisoning of the silt organisms occurred after 48 hours(1). The ratios of BOD5/COD and BOD5/TOC were 1.29 and 1.04, respectively, after 7 days, corresponding to a removal of COD and TOC of 79 and 85 percent(2). [R48] ABIO: *Petroleum ether is classified as reactive and volatile and will participate in smog formation(1). Using a structure estimation method(2) the rate constants for the vapor phase reaction of petroleum ether with photochemically produced OH radicals has been estimated to be 4.05X10-12 cu cm/molecule(SRC), based on pentane and cyclohexane, which correspond to atmospheric half-lives of 4 to 8 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2,SRC). [R49] BIOC: *Based upon estimated water solubilities of 32 to 107 mg/l, for 1,1-dimethylcyclopentane and cyclopentane(1), the bioconcentration factor for petroleum ether is in the range of 44 to 88 from a regression derived equation(1). According to these estimated bioconcentration factors, bioconcentration of petroleum ether in aquatic organisms is not expected to be an important fate process(SRC). [R50] KOC: *Using a structure estimation method based on molecular connectivity indexes, the Koc for petroleum ether can be estimated to be about 81 to 213 using pentane and 1,1-dimethylcyclopentane(1). Based upon estimated water solubilities of 32 to 107 mg/l(2,SRC), the Koc for petroleum ether can be estimated to be 330 to 650 using benzene and 1,1-dimethylcyclopentane. According to a suggested classification scheme(3), these estimated Koc values suggest that petroleum ether components have high to low soil mobility(SRC). [R51] VWS: *The Henry's Law constant for petroleum ether can be estimated to be 0.19 to 1.7 atm-cu m/mole, for cyclopentane and isohexane, using a structure estimation method(1). These Henry's Law constant values indicate that petroleum ether volatilizes rapidly from water(2). Based on these Henry's Law constants, the volatilization half-lives from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 2.5 to 2.7 hours(2,SRC). The volatilization half-life from a model environmental lake (1 meter deep) can be estimated to be about 3.3 to 3.7 days(2,SRC). [R52] EFFL: *On site contamination of petroleum ether has been reported in groundwater through leachate from the Onalaska, Wisconsin municipal landfill, however, no concentrations were reported(1). [R53] RTEX: *Occupational exposure to hydrocarbons, such as petroleum ether, can occur through inhalation, dermal contact, and ingestion(1). Personnel exposure to petroleum ether through various normal household activities and for small businesses in ppm are as follows: average material handling, 0.46; average laboratory, 0.09 (both for a large-scale hazardous waste treatment, storage, and disposal facility); varnishing/sealing household wooden doors, 34.74; activity in a paint mixing booth, 0.16; automotive brake and rotor cleaning, 0.314; emptying/cleaning fuel oil holding tank, 0.17; and refinishing furniture, 2.872; concentrations in various work area monitoring results in ppm are as follows: average work area vapor concentration (for a large-scale hazardous waste treatment, storage, and disposal facility), 0.22; paint booth mixing room, 0.068; wooden door staining-room, 18.721; household remodeling - bathroom, 0.1; and household paint stripping-room, 7.326(2). [R54] *NIOSH (NOES Survey 1981-3) has statistically estimated that 387,363 workers are potentially exposed to petroleum ether in the USA(1). [R55] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +1000 ppm [10% LEL - the IDLH was based on 10% of the lower explosive limit for safety considerations even though the relevant toxicological data indicated that irreversible health effects or impairment of escape existed only at higher concentrations.] [R7] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 100 ppm (400 mg/cu m). [R56] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 100 ppm (400 mg/cu m). [R7] TLV: +8 hr Time Weighted Avg (TWA): 400 ppm. [R57, 2002.51] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R57, 2002.6] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NIOSH Method #1550, analyte: naphtha, hydrocarbons; matrix: air; procedure: adsorption on coconut shell charcoal, desorption with carbon disulfide, gas chromatography with flame ionization detection; range: 0.5-10 mg/sample; estimated LOD: 0.1 mg/sample. /Naphthas/ [R58] CLAB: *Analyte: petroleum distillate; matrix: air; procedure: adsorption on charcoal, desorption with carbon disulfide, gas chromatography; range: 937-3930 mg/cu m. /Petroleum distillate/ [R59] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Lehman-McKeeman LD; Male Rat Specific Hydrocarbon Nephropathy in Hook JB, Goldstein RS (eds). Target Organ Toxicology Series: Toxicology of the Kidney 2nd ed. 558 pp. Raven Press, NY, NY (1993) U.S. Dept Health and Human Services/Agency for Toxic Substances Disease Registry; Toxicological Profile for Stoddard Solvent (1995) NTIS# PB/95/264263 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for stoddard solvent is in progress. Route: inhalation; Species: rats and mice. [R60] HIST: *SURFACE WATER: In 1991, 210 gallons of petroleum ether were released into Newark Bay and its major tributaries(1). [R61] SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 804 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R4: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Manual Two. Washington, DC: U.S. Government Printing Office, Oct., 1978. R5: Pedersen BA, Higgins GM; J Air Waste Manage Assoc 45:89-94 (1995) R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1139 R7: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 220 R8: Chemical Abstracts Service; Registry File. CAS# 8030-30-6. Columbus,OH (1995) R9: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 325M-78 R10: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-128 R11: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1033 R12: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-78 R13: National Fire Protection Guide. Fire Protection Guide on Hazardous Materials. 10 th ed. Quincy, MA: National Fire Protection Association, 1991.,p. 325M-78 R14: Sullivan, J.B. Jr., G.R. Krieger (eds.). Hazardous Materials Toxicology-Clinical Principles of Environmental Health. Baltimore, MD: Williams and Wilkins, 1992. 1122 R15: 49 CFR 171.2 (7/1/96) R16: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3044, 3098 (1988) R17: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.3 R18: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 222 R19: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V47 68 (1989) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V47 66 (1989) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 70 (1993) R23: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985. 124 R24: Klauder JV, Brille FA; Arch Dermatol Syph 56: 197-215 (1947) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.52 (1982) R25: Malten KE et al; Berufsdermatosen 16: 135-47 (1968) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.52 (1982) R26: Beskrovnaja et al; Gig Tr prof Zabol 8: 36-8 (in Russian) (1979) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.57 (1982) R27: Hrustaleva et al; Gig Tr prof Zabol 7: 31-3 (in Russian) (1979) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.57 (1982) R28: Novikov et al; Gig Tr prof Zabol 2 45-8 (in Russian) (1979) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.57 (1982) R29: Daeschner CW Jr et al; Pediatr Clin North Am resp Disorders February: 243-53 (1957) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.60 (1982) R30: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 713 R31: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3389 R32: Rocskay AZ et al; J Occupat Med 35 (6): 617-22 (1993) R33: White RF et al; Occupat Environ Med 51 (2): 102-12 (1994) R34: Hine CH, Zuidema HH; Ind Med 39 (5): 215-20 (1970) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.43 (1982) R35: Lipovskij SM; Gig Tr Prof Zabol 7: 37-40 (in Russian) (1978) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.48 (1982) R36: API; Mutagenicity Study of 13 Petroleum Fractions, Washington DC Am Petrol Ins as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.51 (1982) R37: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 714 R38: Ingram AJ et al; J Appl Toxicol 13 (4): 247-57 (1993) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V47 64 (1989) R40: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 64 (1993) R41: Klauder JV, Brille FA; Arch Dermatol Syph 56: 197-215 (1974) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.52 (1982) R42: Gerarde HW; Arch Environ Health 6: 329-41 (1963) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.40 (1982) R43: Browning E; Toxicity and Metab of Industr Solvents (1965) as cited in WHO; Environ Health Criteria Number 20: Selected Petroleum Products p.42 (1982) R44: (1) Chemical Abstracts Service; Registry File. CAS# 8030-80-6. Columbus, OH (1995) (2) Budavari S; The Merck Index - Encyclopedia of Chemicals, Drugs, and Biologicals. Rahway, NJ: Merck and Co., Inc (1989) (3) Pedersen BA, Higgins GM; J Air Waste Manage Assoc 45: 89-94 (1995) R45: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Singh HB et al; Reactivity/Volatility Classification of Selected Organic Chemicals: Existing Data. Menlo Park, CA; SRI Inter USEPA-600/3-84-082 pp 190 (1984) (5) Karelin YA, Bolotina OT; Nauk Doklady Vysshei Shkoly, Stroitel'stvo 3: 280-9 (1960) (6) Matsui S et al; Wat Sci Tech 20: 201-10 (1988) R46: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) (3) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (4) Karelin YA, Bolotina OT; Nauk Doklady Vysshei Shkoly, Stroitel'stvo 3: 280-9 (1960) (5) Matsui S et al; Wat Sci Tech 20: 201-10 (1988) R47: (1) Singh HB et al; Reactivity/Volatility Classification of Selected Organic Chemicals: Existing Data Menlo Park, CA; SRI Inter USEPA-600/3-84-082 pp 190 (1984) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Environ Toxicol Chem 26: 2293-9(1993) R48: (1) Karelin YA, Bolotina OT; Nauk Doklady Vysshei Shkoly, Stroitel'stvo 3: 280-9 (1960) (2) Matsui S et al; Wat Sci Tech 20: 201-10 (1988) R49: (1) Singh HB et al; Reactivity/Volatility Classification of Selected Organic Chemicals: Existing Data. Menlo Park, CA; SRI Inter USEPA-600/3-84-082 pp 190 (1984) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R50: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soci pp. 4-9, 5-10 (1990) R51: (1) Meylan WM et al; Environ Sci Technol 28: 459-65(1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Residue Reviews 85: 17-28 (1983) R52: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) R53: (1) Wisconsin Division of Health; Health Assessment of Onalaska Municipal Landfill, Onalaska, Wisconsin. Wisconsin Division of Health, Madison, WI 12 pp. (1988) R54: (1) Parmeggiani L; Encycl Occup Health and Safety 3rd ed Geneva, Switzerland: International Labour Office p. 1070-1073 (1983) (2) Pedersen BA, Higgins GM; J Air Waste Manage Assoc 45: 89-94 (1995) R55: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R56: 29 CFR 1910.1000 (7/1/98) R57: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R58: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994.1550 R59: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V3-S380 R60: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 R61: (1) Gunster DG et al; Ecotox Environ Safety 25: 202-13 (1993) RS: 53 Record 199 of 1119 in HSDB (through 2003/06) AN: 2908 UD: 200302 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,4,5-TRIMETHYLANILINE- SY: *BENZENAMINE,-2,4,5-TRIMETHYL-; *PSI-CUMIDINE-; *NCI-C02299-; *PSEUDOCUMIDINE-; *1,2,4-TRIMETHYL-5-AMINOBENZENE- RN: 137-17-7 MF: *C9-H13-N MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PROBABLY BY NITRATION OF PSEUDOCUMENE FOLLOWED BY REDUCTION [R1] MFS: *PROBABLY NOT PRODUCED COMMERCIALLY IN THE US [R1] USE: *Mfr of dyes; organic synthesis [R2] *CHEM INT FOR DYE FORMERLY USED IN FOOD [R1] PRIE: U.S. PRODUCTION: *(1972) NOT PRODUCED COMMERCIALLY IN US [R1] *(1975) NOT PRODUCED COMMERCIALLY IN US [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystals [R2]; *NEEDLES OBTAINED FROM WATER AS SOLVENT [R3] BP: *234.5 deg C [R4] MP: *68 deg C [R4] MW: *135.23 [R5] DEN: *0.957 [R2] DSC: *pKa= 5.09 [R6] OWPC: *log Kow= 2.27 [R6] SOL: *Sol in alcohol and ether; insol in water [R2] OCPP: *Henry's Law constant= 2.48X10-6 atm-cu m/mol @ 25 deg C [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of nitroxides. [R7] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R8] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aniline and related compounds/ [R9, p. 206-7] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Monitor cardiac rhythm and treat arrhythmias as necessary... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation... . /Aniline and related compounds/ [R9, 207] HTOX: *SYMPTOMATOLOGY: 1. GRAYISH BLUE CYANOSIS, WITHOUT SIGNS OF CARDIAC OR PULMONARY INSUFFICIENCY. 2. SEVERE HEADACHE, NAUSEA, SOMETIMES VOMITING, DRYNESS OF THROAT. 3. CNS SYMPTOMS: CONFUSION, ATAXIA, VERTIGO, TINNITUS, WEAKNESS, DISORIENTATION, LETHARGY, DROWSINESS, AND FINALLY COMA. CONVULSIONS...UNCOMMON. /ANILINE/ [R10] *SYMPTOMATOLOGY: 4. CARDIAC EFFECTS: HEART BLOCKS, ARRHYTHMIAS, AND SHOCK. 5. DEATH, ALTHOUGH UNCOMMON, IS USUALLY DUE TO CARDIOVASCULAR COLLAPSE AND NOT RESPIRATORY PARALYSIS. 6. URINARY SIGNS AND SYMPTOMS...PAINFUL MICTURITION, HEMATURIA, HEMOGLOBINURIA (AND METHEMOGLOBINURIA), OLIGURIA, AND RENAL INSUFFICIENCY... /ANILINE/ [R10] *MODERATELY TOXIC. [R11] NTOX: *PONCEAU 3R WAS REDUCED IN VITRO BY FUSOBACTERIUM TO 2,4,5-TRIMETHYLANILINE WHICH IS MUTAGENIC WHEN METABOLICALLY ACTIVATED BY LIVER S9 PREPN IN SALMONELLA/MAMMALIAN-MICROSOME MUTAGENICITY TEST. [R12] *LONG-TERM DIETARY ADMIN TO MALE RATS AND MALE AND FEMALE HAM/ICR MICE LED TO TUMORS IN NOT LESS THAN 1 TISSUE IN ALL 3 ANIMAL MODELS. [R13] *2,4,5-Trimethylaniline was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 2,4,5-Trimethylaniline was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 1.000, 3.000, 10.000 33.000, 100.000, 333.000, and 1000.000 ug/plate. The compound was positive in strains TA100 and TA98 with activation. The lowest positive dose tested was 3.000 ug/plate in strain TA100 with 10% hamster liver S-9. [R14] *... It is concluded that under the conditions of this bioassay, 2,4,5-trimethylaniline was carcinogenic for male and female F344 rats and female B6C3F1 mice, inducing hepatocellular carcinomas or neoplastic nodules in the rats of each sex, alveolar/bronchiolar carcinomas in the female rats, and hepatocellular carcinomas in female mice. ... Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Equivocal; Female Mice: Positive. [R15] NTXV: *LD50 Rat oral 1250 mg/kg; [R7] NTP: *A bioassay of 2,4,5-trimethylaniline for possible carcinogenicity was conducted by admin the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were admin 2,4,5-trimethylaniline at one of two doses, either 200 or 800 ppm for the rats and either 50 or 100 ppm for the mice, for 101 wk. Matched controls consisted of 20 untreated rats and 20 untreated mice of each sex. All surviving animals were /sacrificed/ at the end of admin of the test chemical. It is concluded that under the conditions of this bioassay, 2,4,5-trimethylaniline was carcinogenic for male and female F344 rats and female B6C3F1 mice, inducing hepatocellular carcinomas or neoplastic nodules in the rats of each sex, alveolar/bronchiolar carcinomas in the female rats, and hepatocellular carcinomas in female mice. ... Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Equivocal; Female Mice: Positive. [R15] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,4,5-Trimethylaniline's production and use in the synthesis of dyes may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 9.0X10-3 mm Hg at 25 deg C indicates 2,4,5-trimethylaniline will exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase 2,4,5-trimethylaniline will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2 hrs. If released to soil, 2,4,5-trimethylaniline is expected to have moderate mobility based upon an estimated Koc of 198. However, mobility of 2,4,5-trimethylaniline in soil may be strongly affected by reactions with humic material. Also, a pKa value of 5.09 suggests that 2,4,5-trimethylaniline will exist partially in the protonated form in moist soils and the protonated form of 2,4,5-trimethylaniline is expected to bind strongly to soil surfaces and not volatilize. Volatilization of the neutral species from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 12 and 129 days, respectively. However, volatilization from water surfaces may be attenuated by adsorption to humic material in the water column. The protonated form of 2,4,5-trimethylaniline is not expected to volatilize from water. If released into water, 2,4,5-trimethylaniline is expected to adsorb slightly to sediment and suspended solids in water based upon the estimated Koc. An estimated BCF of 11 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to 2,4,5-trimethylaniline may occur through inhalation and dermal contact with this compound at workplaces where 2,4,5-trimethylaniline is produced or used. (SRC) ARTS: *2,4,5-Trimethylaniline's production and use in the production of dyes(1) may result in its release to the environment through various waste streams(SRC). [R16] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 198(SRC), determined from a structure estimation method(2), indicates that 2,4,5-trimethylaniline is expected to have moderate mobility in soil(SRC). However, aromatic amines (including anilines) bind to humic material found in soil in two phases(3). Initially, a rapid, reversible equilibrium is established, which may represent formation of imine linkages with the humate carbonyls(3). Subsequently, there is a slow reaction that is not readily reversed(3). Also, a pKa value of 5.09(4) suggests that 2,4,5-trimethylaniline will partially exist in the protonated form in moist soils and the protonated form of 2,4,5-trimethylaniline is expected to bind strongly to soil surfaces. Volatilization of the neutral species from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 2.48X10-6 atm-cu m/mole(4). 2,4,5-Trimethylaniline is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 9.0X10-3 mm Hg(4). [R17] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 198(SRC), determined from an estimation method(2), indicates that 2,4,5-trimethylaniline is expected to adsorb very little to sediment and suspended solids in water(SRC). Volatilization of the neutral species from water surfaces is expected(3) based upon a Henry's Law constant of 2.48X10-6 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 12 and 129 days, respectively(SRC). However, volatilization from water surfaces may be attenuated by adsorption to humic material in the water column(4). Aromatic amines (including anilines) bind to humic material found in water in two phases(4). Initially, a rapid, reversible equilibrium is established, which may represent formation of imine linkages with the humate carbonyls(4). Subsequently, there is a slow reaction that is not readily reversed(4). A pKa value of 5.09(5), suggests that 2,4,5-trimethylaniline will exist partially in the protonated form in aqueous environments and the protonated form of 2,4,5-trimethylaniline does not volatilize from water. According to a classification scheme(6), an estimated BCF of 11(SRC), from a log Kow of 2.27(5) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. [R18] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,4,5-trimethylaniline, which has a vapor pressure of 9.0X10-3 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 2,4,5-trimethylaniline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 hrs(SRC), from its rate constant of 2.0X10-10 cu cm/molecule-sec at 25 deg C determined using a structure estimation method(3). [R19] ABIO: *The rate constant for the vapor-phase reaction of 2,4,5-trimethylaniline with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 2,4,5-Trimethylaniline is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). In general, anilines absorb light in the environmental UV spectrum(> 290 nm)(3). Based on this, 2,4,5-trimethylaniline is expected to absorb light and may potentially undergo direct photolysis(SRC). [R20] BIOC: *An estimated BCF of 11 was calculated for 2,4,5-trimethylaniline(SRC), using a log Kow of 2.27(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R21] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 2,4,5-trimethylaniline can be estimated to be 198(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2,4,5-trimethylaniline is expected to have moderate mobility in soil. However, aromatic amines(including anilines) bind to humic material found in soil in two phases(3). Initially, a rapid, reversible equilibrium is established, which may represent formation of imine linkages with the humic carbonyls(3). Subsequently, there is a slow reaction that is not readily reversed(3). Also, a pKa value of 5.09(4) suggests that 2,4,5-trimethylaniline will exist partially in the protonated form in moist soils and the protonated form of 2,4,5-trimethylaniline is expected to bind strongly to soil surfaces(SRC). [R22] VWS: *The Henry's Law constant for 2,4,5-trimethylaniline is 2.48X10-6 atm-cu m/mole(1). This Henry's Law constant indicates that the neutral species of 2,4,5-trimethylaniline is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 12 days(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 129 days(SRC). However, volatilization from water surfaces may be attenuated by adsorption to humic material in the water column(3). Aromatic amines (including anilines) bind to humic material found in water in two phases(3). Initially, a rapid, reversible equilibrium is established, which may represent formation of imine linkages with the humic carbonyls(3). Subsequently, there is a slow reaction that is not readily reversed(3). 2,4,5-Trimethylanilne's Henry's Law constant(1) indicates that volatilization of the neutral species from moist soil surfaces may occur(SRC). A pKa value of 5.09(1), suggests that 2,4,5-trimethylaniline will exist partially in the protonated form in aqueous environments and the protonated form of 2,4,5-trimethylaniline does not volatilize from water or moist soil surfaces(SRC). 2,4,5-Trimethylaniline is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 9.0X10-3 mm Hg(1). [R23] RTEX: *Occupational exposure to 2,4,5-trimethylaniline may occur through inhalation and dermal contact with this compound at workplaces where 2,4,5-trimethylaniline is produced or used in the production of dyes(1,SRC). [R16] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *OSW Method 8270B. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. [R24] *EPA Method EAD 1625. Semivolatile Organic Compounds by Isotope Dilution GCMS. [R25] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of 2,4,5-Trimethylaniline for Possible Carcinogenicity (1979) Technical Rpt Series No. 160 DHEW Pub No. (NIH) 79-1716 SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 938 R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-148 R4: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-26 R5: U.S. Department of Health, Education and Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances. 1977 edition. Washington, D. C.: U.S. Government Printing Office, 1977.100 R6: Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) R7: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3285 R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 73 (1987) R9: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R10: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. III-32 R11: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 731 R12: HARTMAN CP ET AL; INFECT IMMUN 23(3) 686-689 (1979) R13: WEISBURGER EK ET AL; J ENVIRON PATHOL TOXICOL 2(2) 325-356 (1978) R14: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R15: Bioassay of 2,4,5-Trimethylaniline for Possible Carcinogenicity (1979) Technical Rpt Series No. 160 DHEW Pub No. (NIH) 79-1716, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R16: (1) Lewis RJ Sr; Hawley's Condensed Chemical Dictionary. 13th Ed. NY, NY: Van Nostrand Reinhold Co pp. 938 (1997) R17: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) (4) Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) R18: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) (5) Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R19: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R20: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Kondo M; Simulation Studies of Degradation of Chemicals in the Environment Office of Health Studies, Environment Agency, Japan (1978) R21: (1) Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R22: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Parris GE; Environmental Sci Technol 14: 1099-1106 (1980) (4) Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) R23: (1) Jayasinghe DS et al; Environ Sci Technol 26: 2275-81 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Parris GE; Environ Sci Technol 14: 1099-1106 (1980) R24: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R25: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 20 Record 200 of 1119 in HSDB (through 2003/06) AN: 2911 UD: 200302 RD: Reviewed by SRP on 2/28/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DECABROMOBIPHENYL-ETHER- SY: *BENZENE, 1,1'-OXYBIS(2,3,4,5,6-PENTABROMO-; *BERKFLAM-B-10E-; *BIS- (PENTABROMOPHENYL)-ETHER; *BR-55N-; *BROMKAL-82-0DE-; *BROMKAL-83-10DE-; *DECABROMOBIPHENYL-OXIDE-; *DECABROMODIPHENYL-ETHER-; *DECABROMODIPHENYL-OXIDE-; *DECABROMOPHENYL-ETHER-; *ETHER,-BIS- (PENTABROMOPHENYL); *FR-300BA-; *FRP-53-; *PENTABROMOPHENYL-ETHER- RN: 1163-19-5 MF: *C12-Br10-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BROMINATION OF DIPHENYL OXIDE IN THE PRESENCE OF A FRIEDEL-CRAFTS CATALYST. [R1] *Decabromobiphenyl ether is manufactured by the exhaustive bromination of phenyl ether. Lewis acid catalysis and an excess of bromine are used to obtain high conversions of the less reactive under-brominated intermediates to decabromobiphenyl ether. [R2] *Decabromobiphenyl ether can be prepared at atmospheric pressure by reacting bromine with phenyl ether in ethylene dibromide solvent and in the presence of aluminum bromide catalyst. [R2] IMP: *The commercially available grades are > 98% decabromodiphenyl oxide with the remainder being the nonabromo species. [R3, 960] FORM: *Technical product composition: decabromodiphenyl oxide, 77.4%, Nonabromodiphenyl oxide, 21.8%, Octabromodiphenyl oxide, 0.8%. [R4] *Usually contains more than 85 wt% decabromodiphenyl oxide. [R1] MFS: *Albemarle Corporation, Hq, 451 Florida Street, Baton Rouge, LA 70801 (225)388-8011; Production site: Magnolia, AR 71753 [R5] *Great Lakes Chemical Corporation, Hq, Highway 52, North West, PO Box 2200, West Lafayette, IN 47906, (317) 497-6100; Production site: El Dorado, AR 71730 [R6] OMIN: *Often plastic additives may be released by leaching. However, decabromodiphenyl ether in acrylonitrile-butadiene-styrene and acrylonitrile-butadiene-styrene-polystyrene polymers did not leach into water even under conditions of elevated temperatures in the presence of 3% acetic acid (detection limit=0.5 ppm bromide). [R7] USE: *Decabromodiphenyl oxide is an unreactive, additive flame retardant widely used for its thermal stability and its low cost in thermoplastic resins, thermoset resins, textiles and adhesives. The major applications are in high impact polystyrene, glass reinforced thermoplastic polyester and moulding resins, low density polyethylene extrusion coatings, polypropylene (homo- and copolymers), acrylonitrile butadiene styrene rubber, nylon and polyvinyl chloride. [R8] *In the 1990's, two types of flame retardants are preferred for outdoor fabrics, ...an antimony-bromine system based on decabromodiphenyl ether and antimony(III)oxide. [R3, 1003] *The largest volume use of decabromodiphenyl ether is in high impact polystyrene that is used to manufacture television cabinets....used in virtually every class of polymer, including ABS, engineering thermoplastics such as polyamides and polyesters, polyolefins, thermosets (i.e., epoxies and unsaturated polyesters), PVC, and elastomers. It is also widely used in textile applications as the flame retardant in latex-based back coatings. [R3, 960] CPAT: *ESSENTIALLY 100% AS FLAME RETARDANT [R9] PRIE: U.S. PRODUCTION: *(1973) MORE THAN 5X10+5 G [R9] *(1975) MORE THAN 5X10+5 G [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White to off-white powder [R10] MP: *305 deg C [R3, 961] MW: *959.17 [R11] DEN: *3.0 [R4] SOL: *Water: 20-30 ppb; Cottonseed oil: 600 ppm, acetone: 500 ppm, chlorobenzene: 6,000 ppm, o-xylene: 8,700 ppm. [R12]; *In water, 1.0X10-4 mg/l @ 25 deg C [R13] OCPP: *Decomposition point: Ca 425 deg C [R1] *Vapor pressure: 5.03 mm Hg @ 306 deg C [R10] *83% bromine content /commercial product/ [R3, 961] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of decabromodiphenyl oxide. There is limited evidence in experimental animals for the carcinogenicity of decabromodiphenyl oxide. Overall evaluation: Decabromodiphenyl oxide is not classifiable as to its carcinogenicity to humans (Group 3). [R14] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on no human data and limited evidence of carcinogenicity in animals; namely, significantly increased incidences of neoplastic liver nodules in male and female rats and increased incidences of hepatocellular adenomas or carcinomas (combined) in male mice. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Limited. [R15] HTOX: *Thyroid and reproductive dysfunction was investigated in workers exposed for at least 240 hr to decabromobiphenyl and decabromobiphenyloxide over a 4 yr period. The average period of employment was 3.9 yr. Air samples of decabromobiphenyl in the manufacturing area showed 0.18 to 0.23 mg/cu m for an 8 hr time weighted average. Of 18 workers exposed for 3 yr or longer, thyroid nodules were seen in 3; another nodule was seen in a worker exposed to high chlorine concentrations. Significant correlation was seen between length of employment and concentrations of follicle stimulating hormone in workers exposed to decabromobiphenyl. An abnormal follicle stimulating hormone value was found in only one worker. A testicular cyst was found in one exposed worker, and epididymal nodules in two others. No testicular or epididymal nodules were seen among comparisons. No detectable decarbromobiphenyl was found in serum. It was concluded that thyroid hyperplasia may result from exposure to decarbromobiphenyl, but no definite statement can be made concerning adverse effects on the prevalence of testicular and epididymal nodules because of their prevalence in the general population. [R16] NTOX: *30-DAY DIETARY FEEDING STUDY IN RATS ESTABLISHED 8 MG DECARBROMOBIPHENYL OXIDE/KG/DAY AS UNEQUIVOCAL NO EFFECT LEVEL. REPRODUCTIVE CAPACITY OF RATS WAS NOT AFFECTED AT 3, 30 OR 100 MG DECARBROMOBIPHENYL OXIDE/KG/DAY. NO EFFECTS OBSERVED ON CYTOGENETIC EXAM OF BONE MARROW CELLS FROM REPRODUCTIVE STUDY. [R17] *DECABROMODIPHENYL OXIDE HAS LOW ACUTE ORAL TOXICITY AND LOW SKIN ABSORPTION TOXICITY. 30-DAY DIETARY FEEDING STUDY IN RATS ESTABLISHED 80 MG/KG/DAY AS MARGINAL EFFECT LEVEL. [R17] *Daily intubation of pregnant female rats on gestations days 6-15 with 0, 10, 100, or 1,000 mg decabromodiphenyl oxide/kg, suspended in corn oil, caused no teratogenic response. Some fetal toxicity was observed in these studies in the form of subcutaneous edema and delayed ossification of normally developed bones of the fetal skull. These effects were observed at the high dose only. [R4] *Decabromodiphenyl oxide has low acute toxicity. Oral administration of doses up to 2,000 mg/kg as a 10% suspension in corn oil failed to produce any signs of toxicity in rats either directly after dosing or during a 14 day observation period. This chemical is not a dermal irritant to rats or rabbits and is only mildly irritating when placed in the eyes of rabbits. Repeated oral doses of up to 800 mg/kg per day produced no overt indication of toxicity during a 30 day study. [R4] *NTP studies of decabromodiphenyl oxide mutagenicity indicate that it was not mutagenic in Salmonella typhimurium strains TA1535, TA1537, TA98, or TA100 in the presence or absence of Aroclor 1254 induced male Sprague Dawley rat or male Syrian hamster liver S9 when tested according to the preincubation protocol. It was also not mutagenic in the mouse lymphoma L5178y/TK + or - assay in the presence or absence of Aroclor 1254 induced male F344 liver S9. Tests for cytogenetic effects in Chinese hamster ovary cells indicated that this chemical does not cause chromosomal aberrations or sister chromatid exchanges either in the presence or absence of S9 prepared from livers of Aroclor 1254 induced male Sprague Dawley rats. [R18] NTP: *... Carcinogenesis studies of decabromodiphenyl oxide were conducted by exposing groups of 50 male and 50 female F344/N rats and B6C3F1 mice at 0, 25,000 and 50,000 ppm in the diet for 103 weeks. ... The incidences of neoplastic nodules in the liver of low and high dose male rats (1/50; 7/50; 15/49) and high dose female rats (1/50; 3/49; 9/50) were significantly greater than those in the controls. Mononuclear cell leukemia occurred in dosed male rats with a positive trend (30/50; 33/50; 35/50); this marginal increase was not considered biologically significant. Acinar cell adenomas were observed in the pancreas of four high dose male rats, and a sarcoma was observed in the spleen of one low dose and one high dose male rat. Hepatocellular adenomas or carcinomas (combined) occurred at marginally increased incidences in dosed male mice (8/50; 22/50; 18/50). The incidences of thyroid gland follicular cell adenomas or carcinomas (combined) were increased in dosed male mice (0/50; 4/50; 3/50). Under the conditions of these 2 yr studies ... there was some evidence of carcinogenicity for male and female F344/N rats as shown by increased incidences of neoplastic nodules of the liver in low dose (25,000 ppm) males and high dose (50,000 ppm) groups of each sex. There was equivocal evidence of carcinogenicity for male B6C3F1 mice as shown by increased incidences of hepatocellular adenomas or carcinomas (combined) in the low dose group and of thyroid gland follicular cell adenomas or carcinomas (combined) in both dosed groups. There was no evidence of carcinogenicity for female B6C3F1 mice receiving 25,000 or 50,000 ppm in the diet. ... [R19] ADE: *AFTER ADMIN OF (14)C DECABROMODIPHENYL OXIDE BY INTRAGASTRIC INTUBATION, ALL (14)C ACTIVITY WAS ELIMINATED BY WAY OF FECES WITHIN 2 DAYS. [R17] *Studies with (14)C labeled decabromodiphenyl oxide administered orally to Sprague Dawley rats indicate that more than 99% of the administered label was excreted in feces within 2 days following administration. An analysis of bromine in tissues following long term exposure in diets that provided 0.1 mg/kg per day to rats indicated a slight increase in bromine content in liver and adipose tissue at 90 days but no significant increase following 12 months of exposure. A significant increase in the bromine content of adipose, but no other tissues, was observed following a similiar dose of decabromodiphenyl oxide for 2 years but not at lower doses. There was no indication as to whether the failure of decabromodiphenyl oxide to accumulate in tissues was due to lack of absorption from the gastrointestinal tract or rapid metabolism and clearance. [R20] *The disposition of 14(C)-labeled decabromobiphenyl ether in male Fischer rats dosed by feeding (0.025-5.0% of the diet) or intravenously (1 mg/kg) was determined. For rats dosed by feeding, intestinal absorption of decarbromobiphenyl ether was evident in that the intact compound was present in extracts of liver. For these rats, the size of the liver increased with increasing concentration of decarbromobiphenyl ether in the diet. Liver contained a maximum of 0.449% of the administered radioactivity at 24 hr after feeding rats a diet containing 0.0277% 14(C) decarbromobiphenyl ether; no other organ or tissue contained more than 0.26%. The total amount of radioactivity found in tissues was less than 1% of the dose. Of the radioactivity recovered in the feeding experiments, more than 99% was in the feces and gut contents at 72 hr; a maximum of 0.012% of the dose was in the urine. In the feces of rats fed 14(C) decabromobiphenyl ether, there were three metabolites, which together comprised 1.5-27.95% of the radioactivity. Since absorption was minimal, most of the metabolism of 14(C) decarbromobiphenyl ether apparently took place in the gastrointestinal tract. The metabolites increased in percent of total radioactivity with the content of decarbromobiphenyl ether in the diet, an indication that enzyme induction in intestinal bacteria may have occurred at the higher doses. More extensive metabolism of 14(C) decarbromobiphenyl ether occurred after intravenous administration; only 37% of the radioactivity in the feces was unchanged decarbromobiphenyl ether. At 72 hr after dosing, fecal excretion accounted for 70% of the dose; only 0.129% appeared in the urine. Muscle retained 12.9% and skin 7.25% of the radioactivity administered. In 4 hr, rats with biliary cannulas excreted 7.17% of the intravenously administered radioactivity in the bile; less than 1% was excreted as intact decarbrom{biphenyl ether. Biliary excretion was apparently the major route for elimination of the intravenously administered compound. The rapid excretion and extensive metabolism of decabromobiphenyl ether, relative to other polyhalogenated compounds, are advantagenous properties that may allow it to be used in place of structurally similar compounds presently employed in industrial applications. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Decabromobiphenyl ether's production and use as an additive flame retardant, primarily in high impact polystyrene for electronic enclosures, may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.7X10-12 mm Hg at 25 deg C indicates decabromobiphenyl ether will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase decabromobiphenyl ether will be removed from the atmosphere by wet and dry deposition. Direct photodegradation may be fairly rapid based upon studies with sunlight irradiation. If released to soil, decabromobiphenyl ether is expected to be immobile based upon an estimated Koc of 692,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.2X10-8 atm-cu m/mole. No data were located showing the biodegradation of this compound in soil or water evironments; this compound was not biodegraded over 14 days in a single screening biodegradation test. If released into water, decabromobiphenyl ether is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to occur based upon this compound's estimated Henry's Law constant. BCF values ranging from 0.3 to < 50 suggest bioconcentration in aquatic organisms is low to moderate. The fate of decabromobiphenyl ether in the environment needs further study; in the absence of sunlight, the compound persists in soils and sediments while in sunlight, decabromobiphenyl ether readily degrades to the lower brominated congeners, such as tetra- and hexabrominated biphenyl ethers, which readily bioaccumulate. Occupational exposure to decabromobiphenyl ether may occur through inhalation and dermal contact with this compound at workplaces where decabromobiphenyl ether is produced or used. Monitoring data indicate that the general population may be exposed to decabromobiphenyl ether via inhalation of ambient air, ingestion of fish, and dermal contact with products such as television or computer enclosures or textiles containing decabromobiphenyl ether. (SRC) NATS: *Decabromodiphenyl ether does not occur naturally(1). [R22] ARTS: *Decabromobiphenyl ether's production and use as a fire retardant additive for thermoplastic resins, polyethylene, polystyrene, adhesives, polyester fibers and coatings for textiles, and paints(1-3,5) may result in its release to the environment through various waste streams(SRC). It is especially used for high-impact polystyrene such as for television and radio sets and to treat textiles for automobiles and tents(5). Decabromobiphenyl ether is released during the pyrolysis of material containing the flame retardant(4). Plastic additives may be released by leaching. However experiments performed with ABS and ABS-polystyrene polymers containing decabromobiphenyl ether into water at room and elevated temperatures and into 3% acetic acid at elevated temperatures resulted in no leaching at a detection limit of 0.5 ppm of bromine(1). A small amount of leaching was obtained when the polymer was immersed in cottonseed oil at elevated temperatures. [R23] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 692,000(SRC), determined from a measured water solubility of 1.0X10-4(2) and a regression-derived equation(3), indicates that decabromobiphenyl ether is expected to be immobile in soil(SRC). Volatilization of decabromobiphenyl ether from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Decabromobiphenyl ether is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.7X10-12 mm Hg(SRC), determined from a fragment constant method(5). No data were located showing the biodegradation of this compound in soil; this compound was not biodegraded over 14 days in a single screening biodegradation test(6). In the absence of sunlight, the compound persists in soils and sediments(7). In sunlight, decabromobiphenyl ether readily degrades to the lower brominated congeners (such as tetra- and hexabrominated biphenyl ethers) which readily bioaccumulate(7). [R24] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 692,000(SRC), determined from a measured water solubility of 1.0X10-4 mg/l(2) and a regression-derived equation(3), indicates that decabromobiphenyl ether is adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.2X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), BCF values ranging from 0.3(6) to < 50(7), suggests the potential for bioconcentration in aquatic organisms is low to moderate. Photodegradation should occur in the surface layer(8,9). No data were located showing the biodegradation of this compound in water; this compound was not biodegraded over a 14-day period in a single screening biodegradation test(7). In the absence of sunlight, the compound persists in soils and sediments(7). In sunlight, decabromobiphenyl ether readily degrades to the lower brominated congeners (such as tetra- and hexabrominated biphenyl ethers) which readily bioaccumulate(10). [R25] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), decabromobiphenyl ether, which has an estimated vapor pressure of 4.7X10-12 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase decabromobiphenyl ether may be removed from the air by wet and dry deposition(SRC). Direct photodegradation may be fairly rapid(SRC) based upon studies with sunlight irradation(3,4). [R26] BIOD: *AEROBIC: Judged to be moderate to hard to degrade according to results obtained by the "cultivation method" in which 27% and 4% degradation occurred in 3 days in river water and coastal sea water in Japan(1). Decabromobiphenyl ether, present at 100 mg/l, was not biodegraded over 14 days, measured by BOD, using an activated sludge inoculum at 30 mg/l in the Japanese MITI test(2). [R27] ABIO: */Decabromobiphenyl oxide/ is degraded by ultraviolet light in the wavelength range and intensity of light. [R28] *Bromine is released when decabromodiphenyl ether is exposed to sunlight. After 98 days of exposure, the amount of bromine produced is that which corresponds to the breakdown of about 300 times the initial amount of decabromodiphenyl ether soluble in water(1). GC/MS analysis performed at the conclusion of the experiment did not indicate the presence of aromatic bromine compounds. When decabromodiphenyl ether dissolved in octanol was exposed to radiation from a sunlamp, 50% degradation occurred in 4 hr(1). Reductive dehalogenation was the degradative process(1). The products resulting from exposure of a hexane solution of decabromodiphenyl ether to sunlight was the nona-, octa-, hepta-, and hexabrominated compounds(2). However other studies indicate that photohydroxylation is the favored degradative route in aqueous solution and that the hydroxylated degradation products would rapidly decompose. In sunlight, decabromobiphenyl ether readily degrades to the lower brominated congeners such as tetra- and hexabrominated biphenyl ethers)(3). Ethers are generally resistant to hydrolysis(4). [R29] BIOC: *Compound does not accumulate in fish. [R28] *BCF values of < 5 and < 50 were reported in carp during a 6 week study at 60 mg/l and 6 mg/l, respectively(1). Forty-eight hour fish bioconcentration studies with C14-labeled decabromobiphenyl ether revealed no measurable bioconcentration in fish filets(2). The measured BCF was 0.3. Rainbow trout exposed to decabromobiphenyl ether during a 120-day study contained this compound at 38 ng/g of fresh weight in muscle tissue and up to 870 ng/g of fresh weight in the liver(4). An uptake of approximately 0.005% was calculated from decabromobiphenyl ether concentrations in muscle tissue and the mean dietary dose of decabromobiphenyl ether; this value does not include the sum of the metabolites of this compound(4). According to a classification scheme(3), these BCF values suggest the potential for bioconcentration in aquatic organisms is low to moderate. [R30] KOC: *The Koc of decabromobiphenyl ether is estimated as 692,000(SRC), using a measured water solubility of 1.0X10-4 mg/l(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that decabromobiphenyl ether is expected to be immobile in soil. [R31] VWS: *The Henry's Law constant for decabromobiphenyl ether is estimated as 1.2X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that decabromobiphenyl ether is expected to be essentially nonvolatile from water surfaces(2). Decabromobiphenyl ether's estimated Henry's Law constant(1) indicates that volatilization from moist soil surfaces may not occur(SRC). Decabromobiphenyl ether is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.7X10-12 mm Hg(SRC), determined from a fragment constant method(3). [R32] SEDS: *Decabromobiphenyl ether was found in river sediment from the Neya and Second Neya River in Osaka, Japan, 33-375 ppb (dry weight) and one of seven estuary sediments from different rivers in Japan, 20 ppb (dry weight)(1). It was not detected (detection limit 5 ppb) in two samples of marine sediment from Osaka Bay, Japan(1). It was detected in soil and sediment samples near the bromine industry in Magnolia and El Dorado, AR(2). Sediment collected in 1995 and 1996 from 4 UK estuaries, selected because brominated flame retardants are manufactured within their catchments, contained decabromobiphenyl at concentrations ranging from < 0.6 to 3190 ug/kg dry weight (16 of 29 samples below the detection limit)(3). Surficial sediments collected at 8 different locations in the River Viskan and its tributary, River Haggan in 1995, both up and downstream from potential sources of brominated flame retardants, contained decabromobiphenyl ether at mean concentrations from < 20 to 12,000 ng/g (as ignition loss)(4). [R33] ATMC: *SOURCE DOMINATED: Twenty-four hour samples of ambient air on the plant property of two industrial bromine extraction and bromo-organic synthesis facilities had concentrations of decabromobiphenyl ether ranging from not detected to 72 ng/cu m and < 13 to 25,000 ng/cu m for the two facilities(1). Detected in air particulate matter collected near the bromine industry in Magnolia and El Dorado, AK(2). [R34] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Found in 1 of 3 mussels from Osaka Bay, Japan at 1.4 ppb, wet weight, but not found (< 0.5 ppb wet weight) in 14 other samples of fish and shellfish from Osaka Bay and other locations in Japan(1). Fish and shellfish samples collected from 1994 to 1996 from 4 UK estuaries, selected because brominated flame retardants are manufactured within their catchments, did not contain measurable concentrations of decabromobiphenyl (< 1.2 ug/kg wet weight; n=23)(2). Pike sampled at 4 locations along the River Viskan and Lake Skaresjon, Sweden, in 1995, contained decabromobiphenyl ether at non-detectable to trace concentrations in muscle lipid (detection limit=100 ng/g lipid)(3). [R35] OEVC: *Decabromobiphenyl ether was detected in sludge samples from polybrominated biphenyl facilities in New Jersey(1). [R36] RTEX: *Industrial hygiene survey wipe samples (1977-1978) in a decabromobiphenyl ether plant in Sayreville, NJ contained 3.6 mg/sq cm and 5.9 mg/sq cm in the reactor and distillation areas, respectively(1). Personal samples in the mill area were 0.08-0.21 mg/cu m as 8-hr TWA(1). Following a spill, personal airborne levels were 1.3-1.9 mg/cu m(1). [R22] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 19,456 workers (4,710 of these are female) are potentially exposed to decabromobiphenyl ether in the US(1). Exposure to decabromobiphenyl ether is primarily occupational. Occupational exposure to decabromobiphenyl ether may occur through inhalation of dusts and dermal contact with this compound at workplaces where decabromobiphenyl ether is produced or used(SRC). Monitoring data indicate that the general population may be exposed to decabromobiphenyl ether via inhalation of ambient air, ingestion of fish, and dermal contact with products such as television or computer enclosures or textiles containing decabromobiphenyl ether(SRC). [R37] BODY: *Five composite samples of the fiscal year 1987 National Human Adipose Tissue Survey(FY87 NHATS) were analyzed for decabromobiphenyl ether(1). Concentrations of this compound ranged from 73 to 140 pg/g (lipid basis)(1). 3 of 5 selected human adipose tissue samples from the FY87 NHATS contained decabromobiphenyl ether(1). A study of 48 composite samples from the FY87 NHATS contained decabromobiphenyl ether at concentrations of 5 to 20 pg/g (lipid basis) (38 of 48 samples contained undetectable concentrations of this compound)(1). Two samples contained 0.4 and 0.7 ppb of decabromobiphenyl ether in the lipid and one contained trace levels. Detected at concns up to 5 ppb in human hair in communities near the bromine industry in Magnolia and El Dorado, AK(2). Found in human adipose tissue obtained from a hospital in Osaka, Japan(3). Blood serum concentrations of decabromobiphenyl ether in hospital cleaners (n=20), computer clerks (n=20) and electronics dismantlers (n=19) ranged from < 0.3 to 3.9, < 0.3 to 8.0, and < 0.3 to 9.9, respectively(4). Decabromobiphenyl ether was present in nearly all blood serum samples collected during this study(4). [R38] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: *Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 5 mg/cu m. [R39] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Haloethers/ [R40] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R41] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Decabromodiphenyl ether is included on this list. [R42] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Four lots of study material were identified as decabromodiphenyl oxide by infrared and ultraviolet/visible spectroscopy. The purity of all lots of study material was determined by elemental analysis, thin layer chromatography, and high performance liquid chromatography. [R43] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 309 (1986) NIH Publication No. 86-2565 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V10 385 (1980) R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA4 (85) 417 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V10 (93) R4: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.19 (1986) Technical Rpt Series No. 309 NIH Pub No. 86-2565 R5: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 541 R6: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 552 R7: Norris JM et al; Appl Polymer Sympos 22: 195-219 (1973) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 75 (1990) R9: SRI R10: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.18 (1986) Technical Rpt Series No. 309 NIH Pub No. 86-2565 R11: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 259 R12: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.19 (1986)Technical Rpt Series No. 309 NIH Pub No. 86-2565 R13: Hardy ML, Smith RL; Div Environ Chem Preprints of Extended Abstracts 39: 191-192 (1999) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1368 (1999) R15: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Decabromodiphenyl ether (DBOPE) (1163-19-5) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R16: Bialik O; NIOSH; Endocrine Function Of Workers Exposed To PBB And PBBO. Terminal Progress Report. Grant No. I-RO1-OH-01034-01 63 (1982) R17: NORRIS JM ET AL; ENVIRON HEALTH PERSPECT (11): 153-61 (1975) R18: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.20 (1986) Technical Rpt Series No. 309 NIH Pub No. 86-2565 R19: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.11 (1986) Technical Rpt Series No. 309 NIH Pub No. 86-2565 R20: DHHS/NTP; Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.18 (1986) Technical Rpt Series No. 309 Pub No. 86-2565 R21: El Dareer SM et al; J Toxicol Environ Health 22 (4): 405-16 (1987) R22: (1) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 48: 73-84 (1989) R23: (1) Norris JM et al; Appl Polymer Sympos 22: 195-219 (1973) (2) Watanabe I et al; Bull Environ Contam Toxicol 36: 839-42 (1986) (3) Thoma H et al; Chemosphere 16: 277-85 (1987) (4) Thoma H, Hutzinger O; Chemosphere 16: 1353-60 (1987) (5) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 48: 73-84 (1989) R24: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hardy ML, Smith RL; Amer Chem Soc, Div Environ Chem, Preprints of Extended Abstracts 39: 191-192 (1999) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (6) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (7) Hooper K, McDonald TA; Environ Health Perspect 108: 387-92 (2000) R25: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hardy ML, Smith RL; Amer Chem Soc, Div Environ Chem, Preprints of Extended Abstracts 39: 191-192 (1999) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (7) Norris JM et al; Appl Polymer Sympos 22: 195-219 (1973) (8) Norris JM et al; Appl Polymer Sympos 22: 195-219 (1973) (9) Watanabe I et al; Bull Environ Contam Toxicol 36: 839-42 (1986) (10) Hooper K, McDonald TA; Environ Health Perspect 108: 387-92 (2000) R26: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Norris JM et al; Apply Polymer Sympos 22: 195-219 (1979) (4) Watanabe I et al; Bull Environ Contam Toxicol 36: 839-42 (1986) R27: (1) Kondo M et al; Eisei Kagaku 34: 115-22 (1988) (2) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R28: DHHS/NTP; Toxicol and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) Report #309 NIH Pub #86-2565 p.19 (1986) R29: (1) Norris JM et al; Appl Polymer Sympos 22: 195-219 (1973) (2) Watanabe I et al; Bull Environ Contam Toxicol 36: 839-42 (1986) (3) Hooper K, McDonald TA; Environ Health Perspect 108: 387-92 (2000) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 7 (1982) R30: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Norris JM et al; Appl Polymer Sympos 22: 195-219 (1973) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R31: (1) Hardy ML, Smith RL; Amer Chem Soc, Div Environ Chem, Preprints of Extended Abstracts 39: 191-192 (1999) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R32: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R33: (1) Watanabe I et al; Chemosphere 16: 2389-96 (1987) (2) DeCarlo VJ; Ann NY Acad Sci 320: 678-81 (1979) (3) Allchin CR et al; Environ Pollut 105: 197-202 (1999) (4) Sellstrom U et al; Environ Toxicol Chem 17: 1065-72 (1998) R34: (1) Zweidinger RA et al; ACS Symp Ser 94: 217-31 (1979) (2) DeCarlo VJ; Ann NY Acad Sci 320: 678-81 (1979) R35: (1) Watanabe I et al; Chemosphere 16: 2389-96 (1987) (2) Allchin CR et al; Environ Pollut 105: 197-202 (1999) (3) Sellstrom U et al; Environ Toxicol Chem 17: 1065-72 (1998) R36: (1) DeCarlo VJ; Ann NY Acad Sci 320: 678-81 (1979) R37: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R38: (1) Stanley JS et al; Chemosphere 23: 1185-95 (1991) (2) DeCarlo VJ; Ann NY Acad Sci 320: 678-81 (1979) (3) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 48: 73-84 (1989) (4) Sjodin A et al; Environ Hlth Persp 107:643-48 (1999) R39: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R40: 40 CFR 401.15 (7/1/99) R41: 40 CFR 712.30 (7/1/99) R42: 40 CFR 716.120 (7/1/99) R43: DHHS/NTP; Toxicol and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies) Report #309 NIH Pub #86-2565 p.22 (1986) RS: 38 Record 201 of 1119 in HSDB (through 2003/06) AN: 2915 UD: 200302 RD: Reviewed by SRP on 9/9/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORENDIC-ACID- SY: *BICYCLO(2.2.1)HEPT-5-ENE-2,3-DICARBOXYLIC ACID, 1,4,5,6,7,7-HEXACHLORO-; *HET-ACID-; *HEXACHLOROENDOMETHYLENETETRAHYDROPHTHALIC-ACID-; *KYSELINA 3,6-ENDOMETHYLEN-3,4,5,6,7,7-HEXACHLOR-DELTA(SUP 4)-TETRAHYROFTALOVA (CZECH); *KYSELINA-HET- (CZECH); *5-NORBORNENE-2,3-DICARBOXYLIC-ACID,-1,4,5,6,7,7-HEXACHLORO- RN: 115-28-6 RELT: 2920 [CHLORENDIC ANHYDRIDE] (Analog) MF: *C9-H4-Cl6-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DIELS-ALDER REACTION OF MALEIC ANHYDRIDE WITH HEXACHLOROCYCLOPENTADIENE IN TOLUENE FOLLOWED BY HYDROLYSIS OF THE ANHYDRIDE WITH AQUEOUS BASE. [R1] USE: *FIRE-RETARDANT MONOMER [R2] *FIRE-RETARDANT MONOMER IN UNSATURATED POLYESTER RESINS; FIRE RETARDANT MONOMER IN COATINGS, IN EPOXY RESINS, IN POLYURETHANE FOAMS; EXTREME PRESSURE LUBRICANT; CHEM INT FOR DIBUTYL AND DIMETHYLCHLORENDATE (PLASTICIZERS) [R3] *Chlorendic acid used primarily as a chemical intermediate in the manufacture of unsaturated polyester resins, and with special applications in electronic systems, paneling, engineering plastics and paints. A major use is in fiberglass reinforced resins for process equipment in chemical industries. Chlorendic acid is also used to impart flame resistance to polyurethane foams when reacted nonhalogenated glycols to form halogenated polyols and can be used in the manufacture of alkyd resins for special paints and inks. [R4] *In Europe, 80% of the chlorendic acid produced is used in composites for flame retardant building and transport materials. The reminder isused in composites for the manufacture of anti-corrosion equipment, such as tanks, piping and scrubbers. In the USA, Latin American and Far East, the usage pattern is reversed; 70-80% is used for anti-corrosion equipment and 20-30% for flame retardant applications. [R4] *In the textile industry, the primary use for chlorendic acid is for flame retardant treatment fo wool fabrics. The natural flame resistance of wool is enhanced by finishing treatments with chlorendic acid in dimethylformamide. [R5] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R3] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R3] U.S. IMPORTS: *(1973) 1.91X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crytalline solid [R6] MW: *388.84 [R7] OCPP: *Melting point: decomposes to the anhydride. [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R8, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R8, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R8, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R8, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R8, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R8, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R8, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R8, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R8, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R8, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R8, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R8, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R8, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R8, 1979.15] DISP: *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R8, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R8, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R8, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R8, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R8, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *After oral and intravenous administration of radiolabelled chlorendic acid to rats, the substance was rapidly distributed throughout the body and rapidly metabolized. More than 90% of the radiolabel was excreted within 24 hr in the feces, mainly in a conjugated form. Only 3-6% was excreted in the urine. The highest concentrations of radiolabel were found in adipose tisue, liver, kidneys, whole blood and lung. ... The acute oral toxicity /for the rat/ is low ... Chlorendic acid and anhydride are skin irritants and severe eye and respiratory tract irritants in the rabbit. ... Chlorendic acid was tested for mutagenic potential ... in Salmonella typhimurium in the presence and absence of an exogenous metabolism system. Negative results were obtained ... A mouse lymphoma mutation assay in the absence of an exogenous metabolism system was positive. ... Chlorendic acid was positive in a transformation assay using BALB/c3T3 cells without metabolic activation ... Chlorendic acid did not give an increase of replicative DNA synthesis after oral or subcutaneous application ... to rats. ... Chlorendic acid was tested for carcinogenic potential in ... rats ... In addition to significant non-neoplastic changes in a number of organs, such as cystic degeneration and focal cellular changes, and bile duct hyperplasia in the liver, increases in the incidence of hepatocellular adenomas ... and carcinomas, significant at the highest dose level, ... were found. Furthermore, slight increases in acinar cell adenomas of the pancreas and alveolar/bronchiolar adenomas in the lung were found ... Chlorendic acid tested in ... mice ... showed an increased incidence of necrosis and mitotic alteration in the liver. An increase in the incidence of hepatocellular adenomas and carcinomas was found ... An increased incidence of alveolar/bronchiolar adenomas or carcinomas was found ... Tests showed that chlorendic acid has promoting activity. ... Data on the exposure of humans and of organisms in the environment are lacking. Both substances /chlorendic acid and its anhydride/ seem to have low acute and subacute oral toxicity, but they are dermal, eye, and respiratory irritants. From the results of long term toxicity/carcinogenicity studies with chlorendic acid on rats and mice, it is concluded that chlorendic acid induces tumors in rats and mice and is, therefore, considered to have a carcinogenic potential. However, a full hazard assessment for humans and the environment cannot be made in view of the lack of data. [R9] CARC: *Classification of carcinogenicity: 1) No data are available in humans; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. [R10] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R8, 1979.23] NTOX: *IN SHORT TERM FLASK STUDIES,500 MG/L (PH 3.5) COMPLETELY INHIBITED ALGAL GROWTH AND MICROFAUNAL ACTIVITY; 250 MG/L (PH 4.1) INHIBITED MICROFAUNAL ACTIVITY AND REDUCED ABUNDANCE OF ALL BUT 1 ALGAL SPECIES; and 125 MG/L (PH 6.6) HAD NO EFFECTS. IN LONGER TERM MICROCOSM STUDIES 500 and 250 MG/L DECR OXYGEN PRODUCTION AND RESPIRATION, AND ALTEREDCHLOROPHYLL CONCN AND BACTERIAL POPULATIONS. [R11] *Caused a dose-related inhibition of seed germination and early growth of garden cress (Lepidium sativum Leguminatae). Inhibited growth by 0, 20, 60, and 85% during exposure for 7 days at 0.01, 0.1, 1.0 and 10.0 ppm, respectively. [R12] *Subchronic feeding studies using Fischer 344 rats (0.062, 0.125, 0.250, 0.500 and 1.00%) and B6C3F1 mice (0.125, 0.250, 0.5, 1.0 and 2.0%) for 13 weeks, rats in all groups dosed with chlorendic acid gained significantly (p < 0.05) less weight than controls. Male and female mice dosed with chlorendic acid lost weight as compared to controls. Dose related histomorphologic hanges were noted in the livers of male and female rats fed diets containing 0.5 and 1.0% chlorendic acid. Changes included cytomegaly and mitotic alterations. In mice compound related histomorphological changes were observed in the liver. In mice receiving the highest dose (2.0%) 10 males and 2 females exhibited centrolobular cytomegaly, 7 males and 7 females exhibited mitotic alteration, and 8 males an 1 female exhibited coagulative necrosis. Mitotic alteration was noted in 3 males, 1 female, and 2 females in groups fed on diets containing 1.0%, 0.5% and 0.125% of chlorendic acid, respectively. [R13] *Chlorendic acid was nonmutagenic in the Salmonella mutagenicity test (using NTP protocol). [R14] *Moderate toxic effects and slight skin irritation were noted when chlorendic acid was applied to rabbit skin in tests conducted in compliance with the Federal Hazardous Substance Act. [R15] *Severe toxicity to the eyes was noted in an eye irritation study (a score of 9 out of a possible 10) using adult rabbits in test conducted in compliance with the Federal Hazardous Substances Act. [R16] *Chlorendic acid was not mutagenic in strains TA100, TA98, TA1535, or TA1537 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague Dawley rat or male Syrian hamster liver activation when tested according to the preincubation protocol. Chlorendic acid was mutagenic in the L5178Y/TK + or - mouse lymphoma cell forward assay (in the absence of activation) at a dose resulting in toxicity. [R17] *Chlorendic acid was not mutaenic in strains TA100, TA98, TA1535, or TA1537 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat or male syrian hamster liver S9 when tested according to the preincubation protocol. Chlorendic acid was mutagenic in the L5178Y/TK + or - mouse lymphoma assay in the absence of S9; it was not tested in the presence of S9. [R18] *Hepatocytomegaly was observed in mice and rats fed chlorendic acid for 13 weeks. ... In single studies, chlorendic acid induced mutations in mammalian cells in culture but was not mutagenic to bacteria in the presence or absence of an exogenous metabolic system. [R10] NTXV: *LD50 Rat oral 1170 mg/kg; [R19] NTP: *Toxicology and carcinogenesis studies of chlorendic acid (greater than 98% pure) were conducted by administering the chemical in feed to groups of 50 male and 50 female F344/N rats for 103 weeks. The estimated mean daily consumption of chlorendic acid was 27 and 56 mg/kg body weight for low dose male rats and 39 and 66 mg/kg for low dose and high dose female rats. Survival and feed consumption of dosed male and female rats ... were similar to those of controls. Mean body weights of high dose male and female rats ... were lower than those of controls. Mean body weights of high dose female rats 16%-24% lower than those of controls during the second half of the study. Incidences of nonneoplastic lesion of the liver in dosed male rats (cystic degeneration) and dosed female rats (granulomatous inflammation, pigmentation, and bile duct hyperplasia) were increased. The incidences of neoplastic nodules of the liver were significantly increased in dosed male rats (control, 2/50; low dose, 21/50; high dose, 23/50) and high dose female rats (1/50; 3/49; 11/50). The incidence of hepatocellular carcinomas was also increased in high dose female rats (0/50; 3/49; 5/50). The incidences of acinar cell hyperplasia (0/49; 4/50; 4/50) and acinar cell adenomas (0/49; 4/50; 6/50) of the pancreas were increased in dose male rats relative to those of contols. Pancreatic acinar cell adenoma is an uncommon neoplasm in intreated control F344/N rats in NTP studies (3/1667). In dosed male rats, incidences of alveolar/bronchiolar adenomas of athe lung (0/50; 3/50; 5/50) were increased. The incidences of alveolar/bronchillar adenomas of carcinomas (combined) in dosed female mice were also increased (1/50; 5/50; 6/50). Preputial gland carcinomas occurred at a greater incidence in low dose male rats (1/50; 8/50; 4/50) than in controls. An adenoma and a squamous cell papilloma were observed in two low dose male rats. The incidences of sarcomas, fibrosarcomas, or neurofibrosarcomas (combined) of the salivary gland (1/50; 2/49; 4/50) were increased in dosed male rats. The incidences in the dosed groups were not significantly different from that in the controls, but these tumors are uncommon in F344/N rats receiving no treatment (3/1689). There was clear evidence of carcinogenicity of chlorendic acid for male F344/N rats as shown by increased incidences of neoplastic nodules of the liver and acinar cell adenomas of the pancreas. Increased incidences of alveolar/bronchiolar adenomas and preputial gland carcinomas may also have been related to the administration of chlorendic acid. There was clear evidence of carcinogenicity of chlorendic acid for female F344/N rats as shown by increased incidences of neoplastic nodules and of carcinomas of the liver. [R20] *Toxicology and carcinogenesis studies of chlorendic acid (greater than 98% pure) were conducted by administering the chemical in feed to groups of 50 female ... B6C3F1 mice at concentrations of 0, 620, or 1,250 ppm for 103 weeks. ... The estimated daily consumption was 89 and 185 mg/kg for low dose and high dose males and 100 and 207 mg/kg for low dose and high dose females. ... Survival and feed consumption of dosed male and female ... mice ... were similar to those of controls. Mean body weights of high dose male and female rats and mice were lower than those of controls. Mean body weights of high dose female rats were 16%-24% lower than those of controls during the second half of the study. ... The incidences of nonneoplastic lesions of the liver were increased in dosed males (coagulative necrosis) and high dose females (mitotic alterations). The incidences of hepatocellular adenomas (5/50; 9/49; 10/50), hepatocellular carcinomas (9/50; 17/49; 20/50), and hepatocellular adenomas or carcinomas (combined) (13/50; 23/49; 27/50) were increased in dosed male mice. Hepatocellular carcinomas metastasized to the lung in 2/50 control, 4/49 low dose, nad 7/50 high dose male mice. Hepatocellular adenomas or carcinomas (combined) were not significantly increased in female mice (3/50; 7/49; 7/50). ... There was clear evidence of carcinogenicity of chlorendic acid for male B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of hepatocellular carcinomas. There was no evidence of carcinogenicity of chlorendic acid for female B6C3F1 mice given chlorendic acid in the diet at concentrations of 620 or 1250 ppm for 103 weeks. [R20] ADE: *(14)C CHLORENDIC ACID WAS ABSORBED AFTER ORAL DOSE OF 7.7 UMOL/KG BODY WT TO FISCHER 344 RATS. DISTRIBUTION IN VARIOUS TISSUES WAS SIMILAR FROM ORAL AND IV ROUTES. LIVER WAS MAJOR SITE OF DEPOSITION (PRIMARILY AS METABOLITES) WITH SMALLER AMT FOUND IN BLOOD, MUSCLE, SKIN AND KIDNEYS. IT WAS EXCRETED PRIMARILY THROUGH BILE AND FECES. URINE CONTAINED LESS THAN 6% OF TOTAL DOSE. WITHIN 1 DAY, MORE THAN 75% OF DOSE WAS EXCRETED IN FECES, PRIMARILY AS METABOLITES. [R21] *(14)C Chlorendic acid in a solution of apolyoxyethylated vegetable oil, ethanol and water (3 mg/kg body weight) was given to male Fischer 344 rats by intravenous injection or oral intubation. Following intravenous injection, more than 50% of the administered radioactivity was found in the liver within 15 min. Biliary excretion was the primary route of removal of radioactivity from the liver, which occurred with a half-life of 1.19 hr. The blood contained 20% of the administered radioactivity at 1 hr, and this declined with al half-life of 0.84 hr. Muscle contained 14% of the administered radioactivity at 15 min, and this level fell rapidly, with a half-life of 0.57 hr. Smaller amounts were detected in other organs. The highest specific activity per gram of tissue (wet weight) was noted in the adrenal gland early after administration. Administration of the same solution of (14)C chlorendic acid by oral intubation resulted in a somewhat higher liver concentration and a lower blood concentration at 24 hr than those seen after the same time following intravenous administration. The majority of the radioactivity was found in the feces (78% of the total dose) or large intestine. The (14)C chlorendic acid-derived radioactivity in the bile, urine and feces was attached mainly to parent compound or conjugates resistant to beta-glucuronidase and aryl sulfatase. [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ BIOD: *Resistant to hydrolytic dechlorination and may show considerable resistance to degradation. [R23] ABIO: *Would be expected to degrade by direct photolysis or by reaction with hydroxyl radicals and ozone. [R24] BIOC: *Should have low potential for bioconcentration in organisms and food chains. [R25] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R26] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Chlorendic acid is included on this list. [R27] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: TRDB/USEPA; Final Technical Support Document (Draft) Chlorendic Acid (1982) DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorendic Acid in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 304 (1987) NIH Publication No. 87-2560 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V10 388 (1980) R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V10 373 (1980) R3: SRI R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 46 (1990) R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 47 (1990) R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V10 389 (1980) R7: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8307 R8: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R9: Environmental Health Criteria 185: Chlorendic Acid and Anhydride pp. 19-24 (1996) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 50 (1990) R11: HENDRIX PF ET AL; CHEMOSPHERE 12(7-8) 1083 (1983) R12: Koch H; Sci Pharm 38 (2): 79-98 (1970) R13: TRDB/USEPA; Final Technical Support Document (Draft) Chlorendic Acid p.67 (1982) EPA Contract No.68-01-6530 R14: TRDB/USEPA; Final Technical Support Document (Draft) Chlorendic Acid p.68 (1982) Contract No. 68-01-6530 R15: TRDB/USEPA; Final Technical Support Document (Draft) Chlorendic Acid p.74 (1982) Contract No. 68-01-6530 R16: TRDB/USEPA; Final Technical Support Document (Draft) Chlorendic Acid p.74 (1982) EPA Contract No. 68-01-6530 R17: DHHS/NTP; Toxicology and Carcinogenesis Studies of Chrlorendic Acid in F344/N Rats and B6C3F1 Mice (Feed Studies) p.11 (Year) Technical Rpt Series No. 304 NIH Pub No. 87-2560 R18: DHHS/NTP; Toxicology and Carcinogenesis Studies of Chrlorendic Acid in F344/N Rats and B6C3F1 Mice (Feed Studies) p.17 (Year) Technical Rpt Series No. 304 NIH Pub No. 87-2560 R19: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 671 R20: DHHS/NTP; Toxicology and Carcinogenesis Studies of Chrlorendic Acid in F344/N Rats and B6C3F1 Mice (Feed Studies) p.10 (Year) Technical Rpt Series No. 304 NIH Pub No. 87-2560 R21: DECAD GM, FIELDS MT; J TOXICOL ENVIRON HEALTH 9 (5-6): 911 (1982) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 48 (1990) R23: Schuphan I, Ballschmiter K; Metabolism of Polychlorinated Norborenes by Clostridium butyricum. Nature 237 (5350): 100-101 (1972) R24: Parlar H, Korte F; Photoreactions of Cyclodiene Insecticides Under Simulated Environmental Conditions--A Review. Chemosphere 10: 665-705 (1977) R25: TRDB/USEPA; Final Technical Support Document (Draft) Chlorendic Acid p.45 (1982) R26: 40 CFR 712.30 (7/1/91) R27: 40 CFR 716.120 (7/1/91) RS: 35 Record 202 of 1119 in HSDB (through 2003/06) AN: 2922 UD: 200108 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRACHLOROPHTHALIC-ANHYDRIDE- SY: *1,3-DIOXY-4,5,6,7-TETRACHLOROISOBENZOFURAN-; *1,3-ISOBENZOFURANDIONE,-4,5,6,7-TETRACHLORO-; *NCI-C61585-; *NIAGATHAL-; *PHTHALIC-ANHYDRIDE,-TETRACHLORO- RN: 117-08-8 MF: *C8-CL4-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CHLORINATION OF PHTHALIC ANHYDRIDE [R1] MFS: *MONSANTO CO, MONSANTO CHEM INTERMEDIATES CO, BRIDGEPORT NJ 08014, MONSANTO INDUST CHEMS CO, BRIDGEPORT, NJ 08014 [R1] OMIN: *TETRACHLOROPHTHALIC ANHYDRIDE (1 KG/HA) TOTALLY SUPPRESSED THE PHYTOTOXICITY OF AFALON TO SUNFLOWER. [R2] USE: *FLAME RETARDANT IN UNSATURATED POLYESTER RESINS, POLYURETHANE FOAMS AND SURFACE COATINGS; CHEM INT FOR PIGMENT GREEN 7, DRUGS AND PLASTICIZERS [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1972) ND [R1] *(1975) ND [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PRISMS, NEEDLES FROM SUBLIMATION [R3]; *WHITE, FREE-FLOWING POWDER [R4] ODOR: +ODORLESS [R4] BP: *371 DEG C [R4] MP: *255-256.5 DEG C [R3] MW: *285.88 [R5] SOL: *SLIGHTLY SOLUBLE IN ETHER [R3]; *SLIGHTLY SOL IN WATER [R4] SPEC: +SADTLER REF NUMBER: 1271 (IR, PRISM); 228 (IR, GRATING); MAX ABSORPTION (PROPYLENE OXIDE, METHYLCYCLOHEXANE): 240 NM (LOG E= 4.7); 335 NM (LOG E= 3.6); 310 NM (LOG E= 3.1) SHOULDER [R3]; +IR: 3343 (Coblentz Society Spectral Collection) [R6]; +UV: 382 (Sadtler Research Laboratories Spectral Collection) [R6]; +MASS: 1866 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R6] OCPP: +SUBLIMES @ BOILING POINT; DECOMP IN HOT WATER [R3] +NONHYGROSCOPIC [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- TOXC: *THE GENERATION OF SMOKE AND TOXIC GASEOUS COMPD FROM BURNING UNSATURATED POLYESTER RESINS AND THE EFFECT OF FLAME RETARDANTS WERE EXAMINED. CL-CONTAINING POLYESTERS GENERATED HIGHER LEVELS OF HCL THAN BR-CONTAINING RESINS GENERATED HBR. CARBON MONOXIDE LEVEL IS SLIGHTLY LESS FOR CHLORINATED RESINS THAN FOR BROMINATED RESINS. [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *THE PLASTICS INDUSTRY UTILIZES A NUMBER OF ORG CHEM WHICH HAVE THE POTENTIAL OF PRODUCING PULMONARY REACTIONS, PARTICULARLY IN SUSCEPTIBLE INDIVIDUALS. 5 WORKERS IN PRODN OF EPOXY RESINS DEVELOPED RECURRENT RESP SYMPTOMS AND PHYSIOLOGIC ABNORMALITIES FOLLOWING EXPOSURE TO TETRACHLOROPHTHALIC ANHYDRIDE (TCPA). INHALATION CHALLENGE WITH TCPA REPRODUCED THEIR SYMPTOMS AND DEMONSTRATED IMMEDIATE AND LATE (4-6 HR) PHYSIOLOGIC RESPONSE. [R8] *ASTHMA WAS INDUCED IN 7 WOMEN OCCUPATIONALLY EXPOSED TO TETRACHLOROPHTHALIC ANHYDRIDE. INHALATION TESTS AT ATMOSPHERIC CONCN OF LESS THAN 1/10 OF MFR RECOMMENDED EXPOSURE LIMIT PROVOKED ASTHMATIC REACTIONS IN 4 WOMEN. SKIN PRICK TEST REACTIONS WERE ELICITED IN 7 SUBJECTS BY CONJUGATE OF TCPA WITH HUMAN SERUM ALBUMIN (TCPA-HSA) BUT NOT IN OTHERS TESTED. SPECIFIC IGE ANTIBODY LEVELS TO TCPA-HSA, MEASURED BY RADIOALLERGOSORBENT TEST SCORES, WERE SIGNIFICANTLY ELEVATED IN 7 WOMEN. RESULTS IMPLY THAT OCCUPATIONAL ASTHMA CAUSED BY TCPA IS AN ALLERGIC REACTION MEDIATED BY SPECIFIC IGE ANTIBODY. [R9] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of Tetrachlorophthalic Anhydride Administered by Gavage to F344/N Rats and B6C3F1 Mice NTP TOX 28 (1993) NIH Pub No. 93-3351 SO: R1: SRI R2: HERBICIDAL COMPOSITIONS CONTAINING AN ANTIDOTE; BELG PATENT 884879 12/16/80 (NITROKEMIA IPARTELEPEK) R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-438 R4: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 845 R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8307 R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 115 R7: MILLER DP ET AL; SMOKE AND TOXIC-GAS EMISSION FROM BURNING UNSATURATED POLYESTER RESINS; MOD PLAST 53(9) 95, 97, 101, 103 (1976) R8: SCHLUETER DP ET AL; OCCUPATIONAL ASTHMA DUE TO TETRACHLOROPHTHALIC ANHYDRIDE; JOM 20 (3) 183 (1978) R9: HOWE W ET AL; TETRACHLOROPHTHALIC ANHYDRIDE ASTHMA: EVIDENCE FOR SPECIFIC IGE ANTIBODY; J ALLERGY CLIN IMMUNOL 71(1, PART 1) 5 (1983) RS: 5 Record 203 of 1119 in HSDB (through 2003/06) AN: 2923 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRAMETHYLOLPHOSPHONIUM-CHLORIDE- SY: *NCI-C55061-; *PHOSPHONIUM, TETRAKIS(HYDROXYMETHYL)-, CHLORIDE; *PYROSET-TKC-; *TETRAHYDROXYMETHYLPHOSPHONIUM-CHLORIDE-; *TETRAKIS- (HYDROXYMETHYL)PHOSPHOCHLORIDE; *TETRAKIS- (HYDROXYMETHYL)PHOSPHONIUM-CHLORIDE; *THPC- RN: 124-64-1 RELT: 2924 [TETRAMETHYLOLPHOSPHONIUM HYDROXIDE] (Analog) MF: *C4-H12-O4-P.CL MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION BETWEEN PHOSPHINE, HYDROCHLORIC ACID AND FORMALDEHYDE [R1] *Reaction of phosphine, formaldehyde, and hydrochloric acid. [R2] FORM: *May be used in combination with triethylolamine and urea (Roxel process) or with triethanolamine and tris(1-aziridinyl) phosphate oxide. [R2] MFS: *NO LONGER PRODUCED IN THE US [R1] USE: *FLAME RETARDANT FOR TEXTILES- EG, COTTON AND RAYON; FLAME RETARDANT CONDENSATE WITH UREA USED IN FABRICS; CHEM INT FOR THE HYDROXIDE SALT [R1] *BROAD SPECTRUM DISINFECTANT WITH HIGH BACTERICIDAL ACTIVITY AGAINST ESCHERICHIA COLI AND STAPHYLOCOCCUS AUREUS, AND FOOT-AND-MOUTH DISEASE VIRUS OF CATTLE [R3] *Flame-retarding agent for cotton fabrics. /Former use/ [R2] PRIE: U.S. PRODUCTION: *(1973) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crystalline [R2] MP: *154 deg C [R4] MW: *190.56 [R4] CORR: *Corrosive [R5] DEN: *1.341 [R5] SOL: *In water, 40,000 mg/l, temp not specified. [R6] SPEC: *Index of refraction: 1.5120 @ 20 deg C/D [R5]; *IR: u SADP 13510 (Sadtler Research Laboratories IR Prism collection) [R4]; *H1 NMR: SAD 11664 (Sadtler Research Laboratories spetral collection) [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of /phosphorous oxides and hydrogen chloride/. [R7] *TETRAKIS(HYDROXYMETHYL)PHOSPHONIUM CHLORIDE DEGRADES THERMALLY AND UNDER CERTAIN CHEMICAL CONDITIONS TO YIELD HYDROCHLORIC ACID AND FORMALDEHYDE. IN SOLN, THE LATTER 2 CMPDS ARE IN EQUILIBRIUM WITH THE KNOWN POTENT CARCINOGEN BIS(CHLOROMETHYL)ETHER. [R8] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of tetrakis(hydroxymethyl)phosphonium salts were available. There is inadequate evidence in experimental animals for the carcinogenicity of tetrakis(hydroxymethyl)phosphonium salts. Overall evaluation: Tetrakis(hydroxymethyl)phosphonium salts are not classifiable as to their carcinogenicity to humans (Group 3). /Tetrakis(hydroxymethyl)phosphonium salts/ [R9] ANTR: */SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R10] */SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R10] NTOX: *TETRAKIS(HYDROXYMETHYL) PHOSPHONIUM CHLORIDE WAS TESTED FOR CARCINOGENICITY BY SKIN APPLICATION 3 TIMES/WK IN RANDOM BRED FEMALE SWISS ICR/HA MICE FOR 420-496 DAYS (2 MG/APPLICATION, 60 MICE). IT WAS FOUND TO BE INACTIVE. [R11] *APPLICATION OF TETRAKIS(HYDROXYMETHYL)PHOSPHONIUM CHLORIDE (THPC) TO MOUSE SKIN (2 MG IN 0.1 ML DMSO) 3 TIMES/WK FOR 400 DAYS WITH 20 FEMALE ICR/HA SWISS MICE/GROUP, GAVE ONE SQUAMOUS CARCINOMA. THPC WAS INACTIVE AS AN INITIATING AGENT IN TWO-STAGE MOUSE SKIN CARCINOGENESIS WITH PHORBOL MYRISTATE ACETATE AS PROMOTER. THPC WAS ACTIVE AS TUMOR PROMOTER, USING A SINGLE APPLICATION OF 7,12-DIMETHYLBENZ[A]ANTHRACENE (20 MICRO NG IN 0.1 ML ACETONE) AS INITIATOR. WITH THPC AS PROMOTER (2 MG IN 0.1 ML DMSO, THRICE WEEKLY) 3 OF 20 MICE BORE PAPILLOMAS WHICH PROGRESSED TO SQUAMOUS CARCINOMA. [R8] *SPOT TESTS SHOWED TETRAMETHYLOLPHOSPHONIUM CHLORIDE TO BE NONMUTAGENIC IN SALMONELLA TYPHIMURIUM STRAINS TA100, TA98, TA1535 AND TA1537 WITH AND WITHOUT S-9 MIX USING 1,000, 300, 100 and 10 UG/PLATE. [R12] *Tetrakis(hydroxymethyl) phosphonium chloride (TPC) was tested for mutagenicity in Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. TPC was tested over a wide range of doses (0, 0.33, 1.0, 3.3, and 33 ug/plate) in 4 Salmonella typhimurium strains (TA98, TA100, TA1535, AND TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. TPC was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 33 ug/plate. [R13] *Tetrakis(hydroxymethyl)phosphonium chloride was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. No dose-related increase in the incidence of any tumor was observed; however, in male rats receiving the low dose, there was an increased incidence of mononuclear-cell leukemia. Tetrakis(hydroxymethyl)-phosphonium chloride did not show significant promoting activity in a two-stage skin carcinogenicity test in mice. [R14] *Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPS was available as a 72% aqueous soln and THPC as a 75% aqueous soln. Two yr studies were conducted in F344/N rats by admin 0, 5, 10 mg/kg THPS or 0, 3.75 or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days/wk for 103 or 104 wk. Groups of 49 or 50 B6C3F1 mice were admin 0, 5 or 10 mg/kg THPS (each sex), 0, 7.5 or 15 mg/kg (males) or 0, 15 or 30 mg/kg THPC (females). ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of THPS in either sex of F344/N rats or B6C3F1 mice given 5 or 10 mg/kg. There was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg, in male B6C3F1 mice given 7.5 or 15 mg/kg, or in female B6C3F1 mice given 15 or 30 mg/kg. [R15] *During 90 day gavage studies, hepatocyte vacuolar degeneration was seen in rats and mice receiving tetrakis(hydroxymethyl)phosphonium sulfate or chloride. Neurotoxicity was also caused by the latter salt. [R16] *In two-year studies, ... when treated with the chloride salt, mice and rats showed hepatocyte cytoplasmic vacuolization. Moreover, male rats showed liver cystic degeneration, female mice displayed thyroid follicular-cell hyperplasia and female rats spleen hematopoeisis. [R16] *Tetrakis(hydroxymethyl)phosphonium chloride was not mutagenic to bacteria in either the presence or absence of an exogenous metabolic system. It induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in vitro and, in a single study, it induced mutations in mouse lymphoma L5178Y cells in vitro at the tk locus. [R16] *... Erythema and edema of the integumentary system were observed /after a 24 hr dermal exposure to > 4084 mg THPC/kg bw of albino rabbits/. [R17] *Groups of five 6-wk old, F-344/N rats of each sex were admin 0, 9.4, 18.8, 37.5, 75, or 150 mg THPC (as a 75% aqueous soln)/kg bw in deionized water by gavage for 14 days. At the 2 highest dose levels an increased mortality was observed. At 75 mg/kg the mortality for males was 20%, and at 150 mg/kg all males and females died. The body weight gain of the male animals admin 18.8 and 37.5 mg/kg was decreased respectively, by 7 and 11%. This effect was also found in the females admin 75 mg/kg (27%). Rats with 150 mg/kg had yellow to tan or mottled red livers. [R17] *Groups of ten 4-wk old F-344/N rats of each sex were gavaged 5 days/wk for 13 wk with 0, 3.75, 7.5, 15, 30, or 60 mg THPC (as a 75% aqueous soln)/kg. All males and 5/10 females that received 60 mg/kg died. The final mean body weight of males that received 30 mg/kg was 89% of vehicle controls. The final mean body weight of females that received 60 mg/kg was 80% of vehicle controls. At the highest dose level, clinical signs of toxicity included rough coat, hunched back, diarrhea, lethargy, paresis and hyperextension of back legs. Periportal hepatocellular necrosis was observed in 9/10 males and 7/10 females that received 15 mg/kg, all males and females that received 30 mg/kg, and 7/10 males and 8/10 females that received 60 mg/kg. Periportal cytoplasmic vacuolization was observed in 8/10 males that received 7.5 mg/kg, 9/10 males and 8/10 females that received 15 mg/kg, and all rats that received 30 or 60 mg/kg. Degeneration of the axons was found in 2/10 females that received 60 mg/kg. The NOAEL for this study is 2.7 mg/kg bw/day; the LOAEL was 5.4 mg/kg bw/day. [R18] NTXV: *LD50 Rat oral 161 mg/kg; [R7] *LD50 Mouse (female) oral 280 mg/kg bw (75% soln in water) /From table/; [R17] *LD50 Rat (male) oral 185 mg/kg bw (75% soln in water) /From table/; [R17] *LD50 Rabbit (albino) dermal > 4084 mg THPC/kg bw (24 hr exposure); [R17] NTP: *Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPS was available as a 72% aqueous solution and THPC as a 75% aqueous solution. Two yr studies were conducted in F344/N rats by admin 0, 5, 10 mg/kg THPS or 0, 3.75 or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days/wk for 103 or 104 wk. Groups of 49 or 50 B6C3F1 mice were admin 0, 5 or 10 mg/kg THPS (each sex), 0, 7.5 or 15 mg/kg (males) or 0, 15 or 30 mg/kg THPC (females). ... Under the conditions of these 2 year gavage studies, there was no evidence of carcinogenicity of THPS in either sex of F344/N rats or B6C3F1 mice given 5 or 10 mg/kg. There was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg, in male B6C3F1 mice given 7.5 or 15 mg/kg, or in female B6C3F1 mice given 15 or 30 mg/kg. [R15] ADE: *Tetrakis(hydroxymethyl)phosphonium chloride can be absorbed through the skin. [R16] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and Tetrakis(hydroxymethyl)phosphonium chloride in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 296 (1987) NIH Publication No. 87-2522] SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 1089 R3: RAVILOV AZ ET AL; BROAD-SPECTRUM DISINFECTANTS; VETERINARIYA (MOSCOW) (59 26 81979) R4: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V4 4154 R5: Aldrich; Handbook of Fine Chemicals and Laboratory Equipment. 2000-2001. Wilwaukee, WI: Alrich Chem Co p. 1576 (2000) R6: Brown SL et al; Research program on hazard priority ranking of manufactured chemicals. Chemicals 1-120. Menlo Park, CA: Stanford Res Inst. NTIS PB-263 161. pp. 191 (1975) R7: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3117 R8: LOEWENGART G, VAN DUUREN BL; J TOXICOL ENVIRON HEALTH 2 (3): 539 (1977) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 71 1532 (1999) R10: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R11: VAN DUUREN BL ET AL; CANCER RES 38 (10): 3236 (1978) R12: MACGREGOR JT ET AL; ENVRION MUTAGEN 2 (3): 405 (1980) R13: Zeiger E et al; Environ Mutagen 9:1-110 (1987) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1530 (1999) R15: Toxicology and Carcinogenesis Studies of Tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and Tetrakis(hydroxymethyl)phosphonium chloride (THPC) in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 296 (1987) NIH Publication No. 87-2552 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1531 (1999) R17: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.78 (2000) R18: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.79-80 (2000) RS: 15 Record 204 of 1119 in HSDB (through 2003/06) AN: 2928 UD: 200205 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-CHLORO-2-METHYL-1-PROPENE- SY: *ALPHA-CHLOROISOBUTYLENE-; *1-CHLORO-2-METHYLPROPENE-; *BETA,BETA-DIMETHYLVINYL-CHLORIDE-; *ISOCROTYL-CHLORIDE-; *2-METHYL-1-CHLOROPROPENE-; *2-METHYL-1-PROPENYL-CHLORIDE-; *PROPENE,-1-CHLORO-2-METHYL- RN: 513-37-1 MF: *C4-H7-Cl MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...FROM ISOBUTYRALDEHYDE: KIRRMANN, BULL SOC CHIM FRANCE 1948, 163; BY ISOMERIZATION OF 3-CHLORO-2-METHYLPROPENE WITH 80% H2SO4: BACKHURST ET AL, J CHEM SOC 1959, 2742. [R1] *... a by-product from the synthesis of 3-chloro-2-methylpropene from isobutylene ... . [R2, p. 186 (1994)] MFS: *NOT PRODUCED COMMERCIALLY IN US [R3] USE: *IN ORG SYNTHESES [R1] *CHEMICAL INTERMEDIATE FOR ORG ISOBUTYLENE COMPDS (USED IN LABS) [R3] PRIE: U.S. PRODUCTION: *(1972) NOT PRODUCED COMMERCIALLY IN US [R3] *(1975) NOT PRODUCED COMMERCIALLY IN US [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear, colorless liquid [R2, p. 186 (1994)]; *LIQUID [R1] BP: *68 DEG C @ 754 MM HG [R4] MW: *90.55 [R4] DEN: *0.9186 @ 20 DEG C/4 DEG C [R4] SOL: *SOL IN ACETONE; VERY SOL IN CHLOROFORM; SOL IN ALL PROPORTIONS IN ALCOHOL AND ETHER [R5]; *Water solubility = 1000 mg/L [R6] SPEC: *INDEX OF REFRACTION: 1.4221 @ 20 DEG C [R4]; *IR: 3:57G (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R7, p. V2 182]; *NMR: 1:70D (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R7, p. V2 182]; *NMR: 67 (Varian Associates NMR Spectra Catalogue) [R7, p. V1 356] VAP: *158.4 mm Hg at 25 deg C [R8] OCPP: *Extremely volatile and flammable at room temperature [R2, p. 186 (1994)] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition /temperature unspecified/ , dimethylvinyl chloride emits highly toxic fumes of hydrochloric acid and other chlorinated compounds. [R2, p. 186 (1994)] *WHEN HEATED TO DECOMP EMITS HIGHLY TOXIC FUMES OF /HYDROGEN CHLORIDE/. [R9] SERI: *IRRITATES EYES, RESP PASSAGES. [R10] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 1-chloro-2-methylpropene. There is sufficient evidence in experimental animals for the carcinogenicity of 1-chloro-2-methylpropene. Overall evaluation: 1-Chloro-2-methylpropene is possibly carcinogenic to humans (Group 2B). [R11] HTOX: *IRRITATES EYES, RESP PASSAGES. [R10] *HAS ANESTHETIC PROPERTIES. [R10] *LOW BY /ACUTE/ INHALATION... LOW: CAUSES READILY REVERSIBLE TISSUE CHANGES WHICH DISAPPEAR AFTER EXPOSURE STOPS; CAUSES SOME DISCOMFORT. [R12] NTOX: *2,2-Dimethyl vinyl chloride (DVC) was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using a standard protocol approved by the National Toxicology Program. 2,2-Dimethyl vinyl chloride was tested at doses of 0, 33, 100, 333, 1000, 3333, and 10,000 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. DVC was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 10,000 ug/plate. [R13] *When administered by gavage, dimethylvinyl chloride increased the incidences of adenocarcinomas and carcinomas of the nasal cavity and squamous cell papillomas or carcinomas of the oral cavity, esophagus, and forestomach in rats of both sexes. When administered by gavage, the compound increased the incidences of squamous cell carcinomas of the forestomach in mice of both sexes and squamous cell carcinomas of the preputial gland. [R2, p. 185 (1994)] *A number of chemicals have been shown to cause malignant neoplasms in the forestomach of Fischer 344 rats when administered chronically by gavage. The present study was designed to identify early forestomach lesions following 2 wk repeated gavage admin of some of these forestomach carcinogens. ... The hypothesis that early cell proliferation is associated with repetitive gavage administration of these chemicals /was examined/. Groups of 8 or more male F344 rats received 1 of 6 reported forestomach carcinogens (ethyl acrylate, diglycidyl resorcinol ether, 1,2-dibromoethane, 1,2-dibromo-3-chloro-propane, 1-chloro-2-methylpropene, dimethylvinyl chloride and 3-chloro-2-methylpropene, 1 of 2 structurally related chemicals methyl methacrylate and dichloroethane which were negative in chronic carcinogenicity studies or the vehicle corn oil alone 5 days/week for 2 weeks. Histopathologic exam of forestomachs of rats killed 24 hr after the last dose indicated no significant difference in the incidence or severity of epithelial cell proliferation in the rat forestomach between the vehicle control group and the 2 negative control groups. In contrast, the incidence and severity of epithelial cell proliferation of the rat forestomach in every group treated with a forestomach carcinogen was significantly higher than the incidence in the vehicle or negative control groups. These results suggest that early epithelial cell proliferation of the forestomach may be associated with at least some chemicals that induce forestomach neoplasia following chronic administration by gavage. [R14] NTP: *Single admin, 14 day, 13 week, and 2 year gavage studies were performed in F344-N rats and B6C3F1 mice to investigate the toxicology and carcinogenicity of dimethylvinyl chloride. Single exposure studies used doses of 10 to 10,000 mg/kg in rats and 100 to 10,000 mg/kg in mice. In 14 day studies, 500 to 2,500 mg/kg were administered. In 13 week studies, doses were 63 to 750 mg/kg 5 days a week. In 2 year studies, doses were 100 or 200 mg/kg. Two year doses were influenced by body weight depression and histopathologic changes noted in the 13 week studies. Histopathologic alterations indicated a more diffuse pattern of toxicity in mice than in rats in 13 week studies. In 2 year studies in rats, dose related increases occurred in the incidences of malignant epithelial tumors of the nasal cavity and squamous cell carcinomas of the oral cavity, esophagus, and forestomach. In mice, the incidence of squamous cell carcinomas of the forestomach was significantly increased. Both species evidenced invasion and metastasis from primary tumor sites. The /results suggest/that the high incidence of nasal cavity tumors may indicate that some active agent is exhaled. In 2 year studies, one lot of dimethylvinyl chloride was contaminated with small amounts of the animal carcinogen acrylonitrile. In mice, some immunologic parameters were altered by dimethylvinyl chloride exposure, and host resistance was decreased. Biphasic responses were noted in mice; many parameters were enhanced at a low dose and suppressed at a high dose. Studies of genetic toxicity showed no clear relationship to carcinogenicity. The /results/ conclude that there is clear evidence of carcinogenicity in rats and mice of both sexes. [R15] TCAT: ?The mutagenicity of 1-chloro-2-methylpropene was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test) and in Saccharomyces cerevisiae strain D4, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary toxicity determinations, 1-chloro-2-methylpropene, diluted in DMSO, was tested at concentrations of 0.01, 0.1, 1, and 5ul/plate using the plate incorporation technique. 1-Chloro-2-methylpropene did not cause a positive response in any tester strain with or without metabolic activation. [R16] ADE: *A recent 2 yr carcinogenicity study found that gavage admin of 3-chloro-2-methylpropene containing 5% 1-chloro-2-methylpropene (dimethylvinyl chloride), caused forestomach neoplasms in rats and mice. Similar chronic studies revealed that dimethylvinyl chloride caused forestomach neoplasms in both rats and mice; neoplasms of the nasal and oral cavities were observed in rats but not in mice. In the current studies, /the metabolic basis/ of these differences /has been investigated/. Daily doses of 150 mg/kg of 2-(14)C-dimethylvinyl chloride or 2-(14)C-3-chloro-2-methylpropene were admin to rats for 1, 2, or 4 consecutive days. One daily dose of 150 mg/kg of dimethylvinyl chloride was admin to mice. Both /cmpds/ were rapidly metabolized; however, 3-chloro-2-methylpropene was cleared at a slightly lower rate. Rats exhaled approx 25 and 10% of the dimethylvinyl chloride and 3-chloro-2-methylpropene as C02, respectively. Mice exhaled 25% of the dimethylvinyl chloride as C02. Rats expired 30% of the admin dimethylvinyl chloride unchanged in the 24 hr after dosing compared to only 7% of the admin 3-chloro-2-methylpropene. Mice expired 5% of the admin dimethylvinyl chloride in the same time period. This observation may explain the occurrence of tumors in the nasal and oral cavities of rats treated with dimethylvinyl chloride but not in rats treated with 3-chloro-2-methylpropene or in mice treated with dimethylvinyl chloride inn 2 yr carcinogenicity studies. The 24 hr urinary excretion in rats was 35% of the admin dimethylvinyl chloride compared to 58% of 3-chloro-methylpropene. Mice excreted 47% of the admin dimethylvinyl chloride in 24 hr in the urine. An unusual urinary metabolite of dimethylvinyl chloride, 2-amino-6-methyl-4-thia-5-heptene-1,7-dioic acid, was identified. [R17] METB: *An investigation was carried out to determine the metabolic step that influences the stereochemistry of the metabolites of l-chloro-2-methylpropene (DMVC). Studied reactions included DMVC oxidation by rat liver mlcrosomes, Michael reaction of propenals and propenoic acids with N-acetylcysteine (NAC) and glutathione (GSH) and influence of glutathione-S-transferase (GST) enzymes on conugation reactions. Major and minor metabolites were identified as (E)-3-chloro-2-methylpropenol and (Z)-3-chloro-2-methylpropenol which were produced by liver mlcrosomes from phenobarbital treated rats In a ratio of 2:1. Overall yield of alcohol metabolites was about 1%. Microsomes from beta-naphthoflavone treated rats did not produce alcohols from DMVC. Isomeric aldehyde compounds were obtained by oxidation of alcohols and were characterized for Michael reactions with NAC. Both reactions were rapid and yielded single conjugates which were nearly identical for the isomers. Propenoic acid isomers produced by oxidation of propenals were reacted with NAC and GSH. NAC reactions were slow and yielded one conjgate with the (E)-propenoic acid but two conjugates with the (Z)-propenoic acid. Two conjugates in a ratio of 5:95 were reduced by Michael reaction of GSH and the (E)-propenoic-acid. GST enzymes as purified preparations or whole liver homogenates ad low actively in the conjugation reaction of GSH with propenoic acid isomers. The (E)-adduct was the primary product. A metabolic pathway was proposed which involved reactive electrophilic aldehydic species as hidden metabolites. The /results indicate/ that reactivity of haloenoic aldehyde species makes them likely candidates for toxic and carcinogenic products of DMVC. [R18] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1-Chloro-2-methyl-1-propene's use as a chemical intermediate may result in its release to the environment through various waste streams. 1-Chloro-2-methyl-1-propene has been found at trace amounts in water and sediment samples in Japan and at higher concentrations in ambient air near industrial and chemical waste sites. If released to water, volatilization of 1-chloro-2-methyl-1-propene will be rapid with estimated half-lives of 2.9 hours and 3.8 days from a model environmental river and a model lake, respectively. Adsorption to sediment and bioconcentration are not likely fate processes for 1-chloro-2-methyl-1-propene. Insufficient information is available to determine the rate or importance of biodegradation of 1-chloro-2-methyl-1-propene in soil or water. If released to the atmosphere, 1-chloro-2-methyl-1-propene will exist in the vapor phase. Vapor-phase 1-chloro-2-methyl-1-propene will degrade in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of approximately 21 hours and by reaction with atmospheric ozone with an estimated half-life of 26 hours. Removal of atmospheric 1-chloro-2-methyl-1-propene may occur through wet deposition. If released to soil, 1-chloro-2-methyl-1-propene is expected to have high mobility based on estimated Koc values of 68 to 98. Volatilization of 1-chloro-2-methyl-1-propene is expected from both moist and dry soils. Occupational exposure to 1-chloro-2-methyl-1-propene can occur through inhalation, dermal contact, and ingestion. (SRC) ARTS: *1-Chloro-2-methyl-1-propene's use as a chemical intermediate(1) may result in its release to the environment through various waste streams(SRC). [R19] FATE: *TERRESTRIAL FATE: 1-chloro-2-methyl-1-propene will have high mobility(1) in soil based on estimated Koc values of 68 to 98(2,3,SRC). Volatilization of 1-chloro-2-methyl-1-propene is expected from both moist and dry soils based on an experimental vapor pressure of 158.4 mm Hg(4,SRC), and an estimated Henry's Law constant of 0.019 atm-cu m/mole(5,SRC). Insufficient data are available to determine the rate or importance of biodegradation of 1-chloro-2-methyl-1-propene in soil conditions(SRC). [R20] *AQUATIC FATE: Volatilization of 1-chloro-2-methyl-1-propene from water is rapid based upon an estimated Henry's Law constant of 0.019 atm-cu m/mol(1,2,SRC). Volatilization half-lives from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) and a model lake (1 meter deep) can be estimated to be about 2.9 hours(2,SRC) and 3.8 days(2,SRC), respectively. Adsorption to sediment is not a likely fate process based on low estimated Koc values of 68 to 98(2,3,SRC). Bioconcentration of 1-chloro-2-methyl-1-propene in aquatic organisms is also not a likely fate process based on an estimated bioconcentration factor of 12.6(2). Insufficient data are available to determine the rate or importance of biodegradation of 1-chloro-2-methyl-1-propene in natural waters(SRC). [R21] *ATMOSPHERIC FATE: Based on an experimental vapor pressure of approximately 158.4 mm Hg at 25 deg C(1), 1-chloro-2-methyl-1-propene will exist primarily in the vapor phase in the atmosphere(2). It will degrade in the ambient atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of 21 hours(3,SRC). 1-Chloro-2-methyl-1-propene will also react with atmospheric ozone with an estimated half-life of 26 hours(3,SRC). Based on its high water solubility, removal of atmospheric 1-chloro-2-methyl-1-propene may occur through wet deposition(SRC). [R22] ABIO: *The rate constant for the vapor-phase reaction of 1-chloro-2-methyl-1-propene with photochemically produced hydroxyl radicals has been estimated to be approximately 1.85X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 21 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 1-Chloro-2-methyl-1-propene also reacts with atmospheric ozone with an estimated rate constant of 1.06X10-17 cu cm/molecule-sec which corresponds to an atmospheric half-life of 26 hours at an atmospheric concentration of 7X10+11 molecules of ozone per cu cm(1,SRC). [R23] BIOC: *Based upon an experimental water solubility of 1000 mg/L(1), the BCF for 1-chloro-2-methyl-1-propene can be estimated to be 13(2). This BCF value suggests that bioconcentration of 1-chloro-2-methyl-1-propene in aquatic organisms is not expected to be an important fate process(SRC). [R24] KOC: *Using a structure estimation method based on molecular connectivity indexes, the Koc for 1-chloro-2-methyl-1-propene can be estimated to be about 68(1,SRC). Based on an experimental water solubility of 1000 mg/L(2) and a regression derived equation, the Koc for 1-chloro-2-methyl-1-propene can be estimated to be 98(3). According to a suggested classification scheme(4), these estimated Koc values suggest that 1-chloro-2-methyl-1-propene has high soil mobility. [R25] VWS: *The Henry's Law constant for 1-chloro-2-methyl-1-propene can be estimated to be 0.019 atm-cu m/mole using a structure estimation method(1,SRC). This value of Henry's Law constant indicates that volatilization of 1-chloro-2-methyl-1-propene is rapid(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 2.8 hours(2,SRC). The volatilization half-life from a model environmental lake (1 meter deep) can be estimated to be about 3.7 days(2,SRC). [R26] WATC: *A Japanese study has reported trace amounts of 1-chloro-2-methyl-1-propene in water samples at a detection limit of 0.0003 ug/L(1). [R27] EFFL: *1-Chloro-2-methyl-1-propene was detected in ambient air at four industrial and chemical waste sites near Curtis Bay, MD at concentrations of 200, 670, 100, and 90 ug/cu m(1). [R28] SEDS: *A Japanese study has reported trace amounts of 1-chloro-2-methyl-1-propene in sediment samples at a detection limit of 0.015 ug/kg(1). [R27] RTEX: *The primary route of potential human exposure to dimethylvinyl chloride is inhalation. Occupational exposure to dimethylvinyl chloride may occur during the production of 3-chloro-2-methylpropene ... In 1985, the EPA estimated that only 8-12 workers were potentially exposed to dimethylvinyl chloride (noncontinuously) during the production of 3-chloro-2-methylpropene ... . [R2, p. 186 (1994)] *Occupational exposure to unsaturated halogenated hydrocarbons aliphatic hydrocarbons, such as 1-chloro-2-methyl-1-propene, can occur through inhalation, dermal contact, and ingestion(1). [R29] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) NTP TR No 316; Route: oral, gavage; Species: rats and mice. NTIS No PB87115184. [R30] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 331 R2: DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary R3: SRI R4: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-288 R5: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 57th ed. Cleveland: CRC Press Inc., 1976.,p. C-463 R6: Shiu WY et al; Rev Environ Contam Toxicol 116: 15-187 (1990) R7: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R8: Jaber HM et al; Data Acquisition for Environmental Transport and Fate Screening USEPA-600/6-84/009 Menlo Park CA: SRI Inter pp.312 (1984) R9: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1640 R10: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 273 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 63 323 (1995) R12: Sax, N.I. Dangerous Properties of Industrial Materials. 4th ed. New York: Van Nostrand Reinhold, 1975. 615 R13: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R14: Ghanayem BI et al; Cancer Lett 32 (3): 271-8 (1986) R15: Toxicology and Carcinogenesis Studies of Dimethylvinyl Chloride (1-Chloro-2-methylpropene) (CAS No. 513-37-1) in F344-N Rats and B6C3F1 Mice (Gavage Studies) Report # 316 (1986) NIH Pub # 86-2572 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R16: Litton Bionetics Inc.; Mutagenicity of 1-Chloro-2-Methylpropene, Final Report, (1976), EPA Document No. FYI-OTS-0885-0396, Fiche No. OTS0000396-1 R17: Ghanayem BI, Burka LT; Drug Metab Dispos Biol Fate Chem 15 (1): 91-6 (1987) R18: Srinivas P, Burka LT; Drug Metab Disposit 16 (3): 449-54 (1988) R19: (1) Budavari S; The Merck Index 11th ed Rahway, NJ: Merck and Co Inc pg. 331 (1989) R20: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) (4) Jaber HM et al; Data Acquisition for Environmental Transport and Fate Screening USEPA-600/6-84/009 Menlo Park CA: SRI Inter pp.312 (1984) (5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) R21: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) (3) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) R22: (1) Jaber HM et al; Data Acquisition for Environmental Transport and Fate Screening USEPA-600/6-84/009 Menlo Park CA: SRI Inter pp.312 (1984) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Environ Toxicol Chem 26: 2293-9 (1993) R23: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R24: (1) Shiu WY et al; Rev Environ Contam Toxicol 116: 15-187 (1990) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-10 (1990) R25: (1) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (2) Shiu WY et al; Rev Environ Contam Toxicol 116: 15-187 (1990) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R26: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) R27: (1) Hori S et al; Ishikawa-ken Eisei Kogai Kenkyusho Nenpo 26: 457-63 (1990) R28: (1) Pellizzari ED; Environ Sci Technol 16: 781-5 (1982) R29: (1) Parmeggiani L; Encycl Occup Health and Safety 3rd ed Geneva, Switzerland: International Labour Office p. 1076-84 (1983) R30: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.23 RS: 23 Record 205 of 1119 in HSDB (through 2003/06) AN: 2937 UD: 200302 RD: Reviewed by SRP on 05/08/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 3-NITROTOLUENE- SY: *Benzene,-1-methyl-3-nitro-; *M-METHYLNITROBENZENE-; *1-METHYL-3-NITROBENZENE-; *3-METHYLNITROBENZENE-; *m-Nitrotoluene-; *m-Nitrotoluol-; *3-NITROTOLUOL-; *NSC-9578-; *TOLUENE,-M-NITRO- RN: 99-08-1 RELT: 6301 [NITROTOLUENES] MF: *C7-H7-N-O2 SHPN: UN 1664; Nitrotoluenes IMO 6.1; Nitrotoluenes STCC: 49 631 31; m-Nitrotoluene 49 631 55; Nitrotoluene MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN OF M-NITROTOLUENE FROM 3-NITRO-4-AMINO-TOLUENE AND SODIUM NITRITE. [R1] *PREPARED FROM P-TOLUIDINE BY ACETYLATION, NITRATION DEACETYLATION, DIAZOTIZATION, AND BOILING WITH ETHANOL. [R2] MFS: +First Mississippi Corp, Hq, 700 North St, PO Box 1249, Jackson, MS 39205, (601) 948-7550; Subsidiary: First Chemical Corp, (601) 949-0246; Production site: Pascagoula, MS 39567 [R3] OMIN: *IRRADIATION OF A MIXTURE CONTAINING 34 AND 10-310 PPM OF TOLUENE AND NITROGEN DIOXIDE, RESPECTIVELY, IN OXYGEN AND/OR NITROGEN YIELDED M-NITROTOLUENE. THE RELATIVE YIELD OF M-NITROTOLUENE DECR WITH INCR NITROGEN DIOXIDE CONCN, BOTH IN THE PRESENCE AND ABSENCE OF OXYGEN. [R4] *TOLUENE VAPOR (8.93X10-5 MOLES) WAS REACTED WITH 1 ML NITROGEN OXIDE IN A 1 L QUARTZ BOTTLE UNDER A XENON LAMP AT 25-30 DEG. AFTER 5 HR, 6.70X10-5 MOLES TOLUENE REMAINED; 2-METHYL-4-NITROPHENOL WAS THE MAIN REACTION PRODUCT. M-NITROTOLUENE WAS ALSO FORMED. [R5] USE: *MANUFACTURE OF DYES, TOLUIDINES, NITROBENZOIC ACIDS. /NITROTOLUENE/ [R1] *SYNTHESIS OF EXPLOSIVES; CHEMICAL INTERMEDIATE. [R6, 2473] *Organic synthesis [R7] PRIE: U.S. PRODUCTION: *PRODUCTION OF META-ISOMER IS NEGLIGIBLE. /1981 DATA/ [R2] U.S. IMPORTS: *(1983) 1.61X10+8 g [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW LIQUID [R7]; +Yellow liquid. [Note: A solid below 59 degrees F.] [R9, 232] ODOR: *Weak aromatic [R10]; +Weak, aromatic odor. [R9, 232] BP: *231.9 DEG C @ 760 MM HG [R1] MP: *15.5 DEG C [R1] MW: *137.15 [R11] DEN: *1.1581 @ 20 DEG C/4 DEG C [R1] HTC: *11232 Btu/lb = 86.3 cal/g = 3.61x10+5 J/kg [R12] HTV: *11,831.1 gcal/gmole [R13] OWPC: *log Kow= 2.45 [R14] SOL: *SOLUBILITY IN WATER: 0.498 G/L @ 30 DEG C; MISCIBLE IN ALCOHOL AND ETHER; SOL IN BENZENE. [R1]; *0.05 g/100 g of water at 20 deg C. [R15, 1981.2]; *Soluble in ethanol [R16, 1270] SPEC: *INDEX OF REFRACTION: 1.5426 @ 30 DEG C/D [R1]; *MAX ABSORPTION (5% ALCOHOL): 274 NM (LOG E = 3.86); SADTLER REFERENCE NUMBER: 18 (IR, PRISM); 61 (IR, GRATING) [R17]; *IR: 2210 (Coblentz Society Spectral Collection) [R18]; *UV: 73 (Sadtler Research Laboratories Spectral Collection) [R18]; *NMR: 22 (Sadtler Research Laboratories Spectral Collection) [R18]; *MASS: 86 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R18] SURF: *39.07 dynes/cm @ 40 deg C [R12] VAPD: *4.73 (AIR = 1) [R19] VAP: *0.207 mm Hg at 25 deg C (extrapolated) [R20] OCPP: *SOLIDIFIES IN AN ICE AND SALT COOLING MIXTURE [R1] *% in saturated air 0.13 @ 60 deg C. [R6, 2475] *VAPOR PRESSURE: 1.0 MM HG @ 60 DEG C [R6, 2475] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 3-nitrotoluene stem from its toxicologic properties and explosivity. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this yellow liquid may occur from its use as a chemical intermediate in the production of dyes, explosives, pesticides, toluidines, and nitrobenzoic acids. Effects from exposure may include contact burns to the skin and eyes, headache, weakness, dizziness, nausea, increased pulse and respiratory rate, and methemoglobinemia. The onset of symptoms may be delayed up to 4 hours. OSHA has set a time-weighted average (TWA) limit of 2 ppm as a final rule to become effective December 31, 1992. Local exhaust ventilation should be applied to control airborn e 3-nitrotoluene to permissible limits. In activities and situations where over-exposure may occur, wear a positive pressure self-contained breathing apparatus and chemical protective clothing which is specifically recommended by the shipper or manufacturer. If contact should occur, irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes, and wash expose d skin thoroughly with soap and water. Contaminated clothing and shoes should be removed and left at the site for cleaning. While 3-nitrotoluene does not ignite easily, it may burn with the production of irritating or poisonous gases. Also, containers of this substance may explode violently in the heat of a fire. For fires involving 3-nitrotoluene, extinguish with dry chemical, CO2, water spray, fog, or standard foam. Fight fire from as far a distance as possible, and, if fire is advanced, evacuate the area. Dike fire control water. 3-Nitrotoluene should be stored in a cool, dry, well-ventilated area, away from sources of ignition, sources of physical damage, strong oxidizers, and sulfuric acid. Dike to prevent land spills of 3-nitrotoluene from entering water sources or sewers, and take up by absorbing the material in vermiculite, dry sand, or earth. For spills of 3-nitrotoluene in bodies of water, use sand bag barriers to trap material at the bottom, apply activated carbon, and use mechanical dredg es or lifts to remove immobilized masses. DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Nitrotoluenes; Nitrotoluenes, liquid; Nitrotoluenes, solid/ [R21] FPOT: *LOW, WHEN EXPOSED TO HEAT, FLAME OR OXIDIZERS. [R22] *... Contact with strong oxidizers or sulfuric acid may cause fires. /Nitrotoluene/ [R15, 1981.2] NFPA: +Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots, and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R23] +Flammability: 1. 1= This degree includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause frothing that will extinguish the fire. [R23] +Reactivity: 1. 1= This degree includes materials that are normally stable, but that may become unstable at elevated temperatures and pressures and materials that will react with water with some release of energy, but not violently. Fires involving these materials should be approached with caution. [R23] FLPT: +106 DEG C; 223 DEG F (CLOSED CUP) [R23] FIRP: *WATER, CARBON DIOXIDE, DRY CHEMICAL. [R22] *If material is on fire or involved in fire, do not attempt to extinguish fire unless flow can be stopped. Use water in flooding quantities as fog, cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible, solid streams of water may be ineffective. /Nitrotoluene/ [R24] TOXC: *Toxic gases and vapors (such as oxides of nitrogen and carbon monoxide) may be released in a fire involving nitrotoluene. /Nitrotoluene/ [R15, 1981.2] REAC: *Nitrotoluene will attack some forms of plastics, rubber, and coatings. /Nitrotoluene/ [R15, 1981.] *... Contact with strong oxidizers or sulfuric acid may cause fires and explosions. /Nitrotoluene/ [R15, 1981.2] +Strong oxidizers, sulfuric acid. [R9, 232] ODRT: *1.74 ppm [R12] SERI: *Slight eye and skin irritant. [R12] EQUP: *... Butyl rubber gloves may provide protection from exposure to this compound. [R16, 1271] *Wear boots, protective gloves, and goggles. /Nitrotoluene/ [R24] *Wear self contained breathing apparatus when fighting fires involving this material. /Nitrotoluene/ [R24] *Respirators may be used when engineering and work practice controls are not technically feasible. ... Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... Respirators permitted are those that have been approved by the Mine Safety and Health Admin ... or by the NIOSH. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (8-inch min), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with solid or liq nitrotoluene. ... Employees should be provided with and required to use dust- and splash-proof safety goggles where solid or liq nitrotoluene may contact the eyes. /Nitrotoluene/ [R15, 1981.2] +Wear appropriate personal protective clothing to prevent skin contact. [R9, 232] +Wear appropriate eye protection to prevent eye contact. [R9, 232] +Recommendations for respirator selection. Max concn for use: 20 ppm. Respirator Class(es): Any supplied-air respirator. May require eye protection. [R9, 232] +Recommendations for respirator selection. Max concn for use: 50 ppm. Respirator Class(es): Any supplied-air respirator operated in a continuous flow mode. May require eye protection. [R9, 232] +Recommendations for respirator selection. Max concn for use: 100 ppm. Respirator Class(es): Any supplied-air respirator that has a tight-fitting facepiece and is operated in a continuous-flow mode. May require eye protection. Any self-contained breathing apparatus with a full facepiece. Any supplied-air respirator with a full facepiece. [R9, 232] +Recommendations for respirator selection. Max concn for use: 200 ppm. Respirator Class(es): Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. [R9, 232] +Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R9, 232] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R9, 232] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain water flow as necessary. /Nitrotoluene/ [R24] *... A complete respiratory protection program should be instituted which incl regular training, maintenance, inspection, cleaning, and evaluation. ... Non-impervious clothing which becomes contaminated ... should be removed ... and not reworn until nitrotoluene is removed. Eating and smoking should not be permitted in areas where solid nitrotoluene is handled, processed, or stored. Employees who handle solid or liq nitrotoluene should wash ... hands thoroughly with soap or mild detergent and water before eating or smoking. /Nitrotoluene/ [R15, 1981.2] +Contact lenses should not be worn when working with this chemical. [R9, 233] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +The worker should immediately wash the skin when it becomes contaminated. [R9, 232] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R9, 232] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: */Heat contributes/ ... to instability. /Nitrotoluene/ [R15, 1981.2] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R25] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R26] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R27] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. FOR SMALL QUANTITIES OF LIQ NITROTOLUENE, ABSORB ON PAPER TOWELS. FOR SMALL QUANTITIES OF SOLID NITROTOLUENE, SWEEP ONTO PAPER OR OTHER SUITABLE MATERIAL. REMOVE TO A SAFE PLACE (SUCH AS A FUME HOOD) AND BURN PAPER. LARGE QUANTITIES OF LIQUID NITROTOLUENE CAN BE COLLECTED AND ATOMIZED IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. LARGE QUANTITIES OF SOLID NITROTOLUENE CAN BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN A FLAMMABLE SOLVENT (SUCH AS ALC) AND ATOMIZE IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. /NITROTOLUENE/ [R15, 1981.3] *Land Spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with plastic sheet to prevent dissolving in rain or fire fighting water. /Nitrotoluene/ [R28] *Water Spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom, remove trapped material with suction hoses. If dissolved, in region of 10 ppm or greater concentration, apply activated carbon at ten times the spilled amount. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Nitrotoluene/ [R28] DISP: *1. FOR LIQ NITROTOLUENE, BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR A SIMILAR MATERIAL AND DISPOSING IN A SECURED SANITARY LANDFILL. 2. BY ATOMIZING LIQ NITROTOLUENE IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. 3. BY MAKING PACKAGES OF SOLID NITROTOLUENE IN PAPER OR OTHER SUITABLE MATERIAL OR BY DISSOLVING IN A FLAMMABLE SOLVENT (SUCH AS ALC) AND BURNING IN A SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. /NITROTOLUENE/ [R15, 1981.3] *The following wastewater treatment technologies have been investigated for 3-Nitrotoluene: Concentration process: Biological treatment. [R29] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of nitrotoluenes. There is inadequate evidence in experimental animals for the carcinogenicity of 3-nitrotoluene. ... Overall evaluation: Nitrotoluenes are not classifiable as to their carcinogenicity to humans (Group 3). [R30] MEDS: *Routine checking of lips, tongue, and nail beds of exposed personnel for signs of cyanosis. /Nitrotoluene/ [R31] *Initial Medical Exam: A complete history and physical exam: ... Exam of blood, nervous system, GI system, and cardiovascular system should be stressed. Skin should be exam for evidence of chronic disorders. ... A complete blood count should be performed, including red cell count, a white cell count, a differential count of stained smear, as well as hemoglobin and hematocrit. Periodic Medical Exam: The ... /initial med exam/ should be repeated on an annual basis. Methemoglobin determinations should be performed if overexposure is suspected or signs and symptoms of toxicity occur. /Nitrotoluene/ [R15, 1981.1] HTOX: */M-NITROTOLUENE/ TOXICITY IS IDENTICAL WITH THAT OF O-NITROTOLUENE. ... PRODUCES METHEMOGLOBIN CAUSING HYPOXIA, BUT OF A LOW POTENCY. ... SUSPECTED OF CAUSING ANEMIA IN CHRONIC EXPOSURES. [R6, 2475] *Symptoms: Headache, flushing of face; dizziness, dyspnea, ... cyanosis, nausea, vomiting, muscular weakness, increased pulse and respiratory rate, irritability and convulsions. [R31] *... Cases of poisoning from nitrotoluene are uncommon. Some authorities considered it only slightly toxic, esp in comparison with nitrobenzene. There is some evidence that the different isomers vary ... in toxicity. ... It is stated that nitrotoluene is a methemoglobin former of apparently low grade. /Nitrotoluene/ [R32] *... The onset of symptoms of methemoglobinemia is insidious and may be delayed up to 4 hours; headache is commonly the first symptom and may become quite intense as the severity of methemoglobinemia progresses. ... Cyanosis develops early in the course of intoxication, first the lips, the nose, and the ear lobes, and is usually recognized by fellow workers. ... Until the methemeglobinemia concentration approaches approximately 40%, the individual usually feels well, has no complaints, and will insist that nothing is wrong . ... Over 40% ... weakness and dizziness; at up to 70% ... there may be ataxia, dyspnea on mild exertion, tachycardia, nausea, vomiting, and drowsiness. /Nitrotoluene/ [R15, 1981.1] NTOX: *WHEN ADMIN ORALLY AT DOSES CORRESPONDING TO 0.1-0.2 LD50 VALUES IN RATS FOR 1-3 MO, THE HEMOTOXICITY OF TOLUENE DERIV DECR IN THE ORDER: TRINITROTOLUENE, DINITROTOLUENE, M-NITROTOLUENE, P-NITROTOLUENE, AND O-NITROTOLUENE. THEY CAUSED ANEMIA ACCOMPANIED BY RETICULOCYTOSIS AND A DECR IN THE LEVEL OF SH-GROUPS AND AN INCR OF FIBRINOGEN IN THE BLOOD. [R33] *WHEN ADMIN ORALLY TO RATS AT 0.1-0.2 LD50 FOR 30 DAYS, M-NITROTOLUENE CAUSED TRANSFORMATION OF HEMOGLOBIN INTO METHEMOGLOBIN, NITROSYLHEMOGLOBIN, AND SULFHEMOGLOBIN. AN INCR IN THE LEVELS OF METHEMOGLOBINS AND SULFHEMOGLOBINS WAS ACCOMPANIED BY A DECR IN OXYHEMOGLOBIN, BUT THE TOTAL LEVEL OF HEMOGLOBIN REMAINED UNCHANGED. [R34] *BECAUSE INTESTINAL BACTERIA ARE KNOWN TO BE INVOLVED IN THE METABOLIC ACTIVATION OF OTHER NITROAROMATIC COMPOUNDS, THE GENOTOXICITY OF NITROTOLUENE WAS EVALUATED USING AN IN VIVO-IN VITRO HEPATOCYTE DNA REPAIR ASSAY. 3-NITROTOLUENE WAS ADMIN BY GAVAGE TO MALE F344 RATS. AT SELECTED TIMES AFTER TREATMENT, PRIMARY HEPATOCYTE CULTURES WERE PREPARED AND INCUBATED WITH (3)H-THYMIDINE, AND UNSCHEDULED DNA SYNTHESIS WAS ASSESSED BY QUANTITATIVE AUTORADIOGRAPHY. CORN OIL CONTROLS RANGED FROM 3-6 NET GRAINS/NUCLEUS (NG). 3-NITROTOLUENE DID NOT INDUCE DNA REPAIR. [R35] *The mutagenicities of the o, m, and p-isomers of nitrotoluene ... were tested with or without S9 mix and norharman in the Salmonella assay system. None of the cmpds was mutagenic without norharman. ... The induction of mutagenesis with norharman was strong for the o-isomer, weak for the p-isomer, and was not observed for m-isomer. [R36] *p-Nitrotoluene, o-nitrotoluene, and m-nitrotoluene were examined for mutagenic activity in TA92, TA1535, TA100, TA94, and TA98 strains of S Typhimurium in the presence and absence of hepatic 9000 x g supernatant (S9) containing the reduced form of nicotinamide-adenine dinucleotide phosphate generating system. ... The S9 fraction was prepared from livers of rats and mice after induction with KC400. p-Nitrotoluene (0.1-1 mg/plate) increased slightly Hist revertants/plate in TA100 over the spontaneous level in the presence of rat liver S9. ... No mutagenic effects were observed in the remaining chemicals, but these compounds had killing effects at 1-3 mg/plate in both the presence and absence of S9. ... [R37] *To determine whether hepatic macromolecular covalent binding of mononitrotoluene isomers to hepatic DNA in vivo was decreased by inhibitors of sulfotransferase, male Fischer 344 rats were given a single oral dose of ring-U-14C-labeled 2-, 3-, or 4-nitrotoluene, and were killed at various times thereafter. Livers were removed and analyzed for total and covalently bound radiolabel. Maximal concentrations of total radiolabel were observed between 3 and 12 hr after the dose, and there were no large differences among the 3 isomers in peak concentrations achieved. Covalent binding to hepatic macromols was maximal 12 hrs after administration for all 3 isomers. Thereafter, concn of administration for all 3 isomers. Thereafter, concn of covalently bound 2-nitrotoluene derived material were always 2-6 times higher than those of 3- or 4-nitrotoluene derived material. When DNA was isolated from livers of rats given mononitrotoluene isomers 12 hrs previously, only 2-nitrotoluene was observed to covalently bind at concns above the limits of detection of the assay. The covalent binding of 2-nitrotoluene, but not that of 3- or 4-nitrotoluene, to both total hepatic macromols and DNA was markedly decreased by prior administration of pentachlorophenol or 2,6-dichloro-4-nitrophenol. Covalent binding to hepatic DNA was decreased by > 96%. Thus, 2-nitrotoluene, but not 3- or 4-nitrotoluene, induces DNA excision repair. Furthermore, 2-nitrotoluene, like the hepatocarcinogen 2,6-dinitrotoluene, may require the action of sulfotransferase for its conversion to a species capable of covalently binding to hepatic DNA. [R38] ETXV: *LC50 Pimephales promelas (fathead minnow) 25.6 mg/l/96 hr (confidence limit - not reliable), flow-through bioassay with measured concentrations, 25.3 deg C, dissolved oxygen 7.6 mg/l, hardness 45.1 mg/l calcium carbonate, alkalinity 41.6 mg/l calcium carbonate, and pH 7.49; [R39] POPL: *Preclude from exposure those individuals with anemia, cardiovascular or pulmonary diseases. [R31] *Persons with blood disorders may be at increased risk from exposure. /Nitrotoluene/ [R15, 1981.1] ADE: *IT MAY BE ABSORBED THROUGH THE INTACT SKIN AND THROUGH THE RESP TRACT. /SRP: ALSO ABSORBED FOLLOWING INGESTION/. [R40] METB: *... Metabolism and excretion of 2-, 3-, and 4-nitrotoluene ... were studied in male Fischer 344 rats. ... Major metabolites excreted in urine in 72 hr after administration of 3-nitrotoluene were 3-nitrohippuric acid (24% of the dose), 3-nitrobenzoic acid (21% of the dose) and 3-acetamidobenzoic acid (12% of the dose). ... [R41] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *3-Nitrotoluene may be released to the environment during its use as a chemical intermediate in industries producing dyes, explosives and pesticides. If released to the atmosphere, vapor-phase 3-nitrotoluene may degrade by direct photolysis or by reaction with photochemically produced hydroxyl radicals (estimated half-life of 16.9 days). If released on soil, 3-nitrotoluene may leach (estimated Koc of 143), degrade by direct photolysis or evaporate from dry soil surfaces. Data are available which suggest that 3-nitrotoluene may be susceptible to aerobic and anaerobic biodegradation in water with an acclimation sufficient period and the presence of specific degraders in the microbial community. Although these studies are not specific to soil media, they suggest that biodegradation in soil may be important. If released to water, biodegradation, photolysis (photolysis half-life of 0.11 days in near surface water) and volatilization are expected to be the dominant removal processes. Based on monitoring data, the half-life of 3-nitrotoluene in a river 4 to 5 meters deep has been estimated to be 2.7 days. Photolysis will be expected to increase in waters containing humic substances. Volatilization half-lives of 16 hrs and 10 days have been estimated for a model river (one meter deep) and a model environmental pond, respectively. Hydrolysis, adsorption to sediment and bioconcentration in aquatic organisms are not expected to be environmentally significant fate processes in aquatic systems. In occupational settings, exposure to 3-nitrotoluene of vapors and through eye and skin contact. (SRC) ARTS: *3-Nitrotoluene may be released to the environment during its use as a chemical intermediate in industries producing dyes, explosives and pesticides(1). [R42] FATE: *TERRESTRIAL FATE: Based on an extrapolated vapor pressure of 0.207 mm Hg at 25 deg C(7), 3-nitrotoluene may evaporate from most soil surfaces(SRC). Based on the UV absorption spectra(8), 3-nitrotoluene may photolyze if spilled on soil surfaces(SRC). Available data suggest that 3-nitrotoluene may be susceptible to aerobic and anaerobic biodegradation in water with a sufficient acclimation period and the presence of specific degraders in the microbial community(1-4). Although these studies are not specific to soil media, they suggest that biodegradation in soil may be important(SRC). An estimated Koc value of 143 indicates high mobility in soil and significant leaching may occur(5,6,SRC). [R43] *AQUATIC FATE: Based on monitoring data, the half-life of 3-nitrotoluene in a river 4 to 5 meters deep has been estimated to be 2.7 days(1). Volatilization half-lives of 16 hr and 10 days have been estimated for a model river (one meter deep) and a model environmental pond, respectively, indicating that volatilization from water may not be rapid(2,3). 3-Nitrotoluene may be susceptible to aerobic biodegradation in water provided a sufficient acclimation period and the presence of specific degraders in the microbial community(5-8,SRC). It may also be susceptible to anaerobic biodegradation given sufficient acclimation(7); however, data are limited. The photolysis half-life in pure water near the surface at latitude 40 deg N has been experimentally determined to be 0.11 days; furthermore, the photolysis rate has been experimentally determined to increase in waters containing humic substances(9). Aromatic nitro compounds are generally resistant to hyrolysis(2). An estimated Koc of 143(2), estimated BCF of 19-40(2), and an experimental BCF of 16 in fish (Poecilia reticulata)(4), suggest that adsorption to sediment and bioconcentration in aquatic organisms will not be significant(SRC). [R44] *Based on an extrapolated vapor pressure of 0.207 mm Hg at 25 deg C(4), 3-nitrotoluene is expected to exists almost entirely in the vapor-phase in the ambient atmosphere(1,SRC). Vapor phase 3-nitrotoluene is degraded in the ambient atmosphere by reaction with photochemically formed hydroxyl radicals; the half-life for this reaction in air can be estimated to be about 16.9 days(2,SRC). 3-Nitrotoluene exhibits a broad absorption spectrum extending from the UV to the short-wavelength visible region(3) suggesting that photolysis of 3-nitrotoluene will be a dominant removal process in air(SRC). [R45] BIOD: *3-Nitrotoluene (initial concn of 41 ppm) showed approximately 5% biodegradation after an incubation period of 4 weeks when acclimated for 21 days under aerobic conditions in a static test using domestic sewage inoculum at 25 deg C; however, in a die-away test using an inocula consisting of activated sludge and an extract of river mud at 25 deg C, 3-nitrotoluene (initial concn of 41 ppm) exhibited > 90% biodegradation after 3 weeks of incubation when acclimated for 21 days(1). It showed no degradation when unacclimated in a similar die-away test suggesting that acclimation was necessary for significant biodegradation(1). In one aerobic screening study using activated sludge inoculum, 3-nitrotoluene at an initial concn of 200 ppm exhibited 98.5% removal in a 5 day incubation period when acclimated for 20 days at 20 deg C(2). Based on this study, the rate of biodegradation when acclimated was experimentally determined to be 21.0 mg COD/g-hr(2). Based on a 50% loss of UV absorbance after an incubation period of 12 days, 3-nitrotoluene (initial concn of 10 ppm) showed significant biodegradation when acclimated in another aerobic screening study using sewage inoculum at pH 7.3-8.5 and 29 deg C(3). In the same study carried out under anaerobic conditions, 3-nitrotoluene exhibited 95% loss of UV absorbance in 12 days(3). In one aerobic screening study, slow biodegradation (0-29% BODT) was observed for 3-nitrotoluene (initial concn of 100 ppm) when unacclimated using the Japanese MITI test after an incubation period of 14 days using activated sludge inoculum at pH 7 and 25 deg C(4). [R46] ABIO: *The rate constant for the vapor-phase reaction of 3-nitrotoluene with photochemically produced hydroxyl radicals has been experimentally determined to be 9.5E-13 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of 16.9 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). 3-Nitrotoluene exhibits a broad absorption spectrum extending from the UV to the short-wavelength visible region(3) suggesting that photolysis of 3-nitrotoluene will be a dominant removal process when exposed to sunlight(SRC). The photolysis rate constant in pure water for 3-nitrotoluene in near surface water at latitude 40 deg N has been experimentally determined to be 6.5 1/days which corresponds to a half-life of 0.11 days; furthermore, the photolysis rate has been experimentally determined to increase in waters containing humic substances(2). Aromatic nitro compounds are generally resistant to hydrolysis(4). [R47] BIOC: *The BCF for 3-nitrotoluene in fish (Poecilia reticulata) has been experimentally determined to be 16(1). Based on a measured log Kow of 2.45(2) and a measured water solubility of 498 mg/L at 30 deg C(4), the BCF for 3-nitrotoluene can be estimated to range from 19 to 49 using recommended regression derived equations(3,SRC). These BCF values suggest that 3-nitrotoluene would not bioconcentrate significantly in aquatic organisms(SRC). [R48] KOC: *Based on a measured water solubility of 498 mg/L at 30 deg C(2), the Koc for 3-nitrotoluene can be estimated to be 143 using a recommended regression derived equation(1,SRC). This Koc value suggests that 3-nitrotoluene has high mobility in soil and may leach(3). [R49] VWS: *Based on a measured water solubility of 498 mg/L at 30 deg C(1) and an extrapolated vapor pressure of 0.207 mm Hg at 25 deg C(3), the Henry's Law constant for 3-nitrotoluene can be estimated to be approximately 7.5E-5 atm-cu m/mole at 25-30 deg C(SRC). This value of Henry's Law constant suggests that volatilization from water and soil is not rapid but possibly significant(2). Based on this value, the volatilization half-life of 3-nitrotoluene from a model river 1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec has been estimated to be approximately 16 hrs(2,SRC). The volatilization half-life from a model environmental pond has been estimated to be about 10 days(4). [R50] WATC: *SURFACE WATER: 3-Nitrotoluene has been detected at a concn of 1 ug/L in Rhine river water(1). It has also been qualitatively detected in the Rhine river on several other occasions(2). [R51] RTEX: *3-Nitrotoluene is used as a chemical intermediate in industries producing dyes, explosives and pesticides(1). In occupational settings, exposure to 3-nitrotoluene may occur through inhalation of vapors(2) and through eye and skin contact(SRC). [R52] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +200 ppm [R9, 232] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (30 mg/cu m). Skin Designation. /Nitrotoluene (all isomers)/ [R53] +Vacated 1989 OSHA PEL TWA 2 ppm (11 mg/cu m), skin designation, is still enforced in some states. /Nitrotoluene (o-, m-, p- isomers)/ [R9, 369] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 2 ppm (11 mg/cu m), skin. [R9, 232] TLV: +8 hr Time Weighted Avg (TWA): 2 ppm, skin. /Nitrotoluene, all isomers/ [R54, 2002.45] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Nitrotoluene, all isomers/ [R54, 2002.6] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R54, 2002.91] CWA: +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R55] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 2005. Analyte: o-Nitrotoluene. Matrix: Air. Sampler: Solid sorbent tube (silica gel, 150 mg/75 mg). Flow Rate: 0.01 to 0.21 l/min. Sample Size: 1 to 30 liters. Shipment: Routine. Sample Stability: Unknown. [R57] *... Detector tubes certified by NIOSH under 42 CFR part 84 or other direct-reading devices calibrated to measure nitrotoluene may be used /to determine the amount of nitrotoluene in air/. /Nitrotoluene/ [R15, 1981.2] ALAB: *KNOWN MIXT OF O-NITROTOLUENE, M-NITROTOLUENE, AND P-NITROTOLUENE IN AIR OF INDUSTRIAL INSTALLATIONS WERE ANALYZED BY GAS CHROMATOGRAPHY. THE MINIMUM CONCN OF THE ISOMERS WAS 1X10-6 G/ML, TIME FOR EACH DETERMINATION 10 MIN, AND THE ABSOLUTE ERROR 9%. [R58] *NIOSH Method 2005. Analyte: o-Nitrotoluene. Matrix: Air. Procedure: Gas chromatography, flame ionization detection. For o-nitrotoluene, this method has an estimated detection limit of 0.0008 for a 20 liter sample. The precision/RSD is 0.062 and the recovery is not given. Applicability: The working range is 0.25 to 52 mg/ cu m for a 25 liter sample. Interferences: None identified. /o-Nitrotoluene/ [R57] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of o-, m-, and p-Nitrotoluenes Administered in Dosed Feed to F344/N Rats and B6C3F1 Mice Toxicity Rpt Series No. 23 NIH Publication No. 93-3346 (1992) SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1051 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. 929 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 809 R4: AKIMOTO H ET AL; ISS EPA-600/3-77-001B, INT CONF PHOTOCHEM OXID POLLUT CONTROL PROC: VOL 2; PB-264 233: 737-44 (1977) R5: KANAGAWA-KEN TAIKI OSEN CHOSA KENKYU HOKOKU 19: 125-7 (1977) R6: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R7: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 833 R8: USITC IMPORTS OF BENZENOID CHEMICALS AND PRODUCTS 1983 p.24 R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R10: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 670 R11: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 86/8607 R12: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R13: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-676 R14: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, June 1984. 76 R15: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R16: Keith, L.H., D.B. Walters, (eds.). Compendium of Safety Data Sheets for Research and Industrial Chemicals. Parts I,II,and III. Deerfield Beach, FL: VCH Publishers, 1985. R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-527 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 369 R19: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 9th ed. Boston, MA: National Fire Protection Association, 1986.,p. 325M-75 R20: Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Design Inst Phys Prop Data Amer Inst Chem Eng NY,NY: Hemisphere Pub Corp Vol.4 (1989) R21: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-152 R22: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1884 R23: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-74 R24: Bureau of Explosives; Emergency Handling of Haz Matl in Surface Trans p.375 (1981) R25: 49 CFR 171.2 (7/1/96) R26: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 187 R27: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6187 (1988) R28: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.501 R29: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-46 (1982) R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 66 430 (1996) R31: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 381 R32: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.444 R33: KOVALENKO II; FARMAKOL TOKSIKOL (KIEV) 8: 137-40 (1973) R34: VASILENKO NM ET AL; SOVREM PROBL BIOKHIM DYKHANIYA KLIN, MATER VSES KONF, 2ND 1: 411-3 (1972) R35: DOOLITTLE DJ ET AL; CANCER RES 43 (6): 2836-42 (1983) R36: Suzuki J et al; Mutat Res 120 (2-3): 105-110 (1983) R37: Miyata R et al; Eisei Shikensho Hokoku 99: 60-5 (1981) R38: Rickert DE et al; Chem-Biol Interact 52 (2): 131-9 (1984) R39: Geiger D.L., Poirier S.H., Brooke L.T., Call D.J., eds. Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Vol. III. Superior, Wisconsin: University of Wisconsin-Superior, 1986.161 R40: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 2148 R41: Chism JP et al; Drug Metab Dispos 12 (5): 596-602 (1984) R42: (1) Struijs J, Stoltenkamp J; Sci Total Environ 57: 161-70 (1986) R43: (1) Struijs J, Stoltenkamp J; Sci Total Environ 57: 161-70 (1986) (2) Pitter P; Water Res 10: 231-35 (1976) (3) Hallas LE, Alexander M; Appl Environ Microbiol 45: 1234-41 (1983) (4) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-9, 5-10, 7-4, 15-15 to 15-32 (1990) (6) Swann RL et al; Res Rev 85: 17-28 (1983) (7) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Design Inst Phys Prop Data Amer Inst Chem Eng NY,NY: Hemisphere Pub Corp Vol.4 (1989) (8) Sadtler; Sadtler Standard Spectra Philadelphia, PA: Sadtler Research Lab R44: (1) Zoeteman BCJ et al; Chemosphere 9: 231-49 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-9, 5-10, 7-4, 15-15 to 15-32 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) (4) Canton JH et al; Regul Toxicol Pharmacol 5: 123-31 (1985) (5) Struijs J, Stoltenkamp J; Sci Total Environ 57: 161-70 (1986) (6) Pitter P; Water Res 10: 231-35 (1976) (7) Hallas LE, Alexander M; Appl Environ Microbiol 45: 1234-41 (1983) (8) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (9) Simmons MS, Zepp RG; Wat Res 20: 899-904 (1986) R45: (1) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (2) Atkinson R; Kinetics and Mechanisms of the Gas-Phase Reactions of the Hydroxyl Radical with Organic Compounds J Chem Ref Data Monograph No 1 NY: Amer Inst Phy p. 220 (1989) (3) Sadtler; Sadtler Standard Spectra Philadelphia, PA: Sadtler Research Lab (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Design Inst Phys Prop Data Amer Inst Chem Eng NY,NY: Hemisphere Pub Corp Vol.4 (1989) R46: (1) Struijs J, Stoltenkamp J; Sci Total Environ 57: 161-70 (1986) (2) Pitter P; Water Res 10: 231-35 (1976) (3) Hallas LE, Alexander M; Appl Environ Microbiol 45: 1234-41 (1983) (4) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) R47: (1) Atkinson R; Kinetics and Mechanisms of the Gas-Phase Reactions of the Hydroxyl Radical with Organic Compounds J Chem Ref Data Monograoph No 1 NY: Amer Inst Phy p. 220 (1989) (2) Simmons MS, Zepp RG; Wat Res 20: 899-904 (1986) (3) Sadtler; Sadtler Standard Spectra Philadelphia, PA: Sadtler Research Lab (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 7-4 (1990) R48: (1) Canton JH et al; Regul Toxicol Pharmacol 5: 123-31 (1985) (2) Hansch C, Leo AJ; Medchem Project Issue No 26; Pomona College Claremont, CA (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 5-4, 5-10 (1990) (4) Gross PM et al; J Am Chem Soc 55: 650-2 (1933) R49: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1990) (2) Gross PM et al; J Am Chem Soc 55: 650-2 (1933) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R50: (1) Gross PM et al; J Am Chem Soc 55: 650-2 (1933) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill pp. 15-15 to 15-32 (1990) (3) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Design Inst Phys Prop Data Amer Inst Chem Eng NY,NY: Hemisphere Pub Corp Vol.4 (1989) (4) USEPA; EXAMS II Computer Simulation (1987) R51: (1) Piet GJ, Morra CF; pp 31-42 in Artificial Groundwater Recharge (Water Resources Engineering Series) Huisman L, Olsthorn TN eds Pitman Pub (1983) (2) Struijs J, Stoltenkamp J; Sci Total Environ 57: 161-70 (1986) R52: (1) Struijs J, Stoltenkamp J; Sci Total Environ 57: 161-70 (1986) (2) Amoore JE, Hautala E; J Appl Toxicol 3: 272-290 (1983) R53: 29 CFR 1910.1000 (7/1/98) R54: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R55: 40 CFR 116.4 (7/1/90) R56: 40 CFR 302.4 (7/1/90) R57: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2005-1 R58: IVANYUK EG, KOLIEVSKAYA YA; ZAVOD LAB 43 (2): 157-8 (1977) RS: 51 Record 206 of 1119 in HSDB (through 2003/06) AN: 2952 UD: 200208 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-BASIC-RED-9- SY: *BASIC-PARAFUCHSINE-; *BENZENAMINE, 4-((4-AMINOPHENYL)(4-IMINO-2,5-CYCLOHEXADIEN-1-YLIDENE)METHYL)-, MONOHYDROCHLORIDE; *CALCOZINE-MAGENTA-N-; +CI-BASIC-RED-9-; *CI-BASIC-RED-9,-MONOHYDROCHLORIDE-; *CI-42500-; *P-FUCHSIN-; *FUCHSINE-DR-001-; *FUCHSINE-SP-; *FUCHSINE-SPC-; *4,4'-((4-IMINO-2,5-CYCLOHEXADIEN-1-YLIDENE)METHYLENE)DIANILINE MONOHYDROCHLORIDE; *PARA-MAGENTA-; *PARAFUCHSIN-; *PARAFUCHSINE-; *PARAFUCHSIN- (GERMAN); *PARAOSANILINE-HYDROCHLORIDE-; *PARAROSANILINE-; *PARAROSANILINE-CHLORIDE-; *P-ROSANILINE-HYDROCHLORIDE-; *SCHULTZ-TAB-NO-779-; *4-TOLUIDINE, ALPHA-(P-AMINOPHENYL)-ALPHA-(4-IMINO-2,5-CYCLOHEXADIEN-1-YLIDENE)-MONOHYDROCHLORIDE; *4,4',4"-TRIAMINOTRIPHENYLMETHANE HYDROCHLORIDE; *4,4',4"-TRIAMINOTRIPHENYLMETHAN-HYDROCHLORID (GERMAN) RN: 569-61-9 MF: *C19-H17-N3.Cl-H MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ANILINE WITH FORMALDEHYDE, IN THE PRESENCE OF HYDROGEN CHLORIDE, FORMING P,P'-METHYLENEDIANILINE, WHICH IS THEN HEATED WITH ANILINE AND ANILINE HYDROCHLORIDE IN THE PRESENCE OF NITROBENZENE AND FERRIC CHLORIDE [R1] FORM: *Available commercially as a certified biological stain at a purity of approximately 95%; it is also available at a purity of at least 88% [R2] *A mixture of three parts pararosaniline acetate and one part pararosaniline hydrochloride [R3, 124] *Certifiable grade [R3, 124] MFS: *DYE SPECIALTIES, INC, JERSEY CITY, NJ 07306 [R1] *Aldrich Chemical Co, Hq, 101 West Saint Paul Ave, Milwaukee, WI 53233 (800) 558-9160 [R4] OMIN: *A TRIPHENYLMETHANE DYE. ... COMPONENT OF FUCHSIN. [R3, 874] *BASIC FUCHSIN NF XIII [BASIC MAGENTA]- A MIXTURE OF ROSANILINE AND PARAROSANILINE HYDROCHLORIDE. ... POSSESSES MODERATE ANTIFUNGAL AND ANTIBACTERIAL ACTIVITY. [R5] *Produced by one company in Brazil and by two companies in the US (companies not reported) [R6] *No recent data available (1993) on production of CI Basic Red 9 [R6] USE: *DYE FOR TEXTILES (SILKS AND ACRYLICS), LEATHER, AND PAPER; COMPONENT OF MAGENTA (FUCHSIN) DYE; BIOLOGICAL STAIN [R1] *For staining bacilli, especially influenza and tubercle, in tissue and for acid-fast bacteria using methylene blue as counterstain. [R4] *For staining tubercle bacillus and in distinguishing between the coli and aerogenes types of bacteria in the Endo medium; also used in the periodic acid-Schiff (PAS) method, the Feulgen stain, and in Gomoris aldehyde- function method for staining elastic tissue [R3, 124] *Have been used extensively as textile dyes...current use is mainly for non- textile purposes...such as printing inks, high-speed photoduplicating and photoimaging systems; specialty applications such as tinting automobile antifreeze solutions and toilet sanitary preparations, in the mfg of carbon paper, in ink and typewriter ribbons and in jet printing for high-speed computer printers; may be used to color other substrates; extensively used as microbiological stains /Triarylmethane dyes including Basic Parafuchsine/ [R6] *Can be N-phenylated with excess aniline and benzoic acid to form CI Solvent Blue 23 [R6] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1992) No data [R7] *The 1977 production estimate was 1-10 million lbs [R8] U.S. IMPORTS: *(1972) ND [R1] *(1974) 2.0X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] U.S. EXPORTS: *(1972) ND [R1] *(1975) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS TO RED CRYSTALS [R3, 874]; *Dark-green crystalline powder [R9] MP: *268-270 deg C (decomposes) [R9] MW: *323.82 [R9] OWPC: *log Kow = -0.21 [R10] SOL: *SOL IN ALCOHOL; VERY SLIGHTLY SOL IN WATER AND ETHER [R3, 651]; *Soluble in water (2-3 mg/ml), ethanol (2-25 mg/ml) ethylene glycol methyl ether (50-70 mg/ml) and methanol [R9] SPEC: *IR: 3761 (Coblentz Society Spectral Collection) [R11]; *UV: 21403 (Sadtler Research Laboratories Spectral Collection) [R11]; *NMR: 17293 (Sadtler Research Laboratories Spectral Collection) [R11] OCPP: *CATIONIC [R12, 434] *Destroyed by strong oxidizing agents; readily reduced to leuco-bases with a variety of reducing reagents sensitive to photochemical oxidation [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *COMBUSTIBLE. [R13] DCMP: *Destroyed by strong oxidizing agents; readily reduced to leuco-bases with a variety of reducing reagents sensitive to photochemical oxidation [R9] +When heated to decomposition ... emits very toxic fumes of /hydrogen chloride and nitrogen oxides/. [R14] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R15, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R15, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R15, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R15, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R15, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R15, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R15, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R15, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R15, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R15, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R15, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R15, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R15, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R15, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R15, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R15, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R15, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R15, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R15, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. [R16] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R15, 1979.23] NTOX: *...INJURIOUS TO RABBIT EYES. /BY APPLICATION OF 4 TO 8 MG OF POWDERED DYE TO CONJUNCTIVAL SAC OR BY IRRIGATING SURFACE OF EYE FOR 10 MIN/ [R12, 434] *Basic red 9 was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Basic red 9 was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.001, 0.003, 0.010, 0.033, 0.100, 0.666, and 1.000 mg/plate. The compound was positive in strains TA100 and TA98 when tested with hamster liver activation. The lowest positive dose tested was 0.033 mg/plate in strain TA100. [R17] *Groups of 40 male and 40 female Sprague-Dawley rats, 12 weeks old, were treated intragastrically twice a week with 0 or 600 mg/kg body weight CI Basic Red 9 (purity unspecified) in 0.9% saline. The dos of 600 mg/kg was found to be toxic and after 12 weeks, treatment was discontinued for one week.; after a further six weeks, half of the original dose (300 mg/kg body weight) was used for the remaining treatment, for life. Average survival times were 104 weeks for control males, 70 weeks for treated males, 92 weeks for control female and 69 weeks for treated females. No treatment-related increase in the incidence of tumors was observed in rats of either sex. [R18] *Groups of hamsters were treated intrgastrically with 0, 300, or 600 mg/kg body weight CI Basic Red 9 (purity unspecified) in 0.9% saline solution twice a week for life. In the high-dose group, the majority of animals died within the first 10 weeks of treatment; the lower dose was well tolerated, and body weight development and average survival times were similar to those of controls. After 72 weeks of treatment, 17/40 control and 15/40 low-dose males and 3/40 control and 3/40 low-dose females were still alive; by 88 weeks of treatment, all treated and control animals had died. Not treatment-related increase in the incidence of tumors was observed in hamsters of either sex. [R19] *A group of 20 BD III rats (sex unspecified) was treated once a week with 10 mg of an aqueous solution of 1% CI Basic Red 9 (purity unspecified) for a maximum of 515 days (total dose, 650 mg). The mean life span was 545 days in treated rats and 780 days in controls. The first local sarcoma appeared at 300 days, after a total dose 370 mg of the dye. Spindle-cell sarcoma were found in 7/12 rats surviving after the appearance of the first tumor, compared to a spontaneous incidence of sarcomas in these rats of less than 0.5%. [R20] *CI Basic Red 9 induced repairable DNA damage in bacterial differential toxicity assays in the absence of activation. It was generally not mutagenic to Salmonella typhimurium; some activity was observed in the presence of exogenous activating systems, especially those derived from Syrian hamster liver. IT induced forward mutation in Escherichia coli int eh absence of exogenous metabolism. It din not induce mitotic recombination in Saccharomyces cerevisiae. [R21] *Conflicting reports were obtained for induction of unscheduled DNA synthesis in rats hepatocyte in vitro: in a single study, it induced unscheduled DNA synthesis in primary hepatocyte from Syrian hamsters but not from rats. The compound gave inconclusive responses in two tests for mutation at the tk locus in mouse lymphoma L5178Y cells and positive responses in another. CI Basic Red 9 did not induce chromosomal rearrangement or sister chromatid exchange in Chinese hamster ovary cells. It induced morphological transformation of Syrian hamster embryo cell in the presence, but not in the absence, of an exogenous activating system from hamster liver. It also induced transforation of G BALBc/3T3 mouse cells and enhanced Rauscher leukaemia virus-induced cells. [R21] *Oral administration of CI Basic Red 9 to mice or rats resulted in urine that was mutagenic to Salmonella typhimurium. The dye did not induce mitotic recombination in Saccharomyces cerevisiae or mutation in Salmonella typhimurium recovered from the peritoneal cavity of mice, and it did not induce mutation in Salmonella typhimurium after intramuscular administration. [R21] *Detectlon of mutagenic activity of p-rosaniline-hydrochloride in urine of male and female rats and mice without subjecting the urine to extraction or concentration procedures and the utility of pretreating urine with beta-glucuronidase versus incorporating the deconjugating enzyme at the time of plating were evaluated. Male Fischer 344 rats were fed diets with 1000 to 2000 parts per million p-rosaniline; female Fischer 344 rats and male and female B6C3F1 mice were fed diets with 500 to lOOO ppm p-rosaniline. Overnight urine samples were collected weekly over the 4 week treatment period. Neat urine was tested without S9 on Salmonella tester strains TA98, TA100, TA1535 and TA1537 at 0.75, 0.5, 0.2 and 0.05 milliliters per plate. Samples were also tested in the presence of S9 on TA100 when sufficient urine was available. Urine samples were either pretreated with beta-glucuronidase for 18 hours or the enzyme was added to the top agar at the time of plating. When using the nonpretreatment method direct acting mutagenic activity was detected in the urine from male mice. Although direct acting mutagenic activity was not detected in urine of male or female rats or female mice, mutagenic activlty was observed in the presence of S9 in urine of male rats and male and female mice. Detection of mutagenic activity in the presence of S9 was more efficient when the pretreatment method was used. Both the pretreatment and nonpretreatment methods should be used for detection of mutagenic activity in neat urine in order to obtain maximal recovery of induced revertants. [R22] *Thirty agents inducing direct nonreparable DNA damage in repair deficient Escherichia coli failed in reverting strains TA1535 TA1537 TA1538 TA98 and TA100 of Salmonella typhimurium. These compounds were reassayed in the Ames test using strains TA97 and TA102. A dose dependent mutagenic response was detected with p-rosaniline in TA97. p-Rosaniline was the only mutagen requiring metabolic activation. [R23] +... Under the conditions of these 2 yr feed studies, there was ... evidence of carcinogenicity of C.I. Basic Red 9 monohydrochloride in male and female F344/N rats and in male and female B6C3F1 mice. In male rats, /the cmpd/ caused squamous cell carcinomas, trichoepitheliomas and sebaceous adenomas of the skin, subcutaneous fibromas, thyroid gland follicullar cell adenomas and follicular cell carcinomas, Zymbal gland carcinomas, and hepatocellular carcinomas. In female rats, /the cmpd/ caused subcutaneous fibromas, thyroid gland follicular cell adenomas or carcinomas (combined), and Zymbal gland carcinomas. In male mice, /the cmpd/ caused hepatocellular carcinomas. In female mice, /the cmpd/ caused hepatocellular carcinomas and adrenal gland pheochromocytomas or malignant pheochromocytomas (combined). ... [R24] NTP: +... Toxicology and carcinogenesis studies were conducted by administering the test chemical in feed to groups of 50 male and 50 female F344/N rats and B6C3F1 mice for 103 wk at concentrations of 0, 1,000 or 2,000 ppm for male rats and 0, 500 or 1,000 ppm for female rats and mice of each sex. The avg daily doses of C.I. Basic Red 9 monohydrochloride were estimated to be 49 and 103 mg/kg for male rats, 28 and 59 mg/kg for female rats, 196 and 379 mg/kg for male mice, and 149 and 407 mg/kg for female mice. Two lots of the test chemical were used in the 2 yr studies with purities of 93% (water content approx 9%) and 99%. ... Under the conditions of these 2 yr feed studies, there was ... evidence of carcinogenicity of C.I. Basic Red 9 monohydrochloride in male and female F344/N rats and in male and female B6C3F1 mice. In male rats, /the cmpd/ caused squamous cell carcinomas, trichoepitheliomas and sebaceous adenomas of the skin, subcutaneous fibromas, thyroid gland follicullar cell adenomas and follicular cell carcinomas, Zymbal gland carcinomas, and hepatocellular carcinomas. In female rats, /the cmpd/ caused subcutaneous fibromas, thyroid gland follicular cell adenomas or carcinomas (combined), and Zymbal gland carcinomas. In male mice, /the cmpd/ caused hepatocellular carcinomas. In female mice, /the cmpd/ caused hepatocellular carcinomas and adrenal gland pheochromocytomas or malignant pheochromocytomas (combined). ... [R24] INTC: *...0.01 MOLAR NEAR-NEUTRAL SOLN OF PARAROSANILINE...AFTER...BEEN REDUCED AND RENDERED...COLORLESS BY ADDITION OF 1% TO 2% SODIUM HYDROSULFITE CAUSE RELATIVELY SLIGHT CORNEAL OPACIFICATION...WHEREAS...WITHOUT REDUCTION CAUSE SEVERE OPACIFICATION AND VASCULARIZATION. [R12, 436] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A rapid method for assay (Knecht method) is titration with titanium trichloride to a colorless end-point [R9] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I Basic Red 9 Monohydrochloride (Pararosaniline) in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 285 (1986) NIH Publication No. 86-2541 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 218 (1993 ) R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R4: The Aldrich Catalog/Handbook of Fine Chemicals 1994-95, Aldrich Chem Co, Milwaukee, WI, pp 129 (1994) R5: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1169 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 219 (1993) R7: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994. R8: NTP; NTP Technical Report on the Toxicology and Carcinogenesis Studies of C.I. Basic Red 9 Monohydrochloride (Pararosaniline) (CAS No. 569-61-9) in F344/N Rats and B6C3F1 Mice. TR 285, NIH Publ No 86-2541, US Dept of Health and Human Services, NIH, National Toxicology Program, Research Triangle Park, NC p. 18 (1986) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 217 R10: Tsai RS et al; J Chromatogr 538: 119-23 (1991) R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 401 R12: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. R13: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 651 R14: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2884 R15: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 230 (1993) R17: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 223 (1993) R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 224 (1993) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 225 (1993) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 226 (1993) R22: Lawlor TE et al; Environmental Mutagenesis 9 (1): 69-78 (1987) R23: De Flora et al; Mutat Res 134 (2-3): 159-66 (1985) R24: Toxicology and Carcinogenesis Studies of C.I. Basic Red 9 Monohydrochloride (Pararosaniline) in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 285 (1986) NIH Publication No. 86-2541 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 RS: 33 Record 207 of 1119 in HSDB (through 2003/06) AN: 2957 UD: 200302 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: AMOSITE- SY: +AMOSITE-ASBESTOS-; +BROWN-ASBESTOS-; +MYSORITE- RN: 12172-73-5 RELT: 511 [ASBESTOS] (Mixture) MF: +UVCB MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +The mineral is mined or quarried with its parent rock. [R1] +Imbedded asbestos fibers are removed from the ore by a repeated series of crushing, fiberizing, screening, aspirating, and grading operations (milling). ... The ore is crushed, dried, and fiberized in a variety of impact mills. The short fiber and granular material is removed by screening the fiberized mass. The oversized fractions are stratified on a screen where the spherical, granular material of high density seeks the screen's surface and the fluffy, low-density fiber rises to the top of the bed. At the end of the screen, the fiber is separated from the rock by an aspirating hood. ... Fibers recovered from these primary screening operations are rescreened to removed entrapped granular material and classified into grades by fiber length. ... Conventional asbestos milling uses large quantities of air both for separating the fibers as they are freed from the ore and for dust control. Approx 130 cu m/sec (275,000 cfm) are used to process one metric ton of ore. Preconcentration of ore includes selective grinding, screening, and magnetic techniques. /Asbestos cmpd/ [R2, p. 3(78) 279] +The material from the separating mill was largely unopened bundles of fibers. For many purposes it was necessary to open the fiber by separating the bundles into their constituent fibres, which greatly increases the bulk of the material. In the asbestos textile industry the material is passed through several types of mills which separate the fibres before they are passed into the carding machines in which they undergo the 1st stage of asbestos yarn prodn. ... /During/ recent years more of the fibre is "opened" at the mills. /Asbestos cmpd/ [R1] FORM: +CHEMICAL RANGE OF ASBESTOS TYPES: AMOSITE: SILICON DIOXIDE 49-53%; IRON OXIDE 34-44%; MAGNESIUM OXIDE 1-7%; SODIUM MONOXIDE TRACE; POTASSIUM OXIDE 0-0.4%; WATER: 2.5-4.5%. COMMON TRACE ELEMENTS: SILVER, BARIUM, CERIUM, COBALT, CHROMIUM, COPPER, LITHIUM, MANGANESE, MOLYBDENUM, NIOBIUM, NICKEL, SCANDIUM, STRONTIUM, THORIUM, VANADIUM, AND ZIRCONIUM. /FROM TABLE/ [R3] MFS: +AMOSITE IS MINED ONLY IN SOUTH AFRICA. THE FOLLOWING USA COMPANIES, HOWEVER, REPORTEDLY PROCESS THE ORE: ASARCO INC (AMPHIBOLES), NEW YORK, NY 10005; CELLULO CO (AMPHIBOLES), CRANFORD, NJ 07016; COLUMBIA FILTER CO (AMPHIBOLES), KINGSTON, NY 12401 [R4] OMIN: +Amosite is commonly used to refer to a cummingtonite-grunerite asbestos mineral, but it is a discredited mineral name. [R5, 144] +AMOSITE IS AN EXPLOITED VARIETY OF GRUNERITE. AS PART OF GRUNERITE-CUMMINGTONITE SOLID SOLN SERIES /IT/ TENDS TO OCCUR WITH MORE IRON THAN MAGNESIUM ... MANGANESE SUBSTITUTION MAY OCCUR IN CONCN OF UP TO 4% BY OXIDE WEIGHT. [R6] +KNOWN COMMERCIALLY EXPLOITED DEPOSITS: AMOSITE: TRANSVAAL, SOUTH AFRICA, IS THE MAIN SOURCE OF THIS TYPE FIBER. AN IDENTICAL FIBER HAS BEEN FOUND IN INDIA AND WILL BE PRODUCED UNDER THE NAME OF MYSORITE. [R7] USE: +ASBESTOS CEMENT BUILDING PRODUCTS, PRESSURE, SEWAGE AND DRAINAGE PIPES; FIRE RESISTANT INSULATION BOARDS; INSULATION PRODUCTS, INCL SPRAYS [R8] +MANUFACTURE OF FLOOR TILES AND IN DECORATIVE INSULATIONS TO REPLACE TIMBER IN PASSENGER SHIPS [R9, 730] +CONSTRUCTION MATERIAL FOR ASBESTOS CEMENT PIPE AND SHEET [R4] CPAT: +ASBESTOS CEMENT PIPE, 71%; ASBESTOS CEMENT SHEET, 29% (1977) [R4] PRIE: U.S. PRODUCTION: +(1972) 5.18X10+9 G (CONSUMPTION) [R4] +(1975) 1.16X10+10 G (CONSUMPTION) [R4] U.S. IMPORTS: +(1972) 6.53X10+9 G [R4] +(1975) 3.54X10+9 G [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +Structure: lamellar, coarse to fine fibrous and asbestiform; crystal structure: prismatic, lamellar to fibrous; crystal system: monoclinic; ash gray, green, or brown; luster: vitreous, somewhat pearly [R2, p. 3(78) 274] DEN: +3.1-3.25 [R2, p. 3(78) 275] SPEC: +Optical properties: biaxial positive extinction parallel; index of refraction: about 1.64 [R2, p. 3(78) 275] OCPP: +Chemical composition: 11FeO.3MgO.16SiO2.2H2O [R2, p. 3(78) 267] +SPACE GROUP: C2/M; CATION IN M4 SITE: FE+-MG [R10] +CELL LATTICE DIMENSIONS: A= 9.6; B= 18.3; C= 5.3; BETA= 102 DEG; CLEAVAGE: (110) GOOD= 55 DEG /CUMMINGTONITE-GRUNERITE/ [R5, 149] +ELECTRON MICROSCOPE STUDIES OF AMOSITE ASBESTOS FIBERS REVEAL NARROW BANDS OF POLYSYNTHETIC TWINNING AND TRIPLE CHAINS INTERLAYERED WITH THE USUAL DOUBLE CHAIN STRUCTURE OF THE AMPHIBOLES; MOST OF THE NATURAL ASBESTOS (AMOSITE) FIBERS HAVE ORTHORHOMBIC OPTICAL PROPERTIES OF SEVERAL MICRONS [R5, 155] +APPROX MIN FIBER WIDTH: 1500 ANGSTROMS (UICC REFERENCE SAMPLES (UNIO INTERNATIONALE CONTRA CANCRUM)) [R5, 150] +BINDS WELL WITH PLASTICS [R9, 730] +Mohs hardness: 5.5-6.0; cleavage, 110%; Seger cones fusibility: fusible at 6, loses water at moderate temperatures; flexibility: good, less than chyrsotile; fiber length: 5-28 cm; texture: coarse but somewhat pliable; spinnability: fair; specific heat: 908 J/kg deg k (0.217 Btu/lb deg F) [R2, p. 3(78) 275] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: +Asbestos minerals, despite a relatively high fusion temperature, are completely decomposed at temperatures of 1,000 deg C. /Asbestos minerals/ [R11] +The resistance of the asbestos fibers to attack by reagents other than acid as excellent up to temperatures of approximately 100 deg C with rapid deterioration observed at higher temperatures. /Asbestos cmpd/ [R12] EQUP: +PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair-covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R13, 1979.8] OPRM: +... THE INCIDENCE OF CARCINOMA /FROM EXCESSIVE EXPOSURE TO ALL TYPES OF ASBESTOS FIBERS/ ... CAN BE GREATLY REDUCED BY GOOD PLANT HYGIENE. ... THE POSITION OF AMOSITE IS NOT YET CLEAR, SO THAT A HIGH STANDARD OF DUST CONTROL IS REQUIRED WHEN IT IS USED. [R9, 735] +PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R13, 1979.8] +PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used. ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R13, 1979.9] +PRECAUTIONS FOR "CARCINOGENS": Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R13, 1979.9] +PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R13, 1979.10] +PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R13, 1979.10] +PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R13, 1979.10] +PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R13, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R15] STRG: +PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R13, 1979.13] CLUP: +PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R13, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R13, 1979.16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent /amosite/ is carcinogenic to humans. [R16] +A1; Confirmed human carcinogen. /Asbestos, all forms/ [R17, 2002.16] MEDS: +PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R13, 1979.23] +Asbestos workers with clinical symptoms of hoarseness, or pain, or soreness of the throat should be referred to an ear, nose, and throat specialist for a detailed otolaryngologic examination of the upper respiratory tract /for detection of laryngeal cancer/. [R18] +Follow up medical examinations for asbestos exposed workers is /based on/ the following parameters/: Nonsmokers, ex-smokers and smokers who do not inhale: A) No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray, and sputum cytology; B) more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; C) 40 years old and older, at least 20 years from onset of asbestos exposure: Add fecal occult blood testing and an examination of the oral cavity every 6 months. Smokers who inhale: 1) Less than 15 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray and sputum cytology every 4 months. 2) 15-20 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 6 months; more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months. 3) More than 20 years from onset of asbestos exposure: Less than 40 years old a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; 40 years old and older: add fecal occult blood testing and an examination of the oral cavity every 6 months. /Asbestos cmpd/ [R19] HTOX: +IN HUMANS, OCCUPATIONAL EXPOSURE TO ... AMOSITE ... HAS RESULTED IN HIGH INCIDENCE OF LUNG CANCER ... MANY PLEURAL AND PERITONEAL MESOTHELIOMAS HAVE BEEN OBSERVED AFTER OCCUPATIONAL EXPOSURE TO ... AMOSITE ... [R20] +EXPOSURES TO AMOSITE IN FACTORY MAKING INSULATION MATERIALS WERE REPORTED ... 10 MESOTHELIOMAS WERE, AND THERE WAS AN INCREASED RISK OF LUNG CANCER IN WORKERS FOLLOWED UP FOR 20 YR OR LONGER. THE EXCESS LUNG CANCER RISK IN THE AMOSITE WORKERS WAS SHOWN TO INCREASE WITH DURATION OF EMPLOYMENT. THERE WAS A 3.87 FOLD INCR IN LUNG CANCER AMONG THOSE WITH LESS THAN 3 MONTHS' EMPLOYMENT. [R21] +IN A RETROSPECTIVE STUDY OF 914 MEN WHO HAD WORKED FOR VARIOUS PERIODS OF TIME DURING WORLD WAR II IN PLANT MANUFACTURING INSULATING MATERIALS FROM AMOSITE FOR THE US NAVY ... THE GROUP OF 65 MEN WHO HAD WORKED FOR LESS THAN 1 MO HAD AN EXCESS MORTALITY FROM LUNG CANCER (BUT NOT FROM ALL CANCERS OR ALL CAUSES) WHICH BECAME DISCERNIBLE ONLY 30 YR AFTER EXPOSURE. EXCESS MORTALITY FROM LUNG CANCER AND ALL CANCERS THAT SHOWED UP AFTER PROGRESSIVELY SHORTER INTERVALS AFTER THE EXPOSURE WAS REPORTED IN MEN WHO HAD WORKED FOR PERIODS RANGING FROM 1 MO TO MORE THAN 2 YEARS. [R21] +ALL TYPES OF ASBESTOS ARE KNOWN TO CAUSE INFLAMMATORY CHANGES IN LUNGS AND PLEURAE ... AND LUNG CANCER. HOWEVER, THERE IS EXPTL AND EPIDEMIOLOGIC EVIDENCE THAT THERE MAY BE DIFFERENCES IN THE POTENTIAL OF DIFFERENT ASBESTOS TYPES TO PRODUCE DISEASE. ... IT HAS BEEN SUGGESTED THAT CROCIDOLITE HAS GREATEST POTENTIAL TO PRODUCE DISEASE; CHRYSOTILE, THE SMALLEST; WITH AMOSITE OCCUPYING AN INTERMEDIATE POSITION. [R22] +Mesothelioma has been diagnosed in a 44 year old woman exposed to talc over a 12 year period; lung tissue revealed the presence of elevated levels of brown asbestos (amosite). [R23] +In cultured human cells ... amosite ... did not induce DNA strand breaks ... [R24] +Gastrointestinal tract cancers increased in groups exposed occupationally to amosite and excess of cancer of the larynx was also observed in exposed workers. [R25] +Examination of 326 household contacts of amosite asbestos workers /were studied/. Of these, 35% who had no occupational asbestos exposure had chest X-ray abnormalities, with a predominance of pleural changes, fibrosis, and calcification. Contact had presumably been through asbestos dust on the workers' clothing and hair. The level of airborne dust in the homes of workmen has been reported as 100-5000 ng/cu m. [R26] +The /prospective/ study of /17,800/ USA and Canadian insulators /exposed primarily to chrysotile ... and amosite showed that/ lung tumors ... accounted for ... 21% of /2271/ deaths. 8% were from mesothelioma of the pleura or peritoneum, and 7% ... from asbestos ... 675 excess malignacies occurred, constituting 30% of all deaths. In addition ... the incidences of cancers of the larynx, pharynx and buccal cavity, and kidney were significantly elevated. Other tumors ... as a group ... were significantly in excess. [R27] +In a cohort of USA and Canadian insulation workers, the lung cancer incidence rate was 2.5/1000 man years, 5 times the expected rate. Factory workers exposed to amosite asbestos (and not to other materials common to the construction industry) exhibited a six to sevenfold increase in lung cancer incidence over the general population (suggesting that asbestos fibers may have been the cause of the lung cancers in the previous two cohorts). The incidence of deaths among the factory workers was correlated with the duration of exposure to amosite (and hence presumably correlated to the total dose received). [R28] +SPICULES OF ASBESTOS EASILY PENETRATE THE SKIN, ESP THE FINGERS IN THOSE BAGGING THE FIBER. CHRONIC IRRITATION OF THE DERMIS OCCURS WITH THE FORMATION OF CORNS ... CANCERS OF THE SKIN ARE NOT PRODUCED. /ASBESTOS CMPD/ [R29] +AT PRESENT, IT IS NOT POSSIBLE TO ASSESS WHETHER THERE IS A LEVEL OF EXPOSURE IN HUMANS BELOW WHICH AN INCREASED RISK OF CANCER WOULD NOT OCCUR. /ASBESTOS CMPD/ [R30] +Asbestos fibers are toxic to macrophages, cells responsible for cleaning infectious agents and foreign material from the respiratory tract. /Asbestos cmpd/ [R31] +A study of the largest factory of the company but not limited to retirees, shows a considerably different mortality pattern. All 689 maintenance and production employees on January 1, 1959, who were first employed at least 20 years earlier were followed through 1976. In this group, 274 deaths occurred, whereas 188.19 were expected. Fourteen pleural and 12 peritoneal mesotheliomas accounted for nearly 10% of the deaths, most recurring before age 65. A strong correlation with estimated dust exposure was seen in deaths form asbestosis, but not with the asbestos related malignancies. Gastrointestinal cancer was especially high in the lowest of four dust categories (11 observed versus 3.15 expected) and only elevated slightly in the higher exposure categories. In the highest dust category, the overall cancer was not dramatically increased, but 40% of the deaths were from asbestosis. Individuals in this department tended to die of nonmalignant disease before reaching the age of greatest risk for cancer. /Asbestos cmpd/ [R32] NTOX: +... GROUPS OF 69 CHARLES RIVER CD RATS /WERE EXPOSED BY INHALATION/ TO BALL MILLED ... AMOSITE ... FOR 4 HR/DAY ON 4 DAYS/WK FOR 2 YR AT MEAN CONCN OF ABOUT 50 MG/CU M. TWO PLEURAL MESOTHELIOMAS WERE OBSERVED. NO TUMORS WERE OBSERVED IN CONTROLS. (IT IS IMPORTANT TO NOTE THAT THE MATERIAL WAS COMMINUTED BY VIGOROUS MECHANICAL MILLING (BALL MILLING FOR UP TO 240 HR), WHICH UNDOUBTABLY ALTERED THE FIBER PROPERTIES). [R33] +... GROUPS OF CD WISTAR RATS /WERE EXPOSED/ TO 5 UNION INTERNATIONALE CONTRE LE CANCER ASBESTOS SAMPLES (AMOSITE, ANTHOPHYLLITE, CROCIDOLITE, AND RHODESIAN AND CANADIAN CHRYSOTILES) AT CONCN OF ABOUT 12 MG/CU M RESPIRABLE DUST FOR 7 HR/DAY ON 5 DAYS/WK, FOR SEVERAL LENGTHS OF EXPOSURE: 1 DAY (7 HR), 3 MO, 6 MO, 12 MO, OR 24 MO. AT THE END OF EXPOSURES, THE AMT OF DUST IN THE LUNGS OF ANIMALS EXPOSED TO THE 2 CHRYSOTILE SAMPLES WAS MUCH LESS THAN THAT IN ANIMALS EXPOSED TO THE 3 AMPHIBOLE SAMPLES. HOWEVER, ALL TYPES OF FIBER PRODUCED ASBESTOSIS, WHICH WAS PROGRESSIVE AFTER REMOVAL FROM THE DUST. FUTHERMORE, WHEREAS NO CARCINOMAS OF THE LUNG WERE FOUND IN THE CONTROL GROUP, CARCINOMAS OF THE LUNG AND MESOTHELIOMAS WERE DEMONSTRATED IN THE GROUPS EXPOSED TO CANADIAN CHRYSOTILE AND TO THE AMPHIBOLES. ONLY CARCINOMAS OF THE LUNG WERE SEEN WITH RHODESIAN CHRYSOTILE ... AN INCREASING INCIDENCE OF NEOPLASMS WAS OBSERVED WITH INCREASING EXPOSURES TO EACH FORM OF ASBESTOS. EVEN AS LITTLE AS 1 DAY OF EXPOSURE (PROVIDING THE ANIMALS WERE ALLOWED TO SURVIVE AND WERE OBSERVED) PRODUCED NEOPLASIA. [R34] +All commercial types of asbestos have produced mesotheliomas in CD Wistar rats /by intrapleural admin/. A dose of 20 mg of the Union Internationale Contre le Cancer standard reference samples, crocidolite, amosite, anthophyllite, Canadian and Rhodesian chyrsotiles, produced various numbers of mesotheliomas /in rats by intrapleural admin; species not stated/. [R35] +... /It was found that an intrapleural/ dose of 40 mg asbestos dust on gelatin coated fiber-glass pledgets ... /of/ 3 of the Union Internationale Contre le Cancer samples, crocidolite, amosite and Rhodesian chrysotile, all produced mesotheliomas in about 60% of Osborne Mendel rats. ... Mesotheliomas in Sprague Dawley rats treated with a single /intrapleural/ dose of 67 mg of chrysotile, amosite, or crocidolite /were observed/. [R36] +IN GROUPS OF 50 HAMSTERS GIVEN SINGLE INTRAPLEURAL INJECTION OF ... 1 OR 10 MG AMOSITE, 4/50 HAMSTERS DEVELOPED MESOTHELIOMAS AT THE HIGHEST DOSE ONLY. ... /NO DATA FOR CONTROLS ARE GIVEN/ [R37] +... IP INJECTIONS OF 20 MG AMOSITE, CROCIDOLITE OR CHYRSOTILE /WERE GIVEN TO/ GROUPS OF 11, 13 13 CHARLES RIVER CD RATS, RESPECTIVELY. THREE PERITONEAL MESOTHELIOMAS WERE OBSERVED WITH CHRYSOTILE, 3 WITH CROCIDOLITE AND NONE WITH AMOSITE, AFTER 7-17 MONTHS. [R38] +ALL COMMERCIAL FORMS OF ASBESTOS TESTED ARE CARCINOGENIC IN MICE, RATS, HAMSTERS, AND RABBITS. ... THE SIZE AND SHAPE OF FIBERS INFLUENCE THE INCIDENCE OF TUMORS; FIBERS LESS THAN 0.5 UM IN DIAMETER ARE MORE ACTIVE IN PRODUCING TUMORS. /ALL FORMS OF ASBESTOS FIBERS/ [R20] +INTRATRACHEAL INJECTION OF AMOSITE DUST IN GUINEA PIG LUNG AT 40, 80, 120, and 160 DAYS PRODUCED CONTINUOUS INCR IN HEXOSAMINE AND GLUCURONIC ACID THROUGHOUT DEVELOPMENT OF DISEASE AND INITIAL INCR AND LATER DECR IN SIALIC ACID WHICH INDICATE LOCI OF ASBESTOS TOXICITY. [R39] +LONG TERM STUDIES OF RESP FUNCTION AND LUNG MORPHOLOGY ON CONTROL GROUPS OF GUINEA PIGS AND MATCHED GROUPS EXPOSED BY INHALATION TO AEROSOLS OF CHRYSOTILE OR AMOSITE ASBESTOS CONTAINING LARGE NUMBERS OF SHORT FIBERS. NO FIBROTIC REACTION WAS SEEN DURING 70 WK OF AMOSITE EXPERIMENTS. [R40] +RATS WERE FED A DIET SUPPLEMENTED WITH AN ASBESTOS/MARGARINE FORMULATION FOR PERIODS UP TO 1 YR. UNION INTERNATIONALE CONTRE LE CANCER STD REF SAMPLES OF AMOSITE WERE USED. NO EVIDENCE OF ASBESTOS RETENTION WITHIN GUT LUMEN, AND NO SIGN OF CELL PENETRATION OR DAMAGE TO INTESTINAL MUCOSA OBSERVED. [R41] +PULMONARY FIBROGENIC RESPONSE IN MICE WAS INVESTIGATED FOLLOWING INTRATRACHEAL INOCULATION OF AMOSITE OVER 150 DAY PERIOD. ACUTE INFLAMMATORY REACTION IN LUNGS WAS OBSERVED AT EARLY PERIODS WITH THICK RETICULUM FIBERS DEVELOPING LATER. NO ASBESTOS BODIES WERE REPORTED. [R42] +The acute in vivo response of the visceral pleura following intratracheal instillation of amosite asbestos was examined by light microscopy and by transmission and scanning electron microscopy in the guinea pig model. Asbestos fibers were observed close to the pleura or subpleural regions proper. Thus, pleural changes occurred in the absence of direct fiber contact. Morphological changes in the pleural and subpleural areas were seen as early as 2 hr after exposure and were associated with pathological alterations of the underlying parenchyma. The normally squamous mesothelial cells became pleomorphic in experimental animals, ranging from slightly cuboidal, to protruding columnar-like cells, to more abnormal forms. Many organelles remained unaltered, an incr in vacuolization in portions of the pleura, indicated localized and advanced intracellular responses. Beginning at 4 hr post-exposure, varied numbers of particulate-free macrophages were observed on the pleural surface, and were considered an extension of the inflammatory response occurring in the underlying parenchyma. Early proliferation of mesothelial cells, in limited areas of the pleura, and cytoplasmic extensions into pleural space were also observed. Distortions of the basal lamina and smooth muscle bundles accompanied the morphological changes in the pleural cells. A trend towards normality was observed in the longer time frames, but some areas of pleural change persisted through 3 months post-exposure. [R43] +Amosite ... induced transformation of Syrian hamster embryo cells ... Neither amosite nor crocidolite transformed CH3 10T1/2 cells. In cultured rodent cells, amosite ... induced chromosomal aberrations, and ... induced sister chromatid exchanges ... Amosite, chrysotile and crocidolite were inactive or weakly active in inducing mutation in rodent cells in vitro; none was mutagenic to bacteria. [R24] +Amosite exposure can increase the sister chromatid exchange rate in Chinese hamster ovarian fibroblasts. [R44] +... Malignant tumors developed in 5 to 14% of the rats survived 18 months after exposure. ... Lung cancer and mesothelioma were also produced by exposure to amosite. [R45] +The potential carcinogenic effect of taconite tailings, amosite and diatomaceous earth in drinking water /was investigated/. Groups of 20-30 rats were supplied water with these various materials throughout their lifetime. A variety of malignancies were found in each exposure group, although none were attributable to asbestos exposure. However, a pleural mesothelioma was identified in a group exposed to amosite plus chrysotile and a peritoneal mesothelioma was identified in the diatomaceous earth exposed group. [R46] +A study examined the carcinogenic effects of asbestos on groups of 22-24 animals fed 250 mg/week of amosite, crocidolite, or chrysotile in margarine for up to 25 months. No excess malignancies were found in the exposed group compared with the margarine or undosed control groups. [R47] +Viral interferon production was depressed in monkey kidney cells in vitro by exposure to asbestos fibers. A dose response relation was evident and amosite, anthophyllite, crocidolite, and chrysotile all exhibited similar depressant activities. [R48] +Chrysotile, amosite, and anthophyllite showed no mutagenic activity toward tester strains of Escherichia coli or Salmonella typhimurium. [R49] +ALL COMMERCIAL FORMS OF ASBESTOS TESTED ARE CARCINOGENIC IN MICE, RATS, HAMSTERS AND RABBITS. ... THE SIZE AND SHAPE OF FIBERS INFLUENCE THE INCIDENCE OF TUMORS; FIBERS LESS THAN 0.5 UM IN DIAMETER ARE MORE ACTIVE IN PRODUCING TUMORS. /ASBESTOS CMPD/ [R20] +/INTRAPLEURAL ADMIN TO CD WISTAR AND OSBORNE-MENDEL RATS/ ALL COMMERCIAL TYPES OF ASBESTOS HAVE PRODUCED MESOTHELIOMAS IN C/D WISTAR RATS. A DOSE OF 20 MG OF THE FIVE UICC STANDARD REFERENCE SAMPLES (SEE SECTION 1.3B) PRODUCED MESOTHELIOMAS IN VARYING NUMBERS - CROCIDOLITE 61%, AMOSITE 36%, ANTHOPHYLLITE 34%, CANADIAN CHRYSOTILE 30% AND RHODESIAN CHRYSOTILE 19%. WITH A DOSE OF 40 MG OF ASBESTOS DUST ON GELATIN-COATED FIBRE-GLASS PLEDGETS, /IT WAS/ FOUND THAT THREE OF THE UICC SAMPLES, CROCIDOLITE, AMOSITE AND RHODESIAN CHRYSOTILE, ALL PRODUCED MESOTHELIOMAS IN ABOUT 60% OF THEIR OSBORNE-MENDEL RATS. INDUCED MESOTHELIOMAS WITH 60 MG OF RUSSIAN CHRYSOTILE. IN ALL THESE STUDIES THERE WAS A LONG LATENT PERIOD BETWEEN INOCULATION AND APPEARANCE OF THE TUMOURS. EVIDENCE THAT THE RESPONSE WAS DOSE RELATED. MESOTHELIOMAS HAVE ALSO BEEN PRODUCED BY OTHER WORKERS: IN RATS, IN HAMSTERS AND IN RABBITS. [R50] +Carcinogenesis studies of amosite asbestos were conducted by admin diets containing 1 % of the asbestos in pellets from the conception of the mothers through the lifetime of male and female Syrian golden hamsters. Control groups consisted of 127 male and 126 female hamsters and the amosite asbestos groups consisted of 252 male and 254 female hamsters. ... Under the conditions of these studies, the ingestion of amosite asbestos at a level of 1 % in the diet for their lifetime was not toxic and did not cause a carcinogenic response in male and female Syrian golden hamsters. Levels of Evidence of Carcinogenicity: Male Hamsters: Negative; Female Hamsters: Negative. [R51] +Carcinogenesis studies of amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted in male and female rats. Amosite asbestos was admin at a concn of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. One group of amosite asbestos-exposed rats (amosite preweaning gavage) also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. Litter size was the same, but the offspring from mothers exposed to amosite asbestos were smaller at weaning than those from nonexposed mothers and remained smaller throughout their life. The DMH was admin by gavage at a dose of 7.5 mg/kg for males and 15 mg/kg for females every 14 days, starting at 8 weeks of age, for a total of five doses. The admin of DMH did not affect body weight gain either in amosite-exposed or nonexposed animals. The amosite-exposed rats showed enhanced survival compared with that of the nonexposed rats. ... Under the conditions of these feed studies, amosite asbestos was not overtly toxic, did not affect survival, and was not carcinogenic when ingested at a concentration of 1 % in the diet by male or female F344/N rats. The cocarcinogenic studies using DMH were considered inadequate because of the high incidence of DMH-induced intestinal neoplasia in both the amosite asbestos-exposed and nonexposed groups. [R52] NTP: +Carcinogenesis studies of amosite asbestos were conducted by admin diets containing 1 % of the asbestos in pellets from the conception of the mothers through the lifetime of male and female Syrian golden hamsters. Control groups consisted of 127 male and 126 female hamsters and the amosite asbestos groups consisted of 252 male and 254 female hamsters. ... Under the conditions of these studies, the ingestion of amosite asbestos at a level of 1 % in the diet for their lifetime was not toxic and did not cause a carcinogenic response in male and female Syrian golden hamsters. Levels of Evidence of Carcinogenicity: Male Hamsters: Negative; Female Hamsters: Negative. [R51] +Carcinogenesis studies of amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted in male and female rats. Amosite asbestos was admin at a concn of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. One group of amosite asbestos-exposed rats (amosite preweaning gavage) also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. Litter size was the same, but the offspring from mothers exposed to amosite asbestos were smaller at weaning than those from nonexposed mothers and remained smaller throughout their life. The DMH was admin by gavage at a dose of 7.5 mg/kg for males and 15 mg/kg for females every 14 days, starting at 8 weeks of age, for a total of five doses. The admin of DMH did not affect body weight gain either in amosite-exposed or nonexposed animals. The amosite-exposed rats showed enhanced survival compared with that of the nonexposed rats. ... Under the conditions of these feed studies, amosite asbestos was not overtly toxic, did not affect survival, and was not carcinogenic when ingested at a concentration of 1 % in the diet by male or female F344/N rats. The cocarcinogenic studies using DMH were considered inadequate because of the high incidence of DMH-induced intestinal neoplasia in both the amosite asbestos-exposed and nonexposed groups. [R52] POPL: +Special groups at risk may include neonates and children; however, no data exist on the relative sensitivity to asbestos of infants and children undergoing rapid growth. Concern exists because fibers deposited in the tissues of young may have an extremely long residence time during which malignant changes could occur. In addition, risk could be influenced by differential absorption rates which have not been fully studied at this time. Individuals on kidney dialysis machines may also be at greater risk as fluids, potentially contaminated with asbestos fibers can enter the blood stream directly or, in selected instances, the peritoneal cavity (peritoneal dialysis). An increased risk is also associated with increased exposure to asbestos in water in municipalities such as San Francisco or Seattle where asbestos occurs naturally in water, in cities where there is a interaction between aggressive water and asbestos-cement pipe, or in cities whose water may be contaminated as a result of asbestos operations. /Asbestos cmpd/ [R53] ADE: +THE RETENTION OF DIFFERENT TYPES OF ASBESTOS IN RATS FOLLOWING EXPOSURE TO THE SAME CONCN OF RESPIRABLE DUSTS ... /HAS BEEN DESCRIBED/. FOR THE AMPHIBOLES, THERE WAS A SIMILAR PATTERN WITH AN ALMOST PROPORTIONAL INCREASE OF LUNG DUST WITH DOSE. MUCH LESS DUST WAS FOUND FOR THE CHRYSOTILES, AND NO INCREASE OF DUST CONTENT WAS SHOWN IN THE LUNGS. DUST IN THE LUNGS OF ANIMALS WITH 6 MONTHS' EXPOSURE HAD BEEN PARTIALLY CLEARED 18 MO AFTER THE INHALATION PERIOD. ABOUT 74% OF THE AMOSITE AND CROCIDOLITE AND 41% OF THE ANTHOPHYLLITE WERE ELIMINATED. [R54] +Using a minute volume for the rat of 100 ml, it would appear that about 1% of the total amosite inhaled is permanently in the lung. [R55] +Rats fed chrysotile, crocidolite, or amosite exhibited no retention of fibers in the gut lumen and no penetration of the mucosa. The transit time for the majority of fibers was 48 hours, and there was no asbestos either in the feces or in the gut after 7-28 days. [R56] +Asbestos may have effects on organs in addition to the lungs and gastrointestinal tract (which come into obvious contact with the fibers) if the fibers can penetrate from these main sites to the blood or lymphatic systems. Amosite fibers can penetrate epithelial cells in rat jejunum through the luminal surface and can make their way into the highly vascularized lamina propria. The blood or lymph systems may then be involved in the transport of these fibers. [R57] +Twenty female CBA mice were injected subcutaneously in two sites. Each injection contained 10 mg fiber suspended in 0.4 ml saline. Each animal received three injections into each flank. The flank was chosen as a site well distant from the thorax. Three fiber types: crocidolite, amosite, and chrysotile, were tested to study their distribution. All three fiber types were found in the submesothelial tissues of the thorax and abdomen. In addition, extensive inflammatory changes and some sarcomas developed at the injection sites, while transport of fibers to submesothelial tissues culminated in mesothelioma. [R58] +Two human studies gave evidence for the penetration and migration of asbestos. ... Amphibole asbestos /has been detected/ in the urine of Minnesota residents who ingested drinking water contaminated with 5X10+7 fibers/l. ... amphibole asbestos in lung > liver > jejunum of persons exposed to high oral intake of the mineral /has been observed/. /Amphibole asbestos/ [R59] +RATS WERE FED A DIET SUPPLEMENTED WITH AN ASBESTOS/MARGARINE FORMULATION FOR PERIODS UP TO 1 YR. UICC STD REF SAMPLES OF AMOSITE WERE USED. THERE WAS NO EVIDENCE OF ASBESTOS RETENTION WITHIN GUT LUMEN, AND NO SIGN OF CELL PENETRATION OR DAMAGE TO INTESTINAL MUCOSA WERE OBSERVED. [R41] +Fibers were detected in beverages (beer, wine and soft drinks) and were studied to see if such fibers consumed orally can pass through the intestinal wall and enter the bloodstream. A stock solution was made to contain fibers the same length as those found in beverages (0.5-2) and determined to contain 9.4x10+6 fibers/l. An aliquot (assumed to be 350 ml) was then administered intragastrically to rats (number, species and sex not known). Asbestos fibers were found to accumulate in the omentum surrounding the small intestine, brain and lung. ... counts could not be made on the liver and kidneys. /Asbestos cmpd/ [R60] ACTN: +Animal experimentation ... indicated that the important factor in the carcinogenicity was the dimensionality of the fibers rather than their chemical properties. ... Greatest carcinogenicity was related to fibers that were less than 2.5 cu m in diameter and longer than 10 cu m. /Asbestos cmpd/ [R61] INTC: +THE CELL TRANSFORMING ABILITY OF ASBESTOS DUSTS (AMOSITE AND CROCIDOLITE ASBESTOS) WAS INVESTIGATED USING C3H10T1/2 MURINE FIBROBLAST CULTURES. THE DUSTS WERE CAPABLE OF AUGMENTING THE ONCOGENIC EFFECT OF BENZO(A)PYRENE. THIS SYNERGISTIC EFFECT WAS EVIDENT WHEN FIBERS AND CHEMICALS WERE ADDED TO CULTURES AS SIMPLE MIXTURES AND WHEN BENZO(A)PYRENE WAS ADSORBED TO THE SURFACE OF FIBERS. [R62] +Carcinogenesis bioassays of blocky (nonfibrous) tremolite and amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted with male and female Fischer 344 rats. The minerals were administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats starting with the dams of the test animals. One group of amosite rats also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. No toxicity or increase in neoplasia was observed in the controls. Significant increases in the rates of C-cell carcinomas of the thyroid and monocytic leukemia were noted in males. Significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and the positive effect was not observed in the amosite plus preweaning gavage group. [R63] +The relationship between asbestos exposure and smoking indicates a synergistic effect of smoking with regard to lung cancer. Further evaluations indicate that this synergistic effect is close to a multiplicative model. ... The risk of mesothelioma appears to be independent of smoking, and a significantly decreasing trend in risk was observed with the amount smoked in 1 study. /Asbestos cmpd/ [R64] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: +... Amosite occur in metamorphosed sedimentary strata known as banded ironstones. These sedimentary formations vary considerably in composition which accounts for the compositional variations of the associated amphibole fibers. [R2, p. 3(78) 268] RTEX: +OCCUPATIONAL EXPOSURE TO ASBESTOS MAY OCCUR DURING THE MINING OF FIBROUS MINERALS, AS WELL AS OF MINERALS EMBODIED IN ROCKS, WHICH MAY CONTAIN ASBESTIFORM FIBERS AS A CONTAMINANT. /ASBESTOS CMPD/ [R20] +An increased risk is also associated with increased exposure to asbestos in water in municipalities such as San Francisco or Seattle where asbestos occurs naturally in water, in cities where there is an interaction between aggressive water and asbestos cement pipe, or in cities whose water may be contaminated as a result of asbestos operations. /Asbestos cmpd/ [R65] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: +The employer shall ensure that no employee is exposed to an airborne concentration of asbestos in excess of 0.1 fiber/cu cm of air as an 8-hr TWA as determined by the method prescribed in Appendix A to this section, or by an equivalent method. /Asbestos/ [R66] TLV: +8 hr Time Weighted Avg (TWA): 0.1 fibers/cc; respirable fibers: length greater than 5 um; aspect ratio greater than or equal to 3:1. /Asbestos, all forms/ [R17, 2002.16] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Asbestos, all forms/ [R17, 2002.6] +A1; Confirmed human carcinogen. /Asbestos, all forms/ [R17, 2002.16] OOPL: +Regulations regarding asbestos levels in air in the workplace, ... United Kingdom: 2 fibers/cu m average over 4 hr for amosite and also 12 fibers/cu m average over 10 min (for above mentioned fibers). /Data derived from table/ [R67] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: +NIOSH 7402: Analyte: asbestos fibers (including amosite); Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25-mm diameter; conductive cassette); Flow rate: 0.5-16 l/min; Vol: min: 400 l at 0.1 fiber/ml; max: 10,000 l; Sample stability: stable. Shipment is routine (securely packed to reduce shock). [R68, p. V1 7402-1] +NIOSH 7400: Analyte: Fibers (including amosite asbestos); Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25-mm diameter; conductive cowl on cassette); Flow rate: 0.5 to 16 l/min; Minimum vol: 400 l at 0.1 fiber/ml; Maximum vol: 10,000 l; Stability: stable. Shipment is routine (securely packed to reduce shock). [R68, p. V1 7400-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Amosite Asbestos in F344/N Rats (Feed Studies) Technical Report Series No. 279 (1990) NIH Publication No. 91-2535 DHHS/NTP; Toxicology and Carcinogenesis Studies of Amosite Asbestos in Hamsters (Feed Studies) Technical Report Series No. 249 (1987) U.S. Dept Health and Human Services/Agency for Toxic Substances Disease Registry; Toxicological Profile for Asbestos (Update) (1995) NTIS # PB/95-264305 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 186 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 29 (1977) R4: SRI R5: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 25 (1977) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 32 (1977) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 39 (1977) R9: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 24 (1977) R11: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-3 (1980) EPA 440/5-80-022 R12: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-5 (1980) EPA 440/5-80-022 R13: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R14: 49 CFR 171.2 (7/1/96) R15: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.9014 (1988) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 106 (1987) R17: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R18: USDHEW/NCI; Asbestos: An Information Resource p.96 (1978) DHEW Pub No. NIH 79-1681 R19: USDHEW/NCI; Asbestos: An Information Resource P.93 (1978) DHEW Pub No. NIH 79-1681 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 80 (1977) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 67 (1977) R22: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.40 R23: Barnes R, Rogers AJ; Med J Aust 140: 488-90 (1984) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 109 (1987) R25: DHHS/NTP; Fourth Annual Report On Carcinogens p.29 (1985) NTP 85-002 R26: Nat'l Research Council Canada; Asbestos p.46 (1979) NRCC No. 16452 R27: Selikoff IJ et al; Ann NY Acad Sci 330: 91-116 as cited in USEPA; Asbestos Health Assessment Update (Draft) p.11-13 (1984) EPA-600/8-84-003A R28: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.113 (1979) NRCC No. 16452 R29: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. 122 R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 81 (1977) R31: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.19 (1979) NRCC No. 16452 R32: Enterline PE et al; J Occup Med 14: 897 (1972) as cited in USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-76-77 (1980) EPA 440/5-80-022 R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 43 (1977) R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 44 (1977) R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 45 (1977) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 45 (1977) R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 50 (1977) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 51 (1977) R39: MISRA V ET AL; ENVIRON RES 16 (1-3): 55-61 (1978) R40: HIETT DM; BR J IND MED 35 (2): 135-45 (1978) R41: BOLTON RE, DAVIS J MG; ANN OCCUP HYG 19 (2): 121-8 (1976) R42: SAHU AP ET AL; EXP PATHOL (JENA) 11 (1-2): 21-4 (1975) R43: Dodson RF, Ford JO; J Toxicol Environ Health 15 (5): 673-86 (1985) R44: Livingston GK; J Environ Pathol Toxicol 4: 373-82 (1980) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.77 (1984) EPA-600/8-84-003A R45: Reeves AL; Environ Res 8: 178-202 (1974) as cited in USEPA; Asbestos Health Assessment Update (Draft) p.77 (1984) EPA-600/8-84-003A R46: Hilding AC et al; Arch Environ Health 36: 298-303 (1981) as cited in USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.V-12 (1985) R47: Bolton RE et al; Environ Res 29: 134-50 (1982) as cited in USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.V-12 to V-13 (1985) R48: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environment p.19 (1980) NRCC No. 16452 R49: Chamberlain M, Tarmy EM; Mutat Res 43: 159 (1977) as cited in USEPA; Health and Environmental Effects Profile for Asbestos p.12-11 (1979) R50: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V2 27 (1973) R51: Lifetime Carcinogenesis Studies of Amosite Asbestos in Syrian Golden Hamsters (Feed Studies). Technical Report Series No. 249 (1987) NTIS Publication No. PB87-133278/AS U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R52: Toxicology and Carcinogenesis Studies of Amosite Asbestos in F344/N Rats. Technical Report Series No. 279 (1990) NIH Publication No. 91-2535 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R53: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (1989) EPA 440/5-80-022 R54: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 58 (1977) R55: USEPA; Asbestos Health Assessment Update (Draft) p.74 (1984) EPA-600/8-84-003A R56: Bolton RE, Davis JMG; Ann Occup Hyg 19: 121-8 (1976) as cited in Nat'l Research Council Canada; Asbestos p.66 (1979) NRCC No. 16452 R57: Storeygard AR, Brown AL; Mayo Clin Proc 52: 809-12 (1977) as cited in Nat'l Research Council Canada; Asbestos p.68 (1979) NRCC No. 16452 R58: Roe FJC et al; Int J Cancer 2: 628-38 (1967) as cited in USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.III-9 (1985) R59: Seiler, H.G., H. Sigel and A. Sigel (eds.). Handbook on the Toxicity of Inorganic Compounds. New York, NY: Marcel Dekker, Inc. 1988. 604 R60: Cunningham HM, Pontefract RD; J Assoc Off Anal Chem 56: 976 (1973) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.III-8 (1985) R61: USEPA; Asbestos Health Assessment Update (Draft) p.9 (1984) EPA-600/8-84-003A R62: POOLE A ET AL; ENVIRON HEALTH PERSPECT 51: 319-24 (1983) R63: McConnell EE et al; Environ Health Perspect 53: 27-44 (1983) R64: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 108 (1987) R65: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (date) EPA 440/5-80-022 R66: 29 CFR 1910.1001(c) (7/1/98) R67: Zielhuis RL; Public Health Risks of Exposure to Asbestos Comm Eur Commun Report No. LCC 76-5 1964 149 pp. (1977) as cited in Nat'l Research Council Canada; Asbestos p.56 (1979) NRCC No. 16452 R68: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. RS: 58 Record 208 of 1119 in HSDB (through 2003/06) AN: 2966 UD: 200304 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHRYSOTILE-ASBESTOS- SY: *K-6-30-; *5RO4-; *7-45-ASBESTOS-; *AVIBEST-C-; *CALIDRIA-RG-100-; *CALIDRIA-RG-144-; *CALIDRIA-RG-600-; *CASSIAR-AK-; *CHRYSOTILE-; *CHRYSOTILE- (MG3(OH)4(SIO5)); *HOOKER-NO-1-CHRYSOTILE-ASBESTOS-; *K6-30-; *NCI-C61223A-; *PLASTIBEST-20-; *RG-600-; *SERPENTINE-; *SERPENTINE-CHRYSOTILE-; *SYLODEX- RN: 12001-29-5 RELT: 511 [ASBESTOS] (Mixture) SHPN: IMO 9.3; White asbestos UN 2590; White asbestos MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The mineral is mined or quarried with its parent rock. [R1] *Imbedded asbestos fibers are removed from the ore by a repeated series of crushing, fiberizing, screening, aspirating, and grading operations (milling). ... The ore is crushed, dried, and fiberized in a variety of impact mills. The short fiber and granular material is removed by screening the fiberized mass. The oversized fractions are stratified on a screen where the spherical, granular material of high density seeks the screen's surface and the fluffy, low density fiber rises to the top of the bed. At the end of the screen, the fiber is separated from the rock by an aspirating hood. ... Fibers recovered from these primary screening operations are rescreened to remove entrapped granular material and classified into grades by fiber length. ... Conventional asbestos milling uses large quantities of air both for separating the fibers as they are freed from the ore and for dust control. Approx 130 cu m/sec (275,000 cfm) are used to process one metric ton of ore. Preconcentration of ore includes selective grinding, screening, and magnetic techniques. /Asbestos cmpd/ [R2, p. 3(78) 279] *The material from the separating mill was largely unopened bundles of fibers. For many purposes it was necessary to open the fiber by separating the bundles into their constituent fibers, which greatly increases the bulk of the material. In the asbestos textile industry the material is passed through several types of mills which separate the fibers before they are passed into the carding machines in which they undergo the 1st stage of asbestos yarn prodn. ... /During/ recent years more of the fiber is "opened" at the mills. /Asbestos cmpd/ [R1] IMP: *THE IMPURITIES WHICH ARE PRESENT IN CHRYSOTILE MAY BE PART OF THE CRYSTAL STRUCTURE OR DUE TO ASSOC MINERALS. THE MOST COMMON IMPURITY IS IRON, AND THE NEXT IS ALUMINUM; OTHER IMPURITIES ASSOC WITH CHRYSOTILE IN LESSER AMOUNT ARE CALCIUM, CHROMIUM, NICKEL, MANGANESE, SODIUM AND POTASSIUM. [R3] *COMMON MINERAL IMPURITIES FOUND IN COMMERCIAL GRADES OF CRYSOTILE FROM VARIOUS LOCATIONS INCLUDE MAGNETITE, CHROMITE, BRUCITE, CALCITE, DOLOMITE, AND AWARUITE. WITHIN THE CHRYSOTILE LATTICE, NICKEL AND IRON CAN OCCUR AS MINOR ISOMORPHIC SUBSTITUTIONS FOR MAGNESIUM. [R2, p. 3(78) 272] *... Nine Canadian chrysotile samples /were analyzed/ for trace metals ... 2-14 ug/g beryllium, 3-10 ug/g cadmium, 202-771 ug/g chromium, 36-78 ug/g cobalt, 9-26 ug/g copper, 325-1065 ug/g manganese, 299-1187 ug/g nickel, and 35-71 ug/g thallium /were found/ in the asbestos samples. Similar results were found in ... a study of trace elements in the Reserve Mining Company's taconite dumpings in Lake Superior. [R4, p. 7-9] *Samples of commercially used asbestos, especially chrysotile, are frequently contaminated by small amounts of other fibrous minerals. Among these are tremolite and brucite. [R5] *The most commonly occurring mineral impurities are brucite, chlorite, talc, carbonates, magnetite and quartz. ... [R6] FORM: *The chemical compositions vary somewhat, depending on deposit location, from the idealized composition of magnesium disilicon pentadioxide tetrahydoxide. Chemical analyses of chrysotile range approximately as follows: Calcium oxide, 37-44%; Magnesium oxide, 39-44%; Ferrous oxide, 0 to 6.0%; Ferric oxide, 0.1-5.0%; Aluminum oxide, 0.2-1.5%; CaO, trace to 5.0%; water , 12.0-15.0%. Variations in chemical analyses may be due to either associated mineral impurities or to isomorphic substitutions in the crystal lattice. [R2, p. 3(78) 272] OMIN: *The specific surface areas of commercial asbestos fibers vary with the extent of mechanical defibrillation. Surface areas by nitrogen adsorption tests on samples teased by hand from chrysotile crude are 4-12 sq m/g; however, when aggressively milled or fiberized, surface areas of 30-50 sq m/g result. Chrysotile asbestos can be separated into smaller diameter fibrils (higher specific area) more readily under wet processing conditions than under dry mechanical milling. For this reason many asbestos product manufacturing processes utilize wet opening techniques to provide improved fiber reinforcing efficiencies. [R2, p. 3(78) 273] *CHRYSOTILE ASBESTOS WAS TREATED WITH ALUMINUM TRICHLORIDE TO INCREASE ITS SURFACE POTENTIAL, ZETA-POTENTIAL (IN WATER) OF THE CHRYSOTILE WAS INCREASED FROM 80 TO 300 MV, TO GIVE ADSORBENTS FOR THE TREATMENT OF SPENT CUTTING OIL EMULSIONS. [R7] *THE PRINCIPAL TYPE OF ASBESTOS FOUND IN A/C PIPE IS CHRYSOTILE ... FOR REINFORCEMENT PURPOSES. [R8, 46] *Canadian chrysotile crudes are classified as follows: crude #1: 1.9 cm staple and longer; crude #2: 0.95 cm to 1.9 cm staple; crude run of mine: unsorted crudes. Milled Canadian fibers sold from Quebec are classified by a dry screen technique known as the Quebec Standard Asbestos Test. This test method grades fibers roughly by fiber or staple length. Minimum test values are guaranteed for each grade and a numerical classification system has been estabilished for fibers ranging from Group 3, the longest grade, to Group 7, the shortest grade. Chrysotile fibers produced outside Quebec are graded or controlled by screening test methods differing from the Quebec Screen Test; however, these basically identify grade by staple length. [R2, p. 3(78) 280] *In 1977, Canada and Russia ... /were/ the major producers of chrysotile asbestos, AND Africa, China, and the United States provided modest quantities. [R2, p. 3(78) 269] *The term harshness in the asbestos industry refers to the fiber's brittleness, flexibility, form, and modulus of elasticity. [R2, p. 3(78) 273] USE: *IN CEMENT PRODUCTS, FLOOR TILE, PAPER PRODUCTS, PAINT AND CAULKING, TEXTILES, PLASTICS [R9, 152] *IN DIFFERENT TYPES OF PACKINGS, WOVEN BRAKE LININGS TO CLUTCH FACINGS, AND ELECTRIC INSULATION [R10] *COMPONENT OF ASBESTOS CEMENT (EG, IN PIPES AND SHEETS), ROOFING PRODUCTS, COATINGS AND COMPOUNDS, GASKETS, THERMAL INSULATION PRODUCTS, AND TEXTILES AS A FIREPROOFING AGENT [R11] *Chrysotile fibers are frequently used as a reinforcing agent in cement, paper and plastic products. [R12] *Chrysotile is the major type of asbestos used in the manufacture of asbestos products. ... Including asbestos cement pipe, flooring products, paper products ... friction materials ... roofing products, and coating and patching compounds. [R13, 440/5-80-022] *Because of their small diameters and pourous surfaces, these fibers have extremely large surface areas. ... This characteristic is important for filtration and reinforcement applications ... /and/ uses involving aqueous dispersions in the presence of surface active agents such as sodium laurate and dodecylbenzenesulfonate. [R12] CPAT: *ASBESTOS-CEMENT PIPE AND SHEET, 30%; FLOORING PRODUCTS, 23%; FRICTION PRODUCTS, 14%; ROOFING PRODUCTS, 9%; COATING AND COMPOUNDS, 5%; PAPER, 4%; PACKING AND GASKETS, 4%; ELECTRICAL AND THERMAL INSULATION PRODUCTS, 3%; TEXTILES, 1%; PLASTICS, 1%; OTHER, 5% (1977) [R11] *Chrysotile fiber accounts for a very high proportion of total asbestos use (94% in 1974). [R14] PRIE: U.S. PRODUCTION: *(1972) 1.1X10+11 G (ESTIMATED) [R11] *(1975) 8.5X10+10 G (ESTIMATED) [R11] *In 1975, the total consumption of asbestos in the USA was 550,900 metric tons. [R13, 440/5-80-002] U.S. IMPORTS: *(1972) 5.9X10+11 G [R11] *(1975) 4.6X10+11 G [R11] *1.95X10+11 g [R15] U.S. EXPORTS: *(1972) 4.5X10+10 G [R11] *(1975) 3.2X10+10 G [R11] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CURLED SHEET SILICATE, SPIRALED AS HELIX AROUND CENTRAL CAPILLARY; FIBROUS MEMBER OF SERPENTINE MINERAL GROUP POSSESSING ROLLED TRIOCTAHEDRAL CLAY STRUCTURE [R16]; *Crystal system: monoclinic (pseudoorthorhombic); white, gray, green yellow [R2, p. 3(78) 274] DEN: *A RANGE IN THE DENSITIES OF NATURAL CHRYSOTILE FIBERS HAS BEEN OBSERVED: VALUES FROM ARIZONA CHRYSOTILES, DERIVED FROM SERPENTIZED DOLIMITES, HAVE BEEN REPORTED TO BE BETWEEN 2.19 and 2.25 G/ML; THE DENSITY OF CHRYSOTILE FROM CANADA HAS BEEN SHOWN TO BE APPROX 2.56 G/ML. THESE REPORTED RANGES IN DENSITY OF CHYRSOTILE HAVE BEEN ATTRIBUTED ... TO MINERAL IMPURITIES AND TO THE PRESENCE OF MAGNESIUM SILICATE MATERIAL THAT "STUFFS" THE CENTRAL CAPILLARIES AND FIBRIL INTERSTICES IN THE FIBRE BUNDLE. [R17] SOL: *In a laboratory study of the dissolution of chrysotile in water, an activity product of chrysotile (1X10-51.0) in water at 25 deg C was determined. The results suggest that chrysotile is slowly soluble in water under conditions of continuous extraction. [R4, p. 7-8]; *Solubility product constants for chrysotile fibers range from 1.0X10-11 to 3X10-12, indicative of the magnesium hydroxide outer layer. [R2, p. 3(78) 273] SPEC: *Optical properites: biaxial positive extinction parallel; index of refraction: 1.50-1.55 [R2, p. 3(78) 275] OCPP: *ISOELECTRIC POINT OF 11.8 [R9, 147] *AVG OUTER DIAMETER OF FIBRIL IS ABOUT 200 A [R9, 150] *... The kinetics of the dissolution of chrysotile in water over a temp range of 5-45 deg C /was observed/. A parallelism was noted between the rate of dissolution of magnesium from the chrysotile and the rate of pH drift. The rate of the dissolution reaction was directly proportional to the specific surface area of the asbestos minerals. It was noted that magnesium cations may be continuously liberated from the chrysotile fibers, leaving behind an intact silica structure. This original structure could then readsorb metal cations, since it will develop a negative charge. In general ... this readsorption of metal cations is not observed; the smaller the particle, the faster the magnesium is liberated from the asbestos structure. Moreover, the reaction is temp sensitive only in the initial stages of contact between chrysotile and water. [R4, p. 7-3] *Mohs hardness, 2.5 to 4.0; cleavage, 0.10%; Seiger cones fusibility, fusible at 6 (1190-1230 deg C); very flexible; length, short to long; specific heat, 1113 J/kg deg K (0.266 Btu/lb deg F); acid resistance: soluble up to approximately 57% [R2, p. 3(78) 275] *The crystal structure of chrysotile is layered or sheeted similarly to the kaolinite group. It is based on an infinite silica sheet (Si2O5) in which all the silica tetrahedra point one way. On one side of the sheet structure, and joining the silica tetrahedra, is a layer of brucite, Mg(OH)2, in which two out of every 3 hydroxyls are replaced by oxygens at the apices of the tetrahedra. The result is a layered structure. Mismatches and strains between the layers cause the structure to curve and form cylinders or fibers. Individual chrysotile fibers have ultimate diameters of 0.02-0.03 um. [R2, p. 3(78) 269] *Electron microphotographs have shown most chrysotile fibers with a hollow cylindrical form and a single magnesia-silica sheet rather than the earlier double layer concept. The lattice planes have multispiral arrangements as suggested by ... X-ray studies. [R2, p. 3(78) 271] *Dispersions of chrysotile fiber in carbon dioxide free distilled water exhibit alkaline properties. Such suspensions will reach a pH of 10.33. ... The electrokinetic behavior of chrysotile is also related to its surface characteristics. Normally, below its isoelectric point of approx pH 11-12, chrysotile exhibits a positive charge. Above this pH range, it demonstrates a negative charge. Exceptions to this general behavior have been noted with chrysotile fibers from certain locations. [R2, p. 3(78) 272] *Because of its very small fiber diameter, its high specific surface area and its relatively reactive surface, chrysotile is a selectively adsorptive material. Commercial grades ... adsorb as much as 2-3 wt % moisture from saturated air. Adsorption studies of a variety of organic compounds from ... vapor and liquid media show that chrysotile has a greater affinity for polar molecules. Heats of adsorption have been measured ranging from 38 kJ/g (9 kcal/g) for hexane to 67 kJ/g (16 kcal/g) for water. Chrysotile also adsorbs iodine from solutions in a manner similar to magnesium hydroxide or brucite. [R2, p. 3(78) 273] *... Recent information indicates typical chrysotiles have tensil strengths in the order of 3727 Mpa (5.4X10+5 psi) which exceeds corresponding values for steel piano wire and fiber glass. [R2, p. 3(78) 273] *Commercial grades of chrysotile are usually classed as soft or nonharsh. Commonly, they are silky, of fine diameter, and extremely flexible. [R2, p. 3(78) 273] *Because of its hydroxyl outer layer, chrysotile is readily attacked by acid and will, ultimately completely dissolve the magnesium component, leaving essentially a fibrous, but fragile, silica structure. Similarly, because of its alkaline surface, chrysotile is not readily attacked by caustic except under conditions of extreme alkali concentrations and elevated temperatures. [R2, p. 3(78) 272] *Chrysotile, a hydrated silicate, is subject to thermal decomposition at elevated temperatures. This thermal decomposition is a two stage reaction consisting first of a dehydroxylation phase and then a structure phase change. Dehydroxylation or the loss of water occurs at 600-780 deg C. At 800-850 deg C the anhydride breaks down to forsterite and silica. These reactions are irreversible ... . [R2, p. 3(78) 272] *Chrysotile has alkali resistant properties. /From table/ [R18] *Tensile strength 31,000 kg/sq cm; specific gravity 2.55. [R19] *MOLECULAR FORMULA: 3MgO.2SiO2.2H2O H4-Mg3-O9-Si2 [R2, p. 3(78) 267] *... Physical and chemical properties of chrysotile change substantially with < 1 hr exposure to simulated gastric juice (equivalent to 1 N hydrochloric acid). [R20] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Organic acids have a tendency to react slowly with chrysotile. [R21] *Because the outer surface of a chrysotile fiber is essentially composed of magnesium hydroxide (brucite), chrysotile is highly susceptible to acid attack. [R6] *... Resistant to attack by sodium hydroxide. [R6] *Exposure to mineral acids results in liberation of magnesium ions and the formation of a silicous residue. [R6] DCMP: *It is almost completely destroyed within 1 hour in 1 N hydrochloric acid at 95 deg C. [R22] *Thermal decomposition is accomplished through dehydroxylation and dehydration mechanisms. Under dynamic heating conditions, dehydroxylation occurs at 650 deg C and formation of fastering and silica is apparent at 81 deg C. [R6] *Chrysotile is completely decomposed in concentrated potassium hydroxide at 200 deg C. [R21] *Asbestos minerals, despite a relatively high fusion temperature, are completely decomposed at temperatures of 1,000 deg C. [R22] *The resistance of the asbestos fibers to attack by reagents other than acid as excellent up to temperatures of approximately 100 deg C with rapid deterioration observed at higher temperatures. /Asbestos cmpd/ [R21] EQUP: *Wear appropriate eye protection to prevent eye contact. /Asbestos/ [R23] *Wear appropriate personal protective clothing to prevent skin contact. /Asbestos/ [R23] *Recommendations for respirator selection: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R23] *Recommendations for respirator selection: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Asbestos/ [R23] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R24, 1979.8] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R24, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R24, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R24, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R24, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R24, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R24, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R24, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R24, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R24, 1979.11] *Contact lenses should not be worn when working with this chemical. /Asbestos/ [R23] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Asbestos/ [R23] *The worker should wash daily at the end of each work shift. /Asbestos/ [R23] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R25] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R26] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R27] *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R24, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R24, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R24, 1979.13] CLUP: *CHRYSOTILE ASBESTOS FIBERS IN LAB SOLUTIONS WERE DEGRADED BY CHEMICAL TREATMENT. [R28] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms. ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal. ... The plastic bag should be sealed immediately. ... The sealed bag should be labeled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labeled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated. ... The plastic bag should also be sealed and labeled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R24, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R24, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R24, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R24, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R24, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R24, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *... In most production sectors, workplace exposures in the early 1930s were very high. Levels dropped considerably to the late 1970s and have declined substantially to present day values. ... There is potential for exposure of maintenance personnel to mixed asbestos fiber types due to large quantities of friable asbestos in place. ... Most airborne chrysotile fibers are considered respirable because their fiber diameters are less than 3 um ... In laboratory rats, chrysotile fibers are deposited primarily at alveolar duct, bifurcations. In the nasopharyngeal and tracheobronchial regions, chrysotile fibers are cleared via mucociliary clearance. At the alveolar duct bifurcations the fibers are taken up by epithelial cells. Fiber length is an important determinant of alveolar clearance of chrysotile fibers. There is extensive evidence from animal studies that short fibers (less than 5 um long) are cleared more rapidly than long fibers ... It has been hypothesized that short chrysotile fibers are cleared through phagocytosis by alveolar macrophages, while long chrysotile fibers are cleared mainly by breakage and/or dissolution. ... Analyses of human lungs of workers exposed to chrysotile asbestos indicate much greater retention of tremolite, an amphibole asbestos commonly associated with commercial chrysotile in small proportions, than of chrysotile. The more rapid removal of chrysotile fibers from the human lung is further supported by findings from animal studies showing that chrysotile is more rapidly cleared from the lung than are ampohiboles including crocidolite and amosite. ... Various experimental samples of chrysotile fibers have been shown in numerous long term inhalation studies to cause fibrogenic and carcinogenic effects in laboratory rats. These effects include interstitial fibrosis and cancer of the lung and pleura. In most cases there appears to be an association between fibrosis and tumors in the rat lung. Fibrogenic and carcinogenic effects have also been found in long term animal studies (mainly in rats) using other modes of administration (e.g., intratracheal instillation and intrapleural or intraperitoneal injection.) ... In non-inhalation experiments (intrapleural and intraperitoneal injection studies), dose-response relationships for mesothelioma have been demonstrated for chrysotile fibers. ... The mechanisms by which chrysotile and other fibers cause fibrogenic and carcinogenic effects are not completely understood. ... Overall, the available toxicological data provide clear evidence that chrysotile fibers can cause fibrogenic and carcinogenic hazard to humans. The data, however, are not adequate for providing quantitative estimates of the risk to humans. ... /In humans/ commercial grades of chrysotile have been associated with an increased risk of pneumoconiosis, lung cancer and mesothelioma in numerous epidemiological studies of exposed workers. The non-malignant diseases associated with exposure to chrysotile comprise a somewhat complex mixture of clinical and pathological syndromes not readily definable for epidemiological study. The prime concern has been asbestosis, generally implying a disease associated with diffuse interstitial pulmonary fibrosis accompanied by varying degrees of pleural involvement. ... The epidemiological evidence that chrysotile exposure is associated with an increased risk for cancer sites other than the lung or pleura is inconclusive. ... It should be recognized that although the epidemiological studies of chrysotile exposed workers have been primarily limited to the mining and milling, and manufacturing sector, there is evidence, based on the historical pattern of disease associated with exposure to mixed fiber types in western countries, that risks are likely among workers in construction and possibly other user industries. [R29] CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent /chrysotile/ is carcinogenic to humans. [R30] *A1; Confirmed human carcinogen. /Asbestos, all forms/ [R31, 2002.16] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R24, 1979.23] *Pre-employment medical examinations should include the following: Medical history, family history, history of smoking, consumption of alcohol, and an occupational history. Physical examinations should include: oral cavity, cheek, and abdomen which includes a digital examination of the rectum. Spirometry: Including measurements of vital capacity, forced vital capacity, and forced expiratory volume at one second. Chest X-ray: postero-anterior and lateral views (14x17 inch), along /with/ sputum cytology /examination/. /Asbestos cmpd/ [R32] *Follow up medical examinations for asbestos exposed workers is /based on the following parameters/: Nonsmokers, ex-smokers and smokers who do not inhale: A) No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray, and sputum cytology; B) more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; C) 40 years old and older, at least 20 years from onset of asbestos exposure: Add fecal occult blood testing and an examination of the oral cavity every 6 months. Smokers who inhale: 1) Less than 15 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray and sputum cytology every 4 months. 2) 15-20 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 6 months; more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months. 3) More than 20 years from onset of asbestos exposure: Less than 40 years old a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; 40 years old and older: add fecal occult blood testing and an examination of the oral cavity every 6 months. /Asbestos cmpd/ [R32] HTOX: *IN HUMANS, OCCUPATIONAL EXPOSURE TO CHRYSOTILE ... HAS RESULTED IN HIGH INCIDENCE OF LUNG CANCER; ... SMALL AMOUNTS OF CHRYSOTILE HAS ALSO CAUSED AN INCREASED INCIDENCE OF LUNG CANCER. MANY PLEURAL AND PERITONEAL MESOTHELIOMAS HAVE BEEN OBSERVED AFTER OCCUPATIONAL EXPOSURE TO ... CHRYSOTILE. AN EXCESS RISK OF GI TRACT CANCER HAS BEEN DEMONSTRATED IN GROUPS EXPOSED OCCUPATIONALLY TO ... CHRYSOTILE ... [R33] *CHRYSOTILE ASBESTOS CAUSED NO DOSE RELATED INCREASE IN SISTER-CHROMATID EXCHANGE LEVELS IN HUMAN FIBROBLASTS OR LYMPHOBLASTOID CELLS; HOWEVER, MITOTIC DELAY WAS INDUCED IN HUMAN FIBROBLASTS. [R34] *THE BLASTOGENIC RESPONSES OF CON-A AND POKEWEED MITOGEN-STIMULATED HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS WERE INCREASED BY THE INCLUSION OF 6 UG CHRYSOTILE TO THE CULTURE MEDIA. THE ADDITION OF CHRYSOTILE TO PHYTOHEMAGGLUTININ (PHA) CULTURES RESULTED IN AN INCREASE OF THE MITOGENIC RESPONSE. WHEN PERIPHERAL BLOOD MONONUCLEAR CELLS WERE ENRICHED FOR T LYMPHOCYTES, AND AGAIN CULTURED WITH THE MITOGENS AND FIBERS, THE CON-A RESPONSE STILL DISPLAYED IMPRESSIVE ENHANCEMENT WITH CHRYSOTILE. [R35] *SUPERNATANTS FROM PULMONARY ALVEOLAR MACROPHAGES EXPOSED TO CHRYSOTILE ASBESTOS (100 UG/ML) SIGNIFICANTLY INCREASED THE RATE OF HUMAN LUNG FIBROBLASTS DOUBLING. THE DOUBLING TIME DECREASED 5 FOLD FROM A CONTROL OF 310 TO 54 HR. [R36] *ALL TYPES OF ASBESTOS ARE KNOWN TO CAUSE INFLAMMATORY CHANGES IN LUNG AND PLEURAE ... AND LUNG CANCER. HOWEVER, THERE IS EXPERIMENTAL AND EPIDEMIOLOGIC EVIDENCE THAT THERE MAY BE DIFFERENCES IN THE POTENTIAL OF DIFFERENT ASBESTOS TYPES TO PRODUCE DISEASE. ... IT HAS BEEN SUGGESTED THAT CROCIDOLITE HAS GREATEST POTENTIAL TO PRODUCE DISEASE; CHRYSOTILE, THE SMALLEST; WITH AMOSITE OCCUPYING AN INTERMEDIATE POSITION. [R37] *IN STUDY OF 1348 RETIREES FROM THE ASBESTOS INDUSTRY, THE RESPIRATORY CANCER RATE OF MEN EXPOSED ONLY TO CHRYSOTILE WAS 2.4 TIMES THE EXPECTED, WHEREAS THIS RATE WAS 5.3 TIMES THE EXPECTED FOR MEN WHO HAD BEEN EXPOSED TO A COMBINATION OF CHRYSOTILE AND CROCIDOLITE. IN THE ASBESTOS CEMENT INDUSTRY A SIMILAR DIFFERENCE WAS OBSERVED. WORKERS EXPOSED ONLY TO CHRYSOTILE AND CEMENT (SHINGLES AND SHEETS) HAD A RESPIRATORY CANCER RATE OF 1.4 TIMES THE EXPECTED, WHEREAS WORKERS EXPOSED TO BOTH, CHRYSOTILE AND CROCIDOLITE AND CEMENT (ASBESTOS CEMENT PIPES), HAD A RESPIRATORY CANCER RATE 6.1 TIMES THE EXPECTED. [R37] *A case control, interview based study /was conducted relating/ to the risk of developing cancer from asbestos in drinking water. The Everett, Washington area was selected for study because of the unusually high concentration of chrysotile asbestos in the drinking water it draws from the Sultan River. Through a population based tumor registry, /investigators/ identified 382 individuals with cancer of the buccal cavity, pharynx, respiratory system, digestive system, bladder, or kidney, diagnosed between 1977 and 1980, and then interviewed them or their next of kin. /Similar/ interviews of a control group of 462 individuals /were conducted/. Finally, interviews were validated in several ways, including comparing the collected data with that from secondary sources. Estimates of exposure to asbestos in drinking water were based on residence and workplace history, and on individual water consumption. Four different measures of exposure were used. Cancer risk was estimated by logistic regression and other methods. The /investigators/ found no convincing evidence for cancer risk from imbibed asbestos. [R38] *A series of studies have been conducted of the cancer incidence in the San Francisco Bay area, part of which is served by water systems containing concentrations of asbestos up to 36 million fibers/l. The first published report of this research compared cancer incidence in low (16,000-32,000 fibers/l, medium (330,000-4,100,000 fibers/l) and high 5,400,000-36,000,000 fibers/l) fiber groups of census tracts. Correlation coefficients significant at the p < 0.01 level were found between chrysotile asbestos water concentrations and white male lung cancer, white female gall bladder cancer, and pancreatic and peritoneal cancer in both sexes. Weaker correlations (0.01 < 0.05) were found between asbestos levels and female esophagus, pleura and kidney cancer, as well as stomach cancer in both sexes. [R39] *A later follow up extended the observations through 1974 and found a correlation between chrysotile asbestos content and white male cancers of the digestive tract, stomach and pancreas. White female cancers of the esophagus, stomach, digetive related organs and pancreas were also elevated. The associations appeared to be independent of income, education, asbestos occupation, martital status and population mobility. The variables tested, however, were group census data on socioeconomic status and for occupation, the variable was number of construction, electrical and textile workers, as these trades were considered to have a possible occupational exposure to asbestos. [R40] *Cancer mortality for the populations in 40 census tracts of Escambia County, FL that have been receiving drinking water through air conditioning pipes for up to 40 years. Cancer mortality data from these 40 censes tracts were compared with data from other tracts where air conditioning pipe was not in use. No statistical association was observed between cancer deaths and the use of air conditioning pipe. /Asbestos cmpd/ [R41] *The /prospective/ study of /17,800/ USA and Canadian insulators /exposed primarily to chrysotile ... and amosite showed that/ lung tumors ... accounted for ... 21% of /2271/ deaths. 8% were from mesothelioma of the pleura or peritoneum, and 7% ... from asbestos ... 675 excess malignancies occurred, constituting 30% of all deaths. In addition ... the incidences of cancers of the larynx, pharynx and buccal cavity, and kidney were significantly elevated. Other tumors ... as a group ... were significantly in excess. [R42] *SPICULES OF ASBESTOS EASILY PENETRATE THE SKIN, ESP THE FINGERS IN THOSE BAGGING THE FIBER. CHRONIC IRRITATION OF THE DERMIS OCCURS WITH THE FORMATION OF CORNS ... CANCERS OF THE SKIN ARE NOT PRODUCED. /ASBESTOS CMPD/ [R43] *AT PRESENT, IT IS NOT POSSIBLE TO ASSESS WHETHER THERE IS A LEVEL OF EXPOSURE IN HUMANS BELOW WHICH AN INCREASED RISK OF CANCER WOULD NOT OCCUR. /ASBESTOS CMPD/ [R44] *Asbestos fibers are toxic to macrophages, cells responsible for cleaning infectious agents and foreign material from the respiratory tract. /Asbestos cmpd/ [R45] *A study of the largest factory of the company but not limited to retirees, shows a considerably different mortality pattern. All 689 maintenance and production employees on January 1, 1959, who were first employed at least 20 years earlier were followed through 1976. In this group, 274 deaths occurred, whereas 188.19 were expected. Fourteen pleural and 12 peritoneal mesotheliomas accounted for nearly 10% of the deaths, most recurring before age 65. A strong correlation with estimated dust exposure was seen in deaths form asbestosis, but not with the asbestos related malignancies. Gastrointestinal cancer was especially high in the lowest of four dust categories (11 observed versus 3.15 expected) and only elevated slightly in the higher exposure categories. In the highest dust category, the overall cancer was not dramatically increased, but 40% of the deaths were from asbestosis. Individuals in this department tended to die of nonmalignant disease before reaching the age of greatest risk for cancer. /Asbestos cmpd/ [R46] *INITIAL BIOLOGICAL DATA SHOW THAT CHEMICAL TREATMENT OF CHRYSOTILE ASBESTOS TO FORM A SATURATED SYNTHETHIC FERRUGINOUS BODY DECREASES THE CYTOTOXICITY OF ASBESTOS TO HUMAN LUNG MACROPHAGE CELLS. PHYSICAL TEST DATA INDICATE THAT DESIRABLE ATTRIBUTES OF THE FIBERS ARE RETAINED. IF ADDITIONAL IN VITRO AND IN VIVO BIOLOGICAL TESTS ARE SUCCESSFUL IN DEMONSTRATING A DECREASE IN TOXICITY AS A RESULT OF THE CHEMICAL TREATMENT AND PERFORMANCE OF TREATED MATERIAL IS ACCEPTABLE IN PRODUCTS, THIS WOULD ALLOW TREATED FIBERS TO SERVE AS SUBSTITUTES FOR ASBESTOS IN APPROPRIATE APPLICATIONS. [R47] *A second study /was/ reported in Quebec of 86 men whose last chest film was taken within 12 months of leaving employment in 1960-1961, and who were examined again in 1972. In 66 men who had been employed for at least two years, there was evidence of an increase in small irregular parenchymal opacities in 8 men (12%) but in none of the 20 men with shorter employment. Increase of pleural thickening was seen in a further 13 (20%) of the 66 men and 4 (20%) of the 20 men. [R48] *Chest X-ray changes among textile and friction product workers in China were reported. A total of 824 workers employed for at least 3 years in a chrysotile products factory from the start up of the factory in 1958 until 1980, with follow-through to September 1982, were studied. Chest X-ray changes compatible with asbestosis were assessed using the Chinese standard system for interpretation of X-rays. Cases were defined as Grade I asbestosis (approximately equivalent to ILO > or = 1/1). Overall, 277 workers were diagnosed with asbestosis during the follow-up period, corresponding to a period prevalence of 31%. [R49] *In a study of 824 workers employed during 1946 1973 in a factory producing various chrysotile products in Lodz, Poland, and followed up until 1985, there was a significant increase in lung cancer mortality, based on 24 observed and 12.9 expected deaths (SMR 1.86, 95% Cl 1.19 2.77). When workers were grouped according to cumulative asbestos dust exposure, the SMR of lung cancer was 1.55 in the group with exposure to up to 50 mg/cu m years and 3.11 in the group with higher exposure ... . No mesotheliomas were observed among the cohort members in this study. [R50] *In a cohort of 1172 workers in Tianjin, China, exposed to chrysotile in the manufacture of asbestos textiles, friction materials and asbestos cement for at least one year, and followed from January 1972 to December 1987, ... /An/ increased risk of mortality from lung cancer (21 observed/6.67 expected; SMR= 3.15; p < 0.05) and "other" non malignant respiratory disease (29 observed/11.78 expected; SMR=2.46; p < 0.05) was reported. [R50] *... A retrospective cohort mortality study of 1227 men employed at a chrysotile mine in Laiyuen, Hebei province of China, prior to 1972 was conducted. Mortality in this cohort was compared with that from 2754 local residents of Laiyuen who had never been exposed to asbestos. Based on follow up of this cohort from 1972 to 1981, 67 deaths were identified (of which 6 were from lung cancer and 3 from mesothelioma) in the asbestos cohort and 247 deaths in the referent population. The lung cancer rate in the exposed cohort was reported to be significantly greater (p < O. 00 1) than the rate in the referent group. [R51] NTOX: *GROUPS OF 32 WISTAR SPF RATS WERE FED 100 MG/DAY ITALIAN TALC OR UICC CANADIAN CHRYSOTILE IN MALTED MILK POWDER ON 5 DAYS/WK FOR 100 DAYS OVER 6 MO PERIOD; 16 CONTROLS WERE FED ONLY MALTED MILK. THE MEAN LENGTH OF SURVIVAL FROM THE START OF FEEDING WERE 614 DAYS FOR THOSE GIVEN TALC, 619 DAYS FOR THOSE GIVEN CHRYSOTILE AND 641 DAYS IN CONTROLS. TWO GASTRIC LEIOMYOSARCOMAS WERE OBSERVED, 1 IN ANIMAL FED TALC AND THE OTHER IN 1 FED CHRYSOTILE. NONE OF THESE TUMORS OCCURRED IN THE CONTROLS. [R52] *THREE GROUPS OF 25 MALE AND 25 FEMALE 10 WK OLD WISTAR RATS WERE EITHER UNTREATED, GIVEN 50 MG/KG/DAY ASBESTOS FILTER MATERIAL CONTAINING 52.6% CHRYSOTILE ASBESTOS WHICH WAS POWDERED AND ADDED AS A WATER SUSPENSION TO THE DIET, OR GIVEN 50 MG/KG BODY WT/DAY TALC IN THE DIET FOR LIFE. IN THE GROUP GIVEN ASBESTOS FILTER MATERIAL, THE AVG SURVIVAL TIME WAS 441 DAYS. AMONG 42 ANIMALS AVAIL FOR STUDY, 12 MALIGNANT TUMORS WITH METASTASES WERE FOUND (4 KIDNEY CARCINOMAS, 1 LUNG CARCINOMA, 3 RETICULUM CELL SARCOMAS AND 4 LIVER CELL CARCINOMAS). ONE LUNG ADENOMA, 2 CHOLANGIOMAS, 2 PAPILLOMAS OF THE FORESTOMACH AND 2 MAMMARY FIBROADEMONAS WERE ALSO OBSERVED. IN THE GROUP RECEIVING TALC IN THE DIET, THE AVG SURVIVAL TIME WAS 649 DAYS; AMONG 45 RATS EXAMINED, 3 LIVER CELL CARCINOMAS AND 4 MAMMARY FIBROADEMONAS WERE SEEN. IN UNTREATED CONTROLS, AVG SURVIVAL TIME WAS 702 DAYS; 2 LIVER CELL CARCINOMAS AND 5 MAMMARY FIBROADENOMAS OCCURRED AMONG 49 ANIMALS. THE INCREASED INCIDENCE OF MALIGNANT TUMORS IN RATS GIVEN ASBESTOS FILTER MATERIAL IN THE DIET WAS SIGNIFICANT COMPARED WITH THAT IN CONTROLS (P < 0.01). [R52] *... 100 WHITE MICE /WERE EXPOSED/ TO HIGH CONCN OF CHRYSOTILE DUST FOR 72 HR. AFTER 6 WK, ASBESTOS BODIES AND FIBROSIS WERE OBSERVED IN LUNG OF ALL MICE, AND AFTER 13 WK ABOUT 50% HAD HYPERPLASIA OF EPITHELIAL CELLS OF LUNG. TWO CARCINOMAS WERE SEEN IN 10 MICE, SURVIVING 240 DAYS. /NO DATA FOR CONTROLS ARE GIVEN/ [R53] *... 8 WK OLD AC/F1 HYBRID MICE WERE /EXPOSED BY/ INHALATION TO A COMMERCIAL PREPN OF CHRYSOTILE ASBESTOS FOR 8-12 HR/DAY ON 5 DAYS/WK FOR 17 MO. IN ANIMALS KILLED AT THE END OF EXPOSURE, A HIGHER INCIDENCE OF MULTIPLE PULMONARY ADENOMAS WAS OBSERVED IN EXPOSED GROUP (46%, 58/127), THAN IN THE CONTROLS (36%, 80/222). (THIS RESULT IS NOT STATISTICALLY SIGNIFICANT (P > 0.05). [R53] *... TUMORS IN THE LUNG ... /OF MALE WHITE/ RATS EXPOSED REPEATEDLY TO A MEAN CONCN OF 86 MG/CU M CHRYSOTILE DUST FOR 30 HR/WK /WERE OBSERVED/. TWENTY FIVE OF 72 RATS SURVIVING FOR 16 MO (TIME OF APPEARANCE OF 1ST TUMOR) OR LONGER DEVELOPED 28 LUNG TUMORS (17 ADENOCARCINOMAS, 4 SQUAMOUS CELL CARCINOMAS AND 7 FIBROSARCOMAS), WHEREAS NO SUCH TUMORS OCCURRED IN 39 CONTROLS (GROSS ET AL, 1967). THE AUTHORS SUGGESTED THAT THE PRESENCE OF TRACE METALS FROM THE HAMMERS OF THE MILL USED TO PREPARE THE FIBER WAS A FACTOR IN THE INDUCTION OF THESE TUMORS. HOWEVER, THIS SUGGESTION WAS NOT CONFIRMED BY SUBSEQUENT EXPTS. [R53] *... GROUPS OF 69 CHARLES RIVER CD RATS /WERE EXPOSED BY INHALATION/ TO BALL-MILLED ... CHRYSOTILE FOR 4 HR/DAY ON 4 DAYS/WK FOR 2 YR AT MEAN CONCN OF ABOUT 50 MG/CU M. ONE 1 PAPILLARY CARCINOMA, 1 SQUAMOUS CELL CARCINOMA OF LUNG AND 1 PLEURAL MESOTHELIOMA WERE OBSERVED. NO TUMORS WERE OBSERVED IN CONTROLS. (IT IS IMPORTANT TO NOTE THAT THE MATERIAL WAS COMMINUTED BY VIGOROUS MECHANICAL MILLING (BALL MILLING FOR UP TO 240 HR), WHICH UNDOUBTABLY ALTERED THE FIBER PROPERTIES. [R53] *... GROUPS OF CD WISTAR RATS /WERE EXPOSED/ TO 5 UICC ASBESTOS SAMPLES (AMOSITE, ANTHOPHYLLITE, CROCIDOLITE AND RHODESIAN AND CANADIAN CHRYSOTILES) AT CONCN OF ABOUT 12 MG/CU M RESPIRABLE DUST FOR 7 HR/DAY ON 5 DAYS/WK, FOR SEVERAL LENGTHS OF EXPOSURE: 1 DAY (7 HR), 3 MO, 6 MO, 12 MO OR 24 MO. AT THE END OF EXPOSURES, THE AMT OF DUST IN THE LUNG OF ANIMALS EXPOSED TO THE 2 CHRYSOTILE SAMPLES WAS MUCH LESS THAN THAT IN ANIMALS EXPOSED TO THE 3 AMPHIBOLE SAMPLES. HOWEVER, ALL TYPES OF FIBER PRODUCED ASBESTOSIS, WHICH WAS PROGRESSIVE AFTER REMOVAL FROM THE DUST. FUTHERMORE, WHEREAS NO CARCINOMAS OF THE LUNG WERE FOUND IN THE CONTROL GROUP, CARCINOMAS OF THE LUNG AND MESOTHELIOMAS WERE DEMONSTRATED IN THE GROUPS EXPOSED TO CANADIAN CHRYSOTILE AND TO THE AMPHIBOLES. ONLY CARCINOMAS OF THE LUNG WERE SEEN WITH RHODESIAN CHRYSOTILE. ... AN INCREASING INCIDENCE OF NEOPLASMS WAS OBSERVED WITH INCREASING EXPOSURES TO EACH FORM OF ASBESTOS. EVEN AS LITTLE AS 1 DAY OF EXPOSURE (PROVIDING THE ANIMALS WERE ALLOWED TO SURVIVE AND WERE OBSERVED) PRODUCED NEOPLASIA. [R54] *All commercial types of asbestos have produced mesotheliomas in CD Wistar rats /by intrapleural admin/. A dose of 20 mg of the UICC standard reference samples, crociodolite, amosite, anthophyllite, Canadian and Rhodesian chyrsotiles, produced various numbers of mesotheliomas /in rats by intrapleural admin; species not stated/. [R55] *... /It was found that an intrapleural/ dose of 40 mg asbestos dust on gelatin coated fiber glass pledgets ... /of/ 3 of the UICC samples, crocidolite, amosite and Rhodesian chrysotile, all produced mesotheliomas in about 60% of Osborne-Mendel rats. ... 37.5% mesotheliomas /were induced/ with 3 /intrapleural/ doses of 20 mg of Russian chrysotile. ... Mesotheliomas in Sprague Dawley rats treated with a single /intrapleural/ dose of 67 mg of chrysotile, amosite, or crocidolite /were observed/. [R56] *The fiber diameter, length and shape may be important. All of the 8 separate sub-samples which were pooled in the UICC Canadian chrysotile reference sample, when ground separately to a finer powder, produced a higher incidence of mesotheliomas than did the pooled sample. The highest incidence (69%) was produced by 20 mg of a separate, superfine chrysotile sample fractioned from commerical grade 7 asbestos by water sedimentation. [R57] *... In a series of experiments to compare the biological effects of a pure, asbestos free cosmetic talc with those of the superfine chrysotile asbestos used in previous experiments ... 48 Wistar rats /were inoculated/ intrapleurally with each of the 2 dusts. Eighteen of those receiving chrysotile developed mesotheliomas, but no mesotheliomas were seen in those given talc. [R57] *IN GROUPS OF 50 HAMSTERS GIVEN SINGLE INTRAPLEURAL INJECTION OF 1, 10 OR 25 MG CHRYSOTILE, 0, 4 and 9 MESOTHELIOMAS OCCURRED, RESPECTIVELY. ... /NO DATA FOR CONTROLS ARE GIVEN/ [R58] *... 540 NMRI MICE /WERE INJECTED/ IP WITH 2 OR 6 MG CHRYSOTILE ... /AND PRODUCED/ MESOTHELIOMAS. NO MESOTHELIOMAS OCCURRED IN CONTROLS OR IN MICE GIVEN HEMATITE. ... IP INJECTIONS OF 20 MG ... CHRYSOTILE ... /WERE GIVEN TO/ 13 CHARLES RIVER CD RATS ... THREE PERITONEAL MESOTHELIOMAS WERE OBSERVED. /NO DATA FOR CONTROLS ARE GIVEN/. [R59] *After ip injection /into Wistar rats/ of powdered chrysotile (fiber lengths, 99% < 3 ug, 93% < 1 um and 60% < 0.3 um), ball milled for 4 hr, the latent period for the induction of tumors was found to be longer than after ip injection of standard chrysotile (95% < 5 um). The rate of tumor occurrence after injection of chrysotile was not distinctly influenced by the addition of benzo(a)pyrene. [R59] *... THE CYTOTOXICITY OF ASBESTOS FIBERS IN IN VITRO SYSTEMS /HAVE BEEN DEMONSTRATED/. THIS TOXICITY IS THOUGHT TO BE DUE TO THE INTERACTION OF FIBERS WITH PLASMA MEMBRANES. ... THE EFFECTS OF CHRYSOTILE ... ON L CELLS /MOUSE (C3H) FIBROBLASTS/ AND PERITONEAL AND ALVEOLAR MACROPHAGES IN VITRO /WERE STUDIED/. ... ELECTRON MICROSCOPY /REVEALED/ INCOMPLETE PHAGOCYTOSIS, DISTURBED PERMEABILITY OF CELL MEMBRANE AND LOSS OF ENZYME ACTIVITY. POWDERED CHRYSOTILE ... FIBERS HAD MORE EFFECT ON THE CELLS THAN DID UNPOWDERED FIBERS. [R60] *TISSUES FROM GI TRACT OF RATS FED DIETS CONTAINING 0.5 OR 50 MG CHRYSOTILE ASBESTOS PER DAY FOR 1 WK OR 14 MO WERE EXAM BY LIGHT AND ELECTRON MICROSCOPY . ELECTRON MICROSCOPY REVEALED CHANGES IN MUCOSAL LINING CELLS OF ILEUM OF RATS ON DIETS WITH 50 MG/DAY FOR 14 MO (CONSISTENT WITH MINERAL INDUCED CYTOTOXICITY). [R61] *... CHRYSOTILE ... IN CONCN OF 0.01 MG/ML INDUCED CHROMOSOMAL ABERRATIONS IN CULTURED CHINESE HAMSTER CELLS ... [R60] *CHRYSOTILE ASBESTOS INDUCED CHANGES IN DNA, RNA, PROTEIN, AND BRUSH BORDER ENZYMES IN SMALL INTESTINE MUCOSAL LINING CELLS AND GUT LUMEN OF RATS MAINTAINED ON DIET CONTAINING CHRYSOTILE ASBESTOS FOR 10 MONTHS. [R62] *THE SISTER CHROMATID EXCHANGE TEST WAS CARRIED OUT ON RAT PLEURAL MESOTHELIAL CELLS IN CULTURE IN THE PRESENCE OF CHRYSOTILE A FIBERS. NO DIFFERENCE WAS FOUND BETWEEN THE TREATED CELLS AND THE CONTROL CELLS. [R63] *USING ADULT RAT LIVER DERIVED (ARL-6 AND ARL-18) CELLS IN CULTURE, NO CONSISTENT OR SIGNIFICANT INCREASE OCCURRED IN THE NUMBER OF MUTANTS RESISTANT TO THE PURINE ANALOG, 6-THIOGUANINE, AFTER EXPOSURE TO TOXIC LEVELS OF CHRYSOTILE ASBESTOS. THESE RESULTS SUPPORT THE CONCEPT THAT ASBESTOS IS AN EPIGENETIC CARCINOGEN THAT DOES NOT ALTER DNA. [R64] *HEMOLYTIC ACTIVITY OF CHRYSOTILE FIBERS CAUSED A SELECTIVE RELEASE OF BETA-GALACTOSIDASE FROM RABBIT ALVEOLAR MACROPHAGES. [R65] *RATS WERE EXPOSED TO NIEHS SHORT-RANGE AND TO NIEHS INTERMEDIATE-RANGE CHRYSOTILE FIBERS FOR 1 HR TO 1 YR. PHYSIOLOGICAL STUDIES DONE AFTER 1 YR OF CHRYSOTILE ASBESTOS EXPOSURE DEMONSTRATED A FALL IN TOTAL LUNG CAPACITY AND IN VITAL CAPACITY, WHICH WAS MOST MARKED IN THE ANIMALS EXPOSED TO THE INTERMEDIATE RANGE FIBERS. APPARENTLY, BOTH CLASSES OF CHRYSOTILE FIBERS CAUSE LUNG INJURY BUT LONG FIBERS HAVE THE GREATER TOXICITY. [R66] *CHRYSOTILE ASBESTOS CAUSED NO DOSE RELATED INCREASE IN SISTER CHROMATID EXCHANGE LEVELS IN CHINESE HAMSTER OVARY CELLS (CHO-K1); HOWEVER, MITOTIC DELAY WAS INDUCED. THE DECREASING ORDER OF MAGNITUDE OF INDUCED DELAY IN CHO-K1 CELLS WAS CHRYSOTILE, FINE GLASS, CROCIDOLITE, COARSE GLASS. MITOTIC INHIBITION WAS MORE PRONOUNCED IN THESE CELLS IF THEY WERE STILL IN SUSPENSION WHEN INITIALLY EXPOSED TO THE DUSTS COMPARED WITH 1 HR AFTER PLATING. [R34] *LONG-TERM STUDIES OF RESP FUNCTION AND LUNG MORPHOLOGY WERE CARRIED OUT ON CONTROL GROUPS OF GUINEA PIGS AND MATCHED GROUPS EXPOSED BY INHALATION TO AEROSOLS OF CHRYSOTILE FOR 9 OR 18 DAYS. THE MEASUREMENT OF DYNAMIC COMPLIANCE PROVIDED THE MOST SENSITIVE ASSESSMENT OF THE FUNCTIONAL DISTURBANCES, WHICH WERE MORE EXTENSIVE FOLLOWING CHRYSOTILE EXPOSURE THAN TO AMOSITE EXPOSURE. [R67] *THE EFFECTS OF 3 MO INTERMITTENT INHALATIONAL EXPOSURES OF AMPHIBOLE AND SERPENTINE ASBESTOS ON THE CONSTITUENTS OF THE LOWER RESP TRACT WAS STUDIED. BRONCHOALVEOLAR LAVAGE (BAL) ANALYSES WERE PERFORMED ON 3 GROUPS OF RATS: 1 GROUP WAS EXPOSED TO CHRYSOTILE (SERPENTINE) ASBESTOS, 2ND GROUP WAS EXPOSED TO CROCIDOLITE AMPHIBOLE ASBESTOS, WHILE THE 3RD GROUP WAS SHAM EXPOSED. THE TOTAL BAL CELL YIELDS AND MACROPHAGE CONTENT OF BAL CELLS WERE SIGNIFICANTLY LOWER AFTER ASBESTOS EXPOSURE, ESPECIALLY IN THE CHRYSOTILE EXPOSED GROUP. THESE EFFECTS PERSISTED FOR AS LONG AS 1 YR AFTER CESSATION OF EXPOSURE. MULTINUCLEATED MACROPHAGES WERE SEEN IN BAL CELLS FROM BOTH ASBESTOS EXPOSED GROUPS. STRIKING ULTRASTRUCTURAL ALTERATIONS OF MACROPHAGE MORPHOLOGY WERE NOTED IN BAL CELLS FROM BOTH GROUPS OF ASBESTOS EXPOSED RATS. CHRYSOTILE FIBERS WERE NOT SEEN IN ANY BAL CELLS FROM CHRYSOTILE EXPOSED ANIMALS. HOWEVER, 15 MO AFTER TERMINATING THE EXPOSURE REGIMEN, A SIZEABLE PROPORTION OF BAL MACROPHAGES FROM CROCIDOLITE EXPOSED RATS CONTAINED PHAGOCYTOSED ASBESTOS FIBERS. [R68] *THE EFFECTS OF UNION INTERNATIONALE CONTRE LE CANCER CROCIDOLITE AND CHRYSOTILE A, EITHER OXALIC ACID-LEACHED OR UNLEACHED, ON THE VIABILITY, MORPHOLOGY AND GROWTH CHARACTERISTICS OF RAT PLEURAL MESOTHELIAL CELLS WERE EXAMINED. ADDN OF 5 OR 10 UG/ML OF CROCIDOLITE, EITHER LEACHED OR UNLEACHED, DID NOT SIGNIFICANTLY CHANGE THE GROWTH RATE. A SLIGHT VACUOLATION OF THE CELLS OCCURRED. LEACHED CHRYSOTILE INHIBITED GROWTH AT A CONCN OF 50 UG/ML; WITH 5 OR 10 UG/ML, NO SPREADING OCCURRED, BUT A SHRINKAGE OF SOME CELLS WAS OBSERVED. RESULTS CONFIRM THE DIFFERENT IN VITRO REACTIVITIES OF THE 2 KINDS OF UNLEACHED ASBESTOS FIBERS. LEACHING OF CHRYSOTILE FIBERS DECR THEIR REACTIVITY; ALTERNATIVELY, LEACHING OF CROCIDOLITE INCREASED THE EFFECTS ON PLEURAL MESOTHELIAL CELLS. [R69] *An animal inhalation study was initiated to study the chronic biological effects of inhalation of short chrysotile asbestos fibers. Rats and monkeys were exposed for 18 months, 7 hr/day, 5 days/week to a specially prepared, chrysotile asbestos aerosol. Based upon daily chamber measurements, the mean concentration of fibers in the chamber air was 1.0 mg/cu m. By phase contrast microscopy, the number of fibers greater than 5 micron in length was determined to be 0.79 fiber/cc. Rats were autopsied for pathological and histochemical examination at 1, 3, 6, 12, 18, and 24 months after initiating exposures. No significant differences in the histochemical data were seen between the exposed and control groups. Gross and histopathologic examination of exposed and control groups of rats indicated no compound related lesions, including fibrosis. Open lung biopsies were performed on the chrysotile exposed and the control monkeys 28 months after initiating exposures. Histopathologic evaluation of the lung biopsy tissue showed the presence of asbestos bodies adjacent to the terminal bronchioles of the asbestos exposed monkeys. There was no observed fibrosis in pulmonary tissue. All monkeys are being maintained for an indefinite period and observed for signs of latent pulmonary disease. [R70] *A conscious sheep model, recently developed to study sequentially the bronchoalveolar milieu, was further refined to use in the rapid in vivo assessment of the biological effects of respirable particles. In this model, the anatomically isolated tracheal lobe was selectively exposed to either 100 ml phosphate buffered saline (control group of 12 sheep), or 100 mg of Union Internationale Contre le Cancer Canadian chrysotile fibers in 100 ml PBS (asbestos group of 12 sheep). Bronchoalveolar lavages of the tracheal lobe were obtained prior to exposure and at days 1, 8, 15, 21, 29, 45, and 60 after exposure. Whole lung detailed pulmonary function tests were performed at the same times and the histopathology of the lobe was examined in six sheep in each group at days 29 and 60. In the control sheep, there were no significant changes over time in any of the measures, and lung morphology remained normal. In the latex group, there was no significant change in pulmonary function test, the bronchoalveolar lavages analyses documented early transient increase in cellularity (macrophages and neutrophils at day 1) and only macrophages after; lung histology documented an early macrophagic alveolitis which decreased to less than 10% of the initial inflammatory reaction at day 60, without other distortion of the lung and airway architecture. In the asbestos sheep, the only change in whole-lung pulmonary function test was 10 torr fall in arterial O2 pressure. Bronchoalveolar lavages analyses documented persistent increases in macrophages, neutrophils, and lactate dehydrogenase as well as increasing gamma-globulins. Lung histology revealed a macrophagic and neutrophilic peribronchiolar alveolitis at day 30, which regressed substantially by day 60, but persistent peribronchiolar alveolitis, early fibrosis, and severe distortion of the small airways, lesions comparable to those of early asbestosis in sheep or humans. Thus selective exposure and sequential analyses of the sheep tracheal lobe in terms of bronchoalveolar lavages histomorphology should be valuable for rapid in vivo assessment of toxicity of respirable particles. [R71] *A chronic carcinogenicity study was performed using Charles River CD-1 mice, by intravenous injection of chrysotile asbestos. Long fibers were sonified and sieved to produce fibers/fibrils of a size found to be detached from asbestos cellulose filters in a use situation. Mean fiber length was 2.34 micrometers, range 0.1 to 70 micrometers. There were approximately 5X10+9 fibers/fibrils/mg. There were 6 dosed groups of male and female mice given graduated iv doses by tail vein, one or 4 weekly injections. Maximum single dose was 0.8 mg/kg. Concomitant saline controls, a kaolin particulate control, and a positive control (methylnitrosourethane) were run. Terminal sacrifice occurred for each sex/dose group at 2/3 spontaneous mortality. Chrysotile asbestos was oncogenic, dose and time related, with incidence of lung adenomas increased in both males and females, over controls. There was statistically significant increase in lung carcinomas in chrysotile treated males. Methlynitrosourethane, the positive control, produced a high incidence of primary lung tumors, benign and malignant. Kaolin produced no increase in lung tumors at high doses. [R72] *... Up to 143 ug of chrysotile asbestos per ml drinking water /were fed to mice/ and ... no teratogenic effects /were found/. Studies carried out with blastocyst exposure to the material ... /indicated/ some decrease in postimplantation survival. [R73] *Cytotoxicity of chrysotile to murine peritoneal macrophages was neg correlated with the fiber length of the synthetic asbestos. Cytotoxicity of garnierite was similar to that of chrysotile of similar fiber size. In the range 100-3000 ug/ml a direct positive correlation was found between toxicity and the logarithm of asbestos concn. [R74] *Rabbit lung fibroblasts exposed in vitro to chrysotile asbestos exhibited a lack of contact inhibition (cessation of cell division upon contact with other cells). ... Characteristic of cancerous cells. [R75] *A single oral dose of 5-100 mg chrysotile/kg to rats (3-8/dose) produced a subsequent increase in (3)H thymidine in the stomach (5 and 25 mg chrysotile/kg), duodenum (25 and 50 mg chrysotile/kg) and jejunum (5, 25, 50 and 100 mg chrysotile/kg) after 3 days ... /suggesting/ that cellular proliferation and DNA synthesis may, therefore, be stimulated by chrysotile ingestion. [R76] *Viral interferon production was depressed in monkey kidney cells in vitro by exposure to asbestos fibers. A dose response relation was evident and amosite, anthophyllite, crocidolite, and chrysotile all exhibited similar depressant activities. [R77] *Chinese hamster cells exposed to 0.01 ng/ml chrysotile ... had a significantly increased number of chromosome abnormalities. [R77] *Two lifetime feeding studies were conducted on a limited number of male Wistar rats. 1% chrysotile asbestos with 5% corn oil was added to a rat chow diet and fed to groups of 10 and 40 rats in two separate experiments. In the first study, 6 of 7 surviving animals were found with tumors, whereas one malignancy was observed in eight controls. No GI cancers were observed but two malignancies in the asbestos fed animals were kidney nephroblastomas. In the second study, malignancies were observed in 11/40 asbestos fed animals and 11/40 control animals. Two of the malignancies in the asbestos fed group were in the GI tract; one of the malignancies in the control group was a nephroblastoma, which lessens the significance of these tumors in the asbestos group. [R78] *... IP INJECTIONS OF 20 MG AMOSITE, CROCIDOLITE OR CHYRSOTILE /WERE GIVEN TO/ GROUPS OF 11, 13 13 CHARLES RIVER CD RATS, RESPECTIVELY. THREE PERITONEAL MESOTHELIOMAS WERE OBSERVED WITH CHRYSOTILE, 3 WITH CROCIDOLITE AND NONE WITH AMOSITE, AFTER 7-17 MONTHS. [R59] *ALL COMMERCIAL FORMS OF ASBESTOS TESTED ARE CARCINOGENIC IN MICE, RATS, HAMSTERS AND RABBITS. ... THE SIZE AND SHAPE OF FIBERS INFLUENCE THE INCIDENCE OF TUMORS; FIBERS LESS THAN 0.5 UM IN DIAMETER ARE MORE ACTIVE IN PRODUCING TUMORS. /ALL FORMS OF ASBESTOS FIBERS/ [R33] *Chrysotile did not induce micronuclei in bone-marrow cells of mice or chrosomal aberrations in bone-marrow cells of rhesus monkeys treated in vivo .... Chrysotile ... induced transformation of Syrian hamster embryo cells ... transformed BALB/c3T3 mouse cells and ... rat mesothelial cells. In cultured rodent cells, chrysotile ... induced chromosomal aberrations, and ... induced sister chromatid exchanges ... aneuploidy and micronuclei ... unscheduled DNA synthesis in rat hepatocytes. Amosite, chrysotile and crocidolite were inactive or weakly active in inducing mutation in rodent cells in vitro; none was mutagenic to bacteria. [R79] *The potential carcinogenic effect of taconite tailings, amosite and diatomaceous earth in drinking water /was investigated/. Groups of 20-30 rats were supplied water with these various materials throughout their lifetime. A variety of malignancies were found in each exposure group, although none were attributable to asbestos exposure. However, a pleural mesothelioma was identified in a group exposed to amosite plus chrysotile and a peritoneal mesothelioma was identified in the diatomaceous earth exposed group. [R80] *A study examined the carcinogenic effects of asbestos on groups of 22-24 animals fed 250 mg/week of amosite, crocidolite, or chrysotile in margarine for up to 25 months. No excess malignancies were found in the exposed group compared with the margarine or undosed control groups. [R81] *Experimental coniosis was induced by intratracheal administration to rats of 25 mg or 50 mg of Portland cement, asbestos-cement, as well as chrysotile and crocidolite asbestos. The rats were sacrificed 90, 165 and 180 days after dust administration. The weight of wet lungs and hydroxyproline content in lungs were determined. Statistically significant lower values of fibrogenic effects indices following cement dust administration, as compared to those indices for the other dusts, were found. On the other hand, no significant differences were found between fibrogenic effects indices for asbestos cement containing approx 13% of asbestos and pure asbestos dusts (chrysotile or crocidolite). Furthermore, it seems that the duration of dust action is more important than the dust dose in the development of fibrogenic asbestosis. [R82] *Chrysotile, amosite, and anthophyllite showed no mutagenic activity toward tester strains of Escherichia coli or Salmonella typhimurium. [R83] *Syngeneic PVG rats and C57BL6 mice were inoculated with liquid suspensions of UICC chrysotile A asbestos, DQ12 quartz or the inert particulate titanium dioxide. Rats received 10 mg and mice received 2.5 mg dust intraperitoneally on day 0. Injection of the pathogenic dusts asbestos and quartz was associated with a significant reduction in mitogenic response to PHA and Con A detected in splenocytes removed from animals 14 days after inoculation. Injection of titanium dioxide had no significant effect on splenocyte mitogenesis. Pretreatment of C57BL6 mice with asbestos intraperitoneally also impaired subsequent production of antibody to the protein antigen KLH. These data show that intraperitoneal injection of chrysotile A asbestos and DQ12 quartz had a marked effect on generalized T lymphocyte function. An additional immunomodulatory effect of asbestos injection was shown in C57BL6 mice where in vivo humoral immune responses were suppressed. [R84] *Carcinogenesis bioassays of blocky (nonfibrous) tremolite and amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride were conducted with male and female Fischer 344 rats. The minerals were administered at a concentration of 1% in pelleted diet for diet for the entire lifetime of the rats starting with the dams of the test animals. One group of amosite rats also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. ... No toxicity or increase in neoplasia was observed in the ... controls. Significant increases (p < 0.5) in the rates of C-cell carcinomas of the thyroid and monocytic leukemia were noted in males. Significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and the positive effect was not observed in the amosite plus preweaning gavage group. [R85] */INTRAPLEURAL ADMIN TO CD WISTAR AND OSBORNE-MENDEL RATS/ ALL COMMERCIAL TYPES OF ASBESTOS HAVE PRODUCED MESOTHELIOMAS IN C/D WISTAR RATS. A DOSE OF 20 MG OF THE FIVE UICC STANDARD REFERENCE SAMPLES (SEE SECTION 1.3B) PRODUCED MESOTHELIOMAS IN VARYING NUMBERS - CROCIDOLITE 61%, AMOSITE 36%, ANTHOPHYLLITE 34%, CANADIAN CHRYSOTILE 30% AND RHODESIAN CHRYSOTILE 19%. WITH A DOSE OF 40 MG OF ASBESTOS DUST ON GELATIN-COATED FIBRE-GLASS PLEDGETS, /IT WAS/ FOUND THAT THREE OF THE UICC SAMPLES, CROCIDOLITE, AMOSITE AND RHODESIAN CHRYSOTILE, ALL PRODUCED MESOTHELIOMAS IN ABOUT 60% OF THEIR OSBORNE-MENDEL RATS. INDUCED MESOTHELIOMAS WITH 60 MG OF RUSSIAN CHRYSOTILE. IN ALL THESE STUDIES THERE WAS A LONG LATENT PERIOD BETWEEN INOCULATION AND APPEARANCE OF THE TUMOURS. EVIDENCE THAT THE RESPONSE WAS DOSE RELATED. MESOTHELIOMAS HAVE ALSO BEEN PRODUCED BY OTHER WORKERS: IN RATS, IN HAMSTERS AND IN RABBITS. [R86] NTOX: *PET DOGS WITH SPONTANEOUS MESOTHELIOMA WERE USED TO IDENTIFY ENVIRONMENTAL EXPOSURES THAT MIGHT INCR THEIR OWNER'S RISK OF ASBESTOS-RELATED DISEASE. EIGHTEEN HISTOLOGICALLY CONFIRMED CANINE MESOTHELIOMAS WERE DIAGNOSED AT THE VETERINARY HOSPITAL OF THE UNIVERSITY OF PENNSYLVANIA, PHILADELPHIA, FROM APRIL 1977 TO DECEMBER 1981. SIXTEEN OWNERS OF CASES AND 32 OWNERS OF AGE, BREED, AND SEX-MATCHED CONTROLS WERE INTERVIEWED TO DETERMINE THEIR OCCUPATION AND MEDICAL HISTORY AND THEIR DOG'S MEDICAL HISTORY, LIFE STYLE, DIET, AND EXPOSURE TO ASBESTOS. AN ASBESTOS-RELATED OCCUPATION OR HOBBY OF A HOUSEHOLD MEMBER AND USE OF FLEA REPELLANTS ON THE DOG WERE SIGNIFICANTLY ASSOCIATED WITH MESOTHELIOMA. IN ADDITION, THERE WAS A TREND INDICATING AN INCREASED RISK OF MESOTHELIOMA WITH AN URBAN RESIDENCE. LUNG TISSUE FROM THREE DOGS WITH MESOTHELIOMA AND ONE DOG WITH SQUAMOUS CELL CARCINOMA OF THE LUNG HAD HIGHER LEVELS OF CHRYSOTILE ASBESTOS FIBERS THAN LUNG TISSUE FROM CONTROL DOGS. [R87] *... Levels of Evidence of Carcinogenicity: Intermediate Range: Male Hamsters: Negative; Female Hamsters: Negative; Levels of Evidence of Carcinogenicity: Intermediate Range + dimethyl hydrazine: Male Hamsters: Inadequate; Female Hamsters: Inadequate; Levels of Carcinogenicity: Short Range: Male Hamsters: Negative; Female Hamsters: Negative. [R88] *... Under the conditions of these lifetime studies, short-range and intermediate-range chrysotile asbestos did not induce overt toxicity and did not affect survival when ingested at a level of 1 % in the diet by male and female F344/N rats. There was no evidence of carcinogenicity in male or female rats exposed to SR chrysotile asbestos or in female rats exposed to IR chrysotile asbestos. There was some evidence of carcinogenicity in male rats exposed to IR chrysotile asbestos as indicated by an increased incidence of adenomatous polyps in the large intestine. The cocarcinogenesis studies of 1,2-dimethylhydrazine dihydrochloride and IR chrysotile asbestos were considered inconclusive for determining whether IR chrysotile asbestos had either a tumor enhancing or protective effect, although an increased incidence of neoplasms was observed in the kidneys of female rats exposed to DMH plus IR chrysotile as compared with those exposed to DMH alone. [R89] *... In a 6 week inhalation exposure study on rats using about 30 mg/cu m /was/ reported that, over a period of 2 months, the rate of clearance for chrysotile was higher by a factor of 3 than that for amosite or crocidolite. In addition, the retention of chrysotile, as measured a few days after the end of the 6 week exposure period, was only about one third that of the amphiboles. [R90] *... Short fibers (< 10 um in length) are cleared more rapidly than long fibers(> 10 um in length). In this study, rats were exposed by inhalation to chrysotile or amosite fibers at 10 mg/cu m for 12 months. The lung clearance percentages over a 6 months period after exposure were 55 and 90% for long and short chrysotile fibers, respectively. [R91] *... Rats /were/ exposed to 5 mg/cu m of chrysotile B for 24 months. They found that most of the fibers had undergone splitting by the end of the inhalation period and that chrysotile fiber numbers rapidly declined following inhalation [R90] *In an inhalation study on rats (10 mg/cu m UICC chrysotile B for up to 12 months), ... a mean fibrosis grade 4.1 and a 25% incidence of adenomas and carcinomas /was/ observed. ... Using Canadian chrysotile as a positive control in experiments with NMM(V)Fs in rats (5 mg/cu m chrysotile B, 5 hr/day, 5 days/week for 24 months), reported unquantified fibrosis and pulmonary tumors in 2 1 % of male and 17% of female rats. ... Exposed rats to 6 mg/cu m Calidria chrysotile 5 hr/day, four times each week for 12 months, reported the presence of pulmonary fibrosis in 42% of rats, but found no pulmonary tumors. [R92] *... /It was/ found that the alveolar clearance of chrysotile was faster than that of crocidolite. In their study, rats were exposed by inhalation to 10 15 mg/cu m of either chrysotile (6 weeks) or crocidolite (90 days). At the end of exposure, lung fiber concentrations and size distributions were similar for both types of fibers. However, during the subsequent 90 days, 95% of chrysotile (by fiber number) was removed, whereas there was no measurable clearance of crocidolite. Similar findings were reported ... /that/ the fiber retention of chrysotile in the rat lung after 5 and 20 days of inhalation exposure to 8 mg/cu m was considerably lower than the fiber lung retention of crocidolite asbestos. [R93] *Several studies have shown that short fibers are generally cleared at faster rates than long fibers. In their inhalation experiment, ... exposed rats to UICC Canadian chrysotile for 5 hr at 5 mg/cu m. Animals were killed at different intervals over the subsequent 90 days and their lungs lavaged. In the lung tissue, the prevalence of fibers less than 5 gm in length decreased while that of fibers longer than 5 um increased with post exposure time. An opposite pattern of distribution was observed in the bronchoalveolar lavage (BAL) fluids. This indicates that fibers greater than 5 um in length are cleared less efficiently from the rat lung than fibers less than 5 um in length. [R90] *... Rats and monkeys /were/ treated with a specially prepared short fiber sample of chrysotile for 18 months (the mass dose level was only 1 mg/cu m, of which < 1 fiber/ml was longer than 5 um as measured by PCOM). After a total follow up of 24 months the rats had developed neither fibrosis nor pulmonary tumors. No fibrosis was found in monkeys by open lung biopsies after 24 months. [R94] *After exposing rats by inhalation to chrysotile asbestos at a dose level of approximately 10 mg/cu m for up to 91 days, ... /it was/ found that the expression of the Ia antigen on macrophages lavaged from crocidolite treated animals was increased 4 fold in male Fischer 344 rats while chrysotile produced no increase over controls. [R95] NTP: *Carcinogenesis studies of short range (SR), intermediate range (IR), or intermediate range chrysotile asbestos in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted with male and female Syrian golden hamsters. Both forms of chrysotile asbestos were administered at the concentration of 1 % in pelleted diet for the entire lifetime of the hamsters starting with mothers of the test animals. Group sizes varied from 125 to 253. Starting at 6 weeks of age, male and female hamsters in the intermediate range chrysotile/DMH study were given oral doses of DMH (4 mg/kg) every other week for a total of 5 doses. ... The results of the combination study (IR chrysotile plus DMH) did not yield a significant increase in tumors above the background level observed in the DMH group alone or in the untreated control group. The DMH failed to yield a background level of intestinal tumors high enough to provide a valid test of the cocarcinogenic potential of chrysotile asbestos. For this reason, the cocarcinogenic potential of orally administered asbestos should be considered untested. Under the conditions of these studies, neither short range chrysotile nor intermediate range chrysotile asbestos was carcinogenic when ingested at 1% levels in the diet by male and female Syrian golden hamsters. While there were increases in the rates of adrenal cortical adenomas in male and female hamsters exposed to intermediate range chrysotile asbestos compared to the pooled groups, these incidence rates were not different when compared with the concurrent control groups. Additionally, the biologic importance of adrenal tumors in the absence of target organ (gastrointestinal tract) neoplasia is questionable. The cocarcinogenesis studies using IR chrysotile asbestos and 1,2-dimethylhydrazine dihydrochloride were considered inadequate because there was no increase in intestinal neoplasia in the DMH group. Levels of Evidence of Carcinogenicity: Intermediate Range: Male Hamsters: Negative; Female Hamsters: Negative; Levels of Evidence of Carcinogenicity: Intermediate Range + dimethyl hydrazine: Male Hamsters: Inadequate; Female Hamsters: Inadequate; Levels of Carcinogenicity: Short Range: Male Hamsters: Negative; Female Hamsters: Negative. [R88] *Lifetime toxicology and carcinogenesis studies of short-range (SR) and intermediate-range (IR) fiber length chrysotile asbestos were conducted in groups of 88-250 male and female F344/N rats. Both forms of asbestos were administered at a concentration of 1 % in pelleted diet for the lifetime of the rats, starting with the dams of the test animals. Subgroups of 100 male and female IR chrysotile exposed rats also received 0.47 mg/g IR chrysotile asbestos in water by gavage during lactation (preweaning, PW). At 9 weeks of age, additional subgroups (125-175) of control and IR chrysotile exposed rats received 7.5 mg/kg (male) or 15 mg/kg (female) 1,2-dimethylhydrazine dihydrochloride (DMH) by gavage every other week for a total of five doses. When the survival of either the control or test group reached 10%, both groups were killed. Under the conditions of these lifetime studies, short-range and intermediate-range chrysotile asbestos did not induce overt toxicity and did not affect survival when ingested at a level of 1 % in the diet by male and female F344/N rats. There was no evidence of carcinogenicity in male or female rats exposed to SR chrysotile asbestos or in female rats exposed to IR chrysotile asbestos. There was some evidence of carcinogenicity in male rats exposed to IR chrysotile asbestos as indicated by an increased incidence of adenomatous polyps in the large intestine. The cocarcinogenesis studies of 1,2-dimethylhydrazine dihydrochloride and IR chrysotile asbestos were considered inconclusive for determining whether IR chrysotile asbestos had either a tumor enhancing or protective effect, although an increased incidence of neoplasms was observed in the kidneys of female rats exposed to DMH plus IR chrysotile as compared with those exposed to DMH alone. [R89] POPL: *Special groups at risk may include neonates and children; however, no data exist on the relative sensitivity to asbestos of infants and children undergoing rapid growth. Concern exists because fibers deposited in the tissues of the young may have an extremely long residence time during which malignant changes could occur. Individuals on kidney dialysis machines may also be at greater risk as fluids, potentially contaminated with asbestos fibers can enter the blood stream directly or, in selected instances, the peritoneal cavity (peritoneal dialysis). /Asbestos cmpd/ [R96] ADE: *... /AFTER/ CHRYSOTILE /WAS FED/ TO RATS ... THE PRESENCE OF FIBERS OF THE MATERIAL /WAS NOTED/ IN MANY SITES IN COLONIC EPITHELIUM AND LAMINA PROPRIA ... [R9, 164] *In studies in which chrysotile, labelled intrinsically with radioactive trace metals by neutron irridation, was injected intrapleurally into rats. ... Evidence for passage of a small amount of the fiber from the pleural cavity and lungs into such other organs as the liver /was found/; after the intrapleural inoculation ... into rats, as much as 22% of the admin dose was found later in the liver. In a similar expt ... /it was/ reported that a population of radionuclides, consistent with that expected on the basis of the labelled chrysotile, was found in the heart, lungs, diaphragm and chest muscles. [R97] *IN CASES OF LUNG CANCER WITHOUT LUNG FIBROSIS, A HIGHER CONCENTRATION OF ASBESTOS FIBERS, MOSTLY OF THE CHRYSOTILE TYPE, WAS CLEARLY DEMONSTRATED IN PERIPHERAL AREAS OF THE LUNG. OPTICAL AND TRANSMISSION ELECTRON MICROSCOPIC STUDY OF LUNG AND PLEURA REVEALED A PREFERENTIAL ACCUMULATION OF CHRYSOTILE VERSUS AMPHIBOLE FIBERS IN PLEURA; THE MEAN LENGTH OF THE FIBERS WAS GREATER IN THE LUNG AND VISCERAL PLEURA THAN IN THE PARIETAL PLEURA, THIS BEING PARTICULARLY THE CASE FOR THE AMPHIBOLES. THERE WAS NO RELATIONSHIP BETWEEN THE NUMERICAL CONCN OF FIBERS IN LUNG PARENCHYMA AND THAT IN PARIETAL PLEURA. GENERALLY, THE CONCN WAS ALWAYS LESS IN PLEURA THAN IN PARENCHYMA; HOWEVER, THE DISTRIBUTION OF CHRYSOTILE MICROFIBRILS IN THE PLEURA WAS NOT HOMOGENOUS, AND IN SOME AREAS HIGH CONCN IDENTICAL TO THOSE IN THE PARENCHYMA COULD BE OBSERVED. [R98] *THE RETENTION OF DIFFERENT TYPES OF ASBESTOS IN RATS FOLLOWING EXPOSURE TO THE SAME CONCN OF RESPIRABLE DUSTS ... /HAS BEEN DESCRIBED/. FOR THE AMPHIBOLES, THERE WAS A SIMILAR PATTERN WITH AN ALMOST PROPORTIONAL INCREASE OF LUNG DUST WITH DOSE. MUCH LESS DUST WAS FOUND FOR THE CHRYSOTILES, AND NO INCREASE OF DUST CONTENT WAS SHOWN IN THE LUNGS. DUST IN THE LUNGS OF ANIMALS WITH 6 MONTHS' EXPOSURE HAD BEEN PARTIALLY CLEARED 18 MO AFTER THE INHALATION PERIOD. ABOUT 74% OF THE AMOSITE AND CROCIDOLITE AND 41% OF THE ANTHOPHYLLITE WERE ELIMINATED. THE ELIMINATION RATE OF CHRYSOTILES COULD NOT BE DETERMINED EXACTLY, BECAUSE OF THEIR LOW OCCURRENCE IN THE LUNG. [R99] *IN STUDIES IN WHICH CHRYSOTILE, LABELED ... WITH RADIOACTIVE TRACE METALS BY NEUTRON IRRADIATION ... INJECTED INTRAPLEURALLY INTO RATS ... EVIDENCE /FOUND/ FOR PASSAGE OF SMALL AMT OF FIBERS FROM PLEURAL CAVITY AND LUNG INTO SUCH OTHER ORGANS AS LIVER ... IN ... /ANOTHER EXPT IT/ WAS FOUND IN HEART, LUNG DIAPHRAGM AND CHEST MUSCLES. INTRAVENOUS-INJECTED ASBESTOS IS FOUND MOSTLY IN LIVER AND LUNG OF RATS ... CHRYSOTILE INJECTED IV INTO PREGNANT RATS CROSSED PLACENTA AND APPEARED IN LIVER AND LUNG OF FETUS ... [R97] *AFTER ORAL ADMIN OF CHRYSOTILE ASBESTOS INTO NEWBORN BABOON, THE HIGHEST CONCN OF CHRYSOTILE FIBERS WAS FOUND IN THE KIDNEY CORTEX FOLLOWED BY LYMPH NODES, SPLEEN, COLON, ESOPHAGUS, KIDNEY MEDULLA, STOMACH, AND LIVER. FIBER SIZE DISTRIBUTION OF THE FIBERS RECOVERED INDICATED THAT THE LONGEST FIBER WAS RETAINED IN THE KIDNEY CORTEX. [R100] *NEWBORN RATS, FROM MOTHERS GAVAGED WITH CHRYSOTILE ASBESTOS DURING PREGNANCY, WERE GAVAGED TWICE A WK AT 50 MG/KG BEGINNING AT DAY 7 UNTIL THEIR NATURAL DEATH OR SACRIFICE. THE AVERAGE FIBER RECOVERY FROM THE KIDNEY CORTEX OF THE 4 TEST GROUPS WAS 5.34X10+3/MG DRY WT; WHEREAS, THE AVERAGE FIBER LEVEL IN CONTROL TISSUES WAS 0.23X10+3 MG/DRY WT. [R101] *Most inhaled or directly ingested asbestos particles which pass through the gastrointestinal tract are excreted in feces. Some fibers are absorbed by the gastrointestinal tract and are eventually eliminated through the urinary tract. [R102] *After intragastric injection of chrysolite into rats, the largest amount of fiber was found in the omentum surrounding the small intestine; lesser quantities were found in the blood, spleen, heart, brain and lungs. After IV injection, fibers appeared mostly in the liver, lung and spleen. The same type of administration in pregnant rats resulted in fibers in the fetus and fetal liver. [R103] *Dosages of 1-3 mg (1 mg/ml of water) were injected into the femoral vein of female Wistar rats at 2 day intervals from days 10-14 of gestation. Total dose varied from 4-12 mg of asbestos. The fetuses were removed by Caesarean section the day before parturition in a manner that prevented cross-contamination from the mother; the livers and lungs were then analyzed by electron microscopy. Asbestos fibers were found to cross the placenta but the extent of this occurrence was highly variable. The livers and lungs analyzed were selected at random and thus could have come from different fetuses in the same uterus. In the first experiment, the highest number of fibers found in fetal liver and lungs came from a dam administered four 3 mg injections (total dose = 12 mg). Numbers of fibers found in livers and lungs were 27.03X10+6 fibers/g and 139.97X10+6 fibers/g respectively. In a second experiment, the highest number of fibers found in fetal liver and lung came from a dam administered five 2 mg injections (total dose = 10 mg). Numbers of fibers found in the liver and lung were 100.12X10+6 fibers/g and 2.90X10+6 fibers/g, respectively. [R104] *Chrysotile dust injected intraperitoneally into rats was found to migrate into the peribronchial and perivascular tissues of the lung and was observed in alveolar epithelial cells [R105] *Rats fed chrysotile, crocidolite, or amosite exhibited no retention of fibers in the gut lumen and no penetration of the mucosa. The transit time for the majority of fibers was 48 hours, and there was no asbestos either in the feces or in the gut after 7-28 days. [R106] *Twenty female CBA mice were injected subcutaneously in two sites. Each injection contained 10 mg fiber suspended in 0.4 ml saline. Each animal received three injections into each flank. The flank was chosen as a site well distant from the thorax. Three fiber types: crocidolite, amosite, and chrysotile, were tested to study their distribution. All three fiber types were found in the submesothelial tissues of the thorax and abdomen. In addition, extensive inflammatory changes and some sarcomas developed at the injection sites, while transport of fibers to submesothelial tissues culminated in mesothelioma. [R107] ACTN: *Animal experimentation ... indicated that the important factor in the carcinogenicity was the dimensionality of the fibers rather than their chemical properties. ... Greatest carcinogenicity was related to fibers that were less than 2.5 cu m in diameter and longer than 10 cu m. /Asbestos cmpd/ [R108] *HEMOLYSIS BY CHRYSOTILE FIBERS MAY BE RELATED TO ADSORPTION OF THE RED BLOOD CELL MEMBRANES ON THE FIBERS AND NOT TO AN INTERACTION BETWEEN MAGNESIUM FROM THE FIBERS AND SIALIC ACID FROM RED BLOOD CELLS. [R109] */It was/ showed that magnesium is removed from chrysotile fibers following their administration to rats by intratracheal instillation and that leaching rates are much greater during the first month than subsequently. These authors also showed that chrysotile fibers, from which the magnesium had been removed by prior treatment with oxalic acid in vitro, were removed from the lung with a half time of only a few days. This explains the observation that the carcinogenic potency of magnesium leached chrysotile is much reduced, or eliminated completely, compared with that of the untreated fiber ... . [R110] INTC: *... INTRATRACHEAL INJECTION OF 2 MG RUSSIAN CHRYSOTILE ON WHICH 0.44 MG BAP (BENZO(A)PYRENE) WAS ABSORBED (3 TIMES AT MONTHLY INTERVALS) OR OF 2 MG RUSSIAN CHRYSOTILE TOGETHER WITH 5 MG (BENZO(A)PYRENE) (SINGLE INJECTION) PRODUCED LUNG PAPILLOMAS, EPIDERMOID CARCINOMAS, RETICULOSARCOMAS OR PLEURAL MESOTHELIOMAS IN 6/21 and 6/11 RATS, RESPECTIVELY, WITHIN 9-28 MONTHS. NO LUNG TUMORS OR MESOTHELIOMAS OCCURRED IN 49 RATS GIVEN 3 DOSES OF 2 MG OF CHRYSOTILE ALONE OR IN 19 RATS GIVEN A SINGLE DOSE OF 5 MG (BENZO(A)PYRENE) ALONE, DURING, OR UP TO, 28 MONTHS OF OBSERVATION. [R58] *... AMONG 31 HAMSTERS RECEIVING TOTAL DOSE OF 4.5 MG (BENZO(A)PYRENE) PLUS 12 MG CHRYSOTILE /BY INTRACHEAL INJECTION/ OVER PERIOD OF 12 WK, 7 DEVELOPED PULMONARY ADENOMAS, 7 PULMONARY CARCINOMAS, 9 TRACHEAL PAPILLOMAS AND 1 LARYNGEAL PAPILLOMA. NO LUNG TUMORS WERE OBSERVED IN 17 HAMSTERS RECEIVING CHRYSOTILE ALONE, AND ONLY 1 PULMONARY CARCINOMA BUT 9 TRACHEOBRONCHIAL PAPILLOMAS WERE FOUND AMONG 38 HAMSTERS RECEIVING (BENZO(A)PYRENE) ALONE. [R59] *EXPOSURE OF RAT LIVER EPITHELIAL CELLS TO CHRYSOTILE ALONE DID NOT INCREASE THE MUTANT INCIDENCE WHEREAS BENZO(A)PYRENE WAS MUTAGENIC. SIMULTANEOUS EXPOSURE OF THE CELLS TO CHRYSOTILE AND BENZO(A)PYRENE RESULTED IN AN ENHANCED MUTANT RECOVERY COMPARED TO EXPOSURE TO EITHER OF THESE SUBSTANCES ALONE. [R111] *THE COMBINED CARCINOGENIC ACTIVITY OF INTRATRACHEALLY INOCULATED CANADIAN CHRYSOTILE ASBESTOS DUST AND ORALLY OR SC ADMIN N-NITROSODIETHYLAMINE WAS STUDIED IN LONG TERM EXPERIMENTS IN SYRIAN GOLDEN HAMSTERS. IN ANIMALS TREATED WITH ASBESTOS ONLY, NO LUNG TUMORS DEVELOPED, AND SINGLE TRACHEAL OR LARYNGEAL PAPILLOMAS WERE FOUND IN ONLY A VERY FEW CASES. IN ANIMALS TREATED WITH CHRYSOTILE ASBESTOS AND N-NITROSODIETHYLAMINE , A SYNERGISTIC EFFECT WHICH INCREASED THE INCIDENCE OF LUNG TUMORS WAS OBSERVED. [R112] *There is now growing evidence that asbestos fibers could act in association with genotoxic compounds, either as cocarcinogens or promoters, in the process of carcinogenesis. The hepatocyte/unscheduled DNA synthesis assay system has been used to investigate the capacity of fibers to modulate the effects of genotoxic compounds on the cell. The hepatocytes can engage in phagocytosis of chrysotile fibers. Measurement of unscheduled DNA counting was performed by a biochemical procedure involving liquid scintillation counting of a purified DNA fraction as well as by radioautography. Both liquid scintillation counting and radioautography revealed that chrysotile asbestos fibers UICC B at concentrations up to 100 ug/ml do not elicit UDS, whereas 2-acetylaminofluorene at low concentrations (0.05-0.625 ug/ml) significantly induces it in parallel positive controls. In an attempt to test the cocarcinogen hypothesis, cultures of hepatocytes were simultaneously exposed for 20 hr to 2-AAF (0.05 and 0.25 ug/ml) and asbestos fibers (1 and 10 ug/ml) given as simple mixtures. It was found that the 2-AAF-induced unscheduled DNA counting activity was the same whether fibers were present or not. This was observed with both unscheduled DNA synthesis evaluation procedures at all concentration combinations selected. An analysis of variance applied to the data collected from several experiments confirmed that there was no significant 2-acetylaminofluorene fiber interaction. These data suggest the absence of intrinsic genotoxic properties for chrysotile fibers. They also indicate that the modulation of the cellular response to genotoxic agents by asbestos fibers is not detected under the test conditions of this report and may require longer term exposures to be expressed. [R113] *The relationship between asbestos exposure and smoking indicates a synergistic effect of smoking with regard to lung cancer. Further evaluations indicate that this synergistic effect is close to a multiplicative model. ... The risk of mesothelioma appears to be independent of smoking, and a significantly decreasing trend in risk was observed with the amount smoked in 1 study. /Asbestos cmpd/ [R114] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Chrysotile asbestos is a naturally formed mineral. [R2, p. 3(78) 272] *... The origin of asbestos has been the subject of extensive geological research. Serpentine asbestos occurs under widely differing geological conditions from the amphiboles. Similary, the modes of occurrence or the manner in which the fibers are physically imbedded in the host rock also differ widely. The current opinion is that chrysotile fiber resulted from two separate metamorphic reactions in ultrabasic rocks of igneous origin. The initial hydrothermal reaction altered the olivines and pryroxenes to serpentine. At a subsequent point the serpentine was redissolved and the mineral rich solutions flowed into cracks and crevices in the host rock where chrysotile fiber was reprecipitated. In this reprecipitation process, asbestos fiber was usually deposited in a cross-vein mode of occurrence; ie, the fiber is arranged perpendicular to the wall rock. In some cases, chrysotile was either deposited or affected by earth movements such that the fibers lie principally parallel to the wall rock. This mode of occurrence is referred to as slip fiber. The 3rd and unusual mode of occurrence of chrysotile is referred to as a massive or agglomerated form wherein the fibers have been deposited as platelets having no specific fiber orientation. This unique formation has been found and commercially mined in the New Idria serpentine deposits of California and at Stragari, Yugoslavia. In these cases the asbestos content of the ore is abnormally high, but the fiber length is very short as compared to commercially useful cross-vein. [R2, p. 3(87) 267] *OCCURS NATURALLY IN TWO FORMS, PLATY ANTIGORITE AND FIBROUS CHRYSOTILE (COMMON FORM OF ASBESTOS). [R11] FATE: *AQUATIC FATE: ... The leaching of asbestos in distilled water and at body temp (37 deg C) /was determined/. ... although ... chemical equilibrium /could not be reached/ after 2 months of leaching, a significant amount of the chrysotile had dissolved (1,000 umol of Mg/g asbestos had been leached). [R4, p. 7-8] *AQUATIC FATE: ... The effect of milling (done to produce industrial useful fibers) on the chemical structure of asbestos /was determined/. The milling altered the crystallinity of the chrysotile which appeared to include shifts in interlayer bonding between the magnesium and silica sheets and changes in hydroxyl configuration. The changes would theoretically increase the leachability of chrysotile in water and might replicate the effect that transport in the aquatic environment would have on the individual asbestos fiber. [R4, p. 7-8] *AQUATIC FATE: ... In a study of the zeta potentials of natural and synthetic chrysotiles ... a wide variety of zeta potentials /were found/. Strongly positive values were found in samples containing an excess of magnesium in the form of brucite (Mg(OH)2). Synthetic chrysotile and natural samples containing little or no brucite, gave moderately positive zeta potentials over the pH range of 3-11. Feebly positive or weakly negative zeta potentials were found in chyrsotiles which had undergone weathering (due to natural leaching of the brucite layer). Since the pH at the ambient concentration of Mg2+ ions near the surface are the main controlling factors of the chrysotile zeta potential, and since chrysotile's brucite layer is susceptible to leaching in aqueous solution, the zeta potential of chrysotile is a constantly changing value. These results explain the temporary colloidal stability of dilute suspensions of chrysotile in the environmental media and the mutual coagulation of chrysotile and amphibole asbestos slurries. [R4, p. 7-12] *AQUATIC FATE: ... Due to the positive zeta potential of chrysotile in environmental media, low viscosity suspensions could be prepared by means of the inherent charge of the chrysotile surfaces. This charge however, is so small in pure chrysotile that dispension was obtained only with short fibers and low fiber concentrations (1%). By increasing the concn of certain metallic salts ... it was found that low viscosity suspensions could be prepared under almost any environmental conditon. These observations suggest that the presence of trace metals will produce a suspension of chrysotile asbestos in water which will persist until sufficient magnesium has leached from the chrysotile structure to degrade the suspension. ... It is probable that under certain conditions asbestos will persist in the water column until its concentration becomes high enough to destroy the suspension or until leaching of the brucite layer decays the zeta potential to a point where it will become negative. [R4, p. 7-12] WATC: *SURFACE WATER: LEVELS OF UP TO 12.46 UG/L CHRYSOTILE ASBESTOS ... WERE FOUND IN JUMATA AND CONNECTICUT RIVERS. A STUDY OF THE GREAT LAKES AND ST. LAWRENCE RIVER BYWATERS SHOWED AVG CONCN OF ABOUT 1.7 MILLION ASBESTOS FIBERS/L. LOCATIONS WITH HIGHER COUNTS WERE FOUND ALONG THE NORTH SHORE OF LAKE SUPERIOR BETWEEN SILVER BAY AND DULUTH, ALONG THE ST. CLAIR RIVER, DOWNSTREAM FROM MONTREAL, AND IN THE ASBESTOS MINING DISTRICT IN THE PROVINCE OF QUEBEC. [R115] *RAINWATER: RAINWATER SAMPLES FROM RESIDENTIAL AREAS OF 2 SUBURBAN CHICAGO, ILL, LOCATIONS WERE EXAMINED. NONE OF THE SAMPLES CONTAINED LEVELS THAT WERE SIGNIFICANTLY ABOVE LAB CONTAMINATION LEVELS. RAINWATER SAMPLES FROM ONE LOCATION NEAR BUSY INTERSECTION AND BUILDING CONSTRUCTION SITE SHOWED SIGNIFICANT LEVELS OF CHRYSOTILE INDICATING MECHANISM BY WHICH AIRBORNE PARTICLES TRANSFERRED TO SURFACE WATER. [R116] *DRINKING WATER: Samples of raw, treated, and distributed tap water were collected from 71 municipalities across Canada and analyzed for asbestos content by transmission electron microscopy. Chrysotile asbestos was identified as the major asbestos type present in drinking water with some 5% of public water supplies containing asbestos at concentrations greater than 10 million fibers per liter. Improvement factors of up to 300 were observed for the removal of chrysotile fibers from drinking water during treatment, indicating that coagulation/filtration treatment is efficient for this purpose. [R117] *DRINKING WATER: ... THE USE OF A/C PIPE IN CONNECTICUT PUBLIC WATER SUPPLIES ... /WERE STUDIED/. A TOTAL OF 149 PUBLIC WATER SUPPLIES IN 82 TOWNS WERE EVALUATED. PRELIMINARY ELECTRON MICROSCOPY MEASUREMENTS INDICATED THAT 19 WATER SAMPLES EXPOSED TO A/C PIPE CONTAINED CHRYSOTILE FIBER RANGING FROM BELOW DETECTABLE LIMITS (10,000 FIBERS/L) TO 700,000 FIBERS/L. [R8, 51] *The majority (approximately 95%) of water consumers in the United States are exposed to asbestos fiber concentrations of less than 10 fibers/l. In a few areas people are exposed to concentrations between 1 and 10 million fibers/l with intermittent exposures over 100 million fibers/l. There is at least one area where continuous exposure is over 100 million fibers/l. [R118] *Everett, Washington, with concentrations of chrysotile above 1X10+7 fibers/l; Seattle, with from 1X10+6 to 1X10+7 fibers/l; and San Francisco, with chrysotile concentrations about 1X10+7 fibers/l in some systems. [R102] *The mass concentrations of chrysotile asbestos in the water of cities with less than 1X10+6 fibers/l are likely to be less than 0.01 ug/l, corresponding to a daily intake of less than 0.02 ug. However, in areas with significant contamination, whether from natural sources, man's activities, or erosion from A/C pipes, the intake of asbestos from water can exceed 2 ug/day. [R118] *GROUND WATER: In a study of chrysotile asbestos fibers in California waters, analyzed groundwater samples from five wells and the reservoir that recharged them (located in the San Luis Obispo area). The wells were essentially recharged through serpentine rock. The reported range of values was from 2.6-170 million fibers/liter. The reservoir concentration was an order of magnitude higher than the highest well value. [R119] *GROUND WATER: Several studies reported findings for Pacific Coast water supplies. Water supply samples from the Lake Crystal Reservoir in San Francisco contained concentrations of chrysotile fibers as high as 130 million fibers/liter. Erosion of the serpentine rock formation was reported as the primary cause of contamination in the Bay area. A total of 34 finished water samples were found to contain > 1 million fibers/liter > 50% of those samples had concentrations of asbestos > 10 million fibers/liter. [R120] ATMC: *CHRYSOTILE ASBESTOS IS COMMON AIR POLLUTANT IN MOST LARGE URBAN AREAS IN UNITED STATES. [R121] *The distribution of chrysotile concentrations found in samples taken over 4 to 8 hours in 10 schools. Chrysotile asbestos concentrations ranged from 9 ng/cu m to 1950 ng/cu m, with an average of 217 ng/cu m. Outside air sampes at three of the schools varied from 3 ng/cu m, with an average of 14 ng/cu m. [R122] *A study of 187 quarterly composite samples collected in 48 USA cites from 1969 to 1970 showed chrysotile asbestos to be present in virtually all metropolitan areas. [R123] *In study of ambient air in New York City, collected samples in the five boroughs of New York (Manhatian, Brooklyn, Bronx, Queens, Staten Island). Samples were taken during daytime working hours and, due to construction and automobile activities, concentrations may have been higher compared to nightime periods. Of the 22 samples taken in the five boroughs, a range of 2-65 ng/cu m was reported, with an overall average of 17.4 ng/cu m, medium concentration of 13.7 ng/cu m for this study. [R124] *In another study also conducted in lower Manhattan near sites where spraying of asbestos containing fireproofing material was taking place. The study was to determine if such activity contributed to elevated asbestos levels. The results proved that the spraying did increase the air concentrations of asbestos as chrysotile fibers in 22 samples ranged from 3.5-375 ng/cu m, with an overall average concentration of 40.9 ng/cu m. .../With a/ reported median concentration of 22 ng/cu m for this study. [R124] *Air concentrations over 24 HR in metropolitan areas usually are less than 5 ng/cu m but can range up to 20 ng/cu m. Values up to 50 ng/cu m are found during daytime hours in locations where construction activities and traffic can be contributing sources. [R125] OEVC: *Measurements using electron microscopic techniques have established the presence of asbestos /chrysotile/ in the urban ambient air, usually at concentrations less than 10 ng/cu m. Concentrations of 100 ng/cu m to 1000 ng/cu m have been measured near specific asbestos emission sources, in schools where asbestos containing materials are used for sound control, and in office buildings where similar materials are used for fire control. /Asbestos cmpd/ [R126] RTEX: *UNDER CERTAIN WATER QUALITY CONDITIONS, A/C PIPE CAN DETERIORATE. EVIDENCE FROM LABORATORY AND FIELD TESTS HAS SHOWN THAT ASBESTOS FIBERS CAN BE RELEASED FROM DETERIORATED PIPE. ... SINCE ASBESTOS IN A/C PIPE IS PRINCIPALLY THE CHRYSOTILE FORM, THE MAJORITY OF FIBERS RELEASED FROM THE PIPE ARE CHRYSOTILE. [R8, 60] *A significant fraction of the fibers inhaled can be brought up from the respiratory tract and swallowed. This leads to an ingestion exposure from air sources of up to 0.1 ug/day, although most of the population exposure is from 0.01 to 0.05 ug/day. [R125] *... MAY OCCUR DURING MINING OF FIBROUS MINERALS ... [R33] *CHRYSOTILE IS THERMALLY TRANSFORMED TO FORSTERITE WHEN ASBESTOS MATS ARE USED DURING THE INDUCTION GLOWING IN PLANT CONSTRUCTION. BOTH CHRYSOTILE AND FORSTERITE RETAINING CHRYSOTILE MORPHOLOGY CONTRIBUTE TO THE ASBESTOS DUST FORMATION IN THE WORKING PLACE. [R127] *Drugs administered by syringes with chrysotile packed pistons may also be a source of exposure to asbestos fibers. [R128] *DUSTFALL ALONG ROADS AND TRAILS BEING USED RECREATIONALLY IN THE CLEAR CREEK AREA OF SAN BENITO COUNTY, CALIFORNIA, LOCATED IN THE NEW IDRIA SERPENTINITE, WAS GREATER THAN OR EQUAL TO 90% CHRYSOTILE ASBESTOS. THE AVERAGE TOTAL DUST CONCN ESTIMATED FROM PERSONAL SAMPLERS WAS APPROX 20 MG/CU M CONTAINING 90% CHRYSOTILE. THIS IS THE FIRST DEMONSTRATION OF ASBESTOS EXPOSURES OF THIS MAGNITUDE, IN SIZE RANGES KNOWN TO BE PATHOGENIC, RESULTING FROM NATURAL DEPOSITS NOT ASSOCIATED WITH MINING, MILLING, OR INDUSTRIAL USE. [R129] */Individuals/ include asbestos insulation workers miners and millers ... and asbestos factory employees. ... [R130] *... Human exposure to asbestos is limited to drinking water, food and ambient air ... [R131] *An increased risk is also associated with increased exposure to asbestos in water in municipalities such as San Francisco or Seattle where asbestos occurs naturally in water, in cities where there is an interaction between aggressive water and asbestos cement pipe, or in cities whose water may be contaminated as a result of asbestos operations. /Asbestos cmpd/ [R132] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers asbestos to be a potential occupational carcinogen. /Asbestos/ [R23] OSHA: *The employer shall ensure that no employee is exposed to an airborne concentration of asbestos in excess of 0.1 fiber/cu cm of air as an 8-hr TWA as determined by the method prescribed in Appendix A to this section, or by an equivalent method. /Asbestos/ [R133] NREC: *NIOSH considers asbestos to be a potential occupational carcinogen. /Asbestos/ [R23] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Asbestos/ [R23] TLV: *8 hr Time Weighted Avg (TWA): 0.1 fibers/cc; respirable fibers: length greater than 5 um; aspect ratio greater than or equal to 3:1. /Asbestos, all forms/ [R31, 2002.16] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Asbestos, all forms/ [R31, 2002.6] *A1; Confirmed human carcinogen. /Asbestos, all forms/ [R31, 2002.16] OOPL: *Regulations regarding asbestos levels in air in the workplace, United Kingdom: 2 fibers/cu cm average over 4 hr for chrysotile, also 12 fibers/cu m average over 10 min; Federal Republic of Germany: Chrysotile: 0.15 mg/cu m; Italy: 5 fibers/cu m; Denmark: 2 fibers/cu m, (ban asbestos for insulation work). /Data derived from table/ [R134] *In Great Britain, a TWA value of 1 fiber/ml is the accepted level for chrysotile. [R6] ASTD: *Asbestos has been designated as a hazardous air pollutant under section 112 of the Clean Air Act. /Asbestos/ [R135] FDA: *Asbestos fiber, an adjuvant substance employed in the production of the phenolic resins may be safely used as the food contact surface of molded articles intended for repeated use in contact with nonacid food (pH above 5.0) [R136] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 7402: Analyte: asbestos fibers including chyrsotile; Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25-mm diameter; conductive cassette); Flow rate: 0.5-16 l/min; Vol: min: 400 l at 0.1 fiber/ml; max: 10,000 l; Sample stability: stable. Shipment is routine (securely packed to reduce shock). [R137, p. V1 7402-1] *NIOSH 7400: Analyte: Fibers (including chrysotile asbestos); Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25-mm diameter; conductive cowl on cassette); Flow rate: 0.5 to 16 l/min; Minimum vol: 400 l at 0.1 fiber/ml; Maximum vol: 10,000 l; Stability: stable. Shipment is routine (securely packed to reduce shock). [R137, p. V1 7400-1] *NIOSH P and CAM 309: ANALYTE: CHRYSOTILE; MATRIX: AIR; PROCEDURE: COLLECTION ON FILTER. [R138, p. V5 309-1] ALAB: *LEVELS OF 0.5 TO 1.0% CHRYSOTILE ASBESTOS IN PURE TALC AND TALC CONTAINING OTHER MINERALS WAS DETERMINED BY DIFFERENTIAL THERMAL ANALYSIS (DTA). [R139] *NIOSH P and CAM 245: ANALYTE: CHRYSOTILE ASBESTOS; MATRIX: BULK SAMPLE; RANGE: 0.1 TO 10 MG/SAMPLE; PROCEDURE: THERMAL ANALYSIS (DTA); PRECISION (CV): 0.12 AT 3.8 MG (ANALYTICAL). [R138, p. V1 245-1] *RANGE: 25-2500 UG/CU M (FOR AN 800 SAMPLE); REDEPOSITION ON SILVER FILTER, XRAY DIFFRACTION; PRECISION: 7% (ANALYTICAL) [R138, p. V5 309-1] *A METHOD WAS DEVELOPED FOR THE DETERMINATION OF MICROGRAM QUANTITIES OF CHRYSOTILE BY X-RAY DIFFRACTION WHICH WAS PRECISE, ACCURATE AND RAPID. THE DETECTION LIMIT WAS AS LOW AS 2 UG/SQ CM (ON A FILTER). [R140] *DETERMINATION OF CHRYSOTILE ASBESTOS IN AIR BY LASER MICROPROBE MASS ANALYSIS. [R141] *AN IMPROVED METHOD WAS DEVELOPED FOR IDENTIFYING ASBESTOS FIBERS, ESPECIALLY WHEN PRESENT WITH NONASBESTIFORM FIBERS. THE TEST INVOLVES THE USE OF 2 ORGANIC FLUORESCENT DYES AND A FLUORESCENCE MICROSCOPE FOR THE DETECTION OF CHRYSOTILE ASBESTOS. THIS METHOD CAN BE USED AS A SCREENING TECHNIQUE FOR QUICK AND ACCURATE DETECTION OF ASBESTOS-CONTAINING MATERIALS IN PUBLIC BUILDINGS. [R142] *NIOSH 7402: Analyte: asbestos fibers including chrysotile; Matrix: air; Technique: Transmission electron microscopy (TEM); Range: 100-1300 fibers/sq mm filter area; Precision: 0.28 when 65% of fibers are asbestos; 0.20 when adjusted fiber count is applied to PCM count; Est limit of detection: 1 confirmed asbestos fiber above 95% of expected mean blank value; Interferences: Non-asbestiform amphiboles may interfere in the TEM analysis if the individual particles have aspect ratios greater than 3:1. These interferences can only be eliminated by quantitative zone axis electron diffraction analysis. NIOSH method 7400 (phase-contrast microscopy) is designed for use with this method. [R137, p. V1 7402-1] *NIOSH 7400: Analyte: Fibers (including crysotile fibers); Matrix: air; Technique: Light microscopy, phase contrast; Range: 100-1300 fibers/sq mm filter area; Precision: 0.10 to 0.12 (based on OSHA regulations for rule A); Est limit of detection: 7 fibers/sq mm filter area. This method gives an index of airborne fibers in workplace atmospheres. Phase contrast microscopy will not differentiate between asbestos and other fibers; use this method in conjunction with electron microscopy (eg, Method 7402) for positive identification. Fibers < about 0.25 um diameter will not be detected by this method. Any other airborne fiber may interfere. Chain-like particles may appear fibrous. High levels of non-fibrous dust particles may obscure fibers in the field of view and increase the detection limit. [R137, p. V1 7400-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; ASSESSMENT AND CONTROL OF CHRYSOTILE ASBESTOS EMISSIONS FROM UNPAVED EPA-450/3-81-006 (1981). A REVIEW, INCLUDING 85 REFERENCES, OF CHRYSOTILE ASBESTOS EMISSIONS FROM UNPAVED ROADS. DHHS/NTP; Lifetime Carcinogenesis Studies of Chrysotile Asbestos in Syrian Golden Hamsters (Feed Studies) Technical Report Series No.246 (1990) NIH Publication No. 90-2502 DHHS/NTP; Toxicology and Carcinogenesis Studies of Chrysotile Asbestos in F344/N Rats (Feed Studies) Technical Report Series No.295 (1985) NIH Publication No. 86-2551 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) U.S. Dept Health and Human Services/Agency for Toxic Substances Disease Registry; Toxicological Profile for Asbestos (Update) (1995) NTIS # PB/95-264305 SO: R1: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 186 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V2 20 (1973) R4: Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979. R5: Davis JM et al; Carcinogenesis 6 (5): 667-74 (1985) R6: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.II-8 (1980) R7: PAPIRER E; CLAYS CLAY MINER 29 (1): 69-70 (1981) R8: National Research Council. Drinking Water and Health, Volume 4. Washington, DC: National Academy Press, 1981. R9: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R10: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3022 R11: SRI R12: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.II-6 (1980) R13: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-1 (1980) EPA R14: USDHEW/NCI; Asbestos: An Information Resource p.15 DHEW Pub No. NIH 79-1681 (1978) R15: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1984 p.1-396 (1984) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 12 (1977) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 21 (1977) R18: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.II-2 (1980) R19: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.II-5 (1980) R20: Seshan K; Environ Health Pespect 53: 143-48 (1983) as cited in USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.III-12 (1980) R21: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-5 (1980) EPA 440/5-80-022 R22: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-3 (1980) EPA 440/5-80-022 R23: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 22 R24: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R25: 49 CFR 171.2 (7/1/96) R26: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 230 R27: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.9014 (1988) R28: HYATT M ET AL; ENVIRON INT 7 (3): 215-20 (1982) R29: Environmental Health Criteria 203: Chrysotile Asbestos pp. 1-9 (1998) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 106 (1987) R31: American Conference of Governmental Industrial Hygienists. 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Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. 847 R122: Nicholson WJ; Control of Sprayed Asbestos Surfaces in School Buildings: a Feasibility Study Contract 1-ES-2113 (1978) R123: Nicholson WJ; Measurement of Asbestos in Ambient Air (Final Report) Contract CPA 70-92 as cited in USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-20 (1980) EPA 440/5-80-022 R124: Nicholson WJ; Measurement of Asbestos in Ambient Air (Final Report) Contract CPA 70-92 as cited in USEPA; Ambient Water Quality Criteria Doc: Asbestos p.IV-11 (1980) EPA 440/5-80-022 R125: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-98 (1980) EPA 440/5-80-022 R126: USEPA; Asbestos Health Assessment Update (Draft) p.109 (1984) EPA-600/8-84-003A R127: WERNER I, KARSTEN H; STAUB- REINHALT LUFT 41 (7): 262-4 (1981) R128: Bernstein IL, Moteff J; J Allergy Clin Immunol 57 (5): 489-92 (1976) as cited in Nat'l Research Council Canada; Asbestos p.51 (1979) NRCC No. 16452 R129: COOPER WC ET AL; SCIENCE (WASHINGTON, DC) 206 (4419): 685-8 (1979) R130: USEPA; Asbestos Health Assessment Update (Draft) p.61 (1984) EPA-600/8-84-003A R131: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.IV-1 (1980) R132: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (date) EPA 440/5-80-022 R133: 29 CFR 1910.1001(c) (7/1/98) R134: Zielhuis RL; Public Health Risks of Exposure to Asbestos. 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R139: LUCKEWICZ W; J SOC COSMET CHEM 26 (9): 431-7 (1975) R140: LANGE BA, HAARTZ JC; ANAL CHEM 51 (4): 520-5 (1979) R141: DE WAELE J ET AL; MICROBEAM ANAL 17: 371-7 (1982) R142: ALBRIGHT FR ET AL; RESEARCH ON A RAPID AND SIMPLE DETECTION METHOD FOR ASBESTOS; REPORT, ISS NSF/RA-800344, R/D-209-80; ORDER NO PB81-154718 (1980) 33 PAGES RS: 136 Record 209 of 1119 in HSDB (through 2003/06) AN: 2968 UD: 200211 RD: Reviewed by SRP on 1/20/2001 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged also to retrieve the record named COPPER COMPOUNDS, which has additional information relevant to the toxicity and environmental fate of copper ions and copper compounds. For information on the metal itself, refer to the COPPER, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: COPPER- (II)-SULFATE,-PENTAHYDRATE SY: *Blue-Copperas-; *Bluestone-; *Blue-Vicking-; *Blue-vitriol-; *Calcanthite-; *Copper- (II)-sulfate-pentahydrate- (1:1:5); *COPPER-SULFATE-; *COPPER-SULFATE-PENTAHYDRATE-; *COPPER- (2+)-SULFATE-PENTAHYDRATE; *COPPER-SULFATE- (CUSO4)-PENTAHYDRATE; *COPPER-SULPHATE-; *CSP-; *Cupric-sulfate-; *CUPRIC-SULFATE,-PENTAHYDRATE-; *KUPFERSULFAT- (GERMAN); *KUPFERSULFAT-PENTAHYDRAT- (GERMAN); *KUPFERVITRIOL- (GERMAN); *ROMAN-VITRIOL-; *Salzburg-vitriol-; *SULFURIC-ACID,-COPPER- (2+)-SALT,-PENTAHYDRATE; *SULFURIC-ACID-COPPER- (2+)-SALT- (1:1),-PENTAHYDRATE; *TRIANGLE- RN: 7758-99-8 RELT: 6944 [COPPER WORKING RECORD]; 1622 [COPPER, ELEMENTAL] MF: *Cu.H2-O4-S.5H2-O STCC: 49 613 16; Cupric sulfate 49 613 17; Cupric sulfate (copper sulfate and lime combined, dry) 49 613 18; Cupric sulfate (copper sulfate and sulphur) MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Action of dilute sulfuric acid on copper or copper oxide (often as oxide ores) in large quantities, with evaporation and crystallization. [R1] *Commercial prepn of pentahydrate: Faith et al, Industrial Chemicals (John Wiley, NY, 3rd ed, 1965) p288; other prepn: Gmelin's Copper (8th ed) 60B: 491-560 (1958). [R2] *Copper + sulphuric acid (salt formation); byproduct of copper electrolysis and etching process (product is generally only suitable for agricultural purposes) [R3] *Prepared most easily by the reaction of basic copper(II) compound with a sulfuric acid solution (100-200 g/l sulfuric acid); and copper metal, sulfuric acid and air the most common starting materials for the production of copper sulfate pentahydrate. [R4, 577] *Copper(II) sulfate can be prepared by dissolution of oxides, carbonates, or hydroxides in sulfuric acid solutions. Whereas copper metal does not displace hydrogen from acid solution, aeration or oxygenation of hot dilute aqueous sulfuric acid in the presence of copper metal is a commonly used commercial method for copper sulfate preparation. [R5, 510] FORM: *USEPA/OPP Pesticide Code 024401; Trade Names: Blue copperas; Blue vitriol; triangle; Hi-chel; Roman vitrol; and Blue copper AS. [R6] *FOR MOST PURPOSES GRANULATED PRODUCT, SO-CALLED "SNOW" BLUESTONE ... PREFERRED. MOST STD REQUIRE A CONTENT OF 98% COPPER(II) SULFATE, PENTAHYDRATE. [R7] *Grades: Technical; CP; NF; also sold as monohydrate. Available in crystals or powder [R1] *Formulation types: Crystals; WP; SC. Mixtures (copper sulfate+) cymoxanil; cymoxanil+mancozeb; folpet; mancozeb; maneb; sulfur; zineb; copper oxychloride + cymoxanil + mancozeb; copper oxychloride + folpet + oxadixyl; copper oxychloride + mancozeb + oxadixyl; copper carbonate (basic) + copper oxychloride+mancozeb. [R8] *Various crystal sizes: medium, large liquid, powder (snow) form, granular, water soluble [R9] *... Anhydrous form contains nearly 50% copper, the commonly used pentahydrate form contains 25.5% copper. [R10, 136] *Copper and zinc sulfates lotion. ... Copper sulfate 1 g, zinc sulfate 1.5 g, concentrated camphor water 2.5 ml, water to 100 ml. [R11] *Sweitzer's soln. Copper sulfate 1 g, zinc sulfate 2 g, camphor water to 100 ml. [R11] *Potassium Cupri-tartrate Soln. Fehling's soln. Soln number 1: copper sulfate 3.464 g, sulfuric acid 0.05 ml, water to 50 ml. Soln number 2: sodium potassium tartrate 17.6 g, sodium hydroxide 7.7 g, water to 50 ml. Mix equal vol of soln number 1 and soln number 2 immediately before use. [R11] MFS: *IMC/Americhem, One Pitcairn Place, 165 Township Line Road, Jenkintown, PA 19046-3593, (215)517-6000; Production site: Shelby, NC 28152-0648 [R12] *Jost Chemical Company, Inc., 8130 Lackland Rd., St Louis, MO 63114, (314)428-4300; Production site: St Louis, MO 63114 [R12] *Madison Chemicals Inc., Old Waterworks Rd., PO Box 194, Old Bridge, NJ 08857, (732)727-2225; Production site: Old Bridge, NJ 08857 [R12] *OMG Fidelity Chemical Products Corp., 470 Frelinghuysen Ave, Newark, NJ 07114, (973)242-4110; Production site: Newark, NJ 07114 [R12] *Phibro-Tech, Inc., One Parker Plaza, Fort Lee, NJ 07024, (201)944-6000; Production sites: Garland, TX 75040; Joliet, IL 60435; Santa Fe Springs, CA 90670; Sewaren, NJ 07077; Sumter, SC 29154 [R12] OMIN: *INCOMPATIBILITIES: COPPER ION IS PRECIPITATED AS COPPER HYDROXIDE BY ALKALI HYDROXIDES. PRECIPITATE IS RETARDED BY ... CITRATES, TARTRATES, SALICYLATES, GLYCERIN, AND SUGAR. AMMONIUM HYDROXIDE GIVES PRECIPITATE ... ALKALI CARBONATES, PHOSPHATES, BORAX, AND TANNIC ACID CAUSE PRECIPITATION. SOL IODIDES REDUCE CUPRIC ION TO CUPROUS. [R13] *POSSIBLE INCOMPATIBILITIES: EFFECTIVENESS DECR AS WATER HARDNESS INCR. SIGNIFICANT REDUCTION IN EFFECTIVENESS OCCURS WHEN BICARBONATE ALKALINITY EXCEEDS 150 PPM AS CALCIUM CARBONATE. CONVERSELY, TOXICITY TO FISH DECR AS ALKALINITY INCREASES. [R14, 115] *FDA ... REJECTED FEED COMPANY'S APPLICATION TO INCL DRUG IN SWINE FEEDS AT 250 PPM LEVEL ... BECAUSE ITS FULL IMPACT ON ENVIRONMENT OVER PERIOD OF TIME BY WAY OF FECAL WASTES, RECYCLING, ETC HAS NOT BEEN DETERMINED. ... AVOID MANURE APPLICATION TO FROZEN GROUND WHERE RUNOFF COULD BE SERIOUS POLLUTION POTENTIAL TO STREAMS. [R10, 136] *IN CAPSULES LESS TOXIC THAN IN WATER DRENCH FOR CATTLE. [R10, 136] *COPPER(II) CHLORIDE IS A READILY AVAILABLE FORM OF COPPER IN FEEDING TRIALS WHICH COMPARES FAVORABLY WITH COPPER SULFATE IN CATTLE AND SWINE TRIALS. [R10, 134] *... SALTS OF COPPER, INCLUDING THE SUBACETATE, OXYCHLORIDE, CHLORIDE AND OXIDE, HAVE FUNGICIDAL PROPERTIES AND OCCASIONALLY REPLACE THE SULFATE IN SPRAYS. ... [R15, 44] *Method of purification: Recrystallization. [R1] USE: *For Copper(II) sulfate, pentahydrate (USEPA/OPP Pesticide Code: 024401) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R6] *COMPONENT OF FEHLING'S SOLN, TO EST REDUCING SUGAR IN URINE. [R16, 546] *As agricultural fungicide, algicide, bactericide, herbicide; food and fertilizer additive; in insecticide mixtures; in the manufacture of other copper salts; as mordant in textile dying; in preparation of azo dyes; in preserving hides; in tanning leather; in preserving wood; in electroplating soln.; as battery electrolyte; in laundry and metal-marking inks; in petroleum refining; as flotation agent; pigment in paints, varnishes and other materials; in mordant baths for intensifying photographic negatives; in pyrotechnic compositions; in water-resistant adhesives for wood; in metal coloring and tinting baths; in antirusting compositions for radiator and heating systems; as reagent toner in photography and photoengraving; etc. [R2] *Therap Cat: Antidote to phosphorus; antifungal (topical) [R2] *Therap Cat (Vet): Nutritional factor; used in copper deficiency of ruminants; has also been used as an anthelmintic, emetic, fungicide [R2] *Agriculture (soil additive, pesticides, Bordeaux mixture), feed additive, germicides, textile mordant, leather industry, pigments, electric batteries, electroplated coatings, copper salts, reagent in analytical chemistry, medicine, wood preservative, preservation of pulp wood and ground pulp, process engraving, and lithography, ore flotation, petroleum industry, synthetic rubber, steel manufacture, treatment of natural asphalts. [R1] *IN FORM OF BORDEAUX MIXT (WHICH CONTAINS 1-3% COPPER SULFATE) AND SIMILAR PREPN, AS SPRAY AGAINST FUNGUS DISEASES OF VINE AND OTHER FRUIT TREES. [R15, 44] *Control of most species of algae in ponds, lakes, potable water, fish hatcheries, rice fields, streams, ditches, swimming pools, etc. Prevention and control of Dutch elm disease, by tree injection. Used as a general fungicide when mixed with lime to form Bordeaux mixture (q.v.). Also used a wood preservative. [R8] *AN EARLY SEED DRESSING FOR CONTROL OF BUNT OF WHEAT BUT REPLACED BECAUSE OF SEED DAMAGE. [R7] *To control alga growth in impounded waters, lakes, ponds, reservoirs, and irrigation and irrigation drainage conveyance systems. /Copper sulfate/ [R17] *Antifouling paints [R5, 515] *Copper sulfate is used as a fungicide for control of downy mildew, blights, leaf spots, apple scab, bitter rot, and peachleaf curl. [R18, 5] *One of the earliest widely used fungicides, and formerly as a fungicide in copper-lime dust. For control of algae, pond weeds in impounded potable waters. Chem One Corp. and Griffen's labels also for use in potable water, irrigation water conveyance systems, root control in sewers, and for algae, tadpole shrimp in rice. ... for systemic, broad-spectrum bacterial and fungal control on many crops and trees [R9] *MEDICATION *MEDICATION (VET): Molluscicide and top dressing of pasture to control snail intermediate hosts of liver flukes. [R10, 136] PRIE: U.S. PRODUCTION: *(1978) 3.2X10+10 G [R19] *(1982) 3.2X10+10 G [R19] *Production (1998): 44,000 metric tons /Copper sulfate/ [R20] U.S. IMPORTS: *(1978) 3.4X10+9 G [R19] *(1982) 1.5X10+9 G [R19] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Large, blue or ultramarine, triclinic crystals or blue granules or light-blue powder [R2] ODOR: *Odorless [R9] TAST: *Nauseous, metallic taste [R1] BP: *DECOMP ABOVE 150 DEG C WITH -5H2O [R21] MP: *Decomp above 110 deg C [R22, p. 4-56] MW: *249.686 [R22, p. 4-56] CORR: *Very corrosive to plain steel. [R14, 115] DEN: *2.286 @ 15.6 deg C/4 deg C [R2] PH: *pH of 0.2 molar aq soln: 4.0 [R2] SOL: *31.6 g/100 cc water @ 0 deg C, 203.3 g/100 cc @ 100 deg C [R21]; *1 g in about 500 ml alcohol [R23]; *In water: 148 g/kg @ 0 deg C; 230.5 gkg @ 25 deg C; 335 g/kg @ 50 deg C; 736 g/kg @ 100 deg C [R24]; *Practically insol in most organic solvents. [R8]; *1 g in 3 ml glycerine [R23]; *15.6 g/100 cc methanol @ 18 deg C [R21]; *Soluble in methanol (15.6 g/100 ml solution) but insoluble in ethanol; it readily forms soluble alkaline complexes at sufficiently high concentrations of amines or alkali cyanides. [R4, 578]; *In water, 3.2X10+4 mg/l @ 20 deg C [R25] SPEC: *INDICES OF REFRACTION: 1.514, 1.537, 1.543 [R21] OCPP: *Loses 2H2O @ 30 deg C, 2 more H2O @ 110 deg C; becomes anhydrous by 250 deg C; efflorescent in air. [R2] *LOSING WATER BY CRYSTALLIZATION @ 110 DEG C TO FORM WHITE MONOHYDRATE, CUSO4.H2O [R7] *Dielectric constant: 6.60 @ room temperature [R22, p. 12-50] *SOLN ARE STRONGLY CORROSIVE TO IRON AND GALVANIZED IRON. /Cupric sulfate soln/ [R18, 5] *Slowly effloresces in dry air or above 30.6 deg C with the formation of the trihydrate; at 88-100 deg C the trihydrate is produced more quickly; above 114 deg C the monohydrate is formed, and between about 245 and 240 deg C, the anhydrous product copper(II) sulfate results. [R4, 577] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Nonflammable [R26] FIRP: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire (Material itself does not burn or burns with difficulty). /Cupric sulfate/ [R27] REAC: *Anhydrous copper sulfate causes hydroxylamine to ignite and the hydrated salt is vigorously reduced. /Copper sulfate/ [R28, p. 491-66] *Solutions of sodium hypobromite are decomposed by powerful catalytic action of cupric ions, even as impurities. /Cupric salts/ [R28, p. 491-181] DCMP: *DECOMP ABOVE 150 DEG C (BOILING POINT) WITH -5H2O /SPR: TO ANHYDROUS SALT/ [R21] *DECOMP ABOVE 110 DEG C (MELTING POINT) WITH -4H2O /SRP: TO MONOHYDRATE SALT/ [R21] *When heated to decomposition it emits toxic fumes of /sulfur oxides/. [R29] SERI: *May be corrosive to eyes, mucous membranes, skin. [R30] EQUP: *AVOID CONTACT, WEAR PROTECTIVE EQUIPMENT, FREQUENT CLOTHING CHANGE. [R30] *Personnel protection: ... Wear appropriate chemical protective gloves, boots and goggles. /Cupric sulfate/ [R27] OPRM: *Personnel protection: Keep upwind. ... Avoid breathing vapors or dusts. Wash away any material which may have contacted the body with copious amounts of water or soap and water. /Cupric sulfate/ [R27] *If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. /Cupric sulfate/ [R27] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. SSL: *INDEFINITE WHEN KEPT DRY; STABLE TO HEAT, COLD, AND LIGHT. [R14, 115] STRG: *... /Keep/ dry. [R14, 115] CLUP: *Environmental concerns - land spill: Dig a pit, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. /Cupric sulfate/ [R27] *Environmental concerns - water spill: Neutralize with agricultural lime (CaO), crushed limestone (CaCO3), or sodium bicarbonate (NaHCO3). Adjust pH to neutral (pH= 7). Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. /Cupric sulfate/ [R27] *Add slowly to a large container of water. Stir in slight excess of soda ash. Let stand for 24 hr. Decant or siphon into another container and neutralize with 6 molar hydrochloric acid before washing down drain with large excess of water. The sludge may be added to landfill. [R31] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Add slowly to a large container of water. Stir in slight excess of soda ash. Let stand for 24 hr. Decant or siphon into another container and neutralize with 6 M HCl before washing down drain with large excess of water. The sludge may be added to landfill. Recommendable methods: Precipitation, solidification, and landfill. Peer-review: Precipitate with calcium hydroxide. Dilute supernatant and discharge to sewer. Copper can be recovered by cation exchange. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R31] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Copper and related compounds/ [R32, 350] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Start an IV with lactated Ringer's /SRP: "To keep open", minimal flow rate/. Watch for signs of fluid overload. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine, hydrochloride to assist eye irrigation ... . /Copper and related compounds/ [R32, 351] HTOX: *A report of 11 patients who had ingested an estimated 1 to 50 g of copper sulfate: they suffered nausea and vomiting, with epigastric pain in 5, diarrhea in 5, hypotension in 2, hematemesis or melena in 10, pallor in 10, jaundice in 8, delirium in 3, and coma in 2. All had intravascular hemolysis and developed oliguria or anuria. Five patients died despite gastric lavage, intravenous fluids, mannitol, diuretics, and dialysis. /Copper sulfate/ [R11] *... COPPER SULFATE, KNOWN AS BLUESTONE OR BLUE VITRIOL, /WHEN USED WITH MISGUIDED OR SUICIDAL INTENT/ IS GENERALLY INGESTED IN GRAM QUANTITIES. NAUSEA, VOMITING, DIARRHEA, SWEATING, RARELY CONVULSIONS, COMA, AND DEATH MAY RESULT. [R16, 547] *A ... NUMBER OF CASES OF ACUTE POISONING IN MAN FROM INGESTING COPPER SULFATE, SOME OF THEM FATAL, HAVE BEEN REPORTED ... FROM NEW DELHI ... THE REPORT CONCERNS 48 HOSPITALIZED PATIENTS AND 5 AUTOPSY CASES, 2/3 MALE, MOSTLY BETWEEN THE AGES OF 16 and 25 YR. DOSAGE ESTIMATES RANGED FROM 1 TO 12 G ... SWALLOWED IN WATER. SYMPTOMS ... WERE ... METALLIC TASTE, BURNING IN EPIGASTRIUM, AND REPEATED VOMITING. IN MORE SEVERE CASES, DIARRHEA (14 PATIENTS) APPEARED ON THE FIRST OR SECOND DAY AND LASTED 24 HR; 20 ... SHOWED BLOOD IN GI TRACT FROM INJURY TO GASTRIC MUCOSA, LEADING TO ULCERATION IN SEVERE CASES. SUPPRESSION OF URINE FOLLOWED JAUNDICE ... LIVER BIOPSY SHOWED CENTRILOBULAR NECROSIS AND BILIARY STASIS. HYPERTENSION LEADING TO SHOCK ... CONSIDERED A BAD PROGNOSTIC SIGN: 3 OF 4 DIED. COMA DEVELOPED IN 4, PRESUMABLY DUE TO UREMIA FROM RENAL INJURY, AND DEATHS OCCURRED IN 7 (14.6%). /COPPER SULFATE/ [R33] *A CHILD, IN WHOM COPPER SULFATE CRYSTALS WERE APPLIED THERAPEUTICALLY TO SEVERELY BURNED SKIN SEVEN TIMES DURING NINE WK, DEVELOPED SEVERE ANEMIA. AFTER LAST TREATMENT, HEMOLYTIC CRISIS WITH ICTERUS TOOK PLACE. HIGH LEVELS OF COPPER IN SERUM AND URINE ... INDICATED THAT ABSORPTION ... FROM THE WOUND DRESSING WAS RESPONSIBLE. /COPPER SULFATE/ [R34] *Two unusual cases attributed to residues were reported from Hungary. A 9 yr old boy died 10 hr after eating 3 bunches of grapes and a 5 yr old died 24 hr after eating 2 bunches. ... Expressed as copper(II) sulfate, a total of 572 mg, equivalent to 22 mg/kg, was recovered from all tissues in the first case. A total of 463 mg, equivalent to 28.9 mg/kg, was recovered in the second case. /Copper sulfate/ [R18, 5] *Persons who die soon after ingestion of copper sulfate show ... a characteristic staining of the lining of the digestive tract and fatty degeneration of liver, kidney, and to some degree other organs. Persons who develop acute renal failure as part of acute poisoning by copper sulfate may or may not show well established acute tubular necrosis. In those who survive long enough, granulomatous lesions of the kidney may develop. /Copper sulfate/ [R18, 6] NTOX: *... PARAKERATOSIS, WITH SOFTENING OF HAIR AND PRURITIS, FOLLOWED BY DRY EXCEMATOUS-LIKE SKIN CHANGES AND PAPULAR ERUPTIONS /WERE OBSERVED/ IN PIGS FED DIET CONTAINING 0.1% HYDRATED COPPER SULFATE. [R15, 47] *COPPER SULFATE ... WAS EMPLOYED IN TREATMENT OF TRACHOMA BY REPEATED TOPICAL APPLICATION ... TO DISEASED CONJUNCTIVA. THIS RESULTED IN TEMPORARY INFLAMMATION ... AND DISCOLORATION OF CORNEA. ... IF A PARTICLE OF COPPER SULFATE WAS LEFT ACCIDENTALLY IN CONJUNCTIVAL SAC, IF COULD CAUSE LOCAL INFLAMMATION AND NECROSIS, CORNEAL OPACITY, AND SYMBLEPHARON. /COPPER SULFATE/ [R35] */THERE ARE/ ... REPORTS THAT 225 KG STEER DEVELOPED CHRONIC POISONING AND DIED AFTER 122 DAYS ON DAILY DRENCH OF 5 G OF COPPER SULFATE (CUSO4.5H2O). ... COPPER SULFATE FED TO PIGS @ LEVELS UP TO 400 PPM OF COPPER CAUSED NO TOXIC SIGNS, ALTHOUGH LIVER COPPER ROSE SHARPLY. LEVELS ABOVE 1,000 PPM WERE USUALLY LETHAL. [R15, 46] *COPPER SULFATE FED AD LIBITUM IN DIET OF RATS @ LEVEL OF 500 PPM CAUSED RETARDED GROWTH; 4,000 PPM CAUSED STARVATION AND DEATH. ... ACCESS OF SHEEP TO SALT LICKS CONTAINING 5-9% COPPER SULFATE CAUSED SUDDEN ONSET OF ANOREXIA, HEMOLYTIC ANEMIA, ICTERUS, AND HEMOGLOBINURIA FOLLOWED BY DEATH. ... AT NECROPSY LIVER, KIDNEYS, AND SPLEEN SHOWED SEVERE DEGENERATIVE CHANGES. /COPPER SULFATE/ [R33] *GUINEA PIGS WERE EXPOSED FOR 1 HR TO AEROSOLS OF SULFATE SALTS. WITH THE EXCEPTION OF SODIUM SULFATE, ALL THE SULFATES CAUSED SLIGHT INCREASE IN PULMONARY FLOW RESISTANCE AND SLIGHT DECREASE IN PULMONARY COMPLIANCE. COPPER SULFATE WAS LEAST IRRITANT THAN AMMONIUM SULFATE AND AMMONIUM BISULFATE AEROSOLS. /COPPER SULFATE/ [R36] *THE MEDIAN TOLERANCE LIMIT THAT DOES NOT EFFECT GROWTH AND REPRODUCTION OF FATHEAD MINNOWS (PIMEPHALES PROMELAS, RAFINESQUE) UNDER PROLONGED EXPOSURE TO COPPER SULFATE LIES BETWEEN 3 and 7% OF 96 HR MEDIAN TOLERANCE LIMIT. [R37] *COPPER SULFATE WAS TESTED FOR TOXICITY TO 1 WK OLD LARVAE AND 1 MO OLD FINGERLING STRIPED BASS, MORONE SAXATILIS. FINGERLINGS WERE MORE SENSITIVE THAN LARVAE TO COPPER SULFATE. /COPPER SULFATE/ [R38] *INGESTION OF ABOUT 600 MG/KG COPPER SULFATE BY BRANTA CANADENSIS CAUSED NECROSIS AND SLOUGHING OF PROVENTRICULUS AND GIZZARD, AND GREENISH DISCOLORATION OF LUNG. /COPPER SULFATE/ [R39] *DAILY ORAL DOSES OF 20 MG OF COPPER SULFATE/KG BODY WT GIVEN TO SHEEP RESULTED IN HEMOLYSIS AFTER NINE WK. ... HEMOLYSIS ALSO CAUSED ACUTE TUBULAR RENAL DAMAGE IN THE SHEEP. /COPPER SULFATE/ [R40] *Strong solubilized copper cmpd (eg a mixture of copper sulfate, lime, and water) are dangerous to bees. /Copper sulfate/ [R41] *Phytotoxic to most plants. [R24] *In feeding trials, rats ... receiving 1000 mg/kg diet exhibited damage to the liver, kidneys, and other organs. ... Toxic to fish. [R24] *STATIC BIOASSAYS WITH COPPER AS COPPER(II) SULFATE, PENTAHYDRATE WERE CONDUCTED USING FRESHWATER POND SNAIL (VIVIPARUS BENGALENSIS). THE 96 HR LC50 VALUES IN PPM OF COPPER WERE 0.060 @ 32.5 DEG C; 0.066 @ 24 DEG C; 0.09 @ 27.3 DEG C; and 0.39 @ 20.3 DEG C. HIGHER CONCN CAUSED SOME BEHAVIORAL CHANGES SUCH AS SECRETION OF MUCUS, DISCHARGE OF EGGS AND EMBRYOS. [R42] *Fifteen male albino rats of laboratory stock were given a daily dose of 0.1 g/kg copper sulfate by gavage for 30 days. Blood constituents were studied. Percent hemoglobin, plasma corpuscular volume, mean corpuscular volume, total red blood corpuscles, total protein, acid phosphatase and glucose were decreased significantly in the copper-fed rats. Glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, lactate dehydrogenase cholesterol, urea, glucose, bilirubin, and glutamate dehydrogenase were significantly elevated in the copper-fed rats. The levels of white blood corpuscles, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, and alkaline phosphatase did not change significantly. Although weight gain was reduced, rats showed no overt signs of toxicity during the experiment. /Copper sulfate/ [R43] *In a 15 day feeding study in rats involving the admin of up to 16,000 mg/kg copper(II) sulfate pentahydrate in the diet (estimated intakes up to 305 mg Cu/ kg bw per day), weight gain was reduced from 194 mg Cu/kg bw per day, but there were no other overt signs of toxicity. Effects on the forestomach were evident from 45 mg Cu/kg bw per day, on the kidneys from 93 mg Cu/kg bw per day, and on the liver and bone marrow from 194 mg Cu/kg bw per day. The NOEL in this study was 23 mg Cu/kg bw per day. [R44] *In comprehensive 90 day studies in both rats and mice, in which copper(II) sulfate pentahydrate was admin in the feed at up to 8000 mg/kg in rats (up to 138 mg Cu/kg bw per day) and up to 16,000 mg/kg in mice (up to around 1000 mg Cu/kg bw per day), there were no overt signs of toxicity other than a dose-related reduction in growth... . Microscopic exam of the tissues revealed hyperplasia and hyperkeratosis in the forestomach in both species... , and liver and kidney effects in the rats only... . In the rats, iron levels were reduced in the spleen, and hematological changes indicative of microcytic anemia were observed at 34 mg Cu/kg bw per day and higher. The NOEL was 17 mg Cu/kg bw per day in rats, and 44 and 126 mg Cu/kg bw per day in male and female mice, respectively. The liver and kidney effects observed in the rats... included inflammation of the liver and degeneration of the kidney tubule epithelium. [R45] */Groups of 4 male and 12 female standard dark mink/ given 0, 25, 50, 100, 200 mg Cu/kg diet as copper sulfate pentahydrate (approx 3, 6, 12, or 24 mg Cu/kg bw per day), for 9 months before mating and for 3 months after mating. There were no overt toxic effects in the copper-treated adults. ... Kit weight at 4 wk (but not at birth) was significantly reduced in the 100 mg/kg group. ... Kit mortality (birth to 4 wk) in the 100 and 200 mg/kg groups appeared to be incr ..., and in all treated groups litter mass (at weaning) was reduced, with some evidence of a dose-related effect. An adverse effect of copper on lactation was suggested. NOEL: 6 mg Cu/kg bw per day. LOEL: 12 mg Cu/kg bw per day. /from table/ [R46] *A single ip injection of copper(II) sulfate pentahydrate in mice induced a dose-related incr in the incidence of chromatid type chromosome aberrations in the bone marrow 6 hr after dosing between 0.28 and 1.7 mg Cu/kg bw. [R47] *Dietary admin of 250 mg/kg Cu (as copper(II) sulfate pentahydrate) to groups of six male rats for 30 days, providing 5 mg Cu/rat per day (= to about 20 mg Cu/kg bw per day) did not affect their locomotor activity, learning ability or relearning capacity and memory. Analysis of biogenic amines in the brain revealed a significant incr in dopamine and norepinephrine (noradrenaline) levels. [R48] *In hamsters, a single 4 hr exposure to copper(II) sulfate pentahydrate aerosol at 0.3-7.1 mg Cu/cu m resulted in reduced pulmonary macrophage activity and volume from 3.2 mg Cu/cu m within 1 hr after exposure; no effect was observed at 0.3 mg Cu/cu m. [R49] */Researchers/ reported the development of massive hemolysis with high levels of copper in the liver, kidney, and plasma in sheep treated orally with 20 mg copper sulfate pentahydrate/kg body wt/day within 7 weeks. The excess copper caused an incr in the concn of iron in the plasma and spleen, possibly by interfering with iron metabolism and binding. Hepatic damage was observed in three histopathological studies of sheep chronically exposed to copper. /Copper sulfate, pentahydrate/ [R50] *Overdose may be poisonous (enteritis, hepatitis, nephritis). [R10, 136] *Chronic poisoning is not uncommon in sheep grazed in orchards in which fruit sprays containing copper have been used. The spraying program is usually adjusted so that sheep are not introduced into the area until at least 5 days after the last spraying. Cases of poisoning are often accompanied by a history of dry weather, with no growth of herbage, so that animals are forced to consume old grass heavily contaminated with copper. /Copper containing pesticides/ [R15, 45] NTXV: *LD50 RABBITS PERCUTANEOUS > 8.0 G/KG; [R14, 116] *LD50 Rat oral 960 mg/kg body weight /from table/; [R51] ETXV: *LC50 LEPOMIS MACHOCHIRUS (BLUEGILL), WT 1.5 G, 884 UG/L @ 18 DEG C, STATIC BIOASSAY (95% CONFIDENCE LIMIT 707-1,100 UG/L) /TECHNICAL MATERIAL, 100% (ABOUT 25% ELEMENTAL COPPER)/; [R52] *LC50 LEPOMIS CYANELLUS (GREEN SUNFISH), WT 1.1 G, 3,510 UG/L @ 18 DEG C, STATIC BIOASSAY (95% CONFIDENCE LIMIT 2,570-4,800 UG/L) /TECHNICAL MATERIAL, 100% (ABOUT 25% ELEMENTAL COPPER)/; [R52] *LC50 PIMEPHALES PROMELAS (FATHEAD MINNOW), WT 1.2 G, 838 UG/L @ 18 DEG C (272 PPM CACO3), STATIC BIOASSAY (95% CONFIDENCE LIMIT 623-1,000 UG/L) /TECHNICAL MATERIAL, 100% (ABOUT 25% ELEMENTAL COPPER)/; [R52] *LC50 CARASSIUS AURATUS (GOLDFISH), WT 0.9 G, 1,380 UG/L @ 18 DEG C (272 PPM CACO3), STATIC BIOASSAY (95% CONFIDENCE LIMIT 989-1,930 UG/L) /TECHNICAL MATERIAL, 100% (ABOUT 25% ELEMENTAL COPPER)/; [R52] *LC50 SALMO GAIRDNERI (RAINBOW TROUT), WT 1.6 G, 135 UG/L @ 13 DEG C, STATIC BIOASSAY /TECHNICAL MATERIAL, 100% (ABOUT 25% ELEMENTAL COPPER)/; [R52] *LC50 STRIPED BASS 1 PPM OR LOWER/96 HR /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R53] *LD50 Pheasant oral approx 1,000 ppm; [R14, 115] *LC50 Callinectes sapidus (blue crab) 28.0 ppm Copper/96 hr /Conditions of bioassay not specified/; [R14, 116] *LC50 Shrimp 17.0 ppm Copper/96 hr /Conditions of bioassay not specified/; [R14, 116] *LC50 Oysters 5.8 ppm Copper/96 hr /Conditions of bioassay not specified/; [R14, 116] *LC50 VIVIPARUS BENGALENSIS (SNAIL) 0.060 PPM COPPER /96 HR @ 32.5 DEG C; 0.066 PPM COPPER /96 HR @ 24 DEG C; 0.09 @ 27.3 DEG C; and 0.39 PPM COPPER/96 HR @ 20.3 DEG C /STATIC BIOASSAY/; [R42] ADE: *AFTER ADMIN COPPER(II) SULFATE, PENTAHYDRATE FOR 7 DAYS IP, COPPER ACCUMULATED IN MITOCHONDRIAL AND LYSOSOMAL FRACTIONS OF RAT LIVER, MAINLY IN LYSOSOMES. [R54] ACTN: *HUMAN RBC INCUBATED WITH COPPER SULFATE WERE TESTED FOR OSMOTIC FRAGILITY, DEFORMABILITY, AND ELECTROPHORETIC PROPERTIES OF MEMBRANE PROTEINS. COPPER TREATMENT OXIDIZED THE -SH OF THE MEMBRANE PROTEINS TO FORM INTERMOLECULAR DISULFIDE BONDS, CAUSING A REDUCTION IN MEMBRANE FLEXIBILITY. /COPPER SULFATE/ [R55] *COPPER SULFATE INJECTED IP AT 2 MG COPPER/KG INTO VITAMIN E AND SELENIUM DEFICIENT RATS CAUSED A 6 FOLD INCREASE IN THE FORMATION OF THE LIPID PEROXIDATION PRODUCT ETHANE, AND CAUSED ACUTE MORTALITY IN 4/5 RATS. SELENIUM SUPPLEMENTATION OF THE DIET AT 0.5 PPM SELENIUM PREVENTED THE INCREASE IN ETHANE PRODUCTION CAUSED BY COPPER INJECTION AND REDUCED MORTALITY TO 1/5 RATS. THE CORRELATION OF INCREASED PRODUCTION OF ETHANE WITH INCREASED MORTALITY SUGGESTED THAT LIPID PEROXIDATION MAY BE IMPORTANT IN THE INCREASED TOXICITY OF COPPER IN VITAMIN E AND SELENIUM DEFICIENT RATS. /COPPER SULFATE/ [R56] INTC: *MAY CAUSE DRAMATIC INCR IN MORTALITY OF TURKEYS GIVEN BLACKHEAD CONTROL DRUGS CONTAINING ARSENIC AND EXPOSED TO BLACKHEAD. [R10, 136] *COPPER SULFATE POTENTIATED IRRITANT RESPONSE TO SULFUR DIOXIDE IN GUINEA PIGS EXPOSED 1 HR TO AEROSOL. [R36] *IP INJECTION OF 5-10 MG/KG COPPER SULFATE PENTAHYDRATE AND 25-90 MG/KG ETHYLNITROSOUREA INTO RATS CAUSED LOCAL ASCITES SARCOMAS AFTER 190 DAYS. INJECTION OF THE LATTER ALONE OR METAL SALTS ALONE HAD NO CARCINOGENIC EFFECT. SC ADMIN OF 10 MG/KG/WK ETHYLNITROSOUREA WITH 1 MG/KG COPPER SULFATE PENTAHYDRATE INDUCED LOCAL SARCOMAS IN 4 OF 24 ANIMALS TESTED. [R57] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): AS PROPHYLACTIC AND/OR THERAPEUTIC FOOT BATH IN FOOT ROT OF CATTLE AND SHEEP; AS FUNGICIDAL AGENT IN THE THERAPY OF RINGWORM AND FUNGAL SYNDROMES OF SKIN; AS CAUSTIC IN DESTROYING FISTULOUS TRACTS, NECROTIC INTERDIGITAL MASSES IN FOOT ROT, PROUD FLESH, AND ULCERATIVE STOMATITIS; /HAS BEEN USED/ AS AN EMETIC IN CATS, DOGS, AND PIGS OR TO PPT POISONOUS PHORPHORUS CMPD SUCH AS ZINC PHOSPHIDE; AS HEMATINIC WITH IRON CMPD; AS ASTRINGENT IN ANTIDIARRHEALS PARTICULARLY FOR CALVES OR FEEDLOT CATTLE, TO CONTROL INTESTINAL MONILIASIS AND INHIBIT ASCARID GROWTH IN POULTRY; CONTROL TRICHOMONIASIS AND HEXAMITIASIS IN TURKEYS; AND REFLEXLY CLOSE THE ESOPHAGEAL GROOVE IN SHEEP. [R10, 136] *IT MAY RARELY BE USED AS HEMATINIC IN CERTAIN FORMS OF NUTRITIONAL ANEMIAS, ESP IN CHILDREN. [R23] *MEDICATION (VET): NUTRITIONAL FACTOR; IN COPPER DEFICIENCY OF RUMINANTS. [R58] *IN UNITED KINGDOM ITS ANTIBACTERIAL EFFECT IS UTILIZED AS APPROVED FEED ADDITIVE FOR IMPROVING RATE OF GAIN AND FEED EFFICIENCY OF SWINE (NOT APPROVED IN UNITED STATES BECAUSE OF ENVIRONMENTAL CONCERNS REGARDING BIOCONCENTRATION IN SOIL AND SURFACE WATER). [R59] *MEDICATION (VET): IT IS ALSO USED IN TREATMENT OF PARASITIC GASTRITIS IN SHEEP. [R15, 44] WARN: *... Its routine use as an emetic is not recommended, because of the potential toxicity of improperly prepared soln and the hazards attending the use of large, corrosive doses. [R23] *MAY CAUSE DRAMATIC INCR IN MORTALITY OF TURKEYS GIVEN BLACKHEAD CONTROL DRUGS CONTAINING ARSENIC AND EXPOSED TO BLACKHEAD. [R10, 136] *CUPRIC ... SULFATE /AS EMETIC/ OFTEN IS EFFECTIVE, BUT POTENTIAL HEMOLYTIC AND RENAL TOXICITY IS TOO GREAT TO RECOMMEND USE. ... [R60] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Occurs in nature as mineral chalcanthite. [R2] FATE: *Terrestrial Fate: In soil, copper sulfate is partly washed down to lower levels, partly bound by soil components, and partly oxidatively transformed. [R24] WATC: *SITE OF HERBICIDAL USE: IN FLOWING WATER CANALS OR IN RESERVOIRS. LIKELY CONCN IN IRRIGATION WATER REACHING CROP OR FIELD: @ TREATMENT RATE OF 0.5-3.0 MG/L (CONTINUOUS) 0.8-0.04 MG/L IN 10 MILES; @ 1/3 TO 1 LB/CFS (SLUG) 9.0 TO 0.08 MG/L IN 10-20 MILES. /FROM TABLE/ [R61] PFAC: PLANT CONCENTRATIONS: *IT IS MORE PROBABLE THAT CONTAMINATION PERSISTS FOR LONGER THAN IS GENERALLY THOUGHT POSSIBLE; AFTER 5 MO, GRASS, WHICH HAD BEEN SPRAYED WITH COPPER SULFATE AS A MOLLUSCICIDE IN LIVER FLUKE CONTROL, STILL CONTAINED 200 PPM OF COPPER. [R15, 45] *Absorbed by alga. Low foliar absorption on other vegetation. ... Both foliar and soil absorbed copper ions are translocated throughout the plant. Plant roots exclude the absorption of excess copper levels. [R14, 115] MILK: *The milk of female vineyard workers, who were exposed to copper sulfate and a variety of other pesticides, contained 6.2 times as much copper as the milk of milkmaids who did equally hard work but not exposed to pesticides. [R18, 6] BODY: *The milk of female vineyard workers, who were exposed to copper sulfate and a variety of other pesticides, contained 6.2 times as much copper as the milk of milkmaids who did equally hard work but not exposed to pesticides. Placentas from the vineyard workers contained 4.7 times more copper than those from milkmaids. ... Copper ... occurs in all tissues. ... The concn in blood, muscle, and most of the viscera range from 0.85 to 1.90 ppm. Values for plasma lie in the narrow range of 1.16 to 1.42 ppm. The concn in the brain (2.2 to 6.8 ppm), liver (7.1 ppm in adults and 24 ppm in infants), and bone (3.7 to 4.7 ppm in rib and 6.8 ppm in long bones) are higher. [R18, 6] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *When applied to growing crops, in accordance with good agricultural practice, copper sulfate pentahydrate is exempt from the requirement of a tolerance. [R62] NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 mg/cu m. /Copper (dusts and mists)/ [R63] TLV: +8 hr Time Weighted Avg (TWA): 1 mg/cu m. /Copper dusts and mists, as Cu/ [R64, 2002.24] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Copper dusts and mists, as Cu/ [R64, 2002.6] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 1300 ug/l (Action Level) /Copper/ [R65] FEDERAL DRINKING WATER GUIDELINES: +EPA 1000 ug/l /Copper/ [R65] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 1300 ug/l /Copper/ [R65] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Copper and cmpd/ [R66] FIFR: *When applied to growing crops, in accordance with good agricultural practice, copper sulfate pentahydrate is exempt from the requirement of a tolerance. [R62] FDA: *Trace minerals added to animal feeds. These substances added to animal feeds as nutritional dietary supplements are generally recognized as safe when added are levels consistent with good feeding practice. Element: Copper; Source compound: copper sulfate. (All substances listed may be in anhydrous or hydrated form.) [R67] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *ESR spectra are given for copper(II) sulfate, pentahydrate. [R68] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Technical report on toxicity Studies of Cupric Sulfate Administered in Drinking Water and Feed to F344/N Rats and B6C3F1 Mice. toxicity Rpt Series No. 29 NIH publication No. 93-3352 (1993) SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 302 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 447 R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 237 R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA7 (86) R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V7 (93) R6: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Copper(II) sulfate, pentahydrate (7758-99-8). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of Sept 8, 2000. R7: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 135 R8: Tomlin, C.D.S. (ed.). The Pesticide Manual - World Compendium, 11 th ed., British Crop Protection Council, Surrey, England 1997 271 R9: Farm Chemicals Handbook 2000. Willoughby, Ohio: Meister 2000.,p. C 104 R10: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. R11: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 931 R12: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 534 R13: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 746 R14: Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983. R15: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. R16: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R17: Ahrens, W.H. Herbicide Handbook of the Weed Science Society of America. 7th ed. Champaign, IL: Weed Science Society of America, 1994. 71 R18: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. R19: SRI R20: USGS; Minerals Yearbook 1998 Database on Copper. Available from the Database Query page at http://minerals.usgs.gov/minerals/pubs/commodity/myb/ as of August 16, 2000. R21: Weast, R.C. (ed.) Handbook of Chemistry and Physics, 68th ed. Boca Raton, Florida: CRC Press Inc., 1987-1988.,p. B-90 R22: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999. R23: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 748 R24: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A245/AUG 87 R25: Shiu WY et al; Rev Environ Contam Toxicol 116: 15-187 (1990) R26: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R27: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 306 R28: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R29: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 921 R30: Farm Chemicals Handbook 87. Willoughby, Ohio: Meister Publishing Co., 1987.,p. C-69 R31: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 144 R32: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R33: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 1624 R34: Friberg, L., G.R. Nordberg, and V.B. Vouk. Handbook on the Toxicology of Metals. New York: Elsevier North Holland, 1979. 418 R35: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 260 R36: AMDUR MO ET AL; ENVIRON RES 16 (1-3): 1-8 (1978) R37: MOUNT DL; WATER RESEARCH 2: 215-23 (1968) R38: HUGHES JS; PROCEEDING OF THE 24TH ANNUAL CONFERENCE, SOUTHEASTERN ASSOCIATION OF GAME AND FISH COMMISSIONERS, JW WEBB, ED, P.431-8 (1970) R39: HENDERSON BM, WINTERFIELD RW; AVIAN DIS 19 (2): 385-7 (1975) R40: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986.,p. V2 245 R41: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. Old Woking, Surrey, United Kingdom: Royal Society of Chemistry/Unwin Brothers Ltd., 1983.,p. A245/Oct 83 R42: GUPTA PK ET AL; HYDROBIOLOGIA 83 (3): 461-4 (1981) R43: Kumar A, Sharma CB; Toxicol Lett 38 (3): 275-8 (1987) R44: WHO; Environ Health Criteria 200: Copper p.103 (1998) R45: WHO; Environ Health Criteria 200: Copper p.105 (1998) R46: WHO; Environ Health Criteria 200: Copper p.122 (1998) R47: WHO; Environ Health Criteria 200: Copper p.126 (1998) R48: WHO; Environ Health Criteria 200: Copper p.127 (1998) R49: WHO; Environ Health Criteria 200: Copper p.129 (1998) R50: USEPA; Health Issue Assessment: Copper p.26 (1987) EPA/600/8-87/001 R51: WHO; Environ Health Criteria 200: Copper p.101 (1998) R52: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office, 1980.22 R53: HUGHES JS; TOLERANCE OF STRIPED BASS, MORONE SAXATILIS (WALBAUM), LARVAE AND FINGERLINGS TO NINE CHEMICALS USED IN POND CULTURE; IN: PROCEEDINGS OF THE TWENTY-FOURTH ANNUAL CONFERENCE, SOUTHEASTERN ASSOCIATION OF GAME AND FISH COMMISSIONERS, JW WEBB, ED, COLUMBIA, SC: 431-8 (1970) R54: FELDMAN G ET AL; BIOL GASTRO-ENTEROL 5 (1): 37 (1972) R55: NAKASHIMA K ET AL; BIOMED RES 1 (6): 548-551 (1981) R56: DOUGHERTY JJ, HOEKSTRA WG; PROC SOC EXP BIOL MED 169 (2): 201-8 (1982) R57: IVANKOVIC S ET AL; NATURWISSENSCHAFTEN 59 (8): 369 (1972) R58: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 379 R59: Jones, L.M., et al. Veterinary Pharmacology and Therapeutics. 4th ed. Ames: Iowa State University Press, 1977. 885 R60: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. 1436 R61: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 579 R62: 40 CFR 180.1001(b) (7/1/2000) R63: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 76 R64: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R65: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R66: 40 CFR 401.15 (7/1/2000) R67: 21 CFR 582.80 (4/1/2000) R68: Gheorghiu C; Farmacia (Bucharest) 32 (4): 229-32 (1984) RS: 45 Record 210 of 1119 in HSDB (through 2003/06) AN: 3001 UD: 200303 RD: Reviewed by SRP on 6/15/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACETAMINOPHEN- SY: *ABENSANIL-; *ACETAGESIC-; *ACETAMIDE, N-(4-HYDROXYPHENYL)-; *P-ACETAMIDOPHENOL-; *4-ACETAMIDOPHENOL-; *ACETAMINOFEN-; *P-ACETAMINOPHENOL-; *ACETANILIDE,-4'-HYDROXY-; *N-ACETYL-P-AMINOPHENOL-; *N-ACETYL-4-AMINOPHENOL-; *P-ACETYLAMINOPHENOL-; *ALVEDON-; *AMADIL-; *ANAFLON-; *ANELIX-; *APAMIDE-; *CALPOL-; *CLIXODYNE-; *DATRIL-; *DYMADON-; *ENERIL-; *EXCEDRIN-; *FEBRILIX-; *FEBRO-GESIC-; *FEBROLIN-; *FENDON-; *HEDEX-; *P-HYDROXYACETANILIDE-; *4'-HYDROXYACETANILIDE-; *N-(4-HYDROXYPHENYL)ACETAMIDE; *LESTEMP-; *LIQUAGESIC-; *LONARID-; *LYTECA-; *MULTIN-; *NAPA-; *NAPAP-; *NAPRINOL-; *NOBEDON-; *PACEMO-; *PANADOL-; *PANETS-; *PARACETAMOL-; *PARMOL-; *PYRINAZINE-; *TABALGIN-; *TEMPRA-; *TRALGON-; *TUSSAPAP-; *TYLENOL-; *VALGESIC- RN: 103-90-2 RELT: 3152 [PHENACETIN] (METABOLIC PRECURSOR) MF: *C8-H9-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... FROM P-NITROPHENOL BY REDUCTION WITH TIN IN GLACIAL ACETIC ACID ... FROM P-AMINOPHENOL BY ACTION OF GLACIAL ACETIC ACID AND ACETIC ANHYDRIDE ... BY ACTION OF KETENE ON P-AMINOPHENOL ... FROM P-HYDROXYACETOPHENONE HYDRAZONE ... . [R1] FORM: *DRUG AVAILABLE GENERICALLY: CAPSULES 500 MG; DROPS 100 MG/ML; ELIXIR 80, 120, 130, 160 AND 325 MG/5 ML; TABLETS 80 (CHEWABLE) 325, 500, AND 650 MG; SUPPOSITORIES 120, 325, AND 650 MG (ALL FORMS NONPRESCRIPTION). [R2] MFS: *International Minerals and Chemical Corp, Hq, 2315 Sanders Road, Northbrook, IL 60062, (312) 564-8600; Subsidiary: Mallinckrodt, Inc, 675 Brown Rd, St Louis, MO 63134, (314) 895-2000; Drug and Cosmetic Chemicals Division; Production site: Raleigh, NC 27609 [R3] *Penco of Lyndhurst Inc, Hq, 540 New York Ave, Lyndhurst, NJ 07071, (201) 935-6600 [R3] *Rhone-Poulenc, Inc, Hq, 52 Vanderbilt Avenue, New York, NY 10017, (201) 297-0100; Specialty Group, CN 5266, Princeton, NJ 08543; Production site: Luling, LA 70070 [R3] USE: *MFR AZO DYES [R1] *ANALGESIC AGENT FOR HEADACHE AND DYSMENORRHEA; ANTIPYRETIC AGENT; STABILIZER FOR HYDROGEN PEROXIDE; CHEM INT FOR PHARMACEUTICALS, CHEMICALS. [R4] *Stabilizer for hydrogen peroxide, photographic chemicals. [R5] +MEDICATION +MEDICATION (VET) CPAT: *PRINCIPALLY USED AS A MEDICINAL (1976). [R4] *Acetaminophen. Analgesic, 75%; exports, 25%. [R6] *CHEMICAL PROFILE: Acetaminophen. Demand: 1987: 30 million lb; 1988: 30.5 million lb; 1992 /projected/: 31.5 million lb (Includes exports, but not imports, which totaled about 5 million lb last year.) [R6] PRIE: U.S. PRODUCTION: *(1975) 4.5X10+9 GRAMS (INCL PHENACETIN) [R4] *(1976) GREATER THAN 2.27X10+6 GRAMS [R4] U.S. IMPORTS: *(1972) 9.1X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R4] *(1975) 3.46X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LARGE MONOCLINIC PRISMS FROM WATER [R1]; *Needles from benzene petroleum ether [R7] ODOR: *ODORLESS [R5] TAST: *SLIGHTLY BITTER TASTE [R5] MP: *169-170.5 DEG C [R1] MW: *151.16 [R1] DEN: *1.293 @ 21 DEG C/4 DEG C [R1] PH: *SATURATED AQUEOUS SOLN 5.5-6.5 [R5] SOL: *VERY SLIGHTLY SOL IN COLD WATER, CONSIDERABLY MORE SOL IN HOT WATER; SOL IN METHANOL, ETHANOL, DIMETHYLFORMAMIDE, ETHYLENE DICHLORIDE, ACETONE, ETHYL ACETATE; SLIGHTLY SOL IN ETHER; PRACTICALLY INSOL IN PETROLEUM ETHER, PENTANE, BENZENE. [R1] SPEC: *MASS: 467 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R8]; *Intense mass spectral peaks: 80 m/z, 109 m/z, 151 m/z [R9] OCPP: *Melting point= 151 deg C [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *SENSITIVE TO LIGHT [R10] STRG: *Acetaminophen preparations should be stored at a temperature less than 40 deg C, preferably between 15 to 30 deg C; freezing of the oral solution or suspension should be avoided. [R11, 1171] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of paracetamol. There is inadequate evidence in experimental animals for the carcinogenicity of paracetamol. Overall evaluation: Paracetamol is not classifiable as to its carcinogenicity to humans (Group 3). [R12] ANTR: *1. Baseline blood tests for hospitalized patients include CBC, liver function tests (hepatic aminotransferases, prothrombin time, bilirubin), glucose, electrolytes, and creatinine. Repeat liver function tests daily for 3 days, then as indicated by the appearance of hepatic encephalopathy. No further tests are necessary for those patients whose acetaminophen levels fall below the toxic line. Repeat acetaminophen levels are unnecessary once serial levels indicate that peak levels have occurred and the last level is below the toxic line. If hepatic or renal dysfunction develops, monitor laboratory values daily until a clear pattern of improvement is seen. A rise in prothrombin time and unconjugated bilirubin levels are the earliest biochemical markers of hepatotoxicity occurring prior to hepatic enzyme elevation. 2. Watch for development of hypoglycemia. 3. Maintain normal hydration and electrolyte balance and avoid forced diuresis. 4. Administer vitamin K for elevated prothrombin time (1.5 X normal). Fresh frozen plasma should be used for severe prolongation (3 X normal). Following serial hemoglobin and stool guaiac tests for evidence of gastrointestinal bleeding. Prophylactic cimetidine may decrease the incidence of gastrointestinal ulcers. 6. Regular lactulose and enemas assist the elimination of nitrogenous substances and endotoxins from the bowel in encephalopathic patients. 7. Cerebral edema is a major cause of death following the development of hepatic encephalopathy and may be treated with mannitol and fluid restriction. [R13, 164] *Early diagnosis is vital in the treatment of overdosage with acetaminophen, and methods are available for the rapid determination of concentrations of the drug in plasma. However, therapy should not be delayed while awaiting laboratory results if the history suggests a significant overdosage. Vigorous supporting therapy is essential when intoxication is severe. Gastric lavage should be performed in all cases, preferably within 4 hours of the ingestion. Activated charcoal is usually not administered because it can absorb the antidote, N-acetylcysteine, and reduce its efficacy. The principal antidotal treatment is administration of sulfhydryl compounds, which probably act, in part, by replenishing hepatic stores of glutathione. N-acetylcysteine is particularly effective when given orally. The drug is recommended if less than 24 hours has elapsed since ingestion of acetaminophen, although treatment with N-acetylcysteine is more effective when given less than 10 hours after ingestion. An oral loading dose of 140 mg/kg is given, followed by the administration of 70 mg/kg every 4 hours for 17 doses. Treatment should begin immediately upon suspecting a signifiant acetaminophen overdosage, and it is terminated if assays of acetaminophen in plasma indicate that the risk of hepatotoxicity is low. Acetylcysteine is available as a sterile 10 or 20% solution in vials containing 4, 10 and 30 ml. The solution is diluted with soft drinks or water to achieve a 5% solution and should be consumed within 1 hour of preparation. [R14, 658] HTOX: *SKIN RASH AND OTHER ALLERGIC REACTIONS OCCUR OCCASIONALLY. RASH IS USUALLY ERYTHEMATOUS OR URTICARIAL BUT SOMETIMES IT IS MORE SERIOUS AND MAY BE ACCOMPANIED BY DRUG FEVER AND MUCOSAL LESIONS. [R14, 658] *IN A FEW ISOLATED CASES, THE USE OF ACETAMINOPHEN HAS BEEN ASSOCIATED WITH NEUTROPENIA, THROMBOCYTOPENIA, AND PANCYTOPENIA. [R14, 658] *MOST SERIOUS ADVERSE EFFECT OF ACUTE OVERDOSAGE OF ACETAMINOPHEN IS A DOSE-DEPENDENT, POTENTIALLY FATAL HEPATIC NECROSIS. RENAL TUBULAR NECROSIS ... AND HYPOGLYCEMIC COMA MAY ALSO OCCUR. ... IN ADULTS, HEPATOTOXICITY MAY OCCUR AFTER INGESTION OF A SINGLE DOSE OF 10-15 G (140 TO 250 MG/KG) OF ACETAMINOPHEN; DOSES OF 20 TO 25 G OR MORE IS POTENTIALLY FATAL. [R14, 658] *THE HEPATOTOXICITY MAY PRECIPITATE JAUNDICE AND COAGULATION DISORDERS AND PROGRESS TO ENCEPHALOPATHY, COMA, AND DEATH. TRANSIENT AZOTEMIA IS APPARENT IN MOST PATIENTS, AND ACUTE RENAL FAILURE OCCURS IN SOME. HYPOGLYCEMIA MAY OCCUR, BUT GLYCOSURIA AND IMPAIRED GLUCOSE TOLERANCE HAVE ALSO BEEN REPORTED. [R15] *SYMPTOMS ... OF ACUTE POISONING ... BOTH METABOLIC ACIDOSIS AND METABOLIC ALKALOSIS HAVE BEEN NOTED; CEREBRAL EDEMA AND NONSPECIFIC MYOCARDIAL DEPRESSION HAVE ALSO OCCURRED. BIOPSY OF THE LIVER REVEALS CENTRALOBULAR NECROSIS WITH SPARING OF THE PERIPORTAL AREA. [R15] *... REPORT ON 226 INFANTS BORN TO MOTHERS WHO TOOK THE DRUG DURING THE FIRST 4 MO OF PREGNANCY FOUND NO INCR IN MALFORMATIONS. [R16] *The content of acetaminophen in the blood, tissues and body fluid was measured at autopsy of a 25-yr-old female who died from a suicidal overdose of imipramine, acetominophen, codeine diphenhydramine, and ethanol. (Empty bottles of Novopramine 50 mg (imipramine) and Tylenol #1 (acetaminophen 300 mg, codeine 8 mg, caffeine 15 mg) were found; the quantity of alcohol imbibed was not known). Blood samples were taken from at least 10 arterial and venous sites, and other samples were taken from 24 tissues, cerebrospinal fluid, vitreous humor and bile. Acetominophen showed a narrow concentration range (55-65 mg/l) in postmortem blood, but high concentrations were found in the kidney (187 mg/kg in right renal cortex and 148 mg/kg in left renal medulla). [R17] *Symptoms during the first 2 days of acute poisoning by acetaminophen do not reflect the potential seriousness of the intoxication. Nausea, vomiting, anorexia, and abdominal pain occur during initial 24 hr and may persist for wk or more. ... Clinical indications of hepatic damage manifest themselves within 2-4 days of ingestion of toxic doses. Initally, plasma transaminases and dehydrogenase activity may be elevated ... . Concn of bilirubin in plasma may be incr, ... and prothrombin time is prolonged. Perhaps 10% of poisoned patients who don't receive specific treatment develop severe liver damage; of these 10% to 20% eventually die of hepatic failure. ... In nonfatal cases, the hepatic lesions are reversible over a period of weeks or months. [R15] *A 3 YR OLD GIRL WHO INGESTED ABOUT THIRTY FIVE 325 MG TABLETS OF ACETAMINOPHEN WAS ONLY MODERATELY ILL WITH SERUM CONCN OF 94 UG/ML, BUT SHOWED VERY HIGH LEVELS OF HEPATIC ENZYMES. THE IMPORTANCE OF DETERMINING ACETAMINOPHEN PLASMA CONCN AT DIFFERENT TIMES TO EVALUATE PLASMA HALF-LIFE IS DISCUSSED. [R18] *A 3.5 YR OLD GIRL WITH AN UPPER RESP INFECTION DIED OF AN ACETAMINOPHEN OVERDOSE. WHEN THE CHILD'S TEMP REMAINED ELEVATED AFTER TREATMENT WITH 120 MG EVERY 4 HR FOR 3 DOSES, DOSAGE WAS INCR TO 720 MG EVERY 3 HR. OVER THE NEXT 24 HR THE PATIENT RECEIVED 5.04 G. [R19] *A 63 YR OLD MAN WITH ACUTE PSITTACOSIS HAD SEVERE HEPATIC DAMAGE AFTER INGESTING ABOUT 10 G ACETAMINOPHEN OVER A 48 HR PERIOD. TRANSAMINASE LEVELS SHOWED STRIKING ELEVATION, WITH A SERUM GLUTAMIC-OXALOACETIC TRANSAMINASE LEVEL OF OVER 15000 IU/L, AND DECR RAPIDLY, CONSISTENT WITH TOXIC INSULT. THE LIVER SHOWED SEVERE CENTRAL NECROSIS AT AUTOPSY. [R20] NTOX: *... ACETAMINOPHEN WAS ADMIN TO 4 ADULT CATS. A MARKED DEGREE OF CYANOSIS WAS SEEN IN THESE ANIMALS WITHIN 4 HR AFTER ADMIN OF SINGLE TABLET CONTAINING 325 MG ... DUE TO HYPOXIA ASSOC WITH CONVERSION OF HEMOGLOBIN TO METHEMOGLOBIN. IN ADDN, ANEMIA, HEMOGLOBINURIA, AND ICTERUS WERE EVENTUALLY SEEN IN THE CATS. HEMOLYSIS OF RED BLOOD CELLS WAS RESPONSIBLE FOR DEVELOPMENT OF ANEMIA AND HEMOGLOBINURIA. ICTERUS WAS ATTRIBUTED TO BOTH LYSIS OF ERYTHROCYTES AND HEPATIC NECROSIS. FACIAL EDEMA WAS ALSO OBSERVED IN 3 OF THE 4 EXPTL CATS. [R21] *FEMALE RATS WERE TREATED DAILY WITH ACETAMINOPHEN FOR 2 WK PRIOR TO MATING @ 500 OR 1000 MG/KG. TREATMENT WAS CONTINUED UNTIL DAY 11.5 AFTER COPULATION. FETUSES WERE THEN ANALYZED CYTOGENETICALLY, USING A DIRECT METHOD FOR CHROMOSOME PREPN. A SIGNIFICANT DIFFERENCE IN CHROMOSOME ANOMALY WAS FOUND ONLY BETWEEN THE CONTROL GROUP AND THE 500 MG/KG GROUP. ANEUPLOIDY WAS THE MAJOR ANOMALY OBSERVED. [R22] *POSTMITOCHONDRIAL SUPERNATANTS ISOLATED FROM THE LIVERS OF MATURE RATS (3-6 MO OLD) 2 HR OR MORE AFTER ADMIN OF A SINGLE LARGE ORAL DOSE OF PARACETAMOL (800 MG/KG) SHOWED RAPID RATES OF LIPID PEROXIDATION. IN SIMILAR EXPT WITH OLD RATS (27-30 MO OLD) THE TIME BETWEEN ADMIN OF PARACETAMOL AND THE ONSET OF LIPID PEROXIDATION WAS MUCH LONGER, UP TO 6 HR. [R23] *Paracetamol was tested for mutagenicity in the Salmonella/mammalian microsome assay. Six testor strains were used (TA1535, TA1537, TA1538, TA100, TA97 and TA98) and experiments were conducted in the presence and absence of a rat liver microsome activation system. Paracetamol did not show any evidence of mutagenic activity at concentrations ranging from 0.1 to 50 mg per plate. [R24] *Male Wistar rats were fasted 24 hr and administered a single dose of paracetamol/water suspension (2 g paracetamol/kg) by gavage. Rats were killed, and liver and blood samples taken at 0, 6, 9, 12, and 24 hr post paracetamol administration. Hepatic reduced glutathione levels were lowered within 6 hr after paracetamol treatment, and remained so until returning to control levels at 12-24 hr. Serum glutamate pyruvate transaminase (SGPT) levels were increased from control (n= 7) levels of 30-40 mU/ml to 700-3000 mU/ml at 24 hr after paracetamol administration. Blood glucose concentrations of paracetamol treated rats (n= 13) were 5.85 +/- 0.50 mM compared to the control values of 5.28 +/- 0.36 mM. Based on trypan blue exclusion, paracetamol-induced necrosis around the central vein was noted at 9-12 hr and was much more extensive at 24 hr after treatment. A concurrent activation of glycogen phosphorylase in perivenous hepatocytes and an increase in periportal hepatocyte glycogen content was observed at 12 hr post treatment. [R25] *Acetaminophen ... an analgesic and antipyretic, is without known ocular side effects, with the exception that in genetically very special mice it can cause irreversible opacification of the anterior portion of the lens when a large dose is given ip. [R26] *Cats are particularly susceptible to paracetamol intoxication because of their imparied glucuronic acid conjugation mechanism and saturation of their sulfate conjugation pathway. ... The clinical signs associated with experimental paracetamol administration to cats included cyanosis followed by anaemic, haemoglobinuria, icterus and facial oedema in three of four treated cats. ... Paracetamol poisoned cats develop more diffuse liver changes, while hepatic centrilobular lesions are seen in dogs. The abnormal laboratory findings in paracetamol poisoned cats include methaemoglobinaemia and an elevated serum alanine aminotransferase activity. [R27] +... CONCLUSIONS: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on incr incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3Fl mice that received 600, 3,000, or 6,000 ppm. [R28] NTP: +... Toxicology and carcinogenesis studies were conducted by administering acetaminophen (purity > 99%) in feed to groups of F344/N rats and B6C3Fl mice of each sex for ... 2 yr. ... TWO YR STUDIES: Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 wk. ... CONCLUSIONS: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on incr incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3Fl mice that received 600, 3,000, or 6,000 ppm. [R28] +Acetaminophen (ACET) ... was tested for its effects on reproduction and fertility in CD-1 mice, following the RACB protocol. Data on body weights, clinical signs, and food and water consumption from a 2 wk dose-range-finding study (Task 1) were used to set exposure levels for the Task 2 continuous cohabitation phase at 0.25%, 0.5%, and 1.0% in the diet. Feed consumption was reduced only in females at the top dose level, by 10-20%. Measured body weight and feed consumption allowed exposure to be estimated as nearly equal to 370, 770, and 1400 mg/kg/day. During Task 2, 4 animals died: 2, 1, and 1 each in the low, middle, and high dose groups. During Task 2, the number of litters/pair decreased by 3% for the high dose group. No changes were noted in the number of pups/litter, viability, or in adjusted pup weight. The slight reduction in number of litters/pair was judged to be too small to yield a detectable change during the statistically-less-powerful Task 3 crossover mating, so no crossover test was conducted. For the F1 evaluation, the last litter in Task 2 from all dose groups was nursed to weaning, and reared on the diet consumed by their parents. F1 pup body weights were reduced at all doses for both sexes by nearly equal to 6-18%. Pup body weight gain to weaning was also reduced for the medium and high dose males (17% and 34%), and for females at all doses (10-28%). All dose groups were reared consuming the same diet provided to their parents. The body weight differences that were seen during nursing were reduced, but still present, at the time of mating. At the F1 mating, the F2 pup weight adjusted for litter size was decreased by 11% at the high dose level. No other reproductive endpoints were affected. After the F2 pups were delivered and evaluated, the F1 adults from only the control and high dose groups were killed and necropsied. Compared to controls, the high dose males weighed 10% less, while organ weights were not affected. Sperm abnormalities increased from 7% (controls) to 16% at the high dose. High dose females weighed 8% less, while adjusted liver weight was increased by 10%. In summary, the greatest toxicity produced by acetaminophen in the diet of Swiss mice was on the growing neonate (reduced weight gain during nursing). Fertility endpoints (ability to bear normal numbers of normal-weight young) were generally not affected. [R29] POPL: *Paracetamol should be given with care to patients with impaired kidney or liver function. ... Paracetamol should be given with care to patients taking other drugs that affect the liver. [R30] ADE: *HIGH CARBOHYDRATE MEALS REDUCED GI ABSORPTION RATES ... IN MAN ... . POSSIBLE MECHANISM MAY BE REACTION OF DRUG WITH PECTIN, PRESENT IN SOME CARBOHYDRATE MEALS. AS ACETAMINOPHEN IS ABSORBED FROM STOMACH AS WELL AS SMALL INTESTINE, CHANGES IN GASTRIC EMPTYING SHOULD NOT GREATLY ALTER ABSORPTION RATE. [R31, 419] *THE ELIMINATION RATE AND PLASMA CLEARANCE OF PARACETAMOL ARE BOTH SIGNIFICANTLY REDUCED IN INDIVIDUALS AGED 65 YEARS OR OVER. [R32] */Acetaminophen/ distributes uniformly throughout most body fluid and has a volume of distribution of approximately 0.75-1 l/kg. [R13, 157] *Acetaminophen is rapidly and most completely absorbed from the GI tract. Following oral administration of acetaminophen, peak plasma concentrations are attained within 10 to 60 minutes. After 8 hours, only small amounts of drug are detectable in plasma. [R11, 1171] METB: *YIELDS 4-ACETAMIDOCATECHOL IN RAT; YIELDS S-(5-ACETAMIDO-2-HYDROXYPHENYL)-L-CYSTEINE PROBABLY IN MAN. YIELDS P-ACETAMIDOPHENYL-BETA-D-GLUCURONIDE IN RABBIT; YIELDS P-ACETAMIDOPHENYL-BETA-D-GLUCURONIDE IN RAT, IN GUINEA PIG, AND IN FERRET; YIELDS P-ACETAMIDOPHENYL-BETA-D-GLUCURONIDE IN MAN AND IN DOG; YIELDS P-ACETAMIDOPHENYL SULFATE IN RABBIT, GUINEA PIG, AND FERRET; YIELDS P-ACETAMIDOPHENYL SULFATE IN RAT AND IN MAN; YIELDS P-METHOXYACETANILIDE IN GUINEA PIG; YIELDS QUINOL PROBABLY IN RAT. /FROM TABLE/ [R33] *... CONVERTED TO SLIGHT EXTENT TO DEACETYLATED PRODUCTS WHICH ARE PRESUMABLY RESPONSIBLE FOR SMALL AMT OF METHEMOGLOBINEMIA PRODUCED BY THESE DRUGS IN MAN. [R34] *CHILDREN HAVE LESS CAPACITY FOR GLUCURONIDATION OF THE DRUG THAN DO ADULTS. A SMALL PROPORTION OF ACETAMINOPHEN UNDGOES N-HYDROXYLATION TO FORM N-ACETYL-BENZOQUINONEIMINE, A HIGHLY REACTIVE INTERMEDIATE. THIS METABOLITE NORMALLY REACTS WITH SULFHYDRYL GROUPS IN GLUTATHIONE. HOWEVER, AFTER LARGE DOSES OF ACETAMINOPHEN THE METABOLITE IS FORMED IN AMOUNTS SUFFICIENT TO DEPLETE HEPATIC GLUTATHIONE; UNDER THESE CIRCUMSTANCES REACTION WITH SULFHYDRYL GROUPS IN HEPATIC PROTEINS IS INCREASED AND HEPATIC NECROSIS CAN RESULT. [R14, 657] *The liver biotransforms 90% of accetaminophen by conversion in sulfate or glucuronide. The sulfate pathway predominates in children under 12 years of age, whereas adults primarily use the glucuronide pathway. Unchanged renal excretion accounts for less than 5% of the elimination. A small portion of the therapeutic dose (about 5% with an upper limit of 15% to 20%) is metabolized by the p450 mixed-function oxidase pathway to a reactive intermediary. In the presence of adequate glutathione stores, this intermediary is detoxified to mercapturic acid conjugates and cysteine. Formation of oxidative metabolities and renal excretion appear to follow first-order kinetics (ie, elimination rate is concentration dependent); the conjugation of sulfate and glucuronide metabolites follow Michaelis-Menten kinetic (combined zero- and first-order). [R13, 157] BHL: *ACETAMINOPHEN IS RAPIDLY AND ALMOST COMPLETELY ABSORBED FROM THE GI TRACT. THE CONCN IN PLASMA REACHES A PEAK IN 30 TO 60 MIN, AND THE HALF-LIFE IN PLASMA IS ABOUT 2 HR AFTER THERAPEUTIC DOSES ... RELATIVELY UNIFORMLY DISTRIBUTED THROUGHOUT MOST BODY FLUIDS. BINDING OF THE DRUG TO PLASMA PROTEINS IS VARIABLE; 20-50% MAY BE BOUND @ THE CONCN ENCOUNTERED DURING ACUTE INTOXICATION. AFTER THERAPEUTIC DOSES, 90 TO 100% OF THE DRUG MAY BE RECOVERED IN THE URINE WITHIN THE FIRST DAY ... . [R14, 657] ACTN: *... REDUCES FEVER ... BY INHIBITING ACTION OF ENDOGENOUS PYROGEN ON HYPOTHALAMIC HEAT-REGULATING CENTERS. ... MORE ACTIVE THAN ASPIRIN AS INHIBITOR OF PROSTAGLANDIN SYNTHETASE OF BRAIN, BUT ... ONLY VERY WEAK INHIBITOR OF PROSTAGLANDIN SYNTHESIS BY PREPARATION FROM SPLEEN ... . [R35, 344] INTC: *ACETAMINOPHEN ... MAY INDUCE SYNTHESIS OF THE HEPATIC MICROSOMAL ENZYMES, BUT THE EFFECT IS NOT SEEN WITH USUAL DOSES AS A RESULT, THE PROTHROMBINOPENIC EFFECT OF ORAL ANTICOAGULANT AGENTS MAY BE SLIGHTLY INCR BY CHRONIC ADMIN OF FULL DOSES OF ACETAMINOPHEN, BUT INTERMITTENT DOSES OF DRUG HAVE ONLY LITTLE SUCH EFFECT. [R35, 703] *ANTIHISTAMINES INCREASE ACETAMINOPHEN TOXICITY IN ANIMALS. [R35, 346] *... DEMONSTRATED MUTUAL COMPETITIVE INHIBITION IN FORMATION OF SULFATES, AND PROBABLY GLUCURONIDES, OF ACETAMINOPHEN AND SALICYLAMIDE IN MAN. COMPETITION WAS SPECIFIC, BECAUSE NO SUCH INTERACTION OCCURRED BETWEEN ACETAMINOPHEN AND SALICYLATE. [R31, 440] *ACETAMINOPHEN CAUSES DOSE-DEPENDENT DECR IN CONCN OF HEPATIC GLUTATHIONE. AGENTS SUCH AS DIETHYL MALEATE, WHICH DEPLETES HEPATIC GLUTATHIONE, POTENTIATE /HEPATIC AND RENAL TUBULAR/ NECROSIS. CONVERSELY, ADMIN OF CYSTEINE, GLUTATHIONE PRECURSOR, PROTECTS AGAINST DAMAGE. [R36, 544] *AT CERTAIN DOSE LEVELS ... PRETREATMENT WITH PHENOBARBITONE STIMULATED DISAPPEARANCE OF PARACETAMOL FROM TISSUES, BUT MARKEDLY POTENTIATED HEPATIC NECROSIS. BY CONTRAST, PRETREATMENT WITH PIPERONYL BUTOXIDE INHIBITED BOTH METABOLISM AND DISAPPEARANCE OF PARACETAMOL FROM TISSUES, and ... AFFORDED PROTECTION AGAINST HEPATIC NECROSIS. [R36, 612] *RATE AND EXTENT OF ABSORPTION OF PER ORAL DOSED PARACETAMOL IS REDUCED BY ... CONCOMITANT DOSES OF CAFFEINE, BY PROPANTHELINE AND METOCLOPROMIDE, AND ALSO BY ... CHOLESTYRAMINE. [R36, 128] *CONCURRENT INGESTION OF ALCOHOL OR OTHER DRUGS WITH ACETAMINOPHEN MAY ENHANCE ITS TOXICITY BY REDUCING THE METABOLIC CAPACITY OF THE LIVER. [R15] *A SINGLE DOSE OF ETHANOL (200 ML OF 20 AND 40% SOLN) DECR THE BIOAVAILABILITY OF PARACETAMOL (1 G, ORALLY) IN HEALTHY MEN. [R37] *MASSIVE LIVER NECROSIS AND 70% LETHALITY WERE OBSERVED AFTER 800 MG ACETAMINOPHEN/KG IN MICE AND THESE EFFECTS WERE PREVENTED BY EARLIER PRETREATMENT WITH 50 MG FENITROTHION/KG. [R38] *VALUE OF CAFFEINE IN COMBINATION WITH ACETAMINOPHEN IN THE RELIEF OF PAIN FROM UTERINE CRAMPING, EPISIOTOMY, AND THIRD MOLAR EXTRACTION WAS STUDIED. IN THE DENTAL STUDY, 173 PATIENTS RECEIVED TWO OR FOUR TABLETS OF 500 MG ACETAMINOPHEN OR COMBINATION OF 500 MG ACETAMINOPHEN AND 65 MG CAFFEINE. IN 3 POSTPARTUM STUDIES, 1345 PATIENTS RECEIVED ONE, TWO, OR THREE TABLETS OF ACETAMINOPHEN, THE COMBINATION, OR A PLACEBO. CAFFEINE ENHANCED THE ANALGESIC EFFICACY OF ACETAMINOPHEN. [R39] *A preliminary study in four subjects indicated that acetaminophen (3.0 g/day for 5 days) somewhat reduced the 96 hour urinary excretion of diazepam and its metabolites following a single 10 mg dose of diazepam. The effect was greater in the two female subjects, but additional study is needed to confirm these results and to define the magnitude of the interaction. [R40, 379] *In four healthy subjects, concurrent administration of cholestyramine (12 g orally) markedly reduced plasma levels of acetaminophen (2.0 g orally). It seems likely that colestipol (Colestid) would similarly reduce plasma acetaminophen levels. [R40, 379] *Reports of the administration of 1.0 g of acetaminophen with food in four adult male volunteers demonstrated a considerable reduction in the rate of absorption of the drug with little change in the total amount of acetaminophen absorbed. The meal consisted of 200 ml orange juice, 30 g cornflakes, and Pop Tarts. In another study high carbohydrate test meals (crackers, jelly, and dates) significantly delayed absorption of acetaminophen as measured by urinary excretion. It was noted that high protein, high lipid, or balanced meals appeared to have little inhibitory effect on the rate of absorption. [R40, 380] *Chronic ingestion of large doses of acetaminophen has been reported to slightly potentiate the effects of coumarin and indandione-dervative anticoagulants but reports are conflicting. [R11, 1173] *Acetaminophen enhance the action of antidiuretic hormone. [R14, 737] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Analgesics, Non-Narcotic [R41] *The conventional oral dose of ancetaminophen is 325 to 1000 mg (650 mg rectally); the total daily dose should not exceed 4000 mg. For children, the single dose is 40 to 480 mg, depending upon age and weight; no more than five doses should be administered in 24 hours. A dose of 10 mg/kg may also be used [R14, 659] *... RELIEVE PAIN OF MODERATE INTENSITY, SUCH AS USUALLY OCCURS IN HEADACHE AND DYSMENORRHEA, AND IN MANY MUSCLE, JOINT, AND PERIPHERAL NERVE DISORDERS. ... ALSO ... REDUCE FEVER BY DIRECT EFFECT ON HEAT-REGULATING CENTERS TO INCR DISSIPATION OF BODY HEAT. [R35, 344] *ACETAMINOPHEN ... IS SUITABLE SUBSTITUTE FOR ASPIRIN FOR ITS ANALGESIC OR ANTIPYRETIC USES ... IN PATIENTS IN WHOM ASPIRIN IS CONTRAINDICATED (EG, THOSE WITH PEPTIC ULCER) OR WHEN THE PROLONGATION OF BLEEDING TIME CAUSED BY ASPIRIN WOULD BE A DISADVANTAGE. [R14, 659] *THIS DRUG, METABOLITE OF PHENACETIN, IS POSSIBLY RESPONSIBLE FOR ANTIPYRETIC-ANALGESIC ACTIVITY OF PHENACETIN ... . [R42] +MEDICATION (VET): IN ARTHRITIC AND INFLAMMATORY SYNDROMES TO RELIEVE PAIN AND REDUCE FEVER. [R43] *EXPTL USE: IN A DOUBLE BLIND CROSSOVER STUDY, THE ANALGESIC ORAL BUTORPHANOL, 4 MG, AND ACETAMINOPHEN, 650 MG, ALONE OR IN COMBINATION, WAS ASSESSED IN 20 PATIENTS WITH MODERATE TO SEVERE PAIN DUE TO METASTATIC CARCINOMA. ANALYSIS SHOWED ANALGESIC EFFECTS OVER PLACEBO OF EACH DRUG WITH ADDITIVE RELIEF OF PAIN WITH THE BUTORPHANOL/ACETAMINOPHEN COMBINATION UP TO 6 HR DURATION. [R44] *Acute tension-type headaches with mild to moderate pain may be treated with a nonopiate analgesic such as ... acetaminophen ... . [R45, 125] */Acetaminophen/ is used to treat headache, mild to moderate myalgia, arthralgia, chronic pain of cancer, postpartum pain, postoperative pain, and fever. [R45, 110] WARN: *ACETAMINOPHEN SHOULD NOT BE ADMIN FOR MORE THAN 10 DAYS OR TO YOUNG CHILDREN EXCEPT UPON ADVICE OF PHYSICIAN. [R14, 659] *IN THE CAT, ACETAMINOPHEN IS NOT RECOMMENDED AT ANY DOSE. [R21] *... REPORTED AN INFANT WITH POLYHYDRAMINOS AND RENAL FAILURE; THE NEPHROTOXICITY WAS FELT TO BE ASSOC WITH ACETAMINOPHEN WHICH THE MOTHER INGESTED HEAVILY DURING PREGNANCY. [R16] *SEVERE LIVER DYSFUNCTION OCCURRED IN 2 INDIVIDUALS WHO TOOK 3.6 G/DAY ACETAMINOPHEN FOR SYMPTOMS OF INFECTIOUS MONONUCLEOSIS. ALL LAB VARIABLES RETURNED TO NORMAL FOLLOWING ACETAMINOPHEN WITHDRAWAL. [R46] *A CASE OF AN INTERACTION BETWEEN ACETAMINOPHEN AND BLOOD GLUCOSE ANALYSIS IS REPORTED IN A 47 YR OLD WOMAN WHO TOOK AN OVERDOSE. BLOOD ANALYSIS SHOWED BLOOD GLUCOSE OF 54.4 MMOL/L (973 MG/100 ML); ACETAMINOPHEN CONCN OF 4.5 MMOL/L (680 MG/L). A SAMPLE OF VENOUS BLOOD WAS CHECKED FOR GLUCOSE BY OTHER METHODS BECAUSE OF THE DISCREPANCY BETWEEN BLOOD GLUCOSE AND URINALYSIS. THE GLUCOSE RESULTS WERE 44 MMOL/L BY BLOOD GLUCOSE ANALYSIS, 4.3 MMOL/L BY URINALYSIS, AND 2 MMOL/L BY ANOTHER METHOD. [R47] *Paracetamol should be given with care to patients with impaired kidney or liver function. ... Paracetamol should be given with care to patients taking other drugs that affect the liver. [R30] *Acetaminophen shold be discontinued if hypersensitivity reactions occur. [R11, 1171] +Maternal Medication usually Compatible with Breast-Feeding: Acetaminophen: Reported Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/ [R48] +POTENTIAL ADVERSE EFFECTS ON FETUS: None known with short-term use. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Excreted at low concentrations. American Academy of Pediatrics considers safe for breast-feeding. FDA Category: B (B = Studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; or animal studies have shown an adverse effect (other than a decrease in fertility), but controlled studies in pregnant women have not demonstrated a risk to the fetus in the first trimester and there is no evidence of a risk in later trimesters.) /from Table II/ [R49] MXDD: *TOTAL DAILY DOSE SHOULD NOT EXCEED 4000 MG [R14, 659] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION OF ACETAMINOPHEN IN DRUGS USING SPECTROPHOTOMETRIC METHOD. [R50] *High performance liquid chromatography analysis of acetaminophen with UV detector. Flow rate is 215 ml/min, wavelength is 254 nm fixed or 250 nm variable. [R51, 104] *Acetaminophen is determined by reverse phase liquid chromatography using methanol-acetic acid mobile phase and ultraviolet detection at 280 nm in single component drug tablets and in multi-component tablets containing aspirin and caffeine. [R52] CLAB: *URINE, COLORIMETRY; CHROMATOGRAPHY, GAS-LIQUID. [R51, 13] *SAMPLES USED WERE FROM RAT BLOOD. HPLC METHOD IS SENSITIVE ENOUGH TO DETECT 0.05 MG/L OF PHENACETIN AND 0.25 MG/L OF ACETAMINOPHEN IN PRESENCE OF THEIR METABOLITES IN BIOLOGICAL FLUIDS. [R53] *DETERMINATION OF PHENACETIN IN BLOOD PLASMA OF ANIMALS BY GAS CHROMATOGRAPHY. [R54] *THE AMOUNT OF ANALGESIC CONSUMED AND THE TIME IT WAS CONSUMED IS DETERMINED BY URINE ANALYSIS USING EITHER THIN LAYER CHROMATOGRAPHY OR COLORIMETRY. [R55] *HIGH PERFORMANCE LIQUID CHROMATOGRAPHY (HPLC) METHODS WERE DEVELOPED FOR THE ANALYSIS OF ACETAMINOPHEN IN POSTMORTEM BLOOD. [R56] *A METHOD FOR SPECTROMETRIC MEASUREMENT OF ACETAMINOPHEN AT 615 NM IS DESCRIBED WHICH IS RAPID AND PRECISE ENOUGH FOR EMERGENCY LAB USE IN BLOOD ANALYSIS. [R57] *A DIFFERENTIAL PULSE VOLTAMMETRIC METHOD WAS EVALUATED FOR DETERMINATION OF TOXIC LEVELS OF ACETAMINOPHEN IN IN VITRO HUMAN PLASMA SAMPLES. [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: WHO; Environmental Health Criteria 119: Principles and Methods for the Assessment of Nephrotoxicity Associated with Exposure to Chemicals (1991) DHHS/NTP; Toxicology and Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 394 (1993) NIH Publication No. 93-2849 SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 8 R2: American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986. 78 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 735 R4: SRI R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 11 R6: Kavaler AR; Chemical Marketing Reporter 234 (25): 50 (1988) R7: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-16 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 10 R9: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.206 R10: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 86 R11: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992). R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 73 438 (1999) R13: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R14: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R15: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 703 R16: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 3 R17: Jones GR, Pounder DJ; J Anal Toxicol 11 (5): 186-90 (1987) R18: ARENA JM ET AL; PEDIATRICS 61 (JAN): 68 (1978) R19: NOGEN AG, BREMMER JE; J PEDIATR 92 (MAY): 832 (1978) R20: DAVIS AM ET AL; AM J MED 74 (2): 349 (1983) R21: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 304 R22: TSURUZAKI T ET AL; NIPPON EISEIGAKU ZASSHI 37 (5): 787 (1982) R23: BARBER DJ ET AL; TOXICOL LETT 15 (4): 283 (1983) R24: Jasiewicz ML et al; Mutat Res 190: 95-100 (1987) R25: Jepson MA et al; Toxicology 47 (3): 325-37 (1987) R26: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 32 R27: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 91 R28: Toxicology and Carcinogenesis Studies of Acetaminophen in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 394 (1993) NIH Publication No. 93-2849 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R29: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Acetaminophen : (CAS # 103-90-2): Reproduction and Fertility Assessment in CD-1 Mice When Administered in the Feed, NTP Study No. RACB83079 (November 21, 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 15, 2002 R30: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 269 R31: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. R32: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 25 R33: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. A-10 R34: LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971. 347 R35: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R36: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. R37: WOJCICKI J ET AL; POL J PHARMACOL PHARM 30 (6): 749 (1978) R38: GINSBERG GL ET AL; TOXICOL APPL PHARMACOL 66 (3): 383 (1982) R39: LASKA EM ET AL; CLIN PHARMACOL THER 33 (4): 498 (1983) R40: Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985. R41: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R42: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 176 R43: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 1 R44: STAMBAUGH JE; CURR THER RES CLIN EXP 31 (MAR): 386 (1982) R45: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. R46: ROSENBERG DM, NEELON FA; ANN INTERN MED 88 (JAN): 129 (1978) R47: FARAH DA ET AL; BR MED J 285 (JUL 17): 172 (1982) R48: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 140 (1994) R49: Stockton, D.L. and A.S. Paller. J Am Acad Dermatol 23 (1):87-103 (1990) R50: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. 13/615 37.010 R51: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. R52: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. 554 VI 987.12 R53: PANG KS ET AL; J CHROMATOGR 174 (1): 165 (1979) R54: KYO Y, NIWA H; TOHOKU YAKKA DAIGAKU KENKYU NEMPO 25: 71 (1978) R55: KOBBE K, GOENECHEA S; BEITR GERICHTL MED 40: 341 (1982) R56: WONG AS; J ANAL TOXICOL 7 (1): 33 (1983) R57: PRICE CP ET AL; CLIN CHEM (WINSTON-SALEM, NC) 29 (2): 358 (1983) R58: MUNSON JW, ABDINE A; J PHARM SCI 67 (DEC): 1775 (1978) RS: 39 Record 211 of 1119 in HSDB (through 2003/06) AN: 3003 UD: 200303 RD: Reviewed by SRP on 5/11/1995 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ACETYLCYSTEINE- SY: *L-ALPHA-ACETAMIDO-BETA-MERCAPTOPROPIONIC-ACID-; *N-ACETYLCYSTEINE-; *N-ACETYL-L-CYSTEINE-; *N-ACETYL-N-CYSTEINE-; *N-ACETYL-3-MERCAPTOALANINE-; *AIRBRON-; *BRONCHOLYSIN-; *BRONCHOLYSIN-; *L-CYSTEINE,-N-ACETYL-; *CYSTEINE,-N-ACETYL-,-L-; *FLUIMUCETIN-; *FLUIMUCIL-; *MERCAPTURIC-ACID-; *MERCAPTURIC ACID, (R)-; *MUCOLYTICUM-LAPPE-; *MUCOMYST-; *NAC-; *PARVOLEX-; *RESPAIRE- RN: 616-91-1 MF: *C5-H9-N-O3-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DIRECT ACETYLATION OF NATURALLY OCCURRING L-CYSTEINE [R1] *Prepared by reaction of cysteine hydrochloride monohydrate with acetic anhydride in the presence of sodium acetate [R2] FORM: *USP grades [R3] MFS: *Penta Manufacturing Co, PO Box 1448, Fairfield, NJ 07007, (201) 740-2300 /L-Cysteine hydrochloride, pharmaceuticals/ [R4] USE: *MUCOLYTIC AGENT (ADJUVANT) FOR BRONCHOPULMONARY DISORDERS [R1] *Medicine, biochemical research [R5] *Mucolytic; corneal vilnerary; antidote to acetaminophen poisoning [R6] *Secretolytic agent [R2] +MEDICATION +MEDICATION (VET) CPAT: *ESSENTIALLY 100% AS A MUCOLYTIC AGENT [R1] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM WATER [R6]; *WHITE, CRYSTALLINE POWDER [R7] ODOR: *SLIGHT ACETIC ODOR [R7] TAST: *CHARACTERISTIC SOUR TASTE [R7] MP: *109.5 DEG C [R8] MW: *163.20 [R8] DSC: +PKA= 3.24 [R7] PH: *2 TO 2.75 (1 IN 100 ML) [R7] SOL: *1 G IN 5 ML WATER, 4 ML ALC; PRACTICALLY INSOL IN CHLOROFORM AND ETHER [R7]; *Soluble in water, alcohol, hot isopropyl alcohol, methyl acetate, and ethyl acetate [R9] SPEC: *Specific optical rotation: +5 deg at 20 deg C (concn = 3 g/100 mL water) [R2] OCPP: *It is stable in ordinary light, nonhygroscopic (oxidizes in moist air), and stable at temperatures up to 120 deg C [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Acetylcysteine is a reducing agent and is incompatible with oxidizing agents. Solutions of acetylcysteine become discolored and liberate hydrogen sulfide upon contact with rubber, some metals, particularly iron and copper, and/or when subjected to autoclaving. ... Solutions containing amphotericin B, tetracyclines, erythromycin lactobionate, or ampicillin sodium. ... Acetylcysteine solutions are also physically imcompatible with iodized oil, trypsin, hydrogen peroxide. [R10, 1762] SSL: *STABLE IN ORDINARY LIGHT; STABLE @ TEMP UP TO 120 DEG C; NONHYGROSCOPIC (OXIDIZES IN MOIST AIR) [R7] STRG: *Unopened vials of acetylcysteine sodium solution should be stored at 15-30 deg C. Following exposure to air, solutions should be stored at 2-8 deg C to retard oxidation and should be used within 96 hr. [R10, 1762] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a tight container with a glass or polyethylene or polytef-coated elastomeric closure. [R11, 19] *Acetylcysteine solution does not contain an antimicrobial agent; therefore, care must be taken to minimize contamination of the sterile solution. After opening, the vial should be stored in the refrigerator; the opened vial should be discarded after 96 hours. [R11, 19] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *WHEN IT IS ADMIN BY NEBULIZING SOLN IN TREATMENT TENT, EYES ARE EXPOSED TO ITS ACTION. SO FAR THERE APPEAR TO BE NO REPORTS OF IRRITATION OF EYES EVEN AFTER PROLONGED EXPOSURE. WHEN ACETYLCYSTEINE IS NEBULIZED, SMALL QUANTITIES OF HYDROGEN SULFIDE ARE LIBERATED...TOO SMALL TO CAUSE TOXIC KERATITIS EPITHELIALIS... [R12] *Adverse effects of acetylcysteine may include stomatitis, nausea, vomiting, drowsiness, clamminess, severe rhinorrhea and, rarely, fever and chills. [R10, 1763] *The features of n-acetyl-l-cysteine overdose are similar to the anaphylactoid reactions but more severe. Cardiovascular collapse and death were temporally assocated with the administration of intravenous n-acetyl-l-cysteine in a 4 year old with subtoxic plasma acetaminophen levels. Several fatalities occurred following intravenous n-acetyl-l-cysteine administration, but the contribution of fulminant hepatic failure to mortality limits conclusions about n-acetyl-l-cysteine effects. [R13] *A 20-YR-OLD WOMAN DEVELOPED GENERALIZED RASH, NAUSEA, VOMITING, DIZZINESS, AND BRONCHOSPASM 30 MIN AFTER BEGINNING AN INFUSION OF ACETYLCYSTEINE, 20% IN 5% DEXTROSE IN WATER, AS TREATMENT FOR PARACETAMOL OVERDOSAGE. [R14] *A case of serum sickness like illness assoc with acetylcysteine therapy in a 29 yr old man who was admitted with an acetaminophen overdose is reported. Acetylcysteine was started at 5 g orally every 6 hr. Three days after admission, the patient developed fever, diffuse abdominal tenderness, and bilateral, symmetric swelling of the knee and elbow joints. Had a discrete erythematous maculopapular eruption on the chest, abdomen, back and extremities with a few erythematous macules on the palms and face. The platelet count was 233 x 109/l. Twelve hr after antibiotic admin for suspected intraabdominal abscess, his temperature was 40 deg C and he had tender, palpable cervical, axillary and inguinal lymph nodes. a hypersensitivity reaction to acetylcysteine was suspected and the drug was discontinued. ... [R15] NTOX: *IN THE DOG, RABBIT, AND RAT, EXPOSURE TO A CHAMBER ATMOSPHERE PRODUCED BY 30 SEC OF NEBULIZATION OF 20% SOLN OF ACETYLCYSTEINE HAS BEEN EVALUATED. THESE ANIMALS WERE EXPOSED TO THIS ATMOSPHERE FOR 15 MIN TWICE DAILY FOR 35 CONSECUTIVE DAYS. ADDNL GROUPS OF ANIMALS WERE EXPOSED FOR 1 HR DAILY, 5 TIMES A WK FOR 12 WK. NO CLINICAL OR HISTOPHATHOLOGIC CHANGES WERE FOUND THAT COULD BE ASSOC WITH THE EXPOSURE OF THE ANIMALS TO ACETYLCYSTEINE. [R16] *PARENTERAL ADMIN IN RATS OR MICE OF N-ACETYLCYSTEINE SOLUTION WITH ACIDIC PH WAS MORE TOXIC AND LETHAL IF THE SOLUTION WAS NOT ADJUSTED TO PH 7.0. EMESIS WAS SEEN AFTER A LARGE ORAL N-ACETYLCYSTEINE ADMIN IN DOGS. IN ALL THE SPECIES, ORAL N-ACETYLCYSTEINE ADMIN IMPAIRED RESPIRATORY FUNCTION. N-ACETYLCYSTEINE WAS NOT HARMFUL TO THE FETUS WHEN ADMIN TO RABBITS DURING THE CRITICAL PERIOD OF EMBRYOGENESIS. N-ACETYLCYSTEINE APPEARS TO BE A SAFE DRUG FOR THE PREVENTION OR REVERSAL OF POTENTIAL ADVERSE REACTIONS RESULTING FROM CYTOTOXIC COMPOUNDS. [R17] *Although adequately tolerated when applied as drops to alkali burned corneas (as a collagenase inhibitor), a 20% solution was severely damaging when injected into the corneal stroma. In rabbits receiving drops, corneal epithelial wound healing was not retarded. [R18] NTXV: *LD50 Dog oral 1 g/kg; [R16] *LD50 Rat oral 3 g/kg; [R16] *LD50 Mouse oral > 3 g/kg; [R19] *LD50 Rat oral > 6 g/kg; [R19] *LD50 Dog ip 700 mg/kg; [R16] POPL: *Asthmatic patients should be observed closely during acetylcysteine therapy ... The drug should be used with caution in geriatric or debilitated patients with severe respiratory insufficiency. Acetylcysteine solutions are contraindicated in patients hypersensitive to the drug. [R10, 1763] *... /Acetylcysteine/ should be used during pregnancy only when clearly needed. Since it is not known if acetylcysteine is distributed into human milk, the drug should be used with caution in nursing women. [R10, 1763] ADE: *CLINICAL STUDIES SHOW THAT AFTER A SINGLE ORAL DOSE OF 100 MG, THE DRUG IS RAPIDLY ABSORBED, REACHES A PEAK CONCN IN 2 TO 3 HR AND IS AVAIL IN THE LUNG IN HIGH CONCN IN ACTIVE FORM FOR AT LEAST 5 HR. [R7] *Most of an acetylcysteine dose participates in the sulfhydryl-disulfide reaction; the remainder is absorbed from the pulmonary epithelium. [R11, 17] *... N-Acetylcysteine 150 mg/kg iv was admin to the ewe over 15 min. After induction of anesthesia, the fetal head was delivered surgically and a neck vain was cannulated for blood sampling. Maternal and fetal blood samples were obtained at the end of the N-acetylcysteine infusion, at 30 and 60 min intervals for 4 hr. ... Maternal peak plasma levels were 619, 631, 1,757 and 2,512 ug/l, respectively, within 30 min of the infusion. N-Acetylcysteine was only minimally detectable in plasma of two fetal animals and transiently reached quantifiable levels in two others. ... [R20] METB: *...LOW LEVEL OF TOXICITY INDICATES THE VERY RAPID RATE OF CONVERSION TO THE NATURAL AMINO ACID L-CYSTEINE. [R16] *Acetylcysteine undergoes rapid deacetylation in vivo to yield cysteine or oxidation to yield diacetylcystine. [R11, 17] ACTN: *ACETYLCYSTEINE...LIQUEFIES MUCUS AND DNA (THE COMPONENT OF PUS RESPONSIBLE FOR ITS VISCOSITY) BUT HAS NO EFFECT ON FIBRIN, BLOOD CLOTS, OR LIVING TISSUE. IT EXERTS ITS MUCOLYTIC ACTIVITY THROUGH ITS FREE SULFHYDRYL GROUP, WHICH ACTS DIRECTLY ON THE MUCOPROTEINS TO OPEN THE DIFULFIDE BONDS AND LOWER THE VISCOSITY OF THE MUCUS. [R21] *The viscosity of pulmonary mucous secretions depends on the concentration of mucoproteins and, to a lesser extent, of deoxyribonucleic acid (DNA). Acetylcysteine decreases the viscosity of pulmonary secretions and facilitates their removal by coughing, postural drainage, or mechanical means. It exerts its mucolytic action through its free sulfhydryl group, which acts directly on the mucoproteins to open the disulfide bonds and lower the viscosity of the mucus. This action increases with increasing pH and is most significant at pH 7 to 9. The mucolytic action of acetylcysteine is not affected by the presence of DNA. [R11, 17] *Acetylcysteine may protect against acetaminophen overdose-induced hepatotoxicity by maintaining or restoring hepatic concentrations of glutathione. Glutathione is required to inactivate an intermediate metabolite of acetaminophen that is thought to be hepatotoxic. In acetaminophen overdose, excessive quantities of this metabolite are formed because the primary metabolic (glucuronide and sulfate conjugation) pathways become saturated. Acetylcysteine may act by reducing the metabolite to the parent compound and/or by providing sulfhydryl for conjugation of the metabolite. Experimental evidence also suggests that a sulfhydryl-containing compound such as acetylcysteine may directly inactivate the metabolite. [R11, 19] INTC: *GUINEA PIGS WERE TREATED WITH DAILY DRUG INJECTIONS AS FOLLOWS: 1 GROUP RECEIVED 200 MG KANAMYCIN/KG, SC, 1 GROUP RECEIVED N-ACETYLCYSTEINE (300 MG/KG, IP) AND THE 3RD GROUP RECEIVED N-ACETYLCYSTEINE FOLLOWED BY KANAMYCIN 1 HR LATER. AFTER 7-DAY RECOVERY, THRESHOLDS FOR DETECTION OF THE COMPOUND ACTION POTENTIAL WERE MEASURED. N-ACETYLCYSTEINE ALONE HAD NO DETECTABLE EFFECT ON HEARING THRESHOLDS. KANAMYCIN ALONE PRODUCED A MODERATE (10-20-DB) HEARING LOSS BELOW 10 KHZ AND A MORE SEVERE LOSS ABOVE 10 KHZ. ANIMALS RECEIVING BOTH N-ACETYLCYSTEINE AND KANAMYCIN HAD SEVERE HEARING LOSSES (40-60 DB) AT ALL FREQUENCIES BETWEEN 3 and 30 KHZ. THESE DATA INDICATE THAT N-ACETYLCYSTEINE EXERTS A STRONG SYNERGISTIC EFFECT ON KANAMYCIN IN PRODUCING SEVERE HEARING LOSS AND COCHLEAR DAMAGE. [R22] *The major side effect of photodynamic therapy (PDT) using photofrin enhanced skin sensitivity for sunlight which persists for 3-8 weeks after injection. Formation of singlet oxygen and radicals is believed to be involved in the basic mechanism of inducing skin damage. Reducing this side effect would make PDT more widely acceptable particularly for palliative use. Hairless dorsal skin patches of mice injected with 10 mg/kg photofrin ip 24 hr before illumination were used to evaluate the effect of increasing light doses. The light was obtained from a halogen lamp and transmitted via a fiber optic to illuminate a field of 2.5 sq cm. After establishing a dose response relationship for single or fractionated light dose illumination of the skin, drugs known to scavenge radicals, quench singlet oxygen or interfere with histamine release were tested for their protective effect. N-Acetylcysteine, a radical scavenger admin ip (1,000 and 2,000 mg/kg) 1 hr before illumination produced a significant decr in skin damage at light doses > 50 J sq cm (protection factor of 1.3-1.8). When N-acetylcysteine was administered in a dose of 500 mg/kg no protection was observed. Fractionated illumination experiments in combination with multiple injections of N-acetylcysteine (1000 mg/kg) also failed to show any protection. The addition of ranitidine, a histamine blocking agent (25-100 mg/kg) given prior to illumination resulted in a limited protection at higher light doses. From this study /results suggest/ that N-acetylcysteine could be of value in amelioration of the photosensitivity in patients with PDT. [R23] *The action of N-acetylcysteine on hepatic glycogen disposition was investigated. ... Rats fasted for 24 hours were injected ip with (1) vehicle, (2) paracetamol (500 mg/kg), (3) N-acetylcysteine (1200 mg/kg) and (4) paracetamol plus N-acetylcysteine. The rats were refed immediately after the drug injections. Paracetamol inhibited glycogen deposition in the 12 hr following injection. The plasma levels of paracetamol were in the range that inhibits energy metabolism in isolated mitochondria and in the isolated perfused liver. N-Acetylcysteine increased the rate of glycogen deposition either in the presence or in the absence of paracetamol. ... [R24] *The influence of acetylcysteine on cisplatin nephrotoxicity was investigated in female Wistar rats. Admin of 0.6 mg cisplatin/100 mg bw was followed by oliguria and proteinuria, as well as a significant incr of blood urea nitrogen concn. The ip admin of 0.6 mg cisplatin/100 g body wt concomitantly with 100 mg acetylcysteine/100 g body wt sc completely abolished the nephrotoxic effects of cisplatin. However, following this, the platinum concn in the kidney was decr significantly by acetylcysteine treatment. This was caused by a enhanced urinary excretion of platinum. The same effect on cisplatin nephrotoxicity appeared when cisplatin and acetylcysteine were dissolved together in a soln prior to injection. It could be shown that in this soln a ligand exchange reaction of cisplatin by acetylcysteine started immediately, resulting in incr renal excretion and decr platinum concn in the kidney. ... /Results show/ that the protective effect of acetylcysteine on cisplatin nephrotoxicity is based on the formation of a complex unsuitable for tubular resorption. ... [R25] *N-acetylcysteine (NAC) a precursor of glutathione is known to increase the intracellular glutathione levels in cells. Embryotoxicity and teratogenicity of cadmium and modulation of its effect by NAC were evaluated in mice. Pregnant S1c:ICR mice were ip injected with 3.5 mg/kg of CdCl2 on day l0 or ll of gestation (V.P. = day 0). Pregnant mice were pretreated with l60 mg/kg of NAC iv 2 hours before dosing with CdCl2. Fetuses were re-examined for external malformation, especially limb malformations, cleft palate and abnormal palatal rugae on day 17 of gestation. There was little difference in body weight gain of dams during gestation period in groups treated with NAC and plus cadmium as compared with groups treated with cadmium alone. Pretreatment with NAC decr fetal mortality, incidence of oligodactyly, cleft palate, and abnormal palatal rugae induced by cadmium on day 11. On day 10, pretreatment with NAC decr the incidence of cadmium induced palatal rugae. The results /indicate/ that NAC plays a key role in teratogenesis and embryotoxicity of cadmium in mice. [R26] *... Three daily admin of 7,12-dimethylbenz(a)anthracene (DMBA; 15 or 25 mg/kg/day via oral gavage) resulted in expected increases in miocronucleated polychromatic erythrocytes (MPE) in bone marrow of male C57BL/6 mice 24 hr after the final dose. Pretreatment of several groups of mice with N-acetylcysteine (1 g/kg/day via oral gavage) 5 hr before each admin of DMBa had no effect on MPE frequencies. It is concluded that NAC does not have a protective effect on the mouse bone marrow. ... [R27] *Male Sprague-Dawley rats were exposed to cigarette smoke (CS) according to a complex protocol which lasted 40 days. Some of the groups were pretreated with N-acetyl-L-cysteine (NAC) by gavage (1 g/kg/bw) 5 hr before each exposure. Bronchoalveolar lavage was performed in each animal at the end of each exposure period in order to recover pulmonary alveolar macrophages. Cells were identified and counted under the microscope, and the number of micronucleated and binucleated pulmonary alveolar macrophages was registered. The results showed an incr in the number of micronucleated pulmonary alveolar macrophages was already evident after 8 days of cigarette smoke exposure; this incr remained constant after 28 and 40 days of exposure. A significant decr in the number of micronucleated pulmonary alveolar macrophages was observed in animals pretreated with NAC. Binucleated pulmonary alveolar macrophages were significantly incr after 28 and 40 days of exposure; again, a slight yet not significant decr was detected in NAC pretreated animals. ... This study demonstrates that cigarette smoke is clearly clastogenic to alveolar macrophages and that NAC can efficiently prevent this cytogenetic damage. [R28] *... /The following studies were conducted: 1) The Ames test on strains TA98, TA100 and TA104. 1,8-Dinitropyrene and 1-nitropyrene, known to be present in diesel exhaust, were used as standards. Sister chromatid exchange (SCEO) in human lymphocytes. N-Acetylcysteine decreases diesel exhaust mutagenicity in a dose dependent manner in all Salmonella strains. The effect is greater on T104 than on the other strains, suggesting the presence of oxidative type mutagens in diesel extract. The inhibitory effect of N-acetylcysteine is similar or greater than that shown by glutathione. Low doses of N-acetylcysteine (0.1 uM/ml) were effective in inhibiting sister chromatid exchange in human lymphocytes. [R29] */A study was conducted to/ investigate whether the teratogenicity of metals (Hg, Cr and Cd) can be ameliorated by N-acetylcysteine in mice. ... The incidence of congenital malformations produced by these metals was two to three times higher in the mice that were fed N-acetylcysteine (0.2% in the diet). The underlying mechanism or mechanisms are unknown and should be investigated. [R30] *...The potential protective activity of N-acetylcysteine against the well known embryotoxicity induced by methyl mercuric chloride was studied in mice. Three experimental approaches were carried out. ... The first investigation, acute treatment with methyl mercuric chloride (25 mg/kg po) was given to female CD female on day 10 of pregnancy, and was followed immediately and/or after 24, 48 and 72 hr by admin of N-acetylcysteine (800 mg/kg iv). The embryolethal effects caused by methyl mercuric chloride poisoning were completely antagonized by just a single administration of N-acetylcysteine, while the incidence of palatoschisis was reduced in relation to the number of N-acetylcysteine administrations. In the second experiment methyl mercuric chloride was chronically gavaged (3 mg/kg/day po) during the period of organogenesis on days 5 to 14 of gestation. during the same period of time some of these females were also exposed to 1% N-acetylcysteine dissolved in drinking water. Methyl mercuric chloride poisoning reduced body weight of viable fetuses and induced many cases of palatoschisis. The body weight of fetuses from methyl mercuric chloride poisoned mothers treated with N-acetylcysteine was improved and the incidence of palatoschisis was in the normal range. In the last experiment the treatment with N-acetylcysteine (400 mg/kg iv during the period of organogenesis) drastically reduced the severe embryolethality induced by methyl mercuric chloride ( 6 mg/kg/day po) admin during the same period of time. [R31] *... Pregnant ICR mice were ip injected with 3.5 mg/kg of cadmium chloride on day 10 or 11 of gestation (vaginal plug = day 0). Pregnant mice were pretreated with 160 mg/kg of N-acetylcysteine iv 2 hr before dosing with cadmium chloride. Pregnant mice /were sacrificed/ on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations, cleft palate and abnormal palatal rugae. There was little difference in body weight gain of dams during the gestation period in groups treated with cadmium alone. Pretreatment with 160 mg/kg N-acetylcysteine decr the fetal mortality, incidence of cleft palate and abnormal rugae induced by cadmium on day 11. On day 10, pretreatment with N-acetylcysteine decr the incidence of cadmium induced abnormal palatal rugae. These results clearly indicate that N-acetylcysteine exerts protective effects against embryotoxicity and teratogenicity of cadmium. [R32] *... Studies have shown that the in utero admin of alcohol alters the activity of gamma-glutamyl transpeptidase, the major enzyme involved with the break down of glutathione. The implication is that the in utero admin of alcohol interferes with gamma-glutamyl cycle and ultimately alters glutathione levels. ... The in utero admin of alcohol results in a decr in brain and liver glutathione levels in the developing fetus. ... N-Acetylcysteine ... was given to pregnant mothers throughout gestation in a liquid diet concomitantly with a dose of alcohol which produces a decr in body and brain weights. ... N-Acetylcysteine antagonized the effects of alcohol in the developing fetus. [R33] *... Pregnant ICR mice were ip injected with 25 mg/kg of 5-fluorouracil on day 11 of gestation (vaginal plug = day 0). Pregnant mice were pretreated with N-acetylcysteine at dose levels of 80, 160 and 320 mg/kg injected iv 2 hr before dosing with 5-fluorouracil. Pregnant mice were /sacrificed/ on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with 160 and 320 mg/kg of N-acetylcysteine decr the incidence and severity of oligodactyly induced by 5-fluorouracil. There was little difference in maternal body weight gain, fetal mortality, fetal weight gain between the 5-fluorouracil group and the 5-fluorouracil plus N-acetylcysteine groups. Pretreatment with phorone, a glutathione depleting agent, at dose levels of 160 and 320 mg/kg ip, 4 hr before dosing with 5-fluorouracil, incr the incidence and severity of oligodactyly induced by 5-fluorouracil. Cotreatment with N-acetylcysteine 160 mg/kg could not suppress the augmentative effect of phorone on 5-fluorouracil teratogenicity under the severe condition, that is, the excess amount of phorone such as 320 mg/kg. ... The teratogenicity of 5-fluorouracil is mitigated with N-acetylcysteine pretreatment, and also the level of endogenous glutathione is one of the factors which significantly affects teratogenicity of 5-fluorouracil. [R34] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *2. 2= Slightly toxic. Probable oral lethal dose (human) 5-15 g/kg; for 70 kg person (150 lb) between 1 pint and 1 quart. [R19] THER: +Antiviral Agents; Expectorants; Free Radical Scavengers [R35] *THE MUCOLYTIC ACTIVITY IS GREATEST AT PH 7 TO 9. LIQUEFACTION AFTER INHALATION IS APPARENT WITHIN 1 MIN; MAX EFFECT OCCURS IN 5 TO 10 MIN; AFTER DIRECT APPLICATION, THE EFFECT IS IMMEDIATE. IT IS USED BY INHALATION AND DIRECT APPLICATION AS ADJUNCT THERAPY IN PT WITH ABNORMAL, VISCID, OR INSPISSATED MUCOUS SECRETIONS. [R21] *EYEDROPS CONTAINING 20% ACETYLCYSTEINE AT PH 7 HAVE BEEN APPLIED SEVERAL TIMES A DAY FOR 2 MO TO THE EYES OF PATIENTS WITH KERATOCONJUNCTIVITIS SICCA AS A POTENTIAL TREATMENT. THE PATIENTS NOTED ... SOME STINGING, BUT EXAMINATION BY SLIT LAMP AND BY STAINING WITH FLUORESCEIN AND ROSE BENGAL SHOWED NO ADVERSE EFFECTS, AND SOME IMPROVEMENT IN AMT OF FILAMENTS AND MUCOUS SHREDS. [R18] +ACETYLCYSTEINE SEEMS TO BE BENEFICIAL IN TREATING CYSTINURIC STONE-FORMING PATIENTS. IT PROBABLY IS EFFECTIVE IN REDUCING CYSTEINE TO CYSTEINE DISULFIDE, WHICH IS MORE SOL. [R36] +MEDICATION (VET): IN SMALL ANIMALS, AEROSOL THERAPY WITH ACETYLCYSTEINE HAS BEEN USED. ANIMALS ARE ENCOURAGED TO EXERCISE AFTER AEROSOL TREATMENT TO PROMOTE OR INITIATE COUGHING. SHARP PERCUSSION OVER BOTH SIDES OF THE THORAX MAY ALSO INDUCE COUGHING. AEROSOL THERAPY IS USUALLY GIVEN FOR 2-3 DAYS AND MAY BE CONTINUED FOR 7 DAYS; THIS IS FOLLOWED BY REEVALUATION OF THE PATIENTS BY RADIOGRAPHIC AND CLINICAL EXAM. [R16] +EXPTL USE: IN VITRO AND IN VIVO STUDIES WERE PERFORMED TO EVALUATE POTENTIAL OF ACETYLCYSTEINE AS COMPLEXING AGENT FOR HEAVY METALS. RESULTS SUGGEST THAT IT MAY BE AN EFFECTIVE AGENT FOR TREATMENT OF GOLD TOXICITY. [R37] +EXPTL USE: IONTOPHORESIS OF N-ACETYLCYSTEINE IN THE EARS OF GUINEA PIGS CAUSED THE TRANSPORT OF THE COMPOUND ACROSS THE TYMPANIC MEMBRANE. TRANSTYMPANIC IONTOPHORESIS OF N-ACETYLCYSTEINE MAY BE USEFUL IN TREATING SECRETORY OTITIS MEDIA. [R38] +EXPTL USE: RATS WERE INTOXICATED WITH LETHAL DOSES OF ACRYLONITRILE BY DIFFERENT ROUTES OF APPLICATION, AND THE EFFECT OF POTENTIAL ANTIDOTES WAS STUDIED. OF THE SULFHYDRYL COMPOUNDS, THE 2 ANTIDOTES CYSTEINE AND, TO SOME LESSER EXTENT, N-ACETYLCYSTEINE PROVED ESPECIALLY EFFECTIVE. [R39] +EXPTL USE: ADMIN OF 180 OR 200 MG CYCLOPHOSPHAMIDE/KG TO WISTAR RATS CAUSED HEMATURIA AS WELL AS NECROSIS AND EDEMA IN THE URINARY BLADDER. ADMIN OF N-ACETYLCYSTEINE WITH CYCLOPHOSPHAMIDE, WHILE NOT PROTECTING AGAINST LEUKOPENIA, PROTECTED AGAINST THE ENZYMIC INACTIVATION AND UROTOXICITY. USE OF COMBINATIONS INCLUDING CYCLOPHOSPHAMIDE AND AN APPROPRIATE THIOL, SUCH AS N-ACETYLCYSTEINE, MAY INCREASE THE THERAPEUTIC INDEX OF THIS DRUG. [R40] +EXPTL USE: PRETREATMENT OF CDF1 MICE WITH A PHARMACOLOGIC DOSE (2,000 MG/KG) OF N-ACETYLCYSTEINE 1 HR BEFORE DOXORUBICIN (20 MG/KG, IP) DECREASED LETHALITY FROM 100% (N= 44) TO 37,7% (N= 53), P LESS THAN 0.001. PRETREATMENT WITH N-ACETYLCYSTEINE SIGNIFICANTLY REDUCED LONG-TERM MORTALITY IN ANIMALS RECEIVING MULTIPLE DOSES OF DOXORUBICIN, AND DIMINISHED DOXORUBICIN-RELATED LOSSES IN TOTAL BODY WT AND HEART WET WT GAIN BY 55.2% (P LESS THAN 0.05), and 60.9% (P LESS THAN 0.02), RESPECTIVELY, COMPARED WITH ANIMALS PRETREATED WITH SALINE. N-ACETYLCYSTEINE PRETREATMENT ALSO ABLATED ELECTRON MICROSCOPIC EVIDENCE OF DOXORUBICIN CARDIOMYOPATHY WITHOUT ALLEVIATING MORPHOLOGICAL FEATURES OF ITS TOXIC EFFECTS ON THE LIVER OR SMALL INTESTINAL MUCOSA. [R41] +EXPTL USE: N-ACETYLCYSTEINE, IN LOW TO MODERATE CONCN, ACCELERATES THE DEBRIDING ACTION OF BROMELAIN (AN ENZYMIC PREPN FROM PINEAPPLE STEMS). IN HIGHER CONCN, N-ACETYLCYSTEINE CAUSED READY SEPARATION OF THE BURN ESCHAR FROM THE UNDERLYING TISSUE BEFORE SOLUBILIZATION OF THE ESCHAR IS COMPLETE (RAT) OR HAS OCCURRED (PIG). UNBURNED SKIN IS NOT DAMAGED. THERE IS NO APPARENT SYSTEMIC TOXICITY ASSOCIATED WITH THE USE OF N-ACETYLCYSTEINE FOR DEBRIDEMENT OF 10-15% BODY SURFACE AREA THIRD DEGREE BURNS OF RATS OR 15-20% BODY SURFACE AREA THIRD DEGREE BURNS OF PIGS. SULFAMYLON AND SULFADIAZINE CAN BE USED WITH N-ACETYLCYSTEINE WITHOUT INTERFERING WITH ITS DEBRIDING ACTION. THE EFFECTS OF THE MERCAPTANS ARE PROBABLY DUE LARGELY TO THE DEPOLYMERIZATION OF CONNECTIVE TISSUE PROTEOGLYCANS AND PROTEINS, ESPECIALLY AT THE INTERFACE BETWEEN LIVING AND DEAD TISSUE. [R42] +EXPTL USE: IN MICE, ADMIN OF N-ACETYLCYSTEINE (200 MG/KG) 30 MIN AFTER A DOSE OF PARAQUAT RESULTED IN A MARKED DECREASE OF PARAQUAT TOXICITY MANIFESTED BY AN LD50 OF 110.60 MG/KG AFTER PARAQUAT PLUS N-ACETYLCYSTEINE COMPARED TO THE 18.86 MG/KG LD50 VALUE OF PARAQUAT ALONE. [R43] *Penicillamine, tiopronin, tromethamine, and acetylcysteine have been administered to dissolve cystine calculi by pelvicaliceal irrigation. Of these, acetylcysteine in an alkaline solution and tromethamine infusion are most effective. [R44, 878] *Acetylcysteine eyedrops may alleviate symptoms in patients with filamentary keratitis that is usually secondary to severe keratoconjunctivitis sicca. The usefulness of this approach is limited because the solution is irritating, expensive, and malodorous. [R44, 2148] *Acetylcysteine aerosol can be effective for loosening secretions, thus leading to a more productive cough. A 5% to 10% solution also can be instilled into the tracheobronchial tree to treat atelectasis; its mucolytic action coupled with its cough-inducing effect may dislodge mucous plugs. In addition, the free radical scavenging action of this drug may be beneficial in smokers with chronic obstructive pulmonary disease. [R44, 467] *Amyloidosis, primary, of lung (treatment adjunct); bronchiectasis (treatment adjunct); bronchitis (treatment adjunct); brochitis, asthmatic (treatment adjunct); cystic fibrosis, pulmonary complications of (treatment adjunct); emphysema, pulmonary (treatment adjunct); pneumonia (treatment adjunct); tracheobronchitis (treatment adjunct); or tracheostomy care, adjunct. /Included in US product labeling/ [R11, 17] *Lung abscess (treatment adjunct) /NOT included in US product labeling/ [R11, 17] *Acetylcysteine is indicated as a diagnostic aid in bronchial studies, such as bronchograms, bronchospirometry, and bronchial wedge catheterization. /Included in US product labeling/ [R11, 17] *Acetylcysteine is indicated as adjuvant therapy for abnormal, viscid, or inspissated mucous secretions in atelectasis due to mucous obstruction. However, acetylcysteine is of no proven value in atelectasis due to simple hypoventilation, such as postoperative hypoventilation. /Included in US product labeling/ [R11, 17] *Acetylcysteine is indicated as adjuvant therapy for abnormal, viscid, or inspissated mucous secretions in acute bronchopulmonary disease (pneumonia, bronchitis, and tracheobronchitis); chronic bronchopulmonary disease (chronic pulmonary emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis, and primary amyloidosis of the lung); and pulmonary complication of cystic fibrosis. It is also used as an adjunct in tracheostomy care. /Included in US product labeling/ [R11, 17] *Acetylcysteine is indicated in the treatment of acetaminophen overdose to protect against hepatotoxicity. /Included in US product labeling/ [R11, 19] *The incidence of adverse reactions to iv N-acetylcysteine (NAC) was studied in 56 Chinese patients with paracetamol (acetaminophen) poisoning. Eight (14%) patients developed a skin rash (n = 7) or fever (n = l) mostly during the initial high dose infusion of the antidote. In four subjects (three with toxic plasma paracetamol levels) the infusion was continued without a worsening of the adverse reaction. NAC was discontinued in the remaining four subjects in whom the paracetamol levels were subsequently found to be non-toxic. Iv chlorpheniramine was given to six subjects. All eight subjects completely recovered. In the dose that is recommended for the treatment of acute paracetamol poisoning intravenous NAC is generally safe in Chinese but mild side effects are common . /It is recommended/ that the initial loading dose is given over 60 rather than 15 min. [R45] *... 113 patients entered into the study were reported to be pregnant at the time of /acetaminophen/ overdose. Follow up including appropriate laboratory and pregnancy data outcome data, was available in 60 cases. Of these, 19 overdosed during the first trimester, 22 during the second trimester and 19 during the third trimester of pregnancy. Of the 24 patients with acetaminophen levels above the acetaminophen overdose nomogram line, 10 were treated with N-acetylcysteine within 10 hr postingestion; eight delivered normal infants, two had elective abortions. Of ten patients treated with N-acetylcysteine 10-16 hr postingestion, five delivered viable infants, two had elective abortions, and three had spontaneous abortions. Of four women treated with N-acetylcysteine 16-24 hr postingestion, one mother died, and there was one spontaneous abortion, one stillbirth, one elective abortion, and one delivery. ... [R46] *... N-acetylcysteine admin to pregnant rats partially prevents the hepatic GSSG that occurs in the fetal neonatal transition: GSSG incr 11 fold (from 1-12 umol/g) in controls and less than two fold (from 5 to n mol/g) in animals exposed to N-acetylcysteine in utero a. The GSH and GSSG ratio in liver of N-acetylcysteine treated newborns was 411 +/- 216 and in liver of controls it was 238 +/- 176. ... Oxidative stress that occurs in the fetal to neonatal transition is partially prevented by oral N-acetylcysteine admin. [R47] WARN: *SINCE ACETYLCYSTEINE HAS BEEN REPORTED TO INACTIVATE A NUMBER OF ANTIBIOTICS, INCLUDING ALL OF PENICILLIN-TYPE DRUGS TESTED...ANTIMICROBIAL DRUGS SHOULD NOT BE ADMIN IN SAME SOLN. [R48] *...ASTHMATIC PATIENT UNDER TREATMENT WITH ACETYLCYSTEINE SHOULD BE WATCHED CLOSELY. [R21] *ELDERLY AND DEBILITATED PT SHOULD BE OBSERVED CLOSELY TO AVOID ASPIRATION OF EXCESSIVE SECRETIONS. ACETYLCYSTEINE HAS AN UNPLEASANT ODOR THAT MAY CAUSE GI DISTURBANCES. [R49] */Acetylcysteine/ may be useful in patients with severe mucoid impaction of the bronchi or persistent mucus lodgment, but concomitant administration with a beta-adrenergic inhalant is necessary to protect against bronchospasm. Acetylcysteine has an unpleasant sulfurous odor and taste upon nebulization that can produce gagging, nausea, and vomiting. [R44, 509] *The most common complication is the inability to retain n-acetyl-l-cysteine due to vomiting. An alternative route is the administration of n-acetyl-l-cysteine via nasogastric or duodenal tube. Infrequently, anaphylactoid reactions (thrombocytopenia, rash, ... angioedema, hypotension, bronchospasm) occur after intravenous use. These reactions are concentration dependent and probably result from histamine release by a nonimmunologic mechanism. [R13] *Activated charcoal is usually not administered because it can absorb the antidote. [R50] *Risk-benefit should be considered when the following medical problems exist: asthma, bronchial; respiratory insufficiency, severe (obstruction of bronchial airways may be increased, especially in debilitated patients; if acetylcysteine is used in these patients, pretreatment with bronchodilator may be indicated); or sensitivity to acetylcysteine. [R11, 17] *Acetylcysteine has been shown to be incompatible, when mixed in the same solution, with amphotericin B, chlortetracycline hydrochloride, erythromycin lactobionate, oxytetracycline hydrochloride, ampicillin sodium, and tetracycline hydrochloride. These agents should be administered as separate solutions if administration is necessary. [R11, 19] *DRUG...MAY BE INSTILLED DIRECTLY INTO THE TRACHEA IN PT WITH TRACHEOSTOMIES. THIS METHOD OF ADMIN CAN BE MORE EFFECTIVE THAN NEBULIZATION. ... PRODUCTION OF EXCESSIVE SECRETIONS WHICH REQUIRE REMOVAL BY SUCTION (ESP WHEN THE DRUG IS INSTILLED DIRECTLY INTO THE TRACHEA) HAS BEEN REPORTED. FOR THIS REASON, ACETYLCYSTEINE SHOULD NOT BE USED UNLESS SUCTION APPARATUS IS AVAIL. [R49] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R51] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *THREE N-SUBSTITUTED MALEIMIDES, INCLUDING ACETYLCYSTEINE, WERE TESTED AS DERIVATIZING REAGENTS. N-ACETYLCYSTEINE WAS READILY CONVERTED INTO THE ADDUCT WITH N-(4-ANILINOPHENYL)MALEIMIDE. PICROGRAM LEVELS WERE SEPARATED AND QUANTIFIED. [R52] *The following methods have been developed for the analysis of free amino acids in blood, food, and feedstocks: (1) Protein hydrolysis, (2) Chromatographic methods that include high performance liquid chromatography (HPLC), gas chromatography (GC) and thin-layer chromatography (TLC), (3) Colorimetric and Fluorimetric Analysis, (4) Spectrometric Analysis, and (5) Enzymatic Determination and Microbial Assay /amino acids/ [R53] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW WITH 55 REFERENCES ON THE BIOCHEMISTRY AND PHARMACOLOGY OF ACETYLCYSTEINE. [R54] A REVIEW WITH 28 REFERENCES OF THE EFFECT OF N-ACETYLCYSTEINE ON THE ANTITUMOR ACTIVITY OF DOXORUBICIN AND THE LATTER'S CARDIOTOXICITY. [R55] Haddad LM, Winchester JF; Clinical Management of Poisoning and Drug Over Dose 2nd ed (1990). Acetaminophen and the use of N-acetylcysteine in treatment of overdose (review). pp 893-908. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for N-acetylcysteine is completed, and the chemical is in review for further evaluation. Route: gavage; Species: antioxidant model (tramp), mice. [R56] SO: R1: SRI R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA2 83 R3: Kuney, J.H., J.M. Mullican (eds.). Chemcyclopedia. Washington, DC: American Chemical Society, 1994. 250 R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 298 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 12 R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 14 R7: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 805 R8: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-139 R9: Osol A (ed); Remington's Pharmaceutical Sciences. 14th ed. Easton, PA: Mack Publishing Co, p. 871 (1970) R10: McEvoy, G.K. (ed.). American Hospital Formulary Service--Drug Information 94. Bethesda, MD: American Society of Hospital Pharmacists, Inc. 1994 (Plus Supplements). R11: USP Convention. USPDI-Drug Information for the Health Care Professional. 14th ed. Volume I. Rockville, MD: United States Pharmacopeial Convention, Inc., 1994. (Plus Updates). R12: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 86 R13: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 163 R14: WALTON NG ET AL; ANAPHYLACTOID REACTION TO N-ACETYLCYSTEINE; LANCET 2(DEC 15) 1298 (1979) R15: Mohammed S et al; Ann Pharmacother 28: 285 (1994) R16: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 683 R17: JOHNSTON RE ET AL; THE TOXICITY OF N-ACETYLCYSTEINE IN LABORATORY ANIMALS; SEMIN ONCOL 10(1) 17 (1983) R18: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 45 R19: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-380 R20: Selden BS et al; Ann Emerg Med 20 (10): 1069-72 (1991) R21: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 960 R22: BOCK GR ET AL; HEAR RES 9 (3): 255 (1983) R23: Baas P et al; Photochem Photobiol 59 (4): 448-54 (1994) R24: Itinose AM et a; Res Commun Chem Pathol Pharmacol 83 (1): 87-92 (1994) R25: Appenroth D et al; J Appl Toxicol 13 (3): 189-92 (1993) R26: Naya M et al; Teratol 48 (5): 530-1 (1993) R27: Doyle CE et al; Mutagenesis 8 (6): 583-4 (1993) R28: Agostini F et al; Boll Soc Ital Biol Sper 68 (2): 137-42 (1992) R29: Barale R et al; Mutat Res 271 (2): 132-3 (1992) R30: Endo A, Watanabe T; Reprod Toxicol 2 (2): 141-4 (1988) R31: Ornaghi F et al; Fundam Appl Toxicol 20 (4): 437-45 (1993) R32: Naya M et al; Senten Ijo 34: 125-30 (1994) R33: Reyes E et al; Alcohol Clin Exp Res 15 (2): 343 (1991) R34: Naya M et al; Senten Ijo 33: 77-84 (1993) R35: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R36: MULVANEY WP ET AL; J UROL 114 (1): 107 (1975) R37: LORBER A ET AL; J CLIN PHARMACOL NEW DRUGS 13(AUG-SEP) 332 (1972) R38: CRIFO S ET AL; PHARMACOL RES COMMUN 11(5) 389 (1979) R39: APPEL KE ET AL; INT ARCH OCCUP ENVIRON HEALTH 49 (2): 157 (1981) R40: BERRIGAN MJ ET AL; CANCER RES 42(9) 3688 (1982) R41: DOROSHOW JH ET AL; J CLIN INVEST 68(4) 1053 (1981) R42: LEVENSON SM ET AL; J TRAUMA 21(8) 632 (1981) R43: SHUM S ET AL; VET HUM TOXICOL 24(SUPPL) 158 (1982) R44: American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994. R45: Chan TY, Critchley JA; Hum Exp Toxicol 13 (8): 542-4 (1994) R46: Riggs BS et al; Obstet Gynecol 74 (2): 247-53 (1989) R47: Sastre J et al; Life Sci 54 (26): 2055-9 (1994) R48: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 955 R49: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. 472 R50: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 658 R51: 21 CFR 200-299, 300-499, 820, and 860 (4/1/93) R52: SHIMADA K ET AL; SENSITIVE DERIVATIZATION REAGENTS FOR THIOL COMPOUNDS IN HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION; ANAL CHIM ACTA 147: 375 (1983) R53: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V2 531-4 R54: MCKINNEY GR, SISSON GM; ACETYLCYSTEINE; PHARMACOL BIOCHEM PROP DRUG SUBST 2: 479 (1979) R55: OLSON RD ET AL; INFLUENCE OF N-ACETYLCYSTEINE ON THE ANTITUMOR ACTIVITY OF DOXORUBICIN; SEMIN ONCOL 10(1) 29 (1983) R56: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 43 Record 212 of 1119 in HSDB (through 2003/06) AN: 3009 UD: 200302 RD: Reviewed by SRP on 9/14/1995 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: AMPICILLIN- SY: *ALPEN-; *AMFIPEN-; *AMINOBENZYLPENICILLIN-; *D(-)-ALPHA-AMINOBENZYLPENICILLIN; *D-(-)-ALPHA-AMINOPENICILLIN; *6-[D-(2-AMINO-2-PHENYLACETAMIDO)]-3,3-DIMETHYL-7-OXO-4-T HIA-1-AZABICYCLO[3.2.0]HEPTANE-2-CARBOXYLIC ACI; *6-[D(-)-ALPHA-AMINOPHENYLACETAMIDO]PENICILLANIC ACI; *AMPICILLIN-A-; *D-AMPICILLIN-; *AMPICILLIN-ACID-; *AMPICILLIN-ANHYDRATE-; *AMPIMED-; *AMPIPENIN-; *AMPLISOM-; *AMPY-PENYL-; *AY-6108-; *BRL-1341-; *COPHARCILIN-; *GUICITRINA-; *NUVAPEN-; *OMNIPEN-; *PENBRITIN-PAEDIATRIC-; *PENBRITIN-SYRUP-; *PENICILLIN, (AMINOPHENYLMETHYL)-; *PENTREX-; *PENTREXYL-; *POLYCILLIN-; *SEMICILLIN-; *SYNPENIN-; *4-THIA-1-AZABICYCLO(3.2.0)HEPTANE-2-CARBOXYLIC ACID, 6-(2-AMINO-2-PHENYLACETAMIDO)-3,3-DIMETHYL-7-OXO-, D-(-)-; *TOTACILLIN-; *TOTALCICLINA-; *TOTAPEN-; *ULTRABION-; *ULTRABRON-; *VICCILLIN-; *VICILLIN-S-; *WY-5103- RN: 69-53-4 MF: *C16-H19-N3-O4-S ASCH: Ampicillin trihydrate; 7177-48-2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ACYLATION OF 6-AMINOPENICILLANIC ACID WITH D-(-)-GLYCINE [R1] *DOYLE ET AL, US PATENT 2,985,648 (1961); EIDEM, BRITISH PATENT 902,703 (1962 TO BEECHAM); DOYLE ET AL, J CHEM SOC 1962, 1440; KAUFMANN, BAUER, US PATENT 3,079,307 (1963 TO BAYER); JOHNSON, WOLFE, AND JOHNSON, HARDCASTLE, US PATENTS 3,140,282 and 3,157,640 (BOTH 1964 TO BRISTOL-MYERS)... [R2] *...GRANT, ALBURN, US PATENT 3,144,445 (1964 TO AM HOME PRODUCTS); DANE, DOCKNER, BER 98, 789 (1965). ... DL-FORM.../OF SODIUM SALT/ BRITISH PATENT 958,824 (1964 TO PFIZER). [R2] *Ampicillin is produced by the acylation of 6-aminopenicillanic acid with D-(-)-alpha-phenylglycine by either microbiological or chemical synthesis. [R3, (1990)] IMP: *Impurities of ampicillin that occur during preparation of the product are D-(-)-alpha-phenylglycine and 6-aminopenicillanic acid. It has been reported that sodium ampicillin in aqueous solution undergoes a reaction to form oligomeric products. [R3, (1990)] FORM: *USP anhydrous ampicillin contains 900-1050 ug/mg ampicillin (calculated as the anhydrous base). Ampicillin is available in 125-, 200-, 250-, and 500-mg tablets that contain 90-120% labelled active ingredient, in 125-, 250-, and 500-mg capsules containing 90-120% labelled active ingredient, and as oral suspensions of 100, 125, and 250 mg/5 ml containing 90-120% of the labelled active ingredient and probenecid. [R3, (1990)] MFS: *Biocraft Laboratories, Inc, Hq, 92 Route 46, Elmwood Park, NJ 07407, (201) 796-3434; Production site: Waldwick, NJ 07463 [R4] *Bristol-Myers Co, Hq, 345 Park Ave, New York, NY 10022, (212) 546-4000; Industrial Division, PO Box 4755, Syracuse, NY 13221-4755 /Ampicillin, sodium/ [R4] *Bristol-Myers Co, Hq, 345 Park Ave, New York, NY 10022, (212) 546-4000; Industrial Division, PO Box 4755, Syracuse, NY 13221-4755 /Ampicillin, trihydrate/ [R4] OMIN: *HAS BEEN USED CLINICALLY TO IMPROVE FERTILITY IN KENNEL BY TREATING STUD DOG TO ELIMINATE BACTERIAL CONTAMINATION OF SEMEN. ... IN US... NOT RECOMMENDED FOR USE IN FOOD PRODUCING ANIMALS EXCEPT SWINE. TOLERANCE OF 0.01 PPM FOR...RESIDUES IN UNCOOKED EDIBLE TISSUES OF SWINE IS PERMITTED... [R5] USE: *Ampicillin is a broad-spectrum antibiotic. The clinical indications for ampicillin cover a variety of infections, including those of the respiratory and urinary tracts, gonorrhoea, meningitis, septicaemia and enteric infections. [R3, (1990)] +MEDICATION PRIE: U.S. PRODUCTION: *(1977) 5.30X10+8 GRAMS [R1] *(1979) 4.53X10+8 GRAMS [R1] U.S. IMPORTS: *(1977) 3.83X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 2.25X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] U.S. EXPORTS: *(1978) 7.51X10+7 GRAMS (INCL SALTS) [R1] *(1979) 1.89X10+7 GRAMS (INCL SALTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White, crystalline powder [R3, (1990)]; *White crystalline powder or as white, needle-like crystals [R6] ODOR: *Odorless or has a faint odor characteristic of the penicillins [R7] MP: *202 deg C, with decomposition [R3, (1990)] MW: *349.42 [R2] DSC: *pKa = 2.5, 7.3 at 23 deg C [R3, (1990)] SOL: *1 Gm dissolves in about 90 ml of water, 20 ml of methanol, 250 ml of absolute ethanol, 13 ml of dimethylacetamide, and less than 10 ml of dimethylsulfoxide; practically insoluble in ether, ethyl acetate, petroleum ether, benzene, and chloroform. [R7]; *In water, 10.1X10+3 mg/l at 21 deg C [R8] SPEC: *Optical rotation = +287.9 deg at 20 deg C (C=1 in H2O) [R3, (1990)] OCPP: *SOL IN WATER, DIMETHYL SULFOXIDE; DECOMP @ 199-202 DEG C; SPECIFIC ROTATION: +287.9 DEG @ 23 DEG C/D (WATER) /ANHYDROUS FORM/ [R2] *CRYSTALS FROM WATER; SPARINGLY SOL IN WATER @ ROOM TEMPERATURE; DECOMP @ 202 DEG C; SPECIFIC ROTATION: +281 DEG @ 21 DEG C/D (WATER) /MONOHYDRATE/ [R2] *DECOMP @ 199-202 DEG C; SPECIFIC ROTATION: +283.1 DEG @ 20 DEG C/D (WATER) /SESQUIHYDRATE/ [R2] *CRYSTALS; DECOMP ABOUT 205 DEG C; SPECIFIC ROTATION: +209 DEG @ 20 DEG C/D (C= 0.2 IN WATER) /L(+)-FORM, SODIUM SALT/ [R2] *It is not stable in aqueous solutions of alkali hydroxides and carbonates, and is decomposed by dilute solutions of mineral acids. [R7] *pH of 10 g/ml aqueous solution is 3.5-6.0 [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *The stability of ampicillin sodium in soln is concn dependent and decreased as the concn of the drug increases. Ampicillin sodium appears to be especially susceptible to inactivation in soln containing dextrose, which appears to have a catalytic effect on hydrolysis of the drug. [R9, 297] *... When stored @ room temperature (25 deg C), ampicillin sodium soln containing 30 mg or less of ampicillin per ml in sterile water for injection, 0.9% sodium chloride injection, 1/6 M sodium lactate injection, or lactated Ringer's injection lose less than 10% of activity within 8 hr and soln containing 2 mg or less of ampicillin per ml in 5% dextrose, 5% dextrose and 0.45% sodium chloride, or 10% invert sugar lose less than 10% of activity within 4 hr. At concn of 10-20 mg/ml in 5% dextrose, ampicillin loses less than 10% of its activity within 2 hr @ room temperature. [R9, 297] *When refrigerated @ 4 deg C, ampicillin sodium soln containing 30 mg of ampicillin per ml are stable for 48 hr in sterile water for injection or 0.9% sodium chloride injection and soln containing 30 mg or less per ml are stable for 24 hr in lactated Ringer's or 8 hr in 1/6 M sodium lactate injection. Soln of the drug containing 20 mg or less of ampicillin per ml are stable @ 4 deg C for 72 hr in sterile water for injection or 0.9% sodium chloride injection, 4 hr in 5% dextrose, or 3 hr in 10% invert sugar and soln containing 10 mg or less per ml are stable for 4 hr @ 4 deg C in 5% dextrose and 0.45% sodium chloride. [R9, 298] *Following reconstitution of the commercially available 10-g pharmacy bulk package of ampicillin sodium, soln containing 100 mg of ampicillin per ml should either be used or discarded within 2 hr if stored @ room temperature or within 4 hr if refrigerated. [R9, 298] *Aminopenicillins are generally stable in the dry state; however, the drugs are stable only for short periods of time in soln. Like other penicillins, the stability of aminopenicillins is pH and temp dependent. Aminopenicillins are more resistant to acid-catalyzed hydrolysis .. and are generally stable in the presence of acidic gastric secretions following oral admin. /Aminopenicillins/ [R9, 276] *Ampicillin powders are stable when stored in a closed system at 43% and 81% relative humidity at room temperature for six weeks. Ampicillin is also stable at 35 deg C in such closed systems for nine weeks. Stability decreases significantly in the presence of sugars. [R3, (1990)] STRG: *Ampicillin capsules and powder for oral suspension should be stored in tight containers @ 15-30 deg C. Following reconstitution, oral suspensions of either anhydrous ampicillin or ampicillin trihydrate should preferable be refrigerated @ 2-8 deg C but are stable for 7 days @ room temperature or 14 days @ 2-8 deg C. [R9, 297] *Following reconstitution with sterile or bacteriostatic water for injection, ampicillin sodium solutions for IM or direct IV injection should be used within 1 hr after reconstitution and should not be frozen. [R9, 297] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence for the carcinogenicity of ampicillin in humans. There is limited evidence for the carcinogenicity of ampicillin in experimental animals. Overall evaluation: Ampicillin is not classifiable as to its carcinogenicity to humans (Group 3). [R10, p. V50 163] HTOX: *AGRANULOCYTOSIS WITH PERIPHERAL MONOCYTOSIS AND BONE-MARROW HISTIOCYTOSIS HAS BEEN REPORTED FOLLOWING TREATMENT WITH AMPICILLIN. [R11, 1149] *Ampicillin has comparatively few adverse properties, permitting it to be used preferentially over other agents such as chloramphenicol or tetracyclines when a broad-spectrum antibacterial drug is desired. It has been used as treatment for urinary, respiratory, and GI infections and bacterial otitis. Since ampicillin is excreted in bile, it can be used to treat biliary tract infections. Superinfections caused by Enterobacter, Pseudomonas, or Candida have occurred during oral ampicillin therapy, necessitating a reduced dose or substitution of another antibacterial drug. [R12] *Ampicillin reportedly induces environmental or occupational asthma possibly by IgE mediation /from table/ [R13] *GI side effects of ampicillin include diarrhea, nausea/vomiting, epigastric/abdominal pain, and stomatitis/glossitis /from table/ [R14, 939] *Diarrhea appears to be a direct effect of drugs such as ampicillin, tetracycline, chloramphenicol, penicillin, lincomycin, and clindamycin; it occurs in a significant percentage of patients. Usually this is tolerated during the relatively brief course of an antimicrobial treatment. Sometimes, however, a nonspecific mild diarrhea may become severe enough to interfere with absorption of the antimicrobial agent and to cause significant morbidity ... . [R14, 938] *... Seizures, myoclonus, and problems with mentation and level of consciousness have been reported, particularly with penicillins. Most often this toxicity is seen in the setting of renal failure, which may allow drug accumulation. The precise mechanism responsible for these neurologic side effects is unclear, but it is known that direct application of penicillin to the brain is associated with seizures. /Penicillins/ [R14, 934] *In an epidemiologic study from Sweden, about half the cases of pseudomembranous colitis were associated with penicillins, about one third with cephalosporins, and about 14 percent with lincosamides (mostly clindamycin), reflecting the more frequent use of the penicillins and cephalosporins. The clustering of cases in some studies has suggested possible nosocomial transmission of C. difficile. /Penicillins and cephalosporins/ [R14, 940] *Penicillins, which are cleared by both filtration and secretion /by the kidneys/, also accumulate in renal failure if dosages are not adjusted. The acylureidopenicillins are about 60 to 75 percent excreted by tubular secretion. This secretory mechanism is saturable, and at higher concn nonrenal elimination pathways may become important in their clearance. Thus, the half lives of these drugs are dose dependent. /Penicillins/ [R14, 941] *Glomerulonephritis caused by drug allergy is usually seen as part of a serum sickness. Deposition of antigen-antibody complexes occurs nonspecifically along the glomeruli. The nephrotic syndrome has occurred with drug allergy but is rarely associated with antimicrobials, except for penicillin. /Penicillins/ [R14, 946] *Adverse cutaneous reactions to penicillins include morbilliform, macular, urticaria, Stevens-Johnson exfoliation, and angioedema/anaphylaxis /Penicillins; from table/ [R14, 948] *Hemolytic anemia is probably most frequently associated with the penicillins and the cephalosporins ... A Coombs-positive reaction with or without hemolysis occurs with the penicillins. Specific IgG antibodies that react with penicillin-red blood cell complexes can be identified. This occurs in less than 1 percent of patients treated with penicillins. Coombs antibody is present in from 5-25 percent of patients treated with a cephalosporin, with rats depending on the particular cmpd studied. These antibodies are caused by binding of the cephalosporin with the red blood cell as well as by nonselective adsorption of plasma proteins such as immunoglobulins, complement, albumin, and fibrinogen to the red cell membrane. Hemolysis rarely occurs despite the frequency with which these antibodies are expressed ... . /Penicillins and cephalosporins/ [R14, 949] *Drug-related immunologic destruction of granulocytes usually develops after the second wk of therapy but may be delayed and occur weeks or months into a course of therapy. It is characterized by a sudden fall in the peripheral neutrophil count; fever may be present. Absolute neutropenia can be severe and may place the patient at increased risk of infection ... Drug-induced neutropenia may be due to antibodies to the neutrophil ... The neutropenia seen with prolonged high-dose therapy with penicillins and cephalosporins is of uncertain etiology, but it may not have an immunologic basis as rechallenge is not associated with an accelerated recurrence of the neutropenia and the neutrophil count may fall more slowly. /Penicillins and cephalosporins/ [R14, 949] *An antibody-induced immune thrombocytopenia has been described with the penicillins and cephalosporins. These are reversed quickly when the particular drug is discontinued. /Penicillins and cephalosporins/ [R14, 950] *It has been estimated that up to 10 percent of patients treated with a penicillin will experience a hypersensitivity reaction to the drug. This figure may be up to 40 percent in those who have a prior history of an adverse reaction to penicillin. These reactions may vary from a minor rash to fatal anaphylaxis. In one series, 0.04 to 0.2 percent of all acute allergic reactions to penicillin were severe, and 0.001 percent of these had a fatal outcome. /Penicillins/ [R14, 952] *Anaphylaxis presents clinically as the acute onset of peripheral vascular collapse and shock. This may begin minutes after contact with the precipitating allergen. It is the most feared and serious of the allergic reactions and carries with it a significant risk of death. Skin and mucosal lesions, including urticaria and angioedema, may immediately precede the onset of anaphylaxis. Nausea, vomiting, diarrhea, and bronchospasm may occur as part of the acute reaction to the drug. These end-organ responses are initiated by the release of histamine, serotonin, bradykinin and other vasoactive substances released by the basophils and mast cells ... Penicillins, cephalosporins, and sulfonamides are the antimicrobials most often associated with anaphylactic reactions. /Penicillins and cephalosporins/ [R14, 953] *Most experience with desensitization techniques has been with penicillin. Skin testing before initiating therapy may help indicate the likelihood of a persisting allergy. A commercial skin test called PrePen is available for penicillin but it must be combined with a test for the minor penicillin determinants because these may also mediate anaphylaxis. Even with a negative response to these skin tests, desensitization may be the safest way to administer penicillin or a related drug in a patient with a clear history of acute penicillin allergy. /Penicillins/ [R14, 955] *Cross-reactivity between the cephalosporins and the penicillins occurs and may reflect the structural similarities (beta-lactam ring) of these classes of drugs. Up to 20 percent, but probably closer to 5-10 percent, of patients who are allergic to penicillin will be allergic to the cephalosporins. /Penicillins and cephalosporins/ [R14, 955] *Serum sickness is a rare complication of antimicrobial therapy, caused by a delayed hypersensitivity reaction. It usually begins approx 7-10 days after the initiation of therapy ... The rash associated with serum sickness may include urticaria and angioneurotic edema. Palpable skin lesions consistent with a vasculitis are often present and are very suggestive of the diagnosis. This IgG-mediated toxicity also may cause GI signs, pericarditis, myocarditis, polyneuritis, and rarely, myelitis ... Fever is common, and red blood cell casts in the urine confirm the presence of a vasculitis. The offending drug should be stopped and avoided in the future. The penicillins ... are most frequently associated with serum sickness ... . /Penicillins/ [R14, 955] *Erythema nodosum, distinguished by the presence of painful subcutaneous nodules predominately over the lower legs, has a prolonged course and is associated with systemic signs. An Arthus or mixed form of allergic reaction is suggested ... penicillins are associated with erythema nodosum reactions, as are various viral and bacterial infections. /Penicillins/ [R14, 956] *Drug fever is a common sign of drug allergy. It may occur alone or in combination with other signs of allergy, such as rash. Fever may precede the development of other more serious signs of drug allergy, such as serum sickness. The penicillins and cephalosporins lead the list of antimicrobial agents associated with drug fever. The mechanism of drug fever is uncertain. /Penicillins and cephalosporins/ [R14, 957] *Electrolyte abnormalities may occur with antimicrobials that contain large salt loads. The penicillins may cause sodium overload with subsequent fluid retention. This may be very significant clinically, especially in the patient with underlying cardiac disease. Carbenicillin, for example, contains 4.7 mEq of sodium per gram of drug. When the dosage is 20 to 30 g/day, this drug may make a significant contribution to sodium metabolism ... /Penicillins/ [R14, 957] *Another side effect resulting from the electrolyte content of the penicillin salt is the rapid rise in serum potassium that may occur with a large iv bolus of the potassium salt of crystallin penicillin. Cardiac arrest has been precipitated by the rapid infusion of very large doses of aqueous penicillin potassium. In renal failure, the use of potassium penicillin is usually best avoided; even slow infusions here may result in rises of serum potassium to toxic levels. Using the sodium salt avoid this potentially severe side effect. /Penicillins/ [R14, 958] *Hypokalemia may occur during penicillin therapy owing to competition of the penicillin at the distal renal tubule and excessive potassium excretion. /Penicillins/ [R14, 958] *The GI complication of most concern is the development of pseudomembranous enterocolitis. Although this may begin without prior GI complaints, diarrhea in a patient on antimicrobial therapy must be followed closely. The acute development of fever and pain in a patient with copious diarrhea and bloody or mucous stools strongly suggests this diagnosis. Pseudomembranous enterocolitis is diagnosed when proctoscopic examination discloses pseudomembranes (small, yellow-white plaques) along the colonic mucosa ... Various causes have been proposed, and multiple factors appear to be important. However, much data suggest that an alteration in bowel flora induced by the offending antimicrobial may allow the emergence of resistant organisms such as Clostridium difficile. Such organisms can produce cytotoxic substances that affect mucosal function and integrity. Overgrowth of staphylococci may be seen in the stool in some cases, and a toxin has been isolated from the staphylococci that is capable of causing tissue destruction and cell damage. /Antimicrobial agents/ [R14, 938] *Although pseudomembranous colitis is most often associated with oral therapy, parenteral exposure also may be a predisposing factor. Most cases occur during a course of antimicrobial therapy, often a week or two after therapy begins. However, cases have occurred up to 4 wk after discontinuation of a n antimicrobial agent. /Antimicrobial agents/ [R14, 939] *Antimicrobial agents frequently affect the hematopoietic system. These effects may be due to direct effects on stem cells in the bone marrow or on the formed cells in the blood stream. Thus, suppression of each of the three cell lines can occur independently or in combination ... Most often suppression is reversible when the offending drug is discontinued. /Antimicrobial agents/ [R14, 948] *Hematologic toxicity may include aplastic anemia and effects on the erythrocyte (RBC) which may include peripheral destruction - hemolysis due to immune mechanisms and to RBC abnormalities, and marrow suppression; effects on the leukocytes which may include antibody-mediated peripheral destruction and marrow suppression; and effects on the platelets which may include peripheral destruction, marrow suppression, and platelet dysfunction /Antimicrobial agents; from table/ [R14, 948] *Immunotoxic reactions include systemic: anaphylactic shock, serum sickness/vasculitis, and fever/eosinophilia; hematologic: hemolytic anemia, agranulocytosis, and thrombocytopenia; hepatic: hepatitis; renal: interstitial nephritis; respiratory: asthma and eosinophilic pneumonia; autoimmune reactions: SLE syndrome; and skin: maculopapular/maculovesicular rash, contact dermatitis, fixed drug eruptions, erythema multiforme, Stevens-Johnson syndrome, and phototoxicity/photoallergy /Antimicrobial agents; from table/ [R14, 953] *Reversible, nonspecific liver enzyme elevations occur in from 1 to 4 percent of patients treated with the various penicillins, notably with the ureidepenicillins, carbenicillin, ticarcillin, and oxacillin, as well as with the new beta lactams imipenem and aztreonam. Nonspecific mild elevations may also occur with many antimicrobials ... . /Antimicrobials, esp. penicillins/ [R14, 940] *Immune interstitial nephritis can occur with penicillin G, the sulfonamides, ampicillin, methicillin, and rifampin, and less frequently with carbenicillin, cephalexin, caphalothin, trimethoprim/sulfamethoxazole, erythromycin, nafcillin, oxicillin, and trimethoprim. Rash, fever, arthralgias, and eosinophilia frequently accompany the hematuria and proteinuria. Eventually azotemia and oliguria occur. Eosinophils are usually present in the urine. [R14, 946] *Nonspecific skin reactions during a course of antimicrobial therapy occur occasionally and must be differentiated from true allergic reactions to specific agents. Ampicillin, for example, is associated with a nonspecific, apparently nonallergic, maculopapular rash. Almost all patients treated with the drug during an Epstein-Barr virus infection will develop this rash. [R14, 947] *Platelet dysfunction has been described with penicillins and is concn related. The penicillins, especially carbenicillin and ticarcillin, bind to adenosine diphosphate receptor sites on the platelet and can interfere with platelet aggregation. This effect is reversible, unlike the effect of aspirin on platelets. With very-high-dose therapy, significant bleeding may occur. /Penicillins/ [R14, 950] *Safe use of ampicillin during pregnancy has not been established ... ampicillin has been administered to pregnant women, especially in the treatment of urinary tract infections, without evidence of adverse effects to the fetus. Because ampicillin is distributed into milk, the drug should be used with caution in nursing women. [R9, 298] *Hypersensitivity reactions to aminopenicillins are manifested most frequently as eosinophilia or rash (urticarial, erythematous, morbilliform), less frequently as angioedema, exfoliative dermatitis toxic epidermal necrolysis, or erythema multiforme, and rarely as Stevens-Johnson syndrome. Serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever) also have been reported. Eosinophilia has been reported in ... up to 47% of patients receiving ampicillin. [R9, 286] *Rash has been reported in 1.4-10% of patients receiving amoxicillin or ampicillin ... Two different types of rash have been reported with aminopenicillins ... The second type of rash, reported principally with ampicillin and amoxicillin, is a generalized erythematous, maculopapular rash which, in most cases, appears to be nonimmunologic. [R9, 286] *Positive direct antiglobulin (Coombs') test results and hemolytic anemia have been reported rarely with ampicillin. [R9, 286] *Anaphylaxis has been reported rarely with oral or parenteral ampicillin. Anaphylaxis has also been reported in at least one patient who apparently inhaled ampicillin after opening a bottle of the drug for reconstitution. [R9, 286] *Rash has been reported more frequently with ampicillin and amoxicillin than with other currently available penicillins. More than 65% of rashes reported with ampicillin appear to be of the maculopapular type. A maculopapular rash reportedly occurs in 5-10% of children receiving ampicillin. The frequency of rash reported with ampicillin does not appear to be reacted to dosage of the drug, but the rash has been reported more frequently in women than in men. [R9, 286] *A high incidence of rash occurs when aminopenicillins are used in patients with viral disease, including viral respiratory tract infections, infectious mononucleosis, and cytomegalovirus infection. /Aminopenicillins/ [R9, 286] *The frequency of aminopenicillin-induced adverse dermatologic effects, including rash (morbilliform, macular), urticaria, pruritus, and rarely, erythema multiforme is substantially higher (about 10-fold) in patients with human immunodeficiency virus (HIV) infections (including those with ... AIDS) than in other patients. /Aminopenicillins/ [R9, 286] *In addition to eosinophilia and hemolytic anemia ... other adverse hematologic effects including anemia, leukopenia, neutropenia, agranulocytosis, thrombocytopenia, and thrombocytopenic purpura have been reported in patients receiving aminopenicillins. /Aminopenicillins/ [R9, 286] *Abnormal platelet aggregation, prolongation of bleeding time, and prolongation of activated partial thromboplastin time (APTT) have been reported in children and healthy adults receiving ampicillin or amoxicillin. [R9, 286] *Some of the most frequent adverse reactions to orally admin aminopenicillins are GI effects including nausea, vomiting, anorexia, epigastric distress, diarrhea, and gastritis. Black hairy tongue, glossitis, stomatitis, and sore mouth or tongue have also been reported. Adverse GI effects appear to be dose related ... /Aminopenicillins/ [R9, 286] *Antibiotic-associated pseudomembranous colitis, caused by toxin-producing clostridia (e.g., C. difficile, C. perfringens) which may be resistant to the drugs, has been reported during or following discontinuance of ampicillin or amoxicillin. In one study, pseudomembranous colitis occurred in 5% of patients receiving oral ampicillin; however, other studies indicate that pseudomembranous colitis occurs in only 0.3-0.7% of patients receiving the drug. [R9, 287] *Acute, transient enterocolitis with severe abdominal pain and bloody diarrhea, but without evidence of pseudomembranous colitis, has also been reported in several patients receiving oral ampicillin or oral amoxicillin. [R9, 287] *Nausea and diarrhea have occurred in up to 3% of patients receiving IV ampicillin. Acute pancreatitis has been reported in at least one patient receiving IV ampicillin therapy. [R9, 287] *Acute interstitial nephritis has been reported rarely with ampicillin and amoxicillin ... resembled that reported with methicillin and appeared to be a hypersensitivity reaction to the drugs. [R9, 287] *At least one case of glomerulonephritis, which occurred as part of Henoch-Schonlein purpura, has been reported with oral ampicillin. The syndrome appeared to be a hypersensitivity reaction to the drug and was characterized by urticaria, bloody diarrhea, arthralgia, proteinuria, and hyaline and erythrocyte casts in the urine; focal glomerulonephritis was present histologically. [R9, 287] *A moderate increase in serum concn as AST ... and/or ALT ... have been reported rarely during therapy with aminopenicillins, esp when the drugs were admin to infants. Hepatic dysfunction ... has been reported rarely in patients receiving aminopenicillins ... /Aminopenicillins/ [R9, 287] *Headache and dizziness have been reported rarely with ampicillin ... Myoclonic seizures have occurred rarely following IV admin of high doses of ampicillin, esp in patients with impaired renal function. [R9, 287] *Phlebitis has been reported rarely with IV admin of ampicillin. [R9, 287] *Use of aminopenicillins may result in overgrowth of nonsusceptible organisms including Candida. The majority of bacterial superinfections during therapy with aminopenicillins are cause by Enterobacter, Klebsiella, E. coli, Aerobacter, or Pseudomonas. Oral or vaginal candidiasis occurs occasionally with oral aminopenicillins. Superinfections are more likely to occur when large doses of aminopenicillins are used or when therapy is prolonged. /Aminopenicillins/ [R9, 287] *Ampicillin did not induce sister chromatid exchange in human lymphocytes in vitro ... Ampicillin did not induce chromosomal aberrations in human fibroblasts after 50 hr of treatment with a concn of 4000 ug/ml ... but a dose of 28 ug/ml induced chromosomal aberrations in human peripheral lymphocytes in vitro ... It was reported in an abstract that ampicillin did not induce chromosomal aberrations in human lymphocytes in vitro @ concn up to 10 mg/ml ... . [R15] *Skin rashes ... are the most common side-effects of ampicillin treatment and are either urticarial or maculopapular. The allergic nature of the maculopapular rash is uncertain ... Non-allergic fever due to ampicillin occurs rarely ... The overall incidence of skin reactions among a group of patients who received the drug between 1975 and 1982 was 59/1775 (3.3%) ... although higher incidences have been reported. Unusually high incidences of skin rashes occur during treatment with ampicillin of glandular fever and lymphatic leukemia ... . [R16] *Ampicillin commonly affects the GI tract, at least in children (25-35%) ... It has been reported to be one of the drugs most frequently assoc with pseudomembranous colitis ... Seizures have been reported after use of ampicillin in cases of underlying cerebral dysfunction ... or concomitant renal insufficiency resulting in high serum concn of ampicillin ... . [R17] *In a study of 280,000 women belonging to a prepaid health plan in Seattle, WA (USA), all drug prescriptions and all pregnancy outcomes were monitored between July 1977 and December 1979. Among the liveborn babies of 6837 women, 80 (1.2%) had major congenital malformations. Four infants born to 309 women for whom ampicillin had been prescribed in the first trimester had major malformations [types not specified], giving a prevalence of 13 per 1000, which was not significantly different from the overall prevalence in the total population studied (12 per 1000) ... In a second study of the same population covering January 1980 to June 1982, 6509 women had pregnancies ending in livebirths, and 105 (1.5%) of these had major congenital malformations. Three infants born to 409 women for whom ampicillin had been prescribed in the first trimester had major malformations [types not specified], giving a prevalence of seven per 1000, compared with an overall prevalence in the entire group of 15 per 1000 ... . [R17] *In a hospital study of Australian women, 7371 mothers had singleton pregnancies in 1978-81; 1060 of them had used amoxicillin or ampicillin [not recorded separately] at some time during pregnancy: 211 had been treated in the first trimester only and 73 in the first trimester and later. It was stated that there was no evidence of any association between use of these drugs and the incidence or type of congenital malformations, which were observed in 12 of the 284 (4.2%) exposed babies, compared with the nonexposed (297/6311, 4.7%). There was no association with use of these drugs and intrauterine growth retardation or perinatal death, but there was a significant (p < 0.01) difference in the rate of prematurity in the users (8.9%) compared with nonusers (6.5%), which was not due to age or differences in use of alcohol. There was also a significant (p < 0.0001) increase in the prevalence of low-birth-weight (< 2.5 kg) babies among users (9.6%) compared with nonusers (6.6%), which was still significant (p < 0.05) when controlled for length of gestation ... [The Working Group noted that the effects might have been due to underlying infection in the mothers.] [R17] HTOX: *One case each of lymphoproliferative disease and Kaposi's sarcoma has been reported in assoc with use of ampicillin ... . [R18] *Ampicillin was included in a hypothesis-generating cohort study designed to screen a large number (215) of drugs for possible carcinogenicity, which covered more than 140,000 subscribers enrolled in July 1969 to August 1973 in a prepaid medical care program in northern California (USA). Computer records of persons to whom at least one drug prescription was dispensed were linked to cancer records from hospitals and the local cancer registry. Observed numbers of cancers were compared with expected numbers, standardized for age and sex, derived from the entire cohort ... Among 6706 persons who received ampicillin, an assoc was noted with subsequent skin cancer (four cases observed, 0.9 expected; p < 0.05) in the 7-yr report. In the 15-yr report, an assoc was noted with lung cancer (48 cases observed, 273 expected; p < 0.002). The latter assoc, although apparently not explained by cigarette smoking in an analysis of smoking habits carried out specifically for people taking ampicillin, was also seen for several other antibiotics. [The Working Group noted, as did the authors, that, since some 12,000 comparisons were made in this hypothesis-generating study, the assoc should be verified independently. Data on duration of use were not provided.] [R18] NTOX: *DEATH FROM RESP FAILURE WITH OR WITHOUT CONVULSIONS OCCURRED 6-18 HR AFTER SINGLE ORAL DOSES. ACUTE GASTROENTERITIS AND CARDIOVASCULAR SHOCK WERE ASSOCIATED PHENOMENA. ...PATTERN...ALSO TRUE FOR GUINEA PIGS EXCEPT THAT LATE (1-2 WK) AND GRADUALLY DEVELOPING TOXEMIA KILLED ALL SURVIVORS OF ACUTE RESPONSE. /PENICILLINS/ [R19] *IN HAMSTERS...SOMEWHAT MORE TOXIC BY ORAL THAN BY SC ROUTE WHEN OBSERVED FOR 14 DAYS AFTER SINGLE DOSES. TOLERANCE DEVELOPED TO MULTIPLE DOSING. PERHAPS SENSITIVITY OF GUINEA PIGS IS RELATED TO EFFECTS ON INTESTINAL MICROFLORA. SC LD50 IN NEWBORN (LESS THAN 72 HR) RATS WAS 7-FOLD LOWER THAN LD50 IN ADULTS. /PENICILLINS/ [R19] *Ampicillin may have an adverse effect on rabbits when administered orally. Rabbits that consumed 18.8 mg ampicillin/100 ml drinking water developed diarrhea and died within a month. Severe enteritis and renal tubular damage was thought to be related to an antibiotic-induced disturbance of intestinal bacterial equilibrium. The oral dose of ampicillin is approximately 12 mg/kg 4 times daily. [R12] *Ampicillin has been used in a variety of domestic animals at doses ranging from 2 to 50 mg/kg. Blood concentrations are dose dependent and the maintenance dose must be administered at 4- to 6-hour intervals. Although ampicillin disappears from the blood quite rapidly, it appears that tissue concentrations may be greater than blood concentrations for a significant therapeutic effect; eg, /it was/ reported that uterine tissue concentrations in the mare were 10-50% higher than serum. They recommended an IV dose of 11-16 mg ampicillin/kg at 4- to 8-hour intervals. Ampicillin has been used to treat bacterial infections in cattle. A dose of 4.5-11 mg/kg was administered parenterally once daily for 3 days. Clinical improvement was noted in 86% of the cases and adverse effect were noted in experimental tests. [R12] *Ampicillin has been orally administered to dogs and cats at the rate of 11-22 mg/kg 2-3 times daily. Drug-related adverse reactions were reported for 5 of 266 dogs and 2 of 160 cats; 83% of the animals treated had a beneficial response rated from excellent to good for animals suffering from bacterial infections. Doses as high as 50 mg/kg intramuscularly followed by one or more oral doses at 4-hour intervals have been well tolerated by dogs. Repeated oral administration produced blood concentrations of 40 ug/ml or more for more than 12 hours. [R12] *Ampicillin has been used to treat bacterial infections in cattle. A dose of 4.5 to 11 mg/kg was administered parenterally once dailly for 3 days. Clinical adverse effects were noted in experimental tests. Studies involving calves administered an oral dose of 12 mg/kg or an IM dose of 4-10 mg/kg produced peak serum concn within 1 hr and then rapidly declined. It is recommended that maintenance therapy be given at approximately 8 hr intervals. [R12] *Groups of 50 male and 50 female B6C3F1 mice, 7-8 wk of age, were admin ampicillin trihydrate (purity, 97%) by gavage @ 0, 1500, or 3000 mg/kg bw in corn oil on five days per week for 103 weeks. The animals were maintained for a further 1-2 wk, after which time they were killed. Weight gain was similar in all groups, and no significant difference in survival was observed in mice of either sex: at the end of the study period, 32/50, 21/50 and 20/50 males in the control, low-dose and high-dose groups, respectively, and 34/50, 27/50 and 28/50 females in the control, low-dose and high-dose groups, respectively, were still alive. In female mice, a slight increase in the incidence of benign lung tumors was observed (control, 1/50; low-dose, 0/50; high-dose, 4/50; p = 0.049, incidental tumor test). No increase in the incidence of any other neoplasm was recorded ... . /Ampicillin trihydrate/ [R20] *Groups of 50 male and 50 female Fischer 344/N rats, seven to eight weeks old, were administered ampicillin trihydrate (purity, 97%) by gavage at 0, 750 or 1500 mg/kg bw in corn oil on five days per week for 103 weeks. Animals were observed for a further one to two weeks, after which time they were killed. Mean body weights of treated males and females were similar to those of controls. At the end of the study, 31/50, 27/50 and 26/50 control, low-dose and high-dose males, respectively, and 32/50, 31/50 and 31/50 control, low-dose and high-dose females, respectively, were still alive. An increase in the incidence of mononuclear-cell leukemia was observed in treated males: control,5/50; low-dose, 14/50 (p = 0.019, life-table test); high- dose, 13/50 (p = 0.029, life-table test; p = 0.024, life-table test for trend). A dose-related increase in the incidence of combined benign and malignant pheochromocytomas of the adrenal medulla was also observed in males: control, 13/50; low-dose, 16/50; high-dose, 23/49 (p = 0.007, incidental tumor test; p = 0.007, trend test for incidental tumors). The incidences of mammary gland fibroadenomas in females were: control, 16/50; low- dose, 25/50 (p = 0.019, incidental tumor test); high-dose, 19/50. No increase in the incidence of tumors at other sites was observed ... [The Working Group noted the high frequency of spontaneous tumors and that the increase in the incidence of mammary gland fibroadenomas was not dose-related.] /Ampicillin trihydrate/ [R21] *Deaths occurred in 63, 45, and 100% of rabbits that received oral doses of ampicillin @ 5, 15, and 50 mg/kg bw, respectively, for 3 consecutive days ... . [R22] *Ampicillin administered as a single oral or subcutaneous dose of up to 5000 mg/kg bw had no noticeable toxic effect in mice or rats. Intravenous administration of 2000 mg/kg bw to mice caused muscle tremors, slowed respiration and mild convulsions. No biochemical, hematological or histological abnormality was seen in rats administered ampicillin at 100 or 500 mg/kg bw for 12 weeks ... Administration of 25 mg/l in the drinking-water to four-week-old rats for up to eight weeks resulted in an increase in body weight gain; no toxic effect was noted [R10, p. V50 158] *... Intravenous exposures of rats to ampicillin at 1200 mg/kg bw per day for 28 days were well tolerated. Intravenous administration of sulbactam:ampicillin (1:2) at 90-1800 mg/kg bw for 28 days caused caecal enlargement; deposition of glycogen-like droplets in the liver occurred at the higher dose levels. [R22] *In 14-day studies of rats and mice administered ampicillin at 200-2400 mg/kg bw by gavage, dose- related clinical signs included diarrhea and excessive salivation in the high-dose rats immediately after dosing. Diarrhea of minimal severity was observed in high-dose mice given 2400 mg/kg. No dose-related gross pathology or histopathology was observed in either species. [R22] *In 13-week studies, doses of 180-3000 mg/kg bw were administered by gavage on five days per week to rats and mice. All rats given 300 mg/kg bw and one of ten male mice at either 2000 mg/kg or 3000 mg/kg had diarrhea. No compound-related pathology or histopathology was observed grossly in either species. [R22] *In the two-year studies ... ampicillin at doses of 750 or 1500 mg/kg bw (rats) and 1500 or 3000 mg/kg bw (mice) was administered by gavage on five days per week for 103 weeks. Clinical signs observed in treated rats included diarrhea, excessive urination and chromodacryorrhea; those in treated mice included increased salivation and decreased activity. The incidence of C-cell hyperplasia of the thyroid gland was increased in low-dose male and high-dose female rats. High-dose male rats showed increased incidences of hyperkeratosis and acanthosis of the forestomach. In male and female mice, an increased incidence of forestomach lesions, including ulcers, inflammation, hyperkeratosis, acanthosis and evidence of fungal infection, was observed in exposed animals. [R22] *Ampicillin induced lysogenic phage in Staphylococcus aureus ... It did not induce a SOS response in Escherichia coli PQ37 ... and no differential toxicity was observed in E. coli in the absence ... or presence of an exogenous metabolic system ... In Salmonella typhimurium plate incorporation tests, ampicillin was not mutagenic in the presence or absence of an exogenous metabolic system ... . [R15] *Treatment of Vicia faba seeds with a 0.5% solution of ampicillin led to chromosomal aberrations in root-tip meristem cells ... . [R15] *Ampicillin did not induce mutation at the tk locus in L5178Y mouse lymphoma cells in the presence or absence of an exogenous metabolic system at concentrations up to 5000 ug/ml ... No increase in the frequency of sister chromatid exchange was observed in Chinese hamster CHO cells with concentrations of ampicillin up to 1500 ug/ml in the presence or absence of an exogenous metabolic system ... No chromosomal aberration was observed in Chinese hamster CHO cells treated with ampicillin at 0-1500 ug/ml in the presence or absence of an exogenous metabolic system ... It was reported in an abstract that ampicillin at single- or double-dose oral regimens of 5 mg/kg did not induce micronuclei in rats treated in vivo ... . [R15] NTXV: *LD50 Rat oral 10 g/kg bw; [R22] *LD50 Mouse oral 15.2 g/kg bw; [R22] *LD50 Rat ip, 1 day old, 3300 mg/kg bw; [R22] *LD50 Rat ip, 83 day old, 4500 mg/kg bw; [R22] NTP: *Toxicology and carcinogenesis studies of ampicillin trihydrate (97-99% pure) were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days/wk for 103 wk. Male and female rats received doses of 0, 750, or 1,500 mg/kg, and male and female mice received doses of 0, 1,500 or 3,000 mg/kg. ... Under the conditions of these 2 yr gavage studies, there was equivocal evidence of carcinogenicity of ampicillin trihydrate for male F344/N rats as shown by increased incidences of pheochromocytomas of the adrenal medulla and marginally increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for female F344/N rats receiving 750 or 1,500 mg/kg or for male or female B6C3F1 mice receiving 1,500 or 3,000 mg/kg per day. Noneoplastic lesions of the forestomach were seen in male rats and male and female mice. /Ampicillin trihydrate/ [R23] ADE: *INTAKE OF FOOD PRIOR TO INGESTION OF AMPICILLIN RESULTS IN LESS COMPLETE ABSORPTION. ... /IT/ APPEARS IN BILE, UNDERGOES ENTEROHEPATIC CIRCULATION AND IS EXCRETED IN...FECES. BILIARY CONCN...DEPENDENT ON INTEGRITY OF GALLBLADDER AND ITS DUCTS. [R24] *Ampicillin is distributed to liver, bile, muscle, kidney, crop, and fat following absorption from the GI or injection site. Ampicillin has been used therapeutically and prophylactically for avian salmonellosis with promising results. ... Ampicillin is excreted in bile. [R12] *Anhydrous ampicillin and ampicillin trihydrate are generally stable in the presence of acidic gastric secretions, and 30-55% of an oral dose of the drugs is absorbed from the GI tract in fasting adults. Although peak serum concn may occur as soon as 1 hr after administration, the maximum serum concn is usually attained in approx 2 hr. [R9, 298] *Two hr after oral administration of 250 mg of ampicillin in fasting individuals, average peak serum concn of 1.8-2.9 ug/ml are attained. A 500-mg oral dose results in average peak serum concn of 3-6 ug/ml. Concn of the antibiotic in serum are less than 1 ug/ml 6 hr after a 500-mg oral dose. [R9, 298] *Although higher peak serum ampicillin concn and larger areas under the serum concn-time curves (AUCs) have been reported following oral administration of anhydrous ampicillin than following the trihydrate, the differences are generally not considered clinically important. As oral dosage of ampicillin is increased from 500 mg to 2 g, the fraction of the dose absorbed from the GI tract decreased and there is a nonlinear relationship between dosage and peak serum concn or AUCs of ampicillin. [R9, 298] *Presence of food in the GI tract generally decreases the rate and extent of absorption of ampicillin. [R9, 298] *Following IM administration of ampicillin sodium, peak serum concn are generally attained more quickly and are higher than those resulting from equivalent doses of ampicillin given orally. In premature neonates younger than 7 days of age, IM administration of a single ampicillin dose of 50 m/kg has been reported to produce mean serum concn of 104, 87, 60, and 31 ug/ml at 1, 4, 8, and 12 hr, respectively, after the dose. The same dose in full-term neonates younger than 7 days of age produced mean serum concn of 75, 64, 34, and 20 ug/ml at the same time intervals. [R9, 298] *Following IV administration over 20 minutes of a single 2-g dose of ampicillin in healthy adults, serum concn of ampicillin averaged 47.6, 23.3, 10.8, and 3.7 ug/ml at 30 min, 1 hr, 2 hr, and 4 hr, respectively, after the infusion. [R9, 298] *Serum ampicillin concn are higher and the serum half-life is prolonged in patients with impaired renal function. Serum concn of the drug are also higher and more prolonged in premature or full-term neonates younger than 6 days of age than in full-term neonates 6 days of age or older. [R9, 298] *In one study in neonates with meningitis, average ampicillin concn in CSF ranged from 1-28 ug/ml (11-65% of simultaneous serum concn) during the 7-hr period following IV administration of 40-70 mg/kg. Highest CSF concn occurred @ 3-7 hr. [R9, 298] *Ampicillin is distributed into bile. Biliary concn of ampicillin in patients with normal biliary function may be 1-30 times greater than simultaneous serum concn following a single oral dose of ampicillin. [R9, 298] *Assay of serum collected after a single sc dose of sodium ampicillin @ 10 mg/kg bw to guinea-pigs yielded ampicillin levels of approx 10 ug/ml @ 5 min, which fell rapidly to less than 0.2 ug/ml @ 60 min ... . [R21] *Ampicillin is relatively stable in the acid contents of the stomach; anhydrous or trihydrated ampicillin is absorbed incompletely from the gut after oral admin. Peak concn in plasma (2-6 mg/l after an oral dose of 500 mg) occur within 1-2 hr. Ester prodrugs ... and the condensation prodrug ... of ampicillin are absorbed more readily than ampicillin ... Ampicillin @ 500 mg given by im injection as the sodium salt produced plasma peaks of 7-14 mg/l within about 1 hr ... . [R16] *Ampicillin is distributed widely, and therapeutic concn can be achieved in soft tissues, including ascitic, pleural and joint fluids ... Only 20% of ampicillin is bound to plasma proteins ... It crosses the placenta ... and detectable concn of ampicillin occur in the milk of nursing mothers ... . [R16] *Ampicillin is excreted via renal glomerular and tubular routes in the urine ... [R16] *There is a number of studies to suggest that the pharmacokinetics of beta-lactam antibiotics are altered during pregnancy, indicating faster elimination of these antibiotics and lowered plasma concentrations. These changes are largely related to the physiological changes taking place in the maternal body. [R25] METB: *AMPICILLIN IS DEGRADED BY PENICILLINASE... [R11, 1144] *YIELDS ALPHA-AMINOBENZYLPENICILLOIC ACID IN BACILLUS, IN PENICILLIUM, AND L-PHENYLGLYCINE IN ESCHERICHIA. /FROM TABLE/ [R26] *Healthy subjects metabolize about 20% of a given dose (250-500 mg) of ampicillin. Within 12 hr, 7% of the total dose is excreted as metabolites in urine ... Ampicillin is metabolized to 5R,6R-penicilloic acid and 5S,6R-penicilloic acid ... and to piperazine-2,5-dione after oral intake ... Other, unidentified metabolites have been reported ... . [R10, p. V50 160] BHL: *The half-life of all aminopenicillins is approximately 60-90 minutes. [R12] *Following ip injection ... the serum half-life /of ampicillin/ was estimated to be 27 min ... . [R21] *... /ampicillin's/ plasma half-time is usually 1-2 hr ... but is longer in elderly people ... In patients with renal failure, the half-time was as long as 20 hr ... . [R16] ACTN: *SINCE PENICILLIN HAS NO EFFECT ON EXISTING CELL WALLS, BACTERIA MUST BE MULTIPLYING FOR BACTERICIDAL ACTION OF PENICILLIN TO BE MANIFEST. /PENICILLINS/ [R11, 1135] *The penicillins and their metabolites are potent immunogens because of their ability to combine with proteins and act as haptens for acute antibody-mediated reactions. The most frequent (about 95 percent) or "major" determinant of penicillin allergy is the penicilloyl determinant produced by opening the beta-lactam ring of the penicillin. This allows linkage of the penicillin to protein at the amide group. "Minor" determinants (less frequent) are the other metabolites formed, including native penicillin and penicilloic acids. /Penicillins/ [R14, 953] *Bactericidal; inhibit bacterial cell wall synthesis. Action is dependent on the ability of penicillins to reach and bind penicillin binding proteins located on the inner membrane of the bacterial cell wall. Penicillin binding proteins (which include transpeptidases, carboxypeptidases, and endopeptidases) are enzymes that are involved in the terminal stages of assembling the bacterial cell wall and in reshaping the cell wall during growth and division. Penicillins bind to, and inactivate, penicillin binding proteins, resulting in the weakening of the bacterial cell wall and lysis. /Penicillins/ [R27, 2150] INTC: *...AMPICILLIN...MIXED IN VITRO WITH GENTAMICIN.../FOR PROLONGED PERIODS/ CAUSE LOSS OF GENTAMICIN ANTIMICROBIAL ACTIVITY. [R28, 76] *CONCURRENT ADMIN OF PENICILLIN AND PROBENECID RESULTS IN HIGHER AND MORE SUSTAINED SERUM ANTIBIOTIC LEVELS. /AMPICILLIN HAS BEEN SHOWN TO INTERACT IN SIMILAR MANNER/. [R28, 175] */GENTAMICIN/ RELATED DRUGS...KANAMYCIN, NEOMYCIN AND TOBRAMYCIN MAY INTERACT...WITH CARBENICILLIN. /CARBENICILLIN/ [R28, 76] *LIMITED...DATA INDICATE THAT ASPIRIN, IN LARGE DOSES, INCR SERUM LEVEL AND HALF-LIFE OF PENICILLIN WHEN...GIVEN CONCURRENTLY. ALTHOUGH CONCURRENT USE OF HIGH DOSES OF ASPIRIN HAS BEEN SUGGESTED TO INCR CLINICAL BENEFITS OF PENICILLIN, POSSIBLE TOXICITIES DUE TO HIGH-DOSE ASPIRIN ADMIN DISCOURAGE SUCH THERAPY. /PENICILLIN/ [R28, 166] *Ampicillin sodium is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides, but the compatibility depends on several factors (e.g. concn of the drugs, specific diluents used, resulting pH, temperature). [R9, 298] *Concurrent use with ampicillin ... /with allopurinol/ may significantly increase the possibility of skin rash, especially in hyperuricemic patients; however, it has not been established that allopurinol, rather than the presence of hyperuricemia, is responsible for this effect. [R27, 2151] *These have been case reports of reduced oral contraceptive effectiveness in women taking ampicillin, amoxicillin, and penicillin V, resulting in unplanned pregnancy. This is thought to be due to a reduction in enterohepatic circulation of estrogens. Although the association is weak, patients should be advised of this information and given the option to use an alternate or additional method of contraception while taking any of these penicillins. [R27, 2152] *Mixing penicillins with aminoglycosides in vitro has resulted in substantial mutual inactivation; if these groups of antibacterials are to be administered concurrently, they should be administered at separate sites at least 1 hour apart. /Penicillins/ [R27, 2152] *Concurrent of /methotrexate/ with penicillins has resulted in decreased clearance of methotrexate and in methotrexate toxicity; this is thought to be due to competition for renal tubular secretion; patients should be closely monitored; leucovorin doses may need to be increased and administered for longer periods of time. /Pencillins/ [R27, 2152] *Since bacteriostatic drugs /Chloramphenicol, erythromycins, sulfonamides, or tetracyclines/ may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy; however, chloramphenicol and ampicillin are sometimes administered concurrently to pediatric patients. /Penicillins/ [R27, 2152] *Probenecid decreases renal tubular secretion of penicillins when used concurrently; this effect results in increased and prolonged serum concentrations, prolonged elimination half-life, and increased risk of toxicity. Penicillins and probenecid are often used concurrently to treat sexually transmitted diseases or other infections in which high and/or prolonged antibiotic serum and tissue concentrations are required. /Penicillins/ [R27, 2152] *In vitro and animal studies indicate that a synergistic bactericidal effect can occur against some strains of enterococci when ampicillin is used in conjunction with amikacin, gentamicin, netilmicin, streptomycin, or tobramycin ... also ... in vitro against group B streptococci when ampicillin was used in conjunction with amikacin, gentamicin, kanamycin, or tobramycin and against L. monocytogenes when ampicillin was used in conjunction with gentamicin ... in vitro studies indicate that gentamicin and ampicillin may be synergistic against some strains of Enterobacteriaceae ... . [R9, 287] *In vitro and in vivo studies indicate that the combination of amoxicillin or ampicillin with clavulanic acid or the combination of amoxicillin or ampicillin with sulbactam results in a synergistic bactericidal effect against many strains of beta-lactamase-producing bacteria. [R9, 288] *In some in vitro studies, chloramphenicol reportedly antagonized the bactericidal activity of ampicillin against H. influenzae, N. meningitidis, and S. pneumoniae. However, indifferent, additive, or synergistic effects have also occurred in vitro when chloramphenicol was used in conjunction with ampicillin against these organisms. [R9, 288] *In one in vitro study, the combination of ampicillin and moxalactam ... appeared to be synergistic against H. influenzae. [R9, 288] *In one in vitro study using group B streptococci, rifampin used in conjunction with ampicillin resulted in a lower rate of killing than ampicillin alone; however, in another in vitro study using H. influenzae, concomitant use of rifampin and ampicillin resulted in an additive or indifferent effect and no synergism or antagonism. [R9, 288] *In one study, admin of oral ampicillin (250 mg 4 times daily for 5 days) prior to admin of sulfasalazine resulted in a decrease in the area under the serum concn-time curve (AUC) of sulfapyridine ... compared with admin of sulfasalazine alone ... ampicillin may have altered the GI flora and consequently sulfasalazine metabolism. [R9, 288] *Results of one in vitro study indicate that the antibacterial activity of acetohydroxamic acid, a urease inhibitor, and ampicillin or carbenicillin may occasionally be synergistic against some organisms including E. coli, Klebsiella, Morganella morganii ... Providencia rettgeri ... and Ps. aeruginosa; however, indifferent or antagonistic effects also occurred. [R9, 288] *Concomitant use of ampicillin and estrogen-containing oral contraceptives reportedly may decrease efficacy of the contraceptive and increase the incidence of breakthrough bleeding. [R9, 288] *Oral probenecid admin shortly before or simultaneously with aminopenicillins slows the rate of renal tubular secretion of the penicillins and produces higher and prolonged serum concn of the drugs. /Aminopenicillins/ [R9, 288] *An increased incidence of rash reportedly occurs in patients with hyperuricemia who are receiving allopurinol and concomitant ampicillin or amoxicillin compared with those receiving ampicillin, amoxicillin, or allopurinol alone. [R9, 288] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Penicillins [R29] *FOR MILD TO MODERATELY SEVERE DISEASE, ORAL...ADULTS...1-4 G/DAY, DIVIDED INTO EQUAL PORTIONS...EVERY 6 HR. FOR SEVERE INFECTIONS...BEST TO ADMIN... PARENTERALLY...6-12 G/DAY. ...MENINGITIS REQUIRES...300-400 MG/KG/DAY PARENTERALLY (IN EQUALLY DIVIDED PORTIONS...EVERY 4 HR) FOR CHILDREN, and 12 G OR MORE/DAY FOR ADULTS. [R24] *DOSE VARIES WITH TYPE AND SEVERITY OF INFECTION...RENAL FUNCTION AND...AGE. FOR CHILDREN.../NOT/ ON BASIS OF BODY WT OR SURFACE AREA; BECAUSE DRUG...EXCRETED MAINLY BY KIDNEY ...RENAL FUNCTION TO GREAT EXTENT DETERMINES DOSE. VERY YOUNG BABIES...REQUIRE SMALL DOSES ...CHILDREN 3-4 YR.../DOSE/ ALMOST AS LARGE AS...ADULTS. [R24] *Ampicillin /is/ indicated in the treatment of acute otitis media caused by susceptible organisms. /Included in US product labeling/ [R27, 2149] *Ampicillin /is/ indicated in the treatment of bacterial pharyngitis cuased by susceptible organisms. /Included in US product labeling/ [R27, 2149] *Ampicillin /is/ indicated in the treatment of bacterial pneumonia caused by susceptible organisms. /Included in US product labeling/ [R27, 2150] *Ampicillin /is/ indicated in the treatment of sinusitis caused by susceptible organisms. /Included in US product labeling/ [R27, 2150] *Ampicillin /is/ indicated in the treatment of bacterial urinary tract infections caused by susceptible organisms. /Included in US product labeling/ [R27, 2150] *Ampicillin /is/ indicated in the treatment of chlamydia infections in pregnant women who cannot tolerate erythromycin. /Included in US product labeling/ [R27, 2150] *Ampicillin /is/ used in the treatment of typhoid fever caused by Salmonella typhi. /NOT included in US product labeling; Not included in Canadian product labeling/ [R27, 2150] *Ampicillin /is/ indicated in the prophylaxis of bacterial endocarditis caused by susceptible organisms. /Included in US product labeling; Not included in Canadian product labeling/ [R27, 2149] *Ampicillin /is/ indicated in the treatment of bacterial endocarditis caused by susceptible organisms. /Included in US product labeling/ [R27, 2149] *Ampicillin (parenteral) /is/ indicated in the treatment of listeriosis caused by Listeria monocytogenes. /Included in US product labeling; Not included in Canadian product labeling/ [R27, 2149] *Ampicillin (parenteral) /is/ indicated in the treatment of bacterial meningitis caused by susceptible organisms. /Included in US product labeling/ [R27, 2149] *Ampicillin (parenteral) /is/ indicated in the treatment of infections caused by Pasteurella multocida. /Included in US product labeling; Not included in Canadian product labeling/ [R27, 2149] *Ampicillin ... /is/ indicated in the treatment of bronchitis caused by susceptible organisms. /Included in US product labeling/ [R27, 2149] *Ampicillin (parenteral) /is/ indicated in the treatment of bacterial septicemia caused by susceptible organisms. /Included in US product labeling/ [R27, 2150] *Ampicillin (parenteral) /is/ used in the treatment of leptospirosis caused by Leptospira sp. /NOT included in US product labeling; Not included in Canadian product labeling/ [R27, 2150] WARN: *IN 1 INSTANCE, FATAL PSEUDOMEMBRANOUS COLITIS OCCURRED FOLLOWING 5 DAYS OF ORAL AMPICILLIN THERAPY IN DOSAGE OF 2 G DAILY. VERY RARELY, AMPICILLIN HAS PRODUCED INTERSTITIAL NEPHRITIS; 1 CASE OF INTERSTITIAL NEPHRITIS REPORTEDLY PROGRESSED TO ACUTE RENAL FAILURE. ...CRYSTALLURIA HAS BEEN REPORTED... [R30] *PERIODIC ASSESSMENT OF RENAL, HEPATIC AND HEMATOPOIETIC FUNCTION SHOULD BE CONDUCTED DURING PROLONGED THERAPY, ESP IN PREMATURE, NEWBORN AND OTHER INFANTS. [R30] *ABSORPTION EFFICIENCY AND RATE OF ELIMINATION OF AMPICILLIN...DECR IN PT WITH SHIGELLOSIS. POOR ABSORPTION...GENERALLY OBSERVED IN YOUNGER PATIENTS WITH MARKED DIARRHEA. ... DELAYED EXCRETION. MARKED RETENTION...IN PLASMA...NOTED IN PT WITH RENAL FAILURE. [R31] *NATIONAL REGISTRY OF POSSIBLE DRUG INDUCED OCULAR SIDE EFFECTS ESTABLISHED IN 1975 BY FDA IN ORDER TO MAKE PHYSICIANS AWARE THAT SOME DRUGS SUCH AS AMPICILLIN MAY CAUSE SIDE EFFECTS TO EYE IS DISCUSSED. [R32] *Potential Adverse Effects on Fetus: None known. Potential Side Effects on Breast-fed Infant: Significant problems not documented, but may lead to sensitization, diarrhea, candidiasis, or skin rash in infant. Comments: Fetal serum levels 20%-50% of maternal. FDA Category: B (B = Studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; nor animal studies have shown an adverse effect (other than a decrease in fertility), but controlled studies in pregnant women have not demonstrated a risk to the fetus in the first trimester and there is no evidence of a risk in later trimesters.) /Penicillin; from Table II/ [R33] *Penicillins are distributed into breast milk, some in low concentrations. Although significant problems in humans have not been documented, the use of penicillins by nursing mothers may lead to sensitization, diarrhea, candidiasis, and skin rash in the infant. /Penicillins/ [R27, 2151] *Many penicillins have been used in pediatric patients and no pediatric-specific problems have been documented to date. However, the incompletely developed renal function of neonates and young infants may delay the excretion of renally eliminated penicillins. /Penicillins/ [R27, 2151] *Penicillins have been used in geriatric patients and no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may require an adjustment in dosage in patients receiving penicillins. /Penicillins/ [R27, 2151] *Prolonged use of penicillins may lead to the development of oral candidiasis. /Penicillins/ [R27, 2151] *Side/Adverse Effects: Those indicating need for medical attention: Incidence less frequent: Allergic reactions, specifically anaphylaxis (fast or irregular breathing; puffiness or swelling around face; shortness of breath; sudden, severe decrease in blood pressure), exfoliative dermatitis (red, scaly skin), serum sickness-like reactions (skin rash; joint pain, fever), skin rash, hives, or itching. Incidence rare: Hepatotoxicity (fever, nausea and vomiting, yellow eyes or skin); interstitial nephritis (fever, possibly decreased urine output, skin rash); leukopenia or neutropenia (sore throat and fever); mental disturbances (anxiety, confusion, agitation or combativeness, depression, seizures, hallucinations, or expressed fear of impending death) pain at site of injection; platelet dysfunction or thrombocytopenia (unusual bleeding or bruising); Clostridium difficile colitis (severe abdominal or stomach cramps and pain; abdominal tenderness; watery and severe diarrhea, which may also be bloody; fever); seizures. /Penicillins/ [R27, 2153] *Side/Adverse Effects: Those indicating need for medical attention only if they continue or are bothersome: Incidence more frequent: Gastrointestinal reactions (mild diarrhea, nausea or vomiting); headache; oral candidiasis (sore mouth or tongue, white patches in mouth and/or on tongue); vaginal candidiasis (vaginal itching and discharge). /Penicillins/ [R27, 2153] *Prior to initiation of therapy with an aminopenicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs. There is clinical and laboratory evidence of partial cross-allergenicity among bicyclic beta-lactam antibiotics including penicillins, cephalosporins, cephamycins, 1-oxa-beta-lactams, and carbapenems ... Amoxicillin, ampicillin, and bacampicillin are contraindicated in patients who are hypersensitive to any penicillin. [R9, 287] *Because a high percentage of patients with infectious mononucleosis have developed rash during therapy with aminopenicillins ... aminopenicillins probably should not be used in patients with the disease. /Aminopenicillins/ [R9, 287] *Oral or vaginal candidiasis occurs occasionally with oral aminopenicillins. Superinfections are more likely to occur when large doses of aminopenicillins are used or when therapy is prolonged. /Aminopenicillins/ [R9, 287] *Patients receiving antimicrobial agents associated with interstitial nephritis must be followed prospectively for signs of toxicity. Urinalyses to check for hematuria should be obtained at least weekly during long courses of therapy. Signs of eosinophilia should be sought if erythrocytes appear. The drug should be discontinued immediately once nephritis occurs. Most often there will be quick reversal and no permanent damage. [R14, 946] *Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with ampicillin. [R9, 298] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *A tolerance of 0.01 ppm is established for negligible residues of ampicillin in the uncooked edible tissues of swine and cattle and in milk. [R34] FDA: *Oral Dosage Form New Animal Drugs. Specifications and conditions of use for dogs and cats. /Ampicillin capsules/ [R35] *Oral Dosage Form New Animal Drugs. Specifications and conditions of use for dogs. /Ampicillin trihydrate tablets/ [R36] *Oral Dosage Form New Animal Drugs. Specifications and conditions of use for dogs and cats. /Ampicillin trihydrate capsules/ [R37] *Oral Dosage Form New Animal Drugs. Specifications and conditions of use for dogs and cats. /Ampicillin trihydrate for oral suspension/ [R38] *Oral Dosage Form New Animal Drugs. Specifications and conditions of use for swine. /Ampicillin trihyfrate soluble powder/ [R39] *Oral Dosage Form New Animal Drugs. Specifications and conditions of use for nonruminating calves. /Ampicillin trihydrate boluses/ [R40] *Implantation or Injectable Dosage Form New Animal Drugs. Specifications and conditions of use for calves, dogs, and cats. /Ampicillin trihydrate sterile suspension/ [R41] *Implantation or Injectable Dosage Form New Animal Drugs. Specifications and conditions of use for dogs, cats, and cattle. /Ampicillin trihydrate for sterile suspension/ [R42] *Implantation or Injectable Dosage Form New Animal Drugs. Specifications and conditions of use for calves, dogs, and cats. /Ampicillin sodium for aqueous injection/ [R43] *A tolerance is established for negligible residues of ampicillin in the uncooked edible tissues of swine and cattle and in milk. [R34] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R44] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SOLN OF AMPICILLIN WERE ANALYZED BY NICKEL(II)-CATALYZED HYDROXYLAMINOLYSIS. [R45] *ANALYSES OF FORMULATIONS ASSAYED BY MICROBIO AND HYDROXYLAMINE METHODS INDICATED THAT HYDROXYLAMINE ANALYTICAL METHOD IS SUITABLE SUBSTITUTE FOR POTENCY ASSAYS AND STABILITY STUDIES. [R46] *Ampicillin can be analysed in pharmaceutical preparations by microbiological, iodometric, colorimetric, high-performance liquid chromatographic and fluorometric assays and by gas chromatography-mass spectrometry. [R3, (1990)] CLAB: *ANALYSIS OF PENICILLINS IN BIO MATERIAL BY REVERSE PHASE LIQ CHROMATOGRAPHY. DETECTED BY UV-ABSORBANCE AT 310 NM. DERIVATION INVOLVES FORMATION OF MERCURIC MERCAPTIDE OF PENICILLENIC ACID WHICH IS SPECIFIC FOR PENICILLINS WITH INTACT RING SYSTEM. [R47] *FLUOROMETRIC METHOD OF WJ JUSKO (1971) WAS MODIFIED BY EXCHANGING AMPICILLIN INTO CHCL3 ALONE. IT WAS STABLE FOR GREATER THAN 60 MIN. UP TO 50 MUG/L IN BLOOD AND AQ HUMOR MAY BE DETECTED [R48] *Ampicillin can be analysed in biological fluids by high-performance liquid chromatography. [R3, (1990)] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Ampicillin Trihydrate in F344/N Rats and B6C3F1 (Feed Studies) Mice Technical Report Series No. 318 (1987) NIH Publication No. 87-2574 /Ampicillin trihydrate/ SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 93 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 153 R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 724 R5: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 424 R6: Osol A, Hoover JE et al ; Remington's Pharmaceutical Sciences. 14th edition. Easton, PA: Mack Publishing Co., p. 1226 (1975) R7: Osol A, Hoover JE et al; Remington's Pharmaceutical Sciences. 14th edition. Easton, PA: Mack Publishing Co., p. 1226 (1975) R8: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5. College of Pharmacy, University of Arizona-Tucson, AZ (1992) R9: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 95. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R11: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R12: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 735 R13: Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. 78 R14: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 159 (1990) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 160 (1990) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 161 (1990) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 162 (1990) R19: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-171 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 156 (1990) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 157 (1990) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 158 (1990) R23: DHHS/NTP; Toxicology and Carcinogenesis Studies of Ampicillin Trihydrate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 318 (1987) NIH Publication No. 87-2574 R24: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 1079 R25: Heikkila A, Erkkola R; Clin Pharmacokinet 27 (1): 49-62 (1994) R26: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. A-34 R27: USP Convention. USPDI - Drug Information for the Health Care Professional. 15 th ed. Volume 1. Rockville, MD: United States Pharmacopeial Convention, Inc., 1995. (Plus updates.) R28: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R29: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R30: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 8:12:16 R31: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 169 R32: HECHT A; DRUG EFFECTS ON EYE; FDA CONSUM (12): 14 (1978) R33: Stockton DL, Paller AS; J Am Acad Dermatol 23 (1):87-103 (1990) R34: 21 CFR 556.40 (4/1/93) R35: 21 CFR 520.90a (4/1/93) R36: 21 CFR 520.90b (4/1/93) R37: 21 CFR 520.90c (4/1/93) R38: 21 CFR 520.90d (4/1/93) R39: 21 CFR 520.90e (4/1/93) R40: 21 CFR 520.90f (4/1/93) R41: 21 CFR 522.90a (4/1/93) R42: 21 CFR 522.90b (4/1/93) R43: 21 CFR 522.90c (4/1/93) R44: 21 CFR 200-299, 300-499, 820, and 860 (4/1/93) R45: MUNSON JW ET AL; J PHARM SC (68) 1333 (1979) R46: LIN S ET AL; J ASSOC OFF ANAL CHEM (62) 989 (1979) R47: WESTERLUND D ET AL; ACTA PHARM SUEC (16) 187 (1979) R48: KESHAVAN HJ HR ET AL; CLIN CHEM (WINSTON-SALEM, NC) 25: 1674 (1979) RS: 76 Record 213 of 1119 in HSDB (through 2003/06) AN: 3027 UD: 200205 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORAMPHENICOL- SY: *I-337A-; *ACETAMIDE, 2,2-DICHLORO-N-(BETA-HYDROXY-ALPHA-(HYDROXYMETHYL)-P-NITROPHENETHYL)-, D-THREO-(-)-; *ACETAMIDE, 2,2-DICHLORO-N-(2-HYDROXY-1-(HYDROXYMETHYL)-2-(4-NITROPHENYL)ETHYL)-, (R-(R*,R*))-; *AMPHENICOL-; *AMSECLOR-; *CHLOMYCOL-; *D-CHLORAMPHENICOL-; *D-THREO-CHLORAMPHENICOL-; *CHLORAMSAAR-; *CHLOROCAPS-; *CHLOROCID-; *CHLOROCIDE-; *CHLOROCIDIN-C-; *CHLOROCIDIN-C-TETRAN-; *CHLOROMYCETIN-; *CHLORONITRIN-; *CIDOCETINE-; *CIPLAMYCETIN-; *CLORAMFICIN-; *CLORAMICOL-; *CLOROCYN-; *CLOROMISAN-; *CPH-; *CYLPHENICOL-; *DETREOMYCIN-; *D(-)-THREO-2-DICHLOROACETAMIDO-1-P-NITROPHENYL-1,3-PROPANEDIOL; *D-THREO-N-DICHLOROACETYL-1-P-NITROPHENYL-2-AMINO-1,3-PROPANEDIOL-; *D(-)-THREO-2,2-DICHLORO-N-[BETA-HYDROXY-ALPHA-(HYDROXYMETHYL)- P-NITROPHENETHYL]ACETAMID; *D-THREO-N-(1,1'-DIHYDROXY-1-P-NITROPHENYLISOPROPYL)DICHLOROACETAMIDE; *ENTEROMYCETIN-; *FARMICETINA-; *GLOBENICOL-; *ISMICETINA-; *KEMICETINE-; *KLOROCID-S-; *LEUKOMYAN-; *LEUKOMYCIN-; *LEVOMICETINA-; *MICLORETIN-; *NOVOMYCETIN-; *OPHTHOCHLOR-; *PARAXIN-; *QUEMICETINA-; *SINTOMICETINA-; *SYNTHOMYCETINE-; *TEVCOCIN-; *TIFOMYCINE-; *TREOMICETINA-; *UNIMYCETIN- RN: 56-75-7 MF: *C11-H12-Cl2-N2-05 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CHLORAMPHENICOL CAN BE OBTAINED FROM THE FILTRATE OF A STREPTOMYCES VENEZUELAE CULTURE BY EXTRACTION WITH ETHYL ACETATE. IF THE CHARCOAL EXTRACT IS RICH IN CHLORAMPHENICOL, THE LATTER CAN BE CRYSTALLIZED FROM THE ETHYL ACETATE BY DILUTING WITH MANY VOLUMES OF KEROSENE. [R1] *Chloramphenicol can be isolated from Streptomyces venezuelae in soil. [R2] *Chloramphenicol can be synthesized by condensation of para-nitrobenzoyl chloride with ethyl malonate to give para-nitroacetophenone, followed by bromination in acetic acid to form para-nitro-alpha-bromoacetophenone, and reaction of this with hexamethylene tetramine, followed by hydrolysis to give para-nitro-alpha-aminoacetophenone; subsequent acetylation of the amine group and condensation with formaldehyde gives a hydroxymethyl group alpha to the amine group. Treatment with aluminium isopropylate reduces the keto group to a secondary alcohol, and, after deacetylation, condensation of the amine group with methyl dichloroacetate give chloramphenicol ... Chemical syntheses of chloramphenicol usually include a resolution step to separate stereoisomers. [R3] *During the 1960s and 1970s: addition of benzaldehyde to beta-nitroethanol to yield 2-nitro-1-phenyl-1,3-propanediol, reduction to the aminodiol, swing resolution, subsequent nitration, and dichloroacetylation to create chloramphenicol. [R4] *In Western Europe: cinnamyl alcohol converted to its bromohydrin, then to the bromodioxane, reaction with ammonia to the aminodioxane which is resolved, acylated to the dichloroacetamido, nitrated, and gently hydrolyzed to chloramphenicol. [R4] *In Eastern Europe: p-nitrobenzaldehyde is condensed with glycine to obtain the Schiff's base, cleavage followed by esterification gives the D,L-p-nitrophenyl serine methyl ester which is resolved with D-tartaric acid and the ester of the correct configuration reduced by sodium or calcium borohydride to the desired p-nitrophenyl serinol to form chloramphenicol. [R4] FORM: *Chloramphenicol is often formulated as the cinnamate, palmitate (1.7 g equivalent to 1.0 g chloramphenicol) or sodium succinate salt ... . Preparations are available as capsules (50, 100 and 250 mg; USP grade contains 90-120% of the labelled amt of ai), ear drops (soln in propylene glycol), eye drops (0.5% soln or sterile, dry mixture of chloramphenicol and suitable buffers containing 90-130% of the labelled amt of chloramphenicol ... ); and as the palmitate in a suspension for oral administration (USP 5 ml, 30 mg/ml, containing 90-120% of the labelled amt of ai) and the succinate in vials of 1 g for injection (USP grade containing 90-115% of the labelled amt of ai). [R3] MFS: *INTERNATIONAL RECTIFIER CORP, RACHELLE LABS, INC, SUBSID, LONG BEACH, CA 90801 [R5] OMIN: *THE ANTIBIOTIC IS UNIQUE AMONG NATURAL COMPD IN THAT IT CONTAINS NITROBENZENE MOIETY AND IS A DERIVATIVE OF DICHLOROACETIC ACID. [R6, 1191] USE: +MEDICATION +MEDICATION (VET) CPAT: *ESSENTIALLY 100% AS AN ANTIBIOTIC [R5] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 9.08X10+5 G [R5] *(1979) PROBABLY GREATER THAN 9.08X10+5 G [R5] U.S. IMPORTS: *(1977) 8.15X10+6 G (PRINCPL CUSTMS DISTS) [R5] *(1979) 8.20X10+6 G (PRINCPL CUSTMS DISTS) [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW PLATES OR NEEDLES FROM WATER [R7]; *White to greyish-white or yellowish-white fine crystalline powder or fine crystals, needles or elongated plates. Of the four possible stereoisomers, only the alphaR,betaR (or D-threo) form is active ... . [R8] TAST: *BITTER TO TASTE [R9] MP: *150.5-151.5 DEG C [R10] MW: *323.14 [R10] PH: *NEUTRAL TO LITMUS [R11] SOL: *SOL: 2.5 MG/ML OF WATER @ 25 DEG C, 150.8 MG/ML OF PROPYLENE GLYCOL, ABOUT 5% IN 50% ACETAMIDE SOLN ; VERY SOL IN METHANOL, ETHANOL, BUTANOL, ETHYL ACETATE, ACETONE; FAIRLY SOL IN ETHER; INSOL IN BENZENE, PETROLEUM ETHER, VEGETABLE OILS [R10]; *SOL IN CHLOROFORM [R12] SPEC: *SPECIFIC OPTICAL ROTATION: +19 DEG @ 25 DEG C/D (ALCOHOL, 5%); -25.5 DEG @ 25 DEG C/D (ETHYL ACETATE); MAX ABSORPTION: 278 NM (LOG E= 3.99) [R7]; *IR: 2:939D (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R13]; *NMR: 7:71A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R13]; *MASS: 4899 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R13] VAP: *Vapor pressure: 1.73X10-12 mm Hg (est) [R14] OCPP: *SUBLIMES IN HIGH VACUUM [R10] *Water solubility: 3.75X10+3 mg/l(expt) [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R16, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R16, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R16, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R16, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R16, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R16, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R16, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R16, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R16, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R16, 1979.11] SSL: *NEUTRAL AND ACID SOLN ARE STABLE ON HEATING [R17] *SENSITIVE TO LIGHT [R18] *Stable in the solid state as a bulk drug and when present in solid dosage forms. Reasonable precautions taken to prevent excessive exposure to light or moisture are adequate to prevent significant decomposition over an extended period. [R8] *In soln, chloramphenicol undergoes a number of degradative changes related to pH, temperature, photolysis and microbiological effects. [R8] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R16, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R16, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R16, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R16, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R16, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R16, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R16, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R16, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R16, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is limited evidence for the carcinogenicity of chloramphenicol in humans. There is inadequate evidence for the carcinogenicity of chloramphenicol in experimental animals. The Working Group also took note of the following information. Chloramphenicol induces aplastic anemia, and this condition is related to the occurrence of leukemia. Overall Evaluation: Chloramphenicol is probably carcinogenic to humans (Group 2A). [R19] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R16, 1979.23] HTOX: *HYPERSENSITIVITY REACTIONS /MAY INCL/...FEVER...ANGIOEDEMA... HERXHEIMER REACTIONS HAVE BEEN OBSERVED SHORTLY AFTER INSTITUTION OF...THERAPY... [R6, 1193] *...THREE NEWBORN INFANTS...DIED OF "CARDIOVASCULAR COLLAPSE" AFTER RECEIVING DAILY DOSES...OF ABOUT 200 MG/KG OF BODY WT. ..."GRAY SYNDROME" USUALLY BEGINS 2-9 DAYS (AVERAGE, 4 DAYS) AFTER TREATMENT IS STARTED. ... DEATH OCCURS IN ABOUT 40% OF PT, MOST FREQUENTLY ON FIFTH DAY OF LIFE. [R6, 1194] *AMONG RARE TOXIC EFFECTS PRODUCED...ARE BLURRING OF VISION AND DIGITAL PARESTHESIAS. OPTIC NEURITIS OCCURS IN 3-5% OF CHILDREN WITH MUCOVISCIDOSIS WHO ARE GIVEN CHLORAMPHENICOL; THERE IS SYMMETRICAL LOSS OF GANGLION CELLS FROM RETINA AND ATROPHY OF FIBERS IN OPTIC NERVE. [R6, 1194] *...5-YEAR OLD BOY...DIED OF ACUTE MYELOBLASTIC LEUKEMIA FOLLOWING 1-YR HISTORY OF APLASTIC ANEMIA AFTER ADMIN OF CHLORAMPHENICOL. ...MAN AGED 63 WHO RECEIVED 12 G...DEVELOPED MARROW DEPRESSION 4 MO LATER, WHICH WAS FOLLOWED AFTER 3 MO BY ACUTE MYELOBLASTIC LEUKEMIA. [R20, p. V10 92] *PERMANENT VISUAL LOSS AND OPTIC ATROPHY FOLLOWING IRRIGATION OF LOWER CANALICULUS AFTER PROBING, WITH 20% SOLN OF CHLORAMPHENICOL. [R21] */Chloramphenicol/ ... inhibited DNA synthesis in human lymphoblastoid cell lines ... DNA strand breaks were induced in human lymphocytes by chloramphenicol at 2.0 mM ... but not at 0.8 mM in a human lymphoblastoid cell line, in human lymphocytes or in human bone-marrow cells ... . [R22] */Chloramphenicol did not induce sister chromatid exchange/ ... in human leukocytes ... When human white blood cells were treated with low concentrations (10-40 ug/ml) of chloramphenicol, a concentration-dependent increase in the number of cells with chromosomal aberrations was observed ... Chloramphenicol did not induce chromosomal aberrations in human lymphocytes ... or in human fibroblasts ... . [R22] *There have been many case reports of the occurrence of aplastic anemia following administration of chloramphenicol by various routes ... In many of these cases, large doses had been taken repeatedly over periods of many years before the onset of symptoms of aplastic anemia. Case-control studies have also suggested an association between chloramphenicol use and aplastic anaemia ... . [R23] *... Drug intake and pregnancy outcome were studied in a series of 50,282 women in 1959-65, 98 women had been exposed to chloramphenicol during the first trimester of pregnancy. There were 8 malformed children in the exposed group, giving a nonsignificant standardized relative risk (RR) of 1.17. A total of 348 women had had exposure at any time during pregnancy with no evidence of an increase in the incidence of congenital malformations ... . [R23] *No adverse effect was reported in the children of 22 patients treated at various stages of pregnancy with chloramphenicol ... . [R23] *Numerous case reports have been published of leukemia occurring following chloramphenicol-induced aplastic anaemia ... three case reports have been published of leukemia following chloramphenicol therapy in the absence of interceding aplastic anemia ... . [R23] *... A case-control study of 309 childhood leukemia cases (under 15 years) notified to a population-based cancer registry in Shanghai, China, during 1974-86, and 618 age-and sex-matched population controls /has been reported/. Information was obtained from parents or guardians for lifetime use of selected drugs, including prescribed chloramphenicol and syntomycin (a racemic mixture of D- and L-chloramphenicol). The risk for all types of leukemia combined showed a marked increase with accumulated use of chloramphenicol, yielding RRs of 1.7 (95% confidence interval, 1.2-2.5), 2.8 (1.5-5.1) and 9.7 (3.9-24.1) for 1-5 days, 6-10 days and > 10 days treatment, respectively. The association was present in a subgroup in which first use had occurred more than 5 yr prior to diagnosis and in one in which last use had been more than 2 yr before diagnosis. significant trends in risk with dose were observed both for acute lymphocytic leukemia (56% of cases) and for acute nonlymphocytic leukemia (30%). An association with leukemia was also seen for use of syntomycin (RR, 1.9; 1.1-3.2). (The Working Group noted that interview was undertaken up to 10 yr after diagnosis, which adds to the possibility of differential recall between the parents of cases and controls. Little info was available with regard to use of other antibiotics, making it difficult to evaluate the possibility of bias.) [R24] NTOX: *...FAILED TO INDUCE ANY EMBRYOTOXIC OR TERATOGENIC EFFECTS IN OFFSPRING WHEN GIVEN BY STOMACH TUBE TO RATS ON THIRD AND SIXTH DAY OF PREGNANCY. ON 9TH-11TH DAYS OF GESTATION SAME DOSE CAUSED MALFORMATIONS WHICH INCL HYDROCEPHALY AND CLEFT PALATE... /NO INFORMATION ON CONTROLS GIVEN IN TEXT/ [R25] *THREE GROUPS OF 10 3-MO-OLD SWISS MICE WERE GIVEN DAILY IP INJECTIONS OF 20, 40 OR 100 MG/KG BODY WT CHLORAMPHENICOL FOR 3 MO. DURING 2ND MO, GROUPS GIVEN 40 and 100 MG/KG BODY WT DEVELOPED SPLENOMEGALY, HEPATOMEGALY, ADENOPATHY AND HYPERTROPHY OF THYMUS. THESE...NOT FOUND IN ANIMALS RECEIVING LOWEST DOSE UNTIL AFTER 3RD MO... /NO INFORMATION ON CONTROLS GIVEN IN TEXT/ [R26] *IN CHICK EMBRYOS CHLORAMPHENICOL INHIBITS PROTEIN SYNTHESIS AND GROWTH BUT ONLY INFREQUENT DEFECTS OF THE SPLANCHNOPLEURE AND NEURAL TUBE HAVE BEEN REPORTED. GENERALIZED EDEMA WAS FOUND IN THE RAT IN 12 TO 71% OF FETUSES WHOSE MOTHERS RECEIVED 2 TO 4% CHLORAMPHENICOL IN THE DIET DURING THE LATTER HALF OF GESTATION. [R27] *... Groups of 50 male and 50 female BALB/c mice, 6 wk of age, were administered chloramphenicol (purity unspecified) at 0, 500 or 2000 mg/l in drinking water for 104 wk ... The incidences of lymphomas in mice of each sex (combined) were 3% in controls, 6% in low-dose animals and 12% in high-dose animals (p < 0.05). The incidences of other types of tumor were similar in treated and control animals ... . [R28] *... Groups of 50 male and 50 female C57B1/6N mice, 6 wk of age, were administered chloramphenicol (purity unspecified) at 0, 500 or 2000 mg/l in drinking water for 104 wk ... The incidences of lymphomas in mice of each sex (combined) were 8% in controls, 22% in low-dose animals (p < 0.05) and 23% in high-dose animals (p < 0.01). The incidences of malignant liver-cell tumors in mice of each sex (combined) were: control, 0; low-dose, 2/90; and high-dose, 11/91 (p < 0.01) ... . [R28] *Two groups of 45 male BALB/c x AF1 mice, 6-8 wk of age, received four intraperitoneal injections of 0.25 ml acetone in distilled water. After a 20 wk rest period, one group received daily intraperitoneal injections of chloramphenicol (purity unspecified) at 0.25 ml (2.5 mg) in 0.9% saline soln on 5 days/wk for 5 wk. The mice were killed on day 350. Controls received injections of saline soln only. No increase in the incidence of tumors was observed ... . [R28] *Two groups of 45 male BALB/c x AF1 mice, 6-8 wk of age, received intraperitoneal injections every 2 wk of four doses of 0.5 mg busulfan (1,4-butanediol dimethanesulfonate) /known carcinogen/ in 0.25 ml acetone. After a 20-wk rest period (on day 183 of the experiment), one group received chloramphenicol (purity unspecified) at 2.5 mg on 5 days/wk for 5 wk. On day 350 of the experiment, all surviving mice were killed. The incidence of lymphomas was 13/37 in the combined treatment group compared with 4/35 in a group treated with busulfan alone (p=0.02, Fisher's exact test) ... . [R28] *After three groups of ten 3-month old Swiss mice were given daily intraperitoneal injections of chloramphenicol at 20, 40 or 100 mg/kg bw for 3 months, splenomegaly, hepatomegaly, lymph adenopathy and hypertrophy of the thymus occurred in a dose-dependent fashion ... . [R29] *Chloramphenicol caused decreased entry into S-phase in dividing bone-marrow cells of mice treated in vivo ... . The drug had a deleterious effect on bone marrow recovery in mice after X-irradiation ... and after busulfan treatment in one study ... but not another ... . Bone marrow damage has been described in cats and dogs after 14-21 days treatment with chloramphenicol ... . Effects included vacuolation of the myeloid and erythroid precursors and bone marrow hypoplasia in cats, and suppression of erythropoiesis and a reduced rate of granulocyte formation but not bone marrow vacuolation in dogs. [R29] *Chloramphenicol caused dose related inhibition of erythroid and granulocytic colony forming units obtained from LAF1 mice ... . [R29] *Chloramphenicol and nitrosochloramphenicol inhibited DNA synthesis in rat bone marrow cells in vitro. This effect was reversible with chloramphenicol but not with the nitroso cmpd. Similarly, the nitroso cmpd but not chloramphenicol bound irreversibly to bone marrow cells ... . In another study in vitro, chloramphenicol and nitrosochloramphenicol had no effect on mouse hematopoietic precursor cells ... . [R29] *In vitro, chloramphenicol inhibited mitocondrial protein synthesis in rat liver and rabbit bone marrow ... . Nitrosochloramphenicol inhibited rat mitochondrial DNA polymerase in vitro, whereas the arylamine derivative and chloramphenicol itself did not ... . [R29] *High oral doses of chloramphenicol of 500-2000 mg/kg to rats and mice and of 500 and 1000 mg/kg to rabbits produced high incidences of embryonic and fetal deaths and fetal growth retardation in all three species. Teratogenic effects, predominantly umbilical hernia, were observed only in rats. The pregnant animals showed no toxic sign, except that those given the highest dose gained significantly less weight than controls ... . [R30] *Groups of eight pregnant albino mice were given chloramphenicol orally at 25, 50, 100, or 200 mg/kg bw in 10 ml distilled water over the third stage of pregnancy for 7 days. Animals were allowed to give birth, and the young were tested for conditioned avoidance response, electroshock seizure threshold and performance in open-field tests. Dose related effects were seen in all three elements of the test: progeny of chloramphenicol-treated dams had reduced learning ability, higher brain seizure threshold and poorer performance in the open-field test ... . [R30] *Four groups of 15 pregnant Wistar rats each were treated as follows: chloramphenicol was given subcutaneously at 50 mg/kg bw on days 7-21 of gestation; chloramphenicol gas given subcutaneously at 50 and 100 mg/kg bw to pups for the first 3 days after birth; and the fourth group served as controls. No adverse effect on pregnancy or postnatal weight gain was seen, but when the animals were 60 days old, they had significant impairment of avoidance learning ... . [R30] *Chloramphenicol did not induce lysogenic phage in Staphylococcus aureus ... It did not induce differential toxicity in Escherichia coli ... . Salmonella typhimurium ... Proteus mirabilis ... or Bacillus subtilis ... although a contradictory positive result was obtained in the rec assay with E. coli ... Chloramphenicol gave negative results in the SOS chromotest in E. coli ... . It induced breaks in DNA of E. coli B/r and S. typhimurium TA1976 ... It did not induce mutations in E. coli ... and was not mutagenic in plate incorporation assays with S. typhimurium in the presence or absence of an exogenous metabolic system ... . In a liquid pre-incubation assay, chloramphenicol did not induce reversions in E. coli; it did, however, induce forward mutations to azetidine-2-carboxylic acid resistance in the same bacterial strain. In the same assay system, chloramphenicol was weakly mutagenic to Salmonella typhimurium TA98 in the presence or absence of an exogenous metabolic system ... . [R30] *Chloramphenicol induced petite mutations in haploid strains of Saccharomyces cerevisiae ... but not in diploid strains ... . [R22] *Treatment of Arabidopsis seeds with chloramphenicol did not induce lethal mutations ... . Chloramphenicol induced chromosome breakage in root-tip meristem cells of germinating barley ... and Vicia faba seeds ... It did not induce mironuclei in pollen tetrads of Tradescantia paludosa ... . [R22] *Chloramphenicol did not induce sex-linked recessive lethal mutations in Drosophila melanogaster treated either by injection ... or by feeding ... . [R22] */Chloramphenicol/ ... inhibited DNA synthesis ... in rat bone-marrow cells ... and in mouse Ehrlich ascites cells ... . Chloramphenicol did not induce unscheduled DNA synthesis in Syrian hamster embryo cells in the presence or absence of an exogenous metabolic system ... . [R22] */Chloramphenicol/ ... induced mutations at the tk locus of L5178Y mouse lymphoma cells in the presence and absence of an exogenous metabolic system ... . It induced sister chromatid exchange in Syrian hamster embryo cells ... . [R22] *No morphological transformation was observed in Syrian hamster embryo cells after treatment with chloramphenicol at 100-1000 ug/ml ... . Chloramphenicol did not reproducibly enhance the transformation of Syrian hamster embryo cells by simian adenovirus SA7 ... . [R22] *Subcutaneous injections to C57B1/10 mice of chloramphenicol at 320 mg/kg bw three times daily for 3 days led to inhibition of thymidine incorporation in bone-marrow cells ... . Intramuscular injection of chloramphenicol (three times 1000 mg/kg bw) to Wistar rats did not induce chromosomal aberrations in bone-marrow cells ... . At 50 mg/kg bw, the drug induced chromosomal aberrations in bone-marrow cells of mice ... . Intramuscular injection of chloramphenicol at 50 mg/kg to Swiss albino mice ... induced chromosomal aberra tions in mitotic and meiotic germ line cells ... . [R31] *Chloramphenicol did not induce dominant lethal mutations in mice when given twice at up to 15,000 mg/kg intraperitoneally ... but did when given at 500 mg/kg bw ... . [R31] NTXV: *The intravenous and intraperitoneal LD50s for single doses of chloramphenicol in albino mice were 200 and 1320 mg/kg bw, respectively. The intravenous LD50 in rats was 170 mg/kg bw; [R29] ADE: *...COMPARATIVE STUDIES OF PERCUTANEOUS ABSORPTION OF VARIOUS COMPD THROUGH HUMAN SKIN (FOREARM).../INDICATE/ CHLORAMPHENICOL...WAS LOW. [R32] *...RAPIDLY ABSORBED FROM GASTROINTESTINAL TRACT AND PEAK VALUES ARE REACHED IN PLASMA IN 2 HR. ... WHEN CONCENTRATION OF CHLORAMPHENICOL IN BLOOD IS AT ITS PEAK VALUE ABOUT 50% OF THE DRUG IS BOUND TO ALBUMIN. [R6, 1192] *UNALTERED ANTIBIOTIC IS ELIMINATED MAINLY BY GLOMERULAR FILTRATION; INACTIVE DEGRADATION PRODUCTS ARE ELIMINATED PRIMARILY BY TUBULAR SECRETION. [R6, 1193] *In dogs, chloramphenicol was readily absorbed after oral administration of 50 mg/kg bw, giving plasma levels of 16.5 ug/ml 2 hr after dosing ... . Similar finding were made in rabbits ... . [R33] *Five minutes after intravenous administration of 14C-chloramphenicol to newborn pigs at 0.52 mg/kg bw, most tissues had higher levels of 14C label than the blood; however, levels of chloramphenicol in bone marrow did not reach those noted in serum ... . [R33] *Chloramphenicol and its metabolites were excreted in the urine of rats after oral dosing; up to 70% of an oral dose may be excreted in this way ... . About 0.4% of an intramuscular dose of 40 mg/kg to rats was detected in the bile within 4 hr ... . In newborn pigs, most of an intravenous dose of chloramphenicol was excreted in the urine ... . Following intravenous administration to goats, 69% of the dose was excreted in the urine within 12 hr ... . [R33] *Chloramphenicol was detected in the milk of goats and cattle after parenteral administration ... ; however, after oral administration [dose unspecified] to cattle, no chloramphenicol was detected in milk ... . [R33] *Chloramphenicol is readily absorbed from the gastrointestinal tract after oral administration of a crystalline powder of the active drug itself or a palmitate ester; the latter is hydrolysed in the small intestine to active chloramphenicol before absorption ... . Peak levels of 10-20 ug/ml appear 2-3 hr after administration of chloramphenicol orally at 15 mg/kg bw ... . [R31] *Chloramphenicol is also well absorbed by infants and neonates after oral administration. Serum (peak) concentrations of 20-24 ug/ml were noted after oral doses of 40 mg/kg bw to neonates. Infants given 26 mg/kg bw were found to have peak concentrations of 14 ug/ml ... . [R31] *Chloramphenicol is distributed extensively in humans, regardless of its route of administration. The cmpd has been found in heart, lung, kidney, liver, spleen, pleural fluid, seminal fluid, ascitic fluid and saliva ... . It penetrates the blood-brain barrier, and its concentrations in cerebrospinal fluid can reach about 60% of that in plasma ... . The concentrations in brain tissue equal or even exceed those in plasma ... . Chloramphenicol easily crosses the placenta, and it is also excreted in breast milk ... . [R31] *Chloramphenicol is excreted primarily in the urine (90%); up to 15% is excreted as the parent cmpd and the remainder as metabolites, including conjugated derivatives ... . Glomerular excretion is thought to be the major mechanism of excretion ... . [R34] METB: *YIELDS D-THREO-2-AMINO-1-(P-NITROPHENYL)-1,3-PROPANEDIOL AND CHLORAMPHENICOL-BETA-D-GLUCURONIDE IN MAN. IN RAT. /FROM TABLE/ [R35] *CHLORAMPHENICOL IS INACTIVATED PRIMARILY IN LIVER BY GLUCURONYL TRANSFERASE ... . [R6, 1193] *.../UNDERGOES/ DIRECT CONJUGATION. FORMATION OF GLUCURONIDE WAS SHOWN TO OCCUR AT PRIMARY RATHER THAN AT SECONDARY ALCOHOLIC GROUP... IT IS MAJOR REACTION OF INACTIVATION AND DETOXICATION OF DRUG IN MAN, AND ANY FACTOR WHICH DECR ITS IMPORTANCE...RESULTS IN GREATLY INCR TOXICITY. ...IN NEWBORN...BILIRUBIN...ACTS AS COMPETITIVE ENDOGENOUS ACCEPTOR. [R36, 191] *CHLORAMPHENICOL 3-GLUCURONIDE WAS THE MAJOR METABOLITE OF CHLORAMPHENICOL PRODUCED BY ISOLATED RAT HEPATOCYTES ALTHOUGH A MINOR METABOLITE WAS ALSO FORMED. [R37] *In addition to free chloramphenicol and the glucuronide, the oxamic acid, alcohol, base, acetylarylamine and arylamine metabolites have been found in the urine of rats given intramuscular doses of 3H-chloramphenicol (the 1R,2R-isomer). On the basis of recovered radioactivity, the major metabolites were assumed to be chloramphenicol base (approx 26%) and the acetylarylamine derivative (approx 20%) ... . [R33] *In dogs, chloramphenicol base and chloramphenicol glucuronide conjugate were reported to be the major metabolites ... . Chloramphenicol, the glucuronide conjugate and the oxamic acid, acetylarylamine, arylamine and base derivatives were found in the urine of goats given intramuscular injections of chloramphenicol ... . [R33] *The glucuronide is the main metabolic product in isolated rat heptocytes exposed to chloramphenicol ... . A study using perfused rat liver and rat liver microsomes indicated that the arylamine derivative may undergo N-oxidation to form nitrosochloramphenicol ... . [R33] *Approximately 48% of the chloramphenicol excreted in /human/ urine within 8 hr of an oral dosing was the glucuronide conjugate; only 6% was excreted as the parent cmpd and 4% as the base derivative ... . The alcohol derivative has been detected in the urine of neonates ... . [R34] *Human liver microsomes have been shown to reduce the nitro group of chloramphenicol ... . [R34] *Chloramphenicol arylamide is formed by intestinal bacterial reduction of the NO2 groups to NH2, which is acetylated and excreted in urine ... Oxamic acid (formed by oxidative dechlorination of the side chain) was identified as a major metabolite in one human volunteer ... . [R34] *Metabolites of chloramphenicol, such as dehydrochloramphenicol, produced by intestinal bacteria, are more than 20-fold more cytotoxic than the parent drug ... . [R23] BHL: *Chloramphenicol has a half-time /in humnas/ ranging from 1.6 to 4.6 hr; using different techniques and in different adult patients, apparent volumes of distribution ranging from 0.2 to 3.1 l/kg have been measured ... . The half-time is considerably longer in neonates ... in 1- to 8-day-old infants the half-life ranged from 10 to over 48 hr, and in 11-day to 8-wk-old infants the range was 5-16 hr ... . [R31] ACTN: *CHLORAMPHENICOL INHIBITS PROTEIN SYNTHESIS IN BACTERIA AND, TO A LESSER EXTENT, IN EUKARYOTIC CELLS. THE DRUG READILY PENETRATES INTO BACTERIAL CELLS, PROBABLY BY A PROCESS OF FACILITATED DIFFUSION. CHLORAMPHENICOL ACTS PRIMARILY BY BINDING REVERSIBLY TO THE 50 S RIBOSOMAL SUBUNIT (NEAR THE SITE OF ACTION OF THE MACROLIDE ANTIBIOTICS AND CLINDAMYCIN). THIS PREVENTS THE BINDING OF THE AMINO ACID-CONTAINING END OF AMINOACYL T-RNA TO ONE OF ITS BINDING SITES ON THE RIBOSOME. [R6, 1192] *CHLORAMPHENICOL CAN ALSO INHIBIT MITOCHONDRIAL PROTEIN SYNTHESIS IN MAMMALIAN CELLS, PERHAPS BECAUSE MITOCHONDRIAL RIBOSOMES RESEMBLE BACTERIAL RIBOSOMES (BOTH ARE 70 S) MORE THAN THEY DO THE 80 S CYTOPLASMIC RIBOSOMES OF MAMMALIAN CELLS. ... MAMMALIAN ERYTHROPOIETIC CELLS SEEM TO BE PARTICULARLY SENSITIVE TO THE DRUG. [R6, 1192] *MAIN EFFECT ON RETICULOCYTES IS INHIBITION OF CONVERSION OF POLYSOMES TO SINGLE RIBOSOMES AND DECR IN CONTENT OF ADENOSINE TRIPHOSPHATE. SYNTH OF BOTH RNA AND PROTEIN IS INHIBITED. IT IS ALSO CLEAR THAT CHLORAMPHENICOL CAN INHIBIT MITOCHONDRIAL PROTEIN SYNTH IN HIGHER CELLS... [R38, 1195] *WHEN CHLORAMPHENICOL IS GIVEN IN LARGE DOSES BY ORAL ROUTE, CHANGES IN INTESTINAL FLORA MAY BE RESPONSIBLE...FOR DECR IN PLASMA PROTHROMBIN LEVELS AND DECR IN URINE UROBILINOGEN. .../IT/ CAN SUPPRESS ANTIBODY SYNTHESIS...WITHOUT ALTERING NORMAL ANAMNESTIC RESPONSE, AND IT CAN PROLONG HOMOGRAFT SURVIVAL IN ANIMALS... [R38, 1197] INTC: *CHLORAMPHENICOL-TREATED PT MAY RESPOND POORLY TO CYANOCOBALAMIN THERAPY SINCE CHLORAMPHENICOL INTERFERES WITH ERYTHROCYTE MATURATION. [R39] *THE EFFECT OF 48 MG/KG/DAY CHLORAMPHENICOL (I) ON THE SERUM CONCENTRATIONS OF PHENYTOIN (II) AND PHENOBARBITAL (III) WAS STUDIED IN A PATIENT PREVIOUSLY STABILIZED ON ANTICONVULSANT MEDICATIONS. II, 12 UG/KG/DAY, AND III, 5 MG/KG/DAY RESULTED IN SERUM CONCENTRATIONS AVERAGING 10.8 UG/ML BEFORE AND 30.5 UG/ML AFTER THERAPY. A REDUCTION IN DOSE OF BOTH II AND III WAS REQUIRED TO MINIMIZE ADVERSE EFFECTS DURING THE COURSE OF I THERAPY. IT WAS CONCLUDED THAT I INHIBITS THE METABOLISM OF II AND III. [R40] *Pretreatment of rats with chloramphenicol (100 mg/kg, ip) 30 min prior to a single oral LD50 dose of malathion at 340 mg/kg completely protected against malathion induced inhibition of cholinesterase. It appears that the inhibition of malathion toxicity by chloramphenicol pretreatment is attributable to inhibition by chloramphenicol of the metabolic activation of malathion to malaoxon. [R41] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antibiotics; Protein Synthesis Inhibitors [R42] *...FOR TREATMENT OF RICKETTSIAL DISEASES...IN PT SENSITIZED TO... /TETRACYCLINES/ AND IN THOSE WITH REDUCED RENAL FUNCTION, IN PREGNANT WOMEN...CHLORAMPHENICOL IS DRUG OF CHOICE. DRAMATIC EFFECT OF CHLORAMPHENICOL IN RICKETTSIAL INFECTIONS HAS BEEN DEMONSTRATED... [R6, 1196] *THE EFFECT OF AMPICILLIN (I) AND CHLORAMPHENICOL (II) WERE STUDIED IN 21 STRAINS OF HAEMOPHILUS INFLUENZAE TYPE B ISOLATED FROM CSF OF PATIENTS WITH MENINGITIS. EIGHT OF THE 21 STRAINS WERE I RESISTANT, BUT ALL STRAINS WERE SUSCEPTIBLE TO II. I AND II MAY BE SYNERGISTIC AGAINST A SIGNIFICANT NUMBER OF H INFLUENZAE STRAINS DEPENDING ON INOCULUM SIZE, BUT THE EFFECT IS UNPREDICTABLE FOR A GIVEN ISOLATE. THESE DATA SUPPORT THE RECOMMENDATION THAT I AND II BOTH BE USED AS INITIAL THERAPY FOR PATIENTS WITH SUSPECTED BACTERIAL MENINGITIS. [R43] *THERAPEUTIC CONCENTRATIONS OF CHLORAMPHENICOL WILL BE ACHIEVED IN SERUM AND CEREBROSPINAL FLUID WITH DAILY DOSES OF 25 MG/KG IN PRETERM AND TERM INFANTS DURING THE FIRST WEEK OF LIFE AND 37.5-50 MG/KG FOR OLDER TERM BABIES. THE DRUG SHOULD BE ASSAYED AT 48-HOUR INTERVALS, TO MAINTAIN CONCENTRATIONS IN THE THERAPEUTIC, NON-TOXIC RANGE. [R44] *Chloramphenicol is an antibiotic produced by Streptomyces venezuelae ... recommended for serous infections in which the location of the infection, susceptibility of the pathogen or poor response to other therapy indicate restricted antimicrobial option. It has been used since the 1950s for a wide range of microbial infections, including typhoid fever and other forms of salmonellosis, and central nervous system, anaerobic and ocular infections ... . [R3] *In certain indications, eg cystic fibrosis, treatment has been continued for years ... . [R2] +ANTIBACTERIAL; ANTIRICKETTSIAL; MEDICATION (VET): ANTIMICROBIAL AGENT [R10] +ANTIFUNGAL AGENT [R9] +Chloramphenicol is believed to have been widely used as a veterinary antibiotic, despite legal controls in many countries, and there have been a few reports of residual amt in various animal products ... . In countries in which its veterinary use is permitted, food regulations require withdrawal periods so as to avoid residues in the final product ... . [R2] WARN: *MAY HAVE DELETERIOUS AND DANGEROUS SIDE EFFECTS. MUST CONFORM TO FDA LABELLING REQUIREMENTS; USE IS CLOSELY RESTRICTED. [R11] *...DRUG SHOULD NEVER BE EMPLOYED IN DISEASES...TREATABLE WITH OTHER ANTIMICROBIAL AGENTS... 2) REPEATED COURSES OF DRUG MUST BE AVOIDED IF...POSSIBLE, 3) PATIENT...MUST BE SEEN FREQUENTLY...FOR BLOOD STUDIES, AND THERAPY...STOPPED...IF BONE-MARROW EFFECTS BECOME APPARENT... 4) PATIENT MUST REPORT...SYMPTOM...OF NEW /INFECTION/. [R38, 1196] *PRODUCES CHANGES IN NUMBERS AND TYPES OF MICROORGANISMS...OF ALIMENTARY, RESPIRATORY, AND GENITAL TRACTS. ...THIS MAY LEAD TO SUPRAINFECTION BY BACTERIA...AND FUNGI... OROPHARYNGEAL CANDIDIASIS AND ACUTE STAPHYLOCOCCAL ENTEROCOLITIS MAY DEVELOP. ...CHLORAMPHENICOL THERAPY...STOPPED, and ...CHEMOTHERAPY FOR SUPRAINFECTION.../BEGUN/. [R38, 1197] *...CAUSED OPTIC NEURITIS IN SEVERAL CASES... IMPAIRMENT OF CENTRAL VISION HAS BEEN A PROMINENT FEATURE. ...INJURIES OF OPTIC NERVE AND PERIPHERAL NERVES HAD BEEN ASSOCIATED IN NEARLY ALL CASES WITH ADMIN OF CHLORAMPHENICOL AT HIGH DOSAGE FOR LONG TIME. [R45] *RESISTANCE...DUE TO PRESENCE OF SPECIFIC ACETYL-TRANSFERASE, WHICH INACTIVATES DRUG BY USING ACETYL COENZYME A AS DONOR OF ACETYL GROUP. RESISTANCE OF STAPHYLOCOCCI...HAS ALSO INCR IN INCIDENCE... RESISTANT STAPH AUREUS CONTAINS INDUCIBLE FORM OF CHLORAMPHENICOL ACETYL-TRANSFERASE. [R6, 1192] *AMONG 487 PT WITH APLASTIC ANEMIA...INCIDENCE OF BLOOD DISORDERS AFTER CHLORAMPHENICOL THERAPY...WAS HIGHER IN FEMALES (1.6:1, FEMALES:MALES)... MORE RECENT DATA SUGGEST THAT RISK /OF DISORDERS/ IS CONSIDERABLY GREATER: IN ORDER OF 1 IN 40,800 TO 1 IN 24,500... [R20, p. V10 91] *ALTHOUGH THE RATE AT WHICH CHLORAMPHENICOL IS CONJUGATED WITH GLUCURONIC ACID MAY BE REDUCED IN INDIVIDUALS WITH HEPATIC INSUFFICIENCY, THE OVERALL METABOLISM OF THE DRUG IS ESSENTIALLY NORMAL. HOWEVER, THE ADMINISTRATION OF THE DRUG IN THE PRESENCE OF HEPATIC DISEASE FREQUENTLY RESULTS IN DEPRESSION OF ERYTHROPOIESIS; THIS IS MOST INTENSE WHEN ASCITES AND JAUNDICE ARE PRESENT. ABOUT ONE THIRD OF PATIENTS WITH RENAL INSUFFICIENCY EXHIBIT THE SAME REACTION. [R6, 1194] *...MECHANISMS...RESPONSIBLE FOR...TOXIC EFFECT IN NEONATES: 1) FAILURE OF DRUG TO BE CONJUGATED WITH GLUCURONIC ACID, DUE TO INADEQUATE ACTIVITY OF GLUCURONYL TRANSFERASE IN LIVER WHICH IS CHARACTERISTIC OF FIRST 3-4 WK OF LIFE; 2) INADEQUATE RENAL EXCRETION OF UNCONJUGATED DRUG IN NEWBORN BECAUSE TUBULAR SECRETION...IS UNDERDEVELOPED... [R6, 1194] *RESISTANCE OF GRAM-POSITIVE AND GRAM-NEGATIVE ORGANISMS TO CHLORAMPHENICOL IN VIVO IS PROBLEM OF INCR CLINICAL IMPORTANCE. RESISTANCE OF GRAM-NEGATIVE BACTERIA...IS DUE TO...SPECIFIC RESISTANCE (R) FACTOR ACQUIRED BY CONJUGATION. RESISTANCE IS DUE TO PRESENCE OF A SPECIFIC ACETYL-TRANSFERASE WHICH INACTIVATES THE DRUG BY USING ACETYL COENZYME A. [R6, 1192] *...SUBJECTS /WITH REDUCED GLUCURONYL TRANSFERASE ACTIVITY/ HAVE DIFFICULTY IN CONJUGATING AND EXCRETING BILIRUBIN. ... COMPETITION FOR CONJUGATING MECHANISM BY DRUG ADMIN...CAN LEAD TO KERNICTERUS. [R36, 386] *Drugs Whose Effects on Nursing Infants is Unknown but may be of Concern: Chloramphenicol: Possible idiosyncratic bone marrow suppression. /from Table 4/ [R46] *The most important adverse effects of chloramphenicol involve the hematopoietic system ... . Potentially fatal toxicity may develop in neonates exposed to excessive doses of chloramphenicol ... . This so-called 'grey baby syndrome' may also occur in older children and in adults receiving doses resulting in serum concentrations of 40-200 ug/ml ... . [R34] *Other adverse effects include hypersensitivity reactions, gastrointestinal complaints and neurological complications after long-term treatment. Chloramphenicol can also precipitate hemolytic anaemia in subjects with glucose-6-phosphate dehydrogenase deficiency ... . [R34] *Dose-dependent, reversible bone-marrow suppression affects primarily the erythroid series and occurs regularly when plasma concentrations of chloramphenicol are 25 ug/ml or higher ... another hematological side-effect is rare, unpredictable, non-dose-related aplastic anaemia, which often appears after the drug has been discontinued ... . [R34] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Chloramphenicol's use as a medicinal antimicrobial and antibacterial agent may result in its release to the environment through various waste streams. If released to water, chloramphenicol will be essentially non-volatile. Adsorption to sediment and bioconcentration should not be important fate processes. Chloramphenicol may biodegrade in soil and water. If released to the atmosphere, chloramphenicol will exist primarily in the particulate phase. Removal of atmospheric chloramphenicol may occur through dry deposition. If released to soil, chloramphenicol is expected to have very high soil mobility based on estimated Koc values of 10 to 47. Volatilization of chloramphenicol is not expected from either dry or moist soils. Occupational exposure to chloramphenicol can occur through inhalation, dermal contact, and ingestion. (SRC) ARTS: *Chloramphenicol's use as a medicinal antimicrobial and antibacterial agent(1), and antifungal agent(2) may result in its release to the environment through various waste streams(SRC). [R47] FATE: *TERRESTRIAL FATE: Using a structure estimation method based on molecular connectivity indexes, the Koc for chloramphenicol can be estimated to be about 10(1). The Koc for chloramphenicol can also be estimated to be approximately 47, based on an experimental water solubility of 3.75X10+3 mg/l(2) and a regression derived equation(3,SRC). According to a suggested classification scheme(4), these estimated Koc values suggests that chloramphenicol has very high soil mobility. Volatilization of chloramphenicol is not expected from either dry or moist soils based on an estimated vapor pressure of 1.73X10-12 mm Hg(5,SRC), and an estimated Henry's Law constant of 2.29X10-18 atm-cu m/mole(6,SRC). Chloramphenicol may biodegrade in soil conditions based on a variety of biodegradation studies(7,8,SRC). [R48] *AQUATIC FATE: Chloramphenicol will be essentially non-volatile from water(1) based upon an estimated Henry's Law constant of 2.29X10-18 atm cu meter/mol(2,SRC). Adsorption to sediment and bioconcentration in aquatic organisms should not be important fate processes based on low estimated Koc values of 10 to 47(1,3,SRC) and an estimated bioconcentration factor of 6(1,SRC). Chloramphenicol may biodegrade in natural waters based on a variety of biodegradation studies(4,5,SRC). [R49] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of approximately 1.73X10-12 mm Hg at 25 deg C(1,SRC), chloramphenicol will exist primarily in the particulate phase in the atmosphere(2). Removal of atmospheric chloramphenicol would occur through dry deposition(SRC). [R50] BIOD: *Using adapted activated sludge as the inoculum, chloramphenicol degraded 86.2 percent with a biodegradation rate of 3.3 mg COD per gram per hour(1). Chloramphenicol has also been reported to be degraded by intestinal bacteria via amidolysis to 18 observed metabolites with 2-amino-1-(p-nitrophenyl)-1,3-propanediol and its p-aminophenyl reduction product as the major products(2). However, in these experiments, the metabolic studies were carried out in inoculated-aerated nutrient broth media that did not simulate the habitat of the bacteria(2). [R51] ABIO: *The rate constant for the vapor-phase reaction of chloramphenicol with photochemically produced hydroxyl radicals has been estimated to be approximately 3.1X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 12 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Chloramphenicol solutions, when exposed to a UV source (sunlight) or to high temperatures, decompose with the formation of hydrochloric and dichloric acid(2). [R52] BIOC: *Based upon an experimental water solubility of 3.75X10+3 mg/l(1), the bioconcentration factor of chloramphenicol can be estimated to be approximately 6(2,SRC). This estimated bioconcentration factor suggests that bioconcentration in aquatic organisms of chloramphenicol should not be an important fate process(SRC). [R53] KOC: *Using a structure estimation method based on molecular connectivity indexes, the Koc for chloramphenicol can be estimated to be about 10(1). The Koc for chloramphenicol can also be estimated to be approximately 47, based on an experimental water solubility of 3.75X10+3 mg/L(2) and a regression derived equation(3,SRC). According to a suggested classification scheme(4), these estimated Koc values suggests that chloramphenicol has very high soil mobility. [R54] VWS: *The Henry's Law constant for chloramphenicol can be estimated to be 2.29X10-18 atm-cu m/mole using a structure estimation method(1,SRC). This value of Henry's Law constant indicates that chloramphenicol is essentially non-volatile from water(2). [R55] RTEX: *Occupational exposure to antibiotics, such as chloramphenicol(SRC), can occur through inhalation, dermal contact, and ingestion(1). [R56] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *An allowed daily intake (ADI) could not be set for chloramphenicol because of the dose-independence of chloramphenicol-induced aplastic anaemia ... . [R2] OOPL: +Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 0.5 mg/cu m. [R57] FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R58] *Chloramphenicol tablets. Oral dosage form new animal drugs. Specifications and conditions of use provided for dogs. [R59] *Chloramphenicol capsules. Oral dosage form new animal drugs. Specifications and conditions of use provided for dogs. [R60] *Chloramphenicol palmitate oral suspension. Oral dosage form new animal drugs. Specifications and conditions of use provided for dogs. [R61] *Chloramphenicol injection. Implantation or injectable dosage form new animal drugs. Specifications and conditions of use provided for dogs. [R62] *Chloramphenicol ophthalmic ointment. Ophthalmic and topical dosage form new animal drugs. Specifications and conditions of use provided for dogs and cats. [R63] *Chloramphenicol ophthalmic solution. Ophthalmic and topical dosage form new animal drugs. Specifications and conditions of use provided for dogs and cats. [R64] *Chloramphenicol-prednisolone-tetracaine-squalane topical suspension. Ophthalmic and topical dosage form new animal drugs. Specifications and conditions of use provided for dogs and cats. [R65] *Chloramphenicol-prednisolone ophthalmic ointment. Ophthalmic and topical dosage form new animal drugs. Specifications and conditions of use provided for dogs and cats. [R66] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *MICROBIOLOGICAL TURBIDIMETRIC ASSAY FOR CHLORAMPHENICOL IN PREPARATIONS FOR HUMAN AND VETERINARY USE. [R67] *USE OF THIN LAYER CHROMATOGRAPHY AND DENSITOMETRY IN THE ANALYSIS OF PRESCRIPTION DRUGS. [R68] *SPECTROPHOTOMETRIC DETERMINATION OF CHLORAMPHENICOL BY REACTION WITH THIOUREA. [R69] *THIN-LAYER AND HPLC DETERMINATION OF CHLORAMPHENICOL RESIDUES IN EDIBLE TISSUES. [R70] *... Analyzed in pharmaceutical preparations using microbiological turbidimetric and spectrophotometric assays ... . [R2] *Analytical methods for chloramphenicol residues in meat, milk and eggs ... include HPLC ... and radioimmunoassay ... . [R2] CLAB: *HIGH-PERFORMANCE LIQ CHROMATOGRAPHY METHOD FOR DETERMINATION OF CHLORAMPHENICOL IN BLOOD IS DESCRIBED. [R71] *CHLORAMPHENICOL WAS DETECTED IN BLOOD SERUM, PLASMA, OR CSF BY HIGH-PRESSURE LIQ CHROMATOGRAPHY. [R72] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: LIETMAN PS; CHLORAMPHENICOL AND THE NEONATE- 1979 VIEW; CLIN PERINATOL 6 (1): 151 (1979). REVIEW OF CHLORAMPHENICOL USE IN NEWBORN INFANT. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting Chloramphenicol (56-75-7); Reason: Human data considered inadequate. SO: R1: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1152 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 172 (1990) R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 171 (1990) R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 922 R5: SRI R6: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. R7: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-244 R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 170 (1990) R9: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 257 R10: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 319 R11: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 190 R12: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-4 R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 415 R14: SRC; Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (Eds), Boca Raton, FL: CRC Press p 31 (1985) R15: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) R16: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R17: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 261 R18: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 26 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 50 182 (1990) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R21: ROTHKOFF L ET AL; ANN OPHTHALMOL 11(1): 105 (1979) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 177 (1990) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 180 (1990) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 181 (1990) R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V10 91 (1976) R26: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V10 90 (1976) R27: Shepard, T. H. Catalog of Teratogenic Agents. 3rd ed. Baltimore, MD.: Johns Hopkins University Press, 1980. 59 R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 173 (1990) R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 175 (1990) R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 176 (1990) R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 178 (1990) R32: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 131 R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 174 (1990) R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 179 (1990) R35: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. C-14 R36: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. R37: SILICIANO RF ET AL; BIOCHEM PHARMACOL 27 (23): 2759 (1978) R38: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R39: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. 450 R40: KOUP JR ET AL; CLIN PHARMACOL THER 24(NOV) 571 (1978) R41: Gupta RC et al; J Toxicol Environ Health 11 (4-6): 897-905 (1983) R42: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R43: FELDMAN WE; PEDIATRICS 61(MAR) 406 (1978) R44: MULHALL A ET AL; STUDY OF 70 CASES; LANCET 1(8319) 284 (1983) R45: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 253 R46: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 139 (1994) R47: (1) Budavari S; The Merck Index - Encyclopedia of Chemicals, Drugs, and Biologicals Rahway, NJ: Merck and Co., Inc pg 319 (1989) (2) Lewis RJ; The Condensed Chemical Dictionary. 12th ed NY,NY: Van NOstrand Reinhold p 257 (1993) R48: (1) Meylan WM et al; Environ Sci Technol 28: 459-65(1992) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (Eds), Boca Raton, FL: CRC Press p 31 (1985) (6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (7) Pitter P; Water Res 10: 231-5 (1976) (8) Williams PP; Res Rev 66: 63-135 (1977) R49: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc pgs.4-9, 5-10, 15-15 to 15-29 (1990) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (3) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (4) Pitter P; Water Res 10: 231-5 (1976) (5) Williams PP; Res Rev 66: 63-135 (1977) R50: (1) Lyman WJ; in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (Eds), Boca Raton, FL: CRC Press p 31 (1985) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Environ Toxicol Chem 26: 2293-9(1993) R51: (1) Pitter P; Water Res 10: 231-5 (1976) (2) Williams PP; Res Rev 66: 63-135 (1977) R52: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Ehrlich J; in Kirk-Othmer Encycl Chem Technol 3rd ed. NY,NY: John-Wiley and Sons 2: 925 (1986) R53: (1) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Am Chem Soc pp. 5-10 (1990) R54: (1) Meylan WM et al; Environ Sci Technol 28: 459-65(1992) (2) Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R55: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington DC: Amer Chem Soc p.15-15 to 15-29 (1990) R56: (1) Parmeggiani L; Encycl Occup Health and Safety 3rd ed Geneva, Switzerland: International Labour Office p. 170-173 (1983) R57: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R58: 21 CFR 200-299, 300-499, 820, and 860 (4/1/93) R59: 21 CFR 520.390a (4/1/93) R60: 21 CFR 520.390b (4/1/93) R61: 21 CFR 520.390c (4/1/93) R62: 21 CFR 522.390 (4/1/93) R63: 21 CFR 524.390a (4/1/93) R64: 21 CFR 524.390b (4/1/93) R65: 21 CFR 524.390c (4/1/93) R66: 21 CFR 524.390d (4/1/93) R67: UNITED STATES FOOD AND DRUG ADMINISTRATION; FED REGIST 48 (20): 3959 (1983) R68: KESSLER A, KRZEK J; FARM POL 38 (9): 357 (1982) R69: DAS A ET AL; INDIAN J PHARMACOL SCI 44 (6): 149 (1982) R70: JOHANNES B ET AL; ARCH LEBENSMITTELHYG 34 (1): 1 (1983) R71: CRECHIOLO J, HILL RE; J CHROMATOGR 162 (3): 480 (1979) R72: SAMPLE RH BA ET AL; ANTIMICROB AGENTS CHEMOTHER 15 (3): 491 (1979) RS: 69 Record 214 of 1119 in HSDB (through 2003/06) AN: 3032 UD: 200302 RD: Reviewed by SRP on 9/14/1995 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORPHENIRAMINE- SY: *ALLERGICAN-; *ALLERGISAN-; *2-[P-CHLORO-ALPHA-(2-DIMETHYLAMINOETHYL)BENZYL]PYRIDIN; *GAMMA-(4-CHLOROPHENYL)-N,N-DIMETHYL-2-PYRIDINEPROPANAMINE; *CHLOROPHENYLPYRIDAMINE-; *1-(P-CHLOROPHENYL)-1-(2-PYRIDYL)-3-DIMETHYLAMINOPROPANE; *1-(P-CHLOROPHENYL)-1-(2-PYRIDYL)-3-N,N-DIMETHYLPROPYLAMINE; *3-(P-CHLOROPHENYL)-3-(2-PYRIDYL)-N,N-DIMETHYLPROPYLAMINE; *GAMMA-(4-CHLOROPHENYL)-GAMMA-(2-PYRIDYL)PROPYLDIMETHYLAMINE; *CHLOROPROPHENPYRIDAMINE-; *CHLORPHENAMINE-; *CHLORPROPHENPYRIDAMINE-; *HAYON-; *HISTADUR-; *POLARONIL-; *PYRIDINE, 2-(P-CHLORO-ALPHA-(2-(DIMETHYLAMINO)ETHYL)BENZYL)-; *2-PYRIDINEPROPANAMINE, GAMMA-(4-CHLOROPHENYL)-N,N-DIMETHYL- RN: 132-22-9 MF: *C16-H19-Cl-N2 ASCH: Chlorpheniramine maleate; 113-92-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CONDENSATION OF 2-(P-CHLORO-ALPHA-(2-CHLOROETHYL)BENZYL)PYRIDINE WITH DIMETHYLAMINE IN THE PRESENCE OF SODAMIDE [R1] *Synthesis. [R2] FORM: *TABLETS, 4 MG; REPEAT-ACTION TABLETS, 8 and 12 MG, INJECTION; SYRUP /FROM TABLE/ [R3, 609] *GRADE: USP /MALEATE/ [R4] MFS: *HEXAGON LABORATORIES, INC, BRONX, NY 10475 [R1] *SCHERING CORP, UNION, NJ 07033 [R1] *SMITHKLINE CORP, SMITHKLINE CHEMICALS DIV, PHILADELPHIA, PA 19101 [R1] *Lonza Inc, 17-17 Route 208, Fair Lawn, NJ 07410 (201) 794-2400. Production site: Organic Chemicals Division, Conshohocken, PA 19428 /Maleate/ [R5] OMIN: *TREATMENT OF BASE WITH EQUIMOLAR PORTION OF MALEIC ACID RESULTS IN FORMATION OF MALEATE. /MALEATE/ [R6, 1059] USE: +MEDICATION +MEDICATION (VET): PRIE: U.S. PRODUCTION: *(1977) 1.68X10+7 GRAMS (MALEATE) [R1] *(1978) 2.13X10+7 GRAMS (MALEATE) [R1] U.S. IMPORTS: *(1977) 5.0X10+6 G-INCL MALEATE (PRINCPL DISTS) [R1] *(1979) 2.0X10+7 G-INCL MALEATE (PRINCPL DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *OILY LIQUID [R2] BP: *142 DEG C @ 1.0 MM HG [R2] MW: *279.80 [R2] SPEC: *Intense mass spectral peaks: 58 m/z, 72 m/z, 167 m/z, 203 m/z [R7] OCPP: *WHITE CRYSTALLINE POWDER; ODORLESS; SOLN ARE ACID TO LITMUS HAVING PH BETWEEN 4 and 5; MP:BETWEEN 130 DEG C AND 135 DEG C; SLIGHTLY SOL IN ETHER AND BENZENE /MALEATE/ [R6, 1059] *UV max absorption (water): 261 nm (E=5760), Solubility in mg/ml at 25 deg C: Ethanol 330; chloroform 240; water 160; methanol 130; pH of a 2% aqueous solution about 5 /Maleate/ [R2] *MAX ABSORPTION: 265 NM (A= 300, 1%, 1 CM); 263 NM (A= 200, 1%, 1 CM); 258 NM, 268 NM /MALEATE/ [R8, 258] *BOX LIKE PRISMS AND IRREGULAR FRAGMENTS; INDEX OF REFRACTION: 1.533 (ALPHA); 1.668 (BETA; INTERMEDIATE INDEX); LESS THAN 1.734 (GAMMA; INCLINED) /MALEATE/ [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *SENSITIVE TO LIGHT. /MALEATE/ [R8, 31] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *There is no specific therapy for antihistamine poisoning, and treatment is along general symptomatic and supportive lines. ... Should breathing fail, mech support of ventilation offer safer and ... effective means of maintaining resp than use of analeptics which are prone to initiative or intensify convulsive phase. /Antihistamine/ [R3, 608] HTOX: *SYMPTOMATOLOGY: 1. CENTRAL NERVOUS DEPRESSION IS USUALLY DOMINANT REACTION IN ADULTS; IT IS EVIDENCED BY DROWSINESS, LETHARGY, FATIGUE, HYPNOSIS, AND COMA. RELATED NERVOUS SYMPTOMS INCL VERTIGO, ATAXIA, TINNITUS, AND BLURRED VISION. /ANTIHISTAMINICS/ [R10, p. III-39] *SYMPTOMATOLOGY: 2. CENTRAL NERVOUS HYPEREXCITABILITY OFTEN FOLLOWS INITIAL SEDATION; IN CHILDREN EXCITEMENT IS OFTEN FIRST EVIDENCE OF POISONING. STIMULANT PHASE BRINGS TREMORS, ANXIETY, INSOMNIA, EXCITEMENT, HALLUCINATIONS, DELIRIUM, TOXIC PSYCHOSIS AND CONVULSIONS... /ANTIHISTAMINICS/ [R10, p. III-39] *SYMPTOMATOLOGY: 3. DANGEROUS HYPERPYREXIA MAY OCCUR IN POISONED CHILDREN... 4. GASTROINTESTINAL REACTIONS INCL DRY MOUTH, ANOREXIA, NAUSEA, VOMITING, ABDOMINAL DISTRESS, CONSTIPATION, and /OR DIARRHEA. /ANTIHISTAMINICS/ [R10, p. III-39] *SYMPTOMATOLOGY: 5. TERMINAL PHASE IS ONE OF SEVERE CENTRAL NERVOUS DEPRESSION, WITH DEATH FROM RESP ARREST OR CARDIOVASCULAR COLLAPSE. /ANTIHISTAMINICS/ [R10, p. III-39] *EFFECT OF CHLORPHENIRAMINE MALEATE ON VISUAL-MOTOR COORDINATION AND ON SUBJECTIVE ASSESSMENTS OF PERFORMANCE AND WELL-BEING COMPARED TO PLACEBO IN FEMALES FROM 0.5-7.0 HR AFTER MORNING INGESTION OF EACH. PERFORMANCE IMPAIRED 1.5 HR AFTER CHLORPHENIRAMINE. [R11] *... Appears rarely to affect the eyes when taken orally in ordinary dosage. In normal volunteers 8-12 mg chlorpheniramine maleate taken by mouth had no significant effect on pupils or accommodation. One patient developed left-sided blepharospasm and dyskinesia on the left side of the face, which improved after chlorpheniramine was discontinued. [R12] *In acute poisoning with H1 antagonists, their central excitatory effects constitute the greatest danger. The syndrome includes hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions. Fixed, dilated pupils with a flushed face, together with sinus tachycardia, urinary retention, dry mouth, and fever, lend the syndrome a remarkable similarity to that of atropine poisoning. Terminally, there is deepening coma with cardiorespiratory collapse and death, usuallY within 2 to 18 hours. Treatment is along general symptomatic and supportive lines. /Histamine Antagonists: H1 Antagonists/ [R13, 586] *... SIDE EFFECTS INCL DRYNESS OF ... RESP PASSAGES, SOMETIMES INDUCING COUGH; URINARY FREQUENCY AND DYSURIA; PALPITATION; HYPOTENSION; HEADACHE; TIGHTNESS OF CHEST; TINGLING, HEAVINESS, AND WEAKNESS OF HANDS. ... ALLERGIC DERMATITIS IS NOT UNCOMMON. /ANTIHISTAMINES/ [R3, 607] *IN SMALL CHILD ... SYNDROME OF POISONING INCL ... ATAXIA, INCOORDINATION, ATHETOSIS ... FIXED, DILATED PUPILS WITH FLUSHED FACE ... ARE COMMON. /ANTIHISTAMINES/ [R3, 608] *ALTHOUGH H1-BLOCKING DRUGS HAVE RELATIVELY HIGH MARGIN OF SAFETY, ACUTE POISONING WITH THEM IS COMMON. ... IN CHILDREN, 20 TO 30 TABLETS OR CAPSULES OF MOST COMMERCIALLY AVAILABLE ANTIHISTAMINES REPRESENTS LETHAL OR NEAR-LETHAL DOSE. /ANTIHISTAMINES/ [R3, 608] NTOX: *LARGE DOSES PRODUCE CONVULSIONS IN EXPTL ANIMALS. /ANTIHISTAMINES/ [R6, 1057] *SMALL DOSES OF SOME ANTIHISTAMINICS PRODUCE DEPRESSION, DROWSINESS, SALIVATION AND VOMITING. /ANTIHISTAMINICS/ [R14, 155] *CHLORPHENIRAMINE MALEATE DECR ACETYLCHOLINE LEVEL IN BOTH HEMISPHERES AND REST OF BRAIN. RESULTS FOR STYRAMINE ARE ALSO GIVEN. [R15] *... H1 antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. /Histamine Antagonists: H1 Antagonists/ [R13, 584] *CHLORPHENIRAMINE MALEATE, AN ANTAGONIST OF HISTAMINE, INHIBITED DEVELOPMENT OF EHRLICH ASCITES CARCINOMA WHEN GIVEN TO MICE ORALLY FOR 10 DAYS, STARTING ON DAY OF TUMOR IMPLANT. [R16] NTP: *Toxicology and carcinogenesis studies of chlorpheniramine maleate (99% pure) ... were conducted by administering this chemical in deionized water by gavage to 50 male and 50 female F344/N rats and B6C3F1 mice, 5 days/wk for 103 wk. The doses used were: male rats: 0, 15, or 30 mg/kg; female rats: 0, 30, or 60 mg/kg; male mice: 0, 25, or 50 mg/kg; female mice: 0, 100, or 200 mg/kg. ... Under the conditions of these two yr studies, there was no evidence of carcinogenicity for F344/N rats or B6C3F1 mice administered chlorpheniramine maleate in deionized water, 5 days/wk for two yr. Due to high mortality in high dose female rats and high dose male mice, the sensitivity of these groups to detect carcinogenic response was reduced. /The cmpd/ had a proliferative effect on the thyroid gland of female mice, as shown by the increased evidences of follicular cell cysts and hyperplasia in both low dose and high dose groups. /Chlorpheniramine maleate/ [R17] POPL: *Use is not recommended in newborn or premature infants because this age group has an increased susceptibility to anticholinergic side effects, such as central nervous system excitation, and an increased tendency toward convulsions. A paradoxical reaction characterized by hyperexcitability may occur in children taking antihistamines. /Antihistamines/ [R18, 306] *Dizziness, sedation, confusion, and hypotension may be more likely to occur in geriatric patients taking antihistamines. Geriatric patients are especially susceptible to the anticholinergic side effects, such as dryness of mouth and urinary retention (especially in males), of the antihistamines. If these side effects occur and continue or are severe, medication should probably be discontinued. /Antihistamines/ [R18, 306] ADE: *STUDIES IN MAN AND EXPTL ANIMALS INDICATE THAT (3)H-CHLORPHENIRAMINE MALEATE IS RAPIDLY AND QUANT ABSORBED FROM GUT. ALTHOUGH PLASMA LEVELS OF TOTAL RADIOACTIVITY ARE PROLONGED, PLASMA T/2 OF CHLORPHENIRAMINE IS ONLY 12-15 HR IN MAN AND 3 HR IN DOG. T/2 IN MAN IS ABOUT 3 TIMES LONGER THAN THERAPEUTIC EFFECT... [R19] *The H1 antagonists are well absorbed from the GI tract. Following oral administration, peak plasma concn are achieved in 2 to 3 hr and effects usually last 4 to 6 hr; however, some of the drugs are much longer acting ... . /Histamine Antagonists: H1 Antagonists/ [R13, 584] *H1 blockers are among the many drugs that induce hepatic microsomal enzymes, and they may facilitate their own metabolism. /Histamine Antagonists: H1 Antagonists/ [R13, 584] METB: *MAIN SITE OF METABOLIC TRANSFORMATION IS LIVER. /ANTIHISTAMINES/ [R3, 607] BHL: *IN MAN...PLASMA T/2 OF CHLORPHENIRAMINE IS...12-15 HR...ALTHOUGH PLASMA LEVELS OF TOTAL RADIOACTIVITY ARE PROLONGED... [R19] *Elimination: 14 to 25 hours [R18, 305] ACTN: *Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. Antihistamines antagonize, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa. /Antihistamines/ [R18, 304] *H1 antagonists inhibit most responses of smooth muscle to histamine. Antagonism of the constrictor action of histamine on respiratory smooth muscle is easily shown in vivo and in vitro. /Histamine Antagonists: H1 Antagonists/ [R13, 582] *H1 antagonists strongly block the action of histamine that results in increased permeability and formation of edema and wheal. /Histamine Antagonists: H1 Antagonists/ [R13, 583] *Within the vascular tree, the H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by H1 receptors on endothelial cells. Residual vasodilatation reflects the involvement of H2 receptors on smooth muscle and can be suppressed only by the concurrent administration of an H2 antagonist. Effects of the histamine antagonists on histamine induced changes in systemic blood pressure parallel these vascular effects. /Histamine Antagonists: H1 Antagonists/ [R13, 583] *Many of the H1 antagonists tend to inhibit responses to acetylcholine that are mediated by muscarinic receptors. These atropine like actions are sufficiently prominent in some of the drugs to be manifest during clinical usage ... . /Histamine Antagonists: H1 Antagonists/ [R13, 584] INTC: *Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines/ [R18, 307] *Concurrent use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. /Antihistamines/ [R18, 307] *Concurrent use /with alcohol or other CNS depression-producing medications/ may potentiate the CNS depressant effects of either these medications or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamines/ [R18, 306] *Anticholinergic effects may be potentiated when /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines/ [R18, 306] *Concurrent use /of other photosensitizing medications/ with antihistamines may cause additive photosensitizing effects. /Antihistamines/ [R18, 307] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *5. 5= EXTREMELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 5-50 MG/KG, BETWEEN 7 DROPS AND 1 TEASPOONFUL FOR 70 KG PERSON (150 LB). /ANTIHISTAMINICS/ [R10, p. II-15] THER: +Anti-Allergic Agents; Antipruritics; Histamine H1 Antagonists [R20] *Antihistamines are indicated in the prophylactic and symptomatic treatment of perennial and seasonal allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis due to inhalant allergens and foods. /Antihistamines; Included in US product labeling/ [R18, 303] *Antihistamines are indicated for the symptomatic treatment of pruritus associated with allergic reactions and of mild, uncomplicated allergic skin manifestations of urticaria and angioedema, in dermatographism, and in urticaria associated with transfusions. /Antihistamines; Included in US product labeling/ [R18, 303] *Antihistamines are also used in the treatment of pruritus associated with pityriasis rosea. /Antihistamines; NOT included in US product labeling/ [R18, 303] *Antihistamines are indicated for the relief of sneezing and rhinorrhea associated with the common cold. However, controlled clinical studies have not demonstrated that antihistamines are significantly more effective than placebo in relieving cold symptoms. Non-sedating (ie, second generation) antihistamines are unlikely to be useful in the treatment of the common cold symptoms since they do not have clinically significant anticholinergic effects (eg, drying effects on nasal mucosa). /Antihistamines; Included in US product labeling/ [R18, 303] *Antihistamines are indicated as adjunctive therapy to epinephrine and other standard measures for anaphylactic reactions after the acute manifestations have been controlled, and to ameliorate the allergic reactions to blood or plasma. /Antihistamines; Included in US product labeling/ [R18, 303] +MEDICATION (VET): ORALLY...IN ALLERGIC DERMATITIS, RHINITIS, COUGHING, AND ASTHMA IN MANY SPECIES, AND SPECIFICALLY INDICATED IN VIRAL RHINOTRACHEITIS OF CATS. PARENTERAL USE IS PRIMARILY LIMITED TO ITS INCORPORATION IN PENICILLIN-DIHYDROSTREPTOMYCIN SUSPENSIONS TO COUNTERACT HISTAMINE FROM INFECTED OR INJURED TISSUES... [R21] +MEDICATION (VET): POPULAR PARENTERAL THERAPY IN LAMINITIS OF FARM ANIMALS. [R21] +MEDICATION (VET): ALL PRESENTLY AVAILABLE ANTIHISTAMINES...ARE EFFECTIVE IN PREVENTING HISTAMINE SHOCK IN GUINEA PIGS, BRONCHOSPASM INDUCED IN GUINEA PIGS BY NEBULIZED HISTAMINE SOLN, WHEALING ON SKIN, AND MANY OTHER RESPONSES TO HISTAMINE. HYPOTENTION...IS MORE DIFFICULT TO BLOCK... /ANTIHISTAMINES/ [R6, 1057] +ANTIHISTAMINE, EG, FOR RHINITIS AND URTICARIA (AS MALEATE); ANTIHISTAMINE FOR ALLERGIC REACTIONS (AS MALEATE); COMPONENT OF ANTITUSSIVE FORMULATIONS; VETERINARY ANTIHISTAMINE [R1] WARN: *Use is not recommended in newborn or premature infants because this age group has an increased susceptibility to anticholinergic side effects, such as central nervous system excitation, and an increased tendency toward convulsions. A paradoxical reaction characterized by hyperexcitability may occur in children taking antihistamines. /Antihistamines/ [R18, 306] *Dizziness, sedation, confusion, and hypotension may be more likely to occur in geriatric patients taking antihistamines. Geriatric patients are especially susceptible to the anticholinergic side effects, such as dryness of mouth and urinary retention (especially in males), of the antihistamines. If these side effects occur and continue or are severe, medication should probably be discontinued. /Antihistamines/ [R18, 306] *Prolonged use of antihistamines ... may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort. /Antihistamines/ [R18, 306] *ANTIHISTAMINE DRUGS MAY BE OF SOME USE IN MINIMIZING SERUM REACTIONS BUT ARE OF NO THERAPEUTIC VALUE...AND MAY EVEN POTENTIATE TOXIC ACTION OF VENOM... /ANTIHISTAMINES/ [R14, 445] *H1 antagonists are most useful in acute exudative types of allergy that present with symptoms of rhinitis, urticaria, and conjunctivitis. Their effect, however, is purely palliative and confined to the suppression of symptoms attributable to the histaminereleased by the antigen-antibody reaction. The drugs do not diminish the intensity of this reaction, which is the cause of the various hypersensitivity diseases. /Histamine Antagonist: H1 Antagonists/ [R13, 587] *The older H1 antagonists can both stimulate and depress the CNS. Stimulation is occasionally encountered in patients given conventional doses, who become restless, nervous, and unable to sleep. Central excitation is also a striking feature of poisoning, which not uncommonly results in convulsions, particularly in infants. Central depression, on the other hand, is the usual accompaniment of therapeutic doses of the older H1 antagonists. /Histamine Antagonists: H1 Antagonists/ [R13, 584] *The side effect with the highest incidence, and the one common to all H1 antagonists other than terfenadine or astemizole, is sedation ... . Although this may be a desirable adjunct in the treatment of some patients, it may interfere with the patient's daytime activities. Concurrent ingestion of alcohol or other CNS depressants produces an additive effect that impairs motor skills. Other untoward reactions referable to central actions include dizziness, tinnitus, lassitude, incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors. /Histamine Antagonists: H1 Antagonists/ [R13, 586] *... Frequent side effects involve the digestive tract and include loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea. Their incidence may be reduced by giving the drug with meals. ... Other side effects that are apparently caused by the antimuscarinic actions of some of the older agents include dryness of the mouth and respiratory passages, sometimes inducing cough, urinary retention or frequency, and dysuria. These effects are not observed with terfenadine or astemizole. Palpitation, hypotension, headache, tightness of the chest, and tingling and weakness of the hands may also occur with the older agents. /Histamine Antagonists: H1 Antagonists/ [R13, 586] *Drug allergy may develop when H1 antagonists are given orally, but more commonly it results from topical application. Allergic dermatitis is not uncommon; other hypersensitivity reactions include drug fever and photosensitization. Hematological complications such as leukopenia agranulocytosis, and hemolytic anemia are very rare. Teratogenic effects have been noted in response to piperazine compounds, but extensive clinical studies have not demonstrated any association between the use of such H, antagonists and fetal anomalies in man. Since H1 antagonists interfere with skin tests for allergy, they must be withdrawn well before such tests are performed. /Histamine Antagonists: H1 Antagonists/ [R13, 586] *In bronchial asthma, histamine antagonists are singularly ineffectual. /Histamine Antagonist: H1 Antagonists/ [R13, 587] *Alkylamines (Prototype: Chlorpheniramine). These drugs are among the most potent H1 antagonists. The drugs are not so prone as some H1 antagonists to produce drowsiness and are among the more suitable agents for daytime use; but ... a significant proportion of patients do experience sedation. Side effects involving CNS stimulation are more common in this than in other groups. [R13, 586] *Drowsiness most common reaction, but overall incidence low. /Chlorpheniramine maleate/ [R22] *Despite persistent popular belief, H1 antagonists are without value in combating the common cold. The weak anticholinergic effects of the older agents may tend to lessen rhinorrhea, but this drying effect may do more harm than good, as may also their tendency to induce somnolence ... . /Histamine Antagonists: H1 Antagonists/ [R13, 587] *In bronchial asthma, histamine antagonists are singularly ineffective. Similarly, in the treatment of systemic anaphylaxis, in which autacoids other than histamine play major roles, the mainstay of therapy is epinephrine, with histamine antagonists having only a subordinate and adjuvant role. The same is true for severe angioedema, in which laryngeal swelling constitutes a threat to life. /Histamine Antagonists: H1 Antagonists/ [R13, 587] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R23] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HIGH PERFORMANCE LIQUID CHORMATOGRAPHIC ANALYSIS OF CHLORPHENIRAMINE IN OINTMENT. [R24] CLAB: *RAPID QUANTITATIVE ANALYSIS OF CHLORPHEN IN PLASMA, SALIVA, AND URINE BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. [R25] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorpheniramine maleate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 317 (1986) NIH Publication No. 86-2573 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 337 R3: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 275 R5: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 728 R6: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R7: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.307 R8: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R9: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/1031 R10: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R11: CLARKE CH, NICHOLSON AN; BR J CLIN PHARMACOL 6 (1): 31-5 (1978) R12: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 225 R13: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R14: Garner's Veterinary Toxicology. 3rd ed., rev. by E.G.C. Clarke and M.L. Clarke. Baltimore: Williams and Wilkins, 1967. R15: OZDEMIR O, SUNAM G; ISTANBUL UNIV ECZACILIK FAK MECM 12 (1): 174-81 (1976) R16: BERTOLINI A, CASTELLI M; G ITAL CHEMIOTER 22 (1-2): 51-4 (1975) R17: DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorpheniramine maleate in F344/N Rats and B6C3F1 Mice. p.9 Technical Report Series No. 317 (1986) NIH Publication No. 86-2573 R18: USP Convention. USPDI - Drug Information for the Health Care Professional. 15 th ed. Volume 1. Rockville, MD: United States Pharmacopeial Convention, Inc., 1995. (Plus updates.) R19: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 194 R20: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R21: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 108 R22: American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994. 1858 R23: 21 CFR 200-299, 300-499, 820, and 860 (4/1/94) R24: HATTORI ET AL; YAKUGAKI ZASSHI 99 (5): 537-9 (1979) R25: ATHANIKAR ET AL; J CHROMATOGR 162 (3): 367-76 (1979) RS: 25 Record 215 of 1119 in HSDB (through 2003/06) AN: 3047 UD: 200208 RD: Reviewed by SRP on 5/11/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CYCLOPHOSPHAMIDE- SY: *B-518-; *ASTA-B-518-; *1-BIS(2-CHLOROETHYL)AMINO-1-OXO-2-AZA-5-OXAPHOSPHORIDIN; *2-(BIS(2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZOPHOSPHORINE 2-OXIDE; *BIS(2-CHLOROETHYL)PHOSPHAMIDE CYCLIC PROPANOLAMIDE ESTER; *BIS(2-CHLOROETHYL)PHOSPHORAMIDE CYCLIC PROPANOLAMIDE ESTER; *N,N-BIS(BETA-CHLOROETHYL)-N',O-PROPYLENEPHOSPHORIC ACID ESTER DIAMIDE; *N,N-BIS(2-CHLOROETHYL)-N',O-PROPYLENEPHOSPHORIC ACID ESTER DIAMIDE; *N,N-BIS(2-CHLOROETHYL)TETRAHYDRO-2H-1,3,2-OXAZAPHOSPHORIN-2-AMINE 2-OXIDE; *N,N-BIS(BETA-CHLOROETHYL)N',O-TRIMETHYLENEPHOSPHORIC ACID ESTER DIAMIDE; *CLAFEN-; *CLAPHENE-; *CYCLOPHOSPHAMID-; *CYCLOPHOSPHAN-; *CYCLOPHOSPHANE-; *CYTOPHOSPHAN-; *CYTOPHOSPHANE-; *CYTOXAN-; *ENDOXAN-; *GENOXAL-; *NSC-26271-; *2H-1,3,2-OXAZAPHOSPHORIN-2-AMINE, N,N-BIS(2-CHLOROETHYL)TETRAHYDRO-, 2-OXIDE; *2H-1,3,2-OXAZAPHOSPHORINE, 2-(BIS(2-CHLOROETHYL)AMINO)TETRAHYDRO-, 2-OXIDE; *PROCYTOX-; *SENDOXAN- RN: 50-18-0 RELT: 177 [ACROLEIN] (Metabolite) MF: *C7-H15-Cl2-N2-O2-P HAZN: U058; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. ASCH: Cyclophosphamide monohydrate; 6055-19-2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Cyclophosphamide can be prepared by treating N,N-bis(B-chloroethyl)-phosphamide dichloride with propanolamine in the presence of trimethylamine and dioxane. [R1, 167] *Prepn: H. Arnold et al., Naturwiss 45, 64 (1957); eidem, Nature 181, 931 (1958); H. Arnold, F. Bourseaux, Angew Chem. 70, 539 (1958). [R2] FORM: *CYCLOPHOSPHAMIDE IS SUPPLIED AS 25 and 50 MG TABLETS AND AS A POWDER (100 TO 2000 MG) IN STERILE VIALS. [R3, 1217] *Grade: USP, measured as containing 95.0 - 105.0% active ingredient calculated as the monohydrate, 5.7 - 6.8% max. water content, 0.002% max. heavy metals, and producing an aqueous solution (1 in 100) at pH 3.9 - 7.1. [R1, 166] *Available as 25 and 50 mg tablets ... and in vials for injection in amounts of 100, 200 or 500 mg measured as containing 90.0 - 110.0% of the stated amount of anhydrous cyclophosphamide. [R1, 166] USE: *Therap Cat: Antineoplastic [R2] *Immunosupressive [R4] *Antineoplastic for treatment of leukemia, etc; tested for use in chemical shearing of sheep and as an insect chemosterilant. [R5] *MEDICATION *MEDICATION (VET) CPAT: *Total US sales are 600 kg/year (1975) [R6, p. V9 137] PRIE: U.S. PRODUCTION: *Not produced in the US. [R1, 166] U.S. IMPORTS: *No data were available on the quantities imported. [R1, 166] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LIQUEFIES ON LOSS OF ITS WATER OF CRYSTALLIZATION [R7, 1087]; *Crystalline solid [R5] ODOR: *Odorless [R8, 199] TAST: *Slightly bitter [R8, 199] MP: *49.5-53 deg C [R8, 199] MW: *261.10 [R9] OWPC: *log Kow = 0.63 [R10] SOL: *1 in 25 parts water [R8, 199]; *1 in 1 parts alcohol [R8, 199]; *Slightly soluble in benzene, carbon tetrachloride; very slightly soluble in ether and acetone [R11]; *Soluble in chloroform, dioxane and glycols and insoluble in carbon tetrachloride and carbon disulfide. [R6, p. V9 136]; *In water, 40,000 ppm @ 20 deg C [R12] SPEC: *Intense mass spectral peaks: 69 m/z, 147 m/z, 175 m/z, 211 m/z, 260 m/z [R13] OCPP: *Fine, white, crystalline powder; odorless or almost odorless; slightly bitter taste /Monohydrate/ [R14] *MP: 41-45 deg C; MW: 279.10. Solubility: 40 g/l in water; slightly sol in alcohol, benzene, ethylene glycol, dioxane, carbon tetrachloride; sparingly sol in ether and acetone /Monohydrate/ [R2] *Darkens on exposure to light. Hydrolysis occurs at temperatures above 30 deg C, with removal of chlorine atoms. [R12] *Sensitive to oxidation, moisture, and light. [R1, 166] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of cyclophosphamide stem from its toxicologic properties. Exposure to this odorless, white, crystalline powder may occur from its manufacture, formulation, or distribution for use as an antineoplastic drug. Effects from exposure may include fever, chills, shortness of breath, dizziness, fatigue, headache, nausea, hemorrhagic colitis, hepatitis, leukopenia, and pneumonitis or interstitial pulmonary fibrosis. Cyclophosphamide has been indicated as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC). Exposure should be controlled by mechanical ventilation with high-efficiency particulate arrestors (HEPA) or charcoal filters to minimize the amount of the substance in exhausted air. In activities or situations where over-exposure may occur, wear protective clothing and a carefully fitted respirator. Potentially exposed skin should be thoroughly washed with soap and water. Contaminated clothing should be removed and discarded or left at the work site for cleaning before reuse. Smoking, eating, and drinking should be prohibited in cyclophosphamide work areas. Cyclophosphamide should be stored and transported in securely sealed glass bottles or ampoules, which are in turn placed inside strong screw-cap or snap-top containers. Also, the material should be stored cool (below 30 deg C), dry, and shielded from light. This substance is a good candidate for disposal by rotary kiln, or fluidized bed forms of incineration. REAC: */It was/ reported that immersion of a needle with an aluminum component in cyclophosphamide 20 mg/ml resulted in a slight darkening of the aluminum and gas production after a few days at 24 deg C with protection from light. [R15, 306] DCMP: *When heated to decomposition it emits highly toxic fumes of /phosphorus oxides, nitrogen oxides, and hydrogen chloride/. [R16, 973] *The rate constant for decomp of cyclophosphamide when constituted with benzyl alcohol-preserved bacteriostatic water for injection is significantly higher than with sterile water for injection. It was suggested that benzyl alcohol may catalyze somewhat the decomp of cyclophosphamide the rate of decomp is independent of pH over the range of 2-10. [R15, 300] SERI: *A powerful skin irritant. [R16, 973] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one piece and close fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R17, 1979.8] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/ [R18, 757] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one piece and close fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R17, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak tight. Horizontal laminar flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R17, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R17, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be reused ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R17, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R17, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/ [R18, 753] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Appropriate engineering controls should be in place to protect the drug product from microbial contamination and to protect personnel and the environment from the potential hazards of the product. These engineering controls should be maintained according to applicable regulations and standards. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Biological safety cabinets should be cleaned and disinfected regularly to ensure a proper environment for preparation of sterile products. For routine cleanups of surfaces between decontaminations, water should be used (for injection or irrigation) with or without a small amount of cleaner. If the contamination is soluble only in alcohol, then 70% isopropyl or ethyl alcohol may be used in addition to the cleaner. In general, alcohol is not a good cleaner, only a disinfectant, and its use in a biohazard cabinet should be limited. The biohazard cabinet should be disinfected with 70% alcohol before any aseptic manipulation is begun. The excessive use of alcohol should be avoided in biohazard cabinets where air is recirculated ... because alcohol vapors may build up in the cabinet. A lint-free, plastic-backed disposable liner may be used in the biological safety cabinet to facilitate spill cleanup. ... If used, the liner should be changed frequently ... /or/ whenever it is overtly contaminated. /Antineoplastic agents/ [R18, 755] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The biological safety cabinets should be decontaminated on a regular basis (ideally at least weekly) and whenever there is a spill or the biological safety cabinet is moved or serviced, including for certification. ... Currently, no single reagent will deactivate all known hazardous drugs; therefore, decontamination of a biological safety cabinet used for such drugs is limited to removal of contamination from a nondisposable surface (the cabinet) to a disposable surface (eg, gauze or towels) by use of a good cleaning agent that removes chemicals from stainless steel. The cleaning agent selected should have a pH approximating that of soap and be appropriate for stainless steel. Cleaners containing chemicals such as quaternary ammonium compounds should be used with caution, because they may be hazardous to humans and their vapors may build up in any biological safety cabinet where air is recirculated. Similar caution should be used with any pressurized aerosol cleaner; spraying a pressurized aerosol into a biological safety cabinet may disrupt the protective containment airflow, damage the high efficiency particulate air filter, and cause an accumulation of the propellant within a biological safety cabinet where air is recirculated, resulting in a fire and explosion hazard. During decontamination, the operator should wear a disposable closed front gown, disposable latex gloves covered by disposable utility gloves, safety glasses or goggles, a hair covering, and a disposable respirator, because the glass shield of the biological safety cabinet occasionally must be lifted. The blower must be left on, and only heavy toweling or gauze should be used in the biological safety cabinet to prevent it from being "sucked" up the plenum and into the high efficiency particulate air filter. Decontamination should be done from top to bottom (areas of lesser contamination to greater) by applying the cleaner, scrubbing, and rinsing thoroughly with distilled or deionized water. /Antineoplastic agents/ [R18, 755] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The high efficiency particulate air filters /or other exhaust scrubbing system/ of the biohazard cabinet must be replaced whenever they restrict required airflow velocity or if they are overtly contaminated (eg, by a breach in technique that causes hazardous drug to be introduced onto the clean side of the supply high efficiency particulate air filter). Personnel and environmental protection must be maintained during replacement of a contaminated high efficiency particulate air filter. Because replacement of a high efficiency particulate air filter generally requires breaking the integrity of the containment aspect of the cabinet, this procedure may release contamination from the filter into the pharmacy or intravenous preparation area if carried out in an inappropriate manner. Before replacement of a high efficiency particulate air filter contaminated with hazardous drugs, the biological safety cabinet service agent should be consulted for a mutually acceptable procedure for replacing and subsequently disposing of a contaminated high efficiency particulate air filter. One procedure would include moving the biological safety cabinet to a secluded area or using plastic barriers to segregate the contaminated area. Protective clothing and equipment must be used by the servicer. The biological safety cabinet should be decontaminated before filter replacement. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During removal of gloves, ... avoid touching the inside of the glove or the skin with the contaminated glove fingers. ... The worker should wear a protective disposable gown made of lint free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs when preparing hazardous drugs. Washable garments are immediately penetrated by liquids and therefore provide little, if any protection. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ When double gloving, one glove should be placed under the gown cuff and one over. The glove-gown interface should be such that no skin on the arm or wrist is exposed. Gloves and gowns should not be worn outside the immediate preparation area. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Eyewash fountains should be available in areas where hazardous drugs are routinely handled. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Although noninjectable dosage forms of hazardous drugs contain varying proportions of drug to nondrug (nonhazardous) components, there is potential for personnel exposure and environmental contamination with the hazardous components. Procedures should be developed to avoid the release of aerosolized powder or liquid into the environment during manipulation of these drugs. Drugs designated as hazardous should be labeled or otherwise identified as such to prevent their improper handling. Tablet and capsule forms of these drugs should not be placed in automated counting machines, which subject them to stress and may introduce powdered contaminants into the work area. During routine handling of hazardous drugs and contaminated equipment, workers should wear one pair of gloves of good quality and thickness. The counting and pouring of hazardous drugs should be done carefully, and clean equipment dedicated for use with these drugs should be used. ... When hazardous drug tablets in unit-of-use packaging are being crushed, the package should be placed in a small sealable plastic bag and crushed with a spoon or pestle; caution should be used not to break the plastic bag. Disposal of unused or unusable oral or topical dosage forms of hazardous drugs should be performed in the same manner as for hazardous injectable dosage forms and waste. ... Hazardous drug work areas should have a sink (preferably with an eyewash fountain) and appropriate first aid equipment to treat accidental skin or eye contact according to the protocol. /Antineoplastic agents/ [R18, 757] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ A distinctive warning label with an appropriate CAUTION statement should be attached to all hazardous drug materials, consistent with state laws and regulations. This would include, for example, syringes, IV containers, containers of unit-dose tablets and liquids, prescription vials and bottles, waste containers, and patient specimens that contain hazardous drugs. /Antineoplastic agents/ [R18, 757] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Supplies of disposable gloves and gowns, safety glasses, disposable plastic-backed absorbent liners, gauze pads, hazardous waste disposal bags, hazardous drug warning labels, and puncture-resistant containers for disposal of needles and ampuls should be conveniently located for all areas where hazardous drugs are handled. Assembling a "hazardous drug preparation and administration kit" is one way to furnish nursing and medical personnel with the materials needed to reduce the risk of preparing and administering a hazardous drug. /Antineoplastic agents/ [R18, 758] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Prospective temporary and permanent employees who may be required to work with hazardous drugs should be so notified and should receive adequate information about the policies and procedures pertaining to their use. This notification should be documented during the interview process and retained as part of the employment record for all employees. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All personnel involved with the transportation, preparation, administration, and disposal of cytotoxic and hazardous substances should continually be updated on new or revised information on safe handling of cytotoxic and hazardous substances. Policies and procedures should be updated accordingly. /Antineoplastic agents/ [R18, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The work area should be designed to provide easy access to those items necessary to prepare, label, and transport final products; contain all related waste; and avoid inadvertent contamination of the work area. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Each health-care setting should have an established first aid protocol for treating cases of direct contact with hazardous drugs, many of which are irritating or caustic and can cause tissue destruction. Medical care providers in each setting should be contacted for input into this protocol. The protocol should include immediate treatment measures and should specify the type and location of medical follow-up and work-injury reporting. Copies of the protocol, highlighting emergency measures, should be posted wherever hazardous drugs are routinely handled. /Antineoplastic agents/ [R18, 757] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Only individuals trained to administer hazardous drugs should be allowed to perform this function. Training programs should contain information on the therapeutic and adverse effects of these drugs and the potential, long term health risk to personnel handling these drugs. Each individual's knowledge and technique should be evaluated before administration of these drugs. This should be done by written examination and direct observation of the individual's performance. /Antineoplastic agents/ [R18, 757] SSL: *AQ SOLN KEEPS FOR A FEW HR @ ROOM TEMP, BUT HYDROLYSIS OCCURS ABOVE 30 DEG C, REMOVES CHLORINE ATOMS; DARKENS ON EXPOSURE TO LIGHT /MONOHYDRATE/ [R19] *SENSITIVE TO OXIDATION, MOISTURE ... /MONOHYDRATE/ [R14] *Constitute solns should be used within 24 hr if stored at room temp or within 6 days if stored under refrigeration. When constituted with sterile water for injection or paraben-preserved bacteriostatic water for injection to a concn of 21 mg/ml, < 1.5% cyclophosphamide decomposition will occur within 8 hr at 24-27 deg C and within 6 days at 5 deg C. [R15, 300] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R17, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R17, 1979.13] STRG: *Cyclophosphamide should be preserved in tight containers, at a temperature between 2 and 32 deg C. [R20] *Protect from light. [R8, 199] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R17, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is available commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R17, 1979.15] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/ [R18, 758] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/ [R18, 759] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U058, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R21] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R22] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/ [R18, 755] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The gown should be removed and placed in a sealable container before removal of the inner gloves. The inner gloves should be removed last and placed in the container with the gown. /Antineoplastic agents/ [R18, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Hazardous drug waste should be placed in specially marked (specifically labeled CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. These receptacles should be kept in all areas where the drugs are commonly used. All and only hazardous drug waste should be placed in them. Receptacles used for glass fragments, needles, and syringes should be puncture resistant. Hazardous drug waste should not be mixed with any other waste. Waste containers should be handled with uncontaminated gloves. ... Gloves, gowns, drug vials, etc, should be sealed in specially labeled (CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. ... All hazardous waste collected from drug preparation and patient-care areas should be held in a secure place in labeled, leakproof drums or cartons (as required by state or local regulation or disposal contractor) until disposal. This waste should be disposed of as hazardous or toxic waste in an EPA-permitted state-licensed hazardous waste incinerator. Transport to an offsite incinerator should be done by a contractor licensed to handle and transport hazardous waste. ... If access to an appropriately licensed incinerator is not available, transport to and burial in an EPA-licensed hazardous waste dump site is an acceptable alternative. While there are concerns that destruction of carcinogens by incineration may be incomplete, newer technologies and stringent licensing criteria have improved this disposal method. ... Chemical deactivation of hazardous drugs should be undertaken only by individuals who are thoroughly familiar with the chemicals and the procedures required to complete such a task. The IARC recently published a monograph describing methods for chemical destruction of some cytotoxic (antineoplastic) drugs in the laboratory setting. The chemicals and equipment described, however, are not generally found in the clinical setting, and many of the deactivating chemicals are toxic and hazardous. Most procedures require the use of a chemical fume hood. The procedures are generally difficult, and the deactivation is not always complete. Serious consideration should be given to the negative aspects of chemical deactivation before one commits to such a course of action. /Antineoplastic agents/ [R18, 758] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Regulatory agencies such as the EPA and state solid and hazardous waste agencies and local air and water quality control boards must be consulted regarding the classification and appropriate disposal of drugs that are defined as hazardous or toxic chemicals. EPA categorizes several of the antineoplastic agents as toxic wastes, while many states are more stringent and include as carcinogens certain cytotoxic drugs and hormonal preparations. EPA also allows exemptions from toxic waste regulations for small quantity generators, whereas certain states do not. It is critical to research these regulations when disposal procedures are being established. /Antineoplastic agents/ [R18, 759] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If the biological safety cabinets is equipped with a drainpipe and valve, it may be used to collect rinse water. The collection vessel used must fit well around the drain valve and not allow splashing. Gauze may be used around the connection to prevent aerosol from escaping. The collection vessel must have a tight fitting cover, and all rinse water (gauze, if used) must be disposed of as contaminated waste. /Antineoplastic agents/ [R18, 755] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. /From table/ [R23] *The Carcinogen Assessment Group in EPA's Research and Development Office has evaluated cyclophosphamide for carcinogenicity. According to their analysis, the weight of evidence for cyclophosphamide is group C, which is based on inadequate evidence in humans and limited evidence in animals. As a group C chemical, cyclophosphamide is considered a possible human carcinogen. [R24] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R25] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R25] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R17, 1979.23] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/ [R18, 759] HTOX: *LIMB REDUCTION DEFECTS HAVE BEEN OBSERVED IN TWO CASES OF INFANTS EXPOSED TO CYCLOPHOSPHAMIDE IN UTERO. ONE MOTHER RECEIVED 100 MG/DAY DURING HER ENTIRE PREGNANCY: HER INFANT HAD NO BIG TOES OR THEIR RESPECTIVE METATARSALS AND PHALANGES; THE LEFT FIFTH FINGER HAD A HYPOPLASTIC MIDPHALANGE; THE INFANT ALSO HAD A PROMINENT PALATAL GROOVE. /MONOHYDRATE/ [R26] *Paternal use of cyclophosphamide prior to conception has been associated with cardiac and limb abnormalities in an infant. [R27, Inc.1102] *Cyclophosphamide crosses the placenta. Use in humans has resulted in both normal and malformed (missing fingers and/or toes, cardiac anomalies, hernias) newborns; risk seems to be less in the second and third trimesters. Low birth weight is also a risk with exposure of the fetus to antineoplastics. First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic admin during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered. Other hazards to the fetus include adverse reactions seen in adults. [R27, Inc.1102] *... A treated mother gave birth to a 1900 g infant with multiple anomalies including 4 toes on each foot, flattening of the nasal bridge and a hypoplastic 5th finger. The clinical picture was compatible with fetal injury occurring during an intensive course of iv therapy (1,800 mg) given at about the 77th to 82nd day of gestation. [R28] *Patients who receive high dose of cyclophosphamide over prolonged periods may develop interstitial pulmonary fibrosis, which can be fatal. In some cases, discontinuance of the drug and administration of corticosteriods has failed to reverse this syndrome. [R29, 960] *Cardiotoxicity, which is uncommon at usual dosages, has been reported in patients receiving high doses of cyclophosphamide (120 (i.e., 60 mg/kg daily) to 270 mg/kg over a period of a few days), generally as part of an intensive, multiple-drug antineoplastic regimen or in conjunction with transplantation procedures. Potentially fatal cardiotoxicity also has occurred when cyclophosphamide (given concomitantly with mesna /2-mercaptoethane sulfonic acid sodium salt/ and followed with autologous bone marrow transplant) was administered inadvertently in a dosage of 4 g/sq m daily for 4 doses rather than in a total dose of 4 g/sq m administered over 4 days in equally divided doses of 1 g/sq m daily as part of a phase I protocol. Deaths have occurred from diffuse hemorrhagic myocardial necrosis and from a syndrome of acute myopericarditis when cyclophosphamide was used in high doses alone or in combination regimens; severe, sometimes fatal congestive heart failure has occurred rarely within a few days after the first dose of cyclophosphamide in such cases. Hemopericardium secondary to hemorrhagic myocarditis and myocardial necrosis, and pericarditis without evidence of hemopericardium, also has been reported. [R29, 960] *Sister chromatid exchanges (SCE) and lymphocyte subsets of children with acute lymphoblastic leukemia (ALL) were investigated during chemotherapy. The treatment followed protocol ALL-BFM-90. Children with ALL at the time of diagnosis showed statistically significant higher SCE frequencies (4.9 + or - 0.77) than healthy controls (3.6 + or - 0.93; P = 0.002). The in vivo effects of cyclophosphamide (CP) resulted in a dramatic increase of the SCE frequency (20.5 + or - 3.76). This increased SCE level of lymphocytes might reflect an instability of DNA or a deficiency of DNA repair. One could suggest that lymphocytes of children with ALL might have a higher susceptibility to harmful influences; and this could be a co-factor towards the development of the malignant disease. However, immediately 1 wk after the admin of CP, the SCE rate decreased. This decline of SCE frequency correlated with a severe reduction of the absolute number of T lymphocytes. The observed reduction of SCE frequency may be due to a loss of T lymphocytes, or SCE became repaired during 1 week. [R30] *In the present study a cancer risk assessment of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was carried out following two approaches based on (1) data from an animal study and (2) data on primary and secondary tumors in CP-treated patients. Data on the urinary excretion of CP in health care workers were used to estimate the uptake of CP, which ranged from 3.6 to 18 ug/day. Based on data from an animal study, cancer risks were calculated for a health care worker with a body weight of 70 kg and a working period of 40 yr, 200 days/yr (linear extrapolation). The life-time risks (70 yr) of urinary bladder cancer in men and leukemias in men and women were found to be nearly the same and ranged from 95 to 600 per million. Based on the patient studies, cancer risks were calculated by multiplication of the 10-yr cumulative incidence per gram of CP in patients by the estimated mean total uptake in health care workers over 10 yr, 200 days/yr. The risk of leukemias in women over 10 yr ranged from 17 to 100 per million using the secondary tumor data (linear extrapolation). Comparable results were obtained for the risk of urinary bladder tumors and leukemias in men and women when primary tumor data were used. Thus, on an annual basis, cancer risks obtained from both the animal and the patient study were nearly the same and ranged from about 1.4 to 10 per million. In The Netherlands it is proposed that, for workers, a cancer risk per cmpd of one extra cancer case/million/year should be striven for ("target risk") and that no risk higher than 100/million/year ("prohibitory risk") should be tolerated. [R31] *Cyclophosphamide ... commonly cause a severe hemorrhagic cystitis in acute overdose. Nausea and vomiting occur acutely due to destruction of the intestinal epithelium. Myelosuppression with resultant leukopenia, anemia, and variable thrombocytopenia has been reported. Leukocyte counts fall within 1 week after therapeutic treatment; platelets decline soon afterward. Maximum depression occurs in 2-3 weeks, followed by quick recovery. Hair and hearing loss with tinnitus have been reported. [R32] *Alkylating agents are cytotoxic and kill rapidly dividing neoplastic and normal cells and have drastic effects on cells of the immune system. ... In cancer patients, a high CY dose (1000 mg/sq m intravenously (iv)) results in 30 and 40% reduction of B and T cells, respectively, after 7 days ... . A low CY dose (300 mg/sq m iv), on the contrary, had no effect on the number of B and T cells. /Alkylating agents/ [R33, 468] *A newborn exposed in utero to cyclophosphamide during the 1st trimester presented with multiple anomalies. the mother, who was being treated for a severe exacerbation of systemic lupus erythematosus, received 2 IV doses of 200 mg each between 15 and 46 days' gestation. Except for prednisone, 20 mg/day, no other medication was given during the pregnancy. The 3150 g female infant was delivered at 39 wk gestational age with multiple abnormalities, including dysmorphic facies, multiple eye defects including bilateral blepharophimosis with left microphthalmos, abnormally shaped. low-set ears, cleft palate, bilaterally absent thumbs, and dystrophic nails. Borderline microcephaly, hypotonia, and possible developmental delay were observed at 10 months of age. [R34, 234] *Cyclophosphamide is one of the most common causes of chemotherapy-induced menstrual difficulties and azoospermia. Permanent secondary amenorrhea with evidence of primary ovarian damage has been observed after long-term (20 months) use of cyclophosphamide. In contrast, successful pregnancies have been reported following high-dose therapy. Moreover, azoospermia appears to be reversible when the drug is stopped. [R34, 234] *Cyclophosphamide-induced chromosomal abnormalities are also of doubtful clinical significance but have been described in some patients after use of the drug. A study published in 1974 reported chromosome abnormalities in patients treated with cyclophosphamide for rheumatoid arthritis and scleroderma. In contrast, chromosome studies were normal in a mother and infant treated during the 2nd and 3rd trimesters in another report. In another case, a 34 yr old woman with acute lymphoblastic leukemia was treated with multiple antineoplastic agents form 22 wk gestation until delivery of a healthy female infant 18 wk later. Cyclophosphamide was admin 3 times between the 26th and 30th wks of gestation. Chromosome analysis of the newborn revealed a normal karyotype (46,XX) but with gaps and a ring chromosome. The clinical significance of these finding sin unknown, but since these abnormalities may persist for several years, the potential existed for an increased risk of cancer as well as for a risk of genetic damage in the next generation. [R34, 235] *A study published in 1985 examined 30 men to determine the effect of cyclophosphamide on male hormone levels and spermatogenesis. The men had been treated at a mean age of 9.4 yr for a mean duration of 280 days. The mean age of the men at the time of the study was 22 yrs with a mean interval form end of treatment to evaluation of 12.8 yrs. Four of the men were azoospermic, 9 were oligospermic, and 17 were normospermic. Compared to normal controls, however, the 17 men classified as normospermic had lower ejaculate volumes (3.1 vs. 3.3 ml), lower sperm density (54.5*10^6 vs. 79*10^6/ml), decreased sperm motility (42% vs. 61%, p < 0.05), and less normal sperm forms (61% vs. 70%, p < 0.05). concns of testosterone, dehydroepiandrosterone sulfate, and prolactin were not significantly different between patients and controls. One oligospermic man (sperm density 12*10^6/ml) had fathered a child. [R34, 236] *A 1979 report involved a case of an 18 yr old woman with Burkitt lymphoma diagnosed in the 26th wk of gestation. She was treated with a 7 day course of cyclophosphamide, 10 mg/kg/day IV, as a single daily dose (total dose 3.5 g). Six weeks after the last chemotherapy dose, she delivered a normal, 2160 g male infant. Analysis of the newborn's blood counts was not conducted. The tumor recurred in the postpartum period, and treatment with cyclophosphamide, 6 mg/kg/day IV, was started 20 days after delivery. Although she was advised not to nurse her infant, she continued to do so until her sudden death after the third dose of cyclophosphamide. Blood counts were conducted on both the mother and the infant during therapy. Immediately prior to the first dose, the infant's leukocyte and platelet counts were 4,800/cu mm (abnormally low for age) and 270,000/cu mm, respectively. After the third maternal dose, the infant's counts were 3,200/cu mm and 47,000/cu mm, respectively. Both counts were interpreted by the investigator as signs of cyclophosphamide-induced toxicity. It was concluded that breast feeding should be stopped during therapy with the agent. [R34, 237] *Chemotherapy induced pulmonary toxicity: Cyclophosphamide. Histopathology: endothelial swelling, pneumocyte dysplasia, lymphocyte infiltration; fibrosis. Clinical features: Does not appear to be schedule- or does-related and may occur after discontinuation. Clinical presentation: progressive dyspnea, fever, dry cough, tachypnea, fine rales, decr diffusing capacity and restrictive ventilatory defect, bilateral interstitial infiltrates. Treatment/Outcome: Clinical recovery reported in about 50% of patients within 1-8 wk if therapy stopped. Some of these patients received steroid therapy; however, others have died despite steroid therapy. Occasionally, therapy has been restated without recurrence. /from table/ [R35, p. 91-24] *Two patients received four times the lethal dose of cyclophosphamide: one died and the other has residual cardiac damage. [R36] *In order to develop a method for detecting metabolism-mediated embryotoxicity, differentiating embryonic stem (ES) cells were exposed to the well-known proteratogen, cyclophosphamide (CPA). CPA was tested in a scientifically validated embryonic stem-cell test (EST), and in the newly developed reporter-gene assay for developmental cardiotoxicity. Both assays gave false-negative results. Because no metabolic competence (cytochrome P450 activity) was found in the ES cells under the selected culture conditions, a simple biotransformation system was combined with the reporter-gene assay. As the metabolic pathway of CPA is well characterised, the genetically engineered mammalian cell line V79, transfected with CYP2B1 cDNA, was selected as a biotransformation system. CYP2B1 is responsible for transforming CPA into teratogenically active metabolites. The supernatants of genetically engineered V79 cells were analysed in the reporter-gene assay for developmental cardiotoxicity. In preliminary experiments, the combined system was able to detect the embryotoxic potential of the proteratogen, CPA. [R37] *A 3 hr exposure time, in both the absence and presence of metabolic activation, was used for the in vitro Comet assay. ...The Comet assay and the chromosomal aberration tests was found to be satisfactory on a qualitative basis, although positive results in the Comet assay were always at higher doses than in the cytogenetic test. [R38] *These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has long latency of onset (8-13 hr) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors. [R39] NTOX: *TWO GROUPS OF 10 MALE AND 10 FEMALE, 4 TO 24 WEEK OLD NZB/NZW HYBRID MICE /WHICH DEVELOPED AUTOIMMUNE COMPLEX NEPHRITIS/ WERE GIVEN DAILY SC INJECTIONS OF 1 MG/KG BODY WT OR 8 MG/KG BODY WT CYCLOPHOSPHAMIDE IN 0.1 ML SALINE FOR UP TO 93 WK; 20 MALES AND 20 FEMALES WERE INJECTED WITH SALINE ALONE AND SERVED AS CONTROLS. FIFTY PERCENT OF MALE CONTROLS HAD DIED BY THE 31ST WK OF THE STUDY, COMPARED WITH 41 AND 60 WK FOR THOSE GIVEN THE LOW AND HIGH DOSE LEVELS. FIFTY PERCENT OF MALE CONTROLS HAD DIED BY 57 WK, COMPARED WITH 71 AND 80 WK FOR THE TREATED ANIMALS. TUMORS WERE OBSERVED IN TREATED MALES AFTER 60 WK OF TREATMENT AND IN FEMALES AFTER 40 WEEKS. EIGHT MALES AND 9 FEMALES GIVEN THE HIGHEST DOSE LEVEL DEVELOPED NEOPLASMS, INCL 3 GENERALIZED LYMPHORETICULAR NEOPLASMS IN MALES AND 3 IN FEMALES AS WELL AS A POORLY DIFFERENTIATED SARCOMA. 3 SQUAMOUS CELL CARCINOMAS OCCURRED AT THE SITE OF INJECTION IN FEMALES. PULMONARY ADENOMAS WERE ALSO OBSERVED IN 3 MALE AND 1 FEMALE MICE. OF ANIMALS GIVEN THE LOW DOSE LEVEL, 3 MALES AND 1 FEMALE DEVELOPED NEOPLASMS. AMONG CONTROLS 2 MALE AND 1 FEMALE MICE HAD RETICULUM CELL SARCOMAS. /MONOHYDRATE/ [R40] *A GROUP OF 50 FEMALE NMRI MICE, 65 DAYS OLD, RECEIVED 52 WEEKLY SC INJECTIONS OF 26 MG/KG BODY WT (7% OF LD50) CYCLOPHOSPHAMIDE (TOTAL DOSE, 1352 MG/KG BODY WT); ANOTHER GROUP OF 50 FEMALES SERVED AS CONTROLS. THE AVERAGE LIFESPAN OF TREATED AND CONTROL ANIMALS WAS 630 + OR - 130 DAYS. IN THE CONTROL GROUP, 3/46 (6%) MICE DEVELOPED STEM CELL LEUKEMIA AND NO OTHER MALIGNANT TUMOR WAS OBSERVED. OF THE TREATED MICE, 28/46 (61%) DEVELOPED MALIGNANT TUMORS: 3 LEUKEMIAS, 12 MAMMARY CARCINOMAS AND 1 OTHER MAMMARY TUMOR, 4 OVARIAN CARCINOMAS, 1 FIBROSARCOMA OF THE THORAX, 1 SKIN CARCINOMA, 2 SARCOMAS @ INJECTION SITE AND 4 LUNG TUMORS. /MONOHYDRATE/ [R41] *FOUR GROUPS OF 15 MALE AND 15 FEMALE A/J MICE, 4-6 WK OLD, WERE GIVEN IP INJECTIONS OF CYCLOPHOSPHAMIDE IN WATER 3 TIMES A WK FOR 4 WK (TOTAL DOSES, 420, 135, 34 AND 8 MG/KG BODY WT). OF 165 MALE AND 195 FEMALE CONTROLS INJECTED WITH WATER ONLY, 37% OF MALE AND 27% OF FEMALE SURVIVORS DEVELOPED LUNG TUMORS WITHIN 39 WK, WITH 0.48 AND 0.29 TUMORS/MOUSE. AFTER 39 WK, 4/30, 27/30, 26/30 AND 30/30 ANIMALS WERE STILL ALIVE IN THE RESPECTIVE DOSE GROUPS. AMONG SURVIVING ANIMALS, THE NUMBERS WITH LUNG NEOPLASMS WERE 2/4 (2.5 TUMORS/MOUSE), 20/27 (74%; 1.3 TUMORS/MOUSE), 11/26 (42%; 0.6 TUMORS/MOUSE) AND 12/30 (40%; 0.4 TUMOR/MOUSE, RESPECTIVELY. THE INCIDENCE OF LUNG TUMORS IN TREATED MICE WAS SIGNIFICANTLY GREATER THAN THAT IN CONTROLS ONLY FOR THOSE GIVEN THE SECOND HIGHEST DOSE LEVEL. /MONOHYDRATE/ [R41] *A GROUP OF 29 DD MICE AND A GROUP OF 25 A MICE OF BOTH SEXES, 4-5 WK OLD, RECEIVED IP INJECTIONS OF 5 MG/KG BODY WT CYCLOPHOSPHAMIDE IN SALINE TWICE WEEKLY FOR 15 SUCCESSIVE WK; 20 AND 16 CONTROL MICE OF EACH STRAIN WERE INJECTED WITH ISOTONIC SALINE ONLY. NEOPLASMS DEVELOPED IN VARIOUS ORGANS IN 12/22 DD MICE THAT SURVIVED MORE THAN 48 WK AFTER THE BEGINNING OF THE TREATMENT; THESE OCCURRED PREDOMINANTLY IN LUNG, LIVER, TESTIS AND MAMMARY GLAND. 3 OF 10 CONTROL DD MICE THAT LIVED BEYOND THE SAME PERIOD ALSO HAD NEOPLASMS. NEOPLASMS DEVELOPED IN 6/16 STRAIN A MICE THAT SURVIVED MORE THAN 42 WK AND INCLUDED 6 IN THE LUNG AND 1 IN THE ORBIT. TWO OF 11 CONTROL A MICE HAD NEOPLASMS, BOTH IN THE LUNG. /MONOHYDRATE/ [R41] *TWO GROUPS, EACH OF 25 MALE AND 25 FEMALE OUTBRED SWISS-WEBSTER-DERIVED MICE, 6 WK OLD, WERE GIVEN IP INJECTIONS OF 12 OR 25 MG/KG BODY WT CYCLOPHOSPHAMIDE 3 TIMES A WK FOR 6 MO. ANIMALS THAT SURVIVED OVER 100 DAYS WERE OBSERVED FOR UP TO 12 FURTHER MO, AT WHICH TIME THEY WERE KILLED. LUNG NEOPLASMS OCCURRED IN 7/30 MALES COMBINED FROM BOTH TREATMENT GROUPS AND IN 10/35 FEMALES; BLADDER PAPILLOMAS WERE FOUND IN 4/30 MALES. THE INCIDENCES OF THE TWO TUMOR TYPES WERE REPORTED TO BE STATISTICALLY GREATER THAN THOSE IN POOLED CONTROLS. THE WORKING GROUP CONSIDERED THAT THE INADEQUATE REPORTING OF CERTAIN ITEMS, SUCH AS SURVIVAL TIMES, THE AMALGAMATION OF VARIOUS EXPERIMENTAL GROUPS AND TUMOR TYPES, AS WELL AS THE LACK OF ADE-ADJUSTMENT IN THE ANALYSES PRECLUDED A COMPLETE EVALUATION OF THIS STUDY. /MONOHYDRATE/ [R41] *TWO GROUPS, EACH OF 25 MALE AND 25-28 FEMALE CHARLES RIVER CD RATS, 6 WK OLD, WERE GIVEN IP INJECTIONS OF 5 OR 10 MG/KG BODY WT CYCLOPHOSPHAMIDE 3 TIMES A WK FOR 6 MO. ANIMALS THAT SURVIVED OVER 100 DAYS WERE OBSERVED FOR 12 FURTHER MO, AT WHICH TIME THEY WERE KILLED. MAMMARY CARCINOMAS OCCURRED IN 9/53 FEMALES COMBINED FROM BOTH TREATMENT GROUPS AND IN 1/50 MALES, AND MAMMARY ADENOMAS OCCURRED IN 24/53 FEMALES. THE INCIDENCE OF ADENOCARCINOMAS IN CONTROL FEMALES WAS 13/181; THE INCIDENCES OF THE TWO MAMMARY TUMOR TYPES WERE REPORTED TO BE INCR TO A STATISTICALLY SIGNIFICANT EXTENT OVER THOSE IN POOLED FEMALE CONTROLS. THE WORKING GROUP CONSIDERED THAT THE INADEQUATE REPORTING OF CERTAIN ITEMS, SUCH AS SURVIVAL TIMES, THE AMALGAMATION OF VARIOUS EXPERIMENTAL GROUPS AND TUMOR TYPES, AS WELL AS THE LACK OF AGE ADJUSTMENT IN THE ANALYSES PRECLUDED A COMPLETE EVALUATION OF THIS STUDY. /MONOHYDRATE/ [R42] *A GROUP OF 32 MALE SPRAGUE DAWLEY RATS, 3 MO OLD RECEIVED WEEKLY IV INJECTIONS OF 13 MG/KG BODY WT CYCLOPHOSPHAMIDE (TOTAL DOSE, 670 MG/KG BODY WT). A GROUP OF 52 UNTREATED RATS SERVED AS CONTROLS. MALIGNANT TUMORS DEVELOPED IN 14/32 TREATED RATS WITHIN 510 + OR - 90 DAYS: THERE WERE 3 RETICULUM CELL SARCOMAS, 6 HEMANGIOENDOTHELIOMAS IN VARIOUS ORGANS, 1 NEUROGENIC SARCOMA OF MEDIASTINUM, 1 SARCOMA OF THE HEART AND 1 LEUKEMIA; TWO RATS HAD 2 MALIGNANT TUMORS. EACH: ONE HAD OSTEOSARCOMA OF PARANASAL SINUS AND A PHEOCHROMOCYTOMA, AND THE OTHER HAD AN ANGIOSARCOMA OF THE ABDOMEN AND A PHEOCHROMOCYTOMA. OF THE CONTROLS, 6/52 DEVELOPED MALIGNANT TUMORS WITHIN 670 + OR - 150 DAYS: 3 RETICULUM CELL SARCOMAS, 1 PHEOCHROMOCYTOMA, 1 HEMANGIOSARCOMA OF THE LUNG AND 1 SARCOMA OF THE KIDNEY. /MONOHYDRATE/ [R43] *A SINGLE IP DOSE OF CYCLOPHOSPHAMIDE CAUSES MARKED NECROSIS OF THE BLADDER AND OF THE TUBULAR AND PELVIC EPITHELIUM IN MICE, RATS, AND DOGS; RELATIVELY LITTLE DAMAGE WAS OBSERVED IN LIVER, EVEN AFTER PROLONGED ADMINISTRATION. NECROSIS OF BLADDER TISSUE IS FOLLOWED BY RAPID EPITHELIAL REGENERATION OF DIPLOID CELLS AND LATER PRODUCTION OF TETRAPLOID, OCTOPLOID AND OCCASIONAL HYPERPLOID CELLS. /MONOHYDRATE/ [R44] *CYCLOPHOSPHAMIDE IS TERATOGENIC IN SEVERAL SPECIES, INCL MICE, RATS, RABBITS, AND CHICKENS. IT PRODUCES A VARIETY OF SKELETAL, SOFT TISSUE AND OTHER MALFORMATIONS AND INCR NUMBER OF RESORPTIONS; THE TYPE AND FREQUENCY OF MALFORMATIONS ARE STRICTLY DOSE AND TIME DEPENDENT. /MONOHYDRATE/ [R45, (1981)] *CYCLOPHOSPHAMIDE IS ALSO TERATOGENIC IN THE RHESUS MONKEY WHEN GIVEN INTRAMUSCULARLY FOR VARIOUS PERIODS BETWEEN DAYS 25 AND 43 OF PREGNANCY AT DOSES RANGING BETWEEN 2.5 AND 20 MG/KG BODY WT. THE INDUCED ABNORMALITIES INCLUDED CLEFT LIP WITH CLEFT PALATE, EXOPHTHALMUS, A MARKED UNDERDEVELOPMENT OF THE MIDFACIAL BONES AND MENINGOENCEPHALOCELE. /MONOHYDRATE/ [R45, (1975)] *Teratogenic effects were induced in outbred mice by treatment of 8 wk old pregnant females with 1 of 5 different doses (5, 10, 20, 30, and 40 mg/kg, ip) of cyclophosphamide. Most malformations were induced with 20, 30, or 40 mg/kg, whereas 5 and 10 mg of cyclophosphamide/kg caused no alterations of the fetuses. [R46] *TEN PREGNANT FEMALE RABBITS WERE TREATED WITH A DAILY INJECTION OF 50 MG CYCLOPHOSPHAMIDE (DNA SYNTHESIS INHIBITOR), FROM DAY 11 TO DAY 14, WHICH IS A PERIOD THAT PRECEDES FORMATION OF THE FACE. THE CONTROL SAMPLE COMPRISED FIVE FEMALE RABBITS. THE FETUSES WERE OBTAINED BY CESAREAN SECTION ON DAY 28 AND STAINED WITH ALIZARIN. SIX OF THE TEN TREATED ANIMALS PRODUCED OFFSPRING THAT HAD TEMPOROMANDIBULAR JOINT SYNOTOSIS (TMJ). [R47] *Pregnant CBA/CA mice were injected subcutaneously with 0, 4, 20, or 40 mg/kg of cyclophosphamide 60 hr after copulation. At each of the doses tested, cyclophosphamide significantly reduced the number of blastocyst cells and caused dose related increase in chromosome aberrations in the blastocysts. Cyclophoshamide increased the number of cells with chromosome breaks at all three doses and also increased chromosome rearrangements in the 20 and 40 mg/kg treated groups. The number of cells with ring chromosomes in the 40 mg/kg group was significantly increased. Cyclophosphamide inhibited the synthesis of DNA and of histones in the 20 and 40 mg/kg groups. On a subsequent culture study, it was observed that treatment of the mothers with 20 or 40 mg/kg, significantly inhibited the in vitro hatching of blastocysts from the zona pellucida. Trophoblast expansion and the attachment of embryos to the glass coverslip were also inhibited. [R48] *Five groups of C57BL/6J pregnant mice were treated as follows: 1) 1 ug/g daily iv of saline or cyclophosphamide on day 9-12 or 14-17 of gestation (vehicle and drug were given by injection into the tail vein); 2) 5 ug/g iv vehicle or cyclophosphamide on day 12 of gestation; 3) 1, 2.5, or 5 ug/g ip vehicle or cyclophosphamide on day 12 of gestation; 4) 5, 10, or 20 ug/g ip vehicle or cyclophosphamide on day 17 of gestation; and 5) 10 or 20 ug/g ip vehicle or cyclophosphamide on day 17 of gestation. Number of offspring per female at weaning was similar in controls and all groups except for group 2 in which no offspring of treated dams survived. No gross terata were present. No effect on cell mediated or immune function was observed in offsprings of treated dams. The 5 and 9 week old progeny exposed to 20 ug/g on gestational day 17 had reduced body weight. Decreased numbers of antibody forming cells per spleen were found in 8 week old offspring in group 3. [R49] *CYCLOPHOSPHAMIDE ... HAS BEEN TESTED BY INJECTION INTO THE ANTERIOR CHAMBER OF RABBIT EYES, BUT PROVED EXCESSIVELY DAMAGING TO THE CORNEA TO ALLOW ITS USE IN TREATMENT OF EPITHELIAL INVASION OF THE ANTERIOR CHAMBER. HOWEVER, INJECTIONS INTO THE VITREOUS BODY IN RABBITS IN CONCENTRATIONS UP TO 10 MG/ML HAVE BEEN TOLERATED WITHOUT EXCESSIVE INFLAMMATION ... . [R50] *Cyclophosphamide and two of its metabolites, 4-hydroxycyclophosphamide and phosphoramide mustard were analyzed for their ability to induce sister chromatid exchanges in mouse peripheral blood lymphocytes in vitro and in vivo. In the in vivo experiments each animal received a single ip injection of the cmpd in question at varying doses. In the first experiment on phosphoramide mustard effects, the SCEs/metaphase was 16.04 at a dose of 19.0 uM/kg, the only result significantly different from the control (13.24). In a second experiment, exposure to 50 uM/kg of either cyclophosphamide or phosphoramide mustard induced sister chromatid exchange frequencies of 28.06 and 21.81, compared with the control, 12.02. In the third experiment, both phosphoramide mustard and 4-hydroxycyclophosphamide induced dose dependent incr in sister chromatid exchange frequency (max, about 30 at 150 uM/kg for each cmpd compared with the control of about 10). At equimolar concns of 1 uM, the mean sister chromatid exchange frequency was about 10 for the control and cyclophosphamide, about 21 for phosphoramide mustard, and about 26 for 4-hydroxycyclophosphamide. The in vitro exposures used mononuclear lymphocytes isolated from whole blood pooled from 18 male mice. Lymphocytes were then inoculated into 1 ml of culture media containing 1 uM of either cyclophosphamide phosphoramide mustard, or 4-hydroxycyclophosphamide and incubated for 21 hr. The cells were then washed and the medium replenished, this time without mitogen but containing 5 uM 5-bromo-2'-deoxyuridine. [R51] *The carcinogenic agent cyclophosphamide was sc admin at 0 (controls), 13, and 26 mg/kg for life to groups of 30 female AKR mice, and to groups of 30 NMRI mice. No symptoms of acute or subacute toxicity were observed. CPA dose-dependently incr the median life span in AKR mice by 27% at 13 mg/kg (from 188 to 238 days) and 76% at mg/kg (to 330 days), and decr the incidence in leukemias by 17% and 37%. In NMRI mice, cyclophosphamide significantly increased the incidence of leukemias by 46% at the low dose and 26% at the high dose, respectively. The number of benign and malignant tumors for the high, low, and control groups were 16, 19, and 4 an 3 for NMRI mice. For AKR mice, the tumor numbers were 22, 27, and 30, respectively. Histologically, malignant tumors of the lymphoproliferative system were found to be lyphocytic leukemias (98%) and the malignant thymomas (2%). [R52] *Virtually all nonobese diabetic/WEHI mice spontaneously develop a lymphocytic infiltration of pancreatic islets (insulitis), but very few progress to diabetes ( < 10% in females and < 1% in males at 220 days of age). Cyclophosphamide was admin to non-obese diabetic/WEHI mice at 0, 50, 100, 150, 200, or 300 mg/kg ip in 200 ul phosphate-buffered saline. Diabetes was produced in both sexes 10 to 16 days after admin. There were no significant changes in body wt, and the mortality was < 5% within 28 days. Diabetes incidence decr with decr doses of cyclophosphamide and with < 100 mg/kg, there is no incr in incidence over controls. Cells in the insulitis lesion were mainly T-lymphocytes with an initial preponderance of L3T4 cells. Cyclophosphamide dramatically depleted splenic cell numbers from a baseline of (1.2 + or - 0.4) x 10+8 to (1.4 + or - 0.5) x 10+7 by day 4. In expt 2, 3 mice of each sex from the strains Biozzi, BALB/c, BALB/c nude, C3H/He, C3H/HeJ, C57BL/6, C57/Bg, C57 nude, DBA/2, CBA/Ca and CBA nude were injected twice at a 14 day interval with 300 mg/kg ip cyclophosphamide. Non-obese diabetic/WEHI mice (19 female and 15 male) received the same treatment and served as controls. No mice were hyperglycemic 14 days after the second dose, except for the non-obese diabetic mice (13 females and 8 males. Normal islets were found in all non-obese diabetic mice. In exp 3, male non-obese diabetic/WEHI mice were given either an organcultured fetal pancreas isograft, or cyclophosphamide followed 3 days later with a pancreas isograft. Beta cell damage and insulitis in the host pancreas were paralleled in the fetal pancreas isograft. Admin of cyclophosphamide to mice 3 days before grafting caused greater graft infiltration and beta cell loss, and in some cases, no beta-cells were present in the graft. In exp 4, 20 normoglycemic female non-obese diabetic/WEHI mice received a 300 mg/kg ip dose of cyclophosphamide and then either given: (1) (n= 12) iv injections at 8, 24, 48, 96, and 168 hr, with 300 uL of mononuclear cell suspension from female non-obese diabetic/WEHI mice; (2) (n= 12) also injected with phosphate-buffered saline/FCS at the same time; (3) (n= 4) injections with cells obtained from acutely diabetic non-obese diabetic mice. The transfer of lymph node and spleen mononuclear cells to non-obese diabetic mice given cyclophosphamide prevented diabetes. The transfer of sufficient lymphoid cells from young (nondiabetic) mice prevented the [R53] *To investigate the early ovarian changes after cyclophosphamide treatment, immature rats primed for 48 hr with pregnant mare serum gonadotropin were given injections ip of cyclophosphamide (100 mg/kg) at 1, 2, 4, 16, and 24 hr before decapitation. Serum estradiol dropped significantly after 24 hr of exposure to cyclophosphamide (p < 0.001). Following 16 and 24 hr of cyclophosphamide exposure, the number of granulosa cells expressed from each ovary decr (p < 0.05 and p < 0.01, respectively); the number of nucleated bone marrow cells decr (p < 0.01 and p < 0.01), and their median nuclear size was significantly reduced (p < 0.05 and p < 0.05) as measured by Coulter Counter and C-256 channelyzer; and the mean follicular diameter and the number of follicles with diameters > 300 uM were significantly lower than in control. After 4, 16, and 24 hr of exposure, median granulosa cell nuclear size significantly incr (p < 0.05, p < 0.01, and p < 0.01, respectively), DNA cross-link in granulosa cells, measured by alkaline elution, reached a max at 2 hr of exposure and decr thereafter. [R54] *Swiss Webster mice treated orally with cyclophosphamide (1, 2.5 or 5 mg/kg) once daily on gestational days 6 through 18 gave birth to pups which appeared to be normal and the majority of which survived to adulthood. There were no overt signs of maternal toxicity or any changes in maternal body wt gains. Treatment caused a reduction of mean pup weight at birth (1.5 at 5 mg/kg cyclophosphamide vs 1.8 for controls, and an incr in cumulative pup mortality (32/151 at 5 mg/kg cyclophosphamide vs 5/76 for controls). However, pregnancy outcome and mean pup body, spleen, and thymus weights, when measured at 4 weeks of age, were within the control ranges. Hematological profiles, serum immunoglobulin (IgG, IgM) levels and histology of lymphoid tissue (spleen and thymus), assessed at 4 weeks of age, were not affected by the maternal treatment. Treatment with 7.5 mg/kg Cyclophosphamide not only resulted in reduced litter size (5.6 + or - 1.0 vs 12.6 + or - 0.3, but also increased the cumulative pup mortality (71/68 vs 5/76 for controls). With 7.5 mg/kg cyclophosphamide, histopathological changes were observed in the thymus in 2 and 3 week old pups. The morphology of the thymus in 4 week old pups was unremarkable. At the dose of 10 mg/kg, no live births were recorded. Treatment with 7.5 or 10 mg/kg cyclophosphamide resulted in significant reduction in the maternal wt gain, compared with controls. [R55] *The cytostatic agent cyclophosphamide (1X10-5, 10-7 and 10-9 mg/ml) was tested in the initiator tRNA acceptance assay for carcinogens in the presence of 2 concn of microsomal enzymes and NADPH. Treatment of tRNA resulted in a 75% inhibition of its acceptance of L-methionine. Cyclophosphamide also inhibited the charging of unfractionated tRNA from rat liver with L-alanine, L-lysine, L-phenylalanine and L-valine. [R56] *Studies in animals have shown that cyclophosphamide is teratogenic in mice, rats, rabbits, and monkeys given 0.02, 0.08, 0.5, and 0.07 times the human dose, respectively. [R27, Inc.1102] *7 to 10 mg/kg were administered to rats and with treatment on the 11th or 12th day the fetuses developed skeletal defects, cleft palates and exencephaly or encephalocele. This compound was shown to be relatively more embryolethal than chloroambucil when the fetal-maternal toxicity ratios of the two were compared. The compound was found to be teratogenic in mice. In the rabbit, a high incidence of cleft lip and-or palate and reduction defects of the extremities using intravenously 30 mg/kg on single days 11, 12 or 13 was found. In the rhesus monkey, 10 mg/kg on days 27 through 29 produced facial clefts and when given on days 32 through 40, meningoencephalocele was observed. [R28] *A number of studies of the metabolism of cyclophosphamide and its products in in vitro cultures with rat embryos have shown that the cmpd must be bioactivated by a liver monofunctional oxygenase system in order to be teratogenic. The morphologic changes found in vitro were very similar to those seen in vivo. Phosphoramide mustard in equimolar doses caused effects similar to those of bioactivated cyclophosphamide in vitro and when given intraamnioticaly. Acrolein was toxic but its effect was difficult to assess because of protein binding. The other stable metabolite, 4-ketocyclophosphoramide, was only weakly teratogenic in vitro. /It was/ concluded that phosphoramide mustard was the active teratogenic metabolite in a mouse blastocyst system. The monofunctional form of phosphoramide mustard (with only one chloroethyl side chain) has been shown to have the same embryotoxicity as cyclophosphamide. [R28] *1.4, 3.4 or 5.1 mg/kg were administered daily before mating to male rats. On the day of mating the males were not treated. Minimal changes in the male reproductive tract were found but malformations and retardation of growth were found in the offspring of the untreated females they bred with. There was a dose-dependent increase in resorptions and fetal deaths. In the offspring of males treated at 7-9 weeks there were 4 defects in 57 compared to one in 254 of the controls. The defects were hydrocephalus, micrognathia and edema. Growth retardation occurred in 7% of the fetuses in this group. [R28] *When used clinically, the important side effects of cyclophosphamide are bone marrow suppression, with both leukopenia and thrombocytopenia. Nausea and vomiting are rare. Sterile necrotizing hemorrhagic cystitis has been associated with chronic admin and is a cause for stopping therapy. To decr the incidence of this cystitis, which is manifested by bloody urine, the drug should be administered in the morning and animals should be encouraged to urinate frequently. Alopecia occurs occasionally in dogs with continuous hair growth (eg, Poodles, Old English Sheepdogs). [R57, 789] *Treatment of male rats with low dosages of cyclophosphamide causes a dramatic incr in early embryo death among their progeny without significantly affecting the general health of the male. It is hypothesized that cyclophosphamide exerts its effects by targeting specific components of spermatozoal nuclei. The purpose of the present studies was to investigate the effects of chronic cyclophosphamide treatment on spermatozoal DNA. Two approaches were pursued. The first was to determine total DNA damage by using the alkaline elution method. The second was to study spermatozoal DNA template function by using an in vitro DNA synthesis system. Adult male rats were treated with saline or cyclophosphamide (6.1 mg/kg/day) daily for 1 or 6 wk. Cauda epididymal spermatozoa were collected and subjected to alkaline elution using DNA-DNA dot hybridization to quantify the fractionated DNA. One week of treatment with cyclophosphamide caused DNA single strand breaks that could be detected only in the presence of proteinase K in the lysis soln; no DNA cross-links were observed in the animals that received l-wk drug treatment. In contrast, 6 wk of treatment with cyclophosphamide induced a significant incr in both DNA single strand breaks and cross-links in spermatozoal nuclei; the cross-links were attributable primarily to DNA-DNA linkages. The availability of spermatozoal DNA for template function was not affected by 1 wk of treatment with cyclophosphamide but was markedly affected after 6 wk of treatment with this drug. It is proposed that during chromatin transition processes the male genome may be in an open dynamic state with many exposed sites that are vulnerable to alkylating agents. Since there is no DNA repair during spermiogenesis, damage to the genome by alkylation at this stage may be cumulative, resulting in the production of dysfunctional germ cells. [R58] *Exposure of the male germ cell to cyclophosphamide during spermatogenesis and sperm maturation can interfere with development of the embryo. When male rats were treated with a chronic low dose of cyclophosphamide for 4 wk there was a dramatic increase in early postimplantation loss in their progeny, characterized by implantation sites selectively lacking in embryonic tissues. The present study was designed t determine the earliest appearance of a paternal effect of cyclophosphamide treatment and to examine whether the embryonic lineage was selectively affected. Male Sprague-Dawley rats were orally dosed for 4-5 wk with saline or 6 mg/kg per day of cyclophosphamide; their progeny were obtained on Days 2, 2.5, 3, 4, and 4.5 of gestation. Paternal cyclophosphamide treatment had no effect on the mean number of embryos per pregnant female. However, as early as Day 3 of gestation, there was a significant decrease in cell number among the embryos sired by cyclophosphamide-treated males, increasing to a greater than 50% decrease in cell number by Day 4. The cell doubling time in embryos sired by treated males (16 hr) was longer than that of controls (12 hr). This decreased proliferation rate was confirmed by a dramatic decrease in the capacity of both Day 3 and Day 4 embryos sired by cyclophosphamide-treated males to incorporate (3)H-thymidine over a 26-hr culture period. Cytogenetic analysis in a limited number of blastomeres entering metaphase revealed no evidence of chromosomal abnormalities. Both the trophectoderm and the inner cell mass cells were proportionally decreased in Day 4.5 embryos sired by cyclophosphamide-treated males. Thus, paternal cyclophosphamide exposure affected both cell lineages in the conceptus as early as Day 3 of gestation. [R59] NTOX: *A study of cyclophosphamide (CP)-induced DNA damage and repair occurring in vivo was conducted in the brown Norway rat myelocytic leukemia (BNML) model. DNA single-strand breaks (SSB), DNA-DNA interstrand cross-links (DIC), DNA-protein cross-links (DPC), and DNA double-strand breaks (DSB) were measured by alkaline and neutral elution. After ip injection of 50 ng/kg CP, DIC were detectable at 1 hr and peaked at 8 hr. DPC were detectable at 2 hr and peaked at 6 hr. Both DIC and DPC persisted at a relatively high level until 28 hr. Dose-response curves for both DIC and DPC were determined at 4 hr after CP injection over the dose range of 25-150 mg/kg. These doses ranged from the minimally effective dose to doses curative for rats bearing this leukemia (1- to 9-log kill of leukemia cells). No SSB or DSB was observed at 4 hr after CP injection over the dose range of 15-250 mg/kg, but a low level of SSB was observed at 18-28 hr after CP treatment. These data suggest that the cytotoxic effect of CP in vivo is mediated mostly by DIC and DPC. SSB appearing late after CP injection in vivo may be a reflection of repair of DIC and DPC and an indication of the optimal timing for administration of DNA-repair inhibitors. This observation is of interest since our earlier work demonstrated that hydroxyurea can potentiate the therapeutic benefit of CP in this model when it is given over the 4-day period immediately after CP treatment. [R60] *Strain differences in cytochrome P450 (P450) expression were investigated in Sprague-Dawley (SDs) compared with Fischer 344s (F344s) rats after admin of cyclophosphamide (CPA). Animals received a single dose of CPA with sacrifice occurring 6 days post-treatment. At 130 mg/kg, male F344s displayed a greater sensitivity to CPA, as evidenced by a 68% loss of total hepatic microsomal P450 compared with only 35% in SDs. The most dramatic change in P450 was the loss of 2C11 (84% in F344s, 52% in SDs). In the SD, individual rat 2C11 activity was correlated (r sq=0.76), with the level of plasma thyroxine in that animal. In male F344s admin CPA at 50 mg/kg, 43 and 44% losses in 2C11 activity (P < 0.05) and thyroxine (P < 0.01), respectively, were observed, whereas activities characteristic of P450s 2C11, 3A2, 2A2, 2C6 and 2E1/1A2 were unaffected in SDs at this dose. CPA also produced suppression of P450 in female SDs, including female-specific 2C12. Correlation was observed between the loss of P450 expression and change in body weight after treatment in both male and female animals, suggesting that CPA downregulated P450 expression secondary to decr caloric intake. The anorectic effect of CPA is believed to result from potent CNS stimulation, accompanied by a state of adaptive hypothyroidism. [R61] *CP /cyclophosphamide/ decreased the activity of the female rat hepatic enzymes 2A1, 2C6 and /or 2C12 and 2E1, NADPH-P450 oxidoreductase and 17 beta-oxidoreductase and the pulmonary enzyme 2B, 7 days after its admin. The decr in the activity of the enzymes 2E1 AND NADPH-P450 oxidoreductase were accompanied by a corresponding change in the amt of enzyme protein indicating that the alteration in expression of these enzymes occurred via changes in transcription and/or translation or protein degradation ... CP also impaired its own activation 7 days after its admin to the female rat ... The change in female enzyme profile was accompanied by a reduction in the hormones oestradiol, T4 AND T3 7 days after CP admin ... Despite an apparent trend for an incr in activity on day 5, a decr on day 8 and a subsequent incr on day 11, repeat doses of CP to the male rat generally did not alter the P450 isoforms 2A2, 2B1, 2C11, 2E1 and 3A2 or 17 beta-oxidoreductase, NADPH-P450 oxidoreductase and steroid 5 alpha-reductase ... Chronic admin of CP to the male rat significantly reduced erythromycin demethylase and NADPh-P450 oxidoreductase 8 days following commencement of dosing and significantly incr statistically significant incr in pulmonary 2B 5 days following commencement of dosing ... Plasma testosterone and TSH were unchanged following repeated dosing with CP while T3 was significantly decr on days 5, 8 and 11 AND T4 was significantly decr on day 8. [R62] *Paracoccidioidomycosis is an endemic fungal disease widely distributed throughout Latin America. The potent immunosuppressor cyclophosphamide (CY) has been used to modulate host immune response to Paracoccidioides brasiliensis in an experimental model. Inbred male Buffalo/Sim rats weighing 250-300 g were inoculated with 5X10+6 P. brasiliensis cells of the yeast phase form by intracardiac route. One group of animals was treated with 20 mg/kg body weight at days +4, +5, +6, +7, +ll and +l2 post-infection, while a control group was infected alone. No mortality was recorded in either group. Treated rats presented: a) a decrease in granuloma size, which contained less fungal cells; b) a lack of specific antibodies up to 35 days post-infection, and c) a significant increase in the footpad swelling test (DTH) against paracoccidioidin. Splenic cell transfer from CY-treated P. brasiliensis-infected donors to recipients infected alone led to a significant increase in DTH response in the latter versus untreated infected controls. Likewise, in treated infected recipients transferred with untreated infected donor spleen cells, footpad swelling proved greater than in controls. Thus, it would seen that each successive suppressor T lymphocyte subset belonging to the respective cascade may be sensitive to repeated CY doses administered up to 12 days post-infection. Alternatively, such CY schedule may induce the appearance of a T cell population capable of amplifying DTH response. [R63] *Liver microsomes were obtained from male Hooded Wistar rats admin a single dose (ip) of saline or cyclophosphamide (200 mg/kg). Rats receiving cyclophosphamide (CP) were killed 1, 4, 7, 10 or 14 days after CP admin. The O-demethylation of dextromethorphan to dextrorphan was used to monitor 2D1 activity ... The mean Vmax for dextrorphan formation was reduced significantly (p < 0.0001) 7, 10 and 14 days after CP admin compared with the control group (control, 0.32 + or - 0.07; 7-day, 0.20 + or - 0.08; 10-day, 0.11 + or - 0.02; and 14-day group, 0.15 + or - 0.02 nmol/mg/min) ... Western blotting revealed that there was a significant reduction (p < 0.0005) in the microsomal relative 2D1 content 10 days after CP admin compared with the control group (control, 1.25 + or - 0.44; and 10-day group, 0.65 + or - 0.14) ... The activity of reduced nicotinamide adenine dinucleotide phosphate P450 reductase was significantly reduced (p < 0.0001) 7, 10 and 14 days following CP admin (control, 215 + or - 24; 7-day, 102 + or - 20; 10-day, 59 + or - 4 and 14-day group, 76 + or - 8 nmol/mg/min). Cytochrome b5 content was significantly reduced (p < 0.0001) 7 and 10 days following CP admin (control, 0.46 + or - 0.13; 7-day, 0.28 + or - 0.07 and 10-day group, 0.20 + or - 0.03 nmol/mg) ... The significant reductions in the activity or rat hepatic microsomal 2D1 following CP admin, as seen by the alterations in mean Vmax for dextrorphan formation, do not appear to be due to a single factor, but may result from a combo of several events, incl reductions in relative 2D1 content, reduced nicotinamide adenine dinucleotide phosphate P450-reductase activity and cytochrome b5 content. [R64] *The testicular toxicity of cyclophosphamide (Cp) in rats was evaluated by quantitative morphometry of spermatogenic cycle stages. Nine-week-old male Sprague-Dawley rats in Group 1 were given a single oral administration of 100 mg/kg of Cp, and were sacrificed at 1, 7, 14 and 21 days thereafter. Rats in Group 2 were orally given 100 mg/kg/day of Cp for 2 days, followed by 50 mg/kg/day for the next 3 days, and were sacrificed at 1 and 4 days after the last administration. The numbers of seminiferous epithelia were counted in the seminiferous tubules of stages II, V, VII and XII of the spermatogenic cycle. The data were expressed as numbers of spermatogenic cells per Sertoli cells per seminiferous tubule cross section. Animals in Group 1 showed decreased preleptotene spermatocytes at Day 7, decreased zygotene spermatocytes at Day 14, and decreased pachytene spermatocytes at Day 21. In group 2, testicular toxicity could also be clearly detected by this morphometric approach. The present morphometric study thus indicates that testicular toxicity can be detected from Day 7 even after a single administration of Cp. [R65] *As a first step in developing a potentially more sensitive assay, micronucleus induction by cyclophosphamide (CP) was assessed in an in vivo/in vitro system using rat bone marrow and spleen cells. In each of two independent experiments, two rats/dose were treated i.p. with 0, 20, or 40 mg CP/kg and killed 6 hr later. Cultures were then established in the presence of growth stimulants (interleukin-3 and granulocyte-macrophage colony stimulating factor for bone marrow; lipopolysaccharide and concanavalin A for spleen) and cytochalasin B, a cytokinesis inhibitor. Bone marrow cells were harvested and slides prepared 24 hr after initiation, while spleen cells were harvested at 48 hr. One thousand cells/tissue/group were scored for cell cycle kinetics and 1000 binucleate (BN) cells were scored for micronuclei. In addition, spleen cells were concurrently assayed for chromosome aberrations. A dose-related cell cycle delay was observed in both tissues in both experiments. Bone marrow showed a 6% average background frequency of micronucleated BN cells, while the low dose induced an average of 20%, and the high dose 31%. For spleen, the average control frequency of micronucleated BN cells was 3%, the low dose induced a 40% average frequency, and the high dose 65%. Also in splenocytes, a dose-dependent incr in chromosome aberrations was observed, with an almost 40-fold incr observed over the control value at the high dose. [R66] *Cyclophosphamide is a cyclic phosphamide derivative of mechlorethamine that requires metabolic activation by the cytochrome p450 oxidation system in the liver. Cyclophosphamide is given PO or IV, and dose limiting leukopenia associated with bone marrow suppression is the primary toxicity. Sterile hemorrhagic cystitis caused by acrolein, a metabolite of cyclophosphamide, can occur and should be treated by active diuresis and intravesicular administration of N-acetyleysteine. Mesna, a drug that acts to detoxify metabolites of cyclophosphamide, has been used in human medicine to preclude hemorrhagic cystitis. [R67, 1835] *Alkylating agents are cytotoxic and kill rapidly dividing neoplastic and normal cells and have drastic effects on cells of the immune system. For example, CY at high doses (300 mg/kg) can deplete mice of their T and B lymphocytes ... . At lower doses (50-100 mg/kg), CY transiently depletes B but not T cells in mice ... . Compensatory responses result in twice the normal number of lymphocyte in spleens of mice 12-15 days following treatment, whereas normal numbers return by day 30. CY can also reduce macrophage and NK numbers and function ... . /Alkylating agents/ [R33, 468] *There is a need for a rapid assay to identify agents that damage mitochondria because the mitochondrion may be an important target for numerous environmental mitotoxins. Certainly at least one chemotherapeutic regimen (CHOP therapy) that includes doxorubicin can induce cardiomyopathy through mitochondrial genotoxicity in cardiac muscle cells. Yeast cells (1.5 x 10(6)-10(7)) in water are spread on a YEPD plate, and, when the suspension of cells has dried, a small well (12 mm diameter) is cut into the agar; 200-400 microl of a solution of the presumptive mitochondrial genotoxin is placed in the well, and the plates are incubated for 2 days. The genotoxin forms a concentration gradient through the agar and affects the growing cells. An overlay containing tetrazolium chloride is added, and the plates are incubated for 6-24 hr. Respiring cells turn red, and nonrespiring cells, with damaged DNA or inhibited respiratory chains, that are adjacent to the well, are white. A white ring, or a more lightly colored red ring, around the well indicates the presence of cells with lowered respiratory activity which may be fully reversible when the mitochondrial genotoxin is removed. In preliminary experiments, doxorubicin (= adriamycin) shows strong activity with this assay; cyclophosphamide is negative, and 4-hydroxycyclophosphamide, a metabolite of cyclophosphamide, is weakly positive. Ethidium bromide, methotrexate, 5-fluorouracil, and 5-fluorocytosine also are mitochondrial genotoxins. Antifungal agents similar to 5-fluorocytosine and anthelmintic compounds such as pyrvinium iodide can be powerful mitochondrial genotoxins. [R68] *In a previous study, we showed that soluble low-molecular-mass tumor-associated antigens (sTAA) promote the anti-tumor effect of the anticancer drug cyclophosphamide (CPA) on rat mammary carcinogenesis. In this report, we analyzed the underlaying mechanisms. Studies were performed on the spleen and lymph nodes from the following groups of mammary tumor-bearing rats: i) control rats, ii) rats treated with sTAA, iii) rats treated with CPA, iv) rats treated with CPA and sTAA. Different zones of the spleen and lymph nodes were measured and their T cell content (CD4+ and CD8+ cells) was analyzed immunohistochemically. CPA decreased the size and cell content of follicles, splenic areas related to the production of B cells, of the marginal zone and to a lesser extent of the periarterial lymph sheath, and decreased the number of CD4+ and, at a lower rate, of CD8+ T cells in the spleen. Addition of sTAA restored activity in the splenic zones producing these cells. Similar effects of CPA and sTAA were found in lymph nodes with accumulation of B lymphocytes in the primary and secondary follicles and of T lymphocytes, including both CD4+ and CD8+ cells, in the paracortical zone. We suggest that inhibition of the functional activity of the immune system is one of the main reasons for the toxic effects of chemotherapeutic drugs such as CPA and that the tumor-suppressive antitoxic effects of sTAA result from their activation of B- and T-lymphocyte production in this system, particularly in the spleen and lymph nodes. [R69] *Trypanosoma cruzi-infected juvenile rats develop severe cardiac sympathetic denervation in parallel with acute myocarditis. This aspect has not been studied in adult rats, thought to be resistant to this infection. The mechanism involved in T. cruzi-induced neuronal damage remains to be completely elucidated. In juvenile rats, the mortality during the acute phase depends on T. cruzi populations, ranging from 30% to 100%. Therefore, studies of mechanisms through hazardous procedures such as immunosuppression are restricted. The current paper shows that adult rats infected with T. cruzi (Y strain) develop severe acute myocarditis and cardiac sympathetic denervation, despite null mortality and virtual absence of patent parasitaemia followed by negative haemoculture. Recovery from the myocarditis and denervation occurred but PCR studies showed persistence of parasite DNA at least until day 111 post inoculation. Immunosuppression by cyclophosphamide treatment increased the parasitaemia, prevented the acute myocarditis and the sympathetic denervation without significant alteration of the myocardial parasitism. These results argue against a direct role for parasite-derived products and implicate the inflammatory cells in the denervation process. As previous studies in juvenile animals have discarded an essential role for radiosensitive cells, the macrophages remain as the possible effectors for the T. cruzi-induced neuronal damage. [R70] *Cyclophosphamide (Cy) is an alkylating agent widely used in cancer chemotherapy. It has a bimodal effect on the immune system, depending on the dose and schedule of administration. We have previously demonstrated that a single low dose of Cy has an antimetastatic effect, achieved through immunomodulation, in lymphoma bearing rats. Such a treatment reduced the splenic production of IL-10, TGF-beta, and NO, restoring the lymphoproliferative capacity. A shift from immunosuppression to immunopotentiation induced by low-dose Cy treatment was mainly mediated by a decrease in IL-10 production. The present study focused on the analysis of the modulation of type-1 cytokine levels by treatment with a single low dose of Cy and the effect these cytokines (IL-2 and IFN-gamma) and IL-10 have on primary tumor and metastatic cell growth. Our results suggest that a single low dose of Cy induces a Th2/Th1 shift in the cytokine profile of lymphoma-bearing rats, which may be responsible for its antimetastatic effect. A direct action of IL-10 as a growth factor and IFN-gamma as a cytotoxic factor on metastatic cells is also shown. [R71] *ICA69 (islet cell Ag 69 kDa) is a diabetes-associated autoantigen with high expression levels in beta cells and brain. Its function is unknown, but knockout of its Caenorhabditis elegans homologue, ric-19, compromised neurotransmission. We disrupted the murine gene, ica-1, in 129-strain mice. These animals aged normally, but speed-congenic ICA69(null) nonobese diabetic (NOD) mice developed mid-life lethality, reminiscent of NOD-specific, late lethal seizures in glutamic acid decarboxylase 65-deficient mice. In contrast to wild-type and heterozygous animals, ICA69(null) NOD congenics fail to generate, even after immunization, cross-reactive T cells that recognize the dominant Tep69 epitope in ICA69, and its environmental mimicry Ag, the ABBOS epitope in BSA. This antigenic mimicry is thus driven by the endogenous self Ag, and not initiated by the environmental mimic. Insulitis, spontaneous, and adoptively transferred diabetes develop normally in ICA69(null) NOD congenics. Like glutamic acid decarboxylase 65, ICA69 is not an obligate autoantigen in diabetes. Unexpectedly, ICA69(null) NOD mice were resistant to cyclophosphamide (CY)-accelerated diabetes. Transplantation experiments with hemopoietic and islet tissue linked CY resistance to ICA69 deficiency in islets. CY-accelerated diabetes involves not only ablation of lymphoid cells, but ICA69-dependent drug toxicity in beta cells that boosts autoreactivity in the regenerating lymphoid system. [R72] *The selective cytotoxic effect of CY on the different T and B cell subsets results in modulation of the immune response in ... animals. The effect of these agents on nucleic acid synthesis led initial investigators to classify them as immunosuppressants. The surprising finding of Maguire and Ettore that CY augmented guinea pig immune response to contact sensitizers compelled many investigators to test CYinduced immune stimulation in their systems. CY can suppress antibody formation against a variety of antigens when given 2-3 days after immunization. Similarly, when administered after the antigen, CY can also suppress T cell mediated immunity generated against agents producing contact sensitivity allografts and tumors. However, CY administration prior antigen stimulation results in augmented T cell response against contact sensitizing agents and hapten modified syngenetic cells. Under certain conditions, CY can augment T cell mediated antitumor immunity and facilitate adoptive transfer of antitumor immunity. CY, when administered just before or just after tumor implantation, induces complete regression of a CY resistant murine lymphoma growing in normal immunocompetent host. This regression was immunologically mediated because equivalent CY doses have no effect on the growth of this tumor in T cell deficient mice. ... The most likely mechanism by which CY augments immune responses relates to preferential elimination of suppressor and relative sparing of effector and helper cells. Thus, precursors and mature murine suppressor cells are very sensitive to CY whereas the mature effector cells are relatively insensitive. CY induced immunological regression of murine leukemia is reversed by the infusion of normal spleen cells as a source of precursors of suppressor cells. Memory and helper T cells are relatively resistant to the cytotoxic effect of CY. NK activity against YAC lymphoma targets by non T and non B cells is depressed by CY. Melphalan augments antitumor immunity in a fashion similar to CY and increases ADCC. Nitrosoureas (BCNU) have been shown to inhibit ADCC activity. [R33, 469] *It appears that hepatic damage is minimized by these secondary reactions, whereas significant amounts of the active metabolites, such as 4-hydroxycyclophosphamide and its tautomer, aldophosphamide, are transported to the target sites by the circulatory system. In tumor cells, the aldophosphamide cleaves spontaneously, generating stoichiometric amounts of phosphoramide mustard and acrolein. The former is believed to be responsible for antitumor effects. The latter compound may be responsible for the hemorrhagic cystitis seen during therapy with cyclophosphamide. [R73, 1395] NTXV: *LD50 Rat oral 160 mg/kg; [R16, 972] *LD50 Rat ip 40 mg/kg; [R16, 972] *LD50 Rat sc 144 mg/kg; [R16, 972] *LD50 Rat iv 148 mg/kg; [R16, 972] *LD50 Mouse oral 137 mg/kg; [R16, 972] *LD50 Mouse sc 200 mg/kg; [R16, 972] *LD50 Mouse iv 140 mg/kg; [R16, 972] *LD50 Mouse parenteral 315 mg/kg; [R16, 972] TCAT: ?Cyclophosphamide (CAS # 50-18-0) was evaluated for chromosomal effects. The test substance was examined in an in vitro cytogenetic assay with Chinese hamster ovary (CHO) cells with and without S-9 metabolic activation. It was determined that the test substance can be detected as a promutagen efficiently using this method. No further information was available due to the poor reading quality of the document. [R74] ADE: *Cyclophosphamide is well absorbed orally. [R73, 1395] *PLACENTAL TRANSFER OF (14)CARBON-CYCLOPHOSPHAMIDE HAS BEEN DEMONSTRATED IN MICE; AND A POSITIVE CORRELATION BETWEEN THE ALKYLATION OF EMBRYONIC DNA AND PRODUCTION OF CONGENITAL ABNORMALITIES IN MICE HAS BEEN REPORTED. A SIMILAR CORRELATION HAS BEEN FOUND FOR NUCLEAR-DNA-DEPENDENT RNA POLYMERASES IN RAT EMBRYOS. IN MOST SPECIES, CYCLOSPHSPHAMIDE IS RAPIDLY ABSORBED, METABOLIZED AND EXCRETED. IN RATS, THE SPECIFIC ACTIVITY IN TISSUES IS HIGHEST WITHIN 20-30 MIN FOLLOWING IP INJECTION; UP TO 75% OF THE RADIOACTIVITY IS EXCRETED WITHIN 5-8 HR. /MONOHYDRATE/ [R45, (1981)] *AFTER ITS IV INJECTION, THE DRUG IS RAPIDLY ABSORBED FROM THE BLOOD. IN PATIENTS RECEIVING 6.7-80 MG/KG BODY WT PER DAY OF RING LABELLED CYCLOPHOSPHAMIDE, RADIOACTIVITY WAS DISTRIBUTED RAPIDLY TO ALL TISSUES: ITS HALF LIFE IN THE PLASMA WAS 6.5 HOURS. NO RADIOACTIVITY WAS FOUND IN THE EXPIRED AIR OR FECES. RECOVERY OF RADIOACTIVITY IN URINE HAS BEEN REPORTED TO BE BETWEEN 50-68%, MAINLY IN THE FORM OF CARBOXYPHOSPHAMIDE AND PHOSPHORAMIDE MUSTARD; 10-40% OF THE DRUG WAS EXCRETED UNCHANGED; AND 56% OF THE REACTIVE METABOLITES WERE BOUND TO PLASMA PROTEINS. /MONOHYDRATE/ [R75] *In a cross sectional study, the urine of 20 hospital workers occupationally exposed to cyclophosphamide and 21 unexposed controls was monitored for excretion of cyclophosphamide. During the week in which samples were collected, most of the workers handled cyclophosphamide fewer than 5 times and the amount handled each time ranged from 100-1000 mg (mean + or - 350 mg). All workers claimed to have taken regular safety precautions; ie, at least wearing gloves during handling. The drug was identified in 5 cases (range: 0.7-2.5 ug cyclophosphamide excreted/24 hr urine). A clear relationship between cyclophosphamide handling and urinary detection was shown. 4 of 5 persons with detectable urinary cyclophosphamide had handled cyclophosphamide 10 times or more during the week. [R76] *A group of four adult male Sprague Dawley rats received each a bolus iv injection of (14)C-cyclophosphamide (50 uCi/rat) and 10 mg/kg of cyclophosphamide, dissolved in saline. Samples of plasma, seminal fluid, and tissues were obtained and analyzed. Cyclophosphamide was first found in seminal vesicle fluid within 10 min and reached equilibrium with plasma radioactivity within 30 min. These concentrations were maintained after drug administration for at least 2 hr. In a second experiment, male rats received an ip injection of cyclophosphamide in saline (10 mg/kg unlabeled cyclophosphamide plus 50 uCi/rat of (14)C-cyclophosphamide) 1 hr before exposure to females. The males were killed and blood, urine, and seminal fluid samples were obtained. Females were killed and uterus content plus several tissues were obtained for analysis. More than 5 hr after the males received an ip injection of 14(C)-cyclophosphamide the radiolabeled drug was transmitted to the females and was widely distributed in their seminal plug, vagina, cervix, kidney, and other tissues. In a third experiment, groups of 10 male rats were injected ip with 10, 30, or 100 mg/kg cyclophosphamide in saline, and controls were given saline. Each male was mated with 2 females. On day 20 of gestation, fetuses were removed and studied. The number of pregnant females per sperm positive females ranged from 73 to 92%, with no significant difference in any of the treated groups. The number of implantations per pregnant female decreased with cyclophosphamide treatment and at 30 mg/kg, this decrease was significantly different from controls. The highest dose of cyclophosphamide increased the preimplantation loss per litter, while the percentage of implantation loss per total corpora lutea was almost doubled. [R77] *Cyclophosphamide is excreted into breast milk. [R34, 237] *Oral bioavailability approximately =100%; must be activated in liver by microsomal enzymes to active compds and toxic metabolites; renal elimination of 22% parent drug and 60% of metabolites; t1/2 = 3-10 hr (parent); 6.5- > or=8 hr (alkylating activity) /from table/ [R35, p. 90-11] METB: *... /Cyclophosphamide/ is activated by the hepatic cytochrome P450 system. Cyclophosphamide is first converted to 4-hydroxycyclophosphamide, which is in a steady state with the acyclic tautomer aldophosphamide. In vitro studies with human liver microsones and cloned P450 isoenzymes have shown that cyclophosphamide is activated by the CYP2B group of P450 isoenzymes... . 4-hydroxycyclophosphamide may be oxidized further by aldehyde oxidase either in liver or in tumor tissue and perhaps by other enzymes, yielding the metabolites carboxyphosphamide and 4-ketocyclophsphamide, neither of which possesses significant biological activity. It appears that hepatic damage is minimized by theses secondary reactions, whereas significantl amoutns of the active metabolies, such as 4-hydroxycyclophosphamide and its tautomer, aldophosphamed, are transported to the target sites by the circulatory system. In tumor cells, the aldophosphamide cleaves spontaneously, generating stoichiometric amounts of phosphoramide mustard and acrolein. The former is believed to be responsible for antitumor effects. The latter cmpd may be responsible for the hemorrhagic cystitis seen during therapy with cyclophosphamide. Cystitis can be reduced in intensity or prevented by the pareneteral admin of mesna, a sulfhydryl cmpd that reacts readily with acrolein in the acid environment of the urinary tract. ... Urinary and fecal recovery of unchanged cyclophosphamide is minimal after iv admin. Maximal concns in plasma are achieved 1 hr after oral admin, and the half-life in plasma is about 7 hr. [R73, 1395] *SHEEP WERE ORALLY DOSED WITH CYCLOPHOSPHAMIDE. IN COLLECTED URINE, 2 METABOLITES WERE OBSERVED AND CHARACTERIZED AS O-(2-CARBOXYETHYL)-N,N-BIS (2-CHLOROETHYL)PHOSPHORODIAMIDATE AND 2-(BIS (2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZOPHOSPHORINE 2,4-DIOXIDE (4-KETOCYCLOPHOSPHAMIDE). [R78] *A REACTIVE METABOLITE, N,N-BIS-(2-CHLOROETHYL)PHOSPHORODIAMIDIC ACID, WHICH POSSESSES POTENT ALKYLATING AND CYTOTOXIC PROPERTIES, HAS RECENTLY BEEN ISOLATED FROM THE OXYGENATION PRODUCTS OF CYCLOPHOSPHAMIDE AND MOUSE LIVER MICROCHROMOSOMES. [R79] *Cyclophosphamide is well absorbed orally, and peak plasma levels appear about one hour after oral use. It is also administered intravenously. This drug is metabolized in the liver to the cytotoxic metabolite, 4-hydroxycyclophosphamide, which is in equilibrium with the acyclic tautomer, aldophosphamide. Although the major fraction of these metabolites is oxidized further to inactive products, some aldophosphamide is converted to phophoramidemustard, which alkylates DNA, and to acrolein. [R80] *Acrolein is the metabolite of cyclophosphamide (CP) believed to be involved in the bladder toxicity associated with this anticancer drug. The mechanism by which this extremely reactive intermediate is delivered to the bladder is not known. Glutathione (GSH) readily conjugates with acrolein, and the acrolein mercapturate 5-(3-hydroxypropyl)-N-acetylcysteine (3-hydroxy-PrMCA) has been found in the urine of animals and man given CP. The objectives of this study were to prepare and characterize synthetic standards of the GSH acrolein adduct (3-oxopropyl)glutathione (3-oxoPrGSH), the acrolein mercapturates S-(3-oxopropyl)-N-acetylcysteine (3-oxoPrMCA) and 3-hydroxyPrMCA, and the S-oxidation product of 3-oxoPrMCA (3-oxoPrMCA S-oxide). In addition, the release of acrolein from, and the bladder toxicity of, these conjugates was determined. 3-OxoPrGSH and 3-oxoPrMCA were prepared with a 99% yield by condensing acrolein with GSH and N-acetylcysteine, respectively. [R81] *An important feature of cytochrome P450 (CYP) 2B1 is its high ability to convert the prodrug cyclophosphamide (CPA) to therapeutically cytotoxic metabolites, resulting in interstrand DNA-cross-linking and cell death. We have examined whether and how the phosphorylation of CYP2B1 influences CPA metabolic activation in vitro and in vivo. We found first that only part of the total CYP2B1 pool undergoes phosphorylation. This part is fully inactivated. Second, phosphorylation of CYP2B1 in intact hepatocytes reduced by up to 75% toxification of CPA to mutagenic metabolites (totally dependent on the same preferentially CYP2B-catalyzed 4-hydroxylation of CPA as is the generation of highly cytotoxic species). Third, the phosphoacceptor-serine 128 of CYP2B1 in the consensus sequence for interaction with the protein kinase A represents an on/off switch for the activation of CPA depending on the phosphorylation conditions in the cell. Fourth, evidence is presented that the above-described events also occur in vivo. In conclusion, a successful therapy with CPA, helped by forced expression of CYP2B1 in tumor cells (as recently proposed) will, in addition, be profoundly modified by its phosphorylation status. [R82] *Cyclophosphamide (CPA), a widely used oxazaphosphorine anti-cancer prodrug, is inactive until it is metabolized by cytochrome P450 to yield phosphoramide mustard and acrolein, which alkylate DNA and proteins, respectively. Tumor cells transduced with the human cytochrome P450 gene CYP2B6 are greatly sensitized to CPA, however, the pathway of CPA-induced cell death is unknown. The present study investigates the cytotoxic events induced by CPA in 9L gliosarcoma cells retrovirally transduced with CYP2B6, or induced in wild-type 9L cells treated with mafosfamide (MFA) or 4-hydroperoxyifosfamide (4OOH-IFA), chemically activated forms of CPA and its isomer ifosfamide. CPA and MFA were both shown to effect tumor cell death by stimulating apoptosis, as evidenced by the induction of plasma membrane blebbing, DNA fragmentation, and cleavage of the caspase 3 and caspase 7 substrate poly(ADP-ribose) polymerase (PARP) in drug-treated cells. Caspase 9 was identified as the regulatory upstream caspase activated in 9L cells treated with CPA, MFA, or 4OOH-IFA, implicating the mitochondrial apoptotic pathway in oxazaphosphorine-induced tumor cell death. Correspondingly, expression of the mitochondrial proapoptotic factor Bax enhanced caspase 9 activation, plasma membrane blebbing, and drug-induced cytotoxicity. Conversely, overexpression of the mitochondrial antiapoptotic factor Bcl-2 blocked caspase 9 activation, leading to an inhibition of drug-induced plasma membrane permeability and blebbing, terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity, PARP cleavage, Annexin V positivity, and drug-induced cell death. Although Bcl-2 thus blocked the cytotoxic effects of activated CPA, it did not inhibit the drug's cytostatic effects. CPA induced S-phase cell cycle arrest followed by conversion to an apoptotic pre-G1 state in wild-type 9L cells; by contrast, Bcl-2-expressing 9L cells accumulated in G2/M in response to CPA treatment. Intratumoral expression of Bcl-2 and related family members, including both apoptotic and antiapoptotic factors, is thus an important determinant of the responsiveness of tumor cells to CPA and ifosfamide, both in the context of conventional chemotherapy and in patients sensitized to these oxazaphosphorine drugs by the use of cytochrome P450-based gene therapy. [R83] *Specimens of whole bronchial tissue from the main or lobar bronchi and peripheral parenchyma were removed at surgery of 21 male patients undergoing lung resection for lung cancer (n= 18) or other, non-neoplastic,lung diseases (n= 3). Post-mitochondrial S-12 fractions were obtained. In parallel, the same preparations were used to assess the activation of a promutagen, cyclophosphamide (CPA, 4000 ug/plate), to metabolites reverting his(-) Salmonella typhymurium strain TA1535. Parenchyma compared favorably to bronchus preparations in activating CPA to mutagenic metabolites (n= 6 paired observations). [R84] BHL: *Maximal concns in plasma are achieved 1 hr after oral admin, and the half-life in plasma is about 7 hr. [R73, 1395] ACTN: *The chemotherapeutic alkylating agents have in common the property of becoming strong electrophiles through the formation of carbonium ion intermediates or of transition complexes with the target molecules. These reactions result in the formation of covalent linkages by alkylation of various nucleophilic moieties such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazole groups. The chemotherapeutic and cytotoxic effects are directly related to the alkylation of DNA. The 7 nitrogen atom of guanine is particularly susceptible to the formation of a covalent bond with bifunctional alkylating agents and may well represent the key target that determines their biological effects. It must be appreciated, however, that other atoms in the purine and pyrimidine bases of DNA- particularly, the 1 and 3 nitrogens of adenine, the 3 nitrogen of cytosine, and the 6 oxygen of guanine- also may be alkylated, as will be the phosphate atoms of the DNA chains and amino and sulfhydryl groups of proteins. /Alkylating agents/ [R73, 1389] *Cyclophosphamide can be used to cause immunologically mediated regression of the immunogenic, cyclophosphamide-resistant L5178Y lymphoma in syngeneic and semisyngeneic mice (B6D2F1 (C57BL/6 x DBA/2) females). In order to cause tumor regression it was necessary to give cyclophosphamide (125-200 mg/kg of body wt, iv shortly before or shortly after tumor implantation. Regardless of whether cyclophosphamide was given before or after tumor implantation, tumor regression was associated with the presence in the spleen of an incr number of Lyt-2+ T-cells capable of passively transferring immunity to tumor bearing recipients. This augmented level of immunity was sustained throughout the period of tumor regression. In contrast, a lower level of concomitant immunity generated by control tumor bearers decayed after day 12 of tumor growth. Because the therapeutic effect of cyclophosphamide could be inhibited by passive transfer of L3T4+ T-cells from normal donor mice it is apparent that the therapeutic effect of cyclophosphamide is based on its ability to preferentially destroy L3T4+ suppressor T-cells. These putative precursor suppressor T-cells were regenerated 4 days after being destroyed by cyclophosphamide. [R85] *These studies enable the pattern of emesis and nausea for 3 days following high-dose cyclophosphamide to be described and give some insight into the mechanisms of emesis which may be operating. Nausea and vomiting induced by cyclophosphamide-based chemotherapy has long latency of onset (8-13 hr) and continues for at least 3 days. These findings are of particular importance as many of these patients receive chemotherapy as outpatients and emphasize the need for appropriate anti-emetic prophylaxis for patients at home. Ondansetron was extremely effective over this time in the control of emesis and nausea. These results suggest that high-dose cyclophosphamide-induced emesis over days 1-3 is largely mediated via 5-hydroxytryptamine (5-HT) and 5-HT3 receptors. [R39] *The most likely mechanism by which cyclophosphamide augments immune responses relates to preferential elimination of suppressor and relative sparing of effector and helper cells. Thus, precursors and mature murine suppressor cells are very sensitive to cyclophosphamide whereas the mature effector cells are relatively insensitive ... . Cyclophosphamide induced immunological regression of murine leukemia is reversed by the infusion of normal spleen cells as a source of precursors of suppressor cells ... . Memory and helper T cells are relatively resistant to the cytotoxic effect of cyclophosphamide ... . NK activity against YAC lymphoma targets by non T and non B cells is depressed by cyclophosphamide ... . [R33, 469] INTC: *PRIOR TREATMENT WITH ALLOPURINOL SIGNIFICANTLY PROLONGS /THE HALF-LIFE OF CYCLOPHOSPHAMIDE/. [R3, 1217] *CYCLOPHOSPHAMIDE MAY ENHANCE NEUROMUSCULAR BLOCKADE PRODUCED BY SUCCINYLCHOLINE BY INHIBITING ITS METABOLISM. [R86] *THE ENZYME INHIBITOR SKF 525-A, WHICH INCREASES THE TERATOGENICITY OF CYCLOPHOSPHAMIDE, CAUSED AN INCREASE IN THE CONCN OF CYCLOPHOSPHAMIDE IN THE MOUSE EMBRYO AND ALSO CAUSED A DECREASE IN METABOLITE FORMATION AFTER ADMIN OF CYCLOPHOSPHAMIDE TO PREGNANT MICE. [R87] *Cultured human osteosarcoma cell lines (OST strain and HT 1080) and specimens obtained during surgery on humans (osteosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, epithelioid sarcoma, mesenchymal chondrosarcoma, synovial sarcoma, leiomyosarcoma, and malignant giant cell tumor) were used to study the synergistic effect of caffeine on anticancer drugs, including cyclophosphamide as its active form 4-hydroxyperoxycyclophosphamide. Cell concentrations were 10,000 per dish for the osteosarcoma strain, 50,000 per dish for the HT 1080 strain, and 100,000 to 500,000 for the fresh cells. After a 1 hour exposure of the cells to the anticancer agent, caffeine was added to the top layer for the subsequent 10 day to 3 week combined exposure. Treatment with 3.0 ug/ml (1/10 of the usual peak plasma concentration) cyclophosphamide alone showed colony inhibition of 14.2% in the OST strain and 8.5% in the HT 1080 strain. Addition of 0.2 mM caffeine showed synergism, 27.8% and 56.2% inhibition, respectively. When 2 mM caffeine was used with cyclophosphamide, colony inhibition was 57.1% in the OST strain. At a cyclophosphamide concentration of 0.3 ug/ml and either 0.2 or 2 mM caffeine, synergism still was observed. Using fresh human tumor specimens with cyclophosphamide alone (3.0 ug/ml) 4 of 18 specimens showed positive sensitivity. With 2 mM caffeine exposure in combination, 8 of 18 specimens (44.4%) showed a significant synergistic effect; of these, 7 showed positive sensitivity. An additive effect was observed in one specimen and a subadditive effect in 3 specimens. Continuous exposure to 0.2 mM caffeine in combination resulted in significant synergism in specimens. For comparison, caffeine alone at 0.2 mM produced colony inhibition of 9.2% (OST strain) and 12.5% (HT 10890 strain) in the cultured cells; at 2.0 mM, 15.0% (OST strain) and 100.0% (HT 1080 strain). In fresh sarcoma specimens, caffeine alone at 2 mM produced inhibition of 0.0% to 48.2% (mean, 19.1%) and there was no case with positive sensitivity. [R88] *DBA/2NCr1BR F1 mice received a single iv injection of cyclophosphamide (70, 120 or 200 mg/kg) alone or 2 hr before an ip injection of 1,000 mg/kg of diethyldithiocarbamate. 24 hr after, survival of bone marrow colony forming units spleen and granulocyte macrophage colony forming cells, was determined. On the whole, administration of diethyldithiocarbamate reduced the toxic effect of cyclophosphamide on hemopoietic progenitors. The effect was in general more evident at the lower than at the higher doses of the antitumor drug. [R89] *Leukopenic and/or thrombocytopenic effects of cyclophosphamide may be increased with concurrent use or recent therapy if these medications /blood dyscrasia-causing medications/ cause the same effects; dosage adjustment of cyclophosphamide, if necessary, should be based on blood counts. [R27, Inc.1103] *Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are used concurrently or consecutively /with cyclophosphamide/. [R27, Inc.1103] *Cyclophosphamide may raise the concentration of blood uric acid; dosage adjustment of antigout agents /allopurinol or colchicine or probenecid or sulfinpyrazone/ my be necessary to control hyperuricemia and gout; uricosuric antigout agents may increase risk of uric acid nephropathy. Concurrent use with allopurinol may enhance the bone marrow toxicity of cyclophosphamide; if concurrent use is required, close observation of toxic effects should be considered. [R27, Inc.1103] *Inhibition of cholinesterase activity by cyclophosphamide reduces or slows cocaine metabolism, thereby increasing and/or prolonging its effects and increasing the risk of toxicity. [R27, Inc.1103] *Concurrent use of high-dose cytarabine with cyclophosphamide for bone marrow transplant preparation has bee reported to result in an increase in cardiomyopathy with subsequent death. [R27, Inc.1103] *Concurrent use /of daunorubicin or doxorubicin/ with cyclophosphamide may result in increased cardiotoxicity; it is recommended that the total dose of daunorubicin or doxorubicin not exceed 400 mg/sq m of body surface. [R27, Inc.1103] *These agents /hepatic enzyme inducers/ may induce microsomal metabolism to increase formation of alkylating metabolites of cyclophosphamide, thereby reducing the half-life and increasing the activity of cyclophosphamide. [R27, Inc.1103] *Concurrent use of other immunosuppressants such as: azathioprine; chlorambucil; corticosteroids, glucocorticoid; cyclosporine; mercaptopurine; muromonab-CD3/ with cyclophosphamide may increase the risk of infection and development of neoplasms. [R27, Inc.1103] *Concurrent use /of lovastatin with cyclophosphamide/ in cardiac transplant patients may be associated with an increased risk of rhabdomyolysis and acute renal failure. [R27, Inc.1103] *Cyclophosphamide may decrease plasma concentrations or activity of pseudocholinesterase, the enzyme that metabolizes succinylcholine, thereby enhancing the neuromuscular blockage of succinylcholine. Increased or prolonged respiratory depression or paralysis (apnea) may occur but is of minor clinical significance while the patient is being mechanically ventilated; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockage postoperatively. [R27, Inc.1103] *The effect of high molecular carboxymethyl-chitin-glucan (CMCG), admin either ip, iv or orally prior to cyclophosphamide injection, on the frequency of micronucleated reticulocytes was evaluated in peripheral blood of female ICR mice. Both ip and iv admin of CMCG decreased the clastogenic effect of cyclophosphamide. The protective effect of CMCG was concn dependent, with a higher decrease achieved by 100 mg/kg than by 50 mg/kg body weight. On the other hand, no even five peroral pretreatments with CMCG in the dose of 200 mg/kg body weight during the week prior to simultaneous admin of CMCG and cyclophosphamide induced a decrease of micronucleated reticulocytes in peripheral blood. [R90] *Synergistically enhanced sister chromatid exchange (SCE) frequency by cyclophosphamide (CP) was observed when L1210 lymphoid tumor cells were exposed in vivo to a non-toxic concn of 3-aminobenzamide (3-AB). Additive effects in SCE induction in vivo were observed when either Ehrlich ascites tumor (EAT) cells or P388 lymphocytic leukemia cells treated with CP were exposed to 3-AB in vivo. 3-AB enhanced the survival time of L1210 tumor bearing BDF1 mice treated with CP. However, the combined CP plus 3-AB treatment did not increase the survival of either EAT BALB/c- or P388 BDF1-tumor bearing mice compared with the effect on survival by CP alone. Therefore the in vivo differential antitumor effect, by CP in conjunction with 3-AB, appears to correlated well with the in vivo differential effect on cytogenetic damage caused by the combined CP plus 3-AB treatment. In the Salmonella typhimurium/mammalian microsome test CP appears to have a dose dependent ability to induce base-pair substitutions in strains TA 100 and TA 1535 and frameshift mutations in strains TA 98 and TA 1537. Both types of mutation were synergistically increased in the presence of 3-AB. [R91] *Treatment with Caralluma tuberculata extract induced complex biochemical and cytological changes in mice. Its cytotoxicity in the bone marrow cells of mice was comparable with that of the standard drug cyclophosphamide (C); however, unlike C, C. tuberculata was not clastogenic (as shown by the micronucleus assay). A dose-dependent decrease in the RNA content of liver and testes was produced by C. tuberculata treatment whereas there was no effect on the content of nucleic acid and protein in the brain. In the extract-treated animals there was a significant and dose-dependent increase in the DNA content of the liver, with a negligible effect on the protein content. Combined treatment with C. tuberculata and C showed that C. tuberculata diminished the effect of C on DNA levels; however, RNA levels were further suppressed, resulting in increased cytotoxicity. Pretreatment with C. tuberculata extract significantly reduced the clastogenicity of C. These results indicated the involvement of different phytoconstituents acting by different routes. [R92] *The effect of pretreatment with carboxymethylglucan (CMG) on the frequency of micronuclei induced by cyclophosphamide administration in mice was evaluated. Two doses of CMG (50 mg/kg body weight) injected either intraperitoneally 24 hr or intravenously 1 hr prior to two cyclophosphamide administrations (80 mg/kg) significantly decreased the frequency of micronucleated PCE in bone marrow. Of two evaluated derivatives of carboxymethylglucan, the K3 derivative was most efficient. The results show that it is possible to achieve a suppressive effect of soluble carboxymethylglucan prepared from Saccharomyces cerevisiae against cyclophosphamide mutagenicity. The notion may be useful for glucan's effects against pharmacocarcinogenesis. Therapeutic application of glucan with cyclophosphamide therapy may provide a remarkable decrease of the secondary tumor risk. The utilization of these results for human patients needs to be considered. [R93] *The modulatory effect of vitamin C (Vit C) on the mutagenic effect of the antineoplastic drug cyclophosphamide (CP) was assessed in the in vivo micronucleus test in Swiss mice. Simultaneous oral administration of Vit C with ip administration of CP was found to decrease the frequency of micronucleated polychromatic erythrocytes elevated by CP. Vit C exhibited a significant antimutagenic effect over a wide dose range (1.56-200 mg/kg). The dose-response relationship was highly significant. These results demonstrated the ability of the in vivo micronucleus test to detect in vivo modulation of CP mutagenicity by Vit C. Our earlier results and those from other laboratories also indicate that this model system is suitable for primary in vivo screening of modulation of mutagenesis. [R94] *A total of 78 patients with second recurrence or progression of histologically verified breast cancer were treated with single-agent cyclophosphamide given at 2.5 g/sq m by iv infusion every 3 wk along with mesna support. All had previously been treated with epirubicin and cisplatin or epirubicin alone. Toxicity was predominantly hematologic: WHO grade III+IV toxicity was found in 95% of cases. The overall response rate was 26.7% (95% CI, 15.8-41.4%), with 7% of patients achieving a complete response (CR) and 19.7%, a partial response (PR). The median duration of CRs and PRs was 11 and 5 mo, respectively. The response rate observed for patients previously treated with epirubicin alone was 30.5% in contrast to the 8.3% recorded for patients previously treated with cisplatin plus epirubicin. Thus, an indication of cross-resistance was absent between cyclophosphamide and epirubicin but possible between cyclophosphamide and cisplatin. [R95] *The effect of WR-2721 against cyclophosphamide-induced clastogenicity was studied using the in vivo micronucleus assay. The frequency of micronuclei in polychromatic erythrocytes in the peripheral blood of mice treated with WR-2721 and cyclophosphamide (CP), each of the cmpd at a dose of 200 mg/kg body weight, was evaluated during the 15-day period. The suppressing effect of WR-2721, given 30 min prior to CP admin, on micronuclei induced by the alkylating agent was demonstrated ... The modulatory effect of WR-2721 on the clastogenic activity of CP in the erythropoietic system by the mouse micronucleus test was shown. [R96] */It was/ ... demonstrated in an earlier paper that capsaicin, the pungent principle of red hot chili, has a potent anti-oxidant property that interferes with free-radical involved mechanisms. In the present paper we demonstrate that capsaicin significantly inhibits cyclophosphamide-induced (ip) chromosomal aberrations and DNA strand breakages. This protective action of capsaicin against CP-induced toxicity may possibly be linked with its already reported 'desensitization' effect against chemical irritant-induced damages. [R97] *In the rat, the mortality from cyclophosphamide had prevented the administration of sufficient dosages to produce detectible damage to stem spermatogonia. To overcome this problem, we used bone marrow transplantation and sodium 2-mercaptoethanesulfonate (Mesna) treatment to raise the lethal dose for 50% of the animals (LD50) for cyclophosphamide from 275 to > 400 mg/kg body weight. In addition we used irradiation, 2 weeks prior to injection of cyclophosphamide, to greatly enhance the measured toxicity of cyclophosphamide towards stem spermatogonia. Whereas sperm counts at 9 weeks after a 300 mg/kg cyclophosphamide dose were reduced by only a factor of 1.6 without prior irradiation, they were reduced by a factor of 60 when 2.5 Gy of irradiation had been given. Dramatic protection against this toxicity was produced by hormone treatment with a gonadotropin-releasing hormone (GnRH) antagonist (Nal-Glu) and an antiandrogen (flutamide) following the radiation but prior to cyclophosphamide. This hormone treatment did not modify the stem cell toxicity of the radiation and it therefore must be protecting stem cells against cyclophosphamide-induced damage. [R98] *Hamster to rat renal xenotransplantation was performed with recipient nephrectomies. Recipients were treated beginning on day 0 with continuous FK 506 monotherapy, a 7-day or open-ended monotherapeutic course of cyclophosphamide (CP), and the two drug regiments combined. CP alone (10 mg/kg/day) prevented a xenospecific antibody response and tripled median survival of the kidney (defined as recipient death) from 6 (control) to 18.5 days whereas FK 506 alone had no effect. The drugs in combination were no better than CP alone (15 days) unless the 5-day course of CP was given at a higher dose (15 mg/kg) and started 3 days preoperatively (79 days). In further experiments, adjuvant measures were added to the minimally effective FK 506/7-day CP regimen which gave a median survival of only 15 days. In the most successful modification, intraoperative antibody depletion by the temporary transplantation of third party hamster liver or en bloc kidneys increased median survival from 15 to 34 and 48 days, respectively. An intraoperative i.v. dose administration of the anticomplement drug K76 instead of antibody depletion increased survival to 26 days. Although the events of kidney rejection were similar to those of heart xenografts and partially forestalled by the antibody inhibiting CP treatment, or by antibody depletion, survival for > 100 days was accomplished in only 5 of 86 treated animals. [R99] *Hemorrhagic cystitis is a common problem following cyclophosphamide or radiation therapy. Chitosan has been shown to be an effective hemostatic agent and promoter of wound healing in animal experiments. We evaluated the safety and efficacy of intravesical chitosan in an animal model of cyclophosphamide cystitis. Hemorrhagic cystitis was induced in female F344 rats by intraperitoneal cyclophosphamide, 100 mg/kg Chitosan soln (0.3 ml) was instilled intravesically on day 1 (Group 1), on days 1, 3, and 5 (Group 2), or 1 hr after the admin of cyclophosphamide (Group 3). The rats in group 4 were treated with chitosan diluent on day 1 after cyclophosphamide, and the rats in group 5 received intravesical chitosan without cyclophosphamide. Sequential examination revealed decr mortality and lower incidences of severe bladder bleeding, necrosis and inflammation in Group 3. Treatment delayed until after the appearance of the cystitis, esp repeated treatments, appeared to make the cyclophosphamide-induced changes worse. Used within 1 hr of cyclophosphamide admin, before the cystitis develops, chitosan seemed to have the possibility to inhibit the appearance of hemorrhagic cystitis. In addition to the changes in the bladder, severe changes occurred in the kidneys secondary to cyclophosphamide. [R100] *The effect of pretreatment with miltefosine (MIL) on the antineoplastic activity of cyclophosphamide (CPA) was evaluated in sc benzo(a)pyrene-induced sarcomas (BPS) of the rat. MIL alone had no antineoplastic effect on this autochthonous tumor, but enhanced the chemotherapeutic effect of CPA. Conversely, MIL counteracted the myelotoxicity of CPA in normal adult rats. Although the nadir of the leucocyte count remained unchanged, the recovery phase was considerably shortened, an effect which resembled the pharmacological action of GM-CSF. [R101] *The effect of protein malnutrition and alcohol consumption on the yield of chromosomal damage induced by cyclophosphamide (CP) was studied. Chromosomal damage induced in bone marrow cells of BALB/c mice was established by scoring the frequency of dicentric chromosomes in C-banded slides. Results obtained showed that CP induced a significant incr of chromosomal damage in comparison with untreated mice. In addition, the yield of dicentric chromosomes was higher in mice fed with the hypoproteic diet. The animals which received ethanol in drinking water before treatment with CP exhibited the highest frequency of dicentric chromosomes, with no relation with the diet. [R102] *Cyclophosphamide causes lung injury in rats through its ability to generate free radicals with subsequent endothelial and epithelial cell damage. In order to observe the protective effects of a potent anti-inflammatory antioxidant, curcumin (diferuloyl methane) on cyclophosphamide-induced early lung injury, healthy, pathogen free male Wistar rats were exposed to 20 mg/100 g body weight of cyclophosphamide, intraperitoneally as a single injection. Prior to cyclophosphamide intoxication oral administration of curcumin was performed daily for 7 days. At various time intervals (2, 3, 5 and 7 days post insult) serum and lung samples were analyzed for angiotensin converting enzyme, lipid peroxidation, reduced glutathione and ascorbic acid Bronchoalveolar lavage fluid was analyzed for biochemical constituents. The lavage cells were examined for lipid peroxidation and glutathione content. Excised lungs were analyzed for antioxidant enzyme levels. Biochemical analyses revealed time course increases in lavage fluid total protein, albumin, angio+ensin converting enzyme (ACE), lactate dehydrogenase, N-acetyl-beta-D-glucosaminidase, alkaline phosphatase, acid phosphatase, lipid peroxide levels and decreased levels of glutathione (GSH) and ascorbic acid 2, 3, 5 and 7 days after cyclophosphamide intoxication. Increased levels of lipid peroxidation and decreased levels of glutathione and ascorbic acid were seen in serum, lung tissue and lavage cells of cyclophosphamide groups. Serum angiotensin converting enzyme activity increased which coincided with the decrease in lung tissue levels. Activities of antioxidant enzymes were reduced with time in the lungs of cyclophosphamide groups. [R103] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Alkylating Agents; Antineoplastic Agents, Alkylating; Antirheumatic Agents; Carcinogens; Immunosuppressive Agents; Mutagens; Teratogens [R104] *MEDICATION (VET): ... CYTOTOXIC AGENT FOR CARCINOMA, LEUKOSIS, ADENOMA, FIBROMA, AND MIXED MAMMARY TUMORS OF DOGS ... MYCOTIC DERMATITIS ... OF SHEEP AND TRYPANOSOMIASIS ... OF CATTLE ... ALSO ... CYTOTOXIC ... AND IMMUNOSUPPRESSIVE IN RATS ... AGAINST EXPTL ALLERGIC ENCEPHALOMYELITIS. [R105] *The clinical spectrum of activity for cyclophosphamide is very broad. It is an essential component of many effective drug combinations for non-Hodgkin's lymphomas. Complete remissions and presumed cures have been reported when cyclophosphamide was given as a single agent for Burkitt's lymphoma. It is frequently used in combination with methotrexate (or doxorubicin) and fluorouracil as adjuvant therapy after surgery for carcinoma of the breast. Notable advantages of this drug are the availability of the oral route of admin and the possibility of giving fractionated doses over prolonged periods. For these reasons it possesses a versatility of action that allows an intermediate range of use, between that of the highly reactive iv mechlorethamine and that of oral chlorambucil. Beneficial results have been obtained in multiple myeloma; chronic lymphocytic leukemia; carcinomas of the lung, breast, cervix, and ovary; and neuroblastoma, retinoblastoma, and other neoplasms of childhood. Because of its potent immunosuppressive properties, cyclophosphamide has received considerable attention for the control of organ refection after transplantation and in nonneoplastic disorders associated with altered immune reactivity, including Wegener's granulomatosis, rheumatoid arthritis, and the nephrotic syndrome in children. [R73, 1395] *Furosemide may improve, renal blood flow, decrease resorption of sodium and chloride, and increase free water excretion. The initial dose of furosemide is 2 mg/kg, IV. This dosage can be doubled or tripled if urine output does not increase within 1 hr. However, if there is no response to 6 mg/kg, another approach should be tried. If effective, furosemide can be given parenterally at 2 mg/kg, tid., to maintain a diuresis. [R67, 1732] */EXPL THER:/ To find out which anticancer drugs could utilize to the best advantage a syngeneic bone marrow transplantation (BMT) in high-dose chemotherapy for cancer, cyclophosphamide was tested in Sprague Dawley rats. Two or three varying doses of cyclophosphamide (100-400 mg/kg) were administered iv on day 0, followed by the injection of syngeneic bone marrow cells (50,000,000, iv) on day 2, and the animals were observed for over 60 days. A beneficial effect of bone marrow transplantation was observed only with cyclophosphamide (300-400 mg/kg) and nimustine hydrochloride (40 mg/kg). In order to enhance the beneficial effect of bone marrow transplantation observed with cyclophosphamide and nimustine hydrochloride, a way of drug admin was designed and carried out. Consequently a higher survival rate was obtained in the following experimental groups; (cyclophosphamide 200 mg/kg, days 0 and 1) + bone marrow transplantation > (cyclophosphamide 400 mg/kg, day 0) + bone marrow transplantation, (nimustine hydrochloride 20 mg/kg, days 0 and 1) + bone marrow transplantation > (nimustine hydrochloride 40 mg/kg, day 0) + bone marrow transplantation; (cyclophosphamide 200 mg/kg + nimustine hydrochloride 20 mg/kg, day 0) + bone marrow transplantation > (cyclophosphamide 400 mg/kg or nimustine hydrochloride 40 mg/kg, day 0) + bone marrow transplantation; (cyclophosphamide 200 mg/kg, day 0) + (nimustine hydrochloride 20/kg, day 1) + bone marrow transplantation > (nimustine hydrochloride 20 mg/kg, day 0) + (cyclophosphamide 200 mg/kg, day 1) + bone marrow transplantation. [R106] *Cyclophosphamide is indicated for treatment of acute lymphoblastic (stem-cell) leukemia in children (including during remission to prolong the duration), and for treatment of acute myelogenous and acute monocytic leukemia. /Included in US product labeling/ [R27, Inc.1101] *Cyclophosphamide is indicated for treatment of chronic granulocytic leukemia (it is usually ineffective in acute blastic crisis) and chronic lymphocytic leukemia. /Included in US product labeling/ [R27, Inc.1101] *Cyclophosphamide is indicated for treatment of adenocarcinoma of the ovary, breast carcinoma, neuroblastoma (in patients with disseminated disease /NOT included in US product labeling/), retinoblastoma, ... . /Included in US product labeling/ [R27, Inc.1101] *... /Cyclophosphamide is indicated for treatment of/ small cell and non-small cell lung carcinoma, cervical carcinoma, and for endometrial carcinoma, bladder carcinoma, prostatic carcinoma, testicular carcinoma, and Wilms' tumor and adrenocortical carcinoma (Evidence rating: IIID). /NOT included in US product labeling/ [R107] *Cyclophosphamide is indicated for treatment of Stage III and IV (Ann Arbor or Peter's Staging System) Hodgkin's disease and non-Hodgkin's lymphomas including nodular or diffuse lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma, (and lymphoblastic lymphosarcoma /NOT included in US product labeling/). /Included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated for treatment of multiple myeloma. /Included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated for treatment of advanced mycosis fungoides. /Included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated as an immunosuppressant in the treatment of steroid-resistant or frequently relapsing steroid-sensitive biopsy proven minumal-change nephrotic syndrome in children (and adults /NOT included in US product labeling/). /Included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated for treatment of various sarcomas, including Ewing's sarcoma, osteosarcoma, and soft tissue sarcomas. /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated for treatment of Waldenstrom's macroglobulinemia. /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated as first-line therapy, as a single agent or in combination with other chemotherapeutic agents, for treatment of Histiocytosis X (Letterer-Siwe disease). (Evidence rating: IIID) /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is indicated for treatment of thymoma. /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is used for treatment of germ cell ovarian, primary brain, and gestational trophoblastic tumors. /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is used for its immunosuppressant activity, for prevention of rejection in homotransplantation. /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is used as an immunosuppressant in the treatment of rheumatoid arthritis and other autoimmune diseases such as polymyositis (systemic dermatomyositis), multiple sclerosis, Wegener's granulomatosis, systemic lupus erythematosus, and other types of vasculitis. /NOT included in US product labeling/ [R27, Inc.1102] *Cyclophosphamide is used as an antitumor agent and experimentally for removal of fleece in adult sheep. The likelihood that cyclophosphamide residues will occur or pose a problem is remote. [R57, 1095] *Severe aplastic anemia (SAA) can be successfully treated with allogeneic bone marrow transplantation (BMT) or immunosuppressive therapy. However, the majority of patients with SAA are not eligible for BMT because they lack an HLA-identical sibling. Conventional immunosuppressive therapy also has major limitations; many of its remissions are incomplete and relapse or secondary clonal disease is common. Cyclophosphamide is a potent immunosuppressive agent that is used in all BMT conditioning regimens for patients with SAA. Preliminary evidence suggested that high-dose cyclophosphamide, even without BMT, may be beneficial to patients with SAA. Therefore, 10 patients with SAA and lacking an HLA-identical sibling were treated with high-dose cyclophosphamide (45 mg/kg/day) for 4 consecutive days with or without cyclosporine. A complete response (hemoglobin level, > 13 g/dL; absolute neutrophil count, > 1.5 x 10(9)/L, and platelet count > 125 x 10(9)/L) was achieved in 7 of the 10 patients. One of the complete responders died from the acquired immunodeficiency syndrome 44 months after treatment with high-dose cyclophosphamide. The 6 remaining patients are alive and in continuous complete remission, with a median follow-up of 10.8 years (range, 7.3 to 17.8 years). The median time to last platelet transfusion and time to 0.5 x 10(9) neutrophils/L were 85 and 95 days, respectively. None of the complete responders has relapsed or developed a clonal disease. These results suggest that high-dose cyclophosphamide, even without BMT, may be more effective than conventional immunosuppressive therapy in restoring normal hematopoiesis and preventing relapse or secondary clonal disorders. Hence, further studies confirming the efficacy of this approach in SAA are indicated. [R108] *The objective of this study was to determine the tolerance and toxicities of high-dose cyclophosphamide (CPA) at 7 g/sq m given in four fractions over 8 hr in children with advanced solid tumors ... Twenty children aged 1 1/2-19 years (median, 12 years) received 24 courses of high-dose CPA at 7 g/sq m for the treatment of advanced malignant solid tumor. CPA was given in four l-hr infusions of 1.75 g/sq m each, with 1 hr of rest between each dose. MESNA was used as a uroprotective agent and was continued for 24 hr after the final dose of CPA. With only one exception, all patients were discharged at the end of MESNA infusion and received granulocyte colony-stimulating factor, prophylactic ciprofloxacin, and co-trimoxazole ... Severe but transient myelosuppression was observed. The median time to neutrophil and platelet recovery was 17 and 19 days, respectively. Fever developed after 13 of the 24 courses, and hospitalization was required. Extramedullary toxicities were mild. No patient showed cardiomyopathy or hemorrhagic cystitis. Forty-six percent of the courses were managed entirely on an outpatient basis. Objective tumor response was seen in five patients ... CPA at 7 g/sq m is well tolerated by children with advanced malignancies and should be considered in earlier phases of antineoplastic therapy. [R109] *Cyclophosphamide (CTX) is an active drug in breast cancer and presents a well-established dose-response relationship. To explore further this relationship, the present pilot study investigated the therapeutic efficacy of cyclophosphamide at intermediate dose in 2 groups of untreated patients with advanced breast cancer. Nine women received the drug alone at 3-4 g/sq m iv every 2 wk for a total of 3 doses. The same dose schedule was also given to 11 women following the admin of 4 cycles of Adriamycin, at 75 mg/sq m iv every 3 wk. We documented 1 partial remission in untreated women and 4 partial responses in Adriamycin-treated patients. The major toxicity was represented by leukopenia and neutropenia. Myelosuppression was relevant but of short duration, and the use of G-CSF appeared useful in controlling this side effect. In spite of the high dose intensity of the present cyclophosphamide dose schedule (9 g/sq m in 4 wk), i.e., almost 3 times superior to that conventionally employed, present results do not suggest its superiority over the current chemotherapeutic regimens utilized in advanced disease. [R110] *Antineoplastic [R8, 200] *MEDICATION (VET): ANTINEOPLASTIC [R105] *HAS BEEN TESTED AS AN INSECT CHEMOSTERILANT. /MONOHYDRATE/ [R111] *... PROPOSED AS DEFLEECING AGENT FOR SHEEP. [R9] *Most first-line regimens /for treating ovarian cancer/ currently include cisplatin and cyclophosphamide ... . [R35, p. 93-13] *A 78-yr-old man was hospitalized on February 29, 2000 because of dyspnea. A chest radiograph showed diffuse bilateral interstitial shadows associated with pulmonary volume loss. We could not obtain histological evidence of idiopathic interstitial pneumonia (IIP) because of his advanced age and severe respiratory dysfunction. IIP was diagnosed on the basis of radiographic findings and clinical symptoms. The patient was intubated and mechanical ventilation was performed. After one course of pulsed cyclophosphamide (CPM) and methylprednisolone therapy, the hypoxemia improved and it became possible to wean the patient from the ventilator. After 5 courses of pulsed CPM therapy, the dose of oral corticosteroid was tapered. CPM was administered safely without any severe side effects. Pulsed CPM therapy appears to be a viable alternative method of treatment for IIP. [R112] WARN: *Appropriate caution is advised when the drug is considered for use in ... /nonneoplastic/ conditions, not only because of its acute toxic effects but also because of its high potential for inducing sterility, teratogenic effects, and leukemia. ... Administration of the drug should be interrupted at the first indication of dysuria or hematuria. The syndrome of inappropriate secretion of antidiuretic hormone (ADH) has been observed in patients receiving cyclophosphamide, usually at doses higher than 50 mg/kg. It is important to be aware of the possibility of water intoxication, since these patients are usually vigorously hydrated. [R73, 1395] *POTENTIAL ADVERSE EFFECTS ON FETUS: Various fetal malformations, especially skeletal defects and dysmorphic features, but other chemotherapeutic agents given concurrently. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Transient neutropenia from cyclophosphamide with prednisone and vincristine. Potential mutagenicity, carcinogenicity, adverse effects on fetus. FDA Category: D (D = There is evidence of human fetal risk, but the potential benefits from use in pregnant women may be acceptable despite the potential risks (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.)) /from Table II/ [R113] *Drugs that are Contraindicated during Breast-Feeding: Cyclophosphamide: Possible immune suppression; unknown effect on growth or association with carcinogenesis; neutropenia. /from Table 1./ [R114] *THE DRUG IS MOST TOXIC TO THE HUMAN FETUS DURING 1ST 3 MO AND CONGENITAL ABNORMALITIES HAVE BEEN DETECTED AFTER IV INJECTION OF LARGE DOSES TO PREGNANT WOMEN DURING THIS PERIOD OF PREGNANCY. /MONOHYDRATE/ [R115] *For routine clinical use, ample fluid intake is recommended. [R73, 1396] *Cyclophosphamide is distributed into breast milk. Breast-feeding is not recommended during chemotherapy because of the risks to the infant (adverse effects, mutagenicity, carcinogenicity). [R27, Inc.1102] *Prepubescent girls treated with cyclophosphamide usually develop secondary sexual characteristics normally, have regular menses, and subsequently conceive; however, ovarian fibrosis and apparent complete loss of germ cells after prolonged treatment in late prepubescence have been reported. Prepubescent boys treated with cyclophosphamide develop secondary sexual characteristics normally, but may have oligospermia or azoospermia, increased gonadotropin secretion, and some degree of testicular atrophy; azoospermia may be reversible, although possibly not for several years after the end of cyclophosphamide therapy. [R27, Inc.1102] *Although appropriate studies on the relationship of age to the effects of cyclophosphamide have not been performed in the geriatric population, geriatrics-specific problems are not expected to limit the usefulness of this medication in the elderly. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving cyclophosphamide. [R27, Inc.1102] *The bone marrow depressant effects of cyclophosphamide may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular tooth brushes, dental floss, and toothpicks. Cyclophosphamide may also rarely cause stomatitis associated with considerable discomfort. [R27, Inc.1103] *Because normal defense mechanisms may be suppressed by cyclophosphamide therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the cyclophosphamide therapy. The interval between discontinuation of medication that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral polio-virus vaccine should be postponed in persons in close contact with the patient, especially family members. [R27, Inc.1103] *Anorexia, nausea, and vomiting occur commonly with cyclophosphamide, especially at high doses; some clinicians reported that these effects respond to treatment with antiemetics. Occasionally, diarrhea, hemorrhagic colitis, mucosal irritation, and oral ulceration have been reported. Rarely, aphthous stomatitis, enterocolitis, and hepatotoxicity as evidenced by jaundice and hepatic dysfunction have occurred. [R29, 960] *Alopecia occurs frequently in patients who receive cyclophosphamide and patients should be forewarned of this possibility. In usual doses, about 33% of patients who receive the drug experience alopecia, generally beginning about 3 weeks after initiation of therapy; the condition is usually reversible but new hair may be a different color or texture. Transverse ridging, retarded growth, and/or pigmentation of fingernails may occur, as well as skin pigmentation. Nonspecific dermatitis has also been reported. [R29, 960] *Other reported adverse effects of cyclophosphamide include headache, dizziness, and myxedema. Faintness, facial flushing, diaphoresis, and oropharyngeal sensation have occurred following IV administration of cyclophosphamide, have been reported. The drug may interfere with normal wound healing. [R29, p. 960-1] *Some patients who have received cyclophosphamide alone, as part of a combination regimen, or as adjunctive therapy have developed secondary malignancies, most frequently urinary bladder, myeloproliferative, and lymphoproliferative malignancies. Although a causal relationship has not been definitely established, the possibility of development of a secondary malignancy should be considered in weighing the possible benefit from the drug against the potential risk. Secondary malignancies have occurred most frequently in patients who have been treated with cyclophosphamide for primary myeloproliferative and lymphoproliferative malignancies and primary nonmalignant diseases in which immune processes are believed to be involved. Secondary urinary bladder malignancies generally have occurred in patients who previously developed hemorrhagic cystitis. In some cases, the secondary malignancy was not detected until several years after discontinuance of cyclophosphamide therapy. Long-term follow-up of women who received cyclophosphamide-containing adjuvant chemotherapy regimens for the treatment of early breast cancer indicates that the incidence of other solid tumors and secondary leukemia in these women is not substantially greater than that in the general population. [R29, 961] *CAREFUL EVALUATION OF BONE MARROW FUNCTION IS IMPERATIVE AND PROLONGED THERAPY IS GUIDED BY KEEPING THE TOTAL LEUKOCYTE COUNT BETWEEN 2500 AND 4000 CELLS PER CUBIC MILLIMETER OF BLOOD OR BY OBTAINING THE DESIRED RESPONSE OF THE TUMOR. [R3, 1218] *Potentially fatal cardiotoxicity also has occurred when cyclophosphamide (given concomitantly with mesna /2-mercaptoethane sulfonic acid sodium salt/ and followed with autologous bone marrow transplant) was administered inadvertently in a dosage of 4 g/sq m daily for 4 doses rather than in a total dose of 4 g/sq m administered over 4 days in equally divided doses of 1 g/sq m daily as part of a phase I protocol. [R29, 960] *One of the major and dose limiting adverse effects of cyclophosphamide is hematologic toxicity, which is usually reversible after discontinuance of the drug. Hematopoietic adverse effects include leukopenia, thrombocytopenia, hypothrombinemia, and anemia. Leukopenia is considered to be an expected effect of cyclophosphamide therapy and may be severe. Leukopenia nadirs generally occur at 8-15 days following a single dose of cyclophosphamide and recovery usually occurs within 17-28 days. Thrombocytopenia is reportedly less common, with nadirs occurring 10-15 days after administration of the drug. Anemia, particularly after large doses or prolonged therapy, and rarely hypoprothrombinemia have been reported. Rarely, cyclophosphamide has been reported to produce positive direct antiglobulin (Coombs') test results and hemolytic anemia. [R29, 960] *In children treated with cyclophosphamide a transient blurring of vision has been reported in 5 out of 59, coming on in minutes after intravenous injection in two and within 24 hours in the other three. The duration of blurring ranged from one hour to two weeks, but vision returned to normal in all. [R50] *Cyclophosphamide can cause sterility in people of either sex. It can damage the germinal cells in prepubertal, pubertal and adult males, and causes premature ovarian failure in females. [R26] *... To analyse the treatment-related complications of busulphan and cyclophosphamide (BU-CY) as the conditioning regimen for allogeneic peripheral blood stem cell transplantation (allo-PBSCT). ... The clinical data of 40 leukemia patients undergoing allo-PBSCT between June 1997 and May 1999 in our BMT center were retrospectively analysed. ... Recovery of neutrophil and platelet was achieved at a median of day +13 (9 similar 28) and day +12 (7 similar 60) respectively. Acute GVHD occurred in 17 of 40 patients (42.5%) with grade II-IV in 10 patients (25%). Chronic GVHD developed in 21 out of 30 evaluable patients (70%). Mild to severe mucositis occurred in 30 patients (75%), and 4 of them had severe esophagitis with bleeding. Haemorrhagic cystitis developed in 8/40 (20%) patients, the median time of its onset was day +100 (+7 to +165). Six of 40 patients (15%) developed interstitial pneumonia (IP), 5 of them were due to cytomegalovirus infection, and the remaining one due to pneumocystis carinii infection. No hepatic veno-occlusive disease was observed and no seizure occurred. During the median follow-up of 480 (300 similar 1000) days, 4 (10%) patients relapsed and 8 (20%) patients died of the transplant-related complications. The 3 year leukemia-free survival rate was 70%. ... BU (domestic busulfan)-CY regimen is relatively easy to administer and well tolerated, with low extramedullary toxicities. [R116] *... We now described five patients receiving monthly cycles of iv CP /cyclophosphamide/ whose allergic reactions included clinical features of type I hypersensitivity but were atypical in their markedly delayed onset (i.e., 8 to 16 hr in patients 1 to 4 and 10 days in patient 5) ... The objective was to investigate these late-developing clinical reactions by skin testing with CP and two of its major metabolites ... The five patients and a control group receiving iv CP uneventfully were studied by the same skin test protocol ... The four individual in the control group were unreactive to CP or its metabolites. All five patients with late-onset allergic reactions had positive immediate skin test results to CP metabolites but not to CP itself. We propose that the allergic reactions in patients 1 to 4 were mediated, wholly or in major part, by IgE antibodies reactive with allergens derived from time-dependent drug metabolites. [R117] *Sterile hemorrhagic cystitis has been reported to occur in up to 20% of patients (especially children) on long-term cyclophosphamide therapy. The effect, which rarely can be severe and even fatal, is attributed to chemical irritation by active metabolites of cyclophosphamide that accumulate in concentrated urine. Hematuria usually resolves spontaneously within a few days after discontinuance of cyclophosphamide therapy but may persist for several months. Fibrosis of the bladder (sometimes extensive), with or without cystitis, also has occurred, but less frequently. Atypical epithelial cells may be found in the urinary sediment. These adverse effects appear to be related to the dosage and duration of cyclophosphamide therapy. Nephrotoxicity, including hemorrhagic ureteritis and renal tubular necrosis, has been reported; such lesions reportedly resolve in most instances following discontinuance of cyclophosphamide therapy. [R29, 960] *THERE HAVE BEEN AT LEAST 30 CASE REPORTS OF MALIGNANCY IN PATIENTS TREATED WITH CYCLOPHOSPHAMIDE FOR NONMALIGNANT DISORDERS, MAINLY RHEUMATOID ARTHRITIS AND CHRONIC GLOMERULONEPHRITIS. THESE INCLUDED 17 ACUTE NONLYMPHOCYTIC LEUKEMIAS, ONE CHRONIC NONLYMPHOCYTIC LEUKEMIA, ONE ACUTE LYMPHOCYTIC LEUKEMIA, ONE CHRONIC LYMPHOCYTIC LEUKEMIA, TWO BLADDER CANCERS, ONE SQUAMOUS CELL CANCER OF THE SKIN, THREE RETICULUM CELL SARCOMAS, ONE HODGKIN'S DISEASE, ONE MELANOMA, TWO CEREBRAL GLIOMAS, ONE CERVICAL CANCER AND ONE PLEURAL SARCOMA. /MONOHYDRATE/ [R118] *Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. Prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. However, there have been numerous reports of gonadal suppression with use of cyclophosphamide, which seems to depend on dose, duration, and state of gonadal function at the time of therapy, sterility may be irreversible in some patients. [R29, 1102] *THERE WAS INCR IN NUMBER OF CHROMOSOMAL ABERRATIONS IN THE PERIPHERAL BLOOD LYMPHOCYTES OF CHILDREN TREATED WITH CYCLOPHOSPHAMIDE (3-5 MG/DAY FOR 6-8 MONTHS) FOR NONMALIGNANT CONDITIONS AND OF PATIENTS WITH RHEUMATOID ARTHRITIS FOLLOWING CYCLOPHOSPHAMIDE TREATMENT. SIMILAR INCR WERE OBSERVED IN LYMPHOCYTES OF WOMEN WITH RECURRENT OVARIAN OR UTERAL CARCINOMA 3 OR 24 HR AFTER AN IV ADMIN OF 2.0 G AND IN THE BONE MARROW AND LYMPH NODE CELLS OF PATIENTS WITH LYMPHOGRANULOMATOSIS 24-72 HR AFTER SINGLE DOSE OF 400 MG CYCLOPHOSPHAMIDE. INCR LEVELS OF SISTER CHROMATID EXCHANGE IN PERIPHERAL BLOOD LYMPHOCYTES HAVE BEEN OBSERVED IN PATIENTS TREATED WITH CYCLOPHOSPHAMIDE. THESE HAVE INCLUDED PATIENTS WITH MALIGNANT LYMPHOMA AND NEPHROTIC SYNDROME, A PATIENT WITH RETICULOSARCOMA, 3 PATIENTS WITH UNSPECIFIED MALIGNANT TUMORS AND 1 PATIENT WITH ACUTE GLOMERULONEPHRITIS. /MONOHYDRATE/ [R75] *LEUKOPENIA IS INEVITABLE SIDE EFFECT AND IS USED AS INDEX OF DOSAGE ... HYPOPROTHROMBINEMIA ... . [R7, 1088] *Nausea and vomiting, myelosuppression with platelet sparing, and alopecia are common to virtually all regimens using cyclophosphamide. Mucosal ulcerations and, less frequently, interstitial pulmonary fibrosis also may result from cyclophosphamide treatment. Extravasation of the drug into subcutaneous tissues does not produce local reactions, and thrombophlebitis does not complicate iv admin. The occurrence of sterile hemorrhagic cystitis has been reported in 5%-10% of patients. As noted above, this has been attributed to chemical irritation produced by acrolein. Its incidence is significantly reduced by coadministration of mesna. For routine clinical use, ample fluid intake is recommended. Admin of the drug should be interrupted at the first indication of dysuria or hematuria. The syndrome of inappropriate secretion of antidiuretic hormone (ADH) has been observed in patients receiving cyclophosphamide, usually at doses higher then 50 mg/kg. It is important to be aware of the possibility of water intoxication, since these patients usually are vigorously hydrated. [R73, 1395] MXDD: *A total of 23 patients were treated at five dose escalations with high dose combination cyclophosphamide, cis-platin, and melphalan with autologous bone marrow support. The max tolerated doses of cyclophosphamide, cis-platin, and melphalan were 5,525, 180, and 80 mg/sq m, respectively. The dose limiting toxicity was cardiac toxicity. Objective tumor regression occurred in 14 of 18 evaluable cases, with a median duration of 3.5 mo. [R119] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Cyclophosphamide's production and use as antineoplastic may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.5 mm Hg at 25 deg C indicates cyclophosphamide will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase cyclophosphamide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 5.5 hrs. Particulate-phase cyclophosphamide will be removed from the atmosphere by wet and dry deposition. Cyclophosphamide is sensitive to light. If released to soil, cyclophosphamide is expected to have high mobility based upon an estimated Koc of 52. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole. Cyclophosphamide has shown to be non-biodegradable using sewage sludge tests. If released into water, cyclophosphamide is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. The neutral hydrolysis calculated half-life for cyclophosphamide at 25 deg C is 41 days. Occupational exposure to cyclophosphamide may occur through inhalation and dermal contact with this compound at workplaces where cyclophosphamide is produced or used. Workers involved in formulating and dispensing the drug may be exposed through dermal contact (with the dry powder or solutions), or inhalation of dust. Direct human exposure occurs through ingestion of the drug (when dispensed in tablet form) and through injection (when administered intravenously). (SRC) NATS: *Cyclophosphamide is not known to occur in nature(1). [R120] ARTS: *Cyclophosphamide's production and use as an antineoplastic(1) may result in its release to the environment through various waste streams(SRC). [R121] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of 0.63(2) and a regression-derived equation(3), indicates that cyclophosphamide is expected to have high mobility in soil(SRC). Volatilization of cyclophosphamide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Cyclophosphamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.4X10-5 mm Hg(SRC), determined from a fragment constant method(5). Cyclophosphamide has been shown to be non-biodegradable using laboratory-scale sewage treatment studies(6), suggesting that biodegradation in soil may be slow(SRC). [R122] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 52(SRC), determined from a log Kow of 0.63(2) and a regression-derived equation(3), indicates that cyclophosphamide is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.4X10-11 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The neutral hydrolysis calculated half-life for cyclophosphamide at 25 deg C is 41 days(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Cyclophosphamide has been shown to be non-biodegradable using laboratory-scale sewage treatment studies(8). [R123] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), cyclophosphamide, which has an estimated vapor pressure of 4.4X10-5 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase cyclophosphamide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 5.5 hrs(SRC), calculated from its rate constant of 7.0X10-11 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(3). Particulate-phase cyclophosphamide may be removed from the air by wet and dry deposition(SRC). Cyclophosphamide is susceptible to light(4) and therefore the potential for direct photolysis exists(SRC). [R124] BIOD: *AEROBIC: Cyclophosphamide has been shown to be non-biodegradable in a laboratory-scale sewage treatment studies(1-3). During 29 days of 10 ug/l compound addition, a mean effluent recovery of 83% was established(2). Cyclophosphamide, present at 160 mg/l, indicated no DOC elimination in four weeks using an activated sludge inoculum at 0.2 g/l and the Zahn-Wellens test(2). The compound is confirmed to be non-biodegradable according to the OECD confirmatory test using both single compound and compound mixtures run from a period of 10-14 days at concentrations ranging from 150 to 750 mg/l and that employs a sewage sludge inoculum(3). [R125] ABIO: *The rate constant for the vapor-phase reaction of cyclophosphamide with photochemically-produced hydroxyl radicals has been estimated as 7.0X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 5.5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Hydrolysis occurs at temperatures above 30 deg C, with removal of chlorine atoms(2). The neutral hydrolysis rate constant for cyclophosphamide at 25 deg C has been experimentally determined to be 7.1X10-4/hour which corresponds to a calculated half-life of 41 days(3). Cyclophosphamide is reported to be sensitive to oxidation, moisture, and light(4); it darkens on exposure to light(2). [R126] BIOC: *An estimated BCF of 3 was calculated for cyclophosphamide(SRC), using a log Kow of 0.63(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R127] KOC: *The Koc of cyclophosphamide is estimated as 52(SRC), using a log Kow of 0.63(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that cyclophosphamide is expected to have high mobility in soil. [R128] VWS: *The Henry's Law constant for cyclophosphamide is estimated as 1.4X10-11 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that cyclophosphamide is expected to be essentially nonvolatile from water surfaces(2). Cyclophosphamide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.5X10-5 mm Hg(SRC), determined from a fragment constant method(3). [R129] EFFL: *Cyclophosphamide concentrations of 149 ng/l(1) and 19 ng/l to 4.5 ug/l(2) were detected in hospital sewage samples from unspecified locations. [R130] ATMC: *SOURCE DOMINATED: Air monitoring conducted in a West German manufacturing facility in April 1984 found cyclophosphamide levels ranging from 0.1 to 810 ug/cu m(1). Air concentrations of 2-480 ug/cu m were detected in a production area of a plant involved weighing cyclophosphamide and formulating it into tablets(1). [R131] RTEX: */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The danger to health-care personnel from handling a hazardous drug stems from a combination of its inherent toxicity and the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/ [R18, 752] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 30,026 workers (20,745 of these are female) are potentially exposed to cyclophosphamide in the US(1). Occupational exposure to cyclophosphamide may occur through inhalation and dermal contact with this compound at workplaces where cyclophosphamide is produced or used(SRC). Workers involved in formulating and dispensing the drug may be exposed through dermal contact (with the dry powder or solutions), or inhalation of dust(SRC). Direct human exposure occurs through ingestion of the drug (when dispensed in tablet form) and through injection (when administered intravenously)(2). [R132] *Air monitoring conducted in a West German manufacturing facility in April 1984 found cyclophosphamide levels ranging from 0.1 to 810 ug/cu m(1). Air concentrations of 2-480 ug/cu m were detected in a production area of a plant involved weighing cyclophosphamide and formulating it into tablets(1). No detectable levels (detection limit of 0.05 ug/cu m) were found in air samples (taken from flow hoods) from a hospital dispensing and administering cyclophosphamide; however, filter media from the flow hoods contained measurable quantities suggesting that some exposure can occur(1). Concentrations of cyclophosphamide in personal air samplers from a manufacturing facility ranged from less than the detection limit to 97.0 ug/cu m, and in a laminar-flow hood, the concentrations ranged from 0-60 ng/cu m(2). [R133] BODY: *In a cross-sectional study, the urine of 20 hospital workers occupationally exposed to cyclophosphamide and 21 unexposed controls was monitored for excretion of cyclophosphamide. During the week in which samples were collected, most of the workers handled cyclophosphamide fewer than 5 times and the amount handled each time ranged from 100-1000 mg (mean +/- 350 mg). All workers claimed to have taken regular safety precautions, ie, at least wearing gloves during handling. The drug was identified in 5 cases (range: 0.7-2.5 ug excreted/24 hr urine). A clear relationship between cyclophosphamide handling and urinary detection was shown. 4 of 5 persons with detectable urinary cyclophosphamide had handled cyclophosphamide 10 times or more during the week. [R76] *Cyclophosphamide (along with ifosfamide) was detected in the urine of 8 pharmacy technicians and nurses (along with ifosfamide) at amounts ranging from < 0.001-0.5 ug(1). 21 nurses and pharmacy personnel in a Munich, Germany hospital were monitored for compound exposure; on days when 3,900 mg/l cyclophosphamide was mixed, 12 of 31 urine samples tested positive with concentrations ranging from 3.5 to 38 ug/24 hr urine(2). [R134] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R135] RCRA: *U058; As stipulated in 40 CFR 261.33, when cyclophosphamide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R136] FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R137] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SAMPLE MATRIX: IN FORMULATIONS. ASSAY PROCEDURES: HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH ULTRA-VIOLET DETECTION; KENSLER TT ET AL; J PHARM SCI 68: 172 (1979). GAS CHROMATOGRAPHY WITH FLAME IONIZATION DETECTION; US PHARMACOPEIAL CONVENTION, INC. THE US PHARMACOPEIA, 15TH ED, ROCKVILLE, MD, PAGES 189-190. /FROM TABLE/ [R138] *Method 3640A Gel Permeation Chromatography (GPC) Cleanup Procedure. Gel permeation chromatography with high performance liquid chromatography. No detection limit reported. [R139] *Estimation of nitrogen, phosphorus, or chloride content; colorimetric analysis, based on the intensity of a cobalt thiocyanate-cyclophosphamide complex or by use of 4-(4'-nitrobenzyl)pyridine after hydrolysis; titrimetric analysis, after precipitation of the digested material by quinoline and citric-molybdic acid solution; and infrared spectrometry (the method with the most specificity). Also gas-liquid chromatography and mass spectrometry. [R6, p. V9 138] CLAB: *SAMPLE MATRIX: BLOOD AND URINE. ASSAY PROCEDURE: GAS CHROMATOGRAPHY WITH NITROGEN PHOSPHORUS DETECTION; WHITING B ET AL, BR J CLIN PHARMACOL 6: 373 (1978). THIN-LAYER CHROMATOGRAPHY WITH SCINTILLATION SPECTROMETRY; WAGNER T ET AL; CANCER RES 37: 2592 (1977). [R138] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) Anderson D et al; Mutat Res 330 (1-2): 115-81 (1995). Cyclophosphamide: Review of its Mutagenicity for an Assessment of Potential Germ Cell Risks. TEST: *The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for cyclophosphamide monohydrate is completed, and the chemical is in review for further evaluation. Route: gavage; Species: transgenic model evaluation, mice. /Cyclophosphamide monohydrate/ [R140] *The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for cyclophosphamide monohydrate is completed, and the chemical is in review for further evaluation. Route: topical; Species: transgenic model evaluation, mice. /Cyclophosphamide monohydrate/ [R140] SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V26 (1981) R2: O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2001. 479 R3: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R4: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 35 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 327 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R7: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R8: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. R9: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 429 R10: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 35 R11: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 341 R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 (1975) 136 R13: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.436 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V26 166 (1981) R15: Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996. R16: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R17: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R18: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 95. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 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V26 168 (1981) R139: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R140: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 206 Record 216 of 1119 in HSDB (through 2003/06) AN: 3060 UD: 200303 RD: Reviewed by SRP on 5/6/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIETHYLSTILBESTROL- SY: *ANTIGESTIL-; *BIO-DES-; *3,4-BIS(P-HYDROXYPHENYL)-3-HEXENE; *3,4-BIS(PARAHYDROXYPHENYL)-3-HEXENE; *BUFON-; *COMESTROL-; *CYREN-A-; *DAWE'S-DESTROL-; *DEB-; *DES-; *DIBESTROL-"2"-PREMIX-; *DI-ESTRYL-; *ALPHA,ALPHA'-DIETHYLSTILBENEDIOL-; *ALPHA,ALPHA'-DIETHYL-4,4'-STILBENEDIOL-; *TRANS-ALPHA,ALPHA'-DIETHYL-4,4'-STILBENEDIOL-; *TRANS-DIETHYLSTILBESTEROL-; *TRANS-DIETHYLSTILBESTROL-; *4,4'-DIHYDROXY-ALPHA,BETA-DIETHYLSTILBENE-; *DISTILBENE-; *DOMESTROL-; *ESTILBIN-''MCO''-; *ESTROBENE-; *ESTROSYN-; *FONATOL-; *GRAFESTROL-; *HI-BESTROL-; *ISCOVESCO-; *MICROEST-; *MILESTROL-; *NEO-OESTRANOL-I-; *OESTROGENINE-; *OESTROMENIN-; *OESTROMENSYL-; *PALESTROL-; *PHENOL, 4,4'-(1,2-DIETHYL-1,2-ETHENEDIYL)BIS-, (E)-; *SERRAL-; *SEXOCRETIN-; *SIBOL-; *STIL-; *4,4'-STILBENEDIOL, ALPHA,ALPHA'-DIETHYL-, (E)-; *STILBESTROL-; *STILBETIN-; *STILBOEFRAL-; *STILBOESTROFORM-; *STILBOESTROL-; *STILKAP-; *STIL-ROL-; *SYNESTRIN-; *SYNTHOESTRIN-; *SYNTHOFOLIN- RN: 56-53-1 MF: *C18-H20-O2 HAZN: U089; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF SODIUM AMALGAM AND SODIUM HYDROXIDE WITH P-HYROXYPROPIOPHENONE AND REARRANGEMENT OF RESULTING INTERMEDIATE; REARRANGEMENT OF ETHYL DESOXYANISOIN. [R1] *From anethole hyrdobromide, from anisole, from anisoin. [R2] FORM: *Grade: USP [R2] OMIN: *Non-steroid, synthetic estrogen, always in trans form. It is most active of commonly used stilbene cmpd. [R2] USE: *Therap Cat: Estrogen [R3] *Therap Cat (Vet): Formerly in estrogenic hormone therapy. [R3] *Biochemical research, medicine (prevents spontaneous abortion), veterinary medicine. [R2] PRIE: U.S. PRODUCTION: *(1978) GREATER THAN 4.54X10+5 G (DIPHOSPHATE) [R1] U.S. IMPORTS: *(1978) 7.83X10+6 G (PRINCPL CUSTMS DISTS) [R1] *(1982) 1.31X10+5 G (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystalline powder [R2]; *Small plates from benzene [R3] ODOR: *Odorless [R2] MP: *169-172 deg C [R3] MW: *268.36 [R3] OWPC: *log Kow= 5.07 [R4] SOL: *Soluble in alcohol, ether, chloroform, fatty oils, dil hydroxides. [R3]; *SOL @ 25 DEG C IN 95% ETHANOL (1 IN 5); SOL @ 25 DEG C IN CHLOROFORM (1 IN 200), ETHER (1 IN 3); SOL IN ACETONE, DIOXANE, ETHYL ACETATE, METHYL ALCOHOL, SOL IN VEGETABLE OILS AND AQUEOUS SOLN OF ALKALI HYDROXIDES [R5]; *In water, 12 mg/l @ 25 deg C [R6] SPEC: *INDEX OF REFRACTION: 1.594 (ALPHA), 1.611 (BETA), 1.73 (GAMMA) [R7]; *MAX ABSORPTION (ACID): 232 NM (E= 530); (BASE): 245 NM (E= 510) [R8]; *UV: 1-566 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R9]; *Intense mass spectral peaks: 107 m/z, 145 m/z, 159 m/z, 239 m/z, 268 m/z [R10]; *UV max (0.1 N NaOH): 259 nm; E(1%, 1 cm)= 764 [R3] OCPP: *CIS-ISOMER TENDS TO REVERT TO TRANS-FORM [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of diethylstilbestrol stem from its toxicologic properties. Toxic by all routes (ie, inhalation, ingestion, dermal absorption), exposure to this white, crystalline substance may occur from its production, handling, and use as a veterinary drug. Effects from exposure may include headache, dizziness, nausea, leg cramps, and hypersensitivity reactions. More importantly, the International Agency for Research on Cancer (IARC) has designated diethylstilbestrol as a Group 1 carcinogen, meaning, "The agent is carcinogenic to humans." Mechanical ventilation which employs a high efficiency particulate arrestor (HEPA) should be used to minumize airborne levels of diethylstilbestrol. In activities and situations where over-exposure may occur, wear a protective suit and a carefully fitted respirator. Smoking, drinking, and eating should be prohibited in diethylstilbestrol work areas, and cleanliness following the handling of diethylstilbestrol should be emphasized. Diethylstilbestrol should be stored in a securely sealed, watertight container, which should be enclosed in a second, unbreakable, leakproof container. Diethylstilbestrol is a good candidate for rotary kiln or fluidized bed forms of incineration. DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R12] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R13, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R13, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R13, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R13, 1979.11] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R13, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R13, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R13, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R13, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U089, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R14] *Diethylstilbestrol is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. [R15] *A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R16] *The following wastewater treatment technologies have been investigated for 2,2'-diethylstilbenediol: Concentration process: Biological treatment. [R17] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R13, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R13, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R13, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R13, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R13, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated diethylstilbestrol for carcinogenicity. According to their analysis, the weight-of-evidence for diethylstilbestrol is group A, which is based on sufficient evidence in humans and sufficient evidence in animals. As a group A chemical, diethylstilbestrol is considered carcinogenic to humans. [R18] *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. /From table/ [R19] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/ [R20] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R20] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R13, 1979.23] HTOX: *... VAGINAL ADENOSIS IN 13/34 FEMALE PATIENTS EXPOSED IN UTERO TO DES, AND IN 7 THERE WERE TRANSVERSE CERVICAL OR VAGINAL RIDGES. SIMILAR LESIONS ... NOT PRESENT IN 275 GIRLS OF ... NO HISTORY OF DES EXPOSURE IN UTERO. [R21] *AMONG 24 FEMALE PATIENTS WITH GONADAL DYSGENESIS ... TREATED FOR 5 OR MORE YR WITH DES, ENDOMETRIAL CARCINOMA DEVELOPED IN 2 ... THREE OTHER CASES ... PREVIOUSLY ... REPORTED ... OF THE TOTAL OF 5 ... 3 WERE OF UNUSUAL MIXED OR ADENOSQUAMOUS TYPE. [R22] *... PRIMARY CARCINOMA OF BREAST WITH PAGET'S DISEASE OF NIPPLE IN MAN WHO HAD RECEIVED LONG-TERM TREATMENT WITH DES FOR CARCINOMA OF PROSTATE. [R23] *STRUCTURAL CHANGES ... WERE REPORTED ... IN THE UTERUS AND FALLOPIAN TUBE OF 40 TO 60 FEMALES EXPOSED PRENATALLY TO DES. SMALL ENDOMETRIAL CAVITIES, 'T'-SHAPED UTERI AND DILATED CORNUAL AREAS WERE NOTED. THEY FOUND NO SIMILAR CHANGES IN ... UNEXPOSED FEMALES OF THE SAME AGE. [R22] *... REPORTED GREATER FREQUENCY OF ABNORMALITIES IN THE REPRODUCTIVE TRACTS OF MALES EXPOSED PRENATALLY TO DES ... THE MOST COMMON GENITAL LESIONS WERE EPIDIDYMAL CYSTS, HYPOTROPIC TESTES, CAPSULAR INDURATION OF THE TESTES AND CRYPTORCHIDISM ... OBSERVED IN 30% OF 289 EXPOSED SUBJECTS, IN COMPARISON WITH 8% OF 290 UNEXPOSED MALES. [R22] *A 72 yr old white man had received estrogen therapy (1 mg diethylstilbestrol (DES) daily) continuously for 6 yr to treat prostate cancer. The pretreatment prostate biopsy showed well developed acini consistent with normal androgenization and adenocarcinoma. 12 yr later, 6 yr after discontinuation of estrogen treatment, the patient presented with severe hypogonadism, gynecomastia, and primary hypothyroidism. Testicular biopsies showed ghosts of seminiferous tubules with absence of Leydig cells, and prostatic biopsies showed atrophic acini without evidence of malignancy. Despite undetectable serum testosterone levels, serum gonadotropins were inappropriately normal and responded minimally to gonadotropin releasing hormone admin. Replacement therapy with levothyroxine did not correct gonadal dysfunction. [R24] *Toxic effects include thrombocytopenia, gynecomastia, and fluid retention. [R25] *Side effects noted after clinical administration were headache, nausea, vomiting and sometimes vaginal bleeding. Prominent gynecomastia and other feminizing effects were produced in males occupationally exposed to estrogens. Enough material can be absorbed percutaneously or by the respiratory route to produce these effects. Breast enlargement and nodularity occurred in both male and female children after consumption of vitamin capsules contaminated with estrogens. Changes in secondary sexual characteristics are fully reversible on cessation of exposure. /Estrogens (natural and synthetic)/ [R26] *DES can cause serious fetal toxicity when administered to pregnant women. An increased risk of congenital anomalies, including cardiovascular and limb defects, has been reported following use of sex hormones. [R27, 2694] *There is some evidence that in utero exposure of females to DES is associated with an increased incidence of structural abnormalities in the cervicovaginal area and/or uterine cavity. Cervicovaginal structural abnormalities have included transverse cervicovaginal ridges, cervical collars, cervical hoods, cervical hypoplasia, and/or pseudopolyps; cervical incompetence also has been reported. Radiographic findings in females exposed to DES in utero have included T-shaped uterus, small uterine cavity, and/or uterine constrictions. [R27, 2694] *In utero exposure of females to DES is also associated with an increased risk of developing a rare form of vaginal or cervical cancer (clear-cell adenocarcinoma) in later life. In addition, such exposure to DES causes epithelial changes (adenosis) in the vagina and cervix in 30-90% of these exposed female offspring. [R27, 2694] *Daughters of women who took systemic diethylstilbestrol (DES) during pregnancy have developed abnormalities of the reproductive tract and, in rare cases, cancer of the vagina and/or uterine cervix upon reaching childbearing age. In addition, sons of women who took systemic DES during pregnancy have developed urogenital tract abnormalities. [R28, 1384] *... An increased incidence of vaginal and cervical adenocarcinoma was noted in female offspring of mothers who had taken diethylstilbestrol (DES) during the first trimester of pregnancy. This may have resulted from the inability of the fetus to metabolize DES, leading to its accumulation in the fetus. [R29, 1420] *This use has resulted ... in significant complications of the reproductive system in both male and female offspring. [R30] NTOX: *TUMOR INDUCTION TIMES DECR ... WITH INCR DES CONCN. INTACT MALE C3H MICE ... DEVELOPED SIGNIFICANT INCIDENCE OF BREAST TUMORS (23/60) WHEN 500 PPB DES WERE GIVEN IN DIET, ALTHOUGH SOME ... DID OCCUR WITH LOWER CONCN. CASTRATED A STRAIN MALES WERE LESS SUSCEPTIBLE TO ALL DIETARY CONCN OF DES. NO BREAST TUMORS OCCURRED IN GROUPS OF 115 INTACT MALE C3H MICE OR IN 136 CASTRATED MALE A STRAIN CONTROLS. [R31] *NEWBORN MALE AND FEMALE MICE WERE INJECTED SC WITH 2 MG DES IN SALINE SUSPENSION WITHIN THE FIRST 24 HR AFTER BIRTH; CANCERS OF THE CERVIX AND/OR VAGINA OCCURRED IN 6/17 FEMALE BALB/C MICE AGED 13-26 MO, IN 3/10 C3HF FEMALES AT 20-26 MO, AND IN 1/4 CONTROLS. PRECANCEROUS LESIONS WERE FOUND IN 3 BALB/C MICE @ 13-21 MO AND IN 4 FEMALE C3H MICE @ 24-26 MO. GRANULAR-CELL MYOBLASTOMAS OCCURRED IN 1/6 BALB/C FEMALES AGED 24-26 MO AND IN 1/9 C3HF FEMALES @ 24-26 MO; HOWEVER, ONE OF THESE TUMORS ALSO OCCURRED IN 1/2 CONTROLS @ 26 MO. MALE MICE SHOWED NO UNUSUAL TUMORS IN ANY ORGAN; HOWEVER, 5/10 BALB/C AND 7/10 C3HF MICE SHOWED SINGLE OR MULTIPLE, OFTEN BILATERAL, EPIDIDYMAL CYSTS. [R32] *WHEN 0.6 MG DES IN 0.2 ML OF 0.9% SALINE WAS INJECTED SUBCUTANEOUSLY EVERY OTHER DAY FOR 36 WK OR LONGER, 11/11 INTACT MALE GOLDEN HAMSTERS DEVELOPED KIDNEY TUMORS, COMPARED WITH 0/17 IN UNTREATED AND 0/5 IN SALINE-TREATED CONTROLS. [R33] *BITCHES IN KENNELS FED WITH EARS OF CATTLE WHICH HAD BEEN IMPLANTED WITH STILBESTROL FAILED TO CONCEIVE OR HAD DEAD FETUSES ... IN LACTATING CATTLE, PROLAPSE OF VAGINA AND RECTUM ... RECORDED ... FOLLOWING ORAL ADMIN ... OTHER EFFECTS ... ABORTION IN PREGNANT ANIMALS, and , FOLLOWING SUBCUTANEOUS IMPLANTATION ... CHANGES IN PELVIC MORPHOLOGY ... . [R34] *SIDE-EFFECTS @ RECOMMENDED DOSE-RATE IN FOOD ARE RARE BUT, FOLLOWING IMPLANTATION ... MAMMARY AND TEAT DEVELOPMENT WAS EVIDENT AMONG MALE AND FEMALE ANIMALS, WHILE TREATED HEIFERS APPEARED TO BE IN CONSTANT HEAT. OTHER UNDESIRABLE SIDE-EFFECTS INCL REDUCTION IN CARCASS-GRADE AND ELEVATION OF TAIL-HEAD. [R35, 179] *... 5 CASES OF STILBESTROL INTOXICATION ... IN ... PIGS RECEIVING DIETARY SUPPLEMENT ... URETERS ... THICKENED, BLADDER SHOWED GROSS DISTENTION AND ACUTE INFLAMMATION, PELVIC URETHRA ... ENLARGED AND ... PETECHIAL HEMORRHAGES AND THICKENING OF MUCOSA; PROSTATE GLAND AND SEMINAL VESICLES ... ENLARGED. [R35, 181] *LARGE DOSES OF DIETHYLSTILBESTROL, 1.0 MG/WK, WILL OBLITERATE MEDULLARY CAVITIES OF LONG BONES IN MICE. EXTRAMEDULLARY HEMATOPOIESIS OCCURS IN LIVER, SPLEEN, AND ADRENAL GLAND; REMOVAL OF EXCESS BONES DOES NOT OCCUR AT THIS STAGE, EVEN AFTER HORMONE IS DISCONTINUED. [R36] *PREGNANT FEMALE RHESUS MONKEYS (M MULATTA) RECEIVED 1 MG/DAY DIETHYLSTILBESTROL OVER VARYING TIME PERIODS DURING GESTATION. EXPOSURE IN UTERO APPEARS TERATOGENIC; NO CARCINOGENICITY OBSERVED. [R37] *GROUPS OF 20 MALE AND 20 FEMALE WEANLING SPRAGUE-DAWLEY RATS WERE FED DIETS CONTAINING DES AT CONCN PROVIDING INTAKES OF 0 (CONTROL), 0.02 OR 0.2 MG/KG BODY WT PER DAY FOR 2 YR. ... PITUITARY TUMORS OCCURRED IN 4, 5 AND 17 MALES AND IN 4, 9 AND 18 FEMALES IN THE RESPECTIVE GROUPS. TWO HEPATOMAS AND 1 HEMANGIOENDOTHELIOMA OF THE LIVER OCCURRED IN FEMALES GIVEN THE LOW DOSE; NO SUCH TUMORS WERE OBSERVED IN CONTROLS. [R38] *THIRTY MALE AND 30 FEMALE 21-DAY OLD ICR JCL MICE RECEIVED SINGLE SC INJECTIONS OF 10 MG/KG BODY WT DES, AND A FURTHER GROUP OF 20 MALE AND 20 FEMALE MICE RECEIVED 100 MG/KG BODY WT DES. ALL MICE WERE KILLED AT 12 MO OF AGE. THE INCIDENCE OF OVARIAN CYSTADENOMAS WAS INCR IN FEMALE MICE TREATED WITH THE HIGHER DOSE (4/17 VERSUS 1/77 IN CONTROLS). [R33] *OVARIAN LESIONS (6 PAPILLARY CARCINOMAS, 1 PAPILLARY ADENOMA AND 1 HYPERPLASIA) WERE FOUND IN ALL OF 8 FEMALE DOGS GIVEN SC INJECTIONS OF 15-60 MG DES IN PARAFFIN OIL AT 7-8 WK INTERVALS OVER 19 MO (TOTAL DOSE, 90-495 MG). ...10 FEMALE DOGS RECEIVED TOTAL SC DOSES OF 60-495 MG/ANIMAL DES FOR UP TO 455 DAYS: 9 DEVELOPED OVARIAN TUMORS DESCRIBED AS PAPILLARY CARCINOMAS, AND 1 HAD 'PAPILLARY DYSPLASIA'; 3 CARCINOMAS (DIAGNOSED BY BIOPSY) WERE FOUND AT THE TIME OF DES WITHDRAWAL. [R39] *GROUPS OF PREGNANT ICR/JCL MICE WERE GIVEN SINGLE SC INJECTIONS OF 10 MG/KG BODY WT DES ON DAY 7, 9, 11, 13, 15, 17 OR 19 OF PREGNANCY. THE OFFSPRING WERE WEANED @ 4 WK AND OBSERVED UNTIL 12 MO OF AGE. THE INCIDENCE OF TUMORS OF THE LUNG (PAPILLARY ADENOMAS) WAS SIGNIFICANTLY INCR IN MICE OF BOTH SEXES WHOSE MOTHERS HAD BEEN TREATED ON DAY 15 OF PREGNANCY (7/29 VERSUS 0/14 IN CONTROLS). TUMORS OF THE OVARY (CYSTADENOMAS AND GRANULOSA-CELL) WERE SIGNIFICANTLY INCR IN FEMALE OFFSPRING OF MICE TREATED ON DAY 15, 17 OR 19 OF PREGNANCY (3/17, 6/15, 4/33 VERSUS 0/8 CONTROLS). [R40] *PREGNANT SYRIAN GOLDEN HAMSTERS RECEIVED DES...BY INTRAGASTRIC TUBE, EITHER AS A SINGLE DOSE OF 20 OR 40 MG/KG BODY WT DES ON DAY 15 OF GESTATION, OR AS TWO CONSECUTIVE DAILY DOSES OF 20 OR 40 MG/KG BODY WT ON DAYS 14 AND 15 OF PREGNANCY. ... REPRODUCTIVE TRACT NEOPLASMS (2 CERVICAL POLYPS, 2 SQUAMOUS-CELL PAPILLOMAS OF THE CERVIX AND VAGINA, 1 MYOSARCOMA) WERE SEEN IN 38% (4/14) OF FEMALE PROGENY EXPOSED TO A SINGLE 40 MG/KG BODY WT DOSE OF DES; 50% (4/8) OF THOSE EXPOSED TO TWO DOSES OF 40 MG/KG BODY WT HAD 5 GENITAL-TRACT TUMORS (2 CERVICAL POLYPS, 1 ADENOCARCINOMA OF THE UTERUS, 2 SQUAMOUS-CELL PAPILLOMAS OF THE CERVIX AND VAGINA). MALE PROGENY DEVELOPED GRANULOMAS IN THE EPIDIDYMIS (70%) AND TESTIS (40%) AND EPIDIDYMAL CYSTIC FORMATIONS (20%); 1 ADENOMA OF THE COWPER GLAND WAS SEEN IN 1 ANIMAL GIVEN A SINGLE DOSE OF 40 MG/KG BODY WT, AND 1 LEIOMYOSARCOMA OF THE SEMINAL VESICLE WAS SEEN IN 1 ANIMAL GIVEN A SINGLE DOSE OF 20 MG/KG BODY WT DES. [R40] *DOSES OF DES RANGING FROM 0.01-100 UG/KG BODY WT WERE INJECTED SC INTO CD-1 MICE ON DAYS 9-16 OF GESTATION. IN MATURE FEMALE OFFSPRING, A DOSE-DEPENDENT DECR IN REPRODUCTIVE CAPACITY WAS OBSERVED; AT DOSES OF 10 AND 100 UG/KG BODY WT COMPLETE STERILITY OCCURRED. ... OF MATURE MALE OFFSPRING EXPOSED PRENATALLY TO 100 UG/KG BODY WT, 60% WERE STERILE; 80% OF THESE HAD ALTERATIONS OF THE REPRODUCTIVE TRACT ... INTRAABDOMINAL OR FIBROTIC TESTES ALSO OCCURRED. LOWER DOSES HAD NO EFFECT IN MALES. [R41] *INJECTION (SITE NOT SPECIFIED) OF 0.5-5.0 MG DES INTO RABBITS ON DAYS 4-5 OF GESTATION DID NOT PREVENT BLASTOCYST IMPLANTATION, BUT ADMIN BEFORE DAY 12-14 TERMINATED PREGNANCY. [R42] *AN UNUSUAL AND IMPRESSIVE HYPERBILIRUBINEMIA WAS INDUCED IN CHINESE HAMSTERS BY ADMIN OF DES. THIS ICTERUS WAS DOSE-DEPENDENT AND AFFECTED FEMALES MORE SEVERELY THAN MALES. ARMENIAN HAMSTER WAS EVEN MORE SUSCEPTIBLE TO ICTERIC AND LETHAL EFFECTS OF DES. [R43] *THE EFFECTS OF TREATMENT OF MALE MICE WITH DES ON THE PRIMARY ANTIBODY RESPONSE TO SHEEP RED BLOOD CELLS (SRBC) AND LIPOPOLYSACCHARIDE (LPS) WERE INVESTIGATED. DES TREATMENT AT A DAILY DOSE OF 1.4 OR 5.6 MG/KG FROM 2 DAYS PRIOR TO AND UP TO 3 DAYS AFTER IMMUNIZATION REDUCED THE NUMBER OF ANTI-SHEEP RED BLOOD CELLS- AS WELL AS ANTI-LIPOPOLYSACCHARIDE-PRODUCING CELLS PER SPLEEN CELLS. [R44] *ADULT FEMALE B6C3F1 MICE WERE INJECTED (SC) WITH 0.2, 1.0 and 4.0 MG/KG OF DES DAILY FOR 14 DAYS. ALL IMMUNOLOGICAL TESTS AND TOXICOLOGICAL PARAMETERS WERE DETERMINED AT LEAST 24 HR AFTER LAST EXPOSURE. THYMIC INVOLUTION AND HEPATOMEGALY WERE NOTED AT LOWEST DOSE. MOST SENSITIVE INDICATOR OF IMMUNOSUPPRESSION BY DES WAS DELAYED HYPERSENSITIVITY RESPONSE (DHR) TO KEYHOLE LIMPET HEMOCYANIN IN MICE SENSITIZED WITHOUT ADJUVANT. LOWEST DOSE OF DES PRODUCED A 93% DECREASE. [R45] *DES TREATMENT OF WEANLING F344 FEMALE RATS RESULTED IN ENLARGED PITUITARY GLANDS AND DIFFUSE PITUITARY PROLACTIN (PRL) CELL HYPERPLASIA IN ALL ANIMALS AFTER 9 and 12 WK OF TREATMENT. IMMUNOHISTOCHEMICAL STUDIES SHOWED THAT MOST OF PITUITARY GLAND CELLS CONSISTED OF PROLACTIN CELLS. ULTRASTRUCTURAL STUDIES SHOWED INCR NUMBERS OF PROLACTIN CELLS WITH HYPERPLASIA OF ROUGH ENDOPLASMIC RETICULUM AND DECR NUMBERS OF SECRETORY GRANULES. [R46] *Effects of diethylstilbestrol (DES) on the growth and food conversion of common carp, Cyprinus carpio, were investigated. Fingerlings were fed a diet containing DES (0, 1, 3 or 5 ppm) for 98 days. At the end of this period, wt gain, food conversion efficiency and other parameters were measured. Results showed that, compared to control, DES at 1, 3 and 5 ppm levels increased wt gain in carp by 12.61, 42.92 and 21.46%, respectively. It also increased food conversion efficiency, being 43.09, 48.07, 51.21 and 48.84% in control, 1, 3 and 5 ppm treatment groups, respectively. [R47] *The effects of diethylstilbestrol (DES) treatment on myometrial development from the prenatal to adult period were examined in Balb/c mice and in Sprague Dawley rats by histologic and immunocytochemical methods using anti-actin, anti-vimentin, and anti-laminin to assess cytodifferentiation of smooth muscle and fibroblastic cells, and by morphometric procedures to assess quantitatively the effect of diethylstilbestrol on the expression of cellular orientation in the emerging inner circular myometrial layer. Neonatal mice and rats were treated with diethylstilbestrol from day 0 (day of birth) to day 2 with dosages known to perturb myometrial development (1.0 ug diethylstilbestrol in 20 ul peanut oil ip). Neonatal treatment with diethylstilbestrol incr the degree of circular orientation within the uterine mesenchyme, an effect detectable following as little as 24 hr of diethylstilbestrol treatment. This effect on spatial organization of the mesenchyme was followed by an incr in the thickness of the actin-positive middle layer (prospective circular myometrium) of uterine mesenchyme during days 3-15; from day 15 onward, however, the circular myometrial layer began to fragment into irregular bundles of smooth muscle, and the longitudinal myometrial layer became thinner and more irregular bundles of smooth muscle, and the longitudinal myometrial layer became thinner and more irregularly organized than controls. Vimentin localization in rats treated with DES neonatally was more intense than in controls within the circularly orientated uterine mesenchyme at 5 days. By 60 days the circular and longitudinal myometrial layers of diethylstilbestrol treated animals showed strands and bundles of vimentin-pos cells, which were not present in controls. [R48] NTXV: *LD50 Rat oral > 3 g/kg; [R12] *LD50 Rat ip 34 mg/kg; [R12] *LD50 Mouse oral > 3 g/kg; [R12] *LD50 Mouse ip 538 mg/kg; [R12] *LD50 Mouse iv 300 mg/kg; [R12] NTP: +Diethylstilbestrol (DES) ... was tested in Swiss mice using the RACB protocol. This study was one of the first RACB studies conducted. DES was chosen as a known positive, based on the extensive literature ... . There were two laboratories beginning to run RACB studies, and a DES study was performed at each of these laboratories to address the issue of interlaboratory variability. From the range finding study (Task 1), levels of 1.0, 10.0 and 50.0 ppb in feed were selected for the continuous breeding phase of the study. Based on body weights and measures of food consumption, the estimated average doses were approx 0.15, 1.5, and 7.70 mgm/kg/d. In Task 2, no adverse clinical signs were noted; one high dose female died of partner-inflicted wounds. Body weight was unaffected during Task 2. The mean number of litters/pair was reduced to nearly equal to 30% of control at the high dose, while the number of live pups/litter was reduced by 77% and 64% in the medium and high dose grups, respectively. Adjusted live pup weight was unaffected. The high dose group took longer to deliver each of the first 3 litters; no fourth or fifth litters were delivered at 50 ppb. Since adverse effects were noted in Task 2, Task 3 was conducted using the using the control and high dose mice. Compared to controls, only one-third as many exposed female mice delivered a litter, and these litters contained nearly equal to 60% fewer pups. Interestingly, for the exposed-female group, adjusted pup weight was reduced by nearly equal to 20%. The only adverse effect noted in the group containing exposed males was a 10% reduction in adjusted pup body weight. The larger adverse effects were clearly seen in exposed females. After the Task 3 litters were evaluated, the F0 control and high dose mice were killed and necropsied. For females, the only effect noted was a nearly equal to 30% incr in pituitary weight. For females, 25% of controls had an unclear estrous cycle, while more than 75% of treated females did not have a clear estrous cycle. In males, a significant incr in pituitary weight (nearly equal to 15%) was also seen, along with 13-18% reductions in the weight of epididymis, cauda epididymis, and prostate. There were no demonstrable sperm effects. Task 4, the F2 generation assessment, was not conducted. This study replicated all of the salient features of the other DES study: female as the much-more-sensitive gender in the absence of significant weight effects. Differences between the results of the two studies include effects in the middle dose group, different responses in adjusted pup weight (increased at one lab, decreased at the other), and an effect on pup number in the middle dose in Task 2 (unchanged at one lab, reduced by 11% at the other). Nonetheless, in broad strokes, these studies confirmed the general replicability of the data from two different laboratories, and provided a sense of the degree of variation that might be expected across labs. [R49] +Trans-diethylstilbestrol (DES) was evaluated as a model compound in a reproductive toxicology testing scheme which has been designated "Reproductive Assessment by Continuous Breeding". In the present DES study, ... dietary levels of 1, 10 and 50 ppb DES (/about/ 99% pure) were employed in Task 2. Continuous exposure of breeding pairs /of CD-1 mice/ to dietary DES led to rapid onset of infertility in the 50 ppb DES group, whereas fertility was unaffected in the 0, 1, and 10 ppb DES groups. In addition, the 50 ppb DES pairs produced fewer litters and had fewer live pups/litter and a lower proportion of pups born alive/litter than did the pairs in the other treatment groups. Therefore a crossover mating trial was conducted to determine which sex was adversely affected (Task 3). In the crossover mating trial the proportion of detected matings did not differ significantly among treatment groups, but fertility and the number of live pups/litter and the proportion of pups born alive were significantly reduced (p < 0.05),in the control male x 50 ppb DES female group versus the control male x control female group. The proportion of fertile pairs in the 50 ppb DES male x control female group did not differ significantly from either of the above two groups. Hence, exposure to 50 ppb DES in the diet primarily affected fertility in female mice. The sex of pups born alive and the live pups weights, however, did not differ significantly among the three groups. Thus, these data support the conclusion that, under the conditions of this reproductive toxicity study, DES was a reproductive toxicant in female CD-l mice as evidenced by a decreased fertility index, decreased number of litters, decreased number of live pups/litter and a lower proportion of pups born alive/litter. [R50] +... Diethylstilbestrol (CAS No. 56-53-1 ) was administered subcutaneously in corn oil to mated Swiss (CD-1) mice (12/group) on gd 9 through 16 at levels of 0, 2.5, 5, 10, 50, or 100 mg/kg/day. A trioctanoin vehicle control group and 100 mg/kg/day diethylstilbestrol in trioctanoin group (12/group) were dosed concurrently to provide comparison of data using a different vehicle. Animals were observed daily for clinical signs of toxicity on gd 9-17. Food and water weights were recorded for the animals in each group on gd 0, 3, 6, 9, 12, 16, and 17. Body weights were taken on gd 0, 3, 6, and 9-17. All animals in the developmental toxicity study were killed on gd 17 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development (external, visceral and skeletal). For animals dosed with DES in corn oil, no maternal lethality was observed. Pregnancy rates were 100%, 100%, 100%, 83%, 100%, and 70% for the control through high dose groups. maternal body weight gain was decreased in the 50 and 100 mg/kg/day groups compared to the corn oil controls during the gestational period (gd 0-17), and in the high dose compared to the com oil controls during the treatment period (gd 9-16). Corrected maternal body weight gain was decreased in all the DES in corn oil-treated groups compared to the corn oil control group. No dose-related clinical signs were observed. maternal relative food and water consumption for the DES in com oil groups displayed little effect of treatment. At necropsy, relative maternal liver weight was increased in the high dose group, and gravid uterine weight was decreased. The number of implantation sites per dam exhibited a decreasing trend; the number of corpora lutea per dam was decreased at greater than 10 mg/kg/day. The percent resorptions per litter was increased 3, 4, and 5-fold in the 10, 50, and 100 mg/kg/day groups, respectively. Average live litter size was decreased at the high dose, with male and female fetuses equally affected. Live fetal body weight per litter was not affected by administration of diethylstilbestrol in corn oil. The incidence of malformations per litter was increased in the high dose group, with females more severely affected than males. This was due to an increase in the incidence of extemal malformations per litter, observed as an increase in the incidence of prominent nipples in the gd 17 fetuses, a characteristic effect of prenatal diethylstilbestrol exposure. No significant increase in the incidence of visceral or skeletal malformations or variations was observed for the diethylstilbestrol in corn oil-treated litters, except at 5 mg/kg/day diethylstilbestrol in corn oil where an increase in skeletal malformations was noted. Malformations included scrambled sternebrae, perforated sternum, and fused ribs, which have not been shown to be specific to diethylstilbestrol treatment. Failure to detect a statistically significant number of skeletal malformations in the 10, 50, and 100 mg/kg/day groups may have been influenced by a reduced number of fetuses available for examination in these groups, as a result of prenatal mortality. For animals dosed with diethylstilbestrol in trioctanoin, no maternal lethality was observed. Pregnancy rates were 92% and 100% for the control and 100 mg/kg/day dose group, respectively. Maternal body weight gain was decreased in the 100 mg/kg/day diethylstilbestrol in trioctanoin group compared to the trioctanoin control during the gestational period (gd 0-17), and during the treatment period (gd 9-16). Corrected maternal body weight gain was unaffected by treatment with diethylstilbestrol in trioctanoin. No treatment-related clinical signs were observed. Maternal relative food consumption was unaffected. Maternal relative water consumption for the DES in trioctanoin was decreased during the period of gd 9-12, but not at any other time interval during treatment. At necropsy, relative maternal liver weight was unaffected, while gravid uterine weight was decreased in the 100 mg/kg/day diethylstilbestrol in trioctanoin group. The percent resorptions per litter was increased 5-fold in the 100 mg/kg/day diethylstilbestrol in trioctanoin group compared to the trioctanoin control group. Average live litter size was decreased, with male and female fetuses equally affected. Live fetal body weight per litter was decreased by administration of diethylstilbestrol in trioctanoin. The incidence of malformations per litter was not increased by diethylstilbestrol in trioctanoin treatment. However, when external, visceral, and skeletal malformations were analyzed separately, the incidence of external malformations per litter was increased, due to an increase in the incidence of prominent nipples. No significant increase in the incidence of visceral or skeletal malformations or variations was observed for the DES in trioctanoin-treated litters. In summary, maternal toxicity was evident as decreased corrected maternal body weight at greater than 2.5 mg/kg/day DES in corn oil. Thus, for DES administered subcutaneously in corn oil to Swiss mice on gd 9-16, a No Observed Adverse Effect Level (NOAEL) for maternal toxicity was not determined. Gravid uterine weight and live litter size were decreased at the high dose (100 mg/kg/day). However, the incidence of resorptions (early embryo/fetal death) was increased at greater than 10 mg/kg/day. External malformations were increased at the 100 mg/kg/day, and were characterized by an increase in the incidence of prominent nipples, observed primarily in female fetuses. There was no evidence of altered skeletal development in the fetuses of any dose group. Thus, the LOAEL for developmental toxicity was 10 mg/kg/day and the NOAEL for developmental toxicity was 5 mg/kg/day. Comparison of the effects of 100 mg/kg/day diethylstilbestrol administered in corn oil and trioctanoin indicated there was no difference in corn oil or trioctanoin as vehicles for this compound. [R51] TCAT: ?Diethylstilbestrol (CAS # 56-53-1) was evaluated for reproductive effects in sexually mature male Dutch Belted rabbits (6/group) fed 5 doses of 0.1 or 1.0 mg/kg in oil by oral gavage. Semen specimens were collected twice weekly over 12 weeks following dosing for comparison of sperm volume, motility, density, and morphology to baseline values from specimens collected for 4 weeks prior to dosing. Two or more consecutive measurements outside the "normal range", defined as within 2 standard deviations, indicated an effect on semen quality. Total doses of 0.5 mg/kg (5 x 0.1 mg/kg) were associated with slightly increased sperm volume and wider variations of sperm counts, while 5.0 mg/kg dose totals induced a marked increase in abnormal sperm and decreased sperm numbers, volume, and motility. These changes coincided for approximately 7 weeks post-dosing with all returning to near normalcy, except diminished sperm motility which persisted for 10 weeks. Evaluation of time to changes in sperm count or morphology revealed that nonlethal doses affected primarily spermatocytes and spermatogonia rather than epididymal sperm, spermatids and testicular sperm; only a dose of 20 mg/kg (5 x 4 mg/kg) affected the quality of epididymal sperm. Sperm morphology was the most sensitive indicator of reproductive toxicity. [R52] ?Clastogenic activity was evaluated in 3 cultures of RL1 rat liver cells per dose, exposed for 22 hours to diethylstilbestrol at concentrations of 0, 5.0, 10.0, or 20.0 ug/ml of culture medium. Test concentrations were chosen to be 1/4, 1/2, and 1x the GI50 (concentration at which 50% growth inhibition is achieved). Both positive (methylmethanesulfonate) and solvent (dimethylsulfoxide) controls were used. No metabolic activation system was used. Cell division was arrested, and at least 225 metaphases from each test concentration were examined. Neither chromatid aberrations nor chromosome aberrations were increased significantly. The proportions of cells with chromatid aberrations were 0.2%, 0.0%, 0.0%, and 0.6% at 0.0, 5.0, 10.0, and 20.0 ug/ml, respectively. The proportions of cells with chromosome aberrations were 0.0%, 0.0%, 0.3%, and 0.3% at 0.0, 5.0, 10.0, and 20.0 ug/ml, respectively. Although the positive control compound induced chromatid aberrations in 5.4% of cells, no chromosomal aberrations were induced. [R53] ADE: *ONLY TRACES ... COULD BE FOUND IN TISSUES 24 HR AFTER ADMIN TO SHEEP AND GOATS. [R35, 179] *... SMALL AMT EXCRETED UNCHANGED. STILBESTROL LABELLED WITH (14)C IN TWO METHYLENE GROUPS, INJECTED IN SMALL DOSES INTO RATS, IS MOSTLY EXCRETED IN BILE ... ONLY 5% OF DOSE IS EXCRETED IN URINE. NO (14)CO2 IS EXCRETED IN EXPIRED AIR, SO PRESUMABLY MOLECULE IS STABLE. [R54] *DES is readily absorbed from the GI tract following oral administration. The drug is slowly inactivated in the liver and excreted in urine and feces, principally as the glucuronide. [R27, 2693] METB: *IN SMALL DOSES, ABOUT 70% IS CONJUGATED WITH GLUCURONIC ACID AT ONE OF TWO HYDROXYL GROUPS, VERY LITTLE SULFATE CONJUGATION OCCURS, AND ONLY SMALL AMT ARE EXCRETED UNCHANGED. [R54] *MAJOR METABOLITES OF DES IN SEVERAL SPECIES (RAT, MOUSE, HAMSTER, PRIMATES) ARE DIENOESTROL AND OMEGA-HYDROXYDIENOESTROL ... . [R42] *OXIDATIVE METABOLISM OF DES WAS MEASURED IN MALE AND FEMALE GENITAL TRACTS OF FETAL MOUSE IN ORGAN CULTURE. MAJOR OXIDATIVE METABOLITE WAS Z,Z-DIENESTROL, WHOSE FORMATION APPEARED TO BE TIME DEPENDENT IN ISOLATED FETAL GENITAL TRACT OF BOTH SEXES. IN ADDN, FETAL GENITAL TRACTS WERE CAPABLE OF O-METHYLATION OF DES. A NEW METABOLITE, 4'-O-METHYL-DES, WAS FORMED IN FETAL GENITAL TISSUES BUT NOT IN LIVER CULTURES. CONJUGATION OF DES OCCURRED EXTENSIVELY IN FETAL LIVER AND PLACENTA BUT NOT IN FETAL GENITAL TISSUES. [R55] *Microsomes were prepared from livers of untreated male hamsters (8 wk old) by differential centrifugation. Microsome-mediated reactions were carried out using 10 to 250 uM diethylstilbestrol (DES) with (0.5 to 2.0 mM) cumene hydroperoxide or 100 uM DES with 1 to 5 mM nicotinamide adenine dinucleotide phosphate. Diethylstilbestrol-4',4''-quinone formation by fetal liver homogenate was carried out by incubating 100 uM DES, 1.5 mM cumene hydroperoxide and fetal homogenate (4 mg/ml protein) for 10 min. In vitro, the time dependent formation of diethylstilbestrol-4',4''-quinone as a function of microsomal protein, cofactor or substrate concn was demonstrated. Quinone formation was time dependent and increased in linear fashion for up to 10 min, then remained at a plateau level when incubation times were further increased. Diethylstilbestrol-4',4''-quinone was also formed by fetal liver homogenate. The microsome mediated oxidation of DES to quinone was inhibited 93% by 500 uM 2(3-t-butyl-4-hydroxyanisole), 96% by 500 uM N,N,N',N'-tetramethyl-p-phenylenediamine, 83% by 500 uM n-octylamine, 97% by 500 uM potassium cyanide, and 6% by 1 mM cyclohexene oxide. In microsomal incubations with nicotinamide-adenine dinucleotide phosphate, quinone formation was below detection limits (< 0.005 nmol/mg protein/min). [R56] *Radiolabeled diethylstilbestrol when incubated with ram seminal vesical microsomes, a rich source of prostaglandin-H-synthase (PHS), were found to be cooxidized in part to nonextractable metabolites bound to microsomal protein. The nature of this binding as well as reactivity and stability of various estrogen intermediates were examined in vitro with purified prostaglandin-H-synthase-holoenzyme and albumin, a model system that enabled the determination of covalent binding of radiolabeled estrogens to prostaglandin-H-synthase and to competing nucleophile after electrophoretic separation of the proteins. Estrogens with the radiolabel in metabolically stable positions were incubated with prostaglandin-H-synthase, arachidonic acid and bovine serum albumin (BSA). Proteins were isolated by ultrafiltration and separated by SDS-gel electrophoresis; protein-bound radioactivity was determined by liquid scintillation counting after combustion of excised gel slices in a sample oxidizer. Prostaglandin-H-synthase-catalyzed hydroxylation was studied by means of (3)H-H2O-release from regiospecifically labeled diethylstilbestrol. Diethylstilbestrol was metabolically activated by prostaglandin-H-synthase to metabolites which bound covalently to the catalyzing enzyme; in the presence of bovine serum albumin, cooxidation yielded reactive intermediates which bound to both proteins. Addition of bovine serum albumin raised the total amount of protein bound material, but binding of estrogen intermediates to prostaglandin-H-synthase was hardly changed. Practically no binding to bovine serum albumin was found in incubations lacking prostaglandin-H-synthase; in controls lacking cofactor (AA) protein-bound radioactivity was decr. [R57] *To test the role of 7,8-benzoflavone in the metabolic activation of diethylstilbestrol, the biotransformations of diethylstilbestrol and 7,8-benzoflavone in freshly isolated male Syrian golden hamster hepatocytes after various pretreatments were studied. Hamsters (80-100 g body wt) were pretreated with 7,8-benzoflavone (0.4% in the diet), with diethylstilbestrol (20 mg pellets implanted sc every 3 mo) or with both compounds for various time periods. Metabolic studies (1 mg cellular protein/ml) were carried out in triplicate in a total vol of 2 ml standard medium containing 50 uM diethylstilbestrol or 50 uM 7,8-benzoflavone. Incubations were stopped after 30 min at 37 deg C, the metabolites were extracted into organic solvents and analyzed by HPLC and GLC/mass spectrometry. Diethylstilbestrol was metabolized by hamster hepatocytes to several oxidative metabolites and also to sulfates and glucuronides. The oxidative metabolites comprised Z,Z-dienestrol, 1-hydroxy-Z,Z-dienestrol and 3'-hydroxy-diethylstilbestrol. Pretreatment with diethylstilbestrol or 7,8-benzoflavone did not affect diethylstilbestrol metabolism, whereas combined treatment slightly enhanced oxidative diethylstilbestrol metabolism. Hepatocytes from control hamsters metabolized 7,8-benzoflavone to 7,8-dihydrodiol, 7-hydroxy-7,8-benzoflavone and 6-hydroxy-7,8-benzoflavone. Diethylstilbestrol pretreatment enhanced 7,8-benzoflavone metabolism without affecting the metabolic 7,8-benzoflavone pattern. 7,8-Benzoflavone and combined pretreatment markedly incr 7,8-benzoflavone metabolism. These hepatocytes produced large amounts of new metabolites: two 7,8-benzoflavone-catechols and 5,6-dihydrodiol. [R58] *... Free radical intermediates sometimes are formed during the metabolism of chemical carcinogens, and the metabolic reactions of a number of chemical carcinogens may proceed through free radical intermediates. Chemical carcinogens, including ... diethylstilbestrol, may posess ultimate forms that are free radicals in nature. [R59, 214] ACTN: *The precise mechanism(s) of action of DES as a postcoital contraceptive is not fully understood; however, the drug appears to inhibit nidation (implantation) of the fertilized ovum in the endometrium when administered within 72 hours following coitus. The postcoital contraceptive activity of the drug may involve effects mediated via decreased concentrations of circulating progesterone, effects on tubal motility resulting in accelerated passage of the ovum into the uterus, and inhibition of synthesis of carbonic anhydrase in the endometrium. [R27, 2693] *... DES ... inhibited the postcastration rise in plasma FSH amd LH levels ... . In addition, DES stimulated large increases in prolactin secretion ... [R60] INTC: *BILIARY EXCRETION OF METABOLITES OF ... STILBESTROL ... IN RATS WAS SHOWN ... TO BE INCR BY PRE-TREATMENT WITH HEPATIC-MICROSOMAL-ENZYME INDUCERS, AND TO BE DECR BY ENZYME INHIBITORS AFTER DOSING WITH PARENT CMPD, BUT NO EFFECT WAS OBSERVED AFTER DOSING WITH METABOLITES. [R61] *Male and timed pregnant female Syrian hamsters received vitamin C (1% w/v) in drinking water for 4 days or 40 mg/kg alpha-naphthoflavone in corn oil by ip injection daily for 4 days. Male hamsters (1, 20, 85 or 240 days old) then received a single ip injection of diethylstilbestrol (DES, 20 mg/kg containing 250 uCi (3)H-DES). Pregnant hamsters received the same dose of DES ip on the 14th day of gestation. 30 min later animals were killed. Formation of diethylstilbestrol-4',4''-quinone occurred in all tissues investigated, livers and kidneys of male and female adult hamsters, neonates and fetuses, and in uterus and placenta. After injection of 75 umol/kg DES, diethylstilbestrol-4',4''-quinone was identified in liver and kidney extracts of male hamsters (12 wk old) at levels of 76 + or - 14 and 20 + or - 3 pmol/g tissue respectively. In neonates and fetuses, concn of diethylstilbestrol-4',4''-quinone after the same dose of DES were markedly less than those in adults (0.026 and 0.47% of adult levels in neonatal liver and kidney and 0.013 and 0.016% of adult levels in fetal liver and kidney respectively). Quinone metabolite levels were cut in half in response to vitamin C (44 to 60% of controls in kidneys and 41 to 65% of controls in livers). alpha-Naphthoflavone pretreatment decr renal and hepatic diethylstilbestrol-4',4''-quinone concn by 70 and 17% respectively. [R56] *Estrogens may interfere with the effects of bromocriptine; dosage adjustment may be necessary. /Estrogens/ [R28, 1385] *Concurrent use with estrogens may increase calcium absorption and exacerbate nephrolithiasis in susceptible individuals; this can be used to therapeutic advantage to increase bone mass. /Estrogens/ [R28, 1385] *Concurrent use /of glucocorticoid corticosteroids/ with estrogens may alter the metabolism and protein binding of the glucocorticoids, leading to decreased clearance, increased elimination half-life, and increased therapeutic and toxic effects of the glucocorticoids; glucocorticoid dosage adjustment may be required during and following concurrent use. /Estrogens/ [R28, 1385] *Concurrent use /of corticotropin (chronic therapeutic use)/ with estrogens may potentiate the anti-inflammatory effects of endogenous cortisol induced by corticotropin. /Estrogens/ [R28, 1385] *Estrogens have been reported to inhibit cyclosporine metabolism and thereby increase plasma concentrations of cyclosporine, possibly increasing the risk of hepatotoxicity and nephrotoxicity; concurrent use is recommended only with great caution and frequent monitoring of blood cyclosporine concentrations and liver and renal function. /Estrogens/ [R28, 1385] *Concurrent use of these medications /hepatotoxic medications, especially dantrolene and isoniazid/ with estrogens may increase the risk of hepatotoxicity and fatal hepatitis has occurred; risk may be further increased with use in females over 35 years of age, prolonged use, or use in patients with a history of liver disease. /Estrogens/ [R28, 1385] *Estrogens should be used with caution with medications that cause pancreatitis, especially if the patient has pre-existing risk factors such as high triglyceride concentrations; however, physiologic doses of estrogen would not be expected to induce pancreatitis. /Estrogens/ [R28, 1385] *Ritonavir has decreased the area under the plasma concentration-time curve (AUC) of ethinyl estradiol by 40%; similar effects may occur with other estorgens or with other protease inhibitors. /Estrogens/ [R28, 1385] *Data from studies on tobacco smoking and the use of high-dose estrogen oral contraceptives indicate that there is an increased risk of serious cardiovascular side effects, including cerebrovascular accident, transient ischemic attacks, thrombophlebitis, and pulmonary embolism; risk increases with increasing tobacco usage and with age, especially in women over 35 years of age; it is not known whether any elevation of risk occurs with tobacco smoking during the use of ovarian hormone therapy. Metabolism of estrogens may also be increased by smoking, resulting in a decreased estrogenic effect. /Estrogens/ [R28, 1385] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *...DES also have been used in the treatment of prostate cancer to reduce testicular androgen production secondary to inhibition of LH release from the pituitary. [R29, 1421] *... Two major uses are as a component of combination oral contraceptives and for hormone replacement therapy in postmenopausal women. /Estrogens/ [R29, 1421] *Chemotherapeutic agents useful in neoplastic disease /of the/ breast, prostate /from table/ [R29, 1229] *Antineoplastic Agents, Hormonal; Carcinogens; Contraceptives, Postcoital, Synthetic; Estrogens, Non-Steroidal [R62] *MEDICATION (VET): /SRP: FORMER/ REPLACEMENT THERAPY FOR UNDERDEVELOPED FEMALES; INCONTINENCE, VAGINITIS OF SPAYED BITCHES. TO INDUCE HEAT IN ANESTRUS. IN UTERINE INERTIA, PYOMETRA. TO CHECK MILK SECRETION IN PSEUDOPREGNANCY; PREVENT CONCEPTION IN MISMATED BITCHES. ... CHEMICAL CAPONIZATION OF POULTRY. [R63] *IN CONTRAST TO NATURAL ESTROGENS, IT IS HIGHLY ACTIVE WHEN GIVEN BY MOUTH AND DURATION OF ACTION OF SINGLE DOSE IS LONGER, PROPERTIES IN KEEPING WITH ITS SLOWER RATE OF DEGRADATION IN BODY. [R64, 1384] *MEDICATION (VET): ... DIETHYLSTILBESTROL, USP ... /HAS/ BEEN USED IN TREATMENT OF MAMMARY GLAND CANCER, PROSTATIC HYPERPLASIA AND CARCINOMA, AND PERIANAL GLANDULAR NEOPLASMS. [R25] *... FREQUENTLY THE DECLINE IN OVARIAN FUNCTION AT THE MENOPAUSE IS ASSOC WITH SYMPTOMS THAT ARE CLEARLY DUE TO DEFICIENCY OF ESTROGEN ... REPLACEMENT THERAPY CLEARLY RELIEVES THE HOT FLASHES AND OTHER VASOMOTOR SYMPTOMS AND ATROPHIC VAGINITIS ... THE DOSE OF DIETHYLSTILBOESTROL IS ABOUT 0.2 TO 1 MG ONCE DAILY BY MOUTH ... . [R64, 1429] */IN/ ... EXCESSIVE GROWTH OF BODY HAIR IN WOMEN ... ESTROGENS ... USED TO DECR MILK PRODN IN THE POST-PARTUM PERIOD. [R64, 1431] *THE TREATMENT OF CHOICE FOR DISSEMINATED PROSTATE CANCER REMAINS ENDOCRINE MANIPULATION, EITHER BILATERAL ORCHIECTOMY OR EXOGENOUS ESTROGENS. THE RECOMMENDED DOSE OF DIETHYLSTILBESTROL IS 1 MG /THREE TIMES A DAY/. [R65] *ADVANCED CARCINOMA OF THE PROSTATE MAY PRESENT AS DISSEMINATED INTRAVASCULAR COAGULATION AND ITS SEQUELAE. HIGH-DOSE DES PHOSPHATE SUCCESSFULLY REVERESED THIS COAGULOPATHY IN 2 CASES. [R66] *Estrogen; MEDICATION (VET): Formerly in estrogenic hormone therapy. [R11] *Diethylstilbestrol ... /is/ indicated for treatment of advanced prostatic carcinoma. /Included in US product labeling/ [R28, 1383] *Estrogens may be effective in the prevention of cardiovascular disease in postmenopausal women. /Estrogens; NOT included in US product labeling/ [R28, 1383] WARN: *Nausea and vomiting are an initial reaction...Fullness and tenderness of the breast and edema...Severe migraine in some...Reactivate or exacerbate endometriosis and its attendant pain. /Estrogens/ [R29, 1421] *DIETHYLSTILBESTROL TAKEN DURING PREGNANCY HAS BEEN SHOWN TO BE CAUSALLY ASSOC WITH INCR IN VAGINAL AND CERVICAL CLEAR-CELL ADENOCARCINOMA IN DAUGHTERS, PRIMARILY IN THOSE BETWEEN THE AGES OF 10 AND 30 YR. THE RISK APPEARS TO BE IN THE ORDER OF 0.14-1.4/1000 EXPOSED DAUGHTERS UP TO THE AGE OF 24 YR. [R67] *VET: TOXIC EFFECTS INCLUDE THROMBOCYTOPENIA, GYNECOMASTIA, AND FLUID RETENTION. [R25] *... FIVE PATIENTS HAD SYMPTOMS OF PRESBYOPIA ASSOCIATED WITH USE OF DIETHYLSTILBESTROL AND ... THESE SYMPTOMS ABATED ON DISCONTINUANCE OF DRUG. [R68] *SINCE HIGH PROP OF HORMONES ADMIN IN FEEDING-STUFFS IS EXCRETED UNCHANGED IN FECES THERE IS DANGER, ALTHOUGH ... SMALL, THAT RESIDUES CONTAMINATING PASTURE AND HERBAGE MAY ACCUMULATE TO DETRIMENT OF BREEDING STOCK. [R35, 179] *The DES Task Force recommends that women who received DES during pregnancy should perform and receive periodic breast examinations according to the National Cancer Institute guidelines for early detection of breast cancer for women in general. ... Women who received DES during pregnancy should receive annual (or other suitable interval) gynecologic examinations, including pelvic exam, palpation, and Papanicolaou test (Pap smear), consistent with the practice of preventive medicine. [R27, 2694] *Nausea has been frequently associated with estrogen therapy. Other adverse GI effects include vomiting, abdominal cramps, bloating, and diarrhea. Changes in appetite and changes in weight may also occur. /Estrogens/ [R27, 2689] *Acute pancreatitis has been reported in a few women receiving estrogens alone or in conjunction with a progestin. It has been postulated that increased serum triglyceride concentrations (associated wither with familial defects of lipoprotein metabolism or induced by estrogen therapy), may have caused such disease; therefore, some clinicians suggest that serum lipid concentrations be monitored prior to and during estrogen therapy. In addition, some clinicians recommend that estrogen therapy not be used in women whose serum triglyceride concentrations exceed 200 mg/dl. If acute pancreatitis occurs, estrogens should be discontinued. The risk of gallbladder disease appears to be increased 2- to 4-fold in postmenopausal women receiving estrogen replacement therapy. /Estrogens/ [R27, 2689] *The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma or melasma. Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of estrogen therapy. The macules fade more slowly than in melasma gravidarum and may be permanent. Other dermatologic reactions include erythema multiform, erythema nodosum, and hemorrhagic eruption. Hirsutism and alopecia have also occurred. Porphyria cutanea has reportedly been adversely affected in some women receiving estrogen therapy. /Estrogens/ [R27, 2689] *There is no evidence that estrogen replacement therapy in postmenopausal women is associated with elevated blood pressure; in fact, unopposed estrogen therapy in postmenopausal women has been associated with blood pressure reductions in some studies. However, increases in blood pressure may occur in some women receiving estrogens, particularly if high dosages are used. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. Elevated blood pressure may gradually decrease or persist after discontinuance of estrogen therapy. The precise cause of increased blood pressure is not known, but it may result from a stimulatory effect of estrogen on the renin-angiotensin system. /Estrogens/ [R27, 2689] *Women receiving high dosages of estrogens or those with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be increased risk of developing elevated blood pressure during estrogen therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke and those receiving high dosages of estrogens, should have blood pressure measurements before an estrogen is prescribed and at regular intervals during therapy. Estrogens should be discontinued if the patient becomes hypertensive during therapy. /Estrogens/ [R27, 2689] *Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders including thrombophlebitis, pulmonary embolism, stroke, subarachnoid hemorrhage, and myocardial infarction. Retinal thrombosis and mesenteric thrombosis also have been reported in women receiving oral contraceptives. An increased risk of postsurgery thromboembolic complications has also been reported in patients receiving oral contraceptives. /Estrogens/ [R27, 2689] *Estrogens may cause some degree of fluid retention and edema. Estrogen therapy should therefore be used with caution in patients with conditions that might be aggravated by fluid retention. /Estrogens/ [R27, 2690] *Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens. Prediabetic and diabetic patients should be carefully monitored during estrogen therapy. /Estrogens/ [R27, 2690] *Breakthrough bleeding, spotting, changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving estrogen therapy. Dysmenorrhea and a premenstrual-like syndrome also have been reported. In patients with breakthrough bleeding or irregular vaginal bleeding, nonfunctional causes should be considered. Appropriate diagnostic procedures should be performed in patients with undiagnosed persistent or recurrent vaginal bleeding. /Estrogens/ [R27, 2690] *Changes in cervical erosion and secretions may occur during estrogen therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving estrogens. A cystitis-like syndrome has been reported but has not been definitely attributed to estrogens. An increased incidence of Candida vaginitis has been associated with estrogen therapy. /Estrogens/ [R27, 2690] *Headache, especially migraine headache, may occur during estrogen therapy. Estrogens should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops that is recurrent, persistent, and/or severe. /Estrogens/ [R27, 2690] *Estrogens have been reported to produce keratoconus (steepening or corneal curvature) and intolerance to contact lenses. Contact lenses wearers who develop visual disturbances or changes in lens tolerance during estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. /Estrogens/ [R27, 2690] *Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen therapy. The incidence of breast pain may be increased in patients receiving estrogens in conjunction with progestins compared with those receiving estrogens alone; breast pain was reported in about 33% of women receiving conjugated estrogens concomitantly with medroxyprogesterone acetate compared to 12% of women receiving unopposed conjugated estrogen therapy. /Estrogens/ [R27, 2690] *Use of estrogens, especially in large dosages, may be associated with an increased risk of several serious conditions including thromboembolism, stroke, myocardial infarction, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, malignancy, and hypertension. ... If a progestin is administered concomitantly with estrogen therapy, potential risks may include adverse effects on lipid metabolism, glucose tolerance, or possible enhancement of mitotic activity in breast epithelial tissue. /Estrogens/ [R27, 2690] *... In the treatment of prostate cancer...Gynecomastia and feminizing effects may be disturbing to the male pt. [R29, 1421] *... Known health effects of DES exposure ... Well established cervicovaginal clear cell adenocarcinoma ... vaginal epithelial changes ... reproductive tract anomalities ... premature births ... breast cancer [R69, 717] *Acute toxicity ... nausea and vomiting; abdominal cramps; headache ... delayed toxicity ...gynecomastia in males; breast tenderness; loss of libido; thrombophlebitis and thromboembolism; hepatic injury; sodium retention with edema; hypertension; change in menstrual flow /from table/ [R69, 1325] *Estrogen-induced proliferation apperars to be responsible for tumor formation ... during prolonged estrogen exposure. /Cellular dysfunction and resultant toxicities/ [R59, 48] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Diethylstilbestrol's production and use in biochemical research, medicine, and also in veterinary medicine may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.4X10-8 mm Hg at 25 deg C indicates diethylstilbestrol will exist solely in the particulate phase in the ambient atmosphere. If released to soil, diethylstilbestrol is expected to be immobile based upon an estimated Koc of 570,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.8X10-12 atm-cu m/mole. Diethylstilbestrol is not expected to volatilize from dry soil surfaces based upon its vapor pressure. If released into water, diethylstilbestrol is expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. An estimated BCF of 1600 suggests the potential for bioconcentration in aquatic organisms is very high if diethylstilbestrol is not metabolized. Occupational exposure to diethylstilbestrol may occur through inhalation and dermal contact with this compound at workplaces where diethylstilbestrol is produced or used. (SRC) NATS: *Diethylstilbestrol (DES) is not known to occur naturally(1). [R70] ARTS: *Diethylstilbestrol's production and use in biochemical research, medicine, and also in veterinary medicine(1) may result in its release to the environment through various waste streams(SRC). [R71] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 570,000(SRC), determined from a structure estimation method(2), indicates that diethylstilbestrol is expected to be immobile in soil(SRC). Volatilization of diethylstilbestrol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law of 5.8X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Diethylstilbestrol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.4X10-8 mm Hg(SRC), determined from a fragment constant method(4). [R72] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 570,000(SRC), determined from an estimation method(2), indicates that diethylstilbestrol is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.8X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups(3). According to a classification scheme(5), an estimated BCF of 1600(SRC), from its log Kow of 5.07(8) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is very high if diethylstilbestrol is not metabolized. [R73] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diethylstilbestrol, which has an estimated vapor pressure of 1.4X10-8 mm Hg at 25 deg C(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase diethylstilbestrol may be removed from the air by wet and dry deposition(SRC). [R74] BIOD: *AEROBIC: Over a period of 6 days under aerobic conditions at 20 deg C, 500 mg/l diethylstilbestrol was resistant to biodegradation in two activated sludge samples and was slightly inhibitory in a third sample(1). Biodegradation studies of diethylstilbestrol have indicated this hormone is persistant in soil and feces(2). [R75] ABIO: *Diethylstilbestrol is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1). [R76] BIOC: *An estimated BCF of 1600 was calculated for diethylstilbestrol(SRC), using a log Kow of 5.07(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is very high if diethylstilbestrol is not metabolized. [R77] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for diethylstilbestrol can be estimated to be 570,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that diethylstilbestrol is expected to be immobile in soil. [R78] VWS: *The Henry's Law constant for diethylstilbestrol is estimated as 5.8X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that diethylstilbestrol is expected to be essentially nonvolatile from water surfaces(2). Diethylstilbestrol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Diethylstilbestrol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.4X10-8 mm Hg(3), determined from a fragment constant method(SRC). [R79] WATC: *DRINKING WATER: Diethylstilbestrol was detected in German drinking water samples at a concentration of 0.11-0.26 ng/l(1,2). [R80] FOOD: *In 1972 and 1973, diethylstilbestrol was detected in beef livers at the following concentration, number of samples not reported: < 2 ug/kg, 2 and 0.5% pos, respectively(1); in 1972 and 1973, sheep livers, 1900 samples, residual levels, < 2% pos(1); from 1973 to June 1976, beef livers, 9426 samples, greater than or equal to 0.5 ug/kg, 0.6% pos(1). [R70] RTEX: *... food contaminant ... in beef ... chickens [R81] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,478 workers (920 of these are female) are potentially exposed to diethylstilbestrol in the US(1). Occupational exposure to diethylstilbestrol may occur through dermal contact with this compound at workplaces where diethylstilbestrol is produced or used(SRC). Air samples collected inside the plastic suits of full-time workers in a plant manufacturing diethylstilbestrol contained 0.4-1.8 ug/cu m diethylstilbestrol(2). Two sets of air samples collected in areas outside the main work room contained 0.2 ug/cu m and 12.8 ug/cu m(2). An air sample from a finishing room contained 24 ug/cu m diethylstilbestrol(2). Ambient air samples in three plants where diethylstilbestrol was mixed with animal feed contained 0.002-1.03 ug/cu m diethylstilbestrol(2). [R82] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 100 ug/l [R83] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R84] RCRA: *U089; As stipulated in 40 CFR 261.33, when diethylstilbestrol, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R85] FDA: *Drug products withdrawn or removed from the market for reasons of safety or effectiveness. Diethylstilbestrol: All oral and parenteral drug products containing 25 milligrams or more of diethylstilbestrol per unit dose. [R86] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R87] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC Method 956.10. Diethylstilbestrol in feeds. Spectrophotometric method. [R88, 97] *AOAC Method 960.61. Diethylstilbestrol in drugs. Spectrophotometric method. [R88, 1609] *Thin layer chromatography is used for determination of diethylstilbestrol in feeds. Sensitivity of this method is 0.07 mg/kg. [R89] *Ultra-violet spectrometry at a wavelength of 418 nm can be used for determination of diethylstilbestrol in drugs and vegetable oils. [R89] CLAB: *FLUORIMETRIC METHOD USED TO DETECT DIETHYLSTILBESTROL AT 1 PPB IN ANIMAL TISSUES AND URINE. [R90] *DES AT PICOGRAM LEVEL IN BOVINE URINE WAS IDENTIFIED BY CAPILLARY GAS CHROMATOGRAPHY WITH NEGATIVE CHEMICAL IONIZATION MASS SPECTROMETRY USING METHANE OR METHANE-NITROUS OXIDE (4:1) AS REAGENT GAS. [R91] *MODIFIED ELECTRON CAPTURE GAS-LIQ CHROMATOGRAPHIC METHOD USED FOR DETECTION OF DES IN CATTLE URINE. [R92] *Column chromotography/flame ionization detection is used for determination of diethylstilbestrol in biological fluids and animal tissues. Sensitivity of this method is 8 ug/l ml sample. [R89] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for diethylstilbestrol is completed, and the chemical is in review for further evaluation. Route: topical; Species: transgenic model evaluation, mice. /Diethylstilbestrol/ [R93] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for diethylstilbestrol is completed, and the chemical is in review for further evaluation. Route: gavage; Species: transgenic model evaluation, mice. /Diethylstilbestrol/ [R93] SO: R1: SRI R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 380 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 529 R4: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 156 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V6 56 (1974) R6: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ AZ, College of Pharmacy (1992) R7: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/932 52.024 R8: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 261 R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 301 R10: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.454 R11: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 493 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1196 R13: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R14: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R15: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-4 (1981) EPA 68-03-3025 R16: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (1981) EPA 68-03-3025 R17: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-3-E-22 (1982) R18: USEPA; Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to Cercla Section 102 (Final) p.39 (1988) EPA/600/8-89/053 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 68 (1987) R20: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V6 68 (1974) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 205 (1979) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V6 69 (1974) R24: Wortsman J et al; Am J Med Sci 297 (6): 365-8 (1989) R25: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. 796 R26: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-268 R27: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 99. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements). R28: USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc. R29: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R30: Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams and Wilkins 1994. 278 R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V6 60 (1974) R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 194 (1979) R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 188 (1979) R34: Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975. 164 R35: Garner's Veterinary Toxicology. 3rd ed., rev. by E.G.C. Clarke and M.L. Clarke. Baltimore: Williams and Wilkins, 1967. R36: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. 253 R37: HENDRICKX AG ET AL; J REPROD MED 22 (5): 233 (1979) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 187 (1979) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 189 (1979) R40: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 193 (1979) R41: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 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V21 197 (1979) R43: COE JE ET AL; HEPATOLOGY (BALTIMORE) 3 (4): 489 (1983) R44: HAUKAAS SA; PROSTATE (NY) 4 (4): 375 (1983) R45: HOLSAPPLE MP ET AL; J PHARMACOL EXP THER 227 (1): 130 (1983) R46: LLOYD RV; AM J PATHOL 113 (2): 198 (1983) R47: Nanjundappa T, Varghese TJ; Proc Indian Acad Sci (Anim Sci) 98 (2): 85-8 (1989) R48: Brody JR, Cunha GR; Am J Anat 186 (1): 21-42 (1989) R49: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Diethylstilbestrol (CAS #56-53-1): Fertility Assessment in CD-1 Mice When Administered in Feed, NTP Study No. RACB83046 (November 1984) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R50: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive and Fertility Assessment of Trans-Diethylstilbestrol (DES) (CAS No. 56-53-1) in CD-1 Mice When Administered in the Feed, NTP Study No. RACB83094 (November 1983) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R51: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicity of Diethystilbestrol (CAS NO. 56-53-1) in Swiss (CD-1) Mice, NTP Study No. TER93137 (October, 1994) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R52: E I Dupont De Nemours and Co; Laboratory Tests for Testicular Function; 11/25/80; EPA Document No. 88-920010617; Fiche No. OTS0555886 R53: Shell Chem. Co.; The Activity of 27 Coded Compounds in the RL1 Chromosome Assay (1989), EPA Document No. 86-890000950, Fiche No. OTS0520388 R54: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 170 R55: MAYDL R ET AL; ENDOCRINOLOGY 113 (1): 146 (1983) R56: Roy D, Liehr JG; Carcinogenesis 10 (7): 1241-5 (1989) R57: Freyberger A, Degen GH; Arch Toxicol (Suppl) 13: 206-10 (1989) R58: Blaich G, Metzler M; Arch Toxicol (Suppl) 13: 203-5 (1989) R59: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. R60: Thomas, J.A., K.S. Korach, J.A. McLachlan. Endocrine Toxicology. New York, NY: Raven Press, Ltd., 1985. 372 R61: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 436 R62: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R63: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 919 R64: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R65: SCHMIDT JD; PROSTATE 4 (5): 493 (1983) R66: GOLDENBERG SL ET AL; UROLOGY 22 (2): 130 (1983) R67: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 209 (1977) R68: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 941 R69: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R70: (1) IARC; Diethylstilbestrol and Diethylstilbestrol dipropionate 21: 173-80 (1979) R71: (1) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons p. 380 (1997) R72: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10:1283-93 (1991) (4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R73: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 7-4, 7-5, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 156 (1995) R74: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R75: (1) Lutin PA et al; Purdue Univ Eng Bull Ext Ser 118: 131-45 (1965) (2) Halling-Sorensen B et al; Chemosphere 36: 357-93 (1998) R76: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R77: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 156 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R78: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL etal; Res Rev 85: 17-28 (1983) R79: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R80: (1) IARC; Diethylstilbestrol and diethylstilbestrol dipropionate 21: 173-89 (1979) (2) Rurainski RD et al; Gas-Wasserfach, Wasser-Abwasser 118: 288-91 (1977) R81: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2908 R82: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) IARC; Diethylstilbestrol and diethylstilbestrol dipropionate 21: 173-80 (1979) R83: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R84: 40 CFR 302.4 (7/1/99) R85: 40 CFR 261.33 (7/1/99) R86: 21 CFR 216.24 (4/1/99) R87: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R88: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R89: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 182 (1979) R90: VERBEKE R, VANHEE P; J CHROMATOGR 265 (2): 239 (1983) R91: DIEDERIK H ET AL; ARCH TOXICOL SUPPL 6: 315 (1983) R92: TIRPENOU AE ET AL; J ASSOC OFF ANAL CHEM 66 (5): 1230 (1983) R93: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 98 Record 217 of 1119 in HSDB (through 2003/06) AN: 3066 UD: 200303 RD: Reviewed by SRP on 9/14/1995 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIPHENHYDRAMINE- SY: *ALLEDRYL-; *ALLERGAN-; *ALLERGICAL-; *ALLERGIVAL-; *AMIDRYL-; *ANTISTOMINUM-; *ANTOMIN-; *BAGODRYL-; *BARAMINE-; *BENA-; *BENACHLOR-; *BENADRIN-; *BENODIN-; *BENYLAN-; *BENZANTINE-; *BENZHYDRAMINE-; *BENZHYDRIL-; *O-BENZHYDRYLDIMETHYLAMINOETHANOL-; *2-(BENZHYDRYLOXY),-N,N-DIMETHYLETHYLAMINE; *2-(BENZOHYDRYLOXY)-N,N-DIMETHYLETHYLAMINE; *DERMODRIN-; *DESENTOL-; *DIABENYL-; *DIBENDRIN-; *DIFEDRYL-; *DIFENHYDRAMIN-; *DIHIDRAL-; *DIMEDROL-; *BETA-DIMETHYLAMINOETHANOL-DIPHENYLMETHYL-ETHER-; *ALPHA-(2-DIMETHYLAMINOETHOXY)DIPHENYLMETHANE; *BETA-DIMETHYLAMINOETHYLBENZHYDRYLETHER-; *DIPHANTINE-; *DIPHENYLHYDRAMINE-; *2(DIPHENYLMETHOXY)-N,N-DIMETHYLETHYLAMINE; *DRYLISTAN-; *ETANAUTINE-; *ETHYLAMINE, N,N-DIMETHYL-2-(DIPHENYLMETHOXY)-; *HISTAXIN-; *HYADRINE-; *IBIODRAL-; *MEDIDRYL-; *RESTAMIN-; *RIGIDYL-; *S51-; *SYNTEDRIL- RN: 58-73-1 MF: *C17-H21-N-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY HEATING DIPHENYLBROMOMETHANE. BETA-DIMETHYLAMINOETHANOL, AND SODIUM CARBONATE IN TOLUENE @ 120-125 DEG C FOR 5 HR. FREE BASE...OBTAINED FROM REACTION PRODUCT, AFTER DISTILLING OFF TOLUENE, BY DISTILLATION UNDER REDUCED PRESSURE, and ...CONVERTED TO HYDROCHLORIDE BY TREATMENT WITH HYDROGEN CHLORIDE IN ORG SOLVENT. /HYDROCHLORIDE/ [R1, 1060] FORM: *HYDROCHLORIDE...BAX, BENADRYL, BENOCTEN, BENZEHIST, DABYLEN, DOLESTAN, FELBEN, FENYLHIST, HALBMOND, ROHYDRA, SEDOPRETTEN, VALDRENE, WEHYDRYL. /HYDROCHLORIDE/ [R2] *CAPSULES, 25 and 50 MG; INJECTION (SYRINGES AND AMPULS); ELIXIR, 50 MG (SINGLE ADULT DOSES). /HYDROCHLORIDE, FROM TABLE/ [R3, 609] MFS: *Ganes Chemicals, Inc, 611 Broad Street, Carlstadt, NJ 07072, (201) 507-4300 /Citrate/ [R4] *Wyckoff Chemical Co, Inc, 1421 Kalamazoo Street, South Haven, MI 49090, (303) 534-1919 /Citrate/ [R4] USE: +MEDICATION +MEDICATION (VET) PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R5] *(1978) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R5] U.S. IMPORTS: *(1976) 4.10X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R5] *(1978) 4.40X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: *150-165 DEG C @ 2.0 MM HG [R2] MW: *255.35 [R2] SPEC: *Intense mass spectral peaks: 58 m/z, 73 m/z, 152 m/z, 165 m/z, 255 m/z [R6] OCPP: *CRYSTALS FROM ABS ALC + ETHER; MP: 166-170 DEG C; BITTER TASTE; PH OF 1% AQ SOLN ABOUT 5.5; 1 G DISSOLVES IN: 1 ML WATER, 2 ML ALC, 50 ML ACETONE, 2 ML CHLOROFROM; VERY SLIGHTLY SOL IN BENZENE, ETHER /HYDROCHLORIDE/ [R2] *WHITE CRYSTALLINE POWDER; ODORLESS /HYDROCHLORIDE/ [R1, 1060] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *SLOWLY DARKENS ON EXPOSURE TO LIGHT; STABLE UNDER ORDINARY CONDITIONS /HYDROCHLORIDE/ [R2] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *TWO CASES OF PHYSOSTIGMINE REVERSAL OF ANTIHISTAMINE-INDUCED EXCITEMENT AND SEVERE DEPRESSION ARE REPORTED; 0.3 MG BY SLOW IV REVERSED ANTIHISTAMINE EFFECTS. [R7] *THERE IS NO SPECIFIC THERAPY FOR ANTIHISTAMINE POISONING, AND TREATMENT IS ALONG GENERAL SYMPTOMATIC AND SUPPORTIVE LINES. ... SHOULD BREATHING FAIL, MECH SUPPORT OF VENTILATION OFFER SAFER AND ... EFFECTIVE MEANS OF MAINTAINING RESP THAN USE OF ANALEPTICS WHICH ARE PRONE TO INITIATE OR INTENSIFY CONVULSIVE PHASE. /ANTIHISTAMINES/ [R3, 608] HTOX: *NUMEROUS SIDE EFFECTS.../INCL/ DROWSINESS, CONFUSION, RESTLESSNESS, NAUSEA, VOMITING, DIARRHEA, BLURRING OF VISION, DIPLOPIA, DIFFICULTY IN URINATION, CONSTIPATION, NASAL STUFFINESS, VERTIGO, PALPITATION, HEADACHE, INSOMNIA, URTICARIA, DRUG RASH, PHOTOSENSITIVITY, HEMOLYTIC ANEMIA, HYPOTENSION, EPIGASTRIC DISTRESS... . /HYDROCHLORIDE/ [R1, 1061] *NUMEROUS SIDE EFFECTS.../INCL/ ANAPHYLACTIC SHOCK, TIGHTNESS OF CHEST AND WHEEZING, THICKENING OF BRONCHIAL SECRETIONS, DRYNESS OF MOUTH, NOSE, AND THROAT, AND TINGLING, HEAVINESS, AND WEAKNESS OF HANDS. /HYDROCHLORIDE/ [R1, 1061] *EIGHTEEN-MONTH-OLD BABY SWALLOWED 350 MG AND DESPITE...TREATMENT...HAD CONVULSIONS. ...BABY SEEMED QUITE BLIND AND DEAF. ... RECOVERY WAS COMPLETE IN COURSE OF SEVERAL MO. FUNDI, CSF, AND EEGS WERE NORMAL DURING INTOXICATION. [R8] *...POISONING FROM OVERDOSAGE...OCCURRED IN 16 YR OLD GIRL WHO TOOK TEN 50 MG CAPSULES, PUPILS BECAME DILATED AND UNREACTIVE TO LIGHT WHILE PT HAD VISUAL HALLUCINATIONS AND BEHAVIOR SUGGESTIVE OF ACUTE SCHIZOPHRENIC REACTION, ALL REVERSIBLE AND RESEMBLING ATROPINE POISONING. [R8] *ACUTE EXTRAPYRAMIDAL MOVEMENT DISORDER DEVELOPED IN CHILD FOLLOWING ADMIN OF TWO 25 MG DOSES OF DIPHENHYDRAMINE HYDROCHLORIDE. [R9] *INTOXICATION OF 13-MO-OLD MALE WHO INGESTED 150 MG. MUSCULAR TWITCHING THAT PROGRESSED TO CONVULSIONS, HYPERTHERMIA AND PREMATURE VENTRICULAR CONTRACTIONS. [R10] *Diphenhydramine (Benadryl) is an antihistaminic drug which has a slight atropine-like effect on the pupil and on accommodation, particularly when applied in 0.5% aqueous soln to the eye. It seldom causes ocular effects in ordinary doses administered systemically. [R8] *In acute poisoning with H1 antagonists, their central excitatory effects constitute the greatest danger. The syndrome includes hallucinations, excitement, ataxia, incoordination, athetosis, and convulsions. Fixed, dilated pupils with a flushed face, together with sinus tachycardia, urinary retention, dry mouth, and fever, lend the syndrome a remarkable similarity to that of atropine poisoning. Terminally, there is deepening coma with cardiorespiratory collapse and death, usuallY within 2 to 18 hours. Treatment is along general symptomatic and supportive lines. /Histamine Antagonists: H1 Antagonists/ [R11, 586] *... SIDE EFFECTS INCL DRYNESS OF ... RESP PASSAGES, SOMETIMES INDUCING COUGH; URINARY FREQUENCY AND DYSURIA; PALPITATION; HYPOTENSION; HEADACHE; TIGHTNESS OF CHEST; TINGLING, HEAVINESS, AND WEAKNESS OF HANDS. ... ALLERGIC DERMATITIS IS NOT UNCOMMON. /ANTIHISTAMINES/ [R3, 607] *IN SMALL CHILD ... SYNDROME OF POISONING INCL ... ATAXIA, INCOORDINATION, ATHETOSIS ... FIXED, DILATED PUPILS WITH FLUSHED FACE ... ARE COMMON. /ANTIHISTAMINES/ [R3, 608] *ALTHOUGH H1-BLOCKING DRUGS HAVE RELATIVELY HIGH MARGIN OF SAFETY, ACUTE POISONING WITH THEM IS COMMON. ... IN CHILDREN, 20 TO 30 TABLETS OR CAPSULES OF MOST COMMERCIALLY AVAILABLE ANTIHISTAMINES REPRESENTS LETHAL OR NEAR-LETHAL DOSE. /ANTIHISTAMINES/ [R3, 608] *THERE APPEARS TO BE A PLASMA CONCN RANGE, 25-50 MG/ML WITHIN WHICH THERE IS SIGNIFICANT ANTIHISTAMINE EFFECT WITHOUT SIGNIFICANT SEDATION. [R12] *POTENTIAL ADVERSE EFFECTS ON FETUS: Reported cleft palate is unlikely associated. No good evidence of adverse effects to fetus. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: American Academy of Pediatrics considers safe for breast-feeding. FDA Category: B (B = Studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; or animal studies have shown an adverse effect (other than a decrease in fertility), but controlled studies in pregnant women have not demonstrated a risk to the fetus in the first trimester and there is no evidence of a risk in later trimesters.) /From Table II/ [R13] NTOX: *MAX CONCN WHICH COULD BE APPLIED AS A SINGLE DROP TO RABBIT EYES WITHOUT INJURING CORNEA WERE...DIPHENHYDRAMINE HYDROCHLORIDE, 1%... /HYDROCHLORIDE/ [R14] *Administration of diphenhydramine hydrochloride to weanling rats during 12 wk produced no opacities in the lenses. /Diphenhydramine hydrochloride/ [R8] *... Including diphenhydramine hydrochloride (Benadryl) ... have undesirable side-effects, although none is highly toxic. All, but to varying degrees, produce spasmolysis and local anaesthesia and have an antifibrillatory action on the myocardium. Small doses of some antihistamines produce depression, drowsiness, salivation and vomiting. [R15] *H1 blockers are among the many drugs that induce hepatic microsomal enzymes, and they may facilitate their own metabolism. /Histamine Antagonists: H1 Antagonists/ [R11, 584] NTP: *... Toxicology and carcinogenesis studies were conducted by feeding diets containing USP grade diphenhydramine hydrochloride (greater than 99% pure) to groups of /50/ F344/N rats and /50/ B6C3F1 mice of each sex for two yr. ... Male F344/N rats received dietary concn of 0, 313, or 625 diphenhydramine hydrochloride; female F344/N rats received dietary concn of 0, 156, or 313 ppm diphenhydramine hydrochloride; male B6C3F1 mice received dietary concn of 0, 156, or 313 diphenhydramine hydrochloride; female B6C3F1 mice received /the same dietary concn as male mice/. ... Under the conditions of these two yr feed studies, there was equivocal evidence of carcinogenic activity of diphenhydramine hydrochloride for male F344/N rats, based on marginally incr incidences of uncommon brain neoplasm (astrocytomas or gliomas) and of alveolar/bronchiolar neoplasms. There was equivocal evidence of the carcinogenic activity for female F344/N rats based on a marginal incr in the incidence of pituitary gland adenomas. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 156 or 313 ppm diphenhydramine hydrochloride. /Diphenhydramine hydrochloride/ [R16] +... Diphenhydramine hydrochloride (0, 25, 50 or 100 mg/kg/day) in distilled water was administered by oral gavage on gestational days 6 through 15 to 25-27 females per treatment group; these treatment groups are referred to as diphenhydramine hydrochloride-0, diphenhydramine hydrochloride-25, diphenhydramine hydrochloride-50 and diphenhydramine hydrochloride-100, respectively. Dams were weighed on gestational days 0, 6-15 (prior to daily dosing) and 20 (immediately following sacrifice), and were also observed daily during treatment for clinical signs of toxicity. At sacrifice on gestational day 20, dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e. , implantation sites, resorptions, dead fetuses, live fetuses). ... All dams in all treatment groups survived to sacrifice on gestational day 20. Statistically significant dose-response trends were seen for maternal body weight (gestational day 11, 15, and 20), maternal weight gain during gestation, maternal weight gain during treatment and absolute maternal weight gain (i.e., weight gain during gestation minus gravid uterine weight) with significantly lower body weights and smaller weight gains in the high dose group. No significant differences among dose groups were observed for gravid uterine weight or relative maternal liver weight (i.e., % body weight), although a dose-related trend toward decreased absolute maternal liver weight was observed. Weight loss of more than 5 grams/day was observed in 35% (9/26) of DPH-100 dams as early as the second day of treatment. Other clinical signs included sedation, ataxia , respiratory distress and pica (i. e., excessive consumption of woodchip bedding). Examination of uterine implantation sites revealed no statistically significant differences on the following measures: number of implantation sites per dam; number or percent of resorptions, fetal deaths, nonlive fetuses (dead plus resorbed) or affected fetuses (nonlive plus malformed) per litter; proportion of litters with one or more resorptions, fetal deaths, nonlive or affected. There was no difference among treatment groups in the number of live fetuses per live litter (i.e., litters with one or more live fetuses) or in the proportion of males per live litter. Average fetal body weight per litter for live fetuses in live litters was significantly lower than controls only in the DPH-100 dose group with males and females being equally affected on this measure. A small, but statistically nonsignificant increase in the percentage of malformed fetuses per litter was observed with an incidence of 0.83%, 1.07%, 0.65% and 3.43% for the control through high-dose groups, respectively. The proportion of litters with one or more malformed fetuses also failed to show a statistically significant difference among dose groups. Since the majority of malformed fetuses (11/12) in the DPH-100 group exhibited either hydroureter and/or hydronephrosis, the proportion of litters containing one or more fetuses with renal malformation(s) was compared for the control (1/26) vs. the high-dose (4/24) groups, but this comparison also failed to reach statistical significance. In conclusion, when diphenhydramine hydrochloride was administered to pregnant CD rats during organogenesis at oral doses up to 100 mg/kg/day, no clear evidence of a teratogenic effect was observed even at the highest dose, which produced clear signs of maternal and fetal toxicity. /Diphenhydramine hydrochloride/ [R17] +Diphenhydramine HCl (DPH) ... was evaluated for toxic and teratogenic effects in CD-l mice. Diphenhydramine HCL (0, 80, 160 and 200 mg/kg/day, po) in distilled water was administered in a volume of 0.01 ml per gram of body weight on days 11 through 14 of gestation (day of sperm detection = gestational day 0). A total of 137 sperm-positive females were treated. Females were weighed and observed daily during treatment for clinical signs of toxicity. At sacrifice on gestational day 17, pregnant females (n=27, 29, 24 and 28 in the control through high dose groups, respectively) were weighed and examined for clinical signs of toxicity, gravid uterine weight and uterine contents (i.e., number of implantation sites, live fetuses, dead fetuses and resorptions). ... Mortality during the dosing period (i.e., gestational day 11 through 14) was 8.6% (3/35) in the high dose group and 0% in all other treatment groups. Dose-related clinical signs during treatment included lethargy, prone posture, weight loss, tremors, convulsions and death. Maternal weight gain during the treatment period exhibited a significant dose-related reduction for dams treated with 80, 160 or 200 mg/kg/day Diphenhydramine HCL. Absolute maternal weight gain during gestation (i.e., not including gravid uterine weight) was significantly reduced only for dams treated with 160 mg/kg/day. In addition, significant dose-related decreases were observed for maternal body weight on the final day of treatment (i.e., gestational day 14), maternal body weight at sacrifice (i.e., gestational day 17), weight gain during gestation, and gravid uterine weight. A dose-related increase was observed for maternal relative liver weight. Average fetal body weight per litter was significantly below controls for all Diphenhydramine HCL-treated groups, with both male and female fetuses being affected in a dose-related manner. Although the overall incidence of affected fetuses (i.e., resorbed, dead and malformed) did not increase significantly across treatment groups, statistically significant dose-related trends toward increased incidence of gross malformations in general, and of cleft palate in particular, were observed. Although the incidence of cleft palate in the present study was higher than the historical control incidence observed in this laboratory, the incidence was not statistically greater than concurrent controls for any individual treatment group. These results confirm the previous observation in this laboratory that diphenhydramine hydrochloride tends to increase the incidence of cleft palate in CD-l mice, but only at dose levels which produce overt signs of fetal and maternal toxicity and which do not significantly increase the incidence of combined malformations or of affected fetuses. /Diphenhydramine hydrochloride/ [R18] +... Diphenhydramine HCl (DPH) (0, 40, 80, and 160 mg/kg/day, po) in distilled water was administered in a volume of 0.01 ml per gram of body weight on days 6 through 15 of gestation. Dams were weighed and observed daily during treatment for clinical signs of toxicity. At sacrifice on gestational day 17, the gravid uterus for each dam was weighed and the number of implantation sites, and live, dead or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral and skeletal malformations. During treatment DPH-treated dams exhibited dose-related clinical signs of toxicity including hyperactivity, weight loss, convulsions and death. Maternal weight gain during the treatment period was significantly reduced for dams treated with 80 or 160 mg/kg/day diphenhydramine HCl. In addition, dams receiving the high dose (160 mg/kg/day, diphenhydramine HCl) showed significantly decreased maternal body weight on the final day of treatment (i.e., gestational day 15), decreased absolute maternal weight gain during gestation (i.e., not including gravid uterine weight), and decreased average fetal body weight per litter. Although the overall incidence of affected fetuses (i.e., resorbed, dead and malformed) did not increase significantly across treatments, a statistically significant dose-related trend toward increased cleft palate was observed. Although the incidence of cleft palate in the present study was higher than the historical control incidence observed in this laboratory, the incidence was not statistically greater than concurrent controls for any individual treatment group. These results suggest that diphenhydramine hydrochloride may tend to increase the incidence of cleft palate in CD-1 mice, but only at dose levels which produce overt signs of toxicity in the dams. /Diphenhydramine HCl/ [R19] POPL: *Use is not recommended in newborn or premature infants because this age group has an increased susceptibility to anticholinergic side effects, such as central nervous system excitation, and an increased tendency toward convulsions. A paradoxical reaction characterized by hyperexcitability may occur in children taking antihistamines. /Antihistamines/ [R20, 306] *Dizziness, sedation, confusion, and hypotension may be more likely to occur in geriatric patients taking antihistamines. Geriatric patients are especially susceptible to the anticholinergic side effects, such as dryness of mouth and urinary retention (especially in males), of the antihistamines. If these side effects occur and continue or are severe, medication should probably be discontinued. /Antihistamines/ [R20, 306] ADE: *SLOW FEED-BACK OF DIPHENHYDRAMINE INTO BLOOD OF RHESUS MONKEYS TREATED IV PRODUCED, OVER 4 HR PERIOD, CONCN MANY TIMES HIGHER THAN IMMEDIATELY FOLLOWING INJECTION. [R21] *BLOOD, BRAIN, URINE, AND STOMACH CONTENT OF DIPHENHYDRAMINE WERE ANALYZED BY GAS CHROMATOGRAPHY; LEVELS WERE 31.0, 32.0, 6.4, and 554 UG/ML. SUICIDE DUE TO INGESTION OF DIPHENHYDRAMINE WAS RULED CAUSE OF DEATH. [R22] *The H1 antagonists are well absorbed from the gi tract. Following oral administration, peak plasma concn are achieved in 2 to 3 hr and effects usually last 4 to 6 hr; however, some of the drugs are much longer acting ... . /Histamine Antagonists: H1 Antagonists/ [R11, 584] *... H1 antagonists are eliminated more rapidly by children than by adults and more slowly in those with severe liver disease. /Histamine Antagonists: H1 Antagonists/ [R11, 584] *Diphenhydramine, given orally, reaches a maximal concentration in the blood in about 2 hours, remains at about this level for another 2 hours, and then falls exponentially with a plasma elimination half-time of about 8 hours. The drug is widely distributed throughout the body, including the CNS. Little, if any, is excreted unchanged in the urine; most appears there as metabolites. [R11, 584] METB: */THERE HAS BEEN/ RECENT IDENTIFICATION OF GLUTAMINE CONJUGATE OF (DIPHENYLMETHOXY)ACETIC ACID...AS MAJOR METABOLITE OF DIPHENHYDRAMINE (BENADRYL)...IN MONKEY... [R23] *RABBIT AND GUINEA PIG LIVER PREPN WERE FOUND TO CONVERT DIPHENHYDRAMINE TO DIMETHYLAMINOETHANOL...BENZHYDROL, AND FURTHER PRODUCTS FROM BENZHYDROL... [R24] *DIPHENYLMETHOXYACETIC ACID IS MAJOR PLASMA METABOLITE /OF DIPHENHYDRAMINE/ IN RHESUS MONKEYS AND...IN DOGS, GUINEA PIGS, MICE, AND RABBITS, BUT NOT IN RATS... DIPHENYLMETHOXYACETIC ACID IS CONJUGATED WITH GLUTAMINE IN MONKEYS, BUT WITH GLYCINE IN DOGS... [R21] *DIPHENHYDRAMINE YIELDS BENZHYDRYL METHYLAMINOETHYL ETHER IN RABBIT. IT ALSO YIELDS DIPHENHYDRAMINE-N-OXIDE IN MONKEY. /FROM TABLE/ [R25] *MAIN SITE OF METABOLIC TRANSFORMATION IS LIVER. /ANTIHISTAMINES/ [R3, 607] BHL: *Elimination: 1 to 4 hours [R20, 305] ACTN: *Antihistamines used in the treatment of allergy act by competing with histamine for H1-receptor sites on effector cells. They thereby prevent, but do not reverse, responses mediated by histamine alone. Antihistamines antagonize, in varying degrees, most of the pharmacological effects of histamine, including urticaria and pruritus. Also, the anticholinergic actions of most antihistamines provide a drying effect on the nasal mucosa. /Antihistamines/ [R20, 304] *H1 antagonists inhibit most responses of smooth muscle to histamine. Antagonism of the constrictor action of histamine on respiratory smooth muscle is easily shown in vivo and in vitro. /Histamine Antagonists: H1 Antagonists/ [R11, 582] *H1 antagonists strongly block the action of histamine that results in increased permeability and formation of edema and wheal. /Histamine Antagonists: H1 Antagonists/ [R11, 583] *Within the vascular tree, the H1 antagonists inhibit both the vasoconstrictor effects of histamine and, to a degree, the more rapid vasodilator effects that are mediated by H1 receptors on endothelial cells. Residual vasodilatation reflects the involvement of H2 receptors on smooth muscle and can be suppressed only by the concurrent administration of an H2 antagonist. Effects of the histamine antagonists on histamine induced changes in systemic blood pressure parallel these vascular effects. /Histamine Antagonists: H1 Antagonists/ [R11, 583] *Many of the H1 antagonists tend to inhibit responses to acetylcholine that are mediated by muscarinic receptors. These atropine like actions are sufficiently prominent in some of the drugs to be manifest during clinical usage ... . /Histamine Antagonists: H1 Antagonists/ [R11, 584] INTC: *Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines/ [R20, 307] *Concurrent use of monoamine oxidase (MAO) inhibitors with antihistamines may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use is not recommended. /Antihistamines/ [R20, 307] *Concurrent use /with alcohol or other CNS depression-producing medications/ may potentiate the CNS depressant effects of either these medications or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamines/ [R20, 306] *Anticholinergic effects may be potentiated when /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines/ [R20, 306] *Concurrent use /of other photosensitizing medications/ with antihistamines may cause additive photosensitizing effects. /Antihistamines/ [R20, 307] *Prior administration of ... diphenhydramine ... may decrease the emetic response to apomorphine in the treatment of poisoning. [R20, 307] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *...PROBABLY BEST DESCRIBED AS LYING NEAR BORDERLINE BETWEEN TOXICITY CLASSES 4 and 5. 4= VERY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG, BETWEEN 1 TEASPOON AND 1 OZ FOR 70 KG PERSON (150 LB). 5= EXTREMELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 5-50 MG/KG, BETWEEN 7 DROPS AND 1 TEASPOONFUL. /HYDROCHLORIDE/ [R28] THER: +Anesthetics, Local; Anti-Allergic Agents; Antiemetics; Antiparkinson Agents; Antipruritics; Antitussive Agents; Histamine H1 Antagonists; Sedatives, Nonbarbiturate [R26] *Antihistamines are indicated in the prophylactic and symptomatic treatment of perennial and seasonal allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis due to inhalant allergens and foods. /Antihistamines; Included in US product labeling/ [R20, 303] *Antihistamines are indicated for the symptomatic treatment of pruritus associated with allergic reactions and of mild, uncomplicated allergic skin manifestations of urticaria and angioedema, in dermatographism, and in urticaria associated with transfusions. /Antihistamines; Included in US product labeling/ [R20, 303] *Antihistamines are also used in the treatment of pruritus associated with pityriasis rosea. /Antihistamines; NOT included in US product labeling/ [R20, 303] *Antihistamines are indicated for the relief of sneezing and rhinorrhea associated with the common cold. However, controlled clinical studies have not demonstrated that antihistamines are significantly more effective than placebo in relieving cold symptoms. Non-sedating (ie, second generation) antihistamines are unlikely to be useful in the treatment of the common cold symptoms since they do not have clinically significant anticholinergic effects (eg, drying effects on nasal mucosa). /Antihistamines; Included in US product labeling/ [R20, 303] *Antihistamines are indicated as adjunctive therapy to epinephrine and other standard measures for anaphylactic reactions after the acute manifestations have been controlled, and to ameliorate the allergic reactions to blood or plasma. /Antihistamines; Included in US product labeling/ [R20, 303] +MEDICATION (VET): USE: ORALLY AND LESS COMMONLY PARENTERALLY, IN ALLERGIC DERMATOSES AND DRUG OR FOOD ALLERGIES; ORALLY, IN MOTION SICKNESS OF DOGS; TOPICALLY, TO SUPPRESS DERMAL RESPONSES TO HISTAMINE, AND AS LOCAL ANESTHETIC ON SUCH TISSUES (1%). /HYDROCHLORIDE/ [R27] *Diphenhydramine is indicated for the symptomatic treatment of parkinsonism and drug-induced extrapyramidal reactions in elderly patients unable to tolerate more potent antidyskinetic medications, for mild cases of parkinsonism in other age groups and, in combination with centrally acting anticholinergic agents, for other cases of parkinsonism. /Included in US product labeling; NOT included in Canadian product labeling/ [R20, 303] *Diphenhydramine hydrochloride syrup is currently indicated as a non-narcotic cough suppressant for control of cough due to colds or allergy. /Included in US product labeling/ [R20, 303] *Dimenhydrinate and diphenhydramine are indicated for the prevention and treatment of the nausea, vomiting, dizziness, or vertigo of motion sickness. /Included in US product labeling/ [R20, 303] *Diphenhydramine and hydroxyzine are indicated for their sedative and hypnotic effects and as preoperative medications. /Included in US product labeling/ [R20, 303] *Diphenhydramine and doxylamine are indicated as nighttime sleep aids to help reduce the time to fall asleep in patients having difficulty falling asleep. /Included in US product labeling/ [R20, 303] *Despite persistent popular belief, H1 antagonists are without value in combating the common cold. The weak anticholinergic effects of the older agents may tend to lessen rhinorrhea, but this drying effect may do more harm than good, as may also their tendency to induce somnolence ... . /Histamine Antagonists: H1 Antagonists/ [R11, 587] *Ethanolamines (Prototype: Diphenhydramine). The drugs in this group possess significant antimuscarinic activity and have a pronounced tendency to induce sedation. With conventional doses, about half of those who are treated with these drugs experience somnolence. The incidence of gi side effects, however, is low with this group. [R11, 586] *Diphenhydramine can be used to reverse the extrapyramidal side effects caused by phenothiazines. The anticholinergic actions of this agent can also be utilized in the early stages of treatment of patients with Parkinson's disease. [R11, 588] *The tendency of certain of the H1 blockers to produce somnolence has led to their use as hypnotics. H1 antagonists, principally diphenhydramine, are often present in various proprietary remedies for insomnia that are sold "over the counter." While these remedies are generally ineffective in the recommended doses, some sensitive individuals may derive benefit ... . The sedative and mild antianxiety activities of hydroxyzine and diphenhydramine have contributed to their use as weak anxiolytics. [R11, 588] +MEDICATION (VET): ANTIHISTAMINIC, ALSO IN ANTI-MOTION SICKNESS /HYDROCHLORIDE/ [R2] +ANTIHISTAMINIC IN HUMAN AND VETERINARY MEDICINE; ANTIEMETIC (EG, FOR MOTION SICKNESS); SEDATIVE; ANTIPARKINSONISM DRUG [R5] WARN: *Use is not recommended in newborn or premature infants because this age group has an increased susceptibility to anticholinergic side effects, such as central nervous system excitation, and an increased tendency toward convulsions. A paradoxical reaction characterized by hyperexcitability may occur in children taking antihistamines. /Antihistamines/ [R20, 306] *Dizziness, sedation, confusion, and hypotension may be more likely to occur in geriatric patients taking antihistamines. Geriatric patients are especially susceptible to the anticholinergic side effects, such as dryness of mouth and urinary retention (especially in males), of the antihistamines. If these side effects occur and continue or are severe, medication should probably be discontinued. /Antihistamines/ [R20, 306] *Prolonged use of antihistamines ... may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort. /Antihistamines/ [R20, 306] *...PRESCRIPTION ONLY. DO NOT USE WITH ALC OR OTHER CNS DEPRESSANTS. /HYDROCHLORIDE/ [R29] *SINCE DIPHENHYDRAMINE HAS ATROPINE-LIKE ACTION, IT SHOULD BE USED WITH CAUTION IN PT WITH ASTHMA. ... PERSONS SHOULD ALSO BE ADVISED NOT TO OPERATE MOTOR VEHICLE...OR OPERATE HAZARDOUS MACHINERY WHILE ON THIS DRUG. INCIDENCE OF SIDE EFFECTS IS ABOUT 30 TO 60%. [R1, 1061] *H1 antagonists are most useful in acute exudative types of allergy that present with symptoms of rhinitis, urticaria, and conjunctivitis. Their effect, however, is purely palliative and confined to the suppression of symptoms attributable to the histamine-antibody reaction. The drugs do not diminish the intensity of this reaction, which is the cause of the various hypersensitivity diseases. /Histamine Antagonist: H1 Antagonists/ [R11, 587] *The older H1 antagonists can both stimulate and depress the CNS. Stimulation is occasionally encountered in patients given conventional doses, who become restless, nervous, and unable to sleep. Central excitation is also a striking feature of poisoning, which not uncommonly results in convulsions, particularly in infants. Central depression, on the other hand, is the usual accompaniment of therapeutic doses of the older H1 antagonists. /Histamine Antagonists: H1 Antagonists/ [R11, 584] *The side effect with the highest incidence, and the one common to all H1 antagonists other than terfenadine or astemizole, is sedation ... . Although this may be a desirable adjunct in the treatment of some patients, it may interfere with the patient's daytime activities. Concurrent ingestion of alcohol or other CNS depressants produces an additive effect that impairs motor skills. Other untoward reactions referable to central actions include dizziness, tinnitus, lassitude, incoordination, fatigue, blurred vision, diplopia, euphoria, nervousness, insomnia, and tremors. /Histamine Antagonists: H1 Antagonists/ [R11, 586] *... Frequent side effects involve the digestive tract and include loss of appetite, nausea, vomiting, epigastric distress, and constipation or diarrhea. Their incidence may be reduced by giving the drug with meals. ... Other side effects that are apparently caused by the antimuscarinic actions of some of the older agents include dryness of the mouth and respiratory passages, sometimes inducing cough, urinary retention or frequency, and dysuria. These effects are not observed with terfenadine or astemizole. Palpitation, hypotension, headache, tightness of the chest, and tingling and weakness of the hands may also occur with the older agents. /Histamine Antagonists: H1 Antagonists/ [R11, 586] *Drug allergy may develop when H1 antagonists are given orally, but more commonly it results from topical application. Allergic dermatitis is not uncommon; other hypersensitivity reactions include drug fever and photosensitization. Hematological complications such as leukopenia agranulocytosis, and hemolytic anemia are very rare. Teratogenic effects have been noted in response to piperazine compounds, but extensive clinical studies have not demonstrated any association between the use of such H, antagonists and fetal anomalies in man. Since H1 antagonists interfere with skin tests for allergy, they must be withdrawn well before such tests are performed. /Histamine Antagonists: H1 Antagonists/ [R11, 586] *In bronchial asthma, histamine antagonists are singularly ineffectual. /Histamine Antagonist: H1 Antagonists/ [R11, 587] *The ethanolamines (eg, diphenhydramine ... ) are particularly prone to cause sedation. [R11, 584] *In bronchial asthma, histamine antagonists are singularly ineffective. Similarly, in the treatment of systemic anaphylaxis, in which autacoids other than histamine play major roles, the mainstay of therapy is epinephrine, with histamine antagonists having only a subordinate and adjuvant role. The same is true for severe angioedema, in which laryngeal swelling constitutes a threat to life. /Histamine Antagonists: H1 Antagonists/ [R11, 587] *... Certain H1 antagonists ... /have/ the capacity to counter motion sickness. This effect was first observed with dimenhydrinate and subsequently with diphenhydramine (the active moiety of dimenhydrinate), various piperazine derivatives, and promethazine. [R11, 584] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R30] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Diphenhydramine hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 355 (1989) NIH Publication No. 89-2810 /Diphenhydramine hydrochloride/ SO: R1: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 523 R3: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 731 R5: SRI R6: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.427 R7: LEE JH ET AL; ANESTHESIOLOGY 43 (DEC): 683-4 (1975) R8: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 363 R9: LAVENSTEIN BL ET AL; J AM MED ASSOC; 236 (JUL): 291 (1976) R10: HESTAND HE ET AL; J PEDIATR 90 (JUN): 1017-18 (1976) R11: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R12: CARRUTHERS SG ET AL; CLIN PHARMACOL THER 23 (4): 375-82 (1978) R13: Stockton DL, AS Paller; J Am Acad Dermatol 23 (1): 87-103 (1990) R14: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 149 R15: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 104 R16: DHHS/NTP; Toxicology and Carcinogenesis Studies of Diphenhydramine hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 355 (1989) NIH Publication No. 89-2810 R17: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Diphenhydramine Hydrochloride (CAS No. 147-24-0) in CD Rats, NTP Study No. TER82067 (February 11, 1983) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R18: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Diphenhydramine Hydrochloride (CAS No. 147-24-0) Administered to CD-1 Mice on Gestational Days 11 Through 14, NTP Study No. TER82068 (July 23, 1982) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R19: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Diphenhydramine Hydrochloride (CAS No. 147-24-0) in CD-1 Mice, NTP Study No. TER82069 (December 22, 1981 ) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 15, 2002 R20: USP Convention. USPDI - Drug Information for the Health Care Professional. 15 th ed. Volume 1. Rockville, MD: United States Pharmacopeial Convention, Inc., 1995. (Plus updates.) R21: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 226 R22: BACKER RC ET AL; J ANAL TOXICOL 1 (5): 227-8 (1977) R23: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 420 R24: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. 120 R25: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-98 R26: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R27: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 184 R28: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-378 R29: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 315 R30: 21 CFR 200-299, 300-499, 820, and 860 (4/1/94) RS: 39 Record 218 of 1119 in HSDB (through 2003/06) AN: 3086 UD: 200208 RD: Reviewed by SRP on 5/11/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: FUROSEMIDE- SY: *AISEMIDE-; *Aluzine-; *5-(Aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid; *ANTHRANILIC-ACID,-4-CHLORO-N-FURFURYL-5-SULFAMOYL-; *BENZOIC ACID, 5-(AMINOSULFONYL)-4-CHLORO-2-((2-FURANYLMETHYL)AMINO)-; *BERONALD-; *Chlor-N-(2-furylmethyl)-5-sulfamylanthranilsaeure (German); *4-Chloro-N-furfuryl-5-sulfamoylanthranilic-acid-; *4-Chloro-N-(2-furylmethyl)-5-sulfanoylanthranilic acid; *DESDEMIN-; *Discoid-; *DIURAL-; *DRYPTAL-; *Durafurid-; *Endural-; *ERROLON-; *Eutensin-; *FRUSEMIDE-; *FRUSEMIN-; *Frusetic-; *Frusid-; *FULSIX-; *FULUVAMIDE-; *FURANTHRIL-; *FURANTHRYL-; *FURANTRIL-; *FURESIS-; *2-FURFURYLAMINO-4-CHLORO-5-SULFAMOYLBENZOIC-ACID-; *Furo-Puren-; *Furosedon-; *FUROSEMID-; *FURSEMID-; *FURSEMIDE-; *FUSID-; *Hydroled-; *Hydro-rapid-; *KATLEX-; *LASEX-; *LASILIX-; *LASIX-; *LB-502-; *LOWPSTRON-; *MACASIROOL-; *Mirfat-; *"Mita"-; *NC1-C55936-; *NICOROL-; *Odemase-; *Odemex-; *PREFEMIN-; *Profemin-; *RADONNA-; *ROSEMIDE-; *Rusyde-; *SALIX-; *SEGURIL-; *TRANSIT-; *TROFURIT-; *UREX-; *UROSEMIDE- RN: 54-31-9 MF: *C12-H11-Cl-N2-O5-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *2,4-DICHLOROBENZOIC ACID IS REACTED WITH CHLOROSULFONIC ACID, TREATED WITH AMMONIA, THEN REFLUXED WITH EXCESS FURFURYLAMINE. [R1] *2,4-DICHLOROBENZOIC ACID IS HEATED WITH CHLOROSULFONIC ACID AND RESULTING 5-CHLOROSULFONYL DERIV IS REACTED WITH CONCN AMMONIA TO CONVERT IT TO 5-SULFAMOYL ANALOG. REFLUXING WITH FURFURYLAMINE ... YIELDS CRUDE FUROSEMIDE WHICH IS RECRYSTALLIZED FROM AQ ETHANOL. [R2] *Prepn: K. Sturm et al., DE 1122541; eidem US 3058882 (both 1962 to Hoechst) [R3, 765] *Production: 2,4-dichloro-5-sulphamoylbenzoic acid + chlorosulphonic acid + ammonia + furfurylamine (amide formation) [R4] *Synthetically from furfural, hydroxyethylhydrazine, and diethyl carbonate [R5] *Produced by conversion of 2,4-dichloro-5-sulfamoylbenzoic acid with excess furfurylamine, in the absence of solvent, at 120-130 deg C. [R6] *Prepared in 85% yield from 2-fluoro-4-chloro-5-sulfamoylbenzoic acid and furfurylamine at 95 deg C for 2 hr [R7] FORM: *FUROSEMIDE, USP (LASIX), IS AVAILABLE AS 20-, 40- and and 80-MG TABLETS. ... PREPN IS ALSO AVAILABLE FOR PARENTERAL ADMIN, EITHER IV OR IM. [R8, 725] *Oral solution, 40 mg/5 ml furosemide solution (with alcohol 0.2% and sorbitol), Roxane; Lasix (with alcohol 11.5%, parabens, and sorbitol), Hoechst-Roussel; Tablets, 20 mg, Lasix, Hoechst-Roussel; 40 mg, Lasix (scored), Hoechst-Roussel; 80 mg, Lasix, Hoechst-Roussel. [R9, 2570] *Parenteral Injection, 10 mg/ml, Furomide, Hyrex; Lasix (with benzyl alcohol 0.9%), Hoechst-Rousel. [R9, 2571] *Tablets, 20, 40, and 80 mg. Oral solution, 10 mg/ml. Ampules, vials, and syringes, 10 mg/ml. [R10] *Grade: National Formulary grade [R5] MFS: *Hoechst Celanese Corp., Hq, Route 202-206 North, Somerville, NJ 08876, (908) 231-2000; Pharmaceutical Raw Material Div., 1601 West LBJ Freeway, P.O. Box 819005, Dallas, TX 75381-9005, (972) 443-4000; Production site: Coventry, RI 02816 [R11] OMIN: *Pharmaceutical incompatibility: calcium gluconate, ascorbic acid, tetracyclines, urea, epinephrine. [R3, 765] *The first high-ceiling diuretic on the market and is still the most important product in the /diuretic/ group. [R12, 32] *Furosemide use in horses for /the control of exercise-induced pulmonary haemorrhage (EIPH) or bleeding/ is highly controversial and has been criticized by organizations outside and inside of the racing industry. ... The existing literature references suggest that furosemide has the potential of increasing performance in horses without significantly changing the bleeding status. [R13] *Furosemid was on the top ten list of pharmaceuticals used in Denmark in 1995. [R14] USE: *Diuretic drug [R4] *Therap Cat: Diuretic; antihypertensive [R3, 764] *Therap Cat (Vet): Diuretic [R3, 764] *Furosemide has been used empirically and has been legally approved for many years by the US racing industry for the control of exercise-induced pulmonary haemorrhage (EIPH) or bleeding. [R13] *May improve renal blood flow, decrease resorption of sodium and chloride, and increase free-water excretion. [R15] *MEDICATION (VET) *MEDICATION PRIE: U.S. PRODUCTION: *(1976) NOT PRODUCED COMMERCIALLY IN US [R1] *(1978) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1976) 1.82X10+3 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1978) 1.25X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crystals from aqueous ethanol [R3, 764]; *Yellow powder [R5]; *FINE, WHITE TO SLIGHTLY YELLOW, CRYSTALLINE POWDER [R2] ODOR: *Odorless [R5] TAST: *PRACTICALLY TASTELESS [R2] MP: *206 deg C [R3, 764] MW: *330.75 [R3, 764] DSC: *pKa1= 3.8; pKa2= 7.5 [R16] OWPC: *log Kow = 2.03 [R17] SOL: *Slightly soluble in chloroform, ether. Soluble in acetone, methanol, DMF, aqueous solutions above pH 8.0. Less soluble in ethanol. [R3, 764]; *Slightly soluble in polyethylene glycol; insoluble in alcohol, and diethyl carbonate. [R5]; *Soluble in dilute NaOH. [R18]; *Freely sol in alkali hydroxide. [R19]; *In water, 73.1 mg/l @ 30 deg C [R20] SPEC: *UV Max (95% ethanol): 288, 276, 336 nm (E(1%)(1 cm): 945, 588, 144); (0.1N NaOH): 226, 273, 336 (E(1%)(1 cm): 1147, 557, 133). [R3, 764] OCPP: *MELTS BETWEEN 203-205 DEG WITH DECOMP [R2] *A free carboxyl group gives it a strong hydrophilic character [R12, 33] *The sodium salt can be recrystallized from water; the solubility of the salt in water at room temperature is 6%. /Sodium salt/ [R12, 33] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Furosemide is soluble in alkaline soln that is prepared as a mildly buffered alkaline product. It should not be mixed with acidic solns have a pH below 5.5. Furosemide may precipitate if combined with ascorbic acid, epinephrine, norepinephrine, or tetracycline. The acidic pH of aminoglycoside admixtures may cause transient cloudiness or frank precipitation if furosemide is added, depending on which aminoglycoside is used and the concn of the additives. Avoiding the admixture of furosemide and aminoglycosides has been recommended. [R21, 496] *Furosemide may precipitate if mixed with milrinone lactate infusions. [R21, 496] DCMP: *When heated to decomposition it emits very toxic fumes of /hydrogen chloride, nitrogen oxides and sulfur oxides/. [R22] SSL: *UNSTABLE IN LIGHT BUT STABLE IN AIR [R2] *Exposure to light may cause discoloration; protection from light for the syringes once they are removed form the package is recommended. Do not use furosemide solns if they have a yellow color. Furosemide products should be stored at controlled room temp. Refrigeration may result in precipitation or crystallization. However, resolubilization at room temp or on warming may be performed without affecting the drug's stability. Furosemide has been found to be unstable in acidic media but very stable in basic media. Furosemide 10 mg/ml retained potency for 3 months at room temp when 2 ml of soln was packaged in Tubex cartridges. [R21, 488] STRG: *Exposure to light may cause discoloration; protection from light for the syringes once they are removed form the package is recommended. Do not use furosemide solns if they have a yellow color. Furosemide products should be stored at controlled room temp. Refrigeration may result in precipitation or crystallization. However, resolubilization at room temp or on warming may be performed without affecting the drug's stability. [R21, 488] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence for the carcinogenicity of furosemide in humans. There is inadequate evidence for the carcinogenicity of furosemide in experimental animals. Overall evaluation: Furosemide is not classifiable as to its carcinogenicity to humans (Group 3). [R23] ANTR: */SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R24] */SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R24] HTOX: *Furosemide is not known to be hepatotoxic in humans at normal therapeutic doses, but in vitro studies have shown that human liver microsomes are capable of converting furosemide to metabolites that bind irreversibly to microsomal proteins. [R25] *Tinnitus, reversible or permanent hearing impairment, or reversible deafness have occurred, usually following rapid iv or im administration of furosemide in doses greatly exceeding the usual therapeutic dose of 20 to 40 mg. Otic effects are most likely to occur in patients with severe impairment of renal function and/or in patients receiving other ototoxic drugs (eg, aminoglycosides). It has been postulated that administering furosemide by slow iv infusion rather than as a bolus may reduce the ototoxic effects of the drug by preventing high peak plasma concentrations; if high dose parenteral furosemide therapy is necessary in patients with severely impaired renal function, the manufacturers recommend that the drug be infused in adults at a rate not exceeding 4 mg/min. [R9, 2568] *GREATLY AUGMENTS URINARY EXCRETION OF 5-HYDROXYTRYPTAMINE AND DEPLETES IT FROM INTRARENAL STORES. [R26, 835] *An 88 yr old man is described who developed an eruption that clinically and histologically simulated Sweet's syndrome 6 wk after furosemide therapy was started. The rapid resolution of lesions on discontinuation of the medication, as well as several features atypical for Sweet's syndrome in this case, favored the diagnosis of drug eruption. [R27] *The diuretic effect of high doses of furosemide alone and furosemide plus mannitol was analyzed retrospectively in 30 children with acute renal failure. In 10 children (Group 1) renal failure developed mainly during glomerulonephritis, and in 20 children (Group 2) the cause was gastroenteritis. The diuretic effects of furosemide and furosemide plus mannitol were evaluated measuring the 24 hr urine volume at the time of anuria, oliguria or normal diuresis. The highest mean single iv doses of furosemide were 6.5 and 14 mg/kg in Groups 1 and 2, respectively; the highest average daily doses were 10.1 and 25.5 mg/kg, respectively. A broad relationship was observed between single iv dose and diuretic response following admin of furosemide (1.2-30.8 mg/kg). In both groups of patients a statistically significant negative linear correlation was found between the daily iv dose of furosemide and the 24 hr urine volume. Calculations based on the obtained regression equations showed that the expected 24 hr urine volumes corresponding to daily diuresis normal for age could be obtained after admin of daily 2.8-1.4 mg/kg furosemide in Group 1 and 9.3-2.3 in Group 2. It is therefore suggested that the total daily dose of furosemide should not exceed 100 mg in children with acute renal failure. Admin of furosemide plus mannitol did not result in higher daily diuresis as compared to 24 hr urine volume obtained when furosemide was given alone. Furosemide was well tolerated. Electrolyte disturbances, especially in Group 2, were the most frequent side effects due to high doses of furosemide. [R28] *Thirty-five neonates with severe sensorineural hearing loss defined by brain stem auditory evoked response and 70 controls matched for date of birth and birth-weight who had normal brain stem auditory evoked responses were studied. All patients were born during the calendar years 1981-1984 and were tested before discharge from the NICU as part of our screening program to detect hearing loss in high risk neonates. The 35 sensorineural hearing loss infants had their brain stem auditory evoked response results confirmed on at least one occasion following hospital discharge and were the only neonates screened during this time who had no brain stem auditory evokes response to a 60 db click stimulus. Based on the screening program results, the overall incidence of non-hereditary hearing loss was estimated to be 0.93/1000 live births and the incidence in neonates weighing < 2 kg at birth to be 15.54/1000 live births. By multivariate analysis, exposure to furosemide, aminoglycoside and the occurrence of hyponatremia were significantly (p < 0.01) associated with deafness. Although no patient was exposed to furosemide alone, furosemide and aminoglycoside exposure appeared to have a multiplicative effect on increasing the risk of sensorineural hearing loss. If neither exposure is assigned an odds ratio of 1.0, then exposure to aminoglycoside had an odds ratio of 7.7 and exposure to furosemide and aminoglycoside had an odds ratio of 56.7, suggesting an interaction of the two exposures. Peak serum bilirubin concn and benzyl alcohol exposure did not appear to be related to hearing loss. [R29] *Human systemic effects by iv route: change in the sensitivity of the ear to sound, tinnitus, unspecified effects on the heart, constriction of the arteries, and a decr in urine volume, interstitial nephritis, metabolic alkalosis, pulse rate decr, fall in BP. Ingestion can damage the liver. [R22] *During pregnancy, /furosemide/ indicated only for severe cardiovascular disease (e.g., pulmonary edema, severe hypertension, CHF). No fetal toxicity reported, but 1st trimester use limited. [R30, p. 45-12] *BACKGROUND: The use of furosemide is well recognized as a predisposing factor of nephrocalcinosis in infants. Although furosemide is widely used for various medical conditions in adults, its association with nephrocalcinosis in adults is not well established. METHODS: We studied 18 consecutive adult patients (male:female ratio 1:17, age range 21-59 years) who habitually took furosemide to control weight or oedema for long periods of time (range 3-25 years). The daily dose of continuous intake of furosemide ranged from 40 to 2800 mg. Nephrocalcinosis was evaluated using renal ultrasonography (US), computed tomography (CT), or kidney biopsies. RESULTS: Renal US and CT revealed bilateral nephrocalcinosis of the medullary pyramids in 15 (83.3%) out of 18 patients. The duration of furosemide abuse was similar between nephrocalcinosis positive (NC(+)) and nephrocalcinosis negative (NC(-)) groups. The daily dose of furosemide was nearly 10 times higher in the NC(+) group (range 120-2800 mg, mean 538 mg) than the NC(-) group (range 40-80 mg, mean 67 mg). All patients showed variable degrees of renal insufficiency and there was no difference in creatinine clearance between the NC(+) and NC(-) groups (P > 0.05). Kidney biopsies performed in three patients showed focal tubulo-interstitial fibrosis and atrophy and calcifications were observed in outer medullary tubulo-interstitium. CONCLUSIONS: Long-term furosemide abuse can cause medullary nephrocalcinosis in adults, and the risk of developing of nephrocalcinosis seems to be correlated with the daily dose of furosemide. We suggest that long-term furosemide abuse should be suspected in adult patients when medullary nephrocalcinosis is incidentally detected by US or CT. [R31] *BACKGROUND: to report on the possible correlation between incident retinal phototoxicity and the use of photosensitizing drugs. METHODS: 4 patients were examined because of scotomas and visual loss after an incidental exposure to a strong light source. One patient (two eyes) was exposed to standard camera flash; one patient (one eye) had a brief exposure to welding light; one patient (two eyes) underwent uncomplicated phacoemulsifications with intraocular lens implantation. The fourth patient had a severe retinal phototoxicity following a secondary intraocular lens implantation. All 4 patients underwent a thorough assessment including history of systemic drug use. These patients had ophthalmologic evaluation including: best corrected visual acuity (ETDRS charts), fundus examination, fluorescein and indocyanine green angiographies and were followed for 1 yr. RESULTS: on presentation, the mean visual acuity was 7.5/20 (range: 20/400-20/20). Fundus exam disclosed yellow-gray sub-retinal lesions in all affected eyes. Early phase fluorescein angiography showed 1 or multiple hypofluorescent spots surrounded by a halo of hyperfluorescent window defect. In the late phase, some of these spots leaked the fluorescein dye. Indocyanine green angiography demonstrated hypofluorescent spots throughout with ill-defined borders of hyperfluorescence observed during the late stages. The common finding in these 4 patients was the fact that they were all taking one or more photosensitizing drugs (hydrochlorothiazide, furosemide, allopurinol, and benzodiazepines). Three of the patients had a full visual recovery a few months after the phototoxicity. The fourth patient remained with a visual acuity of 20/60 12 months after the light exposure. Despite the visual recovery, non-homogeneous retinal pigment epithelial disturbances persisted in all affected eyes. CONCLUSION: phototoxicity following incidental light exposure may occur in patients taking drugs of photosensitizing potential. Therefore, the thorough history of systemic drug ingestion should be obtained if patients have exposure to strong light sources. [R32] NTOX: *IM USE WILL FREQUENTLY CAUSE TISSUE SLOUGHING /SRP: AT SITE OF INJECTION/. [R33] *Furosemide was tested for mutagenicity in the Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. Furosemide was tested over a wide range of doses (0, 100, 333, 1000, 3333, and 10,000 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Furosemide was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 10,000 ug/plate. At the highest dose, clearing of the background lawn was noted without activation in TA98. [R34] *Furosemide, along with other heterocyclic compounds with a relatively low single electron redox potential, was tested for embryotoxicity in cultured rat embryos, and the effects were compared with those of other heterocycles and nitroheterocycles. Sprague Dawley rat embryos were explanted on day 10 of gestation and grown in culture medium to which the test compounds were added. After 26 hr in culture, the embryos were removed and examined for malformations. Furosemide at a concentration of 1.00 mM produced a 71% incidence of malformations (necrosis in the mandibular arch) but failed to elicit axial asymmetry in the embryos. Nitroheterocycles with a high redox potential (nitrofuroxime, furazolidone, nitrofurazone, niridazole, 2-nitroimidazole and ronidazole) produced axial asymmetric malformations. Nitroheterocycles with low redox potential and heterocyclic compounds not bearing the nitro group with low redox potential failed to elicit axial asymmetry but were embryotoxic. [R35] *Subcutaneous doses of furosemide (5 or 15 mg/kg per day) were given to Sprague Dawley rat pups from day 4 to day 28 after birth. Increased urinary calcium and magnesium excretion was observed, and the total concentration of calcium and magnesium in bone was lower; the growth of the pups was inhibited in a dose-dependent manner, and bone mineral content was appropriate for the smaller bone mass. [R36] *Furosemide at doses of 400 mg/kg given to male Swiss albino mice by intraperitoneal injection produced massive necrosis in both the midzonal and centrilobular areas of the liver, damage that was prevented by prior administration of cytochrome P450 enzyme inhibitors. Covalent binding of furosemide to mouse liver proteins has been shown, and it was enhanced by administration of an inhibitor of epoxide hydrase, suggesting an arene oxide intermediate involving furan ring. Furosemide at 0.5 or 1.0 mM is toxic isolated mouse hepatocytes. Cellular sulfhydryl groups appear to be involved in protecting liver cells from furosemide toxicity at high concentrations. [R25] *Administration of furosemide to pregnant CRCD rats on days 6 through 17 of gestation resulted in increased resorption rates and decreased live fetal weights at doses of 300 or 600 mg/kg; these doses also resulted in maternal deaths. There was no evidence of a teratogenic effect, but wavy ribs were noted in all dosed groups. In studies with other diuretics, skeletal malformations were shown to result from the diuretic effect on the mother. [R25] *In reproduction studies in mice, rats, and rabbits, administration of furosemide caused unexplained abortions and maternal and fetal deaths. In addition, an increased incidence of hydronephrosis occurred in fetuses of animals treated with the drug. [R9, 2569] *Furosemide was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with or without exogenous metabolic activation. In the mouse lymphoma assay for trifluorothymidien resistance, furosemide produced an equivocal response in the absence of metabolic activation and a positive response in the presence of activaton. Furosemide induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in both the presence and absence of exogenous metabolic activation. [R37] *Toxicology and carcinogenesis studies of furosemide, a widely used diuretic, were conducted by administering diets containing the drug to both sexes of F344 rats and B6C3F1 mice in 14 day, 13 wk and 2 yr studies. Deaths occurred among rats and mice receiving diets containing 46,000 ppm furosemide in 14 day studies, and animals given diets containing lower concn lost wt. No deaths were seen in 13 wk studies using top concn ranging from 10,000 to 20,000 ppm, but animals at higher concn had lower wt gains than controls. Nephrosis in rats and mice was the only significant cmpd related lesion observed in the prechronic studies. In 2 yr studies, rats received diets containing 0, 350 or 700 ppm furosemide and mice received diets containing 0, 700 or 1400 ppm furosemide. Survival of dosed and control rats of both sexes and male mice was similar; survival of high dose female mice was lower than controls. Nephropathy was increased in male rats and in male and female mice. In female mice, increased malignant tumors of the mammary gland were associated with furosemide administration. In male rats, marginal increases in tubular cell neoplasms of the kidney and in meningiomas of the brain were observed in dosed animals, but these were not considered to be related clearly to exposure to furosemide. [R38] *This study was designed to observe the initial changes of wavy ribs induced by furosemide, a loop diuretic, in rats. Pregnant Crj:CD females were treated orally with 300 mg/kg of furosemide on day 16 of gestation. The 11th-12th ribs of their fetuses were observed light and electron microscopically at different times after treatment. Morphological features of the initial calcification site were not significantly different between treated and control fetuses during the first 6 hr. At 12 hr, extracellular matrix vesicles, particularly calcified ones, derived from osteoblasts in treated fetuses were fewer than those in control fetuses, although osteoblasts and chondrocytes of treated fetuses were similar in fine structure to those of controls. At 24 hr, while intramembranous and endochondral ossification were observed in control fetuses, they did not appear in treated fetuses. At 48 hr, calcification spread toward both ventral and dorsal sides from the primary ossification center in the control fetuses. Calcification started in the treated fetuses and excessive osteoid wa observed in the periphery of the shaft. Bent ribs first appeared at this stage. These results suggest that defective calcification in furosemide treated fetuses is caused by inhibition of matrix vesicle formation and/or matrix vesicle calcification. [R39] *It was demonstrated that maternal treatment with furosemide produces hypochloremia in both maternal and fetal rats and that there is a negative correlation between maternal serum chloride levels and incidences of fetal wavy ribs. Since furosemide is known to produce hypochloremic metabolic alkalosis in laboratory animals and man, the effect of the cmpd on the acid-base status of maternal rats was investigated. Crj:CD female rats received an oral administration of 150 mg/kg of furosemide on day 16 of gestation and were bled for determination of arterial blood pH about 4 hr after treatment. Fetuses were obtained by Cesarean sectioning on day 20 and examined for the presence of wavy ribs after preparation of cleared specimens. Compared to vehicle treated controls, there was a significant (p < 0.05) elevation in average maternal blood pH in the treatment group (7.48 > 7.39 in controls). The elevation of maternal blood pH among individual females was strongly correlated with the incidence of wavy ribs in their term fetuses (p < 0.005, r = 0.726). In a second study, 2% NaHCO3 was administered via drinking water to furosemide treated females from days 15 (one day prior to treatment with furosemide) to 20. There was a further increase in average maternal pH (7.52) and a marked increase in the incidence of fetal wavy ribs (87.6%) compared to the group treated with furosemide alone (27.6%). These results and the previous findings suggest that extracellular hypochloremic metabolic alkalosis is involved in the pathogenesis of furosemide induced wavy ribs. [R40] *Furosemide, an inhibitor of chlorine dependent sodium, potassium cotransport, is the most frequently used diuretic in newborns. Recently, furosemide was also demonstrated to decrease bronchial hyper-responsiveness in adults, although little is known about the direct effect of furosemide on smooth muscle of immature animals. This in vitro study was designed to determine the action of furosemide on airway and vascular smooth muscle during ontogeny. Extrathoracic trachea, main stem bronchi, main pulmonary artery, and thoracic aorta ring segments from fetal, newborn, and adult Hartley albino guinea pigs were suspended in HEPES solution for measurement of isometric tension. Furosemide (30 or 300 uM) was administered after preconstriction with an ED35-70 concentration of histamine or acetylcholine for airway and ED40-100 concentration of norepinephrine for vessels. Furosemide (30 uM) caused significant relaxation of airway smooth muscle at all ages. After histamine induced preconstriction, fetal airway segments exhibited greatest relaxation (183 + or - 28%), with newborn airway demonstrating 123 + or - 15% relaxation and modest relaxation seen in adults (40 + or - 4%). This pattern was similar for both extrathoracic trachea and bronchus and appeared greater for histamine compared with acetylcholine preconstriction. Epithelial removal slightly enhanced relaxation. Furosemide also relaxed pulmonary artery segments, but at a 10 fold higher concentration. In striking contrast to the pattern seen in airway, adult pulmonary artery relaxed more than newborn and newborn, more than fetus. Cyclooxygenase blockade and endothelium removal did not change pulmonary artery relaxation. Furosemide did not significantly relax aorta after NE preconstriction. Taken together, these results suggest that furosemide may be more effective in relaxing airway compared with vascular smooth muscle, and the ontogeny of these responses indicates a greater efficacy and selectivity in airways of immature animals. [R41] *Four groups of 25 male Fischer 344 rats, five weeks of age, were given drinking water containing 0.01% or 0.05% N-nitrosobutyl-N-(4-hydroxybutyl)-amine for four weeks, followed by no further treatment or administration of furosemide (purity unspecified) dissolved in 0.5% carboxymethyl cellulose by gavage three times per week for 32 weeks (total dose, 250 mg/kg body weight). The experiment was terminated at 36 weeks. One group of 25 male rats was treated with furosemide alone. No treatment-related mortality was observed in any group, but body weights of furosemide-treated groups were significantly lower; almost all rats survived to the end of the experiment. Following sacrifice, all bladders were examined histologically. No significant difference in the incidence of bladder lesions (simple, papillary or nodular hyperplasia, papillomas or carcinomas) was seen in furosemide-treated versus other groups. Treatment with furosemide alone did not induce any lesion in the bladder. [R42] *Furosemide treatment produces glomerular hypertrophy and augments glomerular capillary hydraulic pressure in the normal rat. Similar processes have been implicated in the progression of glomerulosclerosis (GS). Whereas prior experiments with furosemide treatment of 6-8 wks duration have produced no detrimental effects on renal function or structure, the effects of more prolonged treatment are unknown. Male Munich-Wistar rats were pair fed with or without furosemide, 40 mg/d, from the time of weaning through 10 months of age. At selected time points, 24-hr urine collections were obtained for total protein and volume determination. At the end of the study, light and electron microscopic morphometric studies were performed. Renal cortical hypertrophy and glomerular hypertrophy were sustained throughout the 9 months of treatment in the group receiving furosemide. The cortical interstitial area was increased in the furosemide group, but this did not appear to be the result of fibrosis. Proximal and distal tubule diameter were unaffected by treatment. No differences in GS or glomerular ultrastructure were shown. This study provides no evidence of detrimental glomerular effects of furosemide in normal animals. Further studies of furosemide treatment under conditions of preexisting renal pathological conditions are warranted to confirm the safety of this treatment in situations analogous to those seen in the clinical setting. Interstitial expansion also warrants further study in this setting. [R43] *Chronic administration of furosemide 50 mg/kg in rats has caused renal tubular degeneration. Calcification and scarring of the renal parenchyma has occurred in dogs receiving 10 mg/kg for 6 mo. [R9, 2568] NTXV: *LD50 Rat oral 2700 mg/kg; [R25] *LD50 Rat ip 800 mg/kg; [R22] *LD50 Rat iv 800 mg/kg; [R22] *LD50 Mouse oral 2200 mg/kg; [R22] *LD50 Mouse iv 308 mg/kg; [R22] *LD50 Dog oral 2000 mg/kg; [R22] *LD50 Rabbit oral 800 mg/kg; [R22] *LD50 Rabbit iv 400 mg/kg; [R22] NTP: *2 Yr studies were /conducted by feeding/ 0, 350, or 700 ppm furosemide in the diet /to/ groups of 50 F344/N rats of each sex. Groups of 50 B6C3F1 mice of each sex were fed diets containing 0, 700, or 1,400 ppm furosemide for 104 weeks. Mean body weights of dosed and control rats were comparable throughout the studies. No significant differences in survival were observed between any groups of rats of either sex (final survival--male: control, 17/50; low dose, 17/50; high dose, 20/50; female 35/50; 31/50; 34/50). The final survival of all groups of male rats was low, reflecting the large number of moribund animals killed after week 91. Survival at week 90 was 35/50, 28/50, and 34/50. Mean body weights of high dose male mice were up to 17% lower than those of controls, and mean body weights of low dose female mice were 5%-13% lower than those of controls after week 82. The survival ... week 99 (final survival--male: 21/50; 24/50; 26/50; female: 36/50; 29/50; 18/50). Fee consumption by dosed rats was similar to that by controls. The estimated average amount of furosemide consumed per day was approximately 14-16 or 29-31 mg/kg for low dose or high dose rats. Feed consumption by dosed mice was approximately 5%-7% greater than that by controls. The average amount of furosemide consumed per day was approximately 91-99 or 191-214 mg/kg for low dose or high dose mice. Under the conditionss of these 2 yr studies, there was equivocal evidence of carcinogenic activity of furosemide for male F344/N rats, as shown by marginal increases in uncommon tubular cell neoplasms of the kidney and meningiomas of the brain. There was no evidence of carcinogenic activity of furosemide for female F344/N rats fed diets containing 350 or 700 ppm furosemide for 2 years. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 700 or 1,400 ppm furosemide for 2 years. There was some evidence of carcinogenic activity of furosemide for female mice, as shown by an increase in malignant tumors of the mammary gland. Nephropathy was more severe in the kidney of male rats of male and female mice fed diets containing furosemide than in controls. [R44] ADE: *WITH ORAL INGESTION, DIURETIC RESPONSE MAY BE ANTICIPATED WITHIN HR; WITH IV INJECTION, WITHIN 2-10 MIN. ... FUROSEMIDE IS STRONGLY BOUND TO PLASMA PROTEINS. ALTHOUGH URINARY EXCRETION IS ACCOMPLISHED BOTH BY GLOMERULAR FILTRATION AND PROXIMAL TUBULAR SECRETION ... ACCOUNTS FOR ... 2/3 OF INGESTED DOSE. REMAINDER ... IN FECES. [R26, 833] *The oral bioavailability, plasma half life, and route of elimination of /furosemide are as follows: ~60%, ~1.5 hours, and ~65% renal excretion of intact drug, ~35% metabolism. /from table//. Because furosemide ... /is/ extensively bound to plasma proteins, delivery ... to the tubules by filtration is limited. However, /it is/ efficiently secreted by the organic acid transport system in the proximal tubule and thereby gains access to /its/ binding sites on the Na+_K+_2Cl- symport in the luminal membrane of the thick ascending limb. Probenecid shifts the plasma concn-response curve to furosemide to the right by competitively inhibiting furosemide secretion by the organic acid transport system. [R45, 772] *PLACENTAL TRANSFER STUDIED IN 18 PREGNANT WOMEN AFTER ORAL DOSES OF 25-40 MG ON DAY OF DELIVERY. SUBSTANTIAL CONCN OF DRUG DETECTED IN UMBILICAL CORD VEIN PLASMA AND AMNIOTIC FLUID. PENETRATES PLACENTAL MEMBRANE AND REACHES FETUS. [R46] *In one study in patients with normal renal function, approx 60% of a single 80 mg oral dose of furosemide was absorbed from the Gl tract. When admin to fasting adults in this dosage, the drug appeared in the serum within 10 min, reached a peak concn of 2.3 ug/mL in 60-70 min, and was almost completely cleared from the serum in 4 hr. When the same dose was given after a meal, the serum concn of furosemide increased slowly to a peak of about 1 ug/ml after 2 hr and similar concns were present 4 hr after ingestion. However, a similar diuretic response occurred regardless of whether the drug was given with food or to fasting patients. In another study, the rate and extent of absorption varied considerably when 1 g of furosemide was given orally to uremic patients. An avg of 76% of a dose was absorbed, and peak plasma concns were achieved within 2-9 hr (avg 4.4 hr). Serum concns required to produce max diuresis are not known, and it has been reported that the magnitude of response does not correlate with either the peak or the mean serum concns. [R9, 2571] *The diuretic effect of orally administered furosemide is apparent within 30 minutes to 1 hr and is maximal in the first or second hour. The duration of action is usually 6-8 hr. The maximum hypotensive effect may not be apparent until several days after furosemide therapy is begun. After iv administration of furosemide, diuresis occurs within 5 min, reaches a maximum within 20-60 min, and persists for approximately 2 hr. After im administration, peak plasma concentrations are attained within 30 min; onset of diuresis occurs somewhat later than after iv administration. In patients with severely impaired renal function, the diuretic response may be prolonged. [R9, 2570] *Furosemide is approximately 95% bound to plasma proteins in both normal and azotemic patients. [R9, 2570] *In patients with normal renal function, a small amount of furosemide is metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid. Furosemide and its metabolite are rapidly excreted in urine by glomerular filtration and by secretion from the proximal tubule. In patients with normal renal function, approx 50% of an oral dose and 80% of an iv or im dose are excreted in urine within 24 hr; 69-97% of these amounts is excreted in the first 4 hr. The remainder of the drug is eliminated by nonrenal mechanisms including degradation in the liver and excretion of unchanged drug in the feces. In patients with marked renal impairment without liver disease, nonrenal clearance of furosemide is increased so that up to 98% of the drug is removed from the plasma within 24 hr. One patient with uremia and hepatic cirrhosis eliminated only 58% of an iv dose in 24 hr. Furosemide is not removed by hemodialysis. [R9, 2570] *It has been claimed that the absorption, and therefore effectiveness, of furosemide will be further diminished in patients with /congestive heart failure/ due to edema of the bowel and decreased splanchnic blood flow. The has been partially refuted by /a study that/ showed an average bioavailability of 61% in CHF patients, the same as in normal patients. However, total absorption in patients with CHF varies widely (34-80%) and there is a delay in both rate of absorption and time to peak urinary excretion for both furosemide and bumetanide. [R30, p. 15-15] *Not only are there interindividual differences in the rate and extent of absorption, but large intraindividual variability also exists. Ingestion of the same brand of furosemide by the same individual on multiple occasions can show up to a threefold difference in bioavailability. These differences are evident whether considering the innovator's brand (Lasix) or one of several generic brands. One might infer that iv therapy would be the preferred route, giving a better response for any given dose. Surprisingly, this is not always the case. In both normal volunteers and patients with CHF, total daily fluid and electrolyte loss after oral therapy and parenteral therapy are comparable. The major difference is in the time course of response. During the first 2 hr, diuresis from the iv dose far exceeds that from the oral therapy, but by 4-6 hr, the total urinary output is equivalent. [R30, p. 15-15] *In neonates ... a decreased clearance is seen for drugs that are eliminated by proximal tubular secretion (e.g., furosemide ...). [R30, p. 96-7] METB: *SMALL FRACTION /OF ADMIN FUROSEMIDE/ IS METABOLIZED BY CLEAVAGE OF SIDE CHAIN ... AN ADDITIONAL PRODUCT, POSSIBLY A GLUCURONIDE CONJUGATE, HAS ALSO BEEN FOUND. [R26, 832] *MAIN METABOLITE FOUND IN /HUMAN/ URINE ... DEFURFURYLATED DERIVATIVE, 4-CHLORO-5-SULFAMOYLANTHRANILIC ACID. [R47] *In patients with normal renal function, a small amount of furosemide is metabolized in the liver to the defurfurylated derivative, 4-chloro-5-sulfamoylanthranilic acid. Furosemide and its metabolite are rapidly excreted in urine by glomerular filtration and by secretion from the proximal tubule. In patients with normal renal function, approx 50% of an oral dose and 80% of an iv or im dose are excreted in urine within 24 hr; 69-97% of these amounts is excreted in the first 4 hr. The remainder of the drug is eliminated by nonrenal mechanisms including degradation in the liver and excretion of unchanged drug in the feces. In patients with marked renal impairment without liver disease, nonrenal clearance of furosemide is increased so that up to 98% of the drug is removed from the plasma within 24 hr. One patient with uremia and hepatic cirrhosis eliminated only 58% of an iv dose in 24 hr. Furosemide is not removed by hemodialysis. [R9, 2570] BHL: *~1.5 hours /from table/ [R45, 770] *Plasma concentrations of furosemide decline in a biphasic manner. Various investigators have reported a wide range of elimination half-lives for furosemide. In one study, the elimination half-life averaged about 30 min in healthy patients who received 20-120 mg of the drug iv. In another study, the elimination half-life averaged 9.7 hr in patients with advanced renal failure who received 1 g of furosemide iv. The elimination half-life was more prolonged in 1 patient with concomitant liver disease. [R9, 2570] ACTN: *Loop diuretics act to inhibit a specific ion transport protein, the Na+_K+_2Cl- symporter on the apical membrane of renal epithelial cells in the ascending limb of Henle's loop. /Loop diuretics/ [R45, 904] *INCR IN POTASSIUM EXCRETION RESULTS FROM ITS DISTAL SECRETION AND IS APPROX PROPORTIONAL TO INCR RATE OF FLOW IN THIS SEGMENT. EXCRETION OF MAGNESIUM AND CALCIUM IS INCR BY ABOUT SAME % AS THAT OF SODIUM. ... NATRIURESIS INDUCED BY FUROSEMIDE MAY BE ACCOMPANIED BY DECR IN EXCRETION OF PHOSPHATE. /HIGH-CEILING DIURETICS/ [R26, 834] *The pharmacologic effects of furosemide are similar to those of ethacrynic acid. The exact mode of action of furosemide has not been clearly defined; in contrast to ethacrynic acid, it does not bind sulfhydryl groups of renal cellular proteins. Furosemide inhibits the reabsorption of electrolytes in the ascending limb of the loop of Henle. The drug also decreases reabsorption of sodium and chloride and increases potassium excretion in the distal renal tubule and exerts a direct effect on electrolyte transport at the proximal tubule. Furosemide does not inhibit carbonic anhydrase and is not an aldosterone antagonist. [R9, 2570] *Furosemide has some renal vasodilator effect; renal vascular resistance decreases and renal blood flow increases following administration of the drug. A temporary but substantial increase in glomerular filtration rate, as well as decreased peripheral vascular resistance and increased peripheral venous capacitance, has been reported following iv administration of furosemide in patients with congestive heart failure associated with acute myocardial infarction. The renal and peripheral vascular effects may contribute toward the beneficial effects of the drug in these patients, as a decrease in left ventricular filling pressure occurs before the onset of substantial diuresis. In addition, iv administration of furosemide in patients with congestive heart failure results in a decrease in plasma volume, increased hematocrit, and a fall in mean arterial pressure associated with increased cardiac output and decreased peripheral resistance. When large doses of furosemide are administered to patients with chronic renal insufficiency, glomerular filtration rate may be increased temporarily. A fall in renal blood flow and glomerular filtration rate may occur if excessive drug induced diuresis results in a reduction in plasma volume. [R9, 2570] INTC: *Probenecid has been found to increase serum concentrations of furosemide by inhibiting active renal tubular secretion. [R48, Inc.1230] *Administration of chloral hydrate followed by intravenous furosemide may result in diaphoresis, hot flashes, and variable blood pressure, including hypertension due to a hypermetabolic state caused by displacement of thyroxine from its bound state. [R48, Inc.1230] *CONCLUDED THAT INHIBITORY EFFECT OF SINGLE DOSE OF FUROSEMIDE ON DIGOXIN EXCRETION TOO SHORT FOR CLINICAL SIGNIFICANCE; MAY BE POSSIBLE TO ELEVATE SERUM DIGOXIN CONCN IF FUROSEMIDE GIVEN MORE FREQUENTLY. WHEN 6 HEALTHY SUBJECTS RECEIVING 0.006 MG/KG DIGOXIN IV WERE GIVEN ORAL FUROSEMIDE, I CLEARANCE DURING DIURETIC PHASE AND EXCRETION AFTER DIURESIS DECR MUCH. AVG SERUM HALF-LIFE PROLONGED FROM 37 HR IN CONTROL PERIOD TO 86 HR IN FUROSEMIDE PERIOD. [R49] *Diflunisal decreases the hyperuricemic effect of furosemide and hydrochlorothiazide. It has no effect on diuretic activity of furosemide but significantly increases levels of hydrochlorothiazide. [R50] *Concomitant administration of furosemide and most other diuretics results in enhanced effects, and furosemide should be administered in reduced dosage when the drug is added to an existing diuretic regimen. Spironolactone, triamterene, or amiloride hydrochloride may reduce the potassium loss resulting from furosemide therapy; this effect has been used to therapeutic advantage. [R9, 2569] *In patients receiving cardiac glycosides, electrolyte disturbances produced by furosemide (principally hypokalemia but also hypomagnesemia) predispose the patient to glycoside toxicity. Possibly fatal cardiac arrhythmias may result. [R9, 2569] *Furosemide reportedly causes prolonged neuromuscular blockade in patients receiving nondepolarizing neuromuscular blocking agents (eg, tubocurarine chloride, gallamine triethiodide), presumably because of potassium depletion or decreased urinary excretion of the muscle relaxant. Furosemide may also cause decreased arterial responsiveness to pressor amines [R9, 2569] *Some drugs such as corticosteroids, corticotropin, and amphotericin B also cause potassium loss, and severe potassium depletion may occur when one of these drugs is administered during furosemide therapy. [R9, 2569] *Renal clearance of lithium is apparently decreased in patients receiving diuretics, and lithium toxicity may result. [R9, 2569] *Administration of furosemide to diabetic patients may interfere with the hypoglycemic effect of insulin or oral antidiabetic agents, possibly as a result of hypokalemia. [R9, 2569] *The antihypertensive effect of hypotensive agents may be enhanced when given concomitantly with furosemide. This effect is usually used to therapeutic advantage; however, orthostatic hypotension may result. [R9, 2569] *In some patients, indomethacin may reduce the natriuretic and hypotensive effects of furosemide. The mechanism(s) of these interactions is uncertain but has been attributed to indomethacin induced inhibition of prostaglandin synthesis which may result in fluid retention and/or changes in vascular resistance. [R9, 2569] *Concomitant administration of furosemide and aminoglycoside antibiotics or other ototoxic drugs may result in increased incidence of ototoxicity and concomitant use of these drugs should be avoided. In addition, the possibility that iv furosemide may increase aminoglycoside toxicity by altering serum and tissue concentrations of the antibiotic should be considered. It has been proposed, but not proven, that furosemide may enhance the nephrotoxicity of neomycin. [R9, 2569] *Furosemide and salicylates reportedly have competitive renal excretory sites and, therefore, patients receiving high doses of salicylates with furosemide may experience salicylate toxicity at lower dosage than usual. Concomitant administration of furosemide and aspirin reportedly has been associated with a transient reduction in creatinine clearance in a few patients with chronic renal insufficiency; weight gain and increases in BUN, serum creatinine, and serum potassium concentrations also have been reported in patients receiving furosemide in combination with other nonsteroidal antiinflammatory agents. [R9, 2569] *In one study, epileptic patients receiving chronic anticonvulsant therapy had a reduced diuretic response to furosemide as compared to controls. All of the epileptic patients were receiving phenytoin sodium and phenobarbital and some were also receiving other anticonvulsants. It has been postulated that renal sensitivity to furosemide is diminished by these drugs. [R9, 2569] *A reaction characterized by diaphoresis, flushes, variable blood pressure including hypertension, and uneasiness has been reported in some patients with acute myocardial infarction and congestive heart failure who received furosemide iv within 24 hr after administration of an oral hypnotic dose of chloral hydrate. [R9, 2569] *It has been suggested that furosemide, by increasing serum uric acid concentrations, may interfere with the uricosuric effects of probenecid or sulfinpyrazone. [R9, 2569] *This study examined the interaction between lithium and diuretics, comparing both the pharmacokinetic and the pharmacodynamic variable of hydrochlorothiazide, furosemide, and placebo. The study, which took place in an outpatient research clinic of a university hospital, used a double blind, placebo controlled crossover design. The subjects were normal, healthy male volunteers wh responded to recruitment announcements. Thirteen subjects entered and completed the study. All subjects took lithium, 300 mg twice a day, for 6 wk. Hydrochlorothiazide, 25 mg twice a day; furosemide, 20 mg twice a day; and placebo were given during wk 2, 4, and 6 in a random order of assignment. Serum lithium levels and indices of diuretic activity were measured during each wk. The subjects' serum lithium levels after 5 days of taking hydrochlorothiazide were significantly higher than after 5 days of taking furosemide and placebo. At the doses studied, hydrochlorothiazide was also more potent than furosemide in increasing plasma renin activity, increasing sodium excretion, and decreasing lithium excretion. The observed differences between diuretics in effects on serum lithium may have been due to differences in the potency of the diuretics at the doses studied as well as in the site of action of the diuretic effect. The results must be interpreted cautiously, however, because the effects were small and of questionable clinical significance, and the study used healthy volunteers and low doses of lithium instead of psychiatric patients and the usual therapeutic levels of lithium. [R51] *In this study, the diuretic furosemide was used in combination with dietary sodium restriction to quantify the effects of moderate to severe sodium depletion on heat tolerance in a validated model of heat stress in rats. Rats were subjected to an sodium depletion regimen as follows: a control group (I, n = 17) had free access to a normal diet and tap water; group II (n = 20) consumed the same normal diet and tap water, but was treated with the diuretic furosemide at a dose of 10 mg/kg/day, ip; group III (n = 18) had free access to an sodium free diet and deionized drinking water; group IV (n = 21) consumed the same sodium free diet and electrolyte free water, but was also treated with furosemide. Both the dietary and drug manipulations affected significant (p < 0.05) negative electrolyte and water balances. Group IV consistently exhibited the greatest decrements. Following the 4 day depletion all four groups were acutely exposed to a 42 deg C, 25-30% rh environmental heat stress during which time core body temperature increased. The time required for rectal temperature to reach 42.6 deg C was significantly (p < 0.05) decreased from a time of 242 + or - 8 min in the control group to 176 + or - 14, 181 + or - 8, and 111 + or - 11 min in groups II, III and IV, respectively. It was concluded that sodium deprivation and diuretic treatment can elicit a 25-50% reduction in heat tolerance due to electrolyte depletion and dehydration. These data confirm that during environmental heat stress uncompensated negative sodium balance may predispose an individual to heat illnesses. [R52] *The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 x 2.5 mg) and long acting furosemide (2 x 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 + or - 1.6 yr and weighing 68.8 + or - 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concn were determined by HPLC with fluorimetric detection. The rate of absorption (tmax = 3 hr) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half life was 2.77 + or - 1.04 hr after the combination treatment and 2.76 + or - 0.98 hr alone, amiloride plasma half life was respectively 15.7 + or - 4.6 hr and 14.6 + or - 3.7 hr. The urinary elimination of furosemide was significantly higher in the 2-4 hr interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased (p < 0.01) and the potassium excretion was significantly decreased (p= 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes. [R53] *To examine the influence of amikacin induced acute renal damage on the urinary excretion of furosemide and the time dependent variation in the urinary amount of the agent, amikacin (1.2 g/kg) was given ip to Wistar rats. Study I: 3% body wt of 1% sodium chloride solution was given orally before a diuretic after amikacin treatment, and an 8 hr urine for N-acetyl-beta-D-glucosaminidase was collected. Study II: Furosemide (30 mg/kg) in 3% body wt of 1% sodium chloride solution was given orally at 12 am or 12 pm before and after amikacin treatment, and an 8 hr urine for sodium and furosemide was collected. Following amikacin treatment, urinary excretion of N-acetyl-beta-D-glucosaminidase increased, while urine volume and urinary excretion of sodium and furosemide decreased. Urinary excretion of furosemide and its diuretic effects were significantly greater at 12 am than at 12 pm before and after treatment. However the time dependent differences in these parameters were diminished by amikacin treatment. These results suggest that the urinary excretion of furosemide is reduced and the extents of the time dependent variation in the urinary furosemide and its diuretic effects are altered in rats with amikacin induced renal damage. [R54] *To examine the influence of mercuric chloride induced acute renal damage on urinary excretion of furosemide, mercuric chloride (1 mg/kg) or its vehicle alone was given ip to Wistar rats. The following two experiments were done. Study I: 3% body wt of 1% sodium chloride solution or furosemide (30 mg/kg) in 3% body wt of 1% sodium chloride solution was given orally before and after mercuric chloride treatment, and an 8 hr urine was collected. Study II: Furosemide (30 mg/kg) was given orally, and blood samples were obtained at 1, 2, 3, 4, 6 and 8 hr after administration. Urinary excretion of N-acetyl-beta-D-glucosaminidase increased, and urine volume and urinary excretions of furosemide and sodium decreased in the mercuric chloride treated rats. There were significant correlations between the urinary furosemide and its diuretic effects. Regression lines after mercuric chloride were significantly different from those before treatment. The values of absorption as well as elimination rate constant were smaller, while the time to maximum concn and the elimination half life were longer in the mercuric chloride treated rats compared to vehicle treated animals. These results suggest that the urinary excretion of furosemide and the responsiveness of renal tubular cells to this agent are impaired in rats with mercuric chloride induced acute renal damage. [R55] *Circadian variations in the adrenergic nervous system have been reported to be altered by chronic treatment with clorgyline, a monoamine oxidase inhibitor. In the present study, the influence of clorgyline on the chronopharmacology of furosemide, a loop diuretic agent, was examined in rats maintained under conditions of light from 7 am to 7 pm and dark from 7 pm to 7 am. Clorgyline (4 mg/kg/day) or its vehicle alone was infused sc by osmotic minipumps for 14 days. Furosemide (30 mg/kg) was given orally at 12 am (noon) or 12 pm (midnight). Urine was collected for 8 hr after the agent, and urinary excretions of sodium and furosemide were determined. Urine volume and urinary excretions of sodium and furosemide were significantly greater at 12 noon than at 12 midnight in the vehicle infused group of rats. However these administration time dependent changes in the effects of furosemide and its urinary excretion disappeared in the clorgyline infused animals. These results suggest that the mode of the diurnal variation in the effects of furosemide is altered by chronic treatment with clorgyline. As chronic clorgyline is considered to disturb the adrenergic nervous system, the present findings are compatible with the hypothesis that this system is involved in the mechanism responsible for the time dependent change in the effects of furosemide. [R56] *The administration time dependent change in the effects of furosemide, a loop diuretic agent, is observed in normal rats. The present study was undertaken to examine whether an alteration in this phenomenon occurs in rats with desoxycorticosterone acetate-saline hypertension. Unilateral nephrectomized rats were divided into three groups. The first group (desoxycorticosterone acetate-saline) received a 50 mg desoxycorticosterone acetate tablet ip and drank 1% sodium chloride solution. The other two groups were given sham operations. A 1% sodium chloride solution was given as drinking water to the second group (control-saline), while tap water was given to the third group (control-water). Furosemide (30 mg/kg) was given orally to each group at 12 am or 12 pm Urine was collected for 8 hr after the agent, and urinary excretion of sodium and furosemide were determined. Urine volume and urinary excretion of sodium and furosemide following the agent were significantly greater at 12 am than at 12 pm in the control-water and control-saline groups. However, the administration time dependent changes in these parameters disappeared in the desoxycorticosterone acetate-saline rats. These results suggest that the mode of the administration time dependent changes in the effects of furosemide is altered in the desoxycorticosterone acetate-saline hypertensive rats. [R57] *The pharmacokinetics of phenprocoumon was studied with and without co-administration of frusemide and probenecid in two groups of 17 healthy volunteers. Frusemide 40 mg twice a day for 7 days did not interact with phenprocoumon to a significant extent. Probenecid 500 mg four times a day for 7 days significantly accelerated the overall elimination of phenprocoumon, as indicated by a decrease in area under the concentration time curve from 295 to 157 ug hr/ml, and a reduction in the fraction of the dose excreted by the kidneys. The data are consistent with inhibition of the glucuronidation of phenprocoumon by probenecid. Its accelerated elimination may be a consequence of the increased formation of hydroxylated metabolites. [R58] *The pharmacokinetics and the biliary and urinary excretions following iv administration of furosemide (5 mg/kg) were investigated in the anesthetized dogs with normal and experimentally reduced renal function. After the administration, furosemide caused diuretic and choleretic response, and was excreted into urine and bile at almost similar rate to plasma concn decay in normal dogs. Half maximum diuretic response was obtained at 1.5 ug/ml of plasma concn and 100 ug/min of urinary excretion rate of furosemide. Acute renal failure was produced in dogs by the iv administration of mercuric chloride (2 mg/kg). In mercuric chloride treated dogs, the prolongation of half life and the decrease in plasma clearance were noted with the decreased diuretic response. These changes in parameters appeared to be associated with the decrease in excretion of furosemide into the urine, but not into the bile. Plasma level diuretic response relationship was extensively shifted to the right in mercuric chloride treated dogs, while urinary dose response relationship did not change significantly between two groups. These results suggest that the decreased response to furosemide in mercuric chloride treated dogs seems to be due to the decreased renal clearance rather than to the subsensitivity to furosemide on the site of action. [R59] *The interaction between acetylcholine and carbachol, and frusemide, a loop diuretic, have been studied on the rat isolated urinary bladder strip preparation. Acetylcholine (4.36X10-8 to 1.3X10-6 M) and carbachol (5.5X10-8 to 6.9X10-6 M) induced contractions and these were significantly potentiated by frusemide (3.02X10-6 M). The ratio of EC50 in the absence of frusemide to EC50 in the presence of frusemide was 1.58 + or - 0.03 (standard error of mean) for acetylcholine and 1.86 + or - 0.14 for carbachol. Potentiation of acetylcholine and carbachol contractions by frusemide was not observed in tissues treated with hexamethonium (2.5X10-5 M). Rhythmic contractions induced by frusemide alone were markedly reduced by hexamethonium (2.5X10-5 M) and tetrodotoxin (10-6 M) but they were not significantly reduced by atropine (1.7X10-6 M). The result suggests that frusemide increases the sensitivity of the bladder to acetylcholine and carbachol, and that it may have a nicotinic stimulant effect on the bladder. This extra-renal action may contribute to its prompt diuretic property. [R60] *This study examined the effects of pretreatment with probenecid with and without pyrazinamide on the elimination kinetics and diuretic action of frusemide. Six normal male volunteers received 40 mg frusemide iv on three occasions; ie once on its own and twice after pretreatment with 2 g probenecid with and without 3 g pyrazinamide. Both these latter drugs were administered orally 3 hr before frusemide administration thereby attempting optimal suppression of proximal tubular secretion. Urinary losses were replaced iv with isovolumetric amounts of normal saline while insensible losses were compensated for by taking tap water orally. The mean cumulative urinary frusemide excretion was significantly and similarly decreased by pretreatment with probenecid (34.9%) and probenecid plus pyrazinamide (33.6%), but the mean total volume of diuresis and the mean cumulative urinary sodium excretion did not differ significantly between treatments over the 5 hr period. The diuretic efficiency of frusemide was significantly increased with probenecid pretreatment during the first 90 min period after frusemide administration. Furthermore, in the first 30 min after administration the percent sodium fractional excretion was higher after pretreatment with probenecid even though the mean frusemide excretion rate was more than three times with frusemide alone than with probenecid-frusemide (374.4 ug/min versus 119.1 ug/min). Pretreatment with probenecid results in a higher concn on the peritubular or blood side of the tubules and these results lead us to question the unconditional acceptance of a luminal site of action for the loop diuretics. Alternatively, probenecid may act in some other way to increase the effects of frusemide. [R61] *The effects of ketoprofen on frusemide induced diuresis, natriuresis and renin release were studied in 12 healthy male volunteers. Each received frusemide 40 mg once daily with either ketoprofen 100 mg twice daily or placebo for two periods of 5 days separated by a treatment free period according to a randomized, double blind, cross over study design. Ketoprofen significantly reduced frusemide induced diuresis on day 1 but not on day 5 of treatment. The natriuresis induced by frusemide on day 1 or day 5 of treatment did not differ significantly whether ketoprofen or placebo was administered, although the mean urinary sodium excretion values were consistently lower following ketoprofen. Ketoprofen did not affect the kaliuretic response to frusemide on day 1 or day 5 of treatment. The increase in plasma renin activity after frusemide was inhibited by ketoprofen on both day 1 and day 5. These results suggest that ketoprofen reduces the diuresis and renin release induced by frusemide, but that the reduction in diuretic response may become less important after their repeated coadministration. [R62] *Urinary excretion of vitamin B(6), oxalic acid and vitamin C was investigated in 15 healthy subjects during maximal water diuresis and in the group of 12 patients in polyuric stage of chronic renal failure without dialysis treatment receiving a diet containing high sodium chloride (15g/day). Urinary excretions of the same parameters were investigated in another group of 15 patients in polyuric stage of chronic renal failure without dialysis treatment after i.v. admin of 20 mg furosemide. Urinary excretion of vitamin B(6), oxalic acid and vitamin C significantly increased during maximal water diuresis while during high intake of sodium chloride the urinary excretions of these substances were not affected. The results suggest that urinary excretion of vitamin B(6), oxalic acid and vitamin C depends on the urinary excretion of water. Iv admin of 20 mg furosemide led to an incr of urinary excretion of vitamin B(6), oxalic acid and vitamin C in patients with chronic renal failure. The increased urinary excretion of vitamin B(6) and vitamin C is a new negative side effect of furosemide and increased urinary excretion of oxalic acid is a new positive side effect in patients with chronic renal failure. [R63] *To examine whether furosemide affects the plasma concn and urinary excretion of purine bases and oxypurinol, we administered allopurinol (300 mg) orally to 6 healthy subjects and then administered furosemide (20 mg) iv 10 hr later. Furosemide (20 mg) decreased the urinary excretion of uric acid by 40% (P < .01), oxypurinol by 39% (P < .05), and xanthine by 43% (P < .05) and the fractional clearance of uric acid by 45% (P < .01) and oxypurinol by 34% (P < .05) when measured 1-2 hr after admin. Moreover, furosemide increased the plasma concn of uric acid by 6% at 1.5 hr after admin. These results indicate that furosemide may decr the urinary excretion of uric acid and oxypurinol by acting on their common renal transport pathway(s). In addition, it is suggested that the effect of furosemide on oxypurinol is clinically important, since the hypouricemic effect of allopurinol may become more potent as a result. [R64] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Diuretics, Sulfamyl [R65] *Furosemide augments radionucide renography and renal scintigraphy by stimulating the flow of urine and thereby aiding in the differentiation of mechanical obstruction from nonobstructive dilatation in patients with hydroureteronephrosis. /NOT included in US product labeling/ [R48, Inc.1228] *Furosemide /is/ used in the treatment of hypercalcemia. /NOT included in US product labeling/ [R48, Inc.1228] *Furosemide /is/ not considered to be primary agents in the treatment of essential hypertension. However, they may be indicated in combination with other antihypertensives in the treatment of hypertension associated with impaired renal function. In the stepped-care approach to antihypertensive treatment, ... furosemide may be substituted for a thiazide diuretic in patients with renal function impairment. /Included in US product labeling/ [R48, Inc.1228] *Furosemide /is/ indicated in the treatment of mild to moderate hypertension, usually in combination with other antihypertensive agents, and as adjuncts in the treatment of hypertensive crisis. /Included in US product labeling/ [R48, Inc.1228] *Furosemide /is/ especially useful in patients refractory to other diuretics or with existing acid-base disorders, congestive heart failure, or renal disease. /Included in US product labeling/ [R48, Inc.1228] *Furosemide /is/ indicated as adjunct in the treatment of acute pulmonary edema. /Included in US product labeling/ [R48, Inc.1228] *... Furosemide are indicated in the treatment of edema associated with congestive heart failure, hepatic cirrhosis, and renal disease (including nephrotic syndrome). /Included in US product labeling/ [R48, Inc.1227] *... HIGH CEILING ... DIURETICS ... HAVE DISTINCTIVE ACTION ON RENAL TUBULAR FUNCTION. ... (1) PROMPT ONSET OF ACTION, (2) INHIBITION OF SODIUM AND CHLORIDE TRANSPORT IN ASCENDING LIMB OF LOOP OF HENLE, and (3) INDEPENDENCE OF THEIR ACTION FROM ACID-BASE BALANCE CHANGES. /HIGH CEILING DIURETICS/ [R26, 833] *A major use of loop diuretics is in the treatment of acute pulmonary edema. A rapid incr in venous capacitance in conjunction with a brisk natriuresis reduced left ventricular filling pressures and thereby rapidly relieves pulmonary edema. Loop diuretics also are widely used for the treatment of chronic congestive heart failure when diminution of extracellular fluid volume is desirable to minimize venous and pulmonary congestion. Diuretics are widely used for the treatment of hypertension ... . The edema of nephrotic syndrome often is refractory to other classes of diuretics, and loop diuretics often are the only drugs capable of reducing the massive edema associated with this renal disease. Loop diuretics also are employed in the treatment of edema and ascites of liver cirrhosis; however, car must be taken not to induce encephalopathy or hepatorenal syndrome. In patients with a drug overdose, loop diuretics can be used to induce a forced diuresis to facilitate more rapid renal elimination of the offending drug. Loop diuretics- combined with isotonic saline admin to prevent volume depletion- are used to treat hypercalcemia. Loop diuretics interfere with the kidney's ability to produce a concentrated urine. Consequently, loop diuretics combined with hypertonic saline are useful for the treatment of life-threatening hyponatremia. Loop diuretics also are used to treat edema associated with chronic renal insufficiency. /Loop diuretics/ [R45, 773] *IN SYMPTOMATIC HYPERCALCEMIA HIGH CEILING DIURETICS MAY LOWER PLASMA CALCIUM CONCN BY INCR URINARY EXCRETION. /HIGH CEILING DIURETICS/ [R8, 724] *PATIENTS WITH SEVERE ANEMIA ... SHOULD RECEIVE LOOP DIURETIC (FUROSEMIDE ...) SEVERAL HR BEFORE BLOOD TRANSFUSION IS BEGUN. [R66] *FUROSEMIDE IS INDICATED FOR TREATMENT OF EDEMA ASSOC WITH CONGESTIVE HEART FAILURE, CIRRHOSIS OF LIVER, AND RENAL DISEASE, INCL NEPHROTIC SYNDROME. ... IT IS ALSO USEFUL IN MGMNT OF HYPERTENSION. [R2] *VET: TO HELP REDUCE MAMMARY EDEMA IN CATTLE; IN LAMINITIS AND LOCALIZED CONGESTIVE EDEMAS ("STOCKING UP") OF LIMBS IN HORSES; IN CONGESTIVE CARDIAC EDEMAS, ASCITES, AND HYPERTENSIVE SYNDROMES IN DOGS. [R33] *Furosemide is useful in the management of edema associated with congestive heart failure. ... [R9, 2566] *Furosemide may be used orally for the management of hypertension, especially when complicated by congestive heart failure or renal disease. [R9, 2567] *Furosemide has been used iv alone or with 0.9% sodium chloride injection or sodium sulfate to increase renal excretion of calcium in patients with hypercalcemia. [R9, 2567] */It/ is a loop diuretic indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and renal diseases and hypertension. Is also indicated via intravenous use as adjunctive therapy in acute pulmonary edema. [R10] *Treatment of magnesium excess. ... If renal functionis normal, iv furosemide ... may be admin as alternate therapy with replacement of urine volume by 0.90% saline. [R67] *Furosemide is one of the most effective and least toxic diuretics used in pediatric practice. Experimental and clinical data suggest that adrenocorticosteroids and/or endogenous ouabain-like substances may play an important role in its diuretic effect. Also, the drug appears to have anti-inflammatory properties. In children with different diseases who received orally or iv 1-2 mg/kg doses of furosemide, a statistically significant positive linear relationship was found between the drug urinary excretion rate and the urine flow rate, but log dose-response curves to the drug were found to vary depending on the disease and the route of the drug admin. No sigmoid-shaped log dose-response curve (ie, one approaching a zero response at very low furosemide urinary excretion rates and a max response at very high excretion rates) was attained, which may suggest that the capacity of the kidney tubules to respond diuretically to the aforementioned doses of furosemide was not exceeded in these patients. However, in infants with different diseases and reasonably normal renal function who required admin of this diuretic, a very steep log dose-response curve to a 1 mg/kg iv dose of furosemide was found, which may suggest that higher doses may not result in a significant incr in diuretic response. The lowest mean furosemide urinary excretion rate and its concn in urine associated with a significant diuresis were found to be 0.58 +/- 0.33 microg/kg/min and 24.2 +/- 10.5 microg/ml, respectively. Also, a significant correlation was found between the amount (in milligrams) of furosemide excreted in the urine during the first 6 hr after admin and the urine volume collected during that time. Patients with cystic fibrosis appeared to have a markedly more pronounced diuretic response to the average oral dose of 0.835 +/- 0.18 mg/kg than that reported in control children given 2 mg/kg. In children with acute renal failure caused by acute gastroenterocolitis or glomerulonephritis, a broad relationship was observed between a single iv dose and diuretic response after admin of furosemide (1.2 to 30.8 mg/kg). It was suggested that the total daily dose of the drug should not exceed 100 mg in these patients. Furosemide was found to be effective in management of bronchoconstriction accompanying chronic lung disease and narrowing of the upper respiratory airways; in hydrocephalus in infancy to avoid cerebrospinal fluid shunts; in some diagnostic procedures, such as an assessment of fetal and neonatal hydronephrosis; and in evaluation of different types of renal tubular acidosis. Among side effects accompanying clinical use of this drug were cholelithiasis in premature infants receiving total parenteral nutrition concomitantly with the diuretic; secondary hyperparathyroidism and bone disease in infants obtaining long-term furosemide treatment; and drug-induced fever. [R68] WARN: *... DEPRESSION OF COCHLEAR MICROPHONIC AND NEURAL POTENTIALS, AND TRANSIENT INCR IN SODIUM AND POTASSIUM CONCN IN ENDOLYMPH. THIS MAY RESULT FROM DIRECT TOXIC ACTION ON HAIR CELLS. [R8, 723] *FUROSEMIDE IS CONTRAINDICATED IN ANURIA, HEPATIC COMA, AND IN PATIENTS KNOWN TO BE SENSITIVE TO DRUG. [R2] *Furosemide crosses the placental barrier in humans. Although no adequate epidemiologic studies of pregnant women have been conducted, furosemide is not recommended for use during pregnancy. [R25] *Patients receiving furosemide must be carefully observed for signs of hypovolemia, hyponatremia, hypokalemia, hypocalcemia, hypochloremia, and hypomagnesemia. Patients should be informed of the signs and symptoms of electrolyte imbalance and instructed to report to their physicians if weakness, dizziness, fatigue, faintness, mental confusion, lassitude, muscle cramps, headache, paresthesia, thirst, anorexia, nausea, and/or vomiting occur. Excessive fluid and electrolyte loss may be minimized by initiating therapy with small doses, careful dosage adjustment, using an intermittent dosage schedule if possible, and monitoring the patient's weight. To prevent hyponatremia and hypochloremia, intake of sodium may be liberalized in most patients; however, patients with cirrhosis usually require at least moderate sodium restriction while on diuretic therapy. Determinations of serum electrolytes, BUN, and carbon dioxide should be performed early in therapy with furosemide and periodically thereafter. [R9, 2569] *Furosemide should be used with caution in patients with hepatic cirrhosis because rapid alterations in fluid and electrolyte balance may precipitate hepatic precoma or coma. [R9, 2569] *Urine and blood glucose concentration determinations should be made periodically in diabetics and suspected latent diabetics receiving furosemide. [R9, 2569] *Furosemide therapy during the first few weeks of life in premature neonates reportedly may increase the risk of persistent patent ductus arteriosus, possibly through a PGE-mediated process. [R9, 2569] *Furosemide is contraindicated in patients with anuria. The drug is contraindicated for further use if increasing azotemia and/or oliguria occur during the treatment of severe, progressive renal disease. In patients with hepatic coma or electrolyte depletion, therapy should not be instituted until the basic condition is improved or corrected. Furosemide is also contraindicated in patients with a history of hypersensitivity to the drug. [R9, 2569] *There are no adequate and well controlled studies in pregnant women. Furosemide should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. ... Since furosemide is distributed into milk, the manufacturers recommend that nursing be discontinued if admin of the drug is necessary. [R9, 2569] */It/ is contraindicated in anuria. May cause volume and electrolyte depletion. Potential for hypokalemia warrants periodic measurement of serum potassium levels. Reduction in potassium levels may increase the action and toxicity of digoxin and related glycosides. Concurrent use with lithium is best avoided because of an increased risk of lithium toxicity. May increase the action of salicylates when they are used in high doses. Effect may be decreased by the concurrent use of indomethacin. Parenteral therapy is best avoided in patients receiving aminoglycoside antibiotics because of an increased risk of ototoxicity. [R10] */Furosemide/ is distributed into milk. [R9, 2569] *Because of its efficacy, iv furosemide has become a common medication administered to the critically ill adult. It is capable of causing serious complications if given without caution, without prior assessment of the patient's clinical status, or without careful monitoring of response to therapy. Furosemide has the potential to cause problems that are more than fluid and electrolyte imbalances. [R69] *Furosemide may produce hyperglycemia and glycosuria, possibly as a result of hypokalemia, in patients with predisposition to diabetes. Rarely, precipitation of diabetes mellitus has been reported. [R9, 2568] *Diuretics, including furosemide, can increase serum total cholesterol concns in some patients; increases in low density lipoprotein cholesterol and/or very low density lipoprotein cholesterol subfractions appear to be principally responsible for these increases. In addition, the ratio of serum total cholesterol to high density lipoprotein cholesterol has been increased in some patients in whom total serum cholesterol did not appear to be elevated. Increases in serum triglyceride concentrations also can occur. [R9, 2568] *Adverse nervous system effects of furosemide include dizziness, lightheadedness, vertigo, headache, xanthopsia, blurred vision, and paresthesias. [R9, 2568] *Anemia, hemolytic anemia, leukopenia, neutropenia, and thrombocytopenia have occurred in patients receiving furosemide. In addition, rare cases of agranulocytosis and aplastic anemia have been reported. [R9, 2568] *Adverse dermatologic and/or hypersensitivity reactions to furosemide include purpura, photosensitivity, rash, urticaria, pruritus, exfoliative dermatitis, erythema multiforme, and necrotizing angiitis (vasculitis, cutaneous vasculitis). Patients with known sulfonamide sensitivity may show allergic reactions to furosemide. Anaphylaxis, manifested as urticaria, angioedema, and hypotension, occurred within 5 min after iv administration of furosemide in at least one patient; subsequent intradermal skin testing showed sensitivity to furosemide and other sulfonamides. [R9, 2568] *Transient pain at the injection site has been reported after im administration of furosemide. Thrombophlebitis has occurred with iv administration. [R9, 2569] *Other adverse effects of furosemide include increased perspiration, weakness, fever, restlessness, muscle spasm, urinary bladder spasm, and urinary frequency. A few cases of flank and loin pain have been reported in adults receiving oral furosemide, possibly resulting from calyceal dilation, increased bladder pressure, or spasms caused by formation of calcium containing crystals in the urine. Intrahepatic cholestatic jaundice and pancreatitis have also occurred in patients receiving furosemide. Furosemide may possibly exacerbate or activate systemic lupus erythematosus. [R9, 2569] *Furosemide may cause a transient rise in BUN which is usually readily reversible upon withdrawal of the drug. Elevated BUN is especially likely to occur in patients with chronic renal disease. Hyperuricemia may result from furosemide administration and rarely gout has been precipitated; patients with a history of gout or elevated serum uric acid concentrations should be observed closely during therapy. However, large iv doses of furosemide may cause temporary uricosuria. Elevations of BUN and uric acid concentrations may be associated with dehydration, which should be avoided, particularly in patients with renal insufficiency. Allergic interstitial nephritis leading to reversible renal failure has been attributed to furosemide. Blood ammonia concentrations may be increased, especially in patients with preexisting elevations of blood ammonia. [R9, 2568] *Too vigorous diuresis, as evidenced by rapid and excessive weight loss, may induce orthostatic hypotension or acute hypotensive episodes, and the patient's blood pressure should be closely monitored. Excessive dehydration is most likely to occur in geriatric patients and/or patients with chronic cardiac disease treated with prolonged sodium restriction or those receiving sympatholytic agents. The resultant hypovolemia may cause hemoconcentration, which could lead to circulatory collapse or thromboembolic episodes such as possibly fatal vascular thromboses and/or emboli. Pronounced reductions in plasma volume associated with rapid or excessive diuresis may also result in an abrupt fall in glomerular filtration rate and renal blood flow, which may be restored by replacement of fluid loss. Rarely, sudden death from cardiac arrest has been reported following iv or im administration of furosemide. [R9, 2568] *Potassium depletion occurs frequently in patients with secondary hyperaldosteronism which may be associated with cirrhosis or nephrosis and is particularly important in cirrhotic, nephrotic, or digitalized patients. Hypokalemia and hypochloremia may result in metabolic alkalosis, especially in patients with other losses of potassium and chloride due to vomiting, diarrhea, GI drainage, excessive sweating, paracentesis, or potassium losing renal diseases. In patients with cor pulmonale, alkalosis may cause compensatory respiratory depression. [R9, 2568] *Adverse effects unrelated to the diuretic efficacy are rare, and most adverse effects are due to abnormalities of fluid and electrolyte balance. Over zealous use of loop diuretics can cause serious depletion of total body Na+. This may be manifest as hyponatremia ^/or extracellular fluid volume depletion associated with hypotension, reduced GFR, circulatory collapse, thromboembolic episodes, and in patients with liver disease, hepatic encephalopathy. Increased delivery of Na+ to the distal tubule, particularly when combined with activation of the renin-angiotensin system, leads to increased urinary excretion of K+ AND H+, causing a hypochloremic alkalosis. If dietary K+ intake is not sufficient, hypokalemia may develop, and this may induce cardiac arrhythmias, particularly in patients taking cardiac glycosides. Increased Mg2+ AND Ca2+ excretion may result in hypomagnesemia (a risk factor for cardiac arrhythmias) and hypocalcemia (rarely leading to tetany). /Loop diuretics/ [R45, 772] *Other adverse effects include skin rashes, photosensitivity, paresthesias, bone marrow depression, AND GI disturbances. /Loop diuretics/ [R45, 772] *Loop diuretics can cause ototoxicity that manifests itself as tinnitus, hearing impairment, deafness, vertigo, and a sense of fullness in the ears. Hearing impairment and deafness are usually, but not always, reversible. Ototoxicity occurs most frequently with rapid iv admin and least frequently with oral admin. ... Loop diuretics also can cause hyperuricemia (rarely leading to gout) and hyperglycemia (rarely precipitating diabetes mellitus) and can incr plasma levels of low-density lipoprotein (LDL) cholesterol and triglycerides, while decreasing plasma levels of high-density lipoprotein (HDL) cholesterol. /Loop diuretics/ [R45, 773] *... BLURRING OF VISION, POSTURAL HYPOTENSION, NAUSEA, VOMITING, OR DIARRHEA MAY OCCUR. ... WEAKNESS, FATIGUE, LIGHT HEADEDNESS OR DIZZINESS, MUSCLE CRAMPS, THIRST, AND URINARY FREQUENCY. [R2] *ADVERSE EFFECTS WHICH MAY RESULT FROM THERAPY WITH FUROSEMIDE INCL REDN OF RENAL, CEREBRAL, AND CARDIAC BLOOD FLOW ... ELEVATION OF BLOOD URIC ACID AND BLOOD SUGAR LEVELS, ALLERGIC REACTIONS, RARE CASES OF EXFOLIATIVE DERMATITIS, PRURITUS, AND BLOOD DYSCRASIAS (THROMBOCYTOPENIA AND LEUKOPENIA). [R2] *FUROSEMIDE, DIURETIC, HAS BEEN GIVEN SYSTEMICALLY AND TESTED FOR EFFECT ON INTRAOCULAR PRESSURE IN ... NORMAL AND GLAUCOMATOUS PATIENT IT HAS PRODUCED NO ELEVATION, BUT SMALL DECR IN PRESSURE IN GLAUCOMA. [R70] *OF 585 MEDICAL INPATIENTS TREATED WITH FUROSEMIDE, 123 HAD TOTAL OF 177 ADVERSE REACTIONS. MOST COMMON WERE HYPOVOLEMIA (85 CASES), HYPERURICEMIA (54), AND HYPOKALEMIA (21). MOST REACTIONS WERE MILD, AND ONLY 3 PATIENTS HAD POTENTIALLY LIFE THREATENING EFFECTS. [R71] *TWENTY NINE CASES OF DEAFNESS ASSOC WITH ADMIN OF FUROSEMIDE REPORTED TO FDA ARE STUDIED. HAD BEEN ADMIN ORALLY OR IV IN DOSES OF 40 MG TO 21.6 G. DEAFNESS MAY BE TRANSIENT OR PERMANENT. MANY PT HAD RECEIVED OTHER OTOTOXIC DRUGS. [R72] *Adverse GI effects of furosemide include nausea, anorexia, oral and gastric irritation, vomiting, cramping, diarrhea, and constipation. Because furosemide oral solutions contain sorbitol, they may cause diarrhea, especially in children, when high dosages are administered. In children, mild to moderate abdominal pain has been reported after furosemide was administered iv. In addition, rare occurrences of sweet taste have been reported, but a causal relationship to the drug has not been established. [R9, 2568] *Furosemide is contraindicated in patients with anuria. The drug is contraindicated for further use if increasing azotemia and/or oliguria occur during the treatment of severe, progressive renal disease. [R9, 2569] IDIO: *... RARE CASES OF EXFOLIATIVE DERMATITIS, PRURITUS, AND BLOOD DYSCRASIAS (THROMBOCYTOPENIA AND LEUKOPENIA). [R2] *Rarely, sudden death from cardiac arrest has been reported following iv or im administration of furosemide. [R9, 2568] *... Rare cases of agranulocytosis and aplastic anemia have been reported. [R9, 2568] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Furosemide's production and use as a diuretic and antihypertensive may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.2X10-10 mm Hg at 25 deg C indicates furosemide will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase furosemide will be removed from the atmosphere by wet and dry deposition. If released to soil, furosemide is expected to have moderate mobility based upon an estimated Koc of 302. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.9X10-16 atm-cu m/mole. The pKa1 and pKa2 are 3.8 and 7.5, respectively, indicating that this compound will partially exist in the protonated form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts. If released into water, furosemide is expected to adsorb to suspended solids and sediment based upon the estimated Koc. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to furosemide may occur through inhalation and dermal contact with this compound at workplaces where furosemide is produced or used. Direct human exposure occurs through ingestion of the drug when dispensed in tablet form. (SRC) ARTS: *Furosemide's production and use as an diuretic and antihypertensive(1) may result in its release to the environment through various waste streams(SRC). [R73] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 302(SRC), determined from a log Kow of 2.03(2), indicates that furosemide is expected to have moderate mobility in soil(SRC). Volatilization of furosemide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.9X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Furosemide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-10 mm Hg(SRC), determined from a fragment constant method(5). [R74] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 302(SRC), determined from a log Kow of 2.03(2) and a regression-derived equation(3), indicates that furosemide is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.9X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). The pKa1 and pKa2 of furosemide are 3.9 and 7.5, respectively(5), indicating that this compound will partially exist in the protonated form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R75] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), furosemide, which has an estimated vapor pressure of 3.2X10-10 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase furosemide may be removed from the air by wet and dry deposition(SRC). [R76] ABIO: *Furosemide is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(1) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R77] BIOC: *An estimated BCF of 3 was calculated for furosemide(SRC), using a log Kow of 2.03(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R78] KOC: *The Koc of furosemide is estimated as 300(SRC), using a log Kow of 2.03(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that furosemide is expected to have moderate mobility in soil. The pKa1 and pKa2 of furosemide are 3.8 and 7.5, respectively(4), indicating that this compound will partially exist in the protonated form in the environment and cations generally adsorb to organic carbon and clay more strongly than their neutral counterparts(5). [R79] VWS: *The Henry's Law constant for furosemide is estimated as 3.9X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that furosemide is expected to be essentially nonvolatile from water surfaces(2). Furosemide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-10 mm Hg(SRC), determined from a fragment constant method(4). [R80] MILK: *Only limited information is available on the distribution of furosemide. The drug crosses the placenta and is distributed into milk. [R9, 2570] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 14,103 workers (11,997 of these are female) are potentially exposed to furosemide in the US(1). Occupational exposure to furosemide may occur through inhalation and dermal contact with this compound at workplaces where furosemide is produced or used(SRC). Direct human exposure occurs through ingestion of the drug when dispensed in tablet form(SRC). [R81] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R82] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl furosemide, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. [R83] *Furosemide: (a) Each tablet contains 12.5 or 50 mg furosemide. Each tablet contains 2 g furosemide. Each bolus contains 2 g furosemide. Each milliliter of syrup contains 10 mg furosemide. ... (d) Indications for use: In cattle for treatment of physiological parturient edema of the mammary gland and associated sturctures. Limitations: Treatment not to exceed 48 hours post-parturition. Milk taken during treatment and for 48 hours after the last treatment must not be used for food. Cattle must not be slaughtered for food within 48 hours following last treatment. In dogs for treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. For treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency. In cats for treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. [R84] *Furosemide: (a) Each milliliter of solution contains 50 mg of furosemide diethanolamine. ... (d) In dogs and cats for treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. In horses for treatment of edema (pulmonary congestion, ascites) associated with cardiac insufficiency and acute noninflammatory tissue edema. Do not use in horses intended for food. In cattle for treatment of physiological parturient edema of the mammary gland and associated structures. Treatment not to exceed 48 hours post-parturition. Milk taken during treatment and for 48 hours after the last treatment must not be used for food. Cattle must not be slaughtered for food within 48 hours following last treatment. [R85] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *LC/MS DRUG ANALYSIS WITH CONTINUOUS MONITORING BY QUADRUPOLE MS. [R86] *Determination of furosemide using LC equipped with a detector capable of recording at both 254 nm and 272 nm. Flow rate is about 1.0 ml/min. [R87] CLAB: *Determination of furosemide in plasma or urine by HPLC method on a reverse phase column with spectrophotometric detection at 280 nm. [R88] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: BENET LZ; PHARMACOKINETICS/PHARMACODYNAMICS OF FUROSEMIDE IN MAN: REVIEW; J PHARMACOKINET BIOPHARM 7 (FEB): 1-27 (1979); PHARMACOKINETICS IN NORMAL AND DISEASED SUBJECTS, METABOLISM, AND RELATIONSHIPS BETWEEN DOSAGE AND PHARMACOKINETIC RESPONSE ARE REVIEWED. DHHS/NTP; Toxicology and Carcinogenesis Studies of Furosemide in F344/N Rats and B6C3F1 Mice Technical Report Series No. 356 (1989) NIH Publication No. 89-2811 Aranda JV et al; Furosemide and vitamin E. Two problem drugs in neonatology.; Pediatr Clin North Am 33 (3): 583-602 (1986). This article focuses on some of the problems encountered with two of the drugs currently given to newborns. Hammarlund-Udenaes M, Benet LZ; Furosemide pharmacokinetics and pharmacodynamics in health and disease--update; J Pharmacokinet Biopharm 17 (Feb) 1-46 (1989). A review of the pharmacokinetics and pharmacodynamics of furosemide is presented, including iv and oral data for healthy volunteers and for patients with various disease states. Inter and intraindividual variations in bioavailability, the metabolism of furosemide to its glucuronide conjugate, and the pharmacokinetics of furosemide in children are discussed. Ponto LL, Schoenwald RD; Furosemide (frusemide). A pharmacokinetic/pharmacodynamic review (Part II).; Clin Pharmacokinet 18 (6): 460-71 (1990). The pharmacodynamics of the drug furosemide are examined, and various areas for future study are suggested. SO: R1: SRI R2: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 872 R3: O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2001. R4: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 443 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 523 R6: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. V9 (1987) 33 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. 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Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996. R22: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 776 R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 287 (1990) R24: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R25: DHHS/NTP; Toxicology and Carcinogenesis Studies of Furosemide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.17 (1989) Technical Rpt Series No. 356 NIH Pub No. 89-2811 R26: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 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V50 280 (1990) R43: Lane PH; Am J Kidney Dis 33 (6): 1058-1063. 1999. R44: DHHS/NTP; Toxicology and Carcinogenesis Studies of Furosemide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.4 (1989) Technical Rpt Series No. 356 NIH Pub No. 89-2811 R45: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R46: BEERMANN B ET AL; CLIN PHARMACOL THER 24 (NOV): 560-2 (1978) R47: American Society of Hospital Pharmacists. Data supplied on contract from American Hospital Formulary Service and other current ASHP sources. 1970 R48: MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 22nd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2002. Content Reviewed and Approved by the U.S. Pharmacopeial Convention R49: TSUTSUMI E ET AL; J CLIN PHARMACOL 19 (APR): 200-4 (1979) R50: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991.,p. 1706 R51: Crabtree BL et al; Am J Psychiatry 148 (8): 1060-3 (1991) R52: de Garavilla L et al; Aviat Space Environ Med 61 (11): 1012-7 (1990) R53: Flouvat B et al; Fundam Clin Pharmacol 5 (8): 741-52 (1991) R54: Fujimura A et al; Jpn J Pharmacol 60 (3): 153-7 (1992) R55: Fujimura A et al; Life Sci 51 (19): 1501-7 (1992) R56: Fujimura A et al; Life Sci 52 (9): 819-24 (1993) R57: Fujimura A et al; Jpn J Pharmacol 59 (2): 209-12 (1992) R58: Monig H et al; Eur J Clin Pharmacol 39 (3): 261-5 (1990) R59: Miyazaki H et al; Nippon Juigaku Zasshi 52 (2): 265-73 (1990) R60: Okpukpara JN, Akah PA; J Pharm Pharmacol 42 (8): 597-8 (1990) R61: Sommers DK et al; Br J Clin Pharmacol 32 (4): 489-93 (1991) R62: Wa TC et al; Postgrad Med J 67 (789): 655-8 (1991) R63: Mydlik M, et al; Miner Electrolyte Metab 25 (4-6): 352-356. 1999. R64: Yamamoto T, et al; Metabolism 50 (2): 241-245. 2001. R65: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R66: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 96 R67: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 73 R68: Prandota J; Am J Ther 8 (4): 275-289. 2001. R69: DePew CL et al; Crit Care Nurse 9 (2): 63-9 (1989) R70: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 511 R71: LOWE J ET AL; BR MED J 2 (AUG): 360-2 (1979) R72: GALLAGHER KL, JONES JK; ANN INTERN MED 91 (NOV): 744-5 (1979) R73: (1) Budavari S, ed; The Merck Index. 13th ed Whitehouse Station, NJ: Merck and Co., Inc., p. 764 (2001) R74: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R75: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Berthod A et al; Anal Chem 71: 879-88 (1999) (6) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) (8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R76: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R77: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R78: (1) Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R79: (1) Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Berthod A et al; Anal Chem 71: 879-88 (1999) (5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000) R80: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R81: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R82: 21 CFR 200-299, 300-499, 820, and 860 (4/1/2001) R83: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-128 (1992) R84: 21 CFR 520.1010 (4/1/2001) R85: 21 CFR 522.1010 (4/1/2001) R86: HENION JD; ANAL CHEM 50 (OCT): 1687-93 (1978) R87: USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990. 597 R88: U.S. Department of Health, Education and Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances. 1977 edition. Washington, D. C.: U.S. Government Printing Office, 1977.p. V2 47 RS: 109 Record 219 of 1119 in HSDB (through 2003/06) AN: 3096 UD: 200108 RD: Reviewed by SRP on 9/9/1993 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HYDROCHLOROTHIAZIDE- SY: *Aldactazide-25/25-; *Aldectazide-50/50-; *Aldoril-D30-; *Aldoril-D50-; *AQUARILLS-; *AQUARIUS-; *Aquazide-H-; *2H-1,2,4-BENZOTHIADIAZINE-7-SULFONAMIDE,-6-CHLORO-3,4-DIHYDRO-,-1,1-DIOXIDE-; *Bremil-; *Chlorizide-; *6-CHLORO-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE-7-SULFONAMIDE-; *6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide-; *6-Chloro-3,4-dihydro-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-; *6-CHLORO-7-SULFAMOYL-3,4-DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE-; *6-Chloro-7-sulfamoyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-; *6-Chloro-7-sulfamyl-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide-; *CHLOROSULTHIADIL-; *CHLORSULFONAMIDODIHYDROBENZOTHIADIAZINE-DIOXIDE-; *Cidrex-; *Vetidrex-; *Diaqua-; *Dichlorosal-; *DICHLOTIAZID-; *DICHLOTRIDE-; *DICLOTRIDE-; *3,4-Dihydro-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide-; *DIHYDROCHLOROTHIAZID-; *DIHYDROCHLOROTHIAZIDE-; *3,4-DIHYDROCHLOROTHIAZIDE-; *DIHYDROCHLOROTHIAZIDUM-; *DIHYDROXYCHLOROTHIAZIDUM-; *Direma-; *DISALUNIL-; *Diu-melusin-; *DRENOL-; *ESIDREX-; *ESIDRIX-; *Fluvin-; *HCTZ-; *HCZ-; *HIDRIL-; *HIDROCHLORTIAZID-; *Hidroronol-; *HIDROTIAZIDA-; *HYDRIL-; *Hydro-D-; *HYDRO-AQUIL-; *HYDROCHLOROTHIAZID-; *HYDROCHLORTHIAZIDE-; *HYDRODIURETIC-; *HYDRO-DIURIL-; *HYDROSALURIC-; *Hydrothide-; *HYPOTHIAZID-; *HYPOTHIAZIDE-; *HYPOTHIAZIDE-; *IDROTIAZIDE-; *Inderide-80/25-; *Ivaugan-; *Jen-Diril-; *Maschitt-; *Maxzide-; *Mazide-25-mg-; *MEGADIURIL-; *Mictrin-; *Moduretic-; *NC1-C55925-; *NCI-C55925-; *NEFRIX-; *Neo-Codema-; *Neoflumen-; *ORETIC-; *Panurin-; *Ro-Hydrazide-; *Roxane-; *Spironazide-; *SU-5879-; *Thiaretic-; *THIURETIC-; *Urodiazin-; *VETIDREX-; *VETRIDEX-; *ZIDE- RN: 58-93-5 MF: *C7-H8-CL-N3-O4-S2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ACYLATION OF 3-CHLOROANILINE WITH CHLOROSULFONIC ACID FOLLOWED BY TREATMENT WITH AMMONIA AND FORMALDEHYDE. [R1] FORM: *Oral Solution, 50 mg/6 ml, Hydrochlorothiazide Solution, Pharmaceutical Basics. Roxane; Tablets, 25 mg, Aquazide-H, Jones Medical; Esidrix (scored), Ciba; Hydro-D (scored), Halsey; HydroDIURIL (scored), MSD; Oretic, Abbott; 50 mg, Aquazide-H, Jones Medical; Diaqua, Mallard; Esidrix (scored), Ciba; Hydro-D (scored), Halsey; HydroDIURIL (scored), MSD; Mictrin, Econo Med; Oretic, Abbott; 100 mg, Esidrix (scored), Ciba; HydroDIURIL (scored), MSD. [R2, 1612] *Oral Tablets, 5 mg Amiloride Hydrochloride and Hydrochlorothiazide 50 mg, Amiloride Hydrochloride and Hydrochlorothiazide Tablets, Biocraft, Bioline, Geneva, Goldline, Major, Rugby, Schein, United Research, Warner Chilcott; Moduretic (scored), MSD. /Amiloride hydrochloride and hydrochlorothiazide/ [R2, 1612] *Oral Tablets, film-coated, 250 mg Methylodopa and Hydrochlorothiazide 15 mg, Aldoril 15 (with propylene glycol), MSD; 250 mg Methyldopa and Hydrochlorothiazide 25 mg, Aldoril 25 (with propylene glycol), MSD; 500 mg Methyldopa and Hydrochlorothiazide 30 mg, Aldoril D30 (with propylene glycol), MSD; 500 mg Methyldopa and Hydrochlorothiazide 50 mg, Aldoril D50 (with propylene glycol), MSD. /Methyldopa and hydrochlorothiazide/ [R2, 1612] *Oral Capsules, extended-release, 80 mg Propranolol Hydrochloride and Hydrochlorothiazide 50 mg, Inderide LA 80/50, Wyeth-Ayerst; 120 mg Propranolol Hyrochloride Hydrochlorothiazide 50 mg, Inderide LA 120/50, Wyeth-Ayerst; 160 mg Propranolol Hydrochloride and Hydrochlorothiazide 50 mg, Inderide LA 160/50, Wyeth-Ayerst; Tablets 40 mg Propranolol Hydrochloride and Hydrochlorothiazide 25 mg, Inderide 40/25 (scored), Wyeth-Ayerst; 80 mg Propranolol Hydrochloride and Hydrochlorothazide 25 mg, Inderide 80/25 (scored), Wyeth-Ayerst. /Propranolol hydrochloride and hydrochlorothiazide/ [R2, 1612] *Oral Tablets 25 mg Spironolactone and Hydrochlorothiazide 25 mg, Spironazide (scored), Schein; Spirozide, Rugby; Tablets, film-coated, 25 mg Spironolactone and hydrochlorothiazide 25 mg, Aldactazide 25/25, Seale; 50 mg spironolactone and hydrochlorothiazide 50 mg, Aldectazide 50/50 (scored); Searle. /Spironolactone and hydrochlorothiazide/ *Oral Capsules, 50 mg Triamterene and Hydrochlorothiazide 25 mg, Dyazide (with benzyl alcohol and povidone), SmithKline Beecham; Triameterene and Hydrochlorothiazide Capsules, Geneva, Rugby, Zenith; Oral Tablets, 37.5 mg Triamterene and Hydrochlorothiazide 25 mg, Mazide 25 mg (scored), Lederle; Triamterene and Hydrochlorothiazide Tablets, Geneva; 75 mg Triamterene and Hydrochlorothiazide 50 mg, Maxzide (scored), Lederle; Triamterene and Hydrochlorothiazide Tablets, Barr, Danbury, Geneva, Major, Rugby, Schein, Warner Chilcott, Watson. /Triamterene and hydrochlorothiazide (co-triamterzide)/ *Oral Capsules, 25 mg with Hydralazine Hydrochloride 25 mg, Apresazide 25/25 (with parabens), Ciba; Hydralazine Plus 25/25, Rugby; Hydrazide 25/25, Goldline; Hy-zide, 25/25, Bioline; 50 mg with Hydralazine Hydrochloride 50 mg, Apresazide 50/50 (with parabens), Ciba; Hydralazine Plus 50/50, Rugby; Hydrazide 50/50, Goldline; Hy-zide 50/50, Bioline; 50 mg with Hydralazine Hydrochloride 100 mg, Apresazide 100/50 (with parabens), Ciba; Tablets, 15 mg with Captopril 25 mg, Capozide 25/15 (scored), Squibb; 15 mg with Captopril 50 mg, Capozide 50/15 (scored), Squibb; 15 mg with Hydralazine Hydrochloride 25 mg, Apresodex, Rugby; 15 mg with Hydralazine Hydrochloride 25 mg and Reserpine 0.1 mg, Hydroserpazine, Bioline; Ser-A-gen, Goldline; Ser-Ap-Es, Ciba; Serathide, Interstate; Tri-hydroserpine, Ruby; Unipres (scored), Reid-Rowell; 25 mg with Captopril 25 mg, Capozide 25/25 (scored), Squibb; 25 mg with Captopril 50 mg, Capozide 50/25 (scored), Squibb; 25 mg with Deserpidine 0.125 mg, Oreticyl 25 (scored), Abbott; 25 mg with Deserpidine 0.25 mg, Oreticyl Forte (scored), Abbott; 25 mg with Enalapril Maleate, Vaseretic 10-25, MSD. /Hydrochlorothiazide combinations/ [R2, 1613] *Oral Tablets, 25 mg with Guanethidine Monosulfate 10 mg (equivalent to guanethidine sulfate 8.4 mg), Esimil (scored), Ciba; 25 mg with Metoprolol tartrate 50 mg, Lopressor HCT 50/25 (with povidone; scored), Geigy; 25 mg with Metoprolol Tartrate 100 mg, Lopressor HCT 100/25 Geigy; 25 mg with Reserpine 0.125 mg; Hyropres 25 (scored), MSD; Hydro-25 Reserpine, Interstate; Hyroserpine 1, Rugby; 25 mg with Timolol Maleate 10 mg, Timolide 10-25, MSD; 50 mg with Deserpidine 0.125 mg, Oreticyl 50 (scored), Abbott; 50 mg with Metoprolol Tartrate 100 mg, Lopressor HCT 100/50 (with povidone; scored), Geigy; 50 mg with Reserpine 0.125 mg, Hydropres 50 (scored), MSD; Hydro-50 Reserpine Interstate; Hydroserpine 2, Rugby; Tablets film-coated, 25 mg with Labetalol Hydrochlorie 100 mg, Normozide 100/25 (with parabens; scored). Schering; Trandate HCT (with parabens), Allen and Hanburys; 25 mg with Labetalol Hydrochloride 200 mg, Normozide 200/25 (with parabens: scored), Schering; Trandate HCT (with parabens), Allen and Hanburys; 25 mg with Labetalol Hydrochloride 300 mg, Normozide 300/25 (with parabens; scored) Schering; Trandate HCT (with parabens), Allen and Hanburys. /Hydrochlorothiazide combinations/ [R2, 1613] *Tablets, 25, 50, and 100 mg. Oral solution, 50 mg/5 ml. Concentrated oral solution, 100 mg/ml. [R3] MFS: *Abbott Laboratories, Hq, 1400 Sheridan Rd, North Chicago, IL 60064, (800) 323-9065; Chemical and Agricultural Products Division; Chemical Business Unit; Production site: North Chicago, IL 60064 [R4] *Atomergic Chemetals Corp, Hq, 222 Sherwood Ave, Farmingdale, NY 11735-1718, (516) 694-9000; Production site: Farmingdale, NY 11735 [R4] *CIBA-GEIGY Corporation, Hq, 444 Saw Mill River Road, Ardsley, NY 10502, (914) 478-3131; Pharmaceuticals Division; Production site: 556 Morris Ave, Summit, NJ 07901; Production site: Summit, NJ 07901 [R4] *Merck and Co, Inc, Hq, PO Box 2000, Rahway, NJ 07065 (201) 574-4000; Merck Chemical Manufacturing Division (address same as Hq); Production site: Albany, GA 31705 [R4] *Smithkline Beecham, Hq, One Franklin Plaza, PO Box 7929, Philadelphia, PA 19101, Smithkline Beecham Pharmaceuticals, Chemical Div, PO Box 900, Conshohocken, PA 19428; Production site: Guayama, PR 00630 [R4] OMIN: *DECOMPOSITION OCCURS UPON IRRADIATION WITH NEAR UV LIGHT (LAMBDA GREATER THAN 310 NM) BOTH IN METHANOL AND AQ SOLUTIONS. IN PHOTOLYSIS, THE CL SUBSTITUENT IS REPLACED BY EITHER H OR OR FROM THE SOLVENT ROH. HYDROLYSIS OF THE THIADIAZINE RING IS SUPERIMPOSED UPON DECHLORINATION. OXYGEN INHIBITS THE DECOMPOSITION. [R5] USE: *MEDICATION PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 1.36X10+6 GRAMS [R1] *(1978) PROBABLY GREATER THAN 1.82X10+6 GRAMS [R1] U.S. IMPORTS: *(1976) 1.93X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1978) 3.65X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE OR PRACTICALLY WHITE CRYSTALLINE POWDER [R6, 880] ODOR: *ODORLESS [R6, 880] TAST: *Slightly bitter taste [R2, 1611] MP: *MELTS WITH DECOMP @ ABOUT 268 DEG C [R6, 880] MW: *297.72 [R7] DSC: *pKa= 7.9 /and/ 9.2 [R7] SOL: *SOL IN DIL AMMONIA OR SODIUM HYDROXIDE; SOL IN METHANOL, ETHANOL, ACETONE; PRACTICALLY INSOL IN WATER [R7] SPEC: *MAX ABSORPTION (METHANOL AND TRACE HYDROGEN CHLORIDE ): 317 NM (A= 130, 1%, 1 CM), 271 NM (A= 654, 1%, 1 CM), 226 NM (A= 1280, 1%, 1 CM). [R7]; *Intense mass spectral peaks: 221 m/z, 269 m/z, 297 m/z [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of /sulfur oxides, hydrogen chloride, and nitrogen oxides/. [R9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence for the carcinogenicity of hydrochlorothiazide in humans. There is inadequate evidence for the carcinogenicity of hydrochlorothiazide in experimental animals. Overall evaluation: Hydrochlorothiazide is not classifiable as to its carcinogenicity in humans (Group 3). [R10] ANTR: *Thiazide diuretic overdose should be treated by immidiate evacuation of the stomach followed by supportive symptomatic treatment and monitoring of serum electrolyte concn and renal function. /Thiazide diuretics/ [R11] HTOX: *ADVERSE EFFECTS ... GI (ANOREXIA, GASTRIC IRRITATION, NAUSEA, VOMITING, CRAMPING, DIARRHEA, JAUNDICE, PANCREATITIS, SIALADENITIS), CNS (DIZZINESS, VERTIGO, PARESTHESIAS, HEADACHE, XANTHOPSIA), HEMATOLOGIC (LEUKOPENIA, AGRANULOCYTOSIS, THROMBOCYTOPENIA, APLASTIC ANEMIA) ... / and / ORTHOSTATIC HYPOTENSION ... . /BENZOTHIADIAZIDES/ [R6, 878] *ADVERSE EFFECTS ... HYPERSENSITIVITY (PURPURA, PHOTOSENSITIVITY, RASH, URTICARIA, NECROTIZING ANGIITIS, FEVER, RESPIRATORY DISTRESS, ANAPHYLACTIC REACTIONS), OTHER (... GLYCOSURIA ... MUSCLE SPASM, WEAKNESS, RESTLESSNESS ... / and / BLURRED VISION). /BENZOTHIADIAZIDES/ [R6, 878] *SIDE EFFECTS...THAT MOST FREQUENTLY COMPLICATE THEIR USE IN TREATMENT OF HYPERTENSION ARE HYPOKALEMIA, HYPERGLYCEMIA, AND HYPERURICEMIA. /BENZOTHIADIAZIDES/ [R12, 804] *67 YR OLD MALE PATIENTS TAKING ALDORIL (HYDROCHLOROTHIAZIDE AND METHYLDOPA) SHOWED IMMUNE HEMOLYTIC ANEMIA WITH ACUTE INTRAVASCULAR HEMOLYSIS. SPECIFIC DRUG CAUSING RED BLOOD CELL LYSIS WAS THE THIAZIDE FRACTION OF THE COMPD. [R13] *A PATIENT DEVELOPED SUDDEN ONSET OF PULMONARY EDEMA ON TWO SEPARATE OCCASIONS IMMEDIATELY AFTER INGESTION OF HYDROCHLOROTHIAZIDE. A NONCARDIOGENIC ETIOLOGY HAS BEEN SUGGESTED, BUT PRIOR CASES HAVE FAILED TO DOCUMENT CARDIOPULMONARY HEMODYNAMIC MEASUREMENTS. A SWAN-GANZ BALLOON FLOTATION CATHETER DEMONSTRATED CARDIOPULMONARY PRESSURES IN THIS PATIENT CONSISTENT WITH A NONCARDIAC ORIGIN OF THE PULMONARY EDEMA. [R14] *IN HEALTHYSUBJECTS, 50 MG HYDROCHLOROTHIAZIDE ADMIN INCREASED THE PLASMA LEVELS OF URIC ACID, CHOLESTEROL, AND CALCIUM WITHIN THE 1ST FEW HOURS OF ADMINISTRATION. ADMINISTRATION OF 50 MG FOR 10 CONSECUTIVE DAYS ALSO INCREASED THE PLASMA URATE LEVELS. HYDROCHLOROTHIAZIDE HAD DUAL EFFECT ON URINARY URATE EXCRETION; DURING 1ST 3 HR AFTER DRUG ADMINISTRATION URATE EXCRETION INCREASED, THIS WAS LATER FOLLOWED BY A DECREASE. CALCIUM EXCRETION IN THE URINE WAS ALSO INCREASED DURING THE 1ST PHASE OF ADMINISTRATION. [R15] *VOLUNTEERS WERE TESTED FOR PHOTOTOXIC REACTIONS WITH HIGH UVA DOSES AFTER INTAKE OF 4 DRUGS. TWO OUT OF 10 BECAME SENSITIVE TO UVA LIGHT AFTER TAKING HYDROCHLOROTHIAZIDE. [R16] *Side effects ... associated with the use of hydrochlorothiazide include hypokalemia with resultant muscle cramps, cardiac arrhythmia, hyperglycemia, and hyperlipidemia. A variety of hypersensitivity reactions have also been reported. Electrolyte imbalances, in particular hypokalemia and hypomagnesemia, may be involved in increased incidences of sudden death in patients with preexisting electrocardiographic abnormalities. Results of the large Multiple Risk Factor Intervention Trial, a 10 yr, multicenter study of factors involved in heart disease, indicated that high dose hydrochlorothiazide therapy (100 mg/day) was associated with greater incidences of sudden death in patients with both high blood pressure and electrocardiographic abnormalities. The involvement of hypokalemia and hypomagnesemia in this observation remains a point of controversy. [R17] *One electrolyte change that occurs with longterm hydrochlorothiazide therapy in humans is increased calcium ion retention; hypercalcemia occasionally results. A related finding is an association of hydrochlorothiazide treatment with hyperparathyroidism. It has been suggested that thiazides cause a primary hyperparathyroidism, and the reduced calcium ion excretion and increased potassium ion loss seen with these diuretics may, at least in part, be secondary to increased parathyroid hormone secretion. [R17] *Thiazide diuretics also induce a transient increase in serum cholesterol and triglyceride levels, raising the possibility that long term treatment may contribute to atherosclerosis. Hypertensive individuals receiving 50 mg hydrochlorothiazide per day for 4 wk had increased concentrations of total plasma cholesterol, of high density, low density, and very low density lipoproteins, and of triglycerides. [R17] *Immunologic reactions to hydrochlorothiazide therapy were reported, including cases of severe allergic pneumonitis, a photoallergic dermatitis resembling subacute cutaneous lupus erythematosus and several types of hematologic dyscrasias. Neutropenia was reported in several patients with a pattern of onset which suggested a toxic depression of the bone marrow. On the other hand, thromboyctopenia also was reported with hydrochlorothiazide therapy and with other thiazides and appears to be immunologically mediated. In one person, a specific IgM antibody was identified as an antiplatelet factor associated with hydrochlorothiazide-induced thrombocytopenia. [R17] *Limited epidemiologic evaluations have not demonstrated fetotoxic effects attributed to the use of hydrochlorothiazide during pregnancy. Hydrochlorothiazide is known to cross the placenta and to accumulate in amniotic fluid to levels fivefold higher than those in maternal blood. In contrast, breast feeding by a mother on long term hydrochlorothiazide therapy did not result in detectable levels in her infant's blood. [R18] *Hydrochlorothiazide has no consistent pattern of ocular toxicity. As a rare but recognized type of side effect, a young woman under treatment for edema of the legs associated with pregnancy developed acute bilateral myopia of about 3 diopters after taking 100 mg. In 3 to 4 days the myopia cleared after the drug was discontinued. [R19] *A 42 yr old white female developed severe respiratory distress 30 min following the ingestion of hydrochlorothiazide. On her arrival at the emergency room, pulmonary edema was evident by physical examination and chest radiograph. She presented without evidence of a gallop, jugular venous distention, or history suggesting cardiac disease. Normal electrocardiogram and echocardiogram, and a radionuclide ventriculogram showing normal systolic and diastolic functions supported the noncardiac origin. The patient responded to supportive treatment within hours although the radiographic abnormalities persisted for several days. [R20] *The clinical features of 4 unpublished cases and 26 published cases of acute allergic interstitial pneumonitis induced by hydrochlorothiazide were examined. The onset was acute and dramatic; the average time to onset of symptoms was 44 min. Sex was a predominant risk factor, since 27 (90%) of the 30 patients were women. The average age was 56 yr; thus, most of the women were postmenopausal. Over two-thirds of the patients had one to three positive prechallenges or rechallenges, 3 of the 52 documented adverse events occurred after a voluntary rechallenge, some were life threatening and necessitated mechanical ventilation, and 1 was fatal. It was concluded that acute allergic interstitial pneumonitis due to hydrochlorothiazide is extremely rare and potentially fatal. [R21] *A 44 yr old woman was seen on three separate occasions for acute pulmonary edema which had developed 30 min after ingestion of a single hydrochlorothiazide-amiloride (Moduretic) tablet. Eighteen cases of hydrochlorothiazide induced pulmonary edema have been reported previously. Clinical findings and investigations in the present and previous cases indicate a noncardiogenic cause for the pulmonary edema. Increased pulmonary vascular permeability is probably involved. So far, attempts to demonstrate a immunological mechanism have failed and the pathophysiology remains uncertain. [R22] *A 67 yr old man developed non-cardiogenic pulmonary edema after taking a hydrochlorothiazide tablet. The symptoms remitted following supportive treatment but recurred after rechallenge. Immunologic studies showed increased immunoglobulin E, negative lymphocyte transformation test when exposed to hydrochlorothiazide, normal blood lymphocyte subpopulations and complement levels, and negative antinuclear antibodies. [R23] *In 78 patients with mild or moderate hypertension, effect of acebutolol and hydrochlorothiazide on plasma lipids, lipoproteins, fibrinogen and plasma fibrinolysis time were investigated. Forty-two patients were treated with acebutolol for 18 mo and 36 with hydrochlorothiazide for 24 mo. It was shown that neither acebutolol nor hydrochlorothiazide induced significant alterations in investigated biochemical risk factors. [R24] NTOX: *IN ANIMAL EXPT, THE DEMONSTRABLE TOXIC DOSE OF ALL THIAZIDES IS MANIFOLD THAT REQUIRED FOR THEIR PHARMACOLOGICAL ACTION. /BENZOTHIADIAZIDES/ [R12, 902] *... 250 MG/KG ON GESTIONAL DAYS 9, 10, 11, 12 PRODUCED NO DEFECTS IN RAT FETUS. [R25] *Increased plasma levels of fasting glucose and insulin were also observed in Syrian golden hamsterdosed daily with 1, 2, or 4 mg/kg hydrochlorothaizide by gavage for 6 mo. At 6 mo, they observed increased total cholesterol, triglyceride, and high density lipoprotein cholesterol levels. [R17] *Groups of 24 male and 24 female rats were ... fed diets containing 0 or 1000 ppm hydrochlorothiazide for 2 yr. The incidence and severity of chronic progressive nephropathy was increased in the dosed rats, as were lesions secondary to chronic renal disease and polyarteritis and mural thrombosis. No increases in neoplastic lesions were seen in dosed rats. [R17] *When given by subcutaneous injection to two pregnant female Wistar rats at a dose of 250 mg/kg on gestation days 10 and 11, hydrochlorothiazide did not appear to cause fetal malformations. Nine normal pups were born; three were resorbed. [R18] *In the Salmonella typhimurium gene mutation assay, hydrochlorothiazide demonstrated equivocal mutagenicity in strain TA98 in the absence of S9; no increase in revertant colonies was observed in strains TA100, TA1535, or TA1537 treated with up to 10 mg/plate hydrochlorothiazide with or without S9 from Arochlor 1254 induced male Sprague Dawley rat or Syrian hamster liver. The results of the Salmonella tests reported by other laboratories, using lower or unspecified doses of hydrochlorothiazide, were negative a significant increase in p-fluorophenylalanine resistant colonies of Aspergillus nidulans was reported after exposure in a spot test to paper saturated with hydorchlorothiazide; this resistence was attributed to nondisjunctional events induced by chemical exposure. Hyrochlorothiazide did not induce sexlinked recessive lethal mutations in adult male Drosophila melanogaster when administered by feeding or injection. In cytogenetic tests with cultured Chinese hamster ovary cells, hydrochlorothiazide (43-1300 ug/ml) induced sister chromatid exchanges in the presence and absence of Aroclor 1254 induced male Sprague Dawley rat liver S9 but did not induce chromosomal aberrations at doses up to 1000 ug/ml without S9 and 2600 ug/ml with S9. No significant increase was detected in chromosomal aberrations in Chinese hamster lung cells exposed at doses up to 500 ug/ml hydrochlorothiazide with and without S9 but did report induction of polyploidy in 12% of the cells. [R18] *20 Dogs were given daily doses of 50-200 mg hydrochlorothiazide for up to 9 mo. All dogs administered hydrochlorothiazide had enlarged and hyperactive parathyroid glands. [R26] NTP: *2 Year studies were conducted by feeding diets containing 0, 250, 500, or 2000 ppm hydrochlorothiazide to groups of 50 male and 50 female rats for 105-106 weeks. Diets containing 0, 2500, or 5000 ppm hydrochlorothiazide were fed to groups of 50 male and 50 female mice for 103-104 weeks. Mean body weights of dosed rats were 8%-25% lower than those of controls. Mean body weights of dosed and control mice were similar throughout the studies. No significant differences in survival were observed between rats or mice of either sex. Survival of all groups of male rats was low because a large number of animals were killed in a moribund condition late in the study. The average daily feed consumption by dosed rats was 89%-94% that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 11, 23, or 89 mg/kg for low, mid, or high dose rats. The average daily feed consumption by dosed mic e was 100%-105% that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 280 or 575 mg/kg for low dose or high dose mice. Under the conditions of these 2 year feed studies, there was no evidence of carcinogenic activity of hydrochlorothiazide for male or female F344/N rats given feed containing 250, 500, or 2000 ppm hydrochlorothiazide. There was equivocal evidence of carcinogenic activity of hydrochlorothiazide for male B6C3F1 mice, based on increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given diets containing 2500, or 5000 ppm hydrochlorothiazide. Chronic renal disease was more severe in rats administered hydrochlorothiazide, and increased incidences of secondary lesions (parathyroid hyperplasia, fibrous osteodystrophy, and mineralization in multiple organs) occurred in dosed rats. [R27] *2 Year studies were conducted by feeding diets containing 0, 250, 500, or 2,000 ppm hydrochlorothiazide to groups of 50 male and 50 female rats for 105-106 weeks. Diets containing 0, 2500, or 5000 ppm hydrochlorothiazide were fed to groupf of 50 male and 50 female mice for 103-104 weeks. Ten additional rats per sex and dose group were placed on study and killed at 1 yr for blood clotting studies and histopathologic examiniation. One of the 10 female rats in the 1 year study group that received 2000 ppm died with internal hemorrhage. In addition, evidence of hemorrhage was found in 11 of the 16 dosed female rats that died during the first year of the 2 year study. Hematologic analyses revealed no compound related effects; however, activated partial thromboplastin times were highly variable and were lengthened in some dosed male rats. No effects on activated partial thromboplastin times were seen for females and no effects on prothrombin times or on the fibrinogen content of plasma were observed for dosed male or female rats. Nephropathy occurred in dosed and control rats, and the severity was judged to be greater in dosed male and high dose female rats. Increased incidences of mild focal renal mineralization were also seen in mid and high dose male rats and dosed female rats. [R27] *In the absence of exogenous metabolic activation, hydrochlorothiazide produced an equivocal increase in revertant colonies in Salmonella typhimurium strain TA98; no increase was observed in strains TA100, TA1535, or TA1537 with or without activation. Hydrochlorothiazide induced an increase in trifluorothymide resistant cells in a mouse lymphoma L5178Y/TK + or - assay without exogenous metabolic activation; this assay was not performed with activation. In cultured Chinese hamster ovary cells, hydrochlorothiazide induced sister chromatid exchanges in the presence and absence of exogenous metabolic activation but did not induce chromosomal aberrations. Hydrochlorothiazide did not increase the frequency of sex-linked recessive lethal mutations when administered by feeding or injection to adult male Drosophila melanogaster. [R28] *Hydrochlorothiazide produced no teratologic effects in the offspring of CD rats or CD-1 mice after gavage administration to pregnant females on day 6 through day 15 of gestation. [R28] ADE: *THIAZIDES ARE RAPIDLY ABSORBED FROM GI TRACT ... . /BENZOTHIADIAZIDES/ [R12, 902] *URINARY EXCRETION ... IN MAN WAS RAPID, AND NORMAL HUMAN SUBJECTS EXCRETED ALMOST ALL ADMIN (14)C IN 24 HR URINE AFTER IV DOSE AND NEARLY 67% AFTER ORAL DOSE. EXCRETION WAS SLOWER IN HUMAN SUBJECTS WITH RENAL OR HEPATIC DISEASE. [R29] *ORAL ... (3)H]-HYDROCHLOROTHIAZIDE WAS RAPIDLY ABSORBED IN RATS, AS SHOWN BY HIGH LEVELS OF (3)H ... IN LIVER WITHIN 1 HR. THESE FELL WITHIN 5 HR BUT LEVELS IN GI TRACT REMAINED RELATIVELY HIGH. 43-69% OF (3)H WAS EXCRETED IN 48 HR URINE, MOSTLY IN EARLY URINE. PATTERN OF (3)H IN INTESTINES INDICATED BILIARY EXCRETION ... . [R29] *ABSORBED FROM GI TRACT ... DISTRIBUTED IN EXTRACELLULAR SPACE AND CROSS PLACENTA ... ONSET OF DIURETIC ACTION ... WITHIN 2 HR ... PEAK EFFECT /AT/ 3 TO 6 HR ... APPROX DURATION OF ... ACTION /IS/ 6-12 HR. /HUMAN, ORAL/ [R30] *HYDROCHLOROTHIAZIDE ADMIN ORALLY AND IV TO 5 HEALTHY SUBJECTS: GI ABSORPTION WAS 60-80%, MOST IN DUODENUM AND UPPER JEJUNUM. ELIM WAS MAINLY IN URINE. NO SIGNIFICANT BILIARY EXCRETION WAS OBSERVED. GREATER THAN 95% WAS EXCRETED UNCHANGED. LEVELS IN PLASMA DECLINED RAPIDLY IN 1ST 10 HR, SLOWLY THEREAFTER, ACCORDING TO 2 COMPARTMENT MODEL: HALF-LIFE OF ALPHA- AND BETA-PHASES WERE 1.7 and 13.1 HR, RESPECTIVELY. CELLS/PLASMA ACCUMULATION RATIO AVERAGED 3.5. THE FATE OF A SINGLE DOSE IN HYPERTENSIVE AND HEALTHY PATIENT WAS SIMILAR. PATIENT WITH ELEVATED SERUM CREATININE ELIMINATED THE DRUG MORE SLOWLY. [R31] *THE BIOAVAILABILITY OF HYDROCHLOROTHIAZIDE FROM 50 MG ORAL TABLET DOSES WAS EXAMINED IN HEALTHY MALE VOLUNTEERS UNDER FASTING AND NONFASTING CONDITIONS. THE PHARMACOKINETICS OF HYDROCHLOROTHIAZIDE IN PLASMA COULD BE DESCRIBED IN TERMS OF A TRIEXPONENTIAL FUNCTION, AND THE MEAN HALF-LIFE DETERMINED FROM THE 3 EXPONENTS WERE 1.0, 2.2, and 9.0 HR. PLASMA DRUG LEVELS WERE SIGNIFICANTLY REDUCED IN NONFASTED PERSONS, COMPARED WITH THOSE IN FASTED PERSONS. MEAN 48 HR URINARY RECOVERY WAS 70.5% OF THE DOSE IN NONFASTED SUBJECTS, and 75.1% IN FASTED SUBJECTS RECEIVING DRUG WITH 20 and 250 ML OF WATER RESPECTIVELY. CUMULATIVE URINARY EXCRETION CORRELATED POORLY WITH AREAS UNDER PLASMA DRUG LEVEL CURVES. CLOSE SIMILARITY WAS OBSERVED BETWEEN URINARY EXCRETION RATES OF THE DRUG AND THE TIME COURSE OF DRUG CONCENTRATIONS IN PLASMA. [R32] *EVALUATION OF PLACENTAL TRANSFER OF HYDROCHLOROTHIAZIDE AT DELIVERY IN WOMEN ADMIN 50 MG DAILY FOR AT LEAST 2 WK SHOWED THAT THE LEVELS OF THE DRUG IN UMBILICAL CORD PLASMA WERE 0.10-0.80 OF THOSE IN MATERNAL PLASMA. THE CONCENTRATIONS OF HYDROCHLOROTHIAZIDE IN AMNIOTIC FLUID WERE UP TO 5 and 19 TIMES HIGHER THAN IN MATERNAL AND UMBILICAL CORD PLASMA, RESPECTIVELY. THE DRUG APPARENTLY PENETRATES THE PLACENTAL BARRIER EFFICIENTLY AND REACHES LEVELS IN UMBILICAL VEIN PLASMA THAT APPROACH THOSE IN MATERNAL PLASMA. [R33] *In humans, about 70% of an orally administered therapeutic level dose of hydrochlorothiazide is absorbed, primarily from the duodenum and upper jejunum. Absorption is linear over the dose range 12.5-85 mg. Absorption after a meal has been reported to be facilitated or decreased. Approximately 40% of the absorbed hydrochlorothiazide binds to plasma proteins across the therapeutic dose range, and the drug accumulates in erythrocytes. The ratio of this uptake between blood corpuscles and plasma is about 3.5:1. Peak plasma levels are attained approximately 2-3 hr after dosing. The decline of plasma drug levels fits a two compartment model with a terminal elimination phase of 9.5 hr. This relatively long half-life provides a fairly constant, long duration of action (12-24 hr). Renal clearance is over 300 ml/minute, indicating active secretion of the drug by the kidney. Secretion is via the organic anion transport system in the proximal tubules and is sensitive to inhibition by probenecid. Urinary recovery of unchanged hydrochlorothiazide averages about 70% after oral administration and over 90% after IV administration. Biliary excretion is not thought to be significant. Hydrochlorothiazide apparently does not undergo significant metabolism; however, an unidentified nonrenal excretion mechanism apparently is active in patients with severe renal failure. [R34] *Oral availability= 71 + or - 15%; urinary excretion > 95%; bound in plasma= 58 + or - 17%. [R35, 1684] *Renal clearance = 4.9 + or - 1.1 ml/min/kg; decreases in uremia, in congestive heart failure and in the aged. [R35, 1684] *Volume of distribution = 0.83 + or - 0.31 l/kg. [R35, p. 1684] *BENZOTHIADIAZINE DIURETICS, CHLOROTHIAZIDE AND HYDROCHLOROTHIAZIDE, ARE METABOLICALLY STABLE AND FOLLOWING IV ADMIN TO DOGS, RATS AND HUMANS, THEY ARE EXCRETED UNCHANGED IN URINE. [R36] METB: *... HYDROCHLOROTHIAZIDE, /IS/ METABOLICALLY STABLE AND FOLLOWING IV ADMIN TO DOGS, RATS AND HUMANS, /IS/ EXCRETED UNCHANGED IN URINE. [R36] BHL: *THE PHARMACOKINETICS OF HYDROCHLOROTHIAZIDE IN PLASMA COULD BE DESCRIBED IN TERMS OF A TRIEXPONENTIAL FUNCTION, AND THE MEAN HALF-LIFE DETERMINED FROM THE 3 EXPONENTS WERE 1.0, 2.2, and 9.0 HR. [R32] *2.5 + or - 0.2 hr; increases in uremia, incongestive heart failure and in aged. [R35, 1684] ACTN: *... BENZOTHIADIAZIDES HAVE DIRECT EFFECT ON RENAL TUBULAR TRANSPORT OF SODIUM AND CHLORIDE INDEPENDENT OF CARBONIC ANHYDRASE INACTIVATION. ... HAVE PARALLEL DOSE-RESPONSE CURVES AND COMPARABLE MAX CHLORURETIC EFFECTS. /BENZOTHIADIAZIDES/ [R37, 828] *RENAL ACTIONS OF THIAZIDE DIURETICS DECR EXTRACELLULAR FLUID AND PLASMA VOL, CARDIAC OUTPUT, AND TOTAL EXCHANGEABLE SODIUM IN INDIVIDUALS WITHOUT ANY EVIDENCE OF CARDIAC FAILURE. ... SODIUM AND WATER DEPLETION ... BASIS FOR ANTIHYPERTENSIVE EFFECT. ... DIURETIC THIAZIDES RELAX PERIPHERAL ARTERIOLAR SMOOTH MUSCLE. /BENZOTHIADIAZIDES/ [R37, 712] *HYDROCHLOROTHIAZIDE PRODUCED ELEVATED PLASMA ALDOSTERONE AND RENIN LEVELS AND THIS IS THE PRINCIPAL CAUSE OF HYPOKALEMIA IN UP TO 70% OF PATIENTS SO TREATED. THE MECHANISM OF THE OBSERVED SECONDARY ALDOSTERONISM IS DISCUSSED. AMILORIDE RESTORED THE K BALANCE IN PATIENTS WITH PRIMARY ALDOSTERONISM AND CAN BE USED TO AVOID OR TREAT DIURETIC-INDUCED HYPOKALEMIA, AND AVOID THE APPARENT RISKS OF MYOCARDIAL IRRITABILITY AND VENTRICULAR ECTOPIC ACTIVITY IN PATIENTS WITH HYPOKALEMIA. [R38] *The exact mechanism of the diuretic effect of hydrochlorothiazide is not fully understood. Bioelectric studies suggested a direct inhibition of sodium ion reabsorption in the toad bladder and studies of the effects of hydrochlorothiazide on ion movement in the isolated rabbit distal colon suggested specific inhibition of chloride absorption. In micropuncture studies, chloride transport in the medullary collecting duct of the rat kidney was almost completely inhibited by hydrochlorothiazide. To examine the effect of hydrochlorothiazide on Na+ -K+ ATPase activity in seven separate segments along the nephron of spontaneously hypertensive rats and the normotensive control rats. Hydrochlorothiazide was administered at 15 mg/kg for 7 days by an osmotic minipump. Individual nephron segments then were dissected from the kidney and ouabain-sensitive Na+ -K+ ATPase activity was determined. Activity in the normotensive strain was decreased by hydrochlorothiazide administration in the distal convoluted tubule and was increased in the cortical collecting duct. Hydrochlorothiazide decreased Na+ -K+ ATPase activity in all but the proximal straight tubule and medullary collecting duct in the spontaneously hypertensive strain. [R39] *Renal effects of hydrochlorothiazide include increased renin release and increased release of kallikrein. Renin is an enzyme released from the juxtaglomerular apparatus, which is active in the formation of angiotensin I in the blood stream. Angiotensin I is converted to angiotensin II by angiotensin I-converting enzyme in the vasculature in the lung. One of the actions of angiotensin II is to stimulate secretion of aldosterone from the adrenal cortex. Aldosterone acts on the distal convoluted tubule and collecting duct to promote sodium ion reabsorption and potassium ion secretion. This action acts to temper the diuresis induced by hydrochlorothiazide. Prostaglandin biosynthesis is thought to be involved in the increase in renin release in response to loop diuretics such as furosemide, but the renal effects of hydrochlorothiazide do not appear to be mediated by prostaglandins. ... Kallikrein in a protease purportedly released from the kidney and is involved in the formation of vasoactive kinins, including the vasodilator bradykinin. Urinary kallikrein activity was increased in hypertensive volunteers after 2 wk of daily dosing with 50 mg hydrochlorothiazide followed by 2 wk of daily dosing with 100 mg hydrochlorothiazide. This action may be important in the efficacy of hydrochlorothiazide therapy for hypertension. [R39] *Carbonic anhydrase 50% inhibition in vitro at 2x10-5 M. [R35, 720] INTC: *ENTERIC COATED POTASSIUM SUPPLEMENTS GIVEN IN COMBINATION WITH BENZOTHIADIAZIDES MAY LEAD TO ULCERATION OF SMALL BOWEL. /BENZOTHIADIAZIDE DIURETICS/ [R40] *CHLOROTHIAZIDE MAY ENHANCE NEUROMUSCULAR BLOCKADE PRODUCED BY TUBOCURARINE BY CAUSING HYPOKALEMIA. /CHLOROTHIAZIDE/ [R41, 253] *PT RECEIVING CHLOROTHIAZIDE AND RELATED DIURETICS MAY DEVELOP ELECTROLYTE DISTURBANCES...WHICH MAY ENHANCE CARDIOTOXICITY OF DIGITALIS. /CHLOROTHIAZIDE AND RELATED DIURETICS/ [R41, 52] *MANY DIABETIC PT REGULATED BY CHLORPROPAMIDE OR OTHER SULFONYLUREAS EXHIBIT IMPAIRED DIABETIC CONTROL WHEN ANY THIAZIDE DIURETIC /HYDROCHLOROTHIAZIDE/ IS ADDED TO DRUG REGIMEN. [R41, 40] *... CONCURRENT ADMIN OF GUANETHIDINE AND HYDROCHLOROTHIAZIDE IS THERAPEUTICALLY USEFUL IN TREATMENT OF HYPERTENSION. THIAZIDES ENHANCE ANTIHYPERTENSIVE ACTION OF GUANETHIDINE. ... HYDROCHLOROTHIAZIDE ALSO IS USEFUL IN ELIMINATING SODIUM RETENTION, EDEMA, AND EVENTUAL RESISTANCE TO GUANETHIDINE'S ANTIHYPERTENSIVE EFFECT. [R41, 88] *... CORTICOSTEROIDS, CORTICOTROPIN AND AMPHOTERICIN B ALSO CAUSE POTASSIUM LOSS, AND SEVERE POTASSIUM /LOSS/ MAY OCCUR WHEN /ADMIN WITH THIAZIDES/. /THIAZIDES/ [R30] *SULFOBROMOPHTHALEIN RETENTION MAY BE INCREASED IN PATIENTS RECEIVING THIAZIDES, PROBABLY DUE TO DECREASE IN HEPATIC BLOOD FLOW SECONDARY TO DECREASED PLASMA VOLUME ... SPIRONOLACTONE OR TRIAMTERENE /WITH THIAZIDE/ DECREASE POTASSIUM LOSS AND POTENTIATE DIURETIC AND ... HYPOTENSIVE EFFECTS. /THIAZIDES/ [R30] *THIAZIDES MAY ANTAGONIZE EFFECTS OF ORAL ANTICOAGULANTS ... CHOLESTYRAMINE RESIN MAY BIND THIAZIDES AND PREVENT THEIR ABSORPTION FROM GI TRACT. ... A DECREASE IN ARTERIAL RESPONSIVENESS TO VASOPRESSORS HAS BEEN REPORTED DURING THIAZIDE THERAPY. /THIAZIDES/ [R30] *EIGHTEEN PATIENTS WITH LOW RENIN HYPERTENSION WERE TREATED INITIALLY WITH EITHER CAPTOPRIL ALONE (450 MG/DAY) OR HYDROCHLOROTHIAZIDE (UP TO 100 MG/DAY). CAPTOPRIL ALONE ONLY REDUCED AVERAGE PLACEBO STANDING BLOOD PRESSURE FROM 151/100 TO 146/96 MM HG. COMBINATION OF THE TWO REDUCED AVERAGE STANDING BLOOD PRESSURE TO 111/76 MM HG AT 3 MO AND 116/81 MM HG AT 1 YR WHILE ALLOWING REDUCTIONS IN AVERAGE CAPTOPRIL DOSAGE TO 100 MG/DAY AND HYDROCHLOROTHIAZIDE DOSAGE TO 40 MG/DAY. [R42] *THEEFFECT OF CHOLESTYRAMINE AND COLESTIPOL ON THE ABSORPTION OF A SINGLE ORALLY ADMIN DOSE OF HYDROCHLOROTHIAZIDE (75 MG) WAS DETERMINED. BOTH DECREASED THE TOTAL URINARY EXCRETION OF HYDROCHLOROTHIAZIDE 85% and 45%, RESPECTIVELY. SIMILAR EFFECTS WERE NOTED IN PLASMA LEVELS. [R43] *Administration of hydrochlorothiazide and ketoprofen reduced urinary potassium and chloride excretion more than hydrochlorothiazide alone. [R44, 1712] *Diflunisal decreases the hyperuricemic effect of furosemide and hydrochlorothiazide. It has no effect on diuretic activity of furosemide but significantly increases levels of hydrochlorothiazide. [R44, p. 1706] *... When given in association with carbonic anhydrase inhibitors, attention should be paid to the possibility of inducing hypokalemia. [R19] *This multicenter, factorial design trial assessed the safety and additive antihypertensive efficacy of a slow release formulation of diltiazem hydrochloride given alone or in combination with hydrochlorothiazide for treatment of mild to moderate hypertension. After a 4 to 6 wk placebo run-in period, 297 qualifying patients were randomized to receive placebo, 1 of 4 doses of diltiazem slow release monotherapy, 1 of 3 doses of hydrochlorothiazide monotherapy, or 1 of 12 possible combinations of diltiazem slow release and hydrochlorothiazide for 6 wk. A dose related reduction i blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination. Absolute blood pressures of patients who received combination therapy were lower by an overall mean of 3.0 mm Hg diastolic and 8.0 mm Hg systolic vs diltiazem slow release used alone and 3.5 mm Hg diastolic and 4.0 mm Hg systolic vs hydrochlorothiazide used alone. At the largest doses used, 50% of patients achieved goal blood pressure whil taking hydrochlorothiazide, 57% while taking diltiazem slow release, and 75% while taking combination therapy. Combination therapy was well tolerated. This trial clearly demonstrates that diltiazem slow release and hydrochlorothiazide have additive antihypertensive effects. [R45] *In this placebo controlled, randomized double blind, parallel study the effects of the fixed captopril 50 mg + hydrochlorothiazide 25 mg combination on plasma lipids were assessed in 42 hypertensive, type IIa or IIb hyperlipidaemic patients on diets. Some patients received oral hypolipidaemic treatment and some did not. Blood pressure and plasma lipids levels were measured before and after 1, 2 and 3 mo of treatment. From the first mo onward blood pressure decreased more in the treated group than in the placebo group (p < 0.05). Neither the combination nor the placebo altered the following parameters of lipid metabolism: total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides, apolipoprotein A1 and apolipoprotein B. The combination was well tolerated; 2 patients in each group had one or several adverse events. The results of thi study show that treatment with the captopril-hydrochlorothiazide combination in hypertensive, hyperlipidaemic patients has no influence on the normolipidaemic effects of diet and lipid lowering treatment. [R46] *A randomized, double blind multicenter trial was conducted in 146 hypertensive patients to compare the safety and efficacy of: (a) isradipine, 2.5-10 mg given twice daily as oral capsules; (b) hydrochlorothiazide, 25-50 mg given once daily as oral capsules; (c) combined therapy with isradipine and hydrochlorothiazide. Patients with a diastolic blood pressure > 90 mm Hg after 10 wk of active treatment with isradipine or hydrochlorothiazide were given the combination regimen for an additional 10 wk. Blood pressure, ECG and laboratory parameters were evaluated periodically during the study. Isradipine and hydrochlorothiazide monotherapies were equally effective in reducing blood pressure. Both combination therapies (isradipine added to hydrochlorothiazide and hydrochlorothiazide added to isradipine) further lowered blood pressures; no difference between the 2 combination therapies was found. Isradipine produced more adverse effects and changes in laboratory and ECG values than hydrochlorothiazide. It was concluded that 2.5-10 mg daily of isradipine lowers blood pressure as effectively as 25-50 mg daily of hydrochlorothiazide; however, isradipine is associated with a higher rate of adverse effects than hydrochlorothiazide. Converting monotherapy to combined therapy will produce additional blood pressure reductions. [R47] *The combination of captopril and hydrochlorthiazide was assessed in 15 hypertensive patients in a general practice setting. The first aim was to determine whether the fall in blood pressure, noted after the first dose of an angiotensin converting enzyme inhibitor given alone, became unacceptable when the drug was given with a diuretic. The second aim was to assess the impact of the angiotensin converting enzyme inhibitor on the biochemical abnormalities associated with thiazide diuretic therapy. The drug combination markedly reduced blood pressure but not below 110 systolic after the first dose. In the long term the treatment significantly lowered blood pressure but did not produce any significant or clinically relevant changes in serum chemistry. [R48] *This study examined the interaction between lithium and diuretics, comparing both the pharmacokinetic and the pharmacodynamic variable of hydrochlorothiazide, furosemide, and placebo. The study, which took place in an outpatient research clinic of a university hospital, used a double blind, placebo controlled crossover design. The subjects were normal, healthy male volunteers wh responded to recruitment announcements. Thirteen subjects entered and completed the study. All subjects took lithium, 300 mg twice a day, for 6 wk. Hydrochlorothiazide, 25 mg twice a day; furosemide, 20 mg twice a day; and placebo were given during wk 2, 4, and 6 in a random order of assignment. Serum lithium levels and indices of diuretic activity were measured during each wk. The subjects' serum lithium levels after 5 days of taking hydrochlorothiazide were significantly higher than after 5 days of taking furosemide and placebo. At the doses studied, hydrochlorothiazide was also more potent than furosemide in increasing plasma renin activity, increasing sodium excretion, and decreasing lithium excretion. The observed differences between diuretics in effects on serum lithium may have been due to differences in the potency of the diuretics at the doses studied as well as in the site of action of the diuretic effect. The results must be interpreted cautiously, however, because the effects were small and of questionable clinical significance, and the study used healthy volunteers and low doses of lithium instead of psychiatric patients and the usual therapeutic levels of lithium. [R49] *In this study the efficacy and tolerability of the preconstituted association captopril 50 mg + hydrochlorothiazide 25 mg were evaluated in open, for a six mo period, in a population of 201 aged patients affected by isolated systolic hypertension. The results showed a good antihypertensive efficacy of the association captopril-hydrochlorothiazide 25 mg and also an optimal safety of use. [R50] *The efficacy and safety of 50 mg captopril in combination with 25 mg hydrochlorothiazide, administered once to twice daily, in the treatment of mild to moderate essential hypertension were evaluated in 74 patients (mean age, 62.2 yr). Blood pressure was well controlled with the lowest dosage in 65 patients and normalization was achieved in 60 patients. Both captopril and hydrochlorothiazide were well tolerated; only 9.4% reported side effects. No change was observed in biochemical parameters or heart rate. The study indicated that the combination of captopril and hydrochlorothiazide can be usefully employed in the treatment of essential hypertension, without undesirable metabolic effects. [R51] *A randomized, double blind, 4x3 factorial, modified fixed dose multicenter study was conducted to determine dose effect and concn effect relationships for pinacidil and hydrochlorothiazide in 384 patients with essential hypertension who received all combinations of 4 doses of pinacidil (0, 12.5, 25, and 37.5 mg, twice daily) with 3 doses of hydrochlorothiazide (0, 12.5, 25 mg, twice daily). Significant dose and concn effect relationships were seen for pinacidil and hydrochlorothiazide on diastolic blood pressure. For pinacidil, dose and concn effect relationships were steeper after the dose than before the dose. A significant interaction with hydrochlorothiazide was noted such that, when combined with 12.5 mg hydrochlorothiazide, 12.5 mg pinacidil had near maximal effects on blood pressure at both peak an trough. Edema occurred in 47% of patients who received 37.5 mg pinacidil monotherapy. It was concluded that 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appeared to be optimal for efficacy and safety. [R52] *A randomized study of the pharmacokinetics of enalapril and hydrochlorothiazide was conducted in 12 healthy subjects (ages 21-26 yr) who received an oral tablet of 10 mg enalapril and 25 mg hydrochlorothiazide separately, simultaneously, or combined in one tablet. Hydrochlorothiazide was bioequivalent under all conditions and enalapril was bioequivalent when given with hydrochlorothiazide in one or separate tablets. When enalapril was given alone, mean area under the concn time curve and maximum concn of its active metabolite, enalaprilat, were up to 20% higher than when given with hydrochlorothiazide. However, this difference was not statistically significant and total enalaprilat excreted in urine over 96 hr was similar for all treatments. It was concluded that enalapril and hydrochlorothiazide in a combination tablet are bioequivalent to the drugs given simultaneously in separate tablets. [R53] *This study compared enalapril maleate (Enaprin) as a single antihypertensive agent and enalapril plus hydrochlorothiazide in Korean patients to determine if one regimen is superior to the other in terms of efficacy and subjective adverse effects. After a 1 wk washout period, 12 patients were randomized to receive enalapril 10 mg daily and 13 patients to receive enalapril 10 mg daily plus hydrochlorothiazide 25 mg daily. After 2 wk, enalapril was increased to 20 mg daily if diastolic blood pressure was greater than 90 mm Hg. The study period was 12 wk. The mean changes in diastolic blood pressure in mm Hg were enalapril alone -10.7 + or - 10.5 mm Hg and enalapril plus hydrochlorothiazide -25.1 + or - 12.1 mm Hg (difference between the two groups significant at p < 0.01). Mean dose of enalapril required to achieve goal blood pressure was 18.8 mg for monotherapy and 13.0 mg for combination therapy (p < 0.05). Adverse effects were comparable. It was concluded that enalapril in combination with hydrochlorothiazide is more effective and safe, and allows for lower dosing of enalapril than the drug as monotherapy in Korean hypertensives. [R54] *The effect of hydrochlorothiazide, a diuretic which is used in the treatment not only of edema but also of hypertension, on coughs associated with treatment with enalapril was studied in guinea pigs. Chronic treatment with enalapril markedly and dose dependently enhanced the number of capsaicin induced coughs. However, chronic treatment with hydrochlorothiazide significantly reduced the number of coughs associated with enalapril treatment, also in a dose dependent manner. These results suggest that diuretics might be used to reduce the coughing associated with treatment with inhibitors of angiotensin converting enzyme in patients with hypertension. [R55] *Carvedilol has been shown to be effective and safe in patients with essential hypertension when given as monotherapy. In this double blind, randomized, group comparative study, 2 groups of 59 patients with mild to moderate essential hypertension (median supine systolic/diastolic blood pressure at baseline, 168/105 mm Hg) were treated with either 25 mg carvedilol once daily or 50 mg atenolol once daily for 4 wk. Responders at 4 wk (diastolic blood pressure at baseline, less than 90 mm Hg) terminated the study. Nonresponders continued the study. Hydrochlorothiazide was added at 25 mg once daily for a further 6 wk. The median blood pressure decreased under monotherapy with carvedilol (n = 59) from 167/105 at baseline to 155/94 mm Hg after 4 wk, and in the atenolol group (n = 59) it decreased from 168/105 to 162/97 mm Hg. The patients who received carvedilol in combination with hydrochlorothiazide and were evaluated for efficacy (n = 38) showed a decrease in median supine systolic/diastolic blood pressure at baseline from 156/97 at the end of monotherapy to 145/88 mm Hg after 10 wk; the combination of atenolol with hydrochlorothiazide (n = 44) reduced blood pressure from 162/97 to 147/88. Both carvedilol and atenolol were safe when given either alone or in combination with hydrochlorothiazide. In conclusion, after long term administration, 25 mg carvedilol once daily and 50 mg atenolol once daily significantly reduced both median supine systolic and diastolic blood pressure at baseline over 24 hr. The addition of hydrochlorothiazide led to a further increase in antihypertensive efficacy. Combined treatment with carvedilol or atenolol and hydrochlorothiazide was very well tolerated, without hypotensive events or relevant changes in objective safety parameters. [R56] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antihypertensive Agents; Diuretics, Thiazide [R57] *THIAZIDE DRUGS ... USUALLY FIRST DRUG TO BE EMPLOYED IN TREATMENT OF HYPERTENSION. SINCE THIAZIDES INDUCE ONLY LIMITED (10%) REDN IN BLOOD PRESSURE THEY ARE USEFUL EITHER IN MILD CASES OF HYPERTENSION OR AS ADJUNCTIVE THERAPY TO OTHER DRUGS. THIAZIDE DIURETICS ARE EFFECTIVE AS ADJUNCTIVE THERAPY IN EDEMA ASSOC WITH CONGESTIVE HEART FAILURE, HEPATIC CIRRHOSIS, AND CORTICOSTEROID AND ESTROGEN THERAPY, AS WELL AS EDEMA DUE TO VARIOUS FORMS OF RENAL DYSFUNCTION ... . /THIAZIDES/ [R6, 878] *A PATIENT WITH HYPERCALCIURIA WAS TREATED WITH HYDROCHLOROTHIAZIDE, 100 MG/DAY. ON THE 3RD DAY THE URINARY CALCIUM DROPPED FROM A PRETREATMENT VALUE OF 416 TO 55 MG/24 HR. [R58] *Hydrochlorothiazide has been evaluated for use in lessening sodium and water retention in conditions of preeclampsia during pregnancy. Although prophylactic use of hydrochlorothiazide apparently does not prevent preeclampsia, some benefit may be derived when hydrochlorothiazide is administered during the second trimester to pregnant women with underlying hypertension. [R18] *Indicated in the management of hypertension, and as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Is also useful in edema due to various forms of renal dysfunction such as nephrotic syndrome. [R3] *This multicenter study was designed to assess the clinical efficacy and safety of the new once-daily calcium antagonist lacidipine in the treatment of mild to moderate essential hypertension. Patients were randomly assigned to receive, double blind, either lacidipine (n = 180) or hydrochlorothiazide (n = 182) following a 1 mo placebo run-in period. Both drugs were titrated after 1 mo if blood pressure was not controlled: lacidipine, from 4 to 6 mg once daily; hydrochlorothiazide, from 25 to 50 mg once daily. Atenolol was added later if necessary to achieve blood pressure control. Lacidipine and hydrochlorothiazide were equally effective in controlling the blood pressure levels in the majority of patients (approximately 90% after 4 mo). Adverse events were those to be expected with these classes of drug and were reported in 48 (26.7%) of the patients receiving lacidipine treatment and in 34 (18.7%) of those receiving hydrochlorothiazide. The diuretic produced a significantly higher incidence of hypokalemia. [R59] *A double blind, randomized, multicenter study was conducted to compare the safety and efficacy of nicardipine and hydrochlorothiazide in 151 patients (aged 24-74 yr) with essential hypertension who received 30 mg nicardipine 3 times daily or 25 mg hydrochlorothiazide twice daily. After 4 wk, nicardipine reduced arterial pressure by 10/6 mm Hg and 12/6 mm Hg in the supine and standing positions, respectively. In the hydrochlorothiazide group, the reductions were 12/6 mm Hg and 14/6 mm Hg, respectively. The maximum reduction in blood pressure occurred within one hr after administration of nicardipine. Neither drug affected autonomic reflexes associated with maximum exercise. Although adverse effects were twice as common with nicardipine, most symptoms were mild and easily tolerated, including flushing, headach and edema. [R60] WARN: *THIAZIDE DIURETICS ARE CONTRAINDICATED IN ANURIA, PATIENTS HYPERSENSITIVE TO THESE AND OTHER SULFONAMIDE DRUGS, AND IN OTHERWISE HEALTHY PREGNANT WOMEN WITH OR WITHOUT MILD EDEMA. ... SHOULD BE USED WITH CAUTION IN PATIENTS WITH RENAL DISEASE, SINCE THEY MAY PPT AZOTEMIA. ... USE WITH CAUTION IN PATIENTS WITH IMPAIRED LIVER FUNCTION, DIABETES, GOUT OR HISTORY OF LUPUS ERYTHEMATOSUS. /BENZOTHIADIAZINE DIURETICS/ [R6, 878] *PLASMA POTASSIUM CONCN SHOULD BE DETERMINED PERIODICALLY IN PATIENTS WHO RECEIVE THIAZIDE DIURETICS FOR EXTENDED PERIODS. /BENZOTHIADIAZIDES/ [R37, 832] *USE OF HYDROCHLOROTHIAZIDE IN GLAUCOMA DOES MERIT CAUTION. ... IN PRESENCE OF GLAUCOMATOUSLY ELEVATED INTRAOCULAR PRESSURE, IT APPEARS TO BE DISADVANTAGEOUS TO OPTIC NERVE TO REDUCE SYSTEMIC BLOOD PRESSURE EXCESSIVELY BY ANY AGENT. [R61] *CLINICAL TOXICITY ... USUALLY RESULTS FROM UNEXPECTED HYPERSENSITIVITY. CASES OF PURPURA, DERMATITIS WITH PHOTOSENSITIVITY, DEPRESSION OF FORMED ELEMENTS OF BLOOD, ACUTE PANCREATITIS AND NECROTIZING VASCULITIS ... REPORTED. /BENZOTHIADIAZIDES/ [R35, 721] *PLASMA URIC ACID IS FREQUENTLY ELEVATED. ... BORDERLINE RENAL AND/OR HEPATIC INSUFFICIENCY MAY BE UNPREDICTABLY AGGRAVATED BY THIAZIDES. ... THIAZIDES MAY INDUCE HYPERGLYCEMIA AND AGGRAVATE PREEXISTING DIABETES MELLITUS. /BENZOTHIADIAZIDES/ [R35, 721] *DISTAL TUBULE DIURETICS, INCL HYDROCHLOROTHIAZIDE, INCREASED URINARY OUTPUT OF ZINC THROUGH A POORLY UNDERSTOOD MECHANISM WHICH COULD INVOLVE BOTH DIRECT AND HORMONE-MEDIATED PROCESSES. SIGNIFICANT ZN DEPLETION MAY OCCUR DURING LONG-TERM ADMIN OF DISTAL TUBULE DIURETICS PRINCIPALLY IN CONDITIONS ASSOCIATED WITH DIMINISHED TOTAL BODY ZINC LEVELS SUCH AS HEPATIC CIRRHOSIS, DIABETES MELLITUS, GASTROINTESTINAL DISORDERS, AND SEVERAL RENAL DISEASES. [R62] *May cause hypokalemia, and serum potassium levels should be determined periodically. Reduction in potassium levels may increase the action and toxicity of digoxin and related glycosides. Concurrent use with lithium is best avoided because of an increased risk of lithium toxicity. May cause hyperglycemia dn hyperuricemia, and therapy in patients having diabetes or gout should be closely monitored. [R3] *Some commercially available formulations of hydrochlorothiazide contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. [R2, 1612] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R63] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl hydrochlorothiazide, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. [R64] *Hydrochlorothiazide injectable. Implantation or injectable dosage form new animal drugs not subject to certification. Specifications and conditions of use are provided. [R65] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *BENZOTHIAZIDE DIURETICS WAS SEPARATED BY TLC WITH SILICA GEL G OR ALUMINUM OXIDE. THE SPOTS ON AIR DRIED PLATES WERE REVEALED WITH 0.25% METHANOL SOLN OF FLUORESCEIN UNDER UV LIGHT (DETECTION LIMIT 2-5 UG DRUG). [R66] *Hydrochlorothiazide is determined by comparison with standards, using LC method with ultraviolet detection and theobromine internal standard. [R67] CLAB: *A GLC METHOD FOR DETERMINATION OF HYDROCHLOROTHIAZIDE IN PLASMA WAS TESTED IN VITRO AND IN HUMANS. PRECISION WAS DEMONSTRATED OVER THE 5-648 NG/ML RANGE AND WAS LINEAR FOR 5-250 NG/ML RANGE. [R68] *FLUOROMETRICDETERMINATION OF HYDROCHLOROTHIAZIDE IN BODY FLUIDS BY DIRECT MEASUREMENT OF TLC PLATES. [R69] *HYDROCHLOROTHIAZIDE IN PLASMA AND URINE WAS DETERMINED BY HPLC. [R70] *ANALYTICAL METHOD IS PRESENTED WHICH INVOLVES THE EXTRACTION OF THIAZIDE DIURETICS FROM LIVER TISSUE HOMOGENATE, FOLLOWED BY INITIAL SCREENING WITH SENSITIVE BUT NONSPECIFIC COLORIMETRIC TEST, AND THEN IDENTIFICATION AND CONFIRMATION WITH TLC AND GC. QUANTITATION IS DONE BY DERIVATIZING THE THIAZIDE AND INJECTING IT ON GLC. [R71] *HUMAN URINE SAMPLES WERE ANALYZEDFOR THIAZIDE DIURETICS USING HPLC SYSTEM EQUIPPED WITH REVERSE PHASE COLUMN, A VARIABLE WAVELENGHT DETECTOR, OR A FLUORESCENCE DETECTOR. RECOVERY WAS ABOUT 100% AND THE PRECISION OF THE METHOD WAS GOOD. [R72] *AN AUTOMATED HPLCSYSTEM FOR DETERMINING HYDROCHLOROTHIAZIDE IN SERUM OR PLASMA IS DESCRIBED. TECHNIQUE IS BASED ON SEGMENTED STREAM, CONTINUOUS FLOW SAMPLE PREPN COUPLED TO LC. DETECTION IS AT 272 NM. [R73] *Determination of hydrochlorothiazide in urine using TLC on silica gel. [R74] *A rapid, sensitive and specific HPLC method with UV detection is described for the determination of hydrochlorothiazide in human plasma. The method was used to analyze the drug plasma concn from volunteers following oral administration of 12.5 and 25 mg doses of the drug. [R75] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW ON THE DETERMINATION, PREPARATION AND METABOLISM OF HYDROCHLOROTHIAZIDE. [R76] DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice Technical Report Series No. 357 (1989) NIH Publication No. 89-2812 Welling PG; Pharmacokinetics of the Thiazide Diuretics. Biopharm Drug Dispos 7 (Nov-Dec): 501-35 (1986). The chemical and physical properties of the thiazide diuretics are briefly discussed, and a review of their pharmacokinetics is presented, with emphasis on chlorothiazide, hydrochlorothiazide, bendroflumethiazide, hydroflumethiazide, bemetizide, trichlormethiazide, polythiazide, benzthiazide and cyclopenthiazide. Sullivan TJ; Cross-reactions Among Furosemide, Hydrochlorothiazide, and Sulfonamides. JAMA 265 (Jan 2): 120-1 (1991). Immunologic data regarding cross-reactions among furosemide Lasix, hydrochlorothiazide, and sulfonamides are discussed. Kavaru MS et al; Hydrochlorothiazide-Induced Acute Pulmonary Edema. Cleve Clin J Med 57 (2): 181-4 (1990). Hydrochlorothiazide induced acute pulmonary edema has been reported rarely. A case report and review the 16 previously described cases is presented. SO: R1: SRI R2: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). R3: Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 81 R4: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 758 R5: TAMAT SR, MOORE DE; J PHARM SCI 72 (2): 180 (1983) R6: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R7: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 756 R8: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.520 R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 752 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 50 301 (1990) R11: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1259 (1992) R12: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. R13: VILA JM ET AL; JAMA 236 (OCT 11): 1723 (1976) R14: DORN MR, WALKER BK; CHEST 79 (4): 482 (1981) R15: SOERGEL F ET AL; METHODS CLIN PHARMACOL (PROC INT SYMP) 340: (1980) R16: ROSEN K, SWANBECK G; ACTA DERM- VENEREOL 62 (3): 246 (1982) R17: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.16 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812 R18: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.17 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812 R19: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 490 R20: Garcia MJ et al; Conn Med 56 (4): 185-6 (1992) R21: Biron P et al; Can Med Assoc J 145 (1): 28-34 (1991) R22: Nielsen-Kudsk JE et al; Ugeskr Laeger 153 (11): 791-2 (1991) R23: Shieh CM et al; Chung Hua I Hsueh Tsa Chih 50 (6): 495-9 (1992) R24: Witkowska M et al; Kardiol Pol 34 (3): 143-50 (1991) R25: Shepard, T. H. Catalog of Teratogenic Agents. 3rd ed. Baltimore, MD.: Johns Hopkins University Press, 1980. 169 R26: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p. 16 (1989) Technical Rpt Series No. 357 NIH Pub No. 89-2812 R27: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.4 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812 R28: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.5 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812 R29: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 59 R30: American Society of Hospital Pharmacists. Data supplied on contract from American Hospital Formulary Service and other current ASHP sources. 1975 R31: BEERMAN B ET AL; CLIN PHARMACOL THER 19 (MAY): 531 (1976) R32: BARBHAIYA RH ET AL; J PHARM SCI 71 (2): 245 (1982) R33: BEERMANN B ET AL; GYNECOL OBSTET INVEST 11 (1): 45 (1980) R34: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.14 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812 R35: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R36: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 183 R37: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R38: MELBY JC; INT CONGR SYMP SER- R SOC MED 44(ARRHYTHMIAS MYOCARD INFARCTION: ROLE POTASSIUM) 55 (1981) R39: DHHS/NTP; Toxicology and Carcinogenesis Studies of Hydrochlorothiazide in F344/N Rats and B6C3F1 Mice (Feed Studies) p.15 (1989) Technical Rpt Series No.357 NIH Pub No. 89-2812 R40: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-239 R41: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R42: HOLLAND OB ET AL; HYPERTENSION 5 (2): 235 (1983) R43: HUNNINGHAKE DB ET AL; INT J CLIN PHARMACOL THER TOXICOL 20 (4): 151 (1982) R44: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. R45: Burris JF et al; JAMA 263 (11): 1507-12 (1990) R46: Buxtorf JC et al; Presse Med 21 (25): 1146-9 (1992) R47: Carlsen JE, Kober L; Drug Invest 2 (1): 10-6 (1990) R48: Clarke PF et al; J Clin Pharm Ther 16 (5): 361-6 (1991) R49: Crabtree BL et al; Am J Psychiatry 148 (8): 1060-3 (1991) R50: Ferroni C et al; Riv Eur Sci Med Farmacol 14 (1): 39-44 (1992) R51: Giuntoli F et al; Adv Ther 6 (Mar-Apr): 80-6 (1989) R52: Goldberg MR et al; Clin Pharmacol Ther 46 (Aug): 208-18 (1989) R53: Howes LG et al; Biopharm Drug Dispos 12 (Aug-Sep): 447-55 (1991) R54: Jones DW, Sands CD; Pharmacotherapy 11 (2): 127-30 (1991) R55: Kamei J, Kasuya Y; Eur J Pharmacol 213 (1): 137-9 (1992) R56: Widmann L et al; Eur J Clin Pharmacol 38 (Suppl 2): S143-6 (1990) R57: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R58: SALTI IS, HEMADY K; NEPHRON 25 (5): 222 (1980) R59: Chiariello M; J Cardiovasc Pharmacol 17 (Suppl 4): S35-7 (1991) R60: Fagan TC et al; Clin Pharmacol Ther 45 (Apr): 429-38 (1989) R61: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 557 R62: REYES AJ ET AL; S AFR MED J 62 (11): 373 (1982) R63: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91) R64: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-339 (1992) R65: 21 CFR 522.1150 (4/1/91) R66: MISZTAL G ET AL; PHARMAZIE 38 (1): 67 (1983) R67: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. V1 570 R68: REDALIEU E ET AL; J PHARM SCI 67 (MAY): 726 (1978) R69: SCHAFER M ET AL; J CHROMATOGR BIOMED APPL 143 (NOV 1): 615 (1977) R70: BARBHAIYA RH ET AL; J PHARM SCI 70 (3): 291 (1981) R71: MERRIKEN RA; AVIAT, SPACE ENVIRON MED 51 (9): 996 (1980) R72: SHAH VP ET AL; ANAL LETT 15 (B6): 529 (1982) R73: WEINBERGER R, PIETRANTONIO T; ANAL CHIM ACTA 146: 219 (1983) R74: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975.,p. V1 441 R75: Azumaya CT; J Chromatogr Biomed Appl 532 (Oct 26): 168-74 (1990) R76: DEPPELER HP; ANALYTICAL PROFILES OF DRUG SUBSTANCES. HYDROCHLOROTHIAZIDE. ANAL PROFILES DRUG SUBST 10: 405 (1981) RS: 67 Record 220 of 1119 in HSDB (through 2003/06) AN: 3126 UD: 200211 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYLPHENIDATE- SY: *CALOCAIN-; *CENTEDEIN-; *CENTEDRIN-; *4311/B-CIBA-; *MERIDIL-; *METHYLPHENIDAN-; *METHYL-PHENIDATE-; *METHYL-PHENIDYLACETATE-; *METHYL ALPHA-PHENYL-ALPHA-(2-PIPERIDYL)ACETATE; *NCI-C56280-; *PHENIDYLATE-; *ALPHA-PHENYL-2-PIPERIDINEACETIC-ACID-METHYL-ESTER-; *ALPHA-PHENYL-ALPHA-(2-PIPERIDYL)ACETIC ACID METHYL ESTER; *2-PIPERIDINEACETIC-ACID,-ALPHA-PHENYL-,-METHYL-ESTER-; *PLIMASINE-; *RITALIN-; *RITALINE-; *RITCHER-WORKS- RN: 113-45-1 MF: *C14-H19-N-O2 ASCH: Methylphenidate hydrochloride; 298-59-9 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepn: L. Panizzon, Helv Chim Acta 27, 1748 (1944); M. Hartmann, L.Panizzon, U.S. pat 2,507,631 (1950 to Ciba). [R1] FORM: *Oral: tablets: 5 mg, 10 mg, 20 mg; extended release tablets: 20 mg. /Methylphenidate hydrochloride/ [R2, 1913] MFS: *Mallinckrodt Inc., Hq, 16305 Swingley Ridge Drive, Chesterfield, MO 63017-1777, (314) 530-2000; Pharmaceutical Chemicals Division, Hq, 100 Louis Latzer Drive, Greenville, IL 62246, (606) 664-2111; Production site: 2nd and Mallinckrodt Streets, St. Louis, MO 63147. /Methylphenidate Hydrochloride/ [R3] *Novartis Corporation, Hq, 556 Morris Avenue, Summit, NJ 07901 908) 277-5000; Pharmaceuticals Division; Production site: 556 Morris Avenue, Summit, NJ 07901. /Methylphenidate Hydrochloride/ [R3] OMIN: *This is a controlled substance (stimulant) listed in the U.S. Code of Federal Regulations, Title 21 Part 1308.12 (1995). [R1] USE: *This is a drug of abuse. [R4] *MEDICATION (VET) *MEDICATION *THERAP CAT: CNS stimulant. [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: *135 to 137 deg C at 0.6 mm Hg [R1] MP: *74-75 DEG C [R5] MW: *233.31 [R1] DSC: *pKa = 8.77 [R6] OWPC: *log Kow= 0.20 @ pH 7.2 [R7] SOL: *SOL IN ALCOHOL, ETHYL ACETATE, ETHER [R1]; *PRACTICALLY INSOL IN WATER, PETROLEUM ETHER [R1]; *SOL IN CHLOROFORM [R8, 76] SPEC: *MAX ABSORPTION (ACID (SALT)) and (BASE (SALT)): 257 NM (A= 8, 1%, 1 CM) [R8, 272]; +Intense mass spectral peaks: 84 m/z, 91 m/z, 150 m/z [R9] OCPP: *ODORLESS; WHITE, FINE, CRYSTALLINE POWDER /METHYLPHENIDATE HYDROCHLORIDE/ [R10, 1078] *INDEX OF REFRACTION: 1.558 (ALPHA); 1.581 (BETA); 1.585 (GAMMA) /METHYLPHENIDATE HYDROCHLORIDE/ [R8, 312] *CRYSTALS FROM 50% ALCOHOL [R5] *Crystals, melting point 224 to 226 deg C. pKa 8.9. Soluble in water, alcohol, chloroform. A 5% aqueous solution is neutral to litmus. /HYDROCHLORIDE/ [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R11] STRG: *Methylphenidate hydrochloride tablets and extended release tablets should be stored in tight, light-resistant containers at a temperature less than 30 deg C. /Methylphenidate hydrochloride/ [R2, 1912] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *METHYLPHENIDATE ... SHARES ABUSE POTENTIAL OF AMPHETAMINES. [R12] *THE GROWTH IN HEIGHT AND WEIGHT OF 86 HYPERACTIVE CHILDREN RECEIVING METHYLPHENIDATE HYDROCHLORIDE (AVERAGE, 40 MG/DAY FOR UP TO 4 YEARS) WAS COMPARED WITH GENERAL POPULATION NORMS ON RECENTLY UPDATED GROWTH CHARTS. A SIGNIFICANT DECREASE IN HEIGHT PERCENTILE WAS APPARENT AFTER 2, 3, AND 4 YEARS OF TREATMENT BUT NOT AFTER ONE YEAR. [R13] *FOLLOWING TREATMENT WITH STIMULANT MEDICATIONS FOR SYMPTOMS OF ATTENTION DEFICIT DISORDER, GILLES DE LA TOURETTE'S SYNDROME OCCURRED IN 15 PATIENTS. [R14] *INCREASED SISTER CHROMATID EXCHANGES ARE OFTEN SEEN WHEN DNA DAMAGE IS KNOWN TO HAVE OCCURRED. IN THIS STUDY, SEVERAL COMMONLY USED PEDIATRIC DRUGS OF NO KNOWN MUTAGENICITY (INCLUDING METHYLPHENIDATE) WERE TESTED TO DETERMINE THEIR EFFECT ON SISTER CHROMATID EXCHANGE FORMATION IN HUMAN LYMPHOCYTES. CELLS FROM 4 PEDIATRIC SUBJECTS WERE GROWN FOR 66 HOURS IN THE PRESENCE OF 5'-BROMODEOXYURIDINE AND THERAPEUTIC LEVELS OF THE DRUGS. FOR TWO SUBJECTS, SMALL BUT SIGNIFICANT ELEVATIONS IN SISTER CHROMATID EXCHANGE FREQUENCY WERE CAUSED BY METHYLPHENIDATE. [R15] *The abuse of this drug involves both oral and intravenous use, most of the abuse involves the injection of tablets dissolved in water. Complication arising ... since the tablets contain insoluble materials, which when injected, block small blood vessels and cause serious damage ... in the lung and retina of the eye. [R16] *Methylphenidate, a mild CNS stimulant and antidepressant administered orally, was claimed in 1955 to cause a rise of ocular pressure in glaucomatous patients, but without discriminating as to type of glaucoma, and with no control comparisons without medications. [R17] *Acute toxicity due to methylphenidate overdosage results in symptoms similar to those of acute amphetamine intoxication and may be manifested by cardiovascular symptoms including flushing, palpitation, hypertension, cardiac arrhythmias, and tachycardia. Mental disturbances such as confusion, delirium, euphoria, hallucinations, and toxic psychosis may also occur. Other symptoms of overdosage include agitation, headache, vomiting, dryness of mucous membranes, mydriasis, hyperpyrexia, sweating, tremors, hyperreflexia, muscle twitching, and seizures which may be followed by coma. [R2, 1912] NTOX: *INTRAPERITONEAL /INJECTION OF METHYLPHENIDATE/ TO MICE /AT A/ DOSE OF 4 MG/KG SIGNIFICANTLY LOWERS BRAIN CHOLESTEROL /LEVEL/. [R18] *REPEATED IM INJECTIONS OF HIGH DOSES OF METHYLPHENIDATE (6-30 TIMES THE HUMAN CLINICAL DOSE) INTO NORMAL RATS OR RATS WITH TRAUMATIZED (CARBON TETRACHLORIDE OR ALLYL ALCOHOL) OR REGENERATING LIVERS WERE ABLE TO CAUSE LIVER DAMAGE, AS SHOWN BY LIVER FUNCTION TESTS AND SERUM ENZYME DETERMINATIONS. [R19] *Drug Discrimination: Generalization was obtained /in rats/ ... between ... d,l-amphetamine /and/ methylphenidate but not with atropine. [R20] *Behavioral Toxicity: In the squirrel monkey ... d-amphetamine and methylphenidate produce modest increases in masked auditory thresholds. [R20] *... CONCLUSIONS: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/N rats receiving 100, 500 or 1,000 ppm. There was some evidence of carcinogenic activity of methylphenidate hydrochloride in male or female B6C3F1 mice based on the occurrence of hepatocellular neoplasms. /Methylphenidate hydrochloride/ [R21] NTXV: *LD50 Mouse oral 190 mg/kg; [R5] *LD50 Rat ip 430 mg/kg; [R11] *LD50 Mouse ip 32 mg/kg; [R11] *LD50 Mouse sc 218 mg/kg; [R11] *LD50 Mouse iv 41 mg/kg; [R11] NTP: *... Toxicology and carcinogenicity studies were conducted by administering methylphenidate hydrochloride (USP grade) ad libitum in feed to groups of male and female F344/N rats and B6C3F1 mice for ... 2 years. ... 2 YR STUDY IN RATS: ... Groups of 70 male and 70 female F344/N rats were fed diets containing 0, 100, 500, or 1,000 ppm methylphenidate hydrochloride for up to 2 yr. ... 2 YEAR STUDY IN MICE: ... Groups of 70 male and 70 female B6C3F1 mice were fed diets containing 0, 50, 250, or 500 ppm methylphenidate hydrochloride for 2 yr. CONCLUSIONS: Under the conditions of these 2 yr feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/N rats receiving 100, 500 or 1,000 ppm. There was some evidence of carcinogenic activity of methylphenidate hydrochloride in male or female B6C3F1 mice based on the occurrence of hepatocellular neoplasms. /Methylphenidate hydrochloride/ [R21] ADE: *METHYLPHENIDATE IS READILY ABSORBED AFTER ORAL ADMINISTRATION AND REACHES PEAK CONCENTRATIONS IN PLASMA IN ABOUT 2 HOURS. [R12] *IN SIX HYPERKINETIC CHILDREN GIVEN A SINGLE 10-MG DOSE OF /METHYLPHENIDATE/ ... BETWEEN 35 and 98% OF /THE/ INGESTED DOSE (3.5 TO 9.8 MG) WAS RECOVERED FROM URINE EXCRETED DURING 6 HR AFTER DOSING. OF /THE/ TOTAL AMT EXCRETED BY THESE PATIENTS, 0.8 TO 11.0% WAS RECOVERED AS UNCHANGED METHYLPHENIDATE (MEAN 5.7%), /WITH THE/ REMAINDER BEING EXCRETED AS RITALINIC ACID. [R22, 258] *... GAS CHROMATOGRAPHY-MASS SPECTROMETRY ASSAY ... OF METHYLPHENIDATE IN RATS AFTER IV DOSES /INDICATED THAT/ PLASMA LEVELS OF UNCHANGED DRUG DECLINED BI-EXPONENTIALLY. ... DATA WERE FITTED TO THE TWO-COMPARTMENT OPEN MODEL WITH SIMPLE FIRST ORDER KINETICS. THE TERMINAL PLASMA HALF-LIFE OF METHYLPHENIDATE WAS 25 MINUTES AND THE OVERALL DISTRIBUTION VOLUME ... WAS 3.51 KG, THE LATTER VALUE BEING APPROXIMATELY ONE-HALF THAT OF DEXTROAMPHETAMINE. ... THE RELATIVELY STRONG BASE, AMPHETAMINE, MAY ACCUMULATE TO A GREATER EXTENT THAN METHYLPHENIDATE IN INTRACELLULAR WATER, WHICH HAS A LOWER PH THAN EXTRACELLULAR WATER. [R23] *MEN RECEIVED 0.15 OR 0.3 MG/KG OF METHYLPHENIDATE ORALLY, AND METHYLPHENIDATE AND RITALINIC ACID, A METABOLITE, WERE ANALYZED IN PLASMA SAMPLES OBTAINED AT VARIOUS TIMES AFTER TREATMENT. MAXIMAL METHYLPHENIDATE CONCENTRATIONS IN PLASMA WERE FOUND TO OCCUR 2.2 HOURS AFTER ADMINISTRATION OF EITHER DOSE. THE MEAN MAXIMAL CONCENTRATION IN PLASMA FOR METHYLPHENIDATE WAS 3.5 NG/ML AFTER 0.15 MG/KG, AND 7.8 NG/ML AFTER 0.3 MG/KG. METHYLPHENIDATE CLEARANCES WERE HIGH (10.1 L/HOUR/KG) AND VARIABLE (RANGE: 3.6-23.2) FOR THE 0.3 MG/KG DOSE. PHARMACOKINETIC PARAMETERS FOR CHILDREN RECEIVING 0.3 MG/KG WERE ESSENTIALLY THE SAME AS FOR THE ADULTS. RITALINIC ACID PLASMA LEVELS WERE 50-100 TIMES GREATER THAN METHYLPHENIDATE LEVELS IN NORMAL ADULTS. THE CLEARANCE OF RITALINIC ACID IS LESS THAN THAT OF METHYLPHENIDATE. WHEN ADMIN TO THE RAT, THE ABSOLUTE BIOAVAILABILITY OF METHYLPHENIDATE WAS FOUND TO BE 0.19 IN THE RAT AND 0.22 IN THE MONKEY, SUGGESTING SUBSTANTIAL PRESYSTEMIC ELIMINATION OF METHYLPHENIDATE. [R24] *NEUROANATOMICAL DISTRIBUTION OF (14)C-LABELED METHYLPHENIDATE WAS EXAMINED IN RABBIT BRAIN FOLLOWING INTRACEREBROVENTRICULAR ADMINISTRATION AT 15, 60, AND 180 MINUTES AFTER THE INJECTION. THE HIGHEST LEVELS WERE OBSERVED AT THE 1ST SAMPLING TIME (15 MINUTES) IN MEDULLA AND CERVICAL SPINAL CORD. THE PONS, CAUDATE, TEGMENTUM, AND HYPOTHALAMUS ALSO SHOWED SIGNIFICANT UPTAKE OF (14)C-METHYLPHENIDATE. [R25] *Methylphenidate hydrochloride appears to be well absorbed from the GI tract. ... Following oral administration of 20 mg of radiolabeled methylphenidate hydrochloride as a conventional tablet, approx 50%, 80%, and 95% of the dose was recovered as metabolites in urine within 6, 24, and 90 hr, respectively. /Methylphenidate hydrochloride/ [R2, 1912] *The kidney eliminates less than 1% of the methylphenidate dose unchanged, although acidification will somewhat enhance excretion. [R26] *Methylphenidate is absorbed rapidly but incompletely, with a bioavailability of 10.5% to 52.5%. ... The rate of gastrointestinal (GI) absorption ... is increased with food, but there is no difference in response. [R27] METB: *Rapid de-esterification of methylphenidate to ritalinic acid (alpha-phenyl-d-piperidineacetic acid) produces an inactive metabolite that is excreted in the urine unchanged or as 6-oxoritalinic acid. Biotransformation to ritalinic acid accounts for over 80% of the original dose. [R26] BHL: *... HALF-LIFE /OF METHYLPHENIDATE/ IN PLASMA IS 1 TO 3 HOURS, BUT CONCENTRATIONS IN THE BRAIN EXCEED THOSE IN PLASMA. [R12] *THE TERMINAL PLASMA HALF-LIFE OF METHYLPHENIDATE /IN THE RATS FOLLOWING IV ADMIN/ WAS 25 MINUTES ... . [R23] ACTN: *The main sites of CNS action appear to be the cerebral cortex and subcortical structures including the thalamus; stimulation by methylphenidate causes an increase in motor activity, mental alertness, diminished sense of fatigue, brighter spirits, and mild euphoria. /Methylphenidate hydrochloride/ [R2, 1912] *Although the primary mechanism is largely unknown, the effects of methylphenidate appear to be mediated by blockage of the reuptake mechanism of dopaminergic neurons. In children with attention deficit disorder, methylphenidate decreases motor restlessness and enhances the ability to pay attention. In narcolepsy, methylphenidate appears to act at the cerebral cortex and subcortical structures, including the thalamus, to produce CNS stimulation, resulting in increaed motor activity, increased mental alertness, diminished sense of fatigue, brighter spirits, and mild euphoria. [R28, 2010] INTC: *... METHYLPHENIDATE IS /A/ COMPETITIVE INHIBITOR OF HEPATIC METABOLISM OF PHENYTOIN AND OTHER DRUGS. [R29] *In one report, a patient receiving both methylphenidate and guanethidine developed ventricular tachycardia, apparently as a result of /a/ drug interaction. [R30, 180] *... METHYLPHENIDATE (RITALIN) APPEARS TO BE EFFECTIVE IN MONKEYS /AS A SUITABLE ANTAGONIST TO RESERPINE/ @ /A/ DOSE RATE OF 6-8 MG/KG. [R31] *The results of a preliminary study in four volunteers showing a prolongation of the half-life of ethyl biscoumacetate due to methylphenidate could not be confirmed by a subsequent double blind study in 12 healthy volunteers. [R30, 88] *Indirect acting agents such as ... possibly methylphenidate may produce a hypertensive crisis in patients on MAO /monoamine oxidase/ inhibitors ... [R32] *Concurrent use /of methylphenidate with anticholinergics or other medications with anticholinergic activity/ may intensify anticholinergic effects because of secondary anticholinergic effects of methylphenidate. [R28, 2010] *Serum concentrations may be increased when these medications /anticonvulsants, especially phenytoin, phenobarbital, and primidone or anticoagulants, coumarin- or indandione-derivative or phenylbutazone/ are used concurrently with methylphenidate because of metabolism inhibition, possibly resulting in toxicity, dosage adjustments may be necessary. [R28, 2010] *Serum concentrations may be increased when these medications /tricyclic antidepressants, especially desipramine and imipramine/ are used concurrently with methylphenidate because of inhibiton of metabolism; also, concurrent use may antagonize the effects of methylphenidate. [R28, 2011] *Hypotensive effects may be reduced when these medications /antihypertensives or diuretics used as antihypertensives/ are used concurrently with methylphenidate; the patient should be carefully monitored to confirm that the desired effect is being obtained. [R28, 2011] *Concurrent use /of other CNS stimulation-producing medications/ with methylphenidate may result in additive CNS stimulation to excessive levels, causing nervousness, irritability, insomnia, or possibly seizures or cardiac arrhythmias; close observation is recommended. [R28, 2011] *Concurrent use /with monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline/ may potentiate the effects of methylphenidate, possibly resulting in a hypertensive crisis; methylphenidate should not be administered during or with 14 days following the administration of MAO inhibitors. [R28, 2011] *Concurrent use /of pimozide/ with methylphenidate may mask the cause of tics since methylphenidate itself may provoke tics; before therapy with pimozide is initiated, methylphenidate should be withdrawn. [R28, 2011] *Pressor effects may be potentiated when vasopressors are used concurrently with methylphenidate. [R28, 2011] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Adrenergic Agents; Adrenergic Uptake Inhibitors; Central Nervous System Stimulants; Dopamine Agents; Dopamine Uptake Inhibitors; Sympathomimetics [R33] *MILD CENTRAL NERVOUS SYSTEM STIMULANT /WITH A/ POTENCY INTERMEDIATE TO /THAT OF/ CAFFEINE AND AMPHETAMINE. /METHYLPHENIDATE HYDROCHLORIDE/ [R10, 1079] *Methylphenidate has received extensive trial in various types of mental depression, in treatment of overdosage from depressant drugs, and in relieving lassitude from various causes. ... /Is/ important /adjunct/ ... in therapy of hyperkinetic syndromes in children and adults who are characterized as having attention deficit disorder /ADD/; formerly called minimal brain dysfunction. Double blind studies with placebo control have clearly demonstrated that methylphenidate can improve behavior, concentration, and learning ability in 70 to 80% of children with attention deficit disorder ... . However, indiscriminate use of these drugs for "problem" children and sole dependence on drug therapy for attention deficit disorder should be discouraged. [R34, 587] *MEDICATION (VET): IN DOGS, ... WITHOUT ADVERSE PRESSOR EFFECTS; MAY HAVE VALUE IN NEUTRALIZING ANTIHISTAMINE THERAPY DEPRESSION. [R18] *Treatment of cocaine abuse with agonists such as methylphenidate has been attempted, but with litle success except in patients with attention deficit disorders. [R35] *Methylphenidate is used as the primary agent in a total treatment program that includes other remedial measures (psychological, educational, and social) to stabilize some children (and adults /NOT inlcuded in US product labeling/) with attention-deficit hyperactivity disorder (ADHD). This complex behavioral syndrome has been known in the past as hyperkinetic child syndrome, minimal brain damage, minimal cerebral dysfunction, or minor cerebral dysfunction. /Included in US product labeling/ [R28, 2010] *Methylphenidate is indicated in the management of the symptoms of narcolepsy. /Included in US product labeling/ [R28, 2010] *Methylphenidate may be useful in selected patients whose medical condition complicates treatment with conventional antidepressants. /NOT included in US product labeling/ [R28, 2010] WARN: *Methylphenidate should be used with caution in patients with hypertension. Blood pressure should be monitored at appropriate intervals in patients receiving the drug, especially those with hypertension. [R2, 1912] *Results of one study in hyperactive children suggest that prolonged admin of methylphenidate hydrochloride (30 or 40 mg daily) may cause suppression of normal weight gain in children. /Methylphenidate hydrochloride/ [R2, 1912] *... PATIENTS RECEIVING /BOTH METHYLPHENIDATE AND PHENYTOIN/ SHOULD BE OBSERVED CLOSELY FOR UNEXPECTED SYMPTOMS OF PHENYTOIN TOXICITY. [R29] *Safety and efficacy of methylphenidate in children younger than six years of age have not been established. /Methylphenidate hydrochloride/ [R2, 1912] *... VARIOUS SYMPATHOMIMETIC AND RELATED DRUGS THAT DEPRESS APPETITE HAVE BEEN USED TO MAKE LOW CALORIE DIET MORE TOLERABLE. THESE APPETITE DEPRESSANTS ARE OF NO VALUE WITHOUT ACCOMPANYING STRINGENT DIETARY REGIMEN, AND IT HAS BEEN ... DEMONSTRATED THAT, WITHOUT CONSISTENT SUPERVISION, NO PRESCRIBED REGIMEN OF DRUG OR DIET IS PREDICTABLY SUCCESSFUL. /SYMPATHOMIMETIC DRUGS/ [R34, 178] *Methylphenidate is not recommended for the treatment of mental depression amenable to treatment with conventional antidepressants, for the prevention or treatment of normal fatigue states, or for children who exhibit symptoms secondary to environmental factors and/or psychiatric disorder, including psychosis. [R28, 2010] *Long-term effects of methylphenidate in children are not well established. Children are more prone than adults to develop anorexia, insomnia, stomach pain, tachycardia, and weight loss. Monitoring of growth (both height and weight gain) has been recommended during long-term therapy since chronic administration of methylphenidate may be associated with growth inhibition, although data are inadequate to determine this conclusively. Some clinicians may recommend medication-free periods during methylphenidate treatment to evaluate the need for continued therapy. [R28, 2010] *Methylphenidate is contraindicated in patients with a history of marked anxiety, tension, and agitation, since the drug may aggravate these symptoms. Methylphenidate is also contraindicated in patients with glaucoma, in patients with motor tics or a family history or diagnosis of Tourette's disorder, and in those known to be hypersensitive to the drug. /Methylphenidate hydrochloride/ [R36] *Methylphenidate should be used with caution in patients with a history of seizures and/or EEG abnormalities. There is some evidence that the drug may lower seizure threshold in patients with a history of seizures, in those with prior EEG abnormalities in the absence of seizures, and, very rarely, in those without a history of seizures and no prior evidence of EEG abnormalities. /Methylphenidate hydrochloride/ [R2, 1912] *The most frequent adverse effects of methylphenidate appear to be dose-related and include nervousness and insomnia. ... Other adverse effects include anorexia, nausea, abdominal pain, dryness of the throat, dizziness, palpitation, headache, akathisia, dyskinesia, and drowsiness. Angina, tachycardia, cardiac arrhythmias, and increase or decrease in blood pressure and pulse rate may occur. ... Hepatotoxicity was associated with methylphenidate therapy in one patient. Hypersensitivity reactions including rash, urticaria, fever, arthralgia, exfoliative dermatitis, erythema multiform with histopathologic findings of necrotizing vasculitis, and thrombocytopenic purpura may also occur in patients receiving methylphenidate. /Methylphenidate hydrochloride/ [R2, 1912] IDIO: *ACUTE EPISODES OF HALLUCINOSIS EARLY IN THERAPY WITH METHYLPHENIDATE MAY REPRESENT IDIOSYNCRATIC REACTIONS. [R34, 587] TOLR: *Tolerance and psychological dependence with varying degrees of abnormal behavior have been reported in patients chronically taking large doses of methylphenidate. /Methylphenidate hydrochloride/ [R2, 1912] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule II includes Methylphenidate, DEA Code #1724; Drug class: Stimulant. [R37] *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R38] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DRUGS INCLUDING METHYLPHENIDATE WERE CHARACTERIZED BY THEIR HPLC RELATIVE RETENTION TIMES AND BY THE RATIO OF THEIR ULTRAVIOLET ABSORBANCES AT 254 AND 280 NM. [R39] *DRUG SCREENING VIA GAS CHROMATOGRAPHY, FUSED SILICA CAPILLARY COLUMNS COATED WITH A 0.25 UM FILM OF SE 30, YIELDED RETENTION INDICES WHICH WERE REPRODUCIBLE TO WITHIN 4 UNITS OF LIBRARY VALUES. SCREENING WAS PERFORMED ON A TEMP PROGRAMMED COLUMN AT 100 DEG C-295 DEG C AT 5 DEG C/MIN WITH HELIUM CARRIER VELOCITY OF 45 CM/SEC AT 100 DEG C. THE RETENTION INDEX SYSTEM OF E KOVATS WAS USED TO CHARACTERIZE THE DRUGS VIA LINEAR INTERPOLATION BETWEEN ADJACENT HYDROCARBONS. THE RETENTION INDICES OF 175 BASIS OF DRUGS, INCLUDING METHYLPHENIDATE, ARE GIVEN. [R40] CLAB: *A GAS CHROMATOGRAPHY/MASS SPECTROMETRIC PROCEDURE FOR THE DETECTION OF METHYLPHENIDATE IN 1 ML OF SERUM OR PLASMA IS REPORTED EMPLOYING ETHYLPHENIDATE AS INTERNAL STANDARD. A 50/50 (VOL/VOL) MIXTURE OF BENZENE AND HEXANE IS USED TO EXTRACT METHYLPHENIDATE FROM PLASMA. AFTER EVAPORATION OF SOLVENT THE RESIDUE IS REDISSOLVED IN 50 UL HEXANE. METHYL- AND ETHYLPHENIDATE ARE THEN DERIVATIZED BY THE ADDITION OF 50 ML OF TRIFLUOROACETIC ANHYDRIDE AND THE TRIFLUOROACETATE DERIVATIVES ARE INJECTED INTO A QUARDRUPOLE GC/MS FOR ANALYSIS. THIS METHOD HAS A LOWER LIMIT OF SENSITIVITY FOR METHYLPHENIDATE OF 2.0 UG/L. THE ASSAY HAS BEEN USED TO INVESTIGATE THE PHARMACOKINETICS OF METHYLPHENIDATE ADMIN TO 6 CHILDREN FOR TREATMENT OF HYPERKINESIS. [R41] *A GLC-MASS SPECTROPHOTOMETRIC METHOD FOR THE DETERMINATION OF METHYLPHENIDATE IN BIOLOGICAL FLUID AND TISSUE WAS STUDIED FOLLOWING ADMIN OF 0.5 MG/KG IV TO RATS. BRAIN AND PLASMA LEVELS WERE QUANTITATIVELY DETERMINED AND A SENSITIVITY OF 1.2 NG/ML WAS NOTED. [R42] *METHYLPHENIDATE IS EXTRACTED FROM ALKALINE SAMPLE OF URINE AND DETERMINED BY GAS CHROMATOGRAPHY. ITS PRINCIPLE METABOLITE, RITALINIC ACID, IS METHYLATED, AND METHYLPHENIDATE THUS FORMED IS THEN DETERMINED. 1. METHYLPHENIDATE HYDROCHLORIDE CAN BE MEASURED WITH A COEFFICIENT OF VARIATION OF PLUS OR MINUS 3.2% WITHIN ONE RUN AT A CONCENTRATION OF 2 MG/100 ML. ... 3. THE RESPONSE OF THE FLAME-IONIZATION DETECTOR IS LINEAR OVER THE RANGE 0 TO 7 MG OF METHYLPHENIDATE/100 ML URINE. 4. THE LIMIT OF DETECTION IS 0.125 MG OF METHYLPHENIDATE/100 ML. [R22, 256] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability (1984) DHHS Pub No. (ADM)87-1332 DHHS/NIDA; Research Monograph Series 54: Mechanisms of Tolerance and Dependence (1984) DHHS Pub No. (ADM)88-1330 DHHS/NIDA; Research Monograph Series 56: Etiology of Drug Abuse: Implications for Prevention (1987) DHHS Pub No. (ADM)87-1335 DHHS/NIDA; Research Monograph Series 59: Current Research on the Consequences of Maternal Drug Abuse (1985) DHHS Pub No. (ADM)85-1400 DHHS/NIDA; Research Monograph Series 60: Prenatal Drug Exposure: Kinetics and Dynamics (1985) DHHS Pub No. (ADM)85-1413 DHHS/NIDA; Research Monograph Series 65: Woman and Drugs: A New Era for Research (1986) DHHS Pub No. (ADM)87-1447 DHHS/NIDA; Research Monograph Series 73: Urine Testing for Drugs of Abuse (1986) DHHS Pub No. (ADM)87-1481 DHHS/NIDA; Research Monograph Series 90: Problems of Drug Dependence 1988 (1988) DHHS Pub No. (ADM)89-1605 Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 439 (1995) NTIS Publication No. PB96-162615 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for methylphenidate hydrochloride is completed, and the chemical is in review for further evaluation. Route: dosed feed; Species: transgenic model evaluation, mice. /Methylphenidate hydrochloride/ [R43] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1042 R2: McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements). R3: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 728 R4: 21 CFR 1308 4/1/89 R5: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 874 R6: Sangster J; LOGKOW Databank, Sangster Res Lab, Montreal Quebec, Canada (1993) R7: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 124 R8: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R9: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.205 R10: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. R11: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2289 R12: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 221 R13: MATTES JA, GITTELMAN R; ARCH GEN PSYCHIATRY 40 (3): 317-21 (1983) R14: LOWE TL ET AL; JAMA 247 (12): 1729-31 (1982) R15: WALKER AP, DUMARS KW; AM J HUM GENET 29: 110A (1977) R16: USDOJ/DEA; Drugs of Abuse p.40 (1988) R17: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 626 R18: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 359 R19: GRELLA A ET AL; RIV EUR SCI MED FARMACOL 4 (1): 111-16 (1982) R20: DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability p.67 (1984) DHHS Pub No. (ADM)87-1332 R21: Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 439 (1995) NTIS Publication No. PB96-162615 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R22: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. R23: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 55 R24: WARGIN W ET AL; J PHARMACOL EXP THER 226 (2): 382-6 (1983) R25: SHAH NS ET AL; PROG NEURO-PSYCHOPHARMACOL BIOL PSYCHIATRY 7 (1): 101-6 (1983) R26: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 631 R27: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995.,p. 78-2 R28: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R29: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. 204 R30: Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985. R31: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 109 R32: Knoben, J.E. and P.O. Anderson (eds.) Handbook of Clinical Drug Data. 6th ed. Bethesda, MD: Drug Intelligence Publications, Inc. 1988. 138 R33: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R34: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. R35: DHHS/NIDA; Research Monograph Series 88: Mechanisms of Cocaine Abuse and Toxicity p.125 (1988) DHHS Pub No. (ADM)89-1585 R36: American Conference of Governmental Industrial Hygienists. Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents and Biological Exposure Indices (BEIs) for 1996. Cincinnati, OH: ACGIH, 1996.1923 R37: 21 CFR 1308.12 (4/1/97) R38: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R39: BAKER JK ET AL; J CHROMATOGR 168 (2): 417-27 (1979) R40: ANDERSON WH, STAFFORD DT; J HIGH RESOLUT CHROMATOGR CHROMATOGR COMMUN 6 (5): 247-54 (1983) R41: CHAN YM ET AL; CLIN BIOCHEM (OTTAWA) 13 (6): 266-72 (1980) R42: GAL J ET AL; J PHARM SCI 66 (JUNE): 866-9 (1977) R43: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 32 Record 221 of 1119 in HSDB (through 2003/06) AN: 3135 UD: 200303 RD: Reviewed by SRP on 5/7/1998 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NITROFURANTOIN- SY: *BENKFURAN-; *BERKFURAN-; *BERKFURIN-; *CHEMIOFURAN-; *CYANTIN-; *DANTAFUR-; *FURACHEL-; *FURADANTIN-; *FURADANTINE-; *FURADANTINE-MC-; *FURADANTOIN-; *FURADOINE-; *FURADONIN-; *FURADONINE-; *FURADONTIN-; *FURAGIN-; *FURALAN-; *FURANTOIN-; *FURATOIN-; *FURAZIDIN-; *FURINA-; *FUROBACTINA-; *FUR-REN-; *HYDANTOIN, 1-((5-NITROFURFURYLIDENE)AMINO)-; *2,4-IMIDAZOLIDINEDIONE, 1-(((5-NITRO-2-FURANYL)METHYLENE)AMINO)-; *ITURAN-; *MACRODANTIN-; *NCI-C55196-; *NIFURANTIN-; *NITOIN-; *5-NITROFURANTOIN-; *1-(5-NITRO-2-FURFURYLIDENAMINO)HYDANTOIN; *N-(5-NITROFURFURYLIDENE)-1-AMINOHYDANTOIN; *N-(5-NITRO-2-FURFURYLIDENE)-1-AMINOHYDANTOIN; *1-((5-NITROFURFURYLIDENE)AMINO)HYDANTOIN; *1-(5-NITRO-2-FURFURYLIDENEAMINO)HYDANTOIN; *NOVOFURAN-; *NSC-2107-; *ORAFURAN-; *PARFURAN-; *TRANTOIN-; *URANTOIN-; *URIZEPT-; *URODIN-; *UROFURIN-; *UROLONG-; *USAF-EA-2-; *WELFURIN-; *ZOOFURIN- RN: 67-20-9 MF: *C8-H6-N4-O5 ASCH: Nitrofurantoin Hydrate; 17140-81-7; Nitrofurantoin Sodium; 54-87-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *NITROFURANTOIN SODIUM; SODIUM COMPOUNDS, WITH 1-((5-NITROFURFURYLIDENE)AMINO)HYDANTOIN; AND SODIUM FURADANTIN. /SODIUM SALT/ [R1] *NITROFURANTOIN, USP (FURADANTIN, OTHERS), IS AVAIL IN TABLETS CONTAINING 50 OR 100 MG OF DRUG AND IN ORAL SUSPENSION CONTAINING 25 MG/5 ML. NITROFURANTOIN MICROCRYSTALS (MACRODANTIN) ARE AVAIL IN 25-, 50-, and 100-MG CAPSULES. [R2] *Grade: USP [R3] MFS: *Eagle-Picher Industries, Inc, Hq, 580 Walnut St, Cincinnati, OH 45202, (513) 721-7010; Specialty Materials Division; Production site: Chemsyn Science Lab, 13605 West 96th Terrace, Lenexa, KS 66215-1297 [R4] *The Proctor and Gamble Co, Hq, 301 E Sixth St, PO Box 599, Cincinnati, OH 45201, (513) 983-5607; Subsidiary: Norwick Eaton Pharmaceuticals, Inc, 17 Eaton Ave, PO Box 191, Norwich, NY 13815, (607) 335-2111 [R4] USE: *MEDICATION *MEDICATION (VET) CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORANGE-YELLOW NEEDLES FROM DIL ACETIC ACID [R5]; *LEMON-YELLOW CRYSTALS OR FINE POWDER [R6]; *Yellow powder [R3] ODOR: *ODORLESS [R6]; *Slight [R3] TAST: *HAS BITTER AFTERTASTE [R6]; *Bitter [R3] MP: *263 deg C [R7] MW: *238.16 [R8] DSC: *pKa= 7.2 [R9] OWPC: *log Kow= -0.47 [R10] SOL: *Soly (mg/100 ml): water (pH 7) 19.0; 95% ethanol 51.0; acetone 510; DMF 8000; peanut oil 2.1; glycerol 60; polyethylene glycol 1500. [R5]; *Very slightly soluble in alcohol and practically insoluble in ether and water. [R3]; *In water, 79 mg/l at 24 deg C. [R11] SPEC: *MAX ABSORPTION: 370 NM (E= 776, 1%, 1 CM) [R8]; *MAX ABSORPTION (H2O): 266 and 368 NM (A= 753, 1%, 1 CM) [R12, 274] OCPP: *dec 270-272 deg C [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R13] SSL: *SENSITIVE TO HEAT [R12, 80] *DISCOLORED BY ALKALI AND BY EXPOSURE TO LIGHT, AND IS DECOMP UPON CONTACT WITH METALS OTHER THAN STAINLESS STEEL OR ALUMINUM [R6] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence for the carcinogenicity of nitrofurantoin in humans. There is limited evidence for the carcinogenicity of nitrofurantoin in experimental animals. Overall evaluation: Nitrofurantoin is not classifiable as to its carcinogenicity to humans (Group 3). [R14] ANTR: *ADULT RESPIRATORY DISTRESS SYNDROME ASSOCIATED WITH ACUTE NITROFURANTOIN USE IS DESCRIBED. THE PATIENT WAS SUCCESSFULLY MANAGED WITH CONTINUOUS POSITIVE AIRWAY PRESSURE (CPAP) THROUGH A TIGHTLY FITTING FACE MASK; CLINICAL DETERIORATION FOLLOWED DISCONTINUATION OF THE CPAP, WITH IMPROVEMENT OCCURRING WHEN IT WAS RESTARTED. ACUTE NITROFURANTOIN PLEUROPULMONARY REACTIONS ARE REVIEWED. [R15] HTOX: *AN ASYMPTOMATIC PALPABLE LIVER TUMOR DEVELOPED IN A SIX-YEAR-OLD GIRL SEVEN MONTHS AFTER COMMENCEMENT OF PROPHYLACTIC NITROFURANTOIN THERAPY FOR RECURRENT URINARY TRACT INFECTIONS. THE PATHOLOGICAL FINDINGS WERE TYPICAL FOR FOCAL NODULAR HYPERPLASIA (FNH) OF THE LIVER. [R16] *In a study of 757 courses of nitrofurantoin in hospitalized patients, the overall frequency of adverse reactions was 9.2%. Toxic reactions constituted 5.1% of adverse effects; the remainder were allergic. [R17, p. V50 P221] *...drug intake and pregnancy outcome were studied in a series of 50,282 women in 1959-1965, 83 women had been exposed to nitrofurantoin during the first trimester of pregnancy. Six malformed children were born in the exposed group, giving a standardized nonsignificant relative risk of 1.07. [R17, p. V50 P221] *Chronic use...for 6 months to 6 yr has resulted in cases of pulmonary fibrosis. Most cases have been reversible following discontinuation of the drug and institution of steroid therapy. It appears to occur most frequently in postmenopausal women. [R18, p. 22-5] *LARGE DOSES...DEPRESS SPERMATOGENESIS BY ACTING DIRECTLY ON SEMINIFEROUS TUBULES. USUAL THERAPEUTIC DOSES APPEAR TO HAVE NO SUCH EFFECT. [R19] NTOX: *HIGH ORAL DOSAGE PRODUCES SERIOUS NEUROPATHY IN RAT AND THIS MAY PRODUCE NAUSEA OR CNS DEPRESSION IN DOGS. ... POSSIBILITY OF DECR FERTILITY IN MALES BEING TREATED SHOULD NOT BE OVERLOOKED. [R20] *THE CARCINOGENICITY OF NITROFURANTOIN WAS EXAMINED IN BDF1 MICE. THREE HUNDRED MICE WERE DIVIDED INTO 3 GROUPS, EACH GROUP CONSISTING OF APPROXIMATELY 50 MALE AND 50 FEMALE MICE. IT WAS GIVEN IN POWDERED DIET AT 0.3, 0.075, OR 0% TO THE GROUPS. IN MALES, THE TOTAL INCIDENCE OF TUMORS IN 2 GROUPS AND THAT OF HEPATIC ADENOMA IN THE 0.3% GROUP WAS SIGNIFICANTLY DECREASED FROM THAT OF CONTROLS. THERE WAS NO SIGNIFICANT DIFFERENCE IN THE FEMALES. [R21] *NITROFURANTOIN (100 MG/KG) CAUSES RENAL TUBULAR NECROSIS IN SELENIUM-DEFICIENT RATS BUT NOT IN CONTROLS. LETHALITY OF NITROFURANTOIN IN SELENIUM-DEFICIENT RATS IS CAUSALLY LINKED TO LIPID PEROXIDATION. [R22] *Nitrofurantoin, along with several other nitrohetrocyclic compounds, was tested for embryotoxicity in cultured rat embryos, and the effects were compared with those of other 5-membered heterocycles. Sprague-Dawley rat embryos were explanted on day 10 of gestation and grown in culture medium to which the test compounds were added. After 26 hr in culture, the embryos were removed and examined for malformations. Nitrofurantoin exposure was associated with cephalic hypoplasia at 0.2 mM concentration and was embryolethal to 100% of embryos tested at 0.25 mM concentration. Its failure to produce axial symmetry may have been masked due to an extremely steep dose-response curve for embryolethality. All the nitroheterocyclic compounds with high redox potential tested produced axial asymmetric malformations with the exception of nitrofurantoin. All the compounds with nitro groups and low single-electron redox potential tested did not produce the axial asymmetry. [R23] *Groups of 52-53 male and 54 female mice, nine weeks of age, were administered nitrofurantoin at 0, 750 or 3000 mg/kg of diet for 104 weeks, when the experiment was terminated. At that time, survival in males and females combined was 50.5%, 42.5% and 46.2% in control, low-dose and high-dose groups, respectively. Administration of the high dose significantly lowered body weights in mice of each sex in comparison with controls. In males, a reduced incidence of hepatic adenomas was observed: 6/53 controls, 1/52 low-dose and 0/52 high-dose mice. No increase in the incidence of tumors at any site was observed. [R17, p. V50 P213] *Groups of 50 male and 50 female Swiss mice, about 50 days of age, received nitrofurantoin at 0, 50, 100 or 200 mg/kg of diet for 22 months. Increased mortality was observed in males treated with the high-dose. In males, the incidences of malignant lymphomas at all sites were: controls, 2/50; low-dose, 6/50; mid-dose, 4/49; and high-dose, 10/50. [R24] *... Under the conditions of these 2 yr feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. ... There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F1 mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary. [R25] NTXV: *LD50 Rat oral 604 mg/kg; [R13] *LD50 Mouse oral 360 mg/kg; [R13] NTP: *... Toxicology and carcinogenesis studies of nitrofurantoin were conducted by admin nitrofurantoin (greater than 99% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for ... Two yr studies of nitrofurantoin were conducted by feeding diets containing 0, 1,300, or 2,500 ppm nitrofurantoin to groups of 50 male F344/N rats and to groups of 50 male and female B6C3F1 mice for 103 wk. Groups of 50 female F344/N rats were fed diets containing 0, 600, or 1,300 ppm nitrofurantoin on the same schedule. Conclusions. Under the conditions of these 2 yr feed studies, there was some evidence of carcinogenic activity of nitrofurantoin for male F344/N rats as shown by increased incidences of uncommon kidney tubular cell neoplasms. Uncommon osteosarcomas of the bone and neoplasms of the subcutaneous tissue were observed in dosed male rats. Incidences of interstitial cell adenomas of the testis and neoplasms of the preputial gland were decreased in the 2,500-ppm group of male rats. There was no evidence of carcinogenic activity of nitrofurantoin for female F344/N rats fed diets containing 600 ppm or 1,300 ppm for 2 yr. Female rats may have been able to tolerate higher doses. There was no evidence of carcinogenic activity of nitrofurantoin for male B6C3F1 mice fed diets containing 1,300 ppm or 2,500 ppm for 2 yr. There was clear evidence of carcinogenic activity of nitrofurantoin for female B6C3F1 mice as shown by increased incidences of tubular adenomas, benign mixed tumors, and granulosa cell tumors of the ovary. [R25] +Nitrofurantoin, administered via dosed feed, was tested for its effects on fertility and reproduction in Swiss CD-l mice according to the Continuous Breeding protocol. Based on results of a dose-finding study (Task 1), 0.03, 0.06, and 0.12% (300, 600, and 1,200 ppm) levels were chosen to investigate effects on fertility and reproduction. Male and female mice were continuously exposed for a 7-day precohabitation and a 98-day cohabitation period (Task 2). Subsequently, the control and 0.12% groups were used in a cross-over mating trial (Task 3) to determine the sex affected by chemical treatment. The F1 generation from control, 0.06, and 0.12% groups were also evaluated (Task 4). Nitrofurantoin treatment, at up to 0.12% concns, had no apparent effect on parental fertility, number of litters/pair, proportion of pups born alive, sex of live pups, neonatal body weights, and postnatal survival. Nitrofurantoin at 0.12% in feed, significantly reduced dam body weight at delivery and lactation, number of live pups/litter, and pup body weights at postnatal days 7-21. The cross-over mating trial did not reveal any significant effects on mating, fertility or reproduction. Nitrofurantoin disrupted the estrual cycle in the F0 females; there was a significant incr in the % of vaginal smears showing estrus, and a decr in the % of smears indicating diestrus. All parental mice were necropsied. Female body weight was slightly reduced at 0.12%, as was epididymal sperm motility; absolute and adjusted kidney weights of both sexes were increased significantly at 0.12%. There were also testicular lesions in the 0.12% group. The F1 generation showed significant reductions in fertility and live litter size at the 0.12% dose level. Nitrofurantoin at 0.12% significantly increased F1 adjusted kidney weights (both sexes) and reduced testis, epididymis and cauda epididymis weights as well as epididymal sperm concn and motility, and produced testicular lesions. These data show that Nitrofurantoin exhibited reproductive toxicity in the presence of systemic effects. [R26] ADE: *.../IT/ IS RAPIDLY AND COMPLETELY ABSORBED FROM GI TRACT. ... PLASMA HALF-LIFE IS 0.3 TO 1 HR; ABOUT 40% IS EXCRETED UNCHANGED INTO URINE. AVG DOSE OF NITROFURANTOIN YIELDS URINE CONCN OF APPROX 200 UG/ML. ... RATE OF EXCRETION IS LINEARLY RELATED TO CREATININE CLEARANCE... [R27, 1069] *CLINICAL STUDIES...INDICATE THAT IN NORMAL FASTING INDIVIDUALS, LESS NITROFURANTOIN IS ABSORBED AND AT SLOWER RATE FROM MACROCRYSTALLINE THAN MICROCRYSTALLINE FORM. PRESENCE OF FOOD IN INTESTINE DELAYS ABSORPTION OF BOTH FORMS APPRECIABLY, INCR PEAK LEVELS OF MACROCRYSTALLINE COMPD, BUT NOT MICROCRYSTALLINE COMPD, ENHANCES BIOAVAILABILITY OF BOTH FORMS, AND PROLONGS DURATION OF THERAPEUTIC URINARY CONCN. [R19] *ENHANCEMENT OF...ABSORPTION BY FOOD RANGED FROM 20 TO 400%, WITH GREATEST EFFECT OCCURRING WITH LEAST SOLUBLE DOSAGE FORMS. .../IT/ IS INEFFICIENTLY ABSORBED FROM RECTAL SUPPOSITORIES... [R28] *NITROFURANTOIN ABSORPTION IS SIGNIFICANTLY INCR IN MAN FROM A DRUG-DEOXYCHOLIC ACID CO-PRECIPITATE COMPARED WITH PHYS MIXT, AND FASTER ABSORPTION...FROM CO-PRECIPITATE WAS ASSOCIATED WITH FASTER IN VITRO DISSOLUTION RATE. ... EXCRETED IN BILE OF DOGS AND ABOUT 1/3 OF THAT EXCRETED IS REABSORBED FROM INTESTINE WITHIN 3 HR. [R29] *RAPIDLY AND ALMOST COMPLETELY ABSORBED FROM GI TRACT /TABLET FORM/...CROSSES BLOOD-BRAIN...AND PLACENTA BARRIER/S/. IN PT WITH NORMAL RENAL FUNCTION...LEVELS OF 50 TO 100 UG/ML ARE USUALLY OBTAINED IN URINE WITHIN 30 MIN AFTER A SINGLE DOSE OF 100 MG. /HUMAN, ORAL/ [R30] *READILY DEGRADED BY ALL /BODY/ TISSUES (EXCEPT BLOOD) INTO METABOLITES...THAT MAY TINT URINE BROWN...APPROX 30 TO 50%...IS EXCRETED INTACT IN URINE. /HUMAN, ORAL/ [R30] *IN VITRO RELEASE AND BIOAVAILABILITY (IN HUMANS) OF NITROFURANTOIN (I) WERE INVESTIGATED FROM SUSTAINED-RELEASE TABLETS WITH CELLULOSE ACETATE (II) AS THE TABLET MATRIX AND COMPARED WITH THE RESULTS FROM PLAIN TABLETS. THE INNER CORE TABLET CONSISTED OF I AND II AND WAS COATED WITH AN OUTER COATING OF POLY(VINYLPYRROLIDONE). THE IN VITRO DRUG RELEASE WAS 90% IN 8 HOURS FOR SUSTAINED-RELEASE TABLETS AS COMPARED WITH 1.9 HOURS FOR PLAIN TABLETS. THE AMOUNT OF I EXCRETED IN THE URINE REACHED 42 MG IN 2 HOURS WHEN 100 MG PLAIN TABLETS WERE USED. WITH APPROXIMATELY 100 MG SUSTAINED-RELEASE TABLETS, THE I AMOUNT EXCRETED REACHED 71.75 MG IN 24 HOURS. THUS THE II MATRIX WAS EFFECTIVE IN PROLONGING I RELEASE URINARY EXCRETION. [R31] *NITROFURANTOIN IN RATS SHOWED AGE-DEPENDENT RATE OF ELIMINATION. NITROFURANTOIN HALF-LIFE WAS 0.41 HOURS IN ADULTS AND 0.95 HOURS IN 2-WEEK-OLD RATS. NITROFURANTOIN EXCRETION RATE WAS DECREASED IN CHILDREN YOUNGER THAN 2 YEARS. OLDER CHILDREN EXCRETED IN URINE 44.32% AND YOUNGER 25.07% OF THE GIVEN DOSE, INDICATING THE LOWER CAPACITY IN INFANTS FOR NITROFURANTOIN ELIMINATION VIA KIDNEYS. [R32] *NITROFURANTOIN (I) (50 MG) WAS ADMINISTERED IN A 3-WAY RANDOM CROSSOVER DESIGN TO HEALTHY MEN. AFTER A 45-MINUTE IV INFUSION THE PLASMA CONCENTRATION DATA DESCRIBED A 2-COMPARTMENT OPEN-BODY MODEL WITH A TERMINAL HALF-LIFE OF 58.1 MINUTES. ORAL AVAILABILITY OF A TABLET WAS 0.87 ON A FASTING STOMACH AND 0.94 WHEN TAKEN WITH FOOD. AFTER THE IV INFUSION 47% OF THE DOSE WAS EXCRETED UNCHANGED IN THE URINE. [R33] *Microcrystalline - Rapidly and completely absorbed in the small intestine. Macrocrystalline - More slowly absorbed and usually causes less gastrointestinal irritation. The presence of food can increase the bioavailability of both forms of nitrofurantoin; this also increased the duration of therapeutic urinary concentrations. [R34, 2154] *High concentrations are achieved in urine and the kidneys; serum concentrations are very low; crosses the placenta and blood-brain barrier. [R34, 2154] *Primarily excreted by glomerular filtration with some tubular secretion and reabsorption; 30 to 40% rapidly excreted unchanged; the macrocrystalline form is excreted more slowly; active drug accumulates in patients with impaired renal function and may reach toxic concentrations. [R34, 2154] *...excreted in bile, reabsorbed and recirculated enterohepatically. [R17, p. V50 P216] METB: *AFTER DOSE OF 0.200 MG/KG, 22% IS EXCRETED IN URINE AS N-(5-NITROFURFURYLIDENEAMINO)-2-IMIDAZOLINE-ONE. /FROM TABLE/ [R12, 356] *READILY DEGRADED BY ALL /BODY/ TISSUES (EXCEPT BLOOD) INTO INACTIVE METABOLITES-HYDROXYLAMINO COMPD AND AMINOFURALDEHYDENITROFURIC ACID. /HUMAN, ORAL/ [R30] *AFTER NITROFURANTOIN (50 MG) IV INFUSION, 47% OF THE DOSE WAS EXCRETED UNCHANGED IN THE URINE AND 1.2% WAS RECOVERED AS THE REDUCED METABOLITE AMINOFURANTOIN. [R35] *Nitrofurantoin is partially metabolized, mainly in the liver. A small fraction of the drug is reduced to form aminofurantoin. [R36, 632] BHL: *PLASMA HALF-LIFE IS 0.3 TO 1 HR... [R27, 1069] *NITROFURANTOIN HALF-LIFE WAS 0.41 HOURS IN ADULTS AND 0.95 HOURS IN 2-WEEK-OLD RATS. [R32] ACTN: *MICROSOMAL AND SOLUBLE FRACTIONS FROM BOTH RAT LIVER AND LUNG MEDIATED THE COVALENT BINDING OF (14)C-LABELED NITROFURANTOIN (I) TO TISSUE MACROMOLECULES IN VITRO. OXYGEN STRONGLY INHIBITED THE BINDING IN BOTH FRACTIONS, AND CARBON MONOXIDE FAILED TO INHIBIT THE BINDING IN MICROSOMAL PREPARATIONS, INDICATING ACTIVATION OF I IN BOTH SYSTEMS BY NITROREDUCTION RATHER THAN OXIDATION OF THE FURAN RING. MICROSOMAL NITROREDUCTION AND COVALENT BINDING OF I WERE INHIBITED BY AN ANTIBODY AGAINST NADPH-CYTOCHROME C REDUCTASE AND COVALENT BINDING WAS ENHANCED BY THE ADDITION OF FAD. IN SOLUBLE FRACTIONS, MAXIMUM RATES OF COVALENT BINDING WERE OBTAINED IN THE PRESENCE OF NADH AND HYPOXANTHINE, AND IT WAS INHIBITED BY ALLOPURINOL, A XANTHINE OXIDASE INHIBITOR. REDUCED GLUTATHIONE DECREASED COVALENT BINDING OF I IN BOTH MICROSOMAL AND SOLUBLE FRACTIONS OF LIVER AND LUNG, BUT THE RATE OF NITROREDUCTION WAS UNAFFECTED. [R37] *THE HYPOTHESIS IS PRESENTED THAT THE TOXICITY OF NITROFURANS SUCH AS NITROFURANTOIN (I), WHICH ARE USED IN COMMERCIAL POULTRY PRODUCTION, IS DUE TO OXIDATIVE METABOLIC STRESS CAUSED BY THE O2- FREE RADICAL FORMED DURING METABOLISM OF THE COMPOUNDS. [R38] INTC: *CONCURRENT ADMIN OF PROBENECID, PARTICULARLY IN HIGH DOSES, DECR RENAL CLEARANCE OF NITROFURANTOIN AND INCR SERUM LEVEL... INTERACTION MAY LEAD TO NITROFURANTOIN-INDUCED TOXICITY (EG, POLYNEUROPATHIES) OR DECR NITROFURANTOIN EFFICACY AS URINARY TRACT ANTI-INFECTIVE AGENT. [R39, 159] *IN VITAMIN E-DEFICIENT CHICKS, ADMINISTRATION OF SELENIUM HAD A PROTECTIVE EFFECT AGAINST NITROFURANTOIN TOXICITY. [R38] *ACETYLSALICYLIC ACID REDUCED THE SOLUBILITY OF NITROFURANTOIN IN ARTIFICIAL INTESTINAL JUICE. SPECTROPHOTOMETRY INDICATED FORMATION OF A COMPLEX BETWEEN THE TWO IN SOLUTION. IN MODEL ABSORPTION STUDIES IN VITRO, ACETYLSALICYLIC ACID DID NOT AFFECT THE DIFFUSION RATE CONSTANT OF NITROFURANTOIN IN SOLUTION ACROSS AN ARTIFICIAL LIPID MEMBRANE. COADMINISTRATION STUDIES IN ADULT HUMANS SHOWED THAT ACETYLSALICYLIC ACID REDUCED THE TOTAL URINARY EXCRETION OF NITROFURANTOIN. [R40] *Concurrent use of /hemolytics/ with nitrofurantoin may increase the potential for toxic side effects. [R34, 2155] *Concurrent use of nitrofurantoin with other hepatotoxic medications may increase the potential for hepatotoxicity. [R34, 2155] *Magnesium trisilicate reduces both the rate and extent of absorption of nitrofurantoin, probably by absorption of nitrofurantoin to its surface. [R34, 2155] *Nitrofurantoin interferes with the therapeutic effects of nalidixic acid. [R34, 2155] *Concurrent use of nitrofurantoin with other neurotoxic medications may increase the potential for neurotoxicity. [R34, 2155] *These medications /probenecid or sulfinpyrazone/ may inhibit renal tubular secretion of nitrofurantoin, resulting in increased serum concentrations and/or toxicity, prolonged elimination half-life, and reduced urinary concentrations and effectiveness; dosage adjustment of probenecid may be necessary. [R34, 2155] *Concomitant administration of a magnesium trisilicate antacid is reported to decrease the extent and rate of absorption of nitrofuantoin... [R36, 634] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Urinary /SRP: Antibacterial/ [R41] *NITROFURANTOIN IS BACTERIOSTATIC AT CONCN OF 5-10 UG/ML AND BACTERICIDAL AT 100 UG/ML, BUT IT IS NOT KNOWN WHETHER BACTERICIDAL ACTION OCCURS IN VIVO. ANTIBACTERIAL ACTIVITY IS HIGHER IN ACIDIC URINE. ...SUPERSATURATED SOLN OF NITROFURANTOIN DO NOT CAUSE CRYSTALLURIA. [R42, 1008] *NITROFURANTOIN IS ACTIVE AGAINST MANY STRAINS OF COMMON URINARY TRACT PATHOGENS E COLI, PROTEUS SPECIES, PSEUDOMONAS...ENTEROBACTER, AND STAPHYLOCOCCI, AS WELL AS ENTEROCOCCI, STREPTOCOCCI, CLOSTRIDIA, AND BACILLUS SUBTILIS. [R42, 1008] *...APPROVED ONLY FOR TREATMENT OF URINARY TRACT INFECTIONS CAUSED BY MICROORGANISMS THAT ARE KNOWN TO BE SENSITIVE TO DRUG. ... IT HAS BEEN USED EFFECTIVELY TO PREVENT RECURRENT INFECTIONS AND FOR PREVENTION OF BACTERIURIA AFTER PROSTATECTOMY. [R27, 1070] *MEDICATION (VET): ORALLY OR IV, AS A SPECIFIC IN CERTAIN URINARY INFECTIONS WHERE IT MAY BE...BACTERIOSTATIC OR BACTERIOCIDAL DEPENDING ON CONCN. ... SODIUM FORM IS USED IM. ... IT HAS BEEN RECOMMENDED FOR AND HAS SHOWN VARIABLE RESULTS IN TRACHEOBRONCHITIS (KENNEL COUGH) OF DOGS AND TRACHEOPHARYNGITIS (RACE TRACK COUGH) OF HORSES. [R20] *Nitrofurantoin is indicated in the treatment of urinary tract infections caused by susceptible strains of Escherichia coli, enterococci, Staphylococcus aureus, Staphylococcus saprophyticus, Klebsiella species, Enterobacter species, and Proteus species. /Included in US product labeling/ [R34, 2154] *Nitrofurantoin is used in the prophylaxis of urinary tract infections. /NOT included in US product labeling/ [R34, 2154] *VET: Antibacterial [R5] WARN: *A COURSE OF THERAPY SHOULD NOT EXCEED 14 DAYS, AND REPEATED COURSES SHOULD BE SEPARATED BY REST PERIODS. ... PREGNANT WOMEN AT TERM, INDIVIDUALS WITH IMPAIRED RENAL FUNCTION (CREATININE CLEARANCE LESS THAN 40 ML/MIN), AND CHILDREN BELOW 1 MONTH OF AGE SHOULD NOT RECEIVE NITROFURANTOIN. [R27, 1070] *Maternal Medication Usually Compatible with Breast-Feeding: Nitrofurantoin: Hemolysis in infant with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. /from Table 6/ [R43] *...MOST SPECIES OF PROTEUS AND PSEUDOMONAS AND MANY OF ENTEROBACTER AND KLEBSIELLA ARE RESISTANT. ANTIBACTERIAL CONCN ARE NOT ACHIEVED IN PLASMA FOLLOWING INGESTION OF RECOMMENDED DOSES, BECAUSE DRUG IS RAPIDLY ELIMINATED. ...IN PT WITH IMPAIRED GLOMERULAR FUNCTION EFFICACY OF DRUG MAY BE DECR AND SYSTEMIC TOXICITY INCR. [R27, 1069] *INJECTION OF NITROFURANTOIN SODIUM IS INDICATED ONLY FOR USE IN ACUTELY ILL PT WHO CANNOT TOLERATE ORAL NITROFURANTOIN. /SODIUM NITROFURANTOIN/ [R42, 1009] *POLYNEUROPATHY, INCL SEVERE PERIPHERAL.../SRP: NEUROPATHY/, MAY OCCUR, PARTICULARLY IF...GIVEN TO PATIENTS WITH RENAL INSUFFICIENCY, ANEMIA, DIABETES, ELECTROLYTE IMBALANCE, VITAMIN B-COMPLEX DEFICIENCY, OR IN LARGER THAN RECOMMENDED DOSES. [R19] *...THERE SEEMS TO BE NO REPORT OF OPTIC NERVE INVOLVEMENT, AND ONLY 1 OF OCULOMOTOR DISTURBANCE. 1/14 PRESUMABLY NORMAL...VOLUNTEERS TAKING 400 MG/DAY...DEVELOPED VERTICAL DIPLOPIA AND ATAXIC GAIT AFTER 10 DAYS, APPARENTLY RETURNING TO NORMAL AFTER DRUG WAS STOPPED AT 14 DAYS. [R44] *IMMEDIATE EFFECTS OF DECR RENAL CLEARANCE OF NITROFURANTOIN WOULD BE SYSTEMIC ACCUM OF DRUG AND DECR EFFECTIVENESS IN URINARY TRACT INFECTIONS DUE TO LOWER URINE...LEVELS. [R39, 160] *THERE IS SOME EVIDENCE THAT DECR GASTRIC ACIDITY INTERFERES WITH ABSORPTION OF NITROFURANTOIN AND, THEREFORE, EXCESSIVE USE OF ANTACIDS SHOULD BE AVOIDED. ... SYSTEMIC ADMIN...OCCASIONALLY MAY CAUSE BONE MARROW DEPRESSION. HEMOLYTIC ANEMIA HAS BEEN REPORTED IN PATIENTS WITH CONGENITAL ERYTHROCTIC GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY AND MEGALOBLASTIC ANEMIA HAS BEEN OBSERVED RARELY. [R19] *CLINICAL, RADIOGRAPHIC AND HISTOLOGIC FEATURES OF PULMONARY DISEASE INDUCED BY 40 DRUGS ARE DISCUSSED. NITROFURANTOIN IMPLICATED IN INDUCTION OF SYSTEMIC LUPUS ERYTHEMATOSUS. [R45] *A STUDY WAS CARRIED OUT COMPARING THE REPORTING OF ADVERSE REACTIONS TO NITROFURANTOIN IN SWEDEN, HOLLAND, AND THE UNITED KINGDOM. THE SWEDISH DRUG REGULATORY AUTHORITIES RECEIVE MORE REPORTS OF ADVERSE REACTIONS TO NITROFURANTOIN THAN TO ANY OTHER DRUG, AND THE ANNUAL REPORTING RATE IS INCREASING DESPITE A STEADY FALL IN THE PRESCRIPTION OF NITROFURANTOIN. THE CAUSES FOR SUCH DIFFERENCES ARE UNRESOLVED. [R46] *A DRAMATIC INCREASE IN THE NUMBER OF ADVERSE REACTIONS TO NITROFURANTOIN INITIATED A SURVEY OF THE REPORTS TO THE SWEDISH ADVERSE DRUG REACTION COMMITTEE 1966-1976. PULMONARY REACTIONS CONSTITUTED ABOUT HALF OF THESE REPORTS: 398 CASES WITH ACUTE AND 49 WITH CHRONIC REACTIONS. THREE-QUARTERS OF THE PATIENTS WERE HOSPITALIZED IN CONNECTION WITH THE REACTION. SIX REACTIONS WERE FATAL. THE ACUTE PULMONARY REACTIONS CARRY THE CHARACTERISTICS OF AN ALLERGIC REACTION BUT WE SUGGEST THAT THE CHRONIC PULMONARY AND LIVER REACTIONS MAY BE CAUSED BY A TOXIC MECHANISM. CHRONIC REACTIONS DO NOT FOLLOW UPON ACUTE REACTIONS, NOR DO ACUTE REACTIONS PREDISPOSE TO CHRONIC ONES. EARLY RECOGNITION OF THE REACTIONS AND PROMPT WITHDRAWAL OF THE DRUG ARE ESSENTIAL IN BOTH FORMS. [R47] *Nitrofurantoin crosses the placenta. Use is contraindicated in pregnancy at term and during labor and delivery, or when the onset of labor is imminent, because of the possibility of hemolytic anemia due to immature enzyme systems in the fetus. [R34, 2155] *Use of nitrofurantoin is contraindicated in infants up to 1 month of age because of the possibility of hemolytic anemia due to immature enzyme systems. [R34, 2155] *No information is available on the relationship of age to the effects of nitrofurantoin in geriatric patients. However, elderly patients are more likely to have an age related decrease in renal function, which may require a decrease in dosage or change in medication. Side effects, such as acute pneumonitis and peripheral polyneuropathy, may also occur more frequently in elderly patients. [R34, 2155] *Acute pneumonitis is more common in the elderly; symptoms usually occur within the first week of therapy. The pneumonitis is often reversible with discontinuation of the drug; corticosteroids may be beneficial in severe cases. Chronic pulmonary reactions, including diffuse interstitial pneumonitis and fibrosis, are insidious in onset and are more likely to occur in patients who have been on nitrofurantoin therapy for at least 6 months. pulmonary function may be permanently impaired even after the drug has been stopped, especially if pulmonary reactions are not recognized early. [R34, 2155] *Peripheral polyneuropathy is an ascending sensorimotor neuropathy, which may be progressive if the drug is not discontinued immediately. Polyneuropathy occurs more frequently in patients with renal dysfunction and in the elderly; however, it also occurs in patients with normal renal function who have received nitrofurantoin for prolonged periods of time. Demyelination and degeneration of both sensory and motor nerves occur. Nitrofurantoin should be stopped at the first signs of neuritis. [R34, 2155] *The most frequent adverse effects of nitrofurantoin are nausea and flatulence, occurring in about 8 and 1.5% of patients receiving the drug as dual-release capsules, respectively. Vomiting, anorexia, diarrhea, dyspepsia, constipation, and abdominal pain occur less frequently. Adverse GI effects appear to be dose related and may be minimized by reducing dosage or by administering the drug with food or milk. Nausea and vomiting appear to occur less frequently in some patients when nitrofurantoin is administered as macrocrystals rather than microcrystals. Sialadenitis and pancreatitis also have been reported in patients receiving nitrofurantoin. [R36, 633] *Headache is the most frequent adverse nervous system effect of nitrofurantoin, occurring in about 6% of patients receiving the drug as dual-release capsules. Peripheral polyneuropathy, which may become severe and/or irreversible and is potentially fatal, has been reported in patients receiving nitrofurantoin. Fatalities have occurred. Initial symptoms of peripheral polyneuropathy include paresthesia and dysesthesia, usually of the lower extremities, which may progress to muscle weakness and muscle wasting. Severe neuropathy is characterized by edema of interstitial tissues, demyelination of peripheral nerve fibers, and secondary changes in the spinal cord and striated muscles. The severity of symptoms and the rate of recovery are not related to dosage or the total amount of drug administered. Resolution of the polyneuropathy varies inversely with the severity of muscle weakness. Neuropathy occurs most frequently in patients with impaired renal function (creatinine clearance less than 60 mL/minute) or clinically important increases in serum creatinine concentrations), anemia, diabetes mellitus, electrolyte imbalance, vitamin B deficiency, or a debilitating disease. [R36, 633] *Early recognition of manifestations of nitrofurantoin-induced pulmonary reactions and discontinuance of the drug are necessary to prevent progression to more severe, potentially irreversible reactions. The insidious onset of chronic pulmonary reactions warrants close monitoring of patients on long-term nitrofurantoin therapy. Long-term nitrofurantoin therapy should be employed only when the potential benefits justify the possible risks to the patient. If a pulmonary reaction occurs, nitrofurantoin should be discontinued and appropriate measures taken. [R36, 633] *Nitrofurantoin should be used with caution in patients with renal impairment, anemia, diabetes mellitus, electrolyte abnormalities, vitamin B deficiency, or debilitating disease, since these patients are at increased risk of developing peripheral neuropathy; renal function should be monitored periodically during the long-term nitrofurantoin therapy. The drug should also be discontinued at the first sign of numbness or tingling, usually of the extremities, since this may be a symptom of peripheral neuropathy. [R36, 633] *Nitrofurantoin should be used with caution in patients with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, since hemolysis may occur. If hemolysis occurs, nitrofurantoin should be discontinued. [R36, 633] *Because the onset of nitrofurantoin-induced hepatotoxicity may be insidious, liver function should be monitored periodically in patients receiving long-term therapy with the drug. If hepatitis occurs, nitrofurantoin should be discontinued immediately and appropriate measures instituted. [R36, 633] *Use of nitrofurantoin may result in overgrowth of nonsusceptible organisms, especially Pseudomonas. [R36, 634] *Exfoliative dermatitis and erythema multiforme, including Stevens-Johnson syndrome, have been reported rarely with nitrofurantoin. Maculopapular, erythematous, eczematous eruptions; pruritus; urticaria; rash; and transient alopecia also have occurred. [R36, 633] *MOST COMMON UNTOWARD EFFECTS ARE NAUSEA, VOMITING AND DIARRHEA. INCIDENCE IS LESS IF DRUG IS ADMIN WITH MILK OR OTHER FOOD OR IS USED IN SMALLER DOSAGE. HOWEVER, SAME EFFECTS ARE SOMETIMES SEEN AFTER IV ADMIN. [R27, 1069] *VARIOUS NEUROLOGICAL DISORDERS ARE OCCASIONALLY OBSERVED. HEADACHE, VERTIGO, DROWSINESS, MUSCULAR ACHES, AND NYSTAGMUS ARE READILY REVERSIBLE, BUT SEVERE POLYNEUROPATHIES WITH DEMYELINATION AND DEGENERATION OF...SENSORY AND MOTOR NERVES HAVE BEEN REPORTED; SIGNS OF DENERVATION AND MUSCLE ATROPHY RESULT. [R27, 1070] *VARIOUS HYPERSENSITIVITY REACTIONS OCCASIONALLY OCCUR. THEY MAY INVOLVE...BLOOD, LIVER OR LUNGS. THEY INCL CHILLS, FEVER, LEUKOPENIA, GRANULOCYTOPENIA...CHOLESTATIC JAUNDICE AND HEPATOCELLULAR DAMAGE. [R27, 1069] *...HYPERSENSITIVITY REACTIONS (EG, DIFFUSE, ERYTHEMATOUS, MACULOPAPULAR RASH; URTICARIA; ECZEMATOID ERUPTION; PRURITUS), / and / HYPERBILIRUBINEMIA...HAVE BEEN NOTED OCCASIONALLY. ...SERIOUS BUT NONFATAL ANAPHYLACTIC REACTIONS...HAVE BEEN OBSERVED RARELY. [R48] *NITROFURANTOIN...ADMIN ORALLY, IS REPORTED IN SOME PT TO HAVE PRODUCED SEVERE ITCHING AND BURNING OF EYES, WITH EXCESS TEARING. SYMPTOMS ARE SAID TO HAVE PERSISTED IN SOME CASES FOR WEEKS AFTER MEDICATION WAS STOPPED. [R49] *...adverse effects reported rarely with the drug include crystalluria, photosensitization, angioedema, anaphylaxis, eosinophilia, increases in serum inorganic phosphorus concentrations, back pain, rhinitis, fever, and asthmatic attacks in patients with a history of asthma. [R36, 633] *The onset of symptoms of hepatic injury usually abrupt with fever (60%), rash (30%), and eosinophilia (70%). Approximately two-thirds of the patients have had previous exposure to nitrofurantoin. The latent period before the development of symptoms ranges from 2 days to 5 months but usually within the first 5 weeks. Cholestatic jaundice is the most common acute injury observed... [R18, p. 26-11] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R50] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NITROFURANTOIN WAS DETERMINED IN BULK, CAPSULES, TABLETS, AND SUSPENSIONS BY A COLORIMETRIC METHOD BASED ON THE REACTION OF NITROFURANTOIN WITH ORCINOL IN AN ALKALINE MEDIUM AND THE MEASUREMENT OF ABSORBANCE OF THE RESULTING ORANGE COLOR AT 435 NM. [R51] CLAB: *THE HPLC PROCEDURE DESCRIBED FOR DETECTION OF NITROFURANTOIN IN PLASMA, URINE AND BIOLOGICAL FLUIDS REQUIRES 0.2 ML OF SAMPLE, SHOWS LINEAR RELATIONSHIP IN RANGE OF 0.02 TO 200 MG/L AND CAN BE PERFORMED IN 9 MIN. [R52] *AN HPLC CHROMATOGRAPHY METHOD FOR DETECTION OF NITROFURANTOIN AND OTHER NITROFURAN DERIV IN BLOOD AND URINE IS DESCRIBED. DETECTION LIMIT WAS 0.02 MUG/ML. [R53] *NITROFURANTOIN WAS DETERMINED IN BLOOD SERUM BY DIFFERENTIAL PULSE POLAROGRAPHY OR HPLC. THE DETECTION LIMIT WITH 5 ML SERUM WAS 0.2 MUG/ML WITH THE HPLC METHOD AND 0.4 MUG/ML WITH POLAROGRAPHY. [R54] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: GLECKMAN R ET AL; DRUG THERAPY REVIEWS: NITROFURANTOIN; AM J HOSP PHARM 36(MARCH) 342 (1979). REVIEW WITH 237 REFERENCES ON ANTIMICROBIAL SPECTRUM, PHARMACOLOGY, THERAPEUTIC USES, ADVERSE REACTIONS, AND MECHANISM OF ACTION. CADWALLADER DE; BIOAVAILABILITY MONOGRAPH: NITROFURANTOIN; J AM PHARM ASSOC NS15(JULY) 409 (1975). BRIEF REVIEW OF FACTORS AFFECTING NITROFURANTOIN BIOAVAILABILITY IS PRESENTED. DHHS/NTP; Toxicology and Carcinogenesis Studies of Nitrofurantoin in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 341 (1989) NIH Publication No. 89-2597 SO: R1: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/7901 R2: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1122 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 827 R4: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 759 R5: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1134 R6: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1160 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-198 R8: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 857 R9: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992). 1134 R10: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 38 R11: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R12: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R13: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2440 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 50 224 (1990) R15: ISRAEL RH ET AL; RESPIRATION 39 (6): 318-22 (1980) R16: ANTTINEN H ET AL; ACTA MED SCAND 211 (3): 227 (1982) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R18: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995. R19: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. 1323 R20: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 388 R21: ITO A ET AL; TUMORIGENICITY TEST OF N-(5-NITRO-2-FURFURYLIDENE)-1-AMINOHYDANTOIN BY DIETARY ADMINISTRATION IN BDF1 MICE; HIROSHIMA J MED SCI 32(1) 99 (1983) R22: BURK RF, LANE JM; MODIFICATION OF CHEMICAL TOXICITY BY SELENIUM DEFICIENCY; FUNDAM APPL TOXICOL 3(4) 218 (1983) R23: Greenaway JC et al; Toxicol Appl Pharmacol 82:307-315 (1986) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V50 P 213 R25: Toxicology and Carcinogenesis Studies of Nitrofurantoin in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 341 (1989) NIH Publication No. 89-2597 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R26: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Nitrofurantoin (CAS No. 67-20-9): Reproduction and Fertility Assessment in CD-1 Mice When Administered via Feed, NTP Study No. RACB89063 (August 1989) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R27: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R28: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 76 R29: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 187 R30: American Society of Hospital Pharmacists. Data supplied on contract from American Hospital Formulary Service and other current ASHP sources. 1971 R31: KUMAR M ET AL; INDIAN DRUGS 19 (4): 140 (1982) R32: WIERZBA K ET AL; PAEDIATR PAEDOL 17 (2): 293 (1982) R33: HOENER BA, PATTERSON SE; CLIN PHARMACOL THER 29 (6): 808 (1981) R34: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R35: HOENER BA, PATTERSON SE; NITROFURANTOIN DISPOSITION; CLIN PHARMACOL THER 29(6) 808 (1981) R36: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements). R37: BOYD MR ET AL; BIOCHEM PHARMACOL 28 (5): 601 (1979) R38: COMBS GF JR; PROC-CORNELL NUTR CONF FEED MANUF: 9 (1979) R39: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R40: AL-JANABI II ET AL; J FAC MED BAGHDAD 22 (2): 44 (1980) R41: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R42: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R43: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 141 (1994) R44: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 752 R45: FILIPEK WJ; POSTGRAD MED 65 (FEB): 131 and 139 (1979) R46: PENN RG, GRIFFIN JP; BR MED J (CLIN RES) 284 (6327): 1440 (1982) R47: HOLMBERG L, BOWMAN G; PULMONARY REACTIONS TO NITROFURANTOIN. 447 CASES REPORTED TO THE SWEDISH ADVERSE DRUG REACTION COMMITTEE 1966-1976; EUR J RESPIR DIS 62(3) 180 (1981) R48: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 788 R49: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 663 R50: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R51: EMMANUEL J, SHELLY A; EAST PHARM 26 (308): 211 (1983) R52: AUFRERE MB ET AL; CLIN CHEM (WINSTON-SALEM, NC) 23 (12): 2207 (1977) R53: VREE TB ET AL; J CHROMATOGR 162 (1): 110 (1979) R54: EBEL S ET AL; ARCH PHARM (WEINHEIM, GER) 312 (8): 697 (1979) RS: 42 Record 222 of 1119 in HSDB (through 2003/06) AN: 3136 UD: 200303 RD: Reviewed by SRP on 9/9/1993 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NITROFURAZONE- SY: *U-6421-; *Aldomycin-; *Amifur-; *BECAFURAZONE-; *BIOFURACINA-; *BIOFUREA-; *Chemofuran-; *CHIXIN-; *COCAFURIN-; *COXISTAT-; *DERMOFURAL-; *ELDEZOL-F-6-; *FEDACIN-; *FLAVAZONE-; *FURACILLIN-; *Furacin-; *FURACIN-E-; *FURACINETTEN-; *FURACIN-HC-; *FURACOCCID-; *FURACORT-; *2-FURALDEHYDE,-5-NITRO-,-SEMICARBAZONE-; *FURALONE-; *FURAMETRAL-; *FURAN-OFTENO-; *FURAPLAST-; *FURASEPTYL-; *FURAZINA-; *FURAZOL-W-; *FURAZONE-; *Furesol-; *FURFURIN-; *FUROSEM-; *FUVACILLIN-; *HEMOFURAN-; *HYDRAZINECARBOXAMIDE, 2-((5-NITRO-2-FURANYL)METHYLENE)-; *IBIOFURAL-; *MAMMEX-; *MASTOFURAN-; *MONOFURACIN-; *Nefco-; *NF-7-; *NFS-; *NFZ-; *NIFURID-; *Nifuzon-; *NITROFURAL-; *5-Nitro-2-furaldehyde-semicarbazone-; *2-[(5-Nitro-2-furanyl)methylene]-hydrazinecarboxamid; *NITROFURAZAN-; *Nitrozone-; *NSC-2100-; *OTOFURAN-; *RIVAFURAZON-; *RIVOPON-5-; *SANFURAN-; *SPRAY-DERMIS-; *SPRAY-FORAL-; *Vabrocid-; *VADROCID-; *YATROCIN- RN: 59-87-0 MF: *C6-H6-N4-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF ACETONE SEMICARBAZONE WITH 5-NITROFURFURALDOXIME [R1] *PREPARED FROM 2-FORMYL-5-NITROFURAN AND SEMICARBAZIDE HYDROCHLORIDE [R2] FORM: *SOLN GENERALLY CONTAINS 0.2% NITROFURAZONE, EXCEPT FOR OPHTHALMIC OR NASAL SOLN, WHICH ARE 0.02%. TOPICAL AND VAGINAL CREAMS ARE 0.2%. VAGINAL INSERTS AND SUPPOSITORIES CONTAIN 0.3% (6 MG). URETHRAL INSERTS CONTAIN 0.2% (2.6 MG). SOL DRESSINGS CONTAIN 0.2%. [R3] *Topical Cream, 0.2% Furacin (with parabens), Roberts; Ointment, 0.2%, Furacin Soluble Dressing, Roberts; Nitrofurazone Soluble Dressing, CMC, Interstate, Moore, Rugby, United Research; Solution, 0.2%, Nitrofurazone Solution, Clay- Park. [R4, 2213] *Cream and soluble dressing, 0.2% [R5] MFS: *The Proctor and Gamble Co, Hq, 301 E Sixth St, PO Box 599, Cincinnati, OH 45201, (513) 983-5607; Subsidiary: Norwich Eaton Pharmaceuticals, Inc, 17 Eaton Ave, PO Box 191, Norwich, NY 13815, (607) 335-2111 [R6] *Rugby Laboratories Inc, 100 Banks Ave, Rockville Centre, NY 11570 (516) 536-8565, (800) 645-2158 [R4, 2213] OMIN: *IT IS UNSTABLE IN GALVANIZED WATERERS ... ITS SAFETY AS FOOD ADDITIVE IS BEING QUESTIONED. ... FDA HAS PROPOSED THAT IT BE WITHDRAWN AS APPROVED FEED ADDITIVE SINCE IT HAS BEEN SUSPECT AS TUMORIGENIC AGENT UNDER SOME EXPTL CONDITIONS. [R7] *... /IT/ HAS BEEN USED IN USSR AS COMPONENT OF PROTECTIVE PASTE FOR HANDS OF WORKERS IN INDUSTRY. [R8] *IN JAPAN IT IS USED ... AS PRESERVATIVE IN FOODS: THUS ... /DURING/ 1950-1966 IT WAS APPROVED ... /AS PRESERVATIVE/ FOR FISH SAUSAGE, FISH HAM, MEAT SAUSAGE, MEAT HAM AND KAMABOKO (FISH CAKE) AT CONCN OF 5 MG/KG. IT WAS ALSO PERMITTED TO BE INCL IN CRUSHED ICE AT LEVEL OF 20 MG/KG FOR PRESERVATION OF FRESH FISH. [R9] USE: *SENSITIZER AND FOOD ADDITIVE; EXPTL CARCINOGEN [R10] *MEDICATION (VET) *MEDICATION PRIE: U.S. PRODUCTION: *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1978) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW NEEDLES [R2]; *LEMON-YELLOW CRYSTALLINE POWDER [R3] ODOR: *ODORLESS [R3] TAST: *NEARLY TASTELESS BUT DEVELOPS BITTER AFTERTASTE [R3] BP: *236-240 deg C [R11] MW: *198.14 [R2] PH: *6.0-6.5 (SATURATED WATER SOLN) [R3] SOL: *1 G IN 4200 ML WATER, 590 ML ALC, 350 ML PROPYLENE GLYCOL; SOL IN POLYETHYLENE GLYCOL MIXT UP TO ABOUT 1%; PRACTICALLY INSOL IN CHLOROFORM AND ETHER [R3]; *SOL IN ALKALINE SOLN [R2] SPEC: *MAX ABSORPTION: 260 and 375 NM [R2] OCPP: *PRODUCES DARK ORANGE COLOR IN ALKALINE SOLN; DECOMP BETWEEN 236-240 DEG C [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes such as oxides of nitrogen. [R12] SSL: *DARKENS ON PROLONGED EXPOSURE TO LIGHT [R2] *SENSITIVE TO HEAT [R13] *STABLE IN SOLID STATE WHEN PROTECTED FROM LIGHT [R11] *Nitrofurazone darkens slowly on exposure to light; however, discoloration does not appreciably affect the potency of the drug. Light sensitivity is greatest with low concentrations of nitrofurazone in solution. The drug is stable in solutions with a pH of 4-9. Nitrofurazone may be autoclaved with little loss of antibacterial activity. Preparations of nitrofurazone should be stored and dispensed in tight, light resistant containers, avoiding exposure at all times to direct sunlight, strong fluorescent light, prolonged excessive heat, and/or alkaline materials. [R4, 2212] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence for the carcinogenicity of nitrofural in humans. There is limited evidence for the carcinogenicity of nitrofural in experimental animals. Overall evaluation: Nitrofural is not classifiable as to its carcinogenicity to humans (Group 3). [R14] HTOX: *Allergic contact dermatitis has been reported (the overall rate is about 1.1%); hypersensitivity reaction is more common on damaged skin. [R15] *... /NITROFURAZONE/ CAUSES SEVERE POLYNEUROPATHY AND REVERSIBLE DEGENERATION OF SEMINIFEROUS TUBULES. [R16, 1074] */IT/ HAS PRODUCED CONTACT DERMATITIS IN MAN. [R17] *... SYSTEMIC TOXICITY OF NITROFURAZONE IS RELATIVELY LOW ... . [R16, 979] *AVAILABLE EVIDENCE /FROM ANIMAL STUDIES/ IS INSUFFICIENT TO EVALUATE THE CARCINOGENICITY OF THIS COMPD. NO CASE REPORTS OR EPIDEMIOLOGICAL STUDIES WERE AVAILABLE TO THE WORKING GROUP. [R18] *Allergic contact dermatitis is the most frequently reported adverse effect of topical nitrofurazone and has occurred in approximately 1% of patients treated. Initial signs and symptoms of a developing allergic reaction include erythema pruritus, or burning; these reactions may be confused with the condition being treated. More severe manifestations include edema, vesiculation, denudation, and ulceration. Systemic reactions, including exfoliative dermatitis, autosensitization, urticaria and anaphylactoid reactions, have also been reported. Allergic sensitization probably persists throughout the patient's life. Geriatric patients seem especially susceptible to developing systemic reactions to any contact allergen. [R4, 2212] *Contact dermatitis also has been attributed to residual ethylene oxide used for sterilization of nitrofurazone dressings. [R4, 2212] *The polyethylene glycols present in nitrofurazone ointment (but not in the cream) can be absorbed through denuded skin and may not be excreted normally in patients with compromised renal function; accumulation may lead to symptoms of progressive renal impairment such as increased BUN, anion gap, and metabolic acidosis. [R4, 2213] *A discussion was provided of a case report involving a 43 year old man who had worked for 8 yr as a pig keeper on a research farm and who had developed dermatitis of the fingertips 3 mo before consultation. Patch testing of the patient revealed contact allergy to an animal feed additive and to a veterinary pharmaceutical, both having furazolidone as the only common ingredient. Subsequent patch testing with 2% furazolidone in petrolatum vehicle gave completely negative results, but patch testing with 2% furazolidone in polyethylene glycol 400 and in alcohol produced positive reactions. No cross reactions were observed to nitrofurazone, nitrofurantoin, or furfural. A review was presented on reported contact allergies to furazolidone, other nitrofuran derivatives, and furfural. Also reviewed were cross reactions between nitrofurazone, furazolidone, and nifurprazine. It was concluded that polyethylene glycol 400 is preferable to petrolatum for patch testing of furazolidone. [R19] *Allergic contact dermatitis to nitrofurazone has been reported from Europe and elsewhere from the use of eyedrops and topical ointments, and the drug in some livestock feeds and veterinary medications has caused a few cases of allergic contact dermatitis in humans. first case of contact dermatitis from airborne nitrofurazone secondary to a powdered aquarium water additive was reported. [R20] NTOX: *30 WEANLING FEMALE SPRAGUE-DAWLEY RATS /WERE/ FED DIET CONTAINING 1000 PPM ... /NITROFURAZONE, FREE OF DETECTABLE IMPURITY/ FOR 46 WK ... TOTAL DOSE, 4.8 G, 24.2 MMOLES/RAT, 29 RATS SURVIVED 22 OR MORE WK AND 22 DEVELOPED 1 OR MORE BENIGN MAMMARY TUMORS. 2 OF 29 CONTROL RATS DEVELOPED BENIGN MAMMARY TUMORS. [R21] *22 DAY OLD FEMALE HOLTZMAN RATS WERE FED DIET CONTAINING 1000 PPM ... /NITROFURAZONE CONTAINING ABOUT 3% 5-NITRO-2-FURALDEHYDE AZINE/ FOR 44 WK ... TOTAL DOSE, 4.5 G, 22.8 MMOLES/RAT. ALL 24 RATS SURVIVING 36 OR MORE WK DEVELOPED BENIGN MAMMARY TUMORS. 3 BENIGN MAMMARY TUMORS WERE PRESENT AMONG 16 UNTREATED CONTROLS. [R21] *60 DAY OLD FEMALE HOLTZMAN RATS /WERE/ FED A DIET CONTAINING 1000 PPM 5-NITRO-2-FURALDEHYDE SEMICARBAZONE (CONTAINING ABOUT 3% 5-NITRO-2-FURALDEHYDE AZINE) FOR 36 WK FOLLOWED BY CONTROL DIET FOR 19 WK (TOTAL DOSE, 3.5 G, 17.5 MMOLES/RAT), BENIGN MAMMARY TUMORS DEVELOPED IN 11/18 RATS WHICH SURVIVED FOR 36 OR MORE WK. [R9] *DOGS ON HIGH DOSAGE SCHEDULES MANIFESTED CONVULSIONS AND PARALYSIS. [R22] *... /IT HAS/ ABILITY TO PRODUCE NEUROPATHY POSSIBLY DUE TO TIE-UP OF VITAMIN B6 (PYRIDOXINE). ... PHEASANT CHICKS, GOSLINGS, AND DUCKLINGS ARE MORE SUSCEPTIBLE TO DRUG'S TOXIC EFFECTS THAN ARE CHICKENS. [R7] *0.022% FED TO 2 WK OLD ... /DUCKLINGS/ CAUSED 50% MORTALITY. DEATH OCCURRED SUDDENLY WITHOUT PREVIOUS SIGNS OF INTOXICATION. MUCOUS PROVENTRICULITIS, ACUTE CATARRHAL ENTERITIS AND NEPHRITIS ... SEEN AT POST MORTEM. AS LITTLE AS 0.01% WAS FATAL TO DAY OLD DUCKLINGS. 0.06% IN DIET CAUSED HIGH MORTALITY IN TURKEY POULTS. [R23] *SIGNS OF POISONING MAY INCL DEPRESSION, CHICKS STANDING ABOUT "MOTIONLESS, BEDRAGGLED, ROUGH FEATHERED AND DEVOID OF INTEREST IN ... FOOD OR DRINK", OR HYPEREXCITABILITY, WITH WHIRLING IN CIRCLES, ENDING IN "CONVULSIVE MOVEMENTS LIKE THOSE OF DECAPITATED BIRD". ... /POST MORTEM/ PATCHY ENTERITIS AND CARDIAC DEGENERATION. [R23] *ACCIDENTAL POISONING HAS BEEN DESCRIBED IN BABY CHICKS AS RESULT OF ERRORS IN DOSAGE. SINGLE DOSES OF 150-200 MG/KG ... TO TEN 14 WK OLD CHICKS WERE FOUND TO INDUCE TOXIC SYMPTOMS SOMETIMES WITHIN 4 HR. ... /PRC: POLYNEUROPATHY/ AND CURLED TOE PARALYSIS HAVE BEEN DESCRIBED IN CHICKS MAINTAINED ON DRY MASH CONTAINING 0.025% OR MORE. [R23] *ACUTE TOXIC EFFECTS OF HIGH DOSES ... ADMIN TO ANIMALS INCL GROWTH RETARDATION, NEUROTOXICITY, RENAL TUBULAR, HEPATIC, ADRENAL AND TESTICULAR CYTOTOXICITY AND INHIBITION OF IMMUNOCOMPETENCE. [R21] *Nitrofurazone was evaluated in the mammalian cell Chinese hamster ovary/Hypoxanthine Guanine Phosphoribosyl transferase gene mutation assay at a dose range of 25-200 ug/ml. The test protocol used met criteria established for this assay by the Gene-Tox Program. Nitrofurazone was negative at all dose levels tested with and without metabolic activation. [R24] *Nitrofurazone wastested for embryotoxicity in cultured rat embryos, and the effects were compared with those of other 5 membered heterocycles. Sprague Dawley rat embryos were explanted on day 10 of gestation and grown in culture medium to which the test compounds were added. After 26 hr in culture, the embryos were removed and examined for malformations. Nitrofurazone produced axial asymmetry of the cephalic region in the embryos, associated with microphthalmia or anophthalmia and frequently with scoliosis, in concentrations ranging from 0.02 to 0.50 mM. There was a 100% incidence of axial asymmetry at 0.20 mM concentration, along with a significant reduction in embryonic length and somite number. [R25] *In toxicity studies, administration of very large oral doses of nitrofurazone has resulted in mammary tumors in female rats; however, the relevance of this to topical use in humans is not known. [R4, 2213] *When nitrofurazone 30 mg/kg was administered orally to pregnant rabbits once daily on days 7-15 of pregnancy, there was a slight increase in the frequency of stillbirths, but no teratogenic effects were seen. [R4, 2213] *Spermatogenic arrest has occurred in rats receiving oral dosages of 30 mg/kg daily or greater for one year. [R4, 2213] *Nitrofurazone, a topical anti-infective, has been reported to cause an increase in oxygen utilization in vitro by rabbit and pig retina, to cause clumping of retinal pigment in rabbits when injected subcutaneously daily for 20 days, to reduce the alpha and beta waves of the electroretinogram, and to slow the recovery of the electroretinogram from pressure ischemia. [R26] *The concentrations of gamma-amino butyric acid and glutamate were measured in the brains of chickens which were treated with furazolidone or nitrofurazone at oral doses of 12.5, 25 or 50 mg/kg for 5 days. At the end of the treatment, the birds lost about 9% of their body wt when on the small dose of furazolidone or nitrofurazone and about 18% when on the high doses. Both drugs produced dose dependent increases in the concentrations of gamma-amino butyric acid and glutamate which were statistically significant at doses of 25 and 50 mg/kg of nitrofurazone, and 50 mg/kg of furazolidone. [R27] *The present experiments examined the protective effect of the nitrofuran drugs, furazolidone and nitrofurazone, on duodenal ulceration induced by cysteamine or indometacin in rats. Furazolidone at oral doses of 25, 50 or 100 mg/kg for 2 consecutive days significantly reduced, in a dose dependent manner, the incidence and extent of cysteamine induced ulceration. However, oral nitrofurazone (100 mg/kg) given for 2 consecutive days had no significant effect on duodenal ulceration. The duodenal mucus content of rats was not significantly affected by either furazolidone or cysteamine treatments. Furazolidone at an oral dose of 100 mg/kg for 2 consecutive days significantly reduced the incidence and extent of indometacin induced ulceration. Smaller doses of 25 or 50 mg/kg had no significant effects. [R28] *The genotoxic properties of nitrofurazone and furazolidone were studied using the Ames test and SOS-chromotest. Both cmpd were found to act as strong mutagens on the TA97 and TA102 strains of Salmonella typhimurium and to induce the SOS-repair system in the PQ37 strain of Escherichia coli. A good concordance was found between the mutagenic activity and the ability to induce the SOS system. Ascorbic acid and sodium selenite only very slightly lowered the genotoxic effect of the 2 nitrofurans studied both in the Ames test and in the SOS-chromotest. [R29] *The reproductive toxicity of nitrofurazone, a nitrofuran antibiotic, was evaluated in CD-1 Swiss mice by the Continuous Breeding protocol. Mice received nitrofurazone in feed at 100, 375, and 750 ppm (15-124 mg/kg/day). F0 750 ppm pairs had significantly reduced fertility after 7 days exposure to nitrofurazone (17% vs. 98% for controls), and were infertile after the second litter. Mid-dose pairs had progressively decreasing fertility, 47% by the 5th litter, reduced litter size, and reduced proportion of pups born alive. Crossover breeding of control and high dose F0 animals confirmed infertility in high dose males and reduced litter size and pup wt in high dose females. F0 males had reduced testis wt, sperm concentration, and abnormal sperm morphology at all doses of nitrofurazone. Increased liver and kidney plus adrenal wt were observed at 375 and 750 ppm; hepatic hypertrophy was noted microscopically at 750 ppm. F0 females had reduced body and increased kidney plus adrenal wt, hepatic hypertrophy, and altered estrous cycles at 750 ppm, and reduced ovarian wt at all doses. In the second generation, F1 mice at 375 ppm had reduced postnatal survival and body wt, and produced smaller litters compared to controls. At necropsy, F1 males had reduced testes wt and sperm concentration, abnormal sperm morphology, hepatic hypertrophy at 375 ppm, and borderline nephropathy at 100 and 375 ppm. F1 females had decreased body wt and altered estrous cycles at 375 ppm. Thus, nitrofurazone at greater than or euqal to 375 ppm caused significant reproductive effects in F0 and F1 mice in the presence of relatively mild systemic toxicity. Males were more severely affected than females. [R30] *Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice for 14 days, 13 wk or 2 yr. In the 14 day studies, in which doses ranged from 630 to 10,000 ppm, nitrofurazone was more toxic to mice than to rats. Accordingly, in the 13 wk studies, doses for rats ranged from 150 to 2500 ppm and for mice from 70 to 1250 ppm. At the higher doses, convulsive seizures and gonadal hypoplasia were observed in both species. Evidence of toxicity in rats also included degenerative arthropathy. For the 2 yr studies, rats were exposed to 0, 310 or 620 ppm nitrofurazone and the survival of male rats given 620 ppm was lower than that of controls (33/50, 30/50 and 20/50 in the control, 310 and 620 ppm groups, respectively). Nitrofurazone administration increased the incidences of mammary gland fibroadenomas in female rats (8/49, 36/50 and 36/50 in the control, 310 and 620 ppm groups, respectively). In male rats it was associated with a marginal increase in sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and tumors of the perputial gland. Nitrofurazone caused testicular degeneration (atrophy of germinal epithelium and aspermatogenesis) in rats, and degeneration of vertebral and knee articular cartilage in rats of both sexes. In mice, dietary concentrations of nitrofurazone for the 2 yr studies were 0, 150 or 310 ppm. In mice of each sex, nitrofurazone administration induced stimulus sensitive convulsive seizures, primarily during the first yr of study. In male mice, there was no evidence of any chemically related carcinogenic effects, but there was a treatment related decrease in survival (39/50, 31/50 and 27/50 in the control, 150 and 310 ppm groups, respectively). In female mice nitrofurazone induced ovarian lesions with increased incidences of benign mixed tumors (0/47, 17/50 and 20/50 in control, low and high dose groups, respectively) and granulosa cell tumors (1/47, 4/50 and 9/50 in control, low and high dose groups, respectively). [R31] *A review was presented of data for chemicals for which either ovarian toxicity or carcinogenicity, or both, have been documented in recent studies in the NTP. In most cases, ovarian atrophy was commonly found after 90 days of exposure, and ovarian hyperplasia and neoplasia after longer periods. Nitrofurazone administered in feed produced ovarian hyperplasia and neoplasia. It was concluded that treatment associated ovarian lesions are not common and that the evidence suggests that alterations at the conclusion of 90 day studies may herald the ultimate development of ovarian neoplasia upon continued treatment. [R32] +... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of nitrofurazone for male F344/N rats as shown by the occurrence of sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and preputial gland tumors. There was clear evidence of carcinogenic activity o~ mtro~urazone for female F344/N rats as shown by a markedly increased incidence of fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nitrofurazone at concentrations of 150 or 310 ppm. There was clear evidence of carcinogenic activity of nitrofurazone for female B6C3F1 mice as shown by increased incidences of benign mixed tumors and granulosa cell tumors of the ovary. [R33] NTP: +... Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3Fl mice of each sex for ... 2 yr. Body Weight and Survival in the Two-Year Studies: Dietary concentrations for the 2 yr studies were 0, 310, or 620 ppm for rats and 0, 150, or 310 ppm for mice (50 animals per dose group). ... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of nitrofurazone for male F344/N rats as shown by the occurrence of sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and preputial gland tumors. There was clear evidence of carcinogenic activity o~ mtro~urazone for female F344/N rats as shown by a markedly increased incidence of fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nitrofurazone at concentrations of 150 or 310 ppm. There was clear evidence of carcinogenic activity of nitrofurazone for female B6C3F1 mice as shown by increased incidences of benign mixed tumors and granulosa cell tumors of the ovary. [R33] +Nitrofurazone (NTFZ) was evaluated for reproductive toxicity in CD-1 (Swiss) mice using Reproductive Assessment by Continuous Breeding Protocol (RACB). Male and female mice were exposed to NTFZ in feed at doses of 0, 100, 375, and 750 ppm (15-124 mg/kg/day). At 750 ppm in female F0 animals, increased relative kidney plus adrenal weight and hepatic centrilobular hypertrophy were seen. For males, doses of = or > 375 ppm increased kidney effects. Reproductive toxicity was observed in the F0 generation at all dose levels and increased in a dose-related manner. In all NTFZ-treated groups, testicular degeneration, incr in the % abnormal sperm, and reduced relative ovary plus oviduct weight were observed. At 375 and 750 ppm, fertility and fecundity were reduced, as were sperm concn and testis and/or epididymis weight. At the high dose, males were infertile and exhibited testicular hypospermia and epididymal hypo- or azoospermia, and elevated relative intratesticular testosterone concn. During Task 2, adverse effects of treatment on delivery and postnatal care were noted, primarily at 375 ppm NTFZ, and included live or dead pups left inside the amniotic sac or with the placenta attached, pups born prematurely, or an extended (> 24 hrs) delivery period. In Task 3, the treated males were infertile, whereas the treated females exhibited reduced litter size and adjusted pup body weight. For F1 males, 100 ppm produced a borderline incr in nephropathy. For F1 females, 375 ppm decreased postnatal survival and decreased female body weight. Reproductive toxicity, including a decr in the proportion of pups born alive, secondary to a decr in the number of live-born female pups/litter, and a shortened gestational period were observed at 375 ppm. Relative cauda epididymis weight was decreased at both 100 and 375 ppm NTFZ, whereas a decr in sperm concn and incr in the % abnormal sperm, and significant testicular degeneration were observed at 375 ppm. Absolute and relative intratesticular testosterone concns were unaffected. Estrous cycle length and pattern were significantly affected at both 100 and 375 ppm. In summary, the MTD for generalized toxicity was 375 ppm for the F0 generation and 100 ppm for the F1 generation. The No-Observed-Adverse-Effect-Level (NOAEL) for systemic toxicity was 100 ppm for the F0 generation. A NOAEL for the F1 generation could not be determined. Reproductive toxicity was observed at all treatment levels tested for both generations. Thus, there was no NOAEL for reproductive toxicity in this study. NTFZ was a reproductive toxicant to CD-1 mice in both the F0 AND F1 generations at doses at and below those which caused systemic toxicity. [R34] +Nitrofurazone (5-nitro-2-furaldehyde semicarbozone) ... was recommended for immunotoxicological evaluation /using female B6C3F1 mice/. Female B6C3F1 mice were administered nitrofurazone at doses of 40, 60 or 80 mg/kg daily for 14 consecutive days. ... Cyclophosphamide was used as a positive control. ... Nitrofurazone produced a dose-dependent incr (16%) in liver weight, while no changes occurred in body, spleen or thymus weights. Hematological parameters were not affected, with the exception of the reticulocyte count which was increased (27%) in a dose-dependent manner. Serum chemistries were unaffected by nitrofurazone exposure. ... Nitrofurazone produced no changes on indicators of humoral immunity, such as B cell number, proliferative ability or ability to differentiate into antibody-producing cells to a T-dependent antigen. Although some changes were observed in the proliferative capacity of T lymphocytes in one of the mitogenicity studies, no effects on the proliferation capacity were observed in the mixed leukocyte response. There were no changes in the percent or number of T cells or subsets of T cells in mice exposed to nitrofurazone. The differentiation and killing mechanisms of T cells were intact in mice treated with nitrofurazone as seen in a CTL response which did not differ from the control group. With respect to innate immunity, natural killer cell function was unaffected by nitrofurazone exposure. ... The B16F10 pulmonary metastatic melanoma model was unaffected by exposure to nitrofurazone. In summary, nitrofurazone, administered daily for 14 days, did not substantially alter any of the immunological or host resistance parameters measured. [R35] +Nitrofurazone (NF) ... was evaluated for toxic and teratogenic effects in timed-pregnant CD-1 mice. Nitrofurazone (0%, 0.0038%, 0.0075%, 0.0250% or 0.0500%) was administered continuously in the feed (i.e., ground rodent chow) on gestational days (gd) 6-15. Availability of nitrofurazone in the diet resulted in the ingestion of avg doses of 0, 6.28, 13.62, 41.18 and 81.70 mg/kg/day nitrofurazone for the control through highest concn, respectively. Females were weighed and observed during daily treatment for clinical signs of toxicity. At sacrifice on gestational day 17, a total of 20-26 dams (i.e., confirmed pregnant females)/group were evaluated. The gravid uterus for each dam was weighed. Following uterine dissection the number and status of uterine implantation sites was recorded (i.e., resorptions, and live or dead fetuses). Each live fetus was weighed, sexed and examined for external, visceral and skeletal malformations. During nitrofurazone treatment, dams exhibited limited clinical signs of toxicity and no unscheduled deaths occurred during this investigation. Notably, the results of the dose range finding study indicated that exposure to a higher dietary concn (0.0750%) produced mortality or morbidity in 15% of the females on study, and was therefore considered too toxic to be included in the teratology study. In the teratology study, maternal body weight did not differ significantly among groups prior to initiation of nitrofurazone exposure (gestational days O AND 6). Nitrofurazone exposure produced no treatment-related effects on the following parameters: maternal body weight on gestational days 11, 15 or 17; maternal weight gain during gestation (gestational days 0-20); maternal weight gain during treatment (gestational days 6-15); absolute maternal weight gain (i.e., gestational weight gain minus gravid uterine weight), gravid uterine weight, maternal liver weight (g) or relative maternal liver weight (% body weight). Indices of reproductive competence prior to the initiation of treatment on gestational days 6 revealed no statistically significant differences among groups for the number of corpora lutea/dam or for the number of implantation sites/dam. However, the % preimplantation loss was significantly decreased below the control group for dams in the 0.0038%, 0.0250% and 0.0500% nitrofurazone-exposed groups. Since the number of implantation sites/dam did not differ among groups, subjects were considered to be reasonably matched across treatment groups for reproductive status at the time nitrofurazone exposure was initiated. With regard to post-implantation viability, nitrofurazone exposure was not associated with an increased incidence of resorptions. Neither the % resorptions/litter nor the % litters with resorptions showed statistically significant differences among groups. However, both the % dead fetuses/litter and the % litters with dead fetuses exhibited a significant increasing trend as dietary nitrofurazone increased in concn. No statistically significant treatment-related effects were observed for the % nonlive implants (i.e., resorptions plus dead fetuses)/litter, the % litters with nonlive implants, the % adversely affected implants (i.e., nonlive implants plus malformed live fetuses)/litter, or the % litters with adversely affected implants. In litters containing at least 1 live fetus (herein referred to as "live litters"), no statistically significant treatment-related effects were observed for the number of live fetuses/live litter, the % male fetuses/live litter, the % fetuses (male, female or both) malformed/live litter, or the % live litters with malformed fetuses. Avg fetal body weight (males, females or both)/live litter declined as dietary concn of NF increased and the 0.0500% NF group was significantly below the vehicle control group for avg body weight of male fetuses, female fetuses or both sexes combined. In conclusion, exposure of timed-pregnant CD-l mice to NF (0%, 0.0038%, 0.0075%, 0.0250% or 0.0500%) in the diet during major organogenesis (gestational days 6-15) produced no evidence of a teratogenic effect in fetuses evaluated on gestational days 17. Selective embryotoxicity - expressed as an increased risk of late fetal death and intrauterine growth retardation - was observed at exposure levels which were only marginally toxic to the exposed dams. [R36] +... Artificially-inseminated New Zealand White rabbits were exposed to nitrofurazone (O, 5, 10, 15 or 20 mg/kg/day , po) in corn oil vehicle throughout major organogenesis (gestational days (gd) 6-19). At scheduled sacrifice (gestational days 30), the uterine contents of 121 confirmed pregnant does were evaluated (22-27/group). No maternal deaths occurred at 0, 5, 10 or 15 mg nitrofurazone/kg/day; an 8% (2/26) mortality rate was observed at the high dose. Clinical signs were observed more frequently in nitrofurazone-exposed animals, but no clear dose-related pattern was associated with these findings. No differences among groups were observed for maternal body weight (gestational days 0, 6, 12 or 30), maternal weight gain during gestation, or corrected gestational weight gain. On the final day of dosing (gestational days 19), a significant downward trend for maternal body weight was observed due to minor reductions at 10, 15 and 20 mg/kg/day (98.5%, 95.7% and 94.1% of controls, respectively). In addition, a significant downward trend for gravid uterine weight was observed due to reductions at 20 mg/kg/day. The 20 mg/kg/day group exhibited significantly decreased maternal weight gain during treatment, and increased maternal liver weight (both absolute and relative), but no clear treatment-related effects were observed for these paremeters at 5-15 mg/kg/day . Among live litters, nitrofurazone exposure did not affect the number of live fetuses/litter, % of male fetuses/litter, or avg fetal body weight/litter. Among all pregnant females, however, a significant incr was observed in the high-dose group for the % of resorptions/litter. The mean % of resorptions/litter was 7.49%, 2.74%, 13.15%, 8.67% and 30.86% in the vehicle through high-dose groups, respectively. The % of live fetuses malformed/litter was also increased at the high dose (2. 68%, 6.15%, 0.38%, 4.84% and 14.60% for the control through high-dose groups, respectively). A sex-selective effect of nitrofurazone upon morphological development was observed in which male fetuses were not affected, and female fetuses exhibited a significant incr in malformation incidence at 20 mg/kg/day . In summary, no definitive evidence of maternal or embryo/fetal toxicity was observed following admin of nitrofurazone at 5, 10 or 15 mg/kg/day , po. Nitrofurazone exposure at 20 mg/kg/day was associated with 8% (2/26) maternal mortality, reduced maternal weight gain during treatment, increased maternal liver weight (both absolute and relative), increased resorption of implanted conceptuses and an increased incidence of malformed live fetuses/litter Thus, the present investigation provided evidence of adverse embryo/fetal effects only at a dose which was lethal to 8% of the pregnant females. [R37] TCAT: ?Teratogenicity was evaluated in Charles River CD-1 certified time-mated female mice (50 sperm plug positive/group) orally exposed to nitrofurazone (in water) via gavage at 0 and 100 mg/kg/day (the maximum tolerable dose as determined in preliminary tests) once a day in the morning, over days 7-14 inclusive of gestation. There was one treatment related death on day 17, versus none in the controls, and this animal exhibited body tremors, hunching, hypothermia, subdued behavior with piloerection and sunken eyes. Effects observed in other treated animals included hunching, hyperactivity, piloerection and discoloration of fur. Both the reproductive and gestation indices were significantly reduced in the treated group relative to controls (p < 0.05 and p < 0.01, respectively, using 2x2 contingency tables). There were additional differences between treated and control animals in the following: decreased body weight gain (over days 7-18 of gestation, p < 0.01 in the data adjusted for litter size on day 1), and a small decrease in mean litter mean pup weight on day 1 post partum (p < 0.05), which was still apparent at day 3 (though not statistically significant). There were no significant differences between treated and control animals with respect to group litter viability. [R38] POPL: *Nitrofurazone ointment should be used with caution in patients with known or suspected renal impairment, since it contains polyethylene glycols which may be absorbed and may produced adverse effects. [R4, 2213] ADE: *ABOUT 1% OF (14)C WAS RECOVERED FROM URINE, FECES AND BILE AS UNCHANGED 5-NITRO-2-FURALDEHYDE SEMICARBAZONE, SUGGESTING SUBSTANTIAL METABOLISM OF THIS SUBSTANCE IN RAT /AFTER ORAL DOSAGE OF 100 MG/KG/. [R18] *RATS DOSED WITH 100 MG/KG 5-NITRO-2-FURALDEHYDE SEMICARBAZONE- [FORMYL-(14)C] ... EXCRETED ABOUT 66%, 35% and 1% OF ACTIVITY IN URINE, FECES AND IN RESPIRED AIR AS CO2, RESPECTIVELY, WITHIN 96 HR, AND MAJORITY OF (14)C ACTIVITY WAS ELIMINATED WITHIN 48 HR. RECOVERY OF (14)C IN BILE WAS ABOUT 27% AFTER 48 HR. [R18] *IN RATS DOSED WITH 100 MG/KG, PLASMA LEVELS OF 4.5 MG/L ... WERE FOUND AFTER 4 HR, 34% OF WHICH WAS BOUND TO PROTEINS. RATS DOSED WITH 200 MG/KG ... EXCRETED ABOUT 4.6% IN URINE AND 0.5% IN FECES WITHIN 48 HR. ORALLY ADMIN 5-NITRO-2-FURALDEHYDE SEMICARBAZONE WAS DETECTED IN CEREBROSPINAL FLUID OF DOGS WITHIN 2 HR. [R18] METB: */NITROFURAZONE HAS/ BEEN SHOWN TO BE REDUCED BY ENZYMES AND PREPN FROM MAMMALIAN LIVER. ... ISOLATION OF A HYDROXYLAMINE INTERMEDIATE IS NOT UNCOMMON IN IN VITRO STUDIES. [R39] *The disposition of the antibiotic nitrofurazone was studied in the singlepass isolated perfused rat liver. Both the effects of the steady state level of drug and the composition of the perfusate were evaluated. The higher level (120 ug/ml) of nitrofurazone in a perfusion medium lacking the glutathione precursors, glycine, glutamic acid and cysteine, caused a marked increase in bile flow (from 1.01 + or - 0.07 to 2.33 + or - 1.07 ul/min/g), massiv biliary efflux of glutathione disulfide (from 0.55 + or - 0.07 to 60.6 + or - 25.4 nmol/min/g) and a sharp decline in the caval efflux of glutathione (to undetectable levels) and the tissue level of glutathione (from 5.74 + or - 0.20 to 2.68 + or - 0.13 umol/g). Even after the drug was discontinued, these parameters were not restored to control levels. The lower level (30 ug/ml) of nitrofurazone with or without amino acid supplementatio and the higher level with supplementation induced less dramatic effects. Using (35)S methionine, a new conjugated metabolite of nitrofurazone and glutathione was detected. The data suggest that the toxicity of the reactive oxygen species generated by the redox cycling of the nitro group and the reactive metabolites generated by further reduction of nitrofurazone can be mitigated by adequate glutathione levels, but that livers lacking sufficient glutathione to scavenge these reactive species may be damaged. [R40] ACTN: *MECHANISM OF ANTIBACTERIAL ACTION OF FURAN DERIV IS UNKNOWN, BUT IT IS PRESUMED THAT THE COMPD INTERFERES WITH ENZYMATIC PROCESSES ESSENTIAL TO BACTERIAL GROWTH. /FURAN DERIV/ [R41] *The exact mechanism of action of nitrofurazone is not known. It appears, howeverthat the drug acts by inhibiting bacterial enzymes involved in carbohydrage metabolism. Oragnic matter (eg, blood pus, serum) and aminobenzoic acid (p-aminobenzoic acid) inhibit the antibacterial action of nitrofurazone. [R4, 2212] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Local; Anti-Infective Agents, Urinary; Trypanocidal Agents [R42] */NITROFURAZONE/ IS BACTERICIDAL FOR MANY GRAM POSITIVE AND GRAM NEGATIVE ORGANISMS PRESENT IN SURFACE INFECTIONS ... IT HAS BEEN USED TOPICALLY TO TREAT INFECTIONS OF SKIN AND MUCOUS MEMBRANES. [R43] *NITROFURAZONE MAY BE TRIED IN ... /LATE-STAGE TRYPANOSOMIASIS/ WITH SOME CHANCE OF SUCCESS. SINGLE COURSE OF TREATMENT ... AT 6 HR INTERVALS FOR 1 WK. 3 COURSES MAY BE GIVEN WITH A WEEK'S REST BETWEEN EACH. [R16, 1074] *IT FINDS USE, ESP, IN TREATMENT OF 2ND AND 3RD DEGREE BURNS AND IN SKIN GRAFTING IN WHICH THERE ARE COMPLICATIONS FROM BACTERIAL INFECTIONS THAT ARE REFRACTORY TO USUAL DRUGS OF CHOICE BUT IN WHICH SENSITIVITY TO NITROFURAZONE IS DEMONSTRABLE. ... NITROFURAZONE IS USED IN MGMNT OF SUSCEPTIBLE INFECTIONS OF EYE, EAR, NOSE, URETHRA AND VAGINA. ... /IT/ RETAINS ITS ANTIBACTERIAL ACTIVITY IN BLOOD, SERUM AND PUS; PHAGOCYTOSIS IS NOT INHIBITED AND NITROFURAZONE DOES NOT INTERFERE WITH HEALING. [R3] *SOME STUDIES HAVE INDICATED THAT IT IS USEFUL IN CONTROLLING METASTASES OF MALIGNANT TESTICULAR TUMORS AND IN CONTROL OF TROPICAL ILLNESS, CHAGAS DISEASE. [R8] *... IT IS SLOWLY ACTING DRUG, AND AT LEAST 24 HR ARE REQUIRED FOR IT TO TAKE EFFECT PROPERLY. THEREFORE, NO TREATMENT SHOULD BE LESS THAN 2 OR 3 DAYS IN DURATION. [R3] *.... FIVE DAYS IS USUAL DURATION, EXCEPT FOR SEVERE BURNS. EXCEPT IN BURN THERAPY, DURATION OF LESS THAN 1 WK IS USUALLY DESIRABLE, TO AVOID SENSITIZATION. [R3] *MEDICATION (VET): ORALLY, AS COCCIDIOSTAT AND POLLORUM CONTROL IN CHICKENS; INTESTINAL ANTIBACTERIAL IN TURKEYS, SWINE, MINK AND DOGS; AS COCCIDIOSTAT IN DOGS; AS TOPICAL ANTIBACTERIAL ON WOUNDS ... INTRAMAMMARY IN MASTITIS OF COWS; INTRAUTERINE IN METRITIS OF COWS; and ... AS PROPHYLACTIC AND THERAPEUTIC AGENT AGAINST STAPHYLOCOCCI SPECIES IN SWINE. [R7] *MEDICATION (VET): FOR PREVENTION OR TREATMENT OF SURFACE BACTERIAL INFECTIONS; TREATMENT OF BACTERIAL EAR INFECTIONS IN DOGS, OF GENITAL TRACT INFECTIONS, OF ENTERITIS IN SWINE. [R44] *Nitrofurazone has a wide spectrum of activity against a variety of gram positive and gram negative organisms, including some species and strains of Aerobacter aerogenes, Alcaligenes faecalis, Bacillus anthracis, Clostridium, Corynebacterium, Streptococcus pneumoniae, Erysipelothrix insidiosa, Escherichia coli, Gardnerella vaginalis (formerly Haemophilus vaginalis), Klebsiella pneumoniae, Moraxella lacunata, Neisseria, Paracolobactrum, Proteus, Serratia marcescens, Salmonella, Shigella, Staphylococcus, and Streptococcus. It is not, however, particularly active against most strains of Pseudomonas aeruginosa and does not inhibit fungi or viruses. Against susceptible organisms, nitrofurazone generally is bactericidal in concentrations of 13-20 ug/ml and inhibitory in concentrations of 5-10 ug/ml. Nitrofurazone may be active against organisms that have developed resistance to antibiotics and sulfonamides. [R4, 2212] *Nitrofurazone is used topically as adjunctive therapy in patients with second- and third degree burns when bacterial resistance to other anti-infective agents is a real or potential problem. The drug may also be used for prevention of infection of skin grafts and/or donor sites prior to or following surgery, especially in hospitals with a history of epidemics caused by bacteria that are resistant in hospitals with a history of epidemics caused by bacteria that are resistant to other anti-infectives. [R4, 2212] *Although nitrofurazone has been used topically for prophylaxis and treatment of other infections of the skin and mucous membranes, external eye, and middle and external ear caused by susceptible bacteria, the efficacy of the drug in these conditions has not been established and it produces a relatively high risk of contact dermatitis. Nitrofurazone solutions have been used as a bladder irrigant in catheterized patients; however, the value of this practice has been questioned. [R4, 2212] *Nitrofurazone has been administered orally for the treatment of refractory African trypanosomiasis, acute bacillary dysentery, and testicular tumors. /Uses not currently included in the labeling approved by FDA/. [R4, 2212] *Anti-infective agent used topically for adjunctive therapy of patients with second and third degree burns, and in skin grafting where bacterial contamination may cause graft rejection and/or donor site infection. [R5] WARN: *... /TREATMENT AS IN LATE-STAGE TRYPANOSOMIASIS/ IS UNSUITABLE FOR FEBRILE OR DEBILITATED PATIENTS. ... IT PRODUCES HEMOLYTIC ANEMIA IN PATIENTS WITH GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY. [R16, 1074] *WHEN USED TOPICALLY IN EAR ... /NITROFURAZONE/ MAY PRODUCE CUTANEOUS SENSITIVITY REACTIONS. ... THIS TYPE OF REACTION ... FREQUENTLY MIMICS DISEASE BEING TREATED. ... /THIS DRUG REACTION/ CAN USUALLY BE RECOGNIZED BECAUSE THE INFLAMMATORY PROCESS BEGINS TO SPREAD TO LOBULE OF EAR AND INFECTION DOES NOT RESPOND TO TREATMENT. [R45] *... STRAINS OF PSEUDOMONAS AND PROTEUS ARE OFTEN RESISTANT. [R43] *IT HAS NOT YET BEEN SHOWN TO BE USEFUL IN TREATMENT OF MINOR BURNS, WOUNDS, OR CUTANEOUS ULCERS WHICH ARE INFECTED. IT IS PROBABLY NOT EFFECTIVE IN TREATMENT OF PYODERMA. ... APPROX 0.5-2% OF PATIENTS BECOME SENSITIZED TO DRUG, SOMETIMES WITHIN 5 DAYS OF INITIATION OF TREATMENT. ... FOR ALL NITROFURAZONE DOSAGE FORMS, AVOID EXPOSURE AT ALL TIMES TO DIRECT SUNLIGHT, EXCESSIVE HEAT AND ALKALINE MATERIALS. [R3] *VET: ITS USE MAY INTERFERE WITH CERTAIN SALIVA TESTS IN HORSES. [R7] */NITROFURAZONE/ PRODUCES SENSITIZATION IN APPROX 0.5 TO 2% OF PATIENTS, AND THIS SOMETIMES OCCURS WITHIN FEW DAYS AFTER INITIAL APPLICATION. [R16, 979] *The possibility of overgrowth of nonsusceptible organisms including fungi and Pseudomonas should be considered in patients receiving nitrofurazone therapy when the condition does not improve. If superinfection, irritation, or sensitization occurs, the drug should be discontinued and appropriate topical or systemic therapy instituted. [R4, 2213] *Nitrofurazone ointment should be used with caution in patients with known or suspected renal impairment, since it contains polyethylene glycols which may be absorbed and may produced adverse effects. [R4, 2213] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R46] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl nitrofurazone, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. [R47] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION OF NITROFURAZONE IN PHARMACEUTICAL PREPARATIONS BY REVERSE PHASE HPLC ON SPHERISORB S5-ODS WITH UV DETECTION. [R48] *POLAROGRAPHIC METHOD FOR EST ... IN FEED HAS BEEN PROPOSED; AND METHOD FOR IDENTIFICATION USING TLC HAS BEEN DEVELOPED. [R9] *DETERMINATION IN NITROFURAZONE FEEDS BY SPECTROPHOTOMETRY AT 440 NM. [R49] *... DETERMINED IN FEEDS AND PREMIXES COLORIMETRICALLY OVER RANGE OF 0.0055-11% WITH RECOVERY OF /97.7%/ ... SIMILAR METHOD ... /USED FOR/ CHICKEN TISSUES AT 1-5 PPM AND FOR EST OF LEVELS AS LOW AS 0.25 PPM IN MILK. [R9] *... PHOTOMETRIC PROCEDURE ... /CAN DETECT/ LEVELS DOWN TO 0.5 PPM IN MILK. ... /METHOD FOR MILK IS FURTHER IMPROVED/ BY CONCN ON CHROMATOGRAPHIC COLUMN, PERMITTING QUANTITATION TO 0.01 PPM. [R9] *NITROFURAN DERIVATIVES, INCLUDING NITROFURAZONE, WERE CHROMATOGRAPHED ON SILICA GEL THIN LAYERS IN DIOXANE:BENZENE (1:1), FOLLOWED BY SPRAYING THE PLATE WITH PYRIDINE AND VIEWING UNDER UV LAMP AT 366 NM FOR 10 MIN SHOWED BLUE OR GREEN FLUORESCENT SPOTS. THE DETECTION LIMIT WAS 1-10 NG. THE FORMATION OF FLUORESCENT PYRIDINE ADDUCTS ON SILICA GEL TLC PLATES APPEARED TO BE HIGHLY SPECIFIC FOR NITROFURANS. [R50] *DETERMINATION OF NITROFURAZONE IN CHICKEN AND PORK TISSUE BY HPLC. [R51] *Chloramphenicol and nitrofuran residue analysis was performed by HPLC and photodiode array detection in meat and fish. Chloramphenicol and nitrofurans were detected at 280 nm and 360 nm respectively. Blank samples fortified with chloramphenicol and nitrofurans at levels of 5, 10 and 20 ug/kg gave recoveries in the range of 69 to 88%. A quantitation limit of 1 ug/kg for nitrofurazone and furazolidone and of 2 ug/kg for chloramphenicol and furaltadone in meat and fish has been reached. [R52] *A HPLC method for the determination of nitrofuran derivatives and two cyano-metabolites in organic tissue is described. The method is suitable for the analysis of nitrofurazone, nitrofurantoin, furazolidone, furaltadone and the cyano-metabolites of nitrofurazone and furazolidone at the 1 ppb level (1 mug/kg). Nitrofurazone was detected in liver (28.4 ppb), the cyano-metabolite in muscle (4.2 ppb) and in liver (4.1 ppb). Traces o furazolidone were detected in liver (1.5 ppb) and in kidney (1.9 ppb), the cyano-derivative was found in kidney (6.2 ppb) and muscle (8.0 ppb). [R53] CLAB: *AN HPLC METHOD FOR DETECTION OF NITROFURANTOIN AND OTHER NITROFURAN DERIV IN BLOOD AND URINE OF MAN IS DESCRIBED. DETECTION LIMIT WAS 0.02 UG/ML. [R54] *A HPLC METHOD FOR DETECTION OF THERAPEUTIC CONCN OF NITROFURANTOIN AND SOME STRUCTURALLY RELATED DRUGS IN PLASMA AND URINE IS DESCRIBED. [R55] *THE HPLC PROCEDURE DESCRIBED FOR DETECTION OF NITROFURANTOIN IN PLASMA, URINE AND BIOLOGICAL FLUIDS. [R56] *... DETERMINED IN FEEDS AND PREMIXES COLORIMETRICALLY OVER RANGE OF 0.0055-11% WITH RECOVERY OF /97.7%/ ... SIMILAR METHOD ... /USED FOR/ CHICKEN TISSUES AT 1-5 PPM AND FOR EST OF LEVELS AS LOW AS 0.25 PPM IN MILK. [R9] *... PHOTOMETRIC PROCEDURE ... /CAN DETECT/ LEVELS DOWN TO 0.5 PPM IN MILK. ... /METHOD FOR MILK IS FURTHER IMPROVED/ BY CONCN ON CHROMATOGRAPHIC COLUMN, PERMITTING QUANTITATION TO 0.01 PPM. [R9] *DETERMINATION OF NITROFURAZONE IN CHICKEN AND PORK TISSUE BY HPLC. [R51] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Nitrofurazone in F344/N Rats and B6C3F1 Mice Technical Report Series No. 337 (1988) NIH Publication No. 88-2593 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1044 R3: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1105 R4: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). R5: Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 116 R6: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 759 R7: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 389 R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 174 (1974) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 175 (1974) R10: Sax, N.I. Dangerous Properties of Industrial Materials. 5th ed. New York: Van Nostrand Rheinhold, 1979. 697 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 172 (1974) R12: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2019 R13: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 80 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 50 204 (1990) R15: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1413 R16: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. R17: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-387 R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 177 (1974) R19: De Groot AC, Conemans JMH; Contact Dermatitis 22 (4): 202-5 (1990) R20: Lo JS et al; Dermatol Clin 8 (1): 165-8 (1990) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V7 176 (1974) R22: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-237 R23: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 112 R24: Anderson D et al; Fd Chem Toxicol 23: 1091-98 (1985) R25: Greenaway JC et al; Toxicol Appl Pharmacol 82: 307-15 (1986) R26: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 664 R27: Ali BH; Clin Exp Pharmacol Physiol 16 (5): 363-6 (1989) R28: Ali BH; Pharmacology (Basel) 42 (1): 49-53 (1991) R29: Gajewska J et al; Mutat Res 232 (2): 191-7 (1990) R30: George JD et al; Toxicologist 12 (1): 199 (1992) R31: Kari FW et al; Food Chem Toxicol 27 (2): 129-37 (1989) R32: Maronpot RR; Environmental Health Perspectives 73: 125-30 (1987) R33: Toxicology and Carcinogenesis Studies of Nitrofurazone in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 337 (1988) NIH Publication No. 88-2593 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R34: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Nitrofurazone (CAS No. 59-87-0) in CD-1 Swiss Mice, NTP Study No. RACB89020 (July 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R35: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of Nitrofurazone (CAS No. 59-87-0) in Female B6C3F1 Mice, NTP Study No. IMM90011 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 19, 2002 R36: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Nitrofurazone (CAS NO. 59-87-0) Administered to CD-1(R) Mice on Gestational Days 6 through 15, NTP Study No. TER85092 (October 31, 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R37: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Nitrofurazone (CAS No. 59-87-0) Administered to New Zealand White Rabbits on Gestational Days 6 through 19, NTP Study No. TER87093 (August 18, 1987) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R38: Inveresk Research International Ltd.; Screening of Priority Chemicals for Potential Reproductive Hazard. (1983), EPA Document No. FYI-OTS-0483-0240 R39: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 123 R40: Hoener BA; Biochem Pharmacol 37 (8): 1629-36 (1988) R41: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1003 R42: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R43: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. 1026 R44: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1096 R45: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 1000 R46: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91) R47: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-204 (1992) R48: BAGON KR; J HIGH RESOLUT CHROMATOGR CHROMATOGR COMMUN 2 (5): 211 (1979) R49: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. 15 V1 100 R50: VEALE HS, HARRINGTON GW; J CHROMATOGR 208 (1): 161 (1981) R51: SUGDEN EA ET AL; J ASSOC OFF ANAL CHEM 66 (4): 874 (1983) R52: Degroodt JM et al; J Liq Chromatogr 15 (13): 2355-71 (1992) R53: Schmid P et al; Mitt Geb Lebensmittelunters Hyg 84 (4): 461-83 (1990) R54: VREE TB ET AL; J CHROMATOGR 162 (1): 110 (1979) R55: ROSEBOOM H, KOSTER HA; ANAL CHIM ACTA 101 (2): 359 (1978) R56: AUFRERE MB ET AL; CLIN CHEM (WINSTON-SALEM, NC) 23 (12): 2207 (1977) RS: 55 Record 223 of 1119 in HSDB (through 2003/06) AN: 3140 UD: 200201 RD: Reviewed by SRP on 6/15/1992 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: OXAZEPAM- SY: +ADUMBRAN-; +ANSIOLISINA-; +ANSIOXACEPAM-; +ANXIOLIT-; +ANXIOLIT-RETARD-; +APLAKIL-; +ASTRESS-; +2H-1,4-BENZODIAZEPIN-2-ONE,-7-CHLORO-1,3-DIHYDRO-3-HYDROXY-5-PHENYL-; +BONARE-; +7-CHLORO-1,3-DIHYDRO-3-HYDROXY-5-PHENYL-2H-1,4-BENZODIAZEPINE-2-ONE-; +7-CHLORO-1,3-DIHYDRO-3-HYDROXY-5-PHENYL-2H-1,4-BENZODIAZEPIN-2-ONE-; +7-CHLORO-3-HYDROXY-5-PHENYL-1,3-DIHYDRO-2H-1,4-BENZODIAZEPIN-2-ONE-; +DRIMUEL-; +DROXACEPAM-; +ENIDREL-; +HILONG-; +ISODIN-; +LIMBIAL-; +NESONTIL-; +NOCTAZEPAM-; +NOTARAL-; +NOZEPAM-; +OX-; +PACIENX-; +PRAXITEN-; +PROPAX-; +PSICOPAX-; +PSIQUIWAS-; +QUEN-; +QUILIBREX-; +RO-5-6789-; +RONDAR-; +SERAX-; +SERENAL-; +SERENID-; +SERENID-D-; +SEREPAX-; +SERESTA-; +SERPAX-; +SIGACALM-; +SOBRIL-; +TAZEPAM-; +Z-10-TR-; +TRANQUO-BUSCOPAN-WIRKSTOFF-; +Z10-TR-; +VABEN-; +WY-3498- RN: 604-75-1 RELT: DIAZEPAM; TENAZEPAM MF: +C15-H11-Cl-N2-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +2-AMINO-5-CHLOROBENZOPHENONE IS ACYLATED WITH CHLOROACETYL CHLORIDE AND THE PRODUCT IS REFLUXED WITH SODIUM IODIDE TO FORM THE IODOACETAMIDO CMPD. REACTION OF ONE WITH HYDROXYLAMINE EFFECTS DEHYDRATION AND DEHYDROHALOGENATION TO FORM THE BENZODIAZEPINE DERIVATIVE. TREATMENT OF TWO WITH ACETIC ANHYDRIDE CAUSES REARRANGEMENT TO OXAZEPAM WHICH IS SIMULTANEOUSLY ESTERIFIED TO ACETATE. SAPONIFICATION LIBERATES OXAZEPAM. [R1] FORM: +Oral Capsules: 10, 15, 30 mg (Serax); Tablets 15 mg (Serax) [R2, 1351] MFS: *Wyeth-Ayerst, P.O. Box 8299, Philadelphia, PA 19101 [R2, 1351] USE: *MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +CRYSTALS FROM ALCOHOL [R3, 1096]; +CREAMY WHITE TO PALE-YELLOW POWDER [R1] ODOR: +PRACTICALLY ODORLESS [R1] TAST: +BITTER [R1] MP: +205-206 DEG C [R3, 1096] MW: +286.74 [R3, 1096] PH: +BETWEEN 4.8 and 7.0 (1 IN 50 SUSPENSION) [R1] SOL: +SOL IN DIOXANE [R3, 1096]; +1 G SOL IN MORE THAN 10,000 ML WATER, 220 ML ALCOHOL, 270 ML CHLOROFORM, 2200 ML ETHER [R1] SPEC: +MAX ABSORPTION (ETHANOL): 229 NM (A= 124, 1%, 1 CM) [R4]; +Intense mass spectral peaks: 77 m/z, 205 m/z, 233 m/z, 239 m/z, 268 m/z [R5] OCPP: +NONHYGROSCOPIC [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: +STABLE IN LIGHT [R1] +STABLE AS SOLID OR IN NEUTRAL SOLN BUT HYDROLYZED BY ACIDS [R6] STRG: +Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), in a well-closed container. [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of oxazepam. There is sufficient evidence in experimental animals for the carcinogenicity of oxazepam. Overall Evaluation: Oxazepam is possibly carcinogenic to humans (Group 2B). In making the overall evaluation, the Working Group took into account that: (1) uncertainty exists regarding the formation of mouse liver tumors by oxazepam as a relevant end point for evaluation of carcinogenic risks to humans. (2) appropriate mechanistic information in humans is lacking. [R8] ANTR: +Treatment of benzodiazepam overdose is primarily supportive. Establishment of respiration with assisted ventilation if necessary should be instituted immediately. A new antidote, flumazenil, is under final investigation and should be available for use in serious cases ... . Emesis should be considered unless the patient is comatose, is convulsing, or has lost the gag reflex. If these contraindications exist, the patient may be intubated and lavaged followed by administration of activated charcoal and a saline cathartic such as sodium or magnesium sulfate. Hypotension should be treated initially with fluid. Institution of vasopressor agents should be used only if the patient is unresponsive to other measures. Forced diuresis and dialysis are of no value in the treatment of benzodiazepine overdoses. /Benzodiazepines/ [R9, 933] +The iv administration of 5 mg of diazepam generally results in rapid improvement. Oral doses of diazepam (10-60 mg) may require up to several days for improvement. High-dose benzodiazepine abusers have been treated effectively with an initial diazepam dose of 40% maintenance levels followed by a daily tapering by 10%. More gradual reductions are recommended for patients in an outpatient setting who have lower abuse potential Withdrawal program duration ranges from 4 to 16 weeks with a daily reduction of 0.5 to 2.5 mg diazepam. Weekly physician visits are necessary to assess both physical symptoms and coping mechanisms. Important determinants of success are the development of good social support and alternate coping strategies. Anxiety modulation, which concentrates on alleviating anxiety symptoms by altered perceptions and attitudes, may relieve the initial distress that leads to benzodiazepine use. Propranolol and clonidine may attenuate symptoms but usually do not alleviate them. Antidepressants, which may reduce benzodiazepine receptors in the brain, appear to be useful during benzodiazepine withdrawal when they are begun a few months before withdrawal. Careful observation is necessary for evidence of lowered seizure threshold by the antidepressants. Further clinical trials are necessary to evaluate the effectiveness of antidepressants in the treatment of benzodiazepine withdrawal. /Benzodiazepines/ [R10, 585] +Treatment of benzodiazepine intoxication consists of general supportive therapy. If ingestion of the drug is recent and the patient is fully conscious, emesis should be induced. If the patient is comatose, gastric lavage may be done if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Activated charcoal and a saline cathartic may be administered after gastric lavage and/or emesis to remove any remaining drug. Pulse, respiration, and blood pressure should be monitored and the patient should be closely observed. IV fluids should be administered and an adequate airway maintained. Hypotension may be controlled, if necessary, by IV administration of Hemodialysis is not useful in the treatment of benzodiazepine overdosage. /Benzodiazepines/ [R2, 1335] +Although the potential toxicity of benzodiazepines is relatively low, and aggressive therapy for pure overdose is rarely required, flumazenil offers several important potential uses in clinical medicine. Since it reverses only benzodiazepine-induced CNS depression, it is diagnostic as well as therapeutic. The antagonist can confirm a suspected diagnosis of benzodiazepine overdose or exclude benzodiazepine intoxication as a cause of CNS depression in an undiagnosed patient. In coma, secondary to multiple drug overdose, removing the benzodiazepine component may avoid the need for intubation and mechanical ventilation. Flumazenil may be useful postoperatively to reverse the effects of preoperative sedation, or to reverse an inadvertent overdose when benzodiazepines are used for conscious sedation in outpatients. /Benzodiazepines/ [R11, 815] MEDS: +Liver and kidney function tests and blood counts should be performed regularly during long-term therapy. /Benzodiazepines/ [R2, 1334] HTOX: +INCIDENCE OF ADVERSE REACTIONS IS LOW. DROWSINESS IS MOST COMMON AND MAY OCCUR AFTER A DAILY DOSE OF 60 MG. REACTIONS NOTED OCCASIONALLY INCL RASH, NAUSEA, DIZZINESS, SYNCOPE, HYPOTENSION, TACHYCARDIA, EDEMA, NIGHTMARES, LETHARGY, SLURRED SPEECH AND ... EXCITEMENT AND CONFUSION. [R12, 219] +UNTOWARD EFFECTS INCL ... VERTIGO / and / HEADACHE ... OTHER SIDE EFFECTS WHICH HAVE BEEN OBSERVED INCL ... TREMOR AND ALTERED LIBIDO. MORE SEVERE REACTIONS INCL LEUKOPENIA AND JAUNDICE. ... LATTER REACTIONS ARE ONLY OCCASIONALLY OBSERVED. [R1] +INCIDENCE OF ATAXIA IS LESS THAN WITH RELATED DRUGS. ... EOSINOPHILIA AND HEPATIC DYSFUNCTION HAVE OCCURRED RARELY. [R12, 220] +EXCESSIVE AND PROLONGED USE MAY RESULT IN DEVELOPMENT OF PHYSICAL DEPENDENCE ... . [R1] +IN YR 1967-71 INFORMATION ... COLLECTED ON MOTHERS OF 599 CHILDREN WITH ORAL CLEFTS; FOR 590 MATCHED PAIR CONTROLS DATA WERE ... ADEQUATE. ... BENZODIAZEPINES ... /INCL OXAZEPAM, SHOWED/ SIGNIFICANT ASSOCIATION ... BETWEEN INTAKE OF BENZODIAZEPINES DURING 1ST TRIMESTER OF PREGNANCY AND ORAL CLEFTS ... . /BENZODIAZEPINES/ [R13] +NO CASE REPORTS OR EPIDEMIOLOGICAL STUDIES /ON CARCINOGENICITY/ WERE AVAILABLE TO THE WORKING GROUP. [R13] +Following acute overdose, clinical symptoms or manifestations may include sleepiness, which, following larger overdose can range from stage-zero to stage-one coma. Initially, excitement may be seen as a result of the disinhibition effects of these drugs, which then progresses to CNS depression hypotension, respiratory depression, and coma ... . On occasion, anticholinergic symptoms such as dry mouth, tachycardia, dilated pupils, and absent bowel sounds may be seen. Patients who have been receiving or ingesting benzodiazepines on a chronic basis (40 to 80 mg or more per day for one to two months or more) may exhibit mild to moderate symptoms of withdrawal, with severe withdrawal symptoms seen in patients taking the drug for many months to years. Symptoms may include jitteriness, nervousness, anxiety, agitation, confusion, hallucinations, and seizures. Patients exhibiting withdrawal symptoms should be restarted on benzodiazepine and slowly withdrawn over a period of several months ... . In most cases, ingestion of a benzodiazepine agent of up to 1.5 g results in only minor toxicity, ie, CNS depression. Fatality, following oral ingestion, is rare unless a combination of drugs is taken with the benzodiazepine ... . /Benzodiazepines/ [R9, 932] +A study indicating that usual therapeutic doses of oxazepam strongly interfere with color vision. [R14] +A 2 year old girl was admitted to hospital 18 hours after taking 90 mg of oxazepam. She was apathetic and lethargic, though she showed paradoxical excitation. Reflexes were depressed and her face was edematous. Her gait was ataxic. By the third hospital day the deep tendon reflexes had returned to normal, and the ataxia disappeared slowly over 8 days, but at discharge, 2 weeks later, there was still slight facial puffiness. [R14] +A 45 year old man, who ingested large doses (not rated) of oxazepam in an attempted suicide, went into a deep coma and had an apparent blood-glucose concentration of 1.68 g per 100 ml and an electrolyte imbalance. It was later discovered that oxazepam gave a positive reaction for glucose. The patient's condition did not improve until the fourth day when exchange transfusion was carried out. [R14] +Fatal rhabdomyolysis (paroxysmal idiopathic myoglobulinuria) with hyperkalemia and anuria occurred in a man after ingestion of oxazepam 6 g. [R14] +Potentially serious, adverse behavioral effects occasionally have been associated with benzodiazepine use. Such effects include confusion, bizarre or abnormal behavior, agitation, hyperexcitability, auditory and visual hallucinations, paranoid ideation, panic, delirium, agitation, sleepwalking, aggression and antisocial acts; in some cases, amnesia about the behavior may occur. Although it has been suggested that these behavioral effects may be dose related, such a relationship has not been established. Other adverse CNS effects include headache, vivid dreams, dysarthria, mental depression, and suicidal ideation. Encephalopathy reported occured in patients with renal failure receiving both diazepam and flurazepam. Extrapyramidal reactions, tremor, and oral buccal dyskinesia have also been reported. /Benzodiazepines/ [R2, 1333] +Adverse effects reported in patients receiving benzodiazepines include nausea and other GI complaints, hiccups, constipation, increased appetite, anorexia, weight gain or loss, dry mouth, increased salivation and bronchial secretions, swollen tongue, and bitter or metallic taste. Increased or decreased libido, menstrual irregularities, failure to ovulate, gynecomastia, and galactorrhea have been reported. Plasma testosterone concentrations reportedly increase in some men taking oral diazepam chronically. Urticaria, rash, pruritus, photosensitivity, immediate hypersensitivity reactions, hypotension, nonthrombocytopenic purpura, and edema may occur. Genitourinary complaints such as urinary retention, difficulty in micturition, and urinary incontinence have occurred. Conjuctivitis and visual disturbances such as diplopia, nystagmus, and blurred vision have occurred. Body and joints pains, muscle cramps, paresthesia, a lupus erythematosus-like syndrome, palpitation, tachycardia, shortness of breath, diaphoresis, and flushing have been reported. /Benzodiazepines/ [R2, 1334] NTOX: +THREE GROUPS OF 14 MALE AND 14 FEMALE SWISS-WEBSTER MICE RECEIVED OXAZEPAM IN DIET FROM 3-12 MO OF AGE AT CONCN OF 0.05 OR 0.15%, OR ... CONTROL DIET. AT 12 MO OF AGE ALL ... RECEIVED CONTROL DIET FOR ... 2 MO ... LIVER TUMORS DESCRIBED AS LIVER-CELL ADENOMAS WERE FOUND IN 3/12 (25%) MALES RECEIVING THE LOWER DOSE AND IN 8/13 (61%) MALES AND 5/8 (62%) FEMALES RECEIVING 0.15% OXAZEPAM. NO LIVER TUMORS WERE FOUND IN 13 MALE AND 10 FEMALE SURVIVING CONTROLS. [R15] +OXAZEPAM DID NOT CAUSE-DISJUNCTION AND CROSSING-OVER IN ASPERGILLUS NIDULANS; MAMMALIAN METABOLIC ACTIVATING SYSTEMS WERE NOT USED IN THIS TEST. [R16] +... CONCLUSIONS: Under the conditions of these feed studies, there was clear evidence of carcinogenic activity of oxazepam in male and female Swiss-Webster mice based on incr incidences of hepatocellular adenoma and carcinoma. There was clear evidence of carcinogenic activity of oxazepam in male and female B6C3F1 mice based on increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma. Increased incidences of hyperplasia of thyroid gland follicular cells in male and female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were also related to oxazepam exposure. [R17] +... CONCLUSIONS: ... Under the conditions of these 2 yr dosed feed studies, there was equivocal evidence of carcinogenic activity in male F344/N rats based on small incr in the incidences of renal tubule adenomas in exposed groups also exhibiting significantly enhanced nephropathy. There was no evidence of carcinogenic activity of oxazepam in female F344/N rats exposed to feed containing 625, 2,500 or 5,000 ppm for 2 yr or 10,000 ppm for 6 months. [R18] NTXV: +LD50 Rat oral 5 g/kg; [R19] NTP: +... Toxicology and carcinogenesis studies were performed by administering oxazepam (greater than 99% pure) in feed to male and female Swiss-Webster and B6C3F1 mice for ... 57 wk (Swiss-Webster), or 2 yr (B6C3F1). ... CHRONIC STUDIES: Groups of 60 male and 60 female Swiss-Webster and B6C3F1 mice received oxazepam in feed at concentrations of 0, 2,500, or 5,000 ppm. Additional groups of 60 male and 60 female B6C3F1 mice received 125 ppm in feed to allow for study of a group with projected serum concentrations of oxazepam similar to those achieved in humans taking a therapeutic dose. ... Average daily oxazepam consumption varied throughout the studies, and the overall daily average ranged from 10 to 29 mg/kg body weight for the 125 ppm groups, 234 to 512 mg/kg for the 2,500 ppm groups, and 444 to 1,085 mg/kg for the 5,000 ppm groups. ... CONCLUSIONS: Under the conditions of these feed studies, there was clear evidence of carcinogenic activity of oxazepam in male and female Swiss-Webster mice based on incr incidences of hepatocellular adenoma and carcinoma. There was clear evidence of carcinogenic activity of oxazepam in male and female B6C3F1 mice based on increased incidences of hepatoblastoma and hepatocellular adenoma and carcinoma. Increased incidences of hyperplasia of thyroid gland follicular cells in male and female B6C3F1 mice and of follicular cell adenomas in female B6C3F1 mice were also related to oxazepam exposure. [R17] +... Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 625, 2,500 or 5,000 ppm oxazepam for up to 105 wk. A stop exposure group of 50 males and 50 females received 10,000 ppm oxazepam in feed for 26 wk, after which animals received undosed feed for the remainder of the 2 yr study. The continuous exposure concn resulted in average daily doses of 25, 100 or 250 mg oxazepam/kg body wt to males and 25, 110 or 220 mg/kg to females. Stop exposure males and females received an average daily dose of 630 mg/kg during the exposure period. CONCLUSIONS: ... Under the conditions of these 2 yr dosed feed studies, there was equivocal evidence of carcinogenic activity in male F344/N rats based on small incr in the incidences of renal tubule adenomas in exposed groups also exhibiting significantly enhanced nephropathy. There was no evidence of carcinogenic activity of oxazepam in female F344/N rats exposed to feed containing 625, 2,500 or 5,000 ppm for 2 yr or 10,000 ppm for 6 months. [R18] ADE: +... ABSORPTION AND EXCRETION OF OXAZEPAM WERE STUDIED IN HUMAN SUBJECTS. MORE THAN 60% OF DOSE ... WAS RECOVERED IN 48-HR URINE; 50% WITHIN 12 HR. ... STUDIES HAVE SHOWN THAT OXAZEPAM ACCUM IN BRAIN OF MICE, BUT NOT OF RATS ... . [R20, 257] +WHEN SINGLE DOSE OF ... SERENID-D (OXAZEPAM ...) WAS ADMIN ORALLY TO MAMMALS ... /IT/ WAS WELL ABSORBED AND LARGELY ELIMINATED WITHIN 2 DAYS, MOSTLY IN URINE IN DOGS AND PIGS AND IN FECES IN RATS. ... FECES OF ALL ... /3 SPECIES AND MAN/ CONTAINED ONLY UNCHANGED DRUG. [R21] +... 6-CHLORO-4-PHENYL-2(1H)-QUINAZOLINONE AND 2-AMINO-5-CHLOROBENZOPHENONE OCCUR ONLY UNCONJUGATED IN URINE, BUT OTHER ... /METABOLITES/ ARE PRESENT BOTH AS CONJUGATES AND IN FREE FORM /IN MAN AND IN MINIATURE PIG/. ... OXAZEPAM-GLUCURONIDE ACCOUNTS ONLY FOR SMALL PROPORTION OF DOSE OF OXAZEPAM THAT IS EXCRETED IN URINE /OF RATS/. [R20, 257] +EQUAL IV DOSES OF SUCCINATE HALF-ESTERS OF (+)- and (-)-OXAZEPAM TO MICE RESULTED IN BLOOD-LEVELS OF (+)-OXAZEPAM ABOUT 4 TIMES THOSE OBTAINED FOR (-)-OXAZEPAM, RACEMIC MIXT YIELDING INTERMEDIATE LEVELS. ... DIFFERENCES IN LEVELS ... WAS ATTRIBUTED TO POSSIBLE STEREOSPECIFIC ESTERASE IN BLOOD OR LIVER. [R20, 120] +ALL BENZODIAZEPINES BIND TO HUMAN PLASMA ALBUMIN. ... THE BINDING SITE IS STEREOSPECIFIC, AT LEAST FOR OXAZEPAM. BINDING CORRELATES STRONGLY WITH LIPID SOLUBILITY. ... THE PLASMA CONCN OF MOST BENZODIAZEPINES EXHIBIT KINETIC PATTERNS THAT ARE CONSISTENT WITH TWO-COMPARTMENT MODELS ... BUT THREE-COMPARTMENT MODELS APPEAR TO BE MORE APPROPRIATE FOR THE HIGHLY LIPID-SOLUBLE COMPOUNDS. THERE IS A FAST UPTAKE INTO THE GRAY MATTER OF THE BRAIN, FOLLOWED BY A SLOWER PHASE OF REDISTRIBUTION INTO THE WHITE MATTER AND ADIPOSE TISSUE. IN MAN, THIS SLOWER PHASE OF DISTRIBUTION LASTS FROM 11 MINUTES TO 12 HR, DEPENDING ON THE CMPD. ONCE REDISTRIBUTION IS ACHIEVED, THE VOLUMES OF DISTRIBUTION ARE QUITE LARGE, ESPECIALLY FOR THE LIPID-SOLUBLE BENZODIAZEPINES. BENZODIAZEPINES CROSS THE PLACENTAL BARRIER AND ARE ALSO SECRETED INTO HUMAN MILK. [R22, 347] +... OXAZEPAM ... /IS/ ABSORBED RELATIVELY SLOWLY FOLLOWING ORAL ADMIN, AND PEAK CONCN IN PLASMA MAY NOT BE ATTAINED FOR SEVERAL HR. [R23, 425] +CHANGES IN PLASMA AND ERYTHROCYTE OXAZEPAM LEVELS IN RATS FOLLOWING A SINGLE ORAL DOSE (20 MG/KG) OF THE DRUG, AS WELL AS CHANGES IN BLOOD, ERYTHROCYTE, LIVER, AND BRAIN LEVELS OF THE DRUG FOLLOWING SUBCHRONIC TREATMENT (20 MG/KG/DAY FOR 21 DAYS), ARE DESCRIBED. NO INTRAERYTHROCYTE ACCUMULATION OF OXAZEPAM WAS OBSERVED FOLLOWING THE SINGLE DOSE. [R24] +The gastrointestinal tract rapidly and completely absorbs most of the benzodiazepines, but absorption from intramuscular sites is erratic and delayed. Peak plasma levels occur 1 to 3 hours after ingestion. Prazepam and oxazepam are more slowly absorbed, resulting in delayed, less intense single-dose effects. /Benzodiazepines/ [R10, 581] +Benzodiazepines are eliminated almost exclusively by metabolism. Liver biotransformation in hepatic microsomal enzymes occurs via two major pathways: demethylation or conjugation with glucuronide. Some of the subsequent metabolites are active. Diazepam metabolism results in formation of desmethyldiazepam and temazepam which are converted to oxazepam. All of these compounds are pharmacologically active ... Oxazepam and lorazepam do not accumulate as readily and produce no active metabolites. Elimination half-life determines the ability of a drug to accumulate but does not necessarily correlate with drug effect. /Benzodiazepines/ [R10, 581] +Following administration of oxazepam 45 mg to 2 subjects who had undergone cholecystectomy less than 0.1% of a dose was found in the bile. [R14] +A study on the placental passage of oxazepam and its metabolism in 12 women given a single dose of oxazepam 25 mg during labor. Oxazepam was readily absorbed and peak plasma concentrations were in the same range as those reported in healthy males and non-pregnant females given the same dose although the plasma half-life (range 5.3 to 7.8 hours in 8 hours subjects studied) was shorter than that reported for non-pregnant subjects. Oxazepam was detected in the umbilical vein of all 12 patients with the ratio between umbilical to maternal vein concentration of oxazepam reaching a value of about 1.35 and remaining constant beyond a dose-delivery time of 3 hours. All of the babies had a normal Apgar score value. The oxazepam plasma half-life in the newborns was about 3 to 4 times that in the mothers although in 3 /mothers/ the plasma concentration of oxazepam conjugate rose during the first 6 to 10 hours after delivery indicating the ability of the neonate to conjugate oxazepam. [R14] METB: +DIAZEPAM IS METABOLIZED TO ACTIVE PRODUCTS ... 1/3 IS EXCRETED AS OXAZEPAM, and 70% OF THE METABOLITES APPEARS IN URINE. OXAZEPAM REACHES A PEAK PLASMA CONCN IN 4 HR AND IS EXCRETED IN URINE AS THE GLUCURONIDE CONJUGATE. [R25, 191] +THE MAJOR /DIAZEPAM/ METABOLITE, N-DEMETHYL DERIVATIVE, IS ACTIVE; OTHER ACTIVE METABOLITES, ALSO PRODUCED BY HEPATIC MICROSOMAL ENZYMES, INCLUDE THE RING-HYDROXYLATED DERIVATIVE AND OXAZEPAM, THE PRODUCT OF BOTH REACTIONS. [R25, 216] +... MEDAZEPAM YIELDS AT LEAST FIVE ACTIVE METABOLITES (INCLUDING DIAZEPAM, TEMAZEPAM, AND OXAZEPAM). [R22, 347] +GLUCURONIDE OF OXAZEPAM IS MAJOR METABOLITE IN MAN AND IN MINIATURE PIG. IN CONTRAST ... RATS TRANSFORM OXAZEPAM MAINLY BY AROMATIC HYDROXYLATION, FOLLOWED BY GLUCURONIDATION, AND GLUCURONIDE OF 7-CHLORO-1,3-DIHYDRO-3-HYDROXY-5- (P-HYDROXYPHENYL)-2H-1,4-BENZODIAZEPIN-2-ONE IS MAJOR URINARY METABOLITE IN THAT SPECIES OF MAMMAL ... . [R20, 257] +... NEW METABOLIC PATHWAYS FOR BIOTRANSFORMATION OF OXAZEPAM HAVE ... BEEN DISCOVERED IN MAN AND MINIATURE PIGS, WHICH LEAD TO 6-CHLORO-4-PHENYL-2(1H)- QUINAZOLINONE, THREE OPEN-RING METABOLITES, 2-AMINO-5-CHLOROBENZOPHENONE; 2'-BENZOYL-4'-CHLORO-2,2-DIHYDROXYACETANILIDE; and 2'-BENZOYL-4'-CHLORO- 2-HYDROXY-2-UREIDOACETANILIDE ... . [R20, 257] +WHEN SINGLE DOSE OF ... SERENID-D /OXAZEPAM/ ... WAS ADMIN ORALLY TO MAMMALS ... A SINGLE METABOLITE, OXAZEPAM-3-GLUCURONIDE, WAS FOUND IN URINE OF DOGS, PIGS AND MAN, WHEREAS URINE OF RATS CONTAINED AT LEAST 7 METABOLITES ... . [R21] +IN 25-DAY RABBIT FETUSES, APPRECIABLE METABOLISM OF OXAZEPAM BY GLUCURONIDATION ... OCCURS. LIVER, BRAIN, LUNG AND KIDNEY WERE ALL ACTIVE, WHILE LIVER FORMATION OF OXAZEPAM GLUCURONIDE WAS 25% OF ADULT VALUES. ... /IN COMPARISON/ POSTNATAL METAB OF OXAZEPAM ... IN RABBIT TISSUES WAS SIGNIFICANTLY IMPAIRED IN 1ST HOURS OF BIRTH ... . [R26] +... /NEW METABOLIC PATHWAYS OF OXAZEPAM IN MAN AND MINIATURE PIGS ... LEAD TO/ TWO AROMATIC HYDROXYLATION PRODUCTS, 7-CHLORO-1,3-DIHYDRO-3- HYDROXY-5-(P-HYDROXYPHENYL)- 1H-1,4-BENZODIAZEPIN-2-ONE AND 7-CHLORO-1,3-DIHYDRO-3-HYDROXY-5-)3(OR 4)- HYDROXY-4(OR 3)-METHOXYPHENYL)-2H-1,4-BENZODIAZEPIN-2-ONE. [R20, 257] +TRACE AMOUNTS OF A PHENOLIC METABOLITE HAVE BEEN FOUND ONLY WITH OXAZEPAM. [R22, 347] +WITH THE PROBABLE EXCEPTION OF OXAZEPAM AND LORAZEPAM, WHICH ARE PRIMARILY CONJUGATED WITH GLUCURONIC ACID TO FORM INACTIVE METABOLITES, THE BENZODIAZEPINES USED FOR ANXIETY ARE TYPICALLY CONVERTED TO ACTIVE METABOLITES. [R22, 439] +The major metabolite of diazepam, N-desmethyldiazepam, is somewhat less active than the parent drug and may behave as a partial agonist. This metabolite is also produced by the rapid decarboxylation of clorazepate following its ingestion. Both diazepam and N-desmethyldiazepam are slowly hydroxylated to other compounds such as oxazepam. [R23, 455] +Oxazepam is the ultimate pharmacologically active metabolite of diazepam and is itself largely metabolized to the inactive glucuronide; small amounts are excreted unchanged. [R14] BHL: +AFTER ORAL DOSING AS TABLETS OR SUSPENSION, PEAK OXAZEPAM BLOOD-LEVELS WERE OBSERVED WITHIN 1-2 HR. ... /IT/ HAD BIOLOGICAL HALF-LIFE OF ABOUT 4 HR, WHICH IS BETWEEN 1/5 and 1/10 THAT OBSERVED FOR DIAZEPAM. NO ACCUM OF UNCHANGED DRUG OR CONJUGATE WAS OBSERVED IN BLOOD AFTER MULTIPLE DOSING EVERY 4 HR. [R20, 120] +THE PHARMACOKINETICS OF OXAZEPAM IN 12 HEALTHY WOMEN DURING LABOR AND ITS DISPOSITION IN THEIR NEWBORN INFANTS WERE STUDIED. THE RATIO BETWEEN UMBILICAL/MATERNAL VEIN DRUG CONCN PLATEAUED AT 1.35 AFTER 3 HR FROM ADMIN. THE HALF-LIFE WAS 21.9 HR IN NEONATES AND 6.5 HR IN MOTHERS. [R27] +Elimination half-life of oxazepam is 3-21 hr. /From table/ [R2, 1331] +Oxazepam has been reported to have a half-life ranging from about 6 to 25 hours. [R14] ACTN: +THE BENZODIAZEPINES SELECTIVELY ACT ON POLYSYNAPTIC AND NOT MONOSYNAPTIC NEURONAL PATHWAYS THROUGHOUT THE CNS. THE ACTION IS MAINLY THAT OF PRESYNAPTIC INHIBITION, ALTHOUGH AT SOME SITES, SUCH AS IN CUNEATE NUCLEUS, THERE MAY BE POSTSYNAPTIC INHIBITION; WHETHER INHIBITION IS PRESYNAPTIC OR POSTSYNAPTIC, IT SIMULATES THAT OF GAMMA-AMINOBUTYRIC ACID. POLYSYNAPTIC RESPONSES MAY BE DIMINISHED OR AUGMENTED, ACCORDING TO WHETHER SYNAPTIC INHIBITION SUBSERVES AN INHIBITORY OR FACILITATORY FUNCTION IN THE INTEGRATED RESPONSE. /BENZODIAZEPINES/ [R22, 344] +BENZODIAZEPINES FACILITATE A VARIETY OF GABA (GAMMA-AMINOBUTYRIC ACID)-MEDIATED SYNAPTIC SYSTEMS, INVOLVING BOTH PRESYNAPTIC AND POSTSYNAPTIC INHIBITION. IN CULTURED SPINAL CORD NEURONS, DIAZEPAM AUGMENTS THE INCREASE IN CHLORIDE CONDUCTANCE PRODUCED BY GABA, BUT NOT THAT PRODUCED BY GLYCINE, WITHOUT INFLUENCING TIME COURSE OF RESPONSE TO GABA. BASED ON THESE DATA AND ON THE ABILITY OF BENZODIAZEPINES TO INCREASE APPARENT AFFINITY OF GABA FOR BINDING SITES IN PREPARATIONS OF BRAIN MEMBRANES, IT HAS BEEN PROPOSED THAT BENZODIAZEPINES SOMEHOW INCREASE THE POTENCY OR EFFECTIVENESS OF THIS INHIBITORY NEUROTRANSMITTER. /BENZODIAZEPINES/ [R22, 466] +CENTRAL DEPRESSANT ACTIONS...ON SPINAL REFLEXES OCCUR AND ARE IN PART MEDIATED BY THE BRAIN STEM RETICULAR SYSTEM. /BENZODIAZEPINES/ [R22, 437] +MOST BENZODIAZEPINES DECREASE SLEEP LATENCY, ESPECIALLY WHEN FIRST USED, AND DIMINISH THE NUMBER OF AWAKENING AND TIME SPENT IN STAGE 0 (A STAGE OF WAKEFULNESS). THEY HAVE BEEN SHOWN TO INCREASE THE AWAKENING THRESHOLD. TIME IN STAGE 1 (DESCENDING DROWSINESS) IS USUALLY ... INCREASED BY ... OXAZEPAM. TIME SPENT IN STAGE 2 (WHICH IS THE MAJOR FRACTION OF NON-RAPID-EYE-MOVEMENT SLEEP) IS INCREASED BY ALL BENZODIAZEPINES. BENZODIAZEPINES PROMINENTLY DECREASE THE TIME SPENT IN SLOW-WAVE SLEEP (SWS; STAGES 3 and 4); USUALLY BOTH STAGES 3 and 4 ARE SHORTENED ... DESPITE THE SHORTENING OF STAGE 4 AND NONRAPID EYE MOVEMENT SLEEP, THE NET EFFECT OF ADMIN OF BENZODIAZEPINES IS AN INCREASE IN TOTAL SLEEP TIME. [R22, 342] +In animals, benzodiazepines protect against seizures induced by electrical stimulation and by pentylenetetrazol; benzodiazepines appear to act, at least partly, by augmenting presynaptic inhibition. The drugs suppress the spread of seizure activity but do not abolish the abnormal discharge from a focus in experimental models of epilepsy. In usual doses, benzodiazepines appear to have very little effect on the autonomic nervous system, respiration, or the cardiovascular system. /Benzodiazepines/ [R2, 1331] +The exact sites and mode of action of the benzodiazepines are unknown. The drugs appear to act at the limbic, thalamic, and hypothalamic levels of the CNS, producing anxiolytic, sedative, hypnotic, skeletal muscle relaxant, and anticonvulsant effects. The effects of benzodiazepines may be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid. Benzodiazepines are capable of producing all levels of CNS depression from mild sedation to hypnosis to coma. /Benzodiazepines/ [R2, 1330] +Anxiolytic and possibly paradoxical CNS stimulatory effects of benzodiazepines are postulated to result from release of previously suppressed responses (disinhibition). After usual doses of benzodiazepines for several days, the drugs cause a moderate decrease in rapid eye movement sleep. Rapid eye movement rebound does not occur when the drugs are withdrawn. Stage 3 and 4 sleep are markedly reduced by usual doses of the drugs; the clinical importance of these sleep stage alterations has not been established. /Benzodiazepines/ [R2, 1331] +Benzodiazepines appear to produce skeletal muscle relaxation predominantly by inhibiting spinal polysynaptic afferent pathways, but the drugs may also inhibit monosynaptic afferent pathways. The drugs may inhibit monosynaptic and polysynaptic reflexes by acting as inhibitory neuronal transmitters or by blocking exitatory synaptic transmission. The drugs may also directly depress motor nerve and muscle function. /Benzodiazepines/ [R2, 1331] INTC: +CONCURRENT INGESTION OF DIAZEPAM AND ALCOHOL CAUSES INTENSIFICATION OF CNS EFFECTS OF EACH DRUG. ...PATIENTS RECEIVING ANY BENZODIAZEPINE CMPD SHOULD BE WARNED TO AVOID ALCOHOL, SINCE CONCURRENT INGESTION COULD RESULT IN IMPAIRMENT OF THEIR ABILITY TO DRIVE AUTOMOBILE OR OPERATE HAZARDOUS MACHINERY. /BENZODIAZEPINES/ [R28, 47] +0.429 MG/KG ORAL OXAZEPAM WAS STUDIED IN 25 NORMAL AND 12 ALCOHOLIC MEN BEFORE AND AFTER CHRONIC DISULFIRAM (ANTABUSE) ADMIN. IT WAS CONCLUDED THAT OXAZEPAM DISPOSITION IS ALTERED ONLY MINIMALLY BY DISULFIRAM. [R29] +/DRUG INTERACTIONS/ ... ARE INFREQUENT ... EXCEPT FOR AN ADDITIVE EFFECT WITH OTHER CNS DEPRESSANTS ... HEAVY CIGARETTE SMOKING MAY DECREASE THE EFFECTIVENESS OF USUAL DOSES ... /BENZODIAZEPINES/ [R23, 427] +INFLUENCE OF CIMETIDINE ON THE PHARMACOKINETICS OF DESMETHYLDIAZEPAM AND OXAZEPAM OCCURS. [R30] +The disposition of oxazepam (Serax) (45 mg orally) was compared in eight women receiving oral contraceptives and nine comparable women not receiving oral contraceptives. As with lorazepam, the metabolism of oxazepam appeared to be enhanced by concurrent use of oral contraceptives. The oxazepam half-life was shorter (6.8 hours versus 12.4 hours) and the clearance was higher (191 ml/min versus 81 ml/min) in those taking oral contraceptives. The report was preliminary, but the results indicate that oxazepam response may be reduced. ... Although the effect of oral contraceptives on other benzodiazepines is not established, one would theoretically expect an increased effect from benzodiazepines which undergo oxidative metabolism in the liver: eg, alprazolam (Xanax), halazepam (Paxipam), prazepam (Centrax), clorazepate (Tranxene), and flurazepam (Dalmane). Conversely, one might expect a reduced effect from benzodiazepines which undergo glucuronide conjugation. [R31] +In 1 study, 6 healthy volunteers receiving diflunisal (500 mg twice daily) for 7 days were administered a single oral dose of oxazepam (30 mg). The peak plasma concentration of oxazepam was significantly decreased (38%), and the area-under-curve fell 16%. The oxazepam glucuronide area-under-curve and elimination half-life increased 41% and 23%, respectively, and its renal clearance was significantly reduced (38%). Although the clinical significance of this single-dose interaction was not determined, it was suggested that long-term treatment with these agents would lead to a somewhat lower, clinically insignificant, steady-state concentration of oxazepam. [R28, p. 10/66.5] +Additive CNS depression may occur when benzodiazepines are administered concomitantly with other CNS depressants, including other anticonvulsants and alcohol. /Benzodiazepines/ [R2, 1335] +Concomitant administration of some benzodiazepines (ie, alprazolam, chlordiazepoxide, clorazepate, diazepam, triazolam) and cimetidine may result in decreased benzodiazepine plasma clearance and increased plasma half-lives and concentratins of thse benzodiazepines. Cimetidine reduces plasma clearance of the benzodiazepines that undergo oxidative metabolism, apparently via inhibition of hepatic microsomal enzymes involved in oxidative metabolism. Consequently, the elimination of clonazepam, flurazepam, halazepam, and prazepam may also be similarly affected by cimetidine. Although an increased sedative effect has been observed in some patients receiving concomitant therapy with a benzodiazepine and cimetidine, the degree to which the pharmacologic response to the benzodiazepine may be increased is not well established. /Benzodiazepines/ [R2, 1335] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Anxiety Agents, Benzodiazepine; GABA Modulators; Sedatives, Nonbarbiturate [R32] +... IT IS A MILD SEDATIVE USEFUL IN THE MANAGEMENT AND CONTROL OF ANXIETY, TENSION, AGITATION, IRRITABILITY AND RELATED SYMPTOMS. ALSO, IT IS USEFUL FOR CONTROL OF ACUTE TREMULOUSNESS, /CHRONIC ALCOHOL DEPENDENCY/ OR ANXIETY ASSOCIATED WITH ALCOHOL WITHDRAWAL. [R1] +SINCE FORMATION OF GLUCURONIDE IS NOT RESTRICTED TO HEPATIC ENDOPLASMIC RETICULUM, OXAZEPAM AND LORAZEPAM ... MAY BE SAFER AGENTS /THAN THOSE BENZODIAZEPINES THAT FORM ACTIVE METABOLITES/ FOR PATIENTS WITH SEVERELY IMPAIRED HEPATIC FUNCTION, IF THEY ARE GIVEN IN SMALL DIVIDED DOSES. OXAZEPAM MAY BE SAFER FOR ELDERLY PATIENTS BECAUSE OF ITS RELATIVELY SHORT DURATION OF ACTION. [R23, 426] +Oxazepam is used for anxiety, anxiety-depression, and alcohol withdrawal. /From table/ [R10, 582] +Antianxiety agent [R23, 424] WARN: +CAUTION: ABUSE MAY LEAD TO HABITUATION OR ADDICTION. [R3, 994] +AS WITH OTHER SEDATIVE AGENTS, PATIENTS ON THIS DRUG SHOULD BE CAUTIONED AGAINST DRIVING AUTOMOBILES OR OPERATING DANGEROUS MACHINERY. OTHER WARNINGS, CONTRAINDICATIONS AND PRECAUTIONS ARE SIMILAR TO THOSE FOR OTHER BENZODIAZEPINES. ... /OXAZEPAM/ SHOULD BE USED WITH CAUTION IN ELDERLY INDIVIDUALS. PATIENTS ... /USING IT/ SHOULD BE OBSERVED CAREFULLY FOR THE APPEARANCE OF OTHER UNTOWARD EFFECTS CHARACTERISTIC OF BENZODIAZEPINE DRUGS. [R1] +MANY OF SIDE EFFECTS REPORTED FOR THESE DRUGS SO OVERLAP WITH SYMPTOMS OF ANXIETY THAT UNLESS CAREFUL HISTORY IS TAKEN ONE IS HARD PUT TO ASCRIBE THESE EFFECTS TO DRUG. /BENZODIAZEPINES/ [R25, 191] +OXAZEPAM GIVES A FALSE POSITIVE REACTION IN SOMOGYI BLOOD GLUCOSE PROCEDURE (1680 MG "GLUCOSE"/100 ML ... IN ADULT PATIENTS WHO HAD 2250 ML WHOLE BLOOD TRANSFUSION/) BUT NOT WITH GLUCOSE OXIDASE PROCEDURE. [R19] +OXAZEPAM ... HAS BEEN TESTED FOR EFFECTS ON VISION WITH ORAL DOSES OF 30 MG, BUT CAUSED NO CHANGE IN VISUAL ACUITY, ACCOMMODATION, OR EYE MOVEMENT, EXCEPT POSSIBLY ENHANCEMENT OF EXISTING HETEROPHORIAS. VISUALLY INDUCED EEG POTENTIALS HAVE BEEN LITTLE INFLUENCED. [R33] +THE EXPECTED SIDE EFFECTS OF CNS DEPRESSANTS OF DROWSINESS AND ATAXIA ARE EXTENSIONS OF THE PHARMACOLOGICAL ACTIONS OF THESE DRUGS ... AN INCREASE IN HOSTILITY AND IRRITABILITY, AS WELL AS VIVID OR DISTURBING DREAMS, IS OFTEN REPORTED AS POSSIBLE EFFECTS OF THE BENZODIAZEPINES, WITH THE POSSIBLE EXCEPTION OF OXAZEPAM. EQUALLY PARADOXICAL IS AN INCREASE IN ANXIETY ... BOTH PSYCHOSES AND SUDDEN SUICIDAL IMPULSES HAVE OCCASIONALLY BEEN REPORTED IN PATIENTS RECEIVING HIGH DOSES ... IN GENERAL, THE CLINICAL TOXICITY ... IS LOW. /BENZODIAZEPINES/ [R22, 439] +A WITHDRAWAL SYNDROME IN AN ELDERLY PATIENT WHO HAD RECEIVED OXAZEPAM, 30 MG ORALLY 16 TO 18 TIMES DAILY FOR 4 TO 5 YR, WAS REPORTED. AFTER 10 DRUG AND SYMPTOM FREE DAYS THE PATIENT BECAME PROGRESSIVELY INCOHERENT AND SUFFERED APPARENT MYOCLONIC SEIZURES. TREATMENT WITH DIAZEPAM, 20 MG IV, RESULTED IN A STABILIZATION OF THE MENTAL STATE AND 16 HR OF SLEEP. IT WAS CONCLUDED THAT A CAREFUL DRUG HISTORY SHOULD BE TAKEN IN ANY PERSON SUFFERING A SUSPECTED DEMENTING ILLNESS, AND THE WITHDRAWAL FROM BENZODIAZEPINES CAN BE LATE, SPECTACULAR AND AS LIFE THREATENING AS BARBITURATE WITHDRAWAL. [R34] +Dosage of oxazepam must be individualized, and the smallest effective dosage should be used (especially in geriatric or debilitated patients and in those with low serum albumin) to avoid oversedation. [R2, 1351] +Serax 15 mg tablets contain the dye tartrazine (FD and C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin. [R2, 1351] +Safety and efficacy of oxazepam in children younger than 6 years of age have not been established. [R2, 1351] +Benzodiazepine therapy usually should be discontinued if CNS stimulation occurs. [R2, 1334] +Probenecid may impair glucuronide conjugation of oxazepam, resulting in increased effects and possibly excessive sedation. [R7] +Leukopenia is more likely to occur with oxazepam than with most other benzodiazepines. [R7] +EXCESSIVE AND PROLONGED USE MAY RESULT IN DEVELOPMENT OF PHYSICAL DEPENDENCE ... . [R1] IDIO: +Typically, symptoms develop 1 to 11 days after withdrawal (average, 3-4 days) and usually are minor compared with those of ethanol and barbiturate withdrawal. Symptoms include anxiety, insomnia, headache, muscle spasm, anorexia, vomiting, nausea, tremor, postural hypotension, and weakness. A spectrum of affective disorders (psychosis, agitation, confusin, hallucinations, delirum) and motor dysfunction (tremor, restlessness, myoclonic jerk, seizures) may develop in serious cases after withdrawal from high daily doses (60-300 mg). Seizures are rare and most commonly develop 7 to 8 days after withdrawal (rang, 2-12 days). The most common symptoms in minor to moderate withdrawal are mood swings and convulsion. Withdrawal symptoms usually peak in 5 to 6 days and resolve by 4 weeks, but minor symptoms may persist for months. The presence of tinnitus, involuntary movements, or perceptual changes helps differentiate benzodiazepine withdrawal from anxiety. /Benzodiazepines/ [R10, 584] TOLR: +Tolerance develops rapidly to the sedative but not the anxiolytic effects of benzodiazepines. Tolerance to the anticonvulsant and muscle relaxation properties of benzodiazepines has not been extensively studied. /Benzodiazepines/ [R11, 805] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: +Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule IV includes oxazepam, DEA Code #2835. [R35] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: +HIGH-PRESSURE LIQ CHROMATOGRAPHIC PROCEDURE TO SEPARATE MIXT OF PURE BENZODIAZEPINES IS DESCRIBED. [R15] +A REVERSE-PHASE HIGH-PRESSURE LIQUID CHROMATOGRAPHIC METHOD FOR THE DETERMINATION OF OXAZEPAM IN TABLETS AND CAPSULES WAS COLLABORATIVELY STUDIED BY 9 LABORATORIES. MEAN RECOVERIES FROM SYNTHETIC TABLET AND CAPSULE FORMULATIONS WERE 97.2 and 99.0%, RESPECTIVELY. [R36] +A gas chromatography method using electron-capture detection for the analysis of oxazepam. Sensitivity limit is 5 ng/ml. [R37] +Oxazepam is extracted into methanol and determined by liquid chromatography with ultraviolet detector in drug tablets and capsules. [R38] CLAB: +A RAPID METHOD WAS DEVELOPED FOR THE DETERMINATION OF DIAZEPAM, DESMETHYLDIAZEPAM, OXAZEPAM, and 3-HYDROXYDIAZEPAM IN HUMAN PLASMA USING ELECTRON CAPTURE GAS CHROMATOGRAPHY. THE METHOD HAS A SENSITIVITY LIMIT OF 4 NG DIAZEPAM, OXAZEPAM, AND DESMETHYLDIAZEPAM, and 15 NG 3-HYDROXYDIAZEPAM/ML OF PLASMA. [R39] +A GAS CHROMATOGRAPHIC METHOD IS DESCRIBED FOR THE SIMULTANEOUS DETERMINATION OF DIAZEPAM, AND ITS MAJOR METABOLITES N-DESMETHYLDIAZEPAM, OXAZEPAM, AND HYDROXYDIAZEPAM IN HUMAN PLASMA, URINE, AND SALIVA. [R40] +DETERMINATION OF OXAZEPAM IN SERUM BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY USING A RADIALLY COMPRESSED C18 COLUMN AND AN AQUEOUS METHANOLIC MOBILE PHASE. THE DRUG WAS RECOVERED FROM SERUM BY EXTRACTION WITH HEXANE-ETHYL ACETATE 70:30, VOL/VOL. THE METHOD IS LINEAR IN THE RANGE 50-1600 NG/ML. [R41] +A REVERSE-PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC PROCEDURE FOR SIMULTANEOUS ANALYSIS OF EIGHT BENZODIAZEPINES, INCLUDING OXAZEPAM, IS DESCRIBED. THE STANDARD CURVE IS LINEAR TO AT LEAST 8 MG/L FOR EACH DRUG, AND THE DETECTION LIMIT FOR EACH WAS 0.05-0.10 MG/L. EXTRACTION OF EACH DRUG FROM SERUM WAS 95-100% COMPLETE. 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R29: MACLEOD SM ET AL; CLIN PHARMACOL THER 24 (NOV): 583 (1978) R30: KLOTZ U, REIMANN I; EUR J CLIN PHARMACOL 18 (6): 517-20 (1980) R31: Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985. 325 R32: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R33: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 686 R34: MOORE C; MED J AUST 2 (SEP 4): 220 (1982) R35: 21 CFR 1308.14(c) (4/1/91) R36: BARGO ES; J ASSOC OFF ANAL CHEM 66 (4): 864-6 (1983) R37: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 19 R38: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. V1 15/622 R39: LOESCHER W; THER DRUG MONIT 4 (3): 315-8 (1982) R40: VALENTINE JL ET AL; ANAL LETT 15 (B21): 1665-83 (1982) R41: KINBERGER B, WAHRGREN P; ANAL LETT 15 (B6): 549-57 (1982) R42: LENSMEYER GL ET AL; CLIN CHEM 28 (11): 2274-8 (1982) RS: 47 Record 224 of 1119 in HSDB (through 2003/06) AN: 3145 UD: 200303 RD: Reviewed by SRP on 6/15/1992 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: OXYTETRACYCLINE- SY: *ADAMYCIN-; *BERKMYCEN-; *BIOSTAT-; *BIOSTAT-PA-; *DABICYCLINE-; *FANTERRIN-; *GEOMYCIN- (STREPTOMYCESRIMOSUS); *GEOMYCIN- (STREPTOMYCESVIMOSUS); *5-HYDROXYTETRACYCLINE-; *IMPERACIN-; *LENOCYCLINE-; *LIQUAMYCIN-; *MACOCYN-; *2-NAPHTHACENECARBOXAMIDE, 4-(DIMETHYLAMINO)-1,4,4A,5,5A,6,11,12A-OCTAHYDRO-3,5,6,10,12,12A-HEXAHYDROXY-6- METHYL-1,11-DIOXO-; *NSC-9169-; *OKSISYKLIN-; *OTC-; *OXITETRACYCLIN-; *OXY-KESSO-TETRA-; *OXYMYCIN-; *OXYMYKOIN-; *OXYPAM-; *OXYSTECLIN-; *OXYTERRACIN-; *OXYTERRACINE-; *OXYTERRACYNE-; *OXYTETRACYCLIN-; *OXYTETRACYCLINE-AMPHOTERIC-; *PROTEROXYNA-; *RIOMITSIN-; *RYOMYCIN-; *SOLKACICLINA-; *STEVACIN-; *TERRAFUNGINE-; *TERRAMYCIN-IM-; *TETRACHEL-; *TETRAN-; *VENDARCIN- RN: 79-57-2 MF: *C22-H24-N2-O9 ASCH: Oxytetracycline hydrochloride; 2058-46-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ANTIBIOTIC SUBSTANCE ISOLATED FROM ELABORATION PRODUCTS OF ACTINOMYCETE STREPTOMYCES RIMOSUS, GROWN ON SUITABLE MEDIUM. ISOLATION. PRODN FROM STREPTOMYCES RIMOSUS. [R1] *ISOLATION FROM STREPTOMYCES XANTHOPHAEUS. [R1] FORM: *Terramycin IM (Roerig). Solution 50 mg/ml with 2% lidocaine in 2 and 10 ml containers and 125 mg/ml with 2% lidocaine in 2 ml containers. [R2] MFS: *Pfizer Inc, Hq, 235 E 42nd St, New York, NY 10017, (212) 573-2323; Chemical Division; Production site: Terre Haute, IN 47808 [R3] OMIN: *THERAPEUTIC LEVELS PRODUCE RESIDUES IN MILK. DO NOT FEED TO HENS LAYING EGGS FOR HUMAN CONSUMPTION. DO NOT USE HONEY ... FROM BEES WHILE BEING TREATED FOR FOULBROOD. WITHDRAW TREATED WATER FROM POULTRY /PRIOR TO/ SLAUGHTERING. ... DO NOT SLAUGHTER PARENTERALLY TREATED ANIMALS ... UNTIL 20-30 DAYS AFTER INJECTION ... . [R4, 405] *FDA ESTABLISHED 0.1, 0.1, 3.0, 1.0, 0.1 PPM, RESPECTIVELY, AS MAX ALLOWABLE RESIDUES IN UNCOOKED EDIBLE TISSUES OF CATTLE, SWINE; KIDNEYS OF POULTRY; MUSCLE, LIVER, FAT AND SKIN OF POULTRY; AND FISH. [R4, 405] *SENSITIVITY OF PLANT PATHOGENIC BACTERIA TO OXYTETRACYCLINE, PPM: AGROBACTERIUM TUMEFASCIENS, 0.05; ERWINIA AMYLOVORA, 0.6; PSEUDOMONAS PISI, 0.3; XANTHOMONAS PHASEOLI, 0.8. /FROM TABLE/ [R5] *OXYTETRACYCLINE ... MIXED WITH STREPTOMYCIN FORMULATIONS TO FORESTALL DEVELOPMENT OF STRAINS OF BACTERIA RESISTANT TO STREPTOMYCIN. IT WAS SHOWN TO HAVE PROMISE IN CONTROLLING BACTERIAL SPOT OF PEACH ... OXYTETRACYCLINE-STREPTOMYCIN ... ALSO ... AS BARE-ROOT DIPS BY NURSERYMEN TO CONTROL CROWN GALL ... OF WOODY PLANTS. [R6] USE: *Inhibition of lethal yellowing in coconut palm trees. [R7] +MEDICATION (VET) +MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Pale yellow to tan, crystalline powder [R8] MP: *184-185 DEG C [R9] MW: *460.44 [R1] DEN: *1.634 @ 20 DEG C [R9] SOL: *SLIGHTLY SOL IN WATER AND ALCOHOL [R9] SPEC: *MAX ABSORPTION (0.1 N HCL): 267 NM (A= 311, 1%, 1 CM); (0.1 N NAOH): (A= 307, 1%, 1 CM); (H2O): (A= 289, 1%, 1 CM) [R10, 275]; *MASS: 3444 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R11] OCPP: *SATURATED SOLN PH IS ABOUT 6.5; SPECIFIC OPTICAL ROTATION -207 TO -216 DEG (100 MG IN 10 ML 0.1 NORMAL HYDROCHLORIC ACID); PALE YELLOW TO TAN CRYSTALLINE POWDER /OXYTETRACYCLINE DIHYDRATE/ [R12] *DECOMP, MONITORED BY HPLC AND UV SPECTRAL METHODS, FOLLOWED 1ST ORDER KINETICS @ ANY GIVEN PH. [R13] *Dull yellow, crystalline powder; odorless; slightly bitter /Oxytetracycline dihydrate/ [R7] *YELLOW CRYSTALLINE POWDER, ODORLESS, BITTER. /OXYTETRACYCLINE HYDROCHLORIDE/ [R14, 743] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *STABLE IN AIR, BUT EXPOSURE TO STRONG SUNLIGHT CAUSES IT TO DARKEN. /OXYTETRACYCLINE DIHYDRATE/ [R12] *DETERIORATES IN SOLN WITH PH BELOW 2, AND IS RAPIDLY DESTROYED BY ALKALI HYDROXIDES. /OXYTETRACYCLINE DIHYDRATE/ [R12] STRG: *Oxytetracycline hydrochloride preparations should be stored at a temperature less that 40 deg C, preferably between 15-30 deg C; freezing of oxytetracycline injection should be avoided. Oxytetracycline hydrochloride capsules should be stored in tight, light-resistant containers. /Oxytetracycline hydrochloride/ [R8] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *DIARRHEA MAY ALSO RESULT FROM ... TETRACYCLINES GIVEN ORALLY. IN SUCH CASES, STOOLS DO NOT CONTAIN BLOOD OR LEUKOCYTES. IT IS IMPERATIVE THAT THIS TYPE ... BE PROMPTLY DISTINGUISHED FROM THAT WHICH RESULTS FROM SUPRAINFECTION OF BOWEL BY STAPHYLOCOCCI, A LIFE THREATENING COMPLICATION ... . /TETRACYCLINES/ [R15, 1188] *IV ADMIN ... IS FREQUENTLY FOLLOWED BY THROMBOPHLEBITIS ... SEVERE PAIN /IS PRODUCED/ WHEN INJECTED IM WITHOUT LOCAL ANESTHETIC. LONG TERM THERAPY MAY PRODUCE ... LEUKOCYTOSIS, ATYPICAL LYMPHOCYTES, TOXIC GRANULATION OF GRANULOCYTES, AND THROMBOPENIC PURPURA ... . /TETRACYCLINES/ [R16, 1122] *... /CAN/ DELAY BLOOD COAGULATION. ... SUGGESTED THAT /THIS/ ... IS RELATED TO ABILITY OF ... DRUGS TO ALTER PLASMA LIPOPROTEINS. PATIENTS RECEIVING TETRACYCLINE IV HAVE SLIGHT-TO-MARKED DECR IN PROTHROMBIN ACTIVITY AND IMPAIRMENT IN RATE OF THROMBOPLASTIN REGENERATION. /TETRACYCLINES/ [R15, 1189] *BOTH RENAL AND HEPATIC ABNORMALITIES MAY BE ASSOC WITH PREGNANCY ... KIDNEY INFECTION APPEARS TO BE THE CRITICAL FACTOR BECAUSE IT MAY LEAD TO DECR RENAL FUNCTION AND REDUCED EXCRETION OF DRUG, RESULTING IN ACCUM TOXIC CONCN. /TETRACYCLINES/ [R15, 1188] *ADMIN 2.5-3.0 G ... TO UNDERNOURISHED ADULTS RESULTS IN WT LOSS, INCR URINARY BUT NOT FECAL NITROGEN EXCRETION, NEG NITROGEN BALANCE, AND ELEVATED SERUM NONPROTEIN NITROGEN CONCN ... /CMPD INCL/ OXYTETRACYLINE ... . [R15, 1189] *Other effects that have been attributed to hypersensitivity are burning of the eyes, cheilosis, atrophic or hypertrophic glossitis, pruritus ani or vulvae, and vaginitis; these effects often persist for weeks or months after cessation of tetracycline therapy. The exact cause of these reactions is unknown. Fever of varying degrees and eosinophilia may occur when these agents are administered. Asthma has also been observed. /Tetracyclines/ [R16, 1122] *Tetracyclines are excreted in breast milk; although tetracyclines may form nonabsorbable complexes with breast-milk calcium, use is not recommended because of the possiblity of their causing premanent discoloration of teeth, enamel hypoplasia, inhibition of linear skeletal growth, photosensitivity reactions, and oral and vaginal thrush in infants. /Tetracyclines/ [R17] *FDA Pregnancy Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrent use of the drug in pregnancy despite potential risk. /Tetracyclines/ [R17] *Since intramuscular administration of oxytetracycline produces lower serum concentrations than oral administration in recommended doses, patients should be changed to an oral dosage form as soon as feasible. When rapid, high serum concentrations are required, an intravenous form (oxytetracycline hydrochloride) should be used. [R18] *Tetracyclines cross the placenta; use is not recommended during the last half of pregnancy since tetracyclines may cause permanent discoloration of teeth, enamelhypoplasia and inhibition of skeletal growth in the fetus. In addition, fatty infiltration of the liver may occur in pregnant women especially with high iv doses. /Tetracyclines/ [R17] *PATIENT WHO RECEIVED TWO 500 MG DOSES DAILY OF OXYTETRACYCLINE FOR 5 DAYS SHOWED INCR BLOOD UREA NITROGEN AND SERUM CREATININE LEVELS, BUT NOT EXCEEDING NORMAL RANGE. [R19] NTOX: *This antibiotic is capable of crossing the placenta and causing staining of the deciduous teeth. It stains to a lesser degree than tetracycline. [R20] *Oxytetracycline administered iv at a dose rate of 33 mg/kg daily for three successive days has caused signs of nephrotoxicity in feedlot heifers ... . Diffuse renal epithelium necrosis and tubular casts were observed in calves which died after receiving higher doses of this antibiotic ... . [R21] *Treatment of rams with 20 mg/kg of oxytetracycline for six or ten days produced a significant increase in the incidence of tailless spermatozoa, or decreased spermatozoa motility and live spermatozoa count, and an inferior quality after storage of semen. All values returned to normal within 60 days following cessation of the treatment. [R21] *Intravenous administration of 15 g of oxytetracycline to horses has produced profuse diarrhea, an increased pulse rate, apathy and death. [R21] *Inadvertent administration of 130, instead of 25, mg/kg of oxytetracycline to dogs has produced clinical signs which included lacrimation, facial scratching, depression, emesis, diarrhea, bradycardia, oliguria and/or anuria. The pathological changes noted included pulmonary congestion and slightly swollen kidneys, epithelial cast formation at the corticomedullary juction, acute tubular nephrosis and multiple venous thromboemboli in the kidneys. Vomiting and diarrhea /was reported/ in dogs given large daily oral doses of oxytetracycline over a prolonged period. [R21] *Resistance to the tetracyclines produced in vitro appears slowly in a graded, stepwise fashion similar to that observed with penicillin. Microorganisms that have become resistant to one tetracycline frequently exhibit resistance to the others. Resistance to the tetracyclines in Escherichia coli and probably in other bacterial species is medicated by plasmids and is an inducible trait; that is, the bacteria become resistant only after exposure to the drug. A number of transferable resistance determinants for tetracycline have been identified ... and at least two mechanisms of resistance have been detected. /Tetracyclines/ [R16, 1118] +... Under the conditions of these 2 yr feed studies of oxytetracycline hydroch!oride, there was equivocal evidence of carcinogenicity for male F344/N rats, as indicated by incr incidences of pheochromocytomas of the adrenal gland. There was equivocal evidence of carcinogenicity for female F344/N rats fed diets containing oxytetracycline hydrochloride, as indicated by incr incidences of adenomas of the pituitary gland. There was no evidence of carcinogenicity for male or female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm oxytetracycline hydrochloride for 2 years. /Oxytetracycline hydrochloride/ [R22] NTP: +Toxicology and carcinogenesis studies were conducted on oxytetracycline hydrochloride (98.8% pure). The 2 yr toxicology and carcinogenesis studies were conducted by admin diets containing 0 25,000, or 50,000 ppm oxytetracycline hydrochloride to groups of 50 male and 50 female F344/N rats and diets containing 0, 6,300, or 12,500 ppm oxytetracycline hydrochloride to groups of 50 male and 50 female B6C3F1 mice for 103 wk. The highest dose selected for rats was considered to be the maximum level that would not affect the nutritional value of dosed feed. The dietary concentrations correspond to the following approximate doses: rats: 0, 1,000, or 2,000 mg/kg body weight per day; mice: 0, 650, or 1,400 mg/kg per day. Under the conditions of these 2 yr feed studies of oxytetracycline hydroch!oride, there was equivocal evidence of carcinogenicity for male F344/N rats, as indicated by incr incidences of pheochromocytomas of the adrenal gland. There was equivocal evidence of carcinogenicity for female F344/N rats fed diets containing oxytetracycline hydrochloride, as indicated by incr incidences of adenomas of the pituitary gland. There was no evidence of carcinogenicity for male or female B6C3F1 mice fed diets containing 6,300 or 12,500 ppm oxytetracycline hydrochloride for 2 years. /Oxytetracycline hydrochloride/ [R22] +... Timed-pregnant CD rats were dosed by gavage (po) on gestational days (gd) 6-15 with oxytetracycline hydrochloride (0, 1,200, 1,350, 1,500 mg/kg/day) in corn oil. ... Dams were weighed on /gestational day/ 0, 6-15 (prior to daily dosing) and 20 (immediately after sacrifice) and were also observed for clinical signs of toxicity. At sacrifice on /gestational day/ 20, dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e., sites, resorptions, dead fetuses, live fetuses). Live fetuses were dissected from the uterus and evaluated for live litter size, body weight, sex and gross morphological abnormalities. All live fetuses were examined for visceral malformations employing the Staples' fresh tissue dissection method. Half of the fetuses were decapitated prior to dissection and the heads were fixed in Bouin's soln for free-hand sectioning and exam ... . All fetal carcasses were cleared and stained with Alizarin Red S and examined for skeletal malformations. The maternal mortality was 0% (0/37 dams) in OX-0, 5.6% (2/32) in oxytetracycline hydrochloride-1,200, 15.2% (5/33) in oxytetracycline hydrochloride-1,350 and 24.2% (8/33) in oxytetracycline hydrochloride-1,500 dose groups. A significant downward trend for reduction in maternal body weight was seen on /gestational day/ 11, 15 and 20, with values from the oxytetracycline hydrochloride-1,200 and oxytetracycline hydrochloride-1,500 groups significantly lower than controls for all 3 time points; oxytetracycline hydrochloride-1,350 values were also significantly lower than controls for /gestational day/ 11 and 15. Maternal weight gain during gestation and treatment exhibited a significant downward trend with values from oxytetracycline hydrochloride-1,200 and oxytetracycline hydrochloride-1,500 significantly lower than controls for both parameters; oxytetracycline hydrochloride-1,350 values were lower for weight gain during treatment. Maternal liver weight exhibited a significant downward trend with values from all three dose groups significantly lower than controls. Clinical signs during treatment which exhibited a dose-related incidence included weight loss of more than 5 g/24 hrs, respiratory difficulties and rough coat. There were no statistically significant dose-related differences in number or % of implantation sites/dam, resorptions, deaths, nonlives, affected or live fetuses/litter. Fetal body weight (all live fetuses, live male or live female fetuses)/litter at gestational days 20 exhibited a significant downward trend with values from all three dose groups significantly lower than control values for all three parameters. There were no significant differences among treated and control groups in the number or % of males, females or live fetuses malformed/litter nor in the number of litters with malformed fetuses. Exam of malformation incidence by category produced no evidence of dose-response trends, no significant pairwise comparisons, nor any evidence for any malformation unique to or with a higher incidence in any of the treated groups relative to controls. In conclusion, no evidence of teratogenicity of oxytetracycline hydrochloride was seen in pregnant CD rats when administered by gavage during the time of organogenesis (gestational days 6-15) at doses which produced evidence of maternal and fetal toxicity. /Oxytetracycline hydrochloride/ [R23] +... Timed-pregnant CD-1 mice were dosed by oral gavage (po) on gestational days 6-15 with oxytetracycline hydrochloride (0, 1,325, 1,670 or 2,100 mg/kg/day) in corn oil. ... Dams were weighed on gestational days 0, 6-15 (prior to daily dosing) and 17 (immediately after sacrifice) and were also observed for clinical signs of toxicity. At sacrifice on gestational day 17, dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e., sites, resorptions, dead fetuses, live fetuses). ... The maternal mortality rate in the present study was 0.0% (0/42 dams) for the oxytetracycline hydrochloride-0 control group, 2.4% (1/42) for the oxytetracycline hydrochloride-1,325 group, 7.1%, (3/42) for the oxytetracycline hydrochloride-1,670 group and 7.1% (3/42) for the OX-2,100 group. A significant dose response trend (p < 0.05) for reduction in maternal body weight was observed on gestational day 17, but not on gestational days 0, 6 (immediately prior to the first dose), 11 or 15 (at the completion of the dosing period). There were no significant differences, among dose groups for indices of maternal weight gain during the gestation period, during the treatment period, or in absolute weight gain. At sacrifice on gestational day 17 a dose-response trend was evident for reduction in gravid uterine weight, with the oxytetracycline hydrochloride-2,100 dose group values significantly reduced (p < 0.01) relative to control values. Maternal liver weight was similarly reduced in the high dose group relative to controls (p < 0.01) with a significant dose-response trend. Relative maternal liver weight values did not vary among dose groups. Maternal weight loss of more than 1 g/day was considered to be a clinical sign of toxicity in individual dams and was observed in 9.5% (4/42) of the oxytetracycline hydrochloride-2,100 dams, 2.4% (1/42) of the oxytetracycline hydrochloride-1,670 dams and in 4.8% (2/42) of the oxytetracycline hydrochloride-1,325 dams as early as the second day of treatment. One out of 42 dams in the oxytetracycline hydrochloride-0 group (2.4%) exhibited weight loss in the same time period. Other clinical signs observed in a dose-response pattern included alopecia, rough coat, wheezing, hyperpnea, paresis and lethargy. Data concerning the status of uterine implantation sites exhibited a variable response. There were no statistically significant dose-related differences for the following measures: number of implantation sites/dam, number or % of resorptions, fetal deaths, non-live fetuses (dead plus resorbed) or affected fetuses (non-live plus malformed)/litter, or for the proportion of litters with one or more resorptions, fetal deaths, non-live, or affected fetuses. The number of litters with resorptions was significantly elevated in the oxytetracycline hydrochloride-1,325 group relative to controls but not in the two higher dose groups (oxytetracycline hydrochloride-1,670 or oxytetracycline hydrochloride-2,100). In live litters (i.e. litters with one or more live fetuses) there was no difference in the number of live fetuses/litter or in the proportion of males to females/litter across treatment groups. Body weights of live fetuses from oxytetracycline hydrochloride-treated litters exhibited a reduction which was significant for dose-response trend (p < 0.01), but not for any treatment group relative to controls. When separated by sex, avg male and female body weights/litter also exhibited a significant dose-response trend for reduction (p < 0.05), although values for any treatment group were not significantly different from control values. There were no significant differences among treated and control litters in the number or % of males, females or live fetuses malformed nor in the number of litters with malformed fetuses. Exam of malformation incidence by category produced no evidence of dose-response trends nor evidence of any malformation unique to or with higher incidence in any of the experimental groups relative to controls. In conclusion, no evidence for teratogenicity of oxytetracycline hydrochloride was seen in pregnant CD-1 mice when administered by oral gavage during the time of organogenesis at doses which produced little evidence of maternal toxicity (1,325-2,100 mg/kg/day). However, a marginal effect of oxytetracycline on fetal toxicity was detected as evidenced by the significant dose-response trend toward decreased fetal weight, with no significant differences between control and treated groups. /Oxytetracycline Hydrochloride/ [R24] ADE: *SERUM HALF-LIFE ... IN HORSES IS ... 15.7 HR AND 10.5 HR AFTER IV AND IM INJECTIONS, RESPECTIVELY. ... /A FACTOR/ MAY BE THE INFLUENCE OF DOSE-DEPENDENT KINETICS ... . [R25, 174] *RENAL AND HEPATIC ARE ROUTES OF EXCRETION/INACTIVATION. /FROM TABLE/ [R15, 1108] *... OXYTETRACYCLINE /IS/ ... INCOMPLETELY ABSORBED. AFTER A SINGLE ORAL DOSE PEAK PLASMA CONCN ... IN 2-4 HR. ... ADMIN 250 MG EVERY 6 HR PRODUCES PEAK PLASMA CONCN APPROX 3 UG/ML. ... /IT IS/ BOUND TO PLASMA PROTEINS ... APPROX ... 20-25%. [R16, 1119] *... 10-35% OF DOSE OF OXYTETRACYCLINE IS EXCRETED IN ACTIVE FORM IN URINE, IN WHICH IT IS DETECTABLE WITHIN 0.5 HR AND REACHES PEAK CONCN IN ABOUT 5 HR AFTER ... ADMIN. [R16, 1120] *MOST ABSORPTION TAKES PLACE FROM STOMACH AND UPPER SMALL INTESTINE AND IS GREATER IN FASTING STATE ... MUCH LESS COMPLETE FROM LOWER ... TRACT. ... REMOVED FROM BLOOD BY LIVER, WHERE THEY ARE CONCN AND THEN EXCRETED, BY ... BILE, INTO INTESTINE /WHERE/ ... PARTIALLY REABSORBED. BILIARY CONCN ... 5-10 TIMES HIGHER THAN ... PLASMA. /TETRACYCLINES/ [R16, 1119] *INFLAMMATION OF MENINGES IS NOT PREREQUISITE FOR PASSAGE OF TETRACYCLINES INTO CEREBROSPINAL FLUID; ROUTE AND DURATION OF TREATMENT ARE MAJOR DETERMINANTS. IV ... RESULTS IN GRADUAL APPEARANCE ... IN SPINAL FLUID OVER PERIOD OF 6 HR. ORAL THERAPY YIELDS VERY LOW SPINAL FLUID CONCN. /TETRACYCLINES/ [R16, 1119] *PENETRATION ... INTO MOST OTHER FLUIDS /THAN SPINAL/ AND TISSUES IS EXCELLENT. ... STORED IN RETICULOENDOTHELIAL CELLS OF LIVER, SPLEEN AND BONE MARROW, AND IN BONE AND DENTINE AND ENAMEL OF UNERUPTED TEETH. ... CROSS PLACENTA AND ENTER FETAL CIRCULATION AND AMNIOTIC FLUID. /TETRACYCLINES/ [R16, 1119] *CONCN ... UMBILICAL CORD PLASMA REACH 60% AND IN AMNIOTIC FLUID 20% OF THOSE IN CIRCULATION OF MOTHER. RELATIVELY HIGH CONCN ... FOUND IN MILK. ... EXCRETED IN URINE AND FECES, PRIMARY ROUTE FOR MOST BEING KIDNEY. SINCE RENAL CLEARANCE ... IS BY GLOMERULAR FILTRATION ... EXCRETION ... AFFECTED BY STATE OF RENAL FUNCTION. /TETRACYCLINES/ [R16, 1119] *DEPOSITION ... IN TEETH AND BONES IS PROBABLY DUE TO ITS CHELATING PROPERTY AND FORMATION OF TETRACYCLINE-CALCIUM ORTHOPHOSPHATE COMPLEX. ... DEPOSITED IN SKELETON OF HUMAN FETUS AND YOUNG CHILD. /TETRACYCLINES/ [R16, 1119] *EQUILIBRIUM DIALYSIS DETERMINES OXYTETRACYCLINE BINDING TO BE 24%: PROTEIN BINDING OF TETRACYCLINES IS SIGNIFICANT AND VARIES WITHIN THE GROUP. [R26] *INDICATIONS ARE THAT BOTH HYDROPHOBIC AND CHARGE-TRANSFER BINDING ARE INVOLVED. [R27] BHL: *BIOLOGIC HALF-LIFE ... MAY BE 3-4 DAYS IN ANURIA. [R12] *The serum half-life of oxytetracycline is 6 to 10 hours in adults with normal renal function and is reported to be 47 to 66 hours in patients with severe renal impairment. In patients with normal renal function, approximately 60 to 70 percent of a single oral dose of oxytetracycline is excreted in urine within 72 hours as active drug. [R8] ACTN: *IN VITRO, THESE DRUGS ARE PRIMARILY BACTERIOSTATIC; IN HIGH CONCN ... FREQUENTLY BACTERICIDAL. IN GENERAL ... IN VIVO AND IN VITRO EFFICACIES CLOSELY PARALLEL EACH OTHER. ONLY RAPIDLY MULTIPLYING ORGANISMS ARE AFFECTED. ... IN GENERAL, GRAM POSITIVE MICROORGANISMS ARE AFFECTED BY LOWER CONCN ... THAN ARE GRAM NEGATIVE MICROORGANISMS. ... /TETRACYCLINES/ [R16, 1117] *TETRACYCLINES ... INHIBIT BACTERIAL PROTEIN SYNTHESIS AND ... BIND SPECIFICALLY TO 30 S RIBOSOMES. ... APPEAR TO PREVENT ACCESS OF AMINOACYL TRANS-RNA TO MESSENGER-RNA RIBOSOME COMPLEX. ... SMALL PORTION OF DRUG IS IRREVERSIBLY BOUND, AND INHIBITORY EFFECTS ... REVERSED BY WASHING. ... REVERSIBLY BOUND ANTIBIOTIC ... RESPONSIBLE FOR ... ACTION. /TETRACYCLINES/ [R16, 1118] INTC: *SIMULTANEOUS ADMIN IRON AS FERROUS SULFATE REDUCED ABSORPTION AND CAUSED SIGNIFICANT DECR IN SERUM CONCN OF ... OXYTETRACYCLINE ... IN MAN. ... MILK GIVEN SIMULTANEOUSLY REDUCED ABSORPTION OF ... OXYTETRACYCLINE BY ABOUT 50% ... . [R28] *INCR CONCN OF OXYTETRACYCLINE IN NASAL MUCUS DUE TO BROMHEXINE TREATMENT ... ATTRIBUTED TO EVAPORATION OF THE LESS VISCOUS MUCUS, ARISING FROM BROMHEXINE TREATMENT, RATHER THAN INCR MEMBRANE PERMEABILITY. [R25, 174] *... OXYTETRACYCLINE MAY CAUSE UNPREDICTABLE FLUCTUATIONS IN BLOOD GLUCOSE LEVELS ... BY INCR HALF-LIFE OF INSULIN. ... ALSO ... WHEN OXYTETRACYCLINE AND TOLBUTAMIDE ... USED CONCURRENTLY. [R29, 595] *STRIKING ANTAGONISM BETWEEN PENICILLIN AND TETRACYCLINES HAS BEEN OBSERVED CLINICALLY IN PNEUMOCOCCAL MENINGITIS ... . /TETRACYCLINES/ [R15, 1185] *... POSSIBILITY OF ... SEVERE RENAL FAILURE IN PATIENT WHO RECEIVE TETRACYCLINE AFTER BEING ANESTHETIZED WITH METHOXYFLURANE; IN THOSE WHO DIED, KIDNEYS CONTAINED NUMEROUS CALCIUM OXALATE CRYSTALS. /TETRACYCLINES/ [R15, 1189] *SIMULTANEOUS ADMIN ALUMINUM, CALCIUM, OR MAGNESIUM IONS SIGNIFICANTLY DECR GI ABSORPTION OF TETRACYCLINE. /TETRACYCLINE/ [R29, 227] *SODIUM BICARBONATE ADMIN DECR ... ABSORPTION OF TETRACYCLINE ... /AVOID/ CONCURRENT ADMIN OF ANY PREPN THAT COULD RAISE INTRAGASTRIC PH. /TETRACYCLINE/ [R29, 392] *BECAUSE METHOTREXATE BINDS TO PLASMA PROTEINS, IT CAN BE DISPLACED FROM ITS BINDING SITES AND MADE AVAILABLE TO REACT WITH DIHYDROFOLATE REDUCTASE. ... CMPD THAT ... DISPLACE ... INCL ... TETRACYCLINES. /TETRACYCLINES/ [R29, 395] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antibiotics, Tetracycline [R30] *... POSSESS WIDE RANGE OF ANTIMICROBIAL ACTIVITY AGAINST GRAM-POS AND GRAM-NEG BACTERIA ... SOME MICROORGANISMS INNATELY INSENSITIVE TO MANY CHEMOTHERAPEUTIC AGENTS, SUCH AS RICKETTSIAE, MYCOPLASMA, CHLAMYDIA AGENTS OF LYMPHOGRANULOMA VENERUM, PSITTACOSIS, INCLUSION CONJUNCTIVITIS, AND TRACHOMA AND AMEBAE. /TETRACYCLINES/ [R16, 1117] *OXYTETRACYCLINE IS ALSO USED IN TREATMENT OF INTESTINAL AMEBIASIS; IT REMOVES BOTH CYSTS AND MOTILE FORMS FROM INTESTINE AND COMPARES FAVORABLY WITH ARSENICALS AND HALOGENATED QUINOLINES. ... ALL THESE ... HAVE BEEN SUPERSEDED BY METRONIDAZOLE. [R12] *... EFFECTIVE AGAINST ... RICKETTSIAE ... . /TETRACYCLINES/ [R16, 1117] +MEDICATION (VET): "BROAD SPECTRUM" ANTIBIOTIC, INCL GRAM-POS AND GRAM-NEG BACTERIA, SOME LARGE VIRUSES, AND RICKETTSIAE. /USED/ SYSTEMICALLY ... TOPICALLY ... . [R4, 404] *USING DOUBLE BLIND TECHNIQUE, EFFECTS OF OXYTETRACYCLINE WERE COMPARED IN PATIENTS WITH MODERATE AND SEVERE ACNE. AFTER 12 WK TREATMENT, DECR IN ACNE SCORE WAS ABOUT 70%. [R31] +MEDICATION (VET): Clinical Use. A thin film of ointment is applied over the corneal surface 2 to 4 times daily. Treatment is usually restricted to 7 to 10 days. /Oxytetracycline hydrochloride, polymyxin B sulfate ophthalmic ointment (terramycin with polymyxin B)/ [R14, 673] +MEDICATION (VET): Anaplasmosis: Oxytetracycline administered intramuscularly at 11 mg/kg/day for 12 days eliminated Anaplasma marginate from blood of infected animals. Similar results have been obtained in sheep. [R14, 746] +MEDICATION (VET): Bovine hoof diseases: iv administration of oxytetracycline into the common dorsal digital veins represents a new approach for troublesome infections of the hoof ... . [R14, 746] +MEDICATION (VET): Brucellosis: Pregnant cows, when treated with an im injection of 10 g oxytetracycline, had considerable protection against brucella infection; if they received a second injection of 10 g 12 days later, most cows less than 5 months pregnant were protected. [R14, 746] +MEDICATION (VET): East Coast fever: Cattle were effectively immunized against a lethal challenge of several theilerial strains after they were inoculated with 1 ml of an infective stabilate strain and concomitantly received 4 daily injections of 5 mg oxytetracycline starting on the day of infection. [R14, 746] +MEDICATION (VET): Porcine atrophic rhinitis: When administered in 3 im doses on 3, 6, and 12 days of age, oxytetracycline (40 mg/kg) reduced the proportion of clinically affected pigs from 30 percent to 0 within 8 weeks ... . [R14, 746] +MEDICATION (VET): Porcine balantidiosis: Pigs infected with Balantidium coli were free of the organism after receiving acetarsol (20 mg/kg) once daily for 4 days and oxytetracycline (15 mg/kg) twice daily for 4 days ... . [R14, 747] +MEDICATION (VET): ANTIBIOTIC; GROWTH STIMULANT [R4, 404] +MEDICATION (VET): GROWTH PROMOTING AND/OR INCR FEED EFFICIENCY HAVE BEEN NOTED FROM NON-THERAPEUTIC LEVELS IN FEED OF CALVES, FOALS, PIGS, AND POULTRY. [R4, 404] WARN: *GENERIC INEQUIVALENCE HAS BEEN DEMONSTRATED FOR SOME OXYTETRACYCLINE FORMULATIONS, ALTHOUGH INDIVIDUAL VARIATION PREVENTED SIGNIFICANT DIFFERENCES BEING SHOWN IN ALL BUT MOST EXTREME CASES. [R25, 172] *FOOD, MILK, NONSYSTEMIC ANTACIDS AND IRON PREPN INTERFERE WITH ORAL ABSORPTION. [R12] *... NOT ACTIVE AGAINST ANY TRUE VIRUSES, YEASTS, OR FUNGI. /TETRACYCLINES/ [R15, 1184] *TOPICAL ADMIN IS BEST AVOIDED BECAUSE OF HIGH RISK OF SENSITIZATION, EXCEPT FOR USE IN EYE. ... SHOULD NEVER BE INJECTED INTRATHECALLY. /TETRACYCLINES/ [R16, 1120] *BECAUSE OF INCIDENCE OF GI DISTRESS AND ... TETRACYCLINE-RESISTANT BACTERIAL ENTERITIS RISES AS DOSE ... IS INCR, MIN DOSAGE COMPATIBLE WITH DESIRED THERAPEUTIC RESPONSE IS RECOMMENDED. /TETRACYCLINES/ [R16, 1120] *... CROSS-SENSITIZATION AMONG VARIOUS TETRACYCLINES IS EXTREMELY COMMON IF NOT UNIVERSAL. /TETRACYCLINE/ [R16, 1122] *TETRACYCLINES, WITH EXCEPTION OF DOXYCYCLINE, ARE NOT RECOMMENDED FOR ADMIN TO PATIENTS WITH RENAL DYSFUNCTION ... . /TETRACYCLINES/ [R15, 1189] *WITHIN 48 HR AFTER DAILY ADMIN OF CONVENTIONAL DOSES ... ENTERIC FLORA IS MARKEDLY ALTERED. COLIFORM MICROORGANISMS AND GRAM-POS SPORE-FORMING BACTERIA ... SENSITIVE AND MAY BE MARKEDLY SUPPRESSED ... BEFORE RESISTANT STRAINS REAPPEAR. /TETRACYCLINES/ [R16, 1118] *... TETRACYCLINES ADMIN ORALLY OR PARENTERALLY MAY LEAD TO ... SUPRAINFECTIONS ... DUE TO STRAINS OF BACTERIA OR YEASTS RESISTANT TO THESE AGENTS. ORAL, PHARYNGEAL, AND EVEN SYSTEMIC INFECTIONS ... TEND TO OCCUR MOST OFTEN IN ... DIABETES, LEUKEMIA, SYSTEMIC LUPUS ERYTHEMATOSUS, DIFFUSE VASCULITIS, AND LYMPHOMA ... . /TETRACYCLINES/ [R16, 1122] *... SHOULD NOT BE GIVEN TO PREGNANT PATIENT, ... NOT ... EMPLOYED FOR THERAPY OF COMMON INFECTION IN CHILDREN UNDER AGE OF 12 YR, ... SHOULD BE GIVEN PROPHYLACTICALLY WITH GREAT CARE; UNUSED SUPPLIES ... SHOULD BE DISCARDED. /TETRACYCLINES/ [R15, 1191] *PATIENT WHO RECEIVED TWO 500 MG DOSES DAILY OF OXYTETRACYCLINE FOR 5 DAYS SHOWED INCR BLOOD UREA NITROGEN AND SERUM CREATININE LEVELS, BUT NOT EXCEEDING NORMAL RANGE. [R19] *Note: Infants and children up to 8 years of age: All tetracyclines form a stable calcium complex in any bone-forming tissue. Accordingly, tetracyclines may cause permanent yellow-gray-brown discoloration of the teeth, as well as enamel hypoplasia. Also, a decrease in linear skeletal growth rate may occur in premature infants. Therefore, tetracyclines are not recommended in these age groups unless other drugs are unlikely to be effective or are contraindicated. /Tetracyclines/ [R18] *For deep intramuscular use only. Do not administer intravenously. May cause intense pain and local irritation at the site of intramuscular injections. [R18] IDIO: *The ointment is indicated in ocular infections from secondary bacterial complications associated with canine distemper. /Oxytetracycline hydrochloride, polymyxin B sulfate ophthalmic ointment (terramycin with polymyxin B)/ [R14, 673] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ MILK: *Tetracyclines are excreted in breast milk. ... /Tetracyclines/ [R17] BODY: *Tetracyclines are excreted in breast milk. ... /Tetracyclines/ [R17] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *OPP RfD= 1 mg/kg /Oxytetracycline hydrochloride/ [R32] ATOL: *Tolerances are established for residues of the pesticide oxytetracycline in or on the following raw agricultural commodities: peaches: 0.1 ppm; pears: 0.35 ppm. [R33] *Tolerances are established for residues of oxytetracycline in food as follows: (a) In edible tissues of chickens and turkeys: 3 ppm in uncooked kidney; 1 ppm in uncooked muscle, liver, fat and skin; (b) 0.1 ppm in uncooked edible tissues of swine; (c) 0.1 ppm in uncooked edible tissues of swine; (c) 0.1 ppm in uncooked edible tissues of cattle, beef calves, nonlactating dairy cattle and dairy calves; (d) A tolerance of 1 ppm is established for negligible residues of oxytetracycline in uncooked edible tissues of solmonids, catfish, and lobster. [R34] FIFR: *Tolerances are established for residues of the pesticide oxytetracycline in or on peaches and pears. [R33] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Oxytetracycline is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0655; Pesticide type: Fungicide, antimicrobial (bactericide); Registration Standard Date: 12/30/88; Case Status: RED Approved 03/93; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): oxytetracycline; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R35] FDA: *Specifications: The drug is in capsule form with each capsule containing 125 or 250 mg of oxytetracycline hydrochloride. Conditions of use: Used in dogs and cats for the treatment of bacterial pneumonia ... Administered orally to dogs and cats at a dosage level of 25-50 mg per pound of body weight at 12 hr intervals ... Federal law restricts this drug to use by or on the order of a licensed veterinarian. /Oxytetracycline hydrochloride/ [R36] *Specifications: Each tablet contains 250 or 500 mg of oxytetracycline hydrochloride. Conditions of use in beef and dairy cattle: ... For control of bacterial enteritis ... and bacterial pneumonia ... Do not exceed 500 mg per 100 pounds of body weight every 122 hr. Discontinue treatment 7 days prior to slaughter. Not for use in lactating dairy cattle. /Oxytetracycline hydrochloride/ [R37] *Specifications: Each ml of sterile solution contains 200 mg of oxytetracycline base. Conditions of use - Beef cattle and nonlactating dairy cattle ... Treatment of ... pneumonia and shipping fever complex ... diphtheria ... wooden tongue ... leptospirosis ... wound infections ... acute metritis ... leptospirosis ... and pinkeye ... Administer intramuscularly or intrvenously at 3 to 5 mg level; intramuscularly only at 9 mg level ... Discontinue treatment at least 28 days prior to sloughter ... Conditions of use - Swine ... 3 to 5 mg of oxytetracycline per pound of body weight per day ... Treatment of bacterial enteritis ... pneumonia ... and leptospirosis ... Administer intracmuscularly. Do not inject more than 5 ml per site in adult swine ... Discontinue treatment at least 28 days prior to slaughter. [R38] *Tolerances are established for residues of oxytetracycline in chickens, turkeys, swine, beef cattle, nonlactating dairy cattle, dairy calves, salmonids, catfish, and lobsters. [R34] *Conditions of use for oxytetracycline in chicken and turkey feed, cattle feed, and fish feed are given in three tables according to specific amounts of oxytetracycline in grams per ton, indications for use, and limitations. [R39] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *OPTIMUM PH AND BUFFER CONDITIONS FOR POLAROGRAPHIC REDN OF SOME TETRACYCLINE ANTIBIOTICS ARE DISCUSSED. [R40] *MICROSCOPIC ANALYSIS OF OXYTETRACYCLINE IN FEEDS. [R41] CLAB: *FLUORESCENCE ANALYSIS IN SERUM, BONE. [R10, 927] *DETERMINATION OF TETRACYCLINES IN URINE BY HPLC. [R42] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Oxytetracycline Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 315 (1987) NIH Publication No. 87-2571 SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1103 R2: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 1297 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 760 R4: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. R5: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 32 R6: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 2. New York: Marcel Dekker, Inc., 1976. 10 R7: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 866 R8: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992). 319 R9: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-476 R10: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 323 R12: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1142 R13: VEJ-HANSEN ET AL; ARCH PHARM CHEM SCI ED 6 (4): 151-163 (1978) R14: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. R15: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R16: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R17: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.2606 (1992) R18: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.2611 (1992) R19: TANEJA ET AL; CHEMOTHERAPY (BASEL) 20 (4): 201-11 (1974) R20: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 436 R21: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 102 R22: Toxicology and Carcinogenesis Studies of Oxytetracycline Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 315 (1987) NIH Publication No. 87-2571 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R23: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Oxytetracycline Hydrochloride (CAS No. 2058-46-0) in CD Rats, NTP Study No. TER82094 (March 1, 1983) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R24: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Teratologic Evaluation of Oxytetracycline Hydrochloride (CAS No. 2058-46-0) in CD-1 Mice, NTP Study No. TER82095 (July 6, 1982 ) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R25: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. R26: GREEN ET AL; J PHARM PHARMACOL 28: 514-515 (1976) R27: ZIA H, C PRICE; J PHARM SCI 65: 226-30 (1976) R28: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 418 R29: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R30: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R31: MICHAELSSON ET AL; BR J DERMATOL 97: 561-6 (1977) R32: USEPA/OPP; Health Effects Div RfD/ADI Tracking Report p.43 (8/26/91) R33: 40 CFR 180.337 (7/1/90) R34: 21 CFR 556.500 (4/1/91) R35: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.140 (Spring, 1998) EPA 738-R-98-002 R36: 21 CFR 520.1660(b) (4/1/91) R37: 21 CFR 520.1660(c) (4/1/91) R38: 21 CFR 522.1660 (4/1/91) R39: 21 CFR 558.450 (4/1/91) R40: CHATTEN ET AL; J PHARM SCI 65: 1315-19 (1976) R41: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. 15/126 968.50 R42: SHARMA ET AL; J PHARM SCI 66: 1319-22 (1977) RS: 41 Record 225 of 1119 in HSDB (through 2003/06) AN: 3159 UD: 200211 RD: Reviewed by SRP on 9/9/1993 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PHENYLBUTAZONE- SY: *G-13,871-; *G-13871-; *ALINDOR-; *ANTADOL-; *ANUSPIRAMIN-; *ARTHRIZON-; *ARTRIZIN-; *AZOLID-; *BENZONE-; *BETAZED-; *Bizolin-; *BIZOLIN-200-; *BUNETZONE-; *BUTACOTE-; *BUTADION-; *BUTADIONE-; *BUTALIDON-; *BUTAPIRAZOL-; *BUTARTRINA-; *BUTAZINA-; *BUTAZOLIDIN-; *BUTAZOLIDINE-; *BUTIDIONA-; *Butiwas-simple-; *BUTOZ-; *4-Butyl-1,2-diphenyl-3,5-dioxopyrazolidine-; *4-n-Butyl-1,2-diphenyl-3,5-pyrazolidinedione-; *4-Butyl-1,2-diphenylpyrazolidine-3,5-dione-; *BUZON-; *3,5-Dioxo-1,2-diphenyl-4-n-butylpyrazolidine-; *DIPHEBUZOL-; *DIPHENYLBUTAZONE-; *1,2-Diphenyl-4-butyl-3,5-dioxopyrazolidine-; *3,5-Dioxo01,2-diphenyl-4-m-butyl-pyrazolidine-; *ECOBUTAZONE-; *Elmedal-; *Equipalazone-; *Exrheudon-N-; *FENIBUTAL-; *FENIBUTAZONA-; *Fenibutol-; *FENILBUTINA-; *FENOTONE-; *FENYLBUTAZON-; *FLEXAZONE-; *IA-BUT-; *Intrabutazone-; *Intrazone-; *MEPHABUTAZON-; *NC1-C56531-; *PHEBUZINE-; *Phenyzone-; *PIRARREUMOL-"B"-; *Praecirheumin-; *PYRABUTOL-; *3,5-PYRAZOLIDINEDIONE,-4-BUTYL-1,2-DIPHENYL-; *REUDO-; *REUDOX-; *REUMAZIN-; *REUMUZOL-; *ROBIZONE-; *Robizone-V-; *Schemergen-; *SHIGRODIN-; *Spondyril-; *TENCODYNE-; *Tevcodyne-; *TICINIL-; *UZONE-; *VAC-10-; *ZOLAPHEN-; *R-3-ZON- RN: 50-33-9 MF: *C19-H20-N2-O2 ASCH: Phenylbutazone sodium salt; 129-18-0; 3,5-Pyrazolidinedione, 4-butyl-1,2-diphenyl-, compd. with piperazine (2:1); 53700-76-8; 3,5-Pyrazolidinedione, 4-butyl-1,2-diphenyl-, compd. with piperazine(1:1); 4985-25-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF BUTYLMALONYL CHLORIDE WITH HYDRAZOBENZENE IN ETHER SOLUTION, FOLLOWED BY EXTRACTION WITH SODIUM CARBONATE [R1] FORM: *PHENYLBUTAZONE, (BUTAZOLIDIN), IS AVAIL IN 100-MG COATED TABLETS AND CAPSULES FOR ORAL ADMIN. [R2, 655] *National Formulary [R3] *Oral Capsules, 100 mg; Phenylbutazone Capsules, Barr, CMC, Interstate, Major, Rugby; Tablets film-coated, 100 mg; Phenylbutazone Tablets, Barr, CMC, Interstate, Major, Rugby, United Research. [R4, 1197] *Capsules and tablets, 100 mg [R5] MFS: *Barr Pharmaceutical Inc, 2 Quaker Rd, PO Box D-2900, Pomona, NY 10970 (800) 222-4043, (800) 222-0190 [R4, 1197] *Rugby Laboratories Inc, 100 Banks Ave, Rockville Centre, NY 11570 (800) 645-2158 [R4, 1197] OMIN: *A synthetic pyrazolone drivative. [R3] *... Occurs naturally in certain herbs. [R3] USE: +MEDICATION (VET) +MEDICATION PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1978) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1976) 1.20X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1978) 1.40X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM ETHANOL [R6]; *WHITE TO OFF-WHITE CRYSTALLINE POWDER [R7] ODOR: *ODORLESS [R7]; *VERY SLIGHT AROMATIC ODOR [R3] TAST: *SLIGHTLY BITTER TASTE [R3] MP: *105 DEG C [R6] MW: *308.37 [R6] DSC: *PK 4.5 (FROM UV IN WATER), PK 4.89 (TITRATION IN 50% ETHANOL), PK 5.25 (TITRATION IN 80% 2-METHOXYETHANOL) [R6] OWPC: *Log Kow= approx 5.0 [R8] SOL: *SOL IN WATER @ 22.5 DEG C: 0.7 MG/ML (ALSO 2.2 MG/ML) [R6]; *1 G IN ABOUT 20 ML ALCOHOL; FREELY SOL IN ACETONE AND ETHER [R7]; *SOL IN CHLOROFORM AND ETHANOL, VERY SOL IN BENZENE; SOL IN ETHYL ACETATE [R9] SPEC: *MAX ABSORPTION (ACID METHANOL): 239.5 NM (LOG E= 4.19) [R6]; *MAX ABSORPTION (SODIUM HYDROXIDE): 264 NM [R10, p. V13 184]; *INDICES OF REFRACTION: 1.600 (ALPHA), 1.620 (GAMMA) [R11]; *Intense mass spectral peaks: 77 m/z, 183 m/z, 252 m/z, 308 m/z [R12] OCPP: *MP: 140-141 DEG C (SOLIDIFIES AND REMELTS @ APPROX 180 DEG C) /PIPERAZINE SALT OF PHENYLBUTAZONE/ [R6] *PKA= 4.5 [R9] *CRYSTALS; FREELY SOL IN WATER; PH OF AQUEOUS SOLN ABOUT 8.2 /PHENYLBUTAZONE SODIUM SALT/ [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of oxides of nitrogen. [R13] STRG: *STABLE IF STORED @ ROOM TEMP IN CLOSED CONTAINERS IN ABSENCE OF MOISTURE [R3] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Inadequate evidence of carcinogenicity in humans. No data are available in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R14] ANTR: *Emesis may be effective within the first several hours postingestion unless contraindicated. (Watch for depressed sensorium, convulsions, and coma.) ... A reasonable guideline for induction of emesis is the ingestion of 10 times the therapeutic dose in adults and five times the therapeutic dose in children when the overdose has occurred within the last 4 hr. ... Activated charcoal (adults, 60-100 g; children, 30-60 g) should be administered to most nonsteroidal anti-inflammatory drug overdose victims who present soon after ingestion. ... A cathartic (eg, magnesium sulfate: adult, 30 g; children, 250 mg/kg) should be administered concomitantly with activated charcoal. The effectiveness of hemodialysis, hemoperfusion, or peritoneal dialysis appears to be limited because of high protein binding. Hemoperfusion, however, was found to reduce the serum half-life and to increase the clearance of phenylbutazone after an overdose. Since the kidney excretes only a small proportion of the absorbed nonsteroidal anti-inflammatory drug in the urine, forced diuresis or alkalinization of the urine would not be expected to increase clearance. ... There are no antidotes. [R15, 497] HTOX: *MORE SERIOUS FORMS OF ADVERSE EFFECTS INCL PEPTIC ULCER (OR ITS REACTIVATION) WITH HEMORRHAGE OR PERFORATION, HYPERSENSITIVITY REACTIONS OF SERUM-SICKNESS TYPE, ULCERATIVE STOMATITIS, HEPATITIS, NEPHRITIS, APLASTIC ANEMIA, LEUKOPENIA, AGRANULOCYTOSIS, AND THROMBOCYTOPENIA. A NUMBER OF DEATHS HAVE OCCURRED ... . [R2, 655] *NAUSEA, VOMITING, EPIGASTRIC DISCOMFORT, AND SKIN RASHES ARE MOST FREQUENTLY REPORTED UNTOWARD EFFECTS. DIARRHEA, VERTIGO, INSOMNIA, EUPHORIA, NERVOUSNESS, HEMATURIA ... AND BLURRED VISION ... OBSERVED. ... WATER AND ELECTROLYTE RETENTION AND EDEMA FORMATION OCCUR. [R2, 655] *... PHENYLBUTAZONE ... MAY CAUSE INDUCTION OF HEPATIC MICROSOMAL ENZYMES. [R2, 655] *...REDUCES UPTAKE OF IODINE BY THYROID GLAND, APPARENTLY SECONDARY TO INHIBITION OF BIOSYNTHESIS OF ORGANIC COMPOUNDS. GOITER AND MYXEDEMA MAY OCCASIONALLY RESULT FROM THIS. [R2, 654] *... FOLLOW-UP STUDY OF 25 PATIENTS WHO DEVELOPED BONE MARROW DEPRESSION FOLLOWING PHENYLBUTAZONE THERAPY. 18 PATIENTS RECOVERED WITHIN 2 WK-4 YR, 4 WERE STILL UNDER CARE @ TIME OF REPORT AND 3 DIED WITHIN 2 WK-2 YR, 2 OF APLASTIC ANEMIA AND 1 OF MYELOPROLIFERATIVE DISORDER, VERY PROBABLY LEUKEMIA. [R16] *... 4 CASES OF CHRONIC MYELOPROLIFERATIVE DISORDERS (2 OF HODGKIN'S DISEASE, 1 CHRONIC LYMPHATIC LEUKEMIA AND 1 POLYCYTHEMIA VERA) FOLLOWING ADMIN ... FOR PERIODS RANGING FROM FEW WK TO 2 YR. DOSES ... WERE ABOUT 6 and 45 G ... . [R17] *56 YR OLD FEMALE WAS TREATED WITH 300 MG ... DAILY FOR 17 DAYS. AFTER 2 WK SHE ... WAS FOUND TO HAVE APLASTIC ANEMIA ... ACCOMPANIED BY EXTENSIVE BRUISING; SHEDIED WEEK LATER. ... CEREBRAL HEMORRHAGE, AND DIAGNOSIS WAS OF ACUTE LEUKEMIA. [R18] *... PHENYLBUTAZONE ... ASSOC WITH DEVELOPMENT OF STEVENS-JOHNSON SYNDROME OR EPIDERMAL NECROLYSIS WITH INVOLVEMENT OF EYES. ... THEY ARE CHARACTERIZED BY VERY SEVERE KERATITIS WITH INVOLVEMENT OF CONJUNCTIVAE, CORNEAS, AND TEAR GLANDS ... RESULT IN SCARRING OF CORNEAS WITH OPACIFICATION, VASCULARIZATION, AND SYMBLEPHARON. [R19] *Phenylbutazone-associated fatalities have occurred after the appearance of GI distress, convulsions, metabolic acidosis, hepatic necrosis, and renal failure. Serious symptoms in adults developed after ingestions of 4 to 40 g; a 2 g injestion in a 1 yr old resulted in death. [R15, 492] *Nonsteroidal anti-inflammatory drugs nephrotoxicity appears in at least three distinct forms: 1. Acute renal insufficiency resulting from a reduction in renal blood flow. This form of acute renal insufficiency may be insidious in onset, and may not be detected for days or weeks until an elevated serum creatinine or uremic symptoms appear. The group at greatest risk for developing reversible acute renal insufficiency (elderly patients with volume depletion, diuretics, heart failure, liver or renal disease) have a high plasma renin activity with a reduction in blood volume. Such volume depletion initiates an increase in sympathetic activity which may result in renal vasoconstriction. Here local prostaglandins act as vasodilators. A nonsteroidal anti-inflammatory drug overdose will impair renal prostaglandin synthesis and lead to an exaggerated unopposed vasoconstrictive response with decreases in glomerular filtration rate and renal blood flow. 2. Acute tubular necrosis which also may result from decreased prostaglandin-mediated vasodilation. 3. An acute interstitial nephritis with or without proteinuria. This condition develops abruptly with hematuria and flank pain. Most reported cases of interstitial nephritis from nonsteroidal anti-inflammatory drugs have been associated with the carbocyclic and heterocyclic acetic acid class of nonsteroidal anti-inflammatory drugs (tolmetin, sulindac, indomethacin, and zomepirac) as well as fenoprofen (propionic acid derivative). This hypersensitivity form of renal disease may occur with or without rash, fever, eosinophilia, or eosinophiluria. /Nonsteroidal anti-inflammatory drugs/ [R15, 493] *Even large overdoses usually result only in mild CNS depression and GI symptoms which are reversible with supportive care. Residual effects are rare. Neither tolerance nor addiction has been reported. Gastrointestinal distress with nausea, vomiting, and epigastric pain complicate both therapeutic use and overdose. Chronic consumption may lead to peptic ulceration, and gastrointestinal bleeding. The Hemoccult card test usually is not positive in patients receiving therapeutic nonsteroidal anti-inflammatory drug doses. A positive Hemoccult card test should not be ascribed to these drugs until appropriate studies have ruled out the existence of underlying gastrointestinal tract lesion. Drowsiness is a common symptom after large nonsteroidal anti-inflammatory drug overdose. Dizziness, lethargy, and disorientation also have been observed in the overdose setting. /Nonsteroidal anti-inflammatory drugs/ [R15, 494] *Hepatic necrosis with markedly elevated serum aminotransferases and bilirubin has accompanied severe phenylbutazone overdose. [R15, 495] *Serious adverse GI effects (eg, bleeding, ulceration, perforation) can occur at any time in patients receiving chronic nonsteroidal anti-inflammatory agent therapy, and such effects may not be preceded by warning signs or symptoms. Minor upper GI effects (eg, dyspepsia), which usually develop early, occur commonly during nonsteroidal anti-inflammatory agent therapy, but the absence of such early GI manifestations does not preclude the development of serious GI toxicity in patients receiving chronic nonsteroidal anti-inflammatory agent therapy. /Nonsteroidal anti-inflammatory agents/ [R4, 1194] *Results of studies to date are inconclusive concerning the relative risk of various nonsteroidal anti-inflammatory agents in causing serious GI effects. In patients receiving nonsteroidal anti-inflammatory agents and observed in clinical studies of several months' to 2 years' duration, symptomatic upper GI ulcers, gross bleeding, or perforation appeared to occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of those treated for 1 year. High dosages of any nonsteroidal anti-inflammatory agent probably are associated with increased risk of such effects, although controlled studies documenting this probable association are lacking for most nonsteroidal anti-inflammatory agents. /Nonsteroidal anti-inflammatory agents/ [R4, 1194] *Phenylbutazone overdosage may result in the prompt onset of respiratory or metabolic acidosis with hyperventilation which can progress to coma, trismus, tonic clonic seizures, and a shock syndrome (with hypotension and oliguria). Renal failure (with proteinuria, oliguria, and hematuria), liver damage (with hepatomegaly and toxic jaundice), acute bone marrow depression, abnormalities of formed blood elements, ulceration of the buccal or GI mucosa, and acute perforation of peptic ulcer may occur as late manifestations of overdosage. Other signs and symptoms of phenylbutazone overdosage include nausea, vomiting, epigastric pain, excessive perspiration, euphoria, psychosis, headaches,giddiness, vertigo, nystagmus, insomnia, tinnitus, difficulty in hearing, edema (sodium retention), hypertension, cyanosis, respiratory depression, agitation, hallucinations, drowsiness, and stupor. [R4, 1196] *Significant increases in the number of chromosome abnormalities resulting from chromosome breakage events were reported in cultured human peripheral leucocytes from patients treated with phenylbutazone for rheumatic disorders for at least 3 months in doses ranging from 100-500 mg/day. In the same study, a few of the patients were examined for chromosome damage in bone-marrow cells, with negative results. [R20] *Five cases of acute leukemia following phenylbutazone therapy, from a total of 55 cases of acute leukemia observed in Australia in the years 1959-1963 were reported ... ; 3 further cases associated with phenylbutazone treatment were reported ... . Of the total of 8 cases, 5 were in men and 3 in women; the doses ranged from approximately 3-100 g and the duration of treatment lasted from 1 week to 4 years continuously, or 7 years intermittently. The first symptoms related to leukemia were observed from a few weeks to 1 year after cessation of phenylbutazone administration. Four other cases were excluded because of short duration of treatment or prior radiotherapy. Four cases of chronic myleoproliferative disorders (2 of Hodgkin's disease, 1 choronic lymphatic leukaemia and 1 polycythaemia vera) following administration of phenylbutazone for periods ranging from a few weeks to 2 years /were also reported/. The doses in two of these cases were about 6 and 45 g; in the other two they were unknown. [R17] *Borderline elevations of one or more liver function test results may occur in up to 15% of patients treated with nonsteroidal anti-inflammatory agents; meaningful (3 times the upper limit of normal) elevations of serum ALT (SGPT) or AST (SGOT) concentration have occurred in less than 1% of patients receiving nonsteroidal anti-inflammatory agents in controlled clinical studies. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. /Nonsteroidal anti-inflammatory agents/ [R4, 1195] *Phenylbutazone interferes with uptake of iodine by the thyroid gland. Goiters associated with hyperthyroidism or hypothyroidism and thyroid hyperplasia have been reported, but a definite causal relationship to the drug has not been established . [R4, 1195] *Current knowledge on side effects of non-steroidal anti-inflammatory drugs is reviewed. These occur most commonly in the gastrointestinal tract and include peptic ulceration and hemorrhage as well as effects on the small and large bowel. Renal effects with many manifestations are also increasingly described. Photosensitivity is the most common adverse dermatological effect. The role of various non-steroidal anti-inflammatory drugs in causing asthma is now well recognized. Many less common side effects occur, the most significant of which is marrow aplasia. Phenylbutazone and indomethacin are rarely but definitely associated with this, but other non-steroidal anti-inflammatory drugs including ibuprofen are also suspected, but unproven, causes. [R21] *Erythema multiforme is a cutaneous reaction pattern manifested by well demarcated plaques on the trunk and extremities. Target, or iris, lesions, with central clearing, are characteristic of this disorder. Erythema multiforme may be a mild condition (erythema multiforme minor), or it may be a severe, possibly life threatening condition (erythema multiforme major or Stevens-Johnson syndrome). Toxic epidermal necrolysis, manifested by widespread epidermal desquamation, is the most severe form of this disorder. The three most common triggers for erythema multiforme are herpes simplex infection, mycoplasma infection and drug reactions. Drugs that can precipitate erythema multiforme include phenylbutazone. The appearance of the characteristic lesion is usually diagnostic. However, conditions such as tinea corporis, lupus erythematosus, herpetic gingivostomatitis, Behcet' disease and erosive lichen planus, among others, may mimic erythema multiforme. [R22] NTOX: *GASTRIC ULCERATIONS WERE PRODUCED IN DOGS AFTER PROLONGED IM ADMIN OF DOSES OF 3.6-35.2 G PHENYLBUTAZONE OVER 10-103 DAYS. [R23] *...DEATH OF DOG AFTER PHENYLBUTAZONE THERAPY, SYNDROME BEING CHARACTERIZED BY WIDESPREAD HEMORRHAGES, BILIARY STASIS, AND DEGENERATIVE LESIONS IN KIDNEYS. ... THIS COMPD INTERFERES WITH PLATELET AGGREGATION, AND THUS WITH FORMATION OF HEMOSTATIC PLUGS. [R24] *IN EXPTL ANIMALS ... FOUND TO INHIBIT INCORPORATION OF SULFATE INTO SULFOMUCOPOLYSACCHARIDES OF CORNEA ... . IN RABBITS 20% SOLN HAS BEEN FOUND TOO IRRITATING TO ADMIN SUBCONJUNCTIVALLY ... . [R19] *SIGNIFICANT INCR IN NUMBER OF CHROMOSOME ABNORMALITIES RESULTING FROM CHROMOSOME BREAKAGE EVENTS WERE REPORTED IN CULTURED HUMAN PERIPHERAL LEUCOCYTES FROM PATIENTS TREATED WITH PHENYLBUTAZONE FOR RHEUMATIC DISORDERS FOR @ LEAST 3 MO IN DOSES RANGING FROM 100-500 MG/DAY. ... CHROMOSOME DAMAGE IN BONE-MARROW CELLS ... NEGATIVE ... . [R25] *Phenylbutazone was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Phenylbutazone was tested at doses of 0.033, 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S9. Phenylbutazone was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 10 mg/plate. Phenylbutazone was toxic at 3.3 mg/plate in strain TA100. [R26] *Administration of phenylbutazone (50-200 mg/kg) to rats and horses causes renal papillary necrosis, progressive proteinuria, and concomitant hyperplastic changes in the collecting ducts. Acute renal papillary necrosis in horses given phenylbutazne is accentuated by water deprivation. Similar lesions have been /observed/ in dogs and cats ... . [R27] *All reported tests for induction of gene mutation in various strains of Salmonella were negative for phenylbutazone, with or without exogenous metabolic activation (S9). NTP-sponsored Salmonella tests with strains TA98, TA100, TA1535, and TA1537 were also negative, with and without S9. No growth inhibition due to DNA damage was observed in Bacillus subtilis rec -/rec+, with or without S9; mutations were not induced by phenylbutazone in silkworms. [R28] *Positive results have been reported for phenylbutazone-induced chromosomal effects in mammalian cell cultures. Induction of chromosomal aberrations by phenylbutazone was reported in cultured hamster lung fibroblasts in the absence of S9, in Chinese hamster ovary cells in the presence of S9, and in human lymphocyte cultures, but not in human fibroblast cultures. The frequency of sister chromatid exchanges was not increased in CHO cells or human fibroblasts treated with phenylbutazone. [R28] *Phenylbutazone has been tested in several in vivo assays for clastogenicity. There is one positive report of induction of micronuclei in the bone marrow cells of Swiss albino mice given phenylbutazone orally or by intraperitoneal injection, with total doses of 75-200 mg/kg body weight (administered in two equal portions at 24-hour intervals; mice were killed 6 hours after the second administration). All other reports were negative. A micronucleus test for induction of clastogenic damage in bone marrow polychromated erythrocytes of male BALB/c mice administered a dose of 400 mg/kg in a single intraperitoneal injection gave negative results. No induction of chromosomal aberrations was observed in bone marrow cells of mice, hamsters, or rats administered phenylbutazone. Spermatocytes from male mice administered phenylbutazone did not demonstrate an increase in chromosomal aberrations. No induction of dominant lethal mutations was detected in the germ cells of CLFP male mice given intraperitoneal injection of 100 mg/kg phenylbutazone, in male BALB/c mice given intraperitoneal injections of 400 mg/kg phenylbutazone, or in the ovum of female mice administered 400 mg/kg phenylbutazone orally at the time of estrus. [R29] *The long-term toxicity, carcinogenicity, and potential tumor-promoting effects of phenylbutazone were investigated in inbred DONRYU rats. In the carcinogenicity study, rats of each sex were fed diets containing 0, 1250, or 2500 ppm phenylbutazone for 2 years. Control groups of each sex contained 100 animals, and each dosed group contained 50 animals. In the female rats, dose-dependent positive trends were noted in the occurrence of leukemia, neoplastic nodules of the liver, and pheochromocytomas of the adrenal glands. [R29] *Phenylbutazone has exhibited inconclusive evidence of embryotoxicity in animal reproduction studies. Inhibitors of prostaglandin synthesis may have adverse effects on the fetal cardiovascular system (eg, premature closure of the ductus arteriosus). [R4, 1196] *Gastric ulcerations were produced in dogs after prolonged im administration ofdoses of 3.6-35.2 g phenylbutazone over 10-103 days. [R23] *No increase in the number of chromosome abnormalities has been observed in bone-marrow cells of Chinese hamsters after oral administration or of rats after ip administration of phenylbutazone or in germinal cells of male mice after oral administration. [R25] NTP: *Two year studies were conducted by administering 0, 50, or 100 mg/kg phenylbutazone in corn oil by gavage to groups of 50 rats of each sex, 5 days per week for 103 weeks. The doses given groups of 50 mice of each sex on the same schedule were 0, 150, or 300 mg/kg. Mean body weights of high dose rats were generally 6%-11% lower than those of vehicle controls. Mean body weights of mice were similar among all groups except for high dose female mice, which weighed 4%-11% less than vehical controls. The survival of all groups was similar except for that of the low dose group of male rats, which was significantly lower than that of the vehicle controls at the end of the studies; the survival of the top dose group of female rats and the vehicle control of female mice was low but not statistically reduced. ... Under the conditions of these 2 year gavage studies, there was equivocal evidence of carcinogenic activity of phenylbutazone for male F344/N rats as shown by the occurrence of small numbers of rental tubular cell adenomas and arcinomas. There was some evidence of carcinogenic acitivity for female F344/N rats, as shown primarily by the occurrence of two rare transitional cell carcinomas in the top dose group; none has ever been seen in vehicle control or untreated control female rats. Tubular cell adenomas may have been associated with the administration of phenylbutazone to female rats. There was some evidence of carcinogenic activity for male B6C3F1 mice as shown by the increased incidence of hepatocellular adenomas or carcinomas (combined). There was no evidence of carcinogenicity of female B6C3F1 mice administered phenylbutazone in corn oil by gavage at doses of 150 or 300 mg/kg. Phenylbutazone was also nephrotoxic to rats, as shown by the dose-related increase in the severity of age-related nephropathy, necrosis of the renal papila, and mineralization of the collecting ducts in the papilla. [R30] POPL: *TOXIC EFFECTS OF DRUG ARE MORE SEVERE IN ELDERLY PERSONS, AND ITS USE IN THIS GROUP IS INADVISABLE. [R2, 655] ADE: *... SLOWLY EXCRETED IN URINE, SINCE BINDING TO PLASMA PROTEIN LIMITS ... GLOMERULAR FILTRATION, and ... /PHENYLBUTAZONE HAS/ RELATIVELY HIGH PKA, WHICH FAVORS PASSIVE REABSORPTION IN DISTAL TUBULE. ONLY TRACE OF UNCHANGED /PHENYLBUTAZONE/ ... IN URINE; ABOUT 4% ... OXYPHENBUTAZONE AND ABOUT 15% AS URICOSURIC METABOLITE. [R31, 340] *... RAPIDLY AND COMPLETELY ABSORBED FROM GI TRACT, OR RECTUM AND PEAK PLASMA CONCN IS REACHED IN 2 HR. AFTER THERAPEUTIC DOSES MORE THAN 98% BOUND TO PLASMA PROTEINS. PLASMA HALF-TIME ... IS 50 TO 60 HR. [R2, 654] *Nonsteroidal anti-inflammatory drugs are 95% bound to plasma protein, especially albumin. With extensive protein binding, there is a small volume of distribution (0.10-0.17 l/kg). The pKa for nonsteroidal anti-inflammatory drugs ranges from 3.5 to 5.2. /Nonsteroidal anti-inflammatory drugs/ [R15, 493] *Phenylbutazone binds avidly to serum proteins and is found in negligible quantities in saliva. After administration of a single dose to humans (400 mg), the plasma concentration of unaltered drug is characterized by an early maximum of 36 ug/ml at 3 hours and by slow decay between 7 and 336 hours, corresponding to an elimination half-life of 88 hours. Phenylbutazone is extensively metabolized before excretion. Studies in horses and rats indicate that less than 3% of an administered dose of phenylbutazone is excreted unchanged in the urine. Similar studies involving humans revealed that no detectable parent compound was excreted in the urine. [R8] *Phenylbutazone appears to be rapidly and completely absorbed from the Gl tract. Following oral administration of a single 300 mg dose of phenylbutazone to healthy fasting men, peak plasma phenylbutazone concentrations averaging 43.3 ug/ml are reached within 2.5 hours. [R4, 1193] *Administration of 300-400 mg of phenylbutazone daily in patients with rheumatoid arthritis usually produces steady state plasma phenylbutazone concentrations averaging about 95 ug/ml in 3-4 days. Following phenylbutazone administration, steady state plasma concentrations of oxyphenbutazone are about 50% of those for phenylbutazone. In studies of the relationship between plasma concentrations of phenylbutazone and/or oxyphenbutazone and therapeutic effects, no correlation has been shown. [R4, 1193] *In mice, radioactivity after administration of radiolabeled phenylbutazone is highest in the blood, liver, heart, lungs, and kidneys, with lower amounts in the CNS. In patients with rheumatoid arthritis, phenylbutazone concentrations in synovial fluid are 55-80% of those in plasma; the drug may persist in synovial fluid up to 3 weeks after therapy is terminated. [R4, 1193] *In one study in healthy adults, the mean apparent volume of distribution of phenylbutazone was 10.2 l following single 100, 300, and 600 mg oral doses of phenylbutazone. In these patients, steady state phenylbutazone concentrations were lower during multiple dosing than would be expected from predictions based on single dose data. It was suggested that the volume of distribution of the drug may be increased at higher chronic dosages (multiple doses); there was no apparent change in the metabolism of the drug. [R4, 1193] *After therapeutic doses, phenylbutazone and oxyphenbutazone (a metabolite) are approximately 98% bound to serum albumin. In one multiple dose study in patients with rheumatoid arthritis, when the dosage of phenylbutazone was increased from 200 to 400 mg daily, plasma steady state concentrations of unbound phenylbutazone, but not total phenylbutazone, increased proportionally with dosage. These changes in binding of phenylbutazone could not be explained by saturation of protein binding sites or displacement interactions. In one study in geriatric patients, phenylbutazone protein binding was reduced; this reduction was attributed to age related alterations in albumin concentration. [R4, 1194] *Phenylbutazone and oxyphenbutazone cross the placenta. The drug and this metabolite are distributed into milk. [R4, 1194] *Approximately 60% of a single 400-mg oral dose of radiolabeled phenylbutazone is excreted in urine in 21 days; 27% of the dose is excreted in feces. About 40% of the total urinary excretion of phenylbutazone occurs as the C-glucuronide of phenylbutazone, 12% as the C-glucuronide of gamma-hydroxyphenylbutazone, about 10% as the sum of unconjugated metabolites (oxyphenbutazone, gamma-hydroxyphenylbutazone, p,gamma-dihydroxyphenylbutazone), and less than 1% as unchanged phenylbutazone. [R4, 1194] METB: *BIOTRANSFORMATION BY HEPATIC MICROSOMAL SYSTEM YIELDS 2 METABOLITES, OXYPHENBUTAZONE ... AND GAMMA-HYDROXYPHENYLBUTAZONE ... /OXYPHENBUTAZONE/ ... CONTRIBUTES TO PHARMACOLOGICAL AND TOXIC EFFECTS OF PARENT DRUG. ... ONLY TRACE OF UNCHANGED PHENYLBUTAZONE IS EXCRETED ... . [R31, 340] *Major metabolites that have been identified include oxyphenbutazone (ring hydroxylation), Y-hydroxyphenylbutazone (side-chain hydroxylation) Y-hydroxyoxyphenbutazone (dihydroxy metabolite), and 4-hydroxyphenylbutazone. In rats and horses, Y-hydroxyphenylbutazone represents a major (approximately 35%) metabolite and exists in two interchangeable forms; the lactone and the straight-chain forms. The production of the lactone form of Y-phenylbutazone requires cleavage of one of the amide bonds. The formation of this lactone isomer has been shown to be an insignificant reaction in humans. Additional, but apparently minor, products of phenylbutazone oxidation include B-hydroxy- and Y-keto-derivatives of the parent compound. [R27] *Phenylbutazone exists in solution in three forms--a diketo, an enol, and a mesomeric anion form. In solution, it exists primarily in the diketo form, and conversion between the forms is slow. These transformations probably contribute to its chemical instability and the ability of the cyclooxygenase system to generate the 4-hydroxphenylbutazone metabolite by a peroxide-dependent cooxygenation reaction. [R27] *In addition to the primary metabolites, glucuronide/sulfate conjugates of these primary metabolites have been detected in varying proportions. No glucuronide metabolites have been reported in horses; in rats, approximately 35%-40% of the metabolites are excreted in the urine as conjugated metabolites; in humans, conjugates represent about 50% of urinary metabolites. [R27] *Phenylbutazone is metabolized in the liver. Phenylbutazone is oxidized to oxyphenbutazone, gamma-hydroxyphenylbutazone, beta-hydroxyphenylbutazone, gamma-ketophenylbutazone, and p,gamma-dihydroxyphenylbutazone. Glucuronide conjugates of phenylbutazone and its metabolites are also formed. In a multiple-dose study in patients with rheumatoid arthritis, plasma concentrations of total oxyphenbutazone decreased with increasing phenylbutazone dose, suggesting that increased chronic doses of phenylbutazone might stimulate elimination of oxyphenbutazone or inhibit oxyphenbutazone formation. Plasma concentrations of gamma-hydroxyphenylbutazone increased proportionally with phenylbutazone dose and showed large interindividual variations. [R4, 1194] BHL: *BIOLOGICAL T/2 OF PHENYLBUTAZONE IN PLASMA WAS ABOUT 6 HR IN DOGS, 5 HR IN GUINEA-PIGS AND 3 HR IN RABBITS. [R10, p. V13 189] *BIOLOGICAL T/2 OF PHENYLBUTAZONE IN PLASMA IS 72 HR. ... GIVEN @ 2-3 TIMES THERAPEUTIC DOSE IS METABOLIZED SLOWLY, WITH ACCUM OF ... /METABOLITE/ IN PLASMA. [R10, p. V13 190] *... LONGER PLASMA HALF-LIVES OF ... PHENYLBUTAZONE IN GERIATRIC PT COMPARED WITHCONTROL SUBJECTS. [R32, 437] *The plasma half-lives of phenylbutazone and oxyphenbutazone (a metabolite) have been reported to be 50-100 hours with large interindividual and intraindividual variations. The plasma half-life of phenylbutazone has been reported to be shorter in children than in adults and in one study was reported to be about 40 hours in children 1-7 years of age. It was suggested that this may result from enhanced cytochrome p450 enzyme activity in children or a greater liver to body weight ratio in children than in adults. Plasma half-lives of phenylbutazone may be somewhat longer in geriatric patients than in younger adults. Age related biologic and physiologic changes (eg, decreased liver and renal function, decreased serum albumin concentration) may be responsible for altered elimination of the drug in geriatric patients. In patients with severely impaired liver function, plasma phenylbutazone half-lives up to 149 hours have been reported. [R4, 1194] ACTN: *MECHANISM OF ANTI-INFLAMMATORY EFFECTS OF PHENYLBUTAZONE IS NOT KNOWN. ... INHIBITS BIOSYNTHESIS OF PROSTAGLANDINS, UNCOUPLES OXIDATIVE PHOSPHORYLATION, AND INHIBITS ATP-DEPENDENT BIOSYNTHESIS OF MUCOPOLYSACCHARIDE SULFATES IN CARTILAGE. [R31, 339] *URICOSURIC EFFECT, PROBABLY ATTRIBUTABLE TO ONE OF ITS METABOLITES THAT DECREASES TUBULAR REABSORPTION OF URIC ACID. LOW CONCN OF DRUG INHIBIT TUBULAR SECRETION OF URIC ACID AND CAUSE URATE RETENTION. [R2, 654] *Nonsteroidal anti-inflammatory drugs probably act by inhibiting prostaglandin synthesis. Prostaglandins prostaglandins are believed to cause vasodilaton, increased vascular permeability, and increased sensitivity of nerve endings to other inflammatory mediators. By reversibly inhibiting the enzyme cyclooxygenase, nonsteroidal anti-inflammatory drugs block the conversion of the arachidonic acid found in cell membrane phospholipids into varius prostaglandins (E2,F2,D2, thromboxane A2). Since prostaglandins appear to maintain the gastric mucosal barrier nonsteroidal anti-inflammatory drugs inhibition of prostaglandins synthesis may be the cause of the gastritis, peptic ulcerations, and gastrointestinal bleeding observed with nonsteroidal anti-inflammatory drugs. Nonsteroidal anti-inflammatory drugs cause sodium retention, especially in patients with underlying sodium-retaining states such as congestive heart failure. Although the mechanism is not entirely clear, the inhibition of prostaglandins synthesis plays a leading role. These compounds redistribute renal blood flow away from the superficial cortical glomeruli to the juxtamedullary glomeruli, which have a greater capacity to absorb sodium. Stress intensifies the effect of prostaglandins. /Nonsteroidal anti-inflammatory drugs/ [R15, 493] *Phenylbutazone exists in solution in three forms--a diketo, an enol, and a mesomeric anion form. In solution, it exists primarily in the diketo form, and conversion between the forms is slow. These transformations probably contribute to its chemical instability and the ability of the cyclooxygenase system to generate the 4-hydroxphenylbutazone metabolite by a peroxide-dependent cooxygenation reaction. This reaction has been shown to produce reactive intermediates capable of inactivating prostacyclin synthase and prostaglandin H synthase, which may account for phenylbutazone's anti-inflammatory activity. [R27] *The drug exhibits anti-inflammatory, analgesic, antipyretic, and mild uricosuric activity. The exact mechanisms have not been clearly established, but many of the actions appear to be associated principally with the inhibition of prostaglandin synthesis. Many nonsteriodal anti- inflammatory agents inhibit the synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase, an enzyme that catalyzes the formation of prostaglandin precursors (endoperoxides) from arachidonic acid. [R4, 1193] INTC: *MANY STEROIDS ... ARE SUBJECT TO HEPATIC MICROSOMAL MIXED FUNCTION OXIDATION, AND DRUGS SUCH AS ... PHENYLBUTAZONE ... HAVE BEEN REPORTED TO INCR URINARY EXCRETION OF STEROID METABOLITES. [R33, 116] *N-DEMETHYLATION OF ETHYLMORPHINE IS COMPETITIVELY INHIBITED BY ... PHENYLBUTAZONE ... . [R33, 332] *... PHENYLBUTAZONE ... SHOWN TO DECR PLASMA-PROTEIN BINDING OF DIPHENYLHYDANTOININ MAN ... . [R32, 440] *OCCUPATIONAL EXPOSURE TO INSECTICIDES IS REPORTED TO DECR PLASMA T/2 VALUES FOR PHENYLBUTAZONE IN NORMAL SUBJECTS. ... PHENYLBUTAZONE ACCELERATES URINARY EXCRETION OF SODIUM CYCLAMATE IN RABBITS ... . [R34] *OTHER ANTI-INFLAMMATORY AGENTS, ORAL ANTICOAGULANT AGENTS, ORAL HYPOGLYCEMICS, SULFONAMIDES ... MAY BE DISPLACED FROM BINDING TO PLASMA PROTEINS BY PHENYLBUTAZONE. NET RESULT MAY DEPENDS UPON THE DRUG AND ITS DISPOSITION AFTER BEING DISPLACED. [R2, 654] *PHENYLBUTAZONE ENHANCES HYPOPROTHROMBINEMIC EFFECT OF WARFARIN ... COUMARIN ANTICOAGULANTS ACENOCOUMAROL AND PHENPROCOUMON ... INTERACT ... . [R35, 295] *... CHOLESTYRAMINE /WHICH IS A POLYAMINE-METHYLENE RESIN/ DELAYS ABSORPTION OF PHENYLBUTAZONE IN ANIMALS ... . [R35, 185] *IT ... INCR EFFECT OF INSULIN. [R2, 655] *HYPOGLYCEMIC ACTIVITY OF TOLBUTAMIDE ... ENHANCED BY ... PHENYLBUTAZONE ... IN ADDITION...ACETOHEXAMIDE AND CHLORPROPAMIDE ... INTERACT ... TOLAZAMIDE ALSO MAY BE INCR BY PHENYLBUTAZONE. [R35, 247] *... CONCURRENT ADMIN OF SULFINPYRAZONE AND ASPIRIN SHOULD BE AVOIDED. ... PHENYLBUTAZONE ... CHEMICALLY SIMILAR TO SULFINPYRAZONE ... . [R35, 226] *Because phenylbutazone and oxyphenbutazone (a metabolite) are highly protein bound, they could be displaced from binding sites by, or they could displace from binding sites, other protein bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Patients receiving phenylbutazone with any of these drugs should be observed for adverse effects. [R4, 1196] *As microsomal enzyme inducers, phenylbutazone and oxyphenbutazone (a metabolite) may accelerate the metabolism of drugs that are affected by this system. Conversely, the metabolism of phenylbutazone may be enhanced and the plasma half-life shortened by concomitant administration of other agents such as barbiturates, promethazine, chlorpheniramine, rifampin, or corticosteroids, which also induce hepatic microsomal enzymes. ... Phenylbutazone may enhance the metabolism of digitoxin (presumably by induction of hepatic microsomal enzymes), resulting in decreased digitoxin plasma concentrations and half-life. ... Phenylbutazone may also enhance the metabolism of aminopyrine, hexobarbital, or corticosteroids. [R4, 1196] *Administration of phenylbutazone with warfarin or other coumarin or indandione derivative anticoagulants has resulted in increased concentrations of free anticoagulant and an increased risk of serious hemorrhage. Hypoprothrombinemia occurs in almost all patients treated with warfarin and phenylbutazone, usually within the first week and as early as the first day after the initiation of concurrent therapy. This effect has been attributed to displacement of anticoagulants from protein binding sites by phenylbutazone and/or its metabolite, oxyphenbutazone; in addition, phenylbutazone appears to inhibit metabolism of the pharmacologically active S-isomer of warfarin. Phenylbutazone does not affect prothrombin time when administered alone. The ulcerogenic potential of phenylbutazone and the effect of the drug on platelet function further contribute to the hazard of concomitant therapy with any anticoagulant or thrombolytic agent (eg, streptokinase). [R4, 1196] *Phenylbutazone may potentiate the hypoglycemic effects of acetohexamide, tolbutamide, and other sulfonylureas, possibly through competition for protein binding sites or for urinary excretion. Phenylbutazone has been shown to inhibit the metabolism of tolbutamide, possibly by stimulating a cytochrome p450 like enzyme system that has a low metabolic activity for tolbutamide hydroxylation, and to decrease the renal excretion of hydroxyhexamide (the active metabolite of acetohexamide). Phenylbutazone may also potentiate the hypoglycemic effect of insulin. [R4, 1196] *If phenylbutazone is administered with an antidiabetic agent, the patient should be closely monitored for signs of hypoglycemia; dosage adjustment of the antidiabetic agent may be necessary when phenylbutazone therapy is initiated or discontinued. In one study, a decrease in phenylbutazone plasma half-life as well as an increase in tolbutamide plasma half-life occurred following administration of phenylbutazone after pretreatment with tolbutamide; the clinical significance of these results has not been established. Paradoxically, hyperglycemia was reported in one patient after concomitant use of tolbutamide and phenylbutazone. [R4, 1196] *Phenylbutazone may increase serum concentrations or half-life of phenytoin, possibly by competing for hepatic metabolism or by displacing phenytoin from plasma proteins. Since this interaction may increase the risk of phenytoin toxicity, patients receiving this combination should be closely observed. [R4, 1197] *Concomitant administration of methotrexate and phenylbutazone in 2 patients with psoriasis was reportedly followed by development of widespread cutaneous ulcerations and one fatality following bone marrow depression and septicemia. Although a causal relationship has not been established, this combination of drugs should be used cautiously. [R4, 1197] *Concomitant administration of large doses of salicylates with phenylbutazone results in mutual suppression of uricosuric activity; the mechanism of the interaction may involve competition for active renal tubular transport. Salicylates may also displace phenylbutazone from protein binding sites. Nephrotoxicity may develop in patients taking phenylbutazone with other nonsteroidal anti-inflammatory agents. [R4, 1197] *Phenylbutazone may increase the plasma half-life of penicillin G, possibly through competition for urinary excretion. [R4, 1197] *The antibacterial activity of sulfonamides may be increased by concomitant administration of phenylbutazone, but this effect has not been firmly established. [R4, 1197] *In animals, cholestyramine has reduced the Gl absorption of phenylbutazone; this effect has not been evaluated in humans. [R4, 1197] *The sodium and fluid retention properties of phenylbutazone and its active metabolite, oxyphenbutazone, may abolish the antihypertensive effect of some antihypertensive agents. [R4, 1197] *In one study, iv hydrocortisone administered during phenylbutazone therapy was associated with increased urinary excretion of oxidized metabolites of phenylbutazone; the clinical significance of this effect has not been established. [R4, 1197] *Alcohol and phenylbutazone may have additive effects on psychomotor impairment if used concurrently. [R4, 1197] *Hepatotoxic drugs administered concomitantly with phenylbutazone may predispose a patient to liver damage. [R4, 1197] *For the investigation of promoting effects, phenylbutazone was given as a dietary supplement (2,500 ppm) for 2 years subsequent to initiation with N-ethyl-N-nitrosourea (15 ml/day of a 400-ppm solution for 4 weeks to 40 rats) or N-propyl-N-nitrosourea (a single gavage dose of 200 mg propyl-N-nitrosourea/kg body weight to 80 rats). After this exposure to the carcinogen, the groups were subdivided; half were maintained on a basal diet, and half were given a diet containing 2,500 ppm phenylbutazone for the next 104 weeks. In the rats given N-ethyl-N-nitrosourea and propyl-N-nitrosourea, there were increased incidences of ovarian neoplasms, leukemia, renal neoplasms. The incidences of these neoplasms were not increased by phenylbutazone exposure. A slight promoting effect, however, was demonstrated for renal and thyroid gland tumorigenesis. [R29] *Since the first observation in 1978, it has been clearly established that the non-steroidal anti-inflammatory drugs interfere with the pharmacokinetics of lithium: by reducing urinary clearance of the metal, they can raise the plasma lithium level and thus lead to intoxication. Among the non-steroidal anti-inflammatory drugs available in France, this interaction has been reported with phenylbutazone (Butazolidine, Carudol), diclofenac (Voltarene), indomethacin (Indocid) and its antalgic derivative clomethacin (Duperan), ketoprofen (Profenid), mefenamic acid (Ponstyl), niflumic acid (Nifluril) and piroxicam (Feldene). This interaction does not occur with aspirin; this exception suggests that the inhibition of prostaglandins synthesis is not the mechanism responsible for the decrease in the urinary elimination of lithium linked with an increase in its tubular reabsorption. [R36] *Phenylbutazone, like any other nonsteroidal anti-inflammatory drug, is likely to potentiate the effects of warfarin. [R37] *A pilot study in two ponies showed that the plasma concentrations of im administered procaine penicillin were higher if phenylbutazone was administered concurrently. In two other trials, each involving five horses, iv sodium penicillin was administered with and without concurrent iv injected phenylbutazone, and procaine penicillin was injected im with and without oral phenylbutazone. In both cases the plasma concentrations of penicillin were higher when phenylbutazone was given. The pharmacokinetic parameters indicated that the effect was probably due to a lower peripheral distribution because the penetration of penicillin into the tissues was greatly reduced. [R38] *Phenytoin, which is used primarily as an anticonvulsant agent, has a relatively low therapeutic index, and monitoring of plasma phenytoin concentration is often used to help guide therapy. It has properties which predispose it to an involvement in pharmacokinetic interactions. Drugs may modify the pharmacokinetics of phenytoin by altering its absorption, plasma protein binding, or hepatic biotransformation; alterations in the absorption and/or biotransformation may lead to changes in both the unbound plasma phenytoin concentration and, as a result, the clinical effect. Preparations which may decrease the gastrointestinal absorption of phenytoin include nutritional formula and charcoal. There are many reports of drugs which may increase (eg folic acid, dexamethasone and rifampicin) or decrease (eg valproic acid, sulthiame, isoniazid, cimetidine, phenylbutazone, chloramphenicol and some sulphonamides) the metabolism of phenytoin. As a result of its non-linear clearance, changes in phenytoin absorption and/or biotransformation will lead to more than proportionate changes in plasma drug concentration. Drugs which may displace phenytoin from plasma albumin include valproic acid, salicylic acid, phenylbutazone and some sulphonamides. Although an alteration in the unbound fraction of phenytoin in plasma would not, in itself, be expected to alter the unbound plasma phenytoin concentration, the interpretation of total plasma concentrations for therapeutic drug monitoring may be confounded. Some drugs appear to alter phenytoin pharmacokinetics via dual mechanisms (eg valproic acid and phenylbutazone). [R39] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Inflammatory Agents, Non-Steroidal [R40] *EPISCLERITIS AND UVEITIS ASSOC WITH RHEUMATOID ARTHRITIS HAVE SOMETIMES BEEN TREATED SUCCESSFULLY WITH ... PHENYLBUTAZONE ... . [R41] *OCCASIONALLY USED FOR THERAPY OF ACUTE GOUT AND FOR RHEUMATOID ARTHRITIS AND ALLIED DISORDERS. ... PHENYLBUTAZONE SHOULD ONLY BE USED FOR ACUTE EXACERBATIONS OF GOUT OR RHEMATOID ARTHRITIS AND NOT FOR LONG TERM TREATMENT. [R2, 655] *... ALTERNATIVE TO COLCHICINE IN ACUTE GOUT. ... HAS LIMITED ROLE FOR RELIEF OF ACUTE EXACERBATIONS OF RHEUMATOID ARTHRITIS THAT ARE NOT RELIEVED BY OTHER MEASURES. SYNOVITIS IS OFTEN REDUCED BY A BRIEF REGIMEN. IF JUSTIFIED, MAY BE OF SIMILAR BENEFIT FOR ACUTE EXACERBATIONS OF ANKYLOSING SPONDYLITIS AND OSTEOARTHRITIS. [R2, 655] +MEDICATION (VET): ALSO USED IN VET MEDICINE AS ANALGESIC, ANTIPYRETIC AND ANTI-INFLAMMATORY AGENT. [R42] *... USED IN SYMPTOMATIC TREATMENT OF ACUTE SUPERFICIAL THROMBOPHLEBITIS AND FOR SEVERE FORMS OF VARIETY OF ACUTE LOCAL INFLAMMATORY CONDITIONS. [R42] *SYNOVITIS ... REDUCED BY 300-600 MG ON FIRST DAY, FOLLOWED BY NO MORE THAN 400 MG DAILY FOR 3-7 DAYS. [R2, 655] *... HAS MILD URICOSURIC EFFECT THAT DECREASES TUBULAR REABSORPTION OF URIC ACID. PROBABLY ATTRIBUTABLE TO ONE OF ITS METABOLITES. [R2, 654] *Nonsteroidal anti-inflammatory drugs consitute a rapidly expanding group of drugs that are useful for the treatment of rheumatoid arthritis, osteoarthritis, other arthritic conditions, dental pain, primary dysmenorrhea, and postpartum pain. /Nonsteroidal anti-inflammatory drugs/ [R15, 492] *Nonsteroidal anti-inflammatory drugs indicated in the management of active ankylosing spondylitis, acute gouty arthritis, active rheumatoid arthritis, and acute attacks of degenerative joint disease of the hips and knees, in patients whose conditions have not responded satisfactorily with the use of safer agents. /Nonsteroidal anti-inflammatory drugs/ [R5] *Phenylbutazone is used for anti-inflammatory and analgesic effects in the short-term symptomatic treatment of acute gouty arthritis, active rheumatoid arthritis. active ankylosing spondylitis, and acute attacks of osteoarthritis of the hips and knees not responsive to other treatments. Phenylbutazone also has been used for the symptomatic treatment of acute painful shoulder (peritendinitis, capsulitis, bursitis, and acute arthritis of that joint), but other less toxic nonsteroidal anti-inflammatory agents are preferred. [R4, 1194] WARN: *THIS DRUG SHOULD BE TAKEN WITH MILK OR WITH MEALS TO MINIMIZE GASTRIC IRRITATION. [R7] *DRUG SHOULD BE USED WITH CAUTION IN PREGNANT WOMEN, NURSING MOTHERS ... AND PATIENTS KNOWN TO HAVE OTHER ILLNESSES. [R7] *DRUG IS CONTRAINDICATED IN PATIENTS WITH GI PROBLEMS ... AND IN CHILDREN UNDER 14 YR OF AGE. [R7] *IT SHOULD NOT BE EMPLOYED AS GENERAL ANALGESIC OR ANTIPYRETIC. ... PROPHYLACTIC USE ... IS NOT ADVISED, AND DRUG SHOULD NOT BE USES AS URICOSURIC AGENT. ... LONG TERM THEARPY IS NOT RECOMMENDED. [R2, 655] *INDISCRIMINATE USE ... IN THERAPY OF TRIVIAL ACUTE OR CHRONIC MUSCULOSKELETAL DISORDERS CAN ONLY BE CONDEMNED. [R2, 655] *TOXIC EFFECTS OF DRUG ARE MORE SEVERE IN ELDERLY PERSONS, AND ITS USE IN THIS GROUP IS INADVISABLE. [R2, 655] *PATIENT SHOULD BE CLOSELY SUPERVISED AND ... BLOOD SHOULD BE EXAMINED PREQUENTLY; WEIGHT SHOULD ALSO BE CHECKED TO WARN OF UNDUE RETENTION OF SODIUM. THE DRUG SHOULD ONLY BE GIVEN FOR SHORT PERIODS (NOT MORE THAN 1 WEEK) WK ... . DRUG IS CONTRAINDICATED IN PT WITH HYPERTENSION; CARDIAC, RENAL, OR HEPATIC DYSFUNCTION; OR HISTORY OF PEPTIC ULCER, BLOOD DYSCRASIA OR HYPERSENSITIVITY TO DRUG. [R2, 655] *... POORLY TOLERATED BY MANY PATIENTS. SOME TYPE OF SIDE EFFECT IS NOTED IN 10 TO 45% OF PATIENTS, AND MEDICATION MAY HAVE TO BE DISCONTINUED IN 10 TO 15%. [R2, 655] *DISPLACEMENT OF PLASMA PROTEIN-BOUND THYROID HORMONE COMPLICATES INTERPRETATION OF THYROID FUNCTION TESTS. ... IT MAY ALSO INHIBIT INACTIVATION OF OTHER DRUGS THAT ARE HYDROXYLATED BY MICROSOMAL SYSTEM. [R2, 655] *Any substantial change in total leukocyte count, relative decrease in granulocytes, appearance of immature blood cells, or a fall in hematocrit or platelet count are indications for immediate discontinuation of phenylbutazone and a complete hematologic evaluation. Hematologic toxicity may occur shortly after initiation of therapy or after prolonged treatment, it may develop abruptly or gradually, and it may become apparent days or weeks following discontinuance of the drug. [R4, 1195] *Because of potentially serious adverse hematologic effects, phenylbutazone should be used only when other less toxic nonsteroidal anti-inflammatory agents are ineffective. In addition, the drug should be administered only to carefully selected patients who are under close medical supervision. [R4, 1195] *Because serious adverse reactions or aggravation of existing medical problems can occur, and have been reported, phenylbutazone should be used with caution in patients with incipient cardiac failure; blood dyscrasias; pancreatitis; parotitis; stomatitis; polymyalgia rheumatica; temporal arteritis; drug allergy; severe renal, cardiac, or hepatic disease; a history of peptic ulcer disease; or symptoms of Gl inflammation or active ulceration, inflammatory bowel disease, or Crohn's disease. [R4, 1195] *A complete history, physical, and laboratory examination (including complete hematologic studies and urinalysis) should be made before and repeated at regular, frequent intervals and if signs and/or symptoms of adverse hematologic effects appear during phenylbutazone therapy. Regular, frequent hematologic studies are especially important in patients receiving the drug for periods longer than 1 week. The risk of potentially serious adverse GI effects should be considered in patients receiving phenylbutazone, particularly in patients receiving chronic therapy with the drug. Diagnostic tests of the upper GI tract should be performed in patients with persistent or severe dyspepsia. Careful instructions to and observation of the patient are essential to prevent serious and irreversible, possibly fatal, adverse reactions. [R4, 1195] *Patients should be advised that phenylbutazone can cause adverse effects, including some that can cause discomfort, and that, rarely, more serious effects (eg, GI bleeding, hematologic toxicity), which may require hospitalization and may even be fatal, can occur. Clinicians should discuss with their patients the potential risks and likely benefits of phenylbutazone therapy. Patients should be instructed not to exceed the prescribed dosage and to immediately discontinue phenylbutazone and inform their physician if fever, sore throat, mouth lesions, Gl disturbances, unusual bleeding or bruising, symptoms of anemia, black or tarry stools or other evidence of intestinal ulceration, rash, salivary gland enlargement, or sudden weight gain or edema occurs. Adverse reactions (especially aplastic anemia and GI effects) may be particularly likely to occur in patients older than 40 years of age who are receiving phenylbutazone; however, short term therapy with the drug in young, healthy individuals also may result in fatal aplastic anemia. In geriatric patients (older than 60 years of age), phenylbutazone should be used with extreme caution; since the risk of fatal reactions is exceedingly high in this age group, the duration of treatment in such patients should be restricted to a maximum of 1 week if possible. [R4, 1195] *Because severe and sometimes fatal hepatotoxic effects have occurred during phenylbutazone therapy, the drug should be discontinued if signs or symptoms of a severe hepatic reaction occur. [R4, 1196] *Phenylbutazone should be used with caution in patients with severe cardiac or renal disease, since fluid retention may aggravate these conditions. Because renal prostaglandins may have a supportive role in maintaining renal perfusion in patients with prerenal conditions, administration of a nonsteroidal anti-inflammatory agent to such patients may cause a dose dependent reduction in prostaglandin formation and thereby precipitate overt renal decompensation. Patients at greatest risk of this reaction include those with impaired renal function, heart failure, or hepatic dysfunction; those with extracellular fluid depletion (e.g., patients receiving diuretics); those receiving a nephrotoxic drug concomitantly; those with elevated levels of angiotensin II or catecholamines; and geriatric patients. Recovery of renal function to pretreatment levels usually occurs following discontinuance of nonsteroidal anti-inflammatory agent therapy. Patients with significant renal impairment should be closely monitored and a lower daily dosage should be anticipated to avoid excessive drug accumulation . [R4, 1196] *Patients should be warned that phenylbutazone may impair their ability to perform activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). [R4, 1196] *The possibility that the antipyretic and anti inflammatory effects of nonsteroidal anti-inflammatory agents may mask the usual signs and symptoms of infection or other diseases should be considered. Phenylbutazone is contraindicated in patients with a history or suggestion of previous toxicity, hypersensitivity, or idiosyncrasy to the drug or to oxyphenbutazone (no longer commercially available). Phenylbutazone is also contraindicated in patients in whom asthma or bronchospasm is precipitated by aspirin or other nonsteroidal anti-inflammatory agents. Nonsteroidal anti-inflammatory agents generally are contraindicated in patients in whom urticaria, angioedema, bronchospasm, severe rhinitis, or shock is precipitated by aspirin or other nonsteroidal anti-inflammatory agents, although the drugs have occasionally been used in nonsteroidal anti-inflammatory agents sensitive patients who have undergone desensitization. [R4, 1196] *Phenylbutazone is contraindicated in children 14 years of age or younger, since the safety and efficacy of the drug in this age group have not been established . [R4, 1196] *Although there are no adequate controlled studies to date in humans ... Phenylbutazone should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. ... Information on the effects of phenylbutazone on fertility in humans ... is lacking. [R4, 1196] *Phenylbutazone and oxyphenbutazone (a metabolite) are distributed into milk. Because of the potential for serious adverse reactions to phenylbutazone in infants, a decision should be made to discontinue nursing or the drug, taking into account the importance of the drug to the woman. [R4, 1196] *Adverse GI effects of phenylbutazone include abdominal discomfort and distress, GI upset, nausea, and dyspepsia (including indigestion and heartburn). Vomiting, abdominal distention with flatulence, epigastric distress, constipation, diarrhea, esophagitis, gastritis, stomatitis (sometimes with ulceration), dryness of the mouth or throat, and anorexia may also occur. Although a causal relationship has not been directly determined, a case control analysis suggests that nonsteroidal anti-inflammatory agents may contribute to the formation of esophageal stricture in patients with gastroesophageal reflux. [R4, 1194] *Serious adverse renal effects may develop following phenylbutazone therapy and may be most likely to occur in patients taking the drug in high dosages or with other nonsteroidal anti-inflammatory agents such as aspirin. Acute renal failure with azotemia, papillary necrosis, interstitial nephritis (attributed to hypersensitivity), glomerulonephritis, acute tubular necrosis, cortical necrosis, renal calculi, nephrotic syndrome, impaired renal function, hematuria, proteinuria, albuminuria, anuria, pyelitis, cystitis, and ureteral obstruction with uric acid crystals have been reported. [R4, 1195] *Hematologic disorders, including bone marrow depression, are among the most serious adverse effects of phenylbutazone. Aplastic anemia and agranulocytosis (either of which can be fatal) may occur suddenly during therapy despite regular hematologic monitoring or may become apparent several days or weeks after the drug has been discontinued. Most cases of aplastic anemia develop after prolonged use of the drug (3 months to 1 year); however, most cases of agranulocytosis occur within the first 3 months of therapy. ... Some blood dyscrasias appear to be hypersensitivity reactions and are most likely to be fatal in geriatric patients, particularly women. [R4, 1195] *Other hematologic effects attributed to phenylbutazone include leukopenia, pancytopenia, agranulocytic anginal syndrome, and thrombocytopenia with purpura, petechiae, and hemorrhage. Hemolytic anemia and anemia secondary to Gl bleeding or to hemodilution have also been reported with phenylbutazone therapy; macrocytic or megaloblastic anemia responsive to folic acid therapy has been reported rarely. Inhibition of platelet aggregation may occur. Although a causal relationship to the drug has not been established, leukemia, leukemoid reactions, chromosomal damage of lymphocytes, and atypical lymphocytes have been reported. [R4, 1195] *Adverse nervous system effects of phenylbutazone include headache, dizziness, vertigo, drowsiness, agitation, confusion, lethargy, tremors, peripheral neuropathy, numbness, weakness, impairment of psychomotor reactions, insomnia, euphoria, and nervousness. With overdosage, other nervous system effects including coma and seizures may develop. [R4, 1195] *Blurred vision, optic neuritis, toxic amblyopia, scotomata, retinal detachment, retinal hemorrhage (which may result in loss of vision), and oculomotor palsy have been reported rarely following phenylbutazone therapy, although a causal relationship to the drug has not been established. Conjunctivitis, corneal conjunctivitis and scarring, adhesion of the lids to the eyeballs, vascularization of the cornea, optic atrophy, and diplopia have also been reported rarely. If visual disturbances develop, the drug should be discontinued and a complete ophthalmologic examination should be performed. ... Hearing loss and tinnitus have also been reported in patients receiving phenylbutazone. [R4, 1195] *Liver damage including jaundice, hepatitis (which may be fatal) sometimes associated with cholestasis, and increased serum bilirubin, ALT (SGPT), AST (SGOT), and alkaline phosphatase concentrations have been reported rarely with phenylbutazone therapy. Adverse hepatic effects may occur as part of a generalized hypersensitivity reaction. [R4, 1195] *Hypersensitivity reactions occurring with phenylbutazone therapy include anaphylactic shock, arthralgia, fever, angiitis (polyarteritis), vasculitis, serum sickness, adenitis, hepatotoxicity, allergic alveolitis, lymphadenopathy, Lyell's syndrome, activation of systemic lupus erythematosus, and aggravation of temporal arteritis in patients with polymyalgia rheumatica. Asthma may be precipitated or aggravated by phenylbutazone, especially in aspirin sensitive patients. [R4, 1195] *Dermatologic reactions such as erythema multiforme, Stevens-Johnson syndrome, exfoliative dermatitis, or toxic epidermal necrolysis (any of which can be fatal), urticaria, pruritus, rash, erythema nodosum, and nonthrombocytopenic purpura have been reported following phenylbutazone therapy. Angioedema has been reported during phenylbutazone therapy, but a causal relationship to the drug has not been established. [R4, 1195] *Enlargement of the salivary glands and increased concentrations of serum amylase may occur during phenylbutazone therapy. Several cases of phenylbutazone induced sialoadenitis have occurred in association with a systemic disturbance that included fever and varying combinations of pericarditis, pleurisy, rash, conjunctivitis, and hepatic dysfunction. [R4, 1195] *Pancreatitis has been reported, but a causal relationship to phenylbutazone has not been established. Hyperglycemia has occurred in patients receiving phenylbutazone therapy. [R4, 1195] *Chromosomal damage of lymphocytes in patients receiving phenylbutazone for at least 3 months and atypical lymphocytes have been reported. Leukemia and leukemoid reactions have been reported in some patients receiving phenylbutazone and have occurred mainly in patients older than 40 years of age; however a causal relationship of the drug has not been established [R4, 1196] *Phenylbutazone, an antirheumatic, has caused numerous toxic side effects, including agranulocytosis and a variety of eye disturbances. In several instances phenylbutazone has been associated with development of Stevens-Johnson syndrome or epidermal necrolysis with involvement of the eyes characterized by severe keratitis with involvement of the conjunctivae, corneas, and tear glands, which may result in scarring of the corneas with opacification, vascularization, and symblepharon. [R43] *Phenylbutazone may cause serious adverse reactions and should not be used as a simple analgesic. Because of potentially serious adverse effects, phenylbutazone should be used only when other less toxic nonsteroidal anti-inflammatory agent are ineffective. In addition, the drug should only be used in patients who can be closely monitored for potential adverse effects including hematologic, Gl, and hepatic effects. [R4, 1194] +Maternal Medication usually Compatible with Breast-Feeding: Phenylbutazone: Reported Sign or Symptom in Infant or Effect on Lactation: None./from Table 6/ [R44] TOLR: *Tolerance ... has not been reported. [R15, 494] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R45] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl phenylbutazone, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. [R46] *Phenylbutazone tablets and boluses. Oral dosage form new animal drugs not subject to certification. Specifications and conditions of use for dogs and horses. [R47] *Phenylbutazone granules. Oral dosage form new animal drugs not subject to certification. Specifications and conditions of use for horses. [R48] *Phenylbutazone paste. Oral dosage form new animal drugs not subject to certification. Specifications and conditions of use for horses. [R49] *Phenylbutazone gel. Oral dosage form new animal drugs not subject to certification. Specifications and conditions of use for horses. [R50] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determination of phenylbutazone using LC equipped with a 254.nm detector. The flow rate is about 2.4 ml/min. [R51] CLAB: *DETERMINATION OF PHENYLBUTAZONE IN PLASMA BY HIGH-SPEED LC. [R23] *GLC DETERMINATION OF PHENYLBUTAZONE IN HUMAN PLASMA. [R52] *GLC DETERMINATION OF PLASMA CONCN OF GAMMA-OXO METABOLITE OF PHENYLBUTAZONE. [R53] *Determination of phenylbutazone in urine using TLC. [R54, p. V11 303] *Determination of phenylbutazone in plasma or 5 g of homogenized tissue using UV spectrophotometer. [R54, p. V11 304] *An LC procedure for phenylbutazone and its metabolites with a detection limit of 0.1 mg/ml which avoids degradation during the extraction process was described; the method was evaluated in a patient receiving a single oral dose of 200 mg. [R55] *A high performance liquid chromatographic method was developed and used for the quantification of phenylbutazone and its principal metabolite, oxyphenbutazone (oxyphenylbutazone), in the plasma of horses who had been treated with the drugs. [R56] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylbutazone in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 367 (1990) NIH Publication No. 90-2822 Faich GA; Risks and Indications of Phenylbutazone: Another Look. Pharmacotherapy 7 (1): 25-7 (1987). In 1984 an extensive review of phenylbutazone risks was undertaken by the FDA. Since that review, new recommendations for the drug's use have been published. Furet Y et al; Nephrotoxic Potential of Drugs and Chemicals: Pharmacological Basis and Clinical Relevance. Med Toxicol 4 (Jan-Feb): 59-72 (1989). A review of the nephrotoxic potential of drugs and chemicals is presented which includes information on the mechanisms of nephrotoxicity as well as the clinical toxicology of common nephrotoxins, including radiocontrast media, aminoglycosides, vancomycin, amphotericin B, cancer chemotherapy, cyclosporine, nonsteroidal anti-inflammatory agents, analgesics, phenylbutazone, penicillamine (D-penicillamine), and halogenated alkane solvents. Tobin T et al; Phenylbutazone in the Horse: A Review. J Vet Pharmacol Ther 9 (1): 1-25 (1986). A review of phenylbutazone in the horse. Vale JA, Meredith TJ; Acute Poisoning Due to Non-steroidal Anti-inflammatory Drugs. Clinical Features and Management. Med Toxicol 1 (1): 12-31 (1986). A review of clinical features and management of acute poisoning due to non-steroidal anti-inflammatory drugs, including phenylbutazone. SO: R1: SRI R2: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 897 R4: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). R5: Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 129 R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1156 R7: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1052 R8: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylbutazone in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.12 (1990) Technical Rpt Series No. 367 NIH Pub No. 90-2822 R9: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 92 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R11: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/958 R12: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.539 R13: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 583 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 70 (1987) R15: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 194 (1977) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 193 (1977) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 192 (1977) R19: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 815 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. P13 190 (1977) R21: Clinch D, Waller DG; Ir Med J 82 (4): 172-7 (1989) R22: Stampien TM, Schwartz RA; Am Fam Physician 46 (4): 1171-6 (1992) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 189 (1977) R24: Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975. 126 R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 190 (1977) R26: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R27: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylbutazone in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.13 (1990) Technical Rpt Series No. 367 NIH Pub No. 90-2822 R28: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylbutazone in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.15 (1990) Technical Rpt Series No. 367 NIH Pub No. 90-2822 R29: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylbutazone in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.16 (1990) Technical Rpt Series No. 367 NIH Pub No. 90-2822 R30: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylbutazone in F344/N Rats and B6C3F1 Mice (Gavage Studies) p.3 (1990) Technical Rpt Series No. 367 NIH Pub No. 90-2822 R31: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R32: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. R33: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. R34: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 131 R35: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R36: Danion JM et al; Encephale 13 (4): 255-60 (1987) R37: Dukes MN; Drug Saf 5 (Suppl 1): 84-7 (1990) R38: Firth EC et al; J Vet Pharmacol Ther 13 (2): 179-85 (1990) R39: Nation RL et al; Clin Pharmacokinet 18 (1): 37-60 (1990) R40: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R41: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 972 R42: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 188 (1977) R43: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 724 R44: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 141 (1994) R45: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91) R46: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-220 (1992) R47: 21 CFR 520.1720a (4/1/91) R48: 21 CFR 520.1720b (4/1/91) R49: 21 CFR 520.540c (4/1/91) R50: 21 CFR 520.540d (4/1/91) R51: USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990. 1068 R52: SIOUFI ET AL; J PHARM SCI 67 (FEB): 243-5 (1978) R53: MIDHA ET AL; J PHARM SCI 67 (FEB): 279-81 (1978) R54: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. R55: Franssen MJAM et al; Pharm Weekbl Sci Ed 8 (Aug 22): 229-33 (1986) R56: Salvatori MC et al; Rev Farm Bioquim Univ Sao Paulo 26 (Jan-Jun): 16-24 (1990) RS: 75 Record 226 of 1119 in HSDB (through 2003/06) AN: 3160 UD: 200205 RD: Reviewed by SRP on 9/18/1997 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PHENYTOIN-SODIUM- SY: *ALEPSIN-; *ANTILEPSIN-; *ANTISACER-; *AURANILE-; *CITRULLAMON-; *DANTEN-; *DANTOIN-; *DENYL-; *DENYL-SODIUM-; *DERIZENE-; *DIFENIN-; *DIFETOIN-; *DIHYDAN-; *DILANTIN-SODIUM-; *DI-LEN-; *DIPHEDAN-; *DIPHENIN-; *DIPHENINE-; *DIPHENINE-SODIUM-; *DIPHENTOIN-; *DIPHENYLAN-SODIUM-; *5,5'-DIPHENYLHYDANTOIN-; *5,5-DIPHENYLHYDANTOIN-SODIUM-; *DITOIN-; *ENKEFAL-; *EPANUTIN-; *EPELIN-; *EPILAN-D-; *EPINAT-; *EPTOIN-; *FENITOIN-SODIUM-; *HIDANTAL-SODIUM-; *HYDANTOINAL-; *HYDANTOIN,-5,5-DIPHENYL-,-SODIUM-SALT-; *2,4-IMIDAZOLIDINEDIONE,-5,5-DIPHENYL-,-MONOSODIUM-SALT-; *LEPITOIN-SODIUM-; *MINETOIN-; *SODIUM-DIPHENYLHYDANTOIN-; *SODIUM-5,5-DIPHENYL-HYDANTOINATE-; *SODIUM-5,5-DIPHENYL-2,4-IMIDAZOLIDINEDIONE-; *SODIUM-PHENYTOIN-; *SOLANTOIN-; *SOLANTYL-; *SOLUBLE-PHENYTOIN-; *TACOSAL- RN: 630-93-3 MF: *C15-H12-N2-O2.Na ASCH: Diphenylhydantoin (phenytoin); 57-41-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM BENZIL, UREA AND NAOH: BILTZ, BER 41, 1391 (1908); 44, 411 (1911) [R1, 1259] *HENZE, US PATENT 2,409,754 (1946 TO PARKE DAVIS). /PHENYTOIN/ [R1, 1259] FORM: *PHENYTOIN SODIUM, USP (DIPHENYLHYDANTOIN SODIUM; DILANTIN), IS AVAIL AS 30- and 100-MG CAPSULES FOR ORAL USE, AND AS STERILE SOLN OF 50 MG/ML, WITH SPECIAL SOLVENT, FOR PARENTERAL USE. PREPN OF PHENYTOIN, USP, INCL 50-MG TABLETS AND ORAL SUSPENSION CONTAINING 30 MG/5 ML OR 125 MG/5 ML. [R2, 454] MFS: *Polychemical Laboratories, Inc, Hq, 48 South Service Rd, Suite 100, Melville, NY 11747, (516) 420-0505; Production site: Melville, NY 10474 [R3] *Warner-Lambert Co, Hq, 201 Tabor Rd, Morris Plains, NJ 07950, (201) 540-2000; Parke-Davis, division; Specialty Chemicals, 188 Howard Ave, Holland, MI 49423 [R3] USE: *MEDICATION (VET); RECOMMENDED FOR EPILEPTIC SEIZURES IN DOGS [R1, 1260] *MEDICATION *Anticonvulsant in the treatment of epilepsy (oral or intravenous injection) [R4, p. V66 175] CPAT: *Sales in US for 1990: 1,093,250 standard dosage units; sales in US for 1995: 984,527 standard dosage units [R4, p. V66 175] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE POWDER [R1, 1260] TAST: *BITTER, SOAPY TASTE [R1, 1260] MW: *274.27 [R5] DSC: *pKa - 8.06 to 8.33 /Phenytoin/ [R6, 246] PH: *11.7 [R1, 1260] SOL: *INSOL IN BENZENE [R7, 44]; *1 G DISSOLVES IN 10.5 ML ALC, APPROX 66 ML WATER; INSOL IN ETHER, CHLOROFORM [R1, 1260]; *Freely soluble in warm propylene glycol [R4, p. V66 175] SPEC: *Somewhat hydroscopic [R1, 1260] OCPP: *MAX ABSORPTION (WATER): 252 NM SHOULDER (LOG E= 2.99); 258 NM (LOG E= 2.85); 269 NM SHOULDER (LOG E= 2.38); SADTLER REF NUMBER: 5470 (IR, PRISM); 478 (IR, GRATING); 2168 (UV); 3215 (NMR) /PHENYTOIN/ [R8] *WEAK ACID WITH PKA OF APPROX 8.3 /PHENYTOIN/ [R2, 453] *MP: 295-298 DEG C; POWDER /PHENYTOIN/ [R1, 1260] *NEEDLES FROM ALC; SLIGHTLY SOL IN ETHER, BENZENE, CHLOROFORM, ACETIC ACID /PHENYTOIN/ [R8] *1 G DISSOLVES IN APPROX 60 ML ALC, APPROX 30 ML ACETONE; PRACTICALLY INSOL IN WATER /PHENYTOIN/ [R1, 1260] *INDEX OF REFRACTION: 1.600 (ALPHA), 1.635 (GAMMA) /PHENYTOIN/ [R7, 304] *SOMEWHAT HYGROSCOPIC; EASILY DISSOCIATED EVEN BY WEAK ACIDS (INCL CO2 ABSORBED ON EXPOSURE TO AIR) REGENERATING PHENYTOIN; AQ SOLN TURBID UNLESS PH ADJUSTED TO GREATER THAN THE 11.7 PH OF SATURATED SOLN [R1, 1260] *The manufacturers recommend that parenteral phenytoin sodium not be added to iv infusions or mixed with other medication because precipitation of phenytoin may occur. However, some clinicians routinely use infusion solutions of phenytoin in 0.9% sodium chloride in concentrations of 1 to 10 mg of phenytoin per mL, provided the infusion is started immediately after preparation and is completed within 1 hr. The admixture must be carefully observed for signs of precipitation, and use of a 0.45 to 0.22 um in-line filter is recommended. In addition, flushing of all tubing with 0.9% sodium chloride injection before and after infusion of phenytoin is recommended. [R6, 255] *THIS DRUG IS USED EXCLUSIVELY IN THE FORM OF THE SODIUM SALT, SINCE THE FREE ACID IS VIRTUALLY INSOLUBLE IN WATER. SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of NOx and Na2O. [R9] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R10, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R10, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R10, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R10, 1979.11] SSL: *SENSITIVE TO LIGHT /PHENYTOIN/ [R7, 44] *A slight yellowing of the solution will not affect its potency. After being refrigerated, solution may form a precipitate which usually dissolves after being warmed to room temperature; however, do not use if the solution is not clear. /Phenytoin Sodium Injection USP/ [R6, 255] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R10, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R10, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R10, 1979.13] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a tight container. Protect from freezing. /Phenytoin Oral Suspension USP/ [R6, 253] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a well-closed. /Phenytoin Tablets (Chewable) USP/ [R6, 254] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a tight container. /Extended Phenytoin Sodium Capsules USP/ [R6, 254] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a tight container. /Prompt Phenytoin Sodium Capsules USP/ [R6, 255] *Store between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Protect from freezing. /Phenytoin Sodium Injection USP/ [R6, 255] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R10, 1979.15] DISP: *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R10, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R10, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R10, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R10, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R10, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. [R11] ANTR: *Since there is no specific antidote for overdose with hydantoin anticonvulsants, treatment is symptomatic and supportive and may include the following. To decrease absorption - induction of emesis or gastric lavage. Multiple oral doses of charcoal and cathartic may shorten the duration of symptoms. Supportive care - oxygen, vasopressors, and assisted ventilation may be necessary for CNS, respiratory, or cardiovascular depression. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation. Following recovery, careful evaluation of blood-forming organs is advisable. /Hydantoin anticonvulsants/ [R6, 251] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R10, 1979.23] HTOX: *Four cases of malignancies other than neuroblastoma in children exposed in utero to phenytoin have been reported. In six of the 10 recorded cases of cancer associated with prenatal maternal phenytoin ingestion, the drug had not been given alone, but in combination with primidone or phenobarbital. Also, in some cases, there was evidence of alcohol abuse in the mother, which is associated with the fetal alcohol syndrome. /Phenytoin/ [R12] *Although central and peripheral nervous system toxicity is the most consistent effect of acute phenytoin overdosage, the chronic effects of phenytoin on the nervous system are a subject of debate, since it remains unclear if they can be attributed solely to the drug or if and to what extent they result from recurrent seizures. The most severe histopathological feature associated with chronic phenytoin administration is developments of cerebellar atrophy. However, literature on neuropathology from before the introduction of phenytoin documents that convulsions are associated with cerebellar atrophy. The molecular mechanism of phenytoin damage to the cerebellum has not been elucidated and the causal role of phenytoin in the induction of cerebellar atrophy cannot be considered as proven. /Phenytoin/ [R13] *Chronic phenytoin intake may induce a variety of adverse effects on the nervous system, including drowsiness, nystagmus, ataxia, blurred vision and diplopia; in the past when patient were treated with very high doses for many years, intellectual dulling and depression of mood were frequently reported. /Phenytoin/ [R13] *Death from acute phenytoin overdosage in humans in very uncommon. Intravenous administration of high doses of phenytoin (e.g., in the emergency treatment of cardiac arrhythmias or status epilepticus) may induce severe cardiac arrhythmias and hypotension as well as central and peripheral nervous system toxicity. Nystagmus, ataxia, diplopia, dysarthria, vertigo and other cerebellar-vestibular effects are common symptoms of phenytoin intoxication; acute oral overdosage has been reported to cause irreversible cerebellar atrophy. Since phenytoin has a narrow therapeutic range and patients respond with considerable interindividual variability, intoxications are frequently iatrogenic or due to inappropriate self-adjustment of doses. /Phenytoin/ [R14] *In a case-control study of 11,169 pairs of childhood cancer cases and matched controls in 1953-71 in the United Kingdom, use of drugs during pregnancy was assessed through hospital and general practitioners' records. Phenytoin use was reported for mothers of 11 cases and 7 controls (crude odds ratio, 1.6; 95% CI 0.6-4.0). /SRP: Not statistically significant because the 95% CI includes unity//Phenytoin/ [R15, (1996)] *In a cohort study of members of the Kaiser Permanente Medical Care Program, phenytoin was used by 954 subjects (0.7%). Incidence of all cancers were marginally increased among phenytoin users (standard incidence ratio (SIR), 1.2 (95% confidence interval (CI), 0.9-1.5); 61 cases), as were the incidences of brain cancer (SRI, 8.2 (95% CI, 3.3-17); 7 deaths) and of esophageal cancer (SIR, 5.0 (95% CI, 1.0-15); 3 deaths). No other site showed a significant increase of decrease in cancer incidence. In an earlier study, one case of multiple myeloma was reported in these subjects, with 0.6 expected. /SRP: Not statistically significant because the 95% CI includes unity/ /Phenytoin/ [R12] *One hundred and eighty-eight cases of childhood neuroblastoma diagnosed between January 1969 and October 1986 at the Hospital for Sick Children in Toronto, Canada /was examined/. A review of medical records showed that none of the mothers or fathers had had epilepsy or been treated with phenytoin. In North America, the prevalence of epilepsy in the general population is 0.5%, and about half of all epileptic patients receive phenytoin. This serial cohort of 188 children indicates that, statistically, phenytoin cannot be incriminated in more than two cases of this series or in 1.5% of children with this malignancy in general. /Phenytoin/ [R12] *Several case reports have suggested an association between childhood cancer and prenatal exposure to phenytoin. From 1976 to 1981, five cases of neuroblastoma were reported in infants and young children (up to five years of age) exposed in utero to phenytoin. These cases were also adversely affected by the fetal hydantoin syndrome. After four cases had been described since 1976 in the US, /it was calculated that/ it should take 45 years for four to develop by chance. However, no more cases were reported until 1989. /Phenytoin/ [R16] *Most of the malignant lymphomas described in case reports were seen after long-term phenytoin therapy rather than early in therapy. An additional case appeared as an isolated malignant lymphoma of the jejunum. /Phenytoin/ [R16] *Between 1962 and 1980, reports appeared of 79 cases of lymphoma worldwide in patients taking phenytoin, with or without other antiepileptic drugs. Some difficulties were encountered in distinguishing benign lymph node changes from lymphoma; however, the hydantoin-induced lymph node reactions regress after drug withdrawal. The term 'pseudolymphoma' /was introduced/ for this phenomenon. Some patients originally described as developing 'pseudolymphomas' following phenytoin (and in some cases also phenobarbital) treatment were later diagnosed with lymphoma. In 1968, the term pseudo-pseudolymphoma was introduced ... to underline the possibility that what is initially considered a non-malignant phenytoin reaction may, after long-term follow-up, turn out to be a true lymphoma. /Phenytoin/ [R16] *INGESTION OF 4.5 G BY ADULT AND OF 0.6 TO 0.9 G BY CHILDREN BETWEEN 3 and 4 YR OF AGE HAVE PRODUCED TRANSIENT COMA WITH MOTOR RESTLESSNESS; 2 G HAS KILLED 7-YR-OLD CHILD... [R17] *OF 6 PT RECEIVING PHENYTOIN...3 WERE REPORTED TO HAVE DEVELOPED HODGKIN'S DISEASE, 2, LYMPHOSARCOMAS AND 1, RETICULUM-CELL SARCOMA. [R4, p. V13 214] *IN US... CONGENITAL MALFORMATION RATE FOR WIDE RANGE OF DEFECTS, INCL CLEFT LIP AND CLEFT PALATE, WAS 6.12% AMONG BIRTHS TO 98 EPILEPTIC MOTHERS WHO TOOK PHENYTOIN REGULARLY DURING 1ST 4 MO OF PREGNANCY. [R4, p. V13 212] *TWO FATAL CASES OF WIDESPREAD NECROTIZING VASCULITIS ASSOCIATED WITH DIPHENYLHYDANTOIN (DILANTIN) ARE PRESENTED. [R18] *A 52-YR-OLD WOMAN ON PHENYTOIN THERAPY FOR POST-TRAUMATIC EPILEPSY DEVELOPED TRANSIENT HEMIPARESIS CONTRALATERAL TO THE INJURY. THE EPISODE APPEARED TO HAVE BEEN PRECIPITATED BY TOXICITY DUE TO INGESTION OF A LARGE AMOUNT OF PHENYTOIN. A POSSIBLE MECHANISM FOR FOCAL NEUROLOGICAL DEFICIT IN BRAIN-DAMAGED PATIENTS ON PHENYTOIN THERAPY IS DISCUSSED. /PHENYTOIN/ [R19] *ACUTE PULMONARY DISEASE MAY OCCUR AS PART OF THE HYPERSENSITIVITY ANGIITIS PRODUCED BY PHENYTOIN SODIUM. THE CLINICAL FEATURES OF THE PULMONARY INVOLVEMENT ARE FEVER, DYSPNEA, HYPOXEMIA, AND BILATERAL RADIOGRAPHIC INFILTRATES. THE PATHOLOGIC PROCESS IS AN INTERSTITIAL PNEUMONITIS THAT APPEARS REVERSIBLE WITH CESSATION OF THE DRUG AND TREATMENT WITH CORTICOSTEROIDS. [R20] *Clinical effects of overdose include ataxia (clumsiness or unsteadiness) or staggering walk, blurred or double vision, severe confusion, severe dizziness or drowsiness, dysarthria (stuttering) or slurred speech, hyperreflexia, nausea and vomiting, nystagmus (continuous, uncontrolled back-and-forth and/or rolling eye movements), tremor, and unusual tiredness or weakness. /Hydantoin anticonvulsants/ [R6, 251] *Phenytoin administration has been associated with the development of lymphadenopathy (local or generalized) including benign lymph mode hyperplasia, pseudolymphoma, lymphoma, and Hodgkin's disease. Lymph node involvement may occur with or without serum sickness-like signs or symptoms (e.g., fever, rash, liver involvement); however, lymphadenopathy and severe cutaneous reactions rarely have preceded the development of phenytoin-induced systemic lupus erythematosus. Phenytoin has also been associated with a small number of fatalities caused by the liver damage. Toxic hepatitis, periarteritis nodosa, immunoglobulin abnormalities, and Peyronie's disease have also occurred. /Phenytoin/ [R21] *Osteomalacia has been associated with phenytoin therapy and is thought to be caused by phenytoin's interference with vitamin D metabolism. Phenytoin, especially in large doses, may increase blood glucose concentrations resulting in hyperglycemia and glycosuria. Patients with impaired renal function may be most susceptible to this effect. Average doses do not regularly elevate blood glucose or increase insulin requirements in diabetic patients, but a few patients have experienced fatal, hyperosmolar, nonketotic coma in which phenytoin may have played at least an accessory etiologic role. /Phenytoin/ [R21] *The most important signs of toxicity associated with the IV use of phenytoin sodium are cardiovascular collapse and/or CNS depression; hypotension occurs if the drug is administered too rapidly by the IV route. These effects may be minimized by administering the drug slowly, at a rate not exceeding 50 mg/minute. In geriatric patients with heart disease, it has been recommended that the drug be given at a rate of 50 mg over 2-3 minutes. Personnel and equipment should be readily available for administration of artificial respiration. Severe cardiotoxic reactions with reduced cardiac output, atrial or ventricular conduction depression, and ventricular fibrillation have occurred, sometimes resulting in fatalities. periarteritis, nodosa also has been reported. Severe complications are most common in geriatric or debilitated patients. [R21] *Five cases of congenital malformation in the offspring of epileptic women treated with phenytoin /were reported/. Subsequently, a total of 32 children born to mothers who took anticonvulsants, including phenytoin, throughout pregnancy were found to have similar constellation of abnormalities including cleft lip and plate, and cardiovascular and skeletal (limb, skull, face) abnormalities. Subsequent case reports of epileptic women treated during pregnancy with phenytoin and phenobarbital have described affected infants with similar abnormalities. /Phenytoin/ [R22] *Most studies in which epileptic mothers taking phenytoin alone (namely those receiving monotherapy) were identified indicated a significantly higher rate of fetal hydantoin syndrome compared with untreated non-epileptic women. It is difficult to calculate specific teratogenic risk of phenytoin as the drug is frequently given with other anticonvulsants (polytherapy) and because maternal epilepsy itself is teratogenic. The teratogenic risk of polytherapy has consistently been found to be higher than that of monotherapy. /It was/ found that the overall rate of congenital abnormalities was 6.2-6.5% in children born to epileptic women with monotherapy, while the rate was 13.5-15.6% after polytherapy. /Phenytoin/ [R4, p. V66 (1996)] *Hydantoins induce production of liver microsomal enzymes, thereby accelerating the metabolism of concomitantly administered drugs. /Hydantoin anticonvulsants/ [R6, 246] *A case is described in which a 19 yr old man who was incorrectly diagnosed with post-traumatic complex partial seizures experienced altered mental status following treatment with 450 mg/day phenytoin sodium and 600 mg/day carbamazepine. One month after combined therapy, serum levels of phenytoin and carbamazepine were 25.8 and 3.6 mcg/ml, respectively. A diagnosis of absence status epilepticus was made. Phenytoin and carbamazepine were withdrawn and seizure control was maintained with acetazolamide and ethosuximide and then with ethosuximide monotherapy. ... [R23] *Gingival fibromatosis is an uncommon but benign oral disease which causes progressive and non-hemorrhagic enlargement of the gingiva. There are two types of gingival fibromatosis: idiopathic gingival fibromatosis (GF), which is of unknown cause and may be associated with hereditary factors, and drug induced gingival fibromatosis which is caused primarily by phenytoin intake. In cases of gingival fibromatosis, either the teeth are delayed in emergence or most of the crowns are embedded in the soft tissue even after full eruption. The objective of this study was to examine the basis of excess collagen formation in the two types of gingival fibromatosis in four patients admitted to the dental clinic at Kaohsiung Medical College Hospital, Kaohsiung, Taiwan. There were two male patients, aged ten (Case 1) and sixteen (Case 2), with idiopathic gingival fibromatosis and hypertrichosis, and two female patients, aged sixteen (Case 3) and eleven (Case 41, with Dilantin-induced gingival hyperplasia (DGH). Cultures of gingival fibroblast were established either from clinically excised hyperplastic tissues or from pre-orthodontic surgical normal gingiva. The synthesis of collagen and levels of prolyl hydroxylase, a key enzyme in collagen synthesis, were examined in the healthy and affected fibroblasts. /These studies indicated/ ... that after two days in culture, fibroblasts from all four patients multiplied faster than healthy gingival fibroblasts, though the amount of DNA and protein per cell remained unchanged. In addition, all cultures (except Case 11 had a 2 to 3 fold incr of prolyl hydroxylase activity over that of the controls. As in the cases of prolyl hydroxylase activity, Case 1 did not show any change in collagen synthesis when compared to the control. However, Cases 2, 3, and 4 showed appreciable collagen increases in the cell and medium: 61% and 60% for Case 2; 16% and 36% for Case 3; and 21% and 80.7% for Case 4 respectively. [R24] *Cognitive impairment from the use of anticonvulsants has been reported in the literature. Impaired cognitive functioning may result from changes in attention, perception, sensory motor integration, and mental slowing, although diminished motor speed has been noted as a possible contaminant in the study of intellectual functioning. However, the long-term effects of anticonvulsants on neuropsychologic function have not been adequately investigated. Most studies have evaluated patients within one month of initiating dilantin therapy; none of the studies have evaluated the effect of dilantin therapy with respect to duration of use. The purpose of this study is to evaluate long-term changes in cognitive effects with chronic use of phenytoin. The patient population being studied at the Department of Veterans Affairs Outpatient Clinic, Los Angeles is composed of 140 epileptic adult male patients on Dilantin, 80 of whom are on Dilantin monotherapy. These patients have been on Dilantin for an average length of 22 years (range 1-40 years). Neuropsychological function will be assessed by The Neurobehavioral Mental Status Examination (NOSE). The NOSE assesses cognition functions sensitive to brain impairment: language, visual-spatial perception, memory, calculation and reasoning. The NOSE does not assess motor speed. Because of the potential role of motor components in assessing cognitive functioning in patients receiving dilantin, one additional test for the assessment of motor behavior, the Finger Tapping Test, will be included as part of the study. The results from these assessments will be compared to the patients demographics, history, and Dilantin therapy. The major hypothesis posed in this study is that cognitive functioning of patients taking Dilantin will be affected by the length of treatment and dosage. Specifically, it is expected that patients receiving Dilantin in greater dosage or for more extensive periods will exhibit greater cognitive impairment. The use of cluster analysis will permit the results to be analyzed into specific cognitive components that might be affected and also allow further analysis of relationships that might exist among the various measures. [R25] *OBJECTIVE: To determine whether exposure to antiepileptic drugs during pregnancy is associated with poor fetal outcomes (anomalies and death) and to assess the relative risks with phenobarbital, phenytoin sodium, and carbamazepine. DESIGN: The design was a prospective case control cohort study of pregnant women with epilepsy and their offspring. Outcomes were compared with those of a control group of 355 healthy women and their offspring. SETTING: The obstetrics service at Los Angeles County/University of Southern California Medical Center, Los Angeles, a large, inner city, teaching hospital. PATIENTS: Two hundred eleven subjects who were pregnant during the years 1987 through 1990, 174 of whom were delivered of infants, were available for analysis. A control group of 355 healthy women and their offspring from the same hospital were randomly selected from a computerized database. INTERVENTION: None. MAIN OUTCOME MEASURE: Anomalies and fetal death were the primary outcome measures. RESULTS: Offspring of women with epilepsy who were exposed to antiepileptic drugs had a higher rate of fetal death and anomalies than did the control population (p = 0.001). Abnormal outcomes were associated with the three major antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital). In terms of abnormal outcome (death and anomalies), phenobarbital was associated with the highest relative risk, phenytoin with intermediate relative risk, and carbamazepine with the lowest relative risk (p = 0.019). Numbers were insufficient for assessment of risk associated with valproic acid. CONCLUSION: All three major antiepileptic drugs (phenobarbital, phenytoin, and carbamazepine) are associated with an incr risk of fetal death and anomalies. /It was/ ... found phenobarbital to be most associated with poor pregnancy outcome . [R26] NTOX: *GROUPS OF 2-3 MONTH OLD FEMALE C57BL, C3H/F OR SJL/J MICE 48 ANIMALS PER GROUP...WERE FED PHENYTOIN SODIUM @ DOSE LEVEL OF 60 MG/KG BODY WT/DAY...FOR 168 DAYS. 3 OF 24 C57BL...SURVIVING 10 MO DEVELOPED THYMIC LYMPHOMAS, WHEREAS NO PATHOLOGIC LESIONS...FOUND IN 48 CONTROLS. 3 OF 24 C3H/F FEMALE...SURVIVING 10 MO DEVELOPED LOCALIZED THYMIC LYMPHOMAS, WHEREAS NO PATHOLOGIC LESIONS...FOUND IN 48 CONTROLS... 6 OF 42 SJL/J MICE...HAD GENERALIZED LYMPHOMAS. [R4, p. V13 207] *FIFTY...ALBINO MICE...RECEIVED DAILY IP INJECTIONS OF 0.6 MG/ANIMAL PHENYTOIN SUSPENDED IN WATER OR IN SALINE OVER 66 DAYS (TOTAL, 57 INJECTIONS OF 34.2 MG/ANIMAL). ... 10 TREATED MICE DEVELOPED TUMORS...4 THYMIC AND 2 MESENTERIC LYMPHOMAS AND 4 LEUKEMIAS. ... IN CONTROLS, 1 THYMIC LYMPHOMAS AND 1 LUNG ADENOMA WERE OBSERVED. [R4, p. V13 208] *A/JAX MICE WERE INJECTED SC WITH 12.5, 25 OR 50 MG/KG BODY WT PHENYTOIN SODIUM @ VARIOUS TIMES FROM DAYS 9-15 OF PREGNANCY; 50 MG/KG BODY WT PRODUCED CLEFT PALATES IN 26-43% OF OFFSPRING. [R4, p. V13 209] *TOXIC DOSES IN ANIMALS PRODUCE MYDRIASIS, NYSTAGMUS, SALIVATION, INCOORDINATION AND ATAXIA. MUSCULAR SPASTICITY AND RIGIDITY, TREMORS, CONVULSIVE MOVEMENTS AND OPISTHOTONOS MAY PRECEDE DEATH FROM RESPIRATORY FAILURE. [R17] *A MODERATE DEGREE OF POLYPHAGIA, POLYDIPSIA, AND POLYURIA MAY BE SEEN IN ANIMALS MEDICATED WITH THIS DRUG. ANOTHER SIDE EFFECTS INVOLVES INHIBITION OF RELEASE OF ANTIDIURETIC HORMONE... THERE IS ALSO INHIBITION OF INSULIN SECRETION. [R27, 262] *5,5-DIPHENYLHYDANTOIN (DPH) SLIGHTLY INCREASED THE NUMBER OF REVERTANTS PER PLATE ONLY AFTER INCUBATIONS WITH SALMONELLA TYPHIMURIUM STRAIN TA1538 IN THE PRESENCE OF THE S9 FRACTION FROM THE LIVER OF 3-METHYLCHOLANTHRENE AND AROCLOR 1254-PRETREATED ANIMALS. PARALLEL EXPERIMENTS ON THE METABOLISM OF DPH TO 5-(4-HYDROXYPHENYL)-5-PHENYLHYDANTOIN (HPPH) AND OF HPPH TO THE CATECHOL DERIVATIVE IN VITRO SUPPORT THE HYPOTHESIS OF AN INVOLVEMENT OF EPOXIDE INTERMEDIATES IN THE MUTAGENIC ACTIVITY OF DPH. /PHENYTOIN/ [R28] *Diphenylhydantoin was evaluated for its effects on the chromosomes and mitotic spindle of cultured mouse embryonic cells. Diphenylhydantoin was tested at concentrations of 0, 20, 100 and 200 ug/ml and treated cells were exposed for 24 hr. The high dose of 200 ug/ml was found to increase the percentages of hyperdiploidy from 4.8 in the control to 16.0. Abnormal cell divisions and mitotic disturbances were observed to increase in a dose-dependent manner. /Phenytoin/ [R29] *On day 17 of pregnancy, 4 groups of female Sprague-Dawley rats (Charles River Breeding Laboratories) were injected ip with 10, 50, or 100 mg phenytoin sodium/kg body weight. Controls received an equivalent amount (0.93 ml/kg) of diluent (water, pH 11.6). Treatment was continued through postpartum day 7. While 10 and 50 mg phenytoin/kg had no adverse effect on pregnancy or neonatal survival, 50% of the dams receiving 100 mg phenytoin/kg lost all fetuses, and the remaining 50% delivered 2 days late. Litter sizes from all treatment groups were normal. At 8, 28 and 120 days of age, male offspring were sacrificed. Body wt, testes and seminal vesicle wt, and serum concentration of androstenedione, testosterone, and dihydrotestosterone were measured. Throughout the duration of the 120 day study, body wt gains were lower (p < 0.05) in the 50 and 100 mg/kg treatment groups than for the male offspring from control females. The testicular reduction observed for 8 day old offspring was no longer apparent in 28 and 120 day old offspring. Serum concentrations of androstenedione, testosterone, and dihydrotestosterone were not altered by the perinatal exposure to any of the phenytoin doses. Seminal vesicle wt was permanently reduced in offspring exposed to 50 (p < 0.02) and 100 (p < 0.001) mg/kg phenytoin. Female offspring exposed to 50 and 100 mg/kg phenytoin exhibited a reduction in body wt, but ovarian wt, uterine wt, and estrous cycle activity were not affected by the perinatal exposure to phenytoin. The findings that perinatal exposure to phenytoin (therapeutic-like doses) has no effect on the course of pregnancy, neonatal development, and estrous cycle activity are in conflict with some previous reports but may be explained by differences in duration of phenytoin exposure. The presence of a normal estrous cycle following perinatal phenytoin exposure, and the failure of this exposure to alter serum androgen levels do not support previously reported contentions of phenytoin-induced teratogenesis. [R30] *Groups of 48 female C57B1, C3H/F or SJL/J mice, two to three months of age, were given 0 or 60 mg/kg body weight phenytoin sodium (Dilantin) (pharmaceutical grade) in a liquid diet for 168 days. Of those surviving to 10 months, 3/24 treated C57B1 mice as well as 3/24 C3H/F mice developed thymic lymphosarcomas, whereas no pathological lesion was found in 48 controls (p = 0.03). Of the treated SJL/J mice, 6/42 had generalized lymphomas during the fourth to eight months, but no lymphoma was seen in 48 controls after eight months (p = 0.008). After the eighth month, 90% of the treated SJL/J mice developed reticulum-cell sarcomas which appeared 2-3 months earlier than in the controls. [R15, 91996)] *Groups of 30 and 23 female C3H/Sn mice, 3.5 months of age, were given 0 or 2 mg/animal phenytoin sodium (Diphenin) (pharmaceutical grade) in 0.2 ml tap water by gastric instillation five times per week for life. The life span of treated mice was significantly increased (mean: controls, 450 + or - 19 days; treated, 558 + or - 28 days; p < 0.05, Student's t test). The number of mice with mammary gland adenocarcinomas was significantly decreased (19/30 controls, 2/23 treated mice; p , 0.05, chi-square test); the numbers of mice with leukemia were 5/30 controls and 2/23 treated mice; and the numbers of mice with polyps of the endometrium (not otherwise specified) were 4/30 controls and 0/23 treated mice. [R15, (1996)] *Groups of 75 and 34 female rats (strain not specified), 3.5 months of age, were given 0 and 7.5 mg/rat phenytoin (purity not specified) in 5 ml tap-water by gastric instillation five times per week for life. Animals were killed when moribund. Neoplastic tissues were examined histologically. Mean life span was 681 + or 14 days in controls and 724 + or - 36 days in treated animals. No treatment related increase in tumor incidence was observed. /Phenytoin/ [R31] *A group of 50 male and female random-bred albino mice, weighing 18-20 g (age not specified), was given 0.6 mg/animal phenytoin as phenytoin sodium (purity not specified) suspended in water or in saline daily by intraperitoneal injection over a 66 day period( total of 57 injections; 34.2 mg/animal). No weight gain was observed and 10 animals died during this period. The remaining 40 animals were observed for nine months. A group of 50 untreated controls was observed for 11 months. ten treated mice developed tumors, comprising four thymic and two mesenteric lymphomas and four leukemias. The leukemias were found between 60 and 142 days and the lymphomas between 100 and 255 days. In controls, one thymic lymphoma and one lung adenoma were observed. [R32] *The nervous system is the major target of acute phenytoin toxicity in experimental animals. Seizures may be induced after single intraperitoneal administration of 75 mg/kg body weight phenytoin in seven-day-old rats, while doses of about 200 mg/kg body weight are required in 18 day old rats. /Phenytoin/ [R33] *In male D2B6F1 mice given diets containing 250 or 500 mg/kg diet (ppm) phenytoin, hepatic CYP2B-mediated benzyloxyresorufin o-dealkylase activity was induced 30-fold and 43-fold after 30 weeks and 41-fold and 57-fold after 60 weeks, respectively. Male B6C3F1 mice given 125, 250, 500 or 1000 ppm phenytoin for 14 days showed significant increases in liver weights at all but the lowest dose and in hepatic CYP2B-mediated benzyloxyresorufin o-dealkylase activity at all doses relative to controls. /Phenytoin/ [R34, (1996)] *The chronic effects of phenytoin on the peripheral nervous system were investigated in female Sprague-Dawley rats given 300 mg/kg body weight phenytoin per day orally for 180 days. A time-dependent slowing of sensory and motor conduction velocity was observed, and animals with impaired motor conduction velocity also had histopathological changes in the myelinated fibers of the sciatic nerve. In male Wister rats, a single intraperitoneal dose of 150 mg/kg body weight phenytoin induced a complete blockage of muscle action potential in the dorsal segmental muscles of the tail evoked by electric stimulation of the caudal nerve and a 40% decrease in the Na=,K=-ATPase activity of the sciatic nerve compared with control values. /Phenytoin/ [R34, 91996)] *Oral administration of phenytoin (25, 50 or 100 mg/kg body weight per day for seven days) to BALB/c mice significantly depressed both humoral and cellular immune responses compared with control animals, as assessed by the enumeration of direct and indirect splenic plaque-forming cells and the delayed-type hypersensitivity reaction against sheep red blood cells. Furthermore, spleen cells and lymphocytes obtained from mice treated with 100 mg/kg body weight phenytoin suppressed the histological responses of normal cells in these systems. These immunosuppressing effects were observed in spite of the fact that phenytoin induced a rise in spleen cellularity in the treated mice. Similar results concerning the effects of phenytoin on the murine immune system were also obtained in previous studies in mice. /Phenytoin/ [R35] *Dietary administration of phenytoin to male Wistar rats (50 mg/kg body weight for 8 or 20 days) resulted in 20-30% reductions in the serum concentration of thyroxine (T4) and triiodothyronine (T3) but no change in TSH. At the same doses, the pituitary deiodination of T4 to T3 was significantly increased and this increase in the conversion rate is known to inhibit the feedback response of TSH. The observations in rats are consistent with clinical findings. /Phenytoin/ [R35] *Long-term treatment of epileptic patients with phenytoin has been associated with increased thickness mainly of craniofacial bones. This side-effect has been observed in Sprague-Dawley rats given 5 mg/kg body weight per day phenytoin for 36 days by intraperitoneal injection, in which increased histomorphometric (osteoblast number, bone mineral apposition rate) and biochemical parameters (skeletal alkaline phosphatase activity, osteocalcin concentration in the serum) of bone formation were measured. Simultaneous administration of sodium fluoride (50 mg/l (ppm)) in drinking water for 36 days acted in collaboration to stimulate one formation and to increase bone volume. /Phenytoin/ [R35] *... The influence of ... phenytoin /sodium salt/ on immortalized mouse hippocampal neurons in culture /have been studied/. This was done by MTT assays, immunocytochemical and immunoblot analyses, measurements of cell metabolism, measurements of the length of neuronal processes, involving malfunction of an assembly mechanism of cytoskeletal constituents. These accumulated with appendages (blebs) or cytoplasmic condensations, instead of normally forming organized processes. ... /Phenytoin sodium salt/ did not interfere with bulk synthesis of cell proteins and specific cytoskeletal components. [R36] *The limb plates and craniofacial regions in rabbit fetuses were examined shortly after the last dose of phenytoin on day 16 after daily admin by gavage with either 150 mg/kg on days 14-16 or 300 mg/kg on days 15-16. Both treatment regimens resulted in similar changes. Histologically, the digital areas of the limb plates showed extensive edema and dilated blood vessels within 2 hr. After 8 hr, vascular disruption occurred with hemorrhages. At 24-48 hr after dosing, mesenchymal necrosis and, on some occasions, amputation of digits was observed. In the craniofacial region, well defined superficial hemorrhage was seen in the frontal and nasal region at 8 hr. Histologically, subectodermal hemorrhage caused by vascular disruption and microfocal mesenchymal necrosis was observed. At 48 hr, some fetuses showed severe diffuse intracranial and superficial hemorrhage, resulting in massive tissue damage, also in the central nervous system (CNS). Maternal heart rate, blood pressure, P02, and PC02 were also measured in awake pregnant rabbits 6 hr after the last dose on day 16 after daily administration with 150 mg/kg during gestational days 14- 16. An attempt was also made to measure fetal heart rate in anesthetized rabbits. The maternal heart rate and blood pressure decreased with about 15% in phenytoin-treated animals, resulting in a decrease in P02 (approximately 15%) and an increase in PC02 (approximately 15%). A decr in fetal heart rate was also registered. The results thus indicate that phenytoin exerts its teratogenic effects by inducing fetal hypoxia, leading to vascular disrupture and necrosis of existing and developing structures. [R37] *Pregnant Sprague-Dawley rats were administered sodium diphenylhydantoin (DPH) by gavage on gestation days 9-18 in doses of 0, 100, or 200 mg/kg. DPH treated dams /exhibited/ a dose related decr in weight gain throughout the drug treatment period. Offspring had significantly lowered birth weights, along with incr mortality through the first 30 days of life. In one of the experiments specifically designed to measure pup mortality, the rates were 41.4% and 60.7% respectively, for the 100 and 200 mg/kg DPH groups. Shortly after eye opening, many of the DPH treated animals developed chromodacryorrhea, a condition that remained throughout the experiment. Aside from lowered body weights, no differences were observed in the attainment of several standard developmental landmarks. During the neonatal period, the pups exposed in utero to 100 mg/kg DPH showed a significant increase in pivoting locomotion on postnatal days 7 and 9. As adults, the animals exposed to 200 mg/kg DPH showed significant incr in locomotor activity measures. Both DPH groups developed a dose related and highly abnormal spontaneous circling behavior. ... [R38] *Exposure of C57BL/J mice to three anticonvulsant derivatives ... dimethadione, sodium valproate, and sodium diphenylhydantoin, each induced postaxial forelimb ectrodactyly. The agents were administered at gestational days 9, 9 1/3, 9 2/3, and 10. It was determined that administration at day 9, 2/3 induced the highest percentage of forelimb ectrodactyly for each of the three agents. The forelimb ectrodactyly response in the C57BL/J strain was compared with the A/J strain ... it was found that the C57BL/J strain was more sensitive to dimethadione and the A/J strain was more sensitive to diphenylhydantoin and sodium valproate. The position of vertebral defects induced by sodium valproate correlated with the time of drug administration. The overall syndrome of malformations induced by the three anticonvulsant agents was relatively similar in the two mouse strains and differed between each of the anticonvulsant agents. [R39] *The developmental toxicity and pharmacokinetic fate of phenytoin in the pregnant rhesus macaque (Macaca mulatta) were examined. Oral administration of 60 to 600 mg/kg phenytoin once daily from gestational day 21 to 50 resulted in dose dependent maternal toxicity of the central nervous system and gastrointestinal tract and an increase in embryonic loss, but no teratogenic insult. Sustained plasma levels as high as 40 ug/ml of total phenytoin occurred at the beginning of the treatment period. However, significant incr in the rate of elimination resulted in the reduction of total phenytoin exposure as treatment progressed. This was evidenced by large increases in phenytoin clearance, and decreases in elimination half life and area under the time versus plasma concentration curve. Maternal toxicity, but not embryolethality, correlated with plasma phenytoin levels. Interspecies comparisons of these parameters from published data were evaluated in the mouse, rat, rabbit and rhesus macaque. ... [R40] *The antiepileptic drug phenytoin was injected into the yolk sac of White Leghorn chick embryos. A dose response study was followed by a detailed teratological study using a single dose of 3 mg. The surviving embryos were sacrificed on the 19th day of incubation. The embryos /exhibited/ a generalized decrease in body weight together with a wide range of malformations. The malformations could be roughly divided into limb, craniofacial, abdominal, and ocular defects, as well as deficiencies in growth. Skeletal defects included hypoplasia of digital phalanges and nails and shortened wings. [R41] *The effects of age and hepatic function on the pharmacokinetics of phenytoin sodium were studied in normal, sham operated, and partially hepatectomized 8 and 50 wk old rats who received an iv injection of 2 and 20 mg/kg drug. The age of the rats markedly influenced drug distribution and elimination. Partial hepatectomy markedly affected drug elimination in both groups of rats. The terminal half life was increased from 120 min to 360 min by partial hepatectomy in younger rats. The maximum elimination rate ranged from 10 to 75 mcg/min among the sham and partially hepatectomized 8 wk old rats. In contrast, partially hepatectomized 50 wk old rats showed a 5 fold increase with relatively small intraindividual difference in plasma levels compared with age matched sham operated controls. [R42] *The antiepileptic drug phenytoin was injected into the yolk sac of White Leghorn chick embryos. A dose response study was followed by a detailed teratological study using a single dose of 3 mg. The surviving embryos were sacrificed on the l9th day of incubation. The embryos showed a generalized decr in body weight together with a wide range of malformations. The malformations could be roughly divided into limb, craniofacial, abdominal, and ocular defects, as well as deficiencies in growth. Skeletal defects included hypoplasia of digital phalanges and nails and shortened wings. [R41] *Exposure of A/J mice on day 9.5 of gestation to the derivatives of three acidic anticonvulsant agents, namely dimethadione, sodium valproate, and sodium diphenylhydantoin, each induced postaxial forelimb ectrodactyly predominantly of the right side. This specific malformation has previously been associated with the administration of acetazolamide to rodents; however, several agents can induce this same defect including other carbonic anhydrase inhibitors, carbon dioxide, cadmium, ethanol, ammonium chloride, and 13-cis retinoic acid. The relative potency of the three agents indicates no direct relationship to the pKa of the acid. Other than ectrodactyly, each of the anticonvulsant agents induced a cmpd specific spectrum of malformations despite the uniform administration time. ... [R43] *Mice of the A/J and C57BLX6J (C57) strains were dosed with phenytoin (PHT) every 48 hr throughout pregnancy by gastric intubation to test the hypothesis that maternal plasma PHT concentration may be the significant factor in determining PHT reproductive and developmental toxicity. Serial serum samples were obtained from each mouse from gestation day (GD) 10-GD 12 for determination of individual dam PHT pharmacokinetics. Maximum PHT concn and PHT AUC (area under the time concn curve) were regressed to laparotomy and fetal evaluation endpoints to determine whether significant association existed. Although serum PHT concn exceeded levels associated with teratogenicity (greater than 10 ug/ml), few major malformations were induced in either strain. However, in the A/J strain, there was a significant incr incidence of hydrocephaly and open eyelid. Regression of pharmacokinetic parameters with embryo and maternal endpoints indicated significant associations between gestational weight gain and maximum concn measured (Cmax) or AUC in both strains. This association was also found for fetal weight in the C57 strain. In the A/J strain, the induction of decr ossification of the sternebrae was also associated with maternal PHT concn; however, linear regression of hydrocephaly and open eyelid to PHT concn was not statistically significant. These results suggest that maternal plasma PHT concentration may be a quantifiable determinant of certain aspects of PHT developmental toxicity in the mouse. [R44] *Gravid Sprague-Dawley CD (VAF) rats were administered sodium phenytoin suspended in corn oil by gavage once per day on embryonic days 7-18 at a dose of 100 mg/kg. Controls were administered corn oil alone by gavage on E7-18. Litters were randomly culled to 10. Offspring were regularly weighted, mortality noted, and males checked for preputial separation. At approximately 50 days of age offspring were evaluated in a straight water filled channel for swimming proficiency and motivation to escape. Following this, rats were tested in the Cincinnati multiple T water maze and scored for errors, latency to find the goal, and presence of phenytoin induced abnormal circling behavior while swimming. Sodium phenytoin exposed dams gained weight normally and delivered normally. Offspring mortality in the sodium phenytoin group was not increased above controls. No treatment effects on preputial separation or offspring growth were observed. No differences between groups in swimming proficiency in straight channel performance were obtained. In the Cincinnati maze, phenytoin offspring committed significantly more errors and had longer latencies to find the goal than controls. Among the phenytoin offspring, those exhibiting abnormal circling committed more errors than noncircling animals. When compared to previous data using the same maze and test protocol, it was found that 100 mg/kg of sodium phenytoin induced performance deficits similar to those induced by a dose of 200 mg/kg of phenytoin acid. Accordingly, the present data help explain why other investigators have reported sodium phenytoin to be more developmentally neurotoxic than phenytoin acid. Because the prenatal neurotoxic effects seen with the salt of phenytoin occur at lower doses, it suggests that phenytoin is more developmentally neurotoxic than previously believed. [R45] *Previous animal research has suggested that the phenytoin arene oxide metabolite is teratogenic in acute studies and that the fetal effects were incr after injecting an inhibitor of microsomal epoxide hydrolase (mEH). ... The effects of chronic oral phenytoin exposure in utero and the mEH inhibitor trichloropropene oxide (TCPO) on the prenatal growth and development of an inbred mouse strain with a low incidence of spontaneous oral clefting (C57BL/6J). Chronic daily gastric gavage of phenytoin produced a plasma level (mean 10.7 ug/ml on gestation Day 8) within the range recommended to prevent epilepsy in humans; this did not produce an incr in oral clefting or ventricular septal defects in the exposed C57BL/6J pups. It did produce a significant delay in prenatal growth and development including phalangeal ossification. However, except for percentage resorptions/implantation, there was no synergism between phenytoin and TCPO in contrast to the finding reported ... in Swiss mice. This issue was also assessed in a test of the fetal effect of phenytoin injected with TCPO, as had been /previously studied/. ... There were no oral clefts or ventricular septal defects or a difference (p > 0.05) in prenatal growth and development in these C57BL/6J pups compared to the chronic gastric phenytoin plus TCPO group. This suggests either that differences in the genotypes of Swiss and C57BL/6J nice may be a contributing factor or that other teratogenic mechanisms were involved. [R46] *Pregnant Sprague-Dawley CD rats were orally administered either phenytoin (PHT, 200 mg/kg), mephenytoin (MPH, 100 mg/kg), ethotoin (ETH, 600 mg/kg), hydantoin (HYD, 1,200 mg/kg) or vehicle (propylene glycol) on days 7-18 of gestation. Mean (+/- S.E.) maternal serum concentrations of PHT, MPH, and ETH 1 hr after dosing on gestational day 18 were 16.0 +/- 3.3, 10.7 +/- 3.0, and 65.2 +/- 10.45, respectively, and free fractions were 16%, 18%, and 11% respectively. The free fraction for PHT is similar, but was lower for both MPH and ETH than that seen in humans. Preweaning mortality for PHT, MPH, ETH, HYD, and controls was 25%, 6.3%, 12.5%, 2.0% and 0.8%, respectively. The MPH and ETH exposed animals weighed approximately 6.6% less than controls throughout the study; the other groups did not differ significantly. PHT offspring showed incr early locomotor activity. Only PHT exposed animals (27%) exhibited abnormal circling behavior after weaning. PHT-circlers accounted for higher levels of activity in an open field test and for longer straight channel swimming times. PHT-circlers and noncirclers differed from one another and controls on performance of a complex (Cincinnati) maze and on the development of the air-righting reflex. Offspring prenatally exposed to MPH showed an early delay in air-righting. ETH and HYD offspring were not consistently different from controls in behavior. The data suggest the following ordinal relationship among the drugs for behavioral teratogenesis: PHT much greater than MPH greater than ETH congruent to HYD congruent to CON. The effects of PHT are consistent with previous findings. Data on the other drugs suggest that other hydantoins do not possess the behavioral teratogenic efficacy of PHT and that PHT may be unique in its effects on CNS development. [R47] NTXV: *LD50 Mouse oral 490 mg/kg; [R1, 1260] *LD50 Mouse iv 92 mg/kg /Phenytoin/; [R1, 1260] *LD50 Mouse subcutaneous 110 mg/kg /Phenytoin/; [R1, 1260] ADE: *SINGLE INTRAGASTRIC DOSE OF PHENYTOIN TO PREGNANT SPRAGUE-DAWLEY RATS WAS TRANSFERRED TO FETUSES AND WAS CONCN MORE IN KIDNEY THAN IN LIVER... [R4, p. V13 209] *...CROSSES PLACENTA. HIGH CONCN...IN MATERNAL LIVER AND FETAL HEARTS. BRAIN (OSTENSIBLY PRIMARY TARGET ORGAN) CONTAINS NEARLY LOWEST CONCN... [R27, 260] *Absorption of phenytoin is slow and variable among products (poor in neonates) for oral admin, immediate for iv admin, and very slow but complete (92%) for intramuscular admin. It is distributed into cerebrospinal fluid, saliva, semen, GI fluids, bile, and breast milk; it also crosses the placenta, with fetal serum concentrations equal to those of the mother. The protein binding of phenytoin is typically very high (90% or more); however, it may be lower in neonates (84%) and in hyperbilirubinemic infants (80%). Also, protein binding may be altered in patients with hypoalbuminemia (< 37 mg/dL), uremia, or acute trauma, and in pregnant patients. /Phenytoin/ [R6, 247] *The time to peak concentration of phenytoin (tablets or oral suspension) is 1.5 to 3 hours. /Phenytoin/ [R6, 247] *Elimination is primarily via renal route as metabolites; also in feces. Phenytoin excretion is enhanced by alkaline urine. /Phenytoin/ [R6, 247] *The results of a drug regimen review of phenytoin sodium dosing in 27 residents, ages 36-86 yr, in seven skilled nursing facilities are presented. 93% ofthe residents required adjustment of their serum phenytoin dosing secondary to hypoalbuminemia, resulting in an incr level of unbound phenytoin, with 22% having a blood level above the therapeutic range after corrections were made. ... [R48] *A murine embryo culture model was used to investigate phenytoin initiated embryonic DNA oxidation and dysmorphogenesis and to determine the embryoprotective potential of superoxide dismutase and catalase, which detoxify reactive oxygen species. Gestational day 9.5 CD-l embryos were cultured for up to 24 hr at 37 deg C in medium containing phenytoin (20 ug/ml, 80 uM) or its vehicle (0.002 N NaOH). Embryos cultured for 24 hr were examined for embryotoxicity. After varying durations of incubation, embryonic DNA was isolated and purified, and DNA oxidation was determined from the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-2'-dG). Control embryos showed an early increase in 8-OH-2'-dG levels that was maximal between 2 and 4 hr, followed by a small but significant decr over 24 hr, with no evidence of embryopathy. Phenytoin treated embryos within 4 hr also demonstrated maximal 8-OH-2'-dG formation, which was substantially greater than that of controls, with a maximal 3-fold increase over controls at 24 hr (p < 0.05). In wash out studies, embryos removed from the phenytoin containing medium after 4 hr and then cultured in phenytoin free medium for an additional 20 hr period showed no decr in either 8-OH-2'-dG levels or embryotoxicity, compared with embryos incubated in the presence of phenytoin for 24 hr. Embryos exposed to phenytoin demonstrated substantial dysmorphogenesis as evidenced by decr in anterior neuropore closure, turning, yolk sac diameter, crown rump length, and somite development (p < 0.05). Superoxide dismutase and catalase virtually eliminated phenytoin initiated 8-OH-2'-dG formation and reduced or completely eliminated all phenytoin initiated dysmorphological anomalies (p < 0.05). These results suggest that embryonic DNA oxidation constitutes teratologically important molecular target damage, and they provide the first direct evidence that free radical mediated oxidative stress plays a critical role in phenytoin teratogenesis. [R49] *Two nonlinear pharmacokinetic models were developed to study the relationship between single and multiple dose bioequivalency parameters for phenytoin sodium (Dilantin; I); mean time to reach maximum concn (Tmax), maximum concentration (Cmax), and area under the plasma concentration time curve values from O to infinity (AUCO-infinity) were /examined/ in 73 healthy male subjects (aged 18-50 yr) who received single and multiple doses of 100 mg I oral capsule or solution. The 90% confidence interval, expressed as a percentage of the reference mean for Tmax, Cmax and AUCO-infinity, showed model dependent changes from single to multiple dosing in response to the level of data error and absorption changes. Changes in clearance also seemed to have a marked effect on the observed limits of single and multiple dose confidence intervals. The model used to describe I had confidence intervals for Cmax and AUCO-infinity from single to multiple dosing that were similar to those seen for experimental data. However, model predictions for Tmax confidence intervals were at variance with experimental data. [R50] *A prospective study to compare 5 dosage prediction methods for phenytoin (I) was conducted in 9 patients aged 71 to 85 yr, who received oral phenytoin sodium as a tablet or capsule once daily in 3 different doses; steady state plasma concentrations were used to estimate the optimum dose to achieve a concentration of 15 mg/l. Blood levels were drawn 12 to 18 hr after a dose, at 2 wk intervals. Steady state was assumed to have been achieved by 6 wk. The 5 dosage prediction methods were based on the Michaelis-Menten equation using the population mean VMAX (Method A), the population mean KM (B), linearized Bayesian method (C), the Rammbeck nomogram (D), and 2 plasma concentration dose data pairs to estimate both VMAX and KM. Ninety-six of the 126 dosage predictions with the 5 methods were within 25 mg of the optimum dose. The predictive precision was similar for all the methods. Methods B and D tended to over predict dosage, particularly when used to interpret low plasma I levels. [R51] *The in vitro release characteristics of phenytoin and phenytoin sodium from rectal suppositories prepared the different combinations of polyethylene glycol bases and polyethylene glycol 100 stearate (Myrj 59) were investigated and the three formulas with the best release rate were evaluated in vivo rabbits. Phenytoin was well absorbed from the suppositories. Results /indicate/ that rectal administration can be an alternative oral administration. [R52] *The bioavailability of single 100 mg doses of phenytoin sodium (diphenylhydantoin sodium; Epdantoin) admin as an oral tablet or rectal suppository was studied in 5 healthy volunteers. Blood samples were analyzed over a 72 hr period. Evaluation of the AUC, tmax and Cmax values showed that the total absorption after the 2 routes of admin was the same while the Cmax and tmax differed. [R53] *To determine the relative bioavailability of four phenytoin oral preparations, 14 epileptic patients presently taking 200-400 mg/day of oral phenytoin sodium (Dilantin, Taiwan) were given a single 300 mg dose of Dilantin, Taiwan and sampled for 24 hr at phase 1; at phase 2 a single 300 mg dose of Dilantin, USA was given, at phase 3, a 300 mg dose of oral phenytoin (Aleviatin, Taiwan) was used, at phase 4, a 300 mg dose of oral phenytoin (Aleviatin, Japan) was used, and between phases the patients were given Dilantin, Taiwan for 2 wk. Results indicated that plasma levels were higher in both the Dilantin, USA and Aleviatin, Japan phases. In vitro tests showed that these two formulations dissolved much more rapidly than the Taiwan formulations. It was concluded that Dilantin and Aleviatin manufactured in Taiwan are not bioequivalent to the same products from the USA or Japan. [R54] *To demonstrate that the area under the serum concentration time curve from time O to infinity (AUCO-INF) of single doses or tracer doses of drugs with nonlinear pharmacokinetic properties vary directly with serum concentration of drug, the AUCO-INF produced by IV tracer doses of 150 mg of labeled phenytoin sodium was determined in 15 epileptic subjects, ages 18-65 yr, on phenytoin monotherapy, at 30 different values of drug serum concentration. AUCO-INF showed a high degree of direct linear correlation with the phenytoin serum concentration at the time of the study. /Data/ ... show that for a drug cleared by 1 enzyme the AUCO-INF of a test dose can be expressed as AUCO-INF=TDxFx(Km+C)/Vmax where TD is test dose size, F is fraction absorbed, C is drug serum concentration at the time of the study, and Km and Vmax are the Michaelis constant and maximum velocity of the enzyme. Consequences of this observation for relative bioavailability studies of drugs with nonlinear pharmacokinetic properties are discussed. [R55] *A study was conducted to examine the effects of pH on the release of phenytoin sodium from 3 oral sustained release dosage forms, including a capsule (Dilantin) tablet containing polymeric materials, and a solid dispersion in an erodible matrix. The sodium salt converted to practically insoluble phenytoin in the gastrointestinal pH range of 1 to 8. Due to this conversion inside or at the surface of the dosage forms, drug release in this pH range was incomplete. The extent of release also varied with the type of dosage form. In contrast, complete dissolution was obtained in water because the pH gradually rose from about 6 to about 9.2, where drug solubility was higher. It was concluded that the release of sustained action phenytoin is affected by pH and the dosage form used. ... [R56] *To determine the unbound fractions of phenytoin in serum and saliva as well as the total phenytoin in serum of epileptic patients in China, fluorescence polarization immunoassay (FPIA) was used to monitor free phenytoin in 23 serum samples and 13 saliva samples from 14 Chinese epileptic patients treated with phenytoin sodium. A strong correlation existed between the total and free concentrations. The mean value for the phenytoin free fraction was 11.13%. The mean value for the saliva fraction was 9.40%. [R57] *The frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin and an equimolar dose of fosphenytoin, a water soluble phenytoin prodrug, were compared in 12 healthy male volunteers, ages 18-40 yr, given 250 mg of phenytoin sodium (Dilantin) or 375 mg of fosphenytoin in a crossover study. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in 8 subjects; cording occurred in 6 subjects. The time course of phenytoin induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hr. Cording was noted between 24 hr and 1 wk after infusion. In contrast, fosphenytoin was associated with mild pain in 2 subjects, one incident of phlebitis, and no erythema or cording. It was concluded that fosphenytoin resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. [R58] *To evaluate the bioavailability of phenytoin products marketed in Turkey, a randomized, crossover study was conducted in 8 healthy volunteers who received 1 of 3 commercial phenytoin products; 2 in tablet form and a third in capsule form and all of them containing 100 mg of phenytoin sodium. There was no significant difference between the bioavailabilities of these products; ...they were bioequivalent; yet, both the rate and extent of absorption showed large interindividual variability for all 3 products. The amount of phenytoin in the products were found to be within acceptable limits. Thus, the variability in the total amount absorbed (AUCs) was not due to an inconsistency of the amount of active ingredient in the formulas. Determination of in vitro dissolution rates of the products revealed that of 2 of the products were found to comply with given standards, but 1 of the tablet forms did not. It was concluded that there was no correlation between in vitro dissolution and in vivo absorption rates of these phenytoin sodium formulations. [R59] *To determine the pharmacokinetic parameters in critically ill patients receiving concomitant enteral feeding. 11 patients with head injuries, 5 of whom had received enteral feeds for less than 5 days (ages 32-72 yr,) and 8 who received enteral feeding for 5 or more days (ages 19-54 yr), received a median of 300 mg intravenous phenytoin sodium (Dilantin) daily over 10-30 min for 13 doses; blood samples were taken and analyzed for pharmacokinetic parameters. Phenytoin was more rapidly eliminated following intravenous dosing in patients receiving long-term enteral feeding, but volume of distribution was similar in both groups. The pharmacokinetic parameters of phenytoin in the first group were similar to previously published population pharmacokinetic parameters. It was concluded that, in patients receiving long-term enteral feeding, it may be necessary to decrease the dosing interval of phenytoin while increasing the dose. [R60] *The cases of 2 patients with measurable serum concentrations of phenytoin following topical application of phenytoin sodium 100 mg to lesions that had failed previous treatments are reported. Both patients, a 62 yr old man and a 72 yr old man, were prescribed twice daily 20 min whirlpool treatments followed by phenytoin sodium 100 mg sprinkled on each of 2 lesions and covered by bandages. Both patients baseline and posttreatment serum concentrations were reported as LT/0.5 mcg/ml. Treatments were discontinued for reasons unrelated to healing or phenytoin absorption. It was concluded that from the lack of measurable serum phenytoin absorption after 12-22 days of topical phenytoin 100-200 mg therapy of the lesions, it appears that this routine of treatment may be safely used without obtaining undesired blood phenytoin concentrations. [R61] *The release of phenytoin sodium (I) from microspheres formulated with biodegradable acid treated gelatin was examined in vitro and in female Sprague-Dawley rats given im, ip and oral doses of I as the microspheres or as a solution. In vitro data revealed a decr in percent drug retained in the microspheres with an incr in addition of glutaraldehyde ... to the microsphere formulations. In vivo studies showed that I microspheres produced significantly higher maximum plasma concn than I solution in rats. Formulation variables also influenced selected pharmacokinetic parameters. [R62] *A study was conducted in 4 healthy male volunteers, ages 28-41 yr, to determine bioavailability of a freeze dried phenytoin sodium milk formulation and a 200 mg capsule formulation administered with either water or milk (controls); in addition, the interaction of the drug with milk components was evaluated in vitro through binding and solubility as a function of temperature (15, 25, and 37 deg C) and fat content (0.75% and 3.5%) of the milk. The binding of the drug milk components was found to be not dependent on the concn of the drug at the temperatures studied. For both types of milk, binding decr as temperature incr. Elevated fat content contributed consistently to a small but significant incr of the percent bound. Solubilities in both types were significantly higher than those observed in phosphate buffer; fat content did not affect these differences. The solubility of the drug incr with temperature. For the in vivo study, the extent of drug absorbed from the freeze-dried formulations was not significantly different from that of the control formulations. It was concluded that, in contrast to the conclusions suggested by the in vitro data, dissolution characteristics in vivo remain relatively unchanged by the presence of milk. [R63] METB: *...OXIDATIVE METAB OF 1 OF GEMINAL PHENYL RINGS OF DIPHENYLHYDANTOIN... 5-META-HYDROXYPHENYL-(L) and 5-PARA-HYDROXYPHENYL-5-PHENYLHYDANTOIN WERE DETECTED IN URINE OF MAN (APPROX RATIO 1:12)... [R64] *The rate of hepatic biotransformation is increased in younger children, in pregnant women, in women during menses, and in patients with acute trauma; rate decreases with advancing age. The major inactive metabolite of phenytoin is 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). Phenytoin may be metabolized slowly in a small number of individuals due to genetic predisposition, which may cause limited enzyme availability and lack of induction. /Phenytoin/ [R6, 247] BHL: *Because phenytoin exhibits saturable or dose-dependent pharmacokinetics, the apparent half-life of phenytoin changes with dose and serum concentrations. this is due to the saturation of the enzyme system responsible for metabolizing phenytoin, which occurs at therapeutic concentrations of the drug. Thus, a constant amount of drug is metabolized (capacity-limited metabolism), and small increases in dose may cause disproportionately large increases in serum concentrations and apparent half-life, possibly causing unexpected toxicity. /Phenytoin/ [R6, 247] ACTN: *The mechanism of action is not completely known, but it is thought to involve stabilization of neuronal membranes at the cell body, axon, and synapse and limitation of the spread of neuronal or seizure activity. In neurons, phenytoin decreases sodium and calcium ion influx by prolonging channel inactivation time during generation of nerve impulses. In glia and non-neuronal cell types, the efflux of sodium and the uptake of potassium may be increased. At the synapse, phenytoin decreases post-tetanic potentiation and repetitive after-discharge. Hydantoin anticonvulsants have an excitatory effect on the cerebellum, activating inhibitory pathways that extend to the cerebral cortex. This effect may also produce a reduction in seizure activity that is assoc with an increased cerebellar Purkinje cell discharge. /Phenytoin as an anticonvulsant/ [R6, 246] *Phenytoin may act to normalize influx of sodium and calcium to cardiac Purkinje fibers. Abnormal ventricular automaticity and membrane responsiveness are decreased. Also, phenytoin shortens the refractory period, and therefore shortens the QT interval and the duration of the action potential. /Phenytoin as an antiarrhythmic/ [R6, 246] *Exact mechanism is unknown. Phenytoin may act in the CNS to decrease synaptic transmission or to decrease summation of temporal stimulation leading to neuronal discharge (antikindling). Phenytoin raises the threshold of facial pain and shortens the duration of attacks by diminishing self-maintenance of excitation and repetitive firing. /Phenytoin as an antineuralgic/ [R6, 246] *Phenytoin's mechanisms of action as a muscle relaxant is thought to be similar to its anticonvulsant action. In movement disorders, the membrane stabilizing effect reduces abnormal sustained repetitive firing and potentiation of nerve and muscle cells. /Phenytoin as a skeletal muscle relaxant/ [R6, 246] INTC: *METAB OF PHENYTOIN IS ENHANCED BY...CHRONIC ALC USE...INHIBITED BY...AMINOSALICYLIC ACID, WARFARIN, METHYLPHENIDATE, CHLORAMPHENICOL...HALOTHANE, PHENYRAMIDOL, CHLORDIAZEPOXIDE...INCR METAB OF CORTISOL, DDT, VIT D...AND PROTEIN-BOUND PHENYTOIN IS DISPLACED BY SALICYLIC ACID, SULFISOXAZOLE, AND PHENYLBUTAZONE. [R65] *ORAL CONTRACEPTIVE OF ESTROGEN-PROGESTOGEN TYPE BLOCKED OVULATION IN 100% OF HEALTHY WOMEN, BUT ONLY 80% OF EPILEPTIC WOMEN ALSO RECEIVING DIPHENYLHYDANTOIN (400 MG/DAY). [R66] *THE CASE OF A 54-YR-OLD MAN WITH DELIRIUM SECONDARY TO PHENYTOIN AND DISULFIRAM ADMIN IS PRESENTED. THE PHARMACOLOGY, INTERACTION, AND RESULTING TOXICITY OF THESE TWO DRUGS ARE EXPLORED. [R67] *THE EFFECT OF CIMETIDINE ON THE DISPOSITION KINETICS OF PHENYTOIN WAS INVESTIGATED IN 7 HEALTHY VOLUNTEERS. A SLIGHT BUT STATISTICALLY SIGNIFICANT DECR BOTH IN THE RATE OF ELIMINATION AND TOTAL BODY CLEARANCE OF PHENYTOIN WAS OBSERVED DURING THE ADMIN OF CIMETIDINE. THE EFFECT IS PROBABLY DUE TO INHIBITION OF METABOLISM. [R68] *Risk of hepatotoxicity from a single toxic dose or prolonged use of acetaminophen may be increased and therapeutic efficacy may be decreased in patients regularly taking other hepatic enzyme-inducing agents such as phenytoin. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use of alcohol or CNS depression-producing medications with hydantoin anticonvulsants may enhance CNS depression. Chronic use of alcohol may decrease serum concentrations and effectiveness of hydantoins; concurrent use of hydantoin anticonvulsants with acute alcohol intake may increase serum hydantoin concentrations. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use of amiodarone with phenytoin and possibly with other hydantoin anticonvulsants may increase plasma concentrations of the hydantoin, resulting in increased effects and/or toxicity. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use with coumarin- or indandione-derivative anticoagulants, chloramphenicol, cimetidine, disulfiram, influenza virus vaccine, isoniazid, methylphenidate, phenylbutazone, ranitidine, salicylates, or sulfonamide may increase serum concentrations of hydantoin anticonvulsants because of decreased metabolism, thereby increasing the hydantoins' effects and/or toxicity. Dosage adjustments of the anticonvulsant may be necessary. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use of succinimide anticonvulsants, carbamazepine, oral estrogen-containing contraceptives, glucocorticoid and mineralocorticoid corticosteroids, corticotropin (ACTH), cyclosporine, dacarbazine, digitalis glycosides, disopyramide, doxycycline, estrogens, furosemide, levodopa, mexiletine, or quinidine may decrease the therapeutic effects of these medications because of increased metabolism and decreased plasma concentrations, which may result from hydantoin anticonvulsants' induction of hepatic microsomal enzymes. Dosage adjustments of these medications may be necessary. Carbamazepine may also induce metabolism of hydantoin anticonvulsants. Monitoring of blood concentrations is recommended as a guide to dosage, especially when either carbamazepine or the hydantoin is added to or withdrawn from an existing regiment. In addition, concurrent use of hydantoin anticonvulsants with oral, estrogen-containing contraceptives may result in breakthrough bleeding and contraceptive failure due to the increased rate of hepatic enzyme metabolism of steroids induced by hydantoins. The dose of the estrogenic substance in the oral contraceptive may be increased to diminish bleeding and decrease the risk of conception. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use of tricyclic antidepressants, bupropion, clozapine, haloperidol, loxapine, maprotiline, molindone, monoamine oxidase (MAO) inhibitors (including furazolidone and procarbazine), phenothiazines, pimozide, or thioxanthenes may lower the seizure threshold and decrease the anticonvulsant effects of hydantoin anticonvulsants. CNS depression may be enhanced and dosage adjustment of the hydantoin anticonvulsant may be necessary. In addition, concurrent use of phenytoin with tricyclic antidepressants may lower serum concentrations of the antidepressant. Dosage increases of the tricyclic antidepressant may be required to produce improvement of the depressed state. Also, molindone contains calcium ions, which interfere with the absorption of phenytoin. also, concurrent use of phenothiazines may inhibit phenytoin metabolism, leading to phenytoin intoxication. /Phenytoin/ [R6, 248] *Concurrent use of oral antidiabetic agents or insulin with hydantoin anticonvulsants may increase serum glucose concentrations and the possibility of hyperglycemia. Dosage adjustment of either or both medications may be necessary. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use of barbiturates or primidone may produce variable and unpredictable effects on hydantoin metabolism; serum hydantoin concentrations should be closely monitored. /Hydantoin anticonvulsants/ [R6, 248] *Osteopenia induced by hydantoin anticonvulsants may be enhanced upon concurrently use with carbonic anhydrase inhibitors. It is recommended that patients receiving concurrent therapy be monitored for early signs of osteopenia and that the carbonic anhydrase inhibitor be discontinued and appropriate treatment initiated if necessary. /Hydantoin anticonvulsants/ [R6, 248] *Concurrent use of oral diazoxide with hydantoin anticonvulsants may decrease the efficacy of ... /the hydantoin anticonvulsant/ and is not recommended. /Hydantoin anticonvulsants/ [R6, 248] *Chronic use of hydantoin anticonvulsants prior to anesthesia with enflurane, halothane, or methoxyflurane may increase metabolism of anesthetic, leading to increased risk of hepatotoxicity, nephrotoxicity (with methoxyflurane only), and hydantoin toxicity. /Hydantoin anticonvulsants/ [R6, 248] *Although hydantoin anticonvulsants deplete the body of folate stores, supplementation with folic acid may result in lowered serum hydantoin concentrations and possible loss of seizure control. Therefore, an increase in hydantoin dosage may be necessary in patients who receive folate supplementation. /Hydantoin anticonvulsants/ [R6, 249] *Large doses of leucovorin may counteract the anticonvulsant effects of hydantoin anticonvulsants. /Hydantoin anticonvulsants/ [R6, 249] *Concurrent use of lidocaine or propranolol and probably other beta-adrenergic blocking agents with iv phenytoin may produce additive cardiac depressant effects; hydantoin anticonvulsants may also increase hepatic enzyme metabolism of lidocaine, reducing its intravenous concentration. /Phenytoin/ [R6, 249] *Caution is advised when nifedipine or verapamil is used concurrently with hydantoin anticonvulsants, which are highly protein-bound medications, since changes in serum concentrations of the free, unbound medications may occur. /Hydantoin anticonvulsants/ [R6, 249] *There is a risk of additive toxicity when phenacemide is used concurrently with hydantoin anticonvulsants. Concurrent use of phenacemide with ethotoin has been reported to cause paranoid symptoms; extreme caution is recommended during concurrent use of these medications. [R6, 249] *Concurrent use of sucralfate may decrease the absorption of hydantoin anticonvulsants. /Hydantoin anticonvulsants/ [R6, 249] *Sulfinpyrazone may displace hydantoin anticonvulsants from plasma protein-binding sites and decrease their metabolism, possibly leading to increased plasma concentrations and elimination half-life. Although plasma hydantoin concentration is not consistently increased, it is recommended that patients be monitored for signs of hydantoin toxicity. /Hydantoin anticonvulsants/ [R6, 249] *Increased plasma hydantoin concentrations have been reported when hydantoin anticonvulsants are used concurrently with trazodone; caution and close monitoring are suggested. /Hydantoin anticonvulsants/ [R6, 249] *Hydantoin anticonvulsants may reduce effects of vitamin D by accelerating metabolism through hepatic microsomal enzyme induction; patients on long-term anticonvulsant therapy may require vitamin D supplementation to prevent osteomalacia, although rickets is rare. /Hydantoin anticonvulsants/ [R6, 249] *Concurrent use of aluminum-magnesium or calcium carbonate-containing antacids may decrease the bioavailability of phenytoin. Doses of antacids and phenytoin should be separated by about 2 to 3 hours. /Phenytoin/ [R6, 248] *When used as an excipient in phenytoin capsules, calcium sulfate can decrease phenytoin absorption by as much as 20%. Concurrent use of phenytoin with calcium supplements or any tablets or capsules that contain calcium sulfate as an excipient may result in formation of nonabsorbable complexes, thereby decreasing the bioavailability of both calcium and phenytoin. Patients should be advised to take these medications 1 to 3 hours apart. /Phenytoin/ [R6, 248] *Use of iv phenytoin in patients maintained on dopamine may produce sudden hypotension and bradycardia; this reaction is considered to be dose-rate dependent. If anticonvulsant therapy is necessary during admin of dopamine, an alternative to phenytoin should be considered. /Phenytoin/ [R6, 248] *Concurrent use of enteral feeding solutions with phenytoin may decrease phenytoin absorption, possibly necessitating an increase in dosage. Some clinicians recommend that at least 2 hr should elapse between feeding and phenytoin admin. If phenytoin suspension or capsule contents are admin via nasogastric tubing, flushing the tube with 2 to 4 ounces of water before and after admin has been suggested. Phenytoin serum concentrations should be carefully monitored during concurrent therapy. /Phenytoin/ [R6, 248] *Concurrent use of fluconazole with phenytoin may decrease the metabolism of phenytoin, resulting in increased plasma phenytoin concentrations. A 75% increase in the area under the curve of phenytoin was found in volunteers given 200 mg of fluconazole per day. Phenytoin concentrations must be carefully monitored. /Phenytoin/ [R6, 249] *Concurrent use of ketoconazole with phenytoin may result in altered metabolism of either ketoconazole, phenytoin, or both. In addition, time to peak serum concentration of ketoconazole may be delayed. Response to both medications should be closely monitored. /Phenytoin/ [R6, 249] *Serum concentrations of phenytoin have been reported to be increased by miconazole, another imidazole derivative, resulting in phenytoin toxicity. Dosage adjustments may be necessary before and after miconazole therapy. /Phenytoin/ [R6, 249] *Concurrent use of fluoxetine with phenytoin has been reported to cause elevated plasma phenytoin concentrations, resulting in symptoms of toxicity. Caution and close monitoring are suggested. /Phenytoin/ [R6, 249] *Concurrent use of levothyroxine with phenytoin may reduce serum protein binding of levothyroxine and reduce total serum thyroxine (T4) by 15 to 25%. However, most patients remain euthyroid, and dosage of thyroid hormone does not need to be altered. /Phenytoin/ [R6, 249] *Chronic use of phenytoin may increase methadone metabolism, probably by induction of hepatic microsomal enzyme activity, and may precipitate withdrawal symptoms in patients being treated for opioid dependence. Methadone dosage adjustments may be necessary when phenytoin therapy is initiated or discontinued. /Phenytoin/ [R6, 249] *Inhibition of the cytochrome P-450 enzyme system by omeprazole, especially at higher doses, may cause a decrease in the hepatic metabolism of phenytoin. Delayed elimination and increased serum concentrations may result, with considerable interpatient variability. /Phenytoin/ [R6, 249] *One small, single-dose, controlled study found that epileptic patients taking phenytoin had significantly lower plasma concentrations of praziquantel (24% of the control group). This effect is thought to be due to induction of the cytochrome P-450 microsomal enzyme system by phenytoin. Patients on phenytoin may require a larger dose of praziquantel. /Phenytoin/ [R6, 249] *Concurrent use of rifampin with phenytoin may stimulate the hepatic metabolism of phenytoin, increasing its elimination and thus counteracting its anticonvulsant effect. Careful monitoring of serum hydantoin concentrations and dosage adjustments may be necessary. /Phenytoin/ [R6, 249] *Phenytoin may protect pancreatic beta cells from the toxic effects of streptozocin, thus reducing streptozocin's therapeutic effects. Concurrent use is not recommended. /Phenytoin/ [R6, 249] *Valproic acid may displace phenytoin from protein-binding sites and may inhibit the metabolism of phenytoin. Phenytoin, through enzyme induction, may lower valproate levels. There may be an increased risk of liver toxicity, especially in infants. Close monitoring of the patient is required since variable serum phenytoin concentrations have resulted. Monitoring of free phenytoin concentrations is advised by some clinicians. Dosage of phenytoin should be adjusted as required by clinical situation. Caution is advised also for use with other hydantoin anticonvulsants. /Phenytoin/ [R6, 249] *Concurrent use of xanthines, such as aminophylline, caffeine, oxtriphylline, or theophylline, with phenytoin may stimulate hepatic metabolism of the xanthines (except dyphylline), resulting in increased theophylline clearance, especially if plasma phenytoin concentrations are in the usual therapeutic range for at least 5 days. Also, simultaneous use with the xanthines may inhibit phenytoin absorption, resulting in decreased serum phenytoin concentrations. Serum concentrations of phenytoin and theophylline should be monitored during concurrent therapy. Dosage adjustments of both phenytoin and theophylline may be necessary. /Phenytoin/ [R6, 249] *... The effects of multiple dose pantoprazole admin on single dose phenytoin kinetics, 23 healthy volunteers, ages 18-26 yr received 40 mg of oral pantoprazole tablets or placebo for 7 days and then also received a single dose of 300 mg of oral phenytoin sodium capsules on day 4; blood samples were taken frequently and analyzed for phenytoin pharmacokinetic parameters. Pantoprazole did not affect the rate or extent of absorption or elimination of phenytoin. [R69] *A case is presented in which a 29 yr old man with brain metastases secondary to malignant melanoma who was treated with 300-550 mg/day oral phenytoin sodium, exhibited suboptimal phenytoin concentrations, possibly due to the admin of 4 mg oral dexamethasone every 6 hr and 2 cycles of a chemotherapy regimen consisting of 50 mg cisplatin for 3 dats, 300 mg carmustine for 1 day, 440 mg dacarbazine for 3 days, and 20 mg oral tamoxifen twice daily for 3 days. It was /observed/ that the total phenytoin concentration was less than 2.5 mcg/ml 4 days after an incr in the dose of phenytoin to 550 mg/day. ... [R70] *A randomized, double blind, crossover study was conducted in 20 healthy male volunteers, ages 19-38 yr, to assess the effects of multiple oral doses of zileuton 600 mg every 6 hr for 8 days on the single dose pharmacokinetics of phenytoin sodium (Dilantin) 300 mg. Zileuton did not significantly alter the Cmax, Tmax, and area under the plasma concentration time curve of phenytoin. There were no significant effect of zileuton on the Michaelis-Menten parameters of phenytoin. It was concluded that coadministration of zileuton did not significantly alter the single dose pharmacokinetics of phenytoin. [R71] *The case is presented of a 7 yr old boy who was receiving 200 mg/day phenytoin sodium ... and valproate sodium ... and who developed subtherapeutic plasma levels of these anticonvulsant during treatment with 1 g/day oral acyclovir for 6 days. It was noted that the patient was also receiving nitrazepam ... therapy. Three and 6 days after acyclovir withdrawal, plasma levels of the anticonvulsant were still low. On day 7, the patient had 25 serial partial seizures. The dose of phenytoin was increased to 225 mg/day and plasma levels increased until values of 23-24 mcg/ml were reached after 10 days. During this time valproate sodium plasma levels returned to initial values without dose modification. Phenytoin was reduced to 200 mg/day and plasma levels decr to 14-15 mcg/ml without changes in clinical status. [R72] *A case report of a 45 yr old man treated with 7 mcg/kg/min intravenous dopamine hydrochloride for cardiogenic shock in whom admin of 750 mg iv phenytoin sodium daily was not associated with changes in blood pressure is presented. Concomitant therapy included furosemide, dobutamine hydrochloride, cloxacillin, methylprednisolone, digoxin, and ranitidine. Marked hypotension was expected when phenytoin was added to the dopamine infusion, but this effect did not appear either a few min after the beginning of the infusion or over the 7 days of combined treatment. Possibilities as to why the larked hypotension did not occur are also included. [R73] *The possible interaction between ciprofloxacin and phenytoin was studied in 7 healthy volunteers (mean age 24.25 yr) who received single oral doses of 200 mg phenytoin sodium daily for 10 days with 500 mg oral ciprofloxacin hydrochloride twice daily initiated on day 10. On day 14 blood samples were collected. There were no significant differences bet ween area under the concentration time curve (AUC), maximum serum concentration (Cmax ), and time of maximum serum concentration of phenytoin before and during ciprofloxacin administration. However, 1 subject showed marked reductions in both AUC and Cmax. It was concluded that ciprofloxacin was not shown to incr phenytoin plasma concentrations or AUC in healthy volunteers, but the potential for decreasing plasma phenytoin concentrations may exist. [R74] *Based on 23 suspected fluoxetine interactions with phenytoin in the United States, the U.S. Food and Drug Administration required the sponsor to revise package labeling of fluoxetine hydrochloride to reflect these anecdotal observations; 3 recent reports of non-United States patients with both CNS disorders and depression provide descriptive data on these drug interaction cases showing the signs of phenytoin sodium toxicity dissipating 7 to 28 days after fluoxetine hydrochloride dosage reduction or discontinuation. Although the mechanism is not known, ... the need to characterize more completely the interactions of CNS active drugs because the interactions nay have profound clinical consequences. [R75] *To assess the time course of phenytoin's induction of cytochrome p450 CYP3A activity, 8 healthy volunteers, ages 18-42 yr, received 200 mg oral phenytoin sodium capsules ... every 8 hr for 11 doses followed by 100 mg every 8 hr for 8 doses; blood and urine samples were taken frequently and analyzed for drug concentration and 6beta-hydroxycortisol and cortisol levels. Mean 6beta-hydroxycortisol:cortisol ratios incr by a factor of 2.37 from baseline during the course of the study. Values for the ratios on days 4, 5, and 7 were significantly higher than baseline, but the value on day 3 was only borderline significant. It was concluded that phenytoin rapidly induces the activity of CYP3A family of isozymes, with effects apparent within 48 hr after initiation of therapy. [R76] *The purpose of this study was to investigate pharmacological effects of sodium valproic acid (VPA) alone, and in combination with sodium phenytoin (PHT), on the embryonic heart in C57Bl/6J mouse embryos. Embryos, on gestational day 9.5, were cultured in vitro by whole embryo technique. After 16 hr, original heart rate was examined under a dissection microscope connected to a video camera and recorder. VPA and PHT were dissolved in water. In the first experiment, VPA was added to the cultures to give concn 0-20000 uM. Heart rate was examined for 15 sec at 30, 60 and 90 min after the addition of VPA or water (controls). Expressed in percentage of original heart rate, the effects of different concn of VPA were the following (average of heart rate at 30, 60 and 90 min at versus original heart rate): 0 uM (controls): 104%, 1000 uM: 103%, 1300 uM: 101%, 2000 uM: 98%, 5000 uM: 85%, 10000 uM: 80%, 20000 uM: 64%. Statistical analysis showed that only very high concentrations (5000-20000 uM), compared to therapeutic concentrations (400-700 uM), cause a significant (p less than 0.05, paired t-test) decrease in embryonic heart rate. Arrhythmias were not observed at any concentration of VPA. In the second experiment, embryo cultures were simultaneously exposed to 1) VPA (2000 uM) 2) PHT (100 uM) or 3) VPA (2000 uM) and PHT (100 uM). When given alone, neither of the concn of VPA or PHT significantly affected the embryonic heart rate or caused any arrhythmias. Simultaneous exposure to VPA and PHT resulted in a statistical significant (p less than 0.001 paired t-test) bradycardia (89% of original heart rate) and arrhythmias in 12 of the embryos. The results indicate that VPA in contrast to PHT, has no capacity to cause embryonic arrhythmia/cardiac arrest and induces bradycardia only at clinically irrelevant concn. However, VPA seems to potentiate the adverse pharmacological effects of PHT on the embryonic heart at lower concn, resulting in an increased risk for ischemia/reperfusion damage. [R77] *The purpose of this study was to investigate the effect of ciprofloxacin on the pharmacokinetics of steady state phenytoin serum concn. Healthy volunteers were administered phenytoin sodium (200 mg) orally once daily for 14 days. Ciprofloxacin (500 mg) twice daily was administered concomitantly on days 10 through 14. Steady state serum concn of phenytoin were obtained on day 0 and day 5 of ciprofloxacin administration. The following pharmacokinetic parameters were calculated by noncompartmental methods: the maximum concn of drug in serum (Cmax), the time to the maximum concn (Tmax), and the area under the concn time curve (AUC). No significant differences (p > 0.05) were found between the pharmacokinetic parameters of phenytoin alone or after concomitant ciprofloxacin administration. This data indicates there is no pharmacokinetic interaction between ciprofloxacin and steady state phenytoin serum concn in regard to Cmax, Tmax and AUC. ... [R78] *The effects of an oral dextrose (glucose; I) load and an enteral feeding solution on the absorption of 12.5 mg/kg oral phenytoin sodium ... were studied in dogs, and the effect of nutrients on intestinal drug uptake from solution was investigated by rat jejunal perfusion of 80 mu M II at 300 m Osm/kg and pH 6.5. Peak II plasma levels and area under the concn time curves were positively correlated with time to stomach emptying in the fasted dog controls. The enteral feeding solution delayed stomach emptying and II plasma levels continued to rise over the sample period. Plasma II levels were highest with coadministered enteral feeding solution, intermediate with I and lowest in controls. Coperfusion of 20 and 100 mM I resulted in higher II permeabilities in rat perfusion studies. This incr was reversible by inclusion of an inhibitor of active mucosal transport. Permeabilities of I were depressed by 15-100 mM calcium chloride (III ) but were unaffected by 2-5 mM III. [R79] *The visual compatibility of premixed theophylline and heparin solutions with 34 selected drugs was evaluated by simulating the 1:1 mixing of iv solutions at a Y injection site. Results showed that all drugs except phenytoin sodium were visually compatible with the theophylline solution. Mixing the phenytoin immediately produced a cloudy white appearance. The heparin solution was incompatible with doxycycline hyclate, gentamicin sulfate, nitroglycerin, phenytoin sodium, tobramycin sulfate, and vancomycin hydrochloride. [R80] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3-4. 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB); 4= VERY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG, BETWEEN 1 TEASPOON AND 1 OZ FOR 70 KG PERSON (150 LB). [R17] *The lethal dose of phenytoin in adults is estimated to be 2 to 5 g. The lethal dose in children in unknown. /Phenytoin/ [R6, 251] THER: *PHENYTOIN SODIUM...USED FOR PROPHYLACTIC CONTROL OF SEIZURES IN NEUROSURGERY. IT IS ADMIN IM DURING SURGERY AND IS CONTINUED DURING POST-OPERATIVE PERIOD. PHENYTOIN HAS BEEN USED IN TREATMENT OF CHOREA OR PARKINSON'S SYNDROME TO CONTROL INVOLUNTARY MOVEMENTS. [R4, p. V13 205] *MEDICATION (VET): PHENYTOIN IS USED IN VETERINARY MEDICINE TO CONTROL EPILEPTIFORM CONVULSIONS IN DOGS. PHENYTOIN SODIUM HAS ALSO BEEN RECOMMENDED AS ANTICONVULSANT FOR DOGS. [R4, p. V13 206] *MEDICATION (VET): ...IS DRUG OF CHOICE IN DIGITALIS INDUCED TOXICITY AND VENTRICULAR ARRHYTHMIAS IN DOGS UNRESPONSIVE TO PROCAINE AMIDE. IN CASES OF POOR WOUND HEALING IT MAY STIMULATE COLLAGEN FORMATION AND WOUND TENSILE STRENGTH. [R81] *ACCURATE DIAGNOSIS OF SEIZURE TYPE AND DETERMINATION OF MIN EFFICACY AND TOXIC BLOOD CONCN IN USE OF ANTIEPILEPTIC DRUGS SUCH AS PHENYTOIN ALONG WITH PHARMACOKINETICS AND BIOTRANSFORMATION ARE DISCUSSED. [R82] *Hydantoin anticonvulsants are indicated in the suppression and control of tonic-clonic (grand mal) and simple or complex partial (psychomotor or temporal lobe) seizures. /Hydantoin anticonvulsants; Included in US product labeling./ [R6, 246] *Parenteral phenytoin is indicated for the control of tonic-clonic type status epilepticus. Although diazepam is often used initially for rapid control of status epilepticus, phenytoin is indicated for sustained control of seizure activity because of the short duration of diazepam's effect. /Phenytoin; Included in US product labeling./ [R6, 246] *Phenytoin is indicated for the prevention and treatment of seizures during and following neurosurgery. /Phenytoin; Included in US product labeling./ [R6, 246] *Phenytoin is used in the correction of atrial and ventricular arrhythmias, especially those caused by digitalis glycoside toxicity. /Phenytoin; Not included in US or Canadian product labeling./ [R6, 246] *Phenytoin may be effective in treating paroxysmal choreoathetosis, especially the kinesigenic type. This condition, which is considered a form of reflex epilepsy, is characterized by tonic, dystonic, or choreoathetoid contortions of the extremities, trunk, or face, which are usually precipitated by the patient's initiation of sudden voluntary movement. /Phenytoin; Not included in US or Canadian product labeling./ [R6, 246] *Phenytoin has been used in the treatment of episodic dyscontrol and in some behavior disorders characterized by hyperexcitability, which include anger, anxiety, irritability, and insomnia. /Phenytoin; Not included in US or Canadian product labeling./ [R6, 246] *Phenytoin is used alone or with other anticonvulsants to control paroxysmal pain in some patients with trigeminal neuralgia (tic douloureux). Carbamazepine is considered the first-line agent, effectively relieving pain in about 66% of patients. However, since phenytoin relieves pain during long-term use in approx 20% of patients, it may be used alone in some patients or added to carbamazepine therapy when symptoms persist. /Phenytoin; Not included in US or Canadian product labeling./ [R6, 246] *Phenytoin is effective in some patients as a muscle relaxant in the treatment of muscle hyperirritability, characterized by delayed relaxation of muscle after voluntary or mechanically induced contraction and by a state of continuous muscle contraction at rest. Neuromyotonia includes continuous muscle fiber activity syndrome, Isaac's syndrome, and "stiff man" syndrome. /Phenytoin; Not included in US or Canadian product labeling./ [R6, 246] *Intravenous phenytoin loading is used to treat quinidine-like conduction defects, bradyarrhythmias, or heart block, in tricyclic antidepressant overdose. /Phenytoin; Not included in US or Canadian product labeling./ [R6, 246] *Therapeutic serum concentrations range from 10 to 20 ug/mL (40 to 80 umol/L). Steady-state serum concentration is usually achieved in 5 to 10 days with daily oral dosage of 300 mg. Serum concentrations of 20 to 40 ug/mL (80 to 159 umol/L) usually produce symptoms of toxicity; > 40 ug/mL (159 umol/L) usually produce severe toxicity. The serum concentrations of phenytoin needed for efficacy may be influenced by seizure type. Higher concentrations (23 ug/mL (91 umol/L) or greater) may be needed to control simple or complex partial seizures, with or without tonic-clonic seizures, or status epilepticus than are necessary for control of tonic-clonic seizures alone (10 to 20 ug/mL (40 to 80 umol/L)). Occasionally, a patient may have seizure control with serum phenytoin concentrations of 6 to 9 ug/mL (24 to 36 umol/L). Effective treatment, therefore, should be guided by clinical response, not drug serum concentrations. In patients who have hypoalbuminemia and/or renal failure, or who are taking other medications that displace phenytoin from binding sites, hydantoin serum concentrations of 5 to 10 ug/mL (20 to 40 umol/L) may be adequate. For cardiac arrhythmias, plasma concentrations of 10 to 18 ug/mL (40 to 71 umol/L) have been reported to be effective. /Phenytoin/ [R6, 247] *Therapeutic concentrations of free phenytoin, which are frequently monitored in patients with altered protein binding (e.g. in neonates and in patients with renal failure, hypoalbuminemia, or acute trauma), usually fall in the range of 0.8 to 2 ug/mL. /Phenytoin/ [R6, 247] *The case of a 55 yr old morbidly obese man with a massive Grade IV pressure ulcer that responded rapidly to treatment with topical phenytoin is reported. ... [R83] *A review is presented of the effects of sarcodosis of the central and periphral nervous systems, the possible clinical and radiological presentations of sarcoid lesions, and the therapy of neurosarcodosis with prednisone, chloroquine, methotrexate and cyclosporine. The use of phenytoin sodium ... in the therapy of seizures associated with central nervous system sarcoid lesions is included. ... [R84] *In a randomized study to compare iv and im magnesium sulfate with iv and oral phenytoin sodium ... for the prevention of eclampsia in women with pregnancy induced hypertension who had been admitted for delivery, 1049 women were assigned to receive a 10 g im loading dose of magnesium sulfate followed by a maintenance 5 g im dose every 4 hr, and an additional 4 g iv loading dose for those with severe preeclampsia and 1089 women were assigned to a 1000 mg loading dose of phenytoin sodium infused over a period of 1 hr, followed by a 500 mg oral dose 10 hr later. Results showed that 10 women in the phenytoin regimen had eclamptic convulsions, as compared with none assigned to magnesium sulfate. There were no significant differences in any risk factors for eclampsia between the 2 study groups. Maternal and infant outcomes were also similar in the 2 study groups. [R85] WARN: *POSSIBLE ASSOC BETWEEN MATERNAL EPILEPSY, ANTICONVULSANT DRUGS (MAINLY PHENYTOIN...AND CONGENITAL MALFORMATIONS IN OFFSPRING...CHILDREN BORN TO MOTHERS WHO TOOK...PHENYTOIN THROUGHOUT PREGNANCY REVEALED...MALFORMATIONS SUGGESTING SYNDROME INVOLVING LIP AND PALATE, CARDIOVASCULAR SYSTEM AND SKELETAL ABNORMALITIES... [R4, p. V13 210] *TWO PT WITH AGRANULOCYTOSIS ASSOC WITH DIPHENYLHYDANTOIN (DPH) THERAPY WERE INVESTIGATED USING IN VITRO CULTURE TECHNIQUES. [R86] *A SURVEY OF 15 FAMILIES IN THE USA WITH BALTIC MYOCLONUS EPILEPSY SHOWED THAT 27 INDIVIDUALS WERE AFFECTED. THE DISEASE PROGRESSED MORE RAPIDLY IN THESE FAMILIES THAN IT DID IN THE EARLY CASES, SEEN IN THE BALTIC REGION. THIS DIFFERENCE COULD BE DUE TO A TOXIC EFFECT OF PHENYTOIN BECAUSE PHENYTOIN GIVEN ALONE OR WITH OTHER ANTIEPILEPTIC DRUGS WAS ASSOCIATED WITH PROGRESSIVE MOTOR AND INTELLECTUAL DETERIORATION, MARKED ATAXIA, AND DEATH. TREATMENT WITH VALPROIC ACID, AND THE CONCOMITANT REDUCTION OR ELIMINATION OF PHENYTOIN, HAS BEEN ASSOCIATED WITH MARKED IMPROVEMENT IN AT LEAST 8 PATIENTS. BALTIC MYOCLONUS EPILEPSY MUST BE DISTINGUISHED FROM LAFORA BODY DISEASE, WHICH IS INVARIABLY FATAL AND DISCERNIBLE ON CLINICAL GROUNDS. [R87] *A 19-YR-OLD MAN WITH A GENERALIZED SEIZURE DISORDER WAS TREATED WITH PHENYTOIN. A HYPERSENSITIVITY REACTION WAS MARKED BY HEPATITIS, SEVERE MYALGIA, PROXIMAL ARM WEAKNESS, AND HIGH SERUM CREATINE KINASE. BIOPSY WAS DIAGNOSTIC OF MYOPATHY. PATIENTS DEMONSTRATING ABNORMALITIES OF IMMUNE RESPONSIVENESS MAY BEST BE MANAGED BY USE OF AN ALTERNATIVE ANTICONVULSANT. [R88] *Maternal Medication usually Compatible with Breast-Feeding: Phenytoin: Reported Sign or Symptom in Infant or Effect on Lactation: Methemoglobinemia (1 case). /from Table 6/ [R89] *POTENTIAL ADVERSE EFFECTS ON FETUS: May lead to depletion of vitamin K-dependent factors and hemorrhagic disease of newborn. Increased risk of neonatal extrarenal Wilms tumor, ganglioneuroblastoma, mesenchymoma, and neuroblastoma. "Fetal hydantoin syndrome" (anomalies of fingers, toes, and craniofacial abnormalities) and increased risk of cleft palate, cleft lip, and cardiac anomalies may relate to other factors, including seizures during pregnancy. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: No adverse effects known, but secreted in breast milk. Breast -feeding not recommended. FDA Category: D (D = There is evidence of human fetal risk, but the potential benefits from use in pregnant women may be acceptable despite the potential risks (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.)) /from Table II/ [R90] *Hydantoin anticonvulsants are not indicated in the treatment of absence (petit mal) seizures, or as first-line treatment of febrile, hypoglycemic, or other metabolic seizures. When tonic-clonic (grand mal) seizures coexist with absence seizures, combined therapy may be necessary. /Hydantoin anticonvulsants/ [R6, 246] *Although phenytoin has been used in patients with recessive dystrophic epidermolysis bullosa for the treatment of blistering and erosions of the skin that may result from even minor trauma or injury, it is not longer considered preferred therapy. /Phenytoin/ [R6, 246] *Hydantoin anticonvulsants cross the placenta; risk-benefit must be considered, although a definite cause and effect relationship has not been established between the hydantoins and teratogenic effects. Reports in recent years indicate a higher incidence of congenital abnormalities in children whose mothers used anticonvulsant medication during pregnancy, although most epileptic mothers have delivered normal babies. Reported abnormalities include cleft lip, cleft palate, heart malformations, and the "fetal hydantoin syndrome" (characterized by prenatal growth deficiency, microcephaly, craniofacial abnormalities, hypoplasia of the fingernails, and mental deficiency assoc with intrauterine development during therapy). Medication has not been definitively proven to be the cause of "fetal hydantoin syndrome." The reports, to date, relate primarily to the more widely used anticonvulsants, phenytoin and phenobarbital. Pending availability of more precise info, this risk-benefit consideration of anticonvulsant use during pregnancy is extended to the entire family of anticonvulsant medications. /Hydantoin anticonvulsants/ [R6, 247] *Because of altered absorption and protein binding and/or increased metabolic clearance of hydantoin anticonvulsants during pregnancy, pregnant women receiving these medications may experience an increased incidence of seizures. Serum hydantoin concentrations must be monitored and doses increased accordingly. A gradual resumption of the patient's usual dosage may be necessary after delivery. However, some patients may experience a rapid reduction in maternal hepatic phenytoin metabolism at time of delivery, requiring the dosage to be reduced within 12 hr postpartum. /Hydantoin anticonvulsants/ [R6, 247] *Exposure to hydantoins prior to delivery may lead to an increased risk of life-threatening hemorrhage in the neonate, usually within 24 hr of birth. Hydantoins may also produce a deficiency of vitamin K in the mother, causing increased maternal bleeding during delivery. risk of maternal and infant bleeding may be reduced by administering water-soluble vitamin K to the mother during delivery and to the neonate, intramuscularly or sc, immediately after birth. /Hydantoin anticonvulsants/ [R6, 247] *Ethotoin and phenytoin are distributed into breast milk; significant amounts may be ingested by the infant. [R6, 247] *Children and young adults are more susceptible to gingival hyperplasia than older adults. Some reports suggest that children may experience decreased school performance during long-term treatment with hydantoin anticonvulsants, especially at high therapeutic or toxic concentrations. Coarsening of facial features and excessive body hair growth may be more pronounced in young patients. Other anticonvulsants less likely to cause problems should be considered first. /Hydantoin anticonvulsants/ [R6, 247] *Geriatric patients tend to metabolize hydantoins slowly, thereby increasing the possibility of the medication reaching toxic serum concentrations. Also, serum albumin may be low in older patients, causing a decrease in protein binding of phenytoin. Lower dosage and subsequent adjustments may be required. The rate of admin of iv dosage should be no more than 25 mg/min, and possibly as low as 5 to 10 mg/min. /Phenytoin/ [R6, 247] *Gingival hyperplasia, a common complication of phenytoin or mephenytoin therapy, usually starts during the first 6 months of treatment as gingivitis or gum inflammation. The incidence is higher in patients under 23 years of age than in older patients, and severe gingival hyperplasia is less likely to occur with dosage under 500 mg/day. Anterior tissue overgrowth may be greater than posterior overgrowth, creating esthetic and psychological problems for the young patient. A strictly enforced program of teeth cleaning by a professional, combined with plaque control by the patient, if begun within 10 days of initiation of hydantoin anticonvulsant therapy, will minimize growth rate and severity of gingival enlargement. Periodontal surgery may be indicated, and should be followed by careful plaque control to inhibit recurrence of gum enlargement. If gingival hyperplasia cannot be controlled by standard dental procedures, ethotoin may be substituted for phenytoin, without loss of seizure control, usually at doses 4 to 6 times greater than those of phenytoin. /Hydantoin anticonvulsants/ [R6, 247] *... the leukopenic effects of hydantoin anticonvulsants may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. If leukopenia occurs, dental work should be deferred until blood counts have returned to normal. Patient instruction in proper oral hygiene should include caution in use of regular toothbrushes, dental floss, and toothpicks. /Hydantoin anticonvulsants/ [R6, 248] *Adverse hematologic effects, sometimes fatal, have been associated with phenytoin, including thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia (with or without bone marrow suppression). Macrocytosis and megaloblastic anemia which usually respond to folic acid therapy, may also occur. /Phenytoin/ [R21] *Pain, inflammation, and tissue necrosis and/or sloughing at the site of injection may occur; tissue damage has required amputation rarely. Therefore, improper administration resulting in subcutaneous and perivascular injection of phenytoin sodium should be avoided. Soft tissue irritation and inflammation also has occurred at eh site of injection in the absence of extravasation. IV injections of the drug should be followed by administration of sodium chloride injection through the same needle or IV catheter to avoid local irritation of the vein caused by the alkalinity of the phenytoin sodium solution. [R21] *If a rash appears during phenytoin therapy, the drug should be discontinued. IF the rash is exfoliative, purpuric, or bullous or if lupus erythematosus, Steven-Johnson syndrome, or toxic epidermal necrolysis is suspected, phenytoin therapy should not be resumed. If the rash is morbilliform or scarlatiniform, therapy may be restarted after the rash has completely disappeared; if the rash recurs when phenytoin is restarted, further phenytoin therapy is contraindicated. /Phenytoin/ [R21] *In newborns exposed to phenytoin during pregnancy, a tendency to bleeding may develop during the first day of life due to decreased levels of vitamin K-dependent clotting factors, despite normal levels in the mother. Hemorrhage secondary to thrombocytopenia may also be caused occasionally by phenytoin. /Phenytoin/ [R91] *Because acute attacks of porphyria may be precipitated by anticonvulsants, a therapeutic dilemma arises when seizures complicate hepatic porphyria. The list of unsafe agents includes barbiturates, primidone, phenytoin, mephenytoin, ethotoin, ethosuximide, methsuximide, phensuximide, and trimethadione. ... [R92] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R93] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Comparative dissolution of phenytoin using high performance liquid chromatography and UV spectrophotometry. [R94] CLAB: *PROCEDURES DEVELOPED IN PROCESS OF PRODUCING AND CERTIFYING ANTICONVULSANT DRUGS-IN-SERUM STD REF MATERIAL (SRM) ARE DESCRIBED FOR DIPHENYLHYDANTOIN. SERUM MATRIX QUANTITATED BY GAS CHROMATOGRAPHY AND BY LIQUID CHROMATOGRAPHY. [R95] *IMPROVED ISOCRATIC LIQUID-CHROMATOGRAPHIC SIMULTANEOUS MEASUREMENT OF PHENYTOIN, PHENOBARBITAL, PRIMIDONE, CARBAMAZEPINE, ETHOSUXIMIDE, AND N-DESMETHYLMETHSUXIMIDE IN SERUM. [R96] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW OF THE REPORTED RISKS OF PHENYTOIN DURING PREGNANCY. [R97] DHHS/NTP; Toxicology and Carcinogenesis Studies of 5,5-Diphenylhydantoin in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 404 (1993) NIH Publication No. 94-2859 Strasnick B, Jacobson JT; J Am Acad Audiol 6 (1): 28-38 (1995). Teratogenic hearing loss /is reviewed/. Wasfi FA, et al; Med Sci Res 23 (8): 551-3 (1995). Teratogenic effects of phenytoin in the rat: an in vivo and an in vitro study. Maternal factors, medications and drug exposure in congenital limb reduction defects. [R98] Markova IV; Farmakol Toksikol 53 (4): 82-6 (1990). The undesirable actionb of drugs on the embryo, fetus and newborn infant. 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Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V66 203 91996) R92: Reynolds NC Jr, Miska RM; Neurol 31 (4): 480-4 (1981) R93: 21 CFR 200-299, 300-499, 820, and 860 (4/1/96) R94: Morales Hernandez JM, et al; Rev Mex Cien Farm 26: 22-4 (1995) R95: REEDER DJ ET AL; NBS SPEC PUBL (US) 519(ISS TRACE ORG ANAL: NEW FRONT) ANAL CHEM 47 (1979) R96: SZABO GK, BROWNE TR; IMPROVED ISOCRATIC LIQUID-CHROMATOGRAPHIC SIMULTANEOUS MEASUREMENT OF PHENYTOIN, PHENOBARBITAL, PRIMIDONE, CARBAMAZEPINE, ETHOSUXIMIDE, AND N-DESMETHYLMETHSUXIMIDE IN SERUM; CLIN CHEM 28(1) 100 (1982) R97: ALBENGRES E, TILLEMENT JP; PHENYTOIN IN PREGNANCY: A REVIEW OF THE REPORTED RISKS; BIOL RES PREGNANCY PERINATOL 4(2) 71 (1983) R98: Foster UG, Baird PA; Environ Health Perspect 101 (Suppl 3): 269-74 (1993) RS: 137 Record 227 of 1119 in HSDB (through 2003/06) AN: 3169 UD: 200211 RD: Reviewed by SRP on 9/18/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PRIMIDONE- SY: *2-DEOXYPHENOBARBITAL-; *2-DESOXYPHENOBARBITAL-; *DESOXYPHENOBARBITONE-; *5-ETHYLHEXAHYDRO-4,6-DIOXO-5-PHENYLPYRIMIDINE-; *5-ETHYL-5-PHENYLHEXAHYDROPYRIMIDINE-4,6-DIONE-; *HEXADIONA-; *HEXAMIDINE-; *HEXAMIDINE- (THEANTISPASMODIC); *LEPIMIDIN-; *LEPSIRAL-; *LISKANTIN-; *MAJSOLIN-; *MIDONE-; *MILEPSIN-; *MISODINE-; *MISOLYNE-; *MIZODIN-; *MIZOLIN-; *MYLEPSIN-; *MYLEPSINUM-; *MYSEDON-; *MYSOLINE-; *5-PHENYL-5-ETHYLHEXAHYDROPYRIMIDINE-4,6-DIONE-; *PRILEPSIN-; *PRIMACLONE-; *PRIMACONE-; *PRIMAKTON-; *PRIMIDON-; *PRIMOLINE-; *PRYSOLINE-; *4,6(1H,5H)-PYRIMIDINEDIONE, 5-ETHYLDIHYDRO-5-PHENYL-; *PYRIMIDONE-MEDI-PETS-; *ROE-101-; *SERTAN- RN: 125-33-7 MF: *C12-H14-N2-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...BY ELECTROLYTIC PRODUCTION OF PHENOBARBITAL OR BY CATALYTIC DESULFURATION OF CORRESPONDING 2-THIOBARBITURIC ACID. [R1] FORM: *PRIMIDONE, USP (MYSOLINE), IS AVAIL AS 50 and 250 MG TABLETS AND AS ORAL SUSPENSION (250 MG/5 ML). [R2, 211] MFS: *Ganes Chemicals, INc., Hq, 630 Broad Street, Carlstadt, NJ 07072, (201) 507-4300; Production site: Pennsville, NJ 08070 [R3] USE: *Terap Cat: Anticonvulsant; Therap Cat (Vet): Anticonvulsant. Chiefly to control epileptiform seizures. [R1] *Used for the treatment of generalized tonic-clonic seizures. [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS [R1]; *WHITE CRYSTALLINE POWDER [R5] ODOR: *ODORLESS [R5] TAST: *PRACTICALLY TASTELESS [R1]; *SLIGHTLY BITTER TASTE [R5] MP: *281-282 DEG C [R1] MW: *218.26 [R1] OWPC: *Log Kow = 0.91 [R6] PH: *NO ACIDIC PROPERTIES [R1] SOL: *SPARINGLY SOL IN WATER (0.6 G/L @ 37 DEG C); SPARINGLY SOL IN MOST ORG SOLVENTS [R1]; *In water, 5.0X10+2 mg/l at 25 deg C. [R7] SPEC: *MAX ABSORPTION (ACID AND BASE SALT): 257, 251 and 263 NM (A= 10, 8 and 8, 1%, 1 CM) [R8]; *UV: 1299 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) [R9]; *MASS: 2-592 (Archives of Mass Spectral Data, John Wiley and Sons, New York) [R9]; *Intense mass spectral peaks: 117 m/z, 146 m/z, 161 m/z, 190 m/z, 218 m/z [R10] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of NOx. [R11] STRG: *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a tight, light-resistant container. Protect from freezing. /Primidone Oral Suspension USP/ [R12, 2424] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a well-closed container. /Primidone Tablets USP/ [R12, 2424] *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. /Primidone Chewable Tablets/ [R12, 2424] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Treatment is supportive and symptomatic. The use of gastric lavage, activated charcoal, and cathartics has not been studied. Stabilization comprises the following measures: 1. Maintenance of airway, breathing, and circulatory integrity. 2. Endotracheal intubation as needed. 3. Assisted ventilation as required. [R13] HTOX: *THE MORE COMMON COMPLAINTS ARE SEDATION, VERTIGO, DIZZINESS, NAUSEA, VOMITING, ATAXIA, DIPLOPIA AND NYSTAGMUS. ... SERIOUS ADVERSE EFFECTS ARE RELATIVELY UNCOMMON, BUT MACULOPAPULAR AND MORBILLIFORM RASH, LEUKOPENIA, THROMBOCYTOPENIA, SYSTEMIC LUPUS ERYTHEMATOSUS, AS WELL AS LYMPHADENOPATHY HAVE BEEN REPORTED. [R14, 473] *NEWBORN OF MOTHERS WHO RECEIVE.../PRIMIDONE/ DURING PREGNANCY MAY...DEVELOP DEFICIENCY OF VITAMIN K-DEPENDENT CLOTTING FACTORS, AND SERIOUS HEMORRHAGE MAY OCCUR DURING 1ST 24 HR OF LIFE. [R2, 223] *ACUTE PSYCHOTIC REACTIONS, USUALLY IN PT WITH COMPLEX PARTIAL SEIZURES, HAVE ALSO OCCURRED. HEMORRHAGIC DISEASE IN NEONATE, MEGALOBLASTIC ANEMIA AND OSTEOMALACIA SIMILAR TO THOSE.../OF/ PHENYTOIN AND PHENOBARBITAL HAVE ALSO BEEN DESCRIBED. [R14, 473] *AT LEAST 2 CHILDREN HAVE SURVIVED DOSES OF 12.5 G, BUT WERE COMATOSE FOR 24 HR AND REQUIRED UP TO 5 DAYS FOR COMPLETE RECOVERY. A PRIMIDONE CRYSTALLURIA HAS BEEN DESCRIBED WITHOUT RENAL SEQUELAE. [R15] *OCCASIONALLY...FATIGUE, IRRITABILITY /AND DROWSINESS OCCUR/. [R5] *Symptoms of poisoning may include sedation, vertigo, dizziness, nausea, vomiting, ataxia, diplopia, and nystagmus. Massive crystalluria (hexagonal crystals) indicates severe poisoning with primidone. The crystals result from precipitation of primidone in the urine, and this is observed at serum levels greater than 80 ug/ml. [R13] *Overdosage of primidone results in symptoms similar to those of acute barbiturate intoxication. In addition, primidone crystalluria may occur and may facilitate the diagnosis. [R16, 1635] *Neurologic manifestation in the newborn, such as overactivity and tumors, have been associated with use of primidone in pregnancy. Neonatal hemorrhagic disease with primidone alone or in combination with other anticonvulsants has been reported. Suppression of vitamin K1-dependent clotting factors is the proposed mechanism of the hemorrhagic effect. Administration of prophylactic vitamin K1 to the infant immediately after birth is recommended. [R17] *Acardia, the absence of the heart, is one of the rarest medical anomalies. The exact mechanism which causes this anomaly is still unknown. ... The acardiac acephalic fetus of an epileptic mother who was on primidone therapy /is reported/. The mother who received no antenatal care stopped taking primidone (her sole medication) in the third month of pregnancy with the fear of delivering a malformed baby and had three convulsions until delivery. This is the first reported case of acardia associated with anti-epileptic medication. The cause of the anomaly in this patient may be an unknown genetic defect, the maternal epileptic disorder, the convulsions, the anti-epileptic medication, or a combination of these factors. [R18] *Antiepileptic drug (AED) related chronic leukopenia (white blood cell (WBC) count < 4,000/microliters) is a dilemma, especially when the AED is effective in controlling seizures. /The possible mechanisms/ leukopenia in 7 patients /were evaluated/. Mean WBC count was 3,000/microliters with a mean of 42% polymorphonuclear leukocytes (PMN). The AEDs were carbamazepine (CBZ) alone in 1 patient or CBZ combined with phenytoin (PHT), primidone (PRM), phenobarbital (PB) and/or valproate (VPA) in 5 patients; on patient was receiving PHT only. Bone marrow (BM) aspirates and PMN antibody studies using chemiluminescence were normal. Two liver spleen scans showed mild relative splenomegaly. After exercise, WBC count (n = 7) incr by 54% (SEM 12%), while the WBC counts in controls (n = 5) incr by 52 +/- 16%. Antinuclear antibodies (Hep-2) were absent in 6 patients and positive (1:160) in 1. PMN adhesion to nylon wool was decr (54 +/- 10%) in patients vs. 80 +/- 5% in controls: n = 13, p < 0.005). The data, particularly the appropriate WBC response to the stress of exercise, and normal BM examinations suggest that continuation of AED therapy when leukopenia is stable and the percentage of PMN is normal is probably safe. Caution should be used if the absolute PMN count is consistently < 1,000/microliters. BM examinations need not be performed routinely for every patient with neutropenia due to AEDs, especially if the leukopenia fluctuates in the range of 2,000-4,000 cells/microliters. [R19] *... The influence of changes in the prescribing of antiepileptic drugs to pregnant women on frequency and pattern of malformations in their offspring by comparing two consecutive cohorts (1972 to 1979, cohort A; 1980 to 1985, cohort B) /was studied/. In cohort A, 15 (10%) of 151 exposed, live-born infants had one or more congenital anomalies, which consisted primarily of congenital heart defects, facial clefts, and syndromes of dysmorphia with developmental retardation, in association with polytherapy (carbamazepine plus phenobarbitone plus valproate, with or without phenytoin, or phenobarbitone plus phenytoin plus primidone). In cohort B, the prescribing of phenobarbitone, phenytoin, or primidone had dropped markedly, whereas monotherapy with valproate and carbamazepine had incr. Thirteen (7.6%) of 172 exposed, live-born infants had congenital anomalies. The most frequent anomalies were spinal defects (four) and glandular hypospadias (three), all in association with maternal therapy with valproate, carbamazepine, or both. The results underline the need for continuation of prospective studies to monitor the effect of change in prescribing policies and to evaluate the role of metabolic interactions between drugs prescribed in combination. [R20] *A report on a newborn girl with lobar holoprosencephaly and clinical signs of hydantoin syndrome /is described/. During pregnancy the mother was treated with diphenylhydantoin and primidon for psychomotor and petit mal seizures. The possible relationship between hydantoin syndrome, holoprosencephaly, and maternal intake of anticonvulsants during pregnancy is discussed. [R21] NTOX: *.../PRIMIDONE/ IS LIABLE TO PRODUCE NEUROTOXIC SYMPTOMS IN DOGS IF USED AT RATE OF 65-75 MG/KG/DAY, BUT SYMPTOMS RAPIDLY DISAPPEAR IF DOSE IS DECR OR DISCONTINUED. [R22] *CATS SHOW NEUROTOXICITY (ATAXIA, PARALYSIS)... [R23] *Primaclone was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Primaclone was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.100, 0.333, 1.000, 3.333, 6.666, and 10.000 mg/plate. The compound was positive in strain TA1535 without activation. The lowest positive dose tested was 3.333 mg/plate. [R24] *Pregnant Sprague-Dawley rats were admin primidone (PRM) by oral gavage on gestation days 8-17 in doses of 0.40, and 80 mg/kg. Although these doses of PRM did not produce significant differences in litter size, birth weight, mortality, date of attainment of developmental landmarks or measures of preweaning reflex and motor development, there were a number of significant differences that developed as the animals approached and entered adulthood. When tested as adults, the 80 mg/kg male rats showed a deficit in the performance of an eight arm radial maze task. These same animals showed a significant reduction in open field activity when tested as adults. In addition, both male and female PRM treated animals showed reduced body weights at different periods corresponding to onset of sexual maturation during development. These findings are consistent with the larger body of literature reporting on the neurobehavioral teratology of phenobarbital, including its ability to produce lesions in the hippocampus and endocrine dysfunction resulting in reproductive deficits. These results suggest that PRM produces its adverse effects as a result of its metabolism to phenobarbital, which in turn affects the limbic system. [R25] NTP: +Primaclone (PMC) ... was tested for its effects on fertility and reproduction in Swiss CD-1 mice according to the Continuous Breeding Protocol. It was administered via feed. Based on results of an extended dose-finding study which included mating, delivery of 1 litter and data collection on the 4 day survival rate of pups (Task 1), the following dose levels were chosen to investigate effects on fertility and reproduction: 0.015% (24 mg/kg), 0.05% (78 mg/kg), and 0.15% (233 mg/kg). Male and female mice (F0) were continuously exposed for a 7 day precohabitation and a 98 day cohabitation period (Task 2). Treated male and female body weights in Task 2 were always within 10% of control values. Feed consumption was similar in F0 control and treated animals. Fertility and reproduction in F0 animals were not affected. Only the cumulative days to litter value for the 5th litter of the low dose level (0.015% PNC) animals was significantly increased, a finding of questionable biological importance. All other parameters were similar to controls. The F1 pups from the last litter in the control and highest dose groups were weaned. Body weights in the treated groups were higher than controls at weaning, but were similar thereafter. Mating, pregnancy and fertility indices for F1 mice were similar to control values, while absolute and relative liver weights were increased for both sexes. Estrous cycle length was increased by approx 7% in F1 females exposed to 0.15% PMC. Overall, PMC produced mild reproductive toxicity at doses that also caused some systemic changes. These data show that PMC is not a selective reproductive toxicant in Swiss CD-1 mice at concns of up to 0.15% in the diet. [R26] +... 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300 or 2,500 ppm primidone (equivalent to avg daily doses of approx 25, 50 or 100 mg/kg) in feed for two yr. ... Groups of 50 male and 50 /B6C3F1/ female mice were exposed to dietary levels of 0, 300, 600 or 1,300 ppm primidone (equivalent to avg daily doses of approx 30, 65 or 150 mg/kg to males and 25, 50 or 100 mg/kg to females) in feed for two yr. ... CONCLUSIONS: Under the conditions of these two yr feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal incr in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal incr in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300 or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the incr incidences of hepatocellular neoplasms, and incr incidence of thyroid gland follicular adenomas was considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the incr incidences of hepatocellular neoplasms. [R27] ADE: *Absorption is rapid and usually complete with wide individual variation. Indirect estimates of bioavailability range from 90 to 100%. Primidone has a volume of distribution (Vd) of 0.64 to 0.86 L/kg. Primidone and its metabolites pass into breast milk, reaching a mean concentration of 75% of maternal steady-state serum levels. [R12, 2421] *Therapeutic serum concentrations range from 5 to 12 ug primidone/mL (23 to 55 mmol/L), which produces phenobarbital serum concentrations of 20 to 40 ug/mL (86 to 172 mmol/L). Some clinicians have suggested that the optimal mean plasma primidone concentration is 12 ug/mL with an assoc mean derived phenobarbital concn of 15 ug/mL resulting in a primidone-to-phenobarbital ratio of 0.8; however, much variation occurs among patients. [R12, 2421] *Protein binding accounts for 0 to 20% of administered primidone; biotransformation occurs via the liver into the two active metabolites, phenobarbital (15-25%) and PEMA (major metabolite /% not specified/); and elimination is via the kidneys, with 64% as unchanged primidone. /From table/ [R12, 2421] *Primidone is rapidly and almost completely absorbed after oral admin, although individual variability can be great. Peak concn in plasma usually are observed approx 3 hr after ingestion. [R14, 473] *Primidone and PEMA are bound to plasma proteins to only a small extent, whereas about half of phenobarbital is so bound. ... Approx 40% of the drug is excreted unchanged in the urine; unconjugated PEMA and, to a lesser extent, phenobarbital and its metabolites constitute the remainder. [R14, 473] *During long-term therapy, the plasma concn of primidone and phenobarbital average 1 ug/mL and 2 ug/mL, respectively, per daily dose of 1 mg/kg of primidone. The plasma concn of PEMA usually is intermediate between those of primidone and phenobarbital. There is no clear relationship between the concn of primidone or its metabolites is plasma and therapeutic effect. [R14, 473] METB: *ANOTHER METABOLITE HAS BEEN DETECTED IN RAT PLASMA; IT IS A DIAMIDE DERIV OF MALONIC ACID PRODUCED BY.../SRP: REMOVAL OF THE METHYLENE CARBON/. PLASMA LEVEL VS TIME PROFILES STRONGLY SUGGEST THIS METABOLITE...TO BE PRODUCED DIRECTLY FROM PRIMIDONE. [R28] *Primidone is slowly metabolized by the liver and slowly excreted in urine as phenylethylmalonamide, phenobarbital, and p-hydroxyphenobarbital. [R16, 1634] *Primidone is converted to two active metabolites, phenobarbital and phenylethylmalonamide (PEMA). [R14, 473] BHL: *SERUM HALF-LIFE: 10-21 HR. [R29] *Primidone - 3 to 23 hours; phenobarbital metabolite - 75 to 126 hours; and phenylethylmalonamide (PEMA) metabolite - 10 to 25 hours. [R12, 2421] *THE PLASMA HALF-LIFE OF PRIMIDONE IS VARIABLE; MEAN VALUES RANGING FROM 5 TO 15 HOURS HAVE BEEN REPORTED. ... THE HALF-LIFE OF PEMA /PHENYLETHYLMALONAMIDE/ IN PLASMA IS 16 HOURS; BOTH IT AND PHENOBARBITAL ACCUM DURING LONG-TERM THERAPY. THE APPEARANCE OF PHENOBARBITAL IN PLASMA MAY BE DELAYED SEVERAL DAYS UPON INITIATION OF THERAPY. [R14, 473] ACTN: *The antiseizure effects of primidone are attributed to both the drug and its active metabolites, principally phenobarbital. [R14, 472] *The mechanism of action is unknown, but anticonvulsant effects are thought to be due to the parent compound, primidone, as well as its two active metabolites, phenobarbital and phenylethylmalonamide (PEMA), whose actions may be synergistic. [R12, 2421] INTC: *METHYLPHENIDATE RAISES SERUM PHENYTOIN LEVELS AND MAY CAUSE SYMPTOMS OF PHENYTOIN TOXICITY IN SOME CHILDREN... PRIMIDONE HAS BEEN REPORTED TO INTERACT WITH METHYLPHENIDATE IN SIMILAR MANNER. [R30, 204] *LONG-TERM ADMIN OF PHENYTOIN MAY CAUSE LOW SERUM FOLATE LEVELS...AND MAY PPT SYMPTOMS OF FOLIC ACID DEFICIENCY (EG, MENTAL DYSFUNCTION, NEUROPATHY, PSYCHIATRIC DISORDERS AND RARELY, MEGALOBLASTIC ANEMIA). .../PRIMIDONE/ HAS BEEN ASSOC WITH DECR SERUM FOLATE LEVELS. [R30, 197] *...SERUM PHENOBARBITAL (A METAB OF PRIMIDONE) LEVELS ROSE AFTER DISULFIRAM ADMIN /IN 3 PT RECEIVING PRIMIDONE/, INDICATING THAT A MORE RAPID CONVERSION OF PRIMIDONE TO PHENOBARBITAL MAY HAVE OCCURRED. [R30, 196] *When acetaminophen in therapeutic doses is used concurrently in patients receiving chronic primidone therapy, its effects may be decreased because of increased metabolism resulting from induction of hepatic microsomal enzymes by the phenobarbital metabolite; also, risk of hepatotoxicity with single toxic doses or prolonged use of acetaminophen may be increased in chronic alcoholics or in patients regularly using hepatic-enzyme inducing agents. [R12, 2422] *Concurrent use of adrenocorticoids, glucocorticoid and mineralocorticoid; coumarin- or indandione-derivative anticoagulants; tricyclic antidepressants; chloramphenicol; oral estrogen-containing contraceptives; corticotropin (ACTH); cyclosporine; dacarbazine; digitalis glycosides, with possible exception of digoxin; disopyramide; doxycycline; levothyroxine; metronidazole; mexiletine; or quinidine with primidone may decrease the effects of these medications because of increased metabolism resulting from induction of hepatic microsomal enzymes by the barbiturate metabolite. Dosage increases may be necessary during and after primidone therapy. Use of nonhormonal method of birth control or a progestin-only oral contraceptive may be necessary during primidone therapy. Also, concurrent use of tricyclic antidepressants with primidone may enhance CNS depression, lower convulsive threshold, and decrease the effects of primidone; dosage adjustments may be necessary to control seizures. [R12, 2422] *Concurrent use of alcohol or CNS depression-producing medications may potentiate the CNS and respiratory depressant effects of either these medications or primidone; dosage adjustment of primidone may be necessary. [R12, 2422] *Concurrent use of amphetamines may cause a delay in the intestinal absorption of the phenobarbital metabolite. [R12, 2422] *Concurrent use of other anticonvulsants may cause a change in the pattern of epileptiform seizures because of altered medication metabolism; monitoring of plasma concentrations of both medications is recommended, and dosage adjustment may be necessary. Carbamazepine induces metabolism and decreases effects of primidone. Monitoring of plasma concentrations is recommended as a guide to dosage if either medication is added or withdrawn from an existing regimen. Concurrent use of valproic acid with primidone may cause higher serum concentrations of primidone leading to increased CNS depression and neurological toxicity because of protein binding displacement and reduced metabolism. Half-life of valproic acid may be decreased. In addition, primidone may enhance valproic acid hepatotoxicity, presumably through the formation of hepatotoxic valproate metabolites. Dosage adjustment of primidone may be necessary. [R12, 2422] *Osteopenia induced by primidone may be enhanced by concurrent use of carbonic anhydrase inhibitors. It is recommended that patients receiving concurrent therapy be monitored for early signs of osteopenia and that the carbonic acid anhydrase inhibitor be discontinued and appropriate treatment initiated if necessary. [R12, 2422] *Concurrent use of cyclophosphamide with primidone may induce microsomal metabolism to increase the formation of alkylating metabolites of cyclophosphamide, thereby reducing the half-life and increasing the leukopenic activity of cyclophosphamide. [R12, 2422] *Chronic use of primidone prior to anesthesia with enflurane, halothane, or methoxyflurane may increase anesthetic metabolism, leading to increased risk of hepatotoxicity. Also, chronic use of primidone prior to anesthesia with methoxyflurane may increase formation of nephrotoxic metabolites, leading to increased risk of nephrotoxicity. [R12, 2422] *Concurrent use of fenoprofen with primidone may decrease the elimination half-life of fenoprofen, possibly because of increased metabolism resulting from induction of hepatic microsomal enzyme activity; fenoprofen dosage adjustment may be required. [R12, 2422] *Requirements for folic acid may be increased in patients receiving anticonvulsant therapy. /Anticonvulsants/ [R12, 2422] *Antifungal effects may be decreased when griseofulvin is used concurrently with primidone because of impaired absorption resulting in decreased serum concentrations; although the effect of decreased serum concentrations on therapeutic response has not been established, concurrent use preferably should be avoided. [R12, 2422] *Concurrent use of guanadrel or guanethidine with primidone may aggravate orthostatic hypotension. [R12, 2422] *Concurrent use of haloperidol, loxapine, maprotiline, molindone, phenothiazines, or thioxanthenes with primidone may lower the seizure threshold because of altered metabolism; CNS depression may be increased and decreases in primidone dosage may be necessary. Serum concentrations of neuroleptics may be significantly reduced when these medications are used concurrently with primidone because of increased metabolism. [R12, 2422] *Large doses of leucovorin may counteract the anticonvulsant effects of primidone. [R12, 2422] *Concurrent use of methylphenidate may increase serum concentrations of primidone because of metabolism inhibition, possibly resulting in toxicity; dosage adjustments may be necessary. [R12, 2422] *Concurrent use of monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, or selegiline may prolong the effects of primidone because metabolism of the barbiturate metabolite may be inhibited. Changes in the pattern of epileptiform seizures may occur; dosage adjustment of primidone may be necessary. [R12, 2422] *Although concurrent use of phenobarbital with primidone is rarely indicated, since primidone is metabolized to phenobarbital, it may cause a change in the pattern of epileptiform seizures because of altered medication metabolism and also increase the sedative effect of either primidone or the barbiturate anticonvulsant; decreases in primidone dosage may be necessary. [R12, 2423] *Effects of vitamin D may be reduced by primidone, because of accelerated metabolism by hepatic microsomal enzyme induction; vitamin D supplementation may be required in patients on long-term primidone therapy to prevent osteomalacia, although rickets is rare. [R12, 2423] *Concurrent use of xanthines, such as aminophylline, caffeine, oxtriphylline, or theophylline with primidone, because of the barbiturate metabolite, may increase metabolism of the xanthines (except dyphylline) by induction of hepatic microsomal enzymes, resulting in increased theophylline clearance. [R12, 2423] *Carbamazepine is one of the most commonly prescribed antiepileptic drugs and is also used in the treatment of trigeminal neuralgia and psychiatric disorders, particularly bipolar depression. Because of its widespread and long term use, carbamazepine is frequently prescribed in combination with other drugs, leading to the possibility of drug interactions. The most important interactions affecting carbamazepine pharmacokinetics are those resulting in induction or inhibition of its metabolism. Phenytoin, phenobarbital, ... and primidone accelerate the elimination of carbamazepine, probably by stimulating cytochrome P450 (CYP) 3A4, and reduce plasma carbamazepine concn to a clinically important extent. Inhibition of carbamazepine metabolism and elevation of plasma carbamazepine to potentially toxic concn can be caused by stiripentol, remacemide, acetazolamide, macrolide antibiotics, isoniazid, metronidazole, certain antidepressants, verapamil, diltiazem, cimetidine, danazol and propoxyphene. In other cases, toxic symptoms may result from elevated plasma concn of the active metabolite carbamazepine-10,11-epoxide, due to the inhibition of epoxide hydrolase by valproic acid (sodium valproate), valpromide, valnoctamide and progabide. Carbamazepine is a potent inducer of CYP3A4 and other oxidative enzyme system in the liver, and it may also incr glucuronyltransferase activity. This results in the acceleration of the metabolism of concurrently prescribed anticonvulsants, particularly valproic acid, clonazepam, ethosuximide, lamotrigine, topiramate, tiagabine and remacemide. The metabolism of many other drugs such as tricyclic antidepressants, antipsychotics, steroid oral contraceptives, glucocorticoids, oral anticoagulants, cyclosporin, theophylline, chemotherapeutic agents and cardiovascular drugs can also be induced, leading to a number of clinically relevant drug interactions. Interactions with carbamazepine can usually be predicted on the basis of the pharmacological properties of the combined drug, particularly with respect to its therapeutic index, site of metabolism and ability to affect specific drug metabolizing isoenzymes. Avoidance of unnecessary polypharmacy, selection of alternative agents with lower interaction potential, and careful dosage adjustments based on serum drug concn monitoring and clinical observation represent the mainstays for the minimization of risks associated with these interactions. [R31] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *4. 4= VERY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG; BETWEEN 1 TEASPOONFUL AND 1 OZ FOR 70 KG PERSON (150 LB). MEAN LETHAL DOSE IN ADULTS APPEARS TO BE ON ORDER OF 20-30 G. [R15] THER: +Anticonvulsants [R32] *MEDICATION (VET): /USED/ IN DOGS TO CONTROL EPILEPTIFORM, EPILEPTIC, AND VARIOUS VIRAL INDUCED CONVULSIONS, BUT APPARENTLY OF LITTLE VALUE IN CHOREA. OF VALUE AGAINST SOME ELECTRICAL AND CHEM EXPTL INDUCED CONVULSIONS. [R23] *Primidone, either alone or used concomitantly with other anticonvulsants, is indicated in the control of generalized tonic-clonic (grand mal), nocturnal myoclonic, complex partial (psychomotor), and simple partial (cortical focal) epileptic seizures. /Included in US product labeling./ [R12, 2421] *Primidone is used in the treatment of essential (familial) tremor. Although propranolol is considered to be the treatment of choice for essential tremor, primidone provides effective treatment for some patients. /Not included in US or Canadian product labeling./ [R12, 2421] *Primidone is useful against generalized tonic-clonic and both simple and complex partial seizures. ... /and/ is sometimes useful against myoclonic seizures in young children. [R14, 473] WARN: *RELATIONSHIP OF ADVERSE EFFECTS OF DOSAGE IS COMPLEX, SINCE THEY RESULT FROM... THE PARENT DRUG AND ITS TWO ACTIVE METAB AND SINCE TOLERANCE DEVELOPS DURING CHRONIC MEDICATION. SIDE EFFECTS ARE OCCASIONALLY QUITE SEVERE WHEN THERAPY IS INITIATED. [R2, 211] *.../PRIMIDONE IS/ INEFFECTIVE AGAINST ABSENCE SEIZURES ... [R14, 473] *Drugs that have been associated with Significant Effects on some Nursing Infants and should be given to Nursing Mothers with Caution: Primidone: Sedation, feeding problems /from Table 5/ [R33] *Adequate and well-controlled studies in humans have not been done. However, reports have suggested an association between the use of other anticonvulsant drugs and an increased incidence of birth defects (fetal hydantoin syndrome) in newborns. Symptoms similar to fetal hydantoin syndrome, i.e., growth retardation, craniofacial and heart abnormalities, and hypoplasia of the fingernails and distal phalanges, have been shown to occur with primidone also. [R12, 2421] *Neonatal hemorrhage, with a coagulation defect resembling vitamin K deficiency, has been described in newborns whose mothers were taking primidone and other anticonvulsants. Risk may be reduced by administering water-soluble vitamin K prophylactically to the mother 1 month prior to and during delivery and also to the neonate, intramuscularly or subcutaneously, immediately after birth. [R12, 2422] *Primidone is distributed into breast milk in substantial amounts, and the use of primidone by nursing mothers may cause unusual drowsiness in the neonate. [R12, 2422] *Serious adverse reactions to primidone are rare, but mild adverse effects occur frequently. The most common adverse effects are drowsiness, ataxia, vertigo, lethargy, anorexia, nausea, and vomiting; ataxia and vertigo tent to disappear with continued therapy or with reduction of initial dosage. [R16, 1635] *Occasionally, primidone may cause hyperexcitability (especially in children), may include hyperirritability, although it is usually less severe than that associated with phenobarbital. Rarely, primidone therapy has precipitated an acute psychosis-like reaction. Other adverse reactions reported during primidone therapy are fatigue, emotional disturbances, drowsiness, diplopia, nystagmus, morbilliform rash, alopecia, edema of the eyelids, leg edema, leukopenia, eosinophilia, impotence, a malignant lymphoma-like syndrome, and a syndrome resembling system lupus erythematosus, all of which subsided when the drug was discontinued. Megaloblastic anemia (which responds to folic acid therapy), red cell hypoplasia, or aplasia, granulocytopenia, and agranulocytosis have occurred rarely. [R16, 1635] *Primidone is excreted into breast milk. because primidone undergoes limited conversion to phenobarbital, breast milk concentrations of phenobarbital should also be anticipated. A milk:plasma ratio of 0.8 for primidone has been reported. The amount of primidone available to the nursing infant is small with milk concentrations of 2.3 ug/ml. No reports linking adverse effects to the nursing infant have been located, however, patients that breast feed should be instructed to watch for potential sedative effects in the infant. In the American Academy of Pediatrics' 1994 statement, primidone is classified as an agent that may produce significant adverse effects in the nursing infant, thus, should be used with caution in the lactating woman. [R17] IDIO: *MEGALOBLASTIC ANEMIA MAY OCCUR AS RARE IDIOSYNCRASY. [R5] TOLR: *...TOLERANCE DEVELOPS DURING CHRONIC MEDICATION. [R2, 211] MXDD: *...TOTAL DAILY DOSE OF 2 G SHOULD NOT BE EXCEEDED. [R5] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ MILK: *Primidone is distributed into breast milk in substantial amounts, and the use of primidone by nursing mothers may cause unusual drowsiness in the neonate. [R12, 2422] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R34] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC Method 986.36. Primidone in Drug Tablets. Liquid Chromatographic Tablets. [R35] CLAB: *TYPE C PROCEDURE (ELEGANT AND PRECISE, USING REQUIRED EQUIPMENT) FOR BLOOD, PLASMA AND URINE; GC METHOD WITH NO INTERFERENCES. [R36] *COMPARISON OF DETERMINATION OF PRIMIDONE BY ENZYME MULTIPLIED IMMUNOASSAY TECHNIQUE AND GLC METHOD FOR PLASMA IS REPORTED. SUGGESTION IS PROVIDED IN ORDER TO AVOID MAJOR DISCREPANCY IN RESULTS OBSERVED FROM "BOTTOM OF THE BOTTLE" FOR THE IMMUNOASSAY REAGENT. [R37] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Brodie MJ, Dichter MA; N Engl J Med 334: 168-75 (1996). A review of the practical management of epilepsy with established antiepileptic drugs is /presented/. Dessens AB, et al; Acta Paediatr Suppl 404: 54-64 (1994). Studies on long lasting consequences of prenatal exposure to anticonvulsant drugs. Pranzatelli MR, Nadi NS; Adv Neurol 67: 329-60 (1995). Mechanism of action of antiepileptic drugs and antimyoclonic drugs. Pacifici GM, Nottoli R; Clin Pharm 28 (3): 235-69 (1995). Placental transfer of drugs administered to the mother. Laurenson IF, et al; Lancet 344: 332-3 (1994). Delayed fatal agranulocytosis in an epileptic taking primidone and phenytoin. Rutherford JM, Rubin PC; Br J Hosp Med 55 (10): 620-2 (1996). Management of epilepsy in preganancy: therapeutic aspects. Morrell MJ; Epilepsia 37 (Suppl 6): S34-44 (1996). The new antiepileptic drugs and women: efficacy, reproductive health, pregnancy and fetal outcome. A review of clinically significant pharmacokinetic drug interactions of carbamazepine is presented, including the pharmacokinetics of carbamazepine, the effect other drugs on carbamazepine absorption, plasma protein binding, and inhibition and inducement of metabolism, and the effect of carbamazepine on the pharmacokinetics of other drugs; drugs mentioned include antidepressants, antibiotics, calcium antagonists, felbamate, phenytoin, phenobarbital, ... primidone, ethosuximide, valproate sodium,newer antiepileptic drugs, benzodiazepines, other psychotropic drugs, oral contraceptives, glucocorticoids, metyrapone, oral anticoagulants, cyclosporine, ... and neuromuscular blocking agents. [R38] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1330 R2: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R3: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 727 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V13 1090 R5: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1018 R6: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 100 R7: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R8: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 279 R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 226 R10: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.345 R11: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1016 R12: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R13: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 608 R14: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R15: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-242 R16: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements). R17: Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams and Wilkins 1994. 717 R18: Kutlay B, el al; Eur J Obstet Gynecol Reprod 65 (2): 245-8 (1996) R19: O'Connor CR, et al; Epilepsia 35 (1): 149-54 (1994) R20: Lindhout D, et al; Neurology 42 (4 Suppl 5): 94-110 (1992) R21: Kotzot D, et al; Teratology 48 (1): 15-19 (1993) R22: Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975. 150 R23: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 482 R24: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R25: Pizzi WJ, et al; Pharmacol Biochem Behav 55 (4): 481-7 (1996) R26: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Primaclone (CAS No. 125-33-7) in CD-1 Swiss Mice, NTP Study No. RACB90009 (November 1991) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R27: Toxicology and Carcinogenesis Studies of Primidone in F344/N Rats and B6C3F1 Mice p.6-8 Technical Report Series No. 476 (2000) NIH Publication No. 00-3966 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R28: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 94 R29: American Society of Hospital Pharmacists. Data supplied on contract from American Hospital Formulary Service and other current ASHP sources. 1974 R30: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R31: Spina E, et al; Clin Pharm 31 (3): 198-214 (1996) R32: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R33: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 139 (1994) R34: 21 CFR 200-299, 300-499, 820, and 860 (4/1/96) R35: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 576 R36: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 313 R37: NANDEDKAR AKN ET AL; CLIN TOXICOL 12: 483 (1979) R38: Spina E, et al; Rev Clin Pharm 31: 198-214 (1996) RS: 40 Record 228 of 1119 in HSDB (through 2003/06) AN: 3173 UD: 200211 RD: Reviewed by SRP on 5/20/1999 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PROMETHAZINE- SY: *A-91033-; *ALLERGAN-; *APROBIT-; *ATOSIL-; *AVOMINE-; *DIMAPP-; *(2-DIMETHYLAMINO-2-METHYL)ETHYL-N-DIBENZOPARATHIAZINE; *N-(2'-DIMETHYLAMINO-2'-METHYL)ETHYLPHENOTHIAZINE; *10-(2-(DIMETHYLAMINO)-2-METHYLETHYL)PHENOTHIAZINE; *N-DIMETHYLAMINO-2-METHYLETHYL-THIODIPHENYLAMINE-; *(DIMETHYLAMINO-2-PROPYL-10-PHENOTHIAZINE HYDROCHLORIDE (FRENCH); *DIPHERGAN-; *FENETAZINE-; *HIBERNA-; *HISTARGAN-; *IERGIGAN-; *PHENOTHIAZINE, 10-(2-DIMETHYLAMINOPROPYL)-; *10H-PHENOTHIAZINE-10-ETHANAMINE,-N,N,ALPHA-TRIMETHYL-; *PHENSEDYL-; *PILPOPHEN-; *PROAZAIMINE-; *PROAZAMINE-; *PROCIT-; *PROMAZINAMIDE-; *PROMETASIN-; *PROMETAZIN-; *PROMETHAZIN-; *PROMETHIAZINE-; *PROMEZATHINE-; *PROREX-; *PROTAZINE-; *PROTHAZIN-; *PROVIGAN-; *PYRETHIA-; *ROMERGAN-; *RP-3277-; *3389-RP-; *4182-RP-; *SKF-1498-; *SYNALGOS-; *TANIDIL-; *THIERGAN-; *N,N,-ALPHA-TRIMETHYL-10H-PHENOTHIAZINE-10-ETHANAMINE-; *VALERGINE-; *VALLERGINE-; *WY-509- RN: 60-87-7 MF: *C17-H20-N2-S ASCH: Promethazine hydrochloride; 58-33-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *From 10-phenothiazinepropyl chloride and dimethylamine in presence of Cu: Charpentier, Compt Rend 225, 306 (1947). [R1] FORM: *Atosil; Fargan; Fenazil; Diprazin; Provigan; Prorex; Diphergan; Ganphen; Fellozine; Remsed; Dorme; Fenergan; Lergigan; Phenergan; Promantine; Protazine; Prothazin; Thiergan. /Promethazine hydrochloride/ [R1] OMIN: *Patents: US patent 2, 530, 451 (1950 to Rhone-Poulenc). [R1] *The phenothiazines ... used in psychiatry have three carbon atoms interposed between position 10 of the central ring and the first amino nitrogen atom of the side chain at this position ... Antihistaminic phenothiazines ... have only two carbon atoms separating the amino group from position 10 of the central ring. [R2, 403] USE: *MEDICATION (VET) *MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crystals [R1]; *WHITE TO FAINT YELLOW CRYSTALLINE POWDER [R3] BP: *190-192 deg C @ 3 mm Hg [R1] MP: *60 deg C [R1] MW: *284.43 [R1] OWPC: *log Kow = 4.81 [R4] PH: *pH= 4-5.5 /Promethazine HCl/ [R5] SOL: *Practically insol in acetone, ether, ethyl acetate [R1]; *Very sol in dil hydrogen chloride [R6]; *In water, 15.6 mg/l @ 24 deg C [R7] SPEC: *IR: 5185 (Coblentz Society Spectral Collection) [R8, p. V2 74]; *MASS: 2-262 (Archives of Mass Spectral Data, John Wiley and Sons, New York) [R8, p. V2 74]; *MASS: 2088 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R8, p. V2 139]; *Intense mass spectral peaks: 72 m/z, 199 m/z, 213 m/z, 284 m/z [R9] OCPP: *Crystals from ethylene dichloride; Soluble in alcohol, chlorform; MP: 230-232 deg C with some decomp; Max absorption: 249 nm; 10[a(249)/a(298)]= 8.0-8.8; Slightly acid to litmus; pH of 10% aq soln 5.3 /HCl/ [R1] *The osmolality of promethazine HCl 25 mg/ml was determined to be 291 mOsm/kg. /Promethazine HCl/ [R5] *PRACTICALLY ODORLESS /HCL/ [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of nitroxides and sulfoxides. [R10] SERI: *A severe eye irritant. [R10] SSL: *In general, promethazine HCl exhibits increasing stability with decreasing pH. /Promethazine HCl/ [R5] *TURNS BLUE ON PROLONGED EXPOSURE TO AIR AND MOISTURE. [R11] STRG: *The product should be stored at controlled room temperature and protected from freezing and light. /Promethazine HCl/ [R5] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *A 16 months old male weighing 11.5 kg who was treated with 2% promethazine cream for generalized eczema. After approximately 15-20 g of the cream had been applied, the child fell asleep. He woke a few hours later with abnormal behavior, loss of balance, inability to focus, irritability, drowsiness, and failure to recognize his mother. One day later all symptoms had disappeared. A diagnosis of promethazine toxicity through percutaneous absorption was made. Known symptoms of promethazine toxicity include disorientation, hallucinations, hyperactivity, convulsions, and coma. [R12] *In adults, overdosage of promethazine may result in deep sleep and coma and, rarely, seizures and cardiorespiratory symptoms. In children, a paradoxical reaction characterized by hyperexcitability, abnormal movements, nightmares, and respiratory depression may occur. A 12 year old patient who had taken 200 mg of the drug exhibited numbness and pain in the left leg, tactile hallucinations, extreme hyperesthesia and hyperalgesia, and sinus tachycardia. [R13, 1983] NTOX: *...1 OF MORE DISTURBING SIDE EFFECTS OF CHLORPROMAZINE, AKATHISIA, IS MANIFESTED BY MARKED INCR IN MOTOR ACTIVITY... SOME PHENOTHIAZINES PRODUCE CATALEPTIC EFFECTS IN ANIMALS SO THAT BODIES AND LIMBS CAN BE MOLDED INTO VARIOUS POSTURES AND REMAIN IMMOBILE FOR LONG PERIODS OF TIME. /CHLORPROMAZINE/ [R14, 159] *... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of promethazine hydrochloride in male or female F344/N rats receiving 8.3, 16.6, or 33.3 mg/kg. There was no evidence of carcinogenic activity of promethazine hydrochloride in male B6C3Fl mice receiving 11.25, 22.5, or 45 mg/kg. There was no evidence of carcinogenic activity of promethazine hydrochloride in female B6C3F1 mice receiving 3.75, 7.5, or 15 mg/kg. /Promethazine hydrochloride/ [R15] NTP: *... Toxicology and carcinogenicity studies were conducted by administering promethazine hydrochloride (> 99% pure) in distilled water by gavage to groups of male and female F344/N rats and B6C3F1 mice for 2 yr. ... 2 YEAR STUDY IN RATS: ... Doses of promethazine hydrochloride selected for the 2 yr study in rats were 0, 8.3, 16.6, and 33.3 mg/kg. Groups of 60 male or 60 female rats were administered promethazine hydrochloride in deionized water by gavage once daily, 5 days/wk for up to 103 wk. ... 2 YEAR STUDY IN MICE: ... The doses of promethazine hydrochloride selected for the 2 yr study were 0, 11.25, 22.5, and 45 mg/kg for male mice and 0, 3.75, 7.5, and 15 mg/kg for female mice. Groups of 60 male or 60 female mice were administered promethazine hydrochloride in deionized water by gavage once daily, 5 days/wk for up to 103 wk. ... CONCLUSIONS Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of promethazine hydrochloride in male or female F344/N rats receiving 8.3, 16.6, or 33.3 mg/kg. There was no evidence of carcinogenic activity of promethazine hydrochloride in male B6C3Fl mice receiving 11.25, 22.5, or 45 mg/kg. There was no evidence of carcinogenic activity of promethazine hydrochloride in female B6C3F1 mice receiving 3.75, 7.5, or 15 mg/kg. /Promethazine hydrochloride/ [R15] ADE: *APPROX HALF OF METABOLITES OF COMMONLY USED PHENOTHIAZINES ARE FOUND IN URINE AND REST IN FECES. ULTIMATE SOJOURN OF PHENOTHIAZINE DRUGS IN BODY IS EXCEEDINGLY LONG. 6 MO AFTER DISCONTINUATION OF THESE DRUGS, VARIOUS METABOLITES ARE DETECTABLE IN URINE. /PHENOTHIAZINES/ [R14, 163] *PHENOTHIAZINE TRANQUILIZERS CROSS PLACENTA RAPIDLY, AND THEY HAVE BEEN MEASURED FOR MANY YR IN URINE AND TISSUES OF NEONATES OF TREATED MOTHERS, BUT VERY LOW BLOOD LEVELS OF MOTHERS AND FETUSES HAVE BEEN MEASURED ONLY RECENTLY... /PHENOTHIAZINES/ [R16, 634] *...(35)S-PROMETHAZINE...READILY CROSSED BIOLOGICAL MEMBRANES... WHOLE-BODY AUTORADIOGRAPHY SHOWED THAT AFTER IM INJECTION INTO MICE.../IT/ WAS PRESENT IN BRAIN.../ and / EXCRETED IN URINE AND BILE. [R17] METB: *FIRST ORDER KINETICS OBSERVED FOR OXIDATION OF PROMETHAZINE HCL IN AQ SOLN. REACTION RATE WAS PH DEPENDENT UP TO PH 5. CU IONS INCR RATES AS DID FE. UNDER ANAEROBIC CONDITIONS, CU AND FE WERE REQUIRED FOR THE REACTION. ISOLATION OF PRODUCTS CARRIED OUT BY TLC. [R18] BHL: *Half-life: 12 hours [R19] ACTN: *...PHENOTHIAZINES, BLOCK DOPAMINE RECEPTORS AND INCR TURNOVER RATE OF DOPAMINE IN CORPUS STRIATUM. INCR TURNOVER RATE IS BELIEVED TO BE RESULT OF NEURONAL FEEDBACK MECHANISM. ...FIRING OF.../IDENTIFIED DOPAMINERGIC NEURONS IN SUBSTANTIA NIGRA AND VENTRAL TEGMENTAL AREAS/ IS INCR BY ANTIPSYCHOTIC PHENOTHIAZINES. /PHENOTHIAZINES/ [R14, 159] INTC: *PENTOBARBITAL METABOLISM IS...INDUCED BY...PROMETHAZINE... [R16, 123] *PHENERGAN POTENTIATES ACTION OF CENTRAL NERVOUS SYSTEM DEPRESSANTS. /PROMETHAZINE HYDROCHLORIDE/ [R20] *REPORTED THAT IN DRUG ABUSERS SURVEY PENTAZOCINE IM + PROMETHAZINE HCL IM OR ORAL GIVES PSYCHOACTIVE EFFECT. [R21] *INCOMPATIBILITY BETWEEN CARBENICILLIN INJECTION AND PROMETHAZINE INJECTION. [R22] *Concurrent use /with alcohol or other CNS depression-producing medications/ may potentiate the CNS depressant effects of either these medications or antihistamines; also, concurrent use of maprotiline or tricyclic antidepressants may potentiate the anticholinergic effects of either antihistamines or these medications. /Antihistamine, phenothiazine-derivative/ [R23, 369] *Concurrent use may decrease stimulant effects of amphetamines since phenothiazine derivatives produce alpha-adrenergic blockade. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Anticholinergic effects may be potentiated when these medications /anticholinergics or other medications with anticholinergic activity/ are used concurrently with antihistamines; patients should be advised to report occurrence of gastrointestinal problems promptly since paralytic ileus may occur with concurrent therapy. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Phenothiazine derivative may lower the convulsion threshold; dosage adjustment of anticonvulsant medications may be necessary; potentiation of anticonvulsant effects does not occur. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of appetite suppressants/ with phenothiazine derivatives may antagonize the anorectic effect of appetite suppressants. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of beta-adrenergic blocking agents, especially propranolol/ with phenothiazine derivatives may result in increased plasma concentrations of each medication because of inhibition of metabolism; this may result in additive hypotensive effects, irreversible retinopathy, cardiac arrhythmias, and tardive dyskinesia. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /with bromocriptine/ may increase serum prolactin concentrations and interfere with effects of bromocriptine; dosage adjustments of bromocriptine may be necessary. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /with dopamine/ may antagonize peripheral vasoconstriction produced by high dose of dopamine because of the alpha-adrenergic blocking action of phenothiazine derivatives. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Alpha-adrenergic blocking action of phenothiazine derivatives may decrease pressor response to these medications /ephedrine or metaraminol or methoxamine/ then used concurrently. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Alpha-adrenergic effects of epinephrine may be blocked when it is used concurrently with phenothiazine derivatives, possibly resulting in severe hypotension and tachycardia. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of other extrapyramidal reaction-causing medications/ with phenothiazine derivatives may increase the severity and frequency of extrapyramidal effects. /Antihistamines, phenothiazine-derivative [R23, 370] *Neuronal uptake of these medications /guanadrel or guanethidine/ may be inhibited when they are used concurrently with phenothiazine derivatives, causing a decrease of their antihypertensive effect. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use of phenothiazine derivatives with other hepatotoxic medications may increase the potential for hepatotoxicity; patients, especially those on prolonged therapy or with a history of liver disease, should be carefully monitored. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of other hypotension-producing medications/ with phenothiazine derivatives may produce additive hypotensive effects. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Antiparkinsonian effects of levodopa may be inhibited when used concurrently with phenothiazine derivatives because of blockade of dopamine receptors in the brain; levodopa has not been shown to be effective in phenothiazine-induced parkinsonism. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of intrathecal metrizamide/ with phenothiazine derivatives may lower the seizure threshold; phenothiazine derivatives should be discontinued at least 48 hours before, and not resumed for at least 24 hours following, myelograpy. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use of MAO inhibitors with antihistamines in general may prolong and intensify the anticholinergic and CNS depressant effects of antihistamines; concurrent use of MAO inhibitors with phenothiazine-derivative antihistamines may increase the risk of hypotension and extrapyramidal reactions; concurrent use is not recommended. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of ototoxic medications/ with antihistamines may mask the symptoms of ototoxicity such as tinnitus, dizziness, or vertigo. /Antihistamines, phenothiazine-derivative/ [R23, 370] *Concurrent use /of quinidine/ with phenothiazine-derivative antihistamines may result in additive cardiac effects. /Antihistamines, phenothiazine-derivative/ [R23, 370] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3(?). 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB). [R20] THER: *Anti-Allergic Agents; Antiemetics; Antipruritics; Histamine H1 Antagonists; Sedatives, Nonbarbiturate [R24] *IT IS EFFECTIVE FOR USE IN PERENNIAL AND SEASONAL ALLERGIC RHINITIS; VASOMOTOR RHINITIS; ALLERGIC CONJUNCTIVITIS DUE TO INHALANT ALLERGENS AND FOODS; MILD, UNCOMPLICATED ALLERGIC SKIN MANIFESTATIONS OF URTICARIA AND ANGIOEDEMA... /PROMETHAZINE HCL/ [R3] *IT IS EFFECTIVE FOR USE IN...AMELIORATION AND PREVENTION OF ALLERGIC REACTIONS TO BLOOD OR PLASMA IN PT WITH KNOWN HISTORY OF SUCH REACTIONS; DERMOGRAPHISM: THERAPY FOR ANAPHYLACTIC REACTIONS ADJUNCTIVE TO EPINEPHRINE AND OTHER STD MEASURES AFTER ACUTE MANIFESTATIONS HAVE BEEN CONTROLLED... /PROMETHAZINE HCL/ [R3] *IT IS EFFECTIVE FOR USE IN...PREOPERATIVE, POSTOPERATIVE OR OBSTETRIC SEDATION; PREVENTION AND CONTROL OF NAUSEA AND VOMITING ASSOC WITH CERTAIN TYPES OF ANESTHESIA AND SURGERY...MOTION SICKNESS... /PROMETHAZINE HCL/ [R3] *MEDICATION (VET): TREATMENT OF ALLERGIC REACTIONS, URTICARIA, PRURITUS, ETC. USEFUL IN AZOTURIA, LAMINITIS, AND LYMPHANGITIS IN HORSES, BLOAT AND ACUTE METRITIS IN CATTLE, AND CONTROL OF ACUTE NEPHRITIS AND MOTION SICKNESS IN DOGS. /PROMETHAZINE HCL/ [R3] *PROMETHAZINE...HAS NO ANTIPSYCHOTIC ACTIVITY... [R14, 159] *HUMAN FETAL MACROPHAGES APPEAR TO MEDIATE RED BLOOD CELL DESTRUCTION IN ERYTHROBLASTOSIS FETALIS: ABILITY OF PROMETHAZINE TO INHIBIT MACROPHAGE BINDING OF ERYTHROCYTES OFFERS EXPLANATION FOR SUCCESS OF THE DRUG IN THIS DISEASE. [R25] *Antihistamines are indicated as adjunctive therapy to epinephrine and other standard measures for anaphylactic reactions after the acute manifestations have been controlled, and to ameliorate the allergic reactions to blood or plasma. /Antihistamines, phenothiazine-derivative; Included in US product labeling/ [R23, 368] *Intravenous administration of promethazine is indicated in special surgical situations (such as repeated bronchoscopy, ophthalmic surgery, and poor-risk patients) in combination with reduced amounts of meperidine or other narcotic analgesics as an adjunct to anesthesia and analgesia. /Included in US product labeling/ [R23, 368] *Promethazine is indicated as an adjunct to analgesics for control of postoperative pain. /Included in US product labeling/ [R23, 368] *Promethazine /is/ indicated for /its/ sedative and hypnotic effect and as adjunct to preoperative and postoperative medication. /Included in US product labeling/ [R23, 368] *Promethazine is indicated in the control of nausea and vomiting associated with certain types of anesthesia and surgery. /Included in US product labeling/ [R23, 368] *Antihistamines are indicated for the relief of sneezing and rhinorrhea associated with the common cold. However, controlled clinical studies have not demonstrated that antihistamines are significantly more effective than placebo in relieving cold symptoms. /Antihistamines, phenothiazine-derivative; Included in US product labeling/ [R23, 368] *Antihistamines are indicated in the symptomatic treatment of perennial and seasonal allergic rhinitis, vasomotor rhinitis, and allergic conjunctivitis due to inhalant allergens and foods. /Antihistamines, phenothiazine-derivative; Included in US product labeling/ [R23, 368] *Antihistamines are indicated for the symptomatic treatment of pruritus associated with allergic reactions and of mild, uncomplicated allergic skin manifestations of urticaria and angioedema, in dermatographism, and in urticaria associated with transfusions. /Antihistamines, phenothiazine-derivative; Included in US product labeling/ [R23, 368] *Promethazine ... is more potent and more effective /as a treatment of motion sickness/ [R2, 592] *ALL /INCL PROMETHAZINE HCL/, BUT TO VARYING DEGREES, PRODUCE SPASMOLYSIS AND LOCAL ANESTHESIA, AND HAVE ANTIFIBRILLATORY ACTION ON MYOCARDIUM. /ANTIHISTAMINES/ [R26] WARN: *NEUROLEPTIC AGENTS ... SHOULD BE USED WITH EXTREME CAUTION, IF @ ALL, IN UNTREATED EPILEPTIC PT AND IN PT UNDERGOING WITHDRAWAL FROM CENTRAL DEPRESSANT DRUGS SUCH AS ALCOHOL, BARBITURATES, OR BENZODIAZEPINES. MOST ANTIPSYCHOTIC DRUGS ... CAN BE USED SAFELY IN EPILEPTICS IF MODERATE DOSES ARE ATTAINED GRADUALLY AND IF CONCOMITANT ANTICONVULSANT DRUG THERAPY IS MAINTAINED. /PHENOTHIAZINES/ [R2, 408] *...PRECAUTIONS SHOULD BE OBSERVED IN USE OF PHENOTHIAZINES FOR NAUSEA AND VOMITING AS WITH USE OF POTENT ANALGESICS IN TREATMENT OF PAIN, BECAUSE THEY MAY MASK DIAGNOSTIC SYMPTOMS IN ACUTE SURGICAL CONDITIONS OR NEUROLOGICAL SYNDROMES. /PHENOTHIAZINES/ [R14, 166] *DROWSINESS IS MOST COMMON COMPLAINT. CASE IS REPORTED OF 2-YR-OLD CHILD WHO INGESTED 250 MG WITH RESULTING CONFUSION, CONVULSIONS, AND STUPOR, BUT EVENTUAL RECOVERY. [R20] *PHENOTHIAZINES INHIBIT EJACULATION WITHOUT INTERFERING WITH ERECTION. /PHENOTHIAZINES/ [R14, 161] *MOST IMPORTANT /EFFECTS/ OF PHENOTHIAZINES ARE THOSE ON THE CNS, CARDIOVASCULAR SYSTEM, AUTONOMIC NERVOUS SYSTEM, AND ENDOCRINE FUNCTIONS. THERAPEUTIC DOSES ... MAY CAUSE FAINTNESS, PALPITATION, ... NASAL STUFFINESS, DRY MOUTH, BLURRED VISION, CONSTIPATION, AND, IN MALES WITH PROSTATISM, URINARY RETENTION. /PHENOTHIAZINES/ [R2, 414] */JAUNDICE/ REACTION IS PROBABLY A HYPERSENSITIVITY REACTION. ... LEUKOCYTOSIS, LEUKOPENIA, AND EOSINOPHILIA OCCUR WITH ANTIPSYCHOTIC MEDICATIONS ... /PHENOTHIAZINES/ [R2, 416] *DERMATOLOGICAL REACTIONS TO PHENOTHIAZINES ARE COMMON. URTICARIA OR DERMATITIS OCCURS IN ABOUT 5% OF PT RECEIVING CHLORPROMAZINE. ... PHOTOSENSITIVITY OCCURS THAT RESEMBLES SEVERE SUNBURN. /PHENOTHIAZINES/ [R2, 417] *PROMETHAZINE...HAS IN 1 WELL-STUDIED CASE PRODUCED ACUTE TRANSITORY MYOPIA...APPARENTLY AS IDIOSYNCRATIC TYPE OF DRUG REACTION... [R27] *Adverse anticholinergic effects of promethazine include dryness of the mouth, blurring of vision and, rarely, dizziness. Confusion and disorientation may also occur. Extrapyramidal reactions may occur with high doses and usually subside with dosage reduction. Lassitude, fatigue, incoordination, tinnitus, diplopia, oculogyric crises, insomnia, excitation, nervousness, euphoria, hysteria, tremors, seizures, and catatonic-like states have been reported. Restlessness, akathisia, and, occasionally, marked irregular respiration have occurred. Patients with pain who have received inadequate or not analgesia have developed athetoid-like movements of the upper extremities following parenteral administration of promethazine. These symptoms usually disappeared when the pain was controlled. [R13, 1982] *Tachycardia, bradycardia, and faintness have been reported with parenteral promethazine. Although rapid IV administration of promethazine may produce a transient fall in blood pressure, blood pressure is usually maintained or slightly elevated when the drug is given slowly. Venous thrombosis at the injection site has also been reported. [R13, 1982] *Promethazine should be used with caution in patients with cardiovascular disease or impaired liver function or patients who are having an asthmatic attack. ... Promethazine should be used with caution, if at all, in patients with sleep apnea. [R13, 1983] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R28] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TLC OF BASIC DRUGS /INCL PROMETHAZINE/ ON SILICA GEL C. [R29] *ANALYSIS OF PROMETHAZINE HCL FORMULATIONS BY HIGH SPEED LIQUID CHROMATOGRAPHY. [R30] *ULTRAVIOLET SPECTROPHOTOMETRIC DETERMINATION IN DRUGS. [R31] *DIFFERENTIAL PULSE POLAROGRAPHIC ASSAY FOR PROMETHAZINE HCL IN DOSAGE FORMS. [R32] *GAS CHROMATOGRAPHY. [R33] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Promethazine Hydrochloride in F344/N Rats and B6C3F1 Mice Technical Report Series No. 425 (1993) NIH Publication No. 94-3156 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1338 R2: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1063 R4: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 150 R5: Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996. 941 R6: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-260 R7: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R9: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.489 R10: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1293 R11: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1009 R12: Marzulli, F.N., H.I. Maibach. Dermatotoxicology 4th ed. New York, NY: Hemisphere Publishing Corp., 1991. 856 R13: McEvoy, G.K. (ed.). American Hospital Formulary Service-Drug Information 98. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements). R14: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R15: Toxicology and Carcinogenesis Studies of Promethazine hydrochloride in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 425 (1993) NIH Publication No. 94-3156 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R16: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. R17: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 51 R18: UNDERBERG WJ; J PHARM SCI 67(AUG) 1128-1138 (1978) R19: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995.,p. 21-6 R20: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-222 R21: BAILEY WJ; JAMA 242(NOV 30) 2392 (1979) R22: OTTERMAN GE, SAMUELSON DW; INCOMPATIBILITY BETWEEN CARBENICILLIN INJECTION AND PROMETHAZINE INJECTION; AM J HOSP PHARM 36(SEP) 1156 (1979) R23: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R24: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R25: GUSDON ET AL; AM J OBSTET GYNECOL 119(JUN) 543-548 (1974) R26: Clarke, E.G., and M. L. Clarke. Veterinary Toxicology. Baltimore, Maryland: The Williams and Wilkins Company, 1975. 142 R27: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 765 R28: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R29: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 442 R30: POUND NJ, SEARS RW; ANALYSIS OF PROMETHAZINE HCL FORMULATIONS BY HIGH SPEED LIQ CHROMATOGRAPHY; CAN J PHARM SCI 8(JUL) 84-88 (1973) R31: CUREA E, MARTINOVICI M; ANN PHARM FR 33(OCT) 505-511 (1975) R32: TEARE FW, YADAV RN; CAN J PHARM SCI 13(JUL) 69-71 (1978) R33: KREYENBUHL ET AL; PHARM ACTA HELV 33(5) 139-142 (1978) RS: 27 Record 229 of 1119 in HSDB (through 2003/06) AN: 3186 UD: 200302 RD: Reviewed by SRP on 5/7/1998 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SULFAMETHOXAZOLE- SY: *3-(P-AMINOPHENYLSULFONAMIDO)-5-METHYLISOXAZOLE; *BENZENESULFONAMIDE, 4-AMINO-N-(5-METHYL-3-ISOXAZOLYL)-; *GANTANOL-; *N(1)-(5-METHYL-3-ISOXAZOLYL)SULFANILAMIDE; *5-METHYL-3-SULFANILAMIDOISOXAZOLE-; *MS-53-; *RADONIL-; *RO-4-2130-; *SINOMIN-; *SULFAMETHALAZOLE-; *SULFAMETHOXAZOL-; *SULFAMETHOXIZOLE-; *SULFAMETHYLISOXAZOLE-; *SULFANILAMIDE, N(1)-(5-METHYL-3-ISOXAZOLYL)-; *3-SULFANILAMIDO-5-METHYLISOXAZOLE-; *SULFISOMEZOLE-; *SULPHAMETHOXAZOLE- RN: 723-46-6 MF: *C10-H11-N3-O3-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *IT IS PRESENTLY MARKETED IN FIXED-DOSE COMBINATION WITH PHENAZOPYRIDINE (AZO GANTANOL) AS URINARY ANTISEPTIC AND ANALGESIC, AND WITH TRIMETHOPRIM. [R1, 1050] *SULFAMETHOXAZOLE, NF (GANTANOL), IS CLOSE CONGENER OF SULFISOXAZOLE ... SULFAMETHOXAZOLE IS AVAIL FOR ORAL USE, AS 500-MG TABLETS AND AS SUSPENSION (100 MG/ML). [R1, 1050] MFS: *Hoffmann-La Roche Inc, Hq, 340 Kingsland St, Nutley, NJ 07110, (201) 235-5000; Production site: Nutley, NJ 07110 [R2] *Napp Chemicals, Inc, Hq, 199 Main St, Lodi, NJ 07644, (201) 773-3900; Production site: Lodi, NJ 07644 [R2] USE: *MEDICATION *MEDICATION (VET) *Sulfanilanilides with 3',5'-halogen substitutions had Ki values 6- to 57-fold lower than the Ki of sulfamethoxazole when tested against dihydropteroate synthase from Toxoplasma gondii. The compounds acted as competitive inhibitors. These compounds were also active against dihydropteroate synthase from Pneumocystis carinii, Mycobacterium avium, and Escherichia coli but were not significantly more active than sulfamethoxazole. The compounds were significantly more active in culture than were a standard agents. Against T. gondii in culture, 50% inhibitory concentrations were 7- to 30-fold lower than that of sulfadiazine; against P. carinii in culture, a concentration of 100 uM caused 33 to 95% inhibition of growth, compared with 9% inhibition with 100 uM sulfamethoxazole. [R3] PRIE: U.S. PRODUCTION: *(1991) Exceeded 5000 lb or US $5000 in value [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM DILUTE ETHANOL [R4]; *WHITE TO OFF-WHITE CRYSTALLINE POWDER [R5]; *Colorless crystalline powder [R6] ODOR: *PRACTICALLY ODORLESS [R5] TAST: *Bitter [R4] MP: *167 DEG C [R4] MW: *253.28 [R4] DSC: *pKa= 6.0 [R7] OWPC: *log Kow= 0.89 [R8] SOL: *PRACTICALLY INSOL IN WATER, ETHER AND CHLOROFORM; 1 G IN 50 ML ALCOHOL AND ABOUT 4 ML ACETONE; DISSOLVES IN HCL HYDROGEN CHLORIDE OR SODIUM HYDROXIDE SOLN THROUGH SALT FORMATION [R5]; *In water, 610 mg/l at 37 deg C. [R9]; *The solubility interactions of trimethoprim and sulfamethoxazole in binary solvents were studied using hexane (n-hexane)-ethyl acetate, ethyl acetate-methyl alcohol (methanol), and methyl alcohol-water as the solve mixtures. When solubilities were obtained for individual components, trimethoprim exhibited solvation in ethyl acetate-methyl alcohol mixtures, while sulfamethoxazole showed weaker solute-solvent interactions in the solvent series. At its peak, the solubility of sulfamethoxazole was about 8 times higher than that of trimethoprim when the drugs were combined. Sulfamethoxazole lowered trimethoprim solubility by 13-74%. Similarly, trimethoprim suppressed sulfamethoxazole solubility by 10-94%. In water, although mutual solubility was reduced, the solubility ratio of trimethoprim to sulfamethoxazole was 1:4 on the mol fraction scale. [R10] SPEC: *Intense mass spectral peaks: 92 m/z, 156 m/z, 172 m/z, 214 m/z. [R11] OCPP: *MP 209-210 DEG C; CRYSTALS FROM ALCOHOL /N4-ACETYLSULFAMETHOXAZOLE/ [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of nitroxides and sulfoxides. [R12] SSL: *STABLE IN AIR [R5] STRG: *Commercially available sulfamethoxazole tablets and oral suspension should be protected from light and stored at a temperature less than 40 deg C, preferably between 15-30 deg C; freezing of the oral suspension should be avoided. [R13] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of sulfamethoxazole. There is limited evidence in experimental animals for the carcinogenicity of sulfamethoxazole. Overall evaluation: Sulfamethoxazole is not classifiable as to its carcinogenicity to humans (Group 3). [R14] HTOX: *EFFECT UPON EYE MOST COMMONLY PRODUCED BY SYSTEMICALLY ADMIN SULFONAMIDE DRUGS HAS BEEN ACUTE AND COMPLETELY REVERSIBLE MYOPIA. /SULFONAMIDES/ [R15] *The case of a 26 yr old patient with fulminant liver failure and acute hemorrhagic pancreatitis secondary to the use of trimethoprim-sulfamethoxazole (Bactrim DS) is reported. Patient presented with skin rash and decreased C3 and C4 levels, which was believed to be due to a hypersensitivity reaction secondary to the sulfonamide component (sulfamethoxazole). This is the first case reported in which sulfamethoxazole-trimethoprim has been implicated as a cause of fulminant liver failure and acute hemorrhagic pancreatitis simultaneously, and emphasizes the need of discontinuing this medication as soon as there is evidence of liver and pancreatic dysfunction. [R16] *A study was carried out to estimate the incidence of erythema multiforme, Stevens Johnson syndrome, and toxic epidermal necrolysis requiring hospitalization and to determine which drug therapies were associated with these reactions. The clinical records of all patients who were hospitalized with these discharge diagnoses at Group Health Cooperative of Puget Sound, Seattle, WA, from 1972 through 1986 were reviewed. During this 14 yr period, an average of about 260,000 persons, with demographic characteristics similar to those of the general population, received their care from Group Health Cooperative, and there were about 25,000 admissions to hospitals per year at the Group Health Cooperative hospitals. Based on International Classification of Diseases-Adapted coding, a total of 61 suspect cases of erythema multiforme, Stevens Johnson syndrome, or toxic epidermal necrolysis were identified from the computerized hospital discharge file. Based on record review and the application of a uniform set of diagnostic criteria, a total of 37 patients (61%) were classified as having erythema multiforme, Stevens Johnson syndrome, or toxic epidermal necrolysis. Of these, 16 cases (43%) were attributed to drugs administered to these patients prior to hospitalization. The overall incidence of hospitalization for erythema multiforme, Stevens Johnson syndrome, or toxic epidermal necrolysis, due to all causes was 4.2 per 10+6 person-years. The incidence of toxic epidermal necrolysis alone due to all causes was 0.5 per 10+6 person-years. The incidence of erythema multiforme, Stevens Johnson syndrome, or toxic epidermal necrolysis associated with drug use were 7.0, 1.8, and 9.0 per 10+6 person-years, respectively, for persons younger than 20 years of age, 20 to 64 years of age, and 65 years of age and older. Drug therapies with reaction rates in excess of 1 per 100,000 exposed individuals include phenobarbital (20 per 100,000), nitrofurantoin (7 per 100,000), sulfamethoxazole and trimethoprim, and ampicillin (both 3 per 100,000), and amoxicillin (2 per 100,000). Overall, our data suggest that cases of erythema multiforme, Stevens Johnson syndrome, or toxic epidermal necrolysis sufficiently severe to require hospitalization are infrequent among outpatients using well-established drug therapies. A continuing challenge is the evaluation of these severe cutaneous reactions that are associated with newly marketed or less frequently prescribed drug therapies. [R17] *The possible teratogenic effect of co-trimoxazole (sulfamethoxazole and trimethoprim, Bactrim, Roche), Septrin or Septra (Burroughs-Wellcome), Sumetrolim (EGIS), was evaluated using the data set of the Hungarian Case-Control Surveillance of Congenital Anomalies. In the study period of 1980 through 1984, 1.25% of pregnant women who had healthy babies (negative control group) were treated with co-trimoxazole during pregnancy. In those who had babies with congenital anomalies the rate of co-trimoxazole use was 2.31%. The case-control analysis showed a significant increase of co-trimoxazole use only in the groups of cleft lip + or - cleft palate and hypospadias. However, drug use was not higher during the critical period in either of the congenital anomaly groups. The distribution of component congenital anomalies in 13 cases affected by multiple congenital anomalies did not show any characteristic pattern. Respiratory and urinary system diseases were mentioned significantly more frequently in pregnancies of index patients' mothers. This analysis did not indicate any teratogenicity of co-trimoxazole. The higher drug use can probably be explained by maternal disorders. [R18] *Inherited defects in detoxification of reactive metabolites of drugs predispose patients to hypersensitivity reactions. Covalent interaction of metabolites with cell macromolecules leads to cytotoxic and immunologic outcomes, manifested clinically by multisystem syndromes with variable organ involvement. Hypothyroidism developed in 5 of 202 patients (age range, 1 to 81 yr) investigated for hypersensitivity reactions to anticonvulsants or sulfonamides shortly after their reaction. None had previous personal or family histories of autoimmune disease. All had low thyroxine levels, elevated levels of thyroid stimulating hormone, and autoantibodies including antimicrosomal antibodies. Patients were 2 to 18 yr of age at presentation, and two were male. All returned to a euthyroid state within a year of presentation, and all remain well. The demographics, clinical presentation, and course of the patients is atypical of idiopathic lymphocytic thyroiditis. The pathogenesis of thyroid toxicity was investigated using the hydroxylamine metabolite of sulfamethoxazole as a model. The hydroxyalmine was toxic to thyroid cells in vitro, which did or did not express thyroid peroxidase activity, whereas the parent sulfonamide was toxic only to cells with active thyroid peroxidase. The purified enzyme converted sulfamethoxazole to the hydroxylamine. Formation of reactive drug metabolites by thyroid peroxidase in a host who is genetically unable to detoxify the metabolites may lead directly to cytotoxicity. Covalent binding to macromolecules, including thyroid peroxidase, also may lead to expression of neoantigens and formation of autoantibodies. Patients who have sustained hypersensitivity reactions to drugs should be investigated for possible involvement of the thyroid. [R19] *Three cases of aseptic meningitis in 3 women, aged 25, 54, and 57 yr, related to the use of trimethoprim in combination with sulfamethoxazole are reported. Two of the patients developed symptoms of meningitis within one day of beginning therapy with trimethoprim-sulfamethoxazole, while the third patient developed meningitis after receiving 4 doses of trimethoprim-sulfamethoxazole. One patient was treated with dexamethasone. The 57 yr old woman inadvertently received trimethoprim-sulfamethoxazole 4 additional times before the combination was identified as the cause of meningitis. Each time symptoms of meningitis recurred. [R20] *Although liver injury after administration of the trimethoprim-sulfamethoxazole combination is rare, hepatocellular necrosis and cholestasis have developed in a few cases. A patient is described who developed a severe, prolonged cholestatic reaction after trimethoprim-sulfamethoxazole administration. The findings from serial liver biopsy samples showed characteristic abnormalities of phospholipidosis that have not been previously described for trimethoprim-sulfamethoxazole related hepatic injury. The most prominent finding on electron microscopic evaluation of the liver was the presence of prominent hepatocyte lysosomal inclusions characterized by concentric arrangements of membranous and lamellated structures. The patient improved after several courses of exchange plasmapheresis, which may have assisted in the removal of toxic drug lipid complexes. The pathogenesis of this acquired secondary phospholipidosis is unknown. Possible mechanisms include generation of highly lipid soluble metabolites and inhibition of the lysosomal enzyme phospholipase A1. [R21] *The photochemical reactions in vitro of sulfamethoxazole alone and in combination with trimethoprim were studied to obtain information on the photosensitization mechanism. Sulfamethoxazole in aqueous solution, on exposure to UVB radiation, generates free radicals and singlet oxygen, with the neutral molecule being at least twice as active as the sulfamethoxazole anion. Photoexcited sulfamethoxazole can participate in electron transfer to cytochrome-c and nitro blue tetrazolium, and sensitizes the peroxidation of linoleic acid and the hemolysis of human erythrocytes, predominantly by a free radical mechanism. Trimethoprim is relatively inactive in the same photochemical systems. [R22] *It has been suggested that the high rates of adverse reactions to sulfonamides among patients with AIDS may be related to an increased sensitivity to reactive drug metabolites among HIV-infected cells. To study this hypothesis, we investigated the toxicity of the hydroxylamine of sulfamethoxazole in HIV-infected and noninfected MOLT-3 cultured human T-lymphoblasts. Toxicity was assessed by trypan blue dye exclusion. The hydroxylamine of sulfamethoxazole produced concentration-dependent toxicity in HIV-infected cells, with marked toxicity seen when HIV-infected cells were incubated with 400 uM of the hydroxylamine (82 +/- 8%); this was significantly greater than the toxicity seen among noninfected cells (p < 0.01). There was no concentration-dependent toxicity seen among noninfected cells or in cells infected with HTLV-I, suggesting that the concentration-dependent toxicity seen was specifically related to HIV infection. HIV-infected cells had significantly lower glutathione concentration than did noninfected cells (p < 0.05). Incubation with the hydroxylamine of sulfamethoxazole produced a concentration-dependent decline in glutathione content that was similar in infected and non-infected cells. Co-incubation with glutathione or N-acetylcysteine significantly reduced the toxicity of hydroxylamine of sulfamethoxazole in HIV-infected cells (p < 0.05). Our data supports the role or reactive sulfonamide metabolites in the pathogenesis of adverse reactions to sulfonamides among patients with AIDS. [R23] NTOX: *Sulfamethoxazole was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Sulfamethoxazole was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.300, 1.000, 3.000, and 10.000 ug/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 ug/plate. [R24] *Sulfonamide idiosyncratic toxicosis has been reported in 28 dogs. Non-septic polyarthritis and fever occurring after 8 to 21 days therapy was the most common manifestation. Of 22 dogs with this syndrome, 7 were Doberman Pinschers. ... It has been demonstrated that microsomes obtained from the liver of a dog were capable of metabolizing sulfamethoxazole to sulfamethoxazole hydroxylamine. Production of sulfamethoxazole hydroxylamine was an NADPH dependent process and the yield was increased by the presence of 1 mmol/l ascorbic acid. Sulfamethoxazole hydroxylamine was toxic to isolated mononuclear leukocyte from mixed breed dogs and Doberman Pinschers. The toxicity of sulfamethoxazole hydroxylamine to mononuclear leukocyte from Dobermans was significantly different from that to mononuclear leukocyte from mixed breed dogs. Mononuclear leukocyte from 7 out of 15 Dobermans (including a dog with a history of an idiosyncratic reaction to a sulfonamide) had an LD50 (concn of sulfamethoxazole hydroxylamine required to produce 50% cytotoxicity in mononuclear leukocyte) less than 100 umol/l, while mononuclear leukocyte from 0 out of 10 mixed breed dogs had an LD50 less than 100 umol/l. These results suggest that the basis for the observed predisposition of Dobermans to sulfonamide idiosyncratic toxicity may be a limited capacity to detoxify the hydroxylamine metabolites of sulfonamides. [R25] *Groups of 25-26 male and 24-25 female Charles River CD rats received 25, 60, 150, 300, or 600 mg/kg bw/day sulfamethoxazole mixed with the diet for 60 weeks, at which time the animals were killed; two groups of 50 rats were kept untreated. At the end of the treatment, some of the animals were sacrificed and thyroid nodules or adenomas were observed in treated males and females combined as follows: 0/2, 7/30, 20/29, 19/27, 23/23. Lung metastases were observed in 4 rats of the three higher dose groups. No thyroid tumors were observed in the two control groups of 28 and 26 rats that were sacrificed. [R26] *Idiosyncratic toxicity associated with sulfamethoxazole (SMX) is thought to be a consequence of bioactivation to the hydroxylamine metabolite (SMX-NOH) and further oxidation to the ultimate reactive metabolite, nitroso-sulfamethoxazole (SMX-NO). To establish the link between the formation of the ultimate reactive metabolite and sulfamethoxazole hypersensitivity, we have undertaken metabolism and immunogenicity studies in the rat by use of sulfamethoxazole and its metabolites. Sufamethoxazole was excreted in urine as N4-acetyl sulfamethoxazole and hydroxylamine metabolite, with approximately 10% remaining unchanged as parent amine. After administration of hydroxylamine metabolite (54 mg x kg(-1)) and nitroso-sulfamethoxazole (10 mg x kg(-1)), 38.3% and 46.1% of the doses, respectively, were excreted in urine as sulfamethoxazole and N4-acetyl sulfamethoxazole, which indicated extensive reduction of these metabolites in vivo. The immunogenic potential of sulfamethoxazole and its metabolites, hydroxylamine metabolite and nitroso-sulfamethoxazole, were assessed in rats by analyzing serum samples for the presence of anti-sulfamethoxazole IgG antibodies during a 4-week dosing period. No antibodies to sulfamethoxazole were detected in either control or sulfamethoxazole-treated rats. In contrast, a high titer of sulfamethoxazole-specific IgG antibody was present in sera from all the rats administered nitroso-sulfamethoxazole, reaching a maximum 14 to 21 days after the initial dose. Rats administered hydroxylamine metabolite only produced a weak IgG response after 3 wk of dosing. These findings indicate that nitroso-sulfamethoxazole is highly immunogenic and may be responsible for the hypersensitivity reactions associated with sulfamethoxazole. Both hydroxylamine metabolite and nitroso-sulfamethoxazole undergo extensive reduction in vivo which may afford protection against sulfamethoxazole toxicity. [R27] *Sixteen Saimiri sciureus monkeys were administered PS-15-atovaquone, PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. The in vitro antimalarial activity of serum against Plasmodium falciparum obtained from these monkeys at 3, 6, and 12 hr after the administration of drug(s) were measured by bioassay and analyzed by Duncan's and Newman-Keul's tests. PS-15-atovaquone was found to be the most effective antimalarial combination, followed by PS-15-sulfamethoxazole, PS-15-dapsone, PS-15 alone, and atovaquone alone. These dual PS-15 combinations are effective combinations and, in particular, PS-15-atovaquone is worthy of further evaluation. [R28] *A model for the in vivo evaluation of antipneumocystis drugs has been developed in SCID mice infected intratracheally with cyropreserved mouse-derived Pneumocystis carinii. The development of a highly reproducible fatal P. carinii pneumonia occurred within 10 weeks (mean survival time +/- SEM = 72.2 +/- 1.2 days). Continuous administration of dexamethasone (2 mg/l in the drinking water) exacerbated the rate of onset of severe p. carinii pneumonia (mean survival time +/- SEM = 63 +/- 1.3 days) in SCID mice. The number of cysts per g of lung homogenate (homogenate counts) were maximal with an inoculum of 20,000 cysts at 6 weeks post infection. Homogenate counts correlated with infection scores (graded assessments of immunofluorescent cysts on lung impression smears) suggesting that infection scoring accurately and rapidly reflects the severity of P. carinii pneumonia in SCID mice. These studies led to the development of a drug screening protocol in which Pneumocystis-free female SCID mice (20-25 g) were started on dexamethasone 7 days prior to IT inoculation with a single dose of 20,000 cysts. Drugs were evaluated either for: a) prophylaxis (continuously from day 1 post infection) or b) treatment (from day 21 post infection)until day 42 post infection, when all mice were killed and infection scores determined. Co-trimoxazole (at 250 mg sulfamethoxazole + 50 mg trimethoprim/kg/day) given in the drinking water was found to be highly effective in both the prophylaxis and treatment of mouse P.carinii pneumonia. [R29] *The pharmacokinetic behavior of sulfamethoxazole and trimethoprim was studied after combined intravenous (i.v.) administration at doses of 20 mg/kg and 4 mg/kg, respectively, and after oral administration at doses of 50 mg/kg and 10 mg/kg. The serum concentration versus time data after i.v. administration were best described by the biexponential equations C =34.77e-2.655.t + 39.03.e-0.241.t for sulfamethoxazole and C = 3.29e-3.878.t + 0.83.e-0.306.t for trimethoprim. Mean biological half-lives of the drugs were 2.89 +/- 0.11 and 2.38 +/- 0.33 hr, respectively. The distribution volumes (V area) were 0.475 +/- 0.026 l/kg (sulfamethoxazole ) and 3.89 +/- 0.61 l/kg (trimethoprim). Orally administered sulfamethoxazole and trimethoprim were rapidly absorbed. The maximum serum concentrations were reached 0.5-1hr after administration. The bioavailability was 81% for sulfamethoxazole and 41% for trimethoprim. [R30] *PS-15 is a novel biguanide folate antagonist that is metabolized in vivo to WR99210, a metabolite that is extremely active in vitro against multi-drug resistant strains of Plasmodium falciparum. When PS-15 was administered in combination with sulfamethoxazole to healthy Saimiri sciureus monkeys, the serum antimalarial activity was considerably greater than that observed in monkeys that received PS-15 alone. Further studies should be carried out to determine the value of PS-15/sulfonamide combinations in the treatment of human malaria infections and in preventing the emergence of drug-resistant parasites. [R31] NTXV: *LD50 Mouse ipr 2300 mg/kg; [R12] *LD50 Mouse oral 2650 mg/kg; [R12] *LD50 Rat ipr 2690 mg/kg; [R12] *LD50 Rat oral 6370 mg/kg; [R12] *LD50 Mice oral 3662 mg/kg; [R32] *Two different studies are described. The first study deals with the elimination of residues of trimethoprim (TMP), sulfatroxazole (STX) and its main metabolite N4-acetyl-sulfatroxazole (N4-acetyl-sulfatroxazole) in pigs. Thirty-six pigs were treated with trimethoprim/sulfatroxazole IM in the neck at a dosage of 16 mg/kg body weight for five days. Groups of four pigs were slaughtered at different time intervals. The study showed that concentration of sulfatroxazole, N4-acetyl-sulfatroxazole and trimethoprim in edible tissues and at the injection sites were below 0.1 ppm on day nine after the last injection. Sulfatroxazole was eliminated the slowest, and sulfatroxazole can therefore be selected as a marker for residues of the trimethoprim/sulfatroxazole formulation in the tissues. The second study deals with irritation aspects of this trimethoprim/sulfatroxazole formulation. Four pigs of 32-35 kg were treated IM with trimethoprim/sulfatroxazole and benzylpenicillin sodium. Each pig received the same injection volume, namely four trimethoprim/sulfatroxazole injections (16 mg/kg body weight per injection site), two in the back and two in the neck muscle, and two benzylpenicillin sodium injections (20,000 I.U./kg body weight per injection site), in the back muscle. All pigs were slaughtered 14 days after treatment and the extent of the irritation was compared. There were no differences between trimethoprim/sulfatroxazole and benzylpenicillin sodium with regard to irritation at the injection site in the back muscle. The irritation in the neck site was statistically less prominent than that in the back muscle and was considered not to affect the quality of the meat; [R33] ADE: *... ITS RATES OF ENTERIC ABSORPTION AND URINARY EXCRETION ARE SLOWER /THAN SULFISOXAZOLE/. [R34, 1060] *DISTRIBUTION OF FREE SULFAMETHOXAZOLE IN TISSUES INCR IN RENAL INSUFFICIENCY, POSSIBLY OWING TO REDUCED BINDING TO SERUM PROTEINS ... . [R35] *SULFONAMIDES ARE ELIMINATED FROM BODY PARTLY AS SUCH AND PARTLY AS METABOLIC PRODUCTS. LARGEST FRACTION IS EXCRETED IN URINE, AND HALF LIFE ... IS THUS DEPENDENT ON RENAL FUNCTION. SMALL AMT ARE ELIMINATED IN FECES AND IN BILE, MILK, AND OTHER SECRETIONS. /SULFONAMIDES/ [R34, 1059] *ALL SULFONAMIDES ARE BOUND IN VARYING DEGREE TO PLASMA PROTEINS, PARTICULARLY TO ALBUMIN. EXTENT ... IS DETERMINED BY HYDROPHOBICITY ... AND ITS PKA ... IN GENERAL, SULFONAMIDE IS BOUND TO SOMEWHAT GREATER EXTENT IN ACETYLATED THAN IN FREE FORM. /SULFONAMIDES/ [R34, 1059] *SULFONAMIDES ARE DISTRIBUTED THROUGHOUT ALL TISSUES OF BODY. ... READILY ENTER PLEURAL, PERITONEAL, SYNOVIAL, OCULAR, AND SIMILAR BODY FLUIDS, AND MAY REACH CONCN THAT ARE 50-80% OF SIMULTANEOUSLY DETERMINED BLOOD CONCN. ... ATTAIN CEREBROSPINAL FLUID CONCN THAT ARE EFFECTIVE IN MENINGEAL INFECTIONS. /SULFONAMIDES/ [R34, 1059] *SULFONAMIDES READILY PASS THROUGH PLACENTA AND REACH FETAL CIRCULATION. EQUILIBRIUM BETWEEN MATERNAL AND FETAL BLOOD IS USUALLY ESTABLISHED WITHIN 3 HR AFTER SINGLE ORAL DOSE. CONCN ATTAINED IN FETAL TISSUES ARE SUFFICIENT TO CAUSE BOTH ANTIBACTERIAL AND TOXIC EFFECTS. /SULFONAMIDES/ [R34, 1059] *... THIS CLASS OF DRUGS IS RAPIDLY AND ADEQUATELY ABSORBED FROM GI TRACT. INDEED, AGENT CAN OFTEN BE FOUND IN URINE WITHIN 30 MIN AFTER ITS ORAL INGESTION. SMALL INTESTINE IS MAJOR SITE OF ABSORPTION, BUT SOME OF DRUG IS ABSORBED FROM STOMACH. /SULFONAMIDES/ [R34, 1059] *In urine, approximately 20% of the sulfamethoxazole present is unchanged drug, 50-70% is the acetylated derivative, and 15-20% is the glucuronide conjugate. [R13] *Sulfamethoxazole is widely distributed into most body tissues. Sulfamethoxazole crosses the placenta. In general, the total serum protein binding of sulfamethoxazole is considered to be 50-70%; the acetylated metabolite of sulfamethoxazole is protein bound to a somewhat greater extent than is the unmetabolized drug. In uremic patients, serum protein binding of sulfamethoxazole is reduced. Sulfamethoxazole has an apparent volume of 10-16 liters. In uremic patients, the apparent volume of distribution of sulfamethoxazole increases substantially; this increase is partly caused by reduced binding of the drug to serum proteins. [R13] *A study was conducted to determine both the pharmacokinetic parameters and the bioavailability of a newly developed trimethoprim and sulfamethoxazole preparation (cotrimoxazole; Kepinol forte), 160 mg trimethoprim and 800 mg sulfamethoxazole, in comparison with a reference preparation after single oral administration of each to 12 healthy subjects. Both dosage forms led to maximum plasma levels of approximately 1250 ng/ml of trimethoprim and about 40 ug/ml of sulfamethoxazole 1.5-2 hr after administration. Plasma half-lives were about 9 hr for trimethoprim and about 8.5 hr for sulfamethoxazole. No marked side effects were observed [R36] *The disposition kinetics of a single oral dose of sulfamethoxazole administered as a 960 mg dose of a combination product with trimethoprim (co-trimoxazole) were studied in 6 healthy male volunteers (aged 23 to 29 yr) and in 15 untreated pulmonary tuberculosis patients. The elimination half-life in healthy volunteers ranged from 8.67 to 13.7 hr and in patients, 6.5 to 13.5 hr. No significant difference in the elimination half-lives were found in healthy male volunteers and untreated patients with pulmonary tuberculosis. [R37] *The pharmacokinetics of an oral tablet of 20 mg/kg/day trimethoprim and 100 mg/kg/day sulfamethoxazole were studied in 12 healthy male subjects (ages 22-32 yr) who received the drugs for 3 days. Five subjects withdrew from the study due to adverse GI and CNS effects. In those who completed the study, mean maximum serum drug levels after the last dose were 13.6, 372 and 50.1 ug/ml for trimethoprim, sulfamethoxazole and N4-acetylsulfamethoxazole, respectively. Mean half-lives were 13.6, 14 and 18.6 hr, respectively. Changes in absolute neutrophil count were significantly correlated with trimethoprim and sulfamethoxazole minimum serum levels and trimethoprim area under the concn time curve. [R38] *...from 25-50% of sulfamethoxazole are excreted in the urine in 24 hr. The rates of excretion and the concentrations...in the urine are significantly reduced in patients with uremia. [R34, 1064] *Utilizing the in vitro human placental model, we studied the placental transfer of trimethoprim and sulfamethoxazole. At trimethoprim concentrations of 7.2 ug/mL, only 1.4 ug/mL was transported across the placenta after 1 hr, and at concentrations of 1.0 ug/mL, one half the usual serum level, only 0.08 ug/mL was transported across the placenta. Maternal concentrations of sulfamethoxazole of 29.6 and 127.7 ug/mL resulted in concentrations of 5.1 and 14.8 ug/mL on the fetal side, respectively. Thus, it would appear that trimethoprim is slowly transported across the placenta and in low concentrations whereas sulfamethoxazole readily crosses the placenta. The combination of these drugs is useful for treatment of bacteriuria. It may also prove to be especially useful for Pneumocystis carinii infections in pregnant women with AIDS. With a half-life of 13 hr for trimethoprim and 6 hr for sulfamethoxazole, the drugs are not likely to achieve toxic levels in the fetal compartment. Thus, it would appear that trimethoprim and sulfamethoxazole may be both efficacious and safe for the treatment of both these infections during pregnancy. [R39] *The suitability of hydrogel beads based on amidated pectin for potential use as colon-specific drug delivery matrices was investigated using indomethacin and sulfamethoxazole as model insoluble and relatively soluble drugs, respectively. Drug release from the beads was a function of media pH and drug loading. In simulated gastric and small intestinal conditions, drug release was greater with the more soluble sulfamethoxazole, but release of both drugs could be reduced to satisfactory levels by the formation of a chitosan polyelectrolyte complex around the beads. All the preparations released drug in simulated colonic conditions within 135 min. It was concluded that a multiparticulate system with suitable drug release characteristics for site-specific colonic delivery can be prepared. [R40] *Bioavailabilities of oral rumen-protected and non-protected formulations of sulfamethoxazole (SMS) were compared in ruminating calves, since in vitro degradation of sulfamethoxazole in ruminal fluid was confirmed. The coated with a gastric-acid-soluble polymer and uncoated formulations were administered to 3 calves through a catheter. Neither formulation could produce sufficient blood concentration of the drug, though the bioavailability of sulfamethoxazole for the coated formulation was higher than that for the uncoated formulation. It was suggested that the rumen-protected drug could improve the bioavailability by escaping from degradation in the rumen, but scarcely attain the effective levels in blood. [R41] *T cells can recognize small molecular compounds like drugs. It is though that covalent binding to MHC bound peptides is required for such a hapten stimulation. Sulfamethoxazole, like most drugs, is not chemically reactive per se, but is thought to gain the ability to covalently bind to proteins after intracellular drug metabolism. The purpose of this study was to investigate how sulfamethoxazole is presented in an immunogenic form to sulfamethoxazole-specific T cell clones. The stimulation of four CD4+ and two CD8+ sulfamethoxazole-specific T cell clones by different antigen-presenting cells (APC) was measured both by proliferation and cytolytic assays. The MHC restriction was evaluated, first, by inhibition using anti-class I and anti-class II mAb, and second, by the degree of sulfamethoxazole-induced stimulation by partially matched antigen-presenting cells. Fixation by antigen-presenting cells was performed with glutaraldehyde 0.05%. The clones were specific for sulfamethoxazole without cross-reaction to other sulfonamides. The continuous presence of sulfamethoxazole was required during the assay period since pulsing of the antigen-presenting cells was not sufficient to induce proliferation or cytotoxicity. Stimulation of clones required the addition of MHC compatible antigen-presenting cells. The antigen-presenting cells could be fixed without impairing their ability to present sulfamethoxazole. Sulfamethoxazole can be presented in an unstable, but MHC-restricted fashion, which is independent of processing. These features are best explained by a direct, noncovalent binding of sulfamethoxazole to the MHC-peptide complex. [R42] *Influence of the particle size of trimethoprim and sulfamethoxazole on the bioavailability of pharmaceutical suspensions for oral use. [R43] *Pharmacokinetics of trimethoprim and sulfamethoxazole after intravenous administration of a unit-dose from an experimental infusion on volunteers. [R44] *To investigate the effect of sulfamethoxazole in combination with trimethoprim on the pharmacokinetics of lamivudine, 14 subjects with human immunodeficiency virus (HIV) infection, ages 25-50 yr, underwent in random order a 2 period study: in treatment A, subjects received a single oral dose of 330 mg of lamivudine tablets and in treatment B, subjects received 800 mg of oral sulfamethoxazole in combination with 160 mg of trimethoprim on days 1-5 and also received 300 mg of oral lamivudine on day 5; blood and urine samples were collected frequently and analyzed for pharmacokinetic parameters in each treatment. A 43% increase in the area under the concentration-time curve and a 35% decrease in renal clearance of lamivudine were observed when coadministered with sulfamethoxazole and trimethoprim. However, trimethoprim and sulfamethoxazole pharmacokinetics were not significantly altered by coadministration with lamivudine. [R45] *The effect of formulation and process variables on the formation of complex coacervates between the oppositely charged polyions, chitosan and type B gelatin, was investigated. The complex formation was rapid and only observed at very diluted chitosan concentrations over a narrow pH range. The optimum chitosan-gelatin ratio was found to be 1:10 to 1:20, above or below which the coacervate yield decreased significantly. The coacervate yield decreased at higher temperatures and increased ionic strength. Complex coacervation was found to be dependent upon the molecular weight and bloom strength of the polymers. Several model compounds, including clofibrate, piroxicam, and sulfamethoxazole, were successfully encapsulated within the chitosan-gelatin coacervates. [R46] *The various sulfonamides show marked differences in disposition characteristics after administration to ruminants. For use in combination with a diaminopyrimidine derivative such as trimethoprim or baquiloprim, it is essential that sulfonamide has similar pharmacokinetic properties in order to obtain optimal synergy. In the present study the pharmacokinetics of sulfamethoxazole, sulfatroxazole, and sulfamerazine were investigated in dwarf goats (n = 6) after IV and intraruminal administration at a dose of 30 mg/kg bodyweight. In addition, the in vitro binding of sulfamerazine to ruminal contents was studied as a possible explanation for a reduced absorption rate. Sulfamethoxazole showed the most rapid absorption after intraruminal administration (mean tmax +/- SD : 0.8 +/- 0.2 hr). However, the drug was rapidly eliminated from the plasma (t1/2 beta: 2.4 +/- 1.5 hr) and the bioavailability was only 12.4 +/- 4.7%, most likely due to an extensive "first-pass" effect. The bioavailability of orally administered sulfamerazine and sulfatroxazole showed the highest plasma peak concentration (26.1 +/- 2.6 mg/l) and the longest plasma half-life (4.7 +/- 1.8 hr) and mean residence time (13.9 +/- 4.5 hr). Sulfamerazine showed considerable binding to rumen contents in vitro. Based on its pharmacokinetic properties sulfatroxazole appears to be a suitable candidate to be used in combination with the more recently developed diaminopyrimidines such as baquiloprim. [R47] *1. The urinary excretion of sulfamethoxazole and its metabolites was compared between healthy volunteers and HIV-seropositive patients in order to get a better understanding of why HIV seropositives are more predisposed to idiosyncratic toxicity of sulfonamides. 2. A single 800 mg oral dose of sulfamethoxazole was administered to seven health volunteers and seven asymptomatic HIV seropositives without previous use of sulfonamides. 3. Urine was collected for 4 days and drug analysis was by HPLC. 4. No difference was observed between seropositive and seronegative individuals in the urinary recovery of sulfamethoxazole, N4-acetyl-, 5-hydroxy-, N4-acetyl-5-hydroxy-sulfamethoxazole and the N1-glucuronide conjugate. However the recovery of the hydroxylamine metabolite of sulfamethoxazole was significantly lower in the HIV seropositives (0.50 +/- 0.51 vs 2.23 +/- 0.85%; 95% CI on the difference, -0.90 to -2.55; P = 0.0006). 5. Sulfamethoxazole hydroxylamine may be a factor in the susceptibility of HIV infected individuals to sulfonamides. [R48] METB: *SULFONAMIDES UNDERGO METABOLIC ALTERATIONS TO VARYING EXTENT IN TISSUES, ESP IN LIVER. BOTH ACETYLATION AND OXIDATION OCCUR. ... IN NEARLY ALL SPECIES, MAJOR METABOLIC DERIVATIVE IS N4-ACETYLATED SULFONAMIDE. /SULFONAMIDES/ [R34, 1059] *YIELDS N4-ACETYLSULFAMETHOXAZOLE IN BEEF. /FROM TABLE/ [R49] *We previously demonstrated the capacity of the hydroxylamine metabolite of sulfamethoxazole (SMX-HA) to inhibit mitogen-induced T-cell proliferation. We studied the interaction of hydroxylamine metabolite of sulfamethoxazole with the immuno-suppressants cyclosporin A (CsA), FK506 and rapamycin. Human peripheral blood mononuclear leukocytes were treated with hydroxylamine metabolite of sulfamethoxazole and combined in culture with cyclosporin A or FK506 or rapamycin. The cells were stimulated with phytohemaglutinin, and phorbol myristate acetate and proliferation was determined by cellular uptake of 3H-thymidine. Using median-effect analysis and concentration reduction index calculations to assess immunosuppressive drug interactions, we produced synergistic immunosuppression by hydroxylamine metabolite of sulfamethoxazole/cyclosporin A and hydroxylamine metabolite of sulfamethoxazole/FK506. Concentration reductions at the 50% inhibitory level of over 46-fold and 64-fold with cyclosporin A and FK506, respectively, were observed with 25 um hydroxylamine metabolite of sulfamethoxazole, and this effect was not associated with reduced cell viability. Hydroxylamine metabolite of sulfamethoxazole failed to augment the suppressive capacity of rapamycin in inhibiting mitogen-induced cellular proliferation. Hydroxylamine metabolite of sulfamethoxazole at immunosuppressive concentrations also failed to interfere with interleukin-2 mRNA transcription and interleukin-2 protein production, which suggests that signaling events proximal to cytokine production are not affected by the metabolite. Synergy between hydroxylamine metabolite of sulfamethoxazole/FK506 and hydroxylamine metabolite of sulfamethoxazole/cyclosporin A suggests that the mechanism(s) of action of reactive sulfonamide metabolites may occur in later stages of lymphocyte activation. [R50] *The in vitro biotransformation of three sulfonamides, trimethoprim and aditoprim, was studied using primary cultures of pig hepatocytes. Incubation of monolayer cultures with sulfadimethoxine (SDM), sulfamethoxazole (SMZ) and 14C-sulfadimidine (SDD) resulted in the formation of the corresponding N4-acetylsulfonamide to different extents, depending upon the molecular structure of the drug. Addition of the acetylsulfonamides to the cells showed that these compounds were deacetylated, each to a different extent. A relatively low degree of acetylation (in case of 14C-sulfadimidine) was paralleled by extensive deacetylation (i.e. AcSDD), whereas extensive acetylation (i.e.sulfamethoxazole) was in concert with minor deacetylation (i.e.AcSMX). The addition of bovine serum albumin to the medium resulted in a decrease in conversion of sulfonamides as well as acetylsulfonamides. The main metabolic pathway of 14C-trimethoprim (TMP) was O-demethylation with subsequent conjugation. Two hydroxy (demethyl) metabolites were formed, namely 3'- and 4'-demethyl trimethoprim, which were both glucuronidated while 3'-demethyl trimethoprim was also conjugated with sulfate. The capacity to form conjugates with either glucuronic acid or sulfate was at least as high as the capacity for O-demethylation since more than 90% of the metabolites were excreted as conjugates in the urine of pigs. Addition of 14C-aditoprim (ADP) to the hepatocytes led to the N-demethylation of 14C-aditoprim to mono-methyl-14C-aditoprim and didesmethyl-14C-aditoprim. During the incubation another three unknown 14C-aditoprim metabolites were formed. In contrast to 14C-trimethoprim, no hydroxy metabolites or conjugated metabolites of aditoprim were formed. These in vitro results were in agreement with the in vivo biotransformation pattern of the studied sulfonamides and trimethoprim in pigs. [R51] *Potentially serious idiosyncratic reactions associated with sulfamethoxazole (SMX) include systemic hypersensitivity reactions and hepatotoxicity. Covalent binding of sulfamethoxazole to proteins subsequent to its N-hydroxylation to form N4-hydroxysulfamethoxazole (SMX-HA) is thought to be involved in the pathogenesis of these reactions. A polyclonal antibody was elicited in rabbits against a sulfamethoxazole--keyhole limpet hemocyanin conjugate that recognized covalent protein adducts of sulfamethoxazole in microsomal protein and was used to characterize the covalent binding of sulfamethoxazole and its putative reactive metabolites to hepatic protein in vivo and in vitro. In vitro covalent binding of sulfamethoxazole to rat and human liver microsomal protein was NADPH-dependent, while binding of N4-hydroxysulfamethoxazole was not dependent on NADPH. sulfamethoxazole and N4-hydroxysulfamethoxazole produced similar patterns of covalent binding, with major protein targets in the region of 150, 100 (two bands), 70 (two bands), and 45-55 kDa. The pattern of covalent binding to human and rat liver microsomal protein was similar. Binding of N4-hydroxysulfamethoxazole was completely eliminated by GSH or by addition of cytosolic fractions and acetylcoenzyme A. The acetoxy metabolite of sulfamethoxazole also led to covalent binding, but it was primarily attributable to the formation of N4-hydroxysulfamethoxazole from acetoxysulfamethoxazole. In vivo exposure of rats to sulfamethoxazole did not results in detectable covalent binding by the methods employed. When rat liver slices were incubated with 2 mM sulfamethoxazole or 500 uM N4-hydroxysulfamethoxazole, no toxicity was observed and yet covalent binding of N4-hydroxysulfamethoxazole to 130, 100, 70, and 55 kDa proteins could be detected. These results confirm that covalent binding of sulfamethoxazole occurs via the formation of N4-hydroxysulfamethoxazole and that covalent binding of N4-hydroxysulfamethoxazole in vitro results from its conversion to the more reactive nitroso metabolite. Acetylation of N4-hydroxysulfamethoxazole protected against its covalent binding. Further studies are required to determine how this in vitro covalent binding related to in vivo covalent binding in humans and to either direct of immune-mediated cytotoxicity in sulfamethoxazole idiosyncratic drug reactions. [R52] *Two different studies are described. The first study deals with the elimination of residues of trimethoprim (TMP), sulfatroxazole (STX) and its main metabolite N4-acetyl-sulfatroxazole (N4-acetyl-sulfatroxazole) in pigs. Thirty-six pigs were treated with trimethoprim/sulfatroxazole IM in the neck at a dosage of 16 mg/kg body weight for five days. Groups of four pigs were slaughtered at different time intervals. The study showed that concentration of sulfatroxazole, N4-acetyl-sulfatroxazole and trimethoprim in edible tissues and at the injection sites were below 0.1 ppm on day nine after the last injection. Sulfatroxazole was eliminated the slowest, and sulfatroxazole can therefore be selected as a marker for residues of the trimethoprim/sulfatroxazole formulation in the tissues. The second study deals with irritation aspects of this trimethoprim/sulfatroxazole formulation. Four pigs of 32-35 kg were treated IM with trimethoprim/sulfatroxazole and benzylpenicillin sodium. Each pig received the same injection volume, namely four trimethoprim/sulfatroxazole injections (16 mg/kg body weight per injection site), two in the back and two in the neck muscle, and two benzylpenicillin sodium injections (20,000 I.U./kg body weight per injection site), in the back muscle. All pigs were slaughtered 14 days after treatment and the extent of the irritation was compared. There were no differences between trimethoprim/sulfatroxazole and benzylpenicillin sodium with regard to irritation at the injection site in the back muscle. The irritation in the neck site was statistically less prominent than that in the back muscle and was considered not to affect the quality of the meat. [R33] *Antibody- can cell-mediated responses to sulfamethoxazole (SMX) were analyzed in AIDS patients with or without a history of hypersensitivity and in negative controls. In 20 of 20 (P < 0.01) human immunodeficiency virus (HIV)-seropositive patients with skin reactions to cotrimoxazole, we found sulfamethoxazole-specific antibodies, while only 9 of 20 and 17 of 20 HIV-seropositive patients without a history of hypersensitivity to cotrimoxazole had sulfamethoxazole-specific immunoglobulin M (IgM) and IgG, respectively. The levels of specific immunoglobulin M (IgM) and IgG were higher in patients with skin reactions than in patients without reactions (immunoglobulin M, 1.0 +/- 0.19 vs 0.47 +/- 0.23 [P < 0.001]; IgG, 0.68 +/- 0.15 vs 0.47 +/- [P < 0.001] [mean optical density values +/- standard deviations]). Seronegative controls with no history of exposure to sulfa compounds did not have sulfamethoxazole-specific IgG or immunoglobulin M antibodies, and controls with a history of intake of sulfamethoxazole with or without reactions had low levels of IgG or immunoglobulin M. The sulfamethoxazole-specific IgG subclasses were exclusively IgG1 and IgG3. None of the patients had detectable sulfamethoxazole-specific IgE of IgA antibodies nor did they exhibit a cell-mediated response as measured by a lymphocyte proliferation assay. Antibodies to sulfamethoxazole recognized N-acetyl-sulfonamide, N-(2-thiazolyl)-sulfanilamide, sulfadiazine, and sulfisoxazole but did not recognize sulfanilamide or 3-amino-5-methyl isoxazole in an inhibition assay. It is not know whether the sulfamethoxazole-specific antibodies associated with hypersensitivity reactions to sulfamethoxazole in HIV-seropositive patients have a pathogenic role in these reactions. [R53] *There is evidence that T lymphocytes play a critical role in the pathogenesis of drug-induced bullous exanthems. Sulfonamides are known to be among the most frequent aetiological agents in these sever drug-induced cutaneous hypersensitivity reactions. Several studies indicate that cytochrome P450-dependent metabolites of sulfonamides act as the nominal allergens. A 70-yr old woman with a severe blistering exanthem caused by cotrimoxazole (sulfamethoxazole and trimethoprim) was studied. We employed an in vitro approach to determine whether cytochrome P450-dependent enzymes activated drug-specific T lymphocytes from this patient. Immunohistochemical analysis of involved skin revealed a majority of epidermal CD8+ T lymphocytes, whereas the dermal infiltrate was composed of both CD4+ and CD8+ T cells. Dermal T lymphocytes isolated from lesional skin proliferated in response to sulfamethoxazole, but not to trimethoprim, in the presence of autologous mononuclear cells used as antigen-presenting cells. The antigen-specific response of sulfamethoxazole-specific T cells was significantly augmented in the presence of murine liver microsomes with P450-dependent catalytic activities. Our observations suggest that some cutaneous hypersensitivity reactions to sulfamethoxazole are due to drug-specific T lymphocytes. Cytochrome P450-dependent enzymes may play a critical role in the formation of the nominal antigen, which is recognized by antigen-specific T cells. [R54] *Variation in the formation and disposition of the hydroxylamine of (SMX-HA) is though to play an important role in the pathogenesis of sulfamethoxazole (SMX)-induced idiosyncratic adverse drug reactions. We hypothesized that, in analogy to carcinogenic arylamines, N4-hydroxysulfamethoxazole might be further converted to an electrophilic N-acetoxy metabolite which could play a role in mediating sulfamethoxazole toxicity. Accordingly, we chemically synthesized N-acetoxy-sulfamethoxazole, and examined the characteristics of its formation, metabolism, cytotoxicity and mutagenicity in human and bacterial test systems. The human arylamine N-acetyl-transferases, NAT1 and NAT2, were capable of converting N4-hydroxysulfamethoxazole to N-acetoxy-sulfamethoxazole. NAT1 and NAT2 possessed similar affinities for N4-hydroxysulfamethoxazole (apparent Km values of 650 and 520 uM, respectively), but the apparent maximal velocity of the NAT1-mediated acetylation was higher than that of NAT2 (1332 vs 37 nmol/min/U of immunoreactive NAT protein). Human peripheral blood mononuclear cells 12,000 x g supernatant fractions converted N-acetoxy-sulfamethoxazole mainly back to N4-hydroxysulfamethoxazole, and also to a lesser extent to sulfamethoxazole, at clinically relevant concentrations. Similar pathways were observed in human hepatic cytosolic fractions. In a cytotoxicity assay, N-acetoxy-sulfamethoxazole was significantly more toxic to human peripheral blood mononuclear cells than N4-hydroxysulfamethoxazole (16.6 vs 11.5% dead cells at a concentration of 300 uM). N-acetoxy-sulfamethoxazole was weakly mutagenic to the Salmonella typhimurium TA100 strain in the Ames test. These data suggest that the N-acetoxy metabolites of sulfonamides could potentially play a role in mediating sulfonamide idiosyncratic adverse drug reactions. [R55] *It has been suggested, on the basis of work in cell-free systems, that sulfonamide hydroxylamines are metabolized to nitroso metabolites which may be the proximate toxins mediating sulfonamide hypersensitivity reactions. We performed time-course experiments investigating the toxicity of the hydroxylamine and nitroso derivatives of sulfamethoxazole to investigate this hypothesis. The nitroso derivative of sulfamethoxazole was significantly more toxic than the hydroxylamine derivative (P < 0.05). When the LC50 was compared over time, there was a significant decrease in the LC50 of the hydroxylamine of sulfamethoxazole over time, while there was no change in the LC50 of the nitroso derivative. There was an equivalent reduction in toxicity demonstrated when the hydroxylamine or nitroso derivatives were co-incubated with glutathione. This supports the role of the nitroso as a proximate toxin mediating sulfonamide hypersensitivity reactions and suggests as an explanation for the high rate of adverse reactions to sulfonamides among patients with AIDS. [R56] *We measured the urine concentrations of sulfamethoxazole, sulfamethoxazole hydroxylamine, and N-sulfamethoxazole on days 3 and 10 in 15 patients with acquired immunodeficiency syndrome treated with a combination product of trimethoprim (15 mg/kg/day) and sulfamethoxazole (75 mg/kg/day). The percentage of sulfamethoxazole and metabolites excreted on days 3 and 10, respectively, were sulfamethoxazole 17.2% +/- 11.3% vs 15.6% +/- 8.2%; sulfamethoxazole hydroxylamine 2.6+/- 2.0% vs 5.0% +/- 5.2% (p < 0.05); N-acetylsulfamethoxazole 80.0% +/- 12.9% vs 79.8% +/- 11.8%. The percentage of sulfamethoxazole hydroxylamine excreted was similar between the eight patients who discontinued therapy because of toxicity and the seven patients who did not (2.9% +/- 2.3% vs 2.3% +/- 2.0%, p = 0.7). In two patients who had major liver toxicity the percentage of sulfamethoxazole hydroxylamine excreted was significantly lower than that of the 13 patients who did not (0.8% +/- 0.1% vs 2.9% +/- 2.0%, p < 0.05). This is the first report of the formation and excretion of sulfamethoxazole hydroxylamine in patients with acquired immunodeficiency syndrome. With 15 patients we were unable to show a significant correlation between the percentage of sulfamethoxazole hydroxylamine excreted and adverse reactions. However, patients with liver toxicity excreted less sulfamethoxazole hydroxylamine. [R57] BHL: *HALF LIFE OF SULFAMETHOXAZOLE IN BABIES DURING FIRST 10 DAYS OF LIFE IS CONSIDERABLY LONGER THAN IN ADULTS. IT FALLS RAPIDLY, BEING ABOUT 9 HR @ 3 WK OF AGE AND 4-5 HR @ 1 YR. IT THEN INCR TOWARD HALF LIFE CHARACTERISTIC FOR ADULTS, NAMELY, 10-11 HR. [R34, 1060] *In individuals with normal renal function, the elimination half-life of sulfamethoxazole is 7-12 hours. The elimination half-life of sulfamethoxazole begins to increase appreciably when the creatinine clearance rate decreases to about 30 ml/minute, and in patients with creatinine clearances of less than 10 ml/minute, a half-life of 22-50 hours has been reported. [R13] ACTN: *MOST FRUITFUL THEORY OF MECHANISM OF ACTION OF SULFONAMIDES IS KNOWN AS WOODS-FILDES THEORY. /SULFONAMIDES/ [R58, 1115] */SULFONAMIDE INHIBITS BACTERIAL GROWTH BY PREVENTING PARA-AMINOBENZOIC ACID FROM BEING INCORPORATED/ INTO DIHYDROPTEROIC ACID, THE IMMEDIATE PRECURSOR OF FOLIC ACID. SENSITIVE MICROORGANISMS ARE THOSE THAT MUST SYNTHESIZE THEIR OWN FOLIC ACID; BACTERIA THAT CAN UTILIZE PREFORMED FOLATE ARE NOT AFFECTED. BACTERIOSTASIS INDUCED BY SULFONAMIDES IS COUNTERACTED BY PABA COMPETITIVELY. SULFONAMIDES DO NOT EFFECT MAMMALIAN CELLS BY THIS MECHANISM, SINCE THEY REQUIRE PREFORMED FOLIC ACID AND CANNOT SYNTHESIZE IT. /SULFONAMIDES/ [R1, 1048] *Sulfonamides are broad-spectrum, bacteriostatic anti-infectives. They are structural analogs of para-aminobenzoic acid and competively inhibit a bacterial enzyme, dihydropteroate synthetase, that is responsible for incorporation of para-aminobenzoic acid into dihydrofolic acid. This blocks the synthesis of dihydrofolic acid and decreases the amount of metabolically active tetrahydrofolic acid, a cofactor for the synthesis of purines, thymidine, and DNA. /Sulfonamides/ [R59] *VISUAL DISTURBANCES HAVE IN A FEW CASES BEEN ATTRIBUTED TO EFFECTS OF SULFONAMIDES ON THE OPTIC NERVE OR RETINA. /SULFONAMIDES/ [R15] *The hydroxylamine and nitroso metabolites formed by N4-oxidation of sulfonamides are thought to be involved in the pathogenesis of idiosyncratic reactions to this class of drugs. Idiosyncratic reactions to sulfonamides are characterized by multisystemic toxicity, including hepatitis, nephritis, dermatitis, and blood dyscrasias (aplastic anemia, agranulocytosis). Previously it has been shown that cytochrome p-450 in the liver metabolizes sulfamethoxazole to its hydroxylamine metabolite. In this paper the N4-oxidation of sulfamethoxazole by activated monocytes and neutrophils (human and canine) to form sulfamethoxazole hydroxylamine and nitrosulfamethoxazole is reported. The presumed nitroso intermediate was not detected. Purified myeloperoxidase and prostaglandin H synthase were also capable of mediating the oxidation of sulfamethoxazole. The present studies suggest that myeloperoxidase is responsible for the observed oxidation by phagocytic cells. Oxidation by neutrophils may play a role in agranulocytosis, and oxidation by monocytes may facilitate antigen presentation. Extrahepatic bioactivation of sulfonamides by peroxidases in phagocytic cells and other tissues may be important in determining the range of adverse reactions to sulfonamides that occur. [R60] *SULFONAMIDES ARE STRUCTURAL ANALOGS AND COMPETITIVE ANTAGONISTS OF PARA-AMINOBENZOIC ACID (PABA), AND THUS PREVENT NORMAL BACTERIAL UTILIZATION OF PABA FOR THE SYNTHESIS OF FOLIC ACID (PTEROYLGLUTAMIC ACID, PGA). /SULFONAMIDES/ [R34, 1058] *...SULFONAMIDES ARE COMPETITIVE INHIBITORS OF BACTERIAL ENZYME RESPONSIBLE FOR THE CORPORATION OF PABA /PARA-AMINOBENZOIC ACID/ INTO DIHYDROPTEROIC ACID, THE IMMEDIATE PRECURSOR OF FOLIC ACID. SENSITIVE MICROORGANISMS ARE THOSE THAT MUST SYNTHESIZE THEIR OWN PGA /PTEROYLGLUTAMIC ACID/. /SULFONAMIDES/ [R34, 1058] *We previously demonstrated the capacity of the hydroxylamine metabolite of sulfamethoxazole (SMX-HA) to inhibit mitogen-induced T-cell proliferation. We studied the interaction of hydroxylamine metabolite of sulfamethoxazole with the immuno-suppressants cyclosporin A (CsA), FK506 and rapamycin. Human peripheral blood mononuclear leukocytes were treated with hydroxylamine metabolite of sulfamethoxazole and combined in culture with cyclosporin A or FK506 or rapamycin. The cells were stimulated with phytohemaglutinin, and phorbol myristate acetate and proliferation was determined by cellular uptake of 3H-thymidine. Using median-effect analysis and concentration reduction index calculations to assess immunosuppressive drug interactions, we produced synergistic immunosuppression by hydroxylamine metabolite of sulfamethoxazole/cyclosporin A and hydroxylamine metabolite of sulfamethoxazole/FK506. Concentration reductions at the 50% inhibitory level of over 46-fold and 64-fold with cyclosporin A and FK506, respectively, were observed with 25 um hydroxylamine metabolite of sulfamethoxazole, and this effect was not associated with reduced cell viability. Hydroxylamine metabolite of sulfamethoxazole failed to augment the suppressive capacity of rapamycin in inhibiting mitogen-induced cellular proliferation. Hydroxylamine metabolite of sulfamethoxazole at immunosuppressive concentrations also failed to interfere with interleukin-2 mRNA transcription and interleukin-2 protein production, which suggests that signaling events proximal to cytokine production are not affected by the metabolite. Synergy between hydroxylamine metabolite of sulfamethoxazole/FK506 and hydroxylamine metabolite of sulfamethoxazole/cyclosporin A suggests that the mechanism(s) of action of reactive sulfonamide metabolites may occur in later stages of lymphocyte activation. [R50] *Objective and design: To better understand how T cells react o small compounds, we investigated the in vitro T cell reactivity to drugs from drug allergic patients. Material and subjects: Peripheral blood mononuclear cells (PBMC) of three drug allergic individuals were stimulated in vitro by different drugs. Methods: Proliferation was assayed by 3H-thymidine incorporation. Upregulation of activation parameter on T cells was done by immunofluorescence and cytokine release determined via standard ELISA. Results: Drugs can stimulate both CD4 and CD8 T cell subsets. PenG-stimulated peripheral blood mononuclear cells showed a heterogenous cytokine pattern and clones secreted high amounts of INF gamma. In contrast, sulfamethoxazole and lidocaine-stimulated peripheral blood mononuclear cells secreted high levels of IL-5 and lidocaine-specific clones can be Th1 or Th2-like. Conclusion: Drug specific T cells play a pivotal role in drug hypersensitivity reactions, both by regulating the immune response and probably also as specific effector cells with different patterns of cytokine release. [R61] INTC: *... SERUM GLUCOSE LEVELS SHOULD BE OBTAINED FOR DIABETIC PATIENT TAKING SULFONYLUREAS AND SULFONAMIDES CONCURRENTLY TO DETERMINE IF ALTERNATIVE DRUGS SHOULD BE USED OR IF REDN IN DOSE OF SULFONYLUREA IS REQUIRED. /SULFONAMIDES/ [R62, 250] *METHOTREXATE TOXICITY MAY BE INCR BY CONCURRENT ADMIN OF SULFONAMIDES ... . /SULFONAMIDES/ [R62, 391] *... SULFONAMIDES MAY BE AFFECTED BY CONCURRENT USE OF PROBENECID OR SULFINPYRAZONE. /SULFONAMIDES/ [R62, 392] *SALICYLATES REPORTEDLY INCR SERUM SULFONAMIDE LEVELS, PRESUMABLY BY DISPLACEMENT FROM PLASMA PROTEIN BINDING SITES. /SULFONAMIDES/ [R62, 342] *PARA-AMINOBENZOIC ACID IS MOST PROMINENT AMONG SULFONAMIDE ANTAGONISTS. CERTAIN LOCAL ANESTHETICS THAT CONTAIN PARA-AMINOBENZOIC ACID ANTAGONIZE THESE DRUGS IN VITRO AND IN VIVO. /SULFONAMIDES/ [R1, 1048] *ONE OF MOST ACTIVE AGENTS THAT EXERTS SUPRA-ADDITIVE EFFECT WHEN USED WITH SULFONAMIDE IS TRIMETHOPRIM. /SULFONAMIDES/ [R1, 1048] *... ADDITIVE EFFECT WHEN SULFONAMIDE IS COMBINED WITH BACTERIOSTATIC AGENTS SUCH AS TETRACYCLINES AND EITHER ANTAGONISTIC OR SUPRA-ADDITIVE EFFECT WHEN BACTERIA ARE EXPOSED SIMULTANEOUSLY TO SULFONAMIDES AND BACTERICIDAL ANTIBIOTIC. /SULFONAMIDES/ [R1, 1048] *SULFONAMIDES HAVE BEEN REPORTED TO ENHANCE EFFECTS OF ORAL ANTICOAGULANTS ... . /SULFONAMIDES/ [R62, 364] *A study of the effects of albuterol (salbutamol; Cibutamol) on the absorption and disposition of sulfamethoxazole was conducted in 6 healthy volunteers (aged 20-24 yr) who received pretreatment with 4 mg of albuterol 4 times daily for 2 wk, followed by 800 mg albuterol, administered in combination with trimethoprim (Scanprin). The half-life, volume of distribution, and renal and hepatic clearance rates of sulfamethoxazole were not significantly altered by albuterol. However, the absorption rate constant of sulfamethoxazole was significantly altered and was associated with prolongation of the time to reach maximum plasma concn. The maximum plasma concn of sulfamethoxazole was not correspondingly reduced, probably due to a significant increase in the extent of sulfamethoxazole absorption. It was concluded that albuterol did not significantly induce hepatic N-acetyltransferase enzyme, but did reduce the absorption rate and increase the extent of absorption of sulfamethoxazole. [R63] *The utilization of zidovudine in a hospital in the Netherlands was studied, with emphasis on its use in combination with other agents and drug interactions. Antimicrobial agents and central nervous system drugs were frequently combined with zidovudine. Leukopenia and neutropenia were the most frequent clinical abnormalities during treatment with low doses of zidovudine. Only a combination of zidovudine with sulfamethoxazole-trimethoprim (co-trimoxazole) was associated with a higher incidence of granulocytopenia. Patients with acquired immunodeficiency syndrome seemed to have lower plasma levels of phenytoin than other patients, perhaps due to an interaction with zidovudine. [R64] *Increased concn of free phenytoin in serum, attributable to the displacement of this anticonvulsant by other drugs, eg, valproic acid and salicylic acid, have been reported. In vitro and in vivo displacement of phenytoin by the antibiotics ceftriaxone, nafcillin, and sulfamethoxazole was observed. In vitro studies demonstrated statistically significant (P < 0.05) increases in free phenytoin after the addition of specific antibiotics to patients' sera and to phenytoin-supplemented sera from controls. Concn of free phenytoin in vivo, predicted by an equation we have found to be accurate for albumin concn greater than or equal to 32 g/l, were consistently underestimated in patients receiving concomitant therapy with the antibiotics studied. The concn of free phenytoin decreased towards the predicted values when the antibiotic therapy was discontinued. It was concluded that ceftriaxone, nafcillin, and sulfamethoxazole can displace phenytoin from the usual protein carriers found in serum, in vitro and in vivo. [R65] *The pharmacokinetics of nifedipine and its primary oxidized metabolite, 2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (B-4759), were studied in 9 healthy male volunteers, aged 18 to 23 yr, following a single oral dose of 20 mg nifedipine (Adalat) capsule alone or after pretreatment with 960 mg oral co-trimoxazole (sulfamethoxazole, combination, trimethoprim; Septrin) twice daily for 3 days. Following pretreatment with co-trimoxazole, no significant effect was detected on maximum plasma concn, elimination half-life, or area under the plasma concn-time curve of either nifedipine or its metabolite, nor on the blood pressure response to nifedipine. [R66] *The effects of sulfamethoxazole-trimethoprim on the pharmacokinetics of methotrexate were studied in 9 pediatric patients 7 males; aged 2-11 yr with acute lymphoblastic leukemia who received 175 mg/sq m iv or 20 mg/sq m oral methotrexate and sulfamethoxazole-trimethoprim on the first 3 days of the wk or on alternate days, at doses of 2-3 mg/kg/day. Mercaptopurine, 6-mercaptopurine, vincristine and prednisone were administered concomitantly. There was an increase in free methotrexate fraction during sulfamethoxazole-trimethoprim therapy in all patients from 37.4+ or -11% to 52.2+ or -6.4%. Plasma clearance of total methotrexate did not change significantly, whereas clearance of free drug decreased significantly. There was a consistent decrease in the renal clearance of methotrexate from 12.1+ or -6.8 to 5.6+ or -2.4 ml/kg/min. The elimination half-life of the drug was not significantly affected by sulfamethoxazole-trimethoprim. There was a significant correlation between serum levels of sulfamethoxazole-trimethoprim and the percentage of decrease in the renal clearance of free methotrexate. The changes in protein binding and clearance resulted in a mean 66% increase in systemic exposure to methotrexate. It was concluded that sulfamethoxazole-trimethoprim causes a mean 66% increase in systemic exposure to free methotrexate, corresponding to a mean 40% decrease in free methotrexate clearance. [R67] *The disposition of a combination of sulfamethoxazole and trimethoprim (Septra), after constant rate intravenous administration (10 mg/kg/hr sulfamethoxazole and 2 mg/kg/hr trimethoprim) for 1 hr, was investigated in 7 adult patients with cystic fibrosis, aged 21-29 yr, and was compared with that in 8 healthy control subjects, aged 22-27 yr. Blood samples were obtained before infusion, at 15 and 30 min, and at intervals up to 24 hr after the beginning of drug administration. The total plasma clearance of sulfamethoxazole and trimethoprim was found to be increased in patients with cystic fibrosis when compared with that in control subjects. For sulfamethoxazole, this was attributable to an increase in the metabolic clearance to N4-acetylsulfamethoxazole with the renal clearance remaining unchanged; the increase in trimethoprim clearance was found to be attributable to an increase in the renal clearance. It was concluded that the total plasma clearance of both sulfamethoxazole and trimethoprim was increased in cystic fibrosis patients compared to age-matched healthy control subjects. [R68] *Sulfonamides have been reported to augment the hypoglycemic effects of chlorpropamide, glyburide, and tolbutamide. This case report is the first to describe a possible interaction with glipizide. An 83 yr old man receiving glipizide 10 mg bid (twice a day) developed symptomatic hypoglycemia within three days of adding trimethoprim/sulfamethoxazole to his regimen. All other factors, including laboratory data, dietary intake, activity level, and concurrent use of other medications, were stable and noncontributory. This patient may have been at increased risk for this interaction secondary to his age and history of alcohol abuse. The mechanism of the interaction is probably inhibition of glipizide metabolism rather than protein-binding displacement. This case suggests that, when trimethoprim/sulfamethoxazole is combined with glipizide, patients should be closely monitored, especially those at high risk for hypoglycemia. [R69] *These medications /coumarin- or indandione-derivative anticoagulants; hydantoin anticonvulsants or oral antidiabetic agents/ may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy. /Sulfonamides/ [R70, 2695] *Concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered. /Sulfonamides/ [R70, 2695] *Concurrent long-term use of sulfonamides /with estrogen-containing, oral contraceptives/ may result in increased incidence of breakthrough bleeding and pregnancy. /Sulfonamides/ [R70, 2695] *Concurrent use /of cyclosporine/ with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentration and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored. /Sulfonamides/ [R70, 2695] *Concurrent use /of hemolytics/ with sulfonamides may increase the potential for toxic side effects. /Sulfonamides/ [R70, 2695] *Concurrent use /of hepatotoxic medications/ with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored. /Sulfonamides/ [R70, 2695] *In acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended. /Sulfonamides/ [R70, 2695] *The effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations. /Sulfonamides/ [R70, 2695] *Since bacteriostatic drugs amy interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy. /Sulfonamides/ [R70, 2695] *These medications /coumarin- or indandione-derivative anticoagulants; hydantoin anticonvulsants or oral antidiabetic agents/ may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy. /Sulfonamides/ [R70, 2695] *Concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered. /Sulfonamides/ [R70, 2695] *Concurrent long-term use of sulfonamides /with estrogen-containing, oral contraceptives/ may result in increased incidence of breakthrough bleeding and pregnancy. /Sulfonamides/ [R70, 2695] *Concurrent use /of cyclosporine/ with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentration and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored. /Sulfonamides/ [R70, 2695] *Concurrent use /of hemolytics/ with sulfonamides may increase the potential for toxic side effects. /Sulfonamides/ [R70, 2695] *Concurrent use /of hepatotoxic medications/ with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored. /Sulfonamides/ [R70, 2695] *In acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended. /Sulfonamides/ [R70, 2695] *The effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations. /Sulfonamides/ [R70, 2695] *Since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy. /Sulfonamides/ [R70, 2695] *A spectrum of adverse drug reactions that are caused by the combined action of drugs and viruses has been described: ampicillin rash in acute infectious mononucleosis; Reye's syndrome; hypersensitivity reactions to sulfonamides in patients with HIV infection; drug-induced agranulocytosis; paracetamol (acetaminophen) hepatotoxicity; aspirin (acetylsalicyclic acid)-induced asthma; Epstein-Barr virus-associated lymphoma and methotrexate; and AIDS-related Kaposi's sarcoma and nitrite use. Changes in pharmacokinetics have been reported for: caffeine, sulfamethoxazole and fluconazole in patients with HIV infection; theophylline, following influenza and influenza vaccination; and recently, dipyrone metabolites in carriers of the hepatitis B virus. In addition increased drug- and drug metabolite-related toxicity has been observed in virally infected cells. Pathogenetic mechanisms for the interaction between drugs and viruses are varied, and include biological mechanisms (often immunological) and changes in drug metabolism. The combined effects of chemical and biological exposure provide a unique model for the study of disease induction. [R71] *The case of a 28-yr old man, human immunodeficiency virus (HIV) positive, with active cytomegalovirus retinitis who developed nephrogenic diabetes insipidus during intermittent therapy with 5 mg/kg of cidofovir that was administered once weekly the first 2 wk and once every 2 wk thereafter is presented. Concomitant therapy included or probenecid, intravenous injections of sodium chloride (saline), and sulfamethoxazole in combination with trimethoprim (co-trimoxazole). During the first 6 treatment cycles, serum creatinine was stable and proteinuria was mild. After the seventh treatment cycle, the patient suddenly developed polydipsia and polyuria. Nephrogenic diabetes insipidus was diagnosed. Twelve wk after cidofovir was stopped, urine output fell to 1.5 l/24 hr and the proteinuria disappeared. [R72] *1. Cytochrome P450-mediated bioactivation of sulfamethoxazole to a hydroxylamine has been implicated in the hypersensitivity reactions associated with co-trimoxazole administration. Inhibiting the formation of the hydroxylamine may be one method of preventing the high frequency of toxicity which is observed in HIV-infected patients. Therefore, in this study, we have investigated the ability of fluconazole and ketoconazole, known cytochrome P450 inhibitors, to inhibit the formation of sulfamethoxazole hydroxylamine. 2. Ten healthy male volunteers were given co-trimoxazole (800 mg sulfamethoxazole and 160 mg trimethoprim) alone or 1 hr after either fluconazole (150 mg) or ketoconazole (200 mg) in a randomized fashion with a washout period of at least 1 week between each phase. Urine was collected for 24 hr, and sulfamethoxazole and its metabolites were quantified by electrospray LC-MS. 3. Ketoconazole had no effect on the urinary recovery of sulfamethoxazole or any of its metabolites. In contrast, fluconazole significantly (P < 0.0001) inhibited the formation of sulfamethoxazole hydroxylamine by 50.0 +/- 15.1%. Fluconazole also inhibited the oxidation of sulfamethoxazole to the 5-methylhydroxy and 5-methylhydroxy acetate metabolites by 69.9 +/- 15.8% and 64.0 +/- 12.0%, respectively, but had no effect on the amount of sulfamethoxazole, N4-acetyl sulfamethoxazole, or sulfamethoxazole N1-glucuronide excreted in urine. 4. The potential clinical benefit of using fluconazole to prevent hypersensitivity to co-trimoxazole in patients with AIDS needs to be assessed in a prospective study using both metabolite formation and the clinical occurrence of adverse reactions as endpoints. [R73] *Sulfamethoxazole toxicity is putatively initiated by the formation of a hydroxylamine metabolite by cytochromes P450. If this reaction could be inhibited, toxicity may decrease. We have this reaction could be inhibited, toxicity may decrease. We have studied--in vitro and in vivo--fluconazole, ketoconazole, and cimetidine as potentially suitable clinical inhibitors of sulfamethoxazole hydroxylamine formation. Both fluconazole and ketoconazole in human liver microsomal incubations competitively inhibited sulfamethoxazole N-hydroxylation, with the inhibitory constant (Ki) values of 3.5 and 6 umol/L, respectively. Cimetidine exhibited a mixed type of inhibition of sulfamethoxazole hydroxylamine formation in human liver microsomes, with IC 50 values (the concentration required to decrease hydroxylamine formation by 50%) of 80 and 800 umol/L, the lower value being observed when cimetidine was preincubated with microsomes and reduced nicotinamide adenine dinucleotide phosphate. In an in vivo study in six healthy volunteers the inhibition of the cytochrome p450-mediated generation of the toxic metabolite in the presence of fluconazole was shown by a 94% decrease in the area under the plasma concentration-time curve of sulfamethoxazole hydroxylamine. In contrast, the recovery of hydroxylamine in urine decreased by only 60%. Total clearance of sulfamethoxazole was decreased by 26% by fluconazole, most likely because of the inhibition of unidentified P450 elimination pathways. There was close agreement between the predicted (87%) and observed inhibition (94%) of sulfamethoxazole hydroxylamine formation in vivo. Similarly, there was close agreement between in vivo and in vitro Ki values--1.6 and 3.5 micron/L, respectively. [R74] *Fecal samples collected from three populations of healthy adult volunteers 9290 pigfarmers, 316 abattoir workers, 160 suburban residents) living in the south of the Netherlands were analyzed for the prevalence and degree of antibiotic resistance of Escherichia coli. Significant differences in prevalence of resistance to amoxicillin, neomycin, oxytetracycline, sulfamethoxazole and trimethoprim were observed. The pigfarmers showed the highest percentages of resistance and the suburban residents the lowest. In contrast no significant differences in high degrees of resistance were observed, except for neomycin. Although both pigfarmers and abattoir workers have regular contact with pigs differences in prevalence of resistance were observed. However, because abattoir workers with intensive and less intensive pig (carcass) contact did not show significant differences, this is probably no the only important source of resistant E. coli in pigfarmers. The high antibiotic use by pigfarmers (5%) and abattoir workers (8%) than by suburban residents (0%) did not result in significantly different resistance percentages. [R75] *PS-15 is a novel biguanide folate antagonist that is metabolized in vivo to WR99210, a metabolite that is extremely active in vitro against multi-drug resistant strains of Plasmodium falciparum. When PS-15 was administered in combination with sulfamethoxazole to healthy Saimiri sciureus monkeys, the serum antimalarial activity was considerably greater than that observed in monkeys that received PS-15 alone. Further studies should be carried out to determine the value of PS-15/sulfonamide combinations in the treatment of human malaria infections and in preventing the emergence of drug-resistant parasites. [R31] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents /SRP: Antibacterial/ [R76] *...IT IS EMPLOYED FOR BOTH SYSTEMIC AND URINARY TRACT INFECTIONS. [R34, 1060] *IT IS ALSO USED IN COMBINATION WITH PYRIMETHAMINE IN TREATMENT OF CHLOROQUINE-RESISTANT FALCIPARUM MALARIA. [R5] *SULFONAMIDES HAVE WIDE RANGE OF ANTIMICROBIAL ACTIVITY AGAINST BOTH GRAM-POSITIVE AND GRAM-NEGATIVE ORGANISMS. ... IN GENERAL, SULFONAMIDES EXERT ONLY BACTERIOSTATIC EFFECT IN BODY, AND CELLULAR AND HUMORAL DEFENSE MECHANISMS OF HOST ARE ESSENTIAL FOR FINAL ERADICATION OF INFECTION. /SULFONAMIDES/ [R1, 1047] *Pneumocystis carinii pneumonia (PCP) is a major cause of morbidity and the leading cause of death in patients with the acquired immunodeficiency syndrome. The prevention of the occurrence and recurrence of Pneumocystis carinii pneumonia is a cornerstone in the treatment of patients infected with the human immunodeficiency virus. There are few studies comparing Pneumocystis carinii pneumonia prophylactic regimens. The efficacy of three regimens for prophylaxis against Pneumocystis carinii pneumonia was assessed in a retrospective chart review of 211 human immunodeficiency virus infected patients at risk for the disease. Over the course of the 2-year study period, 133 patients were prescribed trimethoprim-sulfamethoxazole (one double-strength tablet twice a day, thrice weekly) for a mean of 7.4 mo (range, 1 to 25 mo). Seventy seven patients received dapsone (50 mg daily) for a mean of 5.7 mo (range, 1 to 23 mo), and 125 patients received aerosolized pentamidine (300 mg via nebulizer once monthly) for a mean of 9.3 mo (range, 1 to 21 mo). The majority of patients (62%) received primary prophylaxis; 38% had one or more previous episodes of Pneumocystis carinii pneumonia; and 73% were receiving concomitant antiretroviral therapy. Pneumocystis carinii pneumonia did not develop in any patient receiving trimethoprim-sulfamethoxazole in 981 patient-months. Five patients receiving dapsone for 437 patient-months and 17 patients receiving aerosolized pentamidine for 1166 patient-months developed Pneumocystis carinii pneumonia. Fifty six percent of the trimethoprim-sulfamethoxazole group and 55% of the dapsone group changed drug due to adverse reactions, while only 2% in the aerosolized pentamidine group required drug change. It was concluded that despite its adverse reaction profile, trimethoprim-sulfamethoxazole is the most effective agent to prevent the occurrence and recurrence of Pneumocystis carinii pneumonia. [R77] *Sulfonamides are indicated in the treatment of chancroid caused by Hemophilus ducreyi. however, other agents such as erythromycin and ceftriaxone, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in the treatment of endocervical and urethral infections caused by Chlamydia trachomatis. However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in the treatment of neonatal inclusion conjunctivitis caused by chlamydia trachomatis. However, other agents, such as erythromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated as adjunctive therapy in the treatment of chloroquine-resistant Plasmodium falciparum. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in the prophylaxis of meningitis caused by susceptible strains of Neisseria meningitidis. However, other agents, such as rifampin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in the treatment of nocardiosis caused by Nocardia asteroides. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in combination with other antibacterials in the treatment of otitis media caused by susceptible strains of H. influenza, streptococci, and pneumococci. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in combination with pyrimethamine in the treatment of toxoplasmosis caused by Toxoplasma gondii. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in the treatment of ocular trachoma caused by Chlamydia trachomatis. However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R70, 2693] *Sulfonamides are indicated in the treatment of acute, uncomplicated urinary tract infections caused by susceptible bacteria. Because sulfamethizole produces low plasma levels and is rapidly eliminated, it is recommended only for use in urinary tract infections, not systemic infections. Sulfadiazine is not recommended for the treatment of urinary tract infections because of its relatively lower urine solubility and the increased chance of crystalluria; other, more soluble agents, such as sulfisoxazole, are generally preferred. /Included in US product labeling/ [R70, 2693] *Sulfonamides are used in the treatment of lymphogranuloma venereum caused by Chlamydia species. However, other agents, such as doxycycline and erythromycin, are considered to be first line agents. /Sulfonamides; NOT included in US product labeling/ [R70, 2693] *VET: Antibacterial [R4] *A secundigravida developed culture-proved Listeria monocytogenes sepsis with signs and symptoms of chorioamnionitis at 13 weeks' gestation. Pregnancy termination was refused, and she was treated with intravenous ampicillin and gentamicin followed by oral trimethoprim/sulfamethoxazole. Fifteen days after initiation of therapy, am amniotic fluid culture was negative, although uterine tenderness persisted for 7 weeks. A healthy, culture-negative infant was delivered at term. [R78] *The purpose of this prospective, randomized, single-blind trial was to assess the clinical efficacy of a single intramuscular dose of ceftriaxone compared with 10 days of oral trimethoprim-sulfamethoxazole (TMP-SMZ) in treating acute otitis media (AOM). Methods: Children aged 3 mos through 3 yr diagnosed with acute otitis media (signs of acute illness plus evidence of middle-ear effusion_ were randomized to treatment with either a single intramuscular dose of ceftriaxone (maximum dose of 50 mg/kg) or 10 days of oral trimethoprim-sulfamethoxazole (8 mg of trimethoprim and 40 mg of sulfamethoxazole/kg/day in two divided doses). Children were evaluated at scheduled visits on days 3, 14 and 28, and the parents were telephoned on day 5. Children were assessed as cured, improved, or failed on day 3, and as cured or failed on days 14 and 28. Children ill at other times during the study period were, if possible, seen and assessed by the study team. Results: Of 596 children enrolled during the study period, 484 were evaluable. Characteristics of evaluable subjects did not differ significantly by drug. On day 3, 223/241 children in the ceftriaxone group (92.5%) and 231/243 (95.1%) in the trimethoprim-sulfamethoxazole group were cured or improved. On day 14, 158/197 (80.2%) in the ceftriaxone group and 174/212 (82.1%) in the trimethoprim-sulfamethoxazole group were cured. On day 28, 108/136 (79.4%) in the ceftriaxone group and 124/155 (80%) in the trimethoprim-sulfamethoxazole group were cured. Persistence of middle-ear fluid did not differ between groups at day 14 (55% in the ceftriaxone group vs 47% in the trimethoprim-sulfamethoxazole group; P= .16) or at day 28 (39% vs 43%; P= .48). Pain at the injection site persisting at day 3 occurred in 8.4% of children receiving ceftriaxone. New diarrhea was more common in the ceftriaxone group (23.6% vs 9.2%; P < .001). Conclusion: A single intramuscular dose of ceftriaxone is comparable in clinical efficacy to 10 days of oral trimethoprim-sulfamethoxazole for treatment of acute otitis media. [R79] *The anti-Pneumocystis carinii activity of atovaquone, dapsone and sulfamethoxazole alone and combined with dihydrofolate reductase (DHFR) inhibitors and macrolides was investigated against five clinical isolates of P. carinii. The susceptibility tests were performed by inoculation of the organisms on to cell monolayer and parasite count after 72 hr incubation at 37 deg C. Culture plates were added to Dulbecco's modified Eagle's medium containing serial dilutions of atovaquone, dapsone and sulfamethoxazole alone or in combination with diaveridine, pyrimethamine, trimethoprim, azithromycin, clarithromycin, and roxithromycin. Atovaquone, dapsone and sulfamethoxazole were found to be effective at levels well below the concentrations that could be achieved clinically, while dihydrofolate reductase inhibitors were shown to combine effectively with dapsone and sulfamethoxazole. No synergy could be demonstrated between atovaquone and dihydrofolate reductase inhibitors or macrolides. A mild synergic effect was noted when macrolides were combined with dapsone and sulfamethoxazole. Pyrimethamine (0.5 mg/L) combined with dapsone and trimethoprim (0.5 mg/L) combined with sulfamethoxazole exerted the strongest inhibitory effect. [R80] *A multicenter, prospective cohort study evaluating the medical outcomes and costs of antimicrobial therapy in outpatients with community-acquired pneumonia who received treatment that was consistent or inconsistent with recent American Thoracic Society (ATS) guidelines was conducted among 546 patients, ages 60 yr or younger, with no comorbidity, and 318 patients, ages older than 60 yr, with 1 comorbidity or more. Patients ages 60 yr. or younger who were prescribed therapy that was consistency with American Thoracic Society guidelines (erythromycin with some exceptions) had 3-fold lower antimicrobial costs and no significant differences in medical outcomes. patients older than 60 yr who were prescribed therapy consistent with American Thoracic Society guidelines (second-generation cephalosporins, sulfamethoxazole-trimethoprim, or beta-lactam and beta-lactamase inhibitor with or without a macrolide) had 10-fold higher antimicrobial costs. Despite trends toward higher mortality and subsequent hospitalization among patients treated according to the guidelines, no significant differences in medical outcomes were observed. [R81] *The case of a 7-yr old girl who was successfully treated with 6-8 mg/kg/day cyclosporine for hypereosinophilic syndrome is presented. The patient was also treated with intravenous injections of antibiotics twice a month, glucocorticoids, and low dose oral sulfamethoxazole-trimethoprim (cotrimoxazole). A brief, unsuccessful attempt to wean the patient off cyclosporine by substituting thalidomide resulted in a sever flare up of the disease on her face, scalp, and eyes, requiring hospital admission and treatment. The disease has been well controlled for the past 6 months by cyclosporine and 15 mg prednisone every other day. [R82] *Background: The mechanism of tolerance to incremental doses of trimethoprim-sulfamethoxazole given to human immunodeficiency virus-infected persons who have had a prior intolerance to this agent has not been studied. Objective: We prospectively evaluated a regimen of incremental doses of oral trimethoprim-sulfamethoxazole in human immunodeficiency virus-infected persons who had a prior trimethoprim-sulfamethoxazole-induced fever and nonexfoliative skin rash to investigate the mechanism by which it permits tolerance. Methods: Oral trimethoprim (0.00004 mg)/sulfamethoxazole (0.00002 mg) was given to 22 human immunodeficiency virus-infected persons on day 1 and gradually increased over eight days to 1 double strength (DS) tablet/day in an outpatient setting. At study entry, skin tests and IgG antibodies to sulfa were performed; the latter was repeated at study week 4. Results: Nineteen patients tolerated trimethoprim/sulfamethoxazole at the completion of the 8-day protocol (86% effective). Moderate toxicities occurred in eight persons during the desensitization protocol; five of these were able to continue trimethoprim/sulfamethoxazole with adjunctive prednisone. Skin tests to sulfa antigen were negative in all persons. Eleven patients at study entry had antibodies to sulfamethoxazole; IgG antibodies appeared at week 4 in 8 of the 11 patients who initially had no antibody detected. Conclusions: The mechanism of tolerance to the incremental doses of trimethoprim/sulfamethoxazole given to previously intolerant human immunodeficiency virus-infected persons is not due to desensitization and remains undetermined. [R83] *A simplified understanding of decision analysis and its potential applications in health care is presented, with an example of an algorithm of treatment for acute uncomplicated cystitis with a 3 day regimen of trimethoprim/sulfamethoxazole or regimens of amoxicillin, cefadroxil, nitrofurantoin, or ofloxacin, to conduct analyses using costs and probabilities from the literature. Studies have suggested that the trimethoprim/sulfamethoxazole regimen is more cost effective; however, the relevance of this conclusion outside of the United States where the studies were conducted is questioned. Decision analysis was used to replicate the U.S. results and apply them to United Kingdom and German costs to determine changes in the outcome. [R84] *A risk/benefit assessment of the use of antimicrobial agents in a metropolitan hospital in Santiago, Chile, was conducted using drug utilization review methodology in 190 patients (mean age 58.1 yr) hospitalized for an average of 17.3 days who had been diagnosed with a total of 216 infections and received a total of 287 antimicrobial treatments. Eight-seven percent of the infections were community acquired. The most serious infections involved respiratory and urinary systems. Ampicillin, penicillin, and sulfamethoxazole in combination with trimethoprim (co-trimoxazole) were the most frequently prescribed antimicrobial agents. Of the antimicrobial treatments, 57.1% were effective, 10.1% were ineffective, and 32.8% were not assessed. The most common reason for therapy failure was the persistence of infection (6.3%). The most effective treatments included culture or antibiogram (58.5%), monotherapies (60%), and treatments lasting 11-14 days (74.6%). [R85] *Following the brief information on a new malaria treatment with the fixed multiple combination Cotrifazid (rifampicin + isoniazid + sulfamethoxazole + trimethoprim) in chemotherapy, very good results are reported for the treatment of 61 patients with various forms of malaria. The tolerance was found to be good. Some relevant fundamental considerations (chemoresistance, synergism/antagonism, fixed multiple combination, switching from monotherapy to combination therapy) and the implementation of the principle of a "multidisease therapy" are discussed. [R86] *HIV infection in children, including transmission, risk factors, evaluation, clinical manifestation, disease progression, prophylaxis against Pneumocystis carinii pneumonia with trimethoprim in combination with sulfamethoxazole, schedules for immunization against other diseases, therapy with zidovudine and didanosine, and reduction of maternal to child transmission, is presented. [R87] *Prescribing practices of 62 general practitioners and 28 pediatricians for the treatment of diarrhea in 996 pediatric patients were studied in Pakistan. Oral rehydration salt was prescribed in more than 50% of encounters by 53% of general practitioners and 61% of pediatricians. Sixty-six percent of general practitioners and 50% of pediatricians prescribed antibacterials, 60% of general practitioners and 28% of pediatricians prescribed antidiarrhea agents, and 39% of general practitioners and 32% of pediatricians prescribed antiamebics in more than 30% of their encounters. A combination of sulfamethoxazole and trimethoprim (cotrimoxazole) was the most frequently prescribed anti-infective therapy by both practitioners. The mean duration of encounters with patients was 3 min for general practitioners and 9 min for pediatricians. [R88] *To compare the incidence of Pneumocystis carinii pneumonia (PCP) in patients infected with human immunodeficiency virus (HIV) receiving 1 of 3 prophylactic agents, a retrospective chart analysis of 200 patients enrolled at one HIV clinic who were prescribed oral sulfamethoxazole in combination with trimethoprim double strength (SMX/TMP DS), oral dapsone, or aerosolized pentamidine during 18 months was conducted; a subset of 110 patients received 1 prophylactic regimen for at least 6 mos. One case of Pneumocystis carinii pneumonia was diagnosed in 1110 patient-months of oral sulfamethoxazole/trimethoprim double strength therapy, 6 in 418 patient-months of dapsone therapy, and 3 in 164 patient-months of aerosolized pentamidine therapy. In the subset population, the incidence of Pneumocystis carinii pneumonia was 0% among 71 sulfamethoxazole/trimethoprim double strength-treated patients, 16% among 25 dapsone-treated patients, and 14% among 14 pentamidine-treated patients. For patients receiving primary prophylaxis, the incidence of Pneumocystis carinii pneumonia was 0% for 58 receiving trimethoprim-sulfamethoxazole, 15% for 20 receiving dapsone, and 17% for 6 receiving pentamidine. It was concluded that sulfamethoxazole/trimethoprim double strength was more effective than oral dapsone or aerosolized pentamidine in preventing Pneumocystis carinii pneumonia in these HIV-infected patients. [R89] *The efficacy and toxicity of trimethoprim-sulfamethoxazole (TMP-SMZ) as primary prophylaxis against Pneumocystis carinii pneumonia (PCP) for patients with human immunodeficiency virus (HIV) infection was assessed by compared the effects of two dosages (480 or 960 mg once a day) of the drug. The multicenter trial involved 260 HIV-infected patients with CD4 cell counts < 0.2 x 10(9)/L and non history of Pneumocystis carinii pneumonia. Patients were randomly assigned to the treatment groups. After a median follow-up of 376 days (range, 1-1219), none of the patients developed Pneumocystis carinii pneumonia. Most adverse reactions that required discontinuation were seen within the first months of trimethoprim-sulfamethoxazole use and were seen more frequently and earlier in the 960-mg group (hazard ratio, 1.4; 95% confidence interval, 0.95-2.02; P= .007). For patients with HIV infection, 480 mg of trimethoprim-sulfamethoxazole is as efficacious as but less toxic than 960 mg of the drug for primary prophylaxis against Pneumocystis carinii pneumonia. [R90] *The efficacy of clarithromycin combined with either pyrimethamine or minocycline for treatment of experimental Toxoplasma gondii infection was investigated. Mice were infected intraperitoneally with 2 x 10(3) to 2 x 10(4) T. gondii strain RH or TS4 tachyzoites. Mortality was recorded for 35 days postinfection. Latency was evaluated by inoculation of brain homogenates from surviving mice into naive untreated mice. The combination of clarithromycin and pyrimethamine therapy caused a significantly greater reduction in mortality than did either drug alone. Similar synergy was observed between clarithromycin and minocycline. A 100% cure rate of active and latent infection was achieved in mice treated with the clarithromycin based combinations. Clarithromycin in combination with either pyrimethamine or minocycline produced efficacy comparable to combined therapy of pyrimethamine with sulfamethoxazole. The in vitro potency of clarithromycin, pyrimethamine, or minocycline against T. gondii on a mouse macrophage monolayer was not predictive of the in vivo efficacy in mice. Clarithromycin combined with minocycline or pyrimethamine could allow greater flexibility for treatment of patients predisposed to the toxicity associated with standard pyrimethamine-sulfonamide or pyrimethamine-sulfonamide therapy. This therapy could be especially useful since clarithromycin-based therapy provides safe and effective treatment against Mycobacterium avium complex infections associated with AIDS patients. [R91] *Trimetrexate is a powerful inhibitor of the dihydrofolate reductase of Pneumocystis carinii. AIDS patients (n = 215) with moderate to severe P. carinii pneumonia were enrolled in a double-blind study of trimetrexate plus leucovorin vs trimethoprim-sulfamethoxazole (TMP-SMZ) for 21 days. By study day 10, study therapy failed because of lack of efficacy in 16% of patients assigned to trimethoprim-sulfamethoxazole and 27% assigned to trimetrexate (P = .064), and the PAO2-PaO2 improved significantly faster with trimethoprim-sulfamethoxazole. By study day 21, failure rates were 20% with trimethoprim-sulfamethoxazole and 38% with trimetrexate (P = .008), with respective mortality rates of 12% and 20% (P = .088). By study day 49, the difference in mortality (16% vs 31%) was significant (P = .028). The cumulative incidence of serious and treatment-terminating adverse events including hematologic toxicities was less with trimetrexate (P < .001). Thus, trimetrexate plus leucovorin was effective, albeit inferior to trimethoprim-sulfamethoxazole, for moderately severe P. carinii pneumonia but was better tolerated than trimethoprim-sulfamethoxazole. [R92] WARN: *OVERALL INCIDENCE OF REACTIONS IS ABOUT 5%. CERTAIN FORMS OF TOXICITY MAY BE RELATED TO INDIVIDUAL DIFFERENCES IN SULFONAMIDE METABOLISM. /SULFONAMIDES/ [R34, 1061] *PRECAUTIONS MUST BE OBSERVED TO AVOID SULFAMETHOXAZOLE CRYSTALLURIA BECAUSE OF HIGH PERCENTAGE OF ACETYLATED, RELATIVELY INSOL FORM OF DRUG IN URINE. [R1, 1052] *DURING THERAPY, IT IS IMPORTANT TO MAINTAIN ADEQUATE URINARY OUTPUT (AT LEAST 1500 ML DAILY IN ADULTS) ... . [R93] *The number of conditions for which the sulfonamides are therapeutically useful and constitute drugs of first choice has been reduced sharply by the development of more effective antimicrobial agents and by the gradual increase in the resistance of a number of bacterial species to this class of drugs. /Sulfonamides/ [R34, 1062] *AGE OF PATIENT MAY BE IMPORTANT DETERMINANT OF RISK OF REACTIONS ASSOC WITH USE OF VARIOUS SULFONAMIDES. ENZYMES THAT ACETYLATE SULFONAMIDES ARE POORLY DEVELOPED IN NEWBORNS. /SULFONAMIDES/ [R58, 1122] *Maternal Medication usually Compatible with Breast-Feeding: Trimethoprim/sulfamethoxazole: Reported Sign or Symptom in Infant or Effect on Lactation: None. /from Table 6/ [R94] *POTENTIAL ADVERSE EFFECTS ON FETUS: May cause jaundice and kernicterus in fetus. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Excreted in low concentrations. Cited by U.S. Pharmacopeia Dispensing Information to be contraindicated in first 2 months of life because of risk of kernicterus, but American Academy of Pediatrics considers safe for breast-feeding. Sulfonamides may cause hemolytic anemia in G6PD /glucose 6-phosphate dehydrogenase/ deficient infants. COMMENTS: Trimethoprimsulfamethoxazole may interfere with folic acid metabolism. FDA Category: C (C = Studies in laboratory animals have revealed adverse effects on the fetus (teratogenic, embryocidal, etc.) but there are no controlled studies in pregnant women. The benefits from use of the drug in pregnant women may be acceptable despite its potential risks, or there are no laboratory animal studies or adequate studies in pregnant women.) /Sulfonamides/ /from table II/ [R95] *Sulfonamides should not be used in the treatment of Group A beta-hemolytic streptococcal tonsillopharyngitis since they may not eradicate steptococci and therefore may not prevent sequelae such as rheumatic fever. /Sulfonamides/ [R70, 2693] *Sulfonamides are also not effective in treating rickettsial, viral, tuberculous, actinomycotic, fungal, or mycoplasmal infections. They are also not effective in the treatment of shigellosis. /Sulfonamides/ [R70, 2693] *Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis, use of sulfonamides is contraindicated in infants up to 2 months of age. Sulfonamides compete for bilirubin binding sites on plasma albumin, increasing the risk of kernicterus in the newborn. Also, because the acetyltransferase system is not fully developed in the newborn, increased blood concentrations of the free sulfonamide can further increase the risk of kernicterus. /Sulfonamides/ [R70, 2694] *Elderly patients may be at increased risk of severe side/adverse effects. Severe skin reactions, generalized bone marrow depression, and decreased platelet count (with or without purpura) are the most frequently reported severe side/adverse effects in the elderly. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients who are receiving diuretics, primarily thiazides, concurrently with sulfamethoxazole. The potential for these problems should also be considered for elderly patients taking other sulfonamide medications. /Sulfonamides/ [R70, 2694] *The leukopenic and thrombocytopenic effects of sulfonamides may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. /Sulfonamides/ [R70, 2694] *Patients with acquired immunodeficiency syndrome (AIDS) may have a grater incidence of side/adverse effects, especially rash, fever, and leukopenia, than do non-AIDS patients. /Sulfonamides/ [R70, 2695] *Effects...acute and reversible myopia; most common ocular side effect, conjunctivitis, optic neuritis, and photosensitivity [R96] *About 75% of the untoward effects involve the skin. ...trimethoprim-sulfamethoxazole has been reported to cause up to three times as many dermatological reactions as does sulfisoxazole when given alone. /co-trimoxazole/ [R34, 1064] *AMONG SKIN AND MUCOUS MEMBRANE MANIFESTATIONS ATTRIBUTED TO SENSITIZATION TO SULFONAMIDE ARE...BEHCET'S SYNDROME, EXFOLIATIVE DERMATITIS, AND PHOTOSENSITIVITY. ...SERUM SICKNESS MAY APPEAR... FEVER, JOINT PAIN, URTICARIAL ERUPTIONS, CONJUNCTIVITIS, BRONCHOSPASM, AND LEUKOPENIA ARE THE OUTSTANDING FEATURES. /SULFONAMIDES/ [R34, 1062] *DRUG FEVER IS A COMMON UNTOWARD MANIFESTATION OF SULFONAMIDE TREATMENT. ... GENERALLY SUDDEN IN ONSET... HEADACHE, CHILLS, MALAISE, PRURITUS, AND SKIN RASH MAY ACCOMPANY THE FEVER. ...CROSS-SENSITIVITY BETWEEN DIFFERENT SULFONAMIDES DOES OCCUR... /SULFONAMIDES/ [R34, 1062] *The sulfonamides readily cross the placenta to the fetus during all stages of gestation. Equilibrium with maternal blood is usually established after 2-3 hr., with fetal levels averaging 70-90% of maternal. Significant levels may persist in the newborn for several days after birth when given near term. The primary danger of sulfonamide administration during pregnancy is manifested when these agents are given close to delivery. Toxicities that may be observed in the newborn include jaundice, hemolytic anemia and, theoretically, kernicterus./Sulfonamides/ [R97, 795] *...sulfonamide excretion into breast milk apparently does not pose a significant risk for the healthy, full-term neonate. Exposure to sulfonamides via breast milk should be avoided in ill, stressed, or premature infants and in infants with hyperbilirubinemia or glucose-6-phosphate dehydrogenase deficiency. [R97, 797] *FOCAL OR DIFFUSE NECROSIS OF LIVER DUE TO DIRECT TOXICITY OR SENSITIZATION OCCURS ... HEADACHE, NAUSEA, VOMITING, FEVER, HEPATOMEGALY, JAUNDICE, AND LAB EVIDENCE OF HEPATOCELLULAR DYSFUNCTION ... AND SYNDROME MAY PROGRESS TO ACUTE YELLOW ATROPHY AND DEATH. /SULFONAMIDES/ [R34, 1062] *DRUG ERUPTIONS OCCUR MOST OFTEN AFTER FIRST WK OF THERAPY ... FEVER, MALAISE, AND PRURITUS ARE FREQUENTLY PRESENT SIMULTANEOUSLY. ... SYNDROME SIMILAR TO SERUM SICKNESS ... FEVER, JOINT PAIN, URTICARIAL ERUPTIONS, CONJUNCTIVITIS, BRONCHOSPASM, AND LEUKOPENIA ARE OUTSTANDING FEATURES. ... DRUG FEVER ... /SULFONAMIDES/ [R34, 1062] *AMONG OTHER UNTOWARD EFFECTS ... ARE GOITER AND HYPOTHYROIDISM, ARTHRITIS, AND VARIOUS NEUROPSYCHIATRIC DISTURBANCES. ... PERIPHERAL NEURITIS IS VERY RARE. ANOREXIA, NAUSEA, AND VOMITING OCCUR IN 1-2% OF PERSONS RECEIVING SULFONAMIDES ... . /SULFONAMIDES/ [R1, 1052] *DEVELOPMENT OF ACUTE HEMOLYTIC ANEMIA IS UNRELATED TO DOSAGE OR BLOOD LEVEL OF DRUG. ... VERTIGO ... PALLOR, HEPATOSPLENOMEGALY, AND SHOCK MAY DEVELOP SUDDENLY. ... ACUTE RENAL TUBULAR NECROSIS MAY FOLLOW HEMOGLOBINURIA. /SULFONAMIDES/ [R1, 1052] *... HYPERSENSITIVITY REACTIONS ... AMONG SKIN AND MUCOUS MEMBRANE MANIFESTATIONS ... ARE MORBILLIFORM, SCARLATINAL, URTICARIAL, ERYSIPELOID, PEMPHIGOID, PURPURIC, AND PETECHIAL RASHES ... /SULFONAMIDES/ [R34, 1062] *AGRANULOCYTOSIS ... CAN FOLLOW USE OF ... SULFONAMIDES. ... COMPLETE SUPPRESSION OF BONE-MARROW ACTIVITY WITH PROFOUND ANEMIA, GRANULOCYTOPENIA, AND THROMBOCYTOPENIA IS EXTREMELY RARE OCCURRENCE WITH SULFONAMIDE THERAPY. /SULFONAMIDES/ [R34, 1062] *PRIMARY FACTOR RESPONSIBLE FOR RENAL DAMAGE ... IS FORMATION AND DEPOSITION OF CRYSTALLINE AGGREGATES IN KIDNEYS, CALYCES, PELVIS, URETERS, OR BLADDER ... TWO OTHER MECHANISMS, TOXIC NEPHROSIS AND HYPERSENSITIVITY REACTION, MAY RARELY BE INVOLVED IN PATHOGENESIS OF URINARY TRACT DISTURBANCES ... ANURIA AND DEATH ... . /SULFONAMIDES/ [R58, 1121] *Alternative drugs to chloroquine are required to prevent the deleterious effects of malaria in pregnancy. Fear of potential toxicity has limited antimalarial drug use in pregnancy. Animal toxicity studies have documented teratogenicity when antimalarials are administered at high dosages. Excepting the tetracyclines, there is no evidence to suggest that, at standard dosages, any of the antimalarial drugs are teratogenic. Primaquine is not recommended because of the potential risk of hemolytic effects in the fetus. Rates of spontaneous abortion and birth defects were comparable in pregnant women taking mefloquine, compared with chloroquine-proguanil, or pyrimethamine-sulfadoxine prophylaxis, in the first trimester of pregnancy. Standard doses of quinine do not increase the risk of abortion or preterm delivery. Therapeutic mefloquine dose not provoke hypoglycemia. There is no evidence in the literature to support the hypothetical risk of kernicterus in the newborn, following exposure to antimalarial drugs containing sulfonamides of sulfones prior to delivery. Documentation of the safety of doxycycline, halofantrine, and the artemisinin derivatives in the treatment of malaria in pregnant women is currently limited. [R98] *Objective: To study the safety and efficacy of desensitization with the use of a combination product of sulfamethoxazole and trimethoprim in previously hypersensitive patients infected with the human immunodeficiency virus. Design: Prospective survey, with a median follow-up of 16 mos (range, 5-24 mos). Setting: Day-care hospital in a referral center. patients: All human immunodeficiency virus-infected patients who had a history of allergic reactions (eg, rash) to sulfamethoxazole-trimethoprim and who required sulfamethoxazole-trimethoprim prophylaxis. Intervention: The desensitization procedure took 2 days. The full dose (sulfamethoxazole-trimethoprim, 400-80 mg) was reached on the third day according to the following schedule: day 1--4-0.8 mg at 9 am, 8-1.6 mg at 11 am, 20-4 mg at 1 pm, and 40-8 mg at 5 pm; day 2--80-16 mg at 9 am, 160-32 mg at 3 pm, and 200-40 mg at 9 pm; and day 3--400-80 mg at 9 am. Main outcome measure: The onset of cutaneous adverse effects attributable to sulfamethoxazole-trimethoprim therapy within 3 mos after desensitization. Results: Of the 48 evaluable patients, 37 (77%) tolerated sulfamethoxazole-trimethoprim desensitization without toxic effects and continued to take sulfamethoxazole-trimethoprim daily. Desensitization failed in 11 cases (5 on day 1, 3 on day 2, and 1 each on days 9, 11, and 90). Acute hypotension and a nonfatal myocardial infarction developed in 1 of these patients. The factors that were predictive of failure were a relatively high CD4+ cell percentage (11% vs 8%; P = .008) and a relatively high CD4+/CD8+ ratio (0.27 vs 0.12; P = 0.02). Conclusions: The efficacy of desensitization with sulfamethoxazole-trimethoprim was confirmed; this desensitization procedure was more often successful in patients with lower CD4+ cell percentages and CD4+/CD8+ ratios. However, sulfamethoxazole-trimethoprim therapy should be reintroduced carefully. [R99] *An overview of the mechanism of hypersensitivity reactions to combined sulfamethoxazole and trimethoprim in patients with human immunodeficiency virus (HIV) infections and clinical studies evaluating reinstitution of this combination for Pneumocystis carinii pneumonia prophylaxis in HIV positive patients who have a history of adverse reactions is presented. The studies included dosages and schedules and the use of premedication with antihistamines, antipyretics, and corticosteroids. A protocol for reinstituting the combination based on the severity of the previous reaction using escalating doses of a commercially available suspension containing 40 mg/mL of sulfamethoxazole and 8 mg/mL of trimethoprim with antihistamines and antipyretics if mild reactions occur was described. [R100] *Hypoglycemia resulting from the combination of sulfonylurea and sulfonamides is a recognized drug interaction. Hypoglycemia induced by sulfonamides alone may be encountered less frequently. Because of their structural similarities to sulfonylureas, sulfonamides are liable to facilitate hypoglycemia by increasing insulin release in susceptible individuals. Sulfonamides can potentiate the hypoglycemic effect of sulfonylurea agents when given in combination. We describe a malnourished patient with severe infection who developed hypoglycemia during high-dose trimethoprim/sulfamethoxazole therapy. Elevated C-peptide concentrations during the hypoglycemic episode indicate that hypoglycemia resulted from increased endogenous insulin secretion. As malnourished patients are prone to hypoglycemia, we suggest that they should be monitored carefully if they are on sulfonamide therapy. /Sulfonamides/ [R101] *The case of a 64-yr old man who developed an allergic reaction to sulfamethoxazole in combination with trimethoprim for treatment of sinusitis reported. The patient noticed a facial rash 3 days after beginning therapy. The rash spread to his shoulders, so he discontinued the antibiotic the next day and began taking diphenhydramine after consulting with his pharmacist. The patient was admitted to the hospital the following day due to severe pruritus, fever, weakness, and syncope; he was immediately treated with methylprednisolone 50 mg every 6 hr and diphenhydramine 50 mg every 6 hr. By this time he had a maculopapular rash over most of his body. The allergic reaction did not progress, and after 2 uneventful days in the hospital the patient was discharged on a tapering dosage schedule of prednisone and diphenhydramine over the next 7 days. The patient did well at home and the rash subsided over the next several wk. [R102] *The case of a 73-yr old comatose man with acute renal failure who developed hypoglycemia secondary to high dose intravenous sulfamethoxazole in combination with trimethoprim therapy 400 mg every 8 hr for nosocomial pneumonia is reported. After 5 days of therapy, the patient presented with severe hypoglycemia that persisted over 8 hr despite multiple intravenous bolus doses and infusions of dextrose. The patient had several risk factors that may have compounded his risk for hypoglycemia, including food deprivation and acute renal failure. After management with dextrose and dose adjustment of the patient's trimethoprim/sulfamethoxazole regimen according to renal function, the hypoglycemia resolved. It was concluded that trimethoprim in combination with sulfamethoxazole may cause reversible hypoglycemia that may be prolonged, particularly in patients with risk factors for hypoglycemia. [R103] *A spectrum of adverse drug reactions that are caused by the combined action of drugs and viruses has been described: ampicillin rash in acute infectious mononucleosis; Reye's syndrome; hypersensitivity reactions to sulfonamides in patients with HIV infection; drug-induced agranulocytosis; paracetamol (acetaminophen) hepatotoxicity; aspirin (acetylsalicyclic acid)-induced asthma; Epstein-Barr virus-associated lymphoma and methotrexate; and AIDS-related Kaposi's sarcoma and nitrite use. Changes in pharmacokinetics have been reported for: caffeine, sulfamethoxazole and fluconazole in patients with HIV infection; theophylline, following influenza and influenza vaccination; and recently, dipyrone metabolites in carriers of the hepatitis B virus. In addition increased drug- and drug metabolite-related toxicity has been observed in virally infected cells. Pathogenetic mechanisms for the interaction between drugs and viruses are varied, and include biological mechanisms (often immunological) and changes in drug metabolism. The combined effects of chemical and biological exposure provide a unique model for the study of disease induction. [R71] *Hypersensitivity syndromes are severe drug induced side effects with skin rashes, fever and/or multiorgan-system abnormalities which are not pharmacologically related. They are well known in relation to allopurinol, anticonvulsants and sulfonamides, but only rarely described with other drugs. These reactions are considered to be immune-mediated but the precise mechanisms are not completely understood. Clinical features, which resemble and EBV infection, and some immunological studies suggest that T-cell mediated immunity is involved in the pathogenesis of this rare disease. In the literature, allopurinol and anticonvulsant hypersensitivity syndromes are clinically well characterized entities, while the definition of hypersensitivity syndrome elicited by other drugs is rather confusing. We present two patients, one with sulfamethoxazole- and one with allopurinol-induced hypersensitivity syndrome. In both cases a lymphocyte transformation test (LTT) was performed and we analyzed the T-cell activation parameters CD25 and HLA-DR on CD4- and CD8- T-cells to demonstrate in vivo activation of T-cells during the active disease. Both patients show increased activation of T-cells with elevated levels of HLA-DR on CD8+ cells. The T-cell activation correlated with the clinical course. Our data support an immunological pathogenesis for hypersensitivity syndromes and the concept that drug specific T-cells are involved in hypersensitivity syndromes. [R104] *Objective: To compare the efficacy of low-dose intravenous (IV) methotrexate (MTX; 0.3 mg/kg once weekly), both with and without concomitant prednisone, versus daily oral trimethoprim/sulfamethoxazole (T/S; 160 mg trimethoprim + 800 mg of sulfamethoxazole twice a day), with and without prednisone, in maintaining remission in patients with generalized Wegener's granulomatosis (WG). Methods: In this study, 65 patients with generalized Wegener's granulomatosis whose disease had entered remission with cyclophosphamide (CYC) and prednisone therapy were started on one of the following remission-maintenance regimens: methotrexate alone (group A; n = 22), trimethoprim/sulfamethoxazole alone (group B; n = 24), methotrexate plus concomitant prednisone (group C; n = 11), and trimethoprim/sulfamethoxazole plus concomitant prednisone (group D; n = 8). Clinical, radiographic, and seroimmunologic data were evaluated to assess the efficacy of the 4 regimens and to seek possible predictive factors concerning outcome in each group. Results: Partial or complete remission was maintained in 86% of the patients in group A, but in only 58% of those in group B (P < 0.05). In group C, 91% of patients remained in remission which is in sharp contrast to group D, in which all patients experienced a relapse after a median of 14.5 months (P < 0.005). Side effects occurred twice as often with methotrexate (n = 12) as with trimethoprim/sulfamethoxazole (n = 6) treatment and could usually be resolved by supplemental folinic acid. Two patients taking methotrexate and 3 patients taking trimethoprim/sulfamethoxazole were withdrawn from the study medication because of side effects. In none of the patients were the adverse effects life threatening. No statistically significant factors predictive of poor outcome emerged in any group. Conclusion: Low-dose methotrexate was found to be superior to trimethoprim/sulfamethoxazole for the safe and effective maintenance of remission in patients with generalized Wegener's granulomatosis. The use of concomitant prednisone was not associated with a worse outcome with methotrexate treatment. Since trimethoprim/sulfamethoxazole, especially with concomitant prednisone, seemed to increase the chance of relapse, neither trimethoprim/sulfamethoxazole alone nor trimethoprim/sulfamethoxazole plus prednisone can be recommended for the maintenance of remission in patients with generalized Wegener's granulomatosis. [R105] *The case of a 49-yr-old human immunodeficiency virus (HIV)-positive patient who developed hyperkalemia after therapy with sulfamethoxazole in combination with trimethoprim 20 mg/kg daily for Pneumocystis carinii pneumonia is reported. On admission, his potassium level was 3.8 mmol/l and his sodium level was 136 mmol/l. On day 12, his potassium level was 6 mmol/l, his sodium level was 131 mmol/l, his blood urea nitrogen level was 22 mg/dl, and his creatinine level was 1 mg/dl. Despite therapy with corticosteroids, electrolyte abnormalities persisted. On day 14, trimethoprim/sulfamethoxazole therapy was discontinued, and pentamidine was started. Two days later, the patient's potassium level was 4 mmol/l and his sodium level was 136 mmol/l. [R106] *The case of a 38-yr old woman, who presented with severe sunburn after receiving sulfamethoxazole in combination with trimethoprim (co-trimoxazole) twice daily for 3 days as therapy for a urinary tract infection, is reported. The photosensitivity reaction may have been avoided through patient education. [R107] *A 69-yr old male was admitted to our hospital on Jan. 10, 1995 complaining of bloody sputum, left back pain and fever of 39 deg C. He had a history of pulmonary tuberculosis 45 yr ago. His chest X-ray and CT showed the presence of air-fluid level in the left pleural cavity with thickening and calcification of the pleura. Salmonella Enteritidis was isolated from the sputum, bronchoalveolar lavage fluid and stool. He was diagnosed as suffering from Salmonella-empyema with an internal fistula. Based on the in vitro sensitivity test, sulfamethoxazole/trimethoprim was started. However, the efficacy of the antimicrobia was not sufficient. He then underwent left pleuropneumonectomy. Salmonella was cultured also from the specimen obtained at the operation. His course after operation was uneventful. Thus, although Salmonella Enteriditis is known as a common pathogen of food poisoning, it can cause epyema, especially in a case with an impaired host defense system. [R108] *Antibody- can cell-mediated responses to sulfamethoxazole (SMX) were analyzed in AIDS patients with or without a history of hypersensitivity and in negative controls. In 20 of 20 (P < 0.01) human immunodeficiency virus (HIV)-seropositive patients with skin reactions to cotrimoxazole, we found sulfamethoxazole-specific antibodies, while only 9 of 20 and 17 of 20 HIV-seropositive patients without a history of hypersensitivity to cotrimoxazole had sulfamethoxazole-specific immunoglobulin M (IgM) and IgG, respectively. The levels of specific immunoglobulin M (IgM) and IgG were higher in patients with skin reactions than in patients without reactions (immunoglobulin M, 1.0 +/- 0.19 vs 0.47 +/- 0.23 [P < 0.001]; IgG, 0.68 +/- 0.15 vs 0.47 +/- [P < 0.001] [mean optical density values +/- standard deviations]). Seronegative controls with no history of exposure to sulfa compounds did not have sulfamethoxazole-specific IgG or immunoglobulin M antibodies, and controls with a history of intake of sulfamethoxazole with or without reactions had low levels of IgG or immunoglobulin M. The sulfamethoxazole-specific IgG subclasses were exclusively IgG1 and IgG3. None of the patients had detectable sulfamethoxazole-specific IgE of IgA antibodies nor did they exhibit a cell-mediated response as measured by a lymphocyte proliferation assay. Antibodies to sulfamethoxazole recognized N-acetyl-sulfonamide, N-(2-thiazolyl)-sulfanilamide, sulfadiazine, and sulfisoxazole but did not recognize sulfanilamide or 3-amino-5-methyl isoxazole in an inhibition assay. It is not know whether the sulfamethoxazole-specific antibodies associated with hypersensitivity reactions to sulfamethoxazole in HIV-seropositive patients have a pathogenic role in these reactions. [R53] *There is evidence that T lymphocytes play a critical role in the pathogenesis of drug-induced bullous exanthems. Sulfonamides are known to be among the most frequent aetiological agents in these sever drug-induced cutaneous hypersensitivity reactions. Several studies indicate that cytochrome P450-dependent metabolites of sulfonamides act as the nominal allergens. A 70-yr old woman with a severe blistering exanthem caused by cotrimoxazole (sulfamethoxazole and trimethoprim) was studied. We employed an in vitro approach to determine whether cytochrome P450-dependent enzymes activated drug-specific T lymphocytes from this patient. Immunohistochemical analysis of involved skin revealed a majority of epidermal CD8+ T lymphocytes, whereas the dermal infiltrate was composed of both CD4+ and CD8+ T cells. Dermal T lymphocytes isolated from lesional skin proliferated in response to sulfamethoxazole, but not to trimethoprim, in the presence of autologous mononuclear cells used as antigen-presenting cells. The antigen-specific response of sulfamethoxazole-specific T cells was significantly augmented in the presence of murine liver microsomes with P450-dependent catalytic activities. Our observations suggest that some cutaneous hypersensitivity reactions to sulfamethoxazole are due to drug-specific T lymphocytes. Cytochrome P450-dependent enzymes may play a critical role in the formation of the nominal antigen, which is recognized by antigen-specific T cells. [R54] *We identified 40 patients (25 men and 15 women) who developed calculi composed totally or partially of sulfonamides (acetylsulfamethoxazole, sulfadiazine, and acetylsulfisoxazole) between 1980 and 11987. The incidence of sulfonamide stones if less than 1% of stones. Patient characteristics were determine from questionnaires sent to the patients and attending physicians. The majority of patients developed symptoms 1 to 4 weeks after beginning sulfonamide therapy. The bladder was the most common stone location. Obstruction of the urinary system by the acetyl derivatives of the drugs is the most serious consequence of sulfonamide therapy. Early recognition of drug-related stones is essential to protect patients from recurrences, reduce the risk of renal complications, and avoid continuing ineffective therapeutic regimens. [R109] *Drug-dependent IgG antibodies (DDAb) induced by sulfamethoxazole (SMX) and sulfisoxazole (SIX) were identified by flow cytometry in 15 patients who developed thrombocytopenia while taking one of these medications. Fourteen of the 15 drug-dependent IgG antibodies were specific solely for the glycoprotein (GP)IIb/IIIa complex, and 13 of these reacted wholly or in part with epitopes present only on the intact glycoproteinIIb/IIIa heterodimer. None of 12 sulfamethoxazole-induced drug-dependent IgG antibodies cross-reacted with sulfisoxazole, but one of three sulfisoxazole-induced antibodies reacted with sulfamethoxazole. Each of 10 sulfamethoxazole-induced drug-dependent IgG antibodies tested reacted with the N1-acetyl metabolite of sulfamethoxazole, but only one reacted fully with the N4-acetyl derivative. Detection of the sulfamethoxazole- and sulfisoxazole-dependent antibodies was facilitated by using bovine serum albumin (BSA) to achieve suspension of these weakly soluble drugs in an aqueous medium. Our findings indicate that drug-dependent IgG antibodies induced by sulfamethoxazole and sulfisoxazole, in contrast to those induced by quinidine and quinine, are mainly specific for glycoproteinIIb/IIIa and react preferentially with calcium-dependent epitopes present only on the intact glycoproteinIIb/IIIa heterodimer. [R110] TOLR: *The frequency of development of bacterial resistance to trimethoprim- sulfamethoxazole is lower than it is to either of the agents alone. [R34, 1063] *Background: The mechanism of tolerance to incremental doses of trimethoprim-sulfamethoxazole given to human immunodeficiency virus-infected persons who have had a prior intolerance to this agent has not been studied. Objective: We prospectively evaluated a regimen of incremental doses of oral trimethoprim-sulfamethoxazole in human immunodeficiency virus-infected persons who had a prior trimethoprim-sulfamethoxazole-induced fever and nonexfoliative skin rash to investigate the mechanism by which it permits tolerance. Methods: Oral trimethoprim (0.00004 mg)/sulfamethoxazole (0.00002 mg) was given to 22 human immunodeficiency virus-infected persons on day 1 and gradually increased over eight days to 1 double strength (DS) tablet/day in an outpatient setting. At study entry, skin tests and IgG antibodies to sulfa were performed; the latter was repeated at study week 4. Results: Nineteen patients tolerated trimethoprim/sulfamethoxazole at the completion of the 8-day protocol (86% effective). Moderate toxicities occurred in eight persons during the desensitization protocol; five of these were able to continue trimethoprim/sulfamethoxazole with adjunctive prednisone. Skin tests to sulfa antigen were negative in all persons. Eleven patients at study entry had antibodies to sulfamethoxazole; IgG antibodies appeared at week 4 in 8 of the 11 patients who initially had no antibody detected. Conclusions: The mechanism of tolerance to the incremental doses of trimethoprim/sulfamethoxazole given to previously intolerant human immunodeficiency virus-infected persons is not due to desensitization and remains undetermined. [R83] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R111] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC 985.48. Sulfamethoxazole in Drug Tablets. 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ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRACYCLINE- SY: *ABRAMYCIN-; *ABRICYCLINE-; *ACHROMYCIN-; *ACHROMYCIN- (NAPHTHACENEDERIVATIVE); *AGROMICINA-; *AMBRAMICINA-; *AMBRAMYCIN-; *BIOCYCLINE-; *BIO-TETRA-; *BRISTACICLIN-ALPHA-; *BRISTACYCLINE-; *CEFRACYCLINE-SUSPENSION-; *CICLIBION-; *CRISEOCICLINA-; *CYCLOMYCIN-; *DEMOCRACIN-; *DESCHLOROBIOMYCIN-; *4-(DIMETHYLAMINO)-1,4,4A,5,5A,6,11,12A-OCTAHYDRO-3,6,1 0,12,12A-PENTAHYDROXY-6-METHYL-1,11-DIOXO-2-NAPHTHACENECARBOXAMIDE; *MERICYCLINE-; *6-METHYL-1,11-DIOXY-2-NAPHTHACENECARBOXAMIDE-; *2-NAPHTHACENECARBOXAMIDE, 4-(DIMETHYLAMINO)-1,4,4A,5,5A,6,11,12A-OCTAHYDRO-3,6,10,12,12A-PENTAHYDROXY-6-METHYL-1,11-DIOXO-; *NEOCYCLINE-; *OLETETRIN-; *OMEGAMYCIN-; *ORLYCYCLINE-; *PANMYCIN-; *POLYCYCLINE-; *POLYCYCLINE- (ANTIBIOTIC); *POLYOTIC-; *PUROCYCLINA-; *ROVICICLINA-; *SIGMAMYCIN-; *SOLVOCIN-; *STECLIN-; *TETRABON-; *TETRA-CO-; *TETRACYCLINE-I-; *TETRACYCLINE-II-; *TETRACYN-; *TETRADECIN-; *TETRAFIL-; *TETRAVERINE-; *TSIKLOMISTSIN-; *VERACIN-; *VETRACYCLINUM- RN: 60-54-8 RELT: 3130 [MINOCYCLINE]; 3145 [OXYTETRACYCLINE] MF: *C22-H24-N2-O8 ASCH: Tetracycline Hydrochloride; 64-75-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Antibiotic substance produce by Streptomyces spp. [R1, 1571] *Production by Streptomyces viridifaciens. [R1, 1571] *Obtained from certain Streptomyces species. It can be prepared from chlorotetracycline or oxytetracycline, which it resembles in its actions and uses. It has been synthesized. [R2] *CATALYTIC HYDROGENATION OF CHLORTETRACYCLINE [R3] FORM: *... TETRACYCLINE HYDROCHLORIDE, USP (ACHROMYCIN, PANMYCIN, STECLIN, SUMYCIN, TETRACHEL, TETRACYN) ... /IS/ AVAIL IN WIDE VARIETY OF FORMS FOR ORAL, TOPICAL AND PARENTERAL ADMIN. ... USUAL CONCN OF TETRACYCLINE FOR OPHTHALMIC USE IS 0.5 TO 1%. [R4, 1186] *Cyclopar 250 AND Cyclopar 500: 250 and 500 mg of tetracycline hydrochloride. /Tetracycline hydrochloride/ [R5] *Achromycin: Ophthalmic suspension sterile contains 10 mg of tetracycline hydrochloride per ml with Plastibage 50W and light mineral oil. /Tetracycline hydrochloride/ [R6] *Achromycin: Intramuscular solution contains 100 mg/vial of tetracycline hydrochloride, procaine HCl: 40 mg/vial; magnesium chloride: 46.84 mg/vial; ascorbic acid: 250 mg/vial. Sterile tetracycline hydrochloride for injection: 250 mg tetracycline hydrochloride with 625 mg ascorbic acid. /Tetracycline hydrochloride/ [R7] *Mysteclin-F capsules: equivalent to 250 tetracycline hydrochloride with 50 mg amphotericin B, and potassium metaphosphate buffer. Mysteclin-F syrup: 5 ml (teaspoon) tetracycline equivalent to 125 mg of tetracycline hydrochloride, buffered with potassium metaphosphate, and 25 mg amphotericin B. /Tetracycline hydrochloride and Amphotericin B/ [R8] *SK-tetracycline HCl capsules 250 and 500 mg. SK-tetracycline syrup: 125 mg/5 ml [R9] *Sumycin 250 and Sumycin 500: tablets; Sumycin syrup 125 mg/5 ml /Tetracycline hydrochloride/ [R10] *Panmycin P, Telotrex, Tetradecin Novum, Tetrex, Upcyclin /Phosphate complex/ [R1, 1572] *Grade: USP [R2] *SOME OF THE TETRACYCLINES ARE...MARKETED AS FLAVORED POWDERS, OPHTHALMIC SOLN AND OINTMENTS, SOLN FOR INJECTION, SOL SALTS FOR PREPN OF ORAL SUSPENSIONS AND DROPS, AND SYRUPS AND ELIXIRS FOR PEDIATRIC USE. /TETRACYCLINES/ [R4, 1186] MFS: *Cytec Industries, Five Garret Mountain Plaza, West Paterson, NJ 07424, (201)357-3100. Production site: Process Chemicals, Fine Chemicals, Contract, Pearl River, NY 10965 /Tetracycline hydrochloride/ [R11] OMIN: *US PATENTS FOR PREPN AND PURIFICATION: 2,699, 054 TO CONOVER (1955); 2,712,517 and 2,886,595 (1955 and 1959 TO BRISTOL LAB); 3,005,023 and 3,019,173 (1961 and 1962 TO AM CYANAMID); 3,301,899 (1967 TO BRYSTOL-MYERS); and 3,053,892 (1962 TO AM CYANAMID). [R12] *This review includes a discussion of the structural requirements for biological activity. A section on the total synthesis covers the more important synthetic efforts in the field. The variables in the manufacturing process, ie, choice of strains of microorganism and choice of medium are described as well as the actual fermentation process and subsequent isolation and purification procedures. The elucidation of the biosynthetic mechanism is detailed including the important contributions of the blocked mutant and co-synthesis approach. [R13, p. 3(78) 64-69] *The tetracyclines are derivatives of the polycyclic naphthacene-carboxamides and include tetracycline, chlortetracycline, demeclocycline, oxytetracycline, and minocycline. [R13, p. 2(78) 813] *Various tetracycline formulations provided different degradation patterns after 2 months storage at 50 deg. ... Ointments, due to inhomogeneity of mixing, varied significantly. This was not so with capsules. Syrups, however, were the most unstable formulations; the content decreased rapidly with a corresponding increase in the content of anhydrotetracycline. Of various systems studied, tetracycline was most stable in citrate-borate buffer when no other ingredients were present in the sample. However, when it was formulated as a syrup, phosphate buffer conferred the greatest ... stability. This may be due to other ingredients present in syrup causing instability of tetracycline. Therefore, tetracycline capsules can be formulated in citrate-borate buffer because no other ingredients are present in the capsules. [R14] *Press-coated tablets are prepared without the use of any liquid phase by compressing a core containing an active ingredient and compressing a second mixture over it. ... Cores containing tetracycline-HCl 0.250, talc 0.003, Avicel FMC 0.018, and calcium stearate 0.004 kg/1000 were prepared and coated with a mixture of talc 0.013, lactose 0.40334, Avicel FMC 0.127, tartrazine 0.00055, indigotin 0.00011, and Ca stearate 0.006 kg/1000. The tablets had 300 mg cores and 550 mg in the outer layer. The tablets dissolved much faster than hard or soft capsules or pills. [R15] *An instant dry pharmaceutical that is an intermediate in the manufacture of aqueous suspensions which contain an active ingredient together with a hydrocolloid forming polysaccharide and a surfactant. Thus, 100 parts guar gum and 30 parts micronized tetracycline were mixed, and the mixture was moistened with 3 parts ethanol containing 0.1 parts sodium dioctylsulfosuccinate. The mixture was heated to 50 degrees in vacuo and 10 parts superheated steam imploded on the rotating mass. Simultaneous addition of buffers can be used to adjust pH. Moistening of the guar gum surface caused binding of the tetracycline, and the mixture was dried, screened, and mixed with sugar and flavorings. [R16] USE: *MEDICATION *MEDICATION (VET) CPAT: *ESSENTIALLY 100% AS A BROAD SPECTRUM ANTIBIOTIC (1976) [R3] PRIE: U.S. PRODUCTION: *(1972) GREATER THAN 1.82X10+6 GRAMS [R3] *(1975) GREATER THAN 1.82X10+6 GRAMS [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW CRYSTALLINE POWDER [R17, 1143]; *Yellow, crystalline powder [R2] ODOR: *Odorless [R2] MP: *170-5 deg C [R18] MW: *444.43 [R1, 1571] DSC: *pKa= 3.30 [R19] OWPC: *log Kow= -1.37 [R20] PH: *3.0-7.0 /saturated solution/ [R2] SOL: *1 G IN ABOUT 2500 ML H2O AND ABOUT 50 ML ALCOHOL; FREELY SOL IN DIL HCL AND ALKALI HYDROXIDE SOLN; PRACTICALLY INSOL IN CHLOROFORM AND ETHER [R17, 1143]; *Practically insoluble in chloroform and ether, very slightly soluble in water, slightly soluble in alcohol, very soluble in dilute hydrochloric acid and alkali hydroxide solutions. [R2]; *In water, 231 mg/l at 25 deg C. [R21] SPEC: *SPECIFIC ROTATION: -254 DEG TO -270 DEG; PH (AQ SUSPENSION, 10 MG/ML) BETWEEN 3 and 7 [R17, 1143]; *MASS: 3365 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R22] OCPP: *SWELLS AT 165 DEG C. DECOMP BETWEEN 170-175 DEG C ; PKA (50% AQ DMF): 8.3, 10.2; SPECIFIC ROTATION: -257.9 DEG @ 25 DEG C/D (0.1 N HCL); and -239 DEG @ 25 DEG C/D (METHANOL); MAX ABSORPTION (0.1 N HCL): 220, 268 and 355 NM (E= 13,000, 18,040 and 13,320) /TRIHYDRATE/ [R1, 1572] *Crystals...Becomes anhydr by drying in vacuo at 60 deg C for 8 hrs. /Trihydrate/ [R1, 1572] *YELLOW CRYSTALLINE POWDER /HYDROCHLORIDE/ [R17, 1143] *YELLOW FINE CRYSTALLINE POWDER /PHOSPHATE COMPLEX/ [R17, 1143] *Stable in neutral and in alkaline soln. Soly at about 28 deg: 1.7 mg/ml water; > 20 mg/l methanol. /Trihydrate/ [R1, 1572] *YELLOW, ODOLESS POWDER. SPARINGLY SOL IN H2O; SLIGHTLY IN ETHANOL /PHOSPHATE COMPLEX/ [R1, 1572] *Freely sol in water, sol in methanol, ethanol. Insol in ether, hydrocarbons. /Hydrochloride/ [R1, 1572] *Crystals from butanol + HCl, dec 214 deg C. Specific rotation: -257.9 deg at 25 deg C/D (0.5 in 0.1 N HCl). pH (2% aq soln): 2.1-2.3. /Hydrochloride/ [R1, 1572] *Melting point: 175-177 deg C /Tetracycline dihydrate/ [R23] *Tetracycline dihydrate is light-sensitive and hygroscopic. /Tetracycline dihydrate/ [R23] *Numerous tetracyclines have been studied in stereostructure-activity relationships. The natural alpha-orientation of the C-4 dimethylamino group is essential for bioactivity. The natural tetracycline configuration at C-5a is alpha; its epimer is less than 2% as active. Hydrofluoric acid-catalyzed inversion of configuration at C-6 of an inactive natural isomer, eg, 5a, 11a- dehydrochlorotetracycline, yields the C-6 epimer which is 1.5 times as potent in vitro as tetracycline. 6 alpha-Fluorine analogs also showed enhanced potency over beta-epimers in vitro. [R13, p. 17(82) 321] *Elemental analysis: About 45% C; 6-8% P; 4.8% N; 3.9% H; 0.7-1.4% Na. [R24] *Melting point: 220-223 deg C /Tetracycline hydrochloride/ [R23] *RAPIDLY DESTROYED BY ALKALI HYDROXIDE SOLN [R17, 1143] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R25] SERI: *Skin irritant. /Tetracycline hydrochloride/ [R26] OPRM: *Leave contaminated area immediately. ... Flood all areas of the body that have contacted the substance with water. Remove the contaminated clothing under the water stream. Use soap to help assure removal. Isolate contaminated clothing /after removal/. ... [R27] SSL: *STABLE IN AIR, BUT EXPOSURE TO STRONG SUNLIGHT CAUSES IT TO DARKEN; POTENCY IS AFFECTED BY SOLN OF PH BELOW 2 [R17, 1143] *RAPIDLY DESTROYED BY ALKALI HYDROXIDE SOLN [R17, 1143] *WITHIN PHYSIOLOGICAL AND MODERATELY ALKALINE RANGE OF PH IT IS MORE STABLE THAN CHLORTETRACYCLINE [R17, 1143] *ITS SOLN DARKEN MORE RAPIDLY THAN CHLORTETRACYCLINE BUT LESS THAN OXYTETRACYCLINE [R17, 1143] *AQ SOLN BECOMES TURBID AFTER SOME TIME BECAUSE OF HYDROLYSIS /HYDROCHLORIDE/ [R17, 1143] *STABLE IN AIR BUT EXPOSURE TO STRONG SUNLIGHT IN MOIST AIR CAUSES IT TO DARKEN /HYDROCHLORIDE/ [R17, 1143] *IN CONTRAST TO CHLORTETRACYCLINE, TETRACYCLINE IS QUITE STABLE IN NEUTRAL AND ALKALINE SOLN /TRIHYDRATE/ [R12] CLUP: *Dampen spilled material with water to avoid dust /generation/, then transfer material to a suitable container. Use absorbent paper dampened with water to pick up remaining material. Wash surfaces with soap and water. Seal all wastes in vapor-tight plastic bags for eventual disposal. /Tetracycline hydrochloride/ [R27] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Eye contact: remove any contact lenses at once. Flush eyes well with copious quantities of water or normal saline for at least 20-30 minutes. ... /Tetracycline hydrochloride/ [R27] HTOX: *LONG-TERM THERAPY WITH TETRACYCLINES MAY PRODUCE CHANGES IN PERIPHERAL BLOOD. LEUKOCYTOSIS, ATYPICAL LYMPHOCYTES, TOXIC GRANULATION OF GRANULOCYTES AND THROMBOPENIC PURPURA HAVE BEEN OBSERVED. /TETRACYCLINES/ [R28, 1130] *CHILDREN RECEIVING LONG OR SHORT TERM THERAPY WITH A TETRACYCLINE MAY DEVELOP BROWN DISCOLORATIONS OF TEETH. LARGER THE DOSE ... RELATIVE TO BODY WT, MORE INTENSE THE DISCOLORATION OF ENAMEL. DURATION OF THERAPY APPEARS TO BE LESS IMPORTANT THAN TOTAL ... /AMT/ ANTIBIOTIC ADMIN. /TETRACYCLINES/ [R28, 1130] *A case is reported in which a 43- year old man developed intravascular hemolysis with hemoglobinemia, hemoglobinuria, thrombocytopenia, hypofibrinogenemia, and transient renal impairment on at least two occasions after oral use of tetracycline. The patient's serum contained an IgG antibody that reacted only with red cells exposed either in vivo or in vitro to tetracycline. [R29] *A case report of a 24-year old man who developed esophageal ulceration after a 7-day treatment of a chest infection with 250 mg tetracycline hydrochloride. /Tetracycline hydrochloride/ [R30] *The effect of four tetracyclines, tetracycline, rolitetracycline, oxytetracycline, and doxycycline, on human natural killer (NK) cell-mediated cytotoxicity was examined in vitro. Doxycycline was the only tetracycline which inhibited the NK cell activity. At concentrations of 10 micrograms/ml the drug caused approximately 50% inhibition of NK cell mediated cytotoxicity against K562 target. The inhibition was not a result of a toxic effect of the drug on NK cells. These results support the previous findings that doxcycline shows immunosuppressive properties. [R31] *Hemolysis induced by long-wave ultraviolet radiation (UVA) and 8 different commercial tetracycline derivatives was studied in a model using human red blood cells. Demethylchlortetracycline and doxycycline were shown to have pronounced hemolytic properties causing 88% and 85% hemolysis, respectively, at a concentration of 50 micrograms/ml and 72 J/sq cm /ultraviolet radiation/ Tetracycline, oxytetracycline, and chlortetracycline caused maximally 18% hemolysis at 200 micrograms/ml and lymecycline only 7% at 100 micrograms/ml. Methacycline showed intermediate hemolytic effect of 36% at 200 micrograms/ml. Minocycline had no hemolytic effect whatsoever. These experimental data, correlate very well with clinical reports and comparative phototoxicity trials in humans. /Tetracycline and derivatives/ [R32] *A report of five young adults who developed benign intracranial hypertension associated with the oral administration of tetracycline 200-1000 mg daily. Four of the patients were taking tetracycline for acne: two were also taking vitamin A, 50,000 units on alternate days. The fifth case is a 14-year old boy who developed papilloedema after taking a short course for bronchitis. All symptoms disappeared soon after stopping the drugs, though in two cases the papilloedema persisted for many months. It was concluded that benign intracranial hypertension should be suspected in young women complaining of headache during tetracycline treatment. Moreover, young women given tetracycline and vitamin A in combination for acne may be at special risk and should be kept under surveillance. [R33] *Based upon 1944 pregnancy exposures, possible associations with congenital anomalies found in 61 infants: hypospadias (5 cases), inguinal hernia (47 cases), limb hypoplasia (6 cases), and clubfoot (3 cases). [R34] NTOX: *RATS GIVEN ... /400 MG/KG/ IP ... DEVELOPED POTENTIALLY LETHAL METABOLIC ACIDOSIS. ACCOMPANYING HYPERKALEMIA RESULTED IN DANGEROUS CARDIAC ARRHYTHMIAS. /TETRACYCLINES/ [R35] *CATS AND DOGS MAY SHOW GASTRIC UPSETS AND OCCASIONALLY DIARRHEA FROM HIGH/OR CHRONIC ORAL DOSAGE. ... /IF INJECTED/ INTO JOINT CAVITIES ... IT MAY PRODUCE ACUTE INFLAMMATORY RESPONSE. IT WILL CAUSE FLUORESCENCE IN GROWING BONE AND TEETH. [R36] *After iv injection of 5 or 10 mg of tetracycline, acute collapse occurred in some cows. In cows that collapsed, blood pressure dropped, sometimes almost to zero, and bradycardia and severe changes in the ECG were observed. ... [R37] *Mature female rhesus monkeys were used to evaluate the effects of a one year course of tetracycline 50 mg/kg/day, im) on the formation, maturation, and mineralization of mandibular bone. The bones from the treated group contained normal concentrations of calcium, inorganic phophorus, and hydroxyproline, and the treatment schedule did not alter the distribution (percentage) of total osteons into slightly, moderately, and highly mineralization classes. Tetracycline impairs bone mineralization and subsequent maturation of the mineral and matrix moieties. The percentage of highly mineralized osteons labeled with tetracycline was subnormal. Density gradient fractionation studies indicated the presence of abnormally high calcium/phosphorus ratios in the temporally young newly formed bone mineral and somewhat higher ratios in the most mature bone fraction. Protracted tetracycline treatment at high dosages impairs bone growth and maturation in adult rhesus monkeys. [R38] *Ante- and postnatal development of anatomical structures and cells of lymphatic nodes have been studied in rat offspring subjected to tetracycline during organogenesis (the 8th-14th days) and during fetogenesis (the 15th-20th days). Tetracycline injection during 8th-14th days of organogenesis results in certain disturbances of the nodular structure formation and the inhibition of lympho- and plasmo-cytopoesis against the background of a sharp increase in number of basophilic granulocytes and tissue basophils. The antibiotic effect on the 15th-20th days of embryogenesis does not disturb lymph node formation, but produces increasing numbers of lymphocytes, plasmocytes, macrophages, eosinophilic granulocytes, and tissue basophils in /rats/. [R39] *Structural /abnormalities/ of the thymus have been studied during antenatal and early postnatal periods of ontogenesis under the effect of tetracycline hydrochloride administered in therapeutic doses to the mother--fetus during pre-implantation period of development (the 1st-6th days). ... Ultrastructural changes of epithelioreticulocytes and thymocytes, a delayed appearance of the subcapsular zone, a delayed division of the thymus lobules into the cortex and medullar substance, a decreasing number of all cellular forms of the lymphoid line during intrauterine development have been /observed/, as well as a decreased number of small lymphocytes at all stages of the antenatal and early postnatal periods. ... /Tetracycline hydrochloride/ [R40] *Forty female Sprague-Dawley rats were randomly divided into two groups. Group 1 animals received tetracycline solution (0.1% during week 1 and 0.01% thereafter) in drinking water. Group 2 animals received double-distilled demineralized water. Animals in both groups were inoculated orally with an equal number of viable, mucosally pathogenic Candida albicans. After 20 weeks, inspection of the tongues showed gross lesions in 16 of the 20 animals in group 1 and 17 of the 20 in group 2. These lesions were confirmed histologically. No significant difference in the number of lesions was noted between the two groups. However, the lesions in group 1 animals were significantly larger than those in group 2 animals. These results suggest that, given this mucosally pathogenic strain of Candida albicans, the establishment of a chronic infection of the rat tongue is apparently not influenced by tetracycline in the drinking water as administered in this study. This suggests that antibiotic exposure is not an essential factor in the pathogenesis of this lesion. The larger size of the lesions, however, does appear to be related to the use of tetracycline in the drinking water. [R41] *Cynomolgus monkeys were used to screen for chemicals which potentially could be used as tubal occluding agents. Intrauterine administrations of solution pellets of tetracycline and its analogs (100 mg doses) were tested for their effects on morphological changes in the reproductive tract of monkeys. These effects were compared to monkeys receiving intrauterine administration of quinacrine pellets (36 mg) since quinacrine has been used successfully in the clip setting. Blood levels of drugs, blood chemistry and hematology determinations, and liver and kidney pathology data were also obtained as indexes for toxicity. Morphological damage to the uterine lining and intramural section of the tube (including necrosis, inflammation, or scarring) was elicited by intrauterine tetracycline and doxycycline in the same frequency and severity as quinacrine. In contrast, saline or sham control monkeys showed no morphological damage of the tube or uterus. Although all drugs could be detected in the blood 4 hr after intrauterine administration, levels were near or below the limit of detection by 1 wk. No evidence was found for toxicity of tetracycline or its analogs for the dosage given. Because of these results and the extensive literature on tetracycline toxicity, further studies should be directed toward the use of tetracycline as a sterilizing agent in women. [R42] *At high concentrations, tetracyclines also inhibit mammalian protein synthesis. [R43, 2110] *Experiments in rats have shown that the newborn can have discoloration of the lens, as well as the cornea and sclera, after administration of tetracycline to the mother during pregnancy. [R44] *In young rabbits, intensive direct exposure of the eyes by wearing tetracycline-impregnated hydrophilic contact lenses for several days has caused the crystalline lenses to become yellowish, with opacification, especially in the nucleus. The corneas also developed yellow-brown discoloration. [R44] NTXV: *LD50 Rat oral 807 mg/kg; [R25] *LD50 Mouse oral 678 mg/kg; [R25] *LD50 Guinea pig oral 1875 mg/kg; [R25] NTP: *... Toxicology and carcinogenesis studies of tetracycline hydrochloride (USP grade, 91% pure) were conducted by feeding diets containing tetracycline hydrochloride to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 years. ... The 2 yr studies of tetracycline hydrochloride were conducted by feeding diets containing 0, 12,500, or 25,000 ppm tetracycline hydrochloride to groups of 50 rats and 50 mice of each sex for 103 wk. Conclusions: Under the condltlons of these 2 yr feed studies, there was no evidence of carcinogenic activity of tetracycline hydrochloride for male or female F344/N rats and B6C3F1 mice fed diets containing 12,500 or 25,000 ppm. Tetracycline hydrochloride dosed female rats and male mice had greater survival rates than the respective controls during these studies. Dosed mice had lower body weight than controls, and dosed female mice had no hepatocellular adenomas or carcinomas. /Tetracycline hydrochloride/ [R45] POPL: *Young women given tetracycline and vitamin A in combination for acne may be at special risk and should be kept under surveillance. [R33] ADE: *ALL TETRACYCLINES ARE ADEQUATELY BUT INCOMPLETELY ABSORBED FROM GI TRACT. MOST ABSORPTION TAKES PLACE FROM STOMACH AND UPPER SMALL INTESTINE AND IS GREATEST IN FASTING STATE. /TETRACYCLINES/ [R28, 1126] *... /TETRACYCLINE IS/ VERY INCOMPLETELY ABSORBED. AFTER SINGLE ORAL DOSE PEAK PLASMA CONCN ARE ATTAINED IN 2-4 HR. ... ADMIN OF 250 MG EVERY 6 HR PRODUCES PEAK PLASMA CONCN OF APPROX 2-2.5 UG/ML. [R28, 1126] *THE PRIMARY ROUTE OF ELIMINATION FOR MOST TETRACYCLINES IS THE KIDNEY, ALTHOUGH THEY ARE ALSO CONCENTRATED IN THE LIVER AND EXCRETED BY ... BILE, INTO INTESTINE, FROM WHICH THEY ARE PARTIALLY REABSORBED. /TETRACYCLINES/ [R28, 1126] *ELIMINATION FROM INTESTINAL TRACT OCCURS EVEN WHEN DRUGS ARE GIVEN PARENTERALLY, AS RESULT OF EXCRETION IN BILE. /TETRACYCLINES/ [R28, 1123] *20-60% OF IV DOSE OF 0.5 G OF TETRACYCLINE IS EXCRETED IN URINE DURING 1ST 24 HR; FROM 20-55% OF ORAL DOSE, REGARDLESS OF SIZE, IS EXCRETED BY THIS ROUTE. [R28, 1126] *DECR HEPATIC FUNCTION OR OBSTRUCTION OF COMMON BILE DUCT RESULTS IN REDUCTION IN BILIARY EXCRETION OF THESE AGENTS AND THEIR CONSEQUENT PERSISTENCE IN BLOOD. BECAUSE OF THEIR ENTEROHEPATIC CIRCULATION, THE TETRACYCLINES MAY BE PRESENT IN BLOOD FOR LONG TIME AFTER CESSATION OF THERAPY. /TETRACYCLINES/ [R28, 1126] *INFLAMMATION OF MENINGES IS NOT PREREQUISITE FOR PASSAGE OF TETRACYCLINES INTO CEREBROSPINAL FLUID. /TETRACYCLINES/ [R28, 1126] *PENETRATION OF THESE DRUGS INTO MOST OTHER FLUIDS AND TISSUES IS EXCELLENT. TETRACYCLINES ARE STORED IN RETICULOENDOTHELIAL CELLS OF LIVER, SPLEEN, AND BONE MARROW, AND IN BONE AND DENTIN AND ENAMEL OF UNERUPTED TEETH. TETRACYCLINES CROSS PLACENTA AND ENTER FETAL CIRCULATION AND AMNIOTIC FLUID. /TETRACYCLINES/ [R28, 1126] *CONCN OF TETRACYCLINE IN UMBILICAL CORD PLASMA REACH 60% AND IN AMNIOTIC FLUID 20% OF THOSE IN CIRCULATION OF MOTHER. RELATIVELY HIGH CONCN OF THESE DRUGS ARE ALSO FOUND IN MILK. /TETRACYCLINES/ [R28, 1126] *DEPOSITION OF DRUG IN TEETH AND BONES IS PROBABLY DUE TO ITS CHELATING PROPERTY AND FORMATION OF A TETRACYCLINE-CALCIUM ORTHOPHOSPHATE COMPLEX. ... TETRACYCLINES ARE DEPOSITED IN SKELETON DURING GESTATION AND THROUGHOUT CHILDHOOD. /TETRACYCLINE/ [R28, 1130] *VOLUME OF DISTRIBUTION OF TETRACYCLINES IS RELATIVELY LARGER THAN THAT OF BODY WATER, INDICATING SEQUESTRATION IN SOME TISSUES. THEY ARE BOUND TO PLASMA PROTEINS IN VARYING DEGREE. APPROX VALUE /FOR TETRACYCLINE IS/ 25-30%. ... [R4, 1185] *SINCE RENAL CLEARANCE OF THESE DRUGS IS BY GLOMERULAR FILTRATION, THEIR EXCRETION IS SIGNIFICANTLY AFFECTED BY STATE OF RENAL FUNCTION. /TETRACYCLINES/ [R28, 1126] *Approximately 75-80% of an oral dose...is absorbed from the GI tract in fasting adults. [R43, 384] *Food and/or milk reduce GI absorption... by 50% or more. ...concurrent oral administration of antacids...may also decrease oral absorption of tetracycline preparations. [R43, 385] *...readily distribute into the skin following intravascular administration. [R46] *ALL TETRACYCLINES ARE REMOVED FROM BLOOD BY LIVER, WHERE THEY ARE CONCENTRATED AND THEN EXCRETED, BY...BILE, INTO INTESTINE, FROM WHICH THEY ARE PARTIALLY REABSORBED. BILIARY CONCN OF THESE AGENTS AVG AT LEAST 5-10 TIMES HIGHER THAN SIMULTANEOUS VALUES IN PLASMA. /TETRACYCLINES/ [R4, 1185] BHL: */IT HAS HALF-LIFE/ IN RANGE OF 6-12 HR... [R28, 1126] *Tetracycline was encapsulated in erythrocytes by a dialysis technique. On encapsulation of (14)C sucrose and (3)H tetracycline, the drug concn (0.2 mg/ml of erythrocytes) decreased the tetracycline encapsulation, but not (14)C sucrose. Carrier erythrocytes containing tetracycline reinjected in calves were studied for their pharmacokinetic constants. the drug half-life was 6.7 hr with an overall elimination constant of 0.104 hr. [R47] *The serum half-life...is 6-12 hr in adults with normal renal funtion and is reported to be 57-120 hr in patients with severe renal impairment. [R43, 385] ACTN: *TETRACYCLINES ARE THOUGHT TO INHIBIT PROTEIN SYNTH BY BINDING SPECIFICALLY TO 30 S RIBOSOMES AND PREVENTING ACCESS OF AMINOACYL TRNA TO... MRNA-RIBOSOME COMPLEX. /TETRACYCLINES/ [R28, 1125] *... IT IS POSSIBLE THAT REVERSIBLY BOUND ANTIBIOTIC IS RESPONSIBLE FOR ANTIBACTERIAL ACTION. /TETRACYCLINES/ [R4, 1185] *TETRACYCLINE COMBINES WITH CELLULAR AND INTRACELLULAR MATERIAL TO FORM A FLUOROPHORE WHICH UNDER UV LIGHT GLOWS WITH YELLOW-GOLD FLUORESCENCE. THE FLUOROPHORE REMAINS IN BONE FOR MANY MO. [R48] *PHOTOALLERGIC REACTIONS ARE BELIEVED TO RESULT FROM LIGHT ENERGY ACTING ON OR ALTERING DRUG AND SKIN PROTEINS IN SUCH MANNER AS TO FORM AN ANTIGEN. THESE ERUPTIONS REQUIRE PREVIOUS CONTACT WITH OFFENDING SUBSTANCE, ARE NOT DOSE-RELATED, AND EXHIBIT CROSS-SENSITIVITY WITH CHEM RELATED COMPD. /TETRACYCLINES/ [R17, 1276] *DNA sequence specifying tetracycline resistance (Tcr) has been identified in Streptococcus mutans. [R49] *The hepatotoxic effects of tetracycline (I), rolitetracycline, and doxycycline were studied in male and female mice. All antibiotics (25-100 ug/g) increased the amount of unconjugated and total bilirubin. This effect was most pronounced after tetracycline, which also reduced the level of conjugated bilirubin. All drugs increased serum transaminase enzyme levels; this effect was more pronounced in females. [R50] INTC: *TETRACYCLINE ITSELF HAS BEEN SHOWN TO HAVE DIRECT, PH-DEPENDENT EFFECT ON RAT INTESTINE, RESULTING IN INCR ABSORPTION OF SULFANILIC ACID. [R51] *ORAL ADMIN OF FERROUS SULFATE (200-600 MG) INTERFERES WITH ABSORPTION OF TETRACYCLINE FROM GI TRACT AND VICE VERSA, LEADING TO DECR SERUM LEVELS OF ANTIBIOTIC AND IRON SALT, RESPECTIVELY. ... OTHER SALTS OF IRON SUCH AS FERROUS FUMARATE AND FERROUS GLUCONATE HAVE BEEN SHOWN TO INTERACT WITH TETRACYCLINE. [R52, 231] *BILIARY EXCRETION OF TETRACYCLINE ... IS INCR IN RATS BY TWO NEW CHOLERETIC AGENTS ALPHA,ALPHA-DIETHYL-1-NAPHTHYLACETIC ACID (DA 808) AND ALPHA-METHYL-ALPHA-(2-MORPHOLINOETHYL)-1-NAPHTHYLACETIC ACID (DA 1627). ... AS DA 808 AND DA 1627 CAUSE NO DECR IN TETRACYCLINE ... CONCN IN BILE, THEY APPEAR TO ACT AS TRUE CHOLERETICS. ... [R53] *ABSORPTION OF THESE AGENTS IS IMPAIRED BY CONCURRENT INGESTION OF DAIRY PRODUCTS; ALUMINUM HYDROXIDE GELS; CALCIUM, MAGNESIUM, AND IRON OR ZINC SALTS; AND BISMUTH SUBSALICYLATE . MECHANISMS RESPONSIBLE FOR DECR ABSORPTION APPEAR TO BE CHELATION OF DIVALENT AND TRIVALENT CATIONS. /TETRACYCLINES/ [R28, 1126] *BECAUSE METHOTREXATE BINDS TO PLASMA PROTEINS, IT CAN BE DISPLACED FROM ITS BINDING SITES AND MADE AVAILABLE TO REACT WITH DIHYDROFOLATE REDUCTASE. ... COMPD THAT ... DISPLACE ... INCL ... TETRACYCLINES. /TETRACYCLINES/ [R52, 395] *STRIKING ANTAGONISM BETWEEN PENICILLIN AND TETRACYCLINES HAS BEEN OBSERVED CLINICALLY IN PNEUMOCOCCAL MENINGITIS. ... /TETRACYCLINES/ [R4, 1185] *... POSSIBILITY OF ... SEVERE RENAL FAILURE IN PT WHO RECEIVE TETRACYCLINE AFTER BEING ANESTHETIZED WITH METHOXYFLURANE; IN THOSE WHO DIED, KIDNEYS CONTAINED NUMEROUS CALCIUM OXALATE CRYSTALS. /TETRACYCLINES/ [R4, 1189] *TETRACYCLINES ALSO INTERACT WITH DIURETICS TO CAUSE AZOTEMIA. /TETRACYCLINES/ [R17, 1138] *In bulls, penicillin, streptomycin, dibiomycin, and oxytetracycline in combination with drugs such as furazolidone and furacilin decreased the activity and adaptability of spermatozoa, increased the number of dead and pathologic sperm, decreased the sperm count, and caused the appearance of dystrophic changes in the reproductive organs. The greatest toxic effect was induced by combinations of the tetracycline antibiotics dibiomycin and oxytetracycline with penicillin and streptomycin. [R54] *... A 39-year old man with recalcitrant psoriasis who was successfully treated with a single weekly oral dose of 25 mg methotrexate for 16 weeks developed a classic cytotoxic reaction to methotrexate when tetracycline was administered concomitantly to treat a suspected mycoplasma pneumonia. Tetracycline is believed to have enhanced the toxicity of methotrexate. [R55] *In 99 male albino rats, ... vitamin E, sodium selenite, and astragalus infusion used separately lowered the toxic effect of tetracycline on the liver, while the use of vitamin E in combination with sodium selenite or astragalus infusion prevented such an effect of the antibiotic. This was evident from the decreased levels of lipid peroxidation products, ie, diene conjugates and malonic dialdehyde in the blood and liver, and a simultaneous incr in the ratio of sulfhydryl and disulfide groups in these biosubstrates. Parallelism of the changes in these indicies of the blood and liver was observed. It is suggested that lipid peroxidation plays an important part in the pathogenesis of liver with tetracyclines. The combined use of vitamin E and selenium-containing drugs is considered advisable for the prophylaxis and treatment of such /effects/. [R56] *The combined effects of ethinyl estradiol (0.5 micrograms/g sc once daily for 4 days) and tetracycline or doxycycline (50 micrograms/g iv) on liver weight and water content, serum transaminases, alkaline phosphatase, urea, triglycerides, and cholesterol as parameters of various liver functions were investigated in mice. It was apparent that, depending on the parameter tested, synergistic and antagonistic effects may occur, eg, synergistic effects were observed with serum transaminases and liver cholesterol; antagonistic effects were seen with serum cholesterol. [R57] *The combined effects of high doses of tetracycline and progesterone on parameters indicative for liver function (serum transaminases and urea, serum and liver triglycerides and cholesterol) have been studied in mice. Apart from disturbance of cholesterol metabolism, tetracycline-induced liver dysfunction was not aggravated by progesterone. [R58] *The interaction between ultraviolet light and tetracycline in producing cell killing and mutation has been studied in V79 Chinese hamster cells. It has been established that these agents act independently of each other. Cycloheximide altered the response to tetracycline in the fractionation experiment: when cycloheximide was not present, fractionation of tetracycline treatment resulted in a higher mutation yield but no change in survival level; in the presence of cycloheximide, however, mutation was greatly reduced but survival increased. The results were taken to indicate that for tetracycline action to take place, de novo protein synthesis during tetracycline treatment was necessary. Caffeine had no influence on tetracycline-induced lethality or mutagenicity. This observation was considered to suggest that tetracycline did not affect cellular repair processes. [R59] *Tetracycline chloride dissolved in saline was injected intravenously to seven cows. Two doses of tetracycline were used: 5 and 10 mg/kg b.wt, and the injections were given over a period of either 10, 60 or 300 sec. A number of the cows collapsed shortly after the injection was completed, usually when the 10 mg dosage was given in 60 sec. When the same dose was given over a period of 5 min none of the cows collapsed. A more or less pronounced drop in blood pressure could be detected during or shortly after the injection; in those cows which collapsed the blood pressure fell almost to zero. The predominant change in pulse rate in connection with the tetracycline administration was a decrease which could be quite marked, pulse rates falling as low as 10-20 per min. Simultaneously with these changes in blood pressure and pulse rate severe abnormalities in ECG could be observed. Pre-treatment with a normal therapeutic dose of calcium borogluconate intravenously prevented collapse in the cows and diminished the drop in blood pressure associated with an ensuing tetracycline injection. It is concluded that intravenous injection of tetracycline is hazardous, but that collapse can be avoided by giving the injection very slowly over a period of no less than 5 min. [R37] *Concurrent use /with antacids or calcium supplements such as calcium carbonate or choline and magnesium salicylates or iron supplements or magnesium salicylate or magnesium-containing laxatives or sodium bicarbonate/ may result in formation of nonabsorbable complexes; also, concurrent use with antacids or sodium bicarbonate may result in decreased absorption of oral tetracyclines because of increased intragastic pH; patients should be advised not to take these medications within 1 to 3 hours of oral tetracyclines. /Tetracyclines/ [R60, 2811] *Concurrent use with cholestyramine or colestipol may result in binding of oral tetracyclines, thus impairing their absorption; an interval of several hours between administration of cholestyramine or colestipol and oral tetracyclines is recommended. /Tetracyclines/ [R60, 2811] *Concurrent long term use /of oral estrogen-containing contraceptives/ with tetracyclines may result in reduced contraceptive reliability and increased incidence of breakthrough bleeding. /Tetracyclines/ [R60, 2811] *Concurrent use /of methoxyflurane/ with tetracyclines may increase the potential for nephrotoxicity. /Tetracyclines/ [R60, 2811] *Since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent use. /Tetracyclines/ [R60, 2811] *Concurrent use /of Vitamin A/ with tetracycline has been reported to cause benign intracranial hypertension. [R60, 2811] *Topical acne preparations containing peeling, desquamating, or abrasive agents (e.g., benzoyl peroxide, tretinoin, resorcinol, salicylic acid, sulfur) should be used cautiously in patients using topical anti-infectives because a cumulative irritant effect could occur. Concurrent use of abrasive or medicated soaps or cosmetic products containing alcohol (e.g., astringents, after-shave lotions) may also cause a cumulative irritant or drying effect in patients using topical anti-infectives. [R43, 2677] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antibiotics, Tetracycline; Protein Synthesis Inhibitors [R61] *Tetracycline hydrochloride ointment is used in the prophylaxis of minor bacterial skin infections and in the treatment of dermal ulcer. /Tetracycline hydrochloride; NOT included in US product labeling/ [R60, 2818] *Tetracycline hydrochloride ointment is indicated in the topical treatment of minor skin infections caused by streptococci, staphylococci, and other susceptible organisms. /Tetracycline hydrochloride; Included in US product labeling/ [R60, 2818] *Tetracycline hydrochloride for topical solution is indicated for the topical treatment of acne vulgaris. It may be effective in grades II and III acne, which are characterized by inflammatory lesions such as papules and pustules. /Tetracycline hydrochloride; Included in US product labeling/ [R60, 2818] *Ophthalmic tetracycline is used in the treatment of chlamydia infections and ocular rosacea. /NOT included in US product labeling/ [R60, 2807] *Ophthalmic tetracycline is used in the treatment of bacterial blepharitis, blepharoconjunctivitis, bacterial conjunctivitis, bacterial keratitis, bacterial keratoconjunctivitis, and meibomianitis. /NOT included in US product labeling/ [R60, 2807] *Ophthalmic tetracycline is indicated in the treatment of trachoma caused by Chlamydia trachomatis. It should be used concurrently with oral tetracyclines. /Included in US product labeling/ [R60, 2807] *Ophthalmic tetracycline is indicated in the prophylaxis of ophthalmia neonatorum caused by Neisseria gonorrhoea and Chlamydia trachomatis. /Included in US product labeling/ [R60, 2807] *Ophthalmic tetracycline is indicated in the treatment of superficial ocular infections caused by Staphylococcus aureus, streptococci including Streptococcus epidermicus (Streptococcus pyogenes) and Staphylococcus pneumonia (Diplococcus pneumonia), Neisseria gonorrhoea, and Escherichia coli. /Included in US product labeling/ [R60, 2807] *ORAL DOSE OF TETRACYCLINE VARIES WITH NATURE AND SEVERITY OF INFECTION. [R28, 1127] *ITS ACTIONS, USES, AND TOXICITY ARE IDENTICAL TO THOSE OF TETRACYCLINE. /TETRACYCLINE PHOSPHATE COMPLEX NF/ [R17, 1143] *IT HAS BEEN CLAIMED THAT ORAL TETRACYCLINE PHOSPHATE COMPLEX YIELDS FASTER AND HIGHER BLOOD LEVELS THAN WITH TETRACYCLINE OR TETRACYCLINE HYDROCHLORIDE. HOWEVER, EFFECT, IF ANY, IS MINOR, AND DOES NOT IN ANY WAY CHANGE DOSAGE SCHEDULE OF THIS AGENT FROM THAT OF TETRACYCLINE. /TETRACYCLINE PHOSPHATE COMPLEX NF/ [R17, 1143] *... /TETRACYCLINES ARE USED/ IN TREATMENT OF ACUTE ATTACK OF MULTIRESISTANT STRAINS OF FALCIPARUM MALARIA ... THEIR RELATIVE SLOWNESS OF ACTION MAKES CONCURRENT TREATMENT WITH QUININE MANDATORY FOR CONTROL OF PARASITEMIA. /TETRACYCLINES/ [R28, 981] *The intrapleural administration of tetracycline solution as a sclerosing agent for the treatment of recurrent malignant pleural effusions is discussed. The usual dose is 500 mg tetracycline hydrochloride diluted in 30-50 ml saline, instilled via a chest tube into the pleural space. Side effects have not been a problem. Considering the effective control rate, toxicity, availability and ease of administration, intrapleural tetracycline appears safe and effective and is considered the first choice for local therapy. [R62] *... Standardized enamel and dentin specimens were impregnated in aqueous solutions of tetracycline HCl, oxytetracycline HCl or doxycyline HCl, rinsed in water, and stored dry for 200 days. Another series of specimens were impregnated in solutions of doxycyline HCl and then rinsed in tap water for varying periods up to 35 days. In addition, drug impregnated specimens were used for reproducibility tests without storage or prolonged rinsing. Impregnated specimens were tested for antimicrobial capacity on agar plates seeded with S. sanguis. After 24 hr aerobic incubation in 10% CO2 atmosphere, the plates were inspected and the diameter of the bacterial growth inhibition zones measured. The drug-impregnated enamel and dentin specimens consistently demonstrated growth-inhibitory capacity. The results of the reproducibility tests showed moderate intrasample and day-to-day variation. Two hundred days of dry storage or 35 days soaking in water reduced, but did not eliminate, the bacterial growth-inhibitory capacity of the impregnated dental specimens. The results show that a short-term exposure of dental hard tissues to tetracyclines may result in a long-lasting antibacterial capacity. /Tetracycline HCl, oxytetracycline HCl, doxycycline HCl/ [R63] *MEDICATION (VET): ANTIAMEBIC; ANTIBACTERIAL [R12] *Although all tetracyclines may be indicated as adjunctive treatment, they are generally no more effective in the initial treatment of acne and are more expensive than tetracycline. However, oral minocycline may be more effective in severe or resistant acne and may be effective in acne unresponsive to oral tetracycline. /Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of actinomycosis caused by Actinomyces israelii. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of anthrax caused by Bacillus anthracis. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of bronchitis. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of brucellosis. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Ststemic tetracyclines are indicated in the treatment of inclusion conjunctivitis. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of genitourinary tract infections (including acute epididymo-orchitis) caused by N. gonorrhoeae. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracycline are indicated in the treatment of necrotizing ulcerative gingivostomatitis (Vincent's infection) caused by Fusobacterium fusiformisans (Fusiformis fusiformisans). /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of granuloma inguinale caused by Calymmatobacterium granulomatis. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are used in the treatment of gonococcal arthritis, bejel, biliary tract infection, Shigella species Enterocolitis, intra-abdominal infections, pinta, plague, mycoplasmal pneumonia, bacterial septicemia, or tularemia infections. /Systemic tetracyclines; NOT including in US product labeling/ [R60, 2809] *Doxycycline, minocycline, oxytetracycline, and tetracycline are indicated in the treatment of uncomplicated rectal infections caused by Chlamydia trachomatis. Minocycline is indicated in the treatment of uncomplicated rectal infections caused by Ureaplasma urealyticum. /Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of yaws caused by Treponema pertenue. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of urinary tract infections caused by (susceptible organisms, including Escherichia coli /NOT included in US product labeling/) and Klebsiella species. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of trachoma. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of syphilis caused by Treponema pallidum. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of skin and soft tissue infections, including burn wound infections, caused by Staphylococcus aureus. However, some USP medical experts do not recommend the use of tetracyclines for infections caused by Staphylococcus aureus. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of relapsing fever caused by Borrelia recurrentis. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of Q fever, rickettsial pox, Rocky Mountain spotted fever (including rick fevers), and typhus infections caused by Rickettsiae. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of psittocosis caused by Chlamydia psittaci. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of acute otitis media, pharyngitis, pneumonia, and sinusitis caused by Haemophilus influenzae and Klebsiella species. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] *Systemic tetracyclines are indicated in the treatment of lymphogranuloma venereum caused by Chlamydia species. /Systemic tetracyclines; Included in US product labeling/ [R60, 2809] WARN: *EXCEPT FOR LOCAL USE IN EYE, TOPICAL USE OF TETRACYCLINES IS NOT RECOMMENDED. /TETRACYCLINES/ [R28, 1127] *MICROORGANISMS THAT HAVE BECOME INSENSITIVE TO ONE TETRACYCLINE FREQUENTLY EXHIBIT RESISTANCE TO OTHERS. /TETRACYCLINES/ [R28, 1126] *CROSS-SENSITIZATION AMONG VARIOUS TETRACYCLINES IS COMMON . /TETRACYCLINES/ [R28, 1130] *... NAUSEA, VOMITING, POLYURIA, POLYDIPSIA, PROTEINURIA, ACIDOSIS, GLYCOSURIA, AND GROSS AMINOACIDURIA, A FORM OF FANCONI SYNDROME, HAS BEEN OBSERVED IN PT INGESTING OUTDATED, AND DEGRADED TETRACYCLINE. [R28, 1130] *INSTANCE OF DISSEMINATED INTRAVASCULAR COAGULATION HAS BEEN REPORTED IN PREGNANT WOMAN WHO DEVELOPED HEPATORENAL FAILURE AFTER BEING GIVEN ONLY 2 DOSES OF 100 MG EACH OF TETRACYCLINE IM. ... CHILDREN UP TO 7 YR AGE MAY BE SUSCEPTIBLE TO ... /DISCOLORATION OF TEETH PRODUCED BY/ TETRACYCLINE THERAPY. [R4, 1189] *TETRACYCLINE IS A POSSIBLE HUMAN TERATOGEN. /FROM TABLE/ [R64] *TETRACYCLINE HAS BEEN LISTED AMONG DRUGS TAKEN DURING PREGNANCY BY 3 MOTHERS WHO HAD INFANTS /BORN/ WITH CONGENITAL CATARACTS, BUT WHETHER TETRACYCLINE WAS RESPONSIBLE IS UNCERTAIN. [R44] *... TETRACYCLINES ADMIN ORALLY OR PARENTERALLY MAY LEAD TO DEVELOPMENT OF SUPRAINFECTIONS THAT ARE USUALLY DUE TO STRAINS OF BACTERIA OR YEASTS RESISTANT TO THESE AGENTS. ... INCIDENCE OF SUPRAINFECTIONS IS MUCH HIGHER WITH TETRACYCLINES THAN WITH PENICILLIN OR STREPTOMYCIN. /TETRACYCLINES/ [R4, 1190] *IT IS IMPERATIVE THAT ... /DIARRHEA RESULTING FROM IRRITATION OF TETRACYCLINES GIVEN ORALLY/ BE PROMPTLY DISTINGUISHED FROM THAT WHICH RESULTS FROM PSEUDOMEMBRANOUS COLITIS, A POTENTIALLY LIFE-THREATENING COMPLICATION. /TETRACYCLINES/ [R28, 1129] *ALTHOUGH IT IS GENERALLY ACCEPTED THAT THE TETRACYCLINES OR OTHER ANITBIOTICS HAVE A BENEFICIAL EFFECT IN ACNE, SOME PLACEBO CROSSOVER STUDIES RAISE DOUBT CONCERNING VALUE OF THIS KIND OF THERAPY. /TETRACYCLINES/ [R28, 1129] *THEY SHOULD NOT BE GIVEN TO PREGNANT PT; THEY SHOULD NOT BE EMPLOYED FOR THERAPY OF COMMON INFECTIONS IN CHILDREN UNDER AGE OF 12 YR; UNUSED SUPPLIES ... DISCARDED. /TETRACYCLINES/ [R28, 1130] *Maternal Medication Usually Compatible with Breast-Feeding: Tetracycline: None; negligible absorption by infant. /from Table 6/ [R65] *Potential adverse effects on fetus: Drug forms complex with calcium orthophosphate and is incorporated into bones and teeth. Causes staining of deciduous teeth if administered after third month of pregnancy. Potential side effects on breast-fed infant: Not recommended. Unbound tetracyclines may cause tooth staining, possible decreased fetal skeletal growth, photosensitivity reactions. Vestibular disturbances reported with minocycline. Comments: Reported case of pregnancy while taking tetracycline and oral contraceptives. Outdated tetracycline may cause nephrotoxicity and a systemic lupus erythematosus-like illness. FDA Category:D (D = There is no evidence of human fetal risk but the potential benefits from use in pregnant women may be acceptable despite the potential risks (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.) /from table II/ [R66] *Tetracyclines cross the placenta; use is not recommended during the last half of pregnancy since tetracyclines may cause permanent discoloration of teeth, enamel hypoplasia, and inhibition of skeletal growth in the fetus. In addition, fatty infiltration of the liver may occur in pregnant women, especially with high intravenous doses. /Tetracyclines/ [R60, 2810] *Tetracyclines are distributed into breast milk; although tetracyclines may form nonabsorbable complexes with breast-milk calcium, use in not recommended because of the possibility of their causing permanent discoloration of teeth, enamel hypoplasia, inhibition of linear skeletal growth, photosensitivity reactions, and oral and vaginal thrush in infants. /Tetracyclines/ [R60, 2810] *In infants and children up to 8 years of age, tetracyclines may cause permanent discoloration of teeth, enamel hypoplasia, and a decrease in linear skeletal growth rate. Therefore, use is not recommended in patients in these age groups unless other antibacterials are unlikely to be effective or are contraindicated. /Tetracyclines/ [R60, 2810] *Bulging fontanels have been reported in young infants who received full therapeutic doses of tetracyclines. This side effect disappeared rapidly upon discontinuation of the drug. /Tetracyclines/ [R60, 2810] *Tetracycline-induced hepatotoxicity is usually seen as a fatty degeneration of the liver. It is more likely to occur in pregnant women, in patients receiving high-dose intravenous therapy, and in patients with renal function impairment. However, hepatotoxicity has also occurred in patients without these predisposing conditions. Tetracycline-induced pancreatitis has also been described in associated with hepatotoxicity, and without associated liver disease. /Tetracyclines/ [R60, 2811] *The most frequent adverse reactions to tetracyclines are dose-related GI effects including nausea, vomiting, diarrhea, bulky loose stools, anorexia, flatulence, abdominal discomfort, and epigastric burning and distress. Stomatitis, glossitis, dysphagia, sore throat, hoarseness, black hairy tongue, pancreatitis, and inflammatory lesions in the anogenital region with candidal overgrowth have also been reported occasionally. [R43, 376] *ONYCHOLYSIS AND PIGMENTATION OF NAILS MAY DEVELOP SIMULTANEOUSLY . ...MILD TO SEVERE REACTIONS IN THE SKIN OF TREATED INDIVIDUALS EXPOSED TO SUNLIGHT; THIS PHENOMENON IS A PHOTOSENSITIVITY REACTION, AND IT MAY BE FOUND IN 1% TO 2% OF PATIENTS TREATED WITH DEMECLOCYCLINE. [R28, 1129] *AFTER SYSTEMIC ADMIN OF TETRACYCLINE, ACUTE TRANSIENT MYOPIA HAS OCCURRED WITHIN 24 HR IN TWO PT. ... BENIGN INTRACRANIAL HYPERTENSION WITH PAPILLEDEMA AND RETINAL HEMORRHAGES HAS OCCURRED OCCASIONALLY AS COMPLICATION OF SYSTEMIC TETRACYCLINE TREATMENT, MORE FREQUENTLY IN CHILDREN AND INFANTS THAN ADULTS. [R44] *GASTROINTESTINAL IRRITATIVE EFFECTS OF TETRACYCLINES ARE OBSERVED MOST COMMONLY WHEN ... TAKEN ORALLY. THEY ALL PRODUCE GI IRRITATION TO VARYING DEGREE IN SOME BUT NOT ALL INDIVIDUALS. EPIGASTRIC BURNING AND DISTRESS, ABDOMINAL DISCOMFORT, NAUSEA AND VOMITING MAY OCCUR. ... DIARRHEA MAY ALSO RESULT FROM IRRITATIVE EFFECTS. ... /TETRACYCLINES/ [R28, 1129] *OTHER EFFECTS THAT MAY HAVE BEEN ATTRIBUTED TO HYPERSENSITIVITY ARE BURNING OF EYES, CHEILOSIS, ATROPHIC OR HYPERTROPHIC GLOSSITIS, PRURITUS ANI OR VULVAE AND VAGINITIS; THESE EFFECTS OFTEN PERSIST FOR WEEKS OR MONTHS AFTER CESSATION OF TETRACYCLINE THERAPY. /TETRACYCLINES/ [R28, 1130] *VARIOUS SKIN REACTIONS, INCL MORBILLIFORM RASHES, URTICARIA, FIXED DRUG ERUPTIONS AND GENERALIZED EXFOLIATIVE DERMATITIS, MAY FOLLOW USE OF ANY OF THE TETRACYCLINES... AMONG MORE SEVERE ALLERGIC RESPONSES ARE ANGIOEDEMA AND ANAPHYLAXIS; ANAPHYLACTOID REACTIONS CAN OCCUR EVEN AFTER ORAL USE OF THESE AGENTS. /TETRACYCLINES/ [R28, 1130] *IV ADMIN OF TETRACYCLINES, IS FREQUENTLY FOLLOWED BY THROMBOPHLEBITIS ESP WHEN SINGLE VEIN IS USED FOR REPEATED INFUSION. /TETRACYCLINES/ [R28, 1130] *TETRACYCLINES HAVE BEEN FOUND TO DELAY BLOOD COAGULATION. ... IT HAS BEEN SUGGESTED THAT IT IS RELATED TO ABILITY OF THESE DRUGS TO ALTER PLASMA LIPOPROTEINS. PT RECEIVING TETRACYCLINE IV HAVE SLIGHT-TO-MARKED DECR IN PROTHROMBIN ACTIVITY AND AN IMPAIRMENT IN RATE OF THROMBOPLASTIN REGENERATION. /TETRACYCLINES/ [R4, 1189] *TETRACYCLINES MAY CAUSE INCR INTRACRANIAL PRESSURE AND TENSE BULGING OF FONTANELS (PSEUDOTUMOR CEREBRI) IN YOUNG INFANTS, EVEN WHEN GIVEN IN USUAL THERAPEUTIC DOSES. EXCEPT FOR ELEVATED PRESSURE, SPINAL FLUID IS NORMAL. DISCONTINUATION OF THERAPY RESULTS IN PROMPT RETURN OF PRESSURE TO NORMAL. /TETRACYCLINES/ [R28, 1130] *40% DEPRESSION OF BONE GROWTH, AS DETERMINED BY MEASUREMENT OF FIBULAS, HAS BEEN DEMONSTRATED IN PREMATURE INFANTS TREATED WITH THESE AGENTS. THIS IS READILY REVERSIBLE IF PERIOD OF EXPOSURE TO DRUG IS SHORT. /TETRACYCLINES/ [R28, 1130] *TREATMENT OF PREGNANT PT WITH TETRACYCLINES MAY PRODUCE DISCOLORATION OF TEETH IN ... OFFSPRING. PERIOD OF GREATEST DANGER ... IS FROM MIDPREGNANCY TO ABOUT 4-6 MO OF POSTNATAL PERIOD. ... /TETRACYCLINES/ [R28, 1130] *PREGNANT WOMEN APPEAR TO BE PARTICULARLY SUSCEPTIBLE TO SEVERE TETRACYCLINE-INDUCED HEPATIC DAMAGE. JAUNDICE APPEARS FIRST, AND AZOTEMIA, ACIDOSIS, AND IRREVERSIBLE SHOCK MAY FOLLOW. /TETRACYCLINE/ [R28, 1129] *ORAL, PHARYNGEAL, AND EVEN SYSTEMIC INFECTIONS WITH YEASTS AND FUNGI, PARTICULARLY CANDIDA, ARE NOT UNCOMMON; THEY TEND TO OCCUR MOST OFTEN IN INDIVIDUALS WITH DISORDERS SUCH AS DIABETES, LEUKEMIA, SYSTEMIC LUPUS ERYTHEMATOSUS, DIFFUSE VASCULITIS, AND LYMPHOMA, ESP IF STEROIDS ARE ALSO BEING ADMIN. /TETRACYCLINES/ [R4, 1190] MXDD: *... QUANTITIES LARGER THAN 2 G/DAY MUST NOT BE GIVEN PARENTERALLY. /TETRACYCLINES/ [R28, 1127] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R67] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *... Tetracycline, oxytetracycline, and chlorotetracycline were analyzed, using an ODS-cartridge extraction device and high performance thin chromatography followed by densitometry. Recoveries of the tetracyclines from fish samples fortified at ppm level were 60.2 to 78.6%. [R68] *Tetracycline detection: meat, fish: liquid chromatography [R69] *AOAC 988.08. Antimicrobial Drugs in Milk. Microbial Receptor Assay. Scintillation counter. DL for tetracycline = 3 ng/ml. /Antibiotics/ [R70] CLAB: *TISSUE; FLUORESCENCE ANALYSIS: KOHN KW, ANAL CHEM (33) 862, 1961. [R71] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tetracycline Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 344 (1989) NIH Publication No. 89-2600 /Tetracycline hydrochloride/ SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1128 R3: SRI R4: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R5: Physicians Desk Reference p.1573 (1985) R6: Physicians Desk Reference p.1075 (1985) R7: Physicians Desk Reference p.1074 (1985) R8: Physicians Desk Reference p.2005 (1985) R9: Physicians Desk Reference p.1971 (1985) R10: Physicians Desk Reference p.2022 (1985) R11: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 735 R12: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1185 R13: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R14: Krainsintu K et al; Warasan Songkhla Nakkharin 5 (2): 111-117 (1983) R15: Hassan G; Patentschrift (Switzerland) No. 645020 (1984) R16: Gerhard G; Austrian Patent No. 36880 (1982) R17: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R18: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-212 R19: Serjeant EP, Dempsey B; Ionisation constants of organic acids in aqueous solution. IUPAC Chem Data Ser No.23. NY,NY: Pergamon pp. 989 (1979) R20: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 177 R21: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R22: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 325 R23: Aldrich; Catalog Hdbk Fine Chem p.1006 (1984) R24: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1316 R25: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3095 R26: Keith LH, Walters DB (eds); Compendium of Safety Data Sheets for Research and Industrial Chemicals #766 p.1562 (1985) R27: Keith LH, Walters DB (eds); Compendium of Safety Data Sheets for Research and Industrial Chemicals #766 p.1563 (1985) R28: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R29: Simpson MB; N Eng J Med 312: 840-842 (1985) R30: Channer KS, Hollanders D; Br Med J 282: 1359-1360 (1981) R31: Goh DH; Ferrante A; Int J Immunopharm 6 (1): 51-54 (1984) R32: Bjellerup M, Ljunggren B; J Invest Dermat 84 (4): 262-264 (1985) R33: Walters BN, Gubbay SS; Br Med J 282: 19-20 (1981) R34: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995.,p. 45-19 R35: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-172 R36: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 587 R37: Smith M et al; Nord Veterin 33 (4-5): 272-273 (1981) R38: Simmons DJ et al; Clin Orthop 180: 253-259 (1983) R39: Savitskaia TN; Arkh Anat Gistol Embriol 87 (11): 66-72 (1984) R40: Petrova TB; Arkh Gistol Embriol 86 (2): 85-92 (1984) R41: Allen CM et al; Infect Immun 47 (2): 480-483 (1985) R42: Dubin NH et al; Contraception 29 (6): 561-571 (1984) R43: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements). R44: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 889 R45: Toxicology and Carcinogenesis Studies of Tetracycline Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 344 (1989) NIH Publication No. 86-2600 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R46: Marzulli, F.N., H.I. Maibach. Dermatotoxicology 4th ed. New York, NY: Hemisphere Publishing Corp., 1991. 180 R47: DeLoach JR, Wagner GG; Am J Vet Res 45 (4): 640-642 (1984) R48: Thienes, C., and T.J. Haley. Clinical Toxicology. 5th ed. Philadelphia: Lea and Febiger, 1972. 141 R49: Hartley DL et al; Infect Immun 45 (1): 13-17 (1984) R50: Bocker R et al; Arzeim Forsch 32 (3): 237-241 (1982) R51: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 418 R52: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R53: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 174 R54: Voskobinikov VM et al; Sb Rab Leningr Vet Inst 66: 18-24 (1981) R55: Turck M; Hosp Pract 19: 175-176 (1984) R56: Skakun NP, Vysotskii II; Antibiotiki 29 (3): 223-227 (1984) R57: Bocker R et al; Res Exp Med 185 (2): 151-162 (1985) R58: Bocker R et al; Acta Pharmacol Toxicol 56 (4): 327-330 (1985) R59: Bhatacharjee SB et al; Mutat Res 135 (3): 211-217 (1984) R60: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R61: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R62: Wichman K; Can J Hosp Pharm 37 (2): 68 (1984) R63: Bjorvatin K et al; Scand J Dent Res 93 (3): 192-197 (1985) R64: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. 322 R65: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 142 (1994) R66: Stockton, D.L. and A.S. Paller. J Am Acad Dermatol 23 (1):87-103 (1990) R67: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R68: Oka H et al; Yakugaku Zasshi 103(5): 531-537 (1983) R69: Onji Y et al; J Assoc Off Anal Chem 67 (6): 1135-1137 (1984) R70: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. 829-31 R71: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 928 RS: 63 Record 231 of 1119 in HSDB (through 2003/06) AN: 3234 UD: 200211 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MELPHALAN- SY: *3025-C-B-; *ALANINE, 3-(P-(BIS(2-CHLOROETHYL)AMINO)PHENYL)-, L-; *ALANINE-NITROGEN-MUSTARD-; *ALKERAN-; *AT-290-; *L-3-(PARA-(BIS(2-CHLOROETHYL)AMINO)PHENYL)ALANINE; *4-(BIS(2-CHLOROETHYL)AMINO)-L-PHENYLALANINE; *3(P-(BIS(2-CHLOROETHYL)AMINO)PHENYL)-L-ALANINE; *P-N-BIS(2-CHLOROETHYL)AMINO-L-PHENYLALANINE; *CB-3025-; *PARA-DI(2-CHLOROETHYL)AMINO-L-PHENYLALANINE; *PARA-DI(2-CHLOROETHYL)AMINOPHENYLALANINE; *MELFALAN-; *MEPHALAN-; *NCI-C04853-; *NSC-8806-; *L-PAM-; *L-PHENYLALANINE, 4-(BIS(2-CHLOROETHYL)AMINO)-; *PHENYLALANINE-MUSTARD-; *L-PHENYLALANINE-MUSTARD-; *PHENYLALANINE-NITROGEN-MUSTARD-; *SARCOCLORIN-; *L-SARCOLYSIN-; *P-L-SARCOLYSIN-; *SARCOLYSINE-; *L-SARCOLYSINE-; *L-SARKOLYSIN-; *SK-15673- RN: 148-82-3 MF: *C13-H18-Cl2-N2-O2 HAZN: U150; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... p-Nitro-L-phenylalanine ethyl ester is treated with phthalic anhydride and then with hydrochloric acid to yield p-nitro-N-phthaloyl-L-phenylalanine ethyl ester. This product is then hydrogenated and treated with ammonia and ethylene oxide to give p-di-(2-hydroxyethyl)amino-N-alpha-phthaloyl-L-phenylalanine ethyl ester. Chlorination with phosphorus oxychloride followed by hydrolysis yields melphalan. [R1] FORM: *MELPHALAN IS AVAIL IN US AS USP GRADE IN FORM OF TABLETS CONTAINING 2 MG ACTIVE INGREDIENT. MELPHALAN POWDER USP, USED TO FORMULATE TABLETS, CONTAINS 93.0-100.5% MELPHALAN ... IN WESTERN EUROPE ... AVAIL IN TABLETS CONTAINING 2 and 5 MG AND AS INJECTIONS EQUIV TO 100 MG ANHYD ACTIVE INGREDIENT. [R2] *A NITROGEN MUSTARD ... GRADE: ND /NEW DRUGS/ (IN MEDICINE, FOR THE ACID). [R3] MFS: *Glaxo Wellcone, Inc., 5 More Drive, Research Triangle Park, NC 27709 (800)334-0089 [R4] OMIN: *PREPN: BERGEL, STOCK; EIDEM, US PATENTS 3,032,584-5 (BOTH 1962 TO NATL RES DEV CORP). [R5] USE: *INSECT CHEMOSTERILANT [R3] +MEDICATION PRIE: U.S. IMPORTS: *(1983) 1.65X10+5 g [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE POWDER [R7]; *OFF-WHITE TO BUFF POWDER [R8] ODOR: *ODORLESS [R7] MP: *182-183 deg C (decomp) [R5] MW: *305.20 [R5] OWPC: *log Kow = -0.52 (@ ph 7) [R9] SOL: *SOL IN ETHANOL, PROPYLENE GLYCOL; PRACTICALLY INSOL IN WATER [R5]; *SLIGHTLY SOL IN METHANOL [R10]; *SOL IN 2% CARBOXYMETHYLCELLULOSE AND IN DIL MINERAL ACID AND ALKALI SOLN; INSOL IN CHLOROFORM AND ETHER [R2] SPEC: *SPECIFIC OPTICAL ROTATION: -31.5 DEG @ 22 DEG C/D (C= 0.67 IN METHANOL); +7.5 DEG @ 25 DEG C/D (C= 1.33 IN 1.0 N HCL) [R5]; *MAX ABSORPTION (AQ SOLN @ PH 7): 260 NM (E= 560, 1%, 1 CM) [R2] OCPP: *NEEDLES FROM METHANOL [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of melphalan stem from its toxicologic properties. Exposure to this odorless, off-white-to-buff powder may occur from its manufacture, formulation, or distribution for use as an insect chemosterilant, or antineoplastic drug. Effects from exposure may include irritation of the eyes and mucous membranes, leukopenia, thrombocytopenia, or anemia. Melphalan has been indicated as a human carcinogen (Group 1) by the International Agency for Research on Cancer (IARC). Exposure should be controlled by mechanical ventilation with high-efficiency particulate arrestors (HEPA) or charcoal filters to minimize the amount of the substance in exhausted air. In activities and situations where over-exposure may occur,wear protective clothing and a carefully fitted respirator. If exposure should occur, immediately irrigate affected eyes with copious amounts of tepid water for at least 15 minutes, and wash affected skin thoroughly with soap and water. Contaminated clothing should be removed and discarded or left at the work site for cleaning before reuse. Smoking, eating, and drinking should be prohibited in melphalan work areas. Melphalan should be stored and transported in securely sealed, light-resistant glass bottles or ampoules, which are in turn placed inside strong screw-cap or snap-top containers, and kept cool (less than 40 deg C). Spills of melphalan should be taken up with a wet mop or vacuum cleaner equipped with a high efficiency particulate filter on the exhaust. Do not sweep, brush, or use any other method which may disperse the substance. DCMP: *When heated to decomp it emits ... fumes of /hydrogen chloride and nitrogen oxides./ [R11] SERI: *STRONG IRRITANT TO EYES AND MUCOUS MEMBRANES. [R12] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R13, 1979.8] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lots; therefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/ [R14, 757] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R13, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak tight. Horizontal laminar flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R13, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R13, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R13, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R13, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents/ [R14, 753] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Appropriate engineering controls should be in place to protect the drug product from microbial contamination and to protect personnel and the environment from the potential hazards of the product. These engineering controls should be maintained according to applicable regulations and standards. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Biological safety cabinets should be cleaned and disinfected regularly to ensure a proper environment for preparation of sterile products. For routine cleanups of surfaces between decontaminations, water should be used (for injection or irrigation) with or without a small amount of cleaner. If the contamination is soluble only in alcohol, then 70% isopropyl or ethyl alcohol may be used in addition to the cleaner. In general, alcohol is not a good cleaner, only a disinfectant, and its use in a biohazard cabinet should be limited. The biohazard cabinet should be disinfected with 70% alcohol before any aseptic manipulation is begun. The excessive use of alcohol should be avoided in biohazard cabinets where air is recirculated ... because alcohol vapors may build up in the cabinet. A lint-free, plastic-backed disposable liner may be used in the biological safety cabinet to facilitate spill cleanup. ... If used, the liner should be changed frequently ... /or/ whenever it is overtly contaminated. /Antineoplastic agents/ [R14, 755] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The biological safety cabinets should be decontaminated on a regular basis (ideally at least weekly) and whenever there is a spill or the biological safety cabinet is moved or serviced, including for certification. ... Currently, no single reagent will deactivate all known hazardous drugs; therefore, decontamination of a biological safety cabinet used for such drugs is limited to removal of contamination from a nondisposable surface (the cabinet) to a disposable surface (eg, gauze or towels) by use of a good cleaning agent that removes chemicals from stainless steel. The cleaning agent selected should have a pH approximating that of soap and be appropriate for stainless steel. Cleaners containing chemicals such as quaternary ammonium compounds should be used with caution, because they may be hazardous to humans and their vapors may build up in any biological safety cabinet where air is recirculated. Similar caution should be used with any pressurized aerosol cleaner; spraying a pressurized aerosol into a biological safety cabinet may disrupt the protective containment airflow, damage the high efficiency particulate air filter, and cause an accumulation of the propellant within a biological safety cabinet where air is recirculated, resulting in a fire and explosion hazard. During decontamination, the operator should wear a disposable closed front gown, disposable latex gloves covered by disposable utility gloves, safety glasses or goggles, a hair covering, and a disposable respirator, because the glass shield of the biological safety cabinet occasionally must be lifted. The blower must be left on, and only heavy toweling or gauze should be used in the biological safety cabinet to prevent it from being "sucked" up the plenum and into the high efficiency particulate air filter. Decontamination should be done from top to bottom (areas of lesser contamination to greater) by applying the cleaner, scrubbing, and rinsing thoroughly with distilled or deionized water. /Antineoplastic agents/ [R14, 755] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The high efficiency particulate air filters /or other exhaust scrubbing system/ of the biohazard cabinet must be replaced whenever they restrict required airflow velocity or if they are overtly contaminated (eg, by a breach in technique that causes hazardous drug to be introduced onto the clean side of the supply high efficiency particulate air filter). Personnel and environmental protection must be maintained during replacement of a contaminated high efficiency particulate air filter. Because replacement of a high efficiency particulate air filter generally requires breaking the integrity of the containment aspect of the cabinet, this procedure may release contamination from the filter into the pharmacy or intravenous preparation area if carried out in an inappropriate manner. Before replacement of a high efficiency particulate air filter contaminated with hazardous drugs, the biological safety cabinet service agent should be consulted for a mutually acceptable procedure for replacing and subsequently disposing of a contaminated high efficiency particulate air filter. One procedure would include moving the biological safety cabinet to a secluded area or using plastic barriers to segregate the contaminated area. Protective clothing and equipment must be used by the servicer. The biological safety cabinet should be decontaminated before filter replacement. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During removal of gloves, ... avoid touching the inside of the glove or the skin with the contaminated glove fingers. ... The worker should wear a protective disposable gown made of lint free, low-permeability fabric with a solid front, long sleeves, and tight-fitting elastic or knit cuffs when preparing hazardous drugs. Washable garments are immediately penetrated by liquids and therefore provide little, if any protection. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ When double gloving, one glove should be placed under the gown cuff and one over. The glove-gown interface should be such that no skin on the arm or wrist is exposed. Gloves and gowns should not be worn outside the immediate preparation area. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Eyewash fountains should be available in areas where hazardous drugs are routinely handled. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Although noninjectable dosage forms of hazardous drugs contain varying proportions of drug to nondrug (nonhazardous) components, there is potential for personnel exposure and environmental contamination with the hazardous components. Procedures should be developed to avoid the release of aerosolized powder or liquid into the environment during manipulation of these drugs. Drugs designated as hazardous should be labeled or otherwise identified as such to prevent their improper handling. Tablet and capsule forms of these drugs should not be placed in automated counting machines, which subject them to stress and may introduce powdered contaminants into the work area. During routine handling of hazardous drugs and contaminated equipment, workers should wear one pair of gloves of good quality and thickness. The counting and pouring of hazardous drugs should be done carefully, and clean equipment dedicated for use with these drugs should be used. ... When hazardous drug tablets in unit-of-use packaging are being crushed, the package should be placed in a small sealable plastic bag and crushed with a spoon or pestle; caution should be used not to break the plastic bag. Disposal of unused or unusable oral or topical dosage forms of hazardous drugs should be performed in the same manner as for hazardous injectable dosage forms and waste. ... Hazardous drug work areas should have a sink (preferably with an eyewash fountain) and appropriate first aid equipment to treat accidental skin or eye contact according to the protocol. /Antineoplastic agents/ [R14, 757] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ A distinctive warning label with an appropriate CAUTION statement should be attached to all hazardous drug materials, consistent with state laws and regulations. This would include, for example, syringes, IV containers, containers of unit-dose tablets and liquids, prescription vials and bottles, waste containers, and patient specimens that contain hazardous drugs. /Antineoplastic agents/ [R14, 757] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Supplies of disposable gloves and gowns, safety glasses, disposable plastic-backed absorbent liners, gauze pads, hazardous waste disposal bags, hazardous drug warning labels, and puncture-resistant containers for disposal of needles and ampuls should be conveniently located for all areas where hazardous drugs are handled. Assembling a "hazardous drug preparation and administration kit" is one way to furnish nursing and medical personnel with the materials needed to reduce the risk of preparing and administering a hazardous drug. /Antineoplastic agents/ [R14, 758] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Prospective temporary and permanent employees who may be required to work with hazardous drugs should be so notified and should receive adequate information about the policies and procedures pertaining to their use. This notification should be documented during the interview process and retained as part of the employment record for all employees. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All personnel involved with the transportation, preparation, administration, and disposal of cytotoxic and hazardous substances should continually be updated on new or revised information on safe handling of cytotoxic and hazardous substances. Policies and procedures should be updated accordingly. /Antineoplastic agents/ [R14, 754] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The work area should be designed to provide easy access to those items necessary to prepare, label, and transport final products; contain all related waste; and avoid inadvertent contamination of the work area. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Each health-care setting should have an established first aid protocol for treating cases of direct contact with hazardous drugs, many of which are irritating or caustic and can cause tissue destruction. Medical care providers in each setting should be contacted for input into this protocol. The protocol should include immediate treatment measures and should specify the type and location of medical follow-up and work-injury reporting. Copies of the protocol, highlighting emergency measures, should be posted wherever hazardous drugs are routinely handled. /Antineoplastic agents/ [R14, 757] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Only individuals trained to administer hazardous drugs should be allowed to perform this function. Training programs should contain information on the therapeutic and adverse effects of these drugs and the potential, long term health risk to personnel handling these drugs. Each individual's knowledge and technique should be evaluated before administration of these drugs. This should be done by written examination and direct observation of the individual's performance. /Antineoplastic agents/ [R14, 757] SSL: *SENSITIVE TO LIGHT, HEAT AND MOISTURE [R8] *SOLN @ 4 DEG C RETAINED FULL ACTIVITY FOR MORE THAN 24 HR; HYDROLYZES IN SOLN: HALF-LIFE, 12.5 HR IN ISOTONIC SALINE @ 20 DEG C AND 1.8 HR @ 37 DEG C; IN 0.001 SODIUM CHLORIDE (10 UG/ML) COMPLETE HYDROLYSIS @ 37 DEG C TAKES PLACE IN 3 HR, and @ 100 DEG C IN 5 MIN. [R2] SHIP: +/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/ [R14, 754] +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R13, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R13, 1979.13] STRG: *Tablets should be stored in well closed, light resistant, glass containers at temp less than 40 deg C, preferably between 15-30 deg C. [R15, 746] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R13, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R13, 1979.15] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair); low-permeability, disposable protective garments (coveralls or gown and shoe covers); safety glasses or splash goggles; respirator; absorbent, plastic-backed sheets or spill pads; disposable toweling; at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label); a disposable scoop for collecting glass fragments; and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad; powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately; a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/ [R14, 758] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/ [R14, 759] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U150, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R16] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R13, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas fired type, in which a first stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R13, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R13, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R13, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R13, 1979.17] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents/ [R14, 755] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The gown should be removed and placed in a sealable container before removal of the inner gloves. The inner gloves should be removed last and placed in the container with the gown. /Antineoplastic agents/ [R14, 756] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Hazardous drug waste should be placed in specially marked (specifically labeled CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. These receptacles should be kept in all areas where the drugs are commonly used. All and only hazardous drug waste should be placed in them. Receptacles used for glass fragments, needles, and syringes should be puncture resistant. Hazardous drug waste should not be mixed with any other waste. Waste containers should be handled with uncontaminated gloves. ... Gloves, gowns, drug vials, etc, should be sealed in specially labeled (CAUTION: HAZARDOUS CHEMICAL WASTE) thick plastic bags or leakproof containers. ... All hazardous waste collected from drug preparation and patient-care areas should be held in a secure place in labeled, leakproof drums or cartons (as required by state or local regulation or disposal contractor) until disposal. This waste should be disposed of as hazardous or toxic waste in an EPA-permitted state-licensed hazardous waste incinerator. Transport to an offsite incinerator should be done by a contractor licensed to handle and transport hazardous waste. ... If access to an appropriately licensed incinerator is not available, transport to and burial in an EPA-licensed hazardous waste dump site is an acceptable alternative. While there are concerns that destruction of carcinogens by incineration may be incomplete, newer technologies and stringent licensing criteria have improved this disposal method. ... Chemical deactivation of hazardous drugs should be undertaken only by individuals who are thoroughly familiar with the chemicals and the procedures required to complete such a task. The IARC recently published a monograph describing methods for chemical destruction of some cytotoxic (antineoplastic) drugs in the laboratory setting. The chemicals and equipment described, however, are not generally found in the clinical setting, and many of the deactivating chemicals are toxic and hazardous. Most procedures require the use of a chemical fume hood. The procedures are generally difficult, and the deactivation is not always complete. Serious consideration should be given to the negative aspects of chemical deactivation before one commits to such a course of action. /Antineoplastic agents/ [R14, 758] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Regulatory agencies such as the EPA and state solid and hazardous waste agencies and local air and water quality control boards must be consulted regarding the classification and appropriate disposal of drugs that are defined as hazardous or toxic chemicals. EPA categorizes several of the antineoplastic agents as toxic wastes, while many states are more stringent and include as carcinogens certain cytotoxic drugs and hormonal preparations. EPA also allows exemptions from toxic waste regulations for small quantity generators, whereas certain states do not. It is critical to research these regulations when disposal procedures are being established. /Antineoplastic agents/ [R14, 759] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If the biological safety cabinets is equipped with a drainpipe and valve, it may be used to collect rinse water. The collection vessel used must fit well around the drain valve and not allow splashing. Gauze may be used around the connection to prevent aerosol from escaping. The collection vessel must have a tight fitting cover, and all rinse water (gauze, if used) must be disposed of as contaminated waste. /Antineoplastic agents/ [R14, 755] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: limited. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent is carcinogenic to humans. /From table/ [R17] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R13, 1979.23] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/ [R14, 759] HTOX: *IN WOMEN, AMENORRHEA OF SEVERAL MO DURATION SOMETIMES FOLLOWS ... THERAPY WITH ALKYLATING AGENTS. IMPAIRMENT OF SPERMATOGENESIS MAY BE NOTED IN MEN. /ALKYLATING AGENTS/ [R18, 1215] *MELPHALAN PRODUCES ... CHROMATID-TYPE ABERRATIONS IN PERIPHERAL BLOOD LYMPHOCYTES TAKEN FROM CANCER PT. [R19] *IN TREATMENT OF PATIENT WITH MYLEOMA, SOME OF WHOM ALSO RECEIVED IRRADIATION, THE DOSE OF MELPHALAN WAS 2-6 MG/DAY FOR 15-102 MO, AND LEUKEMIAS (ALL OF MYELOID OR MONOCYTIC TYPE) DEVELOPED 15-114 MO (MEDIAN, 45 MO) AFTER DIAGNOSIS OF MYELOMA. ANOTHER PATIENT ... DEVELOPED TYPICAL MYELOCYTIC LEUKEMIA WHILE IN REMISSION FROM MYELOMA AFTER HAVING RECEIVED 1.2 G MELPHALAN OVER 4-YR PERIOD. [R20] *THREE CASES OF RETICULOSARCOMA OF PLASMA-CELL TYPE INVOLVING NON-LYMPHORETICULAR TISSUES HAVE ALSO BEEN DESCRIBED IN PATIENT WITH MYELOMA WHO HAD BEEN TREATED WITH MELPHALAN ... [R20] *52 YR OLD WOMAN TREATED WITH MELPHALAN, 1 MG/KG OVER 4 DAYS/MO, DEVELOPED RETICULATED CYANOSIS OF LEFT SECOND TOE. ONE MO LATER, ON THE THIRD DAY OF THE SECOND CYCLE OF THERAPY, THE ACUTE SYMPTOMS RECURRED. SKIN BIOPSY OF THE TOE SHOWED ACUTE VASCULITIS, WHICH PROGRESSED TO GANGRENE DESPITE THERAPY. [R21] *Clinical toxicity of melphalan is mostly hematological and is similar to that of other alkylating agents. Nausea and vomiting are infrequent. Alopecia does not occur, and changes in renal or hepatic function have not been observed. [R18, 1219] *Melphalan produces dose limiting bone marrow depression that results in leukopenia, thrombocytopenia, and anemia. [R22, 2014] *Melphalan is most widely used for treatment of mammary carcinoma, malignant malinoma, multiple myeloma, ovarian carcinoma, and testicular seminoma. It produces anorexia, nausea, and vomiting. Leukopenia, thrombocytopenia, and anemia are the dose limiting toxicities. [R23] *Hematologic toxicity is the major and dose-limiting adverse effect of both oral and IV melphalan and is manifested principally by leukopenia and thrombocytopenia. Anemia, hemolytic anemia, pancytopenia, and agranulocytosis may also occur. Myelosuppression usually occurs after 2-3 weeks of melphalan therapy, but leukopenia may occur after 5 days in a few patients. Leukocyte and platelet counts usually return to normal levels during the fifth week, but leukopenia or thrombocytopenia may persist for 6 weeks or longer after the drug is discontinued. However, irreversible bone marrow depression has been reported in some patients receiving the drug. The patient's hematologic status must be carefully monitored. Melphalan has reportedly caused positive direct Coombs' test results and concurrent hemolytic anemia. Severe leukopenia may occur in patients with renal impairment receiving IV melphalan hydrochloride therapy; dosage reduction (i.e., by 50%) should be considered in these patients. [R15, 745] *Overdosage with melphalan doses up to 290 mg/sq m was associated with severe nausea, vomiting, ulceration of the mouth, decreased consciousness, seizures, muscular paralysis, and cholinomimetic effects. Several fatalities following melphalan overdosage have been reported to date. One child who received standard supportive care survived a single melphalan dose of 254 mg/sq m. In patients receiving high doses of melphalan (i.e., greater than 100 mg/sq m), severe mucositis, stomatitis, colitis, diarrhea, and GI bleeding have been reported. Elevations in liver enzymes, hepatic veno-occlusive disease, nephrotoxicity, and adult respiratory distress syndrome have occurred rarely. In some patients, severe hyponatremia caused by inappropriate antidiuretic hormone secretion has been reported. The principal toxic effect of melphalan is bone marrow suppression. The patients's hematologic status should be monitored carefully for 3-6 weeks following melphalan overdosage. [R15, 748] *The levels of DNA adducts formed in peripheral blood mononuclear cells of 13 patients undergoing high-dose melphalan therapy were determined 0-24 hr after drug admin using a modification of a previously described immunoassay. This assay was validated for DNA extracted from drug-treated cells. Adduct levels in normal mononuclear blood cells 1 hr after drug admin correlated well (r = 0.846) with drug dose (expressed as mg/sq m) and with area under the curve for plasma levels of melphalan during the first hr (r = 0.842). One patient sustained a high degree of toxic side-effects from the melphalan treatment and showed a high level of adducts. Plasma cell leukemia tumor cells from another patient showed a level of adducts approx six times higher than those in the normal blood cells of the other patients. The levels of DNA adducts i normal peripheral blood mononuclear cells did not change markedly between 1 and 24 hr after drug admin. [R24] *Sister-chromatid exchanges (SCEs) and cell kinetics in cultured lymphocytes of patients with an initial epileptic attack, and prior to any anticonvulsant treatment, were studied. Spontaneous melphalan and melphalan-hyperthermia induced SCE frequencies have been studied in 18 adults with an initial epileptic seizure. fifteen age and sex matched healthy subjects were used as the control group. the incidence of spontaneous SCEs in lymphocytes from epileptics was not significantly greater than in those from the control subjects. However, when exposed to melphalan in vitro, cells from both groups showed an incr in SCE frequency. When exposed to melphalan and melphalan-hyperthermia (41 degrees C for 3 hr) in vitro, cells from both groups showed a further incr in SCE frequency with yields from epileptics higher (P < 0.05) than from controls. Melphalan-hyperthermia enhanced synergistically SCEs and cell division delays in both groups with synergistic effects in cells from epileptics (P < 0.01 and P < 0.01, respectively) higher than from controls (P < 0.05 and P < 0.05, respectively). [R25] *Various (32)P-postlabelling methods have been evaluated for the detection of melphalan-DNA adducts in melphalan treated calf thymus DNA and human blood treated in vitro with melphalan. When the butanol extraction procedure was used for the postlabelling studies, incr adduct levels were seen between 0.01 and 1.0 ug/ml melphalan (maximum adduct value = 3.29/10(8) nucleotides at 1.5 ug/ml melphalan). The labelling efficiency however, was thought to be low. Human blood treated in vitro with a dose range of melphalan from 0.01 to 1.5 ug/ml was analyzed for micronuclei, sister chromatid exchanges, chromosome aberrations and DNA adducts. A correlation was seen between melphalan-DNA adducts and cytogenetic damage for each of the endpoints studied. [R26] *Twenty-one previously untreated multiple myeloma (MM) patients and 10 previously treated patients with refractory or relapsed disease received two or three cycles of intermediate-dose melphalan (70 mg/sq m), admin iv every 6 wk. Seven previously untreated patients received three and all other patients received two courses of intermediate-dose melphalan. the objective of the study was to reduce the toxicity of high-dose melphalan (140 mg/sq m) while maintaining its cytotoxic efficacy and secondly to ensure the possibility of collecting sufficient numbers of peripheral blood stem cells (PBSC) for transplantation. Eighteen (85%) previously untreated patients responded, of whom four achieved CR (18%). In addition five out of 10 previously treated patients with refractory or relapsed disease responded although bone marrow toxicity in this category was a major drawback. Toxicity was moderate, consisting of alopecia and moderate bone marrow suppression: the granulocyte count dropped below 0.5X10+9/l and platelets below 25X10+9/l for a median of 8 and 6d, respectively. No serious infections occurred and the majority of patients attended the out-patient clinic. In 12/14 previously untreated patients sufficient peripheral blood CD34+ cells for harvest were present in the repopulation phase after the first intermediate-dose melphalan. In nine patients peripheral blood stem cells were collected and eight patients have undergone successful transplantation. Repeated intermediate-dose melphalan followed by filgrastim is highly effective in untreated MM and may be safely admin to reduce tumor load prior to PBSC collection. [R27] *We evaluated the in vitro cytotoxic effects of combined human tumor necrosis factor alpha, human interferon gamma, melphalan and hyperthermia on human melanoma cell lines using the crystal violet assay ... All cell lines were sensitive to melphalan, with 284 cells being the most sensitive ... [R28] *Chlorambucil and melphalan are structurally related chemicals that are incl in our efforts to identify and assess such hazards among cancer chemotherapy agents. To date, both have been reported to induce specific locus mutations in germ cells of male mice ... and melphalan is one of very few chemicals shown to induce such mutations in spermatogonial stem cells. More recently, both chemicals were found to have strong reproductive effects in female mice ... In the present studies, these chemicals were tested for the induction of dominant lethal mutations and heritable translocations in male mice. Both chemicals were found to have reproductive effects attributable to cytotoxicity in specific male germ cell stages and to induce dominant lethal mutations and heritable translocations in postmeiotic germ cells, particularly in mid to early stage spermatids. [R29] *Toxicities of high-dose melphalan incl myelosuppression, moderate nausea and vomiting, moderate to severe mucositis and diarrhea, and, infrequently, hepatic venoocclusive disease. [R30] *The Amsterdam and Rotterdam perfusion centers, the Netherlands ... All patients with melanoma who were treated between 1978 and 1990 and had a min follow-up of 1 yr after perfusion (n = 367) ... Fifty-four patients (15%) had perfusion of the upper limb, 313 (85) had perfusion of the lower limb, and 164 patients (45%) underwent regional lymph node dissection at the time of perfusion ... Incidence and characteristics of morbidity 1 yr after perfusion and the influence of acute regional toxic reactions on long-term morbidity ... One hundred sixty patients (44%) showed some degree of objective or subjective morbidity; most (104 (28%)) had lymphedema. Other long-term morbidity consisted of muscle atrophy or fibrosis (42 (11%)), limb malfunction (55 (15%)), neuropathy (13 (4%)), pain (28 (8%)), and recurrent infection (11 (3%)). Misc complications were seen in 14 patients (4%). Seventy-one patients (19%) had more than one complication. Acute regional toxic reactions had a statistically significant effect on the incidence of long-term morbidity (P < .01). Moderate to severe acute regional toxic reactions were strongly linked to the occurrence of muscle atrophy or fibrosis (P < .001) and limb malfunction (P < .001). Regional lymph node dissection was statistically significantly related to lymphedema ( P = 0.5). [R31] *Incidence, nature and cause of severe acute regional toxicity were studied in 181 patients who underwent normothermic (37-38 degrees C) or mild hyperthermic (38-40 degrees C) isolated limb perfusion (ILP) with melphalan. The known risk factors for toxicity ... were analyzed. Severe acute regional toxicity occurred in 30 patients (16%). The limb was painful, swollen, red and warm in 19, often with a smooth and glistening aspect. Blistering scattered over the extremity was seen in 11 cases. In another 11 patients, late blistering limited to the footsole or handpalm developed. Twenty-six patients with severe toxicity had undergone ILP at the iliac isolation level (p < 0.05). Sex and tissue temp did not predict toxicity. Venous perfusate blood gas values were severely deteriorated in four patients; high calculated melphalan peak concn occurred in nine patients. Irreversible long-term morbidity as a sequence of severe toxicity occurred in 10 of the 30 patients. Only one of the 11 patients with late blisters limited to sole or palm developed long-term morbidity (p < 0.05). Thus, the only risk factor for severe acute regional toxicity that could be identified was iliac isolation level. However, in 27 of the 30 patients two or more risk factors were found. [R32] *Nine patients with soft tissue tumors of the lower limb not amenable to treatment other than by isolated limb perfusion (ILP) or amputation underwent ILP at the level of the superficial femoral vessels, using a combo of recombinant TNF-alpha and melphalan. In seven patients in whom tumors were superficial, sloughing and necrosis were apparent within 48 hr of perfusion. All patients experienced a complete tumor response. There were no systemic side effects assoc with the use of TNF-alpha, although local side effects, particularly edema, were pronounced. Four patients ultimately required amputation, three because of large soft tissue defects resulting from necrosis of tumor and overlying skin and one because of tumor recurrence. [R33] *A 29-yr-old woman, with a slightly elevated temp for 3 wk, incr dyspnea at rest, markedly reduced general condition and in heart failure, was found to have a leucocytosis of 100,000/ul, anemia (hemoglobin 6.3 g/dl) and thrombocytopenia (41,000/ul). There were 62% plasma cells in the blood smear. Immunoelectrophoresis of serum and urine revealed kappa-light chains and immunocytology demonstrated IgG-kappa. There was no radiological evidence of osteolysis, while ultrasound exam showed multiple abdominal lymphomas and marked hepatosplenomegaly. Bone marrow smear showed a 90% infiltration of plasma cells. High-dosage melphalan treatment (single iv injection of 140 mg/sq m) resulted in complete remission after myelodepression over several wk. Two extramedullary recurrences 5 and 12 mo after the diagnosis had been made were successfully treated with high-dosage melphalan, but it was assoc with severe and long-lasting melphalan, but it was assoc with severe and long-lasting myelodepression. Septicemia with renal and hepatic failure developed and the patient died 6 wk after the third course of high-dosage melphalan, 14 mo after the diagnosis. [R34] NTOX: *MELPHALAN PRODUCES STRUCTURAL ABERRATIONS OF CHROMATID AND CHROMOSOME TYPES IN BONE MARROW CELLS OF TREATED WISTAR RATS ... [R19] *... 25 MICE RECEIVED 10 WEEKLY /SKIN/ APPLICATIONS OF 0.01-0.1% WT/VOL SOLN OF MELPHALAN IN METHANOL (TOTAL DOSE, 1.44 MG) ... 2/19 SURVIVORS DEVELOPED ... 7 SKIN PAPILLOMAS. OF 13 SURVIVORS KILLED ... 11 HAD ... 57 PULMONARY ADENOMAS (5.1/MOUSE). IN 1/5 OF REMAINING ... UNDIFFERENTIATED SKIN CARCINOMA DEVELOPED 3 WK AFTER END OF TREATMENT. THE INCIDENCE OF LUNG TUMORS IN TREATED ANIMALS WAS NOT STATISTICALLY DIFFERENT FROM CONTROLS. [R35] *FOUR GROUPS OF 60 A/J MICE OF BOTH SEXES, 4-6 WKS OF AGE, WERE GIVEN IP INJECTIONS OF MELPHALAN THRICE WEEKLY FOR 4 WK (TOTAL DOSES, 0.27, 1.07, 4.27 and 17.1 MG/KG BODY WT). AT 39 WK AFTER 1ST DOSE THERE WERE 58, 56, 56 and 41 SURVIVORS, RESPECTIVELY, and 44%, 66%, 77% and 98% HAD DEVELOPED LUNG TUMORS, WITH AVG OF 0.6, 1.0, 2.1, and 4.0 TUMOR/MOUSE. IN 385 MALE AND 392 FEMALE CONTROLS RECEIVING VEHICLE ONLY, TUMOR INCIDENCES AT 39 WK WERE 39.5% (0.5 TUMORS/MOUSE) FOR MALES AND 31.4% (0.36 TUMORS/MOUSE) FOR FEMALES. THE POTENCY OF MELPHALAN WAS REPORTED TO BE ABOUT ONE QUARTER THAT OF URACIL MUSTARD ON A MOLAR BASIS. [R36] *TWO GROUPS OF 25 MALE AND 25 FEMALE CHARLES RIVER CD RATS WERE GIVEN THRICE WEEKLY IP INJECTIONS OF 0.9 OR 1.8 MG/KG BODY WT MELPHALAN FOR 6 MO, FOLLOWED BY OBSERVATION FOR A FURTHER 12 MO, @ WHICH TIME ANIMALS WERE KILLED. PERITONEAL SARCOMAS OCCURRED IN 11/20 MALES AND 10/23 FEMALES, AND THESE INCIDENCES WERE STATISTICALLY GREATER THAN THOSE IN CONTROLS (P < 0.001). [R36] *TWO GROUPS OF 25 MALE AND 25 FEMALE SWISS MICE WERE GIVEN THRICE WEEKLY IP INJECTIONS OF 0.75 OR 1.5 MG/KG BODY WT MELPHALAN FOR 6 MO, FOLLOWED BY OBSERVATION FOR A FURTHER 12 MO, @ WHICH TIME ANIMALS WERE KILLED. LUNG TUMORS OCCURRED IN 11/44 MALES AND 10/23 FEMALES, AND LYMPHOSARCOMAS WERE FOUND IN 13/44 MALES. THE INCIDENCES FOR EACH TUMOR TYPE WERE SIGNIFICANTLY GREATER IN ALL CASES THAN THOSE IN CONTROLS (P= 0.012, P= 0.001, AND P < 0.001). [R36] *ALL NITROGEN MUSTARDS HAVE EFFECTS ON THE CNS. ... CONVULSIONS, PROGRESSIVE MUSCULAR PARALYSIS, AND VARIOUS CHOLINOMIMETIC EFFECTS HAVE BEEN OBSERVED. ... THESE EFFECTS AND A "DELAYED-DEATH" SYNDROME REPORTED IN ANIMALS INDICATE THAT CYTOTOXICITY OF ALKYLATING AGENTS EXTENDS TO CELLULAR FUNCTIONS UNRELATED TO PROLIFERATIVE ACTIVITY. /ALKYLATING AGENTS/ [R18, 1215] *INTESTINAL MUCOSA CAN BE DAMAGED BY PARENTERAL ADMIN OF MINIMAL LETHAL DOSES OF A NITROGEN MUSTARD IN EXPTL ANIMALS; MITOTIC ARREST, CELLULAR HYPERTROPHY, PYKNOSIS, DISINTEGRATION, AND DESQUAMATION OF EPITHELIUM ARE EVIDENT. /ALKYLATING AGENTS/ [R18, 1215] *TOPICALLY APPLIED MELPHALAN TO NEW ZEALAND WHITE RABBITS @ CONCN OF 1, 3, and 9% PRODUCED MILD TO MODERATE SKIN IRRITATION. HISTOPATHOLOGICAL EXAM OF SKIN TEST SITES CONFIRMED THAT MELPHALAN WAS MILD IRRITANT. [R37] *IN 14-DAY MORTALITY STUDIES ON MALE AND FEMALE RATS, MELPHALAN WAS ADMIN IV (LD50 5.6 AND 6.6 MG/KG, RESPECTIVELY), IP (LD50 5.4 and 6.1 MG/KG, RESPECTIVELY), AND ORALLY (LD50 13.0 AND 16.0 MG/KG, RESPECTIVELY). GENERAL TOXIC SIGNS: DEPRESSION OF SPONTANEOUS MOVEMENT, BLEPHAROPTOSIS, PILOERECTION, ROUGHING OF HAIR, PALLOR OF SKIN (EAR), HYPOTHERMIA, LACRIMATION, DIARRHEA WITH WT LOSS, PIGMENTATION AROUND EYES AND NOSE, ABNORMAL GAIT AND PROSTRATION. DEATHS OCCURRED FROM 4TH TO 10TH DAY FOLLOWING ADMIN AND WERE ASSOC WITH DYSPNEA. PETECHIAL HEMORRHAGES IN MUCOSA OF DISTAL INTESTINAL TRACT AND DECR IN CELLULARITY OF BONE MARROW, SLIGHT ATROPHY OF SPLEEN AND CONGESTION OF LIVER, KIDNEY AND ADRENALS. [R38] *DELETION OF GLUTAMINE OR LEUCINE FROM RPMI 1630 MEDIUM INCR CYTOTOXICITY PRODUCED DURING 35 MIN EXPOSURE OF MURINE L1210 CELLS TO MELPHALAN BY 10 FOLD AND 2 FOLD, RESPECTIVELY, INDICATING SUBSTANTIAL PROTECTION FROM MELPHALAN CYTOTOXICITY BY THESE AMINO ACIDS. [R39] *Melphalan, a known human carcinogen, was tested for the induction of micronuclei and chromosomal aberrations in the bone marrow cells of male B6C3F1 mice. At 2.5 mg/kg, it induced a frequency of cells with chromosomal aberrations that exceeded 25%; the predominant types of aberrations observed were chromatid breaks and rearrangements. At the same dose, an approximately tenfold increase in micronucleated bone marrow cells was induced. Melphalan also induced a significant depression in the percentage of polychromatic erythrocytes among all erythrocytes in bone marrow cells. [R40] *Transient zinc deficiency is known to adversely affect embryonic development. The effect of urethane, melphalan and arsenic on the distribution of absorbed (65)zinc and non-radioactive zinc in maternal and embryonic tissues of SD rats was examined. Gestation day 11, rats were dosed ip with 1 g urethane/kg bw, 9 mg melphalan/kg bw, 50 mg sodium arsenate/kg bw, or 10 ml saline/kg bw (control). Dams were gavage-fed 32 uCi (65)zinc 8 hr following treatment and then killed on gestation day 12. With regard to the distribution of the absorbed (65)zinc, exposure to all 3 toxicants resulted in an incr % of (65)zinc in the livers of treated dams (urethane greater than melphalan greater than arsenic) compared to controls, while no changes occurred in % of (65)zinc in plasma. Compared to controls, maternal plasma and liver cytosol nonradioactive zinc concn were decr and incr, respectively, in the toxicant-treated dams. Embryos from toxicant-treated dams were smaller than those from controls. the % of absorbed (65)zinc was lower in embryos from urethane, melphalan and arsenic dams than in control embryos. Consistent with the maternal liver (65)zinc data, liver levels of the metal binding ligand metallothionein increased (urethane greater than arsenic greater than control); an inverse relationship existed between embryo (65)zinc content and maternal liver metallothionein. These results suggest that the developmental toxicity of these diverse toxicant may, in part, be mediated by their similar ability to effect a transient zinc deficiency in the embryo. [R41] *Chlorambucil and melphalan are structurally related chemicals that are included in our efforts to identify and assess such hazards among cancer chemotherapy agents. To date, both have been reported to induce specific locus mutations in germ cells of male mice ... and melphalan is one of very few chemicals shown to induce such mutations in spermatogonial stem cells. More recently, both chemicals were found to have strong reproductive effects in female mice ... In the resent studies, these chemicals were tested for the induction of dominant lethal mutations and heritable translocations in male mice. Both chemicals ere found to have reproductive effects attributable to cytotoxicity in specific male germ cell stages and to induce dominant lethal mutations and heritable translocations in postmeiotic germ cells, particularly in mid to early stage spermatids. [R29] *In previous work, we established that treatment with melphalan (L-phenylalanine mustard) produced a predominance of A.T -- > T.A transversions in the Simian virus 40 (SV40)-based shuttle vector pZ189 during replication in human 293 cells. Mutations wee induced with varying doses (4-12 uM) melphalan in the aprt gene of the hemizygous Chinese hamster ovary (CHO) cell line D422 to determine whether a similar mutation spectrum would be observed in an endogenous gene. DNA sequence alterations were determined for 39 spontaneous and 41 melphalan-induced independent mutant clones. Other than a predominance of transversions in both systems, the spectrum of melphalan-induced aprt mutations bears little resemblance to the spectrum observed in the supF gene of the shuttle plasmid pZ189. In aprt, mutations at G.C base pairs (bp) predominated (29 of 41 base substitutions). Significantly enhanced mutagenesis was observed at 5' G-G-C 3' and 5' G-G-C-C 3' sites in the aprt gene. Almost half of the melphalan-induced base substitutions occurred at 5' G-N-C 3' sequences, which are believed to be potential interstrand crosslink sites. [R42] *Using melphalan given intraarterially (ia), we studied the therapy of intracranial human glioma xenografts in male athymic nude rats ... which were inoculated intracerebrally with D-54 MG and D-456 MG. On Days 6 and 7 (D-54 MG) or Days 9 and 10 (D-456 MG), rats randomized by body weight and treated with single-dose melphalan given ia at 0.5 or 0.75 mg produced significantly higher median survival (D-54 MG, Days 33 and 32; D-456 MG, Days 52 and 54, respectively) compared with ia saline (D-54 MG, Day 14, P < 0.001; D-456 MG, Day 24, P = 0.000) or melphalan given iv at 0.75 mg and 0.9 mg (D-54 MG only; Day 19, P < 0.001; Day 23, P < 0.001, respectively) and at 0.5 and 0.75 mg (D-456 MG only; Day 26 for both doses, P = 0.00). Although a dose-dependent incr in median survival (D-54 MG, 0.25 mg, Day 18; 0.5 mg, Day 28.5; 0.75 mg, Day 32.5) was observed with ia admin melphalan, no significant difference was apparent between 0.5 and 0.75 mg in either tumor model (D-54 MG, P = 0.15; D-456 MG, P = 0.37). Toxicity studies in nontumor-bearing athymic rats yielded a max tolerated dose of 0.8 mg for ia admin melphalan. This dosage was superior in spite of different xenograft permeabilities (apparent mean blood-to-tissue transport (K) values for alpha-aminoisobutyric acid, 5.8 for D-54 MG and 1.3 for D-456 MG). Pharmacokinetic experiments demonstrated a significant first pass advantage for ia (versus iv) melphalan. The short plasma half-life, marked antiglioma activity, and lack of requirement for metabolic activation indicate that ia melphalan holds considerable promise for human glioma therapy. [R43] *We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5X10+5 or 5X10+6 TE-671 human rhabdomyosarcoma cells or 5X10+6 D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mM soln, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mM levels. Multiple-dose toxicity studies using a dosing schedule of twice a wk for 2 wk with a 0.25, 0.5, 0.75, 1.0, 1.5, or 2 mM soln revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mM intrathecal melphalan produced an incr in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mM melphalan with a multiple dose regimen at 0.25 or 0.5 mM melphalan in the treatment of TE-671 revealed incr in median survival of 50% for 1.0 mM, 57% for 2.0 mM, 79% for 0.5 mM, and 111% for 0.25 mM concn. Comparison of a single dose of 1 mM melphalan with multiple doses of 1.25 mM melphalan in the treatment of D-54 MG revealed an incr in median survival of 475+% for each of the regiments. [R44] *The tolerated dose of melphalan is limited by bone marrow suppression; when this complication is ameliorated by bone marrow transplantation, the dose-limiting toxicity becomes gastrointestinal mucositis. No intervention to date has been successful in modulating this life-threatening complication of melphalan. We conducted studies to develop a murine model of melphalan-induced gastrointestinal toxicity to facilitate the preclinical identification of effective strategies for reducing this toxicity. Melphalan given at the 90% lethal dosage produced severe gastrointestinal mucositis and mortality (13 of 23 treated mice). Syngeneic bone marrow transplantation, effective in preventing the myeloablation produced by total-body irradiation, was ineffective in preventing melphalan-induced mortality (16 of 23 treated mice), indicating that gastrointestinal mucositis was the dose-limiting toxicity. [R45] NTXV: *LD50 RAT MALE INTRAVENOUS 5.1 MG/KG; [R38] *LD50 RAT FEMALE INTRAVENOUS 6.6 MG/KG; [R38] *LD50 RAT MALE INTRAPERITONEAL 5.4 MG/KG; [R38] *LD50 RAT FEMALE INTRAPERITONEAL 6.1 MG/KG; [R38] *LD50 RAT MALE ORAL 13.0 MG/KG; [R38] *LD50 RAT FEMALE ORAL 16.0 MG/KG; [R38] POPL: *No geriatrics-specific information is available on the use of melphalan in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving melphalan. [R46, 1985] ADE: *When given orally, melphalan is absorbed in an incomplete and variable manner, and 20-50% of the drug is recovered in the stool. ... 10-15% of the admin dose is excreted unchanged in urine. [R18, 1219] *AFTER ADMIN OF (3)H-LABELED MELPHALAN TO WALKER CARCINOMA-BEARING RATS, RADIOACTIVITY WAS FOUND IN LIVER, SPLEEN, KIDNEY, INTESTINE AND WALKER CARCINOMA AND TO LESSER EXTENT IN BONE MARROW, MUSCLE, SKIN, TESTIS AND BRAIN, BUT NOT IN DNA FRACTION OF ANY OF THESE TISSUES. APPROX 25% OF ADMIN RADIOACTIVITY WAS EXCRETED IN URINE DURING 1ST 48 HR. [R19] *IN 2 CANCER PATIENTS ADMIN (14)C-LABELED MELPHALAN, 80-100% OF PLASMA AND URINE RADIOACTIVITY, MEASURED FOR UP TO 24 HR AFTER TREATMENT, COULD BE ACCOUNTED FOR BY SUM OF MELPHALAN, ITS MONO- AND DIHYDROXY METABOLITES, AND PROTEIN-BOUND RADIOACTIVITY. FOLLOWING IV INJECTION, THE COMPOSITE VOL OF DISTRIBUTION WAS 0.66 L/KG, BEVERLY DUVALL RANCE RATE 4.23 ML/MIN/KG, AND MEAN 24-HR URINARY EXCRETION 13.0% OF TOTAL DOSE. [R47] *AFTER IV ADMIN OF (14)C-LABELED MELPHALAN IN FEMALE, WEANLING YORKSHIRE WHITE PIGS, TISSUE SAMPLES INDICATED BONE AND FAT MAY BE ACTING AS DEPOTS FOR THE DRUG. AFTER 8 DAYS, AVG OF 70% ELIMINATED IN URINE. AN AVG OF 4.02% OF APPLIED DOSE WAS ABSORBED AFTER 14 DAYS. SIGNIFICANT LEVELS OF RADIOACTIVITY WERE ALSO DETECTED IN SKIN SURROUNDING SITE OF APPLICATION. [R48] *FOLLOWING ORAL ADMIN OF (14)C-LABELED MELPHALAN IN PATIENT WITH DISSEMINATED MALIGNANT DISEASE, PEAK BLOOD LEVELS WERE SEEN @ 2 HR; 30% OF LABEL WAS RECOVERED IN URINE OVER 9 DAYS AND 20-50% OF LABEL IN FECES OVER 6 DAYS. ABSORPTION FOLLOWING ORAL TREATMENT IS INCOMPLETE. [R49] *FOLLOWING IV ADMIN OF (14)C-LABELED MELPHALAN TO DOGS, URINARY EXCRETION ACCOUNTED FOR 44% OF TOTAL RADIOACTIVITY AND 25% APPEARED IN FECES. APPROX 8% EXCRETED UNCHANGED IN URINE. BILIARY EXCRETION WAS RAPID, WITH 11% OF DOSE ACCOUNTED FOR IN BILE AFTER 30 MIN. AFTER ORAL DOSING, (14)C-LABELED MELPHALAN WAS RAPIDLY ABSORBED FROM GUT OF DOGS AND REACHED MAX CONCN IN SERUM BY 30 MIN. [R50] *Melphalan elimination is significantly correlated with the glomerular filtration rate. [R51, 398] *Melphalan is rapidly distributed throughout total body water. ... Following oral admin of (14)C-labeled melphalan, approx 50-60% of radioactivity is bound to plasma proteins initially and 80-90% is bound within 4-12 hr. [R15, 746] *Melphalan ... is taken up by at least two active transport systems that normally react with leucine and other neutral amino acids. [R52, 1253] *The pharmacokinetics of melphalan were studied in 20 patients with multiple myeloma, primary amyloidosis or lymphoma after iv dose of 140 mg/sq m infused over 30 min (two patients were treated with a higher dose) ... Sox patients received melphalan alone, 8 received melphalan combined with total body irradiation, 2 received busulphan plus melphalan and 4 received the BEAM assoc (BCNU + etoposide + high dose aracytine + high dose melphalan). Creatinine clearance was measured immediately before the infusion of melphalan, and 9 blood samples were taken to monitor elimination kinetics ... Pharmacokinetic parameters ... and areas under the curve (AUC) were comparable to those obtained by Ardiet at al after rapid iv injection. For all patients, AUC, CIT, Vdss, beta half-life and MRT were significantly correlated with creatinine clearance; the different pharmacokinetic parameters calculated showed great interindividual variations ... Renal insufficiency did not lead to a large decr in melphalan clearance compared to interindividual variations in systemic clearance. [R53] *In 14 consecutive patients with recurrent melanoma of the lower limb a total of 35 biopsies were taken at the end of perfusion treatment to assess melphalan tissue concn in tumor, skin/subcutis and muscle tissue. In tumor tissue (n=12) the mean melphalan concn was 6.8 ug/g, which was significantly higher than that of healthy skin/subcutis (3.2 ug/g; n=10), but equal to that of muscle tissue (6.5 ug/g; n=13). The correlation between melphalan concn in the tissues and the concn in the perfusate was studied. The latter was assessed in the form of melphalan peak concn and the area under the curve ... of the melphalan concn-time curve. Tumor concn proved to be correlated linearly with area under the curve (R=0.6, P=0.002) and muscle concn with melphalan peak concn (R=0.8, P=0.04). there was no relation between skin/subcutis concn and the perfusate parameters. [R54] METB: *... Most of administered dose is chemically altered and metabolites persist in the body. [R22, 2015] *IN 2 PATIENTS ADMIN (14)C-LABELED MELPHALAN, 80-100% OF PLASMA AND URINE RADIOACTIVITY, MEASURED FOR UP TO 24 HR AFTER TREATMENT, COULD BE ACCOUNTED FOR BY SUM OF MELPHALAN, ITS MONO- AND DIHYDROXY METABOLITES, AND PROTEIN-BOUND RADIOACTIVITY. [R47] *Monohydroxy and dihydroxy derivatives of melphalan are present in plasma within 30 min after oral admin ... [R15, 746] BHL: *FOLLOWING IV INJECTION OF MELPHALAN IN CANCER PT, COMPOSITE PLASMA INITIAL AND TERMINAL HALF-LIVES WERE 7.7 and 107.6 MIN, RESPECTIVELY. [R47] *IV ADMIN (14)C-LABELED MELPHALAN IN FEMALE, WEANLING YORKSHIRE WHITE PIGS INDICATED VERY SLOW ELIMINATION PHASE (HALF-LIFE= 214 HR). [R48] *AFTER IV ADMIN IN HUMANS, THE DRUG WAS DISTRIBUTED IN TOTAL BODY WATER AND DISAPPEARED WITH HALF-LIVES OF APPROX 67 MIN AND 160 HR. UP TO 65% OF LABEL WAS RECOVERED IN URINE OVER PERIOD OF 7 DAYS. [R49] *DISAPPEARANCE OF L-PAM (INTACT DRUG) FROM SERUM WAS BIPHASIC AFTER IV ADMIN TO DOGS, WITH HALF-LIVES OF 14 and 66 MIN FOR ALPHA AND BETA PHASES, RESPECTIVELY. [R50] *When given orally melphalan has a half-life in plasma of approx 90 min ... [R18, 1219] *High-dose melphalan has a distribution half-life ... of 5 to 15 min and an elimination half-life ... of 17 to 75 min at doses of 140 to 180 mg/sq m, with significant intrapatient variability. [R30] ACTN: *CAPACITY ... TO INTERFERE WITH NORMAL MITOSIS AND CELL DIVISION IN ALL RAPIDLY PROLIFERATING TISSUES PROVIDES BASIS FOR ... THERAPEUTIC APPLICATIONS ... THEY ARE MOST CYTOTOXIC TO RAPIDLY PROLIFERATING TISSUES IN WHICH LARGE PROPORTION OF CELLS ARE IN DIVISION. /ALKYLATING AGENTS/ [R18, 1213] *WITHIN 8 HR AFTER ADMIN OF SUBLETHAL DOSE OF A NITROGEN MUSTARD, CESSATION OF MITOSIS AND DISINTEGRATION OF FORMED ELEMENTS MAY BE EVIDENT IN MARROW AND LYMPHOID TISSUES. /ALKYLATING AGENTS/ [R18, 1214] *Melphalan is an alkylating agent of the nitrogen mustard type. Melphalan is a bifunctional alkylating agent and is cell cycle-phase nonspecific. Activity occurs as a result of formation of an unstable ethylenimmonium ion, which alkylates or binds with many intracellular molecular structures including nucleic acids. Its cytotoxic actin is primarily due to cross-linking of strands of DNA and RNA, as well as inhibition of protein synthesis. [R46, 1984] INTC: *Additive bone marrow suppression can be expected when melphalan is admin with other cancer chemotherapeutic agents. [R55] *Renal failure occurred in 13 of 17 patients who received cyclosporine and high-dose melphalan therapy ... felt reaction resulted from drug interaction between cyclosporine and melphalan. [R56] *The effects of the vasoactive agents hydralazine, nifedipine, and verapamil on the tumor cytotoxicity of melphalan were studied in mice with experimental tumors. Treatment with hydralazine (5 mg/kg) 15 min after melphalan dosing (up to about 12 mg/kg) increased the melphalan induced delay of growth in either RIF-1 or KHT tumors by a factor of about 2.5. Similar enhancements were obtained with measurement of the surviving fraction of tumor cells in vitro following treatment in vivo with hydralazine and melphalan. Tumor cell kill was also increased when nifedipine was administered with melphalan compared to melphalan alone. These enhanced effects were seen when the vasoactive agents were given before or after melphalan. Hydralazine (5 mg/kg) induced nearly 100% radiobiological hypoxia in the tumors. Nifedipine had no effect on tumor hypoxic fraction at a dose of 10 mg/kg, although the antitumor effect of melphalan was substantially increased. A dose of 50 mg/kg nifedipine produced a large increase in tumor hypoxic fraction which persisted for several hours. Verapamil did not change the fraction of hypoxic cells in the KHT tumor and produced only slightly enhanced the antitumor effect of melphalan. [R57] *Melphalan may raise the concentration of blood uric acid; dosage adjustment of antigout agents /allopurinol or colchicine or probenecid or sulfinpyrazone/ may be necessary to control hyperuricemia and gout; allopurinol may be preferred to prevent or reverse melphalan-induced hyperuricemia because of risk of uric acid nephropathy with uricosuric antigout agents. [R46, 1985] *Leukopenic and/or thrombocytopenic effects of melphalan may be increased with concurrent use or recent therapy if these medications /blood dyscrasia-causing medications/ cause the same effects; dosage adjustment of melphalan, if necessary, should be based on blood counts. [R46, 1985] *Additive bone marrow depression may occur; dosage reduction may be required when two or more bone marrow depressants, including radiation, are use concurrently or consecutively /with melphalan/. [R46, 1985] *The effect of both hyperthermia and verapamil on cytotoxicity and transport of melphalan was studied in a pleiotropic drug-resistant Chinese hamster ovary cell line (CHRC5) and in the drug-sensitive parent line (AuxB1). The CHRC5 cell line was selected for resistance to colchicine but is also cross-resistant to other drugs including melphalan. Verapamil (10 uM) incr melphalan cytotoxicity in drug-resistant cells but not in drug-sensitive cells. Hyperthermia (40 to 45 degrees C) incr melphalan cytotoxicity in both cell lines ... melphalan cytotoxicity was incr further when verapamil was combined with hyperthermia (40 to 45 degrees C). The incr cytotoxicity caused by verapamil in drug-resistant cells was accompanied by alterations in membrane permeability to melphalan. The cellular uptake of melphalan after 14 min incr in the presence of verapamil (7 to 30 uM) at 37 and 42 degrees C. When verapamil (10 uM) was present, the rate of efflux of melphalan from CHRC5 cells decr by almost 40% at 37 degrees C. The rate of efflux was incr at 42 degrees C relative to 37 degrees C, but with verapamil the rate decr to that obtained at 37 degrees C in CHRC5 cells. In drug-sensitive cells, verapamil (< or = 50 uM) did not affect either uptake or efflux of melphalan. These findings suggest that verapamil could be beneficial by incr the effectiveness of melphalan in the elimination of multidrug-resistant cells the combo of hyperthermia and verapamil could be especially advantageous by incr melphalan cytotoxicity in a localized target region. [R58] *A2780 and COLO-316 ovarian adenocarcinoma cell lines were exposed to 1.0 mM 1-octanol for 12 hr in order to evaluate the potential effects of inhibition of gap junction-mediated intercellular communication (GJIC) on cellular responses to the chemotherapeutic drug melphalan ... In cells which were sensitive to melphalan, octanol enhanced melphalan toxicity in the GJIC-competent (A2780/S) but not GJIC-incompetent (COLO-316/S) sensitive cells. Although octanol incr plasma membrane lipid mobility in A2780/S and COLO-316/S, it appears that enhancement of A2780/S sensitivity to melphalan may be due to inhibition of GJIC. In melphalan-resistant cells (A2780/R and COLO-316/R), 1.0 mM octanol treatment for 12 hr combined with melphalan reversed the resistance of the cells to the drug. Therefore, alterations in cellular glutathione metabolism and effects on the plasma membrane in addition to uncoupling of GJIC may be involved in sensitizing communication-competent and communication-incompetent resistant cells because COLO-316/R lacks gap junction-mediated intercellular communication. [R59] *We have investigated the effect of mild hyperthermia (42 degrees C) on the cytotoxic activity of a 1 hr melphalan exposure in human melanoma cell lines. Hyperthermia did not affect cell growth of any culture, but it incr, to a different extent, melphalan cytotoxicity in all cell lines, with a reduction in the IC50 of 1.7 to 2.6-fold. Flow cytometric analysis showed that in normal temp conditions melphalan caused S phase cell accumulation, which was evident only at 24 hr in JR8, M14 and 2/21 cell lines and was still persistent at 72 hr in 2/60 cells. Moreover, in all cell lines, the delay in S phase was paralleled, or followed, by an accumulation of cells in G2+M, which was transient in JR8 and M14 cells and persisted until 72 hr in 2/21 and 2/60 melanoma clones. Hyperthermia caused a stabilization and prolongation of melphalan induced G2+M accumulation in JR8 and M14 cells. Conversely, in 2/21 and 2/60 clones, cell cycle perturbations induced by the drug were similar under normothermic or hyperthermic conditions. Specifically, in JR8, for which the max enhancement by hyperthermia on melphalan cytotoxicity was observed, cell accumulation in G2+M was still present 120 hr after treatment. The accumulation was accompanied by an inhibition in the G2-M transition, as demonstrated by the significant reduction in the mitotic index of cells exposed to combined treatment compared to controls. Moreover, a bivariate distribution of cells stained for DNA and cyclin B1 showed that, following melphalan and hyperthermia treatment, the fraction of cyclin B1-expressing cells paralleled the fraction of G2+M phase cells, thus indicating that the inability of cells to enter mitosis was not ascribable to a reduction of cyclin B1 expression. On the whole, our results indicate that hyperthermia can stabilize the G2 accumulation induced by melphalan in human melanoma cells. Such a stabilization could contribute to the enhancement of melphalan cytotoxicity by heat ... [R60] *Experience with limb perfusion-hyperthermia, TNF, and L-PAM suggests dramatic clinical responses in sarcoma and malignant melanoma ... we studied the cytotoxic interactions of TNF, L-PAM and hyperthermia in L929 cells. The optimal sequence was TNF preceding 41.8 degrees C hyperthermia by 48 hr, and L-PAM given simultaneously with heat. Trimodality synergism between TNF, hyperthermia and L-PAM was demonstrated. Non-cytotoxic doses of TNF had a super-additive interaction with L-PAM/heat. Conversely, non-cytotoxic doses of L-PAM had super-additive interactions with TNF followed by hyperthermia. Relative to therapeutic index, we studied WBH, L-PAM and TNF in non-tumor bearing mice. The optimal trimodality sequence did not result in incr normal tissue toxicity compared to L-PAM alone. [R61] *The matrix protein tenascin-C (TN-C) is present in the blood of healthy individual at concn around 1 mg/l. Elevated serum levels have been reported in cancer patients. In this study we have measured the concn of circulating TN-C in 40 patients with melanoma, soft-tissue sarcoma (STS) or squamous-cell carcinoma (SCC) of the limbs, and have found a minor incr in the mean concn compared with healthy subjects. Only 10 patients had TN-C levels above the normal range. No correlation was observed between TN-C levels above the normal range. No correlation was observed between TN-C levels and tumor burden. Nineteen patients were treated by isolation limb perfusion (ILP) with TNF, IFN gamma, melphalan (11 melanoma, 2 SCC and I STS), melphalan alone (3 melanoma) or hyperthermia at 41.5 degrees C (2 melanoma). ILP with TNF, IFN gamma and melphalan induced a rapid incr in plasma TN-C levels, peaking in most patients between 24 or 48 hr after ILP. Two patients treated with hyperthermia only had a slow incr in TN-C concn peaking at day 4, while the patients treated with melphalan alone had no significant change. [R62] *On the basis of the results of previous studies, which revealed that depletion of glutathione enhances the antineoplastic activity of melphalan and that glutathione is required for murine intestinal function, we attempted to modulate melphalan-induced gastrointestinal toxicity by the admin of glutathione (8-10 mmol/kg given in 1 ml sterile water by gavage at 12-hr intervals for 4-8 doses). Glutathione therapy failed to produce a significant incr in mucosal glutathione content in animals treated with melphalan plus glutathione gavage as compared with those receiving melphalan alone (P > 0.05), and histologic mucosal injury secondary to melphalan was not reduced. The admin of glutathione in the presence or absence of concomitant bone marrow transplantation did not decr melphalan-induced mortality (melphalan alone, 16/26 deaths; melphalan plus glutathione, 14/25 deaths; melphalan plus glutathione plus bone marrow transplantation, 20/26 deaths). Studies using a reduced melphalan dose (50% lethal dosage) produced similar results, with no survival benefit being seen following glutathione admin. Our studies suggest that melphalan-induced mucositis can be studied in a mouse model in which this complication is dose-limiting. [R45] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antineoplastic Agents, Alkylating; Carcinogens [R63] *... ADVANTAGES OF GRADUAL BUT CONTINUOUS ADMIN BY ORAL ROUTE HAVE MADE /MELPHALAN/ USEFUL IN TREATMENT OF MULTIPLE MYELOMA. BENEFICIAL EFFECTS HAVE ALSO BEEN REPORTED IN MALIGNANT MELANOMA AND IN CARCINOMA OF BREAST ... [R18, 1219] *SINCE LARGE AMT OF (14)C-LABELED MELPHALAN APPEARED IN BILE OF DOGS, AGENT MAY PROVE TO BE ACTIVE AGAINST CANCERS OF GALL BLADDER, BILE DUCTS, AND DUODENUM. [R50] *In combination with prednisone, /melphalan/ or cyclophosphamide is the drug of choice for treatment of multiple myeloma. ... It is occasionally used in the treatment of tumors of the testis, ... and chronic granulocytic leukemia. [R64] *Although activity against testicular seminoma has been reported, the drug is not used clinically for this disease. [R22, 2014] *Melphalan is indicated for the palliative treatment of nonresectable epithelial carcinoma of the ovary. /Included is US product labeling/ It is also used for treatment of breast carcinoma and testicular carcinoma. /NOT included in US or Canadian product labeling/ [R46, 1984] *Melphalan is indicated for the palliative treatment of multiple myeloma. /Included in US product labeling/ [R46, 1984] *... four patients who had prompt engraftment after conditioning with melphalan-based chemotherapy regiments (BEAM or busulfan/melphalan). Two patients survived without disease for a prolonged period, indicating that these melphalan regimens are sufficiently immunosuppressive to allow sustained engraftment and donor hematopoiesis. [R65] *To present long-term follow-up data of patients with myeloma treated with high-dose melphalan HDM, incl an assessment of prognostic factors ... Between Nov 1981 and Apr 1986, 63 previously untreated patients with multiple myeloma received HDM 140 mg/sq m without autologous bone marrow transplantation ... The overall response rate was 82% (51 of 62), with 32% (20 of 62) patients entering complete remission (CR). The median duration of response was 18 mo, and six patients remain alive and free from disease progression at 60+ to 84+ mo. Improvements in quality of life assoc with remission were immediate in terms of pain grade (89% of patients) and performance status (92%), and later in terms of bone healing (29%). Currently, at a median follow-up duration of 74 mo (range, 63- to 100) since HDM, 23 patients are alive with a median survival duration of 47 mo, and 35% of patients are expected to be alive at 9 yr. Apart from early-stage disease, no factors ere found to predict long-term survival. No second malignancies or other late side effects have been recorded ... Single-agent HDM without autologous bone marrow transplantation is a feasible therapeutic option in myeloma, and is assoc with a high objective response rate, relatively long remission durations, and good symptom control. [R66] *A kappa light-chain myeloma was diagnosed as the underlying disease in a 52-yr-old woman with acute oliguric renal failure. The patient was erroneously treated with high-dose iv melphalan (60 mg/sq m). Because of this overdose treatment with granulocyte colony-stimulating factor was initiated, but pronounced absolute leukopenia (white blood cell count < 0.5X10+9/l) developed and lasted for 13 days. Following melphalan treatment a continuous incr in urine volume was accompanied by a decr of serum creatinine and blood urea nitrogen. Within 10 days after the admin of melphalan the patient no longer required hemodialysis. [R67] +MEDICATION: ALKYLATING AGENT [R52, 1243] WARN: *GENERAL PHARMACOLOGICAL AND CYTOTOXIC ACTIONS OF MELPHALAN ARE MOSTLY HEMATOLOGICAL AND ARE SIMILAR TO THAT OF OTHER NITROGEN MUSTARDS. [R18, p. 1218-9] *Although its safety during pregnancy has not been evaluated, melphalan is potentially teratogenic and should not be used during this period unless absolutely necessary. [R22, 2015] *Melphalan should be used cautiously in patients with severe renal insufficiency. [R22, 2015] *With prolonged use, sterility occurs with all alkylators; females appear more sensitive than males. /Alkalating agents, oral/ [R51, 400] *Melphalan should be used with extreme caution in pt whose bone marrow reserve may have been compromised by prior irradiation or chemotherapy, or whose bone marrow function is recovering from previous cytotoxic therapy. [R15, 747] *Gonadal suppression, resulting in amenorrhea or azoospermia, may occur in patients taking antineoplastic therapy, especially with the alkylating agents. In general, these effects appear to be related to dose and length of therapy and may be irreversible. prediction of the degree of testicular or ovarian function impairment is complicated by the common use of combinations of several antineoplastics, which makes it difficult to assess the effects of individual agents. Melphalan causes gonadal suppression in humans. [R46, 1984] *First trimester: It is usually recommended that use of antineoplastics, especially combination chemotherapy, be avoided whenever possible, especially during the first trimester. Although information is limited because of the relatively few instances of antineoplastic administration during pregnancy, the mutagenic, teratogenic, and carcinogenic potential of these medications must be considered. Other hazards to the fetus include adverse reactions seen in adults. In general, use of a contraceptive is recommended during cytotoxic drug therapy. [R46, 1984] *Although very little information is available regarding excretion of antineoplastic agents in breast milk, breast-feeding is not recommended while melphalan is being administered because of the risk to the infant (adverse effects, mutagenicity, carcinogenicity). It is not known whether melphalan is excreted in breast milk. [R46, 1984] *No geriatrics-specific information is available on the use of melphalan in geriatric patients. However, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving melphalan. [R46, 1985] *The bone marrow depressant effects of melphalan may result in an increased incidence of microbial infection, delayed healing, and gingival bleeding. Dental work, whenever possible should be completed prior to initiation of therapy or deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene during treatment, including caution in use of regular tooth brushes, dental floss, and toothpicks. Melphalan may also rarely cause stomatitis associated with considerable discomfort. [R46, 1985] *Because normal defense mechanisms may be suppressed by melphalan therapy, concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effects of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine; immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the melphalan therapy. The interval between discontinuation of medication that cause immunosuppression and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors; estimates vary from 3 months to 1 year. Patients with leukemia in remission should not receive live virus vaccine until at least 3 months after their last chemotherapy. In addition, immunization with oral polio-virus vaccine should be postponed in persons in close contact with the patient, especially family members. [R46, 1985] *Mild nausea and vomiting occur infrequently after usual doses but may be common after large doses of melphalan. Occasional diarrhea, stomatitis, and oral ulceration also have been reported. [R15, 747] *Dermatologic reactions including maculopapular and urticarial rashes, dermatitis, skin hypersensitivity, allergic reactions, pruritus, and rarely, alopecia have been reported in patients receiving melphalan. Anaphylaxis has also been reported. Hypersensitivity reactions including urticaria, pruritus, exanthema, rash, edema, tachycardia, bronchospasm, dyspnea, hypotension, and anaphylaxis have been reported in about 2% of patients receiving the drug IV; in several patients, rechallenge with oral melphalan produced rash, pruritus, and chest pain. Hypersensitivity reactions occur most commonly after several courses of IV therapy with the drug. If a hypersensitivity reaction to IV melphalan hydrochloride occurs, the drug should be discontinued and appropriate symptomatic treatment initiated (e.g., plasma volume expanders, vasopressor, corticosteriods, antihistamines) at the discretion of the clinician. Skin ulceration at the injection site and skin necrosis (rarely requiring skin grafting) have been reported in patients receiving IV melphalan therapy. [R15, 747] TOLR: *ACQUIRED RESISTANCE TO ALKYLATING AGENTS IS COMMON EVENT, AND ACQUISITION OF RESISTANCE TO ONE ALKYLATING AGENT MAY IMPART CROSS-RESISTANCE TO OTHER ALKYLATORS. /ALKYLATING AGENTS/ [R18, 1214] MXDD: *Overdosage with melphalan doses up to 290 mg/sq m was associated with severe nausea, vomiting, ulceration of the mouth, decreased consciousness, seizures, muscular paralysis, and cholinomimetic effects. Several fatalities following melphalan overdosage have been reported to date. One child who received standard supportive care survived a single melphalan dose of 254 mg/sq m. In patients receiving high doses of melphalan (i.e., greater than 100 mg/sq m), severe mucositis, stomatitis, colitis, diarrhea, and GI bleeding have been reported. Elevations in liver enzymes, hepatic veno-occlusive disease, nephrotoxicity, and adult respiratory distress syndrome have occurred rarely. In some patients, severe hyponatremia caused by inappropriate antidiuretic hormone secretion has been reported. The principal toxic effect of melphalan is bone marrow suppression. The patients's hematologic status should be monitored carefully for 3-6 weeks following melphalan overdosage. [R15, 748] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Melphalan's production and use as an alkylating agent, an antineoplastic, and an insect chemosterilant may result in its release to the environment through various waste streams. If released to soil, melphalan should have moderate mobility. Volatilization of melphalan should not be important from moist or dry soil surfaces. Insufficient data are available to determine the rate or importance of biodegradation of melphalan in soil or water. Hydrolysis in water and in moist soil will be an important fate process according to melphalan's experimental neutral aqueous hydrolysis rate constant of 0.15/hr which corresponds to a half-life of 4.6 hrs at pH 7. If released to water, melphalan may adsorb to suspended solids and sediment. Melphalan will be essentially non-volatile from water surfaces. An estimated BCF value of 0.24 suggests that melphalan will not bioconcentrate in aquatic organisms. If released to the atmosphere, melphalan will exist almost entirely in the particulate phase. Vapor-phase melphalan is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 1.7 hours. Particulate-phase melphalan may be physically removed from the air by wet and dry deposition. Direct human exposure to melphalan occurs through ingestion of the drug, which is dispensed in tablet form. Workers involved in formulating and dispensing the drug may be exposed through dermal contact or inhalation of dust. (SRC) NATS: *MELPHALAN IS NOT KNOWN TO OCCUR IN NATURE. [R1] ARTS: *Melphalan's production and use as an alkylating agent(1), an antineoplastic(2), and an insect chemosterilant(3) may result in its release to the environment through various waste streams(SRC). [R68] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 355(SRC), determined from a structure estimation method(2), indicates that melphalan should have moderate mobility in soil(SRC). Volatilization of melphalan should not be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 4.2X10-13 atm-cu m/mole(3,SRC), or from dry soil surfaces(SRC), based on an estimated vapor pressure of 3X10-10 mm Hg(4,SRC). Insufficient data are available to determine the rate or importance of biodegradation of melphalan in soil(SRC). Hydrolysis in moist soil may be an important fate process according to melphalan's experimental neutral aqueous hydrolysis rate constant of 0.15/hr which corresponds to a half-life of 4.6 hrs at pH 7(5). [R69] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 355(SRC), determined from a structure estimation method(2), indicates that melphalan may adsorb to suspended solids and sediment(SRC) in the water. Melphalan will be essentially non-volatile from water surfaces based on an estimated Henry's Law constant of 4.2X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). An estimated BCF value of 0.24(1,SRC), from an experimental log Kow(4), suggests that melphalan will not bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(5). Insufficient data are available to determine the rate or importance of biodegradation of melphalan in water(SRC). At 25 deg C, the neutral aqueous hydrolysis rate constant for melphalan has been experimentally determined to be 0.15/hr which corresponds to a half-life of 4.6 hrs at pH 7(6). [R70] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), melphalan, which has an estimated vapor pressure of 3X10-10 mm Hg at 25 deg C(2,SRC), will exist almost entirely in the particulate phase in the ambient atmosphere. Vapor-phase melphalan is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 1.7 hours(3,SRC). Particulate-phase melphalan may be physically removed from the air by wet and dry deposition(SRC). [R71] ABIO: *The rate constant for the vapor-phase reaction of melphalan with photochemically produced hydroxyl radicals has been estimated as 2.25X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 1.7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). At 25 deg C, the neutral aqueous hydrolysis rate constant for melphalan has been experimentally determined to be 0.15/hr which corresponds to a half-life of 4.6 hrs at pH 7(2). [R72] BIOC: *An estimated BCF value of 0.24 was calculated for melphalan(SRC), using an experimental log Kow of -0.52(1) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms will not be an important fate process(SRC). [R73] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for melphalan can be estimated to be about 355(SRC). According to a recommended classification scheme(2), this estimated Koc value suggests that melphalan should have medium mobility in soil(SRC). [R74] VWS: *The Henry's Law constant for melphalan is estimated as 4.2X10-13 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that melphalan will be essentially nonvolatile from water surfaces(2,SRC). Melphalan's vapor pressure, 3X10-10 mm Hg(3,SRC) and Henry's Law constant(1,SRC) indicate that volatilization from dry and moist soil surfaces should not occur(SRC). [R75] RTEX: *Melphalan is used in human medicine as an antineoplastic agent for the treatment of various malignant diseases(1). Therefore, direct human exposure occurs through ingestion of the drug, which is dispensed in tablet form. Workers involved in formulating and dispensing the drug may be exposed through dermal contact or inhalation of dust(SRC). [R76] *Human exposure occurs ... principally during use in cancer treatment. [R77] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,416 workers (975 of these are female) are potentially exposed to melphalan in the USA(1). [R78] */PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The danger to health-care personnel from handling a hazardous drug stems from a combination of its inherent toxicity and the extent to which workers are exposed to the drug in the course of carrying out their duties. This exposure may be through inadvertent ingestion of the drug on foodstuffs (eg, workers' lunches), inhalation of drug dusts or droplets or direct skin contact. /Antineoplastic agents/ [R14, 752] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or .454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R79] RCRA: *U150; As stipulated in 40 CFR 261.33, when melphalan, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R80] FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R81] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *UV-SPECTROPHOTOMETRY, SPECTROFLUOROMETRY (DETECTION LIMIT, 0.05 UG/ML) ... CAN BE USED TO DETERMINE PURE CMPD IN AQUEOUS SOLN. [R35] *PHENYLALANINE MUSTARDS AND THEIR HYDROLYSIS PRODUCTS HAVE BEEN SEPARATED BY GAS-LIQ CHROMATOGRAPHY OF TRIMETHYLSILYL DERIVATIVES (GORAS JT ET AL, J PHARM SCI, 59, 561-563) AND BY TWO-DIMENSIONAL THIN-LAYER CHROMATOGRAPHY ON KIESELGEL G, (WALTHIER J AND JENEY A (1968) ACTA PHARM HUNG, 38, 236-244). [R35] CLAB: *HIGH PRESSURE LIQUID CHROMATOGRAPHIC ANALYSIS OF MELPHALAN IN PLASMA IS DESCRIBED. RECOVERY OF 1 UG ADDED TO 1 ML OF PLASMA WAS 94%. [R82] *A sensitive HPLC assay was developed for the measurement of the alkylating cytostatic drug melphalan ad its 2 hydrolysis products, monohydroxymelphalan and dihydroxymelphalan. A reversed-phase column and a mobil phase consisting of acetonitrile/citrate buffer made possible an isocratic separation dn quantification. N,N-bis(2-hydroxyethyl) toluidine was synthesized as an internal standard structurally related to dihydroxymelphalan. A new, accurate kinetic calibration procedure enabled the /detection/ of a concn of the unstable monohydroxymelphalan. The lower limit of quantification was 30 ng/ml for melphalan and 20 ng/ml for both dihydroxymelphalan and monohydroxymelphalan with fluorescence detection. The use of this method is illustrated by some pharmacokinetic data in systemic and locoregional melphalan therapy. [R83] *A rapid and sensitive HPLC method for detection melphalan in plasma and tissue samples by employing o-phthaladehyde derivatization and fluorescent detection is described. Derivatiation with o-phthalaldehyde yielded a product whose fluorescence was greater than that of melphalan alone. After simple methanol extraction of biological samples containing melphalan, the drug was derivatized by addition of acetate buffer and methanol containing o-phthalaldehyde to the extraction. Chromatographic analysis was performed on a 10 um Partisil 10 DDS 3 column with a guard column packed with pellicular C18 material. A mobile of methyl cyanide 15 mM phosphate buffer (36:64) with a flow rate of 3 ml/min was used. In plasma and brain samples of rats treated with melphalan, concentrations of 5.16 ug/ml and 0.82 ug/g for plasma and brain, respectively were detected when calculated against standard samples. No melphalan metabolites could be quantitated in biological samples because they co-eluted with the solvent front. The coefficient of variation for plasma (1 ug/ml) was 5.9% of the mean and for tissue (brain) (100 ng/150 mg) was 5.3% of the mean. [R84] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for melphalan. Route: gavage; Species: transgenic model evaluation, mice. [R85] SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 170 (1975) R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 168 (1975) R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. 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Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 453 R12: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 738 R13: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R14: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 95. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1995 (Plus Supplements 1995). R15: McEvoy G.K. (ed.). American Hospital Formulary Service-Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1996 (Plus Supplements). R16: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R17: IARC. 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USEPA-600/3-88-028. p. 15-17 (1988) R73: (1) Selassie, CD et al; J Med Chem 33: 1914-1919 (1990) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R74: (1) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) R75: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R76: (1) IARC; IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. 9: 167-180 (1975) R77: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 564 R78: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R79: 40 CFR 302.4 (7/1/94) R80: 40 CFR 261.33 (7/1/94) R81: 21 CFR 200-299, 300-499, 820, and 860 (4/1/93) R82: CHANG SY ET AL; J PHARM SCI 67 (MAY): 679-82 (1978) R83: Osterheld HKO et al; Cancer Chemother Pharmacol 21 (2): 156-62 (1988) R84: Sweeney DJ et al; J Chromatogr 339 (2): 434-9 (1985) R85: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.20 RS: 124 Record 232 of 1119 in HSDB (through 2003/06) AN: 3241 UD: 200211 RD: Reviewed by SRP on 5/7/1998 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NALIDIXIC-ACID- SY: *BETAXINA-; *3-CARBOXY-1-ETHYL-7-METHYL-1,8-NAPHTHYRIDIN-4-ONE-; *DIXIBEN-; *1-ETHYL-7-METHYL-1,8-NAPHTHYRIDIN-4-ONE-3-CARBOXYLIC-ACID-; *NALIDIC-ACID-; *NALIDIXAN-; *NALIDIXIN-; *NALIDIXINIC-ACID-; *NALIX-; *NALURIN-; *1,8-NAPHTHYRIDINE-3-CARBOXYLIC-ACID,-1-ETHYL-1,4-DIHYDRO-7-METHYL-4-OXO-; *NAXURIL-; *NEGGRAM-; *NEGRAM-; *NEVIGRAMON-; *NOGRAM-; *SPECIFIN-; *URALGIN-; *URICLAR-; *URISAL-; *URODIXIN-; *URONEG-; *WIN-18,320-; *WINTOMYLON- RN: 389-08-2 MF: *C12-H12-N2-O3 ASCH: Sodium Nalidixate; 3374-05-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CONDENSATION OF 2-AMINO-6-METHYLPYRIDINE WITH DIETHYL ESTER OF (ETHOXYMETHYLENE) MALONIC ACID, THEN CYCLIZATION TO ETHYL 1 ,4-DIHYDRO-7-METHYL-4-OXO-1,8-NAPHTHYRIDINE-3-CARBOXYLATE, FOLLOWED BY ETHYLATION WITH ETHYL BROMIDE AND SAPONIFICATION [R1] *...derived from 2-amino-6-methylpyridine. [R2, p. V20 669] MFS: *STERLING DRUG INC, THE HILTON-DAVIS CHEM CO, DIV, CINCINNATI, OHIO 45237 [R1] OMIN: *NALIDIXIC ACID, NF (NEGGRAM), IS AVAIL AS NALIDIXIC ACID TABLETS, NF, CONTAINING 250 OR 500 MG OF DRUG. [R3, 1008] USE: *MEDICATION *MEDICATION (VET) CPAT: *20 mg/kg/day /Japanese aquaculture/ [R2, p. V3 620] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1978) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1978) 6.50X10+5 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE BUFF, CRYSTALLINE POWDER [R4]; *WHITE TO SLIGHTLY YELLOW, CRYSTALLINE POWDER [R5] ODOR: *ODORLESS [R5] MP: *229-230 DEG C [R4] MW: *232.24 [R4] DSC: *PKA 8.6 [R5] OWPC: *log Kow= 1.41 [R6] SOL: *Soly at 23 deg C (mg/ml): chloroform 35; toluene 1.6; methanol 1.3; ethanol 0.6; water 0.1; ether 0.1. [R4]; *PRACTICALLY INSOL IN WATER; SOL IN SOLN OF CARBONATES [R5] SPEC: *MAX ABSORPTION: 333 NM (A= 1138, 1%, 1 CM) [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R8] STRG: *NALIDIXIC ACID TABLETS AND ORAL SUSPENSION SHOULD BE STORED IN TIGHT CONTAINERS AT A TEMPERATURE LESS THAN 40 DEG C, PREFERABLY BETWEEN 15-30 DEG C; FREEZING OF THE SUSPENSION SHOULD BE AVOIDED. [R9, 592] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Recommended treatment consists of the following: To decrease absorption - Performing gastric lavage if overdose is noted early. Specific treatment - Administering anticonvulsants if needed for seizures. Supportive care - Administering fluids and supportive measures such as oxygen and artificial respiration if absorption has occurred. Patients in whom intentional overdose is known or suspected should be referred for psychiatric consultation. [R10, 2093] HTOX: *Acute toxicity from nalidixic acid may be manifested by toxic psychoses, convulsions, increased intracranial pressure, or metabolic acidosis. Vomiting, nausea, and lethargy may also occur. Because of the rapid excretion of nalidixic acid, such reactions are usually short-lived, persisting only 2-3 hours. [R9, 594] *Human systemic effects: convulsions, hyperglycemia, sweating, and blood changes in children. [R8] NTOX: *Nalidixic acid causes lameness in immature dogs due to permanent damage of the cartilage of weight-bearing joints. [R10, 2092] *...prolonged use of the drug /in dogs and cats/ has caused retinal degeneration leading to blindness in some cases. [R9, 593] NTXV: *LD50 MOUSE ORAL 3.3 G/KG; [R11] *LD50 MOUSE SUBCUTANEOUS 0.5 G/KG; [R11] *LD50 MOUSE INTRAVENOUS 0.176 G/KG; [R11] *LD50 Rat oral 1160 mg/kg; [R8] NTP: *... Toxicology and carcinogenesis studies were conducted by feeding diets containing nalidixic acid (approximately 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... Two yr studies of nalidixic acid were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 male and 50 female F344/N rats and 50 male and 50 female B6C3F1 mice. Conclusions: Under the conditions of these 2 yr feed studies, there was clear evidence of carcinogenic activity of nalidixic acid for F344/N rats, as indicated by increased incidences of preputial gland neoplasms in males and clitoral gland neoplasms in females. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nalidixic acid, as indicated by marginally increased incidences of subcutaneous tissue neoplasms There was no evidence of carcinogenic activity for female B6C3F1 mice fed diets containing 2,000 or 4,000 ppm nalidixic acid for 2 yr. [R12] ADE: *ABSORPTION AND ELIMINATION RATES OF NALIDIXIC ACID WERE SHOWN TO BE LOW IN NEWBORN CHILDREN COMPARED WITH ADULTS, AND ADULT VALUES WERE NOT OBTAINED UNTIL ABOUT THIRD YR OF LIFE. RELATIVE DISTRIBUTION VOL, HOWEVER, WERE SIMILAR IN BOTH AGE GROUPS. [R13, 437] *IN RATS AND MICE ORAL DOSES ARE RAPIDLY ABSORBED WITH PEAK BLOOD CONCN ABOUT 1 HR LATER. ...ELIMINATION IS VIA KIDNEYS, PEAKING @ ABOUT 6TH HR. 80% OF ADMIN DOSE IS ELIMINATED IN 1ST 8 HR. IN DOGS HIGHLY EFFECTIVE CONCN APPEAR IN URINE WITHIN 2-3 HR AFTER ORAL ADMIN. [R14] *ABSORPTION EFFICIENCY AND RATE OF ELIMINATION OF...NALIDIXIC ACID...DECR IN PT WITH SHIGELLOSIS. POOR ABSORPTION WAS GENERALLY OBSERVED IN YOUNGER PT WITH MARKED DIARRHEA BUT THERE WAS NO READY EXPLANATION FOR DELAYED EXCRETION. [R15] *Rapidly and almost completely absorbed from the gastrointestinal tract; bioavailability is approximately 96%. Absorption may be delayed if taken with antacids. [R10, 2092] *Parent drug and active metabolite are distributed to most tissues, especially to the kidneys and to urine; serum concentrations are low; traces of drug cross the placenta. Excreted in breast milk. Drug does not penetrate into prostatic fluid. [R10, 2092] *Elimination: Renal - 2 to 3% excreted unchanged. 13% as active metabolite and more than 80% as inactive metabolites; rapidly and almost completely excreted within 24 hours; active drug does not accumulate in patients with impaired renal function, but inactive metabolites accumulate and may be toxic. Fecal - Approximately 4%. [R10, 2092] *...rapidly absorbed from the GI tract, with essentially the entire dose being absorbed. [R9, 593] METB: *WHEN NALIDIXIC ACID...IS INGESTED BY MAN, IT IS PARTLY EXCRETED AS FREE... /ACID/ BUT MUCH BIGGER PROPORTION IS EXCRETED AS MONOGLUCURONIDE...AND CONSIDERABLE FRACTION AS 7-HYDROXYMETHYL METABOLITE...TOGETHER WITH SMALLER AMT OF LATTER IN CONJUGATED FORM. 3,7-DICARBOXYLIC ACID...IS MINOR METABOLITE. [R16] *Nalidixic acid is partially metabolized in the liver to hydroxynalidixic acid and the glucuronic acid conjugates of nalidixic acid and hydroxynalidixic acid. The drug is also partially metabolized to the dicarboxylic acid derivative; there is some evidence suggesting that this metabolite is formed in the kidney. [R9, 593] BHL: *APPROX 96% OF ORALLY ADMIN...IS ABSORBED. PLASMA CONCN OF 20-50 UG/ML MAY BE ACHIEVED, BUT ACID IS 93-97% BOUND TO PLASMA PROTEINS. IN BODY SOME... CONVERTED TO ACTIVE HYDROXYNALIDIXIC ACID, AND BOTH ARE EXCRETED INTO URINE. MOST...IS CONJUGATED IN LIVER. PLASMA T/2 IS...8 HR...MAY BE...21 HR IN...RENAL FAILURE. [R3, 1007] ACTN: *IT APPEARS TO ACT BY INHIBITING DNA SYNTH. [R3, 1007] INTC: *...AT PHYSIOLOGICAL CONCN...NALIDIXIC ACID...DISPLACED SUBSTANTIAL AMT OF WARFARIN FROM HUMAN ALBUMIN BY NON-COMPETITIVE MECHANISM. [R13, 469] *SYSTEMIC AND URINARY ALKALINIZERS REDUCE ITS EFFECTIVENESS BY INCR ITS EXCRETION RATE. SYSTEMIC EFFECTIVENESS INCR IF URINE IS ACID. [R14] *METABOLIC ACIDOSIS WAS INDUCED IN AN 18-YEAR-OLD MALE BY AN OVERDOSE OF NALIDIXIC ACID. SIMULTANEOUS INGESTION OF PROBENECID MAY HAVE ACCENTUATED EFFECT OF INGESTED NALIDIXIC ACID BY PROLONGING ITS SERUM T/2. [R17] *Coumarin- or indandione-derivative anticoagulants, especially warfarin and dicumarol, may be displaced from protein-binding sites by nalidixic acid, resulting in increased anticoagulant effect; dosage adjustments may be necessary during and after nalidixic acid therapy. [R10, 2092] *Nitrofurantoin interferes with the therapeutic effects of nalidixic acid. [R10, 2092] *Concomitant administration of antacids is reported to decrease the absorption of nalidixic acid. [R9, 594] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Quinolone /SRP: Antibacterial/ [R18] *IN US, NALIDIXIC ACID IS APPROVED ONLY FOR TREATMENT OF URINARY TRACT INFECTIONS CAUSED BY SUSCEPTIBLE MICROORGANISMS. EFFECTIVENESS AGAINST INDOLE-POSITIVE PROTEUS IS ESP IMPORTANT. APPARENT CURES...IN 30-50% OF UNCOMPLICATED URINARY TRACT INFECTIONS. [R3, 1007] *...BRUCELLOSIS HAS BEEN SUCCESSFULLY MANAGED WITH ORAL NALIDIXIC ACID. DRUG HAS BEEN GIVEN IV TO TREAT GRAM-NEGATIVE SEPTICEMIAS. [R3, 1008] *...BACTERICIDAL TO MOST OF COMMON GRAM-NEGATIVE BACTERIA THAT CAUSE URINARY TRACT INFECTIONS. ...99% OF STRAINS OF E COLI, 98% OF PROTEUS MIRABILIS AND 75-97% OF OTHER PROTEUS SPECIES, 92% OF KLEBSIELLA-ENTEROBACTER, and 80% OF OTHER COLIFORM BACTERIA ARE SENSITIVE TO DRUG. ... SOME STRAINS OF SALMONELLA AND SHIGELLA...SENSITIVE. [R3, 1007] *MEDICATION (VET): ITS USE IN POULTRY DRINKING WATER HAS BEEN PROPOSED TO AID IN CONTROL OF GRAM-NEGATIVE BACTERIAL INFECTIONS ASSOC WITH CHRONIC RESPIRATORY OR AIR-SAC INFECTIONS. [R14] *Nalidixic acid is indicated in the treatment of urinary tract infections caused by susceptible strains of gram-negative organisms, including Proteus species, Klebsiella species, Enterobacter species, and Escherichia coli. /Included in US product labeling/ [R10, 2092] *Since nalidixic acid achieves only low concentrations in the serum and is concentrated in the urine, it is indicated only in the treatment of urinary tract infections. [R10, 2092] *Vet: Antibacterial; has been used in urinary tract infections. [R4] WARN: *BECAUSE...MAY ACCUMULATE IN PT WITH RENAL OR HEPATIC INSUFFICIENCY, IT SHOULD BE USED VERY CAUTIOUSLY IN THESE PT, ESP IF NEUROLOGIC DAMAGE IS PRESENT. ... CAUTION IS INDICATED IF THIS DRUG IS USED DURING PREGNANCY, ALTHOUGH SOME... HAVE TAKEN IT DURING 2ND AND 3RD TRIMESTERS WITHOUT ADVERSELY AFFECTING MOTHER OR FETUS. [R19] *BY ORAL ROUTE IT IS DIFFICULT TO ACHIEVE EFFECTIVE PLASMA LEVELS. FUTHERMORE, BINDING TO PLASMA PROTEIN INHIBITS ACTIVITY. ... 4% THAT PASSES INTO BOWEL IS INSUFFICIENT TO BE EFFICACIOUS IN TREATMENT OF INTESTINAL SHIGELLOSIS... [R5] *PSEUDOMONAS SPECIES ARE RESISTANT. ... ACQUIRED RESISTANCE TO DRUG OCCURS, BUT IT DOES NOT SEEM TO BE TRANSFERABLE. [R3, 1007] *DETERMINATION OF URINARY LEVELS OF 17-KETOSTEROIDS AND 17-KETOGENIC STEROIDS MAY BE FALSELY ELEVATED WHEN NALIDIXIC ACID HAS BEEN PRESCRIBED. [R20] *DRUG SHOULD NOT BE USED IN INFANTS UNDER 3 MO OF AGE. [R3, 1008] *FAILURES IN MEN MAY BE, IN PART, RESULT OF INFECTION FROM PROSTATE GLAND, WHICH IS NOT PENETRATED. ... USE OF ORAL NALIDIXIC ACID IN TREATMENT OF SYSTEMIC INFECTIONS IS NOT USUALLY ADVISED, EVEN WHEN SENSITIVITY TESTING AND BLOOD CONCN SEEM FAVORABLE. [R3, 1007] *LIVER FUNCTION TESTS AND BLOOD-CELL COUNTS ARE ADVISABLE IF TREATMENT LASTS LONGER THAN 2 WK. ... PRESENCE OF DRUG RESULTS IN FALSE-POSITIVE RESPONSES IN SOME URINE GLUCOSE TESTS. [R3, 1007] *Maternal Medication Usually Compatible with Breast-Feeding: Nalidixic acid: Hemolysis in infant with glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. /from Table 6/ [R21] *Studies performed to date have not demonstrated geriatrics-specific problems that would limit the usefulness of nalidixic acid in the elderly. However, elderly patients are more likely to have age-related decrease in renal function, resulting in a prolonged half-life and decreased drug clearance. [R10, 2092] *Neurologic reactions which occasionally have been reported in patients receiving the drug include headache, malaise, drowsiness, dizziness, vertigo, syncope, weakness, myalgia, peripheral neuritis, excitement, confusion, hallucinations, mental depression, insomnia, and sensory abnormalities. [R9, 593] *Visual disturbances including overbrightness of lights, blurred vision, difficulty in focusing, decreased visual acuity, double vision, and alteration of color perception have been reported in patients receiving nalidixic acid. If subjective visual disturbances without objective findings occur during nalidixic acid therapy, they may be apparent with each dose of the drug during the first few days of therapy, usually are reversible, and generally disappear promptly after reduction in dosage or discontinuance of the drug. Nystagmus and eye pain or burning have also occurred. [R9, 593] *Allergic reactions to nalidixic acid commonly include rash and urticaria. Eosinophilia, pruritus, and photosensitivity occur occasionally. Photosensitivity reactions, consisting of erythema and bullae on exposed skin surfaces, usually resolve completely within 2-8 weeks following discontinuance of nalidixic acid therapy; however, successive exposures to sunlight or mild skin trauma may induce the appearance of bullae for up to 3 months after discontinuance of the drug. Less frequently, angioedema, arthralgia with joint stiffness and swelling or arthritis, and rarely anaphylaxis have been reported. [R9, 593] *If severe adverse nervous system reactions including brief convulsions, increased intracranial pressure, or toxic psychosis occur during nalidixic acid therapy, the drug should be discontinued and appropriate therapeutic measures instituted; diagnostic procedures which involve risk to the patient should only be undertaken if CNS symptoms do not disappear within 48 hours. Nalidixic acid should be used with caution in patients with impaired hepatic function, epilepsy, or severe cerebral arteriosclerosis. Patients with impaired renal function should also receive nalidixic acid with caution, although patients with severe impairment (i.e., creatinine clearance of 2-8 ml/minute) have received full doses of the drug without increased toxicity. Nalidixic acid reportedly may increase respiratory depression in patients with respiratory insufficiency, and the drug should be given with caution to these patients. Patients should be cautioned to avoid undue exposure to direct sunlight while receiving the drug; therapy should be discontinued if photosensitivity occurs. Patients who receive nalidixic acid for longer than 2 weeks should have blood counts and renal and hepatic function tests performed periodically. [R9, 594] *Patients should be cautioned to avoid undue exposure to direct sunlight while receiving the drug; therapy should be discontinued if photosensitivity occurs. [R9, 594] *Visual disturbances including overbrightness of lights, blurred vision, difficulty in focusing, decreased visual acuity, double vision, and alteration of color perception have been reported... [R9, 593] *ORAL NALIDIXIC ACID IS USUALLY WELL-TOLERATED, BUT NAUSEA, VOMITING, AND ABDOMINAL PAIN MAY OCCUR. ALLERGIC REACTIONS SUCH AS PRURITUS, URTICARIA, VARIOUS RASHES, PHOTOSENSITIVITY, EOSINOPHILIA, AND FEVER OCCASIONALLY OCCUR, AND CHOLESTASIS, THROMBOCYTOPENIA, LEUKOPENIA, AND HEMOLYTIC ANEMIA RARELY OCCUR. [R3, 1007] *EFFECTS ON CNS, SUCH AS HEADACHE, DROWSINESS, MALAISE, VERTIGO, VISUAL DISTURBANCES, ASTHENIA, AND MYALGIA, ARE EXPERIENCED INFREQUENTLY. IN PT WITH CEREBRAL VASCULAR INSUFFICIENCY, PARKINSONISM, OR EPILEPSY, OR IN NORMAL CHILDREN GIVEN EXCESSIVE DOSES, CONVULSIONS OCCUR, PERHAPS AS RESULT OF INTRACRANIAL HYPERTENSION. [R3, 1007] *Elevated intracranial pressure has produced papilledema and sixth nerve palsies. Principally infants and children have been affected. [R22] *...brightly colored appearance of objects which appeared soon after the drug was taken. .../also/ blurring, photophobia, and disturbance of color vision... [R22] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R23] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC 970.84. Nalidixic Acid Residues in Animal Tissues. Spectrofluormetric Method. Applicable to chicken liver and muscle contg > /= 100 ppb nalidixic acid. [R24] CLAB: *HIGH PRESSURE LIQUID CHROMATOGRAPHIC METHOD WAS DEVELOPED FOR ASSAY OF NALIDIXIC ACID (NEGGRAM) AND HYDROXYNALIDIXIC ACID IN HUMAN PLASMA AND URINE. LOWER LIMITS OF DETECTION FOR EACH WERE 0.25 MCG/ML OF EACH IN PLASMA AND 2.5 MCG/ML OF EACH IN URINE. [R25] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Nalidixic Acid in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 368 (1989) NIH Publication No. 90-2823 SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R3: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R4: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1092 R5: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1152 R6: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 99 R7: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 273 R8: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1536 R9: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 97. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1997 (Plus Supplements). R10: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R11: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 826 R12: Toxicology and Carcinogenesis Studies of Nalidixic Acid in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 368 (1989) NIH Publication No. 90-2823 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R13: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. R14: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 375 R15: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 169 R16: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 205 R17: DASH H, MILLS J; ANN INTERN MED 84 (MAY) 570-571 (1976) R18: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R19: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 793 R20: Miller, R. R., and D. J. Greenblatt. Handbook of Drug Therapy. New York: Elsevier North Holland, 1979. 182 R21: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 141 (1994) R22: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 649 R23: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R24: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 631 R25: SHARGEL L ET AL; J PHARM SCI 62 (SEP): 1452-4 (1976) RS: 21 Record 233 of 1119 in HSDB (through 2003/06) AN: 3258 UD: 200302 RD: Reviewed by SRP on 02/06/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: THIO-TEPA- SY: *AZIRIDINE,-1,1',1''-PHOSPHINOTHIOYLIDYNETRIS-; *GIROSTAN-; *NCI-C01649-; *NSC-6396-; *ONCOTEPA-; *ONCOTIOTEPA-; *PHOSPHINE SULFIDE, TRIS(1-AZIRIDINYL)-; *1,1',1''-PHOSPHINOTHIOYLIDYNETRISAZIRIDINE-; *PHOSPHOROTHIOIC-ACID-TRIETHYLENETRIAMIDE-; *PHOSPHOROTHIOIC-TRIAMIDE,-N,N',N''-TRI-1,2-ETHANEDIYL-; *PHOSPHOROTHIOIC-TRIAMIDE,-N,N',N''-TRIETHYLENE-; *TESPA-; *TESPAMIN-; *TESPAMINE-; *THIOFOZIL-; *THIOPHOSPHAMIDE-; *THIOPHOSPHORAMIDE,-N,N',N''-TRI-1,2-ETHANEDIYL-; *THIOTEF-; *THIO-TEP-; *THIOTEPA-; *THIOTRIETHYLENEPHOSPHORAMIDE-; *TIFOSYL-; *TIOFOSFAMID-; *TIOFOSYL-; *TIOFOZIL-; *TIO-TEF-; *TRIAZIRIDINYLPHOSPHINE-SULFIDE-; *N,N',N''-TRI-1,2-ETHANEDIYLPHOSPHOROTHIOIC-TRIAMIDE-; *TRI- (ETHYLENEIMINO)THIOPHOSPHORAMIDE; *N,N',N''-TRIETHYLENEPHOSPHOROTHIOIC-TRIAMIDE-; *N,N',N''-TRIETHYLENETHIOPHOSPHAMIDE-; *TRIETHYLENETHIOPHOSPHORAMIDE-; *N,N',N''-TRIETHYLENETHIOPHOSPHORAMIDE-; *TRIETHYLENETHIOPHOSPHOROTRIAMIDE-; *N,N',N''-TRIETHYLENETHIOPHOSPHORTRIAMIDE-; *TRIS(1-AZIRIDINYL)PHOSPHINE SULFIDE; *TSPA- RN: 52-24-4 MF: *C6-H12-N3-P-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ETHYLENIMINE IS CONDENSED WITH THIO-PHOSPHORYL CHLORIDE (SPCL3) IN PRESENCE OF TRIETHYLAMINE AS ACID ACCEPTOR. [R1] FORM: *THIOTEPA (LEDERLE). INJECTION: POWDER 15 MG. [R2] *Thiotepa for injection is a sterile mixture of 1 part of thiotepa, 5.33 parts of sodium chloride, and 3.33 parts sodium bicarbonate. It contains not less than 95.0% and not more than 110.0% of the labeled amount of thiotepa. [R3] *Thiotepa contains not less than 97.0% and not more than 102.0% of thiotepa, calculated on the anhydrous basis. [R3] USE: *Insect sterilant [R4] *MEDICATION (VET) *MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM PENTANE OR ETHER [R4]; *FINE, WHITE CRYSTALLINE FLAKES [R1] ODOR: *FAINT ODOR [R1] MP: *51.5 DEG C [R4] MW: *189.23 SOL: *19 G/100 ML WATER @ 25 DEG C; FREELY SOL IN ALC; SOL IN BENZENE, ETHER, CHLOROFORM [R4] OCPP: *IN DIL SOLN @ PH 1 HYDROGEN SULFIDE IS RELEASED (T/2, APPROX 3 HR) [R5, p. V9 86(1975)] *Polyfunctional alkylating agent. [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R7, 1979.8] OPRM: *Great care should be taken to prevent inhaling particles of thiotepa or exposing the skin to it. [R3] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R7, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R7, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R7, 1979.11] SSL: *DIL AQ SOLN (0.1%) ARE STABLE FOR MONTHS @ TEMP BELOW 20 DEG C; FOR 45 HR @ 30 DEG C. [R8] *DIL AQ SOLN (0.1%) ARE STABLE FOR 2 HR IN PRESENCE OF OXYGEN, CARBON DIOXIDE OR LIGHT. [R8] *DIL AQ SOLN (0.1%) ARE STABLE FOR 30 MIN WHEN EXPOSED TO UV-LIGHT; BOILING FOR 10 MIN INACTIVATES 36% OF AGENT. [R8] *UNSTABLE @ PH 4.2 [R9] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R7, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R7, 1979.13] STRG: *Preserve in tight, light-resistant containers, and store in a refrigerator. [R3] *Both thiotepa powder for injection and reconstituted solutions of the drug should be stored at 2-8 deg C protected from light. [R6] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R7, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R7, 1979.15] DISP: *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R7, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R7, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R7, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R7, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R7, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is sufficient evidence for the carcinogenicity of thiotepa in humans. There is sufficient evidence for the carcinogenicity of thiotepa in experimental animals. Overall evaluation: Thiotepa is carcinogenic to humans (Group 1). [R10] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R7, 1979.23] HTOX: *SIDE EFFECTS INCL ... VOMITING, ... FEVER, AND SERIOUS DEPRESSION OF BONE MARROW, CHARACTERIZED BY NEUTROPENIA, THROMBOCYTOPENIA, AND VARIABLE ANEMIA. [R1] *THIOTEPA MAY PRODUCE NAUSEA, ANOREXIA, AND HEADACHE. ... IT HAS TOXIC EFFECT ON HEMATOPOIETIC SYSTEM THAT IS DOSE RELATED. INITIAL EFFECTS ON BONE MARROW MAY NOT BECOME EVIDENT FOR 5 TO 30 DAYS /MEDIAN, 15 DAYS). ... WHITE BLOOD CELL AND PLATELET COUNTS ARE RELIABLE GUIDES. [R11] *AT LEAST 9 CASES OF ACUTE LEUKEMIA (7 MYELOBLASTIC, 1 MYELOMONOCYTIC, 1 ERYTHROMEGAKARYOCYTIC) HAVE BEEN REPORTED IN PATIENTS WITH MALIGNANCIES OF OVARY, BREAST OR LUNG WHO HAD BEEN TREATED WITH THIOTEPA FOR 13-60 MO. IN 6 OF THE CASES, THIOTEPA WAS USED WITH OTHER CHEMOTHERAPEUTIC AGENTS AND/OR RADIATION. [R12] *OCCURRENCE OF 2 CASES OF ACUTE LEUKEMIA AMONG 400 PATIENTS WITH OVARIAN CANCER ... SUGGESTS INCR INCIDENCE OF ACUTE LEUKEMIA AMONG WOMEN WITH OVARIAN CANCER GIVEN CHEMOTHERAPEUTIC REGIMENS WHICH INCL THIOTEPA. [R12] *UNTOWARD SIDE EFFECTS OF REPEATED APPLICATION OF THIOTEPA EYEDROPS HAVE CONSISTED OF CONTACT ALLERGIC REACTIONS, DEPIGMENTATION OF EYELIDS AND EYELASHES AND ... KERATITIS AND CORNEAL EDEMA. [R13, 911] *An increased frequency of chromosomal aberrations was observed in one study of cancer patients receiving therapeutic doses of this compound. [R14] *A 76 year old man developed ureteral obstruction and renal failure after topical treatment with thiotepa following bladder resection. [R15, 228] *A myasthenic patient who received pancuronium and 90 minutes later an intraperitoneal thiotepa injection developed rapid and prolonged respiratory depression. [R16] *TREATMENT WITH ... /THIOTEPA/ OF CULTURED HUMAN LYMPHOCYTES RESULTED IN SIGNIFICANT INCR IN FREQUENCY OF CHROMOSOME ABERRATIONS. [R17] NTOX: *CARCINOGENESIS BY ALKYLATING AGENT THIO-TEPA, LUNG TUMORS DEVELOPED IN A/J MICE AFTER IP ADMIN OF 60 UMOL/KG FOR 273 DAYS. /FROM TABLE/ [R18, 228] *IMPAIRMENT OF SPERMATOGENESIS HAS BEEN NOTED ... IN EXPTL ANIMALS. [R19] *... CARCINOGENS WHICH CROSS-LINK DNA INCL ... THIO-TEPA (CARCINOGENESIS, STRAIN BR46 RATS; CROSS-LINKING OF DNA IN CHICK EMBRYOS) ... . [R18, 110] *THIOTEPA INCR FREQUENCY OF INHERITED RECESSIVE LETHALS IN DROSOPHILA MELANOGASTER. TREATMENT OF MALE CFLP MICE WITH SINGLE IP INJECTIONS OF 5 OR 10 MG/KG BODY WT ... INDUCED HIGH FREQUENCY OF DOMINANT LETHALS. INSEMINATION OF FEMALE RABBITS WITH SPERM TREATED WITH THIOTEPA ... LED TO INCR IN FREQUENCY OF DOMINANT LETHALS. [R17] *... IN PREGNANT MICE INJECTED IP WITH SINGLE DOSES OF 0.5-30 MG/KG BODY WT ON VARIOUS DAYS OF GESTATION. /MINIMUM/ TERATOGENIC DOSE WAS 1 MG/KG BODY WT; AFTER ADMIN 10 MG/KG BODY WT ALL FETUSES WERE MALFORMED. ... RATS WERE GIVEN 5 MG/KG BODY WT ... GROSS DEVELOPMENTAL ABNORMALITIES AND SKELETAL DEFECTS WERE OBSERVED IN FETUSES. [R17] *THIOTEPA ... ADMIN /IV/ TO ... BR 46 RATS @ ... (1 MG/KG BODY WT) ONCE WEEKLY FOR 52 WK. MALIGNANT TUMORS DEVELOPED IN 9/30 (30%) TREATED ANIMALS: 1 SARCOMA OF MAMMARY GLAND, 1 PHEOCHROMOCYTOMA AND 1 MYELOSIS; 5/30 (17%) HAD BENIGN TUMORS. 2 SARCOMAS OF ABDOMINAL CAVITY, 1 LYMPHOSARCOMA, 1 SEMINOMA, 1 HEMANGIOENDOTHELIOMA, 1 FIBROSARCOMA OF SALIVARY GLAND ... . IN CONTROLS, MALIGNANT TUMORS WERE FOUND IN 4/65 (6%) ... . [R20] *... A/HE MICE ... TREATED WITH THIOTEPA IN TRICAPRYLIN IP THRICE WEEKLY FOR TOTAL OF 12 INJECTIONS. AFTER 24 WK ... 19, 47 and 94 MG/KG BODY WT PRODUCED 0.70, 0.74 and 1.50 LUNG ADENOMAS/MOUSE IN 11/20, 20/20 and 16/20 MICE, RESPECTIVELY. IN CONTROLS ... MALES AND ... FEMALES ... DEVELOPED LUNG TUMORS ... 0.24 and 0.20 ... TUMORS/MOUSE. [R20] *Weanling rats treated with 1:445 or 1:1000 thiotepa eyedrops during six weeks have developed corneal vascularization and cataract. [R13, 911] *Intravitreal injection of thiotepa in rabbits /at/ a concentration of 8 mg/ml has been reported to be tolerated without excessive inflammation or alteration of the electroretinogram. [R13, 911] *Thiotepa induced dominant lethal mutations, chromosomal aberrations, micronuclei and sister chromatid exchanges in rodents treated in vivo. It induced sister chromatid exchanges and chromosomal aberrations in human and rodent cells in vitro and transformation of C3H 10T1/2 mouse cells. It was mutagenic to Chinese hamster cells in vitro and to mouse lymphoma cells in a host-mediated assay. Thiotepa induced sex-linked recessive lethal mutations in Drosophila, caused sister chromatid exchanges and chromosomal aberrations in plant cells and was mutagenic to fungi and to bacteria in vitro and in host-mediated assays. [R14] *An aqueous solution of thiotepa iso-osmotic with serum (5.67%) caused 10% hemolysis of erythrocytes cultured in it for 45 minutes. [R15, 228] NTXV: *LD50 Rat iv 15 mg/kg; [R4] NTP: +A bioassay of thio-TEPA for possible carcinogenicity was conduced by admin the test chemical by ip injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 31-39 rats of each sex were admin thio-TEPA in phosphate buffered saline at one of three doses, either 0.7, 1.4 or 2.8 mg/kg body weight, three times per wk for a maximum of 52 wk, then observed for an additional periods of time. The maximum time on study (admin of chemical and observation) was 86 wk. The groups at the low dose were started 69 wk after those at the mid and high doses, because of high mortalities observed in the groups at the higher doses. Matched controls consisted of groups of 10 untreated rats and 10 vehicle control rats of each sex. Pooled control groups were also used. Surviving control rats were /sacrificed/ at 82-87 wk; surviving dosed rats were /sacrificed/ at 81 or 82 wk. Groups of 35 mice of each sex were admin thio-TEPA at one of two doses 1.15 or 2.3 mg/kg body wt, three times per wk for a maximum of 52 wk, then observed for a maximum additional period of 34 wk. Matched controls consisted of groups of 15 untreated mice and 15 vehicle control mice of each sex. Pooled controls also were used. Surviving control and dosed mice were /sacrificed/ at 86 or 87 wk. Thio-TEPA was toxic to both rats and mice, causing decr mean body wt gains and early deaths in the mid and high dose rats and in the high dose mice. Because of early deaths, statistical analyses were based only on time adjusted incidences of tumors. Since all high dose male and female rats died by 21 wk, microscopic evaluation of tissues was performed only on the low and mid dose animals. ... It is concluded that under the conditions of this bioassay, thio-TEPA was carcinogenic in both Sprague-Dawley rats and B6C3F1 mice. In the rats, the chemical induced squamous cell carcinoma of the skin or ear canal in both males and females, and hematopoietic neoplasms in the males; in the mice, it induced lymphoma or lymphocytic leukemia in both sexes and squamous cell carcinoma in the skin and associated glands of males. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R21] ADE: *IN MAN, 50% OF INJECTION OF (14)C-THIOTEPA EITHER IV OR LOCALLY INTO TUMOR WAS EXCRETED IN 1ST 6 HR, AND BY 48 HR ONLY LOW LEVELS PERSISTED. ABSORPTION OF ORALLY ADMIN DOSE OF (14)C-THIOTEPA WAS VARIABLE: LESS THAN 1% OF INJECTED DOSE WAS RECOVERED AS UNCHANGED DRUG IN URINE. [R17] *IN RATS, THIOTEPA WAS EVENLY DISTRIBUTED THROUGHOUT ORGANS, BUT HIGHEST PROPORTION WAS FOUND IN LIVER. MOST OF DRUG AND ITS PRINCIPAL METABOLITE, TEPA, ARE EXCRETED IN URINE DURING 1ST FEW HOURS, BUT SMALL FRACTION OF RADIOACTIVITY WAS RETAINED IN BLOOD HEMOGLOBIN AFTER 9 DAYS. [R17] *LEVELS OF IV ADMIN (14)C-THIO-TEPA FELL RAPIDLY IN DOG PLASMA WITHIN 3 HR. EXCRETION OF THIO-TEPA AND ITS METABOLITES WAS RAPID. 6-HR URINE CONTAINED 65-80% OF (14)C, and 5-10% MORE WAS EXCRETED IN NEXT 18 HR. THERE WAS LITTLE EXCRETION OF UNCHANGED THIO-TEPA. [R22] *... THIO-TEPA WAS ONLY WELL ABSORBED IN SUBJECT WITH GASTRIC CARCINOMA AND PROBABLE REDUCED GASTRIC ACIDITY. WHETHER THIO-TEPA WAS ADMIN TO RATS IV OR INTRA-ARTERIALLY, DISTRIBUTION OF (14)C IN TISSUES WAS RAPID AND UNIFORM. 94-98% OF (14)C WAS EXCRETED IN 8-HR URINE; MUCH AS UNCHANGED THIO-TEPA. [R22] *PLASMA LEVELS OF THIO-TEPA WERE MAXIMAL 1 HR AFTER ORAL ADMIN TO HUMAN SUBJECTS, BUT ABSORPTION OF DRUG WAS INCONSISTENT IN DIFFERENT SUBJECTS. URINARY EXCRETION OF (14)C FOLLOWED PLASMA LEVELS OF (14)C, AND POOR ABSORPTION THAT RESULTED IN SOME CASES WAS PROBABLY DUE TO GASTRIC DESTRUCTION OF THIO-TEPA, WHICH IS ACID-LABILE. [R22] *ONSET OF ACTION IS SLOW ... RESULTS OF THERAPY BECOMING INCREASINGLY APPARENT FOR SEVERAL WEEKS ... SLOW ONSET LIMITS ITS VALUE IN ACUTE COMPLICATIONS OR FAR-ADVANCED DISEASE. /HUMAN, PARENTERAL/ [R23] *Thiotepa is incompletely absorbed from the GI tract. Variable absorption also occurs through serous membranes, such as the pleura and bladder, and from im injection sites. Absorption through the bladder mucosa may range from 10% to almost 100% of the instilled dose and is enhanced by extensive tumor infiltration or acute mucosal inflammation, following endoscopic surgical procedures or radiation therapy, and in the presence of vesicoureteral reflux. Following IV administration of thiotepa (14)C, serum concentrations of radioactivity reportedly begin to decline within 10 minutes, but detectable concentrations persist 72 hours. [R6] *Thiotepa is apparently extensively metabolized. About 60% of an iv dose is excreted in the urine within 24-72 hours. Traces of unchanged thiotepa and triethylene phosphoramide appear in the urine; the remainder is excreted as unidentified metabolites. [R6] *A phase I trial of thiotepa administered as an iv bolus was performed in 19 children with refractory malignancies who received initial doses of 25 mg/sq m with escalations to 50, 65, and 75 mg/sq m and thiotepa pharmacokinetics were studied; 7 additional patients were treated with 50 or 65 mg/sq m of thiotepa infused over 8 hr. The maximum tolerated bolus dose was 65 mg/sq m. Reversible myelosupression was the dose limiting toxicity. The plasma and cerebrospinal fluid pharmacokinetic parameters of thiotepa and its major active metabolite triethylenephosphoramide were also evaluated. When the bolus and infusion methods of thiotepa administration were compared, there was little difference observed in any pharmacokinetic parameter for either thiotepa or triethylenephosphoramide. The plasma disappearance of thiotepa was rapid and biphasic with half-lives of 0.14-0.32 and 1.34-2 hr. Dose dependent pharmacokinetics were demonstrated by steadily declining plasma clearance with increasing thiotepa dose. Clearance values declined from 28.6 l/sq m/hr at the 25 mg/sq m dose to 11.9 1/sq m/hr at 75 mg/sq m dose. The half-live of triethylenephosphoramide was longer than that of thiotepa and ranged between 4.3 and 5.6 hr. There was evidence of the saturation of triethylenephosphoramide production. Both thiotepa and triethylenephosphoramide both exhibited excellent penetration into the cerebrospinal fluid, producing lumbar and ventricular concentrations which were nearly identical to simultaneous plasma concentrations. In one patient with a Rickham reservoir, the cerebrospinal fluid:plasma area under the concentrationxtime curve ratios for thiotepa and triethylenephosphoramide were 1.0 and 0.95, respectively. The above data indicated that thiotepa can be safely administered to pediatric patients at doses higher than conventionally used. The favorable cerebrospinal fluid penetration for thiotepa and triethylenephosphoramide suggest that Phase II studies of thiotepa be considered in patients with central nervous system tumors. [R24] *A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with thio-tepa in a phase I study. A total of 50 courses of thio-tepa were given ip in doses ranging from 30 to 80 mg/sq m. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/sq m and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. Thio-tepa concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 + or - 0.1 hr. A mean of 93% of the drug was absorbed during the 4 hr dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for ip delivery was detected for peak drug concentration (24.9 + or - 8.5) and area under the curve (9.2 + or - 4.8). Based on this study, the recommended dose for ip thio-tepa is 60 mg/sq m every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thio-tepa's small molecular weight and lipophilic nature, suggests that it has only a limited role in ip therapy. [R25] METB: *IN MICE, THIOTEPA IS RAPIDLY METABOLIZED TO TRIS(1-AZIRIDINYL)PHOSPHINE OXIDE (TEPA): WITHIN 30 MIN ONLY TEPA AND INORG PHOSPHATE WERE DETECTED IN URINE AND PLASMA. MOUSE IS EXCEPTIONAL IN ITS ABILITY TO DEGRADE DRUG COMPLETELY TO INORG PHOSPHATE. [R17] *Thiotepa is metabolized primarily to TEPA /Thiotriethylenephosphoramide/. The total body clearance is 8.5 l/hr/sq M, with 15% recovered in the urine as /Thiotriethylenephosphoramide/ in 24 hr. [R26] *Thiotepa is unstable in acid and poorly absorbed from the gastrointestinal tract. It has a plasma half-life of 2 to 3 hours. It is not a vesicant and can be administered by direct intravenous injection, intracavitary or intravesical administration, or injection directly into a tumor site. Approximately 85% is excreted in the urine in 24 hours, primarily as metabolites. [R11] BHL: */Thiotepa/ has an alpha half-life of 7.5 min and a beta half-life of 109 min. [R26] ACTN: *Thiotepa, as an alkylating agent, interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function. [R6] *The megakaryocytopoiesis in rats was studied following a single dose of thio-tepa to determine the mechanisms for the thrombocytopenia and subsequent recovery. The blood platelet number, platelet production (measured by (35)S incorporation into platelets), mean platelet volume, and the number and DNA content of bone marrow megakaryocytes were observed. The blood platelet counts, platelet production, and total megakaryocytes number decreased to low values following the administration of thio-tepa, and stayed low until regeneration started around day 10. The mean platelet volume increased from the normal 6.6 fl to 7.8 fl during the early regeneration days 8-14. The megakaryocytes were divided into four ploidy classes: 2N-4N, 8N, 16N, and 32N-64N. The number of megakaryocytes within all ploidy classes decreased to nearly zero within four days after the injection of thio-tepa. The regeneratin started around day 10 with increasing numbers of 2N-4N and 8N megakaryocytes, while the number of 16N and 32N-64N megakaryocytes increased more than four days later. It is concluded that decreased or blocked influx or progenitor cells into the megakaryocytes compartment is the main reason for thrombocytopenia after exposure to thio-tepa. [R27] INTC: *PENTOBARBITAL GIVEN CONCOMITANTLY REDUCED LD50 OF THIOTEPA IN MICE. [R20] *Methylxanthines enhance lethality of alkylating agents in human cancer cells, a phenomenon attributed to the prevention of DNA repair. Pentoxifylline is a nontoxic methylxanthine, used clinically for claudication. Using human cancer cells in culture or in a mouse xenograft model, combination treatments with alkylating agents and pentoxifylline or other methylxanthines /was examined/ With human bladder cancer cells in culture, cytotoxicity of thiotepa was increased up to ten fold (p < 0.01) by posttreatment with pentoxifylline, with a major clinical metabolite of pentoxifylline, or with caffeine; the pentoxifylline concentrations required (0.4-1.0 mM) are clinically achievable in the bladder after nontoxic po doses. With human bladder or breast cancer xenografts in a modified subrenal capsule assay, enhancement of thiotepa was also observed by in vivo posttreatment with pentoxifylline. In contrast, these combinations produce no increased toxicity to normal tissues in these animals, measured by weight, lethality, or histological changes of the normal bladder urothelium. These results provide evidence for a novel approach to improve the therapeutic index of thiotepa and other alkylators, used for topical therapy of bladder cancer and, possibly systemic therapy of other malignancies. [R28] *Vitamin C at 2 mM enhanced sister chromatid exchange frequencies induced by thiotepa or L-ethionine in cultured human lymphocytes. However, when vitamin C was tested at 0.02 mM and 0.2 mM a rather protective effect on sister chromatid exchange rates induced by thiotepa or L-ethionine was identified. Vitamin C (2 mM) caused a cell division delay in cultures treated with thiotepa or L-ethionine. Division delays caused by thiotepa or L-ethionine were reversed in the presence of 0.02 mM or 0.2 mM vitamin C. Mitotic indices in cultures treated with thiotepa or L-ethionine continued to be suppressed in the presence of 2 mM vitamin C. However, vitamin C at 0.02 mM reversed suppression of mitotic indices caused by L-ethionine or thiotepa. These findings illustrate the complexity of the interactions of vitamin C in biological systems and indicate that with different concentrations vitamin C can cause or prevent genetic toxicity. [R29] *The food components chlorophyllin, beta-carotene and alpha-linolenic acid (in its methyl ester form) were tested in Chinese hamsters for antimutagenic activity on the powerful mutagen thio-tepa. Each of these natural protective compounds inhibited by 70-85% the clastogenic effects induced by the mutagen. When 2 or 3 of these antimutagens were administered sumultaneously no additive effects were observed. alpha-Linolenic acid methyl ester was the most effective antimutagen under the experimental conditions. [R30] *After receiving N,N',N"-triethylenethiophosphoramide (thiotepa) and cyclophosphamide iv, five women with metastatic adenocarcinoma of the breast developed a pattern hyperpigmentation confined to skin occluded by adhesive-containing materials. Determinations of thiotepa concentrations in occluded and nonoccluded skin, plasma, bandage with adhesive, and guaze containing sweat were performed. The results suggest that this alkylating agent is excreted onto the skin surface in sweat, accumulated beneath adhesive-containing bandages and electrocardiogram pads, and exerts a local toxic effect resulting in hyperpigmentation. [R31] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Alkylating Agents; Antineoplastic Agents, Alkylating; Carcinogens; Chemosterilants [R32] *WHILE ... /ETHYLENIMINE DERIV/ CMPD HAVE CYTOTOXIC ACTIVITY, THEY POSSESS NO PARTICULAR ADVANTAGE /OVER OTHER ALKYLATING AGENTS/. /ETHYLENEIMINE DERIV/ [R33, 1212] *THIOTEPA IS EFFECTIVE IN PALLIATIVE MANAGEMENT OF CARCINOMA OF BREAST AND OVARY. ... LIMITED USEFULNESS IN LYMPHOMAS. INTRAVESICAL INSTILLATION MAY CONTROL PLEURAL OR PERITONEAL EFFUSIONS. USEFUL IN SUPERFICIAL PAPILLARY CARCINOMAS OF URINARY BLADDER. ALSO UTILIZED IN CARCINOMATOUS MENINGITIS. [R11] *... /THIOTEPA'S/ MAIN OPHTHALMOLOGIC INTEREST HAS BEEN IN LOCAL THERAPEUTIC APPLICATION FOR PREVENTION OF CORNEAL VASCULARIZATION AND PREVENTION OF RECURRENCE OF PTERYGIUM. [R13, 910] *MEDICATION (VET): ... HAS SHOWN USEFULNESS PARTICULARLY AGAINST MALIGNANT LYMPHOMAS, ADENOMAS, AND MASTOCYTOMAS. TOPICALLY, ON EYE POSTSURGICALLY TO PREVENT RECURRENCE OF PTERYGIUM. ... SOME VALUE IN PREVENTING OCULAR MELANIN PROLIFERATION AND VASCULARIZATION ... . [R34] *TEMPORARY REGRESSION OF CARCINOMA OF LUNG ... OCCASIONAL FAVORABLE RESPONSES /TO TUMORS OF HEAD AND NECK, GI TRACT, PROSTATE, KIDNEY, LIVER, BILIARY TRACT, AND PANCREAS/ ... INTRACAROTID INJECTIONS ... AT INTERVALS OF 6 TO 9 WEEKS IN TREATMENT OF CEREBRAL LESIONS. [R23] *To ensure "non-toxic" infusion fluid for lens extraction and vitrectomy the concentration was limited to 8 ug/ml. [R13, 911] *Used ... intrathecally for CNS disease. [R26] *Thiotepa can be administered iv, im or sc ... The dosage by all routes should be reduced with pre-existing bone marrow suppression. ... intracavitary ... intrathecal ... [R26] *Fourteen patients with severe psoriasis unresponsive to other treatment were treated by the application once daily of thiotepa 0.4% in yellow soft paraffin containing 20% of wool fat; occlusive dressings were applied for 8 hours. Total clearing of the lesions occurred in 11 patients in an average of 19 days. [R15, 229] *N,N'N''-triethylenethiophosphoramide (thiotepa) is a polyfunctional alkylating agent similar in structure to nitrogen mustard. Thiotepa (synthesized by American Cyanamid Company, Wayne, NJ) underwent clinical trials in the 1960s that showed that it was active against a wide variety of tumors. At a standard dose level (10 to 30 mg/sq m), the dose-limiting toxicity is myelosuppression; other toxicities are infrequent. Therefore, high-dose phase I evaluation was encouraged by these observations. Approximately 217 patients have been treated with single-agent high-dose thiotepa administered iv daily over 2 hours for 3 days followed by hematopoietic stem cell rescue to prevent prolonged myelotoxicity. The total doses administered ranged from 135 to 1,575 mg/sq m. As anticipated, myelotoxicity was substantial, with 180 mg/sq m being the highest dose not requiring stem cell rescue to ensure of hematopoietic recovery. Extramedullary toxicities consisted of stomatitis, dermatitis, hepatoxicity, and CNS toxicity. CNS toxicity was dose-limiting; other toxicities were problematic, ie, dose-dependent but not truly dose-limiting. The maximal tolerated dose of thiotepa is 900 to 1,125 mg/sq m, with the lowered dose being the maximal dose for evaluation in combination chemotherapy. In high-dose phase I evaluation, the overall response rate was approximately 50% with responses seen in a wide variety of solid tumors, lymphomas, and pediatric tumors. High-dose thiotepa appears to be an alkylating agent with broad-spectrum antitumor efficacy, which should add to the cytoreductive regimens for both solid and hematopoietic tumors. [R35] *MEDICATION (VET): ANTINEOPLASTIC, RADIOMIMETIC, ALKYLATING AGENT. [R34] WARN: *THIOTEPA IS CONTRAINDICATED DURING 1ST TRIMESTER OF PREGNANCY. [R11] *MAX LEUKOPENIA MAY OCCUR 2 TO 3 WK OR AS MUCH AS A MONTH AFTER THERAPY HAS BEEN DISCONTINUED. HEMOGLOBIN LEVEL AND LEUKOCYTE AND THROMBOCYTE COUNTS ... DETERMINED DAILY FOR 1ST 7 TO 10 DAYS ... THEN WEEKLY DURING MAINTENANCE THERAPY AND FOR 4 WK AFTER WITHDRAWAL. [R23] *IF LEUKOCYTE COUNT FALLS TO 4000 OR IF THROMBOCYTE LEVEL FALLS TO 150000, DRUG SHOULD BE DISCONTINUED OR DOSAGE GREATLY REDUCED ... . SPECIAL CAUTION ... IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA SINCE THIS DISEASE IS MORE SUSCEPTIBLE TO CYTOTOXIC DRUGS THAN IS CHRONIC GRANULOCYTIC LEUKEMIA. [R23] *SPECIAL CAUTION /IN/ PATIENTS WHOSE BONE MARROW HAS BEEN DEPRESSED BY INVASION OF TUMOR CELLS OR BY PRIOR TREATMENT WITH RADIATION OR OTHER ANTINEOPLASTIC AGENTS ... CONTRAINDICATED IN PREGNANCY BECAUSE OF ITS DELETERIOUS EFFECTS ON FETUS. [R23] TOLR: *ACQUIRED RESISTANCE TO ALKYLATING AGENTS IS COMMON EVENT ... RESISTANCE TO ONE ... USUALLY IMPARTS CROSS-RESISTANCE TO OTHER ALKYLATORS. ... CHANGES IDENTIFIED IN CELLS RESISTANT ... ARE DECR PERMEABILITY TO DRUGS AND INCR PRODUCTION OF NUCLEOPHILIC SUBSTANCES THAT CAN COMPETE WITH TARGET DNA FOR ALKYLATION. /ALKYLATING AGENTS/ [R33, 1214] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *ION-EXCHANGE CHROMATOGRAPHY PROCEDURES, WHICH MAY BE POTENTIALLY USEFUL IN IDENTIFICATION OF METABOLITES, HAVE BEEN DESCRIBED. [R5, p. V9 88] *... METHODS OF ANALYSIS INCL ... THIN-LAYER CHROMATOGRAPHY. ... MOST SENSITIVE ... GAS CHROMATOGRAPHIC TECHNIQUES ... DETECTING SUB-NG QUANTITIES ... . [R5, p. V9 87] *COLORIMETRIC DETERMINATIONS USING 4-(4'-NITROBENZYL)PYRIDINE ... SENSITIVE SPECTROPHOTOFLUORIMETRIC PROCEDURE (RANGE, 0.05-0.2 UG/ML BODY FLUID). [R5, p. V9 87] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Balis FM, Poplack DG; Am J Pediatr Hematol Oncol 2 (1): 74-86 (1989). A review of literature on the central nervous system pharmacology of antileukemic drugs. NTP TR No 058; Route: injection, ip; Species: rats and mice. NTIS No PB285702/AS. [R36] U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1084 R2: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 1117 R3: USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990. 1367 R4: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1522 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R6: McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990). 555 R7: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 85 (1975) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 86 (1975) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 50 133 (1990) R11: American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986. 1188 R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 90 (1975) R13: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S6 549 (1987) R15: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. R16: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978.,p. 2/33 R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 89 (1975) R18: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. R19: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1259 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 88 (1975) R21: Bioassay of Thio-TEPA for Possible Carcinogenicity (1978) Technical Rpt Series No. 58, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R22: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 66 R23: American Society of Hospital Pharmacists. Data supplied on contract from American Hospital Formulary Service and other current ASHP sources. 1962 R24: Heideman RL et al; Cancer Res 49: 736-41 (1989) R25: Lewis C et al; Cancer Chemother Pharmacol 26 (4): 283-7 (1990) R26: Knoben, J.E. and P.O. Anderson (eds.) Handbook of Clinical Drug Data. 6th ed. Bethesda, MD: Drug Intelligence Publications, Inc. 1988. 426 R27: Tanum G; Exp Hematol 14 (3): 202-6 (1986) R28: Fingert HJ et al; Cancer Res 48 (15): 4375-81 (1988) R29: Lialiaris T et al; Cytogenet Cell Genet 44 (4): 209-14 (1987) R30: Renner HW; Mutat Res 244 (2): 185-8 (1990) R31: Horn TD et al; Arch Dermatol 125 (4): 524-7 (1989) R32: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R33: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R34: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 600 R35: Wolff SN et al; Semin Oncol 17 (1) Suppl 3: 2-6 (1990) R36: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.27 RS: 47 Record 234 of 1119 in HSDB (through 2003/06) AN: 3287 UD: 200211 RD: Reviewed by SRP on 9/23/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: AMPHETAMINE- SY: *ACTEDRON-; *ADIPAN-; *ALLODENE-; *BETA-AMINOPROPYLBENZENE-; *DL-AMPHETAMINE-; *ANOREXIDE-; *ANOREXINE-; *BENZEBAR-; *BENZEDRINE-; *DL-BENZEDRINE-; *BENZENEETHANAMINE, ALPHA-METHYL-, (+-)-; *BENZOLONE-; *Desoxynorephedrine-; *(+-)-DESOXYNOREPHEDRINE; *ELASTONON-; *FINAM-; *ISOAMYNE-; *ISOMYN-; *MECODRIN-; *(+-)-ALPHA-METHYLBENZENEETHANAMINE; *alpha-Methylphenethylamine-; *(+-)-ALPHA-METHYLPHENETHYLAMINE; *DL-ALPHA-METHYLPHENETHYLAMINE-; *(+-)-ALPHA-METHYLPHENYLETHYLAMINE; *NOREPHEDRANE-; *NOREPHEDRINE,-DEOXY-; *NOVYDRINE-; *OKTEDRIN-; *ORTEDRINE-; *PERCOMON-; *PHENEDRINE-; *PHENETHYLAMINE, ALPHA-METHYL-, (+-)-; *DL-1-PHENYL-2-AMINOPROPANE-; *1-PHENYL-2-AMINOPROPANE-; *1-Phenyl-2-amino-propan- (German); *PHENYLISOPROPYLAMINE-; *beta-Phenylisopropylamine-; *(+-)-BETA-PHENYLISOPROPYLAMINE; *beta-Phenylisopropylamin- (German); *PROFAMINA-; *PROPISAMINE-; *PSYCHEDRINE-; *RACEMIC-DESOXY-NOR-EPHEDRINE-; *RAPHETAMINE-; *RHINALATOR-; *SIMPATEDRIN-; *SIMPATINA-; *SYMPAMINE-; *SYMPATEDRINE-; *WECKAMINE- RN: 300-62-9 MF: *C9-H13-N ASCH: Amphetamine sulfate; 60-13-9; Amphetamine phosphate; 139-10-6; Amphetamine sulfate (d); 51-63-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD BY TREATING ACETONE SOLN OF AMPHETAMINE WITH 85% PHOSPHORIC ACID: GOGGIN, US PATENT 2,507,468 (1950 TO CLARK AND CLARK). /AMPHETAMINE PHOSPHATE/ [R1] *U.S patents 1,879,003 (1932); 1,921,424 (1933); 2,015,408 (1935); Hartung, Munch, J. Am. Chem. Soc. 53,1875 (1931). [R2, 98] *Phenylacetone + hydroxylamine sulphate (oxime formation/hydrogenation) [R3] IMP: *Di(1-phenylisopropyl)formamide is a by-product in the Leuckart synthesis of N-formylamphetamine, which is a reaction precursor to illegally produced dl-amphetamine. Side reactions and incomplete conversions lead to a variety of impurities and intermediate products, including benzyl methyl ketone, dibenzyl ketone, formamide, formic acid, methylamine, N,N-dimethylamphetamine, N-formylamphetamine, di(1-fenylisopropyl)amine, benzylamine, and several pyrimidine, pyridine, and pyridone compounds. Analysis of street samples suggests that amphetamines may be present in as little as 60% of purported samples. These illicit drugs contain varying amt of phencyclidine, LSD, STP, cocaine, atropine, mescaline, strychnine, and adulterants (eg, cornstarch, maltose, lactose, magnesium silicate, quinine, fibrous material). [R4, 627] FORM: *The mixtures avail for wt control combine more than one amphetamine (which may be considered essentially a single-entity drug). ... Obetrol; tablets containing 2.5 or 5 mg each of dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate, and amphetamine sulfate. [R5, 935] *... Heroin-amphetamine ("poor man's speedball") combinations. [R6, 342] *Grade: Dextro-, dextrolevo-. Also available as phosphate and sulfate. [R7] *Available commercially as the racemic free base, phosphate or sulFate salts. Also available as the separate (+)- or (-)- enantiomers. [R3] MFS: *Arenol Corp., 189 Meister Ave., Somerville, NJ 08876 (908) 526-5900; Production site: Somerville, NJ 08876 [R8] *Zeeland Chemicals, Inc., 215 North Centennial St., Zeeland, MI 49464 (616) 772-2193; Production site: Zeeland, MI 49464 [R8] OMIN: *Amphetamine is the prototype of a class of noncatecholamine compounds that produce strong CNS stimulation. [R6, 340] *The illicit manufacture, trafficking, and abuse of amphetamine increased during 1988 after remaining relatively stable during the previous 4 years. /The highest number of seizures/ occured in the Dallas Field Division. The second highest number of seizures occurred in the Houston Field Division. [R9] *Manufacture is restricted in most countries. [R3] *This is a controlled substance (stimulant) listed in the U.S. code of Federal Regulations, Title 21 Part 1308.12 (1995). [R2, 98] USE: *Amphetamines have been used in sports ... as "energy" chemicals. Athletes trying to achieve the "competitive edge" may use amphetamines to increase their sports performances, especially in track and field, football, and swimming. The use of amphetamines ... has been banned by the International Olympic Committee (IOC), the National Collegiate Athletic Association (NCAA) and most professioinal sport organizations. /Amphetamines/ [R10, p. 84-1] *Medicine [R7] *In the past, amphetamine ... was sometimes used to treat depression ... [R11] *... Have classically been employed as appetite supressants. Amphetamine /has/ no legitimate role in antiobesity therapy, because of the pronounced potential for misuse. [R12] *MEDICATION: VET [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Mobile liquid [R2, 98]; *Colorless, volatile liquid [R7] ODOR: *Amine odor [R2, 98]; *Characteristic strong odor [R7] TAST: *Acrid, burning taste [R2, 98]; *Slightly burning taste [R7] BP: *200-203 deg C @ 760 mm Hg [R2, 98] MW: *135.21 [R2, 98] DEN: *0.913 @ 25 deg C/4 deg C [R2, 98] DSC: *pKa = 10.13 [R13] OWPC: *log Kow= 1.76 [R14] PH: *Aq soln are alkaline to litmus [R2, 98] SOL: *Sparingly sol in water (1:50) [R15, 1905]; *SOL IN DIETHYL ETHER, ETHANOL [R16]; *Slightly sol in water; sol in alc, ether; readily sol in acids. [R2, 98]; *Slightly soluble in water and ethyl ether; soluble in ethanol and chloroform. [R17] SPEC: *Index of refraction: 1.518 @ 26 deg C/D [R17]; *MASS: 2-760 (Archives of Mass Spectral Data, John Wiley and Sons, New York) [R18, p. V1 65]; *IR: 2:673F (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R18, p. V2 48]; *NMR: 5:104A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R18, p. V2 48]; *MASS: 305 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R18, p. V2 48]; *Intense mass spectral peaks: 44 m/z, 65 m/z, 91 m/z, 120 m/z, 135 m/z [R19] OCPP: *Volatilizes slowly at room temp [R2, 98] *Crystals; bitter taste; sinters at about 150 deg C; decomp around 300 deg C; pH of 10% soln is about 4.6; More sol in water than amphetamine sulfate; slightly sol in alc; practically insol in benzene, chloroform, ether /Amphetamine phosphate/ [R2, 98] *Crystals; slightly bitter taste followed by sensation of numbness; mp above 300 deg C (decomp); soln of 1 g/10 ml water has pH 5-6; 1 part dissolves in 8.8 parts water, 515 parts 95% alc /Amphetamine sulfate/ [R2, 98] *INSOL IN DIETHYL ETHER /AMPHETAMINE SULFATE/ [R16] *UV: 1295 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) /Amphetamine sulfate (d)/ [R18, p. V1 65] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flammable, moderate fire risk. [R7] *Combustible when exposed to heat, flame, or oxidizers. [R20] FLPT: *80 deg F (26.6 deg C) [R7] FIRP: *To fight fire, use carbon dioxide, dry chemical, alcohol foam, water mist, fog. [R20] DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R20] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... Anticipate seizures and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... Cover skin burns with dry sterile dressings after decontamination ... /Poisons A and B/ [R21] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... Treat seizures with diazepam (Valium) ... Use proparacame hydrochloride to assist eye irrigation ... /Poisons A and B/ [R21] HTOX: *The toxic dose of amphetamine varies widely. ... Severe reactions have occurred with 30 mg, yet doses of 400 to 500 mg are not uniformly fatal. Larger doses can be tolerated after chronic use of the drug. [R22, 220] *The acute toxic effects of amphetamine are usually extensions of its therapeutic actions and, as a rule, result from overdosage. The central effects commonly include restlessness, dizziness, tremor, hyperactive reflexes, talkativeness, tenseness, irritability, weakness, insomnia, fever, and sometimes euphoria. Confusion, assaultiveness, changes in libido, anxiety, delirium, paranoid hallucinations, panic states, and suicidal or homicidal tendencies occur, esp in mentally ill pt. However, these psychotic effects can be elicited in any individual if sufficient quantities of amphetamine are ingested for a prolonged period. Fatigue and depression usually follow central stimulation. Cardiovascular effects are common and include headache, chilliness, pallor or flushing, palpitation, cardiac arrhythmias, anginal pain, hypertension or hypotension, and circulatory collapse. Excessive sweating occurs. Symptoms referable to the GI system include dry mouth, metallic taste, anorexia, nausea, vomiting, diarrhea, and abdominal cramps. Fatal poisoning usually terminates in convulsions and coma, and cerebral hemorrhages are the main pathological findings. [R6, 220] *AMPHETAMINE GIVEN ORALLY RAISES BOTH SYSTOLIC AND DIASTOLIC BLOOD PRESSURES. HEART RATE IS OFTEN REFLEXLY SLOWED; WITH LARGE DOSES, CARDIAC ARRHYTHMIAS MAY OCCUR. CARDIAC OUTPUT IS NOT ENHANCED BY THERAPEUTIC DOSES, AND CEREBRAL BLOOD FLOW DOES NOT CHANGE MUCH. THE L-ISOMER IS SLIGHTLY MORE POTENT THAN THE D-ISOMER IN ITS CARDIOVASCULAR ACTIONS. IN GENERAL, SMOOTH MUSCLES RESPOND TO AMPHETAMINE AS THEY DO TO OTHER SYMPATHOMIMETIC AMINES. ... PAIN AND DIFFICULTY IN MICTURITION OCCASIONALLY OCCUR. THE GI EFFECTS OF AMPHETAMINE ARE UNPREDICTABLE. IF ENTERIC ACTIVITY IS PRONOUNCED, AMPHETAMINE MAY CAUSE RELAXATION AND DELAY THE MOVEMENT OF INTESTINAL CONTENTS; IF THE GUT IS ALREADY RELAXED, THE OPPOSITE EFFECT MAY OCCUR. THE RESPONSE OF THE HUMAN UTERUS VARIES, BUT USUALLY THERE IS AN INCREASE IN TONE. [R22, 219] *Because tolerance develops to the hyperthermic and cardiovascular effects of amphetamine, acute intoxication is more likely to occur in the neophyte. The syndrome includes dizziness, tremor, irritability, confusion, hallucinations, chest pain, palpitation, hypertension, sweating, and cardiac arrhythmias. There may be hyperpyrexia and convulsions. Death is usually preceded by hyperpyrexia, convulsions, and shock. [R23, 554] *Perivascular infiltration of amphetamines can produce local necrosis, cellulitis, granulomas, and abscess formation. Intra-arterial injection causes intense vasospasm with distal cyanosis, ecchymosis, petechiae, edema, paresthesias, pain, weakness, necrosis, and decreased capillary filling. Immediate intense vasospasm is obvious after intra-arterial injections. [R4, 635] *Chronic intoxication with amphetamine causes symptoms similar to those of acute overdosage, but abnormal mental conditions are more common. Weight loss may be marked. A psychotic reaction with vivid hallucinations and paranoid delusions, often mistaken for schizophrenia, is the most common serious effect. Recovery usually is rapid after withdrawal of the drug, but occasionally the condition becomes chronic. In these persons, amphetamine may act as a precipitating factor hastening the onset of an incipient schizophrenia. [R22, 220] *Chronic use of high doses of amphetamines has been reported to produce microvascular damage, neuronal chromatolysis (primarily in brain areas rich in adrenergic neurons), and profound and long lasting (or permanent) depletion of dopamine in the caudate nucleus. [R23, 554] *The psychic effects depend on the dose and the mental state and personality of the individual. The main results of an oral dose of 10-30 mg include wakefulness, alertness, and a decreased sense of fatigue; elevation of mood with increased initiative, self-confidence, and ability to concentrate; often, elation and euphoria; and increase in motor and speech activities. Performance of simple mental tasks is improved, but, although more work may be accomplished, the number of errors may increase. Physical performance - in athletes, for example - is improved, and the drug is often abused for this purpose. These effects are not invariable, and may be reversed by overdosage or repeated usage. Prolonged use or large doses are nearly always followed by depression and fatigue. Many individuals given amphetamine experience headache, palpitation, dizziness, vasomotor disturbances, agitation, confusion, dysphoria, apprehension, delirium, or fatigue. [R22, 219] *The fully developed toxic syndrome from amphetamine is characterized by vivid visual, auditory, and sometimes tactile hallucinations; picking and excoriation of the skin and delusions of parasitosis are not uncommon. There is also paranoid ideation, loosening of assoc, and changes in affect occurring in assoc with clear sensorium. In chronic users, there may be a striking paucity of sympathomimetic effects, and the blood pressure is not unduly elevated. It is often extremely difficult to differentiate this syndrome from a schizophrenic reaction. The syndrome may be seen as early as 36 to 48 hr after the ingestion of a single large dose of amphetamine; in apparently sensitive individuals, psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone. Unless the individual continues to use the drug, the psychosis usually clears within a week, the hallucinations being the first symptoms to disappear. [R23, 553] *Amphetamine ... in large doses systemically can dilate the pupils and cause slight blurring of near vision. Applied to the eye, amphetamine dilates the pupil and retracts the upper lid, but these actions are prevented by previous depletion of catecholamines such as is brought about by local guanethidine. [R24] *Renal failure assoc with amphetamine use is usually the result of rhabdomyolysis, but it has also been found in patients without evidence of muscle damage or other apparent predisposing factors. [R25, 90] *Data on the effect of prenatal amphetamines, both prescribed and abused, are conflicting; however no consistent pattern of abnormalities has emerged. A large prospective evaluation of amphetamines prescribed during pregnancy found no incr in severe congenital malformations, but did report three cases of oral clefts. Another prospective study evaluating infants of amphetamine addicted women failed to demonstrate an incr in birth defects, but did note an incr in premature births, respiratory distress and jitteriness. The use of other drugs and alcohol may have confounded these findings. /Amphetamines/ [R25, 203] *In an acute poisoning in a child ... external stimuli precipitated increased hyperactivity. [R26] *Abrupt discontinuation of amphetamines produces neither seizures nor life threatening symptoms, even in those patients who habitually consume large quantities. The abstinence syndrome assoc with chronic use of amphetamine ... is characterized by apathy, depression, lethargy, anxiety, and sleep disturbances. Myalgias, abdominal pain, voracious appetite, and a profound depression with suicidal tendencies may complicate the immediate postwithdrawal period and peak in 2-3 days. Symptoms persisting 6-7 days indicate an underlying disease process. [R4, 636] *During the early phases of iv use, 3 to 4 doses of 20 to 40 mg of amphetamine are usually considered sufficient /by abusers to produce euphoric effects/. In addition to the marked euphoria, the user experiences a sense of markedly enhanced physical strength and mental capacity, and feels little need for either sleep or food. Difficult to substantiate by objective means is the claim made by many users that orgasm in both male and female is delayed, permitting extended periods of sexual activity finally culminating in orgasms reported to be more intense and pleasurable. The sensation of "flash" or "rush" that immediately follows iv admin, while qualitatively distinct from the opioid "rush", is nevertheless described as being intensely pleasurable and somewhat akin to sexual orgasm. [R23, 551] *Many of those who use amphetamine ... are best described as "recreational" or occasional users, but some become dependent. A small percentage of the latter (eg, those taking the drugs for control of obesity) seem able to restrict drug intake and function productively (stabilized addicts). Others show progressive social and occupational deterioration, punctuated by periods of hospitalization for toxic psychosis. In terms of the compulsion to continue use, the degree to which a drug pervades the life of the user, and the tendency to relapse following withdrawal, some compulsive users of amphetamine ... are addicts. The risk of developing patterns of compulsive use is not limited to those who use drugs intravenously ... It is not clear whether the dependence syndromes caused by amphetamine ... are as persistent as that produced by opioids. In the US the waves of amphetamine use did not leave large numbers of chronic users in their wake. However, many iv users eventually became heroin users. [R23, 552] *ANOREXIA IS A COMMON FINDING /IN CHRONIC TOXICITY FROM ABUSE/. OCCASIONALLY IT MAY BE SO PRONOUNCED THAT THE AMPHETAMINE ABUSER EXPERIENCES CONSIDERABLE DIFFICULTY IN SWALLOWING. CHRONIC ABUSERS ARE REPORTED TO FORCE THEMSELVES TO EAT SMALL AMT OF HIGHLY NUTRITIOUS FOOD AND TAKE VITAMIN SUPPLEMENTS TO COMPENSATE FOR DECR IN APPETITE. ... CONSTANT GRINDING OF TEETH IS ALSO A COMMON FINDING ... [R27, 630] *THE HISTORY, CHEMISTRY, PHARMACOLOGY, MEDICAL USE, ILLICIT USE AND ADDICTION AND TOLERANCE POTENTIAL OF AMPHETAMINES ARE PRESENTED. ALTHOUGH THERE ARE FEW PUBLISHED ACCOUNTS OF DEATH KNOWN TO RESULT DIRECTLY FROM AMPHETAMINES, DEATHS MAY RESULT INDIRECTLY FROM EFFECTS SUCH AS VIOLENT BEHAVIOR AND HEPATITIS. [R28] *Few deaths have ... been attributed to amphetamine overdose. Amphetamines have a relatively low ratio of effective dose to fatal dose. Fatalities resulting from amphetamine use are usually the result of one of the following processes: 1) combinations with other drugs; 2) complications of iv injections, such as septicemia, bacterial endocarditis, or homicide, during withdrawal depression. [R27, 629] *Although comparable clinical data are lacking, hyperpyrexia has been noted as a frequent and prominent sign in acute human intoxication. During a grueling bicycle race a cyclist collapsed with symptoms closely resembling heat exhaustion, and , despite vigorous treatment, he died /after/ cardiovascular collapse; it was learned subsequently that he had consumed 105 mg of amphetamine during the race. [R26] *Bleeding within the cranial vault is a rare but well-reported complication of amphetamine use. About 20 cases, which are about evenly divided between iv and oral exposures, have been reported in the American literature. Ages range from 16-60, and most patients are habitual and often multidrug abusers. However, intracranial hemorrhages have been reported after the ingestion of as few as 2-4 tablets of amphetamine or structurally related anorectic drugs ... [R4, 634] *The etiology of intracerebral and subarachnoid hemorrhages associated with amphetamine use appears multifactorial. Inflammation and necrosis of small cerebral arteries (ie, vasculitis) secondary to particulate foreign bodies or bacterial endocarditis can develop after iv drug use. Subsequently, the hypertension seen in amphetamine use may lead to vessel rupture and hemorrhage. However, vasculitis has occurred in the setting of oral acute dextroamphetamine overdose, amphetamine withdrawal, and therapeutic use as an anorectic drug. The presence of vasculitis after exposure by different routes suggests an immunopathological abnormality. Direct toxic damage to vessels seems unlikely because of the dilution that occurs before the drug reaches the cerebral circulation. [R4, 633] *Repetitive behavior may occur /from the use of amphetamines/ (e.g. repeatedly cleans dishes or continually grooms hair). Amphetamines also will extenuate hostile, aggressive, and antisocial behavior. Progression to paranoia, panic states, violence, and even suicide may occur. /Amphetamines/ [R10, p. 84-3] *Amphetamines used in large doses over a long period of time may lead to substantial weight loss, liver disease, hypertensive disorders, kidney damage, stroke, heart attack, nonhealing ulcers, and sores in the skin. /Amphetamines/ [R10, p. 84-3] *The abuse of amphetamines by combining the oral and inhalation routes of administration usually leads to a more intense effect and/or more toxic effect than if either was taken alone. /Amphetamines/ [R10, p. 84-4] *Doses as little as 2 mg, but more likely between 15 and 30 mg, may induce toxic effects. However, even doses of 400-500 mg are not uniformly fatal. [R10, p. 84-5] *Illicit maternal use /of amphetamines is/ associated with intrauterine growth retardation, premature birth, and increased fetal and newborn morbidity. /Amphetamines, from table/ [R10, p. 45-7] *Intrauterine ... amphetamine exposure may cause neonates to exhibit abnormal sleep patterns, tremors, poor feeding, hypotonia, fever, and vomiting. [R10, p. 81-9] NTOX: *EPHEDRINE AND OTHER SYMPATHOMIMETIC DRUGS SUCH AS AMPHETAMINE AND METHYLAMPHETAMINE, IF GIVEN IN EXCESSIVE AMT, PRODUCE SIGNS OF SYMPATHETIC STIMULATION, MANIFESTED BY ANXIETY AND RESTLESSNESS. IF THE DOSAGE INVOLVED IS LARGER, MUSCULAR TREMORS AND EVEN CONVULSION MAY OCCUR. [R29] *EXCESSIVE USE MAY CAUSE DANGEROUS EXCITEMENT, RESTLESSNESS, AND AGGRESSIVENESS. ... CAUSES SECOND DEGREE ATRIOVENTRICULAR BLOCK AND ECTOPIC BEATS IN HORSES DURING POST-EXERCISE PERIOD ... [R30] *THE ACUTE TOXICITY OF AMPHETAMINE IS STRONGLY INFLUENCED BY CERTAIN ENVIRONMENTAL FACTORS. FOR EXAMPLE, CROWDING OR AGGREGATION MARKEDLY INCREASES THE TOXICITY IN MICE. ... ELEVATED ENVIRONMENTAL TEMPERATURES ARE ASSOCIATED WITH INCR ACUTE TOXICITY IN ANIMALS. HYPERPYREXIA, PERHAPS SECONDARY TO A HYPERMETABOLIC STATE PRODUCED BY RELEASE OF ENDOGENOUS CATECHOLAMINES, IS A PROMINENT FEATURE OF AMPHETAMINE POISONING IN MANY SPECIES. ... DEHYDRATION HAS BEEN FOUND TO INCR AMPHETAMINE TOXICITY IN ANIMALS, AS DOES FORCED EXERCISE, VARIOUS STRESSES INCL COLD AND HIGH ALTITUDE. [R26] *Testing for toxicity to the retina has been negative; 10 mg/kg given daily to dogs for three months caused occasional slight ophthalmoscopic appearance of blanching of the fundus, but no histologic change in the retina. [R24] *Experimental regeneration of the lens in amphibian eyes is found to be delayed when the animals are placed in a solution containing amphetamine. [R24] *Amphetamine given intramuscularly has been claimed to cause elevation of pressure in eyes with primary glaucoma and not in normal eyes, but this claim needs further investigation with careful attention to gonioscopy and comparative observations with amphetamine. In monkeys no elevation of ocular pressure has been found when amphetamine is given systemically unless given in doses so large that a rapid rise of blood pressure is induced, which is reflected in a brief small elevation of ocular pressure. [R24] *CHRONIC AMPHETAMINE USE RESULTS IN COMPULSIVE BEHAVIOR PATTERNS OF SEARCHING AND EXAMINING. IN LOWER ANIMALS THIS STEREOTYPED BEHAVIOR CONSISTS PRIMARILY OF SNIFFING, BUT BITING AND LOOKING MOVEMENTS ARE ALSO FREQUENT. IN PRIMATES, HAND EYE EXAMINATION PATTERNS, IN ADDN TO THE ABOVE, ARE CHARACTERISTIC OF AMPHETAMINE INDUCED STEREOTYPED BEHAVIOR. [R27, 630] *In rats, continuous admin of amphetamine for 10 days can cause a significant decr in the activity of tyrosine hydroxylase in the nigrostriatum that lasts for more than 3 mo. After chronic use, animals ... begin to exhibit behaviors not seen after initial doses; these incl exaggerated "startle" reactions, dyskinesias, and postural abnormalities. [R23, 554] *Animals self administering ... amphetamine often show a cyclic pattern of use, with periods of spontaneous abstinence interposed between periods of use. A small priming dose during abstinence will reinitiate self admin. With round the clock access to the /drug/ ... there is weight loss, self mutilation, and death within about 2 weeks. [R23, 552] *Behavioral, electrophysiological, and biochemical techniques were employed before, during, and after 7 days of continuous sc administration of D-amphetamine sulfate (6.0 mg/day) to male Sprague-Dawley rats. Significant changes were observed using all three protocols. Behavioral alterations were greatest on the second day of treatment and progressively normalized during the remainder of treatment. Electrophysiological changes in the striatum were significant only on the second day of treatment, while electrophysiological alterations in the nucleus accumbens were significant on all treatment and recording days, and the magnitude of the changes paralleled the pattern of overt behavioral changes. Levels of dopamine in the striatum progressively decr from normal throughout the treatment, declining to less than half of the control level by the sixth day of treatment. In contrast, dopamine levels in the nucleus accumbens were incr on the second day of treatment and progressively approached the control level as treatment continued, again paralleling behavior and changes in the electrophysiology of the nucleus accumbens. [R31] *Seven adult male Long Evans rats were deprived of food and offered food only in small meal segments. Latency to initiate feeding and time to complete it were recorded for each segment. Bilateral microinjections of d-amphetamine (2.5, 10, or 20 ug) into nucleus accumbens 10 min before feeding dramatically increased the mean speed with which meal segments were eaten, but had no reliable effects on mean latency to initiate eating of new segments; l-amphetamine (10 ug) had similar but weaker effects. For d-amphetamine, mean latency under 20 ug was 0.52 sec and control latency was 0.97 sec. Median feeding duration under 20 ug d-amphetamine was 12.3 sec vs 20.7 sec for controls. While mean eating speed was increased, this incr resulted from a decr in the frequency of slow trials and not from an incr in the absolute speed of the fastest trials. [R32] *Apomorphine and (+)-amphetamine produce circling in naive rats. Frame by frame analysis of videotape recordings of the behavior of male Wistar rats treated with a sc injection of apomorphine (1.1 mg/kg; n= 8) or (+)-amphetamine (0.5 and 1.0 mg/kg; n= 8 and n= 8) was used to study this behavior in more detail. In line with previously reported studies, apomorphine was found to change the functioning of hindlimb stepping. In contrast, (+)-amphetamine was found to change the functioning of forelimb stepping, suggesting that apomorphine and (+)-amphetamine produce their drug specific circling via different substrates within the brain. [R33] *Linear sweep voltammetry with carbon paste electrodes was used to monitor extracellular ascorbic acid in the caudate nucleus and nucleus accumbens of behaving male Sprague Dawley rats. Amphetamine (2 or 5 mg/kg) was administered 4, 6 and 8 days after surgery. In general the amphetamine-induced incr in ascorbic acid was greater in the caudate /nucleus/ than in the nucleus accumbens. In the nucleus accumbens the amphetamine-induced incr in ascorbic acid was very similar on all test days, but in the caudate /nucleus/ the incr in ascorbic acid produced by 5 mg/kg amphetamine was progressively larger on each test day. [R34] *The behavioral effects of d-amphetamine administration were studied in 17 adult cats. The doses of amphetamine administered were 0.1, 0.5, 1.0 and 5.0 mg/kg sc. Amphetamine administration induced a dose-dependent hypomotility, which was marked with the higher doses. In addition, rhythmic, bilateral slow movements of the head as a mode of stereotype, indifference to the environment and dose-dependent incr in respiratory rate were observed in amphetamine-treated cats. [R35] *Male Sprague Dawley rats were prepared for single unit electrophysiology and allowed a recovery period of 1 wk. On the recording day, a microelectrode was lowered into the anterior neostriatum. Each rat was placed in an open field arena. Following a period of quiet rest (5 to 10 min), each rat received a sc injection of 1.0 mg/kg d-amphetamine sulfate (free base). Neuronal activity and behavior were monitored for another 30 min. A majority (62%) of the 24 recorded neurons were activated during motor behavior such as locomotion (n= 11) or head movements (n= 4). The behavioral response to amphetamine, including sniffing, locomotion, rearing and head bobbing, was associated with incr (n= 17) or decr (n= 7) in firing rate. Both behavioral and neuronal responses developed gradually 5 to 15 min after drug injection. Amphetamine-induced neuronal excitations peaked at 1523 + or - 593% of the baseline rate, whereas inhibitions reached 11.5 + or - 6.4% of baseline. Amphetamine excited almost all (14 or 15) motor responsive neurons, but only 3 of 9 nonmotor related units. [R36] *Drug Discrimination: Rats learned to discriminate between injection of d,l-amphetamine and saline, and in addition, generalization was obtained with methylphenidate but not with atropine. [R37] *Drug Discrimination: Animals trained to respond to sedative/hypnotics responded to amphetamine as if it were saline (ie, no cross generalization between drug classes was observed). [R38] *Amphetamine ... damages cerebral arteries in experimental animal models. [R39] HTXV: *Therapeutic or normal amphetamine blood concentration: 2-3 ug/dL; Toxic amphetamine blood concentration: 50 ug/dL; Lethal amphetamine blood concentration: 200 ug/dL /From table/ [R40, 420] NTXV: *LD50 Rat oral 30 mg/kg; [R20] *LD50 Rat sc 180 mg/kg; [R20] *LD50 Mouse oral 21 mg/kg; [R20] *LD50 Mouse ip 5500 ug/kg; [R20] *LD50 Mouse sc 15 mg/kg; [R20] *LD50 Mouse iv 15 mg/kg; [R20] NTP: *Toxicology and carcinogenesis studies were conducted by administering dl-amphetamine sulfate (USP grade) in feed to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... Diets containing 0, 20, or 10 ppm dl-amphetamine sulfate was administered to groups of 50 rats or 50 mice of each sex. ... Under the conditions of these 2 yr studies, there was no evidence of carcinogenic activity of dl-amphetamine sulfate for male or female F344/N rats or male or female B6C3F1 mice. /dl-Amphetamine sulfate/ [R41] ADE: *Single pharmacological doses of amphetamines (ie, 10-25 mg) given to human volunteers produce peak plasma levels within 1-2 hr and are rapidly absorbed from the gi tract. Amphetamine absorption usually is complete by 4-6 hr. The illicit use of amphetamines ... by insertion into the vagina (termed "balling") before intercourse suggests that these compounds are also absorbed through mucosal surfaces. ... Pharmacokinetics in overdose are not well described. [R4, 631] *The efficiency of absorption of amphetamine and phentermine is unchanged from resin bound dosage forms compared with soluble salt formulations. However, the absorption rates of these compounds are slower from the resinates, giving rise to flatter and more prolonged blood levels. ... Renal clearance of amphetamine in dogs is less than creatinine clearance, owing to kidney reabsorption which is pH dependent. Plasma protein binding is similar in all 3 species, 40% in goats and pigs and 23% in dogs, and appears to be independent of drug concn. The drug distributes extensively into tissues and plasma-drug profiles are described by means of two compartment model kinetics. [R42] *Amphetamine concentrates in the kidney, lungs, and brain. The extent of protein binding and the vol of distribution are not well understood for many amphetamine compounds and analogues. Reported variations in protein binding range from 15% (methylphenidate) and 16% (amphetamine) to 34% (fenfluramine). The vol of distribution of amphetamine and phentermine in therapeutic doses ranges from 3-5 l/kg. ... Plasma protein binding, rate of absorption, and volumes of distribution of amphetamine isomers are similar. [R4, 631] *There was considerable species difference in biotransformation, but not in the excretion of (14)C, after admin of (14)C-amphetamine. ... Much of the (14)C was excreted in the 24 hr urine after ip admin of amphetamine to dogs and guinea pigs, and oral admin to other species. Three days after a dose of (+ or -)-amphetamine, human subjects had excreted 91% of the (14)C in the urine, rats 86%, rabbits 86%, and dogs 78%. The last 3 species excreted 5%, 7%, and 0% of the dose respectively in 3-day feces. Since excretion of (14)C over broad time intervals its optical isomers was given, the above data can be compared with results obtained when an optical isomer was given to monkeys, mice, and guinea pigs. Thus, after a dose of (+)-amphetamine, (also known as dexamphetamine ...), guinea pigs excreted 88% of the (14)C in the 2-day urine, mice excreted 87% in the 3-day urine, and a monkey excreted 80% in the 3-day urine. Another monkey excreted less than 58%. Of interest was that man, monkey, dog, and mouse excreted about 30% of the (14)C as unchanged amphetamine in 24 hr, whereas guinea pig excreted 22%, rat excreted 13%, and rabbit only excreted 4%. These results confirmed an earlier study of the excretion of (14)C and of unchanged amphetamine in rats given (+ or -)-amphetamine at 4 different dose levels orally and at 1 level sc. ... These earlier studies showed that rates of excretion of (14)C were similar after oral or ip dosing, thus indicating comparable and rapid absorption of amphetamine in these animals by two routes. [R43] *ALTHOUGH SEVERAL PATHWAYS, INCLUDING P-HYDROXYLATION, N-DEMETHYLATION, DEAMINATION, AND CONJUGATION IN THE LIVER, TAKE PART IN THEIR DISPOSAL, A SUBSTANTIAL FRACTION OF THESE DRUGS /NONCATECHOLAMINES/ IS EXCRETED IN THE URINE UNCHANGED. URINARY EXCRETION OF AMPHETAMINE AND MANY OTHER NONCATECHOLAMINES IS GREATLY INFLUENCED BY URINARY PH. FOR EXAMPLE, PKA OF AMPHETAMINE IS 9.9, AND AT PH 8.0 ONLY 2-3% IS EXCRETED. IF THE URINE IS ACIDIC, URINARY EXCRETION MAY BE AS MUCH AS 80%. [R23, 166] *The excretion of a drug into saliva depends on the ability of the drug to pass through the epithelial cells of the salivary glands into the saliva. The concentration of a drug in saliva could be higher, such as amphetamine, or lower, such as methaqualone, than that in plasma. /Drugs/ [R44] *... /Amphetamine/ usually is eliminated in the urine within two days after the last oral dose. ... Renal excretion is enhanced by an acidic urine and approximately 99% of a dose is ionized by glomerular filtration and only the remaining nonionized portion of the drug is reabsorbed into the circulatory system. [R10, p. 84-4] METB: *THE MAJOR ROUTES OF METABOLISM /OF AMPHETAMINE/ ARE HYDROXYLATION OF AROMATIC RING TO P-HYDROXYAMPHETAMINE AND DEAMINATION TO BENZYL METHYL KETONE, FOLLOWED BY OXIDATION TO BENZOIC ACID. A CONSIDERABLE SPECIES DIFFERENCE IN METABOLISM OCCURS. IN MAN A LARGE AMOUNT OF THE DRUG IS EXCRETED UNCHANGED (30%) AND THE MAJOR METABOLITES ARE BENZOIC ACID (20%), BENZYL METHYL KETONE (3%) AND P-HYDROXY-AMPHETAMINE (3%). IN THE RAT THE MAJOR METABOLITE IS P-HYDROXY-AMPHETAMINE (60%), IN THE RABBIT IT IS BENZYL METHYL KETONE (22%) AND BENZOIC ACID (27%), AND IN THE DOG IT IS BENZOIC ACID (32%) AND UNCHANGED AMPHETAMINE (38%). [R45] *CARBONYL REDUCTION ... /CAN INVOLVE/ COMPOUNDS WHICH ARE THEMSELVES DRUG METABOLITES. OF PARTICULAR SIGNIFICANCE ARE THE CARBONYL DERIVATIVES RESULTING FROM DEAMINATION. ... WHEN THE PRODUCT OF DEAMINATION IS A KETONE, IT /IS/ OFTEN RECOVERED IN SIGNIFICANT AMOUNTS TOGETHER WITH ITS REDUCED METABOLITE. A CLASSIC EXAMPLE IS THAT OF AMPHETAMINE; THE TWO METABOLITES, PHENYLACETONE AND PHENYLISOPROPANOL ARE EXCRETED IN A RATIO WHICH SHOWS A MARKED SPECIES DEPENDENCY. [R46] *THE INTERACTION BETWEEN AMPHETAMINE ANALOGS AND CYTOCHROME P450 WAS STUDIED. IT WAS FOUND THAT SOME PARTS OF SUBSTRATE MOLECULES CONTRIBUTE TO THE BINDING OF THE ENZYME. ON THE OTHER HAND, THE STEREOCHEMICAL CONFIGURATION OF THE DRUG MOLECULE COMPLEXED AT THE ACTIVE SITE APPEARS TO BE THE DETERMINING FACTOR IN DECIDING WHICH MECHANISM OF OXIDATION WILL BE UTILIZED, FOR INSTANCE, ALPHA-C-OXIDATION OR N-OXIDATION. [R47] *Smaller amounts of amphetamine are converted to norephedrine by oxidation. beta-Hydroxylation produces the active metabolite O-hydroxynorephedrine, which acts as a false neurotransmitter and may account for some drug effect especially in chronic users. ... The (+)-amphetamine isomer is more rapidly metabolized than the (-)-isomer ... [R4, 631] *Metabolic pathways for amphetamines include aromatic hydroxylation, beta-hydroxylation, and deamination. /Amphetamines/ [R10, p. 84-4] BHL: *The biological half-life of amphetamine is greater in drug dependent individuals than in control subjects, and distribution volumes are increased, indicating that greater affinity of tissues for the drug may contribute to development of amphetamine tolerance. [R42] *Concentrations of (14)C-amphetamine declined less rapidly in the plasma of human subjects maintained on an alkaline diet (urinary pH > 7.5) than those on an acid diet (urinary pH < 6). Plasma half-lives of amphetamine ranged between 16-31 hr and 8-11 hr, respectively, and the excretion of (14)C in 24 hr urine was 45 and 70%. [R48] *Considerable species differences in amphetamine clearance are indicated by a biological half-life of 30 minutes in goats compared with over 1 hr in pigs and almost 5 hr in dogs. [R42] *... The (+)-amphetamine isomer is more rapidly metabolized than the (-)-isomer, and under alkaline conditions, the (+)-isomer elimination half-life is significantly shorter (17.0 hr vs 12.7 hr). Under acidic urine conditions, renal excretion is the major route of elimination and thus the difference in isomer half-life is minimized. [R4, 631] *Biological half-life is between 10-12 hr ... /Amphetamines/ [R10, p. 84-4] ACTN: *The reinforcing and euphorigenic effects of amphetamine, methylphenidate, and cocaine appear to involve the actions of catecholamines in the CNS, esp those of dopamine. They can be blocked, at least partially, by pimozide and other dopaminergic antagonists but are relatively unaffected by phenoxybenzamine. Furthermore, both amphetamine and apomorphine facilitate electrical self-stimulation of "reward" areas of the brain. Amphetamine and cocaine share with morphine the capacity to lower the amt of electrical current required to produce "rewarding" effects in these brain areas. The mechanisms of reinforcement are still uncertain. Amphetamine, methylphenidate, and cocaine all block the re-uptake of catecholamines, but so do the tricyclic antidepressants, which do not produce euphoria or stereotype and are not abused. Amphetamine and phenmetrazine appear to release newly synthesized neurotransmitters selectively, and their effects can be blocked by inhibition of tyrosine hydroxylase, a procedure that does not block the central effects of methylphenidate or cocaine. Prior treatment with reserpine blocks the effects of the last-named drugs but not those of amphetamine. Microinjections of amphetamine into the nucleus accumbens, an area where ascending dopaminergic fibers terminate, are reinforcing. In contrast, microinjections of cocaine are reinforcing at medial prefrontal cortex, but not at nucleus accumbens. However, both drugs appear to depend on activation of dopaminergic neurons, since destruction of nucleus accumbens or microinjections of dopamine antagonists into cortex or nucleus accumbens reduce or eliminate their reinforcing effects. [R23, 553] *Amphetamine appears to exert most or all of its effects in the CNS by releasing biogenic amines from their storage sites in the nerve terminals. The alerting effect of amphetamine, its anorectic effect, and at least a component of its locomotor stimulating action are presumably mediated by release of norepinephrine from central noradrenergic neurons. These effects can be prevented in experimental animals by treatment with alpha-methyltyrosine, an inhibitor of tyrosine hydroxylase and, therefore, of catecholamine synthesis. Some aspects of locomotor activity and the stereotyped behavior induced by amphetamine are probably a consequence of the release of dopamine from dopaminergic nerve terminals, particularly in the neostriatum. Higher doses are required to produce these behavioral effects, and this correlates with the higher concn of amphetamine required to release dopamine from brain slices or synaptosomes in vitro. With still higher doses of amphetamine, disturbances of perception and overt psychotic behavior occur. These effects may be due to release of 5-hydroxytryptamine from tryptaminergic neurons and of dopamine in the mesolimbic system. In addition, amphetamine may exert direct effects on central receptors for 5-hydroxytryptamine. [R22, 220] *WT LOSS IN OBESE HUMANS TREATED WITH AMPHETAMINE IS ALMOST ENTIRELY DUE TO REDUCED FOOD INTAKE AND ONLY IN SMALL MEASURE TO INCREASED METABOLISM. THE SITE OF ACTION IS PROBABLY IN THE LATERAL HYPOTHALAMIC FEEDING CENTER; INJECTION OF AMPHETAMINE INTO THIS AREA, BUT NOT INTO THE VENTROMEDIAL SATIETY CENTER, SUPPRESSES FOOD INTAKE. IN HUMAN BEINGS, TOLERANCE TO THE APPETITE SUPPRESSION DEVELOPS RAPIDLY. HENCE, CONTINUOUS WEIGHT REDUCTION USUALLY IS NOT OBSERVED IN OBESE INDIVIDUALS WITHOUT DIETARY RESTRICTION. [R22, 220] *Although large doses of amphetamine increase oxygen consumption in animals, conventional therapeutic doses cause either no change, a small fall, or a modest rise (10-15%) in the metabolic rate in man. Some patients show a slight increase in body temp. The apparent calorigenic action may be due to restlessness caused by the drug. [R23, 167] *THEY DECREASE APPETITE BY STIMULATING THE HYPOTHALAMUS TO RELEASE CATECHOLAMINES IN THE CNS. ... ANOREXIANT DRUGS (EXCEPT FENFLURAMINE) INCREASE PHYSICAL ACTIVITY, AND ALL OF THESE AGENTS HAVE METABOLIC EFFECTS INVOLVING FAT (INHIBITING LIPOGENESIS, ENHANCING LIPOLYSIS) AND CARBOHYDRATE METABOLISM, BUT THESE PROBABLY ARE SECONDARY TO SUPPRESSION OF APPETITE. /ANOREXIANTS/ [R5, 929] INTC: *The effects of D-Trp11-neurotensin (0-8 ug/rat, iv, ventricle) and alpha-flupenthixol (0-1 mg/kg ip) on hyperactivity induced by d-amphetamine (1.5 mg/kg, ip) was studied in male Wistar rats. The usual total counts index of activity suggested that alpha-flupenthixol and D-Trp11-neurotensin blocked the incr activity. In contrast, conditional count data suggested that only alpha-flupenthixol was effective. Both measures indicated that amphetamine, administered separately, enhanced activity. [R49] *Concurrent use /with gastrointestinal acidifiers, such as: ascorbic acid, fruit juices, glutamic acid hydrochloride or urinary acidifiers such as: ammonium chloride, sodium acid phosphate/ may decrease the effects of amphetamines as a result of decreased absorption and increased elimination. /Amphetamines/ [R50, p. 94-5] *Concurrent use /with urinary alkalizers such as calcium- and/or magnesium-containing antacids, carbonic anhydrase inhibitors, citrates, sodium bicarbonate/ may increase the effects of amphetamines as a result of decreased elimination caused by alkalinization of urine. /Amphetamines/ [R50, 95] *Halothane and to a much lesser extent enflurane, isoflurane, and methoxyflurane, may sensitize the myocardium to the effects of sympathomimetics, including chronic use of amphetamines prior to anesthesia, so that the risk of severe ventricular arrhythmias is increased; sympathomimetics should be used with caution and in substantially reduced dosage in patients receiving these agents. /Amphetamines/ [R50, 95] *Although tricyclic antidepressants may be used concurrently with amphetamines for therapeutic effect, concurrent use may potentiate cardiovascular effects due to the release of norepinephrine, possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia; close monitoring is recommended and dosage adjustments may be necessary. /Amphetamines/ [R50, 95] *Hypotensive effects may be reduced when these medications /antihypertensives or diuretics used as antihypertensives/ are used concurrently with amphetamines; the patient should be carefully monitored to confirm that the desired effect is obtained. /Amphetamines/ [R50, 95] *Concurrent use /of beta-adrenergic blocking agents, including ophthalmics/ with amphetamines may result in unopposed alpha-adrenergic activity with a risk of hypertension and excessive bradycardia and possible heart block; risk may be less with labetalol because of its alpha-blocking activity. /Amphetamines/ [R50, 95] *Additive CNS stimulation to excessive levels may result in nervousness, irritability, insomnia, or possibly seizures /if other CNS stimulation-producing medications are used with amphetamines/; close observation is recommended. Also, concurrent use of amphetamines with other sympathomimetics may increase cardiovascular effects of either medication. In addition to possibly increasing CNS stimulation, concurrent use of norepinephrine with large doses of amphetamines may enhance the pressor response to norepinephrine; caution may also be warranted in patients receiving usual doses of amphetamines. /Amphetamines/ [R50, 95] *Concurrent use /of digitalis glycoside/ with amphetamines may cause additive effects, resulting in cardiac arrhythmias. /Amphetamines/ [R50, 95] *Concurrent use /of ethosuximide or phenobarbital or phenytoin/ with amphetamines may cause a delay in the intestinal absorption of ethosuximide, phenobarbital, or phenytoin. /Amphetamines/ [R50, 95] *Central stimulant effects of amphetamines may be inhibited because of alpha-adrenergic blockade by these agents /haloperidol or loxapine or molindone or phenothiazines or pimozide or thioxanthenes/; also, concurrent use with amphetamines may reduce the antipsychotic effects of these agents. /Amphetamines/ [R50, 95] *The risk of cardiac arrhythmias may be increased /when levodopa is used with amphetamines/; dosage reduction of amphetamines is recommended. /Amphetamines/ [R50, 95] *Central stimulant effects of amphetamines may be antagonized by lithium. /Amphetamines/ [R50, 95] *The analgesic effects of meperidine may be potentiated by amphetamines; however, concurrent use of meperidine is not recommended, as it may potentially result in hypotension, severe respiratory depression, coma, convulsions, hyperpyrexia, vascular collapse, and death in some patients due to the monoamine oxidase inhibition properties of amphetamines. /Amphetamines/ [R50, 95] *Intrathecal administration of metrizamide may increase the risk of seizures because of lowered seizure threshold; it is recommended that amphetamines be discontinued for at least 48 hours before and 24 hours after myelography. /Amphetamines/ [R50, 95] *Concurrent use may /with monoamine oxidase (MAO) inhibitors, including furazolidone, procarbazine, and selegiline/ prolong and intensify cardiac stimulant and vasopressor effects (including headache, cardiac arrhythmias, vomiting, sudden and severe hypertensive and hyperpyretic crises) of amphetamines because of the release of catecholamines that accumulate in intraneuronal storage sites during MAO inhibitor therapy; amphetamines should not be used during or within 14 days following the administration of an MAO inhibitor. /Amphetamines/ [R50, 95] *Overdosage of propoxyphene may potentiate central stimulant effects of amphetamines; fatal convulsions can occur. /Amphetamines/ [R50, 95] *The effects of either these medications /thyroid hormones/ or amphetamines may be increased; thyroid hormones enhance the risk of coronary insufficiency when amphetamines are administered to patients with coronary artery disease. /Amphetamines/ [R50, 95] *Amphetamine users may combine amphetamine use with heavy use of alcohol, cigarette smoking, and marijuana. Alcohol will enhance the irritability from amphetamine usage. [R10, p. 84-4] *In animals ibogaine enhances amphetamine ... induced increases in brain dopamine levels. [R6, 935] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The minimal lethal amphetamine dose varies with age and animal species. Children appear more susceptible than adults. [R6, 343] *The acute lethal dose in adults has been reported at 20-25 mg/kg, and in children, 5 mg/kg. Death from as little as 1.5 mg/kg in an adult has also been noted. [R40, 348] *Toxic amphetamine blood concentration: 50 ug/dL; Lethal amphetamine blood concentration: 200 ug/dL /From table/ [R40, 420] THER: *Adrenergic Agents; Adrenergic Uptake Inhibitors; Appetite Depressants; Central Nervous System Stimulants; Dopamine Agents; Dopamine Uptake Inhibitors; Sympathomimetics [R51] *Methylphenidate and amphetamines are accepted for chronic therapeutic use in properly documented adult narcolepsy in adults and attention deficit disorder in children. Occasionally, both these drugs may be indicated when the attention disorder extends into adulthood. In addn, they may be useful as 2 to 3 day trials to gauge the effectiveness of certain tricyclic antidepressants in mild depression or senile withdrawn behavior in the elderly. [R6, 340] *The use of amphetamines for short term (8-12 weeks) suppression of appetite remains a legal indication, although this use is highly controversial. Long term benefit of amphetamines for appetite suppression is clinically insignificant because of tolerance and is potentially harmful because of the common complication of abuse. [R6, 340] *VET: TO ALLEVIATE ANESTHETIC OVERDOSAGE, PARTICULARLY WITH BARBITURATES. TO INCR ... RESPONSE TO EXTERNAL STIMULI SUCH AS DEPRESSIVE STATES AND MILK FEVER IN COWS. MAY HAVE VALUE IN SELECTED CASES OF ENCEPHALOMYELITIS (HORSES) AND EPILEPTIC (CATTLE) OR HYPERKINETIC SYNDROMES. [R30] *Male and female mongrel adult cats pretested for beam walking ability were given bilateral frontal cortex ablations. Following recovery from surgery, the cats were injected with d-amphetamine (5 mg/kg, ip) or 0.9% saline (1 ml, ip). Beam walking trials were conducted at 1, 2, 3, 6, and 24 hr postinjection. Cats given injections of d-amphetamine showed an enduring acceleration of recovery of beam walking ability relative to saline controls. In general, rates of spontaneous and drug induced recovery in cats with bilateral lesions were similar to those previously reported for cats with unilateral ablations. [R52] *MEDICATION (VET): CNS STIMULANT, IN NARCOTIC POISONING, ANESTHETIC COLLAPSE, IN DEPRESSION FROM ENCEPHALITIS [R2, 98] *... Amphetamine /is/ indicated in the treatment of well-established and proven narcolepsy. /Included in US product labeling/ [R50, 94] *Amphetamines are indicated as an integral part of a total treatment program that includes other remedial measures (psychological, educational, social) for a stabilizing effect in children (and adults /NOT included US product labeling/) with attention-deficit hyperactivity disorder, characterized by moderate to severe distractibility, short attention span, hyperactivity, emotional lability, and impulsivity. Nonlocalizing neurological signs, learning disability, and abnormal electroencephalogram may be present also. Amphetamines usually are not indicated when the above symptoms are associated with acute stress reactions. /Amphetamines; Included in US product labeling/ [R50, 94] *THERAP CAT: CNS stimulant; anorexic [R2, 98] WARN: *These drugs /methylphenidate and amphetamines/ cannot be legally prescribed for the treatment of drug dependence, fatigue, anxiety reactions, or chronic anxiety or to generate a sense of well-being. [R6, 340] *Amphetamines are esp appealing to individuals who interact poorly in social settings and have difficulty internalizing new experiences. These drugs /amphetamines/ reduce the need for external stimuli by increasing internal arousal mechanisms. In contrast to asocial, schizoid personalities who tend to abuse amphetamines (ie, the drug interferes with their social, economic, or medical welfare), misuse of amphetamines (ie, using these drugs for nonmedically indicated purposes) occurs frequently in individuals trying to enhance performance. [R6, 340] *Today, amphetamines rank about 10th to 11th in the groups of abused drugs. [R4, 626] *The abuse of amphetamine as a means of overcoming sleepiness and of incr energy and alertness should be discouraged. The drug should be used only under medical supervision. ... The additional contraindications and precautions for the use of amphetamine generally are similar to those described ... for epinephrine. Its use is inadvisable in patients with anorexia, insomnia, asthenia, psychopathic personality, or a history of homicidal or suicidal tendencies. [R22, 220] *In one case report of a mother taking amphetamine 20 mg/day therapeutically, milk levels were found to be less than plasma levels and no adverse effects on the infant was noted. However, there is likely to be substantial intersubject variation in excretion, and levels during high dose and use and abuse of amphetamines have not been studied. It is likely that some infants would experience agitation and fussiness. [R25, 176] *When possible, therapy should be interrupted occasionally to determine if there is a recurrence of behavioral symptoms sufficient to require continued treatment. [R15, 1906] *... VARIOUS SYMPATHOMIMETIC AND RELATED DRUGS THAT DEPRESS APPETITE HAVE BEEN USED TO MAKE LOW CALORIE DIET MORE TOLERABLE. THESE APPETITE DEPRESSANTS ARE OF NO VALUE WITHOUT ACCOMPANYING STRINGENT DIETARY REGIMEN, AND IT HAS BEEN ... DEMONSTRATED THAT, WITHOUT CONSISTENT SUPERVISION, NO PRESCRIBED REGIMEN OF DRUG OR DIET IS PREDICTABLY SUCCESSFUL. /SYMPATHOMIMETIC DRUGS/ [R23, 178] *Drugs of Abuse: Contraindicated during Breast-Feeding: Amphetamine: Irritability, poor sleeping pattern. Note: the drug is concentrated in human milk. (The Committee on Drugs strongly believes that nursing mothers should not ingest any compounds listed /drugs of abuse/ ... Not only are they hazardous to the nursing infant, but they are also detrimental to the physical and mental health of the mother ... No drug of abuse should be ingested by nursing mothers even though adverse reports are not in the literature.) /From Table 2/ [R53] *Due to their high potential for abuse, amphetamines are not recommended for use as appetite suppressants. /Amphetamines/ [R50, 94] *Amphetamines should not be used to combat fatigue or to replace rest in normal subjects. /Amphetamines/ [R50, 94] *Data suggest that prolonged administration of amphetamines to children may inhibit growth. Careful monitoring during treatment is recommended. Psychotic children may experience exacerbation of symptoms of behavior disturbance and thought disorder. Amphetamines may provoke or exacerbate motor and vocal tics and Tourette's syndrome, necessitating clinical evaluation before administration of amphetamines. /Amphetamines/ [R50, 94] IDIO: *Toxic manifestations /of amphetamine/ occasionally occur as an idiosyncrasy after as little as 2 mg, but are rare with doses of less than 15 mg. [R22, 220] TOLR: *Tolerance develops to some of the central effects of amphetamines, and the chronic user often incr the dose to continue to obtain the desired effect. Some users are able to take several hundred milligrams per day over prolonged periods. By supressing appetite, high doses of amphetamine may foster ketosis; and, since amphetamine is excreted much more rapidly in acidic urine, some of the apparent tolerance may be due to more rapid elimination of the drug. At the same time there is increased sensitivity to other effects on the CNS. ... Cross tolerance between the amphetamine-like sympathomimetic agents has been observed clinically, and cross tolerance between the anorectic effect of cocaine and amphetamine has been demonstrated in rats. [R23, 553] *Tolerance does not develop to certain of the toxic effects of amphetamine on the CNS, and a toxic psychosis may occur after periods of weeks to months of continued use. Those who develop such a psychosis may have a lowered threshold during subsequent episodes if they resume use of amphetamine. [R23, 553] *Psychological dependence often occurs when amphetamine or dextroamphetamine is used chronically. ... Tolerance almost invariably develops to the anorexigenic effect of amphetamines, and is often seen also in the need for increasing doses to maintain improvement of mood in psychiatric patients. Tolerance is striking in individuals who are dependent on the drug, and a daily intake of 1.7 g without apparent ill effects has been reported. Development of tolerance is not invariable, and cases of narcolepsy have been treated for years without requiring an incr in the initially effective dose. [R22, 220] *With time, tolerance develops to the euphorigenic effects of amphetamine; higher and more frequent doses are used, and toxic symptoms and signs then appear. These include bruxism, touching, and picking of the face and extremities, suspiciousness, and a feeling of being watched. [R23, 552] *A detailed examination of the effects of single (0.1 ml/g of body wt) and repeated equiactive doses (1.25, 2.5 and 5.0 mg/kg, sc of d-amphetamine and 2.50, 5.0 and 10.0 mg/kg, sc of l-amphetamine) of d- and l-amphetamine on food consumption by adult male Sprague Dawley rats was undertaken with emphasis on aspects of tolerance development. Wt loss and pattern of daily food intake differed depending upon the isomer, dose, and degree of tolerance. Two types of tolerance were seen with both isomers, an initial tolerance with a decr in efficacy between days 1 and 2, and a later gradual decr in efficacy over 12 days of repeated dosage. Rats tolerant to the anorectic effects of d-amphetamine were only minimally affected when challenged with an equiactive anorectic dose of l-amphetamine, while rats tolerant to the anorectic effects of l-amphetamine showed a significantly depressed food intake and modified eating pattern when challenged with an equiactive dose of d-amphetamine. [R54] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ MILK: *The drug is concentrated in human milk. /From Table 2/ [R53] *Amphetamine readily passes into and is concentrated in breast milk. [R10, p. 84-6] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Amphetamine is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 1,000 lbs. [R55] FDA: *Schedules of controlled substances are established by section 202 of the Controlled Substances Act (21 U.S.C. 812). Schedule II includes amphetamine, its salts, optical isomers, and salts of its optical isomers, DEA Code #1100; Drug class: Stimulants. [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *AOAC Method 954.14. Amphetamine drugs. Stereochemical composition. [R57, 520] *AOAC Method 972.47. Amphetamine in drugs. Gas chromatographic method. /d-Amphetamine sulfate; dl-amphetamine sulfate/ [R57, 520] *AOAC Method 974.39. Amphetamine in presence of antihistamines and barbituates and other drugs. [R57, 521] *AOAC Method 960.55. Sympathomimetic drugs. Microchemical tests. /dl-Amphetamine/ [R57, 536] *AOAC Method 988.28. Enantionmers of amphetamine in bulk drugs, syrups, and capsules. Liquid chromatographic method. /d-Amphetamine sulfate; dl-amphetamine sulfate/ [R57, 622] *USE OF ELECTRON CAPTURE NEGATIVE ION CHEM IONIZATION MASS SPECTROMETRY IN ANALYZING AMPHETAMINE, AMPHETAMINE HYDROCHLORIDE, DOPAMINE HYDROCHLORIDE, AND TETRAHYDROCANNABINOL IS DISCUSSED. DATA ARE PROVIDED WHICH DEFINE THE LOWEST LEVEL OF SAMPLE DETECTION ACHIEVED AND FURNISH EXPERIMENTAL DETAILS ON THE OPERATION OF A NEGATIVE ION CHEMICAL IONIZATION QUADRUPOLE MASS SPECTROMETER. DETECTION AT THE ATTOMOLE (10-18) LEVEL BY CONVENTIONAL GC/MS SELECTED ION MONITORING METHODOLOGY IS REPORTED. [R58] *A GLC PROCEDURE WAS DEVELOPED TO DETERMINE AMPHETAMINE SALTS IN TABLETS AND CAPSULES. AMPHETAMINE WAS EXTRACTED FROM THE SOLID MATRIX WITH DILUTE HYDROCHLORIC ACID AND REACTED WITH CYCLOHEXANONE IN A STRONGLY BASIC AQUEOUS METHANOLIC SOLUTION. THE SCHIFF BASE REACTION PRODUCT WAS EXTRACTED WITH HEXANE FOR GLC DETERMINATION. REACTION TIME AND OPTIMUM CONDITIONS WERE STUDIED. PHENETHYLAMINE WAS USED AS AN INTERNAL STD. RESULTS COMPARED FAVORABLY WITH THOSE OBTAINED BY USING USP METHODS. [R59] *A METHOD OF ACETYLATING AMPHETAMINES QUICKLY TO PERMIT RAPID ANALYSIS BY GAS CHROMATOGRAPHY/MASS SPECTROMETRY IS PRESENTED. AMPHETAMINE, METHAMPHETAMINE, METHYLENEDIOXYAMPHETAMINE, AND MESCALINE WERE ACETYLATED WITH TRIFLUORACETIC ANHYDRIDE IN THE PRESENCE OF MERCURIC TRIFLUORACETATE AS A CATALYST. THE REAGENT CAN ACETYLATE THE AMINE DIRECTLY IN THE FORM OF FREE BASE OR SALT. SLIGHTLY VARYING PROCEDURES WERE USED, DEPENDING ON WHETHER THE DRUGS WERE IN SOLID FORM OR WERE OBTAINED IN ORGANIC FLUIDS SUCH AS URINE. SAMPLES WERE ANALYZED ON A GAS CHROMATOGRAPHY/MASS SPECTROMETRY WITH AN ELECTRON IMPACT SOURCE. ADVANTAGES OF THIS METHOD OF ANALYSIS ARE: RAPIDITY, NO PREVIOUS CLEANUP TO REMOVE ADULTERANTS, AND DETECTION AT THE PICOMOLE LEVEL. [R60] *AMPHETAMINES AND RELATED ARYLALKYLAMINES WERE CONVERTED IN HIGH YIELDS TO THE CORRESPONDING 4-NITROBENZAMIDES TO ENHANCE THEIR UV DETECTABILITY. THE DERIVATIVES ARE CHEMICALLY STABLE AND CAN BE RAPIDLY PREPARED AND PURIFIED BY EXTRACTION. THESE AMIDES WERE SEPARATED BY REVERSE PHASE HIGH PRESSURE LIQUID CHROMATOGRAPHY USING AN ISOCRATIC SOLVENT SYSTEM. THE DERIVATIVES EXHIBITED EXCELLENT GAS CHROMATOGRAPHIC PROPERTIES ON 3% OV-17 LIQUID PHASE. THE AMIDES ARE MUCH LESS VOLATILE THAN THE PARENT AMINES REQUIRING COLUMN TEMPERATURES IN EXCESS OF 240 DEG C FOR ELUTION. THE DERIVATIVES WERE THERMALLY STABLE AT THESE TEMPERATURES. [R61] *A COMPARISON OF FLUOROMETRIC PROCEDURES FOR ASSAY OF AMPHETAMINE IS PRESENTED. [R62] CLAB: *AN ALTERNATE TO TYPE C PROCEDURE (IMMUNOASSAY) IS AVAIL FOR THE DIRECT ANALYSIS OF A BIOLOGICAL SPECIMEN (URINE). IMMUNOASSAY OF DRUGS IS BASED ON CLASSICAL IMMUNOCHEMICAL PROCEDURES AND UTILIZES AN ANTIGEN-ANTIBODY REACTION AS AN ANALYTICAL TOOL. THE REAGENTS FOR THE ENZYME MULTIPLIED IMMUNOASSAY TECHNIQUE (EMIT) USED FOR THE ANALYSIS OF AMPHETAMINE IN URINE IS AVAIL COMMERCIALLY. THE SENSITIVITY OF THE EMIT FOR THE ANALYSIS OF AMPHETAMINE IS 1.0 UG/ML. THE REAGENTS FOR THE RADIOIMMUNOASSAY (RIA) PROCEDURE USED FOR THE ANALYSIS OF AMPHETAMINE ARE AVAIL COMMERCIALLY. THE SENSITIVITY OF RIA FOR AMPHETAMINE IS 0.1 UG/ML. [R63] *A METHOD OF ACETYLATING AMPHETAMINES QUICKLY TO PERMIT RAPID ANALYSIS BY GAS CHROMATOGRAPHY/MASS SPECTROMETRY IS PRESENTED. AMPHETAMINE, METHAMPHETAMINE, METHYLENEDIOXYAMPHETAMINE, AND MESCALINE WERE ACETYLATED WITH TRIFLUORACETIC ANHYDRIDE IN THE PRESENCE OF MERCURIC TRIFLUORACETATE AS A CATALYST. THE REAGENT CAN ACETYLATE THE AMINE DIRECTLY IN THE FORM OF FREE BASE OR SALT. SLIGHTLY VARYING PROCEDURES WERE USED, DEPENDING ON WHETHER THE DRUGS WERE IN SOLID FORM OR WERE OBTAINED IN ORGANIC FLUIDS SUCH AS URINE. SAMPLES WERE ANALYZED ON A GAS CHROMATOGRAPHY/MASS SPECTROMETRY WITH AN ELECTRON IMPACT SOURCE. ADVANTAGES OF THIS METHOD OF ANALYSIS ARE: RAPIDITY, NO PREVIOUS CLEANUP TO REMOVE ADULTERANTS, AND DETECTION AT THE PICOMOLE LEVEL. [R60] *When using capillary gas chromatography with nitrogen-specific detection for rapid screening of drugs, to overcome problems associated with the use of retention indices based on homologous series determined with nitrogen-specific detectors, a retention indices reference system was developed based on molecular masses and retention times of nitrogen-containing compounds. The standards chosen are readily available in highly purified form and can be detected by the unmodified nitrogen-specific detector. By using temperature programming, a linear relationship can be obtained between the molecular masses of standards and their retention times. Used in conjunction with microcomputer data handling, this screening system is rugged and reliable, operating 22 hr/day. Using the present method the retention time in min for amphetamine standard was 3.340 on a DB-1 column, and 1.295 on a DB-17 column with retention indices of 1350 (initial temperature 120 deg C for 1 min, incr by 8 deg C/min and held for 22 min). [R64] *A multi-column system has been developed for automated analysis of basic drugs in urine. Two polymeric precolumns, containing PRP-1 and Aminex A-28, were used to isolate the drugs. A short reversed phase column, coupled to a 150 x 4.6 mm I.D. silica column, produced the analytical separation. Sample preparation consisted of dilution and centrifugation. The entire procedure required less than 30 min. Urine from healthy laboratory employees was spiked with amphetamine. Levels of 0.2 mg/l produced peaks that could be matched against stored spectra with a computerized library search program. The retention value k' for amphetamine on a 10 x 3.2 mm I.D. Aminex A-28 column was 0.1 at a phase ratio of from 0.1 to 0.7. The retention value k' for amphetamine was 2.5 for the fully automated four column system, for isocratic analysis on the reversed phase and silica columns only, and for isocratic analysis on the silica column only. 2.5 ug amphetamine added to 500 ul urine had a retention time of 10.43 + or - 0.012 min for 10 consecutive injections. When concn from 0.3 to 10 mg/l were analyzed, the slope of the regression line was 4.5X10-5 for amphetamine. [R65] *THE USE OF A GAS CHROMATOGRAPHY SYSTEM EQUIPPED WITH DUAL FLAME IONIZATION AND NITROGEN SELECTIVE RUBIDIUM BEAD DETECTORS IN THE IDENTIFICATION OF DRUGS IS PRESENTED. WITH THE METHOD, DRUGS ARE CHROMATOGRAPHED ALONG WITH A CAFFEINE STD ON A 3% OV-17 COLUMN PROGRAMMED FROM 100 TO 250 DEG C AT 4 DEG/MIN. IN ADDN TO CHARACTERIZING THE DRUG IN TERMS OF RETENTION TIME RELATIVE TO CAFFEINE, THE DRUG CAN ALSO BE CHARACTERIZED BY THE RATIO OF THE NITROGEN/FLAME IONIZATION DETECTOR RESPONSE OF THE DRUG TO THE RESPONSE OF THE CAFFEINE STD. THE RESPONSE INDEX AND RELATIVE RETENTION TIME OF 71 NITROGEN CONTAINING DRUGS COMMONLY ENCOUNTERED IN FORENSIC AND TOXICOLOGY APPLICATIONS ARE PRESENTED. THE DRUGS ANALYZED INCL AMPHETAMINE. [R66] *THIN LAYER CHROMATOGRAPHY- AS BASIC DRUGS, AMPHETAMINES ARE EXTRACTED FROM ALKALINE URINE BY AN ORGANIC SOLVENT. THIS SOLVENT MAY BE EVAPORATED TO DRYNESS AND THE RESIDUE THIN-LAYER CHROMATOGRAPHED. ... AMPHETAMINE IS PRESENT (PROCEDURE A). AMPHETAMINE, AMPHETAMINE SULFATE, AMPHETAMINE HYDROCHLORIDE, AND METHAMPHETAMINE ARE DETERMINED BY THIS PROCEDURE. ... AMPHETAMINE CAN BE DETECTED IN URINE SAMPLES UP TO 24 HR AFTER ADMIN OF A 10.0 MG THERAPEUTIC DOSE. THE NINHYDRIN-PHENYLACETALDEHYDE SPRAY TEST IS USED IN THIS PROCEDURE AND IS SENSITIVE TO AS LITTLE AS 0.3 UG OF AMPHETAMINE. [R63] *GAS CHROMATOGRAPHY. AS BASIC DRUGS, AMPHETAMINES ARE EXTRACTED FROM ALKALINE URINE BY AN ORGANIC SOLVENT. ... BACK-EXTRACTION OF THE ORGANIC SOLVENT EXTRACT INTO AN ACID, THE ADDN OF BASE TO MAKE THE ACID EXTRACT BASIC ONCE AGAIN, AND REEXTRACTION WITH A SMALL VOL OF ORGANIC SOLVENT SUFFICIENTLY CLEANS THE SPECIMEN FOR GAS-CHROMATOGRAPHIC ANALYSIS. FREE AMPHETAMINE DRUGS ARE SEPARATED BY A 10% APIEZON-10% POTASSIUM HYDROXIDE COLUMN. FURTHER CONFIRMATION IS OBTAINED BY REACTING THE AMPHETAMINE DRUGS WITH TRICHLOROACETYL CHLORIDE TO OBTAIN AMPHETAMINE N-TRICHLOROAMIDE DERIVATIVES WHICH ARE SEPARATED BY A 3% OV-17 COLUMN. AMPHETAMINE, AMPHETAMINE SULFATE, METHAMPHETAMINE HYDROCHLORIDE, AND METHAMPHETAMINE IN BLOOD OR URINE ARE DETERMINED BY THIS PROCEDURE. THE METHOD IS SENSITIVE TO 0.1 UG/ML OF ... METHAMPHETAMINE. THE QUANTITATION IS ACCURATE TO + OR - 7%. GREATER SENSITIVITY MAY BE OBTAINED IF AN ELECTRON-CAPTURE DETECTOR IS USED INSTEAD OF A FLAME IONIZATION DETECTOR. THIS METHOD OF AMPHETAMINE ANALYSIS SHOWS A COEFFICIENT OF VARIATION OF 6.5% OVER THE RANGE OF 0.025 TO 5.0 UG/ML. RECOVERIES OVER THE RANGE 0.1 TO 5.0 UG/ML ARE 60 TO 65%. BELOW 0.1 UG/ML THEY GRADUALLY DECREASE TO A VALUE OF 40 TO 45% AT O.025% UG/ML. SENSITIVITY IS LIMITED BY THE DECREASING RECOVERY AND THE PRESENCE OF SOLVENT IMPURITIES. IF A SAMPLE IS KNOWN TO CONTAIN AMPHETAMINE, IT CAN USUALLY BE QUANTITATED IN CONCN AS LOW AS 0.005 TO 0.010 UG/ML. IF THE ANALYSIS MUST IDENTIFY AS WELL AS QUANTITATE AMPHETAMINE, THEN 0.015 TO 0.020 UG/ML IS A REASONABLE LIMIT OF SENSITIVITY. [R63] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: CALDWELL J, SEVER PS; CLIN PHARMACOL THER 16 (10): 625-38 (1974). PHARMACOLOGY, METABOLISM, TOLERANCE AND MANIFESTATION OF ABUSE OF AMPHETAMINES, COCAINE AND LYSERGIC ACID DIETHYLAMIDE ARE REVIEWED. DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability (1984) DHHS Pub No. (ADM)87-1332 DHHS/NIDA; Research Monograph Series 54: Mechanisms of Tolerance and Dependence (1984) DHHS Pub No. (ADM)88-1330 DHHS/NIDA; Research Monograph Series 56: Etiology of Drug Abuse: Implications for Prevention (1987) DHHS Pub No. (ADM)87-1335 DHHS/NIDA; Research Monograph Series 59: Current Research on the Consequences of Maternal Drug Abuse (1985) DHHS Pub No. (ADM)85-1400 DHHS/NIDA; Research Monograph Series 60: Prenatal Drug Exposure: Kinetics and Dynamics (1985) DHHS Pub No. (ADM)85-1413 DHHS/NIDA; Research Monograph Series 65: Woman and Drugs: A New Era for Research (1986) DHHS Pub No. (ADM)87-1447 DHHS/NIDA; Research Monograph Series 73: Urine Testing for Drugs of Abuse (1986) DHHS Pub No. (ADM)87-1481 DHHS/NIDA; Research Monograph Series 90: Problems of Drug Dependence 1988 (1988) DHHS Pub No. (ADM)89-1605 DHHS/NTP; Toxicology and Carcinogenesis Studies of dl-Amphetamine Sulfate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 387 (1991) NIH Publication No. 91-2842 SO: R1: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 84 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 84 R4: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R5: American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986. R6: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R7: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 72 R8: SRI. 1998 Directory of Chemical Producers -United States of America. 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Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1998 (Plus Supplements). R16: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 8 R17: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-45 R18: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R19: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.174 R20: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 332 R21: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R22: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R23: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. R24: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 96 R25: Knoben, J.E. and P.O. Anderson (eds.) Handbook of Clinical Drug Data. 6th ed. Bethesda, MD: Drug Intelligence Publications, Inc. 1988. R26: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-27 R27: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. R28: HART JB, WALLACE J; CLIN TOXICOL 8 (2): 179-90 (1975) R29: Humphreys, D.J. Veterinary Toxicology. 3rd ed. London, England: Bailliere Tindell, 1988. 87 R30: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 17 R31: Cass WA et al; Neuropharmacol 28 (1): 217-27 (1989) R32: Wise RA et al; Pharmacol Biochem Behav 32 (3): 769-72 (1989) R33: Cools AR et al; Behav Brain Res 34 (1/2): 111-6 (1989) R34: Mueller K; Brain Res 494 (1): 30-5 (1989) R35: Motles E et al; Pharmacol Biochem Behav 33 (1): 115-21 (1989) R36: Haracz JL et al; Brain Res 489 (2): 365-8 (1989) R37: Harris LS, Balster RL; p.111-32 in Stimulus Properties of Drugs; Thompson T, Pickens R, eds (1971) as cited in DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability p.67 (1984) DHHS Pub No. (ADM)87-1332 R38: Overton DA, Lebman RI; Proc Amer Psychol Assoc (1973) as cited in DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability p.67 (1984) DHHS Pub No. (ADM)87-1332 R39: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 519 R40: Gossel, T.A., J.D. Bricker. Principles of Clinical Toxicology. 3rd ed. New York, NY: Raven Press, Ltd., 1994. R41: DHHS/NTP; Toxicology and Carcinogenesis Studies of dl-Amphetamine Sulfate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 387 (1991) NIH Publication No. 91-2842 R42: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 157 R43: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 65 R44: DHHS/NIDA; Research Monograph Series 73: Urine Testing for Drugs of Abuse p.70 (1986) DHHS Pub No. (ADM)87-1481 R45: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 177 R46: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 119 R47: HENDERSON PT, VREE TV; PHARM WEEKBL 109 (AUG 23): 813-23 (1974) R48: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 114 R49: Sahgal A et al; Neuropharmacol 28 (3): 283-9 (1989) R50: USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc. R51: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R52: Sutton RL et al; Behav Neurosci 103 (4): 837-41 (1989) R53: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 138 (1994) R54: Nichols MB, Maickel RP; Pharmacol Biochem Behav 33 (1): 181-8 (1989) R55: 40 CFR 355 (7/1/98) R56: 21 CFR 1308.12(d) (4/1/98) R57: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 R58: HUNT DF, CROW FW; ANAL CHEM 50 (11): 1781-4 (1978) R59: CLARK CC; J ASSOC OFF ANAL CHEM 58 (11): 1174-7 (1975) R60: WU A; CLIN TOXICOL 8 (2): 225-32 (1975) R61: CLARK CR ET AL; ANAL CHEM 49 (6): 912-5 (1977) R62: MEHTA AC, SCHULMAN SG; J PHARM SCI 63 (7): 1150-1 (1975) R63: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 22 R64: Manca D et al; Clin Chem 35 (4): 601-7 (1989) R65: Binder SR et al; J Chromatogr 473 (2): 325-41 (1989) R66: BAKER JK; ANAL CHEM 49 (6): 906-8 (1977) RS: 79 Record 235 of 1119 in HSDB (through 2003/06) AN: 3324 UD: 200303 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ESTRONE- SY: *AQUACRINE-; *CRINOVARYL-; *CRISTALLOVAR-; *CRYSTOGEN-; *DESTRONE-; *DISYNFORMON-; *ENDOFOLLICULINA-; *ESTERONE-; *delta-1,3,5-Estratrien-3-beta-ol-17-one-; *1,3,5-ESTRATRIEN-3-OL-17-ONE-; *1,3,5(10)-Estratrien-3-ol-17-one; *ESTRA-1,3,5(10)-TRIEN-17-ONE, 3-HYDROXY-; *ESTROL-; *ESTRON-; *Estrona- (Spanish); *ESTROVARIN-; *ESTRUGENONE-; *ESTRUSOL-; *FEMESTRONE-INJECTION-; *FEMIDYN-; *FOLIKRIN-; *FOLIPEX-; *FOLISAN-; *FOLLESTRINE-; *FOLLESTROL-; *FOLLICULAR-HORMONE-; *FOLLICULIN-; *FOLLICUNODIS-; *FOLLIDRIN-; *Follidrin- (tablets); *GLANDUBOLIN-; *HIESTRONE-; *HORMOFOLLIN-; *HORMOVARINE-; *3-Hydroxyestra-1,3,5(10)-trien-17-one; *3-Hydroxy-17-keto-estra-1,3,5-triene-; *3-Hydroxy-17-keto-oestra-1,3,5-triene-; *3-Hydroxy-oestra-1,3,5(10)-trien-17-one; *KESTRONE-; *KETODESTRIN-; *KETOHYDROXYESTRIN-; *KOLPON-; *MENAGEN-; *MENFORMON-; *delta-1,3,5-Oestratrien-3-beta-ol-17-one-; *1,3,5-Oestratrien-3-ol-17-one-; *1,3,5(10)-Oestratrien-3-ol-17-one; *OESTRIN-; *OESTROFORM-; *OESTRONE-; *OESTROPEROS-; *OVEX- [TABLETS; *OVIFOLLIN-; *PERLATAN-; *SOLLICULIN-; *THEELIN-; *Thelestrin-; *THELYKININ-; *THYNESTRON-; *TOKOKIN-; *Unden-; *UNDEN- (PHARMACEUTICAL); *WYNESTRON- RN: 53-16-7 MF: *C18-H22-O2 ASCH: Estropipate; 7280-37-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... FROM MEXICAN YAM ... VIA 16-DEHYDROPREGNENOLONE ACETATE ... SIDE CHAIN @ POSITION-17 ... DEGRADED BY ... FORMING 2-OXIME AND THEN ... BECKMANN REARRANGEMENT WITH P-ACETAMIDOBENZENESULFONYL CHLORIDE TO 17-ACETAMIDO ... WHICH ... WITH ... SULFURIC ... FORMS ENAMINE ACETATE ... HYDROLYZED TO ... ESTRONE. [R1] *Isolated from pregnant human urine, synthesis from ergosterol. [R2] *Occurs in pregnancy urine on women and mares, in follicular liquor of many animals, in human placenta, in urine of bulls and stallions, in palm-kernel oil. Isoln: Butenandt, Naturwiss. 17, 879 (1929); Doisy et al., Am. J. Physiol. 90, 329 (1929). [R3] *Also isolated from moghat roots and date palm pollen grains: Amin et al., Phytochemistry 8, 295 (1969). [R3] *Estrone is synthesized from androstenolone, which is first hydrogenated with palladium charcoal to give epiandro sterone... [R4] FORM: *GRADES: NF [R5] *VARIOUS SULFATE ESTERS OF ESTRONE, NF ... AVAILABLE IN TABLETS CONTAINING 0.75 TO 5 MG (MORESTIN, OGEN) ... THESE ESTERS AND ESTRONE ... ALSO SUPPLIED UNDER VARIOUS TRADE NAMES IN AQUEOUS SUSPENSION AND OILY SOLN CONTAINING 1 TO 5 MG/ML FOR IM INJECTION. [R6, 1431] *Parenteral suspension: 5 mg/ml [R7, 2702] *Vials, 2 mg/ml and 5 mg/ml. [R8] MFS: *Estrone (Abbott, Lilly, Wyeth); Glandubolin (Gedeon Richter); Kolpon (Organon); Ovex (Leo Danmark); Theelin (Parke Davis). [R4] OMIN: *... ESTROGENIC ACTIVITY OF 0.1 UG OF CRYSTALLINE ESTRONE CONSTITUTES THE INTERNATIONAL UNIT OF ESTROGENIC ACTIVITY. [R1] *AQUEOUS MIXT OF WATER-INSOL ESTRONE AND WATER-SOL POTASSIUM SALT OF THE SULFATE ESTER ... CLAIMED ... MORE PROMPT EFFECT THAN INSOL ESTRONE SUSPENSIONS. POTENCY OF MOST ORAL MIXT IS EXPRESSED IN TERMS OF THEIR ESTRONE SODIUM SULFATE CONTENT. [R9] *U.S. pats. 1,967,350, 1,967,351 (1934 both to St. Louis University); Fr. pat. 1,305,992 (1962 to Roussel-Uclaf) [R3] USE: *In the preparation of commercial 19-norsteriods. [R3] *Therap cat: Estrogen [R3] *Therap cat (Vet): Estrogen [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Small, white crystals, or white to creamy white, crystalline powder. [R2]; *ALPHA: MONOCLINIC CRYSTALS FROM ALC; BETA AND GAMMA: ORTHORHOMBIC CRYSTALS FROM ALC [R10]; *Crystals from acetone [R3]; *Exists in three crystalline phases, one monoclinic, the other two orthorhombic. [R3] ODOR: *Odorless [R2] MP: *260.2 deg C [R11] MW: *270.37 [R3] DEN: *1.236 g/cu cm @ 25 deg C [R11] OWPC: *log Kow= 3.13 [R12] SOL: *SOL IN HOT ACETONE, SECONDARY PYRIMIDINE; SLIGHTLY SOL IN ETHER, BENZENE, HOT CHLOROFORM, HOT ALC; INSOL IN WATER. [R13]; *Slightly soluble in ethanol and ethyl ether; soluble in acetone. [R11]; *One gram of estrone dissolves in 250 ml of 96% alcohol at 15 deg C, in 50 ml of boiling alcohol; in 50 ml of acetone at 15 deg C, in 110 ml chloroform at 15 deg C, in 145 ml boiling benzene. Sol in dioxane, pyridine, fixed alkali hydroxide solutions; slightly sol in ether, vegetable oils. [R3]; *Solubility in water: (25 deg C): 0.003 g/100 ml [R3] SPEC: *SPECIFIC OPTICAL ROTATION: +158 TO +165 DEG @ 25 DEG C/D (DIOXANE) [R1]; *Specific optical rotation: +152 deg @ 22 deg C/D (concentration by volume = 0.995 g in 100 ml chloroform) [R3]; *SADTLER REF NUMBER: 1288 (IR, PRISM); MAX ABSORPTION (ALC): 280 NM (LOG E= 3.37) [R13]; *IR: 5481 (Coblentz Society Spectral Collection) [R14]; *UV: 20783 (Sadtler Research Laboratories Spectral Collection) [R14]; *MASS: 1958 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R14]; *Maximum absorption (p-dioxane): 282, 296 nm (E 2300, 2130); (concentrated sulfuric acid): 300, 450 nm; (0.1M sodium hydroxide): 239, 293 nm [R3] OCPP: *Crystals from acetone; mp: 251-254 deg C /dl-Estrone/ [R3] *Precipitated by digitonin [R3] *Stable in air. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits acrid smoke and fumes. [R15] EQUP: *... SPECIAL UNIFORM INCL UNDERWEAR, SOCKS, LONG-SLEEVED OVERALLS (WITH NO POCKETS, BUTTONED TO NECK AND WITH TIES @ BOTTOM OF TROUSERS FOR TYING OVER BOOTS), RUBBER GLOVES, AND DUST RESPIRATORS. /ESTROGENS/ [R16, 977] OPRM: *WORKROOMS MUST BE KEPT VERY CLEAN, AND CONTAMINATED CLOTHING SHOULD BE DESTROYED OR CLEANED. ... COMPLETE PREVENTION OF ENVIRONMENTAL POLLUTION IS NEVERTHELESS NOT EASY, BECAUSE OF PERSISTENCE OF LIGHT POWDER IN AIR. WORKER MUST THEREFORE CO-OPERATE IN PREVENTION OF CHRONIC INTOXICATION ... . /ESTROGENS/ [R16, 978] *HERMETICALLY SEALED MACHINES, DUST ASPIRATION AND AIR CONDITIONING ARE IMPORTANT SAFETY MEASURES. [R16, 977] SSL: *STABLE IN AIR. [R1] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Based on the evaluation conducted by the National Toxicology Program (NTP), the chemical compound estrone is listed as "substances or groups of substances, and medical treatments which may reasonably be anticipated to be carcinogens." [R17] *Evaluation: There is sufficient evidence in humans for the carcinogenicity of post-menopausal estrogen therapy. There is sufficient evidence in experimental animals for the carcinogenicity of estradiol and estrone. There is limited evidence in experimental animals for the carcinogenicity of conjugated equine estrogens, equilin and estriol. There is inadequate evidence in experimental animals for the carcinogenicity of d-equilenin. Overall evaluation: Post-menopausal estrogen therapy is carcinogenic to humans (Group 1). /Post-menopausal estrogen therapy/ [R18] HTOX: *Independent studies have shown an increased risk of endometrial cancer in postmenopausal women placed on unopposed (without a progestin) systemic estrogen replacement therapy for prolonged periods. Since estrogens applied vaginally are extensively absorbed, the risk may apply to them also. The risk of endometrial cancer in systemic estrogen users, which appears to depend on duration of treatment and dose, was 5 to 10 times greater than in nonusers. However, studies have shown that administration of a progestin for 10 to 14 days of an estrogen cycle is associated with a lower incidence of endometrial hyperplasia and endometrial carcinoma than an estrogen-only cycle. There is no risk of endometrial cancer in patients who have undergone hysterectomies and, therefore, no documented need for concurrent progestin therapy. /Estrogens/ [R19, 1384] *Whether the use of systemic estrogens increases the incidence of breast cancer in some postmenopausal women is unresolved. Some large studies reported an increase in the relative risk for development of breast cancer. At present, however, the majority of data available does not seem to support this conclusion. /Estrogens/ [R19, 1384] NTOX: *MICE ... IMPLANTED WITH PELLETS OF ESTRONE (1-7 MG) ... INCIDENCE OF LYMPHOID TUMORS OF 19/105 ... TUMORS OF BREAST IN ... RATS ... IMPLANTED WITH SINGLE PELLET OF ESTRONE (8-12 MG) ... ADRENAL CORTICAL TUMORS WERE FOUND ... IN RATS ... OCCURRENCE OF BLADDER STONES /IN RATS/ IS ATTRIBUTABLE TO ESTRONE TREATMENT ... . [R20] *Mammary tumors were observed in 5/5 male RIII mice (MTV+) after skin application of estrone as a 0.01% solution in chloroform twice weekly for 16 or more weeks. Female RIII mice had no mammary tumors after receiving the same treatment for more than 6 months, although the incidence in untreated females was 60-70%. Three pituitary tumors were observed among 12 mice of both sexes treated with estrone. In a mixed strain of mice with a low incidence of mammary tumors, none were induced by estrone treatment after 44 weeks. [R21] *Malignant kidney tumors of different structures were found after 8 months in about 60% of 86 castrated male golden hamsters injected with estrone (dose not stated). Pituitary adenomas also occurred in about 25% of the animals. [R22] *Mammary tumors were observed in AxC rats (3/32 females, 4/30 males), Fischer rats (3/29 females, 2/29 males) and August rats (5/12 females, 9/25 males) implanted with a single pellet of 8-12 mg estrone; average latent periods ranged from 50-97 weeks. Mammary cancer incidence was doubled in AxC rats by the implantation of two such pellets, and the latent period was reduced by about 50%. Adrenal cortical tumors were found in small numbers of rats with one pellet, but the incidence was greatly reduced with two pellets. No mammary tumors were seen in either sex of rats of the Copenhagen strain, but 6/10 males and 1/11 female had bladder cancer associated with bladder stones. The amount of estrone absorbed was calculated to be between 3.2 and 9.6 mg per rat. [R23] *In the rat and other rodent species, the persistent estrous syndrome appears to result from the action of estrogens on hypothalamic development during the neonatal period. The effect of androgens is also believed to stem from their aromatization to estrogens in the CNS. Neonatal exposure to estrogenic substances stimulates uterine growth and early vaginal opening. These two responses are good indicators of estrogenic action, and when they occur during the neonatal period they can be predictive of persistent estrous and reproductive tract anomalies in the adult. Physiological estrogens (such as ... estrone), ... are known to cause these effects in the rat. [R24] *12.4 % Cleft palate /were observed/ in mouse fetuses whose mother were injected with 1 mg estrone on the 11th through 16th gestational days. Among injection control fetuses, the incidence of cleft palate was 0.7%. [R25] *In certain animal species, long-term, continuous administration of estrogens increases the frequency of cancers of the breast, cervix, liver, pancreas, testis, uterus, and vagina. /Estrogens/ [R19, 1384] *Liver homogenates from female rat strains (Sprague Dawley, Wistar and Fisher) were incubated in a reduced nicotinamide adenine dinucleotide phosphate regenerating medium in the presence of labelled and unlabelled estrone. Liver microsomes isolated from male rats and female mice were used as positive controls. Using HPLC and paper chromatography, under the experimental conditions used it was found that liver homogenates from female rats were able to convert estrone to various metabolites such as 16 alpha-hydroxyestrone. In a mutagenicity assay (Ames test), with 16 alpha-hydroxyesterone as test substance, two strains (TA98 and TA1538) of the five strains tested showed a 2 to 3-fold increase in the number of his+ revertants relative to the control values. Estrone did not cause any mutagens in the test used. It is concluded that female rats are able to synthesize 16 alpha-hydroxyestron in vitro. Whether this compound is risk factor for breast cancer remains unclear. [R26] *... In this study, the ability of exogenously administered estrone sulfate to stimulate growth of a carcinogen induced, hormone dependent rat mammary tumor was examined and the rate of conversion of estrone sulfate to free estrone and estradiol was measured. Castrate rats bearing nitrosomethylurea induced mammary tumors were infused with estradiol as a control or estrone sulfate over a 14 day period. Estradiol at low doses significantly increased tumor volume whereas higher amounts paradoxically inhibited growth. By comparison, estrone sulfate infusions significantly increased tumor volume over that observed in castrated animals on both days 7 and 14 of infusion. To determine whether estrone sulfate was converted to free estrone and estradiol during this protocol, (3)H estrone sulfate was substituted for unlabelled steroid and castrate animals were again infused for 14 days. At 7, 10 and 14 days of infusion, 18-26% of estrone sulfate was converted to free estrone and 9-16% to free estradiol. There were no significant differences between the 2 doses used and the rates of conversion were stable over the infusion period. Conversion of estrone sulfate to free estradiol was also demonstrated by radioimmunoassay of free estradiol in plasma during estrone sulfate infusions. These data demonstrate that exogenously administered estrone sulfate can stimulate mammary tumor growth in castrate animals and support the possibility that estrone sulfate may serve as an important source of tumor tissue estradiol. [R27] *A series of nine chemicals of varying structure and estrogenicity was investigated for biochemical determinants of their relative capacities to alter normal embryonic growth and developmental patterns during organogenesis in rats. In order to circumvent the potentially confounding influences of maternal factors, the direct effects of steroidal and nonsteroidal estrogens on cultured whole embryos were compared at concentrations producing readily measurable embryotoxicity but low embryolethality (2-20%). Nonsteroidal estrogens included were diethylstilbestrol, hexestrol, E,E-dienestrol, and tamoxifen. Steroidal estrogens were estradiol (17) beta, estrone, and (17) alpha-ethinylestradiol (17) beta. For comparative purposes, the effects of two essentially nonestrogenic phenols, Z,Z-dienestrol and phenol, were also studied. Tamoxifen, a weak estrogen which also exhibits antiestrogenic properties, was studied for possible interactive effects with potent estrogens. Prosencephalic hypoplasia was the abnormality most consistently observed and was elicited by each of the chemicals investigated. Embryotoxicity was neither attenuated by tamoxifen nor related to estrogenic potency or steroidal structure, but was strongly and unpredictably influenced by biotransformational determinants. Presence of a cytochrome p450-dependent oxidizing system in the culture medium resulted in marked increases in embryotoxicity of estrone, estradiol (17) beta, and phenol, only minor increases for Z,Z-dienestrol and E,E dienestrol, but in strikingly decreased effects of (17) alpha-ethinylestradiol (17) beta, tamoxifen, and hexestrol. It produced no statistically significant differences in effects of diethylstilbestrol. The results obtained were compatible with the concept that effects of these agents on growth and development during the earlier stages of organogenesis are independent of steroid structure or estrogenic activity but strongly dependent upon pathways and rates of biotransformation of some (but not all) of the parent chemicals. [R28] *CHRONIC ADMIN OF CHLORDANE, DIELDRIN, HEPTACHLOR, LINDANE, TOXAPHENE, OR SOME DDT ANALOGUES TO RATS ENHANCED HEPATIC METABOLISM, BOTH IN VIVO AND IN VITRO, OF ... ESTRONE AND DECR ... UTEROTROPIC ACTION. [R29, 473] *Administration of 125 ug/l estrone in the drinking-water resulted in the appearance of mammary tumors in 33/68 gonadectomized male C3H and C3He mice (MTV-). With a concentration of 2000 ug/l, the incidence of these tumors increased to 119/169. No data were given on controls. [R21] *Daily injection of 50-200 ug estrone in oil (total dose, 30-40 mg) resulted in mammary cancers in 6/6 castrated male rats and in 4/5 ovariectomized females. A lower incidence was found in intact males (2/6) and in intact females (3/8). The average induction time ranged from 83 weeks with the lowest dose to 31 weeks with the highest. Mammary cancers were found in 1/2 male and 5/8 female rats given twice-weekly s.c. injections of 50-100 ug estrone benzoate in oil for 20 months. Pituitary tumors (140-271 mg in weight) were present in all rats. [R22] *Mice of various hybrids between the A, C3H, C57 and JK strains, which were implanted with 1-7 mg pellets of estrone, had an overall incidence of lymphoid tumors of 19/105, compared with 21/391 in corresponding control mice. [R22] *Adrenal cortical tumors were found in 20% of female hooded rats implanted with pellets of estrone (dose not stated). The tumors frequently metastasized and were transplantable, but they regressed if the estrone treatment was withdrawn. Adrenal tumors occurred in about 5% of untreated rats in that colony. [R30] *Black hooded rats (Nb strain) were given subcutaneously implanted pellets containing 90% estrone and 10% cholesterol, weighing approximately 10 mg each. Pellets were implanted for 10-53 weeks or more in small groups of animals 3, 8, 12 or 38 weeks of age. An increased incidence of tumors was observed in treated rats of both sexes, as compared with 32 controls; the incidences of adrenal carcinomas, mammary carcinomas and pituitary tumors were increased. The incidence of mammary adenomas was increased in treated males and females up to 1 yr but was lower than that in the controls thereafter. The duration of the experiment was not stated. Most of the tumors arising in the estrogen-treated rats proved to be hormone-dependent upon transplantation into syngeneic hosts. [R30] *When mice were injected subcutaneously with estrone between days 11-16 of gestation at alternating doses of 0.1 and 0.2 mg, 12.4% of the offspring had cleft palates, compared with 1.1% in controls. [R31] *Single doses of 0.02 mg/kg bw estrone injected into rats during the early phase of gestation (time of tubal transport) terminated pregnancy. Injection of a single dose of 0.4 mg/kg bw estrone on day 8-11 of gestation resulted in a marked reduction in the number of surviving fetuses and delayed delivery but had no effect on surviving fetuses. [R31] *Single sc injections of 1-140 ug/rat were given at different times of gestation between days 1-10. Termination of pregnancy (100%) was achieved by administration of 20 ug on days 1 and 2, by 40 ug on day 3, by 80 ug on day 4 and by 50 ug on day 5. An injection of 140 ug estrone did not terminate pregnancy when given between days 6-10 but induced a decreased number of implantations, an increased number of dead fetuses and abnormal growth and spacing of the fetuses. [R31] *SC injection of 0.0175 mg/kg per day estrone into rats during days 1-7 of gestation terminated 50% of pregnancies. [R31] *Implantation of 20 mg pellets of estrone resulted in microscopic renal carcinomas in 8/10 male castrated Syrian hamsters after 8.5 months of treatment. [R32] NTXV: *TDLO GUINEA PIGS IMPLANT 2 MG/KG, TOXIC EFFECTS: NEOPLASTIC EFFECTS; [R33] ADE: *Estrogens are available for oral, parenteral, transdermal, or topical administration ... absorption is generally good withthe appropriate preparation. /Estrogens/ [R34, 1419] *URINARY EXCRETION RATE OF ESTROGENS IS QUITE SIMILAR WHETHER AGENTS ARE GIVEN ORALLY OR IV, WHICH SUGGESTS THAT ABSORPTION ... FROM GI TRACT IS PROMPT AND QUITE COMPLETE. /ESTROGENS/ [R6, 1429] *LIMITED ORAL EFFECTIVENESS OF NATURAL ESTROGENS AND THEIR ESTERS IS ... DUE TO HEPATIC METABOLISM. ESTROGENS ... WHEN DISSOLVED IN OIL AND INJECTED, ... ARE RAPIDLY ABSORBED AND QUICKLY METABOLIZED. /ESTROGENS/ [R35, 1391] *ESTROGENS AND THEIR ESTERS ARE HANDLED IN BODY IN MUCH THE SAME WAY AS ARE ENDOGENOUS HORMONES. INACTIVATION OF ESTROGEN IS CARRIED OUT MAINLY IN LIVER. CERTAIN PROPORTION ... IS EXCRETED INTO BILE, AND THEN REABSORBED FROM INTESTINE. /ESTROGENS/ [R35, 1391] *NATURAL ESTROGENS CIRCULATE IN BLOOD IN ASSOC WITH PROTEINS, INCL SEX HORMONE-BINDING GLOBULIN AND ALBUMIN. A SIGNIFICANT PROPORTION ... IS IN FORM OF CONJUGATES, PARTICULARLY SULFATE, WHICH ARE EXCRETED BY THE KIDNEY. /ESTROGENS/ [R35, 1391] *Distribution: To most tissues, especially breast, uterine, vaginal, hypothalamic, and pituitary tissues; high affinity for adipose tissue. /Estrogens/ [R19, 1384] *Protein binding: Moderate to high (50 to 80% to albumin and sex hormone binding globulin. /Estrogens/ [R19, 1384] *Elimination: Primarily renal excretion of metabolites, some fecal; undergo extensive enterohepatic recirculation. Prolonged in obese patients. /Estrogens/ [R19, 1384] *Estrogens are excreted in milk. Potential for decreased milk volume and decreased nitrogen and protein content; ... /Estradiol; from table/ [R36, p. 45-12] METB: *TWO NEW METABOLITES, ISOMERIC 2,16 ALPHA-DIHYDROXYESTRONE METHYL ETHERS ... OF ESTRONE HAVE BEEN IDENTIFIED IN BILE OF TREATED RATS. [R37] *YIELDS ESTRONE-3-BETA-D-GLUCURONIDE IN MAN; ESTRONE-3-SULFATE IN MAN. /FROM TABLE/ [R38] *YIELDS 16BETA-HYDROXYESTRONE PROBABLY IN MAN; 17 ALPHA-ESTRADIOL AND 17 BETA-ESTRADIOL IN RAT; ESTRONE-3-BETA-D-GALACTOSIDE AND ESTRONE-3-BETA-D-GLUCOSIDE IN RABBIT. /TABLE/ [R38] *YIELDS 16-EPIESTRIOL AND 2-HYDROXYESTRONE IN MAN. /FROM TABLE/ [R38] *YIELDS 1-(S-GLUTATHIONYL)-2-HYDROXYESTRONE AND 4-(S-GLUTA THIONYL)-2-HYDROXYESTRONE PROBABLY IN RAT; 16 ALPHA-HYDROXYESTRONE IN MAN. /FROMTABLE/ [R38] *IN DOGS, MAJOR METABOLITE OF ESTRONE IN PLASMA WAS ITS GLUCURONIDE, ACCOMPANIED BY SMALL AMT OF ESTRADIOL-17 BETA 3-GLUCURONIDE, ESTRONE SULFATE, AND ESTRADIOL-17 BETA 17-GLUCURONIDE. [R29, 232] *AFTER IP INJECTION OF ESTRONE INTO FEMALE WISTAR RATS, 2-HYDROXYESTRONE GLUCURONIDE WAS MAJOR URINARY METABOLITE. [R29, 232] */Estrone is/ a metabolite of 17-beta-estradiol, possessing considerably less biological activity. [R39, 584] *Biotransformation: Primarily hepatic; some metabolism also occurs in muscle, kidneys, and gonads. The metabolic sites for all synthetic estrogens have not been completely determined, although some seem to undergo hepatic change. /Estrogens/ [R19, 1384] *... Estrone ... undergoes conversion and reduction to estriol, which is the major urinary metabolite. /Estrogens/ [R34, 1420] *... Estrone was converted substantially to estradiol (67%), while on 23% was collected as the parent compound. [R40] *The 17beta-hydroxy steroid dehydrogenase transforms estrone to estradiol reversibly. This enzyme occurred in all tissues of all species examined and is linked to either the cytosolic or microsomal subcellular compartment. In human liver, a NAD-linked 17beta-hydroxy steroid 3-hydrogenase occurs in cytosol and in microsomes, and a further NADP-linked enzyme has been found in cytosol. Hence, estrone and estradiol are largely biologically equivalent; they are also metabolized via the same pathways. [R41] *Using HPLC and paper chromatography, under the experimental conditions used it was found that liver homogenates from female rats were able to convert estrone to various metabolites such as 16 alpha-hydroxyestrone. [R26] ACTN: *INCR IN SYNTHESIS OF VARIOUS TYPES OF RNA AND PROTEIN ... STIMULATION OF DNA SYNTHESIS ... IT IS NOT CLEAR WHETHER PROMINENT ... STIMULATION OF RNA SYNTHESIS RESULT OF INCR RNA POLYMERASE ACTIVITY, INCR CHROMATIN TEMPLATE ACTIVITY, ALTERED NUCLEAR TRANSPORT PHENOMENA, OR COMBINATIONS THEREOF. /ESTROGENS/ [R6, 1429] *At the cellular level, estrogens increase the cellular synthesis of DNA, RNA, and various proteins in responsive tissues. Estrogens reduce the release of gonadotropin-releasing hormone from the hypothalamus, leading to a reduction in release of follicle-stimulating hormone and luteinizing hormone from the pituitary. /Estrogens/ [R19, 1384] *ESTRONE (1X10(-8) M) INHIBITED BOTH CELL DIVISION AND NUCLEOSIDE INCORP INTO DNA OF BREAST CANCER LINE MCF-7. [R42] INTC: *ESTROGEN-RECEPTOR BINDING REACTION IS INHIBITED BY ANTIESTROGENS SUCH AS CLOMIPHENE. ... EFFECTS OF ESTROGENS CAN BE BLOCKED BY INHIBITORS OF RNA SYNTHESIS (DACTINOMYCIN) OR PROTEIN SYNTHESIS (CYCLOHEXIMIDE). /ESTROGENS/ [R6, 1429] *... ACUTE DOSAGE WITH CARBON TETRACHLORIDE ... INHIBITS THE MICROSOMAL HYDROXYLATION OF ... ESTRONE. [R29, 460] *Within the framework of experiments related to the association between dietary fiber and breast cancer an in vitro test system was used to study the binding of estrogens to various fibers (eg cholestyramin, lignin and cellulose) and fiber sources (eg wheat bran, cereals, seeds and legumes). Furthermore, the in vivo apparent digestibility of the different fiber sources was tested using a mobile nylon bag technique in intestine-cannulate pigs. Estradiol-(17) beta bound more strongly to the various fibers than did estrone, estriol or estrone-3-glucuronide. At increasing pH (greater than 7) binding of both estrone and estradiol-(17) beta to wheat bran decreased significantly. Cholestyramine and lignin bound almost all estrogens present in the medium. Linseed (91%), oats (83%), barley chaff (88%) and wheat bran (82%) are other excellent binders of estradiol-(17) beta. Corn rye and white wheat flour showed lower binding capacity with a relatively low affinity. Cereals with the highest percentage of lignin in the fiber (greater than 3%) were also the fiber sources with the lowest apparent digestibility. Estrogens bound with the highest affinity (relative to bovine serum albumin) to these fiber sources. Together with wheat bran and lignin, oats, linseed and soybean seem to be products with good perspectives for in vivo evaluation of the lowering effect of dietary fiber on estrogen exposure of estrogen sensitive tissues. [R43] *Estrogens may interfere with the effects of bromocriptine; dosage adjustment may be necessary. /Estrogens/ [R19, 1385] *Concurrent use with estrogens may increase calcium absorption and exacerbate nephrolithiasis in susceptible individuals; this can be used to therapeutic advantage to increase bone mass. /Estrogens/ [R19, 1385] *Concurrent use /of glucocorticoid corticosteroids/ with estrogens may alter the metabolism and protein binding of the glucocorticoids, leading to decreased clearance, increased elimination half-life, and increased therapeutic and toxic effects of the glucocorticoids; glucocorticoid dosage adjustment may be required during and following concurrent use. /Estrogens/ [R19, 1385] *Concurrent use /of corticotropin (chronic therapeutic use)/ with estrogens may potentiate the anti-inflammatory effects of endogenous cortisol induced by corticotropin. /Estrogens/ [R19, 1385] *Estrogens have been reported to inhibit cyclosporine metabolism and thereby increase plasma concentrations of cyclosporine, possibly increasing the risk of hepatotoxicity and nephrotoxicity; concurrent use is recommended only with great caution and frequent monitoring of blood cyclosporine concentrations and liver and renal function. /Estrogens/ [R19, 1385] *Concurrent use of these medications /hepatotoxic medications, especially dantrolene and isoniazid/ with estrogens may increase the risk of hepatotoxicity and fatal hepatitis has occurred; risk may be further increased with use in females over 35 years of age, prolonged use, or use in patients with a history of liver disease. /Estrogens/ [R19, 1385] *Estrogens should be used with caution with medications that cause pancreatitis, especially if the patient has pre-existing risk factors such as high triglyceride concentrations; however, physiologic doses of estrogen would not be expected to induce pancreatitis. /Estrogens/ [R19, 1385] *Ritonavir has decreased the area under the plasma concentration-time curve (AUC) of ethinyl estradiol by 40%; similar effects may occur with other estorgens or with other protease inhibitors. /Estrogens/ [R19, 1385] *Data from studies on tobacco smoking and the use of high-dose estrogen oral contraceptives indicate that there is an increased risk of serious cardiovascular side effects, including cerebrovascular accident, transient ischemic attacks, thrombophlebitis, and pulmonary embolism; risk increases with increasing tobacco usage and with age, especially in women over 35 years of age; it is not known whether any elevation of risk occurs with tobacco smoking during the use of ovarian hormone therapy. Metabolism of estrogens may also be increased by smoking, resulting in a decreased estrogenic effect. /Estrogens/ [R19, 1385] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Estrogens may be effective in the prevention of cardiovascular disease in postmenopausal women. /Estrogens; NOT included in US product labeling/ [R19, 1383] *Estrone ... /is/ indicated to replace estrogen in the treatment of atrophic vaginitis, vulvar atrophy (also called kraurosis vulvae), and moderate to severe vasomotor symptoms associated with menopause. ... /Included in US product labeling/ [R19, 1383] *Estrone ... /is/ indicated to replace estrogen in the treatment of female hypogonadism, primary ovarian failure, or ovariectomy. ... /Included in US product labeling/ [R19, 1383] *Estrone ... /is/ indicated for treatment of advanced prostatic carcinoma. /Included in US product labeling/ [R19, 1383] *Estrone /is/ indicated in the treatment of abnormal uterine bleeding associated with a hypoplastic or atrophic endometrium without organic pathology. Continuous treatment with estrogen without a progestin may cause abnormal uterine bleeding with or without organic pathology. /Included in US product labeling/ [R19, 1383] *OSTEOPOROSIS ... SENILE OSTEOPOROSIS ... / and / ... POSTMENOPAUSAL OSTEOPOROSIS. ... AFTER SEVERAL MO OF ESTROGEN REPLACEMENT IN POSTMENOPAUSAL PATIENTS, CALCIUM BALANCE BECOMES POSITIVE AND BONE RESORPTION DECR TO NORMAL, AND INCIDENCE OF HIP FRACTURES IS DECR. /ESTROGENS/ [R35, 1394] *MAJOR USE OF ESTROGENS IS IN COMBINATION WITH PROGESTINS AS ORAL CONTRACEPTIVES. ... TREATMENT /DURING AND/OR FOR MENOPAUSE/ WITH ESTROGEN IS SPECIFIC AND EFFECTIVE. ... SENILE OR ATROPHIC VAGINITIS, OFTEN ASSOC WITH CHRONIC INFECTION OF ATROPHIC STRUCTURES, RESPONDS WELL TO ESTROGEN. /ESTROGENS/ [R35, 1392] *Dysmenorrhea can be relieved by inhibition of ovulation with estrogen. ... Although estrogen can be used with some success /in endometriosis/, the cyclic use of a progestin is logically preferred. /Estrogen/ [R35, 1393] *The common form of acne is a feature of puberty in both sexes, and androgens seem to be the essential factor, operating through stimulation of sebaceous glands. Treatment with estrogen is effective in both sexes by suppressing gonadotropins and gonadal androgen secretion, but its usefulness in the male is obviously limited. /Estrogen/ [R35, 1394] *INTRAMUSCULAR: ... FOR DYSFUNCTIONAL UTERINE BLEEDING, ... SEVERAL DAYS UNTIL BLEEDING ... CONTROLLED, FOLLOWED BY ADMIN OF PROGESTAGEN FOR ONE WEEK. /ESTROGENS/ [R44] *FOR PROSTATIC CARCINOMA /ESTROGENS/ [R9] *Estrogen indicated for im use for moderate to severe vasomotor symptoms associated with the menopause, atrophic vaginitis, kraurosis vulvae, female hypogonadism, female castration, and primary ovarian failure. [R8] *MEDICATION (VET): estrogenic hormone therapy. [R39, 585] *ESTROGENS ARE LARGELY RESPONSIBLE FOR CHANGES THAT TAKE PLACE @ PUBERTY IN GIRLS, AND THEY GO A LONG WAY TOWARD ACCOUNTING FOR THE ATTRIBUTES OF FEMININITY. BY A DIRECT ACTION, THEY CAUSE GROWTH AND DEVELOPMENT OF VAGINA, UTERUS, AND FOLLOPIAN TUBES. /ESTROGENS/ [R35, 1386] *Alteration of the hormonal environment can be used as a palliative measure in the therapy of metastatic breast cancer. ... Administration of estogens can prolong both the quality and the duration of life. Favorable responses can be obtained in about 60 to 70% of patients if estrogen or progesterone receptors are present in the tumor, while such responses are observed in only 10 to 20% if receptors are absent. /Estrogen/ [R35, 1395] *Since the prostate is a target organ for the actions of androgens, the inhibition of androgen secretion can be used as palliative therapy in patients with metastatic prostatic carcinoma. This can be accomplished by orchiectomy and/or the administration of an estrogen such as diethylstilbestrol. /Estrogen/ [R35, 1395] *Conjugated estrogens have been used to induce ovulation in anovulatory women. They have also been used as partially sucessful contraceptives when given within 72 hours of unprotected, midcycle coitus. /Estrogens, conjugated/ [R45, 340] WARN: *Nausea and vomiting ... fullness and tenderness of the breasts and edema may occur, ... severe migraine in some. [R34, 1421] *FREQUENT, MILD SIDE EFFECTS ... DIZZINESS, HEADACHE, DISCOMFORT IN BREAST, AND WT GAIN. /ESTROGENS/ [R35, 1407] *ESTROGENS EMPLOYED MEDICALLY HAVE IN RARE INSTANCES CAUSED TRANSITORY IMPAIRMENT OF ACCOMMODATION FOR NEAR /VISION/. [R46] *... ESTRONE (FOLLICULIN) HAS BEEN CLAIMED TO HAVE ADVERSE EFFECT ON GLAUCOMA WHEN GIVEN IN LARGE AMT OR INJECTED TO FORM A DEPOT. [R46] *Estrogens are not recommended for use during pregnancy or during the immediate postpartum period. Studies suggest an association of congenital malformations with use of some estrogens during pregnancy. (FDA Pregnancy Category X). ... Patients who become pregnant while taking estrogens should be informed of the potential risks to the fetus. /Estrogens/ [R19, 1384] *Estrogens are distributed into breast milk. Use by breast-feeding women is not recommended with estrogen doses larger than those used in oral contraceptives. /Estrogens/ [R19, 1384] *Estrogens may predispose the patient to bleeding of the gingival tissues. In addition, gingival hyperplasia may occur during estrogen therapy, usually starting as gingivitis or gum inflammation. A strictly enforced program of teeth cleaning by a professional, combined with plaque control by the patient, will minimize growth rate and severity of gingival enlargement. /Estrogens/ [R19, 1385] *Nausea has been frequently associated with estrogen therapy. Other adverse GI effects include vomiting, abdominal cramps, bloating, and diarrhea. Changes in appetite and changes in weight may also occur. /Estrogens/ [R7, 2689] *Acute pancreatitis has been reported in a few women receiving estrogens alone or in conjunction with a progestin. It has been postulated that increased serum triglyceride concentrations (associated wither with familial defects of lipoprotein metabolism or induced by estrogen therapy), may have caused such disease; therefore, some clinicians suggest that serum lipid concentrations be monitored prior to and during estrogen therapy. In addition, some clinicians recommend that estrogen therapy not be used in women whose serum triglyceride concentrations exceed 200 mg/dl. If acute pancreatitis occurs, estrogens should be discontinued. The risk of gallbladder disease appears to be increased 2- to 4-fold in postmenopausal women receiving estrogen replacement therapy. /Estrogens/ [R7, 2689] *The most frequent adverse dermatologic reaction associated with estrogen therapy is chloasma or melasma. Women who have had melasma during pregnancy appear to be most susceptible. Irregular brown macules may develop slowly on the face within 1 month to 2 years following initiation of estrogen therapy. The macules fade more slowly than in melasma gravidarum and may be permanent. Other dermatologic reactions include erythema multiform, erythema nodosum, and hemorrhagic eruption. Hirsutism and alopecia have also occurred. Porphyria cutanea has reportedly been adversely affected in some women receiving estrogen therapy. /Estrogens/ [R7, 2689] *There is no evidence that estrogen replacement therapy in postmenopausal women is associated with elevated blood pressure; in fact, unopposed estrogen therapy in postmenopausal women has been associated with blood pressure reductions in some studies. However, increases in blood pressure may occur in some women receiving estrogens, particularly if high dosages are used. Blood pressure elevations are usually minor, but clinically important hypertension may occur in some women. Elevated blood pressure may gradually decrease or persist after discontinuance of estrogen therapy. The precise cause of increased blood pressure is not known, but it may result from a stimulatory effect of estrogen on the renin-angiotensin system. /Estrogens/ [R7, 2689] *Women receiving high dosages of estrogens or those with a history of hypertension, preexisting renal disease, a history of toxemia or elevated blood pressure during pregnancy, a familial tendency toward hypertension or its consequences, or a history of excessive weight gain or fluid retention during the menstrual cycle may be increased risk of developing elevated blood pressure during estrogen therapy and, therefore, should be monitored closely. Even though elevated blood pressure may remain within the normal range, the clinical implications of elevations should be considered in all patients. All women, but particularly those with other risk factors for cardiovascular disease or stroke and those receiving high dosages of estrogens, should have blood pressure measurements before an estrogen is prescribed and at regular intervals during therapy. Estrogens should be discontinued if the patient becomes hypertensive during therapy. /Estrogens/ [R7, 2689] *Oral contraceptive use is associated with an increased risk of thromboembolic and thrombotic disorders including thrombophlebitis, pulmonary embolism, stroke, subarachnoid hemorrhage, and myocardial infarction. Retinal thrombosis and mesenteric thrombosis also have been reported in women receiving oral contraceptives. An increased risk of postsurgery thromboembolic complications has also been reported in patients receiving oral contraceptives. /Estrogens/ [R7, 2689] *Estrogens may cause some degree of fluid retention and edema. Estrogen therapy should therefore be used with caution in patients with conditions that might be aggravated by fluid retention. /Estrogens/ [R7, 2690] *Decreased glucose tolerance has occurred in women receiving estrogen-containing oral contraceptives and may occur in patients receiving large dosages of estrogens. Prediabetic and diabetic patients should be carefully monitored during estrogen therapy. /Estrogens/ [R7, 2690] *Breakthrough bleeding, spotting, changes in menstrual flow, missed menses (during use), or amenorrhea (after use) may occur in women receiving estrogen therapy. Dysmenorrhea and a premenstrual-like syndrome also have been reported. In patients with breakthrough bleeding or irregular vagianl bleeding, nonfunctional causes should be considered. Appropriate diagnostic procedures should be performed in patients with undiagnosed persistent or recurrent vaginal bleeding. /Estrogens/ [R7, 2690] *Changes in cervical erosion and secretions may occur during estrogen therapy. In addition, preexisting uterine leiomyoma may increase in size in women receiving estrogens. A cystitis-like syndrome has been reported but has not been definitely attributed to estrogens. An increased incidence of Candida vaginitis has been associated with estrogen therapy. /Estrogens/ [R7, 2690] *Headache, especially migraine headache, may occur during estrogen therapy. Estrogens should be discontinued and the cause evaluated when migraine occurs or is exacerbated, or when a new headache pattern develops that is recurrent, persistent, and/or severe. /Estrogens/ [R7, 2690] *Estrogens have been reported to produce keratoconus (steepening or corneal curvature) and intolerance to contact lenses. Contact lenses wearers who develop visual disturbances or changes in lens tolerance during estrogen therapy should be assessed by an ophthalmologist; temporary or permanent cessation of contact lens wear should be considered. /Estrogens/ [R7, 2690] *Breast changes, including tenderness, enlargement, and secretion, may occur during estrogen therapy. The incidence of breast pain may be increased in patients receiving estrogens in conjunction with progestins compared with those receiving estrogens alone; breast pain was reported in about 33% of women receiving conjugated estrogens concomitantly with medroxyprogesterone acetate compared to 12% of women receiving unopposed conjugated estrogen therapy. /Estrogens/ [R7, 2690] *Use of estrogens, especially in large dosages, may be associated with an increased risk of several serious conditions including thromboembolism, stroke, myocardial infarction, liver tumor, gallbladder disease, visual disturbances, fetal abnormalities, malignancy, and hypertension. ... If a progestin is administered concomitantly with estrogen therapy, potential risks may include adverse effects on lipid metabolism, glucose tolerance, or possible enhancement of mitotic activity in breast epithelial tissue. /Estrogens/ [R7, 2690] *Estrogens may predispose the patient to bleeding of the gingival tissues. In addition, gingival hyperplasia may occur during estrogen therapy, usually starting as gingivitis or gum inflammation. /Estrogen/ [R19, 1385] *[US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1348 (1992)] Adverse effects ... incidence more frequent: Breast pain or tenderness, enlargement of breasts, peripheral edema (swelling of feet and lower legs, rapid weight gain). /Estrogen/ [R19, 1348] *[US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.I p.1348 (1992)] Adverse effects ... incidence less frequent or rare: Amenorrhea (stopping of menstrual bleeding) or breakthrough bleeding (heavier vaginal bleeding between regular menses) or menorrhagia (prolonged or heavier menses) or spotting (lighter vaginal bleeding between regular menses); Breast tumors (breast lumps, discharge from breast); Chorea (involuntary jerky muscular movements); Gallbladder obstruction or Hepatitis (yellow eyes or skin; pains in stomach, side, or abdomen); Local irritation, such as swelling, redness, or itching. /Estrogen/ [R19, 1348] *Withdrawal bleeding will occur in many postmenopausal patients with an intact uterus who are placed on cyclic estrogen therapy with a progestin. ... Signs of potential side effects, /include/ especially menstrual irregularities chorea, breast tumors, peripheral edema, gallbladder obstruction, or hepatitis. /Estrogen/ [R19, 1348] *Contraindicated in pregnancy. A study found an association between estrogen exposure and cardiovascular defects, eye and ear anomalities, and Down's syndrome. /Estradiol; from table/ [R36, p. 44-12] *Long-term heparin therapy during pregnancy has been associated with maternal osteopenia. [R45, 412] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *OCCURS IN PREGNANCY URINE OF WOMEN AND MARES, IN FOLLICULAR LIQUOR OF MANY ANIMALS, IN HUMAN PLACENTA, IN URINE OF BULLS AND STALLIONS, IN PALM-KERNEL OIL. [R39, 584] *... FROM MEXICAN YAM ... VIA 16-DEHYDROPREGNENOLONE ACETATE. [R1] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R47] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION OF ESTRONE AS SODIUM ESTRONE SULFATE /AND AS ESTRONE BY SPECTROPHOTOMETRY/. [R48] *STEROLS WERE IDENTIFIED IN DATE PALM POLLEN OF PHOENIX DACTYLLIFERA. ESTERONE WAS IDENTIFIED BY TLC. [R49] *Determination of estrone by using liquid chromatography equipped with a 280 nm detector. The flow rate is about 1 ml/min. [R50] *Sample matrix: Aqueous suspensions. Sample preparation: Dissolve (acetone); filter; derivative (dansyl). Assay procedure: Fluorimetry at 502 nm. Limit of detection: 0.5 ug/ml. /From table/ [R51] *Sample matrix: Bulk chemical. Sample preparation: Derivative (dimethylphosphinyl); purify (TLC). Assay procedure: GC (alkaline flame ionization detector). Limit of detection: 10 pg. /From table/ [R51] CLAB: *Sample matrix: Serum. Sample preparation: Extract. Assay procedure: TLC. Limit detection: 20 ng. /From table/ [R52] *Sample matrix: Plasma. Sample preparation: Add radiolabelled estrone; hydrolyse(hydrochloric acid); perform a series of extractions, washings and evaporations; TLC; elute (diethyl ether); add Ittich reagent. Assay procedure: Fluorimetry. Limit of detection: 50 ng (1 ml sample). /From table/ [R52] *Sample matrix: Urine. Sample preparation: Hydrolyse (enzyme); extract (ethyl acetate-hexane-ethanol); column chromatography (anion-exchange); derivatize(trimethylsilyl). Assay procedure: Gas chromatography/flame ionization detector. Limit of detection: 40 ug/l (50 ml sample). /From table/ [R53] *Measurement of estrone in human plasma by capillary gas chromatography-negative ion chemical ionization mass spectrometry. Selected ion monitoring of the intense negative molecular ions enabled levels of 1 ng/ml to be measured with relative standard deviation of 9.3% for estrone. [R54] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Services, Research Triangle Park, NC. (2000) SO: R1: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 916 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 455 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 632 R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA13 (95) 120 R5: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 348 R6: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R7: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 99. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements). R8: Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 66 R9: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 942 R10: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-233 R11: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-150 R12: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 157 R13: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-290 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 600 R15: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1302 R16: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R17: DHHS/NTP; Sixth Annual Report on Carcinogens (Summary) p.vii (1991) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V72 503 (1999) R19: USP. Convention. USPDI - Drug Information for the Health Care Professional. 19th ed. Volume I.Micromedex, Inc. Englewood, CO., 1999. Content Prepared by the U.S. Pharmacopieal Convention, Inc. R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V6 128 (1979) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 352 (1979) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 353 (1979) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V221 353 (1979) R24: National Research Council. Drinking Water and Health, Volume 6. Washington, D.C.: National Academy Press, 1986. 46 R25: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 238 R26: Arts CJ et al; J Steroid Biochem 36 (6): 527-31 (1990) R27: Santner SJ et al; Int J Cancer 46 (1): 73-8 (1990) R28: Beyer BK et al; Toxicol Appl Pharmacol 98 (1): 113-27 (1991) R29: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 354 (1979) R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 355 (1979) R32: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V72 473 (1999) R33: Martin, H. and C.R. Worthing (eds.). Pesticide Manual. 5th ed. Worcestershire, England: British Crop Protection Council, 1977. 385 R34: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R35: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R36: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995. R37: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 281 R38: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. 0-6 R39: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R40: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995. 532 R41: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 356 (1979) R42: JOZAN S ET AL; J STEROID BIOCHEM 10 (3): 341-2 (1979) R43: Arts CJ et al; J Steroid Biochem Mol Biol 38 (5): 621-8 (1991) R44: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 561 R45: Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams and Wilkins 1994. R46: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 457 R47: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R48: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/743 R49: MAHRAN GH ET AL; PLANTA MED 29 (MAR): 171-5 (1976) R50: USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990. 537 R51: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 349 (1979) R52: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 346 (1979) R53: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V21 350 (1979) R54: Robinson PR et al; J High Resolut Chromatogr Chromatogr Commun 10 (1): 6-11 (1987) RS: 54 Record 236 of 1119 in HSDB (through 2003/06) AN: 3383 UD: 200302 RD: Reviewed by SRP on 11/07/1991 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PHENYLEPHRINE- SY: *ADRIANOL-; *BENZENEMETHANOL, 3-HYDROXY-ALPHA-((METHYLAMINO)METHYL)-, (R)-; *BENZYL ALCOHOL, M-HYDROXY-ALPHA-((METHYLAMINO)METHYL)-, (-)-; *L-ALPHA-HYDROXY-BETA-METHYLAMINO-3-HYDROXY-L-ETHYLBENZENE-; *L-M-HYDROXY-ALPHA-((METHYLAMINO)METHYL)BENZYL ALCOHOL; *(-)-M-HYDROXY-ALPHA-(METHYLAMINOMETHYL)BENZYL ALCOHOL; *L-1-(M-HYDROXYPHENYL)-2-METHYLAMINOETHANOL; *L-(3-HYDROXYPHENYL)-N-METHYLETHANOLAMINE; *ISOPHRIN-; *MESATON-; *MESATONE-; *METAOXEDRIN-; *METAOXEDRINE-; *METASYMPATOL-; *METASYNEPHRINE-; *M-METHYLAMINOETHANOLPHENOL-; *MEZATON-; *NEOSYNEPHRINE-; *M-OXEDRINE-; *(-)-PHENYLEPHRINE; *(R)-PHENYLEPHRINE; *M-SYMPATHOL-; *M-SYMPATOL-; *M-SYNEPHRINE-; *VISADRON- RN: 59-42-7 MF: *C9-H13-N-O2 ASCH: Phenylephrine hydrochloride; 61-76-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF M-HYDROXYPHENACYL BROMIDE WITH METHYLAMINE FOLLOWED BY CATALYTIC HYDROGENATION, THEN DISSOLUTION IN ETHER, AND TREATMENT WITH HYDROGEN CHLORIDE [R1] *MAY BE PREPD FROM M-HYDROXY-OMEGA-CHLOROACETOPHENONE AND METHYLAMINE. SYNTHESIS FROM M-BENZYLOXYBENZALDEHYDE. /PHENYLEPHRINE HYDROCHLORIDE/ [R2] *M-HYDROXYPHENACYL BROMIDE IS CONDENSED WITH METHYLAMINE VIA DEHYDROBROMINATION AND CARBONYL GROUP IS THEN REDUCED TO CARBINOL VIA CATALYTIC HYDROGENATION. PHENYLEPHRINE SO FORMED IS DISSOLVED IN SUITABLE SOLVENT SUCH AS ETHER AND TREATED WITH HYDROGEN CHLORIDE. /PHENYLEPHRINE HYDROCHLORIDE/ [R3] FORM: *IT IS AVAILABLE AS STERILE SOLN (10 MG/ML) FOR PARENTERAL USE ... /PHENYLEPHRINE HYDROCHLORIDE/ [R4] *GRADE: USP. /PHENYLEPHRINE HYDROCHLORIDE/ [R5] MFS: +Ganes Chemicals, Inc, Hq, 1114 Ave of the Americas, New York, NY 10036, (212) 391-2580; Production site: 611 Broad St, Carlstadt, NJ 07072 [R6] +Sterling Drug, Inc, Sterling Organics Div, 90 Park Ave, New York, NY 10016 (212) 907-2000 [R7] USE: +MEDICATION PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 9.08X10+5 G [R1] *(1978) PROBABLY GREATER THAN 9.08X10+5 G [R1] *(1988) No data published for phenylephrine (bitartrate, hydrochloride, tannate) [R7] U.S. IMPORTS: *(1976) 1.30X10+6 G (PRINCPL CUSTMS DISTS) [R1] *(1978) 4.43X10+6 G (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MP: *169-172 DEG C [R2] MW: *167.23 [R8] SPEC: *MAX ABSORPTION (PH 9.4 BORATE BUFFER): 237 NM (A= 258, 1%, 1 CM); 291 NM (A= 140, 1%, 1 CM); MAX ABSORPTION (0.2 M H3BO3): 272 NM (A= 83, 1%, 1 CM) [R9, 818] OCPP: *CRYSTALS; BITTER; MP: 140-145 DEG C; FREELY SOL IN WATER OR ALCOHOL; SPECIFIC OPTICAL ROTATION: -46.2 TO -47.2 DEG @ 25 DEG C/D; AQ SOLN IS NEUTRAL TO LITMUS PAPER /PHENYLEPHRINE HYDROCHLORIDE/ [R2] *WHITE TO OFF-WHITE, CRYSTALLINE POWDER; PKA: 7.6 /PHENYLEPHRINE HYDROCHLORIDE/ [R3] *ODORLESS, /PHENYLEPHRINE HYDROCHLORIDE/ [R5] *FREELY SOL IN GLYCERIN /PHENYLEPHRINE HYDROCHLORIDE/ [R9, 92] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- STRG: *SENSITIVE TO LIGHT. /PHENYLEPHRINE HYDROCHLORIDE/ [R9, 93] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *WITH SYSTEMIC ADMIN, OVERDOSAGE CAN CAUSE ... VENTRICULAR EXTRA-SYSTOLES AND BURSTS OF VENTRICULAR TACHYCARDIA, PALLOR, WEAKNESS, AND RESPIRATORY DISTRESS. [R3] *SYSTEMIC REACTIONS TO 10% PHENYLEPHRINE HYDROCHLORIDE EYEDROPS HAVE BEEN REPORTED IN FEW CASES, CONSISTING OF TEMPORARY INCR IN BLOOD PRESSURE AND PULSE RATE, WITH HEADACHE, TREMBLING, AND PERSPIRATION. /PHENYLEPHRINE HYDROCHLORIDE/ [R10, 726] *POSSIBLE ADVERSE REACTIONS TO TOPICAL OCULAR 10% PHENYLEPHRINE INCLUDE SEVERE HYPERTENSION, SUBARACHNOID HEMORRHAGE, AND VENTRICULAR ARRHYTHMIA. /PHENYLEPHRINE HYDROCHLORIDE/ [R11, (1968)] *... PROLONGED USE OFTEN RESULTS IN CHRONIC RHINITIS. /SYMPATHOMIMETIC AMINES/ [R12, 506] NTOX: *... EMBRYONATED CHICKEN EGGS /WERE USED/ AS TEST OBJECT FOR STRUCTURE-FORMATION STUDY OF TERATOGENIC PROPERTIES OF SYMPATHOMIMETIC AMINES. IN THIS SYSTEM... PHENYLEPHRINE ... EFFECTED TERATOGENIC CHANGES THAT CONSISTED OF CEPHALIC HEMATOMA AND SKIN AND EXTREMITY HEMORRHAGES. [R13, 325] *... SYMPATHOMIMETIC DRUGS ... IF GIVEN IN EXCESSIVE AMT, PRODUCE SYMPTOMS OF SYMPATHETIC STIMULATION, MANIFESTED BY ANXIETY AND RESTLESSNESS. IF DOSAGE IS LARGE, MUSCULAR TREMORS AND EVEN CONVULSIONS MAY OCCUR. /SYMPATHOMIMETIC DRUGS/ [R14] NTP: *Carcinogenesis studies of USP grade phenylephrine hydrochloride were conducted by administering diets containing the chemical (99% pure) to F344/N rats and B6C3F1 mice of each sex ... for 2 yr. ... Doses of 0, 620, and 1,250 ppm for rats and 0, 1,250, and 2,500 ppm for mice. ... In the 2 yr studies, the approx amount of /cmpd/ consumed per day was 24 mg/kg for low dose rats, 50 mg/kg for high dose rats, 133 mg/kg for low dose mice, and 270 mg/kg for high dose mice. ... Under the conditions of these 2 yr studies, there was no evidence of carcinogenicity of phenylephrine hydrochloride for male or female F344/N rats given 620 or 1,250 ppm in feed or for male or female B6C3F1 mice given 1,250 or 2,500 ppm in feed. ... /Phenylephrine hydrochloride/ [R15] ADE: *PHENYLEPHRINE IS ABSORBED ORALLY ... BY IV ROUTE DURATION OF ACTION IS ABOUT 15-20 MIN AND BY IM ROUTE 30-60 MIN. [R3] METB: *YIELDS ADRENALINE IN RABBIT; N-METHYLPHENYLETHANOLAMINE-3-YL SULFATE IN MAN. [R16] *YIELDS N-METHYL-M-SYMPATOL IN RABBIT; IN MONKEY. [R16] *SINCE L-PHENYLEPHRINE ALREADY POSSESSES PHENOLIC HYDROXYL, IT IS READILY CONJUGATED IN HUMANS, PRINCIPALLY AS SULFATE WITH SOME GLUCURONIDE, AND EXCRETED IN URINE. /L-PHENYLEPHRINE/ [R13, 123] ACTN: *PHENYLEPHRINE IS POWERFUL ALPHA-RECEPTOR STIMULANT WITH LITTLE EFFECT ON BETA RECEPTORS OF HEART. DIRECT ACTION ON RECEPTORS ACCOUNTS FOR GREATER PART OF ITS EFFECTS, ONLY SMALL PART BEING DUE TO ITS ABILITY TO RELEASE NOREPINEPHRINE. CENTRAL STIMULANT ACTION IS MINIMAL. [R12, 503] *IT ELEVATES BLOOD PRESSURE THROUGH ARTERIOLAR CONSTRICTION; IT ALSO CONSTRICTS CAPACITANCE VESSELS AND INCR VENOUS RETURN TO HEART. HEART RATE IS SLOWED REFLEXLY ... THIS REFLEX BRADYCARDIA IS BASIS OF USE OF PHENYLEPHRINE IN TREATMENT OF PAROXYSMAL ATRIAL TACHYCARDIA. [R3] *ADRENERGIC NASAL DECONGESTANTS ACT BY STIMULATING ALPHA ... ADRENERGIC RECEPTORS OF VASCULAR SMOOTH MUSCLE, THUS CONSTRICTING DILATED ARTERIOLES WITHIN NASAL MUCOSA AND REDUCING BLOOD FLOW IN ENGORGED, EDEMATOUS AREA. /ADRENERGICS/ [R17, 644] */SYMPATHOMIMETICS SLOW/ ... ABSORPTION OF LOCAL ANESTHETIC BY LOCAL VASOCONSTRICTION AND THUS PROLONG DURATION OF ANESTHESIA, DECR AMT OF ANESTHETIC NEEDED, AND LESSEN DANGER OF SYSTEMIC TOXICITY. /SYMPATHOMIMETICS/ [R12, 506] INTC: *CAUTION: CONCOMITANT USE IN ATROPINIZED PATIENTS CAN ENHANCE PRESSOR EFFECTS AND INDUCE TACHYCARDIA IN SOME PATIENTS. [R11, (1978)] *Markedly increased pressor response occurs when iv phenylephrine is administered to patients receiving tricyclics. /From table/ [R18, 407] *Reserpine alkaloids interact with ... phenylephrine /and/ may increase effects. [R18, 296] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Adrenergic alpha-Agonists; Cardiotonic Agents; Mydriatics; Nasal Decongestants; Sympathomimetics; Vasoconstrictor Agents [R19] *PHENYLEPHRINE IS USED MAINLY AS NASAL DECONGESTANT, PRESSOR AGENT IN HYPOTENSIVE STATES, MYDRIATIC, LOCAL VASOCONSTRICTOR (0.005%) IN SOLN OF LOCAL ANESTHETICS, AND IN RELIEF OF PAROXYSMAL ATRIAL TACHYCARDIA. [R12, 503] *FOR TREATMENT OF HYPOTENSION DURING SPINAL ANESTHESIA ... ADMIN IM. RATE OF IV INFUSION IN HYPOTENSIVE STATES SHOULD BE REGULATED ACCORDING TO PATIENT'S RESPONSE. [R12, 503] *PRESSOR ACTIONS ... HAS BEEN USED IN TREATMENT OF SHOCK. AS WITH ALL VASOCONSTRICTORS, THERE IS SERIOUS QUESTION WHETHER PHENYLEPHRINE SHOULD BE USED TO TREAT NOT ONLY HYPOVOLEMIC BUT ALSO TRAUMATIC, ENDOTOXIN, AND CARDIOGENIC SHOCK, EVEN WHEN PLASMA VOL IS MAINTAINED. [R3] *LOCAL APPLICATION ... TO CONJUNCTIVA IS USED TO DILATE PUPIL ... MYDRIATIC EFFECT OF ... PHENYLEPHRINE (1-2%), LASTS FOR ONLY FEW HR. ... SYMPATHOMIMETIC MYDRIATICS ARE ALSO USED TO REDUCE INCIDENCE OF POSTERIOR SYNECHIAE IN UVEITIS ... [R12, 510] *SUGGESTED GUIDELINE FOR CLINICAL USE BASED ON AVAILABLE DATA: ONLY 1 TOPICAL APPLICATION OF 10% SOLN IS ALLOWABLE/HR TO EACH EYE. [R11, (1978)] *CHRONIC SIMPLE GLAUCOMA AND SECONDARY GLAUCOMA REQUIRE CAREFUL CONSIDERATION OF NEEDS OF INDIVIDUAL PATIENT IN SELECTING DRUG OR COMBINATION OF DRUGS EMPLOYED. CHOICES AVAILABLE INCL ... PHENYLEPHRINE, 10%. /IT REDUCES/ ... INTRAOCULAR PRESSURE BOTH BY INCR OUTFLOW AND BY DECR RATE OF SECRETION OF AQUEOUS HUMOR. [R12, 461] *PHENYLEPHRINE MAY BE USED IN MILD POSTOPERATIVE INFLAMMATION (EG, AFTER IRIDECTOMY). AFTER SURGERY FOR CONGENITAL CATARACTS, PROLONGED ADMIN OF BOTH ATROPINE (OR SCOPOLAMINE) AND PHENYLEPHRINE HAS BEEN RECOMMENDED. [R17, 939] *LOCAL VASOCONSTRICTOR ACTIONS ... ARE USED FOR ... SCLEROCONJUNCTIVAL DECONGESTION, AND UVEAL DECONGESTION. [R3] *SOME NASAL DECONGESTANTS AND ... USUAL CONCN AS NASAL DROPS OR SPRAYS ARE AS FOLLOWS ... PHENYLEPHRINE, 0.125, 0.25, and 0.5%. [R12, 503] *ATTACK OF PAROXYSMAL ATRIAL OR NODAL TACHYCARDIA MAY BE ENDED BY REFLEX VAGAL DISCHARGE CAUSED BY PRESSOR RESPONSES TO PHENYLEPHRINE... [R12, 508] *GIVEN BEFORE SPINAL ANESTHESIA, IM INJECTIONS OF ... PHENYLEPHRINE ... EFFECTIVE IN PREVENTING SUBSTANTIAL FALL IN BLOOD PRESSURE ... THIS IS NOT RECOMMENDED AS ROUTINE PROCEDURE, BUT ONLY IN THOSE CASES WHERE SIGNIFICANT FALL IN BLOOD PRESSURE IS PREDICTABLE. [R12, 506] *SUGGESTED GUIDELINE FOR CLINICAL USE: ONLY USE 2.5% SOLN IN INFANTS AND ELDERLY. [R11, (1978)] WARN: *TREATMENT WITH SYMPATHOMIMETICS IS UNWISE IN CASES OF HYPOTENSION OCCURRING IN PATIENTS UNDER GENERAL ANESTHESIA WITH CYCLOPROPANE, HALOTHANE, AND OTHER DRUGS THAT SENSITIZE HEART TO ARRHYTHMIC ACTION. EVEN FEEBLE CARDIAC-STIMULANT ACTION OF PHENYLEPHRINE MAY ... PPT VENTRICULAR ARRHYTHMIAS. [R12, 506] *ADMIN ... FOR THEIR PRESSOR EFFECT MAY BE USEFUL EMERGENCY MEASURE ... IN CERTAIN HYPOTENSIVE STATES (EG, IN ACUTE HEMORRHAGE). ... THIS THERAPY ... CAN OBSCURE EXTEND OF BLOOD VOL REPLACEMENT REQUIRED AND CAN ITSELF CAUSE LOSS OF FLUID FROM VASCULAR COMPARTMENT. ... INCR RISK OF FURTHER CIRCULATORY DETERIORATION. /SYMPATHOMIMETICS/ [R12, 506] *ALL HAVE DISADVANTAGE THAT THEIR USE /AS DECONGESTANTS/ MAY BE FOLLOWED BY "AFTERCONGESTION" AND THAT PROLONGED USE OFTEN RESULTS IN CHRONIC RHINITIS. /SYMPATHOMIMETIC AMINES/ [R12, 506] *IN CONCN PRESENT IN DECONGESTANT PRODUCTS, ADRENERGIC DRUGS RARELY CAUSE SERIOUS UNTOWARD EFFECTS. HOWEVER, PROLONGED OR INDISCRIMINATE USE OF THESE PREPN SHOULD BE AVOIDED, AS THIS COULD LEAD TO NEGLECT OF SYMPTOMS OF SERIOUS EYE DISEASE. /ADRENERGICS/ [R17, 994] *BASED ON AVAILABLE DATA, IT IS SUGGESTED THAT PRACTICE OF USING 10% SOLN TO IRRIGATE, WITH CONJUNCTIVAL PLEDGET, OR INJECTED SUBCONJUNCTIVALLY SHOULD BE DISCOURAGED. [R11, (1978)] *TREATMENT OF ACUTE CARDIAC FAILURE DOES NOT INCL ... SYMPATHOMIMETIC DRUGS. /SYMPATHOMIMETICS/ [R12, 506] *IN PATIENTS WITH CORONARY INSUFFICIENCY IT CAN CAUSE ANGINAL PAIN. IT SHOULD ALSO BE USED WITH CARE IN PATIENTS WITH ANY KIND OF ARTERIOSCLEROSIS OR WITH HYPERTHYROIDISM, BRADYCARDIA, PARTIAL HEART BLOCK, OR MYOCARDIAL DISEASE. IT IS CONTRAINDICATED IN NARROW-ANGLE GLAUCOMA. [R3] *CONCOMITANT USE IS CONTRAINDICATED WITH TRICYCLIC ANTIDEPRESSANTS AND MOA INHIBITORS AND EVEN UP TO 21 DAYS AFTER CESSATION OF MAO INHIBITORS. [R11, (1978)] *IN HUMAN EYES WITH ABNORMALLY SHALLOW ANTERIOR CHAMBERS AND ABNORMALLY NARROW ANTERIOR CHAMBER ANGLES, PHENYLEPHRINE HAS PPT ANGLE-CLOSURE GLAUCOMA ... . [R10, 725] *... ABSORPTION AFTER ORAL ADMIN IS UNRELIABLE. [R12, 503] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *THIN LAYER CHROMATOGRAPHY AND GAS LIQUID CHROMATOGRAPHY. [R9, 93] *38.180-38.193. 38.180: ULTRAVIOLET SPECTROPHOTOMETRY; 38.181-38.183: COLORIMETRY; 38.184- 38.193: AUTOMATED METHOD /PHENYLEPHRINE HYDROGEN CHLORIDE/ [R20] *HIGH PERFORMANCE LIQUID CHROMATOGRAPHY IN PARTIAL ELECTROLYSIS ELECTROCHEMICAL DETECTOR. [R21] CLAB: *URINE-BLOOD, FLUOROMETRY, EXCITATION 525 NM/EMISSION 570 NM. [R9, 93] *DETERMINATION IN URINE USING GAS CHROMATOGRAPHY. [R22] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylephrine Hydrochloride in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 322 (1987) NIH Publication No. 87-2578 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1158 R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 819 R4: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. 207 R5: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 672 R6: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 761 R7: United States International Trade Commission. Synthetic Organic Chemicals- United States Production and Sales, 1988. USITC Publication 1989. Washington, DC: United States International Trade Commission, 1989.p. 6-7 R8: U.S. Department of Health, Education and Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances. 1977 edition. Washington, D. C.: U.S. Government Printing Office, 1977.221 R9: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R10: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R11: FRAUNFELDER FT, SCAFIDI AF; AMERICAN J OF OPHTHALMOLOGY 85: 447-453 R12: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R13: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. R14: Garner's Veterinary Toxicology. 3rd ed., rev. by E.G.C. Clarke and M.L. Clarke. Baltimore: Williams and Wilkins, 1967. 135 R15: DHHS/NTP; Toxicology and Carcinogenesis Studies of Phenylephrine Hydrochloride in F344/N Rats and B6C3F1 Mice p.3-4 (1987) NTP TR#322 NIH Pub No 87-2578 R16: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. S-17 R17: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. R18: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R19: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R20: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 12/735 R21: BOLLET ET AL; J CHROMATOGR 149: 625-644 (1978) R22: BERTRAND M ET AL; FARM TIJDSCHR BELG 55 (3): 55-83 (1978) RS: 16 Record 237 of 1119 in HSDB (through 2003/06) AN: 3387 UD: 200211 RD: Reviewed by SRP on 9/9/1993 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PROBENECID- SY: *APURINA-; *BENECID-; *BENEMID-; *BENURYL-; *Benzoic acid, 4-((dipropylamino)sulfonyl); *BENZOIC ACID, P-(DIPROPYLSULFAMOYL)-; *Colbenemid-; *Col-Probenecid-; *4-[(Dipropylamino)sulfonyl]benzoic aci; *P-(DIPROPYLSULFAMOYL)BENZOIC ACID; *4-(Dipropylsulfamoyl) benzoic acid; *P-(DIPROPYLSULFAMYL)BENZOIC ACID; *ETHAMIDE-; *NC1-C56097-; *Polycillin-BRB-; *Probalan-; *Probampacin-; *PROBECID-; *PROBEN-; *PROBENECID-ACID-; *PROBENEMID-; *PROLONGINE-; *SYNERGID-R-; *TUBOPHAN-; *URICOSID- RN: 57-66-9 MF: *C13-H19-N-O4-S ASCH: Probenecid sodium salt; 23795-03-1 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF TOLUENE WITH CHLOROSULFONIC ACID FOLLOWED BY HYDROLYSIS AND OXIDATION YIELDS P-CARBOXYBENZENESULFONICACID, THEN TREATMENT OF THIS ACID WITH CHLOROSULFONIC ACID AND CONDENSATION WITH DI-N-PROPYLAMINE [R1] *PREPARATION FROM P-CARBOXYBENZENESULFONYL CHLORIDE AND DIPROPYLAMINE. [R2] FORM: *PROBENECID (BENEMID, PROBALAN) IS MARKETED AS ORAL TABLETS (500 MG). [R3, 746] *Oral Tablets, 500 mg, Benemid (scored), MSD; Probalan, Lannett; Tablets, film coated 500 mg. [R4, 1654] *Oral For suspension, Ampicillin (trihydrate) 3.5 g (of ampicillin) with Probenecid 1 g, Amplicillin and Probenecid Oral Suspension, Biocraft; Polycillin-BRB, Bristol-Myers; Probampacin, Goldline. /Ampicillin (Trihydrate) and Probenecid/ [R4, 1654] *Oral Tablets 500 mg Probenecid and Colchincine 0.5 mg, ColBENEMID (scored), MSD; Col-Probenecid, Danbury, Goldline, United Research; Proben-C Rugby. /Probencid and Colchicine/ [R4, 1654] *Tablets, 500 mg [R5] MFS: *Merck and Co, Inc, Hq, PO Box 2000, Rahway, NJ 07065, (908) 574-4000; Merck Chemical Manufacturing Division (address same as Hq); Production site: Albany, GA 31705 [R6] USE: +MEDICATION PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] *(1978) PROBABLY GREATER THAN 9.08X10+5 GRAMS [R1] U.S. IMPORTS: *(1976) 6.15X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1978) 9.09X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM DIL ALCOHOL [R2]; *WHITE OR NEARLY WHITE, FINE, CRYSTALLINE POWDER [R7] ODOR: *PRACTICALLY ODORLESS [R7] TAST: *SLIGHTLY BITTER; PLEASANT AFTERTASTE [R2] MP: *194-196 DEG C [R2] MW: *285.36 [R2] DSC: *pKa= 5.8 [R2]; *pKa= 3.4 [R4, 1651] SOL: *SOL IN DIL ALKALI, ALCOHOL, CHLOROFORM AND ACETONE; PRACTICALLY INSOL IN WATER AND DIL ACIDS [R7] SPEC: *MAX ABSORPTION (BASE): 243 NM (A= 360, 1%, 1 CM), (ETHANOL): 227 NM AND 247 NM [R8] OCPP: *FREELY SOL IN WATER /SODIUM SALT/ [R9, 863] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of oxides of sulfur and oxides of nitrogen. [R10] SSL: *Probenecid tablets should be stored in well closed containers at a temperature less than 40 deg C, preferably between 15-30 deg C. Commercially available preparations containing probenecid and colchicine should be protected from light. Following the date of manufacture, commercially available probenecid tablets have an expiration date of 3-5 yr depending on the packaging. [R4, 1651] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *In acute probenecid overdosage, it has been recommended that the stomach be emptied immediately by inducing emesis or by gastric lavage. [R4, 1653] HTOX: *HUGE OVERDOSAGE OF PROBENECID RESULTS IN STIMULATION OF CNS, CONVULSIONS, AND DEATH FROM RESP FAILURE. [R3, 746] *... /OCCASIONALLY/ PATIENTS MAY EXPERIENCE ANOREXIA, NAUSEA, VOMITING, URINARY FREQUENCY, HYPERSENSITIVITY REACTIONS, SORE GUMS, FLUSHING, DIZZINESS AND ANEMIA. NEPHROTIC SYNDROME, HEPATIC NECROSIS AND APLASTIC ANEMIA OCCUR RARELY. [R7] *The most frequent adverse effects include headache, anorexia, nausea, and vomiting. Other reported adverse effects include dizziness, flushing, sore gums, alopecia, urinary frequency, leukopenia, and anemia. Nephrotic syndrome, hepatic necrosis, and aplastic anemia occur rarely. Mild to moderately severe hemolytic anemia, which in some patients could be related to genetic deficiency of glucose-6-phosphate dehydrogenase, has also been reported. [R4, 1653] *Hypersensitivity reactions which may be characterized by dermatitis, pruritus, fever, sweating, hypotension, and anaphylactic reaction occur rarely. Most cases of severe allergic reactions and anaphylaxis have been reported to occur within several hours after administration in patients who had previously received the drug. If a hypersensitivity reaction occurs in patients receiving probenecid, the drug should be discontinued. If rash occurs during administration of penicillin with probenecid and the causative agent cannot be determined, discontinuance of both drugs may be necessary. [R4, 1653] *Probenecid increases the concentration of uric acid in the renal tubules and, in some gouty patients, may promote development of uric acid stones which may cause renal colic, hematuria, and costovertebral pain. This is most likely to occur when probenecid therapy is initiated. Maintenance of a large volume of alkaline urine increases the solubility of uric acid and thus reduces the risk of stone formation in the kidneys. The drug may also increase the frequency of acute gouty attacks during the first 6-12 mo of therapy. [R4, 1653] *In one report of probenecid overdosage, toxic symptoms following ingestion of 47.5 g of the drug included copious vomiting followed by stupor and coma. Several tonic-clonic (grand mal) seizures occurred, each lasting approximately 30 sec, and were treated with iv phenobarbital sodium and phenytoin. Serum urate decreased to very low concentrations. [R4, 1653] *The possible enzyme induction by probenecid was studied using antipyrine clearance and urinary excretion of 6beta-hydroxycortisol as markers of induction in 14 healthy male subjects (aged 19-37 yr) who received 2 g/day oral probenecid for 7 days. Seven days after starting probenecid, antipyrine clearance increased significantly from 40.7 + or - 2.9 ml/min at baseline to 52.3 + or - 4.7 ml/min. Accordingly, antipyrine half life was shortened from a baseline value of 13 + or - 0.6 hr to 9.3 + or - 0.8 hr. There was no significant alteration in antipyrine volume of distribution. The urinary excretion of 6beta-hydroxycortisol corrected for 17-hydroxycorticosteroids was 448 + or - 65 ug/day before probenecid and 721 + or - 52 ug/day after one wk of probenecid administration. It was concluded that probenecid appears to be an inducer of the mixed function oxidase system. [R11] NTOX: *... /STUDIES HAVE SHOWN THAT PROBENECID BLOCKS/ THE TRANSPORT SYSTEM FOR ELIMINATION OF 5-HYDROXYINDOLEACETIC ACID (5HIAA) FROM BRAIN IN RATS. [R12, 521] *Probenecid was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Probenecid was tested at doses of 0.033, 0.10, 0.33, 1.0, and 3.3 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Probenecid was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain mg/plate. [R13] +... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of probenecid for male or female F344/N rats receiving 100 or 400 mg/kg in corn oil. There was no evidence of carcinogenic activity of probenecid for male B6C3F1 mice given 100 or 400 mg/kg probenecid in corn oil. There was some evidence of carcinogenic activity of probenecid for female B6C3F1 mice based on an increased incidence of hepatocellular adenomas. [R14] NTP: +... Toxicology and carcinogenicity studies were conducted by administering probenecid (> 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex ... 5 days/wk ... for ... 2 yr. ... Doses of 0, 100, and 400 mg/kg were used for the 2 yr studies in rats and mice. These doses were administered once daily, 5 days/wk for up to 103 wk to groups of 50 males or 50 females of each species. Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of probenecid for male or female F344/N rats receiving 100 or 400 mg/kg in corn oil. There was no evidence of carcinogenic activity of probenecid for male B6C3F1 mice given 100 or 400 mg/kg probenecid in corn oil. There was some evidence of carcinogenic activity of probenecid for female B6C3F1 mice based on an increased incidence of hepatocellular adenomas. [R14] POPL: *... /PROBENECID/ IS CONTRAINDICATED IN PATIENTS WITH HISTORY OF RENAL CALCULI, ESP URIC ACID STONES, BECAUSE IT MAY AGGRAVATE OR PRECIPITATE THIS CONDITION. [R15, 1732] ADE: *PROBENECID IS COMPLETELY ABSORBED AFTER ORAL ADMIN. PEAK PLASMA CONCN ARE REACHED IN 2-4 HR. THE HALF-LIFE OF THE DRUG IN PLASMA IS DOSE DEPENDENT AND VARIES FROM LESS THAN 5 HR TO MORE THAN 8 HR. [R3, 746] *BETWEEN 85 and 95% OF DRUG IS BOUND TO PLASMA ALBUMIN, LARGELY TO ALBUMIN. SMALL UNBOUND PORTION GAINS ACCESS TO GLOMERULAR FILTRATE; A MUCH LARGER PORTION IS ACTIVELY SECRETED BY PROXIMAL TUBULE. [R3, 746] *IN SPITE OF ITS LOW PKA (3.4), HIGH LIPID SOLUBILITY OF UNDISSOCIATED FORM RESULTS IN VIRTUALLY COMPLETE ABSORPTION BY BACK DIFFUSION UNLESS URINE IS MARKEDLY ALKALINE. SMALL AMOUNT OF PROBENECID GLUCURONIDE APPEARS IN URINE. [R3, 746] *... /ORG ACID CMPD SUCH AS PROBENECID /ARE/ NOT TAKEN UP SO AVIDLY BY /PARENCHYMATOUS OR RETICULO-ENDOTHELIAL TISSUES/ AND EXHIBIT HIGHER PLASMA CONCN ... . [R12, 372] *Probenecid is rapidly and completely absorbed from the GI tract. Plasma probenecid concentrations of 40-60 ug/ml produce maximal inhibition of renal penicillin excretion, while concentrations of 100-200 ug/ml produce a uricosuric effect. Plasma probenecid concentrations of 25 ug/ml are reached 30 min after a single 1-g oral dose; plasma concentrations peak in 2-4 hr and remain above 30 ug/ml for 8 hr. Following a single 2-g oral dose, peak plasma concentrations of 150-200 ug/ml are reached in 4 hr and concentrations above 50 ug/ml are sustained for 8 hr. [R4, 1652] *At a plasma concentration of 14 ug/ml, about 75% of the drug is bound to proteins. Probenecid concentrations in the CSF are approximately 2% of plasma concentrations. The drug also crosses the placenta. [R4, 1652] *Small amounts of probenecid are filtered at the glomeruli, but most of the drug is actively secreted at the proximal tubule. Renal tubular reabsorption of the drug is nearly complete in acidic urine; however, probenecid metabolites are not reabsorbed as extensively as the parent compound. Alkalinization of the urine decreases reabsorption of probenecid. Although this also increases excretion of the drug, probenecid's efficacy is not appreciably decreased. After 2 days, 5-11% of a single 2-g oral probenecid dose is excreted in urine as unchanged drug, 16-33% as its monoacyl glucuronide, and the remainder as approximately equal amounts of the 4 other metabolites. [R4, 1652] *The pharmacokinetics of probenecid and its metabolites and dose dependent drug elimination were studied in a 40 yr old male subject who received an oral tablet of 250, 500, 1000, and 1500 mg probenecid (Benemid). Half life for the 250 mg dose was 3 hr, compared with 6 hr for 1500 mg. Maximum concn ranged from 14 ug/ml to 120 ug/ml with 1400 mg. Total body clearance was 64.5 ml/min for 250 mg and 26 ml/min for 1500 mg. Renal clearance stayed constant at 0.6-0.8 ml/min. Probenecid glucuronide was present in urine, but not in the plasma. The renal excretion rate-time profile of probenecid glucuronide showed a plateau value of about 700 ug/min. Duration of this value was dependent on dose. It was shown that probenecid glucuronide is formed in the kidney. The plateau in the renal excretion rate of probenecid value reflected its maximal rate of formation. It was concluded that the maximum renal excretion rate of probenecid glucuronide by the kidney represents its maximal rate of formation. [R16] METB: *YIELDS P-DIPROPYLSULFAMOYLBENZOYL-BETA-D-GLUCURONIC ACID; P-(2-HYDROXYPROPYL N-PROPYLSULFAMOYL) BENZOIC ACID; P-(3-HYDROXYPROPYL N-PROPYLSULFAMOYL) BENZOIC ACID; AND P-PROPYLSULFAMOYLBENZOIC ACID IN MAN. /FROM TABLE/ [R17] *STRUCTURES OF ALL OF METAB OF PROBENECID IN RAT BILE AND HUMAN URINE HAVE BEEN ELUCIDATED. PROPIONIC ACID HAS NOW BEEN IDENTIFIED AS ANOTHER PROBENECID METAB. MAJOR METABOLIC PATHWAYS INVOLVE SIDE-CHAIN OXIDATION AND GLUCURONIDE CONJUGATION ... . [R18] *... BETA-GLUCURONIDES OF 2- and 3-HYDROXYLATED METAB AND ACYL GLUCURONIDE OF PROBENECID PER SE HAVE NOW BEEN IDENTIFIED. ... THERE IS CONSIDERABLE SPECIES DIFFERENCE IN METABOLISM. IN RATS AND MONKEYS OXIDATION IS FAVORED. ... IN DOGS CONJUGATION ... /IS/ MAJOR PATHWAY, WHEREAS IN MAN, OXIDATIVE ... PATHWAY ... IS AS IMPORTANT AS GLUCURONIDATION. [R18] *CHRONIC ADMIN OF DRUGS NOT ONLY STIMULATES METAB OF OTHER CMPD, BUT IN SOME INSTANCES PHARMACOLOGICAL OR TOXIC EFFECT OF A DRUG WHEN GIVEN CHRONICALLY, DIMINISHES, BECAUSE IT STIMULATES ITS OWN METABOLISM EXAMPLE OF DRUG THAT EXERT THIS EFFECT IN DOGS ... /IS/ ... PROBENECID ... . [R12, 258] *...PROBENECID FAILED TO REVEAL ANY METAB RESULTING FROM RING OXIDATION IN ANIMALS STUDIED. RESULTS ARE EXPLAINED IN TERMS OF DEACTIVATING INFLUENCE OF CARBOXY AND SULFONAMIDE SUBSTITUENTS, WHICH ARE ELECTRON-WITHDRAWING GROUPS. [R19] *Probenecid is slowly metabolized by the liver to probenecid monoacyl glucuronide, two monohydroxylated compounds, a carboxylated metabolite, and an N-depropylated compound. These metabolites may possess some uricosuric activity. [R4, 1652] BHL: *THE HALF-LIFE OF /PROBENECID/ IN PLASMA IS DOSE DEPENDENT AND VARIES FROM LESS THAN 5 HR TO MORE THAN 8 HR ... . [R3, 746] *Following oral administration of 2 g of probenecid, plasma half-life of the drug ranges from 4-17 hr; the half-life decreases as the dose decreases from 2 g to 500 mg. [R4, 1652] ACTN: *IN HIGHER DOSES THAN ARE REQUIRED FOR URICOSURIC EFFECT, PROBENECID ALSO INHIBITS TRANSPORT OF ORG ACIDS AT OTHER SITES, IE, TRANSPORT SYSTEM THAT REMOVES ORG ACIDS FROM CEREBROSPINAL FLUID. [R9, 862] *IT INHIBITS TUBULAR REABSORPTION OF URATE, THUS INCR URINARY EXCRETION OF URIC ACID AND DECR SERUM URIC ACID LEVELS. [R7] *Probenecid is a renal tubular blocking agent. The drug competitively inhibits active reabsorption of uric acid at the proximal convoluted tubule, thus promoting urinary excretion of uric acid and reducing serum urate concentrations. Probenecid may reduce plasma protein binding of urate and, in subtherapeutic doses, may inhibit renal secretion of uric acid. In healthy individuals, probenecid has no effect on the glomerular filtration rate or on the tubular reabsorption of normal urinary constituents such as glucose, arginine, urea, sodium, potassium, chloride, or phosphate. [R4, 1651] *At the proximal and distal tubules, probenecid competitively inhibits the secretion of many weak organic acids including penicillins, most cephalosporins, and some other beta-lactam antibiotics. In general, the net effect of probenecid on the plasma concentration of weak acids depends on the ratio of the amount of organic acid secreted by the kidneys to that amount filtered at the glomeruli. Thus, probenecid substantially increases plasma concentrations of acidic drugs eliminated principally by renal secretion, but increases plasma concentrations only slightly if the drug is eliminated mainly by filtration. Plasma concentrations of penicillins are often more than doubled by probenecid; the concentration of penicillin in the CSF is also increased. Probenecid also substantially increases plasma concentrations of most cephalosporins and some other beta-lactam antibiotics. In addition, half-lives of the penicillins and cephalosporins are prolonged and their volumes of distribution may be reduced by probenecid. ... The cellular mechanism(s) responsible for the inhibition of renal tubular transport by probenecid is not known. The drug may inhibit transport enzymes that require a source of high energy phosphate bonds and/or nonspecifically interfere with substrate access to protein receptor sites on the kidney tubules. [R4, 1652] *CSF concentrations of 5-hydroxyindoleacetic acid, homovanillic acid, cyclic adenosine monophosphate, and 4-hydroxy-3-methoxyphenylglycol are elevated following administration of probenecid. It has been proposed that probenecid blocks the active transport of these organic acids from the CSF into blood. Probenecid-induced elevations of homovanillic acid (a dopamine metabolite) in the CSF of patients with parkinsonian syndrome and of 5-hydroxyindoleacetic acid(a metabolite of serotonin) in the CSF of mentally depressed patients are substantially lower than those in healthy patients. [R4, 1652] INTC: *PROBENECID INHIBITS RENAL TRANSPORT OF ... PANTOTHENIC ACID, IODOMETHAMATE AND RELATED IODINATED ORG ACIDS, AMINOHIPPURIC ACID, 17-KETOSTEROIDS PHENOLSULFONPHTHALEIN AND SULFOBROMOPHTHALEIN. DOSAGE OF THESE AGENTS ... SHOULD BE MODIFIED WHEN THEY ARE ADMIN WITH PROBENECID. ... /IT ALSO/ INCR RENAL EXCRETION OF OXIPURINOL ... . [R15, 1732] *CONCURRENT ADMIN OF CEPHALEXIN AND PROBENECID RESULTS IN HIGHER AND PROLONGED SERUM ANTIBIOTIC LEVELS. ... CONCURRENT THERAPY DOES NOT APPEAR TO HAVE ANY CLINICAL ADVANTAGE OVER INCR IN ANTIBIOTIC DOSE. [R20, 522] */IN ADDN TO CEPHALEXIN/ OTHER CEPHALOSPORIN ANALOGS WHOSE SERUM LEVELS ARE ENHANCED BY PROBENECID ARE CEFAZOLIN, CEPHACETRILE, CEPHALOGLYCIN, CEPHALORIDINE, CEPHALOTHIN AND CEPHRADINE. [R20, 522] *CONCURRENT ADMIN OF PROBENECID, PARTICULARLY IN HIGH DOSES, DECR RENAL CLEARANCE OF NITROFURANTOIN AND INCR SERUM LEVEL. ... INTERACTION MAY LEAD TO NITROFURANTOIN-INDUCED TOXICITY (EG, POLYNEUROPATHIES) OR DECR NITROFURANTOIN EFFICACY AS URINARY TRACT ANTI-INFECTIVE AGENT. [R20, 159] *LONG TERM USE OF CHLOROTHIAZIDE AND OTHER THIAZIDE DIURETICS FREQUENTLY CAUSE MILD URIC ACID RETENTION AND DIMINISHES SOME OF URICOSURIC EFFECTS OF PROBENECID. [R20, 208] *ASPIRIN ANTAGONIZES ABILITY OF PROBENECID ... TO INCR RENAL EXCRETION OF URIC ACID AND TO REDUCE SERUM URATE LEVELS. THESE INTERACTIONS APPEAR TO BE CLINICALLY SIGNIFICANT. [R20, 448] *PROBENECID AND SULFINPYRAZONE COMPETE WITH URIC ACID AT RENAL TUBULE TRANSPORT SITES. [R20, 392] *PROBENECID MAY INHIBIT RENAL EXCRETION OF AMINOSALICYLIC ACID AND RESULT IN TOXIC REACTIONS TO ANTI-INFECTIVE DRUG. ... /THIS/ INTERACTION MAY BE CLINICALLY SIGNIFICANT AND REDN IN DOSE OF AMINOSALICYLIC ACID MAY BE NECESSARY. [R20, 448] *ONE STUDY SUGGESTED THAT PROBENECID INTERFERES WITH HEPATIC UPTAKE OF RIFAMPIN RESULTING IN INCR SERUM LEVELS OF THE ANTI-INFECTIVE. ... UNRECOGNIZED ... /THIS DRUG INTERACTION/ COULD LEAD TO INCR INCIDENCE OF ADVERSE REACTIONS DUE TO RIFAMPIN. [R20, 392] *... /PROBENECID/ DECR URINARY EXCRETION OF AMINOSALICYCLIC ACID, AMINOHIPPURIC ACID, PHENOLSULFONPHTHALEIN, PANTOTHENIC ACID, 17-KETOSTEROIDS, AND SODIUM IODOMETHAMATE. HOWEVER, IT IS RARELY NECESSARY TO RESORT TO PROBENECID TO INCR BLOOD AND TISSUE LEVELS OF THESE AGENTS OR TO LENGTHEN INTERVAL BETWEEN DOSES. [R7] *PROBENECID (REPEATED 50 MG/KG, IP TO DOGS) INHIBITED CSF CLEARANCE OF SODIUM METHOTREXATE FROM PLASMA AND CSF LEVELS FOLLOWING INTRATHECAL INJECTION. FROM PRETREATMENT MEAN PEAK PLASMA METHOTREXATE CONCN WAS LOWER AND PLASMA DISAPPEARANCE PROLONGED. [R21] *PROBENECID CAUSED MARKED CHANGES IN PHARMACOKINETIC PARAMETERS OF FUROSEMIDE (INCR AREA UNDER CURVE, DECR PLASMA AND RENAL CLEARANCE, INCR HALF-LIFE, AND DECR FRACTION EXCRETED UNCHANGED IN URINE), BUT NO SIGNIFICANT DIFFERENCE IN ITS GROSS 8 HR NATRIURETIC AND DIURETIC EFFECT. [R22] *PROBENECID INCR MEAN TERMINAL HALF-LIFE AND AREA UNDER SERUM CEFOXITIN NA CONCN-TIME CURVE (AUCO-24) AND DECR RENAL CLEARANCE, BUT DID NOT ALTER VOL OF CENTRAL COMPARTMENT OR TOTAL URINARY RECOVERY OF IV ADMIN CEFOXITIN. [R23] *PROBENECID, 0.5 G TWICE DAILY IMPROVED THERAPEUTIC RESPONSE TO INDOMETHACIN 25 MG THREE TIMES DAILY FOR 3 WK. [R24] *Increases aminosalicylic acid toxicity, possible decreased diuretic effect of bumetanide, increased methotrexale effect, decreased uricosuric effect of salicylates. [R25, 126] *Enhances excretion of calcium, magnesium, and citrate during thiazide therapy. [R25, 272] *Simultaneous administration of oral probenecid competitively inhibits tubular secretion, resulting in higher and more prolonged serum concentration of cephalosporins. [R25, 335] *Decreased urinary excretion of sulfonylureas. [R25, 445] *Total plasma sulfonamide concentrations are also elevated by probenecid; however, free sulfonamide concentrations are not altered and concomitant use of the drugs is not therapeutically useful. [R4, 1653] *Theoretically, hypoglycemia may result from probenecid-induced elevations of plasma concentrations of chlorpropamide and other oral sulfonylurea antidiabetic agents. In one patient, probenecid reportedly prolonged clotting time by inhibiting secretion of heparin during concomitant therapy. Elevated plasma concentrations of aminosalicylic acid and dapsone may be caused by concomitant administration of probenecid, thus increasing the possibility of toxic effects from these agents. Probenecid also inhibits tubular secretion of pantothenic acid and riboflavin, and intestinal absorption of riboflavin, but the importance of these interactions is not known. [R4, 1653] *The uricosuric actions of probenecid and salicylates are mutually antagonistic. Salicylate-induced uricosuria is inhibited by usual doses of probenecid. However, probenecid-induced uricosuria appears to be inhibited principally when the serum salicylate concentration exceeds 50 ug/ml. Salicylates are generally contraindicated during uricosuric therapy, but occasional doses of salicylates for analgesia or antipyresis in patients receiving probenecid may be insufficient to produce a clinically important interaction; alternatively, if an analgesic or antipyretic is required during probenecid therapy, acetaminophen may be used. [R4, 1653] *When probenecid is administered concomitantly with indomethacin, plasma concentration, plasma half-life, and therapeutic effects of indomethacin have been reported to increase. The mechanisms of this interaction remain unknown but have been attributed to blockade of renal tubular secretion of indomethacin and to an interference with the biliary clearance of indomethacin. Although the clinical importance of the interaction has not been established, a decreased total daily dose of indomethacin may produce a satisfactory therapeutic response when indomethacin and probenecid are used concurrently and increases in indomethacin dosage, if necessary, should be made carefully and in small increments. Indomethacin does not interfere with the uricosuric action of probenecid. [R4, 1653] *Although the clinical importance has not been determined to date, concomitant administration of probenecid with some other nonsteroidal antiinflammatory agents (eg, ketoprofen, meclofenamate, naproxen, sulindac) increases the plasma elimination half-lives and plasma concentrations of these agents. Concomitant administration of probenecid and sulindac increases plasma concentrations of sulindac and its sulfone metabolite but has only a slight effect on plasma concentrations of the sulfide metabolite. Sulindac causes a slight reduction in the uricosuric action of probenecid, but this effect is probably not clinically important in most patients. When probenecid is administered concomitantly with ketoprofen, total and free plasma concentrations of ketoprofen are substantially increased as a result of decreased protein binding of ketoprofen, decreased total apparent plasma clearance of ketoprofen, and decreased apparent plasma clearance of free ketoprofen. In addition, probenecid appears to inhibit conjugation of ketoprofen and renal excretion of ketoprofen conjugates. ... Concomitant use of the drug and probenecid is not recommended. [R4, 1653] *Many drugs may increase serum urate concentrations, including most diuretics, pyrazinamide, diazoxide, alcohol, and mecamylamine. If these drugs are administered during uricosuric therapy, probenecid dosage may need to be increased. Antineoplastic agents also increase serum urate concentrations; however, uricosurics may increase the risk of uric acid nephropathy and should not be used in patients receiving cancer chemotherapy. [R4, 1653] *Probenecid inhibits the renal secretion of sulfinpyrazone and its active metabolite, but these 2 uricosuric drugs may be given concurrently without adverse interaction. Uricosuric drugs promote excretion of allopurinol's active metabolite, but it is generally agreed that the effects of allopurinol and uricosurics are additive and the combination is usually used to therapeutic advantage. [R4, 1653] *Although the clinical importance has not been determined, concomitant administration of probenecid with acetaminophen or lorazepam reportedly increases the plasma elimination half-lives and peak plasma concentrations of these drugs. [R4, 1653] *Probenecid increases the urinary excretion of insulin, but this effect is not clinically important. Furosemide and ethacrynic acid naturesis is inhibited by probenecid. Probenecid increases excretion of calcium, magnesium, and citrate in patients taking thiazide diuretics, but does not antagonize thiazide-induced naturesis. [R4, 1653] *It has been reported that patients receiving probenecid may require substantially lower amounts of thiopental sodium for induction of anesthesia. Ketamine and thiopental sodium anesthesia is substantially prolonged in rats receiving probenecid. [R4, 1653] *Probenecid usually produces maximal renal clearance of uric acid 30 min after being administered and exerts its effect on plasma penicillin concentrates after about 2 hr. [R4, 1652] *The ability of probenecid to protect against hexachloro-1,3-butadiene and methylmercury nephrotoxicity was studied in mice. Male Swiss-OF1 mice were injected ip with 0 or 0.75 mmol/kg probenecid 30 min before and 10 min and 5 hr after being given 80 mg/kg hexachloro-1,3-butadiene or 40 mg/kg methylmercury chloride by oral gavage. They were killed 8 or 8.5 hr after dosing and the kidneys were removed. The effects of probenecid on hexachloro-1,3-butadiene and methylmercury chloride nephrotoxicity were evaluated by determining renal alkaline phosphatase by an histochemical technique. No mortality was recorded. Hexachloro-1,3-butadiene and methylmercury chloride induced damage to about 50% of the cortical and outer medullary proximal tubules as indicated by staining for alkaline phosphatase. Probenecid reduced the number of hexachloro-1,3-butadiene or methylmercury chloride damaged proximal tubules by 80 and 90%, respectively. It was concluded that the nephrotoxicity of hexachloro-1,3-butadiene and methylmercury chloride in mice is linked to a probenecid sensitive transport system. [R26] *Two human volunteer studies were performed with meropenem: a dose proportionality study of 0.25, 0.5 and 1.0 g and a probenecid interaction study. Six volunteers took part in each study. Meropenem was generally well tolerated: One volunteer was withdrawn from the dose proportionality study because of looseness of stool and abdominal pain after a dose of 1.0 g. The plasma concn of meropenem were linearly related to dose. The half life of meropenem was approximately 1 hr and the urinary recovery of unchanged drug was 79%. In the presence of probenecid the plasma half life of meropenem was increased by 33% but the urinary recovery was unaffected. [R27] *Metabolic studies of 3'-azido-3'-deoxythymidine in humans have demonstrated that this cmpd is primarily eliminated as a 5'-O-glucuronide, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine, accounting for approximately 80% of the administered dose. Recently, the complete catabolic pathway of 3'-azido-3'-deoxythymidine in freshly isolated rat hepatocytes in suspension was characterized, demonstrating extensive formation of three catabolites, including 5'-O-glucuronide, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine, 3'-amino-3'-deoxythymidine, and 3'-amino-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine. The present study evaluated the effects of probenecid and acetaminophen, two agents which are also metabolized by UDP-glucuronyltransferase, on the metabolism and transmembrane distribution of 3'-azido-3'-deoxythymidine in rat hepatocytes. Pre-exposure of cells to 350 uM probenecid 30 min prior to the addition of 10 uM (3)H 3'-azido-3'-deoxythymidine decreased intracellular 5'-O-glucuronide, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine levels by approximately 10 fold. Interestingly, 3'-amino-3'-deoxythymidine formation was enhanced approximately 1.5 fold in the presence of probenecid, probably resulting from increased 3'-azido-3'-deoxythymidine availability. In contrast, pre-exposure to 50 uM acetaminophen 30 min prior to addition of 10 uM (3)H 3'-azido-3'-deoxythymidine did not substantially alter 3'-azido-3'-deoxythymidine glucuronidation. Additionally, decreased 3'-azido-3'-deoxythymidine catabolism by probenecid did not contribute to the formation of 5'-phosphorylated derivatives of 3'-azido-3'-deoxythymidine. Agents which undergo glucuronidation may thus not necessarily affect 3'-azido-3'-deoxythymidine conversion to 5'-O-glucuronide, 3'-azido-3'-deoxy-5'-beta-D-glucopyranuronosylthymidine, and their potential interactions should be investigated using in vitro systems prior to co-administration with 3'-azido-3'-deoxythymidine. [R28] *The mechanism of dichlorovinyl cysteine nephrotoxicity was studied in mice. Female C57BL mice were given 0 or 8.0 mg/kg (14)C labeled dichlorovinyl cysteine by gavage. Some had been pretreated with three 225 mg/kg doses of L-buthionine-S,R-sulfoximine, an inhibitor of glutathione synthesis or once with 0.5 ml/kg diethyl maleate, a glutathione depleting agent, or 150 mg/kg probenecid, an inhibitor of organic ion transport. They were killed 3 o 24 hr after dichlorovinyl cysteine exposure and the kidneys were removed. The right kidney was examined for (14)C/tissue macromolecule binding. The left kidney was examined by microautoradiography. Mice pretreated as before were given 0, 5, or 25 mg/kg dichlorovinyl cysteine. They were killed 24 hr later and the kidneys were removed. Some kidneys were assayed for nonprotein thiols, used as an index of glutathione concn. Other kidneys were examined by light microscopy and scored for histological damage. Diethyl maleate and probenecid significantly decreased uptake and binding of dichlorovinyl cysteine derived (14)C activity at 3 and 24 hr. L-Buthionine-S,R-sulfoximine caused slight increases after 24 hr. Both the 5 and 25 mg/kg dichlorovinyl cysteine doses caused similar degrees of kidney damage with moderate desquamation of the straight proximal tubular epithelium. L-buthionine-S,R-sulfoximine significantly enhanced the kidney damage. Epithelial cells in the straight proximal tubules were completely desquamated. Necrotic epithelial cells and cell debris were found in the subcapsular region. Probenecid significantly reduced dichlorovinyl cysteine induced kidney damage. Diethyl maleate tended to reduce the damage. L-Buthionine-S,R-sulfoximine and diethyl maleate decreased renal nonprotein thiols concn. Probenecid did not affect renal nonprotein thiols concn. Dichlorovinyl cysteine was bound to the pars recta, the last part of the proximal tubule. L-Buthionine-S,R-sulfoximine did not affect the dichlorovinyl cysteine binding site. It was suggested that organic acid transport may be involved in dichlorovinyl cysteine nephrotoxicity. Tissue glutathione may protect against dichlorovinyl cysteine nephrotoxicity. [R29] *Male OF1 mice were injected sc with 80 mg/kg potassium dichromate. Examination of cryostat kidney sections stained for alkaline phosphatase revealed damage to about 40-70% of the proximal tubules after 8 hr. Pretreatment with the organic anionic transport inhibitor probenecid (ip, 3 x 0.75 mmol/kg) reduced the number of damaged tubules by 60% in mice treated with potassium dichromate. Pretreatment with the gamma-glutamyltranspeptidase inactivator acivicin (AT-125, 50 mg/kg orally, plus 50 mg/kg ip) failed to prevent chromate induced renal toxicity. These results support the conclusion that a probenecid sensitive transport process, but not a gamma-glutamyltranspeptidase catalyzed degradation, is involved in the mouse renal toxicity of potassium dichromate. [R30] *The anti-human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5'-glucuronide and is cleared rapidly, resulting in a short half life and the need for frequent dosing. This study explores whether probenecid, which is also metabolized by glucuronidation, reduces zidovudine clearance when zidovudine is administered orally to patients with AIDS or AIDS related complex. The mean zidovudine plasma levels were significantly higher after concurrent administration of probenecid than in its absence, resulting in a twofold increase in the mean area under the concentration time curve, a corresponding decline in the apparent total clearance, and a prolongation in the mean half life. Similar alterations were observed in 5'-glucuronide zidovudine disposition. There was a marked reduction in the urinary excretion ratio of 5'-glucuronide zidovudine to zidovudine and a decline in the renal clearance of 5'-glucuronide zidovudine after probenecid coadministration. Probenecid inhibits zidovudine glucuronidation and renal excretion of 5'-glucuronide zidovudine. [R31] *A randomized crossover study of the effects of probenecid on the pharmacokinetics of cimetidine was conducted in 6 healthy male subjects (aged 22-29 yr) who received an iv infusion of 300 mg cimetidine alone or 3 hr following 500 mgprobenecid administered every 6 hr for 13 doses. There were no significant differences between treatments in cimetidine plasma concn, apparent volume of distribution, systemic clearance, half life, amount of probenecid excreted unchanged in the urine or nonrenal clearance. Probenecid significantly decreased the renal clearance of cimetidine by decreasing the filtration clearance and net secretory clearance. This effect was most evident in the first 0.5-1 hr after cimetidine administration, when probenecid blood and renal tissue levels were highest. [R32] *The effect of probenecid on the pharmacokinetics of digoxin was studied in 6 healthy male volunteers, ages 25 to 35 yr, who, after receiving 0.5 to 1.0 mg oral digoxin (Lanacrist) daily alone or in combination with 2 g oral probenecid (Probecid) daily for 8 days, were given an iv injection of digoxin that was 0.7 of their usual oral dose on day 7. Probenecid did not affect the plasma clearance, renal clearance, biliary clearance, elimination half life, or volume of distribution of digoxin. The results suggest that different systems exist in man for the renal and biliary secretion of probenecid and digoxin. [R33] *Cephapirin (20 mg/kg of body wt, iv) was administered before and after 3 doses of probenecid (25, 50, or 75 mg/kg, intragastrically, at 12 hr intervals) to 2 mares. Clearance and apparent volume of distribution, based on area under the curve, were negatively correlated with probenecid dose. Clearance of cephapirin was decreased by approximately 50% by administration of 50 mg of probenecid/kg. Serum, synovial fluid, peritoneal fluid, CSF, urinary, and endometrial concn of cephapirin were determined after 5 doses of cephapirin (20 mg/kg, im, at 12 hr intervals) without and with concurrently administered probenecid (50 mg/kg, intragastrically) to 6 mares, including the 2 mares given cephapirin, iv. Highest mean serum cephapirin concn were 16.1 + or - 2.16 ug/ml at 0.5 hour after the 5th cephapirin dose (postinjection (initial) hr 48.5) in mares not given probenecid and 23.7 + or - 1.30 ug/ml at 1.5 hr after the 5th cephapirin dose (postinjection (initial) hr 49.5) in mares given probenecid. Mean peak peritoneal fluid and synovial fluid cephapirin concn were 6.2 + or - 0.57 ug/ml and 6.6 + or - 0.58 ug/ml, respectively, without probenecid administration and 12.3 + or - 0.46 ug/ml and 10 + or - 0.78 ug/ml, respectively, with concurrent probenecid administration. Mean trough cephapirin concn for peritoneal and synovial fluids in mares given probenecid were 2 to 3 times higher than trough concn in mares not given probenecid. Overall mean cephapirin concn were significantly higher for serum, peritoneal fluid, synovial fluid, and endometrium when probenecid was administered concurrently with cephapirin (p < 0.01). [R34] *The effects of probenecid and quinine sulfate on the pharmacokinetics of zidovudine were studied in 8 patients with HIV infection who were receiving zidovudine alone, 500 mg of probenecid every 8 hr after 3 days of zidovudine, 500 mg of probenecid and 260 mg of quinine sulfate every 8 hr after 3 days of zidovudine. A median increase of 80% in the area under the zidovudine plasma concn/time curve occurred with the addition of probenecid. Quinine sulfate prevented the probenecid effect but had no effect on zidovudine kinetics when taken without probenecid by 4 other subjects. All of the other effects were secondary to changes in zidovudine metabolism, since neither probenecid nor quinine sulfate changed the renal elimination of zidovudine. It was concluded that probenecid could be used in combination with zidovudine to extend the interval between doses and reduce the daily requirement for zidovudine, thus enhancing convenience and reducing costs. [R35] *The effect of probenecid on the pharmacokinetics and pharmacodynamics of procainamide was studied in a randomized crossover study in 6 healthy subjects, aged 24 to 36 yr, who received a single 750 mg iv dose of procainamide with and without prior administration of 2 g oral probenecid. Coadministration of probenecid did not result in any significant change in the overall disposition of procainamide. In particular, renal clearance was not significantly different. The data suggest an interaction between probenecid and procainamide in the proximal renal tubule does not exist. [R36] *The pharmacokinetics of phenprocoumon were studied with and without co-administration of frusemide and probenecid in two groups of 17 healthy volunteers. Frusemide 40 mg twice a day for 7 days did not interact with phenprocoumon to a significant extent. Probenecid 500 mg four times a day for 7 days significantly accelerated the overall elimination of phenprocoumon, as indicated by a decrease in area under the concentration time curve from 295 to 157 ug h/ml, and a reduction in the fraction of the dose excreted by the kidneys. The data are consistent with inhibition of the glucuronidation of phenprocoumon by probenecid. Its accelerated elimination may be a consequence of the increased formation of hydroxylated metabolites. [R37] *The mechanism of renal excretion of 10-60 mg/kg (iv) diprophylline and the effect of an iv infusion of probenecid at various rates on the active transport of diprophylline in renal tubules were studied in rats. Plasma levels of diprophylline increased in proportion to the dose. Pharmacokinetics and urinary drug excretion did not significantly change with the dose. Pharmacokinetics for tubular drug secretion were 21.25 ug/ml for the Michaelis Menten constant and 102.38 ug/min for maximum velocity. Probenecid decreased the total body clearance of diprophylline, but did not change the steady state volume of distribution of diprophylline. The renal clearance of diprophylline decreased as probenecid concn increased, indicating that probenecid inhibits tubular secretion. It was concluded that dose independent pharmacokinetics of diprophylline are probably due to active transport in the renal transport system. [R38] *Muzolimine (60 mg, administered orally) was administered to eight healthy volunteers, under conditions of altered fluid load, to elucidate its renal site of action. The duration of action and the effect of probenecid pretreatment on muzolimine response was also investigated. Muzolimine had a rapid onset of action, with the diuresis complete within 4 hr after dosing. At peak natriuresis, under hydrated conditions, fractional excretion of free water remained unaltered (9.72% + or - 0.59% versus 9.07% + or - 0.44%; difference not significant) but was accompanied by a significant increase in the delivery of sodium out of the proximal tubule, as measured by fractional excretion of lithium (22% + or - 2% to 31% + or - 1%; p < 0.01). The fraction of sodium reabsorbed in the distal tubule also decreased from 94% + or - 1% to 67% + or - 1% (p < 0.001) of the delivered load. The fractional reabsorption of free water during hydropenia decreased after muzolimine (5.63% + or - 0.26% to 2.00% + or 0.81%; p < 0.05). Pretreatment with probenecid resulted in a prominent decrease in urinary sodium excretion (246 + or - 25 mmol/24 hr for muzolimine alone 161 + or - 24 mmol/24 hr for muzolimine and probenecid; p < 0.01). These findings suggest that muzolimine has a major site of action in the medullary portion of the thick ascending limb of Henle with additional inhibitory activity on the proximal tubule. It is likely that the active secretion of one or more of the acidic metabolites of muzolimine, by way of the probenecid sensitive organic acid pathway, is responsible for mediating the renal actions this basic drug. [R39] INTC: *An increased incidence of probenecid adverse reactions among patients infected with the HIV is reported among 8 male patients with HIV infection who were enrolled in a study investigating the effects of probenecid on zidovudine metabolism over 28 days. The patients were initially receiving oral zidovudine (100-200 mg) every 4 hr when they were started on 500 mg of probenecid every 8 hr. The patients were advised to take the same zidovudine dosage with probenecid every 8 hr instead of every 4 hr, thus halving the daily zidovudine dosage. Results showed that during treatment with the combination, 6 of the 8 men had a rash. Two had minor rashes during the first wk of combination treatment. In 4 patients the rash began in the second wk; the rash led to discontinuation of probenecid. Biopsy of the 2 most extensive and symptomatic cases revealed intradermal perivascular mononuclear infiltration, compatible with a drug eruption. No other significant toxicity or intolerance was noted. [R40] *The effects of probenecid on the pharmacokinetics of zidovudine were studied in monkeys following a single intragastric or iv dose of 20 mg/kg zidovudine in the presence and absence of 50 mg/kg intragastric probenecid. In the presence of probenecid, the total clearance of zidovudine decreased by 50%, renal clearance decreased, and elimination half life increased. The steady state volume of distribution and systemic bioavailability of zidovudine were not significantly affected by probenecid. Area under the concn time curve and terminal half life of the 5'-glucuronide metabolite of zidovudine were increased and its renal clearance decreased. It was concluded that probenecid inhibits the metabolism and renal tubular secretion of zidovudine. [R41] *Plasma kinetics and renal excretion of iv iodopyracet (3.0 g) with and without concomitant administration of iv probenecid (75 mg followed by 2.5 or 5 ml/hr of 0.5% solution) were studied in beagle dogs. Tubular secretion was found to be the predominant route of excretion for iodopyracet. The model enabled an accurate description and analysis of the measured plasma levels and renal excretion rates. The interaction with probenecid could be adequately described with the model by competitive inhibition of the carrier mediated uptake of iodopyracet into the tubular cells. Model calculations showed that in the control experiments tubular secretion was accompanied by a pronounced accumulation of iodopyracet within the cells, which was clearly diminished in the presence of probenecid. [R42] *The effect of an oral dose of probenecid on the disposition kinetics of ampicillin was determined in four horses. An iv bolus dose (10 mg/kg) of ampicillin sodium was administered to the horses on two occasions. On the first occasion the antibiotic was administered on its own, and on the second occasion it was administered one hr after an oral dose of 75 mg/kg probenecid. The plasm concn of probenecid reached a mean (+ or - standard error) maximum concn of 188-6 + or - 19.3 ug/ml after 120.0 + or - 21.2 minutes and concn greater than 15 ug/ml were present 25 hr after it was administered. The disposition kinetics of ampicillin were altered by the presence of probenecid and as a result the antibiotic had a slower body clearance (109.4 + or - 6.71 ml/kg hr compared with 208.9 + or - 26.2 ml/kg hr) a longer elimination half life (1.198 hr compared with 0.701 hr) and consequently larger area under the plasma concn versus time curve (92.3 + or - 5.09 mg/ml hr compared with 35.95 + or - 3.45 mg/ml hr) when compared with animals to which ampicillin was administered alone. The ampicillin concn observed suggest that the dosing interval for horses may be increased from between six and eight hr to 12 hr when probenecid is administered in conjunction with the ampicillin. [R43] *To assess the effects of concomitant administration of cefprozil with food, metoclopramide hydrochloride (Reglan), propantheline bromide (Pro-banthine), and probenecid (Benemid), an open, 4 way study was conducted in 15 healthy male volunteers, ages 19-47 yr, who received a single oral dose of 1000 mg of cefprozil as an oral capsule; single oral doses of either 30 mg metoclopramide, 30 mg propantheline, or 1 g probenecid and the standard breakfast were administered 0.5 hr before the cefprozil dose, and blood samples and total urine output were collected and assayed for pharmacokinetic parameters. Results indicated that probenecid significantly prolonged the half life of cefprozil. Metoclopramide reduced the Tmax, but did not affect other pharmacokinetic parameters. Propantheline delayed the Tmax, but did not affect other parameters. Food delayed the time to reach Cmax but did not have a significant effect on other pharmacokinetic parameters. It was concluded that the extent of absorption of cefprozil was not affected by changes in gastric motility and concurrent administration of food. Renal tubular secretion is a significant pathway in elimination of cefprozil. [R44] *Ceftazidime pharmacokinetic values were studied in unweaned calves given the antibiotic alone or in combination with probenecid. Ceftazidime was administered iv to 9 calves at a dosage of 10 mg/kg of body wt and im (10 mg/kg) to 8 calves, to 7 calves (10 mg/kg plus probenecid (40 mg/kg)), and to 9 calves (10 mg/kg plus probenecid (80 mg/kg)). Serum concn vs time data were analyzed, using noncompartmental methods based on statistical moment theory. The data for iv ceftazidime administration also were fitted by use of a linear, open 2 compartment model. The mean (+ or - standard deviation) terminal half life was 138.7 + or - 23.6 min and 126.3 + or - 10.5 min after iv and im administrations, respectively. The mean residence time was 167.3 + or - 21.1 min and 201.4 + or - 16.8 min after iv and im administrations, respectively. Coadministeration of probenecid did not affect the terminal half life or mean residence time values. The total body clearance was 1.75 + or - 0.26 ml/min/kg, and the volume of distribution at steady state was 0.294 + or - 0.064 l/kg. The estimated mean absorption time was 34.1 min. There were no significant differences between the mean residence time calculated by statistical moment theory or by compartmental analysis, indicating central compartment output of ceftazidime. The 90% minimal inhibitory concn values of ceftazidime determined for Escherichia coli, Salmonella sp, Pasteurella multocida, and Pasteurella haemolytica isolates ranged from less than 0.01 to 0.1 ug/ml. [R45] *Cefuroxime pharmacokinetics were studied in unweaned calves. The antibiotic was administered at 10 mg/kg to six calves iv, to 12 calves im and to ten of the previous 12 calves im at 10 mg/kg together with probenecid at 40 mg/kg. Im doses of cefuroxime alone at 20 mg/kg were given to seven calves; to five of these calves cefuroxime was also given together with probenecid at 40 mg/kg and at 80 mg/kg. The serum concn-time data were analyzed using statistical moment theory. The elimination half life was 69.2 min (harmonic mean) after iv and 64.8 min and 64.9 min following im administration of the lower and higher dose, respectively. Co-administration of probenecid did not affect the half life. The mean residence time was 80.9 + or - 23.5 min (mean + or - standard deviation) after iv and 117.8 + or - 9.3 min and 117.7 + or - 5.4 min after im administration of cefuroxime at 10 and 20 mg/kg, respectively. The mean residence time (im) following administration of cefuroxime at 10 mg/kg together with probenecid at 40 mg/kg was 140.0 + or - 8.8 min. The mean residence time (im) values were 132.8 + or - 2.3 min and 150.8 + or - 5.1 min after cefuroxime was given at 20 mg/kg together with probenecid at 40 mg/kg or 80 mg/kg, respectively. The total body clearance was 3.56 + or - 1.11 ml/min/kg and the volume of distribution at steady state was 0.270 + or - 0.051 l/kg. The minimal inhibitory concn values of cefuroxime were 16 ug/ml for Escherichia coli and Salmonella isolates, 0.5 ug/ml for Pasteurella multocida and 2.0 ug/ml for Pasteurella haemolytica. [R46] *The effect of 500 mg of probenecid 3 times a day for 2 days on the pharmacokinetics of single 150 mg oral doses of carprofen enantiomers was studied in 3 healthy females, aged 26-31 yr; probenecid was administered beginning the day before carprofen was administered. Probenecid reduced apparent total and renal clearances for both enantiomers. It also reduced clearances of the carprofen enantiomers to their glucuronides and the renal clearances of the glucuronides. The differences caused by probenecid were significant, but few stereoselective effects were observed [R47] *2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline was studied following iv administration to mice. Maximal electroshock seizures were suppressed by low doses of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (ED50 = 13 mg/kg) but effects had dissipated by 10 min after a dose of 25 mg/kg. Coadministration of the transport inhibitor probenecid (p-(dipropylsulphamoyl)-benzoic acid) enhanced and prolonged the anticonvulsant action of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline an also enhanced and prolonged ataxia. 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline may be rapidly eliminated by a process sensitive to probenecid. [R48] *Furosemide causes not only natriuresis, but a rapid (5-10 min) increase in plasma renin activity. The latter has been attributed both to the release of eicosanoids from renal blood vessels and to changes in sodium delivery to the macula densa. Drugs like indomethacin abolish the renin increment and could potentially affect both mechanisms: they inhibit cyclooxygenase but could also compete with furosemide for transport into the tubular lumen, reducing furosemide concn at its site of action. The effects of probenecid, a weak acid without cyclooxygenase activity, on the responses to furosemide were studied in 20 healthy young men. Each received placebo and low (1000 mg/day) or high (2000 mg/day) doses of probenecid for one wk in double blind, randomized trials, crossover fashion. One hr after the last dose, all participants were given furosemide 0.5 mg/kg iv. Probenecid reduced serum uric acid in a dose dependent manner but did not change platelet thromboxane B2 production. Similarly, there was no change in urine excretion rates of thromboxane B2 or 6ketoprostaglandin F1 alpha, or in baseline or stimulated plasma renin activity. The total natriuresis in 4 hr was also unchanged. By contrast, the sodium excretion rate in the first 30 min was reduced after both probenecid regimens while that of later periods was increased. These findings are consistent with the proposed effect of probenecid as reducing furosemide secretion in the proximal tubule, which reduces its concn at the lumenal surface of the thick ascending limb of Henle's loop, but also prevents its excretion from the body. [R49] *Numerous drug interactions with the new 4-quinolone antimicrobial agents have now been established. Many, but not all, quinolones are extensively metabolized and can have inhibitory effects on the liver cytochrome p450 enzyme system, leading to reduced metabolism and clearance of certain other drugs that are normally thus eliminated. Probenecid reduces the renal elimination of some quinolones by inhibiting tubular secretion. [R50] *The effect of probenecid on the disposition of AZT was investigated in a pilot study in two healthy volunteers. The pharmacokinetics of AZT were examined after a single oral dose of 200 mg with and without probenecid coadministration in a balanced crossover study. Administration of 500 mg probenecid every 6 hr prior to and during AZT dosing resulted in an increase in the average area under the concentration time curve AZT from 89 ug min/ml (control) to 191 ug min/ml during probenecid treatment. This was manifested by a corresponding decrease in total clearance/F, which is attributed to the inhibitory effect of probenecid on the glucuronidation and renal excretion of AZT. Average renal clearance and total clearance/F of AZT decreased from 4.76 and 28.7 to 2.98 and 14.1 ml/min/kg during control and probenecid treatment, respectively. AZT glucuronidation was affected to a greater extent than its renal excretion, as reflected by the decreased ratio of the glucuronide metabolite of AZT/AZT urinary recoveries. The terminal half life of AZT was slightly longer during probenecid administration. That only a small change in the half life occurred indicates that probenecid also reduced the volume of distribution of AZT. The renal clearance of the glucuronide metabolite of AZT decreased from an average of 11.3 ml/min/kg (control) to 2.63 ml/min/kg during probenecid treatment, resulting in a greater than 3.5 fold increase in area under the concentration time curve of the glucuronide metabolite of AZT. Probenecid did not affect the blood/plasma distribution or the plasma protein binding of AZT. These preliminary findings suggest that it may be possible to maintain effective plasma AZT concentrations in AIDS patients receiving a reduced daily dose, in combination with probenecid. [R51] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Renal Agents; Uricosuric Agents [R52] *IT HAS BEEN WIDELY USED IN LAB AND CLINICAL INVESTIGATION OF EXCRETION OF A NUMBER OF SUBSTANCES. ... IT IS POTENT INHIBITOR OF CERTAIN GLYCINE CONJUGASES. HOWEVER, ITS THERAPEUTIC APPLICATIONS HAVE BEEN LIMITED PRINCIPALLY TO MODIFICATION OF RENAL EXCRETION OF PENICILLIN AND URIC ACID. [R9, 862] *... URICOSURIC AGENT FOR TREATMENT OF GOUT AND GOUTY ARTHRITIS. ... /SRP: THEORETICAL (BUT NOT PRACTICAL) USE/ AS ADJUVANT THERAPY WITH PENICILLIN G, O OR V OR WITH AMPICILLIN, METHICILLIN, OXACILLIN, CLOXACILLIN, OR NAFCILLIN, FOR ELEVATION AND PROLONGATION OF PENICILLIN PLASMA LEVELS BY ... ROUTE ANTIBIOTIC IS GIVEN. [R7] *ITS SUPPRESSION OF RENAL CLEARANCE OF PHENOLSULFONPHTHALEIN (PHENOL RED) IS OF SIGNIFICANCE IN APPLICATION OF THAT KIDNEY EXCRETION TEST AS CLINICAL GUIDE TO EFFECTIVENESS OF PROBENECID. ... /IT/ IS WELL TOLERATED /BY MOST PATIENTS ... . [R7] *... /PROBENECID/ HAS BEEN TOLERATED IN DAILY DOSES OF 2 G FOR AS LONG AS 4 YR. NO FATALITIES WERE REPORTED FROM ITS USE IN REVIEW OF 2502 PATIENTS PUBLISHED IN 1955. [R53] *PROBENECID IN SINGLE OR REPEATED DOSES DID NOT MODIFY LEVELS OF PGF2ALPHA AND THROMBOXANE B2 IN RAT BRAIN CORTEX. [R54] *Uricosuric agent indicated for the treatment of hyperuricemia associated with gout and gouty arthritis. Has also been used to increase the plasma levels and activity of the penicillin derivatives. [R5] *Probenecid is used to lower serum urate concentrations in the treatment of chronic gouty arthritis and tophaceous gout. The drug is indicated in patients with frequent disabling attacks of gout. [R4, 1652] *Probenecid has been used effectively and is commonly employed to promote uric acid excretion in hyperuricemia secondary to the administration of thiazide and related diuretics, furosemide, ethacrynic acid, pyrazinamide, or ethambutol [R4, 1652] *Probenecid is used as an adjuvant to therapy with penicillin G or V, ampicillin, oxacillin, cloxacillin, methicillin, or nafcillin to elevate and prolong the plasma concentrations of these antibiotics when administered orally or parenterally. Probenecid is also used concomitantly with amoxicillin, cephalosporin antibiotics, or some other beta-lactam antibiotics (eg, cefoxitin). Combined antibiotic and probenecid therapy is rarely necessary and should be limited to those situations in which high plasma and tissue antibiotic concentrations are necessary. Combined therapy with penicillin antibiotics and probenecid may be indicated for infections caused by bacteria that are only moderately sensitive to the antibiotic. In addition, probenecid is used concurrently with amoxicillin as one of the US Centers for Disease Control's (CDC) recommended alternative treatments for uncomplicated gonococcal infections caused by susceptible nonpenicillinase producing Neisseria gonorrhoeae; with cefuroxime axetil as part of one CDC recommended alternativ treatment for uncomplicated gonococcal infections caused by susceptible penicillinase producing Neisseria gonorrhoeae; and with cefoxitin as part of the CDC recommended treatment for acute pelvic inflammatory disease in ambulatory adults and adolescents. Probenecid is also used concurrently with penicillin G procaine as part of one CDC recommended treatment for neurosyphilis in ambulatory patients in whom compliance with therapy can be ensured. Although not currently included in the CDC's recommended regimens for the treatment of gonococcal infections, probenecid also has been used concurrently with amoxicillin or penicillin G procaine for the management of infections caused by penicillin susceptible Nelsseria gonorrhoeae. [R4, 1652] *Because blood probenecid concentrations are difficult to determine, serum urate concentrations should be used to monitor uricosuric therapy. The 15 min iv phenolsulfonphthalein excretion test can be used as an index to the probenecid dosage required to decrease penicillin secretion. Probenecid dosage is adequate when renal clearance of the dye is reduced to approximately 20% of the normal rate. [R4, 1652] *The prevalence and incidence of adverse drug interactions involving nonsteroidal anti-inflammatory drugs remains unknown. To identify those proposed drug interactions of greatest clinical significance, it is appropriate to focus on interactions between commonly used and/or commonly coprescribed drugs, interactions for which there are numerous well documented case reports in reputable journals, interactions validated by well designed in vivo human studies and those affecting high risk drugs and/or high risk patients. While most interactions between nonsteroidal anti-inflammatory drugs and other drugs are pharmacokinetic, nonsteroidal anti-inflammatory drug related pharmacodynamic interactions may be considerably more important in the clinical context, and prescriber ignorance is likely to be a major determinant of many adverse drug interactions. Digoxin, aminoglycosides and probenecid may be coprescribed with nonsteroidal anti-inflammatory drugs, but close monitoring is required, particularly for high risk patients such as the elderly. [R55] WARN: *SINCE ... /1955/ A SINGLE FATALITY HAS BEEN ATTRIBUTED TO HYPERSENSITIVITY TO PROBENECID. IN THIS PATIENTS, JAUNDICE, ASTHMA, SKIN RASH AND EOSINOPHILIA PRECEDEDMASSIVE HEPATIC NECROSIS. PATHOLOGY RESEMBLED FEW REPORTED CASES OF HEPATIC NECROSIS FROM SULFONAMIDES. [R53] *USE OF PROBENECID AND COLCHICINE IN TABLET COMBINATION (COLBENEMID) SHOULD BE AVOIDED IN TREATMENT OF INITIAL ATTACK OF GOUT, SINCE ACUTE LOWERING OF URIC ACID LEVEL MAY PERPETUATE ATTACK. RATIONALE FOR LONG TERM THERAPY ... IS QUESTIONABLE. [R56] *CAUTION IS WARRANTED WHEN PROBENECID IS GIVEN TO ACHIEVE HIGHER SERUM PENICILLIN LEVELS, SINCE THE CAUSE OF SUBSEQUENT DRUG RASH WILL BE DIFFICULT TO INTERPRET. [R56] *SOME DEGREE OF GI IRRITATION IS EXPERIENCED BY AT LEAST 2% OF PATIENTS; INCIDENCE IS CONSIDERABLY HIGHER AFTER LARGE DOSES. CAUTION IS ADVISED IN ADMINISTERING PROBENECID IN PATIENTS WITH HISTORY OF PEPTIC ULCER. MOST REPORTS PLACE INCIDENCE OF HYPERSENSITIVITY REACTIONS, USUALLY MILD SKIN RASHES, BETWEEN 2 and 4%. [R3, 746] *PROBENECID HAS NO SIGNIFICANT URICOSURIC ACTIVITY IN INDIVIDUALS WITH GLOMERULARFILTRATION RATE OF LESS THAN 30 ML/MIN AND THUS MAY NOT BE EFFECTIVE IN CHRONIC RENAL INSUFFICIENCY. ... /IT/ IS NOT INDICATED IN IN ACUTE ATTACKS OF GOUTY ARTHRITIS. ... ACUTE ATTACKS OF GOUT MAY OCCUR, ESP DURING EARLY MO OF THERAPY ... . [R15, 1731] *... /IT/ IS CONTRAINDICATED IN PATIENTS WITH HISTORY OF RENAL CALCULI, ESP URIC ACID STONES, BECAUSE IT MAY AGGRAVATE OR PRECIPITATE THIS CONDITION. [R15, 1732] *DIMINISHED TUBULAR SECRETION OF ... /SULFONAMIDES MAY BE AFFECTED BY CONCURRENT USE OF PROBENECID AND/ COULD RESULT IN HIGHER AND MORE SUSTAINED SERUM LEVELS AND, HENCE, AN INTENSIFICATION OF DRUG ACTIVITY. [R20, 392] *Probenecid should be used cautiously in patients with a history of peptic ulcer. The drug should not be used in patients with blood dyscrasias or uric acid kidney stones. It is also recommended that the drug not be used with a penicillin in patients with known renal impairment. Probenecid should be discontinued if a hypersensitivity reaction occurs and is contraindicated in patients with known hypersensitivity to the drug. [R4, 1653] *Probenecid is contraindicated in children younger than 2 yr of age. [R4, 1653] *With the exception of one neonatal death not definitely related to probenecid therapy, the drug has been used during pregnancy without adverse effect to the mother or child. [R4, 1653] *Several drugs may interfere with certain urine glucose tests, but the interactions are poorly documented. These drugs include chloral hydrate, hyaluronidase, nalidixic acid, nitrofurantoin, p-aminosalicylic acid, phenazopyridine, probenecid, and X-ray contrast media. [R57] MXDD: *IN SOME PATIENTS IT MAY BE NECESSARY TO INCR DAILY DOSE GRADUALLY TO MAX OF 2 G, GIVEN IN 4 DIVIDED PORTIONS. [R3, 8746] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R58] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl probenecid, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. [R59] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *RAPID HPLC METHOD FOR DETERMINATION OF PROBENECID IN BIOLOGICAL FLUIDS. LOWER LIMIT OF REPRODUCIBLE DETECTION OF 0.5 UG/ML. [R60] *DETERMINATION OF PROBENECID IN SERUM BY HPLC. [R61] *A FLUOROMETRIC METHOD FOR DETERMINATION OF PROBENECID IN BIOLOGICAL FLUIDS WAS FOUND TO BE MORE SENSITIVE THAN CONVENTIONAL METHODS FOR CEREBROSPINAL FLUID, BUT LESS SENSITIVE FOR BLOOD. [R62] *A HPLC method was developed and used for the analysis of probenecid (Benemid) and its glucuronide metabolite in the blood and urine of a subject following administration of the drug. [R63] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Probenecid in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 395 (1991) NIH Publication No. 91-2850 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1230 R3: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R4: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 93. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1993 (Plus Supplements, 1993). R5: Hussar, D.A. (ed.). Modell's Drugs in Current Use and New Drugs. 38th ed. New York, NY: Springer Publishing Co., 1992. 136 R6: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 767 R7: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 873 R8: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 279 R9: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R10: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1247 R11: Bammel A et al; Br J Clin Pharmacol 31 (Jan): 120-1 (1991) R12: LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971. R13: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R14: Toxicology and Carcinogenesis Studies of Probenecid in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 395 (1991) NIH Publication No. 91-2850 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. R16: Vree TB et al; Pharm Weekbl Sci Ed 14 (Oct 16): 325-31 (1992) R17: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-100 R18: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 288 R19: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 41 R20: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R21: RAMU A ET AL; J PHARMACOKINET BIOPHARM 6 (5): 389 (1978) R22: SMITH DE ET AL; J PHARM SCI 69 (5): 571 (1980) R23: VLASSES PH ET AL; ANTIMICROB AGENTS CHEMOTHER 17 (5): 847 (1980) R24: BABER N ET AL; CLIN PHARMACOL THER 24 (3): 298 (1978) R25: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. R26: Ban M, de Ceaurriz J; Toxicol Let 40 (1): 71-76 (1988) R27: Bax RP et al; J Antimicrob Chemother 24 (Suppl A): 311-20 (1989) R28: Cretton EM, Sommadossi JP; Biochem Pharmacol 42 (7): 1475-80 (1991) R29: Darnerud PO et al; Arch Toxicol 63 (5): 345-50 (1989) R30: De Ceaurriz J, Ban M; Toxicol Lett 59 (1-3): 139-45 (1991) R31: de Miranda P et al; Clin Pharmacol Ther 46 (5): 494-500 (1989) R32: Gisclon LG et al; Clin Pharmacol Ther 45 (Apr): 444-52 (1989) R33: Hedman A et al; Br J Clin Pharmacol 32 (Jul): 63-7 (1991) R34: Juzwiak JS et al; Am J Vet Res 50 (10): 1742-7 (1989) R35: Kornhauser DM et al; Lancet 2 (Aug 26): 473-5 (1989) R36: Lam YW et al; J Clin Pharmacol 31 (May): 429-32 (1991) R37: Monig H et al; Eur J Clin Pharmacol 39 (3): 261-5 (1990) R38: Nadai M et al; J Pharm Sci 81 (Oct): 1024-27 (1992) R39: Noormohamed FH, Lant AF; Clin Pharmacol Ther 50 (5 Pt 1): 564-72 (1991) R40: Petty BG et al; Lancet 335 (Apr 28): 1044-45 (1990) R41: Qian M et al; J Pharm Sci 80 (Nov): 1007-11 (1991) R42: Russel FG et al; Biopharm Drug Dispos 10 (Mar-Apr): 137-52 (1989) R43: Sarasola P, McKellar QA; Vet Rec 131 (8): 173-5 (1992) R44: Shukla UA et al; J Clin Pharmacol 32 (Aug): 725-31 (1992) R45: Soback S, Ziv G; Am J Vet Res 50 (9): 1566-9 (1989) R46: Soback S et al; J Vet Pharmacol Ther 12 (1): 87-93 (1989) R47: Spahn H et al; Clin Pharmacol Ther 45 (May): 500-5 (1989) R48: Taylor CP, Vartanian MG; Eur J Pharmacol 213 (1): 151-3 (1992) R49: Walshaw PE et al; Clin Invest Med 15 (1): 82-7 (1992) R50: Davies BI, Maesen FP; Rev Infect Dis 11 (Suppl 5): S1083-90 (1989) R51: Hedaya MA et al; Pharm Res 7 (4): 411-7 (1990) R52: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R53: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-405 R54: SPAGNUOLO C ET AL; PROSTAGLANDINS 18 (2): 311 (1979) R55: Johnson AG et al; Drug Saf 8 (2): 99-127 (1993) R56: Miller, R. R., and D. J. Greenblatt. Handbook of Drug Therapy. New York: Elsevier North Holland, 1979. 482 R57: Rotblatt MD, Koda-Kimble MA; Diabetes Care 10 (1): 103-10 (1987) R58: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91) R59: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-232 (1992) R60: HEKMAN P ET AL; J CHROMATOGR 182 (2): 252 (1980) R61: HARLE RK, COWEN T; ANALYST (LONDON) 103 (5): 492 (1978) R62: CUNNINGHAM RF ET AL; J PHARM SCI 67 (3): 434 (1978) R63: Vree TB, Beneken Kolmer EW; Pharm Weekbl Sci Ed 14 (Jun 19): 83-7 (1992) RS: 70 Record 238 of 1119 in HSDB (through 2003/06) AN: 3393 UD: 200302 RD: Reviewed by SRP on 5/6/2000 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TOLBUTAMIDE- SY: *D-860-; *U-2043-; *AGLICID-; *ARKOZAL-; *ARTOSIN-; *ARTOZIN-; *BENZENESULFONAMIDE, N-((BUTYLAMINO)CARBONYL)-4-METHYL-; *BUTAMID-; *BUTAMIDE-; *N-[(BUTYLAMINO)CARBONYL]-4-METHYLBENZENESULFONAMID; *1-BUTYL-3-(P-METHYLPHENYLSULFONYL)UREA; *N-BUTYL-N'-TOLUENE-P-SULFONYLUREA-; *1-BUTYL-3-(P-TOLYLSULFONYL)UREA; *1-BUTYL-3-TOSYLUREA-; *DIABEN-; *DIABESAN-; *DIABETAMID-; *DIABETOL-; *DIABUTON-; *DOLIPOL-; *DRABET-; *HLS-831-; *IPOGLICONE-; *N'-4-METHYLBENZENESULFONYL-N''-BUTYLUREA-; *N-(4-METHYLPHENYLSULFONYL)-N'-BUTYLUREA; *MOBENOL-; *NCI-C01763-; *ORABET-; *ORALIN-; *ORINASE-; *ORINAZ-; *OTERBEN-; *PRAMIDEX-; *RASTINON-; *N-(SULFONYL-P-METHYLBENZENE)-N'-BUTYLUREA; *TARASINA-; *TOLBET-; *TOLBUSAL-; *TOLBUTONE-; *1-P-TOLUENESULFONYL-3-BUTYLUREA-; *TOLUINA-; *TOLUMID-; *TOLUVAN-; *N-(P-TOLYLSULFONYL)N'-BUTYLCARBAMIDE; *TOLYLSULFONYLBUTYLUREA-; *3-(P-TOLYL-4-SULFONYL)-1-BUTYLUREA; *UREA, 1-BUTYL-3-(P-TOLYLSULFONYL)-; *WILLBUTAMIDE- RN: 64-77-7 MF: *C12-H18-N2-O3-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FROM BUTYL ISOCYANATE AND 4-TOLUENESULFONAMIDE SODIUM... [R1] *British patent 808,071 and Aumuller, Herr, German patent 1,066,575 (both 1959 to Hoechst); Ruschig et al, US patent 2,968,158 (1961 to Upjohn). [R2] MFS: *The Upjohn Company, Hq, 7000 Portage Rd, Kalamazoo, MI 49001, (616) 323-4000; Fine Chemical Division; Production site: Kalamazoo, MI 49001 [R3] *Mylan Pharmaceuticals, Inc., 781 Chestnut Ridge Road, P.O. Box 4310, Morgantown, WV 26504-4310 [R4] USE: *Therap cat: Antidiabetic [R2] *Therap cat (Vet): Hypoglycemic agent [R2] *An orally effective hypoglycemic drug. [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE OR PRACTICALLY WHITE CRYSTALLINE POWDER [R6]; *Crystals [R2] MP: *128.5-129.5 deg C [R2] MW: *270.35 [R2] DEN: *1.245 g/cu cm @ 25 deg C [R7] DSC: *pKa= 5.16 [R8] OWPC: *log Kow= 2.34 [R9] SOL: *DISSOLVES READILY IN AQ NAOH TO FORM SODIUM DERIV [R6]; *SOL IN ETHANOL, CHLOROFORM; FREELY IN DIMETHYL CARBONATE; INSOL IN WATER [R10, 116]; *Sol in ethanol, ethyl ether, and chloroform. [R7]; *In water, 109 mg/l @ 37 deg C [R11] SPEC: *MAX ABSORPTION (ACID): 229 and 263 NM (A= 503 and 27, 1%, 1 CM); (BASE): 226, 256, 262 and 274 NM (A= 405, 23, 22 and 21, 1%, 1 CM) [R10, 285]; *IR: 3486 (Coblentz Society Spectral Collection) [R12]; *UV: 5797 (Sadtler Research Laboratories Spectral Collection) [R12]; *NMR: 602 (Varian Associates NMR Spectra Catalogue) [R12] OCPP: *PRACTICALLY ODORLESS; HAS SLIGHTLY BITTER TASTE /SODIUM SALT/ [R6] *MP: 41-43 deg C; when anhyd, mp range is 130-133 deg C /Sodium salt tetrahydrate/ [R2] *SOL IN ALC AND CHLOROFORM; FREELY SOL IN WATER; VERY SLIGHTLY SOL IN ETHER /SODIUM SALT/ [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *HYPOGLYCEMIA INDUCED BY EVEN HIGH DOSES OF TOLBUTAMIDE IS GENERALLY NOT AS SEVERE AS CAN BE INDUCED BY INSULIN, HENCE INCIDENCE OF ACUTE HYPOGLYCEMIC REACTIONS IS LOWER WITH TOLBUTAMIDE. [R6] *Coma or altered mental status is generally the most important presenting sign in the majority (90%) of patients who have ingested excessive doses of the sulfonylureas ... /Sulfonylurea/ [R13, 723] NTOX: *CHRONIC ADMIN OF 30 MG/KG OR OVER TO NORMAL DOGS IS HEPATOTOXIC... [R14] *.../CHRONIC STUDY WAS PERFORMED/ WITH TOLBUTAMIDE IN DOG. MARKED REDN IN PLASMA LEVELS OF DRUG OCCURRED AFTER.../ADMIN/ 100 MG/KG FOR 12 DAYS. WHEN... INCR GRADUALLY TO 300 MG/KG OVER PERIOD OF 10 DAYS, PLASMA LEVELS INCR BUT DID NOT ACHIEVE INITIAL VALUES. AT THIS HIGH DOSAGE...SIDE EFFECTS OCCURRED AND DOG DIED ON 23RD DAY. [R15] *EXPTL, LIFELONG ADMIN OF TOLBUTAMIDE TO RATS AT DOSAGE LEVELS 5 TO 40 TIMES THOSE EMPLOYED IN HUMAN...HAS CAUSED OPACIFICATION OF LENS AND CORNEA, VASCULARIZATION OF CORNEA, AND POSTERIOR SYNECHIAS, USUALLY OBSERVABLE AT 8 TO 24 MO. [R16] *Tolbutamide was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Tolbutamide was tested at doses of 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Tolbutamide was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 10 mg/plate. [R17] NTP: *A bioassay of tolbutamide for possible carcinogenicity was conducted by admin the test material in the diet to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats of each sex were admin tolbutamide at one of two doses, either 12,000 or 24,000 ppm, 5 days/wk for 78 wk, then observed for an additional 28 wk. Matched control groups consisted of 15 untreated rats of each sex. All surviving rats were /sacrificed/ at 102-104 wk. Groups of 35 mice of each sex were admin tolbutamide at one of two doses, either 25,000 or 50,000 ppm, 5 days/wk for 78 wk, then observed for an additional 24-26 wk. Matched control groups consisted of 15 untreated mice of each sex. All surviving mice were /sacrificed/ at 102-104 wk. Mean body weights of the treated rats and mice were lower than those of the corresponding matched controls during the entire study; however, survival was not significantly affected by treatment in either species. In both sexes of both species, survival was considered to be adequate for meaningful statistical analyses of the incidence of tumors. In both the rats and mice, a variety of neoplasms were found in both the tolbutamide treated and control groups. None of the neoplasms were present in statistically significant incr incidence in treated groups of either species as compared with control groups and were not considered to be cmpd related. It is concluded that under the conditions of this bioassay, tolbutamide was not carcinogenic for either Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R18] ADE: *AFTER ORAL ADMIN, SULFONYLUREAS ARE RAPIDLY ABSORBED. /SULFONYLUREAS/ [R19] *TOLBUTAMIDE CAN BE DETECTED IN BLOOD WITHIN 30 MIN AFTER ORAL ADMIN; PEAK CONCN ARE REACHED WITHIN 3 TO 5 HR. .../IT/ IS BOUND TO PLASMA PROTEINS. ... HALF-LIFE OF TOLBUTAMIDE IS ABOUT 5 HR. [R20, 1521] *IN CONTRAST TO STUDIES REPORTED IN ANIMALS, METABOLIC CLEARANCE OF...TOLBUTAMIDE IN MAN HAS BEEN SHOWN TO BE UNALTERED BY FASTING. [R21, 350] *Excreted (percentage)...100 /from table/ [R13, 722] METB: *...MAJOR TOLBUTAMIDE METAB IN MAN HAS BEEN IDENTIFIED AS 1-BUTYL-3-P-CARBOXYPHENYLSULFONYLUREA... 1-BUTYL-3-P-HYDROXYMETHYLPHENYLSULFONYLUREA IS ALSO FORMED IN SMALL AMT. [R22, 218] *IN RAT, MAJOR URINARY METAB, 1-BUTYL-3-P-HYDROXYMETHYLPHENYLSULFONYLUREA COMPRISED 75% OF DOSE, BUT SMALL AMT OF 1-BUTYL-3-P-CARBOXYPHENYLSULFONYLUREA AND P-TOLYLSULFONYLUREA, COMPRISING 5% OF DOSE, WERE ALSO PRESENT. [R22, 219] *ALTHOUGH 1-BUTYL-3-P-HYDROXYMETHYLPHENYLSULFONYLUREA HAS BEEN REPORTED AS PRINCIPAL METAB IN CAT.../IT IS CLAIMED/ THAT CAT METABOLIZES TOLBUTAMIDE IN SAME WAY AS DOG. .../IT HAS BEEN SHOWN/ THAT TOLBUTAMIDE IS TRANSFORMED INTO 1-BUTYL-3-P-CARBOXYPHENYLSULFONYLUREA IN GUINEA PIGS AND RABBITS. [R22, 219] *IN CONTRAST TO RATS, RABBITS AND MAN, DOGS METABOLIZE TOLBUTAMIDE...INTO P-TOLYLSULFONYLUREA AND P-TOLYLSULFONAMIDE BY MECHANISM INVOLVING HYDROLYSIS. [R22, 417] *.../IT/ STIMULATES ITS OWN METABOLISM IN DOG... [R14] *Sulfonylureas are rapidly absorbed from the gastrointestinal tract, transported in the blood in highly protein-bound complexes, and subjected to extensive hepatic metabolism (except for chlorpropamide). Wide variation exists among the sulfonylureas in hepatic metabolism and remnal clearance, factors that tend to alter the steady-state serum levels. Metabolites may be active, so there may be a variation between the plasma half-life of the parent drug and the degree of hypoglycemia encountered. /Sulfonylurea/ [R13, 722] *Metabolized to compounds with negligible activity. /from table/ [R23, p. 48-37] BHL: *Half-life...3-25 /hours/ /from table/ [R13, 722] ACTN: *SULFONYLUREAS STIMULATE ISLET TISSUE TO SECRETE INSULIN. ... SULFONYLUREAS CAUSE DEGRANULATION OF BETA CELLS, A PHENOMENON ASSOC WITH INCR RATE OF SECRETION OF INSULIN. /SULFONYLUREAS/ [R20, 1520] *ALTHOUGH MOLECULAR MECHANISM...NOT UNDERSTOOD, SEVERAL PERTINENT OBSERVATIONS HAVE BEEN MADE. ...TOLBUTAMIDE IS RESTRICTED IN ITS ACTION TO EXTRACELLULAR SPACE AND DOES NOT NEED TO ENTER BETA CELL. INVOKED RELEASE OF INSULIN IS IMMEDIATE AND INTIMATELY RELATED TO ACTION OF GLUCOSE...MAY SENSITIZE CELL TO NORMAL SECRETAGOGUE. [R20, 1520] *Sulfonylureas are now...thought to act by a number of different mechanisms. 1. ...produce a depolarization of the pancreatic islet beta cell membrane potassium ion permeability. This results in a release of preformed insulin into the circulation and occurs mostly in non-insulin dependent diabetics. 2. ...reduce basal glucose output from the liver... 3. increase insulin receptor binding... 4. ...increasing intracellular levels of AMP... 5. increase insulin secretion by suppressing the release of glucagon and somatostatin from alpha and delta pancreatic cells. /Sulfonylureas/ [R13, 723] INTC: *SULFAPHENAZOLE ENHANCES ACTION OF TOLBUTAMIDE AND MAY CAUSE SYMPTOMS OF SEVERE HYPOGLYCEMIA IN DIABETIC PT. IT IS UNCLEAR WHETHER THIS INTERACTION ALSO OCCURS WITH OTHER SULFONAMIDES OR SULFONYLUREA COMPD. [R24, 250] *HYPOGLYCEMIC ACTIVITY OF TOLBUTAMIDE MAY BE ENHANCED BY CONCURRENT ADMIN OF PHENYLBUTAZONE, AND DOWNWARD ADJUSTMENT OF TOLBUTAMIDE DOSAGE MAY BE INDICATED. ... ALTHOUGH NOT DOCUMENTED, OXYPHENBUTAZONE AND POSSIBLY SULFINPYRAZONE CAN BE EXPECTED TO INTERACT SIMILARLY TO PHENYLBUTAZONE. [R24, 247] *SINCE MAO INHIBITORS MAY ENHANCE HYPOGLYCEMIC ACTION OF INSULIN IN ANIMALS AND IN HUMAN DIABETIC PT, CONCURRENT ADMIN OF MAO INHIBITORS AND INSULIN TO DIABETIC SUBJECTS MAY BE POTENTIALLY DANGEROUS. .../TOLBUTAMIDE HAS/ BEEN REPORTED TO INTERACT WITH MAO INHIBITORS. [R24, 111] *DICUMAROL INCR SERUM HALF-LIFE OF TOLBUTAMIDE AND MAY CAUSE SYMPTOMS OF HYPOGLYCEMIA. THIS EFFECT USUALLY OCCURS 3-4 DAYS AFTER INITIATING DICUMAROL THERAPY. ...PHENPROCOUMON INTERACTS WITH TOLBUTAMIDE IN ANIMALS. ...TOLBUTAMIDE DISPLACES WARFARIN FROM PROTEIN BINDING SITES IN VITRO. [R24, 245] *TOLBUTAMIDE AND ALCOHOL INTERACT BY MULTIPLE MECHANISMS AND CAUSE UNPREDICTABLE FLUCTUATIONS IN SERUM GLUCOSE LEVELS. MOST SERIOUS EFFECTS ARE SYMPTOMS OF SEVERE HYPOGLYCEMIA. ALCOHOL INGESTION MAY ALSO PRECIPITATE A DISULFIRAM-LIKE REACTION (EG, FLUSHING, HEADACHE, PALPITATIONS, AND FEELING OF BREATHLESSNESS)... [R24, 240] *HYPOGLYCEMIC ACTIVITY OF CHLORPROPAMIDE MAY BE ENHANCED BY CONCURRENT ADMIN OF ASPIRIN. ... TOLBUTAMIDE HAS ALSO BEEN SHOWN TO INTERACT WITH SALICYLATES. [R24, 36] *CO-ADMIN OF SULFAMETHIZOLE INCR ELIMINATION HALF-LIFE VALUES AND DECR METABOLIC CLEARANCES OF...TOLBUTAMIDE... [R21, 61] *HYPOGLYCEMIC ACTIVITY OF CHLORPROPAMIDE MAY BE ENHANCED BY CONCURRENT ADMIN OF CLOFIBRATE. .../TOLBUTAMIDE HAS/ DEMONSTRATED A SIMILAR INTERACTION WITH CLOFIBRATE. [R24, 529] *HALOFENATE, A HYPOLIPIDEMIC AGENT...WAS REPORTED TO ENHANCE HYPOGLYCEMIC EFFECT OF SULFONYLUREAS TO GREATER DEGREE THAN CLOFIBRATE. /SULFONYLUREA COMPD/ [R24, 529] *MANY DIABETIC PT REGULATED BY...SULFONYLUREAS EXHIBIT IMPAIRED DIABETIC CONTROL WHEN ANY THIAZIDE DIURETIC IS ADDED TO THE DRUG REGIMEN. ... ALL THIAZIDE DIURETICS HAVE POTENTIAL FOR PRODUCING KALIURESIS AND HYPOKALEMIA WHICH ARE PROBABLY ESSENTIAL STEPS IN PATHOGENESIS OF THE DRUG INTERACTION. /SULFONYLUREA COMPD/ [R24, 40] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Hypoglycemic Agents [R25] *IT IS USEFUL IN TREATMENT OF SELECTED CASES OF DIABETES MELLITUS, NAMELY MILD UNCOMPLICATED, STABLE DIABETES OF ADULT ONSET AND WHICH CANNOT BE CONTROLLED BY DIET ALONE. ... IN DIABETIC PT PEAK EFFECT IS REACHED IN 5 TO 8 HR. DURATION OF ACTION IS USUALLY LESS THAN 24 HR... [R6] *THERE IS NO FIXED DOSAGE OF SULFONYLUREA TO BE USED IN DIABETES MELLITUS. TREATMENT IS GUIDED BY INDIVIDUAL PATIENT'S RESPONSE... /SULFONYLUREAS/ [R20, 1523] *...REPORTS HAVE APPEARED OF SUCCESSFUL TREATMENT OF REACTIVE HYPOGLYCEMIAS DUE TO A VARIETY OF CAUSES WITH SULFONYLUREAS. /SULFONYLUREAS/ [R20, 1523] *VET: OCCASIONAL, AS AN ORAL HYPOGLYCEMIC AGENT FOR DOGS. [R14] WARN: *TOXIC EFFECTS OF TOLBUTAMIDE INCL GI UPSET, WEAKNESS, HEADACHE, TINNITUS, PARESTHESIAS, ALLERGIC REACTIONS (PRURITUS, ERYTHEMA MULTIFORME, MACULOPAPULAR RASH, ALL USUALLY TRANSIENT)...CHOLESTATIC JAUNDICE MAY OCCUR (RARELY)... RARE LEUKOPENIA, THROMBOCYTOPENIA, PANCYTOPENIA AND AGRANULOCYTOSIS OCCUR. [R6] *Despite this relative lack of teratogenicity, tolbutamide should be avoided in pregnancy since the drug will not provide good control in patients who cannot be controlled by diet alone. [R26] *SULFONYLUREAS SHOULD NOT BE USED IN PT WITH HEPATIC OR RENAL INSUFFICIENCY BECAUSE OF IMPORTANT ROLE OF LIVER IN THEIR METAB AND OF KIDNEY IN EXCRETION OF DRUG AND THEIR METABOLITES. ... THESE AGENTS ARE ALSO NOT RECOMMENDED FOR USE IN PREGNANCY... /SULFONYLUREAS/ [R20, 1522] *Maternal Medication Usually Compatible with Breast-Feeding: Tolbutamide: Possible jaundice. /from Table 6/ [R27] *...STUDIES HAVE CONTINUED TO INDICATE AN INCR INCIDENCE OF SERIOUS DIFFICULTIES IN PT TAKING ORAL HYPOGLYCEMIC DRUGS. MORE EPISODES OF VENTRICULAR TACHYCARDIA AND VENTRICULAR FIBRILLATION WERE NOTED IN SUCH DIABETIC SUBJECTS, USUALLY DURING EARLY STAGES OF ACUTE MYOCARDIAL INFARCTION... /SULFONYLUREAS/ [R20, 1522] *...WHATEVER AGE OF ONSET, IN UNSTABLE, KETOACIDOTIC DIABETES, SULFONYLUREAS WILL NOT PROVIDE ADEQUATE CONTROL. SUCH PT REQUIRE INSULIN, AND ATTEMPTS TO CONTROL THEM WITH ORAL THERAPY ARE DANGEROUS AND DOOMED TO FAILURE. /SULFONYLUREAS/ [R20, 1523] *IF PT REQUIRES MORE THAN 40 UNITS OF INSULIN/DAY, HE GENERALLY WILL NOT RESPOND TO TOLBUTAMIDE. ... REFRACTORINESS TO TOLBUTAMIDE SOMETIMES DEVELOPS. [R6] *Use near term may result in prolonged neonatal hypoglycemia. Not recommended in pregnancy since it will not provide better control than diet alone. /from table/ [R23, p. 45-7] *Nausea, epigastric fullness, heartburn, and headache have occurred in patients receiving tolbutamide. These adverse effects appear to be dose related and frequently subside following a reduction in dosage 6 maintenance levels or by administering the total daily dosage of the drug in divided doses after meals. [R28] *Allergic skin reactions including pruritus, erythema, and urticarial, morbilliform, or maculopapular eruptions have also been reported. These adverse dermatologic effects are usually transient and frequently subside during continued administration of the drug; however, if adverse dermatologic effects persist or are severe, tolbutamide should be discontinued. [R28] *Hypoglycemia, which may be severe, has occurred in patients receiving tolbutamide and may resemble acute neurologic disorders such as cerebral thrombosis. Hypoglycemia may result from excessive dosage; however since the development of hypoglycemia is a function of many factors including diet, this effect may occur in some patients receiving usual dosages of the drug. Hypoglycemia is readily controlled by administration of glucose. If hypoglycemia occurs during therapy with the drug, immediate reevaluation and adjustment of tolbutamide dosage are necessary. [R28] *The cardiovascular risks associated with use of oral sulfonylurea antidiabetic agents have not been fully determined. The American Diabetes Association currently recommends that clinicians continue to emphasize dietary management and weight reduction as the principal therapy for the management of type 2 diabetes mellitus, and that oral sulfonylurea antidiabetic agents or insulin be used only after these measures have failed; the decision to use a sulfonylurea or insulin should be made by the clinician in consultation with the patient. [R28] *Photosensitivity reactions, hepatic porphyria, and porphyria cutanea tarda have also been reported in patients receiving tolbutamide. Although tolbutamide is mildly goitrogenic in animals receiving large doses and has caused decreased radioactive iodine uptake in humans, clinical hypothyroidism or thyroid enlargement has not been reported in humans. [R28] *Patients should be properly instructed in the early detection and treatment of hypoglycemia, since hypoglycemic reactions may occasionally occur during therapy with tolbutamide. Debilitated, malnourished, or geriatric patients and patients with impaired hepatic and/or renal function should be carefully monitored and dosage of tolbutamide carefully adjusted, since these patients may be predisposed to developing hypoglycemia (sometimes severe). Alcohol ingestion and adrenal or pituitary insufficiency may also predispose patients to the development of hypoglycemia. Intensive treatment (e.g., IV dextrose) and close medical supervision may be required in some patients who develop severe hypoglycemia during tolbutamide therapy. [R28] *To maintain control of diabetes during periods of stress (e.g., fever of any cause, trauma, infection, surgery), temporary use of insulin, either alone or in combination with tolbutamide, may be required. [R28] *Tolbutamide should be used with caution in patients with a history of hepatic porphyria since, like sulfonamides and barbiturates, sulfonylurea, antidiabetic agents may exacerbate this condition. Tolbutamide is contraindicated as sole therapy in patients with type I diabetes mellitus and in those with diabetes complicated by ketosis, acidosis, diabetic coma, or other acute complications such as major surgery, severe infection, or severe trauma. Tolbutamide is also contraindicated in patients with severe renal insufficiency. [R28] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R29] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *TYPE C PROCEDURE FOR PLASMA SAMPLES USING GAS CHROMATOGRAPH, FITTED WITH FLAME IONIZATION DETECTORS. TOLAZAMIDE AND BARBITURATES ARE INTERFERING SUBSTANCES. [R30] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP TR No 031; Route: oral in feed; Species: rats and mice. NTIS No PB274483/AS. [R31] SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1223 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1622 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 768 R4: Arky R, Davidson CS; Physician's Desk Reference, 53rd ed. p. 1958 (1999) R5: Gennaro AR et al, eds; Blakiston's Gould Medical Dictionary 4th ed p. 1380 (1979) R6: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 905 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-62 R8: Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) R9: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 105 R10: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R11: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth ed, Tucson, AZ: Univ AZ, College of Pharmacy (1992) R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 359 R13: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R14: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 608 R15: LaDu, B.N., H.G. Mandel, and E.L. Way. Fundamentals of Drug Metabolism and Disposition. Baltimore: Williams and Wilkins, 1971. 355 R16: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 1025 R17: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R18: Bioassay of Tolbutamide for Possible Carcinogenicity (1977) Technical Rpt Series No. 31 U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R19: Miller, R. R., and D. J. Greenblatt. Handbook of Drug Therapy. New York: Elsevier North Holland, 1979. 689 R20: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R21: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. R22: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. R23: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995. R24: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R25: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R26: Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams and Wilkins 1994. 832 R27: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 142 (1994) R28: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 99. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 1999 (Plus Supplements). 2750 R29: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) R30: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 354 R31: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/07/93; p.27 RS: 23 Record 239 of 1119 in HSDB (through 2003/06) AN: 3405 UD: 200201 RD: Reviewed by SRP on 9/18/1998 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIAMTERENE- SY: *ADEMIN- (E); *ADEMINE-; *DIREN-; *DITAK-; *DIURENE-; *DYREN-; *DYTAC-; *JATROPUR-; *NORIDIL-; *NORIDYL-; *6-PHENYL-2,4,7-PTERIDINETRIAMINE-; *6-PHENYL-2,4,7-TRIAMINOPTERIDINE-; *2,4,7-PTERIDINETRIAMINE,-6-PHENYL-; *PTERIDINE,-2,4,7-TRIAMINO-6-PHENYL-; *PTEROFEN-; *PTEROPHENE-; *SKF-8542-; *TATURIL-; *TERIAM-; *TERIDIN-; *2,4,7-TRIAMINO-6-PHENYLPTERIDINE-; *TRIAMPUR-; *TRIAMTEREN-; *TRIAMTERIL-; *TRIAMTERIL-COMPLEX-; *TRI-SPAN-; *TRITEREN-; *UROCAUDAL- RN: 396-01-0 MF: *C12-H11-N7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *SPICKETT, TIMMIS, J CHEM SOC 1954, 2887; PACHTER, J ORG CHEM 28, 1191 (1963); WEINSTOCK, WIEBELHAUS, US PATENT 3,081,230 (1963 TO SK AND F); OSDENE ET AL, J MED CHEM 10, 431 (1967). [R1] *By condensation of 2,4,6-triamino-5-nitrosopyrimidine with benzyl cyanide. [R2] FORM: *DYRENIUM (SMITH KLINE AND FRENCH). ORAL: CAPSULES 50 and 100 MG. TRIAMTERENE AND HYDROCHLOROTHIAZIDE: DYAZIDE (SMITH KLINE AND FRENCH). ORAL: EACH CAPSULE CONTAINS TRIAMTERENE 50 MG AND HYDROCHLOROTHIAZIDE 25 MG. [R3] MFS: *Lonza Inc., Hq, 17-17 Route 208, Fair Lawn, NJ 07410, (201) 794-2400; Organic Chemicals Division; Production site: Conshohocken, PA 19428. [R4] USE: *MEDICATION (VET): DIURETIC AND NATRIURETIC AGENT [R5] *THERAP CAT: DIURETIC. [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW PLATES FROM BUTANOL [R1]; *CRYSTALS FROM DIMETHYLFORMAMIDE [R1]; *YELLOW CRYSTALLINE POWDER [R6] ODOR: *ODORLESS [R6] MP: *316 DEG C [R1] MW: *253.27 [R1] OWPC: *log Kow = 0.98 [R7] SOL: *Soluble in formic acid and sparingly soluble in methoxyethanol. Practically insoluble in benzene, chlorofrom, ether, and dilute alkali hydroxides. Very slightly soluble in acetic acid, alcohol, and dilute mineral acids. [R8, p. 694 (1998)]; *In water, less than 0.1% at 50 deg C [R8, p. 2817 (1998)]; *Soluble in dilute ammonia, dilute aqueous sodium hydroxide, and dimethylformamide. Sparingly soluble in methanol. [R8, p. 2819 (1998)] SPEC: *MAX ABSORPTION (4.5% FORMIC ACID): 356 NM (E= 21,000) [R1] OCPP: *Melting point = 327 deg C (crystals from DMF) [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R9] SSL: *STABLE TO TEMP AND LIGHT [R6] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *Triamterene was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Triamterene was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.100, 0.333, 1.000, 2.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 10.000 mg/plate. Precipitate was observed in cultures containing the 4 high doses. [R10] *... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of triamterene in male F344/N rats based on a marginal increase in the incidence of hepatocellular adenoma. There was no evidence of carcinogenic activity of triamterene in female F344/N rats administered 150, 300, or 600 ppm. There was some evidence of carcinogenic activity of triamterene in male B6C3F1 mice based on a marginal increase in the incidence of hepatocellular carcinoma in the first study and a significantly increased incidence of hepatocellular adenoma in the second study. There was some evidence of carcinogenic activity of triamterene in female B6C3F1 mice based on significantly increased incidences of hepatocellular adenoma and of adenoma and carcinoma (combined). [R11] NTXV: *LD50 Rat oral 400 mg/kg; [R9] *LD50 Rat ip 200 mg/kg; [R9] *LD50 Mouse oral 285 mg/kg; [R9] *LD50 Mouse ip 249 mg/kg; [R9] *LD50 Mouse sc 620 mg/kg; [R9] NTP: *... Toxicity and carcinogenicity studies were conducted by administering triamterene (greater than 99% pure) in feed to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. ... 2-Year Studies: ... Groups of 70 male and 70 female rats were fed diets containing 0, 150, 300, or 600 ppm triamterene and groups of 70 male and 70 female mice were fed diets containing 0, 100, 200, or 400 ppm. ... Because of a dosing error involving the high-dose mice at week 40, a second study was conducted with groups of 60 male and 60 female mice fed diets containing 0 or 400 ppm triamterene. In the 2 yr studies, rats exposed to 150, 300, or 600 ppm triamterene received approximately 5,10, or 25 mg/kg body weight per day (males) and 5, 15, or 30 mg/kg (females) and mice exposed to 100, 200, or 400 ppm received approximately 10, 25, or 45 mg/kg (males) and 15, 30, or 60 mg/kg (females) per day. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of triamterene in male F344/N rats based on a marginal increase in the incidence of hepatocellular adenoma. There was no evidence of carcinogenic activity of triamterene in female F344/N rats administered 150, 300, or 600 ppm. There was some evidence of carcinogenic activity of triamterene in male B6C3F1 mice based on a marginal increase in the incidence of hepatocellular carcinoma in the first study and a significantly increased incidence of hepatocellular adenoma in the second study. There was some evidence of carcinogenic activity of triamterene in female B6C3F1 mice based on significantly increased incidences of hepatocellular adenoma and of adenoma and carcinoma (combined). [R11] ADE: *IT IS RAPIDLY ABSORBED FROM GI TRACT AND IS THEN EXCRETED IN URINE, WITH PEAK IN RENAL EXCRETION WITHIN 1-2 HR AFTER ORAL INGESTION. FROM 10-88% OF ORAL DOSE CAN BE RECOVERED FROM URINE WITHIN 24 HR. IT IS PROBABLE THAT THIS WIDE RANGE OF VALUES IS REFLECTION OF VARIABLE INTESTINAL ABSORPTION. [R12, 838] *IN PLASMA, TRIAMTERENE IS ABOUT 2/3RD BOUND TO PROTEIN. RENAL EXCRETION IS ACCOMPLISHED BOTH BY FILTRATION AND TUBULAR SECRETION... [R12, 838] *...IT HAS BEEN NOTED THAT TRIAMTERENE IS TRANSFERRED FROM FETUS MUCH MORE RAPIDLY THAN TO FETUS... [R13] *IN VOLUNTEERS, 2-4 HR AFTER ORAL ADMIN OF 100-200 MG OF TRIAMTERENE PLASMA CONCN WAS 50-280 NG/ML. [R14] *150 MG AND 300 MG WERE GIVEN ORALLY. URINARY EXCRETION COMPLETED AFTER 48 HR. ... [R15] *AFTER IV ADMIN IN RATS OF (14)C-TRIAMTERENE, HIGH CONCN RATIOS BETWEEN TISSUES AND BLOOD IN MOST TISSUES EXCEPT BRAIN, FAT AND TESTES. MAX CONCN OF DRUG IN KIDNEY, LIVER, HEART, LUNGS, AND SKELETAL MUSCLE WITHIN 1ST 20 MIN. NO METABOLITE DETECTED IN THESE TISSUES. [R16] *VOL OF DISTRIBUTION FOLLOWING IV ADMIN TO RATS WAS GREATER IN CENTRAL COMPARTMENT (60% OF DOSE) THAN IN PERIPHERAL COMPARTMENT (40%). BINDING TO SKELETAL MUSCLE IS RESPONSIBLE FOR FRACTION OF DOSE IN PERIPHERAL COMPARTMENT. SLOW ELIMINATION IS RELATED TO ITS BINDING TO TISSUE [R16] *PROFILE SHOWED PEAK @ 3 HR FOR PLASMA (16.2 NG/ML) AND WHOLE BLOOD (20.3 NG/ML) DECLINING TO 6.1 and 10.8 NG/ML @ 7.6 HR, RESPECTIVELY. [R17] METB: *150 MG AND 300 MG WERE GIVEN ORALLY. URINARY EXCRETION OF ITS METABOLITE, P-HYDROXYTRIAMTERENE SULFATE CONJUGATE, VARIED BETWEEN 25.0 and 17.5% OF DOSE. [R15] BHL: *4.2 hr /From table/ [R18, 705] *150 MG AND 300 MG WERE GIVEN ORALLY. ... EST T/2 LONGER THAN 2 HR. [R15] ACTN: *...DIURESIS IS CHARACTERIZED BY INCR IN EXCRETION OF SODIUM, MOSTLY ACCOMPANIED BY CHLORIDE AS ANION... IT IS PRESUMED...THAT ACTION OF TRIAMTERENE IS DIRECTLY ON TUBULAR TRANSPORT AND IS INDEPENDENT OF ALDOSTERONE. REDUCED RATE OF POTASSIUM EXCRETION RESULTS FROM INHIBITION OF SECRETION OF POTASSIUM IN DISTAL NEPHRON. [R12, 838] *...TRIAMTERENE MAY BE SLIGHTLY URICOSURIC, BUT MECHANISM OF THIS ACTION HAS NOT BEEN EXAMINED. UNLIKE OTHER DIURETICS, TRIAMTERENE DOES NOT APPEAR TO CAUSE URATE RETENTION. [R12, 839] INTC: *ANTAGONIZES SODIUM RETAINING EFFECTS OF ALDOSTERONE AND FLUDROCORTISONE. [R5] *CONCURRENT ADMIN OF SPIRONOLACTONE AND POTASSIUM CHLORIDE MAY INCR INCIDENCE OF HYPERKALEMIA. ... OTHER DIURETICS THAT DECR POTASSIUM EXCRETION SUCH AS...TRIAMTERENE MAY BE EXPECTED TO INCR POTASSIUM LEVELS IN SIMILAR MANNER. [R19] *BASELINE POTASSIUM EXCRETION DID NOT INCR WHEN FUROSEMIDE GIVEN ALONE, BUT FELL WHEN 50 M OR 100 MG OF TRIAMTERENE ALSO GIVEN. TRIAMTERENE AUGMENTED NATRIURETIC EFFECT OF FUROSEMIDE. [R20] *TESTS ON ISOLATED, PERFUSED GUINEA PIG HEARTS. IN PRESENCE OF TRIAMTERENE, THE DOSE-RESPONSE CURVE FOR INOTROPIC EFFECT OF OUABIN WAS SHIFTED SLIGHTLY TO HIGHER CONCN AND NONTOXIC RANGE WAS APPRECIABLY EXTENDED. [R21] *Renal toxicity may be exacerbated with NSAIDs. /From table/ [R22] *Triamterene may raise the concentration of blood uric acid, but to a lesser extent than thiazide diuretics or etharynic acid or furosemide; dosage adjustment of antigout medications may be necessary to control hyperuricemia and gout. [R23, 1252] *Anticoagulant effects may be decreased when these medications /coumarin- or indandione-derivative anticoagulants or heparin/ are used concurrently with potassium-sparing diuretics, as a result of reduction of plasma volume leading to concentration of procoagulant factors in the blood; in addition, diuretic-induced improvement of hepatic congestion may lead to improved hepatic function, resulting in increased procoagulant factor synthesis; dosage adjustments may be necessary. /Potassium-sparing diuretics/ [R23, 1252] */Nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin/ may reduce the antihypertensive effects of the potassium-sparing diuretics; indomethacin may also reduce the natriuretic and diuretic effects of potassium-sparing diuretics, possibly because of renal prostaglandin synthesis inhibition and/or sodium and fluid retention; the patient should be carefully monitored to confirm that the desired effect is being obtained. Concurrent use of NSAIDs with a diuretic may increase the risk of renal failure secondary to a decrease in renal blood flow caused by inhibition of renal prostaglandin synthesis. /Potassium-sparing diuretics/ [R23, 1252] *Concurrent administration /of angiotensin-converting enzyme (ACE) inhibitors or nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin or blood from blood bank (may contain up to 30 mEq (mmol) or potassium per liter of plasma or up to 65 mEq (mmol) per liter of whole blood when stored for more than 10 days or cyclosporine or other potassium-sparing diuretics or heparin or low-salt milk (may contain up to 60 mEq (mmol) of potassium per liter) or potassium-containing medications or potassium supplements or substances containing high levels of potassium or salt substitutes (most contain substantial amounts of potassium/ with potassium-sparing diuretics tends to promote serum potassium accumulation; hyperkalemia may result, especially in patients with renal insufficiency. /Potassium-sparing diuretics/ [R23, 1252] *Antihypertensive and/or diuretic effects may be potentiated when these medications /other hypotension-producing medications/ are used concurrently with potassium-sparing diuretics; although some antihypertensive and/or diuretic combinations are frequently used for therapeutic advantage, dosage adjustments may be necessary during concurrent use. /Potassium-sparing diuretics/ [R23, 1252] *Concurrent use /of lithium/ with potassium-sparing diuretics is not recommended, as they may provoke lithium toxicity by reducing renal clearance. /Potassium-sparing diuretics/ [R23, 1252] */Sympathomimetics/ may reduce the antihypertensive effects of potassium-sparing diuretics; the patient should be carefully monitored to confirm that the desired effect is being obtained. /Potassium-sparing diuretics/ [R23, 1252] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Diuretics [R24] *IN TREATMENT OF EDEMA ASSOC WITH CONGESTIVE HEART FAILURE, CIRRHOSIS, AND NEPHROTIC SYNDROME. IT IS ALSO INDICATED IN STEROID-INDUCED EDEMA, IDIOPATHIC EDEMA, EDEMA DUE TO SECONDARY HYPERALDOSTERONISM, AND IN EDEMATOUS PATIENTS UNRESPONSIVE TO OTHER THERAPY. [R6] *SOME PT WITH EDEMA HAVE SATISFACTORY DIURETIC RESPONSE TO TRIAMTERENE ALONE. HOWEVER, AVAILABLE CLINICAL DATA SUGGEST THAT GREATEST USEFULNESS OF THIS DRUG MAY BE IN CONJUNCTION WITH OTHER DIURETIC AGENTS. IN GENERAL ADMIN...WITH ANOTHER NATRIURETIC COMPD AUGMENTS NATRIURESIS AND REDUCES POTASSIUM LOSS. [R12, 839] *MEDICATION (VET): DIURETIC, NATRIURETIC. IN EXPTL MEDICINE CAUSING SODIUM DIURESIS IN RATS, DOGS... [R5] *Triamterene /is/ indicated as adjunct in the management of edematous states, especially when a potassium-sparing diuretic effect is desired. These may include congestive heart failure, hepatic cirrhosis, and nephrotic syndrome, which often involve secondary hyperaldosteronism, as well as idiopathic edema. /Included in US product labeling/ [R23, 1250] *Traimterene /is/ indicated as adjunct in the treatment of hypertension ... especially when a potassium-sparing diuretic effect is desired. /NOT included in US product labeling/ [R23, 1250] *Triamterene /is/ indicated for the prevention and treatment of hypokalemia in patients for whom other measures are in appropriate or inadequate. /NOT included in US product labeling/ [R23, 1250] WARN: *...SHOULD PROBABLY BE AVOIDED IN DIABETIC PT, EVEN WHEN RENAL FUNCTION IS NORMAL, SINCE DIABETICS ARE UNUSUALLY PRONE TO DEVELOPMENT OF HYPERKALEMIA. [R25] *...IT IS BELIEVED TO CONSERVE POTASSIUM BY REDUCING TRANSPORT OF THIS ION FROM TUBULAR CELL TO TUBULAR LUMEN. HENCE, IT SHOULD NOT BE USED WITH POTASSIUM SUPPLEMENTS AND SHOULD BE USED WITH CAUTION IN PATIENTS WITH PREEXISTING ELEVATED SERUM POTASSIUM. IT IS...CONTRAINDICATED IN PATIENTS WITH SEVERE KIDNEY AND LIVER DISEASES. [R6] *Although appropriate studies on the relationship of age to the effects of potassium-sparing diuretics have not been performed in the geriatric population, the elderly may be at increased risk of developing hyperkalemia. In addition, elderly patients are more likely to have age-related renal function impairment, which may require caution in patients receiving potassium-sparing diuretics. /Potassium-sparing diuretics/ [R23, 1251] *SIDE EFFECTS ARE USUALLY MILD AND CONSISTS OF...GI DISTURBANCES, WEAKNESS, HEADACHE, DRY MOUTH, AND RASH. [R6] *MOST COMMON /SIDE EFFECTS/ ARE NAUSEA, VOMITING, LEG CRAMPS, AND DIZZINESS. [R18, 706] *TRIAMTERENE MAY INCR BLOOD UREA NITROGEN LEVELS AND SERUM URIC ACID CONCN IN SOME PATIENTS. [R3] *TRIAMTERENE (5X10-6 MOL/L) AND ITS METABOLITES, HYDROXYTRIAMTERENE AND HYDROXYTRIAMTERENE SULFURIC ACID ESTER (7X10-5 MOL/L) INHIBITED DIHYDROFOLATE REDUCTASE OF HUMAN LEUKOCYTE BY 50%. [R26] *TRIAMTERENE INDUCED IMMUNE HEMOLYTIC ANEMIA WITH ACUTE INTRAVASCULAR HEMOLYSIS AND ACUTE RENAL FAILURE. [R27] *TRIAMTERENE INDUCED NEPHROLITHIASIS. [R28] *Triamterene also can reduce glucose tolerance and induce photosensitization and has been associated with interstitial nephritis and renal stones (1 in every 200 to 250 cases of renal stones may be due to triamterene). ... can cause CNS, gastrointestinal, musculoskeletal, dermatological, and hematological adverse effects. [R18, 706] *Variety of adverse renal effects, such as abnormalities in urinary sediment, nephrolithiasis, interstitial nephritis, and /SRP: acute renal failure (ARF). /From table/ [R22] *Danger from renal calculi /From table/ [R29, 555] *May cause hyperkalemia, and this may be exaggerated when combined with ACE inhibitors or potassium supplements. /From table/ [R29, 552] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R30] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *FLUORESCENCE RESPONSE @ 415 NM IS LINEAR IN CONCN RANGE OF 0 TO 0.1 UG/ML. [R31] CLAB: *DETERMINATION OF TRIAMTERENE IN PLASMA AND URINE OF HUMANS BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. [R32] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Triameterene in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 420 (1993) NIH Publication No. 94-3151 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1638 R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA9 35 R3: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 90 R4: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 736 R5: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 612 R6: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 872 R7: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 98 R8: PDR; Physician's Desk Reference 52nd ed. p R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3355 R10: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R11: Toxicology and Carcinogenesis Studies of Triamterene in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 420 (1993) NIH Publication No. 94-3151 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R12: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. R13: Casarett, L.J., and J. Doull. Toxicology: The Basic Science of Poisons. New York: MacMillan Publishing Co., 1975. 38 R14: CHASSEAUD LF; ERGEB ANGIOL 16: 43 (1977) R15: GUNDERT-REMY ET AL; EUR J CLIN PHARMACOL 16 (1): 39 (1976) R16: KAU ST, SASTRY BVR; J PHARM SCI 66: 53 (1977) R17: SVED ET AL; NBS SPEC PUBL (US) 519 (ISS TRACE ORG ANAL: NEW FRONT ANAL CHEM): 477 (1979) R18: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. R19: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. 569 R20: THOMPSON ET AL; CLIN PHARMACOL THER 21: 392 (1977) R21: GUETTLER ET AL; ARZNEIM-FORSCH 29 (4): 623 (1979) R22: Young, L.Y., M.A. Koda-Kimble (eds.). Applied Therapeutics. The Clinical Use of Drugs. 6th ed. Vancouver, WA., Applied Therapeutics, Inc. 1995.,p. 29-14 R23: USP Convention. USPDI - Drug Information for the Health Care Professional. 17th ed. Volume I. Rockville, MD: Convention, Inc., 1997. (Plus Updates). R24: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R25: Miller, R. R., and D. J. Greenblatt. Handbook of Drug Therapy. New York: Elsevier North Holland, 1979. 406 R26: SCHALHORN A, WILMANNS W; ARZNEIM-FORSCH 29 (9): 1409 (1979) R27: TAKAHASKI H, TSUKADA T; SCAND J HAEMATOL 23 (2): 169 (1979) R28: ETTINGER ET AL; ANN INTERN MED 91 (5): 745 (1979) R29: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R30: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R31: RAO ET AL; INDIAN J PHARM SCI 41 (4): 156 (1979) R32: BRODIE ET AL; J CHROMATOGR 164 (4): 527 (1979) RS: 21 Record 240 of 1119 in HSDB (through 2003/06) AN: 3432 UD: 200302 RD: Reviewed by SRP on 3/2/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GLYPHOSATE- SY: *GLIALKA-; *Glifonox-; *Glycel-; *GLYCINE, N-(PHOSPHONOMETHYL)-; *MON-0468-; *MON-0573-; *MON-2139-; *Muster-; *N-PHOSPHONOMETHYLGLYCINE-; *PHOSPHONOMETHYLIMINOACETIC-ACID-; *Rodeo-; *Rondo-; *Roundup-; *Sonic-; *Spasor-; *Sting-; *Tumbleweed- RN: 1071-83-6 MF: *C3-H8-N-O5-P ASCH: Glyphosate sesquisodium salt (Polado); 70393-85-0 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *Soluble concentrate; water-soluble powder. [R1] *Mixed formulations: (glyphosate +) simazine [R1] *Polado (plant growth regulator), water soluble powder (750 g glyphosate-sesquisodium/kg) /Glyphosate sesquisodium/ [R2, 450] MFS: *Monsanto Co, Hq, 800 North Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Monsanto Agricultural Co (address same as Hq); Production site: Fayetteville, NC 28302 [R3] OMIN: *EXCELLENT CONTROL OF MOST SPECIES HAS BEEN OBTAINED @ RATES OF 0.34-1.12 KG AE/HA WITH ANNUAL SPECIES, 1.68-2.24 KG/HA FOR SOME PERENNIAL SPECIES. IN ADDITION, BETTER CONTROL OF MOST WEEDS IS OBTAINED IF APPLICATIONS ARE MADE @ LATER STAGES OF PLANT MATURITY. WIPING DEVICES ARE USED WHERE HEIGHT DIFFERENCES ALLOW SELECTIVE REMOVAL OF WEEDS FROM CROPS. [R2, 449] *Crop safety evident when applied prior to planting or after harvest or when directed applications made to tree and vine crops. [R4] *Mixing with other herbicides may reduce the activity of glyphosate. [R1] *Tank mixtures with residual type herbicides, such as substituted ureas, triazines, or others may reduce activity of glyphosate. Other combinations with foliage absorbed herbicides such as paraquat, dalapon, MSMA, phenoxy, or other hormone type herbicides may modify or lower action of glyphosate. [R5, 259] USE: *NON-SELECTIVE, NON-RESIDUAL POST-EMERGENCE HERBICIDE. [R2, 449] *Very effective on deep-rooted perennial species. [R2, 449] *Non-selective systemic herbicide, ... /for/ control of a great variety of annual, biennial, and perennial grasses, sedges, broad-leaved weeds, and woody shrubs. Used in fruit orchards, vineyards, conifer plantations, and many plantation crops (eg coffee, tea, bananas, rubber, coconut, palms, cocoa, mangoes); post-weed emergence but pre-crop-emergence in a wide range of crops (including vegetables, beet, lucerne, okra, soya beans, figs, kiwi fruit, olives, cucurbits, cereals, cotton, etc); on non crop areas; immediately pre-harvest in ripened cereals; in cereal stubble; and in pasture renovation. Also used for pre-harvest desiccation of cotton, cereals, peas, beans, etc; for destruction of rye sown to prevent wind erosion of the soil; for control of suckers on fruit trees; and for aquatic weed control. [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WHITE SOLID [R6]; *Colorless crystals [R1] ODOR: *Odorless [R5, 259] MP: *230 DEG C (DECOMP) [R6] MW: *169.07 [R6] DEN: *0.5 G/CU CM [R2, 449] SOL: *12 G/L WATER AT 25 DEG C; INSOL IN COMMON ORGANIC SOLVENTS [R6] VAP: *Negligible [R1] OCPP: *Pure glyphosate has a zwitterion structure. [R7] *The alkali metal and amine salts are readily soluble in water. [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flammability: Commercial is a water based formulation /thus nonflammable/. [R5, 259] DCMP: *When heated to decomp it emits very toxic fumes of oxides of nitrogen and oxides of phosphrous. [R8] OPRM: +Avoid contacting the skin or eyes with the undiluted substance ... Keep out of the reach of children. Prevent drifting over neighboring crops. [R9] SSL: *NEGLIGIBLE VOLATILITY [R4] *The commercial product shows 5% loss after storage for 2 yr at 60 deg C. [R9] *Formulations of glyphosate are quite stable under temperatures up to 60 deg C, however will freeze at -29 deg C but will go back into solution upon thawing. [R5, 260] STRG: *Contact of the salt soln with galvanized metal causes loss of activity. Store in synthetic containers. [R9] *Mix, store, and apply glyphosate solutions in stainless steel, aluminum, fiberglass, plastic or plastic-lined containers. [R5, 260] DISP: *WASTE STREAMS WERE SUBJECTED TO BIOL TREATMENTS FOLLOWING LIME-PRETREATMENT TO REDUCE AMT OF GLYPHOSATE. GLYPHOSATE ITSELF SHOWED ONLY PARTIAL REDUCTION WITH BIOL TREATMENT. [R10] *THE FIRST TWO THERMAL DEGRADATION STEPS LED TO THE FORMATION OF POLYCONDENSATE AND OF AN INTERNAL SALT. RESIDUES WERE IDENTIFIED BY IR SPECTROMETRY AND ELEMENTAL ANALYSIS AND WERE SIMILAR TO HEATING RESIDUES OF PHOSMET AND DITALIMPHOS. [R11] *Hydrolysis: Mix glyphosate with excess CaO /calcium oxide/ or NaOH /sodium hydroxide/ and sand or lye and sand or other adsorbent in a pit or trench at least 0.5 m deep in a clay soil. NaOH (or Na2CO3) /sodium carbonate/ can also be added to the mixture to help speed the reactions when CaO is used as the main alkali. The amt of CaO or NaOH to use depends on the amt of pesticide to be disposed of and, to some extent, the concentration of active ingredient in the pesticide and the actual chemical nature of the active ingredient. A practical guideline, in the absence of specific directions, is to use an approx volume or weight of alkali from one-half of to the same as that of the pesticide. For dilute formulations, such as a 1% soln or dust, the amount of CaO of NaOH can be reduced by one-half. For very concentrated pesticides (over 80% active ingredient) the amount of CaO or NaOH can be doubled, but the concentrate should be mixed first with water (or soapy water) before reaction with the alkali. For safety, a preliminary test should be made in which very small amt of the pesticide and alkali are mixed and observed briefly to make sure it does not react too vigorously. Sizable quantities of pesticides can be disposed of in several smaller batches, rather than all at once, for added safety. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R12] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Inadequate evidence for oncogenicity in animals. Glyphosate was originally classified as C, possible human carcinogen, on the basis of increased incidence of renal tumors in mice. Following independent review of the slides, the classification was changed to D on the basis of a lack of statistical significance and uncertainty as to a treatment-related effect. HUMAN CARCINOGENICITY DATA: None. [R13] ANTR: *1. SKIN CONTAMINATION SHOULD BE REMOVED PROMPTLY BY WASHING WITH SOAP AND WATER. CONTAMINATION OF THE EYES SHOULD BE TREATED IMMEDIATELY BY PROLONGED FLUSHING OF THE EYES WITH COPIOUS AMOUNTS OF CLEAN WATER. IF DERMAL OR OCULAR IRRITATION PERSISTS, MEDICAL ATTENTION SHOULD BE OBTAINED WITHOUT DELAY. /OTHER HERBICIDES/ [R14] *2. INGESTIONS OF THESE HERBICIDES ARE LIKELY TO BE FOLLOWED BY VOMITING AND DIARRHEA DUE TO THE IRRITANT PROPERTIES OF MOST OF THE TOXICANTS. ... A. IF LARGE AMOUNTS OF HERBICIDE HAVE BEEN INGESTED, AND IF THE PATIENT IS FULLY ALERT INDUCE EMESIS WITH SYRUP OF IPECAC, FOLLOWED BY SEVERAL GLASSES OF WATER. DOSAGE FOR ADULTS AND CHILDREN OVER 12 YEARS: 30 ML; DOSAGE FOR CHILDREN UNDER 12 YEARS 15 ML. WHEN VOMITING HAS STOPPED, GIVE ACTIVATED CHARCOAL. ADD SORBITOL TO THE CHARCOAL SLURRY UNLESS DIARRHEA HAS ALREADY COMMENCED. IF, FOR SOME REASON, THE PATIENT IS NOT FULLY ALERT, PUT IN PLACE A CUFFED ENDOTRACHEAL TUBE TO PROTECT THE AIRWAY, THEN ASPIRATE AND LAVAGE THE STOMACH WITH A SLURRY OF ACTIVATED CHARCOAL. LEAVE A QUANTITY OF CHARCOAL, WITH SORBITOL, IN THE STOMACH BEFORE WITHDRAWING THE STOMACH TUBE. REPEATED ADMINISTRATION OF CHARCOAL AT HALF OR MORE THE INITIAL DOSAGE EVERY 2-4 HOURS MAY BE BENEFICIAL. /OTHER HERBICIDES/ [R15] *2. B. IF THE AMOUNT OF INGESTED HERBICIDES WAS SMALL, IF EFFECTIVE EMESIS HAS ALREADY OCCURRED, OR IF TREATMENT IS DELAYED, ADMINISTER THE ACTIVATED CHARCOAL AND SORBITOL BY MOUTH. C. IF SERIOUS DEHYDRATION AND ELECTROLYTE DEPLETION HAVE OCCURRED AS A RESULT OF VOMITING AND DIARRHEA, MONITOR BLOOD ELECTROLYTES AND AND FLUID BALANCE AND ADMINISTER IV INFUSIONS OF GLUCOSE, NORMAL SALINE RINGER'S SOLUTION, OR RINGER'S LACTATE TO RESTORE EXTRACELLULAR FLUID VOLUME AND ELECTROLYTES. FOLLOW THIS WITH ORAL NUTRIENTS AS SOON AS FLUIDS CAN BE RETAINED. FLUIDS SERVE TO SUPPORT EXCRETION OF THE TOXICANTS. D. SUPPORTIVE MEASURES ARE ORDINARILY SUFFICIENT FOR SUCCESSFUL MANAGEMENT OF EXCESSIVE EXPOSURES TO THESE HERBICIDES. /OTHER HERBICIDES/ [R15] HTOX: *In some 48 suicide attempts by ingestion of the herbicide glyphosate, the average volume of the product (concentrate cotaining active ingedient and a surfactant) ingested was 120 ml (range 104 ml (nonfatal) to 206 ml (fatal)). [R16, 571] *The irritation, sensitization, photoirritation, and photosensitization potential of glyphosate was studied in 346 volunteers. A formulation that contained 41% glyphosate was applied to intact or Draize-type abraded skin. Single and 21 day cumulative irritancy and modified Draize-type skin irritation assays were performed. A phototoxicity study and a modified photo Draize skin sensitization study were also performed. On unabraded skin, glyphosate showed no greater irritation potential than either an all-purpose cleaner, a dishwashing detergent, or a baby shampoo. When tested on abraded skin, glyphosate resulted in a slightly greater incidence of erythema at 24 hr; however, the 48 hr reading indicated that the irritancy potential was similar to that of the cleaner and dishwashing liquid. In the 21 day cumulative irritancy assay, glyphosate and the baby shampoo were less irritating than either the cleaner or the dishwashing liquid. No evidence of skin sensitization was seen. Glyphosate demonstrated no potential for photoirritation or photosensitization. [R17] *Ninety-three cases of exposure to herbicides containing glyphosphate and surfactant (Roundup) were treated. The average amount of the 41% solution of glyphosate herbicide ingested by non-survivors was 184 + or - 70 ml (range 85-200 ml), but much larger amounts (500 ml) were reported to have been ingested by some patients and only resulted in mild to moderate symptomatology. Accidental exposure was asymptomatic after dermal contact with spray (six cases), while mild oral discomfort occurred after accidental ingestion (13 cases). Intentional ingestion (80 cases) resulted in erosion of the GI tract (66%), seen as sore throat (43%), dysphagia (31%), and GI haemorrhage (8%). Other organs were affected less often (non-specific leucocytosis 65%, lung 23%, liver 19%, cardiovascular 18%, kidney 14%, and CNS 12%). There were seven deaths, all of which occurred within hr of ingestion, two before the patient arrived at the hospital. Deaths following ingestion of 'Roundup' alone were due to a syndrome that involved hypotension, unresponsive to iv fluids or vasopressor drugs, and sometimes pulmonary edema, in the presence of normal central venous pressure. [R18] NTOX: *TOXICITY INCR WITH INCR TEMP; GLYPHOSATE WAS TWICE AS TOXIC TO RAINBOW TROUT @ 17 DEG C THAN @ 7 DEG C AND TO BLUEGILLS @ 27 DEG C THAN @ 17 DEG C. TOXICITY WAS 2 TO 4 TIMES GREATER TO BLUEGILLS AND RAINBOW TROUT @ PH 7.5 TO 9.5 THAN @ PH 6.5. [R19] *ROUNDUP (GLYPHOSATE) WAS TESTED FOR INDUCTION OF SEX-LINKED RECESSIVE LETHALS ON DROSOPHILA MELANOGASTER. RESULT WAS NEGATIVE. DIFFERENCES IN SCORES OF 4 PHENOTYPIC CLASSES OF FLIES IN F2 WERE SIGNIFICANT. ROUNDUP (GLYPHOSATE) INDUCED ANAPHASE BRIDGE FORMATION, PREMATURE CHROMOSOME CONDENSATION AND VARIETY OF MITOSTATIC EFFECTS IN VICIA FABA. [R20] *EXCEPT FOR TOXICOLOGICAL EFFECTS AT HIGH DOSAGE, THE HERBICIDE ROUNDUP DID NOT APPEAR TO EXPRESS GENETIC ACTIVITY IN THE AMES TEST. [R21] *THE HERBICIDE ROUNDUP (GLYPHOSATE) HAD NO APPARENT ADVERSE EFFECTS ON REPRODUCTION, GROWTH, OR SURVIVAL OF DEER MICE 1 YR AFTER TREATMENT OF FOREST. FIELD DOSE APPLICATIONS SHOULD NOT HAVE A DIRECT EFFECT ON THE DYNAMICS OF DEER MOUSE POPULATIONS. [R22] *ALTHOUGH THERE WAS NO APPRECIABLE INHIBITION OF REDN OF PYRIDINE NUCLEOTIDE IN RAT LIVER MITOCHONDRIA AFTER IP ADMIN (BELOW 150 MG/KG), INHIBITION INCR AS DOSE LEVEL WAS RAISED TO 240 MG/KG. ADDITION OF ATP AND HIGH ENERGY INTERMEDIATE INCR INHIBITION. THESE FINDINGS SUGGEST THAT INHIBITORY EFFECT MAY BE DUE TO ITS UNCOUPLING EFFECT ON OXIDATIVE PHOSPHORYLATION. [R23] *Not toxic to bees. [R1] *Rats ... were administered glyphosate continuously for 3 successive generations. Dietary concentrations of glyphosphate were adjusted weekly during growth, and between mating rest periods to achieve dose levels of 0, 3, 10, and 30 mg/kg/D. Each generation (F0, F1, F2) consisted of 12 male and 24 female rats. Each parent generation was mated to produce two litters. Offspring from the second litters of the F0 and F1 parents ... were selected to be parents for subsequent generations. ... No treatment-related effects on fertility were noted, nor were any systemic effects in adult rats apparent. Male pups from the /second litter of the F2 generation/ mating of the high dose group (30 mg/kg/D) showed an increase in the incidence of unilateral renal tubular dilation. Based on this finding, the NOEL and LEL for this study are 10 and 30 mg/kg/D, respectively. [R24] *Glyphosate was not mutagenic for Salmonella, Escherichia coli, or Chinese hamster ovary cells. It was also negative in DNA repair assays in Bacillus subtilis and hepatocyte cultures. [R24] *The genotoxic potential of the herbicide Roundup and its active agent, glyphosate isopropylamine salt, was studied in three different assays. No clastogenic effects were found in the mouse bone marrow micronucleus test for either of the two agents. In the Salmonella assay only Roundup was tested. It showed a weak mutagenic effect for the concn 360 ug/plate in TA98 (without S9) and 720 ug/plate in TA100 (with S9). These concn are close to the toxic level. The anaphase-telophase Allium test showed no effect for the glyphosate isopropylamine salt, but a significant increase in chromosome aberrations appeared after treatment with Roundup at concn of 1.44 and 2.88 mg/l when calculated as glyphosate isopropylamine. The most frequent aberrations observed could be characterized as disturbances of the spindle. [R25] *Glyphosate was applied to panicles of wild oats (Avena fatua) before, at and after anthesis. The florets in spikelets exposed to the herbicide before, at and immediately after anthesis produced seeds with abnormal embryos and endosperm. Histological and embryological studies showed that in all cases the chemical did not stop the normal process of double fertilization in the florets. The zygote divided, but did not proceed beyond the proembryo stage. The development of both the proembryo and the endosperm was abnormal. The proembryos and the early stages of embryos showed no normal provascular or vascular time differentiation. Externally also there was no proper development of embryo parts, such as the scutellum, epiblast, shoot and root apices. The embryonic tissues showed considerable obliteration and shrinkage and the nuclei in cells appeared small and shrunken. The cells, especially in the meristem regions, appeared lacunose. The embryo and the endosperm in the caryopses treated with glyphosate 9 days after anthesis or later, were morphologically and structurally very similar to those of the controls of comparable age. It was concluded that the greater the delay of glyphosate application after anthesis, the less was the effect on seed development. [R26] *The toxicity and disposition of glyphosate was studied in rats and mice. Male F344/N rats were gavaged with 5.6 or 56 mg/kg radiolabeled glyphosate. Urine and feces were collected at 24 hr intervals for 72 hr and analyzed for activity. Selected rats were killed 3 to 96 hr post dosing to determine the tissue distribution of radioactivity. Ten F344/N rats and B6C3F1 mice were administered 3125, 6250, 12,500, 25,000, or 50,000 ppm glyphosate in their diet for 13 weeks. Surviving animals were killed at the end of the study and necropsied. Blood samples were collected from the rats at necropsy to determine hematological and serum chemistry parameters. Glyphosate mutagenicity was evaluated in the Ames/Salmonella assay with or without S9 metabolic activation and by the mouse peripheral blood micronucleus test. All rats survived until the end of the study. Glyphosate doses of 12,500 ppm or higher caused slight increases in hematocrit and hemoglobin. Serum bile acid concentrations and alkaline phosphatase and alanine aminotransferase activities were significantly increased. One mouse treated with 50,000 ppm died. The major pathological change induced by glyphosate was a dose related increase in basophilic changes and hypertrophy of acinar cells (cytoplasmic alterations) in the parotid and submandibular salivary glands of rats and the parotid salivary glands in mice. All doses caused these changes in rats. In mice, doses of 6250 ppm or higher caused these effects. No histopathological changes were seen in the liver. Glyphosate was not mutagenic. [R27] *The herbicide glyphosate was administered into the sapwood around the root collar of lodgepole pine trees, Pinus contorta variety latifolia Engelum, to determine its effect on invasion by the blue stain fungus Ophiostoma clavigerum. In two experiments, lesions in the sapwood were longer and wider in trees treated with glyphosphate before inoculation with Ophiostoma clavigerum than in untreated, control trees. Ophiostoma clavigerum was recovered in a third experiment at seven times the distance from the point of inoculation in trees treated with glyphosate 3 wk before inoculation as in untreated, control trees. We conclude that previously observed enhancement of brood development of the mountain pine beetle, Dendroctonus ponderosae, was caused by glyphosate induced inhibition of the trees' secondary defense response to invasion by the beetle's symbiotic fungi. [R28] NTXV: *LD50 Rat oral 4320 mg/kg; [R29] *LD50 Rabbit percutaneous > 5000 mg/kg; [R1] *LC50 Rat inhalation > 12.2 mg/l air/4 hr; [R1] *LD50 Rat oral > 5000 mg/kg /Glyphosate sesquisodium salt/; [R2, 449] *LD50 Rabbit percutaneous > 5000 mg/kg /Glyphosate sesquisodium salt/; [R2, 449] ETXV: *LC50 SALMO GAIRDNERI (RAINBOW TROUT), WT 0.8 G, 130 MG/L/96 HR @ 12 DEG C (95% CONFIDENCE INTERVAL 108-156 MG/L) STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L. /TECHNICAL MATERIAL, 96.7%/; [R19] *LC50 PIMEPHALES PROMELAS (FATHEAD MINNOW), WT 0.6 G, 97 MG/L/96 HR @ 20 DEG C (95% CONFIDENCE INTERVAL 79-120 MG/L) STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L. /TECHNICAL MATERIAL, 96.7%/; [R19] *LC50 ICTALURUS PUNCTATUS (CHANNEL CATFISH), WT 2.2 G, 130 MG/L/96 HR @ 22 DEG C (95% CONFIDENCE INTERVAL 108-156 MG/L) STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L. /TECHNICAL MATERIAL, 96.7%/; [R19] *LC50 LEPOMIS MACROCHIRUS (BLUEGILL), WT 0.9 G, 135 MG/L/96 HR @ 22 DEG C (95% CONFIDENCE INTERVAL 113-162 MG/L) STATIC BIOASSAY WITHOUT AERATION, PH 7.2-7.5, WATER HARDNESS 40-50 MG/L AS CALCIUM CARBONATE AND ALKALINITY OF 30-35 MG/L. /TECHNICAL MATERIAL, 96.7%/; [R19] *LC50 Coturnix japonica (Japanese quail), 14 days old, oral (5 day ad libitum in diet) > 5,000 ppm (commercial formulation, 41% ai); [R30] *LC50 Quail dietary > 4640 ppm/8 day /Technical glyphosate/; [R5, 261] *LD50 Bobwhite quail oral > 3850 mg/kg /Technical glyphosate/; [R5, 261] *LC50 Daphnia > 1000 mg/l/48 hr /Conditions of bioassay not specified/ /Glyphosate sesquisodium salt/; [R2, 450] ADE: *IN CONTRAST TO FLURIDONE, HIGHLY MOBILE GLYPHOSATE TRANSLOCATED FROM THE SHOOTS TO THE ROOTS IN SAGO PONDWEED. [R31] *... Absorbed by foliage and translocated throughout plants. [R2, 449] *Translocation to underground propagules of perennial species prevents regrowth from these sites and results in their subsequent destruction. Root uptake is precluded by soil inactivation of glyphosate. [R5, 260] *The percutaneous absorption of glyphosate was studied in vivo and in vitro. The ability of Roundup, a commercial glyphosate formulation, applied neat and in 1:20 to 1:32 dilutions to penetrate human thigh skin samples obtained at autopsy was evaluated using flow through cells containing human plasma as the receptor fluid. The ability of (14)C-labeled Roundup and the 1:20 and 1:32 dilutions to bind to powdered human stratum corneum was investigated. Adult female rhesus monkeys were administered 500 or 5400 ug per 200 sq cm labeled glyphosate topically or 9 or 93 ug glyphosate iv. Blood and urine samples were collected starting 24 hr before dosing and up to 8 days post dosing and assayed for (14)C activity. Selected monkeys were killed 7 days after topical exposure to determine the tissue distribution of glyphosate derived (14)C activity. Other monkeys were topically administered a 1:20 dilution of (14)C-labeled glyphosate.The application sites were washed with soap and water or water 0 to 24 hr later to assess the ability of these treatments to remove glyphosate. In vitro, less than 2% of the applied glyphosate penetrated human skin. Glyphosate as Roundup or in diluted form did not bind to powdered stratum corneum. Around 95 to 99% of iv administered glyphosate was excreted in the urine, mostly within the first 24 hr. Following topical application only 2.2% of the 5400 ug/200 sq cm dose and 0.8% of the 500 ug/200 sq cm dose were excreted in the urine over 8 days. Based on the intravenous data, 0.8 to 2.2% of the applied doses was estimated to have been absorbed. Glyphosate was detected in the blood after iv administration, but not topical application. No glyphosate derived radioactivity was detected in any internal organs after topical application. Soap and water, or G water removed 89.6 and 83.6% of the applied dose, respectively, 12 hr after ts removed about 50% of the applied dose 24 hr after concluded that the amounts of glyphosate absorbed through the skin of rhesus monkeys is low, on the order of 0.8 to 2.2%. ... [R32] *The disposition of glyphosate was studied in rats. Male F344/N rats were gavaged with 5.6 or 56 mg/kg radiolabeled glyphosate. Urine and feces were collected at 24 hour intervals for 72 hr and analyzed for activity. Selected rats were killed 3 to 96 hr post dosing to determine the tissue distribution of radioactivity. Approximately 20 to 30% of either dose was eliminated in the urine and 70 to 80% in the feces over 72 hr. Only about 1% of the dose remained in the tissues, mostly in the liver and small intestine. [R27] METB: *Parent compound is N-methylated and degraded into three compounds at the initial metabolic sequence. These are further metabolized to N-methylated glycines and some phoshonic acids in plants, soil, and water. [R33] *When applied to leaves, glyphosate moved to other leaves, buds and developing fruit on the same branch. Analyses indicated the presence of one metabolite in addition to unchanged glyphosate. The metabolite was identified as aminomethylphosphonic acid. [R34] *One week after application of glyphosate to Canada thistle (Cirsium arvense) and leafy spurge (Euphorbia esula) analyses did not reveal the presence of metabolites. [R34] *Field bindweed, Canada thistle, and tall morning glory were treated with (14)C glyphosate. Each test species contained traces of aminomethylphosphonic acid and sarcosine. [R34] *The major glyphosate metabolites in sugarcane were identified as amino-bis-methylenephosphonic acid, N-methylamino-bis-methylenephosphonic acid, N-phosphonomethylglycine, and N-methyl-N-phosphonomethylglycine. [R34] *Glyphosate is metabolized to aminomethyl phosphonic acid. [R17] ACTN: *INCORPORATION OF (14)C-LABELEDGLUTAMATE, ALPHA-KETOGLUTARATE, AND GLYCINE INTO DELTA-AMINOLEVULINIC ACID SHOWED 77, 92, and 91% INHIBITION, RESPECTIVELY, IN BARLEY SHOOTS TREATED WITH 1 MMOL GLYPHOSATE. INHIBITION OF DELTA-AMINOLEVULINIC ACID BLOCKS SYNTHESIS OF CHLOROPHYLL. THE SITE OF ACTION OF GLYPHOSATE MAY INVOLVE 2 ENZYME PATHWAYS: ONE CONTROLLING CONVERSION OF ALPHA-KETOGLUTARATE TO DELTA-AMINOLEVULINIC ACID, AND THE OTHER CONTROLLING CONDENSATION OF GLYCINE WITH SUCCINYL CO-ENZYME A TO FORM DELTA-AMINOLEVULINIC ACID AND CARBON DIOXIDE. [R35] *AFTER GROWTH IN 0.5 MMOL GLYPHOSATE FOR 10 DAYS, GALIUM MOLLUGO CELLS CONTAINED THE ORG ACID SHIKIMATE APPROX 10% OF THEIR DRY WT. GLYPHOSATE INHIBITS A STEP IN THE BIOSYNTHETIC SEQUENCE FROM SHIKIMATE TO CHORISMATE. CHORISMATE AND O-SUCCINYLBENZOATE ALLEVIATED INHIBITION. [R36] *0.001, 0.01, 0.1 MMOLE OF GLYPHOSATE DECREASED THE CHLOROPHYLL CONTENT OF 7 DAY OLD ETIOLATED BARLEY FOLLOWING 8 HR DARK INCUBATION AND 24 HR ILLUMINATION. THESE RAPID AND SUBSTANTIAL EFFECTS ON CHLOROPHYLL ACCUM SUGGEST THAT INTERFERENCE WITH GREENING MAY BE IMPORTANT IN MECHANISM OF ACTION. [R37] *Appears to inhibit the aromatic amino acid biosynthesis pathway and may inhibit or repress chlorismate mutase and/or prephenate dehydratase. [R5, 260] *Acts on various enzyme systems, thus interfering with the formation of amino acids and other important endogenous chemicals. [R1] *Using intact mitochondria isolated from rat liver, /it was/ found that glyphosate ... acts as /an/ uncoupler of oxidative phosphorylation. This occurs as a result of both interactions with oxidative phosphorylation and energy-dependent transhydrogenase reaction. [R17] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Glyphosate is released to the environment in its use as a non-selective, post emergent herbicide for controlling woody and herbaceous weeds on forestry, right-of-way, cropped and non-cropped sites. It is applied as a spray of the isopropylamine salt and is removed from the atmosphere by gravitational settling. After glyphosate is applied to forests, fields, and other land by spraying, it is strongly adsorbed to soil, remains in the upper soil layers, and has a low propensity for leaching. Glyphosate readily and completely biodegrades in soil. Its average half-life in soil is about 60 days. Biodegradation in foliage and litter is somewhat faster. In field studies, residues are often found the following year. Glyphosate may enter aquatic systems through accidental spraying, spray drift, or surface runoff. It dissipates rapidly from the water column as a result of adsorption and possibly biodegradation. The half-life in water is a few days. Sediment is the primary sink for glyphosate. After spraying, glyphosate levels in sediment rise and then decline to low levels in a few months. Glyphosate does not bioconcentrate in aquatic organisms or bioaccumulate in species in higher tropic levels. Occupational workers and home gardeners may be exposed to glyphosate by inhalation and dermal contact during spraying, mixing, and cleanup. They may also be exposed by touching soil and plants to which glyphosate was applied. Occupational exposure may also occur during glyphosate's manufacture, transport storage, and disposal. (SRC) ARTS: *Glyphosate is released to the environment in its use as a non-selective, postemergence herbicide for controlling woody and herbaceous weeds on forestry, right-of-way, cropped and non-cropped sites(1,4,5). These sites may be around water and in wetlands(4). It may also be released to the environment during its manufacture, formulation, transport, storage, disposal and cleanup, and from spills. Glyphosate is generally sold as the isopropylamine salt and applied as a liquid foliar spray(4-5). In 1986, an estimated 6,308,000 pounds of glyphosate was used in the United Sates(2). Usage in 1990 was estimated to be 11,595,000 pounds(3). [R38] FATE: *TERRESTRIAL FATE: APPLIED AT 2.6 KG/HA FOR QUACKGRASS ON LOAM AND FINE SILT SOILS, GLYPHOSATE WAS IMMEDIATELY DETECTABLE BY GAS CHROMATOGRAPHY AFTER APPLICATION AS WELL AS AT 28 DAYS AND 8 MO LATER. UNCHANGED GLYPHOSATE AND AMINOMETHYLPHOSPHONIC ACID WERE IDENTIFIED BY GC IN THE SOILS. [R39] *TERRESTRIAL FATE: After 16 wk, < 3% of the starting material is detectable. Strong soil adsorption, slight washing-out or displacement. [R9] *Would not be expected to persist from one growing season to the next. [R16, 885] *TERRESTRIAL FATE: Half-life in soil is normally less than 60 days. [R1] *TERRESTRIAL FATE: After glyphosate is applied to forests, fields, and other land by spraying, its mobility in soil is limited and is affected by pH and phosphate levels, as well as by soil type(3). In addition to binding to organic matter and clay in soil, it may also form insoluble complexes with metal ions in the soil. Distribution data for glyphosate after spraying in a coastal forest ecosystem indicate that glyphosate is strongly adsorbed to the upper layers of soil and has a low propensity for leaching(2). Glyphosate residues dissipated with a half-life of 45-60 days. After 360 days, residues levels were 6-18% of initial levels(2). Field studies on eleven different soils covering a full range of soil types and geographical areas indicates an avg half-life of 60 days for glyphosate in soil(4). Other sources also report an avg half-life of 60 days from literature surveys(1,5). [R40] *TERRESTRIAL FATE: The half-life of glyphosate applied to forest foliage was 14.4 days(1) and that applied to two Finnish agricultural fields were 69 and 127 days, respectively(2). Persistence studies with glyphosate in sandy test sites in a boreal forest in Ontario, Canada indicate that the half-life of glyphosate was 24 days and residues were reduced to < 10% of that applied after 78 days(3). More than 95% of residues were found in the upper organic layer of soil. In aerially treated forest brush fields in the Oregon coast range, the half-life of glyphosate ranged from 10.4-26.6 days in foliage and litter. The half-life of glyphosate on exposed soil and litter-covered soil was 40.2 and 29.2 days, respectively(4). Glyphosate degrades even under low temperature conditions. [R41] *TERRESTRIAL FATE: In a Finnish study where the glyphosate was applied to two agricultural fields in September to control quackgrass and the fields plowed after six days, 76% and 10% remained in the field containing loam soil after 28 days and 8 months, respectively(1). The corresponding values for the field with fine silt was 92% and 53%. The loam soil in which degradation was more rapid had a higher respiration rate. In a similar study in eight forest soils in Sweden at higher temperatures, an avg 20% of the glyphosate applied in August was present in samples taken the following May(1). [R42] *AQUATIC FATE: When glyphosate enters water as runoff or inadvertent overspray or spray drift, it adsorbs strongly to sediment and particulate matter in the water column. It may also form insoluble complexes with metal ions and precipitate. Evidence from microcosm studies suggests that sediment adsorption and/or biodegradation represents the major dissipation process in aquatic systems(2). Glyphosate levels in sediment rise at first and then fall to very low or undetectable levels(2). After glyphosate was sprayed over two streams in the rainy coastal watershed of British Columbia, glyphosate levels in the streams rose dramatically after the first rain event, 27 hr postapplication, and fell to undetectable levels 96 hr postapplication(1). The highest residues were associated with sediments, indicating that they were the major sink for glyphosate. Residues persisted throughout the 171 day monitoring period. Suspended sediment is not a major mechanism for glyphosate transport in rivers(1). The half-lives of glyphosate in three forest ponds in Manitoba, Canada that were aerially spray in August was 1.51 to 1.99 days and glyphosate was not detected in any sample by day 38(2). The pond in which glyphosate had the longest half-life had much higher levels of calcium and magnesium than the other ponds. [R43] *AQUATIC FATE: In aerially treated forest brush fields in the Oregon Coast range, the concentration in streamwater peaked at 0.28 ppm shortly after spraying and declined sharply to undetectable levels in about 6 days(1). Concentrations in sediment increased slowly to a peak value of 0.55 ppm after 14 days and then slowly declined; at the end of the 55 day study the level was about 0.1 ppm. The concn pattern for aminomethylphosphonic acid, a glyphosphate metabolite in sediment was similar to that of glyphosate, but at much lower levels. Sediments adsorb glyphosate from flowing water; once adsorbed, it is not readily eluted. In experiments where glyphosate was added to water in two irrigation canals, the fractional reduction in load was 13 and 27% per km with uptake by the benthic sediment being 365 and 603 g/km(2). In two other experiments in which glyphosate was added to flowing water to simulate contamination during foliar spaying, 63% of the glyphosate was scavenged by sediment in 14 km and 43% was removed in 14 km(2). In a field study, glyphosate was sprayed on sediment in an irrigation channel in spring and 4 days afterwards the channel was filled with water. Based on the observed concentration levels, less than 7% of the applied glyphosate eluted with water(2). [R44] *ATMOSPHERIC FATE: Glyphosate will be released into the atmosphere as an aerosol during spraying and removed by gravitational settling. It will occur in the atmosphere only as an aerosol and may degrade by photolysis. (SRC) BIOD: *Biodegradation represents the major dissipation process Glyphosate levels in sediment rise at first and then fall to very low or undetectable levels(2). After glyphosate was sprayed over two streams in the rainy coastal watershed of British Columbia, glyphosate levels in the streams rose dramatically after the first rain event, 27 hr postapplication, and fell soil. Depending on soil and microfloral population types, varying rates of decomposition occur, producing, for example, from 10 to 60% (14)CO2 from (14)C glyphosate over growing season time periods or less. Normally, the half-life [R5, 261] *In shake-flask metabolism studies, glyphosate was rapidly and completely biodegraded in the presence of soil microorganisms under both aerobic and anaerobic conditions(2). All three glyphosate carbons biodegraded at comparable rates. After 28 days under aerobic conditions, 45-55% of the glyphosate was mineralized using Ray silt loam soil, Lintonia sandy loam soil, and Drummer silty clay loam soil. Norfolk sandy loam mineralized glyphosate at a much slower, but still significant, rate. Under anaerobic conditions, 37.3% of glyphosate incubated with Ray silt loam soil was released as CO2. In greenhouse experiments, the half-lives of glyphosate in Ray, Drummer and Norfolk soil was 3, 27, and 130 days, respectively(2). When glyphosate was incubated in Williams silt loam soil (pH 6.4, 1.9% organic matter), 19% degradation occurred in 9 days(1). No degradation was noted in sterilized soil. [R45] *In experiments in which C14-glyphosate was incubated with several soils, 17.4 to 45.5% of the glyphosate was released as CO2 in 28 days(2). CO2 release did not occur in sterilized soil. The addition of phosphate, which competes with glyphosate for soil binding sites, increased the rate of CO2 release, although both bound and free glyphosate were degraded(2). The pattern of biodegradation suggests that glyphosate does not support microbial growth, but is co-metabolized(2). Glyphosate's only significant metabolite is aminomethylphosphosphonic acid (AMPA), which also rapidly degrades in soil(1,3). When radiolabeled glyphosate was incubated in three Saskatchewan soils, 50% of the herbicide was mineralized in 30-40 days; the half-life of glyphosate, itself, would be shorter(4). After 90 days when 69-75% of radioactivity had been released, 7-16% of the activity was in a solvent-extractable fraction and 7-14% was in a non-extractable fraction. [R46] ABIO: *Glyphosate is zwitterionic with pKa values of < 2, 2.6, 5.6 and 10.6(1). In the environmental pH range, 5 to 9, glyphosate has a net negative charge that increases with pH. The nitrogen atom is positively charged and both the carboxylic acid group and phosphonic acid group are deprotonated; above pH 5.6 the latter is predominantly doubly ionized and below pH 5.6 it is singly ionized(1). Glyphosate has three groups (amine, carboxylate and phosphonate) that may coordinate strongly as tridentate or tetradentate ligands with transition metal and alkaline earth ions(2). It has been demonstrated that insoluble complexes are formed between glyphosate and ferric, cupric, calcium, and magnesium ions at near neutral pH. Ferrous salts are oxidized to the ferric salt yielding the ferric-glyphosate complex. Since groundwater may contain high concentrations of iron, calcium, and magnesium, glyphosate would form insoluble complexes with these ions and precipitate out. A similar fate would occur to glyphosate in soil and some surface waters. [R47] *Experiments using sterile controls in biodegradability studies indicate that glyphosate does not chemically degrade in soil(1). Glyphosate photodegrades when exposed to UV radiation, but not visible light(2). The photolytic half-life of glyphosate in deionized water exposed outdoors to sunlight was approximately 5 wk at 100 ppm and 3 wk at 2000 ppm(2). The degradation product was aminomethylphosphonic acid. In contrast, no degradation occurred when exposed to light equivalent of 16 8-hr days of sunlight in a photoreactor(1). Another source reports that negligible losses of glyphosate on soil occur as a result of photodegradation(3). A possible explanation for these discrepancies may be that the spectral distribution of light used in the photoreactor and soil experiments did not encompass the UV range(SRC). Additionally, photodegradation of tightly bound or complexed glyphosate may be different than the free molecule(SRC). [R48] BIOC: *Based on its water solubility, glyphosate is not expected to bioconcentrate in aquatic organisms(2). It is minimally retained and rapidly eliminated in fish, birds, and mammals(3). The BCF of glyphosate in fish following a 10-14 day exposure period was 0.2 to 0.3(3). In a study of the fate of glyphosate that was applied to two hardwood communities in the Oregon coastal forest, none of the ten Coho salmon fingerlings analyzed had detectable levels of glyphosate or its metabolite, aminomethylphosphonic acid (DL 0.05 ppm), despite glyphosate levels in stream water that were detectable for 3 days and levels in sediment that weredetectable throughout the 55 day study period(1). Levels in herbivores, carnivores, and omnivores were at or below that in ground cover and litter, indicating that glyphosate does not bioaccumulate in higher tropic levels(1). [R49] KOC: *When applied to clay loam or muck soil, 56 kg/ha of glyphosate was rapidly inactivated. This inactivation was probably the result of reversible adsorption to clay and organic matter. Iron and aluminum clays and organic matter adsorbed more glyphosate than sodium and calcium clays and was readily bound to kaolinite, illite, bentonite, charcoal and muck but not to ethyl cellulose. (14)C-Labeled glyphosate was degraded in soil and (14)CO2 was released. [R50] *Glyphosate is an acid and ionized in water; interactions with soil and sediment are primarily ionic, rather than hydrophobic and pH dependent. Laboratory and field studies indicate that glyphosate is strongly and reversibly adsorbed by soil, sediment and suspended sediment(1,6). The Freundlich K for 9 soils ranged from 18 to 377, while that to particulate matter from Australian waters ranged from 1260 to 2080(1). Glyphosate was strongly adsorbed to Drummer silty clay loam, Norfolk sandy loam, and Ray silt loam soil in soil thin layer chromatography experiments and would therefore possess no propensity for leaching(7). In soil column studies, no glyphosate was detected in leachate after elution with water for 45 days(1). It is adsorbed at positively charged sites in clay minerals and other soil components(1). [R51] *The Freundlich K and Koc for Houston clay loam (pH 7.5, OC 1.56%), Muskingum silt loam (pH 5.8, OC 1.64%), and Sassafras sandy loam (pH 5.6, OC 1.24%) were 76, 56, and 33 and 4900, 3400, and 2600, respectively(1). The adsorptivity correlated with clay content, cation exchange capacity (CEC) and pH(1). Decreasing adsorption to five clays with increasing pH is due to decreased interaction as the clay surface and glyphosate become more negatively charged(2). Another investigator found that the extractability of glyphosate from soil and various clay minerals increased with pH, but the degree of adsorption did not correlate with CEC or surface area of the sorbent, indicating that adsorption to clays was via a specific sorption mechanism, rather than a general one and that the mechanism is H-bonding and ion exchange(3). [R52] *Glyphosate has been shown to compete with phosphate for binding sites(2). The latter suggests that binding occurs through the phosphonic acid moiety of the glyphosate. Analysis of soil core samples from a coastal forest watershed in British Columbia that had been sprayed with glyphosate indicated that > 90% of glyphosate residues were found in the 0-15 cm organic soil layer both in seasonally flooded and well drained sites(1). Glyphosate's binding to soil makes it unavailable to growing plants(2). Proof that its unavailability to plants is a result of binding is demonstrated by the fact that plant uptake occurs in quartz sand but not in sterile soil(2). [R53] VWS: *Due to its ionic state in water, glyphosate would not be expected to volatilize from water or soil. (SRC) WATC: *GROUNDWATER: Glyphosate was detected in groundwater and water supply monitoring programs in Texas(2). The concn and site details were not reported(2). In a survey of farm wells in Ontario, Canada, 103 in 1986 and 76 in 1987, glyphosate was not detected in any wells(1). However, glyphosate was only used on crops on 28 farms in 1986 and 1987(1). [R54] SEDS: *The concn of glyphosate on barley fields, two days after application in September, 58 days post treatment, and 7 months posttreatment were 1.6 ppm, 0.5, and 0.2 ppm(1). The corresponding levels of its main metabolite, aminomethylphosphonic acid were 0.2, 0.14, and 0.1 ppm(1). [R55] FOOD: *Glyphosate enters plants through its foliage and moves throughout the plant and into the root system(1-2). Therefore all parts of the plant treated with glyphosate may contain the herbicide(1). Glyphosate is applied to crops before emergence as otherwise crop destruction would result(1-2). Uptake through the root system is precluded by soil inactivation(2). Therefore, food crops should not contain glyphosate. [R56] PFAC: PLANT CONCENTRATIONS: *GLYPHOSATE WAS NOT DETECTED IN EITHER COWBERRIES OR BILBERRIES AT 1 YR AFTER APPLICATION. IN THE LICHEN CLADONIA RANGIFERINA, SAMPLED FROM BILBERRY PLOTS, GLYPHOSATE LEVELS WERE MUCH HIGHER THAN THOSE OF TRICLOPYR, NOT SO IN BERRIES. [R57] *Glyphosate resides in cowberries and billberies that were treated at 0.75 kg/ha in mid July, August, and September were 1.6 ppm and 2.1 ppm, respectively 6-7 days after application and 0.1 to 0.3 ppm, when sampled 1 to 2 months after application(2). No residue were found in cowberries treated at 0.25 kg/ha and sampled 1 year later. No residues of aminomethylphosphonic acid (AMPA), the glyphosate metabolite were found in cowberries and billberries at any of the sampling intervals. Glyphosate residues in reindeer lichen, sampled in the spring, 9 months after application at rates of 0.25, 0.75 and 2.25 kg/ha were 2.5, 14, and 45 ppm, respectively; the residue increased with dose(2). The concn of AMPA were 0.25, 0.85, and 2.1 ppm, respectively. Thirteen months after being treated with glyphosate at a rate of 0.75 kg/ha, residues of glyphosate and AMPA in one sample of reindeer lichen was 6.4 and 0.3 ppm, respectively. Initial foliar residues on alder and salmonberry sprayed with glyphosate at 2.0-2.1 kg/ha were 262 and 448 ppm (dry wt)(1). Leaf litter collected 15 days post application were 12.5 and 19.2 ppm which declined logarithmically with a 50% dissipation time of about 8 days for alder and 9 days for salmonberry. AMPA levels in litter also declined and were undetectable 29 days postapplication(1). [R58] RTEX: *Occupational workers and home gardeners may be exposed to glyphosate by inhalation and dermal contact during spraying, mixing, and cleanup. They may also be exposed by touching soil and plants to which glyphosate was applied. Dermal exposure may also occur during glyphosate's manufacture, transport, storage, and disposal. In a 1987 California survey of pesticide-related occupational exposures, exposures to glyphosate were (work activity, number exposed): ground applicator, ground, 13; applicator hand-held, 8; applicator, other, 1; coincidental exposure, 4; mixer/loader, ground application, 4(1). [R59] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine of glyphosate and/or the monoammonium salt of glyphosate in or on the following agricultural commodities: acerola, 0.2 ppm; alfalfa, 200.0 ppm; alfalfa (fresh and hay), 0.2 ppm; almonds (hulls), 1 ppm; artichokes (Jerusalem), 0.2 ppm; asparagus, 0.5 ppm; atemoya, 0.2 ppm; avocados, 0.2 ppm; bahiagrass, 200.0 ppm; bananas, 0.2 ppm; beets, 0.2 ppm; beets (sugar), 0.2 ppm; bermudagrass, 200.0 ppm; bluegrass, 200.0 ppm; breadfruit, 0.2 ppm; bromegrass, 200.0 ppm; canistel, 0.2 ppm; carambola, 0.2 ppm; carrots, 0.2 ppm; cherimoya, 0.2 ppm; chicory, 0.2 ppm; citrus fruits, 0.2 ppm; clover, 200.0 ppm; cocoa beans, 0.2 ppm; coconut, 0.1 ppm; coffee beans, 1 ppm; cotton (forage and hay), 15 ppm; cottonseed, 15 ppm; cranberries, 0.2 ppm; dates, 0.2 ppm; fescue, 200.0 ppm; figs, 0.2 ppm; forage grasses, 0.2 ppm; forage legumes, 0.4 ppm; fruits (small) and berries, 0.2 ppm; genip, 0.2 ppm; grain crops (except wheat), 0.1 ppm (negligible residue (N)); grapes, 0.2 ppm; grasses (forage), 0.2 ppm (N); guavas, 0.2 ppm; horseradish, 0.2 ppm; jaboticaba, 0.2 ppm; jackfruit, 0.2 ppm; kiwifruit, 0.2 ppm; leafy vegetables, 0.2 ppm (N); longan, 0.2 ppm; lychee, 0.2 ppm; mamy sapote 0.2 ppm; mangoes, 0.2 ppm; nuts, 0.2 ppm; olives, 0.2 ppm; orchardgrass, 200.0 ppm; papayas, 0.2 ppm; parsnips, 0.2 ppm; passion fruit, 0.2 ppm; peanut (forage), 0.5 ppm; persimmons, 0.2 ppm; pineapple, 0.1 ppm; pistachio nuts, 0.2 ppm; pome fruits, 0.2 ppm; potatoes, 0.2 ppm; radishes, 0.2 ppm; rutabagas, 0.2 ppm; ryegrass, 200. ppm; salsify, 0.2 ppm; sapodilla, 0.2 ppm; sapote (black and white), 0.2 ppm; seed and pod vegetables (including forage and hay), 0.2 ppm (N); soursoup, 0.2 ppm; soybeans, 6 ppm; soybeans (forage and hay), 15 ppm; stone fruit, 0.2 ppm; sugar apple, 0.2 ppm; sweet potatoes, 0.2 ppm; tamarind, 0.2 ppm; timothy, 200.0 ppm; turnips, 0.2 ppm; vegetables (bulb), 0.2 ppm; vegetables (curcubit), 0.5 ppm; vegetables (fruiting group), 0.1 ppm; vegetables (leafy, Brassica (cole)), 0.2 ppm; wheatgrass, 200.0 ppm; and yams, 0.2 ppm. [R60] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine of glyphosate and/or the monoammonium salt of glyphosate in or on the following agricultural commodities: pomegranates, 0.2 ppm. [R61, (5/28/92)] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid resulting from the application of the glyphosate isopropylamine and/or glyphosate monoammonium salt for herbicidal and plant growth regulator purposes and/or the sodium sesqui salt for growth regulator purposes in or on the following agricultural commodities: cattle (kidney and liver), 0.5 ppm; fish, 0.25 ppm; goats (kidney and liver), 0.5 ppm; hogs (kidney and liver), 0.5 ppm; horses (kidney and liver), 0.5 ppm; peanuts, 0.1 ppm; peanut (hay and hulls), 0.5 ppm; poultry (kidney and liver) 0.5 ppm; sheep (kidney and liver), 0.5 ppm; shellfish, 3.0 ppm; and sugarcane, 2.0 ppm. [R62] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid, resulting from the use of irrigation water containing residues of 0.5 ppm following applications on or around aquatic sites, at 0.1 ppm on the crop groupings citrus, curcurbits, forage grasses, forage legumes, fruiting vegetables, grain crops, fruiting vegetables, grain crops, leafy vegetables, nuts, pome fruits, root crop vegetables, seed and pod vegetables, stone fruit, and the individual commodities cottonseed, hops, and avocadoes. When tolerances are established at higher levels from other uses of glyphosate in or on subject crops, the higher tolerance should also apply to residues from the aquatic uses cited in this paragraph. [R63] *Tolerances are established for residues of glyphosate (N-(phosphonomethyl)glycine) resulting from the application of the isopropylamine of glyphosate and/or the monoammonium salt of glyphosate in or on the following agricultural commodities: almond hulls, 25 ppm; tree nut crop group, 1.0 ppm; wheat (grain), 5.0 ppm; and wheat (straw), 85 ppm. [R64, (7/7/93)] *Tolerances are established for the combined residues of the herbicide glyphosate and the metabolites as indicated when present therein as a result of the herbicide application to growing crops. Glyphosate [N-(phosphonomethyl)glycine] and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine salt of glyphosate for herbicidal purposes and/or the sodium sesqui salt for plant growth regulator purposes: molasses (sugarcane), 30.0 ppm. [R65] *Tolerances are established for the combined residues of the herbicide glyphosate and the metabolites as indicated when present therein as a result of the herbicide application to growing crops. Glyphosate [N-(phosphonomethyl)glycine] and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine salt of glyphosate for herbicidal purposes: oil (palm), 0.1 ppm; olives (imported), 0.1 ppm; tea (dried), 1.0 ppm; and tea (instant), 4.0 ppm. [R66] *Tolerances are established for the combined residues of the herbicide glyphosate and the metabolites as indicated when present therein as a result of the herbicide application to growing crops. Glyphosate [N-(phosphonomethyl)glycine] resulting from the application of the isopropylamine salt of glyphosate and/or the monoammonium salt of glyphosate for herbicidal purposes: wheat milling fractions (excluding flour), 20.0 ppm. [R67] *A feed additive regulation is established permitting the combined residues of the herbicide glyphosate (N-(phosphonomethyl) glycine) and its metabolite aminomethylphosphonic acid in or on the following feed commodities: citrus pulp (dried), 0.4 ppm; and soybean hulls, 20 ppm. [R68] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 700 ug/l [R69] FEDERAL DRINKING WATER GUIDELINES: +EPA 700 ug/l [R69] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 700 ug/l [R69] +(ME) MAINE 700 ug/l [R69] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Glyphosphate is found on List A, which contains most food use pesticides and consists of the 194 chemical cases (or 350 individual active ingredients) for which EPA issued registration standards prior to FIFRA, as amended in 1988. Case No: 0178; Pesticide type: Herbicide (growth regulator); Registration Standard Date: 06/01/86; Case Status: RED Approved 09/93; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Isopropylamine glyphosate; Data Call-in (DCI) Date(s): 01/24/94, 02/16/94; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R70] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine of glyphosate and/or the monoammonium salt of glyphosate in or on the following agricultural commodities: acerola, alfalfa, alfalfa (fresh and hay), almonds (hulls), artichokes (Jerusalem), asparagus, atemoya, avocados, bahiagrass, bananas, beets, beets (sugar), bermudagrass, bluegrass, breadfruit, bromegrass, canistel, carambola, carrots, cherimoya, chicory, citrus fruits, clover, cocoa beans, coconut, coffee beans, cotton (forage and hay), cottonseed, cranberries, dates, fescue, figs, forage grasses, forage legumes, fruits (small) and berries, genip, grain crops (except wheat), grapes, grasses (forage), guavas, horseradish, jaboticaba, jackfruit, kiwifruit, leafy vegetables, longan, lychee, mamy sapote, mangoes, nuts, olives, orchardgrass, papayas, parsnips, passion fruit, peanut (forage), persimmons, pineapple, pistachio nuts, pome fruits, potatoes, radishes, rutabagas, ryegrass, salsify, sapodilla, sapote (black and white), seed and pod vegetables (including forage and hay), soursoup, soybeans, soybeans (forage and hay), stone fruit, sugar apple, sweet potatoes, tamarind, timothy, turnips, vegetables (bulb, curcubit, fruiting group, and leafy, Brassica (cole)), wheatgrass, and yams. [R60] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine of glyphosate and/or the monoammonium salt of glyphosate in or on the following agricultural commodities: pomegranates. [R61, (5/28/92))] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid resulting from the application of the glyphosate isopropylamine and/or glyphosate monoammonium salt for herbicidal and plant growth regulator purposes and/or the sodium sesqui salt for growth regulator purposes in or on the following agricultural commodities: cattle (kidney and liver), fish, goats (kidney and liver), hogs (kidney and liver), horses (kidney and liver), peanuts, peanut (hay and hulls), poultry (kidney and liver), sheep (kidney and liver), shellfish, and sugarcane. [R62] *Tolerances are established for the combined residues of glyphosate (N-(phosphonomethyl)glycine) and its metabolite aminomethylphosphonic acid, resulting from the use of irrigation water containing residues of 0.5 ppm following applications on or around aquatic sites, on the crop groupings citrus, curcurbits, forage grasses, forage legumes, fruiting vegetables, grain crops, fruiting vegetables, grain crops, leafy vegetables, nuts, pome fruits, root crop vegetables, seed and pod vegetables, stone fruit, and the individual commodities cottonseed, hops, and avocadoes. When tolerances are established at higher levels from other uses of glyphosate in or on subject crops, the higher tolerance should also apply to residues from the aquatic uses cited in this paragraph. [R63] *Tolerances are established for residues of glyphosate (N-(phosphonomethyl)glycine) resulting from the application of the isopropylamine of glyphosate and/or the monoammonium salt of glyphosate in or on the following agricultural commodities: almond hulls, tree nut crop group, and wheat (grain and straw). [R64, (7/7/93))] *Tolerances are established for the combined residues of the herbicide glyphosate and the metabolites as indicated when present therein as a result of the herbicide application to growing crops. Glyphosate [N-(phosphonomethyl)glycine] and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine salt of glyphosate for herbicidal purposes and/or the sodium sesqui salt for plant growth regulator purposes: molasses (sugarcane). [R65] *Tolerances are established for the combined residues of the herbicide glyphosate and the metabolites as indicated when present therein as a result of the herbicide application to growing crops. Glyphosate [N-(phosphonomethyl)glycine] and its metabolite aminomethylphosphonic acid resulting from the application of the isopropylamine salt of glyphosate for herbicidal purposes: oil (palm), olives (imported), tea (dried and instant). [R66] *Tolerances are established for the combined residues of the herbicide glyphosate and the metabolites as indicated when present therein as a result of the herbicide application to growing crops. Glyphosate [N-(phosphonomethyl)glycine] resulting from the application of the isopropylamine salt of glyphosate and/or the monoammonium salt of glyphosate for herbicidal purposes: wheat milling fractions (excluding flour). [R67] *A feed additive regulation is established permitting the combined residues of the herbicide glyphosate (N-(phosphonomethyl) glycine) and its metabolite aminomethylphosphonic acid in or on the following feed commodities: citrus pulp (dried) and soybean hulls. [R68] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *COLORIMETRIC DETERMINATION OF GLYPHOSATE IN WATER AFTER OXIDATION TO ORTHO PHOSPHATE. [R71] *Residues and products may be determined by HPLC. [R2, 450] *... By measuring fluorescence of the nitroso derivative. [R4] *EPA Method 547. Determination of Glyphosate in Drinking Water by Direct Aqueous Injection HPLC with a post column derivatization, and a fluorescence detection. Under the prescribed conditions, glyphosate has a method detection limit of 6.0 ug/l as defined by EPA. [R72] *Determination of glyphosate (technical) and pesticide formulations using liquid chromatographic method. Samples are dissolved in phosphate buffer mobile phase and injected directly into ion exchange chromatographic system using fixed volume loop. Peak area response as measured by UV detector is quantitated by external standard technic. The flow rate is 2.5-4.0 ml/min. [R73] *Determination of glyphosate and aminomethylphosphonic acid residues in forages, grains, soil, and water by using gas liquid chromatography with a phosphorus specific flame photometric detector. The detection limit is 0.05 ppm (50 g sample), 0.10 g ppm (25 g sample), and 2.5 ppb (1 kg water sample). Recovery was 55-70%. [R74] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of Glyphosate Administered in Dosed Feed to F344/N Rats and B6C3F1 Mice NTP Tox 16 (1992) SO: R1: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. 2nd ed. Lechworth, Herts, England: The Royal Society of Chemistry, 1987.,p. A222/Aug 87 R2: Worthing, C.R. and S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 8th ed. Thornton Heath, UK: The British Crop Protection Council, 1987. R3: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 834 R4: Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 317 R5: Weed Science Society of America. Herbicide Handbook. 5th ed. Champaign, Illinois: Weed Science Society of America, 1983. R6: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 709 R7: Worthing, C.R., S.B. Walker (eds.). The Pesticide Manual - A World Compendium. 7th ed. Lavenham, Suffolk, Great Britain: The Lavenham Press Limited, 1983. 303 R8: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2212 R9: Hartley, D. and H. Kidd (eds.). The Agrochemicals Handbook. Old Woking, Surrey, United Kingdom: Royal Society of Chemistry/Unwin Brothers Ltd., 1983.,p. A222/Oct 83 R10: MONNIG E ET AL; TREATABILITY STUDIES OF PESTICIDE MANUFACTURING WASTEWATERS: GLYPHOSATE; REPORT: 54 PAGES (1980) ISS EPA-600/2-80-077D; ORDER NUMBER PB81-159097 R11: FLORA T, SIMON Z; MAGY KEM FOLY 87 (9): 419-24 (1981) R12: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 187 R13: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Glyphosphate (1071-83-6) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R14: MORGAN DP; RECOGNITION AND MANAGEMENT OF PESTICIDE POISONINGS. 4TH ED, P.87 EPA 540/9-88-001. WASHINGTON, DC: U.S. GOVERNMENT PRINTING OFFICE, MARCH 1989 R15: MORGAN DP; RECOGNITION AND MANAGEMENT OF PESTICIDE POISONINGS. 4TH ED, P.88 EPA540/9-88-001. WASHINGTON, DC: U.S. GOVERNMENT PRINTING OFFICE, MARCH 1989 R16: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. R17: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 3. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 1340 R18: Talbot AR et al; Hum Exp Toxicol 10 (1): 1-8 (1991) R19: U.S. Department of Interior, Fish and Wildlife Service. Handbook of Acute Toxicity of Chemicals to Fish and Aquatic Invertebrates. Resource Publication No. 137. Washington, DC: U.S. Government Printing Office, 1980.43 R20: GOPALAN HNB, NJAGI GDE; GENETICS 97 (S1): S44 (1981) R21: NJAGI GDE, GOPALAN HNB; BANGLADESH J BOT 9 (2): 141-6 (1980) R22: SULLIVAN TP, SULLIVAN DS; CAN J ZOOL 59 (6): 1148-54 (1981) R23: OLORUNSOGO OO, BABABUNMI EA; TOXICOL LETT 7 (2): 149-52 (1980) R24: Sax, N.I. Dangerous Properties of Industrial Materials Reports. New York: Van Nostrand Rheinhold, 1987.,p. 10:5 (1990) R25: Rank J et al; Mutat Res 300 (1): 29-36 (1993) R26: Shuma JM, Raju M VS; Weed Res 33 (1): 43-51 (1993) R27: NTP; Toxicology and Carcinogenesis Studies of Glyphosate p.55 Report #16 (1992) NIH Pub #92-3135 R28: Bergvinson DJ, Borden JH; Can J For Res 22 (2): 206-9 (1992) R29: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V18 7 (1982) R30: Hill, E.F. and Camardese, M.B. Lethal Dietary Toxicities of Environmental Contaminants and Pesticides to Coturnix. Fish and Wildlife Technical Report 2. Washington, DC: United States Department of Interior Fish and Wildlife Service, 1986.82 R31: MARQUIS LY ET AL; WEED SCI 29 (2): 229-36 (1981) R32: Wester RC et al; Fund Appl Toxicol 16 (4): 725-43 (1991) R33: Aizawa, H. Metabolic Maps of Pesticides. New York, NY: Academic Press, 1982. 140 R34: Menzie, C.M. Metabolism of Pesticides-Update III. Special Scientific Report- Wildlife No. 232. Washington, DC: U.S.Department of the Interior, Fish and Wildlife Service, 1980. 318 R35: KITCHEN LM ET AL; WEED SCI 29 (5): 571-7 (1981) R36: AMRHEIN ET AL; PLANT PHYSIOL 66 (5): 830-4 (1980) R37: KITCHEN LM ET AL; WEED SCI 29 (4): 513-6 (1981) R38: (1) Worthing CR, Walker SB; The Pesticide Manual 8th ed.; pp. 449-50 Suffolk, England: Lavenham Press Ltd (1987) (2) Gianessi LP; A National Pesticide Usage Data Base Washington,DC: Resources for the Future Feb., 1986 (1986) (3) Gianessi LP, Puffer P; Herbicide Use in the United States: National Summary Report. Washington,DC: Resources for the Future. Dec. 1990, Rev Apr 1991 (1991) (4) Crop Protection Chemicals Reference 8th ed.; Chemical and Pharmaceutical Press pp. 1309-12, 1423-4, 1435, 444-61 (1992) (5) WSSA; Herbicide Handbook 6th ed.; Champaign,IL: Weed Sci Soc Amer pp. 146-9 (1989) R39: MUELLER MM ET AL; BULL ENVIRON CONTAM TOXICOL 27 (5): 724-30 (1981) R40: (1) Neary DG et al; Environ Toxicol Chem 12: 411-28 (1993) (2) Feng JC, Thompson; J Agric Food Chem 38: 1118-25 (1990) (3) Spankle P; Weed Sci 23: 224-8 (1975) (4) Rueppel ML et al J Agric Food Chem 25: 517-28 (1977) (5) Reinert KH, Rodgers JH; Rev Environ Contam Toxicol 98: 61-98 (1987) R41: (1) Willis GH, McDowell LL; Rev Environ Contam Toxicol 100: 23-73 (1987) (2) Muller MM et al; Bull Environ Contam Toxicol 27: 724-30 (1981) (3) Roy DN et al; J Agric Food Chem 37: 437-40 (1989) (4) Newton M et al; J Agric Food Chem 32: 1144-51 (1984) R42: (1) Muller MM et al; Bull Environ Contam Toxicol 27: 724-30 (1981) R43: (1) Feng JC et al; J Agric Food Chem 38:1110-8 (1990) (2) Goldsborough LG, Beck AE; Arch Environ Contam Toxicol 18: 537-44 (1989) R44: (1) Newton M et al; J Agric Food Chem 32: 1144-51 (1984) (2) Bowmer KH et al; Pestic Sci 17: 79-88 (1986) R45: (1) Tate RL, Alexander M; Soil Sci 118: 317-21 (1974) (2) Rueppel ML et al J Agric Food Chem 25: 517-28 (1977) R46: (1) Feng JC, Thompson; J Agric Food Chem 38: 1118-25 (1990) (2) Spankle P; WeedSci 23: 224-8 (1975) (3) Rueppel ML et al J Agric Food Chem 25: 517-28 (1977) (4) Smith AE, Aubin AJ; Bull Environ Contam Toxicol 50: 499-505 (1993) R47: (1) Spankle P; Weed Sci 23: 224-8 (1975) (2) Subramaniam V, Hoggaard PE; J Agric Food Chem 36: 1326-9 (1988) R48: (1) Rueppel ML et al J Agric Food Chem 25: 517-28 (1977) (2) Lund-Hoie K, Friestad HO; Bull Environ Contam Toxicol 36: 723-9 (1986) (3) WSSA; Herbicide Handbook 6th ed.; Champaign,IL: Weed Sci Soc Amer pp. 146-9 (1989) R49: (1) Newton M et al; J Agric Food Chem 32: 1144-51 (1984) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 5 (1982) (3) Reinert KH, Rodgers JH; Rev Environ Contam Toxicol 98: 61-98 (1987) R50: Menzie, C.M. Metabolism of Pesticides, Update II. U.S. Department of the Interior, Fish Wildlife Service, Special Scientific Report - Wildlife No. 2l2. Washington, DC: U.S. Government Printing Office, 1978.146 R51: (1) Reinert KH; pp. 335-48 in Reactions and Movement of Organic Chemicals in Soils. Soil Sci Soc Amer Spec Publ.22 (1989) (2) Glass RL; J Agric Food Chem 35: 497-500 (1987) (3) McConnell JS, Hossner LR; J Agric Food Chem 33: 1075-8 (1985) (4) Feng JC, Thompson; J Agric Food Chem 38: 1118-25 (1990) (5) Spankle P; Weed Sci 23: 224-8 (1975) (6) Miles CJ, Moye HA; J Agric Food Chem 36: 486-91 (1988) (7) Rueppel ML et al J Agric Food Chem 25: 517-28 (1977) R52: (1) Glass RL; J Agric Food Chem 35: 497-500 (1987) (2) McConnell JS, Hossner LR; J Agric Food Chem 33: 1075-8 (1985) (3) Miles CJ, Moye HA; J Agric Food Chem 36: 486-91 (1988) R53: (1) Feng JC, Thompson; J Agric Food Chem 38: 1118-25 (1990) (2) Spankle P; WeedSci 23: 224-8 (1975) R54: (1) Frank R et al; Bull Environ Contam Toxicol 44: 410-9 (1990) (2) Hallberg GR; Agr Ecossys Environ 26: 299-367 (1989) R55: (1) Heinonen-Tanski H et al; Pestic Sci 16: 341-8 (1985) R56: (1) Crop Protection Chemicals Reference 8th ed.; Chemical and Pharmaceutical Press pp. 1309-12, 1423-4, 14351444-61 (1992) (2) WSSA; Herbicide Handbook 6th ed.; Champaign,IL: Weed Sci Soc Amer pp. 146-9 (1989) R57: SILTANEN H ET AL; BULL ENVIRON CONTAM TOXICOL 27 (5): 731-7 (1981) R58: (1) Feng JC, Thompson; J Agric Food Chem 38: 1118-25 (1990) (2) Siltanen H et al; Bull Environ Contam Toxicol 27: 731-7 (1981) R59: (1) Maddy KT et al; Rev Environ Contam Toxicol 114: 57-123 (1990) R60: 40 CFR 180.364(a) (7/1/91) (amended in 58 FR 36359 (7/7/93)) R61: 40 CFR 180.364(a) (57 FR 22437 R62: 40 CFR 180.364(b) (7/1/91) R63: 40 CFR 180.364(c) (7/1/91) R64: 40 CFR 180.364(d) (58 FR 36359 R65: 40 CFR 185.3500(a)(1) (7/1/91) R66: 40 CFR 185.3500(a)(2) (7/1/91) R67: 40 CFR 185.3500(a)(3) (58 FR 26359 (7/7/93)) R68: 40 CFR 186.3500(a) (7/1/91) R69: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R70: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.123 (Spring, 1998) EPA 738-R-98-002 R71: GLASS RL; ANAL CHEM 53 (6): 921-3 (1981) R72: USEPA/SCC; Environmental Monitoring Methods Index p.19 (1992) R73: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. V1 205 R74: FDA Pesticide Analytical Manual 2.1 (180.364): (1989) RS: 69 Record 241 of 1119 in HSDB (through 2003/06) AN: 3529 UD: 200211 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: QUERCETIN- SY: *4H-1-BENZOPYRAN-4-ONE, 2-(3,4-DIHYDROXYPHENYL)-3,5,7-TRIHYDROXY-; *CI-NATURAL-YELLOW-10-; *CI-75670-; *CYANIDELONON-1522-; *FLAVONE,-3,3',4',5,7-PENTAHYDROXY-; *MELETIN-; *NCI-C60106-; *3,3',4',5,7-PENTAHYDROXYFLAVONE-; *3,5,7,3',4'-PENTAHYDROXYFLAVONE-; *QUERCETINE-; *QUERCETOL-; *QUERCITIN-; *QUERTINE-; *SOPHORETIN-; *3',4',5,7-TETRAHYDROXYFLAVAN-3-OL-; *XANTHAURINE- RN: 117-39-5 MF: *C15-H10-O7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +SHAKHOVA ET AL, ZH OBSHCH KHIM 32, 390 (1962), CA 58, 1426F (1963). BIOSYNTHESIS: WATKIN ET AL, CAN J BIOCHEM PHYSIOL 35, 229 (1957); GRISEBACH, BIOCHEM J 85, 3 P (1962); PATSCHKE ET AL, Z NATURFORSCH 21B, 201 (1966). [R1] MFS: +R S A Corporation, 690 Saw Mill River Road, Ardsley, NY 10502, (914) 693-1818, (914) 693-2493 [R2] USE: *MEDICATION: QUERCETIN AND PENTABENZYL ETHER DERIV TO DECR CAPILLARY FRAGILITY /PRC: FORMER USE/ [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: +SUBLIMES @ BOILING POINT [R3] MP: *316-317 DEG C (ANHYD) [R3] MW: *302.25 [R4] SOL: *SLIGHTLY SOL IN ETHER, METHANOL, HOT WATER, HOT ALCOHOL; SOL IN ACETONE, PYRIMIDINE, ACETIC ACID [R3] SPEC: +MAX ABSORPTION (ALCOHOL): 256 NM (LOG E= 4.32); 301 NM (LOG E= 3.89); 373 NM (LOG E= 4.32); SADTLER REF NUMBER: 594 (IR, PRISM) [R3]; +IR: 18403 (Sadtler Research Laboratories IR Grating Collection) [R5]; +UV: 7-578 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R5]; +MASS: 227 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R5] OCPP: *YELLOW NEEDLES FROM DIL ALCOHOL /DIHYDRATE/ [R1] *1 G DISSOLVES IN 290 ML ABSOLUTE ALC, IN 23 ML BOILING ALC; SOL IN GLACIAL ACETIC ACID, AQ ALKALINE SOLN; PRACTICALLY INSOL IN WATER /DIHYDRATE/ [R1] *MAX ABSORPTION (ALCOHOL): 258 NM (LOG E= 2.75); 375 NM (LOG E= 2.75); ALCOHOLIC SOLUTIONS TASTE VERY BITTER; WHEN ANHYD IT DECOMPOSES @ 314 DEG C; BECOMES ANHYD @ 95-97 DEG C /DIHYDRATE/ [R1] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of quercetin. There is limited evidence in experimental animals for the carcinogenicity of quercetin. Overall evaluation: Quercetin is not classifiable as to its carcinogenicity to humans (Group 3). [R6] HTOX: *QUERCETIN INDUCED CHROMOSOME ABERRATIONS AND SISTER CHROMATID EXCHANGE (SCE) IN HUMAN CELLS (FIBROBLASTS AND LYMPHOCYTES) WITHOUT METABOLIC ACTIVATION. THE INCREMENT IN FREQUENCY OF SCE WAS DOSE-DEPENDENT AND MAX FREQUENCY WAS 1.7-3.3-FOLD GREATER THAN THAT OF THE CONTROL VALUES. THE FREQUENCY OF CHROMOSOME ABERRATIONS WAS ELEVATED 1.7-7.8-FOLD COMPARED WITH CONTROLS. [R7] NTOX: *QUERCETIN...CAUSED CATARACT IN 50% OF THE RATS TO WHICH IT WAS ADMIN IN IMPURE COMMERCIAL FORM, BUT ONLY ONE EYE OF EACH RAT WAS AFFECTED, AND PURIFIED QUERCETIN DID NOT PRODUCE CATARACTS. AN EXPLANATION HAS NOT YET BEEN FOUND. [R8] *QUERCETIN WAS MUTAGENIC TO V79 CHINESE HAMSTER CELLS IN THE ABSENCE OF RAT-LIVER (S-9) MIX...AND QUERCETIN...SHOWED UNEQUIVOCAL MUTAGENIC ACTIVITY IN SALMONELLA TYPHIMURIUM TA98 STRAIN; QUERCETIN.../WAS/ ACTIVE WITHOUT METABOLIC ACTIVATION. [R9] *PURIFIED QUERCETIN AS WELL AS DIETS CONTAINING 0.1% and 0.2% ARE MUTAGENIC TO SALMONELLA TYPHIMURIUM TA 100. RATS FED QUERCETIN DIETS FOR 64 WEEKS SHOWED NO CONSISTENT TISSUE LESIONS, CARCINOGENICITY OR REPRODUCTIVE PROBLEMS. [R10] *MICE GIVEN QUERCETIN ORALLY AT CONCENTRATIONS THAT WERE ABOUT 10+3 TIMES GREATER THAN THE ESTIMATED AVG HUMAN INTAKE OF TOTAL FLAVONOLS WERE TESTED FOR MUTAGENICITY WITH 2 COMPLEMENTARY IN VIVO MUTAGENICITY/CARCINOGENICITY SCREENING TESTS: THE MICRONUCLEUS TEST AND THE HOST-MEDIATED ASSAY EMPLOYING THE AMES SALMONELLA TESTER STRAIN TA98. NO MUTAGENIC EFFECT WAS DETECTED WITH EITHER TEST. [R11] *THE GENOTOXICITY OF SELECTED FLAVONOLS WAS STUDIED. CHROMOSOMAL ABERRATIONS, SISTER-CHROMATID EXCHANGE (SCE) AND FORWARD MUTATION AT 4 GENE LOCI WERE MEASURED IN A SINGLE POPULATION OF CHINESE HAMSTER OVARY CELLS (CHO) EXPOSED TO QUERCETIN FOR 15 HR WITH AND WITHOUT METABOLIC ACTIVATION. INCIDENCE OF CHROMOSOMAL ABERRATIONS WAS SIGNIFICANTLY INCREASED IN THE ABSENCE OF ACTIVATION. FLAVONOL TREATMENT AFFECTED SCE AND MUTATION AT THE HGPRT, APRT, OR NA+/K+-ATPASE LOCI ONLY MARGINALLY, BUT SIGNIFICANTLY INCREASED MUTATION FREQUENCIES AT THE TK LOCUS. THE RESPONSE AT THE TK LOCUS SUGGESTS THAT THE CHO CELLS MAY BEHAVE SIMILARLY TO L5178Y CELLS, IN WHICH THE TK LOCUS IS THOUGHT TO REFLECT CHROMOSOMAL LESIONS IN ADDITION TO POINT MUTATION. THESE EXPERIMENTS INDICATE THAT, AT LEAST UNDER THESE CONDITIONS EXAMINED, FLAVONOLS INDUCE CHROMOSOMAL ABERRATIONS IN CHO CELLS, BUT HAVE LITTLE EFFECT ON POINT MUTATION OR SCE. [R12] *RATS WERE MAINTAINED ON A DIET CONTAINING 1 0R 5% QUERCETIN FOR 540 DAYS, OR 10% FOR 850 DAYS. MOST TUMORS FOUND IN EXPERIMENTAL GROUPS WERE ALSO FOUND IN THE CONTROL GROUPS. THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN THE INCIDENCE OF TUMORS IN THE EXPERIMENTAL OR CONTROL GROUPS (P= 0.05). QUERCETIN WAS NOT CARCINOGENIC TO ACI RATS. [R13] *QUERCETIN WAS ACTIVE IN THE MOUSE LYMPHOMA TK+/- MUTATION ASSAY, INCREASING THE FREQUENCY OF TFT-RESISTANT COLONIES FROM A CONTROL VALUE OF 37/106 VIABLE CELLS TO 355/106 VIABLE CELLS AT 20 MUG/ML. WHEN S9 WAS PRESENT, THE ACTIVITY WAS DECREASED AT EACH CONCN USED. AS THE S9 CONCN EMPLOYED DECREASED, THE INDUCED MUTANT FREQUENCY INCREASED. DNA SINGLE-STRAND BREAKAGE WAS OBSERVED WITHOUT S9 AT 10 MUG/ML, USING THE ALKALINE ELUTION TECHNIQUE; A MAXIMAL RATE OF ELUTION WAS REACHED AT 20 MUG/L. IN THE BALB/C 3T3 CHEMICAL TRANSFORMATION EXPERIMENTS, TRANSFORMATION JUST AT THE LEVEL OF 0.05% (IF BOTH INTERMEDIATE AND TYPICAL TRANSFORMED COLONIES WERE COMBINED) WAS OBSERVED. [R14] *QUERCETIN WAS TESTED FOR CARCINOGENICITY IN NON-INBRED GOLDEN HAMSTERS. IN EXPERIMENT I, 10% QUERCETIN OR CONTROL DIET WAS ADMIN FOR 735 DAYS. TUMORS APPEARED MAINLY IN THE FORESTOMACH, BUT WAS NOT STATISTICALLY DIFFERENT AMONG THE GROUPS. IN EXPERIMENT II, ONE GROUP WAS ADMIN 4% FOR 709 DAYS. GROUP 2 WAS GIVEN 1% IN DIET FOR 351 DAYS AND THEN THE BASAL DIET FOR 350 DAYS. GROUP 3 RECEIVED 1% QUERCETIN DIET AND THE 1% CROTON OIL DIET AND GROUP 4 WAS GIVEN BASAL DIET FOLLOWED BY 1% CROTON OIL, FOR SAME PERIODS AS GROUP 2. GROUP 5 WAS GIVEN BASAL DIET FOR 701 DAYS. THERE WAS NO STATISTICAL DIFFERENCES AMONG EXPERIMENTAL GROUPS AND RESPECTIVE CONTROLS. [R15] *QUERCETIN (50, 100, OR 150 MG/KG, ORALLY) FAILED TO INDUCE MUTATION IN THE GERM CELLS OF MICE USING THE SPERM ABNORMALITY ASSAY. [R16] *QUERCETIN WAS NEGATIVE IN BACILLUS SUBTILIS. [R17] *FOUR FLAVONOID COMPOUNDS, QUERCETIN, KAEMPFEROL, NEOHESPERIDIN DIHYDROCHALCONE, AND RUTIN, WERE ADMINISTERED TO MALE MICE FOR DETECTION OF GROSS CHROMOSOMAL ANOMALIES BY THE MICRONUCLEUS TEST. THE FIRST 3 COMPOUNDS WERE POSITIVELY CLASTOGENIC TO DIFFERENT EXTENTS, WHEREAS THE 4TH WAS NEGATIVE. [R18] *GROUPS OF 38 MALE AND 35 FEMALE DDY MICE, SIX-WEEKS OLD, WERE GIVEN PELLETS CONTAINING 2% QUERCETIN THROUGHOUT THEIR LIFE SPAN. AS CONTROLS, 16 MALES AND 15 FEMALES WERE GIVEN BASAL DIET. ANIMALS IN THE EXPERIMENTAL AND CONTROL GROUPS DEVELOPED LEUKEMIA AND TUMORS OF THE LUNG, FORESTOMACH, MAMMARY GLAND, ADRENAL AND SOFT PART TISSUES. IN ADDITION, SOME ANIMALS IN TREATED GROUPS DEVELOPED TUMORS OF THE HEART, LIVER, SALIVARY GLAND, OVARY, AND UTERUS. THE INCIDENCES OF THESE TUMORS IN TEST AND CONTROL GROUPS WERE NOT STATISTICALLY DIFFERENT. [R19] *TWO OF THE FLAVONOLS FOUND IN FOODS, QUERCETIN AND KAEMPFEROL, WERE MUTAGENIC AS MEASURED BY THE RECESSIVE SEX-LINKED LETHAL TEST. SINCE DROSOPHILA APPEARS TO POSSESS METABOLIZING CAPACITIES SIMILAR TO THOSE OF MAMMALS, THERE IS CLEARLY A POTENTIAL HAZARD THAT THESE FLAVONOLS MAY BE CARCINOGENIC TO MAN. [R20] *SINGLE ORAL DOSE OF 2, 20, 200 OR 2000 MG QUERCETIN/KG WAS ADMIN TO RATS ON THE MORNING OF DAY 9 OF GESTATION. OTHER PREGNANT RATS RECEIVED SIMILAR DOSES DAILY, ON DAYS 6-15 OF GESTATION. SOME TREATED GROUPS SHOWED A SIGNIFICANT DECREASE IN AVG WEIGHT OF DAY-20 FETUSES COMPARED WITH CONTROLS. HOWEVER, STUDIES OF FETUSES RECOVERED ON DAY 20 OF GESTATION FAILED TO SHOW ANY REPRODUCIBLE DOSE-RELATED SYNDROME OF TERATOGENIC EFFECTS ATTRIBUTABLE TO QUERCETIN TREATMENT. [R21] *QUERCETIN INDUCED CHROMOSOME ABERRATIONS AND SISTER CHROMATID EXCHANGE (SCE) IN HAMSTER CELLS (FIBROBLASTS AND LYMPHOCYTES) WITHOUT METABOLIC ACTIVATION. THE INCREMENT IN FREQUENCY OF SCE WAS DOSE-DEPENDENT AND MAX FREQUENCY WAS 1.7-3.3-FOLD GREATER THAN THAT OF THE CONTROL VALUES. THE FREQUENCY OF CHROMOSOME ABERRATIONS WAS ELEVATED 1.7-7.8-FOLD COMPARED WITH CONTROLS. [R7] +.... Conclusions Under the conditions of these 2 year feed studies there was some evidence of carcinogenic activity of quercetin in male F344/N rats based on an increased incidence of renal tubule cell adenomas. There was no ev dence of carcinogenic activity of quercetin in female F344/N rats receiving 1,000, 10,000 or 40,000 ppm. [R22] NTP: +2 Year studies were conducted by administering 0, 1,000, 10,000, or 40,000 ppm quercetin (> 95% pure) in feed to groups of 50 male and female rats for 104 weeks. .... Conclusions Under the conditions of these 2 year feed studies there was some evidence of carcinogenic activity of quercetin in male F344/N rats based on an increased incidence of renal tubule cell adenomas. There was no ev dence of carcinogenic activity of quercetin in female F344/N rats receiving 1,000, 10,000 or 40,000 ppm. [R22] ADE: +WHEN (14)C-QUERCETIN WAS ADMIN ORALLY TO ACI RATS, ABOUT 20% OF THE ADMIN DOSE WAS ABSORBED FROM DIGESTIVE TRACT, MORE THAN 30% WAS DECOMPOSED TO YIELD (14)CO2 AND ABOUT 30% WAS EXCRETED UNCHANGED IN FECES. [R23] METB: *THE GLYCOSIDES ARE HYDROLYZED IN THE BODY TO CORRESPONDING AGLYCONES, WHICH ARE THEN FURTHER METABOLIZED BY SCISSION OF THE HETEROCYCLIC RING TO GIVE 3,4-DIHYDROXY-PHENYL-SUBSTITUTED ACIDS... THE SITE OF RING SCISSION DEPENDS ON STRUCTURE. ... WITH FLAVONOLS (QUERCETIN) SCISSION OCCURS AT THE 1,2 and 3,4 BONDS TO YIELD HOMOPROTOCATECHUIC ACID... THESE ACIDS ARE FURTHER METABOLIZED BY BETA-OXIDATION OF ACYL SIDE-CHAIN, O-METHYLATION AND DEMETHYLATION, AND AROMATIC DEHYDROXYLATION. [R24] *YIELDS DIHYDROQUERCETIN PROBABLY IN CICER: HOSEL W, BARZ W; BIOCHIM BIOPHYS ACTA; 261: 294 (1972); YIELDS 3,4-DIHYDROXYPHENYLHYDRACRYLIC ACID PROBABLY IN PIG: KALLIANOS AG ET AL; ARCHS BIOCHEM BIOPHYS 81: 430 (1959); YIELDS 3,4-DIHYDROXYPHENYLACETIC ACID IN RABBIT: MURRAY CW ET AL; J AM PHARM ASS 43: 361 (1950); YIELDS 3',7-DIMETHYLQUERCETIN IN ASPERGILLUS: HALUK JP, METCHE M; BULL SOC CHIM BIOL 52: 667 (1970); YIELDS M-HYDROXYPHENYLPROPIONIC ACID AND M-HYDROXYPHENYLACETIC ACID IN MICROORGANISM: SCHELINE RR; ACTA PHARMAC TOX 26: 332 (1968); YIELDS ISORHAMNETIN IN PARSLEY: EBEL J ET AL; BIOCHIM BIOPHYS ACTA 269: 313 (1972); YIELDS PHLOROGLUCINOLCARBOXYLIC ACID IN RAT: KALLIANOS AG ET AL; ARCH S BIOCHEM BIOPHYS 81: 430 (1959); YIELDS PROTOCATECHUOYLPHLOROGLUCINOLCARBOXYLIC ACID IN ASPERGILLUS: OKA T ET AL; CAN J MICROBIOL 18: 493 (1972). /FROM TABLE/ [R25] *O-BETA-HYDROXYETHYLATED DERIVATIVES OF QUERCETIN WERE ISOLATED FROM URINE SAMPLES AND SEPARATED BY HPLC. THE 5,7,3',4'-TETRA COMPD WAS SEPARATED FROM 3,7,3',4'-TETRA DERIVATIVE. THE 7,3',4'-TRI AND 7'-MONO COMPOUNDS GAVE 1 COMMON PEAK, SEPARATED FROM THE PEAK FOR THE 7,4'-DI COMPD. [R26] +AFTER ORAL ADMIN TO ACI RATS, THE ABSORBED (14)C-QUERCETIN WAS RAPIDLY EXCRETED INTO THE BILE AND URINE WITHIN 48 HR AS THE GLUCURONIDE AND SULFATE CONJUGATES OF (14)C-QUERCETIN, 3'-O-MONOMETHYL QUERCETIN AND 4'-O-MONOMETHYL QUERCETIN. EFFICIENT METABOLISM AND ELIMINATION OF QUERCETIN MAY BE ONE REASON FOR THE LACK OF CARCINOGENICITY IN RATS [R23] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: +THE AGLUCON OF QUERCITRIN, OF RUTIN, AND OTHER GLYCOSIDES. WIDELY DISTRIBUTED IN THE PLANT KINGDOM, ESP IN RINDS AND BARKS, IN CLOVER BLOSSOMS AND RAGWEED POLLEN. ISOLATION FROM RHODODENDRON CINNABARINUM HOOK, ERICACEAE: RANGASWAMI ET AL, PROC INDIAN ACAD SCI 56A, 239 (1962), CA 58, 9414A (1963). [R1] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HIGH-PRESSURE LIQUID CHROMATOGRAPHY WAS USED TO ANALYZE FLAVONOIDS FROM PROPOLIS. [R27] *QUERCETIN WAS DETERMINED BY GAS CHROMATOGRAPHY/FLAME IONIZATION DETECTION. THE SAMPLE WAS DERIVATIZED WITH TRIMETHYLSILYLIMIDAZOLE AND CHOLESTEROL WAS USED AS INTERNAL STD. THE CALIBRATION CURVE WAS LINEAR FOR 4-16 MUG, AND THE MINIMUM DETECTABLE AMT WAS 6.64X10-10 MOLE WITH 98.5% RECOVERY. [R28] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Quercetin in F344/N Rats (Feed Studies) Technical Report Series No. 409 (1992) NIH Publication No 92-3140 SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1043 R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 932 R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-306 R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8303 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 634 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 73 510 (1999) R7: YOSHIDA MA ET AL; CYTOGENETIC EFFECTS OF QUERCETIN ON CULTURED MAMMALIAN CELLS; PRC JPN ACAD, SER B 56(7) 443 (1980) R8: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 869 R9: The Royal Society of Chemistry. Foreign Compound Metabolism in Mammals. Volume 6: A Review of the Literature Published during 1978 and 1979. London: The Royal Society of Chemistry, 1981. 194 R10: STOEWSAND GS ET AL; QUERCETIN: A MUTAGEN- NOT A CARCINOGEN IN FISCHER RATS; J TOXICOL ENVIRON HEALTH (IN PRESS) (1984) R11: AESCHBACHER HU ET AL; NONMUTAGENICITY IN VIVO OF THE FOOD FLAVONOL QUERCETIN; NUTR CANCER 4(2) 90 (1982) R12: CARVER JH ET AL; GENETIC EFFECTS OF THE FLAVONOLS QUERCETIN, KAEMPFEROL, AND GALANGIN ON CHINESE HAMSTER OVARY CELLS IN VITRO; MUTAT RES 113(1) 45 (1983) R13: HIRONO I ET AL; CARCINOGENICITY EXAMINATION OF QUERCETIN AND RUTIN IN ACI RATS; CANCER LETT 13(1) 15 (1981) R14: MELTZ ML, MACGREGOR JT; ACTIVITY OF THE PLANT FLAVONOL QUERCETIN IN THE MOUSE LYMPHOMA L5178Y TK+/- MUTATION, DNA SINGLE-STRAND BREAK AND BALB/C 3T3 CHEMICAL TRANSFORMATION ASSAYS; MUTAT RES 88(3) 317 (1981) R15: MORINO K ET AL; CARCINOGENICITY TEST OF QUERCETIN AND RUTIN IN GOLDEN HAMSTERS BY ORAL ADMINISTRATION; CARCINOGENESIS 3(1) 93 (1982) R16: NANDAN SD, RAO MS; LACK OF MUTAGENIC EFFECTS OF QUERCETIN IN THE GERM CELLS OF MICE; IRCS MED SCI COMPEND 11(3) 210 (1983) R17: SACKS LE, MACGREGOR JT; THE B SUBTILIS MULTIGENE SPORULATION TEST FOR MUTAGENS: DETECTION OF MUTAGENS INACTIVE IN THE SALMONELLA HIS REVERSION TEST; MUTAT RES 95(2-3) 191 (1982) R18: SAHU RK ET AL; GENETIC TOXICOLOGICAL TESTING OF SOME PLANT FLAVONOIDS BY THE MICRONUCLEUS TEST; MUTAT RES 89(1) 69 (1981) R19: SAITO D ET AL; TEST OF CARCINOGENICITY OF QUERCETIN, A WIDELY DISTRIBUTED MUTAGEN IN FOOD; TERATOGENESIS CARCINOG MUTAGEN 1(2) 213 (1980) R20: WATSON WA F; THE MUTAGENIC ACTIVITY OF QUERCETIN AND KAEMPFEROL IN DROSOPHILA MELANOGASTER; MUTAT RES 103(2) 145 (1982) R21: WILLHITE CC; TERATOGENIC POTENTIAL OF QUERCETIN IN THE RAT; FOOD CHEM TOXICOL 20(1) 75 (1982) R22: Toxicology and Carcinogenesis Studies of Quercetin in F344/N Rats (Feed Studies). Technical Report Series No. 409 (1992) NIH Publication No. 92-3140 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R23: UENO K ET AL; METABOLIC FATE OF (14)C-QUERCETIN IN THE ACI RAT; JPN J EXP MED 53(1) 41 (1983) R24: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 151 R25: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. Q-1 R26: KUHNZ W ET AL; QUANTITATIVE DETERMINATION OF O-(BETA-HYDROXYETHYL)QUERCETINS IN URINE BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; STUD ORG CHEM (AMSTERDAM) 11(FLAVONOIDS BIOFLAVONOIDS) 293 (1982) R27: BANKOVA VS ET AL; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHIC ANALYSIS OF FLAVONOIDS FROM PROPOLIS; J CHROMATOGR 242(1) 135 (1982) R28: LEE SY, KIM SK; MICROQUANTITATIVE ANALYSIS OF QUERCETIN BY GAS CHROMATOGRAPHY; JAKHAK HOE CHI 26(2) 117 (1982) RS: 18 Record 242 of 1119 in HSDB (through 2003/06) AN: 3542 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 12-O-TETRADECANOYLPHORBOL-13-ACETATE- SY: *13-O-ACETYLPHORBOL-12-MYRISTATE-; *5H-CYCLOPROPA(3,4)BENZ(1,2-E)AZULEN-5-ONE, 1,1A-BETA,1B-ALPHA,4,4A,7A-BETA, 7B,8,9,9A-DECAHYDRO-4A-ALPHA,7B-BETA,9-ALPHA,9A-BETA-TETRAHYDROXY-3- (HYDROXYMETHYL)-1,1,6,8-BETA-TETRAMETHYL-, 9A-ACETATE 9-MYRISTATE; *FACTOR-A1-; *FACTOR-A1-; *MYRISTIC ACID, 9-ESTER WITH 1,1AALPHA,1BBETA,4,4A,7AALPHA,7B,8,9,9A-DECAHYDRO-4ABETA,7BALPHA,9BETA,9AALPHA- TETRAHYDROXY-3-(HYDROXYMETHYL)-1,1,6,8ALPHA-TETRAMETHYL-5H-CYCLOPROPA(3,4)BENZ (1,2-E)AZULEN-5-ONE 9A-ACETATE, (+)-; *PENTAHYDROXY-TIGLIADIENONE-MONOACETATE(C)MONOMYRISTATE(B); *PHORBOL-ACETATE,-MYRISTATE-; *PHORBOL-MONOACETATE-MONOMYRISTATE-; *PHORBOL-MYRISTATE-ACETATE-; *PHORBOL-12-MYRISTATE-13-ACETATE-; *PHORBOL-12-TETRADECANOATE-13-ACETATE-; *PMA-; *TETRADECANOIC ACID, 9A-(ACETYLOXY)-1A,1B,4,4A,5,7A,7B,8,9,9A-DECAHYDRO-4A,7B-DIHYDROXY-3- (HYDROXYMETHYL)-1,1,6,8-TETRAMETHYL-5-OXO-1H-CYCLOPROPA(3,4)BENZ(1,2-E)AZULEN -9-YL ESTER, (1AR-(1AALPHA,1BBETA,4ABETA,7AALPHA,7BALPHA,8ALPHA,9BETA,9AALPHA))-; *12-TETRADECANOYLPHORBOL-13-ACETATE-; *12-O-TETRADEKANOYLPHORBOL-13-ACETAT- (GERMAN); *TPA- RN: 16561-29-8 MF: *C36-H56-O8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +...RAPID METHOD FOR PREPARING HIGHLY PURIFIED PMA FROM CROTON OIL: VAN DUUREN ET AL; CANCER RES 33: 2166 (1973). STARTING WITH PHORBOL...SEMISYNTHETIC PMA /CAN BE PREPARED/: BRESCH H ET AL; Z NATURFORSCH B 23: 538 (1968). [R1, 27] USE: *IN CANCER RESEARCH TO STUDY MECHANISMS OF TUMOR PROMOTION, TO SCREEN FOR POTENTIAL INHIBITING AGENTS, AND AS POSITIVE CONTROL FOR TUMOR PROMOTING AGENTS CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *616.92 [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *PMA IS A HUMAN PLATELET AGGREGATING AGENT. LOW CONCN...AGGREGATED HUMAN PLATELETS SLOWLY AT FIRST, BUT THEN MORE RAPIDLY AS ADENOSINE DIPHOSPHATE (ADP) WAS RELEASED. ADP ALONE ALSO INDUCED PLATELET AGGREGATION, BUT UNLIKE ADP-INDUCED AGGREGATION PMA-INDUCED EFFECT COULD BE READILY INHIBITED BY CHELATION OF CALCIUM IONS. ...IT WAS SUGGESTED THAT PMA-AGGREGATING EFFECT WAS MEDIATED BY PLATELET ACTOMYOSIN. ... BLOOD PLATELET-AGGREGATING EFFECT IS PROBABLY NOT RELATED TO TUMOR-PROMOTING ACTIVITY... [R1, 42] *PMA IS MOST POTENT TUMOR PROMOTOR OF KNOWN NATURAL PRODUCT AND SEMISYNTHETIC DIESTERS OF PHORBOL. AFTER PHORBOL ESTERS, ANTHRALIN IS MOST POTENT TUMOR PROMOTOR. ... IN OPERATIONAL TERMS CLEARCUT DISTINCTION CAN BE MADE BETWEEN TWO-STAGE CARCINOGENESIS AND CO-CARCINOGENESIS. ...NOT ALL PROMOTERS ARE CO-CARCINOGENS AND VICE-VERSA. .../PMA HAS/ BOTH TYPES OF ACTIVITY. [R1, 46] NTOX: *STUDIES WITH TPA ON MOUSE SKIN AND CELL CULTURES SHOWED INDUCTION OF SEVERAL PHENOTYPIC CHANGES RESEMBLING THOSE SEEN IN CELLS TRANSFORMED BY VIRUSES OR CHEM CARCINOGENS. ...CHANGES INCL ALTERED CELL MORPHOLOGY, LIPID METABOLISM, AND CELL SURFACE GLYCOPROTEINS, INCR MEMBRANE TRANSPORT OF 2-DEOXYGLUCOSE, INDUCTION OF THE ENZYMES ORNITHINE DECARBOXYLASE AND PLASMINOGEN ACTIVATOR, AND INDUCTION OF PROSTAGLANDIN SYNTHESIS. [R3] *USING PURE PMA, IT WAS SHOWN THAT DEGREE OF INFLAMMATION /IRRITANT EFFECTS/ IS DOSE RELATED AND THAT MAXIMAL INFLAMMATION OCCURS WITHIN 24 HR AFTER SINGLE APPLICATION OF 2.5 UG... AT THAT STAGE THERE ARE MANY NEUTROPHILS AND FOCAL SLOUGHING OF EPIDERMIS. SINGLE DOSES OF 0.5, 0.1, OR 0.02 UG CAUSE MILD INFLAMMATION IN WHICH MOST OF INFLAMMATORY CELLS ARE LYMPHOCYTES. CONTINUED USE OF 2.5 UG APPLICATIONS...3 TIMES/WK MAINTAINED DIFFUSE LOW-LEVEL EPIDERMAL HYPERPLASIA PERSISTING UNTIL 1ST PAPILLOMA APPEARS. ONE YR AFTER PROMOTING TREATMENT BEGAN, TISSUE SECTIONS REVEALED THAT PAPILLOMAS CAN OCCUR IN ESSENTIALLY NORMAL SKIN WHERE NEITHER GENERAL INFLAMMATORY RESPONSE NOR EPIDERMAL HYPERPLASIA WAS EVIDENT. [R1, 42] *A GOOD MODEL OF THE ADULT RESP DISTRESS SYNDROME IS IV INJECTED PHORBOL MYRISTATE ACETATE, WHICH CAUSES PULMONARY SEQUESTRATION OF NEUTROPHILS AND A NEUTROPHIL-DEPENDENT ACUTE EDEMATOUS LUNG INJURY IN RABBITS. [R4] *TPA IS A WEAK SKIN CARCINOGEN FOR BOTH BALB/CA AND HAIRLESS MICE, AND MULTIPLE SKIN APPLICATIONS OF 18 NMOL FOR 17 MONTHS OF TPA DID NOT ALTER THE FREQUENCEY OF SPONTANEOUS INTERNAL TUMORS IN THESE MOUSE STRAINS. ONLY TPA-TREATED MICE DEVELOPED EPIDERMAL TUMORS, SQUAMOUS CELL PAPILLOMAS AND CARCINOMAS. [R5] ADE: *...MOUSE SKIN LOCALIZATION EXPT...DETERMINED THAT AT 3-6 HR AFTER SKIN APPLICATION /WITH TRITIATED PMA/ THE KERATIN LAYER JUST ABOVE BASAL CELLS WAS HIGHLY LABELED, AND SEBACEOUS GLANDS AND HAIR FOLLICLES WERE MODERATELY LABELED. AFTER 48 HR THERE WAS STILL SOME LABELING IN SEBACEOUS GLANDS AND HAIR FOLLICLES. HALF-LIFE OF...PROMOTER WAS CLOSE TO 24 HR. [R1, 38] ACTN: *.../IT IS SPECULATED/ THAT TPA ACTS BY COMPETING WITH AN ENDOGENOUS EPIDERMAL GROWTH FACTOR (EGF) FOR CELL RECEPTOR SITE(S) THAT NORMALLY MEDIATE ITS ACTION. EGF HAS BEEN REPORTED TO... /PRC: PROMOTE SKIN TUMOR FORMATION IN MICE/, TO INDUCE ORNITHINE DECARBOXYLASE AND PROSTAGLANDIN SYNTH, AND TO BE POTENT INDUCER OF PLASMINOGEN ACTIVATOR, ALL FUNCTIONS OF TPA. SOME TPA EFFECTS, HOWEVER, ARE NOT SHARED BY EGF, FOR SOME CELL TYPES LACK EGF RECEPTORS, YET RESPOND TO TPA. [R3] *THE FREE HYDROXYL GROUP AT C20, THE 4BETA,10ALPHA-CONFIGURATION OF THE JUNCTION BETWEEN THE 5 and 7-MEMBERED RINGS, AND THE DOUBLE BOND.../BETWEEN 6TH AND 7TH CARBON ATOM/ ARE ESSENTIAL FOR CO-CARCINOGENIC ACTION. ... MECHANISM OF TUMOR PROMOTING ACTIVITY MAY BE RELATED TO INTERACTION...WITH CERTAIN SPECIFIC RECEPTORS ON MEMBRANES OF SENSITIVE CELLS. ... THE ESSENTIAL DOUBLE BOND.../BETWEEN CARBON ATOM 6 and 7/ WOULD BE EXPECTED TO BECOME METABOLICALLY EPOXIDIZED AND...PROBABLY INVOLVED IN BINDING TO CELLULAR ELEMENTS. [R1, 656] *IT IS SHOWN THAT PMA INHIBITS NATURAL KILLER (NK) CELL-MEDIATED CYTOTOXICITY (CMC) IN A DOSE-DEPENDENT MANNER WHETHER THE COMPD IS PRESENT THROUGHOUT THE 4 HR CYTOTOXIC ASSAY OR THE EFFECTOR CELLS ARE PRETREATED WITH PMA. [R6] *THE MECHANISM OF PHORBOL ESTER TUMOR PROMOTION MAY BE THE INHIBITION OF T-CELL IMMUNITY AGAINST TUMOR CELLS INITIATED BY CARCINOGENS. [R7] *TREATMENT OF CULTURED EPIDERMAL CELLS WITH THE TUMOR PROMOTER, PHORBOL MYRISTATE ACETATE (PMA), RESULTS IN A 75% INHIBITION OF THE NORMAL ISOPROTERENOL STIMULATED 7-FOLD INCR IN CAMP ACCUMULATION. MAX INHIBITION OCCURRED 3 HR AFTER PMA TREATMENT. THE EFFECT OF PHORBOL ESTER ON THE BETA-ADRENERGIC SYSTEM IN MOUSE EPIDERMIS THUS APPEARS TO BE DUE TO ITS ACTION ON THE EPIDERMAL CELL MEMBRANE AND DOES NOT REQUIRE MEDIATION BY MACROPHAGES. [R8] INTC: *DOSAGES OF 0.1, 0.5, 2.5, 5.0 and 25.0 UG PMA IN 0.1 ML ACETONE WERE APPLIED TO DORSAL SKIN OF 20 FEMALE ICR/HA SWISS MICE IN EACH DOSE GROUP THREE TIMES/WK FOR 365 DAYS BEGINNING 14 DAYS AFTER INITIAL SINGLE TREATMENT OF 5 UG 7,12-DIMETHYLBENZ(A)ANTHRACENE (DMBA). MEDIAN SURVIVAL TIME WAS 365 DAYS EXCEPT 246 DAYS FOR 25.0 UG DOSE LEVEL. CONTROL GROUPS WERE: A) DMBA ONCE, FOLLOWED BY ACETONE 3 TIMES/WK; B) ACETONE ONLY 3 TIMES/WK; AND C) NO-TREATMENT GROUP. NO SKIN TUMORS WERE OBSERVED IN ANY CONTROL GROUP. AT TIME OF 1ST APPEARANCE OF TUMORS IN EACH TEST GROUPS THERE WERE 17 TO 20 SURVIVORS. NUMBER OF MICE WITH PAPILLOMAS: 0, 13, 19, 20 and 20 RESPECTIVELY. TOTAL NUMBER OF PAPILLOMAS: 0, 54, 127, 155 and 245 RESPECTIVELY. NUMBER OF MICE WITH SQUAMOUS CELL CARCINOMA: 0, 3, 4, 9 and 11 RESPECTIVELY. DAYS TO 1ST TUMOR: NONE, 36, 41, 35 and 27 RESPECTIVELY. /FROM TABLE/ [R1, 28] *TO DETERMINE EFFECT OF INTERVAL BETWEEN INITIATION AND PROMOTION AND THE EFFECT OF AGING OF MICE IN TWO-STAGE CARCINOGENESIS, 20 UG 7,12-DIMETHYLBENZ(A)ANTHRACENE (INITIATOR) WAS APPLIED ONCE ONLY AND 2.5 UG PMA WAS APPLIED 3 TIMES/WK TO DORSAL SKIN OF 5 GROUPS OF FEMALE ICR/HA SWISS MICE. FOR GROUPS 1, 2, 3, 4 and 5, AGE (IN WK) AT PRIMARY TREATMENT (INITIATOR) WAS 6, 44, 56, 6 and 6 RESPECTIVELY; INTERVAL (IN WK) TO SECONDARY TREATMENT (PROMOTOR) WAS 2, 2, 2, 36 and 56 RESPECTIVELY; NUMBER OF MICE/GROUP WERE 120, 20, 50, 35 and 35 RESPECTIVELY; % MICE WITH PAPILLOMAS WAS 100, 100, 56, 90 and 57 RESPECTIVELY; % MICE WITH SQUAMOUS CARCINOMA WAS 50, 30, 6, 25 and 11 RESPECTIVELY. APPROPRIATE CONTROL GROUPS CONSISTED OF ONE AGENT ONLY GIVEN AT VARIOUS TIME INTERVALS. RESULTS SHOW THAT SKIN CARCINOMAS ARE INDUCED WHETHER INTERVAL BETWEEN INITIATION AND PROMOTION IS 2, 36 OR 56 WK. CARCINOMA INCIDENCES ARE SIGNIFICANTLY LOWER IN GROUPS 3 and 5 WHERE SECONDARY TREATMENT WAS STARTED WHEN ANIMALS WERE 58 and 62 WK OLD. /FROM TABLE/ [R1, 30] *BECAUSE ENDOGENOUS PROTEASES MAY PLAY ROLE IN MECHANISM OF ACTION OF TUMOR PROMOTORS, 3 KNOWN PROTEASE INHIBITORS WERE TESTED FOR...INHIBITORY EFFECTS IN TWO-STAGE CARCINOGENESIS. PROTEASE INHIBITORS...TOSYL CHLOROMETHYL KETONE, TOSYL PHENYLALANINE CHLOROMETHYL KETONE, AND TOSYL ARGININE METHYL ESTER...WERE APPLIED TO MOUSE EARS AFTER INITIATION WITH SINGLE DOSE OF 7,12-DIMETHYLBENZ(A)ANTHRACENE FOLLOWED BY PROMOTION WITH...PMA. INHIBITORS WERE APPLIED 3 TIMES/WK IMMEDIATELY AFTER APPLICATION OF PROMOTING AGENT. PROTEASE INHIBITORS DELAYED APPEARANCE OF 1ST TUMORS, CHANGED GENERAL PATTERN OF RATE OF TUMOR APPEARANCE, AND CAUSED SOME DECR IN TUMOR INCIDENCES. [R1, 45] *LOW DOSAGES OF SULFUR MUSTARD, BIS(BETA-CHLOROETHYL)SULFIDE COMPLETELY INHIBITED TWO-STAGE CARCINOGENESIS IN MOUSE SKIN. 30 FEMALE ICR/HA MICE PER GROUP RECEIVED EITHER CONTROL APPLICATIONS OR DIFFERENT COMBINATIONS OF INITIATOR, PROMOTOR AND INHIBITOR TEST COMPD FOR 400 DAYS. 7,12-DIMETHYLBENZ(A)ANTHRACENE (DMBA), 20 UG/0.1 ML ACETONE, APPLIED ONCE ONLY WAS USED AS INITIATOR. PMA, THE PROMOTOR, WAS APPLIED AT 2.5 UG/0.1 ML ACETONE 3 TIMES/WK. BCS, BIS(BETA-CHLOROETHYL)SULFIDE, AT 20 UG/0.1 ML ACETONE WAS APPLIED BEGINNING 14 DAYS AFTER INITIATOR. DMBA + PMA + BCS (2 TIMES/WK) PRODUCED PAPILLOMAS IN 1 MOUSE WITH 1ST TUMOR OCCURRING AT 90 DAYS; DMBA + PMA + BCS (3 TIMES/WK) PRODUCED PAPILLOMAS IN 2 MICE OCCURRING AT 209 DAYS; DMBA + PMA ONLY PRODUCED PAPILLOMAS IN 27 MICE AND SQUAMOUS CELL CARCINOMAS IN 16 OCCURRING AT 40 DAYS; PMA ALONE PRODUCED PAPILLOMAS IN 4 MICE OCCURRING AT 218 DAYS; DMBA + BCS (2 TIMES/WK) PRODUCED PAPILLOMAS IN 1 MOUSE AT 385 DAYS; DMBA + BCS (3 TIMES/WK) PRODUCED NO PAPILLOMAS; BCS ALONE (3 TIMES/WK) PRODUCED PAPILLOMAS IN 1 MOUSE AT 323 DAYS; DMBA + ACETONE ONLY PRODUCED PAPILLOMAS IN 1 MOUSE AT 219 DAYS; NO PAPILLOMAS WERE OBSERVED IN CONTROL GROUP ADMIN ACETONE ALONE OR IN GROUP WHICH DID NOT RECEIVE EITHER OF THE TEST COMPD. /FROM TABLE/ [R1, 45] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *...CROTON OIL.../DERIVED/ FROM SEEDS OF CROTON TIGLIUM L...ACTIVE CONSTITUENTS...ARE DIESTERS OF A TETRACYCLIC DITERPENE, PHORBOL. FOURTEEN DIESTERS HAVE BEEN ISOLATED FROM CROTON OIL.../OF WHICH/ MOST ACTIVE BIOLOGICALLY IS 12-O-TETRADECANOYLPHORBOL-13-ACETATE... [R1, 656] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for tetradecanonyl phorbol acetate (TPA) is completed, and the chemical is in review for further evaluation. Route: topical; Species: mice. [R9] SO: R1: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. R2: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8212 R3: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2905 R4: CANHAM EM ET AL; MEPACRINE BUT NOT METHYLPREDNISOLONE DECREASES ACUTE EDEMATOUS LUNG INJURY AFTER INJECTION OF PHORBOL MYRISTATE ACETATE IN RABBITS; AM REV RESPIR DIS 127(5) 594 (1983) R5: ASTRUP EG, IVERSEN OH; THE TUMORIGENIC AND CARCINOGENIC EFFECT OF 12-0-TETRADECANOYLPHORBOL-13-ACETATE WHEN APPLIED TO THE SKIN OF BALB/CA AND HAIRLESS (HR/HR) MICE; ACTA PATHOL MICROBIOL IMMUNOL SCAND (A) 91(2) 103 (1983) R6: ABRAMS SI ET AL; MECHANISM OF ACTION OF PHORBOL MYRISTATE ACETATE ON HUMAN NATURAL KILLER CELL ACTIVITY; CELL IMMUNOL 80(2) 230 (1983) R7: FREDRICKSON GG, BENNETT M; SUPPRESSION OF THE CYTOTOXIC RESPONSE OF MOUSE LYMPHOCYTES TO SYNGENEIC TUMOR CELLS BY TUMOR-PROMOTING PHORBOL ESTER; CANCER RES 42(9) 3601 (1982) R8: GARTE SJ ET AL; INHIBITION OF BETA-ADRENERGIC RESPONSE IN CULTURED EPIDERMAL CELLS BY PHORBOL MYRISTATE ACETATE; CARCINOGENESIS 4(7) 939 (1983) R9: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 13 Record 243 of 1119 in HSDB (through 2003/06) AN: 3915 UD: 200211 RD: Reviewed by SRP on 1/31/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ASPARTAME- SY: *3-AMINO-N-(ALPHA-CARBOXYPHENETHYL)SUCCINAMIC ACID N-METHYL ESTER; *3-Amino-N-(alpha-methoxycarbonylphenethyl) succinamic acid; *APM-; *ASPARTYLPHENYLALANINE-METHYL-ESTER-; *L-aspartyl-L-phenylalanine-methyl-ester-; *N-L-ALPHA-ASPARTYL-L-PHENYLALANINE,-1-METHYL-ESTER-; *CANDEREL-; *EQUAL-; *Methyl-N-L-alpha-aspartyl-L-phenylalaninate-; *NUTRASWEET-; *L-PHENYLALANINE,-N-L-ALPHA-ASPARTYL-,-1-METHYL-ESTER-; *SC-18862-; *SUCCINAMIC ACID, 3-AMINO-N-(ALPHA-CARBOXYPHENETHYL)-, N-METHYL ESTER, STEREOISOMER; *SWEET-DIPEPTIDE-; *TRI-SWEET- RN: 22839-47-0 RELT: 93 [METHANOL] (Metabolite); 1825 [(L)-PHENYLALANINE] (L) MF: *C14-H18-N2-O5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *METHOD FOR LARGE-SCALE PRODN OF ASPARTAME ... L-ASPARTIC ACID ANHYDRIDE IS CONDENSED WITH L-PHENYLALANINE METHYL ESTER TO FORM A MIXT OF BETA-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER AND ALPHA-L-ASPARTYL-L-PHENYLALANINE METHYL ESTER. ON ACIDIFICATION WITH HYDROCHLORIC ACID, THE LATTER PRECIPITATES AND THE PRECIPITATE IS NEUTRALIZED TO FORM ASPARTAME. /FROM TABLE/ [R1, 195] FORM: *As a table-top sweetener ... /aspartame/ is spray-dried with partially hydrolyzed corn starch. [R2, p. V23 558] MFS: *Monsanto Co, Hq, 800 North Lindbergh Blvd, St Louis, MO 63167, (314) 694-1000; Subsidiary: The Nutrasweet Co, PO Box 730, 1751 Lake Cook Rd, Deerfield, IL 60015-5239, (800) 323-5321; Production sites: Augusta, GA 30901; University Park, IL 60466 [R3] *Takasago International Corp., 2600 Bond St., Univeristy Park, IL 60466 (708) 534-0174. Production site: Univeristy Park, IL 60466 [R3] OMIN: *A COMBINATION OF ASPARTAME WITH EITHER GRANULAR OR FUSED MANNITOL IN 1:9 RATIO CAN PROVIDE A SUITABLE BASE FOR CHEWABLE TABLETS WITH RESPECT TO SWEETNESS, MOUTH FEEL, ABSENCE OF UNPLEASANT AFTERTASTE, AND LOW CALORIC VALUE. BOTH CMPD ARE COMPATIBLE WITH LEUCINE. [R4] *... IN THE JULY 26, 1974, DECISION BY THE FDA TO APPROVE THE USE OF ASPARTAME, LABELING PROVISIONS WERE MADE IN WHICH FOODS NOT CONTAINING PROTEIN OR INTENDED FOR ADMIXTURE TO PROTEIN SWEETENED WITH ASPARTAME SHOULD BEAR THE STATEMENT "CONTAINS PROTEIN." [R1, 198] USE: *Sweetening agent about 200 times as sweet as sugar. [R5] *... USED AS A TABLE SWEETENER FOR COFFEE, TEA, BREAKFAST CEREALS, ETC ... OTHER FOOD APPLICATIONS IDENTIFIED INCL PRESWEETENED BREAKFAST CEREALS, CHEWING GUM, AND DRY BASES FOR BEVERAGES SUCH AS INSTANT COFFEE AND TEA, GELATINS, PUDDINGS AND FILLINGS, AND DAIRY-PRODUCT ANALOGUE WHIPPED TOPPINGS. [R1, 198] CPAT: *(1992) 8,040 tons in US [R2, p. V23 559] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless needles from water [R6]; *Off-white crystalline powder [R7] ODOR: *Odorless [R7] TAST: *Intensely sweet [R7] MP: *246-247 deg C [R6] MW: *294.30 [R6] PH: *0.8% Solution in water has a pH of about 5.3. [R7] SOL: *SOLUBILITY IN WATER IN MG/ML @ 25 DEG C: 18.2 @ PH 3.72, 16.1 @ PH 4.00, 15.2 @ PH 4.05, 14.5 @ PH 4.27, 13.8 @ PH 4.78, 13.5 @ PH 5.30, 13.7 @ PH 5.70, 14.2 @ PH 6.00; 10.20 @ PH 7.00 IN DISTILLED WATER [R1, 195]; *More soluble in acidic solutions and hot water; slightly soluble in alcohol; very slightly soluble in chloroform; practically insoluble in oils. [R7] SPEC: *Specific optical rotation: -2.3 deg @ 22 deg C/D (1 N HCl) [R6] OCPP: *Dipeptide ester about 160 times sweeter than sucrose in aq soln [R6] *DOUBLE MP: ABOUT 190 AND 245 DEG C [R1, 195] *In the presence of moisture it hydrolyzes to form aspartylphenylalanine and a diketopiperazine derivative, with a resulting loss of sweetness. [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R8] *Photodecomposition of aspartame in aqueous solutions under different conditions of light intensity and pH were studied. The effects of photosensitizers (riboflavin and methylene blue) and ascorbic acid on aspartame stability in aqueous solutions at different pH under light were also studied. Light illumination significantly increased aspartame degradation in an aqueous solution (pH 7), indicating that aspartame was very unstable under the illuminated conditions. In the dark, 91% of aspartame in an aqueous solution at pH 7 remained after 10 h of storage. Under 5500 lx of light, however, 39% of aspartame in the solution was destroyed after 10 h of storage. Aspartame degradation under light followed simple zero-order reaction kinetics. The higher the light intensity, the greater the degradation of aspartame. The relative reaction rate for the destruction of aspartame under 0, 1100, 3300 and 5500 lx was 1:1-42:2.80:4.61. The photodecomposition rate of aspartame varied with the pH of the system. Aspartame degradation was fastest at pH 7.0, followed by pH 4.0 and pH 6.0, in decreasing order. Addition of 4.8 ppm riboflavin or 4.8 ppm methylene blue significantly accelerated the aspartame decomposition at pH 7 in the presence of light. There were, however, no significant photosensitizing effects of these sensitizers on aspartame destruction at pH 6 and pH 4. Addition of 1.2ly increased the aspartame degradation at pH 7.0, but did not affect the destruction rate of aspartame at pH 6.0 and pH 4.0. [R9] SSL: *It is most stable in solution at about pH 4.3. [R7] *THE STABILITY OF ASPARTAME IN AQ MEDIA IS NOT ENTIRELY SATISFACTORY, ESP FOR CERTAIN FOODS, SUCH AS CARBONATED AND STILL BEVERAGES, WHICH ARE OFTEN SUBJECTED TO MANY MONTHS OF STORAGE PRIOR TO CONSUMPTION. AS A DIPEPTIDE ESTER, ASPARTAME UNDERGOES BOTH HYDROLYSIS AND CYCLIZATION REACTIONS. UNDER ACIDIC CONDITIONS, HYDROLYSIS OF THE ESTER AND AMIDE BONDS IS FAVORED, RESULTING IN FORMATION OF ITS CONSTITUENT AMINO ACIDS WITH A CONCOMITANT LOSS IN SWEETNESS. UNDER MORE NEUTRAL AND ALKALINE ENVIRONMENTS, THE DIPEPTIDE CYCLIZES TO THE CORRESPONDING DIKETOPIPERAZINE WHICH IS ALSO DEVOID OF SWEETNESS. APPARENTLY, NO NEW OBJECTIONABLE TASTE IS IMPARTED TO ASPARTAME AS A RESULT OF EITHER TRANSFORMATION. [R1, 197] *... MAX STABILITY OF ASPARTAME IN AQ SOLN OCCURS WITHIN THE PH VALUE RANGE OF 4 TO 5. THE HALF-LIFE UNDER THESE CONDITIONS IS REPORTED TO BE AT LEAST 8 MO AT ROOM TEMP. ANOTHER REPORT INDICATES THAT AT PH 4 THE HALF-LIFE IS IN EXCESS OF 10 MO AT 25 DEG C. [R1, 197] STRG: *Store in air-tight containers. [R7] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *... THERE IS SOME CONCERN THAT PHENYLALANINE RELEASED DURING THE COURSE OF NORMAL METAB /OF ASPARTAME/ OR GENERATED DURING EXTERNALLY INDUCED HYDROLYSIS REACTIONS MAY AFFECT PERSONS WITH PHENYLKETONURIA (PKU). ABOUT 1 IN 10000 HUMANS IS AFFLICTED WITH THIS GENETICALLY INDUCED METABOLIC DEFECT. AS A RESULT, THEY CANNOT METABOLIZE PHENYLALANINE AND MUST RESTRICT INTAKE OF THIS AMINO ACID. [R1, 198] *IT HAS BEEN POSTULATED THAT INDIVIDUALS REPORTING AN IDIOSYNCRATIC SYMPTOM RESPONSE AFTER GLUTAMATE INGESTION MIGHT ALSO EXPERIENCE SUCH SYMPTOMS AFTER ASPARTAME INGESTION. SIX SUBJECTS REPORTING VARIOUS SYMPTOMS AFTER GLUTAMATE INGESTION WERE ADMIN ASPARTAME (34 MG/KG BODY WT) IN A RANDOMIZED, CROSS-OVER, DOUBLE-BLIND STUDY. NO SUBJECT REPORTED SYMPTOMS TYPICAL OF A GLUTAMATE RESPONSE. [R10] *43 ADULT DIABETICS BETWEEN THE AGES OF 21 AND 70 TOOK 2 CAPSULES OF A PREPN OF ASPARTAME OR PLACEBO 3 TIMES DAILY WITH MEALS FOR 90 DAYS. THE 1.8 G OF ASPARTAME WAS APPROX 3 TIMES THE EXPECTED DAILY CONSUMPTION IF USED AS A SWEETENER TO REPLACE SUGAR. SUBJECTS EXHIBITED NO SYMPTOMS THAT COULD BE TRACED TO THE ADMIN OF ASPARTAME OR THE PLACEBO, AND DIABETIC CONTROL WAS UNAFFECTED BY CHRONIC ADMIN OF THESE SUBSTANCES. [R11] *Adverse effects: urticaria, angiodema, granulomatous panniculitis, cross-reactivity with sulfonamides, renal tubular acidosis (with large amounts) /From table/ [R12] *The neurotoxicity of aspartame and its constituent amino acids aspartic acid and phenylalanine is reviewed. When aspartame is consumed at levels within the acceptable daily intake limit of 40 mg/kg body wt, there is no significant risk for an aspartate induced neurotoxic effect in the brain. When aspartame is consumed at levels within the acceptable daily intake limit by normal subjects or persons heterozygous for phenylketonuria the resultant plasma phenylalanine concentrations are practically always within the normal postprandial range; elevation to plasma concentrations commonly associated with adverse effects has not been observed. Persons suffering from phenylketonuria (phenylketonuria-homozygotes) on a phenylalanine restricted diet should avoid consumption of aspartame. phenylketonuria homozygotes on the (less strict) phenylalanine liberalized diet should be made aware of the phenylalanine content of aspartame. In the available behavioral studies in humans with acute dosing, no adverse effects were observed. Long term studies on behavior and cognitive function in (sensitive) humans are lacking. Analyses of adverse reaction reports made by consumers in the USA have not yielded a specific constellation of symptoms clearly related to aspartame that would suggest a widespread public health hazard associated with aspartame use. [R13] *Two hundred and thirty one consumer complaints associated with the food additive aspartame were analyzed. A methodologic approach to evaluate all complaints by adapting general criteria used to investigate adverse reactions to medications was developed. Complaints were ranked according to the effects of cessation and rechallenge. Using this method, no clear symptom complex that suggests a widespread public health hazard associated with aspartame use was found; however, some case reports in which the symptoms may be attributable to aspartame in commonly consumed amounts were identified. The systematic application of pre-defined review criteria, such as those described here, to monitor consumer complaints related to food additives will help identify products that warrant more focused clinical studies. [R14] *There are anecdotal reports of increased seizures in humans after ingestion of aspartame. We studied 10 children with newly diagnosed but untreated generalized absence seizures. Ambulatory cassette recording of EEG allowed quantification of numbers and length of spike-wave discharges in a double-blind study on two consecutive days. On one day the children received 40 mg/kg aspartame and on the other day, a sucrose-sweetened drink. Baseline EEG was the same before aspartame and sucrose. Following aspartame compared with sucrose, the number of spike-wave discharges per hour and mean length of spike-wave discharges increased but not to a statistically significant degree. However, the total duration of spike-wave discharge per hour was significantly increased after aspartame (p=0.028), with a 40% : 17% (SEM) increase in the number of seconds per hour of EEG recording that the children spent in spike-wave discharge. Aspartame appears to exacerbate the amount of EEG spike wave in children with absence seizures. Further studies are needed to establish if this effect occurs at lower doses and in other seizure types. [R15] *Background. Both dietary sucrose and the sweetener aspartame have been reported to produce hyperactivity and other behavioral problems in children. Methods. We conducted a double-blind controlled trial with two groups of children: 25 normal preschool children (3 to 5 years of age), and 23 school-age children (6 to 1 0 years) described by their parents as sensitive to sugar. The children and their families followed a different diet for each of three consecutive three-week periods. One diet was high in sucrose with no artificial sweeteners, another was low in sucrose and contained aspartame as a sweetener, and the third was low in sucrose and contained saccharin (placebo) as a sweetener. All the diets were essentially free of additives, artificial food coloring, and preservatives. The children's behavior and cognitive performance were evaluated weekly. Results. The preschool children ingested a mean : SD) of 5600 : 2100 mg of sucrose per kilogram of body weight per day while on the sucrose diet, 38:13 mg of aspartame per kilogram per day while on the aspartame diet, and 12:4.5 mg of saccharin per kilogram per day while on the saccharin diet. The school-age children considered to be sensitive to sugar ingested 4500:1200 mg of sucrose per kilogram, 32:8.9 mg of aspartame per kilogram, and 9.9:3.9 mg of saccharin per kilogram, respectively. For the children described as sugar sensitive, there were no significant differences among the three diets in any of 39 behavioral and cognitive variables. For the preschool children, only 4 of the 31 measures differed significantly among the three diets, and there was no consistent pattern in the differences that were observed. Conclusions. Even when intake exceeds typical dietary levels, neither dietary sucrose nor aspartame affects children's behavior or cognitive function. [R16] *Aspartame, a high intensity sweetener, is used extensively worldwide in over 5,000 products. The effects of aspartame on cognitive function, electroencephalograms (EEGs) and biochemical parameters were evaluated in 48 adult (21 men, 27 women) heterozygotes for phenylketonuria (PKUH). Heterozygotes for phenylketonuria subjects whose carrier status had been proven by DNA analysis ingested aspartame (either 15 or 45 mg/kg/day) and placebo for 12 weeks on each treatment using a randomized, double-blind, placebo-controlled, crossover study. A computerized battery of neuropsychological tests was administered at baseline weeks -2 and -1, and during treatment at weeks 6, 12, 18, and 24. Samples for plasma amino acids and urinary organic acids were also collected during these visits. EEGs were evaluated by conventional and spectral analysis at baseline week -1 and treatment weeks 12 and 24. The results of the neuropsychological tests demonstrated that aspartame had no effect on cognitive function. Plasma phenylalanine significantly increased, within the normal range for heterozygotes for phenylketonuria, at 1 and 3 h following the morning dose of aspartame in the group receiving the 45 mg/kg per day dose only. There were no significant differences in the conventional or spectral EEG analyses, urinary organic acid concentrations, and adverse experiences when aspartame was compared with placebo. This study reaffirms the safety of aspartame in heterozygotes for phenylketonuria and refutes the speculation that aspartame affects cognitive performance, EEGs, and urinary organic acids. [R17] *The high intensity sweetener aspartame has been implicated anecdotally in seizure provocation. This possibility was investigated with a randomized, double-blind, placebo-controlled, cross-over study. After an extensive search, 18 individuals (16 adults and 2 children) who had seizures allegedly related to aspartame consumption were admitted to adult or pediatric epilepsy monitoring units where their EEG was monitored continuously for 5 days. Aspartame (50 mg/kg) or identically enpackaged placebo was administered in divided doses at 0800, 1000, and 1200 hr on study days 2 and 4. All meals were uniformly standardized on treatment days. No clinical seizures or other adverse experiences were observed after aspartame ingestion. Mean plasma phenylalanine (Phe) concentrations increased significantly after aspartame ingestion (83.6 uM) as compared with placebo (52.3 uM). Results suggest that aspartame, in acute dosage of 50 mg/kg, is no more likely than placebo to cause seizures in individuals who reported that their seizures were provoked by aspartame consumption. [R18] *Aspartame, a popular dietetic sweetener, may provoke headache in some susceptible individuals. Herein, we describe three cases of young women with migraine who reported their headaches could be provoked by chewing sugarless gum containing aspartame. [R19] NTOX: *ASPARTAME AND A 3:1 COMBINATION OF ASPARTAME WITH ITS DECOMP PRODUCT, 5-BENZYL-3,6-DIOXO-2-PIPERAZINE ACETIC ACID, WERE INCORPORATED AT LEVELS OF LESS THAN OR EQUAL TO 4 G/KG IN THE DIET OF MALE AND FEMALE RATS FROM 6 WK TO 104 WK OF AGE. THESE TREATMENTS WERE WITHOUT TOXIC EFFECTS. [R20] *NEONATAL MICE RECEIVED ORAL DOSES OF ASPARTAME AT LEVELS OF 0.5, 1.0, 1.5 AND 2.0 G/KG. HYPOTHALAMIC LESIONS WERE ENCOUNTERED AT DOSE LEVELS EQUAL TO OR EXCEEDING 1.0 G/KG. INFANT (MACAQUE) MONKEYS RECEIVED ASPARTAME (2 G/KG) BY STOMACH TUBE. HYPOTHALAMIC MORPHOLOGY REMAINED NORMAL AT THE MICROSCOPIC AND ULTRASTRUCTURAL LEVEL. [R21] *ASPARTAME DID NOT AFFECT FOOD CONSUMPTION AT ONE HR FOLLOWING A SINGLE INTRAGASTRIC DOSE OF 200 MG/KG IN RATS. THERE WAS NO EVIDENCE OF INHIBITION OR STIMULATION OF THE GASTRIC JUICE SECRETION RATE, THE CONCN OF GASTRIC ACID, ACID OUTPUT OR PROTEOLYTIC ACTIVITY FOLLOWING AN INTRAGASTRIC DOSE OF 250 MG/KG IN FIVE-HR PYLORUS-LIGATED RATS. [R22] *THE BRAIN TUMORIGENICITY OF ASPARTAME AND OF ITS DIKETOPIPERAZINE WAS STUDIED IN 860 SLC WISTAR RATS. ASPARTAME AT DIETARY LEVELS OF 1 G/KG, 2 G/KG, 4 G/KG OR ASPARTAME + DIKETOPIPERAZINE (3:1) 4 G/KG WAS FED FOR 104 WK. ONE ATYPICAL ASTROCYTOMA WAS FOUND IN A CONTROL RAT AND 2 ASTROCYTOMAS, 2 OLIGODENDROGLIOMAS AND 1 EPENDYMOMA WERE SCATTERED AMONG THE 4 TEST GROUPS. THERE WAS NO SIGNIFICANT DIFFERENCE IN THE INCIDENCE OF BRAIN TUMORS BETWEEN CONTROL AND TEST GROUPS. [R23] *Aspartame is a widely used high potency dipeptide sweetener. Developmental toxicology studies have been performed in several species documenting no effects of high doses of aspartame. Recently, a study reported a delay in the achievement age for the visual placing response in mice pups after maternal administration of high dosages of aspartame during late gestation. In the present study developmental parameters were determined in offspring of CF-1 Swiss mice after maternal administration of aspartame at 500, 1000, 2000, and 4000 mg/kg body wt by oral gavage. Aspartame was administered on days 15 through 18 of gestation. Maternal body weight, food consumption, gestation length, reproductive indices, and litter size were not affected by aspartame treatment. In the pups, body weights, negative geotaxis, and surface and midair righting reflexes were not altered by treatment. There was no delay in the development of the visual placing response regardless of the method employed for assessment (grid or rope) or the manner by which the data were analyzed. There were also no changes in time of eye opening, reflex pupil closure, and ophthalmoscopic examination in the offspring. Thus, neither physical nor functional development was altered in mice after in utero exposure to extremely large dosages of aspartame. More specifically, in utero exposure to aspartame did not affect the development of the visual system in mice, in the offspring. Thus, neither physical nor functional development was altered in mice after in utero exposure to extremely large dosages of aspartame. More specifically, in utero exposure to aspartame did not affect the development of the visual system in mice. [R24] *Pregnant guinea pigs were administered aspartame (500 mg/kg) in sesame oil by gavage or sesame oil alone between the day of conception and parturition. A nontreated control group was also maintained. There were no statistically significant effects of the treatment on maternal weight gain, litter size, or birth weight of the pups. Newborn pups were weighed daily and on day 15 were injected with either lithium chloride or saline and placed in a cag e with vanilla odor for 30 min. Twenty-four hr later the pups were permitted to choose between vanilla and lemon odors in a preference test. While both the vehicle treated control and nontreated control groups injected with lithium chloride showed a conditioned aversion to vanilla, the aspartame treated pups injected with lithium chloride did not. These data indicate that aspartame exposure at 500 mg/kg throughout gestation disrupts odor associative learning in 15 day old guinea pigs. [R25] *Possible effects of perinatal exposure to aspartame on rat pups were investigated. Adult female rats, and later their pups, were exposed via their drinking water, to aspartame (0.007%, 0.036%, 0.18% or 0.9% w/v) or phenylalanine (0.45% w/v) for 12 days prior to conception until the pups were 38 days old. Control rats were given plain water. The adults exposed to aspartame consumed an average of 14, 68, 347 and 1614 mg/kg/day of aspartame and those exposed to phenylalanine consumed an average of 835 mg/kg/day of phenylalanine. After weaning the pups given aspartame consumed an average of 32, 154, 836, and 3566 mg/kg/day of aspartame and those given phenylalanine consumed an average of 1795 mg/k g/day of phenylalanine. No effect of aspartame or phenylalanine was detected on either two measures of morphological development (ie, latencies to pinnae detachment and eye opening) or two tests of reflex development (ie, latencies for surface righting at 7 days of age and negative geotaxis at 8 days of age). All groups were similar in spatial memory as assessed with two different mazes with pups 30-36 days old. The number of arms be fore reentry in an 8 arm radial arm maze and the acquisition curves from a milk maze did not differ between groups. Furthermore, the latencies of mothers to retrieve their litters was also unaffected by the aspartame and phenylalanine. These results indicate that perinatal exposure to aspartame, when voluntarily consumed by mothers (14 to 1614 mg/kg/day) and later directly by the rat pups (32 to 3566 mg/kg/day) does not affect reflex development, morphological development or spatial memory. [R26] *Six experiments with rats assessed the toxicity of aspartame with behavioral measures. The first three experiments used a conditioned taste aversion procedure since taste aversions are typically observed after a taste is followed by a toxin. Thirty min after thirsty rats drank a sweet solution they were intraperitoneally injected (Experiment 1) or intragastrically intubated (Experiment 2) with saline or 176, 352, or 704 mg/kg of aspartame. Relative to rats given saline, rats injected with 704 and 352 mg/kg aspartame showed strong and mild aversions, respectively. Rats injected with 176 mg/kg of aspartame or intubated with any dose of aspartame did not show taste aversions. In Experiment 3, rats voluntarily consumed an aspartame solution sweetened with saccharin for 7 hr each day. Consumption of the taste paired with aspartame was not reduced. When 352 mg/kg aspartame was injected (Experiment 4), but not when intubated (Experiment 5), 5 min prior to access to a running wheel, running was reduced. Wheel running was not affected by the voluntary consumption of aspartame (Experiment 6). The route of administration effect (intraperitoneal vs. intragastric) on behavior corresponded with the amino acid levels in blood plasma (Experiment 7). Aspartate, phenylalanine, tyrosine and glutamate levels increased more after the injection, than the intubation, of aspartame (176 mg/kg). Overall, the results suggest that aspartame may have adverse effects when intraperitoneally injected but not when the route of administration is oral. [R27] *The artificial sweetener aspartame (L-aspartyl-L-phenylalanyl-methyl ester), is consumed, primarily in beverages, by a very large number of Americans, causing significant elevations in plasma and, probably, brain phenylalanine levels. Anecdotal reports suggest that some people suffer neurologic or behavioral reactions in association with aspartame consumption. Since phenylalanine can be neurotoxic and can affect the synthesis of inhibitory monoamine neurotransmitters, the phenylalanine in aspartame could conceiveably mediate neurologic effects. If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine (which probably occurs after any aspartame dose in humans), the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock. Perhaps regulations concerning the sale of food additives should be modified to require the reporting of adverse reactions and the continuing conduct of mandated safety research. [R28] *The present paper describes the possible clastogenic activity of the following synthetic sugar substitutes, such as cyclamate in daily doses of 11 and 110 mg/kg, saccharin, 5 and 50 mg/kg, acesulfam, 15 and 150 mg/kg, sucralose, 15 and 150 mg/kg, aspartame, 40 and 400 mg/kg, orally given to C57Bl/6 mice during 5 days. No clastogenic activity was found in the compounds tested. [R29] *It has been suggested that aspartame facilitates seizures in man and animals because phenylalanine, one of its major metabolites, interferes with brain transport of neurotransmitter precursors and alters the synthesis of monoamine neurotransmitters such as norepinephrine, dopamine and/or serotonin. This facilitation is purportedly more likely in subjects predisposed to seizures. One test of this hypothesis would be to administer a wide range of aspartame doses to subjects whose seizure predisposition is dependent on abnormalities in monoaminergic function. Genetically epilepsy-prone rats (GEPRs) have a broadly based seizure predisposition that is based, in part, on widespread central nervous system noradrenergic and serotonergic deficits. Further reductions in the functional state of these neurotransmitters increases seizure severity in genetically epilepsy-prone rats. Thus, genetically epilepsy-prone rats appear ideally suited for testing the hypothesis that aspartame facilitates seizures by interfering with central nervous system monoamines. Oral administration of acute (50-2000 mg/kg) or sub-chronic (up to 863 mg/kg/day for 28 days) doses of aspartame did not alter seizure severity in either of two types of GEPRs. Not surprisingly, acute aspartame doses produced dramatic changes in plasma and brain amino acid concentrations. Hypothesized alterations in monoamine neurotransmitter systems were largely absent. Indeed, increases in norepinephrine concentration, rather than the hypothesized decreases, were the most evident alterations in these neurotransmitter systems. We conclude that aspartame does not facilitate seizures in genetically epilepsy-prone rats and the convincing evidence of seizure facilitation in any species is lacking. [R30] *Seizure facilitation has been proposed as a possible adverse effect of dietary consumption of aspartame. The conversion of this sweetener to phenylalanine and aspartate in the gastrointestinal tract, and subsequent absorption, elevates plasma levels of these two amino acids. Absorbed phenylalanine competes with other large neutral amino acids, including tyrosine and tryptophan, for transport into brain. Theoretically, this completion might reduce brain tyrosine and tryptophan which could decrease synthesis of norepinephrine, dopamine and serotonin. Diminished synaptic release of these monoaminergic neurotransmitters facilitates seizures in many seizure models. Our present study evaluates effects of oral aspartame on amino acids and electroshock seizures in normal and seizure predisposed rats. Heroic doses of aspartame produced predictable changes in plasma amino acids. However, none of the aspartame doses altered seizure indices. We conclude that aspartame does not alter maximal electroshock seizures in normal rats or in rats predisposed to seizures. [R31] ADE: *Adult male rats were given an oral dose of 10 mg/kg aspartame 14C-labelled in the methanol carbon. At timed intervals of up to 6 hours, the radioactivity in plasma and several organs was investigated. Most of the radioactivity found (> 98% in plasma, > 75% in liver) was bound to protein. Label present in liver, plasma and kidney was in the range of 1-2% of total radioactivity administered per g or mL, changing little with time. Other organs (brown and white adipose tissues, muscle, brain, cornea and retina) contained levels of label in the range of 1/12 to 1/10th of that of liver. In all, the rat retained, 6 hours after administration about 5% of the label, half of it in the liver. The specific radioactivity of tissue protein, RNA and DNA was quite uniform. The protein label was concentrated in amino acids, different from methionine, and largely coincident with the result of protein exposure to labelled formaldehyde. DNA radioactivity was essentially in a single different adduct base, different from the normal bases present in DNA. The nature of the tissue label accumulated was, thus, a direct consequence of formaldehyde binding to tissue structures. The administration of labelled aspartame to a group of cirrhotic rats resulted in comparable label retention by tissue components, which suggests that liver function (or its defect) has little effect on formaldehyde formation from aspartame and binding to biological components. The chronic treatment of a series of rats with 200 mg/kg of non-labelled aspartame during 10 days resulted in the accumulation of even more label when given the radioactive bolus, suggesting that the amount of formaldehyde adducts coming from aspartame in tissue proteins and nucleic acids may be cumulative. It is concluded that aspartame consumption may constitute a hazard because of its contribution to the formation of formaldehyde adducts. [R32] METB: *ALTHOUGH ASPARTAME WAS HYDROLYZED IN THE GUT OF THE MONKEY TO ITS CONSTITUENT MOIETIES, METHANOL, ASPARTIC ACID, AND PHENYLALANINE, THE INGESTION OF 15 OR 60 MG/KG DOSES FOR 10 DAYS DID NOT MODIFY PHENYLALANINE METAB. ASPARTAME HAD LITTLE EFFECT ON THE DISAPPEARANCE OF IV ADMIN (14)C-PHENYLALANINE FROM THE PLASMA, IT DID NOT SUBSTANTIALLY AFFECT THE CONVERSION OF PHENYLALANINE INTO TYROSINE OR CARBON DIOXIDE, AND IT DID NOT ALTER THE RATE OF INCORPORATION OF LABEL INTO PROTEIN. THE MAJORITY OF PHENYLALANINE DERIVED FROM ASPARTAME WAS INCORPORATED INTO BODY PROTEIN, WITH ONLY 20-25% OF THE CMPD BEING EXCRETED. 60-80% OF THE DERIVED METHANOL AND ASPARTIC ACID WAS OXIDIZED TO CARBON DIOXIDE. [R33] *BLOOD METHANOL CONCN WERE MEASURED IN 24 1-YR-OLD INFANTS ADMINISTERED ASPARTAME. THE DOSES STUDIED INCL A DOSE PROJECTION TO BE THE 99TH PERCENTILE OF DAILY INGESTION FOR ADULTS (34 MG/KG), A VERY HIGH USE DOSE (50 MG/KG), AND A DOSE CONSIDERED TO BE IN THE ABUSE RANGE (100 MG/KG). METHANOL CONCN WERE BELOW THE LEVEL OF DETECTION (0.35 MG/DL) IN THE BLOOD OF 10 INFANTS ADMIN ASPARTAME AT 34 MG/KG, BUT WERE SIGNIFICANTLY ELEVATED AFTER INGESTION AT 50 AND 100 MG/KG. BLOOD METHANOL VALUES IN INFANTS WERE SIMILAR TO THOSE OBSERVED IN NORMAL ADULTS. [R34] *PLASMA AND ERYTHROCYTE LEVELS OF FREE AMINO ACIDS WERE MEASURED IN FIVE FEMALE SUBJECTS KNOWN TO BE HETEROZYGOUS FOR PHENYLKETONURIA AND SIX SUBJECTS ASSUMED TO BE NORMAL WHO WERE ADMIN AN ABUSE DOSE OF ASPARTAME (100 MG/KG) IN ORANGE JUICE. SMALL INCR IN PLASMA ASPARTATE LEVELS WERE NOTED 30 MIN AFTER ASPARTAME LOADING IN BOTH GROUPS. HOWEVER, PLASMA ASPARTATE LEVELS REMAINED WITHIN NORMAL POSTPRANDIAL LEVELS IN EACH CASE. ERYTHROCYTE ASPARTATE LEVELS WERE UNCHANGED IN BOTH GROUPS. PEAK PLASMA PHENYLALANINE LEVELS WERE BELOW THOSE ASSOCIATED WITH TOXIC EFFECTS. THE DATA INDICATE SLOWER BUT ADEQUATE METAB AND CLEARANCE OF AN ABUSE DOSE OF ASPARTAME BY THE PHENYLKETONURIC HETEROZYGOTE. [R35] *Upon ingestion, aspartame is completely metabolized to two amino acids and methanol (approximately 50% phenylalanine, 40% aspartic acid, and 10% methanol). [R17] INTC: *THE POTENCY OF ASPARTAME RELATIVE TO SUCROSE DECR WITH INCR CONCN OF SUCROSE. ... DATA SUGGEST THAT ASPARTAME MAY DISPLAY SYNERGISM IN SWEETENING POTENCY AS COMPARED TO SUCROSE WHEN COMBINED WITH OTHER INGREDIENTS EMPLOYED IN FOODS. FOR EXAMPLE ... ASPARTAME AND SORBITOL. [R1, 194] *POTENTIAL INTERACTIONS BETWEEN ANHYDROUS AMPICILLIN OR AMPICILLIN TRIHYDRATE AND ASPARTAME WERE INVESTIGATED. COMPLEXES WERE FORMED BETWEEN ASPARTAME AND BOTH FORMS OF AMPICILLIN. [R36] *THE POSSIBLE INTERACTIONS OF CEPHALEXIN WITH ASPARTAME WAS INVESTIGATED. A COMPLEX WAS FORMED BETWEEN THE 2 CMPD. [R37] *THE POSSIBLE INTERACTION BETWEEN ASPARTAME (I) AND CAFFEINE (II) WAS INVESTIGATED. SEVERAL I-II COMPLEXES WERE OBSERVED. THESE COMPLEXES WERE FOUND TO BE DEPENDENT ON THE MOLAR RATIOS OF I TO II. [R38] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ WARN: *Excessive use of aspartame should be avoided by patients with phenylketonuria. [R7] *Aspartic acid and sodium glutamate were both neuroexcitatory amino acids which had an additive toxic effect on hypothalamic neurones. As this might be specially damaging to young children, who already receive sodium glutamate in gram quantities in their diet, aspartame should not generally be added to children's food. [R7] *Recent published and unpublished reports of headaches, seizures, blindness, and cognitive and behavioral changes with long term, high dose aspartame may be cause for concern. Physician awareness of the present clinical and research status of aspartame is important. [R39] *Food and Environmental Agents: Effect on Breast-Feeding: Aspartame: Caution if mother or infant has phenylketonuria. /from Table 7/ [R40] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Aspartame's production and use as a low-calorie dietary sweetener and sugar substitute may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 4.5X10-12 mm Hg at 25 deg C indicates aspartame will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase aspartame will be removed from the atmosphere by wet and dry deposition. If released to soil, aspartame is expected to have high mobility based upon an estimated Koc of 60. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.5X10-18 atm-cu m/mole. Aspartame is not expected to volatilize from dry soil surfaces based on its vapor pressure. If released into water, aspartame is not expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. Aspartame is expected to degrade in water to diketopiperazine at pH 7 or greater, with a half-life of about 1 day. An estimated BCF of 1 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to aspartame may occur through inhalation of dust particles and dermal contact with this compound at workplaces where aspartame is produced or used. The general population may be exposed to aspartame through the ingestion of food products such as soft drinks, table sweeteners and candy that contain this product. (SRC) ARTS: *Aspartame's production and use as a low-calorie dietary sweetener and sugar substitute(1) may result in its release to the environment through various waste streams(SRC). [R41] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 60(SRC), determined from a structure estimation method(2), indicates that aspartame is expected to have high mobility in soil(SRC). Volatilization of aspartame from moist soil surfaces is not expected to be an important fate process(SRC) given a an estimated Henry's Law constant of 2.5X10-18 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Aspartame is expected to degrade in moist soil surfaces to diketopiperazine at pH 7 or greater, with a half-life of about 1 day(4). Aspartame is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.5X10-12 mm Hg(SRC), determined from a fragment constant method(5). [R42] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 60(SRC), determined from a structure estimation method(2), indicates that aspartame is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 2.5X10-18 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Aspartame is expected to degrade in water to diketopiperazine at pH 7 or greater, with a half-life of about 1 day(5). According to a classification scheme(6), an estimated BCF of 1(SRC), from an estimated log Kow of 0.07(SRC) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R43] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), aspartame, which has an estimated vapor pressure of 4.5X10-12 mm Hg at 25 deg C(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase aspartame may be removed from the air by wet and dry deposition(SRC). [R44] ABIO: *Aspartame is unstable in water and decomposes to diketopiperazine; the rate of decomposition is temperature and pH dependent(1). At 25 deg C and a pH of 5 the half-life of decomposition is 245 days, but the value is 120 days at pH 6(1). At 25 deg C and a pH of 7 and above, the decomposition of aspartame is about 1 day(1). Therefore, aspartame will be unstable in natural waters having pH 7 or higher(SRC). [R41] BIOC: *An estimated BCF of 1 was calculated for aspartame(SRC), using an estimated log Kow of 0.07(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R45] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for aspartame can be estimated to be about 60(SRC). According to a classification scheme(2), this estimated Koc value suggests that aspartame is expected to have high mobility in soil(SRC). [R46] VWS: *The Henry's Law constant for aspartame is estimated as 2.5X10-18 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that aspartame is expected to be essentially nonvolatile from water surfaces(2). Aspartame's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is not expected(SRC). Aspartame is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 4.5X10-12 mm Hg(SRC), determined from a fragment constant method(3). [R47] RTEX: *Occupational exposure to aspartame may occur through inhalation of dusts and dermal contact with this compound at workplaces where aspartame is produced or used. The general population may be exposed to aspartame through the ingestion of food products such as soft drinks, table sweeteners and candy that contain this product. (SRC) BODY: *Aspartame was detected in blood/plasma of surgery patients at a concn range of 0-42 mg/l following application of 1 g rectal suppository/12 hr(1). [R48] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Aspartame is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity of the substance added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) any substance intended for use in or on food is of appropriate food grade and is prepared and handled as a food ingredient. [R49] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *PURITY OF ASPARTAME WAS DETERMINED USING THIN LAYER CHROMATOGRAPHY, LIQ CHROMATOGRAPHY, AND OPTICAL ROTATION. [R50] *ASPARTAME WAS ANALYZED BY LIQUID CHROMATOGRAPHY. [R51] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: CITATION: Poulsen E; Safety Evaluation of Substances Consumed as Technical Ingredients (Food Additives); Food Addit Contam 8 (2): 125-33 (1991). The different types of acceptable daily intakes are described as used by the FAO/WHO Expert Committee on Food Additives and the European Economic Community Scientific Committee for Food. The allocation is discussed of a full acceptable daily intake or a temporary acceptable daily intake, and examples are given for the establishment (or withdrawal) of these acceptable daily intakes. Sze PY; Pharmacological Effects of Phenylalanine on Seizure Susceptibility: An Overview; Neurochem Res 14 (2): 103-11 (1989). In the last three years, a number of studies involving as many as nine animal models of seizures have reexamined the effects of phenylalanine (and aspartame) on seizure thresholds. This article provides a detailed review of the data from both early and recent studies and points out the methodological problems apparent at high doses. Aguas-Compaired M et al; Review of Sweeteners and Their Use in Some Rral Liquid Preparations; Rev Soc Esp Farm Hosp 13 (Nov-Dec): 429-36 (1989). Sweetening agents commonly used in liquid oral products are discussed, including aspartame. Franz M; Is It Safe to Consume Aspartame During Pregnancy? Review; Palmetto Pharm 25 (Dec): 21-3 (1986). The safety of aspartame consumption during pregnancy and breast feeding is discussed Garriga MM, Metcalfe DD; Aspartame Intolerance; Ann Allergy 61 (6 Pt 2): 63-9 (1988). Stegink LD; The Aspartame Story: A Model For the Clinical Testing of a Food Additive; Am J Clin Nutr 46 (1 Suppl): 204-15 (1987). This paper reviews clinical studies testing the effects of various doses of aspartame upon blood levels of aspartate, phenylalanine, and methanol. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for aspartame is completed, and the chemical is in review for further evaluation. Route: dosed feed; Species: transgenic model evaluation II, mice. [R52] SO: R1: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R3: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 612 R4: EL-SHATTAWY HH ET AL; DRUG DEV IND PHARM 8 (3): 429-43 (1982) R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 200 R6: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 141 R7: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 425 R8: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 285 R9: Kim SK et al; Food Chemistry 59 (2): 273-8 (1997) R10: STEGINK LD ET AL; AM J CLIN NUTR 34 (9): 1899-905 (1981) R11: STERN SB ET AL; J TOXICOL ENVIRON HEALTH 2 (2): 429-39 (1976) R12: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 996 R13: Janssen PJ, van der Heijden CA; Toxicology 50 (1): 1-26 (1988) R14: Bradstock MK et al; Am J Clin Nutr 43 (3): 464-9 (1986) R15: Camfield PR et al; Neurology 42 (5): 1000-3 (1992) R16: Wolraich ML et al;New England J Of Medicine 330 (5): 301-7 (1994) R17: Trefz F et al; Human Genetics 93 (4): 369-74 (1994) R18: Rowan AJ et ak; Epilepsia 36 (3): 270-5 (1995) R19: Blumenthal HJ et al; Headache 37 10: 665-6 (1997) R20: ISHII H ET AL; TOXICOLOGY 21 (2): 91-4 (1981) R21: REYNOLDS WA ET AL; J TOXICOL ENVIRON HEALTH 2 (2): 471-80 (1976) R22: BIANCHI RG ET AL; J ENVIRON PATHOL TOXICOL 3 (5-6): 355-62 (1980) R23: ISHII H; TOXICOL LETT 7 (6): 433-7 (1981) R24: McAnulty PA et al; Fundam Appl Toxicol 13 (2): 296-302 (1989) R25: Dow-Edwards DL et al; Neurotoxicol Teratol 11 (4): 413-6 (1989) R26: Holder MD; Neurotoxicol Teratol 11 (1): 1-6 (1989) R27: Holder MD, Yirmiya R; Pharmacol Biochem Behav 32 (1): 17-26 (1989) R28: Maher TJ, Wurtman RJ; Environ Health Perspect 75 53-7 (1987) R29: Durnev AD et al; Vapor Med Khim 41 (4): 31-3 (1995) R30: Dailley JW et al; Epilepsy Res 8 (2): 122-33 (1991) R31: Jobe PC et al; Amino Acids (Vienna) 3 (2): 155-72 (1992) R32: Trocho C et al; Life Sci 63 (5): 337-49 (1998) R33: OPPERMANN JA ET AL; J NUTR 103 (10): 1460-6 (1973) R34: STEGINK LD ET AL; J NUTR 113 (8): 1600-6 (1983) R35: STEGINK LD ET AL; J NUTR 110 (11): 2216-24 (1980) R36: EL-SHATTAWY HH ET AL; DRUG DEV IND PHARM 8 (6): 857-68 (1982) R37: EL-SHATTAWY HH ET AL; DRUG DEV IND PHARM 8 (6): 923-35 (1982) R38: EL-SHATTAWY HH ET AL; DRUG DEV IND PHARM 8 (5): 651-62 (1982) R39: Potenza DP, el-Mallakh RS; Conn Med 53 (7): 395-400 (1989) R40: Report of the American Academy of Pediatrics Committee on Drugs in Pediatrics 93 (1): 142 (1994) R41: (1) Lee TD; Kirk-Othmer Encycl Chem Tech 4th ed. Kroschwitz JI ed. NY,NY: John Wiley and Sons 23: 558-563 (1997) R42: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lee TD; Kirk-Othmer Encycl Chem Tech 4th ed. Kroschwitz JI ed. NY,NY: John Wiley and Sons 23: 558-563 (1997) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) R43: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lee TD; Kirk-Othmer Encycl Chem Tech 4th ed. Kroschwitz JI ed. NY,NY: John Wiley and Sons 23: 558-563 (1997) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) R44: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R45: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R46: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) R47: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) R48: (1) Cone MV et al; National Body Burden Database. Chemicals Identified in Human Biological Media, Vol 7 part 3, SAI Corp, Oak Ridge, TN, NTIS DE86-004686 (1986) R49: 21 CFR 172.804 (4/1/97) R50: CIRANNI SIGNORETTI E ET AL; FARM 122 (6): 289-96 (1983) R51: SCHERZ JC ET AL; Z LEBENSM-UNTERS FORSCH 177 (2): 124-8 (1983) R52: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 48 Record 244 of 1119 in HSDB (through 2003/06) AN: 3946 UD: 200201 RD: Reviewed by SRP on 5/6/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,2',4,4',5,5'-HEXACHLOROBIPHENYL- SY: *1,1'-BIPHENYL,-2,2',4,4',5,5'-HEXACHLORO-; *BIPHENYL,-2,2',4,4',5,5'-HEXACHLORO-; *2,2',4,4',5,5'-HEXACHLORO-1,1'-BIPHENYL- RN: 35065-27-1 RELT: 3945 [POLYCHLORINATED BIPHENYLS] MF: *C12-H4-Cl6 SHPN: UN 2315; Polychlorinated biphenyls, liquid or solid IMO 9.0; Polychlorinated biphenyls, liquid or solid MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPARED BY THE DIAZOTIZATION OF 2,2',5,5'-TETRACHLOROBENZIDENE FOLLOWED BY Cl REPLACEMENT [R1] FORM: *DETECTED IN COMMERICAL MIXTURES OF CHLORINATED BIPHENYLS, MOLAR PERCENTAGE ARE: AROCLOR 1248 (0.13%), AROCLOR 1254 (3.32%), AROCLOR 1260 (8.22%) [R2] OMIN: *DOMESTIC /USA/ PRODUCTION OF POLYCHLORINATED BIPHENYLS WAS STOPPED IN OCTOBER 1977. /POLYCHLORINATED BIPHENYLS/ [R3] *Aroclor 1260 contained nearly 80 different polychlorinated biphenyl congers. [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *360.86 [R5] SPEC: *MAX ABSORPTION: 211, 282, 290 NM (A= 1260, 44.3, 31, 1%, 1 CM) [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flame resistant [R7] REAC: +Liquid chlorine reacts exothermically with polychlorinated biphenyl heat transfer liquid. /Polychlorinated biphenyls/ [R8] SERI: *Irritating to skin and eyes. [R9] EQUP: *... Workers should be provided with suitable protective clothing: long-sleeved overalls, boots, overshoes, and bib-type aprons that cover the boot tops, /and/ gloves. ... Safety glasses with side shields ... for eye protection. Respirators should be used in areas with PCB vapors and during installation and repair of containers and emergency activities. ... [R10, 1755] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. */In a confined space: The worker/ should wear appropriate protective equipment and be connected by a lifeline harness to an outside worker. [R10, 1754] *Employees should wash their hands before eating, drinking and smoking ... and refrain from such activities in the polluted rooms. ... [R10, 1754] SSL: *... PCB's are chemically very inert and are stable to conditions of hydrolysis and oxidation in industrial use. [R11] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R12] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R13] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R14] STRG: *PCB material should be stored in closed containers, in ventilated areas ... /SRP: With appropriate air pollution control equipment./ [R10, 1753] CLUP: *... Dry sand or earth should be spread on the leak, or spill area. ... [R10, 1754] *Survey reports six case histories employing EPA's hazardous materials spills treatment trailer are reviewed. The trailer's ... treatment system has three mixed-media filters and three activated carbon columns to remove suspended, precipitated, and organic soluble materials. Spills of PCB, pentachlorophenol, kepone, termide (chlordane), heptachlor, aldrin, and dieldrin, toxaphene, and dinitrobutylphenol were treated by the EPA trailer, which was generally successful in mitigating environmental effects by filtering and carbon-adsorption. 90% removal was achieved for 21 of 23 compounds. [R15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *EXPERIMENTS ON THE COMBUSTION OF POLYCHLORINATED BIPHENYLS (PCB) IN 1 M-LONG TUBE FURNACE INDICATED THAT PCB CONTAINING APPROX 40% CL IS DESTROYED WITHIN 3-4 MIN AT 900-1000 DEG C USING 100% EXCESS AIR. TEMPERATURES GREATER THAN 1000 DEG C ARE REQUIRED TO DESTROY PCB CONTAINING APPROX 60% CL AND DISTILLATION RESIDUES ARISING FROM PCB MFR. DOMESTIC WASTE INCINERATORS OPERATING AT 800-900 DEG C ARE UNLIKELY TO PROVE SUITABLE FOR INCINERATING WASTE CONTAINING TRACE AMT OF PCB. PYROLYSIS EXPERIMENTS AT 900 DEG C WITH NOMINAL RESIDENCE TIME OF 3.5 SEC GAVE 40-60% RECOVERY OF CL AS HCL FROM PCB. [R16] *POLYCHLORINATED BIPHENYLS CAN BE DESTROYED BY INCINERATION IF THE TRANSIT TIME IS LONG ENOUGH. DURING INCINERATION HEXACHLOROBENZENE IS FORMED; ITS RATE OF FORMATION INCR AT HIGH TEMP. IN ORDER FOR THE HEXACHLOROBENZENE TO BE DESTROYED, A TEMP OF 950 DEG C IS NEEDED. THIS RESULTS IN THE FORMATION OF A RESIDUE LESS THAN 100 MG OF HEXACHLOROBENZENE/KG. AT 800 DEG C AND A TRANSIT TIME OF 2 SEC, A RESIDUE OF ABOUT 1200 MG/KG REMAINS. [R17, 3668] *Investigations were conducted of new and emerging technologies for the disposal of hazardous wastes, ... including molten salt combustion, fluidized bed incineration, high energy electron treatment of trace organic compounds in aqueous solution, the catalyzed wet oxidation of toxic chemicals, dehalogenation of compounds by treatment with ultraviolet (UV) light and hydrogen, UV/chlorinolysis of organics in aqueous solution, the catalytic hydrogenation-dechlorination of polychlorinated biphenyls (PCBs), and ultraviolet-ozone destruction. Theory, specific wastes treated, and economics are discussed. The major technologies investigated in detail were molten salt combustion, fluidized bed incineration, and ultraviolet/ozone destruction. Among wastes treated by emerging technologies are PCBs, various dioxins, pesticides and herbicides, chemical warfare agents, explosives and propellants, nitrobenzene, and hydrazine plus its derivatives. [R18] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: *Medical records should be kept for the entire length of employment of each worker and for the following 30 yr. [R10, 1755] HTOX: *2,4,5,2',4',5'-Hexachlorobiphenyl induced cytoplasmic inclusions and lipidosis in normal (AG1437) and hypercholesterolemic (GM488) human skin fibroblasts. Quantitative and qualitative microscopic fluorescence analysis showed that the cytoplasmic inclusions are formed as early as 3 hr after treatment with 2,2',4,4',5,5'-hexachlorobiphenyl. The inclusions contain lipids but no detectable nonesterified cholesterol or cholesterol ester. High density lipoproteins, low density lipoproteins, and very low density lipoproteins, facilitate the apparent uptake of 2,2',4,4',5,5'-hexachlorobiphenyl by skin fibroblasts. High density lipoproteins and low density lipoproteins appeared to reverse the induction of cytoplasmic inclusions and lipidosis when cells were pretreated with 2,2',4,4',5,5'-hexachlorobiphenyl, and were then incubated with low density lipoproteins or high density lipoproteins. The results suggest that lipoproteins participate in the uptake and egress of 2,2',4,4',5,5'-hexachlorobiphenyl from skin fibloblasts. [R19] *Nursing /by women exposed to PCB's/ ... should be discouraged because of the high amount of PCB's excreted with milk. ... [R10, 1754] NTOX: *5-WK OLD MALE MICE WERE ADMIN 10, 30, 100 OR 300 PPM 3,4,5,3',4',5'-HEXACHLOROBIPHENYL (3,4,5-HCB) OR 10, 30, 100, 300 PPM 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (2,4,5-HCB) IN FEED DAILY FOR 28 DAYS. 3,4,5-HCB CAUSED MORTALITY AND BODY AND ORGAN WT CHANGES AT ALL DOSE LEVELS AND PRODUCED EXCESS PORPHYRIN ACCUMULATION. IT CAUSED SC EDEMA, ENLARGEMENT OF LIVER WITH ACCENTUATED HEPATIC LOBULAR MARKINGS, FATTY LIVER, HEPATOCELLULAR SWELLING AND NECROSIS, AND ATROPHY OF THYMUS. 2,4,5-HCB CAUSED THE SAME LESIONS BUT TO LESSER DEGREE. [R20] *ORGANOHALOGENS WERE ADMIN TO PREGNANT RATS AND ENZYME ACTIVITIES WERE MEASURED IN FETUSES AND OFFSPRINGS (6, 20 and 55 DAYS AFTER BIRTH). 3,4,3'4'-TETRACHLOROBIPHENYL (TCB) INDUCED P448-DEPENDENT ENZYMES IN 6 and 20 DAY-OLD RATS WHEREAS 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (HCB) INDUCED P450-DEPENDENT ENZYMES. TCB PRODUCED BEHAVIORAL CHANGES AND KIDNEY ABNORMALITIES BUT HCB PRODUCED NO DEVELOPMENTAL EFFECTS. TCB MIGHT ALSO ALTER NORMAL IMPRINTING OF SEXUAL HEPATIC METABOLISM AS EVIDENCED BY FEMINIZATION (DECREASE) OF UDPGT IN ADULT MALE RATS WHICH WERE EXPOSED NEONATALLY TO TCB. [R21] *TOPICAL APPLICATION OF 2,2',4,4',5,5'-HEXACHLOROBIPHENYL (HCB) OR AROCLOR 1260 (120 MG DAILY, 5 TIMES/WK FOR 28 DAYS) PRODUCED SKIN LESIONS IN RABBITS WITH THE EFFECT BEING MORE SEVERE IN THE LATTER GROUP. BOTH CAUSED ACCUMULATION OF COPROPORPHYRIN. LIVER INJURY AND ELEVATION OF SERUM TRANSAMINASE LEVELS WERE MORE SEVERE IN THE HCB-TREATED GROUP. [R22] *2,4,5,2',4',5'-HEXACHLOROBIPHENYL FED TO PREGNANT GUINEA PIGS DID NOT CAUSE FETAL DEATH (TOTAL DOSE 25 MG OR 100 MG). [R23] *CHLORINATED BIPHENYLS DISSOLVED IN CORN OIL WERE INJECTED IP INTO MALE RATS. 2,4,5,2',4',5'-HEXACHLOROBIPHENYL INDUCED A CHANGE IN PROGESTERONE METABOLISM. [R24] *From day 45 to day 62 of gestation, three groups of primiparous pregnant Dunkin Hartley guinea pigs were fed once daily 0.1 ml of peanut oil containing 0 (control group), 0.176, or 1.76 mg of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB), which correlated to 0, 3, and 30 mg HCB per animal per treatment period. At day 60 of gestation, the dams were catheterized, and three days later the blood flow was determined by use of labeled microspheres. Blood samples were taken to determine hematological parameters, after which the dams were killed. The levels of HCB in the liver, myometrium, and placenta were determined. HCB accumulated in the placenta of tissue fat (33.9 ug/g) in the animals given the higher dose. In both treatment groups, there was a higher incidence of resorptions and abnormal maternal and fetal livers, compared with the controls. About 50% of the animals in the high-dose group had aberrant placentas. A statistically significant decrease in the placental blood flow and an increase in the lung perfusion were found in the high-dose group. [R25] *ISOMERICALLY PURE PCBS WERE TESTED AS INDUCERS OF HEPATIC DRUG-METABOLIZING ENZYMES IN THE RAT. THE CHLORINATED BIPHENYL ISOMERS CAN BE CATEGORIZED INTO 2 DISTINCT GROUPS OF INDUCERS, WHILE COMMERCIAL PCB MIXT HAVE CHARACTERISTICS OF BOTH GROUPS. BIPHENYLS CHLORINATED SYMMETRICALLY IN BOTH THE META AND PARA POSITIONS INCREASE THE FORMATION OF CYTOCHROME P448, BUT DECREASE THE AMINOPYRINE N-DEMETHYLASE ACTIVITY. BIPHENYL ISOMERS CHLORINATED IN BOTH THE PARA AND ORTHO POSITIONS INDUCE THE FORMATION OF CYTOCHROME P450 AND N-DEMETHYLASE ACTIVITY. ISOMERS WHICH ARE CHLORINATED IN ONLY 1 RING, OR ARE CHLORINATED IN BOTH RINGS BUT NOT IN THE PARA POSITIONS, HAVE VERY LITTLE ACTIVITY AS INDUCERS OF LIVER ENZYMES. [R26] *Adult female mink were fed diets that contained 2.5 ppm Aroclor 1254, 0.1 or 0.5 ppm 3,4,5,3',4',5'-hexachlorobiphenyl, 2.5 or 5.0 ppm 2,4,5,2',4',5'-hexachlorobiphenyl, or 2,3,6,2',3',6'-hexachlorobiphenyl, or a control diet from 1 month prior to breeding through parturition. All mink fed 0.5 ppm 3,4,5,3',4',5'-hexachlorobiphenyl died within 60 days, while those fed 0.1 ppm showed 50% mortality after 3 month exposure. Only one stillborn kit was whelped in the Aroclor 1254 group. No adverse reproductive effects were observed in the animals fed 2,3,6,2',3',6'-hexachlorobiphenyl or 2,4,5,2',4',5'-hexachlorobiphenyl. ... Aminopyrine N-demethylase activity was elevated by /admin of/ 5.0 ppm 2,4,5,2',4',5'-hexachlorobiphenyl. Benzo(a)pyrene hydroxylase activities were also significantly elevated in milk fed 2,4,5,2',4',5'-hexachlorobiphenyl and 3,4,5,3',4',5'-hexachlorobiphenyl. Norepinephrine concentrations were significantly elevated by ... 5.0 ppm 2,4,5,2',4',5'-hexachlorobiphenyl in the medulla. [R27] *The kinetics of liver and kidney retinol and retinyl palmitate levels were examined following single ip injections of DDT, 2,2',5,5'-tetrachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl, or 2,2',4,4',5,5'-hexachlorobiphenyl to male Sprague Dawley rats. The polychlorinated biphenyls (PCBs) were given in doses of 300 umol/kg, and DDT was given at a dose of 150 umol/kg. ... The induction of various drug metabolizing enzymes or retinyl palmitate hydrolase activity, a key enzyme in hepatic retinyl palmitate hydrolysis, was not implicated in the depletion of hepatic vitamin A. It is suggested that chemical or redox changes in the liver as a result of the toxicity of the xenobiotic may result in the nonenzymatic destruction of the liver vitamin A stores. [R28] *Treatment of C57BL/6J mice with 2,2',4,4',5,5'-hexachlorobiphenyl (500 umol/kg) elevated hepatic cytosolic Ah receptor levels 82-107% for up to 14 days. ... Administration of 2,2',4,4',5,5'-hexachlorobiphenyl to DBA/2J mice did not result in detectable hepatic cytosolic Ah receptor levels. Cotreatment of C57BL/6J mice with 2,2',4,4',5,5'-hexachlorobiphenyl (500 umol/kg) at a dose level of 2,3,7,8-tetrachlorodibenzo-p-dioxin (1 nmol/kg) which elicited less than 10% of the maximum induction response resulted in significant synergistic induction of hepatic EROD and AHH (compared to animals treated only with 2,3,7,8-tetrachlorodibenzo-p-dioxin (1 nmol/kg)). ... Cotreatment of DBA/2J mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,2',4,4',5,5'-hexachlorobiphenyl (500 umol/kg) resulted in significant synergistic induction of AHH and EROD at both submaximal (10-500 nmol/kg) and maximal (5000 nmol/kg) induction levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. The only significant interactive effect of 2,2',4,4',5,5'-hexachlorobiphenyl (500 umol/kg) on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in C57BL/6J and DBA/2J was protection from body weight loss observed after cotreatment of 2,2',4,4',5,5'-hexachlorobiphenyl and 2,3,7,8-tetrachlorodibenzo-p-dioxin in DBA/2J mice. [R29] *The cytochrome p450 isozymes, cytochrome p450 MC1 and MC2, purified from rats treated with 3-methylcholanthrene, were found by immunohistochemical staining to be strongly induced in the livers of rats treated with 3,3',4,4'-tetrachlorobiphenyl, while the cytochrome p450 isozymes, PB1 and PB2, purified from the livers of rats treated with phenobarbital, were shown to be induced in the livers of rats treated with 2,2',4,4',5,5'-hexachlorobiphenyl. The latter compound also strongly induced reductase nicotinamide adenine dinucleotide phosphate cytochrome p450-reductase. Following induction, all 5 enzymes were located preferentially in the centrilobular and midzonal region of the liver acinus. ... In addition, Diethylnitrosamine alone produced very few islets, the administration of either polychlorinated biphenyls congener (150 umol/kg, ip, once weekly over a period of 8 weeks) subsequent to diethylnitrosamine treatment (50 ppm in the drinking water, 10 days) strongly enhanced the number of islets as well as the relative volume of liver occupied by islet tissue. These effects were evident, both 1 and 9 weeks, after cessation of PCB treatment. ... [R30] *The influences of in vivo treatment with two pure polychlorinated biphenyls congeners on the lethal cytotoxicity of bromobenzene and acetaminophen were examined in short-term primary cultures of isolated rat hepatocytes. Lethal injury was measured by release of lactate dehydrogenase into culture medium after 20 hr exposure to the hepatotoxins. The 2,2',4,4',5,5'-hexachlorobiphenyl, a phenobarbital-type inducer of cytochrome p450, resembled phenobarbital in its ability to increase susceptibility of hepatocytes to bromobenzene (0.5 to 1.6 mM) and acetaminophen (1 to 16 mM). This induced sensitivity was consistently inhibited by SKF-525-A (10 uM) but not alpha-naphthoflavone (ANF, 10 uM) in culture. [R31] *Three groups of primaparous pregnant guinea pigs were fed once daily with a total of either 0 (control group, n= 9), 3 mg (n= 8), or 30 mg (n= 9) of 2,2',4,4',5,5'-hexachlorobiphenyl starting at day 45 of gestation to evaluate the effects of 2,2',4,4',5,5'-hexachlorobiphenyl on placental perfusion. The guinea pigs were separated into their groups randomly. At day 63 of gestation the organ blood flow was determined with microsphere technique in the awake animal. The results show a statistically significant decrease in the placental blood flow and an increase in the pulmonary blood flow in the animals fed with 30 mg 2,2',4,4',5,5'-hexachlorobiphenyl compared to the control group. A higher incidence of resorptions in fetuses was shown in both treatment groups compared to the control group. [R32] *... The weight of in vitro evidence suggests lipoproteins as the principal carriers of 2,4,5,2',4',5'-hexachlorobiphenyl in plasma from normolipidemic rats and humans. The present study examined the in vivo distribution of 2,4,5,2',4',5'-hexachlorobiphenyl among lipoproteins as well as the influence of time on the absolute amount and proportion of 2,4,5,2',4',5',-hexachlorobiphenyl associated with each density fraction. Plasma obtained between 1 min and 24 hr after an iv injection of 6-(14)C-CB was separated into very low density lipoprotein, low density lipoprotein, and high density lipoprotein fractions by sequential ultracentrifugation. The in vivo results corroborate the in vitro data which suggest low density lipoprotein to be a major transport vehicle for 2,4,5,2',4',5'-hexachlorobiphenyl in plasma. However, the preference of 2,4,5,2',4',5',-hexachlorobiphenyl for low density lipoprotein existed for only a short time following injection. ... Analysis of the decay curves of 2,4,5,2',4',5'-hexachlorobiphenyl among the various lipoproteins further substantiated a change in the distribution of 2,4,5,2',4',5'-hexachlorobiphenyl over time. The decay of 2,4,5,2',4',5'-hexachlorobiphenyl in low density lipoprotein most closely resembled its disappearance from plasma. The content of 2,4,5,2',4',5'-hexachlorobiphenyl remaining in plasma at 24 hr was equally distributed among low density lipoprotein, high density lipoprotein, and the bottom fraction. ... [R33] *2,2',4,4',5,5'-Hexachlorobiphenyl (HCB) dissolved in corn oil was administered intragastrically to two groups of 6 to 8 female Sprague Dawley rats at doses of 40 ug/kg/day or 400 ug/kg/day for 3 days each. The animals were killed 6 days after treatment. Control animals were used, but no details of treatment are provided. Lipid peroxidation and glutathione peroxidase (GSH-PX) activity were determined in liver and kidneys. Hepatic aryl hydrocarbon hydroxylase (AHH) activity was determined in two rats 48 hr following the administration of 400 ug/kg of HCB. No changes were noted in these parameters and there was no significant effect on thymus weight or body weight relative to the control group. [R34] NTXV: *LD50 Mouse (C57B1/6J) male oral > 64.3 mg/kg/28 day; [R35] ADE: *THE DISPOSITION OF MULTIPLE ORAL DOSES OF ... 2,4,5,2',4',5'-HEXACHLOROBIPHENYL ... STUDIED IN MICE ... INVESTIGATORS FOUND THAT THE RATE OF METABOLISM AND EXCRETION DECREASED WITH INCREASING CHLORINATION, BUT WAS MOST PROFOUNDLY AFFECTED BY ELIMINATION OF ADJACENT UNSUBSTITUTED CARBON ATOMS. ACCUMULATION OCCURRRED MAINLY IN ADIPOSE TISSUE, SKIN, MUSCLE. [R17, 3657] *EFFECTS OF RESTRICTING FOOD INTAKE ON THE DISTRIBUTION OF 2,2',4,4',5,5'-HEXACHLOROBIPHENYL (6-CB) IN RATS ADMIN A SINGLE DOSE OF 0.6 MG/KG, IV. GRADUAL DISAPPEARANCE OF ADIPOSE TISSUE WAS INDUCED BY RESTRICTING FOOD INTAKE TO 25% OF AD LIBITUM CONSUMPTION. IN FIRST SERIES OF EXPERIMENTS, 6-CB WAS ADMIN SIMULTANEOUSLY WITH START OF FOOD RESTRICTION. FECAL EXCRETION RATE OF 6-CB INCR, REACHED A MAX IN 2ND WK, AND THEN LEVELED OFF. AFTER 7 WK, SOME 50% OF THE DOSE WAS EXCRETED AND 26% WAS LOCATED IN SKIN. AMOUNTS IN MUSCLE, LIVER, LUNG, KIDNEY, BRAIN, GI CONTENTS, AND RESIDUAL ADIPOSE TISSUE WERE BETWEEN 2.5 and 0.1% OF ADMIN DOSE. IN 2ND SERIES OF EXPERIMENTS, 6-CB WAS ADMIN 2 WK AFTER FOOD RESTRICTION STARTED, IE WHEN ADIPOSE TISSUE RESERVES HAD ALREADY LARGELY DISAPPEARED. FECAL EXCRETION RATE WAS MAXIMAL AT OUTSET AND GRADUALLY DECR. CUMULATIVE EXCRETION AND DISTRIBUTION VALUES FOR SKIN AND OTHER TISSUES WERE NOT SIGNIFICANTLY DIFFERENT FROM VALUES DETERMINED IN ABOVE SERIES AFTER 7 WK. PHARMACOKINETIC OF 6-CB IS INFLUENCED BY ADIPOSE TISSUE MASS. [R36] *RESULTS FROM A PROCEDURE FOR ANALYZING THE BINDING OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (HCB) TO LOW DENSITY LIPOPROTEINS AND SERUM ALBUMIN INDICATE THAT ALBUMIN AND LOW DENSITY LIPOPROTEIN EFFECTIVELY BIND THIS POLYCHLORINATED BIPHENYL AND SUGGEST THAT PLASMA PROTEINS MAY PLAY A ROLE IN ITS DISTRIBUTION TO PERIPHERAL CELLS. LOW DENSITY LIPOPROTEINS BOUND HCB AT SEVERAL NONINTERACTIVE SITES AND BOVINE SERUM ALBUMIN AT 1 NONINTERACTIVE SITE. [R37] *OF ... 2,2',4,4'5,5'-HEXACHLOROBIPHENYL FED TO RATS, LESS THAN 10% WAS EXCRETED IN FECES, INDICATING A HIGH DEGREE OF ABSORPTION, METABOLISM OR LOCALIZATION IN THE TISSUES. ... FOLLOWING IV INJECTION TO RATS OF ... /2,2',4,4',5,5'-HEXACHLOROBIPHENYL, IT WAS/ FOUND IN HAIR, SUGGESTING THAT THIS MAY SERVE AS A ROUTE OF PCB EXCRETION. [R38] *(14)C-2,4,5,2',4',5'-HEXACHLOROBIPHENYL WAS ADMIN ORALLY TO BILE-CANNULATED RATS. ABSORPTION FROM GI TRACT WAS 28.2% +/- 1.4 WHILE BILIARY EXCRETION WAS 18.6% +/- 1.3. URINARY EXCRETION WAS LOW. DISPOSITION OF RADIOACTIVE RESIDUES IN EVISCERATED CARCASSES INCREASES WITH THE CL CONTENT OF BIPHENYLS. [R39] *DISPOSITION OF 2,3,6,2',3',6'-HEXACHLOROBIPHENYL (2,3,6-HCB) and 2,4,5,2',4',5'-HCB (2,4,5-HCB) IN 24-MO OLD MALE SPRAGUE-DAWLEY RATS AFTER IV ADMIN WAS COMPARED TO DATA OBTAINED FROM 2-3 MO OLD RATS. ALTHOUGH THE PATTERN OF HCB DISPOSITION DID NOT CHANGE WITH AGE, IE, METABOLISM AND EXCRETION OF 2,3,6-HCB VERSUS PERSISTENCE OF 2,4,5-HCB, THERE WERE DIFFERENCES IN RATES OF ELIM AND IN TISSUE LEVELS. THERE WAS ENHANCED METABOLITE RETENTION IN MUSCLE, SKIN, AND ADIPOSE TISSUE OF OLDER RATS WHICH SUGGESTED AN AGE-RELATED DECREASE IN TISSUE CLEARANCE. THE LARGER VOLUME OF ADIPOSE TISSUE IN THESE OLDER RATS COULD IN PART EXPLAIN THIS OBSERVATION. THERE WERE FEW CHANGES IN DECAY RATES FROM TISSUES OR IN BILIARY EXCRETION. AGE HAD A GREATER EFFECT ON DISPOSITION OF 2,4,5-HCB THAN ON 2,3,6-HCB. [R40] *TRANSPLACENTAL TRANSFER OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (HCB) WAS MINIMAL IN MICE WHO HAD RECEIVED HCB 2 WK PRIOR TO MATING. HOWEVER, IT WAS RAPIDLY TRANSFERRED TO SUCKLING OFFSPRING THROUGH THE LACTATING MAMMARY GLAND. [R41] *TISSUE DISTRIBUTION, METABOLISM AND EXCRETION OF LABELED 2,4,5,2',4',5'-HEXACHLOROBIPHENYL WERE STUDIED IN BEAGLE DOGS AND CYNOMOLGUS MONKEYS FOLLOWING SINGLE IV ADMIN OF 0.6 MG/KG. ELIMINATION OF THE PARENT PCB FROM BLOOD OF BOTH SPECIES WAS BIPHASIC WITH TERMINAL PHASE ELIMINATION RATE CONSTANT OF 0.045/DAY FOR DOG AND 0.015/DAY FOR MONKEY. PERCENTAGE OF DOSE REMAINING WAS FOUND LARGELY AS PARENT CMPD IN ADIPOSE TISSUE (16%), SKIN (6%), AND MUSCLE (2%). BY 90 DAYS, THE MONKEY HAD EXCRETED ONLY 18% OF THE DOSE (17% IN FECES, 1% IN URINE). [R42] *UPTAKE, DISTRIBUTION, AND EXCHANGE OF CHLORINATED INSECTICIDES DIELDRIN AND CHLORDECONE AND BIPHENYLS 2,4,5,2',4',5-HEXACHLOROBIPHENYL AND 3-CHLOROBIPHENYL AMONG HUMAN LIPOPROTEINS WAS EXAMINED BY FLUORESCENCE QUENCHING, GEL FILTRATION, AND ULTRAFILTRATION. THE CHLORINATED HYDROCARBONS ATTACHED TO ALBUMIN OR ONE OR MORE OF THE LIPOPROTEINS WERE RAPIDLY TRANSFERRED TO ALL OTHER LIPOPROTEINS. THE EXCHANGE WAS COMPLETE IN LESS THAN 1 MIN. [R43] *LAKE TROUT AND CHINOOK SALMON SAC FRY WERE EXPOSED TO WATER CONTAINING LOW PPB CONCENTRATIONS OF (14)C-2,4,5,2',4',5'-HEXACHLOROBIPHENYL (2,4,5-HCB). THE 2,4,5-HCB WAS ADDED TO WATER IN STATIC SYSTEM 3 TIMES DAILY FOR 15 DAYS, EACH ADDN BEING A CALCULATED WATER CONCN OF 5 PPB. ALTHOUGH IT DID NOT ACCUMULATE IN WATER, IT DID ACCUMULATE IN FRY OF BOTH SPECIES, REACHING CONCN OF 7.6 PPM IN LAKE TROUT FRY AND 3.6 PPM IN CHINOOK SALMON, 1 DAY AFTER THE LAST ADDITION. FOR EACH SPECIES IT WAS FOUND THAT AMT OF 2,4,5-HCB PRESENT AT TIME OF DEATH WAS CONSTANT, NO MATTER WHEN ANIMALS HAD DIED. [R44] *2,4,5,2'4',5'-HEXACHLOROBIPHENYL CLEARLY PREDOMINATED IN THE FAT OF CHICKENS FED FAT FROM AROCLOR 1254-TREATED SWINE. [R45] *IN C57BL AND DBA MICE THE ROLE OF ADIPOSE TISSUE AS MODIFIER OF TISSUE DISTRIBUTION, BIOLOGICAL EFFECTS, AND ELIMINATION OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (2,4,5-HCB) WAS STUDIED. SINCE 2,4,5-HCB WAS PRIMARILY SEQUESTERED BY THE ADIPOSE TISSUE, DBA MICE REQUIRED GREATER DOSES OF 2,4,5-HCB THAN DID C57 MICE TO REACH SIMILAR TISSUE LEVELS OF CHEMICAL. ACCORDINGLY, GREATER 2,4,5-HCB DOSES WERE REQUIRED BY DBA MICE FOR ELEVATION OF DRUG-METABOLIZING ENZYME ACTIVITIES. [R46] *THE AVAILABILITY OF RADIOLABELED 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (2,4,5-HCB) TO BENTHIC AMPHIPODS WAS DETERMINED FROM EXPTL CONTAMINATED NATURAL SEDIMENTS. AMPHIPODS ACCUM 2,4,5,2',4',5'-HEXACHLOROBIPHENYL PRIMARILY BY DIRECT UPTAKE FROM WATER AS A FUNCTION OF EXPOSURE TIME. ORGANISMS THAT WERE DIRECTLY EXPOSED TO SEDIMENTS HAD CONSISTENTLY HIGHER CONCN THAN DID ORGANISMS EXPOSED ONLY TO THE SEDIMENT-DESORBED RESIDUES IN THE WATER. THE SUBSTRATE ORG MATTER CONTENT AND PARTICLE SIZE AFFECTED THE CONCN OF 2,4,5-HCB IN THE WATER AND ORGANISM. REMOVAL OF SEDIMENT ORG MATTER ENHANCED 2,4,5-HCB ACCUM BY SUBSTRATE AND WATER EXPOSED ORGANISMS. AMPHIPODS ACCUM THE LEAST 2,4,5-HCB WHEN EXPOSED TO SILT-CLAY PARTICLE SIZE FRACTIONS WHICH CONTAINED ORG MATTER. THE SUBSTRATE PARTICLE SIZE WAS LESS IMPORTANT THAN THE ORG MATTER IN DETERMINING 2,4,5-HCB AVAILABILITY TO THE AMPHIPODS. [R47] *DISPOSITION OF 37 PCB CONGENERS AND ADIPOSE TISSUE-PLASMA PARTITION OF 28 PCB CONGENERS WERE STUDIED IN 26 PERSONS OCCUPATIONALLY EXPOSED TO VARIOUS PCBS (20-54% CL). CONCN OF PCBS IN ADIPOSE TISSUE AND PLASMA WERE RELATED TO DURATION AND INTENSITY OF EXPOSURE. PCB CONCN IN ADIPOSE TISSUE WAS PROPORTIONAL TO THAT IN PLASMA, WITH A PARTITION FOR TOTAL PCBS OF APPROX 190:1 INDICATED FROM REGRESSION ANALYSIS. PCB CONGENERS WITH CL IN BOTH 4-POSITIONS OF BIPHENYL RING WERE MAJOR COMPONENTS IN PLASMA AND ADIPOSE TISSUE. CONGENERS WITH UNSUBSTITUTED 3,4-POSITIONS ON 1 OR BOTH OF BIPHENYL RINGS WERE OBSERVED AT LOWER CONCENTRATIONS. IN CONTRAST, THOSE COMPOUNDS WITH SUBSTITUENTS AT 2,4- and 3,4-POSITIONS ON BOTH RINGS WERE PRESENT IN MUCH HIGHER PROPORTIONS IN BLOOD OR ADIPOSE TISSUE THAN IN PCB MIXTURES USED. THESE COMPONENTS ALSO HAD HIGHER ADIPOSE TISSUE-PLASMA PARTITION THAN THOSE WITH UNSUBSTITUTED 3,4-POSITIONS, REGARDLESS OF DEGREE OF CHLORINATION. [R48] *... Normal skin fibroblasts and familial hypercholesterolemic cells were cultured and incubated with 5.5, 27, or 55 micromolar concentrations of radiolabeled hexachlorobiphenyl for 3 or 24 hours. Radiolabeled acetate and glycerol-3-phosphate were used as substrates in different experiments. Cells were analyzed for phospholipids and triglyceride. When acetate was the substrate, synthesis of triglyceride and phospholipids increased dramatically with hexachlorobiphenyl. Incorporation of glycerol-3-phosphate into phospholipids and diglycerides was decreased but no significant change in triglyceride formation was noted. Hypercholesterolemic skin fibroblasts showed increased incorporation of acetate into phospholipids and triglycerides at low concentrations of hexachlorobiphenyl and decreased incorporation at higher concentrations. There was a significant increase in triglyceride content when skin fibroblasts were treated with hexachlorobiphenyl. There was no significant change in phospholipid content of skin fibroblasts after treatment with hexachlorobiphenyl at lower concentrations. ... [R49] *... Pharmacokinetic analysis of 4,4'-dichlorobiphenyl, 2,2',3,3',6,6'-hexachlorobiphenyl and 2,2',4,4',5,5'-hexachlorobiphenyl is presented for the dog and monkey, and the results are compared with previous similar analyses for the rat and mouse. The normalized clearances (ml/min per kg body wt) vary considerably between the dog and the monkey; the rat and the mouse show less species variation. The equilibrium tissue-to-blood distribution ratios for parent and metabolite are generally similar for all 4 species. The fat compartment has the highest parent distribution ratio for all 4 species, and the metabolite distribution ratios are much smaller than the parent distribution ratios. Metabolism appears to be a prerequisite to urinary and biliary excretion for all 3 compounds in each species. Elimination from the body occurs predominantly by the fecal route. The 2,2'4,4'5,5'-hexachlorobiphenyl is more slowly metabolized than the 2,2',3,3',6,6'-isomer in all species. ... [R50] *Uptake of the persistent environmental chemicals 2,2',4,4',5,5'-hexachlorobiphenyl and DDT by Chang liver cells, an established human cell line, was investigated. Monolayer cells were incubated with culture medium to which the lipophilic model cmpd were added. The time course of uptake of either cmpd was biphasic, reaching equil after approx 5 hr of incubation. The ratio of DDT: hexachlorobiphenyl uptake was dependent on the presence of serum proteins. Increasing concn of serum proteins in the culture medium progressively inhibited uptake. Efflux from the cells was not entirely reversible: 10-20% of the chemicals were not released. Uptake was a linear function of the external concn of the cmpd. Absorptive binding to the outer cell plasma membrane could be determined by removing bound chemicals with fetal calf serum (back exchange). With this method, temp-dependent translocation through the cell plasma membrane could directly be demonstrated. The effect of low temp as well as the influence of metabolic inhibitors point out the contribution of energy-driven uptake pathways. Demonstration of low density lipoprotein receptor-like binding protein on Chang liver cells facilitated estimation of the role of receptor-mediated uptake. ... [R51] *A physiologically based human pharmacokinetic model of chem intake via ingestion of food and water and inhalation of air is presented. The model takes the form of a series of algebraic equations that describe the steady state, constant exposure, transport rates, and physiological distribution in arterial and venous blood, lung, fat, skin, muscle, liver, gut tissue, gut lumen, and richly perfused tissues. It is assembled using the fugacity concept and is applied to 2,2',4,4',5,5'-hexachlorobiphenyl and styrene. The model can be used to elucidate how tissue concn respond to these intake routes. [R52] *The disposition and biotransformation of 4,4'-dichlorobiphenyl, 2,2',3,3',6,6'-hexachlorobiphenyl, 2,2',4,4',5,5'-hexachlorobiphenyl were studied in isolated rat hepatocyte suspensions. The PCBs were taken up rapidly by the cells but 2,2',4,4',5,5'-hexachlorobiphenyl was not metabolized (0.1-200 uM). ... Analysis of absorbance differences (DELTA absorbance 390-240 nm) of equimolar concn of congener (100 uM) revealed that 2,2',3,3',6,6'-hexachlorobiphenyl displayed the greatest affinity of binding to cytochrome p450 followed by 4,4'-dichlorobiphenyl, while 2,2',4,4',5,5'-hexachlorobiphenyl showed virtually no binding. [R53] *Longterm (280 days) pharmacokinetics of 2,2',4,4',5,5'-hexachlorobiphenyl was studied in rats with const adipose tissue mass. This was achieved by feeding the animals 50% of their mean ad libitum food intake, 2,2',4,4',5,5'-hexachlorobiphenyl was administered as a single iv injection of 0.6 mg/kg. Tissues and excreta were analyzed at various time points from 4 to 280 days. After the redistribution phase, all tissue concentrations declined with terminal half-lives of 431-478 days, and concn in adipose tissue was 1000 times higher than in blood. The corresponding ratios were: for skin 40, lung 30, liver 25, brain 10, and muscle 10. From day 4 on only adipose tissue, skin, and muscle contained significant amts of 2,2'4,4',5,5'-hexachlorobiphenyl. Between 2 and 4 wk adipose tissue and skin reached a max corresponding to 68 and 15% of the dose, respectively. After 280 days these values declined to 38 and 7% of the dose. Fecal excretion during this period was 43% of the dose with a terminal half-life of 478 days. Polar metabolites (1.5% of dose) were detectable in urine only. Extrapolation of fecal excretion kinetics yields a total excretion value of 99% of the dose at infinite time. ... [R54] *Male Sprague-Dawley rats were ... treated with a first dose of 0.6 mg/kg 2,4,5,2',4',5'-hexachlorobiphenyl intravenously, followed by an identical dose 14 days later. Similar distribution and elimination patterns were recorded, regardless of the order or number of 2,4,5,2',4',5'-hexachlorobiphenyl doses administered to the animals. The administration of a second dose of unlabeled 2,4,5,2',4',5'-hexachlorobiphenyl did not affect the tissue distribution or excretion of the product administered 14 days earlier. The body weight of the animals increased by 36 % during the first 14 days of the study and by 56% for the entire 28 day experimental period. The percent distribution of the total dose of 2,4,5,2',4',5'-hexachlorobiphenyl in the fat, muscle, skin, liver, and plasma was similar for all groups. [R55] *The effects of age on intestinal absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin were studied using adult male Fischer 344 rats of 3 different age groups: 13 weeks old (young), 13 months old (mature), and 26 months old (senescent). Absorption was measured with an in situ intestinal recirculation perfusion procedure. Absorption expressed in terms of ng 2,3,7,8-tetrachlorodibenzo-p-dioxin absorbed/g intestinal dry weight/hr was 166, 149, and 143 ng/g/hr in the young, mature and senescent groups, respectively . When absorption was calculated in terms of ng 2,3,7,8-tetrachlorodibenzo-p-dioxin absorbed/g mucosal dry weight/hr, the decrease between the senescent rats and the 2 younger age groups, from 544 ng/g/hr (young) to 351 ng/g/hr (senescent), was not statistically significant (p < 0.05). Absorption of 2,3,7,8-tetrachlorodibenzo-p-dioxin was unaffected by the presence of 2,4,5,2',4',5'-hexachlorobiphenyl in the perfusate, but that 2,4,5,2',4',5'-hexachlorobiphenyl absorption was (p < 0.01) enhanced by the presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin. [R56] *Studies of polychlorinated biphenyls (PCB) toxicity in laboratory animals indicate a wide species variability in sensitivity to physiological intoxication by these compounds. For example, rats are largely resistant to PCB intoxication, whereas rhesus monkeys are quite sensitive. Human sensitivity to PCB toxicity appears to be related to the source of exposure. All PCB congeners are highly lipophilic, and most are readily distributed to all tissues. PCBs are cleared from tissues at very different rates. ... Rates of PCB metabolism vary widely, depending on the animal species and the degree and positions of chlorination. The ability of animals to metabolize PCBs increases in the order, fish, birds, and mammals. PCBs that are not readily cleared concentrate in fatty tissue. Pharmacokinetic modeling of PCBs is discussed. A pharmacokinetic model for PCBs in the rat show that compartment sizes and blood flows are independent of the chemical being modeled. The amounts stored in tissues depends on the tissue to blood distribution coefficients and the body burden. The metabolic clearance constants show a considerable range, from 10 ml/min for 4-chlorobiphenyl to 0.045 ml/min for 2,4,5,2',4',5'-hexachlorobiphenyl for a rat weighing 250 g. [R57] *... Male beagle dogs and male Macaca fascicularis monkeys were given a single intravenous bolus in the radial and saphenous vein, respectively, of 6 mg/kg radiolabeled 2,2',4,4',5,5'-hexachlorobiphenyl. Blood and adipose tissue samples of pericardial, perirenal, peritesticular, and subcutaneous fat and omentum were collected at different times. Samples were analyzed for total radioactivity and parent polychlorinated biphenyl (PCB). There were significant differences for 2,2',4,4',5,5'-hexachlorobiphenyl concentrations between the sampled adipose tissue depots at equivalent times and between collection times for the same depot for dog and monkey. Mean concentrations of radiolabel in testicular fat were consistently lower than the concentration in other adipose tissues analyzed. All other concentrations of radiolabel were similar at all times. ... For fat depots that were analyzed, the parent to metabolite ratio for 2,2',4,4',5,5'-hexachlorobiphenyl in dogs was approximately 25.2 and for monkeys, 101. Fat to blood ratios for parent 2,2',4,4',5,5'-hexachlorobiphenyl for dogs and monkeys increased over the time course of the experiment. [R58] *Rats were treated by gavage, with a single dose of 14 C-2,4,5,2',4',5',-hexachlorobiphenyl at 0.6 or 3.6 mg/kg body weight. The rats were examined 1 h, 24 h, 6 weeks, 20 weeks, or 40 weeks after dosing. The highest levels of PCBs were found in the muscle, liver, adipose tissue, and skin, early in study. ... The highest PCB levels were found in the adipose tissue followed by the skin, muscle, and liver. During the 40 week study period, only 16% of the total dose was excreted. [R59] *The transfer of 2,4,5,2',4',5' hexachlorobi[14 C]phenyl across the placenta during the course of pregnancy in Sprague Dawley mice was studied. The PCB was injected intraperitoneally at 100 mg/kg body weight, in corn oil, 2 weeks prior to mating. The concentrations of 14 C PCB in the fetuses from 12 and 18 day pregnant animals were 0.71 and 2.45 mg/kg tissue, respectively. At birth, the total carcass concentration for all newborn animals was less than 3 mg/kg tissue, which represents less than 3 % of the dose present in the mothers at birth. [R60] *The distribution, metabolism, and excretion of 14C labeled 2,4,5,2'4'5' hexachloro, or 2,3,6,2'3',6' hexachlorobiphenyl in beagle dogs and cynomolgus monkeys, were studied after a single intravenous dose. The elimination of the test substances from the blood of both species was shown to be biphasic. The results for dichlorobiphenyl showed that the dog eliminated 50% of the dose (urine, 7 %; feces, 43 %) within 24 hr, while the remainder was found mainly in the adipose tissue. By 5 days, 90% had been eliminated. The monkey eliminated less than 15% of the dose within 24 hr, with less than 1% in the feces. The remainder was found in the adipose tissue. Within 28 days, 59% of the dose had been eliminated, chiefly in the urine. Biliary excretion after 24 hr was shown to be 33 % in the dog and only 0.4% in the monkey. The data for 2,4,5,2',4',5' hexachlorobiphenyl showed that the dog eliminated 66% (urine, 3%; feces, 63%) within 3 days; the monkey eliminated 18 % of the dose (of which 17 % was in the feces), 90 days following administration. The remainder was found in the adipose tissue. In the studies with 2,3,6,2',3',6' hexachlorobiphenyl, the dog eliminated 52% of the dose within 24 hr (urine, 11%; feces, 41%) and 70% in 3 days. The monkey eliminated 19% during the first 24 hr, divided equally between urine and feces. By 15 days, 61% had been eliminated, primarily in the feces. The 24 hr biliary excretion was 26% and 2.4% in the dog and the monkey, respectively. [R61] METB: *METABOLISM OF 2,2',4,4',5,5'-HEXACHLOROBIPHENYL (245-HCB) BY HUMAN HEPATIC MICROSOMES WAS STUDIED. 245-HCB WAS NOT METABOLIZED UNDER VARIOUS CONDITIONS. THE FACT THAT IT WAS NOT METABOLIZED EXPLAINS WHY IT IS THE PREDOMINANT PCB FOUND IN HUMAN ADIPOSE TISSUE. [R62] *IN MICE AND RATS, 2,2',4,4',5,5'-HEXACHLOROBIPHENYL (HCB) IS METABOLIZED TO 2,2',4,4',5,5'-HEXACHLORO-3-BIPHENYLOL. IN RABBITS, THE METABOLIC PRODUCTS ARE A MONOHYDROXYLATED DERIVATIVE, A MONOHYDROXY WITH CHLORINE SHIFT, AND A MONOHYDROXYMETHOXYLATED DERIVATIVE. PRODUCTS IN CHICKENS ARE A META-HYDROXYLATED DERIVATIVE, A PENTA-CHLOROBIPHENYL DERIVATIVE, AND A PENTA-CHLOROTRIHYDROXYLATED DERIVATIVE. [R63] *METABOLISM OF (3)H-LABELED 2,2',4,4',5,5'-HEXACHLOROBIPHENYL (2,4,5-HCB) WAS STUDIED IN 2 MONKEYS. 2,4,5-HCB WAS EXCRETED IN THE BILE AS PARENT 2,4,5-HCB, 2,2',4,4',5,5'-HEXACHLORO-3-HYDROXYBIPHENYL, AND WATER-SOL CONJUGATES OF 2,4,5-HCB GLUCURONIDE, PROBABLY 2,2',4,4',5,5'-HEXACHLORO-3-HYDROXYBIPHENYL GLUCURONIDE. METABOLISM OF 2,4,5-HCB MAY OR MAY NOT INCLUDE THE FORMATION OF AN ARENE OXIDE. [R64] *A strain of Alcaligenes eutrophus, designated H850, that rapidly degrades a broad and unusual spectrum of polychlorinated biphenyls (PCBs) has been isolated and characterized. .... This strain was isolated from PCB-containing dredge spoils, grows well on biphenyl and 2-chlorobiphenyl but poorly on 3- and 4-chlorobiphenyl. Capillary gas-chromatographic analysis showed that biphenyl- grown resting cells of H850 degraded the components of 38 of the 41 largest peaks of Aroclor 1242 and 15 of the 44 largest peaks of Aroclor 1254, resulting in an overall reduction of PCBs by 81% for Aroclor 1242 (10 ppm) and 35% for Aroclor 1254 (10 ppm) in 2 days. H850 metabolized the predominantly ortho- substituted PCB congeners. ... The congener selectivity patterns indicate that a two-step process consisting of anaerobic dechlorination followed by oxidation by H850 can effectively degrade all of the congeners in Aroclor 1242 and possibly all those in Aroclor 1254. [R65] *(14)C-labeled 2,4,5,2',4',5'-hexachlorobiphenyl (2,4,5-HCB), a slowly metabolized polychlorinated biphenyl (PCB), was given to rats by gastric incubation. The hepatocyte nuclei were then isolated and treated with specific hydrolytic enzymes to separate the nucleic macromols, (protein, RNA, and DNA). 2,4,5-HCB was shown to bind in vivo to hepatocyte nuclei. Liver nuclear proteins bind 70% of 2,4,5-HCB and 30% is found in the DNA fraction. No radioactivity was found in the nuclear RNA fraction. ... [R66] *The biochemical basis for the marked difference in the rate of the hepatic metabolism of 2,2',4,4',5,5'-hexachlorobiphenyl by beagle dogs and Sprague-Dawley rats has been investigated. Control dog liver microsomes metabolize this substrate 15 times faster than control rat liver microsomes. Upon treatment with phenobarbital, at least two cytochrome p450 isozymes are induced in the dog, and the hepatic microsomal metabolism of 2,2',4,4',5,5'-hexachlorobiphenyl is increased on both a per nanomole p450 basis (two-fold) and a per milligram protein basis (five-fold). ... Antibody inhibition studies have shown that /one of the phenobarbitol induced isozymes/, PBD-2, accounts for > 90% of the hepatic microsomal metabolism of 2,2',4,4',5,5'-hexachlorobiphenyl in control and phenobarbital induced dogs, while /the major isozyme induced by phenobarbitol/, PB-B, only accounts for about half of the metabolism of this compound by microsomes obtained from phenobarbital treated rats. ... [R67] BHL: *THE HALF-LIFE OF (14)C-LABELED 2,5,2',4',5'-PENTACHLOROBIPHENYL AND 2,3,4,2',4',6'-HEXACHLOROBIPHENYL FOLLOWING ORAL ADMIN TO MICE WERE APPROX 6 and 1 DAY RESPECTIVELY, WHEREAS THE T 1/2 OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL WAS MUCH HIGHER (SLOW EXCRETION). [R68] *Half-lives of the metabolites of 2,4,5,2',4',5'-HCB in Sprague-Dawley rats are as follows: Fecal: metabolite I= 0.9 days, metabolite II= 8.8 days, metabolite III= 100.5 days; urine I= 0.3 days II= 7.4 days. Metabolites were not characterized. /From table/ [R69] *BIOLOGICAL HALF-LIFE OF 31 DICHLORO- TO DECHLOROBIPHENYL CONGENERS WERE MONITORED FOR 105 DAYS IN ADULT RAINBOW TROUT THAT WERE EXPOSED TO A SINGLE ORAL DOSE. IN WHOLE FISH, HALF-LIFE INCR FROM 5 DAYS TO NO APPARENT ELIM AS THE NUMBER OF CHLORINES ON THE BIPHENYL INCR. THIS STRUCTURE-ACTIVITY RELATION WAS NOT AS EVIDENT IN MUSCLE WHERE HALF-LIFE RANGED FROM LESS THAN 5 DAYS TO 127 DAYS. DECLINE IN MUSCLE PCB MAY BE RELATED TO THE DECR IN LIPID LEVELS AND REDISTRIBUTION OF CONGENERS WITHIN THE FISH. FROM STRUCTURE-ACTIVITY ANALYSIS OF HALF-LIFE IN WHOLE FISH, ELIM IS ENHANCED FOR THOSE CONGENERS WITH LOWER CHLORINE CONTENT, WITH NO CHLORINE SUBSTITUTIONS IN THE ORTHO POSITIONS, AND THOSE WITH 2 UNSUBSTITUTED CARBONS THAT ARE ADJACENT (VICINAL) ON THE BIPHENYL. A SIGNIFICANT DECLINE IN TOTAL PCB CONTENT IN WHOLE FISH, EQUIV TO HALF-LIFE OF 219 DAYS, WAS PARTLY DUE TO DECOMP OF THE PCB MIXTURE ADMIN, AND SELECTIVE ELIM OF LOWER CHLORINATED BIPHENYLS. [R70] ACTN: *RAT AND RAINBOW TROUT HEPATIC MONOOXYGENATION ACTIVITIES WERE INDUCED BY INJECTION OF 150 MG/KG OF 2,4,5,2',4'5'-HEXACHLOROBIPHENYL. RODENT STUDIES INDICATED THAT NONCOPLANAR PCB ISOMERS INDUCED CYTOCHROME P-450, WHILE COPLANAR ISOMERS INDUCE CYTOCHROME P-488. [R71] *MOUSE LIVER EPOXIDE HYDROLASE AND GLUTATHIONE S-TRANSFERASE WERE INCREASED BY PCBS (0.32 MMOLE/KG, IP). ACTIVITIES REACHED MAX LEVELS 1 WK AFTER DOSAGE. GREATEST ENHANCEMENT OF BOTH ENZYME ACTIVITIES WAS ACHIEVED WITH HEXACHLOROBIPHENYLS. /HEXACHLORO BIPHENYLS/ [R72] INTC: *PRETREATMENT OF RATS WITH 3,4,3'4'-TETRACHLOROBIPHENYL (TCB) OR 2,4,5,2'4'5'-HEXACHLOROBIPHENYL PROTECTED RATS AGAINST BENZENE-INDUCED LYMPHOCYTOPENIA FOR AS LONG AS 7 DAYS, BUT NOT AFTER 10 DAYS OF REPEATED DOSING. [R73] *The induction of cytochrome p450 b,e-type antigen and mRNA by phenobarbital, 4,4'-dichlorobiphenyl and 2,4,5,2',4',5'-hexachlorobiphenyl in male Wistar rat liver was studied. Treatment of rats with phenobarbital or 2,4,5,2',4',5'-hexachlorobiphenyl results in a pronounced increase of cytochrome p450 b,e-type antigen and mRNA levels. 2,4,5,2',4',5'-Hexachlorobiphenyl appears to induce primarily a cytochrome p450 b-type sequence. [R74] *... A comparison of the time course of monooxygenase enzyme induction and receptor protein elevation by phenobarbital and 2,2',4,4',5,5'-hexachlorobiphenyl showed significant differences in their activities. Five days after administration of the hexachlorobiphenyl, receptor levels were significantly elevated; these increased levels persisted for 14 days. No correlation existed between increased levels of hepatic receptor protein and induction of the cytochrome-p450 dependent monooxygenases, aldrin epoxidase, or dimethylaminoantipyrine-N-demethylase. [R75] *Fecal excretion of 2,4,5,2',4',5'-hexachlorobiphenyl was followed for 19 weeks in rats fed a control diet, or a squalane-supplemented diet, for up to 17 weeks. In 3 days after a single oral dose of 8 mg/kg of 2,4,5,2',4',5'-hexachlorobiphenyl, 20% dose was excreted in feces as unchanged 2,4,5,2',4',5'-hexachlorobiphenyl, which probably represents that not absorbed. From day 4 to 133 only an additional 2-4% dose was excreted in feces by control animals. Addition of 8% squalene to the diet 2, 6 and 15 weeks after dosing resulted in a five-fold increase of daily 2,4,5,2',4',5'-hexachlorobiphenyl excretion in feces independent of the time of beginning the treatment. Total excretion of 2,4,5,2',4',5'-hexachlorobiphenyl in feces from day 4 to 133 was 3.6, 6-7 and 9.3% dose after 4, 13 and 17 weeks of squalane treatment, respectively. No adverse effects of long-term squalane treatment on body-weight gain, feed efficiency and organ weights were observed. Plasma cholesterol and triglycerides were significantly lowered. Independent of the duration of treatment, the livers of rats fed the squalene-supplemented diet contained 40-50 ug/g squalene. Within the limits of detection no squalane could be found in lung, kidneys, abdominal fat, spleen, and blood. ... [R76] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ WARN: *Food and Environmental Agents: Reported Sign or Symptom in Infant or Effect on Lactation: Polychlorinated biphenyls and polybrominated biphenyls: Lack of endurance, hypotonia, sullen, expressionless facies. /From Table 7/ [R77] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ARTS: */SRP: THIS PCB HAS ENTERED THE USA ENVIRONMENT/ MAINLY THROUGH USE OF AROCLOR 1248, 1254, AND 1260 ... FROM MANUFACTURING PLANTS, DURING DESTRUCTION OF MANUFACTURED ARTICLES CONTAINING PCBS IN MUNICIPAL AND INDUSTRIAL WASTE-DISPOSAL BURNERS, THROUGH GRADUAL WEAR AND WEATHERING OF PCB-CONTAINING PRODUCTS, AND THROUGH LEACHING FROM LAND-FILL DUMPS. /POLYCHLORINATED BIPHENYLS/ [R17, 3661] FATE: *When uniformly (14)C-labeled ... 2,2',4,4',5,5'-hexachlorobiphenyl was incubated for 98 days in soil ... 0.1% (14)CO2 was evolved in a closed system. Biphenyl and the monochlorobiphenyls were moderately degraded whereas the polychlorinated cmpd were virtually inert. [R78] BIOC: *BIOCONCENTRATION OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL (2,4,5-HCB) WAS EXAMINED IN THE GREAT LAKES (USA) ALGAE FRAGILARIA CROTONENSIS, ANKISTRODESMUS FALCATUS AND MICROCYSTIS SPECIES. THE BIOCONCENTRATION FACTORS VARIED WITH SPECIES, WHETHER THEY WERE EXPRESSED IN TERMS OF CELL NUMBER, DRY WT, CELLULAR C, OR CELLULAR LIPID, THE FACTORS WERE IN RANGE OF 105-106 AND INCREASED WITH DECREASING BIOMASS. SURFACE ADSORPTION APPARENTLY CONTRIBUTED ONLY SLIGHTLY TO BIOACCUMULATION OF 2,4,5-HCB. 2,4,5-HCB DESORBED FROM ALL SPECIES BUT AT A MUCH SLOWER RATE THAN ITS ADSORPTION. [R79] PFAC: ANIMAL CONCENTRATIONS: *A PCB CONCN OF 3608 PPM WAS FOUND IN FAT FROM SNAPPING TURTLE COLLECTED FROM UPPER HUDSON RIVER (HIGH POLLUTION LEVEL). THIS TURTLE REFLECTS THE HIGH PCB LEVELS FOUND IN THE REGION AS COMPARED TO THE 633 PPM PCB LEVEL FOUND IN FAT FROM SNAPPING TURTLE FROM LAKE ONTARIO (LOW POLLUTION LEVEL). 2,2'4,4'5,5'-HEXACHLOROBIPHENYL WAS THE MOST COMMON PCB FOUND IN BOTH TURTLES. [R80] MILK: *... The percent found in human milk extract was 12 ... [R81] BODY: *... The percent found in human milk extract was 12. ... [R81] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers chlorodiphenyl containing 54% chlorine to be a potential occupational carcinogen. /Aroclor 1254/ [R82] NREC: *NIOSH considers chlorodiphenyl containing 54% chlorine to be a potential occupational carcinogen. /Aroclor 1254/ [R82] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. /Aroclor 1254/ [R82] *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.001 mg/cu m. /Aroclor 1254/ [R82] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *High resolution capillary gas chromatography was performed by using a gas chromatograph equipped with a (63)Ni electron capture detector. A 50 m coated fused silica capillary column was used to separate the polychlorinated biphenyls (PCB) isomers and congeners. The oven temperature was programmed at a rate of 1.0 deg/min from 100 to 240 deg C. The injector and detector temperatures were 270 and 330 deg, respectively. [R81] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: ALVARES AP ET AL; NATL RES COUNC CAN, (REP) NRCC/CNRC 18978, WORKSHOP COMB EFF XENOBIOTICS, 127-49 (1982). REVIEW ON ENZYME INDUCTIVE PROPERTIES OF PCBS. /POLYCHLORINATED BIPHENYLS/ TSCA CHIPs present a preliminary assessment of polychlorinated biphenyl's potential for injury to human health and the environment (available at EPA's TSCA Assistance Office: (202) 554-1404 or (800) 424-9065) /Polychlorinated biphenyls/ TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for 2,2',4,4',5,5'-hexachlorobiphenyl is in progress. Route: gavage; Species: toxic equivalency factor evaluation, rats. [R83] SO: R1: MULLIN MD ET AL; ENVIRON SCI TECHNOL 18 (6): 468-476 (1984) R2: ALBRO PW ET AL; J CHROMATOG 205: 103-11 (1981) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 844 R4: Safe S et al; J Agric Food Chem 33:24-9 (1985) R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 87/8609 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V18 50 (1978) R7: American Conference of Governmental Industrial Hygienists. TLV's Threshold Limit Values for Chemical Substances and Physical Agents in the Work Environment with Intended Changes for 1983-84. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1983.1753 R8: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-53 R9: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R10: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V18 52 (1978) R12: 49 CFR 171.2 (7/1/99) R13: IATA. Dangerous Goods Regulations. 40th Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 1999. 196 R14: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.9034 (1998) R15: Lafornara JP; WPCF J 50 (4): 617 (1978) R16: JONES CJ ET AL; J HAZARD MATER 2 (3): 291-5 (1978) R17: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R18: Edwards BH et al; J Haz Mater 12 (2): 201-5 (1985) R19: Kling D et al; Environ Res 34 (1): 87-102 (1984) R20: BIOCCA M ET AL; TOXICOL APPL PHARMACOL 58 (3): 461-74 (1981) R21: LUCIER GW, MCDANIEL OS; ANN NY ACAD SCI 320: 449-57 (1979) R22: VOS JG, NOTENBOOM-RAM E; TOXICOL APPL PHARMACOL 23 (4): 563-78 (1972) R23: BRUNSTROEM B ET AL; ACTA PHARMACOL TOXICOL 50 (2): 100-3 (1982) R24: NAGATA K ET AL; J PHARMACOBIO-DYN 4 (5): S-64 (1981) R25: Hedman C et al; Environ Res 38: 293-300 (1985) R26: GOLDSTEIN JA ET AL; CHEM-BIOL INTERACT VOL 17 (1): 69-87 (1977) R27: Aulerich RJ et al; J Toxicol Environ Health 15 (1): 63-79 (1985) R28: Azais V et al; Chemosphere 15 (9-12): 1905-8 (1986) R29: Bannister R, Safe S; Toxicol 44 (2): 159-69 (1987) R30: Buchmann A et al; Cancer Lett 32 (3): 243-53 (1986) R31: Hayes MA et al; Toxicol Appl Pharmacol 76 (1): 118-27 (1984) R32: Hedman C et al; Environ Res 38 (2): 293-300 (1985) R33: Spindler-Vomachka M et al; Toxicol Appl Pharm 74 (1): 70-7 (1984) R34: Shara MA, Stohs SJ; Arch Environ Contam Toxicol 16: 599-605 R35: USEPA, Office of Drinking Water; Criteria Document (Draft): Polychlorinated Biphenyls p.V-4 (1985) EPA-600/X-84-198-2 R36: JONDORF WR ET AL; DRUG METAB DISPOS 11 (6): 597-601 (1983) R37: BECKER MM, GAMBLE W; J TOXICOL ENVIRON HEALTH 9 (2): 225-34 (1982) R38: IARC. 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V18 73 (1978) R39: BERGMAN A ET AL; CHEMOSPHERE 11 (3): 249-54 (1982) R40: BIRNBAUM LS; TOXICOL APPL PHARMACOL 70 (2): 262-72 (1983) R41: VODICNIK MJ, LECH JJ; TOXICOL APPL PHARMACOL 54 (2): 293-300 (1980) R42: SIPES IG ET AL; TOXICOL APPL PHARMACOL 65 (2): 264-72 (1982) R43: MALIWAL BP, GUTHRIE FE; J LIPID RES 23 (3): 474-9 (1982) R44: BROYLES RH, NOVECK MI; TOXICOL APPL PHARMACOL 50 (2): 299-308 (1979) R45: HANSEN LG ET AL; J AGRIC FOOD CHEM 31 (2): 254-60 (1983) R46: AHOTUPA M, MANTYLA E; MOL PHARMACOL 24 (3): 464-70 (1983) R47: LYNCH TR, JOHNSON HE; ASTM SPEC TECH PUBL 766 (AQUAT TOXICOL HAZARD ASSESS): 273-87 (1982) R48: WOLFF MS ET AL; TOXICOL APPL PHARMACOL 62 (2): 294-306 (1982) R49: Beranek SR et al; Environ Research 34 (1): 103-9 (1984) R50: Lutz RJ et al; Drug Metab Dispos 12 (5): 527-35 (1984) R51: Mangelsdorf I et al; Biochem Pharmacol 36 (13): 2071-8 (1987) R52: Paterson S, Mackay D; Environ Toxicol Chem 6 (5): 395-408 (1987) R53: Vickers AE M et al; Biochem Pharmacol 35 (2): 297-306 (1986) R54: Wyss PA et al; Drug Metab Dispos 14 (3): 361-5 (1986) R55: Gallenberg LA, Vodicnik MJ; Drug Metab Dispos 15 (3): 363-6 (1987) R56: Hebert CD, Birnbaum LS; Toxicol Lett 37 (1): 47-55 (1987) R57: Matthews HB, Dedrick RL; Annual Rev Pharmacol Toxicol 24: 85-103 (1984) R58: Ryerson BA et al; Fund Appl Toxicol 4 (1): 120-4 (1984) R59: WHO; Environ Health Criteria 140: Polychlorniated Biphenyls and Terphenyls p.226 (1993) R60: WHO; Environ Health Criteria 140: Polychlorniated Biphenyls and Terphenyls p.230 (1993) R61: WHO; Environ Health Criteria 140: Polychlorniated Biphenyls and Terphenyls p.238 (1993) R62: SCHNELLMANN RG ET AL; BIOCHEM PHARMACOL 32 (21): 3233-9 (1983) R63: IARC. 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NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 64 R83: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 60 Record 245 of 1119 in HSDB (through 2003/06) AN: 4011 UD: 200301 RD: Reviewed by SRP on 6/15/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HEXACHLOROCYCLOPENTADIENE- SY: *C-56-; *1,3-CYCLOPENTADIENE,-1,2,3,4,5,5-HEXACHLORO-; *GRAPHLOX-; *HCCP-; *HCCPD-; *Hex-; *HEXACHLORCYKLOPENTADIEN- (CZECH); *Hexachloropentadiene-; *HRS-1655-; *NCI-C55607-; *PCL-; *PERCHLOROCYCLOPENTADIENE- RN: 77-47-4 MF: *C5-Cl6 SHPN: UN 2646; Hexachlorocyclopentadiene IMO 6.1; Hexachlorocyclopentadiene STCC: 49 330 15; Hexachlorocyclopentadiene HAZN: U130; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CHLORINATION OF CYCLOPENTADIENE, FOLLOWED BY CATALYTIC CHLORINATION OVER PHOSPHORUS PENTACHLORIDE OR ARSENIC OXIDE, THEN THERMAL DECHLORINATION. [R1] *Freshly prepared cyclopentadiene is mixed with about 6-10 moles of alkaline hypochlorite solution per mole of cyclopentadiene using vigorous agitation at 40 deg C. The hexachlorocyclopentadiene is recovered by fractional distillation ... the maximum yield of hexachlorocyclopentadiene was 75%. [R2] *Liquid phase chlorination of pentane to form polychloropentanes. Then, vapor phase chlorination and ring closure using a porous surface active inorganic catalyst. ... A similar process was patented in the USSR in 1957 using tetrachloropentene as the feed. [R3] IMP: *Technical grade Hex usually contains other chemicals as contaminants of manufacture (eg, hexachlorobenzene and octachlorocyclopentene). The nature and levels of contaminants will vary with the method of production. [R4] FORM: *GRADES: TECHNICAL [R5] MFS: *Velsicol Chemical Corp, Hq, 5600 N River Rd, Rosemont, IL 60018-5119, (312) 698-9700; Production site: 1199 Warford St, Memphis, TN 38103 [R6] OMIN: *... Technical chlordane has contained ... hexachlorocyclopentadiene ... /as impurity/. [R7] USE: *Intermediate for many insecticides, polyester resins, and flame retardants. [R8] *Intermediate for resins, dyes, pharmaceuticals. [R5] */Used to make/ shock proof plastics, acids, esters, ketones, and fluorocarbons. [R9] CPAT: *ESSENTIALLY 100% AS A CHEMICAL INTERMEDIATE [R1] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 4.54X10+6 G [R1] *(1982) PROBABLY GREATER THAN 2.27X10+6 G [R1] U.S. IMPORTS: *(1977) AT LEAST 4.54X10+6 G [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW GREEN LIQUID [R10]; *Dense, oily liquid [R11]; +Pale-yellow to amber-colored liquid. [R12, 158] ODOR: *Pungent odor [R5]; +Pungent, unpleasant odor. [R12, 158] BP: *239 DEG C AT 753 MM HG [R10] MP: *-9 DEG C [R10] MW: *272.77 [R10] CORR: *In presence of moisture, will corrode iron and other metals. [R13] DEN: *1.7019 AT 25 DEG C/4 DEG C [R10] HTV: *1.8X10+5 J/kg (est) [R13] OWPC: *log Kow= 3.99 [R14, p. 57-2] SOL: *2 ppm at 25 deg C. [R15]; *Soluble in all proportions in acetone, carbon tetrachloride, methanol and hexane. [R15] SPEC: *INDEX OF REFRACTION: 1.5658 AT 20 DEG C/D [R16]; *MAX ABSORPTION (HEPTANE): 323 NM (LOG E= 3.2) [R17]; *Intense mass spectral peaks: 237 m/z (100%), 239 m/z (64%), 235 m/z (63%), 95 m/z (41%) [R18]; *IR: 1918 (Coblentz Society Spectral Collection) [R19]; *UV: 5-25 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R19]; *NMR: 102 (Johnson and Jankowski, Carbon-13 NMR Spectra, John Wiley and Sons, New York) [R19]; *MASS: 1947 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R19] SURF: *37.5 dynes/cm= 0.0375 N/m @ 20 deg C [R13] VAPD: *9.4 (AIR= 1) [R20, 3749] VAP: *0.080 MM HG AT 25 DEG C; 1 MM HG AT 60 DEG C [R20, 3749] OCPP: *Henry's Law constant= 2.7X10-2 atm-cu m/mol at 25 deg C (measured) [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R22, p. G-151] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. [R22, p. G-151] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R22, p. G-151] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R22, p. G-151] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R22, p. G-151] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. [R22, p. G-151] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R22, p. G-151] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R22, p. G-151] +Initial Isolation and Protective Action Distances: Small Spills (from a small package or small leak from a large package): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.2 kilometers (0.1 miles) and NIGHT 0.2 kilometers (0.1 miles). LARGE SPILLS (from a large package or from many small packages): First, ISOLATE in all Directions 30 meters (100 feet); then, PROTECT persons Downwind during DAY 0.3 kilometers (0.2 miles) and NIGHT 0.3 kilometers (0.2 miles). [R22, p. TABLE] FPOT: *Nonflammable [R8] FIRP: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire (material itself does not burn or burns with difficulty). Use water spray to knock-down vapors. If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock down vapors. [R23] TOXC: *Toxic hydrogen chloride, chlorine, and phosgene gases may form in fires. [R13] OFHZ: *If water is used on adjacent fires, do not allow water to enter drums or storage tanks. [R13] EXPL: *In presence of moisture explosive hydrogen gas may collect in enclosed space. [R13] REAC: *Reacts slowly with water to form hydrochloric acid. [R13] +Water, light [Note: Reacts slowly with water to form hydrochloric acid; will corrode iron and most metals in presence of moisture. Explosive hydrogen gas may collect in enclosed spaces in the presence of moisture]. [R12, 158] ODRT: *0.15 ppm or 1.7 mg/cu m [R15] *Odor low: 1.5 mg/cu m; Odor high: 3.3 mg/cu m [R24] SERI: *Inhalation of mist is highly irritating to mucous membranes, causing lacrimation, sneezing and salivation. Contact with eye causes severe irritation. Liquid is extremely irritating to skin ... [R13] EQUP: *Protective clothing, including rubber gloves and rubber shoes or boots, self-contained breathing apparatus, face shield. [R13] *Self-contained air-masks or full face canister gas masks of the acid gases and organic vapors type should be available at all times. [R25, (1979)] +Wear appropriate personal protective clothing to prevent skin contact. [R12, 158] +Wear appropriate eye protection to prevent eye contact. [R12, 158] +Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R12, 158] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R12, 158] OPRM: *Avoid breathing vapors. Keep upwind. Avoid bodily contact with the material. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R23] *Adequate ventilation should be provided when HCCP is handled in a closed area. [R25] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +Contact lenses should not be worn when working with this chemical. [R12, 158] +The worker should immediately wash the skin when it becomes contaminated. [R12, 158] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R12, 158] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R26] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R27] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R28] CLUP: *Environmental considerations. Land spill: Dig a pit, pond, lagoon, holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Cover solids with a plastic sheet to prevent dissolving in rain or fire fighting water. Absorb bulk liquid with fly ash or cement powder. [R23] *Environmental considerations. Water spill: Use natural deep water pockets, excavated lagoons or sand bag barriers to trap material at bottom. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R23] *Environmental considerations. Air spill: Apply water spray or mist to knock down vapors. [R23] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U130, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R29] *A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R30] *The following wastewater treatment technology have been investigated for hexachlorocyclopentadiene: Concentration process: Stripping. [R31] *Recommendable Treatment and Disposable Methods: Incineration. Incineration after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. [R32] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Inadequate data in humans and no data in animals concerning carcinogenicity of hexachlorocyclopentadiene. HUMAN CARCINOGENICITY DATA: Inadequate. [R33] +A4; Not classifiable as a human carcinogen. [R34, 2002.35] HTOX: */Hexachlorocyclopentadiene is a/ ... potent irritant. Industrial workers have experienced irritation of the eye, irritation of the upper airway passages and headaches upon exposure to /its/ vapors and burns upon contact of skin with the liquid. [R11] NTOX: *... IN MICE EXPOSED EXPERIMENTALLY TO VAPORS HAS CAUSED "APPARENT BLINDNESS". [R35] *APPROX LETHAL DOSE FOR RATS AND RABBITS BY SINGLE ORAL ADMIN OF 93.3% PURE COMPOUND WAS BETWEEN 420 and 620 MG/KG. THE ANIMALS SHOWED DIARRHEA, LETHARGY, and ... /DECREASED/ RESPIRATION. RABBITS SHOWED DIFFUSE DEGENERATIVE CHANGES IN BRAIN, HEART, LIVER, AND ADRENALS, NECROSIS OF THE EPITHELIUM OF RENAL TUBULES, AND SEVERE HYPEREMIA AND EDEMA OF LUNGS. ... BY SKIN ABSORPTION, THE LETHAL DOSE IN RABBITS LIES BETWEEN 430 and 610 MG/KG. THE MATERIAL WAS EXTREMELY IRRITATING. [R20, 3750] *FOUR ANIMAL SPECIES DIED WHEN THEY INHALED VAPORS OF 89.5% HEXACHLOROCYCLOPENTADIENE IN THE FOLLOWING CONCN AND FOR THE FOLLOWING PERIODS: RABBITS- 1.5 PPM (15.9 MG/CU M) FOR 7 HR; MICE- 1.4 PPM (15.2 MG/CU M) FOR THREE 7-HR PERIODS; RATS- 1.0 PPM (10.9 MG/CU M) FOR FIVE 7-HR PERIODS OR 3.2 PPM (35.1 MG/CU M) FOR TWO 7-HR PERIODS; GUINEA PIGS- 3.2 PPM FOR TWO 7-HR PERIODS. RABBITS, RATS AND GUINEA PIGS SURVIVED EXPOSURES AT 0.15 PPM (1.7 MG/CU M) FOR 7 HR ON EACH OF 150 DAYS OVER A PERIOD OF 216 DAYS, BUT 4 OF 5 MICE DIED DURING THE PROLONGED INTERMITTENT EXPOSURE. WHEN EXPOSURE CONCN WAS ESSENTIALLY DOUBLED, IE, AT 0.34 PPM FOR 7 HR/DAY ON EACH OF 5 DAYS/WK, NONE OF THE MICE OR RATS SURVIVED 20 EXPOSURES; 4 OF 6 RABBITS DIED BY 25TH EXPOSURE, WHILE GUINEA PIGS SURVIVED THE ENTIRE 30 EXPOSURES. [R15] *EXPOSURE TO HEXACHLOROCYCLOPENTADIENE VAPORS CAUSED LACRIMATION, SALIVATION AND GASPING RESPIRATION, AND AT HIGH CONCN, TREMORS. DIFFUSE DEGENERATIVE CHANGES WERE OBSERVED IN THE BRAIN, HEART, LIVER, ADRENAL GLANDS AND KIDNEYS. SEVERE PULMONARY EDEMA AND HYPEREMIA AND ACUTE NECROTIZING BRONCHITIS AND BRONCHIOLITIS DEMONSTRATED THE SEVERITY OF IRRITATION WITH INCIDENCE AND SEVERITY DEPENDENT ON DOSE. EVEN AT LOWEST CONCN (0.15 PPM), THERE WERE SOME DEGENERATIVE CHANGE IN LIVER AND KIDNEYS OF ALL SPECIES AND MICROSCOPIC EVIDENCE OF PULMONARY IRRITATION IN MICE. [R15] *HEXACHLOROCYCLOPENTADIENE WAS NOT MUTAGENIC IN AN IN VITRO TEST SYSTEM COMPRISING MOUSE LIVER MICROSOMES FOR METABOLIC ACTIVATION AND ESCHERICHIA COLI K12 (343/113). [R36] *WHEN INCUBATED WITH MOUSE LIVER MICROSOMES, HEXACHLOROCYCLOPENTADIENE WAS NONMUTAGENIC IN SALMONELLA TYPHIMURIUM AND ESCHERICHIA COLI. [R37] *... Pregnant mice and rabbits ... /admin by gavage/ up to 75 mg/kg/day during active organogenesis and ... no teratogenic effects /were observed/. [R38] *Acclimated normal rainbow trout were exposed to 130 ppb hexachlorocyclopentadiene in a flow through well water circuit which was designed to permit measurements of oxygen consumption by the fish. Compared to pre-hexachlorocyclopentadiene values, hexachlorocyclopentadiene increased oxygen consumption rates by 186 + or - 24%, with maximum oxygen consumption rates being reached in 84 min after hexachlorocyclopentadiene exposure. Oxygen consumption subsequently decreased, and all hexachlorocyclopentadiene exposed fish died within 6.5 hr of exposure. Fish exposed to hexachlorocyclopentadiene free vehicle (acetone) showed no changes of oxygen consumption. When added to normal isolated trout heart mitochondria, hexachlorocyclopentadiene appeared to uncouple oxidative phosphorylation, with calculated respiratory control ratios being decreased 50% from control values at a hexachlorocyclopentadiene concn of 0.41 umole. [R39] *Inhalation studies on toxicity of high purity hexachlorocyclopentadiene (97.7%) in rats and monkeys were conducted to provide information on the potential hazards of accidental exposure of workers to vapors. Acute, range finding (14 day) and subchronic (90 day) inhalation studies were conducted with Sprague-Dawley rats and subchronic (90 day) inhalation studies were conducted with monkeys. Both acute and range finding studies with rats showed a steep dose response curve, and male rats were more sensitive than females. In the range finding study with rats the threshold of toxicity was 0.11-0.5 ppm. Histopathologic exam on rats in the 0.5 ppm group showed lesions in the olfactory and bronchiolar epithelium as well as inflammatory exudate in the lumens of the respiratory tract; these changes were consistent with observed impaired respiratory function, confirming the lung as the main target organ. In the 90 day study, inhalation of 0.2 ppm for 6 hr/day 5 days/wk, produced no detectable physical or clinical effect and no remarkable gross or histological alterations in rats or monkeys. [R40] *Toxicity of hexachlorocyclopentadiene was studied in rats and mice. F344 rats and B6C3F1 mice were exposed to the chemical by gavage at 0 to 150 mg/kg and at 0 to 300 mg/kg, respectively. A dose related decrease in mean body weight gain occurred in both sexes of rats and mice. Male rats in the 150 mg/kg dose group and one in 75 mg/kg group died after exposure. All mice exposed to HCCP at 300 mg/kg died. Liver/brain weight ratios were significantly increased in the 38, 75, and 150 mg/kg exposed groups of female rats and the kidney/brain weight ratios in females significantly increased after 75 and 150 mg/kg exposure. No significant difference in relative weight of other organs was observed. In female mice, the kidney/brain weight ratios were significantly increased at all doses and the lung/brain weight increased after exposure at 300 mg/kg dose. Clinical signs, foci of discoloration, cysts and ulceration were seen after exposure. Histopathologically, lesions in the stomach, inflammation in the submucosa, edema, neovascularization and hyperplasia were noted. Toxic nephrosis of the kidney and acute tubular necrosis were also seen. /It was/ concluded that exposure to HCCP causes overt signs of toxicity in rats and mice. [R41] +... CONCLUSIONS: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of hexachlorocyclopentadiene in male or female F344/N rats or B6C3F1 mice exposed to 0.01, 0.05, or 0.2 ppm. [R42] NTXV: *LD50 Albino Rat oral 300-630 mg/kg; [R25, (1979)] ETXV: *LC50 FATHEAD MINNOWS, EARLY JUVENILE, 6.7 UG/L/30 DAYS /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R43] *LC50 FATHEAD MINNOWS, LARVAL, 7.0 UG/L/96 HR /CONDITIONS OF BIOASSAY NOT SPECIFIED/; [R43] NTP: +... Toxicology and carcinogenesis studies were conducted by exposing male and female F344/N rats and B6C3F1 mice to atmospheres containing hexachlorocyclopentadiene (approximately 98% pure) for 6 hr/day, 5 days/wk, for ... 2 yr. ... 2 YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were exposed to atmospheres containing 0, 0.01, 0.05, or 0.2 ppm (equivalent to 0, 0.11, 0.56, and 2.28 mg/cu m) hexachlorocyclopentadiene. ... 2 YEAR STUDY IN MICE: ... Groups of 60 male and 60 female mice were exposed to atmospheres containing 0, 0.01, 0.05, or 0.2 ppm (equivalent to 0, 0.11, 0.56, and 2.28 mg/cu m) hexachlorocyclopentadiene. ... CONCLUSIONS: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of hexachlorocyclopentadiene in male or female F344/N rats or B6C3F1 mice exposed to 0.01, 0.05, or 0.2 ppm. [R42] TCAT: ?Chronic toxicity was evaluated in groups of male and female Wistar rats (18/sex/group) exposed by inhalation 6 hrs/day, 5 days/week to 0, 0.05, 0.1 or 0.5 ppm hexachlorocyclopentadiene (90 - 96% purity) for 30 weeks. Immediately following exposure, males in the high and medium exposure groups had statistically significantly higher mean erythrocyte counts, haemoglobin concentration, haematocrits and absolute neutrophils, and significantly lower mean absolute lymphocytes. No atypical cells were observed in blood films of either sex. Females in the medium exposure group had a significantly reduced level of alkaline phosphatase in the blood when compared to controls. Urine analysis did not show any changes that could be attributed to exposure. Kidney weights were significantly increased in females in the high exposure group. Following exposure, and after a 14 week recovery period, significant effects were observed on heart, spleen, and testes weights in males but these were not considered to be biologically significant by the investigators. Following termination of exposure, animals at the high dose level exhibited pulmonary degenerative changes; additionally, mild degenerative changes were seen in the liver and kidney of some high exposure rats. [R44] ?Subchronic toxicity was determined in male and female B6C3F1 mice exposed by gavage to hexachlorocyclopentadiene. Twenty animals per group (10 male and 10 female) received single daily doses of hexachlorocyclopentadiene (94-97% purity) in corn oil at 300,150,75, 38 or 19 mg/kg, 5 days a week for 13 consecutive weeks. No statistically significant effect on organ weight was observed for the kidneys, thymus, heart, brain or lungs of either sex. A statistically significant dose related increase in liver to body weight ratios in female animals was observed. Histopathology was performed on all groups; pathology was observed in kidneys of female mice at doses greater than 38 mg/kg, and in forestomachs of mice of both sexes at doses greater than 19 mg/kg. No pathology in kidneys of males was observed at any dose level. [R45] ?Subchronic toxicity was determined in male and female Fischer-344 rats exposed by gavage to hexachlorocyclopentadiene. Twenty animals per group (10 male and 10 female) received single daily doses of hexachlorocyclopentadiene (94-97% purity) in corn oil at 150,75,38 19 or 10 mg/kg, 5 days/week for 13 consecutive weeks. Analysis of organ to body weight and organ to brain weight ratios was performed for all groups except the 150 mg/kg group, where high mortality was observed. Minor changes in liver, thymus, heart and lung weight ratios were observed but judged not to be significant due to the inconsistency of the data. A statistically significant slight enlargement of the kidneys in females treated at 75 mg/kg was observed; males at this dose level showed kidney enlargement only if the data were expressed as the kidney to body weight ratio. Histopathology was performed on all groups. Pathology was observed in the kidneys of males and females and in the forestomachs of males receiving daily doses greater than 19 mg/kg. Pathology was observed in the forestomachs of females receiving doses greater than 10 mg/kg. [R46] ?Chronic toxicity was evaluated in male and female Wistar rats (18/sex/group) exposed to nominal concentrations of 0, 0.05, 0.1 and 0.5 ppm hexachlorocyclopentadiene for 6 hrs/day, 5 days/week for 30 weeks. Animals in the high-dose groups were sneezing and lethargic and 4 males and 2 females died during exposure. There were significant increases observed in the treated animals versus controls in the following: mean erythrocyte counts, hemoglobin concentration, hematocrit and absolute numbers of neutrophils (males at 0.5 and 0.1 ppm), pulmonary degenerative changes ranging from epithelial hyperplasia, to edema and sloughing of the bronchiolar epithelium (both sexes at 0.5 ppm), epithelial ulceration and necrosis (males at 0.5 ppm), kidney weights (females at 0.5 ppm), and testes weights (males at 0.5 and 0.1 ppm). There were significant decreases in the following: body weights (males at 0.5 ppm and females at 0.5 and 0.1 ppm), percentage lymphocyte counts (males at 0.5 and 0.1 ppm), mean absolute numbers of lymphocytes (females at 0.5 ppm), heart weight (males at 0.5 ppm) and spleen weight (males at 0.5 and 0.2 ppm). Mild degenerative changes were observed in the liver and kidney of some high exposure group rats after 30 weeks. There were no significant effects reported in the urinalysis results. [R47] ?The disposition of hexachlorocyclopentadiene (HCCP) was evaluated in male Fischer 344 rats administered 14C-HCCP by oral gavage, by intravenous injection or inhalation. The doses employed for the gavage study were approximately 0.01 of the LD50, 4.1mg/kg (low dose) or 0.1 of the LD50, 61mg/kg (high dose) and 0.59mg/kg for the intravenous study. After oral and intravenous exposures, animals (numbers not reported) were placed in Roth metabolism cages for 3 days. The calculated average dose of the animals exposed by inhalation for two hours in metabolism cages and sacrificed after six hours post-treatment was 1.4mg/kg, while 1.0mg/kg was the dose in the 72 hour post-treatment group. Despite the route of administration, the majority of the radioactivity was excreted in the urine and feces within 72, with only small amounts eliminated as exhaled carbon dioxide or volatile compounds. The elimination after low and high oral doses were similar and some of the radioactivity in feces was volatile. After inhalation of 14C-HCCP, rats retain a considerable portion as non-extractable radioactivity in the lung tissue. [R48] ?The effect of hexachlorocyclopentadiene (HCCP) was examined in the rat primary culture/DNA repair assay. Based on preliminary toxicity tests, HCCP was tested at 8 concentrations ranging from 1x10(-8)% to 1x10(-4)% (v/v). Concentrations of 1x10(-4)% and 5x10(-5)% were cytotoxic and the highest concentration for which data were obtained was 1x10(-5)%. The test compound is reported positive when the minimum net grain count of 5 per nucleus is consistently observed in triplicate coverslips throughout the experiment. The mean net nuclear grain counts on the slides exposed at 1x10(-5)% and lower did not exceed 5. The counts on the solvent (DMSO) and medium controls were 0.9 (+/-1.6) and 0, respectively. HCCP was concluded to not be genotoxic to the hepatocytes in this assay. [R49] ADE: *RATS GIVEN 6 MG/KG HEXACHLOROCYCLOPENTADIENE ORALLY EXCRETED 33% IN URINE, 10% IN FECES IN 7 DAYS. MOST EXCRETION OCCURRED DURING 1ST 24 HR AFTER DOSING. KIDNEY RETAINED 0.5%, LIVER GREATER THAN 0.5%. BILIARY EXCRETION OF ONLY 16% WITH 66% STILL VOIDED IN THE FECES OF BILE DUCT CANNULATED RATS SUGGESTED THAT THE MAJORITY OF ORALLY CONSUMED HEX WAS NOT ABSORBED. DEGRADATION APPARENTLY OCCURRED IN THE GUT SINCE LITTLE OF THE FECAL MATERIAL WAS OF AN APOLAR NATURE. THE KIDNEY, LIVER, OVARIES AD FAT WERE THE MAJOR SITES OF DEPOSITION OF (14)C-HEX EQUIVALENTS. IN RATS, THE KIDNEY CONTAINED THE HIGHEST LEVELS OF RESIDUES, WHEREAS IN MICE THE RESIDUES IN THE LIVER EXCEEDED THOSE IN THE KIDNEY. OTHER THAN THIS DIFFERENCE, THE FATE OF HEX IN RATS AND MICE, BOTH MALE AND FEMALE, WAS QUITE SIMILAR AND IN EACH CASE THE TISSUE RESIDUES REACHED A PLATEAU AFTER ABOUT TWO WEEKS ON THE HEX-CONTAINING DIETS. [R50] *Studies were conducted to determine the fate and retention time of (14)C-hexachlorocyclopentadiene in rats. The test animals were either exposed to (14)C-hexachlorocyclopentadiene vapors for single 1 hr periods, or dosed orally with (14)C-hexachlorocyclopentadiene in corn oil. Tissue, urine, and feces samples were analyzed, as well as expired air, to assess the fate and retention time. Approx 84% of the inhaled cmpd is retained. Inhaled (14)C-hexachlorocyclopentadiene excreted in the urine; orally administered (14)C-hexachlorocyclopentadiene eliminated in the feces. In rats exposed by inhalation, the trachea and lung had the highest residue accumulation. In animals receiving oral doses kidneys and liver were major sites of accumulation. These studies indicate that the route of exposure is critical to the pattern of retention and elimination. [R51] *The differential disposition of hexachlorocyclopentadiene (C56) following oral administration, as contrasted to inhalation or iv administration, may account for its lower toxicity by this route. After iv dose of (14)C labeled C56 to rats at 0.59 mg/kg, 39% of the radioactivity remained in the tissues at 72 hr; after inhalation of vapors of (14)C C56 (1.3-1.8 mg/kg), this amount was 11.5%. After oral doses of 4.1 or 61 mg/kg, the amount was only 2.4%. [R52] *(14)C-Hexachlorocyclopentadiene (HEX, C56) was administered as a single oral dose (2.5 and 25 mg/kg) as a component of the diet (1, 5 and 25 ppm) for a maximum of 30 days. Route of excretion was via the feces (-70% of dose) with low elimination in the urine (approximately 15%). Biliary excretion of only 16% still voided in the feces of bile duct cannulated rats suggested that the majority of orally consumed HEX was not absorbed. Degradation apparently occurred in the gut since little of the fecal material was of an apolar nature. The kidney, liver, ovaries and fat were the major sites of deposition of (14)C-HEX equivalents. In rats, the kidney contained the highest levels of residues, whereas in mice the residues in the liver exceeded those in the kidney. Other than this difference, the fate of HEX in rats and mice, both male and female, was quite similar and in each case the tissue residues reached a plateau after about two weeks on the HEX-containing diets. [R53] *Fate of hexachlorocyclopentadiene was studied in freshwater fish using in vivo and in vitro systems. Hexachlorocyclopentadiene injected ip into goldfish is readily distributed, stored, and metabolized (> 11 organosoluble and hydrophilic metabolites). The body radioactivity in tissues declines, but levels in bile remain high, indicating biliary excretion as a major route of elimination for hexachlorocyclopentadiene and its metabolites. Total radioactivity eliminated in water indicated three phases with a calculated half life of 7 days and predicted 90 and 95% clearance of 162 and 211 days, respectively. A 3 segment straight line model gave the best fit of the elimination and one reabsorption phase. For a static system, two phases of elimination were detected with a calculated half life of 9 days and predicted 90 and 95% clearance of 77 and 107 days, respectively. A compartmental model indicated that one elimination and one reabsorption phase were involved. [R54] METB: *Hexachlorocyclopentadiene underwent chemical alterations in water forming both lipophilic and hydrophilic products. The lipophilic nonpolar products in fish were extremely volatile. Three days after the ip injection of (14)C hexachlorocyclopentadiene, the ethyl acetate extractable radioactivity was approx 47% while water solubles and unextractables were 11 and 20% of the injected radioactivity, respectively. Ethyl acetate extracts of fish included at least 8 unidentified breakdown products. Water solubles from fish included at least 4 unidentified products. [R55] BHL: *Its half-life was approx 9 days in goldfish. [R55] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Potential sources of release of hexachlorocyclopentadiene are emissions and effluent discharges from: those facilities which manufacture or use this compound as an intermediate; application and disposal of contaminated pesticides; and emissions from the combustion of certain chlorinated wastes. Hexachlorocyclopentadiene is not a persistent environmental contaminant. If released to soil, hexachlorocyclopentadiene is predicted to be relatively immobile. Hexachlorocyclopentadiene has the potential to photolyze on soil surfaces. Volatilization from soil surfaces is expected to be dependent upon organic carbon content. In moist soil, this compound would be subject to chemical hydrolysis (half-life hours to weeks) and biodegradation. If released to water, this compound will degrade primarily by photolysis and chemical hydrolysis. During daylight hours, in clear shallow water, the photolytic half-life is expected to be on the order of 2-8.5 minutes. 2,3,4,4,5-Pentachloro-2-cyclopentenone, hexachloro-2-cyclopentenone, and hexachloro-3-cyclopentenone have been identified as primary photodegradation products. In unlit or deep, turbid water, chemical hydrolysis is expected to be an important fate process. Hydrolytic half-lives range from several hours to 2-3 weeks in waters with temperature in the range of 20-30 deg C. Hexachlorocyclopentadiene has the potential to adsorb extensively to suspended solids and sediments; nevertheless, adsorption does not significantly affect the rate of hydrolysis. Volatilization from water is expected to be a significant removal mechanism, although in highly turbid waters adsorption to suspended solids and sediments could substantially limit losses volatilization. The volatilization half-lives from a model river and a model pond with or without adsorption have been estimated to be 5 hours, 37 days and hours, respectively. Biodegradation is expected to be of minor importance. Hexachlorocyclopentadiene could potentially bioaccumulate in some aquatic organisms depending upon the species. If released to the atmosphere, this compound is expected to exist almost entirely in the vapor phase. In the atmosphere, direct photolysis is expected to be the dominant removal mechanism. Reaction with photochemically generated hydroxyl radicals, reaction with ozone molecules, washout, and dry deposition are not expected to be environmentally significant fate processes. Certain segments of the population may be exposed through ingestion of contaminated drinking water or contaminated fish. People living in the vicinity of hazardous waste disposal sites containing this compound may be exposed through inhalation of contaminated air. Workers involved in the manufacture or handling of this compound or treatment of wastes containing this compound could potentially be exposed by inhalation or dermal exposure. (SRC) ARTS: *Major sources of release of hexachlorocyclopentadiene to the environment are emissions and contaminated wastewater from facilities which manufacture or use this compound as a chemical intermediate(1). Small concentrations of hexachlorocyclopentadiene are occasionally present as impurities in the pesticides made from this compound and some hexachlorocyclopentadiene may enter via these pesticides(1). This compound has been identified as a combustion product in emissions from a waste incinerator(2). Emissions at an abandoned waste site in Michigan averaged 0.26 g/hr(3). Emissions of hexachlorocyclopentadiene in the U.S. during 1978 have been estimated to be 59,500 lb, 94% due to its manufacture and 6% due to its use(4). Estimated stationary source emissions of hexachlorocyclopentadiene into the atmosphere of the Netherlands during 1980 amount to 1.4 tons(5). [R56] FATE: *AQUATIC FATE: Hexachlorocyclopentadiene underwent chemical alterations in water forming both lipophilic and hydrophilic products. The water soluble substances included at least 11 unidentified breakdown products. [R55] *TERRESTRIAL FATE: If released to soil, hexachlorocyclopentadiene should be immobilized by strong adsorption to organic matter. Potential exists for significant losses via photolysis on soil surfaces. Below the soil surface, photolysis would not be a significant fate process due to light attenuation. Volatilization from soil surfaces is expected to be of minor importance. In moist soil, this compound would be subject to chemical hydrolysis (half-life hours to weeks) and biodegradation under aerobic and anaerobic conditions(SRC). Radiolabelled hexachlorocyclopentadiene at an initial concn of 1 mg/kg was added to soil contained in a glass flask covered with perforated aluminum foil and kept on a laboratory shelf which was exposed to sunlight. After 7 days incubation, recovery of nonpolar compounds (hexachlorocyclopentadiene and nonpolar metabolites) was 6.1% in unaltered, nonsterile soil (approx 72% was polar and nonextractable), approx 6% in nonsterile soil at pH 4, approx 9% in nonsterile soil at pH 8, 36.1% in autoclaved soil (33.5% was polar and nonextractable), approx 15% in sodium azide treated soil, and approx 3% in flooded soil. These data indicate that loss of hexachlorocyclopentadiene from soil is the result of abiotic and biotic degradation as well as partitioning within the media(1). [R57] *AQUATIC FATE: If released to water, hexachlorocyclopentadiene will degrade primarily by photolysis and chemical hydrolysis. During daylight hours, hexachlorocyclopentadiene found in clear, shallow water is expected to photodegrade with a half-life on the order of 2-8.5 minutes(1,2). 2,3,4,4,5-Pentachloro-2-cyclopentenone, hexachloro-2-cyclopentenone, and hexachloro-3-cyclopentenone have been identified as primary photodegradation products of hexachlorocyclopentadiene. In unlit or deep, turbid water, chemical hydrolysis is expected to be an important fate process. Hydrolytic half-lives ranging from several hours to 2-3 weeks are predicted for waters with temperatures in the range of 20-30 deg C(1,3-5). Hexachlorocyclopentadiene has the potential to adsorb extensively to suspended solids and sediments; nevertheless, adsorption does not significantly affect the rate of hydrolysis(1). Volatilization from water is expected to be a significant removal mechanism, although in highly turbid waters adsorption to suspended solids and sediments could substantially limit losses via volatilization. The volatilization half-lives from a model river and a model pond with and without adsorption have been estimated to be 5 hours, 37 days and 58 hours, respectively(6,7,SRC). It appears as though hexachlorocyclopentadiene may also be susceptible to biodegradation. Potential exists for bioaccumulation in some aquatic organisms depending upon the organism and the species(SRC). [R58] *ATMOSPHERIC FATE: Organic compounds having a vapor pressure of greater than 1X10-4 mm Hg at ambient temperature are expected to exist almost entirely in the vapor phase in the atmosphere(1). Hexachlorocyclopentadiene has a vapor pressure of 0.063 mm Hg at 25 deg C(2); therefore, it is expected to exist predominantly in the vapor phase in the atmosphere(SRC). If released to the atmosphere, direct photolysis is expected to be the dominant removal mechanism. Reaction of hexachlorocyclopentadiene with photochemically generated hydroxyl radicals or ozone molecules is predicted to be too slow to be environmentally significant. The relatively low water solubility of hexachlorocyclopentadiene, suggests that there is little potential for washout in precipitation(SRC). [R59] BIOD: *In a static-screening study, BOD dilution water containing nutrient broth, settled domestic wastewater as inoculum, initial hexachlorocyclopentadiene concn 5 and 10 mg/l, during a 7 day incubation period in the dark, 100% loss was observed(1). Based on hydrolytic half-life data for this compound, hydrolysis alone does not necessarily account for the 100% observed loss of hexachlorocyclopentadiene. Volatilization was reported to be insignificant. Thus, some of the observed loss may have been due to biodegradation(SRC). Hexachlorocyclopentadiene has been found to degrade more quickly in nonsterile soils than sterile soils, suggesting that degradation was partially due to biodegradation(2). [R60] ABIO: *(14)C labeled hexachlorocyclopentadiene was photolyzed rapidly when dissolved in water and irradiated with a mercury vapor light source. The photolytic half-life was less than 1.03 min. 2,3,4,4,5-Pentachlorocyclopentenone was tentatively identified as the primary photolysis product. After 10 min of irradiation, 44% of HEX radiocarbon equivalents were converted to water soluble photoproducts. Neither mirex nor kepone were detected as photoproducts. /Wavelength not specified/ [R61] *Hydrolysis of hexachlorocyclopentadiene has been found to be independent over the pH range 5 to 9(1,2). Using distilled water or tap water, the hydrolytic half-life has been determined to be 16.1 days at 22 deg C(3), 14 days at 25 deg C(1), and 5.3 days at 30 deg C(2). Measured hydrolysis rate constants for hexachlorocyclopentadiene in sediment suspensions at 30 deg C range from 1.3X10-4 to 3.24X10-3 l/min(2,4). These values correspond to hydrolytic half-lives ranging from 3.6 hours to 3.7 days. No hydrolysis products were identified; although, high molecular weight polyhydroxy compounds appeared to be the major products(5). [R62] *Rate constants for photolysis of hexachlorocyclopentadiene in distilled water and natural water samples exposed to midday sunlight during Nov-Dec in Athens, GA (latitude 34 deg N) were found to range between 3.8-19.9 l/hr and 4.9-19.7 l/hr, respectively(1). These values correspond to photolytic half-lives of 2-11 minutes for distilled water and 2-8.5 minutes for natural waters(SRC). These data indicate that suspended solids had little effect on photolysis rates as compared to photolysis rates in distilled water(1). As part of this same study photolysis of hexachlorocyclopentadiene on an overcast November day was found to be slightly slower in natural waters containing humic materials (half-life 8 minutes) compared to distilled water (half-life 6 minutes), probably due to light attenuation(1). Photolysis half-lives for hexachlorocyclopentadiene in tap water, natural water, and deionized water exposed to sunlight on a sunny day in Champaign, IL were < 4 minutes(2). 2,3,4,4,5-Pentachloro-2-cyclopentenone, hexachloro-2-cyclopentenone, and hexachloro-3-cyclopentenone were identified as primary photodegradation products, pentachloro-cis-2,4-pentadienoic acid, Z- and E-pentachlorobutadiene and tetrachlorobutyne were identified as secondary photodegradation products and hexachloroindenone was identified as a minor photodegradation product(2). [R63] *Hexachlorocyclopentadiene in cyclohexane strongly absorbs UV light in the environmentally significant range (wavelengths greater than 290 nm)(1). Strong absorption of UV light wavelength and observed rapid photolysis in aqueous solution suggest that direct photolysis would probably be the dominant removal process in the atmosphere and on soil surfaces. Hexachlorocyclopentadiene adsorbed onto silica gel, underwent 46.0% photomineralization when irradiated with UV light (> 290 nm) for 17 hours(2). These data indicate that hexachlorocyclopentadiene adsorbed onto sunlight-exposed particles (e.g. dust, soil surfaces) may be subject to rapid photodegradation(SRC). The rate constant for the reaction of hexachlorocyclopentadiene vapor with photochemically generated hydroxyl radicals in the atmosphere has been estimated to be 5.6X10-13 cu cm/molecule-sec at 25 deg C(3,SRC). Assuming an average ambient hydroxyl radical concentration of 5X10+5 molecules/cu cm(4) the half-life for this reaction has been estimated to be 29 days(SRC). Based on the highly chlorinated structure of hexachlorocyclopentadiene, it is expected that reaction of this compound with ozone molecules in the atmosphere would be too slow to be environmentally significant(SRC). [R64] *Rate constants for reaction of hexachlorocyclopentadiene with singlet oxygen and peroxy radicals in water have been estimated to be < 1X10+3 and 12 L/mole-hr, respectively(1). These values correspond to reaction half-lives of 79,000 and 6,600 years, respectively, assuming average ambient concentrations of singlet oxygen and peroxy radicals of 1X10-12 and 1X10-9 mol/l (2), respectively, under typical environmental conditions(SRC). [R65] BIOC: *Bioconcentration factor of hexachlorocyclopentadiene in a laboratory model ecosystem: alga (Edogonium) 341; snail (Physa) 929; mosquito (Culex) 1634; and fish (Gambusia) 448(1). BCF in other aquatic species: green alga (Chlorella fusca) 1090(2); fathead minnow (Pimephales promelas) < 11(3) and 29(4); goldfish (Carassius auratus) 100-323(5), golden orfe (Leuciscus idus) 1230(6). These data indicate that hexachlorocyclopentadiene is subject to moderate to extensive bioaccumulation in aquatic organisms depending upon the organism and its species. [R66] KOC: *The attenuation mechanisms and capacity of selected clay minerals and soils for hexachlorocyclopentadiene (C-56) adsorption, a chemical model to predict C-56 migration through soil materials, and the major degradation products of C-56 in the environment were investigated. C-56 was readily adsorbed by soil materials; the adsorption capacity of C-56 was highly correlated with the total organic carbon content. Adsorbed C-56 remained immobile in the earth materials when leached with water, landfill leachates, and caustic soda brine solutions, but was highly mobile when leached with organic solvents. [R67] *The average soil adsorption coefficient (Koc) for hexachlorocyclopentadiene, based on measurements made in 15 different soils, was determined to be 4,265(1). Measured Rf values for hexachlorocyclopentadiene in muck, silt, silt loam, silt clay, loam, and sandy soils leached with tap water and landfill leachate range between 0.001-0.005(1). These Koc and Rf values indicate that hexachlorocyclopentadiene is immobile in soil and has the potential to adsorb extensively to suspended solids and sediments in water(1,2,3). BCF in sludge is 2350(4). The bioconcentration factor of hexachlorocyclopentadiene in sludge suggests that bioconcentration in sludge may be a significant removal process during wastewater treatment(SRC). [R68] VWS: *Losses of hexachlorocyclopentadiene, initial conc 0.41 mg/L, from half-full glass-stoppered and unstoppered bottles shaken at room temperature over a 24 hour period were equivalent to 15-16% and of the original amount of compound, respectively(1). Loss was presumably due to volatilization(1). Volatilization losses of 5.3-9.9% were observed over a two hr period from a static aqueous solution of hexachlorocyclopentadiene at an intial concn 50 ng/l at 25 deg C(2). These data as well as a measured Henry's Law constant of 2.7X10-2 atm-cu m/mol at 25 deg C(3) suggest that chlorocyclopentadiene would be susceptible to volatilization from natural water systems(4,SRC). Based on this value of Henry's Law constant the volatilization half-life from a model river 1 m deep, flowing 1 m/sec with a wind speed of 3 m/sec has been estimated to be about 5 hours(4,SRC). An EXAMS II simulation of a model environmental pond estimated a volatilization half-life of 37 days, but if adsorption to suspended solids and sediments in the pond is disregarded, then the volatilization half-life is estimated to be 58 hours(5,SRC). These data suggest that in turbid waters adsorption to suspended solids and sediments could substantially limit the extent of volatilization(SRC). [R69] *Volatilization losses of 0.84-1.60% from moist sand, 0.35-0.67% from moist loam, and 0.15-0.285% from moist humus were observed over a two hour period in a laboratory study, carried out at 25 deg C, where the initial hexachlorocyclopentadiene concn was 50 ug/kg soil on a dry weight basis(1). These data indicate that some volatilization from moist soil surfaces may occur and that volatilization rates are related to the organic carbon content of soils Following application of 100 mg of radiolabelled hexachlorocyclopentadiene to Maury silt loam, the cumulative evaporative losses of this compound and its nonpolar metabolites (penta- and tetrachlorocylopentadiene) 1, 2, 3, 5, 7, and 14 days after application were 9.3, 10.2, 10.6, 10.8, 11.0, and 11.2%, respectively(2). [R70] *The ratio of the volatilization rate to the reaction rate constant for hexachlorocyclopentadiene in natural waters /was determined/ to be 0.58. ...Results indicated that on the order of 15% of the hexachlorcyclopentadiene load in a turbid river would be removed by volatilization, as compared to less than five percent for a pond or a eutrophic lake. [R14, p. 57-3] WATC: *SURFACE WATER: U.S EPA STORET Data Base - 85 samples, 0.1% pos., median concn < 10 ug/L(1). 1978-79, Ohio River at Wheeling, WV, Huntington, WV, Louisville, KY, Evansville, IN and 10 other locations, 106 samples, 5.7% pos., detection limit 0.04 ug/L, max concn 0.1 ug/L(2). Qualitatively identified in water samples from Lake Ontario, but not found in water samples from Lake Erie and Lake Michigan(3). Detected in Rhine River water samples collected during January 1978(4). [R71] *DRINKING WATER: Identified in drinking water obtained from Athens, GA during Nov. and Dec. 1976, 4 samples, 100% pos., avg concn 37.5 ng/L(1). Tentatively identified in drinking water obtained from the Torresdale Water Treatment Plant in Philadelphia, PA during Oct. 1976(2). Qualitatively identified in drinking water obtained from an undisclosed location in the United Kingdom during Nov. 1978(3). [R72] *GROUNDWATER: Identified in leachate from the Occidental Chem Co. S-Area landfill in Niagara Falls, NY which is located adjacent to the Niagara Falls drinking water treatment plant(1). [R73] EFFL: *USEPA STORET Data Base - 1,228 samples, 0.9% pos., median concn < 10 ug/L(1). Qualitatively identified in stack emissions from an hazardous waste incinerator test burn(2). Air samples collected during May and June 1978 at the Memphis (TN) North Treatment Plant contained hexachlorocyclopentadiene(3). Hexachlorocyclopentadiene was identified in samples of wastewater effluent from a chemical plant in Michigan which was manufacturing this compound(4). [R74] SEDS: *USEPA STORET Data Base - 344 samples, 0% pos.(1). [R75] ATMC: *Qualitatively identified in air samples collected from homes in the Love Canal area of Buffalo, NY during 1980(1). Nov. 1978, detected in indoor air of 3 out of 5 houses with contaminated groundwater supplies in the Toone-Teague Area of Hardeman County, TN, concn range 0.06-0.1 ug/cu m. The origin of contamination was a hazardous waste landfill which was operated by Velsicol Chemical Corporation(2,3). Air samples collected during May and June 1978 at the Memphis (TN) North Treatment Plant contained hexachlorocyclopentadiene(2). This plant served an area which included Velsicol Chemical(2). [R76] PFAC: FISH/SEAFOOD CONCENTRATIONS: *U.S EPA STORET Data Base - 116 samples, 0% pos.(1). Qualitatively identified in fish collected from the Great Lakes and major watersheds of the Great Lakes during 1979, 28 whole fish composite samples, 7% pos., detection limit not reported(2). Qualitatively identified in fish taken from water near Hooker Chemical in Michigan(3). Not detected in fish taken from waters near Velsicol Chemical in Memphis, TN(3). [R77] RTEX: *Certain segments of the population may be exposed through ingestion of contaminated drinking water(1,2) or contaminated fish(3,4). People living in the vicinity of hazardous waste disposal sites containing this compound may be exposed through inhalation of contaminated air(5). Workers involved in the manufacture or handling of this compound or treatment of wastes containing this compound could potentially be exposed by inhalation or dermal exposure(6,7). [R78] *The use of municipal wastewater treatment plants for the disposal of industrial wastes creates the potential for the exposure of treatment plant workers to hazardous chemical compounds that may be present in these wastes. Urine from workers and air and wastewater samples from a municipal wastewater treatment plant receiving wastes from a pesticide manufacturer were analyzed on several occasions by electron-capture gas chromatography for the presence of hexachlorocyclopentadiene and hexachlorobicycloheptadiene present in the waste stream from this industry. hexachlorobicycloheptadiene was detected more frequently in urine from these workers than in urine from workers at another municipal wastewater treatment plant in the same city. Urine concn of hexachlorobicycloheptadiene were higher in specimens collected late in the work shift. The primary route of exposure was probably inhalation. This was the 1st known report of these compounds being detected in human urine and it demonstrated the potential for wastewater treatment plant worker exposure to industrial wastes. [R79] *Workers at the Morris Forman Wastewater Treatment Plant in Louisville, KY were exposed to unspecified levels of hexachlorocyclopentadiene in the air of the plant during March 1977(1). NIOSH (NOHS Survey 1972-1974) has statistically estimated that 1427 workers are potentially exposed to hexachlorocyclopentadiene in the USA(2). [R80] *Occupational exposures appear to constitute the only documented source of human exposure to hexachlorocyclopentadiene (Hex). Dermal and inhalation exposures are recognized hazards for the following groups: workers engaged directly in Hex manufacture; those engaged in the formulation and use of other related pesticides where Hex may be present as an impurity; flame retardant workers; and those having quasi-occupational exposure such as sewage treatment workers, industrial hygienists and etc. [R11] BODY: *... Limited uses ... are not expected to result in significant levels of residues in humans ... except in factory and other workers who may be directly exposed at work. [R20, 3751] *Urine samples obtained during May and June 1978 from workers at the Memphis (TN) North Treatment Plant contained hexachlorocyclopentadiene(1). [R81] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *Assuming a human body wt of 70 kg, the acceptable daily intake for hexachlorocyclopentadiene is 0.00462 mg/day. /Inhalation, Acceptable Intake Chronic/ [R82] OSHA: +Vacated 1989 OSHA PEL TWA 0.01 ppm (0.1 mg/cu m) is still enforced in some states. [R12, 365] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.01 ppm (0.1 mg/cu m). [R12, 158] TLV: +8 hr Time Weighted Avg (TWA): 0.01 ppm. [R34, 2002.35] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R34, 2002.6] +A4; Not classifiable as a human carcinogen. [R34, 2002.35] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Hexachlorocyclopentadiene is included on this list. [R83] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 50 ug/l [R84] STATE DRINKING WATER GUIDELINES: +(ME) MAINE 50 ug/l [R84] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. [R85] +Designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. [R86] +... Based on available toxicity data, to protect public health the derived /criterion/ level is 206 ug/l ... . [R87] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R88] +Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Hexachlorocyclopentadiene is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100 lbs. [R89] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Hexachlorocyclopentadiene is included on this list. [R90] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R91] RCRA: *U130; As stipulated in 40 CFR 261.33, when hexachlorocyclopentadiene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R92] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *This review describes the development and validation of personal sampling and analytical methods for 3 organochlorine compounds over substantially lower ranges of concentration levels. Hexachlorocyclopentadiene is 1 of the 3 compounds discussed. [R93] *NIOSH Method 2518. Analyte: Hexachlorocyclopentadiene. Matrix: Air. Sampler: Solid sorbent tubes (2 tubes, porapak T, 75 mg and 25 mg). Flow Rate: 0.05 to 0.2 l/min. Sample Size: 5 liters. Shipment: Separate tubes of each sampler; seal each tube; ship @ 25 deg C; store @ 0 deg C in the dark. Sample Stability: Equal to or more than 7 days @ 25 deg C; greater than or equal to 28 days @ 0 deg C. [R94] ALAB: *A GC/MS procedure was used to identify the constituents of waste products collected during the chlorinolysis of propylene in the manufacture of carbon tetrachloride and tetrachloroethylene. Hexachlorocyclopentadiene was one of the cmpd that was positively identified. [R95] *This review describes the development and validation of sampling and analytical methods for 3 organochlorine compounds over substantially lower ranges of concentration levels. Hexachlorocyclopentadiene is 1 of the 3 compounds discussed. [R93] *EPA Method 612. GC with ECD for the analysis of chlorinated hydrocarbons including hexachlorocyclopentadiene in municipal and industrial discharges. Under the prescribed conditions for hexachlorocyclopentadiene, the method has a detection limit of 0.40 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R96] *EPA Method 625. GC/MS for the analysis of acid/base/neutral extractables including hexachlorocyclopentadiene in municipal and industrial discharges. Under the prescribed conditions for hexachlorocyclopentadiene, the method detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. Interferences: PCBs. [R96] *EPA Method 1625. Isotope Dilution Capillary Column GC/MS for the determination of semivolatile organic compounds in municipal and industrial discharges. By adding a known amount of an isotopically labeled compound to every sample prior to purging, a correction of recovery of the pollutant can be made. If isotopically labeled compounds are not available, an internal standard method is used. Under the prescribed conditions, hexachlorocyclopentadiene detection level is 10 ug/l. [R96] *EPA Method 3540. Soxhlet Extraction. A solid sample is mixed with anhydrous sodium sulfate and extracted using an appropriate solvent in a Soxhlet extractor. The sample is then dried and concentrated using a Kuderna-Danish apparatus. This is a procedure for extracting nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. [R97] *EPA Method 3550. Sonication Extraction. A 2- to 3-g solid sample is mixed with anhydrous sodium sulfate to form a free-flowing powder, then solvent extracted using a horn-type sonicator, followed by vacuum filtration or centrifugation for organic components of equal or less than 20 mg/kg. This method is applicable to the extraction of nonvolatile and semivolatile organic compounds from solids such as soils, sludges, and waste. Interferences include chlorofluorocarbons and methylene chloride. [R97] *EPA Method 8120. GC Method with an ECD for the detection of ppb levels of certain chlorinated hydrocarbons including hexachlorocyclopentadiene in solid waste using the solvent flush technique. Under the prescribed conditions hexachlorocyclopentadiene, the method has a detection limit of 0.40 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R97] *EPA Method 8250. Packed Column GC/MS Technique for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soil, andgroundwater. This method is applicable to quantify most neutral, acidic, and basic organic compounds that are soluble in methylene chloride and capable of being eluted with derivatization as sharp peaks from a gas chromatographic packed column. Under the prescribed conditions, hexachlorocyclopentadiene detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R97] *EPA Method 8270. Capillary Column GC/MS. This method is used for the determination of semivolatile organic compounds in extracts prepared from all types of solid waste matrices, soils, and groundwater. This method is applicable to quantify most acidic, basic, and neutral organic compounds that are soluble in methylene chloride and are capable of being eluted without derivatization as sharp peaks from a capillary column (DB-5 or equivalent). The Practical Quantitation Limit for hexachlorocyclopentadiene is 10 ug/l in ground water and 660 ug/kg in low soil/sediment. The precision and a method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R97] *NIOSH Method 2518. Analyte: Hexachlorocyclopentadiene. Matrix: Air. Procedure: Gas chromatography, nickel electron capture detector. For hexachlorocyclopentadiene this method has an estimated detection limit of 5 ng/sample. The precision/RSD is 0.030 and the recovery is not given. Applicability: The working range is 5 to 2400 ug/cu m (0.005 to 0.2 ppm) for a 5 liter air sample. Interferences: None identified. [R94] CLAB: *... Three analytical methods ... have been used for urine, fish fillet, beef liver, beef skeletal muscle, beef adipose tissue, beef kidney, chicken liver, chicken skeletal muscle and chicken adipose tissue. The respective recoveries were: 80 + or - 10/%/ (1-50 ppb), 81 + or - 1/%/, 69 + or - 4/%/, 88 + or - 5/%/, 71 + or - 3/%/, 55 + or - 9/%/, 76 + or - 4/%/ and 95 + or - 2%. [R98] *Urine was extracted with hexane, the hexane passed through anhydrous sodium sulfate, and evaporated to 1 ml. The limit of detection for hexachlorocyclopentadiene without concentrating the extract was 0.5 ppb. For cattle, poultry and fish tissues, the tissues were extracted with 2:1 pentane/acetone, the homogenate diluted with 10% sodium chloride solution, centrifuged, and the pentane layer transferred into a separatory funnel. The residues were then partitioned into acetonitrile ... and then back-extracted with pentane. The pentane extract was treated with concentrated sulfuric acid and then water, and concentrated to 3 ml. Upon dilution to 10 ml with hexane, the solution was treated with a 1:1 concentrated sulfuric acid/fuming sulfuric acid solution, water, and a 9:1 mixture (solid) of sodium sulfate/sodium carbonate. Packed columns (3% OV-1 on Gas Chrom Q-100/120 mesh-in 2 m X 2 mm i.d. glass column) or capillary columns (30 m X 0.25 mm SE-30 WCOT) can be used for gas chromatography using a nickel(63)-electron capture detector. [R98] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Atallah YH et al; Toxicol Halogenated Hydrocarbons: Health Ecol Eff (Pap Symp): 344-55 (1981). A review on the environmental fate of hexachlorocyclopentadiene. USEPA; Health Effects Assessment for Hexachlorocyclopentadiene (1986) EPA 540/1-86/001. $null$ [R99] USEPA; Chemical Profile: Hexachlorocyclopentadiene (1985) DHHS/NTP; Toxicology and Carcinogenesis Studies of Hexachlorocyclopentadiene in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 437 (1994) NIH Publication No. 94-3168 HIST: *In March 1977, a large volume of industrial ... hexachlorocyclopentadiene was dumped into a municipal sewage system in Kentucky. ... Health effects of exposure ... /were evaluated/ in 145 sewage treatment plant workers. ... 85 (59%) had noted eye irritation, 65 (45%) had headaches, and 39 (27%) had throat irritation. Symptoms occurred throughout the plant; however, highest attack occurred in primary sewage treatment areas. Medical exam of 41 employees 3 days after plant was closed showed proteinuria and elevation of serum lactic dehydrogenase levels; these findings were not present 3 weeks later. [R20, 3751] SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 792 (1979) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 793 (1979) R4: USEPA; Health Assessment Document for Hexachlorocyclopentadiene EPA-600/8-84-001F p.4-1 (1984) R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 597 R6: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 682 R7: Hayes, Wayland J., Jr. Pesticides Studied in Man. Baltimore/London: Williams and Wilkins, 1982. 229 R8: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 791 (1979) R9: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 726 R10: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-233 R11: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 489 R12: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R13: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R14: Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume II. EPA-440/4-79-029b. Washington, D.C.: U.S. Environmental Protection Agency, December 1979. R15: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.300 R16: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 64th ed. Boca Raton, Florida: CRC Press Inc., 1983-84.,p. C-256 R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-267 R18: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 91 R19: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 513 R20: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R21: Wolfe NL et al; Chemos 11: 91-101 (1982) R22: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000 R23: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.361 R24: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R25: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V5 796 R26: 49 CFR 171.2 (7/1/96) R27: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 158 R28: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6144 (1988) R29: 40 CFR 240-280, 300-306, 702-799 (7/1/90) R30: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-13 (1981) EPA 68-03-3025 R31: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-103 (1982) R32: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 154 R33: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Hexachlorocyclopentadiene (77-47-4) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R34: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R35: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 479 R36: GOGGELMAN W ET AL; BIOCHEM PHARMACOL 27 (24): 2927-30 (1978) R37: GREIM H ET AL; ARCH TOXICOL 39 (1): 159-69 (1977) R38: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 289 R39: Sinhaseni P et al; Toxicol Appl Pharmacol 67 (2): 215-23 (1983) R40: Rand GM et al; J Toxicol Environ Health 9 (5-6): 743-60 (1982) R41: Abdo KM et al; J Applied Toxicol 4 (2): 75-81 (1984) R42: Toxicology and Carcinogenesis Studies of Hexachlorocyclopentadiene in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 437 (1994) NIH Publication No. 94-3168 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R43: SPEHAR RL ET AL; BULL ENVIRON CONTAM TOXICOL 21 (4-5): 576-83 (1979) R44: Shell Research Ltd.; Thirty Week Chronic Inhalation Study of Hexachlorocyclopentadiene (HEX) in Rats. (1982), EPA Document No. 40-8349132, Fiche No. OTS0507496 R45: Southern Research Inst.; Subchronic Toxicity Report on Hexachlorocyclopentadiene (C53607) in B6C3F1 Mice. (1981), EPA Document No. 40-8349130, Fiche No. OTS0507497 R46: Southern Research Inst.; Subchronic Toxicity Report on Hexachlorocyclopentadiene (C53607) in Fischer-344 Rats. (1981), EPA Document No. 40-8349130, Fiche No. OTS0507497 R47: Shell Oil Company; Thirty Week Chronic Inhalation Study of Hexachlorocyclopentadione (HEX) in Rats. (1981), EPA Document No. 878210123, Fiche No. 206204 R48: Southern Research Institute; Disposition of Hexachlorocyclopentadiene in Rats Dosed by Gavage, by Intravenous Injection, or by Inhalation, (no date reported), EPA Document No. 878216391, Fiche No. OTS510319 R49: Naylor Dana Institute; Hepatocyte Primary Culture/DNA Repair Assay on Compound Hexachlorocyclopentadiene Using Rat Hepatocytes in Culture. (1983), EPA Document No. 878213752, Fiche No. OTS0206296 R50: MEHENDALE HM; ENVIRON HEALTH PERSPECT 21: 275-78 (1977) R51: Lawrence LJ, Dorough HW; Bull Environ Contam Toxicol 26 (5): 663-8 (1981) R52: El Dareer SM et al; J Toxicol Environ Health 12 (2-3): 203-12 (1983) R53: Dorough HW, Ranieri TA; Drug Chem Toxicol 7 (1): 73-89 (1984) R54: Podowski AA et al; Arch Environ Contam Toxicol 20 (4): 488-96 (1991) R55: Podowski AA, Khan MA Q; Arch Environ Contam Toxicol 13 (4): 471-81 (1984) R56: (1) Bell MA et al; Reviews of the Environmental Effects of Pollutants: XII. Hexachlorocyclopentadiene. USEPA-600/1-78-047. NTIS PB80-12296 p. 1 (1978) (2) Junk GA, Ford CS; Chemos 9: 187-230 (1980) (3) USEPA; Health Assessment Documentfor Hexachlorocyclopentadiene. USEPA-600/8-84-001A p. 4-4 (1984) (4) Anderson GC; Human Exposure to Atmospheric Concentrations of Selected Chemicals. Vol. 2 NTIS PB83-265249 pp. 16-4 to 16-13 (1983) (5) Guicherit R, Shulting FL; Sci Total Environ 43: 193-219 (1985) R57: (1) USEPA; Health Assessment Document for Hexachlorocyclopentadiene. USEPA-600/8-84-001A pp. 5-14 to 5-16 (1984) R58: (1) Wolfe NL et al; Chemos 11: 91-101 (1982) (2) Chou SFJ et al; Environ Toxicol Chem 6: 371-6 (1987) (3) Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants - Vol. II USEPA-440/4-79-029B p. 57-3 (1979) (4) Chou SFJ et al; Aqueous Chemistry and Adsorption of Hexachlorocyclopentadiene by Earth Materials NTIS PB81-173882 (1981) (5) Zepp RG, Wolfe NL; Aquatic Surf Chem 423-55 (1987) (6) Lyman WJ et al; Handbook of Chemical Estimation Methods. NY: Mc-Graw-Hill p. 15-12 to 15-28 (1982) (7) USEPA; EXAMS II computer simulation (1987) R59: (1) Eisenreich SJ et al; Environ Sci Tech 15: 30-8 (1981) (2) Bell MA et al; Reviews of the Environmental Effects of Pollutants: XII. Hexachlorocyclopentadiene. USEPA-600/1-78-047. NTIS PB80-12296 p. 8 (1978) R60: (1) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (2) Health Assessment Document for Hexachlorocyclopentadiene. USEPA-600/8-84-001A p. 5-16 (1984) R61: Butz RG et al; Ecotoxicol Environ Saf 6 (4): 347-57 (1982) R62: (1) Callahan MA et al; Water-Related Environmental Fate of 129 Priority Pollutants - Vol. II EPA-440/4-79-029B p. 57-3 (1979) (2) Wolfe NL et al; Chemos 11: 91-101 (1982) (3) Chou SFJ et al; Aqueous Chemistry and Adsorption of Hexachlorocyclopentadiene by Earth Materials NTIS PB81-173882 (1981) (4) Zepp RG, Wolfe NL; Aquatic Surf Chem 423-55 (1987) (5) Basu DK, Eisenmann C; Health and Environmental Effects Document on Chlorinated Cyclopentadienes (Final Draft). EPA Contract No. 68-03-3521 p 9 (1987) R63: (1) Wolfe NL et al; Chemos 11: 91-101 (1982) (2) Chou SFJ et al; Environ Toxicol Chem 6: 371-6 (1987) R64: (1) Sadtler; UV Spectra No. 1397. Sadtler Res Lab Philadelphia, PA (1960) (2) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) (3) Atkinson R; Intern J Chem Kinet 19: 799-828 (1987) (4) Atkinson R; Chem Rev 85: 71 (1985) R65: (1) Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants USEPA-440/4-81-014 pp. 173-4 (1981) (2) Mill T, Mabey W; Environmental Exposure from Chemicals Vol. 1; Neely WB, Blav GE eds Boca Ruton, FL: CRC Press p. 207 (1985) R66: (1) Lu PY et al; J Agric Food Chem 5: 967-73 (1975) (2) Geyer H et al; Chemos 10: 1307-13 (1981) (3) Spehar RL et al; Bull Environ Toxicol Contam 21: 576-83 (1979) (4) Veith GD et al; J Fish Res Board Can 36: 1040-8 (1979) (5) Podowski AA, Khan MAQ; Arch Environ Contam Toxicol 13: 471-82 (1984) (6) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) R67: Chou SF J, Griffin RA; Soil, Clay, and Caustic Soda Effects on Solubility, Sorption, and Mobility of Hexachlorocyclopentadiene Report (ISS IL/SGS/EGN-104): 1-62 (1983)NTIS PB84-116060 R68: (1) Chou SFJ et al; Soil, Clay, and Caustic Soda Effects on Solubility, Sorption, and Mobility of Hexachlorocyclopentadiene. NTIS PB84-116060 pp. 41-53 (1983) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Reinbold KA; Adsorption of Energy-Related Organic Pollutants. A Literature Review. NTIS PB80-105117 (1979) (4) Freitag D et al; Ecotox Environ Safety 6: 60-81 (1982) R69: (1) USEPA; Health Assessment Document for Hexachlorocyclopentadiene. USEPA-600/8-84-001A p 5-20 (1984) (2) Kilzer L et al; Chemos 10: 751-61 (1979) (3) Wolfe NL et al; Chemos 11: 91-101 (1982) (4) Lyman WJ et al; Handbook of Chemical Estimation Methods NY: McGraw-Hill p. 15-12 to 15-28 (1982) (5) USEPA; EXAMS II Computer Simulation (1987) R70: (1) Kilzer L et al; Chemos 10: 751-61 (1979) (2) USEPA; Health Assessment Document for Hexachlorocyclopentadiene. USEPA-600/8-84-001A p. 5-23 (1984) R71: (1) Staples CA et al; Environ Toxicol Contam 4: 1313-42 (1985) (2) Ohio R Valley Sanit Comm; Assessment of Water Quality Conditions. Ohio River Mainstream 1978-79 p. T-48 (1980) (3) Great Lake Water Quality Board;An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem Vol. 1 - Summary; Windsor Ontario, Canada p. 70 (1983) (4) Haberer K, Normann S; Gas-Wasserfach: Wasser/Abwasser 120: 302-7 (1979) R72: (1) Thruston AD; J Chromat Sci 16: 254-9 (1978) (2) Suffet IH et al.; Water Res 14: 853-67 (1980) (3) Fielding M et al; Organic Micropollutants in Drinking Water. TR-159; Medmenham, England: Water Res Center p. 26 (1981) R73: (1) Talian SF et al; pp. 525-42 in Proc AWWA Water Qual Technol Conf Harrisburg, PA: Gannett Fleming Water Res Eng Inc (1986) R74: (1) Staples CA et al; Environ Toxicol Contam 4: 1313-42 (1985) (2) James RH et al; J Proc APCA 77th Annual Mtg Paper 84-18.5 pp. 1-15 (1984) (3) Clark CS et al; Arch Environ H 37:9-18 (1982) (4) Bell MA et al; Reviews of the Environmental Effects of Pollutants: XII. Hexachlorocyclopentadiene. USEPA-600/1-78-047 NTIS PB80-12296 p. 34 (1978) R75: (1) Staples CA et al; Environ Toxicol Contam 4: 1313-42 (1985) R76: (1) Hauser TR, Bomberger SM; Env Monit Assess 2: 249-72 (1982) (2) Clark CS et al; Arch Environ H 37: 9-18 (1982) (3) Harris RH et al; Haz Waste 1: 183-204 (1984) R77: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Kuehl DW et al; Environ Internat 9: 293-9 (1983) (3) USEPA; Health Assessment Document for Hexachlorocyclopentadiene USEPA-600/8-84-001A p. 4-7 (1984) R78: (1) Thruston AD; J Chromat Sci 16: 254-9 (1978) (2) Suffet IH et al.; Water Res 14: 853-67 (1980) (3) Kuehl DW et al; Environ Internat 9: 293-9 (183) (4) USEPA; Health Assessment Document for Hexachlorocyclopentadiene USEPA 600/8-84-001A p. 4-7 (1984) (5) Hauser TR, Bomberger SM; Env Monit Assess 2: 249-72 (1982) (6) Deichmann WB; Patty's Industrial Hygiene and Toxicology 3rd ed. Vol. 2B; Clayton GD, Clayton FE eds. NY: Wiley p. 3749 (1981) (7) Clark CS et al; Arch Environ H 37: 9-18 (1982) R79: Elia VJ et al; Environ Res 32 (2): 360-71 (1983) R80: (1) Bell MA et al; Reviews of the Environmental Effects of Pollutants: XII. Hexachlorocyclopentadiene. USEPA-600/1-78-047 NTIS PB80-12296 p. 63 (1978) (2) NIOSH; National Occupational Hazard Survey (NOHS) (1974) R81: (1) Clark CS et al; Arch Environ Health 37: 9-18 (1982) R82: USEPA; Health Effects Assessment: Hexachlorocyclopentadiene p.25 Sept 1984 EPA/540/1-86/001 R83: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R84: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R85: 40 CFR 401.15 (7/1/90) R86: 40 CFR 116.4 (7/1/90) R87: USEPA; Quality Criteria for Water 1986: Hexachlorocyclopentadiene (May 1,1986) EPA 440/5-86-001 R88: 40 CFR 302.4 (7/1/90) R89: 40 CFR 355 (7/1/97) R90: 40 CFR 716.120 (7/1/90) R91: 40 CFR 712.30 (7/1/90) R92: 40 CFR 261.33 (7/1/90) R93: Boyd KW et al; ACS Symp Ser 149 (Chem Hazards Workplace: Meas Control): 49-64 (1981) R94: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 2518-1 R95: Beranek I et al; Chem Prum 31 (10): 541-2 (1981) R96: 40 CFR 136, App. A (7/1/90) R97: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R98: USEPA; Health Assessment Document: Hexachlorocyclopentadiene p.3-13 (1984) EPA-600/8-84-001F R99: WHO; Environmental Health Criteria 120: Hexachlorocyclopentadiene (1991) RS: 84 Record 246 of 1119 in HSDB (through 2003/06) AN: 4025 UD: 200303 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MERCAPTOBENZOTHIAZOLE- SY: *ACCEL-M-; *ACCELERATOR-M-; *2-BENZOTHIAZOLETHIOL-; *BENZOTHIAZOLE-2-THIONE-; *2(3H)-BENZOTHIAZOLETHIONE; *2-BENZOTHIAZOLINETHIONE-; *2-BENZOTHIAZOLYL-MERCAPTAN-; *CAPTAX-; *DERMACID-; *EKAGOM-G-; *KAPTAKS-; *KAPTAX-; *MBT-; *2-MBT-; *MEBETIZOLE-; *MEBITHIZOL-; *2-MERCAPTOBENZOTHIAZOLE-; *MERCAPTOBENZTHIAZOLE-; *2-MERCAPTOBENZTHIAZOLE-; *2-MERKAPTOBENZOTIAZOL- (POLISH); *MERTAX-; *NCI-C56519-; *NUODEX-84-; *PNEUMAX-MBT-; *ROTAX-; *ROYAL-MBT-; *SOXINOL-M-; *THIOTAX-; *USAF-GY-3-; *USAF-XR-29-; *VULKACIT-M-; *VULKACIT-MERCAPTO-; *VULKACIT-MERCAPTO/C- RN: 149-30-4 RELT: 5419 [ZINC MERCAPTOBENZOTHIAZOLE] (Analog) MF: *C7-H5-N-S2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD INDUSTRIALLY BY REACTING ANILINE, CARBON DISULFIDE, AND SULFUR AT ELEVATED PRESSURE AND TEMP. PURIFICATION BY TREATMENT WITH A PER-ACID SALT IN ALKALINE MEDIUM. [R1, 922] FORM: *GRADES: TECHNICAL; 97% [R2] *Nuodex 84 contains the sodium salt for use in water base adhesives, paper sizings. Niacides are mixtures with carbamate fungicides for control of apple scab and rust. [R3] OMIN: *(VET): AT 1-2% CONCN IN OINTMENTS AND LOTIONS APPLIED IN WIDE VARIETY OF CANINE DERMATOSES AND ON TEATS OF COWS. [R4] *IT IS WEAK ACID AND FORMS SALTS WITH BASES ... THESE SALTS ARE EFFECTIVE IN MILDEW-PROOFING OF FABRICS, IN SLIME AND ALGAE CONTROL, and , IN CASE OF DIMETHYLDITHIOCARBAMATE SALTS, AS SEED TREATMENT AND FOLIAR FUNGICIDE FOR FRUITS AND VEGETABLES. [R5] *SODIUM SALT (EG, NACAP, 50% SOLN) IS CORROSION INHIBITOR IN ANTIFREEZE, COOLANTS AND OTHER AQUEOUS SYSTEMS WHERE CORROSION IS PROBLEM, PARTICULARLY WITH COPPER AND BRASS. MONOETHANOLAMINE SALT ... AND LAURYLPYRIDINIUM SALT ... ARE MARKETED AS COMMERCIAL FUNGICIDES AND BACTERICIDES. [R6] USE: *SALTS USED AS FUNGICIDE/S/ [R1, 923] *FUNGICIDE FOR PRESERVING TEXTILES /SRP: FORMER USE/ [R7] *Vulcanization accelerator for rubber (requires use of stearic acid for full activation), tire treads and carcasses, mechanical specialities; corrosion inhibitor in cutting oils and petroleum products, extreme pressure additive in greases. [R2] +MEDICATION (VET) PRIE: U.S. PRODUCTION: *(1975) 1.20X10+9 GRAMS [R7] *(1977) 2.72X10+9 GRAMS (SALES) [R7] U.S. IMPORTS: *(1975) 1.90X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R7] *(1977) 1.00X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE, YELLOW MONOCLINIC NEEDLES OR LEAFLETS [R1, 922]; *YELLOWISH POWDER [R2]; *NEEDLES FROM ALC OR DILUTE METHANOL [R8]; *Yellowish to tan crystalline powder [R9, 565] ODOR: *DISAGREEABLE ODOR [R1, 922]; *DISTINCTIVE ODOR (DEPENDS ON DEGREE OF PURIFICATION) [R2] MP: *180.2-181.7 DEG C [R1, 913] MW: *167.25 [R1, 922] DEN: *1.42 [R1, 913] DSC: *The dissociation constant for 2-mercaptobenzothiazole is between 6.7 and 7.2. [R10] OWPC: *log Kow = 2.41 [R11] SOL: *PRACTICALLY INSOL IN WATER; SOLUBILITY @ 25 DEG C (G/100 ML): ALC 2.0; ETHER 1.0; ACETONE 10.0; BENZENE 1.0; CARBON TETRACHLORIDE LESS THAN 0.2; NAPHTHA LESS THAN 0.5; MODERATELY SOL IN GLACIAL ACETIC ACID; SOL IN ALKALIES AND ALKALI CARBONATE SOLN [R1, 923]; *SOL IN DIL CAUSTIC SODA, ALCOHOL, CHLOROFORM; INSOL IN GASOLINE [R2]; *SOL IN HOT ACETIC ACID [R12]; *MORE SOL IN CRUDE SWEAT THAN IN WATER [R13] SPEC: *MAX ABSORPTION (METHANOL): 235 NM (LOG E= 4.12); 282 NM SHOULDER (LOG E= 3.34); 320 NM (LOG E= 4.43); SADTLER REF NUMBER: 11493 (IR, PRISM); 8139 (IR, GRATING) [R12]; *Intense mass spectral peaks: 167 m/z (100%), 69 m/z (33%), 45 m/z (23%), 63 m/z (20%) [R14]; *IR: 6034 (Coblentz Society Spectral Collection) [R15]; *UV: 390 (Sadtler Research Laboratories Spectral Collection) [R15]; *NMR: 10149 (Sadtler Research Laboratories Spectral Collection) [R15]; *MASS: 1092 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R15] OCPP: *CONVERSION FACTOR: 6.83 MG/CU M= 1 PPM [R16, 2067] *MP: 170-173 deg C /Technical mercaptobenzothiazole/ [R1, 923] *Light yellow powder; specific gravity: 1.70 @ 25 deg C/4 deg C. /Zinc salt of mercaptobenzothiazole/ [R1, 923] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EXPL: *COMBUSTIBLE [R2] REAC: *DANGEROUS ... ON CONTACT WITH ACID OR ACID FUMES, EMITS HIGHLY TOXIC FUMES OF OXIDES OF SULFUR AND OXIDES OF NITROGEN. [R17] DCMP: *DANGEROUS; WHEN HEATED TO DECOMP ... EMITS HIGHLY TOXIC FUMES OF OXIDES OF SULFUR AND OXIDES OF NITROGEN. [R17] SERI: *2-MERCAPTOBENZOTHIAZOLE ... IS REPORTED TO BE VERY IRRITATING TO EYES. [R18] EQUP: *Respirators approved by the US Bureau of Mines for nuisance dust and safety spectacles are recommended in the event of excessive dustiness in handling the compounds. [R9, 566] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *The recommended disposal method is burial in a landfill. Incineration is not recommended unless provision can be made to insure that sulfur and nitrogen oxides will not be emitted to the atmosphere. [R9, 566] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *ALLERGIC CONTACT DERMATITIS CAN OCCUR IN PERSON USING IT. SAME PERSON IS ALSO APT TO BE ALLERGIC TO NUMBER OF RUBBER ITEMS INCL SPANDEX. [R4] *AN IMPURITY DISCOVERED IN SAMPLE OF DIGOXIN INJECTABLE SOLN COMMERCIALLY PACKAGED IN SYRINGE FOR SINGLE-DOSE DELIVERY ORIGINATED FROM THE RUBBER CLOSURE OF THE SYRINGE AND WAS IDENTIFIED AS 2-MERCAPTOBENZOTHIAZOLE. THE PRESENCE OF THIS IMPURITY MAY HAVE IMPLICATIONS WITH REGARD TO TOXICITY. [R19] *CONTACT ALLERGY TO RUBBER CONDOMS AND/OR THE ADHESIVES IS A COMMON PROBLEM AND CAN CAUSE CONSIDERABLE MORBIDITY IN PARALYZED PATIENTS. RESULTS FROM PATCH TEST AND QUESTIONNAIRES SHOWED THAT ALLERGY TO MERCAPTOBENZOTHIAZOLE AND THIURAM-CONTAINING ADHESIVES WAS RELATIVELY COMMON. [R20] *A case of occupational allergic contact dermatitis and anaphylactic shock caused by rubber latex was described. A 54 year old male who worked in the Spanish construction industry for 20 yr had a 1 yr history of hand and foot eczema. Patch testing revealed chromate sensitization as well as positive responses to rubber chemicals such as thiurams, carbamates, and mercaptobenzothiazole. In 1981 he was admitted to the urology department of a Madrid hospital with symptoms of prostatitis and acute urinary retention. Vesical catheterization with a Foley catheter was performed. Upon insertion of the catheter the patient went into anaphylactic shock. This was considered to be an anaphylactic reaction to latex in the catheter, which was confirmed by a histamine release assay and radioallergosorbent test following exposure to latex samples. Elevated latex specific serum immunoglobulin-E antibodies were also detected. [R21] *A case report was presented of a 56 yr old man who had worked as a mold maker in the pottery industry for 40 yr. As such he handled plaster of Paris and an oil which was used to release the plaster mold from the original epoxy cast. He did not wear gloves in his work and reported no other skin disease than the hand eczema which he had experienced for the prior 3 mo. He reacted positively on patch testing to neomycin and mercaptobenzothiazole. Mercaptobenzothiazole was present in the oil at 1%. [R22] *An outbreak of occupational dermatitis in a rubber tire factory is reported. An unusual clinical picture was recognized. Patch tests revealed a high sensitization rate to the mercaptobenzothiazole derivative used: 2-(2-4'dinitrophenylthio)benzothiazole. Since tests with mercaptobenzothiazole mix and dinitrophenol were negative, sensitization to a contaminant was suspected. Dinitrochlorobenzene, a starting material for manufacture of the dinitrophenylthiobenzothiazole, was traced as the substance responsible. [R23] *Consumer exposure to rubber products has resulted in shoe and glove dermatitis, and reactions to scuba diving masks, wet suits, swim caps and goggles, and many cosmetic products. The health effects of 2-mercaptobenzothiazole and other benzothiazole cmpd are discussed. Occupational exposure to 2-mercaptobenzothiazole may result in hand dermatitis in hospital nurses and other medical personnel. A study of Spanish construction workers sensitive to rubber also cited 2-mercaptobenzothiazole as the cause. [R24] NTOX: *THE RELATIVE MUTAGENIC POTENCY OF 4 RUBBER ACCELERATORS AT A SPECIFIC DOSE ARE AS LISTED IN DECREASING ORDER: N-OXYDIETHYLENETHIOCARBAMYL-N-OXYDIETHYLENESULFENAMIDE (PURIFIED), 2-MERCAPTOBENZOTHIAZOLE, N-OXYDIETHYLENE-2-BENZOTHIAZOLESULFENAMIDE,N-BUTYL-2-BENZOTHIAZOLESULFENAMIDE. THE MUTAGENIC ASSAYS USED WERE: ESCHERICHIA COLI POL A+ /POL A- DNA REPAIR, MOUSE LYMPHOMA L 5178 Y TK + OR - FORWARD MUTATION, BALB/3T3 CELL TRANSFORMATION, CHINESE HAMSTER OVARY CELL CHROMOSOME ABERRATIONS, AND SALMONELLA TYPHIMURIUM PLATE TESTS. ALL THE CHEMICALS SHOWED NEGATIVE MUTAGENICITY RESULTS IN SALMONELLA OR E SCHERICHIA COLI WP2 UVRA- STRAIN TESTS. SINCE ALL THESE CHEMICALS WERE MUTAGENIC IN AT LEAST 1 ASSAY, THEY CAN BE REGARDED AS POSSIBLE HUMAN HEALTH HAZARDS. [R25] *THREE GUINEA PIG SENSITIZATION TESTS, MAXIMIZATION TEST, SINGLE INJECTION ADJUVANT TEST AND MODIFIED DRAIZE TEST, WERE COMPARED FOR THEIR ABILITY TO DETECT 19 KNOWN HUMAN CONTACT SENSITIZERS. 1 OF THE 19 COMPOUNDS WAS MERCAPTOBENZOTHIAZOLE. THE MAXIMIZATION PROCEDURE IS A VERY STRINGENT TEST OF SENSITIZATION POTENTIAL, ABLE TO DETECT SOME MARGINAL SENSITIZERS. THE SENSITIVITY OF THE SINGLE INJECTION ADJUVANT TEST PROCEDURE IS SUFFICIENTLY SIMILAR TO THAT OF THE MAXIMIZATION TEST. THE MODIFIED DRAIZE PROCEDURE IS A GOOD SCREENING TEST PARTICULARLY FOR STRONG SENSITIZERS. [R26] *NO TERATOGENIC EFFECTS WERE OBSERVED IN FETUSES OF SPRAGUE DAWLEY RATS ADMIN 200 MG/KG OF MERCAPTOBENZOTHIAZOLE IP ON DAYS 1-15 OF GESTATION. [R27] *THREE DAY OLD WHITE LEGHORN CHICKEN EMBRYOS WERE INJECTED WITH MERCAPTOBENZOTHIAZOLE. NO ED50 (MEDIAN EFFECTIVE DOSE) COULD BE CALCULATED. MAXIMUM EFFECTIVE DOSE WAS 2.0UMOLE/EGG. MAXIMUM PERCENTAGE OF MALFORMED EMBRYOS WAS 20%. [R28] *2-Mercaptobenzothiazole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. In the presence of rat liver S9, 2-mercaptobenzothiazole increased the frequency of chromosomal aberrations and sister chromatid exchanges in Chinese hamster ovary cells, as well as mutations at the TK locus of mouse L5178Y lymphoma cells. [R29] *The sensitizing abilities of 2-mercaptobenzothiazole were evaluated using the murine local lymph node assay. Exposure to 2-mercaptobenzothiazole induced moderate proliferative responses. The sensitizing potency was described in terms of the concn that increased lymph node cell proliferation by a factor of 2 over that in the vehicle treated control group. The concn of 2-mercaptobenzothiazole was 4.2%. [R30] *2-Mercaptobenzothiazole has been used mainly as a vulcanization accelerator in rubber manufacture and an intermediate in the production of other accelerators. Acute and chronic toxicity studies were performed to evaluate its potential to induce toxicological effect using Slc:ddY mice. The oral LD50 values of 2-mercaptobenzothiazole (mg/kg) were as follows: (1) suspension in 5% gum arabic solution: 1558 for males and 1490 for females. (2) suspension in olive oil: 3148 for males. Convulsion was the major change in general conditions observed. The acute toxicity of 2-mercaptobenzothiazole in males was stronger when suspended in 5% gum arabic solution than that when suspended in olive oil. A 20 mo chronic toxicity study of 2-mercaptobenzothiazole on mice was carried out with dose levels of 30, 120, 480 and 1920 ppm in the diet. Inhibition of body wt gain was observed in the 1920 ppm group of the males from the initial stage of treatment. Histopathologically, cell infiltration in the interstitium of kidney in the 1920 and 480 ppm groups of the males were found at 20th mo. It was concluded that the no observable effect level of 2-mercaptobenzothiazole was 120 ppm (14.6 mg/kg/day for males and 13.52 mg/kg/day for females). [R31] *An investigation of a possible genotoxic mechanism for the carcinogenicity of mercaptobenzothiazole was conducted by examining the covalent binding of mercaptobenzothiazole to DNA from rat tissues. Male and female Fischer 344 rats were dosed via gavage with 375 mg/kg body wt of radiolabeled mercaptobenzothiazole. Eight hr after dosing the animals were killed and the liver, adrenal glands, pancreas, pituitary gland and femur removed. Subsequently, the various tissue samples were assayed for DNA by spectrophotometry and for radioactive DNA by liquid scintillation spectroscopy. Assay results from the liver demonstrated only 0.6% of the mercaptobenzothiazole radioactivity from the administered mercaptobenzothiazole, while the pancreas, adrenal gland, pituitary gland, and bone marrow exhibited less than 0.03% of this dose. Results indicated that the overall DNA binding of mercaptobenzothiazole was highest in the livers of male and female rats, with the covalent binding indices being 3.11 and 1.65, respectively. It was concluded that mercaptobenzothiazole does not significantly bind to liver, pancreas, bone marrow, adrenal or pituitary gland DNA and suggest that mercaptobenzothiazole does not follow a genotoxic mechanism for carcinogenicity. [R32] *The skin sensitization potentials of morpholine, 2-mercaptobenzothiazole and their derivatives, 4,4'-dithiodimorpholine and morpholinyl-mercaptobenzothiazole were examined using male Hartley albino guinea pigs. Preparations of 0.5, 2, 5, and 10% were used to determine the threshold irritation concn of each cmpd on the skin with 0.1 g of each applied on gauze pads of 1.5 sq cm dimensions. Materials were removed after 24 hr and readings taken at 1, 24, and 48 hr after removal. For sensitization studies the animals were exposed to about 0.1 g of each cmpd in a concn of 5% of the amt needed to produce minimal intensity erythema from the irritant test. Test materials were removed after 24 hr. The procedure was repeated 3 times a wk for 2 wk. Two wk after the final induction, the challenge test was performed. The left flank of the test animals was shaved, and 0.1, 0.5, and 2% dose preparations of each induction cmpd were applied. Materials were removed after 24 hr and readings taken at 1, 24, 48 hr and 7 days after removal. Cross sensitization studies were also performed. The sensitization potential was greatest for 4,4'- dithiodimorpholine, with morpholinyl-mercaptobenzothiazole being the next strongest. 2-Mercaptobenzothiazole was also a sensitizer, but morpholine was not. The intensity and percent of reactions to challenge depended on the concentration of the test cmpd. A variety of cross sensitization reactions occurred suggesting that the morpholine ring alone was not able to induce sensitization; on association with a disulfide bond, it became a strong sensitizing agent. The sensitizatio potential of 2-mercaptobenzothiazole appeared directly related to the sulfhydryl functional group in the benzothiazole structure. [R33] NTXV: *LD50 Mice (Slc:ddY) male oral LD50 1558 (mg/kg) /suspension in 5% gum arabic solution/; [R31] *LD50 Mice (Slc:ddY) male oral LD50 3148 (mg/kg) /suspension in olive oil/; [R31] *LD50 Mice (Slc:ddY) female oral LD50 1490 (mg/kg) /suspension in 5% gum arabic solution/; [R31] ETXV: *Approximate fatal concentration, Carassius auratus (Goldfis) 2 mg/l/48 hr /Conditions of bioassay not specified/; [R34] NTP: *Fifty /F344/N rats/ of each sex were administerd 2-mercaptobenzothiazole /96%-97% pure/ in corn oil by gavage 5 days per week for 103 weeks. Administration of 2-mercaptobenzothiazole resulted in decreased survival in dosed male rats (vehicle control, 42/50; low dose, 22/50; high dose, 20/50) ... but not in female rats (28/50; 31/50; 25/50). ... No effect on body weight in dosed rats was observed. ... Postgavage lethargy and prostration occurred frequently in dosed rats. ... The severity of nephropathy was increased in dosed male rats. Ulcers and inflammation of the forestomach were pervalent in dosed rats, as were increased incidences of epithelial hyperplasia and hyperplasia and hyperkeratosis in male rats, but no neoplasms of the forestomach were observed. ... The incidences of a variety of tumors were increased in rats dosed with 2-mercaptobenzothiazole; some of the increased incidences were not dose related. In low dose male rats, increased incidences (p < 0.01) were observed for mononuclear cell leukemia (7/50; 16/50; 3/50) and pancreatic acinar cell adenomas (2/50; 13/50; 6/49). Increased tumor incidences with dose related trends (p < 0.05) included pituitary gland adenomas in females (15/49; 24/50; 25/50), preputial gland adenomas or carcinomas (combined) in males (1/50; 6/50; 5/50), adrenal gland pheochromocytomas or malignant pheochromocytomas (combined) in males (18/50; 27/50; 24/49), and pheochromocytomas in females (1/50; 5/50; 6/50). These tumors were observed at significantly greater incidences (P less than or equal to 0.05) in the high dose groups than in the vehicle controls. Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of 2-mercaptobenzothiazole for male F344/N rats, indicated by increased incidences of mononuclear cell leukemia, pancreatic acinar cell adenomas, adrenal gland pheochromocytomas, and preputial gland adenomas or carcinomas (combined). There was some evidence of carcinogenic activity for female F344/N rats, indicated by increased incidences of adrenal gland pheochromocytomas and pituitary gland adenomas. [R35] *Fifty /B6C3F1 mice/ of each sex were administered 2-mercaptobenzothiazole /96-97% pure/ in corn oil by gavage 5 days per week for 103 weeks. Administration of 2-mercaptobenzothiazole resulted in decreased survival ... in high dose group of female mice (37/50; 39/50; 22/50) but not in ... male mice (38/50; 33/50; 30/50). ... In dosed mice, minor reductions /in body weight/ occurred between weeks 3 and 64, with recovery thereafter. Postgavage lethargy and prostration occurred frequently in dosed mice. ... There were no increases of nonneoplastic lesions in mice which were considered to be compound related. ... An increased incidence (p= 0.028) of hepatocellular adenomas or carcinomas (combined) was observed only in low dose female mice (4/50; 12/49; 4/50). No significant increases in tumor incidences were seen in male mice. ... Under the conditions of these 2 yr gavage studies ... there was no evidence of carcinogenic activity of 2-mercaptobenzothiazole for male B6C3F1 mice dosed with 375 or 750 mg/kg. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice, indicated by increased incidences of hepatocellular adenomas or carcinomas (combined). [R36] +... There are a number of reports indicating contact dermatitis associated with 2-mercaptobenzothiazole in humans following exposure to rubber ... . Primary irritancy studies indicated that concentrations of 2-mercaptobenzothiazole up to 7.5% were non-irritating, which was the highest concentration which remained soluble at room temperature. Female B6C3F1 mice were sensitized dermally to either 0, 1%, 3%, or 7.5% 2-mercaptobenzothiazole for 5 consecutive days and challenged 7 days later with a 7.5% solution. Site preparation included dermabrasion as well as intradermal injection of Freund's complete adjuvant in some mice. A 0.5% solution of 1-fluoro-2,4-dinitrobenzene ... was used as a positive control. The mice were divided into 10 treatment groups of 8 mice/group ... . The irritancy response was determined by monitoring the extravasation of 125I-bovine serum albumin into the treated area. The contact hypersensitivity response was determined by monitoring the infiltration of 125I-iododeoxyuridine labeled cells into the challenge site and the mouse ear swelling test (MEST). ... A hypersensitivity response was observed in B6C3F1 female mice sensitized with 2-mercaptobenzothiazole, without pretreatment with adjuvant, when the mice were tested by the MEST 2 days after sensitization, but not after 1 day ... . No statistically significant or dose-related response could be detected with the radioisotopic assay following challenge, with or without adjuvant. ... Under these experimental conditions, a statistically significant contact hypersensitivity response to 2-mercaptobenzothiazole was observed in mice when the site of sensitization was prepared by shaving and dermabrasion without adjuvant. For unknown reasons, the response was detected by the MEST, but not by the radioisotopic assay. [R37] TCAT: ?The ability of mercaptobenzothiazole to induce specific locus mutations at the HGPRT locus of Chinese hamster ovary (CHO) cells was evaluated in the presence and absence of S9 metabolic activation (tissue unspecified). Based on preliminary toxicity tests, nonactivated cultures were treated in duplicate with 1, 5, 10, 30 and 50ug/ml, producing a range of 99.0 - 29.0% survival. S9 activated cultures treated in duplicate with 10, 25, 75, 150 and 300ug/ml produced a range of 87.5 - 9.0% survival. None of the cultures produced mutant frequencies significantly greater than the solvent control (DMSO). [R38] ?The ability of mercaptobenzothiazole to induce specific locus mutation at the TK locus in cultured L5178Y mouse lymphoma cells (Mouse Lymphoma Mutagenicity Assay) was evaluated in the presence and absence of Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity determinations, nonactivated and S9 activated cultures were evaluated at concentrations up to 150ug/ml and 120ug/ml, respectively, producing a wide range of toxicities. Nonactivated cultures at the highest toxicities (less than 10% relative growth) produced 1.8- to 8.7-fold increases in the mutant frequency relative to the solvent (DMSO) and untreated controls. With S9 activation, treatments producing 7 - 20% relative growth increased the mutant frequency 1.7- to 2.7-fold compared to the solvent and untreated controls. [R39] ?The mutagenicity of mercaptobenzothiazole was evaluated in Salmonella tester strains TA1535, TA1537, TA1538, TA98 and TA100 (Ames Test), both in the presence and absence of added Aroclor-induced rat liver S9 metabolic activation. Based on preliminary toxicity determinations, mercaptobenzothiazole, diluted in DMSO, was tested at concentrations up to 300ug/plate using the plate incorporation technique. Mercaptobenzothiazole did not cause a positive response in any of the tester strains with or without metabolic activation. [R40] ?2-Mercaptobenzothiazole was evaluated for the ability to increase the incidence of micronucleated polychromatic erythrocytes in bone marrow of male and female CD-1 mice treated by single i.p. injection (Micronucleus Test). Two groups of mice (4/sex/group) were given a single intraperitoneal injection at 300 mg/kg and were sacrificed 30 and 48 hrs following dosing. Two additional groups (4/sex/group) were given two injections/animal of 300 mg/kg at 0 and 24 hrs after initial dosing and were sacrificed 48 and 72 hrs following initial dosing, respectively. No statistically significant differences between treated and control animals were observed with respect to the number of micronuclei/1000 polychromatic erythrocytes. [R41] ?The disposition of 2-mercaptobenzothiazole (MBT) was evaluated in male and female Fischer 344 rats ingesting [14C] MBT via gavage at a single dose of 55.5 or 0.592mg/kg. Four animals/sex were sacrificed at 8, 24, 48, 72 and 96 hours post treatment, at which time whole blood and plasma were also collected. For rats that were sacrificed 96 hours post treatment, urine and feces was collected at 8, 24, 48, 72 and 96 hours. The primary route of elimination of radioactivity during the 96 hour test period was via the urine, accounting for 72.1% to 106% of the administered radioactivity. Only 4.03% to 10.3% of the administered radioactivity was excreted in the feces over the 96 hour period. A small portion of the administered radioactivity (0.432 to 2.04% of dose) remained associated with the erythrocytes. Low dose animals had a greater percentage of the dose retained in whole blood and plasma relative to the high dose animals, indicating an saturation process at the high dose. Although tissue was not examined, it was concluded that the data did not indicate that any appreciable amounts of radioactivity is retained in the tissue [R42] ?The disposition of 2-mercaptobenzothiazole (MBT) was evaluated in male and female Fischer 344 rats receiving a single intravenous dose of [14C] MBT at 0.602mg/kg. Additional animals were also employed and dosed with 0.519mg/kg. Four rats/sex were sacrificed at 5min, 15min, 1hr, 2hr, 4hr, 24hr and 72hr post treatment, at which time whole blood and plasma were also collected. For rats sacrificed at 72 hours, urine and feces were collected at 8, 24, 48 and 72 hours. The primary route of elimination of radioactivity during the 72 hour test period was via the urine, accounting for 90.9 to 101% of the administered radioactivity. Only 3.79 to 15.1% of the administered radioactivity was excreted in the feces. A small portion of the administered radioactivity (1.52 to 1.96% of the dose) remained associated with the erythrocytes. Although tissue was not examined, it was concluded that the data did not indicate that any appreciable amounts of radioactivity is retained in the tissue [R43] ADE: *WHEN CARP WERE STARVED AFTER ADMIN OF (14)C-2-MERCAPTOBENZOTHIAZOLE, THE RADIOACTIVITY IN THE INTESTINE WAS 45% OF DOSE AFTER 1 HR, IN BILE 9% AND IN OTHER TISSUES WAS LESS THAN 0.05% OF DOSE AFTER 72 HR. WHEN CARP WERE FED AFTER ADMIN OF (14)C 2-MERCAPTOBENZOTHIAZOLE, RADIOACTIVITY IN BILE WAS LESS THAN 0.3% AND IN OTHER TISSUES WAS NEGLIGIBLE IN AMT AFTER 72 HR. ABOUT 100% OF DOSE WAS EXCRETED INTO WATER. [R44] *The absorption, distribution, metabolism, and rates and routes of excretion of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide were investigated in male and female Fischer 344 rats dosed iv, orally, and topically and in Hartley guinea pigs dosed topically. The topical doses used were 36.1 ug/animal for 2- mercaptobenzothiazole and 33.6 ug/animal for 2- mercaptobenzothiazole disulfide. More 2- mercaptobenzothiazole passed through the skin than 2- mercaptobenzothiazole disulfide and the guinea pigs absorbed a greater percentage of the dose of 2- mercaptobenzothiazole than 2-mercaptobenzothiazole disulfide; the disposition of radioactivity derived from the two cmpd was similar. The iv studies with 0.602 mg/kg 2-mercaptobenzothiazole or 0.571 mg/kg 2- mercaptobenzothiazole disulfide showed a similar disposition of the cmpd in both sexes of rats. Between 90 and 101% of the dose appeared in the urine in 72 hr and from 3.79 to 15.1% in the feces. The erythrocytes retained a small portion of the radioactivity. In the oral dosing studies, the rats were treated with unlabeled 2-mercaptobenzothiazole at 0.510 mg/kg/day for 20 days prior to a single dose of (14)C labeled 2- mercaptobenzothiazole at 0.503 mg/kg or with unlabeled 2- mercaptobenzothiazole disulfide at 0.521 mg/kg/day prior to a single dose of (14)C labeled 2-mercaptobenzothiazole disulfide at 0.630 mg/kg/day. The disposition of the cmpd was similar for both sexes. A small portion of the radioactivity remained associated with erythrocytes at 96 hr after dosing, most bound to the membranes. Between 60.8 and 101% of the administered dose appeared in the urine and between 3.46 and 9.99% in the feces in 96 hr. Only trace amounts remained in tissues other than blood, with the thyroid retaining the highest concentration. It was concluded that 2-mercaptobenzothiazole disulfide was readily converted to 2-mercaptobenzothiazole in both sexes of rats and in both species tested. [R45] METB: *ABSORPTION, TISSUE DISTRIBUTION AND EXCRETION OF (14)C 2-MERCAPTOBENZOTHIAZOLE WAS INVESTIGATED AFTER ADMIN TO CARP. THE RADIOACTIVE CHEMICAL IN BILE WAS DETERMINED TO BE BENZOTHIAZOLE-2-MERCAPTOGLUCURONIDE. [R44] *Cysteine conjugate beta-lyases, enzymes that are present in mammalian liver, kidneys, and intestinal microflora, were exploited recently for site selective delivery of 6-mercaptopurine to the kidneys. In this study, in vivo cysteine conjugate beta-lyase activity was assessed using S-(2-benzothiazolyl)-L-cysteine. 2-Mercaptobenzothiazole and 2-mercaptobenzothiazole S-glucuronic acid were major metabolites of S-(2-benzothiazolyl)-L-cysteine in rat liver, kidney, plasma, and urine. Total metabolite concn in liver, kidney, or plasma at 30 min were similar and were higher than that detected at 3 hr; metabolites were mostly in the glucuronide form. The portions of metabolites excreted in urine at 8 and 24 hr were nearly 93 and 99% of that excreted at 40 hr, respectively. Pretreatment of rats with aminooxyacetic acid did not alter kidney, liver, plasma, or urinary metabolite concn. The portion of the S-(2 benzothiazolyl)-L-cysteine dose excreted as metabolites at 24 hr was independent of the S-(2-benzothiazolyl)-L- cysteine dose (100-400 umol/kg), age (5-12 wk), or sex of the rats. The rates of in vitro S-(2-benzothiazolyl)-L- cysteine metabolism by guinea pig hepatic and renal cysteine conjugate beta-lyases were slower than those of rats, but the portion of the S-(2-benzothiazolyl)-L- cysteine dose recovered as metabolites in guinea pig urine at 24 hr was nearly 60%, which was nearly 2 fold higher than that recovered in urine of rats, mice, or hamsters. The amounts of total metabolites excreted into urine by mice or hamsters were similar, but the portion of metabolites that was in the glucuronide form in hamster urine was higher than that in mouse urine. [R46] *The metabolic fate of the sulfur atom in the sulfhydryl group of 2-thiobenzothiazole metabolites was examined in a series of experiments in rats using (14)C and (35)S labeled L-cysteine and 2-thiobenzothiazole metabolites. Male Wistar rats were orally administered (35)S labeled 2-mercaptobenzothiazole. Glutathione conjugates of 2-mercaptobenzothiazole from biliary metabolites were determined in rat liver in vitro. The (35)S retention ratios in 2-mercaptobenzothiazole was over 90%. [R47] *Renal cysteine conjugate beta-lyase catalyzes the bioactivation of nephrotoxic cysteine S-conjugates. Cysteine conjugate beta-lyase activity is present in both renal cytosolic and mitochondrial fractions, and, although the cytosolic cysteine conjugate beta-lyase is identical to glutamine transaminase K, the mitochondrial cysteine conjugate beta-lyase has not been characterized. Because cysteine conjugate beta-lyase is a pyridoxal phosphate dependent enzyme, pyridoxamine phosphate formation may occur during the metabolism of cysteine S-conjugates. In this study, the effects of alpha-ketoacids, which may convert the pyridoxamine phosphate form of the enzyme to the pyridoxal phosphate form, on the metabolism and cytotoxicity of cysteine S-conjugates were examined; the pyridoxamine phosphate enzyme is catalytically inactive in beta-elimination reactions, but is catalytically active in transamination reactions. Both alpha-keto-gamma-methiolbutyrate and alpha-ketobutyrate enhanced the metabolism of S-(2-benzothiazolyl)-L-cysteine to 2-mercaptobenzothiazole by rat renal cytosol or mitochondria. alpha-Keto-gamma-methiolbutyrate and phenylpyruvate potentiated both the cytotoxicity of S-(1,2-dichlorovinyl)-L-cysteine in isolated rat renal proximal tubular cells and the inhibition of mitochondrial respiration produced by S-(1,2-dichlorovinyl)-L-cysteine. These results are consistent with the formation of pyridoxamine phosphate during the renal cytosolic or mitochondrial metabolism of cysteine S-conjugates Mitochondrial cysteine conjugate beta-lyase was previously localized in the outer membrane. To examine whether cysteine conjugate beta-lyase activity is present in mitoplasts, but in the pyridoxamine phosphate form, the effects of alpha-keto-gamma-methiolbutyrate on the metabolism of S-(2-benzothiazolyl)-l-cysteine to 2-mercaptobenzothiazole and on the S-(1,2-dichlorovinyl)-L-cysteine induced inhibition of state 3 respiration in mitoplasts were studied. The majority of the mitochondrial cysteine conjugate beta-lyase activity was present in the outer membrane, and the specific activity of the outer membrane cysteine conjugate beta-lyase was greater than that of the mitoplast cysteine conjugate beta-lyase. alpha-Keto-gamma-methiolbutyrate produced equivalent stimulation of cysteine conjugate beta-lyase activity in intact mitochondria, in mitochondrial outer membranes, and in mitoplasts and potentiated S-(1,2-dichlorovinyl)-L- cysteine induced inhibition of respiration in intact mitochondria, but not in mitoplasts. These results provide additional evidence for the central role of cysteine conjugate beta-lyase in the bioactivation of nephrotoxic cysteine S-conjugates. [R48] INTC: *ADJUVANTS ARE FORMULATION FACTORS THAT ARE USED TO ENHANCE PHARMACOLOGIC OR TOXIC EFFECT OF ACTIVE INGREDIENT. ... EXAMPLES OF ADJUVANTS USED IN TOXICOLOGIC FORMULATIONS INCL ... USE OF MERCAPTOBENZOTHIAZOLE TO ENHANCE FUNGICIDAL ACTIVITY OF DITHIOCARBAMATES [R49, 71] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Antifungal Agents [R50] *(VET): AT 1-2% CONCN IN OINTMENTS AND LOTIONS APPLIED IN WIDE VARIETY OF CANINE DERMATOSES AND ON TEATS OF COWS. [R4] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Mercaptobenzothiazole may be released to the environment in wastewater during its production, transport, disposal, and use as a rubber vulcanization accelerator, fungicide and a chemical intermediate. 2-Mercaptobenzothiazole has a low to moderate mobility in soil, so if released on land it may leach, especially in alkaline soil. While 2-mercaptobenzothiazole is considered difficult to biodegrade, biodegradation may occur when low concns of the chemical are released in acclimated soil. Its half-lives in three standard soils ranged from 92 to 248 days. If released in water, 2-mercaptobenzothiazole would be partially dissociated and may partially absorb to sediment, especially in acidic water. It would rapidly photodegrade in surface water with a half-life of 0.05 days in summer and 0.21 days in winter. It may very slowly biodegrade in acclimated waters. It would not be expected to bioconcentrate in fish. If the atmosphere, 2-mercaptobenzothiazole will react with photochemically-produced hydroxyl radicals resulting in an estimated atmospheric half-life of 8.4 hr. Exposure to 2-mercaptobenzothiazole would be primarily occupational by dermal contact or inhalation of aerosols. (SRC) ARTS: *2-Mercaptobenzothiazole may be released to the environment in wastewater(SRC) during its production, transport, disposal, and use as a rubber vulcanization accelerator(1), fungicide and a chemical intermediate(1,2). It is also contained in some antifreeze mixtures in automobile cooling systmes as a corrpsion inhibitor(3). It may also be released as a result of the hydrolysis or photolysis of 2-(thiocyanomethylthio)benzothiazole, an alternative to pentachlorophenol as an antisapstain agent in the lumber industry(2). [R51] *Mercaptobenzothiazole compounds, e.g. sodium mercaptobenzothiazole, enter the environment through plant effluents and emissions associated with their manufacture, use, and end product processing and through the degradation and wear of end products, such as tire dust. /Mercaptobenzothiazole/ [R52] FATE: *TERRESTRIAL FATE: 2-Mercaptobenzothiazole has a low to moderate mobility in soil, so if released on land it may leach. Leaching is more likely to occur in alkaline soil. While 2-mercaptobenzothiazole is considered difficult to biodegrade, biodegradation may occur when low concns of the chemical are released to acclimated soil. The half-lives of 2-mercaptobenzothiazole in three standard soils ranged from 92 to 248 days(1). [R53] *AQUATIC FATE: If released in water, 2-mercaptobenzothiazole would be partially dissociated and may partially adsorb to sediment, especially in acidic water. It would rapidly photodegrade in surface water with a half-life of 0.05 days in summer and 0.21 days in winter(1). It may very slowly biodegrade in acclimated waters. It would not be expected to volatilize appreciably. [R54] *ATMOSPHERIC FATE: If released into the atmosphere, 2-mercaptobenzothiazole would be in the form of an aerosol and be removed by gravitational settling. Vapor-phase 2-mercaptobenzothiazole will react with photochemically-produced hydroxyl radicals resulting in an estimated atmospheric half-life of 8.4 hr(1). [R55] BIOD: *Biodegradation studies with 2-mercaptobenzothiazole using an activated sludge seed indicates little or no biodegration(2-4). Only 2.5% of the 2-mercaptobenzothiazole (100 ppm) degraded in a 2-week period in the standard biodegradability test of the Japanese Ministry International Trade and Industry (MITI), a BOD test utilizing a mixed inoculum of activated sludge, sewage and surface water(6). On this basis, 2-mercaptobenzothiazole was judged to be difficult to biodegrade(5,6). It has been suggested that at the concns used in these studies, 56-100 ppm, 2-mercaptobenzothiazole is toxic to the microorganisms in the sludge(1). A more detailed study indicated that inhibitory effects occur between 20 and 50 ppm of 2-mercaptobenzothiazole(1). When the sludge is well acclimated and the concn low enough, 2-mercaptobenzothiazole may completely biodegrade forming 2-benzothiazolesulfonate or dibenzothiazole-2,2-disulfide, depending on conditions(1). [R56] *2-Mercaptobenzothiazole (20 ppm) was judged to be moderate and difficult to biodegrade in sea water and river water, respectively based on the results of the 3-day Cultivation method by 4 Japanese institutes(3). The half-life of 2-mercaptobenzothiazole in three standard soils was 248, 238, and 92 days, respectively(1). In two of the soils, 1-methyl-1-benzthiazolylurea was detectable after 15 days and reached levels of 0.3 ppm after 3 mo; only traces of this metabolite were detected in the third soil(1). In a 1-week pilot ground water recharge experiment, 2-mercaptobenzothiazole (5 ppb) flowed through the sand without any sign of microbial degradation(1). When 2-mercaptobenzothiazole was incubated with Canagagigur Creek, Ontario, Canada suspended sediment at room temperature in the dark, 2% of the chemical was biotically methylated to 2-(methylthio)benzothiazole in 1 week(2). [R57] ABIO: *2-Mercaptobenzothiazole has a UV absorption band at 312.5 nm(4) and therefore may undergo direct photolysis in the environment. When dissolved in air-saturated 96% ethanol, methanol, or acetonitrile and exposed to radiation > 290 nm for 22 hr, bis(2-benzothioyl) disulfone was obtained as an intermediate, which after cleavage and hydrolysis forms benzothiazole sulfate as the final product(2). Photolysis experiments were conducted outdoors with 2-mercaptobenzothiazole in buffered water (pH 7) with and without sterilized dissolved organic matter and in filtered sterilized natural water (pH 7.1). The total solar radiation (400-700 nm) for these experiments ranged from 20.9 to 62.8 Einsteins/sq m and resulted in > 95% to > 99% degradation(1). The photolysis half-lives of 2-mercaptobenzothiazole in pure water and water with 10 mg/L organic matter were calculated from the molar absorptivities at 40 deg N latitude(1). For pure water the half-lives are 0.22, 0.18, 0.40, and 0.71 days for spring, summer, fall and winter respectively. The respective values for water with the dissolved organic matter is 0.17, 0.13, 0.30, and 0.53 days, respectively. The presence of dissolved organic matter may result in longer half-lives by attenuating light(SRC). The dark controls for the photolysis experiments indicated the absence of hydrolysis(1). Irradiation in both phosphate buffer (pH7) with and without the addition of dissolved organic matter and in natural water produced 3 products: benzothiazole (11-18% which increased to 29-47% after acidification), 2-hydroxylbenzothiazole (4-5%) and an unidentified product(1). [R58] *The dissociation constant for 2-mercaptobenzothiazole is between 6.7 and 7.2 (4,5) and therefore in the environmental pH range 2-mercaptobenzothiazole can exist in the ionized thiolate form as well as the two unionized thiol and thione tautomers. The thione form is believed to be responsible for its ligand formation with several metals, and this could affect its behavior in aquatic systems(3). In the atmosphere, 2-mercaptobenzothiazole will exist primarily as the vapor(2). There it will react with photochemically-produced hydroxyl radicals with an estimated rate constant of 45.8X10-12 cu cm/molecule-s(1). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of 2-mercaptobenzothiazole in the atmosphere would be 8.4 hr(SRC). [R59] BIOC: *In a 6-week test performed at two concn levels, the BCF of 2-mercaptobenzothiazole in carp was < 8(1). Another investigator also reported little or no bioconcentration in fish(2). These experimental results are in agreement with the BCF of 41 estimated from the log Kow of 2.41(3) using a recommended regression equation(4). Since the dissociation constant (pKa) for 2-mercaptobenzothiazole is between 6.7 and 7.2 (5,6), the percentage of ionized 2-mercaptobenzothiazole, will increase with pH and its Kow and BCF may be pH sensitive(SRC). [R60] KOC: *No experimental soil adsorption data were located for 2-mercaptobenzothiazole. Since the dissociation constant for 2-mercaptobenzothiazole (pKa) is between 6.7 and 7.2(5,6), the percentage of ionized 2-mercaptobenzothiazole, and therefore its solubility, will increase with pH. The Koc, which is generally inversely proportional to the water solubility(1), may be pH sensitive(SRC). Using the water solubilities of 2-mercaptobenzothiazole in creek water at pH 6.5 (190 ppm), 7.5 (230 ppm) and 8.5 (260 ppm)(4), the respective Koc values are estimated to be 342, 219, and 205 using a recommended regression equation (1). The Koc for 2-mercaptobenzothiazole estimated from molecular structure is 1600(2), which would be for the unionized molecule (less then about pH 4.7). According to a suggested classification scheme(3), the above Koc values indicate that the mobility of 2-mercaptobenzothiazole in soil will range from medium to low, depending on the pH. [R61] VWS: *The Henry's Law constant for 2-mercaptobenzothiazole estimated from structure activity relationships is 3.6X10-8 atm-cu-m/mol(1). Chemicals with such low Henry's Law constants are nonvolatile from water(2). [R62] EFFL: *MERCAPTOBENZOTHIAZOLE HAS BEEN IDENTIFIED IN THE WASTE WATER OF TIRE MANUFACTURERS. [R16, 2107] *In a comprehensive survey of wastewater from 4000 industrial and publicly owned treatment works (POTWs) sponsored by the Effluent Guidelines Division of the U.S. EPA, 2-mercaptobenzothiazole was identified in one discharges each of the rubber processing and pesticides manufacturing industries at a concn of 1.27 and 0.86 ppm, respectively(4). The concn of 2-mercaptobenzothiazole in the effluent from a Kraft paper mill was 0.025 ppm(5). 2-Mercaptobenzothiazole was detected in effluent from an industrial dump at a concn of about 0.03 mg/L(1). The effluent from a sewage treatment plant discharging into the River Lee in England contained trace amounts of 2-mercaptobenzothiazole(3). It was also found in wastewater from a tire plant(2). [R63] *Mercaptobenzothiazole has been found at a concentration of 30 ug/l in the wastewater from a tire manufacturing plant. /Mercaptobenzothiazole/ [R64] SEDS: *Detected in sediment in Japan; levels and percentage of positive samples not reported(1). [R65] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Detected in fish in Japan; levels and percentage of positive samples not reported(1). [R65] RTEX: *Exposure to 2-mercaptobenzothiazole would be primary occupational via dermal contact with wastewater and inhalation of aerosols containing this chemical. (SRC) *IN RUBBER INDUSTRY, NUMBER OF CHEMICAL AGENTS USED IN PREPARING RUBBER CAN SENSITIZE EXPOSED WORKERS. THESE INCL ACCELERATORS SUCH AS MERCAPTOBENZOTHIAZOLE. ... [R49, 583] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 62,970 workers are exposed to 2-mercaptobenzothiazole in the USA(1). [R66] BODY: *Detected in human tissue samples examined between 1977 and 1985 in Japan; levels and percentage of positive samples not reported(1). [R65] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: +Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 5 mg/cu m, skin. [R67] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Mercaptobenzothiazole is included on this list. [R68] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Mercaptobenzothiazole is included on this list. [R68] *Manufacturers and processors of 2-mercaptobenzothiazole are required to conduct chemical fate, environmental effects, and health effects testing under TSCA section 4. [R69] FIFR: *In 1988, Congress amended FIFRA to strengthen and accelerate EPA's reregistration program. The nine-year reregistration scheme mandated by "FIFRA 88" applies to each registered pesticide product containing an active ingredient initially registered before November 1, 1984. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA '88 were divided into three lists based upon their potential for exposure and other factors, with List B being of highest concern and D of least. List: B; Case: 2-Mercaptobenzithiazole, salts; Case No.: 2380; Pesticide type: Fungicide and antimicrobial; Case Status: Awaiting Data/Data in Review: OPP awaits data from the pesticide's producer(s) regarding its human health and/or environmental effects, or OPP has received and is reviewing such data, in order to reach a decision about the pesticide's eligibility for reregistration. Active Ingredient (AI): 2- Mercaptobenzothiazole; AI Status: The active ingredient is no longer contained in any registered products. Therefore, EPA is characterizing it as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees, to make or meet certain reregistration commitments, or when the Agency reaches findings of unreasonable adverse effects. [R70] FDA: *2-Mercaptobenzothiazole is an indirect food additive for use only as a component of adhesives. [R71] *2-Mercaptobenzothiazole solution. Opthalmic and topical dosage form new animal drugs not subject to certification. Specifications and conditions of use provided for dogs. [R72] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *PROBLEMS IN DETERMINATION OF 2-MERCAPTOBENZOTHIAZOLE IN WATER FROM REFUSE DUMP WERE OVERCOME BY DEVELOPMENT OF A PROCEDURE INVOLVING THE USE OF HPLC WITH UV ABSORPTION AT A MAX WAVELENGTH OF 325 NM. [R73] *2-MERCAPTOBENZOTHIAZOLE WAS DETERMINED IN RUBBER BABY BOTTLE NIPPLES BY HPLC. [R74] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole in F344/N Rats and B6C3F1 Mice Technical Report Series No. 332 (1988) NIH Publication No. 88-2588. SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 739 R3: Farm Chemicals Handbook 1992. Willoughby, OH: Meister Publishing Co., 1992.,p. C-214 R4: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 339 R5: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 26 R6: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-202 R7: SRI R8: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-114 R9: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R10: Danehy JP, Parameswaran KN; J Chem Eng Data 13: 386-9 (1968); Lomakina LN, Yakovskaya EK; Vestn Mosk Univ, Khim 24: 73-6 (1969) R11: Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) R12: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-206 R13: ITO M ET AL; AICHI IKA DAIGAKU IGAKKAI ZASSHI 7 (3): 183-9 (1979) R14: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 391 R15: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 259 R16: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 390 R18: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 649 R19: REEPMEYER JC, JUHL YH; J PHARM SCI 72 (11): 1302-5 (1983) R20: BRANSBURY AJ; CONTACT DERMATITIS 5 (5): 317-23 (1979) R21: Guimaraens D et al; Contact Dermatitis 26 (4): 268-9 (1992) R22: Wilkinson SM et al; Contact Dermatitis 23 (5): 370 (1990) R23: Zina AM et al; Contact Dermatitis 17 (1): 17-20 (1987) R24: Feinman SE; J Toxicol Cutaneous Ocular Toxicol 6 (2): 117-53 (1987) R25: HINDERER RK ET AL; ENVIRON MUTAGEN 5 (2): 192-215 (1983) R26: GOODWIN BF J ET AL; CONTACT DERMATITIS 7 (5): 248-58 (1981) R27: HARDIN BD ET AL; SCAND J WORK ENVIRON HEALTH 7 (SUPPL 4): 66-75 (1981) R28: KORHONEN A ET AL; SCAND J WORK ENVIRON HEALTH 9 (2): 115-9 (1983) R29: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (Gavage Studies) p.6 (1988) Technical Rpt Series No. 332 NIH Pub No. 88-2588 R30: Ikarashi Y et al; Contact Dermatitis 28 (2): 77-80 (1993) R31: Ogawa Y et al; Bull Natl Inst Hyg Sci (Tokyo) (107): 44-50 (1989) R32: Brewster DW et al; Biochem Biophys Res Commun 165 (1): 342-8 (1989) R33: Wang X, Suskind RR; Contact Dermatitis 19 (1): 11-5 (1988) R34: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 810 R35: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (Gavage Studies) p.5 (1988) Technical Rpt Series No. 332 NIH Pub No. 88-2588 R36: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (Gavage Studies) p. 5 (1988) Technical Rpt Series No. 332 NIH Pub No. 88-2588 R37: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of 2-Mercaptobenzothiazole (CAS No. 149-30-4) Contact Hypersensitivity Studies in Female B6C3F1 Mice, NTP Study No. IMM90003 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 20, 2002 R38: Pharmakon Research International Inc.; CHO/HGPRT Mammalian Cell Forward Gene Mutation Assay, (1983), EPA Document No. 40-8472012, Fiche No. OTS0510916 R39: Litton Bionetics Inc.; Mutagenicity Evaluation of Mercaptobenzothiazole in the Mouse Lymphoma Forward Mutation Assay, Final Report, (1985), EPA Document No. FYI-AX-0285-0308, Fiche No. OTS0000308-1 R40: Pharmakon Research International Inc.; Ames Salmonella/Microsome Plate Test, (1984), EPA Document No. 40-8472010, Fiche No. OTS0510914 R41: Pharmakon Research International, Inc.; Genetic Toxicology Micronucleus Test (MNT), Mercaptobenzothiazole. (1984), EPA Document No. 40-8472011, Fiche No. OTS0510915 R42: Southern Research Institute; Disposition of 2-Mercaptobenzothiazole-Ring-UL-14C in Fischer 344 Rats Dosed Orally, Final Report, (1986), EPA Document No. 40-8672120, Fiche No. OTS0510971 R43: Southern Research Institute; Disposition of 2-Mercaptobenzothiazole-Ring-UL-14C in Fischer 344 Rats Dosed Intravenously, Final Report, (1986), EPA Document No. 40-8672124, Fiche No. OTS0510973 R44: HASHIMOTO K ET AL; BULL JPN SOC SCI FISH 44 (6): 623-30 (1978) R45: El Dareer SM et al; J Toxicol Environ Health 27 (1): 65-84 (1989) R46: Elfarra AA, Hwang IY; Drug Metab Dispos Biol Fate Chem 18 (6): 917-22 (1990) R47: Fukuoka M, Tanaka A; Arch Toxicol 61 (2): 158-60 (1987) R48: Elfarra AA et al; Mol Pharmacol 31 (2): 208-12 (1987) R49: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. R50: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R51: (1) Engels HW; in Ullmann's Encyclopedia of Industrial Chemistry. Weinheim, Germany: VCH mbH. A23: 370 (1993) (2) Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) (3) Folasy RT, Brown,BF; Kirk-Othmer Encycl Chem Technol 3rd ed NY,NY: Wiley-Intersceince 7:135 (1979) R52: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.12 (1983) R53: (1) Kettrup et al; Analytical Techniques in Environmental Chemistry II, Albaiges J (ed) New York, NY: Pergamon Press pp. 231-9 (1982) R54: (1) Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) R55: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R56: (1) DeVos D et al; Appl Macrobiol Biotechnol 39: 622-6 (1993) (2) Mainprize J et al; J Appl Bacteriol 40: 285-91 (1976) (3) Chudoba J et al; Act Hydrochem Hydrobiol 5: 495-8 (1977) (4) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (5) Kondo M et al; Eisei Kagaku 34: 115-22 (1988) (6) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 5-6 (1992) R57: (1) Kettrup et al; Analytical Techniques in Environmental Chemistry II, Albaiges J (ed) New York, NY: Pergamon Press pp. 231-9 (1982) (2) Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) (3) Kondo M et al; Eisei Kagaku 34: 115-22 (1988) R58: (1) Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) (2) Parkanyi C, Abdelhamid AO; Heterocycles 23: 2917-26 (1985) R59: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Brownlee B et al; A review of benothiazoles in the aquatic environment. No. 126, Sci Ser Canada, Burlington, Ont, Canada: Inland Water Directorate (1981) (4) Danehy JP, Parameswaran KN; J Chem Eng Data 13: 386-9 (1968) (5) Lomakina LN, Yakovskaya EK; Vestn Mosk Univ, Khim 24: 73-6 (1969) R60: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 p. 5-6 (1992) (2) Sasaki S; pp. 283-98 in Aquatic Pollutants Hutzinger O et al, eds Oxford: Pergamon Press (1978) (3) Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) (4) Lyman WJ et al (eds); Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5, Eqn 5-2 (1982) (5) Danehy JP, Parameswaran KN; J Chem Eng Data 13: 386-9 (1968) (6) Lomakina LN, Yakovskaya EK; Vestn Mosk Univ, Khim 24: 73-6 (1969) R61: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. pp. 4-1 to 4-34 NY,NY: McGraw-Hill (1982) (2) Meylan WM et al; Environ Sci Technol 26: 1560-7 (1992) (3) Swann RL et al; Res Rev 85: 17-28 (1983) (4) Brownlee BG et al; Environ Toxicol Chem 11: 1153-68 (1992) (5) Danehy JP, Parameswaran KN; J Chem Eng Data 13: 386-9 (1968) (6) Lomakina LN, Yakovskaya EK; Vestn Mosk Univ, Khim 24: 73-6 (1969) R62: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) R63: (1) Cox GB; J Chromatography 116: 244-7 (1976) (2) Brownlee B et al; A review of benothiazoles in the aquatic environment. No. 126, Sci Ser Canada, Burlington, Ont, Canada: Inland Water Directorate (1981) (3) Waggott A; Chem Water Reuse 2: 55-9 (1981) (4) Shackelford WM et al; Anal Chim Acta 146: 15-27 (Supplementary data) (1983) (5) Keith LH; Environ Sci Technol 10: 555-64 (1976) R64: Jungclaus GA et al; Anal Chem 48(13): 1894-6 (1976) as cited in ITC/USEPA; Information Review #351 (Draft Addendum) Sodium Mercaptobenzothiazole (1983) R65: (1) Sumino K; Proc ICMR Semin 8(Proc Asia-Pac Symp Occup Toxicol): 91-6 (1988) R66: (1) NIOSH; National Occupational Exposure Survey (1989) R67: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.40 R68: 40 CFR 716.120 (7/1/94) R69: 40 CFR 799.2475 (7/1/94) R70: USEPA/OPP; Status of Pesticides in Reregistration and Special Review p.142 (Mar, 1992) EPA 700-R-92-004 R71: 21 CFR 175.105 (4/1/93) R72: 21 CFR 524.1376 (4/1/93) R73: COX GB; J CHROMATOGR 116 (1): 244-7 (1976) R74: BLOSCZYK G, DOEMLING HJ; LEBENSMITTELCHEM GERICHTL CHEM 36 (4): 90 (1982) RS: 59 Record 247 of 1119 in HSDB (through 2003/06) AN: 4057 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-DIRECT-BLUE-6- SY: *AIREDALE-BLUE-2BD-; *AIZEN-DIRECT-BLUE-2BH-; *AMANIL-BLUE-2BX-; *ATLANTIC-BLUE-2B-; *ATUL-DIRECT-BLUE-2B-; *AZOCARD-BLUE-2B-; *AZOMINE-BLUE-2B-; *BELAMINE-BLUE-2B-; *BENCIDAL-BLUE-2B-; *BENZANIL-BLUE-2B-; *BENZO-BLUE-BBA-CF-; *BENZO-BLUE-BBN-CF-; *BENZO-BLUE-GS-; *BLUE-2B-; *BLUE-2B-SALT-; *BRASILAMINA-BLUE-2B-; *CALCOMINE-BLUE-2B-; *CHLORAMINE-BLUE-2B-; *CHLORAZOL-BLUE-B-; *CHLORAZOL-BLUE-BP-; *CHROME-LEATHER-BLUE-2B-; *CI-DIRECT-BLUE-6-; *C.I.-DIRECT-BLUE-6,-TETRASODIUM-SALT-; *C.I.-22610-; *CRESOTINE-BLUE-2B-; *DIACOTTON-BLUE-BB-; *DIAMINE-BLUE-2B-; *DIAMINE-BLUE-BB-; *DIAPHTAMINE-BLUE-BB-; *DIAZINE-BLUE-2B-; *DIAZOL-BLUE-2B-; *DIPHENYL-BLUE-2B-; *DIPHENYL-BLUE-KF-; *DIPHENYL-BLUE-M2B-; *DIRECT-BLUE-A-; *DIRECT-BLUE-6-; *DIRECT-BLUE-2B-; *DIRECT-BLUE-GS-; *DIRECT-BLUE-M2B-; *ENIANIL-BLUE-2BN-; *FENAMIN-BLUE-2B-; *FIXANOL-BLUE-2B-; *HISPAMIN-BLUE-2B-; *INDIGO-BLUE-2B-; *KAYAKU-DIRECT-BLUE-BB-; *MITSUI-DIRECT-BLUE-2BN-; *NAPHTAMINE-BLUE-2B-; *2,7-NAPHTHALENEDISULFONIC ACID, 3,3'-((1,1'-BIPHENYL)-4,4'-DIYLBIS(AZO))BIS(5-AMINO-4-HYDROXY-,TETRASODIUM SALT; *NIPPON-BLUE-BB-; *PARAMINE-BLUE-2B-; *PHENAMINE-BLUE-BB- RN: 2602-46-2 RELT: 948 [BENZIDINE] (Analog) MF: *C32-H2O-N6-O14-S4.4Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared commercially by coupling diazotized benzidine with 2 mol H-acid (8-amino-1-naphthol-3,6-disulfonic acid) under alkaline conditions. [R1] MFS: *FABRICOLOR MFR CORP, PATERSON, NJ 07505 [R2] OMIN: *The commercial material is a reaction product and is not to be regarded as a single substance... [R3] USE: *In hair dyes [R4] *Dyeing or staining silk, wool, cotton, nylon, leather, paper, biologic stains, and writing inks. [R5, 710] PRIE: U.S. PRODUCTION: *(1973) 1.49X10+8 G (SALES) [R2] *(1977) PROBABLY GREATER THAN 4.54X10+6 G [R2] *Domestic production figures for Direct Blue 6 indicated that 150,000 kg were produced in 1973. [R5, 710] U.S. IMPORTS: *(1978) 2.00X10+6 G [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Blue violet solid [R3] MW: *936.8 [R3] SOL: *Sol in water; slightly sol in ethanol and ethylene glycol monoethyl ether; insol in other organic solvents. [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: +Red fuming nitric acid. /Benzidine based dyes/ [R6, 26] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R7, 1979.8] +Wear appropriate personal protective clothing to prevent skin contact. /Benzidine based dyes/ [R6, 26] +Wear appropriate eye protection to prevent eye contact. /Benzidine based dyes/ [R6, 26] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. /Benzidine based dyes/ [R6, 26] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.) /Benzidine based dyes/ [R6, 26] +Recommendations for respirator selection: Conditon: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Benzidine based dyes/ [R6, 27] +Recommendations for respirator selection: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Benzidine based dyes/ [R6, 27] OPRM: *The most effective control of Direct Black 38, Direct Brown 95, and Direct Blue 6, where feasible, is at the source of contamination by enclosure of the operation and/or local exhaust ventilation. If feasible, the process or operation should be enclosed with a slight vacuum so that any leakage will result in the flow of air into the enclosure. The next most effective means of control would be a well designed local exhaust ventilation system that physically encloses the process as much as possible, with sufficient capture velocity to keep the contaminant from entering the work atmosphere. To ensure that ventilation equipment is working properly, effectiveness (eg, air velocity, static pressure, or air volume) should be checked at least every three months. System effectiveness should be checked soon after any change in production, process, or control that might result in significant increases in airborne exposures to Direct black 38, Direct Brown 95, and Direct Blue 6. ... Exposure to Direct Black 38, Direct Brown 95, and Direct Blue 6 should not be controlled with the use of respirators except during the time period necessary to install or implement engineering or work practice controls, or in work situation in which engineering and work practice controls are technically not feasible, or for maintenance, or for operations that require entry into tanks or closed vessels or in emergencies. [R8] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R7, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R7, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R7, 1979.11] +The worker should immediately wash the skin when it becomes contaminated. /Benzidine based dyes/ [R6, 27] +The worker should wash daily at the end of each work shift. /Benzidine based dyes/ [R6, 27] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Benzidine based dyes/ [R6, 27] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Benzidine based dyes/ [R6, 27] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R7, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R7, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R7, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R7, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R7, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R7, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R7, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R7, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R7, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) No data for evidence in animals. Overall summary evaluation of carcinogenic risk to humans is Group 2A: The agent is probably carcinogenic to humans. /From table; Benzidine-based dyes/ [R9] MEDS: *Urine cytology surveillance has proved useful in evaluating tumors in dyestuff plant workers. The system consists of two-stage tests: periodic urine cytology, followed by, in suspicious cases, urological examinations. /Benzidine/ [R10] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R7, 1979.23] HTOX: *A strong association relating human exposure to benzidine based dyes with the subsequent development of bladder tumors was presented after a case control mortality study of 200 bladder cancer patients in Japan. The patients were found to have been predominantly kimono painters and dyers. The kimono painters had a habit of forming a point on their brushes by drawing the brush between their lips, which allowed for ingestion of the dyes. Several other case control mortality studies indicate an increased risk of developing bladder cancer in the textile and leather industries, both large users of direct dyes. However, only a few references have been made concerning benzidine derived dyestuffs. In Russia, a medical study concerning the early detection of bladder tumors among textile dyers using benzidine derived dyes revealed an unusual incidence of bladder lesions, some of which were suggested as being of a precancerous nature. The greatest number of such lesions were found in those workers with the highest potential exposure to these dyes. /Benzidine based dyes/ [R8] NTOX: *Groups of 10 male and 10 female Fischer 344 rats, 6 weeks old, were fed a diet containing 0, 190, 375, 1500 or 3000 mg/kg (ppm) Direct Blue 6 and 1.3% corn oil. Survivors were killed at 13 weeks. All male and female animals administered 3000 mg/kg Direct Blue 6 and 1 male administered 1500 mg/kg diet of the dye died prior to termination of the study; all males given the highest dose died before 5 weeks on the study, and all females at the dose were dead by 10 weeks on test. Liver cell tumors were seen in 8 to 10 males given 1500 mg/kg; 2 were hepatocellular carcinomas and 6, neoplastic nodules. Of animals given 3000 mg/kg, 1 of 9 males and 7 out of 9 females were found to have liver cell tumors at autopsy prior to the termination of the experiment; 4 of the tumors in females were hepatocellular carcinomas and 3 were neoplastic nodules. No neoplastic lesion was seen in animals of either sex given lower doses. The first tumors appeared after 4 weeks of feeding in the males and after 5 weeks of feeding in the females. Almost all animals fed 750 or 1500 mg/kg exhibited foci of cellular alterations in the liver and some basophilic foci were seen in the livers of animals receiving 3000 mg/kg. [R11] *Twenty female Wistar rats (age unspecified) were given 400 mg/l Direct Blue 6 (purity unspecified) in their drinking water (0.04%) for 14 months. At 12 months, 12 animals were still alive, and 1 exhibited a glandular tumor of the outer ear. No other neoplasm was found. (The Working Group noted the small number of animals and lack of a control group.) [R11] *Nine dyes structurally related to Congo red were examined for developmental testicular toxicity. The structural component of the dyes responsible for the prenatal induction of germ cell aplasia was identified. Only benzidine-based dyes altered testicular development and caused hypospermatogenesis in mice during adulthood. Dimethyl- and dimethoxybenzidine-based dyes were without effect. Pregnant mice were dosed orally on Days 8-12 of gestation with a benzidine-, dimethylbenzidine-, or a dimethoxybenzidine-based dye and the testes of 45- to 50-day-old male offspring were examined. The testes of postpubertal male offspring exposed to the benzidine-based dyes, Congo red, diamine blue, and Chlorazol Black E, were small and contained some tubules completely devoid of germ cells, but the dimethylbenzidine-based dyes, trypan blue, Evans blue, and benzopurpurin 4B, and the dimethoxybenzidine-based dye, Chicago sky blue, did not alter testicular development in this manner. [R12] *The mutagenicity of 13 commercial azo dyes was investigated. Blue-2B was tested for mutagenicity in the Ames/Salmonella Assay utilizing strains (TA-98) or (TA-100) with or without metabolic activation by liver S9 mix from phenobarbital treated rats. Concentrations ranged from 1 to 500 micrograms per plate. Direct-Blue-2B was mutagenic at high concentrations in (TA-100) in the absence of liver S9 mix, but not when S9 mix was added to the system. [R13] *The DNA binding of 2 benzidine azodyes, Congo Red and Direct Blue 6, was compared in rat liver. Both dyes showed binding consequent upon metabolism to benzidine, and in each case hydrolysis of the liver DNA yielded N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. The majority of Direct Blue 6-derived radioactivity bound to DNA was present as at least one other novel species. Work on the major Direct Blue 6 DNA adduct suggests its structure may be disodium 8-amino-2-[4-(N-deoxyguanosin-8-yl)-aminobiphenyl-4'-yl]azo-l-hydroxynaphthalene -3,6-disulphonate. This adduct may form as a result of the susceptibility of the dye to hepatic azoreductase and its apparent existence may explain the observed potent carcinogenicity of dyes such as Direct Blue 6. [R14] *Studies were performed to assess covalent binding of [3H]benzidine, [14C]N-acetylbenzidine, [14C]N, N'-diacetylbenzidine, and the benzidine-derived azo dye Direct Blue 6 to rat hepatic DNA. Following IP injection into male Sprague-Dawley rats, benzidine and N-acetylbenzidine bound to liver DNA to yield the same adduct: N-(deoxyguanosin-8-yl)-N'-acetylbenzidine. The isomeric N-(deoxyguanosin-8-yl)-N-acetylbenzidine and the deacetylated adduct N-(deoxyguanosin-8-yl) benzidine were also synthesized, but neither of these adducts was detected in vivo. Injection of N,N'-diacetylbenzidine resulted in only barely detectable binding which was insufficient for adduct analysis. [3H]Direct Blue 6 was administered to male Wistar rats either by IP injection or by gavage. In both instances, Direct Blue 6 bound covalently to liver DNA; however, binding occurred at a much higher level in the IP injected animals. With IP injected animals, high pressure liquid chromatographic analysis indicated that approximately 70% of the radioactivity was associated with N-(deoxyguanosin-8-yl) benzidine. [R15] NTP: *Thirteen wk subchronic toxicity study of Direct Blue 6 ... was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 10 rats and 10 mice of each sex were administered /the test cmpd/ at one of five concentrations for 13 wk and then necropsied, beginning the second day after the end of the dosing period. The concentrations used for the rats were 190, 375, 750, 1,500, 3,000. The concentrations used for the mice ... were 375, 750, 1,500, 3,000 and 6,000 ppm. Matched controls consisted of groups of 10 untreated rats and 10 untreated mice of each sex. ... It is concluded that under the conditions of these 13 wk subchronic toxicity studies, direct blue 6 ... was carcinogenic in male and female Fischer 344 rats. ... Direct blue 6 induced hepatocellular carcinomas and neoplastic nodules in the liver. Direct blue 6 was not carcinogenic for B6C3F1 mice in the 13 wk subchronic toxicity studies. [R16] TCAT: ?Acute oral toxicity was evaluated in groups of male and female albino SASCO rats (5 animals/group) administered single doses of Niagara Blue 2B Conc. 250% (direct blue 6) as a 50% w/w aqueous solution by oral gavage at levels of 7.10, 8.60, 10.41 and 12.62 g/kg of body weight. Mortality was observed in 2 animals in the 8.60 g/kg dose group, and all animals in both the 10.41 and 12.62 g/kg dose groups. The LD50 value was calculated to be 8.76 g/kg with confidence limits of 7.98 to 9.62 g/kg by the method of Weil. Clinical observations included prostration, labored breathing, wobbly legs, lethargy, hypersensitivity, moribundity and malaise. Gross necropsy revealed congestion of the lungs and liver, and purple staining of the kidneys and gastrointestinal tract in decedents. [R17] ?Acute oral toxicity was evaluated in groups of New Zealand albino rabbits (1 female and 1 male/group) administered single doses of Niagara Blue 2B Conc. 250% (direct blue 6) as a 50% w/w aqueous solution by oral gavage at levels of 2.0, 4.0, 8.0 and 16.0 g/kg of body weight. Mortality was observed in 1 animal in the 4.0 g/kg dose group, 1 in the 8.0 g/kg dose group, and both animals in the highest dose group. The MLD was reported to be 8.76 g/kg with confidence limits of 7.98 to 9.62 g/kg. Clinical observations were not reported. Gross necropsy revealed blue staining of all major organ systems and other tissues in decedents. [R18] ?Acute dermal toxicity was evaluated in groups of 2 male and 2 female New Zealand albino rabbits receiving single occluded applications of diluted Niagara Blue 2B, Conc. 250% (Direct Blue 6) at dose levels of 2.0 or 8.0 g/kg of body weight. The test article was held in contact with the intact or abraded skin (evenly divided) for a 24-hour period. Mortality was observed in 1 animal in the 2.0 g/kg dose group and 1 animal in the 8.0 g/kg dose group. The LD50 value was reported to be greater then 8.0 g/kg. Clinical observations included ventral soiling. Gross necropsy revealed blue stained liver, kidneys, intestines, urine and stomach in decedents; blue to purplish staining of the kidneys was observed in survivors. [R19] ?Acute inhalation toxicity was evaluated in 10 SASCO albino rats (sex not reported) exposed to Niagara Blue 2B, Conc. 250% (Direct Blue 6) at a flow concentration of approximately 154 mg/liter for 1 hour (plus a 6-min equilibration period). The test atmosphere was generated by passing a metered air supply through a dust generating device. Mortality was not observed in any animal; an LC50 value was not reported. The clinical observation period was uneventful. Gross necropsy revealed some darkening of the lung tissue. [R20] ?The mutagenicity of 3,3'-((1,1'-biphenyl)-4,4'-diylbis(azo))bis(5-amino-4-hydroxy-2,7-naphthalenedis ulfonic acid), tetrasodium salt (direct blue 6) was evaluated in Salmonella tester strains TA1535, TA100, TA1535 and TA100, both in the presence and absence of metabolic activation provided by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, direct blue 6 was tested for mutagenicity at concentrations of 1000, 2500, 5000, 7500, and 10,000 ug/plate using the plate incorporation method. The investigators reported weak mutagenic activity for strain TA1537 in the presence of metabolic activation. [R21] ?The mutagenicity of 3,3'-((1,1'-biphenyl)-4,4'-diylbis(azo))bis(5-amino-4-hydroxy-2,7-naphthalenedis ulfonic acid), tetrasodium salt (direct blue 6) was evaluated in Salmonella tester strains TA1535, TA100, TA1537 and TA98, both in the presence and absence of Aroclor-induced rat liver S9 fraction to provide metabolic activation. Based on preliminary bacterial toxicity determinations, direct blue 6 was tested for mutagenicity at concentrations of 250, 500, 1000, 2500, 3500 and 5000 ug/plate using the plate incorporation method. The investigators reported weak mutagenic activity in strains TA1538 and TA98 in the absence of metabolic activation. 4.9 times the spontaneous reversion frequency (0.009 revertants/nmole) was observed in strain TA1538 without activation, and 2.9, 1.6, and 3.2 times the spontaneous reversion frequency (0.01 revertants/nmole) was observed in strain TA98 in successive trails. [R22] ?The mutagenicity of 3,3'-((1,1'-biphenyl)-4,4'diylbis(azo))bis(5-amino-4-hydroxy-2,7-naphthalenedisu lfonic acid), tetrasodium salt (direct blue 6) was evaluated in Salmonella tester strains TA1535, TA100, TA1537 and TA98, both in the presence and absence of Aroclor-induced rat liver S9 fraction to provide metabolic activation. Based on preliminary bacterial toxicity determinations, direct blue 6 was tested for mutagenicity at concentrations of 250, 500, 1000, 2500, 3000, 5000, 7500, and 10,000 ug/plate using the plate incorporation technique. Weak mutagenic activity was observed in strain TA1537 in the presence of metabolic activity where 1.9, 2.3, and 2.0 times the spontaneous reversion frequency was observed in 3 successive trials. [R23] ?The mutagenicity of 3,3'-((1,1'-biphenyl)-4,4'-diylbis(azo))bis(5-amino-4-hydroxy-2,7-naphthalenedis ulfonic acid), tetrasodium salt (direct blue 6) was evaluated in Salmonella tester strains TA1535, TA100, TA1537 and TA98, both in the presence and absence of Aroclor-induced rat liver S9 fraction to provide metabolic activation. Based on preliminary bacterial toxicity determinations, direct blue 6 was tested for mutagenicity at concentrations of 250, 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000 and 5000 ug/plate using the plate incorporation technique. Weak mutagenic activity was observed in strains TA1538 and TA98 in the absence of metabolic activation. In strain TA1538, 4.9 times the spontaneous reversion frequency (0.009 revertants/nmole) was observed and in strain TA98, 2.9, 1.6, and 3.2 times the spontaneous reversion frequency was observed in 3 successive trials. [R24] ?Direct Blue 6 (2602-46-2) was evaluated for developmental effects in groups of mice administered the test substance at dose levels of 0 (88 mice), 50 (35 mice), 75 (28 mice), 100 (29 mice), or 200 (38 mice) mg/kg/day on days 6 through 15 of gestation. Animals were sacrificed on day 18 of gestation. There were three mortalities at 200 mg/kg/day. Maternal animals at 100 and 200 mg/kg/day showed significantly decreased average weight gain (p < 0.01). Average maternal liver weight was significantly increased at all dose levels (p < 0.0001) and showed a dose related trend (p < 0.001). Fetal weight was significantly decreased at all treatment levels (p < 0.05) and exhibited a dose related trend (p < 0.0001). The percentage of resorptions was increased (p < 0.001) and the number of live fetuses was decreased at 100 and 200 mg/kg/day, while the percent malformed fetuses was significantly increased at 75, 100, and 200 mg/kg/day (p < 0.03) (all three parameters showed a dose related trend). Significantly increased malformations observed included cleft palate (p < 0.02) and wavy ribs (p < 0.01). [R25] ADE: *Rhesus monkeys excreted an average of 1.25% benzidine plus monoacetylbenzidine of the benzidine moiety in Direct Blue 6 in the urine after receiving two different doses by gavage, whereas gavage with pure benzidine yielded 1.45%. [R11] METB: *Benzidine derived azo dyes may be degraded metabolically in the gut or liver in man to free benzidine or monoacetylbenzidine. /Benzidine derived azo dyes/ [R26] *Environmental and urine samples were collected at six factories where workers were potentially exposed to benzidine based dyes (two benzidine based dye manufacturers, two textile dyeing plants, a leather dyeing plant and a mill where paper was dyed). Monoacetylbenzidine was detected in the urine of 2/8 workers at one of the dye manufacturing plants at levels of 3 and 7 ppb. At the second factory, 4 workers exposed to average levels of 7.9, 5.2, 11.7 and 17.4 mg total particulate/cu m had corresponding urinary concentrations of 52, 11, 10 and 112 ppb benzidine; 590, 248 and 22 ppb monoacetylbenzidine were detected in urine samples containing 112, 52 and 11 ppb benzidine. Traces of diacetylbenzidine, ortho-tolidine and ortho-dianisidine were also detected. Benzidine (0-39 ppb) and/or monoacetylbenzidine was detected in the urine of workers in one textile dyeing factory where Direct Black 38 and Direct Blue 2 were being used. The total level of airborne particulates (measured gravimetrically) was 1-4 mg/cu m. Benzidine was not detected in the urine of workers from the other facilities. Minute levels of impurities in the dyestuffs could not account for the quantity of benzidine and its derivatives that were found in the urine samples. [R27] *Six azodyes derived from benzidine, o-tolidine or o-dianisidine were separately administered orally by gavage to rats. Urine was collected over a 24 hr period. All six dyes, direct black 38, direct brown 95, direct blue 6, Congo red, trypan blue and Chicago sky blue were found to be reduced, N-acetylated and N-conjugated. However, no N,N'-diacetylated metabolites were detected. After administration of the same dyes via injection into the hepatic portal vein, bile was collected over a 3 hr period by cannulation of the bile duct. Urine was withdrawn from the bladder by syringe at the end of the three hours. Both body fluids were analyzed for reduction products which were found only in the case of direct black 38, direct brown 95 and direct blue 6. Of the six dyes examined only the three direct dyes were mutagenic to S. typhimurium strains TA98 and TA1538 in the absence of flavin mononucleotide. The same three dyes were also substrates for rat liver microsomal azoreductase enzymes whereas Congo red, trypan blue and Chicago sky blue were shown to be inactive. [R28] *The azo reduction and acetylation in vitro and the mutagenic activation in vivo of three azo dyes were studied. In the presence of rat-liver 9000 g supernatant benzidine was released from direct black 38 and direct brown 95, whereas hardly any benzidine was produced during incubation of direct blue 6. Incubation of benzidine with isolated rat hepatocytes resulted in the appearance of diacetylbenzidine. No diacetylbenzidine was formed during incubation of benzidine with rat-liver 9000 g supernatant, unless the cofactor for the acetylation reaction, acetyl coenzyme A, was added to the incubation medium. Isolated rat hepatocytes were capable to produce diacetylbenzidine from direct black 38, direct blue 6 or direct brown 95 without supplementation with acetyl coenzyme A. Rat liver has a considerable capacity to reduce azo compounds. [R29] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Beauticians exposed to paraphenylenediamine derivatives in hair dyes, workers dyeing texitle resins, and photographic film developers exposed to color developing solutions not infrequently become sensitized to azo dyes. /Organic dyes/ [R5, 147] *The national Occupational Hazard Survey (NOHS), conducted between 1972 and 1974 by the National Institute for Occupational Safety and Health, indicates that workers are occupationally exposed to Direct Black 38, Direct Brown 95, and Direct Blue 6 in a variety of industries, including: paper and allied products, petroleum and related industries, rubber and plastic products, leather and leather products, instrumentation and measuring devices, and banking. In addition, the textile industry accounts for a substantial occupational exposure. It is estimated that 25% of the benzidine derived azo dyes are applied to textiles, 40% to paper, 15% to leather, and the remainder to other diverse applications. ... In the general population, unspecified exposure levels to the three dyes are thought to occur through the use of retail packaged dyes for home dyeing and for home and school use in art and craft projects such as tie dyeing or batik. [R5, 709] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers benzidine based dyes to be potential occupational carcinogens. /Benzidine based dyes/ [R6, 26] NREC: *NIOSH recommends that three widely used benzidine derived dyes, Direct Black 38, Direct Blue 6, and Direct Brown 95, be handled in the workplace as if they were human carcinogens. [R30] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. [R6, 26] +NIOSH considers benzidine based dyes to be potential occupational carcinogens. /Benzidine based dyes/ [R6, 26] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2,7-Naphthalenedisulfonic acid, 3,3'((1,1'-biphenyl)-4,4'-diylbis(azo)bis)5-amino-4-hydroxy-, tetrasodium salt is included on this list. [R31] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 325. Analyte: Direct Blue 6. Matrix: Air. Procedure: Filter collection, sodium hydrosulfite reduction. Flow Rate: 1.5 to 2.0 l/min. Sample Size: 500 liters. /From table/ [R32] *NIOSH Method 5013. Analyte: Direct Blue 6. Matrix: Air. Sampler: Filter (5 um polytetrafluoroethylene membrane). Flow Rate: 1 to 3 l/min. Sample Size: 500 liters. Shipment: Keep samples dry and cool; protect from light. Sample Stability: Greater than or equal to 7 days @ 25 deg C in the dark. /From table/ [R33] ALAB: *NIOSH Method 325. Analyte: Direct Blue 6. Matrix: Air. Procedure: High performance liquid chromatography, ultra violet detector. Method Evaluation: Method was validated over the range of 30 to 600 mg/cu m using a 500 liter sample. Method detection limit: 3.8 ng (benzidine). Precision (CVt): 0.06. Interferences: No specific interferences. /From table/ [R32] *NIOSH Method 5013. Analyte: Direct Blue 6. Matrix: Air. Procedure: High performance liquid chromatography, ultra violet detection. Estimated level of detection: Not determined.on The precision/RSD is 4.34% and the recovery is 100.3%. Applicability: The working range is 30 to 600 ug/cu m for a 250 liter air sample. Interferences: Aniline, azobenzene, p-aminophenol, p-phenylenediamine or p-nitroaniline do not interfere in the measurement when present in equimolar amounts. /From table/ [R34] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.21. NTP TR No 108; Route: oral in feed; Species: rats and mice. NTIS No PB280204/AS. Uziel M et al; DNA Adduct Formation by 12 Chemicals with Populations Potentially Suitable for Molecualr Epidemiological Studies; Mutat Res 277 (1): 35-90 (1992). U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) Chung KT et al; The Reduction of Azo Dyes by the Intestinal Microflora; Crit Rev Microbiol 18 (3): 175-90 (1992). The significance of the capacity of intestinal bacteria to reduce azo dyes and the conditions of azo reduction is examined. SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 312 (1982) R2: SRI R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 311 (1982) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 313 (1982) R5: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. R6: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R7: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R8: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 699 R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 58 (1987) R10: Yamaguchi N et al; Am J Ind Med 3 (2): 139-48 (1982) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 314 (1982) R12: Gray LE Jr, Ostby JS; Fundam Appl Toxicol 20 (2): 177-83 (1993) R13: Kaur A et al; Environ and Mol Mutagen 22 (3): 188-90 (1993) R14: Kennelly JC et al; Toxicology 32 (4): 315-24 (1984) R15: Martin CN et at; Environ Health Perspect 49: 101-6 (1983) R16: DHEW/NCI; Bioassay of Direct Blue 6, Direct Black 38, and Direct Brown95 Dyes for Possible Carcinogenicity p.vii (1978) Technical Rpt Series No. 108 DHEW Pub No. (NIH) 78-1358 R17: Scientific Associates, Inc.; Acute Oral Toxicity (LD50) in Rats. (1973), EPA Document No. 878221046, Fiche No. OTS0215154 R18: Scientific Associates, Inc.; Acute Oral Toxicity (MLD) in Rabbits. (1973), EPA Document No. 878221046, Fiche No. OTS0215154 R19: Scientific Associates, Inc.; Acute Dermal Toxicity (LD50) in Rabbits, (1973), EPA Document No. 878221046, Fiche No. OTS0215154 R20: Scientific Associates, Inc.; Inhalation Toxicity in Rats, (1973), EPA Document No 878221046, Fiche No. OTS0215154 R21: E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine; Mutagenic Activity in the Salmonella/Microsome Assay, (1979), EPA Document No. 878220312, Fiche No. OTS0215029 R22: E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine; Mutagenic Activity in the Salmonella/Microsome Assay, (1979), EPA Document No. 878220313, Fiche No. OTS0215029 R23: E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine; Mutagenic Activity in the Salmonella/Microsome Assay, (1979), EPA Document No. 878220345, Fiche No. OTS0215029 R24: E. I. du Pont de Nemours and Company Haskell Laboratory for Toxicology and Industrial Medicine; Mutagenic Activity in the Salmonella/Microsome Assay, (1979), EPA Document No. 878220346, Fiche No. OTS0215029 R25: Research Triangle Institute; Initial Submission: Teratogenicity Study with Direct Blue 6 in Mice with Cover Letter Dated 072292, (1979), EPA Doc. No. 88-920005532, Fiche No. OTS0544786 R26: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 316 (1982) R27: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 317 (1982) R28: Kennelly JC et al; Carcinogenesis 3 (8): 947-51 (1982) R29: Bos RP et al; Toxicology 31 (3-4): 271-82 (1984) R30: NIOSH; Current Intelligence Bulletin (Reprints-Bulletins 19 thru 30), Sept 1979 No. 24 - Direct Blue 6, Direct Black 38, Direct Brown 95 - Benzidine Derived Dyes p.1 (1978) R31: 40 CFR 716.120 (7/1/94) R32: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V6 325-1 R33: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5013-1 R34: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 49 Record 248 of 1119 in HSDB (through 2003/06) AN: 4073 UD: 200208 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 8-HYDROXYQUINOLINE- SY: *1-AZANAPHTHALENE-8-OL-; *BIOQUIN-; *Pesticide-Code:-059803-; *FENNOSAN-H-30-; *HYDROXYBENZOPYRIDINE-; *8-HYDROXYCHINOLIN-; *NCI-C55298-; *8-OQ-; *OXIN-; *OXINE-; *OXYBENZOPYRIDINE-; *OXYCHINOLIN-; *o-OXYCHINOLIN- (GERMAN); *OXYQUINOLINE-; *8-OXYQUINOLINE-; *Phenopyridine-; *8-QUINOL-; *QUINOLINE,-8-HYDROXY-; *8-QUINOLINOL-; *QUINOPHENOL-; *TUMEX-; *USAF-EK-794- RN: 148-24-3 MF: *C9-H7-N-O ASCH: 8-Hydroxyquinoline sulfate; 134-31-6 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF O-AMINOPHENOL WITH O-NITROPHENOL, GLYCEROL AND SULFURIC ACID; OR BY HYDROLYSIS OF QUINOLINE-8-SULFONIC ACID [R1] *By sulfonation fusion of quinoline, by hydrolysis of 8-chloroquinoline (93% (yield) or by a modified Skraup method with o-aminophenol (80% yield). [R2] *Acid hydrolysis of the appropriate aminoquinoline at temps 180-235 deg C. [R3, 784] FORM: *USEPA/OPP Pesticide Code 059803; Trade Names: Fennosan H 30, NCI-C55298, Tumex, USAF EK-794, Quinophenol. [R4] *... AVAILABLE IN USA IN TECHNICAL AND REAGENT GRADES. IT IS ALSO AVAILABLE AS 0.5% SOLN (OR AEROSOL) SUITABLE FOR TOPICAL USE. [R5] MFS: *Napp Chemicals, Inc, Hq, 199 Main St, Lodi, NJ 07644, (201) 773-3900; Production site: Lodi, NJ 07644 [R6] OMIN: *... /Has been/ discontinued by Ashland Chemical Co. [R7] *BACTERIOSTATIC AND ANTIMYCOTIC ACTIVITY OF 8-HYDROXYQUINOLINE SULFATE IN DERMATOSES IS BLOCKED BY INCORPORATION OF 8-HYDROXYQUINOLINE SULFATE IN EXSICCANT PASTE SR71, ZINC OXIDE-OIL, AND ZINC OXIDE LOTION. IT IS NOT RELEASED OR IS RELEASED IN ONLY SMALL AMOUNTS FROM LIPOPHILIC BASES (EXCEPT OLEOGELS), PREPARATIONS WITH EXTERNAL LIPID PHASE AND ZINC OXIDE-CONTAINING VEHICLES. /8-HYDROXYQUINOLINE SULFATE/ [R8] USE: *For 8-Hydroxyquinoline (USEPA/OPP Pesticide Code: 059803) there are 0 labels match. /SRP: Not registered for current use in the U.S., but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R4] *CHEMICAL INTERMEDIATE FOR THE ANTI-INFECTIVE AGENT, OXYQUINOLINE BENZOATE; FOR THE FUNGICIDE, COPPER 8-QUINOLINATE; FOR DIIODOHYDROXYQUIN; FOR FUNGICIDAL SALTS IN TEXTILE PRODUCTS; ANTISEPTIC IN NUMEROUS APPLICATIONS; STABILIZER FOR HYDROGEN PEROXIDE. [R1] *ANALYTICAL COLORIMETRIC REAGENT AND FOR PRECIPITATION AND SEPARATION OF METALS; PREPN OF NUMBER OF DERIVATIVES USED IN MEDICINE AND INDUSTRIAL APPLICATIONS; USED TO MAKE ITS COPPER CHELATE, COPPER 8-HYDROXYQUINOLATE FOR FUNGICIDE IN AGRICULTURAL AND INDUST APPLICATIONS; USED IN MFR OF DYES. [R9] *Corrosion inhibitor. [R10] *Stabilizer in nylon [R11] *Used to determine metal ion concentration ... ligand forming five-membered chelate ring. ... Group reagent and forms complexes of varying intensity with more than 40 ions. [R12] *Chelating agent [R13] *Employed as a brightener in a bright tin electroplating bath for steel sheets. [R3, 779] *Heterocyclic coupling component in azo dyes. [R14] *Therap Cat: Antiseptic [R15] *Fungicide, bactericide /Copper salt/ [R16] *MEDICATION PRIE: U.S. IMPORTS: *(1972) 2.51X10+7 G (PRINCPL CUSTMS DISTS) [R1] *(1975) 2.98X10+7 G (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystals or white crystalline powder [R17] ODOR: *Phenolic odor [R17] BP: *Approx 267 deg C [R18] MP: *73-75 deg C [R17] MW: *145.16 [R18] DEN: *1.034 @ 20 deg C [R19] DSC: *pKa 5.017; Ka 1.21X10-6 at 20 deg C [R20]; *pKa1= 5.017; pKa2= 9.812 [R21] OWPC: *log Kow = 2.02 [R22] SOL: *Soluble in alcohol, acetone, chloroform, benzene, and in formic, acetic, hydrochloric, and sulfuric acids and alkalies. [R17]; *1 part in 1500 parts water [R23]; *In water, 556 mg/l @ 20 deg C [R24] SPEC: *SADTLER REF NUMBER: 187 (IR, PRISM); 63 (IR, GRATING); MAX ABSORPTION (ALCOHOL): 240 NM (LOG E= 4.60); 308 NM (LOG E= 3.47) [R25]; *Intense mass spectral peaks: 145 m/z (100%), 117 m/z (78%), 90 m/z (30%), 89 m/z (29%) [R26, p. V5 4886]; *IR: 5568 (Coblentz Society Spectral Collection) [R26, p. V5 4886]; *UV: 76 (Sadtler Research Laboratories Spectral Collection) [R26, p. V5 4886]; *1H NMR: 24 (Sadtler Research Laboratories Spectral Collection) [R26, p. V% 4886]; *MASS: 65043 (NIST/MSDC/EPA Mass Spectral Database, 1990 version) [R26, p. V5 4886] VAP: *1.66X10-3 mm Hg @ 25 deg C [R27] OCPP: *Readily forms stable metal chelates [R28] *Usually tan /Technical grade/ [R17] *Pale yellow, crystalline powder; slight saffron odor; burning taste; MP: 175-178 deg C; freely sol in water; insol in ether; sol in about 100 parts glycerol; slightly sol in alcohol /8-Hydroxyquinoline sulfate/ [R18] *Darkens when exposed to light [R17] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat or flame. [R29, 2854] DCMP: *WHEN HEATED TO DECOMP EMITS HIGHLY TOXIC FUMES OF /NITROGEN OXIDES/. [R29, 2854] SSL: *DARKENS WHEN EXPOSED TO LIGHT. [R30] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R31] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R32, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatic hydrocarbons and related compounds/ [R32, 182] HTOX: *VARIOUS HALOGENATED DERIVATIVES USED IN TREATING AMEBIASIS IN MAN ARE ... COMPARATIVELY BENIGN EXCEPT FOR FREQUENT ALLERGIC REACTIONS ... /8-HYDROXYQUINOLINE SULFATE/ [R33] NTOX: *Hydroxyquinoline is moderately toxic in rats (oral LD50 1.2 g/kg). When injected, it is distinctly toxic (rat ip LD50 50 mg/kg) and causes marked stimulation of CNS. Mice given large doses exhibited confusion, resp difficulty, hind leg paralysis and violent convulsions, with death within 2 hr. After smaller fatal doses, death was delayed several days. Toxic symptoms then included anorexia, malaise, and general indifference to sound or light. [R33] *TESTS BY INJECTION OF 0.01 MOLAR SOLN INTO RABBIT CORNEA CAUSED VERY SLIGHT REACTION, GRADED 5 ON A SCALE OF 0-100. IV INJECTIONS OF /0.04-0.075 G/KG/ IN RABBITS CAUSED PROMPT AND TRANSIENT PROPTOSIS ASSOC WITH VENOUS ENGORGEMENT, HYPERPNEA, RAPID PULSE, AND SALIVATION. [R34] *A GROUP OF 49 CC57W MICE WERE GIVEN 1.5 MG/ANIMAL ... /ORALLY/ IN SUNFLOWER OIL 6 TIMES/WK FOR 660 DAYS (TOTAL DOSE, 852 MG/ANIMAL). OF 21 SURVIVING AT ... APPEARANCE OF 1ST TUMOR (460 DAYS) 4 DEVELOPED 2 LYMPHOMAS, 2 LUNG ADENOMAS AND 1 HEMANGIOMA OF LIVER. TUMOR INCIDENCE IN UNTREATED CC57W MICE ... WAS ... 17%. (ABSENCE OF CONCURRENT CONTROLS WAS NOTED) [R35] *A GROUP OF 15 6-WK OLD MALE FISCHER F344 RATS RECEIVED 0.8% ... IN DIET FOR 78 WK, AT WHICH TIME 13 SURVIVED. ... 4 LEYDIG-CELL TUMORS OF THE TESTIS /WERE OBSERVED/. HYPERPLASIA OF INTERSTITIAL CELLS OF TESTIS WAS OBSERVED IN 2/8 SURVIVING CONTROLS. (THE SMALL NUMBER OF ANIMALS AND SHORT DURATION OF EXPT WERE NOTED) [R36] */12 MALE AND 12 FEMALE FISCHER RATS WERE ORALLY TREATED AT/ ... DOSE LEVELS ... OF 0.1, 3, 10, and 30 MG/ANIMAL/DAY. MAX SURVIVAL RANGED FROM 384-563 DAYS. 1 HEPATOMA WITH LUNG METASTASES OCCURRED AFTER 456 DAYS IN 1 MALE RAT GIVEN HIGHEST DOSE LEVEL. 3 CYSTIC ADENOMAS OF LUNG, 15 TESTICULAR TUMORS AND 4 MAMMARY TUMORS OCCURRED AMONG RATS IN OTHER GROUPS; THESE TUMORS ALSO OCCURRED IN CONTROLS SURVIVING UP TO 600 DAYS. THE INCIDENCE IN TREATED ANIMALS WAS SLIGHTLY BUT NOT SIGNIFICANTLY INCREASED. [R36] *A GROUP OF 39 RANDOM-BRED RATS WERE GIVEN 15 MG/ANIMAL ... IN SUNFLOWER OIL 6 TIMES/WK FOR 729 DAYS (TOTAL DOSE, 9.36 G/ANIMAL). OF 21 RATS SURVIVING AT ... APPEARANCE OF 1ST TUMOR (589 DAYS), 11 DEVELOPED 2 LYMPHOMAS, 1 LUNG TUMOR (PLASMOCYTOMA), 2 PARASITIC SARCOMAS OF LIVER, 1 RETICULOSARCOMA OF INTESTINE, 1 ADENOCARCINOMA OF UTERUS AND 5 MAMMARY FIBROADENOMAS. IN UNTREATED RATS ... NO TUMORS OF UTERUS, LUNG OR INTESTINE OR LYMPHOMAS WERE OBSERVED. (ABSENCE OF CONCURRENT CONTROLS WAS NOTED). [R36] *A GROUP OF 32 CC57W MICE RECEIVED SC INJECTIONS OF 1.5 MG/ANIMAL ... IN SUNFLOWER OIL 3 TIMES/MO FOR 660 DAYS (TOTAL DOSE, 97.5 MG/ANIMAL). OF 23 MICE SURVIVING AT ... APPEARANCE OF 1ST TUMOR (148 DAYS), 10 DEVELOPED A TOTAL OF 2 LYMPHOMAS, 5 LUNG ADENOMAS, 1 SC HEMANGIOMA, 1 FOLLICULAR ADENOMA OF OVARY AND 2 HEMANGIOMAS OF LIVER. IN UNTREATED CC57W MICE ... TUMOR INCIDENCE WAS ... LESS THAN 17%. (ABSENCE OF CONCURRENT CONTROLS WAS NOTED). [R36] *A GROUP OF 70 RANDOM-BRED RATS RECEIVED WEEKLY SC INJECTIONS OF 100 MG/ANIMAL ... IN SUNFLOWER OIL FOR 730 DAYS (TOTAL DOSE, 10.5 G/ANIMAL). OF 24 RATS SURVIVING AT APPEARANCE OF FIRST TUMOR (624 DAYS), 4 DEVELOPED 3 LYMPHOMAS AND 1 FIBROSARCOMA AT INJECTION SITE. (ABSENCE OF CONCURRENT CONTROLS WAS NOTED). [R37] *A GROUP OF 46 CC57W MICE RECEIVED 3 APPLICATIONS/WK OF 1.2 MG OF 8-HYDROXYQUINOLINE AS 0.75% SOLN IN BENZENE FOR 656 DAYS (TOTAL DOSE, 335 MG/ANIMAL). A CONTROL GROUP OF 22 MICE RECEIVED BENZENE ALONE FOR 656 DAYS. OF 27 TREATED MICE SURVIVING AT THE APPEARANCE OF 1ST TUMOR (350 DAYS), 8 DEVELOPED 2 LYMPHOMAS, 2 SC HEMANGIOMAS, 1 SC LYMPHANGIOMA, 1 FOLLICULAR ADENOMA OF OVARY AND 2 HEMANGIOMAS OF LIVER; 2/22 CONTROL MICE RECEIVING BENZENE ALONE DEVELOPED LUNG ADENOMAS AFTER 427 and 619 DAYS (P > 0.05). [R37] *A GROUP OF 20 STOCK MICE ... RECEIVED BLADDER IMPLANT OF 9-11 MG CHOLESTEROL PELLET CONTAINING 20% 8-HYDROXYQUINOLINE. OF 13 MICE SURVIVING 40 OR MORE WK, 5 DEVELOPED BLADDER TUMORS (3 CARCINOMAS AND 2 PAPILLOMAS), COMPARED WITH 1 CARCINOMA IN 21 CONTROLS ALIVE AT 40 WEEKS (P < 0.01). [R37] *A GROUP OF 20 FEMALE STOCK MICE RECEIVED VAGINAL INSTILLATIONS OF 0.1 ML OF 1% SOLN ... IN POLYETHYLENE GLYCOL TWICE WEEKLY FOR 18 MO. TEN ... SURVIVED 12 MO AND 2 FOR 18 MO; 7 DEVELOPED CARCINOMAS OF VAGINA AND CERVIX. IN CONTROLS GIVEN POLYETHYLENE GLYCOL ALONE, 11 MICE SURVIVED 12 MO AND 7 FOR 18 MO; 5 DEVELOPED CARCINOMAS OF VAGINA AND CERVIX. IN A LATER TEST, 20 BALB/C MICE RECEIVED SIMILAR TWICE WEEKLY /VAGINAL/ INSTILLATIONS OF 0.1 ML OF 1% SOLN ... IN GUM TRAGACANTH FOR 50 WK. ONE MOUSE DEVELOPED SQUAMOUS PAPILLOMA OF UTERINE CERVIX AFTER 20 MO. NO INCREASE IN INCIDENCE OF TUMORS AT OTHER SITES WAS OBSERVED. [R38] *A GROUP OF 46 CC57W MICE RECEIVED TWICE WEEKLY INTRAVAGINAL APPLICATIONS OF 2 MG/ANIMAL 8-HYDROXYQUINOLINE AS 20% SUSPENSION IN DISTILLED WATER APPLIED TO SMALL PIECE OF COTTON WOOL; TREATMENT CONTINUED TO 812 DAYS (TOTAL DOSE, 428 MG/ANIMAL); 27 CONTROLS RECEIVED AN INSERTION OF COTTON WOOL AND DISTILLED WATER. OF 42 MICE STILL ALIVE AT ... APPEARANCE OF 1ST TUMOR (242 DAYS), 11 DEVELOPED 4 LYMPHOMAS, 4 LUNG ADENOMAS, 5 FOLLICULAR ADENOMAS AND THECOMAS OF OVARY AND 1 HEMANGIOMA OF LIVER; 2 LYMPHOMAS, 1 HEMANGIOMA OF LIVER OCCURRED IN 27 CONTROLS (P > 0.05). [R38] *A GROUP OF 30 FEMALE BETHESDA BLACK RATS RECEIVED VAGINAL INSTILLATIONS OF 0.2 ML OF 20% SUSPENSION ... IN 20% AQ GELATIN TWICE WEEKLY FOR 2 YR; 16 SURVIVED 22-24 MO. FOUR SQUAMOUS CELL CARCINOMAS OR ADENOCARCINOMAS OF ENDOMETRIUM WERE OBSERVED IN 22 RATS THAT DIED AFTER 19 MO; 1 UTERINE CARCINOMA WAS SEEN IN A GROUP OF 21 CONTROLS THAT DIED BETWEEN 19 and 24 MO. [R38] *A GROUP OF 62 RANDOM-BRED RATS RECEIVED TWICE WEEKLY INTRAVAGINAL INSTILLATIONS OF 20 MG/ANIMAL 8-HYDROXYQUINOLINE AS 20% SUSPENSION IN DISTILLED WATER; TREATMENT CONTINUED FOR 729 DAYS (TOTAL DOSE, 3.86 G/ANIMAL). OF 24 RATS STILL ALIVE AT APPEARANCE OF 1ST TUMOR (647 DAYS), 4 DEVELOPED 1 LYMPHOMA, 1 FOLLICULAR ADENOMA OF OVARY, 1 CARCINOMA OF UTERUS, 2 MAMMARY FIBROADENOMAS AND 1 THYROID CARCINOMA. IN UNTREATED RATS ... NO TUMORS OF UTERUS OR LYMPHOMAS WERE REPORTED. (ABSENCE OF CONCURRENT CONTROLS WAS NOTED). [R38] *IN RATS, ORALLY ADMIN 8-HYDROXYQUINOLINE PRODUCED DEPOSITION OF IRON IN MANY TISSUES ... THIS EFFECT WAS INCR BY INCREASING AMT OF AVAILABLE IRON IN DIET. ... A DOSE OF 20-40 UG/PLATE, CAUSED POINT MUTATIONS IN SALMONELLA TYPHIMURIUM TA100 IN PRESENCE OF RAT LIVER HOMOGENATE. [R39] *RABBITS TOLERATE SINGLE DOSES OF 3.7 G/KG (AS SULFATE, MIXED WITH POTASSIUM SULFATE). /8-HYDROXYQUINOLINE SULFATE/ [R33] *8-HYDROXYQUINOLINE WHICH IS NOT KNOWN TO BE CARCINOGENIC, WAS MUTAGENIC WITH S9 MIXT TO SALMONELLA TYPHIMURIUM STRAINS TA100 AND TA98. [R40] *8-HYDROXYQUINOLINE WAS MUTAGENIC TO SALMONELLA TYPHIMURIUM TA100 WHEN AROCLOR 1254-INDUCED RAT LIVER HOMOGENATE WAS PRESENT IN THE INCUBATION MIXTURE. [R41] *The Ames Salmonella assay was used to detect mutagenic activity in urine collected both from male and female B6C3F1 mice treated with 8-hydroxyqiunoline (dose in feed) ... Urine from 8-hydroxyquinoline-treated animals exhibited mutagenic activity on TA100 in male mice. The activity was greatly enhanced by the addition of rat S-9. [R42] *Hydroxyquinoline ... Completely inhibited in vitro the growth of yeast Malassezia ovalis, which is associated with dandruff. /Hydroxyquinoline/ [R23] *2-Chlorethanol, 8-hydroxyquinoline, 2,6-toluenediamine, and eugenol, previously found to behave as genotoxins in in vitro systems and as noncarcinogens in rodents, were evaluated for their ability to induce genotoxic effects in vivo. Rats were given by gavage a single or two successive doses equal to one-half the corresponding LD50, killed at different times after treatment, and examined for the following end points: the frequency of both micronucleated polychromatic erythrocytes in the bone marrow and micronucleated hepatocytes (after partial hepatectomy); the in vivo-in vitro induction of DNA fragmentation, as measured by the alkaline elution technique, and of unscheduled DNA synthesis, as measured by autoradiography, in hepatocyte primary cultures. The two latter end points were also evaluated after in vitro exposure of hepatocytes to log-spaced subtoxic concentrations. 2-Chloroethanol, 8-hydroxyquinoline, and eugenol never produced effects indicative of genotoxic activity. The same happened with 2,6-toluenediamine, with the exception of a significant increase over controls in the amounts of DNA damage and repair displayed by hepatocyte cultures obtained from rats given two 1/2 LD50 doses separated by a 24 hr interval. Our results, which, part the above mentioned exception, are in concordance with the rodent carcinogenicity results, contribute to underline the role of in vivo short-term tests for the detection of potential genotoxic carcinogens. [R43] *Quinoline is a specific and potent carcinogen to the rat and mouse liver. Studies are described here in which it was evaluated for its ability to initiate unscheduled DNA synthesis in the rat liver in vivo. Although some individual animals showed indications of a marginal response, the absence of clear group positive responses and the lack of an obvious dose relationship precluded the classification of quinoline as positive. The analogous NTP non-carcinogen 8-hydroxyquinoline was shown also to be devoid of unscheduled DNA synthesis activity. Quinoline did, however, induce a potent mitogenic response in the rat liver between 24 and 48 hr after oral dosing of 200-500 mg/kg. Under similar conditions of test, 8-hydroxyquinoline was essentially inactive. These data represent a further instance in which mitogenicity in the liver appears to correlate better with carcinogenicity than does genotoxicity; but it may not be that simple, as discussed in the text. A single dose of quinoline was shown to act as a replacement for surgical partial hepatectomy in the liver micronucleus assay consistent with its potent mitogenicity. [R44] *Chinese hamster ovary cells were used to test eight chemicals with different ratios of cytotoxicity to clastogenicity in an effort to investigate the utility and limitations of various cytotoxicity indicators. Immediate or delayed cell killing and growth inhibition were measured along with cell cycle perturbations. All compounds were used at concentrations that reduced cell growth at 24 hr by 50% or less. Colony forming efficiency was reduced 0 to 20% for concentrations of mitomycin-C, adriamycin, cadmium sulfate and 2,6-diaminotoluene which induced at least 15% of the cells with aberrations. In contrast, a marked loss of colony forming efficiency of 70 to 80% following treatment with eugenol, 2-aminobiphenyl, and 8-hydroxyquinoline. Intermediate loss was noted with 2,4-diaminotoluene. At 24 hr higher aberration yields were found than at 10 hr, even when minimal cell cycle delay was detected by average generation time estimate from BrdUrd labeled cells. Cells with multiple aberrations were seen at 24 but not at 10 hr. The mitotic index suppression often did not correlate with average generation time. Marked mitotic accumulation was seen at 10 hr for 2,4-diaminotoluene, indicating cell synchrony. It was concluded that the mitotic index had limited value for dose selection. Even weakly active chemicals were detected at a single time without exceeding a 50% growth reduction at 24 hr. [R45] *... Compounds were selected for evaluation of their activity against fungi on eggs of rainbow trout Oncorhynchus mykiss. 8-Quinolinol sulfate ... demonstrated the greatest potential as replacements for malachite green. The quinolinols cannot be considered for use as aquatic antifungal agents, however, because they were toxic to eggs at efficacious concn > 1.0 mg/l. /8-Quinolinol sulfate/ [R46] *This study was designed to determine the ability of two related cmpd, quinoline and 8-hydroxyquinoline, to induce micronuclei in mouse bone marrow erythrocytes. 6-8 wk old male CD1 mice were treated ip with single injections of 25, 50, 100 mg/kg of each /cmpd/. Samples of bone marrow were taken at 24, 48, and 72 hr after injection. A significant dose related incr was noted in the number of micronucleated polychromatic erythrocytes (MPCE) at the 24 hr sampling time for all dose levels. Statistically significant incr were caused in the number of MPCEs by exposure to 50 and 100 mg/kg dose levels at 48 hr. At 24 hr, the ratios of polychromatic to normochromatic erythrocytes were lower for treated than control animals. Hydroxyquinoline resulted in some incr in the number of micronucleated normochromatic erythrocytes (MNCEs) at all three dose levels at 24 hr after treatment. Higher incidence of MNCEs at 48 and 72 hr points were noted following exposure to both the low and medium dose levels. [R47] *In vitro assays of the genotoxicity of quinoline compounds have yielded varying indications of their potency, and only limited determinations have been reported following in vivo administrations. ... Chromosome aberrations and sister chromatid exchanges (SCE) in marrow cells of mice that had been injected with 8-hydroxyquinoline ... up to levels approaching lethality. /The cmpd/ had no measurable effect on either chromosome aberrations or sister chromatid exchanges. [R48] *Both quinoline and 8-hydroxyquinoline (HOQ) were tested for their genotoxicity in CD1 male mice by using a bone marrow micronucleus assay. Mice were intraperitoneally treated in single injections with three dose levels (25, 50, and 100 mg/kg) of each chemical with corn oil as solvent vehicle. Bone marrow was sampled at 24, 48, and 72 hr postinjection. Quinoline resulted in a significant dose-related increase in the number of micronucleated polychromatic erythrocytes (MPCE) at the 24 h sampling time for all doses tested. The high dose (100 mg/kg) and the medium dose (50 mg/kg) also induced statistically significant increases (P < .05) in the number of MPCEs at 48 hr interval. The ratios of polychromatic to normochromatic erythrocytes at the 24 h sampling time were lower for the treated than the control animals. Although HOQ resulted in some increases in the number of MPCEs over the control, this compound induced a statistically significant increase in the number of micronucleated normochromatic erythrocytes (MNCEs) at all three doses following 24 hr treatment. Both low and medium doses also induced a higher incidence of MNCEs at the 48 and 72 hr sampling times. No data were available for the high dose at these times. The cytotoxic effect of this compound was expressed as low PCE/NCE ratios with all doses at 24 hr after injection and as a high mortality rate in animals treated with the high dose (100 mg/kg). [R49] *Tropolone forms a lipophilic complex with indium-111 which is capable of mediating the labelling of polymorphonuclear leucocytes (PMNs) by this isotope; labelling efficiencies are comparable with the best achieved using 8-hydroxyquinoline and acetylacetone. However, in terms of PMN chemotaxis and phagocytosis, tropolone is significantly less toxic than either of the other ligands. 8-Hydroxyquinoline was found to reduce PMN chemotaxis and phagocytosis to approximately 70% of the control values at a concentration of 20 micro M. Tropolone may prove a superior labelling reagent. [R50] *The influence of the anticlastogens beta-aminoethylisothiouronium (AET), d,l-homocysteinethiolactone (HCT), and 1-cysteine (CYS) on the frequency of sister chromatid exchanges (SCEs) induced by the chromosome damaging chemicals Trenimon and 8-hydroxyquinoline sulfate (8-HQS), was investigated in human lymphocyte cultures. None of the anticlastogens significantly influenced the SCE rate, whereas in the same or previous experiments the chromosome-breaking effect of these clastogens was distinctly reduced by the anticlastogens. These results suggest that the sites of anticlastogenic activity do not coincide with the sites of SCE formation. SCE analysis, although it yields interesting and important information about the action of chemicals on genetic material, cannot replace classical aberration analysis, because the two parameters apparently reflect different patterns of molecular and cytogenetic activity of mutagens. /8-hydroxyquinoline sulfate/ [R51] *The influence of antidiuretic hormone (ADH) and papaverine on hydroxyquinoline-induced nephropathy in rats was tested. Hydroxyquinoline causes a marked increase in renal weight, the development of wedge-shaped foci with severely dilated tubule segments, and a simultaneous reduction in dehydrogenases, alkaline phosphatase, and alpha-naphthyl esterase. Both ADH and papaverine produced a significant inhibition of renal damage. The subjective findings were quantitatively confirmed by measurement of enzyme activity, using the microscope photometer, and by morphometric studies with the Leitz-Classimat (determination on the basis of the alkaline phosphatase reaction) of the surface percentage of brush border in the proximal tubules. A disturbance of the hairpin counter-current system is to be considered as the cause of the renal lesion. This disturbance is caused by hydroxyquinoline-induced impairment of Na+/K+ transport, especially in the thick ascending limb of Henle's loop. Our results show that the hydroxyquinoline nephropathy can be favourably influenced both by stimulation of water re-absorption and possibly also transepithelial Na+ transport (ADH), and by increasing the blood flow of the arteriolae rectae with a resultant lowering of the intratubular urine concentration (papaverine). The dependency of hydroxyquinoline nephropathy on the phylogenetically determined concentration capacity of the kidney, and the effective influencing of the condition by ADH and papaverine indicate the importance of the degree of efficiency of the medullary countercurrent system in the pathogenesis of this renal lesion. [R52] *The effect of 8-hydroxyquinoline sulfate on the formation of artificial calculi, rat calculus, and dog plaque plus its ability to remove dog plaque were studied. Several chemically related agents were also evaluated for their anticalculus effects. The most effective anticalculus agent was 8-hydroxyquinoline sulfate. At concentrations of 4 or 5%, swabbed over molar teeth, it was essentially equally effective in retarding the formation of rat calculus. Significant (1% level) reduction occurred with concentration as low as 3% in rats. When used so as to mimic mouthrinse use, 4% 8-hydroxyquinoline sulfate also significantly (5% level) reduced formation of calculus in rats. All rats showed normal behavioral and weight-gain patterns. Visual evaluation of oral tissues in the swabbing tests plus visual and histopathological evaluation of oral tissues in the mouthrinse procedure showed 8-hydroxyquinoline sulfate had no irritating or toxic effects. In dogs, the teeth treated with 4% 8-hydroxyquinoline sulfate nine times during a five-day period had 93.7 to 98.4% less buccal plaque than vehicle-treated teeth. The antiplaque effect was considerable in both canines and fourth premolars. In older dogs, teeth treated with 4% 8-hydroxyquinoline sulfate 15 times during a ten-day period had 33 to 46.1% less plaque than when treated with the vehicle. The effect was considerable on canines but slight on fourth premolars. In older dogs after 24 treatments during a 15-day period, 4% 8-hydroxyquinoline sulfate removed 25 to 57.5% of established plaque whereas the vehicle removed 2.5 to 22.5%. Again, 8-hydroxyquinoline sulfate was more effective on canine buccal plaque. These results show that 8-hydroxyquinoline sulfate is an effective anticalculus and antiplaque agent that is nontoxic to animal oral tissue. The results also indicate that the dog is a suitable animal model for the evaluation of antiplaque agents. /8-Hydroxy quinoline sulfate/ [R53] NTXV: *LD50 Rat oral 1200 mg/kg; [R54] *LD50 Mice ip 48 mg/kg; [R54] *LD50 Rat ip 50 mg/kg; [R33] *LD50 Mouse sc 83,600 ug/kg; [R29, 2855] *LD50 Mouse oral 20 g/kg; [R29, 2854] *LD50 Guinea pig oral 1205 mg/kg; [R29, 2855] NTP: *8-Hydroxyquinoline, given at 1500-3000 ppm in the feed of male and female F344/N rats and B6C3F1 mice for 103 wk, showed no evidence of carcinogenicity. Survival was similar to that of controls, with slight decreases in appetite and body weight with the high dose level. [R55] TCAT: ?The mutagenicity of 8-hydroxyquinoline was evaluated in Salmonella tester strains TA1535, TA1537, TA92, TA98 and TA100 (Ames Test), both in the presence and absence of added metabolic activation by either Aroclor or phenobarbital-induced rat liver S9 fraction. 8-Hydroxyquinoline, diluted in DMSO, was tested at concentrations up to 60ug/plate. 8-Hydroxyquinoline produced a positive response in Salmonella tester strain TA100 in the presence of added metabolic activation. The treatments failed to produce a positive response in any of the remaining tester strains with or without metabolic activation. [R56] ?The mutagenicity of 8-hydroxyquinoline was evaluated in Salmonella tester strains TA1537, TA92, TA98 and TA100 (Ames Test), both in the presence and absence of metabolic activation by Aroclor or phenobarbital-induced rat liver preparation. 8-Hydroxyquinoline, diluted in DMSO, was tested at concentrations up to 100mcg/plate. 8-Hydroxyquinoline produced a positive response only in Salmonella tester strains TA92 with metabolic activation and TA100 with and without metabolic activation. [R57] ADE: *IN RATS /MALE, DONRYU STRAIN, IV INJECTION/ 8-HYDROXYQUINOLINE WAS METABOLIZED TO GLUCURONIDE AND SULFATE CONJUGATES. MORE 8-HYDROXYQUINOLINE GLUCURONIDE WAS EXCRETED IN URINE THAN 8-HYDROXYQUINOLINE SULFATE CONJUGATE. ONLY THE GLUCURONIDE CONJUGATE WAS EXCRETED IN BILE. [R58] *8-HYDROXYQUINOLINE WAS METABOLIZED TO GLUCURONIDE AND SULFATE CONJUGATES AFTER IV ADMIN IN RATS /MALE, DONRYU STRAIN/. THE GLUCURONIDES WERE EXCRETED IN BILE AND URINE, BUT THE SULFATES WERE EXCRETED EXCLUSIVELY IN THE URINE. UNMETABOLIZED FORMS WERE ONLY SLIGHTLY EXCRETED. [R59] METB: *IN RATS /MALE, DONRYU STRAIN, IV INJECTION/ 8-HYDROXYQUINOLINE WAS METABOLIZED TO GLUCURONIDE AND SULFATE CONJUGATES. [R58] *8-HYDROXYQUINOLINE WAS METABOLIZED TO GLUCURONIDE AND SULFATE CONJUGATES AFTER IV ADMIN IN RATS /MALE, DONRYU STRAIN/. UNMETABOLIZED FORMS WERE ONLY SLIGHTLY EXCRETED. [R59] INTC: *AFTER LETHAL IM DOSES IN MICE (30 MG/KG) INJECTED D-PENICILLAMINE (1 G/KG) PREVENTED /TOXIC/ SYMPTOMS AND DEATH BUT NOT TRANSIENT HYPERGLYCEMIA. [R33] *THE INFLUENCE OF RADIOPROTECTORS, CYSTEAMINE AND AMINOETHYLISOTHIOURONIUM AS WELL AS OF THE AMINO ACIDS L-ALANINE, L-CYSTEINE, L-ARGININE, L-ASPARAGINE, L-GLUTAMIC ACID, L-HISTIDINE, AND L-METHIONINE, ON THE CYTOGENETIC ACTION OF 8-HYDROXYQUINOLINE SULFATE WAS TESTED IN HUMAN LYMPHOCYTE CULTURES IN VITRO. EXCESS L-CYSTEINE, CYSTEAMINE, AND L-ASPARAGINE ADDED SIMULTANEOUSLY WITH 8-HYDROXYQUINOLINE SULFATE DISTINCTLY REDUCED THE CHROMOSOME. DAMAGING EFFECT OF 8-HYDROXYQUINOLINE. L-GLUTAMIC ACID AND AMINOETHYLISOTHIOURONIUM EXERTED LESSER PROTECTIVE ACTIVITY. L-METHIONINE DISPLAYED SOME EFFECT ONLY IN REDUCING THE RELATIVELY RARE ISOCHROMATID ABERRATIONS INDUCED BY 8-HYDROXYQUINOLINE SULFATE. THE OTHER AMINO ACIDS HAD NO EFFECT. [R60] *The formation of DNA-strand breaks was studied in cultured human lung cells (A 549) subjected to iron, either in the form of iron(III) citrate or in combination with the metal chelators ethylene diamine tetra-acetic acid (EDTA), nitrilo triacetic acid (NTA), or 8-hydroxyquinoline (8HQ). After 15 min exposure to 5 uM iron(III) citrate or iron chelate, the cellular levels of iron were found to be three times higher in cells subjected to iron-8HQ than in cells subjected to iron(III) citrate, iron-EDTA or iron-NTA. Exposure to iron-8HQ caused extensive DNA-strand breakage, whereas no such breakage was found in cells exposed to iron-EDTA or iron-NTA. The DNA damage caused by iron-8HQ increased with time and dose, and DNA-strand breakage was clearly demonstrable in cells after 15 min exposure to as little as 0.1 uM iron-8HQ. Moreover, iron-8HQ was strongly toxic to the cells and inhibited their growth after exposure. Along with the formation of DNA-strand breaks, the concentration of cellular malondialdehyde increased four-fold after exposure to iron-8HQ and two-fold after exposure to iron-EDTA or iron-NTA, suggesting that reactive oxygen metabolites might be involved in the toxic action. Moreover, both iron-EDTA and iron-NTA caused a considerable hydroxylation of deoxyguanosine (dG) residues in DNA in vitro, whereas iron(III) citrate and iron-8HQ only caused a minor hydroxylation of dG. This points to the possibility that iron-8HQ-mediated DNA-strand breakage in cells might be due to the action of a metal-bound oxyl radical formed from the iron-8HQ complex rather than to the formation of hydroxyl radicals. Altogether, these findings indicate that iron bound to the lipophilic chelator, 8HQ, has strong toxic properties and that it may cause substantial DNA-strand breakage and lipid peroxidation in living cells. [R61] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *A BACTERIOSTATIC AND FUNGISTATIC COMPOUND; USED PRINCIPALLY IN TREATMENT OF MINOR BURNS AND OF HEMORRHOIDS. [R62] *OXYQUINOLINE SULFATE ... IS ... USED ... IN TREATMENT OF ATHLETE'S FOOT, VAGINITIS, AND AS A GARGLE, EYEWASH, NASAL DOUCHE, AND IN HEMORRHOIDAL PREPARATIONS ... /OXYQUINOLINE SULFATE/ [R62] */OVER THE COUNTER/ HYDROXYQUINOLINE IS 1 OF 4 ANTIFUNGAL AGENTS RECOMMENDED FOR ACTIVE TREATMENT OF FUNGUS ASSOCIATED WITH DIAPER RASH AND PRICKLY HEAT IN BABIES. /HYDROXYQUINOLINE/ [R63] *8-HYDROXYQUNIOLINE SULFATE INHIBITED FORMATION OF ARTIFICIAL CALCULUS IN VITRO AND RAT CALCULUS IN VIVO. IN RATS, IT PREVENTED CALCULUS FORMATION WHEN APPLIED BY SWABBING OR BY INTRAORAL INSTILLATION. IN DOGS, FORMATION OF DENTAL PLAQUE WAS INHIBITED 33 TO 98% IN COMPARISON TO PLACEBO. ALSO, 25 TO 58% OF ESTABLISHED PLAQUE ACCUMULATIONS WERE REMOVED, WHEREAS PLACEBO REMOVED 2 TO 22%. [R53] *TREATMENT OF MINOR BURNS AND HEMORRHOIDS; USED AS BACTERIOSTATIC ADDITIVE IN HAIRDRESSING PREPN FOR DANDRUFF; ANTISEPTIC SPRAY; PREPN OF NUMBER OF DERIVATIVES USED IN MEDICINE; CHEM INTERMEDIATE FOR PREPN OF AMEBACIDE, DIIODOHYDROXYQUIN [R9] *FOR TREATMENT OF DYSENTERY, MEN HAVE RECEIVED ORAL DOSES OF 3 G IN SOLN 4 TIMES DAILY, WITHOUT APPARENT ILL-EFFECT. /FORMER USE/ [R33] *The effect of oxyquinoline ointment for diaper dermatitis was tested in a randomized double-blind trial. Compared to a combined control treatment group using Desitin or A and D ointment, use of oxyquinoline significantly improved rash resolution. [R64] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *8-Hydroxyquinoline's production and use as a chemical intermediate and in steel electroplating may result in its release to the environment through various waste streams. It's former use as a fungicide may have resulted in its direct release to the environment. If released to air, a vapor pressure of 1.66X10-3 mm Hg at 25 deg C indicates 8-hydroxyquinoline will exist solely as a vapor. Vapor-phase 8-hydroxyquinoline will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2.0 hrs. 8-Hydroxyquinoline is expected to undergo photolysis in the atmosphere based upon aquatic photolytic experiments. The half-life for the photolytic degradation of 8-hydroxyquinoline in aqueous solution illuminated with filtered light, simulating daylight, ranged from 40-64 hours. If released to soil, 8-hydroxyquinoline is expected to have slight mobility based upon an estimated Koc of 3,000. Volatilization from water and moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 5.7X10-7 atm-cu m/mole. Biodegradation in soil or water is not likely to be an important environmental fate process based on a 0% theoretical BOD using sewage sludge. If released into water, 8-hydroxyquinoline is expected to adsorb to suspended solids and sediment based upon the estimated Koc. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to 8-hydroxyquinoline may have occured through inhalation of dust and dermal contact with this compound at workplaces where 8-hydroxyquinoline was produced or used. (SRC) NATS: *... IS NOT KNOWN TO OCCUR IN NATURE. [R35] ARTS: *8-Hydroxyquinoline's production and use as a chemical intermediate(1-3) and in steel electroplating(4) may result in its release to the environment through various waste streams(SRC). It's former use as a fungicide(5) may have resulted in its direct release to the environment(SRC). [R65] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3,000(SRC), determined from a structure estimation method(2), indicates that 8-hydroxyquinoline is expected to have slight mobility in soil(SRC). Volatilization of 8-hydroxyquinoline from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.7X10-7 atm-cu m/mole(SRC), based upon its vapor pressure, 1.66X10-3 mm Hg(3), and water solubility, 556 mg/l(4). 8-Hydroxyquinoline is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(3). Biodegradation in soil is not an important environmental fate process based on a 0% theoretical BOD using sewage sludge(5). [R66] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3,000(SRC), determined from a structure estimation method(2), indicates that 8-hydroxyquinoline is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.7X10-7 atm-cu m/mole(SRC) derived from its vapor pressure, 1.66X10-3 mm Hg(4) and water solubility, 556 mg/l(5). According to a classification scheme(6), an estimated BCF of 7(SRC), from its log Kow of 2.02(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low(SRC). To test for photolytic degradation in aqueous solution, 8-hydroxyquinoline was illuminated with filtered light, simulating daylight(9). The half-life for the photolytic degradation of 8-hydroxyquinoline ranged from 40-64 hours. Biodegradation in water is not an important environmental fate process based on a 0% theoretical BOD using sewage sledge(10). [R67] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 8-hydroxyquinoline, which has a vapor pressure of 1.66X10-3 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 8-hydroxyquinoline is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.0 hrs(SRC), calculated from its rate constant of 2.0X10-10 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). 8-Hydroxyquinoline is expected to undergo photolysis in the atmosphere based upon aquatic photolytic experiments. The half-life for the photolytic degradation of 8-hydroxyquinoline in aqueous solution illuminated with filtered light, simulating daylight, ranged from 40-64 hours(4). [R68] BIOD: *AEROBIC: 8-Hydroxyquinoline, concentration not specified, reached 0% of its theoretical BOD in 5 days using a sewage sludge inoculum and standard dilution method(1). [R69] ABIO: *The rate constant for the vapor-phase reaction of 8-hydroxyquinoline with photochemically-produced hydroxyl radicals has been estimated as 2.0X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2.0 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 8-Hydroxyquinoline is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2). To test for photolytic degradation in aqueous solution, 8-hydroxyquinoline was illuminated with filtered light, simulating daylight(3). The half-life for the photolytic degradation of 8-hydroxyquinoline ranged from 40-64 hours. [R70] BIOC: *An estimated BCF of 7 was calculated for 8-hydroxyquinoline(SRC), using a log Kow of 2.02(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R71] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 8-hydroxyquinoline can be estimated to be 3,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that 8-hydroxyquinoline is expected to have slight mobility in soil. [R72] VWS: *The Henry's Law constant for 8-hydroxyquinoline is estimated as 5.7X10-7 atm-cu m/mole(SRC) derived from its vapor pressure, 1.66X10-3 mm Hg(1), and water solubility, 556 mg/l(2). This Henry's Law constant indicates that 8-hydroxyquinoline is not expected to volatilize from water surfaces(3). 8-Hydroxyquinoline estimated Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). 8-Hydroxyquinoline is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R73] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 13,728 workers (9,645 of these are female) were potentially exposed to 8-hydroxyquinoline in the US(1). Occupational exposure to 8-hydroxyquinoline may have occured through inhalation of dust and dermal contact with this compound at workplaces where 8-hydroxyquinoline was produced or used(SRC). [R74] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: *As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA '88 were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Quinolinol is found on List D. Case No: 4047; Case Status: No products containing the pesticide are actively registered. Therefore, we are characterizing the case as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): quinolinol; AI Status: The active ingredient is no longer contained in any registered products. Thus, we characterize it as "cancelled." [R75] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A spectrophotometric procedure is described for the detection of 8-hydoxyquinoline and three of its halogenated derivatives: clioquinol, iodoquinol, and chiniofon. The proposed method involves the use of 2,6-dichloroquinone chlorimide as the chromogenic reagent. 8-Hydroxyquinoline produces a blue color peaking at 595 nm and the other compounds yield a green-blue color with max absorption at 650 nm. The colors produced obey Beer's law. The procedure was applied to the detection of the compounds in dosage forms. [R76] *Of 6 colorimetric methods for the determination of 8-hydroxyquinoline in pharmaceutical products and tissues, one using Gibbs reagent (2,6-dibromo-benzoquinone chlorimine) was reported to be the most sensitive, with a detection limit of 0.5 ug/l. A colorimetric method for its determination in galenical preparations containing other phenols is based on its complex with a vanadium ion. Non-aqueous titration methods have been described to determine 8-hydroxyquinoline and its oxidation products and to determine 8-hydroxyquinoline and some of its metal chelates. An aqueous titration method for the determination of 8-hydroxyquinoline sulfate has been outlined and it can be determined fluorimetrically as its chelate compound with tin(2+). A fluorimetric determination of 8-hydroxyquinoline is based on its luminescence in sulfuric acid at 77 deg K and has a sensitivity of 0.12 uM. A spectrophotometric method for the determination of 8-hydroxyquinoline as the copper chelate can be used in the presence of some other metals. Paper, thin-layer and gas-liquid chromatography can also be used to determine 8-hydroxyquinoline. [R35] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology Review; Internist 15 (1): 7 (1974) Toxicology Review; Archives of Environmental Health 23: 6 (1971) DHHS/NTP; Toxicology and Carcinogenesis Studies of 8-Hydroxyquinoline in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 276 (1985) NIH Publication No. 85-2532 SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. VV20 (1996) 784 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V20 (1996) R4: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on 8-Hydroxyquinoline (148-24-3). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of September 26, 2001. R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 102 (1977) R6: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 759 R7: Farm Chemicals Handbook 1992. Willoughby, OH: Meister Publishing Co., 1992.,p. C-285 R8: HORSCH W, METTE B; PHARMAZIE 29 (8): 546-7 (1974) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 103 (1977) R10: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V19 546 (1982) R11: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V18 382 (1982) R12: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA14 (1989) 142 R13: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V5 (1993) 768 R14: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA3 (1985) 254 R15: O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2001. 868 R16: Farm Chemicals Handbook 2001. Willoughby, Ohio: Meister 2001.,p. C 353 R17: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 600 R18: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 832 R19: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-309 R20: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 8-38 R21: Perrin DD; Dissociation constants of organic bases in aqueous solution. IUPAC Chem Data Ser: Suppl 1972. Buttersworth, London. (1972) R22: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 51 R23: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 495 R24: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Ver 5. Tucson, AZ: Univ AZ, College of Pharmacy (1992) R25: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-485 R26: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994. R27: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 101 (1977) R29: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R30: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 626 R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 64 (1987) R32: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R33: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-383 R34: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 503 R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 104 (1977) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 105 (1977) R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 106 (1977) R38: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 107 (1977) R39: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 108 (1977) R40: NAGAO M ET AL; MUTAT RES 43 (3): 335-41 (1977) R41: HOLLSTEIN M ET AL; J NATL CANCER INST 60 (2): 405-10 (1978) R42: Haworth SR et al; Environ Mutag 3: 379 (1981) R43: Allavena A et al; Teratog Carcinog Mutagen 12 (1): 31-41 (1992) R44: Ashby J et al; Environ Mol Mutagen 14 (4): 221-8 (1989) R45: Armstrong MJ et al; Mutation Research 265 (1): 45-60 (1992) R46: Bailey TA, et al.; Investigations of Fish Control 99. Evaluation of 215 Candidate Fungicides for Use in Fish Culture. Govt Rpts Announcements and Index 10 (1990) R47: Hamoud MA et al; Terat Carcin Mutagen 9 (2): 111-18 (1989) R48: McFee AF; Environ Mol Mutagen 13 (4): 325-31 (1989) R49: Hamoud MA et al; Teratog Carcinog Mutagen 9 (2): 111-8 (1989) R50: Burke JE et al; Eur J Nucl Med 7 (2): 73-6 (1982) R51: Gebhart E, Kappauf H; Environ Mutagen 2 (2): 191-200 (1980) R52: Buchner SA, Meier-Ruge W; Beitr Pathol 160 (2): 109-28 (1977) R53: Depalma PD et al; J Dent Res 55 (2): 292-8 (1976) R54: DHHS/NTP; Toxicology and Carcinogenesis Studies of 8-Hydroxyquinoline in F344/N Rats and B6C3F1 Mice (Feed Studies) p.15 (1985) Technical Rpt Series No. 276 NIH Pub No. 85-2532 R55: DHHS/NTP; Toxicology and Carcinogenesis Studies of 8-Hydroxyquinoline in F344/N Rats and B6C3F1 Mice (Feed Studies) p.9 (1985) Technical Rpt Series No. 276 NIH Pub No. 85-2532 R56: H.R. Skeggs and M.M. Cook; Microbial Mutagen Tests, (1978), EPA Document No. FYI-OTS-0584-0315, Fiche No. OTS0000315-0 R57: H.R. Skeggs; Microbial Mutagen Tests, (1977), EPA Document No. FYI-OTS-0584-0315, Fiche No. OTS0000315-0 R58: KIWADA H ET AL; CHEM PHARM BULL 25 (7): 1566-73 (1977) R59: SAWADA Y ET AL; CHEM PHARM BULL 26 (5): 1357-63 (1978) R60: GEBHART E; MUTAT RES 18 (3): 353-61 (1973) R61: Leanderson P, Tagesson C; Carcinogenesis 17 (3): 545-50 (1996) R62: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1111 R63: SADIK F; J AM PHARM ASSOC NS10 (JAN): 19-24 (1970) R64: Minnich SM et al; Dermatol Nurs 3 (1): 25-8 (1991) R65: (1) Ross E et al; Ullmann's Encycl Indus Chem. 5th ed. Gerhartz W, ed. Deerfield Beach, FL: VCH Publ A14: 142 (1989) (2) Hunger K et al; Ullmann's Encycl Indus Chem. 5th ed. Gerhartz W, ed. Deerfield Beach, FL: VCH Publ A3: 254 (1985) (3) Howard WL, Wilson DA; Kirk-Othmer Encycl Chem Tech. 4th ed. NY, NY: John Wiley and Sons 5: 768 (1993) (4) Finley KT; Kirk-Othmer Encycl Chem Tech. 4th ed. NY, NY: John Wiley and Sons 20: 779 (1996) (5) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva, Switzerland: World Health Organization, Inter Agency Res Cancer 19: 103 (1977) R66: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Daubert, TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) (4) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (5) Heukelekian H, Rand MC; J Water Pollut Control Assoc 27: 1040-53 (1955) R67: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert, TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 51 (1995) (8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (9) Svenson A, Bjorndal; Chemosphere 17: 2397-2405 (1988) (10) Heukelekian H, Rand MC; J Water Pollut Control Assoc 27: 1040-53 (1955) R68: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert, TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Svenson A, Bjorndal; Chemosphere 17: 2397-2405 (1988) R69: (1) Heukelekian H, Rand MC; J Water Pollut Control Assoc 27: 1040-53 (1955) R70: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Svenson A, Bjorndal; Chemosphere 17: 2397-2405 (1988) R71: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 51 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R72: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R73: (1) Daubert, TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, DC: Taylor and Francis (1989) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R74: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R75: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.315 (Spring, 1998) EPA 738-R-98-002 R76: Belal F; Analyst (London) 109 (5): 615-8 (1984) RS: 57 Record 249 of 1119 in HSDB (through 2003/06) AN: 4090 UD: 200302 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-VAT-YELLOW-4- SY: *AHCOVAT-PRINTING-GOLDEN-YELLOW-GK-; *AMANTHRENE-GOLDEN-YELLOW-GK-; *ANTHRAVAT-GOLDEN-YELLOW-GK-; *ARLANTHRENE-GOLDEN-YELLOW-GK-; *BENZADONE-GOLD-YELLOW-GK-; *Calcoloid-Golden-Yellow-; *Calcoloid-Golden-Yellow-GKWP-; *CALEDON-GOLDEN-YELLOW-GK-; *CALEDON-PRINTING-YELLOW-GK-; *CARBANTHRENE-GOLDEN-YELLOW-GK-; +CI-Vat-Yellow-4-; *CI-59100-; *CIBANONE-GOLDEN-YELLOW-FGK-; *CIBANONE-GOLDEN-YELLOW-GK-; *1,2,6,7-DIBENPYRENE-7,14-QUINONE-; *DIBENZO(B,DEF)CHRYSENE-7,14-DIONE; *Dibenzo(a,b)pyrene-7,14-dione; *3,4:8,9-DIBENZOPYRENE-5,10-DIONE; *2,3,7,8-DIBENZOPYRENE-1,6-QUINONE-; *DIBENZPYRENEQUINONE-; *FENANTHREN-GOLDEN-YELLOW-GK-; *GOLDEN-YELLOW-ZHKH-; *HELANTHRENE-YELLOW-GOK-; *HOSTAVAT-GOLDEN-YELLOW-GK-; *INDANTHRENE-GOLDEN-YELLOW-GK-; *INDANTHRENE-GOLD-YELLOW-GK-; *INDANTHREN-GOLDEN-YELLOW-GK-; *INDANTHREN-PRINTING-YELLOW-GOK-; *LEUCOSOL-GOLDEN-YELLOW-GK-; *MAYVAT-GOLDEN-YELLOW-GK-; *MIKETHRENE-GOLD-YELLOW-GK-; *NCI-C03565-; *NIHONTHRENE-GOLDEN-YELLOW-GK-; *NSC-30987-; *NYANTHRENE-GOLDEN-YELLOW-GK-; *PALANTHRENE-GOLDEN-YELLOW-GK-; *PARADONE-GOLDEN-YELLOW-GK-; *PHARMANTHRENE-GOLDEN-YELLOW-GK-; *ROMANTRENE-GOLDEN-YELLOW-GOK-; *SANDOTHRENE-GOLDEN-YELLOW-NGK-; *SANDOTHRENE-PRINTING-YELLOW-NH-; *SOLANTHRENE-BRILLIANT-YELLOW-J-; *TINON-GOLDEN-YELLOW-GK-; *TYRIAN-YELLOW-I-GOK-; *VAT-GOLDEN-YELLOW-ZHKH-; *VAT-GOLDEN-YELLOW-ZHKHD-; *VAT-YELLOW-ZHKH-; *YELLOW-GK-BASE- RN: 128-66-5 MF: *C24-H12-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 3-BENZOYLBENZANTHRONE WITH ALUMINUM CHLORIDE AND AN OXIDIZING AGENT; REACTION OF 1,5-DIBENZOYLNAPHTHALENE WITH SODIUM AND ALUMINUM CHLORIDES [R1] MFS: *BASF Corp, Hq, 8 Campus Drive, Parsippany, NJ 07054 (201) 397-2700; Coatings and Colorants Div, 1255 Broad St, Clifton, NJ 07011; Production sites: Charlotte, NC 28208; Rensselaer, NY 12144 /Vat dyes/ [R2] *Buffalo Color Corp, Hq, 959 Route 46 East, Suite 463, Parsippany, NJ 07054, (201) 316-5600, (800) 631-0171; Production site: Buffalo, NY 14240 /Vat dyes/ [R2] *Crompton and Knowles Corp, Hq, One Station Place, Metro Center, Stanford, CT 06902, (203) 353-5400; Dyes and Chemical Div, PO Box 33188, Charlotte, NC 28233; Production sites: Gibraltar, PA 19524; Newark, NJ 01705; Nutley, NJ 07110; Reading, PA 19603 /Vat dyes/ [R2] *Hoechet Celanese Corp, Hq, Route 202-206 North, Somerville, NJ 08876, (908) 231-2000; Chemicals Group, Speciality Chemicals, Bldg 5200, 77 Center Drive, Charlotte, NC 28217; Production sites: Coventry, RI 02816; Mount Holly, NC 28120 /Vat dyes/ [R2] *ICI America Holdings Inc, Hq, ICI Americas Inc, PO Box 751, Wilmington, DE 19897, (302) 886-3000; ICI Specialties Group; ICI Blended Specialties; Production site: Dighton, MA 02715 /Vat dyes/ [R2] *Royce Associates, Hq, 37 Carlton Ave, East Rutherford, NJ 07073, (201) 438-5200; Subsidiary: Passaic Color and Chemical Co, 28-36 Paterson Street, Paterson, NJ 07501; Production site: Paterson, NJ 07501 /Vat dyes/ [R2] *Sandoz Inc, 608 Fifth Ave, NY, NY 10020, (212) 307-1122; Sandoz Chemical Corp, 4000 Monroe Rd, Charlotte, NC 28205; Production site: Charlotte, NC 28214 /Vat dyes/ [R2] USE: *DYE FOR COTTON, SILK, WOOL AND PAPER, FOR PRINTING COTTON [R1] CPAT: *ESSENTIALLY 100% AS A DYE [R1] PRIE: U.S. PRODUCTION: *(1978) PROBABLY GREATER THAN 2.27X10+6 G [R1] *(1979) PROBABLY GREATER THAN 2.27X10+6 G [R1] U.S. IMPORTS: *(1977) 3.88X10+6 G (PRINCPL CUSTMS DISTS) [R1] *(1979) 3.50X10+6 G (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *332.36 [R3] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is limited evidence for the carcinogenicity of Vat Yellow 4 in experimental animals. No data were available from studies in humans on the carcinogenicity of Vat Yellow 4. Overall evaluation: Vat Yellow 4 is not classifiable as to its carcinogenicity to humans (Group 3). [R4] HTOX: *Most organic azo dyes are potential skin sensitizers, the most important of which are paraphenylenediamine and its analogs. Water soluble azo dyes are more likely to cause clinical sensitization than insoluble dyes. ... In addition to allergic eczematous contact dermatitis, color developing solutions have caused lichen planus like eruptions. /Organic dyes/ [R5] NTOX: *Vat yellow 4 (C.I. 59100) was tested for mutagenicity in the Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. Vat yellow 4 was tested over a wide range of doses (0, 100, 333, 1000, 3333, and 10,000 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Vat yellow 4 was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 10,000 ug/plate. [R6] *Despite their widespread use and potential for significant human exposure, genotoxicity data on anthraquinones and other dyes are limited. In this study, 16 anthraquinones and one azo dye (Solvent Red 1) were selected for testing using the thymidine locus and micronucleus (MN) analysis in L5178Y/TK(+ or -)-3.7.2C mouse lymphoma cells. Six of the dyes were from the same lot used in the NTP rodent bioassay. The dyes used were all production lots and thus varied in their purity. Disperse Blue 7, 2-aminoanthraquinone; 1-amino-2-methylanthraquinone, Disperse Blue 3 and Disperse Red 11 were genotoxic (inducing 1814 mutants/10(6) survivors, 369 MN/1000 cells at 13% survival; 397 mutants/10(6) survivors, 196 MN/1000 cells at 21% survival; 178 mutants/10(6) survivors, 119 MN/1000 cells at 51% survival; 264 mutants/10(6) survivors, 109 MN/1000 cells at 15% survival, respectively). Reactive Blue 19 was weakly mutagenic (inducing 144 mutants/10(6) survivors, but only 8 MN/1000 cells at 13% survival). Vat Yellow 4 and Solvent Red 1, with exogenous activation, were also mutagenic (inducing 300 mutants/10(6) survivors, 18 MN/1000 cells at 57% survival, and 100 mutants/10(6) survivors and 16 MN/1000 cells at 22% survival, respectively). With activation 1-nitro-2-methylanthraquinone was judged to give an equivocal mutagenicity response. The maximum test concentration was limited for some compounds by their solubility. Those chemicals that did not induce mutation or cytotoxicity at the limits of solubility were classified separately. Compounds which were not evaluated without exogenous activation because of insolubility but were evaluated with activation include 1-nitro-2-methylanthraquinone, Solvent Red 1 and Vat Yellow 4. [R7] NTP: *FISCHER 344 RATS OF EACH SEX ADMIN FORMULATED PRODUCT CONTAINING CI VAT YELLOW 4 IN DIET FOR 104 WK OR 106 WK @ 3500 OR 7000 PPM. TUMOR INCIDENCE WAS NOT HIGHER THAN THAT OF CONTROLS. [R8] *B6C3F1 MICE ADMIN FORMULATED PRODUCT CONTAINING CI VAT YELLOW 4 IN DIET FOR 104 WK OR 106 WK, (25,000 OR 50,000 PPM FOR MALES AND 12,500 OR 25,000 PPM FOR FEMALES). IT WAS CARCINOGENIC FOR MALES, BUT NOT FEMALES, INDUCING LYMPHOMAS. [R9] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Beauticians exposed to paraphenylenediamine derivatives in hair dyes, workers dyeing texitle resins, and photographic film developers exposed to color developing solutions not infrequently become sensitized to azo dyes. /Organic dyes/ [R5] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *RAPID AND SIMPLE METHOD DESCRIBED FOR ANAL OF POLYCYCLIC QUINONES IN AIR DERIVED FROM POLYNUCLEAR AROMATIC HYDROCARBONS INVOLVING RESOLUTION BY COLUMN AND THIN-LAYER CHROMATOGRAPHY AND SPECTRAL ANAL BY UV, VISIBLE AND FLUORESCENCE SPECTROPHOTOMETRY, AND MASS SPECTROMETRY. [R10] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: REVIEW OF INHALATION (TOTAL-BODY-EXPOSURE) STUDIES OF COLORED CHEM SMOKES. ACUTE TOXICITIES, TIME TO DEATHS, AND GROSS SIGNS COMPARED. TOXICOLOGICAL EVALUATION OF DYES IN SMOKE MIXT INCL. ONE OF THE DYES USED IN CHEM SMOKES IS DIBENZO(B,DEF)CHRYSENE-7,14-DIONE. [R11] DHEW/NCI; Bioassay of C.I. Vat Yellow 4 for Possible Carcinogenicity (1979) Technical Rpt Series No. 134 DHEW Pub No. (NIH) 79-1389 SO: R1: SRI R2: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 595 R3: U.S. Department of Health, Education and Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances. 1978 edition. Washington, DC: U.S. Government Printing Office, 1979.434 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 48 157 (1990) R5: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 147 R6: Zeiger E et al; Environ Mutagen 9:1-110 (1987) R7: Harrington-Brock K et al; Mutagenesis 6 (1): 35-46 (1991) R8: DHEW/NCI; BIOASSAY OF CI VAT YELLOW 4 FOR POSSIBLE CARCINOGENICITY P. V (1979) TECHNICAL RPT SERIES NO. 134 DHEW PUB NO. (NIH) 79-1379 R9: DHEW/NCI BIOASSAY OF CI VAT YELLOW 4 FOR POSSIBLE CARCINOGENICITY P.V (1979) TECHNICAL RPT SERIES NO. 134 DHEW PUB NO. (NIH) 79-1379 R10: PIERCE RC, KATZ M; ENVIRON SCI TECHNOL 10 (1): 45 (1976) R11: OWENS EJ, WARD DM; USNTIS AD/A REP ISS NO 003827/3GA 72 PP 1974 RS: 9 Record 250 of 1119 in HSDB (through 2003/06) AN: 4091 UD: 200302 RD: Reviewed by SRP on 03/16/1990 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-DIETHYLDITHIOCARBAMATE- SY: *CARBAMIC-ACID,-DIETHYLDITHIO-,-SODIUM-SALT-; *CARBAMODITHIOIC-ACID,-DIETHYL-,-SODIUM-SALT-; *CUPRAL-; *DDC-; *DEDC-; *DEDK-; *DIETHYLCARBAMODITHIOIC-ACID,-SODIUM-SALT-; *Diethyldithiocarbamate-sodium-; *DIETHYLDITHIOCARBAMIC-ACID-SODIUM-; *DIETHYLDITHIOCARBAMIC-ACID-SODIUM-SALT-; *N,N-DIETHYLDITHIOCARBAMIC-ACID,-SODIUM-SALT-; *DIETHYL-SODIUM-DITHIOCARBAMATE-; *DITHIOCARB-; *DITHIOCARBAMATE-; *NA-DDTC-; *NCI-CO2835-; *SODIUM-DEDT-; *SODIUM-DIETHYLAMINOCARBODITHIOATE-; *SODIUM-N,N-DIETHYLDITHIOCARBAMATE-; *Sodium-N,N-diethyldithiocarbamic-acid-; *SODIUM-N,N-DIETHYLDITHIOCARBMATE-; *SODIUM-SALT-OF-N,N-DIETHYLDITHIOCARBAMIC-ACID-; *THIOCARB-; *USAF-EK-2596- RN: 148-18-5 MF: *C5-H10-N-S2.Na ASCH: Sodium diethyldithiocarbamate trihydrate; 20624-25-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *THE FIRST REPORTED PREPARATION OF SODIUM DIETHYLDITHIOCARBAMATE WAS BY THE ADDITION OF CARBON DISULFIDE TO AN AQUEOUS SOLUTION OF DIETHYLAMINE AND SODIUM HYDROXIDE. THE SAME METHOD IS BELIEVED TO BE USED FOR ITS COMMERCIAL PRODUCTION. [R1] MFS: +Alco Industries Company, Hq, PO Box 937, Valley Forge, PA 19482, (215) 666-0760; Alco Chemical Corporation, division, 909 Mueller Drive, Chattanooga, TN 37406 [R2] +Frank Enterprises, Inc, Hq, 1960 Birkdale Drive, Columbus, OH 43232, (614) 861-7010; Production site: Columbus, OH 43219 [R2] +United Guardian, Inc, PO Box 2500, Smithtown, NY 11787, (516) 273-0900; Guardian Chemical Division, Eastern Chemical Division, Department ST, PO Box 2500, Smithtown, NY 117887; Production site: Hauppauge, NY 11787 [R2] +RT Vanderbilt Company, Inc, Hq, 30 Winfield Street, Norwalk, CT 06855, (203) 853-1400; Subsidiary: Vanderbilt Chemical Corporation, 30 Winfield Street, Norwalk, CT 06855; Production site: Bethel, CT 06801 [R2] OMIN: *SODIUM DIETHYLDITHIOCARBAMATE IS AVAILABLE IN THE US FOR USE IN RUBBER PROCESSING AS A 25% ACTIVE AQUEOUS SOLUTION ... [R1] *SODIUM DIETHYLDITHIOCARBAMATE IS USED AS THE TRIHYDRATE. [R3] USE: *FOR COLORIMETRIC DETERMINATION OF SMALL QUANTITIES OF COPPER AND FOR ITS SEPARATION FROM OTHER METALS; EXPERIMENTAL IN WILSON'S DISEASE [R3] *Complexing agent; oxidation inhibitor in ethyl ether [R4, 939] *CHEMICAL INT IN PRODUCTION OF BIS(THIOCARBAMOYL)SULFIDES (RUBBER-PROCESSING ACCELERATORS AND FUNGICIDES) [R1] *OXIDATION INHIBITOR AND ACCELERATOR FOR RUBBER PROCESSING; CHEM INT FOR OTHER DIETHYLDITHIOCARBAMATE SALTS; REAGENT FOR QUANTITATIVE ANALYSIS OF VARIOUS HEAVY METALS, COLORIMETRY OF VITAMIN K [R5] +MEDICATION *BY ADDING A SMALL AMT OF SODIUM DIETHYLDITHIOCARBAMATE (NA-DDTC) IN THE ORDINARY DECONTAMINATION PROCESS OF LOW LEVEL RADIOACTIVE WASTEWATER BY FERRIC HYDROXIDE COAGULATION FLOCCULATION, REMOVAL OF (60)CO IS REMARKABLY IMPROVED. [R6] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 G [R5] *(1978) PROBABLY GREATER THAN 2.27X10+6 G [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PLATELETS [R7] MP: *94-96 DEG C [R3] MW: *171.27 [R3] DEN: *1.1 at 20 deg C/20 deg C [R8, 2425] PH: +AQUEOUS SOLN IS ALKALINE TO LITMUS AND PHENOLPHTHALEIN [R4, 1234] SOL: +FREELY SOL IN WATER; SOL IN ALCOHOL [R4, 1234] SPEC: *MAX ABSORPTION: 257 NM AND 290 NM (E= 700 and 760) [R7] VAPD: *5.9 [R8, 2424] OCPP: *The addition of an acid to the aq soln produces a white turbidity due to the liberation of carbon disulfide [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of NO(x), SO(x) and sodium oxide (Na2O). [R8, 2425] SSL: *AQUEOUS SOLUTIONS DECOMPOSE SLOWLY [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R9] NTOX: *SODIUM DIETHYLDITHIOCARBAMATE REDUCES BLOOD COPPER CONCENTRATIONS. PREGNANT RABBITS INJECTED INTRAVENOUSLY WITH 0.5 G SODIUM DIETHYLDITHIOCARBAMATE/DAY ON 5 DAYS PER WEEK THROUGHOUT PREGNANCY FAILED TO DELIVER LITTERS. [R10] *A SMALL BUT SIGNIFICANT INCREASE IN THE NUMBER OF CHROMOSOME BREAKAGES AND ABERRATIONS WAS FOUND IN VICIA FABA. [R10] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF)FI MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR)FI MICE RECEIVED SODIUM DIETHYLDITHIOCARBAMATE (MP 94-96 DEG C) ... 215 MG/KG BODY WT IN WATER AT 7 DAYS OF AGE BY STOMACH TUBE AND SAME AMT (NOT ADJUSTED FOR INCREASING BODY WT) DAILY UP TO 4 WK OF AGE; SUBSEQUENTLY, THE MICE WERE GIVEN 692 MG SODIUM DIETHYLDITHIOCARBAMATE PER KG OF DIET. THE DOSE WAS THE MAXIMUM TOLERATED DOSE FOR INFANT AND YOUNG MICE BUT NOT NECESSARILY SO FOR ADULTS. THE EXPT WAS TERMINATED WHEN THE ANIMALS WERE ABOUT 78 WK OF AGE, AT WHICH TIME 17, 18, 18 and 16 MICE IN THE 4 GROUPS, RESPECTIVELY, WERE STILL ALIVE. TUMOR INCIDENCES WERE COMPARED WITH THOSE IN 79-90 NECROPSIED MICE OF EACH SEX AND STRAIN, WHICH ... HAD BEEN UNTREATED OR HAD RECEIVED GELATINE. PULMONARY ADENOMAS OCCURRED IN 3/17 (P < 0.05) and 5/18 (P < 0.05) MALES OF THE 2 STRAINS, RESPECTIVELY, COMPARED WITH 5/79 and 9/90 IN CONTROLS. HEPATOMAS DEVELOPED IN 7/17 MALES OF THE FIRST STRAIN, COMPARED WITH 8/79 IN CONTROL MALES (P < 0.01). THERE WAS NO INCR IN THE INCIDENCE OF LIVER TUMORS AMONG MALES OF ... /2ND/ STRAIN ... /NOR/ IN FEMALES /OF BOTH STRAINS/ (INNES ET AL, 1969; NTIS, 1968). [R11] *GROUPS OF 18 MALE AND 18 FEMALE (C57BL/6XC3H/ANF)F1 MICE AND 18 MALE AND 18 FEMALE (C57BL/6XAKR)F1 MICE WERE GIVEN SINGLE SC INJECTIONS OF 464 MG/KG BODY WT SODIUM DIETHYLDITHIOCARBAMATE (MP 94-96 DEG C) IN WATER ON 28TH DAY OF LIFE AND WERE OBSERVED UNTIL THEY WERE 78 WK OF AGE, AT WHICH TIME 16, 18, 18 and 16 MICE IN THE 4 GROUPS, RESPECTIVELY, WERE STILL ALIVE. TUMOR INCIDENCES WERE COMPARED WITH THOSE IN GROUPS OF 141, 154, 161 and 157 UNTREATED OR VEHICLE INJECTED CONTROLS THAT WERE NECROPSIED. INCIDENCES WERE NOT INCR (P > 0.05) FOR ANY TUMOR TYPE IN ANY SEX STRAIN SUBGROUP OR IN THE COMBINED SEXES OF EITHER STRAIN (NTIS, 1968) (THE WORKING GROUP NOTED THAT NEGATIVE RESULT OBTAINED WITH A SINGLE SC INJECTION MAY NOT BE AN ADEQUATE BASIS FOR DISCOUNTING CARCINOGENICITY) [R12] *DIETHYLDITHIOCARBAMATE SODIUM ... HAS BEEN TESTED ON RABBIT CORNEAS AT 0.01 TO 0.05 MOLAR CONCENTRATIONS BY INJECTION OR APPLICATION TO THE DENUDED SURFACE AND WAS FOUND NONTOXIC. ADMINISTERED SYSTEMICALLY, IT IS REPORTED TO HAVE CAUSED DETACHMENT OF THE RETINA IN DOGS, BUT NO DAMAGE TO THE RETINA IN MONKEYS. IN ALBINO RATS AND BEAGLE DOGS, IT CAUSED NO IMPAIRMENT OF VISION OR STRUCTURAL ALTERATION IN THE EYE AFTER ADMINISTRATION DAILY FOR NINETY DAYS. [R13] *IN 6-WK EXPERIMENT IN MICE, DAILY SC INJECTIONS OF 50 MG/KG BODY WEIGHT HAD MARKED ANTI-THYROID ACTIVITY. [R12] *SODIUM DIETHYLDITHIOCARBAMATE ADMIN TO RABBITS AT 100, 200, and 400 MG/KG DAILY FOR 4 WK INCREASED TRIGLYCERIDE AND PHOSPHOLIPID LEVELS. NO CHANGES WERE FOUND IN SERUM CHOLESTEROL CONCN. [R14] *MACROPHAGE LISTERICIDAL CAPACITY, SPLENIC IGG-ANTIBODY FORMING CAPACITY, AND DELAYED HYPERSENSITIVITY LEVELS WERE FOUND TO BE ENHANCED IN SEVERAL TEST SYSTEMS BY SODIUM DIETHYLDITHIOCARBAMATE(DEDC) OVER A WIDE RANGE OF CONCN. THE IMMUNOPOTENTIATING EFFECTS OF DEDC WERE NOT CONNECTED WITH INCREASED LYMPHOCYTE COUNTS OR SPLENOMEGALY. WHEN DIETHYLAMINE OR CARBON DISULFIDE WAS ADMIN ALONE OR ON SEPARATE BODY SITES, NO IMMUNOPOTENTIATION WAS FOUND. DEDC CAUSED AN ANABOLIC EFFECT IN MICE EMACIATED AFTER DOSING WITH A CELL WALL FRACTION OF BACILLUS MELITENSIS. [R15] *SODIUM DIETHYLDITHIOCARBAMATE CONCN GREATER THAN 3 MG/L APPLIED TO DEVELOPING FROG EMBRYOS WERE LETHAL IN 24 HR. BETWEEN 1-3 MG/L CAUSED SEVERELY MALFORMED EMBRYOS. RETARDATION OF GROWTH, CURVATURE OF BODY AXIS, GENERAL EDEMIC CONDITION, PIGMENTATION DISORDERS, AND ABNORMAL NOTOCHORDS WERE NOTED. [R16] *THE MUTAGENICITY OF DIMETHYLDITHIOCARBAMATES AND RELATED FUNGICIDES (EG, FERBAM, ZIRAM, SODIUM DIMETHYLDITHIOCARBAMATE) WERE TESTED USING ESCHERICHIA COLI WP2 HCR, SALMONELLA TYPHIMURIUM TA1535, TA1537, TA1538, TA98, AND TA100. SODIUM DIMETHYLDITHIOCARBAMATE WAS MUTAGENIC FOR SALMONELLA TYPHIMURIUM STRAIN TA100. IT WAS NOT MUTAGENIC FOR THE FRAMESHIFT STRAINS TA1537, TA1538, AND TA98. THE N-DIETHYL DERIVATIVE OF DDC WAS NOT MUTAGENIC TOWARD TA100. THE N-DIMETHYL GROUP IS ESSENTIAL FOR THE MUTAGENICITY OF THESE COMPOUNDS. /SODIUM DIMETHYLDITHIOCARBAMATE/ [R17] *A BIOASSAY OF SODIUM DIETHYLDITHIOCARBAMATE FOR POSSIBLE CARCINOGENICITY WAS CONDUCTED BY ADMIN IT IN FEED TO RATS AND MICE. RATS OF EACH SEX WERE ADMIN 1 OF 2 DOSES, 1250 OR 2500 PPM FOR 104 WEEKS. MICE OF EACH SEX WERE ADMIN 1 OF 2 DOSES ALSO, EITHER 500 OR 4000 PPM FOR 108 OR 109 WEEKS. NO TUMORS OCCURRED IN RATS OR MICE OF EITHER SEX AT INCIDENCES THAT WERE SIGNIFICANTLY HIGHER IN THE DOSED GROUPS THAN IN THE CONTROL GROUPS. THUS, UNDER THE CONDITIONS OF THIS BIOASSAY SODIUM DIETHYLDITHIOCARBAMATE WAS NOT CARCINOGENIC FOR RATS OR MICE OF EITHER SEX. [R18] *Sodium diethyldithiocarbamate was found to be negative when tested for mutagenicity a/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Sodium diethyldithiocarbamate Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98 and TA100) in the presence and absence of rat and hamster liver S-9, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. [R19] *Male and female mice, strains B6C3F1 and B6AKF1, were gavaged with 215 mg dithiocarb/kg/day; the maximum tolerated dose (MTD), which was calculated using the average body weight of mice at the start of the study and not corrected for weight gain from days 7-28 of age. Dithiocarb was then administered in the diet at a level of 692 ppm for about 18 months. Negative controls consisted of untreated and vehicle treated mice of both sexes of both strains. At 78 weeks of age, the mice were sacrificed and necropsied. Total tumor incidences for B6C3F1 mice were 10/17 treated males and 1/18 treated females versus 22/79 control males and 8/87 control females. Hepatomas were found in 7/17 treated males compared with 8/79 in control males. Pulmonary adenomas were found in 3/17 treated males and 5/79 control males. Reticulum cell sarcoma was present in 1/18 treated females versus 4/87 control females. For strain B6AKF1, total tumor incidences were 6/18 treated males, 2/18 treated females, 16/90 control males and 7/82 control females. No hepatomas were present in treated mice of this strain, but pulmonary adenomas were found in 5/18 and 1/18 treated males and females, respectively, compared with 9/90 and 3/82 control males and females, respectively. The incidence of reticulum cell sarcoma was 1/18 treated males, 1/18 treated females, 1/90 control males and 3/82 control females. [R20] *Ten Dutch male rabbits receivd 330 mg dithiocarb/kg by gavage 5 days/ week for 4, 6 or 9 weeks, after which time they were sacrificed and necropsied. An additional 10 rabbits served as controls. Histological examination revealed lesions of Wallerian degeneration and eosinophilic bodies in the medulla and spinal cord becoming progressively worse with long exposures. In rabbits receiving dithiocarb for 9 weeks, significant decreases in nerve fiber diameters were seen when compared with conrol animals. [R21] +... It is concluded that under the conditions of this bioassay, sodium diethyldithiocarbamate was not carcinogenic for F344 rats or B6C3Fl mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R22] NTP: +A bioassay of sodium diethyldithiocarbamate for possible carcinogenicity was conducted by admin the test chemical in feed to F344 rats and B6C3Fl mice. Groups of 50 rats of each sex were admin sodium diethyldithiocarbamate at one of two doses, either 1,250 or 2,500 ppm, for 104 wk. Groups of 50 mice of each sex were admin sodium diethyldithiocarbamate at one of two doses, either 500 or 4,000 ppm, for 108 or 109 wk. Matched controls consisted of 16 untreated male rats, 20 untreated female rats and 20 untreated mice of each sex. All surviving rats and mice were /sacrificed/ at the end of administration of the test chemical. ... It is concluded that under the conditions of this bioassay, sodium diethyldithiocarbamate was not carcinogenic for F344 rats or B6C3Fl mice of either sex. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R22] ADE: *Rats receiving levels of 500 mg of dithiocarb in 1-2 ml water/kg body weight by gavage reached plasma levels of 2 mg/l dithiocarb in 3 hours. [R23] *A half life for absorption of 26 minutes was determined when S-dithiocarb dissolved in 2M phosphate buffer was injected into the small intestinal lumen of adult male Wistar rats at a dose of 25 mg/kg. [R24] *Within 15 minutes of dosing rats with 25 mg (222 moles S)/rat S-dithiocarb i.p., nonprotein bound radiolabel was detected in the plasma (1561 nmoles/ml plasma) and in the liver (3211 nmoles/g liver). A substantial amount (> 45% within 15 minutes of dosing) of radioactivity also was found to be bound reversibly to soluble proteins of liver and plasma. [R25] *A small amount (< 0.1%) of unchanged dithiocarb was detected in the urine of rats receiving ip injections of 25 mg (35)S-dithiocarb/rat. One hr after dosing, 96.1% of the radiolabeled urinary metabolites was of S-glucuronide conjugate and 3.9% inorganic sulfate. Within 1 hr after dosing, 7% of the administered (35)S-dithiocarb was recovered as carbon disulfide in the expired air. [R25] METB: *IN RATS, FOUR METABOLITES, DIETHYLDITHIOCARBAMATE, DIETHYLDITHIOCARBAMATE-S-GLUCURONIDE, INORGANIC SULFATE AND CARBON DISULFIDE WERE IDENTIFIED; THESE ARE ALSO METABOLITES OF DISULFIRAM. [R10] INTC: *SODIUM DIETHYLDITHIOCARBAMATE (DEDC) PRETREATMENT OF RATS PREVENTED THE ETHYLENE DIBROMIDE DEPRESSION OF LIVER GLUTATHIONE (GSH) 2 HR AFTER INTOXICATION. THE LEVELS OF CYTOCHROME P450 SEEM TO BE UNAFFECTED BY ETHYLENE DIBROMIDE. THE INHIBITION OF GLUTATHIONE-S-TRANSFERASE BY DEDC IS NONCOMPETITIVE, PRODUCING A CHANGE IN VMAX WITHOUT A CHANGE IN KM. DEDC ALSO INHIBITED THE COVALENT BINDING OF (14)C-ETHYLENE DIBROMIDE TO MICROSOMAL PROTEINS IN THE MICROSOMAL SYSTEM SUPPLEMENTED WITH NADPH. [R26] *RATS EXPOSED TO ENFLURANE (100 PPM) OR METHOXYFLURANE (300 PPM) IN A CLOSED ALL GLASS SYSTEM ELIMINATED THESE ANESTHETICS FROM ATMOSPHERE WITH HALF LIFE OF 6.84 HR FOR ENFLURANE AND 0.64 FOR METHOXYFLURANE. PRETREATMENT WITH DITHIOCARB (100 MG/KG IP) PROLONGED ELIMINATION HALF LIFE OF BOTH CMPD. [R27] *RAT LIVER MICROSOMES CATALYZE COVALENT BINDING OF (14)C-CARBON TETRACHLORIDE METABOLITES TO THE MICROSOMAL PROTEIN; THIS BINDING WAS INHIBITED BY DITHIOCARB AT AN I50 (50% INHIBITION) OF 2.3X10-5 MOLES. DITHIOCARB EFFECTIVELY INHIBITED METABOLIC ELIMINATION OF CARBON TETRACHLORIDE AT A DOSE OF 100 MG/KG. [R28] *DITHIOCARB INCREASED T-CELL ASSOCIATED RESPONSES IN MICE TREATED WITH AZATHIOPRINE OR HYDROCORTISONE ACETATE. SUCH A BENEFICIARY EFFECT CONTRASTED WITH ITS INEFFICIENCY TO RESTORE FUNCTIONS ABROGATED BY CYCLOPHOSPHAMIDE. THE RESULTS RAISE THE POSSIBILITY OF DEVELOPING A RATIONAL CHEMOIMMUNOTHERAPY USING DITHIOCARB WITH A COMPATIBLE CYTOREDUCTIVE DRUG. [R29] *SC INJECTION OF 0.5 MMOLES DITHIOCARB, 30 MIN BEFORE AN IP INJECTION OF 280 MG ANILINE- HYDROCLORIC ACID/KG, AFFECTED ANILINE TOXICITY TO RATS BY INCREASING MORTALITY FROM 41.6 TO 75%, DECREASING METHEMOGLOBIN FORMATION BY 67.72%, AND INHIBITING HEPATIC ANILINE HYDROXYLASE BY 47.6%. [R30] *IN MICE INJECTED WITH (63)NICKEL DICHLORIDE, DITHIOCARB CAUSED A RETENTION AND REDISTRIBUTION OF (63)NI+2 IN TISSUES. [R31] *THE NEPHROTOXIC EFFECTS OF NSC-119875 (CIS-DICHLORODIAMINEPLATINUM(II), DDP) IN FEMALE F344 RATS WERE EFFECTIVELY INHIBITED BY ADMIN OF DITHIOCARB IN DOSES OF 750 MG/KG, IP OR 100 MG/KG, IV 2 HR AFTER ADMIN OF DDP. THE RESULTS OF THIS STUDY DEMONSTRATE THE FEASIBILITY OF INHIBITION OF CIS-PT TOXICITY BY DITHIOCARB WITHOUT INHIBITION OF THE ANTITUMOR EFFECT. [R32] *FEMALE RATS WERE USED TO STUDY THE IMPACT OF DITHIOCARB ON EXCRETION KINETICS AND DISTRIBUTION PATTERN OF (203)MERCURY INJECTED IV AT DOSE OF 120 UG. DITHIOCARB ENHANCED MERCURY EXCRETION THROUGH THE INTESTINAL WALL CELLS. PRETREATMENT CAUSED CONSIDERABLE CHANGES IN THE PATTERN OF MERCURY DISTRIBUTION. [R33] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Adjuvants, Immunologic; Antidotes; Antiviral Agents; Chelating Agents [R34] *EXPTL USE: CHELATING AGENT EXPERIMENTALLY USED IN WILSON'S DISEASE /SODIUM DIETHYLDITHIOCARBAMATE REDUCES BLOOD COPPER CONCENTRATIONS/. /SRP: USED AS A CARRIER FOR RADIOACTIVE IMAGING/ [R3] *IN THALLIUM POISONING, SODIUM DIETHYLDITHIOCARBAMATE GIVEN ORALLY HAS BEEN FOUND MORE EFFECTIVE THAN DIMERCAPROL IN RAISING URINARY EXCRETION OF THALLIUM, AND AT LEAST IN ONE CASE APPEARED TO BENEFIT THE NEUROLOGIC STATUS AND TO INCREASE VISUAL ACUITY, WHICH HAD BEEN IMPAIRED BY THE THALLIUM POISONING. [R35] *... /Sodium diethyldithiocarbamate/ has been used as a chelating agent in human therapy, for the treatment of nickel carbonyl poisoning. [R1] *USE OF DITHIOCARB ORALLY IN 11 CASES OF NI(CO)4 /NICKEL CARBONYL/ EXPOSURES RELIEVED THE SYMPTOMS OF POISONING, DELAYED REACTIONS WERE MINIMAL, AND CONVALESCENCE UNEVENTFUL. /SODIUM DIETHYLDITHIOCARBAMATE TRIHYDRATE/ [R36] +CHELATING AGENT IN HUMAN THERAPY, FOR THE TREATMENT OF NICKEL CARBONYL POISONING [R1] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Sodium diethyldithiocarbamate is not known to occur as a natural product. [R11] FATE: *AQUATIC FATE: The fate of dithiocarb in the aqueous media depends on its ability to undergo chemical and photochemical reactions as well as microbial degradation. [R37] BIOD: *The fate and transport of dithiocarb in the soil is likely to be determined by its ability to undergo biological transformation and chemical reactions. Microbial degradation of dithiocarb is likely to occur slowly in the soil environment because of the inherent microbial toxicity of the dithiocarbamates. [R38] *Dithiocarb can be converted in soils to diethylamine, a nitrosamine precursor ... however, the biodegradation half life of this compound was not established. [R39] ABIO: *Dithiocarb may undergo hydrolysis in soils, though no quantitative estimate of the rate of this reaction was made. [R40] *Dithiocarb was found to be stable in aqueous solution at pH 7 but decomposed under slightly acidic conditions (pH 5-6.7), producing carbon disulfide and a salt of diethylamine. [R41] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Concentrations of 5X10-5 to 5X10-4 M dithiocarbamates have been analyzed by direct current polarographic methods in which anodic waves correspond to the formation of mercury compounds: Halls DJ et al; Analyt Chim Acta 41: 51-62 (1968); when short, controlled drop times are used, concentrations of 1.6X10-3 molar can be determined by this method: Canterford DR et al; Analyt Chem 45: 1327-31 (1973). The application of differential pulse polarography has increased the sensitivity of the method to a detection limit of 1X10-6 molar and a quantitiative limit of 2X10-6 M: Canterford DR, Buchanan AS; Electroanalyt Chem Interfacial Electrochem 44: 291-8 (1973). [R11] *SODIUM DIETHYLDITHIOCARBAMATE CAN BE DETERMINED BY TITRATION OF THE EXCESS IODINE SOLUTION RESULTING FROM THE SODIUM DIETHYLDITHIOCARBAMATE-INDUCED IODINE-AZIDE REACTION. THE RANGE WHICH COULD BE DETERMINED WAS FROM 5-160 UG IN 50 OR 100 CU M OF SOLUTION, WITH A RELATIVE ERROR OF +/- 3%: KURZAWA Z ET AL; CHEM ANALYT, WARSAW 19: 263 (1974). [R10] *A GAS CHROMATOGRAPHIC METHOD FOR DETERMINING N,N-DIALKYL DITHIOCARBAMATES (FUNGICIDE, VULCANIZATION, ACCELERATORS, ANTIOXIDANT) IN INDUSTRIAL WASTEWATER AT THE NG LEVEL IS DESCRIBED. THE SAMPLE IS FREEZE-DRIED, EXTRACTED WITH ETHANOL AND THEN ESTERIFIED WITH 1-IODOPROPANE. SENSITIVITY OF THE METHOD IS ABOUT 1 NG. /SODIUM N,N-DIALKYL DITHIOCARBAMATES AND THEIR S-N-PROPYL ESTERS/ [R42] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of Sodium Diethyldithiocarbamate for Possible Carcinogenicity (1979) Technical Rpt Series No. 172 DHEW Pub No. (NIH) 79-1728 SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 218 (1976) R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 937 R3: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1234 R4: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. R5: SRI R6: MOTOJIMA K ET AL; ANN NUCL ENERGY 4 (9-10): 453-6 (1977) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 217 (1976) R8: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 71 (1987) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 221 (1976) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 219 (1976) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V12 220 (1976) R13: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 335 R14: DABROWSKI R ET AL; ACTA PHYSIOL POL 30 (2): 327-9 (1979) R15: RENOUX G, RENOUX M; J IMMUNOPHARMACOL 1 (2): 247-67 (1979) R16: GHATE HV, MULHERKAR L; INDIAN J EXP BIOL 18 (9): 1040-2 (1980) R17: MORIYA M ET AL; MUTAT RES 54: 221 (1978) R18: BIOASSAY OF SODIUM DIETHYLDITHIOCARBAMATE FOR POSSIBLE CARCINOGENICITY; REPORT; ISS DHEW/PUB/NIH-79-1728, NCI-CG-TR-172; ORDER NUMBER PB-293833, 93 PP (1979) R19: Mortelman K et al; Environ Mutagen 8: 1-119 (1986) R20: Innes JRM et al; J Natl Cancer Inst 42: 1101-14 (1969) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.9 (1983) ECAO-CIN-016 R21: Rasul AR et al; Acta Neuropathol 24 (2): 161-73 (1973) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.15 (1983) ECAO-CIN-016 R22: Bioassay of Sodium Diethyldithiocarbamate for Possible Carcinogenicity (1979) Technical Rpt Series No. 172 DHEW Pub No. (NIH) 79-1728, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R23: Baselt RC, Hanson VW; Res Commun Chem Patbol Pharmacol 38 (1): 113-24 (1982) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.7 (1983) ECAO-CIN-016 R24: Craven MR et al; J Pharm Pharmacol 28 (Suppl): 38 (1976) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.7 (1983) ECAO-016 R25: Stromme JH; Biochem Pharmacol 14: 393-410 (1965) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.7 (1983) ECAO-CIN-016 R26: NACHTOMI E; TOXICOL APPL PHARMACOL 57 (2): 247-53 (1981) R27: SIEGERS CP ET AL; ANAESTHESIST 30 (2): 83-7 (1981) R28: SIEGERS CP ET AL; TOXICOL APPL PHARMACOL 46 (3): 709-16 (1979) R29: RENOUX G, RENOUX M; CURR CHEMOTHER INFECT DIS, PROC INT CONGR CHEMOTHER 11TH, VOL 2, 1732-4 (1980) R30: MICHEVA M, STOICHEV C; EKSP MED MORFOL 19 (1): 36-40 (1980) R31: OSKARSSON A, TJALVE H; ARCH TOXICOL 45 (1): 45-52 (1980) R32: BORCH RF ET AL; PROC NATL ACAD SCI USA 77 (9): 5441-4 (1980) R33: CIKRT M, TICHY M; J HYG, EPIDEMIOL, MICROBIOL, IMMUNOL 24 (3): 346-55 (1980) R34: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R35: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 382 R36: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1111 R37: Lopatecki LE, Newton W; Can J Bot 30: 131-8 (1952) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.4 (1983) ECAO-CIN-016 R38: Kaufman DD; J Agr Food Chem 15: 582-91 (1967) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.4 (1983) ECAO-CIN-016 R39: Tate RL, Alexander M; Soil Sci 118 (5): 317-21 (1974) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.4 (1983) ECAO-CIN-016 R40: Tate RL, Alexander M; Soil Sci 11 (5): 317-21 (1979) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.4 (1983) ECAO-CIN-016 R41: Lopateck LE, Newton W; Can J Bot 30: 131-8 (1952) as cited in USEPA; Health and Environmental Effects Profile for Sodium Diethyldithiocarbamate p.4 (1983) ECAO-CIN-016 R42: ONUSKA FI; INT J ENVIRON ANAL CHEM 3 (1): 19-28 (1973) RS: 26 Record 251 of 1119 in HSDB (through 2003/06) AN: 4096 UD: 200302 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-DISPERSE-YELLOW-3- SY: *ACETAMIDE, N-(4((2-HYDROXY-5-METHYLPHENYL)AZO)PHENYL)-; *4-ACETAMIDO-2'-HYDROXY-5'-METHYLAZOBENZENE-; *ACETAMINE-YELLOW-CG-; *ACETATE-FAST-YELLOW-G-; *ACETOQUINONE-LIGHT-YELLOW-4JLZ-; *ALTCO-SPERSE-FAST-YELLOW-GFN-NEW-; *AMACEL-YELLOW-G-; *ARTISIL-YELLOW-2GN-; *ATRISIL-DIRECT-YELLOW-G-; *CALCOSYN-YELLOW-GC-; *CELLITON-DISCHARGE-YELLOW-GL-; *CELLITON-FAST-YELLOW-GA-CF-; *CELLUTATE-YELLOW-GH-; *CI-Disperse-Yellow-3-; *CI-SOLVENT-YELLOW-77-; *CI-SOLVENT-YELLOW-92-; *CI-SOLVENT-YELLOW-99-; *CI-SOLVENT-YELLOW-14-CYTEMBENA-; *CI-11855-; *CIBACETE-YELLOW-GBA-; *CIBACET-YELLOW-2GC-; *CILLA-FAST-YELLOW-G-; *DIACELLITON-FAST-YELLOW-G-; *DISPERSE-YELLOW-G-; *DISPERSE-YELLOW-Z-; *DISPERSOL-FAST-YELLOW-G-; *DISPERSOL-PRINTING-YELLOW-G-; *DURGACET-YELLOW-G-; *DUROSPERSE-YELLOW-G-; *EASTONE-YELLOW-GN-; *ESTEROQUINONE-LIGHT-YELLOW-4JL-; *ESTONE-YELLOW-GN-; *FENACET-FAST-YELLOW-G-; *HISPACET-FAST-YELLOW-G-; *HISPERSE-YELLOW-G-; *4-(2-HYDROXY-5-METHYLPHENYLAZO)ACETANILIDE; *N-(4-((2-HYDROXY-5-METHYLPHENYL)AZO)PHENYL)ACETAMIDE; *4'-((6-HYDROXY-M-TOLYL)AZO)ACETANILIDE; *INTERCHEM-ACETATE-YELLOW-G-; *INTERCHEM-HISPERSE-YELLOW-GH-; *KAYALON-FAST-YELLOW-G-; *KCA-ACETATE-FAST-YELLOW-G-; *MICROSETILE-YELLOW-GR-; *MIKETON-FAST-YELLOW-G-; *NACELAN-FAST-YELLOW-CG-; *NOVALON-YELLOW-2GN-; *NYLOQUINONE-YELLOW-4J-; *OSTACET-YELLOW-P2G-; *PALACET-YELLOW-GN-; *PALANIL-YELLOW-G-; *PAMACEL-YELLOW-G-3-; *PERLITON-YELLOW-G-; *RELITON-YELLOW-C-; *RESIREN-YELLOW-TG-; *SAFARITONE-YELLOW-G-; *SAMARON-YELLOW-PA3-; *SERINYL-HOSIERY-YELLOW-GD-; *SERIPLAS-YELLOW-GD-; *SERISOL-FAST-YELLOW-GD-; *SETACYL-YELLOW-G-; *SETACYL-YELLOW-P-2GL-; *SILOTRAS-YELLOW-TSG-; *SUPRACET-FAST-YELLOW-G-; *TERASIL-YELLOW-2GC-; *TERTRANESE-YELLOW-N-2GL-; *TULADISPERSE-FAST-YELLOW-2G-; *VONTERYL-YELLOW-G-; *VONTERYL-YELLOW-R-; *YELLOW-Z-; *YELLOW-RELITON-G-; *ZLUT-DISPERZNI-3- (CZECH); *ZLUT-ROZPOUSTEDLOVA-77- (CZECH) RN: 2832-40-8 MF: *C15-H15-N3-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CONDENSATION OF DIAZOTIZED P-AMINOACETANILIDE WITH P-CRESOL [R1] MFS: *AMERICAN COLOR AND CHEM CO, CHARLOTTE, NC 28232 [R1] *CROMPTON AND KNOWLES CORP, DYES AND CHEMICALS DIV, READING, PA 19603 [R1] *E I DU PONT DE NEMOURS AND CO, CHEMICALS, DYES, AND PIGMENTS DEPT, WILMINGTON, DE 19898 [R1] *TOMS RIVER CHEMICAL CORP, TOMS RIVER, NJ 08753 [R1] OMIN: *TRADEMARK FOR SERIES OF DISPERSE DYESTUFFS CHARACTERIZED BY GOOD FASTNESS TO LIGHT, WASHING, ETC. USED FOR DYEING AND PRINTING ACETATE FIBERS. /CELLITON/ [R2] USE: *FOR DYEING TEXTILES, SHEEPSKINS AND FURS, FOR COLORING POLYMETHYL METHACRYLATE AND NYLON. [R3] *IN SURFACE DYEING OF CELLULOSE ACETATE [R3] *DYE FOR COLORING AND PRINTING ACETATE AND TRIACETATE FIBERS, NYLON AND ACRYLIC FIBERS, POLYESTER FIBERS; DYE FOR POLYVINYL CHLORIDE FIBERS, CELLULOSE ACETATE, POLYSTYRENE AND OTHER PLASTICS [R1] CPAT: *ESSENTIALLY 100% AS A DYE [R1] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 1.36X10+7 G [R1] *(1979) 1.46X10+9 G [R1] U.S. IMPORTS: *(1977) 8.99X10+4 G (PRINCPL CUSTMS DISTS) [R1] *(1979) 1.12X10+7 G (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *269.33 SOL: *SOL IN ACETONE, ETHANOL AND BENZENE [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- CLUP: *COLOR FROM DISPERSE YELLOW 3 WAS REMOVED BY COAGULATION WITH CATIONIC POLYMERS, EG NALCO 603, NALCO 7132, AND CAT-FLOC. POLYMER REQUIREMENTS FOR DISPERSE DYES ARE DETERMINED BY CONCN OF DISPERSING AGENT, EG REAX 85A. [R5] *CATIONIC POLYMERS AND ALUM EFFECTIVELY DESTABILIZED DISPERSE YELLOW 3 OVER BROAD PH RANGE. RELATION BETWEEN OPTIMUM DOSAGE OF EACH CATIONIC POLYMER AND DISPERSANT CONCN WAS DIRECT OR STOICHIOMETRIC. [R6] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is limited evidence for the carcinogenicity of Disperse Yellow 3 in experimental animals. No data were available from studies in humans on the carcinogenicity of Disperse Yellow 3. Overall evaluation: Disperse Yellow 3 is not classifiable as to its carcinogenicity to humans (Group 3). [R7] HTOX: *IT APPEARS TO BE RESPONSIBLE FOR ALLERGIC, CONTACT TYPE DERMATITIS INDUCED BY NYLON STOCKINGS TINTED BY THIS COLOR. CROSS HYPERSENSITIVITY WAS FOUND WITH PARA-PHENYLENEDIAMINE AMONGST 13 REPORTED CASES OF SENSITIVITY TO CI DISPERSE YELLOW 3. [R8] *CLOTHING CONTACT ALLERGY TO DISPERSE YELLOW 3 IS OBSERVED. LITERATURE INDICATES ALLERGY CONFINED TO FEMALES, CASES OBSERVED HAVE SHOWN THAT IT CAN ALSO AFFECT MALES. CHEMICAL INVESTIGATIONS (CHROMATOGRAPHY, IR AND NMR SPECTRA) AND ALLERGOLOGICAL INVESTIGATION SHOW THAT THE DYE ITSELF IS SENSITIZER, AND NOT ANY IMPURITIES. [R9] *Most organic azo dyes are potential skin sensitizers, the most important of which are paraphenylenediamine and its analogs. Water soluble azo dyes are more likely to cause clinical sensitization than insoluble dyes. ... In addition to allergic eczematous contact dermatitis, color developing solutions have caused lichen planus like eruptions. /Organic dyes/ [R10] *The prevalence of textile dye contact sensitization was studied in 145 patients suspected of having allergic contact dermatitis from textile chemicals and in 576 patients with various eczemas. In patch tests, 23 allergic contact dermatitis patients (15.9%) reacted to at least one dye. All showed strong reactions. The dyes producing the most reactions were Disperse Blue 124, Disperse Red 1, Disperse Orange 3, and Disperse Yellow 3. Patch testing of the eczematous patients with these four dyes and a standard series elicited reactions in 19 with eight patients reacting to dyes only. Disperse Blue 124 produced the most reactions in this group. In the standard series, para-phenylenediamine produced the most positive reactions. All para-phenylenediamine positive subjects also reacted to Disperse Orange 3; this was considered to be a cross reaction. It was suggested that contact sensitization to textile disperse dyes is not rare. Females appear to be more susceptible to developing a contact allergy to textile disperse dyes than males. [R11] NTOX: *1 ADENOMA AND 6 CARCINOMAS OF BLADDER ... IN 7/23 STOCK MICE SURVIVING 25 WK AFTER IMPLANTATION OF PELLETS OF CI DISPERSE YELLOW 3 IN CHOLESTEROL. ... 4 PAPILLOMAS AND 5 CARCINOMAS OF BLADDER OCCURRED IN 77 MICE GIVEN IMPLANTS OF CHOLESTEROL ALONE AND SURVIVING @ 25 WK. RESULTS WERE OF BORDERLINE SIGNIFICANCE. [R8] *POLLUTANT IN RIVER WATER SUPPLY OF NORTHERN GEORGIA CAUSED ABERRATIONS IN SQUASH PREPN FROM R CLAMITANS, INCL ARE GAPS, DICENTRICS, RINGS AND BREAKS. [R12] NTP: *A carcinogenesis bioassay of C. I. Disperse Yellow 3 (87.6% dye), a textile dye, was conducted by feeding diets containing 5,000 or 10,000 ppm of the test substance to groups of 50 F344 rats of either sex for 103 weeks. Similar groups of 50 B6C3F1 mice received diets containing 2,500 or 5,000 ppm of the test substance for 103 weeks. Groups of 50 untreated rats and mice of each sex served as controls. Throughout the bioassay, mean body weights of dosed rats and mice of either sex were lower than those of the controls. Survival of dosed rats of either sex was significantly greater than that of the corresponding controls. No other compound-related clinical signs or effects on survival were observed. Under the conditions of this bioassay, C. I. Disperse Yellow 3 was considered carcinogenic for male F344 rats, causing an increased incidence of neoplastic nodules of the liver; this dye was not carcinogenic for female F344 rats. In addition, the stomach tumors found in the male rats may have been induced by the administration of the test chemical. C. I. Disperse Yellow 3 was carcinogenic for female B6C3F1 mice, as evidenced by the increased incidence of hepatocellular adenomas; C. I. Disperse Yellow 3 was not carcinogenic for male B6C3F1 mice. Also, the increased incidence of lymphoma in female mice may have been associated with the administration of C. I. Disperse Yellow 3. [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Beauticians exposed to paraphenylenediamine derivatives in hair dyes, workers dyeing texitle resins, and photographic film developers exposed to color developing solutions not infrequently become sensitized to azo dyes. /Organic dyes/ [R10] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Today, paper chromatography has largely been displaced by TLC, which is more rapid, sensitive and reproducible. Separations have been carried out on a large variety of sorbents, including silica gel, alumina, Kieselgur, cellulose and polyamide, and mixtures of these, using various solvent systems. ... Isolation of water-soluble azo colors from the food matrix has been carried out by the so-called wool-thread method, by adsorption on alumina columns, by liquid-liquid extraction using quinoline, by quarternary ammonium compounds, and by liquid ion exchanges. It was claimed that polyamide is a relatively more selective adsorbent for water-soluble acidic dyes and carboxymethylcellulose for basic dyes. [R14] *Earlier methods relied on paper chromatography. ... More recent work involves thin-layer chromatography. A survey of separation characteristics of various sorbents, such as silica gel, alumina, 1:1 mixtures of silica gel and alumina, starch, cellulose and polyamide powder, used with a wide variety of solvents indicates the techniques capable of separating most lipid-soluble azo colors. ... A method was described for the isolation of lipid-soluble colors from fats and chocolate by liquid/liquid partition and adsorption chromatography followed by identification by thin-layer chromatography. [R14] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Feinman SE, Doyle EA; Sensitization to Dyes in Textiles and Other Consumer Products; J of Toxicol 7 (3): 195-222 (1988). DHHS/NTP; Carcinogenesis Studies of C.I. Disperse Yellow 3 in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 222 (1982) NIH Publication No. 82-1778] SO: R1: SRI R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 235 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 98 (1974) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 97 (1974) R5: CROWE T ET AL; PROC IND WASTE CONF 32: 655 (1978) R6: CROWE T ET AL; AM DYEST REP 67 (12): 52 (1978) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 48 157 (1990) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 99 (1974) R9: FOUSSEREAU J ET AL; TRANS ST JOHN'S HOSP DERMATOL SOC 58 (1): 75 (1972) R10: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 147 R11: Balato N et al; Contact Dermatitis 23 (2): 111-2 (1990) R12: GRAY PS ET AL; CYTOBIOS 25 (99-100): 175 (1979) R13: DHHS/NTP; Carcinogenesis Bioassay of C.I. Disperse Yellow 3 in F344 Rats and B6C3F1 Mice (Feed Study) p.7 (1982) Technical Rpt Series No. 222 NIH Pub No. 82-1778 R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 154 (1975) RS: 11 Record 252 of 1119 in HSDB (through 2003/06) AN: 4101 UD: 200205 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-AMINO-2-METHYLANTHRAQUINONE- SY: *ACETATE-FAST-ORANGE-R-; *ACETOQUINONE-LIGHT-ORANGE-JL-; *1-Amino-2-methyl-9,10-anthracenedione-; *1-Amino-2-methyl-9,10-anthraquinone-; *9,10-ANTHRACENEDIONE,-1-AMINO-2-METHYL-; *ANTHRAQUINONE,-1-AMINO-2-METHYL-; *ARTISIL-ORANGE-3RP-; *CELLITON-ORANGE-R-; *CI-DISPERSE-ORANGE-11-; *CI-60700-; *CILLA-ORANGE-R-; *DISPERSE-ORANGE-; *DISPERSE-ORANGE- (ANTHRAQUINONEDYE); *DURANOL-ORANGE-G-; *2-METHYL-1-ANTHRAQUINONYLAMINE-; *MICROSETILE-ORANGE-RA-; *NCI-C01901-; *NYLOQUINONE-ORANGE-JR-; *PERLITON-ORANGE-3R-; *SERISOL-ORANGE-YL-; *SUPRACET-ORANGE-R- RN: 82-28-0 MF: *C15-H11-N-O2 ASCH: 1-Amino-4-methylanthraquinone; 4947-16-4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF 2-METHYL-1-NITROANTHRAQUINONE WITH AQUEOUS SODIUM SULFIDE. [R1] MFS: *NOT PRODUCED COMMERCIALLY IN THE USA [R1] OMIN: *ONE GROUP COMPRISES WATER INSOL AZO OR ANTHRAQUINONE DYES THAT HAVE BEEN HIGHLY DISPERSED TO MAKE THEM CAPABLE OF PENETRATING AND DYEING ACETATE FIBERS. /ACETATE DYE/ [R2] USE: *CHEM INT FOR DYES-EG, C.I. SOLVENT BLUE 13, DYE FOR SYNTHETIC FIBERS, FURS, AND THERMOPLASTIC RESINS [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R1] *(1979) NOT PRODUCED COMMERCIALLY IN USA [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MP: *205-6 deg C [R3] MW: *237.3 SOL: *Sol in alcohol, ether, benzene, chloroform, acetic acid [R3] SPEC: *IR: 19527 (Sadtler Research Laboratories Prism Collection) [R4]; *UV: 7792 (Sadtler Research Laboratories Spectral Collection) [R4]; *MASS: 193 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R4] OCPP: *UV: 1371 (Absorption Spectra in the UV and Visible Regions, Academic Press, New York) /1-Amino-4-methylanthraquinone/ [R4] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R5] NTP: *A bioassay for possible carcinogenicity of technical-grade 1-amino-2-methylanthraquinone was conducted using Fischer 344 rats and B6C3F1 mice. 1-Amino-2-methylanthraquinone was administered in the feed, to 45 to 50 males and females of each species. The high and low time weighted average concentrations of 1-amino-2-methylanthraquinone were 0.20 and 0.10%, respectively, for male and female rats. For mice, two dosage regimens (designated A and B) were used, but the time weighted average concentrations were the same, 0.06%. A statistically significant positive association between compound administration and mortality was established for the male and female dose A mice. Dose A mice did not survive sufficiently long to be at risk from late developing tumors. Survival in all other groups was adequate. Under the conditions of this bioassay, 1-amino-2-methylanthraquinone was carcinogenic in Fischer 344 rats, inducing hepatocellular carcinomas in rats of both sexes, and kidney tumors in male rats. The compound was carcinogenic in female B6C3F1 mice, producing an increased combined incidence of hepatocellular carcinomas and neoplastic nodules. [R6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Sendelbach LE; A Review of the Toxicity and Carcinogenicity of Anthraquinone Derivatives; Toxicology 57 (3): 227-40 (1989) DHHS/NTP; Bioassay of 1-Amino-2-methylanthraquinone for Possible CarcinogenicityTechnical Report Series No. 111 (1978) NIH Publication No. 78-1366 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: SRI R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 6 R3: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-51 R4: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 103 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 57 (1987) R6: DHEW/NCI; Bioassay of 1-Amino-2-Methylanthraquinone for Possible Carcinogenicity p.V11 (1978) Technical Rpt Series No. 111 DHEW Pub No. (NIH) 78-1366 RS: 5 Record 253 of 1119 in HSDB (through 2003/06) AN: 4104 UD: 200302 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 5-NITRO-O-ANISIDINE- SY: *AI3-08934-; *2-AMINO-1-METHOXY-4-NITROBENZENE-; *3-Amino-4-methoxynitrobenzene-; *2-AMINO-4-NITROANISOLE-; *o-Anisidine-nitrate-; *O-ANISIDINE,-5-NITRO-; *Azoamine-scarlet-; *AZOAMINE-SCARLET-K-; *Azogene-Ecarlate-R-; *Azoic-diazo-component-13,-base-; *BENZENAMINE,-2-METHOXY-5-NITRO-; *CCRIS-440-; *CI-Azoic-diazo-component-13-; *Fast-scarlet-R-; *2-METHOXY-5-NITROANILINE-; *2-Methoxy-5-nitrobenzenamine-; *NCI-C01934-; *3-NITRO-6-METHOXYANILINE-; *5-NITRO-2-METHOXYANILINE-; *NSC-5510- RN: 99-59-2 MF: *C7-H8-N2-O3 SHPN: UN 2431; o-Anisidine; Anisidines, liquid or solid. IMO 6.1; o-Anisidine; Anisidines, liquid or solid. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PARTIAL REDUCTION OF 2,4-DINITROANISOLE; NITRATION OF O-ANISIDINE; BY-PRODUCT IN MANUFACTURE OF 5-NITRO-2-AMINOANISOLE [R1] *Prepared either by partial reduction of 2,4-dinitroanisole with ammonium or sodium sulfide or by nitration of 2-methoxyaniline. [R2] USE: *CHEM INT FOR DYES AND PIGMENTS (EG, CI PIGMENT RED 23); COMPONENT IN AZOIC DYE COMPOSITIONS FOR COTTON AND NYLON, ACETATE AND SILK. [R1] *Dye and pigment manufacture [R3] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 4.54X10+6 GRAMS [R1] U.S. IMPORTS: *(1977) 2.46X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 4.96X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORANGE-RED NEEDLES FROM ALC, ETHER, WATER [R4]; *Red needles from alcohol [R5] MP: *118 deg C [R6] MW: *168.16 [R6] DEN: *1.2068 @ 156 DEG C [R4] DSC: *pKa = 2.49 [R7] OWPC: *log Kow= 1.47 [R8] SOL: *Very sol in alcohol, acetone, benzene, acetic acid, ethyl acetate; soluble in ligroine [R9]; *SLIGHTLY SOL IN PETROLEUM ETHER [R10]; *In water, 115 mg/l @ 23 deg C [R11] SPEC: *MAX ABSORPTION (WATER, PH 7): 219 NM (LOG E= 3.90); 257 NM (LOG E= 3.78); 310 NM SHOULDER (LOG E= 3.38); 400 NM (LOG E= 4.09) [R4]; *IR: 3:826G (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R9]; *UV: 17651 (Sadtler Research Laboratories Spectral Collection) [R9]; *NMR: 11061 (Sadtler Research Laboratories Spectral Collection) [R9]; *MASS: 70828 (NIST/EPA/MSDC Mass Spectral Database, 1990 version) [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: *Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Anisidines; Anisidines, liquid or solid/ [R12] *Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Some may polymerize (P) explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. /Anisidines; Anisidines, liquid or solid/ [R12] *Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Anisidines; Anisidines, liquid or solid/ [R12] *Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. Structural firefighters' protective clothing is recommended for fire situations ONLY; it is not effective in spill situations. /Anisidines; Anisidines, liquid or solid/ [R12] *Evacuation: Spill: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Anisidines; Anisidines, liquid or solid/ [R12] *Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from the ends of tanks. /Anisidines; Anisidines, liquid or solid/ [R12] *Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. /Anisidines; Anisidines, liquid or solid/ [R12] *First aid: Move victim to fresh air. Call emergency medical care. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Anisidines; Anisidines, liquid or solid/ [R12] FIRP: *Extinguishant: Foam, carbon dioxide, dry chemical. /o-Anisidine/ [R13, 1981.2] *If material is involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Keep run-off water out of sewers and water sources. /Anisidines/ [R14] TOXC: *When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [R15] REAC: *Contact with strong oxidizers may cause fires and explosions. /o-Anisidine/ [R13, 1981.2] *Liquid anisidine will attack some forms of plastics, rubber, and coatings. /o-Anisidine/ [R13, 1981.2] DCMP: *When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [R15] EQUP: *Wear butyl rubber gloves, plastic coveralls, and self-contained breathing apparatus. /o-Anisidine/ [R16] *Respirator selection: 2.5 mg/cu m or less: Any dust and mist respirator, except single use. 5 mg/cu m or less: Any dust and mist respirator, except single use or quarter mask respirator. Any supplied air respirator or any self contained breathing apparatus. 25 mg/cu m or less: Any high efficiency particulate filter respirator with full facepiece. Any supplied air respirator with a full facepiece, helmet, or hood or any self contained breathing apparatus with full facepiece. 50 mg/cu m or less: A powered air purifying respirator with high efficiency particulate filter or a Type C supplied air respirator operated in pressure demand or other positive pressure or continuous flow mode. Greater than 50 mg/cu m or entry and escape from unknown concentrations: Self contained breathing apparatus with full facepiece operated in pressure demand or other positive pressure mode or a combination respirator which includes a Type C supplied air respirator with a full facepiece operated in pressure demand or other positive pressure or continuous flow mode and an auxiliary self contained breathing apparatus operated in pressure demand or other positive pressure mode. /o-Anisidine/ [R13, 1981.4] *Employees should be provided with and required to use dust- and splash-proof safety goggles where solid or liquid anisidine or liquids containing anisidine may contact the eyes. /o-Anisidine/ [R13, 1981.2] *If employee's clothing ... contaminated ... change /them/ ... . Clothing contaminated with anisidine should be placed into closed containers for storage until it can be discarded or until provision is made for removal of anisidine from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the anisidine, the person performing the operation should be informed of anisidine's hazardous properties. /o-Anisidine/ [R13, 1981.2] OPRM: *Where exposure of ... body to solid or liquid anisidine or liquids containing anisidine may occur, facilities for quick drenching of the body should be provided within the immediate work area ... . /o-Anisidine/ [R13, 1981.2] *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personal hazard. /Anisidines/ [R14] *Personnel protection: Keep upwind. Avoid breathing vapors or dusts. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Avoid bodily contact with the material. /Anisidines/ [R14] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R17] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R18] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R19] CLUP: *1. Ventilate area of spill or leak. 2. Collect spilled material in most convenient and safe manner for reclamation or for disposal. Liquids containing anisidine should be absorbed in vermiculite, dry sand, earth, or a similar material. Large quantities may be reclaimed; however, if this is not practical, dissolve in flammable solvent (such as alcohol) and atomize in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device. /o-Anisidine/ [R13, 1981.3] *Cover with the 9:1 mixture of sand and soda ash. After mixing, transfer into a paper carton, stuffed with ruffled paper. Burn in an open furnace with the utmost care or in the furnace with afterburner and scrubber. /o-Anisidine/ [R16] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R20] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R21] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R21] NTOX: *Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Equivocal; Female Mice: Positive. [R22] *5-Nitro-ortho-anisidine induced reverse mutations in Salmonella typhimurium strain TA98 in the absence of metabolic activation. [R23] NTXV: *LD50 Rat oral 2250 mg/kg; [R15] *LD50 Mouse oral 1060 mg/kg; [R15] NTP: *A bioassay of 5-nitro-o-anisidine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. /The cmpd/ was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The dietary concentrations used ... for low and high dose rats were 0.4 and 0.8%, respectively. Dose A and B mice were fed dietary concentrations of 0.8 and 1.6% when initially placed on test, but after wk 15 the concn fed to dose B mice was reduced to 0.4%. After a 78 wk period of chemical administration, observation of rats continued for up to an additional 28 wk and observation of mice continued for up to an additional 19 wk. For each species, 50 animals of each sex were placed on test as controls for the group receiving the higher concn and 49-50 animals of each sex were placed on test as controls for the group receiving the lower concn. ... Under the conditions of this bioassay, dietary administration of 5-nitro-o-anisidine was carcinogenic in Fischer 344 rats, causing tumors of the integumentary system in males and females and of the clitoral gland in females. The cmpd was carcinogenic to female B6C3F1 mice, causing hepatocellular carcinomas. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Equivocal; Female Mice: Positive. [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *5-Nitro-o-anisidine's production and use as a chemical intermediate for dyes and pigments may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 3.2X10-4 mm Hg at 25 deg C indicates 5-nitro-o-anisidine will exist solely as a vapor. Vapor-phase 5-nitro-o-anisidine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3.3X10-11. If released to soil, the amino group of 5-nitro-o-anisidine is expected to bind strongly to humic materials resulting in low mobility for the compound. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.2X10-8 atm-cu m/mole. No biodegradation data for 5-nitro-o-anisidine were found. If released into water, the amino group of 5-nitro-o-anisidine is expected to adsorb to humic materials in suspended solids and sediment. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 2.7 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to 5-nitro-o-anisidine may occur through inhalation and dermal contact with this compound at workplaces where 5-nitro-o-anisidine is produced or used. (SRC) ARTS: *5-Nitro-o-anisidine's production and use in the production of dyes(1) may result in its release to the environment through various waste streams(SRC). 5-Nitro-o-anisidine may be released to the environment in wastewater(2). [R24] FATE: *TERRESTRIAL FATE: The amino group of 5-nitro-o-anisidine may bind covalently with active sites in soil which will result in low mobility(1). Volatilization of 5-nitro-o-anisidine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(2). 5-Nitro-o-anisidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-4 mm Hg(3), determined from a fragment constant method(3). No biodegradation data were found for 5-nitro-o-anisidine(SRC). [R25] *AQUATIC FATE: The amino group of 5-nitro-o-anisidine may bind covalently with active sites in soil which will result in low mobility in suspended solids and sediments(1). Volatilization from water surfaces is not expected(2) based upon an estimated Henry's Law constant of 1.3X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). According to a classification scheme(4), an estimated BCF of 2.7(SRC), from its log Kow of 1.5(5) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low (SRC). No biodegradation data were found for 5-nitro-o-anisidine(SRC). [R26] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 5-nitro-o-anisidine, which has an estimated vapor pressure of 3.2X10-4 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely as a vapor. Vapor-phase 5-nitro-o-anisidine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 12 hours(SRC), calculated from its rate constant of 3.3X10-11 cu cm/molecule-sec at 25 deg C(SRC), determined using a structure estimation method(3). [R27] ABIO: *The rate constant for the vapor-phase reaction of 5-nitro-o-anisidine with photochemically-produced hydroxyl radicals has been estimated as 3.3X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 12 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2). 5-Nitro-o-anisidine is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). Aromatic amines such as aniline have weak absorption bands that extend beyond 290 nm(4), therefore p-anisidine may be susceptible to direct photolysis, but the kinetics of this reaction are unknown. Aniline has been shown to undergo indirect photolysis in natural waters containing humic acids(5), therefore it is expected that p-anisidine may also undergo indirect photolysis in natural water. [R28] BIOC: *An estimated BCF of 2.7 was calculated for 5-nitro-o-anisidine(SRC), using a log Kow of 1.5(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R29] KOC: *The Koc of 5-nitro-o-anisidine is estimated as 150(SRC), using a log Kow of 1.47(2) and a regression-derived equation(3). According to a classification scheme(4), this estimated Koc value suggests that 5-nitro-o-anisidine is expected to have high mobility in soil. Aromatic amines, however, become strongly and irreversibly bound to humic materials when added to soil(5,6). This binding results from formation of covalent bonds between soil humus and the amine group of the aniline(5). As a result, 5-nitro-o-anisidine is expected to be relatively immobile in some soils and to be strongly bound to humic material found in suspended solids and sediments in water(SRC). [R30] VWS: *The Henry's Law constant for 5-nitro-o-anisidine is estimated as 1.3X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 5-nitro-o-anisidine is expected to be essentially nonvolatile from water surfaces(2). 5-Nitro-o-anisidine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 3.2X10-4 mm Hg(3), determined from a fragment constant method(3). [R31] RTEX: *Occupational exposure to 5-nitro-o-anisidine may occur through inhalation and dermal contact with this compound at workplaces where 5-nitro-o-anisidine is produced or used(1). [R32] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 50 ug/l [R33] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *5-Nitro-o-anisidine can be gas chromatographed as determined by EPA Athens Environmental Research Laboratory or S-Cubed, Alexandria Va. [R34] *OSW Method 8270B. Determination Semivolatile Organic compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit - 10.000 ug/l. [R35] *OSW Method 8270C. Semivolatile Organic Compounds by Gas Chromatography/ Mass Spectrometry (GC/MS): Capillary Column Technique. [R35] *SFSAS method SFSAS 29. Extraction and Analysis of Organics in Biological Tissue. Detection limit = 2.000 mg/kg. [R35] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Bioassay of 5-Nitro-o-anisidine for Possible Carcinogenicity (1978) Technical Rpt Series No. 78-1382 DHEW Pub No. (NIH) 78-1382, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. p.B1 (2000) Available from http://ntp-server.niehs.nih.gov/NewHomeRoc/AboutRoC.html Reason for Delisting 5-Nitro-o-anisidine(99-59-2); Reason: Insufficient evidence of carcinogenicity. SO: R1: SRI R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA2 107 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 (1978) 419 R4: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-45 R5: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2502 R6: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-24 R7: Perrin DD; Dissociation constants of organic bases in aqueous solution. IUPAC Chem Data Ser: Suppl 1972. Buttersworth, London. (1972) R8: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 31 R9: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V1 531 R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-117 R11: Beilstein; (NA--) R12: U.S. Department of Transportation. 1996 North American Emergency Response Guidebook. A Guidebook for First Responders During the Initial Phase of a Hazardous Materials/Dangerous Goods Incident. U.S. Department of Transportation (U.S. DOT) Research and Special Programs Administration, Office of Hazardous Materials Initiatives and Training (DHM-50), Washington, D.C. (1996).. G-153 R13: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R14: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 88 R15: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2425 R16: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 45 R17: 49 CFR 171.2 (7/1/2000) R18: IATA. Dangerous Goods Regulations. 42nd Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2001. 116 R19: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6069 (1998) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 67 (1987) R21: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R22: Bioassay of 5-Nitro-o-anisidine for Possible Carcinogenicity (1978) Technical Rpt Series No. 78-1382 DHEW Pub No. (NIH) 78-1382, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 137 (1981) R24: (1) Catino SC, Farris DE; Kirk-Othmer Encycl Chem Tech 3rd ed. NY: Wiley 3: 419 (1978) (2) Steadman TR et al; Industrial Process Profiles for Environmental Use Chpt 7 USEPA 66/2-77-023g NTIS PB-281-479 (1977) R25: (1) Parris GE et al; Bull Environ Contam Toxicol 24: 497-503 (1980) (2) Hine J, Mookerjee PK; J Org Chem 40: 292-298 (1975) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R26: (1) Parris GE et al; Bull Environ Contam Toxicol 24: 497-503 (1980)(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (3) Hine J, Mookerjee PK; J Org Chem 40: 292-298 (1975) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) (5) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 31 (1995) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R27: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Atkinson R; Environ Toxicol Chem; 7: 435-62 (1988) R28: (1) Atkinson R; Environ Toxicol Chem 7: 435-62 (1988) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (4) Meallier P et al; Ann Chim 4: 15-28 (1969) (5) Kotzias D et al; Naturwissenschaften 69: 444-5 (1982) R29: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 31 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R30: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. nn (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) Berry DF; Diss Abst Int B 45: 3799 (1985) (6) Parris GE; Environ Sci Tech 14: 1099-106 (1980) R31: (1) Hine J, Mookerjee PK; J Org Chem 40: 292-298 (1975) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R32: (1) Schulte PA et al; Proc Int Conf Carcinog Mutagen 3: 23-35 (1988) R33: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R34: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.360 (1991) OST Pub 21W-4005 R35: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 30 Record 254 of 1119 in HSDB (through 2003/06) AN: 4105 UD: 200211 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-PHENYL-2-THIOUREA- SY: *U-6324-; *NCI-C02017-; *PHENYLTHIOCARBAMIDE-; *PHENYLTHIOUREA-; *ALPHA-PHENYLTHIOUREA-; *N-PHENYLTHIOUREA-; *1-Phenyl-Thiourea-; *PTC-; *THIOUREA,-PHENYL-; *UREA,-1-PHENYL-2-THIO-; *USAF-EK-1569- RN: 103-85-5 MF: *C7-H8-N2-S SHPN: IMO 6.1; Phenyl urea pesticides, liquid or solid, toxic IMO 6.1; Phenyl urea pesticides, liquid, toxic, flammable, flash point not less than 23 deg C or more UN 2767; Phenyl urea pesticides, solid, toxic IMO 3.2; Phenyl urea pesticide, liquid, flammable, toxic, flash point less than 23 deg C UN 3002; Phenyl urea pesticides, liquid, toxic UN 3001; Phenyl urea pesticides, liquid, flammable, toxic, flash point not less than 23 deg C HAZN: P093; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by evaporating an aqueous solution of aniline hydrochloride and ammonium thiocyanate and carefully heating the residue. [R1] MFS: *United-Guardian, Inc, Hq, PO Box 2500, Smithtown, NY 11787, (516) 273-0900; Guardian Laboratories; Eastern Chemical Division, Department ST, PO Box 2500, Smithtown, NY 11787; Production site: Hauppauge, NY 11787 [R2] OMIN: *PHENYLTHIOUREA IS A REPELLENT FOR RATS, RABBITS, AND WEASELS. EFFECTIVE CONCN ARE 0.012-0.014%, AND CAN BE LOWERED TO 0.002-0.003% BY ADDITION OF 5% SUCROSE. [R3] USE: *In medical genetics. [R1] PRIE: U.S. PRODUCTION: *(1975) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R4] U.S. IMPORTS: *(1976) 1.03X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R4] *(1978) 1.00X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEEDLES FROM WATER, PRISMS FROM ALCOHOL [R5]; *Needles [R1] TAST: *Bitter or tasteless ... Depending upon heredity of taster [R1]; *Taste threshold (detection in water): 2.00X10-5 moles/l; 2.03X10+1 mg/l; (recognition in water): 3.10X10-4 g/100 ml water. [R6] MP: *154 deg C [R1] MW: *152.22 [R1] DEN: *1.3 [R1] OWPC: *log Kow= 0.71 [R7] SOL: *Sol in 400 parts cold water, 17 parts boiling water; sol in alcohol [R1]; *Sol in ethanol and NaOH [R8]; *In water, 2.47X10+3 mg/l @ 25 deg C [R9] SPEC: *MAX ABSORPTION (ALCOHOL): 245 NM SHOULDER (LOG E= 4.0); 266 NM (LOG E= 4.19) [R10]; *IR: 3:1106F (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R11]; *NMR: 5-102 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R11]; *MASS: 477 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *... On contact with acid or acid fumes, it emits highly toxic fumes of sulfoxides and nitroxides. [R12, 2678] DCMP: *When heated to decomposition ... it emits highly toxic fumes of sulfoxides and nitroxides. [R12, 2678] OPRM: *... Eating, drinking and smoking should be prohibited /when pesticides are being handled./ [R13] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] STRG: *Rooms used only for storage should be soundly constructed and fitted with secure locks. Floors should be kept clear and the pesticides clearly identified. /Pesticides/ [R13] CLUP: *Spillages often occur in storage and repacking rooms, and they must be cleaned up with care. /Pesticides/ [R13] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number P093, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R15] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquidsand gases, and longer for solids. [R16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . /SRP: Organic bases/amines and related compounds/ [R17, 168] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or has severe pulmonary edema. Positive-pressure ventilation techniques with a bag-valve-mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. If patient is unresponsive to these measures, vasopressors may be helpful. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /SRP: Organic bases/amines and related compounds/ [R17, 169] HTOX: *In the manufacture of rubber, irritant contact dermatitis may occur from a variety of acids, alkalis, detergents, and solvents used in the process. Allergic contact dermatitis occurs not infrequently and is almost always due to an organic accelerator or antioxidant. While the list of potential sensitizing accelerators and antioxidants is enormous, common allergens include ... thioureas. /Thioureas/ [R18] NTOX: *POISONED RATS EXHIBITED PLEURAL EFFUSIONS AND PULMONARY EDEMA. ... MICE GIVEN MASSIVE DOSES OF PTU (100 MG/KG) IP SURVIVED AT LEAST 8 HR ALTHOUGH ALL HAD DIED BY 22 HR. SIMILARLY, RATS GIVEN 25 MG/KG IP SURVIVED MANY HR. [R19] *... DESTROYS CYTOCHROME p450 IN VIVO ... . [R20] *WHEN ADMIN IN DIET FOR 18 WK AT CONCN OF 120 and 60 PPM TO RATS AND 300 and 150 PPM TO MICE, 1-PHENYL-2-THIOUREA WAS NOT CARCINOGENIC TO EITHER SPECIES. [R21] *PHENYLTHIOUREA PRODUCED A CONCN-DEPENDENT INHIBITION OF RAT LUNG ACETYLCHOLINESTERASE ACTIVITY IN VITRO. [R22] *A STIMULATION OF RAT LIVER HEME OXYGENASE WAS FOUND AFTER ADMIN OF PHENYLTHIOUREA. [R23] *The mutagenicity of 1-phenyl-2-thiourea was tested on Salmonella typhimurium TA100 without activation with S9 mixture. 1-Phenyl-2-thiourea showed moderate mutagenicity. [R24] *BECAUSE ANIMALS AND MAN HAVE VERY LARGE CAPACITY TO DETOXIFY SULFIDES, A LETHAL DOSE PRESENTED SLOWLY (AS BY METABOLISM OF PTU) WOULD HAVE TO BE MANY TIMES LARGER THAN IV LETHAL DOSE. [R19] *THE PLANT GROWTH-INHIBITORY ACTIVITY IS GIVEN FOR 1-PHENYL-2-THIOUREA. THE SELECTIVITY ACTIVITY IS EXPRESSED AS THE RATIO OF WHEAT VS CUCUMBER ROOT INHIBITION. [R25] *DOMINANT GENE THAT CONFERS INSECT RESISTANCE TO DDT, BENZENE HEXACHLORIDE, AND PARATHION HAS ALSO CONFERRED ABNORMAL SUSCEPTIBILITY TO LETHAL EFFECTS OF PHENYLTHIOUREA. [R26] *IN DROSOPHILA MELANOGASTER ... RI RESISTANCE ALLELE ... CONFERRED UNUSUAL SUSCEPTIBILITY TO PTU ... THUS, SELECTION WITH PTU RESTORED DDT SUSCEPTIBILITY BY SELECTING FOR THE WILD-TYPE, PTU-TOLERANT ALLELE; AND MIXT OF PTU AND DDT COULD KILL ANY OF GENOTYPES. ... CMPD OF THIS TYPE ... BEST PROSPECT ... TO COUNTER DIRECTLY RESISTANCE PROBLEM. [R27] *1-Phenyl-2-thiourea was found to be negative when tested for mutagenicity using the Salmonella/ microsome preincubation assay. This reference reports on the testing of 270 chemicals, including 1-phenyl-2-thiourea, using the standard protocol approved by the National Toxicology Program (NTP). The tests were performed by one or more of 3 different laboratories under contract to NTP. This test procedure includes testing of the chemical using a wide range of doses in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S9. 1-Phenyl-2-thiourea was tested at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any Salmonella typhimurium strain was 10.000 mg/plate. At the high dose, slight clearing of the background bacterial lawn occurred in most cultures. [R28] *Pigmented epithelial cells isolated from 8-9 day old chick embryos can trans-differentiate into lens-like cells at the terminal period of the third generation of culture. However, efficiency of this trans-differentiation is usually rather low. Phenylthiourea, a potent inhibitor of melanin synthesis, effectively enhances trans-differentiation of pigmented epithelial cells into lens-like cells in vitro. Lentoid bodies began to appear in the multilayered region of primary cultures of pigmented epithelial cells maintained in medium containing phenylthiourea at concn between 0.5 and 1.0 mM. Furthermore, the enhancing effect of phenylthiourea can be amplified with testicular hyaluronidase. Under these conditions, pigmented epithelial cells grow vigorously and lose their differentiative properties, efficiently switching their phenotype into lens-like cells some 20 days after initiation of culture in the presence of both substances. Semiquantitative analysis revealed that testicular hyaluronidase amplified the effect of phenylthiourea more than 100 fold. It has been suggested that phenotypic expression of pigmented epithelial cells during trans-differentiation can be regulated by manipulating the microenvironment in which these cells reside. [R29] NTXV: *LD50 Rat oral 3 mg/kg; [R1] *LD50 Rabbit oral 40 mg/kg; [R1] *LD50 Rat ip 5 mg/kg; [R12, 2677] *LD50 Mouse oral 10 mg/kg; [R12, 2677] *LD50 Mouse ip 25 mg/kg; [R12, 2678] NTP: *A bioassay of 1-phenyl-2-thiourea for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 1-Phenyl-2-thiourea was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The high and low concentrations of 1-phenyl-2-thiourea utilized in the chronic studies were, respectively, 120 and 60 ppm for rats and 300 and 150 ppm for mice. Twenty animals of each species and sex were placed on test as controls. A 78 wk period of chemical administration was followed by an additional observation period of 26 wk for rats and 13 wk for mice. ... There were no tumors in either sex of rats or mice for which a significant positive association could be established between chemical administration and tumor incidence. Under the conditions of this bioassay, 1-phenyl-2-thiourea was not carcinogenic to Fischer 344 rats or B6C3F1 mice. [R30] ADE: *EXTENSIVELY METABOLIZED IN RABBITS AND 86% EXCRETED IN URINE OVER 2 DAYS WITH ADDNL 10% IN FECES. DESULFURATION OF THE MOLECULE IS EXTENSIVE, AND THE SULFUR LABEL IS EXCRETED MORE SLOWLY. EVENTUALLY 60% IS RECOVERED AS URINARY SULFATE. [R19] *AFTER ADMIN OF (35)SULFUR-CMPD TO ... /RATS AND RABBITS/ EXCRETION OF (35)SULFUR WAS SLOWER COMPARED TO THAT OF (14)CARBON AFTER (14)CARBON-CMPD. ... /RESULTS/ INDICATED THAT DESULFURATION OF 1-PHENYL-2-THIOUREA OCCURRED IN VIVO AND ... SUGGESTED THAT SOME HYDROGEN SULFIDE WAS LIBERATED ... AND MAY BE RESPONSIBLE FOR TOXIC EFFECTS ... 2 HR AFTER IP ADMIN OF (35)SULFUR-CMPD TO RATS, LEVELS OF (35)SULFUR WERE HIGH IN ORGANS OF BIOTRANSFORMATION AND EXCRETION (LIVER AND KIDNEYS) AND ALSO IN LUNG AND THYROID GLAND, ORGANS AFFECTED BY 1-PHENYL-2-THIOUREA. [R31] METB: *YIELDS ANILINE, P-HYDROXYPHENYLTHIOUREA, PHENYLCYANAMIDE, AND PHENYLUREA IN RABBIT. /FROM TABLE/ [R32] *... Investigated S-oxidation of N-substituted thioureas by purified hog liver mixed-function amine oxidase and pig and hamster liver microsomal fractions. In the presence of enzyme, O2, and nicotinamide adenine dinucleotide phosphate reductase, phenylthiourea ... metabolized to the corresponding formamidine sulfinic acid ... reaction ... occurred through intermediary sulfenic acids, indicating two consecutive oxidations. The formamidine sulfinic acid products then auto-oxidized slowly to the corresponding sulfonic acids. [R33] INTC: *PRETREATMENT OF ANIMALS WITH 1-METHYL-1-PHENYLTHIOUREA PREVENTS DESULFURATION AND REDUCES TOXICITY OF PTU. [R19] *CYSTEINE AND REDUCED GLUTATHIONE PARTIALLY REDUCED THE LIVER GLYCOGEN-DEPLETING EFFECT OF A TOXIC PHENYLTHIOUREA DOSE IN RATS. [R34] *IN VITRO BINDING OF (14)CARBON THIOUREA TO RAT LUNG PROTEIN WAS ANTAGONIZED BY THE PRESENCE OF PHENYLTHIOUREA. [R35] *DL-ISOPROTERENOL-HCL INHALATION INCR PULMONARY EDEMA INDUCED IN RATS BY PHENYLTHIOUREA; PROPRANOLOL DECR THIS EFFECT. [R36] *PRETREATMENT OF RATS WITH SUBLETHAL DOSE OF 5 MG/KG PHENYLTHIOUREA, IP, CONFERRED 80% PROTECTION TO THE TOXIC EFFECT OF 125 MG/KG PHENYLTHIOUREA, IP. THIS PROTECTION WAS ABOLISHED BY TREATING THE RATS WITH DACTINOMYCIN. [R37] *1-PHENYL-2-THIOUREA MARKEDLY ENHANCED THE CYTOTOXIC EFFECTS OF COPPER CHLORIDE ON CHICK EMBRYONIC PRIMARY EMBRYONIC CELLS CULTURED IN VITRO. MOST PRIMARY EMBRYONIC CELLS MAINTAINED IN MEDIUM CONTAINING 0.5 MM 1-PHENYL-2-THIOUREA WERE LYSED WITHIN 4 HR BY THE ADDITION OF 0.1 MM COPPER CHLORIDE, WHICH ADDITION KILLED NO PRIMARY EMBRYONIC CELLS IN THE ABSENCE OF 1-PHENYL-2-THIOUREA. THE EFFECT OF 1-PHENYL-2-THIOUREA WAS NOT SPECIFIC TO PRIMARY EMBRYONIC CELLS. ALL THE CELL LINES TESTED, KB, N-18, N-155, AND B-16, REACTED AGAINST EXOGENOUS COPPER IN THE PRESENCE OF 1-PHENYL-2-THIOUREA AS DID THE PRIMARY EMBRYONIC CELLS. 1-PHENYL-2-THIOUREA DID NOT AFFECT THE CYTOLYSIS INDUCED BY THE ADDITION OF THE DIVALENT CATIONS MANGANESE, COBALT, OR ZINC ABOUT 6 FOLD. [R38] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1-Phenyl-2-thiourea's production and use in medical genetics may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 2.1X10-3 mm Hg at 25 deg C indicates 1-phenyl-2-thiourea will exist solely in the vapor phase in the ambient atmosphere. Vapor-phase 1-phenyl-2-thiourea will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 6 hours. If released to soil, 1-phenyl-2-thiourea is expected to have very high mobility based upon an estimated Koc of 20. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.0X10-10 atm-cu m/mole. No data are available regarding biodegradation in soil or water. If released into water, 1-phenyl-2-thiourea is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc, although 1-phenyl-2-thiourea may adsorb onto suspended humic material. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3.2 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to 1-phenyl-2-thiourea may occur through inhalation and dermal contact with this compound at at workplaces where 1-phenyl-2-thiourea is produced or used. (SRC) ARTS: *1-Phenyl-2-thiourea's production and use in medical genetics(1) may result in its release to the environment through various waste streams(SRC). [R39] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 20(SRC), determined from a structure estimation method(2), indicates that 1-phenyl-2-thiourea is expected to have very high mobility in soil(SRC). Volatilization of 1-phenyl-2-thiourea from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.0X10-10 atm-cu m/mole(SRC), using a fragment constant estimation method(3). 1-Phenyl-2-thiourea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-3 mm Hg(SRC), determined from a fragment constant method(4). [R40] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 20(SRC), determined from an estimation method(2), indicates that 1-phenyl-2-thiourea is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.0X10-10 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3.2(SRC), from a log Kow of 0.71(6), suggests the potential for bioconcentration in aquatic organisms is low. [R41] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1-phenyl-2-thiourea, which has an estimated vapor pressure of 2.1X10-3 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1-phenyl-2-thiourea is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 6 hours(SRC), calculated from its rate constant of 6.4X10-13 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). [R42] ABIO: *The rate constant for the vapor-phase reaction of 1-phenyl-2-thiourea with photochemically-produced hydroxyl radicals has been estimated as 6.4X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). [R43] BIOC: *An estimated BCF of 3.2 was calculated for 1-phenyl-2-thiourea(SRC), using a log Kow of 0.71(2) and a regression-derived equation(3). According to a classification scheme(4), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R44] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 1-phenyl-2-thiourea can be estimated to be 20(SRC). According to a classification scheme(2), this estimated Koc value suggests that 1-phenyl-2-thiourea is expected to have very high mobility in soil. [R45] VWS: *The Henry's Law constant for 1-phenyl-2-thiourea is estimated as 1.0X10-10 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 1-phenyl-2-thiourea is expected to be essentially nonvolatile(2). 1-Phenyl-2-thiourea is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.1X10-3 mm Hg(3). [R46] RTEX: *Occupational exposure to 1-phenyl-2-thiourea may occur through inhalation and dermal contact with this compound at at workplaces where 1-phenyl-2-thiourea is produced or used(SRC). EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R47] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Phenylthiourea is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100/10,000 lbs. [R48] RCRA: *P093; As stipulated in 40 CFR 261.33, when phenylthiourea, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R49] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *POLAROGRAPHIC BEHAVIOR OF PHENYLTHIOUREA IN BRITTON-ROBINSON BUFFER AND SODIUM HYDROXIDE SOLUTIONS WAS INVESTIGATED. DIFFERENTIAL PULSE VOLTAMMETRY WAS USED TO RESOLVE A MIXT CONTAINING PHENYLTHIOUREA. THIS TECHNIQUE CAN BE USED TO DETERMINE CONCN DOWN TO 0.1 UM. [R50] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of 1-Phenyl-2-thiourea for Possible Carcinogenicity (1978) Technical Rpt Series No. 148 DHEW Pub No. (NIH) 78-1704 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1259 R2: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 847 R3: MURATA T ET AL; JAPAN KOKAI PATENT NO 77 72818 06/17/77 (TOYO CHEMICAL INDUSTRY CO, LTD) R4: SRI R5: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-486 R6: Fazzalari, F.A. (ed.). Compilation of Odor and Taste Threshold Values Data. ASTM Data Series DS 48A (Committee E-18). Philadelphia, PA: American Society for Testing and Materials, 1978. 136 R7: Grovers H et al; Chemosphere 15: 383-93 (1986) R8: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-323 R9: Seidell A; Solubilities of Organic Compounds NY: Van Norstrand Co p. 544 (1941) R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-539 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 355 R12: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R13: International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998.,p. 62.15 R14: 49 CFR 171.2 (7/1/99) R15: 40 CFR 240-280, 300-306, 702-799 (7/1/96) R16: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-10 (1981) EPA 68-03-3025 R17: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R18: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 106 R19: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-350 R20: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 4: A Review of the Literature Published during 1974 and 1975. London: The Chemical Society, 1977. 280 R21: BIOASSAY OF 1-PHENYL-2-THIOUREA FOR POSSIBLE CARCINOGENICITY; REPORT: 1-88 DHEW/PUB/NIH-78-1704, NCI-CG-TR-148; ORDER NO PB-287357 R22: GIRI SN ET AL; BIOCHEM PHARMACOL 26 (4): 313-7 (1977) R23: JARVISALO J ET AL; MOL PHARMACOL 14 (6): 1099-106 (1978) R24: Yamaguchi T; Agric Biol Chem 44 (12): 3017-8 (1980) R25: VASILEV G, IONOVA P; WIRKUNGSMECH HERBIZ SYNTH WACHSTUMSREGUL, (BER SYMP WISS KOORDINIERUNGSKONF), 12TH: 34-40 (1979) R26: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 452 R27: White-Stevens, R. (ed.). Pesticides in the Environment: Volume 1, Part 1, Part 2. New York: Marcel Dekker, Inc., 1971. 532 R28: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R29: Itoh Y, Eguchi G; Cell Differ 18 (3): 173-82 (1986) R30: DHEW/NCI; Bioassay of 1-Phenyl-2-thiourea for Possible Carcinogenicity p.vii (1978) Technical Rpt Series No. 148 DHEW Pub No. (NIH) 78-1704 R31: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969. London: The Chemical Society, 1970. 95 R32: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-32 R33: The Royal Society of Chemistry. Foreign Compound Metabolism in Mammals. Volume 6: A Review of the Literature Published during 1978 and 1979. London: The Royal Society of Chemistry, 1981. 78 R34: GIRI SN, COMBS AB; TOXICOL APPL PHARMACOL 16 (3): 709-17 (1970) R35: HOLLINGER MA ET AL; DRUG METAB DISPOS 4 (2): 119-23 (1976) R36: COMBS AB, JONES J; RES COMMUN CHEM PATHOL PHARMACOL 12 (1): 177-80 (1975) R37: GIRI SN, BURKHALTER A; ARCH ENVIRON HEALTH 18 (5): 730-7 (1969) R38: MASUDA A, EGUCHI G; CELL STRUCT FUNCT 9 (1): 25-35 (1984) R39: (1) Budavari S, ed; The Merck Index. 12th ed Whitehouse Station, NJ: Merck and Co. Inc. p. 1259 (1996) R40: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE eds, Boca Raton, FL: CRC Press (1985) R41: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Govers H et al; Chemosphere 15: 383-93 (1986) R42: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R43: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R44: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2)Govers H et al; Chemosphere 15: 383-93 (1986) (3) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) R45: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R46: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R47: 40 CFR 302.4 (7/1/99) R48: 40 CFR 355 (7/1/99) R49: 40 CFR 261.33 (7/1/99) R50: SMYTH MR, OSTERYOUNG JG; ANAL CHEM 49 (14): 2310-4 (1977) RS: 28 Record 255 of 1119 in HSDB (through 2003/06) AN: 4129 UD: 200208 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,6-DICHLORO-1,4-BENZENEDIAMINE- SY: *1,4-BENZENEDIAMINE,-2,6-DICHLORO-; *CI-37020-; *DAITO-BROWN-SALT-RR-; *2,6-DICHLORO-P-PHENYLENEDIAMINE-; *2,6-DICHLORO-1,4-PHENYLENEDIAMINE-; *3,5-DICHLORO-1,4-PHENYLENEDIAMINE-; *NCI-C50260-; *P-PHENYLENEDIAMINE,-2,6-DICHLORO- RN: 609-20-1 MF: *C6-H6-CL2-N2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF 2,6-DICHLORO-4-NITROANILINE [R1] MFS: *NOT PRODUCED COMMERCIALLY IN US [R1] USE: *CHEM INT FOR CI AZOIC DIAZO COMPONENT 117 [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *177.04 SPEC: +IR: 19962 (Sadtler Research Laboratories Prism Collection) [R2]; +MASS: 4300 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R3] NTOX: +2,6-Dichloro-p-phenylenediamine was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 2,6-Dichloro-p-phenylenediamine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.0033, 0.010, 0.033, 0.100, 0.333, 1.000, and 2.200 mg/plate. It was positive in strains TA98, TA1537, and TA100 with either activation system (rat or hamster liver S-9). The lowest positive dose tested was 0.033 mg/plate in strain TA98 with rat liver S-9. [R4] +... Under the conditions of this bioassay, 2,6-dichloro-p-phenylenediamine was carcinogenic for male and female B6C3Fl mice, causing incr incidences of combined hepatocellular adenomas and carcinomas, and for male B6C3F1 mice, causing an incr incidence of hepatocellular adenomas alone. 2,6-Dichloro-p-phenylenediamine was not carcinogenic for male or female F344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Positive; Female Mice: Positive. [R5] NTP: +A carcinogenesis bioassay of 2,6-dichloro-p-phenylenediamine, a chemical intermediate, was conducted in groups of 50 F344 rats and B6C3F1 mice of either sex. Male rats were fed diets containing 1,000 or 2,000 ppm 2,6-dichloro-p-phenylenediamine and female rats were fed 2,000 or 6,000 ppm for 103 weeks. Mice were fed 1,000 or 3,000 ppm of the test chemical for 103 weeks and observed for an additional 8 weeks. Controls consisted of 50 untreated rats and 50 untreated mice of each sex. Under the conditions of this bioassay, 2,6-dichloro-p-phenylenediamine was carcinogenic for male and female B6C3Fl mice, causing incr incidences of combined hepatocellular adenomas and carcinomas, and for male B6C3F1 mice, causing an incr incidence of hepatocellular adenomas alone. 2,6-Dichloro-p-phenylenediamine was not carcinogenic for male or female F344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Positive; Female Mice: Positive. [R5] METB: *2,6-DICHLORO-4-NITROANILINE DCNA WAS ABSORBED BY ROOTS OF LETTUCE AND TOMATOES GROWN IN TREATED SOIL AND WAS TRANSLOCATED TO LEAVES, WHERE IT UNDERWENT RAPID DEGRADATION TO POLAR METABOLITES. TRANSIENT METABOLITES 2,6-DICHLORO-P-PHENYLENEDIAMINE WAS NOT DETECTED. [R6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Carcinogenesis Bioassay of 2,6-Dichloro-p-Phenylenediamine in F344/N Rats and B6C3F1 Mice Technical Report Series No. 219 (1982) NTIS Publication No. PB82184052 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 SO: R1: SRI R2: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 92 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 62 (1987) R4: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R5: Carcinogenesis Bioassay of 2,6-Dichloro-p-Phenylenediamine in F344/N Rats and B6C3F1 Mice Technical Report Series No. 219 (1982) NTIS Publication No. PB82184052 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R6: LEMIN AJ; J AGRIC FOOD CHEM 13(6) 557 (1965) RS: 5 Record 256 of 1119 in HSDB (through 2003/06) AN: 4132 UD: 200302 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-SOLVENT-YELLOW-14- SY: *BENZENEAZO-BETA-NAPHTHOL-; *BENZENE-1-AZO-2-NAPHTHOL-; *1-BENZOAZO-2-NAPHTHOL-; *BRASILAZINA-OIL-ORANGE-; *BRILLIANT-OIL-ORANGE-R-; *CALCOGAS-M-; *CALCOGAS-ORANGE-NC-; *CALCO-OIL-ORANGE-7078-Y-; *CALCO-OIL-ORANGE-Z-7078-; *CALCO-OIL-ORANGE-7078-; *CAMPBELLINE-OIL-ORANGE-; *CARMINAPH-; *CERES-ORANGE-R-; *CEROTINORANGE-G-; *CI-12055-; *DISPERSOL-YELLOW-PP-; *DUNKELGELB-; *ENIAL-ORANGE-I-; *FAST-OIL-ORANGE-; *FAST-OIL-ORANGE-I-; *FAST-ORANGE-; *FAT-ORANGE-I-; *FAT-ORANGE-R-; *FAT-ORANGE-4A-; *FAT-SOLUBLE-ORANGE-; *FETTORANGE-R-; *FETTORANGE-4A-; *FETTORANGE-IG-; *GRASAL-ORANGE-; *GRASAN-ORANGE-R-; *HIDACO-OIL-ORANGE-; *2-HYDROXYNAPHTHYL-1-AZOBENZENE-; *2-HYDROXY-1-PHENYLAZONAPHTHALENE-; *LACQUER-ORANGE-VG-; *MOTIORANGE-R-; *2-NAPHTHALENOL, 1-(PHENYLAZO)-; *NCI-C53929-; *NSC-11227-; *NSC-51524-; *OIL-ORANGE-; *OIL-ORANGE-Z-7078-; *OIL-ORANGE-31-; *OIL-ORANGE-PEL-; *OIL-SOLUBLE-ORANGE-; *OLEAL-ORANGE-R-; *ORANGE-R-FAT-SOLUBLE-; *ORANGE-A-L'HUILE-; *ORANGE-2-INSOLUBLE-; *ORANGE-INSOLUBLE-OLG-; *ORANGE-PEL-; *ORANGE-RESENOLE-3-; *ORANGE-SOLUBLE-A-L'HUILE-; *ORANGE-3RA-SOLUBLE-IN-GREASE-; *ORGANOL-ORANGE-; *ORIENT-OIL-ORANGE-PS-; *PETROL-ORANGE-Y-; *ALPHA-PHENYLAZO-BETA-NAPHTHOL-; *1-PHENYLAZO-BETA-NAPHTHOL-; *1-(PHENYLAZO)-2-NAPHTHOL; *PLASTORESIN-ORANGE-F4A-; *PYRONALORANGE-; *RESINOL-ORANGE-R-; *SANSEL-ORANGE-G-; *SCHARLACH-B-; *SILOTRAS-ORANGE-TR-; *SOLVENT-YELLOW-14-; *SOMALIA-ORANGE-I-; *SOUDAN-I-; *SPIRIT-ORANGE-; *SPIRIT-YELLOW-I-; *STEARIX-ORANGE-; *SUDAN-J-; *SUDAN-1-; *SUDAN-ORANGE-R-; *SUDAN-YELLOW-; *TERTROGRAS-ORANGE-SV-; *TOYO-OIL-ORANGE-; *WAXAKOL-ORANGE-GL-; *WAXOLINE-YELLOW-I- RN: 842-07-9 MF: *C16-H12-N2-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *COUPLING OF DIAZOTIZED ANILINE WITH 2-NAPHTHOL [R1] MFS: *AMERICAN CYANAMID CO, WAYNE, NJ 07470 [R1] *ATLANTIC CHEMICAL CORP, NUTLEY, NJ 07110 [R1] *E I DU PONT DE NEMOURS AND CO, INC, WILMINGTON, DEL 19898 [R1] *PASSAIC COLOR AND CHEMICAL CO, PATERSON, NJ 07501 [R1] *MOBAY CHEMICAL CORP, DYESTUFF DIV, UNION, NJ 07083 [R1] OMIN: *ACCORDING TO USA INDUST SOURCES, WHEN SUDAN I IS NOT USED IN DRUGS OR COSMETICS, ITS MFR AND TESTING DO NOT CONFORM TO RIGID CHEM SPECIFICATIONS, AND ITS COMPOSITION MAY VARY IN ORDER TO MEET CUSTOMER SHADE AND INTENSITY REQUIREMENTS. [R2] USE: *DYE FOR HYDROCARBON SOLVENTS, OILS, FATS, WAXES, SHOE AND FLOOR POLISHES, GASOLINE, SOAP, COLORED SMOKES, CELLULOSE ETHER VARNISHES, AND STYRENE RESINS [R1] CPAT: *ESSENTIALLY 100% AS A DYE [R1] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 1.59X10+7 GRAMS [R1] *(1979) 1.59X10+8 GRAMS [R1] U.S. IMPORTS: *(1977) 8.25X10+5 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 1.14X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *BRICK-RED CRYSTALS (LEAFLETS FROM ETHANOL) [R2] MP: *134 DEG C [R2] MW: *248.3 SOL: *SOL IN ETHANOL, ACETONE, ETHER AND BENZENE; INSOL IN WATER [R2]; *SOL IN PETROLEUM ETHER, CARBON DISULFIDE, CONCN HYDROCHLORIC ACID [R3] SPEC: *MAX ABSORPTION (ETHANOL): 514-516 NM [R2]; *MAX ABSORPTION (ALCOHOL): 315 NM (LOG E= 3.9); 422 NM (LOG E= 4.1); 480 NM (LOG E= 4.3) [R3] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R4] HTOX: *SKIN SENSITIVITY OF RED 225 AND ITS IMPURITIES DETERMINED BY PATCH TEST. COMMERCIAL PREPN SHOWED POSITIVE REACTIONS IN ALL 6 SUBJECTS. SUDAN I ISOLATED AND IDENTIFIED. SUDAN I ALSO SHOWED POSITIVE REACTIONS IN ALL 6 SUBJECTS. [R5] *Most organic azo dyes are potential skin sensitizers, the most important of which are paraphenylenediamine and its analogs. Water soluble azo dyes are more likely to cause clinical sensitization than insoluble dyes. ... In addition to allergic eczematous contact dermatitis, color developing solutions have caused lichen planus like eruptions. /Organic dyes/ [R6] *"Kumkums" are colored cosmetics frequently applied to the center of the forehead by Hindu women. Pigmented allergic contact dermatitis to "kumkum" was reported recently. It was associated with Brilliant Lake Red R and Sudan I allergy. These might be the causitive allergens. Three of 7 brands of red "kumkums" analyzed by gas chromatography-mass spectrophotometry were found to contain various concentrations of Sudan I. They ranged from 2.789 mg/g to 8.694 mg/g. Sudan I is probably the cause of pigmented allergic contact dermatitis in red "kumkum". [R7] NTOX: *PARAFFIN WAX PELLETS CONTAINING 12.5% ... IMPLANTED INTO URINARY BLADDERS OF FEMALE (C57XIF)F1 MICE; 14/100 SURVIVING 25 OR MORE WK DEVELOPED CARCINOMAS OF BLADDER, and 2 ... SHOWED SQUAMOUS METAPLASIA OF BLADDER. ... BLADDER CARCINOMA IN CONTROLS ... WAS 4/89 ... . [R8] *GROUPS OF 47 CBA AND 35 STOCK MICE ... 10 WK OLD, RECEIVED DIET ... @ CONCN OF 1000 MG/KG OF DIET FOR 12 MO (TOTAL DOSE, 1400 MG/ANIMAL). ... INCIDENCE OF HEPATOMAS AFTER 120 WK ... WAS LOWER IN TREATED THAN IN UNTREATED ... GROUP OF 20 RATS ... FED ... @ CONCN OF 1000 MG/KG OF DIET FOR LIFESPAN. ... NO TUMORS WERE FOUND. [R9] *... 18 MALE AND 18 FEMALE STOCK MICE, 2-3 MO OF AGE ... GIVEN 17-20 SC INJECTIONS OF 0.25 ML OF 3% SOLN ... IN ARACHIS OIL @ 3-WK INTERVALS. BETWEEN 305TH AND 615TH DAY ... 8/12 MALES HAD DEVELOPED ... 6 HEPATOMAS, 1 ADENOCARCINOMA OF LUNG AND 1 SQUAMOUS CARCINOMA @ INJECTION SITE. ... 3 FEMALES DEVELOPED /SIMILAR/ TUMORS ... . [R9] *PARAFFIN WAX PELLETS WEIGHING 10-18 MG AND CONTAINING 12% SUDAN I WERE IMPLANTED INTO URINARY BLADDERS OF 32 ALBINO MICE FOR 40 WK. 8 ... DEVELOPED CARCINOMAS OF BLADDER, 6 ... HAD BENIGN TUMORS AND 5 SHOWED SQUAMOUS METAPLASIA OF BLADDER. IN 56 CONTROLS ... 2 CARCINOMAS, 9 SQUAMOUS METAPLASIA AND 3 BENIGN TUMORS ... . [R8] *Twenty-seven chemicals were tested for their mutagenic potential in the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine, 3 micrograms/ml. The chemicals were tested at least twice. Statistically significant responses were obtained with solvent yellow 14. Apart from phenazopyridine hydrogen chloride, acid orange 10, and solvent yellow 14, rat liver S9 mix was not a requirement for the mutagenic activity of these compounds. [R10] *Solvent Yellow 14 is carcinogenic in rats, inducing neoplastic nodules of the liver, but is non-carcinogenic in mice. Solvent Yellow 14 induces micronuclei in the bone marrow of rats after a single oral dose of 250 mg/kg and above. In mice, however, there was no increased incidence of micronuclei after single oral doses of up to 2000 mg/kg Solvent Yellow 14, thus reflecting the species specific carcinogenic effect of the compound. The structurally related azo dye FD AND C Yellow No. 6 is noncarcinogenic to rats and mice and gave a negative result in both rat and mouse bone marrow micronucleus tests after a single oral dose of up to 2000 mg/kg. The rat bone marrow micronucleus test is therefore capable of discrimination between the carcinogenic and the non-carcinogenic azo dye. A negative result was obtained for Solvent Yellow 14 in an in vivo liver unscheduled DNA synthesis assay after oral doses up to 1000 mg/kg. [R11] *The in vivo/in vitro hepatocyte DNA repair assay has been shown to be useful for studying genotoxic hepatocarcinogens. In addition, measurement of S-phase synthesis provides an indirect indicator of hepatocellular proliferation, which may be an important mechanism in rodent carcinogenesis. This assay was used to examine 24 chemicals for their ability to induce unscheduled DNA synthesis or S-phase synthesis in Fischer 344 rats or B6C3F1 mice following in vivo treatment. Hepatocytes were isolated by liver perfusion and incubated with 3(H)-thymidine following in vivo treatment by gavage. Unscheduled DNA synthesis was measured by quantitative autoradiography as net grains/nucleus. Controls from both sexes of both species yielded less than 0.0 net grains/nucleus. Chemicals chosen for testing were from the NTP genetic toxicology testing program and most were also evaluated in long-term animal studies conducted by the NTP. 11-Aminoundecanoic acid, benzyl acetate, bis(2-chloro-1-methylethyl)ether, C.I. Solvent Yellow 14, cinnamaldehyde, cinnamyl anthranilate, dichloromethane, dichlorvos, glutaraldehyde, 4,4'-methylenedianiline, 4-nitrotoluene, 4,4'-oxydianiline, a polybrominated biphenyl mixture, reserpine, 1,1,2,2-tetrachloroethane, 1,1,2-trichloroethane, trichloroethylene, and 2,6-xylidine all failed to induce unscheduled DNA synthesis in rats and/or mice. Dinitrotoluene and Michler's Ketone induced positive unscheduled DNA synthesis response in rat, while N-nitrosodiethanolamine and selenium sulfide induced equivocal unscheduled DNA synthesis results in mouse and rat, respectively. Bis(2-chloro-1-methylethyl)ether, bromoform, chloroform, biphenyl mixture, 1,1,2-trichloroethane, and trichloroethylene were all potent inducers of S-phase synthesis in mouse liver, while C.I. Solvent Yellow 14, and 1,1,2,2-tetrachloroethane yielded equivocal S-phase synthesis results in rat and mouse, respectively. These results indicate that most of the test compounds do not induce unscheduled DNA synthesis in the liver; however, the significant S-phase responses by many of these compounds, especially the halogenated solvents, may be an important mechanism in their hepatocarcinogenicity. [R12] *The reversible stage of tumor promotion, which follows the stage of initiation and precedes that of progression in multistage carcinogenesis, is a unique example of reversible toxicity in biological systems. In order to study the molecular mechanisms involved in the action of promoting agents during this stage, the regulation of the expression of genes for two enzymes of glutathione metabolism, gamma-glutamyl transpeptidase and the placental isozyme of glutathione S-transferase, was studied under several different conditions of promotion during multistage hepatocarcinogenesis in the rat. Promotion by phenobarbital caused an increased expression of both of these genes in altered hepatic focal lesions, although this was somewhat more variable in the case of the gamma-glutamyl transpeptidase gene. C.I. Solvent Yellow 14, an industrial dye, served as an effective promoting agent. Feeding this dye resulted in a dramatic increase in the expression of glutathione s-transferase, but not that of gamma-glutamyl transpeptidase in altered hepatic foci. Factors in crude, cereal-based diets inhibited the stage of promotion by diethylnitrosamine, but enhanced promotion by phenobarbital in a synergistic manner. In contrast, at least one purified diet had the converse effect during this stage. The mRNA levels of glutathione s-transferase were uniformly elevated dramatically in reversible nodules and neoplasms of rat liver that had been induced by diethylnitrosamine and phenobarbital promotion. In contrast, the level of gamma-glutamyl transpeptidase mRNA was somewhat variable, with an occasional neoplasm exhibiting almost a background level of expression of this gene. Therefore, the altered regulation of multiple genes in hepatocytes during the stage of promotion can vary with the promoting agent itself; this process may be related to the heterogeneous gene expression seen in hepatic neoplasms possible role for specific DNA sequences in the 5' flanking regions of such genes is considered. In addition, a cDNA clone to the mRNA of human liver gamma-glutamyl transpeptidase was isolated and sequenced. The homology of the coding sequence of the human liver gamma-glutamyl transpeptidase mRNA to that of rat kidney gamma-glutamyl transpeptidase mRNA was striking. [R13] *Fifteen chemicals were tested, with and without exogenous metabolic activation by the sister chromatid exchange assay and the chromosome aberration assay in Chinese hamster ovary cells, to evaluate their in vitro cytogenetic damage. These compounds were tested at doses up to 5 mg/ml or as limited by solubility and/or toxicity. Solvent and positive controls were run concurrently with each trial. Descriptions of the sister chromatid exchange and chromosome aberration assays used and of the data analysis were provided. Solvent yellow 14 did not induce sister chromatid exchange without activation using standard harvest times, but were positive after delayed harvest times. [R14] NTP: *A carcinogenesis bioassay of C.I. solvent Yellow 14 (94.1% pure), a widely used monoazo dye, was conducted by feeding diets containing 250 or 500 ppm of C.I. Solvent Yellow 14 to groups of 50 F344 rats of either sex for 103 weeks. Similar groups of 50 B6C3F1 mice received diets containing 500 or 1,000 ppm of C.I. Solvent Yellow 14 for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. Throughout the bioassay, mean body weights of dosed rats and mice were slightly lower than those of controls. No compound-related clinical signs or effects on survival were observed. Increases in nonneoplastic lesions included cardiac valve fibrosis for male and female rats, lymphoid hyperplasia of the lung for male rats, and for female rats, bile duct hyperplasia, focal atrophy of the pancreatic acinus, and nephropathy. None of these effects were observed in mice. Under the conditions of this bioassay, C.I. Solvent Yellow 14 was carcinogenic in male and female F344/N rats, as evidenced by increaed incidences of neoplastic nodules of the liver. C.I. Solvent Yellow 14 was not carcinogenic for B6C3F1 mice of either sex. [R15] METB: *ADMIN ORALLY TO RABBITS, THIS DYESTUFF ... UNDERGOES REDUCTIVE SCISSION, BUT IS ALSO METABOLIZED BY HYDROXYLATION OF BENZENE RING. [R16] *YIELDS 2,6-DIHYDROXY-1-PHENYLAZONAPHTHALENE, 2-HYDROXY -1-(PARA-HYDROXYPHENYLAZO)NAPHTHALENE, and 1-PHENYLHYDRAZO-2-NAPHTHOL IN RABBITS AND RATS. /FROM TABLE/ [R17] *... ORAL ADMIN IN RABBITS, 1.2% ... UNCHANGED, 1.5% AS 1-PARA-HYDROXYPHENYLAZO-2-NAPHTHOL, 44% AS FREE AND CONJUGATED PARA-AMINOPHENOL, 24% AS PARA-AMINOPHENYLGLUCURONIDE, 0.5% AS ORTHO-AMINOPHENOL AND 1.1% AS ANILINE; PARA-ACETAMIDOPHENYL GLUCURONIDE, 1-PARA-HYDROXYPHENYLAZO-2-NAPHTHOL GLUCURONIDE AND 1-AMINO-2-NAPHTHOL ... . [R8] *... GLUCURONIDES OF 4',6-DIHYDROXY-1-PHENYLAZO-2-NAPHTHOL AND 4'- and 6-HYDROXY-1-PHENYLAZO-2-NAPHTHOL WERE PRESENT IN ... BILE AND URINE OF RABBITS. URINE ALSO CONTAINED 1-AMINO-2-NAPHTHYL HYDROGEN SULFATE, 1-AMINO-2-NAPHTHYL GLUCURONIDE AND N-GLUCURONIDES OF 1-PHENYLHYDRAZO-2-NAPHTHOL AND OF 4'-HYDROXY-1-PHENYLHYDRAZO-2-NAPHTHOL ... . [R18] *Horseradish peroxidase in the presence of hydrogen peroxide oxidizes a carcinogenic non-aminoazo dye, 1-phenylazo-2-hydroxynaphthalene (Sudan I) to the ultimate carcinogen, which binds to calf thymus DNA. The principal product of Sudan I oxidation by the horseradish peroxidase in the presence of hydrogen peroxide system is the benzenediazonium ion. Minor products are hydroxy derivatives of Sudan I, in which the aromatic rings are hydroxylated. The principal oxidative product (the benzenediazonium ion) is responsible for the carcinogenicity of Sudan I, because this ion, formed from this azo dye, binds to DNA. [R19] *A metabolite of Sudan I was isolated after in vitro incubation with the supernatant of guinea pig liver homogenate (S-9). The metabolite was found to be 4'-hydroxy-1-phenylazo-2-naphthol by gas chromatography-mass spectrometry, and proton and carbon-13 nuclear magnetic resonance analyses. It elicited positive reactions in guinea pigs sensitized to Sudan I. It was also shown to be allergenic. The results suggest that para-hydroxylation of the phenyl group of Sudan I may play an important role in its allergenicity. [R20] ACTN: *Sudan I activated by pre-incubation with microsomal enzymes of rat livers covalently binds to DNA from calf thymus. Benzenediazonium ion formed from Sudan I by activation with microsomal enzymes is the principal active metabolite, which binds to DNA. Enzymatic hydrolysis of modified 14(C)-labelled DNA, followed by separation of deoxynucleosides on a Sephadex G-10 column revealed that deoxyguanosine is the principal target for the binding of activated Sudan I. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Beauticians exposed to paraphenylenediamine derivatives in hair dyes, workers dyeing textile resins, and photographic film developers exposed to color developing solutions not infrequently become sensitized to azo dyes. /Organic dyes/ [R6] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *JOINT FAO/WHO EXPERT COMMITTEE ON FOOD ADDITIVES ... CONSIDERS SUDAN I, ON BASIS OF TOXICOLOGICAL EVIDENCE, TO BE UNSAFE FOR USE IN FOOD. [R22] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY, THIN LAYER CHROMATOGRAPHY. [R23] *Standard soln of Sudan I were prepared by dissolving 0.025 g of the dye in 50 ml of acetone, and then diluting with methanol. After distillation of 500 ml water containing Sudan I, residual dye in the condenser and other apparatus were washed with up to 100 ml acetone, which also improved formation of emulsion. Recovery of Sudan I was 88.5 to 93.9% in the pH range 1 to 11. Sudan I was then extracted by modified mixing extraction using hexane as solvent. Constant recoveries of 92.5 to 93.3% were obtained if the volume of distillate was in the range 400 to 450 ml. Recovery of Sudan I was also constant when the pH of the initial water varied from 1 to 13 (92.8 to 98.8%). Mean recovery of 2 ug Sudan I added to river water and to sea water was 96.4%. Detection of Sudan I was possible by high performance liquid chromatography (HPLC) with a methanol/water ratio of 90:10. The detection limit for a 500 ml water sample was 0.2 ug/l. [R24] *The identification of lipid soluble colors is usually carried out by chromatographic methods. ... Earlier methods relied on paper chromatography. ... More recent work involves thin-layer chromatography. A survey of separation characteristics of various sorbents, such as silica gel, alumina, 1:1 mixtures of silica gel and alumina, starch, cellulose and polyamide powder, used with a wide variety of solvents indicates the techniques capable of separating most lipid soluble azo colors. ... A method was described for the isolation of lipid soluble colors from fats and chocolate by liquid/liquid partition and adsorption chromatography followed by identification by thin-layer chromatography. /Lipid soluble cmpd/ [R25] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I. Solvent Yellow 14 in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 226 (1982) NIH Publication No. 82-1782 SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 225 (1975) R3: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-132 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 72 (1987) R5: KOZUKA T ET AL; HIFU 21 (3): 293 (1979) R6: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 147 R7: Kozuka I et al; Ann Acad Med Singapore 17 (4): 492-94 (1988) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 228 (1975) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 227 (1975) R10: McGregor DB et al; Environ Mol Mutagen 17 (3): 196-219 (1991) R11: Westmoreland C, Gatehouse DG; Carcinogenesis 12 (8): 1403-7 (1991) R12: Mirsalis JC et al; Environ Mol Mutagen 14 (3): 155-64 (1989) R13: Pitot HC et al; Toxicol Appl Pharmacol 97 (1): 23-34 (1989) R14: Ivett JL et al; Environmental and Molecular Mutagenesis 14 (3): 165-87 (1989) R15: DHHS/NTP; Carcinogenesis Bioassay of C.I. Solvent Yellow 14 in F344/N Rats and B6C3F1 Mice (Feed Study) p.VII (1982) Technical Rpt Series No. 226 NIH Pub No. 82-1782 R16: Parke, D. V. The Biochemistry of Foreign Compounds. Oxford: Pergamon Press, 1968. 162 R17: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-21 R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 229 (1975) R19: Stiborova M et al; FEBS Lett 232 (2): 387-90 (1988) R20: Kato S et al; Contact Dermatitis 15 (4): 205-10 (1986) R21: Stiborova M et al; Cancer Lett 40 (3): 327-33 (1988) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 226 R23: ITO K ET AL; TOKYO-TORITSU EISEI KENKYUSHO KENKYU NEMPO ISS 30-1: 106 (1979) R24: Nagase M et al; J Chromatogr 465 (2): 434-7 (1989) R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 28 (1975) RS: 21 Record 257 of 1119 in HSDB (through 2003/06) AN: 4134 UD: 200211 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CYTEMBENA- SY: *ACRYLIC ACID, 3-P-ANISOYL-3-BROMO-, SODIUM SALT, (E)-; *2-BUTENOIC ACID, 3-BROMO-4-(4-METHOXYPHENYL)-4-OXO-, SODIUM SALT, (E)-; *CYTEMBENE-; *NSC-104801- RN: 21739-91-3 MF: *C11-H9-BR-O4.NA MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *NOT PRODUCED COMMERCIALLY IN US [R1] USE: *FOLATE INHIBITOR IN CANCER TREATMENT (NON-US USE) [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *440.22 TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *17 PT WITH STAGES 3 and 4 ALKYLATING AGENT RESISTANT OVARIAN CARCINOMAS WERE TREATED WITH CYTEMBENA IN DOSES OF 200 MG/SQ M TWICE DAILY FOR 5 DAYS EVERY 5 WK. NAUSEA AND VOMITING OCCURRED IN ALL EXCEPT 1 PT, and 3 PT HAD MILD DIARRHEA. 2 HAD ALOPECIA. [R2] *22 PT RECEIVED DAILY IV INJECTIONS FOR 5 DAYS. TOXICITY WAS DOSE RELATED, BECOMING PROMINENT @ 300 MG/SQ M; NAUSEA AND VOMITING WERE SEEN. HYPERTENSION, TACHYCARDIA, CHEST PAIN, AND ECG CHANGES OCCURRED @ DOSES OF 475 MG/SQ M. [R3] *30 WOMEN WITH HISTOLOGICALLY PROVEN ADVANCED OVARIAN OR BREAST CANCER WERE TREATED WITH CYTEMBENA, DOSE OF 250 MG/SQ M/DAY FOR 5 DAYS REPEATED @ WEEKLY INTERVALS. NO HEMOPOIETIC TOXICITY. NAUSEA AND VOMITING AND AUTONOMIC STORM PHENOMENON ARE DOSE-LIMITING FACTORS. [R4] *PT WITH VARIOUS TYPES OF MALIGNANCY RECEIVED 20 MG CYTEMBENA/KG, IV. THE FREQUENCY OF ABNORMAL METAPHASES AND CHROMOSOMAL BREAKS 24 HR AFTER CYTEMBENA TREATMENT WAS LOW. [R5] NTOX: *CHRONIC IV ADMIN OF 12.5-200 and 6.25-50 MG/KG/DAY IN DOGS AND MONKEYS DAMAGED DISTAL RENAL TUBULES, AND DEPLETED GERMINAL CELLULAR ELEMENTS OF LYMPHOID TISSUES; @ HIGH DOSES PRODUCED EMESIS, ANOREXIA, AND WT LOSS. BONE MARROW AND LIVER INVOLVEMENT NOTED IN MONKEYS. [R6] *THERAPEUTIC DOSE CAUSED RAPID AND EXTENSIVE INHIBITION OF DNA BIOSYNTHESIS. HIGH DOSES CAUSED INHIBITION OF PROTEIN BIOSYNTHESIS. DEOXYRIBONUCLEOSIDE TRIPHOSPHATES ACCUM SUGGESTING THAT INHIBITION OF DNA BIOSYNTHESIS WAS AT POLYMERIZATION STAGE. [R7] *CYTEMBENA INHIBITED DNA SYNTHESIS IN PERMEABLE CELLS; THIS DEMONSTRATED THAT THIS AGENT FUNCTIONED AS DIRECT INHIBITOR OF DNA REPLICATION COMPLEX, USING MOUSE L-CELLS MADE PERMEABLE WITH TRIS, PH 7.8. [R8] *RATS INJECTED IP WITH 50 OR 150 MG/KG SHOWED URINARY PROTEIN AND GLUCOSE EXCRETION, INCR URINE VOL AND DECR URINE OSMOLALITIES. NO CHANGES IN URINARY PH WERE NOTED. [R9] *CYTEMBENA WAS GIVEN IP TO RATS, MICE, AND HAMSTERS. FREQUENCY OF ABNORMAL METAPHASES AND CHROMOSOMAL BREAKS 24 HR AFTER TREATMENT WAS LOW. HIGHEST FREQUENCIES OF INDUCED ABERRATIONS WERE IN MICE. [R5] ADE: *IN NORMAL SUBJECTS RENAL EXCRETION WAS APPROX 7.8% OF GIVEN DOSE IN 15 HR FOLLOWING SINGLE IV INJECTION OF 200 MG. IN PT WITH IMPAIRED RENAL FUNCTION, URINARY EXCRETION WAS LESS AND DIRECTLY CORRELATED WITH DECR IN ENDOGENOUS CREATININE CLEARANCE RATE. [R10] *WHEN (14)C-LABELED CYTEMBENA WAS ADMIN, RATS EXCRETED GREATER THAN 70% AND DOGS GREATER THAN 50% OF RADIOACTIVE DOSE IN 24 HR; MOST OF LABEL WAS FOUND IN URINE. KIDNEY RETAINED HIGHEST LEVEL OF RADIOACTIVITY AFTER 24 HR. [R11] METB: *CYTEMBENA WAS DEMETHYLATED BY RABBIT LIVER MICROSOMES AND WAS DEBROMINATED AND SATURATED BY 100,000-G SUPERNATANT FRACTION IN PRESENCE OF GLUTATHIONE AND NADPH. STRUCTURES OF METABOLITES TENTATIVELY IDENTIFIED BY MASS SPECTROMETRY. [R11] *CYTEMBENA UNDERGOES RAPID REACTION WITH THIOL COMPD INCL GLUTATHIONE AND CYSTEINE, RESULTING IN ALKYLATION OF SULFUR. PRODUCT OF CYTEMBENA AND GLUTATHIONE WAS ISOLATED AND TESTED FOR CYTOTOXICITY; IT WAS LESS EFFECTIVE THAN FREE CYTEMBENA. REACTION MAY BE DETOXIFICATION PROCESS. [R12] BHL: *IN 8 SUBJECTS WITH NORMAL RENAL FUNCTION, CYTEMBENA HAD A SERUM HALF-LIFE OF APPROX 13.5 HR. [R13] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP TR No 207; Route: intraperitoneal injection; Species: rats and mice. NTIS No PB82163312. [R14] SO: R1: SRI R2: EDMONSON JH ET AL; J NATL CANCER INST 59(DEC) 1619 (1977) R3: FRYTAK S ET AL; CANCER (PHILADELPHIA) 37(MAR) 1248 (1976) R4: FALKSON HC, FALKSON G; CANCER TREAT REP 60(11) 1655 (1976) R5: GOETZ P ET AL; MUTAT RES 41(1) 143 (1976) R6: GRALLA EJ, COLEMAN GL; USNTIS, PB REP; ISS NO 232448/IGA, 351 (1973) R7: JACKSON RC ET AL; NEOPLASMA 22(3) 259 (1975) R8: BERGER NA, WEBER G; J NATL CANCER INST 58(4) 1167 (1977) R9: BERNDT WO; TOXICOL APPL PHARMACOL 39(2) 207 (1977) R10: SCHUECK O ET AL; NEOPLASMA 23(2) 161 (1976) R11: MITOMA C ET AL; XENOBIOTICA 7(3) 165 (1977) R12: JACKSON RC ET AL; NEOPLASMA 23(4) 355 (1976) R13: SCHUCK O ET AL; ADVAN ANTIMICROB ANTINEOPLASTIC CHEMOTHER, PROC INT CONGR CHEMOTHER, 7TH 2, 365 (1972) R14: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.23 RS: 6 Record 258 of 1119 in HSDB (through 2003/06) AN: 4137 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-ACID-RED-14- SY: *ACID-CHROME-BLUE-BA-; *ACID-CHROME-BLUE-BA-CF-; *ACID-FAST-RED-FB-; *ACID-RED-14-; *ACID-RUBINE-; *AIREDALE-CARMOISINE-; *ATUL-ACID-CRYSTAL-RED-; *AZO-RUBINE-FOR-FOOD-; *AZO-RUBINE-S-SPECIALLY-PURE-; *BRASILAN-AZO-RUBINE-2NS-; *BRILLIANT-ACID-RUBINE-M-; *BRILLIANT-CRIMSON-RED-; *BUCACID-AZO-RUBINE-; *CALCOCID-RUBINE-XX-; *CARMOISINE-; *CARMOISINE-S-; *CERTICOL-CARMOISINE-S-; *OMEGA-CHROME-BLUE-FB-; *CHROME-FAST-BLUE-2R-; *CHROMOTROPE-FB-; *CI-Acid-Red-; *CI-ACID-RED-14,-DISODIUM-SALT-; *CI-FOOD-RED-3-; *CI-14720-; *CILEFA-RUBINE-R-; *CRIMSON-2EMBL-; *DIADEM-CHROME-BLUE-G-; *DIADEM-CHROME-BLUE-R-; *EDICOL-SUPRA-CARMOISINE-W-; *ENIACID-BRILLIANT-RUBINE-3B-; *ERIO-RUBINE-B-; *EUROCERT-AZORUBINE-; *FENAZO-RED-C-; *HD-CARMOISINE-; *HEXACOL-CARMOISINE-; *HIDACID-AZO-RUBINE-; *HISPACID-RUBINE-F-; *4-HYDROXY-3-[(4-SULFO-1-NAPHTHALENYL)AZO]-1-NAPHTHALENESULFONIC ACID, DISODIUM SAL; *JAVA-RUBINE-N-; *KARMESIN-; *KENACHROME-BLUE-2R-; *KITON-CRIMSON-2R-; *LIGHTHOUSE-CHROME-BLUE-2R-; *NACARAT-; *NACARAT-A-EXPORT-; *NACARAT-EXTRA-PURE-1A-; *1-NAPHTHALENESULFONIC ACID, 4-HYDROXY-3-((4-SULFO-1-NAPHTHALENYL)AZO)-, DISODIUM SALT; *NEKLACID-AZORUBINE-W-; *11959-RED-; *2-(4-SULFO-1-NAPHTHYLAZO)-1-NAPHTHOL-4-SULFONIC ACID, DISODIUM SALT; *2-(4-SULPHO-1-NAPHTHYLAZO)-1-NAPHTHOL-4-SULPHONIC ACID, DISODIUM SALT RN: 3567-69-9 MF: *C20-H14-N2-O7-S2.2NA MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *COUPLING OF DIAZOTIZED NAPHTHIONIC ACID WITH 1-NAPHTHOL-5-SULFONIC ACID [R1] *IT CAN BE MADE BY COUPLING DIAZOTIZED 4-AMINONAPHTHALENE SULFONIC ACID WITH 4-HYDROXYNAPHTHALENE SULFONIC ACID, BUT IT IS NOT KNOWN WHETHER THIS METHOD IS USED FOR COMMERCIAL PRODN. RICHTER, F (1951) BEILSTEINS HANDBUCH DER ORGANISCHEN CHEMIE, BERLIN, SPRINGER VERLAG, VOL 16, II, P 129. [R2, p. V8 84] MFS: *ATLANTIC CHEMICAL CORP, NUTLEY, NJ 07110 [R1] *BASF WYANDOTTE CORP, PIGMENTS DIV, HOLLAND, MI 49423 [R1] OMIN: *SPECIFICATIONS...BY BRITISH STANDARDS INSTITUTION (1960)...PRODUCT MUST CONTAIN MIN OF 85% CARMOISINE. FAO/WHO (1966)...ALSO...MIN OF 85% PURE COLOR. ...WHEN...NOT USED IN FOODS, DRUGS OR COSMETICS, ITS MFR AND TESTING DO NOT CONFORM TO RIGID CHEM SPECIFICATIONS AND ITS COMPOSITION MAY VARY... [R2, p. V8 83] *...DYING WOOL, LEATHER AND TO STAIN WOOD. IN US...USED TO COLOR COSMETICS UNTIL...1966, WHEN...REMOVED FROM APPROVED LIST FOR THIS USAGE (US CODE OF FEDERAL REGULATIONS, 1974). ... APPROVAL FOR ITS USE IN FOOD WAS WITHDRAWN IN JAPAN PRIOR TO 1966...FINLAND, NORWAY AND SWEDEN...NO LONGER PERMIT USE...IN FOODSTUFFS. [R2, p. V8 84] USE: *INKS AND DRUG COLORANTS [R3] *DYE FOR WOOL, NYLON, SILK, LEATHER, PAPER, PRINTING NYLON, SILK AND WOOL; COLORANT IN ANODISED ALUMINUM, INKS AND WOOD STAINS; BIOLOGICAL STAIN; DYE FOR FOODS (DISCONTINUED IN US IN 1966) [R1] CPAT: *ESSENTIALLY 100% AS A DYE [R1] PRIE: U.S. PRODUCTION: *(1977) 3.50X10+7 GRAMS [R1] *(1978) 2.32X10+7 GRAMS [R1] U.S. IMPORTS: *(1978) 4.90X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 8.21X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *REDDISH-BROWN CRYSTALS [R2, p. V8 83] MW: *504.44 SOL: *SOL IN WATER; SLIGHTLY SOL IN ETHANOL; INSOL IN VEGETABLE OILS [R2, p. V8 83] SPEC: *MAX ABSORPTION (0.02 N AMMONIUM ACETATE SOLN): 516 NM [R2, p. V8 83] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R4] NTOX: *...30 MALE AND 30 FEMALE ASH/CS1 MICE...FED...100, 500, 2500 OR 12,500 MG CARMOISINE/KG OF DIET FOR 80 WK. ...60 MALES AND 60 FEMALES...AS CONTROLS. ... TUMORS OCCURRING IN TREATED MICE BUT NOT IN CONTROLS INCL 1 MAMMARY ADENOCARCINOMA IN 1 FEMALE...HIGHEST DOSE AND LYMPHOSARCOMA IN MALE GIVEN 2500 MG.../KG OF DIET. [R2, p. V8 85] *...10 RATS RECEIVED TWICE WEEKLY SC INJECTIONS OF 0.5 ML OF 1% AQ SOLN...FOR 1 YR (TOTAL DOSE, 500 MG). OF RATS OBSERVED UP TO 938 DAYS, 1 DEVELOPED AXILLARY TUMOR DIAGNOSED AS SPINDLE-CELL SARCOMA. IN FURTHER EXPT INVOLVING SAME TREATMENT, NO TUMORS...OCCURRED IN RATS OBSERVED UP TO 521 DAYS. [R2, p. V8 86] *...10 RATS FED...2000 MG.../KG OF DIET FOR 417 DAYS (EQUIV TO APPROX DAILY INTAKE OF 100 MG/KG BODY WT, AND TOTAL INTAKE OF 11 G...), NO TUMORS... OCCURRED... 10...GIVEN DRINKING-WATER CONTAINING 1% OF COLOR FOR 209 OR 250 DAYS (EQUIV TO DAILY INTAKE OF 1.2 OR 0.94 G/KG BODY WT, AND TOTAL...51 OR 52 G...), NO TUMORS...OCCURRED. [R2, p. V8 86] *...15 MALE AND 15 FEMALE MICE...GIVEN TWICE WEEKLY SC...0.1 ML OF 3% SUSPENSION...IN ARACHIS OIL...FOR 6 MO. /THEN/...DOSE WAS INCR TO 6%...FOR...6 MO. ...60 CONTROLS...WITH 0.1 ML ARACHIS OIL. ... NO SC TUMORS OR HEPATOMAS...IN 12 TREATED... LYMPHOMAS...IN 0/1 MALES AND 7/11 FEMALES...1/9 and 4/9 CONTROLS. [R2, p. V8 86] *IN GROUPS OF 16 MALE AND 16 FEMALE RATS FED DIETS 0 (CONTROL), 500, 1000, 5000 and 10,000 MG CARMOISINE/KG OF DIET FOR 3 MO, ONLY ADVERSE EFFECT SEEN WAS KIDNEY ENLARGEMENT IN FEMALES FED...HIGHEST LEVEL. [R2, p. V8 87] *CARMOISINE WAS FED @ 0, 0.35, 0.8 and 2.0% IN DIET OF RATS THROUGHOUT MULTIGENERATION REPRODUCTION STUDY. DYE HAD NO UNTOWARD EFFECTS ON REPRODUCTION CAPACITY OF ANY OF GENERATIONS. FERTILITY, LACTATION, AND VIABILITY INDICES OF ALL GROUPS DID NOT DIFFER FROM CONTROLS. [R5] *CARMOISINE WAS FED TO MICE @ DIETARY LEVELS OF 0 (CONTROL), 0.01, 0.05, 0.25 OR 1.25% FOR 80 WK. THERE WERE NO ADVERSE EFFECTS ON MORTALITY, WEIGHT GAIN, ORGAN WEIGHTS OR INCIDENCE OF HISTOPATHOLOGICAL FINDINGS, INCLUDING TUMORS. [R6] *IN ALLIUM CEPA ROOTS PLACED IN CONTACT WITH 100 ML OF SOLN OF AZO RUBINE (100-10,000 PPM) FOR 7-20 DAYS CHROMOSOMAL ELONGATION AND DISSARRAY WERE OBSERVED IN CELLS EXPOSED TO 100-1000 PPM. THUS, THE DYE MAY CAUSE CHROMOSOMAL DAMAGE. [R7] *AMES TEST WAS USED TO DETERMINE POSSIBLE MUTAGENIC ACTIVITY OF FOOD RED NO 3 (CARMOISINE). USING THIS TEST THIS COLORANT SHOWED NO MUTAGENIC OR CYTOTOXIC ACTIVITY. [R8] *AZORUBIN S WAS MORE TOXIC IN BILE DUCT-LIGATED NEWBORN MICE THAN IN SHAM-OPERATED NEWBORN MICE. A DECR IN HEPATIC EXCRETORY FUNCTION INCREASED TOXICITY OF DRUG EXCRETED INTO BILE, AND MAY CONTRIBUTE TO INCR SENSITIVITY OF NEWBORN TO TOXIC PROPERTIES OF CHEMICALS. [R9] +... Under the conditions of this bioassay, C.I. Acid Red 14 was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Synonym: 4-hydroxy-3-(4-Sulfo-1-naphthalenyl)azo-1-naphthalenesulfonic acid, disodium. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R10] NTP: +A carcinogenesis bioassay of textile grade C.I. Acid Red 14 (67%-71% purity) was conducted by feeding diets containing 6,000 or 12,500 ppm of this dye for 103-104 wk to groups of 50 male F344 rats, 12,500 or 25,000 ppm to groups of 50 female F344 rats, and 3,000 or 6,000 ppm to groups of 50 B6C3F1 mice of either sex. Groups of 90 untreated rats of either sex and 50 untreated mice of either sex served as controls. ... Under the conditions of this bioassay, C.I. Acid Red 14 was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Synonym: 4-hydroxy-3-(4-Sulfo-1-naphthalenyl)azo-1-naphthalenesulfonic acid, disodium. Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative. [R10] ADE: *FOLLOWING IV ADMIN OF 1 MG...TO RATS, 30-40% OF COLOR WAS EXCRETED UNCHANGED IN BILE. IT IS REDUCED BY LACTIC ACID BACTERIA. [R2, p. V8 87] *BILIARY EXCRETION RATE OF AZO RUBINE S ADMIN IV TO RATS WITH LIGATED RENAL PEDICLES, REACHED APPARENT MAX WHICH WAS DEPRESSED BY PHENOLPHTHALEIN GLUCURONIDE OR PROBENECID. BILIARY EXCRETION OF THE DYE MAY INVOLVE AN ACTIVE TRANSPORT PROCESS. [R11] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ADI: *TEMPORARY ACCEPTABLE DAILY INTAKE: 0-2 MG/KG (1978). /FROM TABLE/ [R12] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *MIXTURES OF THE ANTISEPTIC CHLORHEXIDINE ACETATE WITH DYES TARTRAZINE, CARMOISINE, OR METHYLENE BLUE WERE ANALYZED BY HIGH-PRESSURE LIQ CHROMATOGRAPHY. [R13] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of C.I. Acid Red 14 in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 220 (1982) NIH Publication No. 82-1776 SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R3: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. VI-180 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 59 (1987) R5: HOLMES PA ET AL; TOXICOLOGY 10: 169 (1978) R6: MASON PL ET AL; FOOD COSMET TOXICOL 12(5) 601 (1974) R7: MANCINELLI R ET AL; NUOVI ANN LG MICROBIOL 28(6) 447 (1977) R8: VIOLA M ET AL; BOLL CHIM FARM 117 (JUL) 402 (1978) R9: KLAASSEN CD; TOXICOL APPL PHARMACOL 24(1) 37 (1973) R10: Carcinogenesis Bioassay of C.I. acid Red 14 in F344/N Rats and B6C3F1 Mice Technical Report Series No. 220 (1982) NIH Publication No. 82-1776 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R11: IKEDA M ET AL; BIOCHEM PHARMACOL 22(21) 2743 (1973) R12: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 350 R13: PEREZ RL; ANALYSIS OF COLORED CHLORHEXIDINE SOLN BY ION-PAIRING REVERSE-PHASE HIGH PRESSURE LIQUID CHROMATOGRAPHY; J LIQ CHROMATOGR 3(8) 1227 (1980) RS: 10 Record 259 of 1119 in HSDB (through 2003/06) AN: 4138 UD: 200303 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-PIGMENT-RED-53:1- SY: *D-AND-C-RED-NO-9-; *ASTRO-ORANGE-; *ATOMIC-RED-; *BENZENESULFONIC ACID, 5-CHLORO-2-((2-HYDROXY-1-NAPHTHALENYL)AZO)-4-METHYL-, BARIUM SALT (2:1); *BRILLIANT-RED-; *BRONZE-SCARLET-CA-; *BRONZE-SCARLET-CBA-; *BRONZE-SCARLET-CTA-; *CARNATION-RED-; *5-CHLORO-2-((2-HYDROXY-1-NAPHTHYL)AZO)-P-TOLUENESULFONIC ACID, BARIUM SALT; *1-(4-CHLORO-O-SULFO-5-TOLYLAZO)-2-NAPHTHOL, BARIUM SALT; *CI-PIGMENT-RED-53,-BARIUM-SALT- (2:1); *COSMETIC-CORAL-RED-KO-BLUISH-; *COSMETIC-DVR-; *COSMETIC-PIGMENT-YELLOW-RED-DVR-; *DAINICHI-LAKE-RED-C-; *D-and-C-RED-#9-; *DESERT-RED-; *DUPLEX-RED-LAKE-C20-5925-; *ELJON-LAKE-RED-C-; *HELIO-RED-TONER-LCLL-; *IRGALITE-RED-CBN-; *IRGALITE-RED-CBR-; *LAKE-RED-C-18287-; *LAKE-RED-C-21245-; *LAKE-RED-C-27200-; *LAKE-RED-C-27217-; *LAKE-RED-C-27218-; *LAKE-RED-CBA-; *LAKE-RED-C-RLC-232-; *LAKE-RED-TONER-LCLL-; *LAKE-RED-ZHB-; *LATEXOL-SCARLET-R-; *LD-RUBBER-RED-16913-; *LUTETIA-RED-CLN-; *MICROTEX-LAKE-RED-CR-; *MOHICAN-RED-A-8008-; *NO-3-CONC-BRONZE-SCARLET-; *PIGMENT-LAKE-RED-BFC-; *PIGMENT-LAKE-RED-LC-; *PIGMENT-RED-53:1-; *1860-RED-; *RED-NO-204-; *RED-ZHB-; *SANYO-LAKE-RED-C-; *SEGNALE-RED-LC-; *VULCAFIX-SCARLET-R-; *VULCAFOR-RED-2R- RN: 5160-02-1 MF: *C17-H13-Cl-N2-O4-S.1/2Ba MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *COUPLING OF DIAZOTIZED 2-AMINO-5-CHLORO-PARA-TOLUENESULFONIC ACID WITH 2-NAPHTHOL, THEN BOILING WITH BARIUM CHLORIDE [R1] *Involves three steps...the diazotization step involves reacting 2-amino-4- methyl-5-chlorobenzenesulfonic acid with hydrochloric acid and sodium nitrite to form the diazonium chloride moeity...the coupling step involves mixing the diazonium chloride solution with the coupling component (2-naphthol)...then adding barium chloride to form CI Pigment Red 53:1 [R2, p. V57 204] IMP: *Analysis of commercial samples of D and C Red No 9 revealed the presence of 11 aromatic azo compounds (subsiduary colours), at levels up to 27 ppm (mg/kg), derived from aromatic impurities in the Red Lake C Amine (2-amino- 4-methyl-5-chlorobenzenesulfonic acid) precursor [R2, p. V57 204] FORM: *D AND C RED NO 9 USED IN DRUGS AND COSMETICS MUST CONTAIN MIN OF 87% PURE COMPD. SPECIFICATIONS FOR COLOR REFERENCE STANDARD...REQUIRE MIN OF 96.5% PURE COLOR. [R2, p. V8 107] *GRADES: RESINATED AND NON-RESINATED /LAKE RED C/ [R3] *D and C Red No 9 is required to contain a minimum of 87% pure colour for sale as a drug and cosmetic colorant [R2, p. V57 204] MFS: *H KOHNSTAMM AND CO, INC, NEW YORK, NY 10013 [R1] *MAX MARX COLOR AND CHEMICAL CO, IRVINGTON, NJ 07111 [R1] *STERLING DRUG CO INC, HILTON DAVIS CHEMICAL CODIV, CINCINNATI, OHIO 45237 [R1] *SUN CHEMICAL CORP, CINCINNATI, OHIO 45232 [R1] *Apollo Colors Inc, Hq, 3000 W Dundee Rd, Suite 415, Northbrook, IL 60062 (708) 564-9190 [R4] *BASF Corp Chemicals Div, 1255 Broad St, Clifton, NJ 07015, (210) 316-2937, Production site: Parsippany, NJ [R4] *CDR Pigments and Dispersions, 410 Glendale Milford Rd, Cincinnati, OH 45215, (513) 771-1900 [R4] *Engelhard Corp, 3400 Band St, Louisville, KY 40212, (201) 632-6000 [R4] *Hilton Davis Chem Co, 2335 Langdon Farm Rd, Cincinnati, OH 45237, (513) 841-4000 [R4] *Sun Chemical Corp, Pigments Div, 411 Sun Ave, Cincinnati, OH 45232 (212) 986-5500 [R4] *Paul Uhlich and Co Inc, 1 Railroad Ave, Hastings-on-Hudson, NY 10706 (914) 478-2000 [R4] *Max Marx Color Corp, 1200 Grove St, Irvington, NJ 07111, (201) 373-7801 [R4] *Magruder Color Co Inc, 1029 Newark Ave, Elizabeth, NJ 07208, (201) 242-1300 [R4] *Industrial Color Inc, 50 Industry Ave, Joliet, IL 60435, (815) 722-7402 [R4] OMIN: *PROPERTIES: GOOD RESISTANCE TO BLEEDING; REASONABLE LIGHT RESISTANCE, GOOD TRANSPARENCY; PRODUCES INKS WITH GOOD FLOW. /LAKE RED C/ [R3] USE: *IN MFR OF ALKALINE EARTH METAL SALTS, WHICH ARE USED IN MFR OF COLORING INKS, PLASTICS AND RUBBER; IN COSMETICS AND DRUGS [R2, p. V8 108] *IN PAINTS [R5] *Used in some countries in the cosmetics and drug industry in such applications as a lipstick colorant, mouthwashes, dentrifrices and drugs...the last year in which it was approved as a D and C color (in the US) was 1988. [R2, p. V57 204] *Widely used in printing inks; has been used extensively in letter press and offset inks and also in gravure inks; the non-resinated form is used in water- and solvent-based flexographic inks; finds substantial use in coated papers and crayons; used in polystyrene and rubber, in tin printing and in baking enamels; resinated CI Pigment 53:1 (as Red Lake C) is also used extensively in flexographic inks [R2, p. V57 204] CPAT: *ESSENTIALLY 100% AS A DYE [R1] PRIE: U.S. PRODUCTION: *(1977) 5.18X10+7 GRAMS [R1] *(1979) 4.24X10+7 GRAMS [R1] *1,500,000 kg (1992) [R4] U.S. IMPORTS: *(1977) 1.67X10+6 GRAMS [R1] *(1979) 1.30X10+7 GRAMS [R1] *119,553 lbs (principal US custom districts) [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Red powder [R2, p. V57 203] MP: *343-345 deg C (decomposes) [R2, p. V57 203] MW: *888.6 [R2, p. V57 203] DEN: *1.66 g/cu cm [R2, p. V57 203] SOL: *SLIGHTLY SOL IN WATER AND ETHANOL; INSOL IN ACETONE AND BENZENE [R2, p. V57 204] SPEC: *MAX ABSORPTION (IN ACIDIFIED, DIL ETHANOL): 487 NM [R2, p. V8 107] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of D and C Red No. 9. There is limited evidence in experimental animals for the carcinogenicity of D and C Red No. 9. Overall evaluation: D and C Red No. 9 is not classifiable as to its carcinogenicity to humans (Group 3). [R7] NTOX: *...5 MALE AND 5 FEMALE OSBORNE-MENDEL RATS WERE FED 2500, 5000, 10,000 OR 20,000 MG D AND C RED NO 9 PER KG OF DIET FOR 20 WK. SPLENOMEGALY OCCURRED IN ALL TREATED RATS. [R8] *...25 MALE AND 25 FEMALE OSBORNE-MENDEL RATS WERE FED 0 (CONTROL), 100, 500, 2500 OR 10,000 MG.../KG OF DIET. ...RATS DEVELOPING TUMORS IN RESPECTIVE GROUPS...22/50 (CONTROLS), 19/50, 23/50, 27/50 and 21/50. ... TUMORS NOT OCCURRING IN CONTROL...INCL FIBROSARCOMAS...EPIDERMOID CARCINOMAS...INTERSTITIAL-CELL ADENOMA OF TESTIS... [R9] *Groups of 25 male and 25 female Osborne-Mendel rats, three weeks of age, were fed 1, 100, 500, 2500, or 10,000 mg/kg of diet (ppm) D and C Red No. 9 (purity, greater than or equal 86% (impurities unspecified)) for up to 103-108 weeks, when all surviving animals were killed. About 80% of rats in all groups survived 18 months or longer. There was no significant increase in the incidence of tumors at any sites. [R10] *Groups of 50 male and 50 female ICR (Swiss Webster-derived) mice (age unspecified) received topical application of 1 mg D and C Red No. 9 (90.0% pure (impurities unspecified)) in 0.1 ml water to an area of approximately 6 cm sq of clipped back skin, twice a week for 18 months. Three groups of 50 male and 50 female controls received applications of water alone. No differences in survival was observed at 18 months. No skin tumor was found. Although various tumors developed in the mammary glands and internal organ, no treatment-related difference in incidence was found. [R11] *In Osborne Mendel rats, splenomegaly was a common finding after two years feeding of up to 20,000 ppm (mg/kg) D and C Red No. 9. [R12] *D and C Red No. 9 was not mutagenic to Salmonella typhimurium in most studies; the two weakly positive responses that were recorded were obtained to doses well above those at which precipitation was first observed (100 ug per plate). [R12] *D and C Red No. 9 did not induce nutation at the tk locus in mouse lymphoma L5178Y cells, sister chromatid exchange or chromosomal damage n Chinese hamster ovary cells or unscheduled DNA synthesis in rat hepatocytes in vitro. [R12] *After oral administration to rats, D and C Red No. 9 did not induce unscheduled DNA, synthesis in the liver or micronucleus formation in bone marrow. [R12] +A carcinogenesis bioassay of D and C Red No. 9 ... was conducted by feeding diets containing 1,000 or 3,000 ppm of the test substance (89.8% pure) to groups of 50 F344 rats of either sex for 103 wk. Similar groups of 50 B6C3F1 mice received diets containing 1,000 or 2,000 ppm of the test substance for 103 wk. Groups of 50 untreated rats and mice of either sex served as controls. ... Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Equivocal; Male Mice: Negative; Female Mice: Negative. [R13] NTP: +A carcinogenesis bioassay of D and C Red No. 9 ... was conducted by feeding diets containing 1,000 or 3,000 ppm of the test substance (89.8% pure) to groups of 50 F344 rats of either sex for 103 wk. Similar groups of 50 B6C3F1 mice received diets containing 1,000 or 2,000 ppm of the test substance for 103 wk. Groups of 50 untreated rats and mice of either sex served as controls. ... Under the conditions of this bioassay, D and C Red No. 9 was carcinogenic in male F344 rats causing an incr incidence of sarcomas of the spleen and a dose related incr in neoplastic nodules of the liver. D and C Red No. 9 was not considered carcinogenic to female F344 rats, although the incr incidence of neoplastic nodules of the liver may have been associated with the administration of the test chemical. D and C Red No. 9 was not carcinogenic in B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Equivocal; Male Mice: Negative; Female Mice: Negative. [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *D AND C RED NO 9 IS NOT KNOWN TO OCCUR IN NATURE. [R2, p. V8 107] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TITRATION, SPECTROPHOTOMETRY. (SEE: 34.019(F) and 34.027.) [R14] *TWELVE DYES INCL D AND C RED #9 WERE TESTED FOR SEPARATION AND IDENTIFICATION BY THIN-LAYER CHROMATOGRAPHY. [R15] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Bioassay of D and C Red No.9 in F344/N Rats and B6C3F1 Mice Technical Report Series No. 225 (1982) NIH Publication No. 82-1781 SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R3: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 498 R4: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994.p. 3-230 R5: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. VI-184 R6: USITC; Imports of Benzenoid Chemicals and Products 1983. USITC Publication 1548, Washington, DC: US International Trade Commission, p. 73 (1984) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 210 (1993) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 109 (1`975) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 109 (1975) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 206 (1993) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 207 (1993) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 208 (1993) R13: Carcinogenesis Bioassay of D AND C Red No. 9 in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 255 (1982) NIH Publication No. 82-1781 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R14: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/574 R15: ZIVANOV-STAKIC D, PAVLOVIC M; SEPARATION AND IDENTIFICATION OF LIPSTICK DYES BY THIN-LAYER CHROMATOGRAPHY; FARM VESTN (LJUBLJANA) 28(2) 147 (1977) RS: 13 Record 260 of 1119 in HSDB (through 2003/06) AN: 4148 UD: 200302 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,1,1,2-TETRACHLOROETHANE- SY: *ETHANE,-1,1,1,2-TETRACHLORO-; *NCI-C52459- RN: 630-20-6 RELT: 6829 [TETRACHLOROETHANES] (Mixture) MF: *C2-H2-Cl4 SHPN: UN 1702; Tetrachloroethane IMO 6.1; Tetrachloroethane HAZN: U208; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *1,1,1,2-Tetrachloroethane is not produced on an industrial scale...it is an undesired byproduct mainly from the production of 1,1,1-trichloroethane from 1,1-dichloroethane, 1,1,2-trichloroethane and 1,1,2,2-tetrachloroethane from 1,2-dichloroethane [R1] FORM: *99%; Neat standard for EPA methods [R2] MFS: *1,1,1,2-Tetrachloroethane is not produced on an industrial scale. [R1] OMIN: *1,1,1,2-Tetrachloroethane is often an incidental by-product in the manufacture of chlorinated ethanes. It can be prepared by heating the 1,1,2,2-isomer with anhydrous aluminum chloride or chlorination of 1,1-dichlooethylene at 40 deg C. [R3, p. V6 25] *Not produced for sale in bulk quantities ... It is present as an unisolated intermediate in some processes for the manufacture of trichloroethylene and tetrachloroethylene from ethylene dichloride. [R4] *1,1,1,2-Tetrachloroethane has no known commercial use other than as an unisolated process intermediate. [R5, p. V41 88] USE: *AS SOLVENT; MFR OF INSECTICIDES, HERBICIDES, SOIL FUMIGANTS, BLEACHES, PAINTS AND VARNISHES [R6, 765] *LABORATORY REAGENT; CHEM INT FOR CHLOROCARBON SOLVENTS (NON-USA USE) [R7] *1,1,1,2-Tetrachloroethane is used primarily as a feedstock for the production of solvents such as trichloroethylene and tetrachloroethylene. [R3, p. V6 25] CPAT: *NOT USED COMMERCIALLY IN USA [R5, p. V40 88] PRIE: U.S. PRODUCTION: *(1978) ND [R7] *(1982) NOT PRODUCED COMMERCIALLY IN USA [R7] *(1992) ND [R8] U.S. IMPORTS: *(1978) ND [R7] *(1982) ND [R7] *(1987) ND U.S. EXPORTS: *(1978) ND [R7] *(1982) ND [R7] *(1987) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, heavy liquid [R1]; +Yellowish-red liquid [R9, 300] BP: *130.5 DEG C @ 760 MM HG [R10] MP: *-70.2 DEG C [R10] MW: *167.85 [R10] CTP: *Critical temperature = 624 K; Critical pressure = 4.02X10+06 Pa [R11] DEN: *1.5406 @ 20 DEG C/4 DEG C [R10] HTC: *-8.3784X10+08 J/Kmol [R11] HTV: *243.50 joules/g @ 20 deg C [R3, p. V624] OWPC: *Log Kow = 2.66 [R5, p. V40 88] SOL: *SOL IN ALC, ETHER, ACETONE, BENZENE, CHLOROFORM [R12]; *Water solubility = 1.1x10+3 mg/l @ 25 deg C. [R13] SPEC: *INDEX OF REFRACTION: 1.4821 @ 20 DEG C/D [R12]; *MASS: 1074 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R14] SURF: *32.9 dynes/cm @ 20 deg C [R3, p. V6 24] VAP: *14 Torr at 25 deg C. [R15] VISC: *1.501 cP @ 20 deg C [R3, p. V6 24] OCPP: *Solubility 0.056 g of water/100 g 1,1,1,2-tetrachloroethane @ 20 deg C; Melting point = -68.7 deg C [R3, p. V6 24] *Partition coefficients at 37 deg C for 1,1,1,2-tetrachloroethane into blood= 30.4; into oil= 4,310. [R16] *Vapor pressure = 12.03 mm Hg at 25 deg C (calculated from experimentally derived coefficients); Liquid molar volume = 0.109378 cu m/kmol [R11] *Conversion factor: mg/cu m = 6.87 x ppm; Stability: emits toxic fumes when heated to decomposition [R5, p. V40 88] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Tetrachloroethane/ [R17] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Containers may explode when heated. Runoff may pollute waterways. /Tetrachloroethane/ [R17] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. /Tetrachloroethane/ [R17] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Tetrachloroethane/ [R17] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Tetrachloroethane/ [R17] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible withdraw from area and let fire burn. /Tetrachloroethane/ [R17] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Tetrachloroethane/ [R17] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Tetrachloroethane/ [R17] FIRP: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam, dry chemical, or carbon dioxide. Apply water from as far a distance as possible. Keep run-off water out of sewers and water sources. /Tetrachloroethane/ [R18, 1992.887] REAC: *Mixtures of potassium with tetra- and pentachloroethane will often explode spontaneously after a short delay during which a voluminous solid separates out. [R19] +Tetrachloroethane may explode with potassium or sodium. [R20, p. 491-176] +Mixtures of sodium-potassium alloy and ... tetrachloroethane ... can explode on standing at room temperature. They are especially sensitive to impact. [R20, p. 491-183] *Incompatability: Dinitrogen tetraoxide. [R21] +Potassium; sodium; dinitrogen tetraoxide; potassium hydroxide; nitrogen tetroxide; 2,4-dinitrophenyl disulfide. [R9, 300] DCMP: *... When in contact with flame, incandescent material or red hot metal surfaces, it decomp to form hydrochloric acid, carbon dioxide, and carbon monoxide. [R22] *When heated to decomp it emits very toxic fumes of /hydrogen chloride/. [R23] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R9, 300] +Wear appropriate eye protection to prevent eye contact. [R9, 300] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R9, 300] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R9, 300] OPRM: +Contact lenses should not be worn when working with this chemical. [R9, 301] */1,1,1,2-Tetrachloroethane should be/ handled in the workplace with caution. Exposures should be minimized due to the structural similarity to the carcinogenic chloroethanes. [R24] *If material not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. /Tetrachloroethane/ [R25] *Personnel protection: Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. /Tetrachloroethane/ [R18, 1992.888] +The worker should immediately wash the skin when it becomes contaminated. [R9, 300] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R9, 300] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R26] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R27] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Disposal of toxic chemical wastes by incineration is discussed. [R28] *A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R29] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. Recommendable methods: Incineration and evaporation. Not recommendable method: Discharge to sewer. Peer-review: Dilute with kerosene or fuel oil due to high chlorine content. Evaporate small amt only. (Peer review conclusions of an IRPTC expert consultation (May 1985)) [R30] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of 1,1,1,2-tetrachloroethane were available. There is limited evidence in experimental animals for the carcinogenicity of 1,1,1,2-tetrachloroethane. Overall evaluation: 1,1,1,2-Tetrachloroethane is not classifiable as to its carcinogenicity to humans (Group 3). [R31] *CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Increased incidence of combined hepatocellular adenomas and carcinomas in female mice; inadequate evidence from human studies. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited. [R32] HTOX: *... HIGH PERCENTAGE OF LARGE MONONUCLEAR CELLS FOUND IN CIRCULATING BLOOD OF PT SUFFERING FROM EARLY STAGES OF TETRACHLOROETHANE POISONING. ... OCCASIONAL COMPLAINTS OF TIRED FEELING AND, MORE OFTEN, GASTRIC SYMPTOMS ... LACK OF APPETITE AND SLIGHT NAUSEA ... SLIGHT HEADACHE, AND INTERCURRENT REMISSIONS AND EXACERBATIONS ... /TETRACHLOROETHANE/ [R6, 767] *IN STUDY OF 380 WORKERS ... IN SMALL FACTORIES IN INDIA ... TRIED TO DETERMINE DEGREE OF INHALATION OF TETRACHLOROETHANE...USED AS CLEANING AGENT. ... HIGH % ... WITH NERVOUS SYMPTOMS, SUCH AS HEADACHE, VERTIGO, NERVOUSNESS, NUMBNESS AND TREMORS. TETRACHLOROETHANE @ 9-17 PPM INDUCED TREMORS IN 14% OF THE PERSONNEL; @ 40-74 PPM, IN 33%; @ 50-61 PPM, IN 41%; AND @ 65-98 PPM, IN 50%. /TETRACHLOROETHANE/ [R6, 768] NTOX: *IN A STUDY OF THE EFFECTS OF CHRONIC ACTION OF LOW CONCN OF CHLORINATED HYDROCARBONS ON PRODN OF VARIOUS CLASSES OF IMMUNOGLOBULINS ... RABBITS ... INHALED CHLORINATED HYDROCARBONS @ 2 MG/CU M FOR 3 HR/DAY FOR 8-10 MO. TETRACHLOROETHANE WAS FOUND TO BE MORE HARMFUL TO TOTAL ANTIBODY FORMATION THAN ITS PENTACHLORO- OR DICHLORO- ANALOGUES. /TETRACHLOROETHANE/ [R6, 768] *IN RABBITS, 1,1,1,2-TETRACHLOROETHANE WAS ONLY SLIGHTLY IRRITATING TO SKIN AND OCULAR MUCOUS MEMBRANES; ITS CUTANEOUS LD50 WAS 20 G/KG. ACUTE TOXICITY BY INHALATION FOR EXPOSURE OF 4 HR WAS SIMILAR IN RATS AND RABBITS, THE LC50 BEING 2500 MG/CU M. AFTER INGESTION OF 1,1,1,2-TETRACHLOROETHANE BY RATS AND MICE, LD50 VALUES WERE 800 and 1500 MG/KG RESPECTIVELY. HEPATOTOXIC ACTIVITY, INCL FORMATION OF MICROVACUOLIZATIONS AND CENTROLOBULAR NECROSIS WAS REVEALED. [R33] *1,1,1,2-TETRACHLOROETHANE (100-800 MUMOLE/KG/DAY FOR 7 DAYS, IP) IN MALE RATS INCR LIVER SUCCINATE DEHYDROGENASE, ACID PHOSPHATASE AND GLUCOSE 6-PHOSPHATASE ACTIVITIES. LIVER DNA CONTENT DECR. WHITE CELL COUNT INCR; RED BLOOD CELL COUNT AND BLOOD CHOLESTEROL DECR. [R34] *1,1,1,2-TETRACHLOROETHANE, GIVEN ORALLY IN AMT OF 0.30 G/KG BODY WT 5 DAYS/WK DURING 2 WK, INDUCES STEATOSIS ONLY IN FEMALE WISTAR RATS, WITH INCR IN TRIGLYCERIDES AND DECR IN SOME LIVER ENZYMIC ACTIVITIES. MALE RATS SEEM TO BE RESISTANT. [R35] *AT 24 HR AFTER ORAL ADMIN OF 0.5 G 1,1,1,2-TETRACHLOROETHANE/KG TO RABBITS, BLOOD CHOLESTEROL AND TOTAL LIPID LEVELS INCR AND GLUTAMIC-PYRUVIC TRANSAMINASE, GLUTAMIC-OXALACETIC TRANSAMINASE, CREATINE PHOSPHOKINASE, LACTATE DEHYDROGENASE, AND ALPHA-HYDROXYBUTYRATE DEHYDROGENASE ACTIVITY WAS ENHANCED. EXCEPT FOR CREATINE PHOSPHOKINASE, ENZYME ACTIVITIES REMAIN ELEVATED @ 72 HR AFTER POISONING. [R36] *Rat microsomes were prepared from livers of non-induced male Wistar rats; rabbit microsomes were from the livers of New Zealand white rabbits pretreated with three daily 20 mg/kg intraperitoneal injections of beta-naphthoflavone or with phenobarbital added to drinking water. Data was compared with purified cytochrome p450 enzymes isolated from rabbit liver in a reconstituted system of vesicles containing reductase, lipid, and cytochrome. The effects of the mixed function oxidase inhibitors, carbon monoxide and 100 micromolar SKF-525A, were also examined. In the absence of added substrate the rate of nicotinamide adenine dinucleotide phosphate (NADPH) oxidation was negligible, and on addition of substrate it proceeded linearly for at least 2 minutes. Using rat liver microsomes with hexachloroethane as substrate, 98% was inhibited by saturation with carbon monoxide and 37% inhibited by SKF-525A. The major product was tetrachloroethane, being produced in greater amounts anaerobically than aerobically. [R37] *INDUCTION HEPATOCARCINOGENESIS PRIMARILY THROUGH A PROMOTING MECHANICM. [R38] *Effects of organohalogenated hydrocarbons on ethane and pentane emission in exhaled air of rats were studied. 1,1,1,2-Tetrachloroethane at 700 mg/kg, induced the prodn of ethane and pentane (ethane was produced more). [R39] *The genotoxic activity of 1,1,1,2-tetrachloroethane was studied by intraperitoneal administration of 127 uCi/kg body weight to male Wistar rats, followed by sacrifice at 22 hours and examination of covalent binding to tissues. The compound was bound covalently to DNA, RNA, and proteins of liver, lung, kidney, and stomach. The covalent binding index value was 40 in rat liver DNA, classifying it as a weak to moderate initiator. Both microsomal and cytosolic enzymatic systems from rat organs were capable of bioactivating 1,1,1,2-tetrachloroethane in vitro. Liver fractions were most effective. Synergism was observed when both activating systems were present in the incubation mixture. This compound was metabolized by oxidative and reductive pathways, both dependent on cytochrome P450. It was also bioactivated by microsomal GSH transferases from liver and lung. [R40] *DOGS EXPOSED TO VAPORS OF TETRACHLOROETHANE HAVE DEVELOPED NO CORNEAL INJURY EVEN THOUGH THEY UNDERWENT REPEATED /CNS DEPRESSION/ ... . /TETRACHLOROETHANE/ [R41] *1,1,1,2-Tetrachloroethane (> 99% pure) was not mutagenic to Salmonella typhimurium TA1535, TA1537, TA98 or TA100 when tested at up to toxic doses (1000 ug/plate) in a preincubation assay without an exogenous metabolic system (S9). It was also reported to be nonmutagenic when tested in Salmonella typhimurium TA1535, TA1537, TA1538, TA98 and TA100 (using an unspecified protocol) in the presence or absence of Aroclor induced liver S9 (values not given). [R42] *Effects of chlorinated aliphatic hydrocarbons on mitochondrial energy transfer reactions in the rat were examined. The effect of chlorinated aliphatic hydrocarbons on the respiratory control was in the order of tetrachloroethylene greater than 1,1,1,2-tetrachloroethane greater than trichloroethylene greater than 1,1,1,2-trichloroethane. Chlorinated aliphatic hydrocarbons acted as uncouplers of mitochondrial oxidative phosphorylation. The difference between the effects of chlorinated aliphatic and chlorinated aromatic hydrocarbons on the energy transfer reactions of rat liver mitochondria was discussed. [R43] NTXV: *LD50 RABBIT PERCUTANEOUS 20 G/KG; [R33] *LC50 RABBIT INHALATION 2500 MG/CU M/4 HR; [R33] *LC50 RAT INHALATION 2500 MG/CU M/4 HR; [R33] *LD50 RAT ORAL 800 MG/KG; [R33] *LD50 MOUSE ORAL 1500 MG/KG; [R33] ETXV: *LC50 Bluegill 20 mg/l/24 hr (95% confidence limit 16-24 mg/l) /Conditions of bioassay not specified/; [R44] *LC50 Bluegill 20 mg/l/96 hr (95% confidence limit 16-24 mg/l) /Conditions of bioassay not specified/; [R44] NTP: *1,1,1,2-Tetrachloroethane at 125 or 250 mg/kg (5 times/wk for 103 wk) was not carcinogenic in F344/N rats, although the observed increase in the proportion of male rats with liver tumor may be associated with the administration of 1,1,1,2-tetrachloroethane. The cmpd at 250 or 500 mg/kg was carcinogenic in B6C3F1 mice, causing an increased proportion of female mice with hepatocellular carcinoma and an increased proportion of male and female mice with hepatocellular adenoma. [R45] TCAT: ?The ability of 1,1,1,2-tetrachloroethane to induce morphological transformation in the BALB/3T3 mouse cell line (Cell Transformation Assay) was evaluated. Based on preliminary toxicity determinations (exposure time= 3 days), 1,1,1,2-tetrachloroethane was tested at 0, 2, 10, 50 and 250 ug/ml, with cell survival ranging from 116% to 98% relative to untreated controls. None of the concentrations tested produced significantly greater transformation frequencies relative to untreated controls. [R46] ?The mutagenicity of 1,1,1,2-tetrachloroethane was evaluated in Salmonella tester strains TA1535, TA1537, TA98 and TA100 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat and mouse liver S9 fraction. Based on preliminary toxicity determinations, 1,1,1,2-tetrachloroethane, was tested at concentrations up to 10 mg/plate using the plate incorporation technique. 1,1,1,2-Tetrachloroethane did not cause a positive response in any tester strains with or without metabolic activation. [R47] ?The effects of 1,1,1,2-tetrachloroethane were examined in the rat hepatocyte primary culture/DNA repair assay. Based on preliminary toxicity tests, 1,1,1,2-tetrachloroethane was tested at concentrations of 1, 0.1, 0.01, 0.001, 1x10(-4) and 1x10(-5)% in DMSO solvent as the vehicle. The highest two levels were too cytotoxic to be evaluated in the assay. The concentrations at 0.01% or lower were nontoxic and did not cause a significant increase in the unscheduled DNA synthesis over the solvent control. [R48] ADE: *WHEN ADMIN SC TO MICE, HALF OF DOSE OF 1,1,1,2-TETRACHLOROETHANE WAS EXHALED UNCHANGED, AND PART METABOLIZED WAS EXCRETED MAINLY AS TRICHLOROETHANOL AND TO MINOR EXTENT AS TRICHLOROACETIC ACID. [R49] *INHALATION OR INGESTION OF 1,1,1,2-TETRACHLOROETHANE BY PREGNANT RATS AND RABBITS RESULTED IN PRESENCE OF HIGH LEVELS OF CHEM IN FETUSES, INDICATING TRANS-PLACENTAL PASSAGE. [R33] METB: *... /1,1,1,2-TETRACHLOROETHANE WAS/ METAB ... TO GIVE FIRST DICHLOROACETIC ACID AND THEN GLYOXYLIC ACID. WITH PART OF TETRACHLOROETHANE, NONENZYMIC DEHYDROCHLORINATION OCCURS, WITH FORMATION OF TRICHLOROETHYLENE, WHICH IS ALSO FOUND IN BREATH. [R6, 767] *1,1,1,2-TETRACHLOROETHANE WAS SC INJECTED INTO MICE AND EXCRETION WAS FOLLOWED FOR 3 DAYS. THE PART METABOLIZED WAS EXCRETED MAINLY AS 2,2,2-TRICHLOROETHANOL (17-49% OF DOSE) AND TO LESSER EXTENT AS TRICHLOROACETIC ACID. [R50] *IN RATS, GUINEA PIGS AND RABBITS, 1,1,1,2-TETRACHLOROETHANE UNDERWENT DEHALOGENATION BY PRODUCING TRICHLOROETHANOL WHICH IS ELIMINATED PRINCIPALLY IN URINE IN FORM OF CONJUGATED GLUCURONIC DERIVATIVE (UROCHLORALIC ACID). OXIDN TO TRICHLOROACETIC ACID IS CONSIDERABLE ONLY IN RATS. [R51] *1,1,1,2-TETRACHLOROETHANE, WHEN ADMIN FOR 8 HR AS VAPOR @ 200 PPM TO RATS AND MICE, PRODUCED THE FUJIWARA REACTION-POSITIVE URINARY METABOLITES TRICHLOROACETIC ACID, TRICHLOROETHANOL, AND TOTAL TRICHLORO CMPD. [R52] *The activity in vitro of liver microsomal enzymes to metabolize 1,1,1,2-tetrachloroethane was enhanced remarkably in 1-day fasted rats of both sexes, although fasting produced no significant increase in the microsomal protein and cytochrome p450 contents. Even the activity per whole liver was at a significantly increased level. A sex difference was noted in the metabolism of 1,1,1,2-tetrachloroethane both in fed and 1-day fasted rats. [R53] *In mice given a subcutaneous dose of 1.2-2.0 g/kg body weight 1,1,1,2-tetrachloroethane (< 0.1% impurities, including 0.03% trichloroethylene), 21-62% was eliminated unchanged in exhaled air within 72 hours. The major urinary metabolite (17-49% of the dose, although some fecal material was collected in the urine) was trichloroethanol and its glucuronide conjugate; trichloroacetic acid (1-7% of the dose) was also excreted in the urine. Trichloroethanol has also been isolated as the major metabolite, with trichloroacetic acid, from the urine of rats, rabbits and guinea pigs. After intraperitoneal administration of 1,1,1,2-tetrachloroethane to phenobarbital-treated rats, 1,1-dichloroethylene and 1,1,2-trichloroethane were detected in the blood. [R42] *In the presence of oxygen NADPH and rat liver microsomes, 1,1,1,2-tetrachloroethane undergoes little dechlorination. In contrast, NADPH-dependent reductive metabolism of 1,1,1,2-tetrachloroethane by hepatic microsomal fractions from rats yields 1,1,-dichloroethylene as the major metabolite. [R42] *A spectrophotometric assay of the reductive dechlorination of halocarbons was developed and used to determine the kinetic characteristics of dechlorination of a range of haloethanes catalyzed by microsomes from rat and rabbit liver. The dechlorination of haloethanes catalyzed by a vesicular reconstituted system of cytochrome p450 enzymes from rabbit liver was also studied and found to be similar to that catalyzed by microsomes: both reductase and a phenobarbital induction. The main factor in determining the apparent binding constant to the enzyme is the partition coefficient into the lipid membrane, as assessed by calculated log p values. [R54] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *It does not appear that 1,1,1,2-tetrachloroethane is presently produced in the USA or is used commercially. It may, however, be formed incidentally during the manufacture of other chlorinated ethanes and released into the environment as air emissions or in wastewater. If released on land, 1,1,1,2-tetrachloroethane would be expected to leach through soil and volatilize from the soil surface. If released into water, it would be primarily lost by volatilization (estimated half-life 4.2 hr from a model river). Adsorption to sediment is expected to be relatively low and bioconcentration in aquatic organisms would not be significant. 1,1,1,2-Tetrachloroethane is extremely stable in the atmosphere, reacting with photochemically produced hydroxyl radicals with an estimated half-life of 550 days. However, it will be susceptible to washout by rain. Due to its persistence, it will disperse over long distances and slowly diffuse into the stratosphere where it would be rapidly degraded. (SRC) ARTS: *1,1,1,2-Tetrachloroethane has no commercial applications(1). However it is formed as an incidental product in the manufacture of other chloroethanes and, therefore, may be released to the environment as air emissions or in wastewater during the manufacture of these chloroethanes(2). [R55] FATE: *TERRESTRIAL FATE: If released on land, 1,1,1,2-tetrachloroethane would be expected to leach into the ground and volatilize from the soil surface. (SRC) *AQUATIC FATE: If released into water, 1,1,1,2-tetrachloroethane would be primarily lost by volatilization (estimated half-life 4.2 hr from a model river). Adsorption to sediment is expected to relatively low. (SRC) *ATMOSPHERIC FATE: 1,1,1,2-Tetrachloroethane is extremely stable in the atmosphere (estimate half-life 550 days). It will be subject to washout by rain. Due to its persistence, it will disperse over long distances and slowly diffuse into the stratosphere where it would be rapidly degraded. (SRC) ABIO: *Hydrolysis of 1,1,1,2-tetrachloroethane is not significant at environmental temperatures and pHs; the half-life for this process exceeding 50 yr(1). The estimated rate of reaction of 1,1,1,2-tetrachloroethane with photochemically produced hydroxyl radicals is 2.9x10-14 cu cm/molecule-sec, resulting in a half- life of 550 days(2). Degradation is rapid when irradiated in the presence of chlorine with 20% removal in 3.0 min(3). Chlorine radicals are formed during the irradiation and are the reactive species. These radicals are also formed by the photolysis of chlorinated aliphatic compounds in the stratosphere. [R56] *The hydrolysis rate constant of 1,1,1,2-tetrachloroethane was measured in dilute aqueous solutions within the temperature ranges of 147 to 190 C (neutral range) and 52 to 87 C (basic range), and at pH values of 3 to 12. The rate constant value was determined by 5 to 20 time-concn points, with each sample analyzed in triplicate. Arrhenius parameters were determined for both neutral and alkaline hydrolysis reactions. The hydrolysis rate constant k (neutral, 25 C) was determined to be 2.60X10-8/min, while the basic k (pH 7, 25 C) was 2.15X10-9/min. The environmental half life of 1,1,1,2-tetrachloroethane (at 25 C, pH 7) is 46.8 yr. [R57] BIOC: *No experimental data are available on the bioconcentration of 1,1,1,2-tetrachloroethane in aquatic organism. Based on the water solubility of 1.1X10+3 mg/l(1), a BCF of 12 can be estimated using a recommended regression equation(2,SRC). Confidence in this estimate is increased since similar compounds such as 1,1,1-trichlorethane and 1,1,2,2-tetrachlorethane have BCFs < 10 and tissue half-lives of < 1 day(3). [R58] KOC: *The experimentally determined KOC for 1,1,1,2-tetrachloroethane is reported to be 399(1). Based on the water solubility of 1.1X10+3 mg/l(3), a KOC of 93 can be estimated using a recommended regression equation(2,SRC). Therefore 1,1,1,2-tetrachloroethane should be moderately mobile in soil and may be expected to leach into the groundwater. [R59] VWS: *The Henry's Law constant for 1,1,1,2-tetrachloroethane which has been calculated from its vapor pressure and water solubility is 2.7X10-3 atm-cu m/mole(1). The half-life for evaporation of the solute from a stirred dilute solution 6.5 cm deep into still air was 42.3 min(1) which translates into a half-life of 10.8 hr from a body of water 1 m deep(SRC). From the Henry's Law Constant one would estimate a volatilization half-life of 4.2 hr from a river 1 m deep with a 1 m/sec current with a wind speed of 3 m/sec with diffusion through the liquid phase controlling the rate of evaporation(2,SRC). Since 1,1,1,2-tetrachloroethane has a moderate vapor pressure, 14 torr at 25 deg C(1), and does not adsorb strongly to soil, it would be expected to volatilize from dry soil(SRC). [R60] WATC: *DRINKING WATER: US Groundwater Supply Survey (945 supplies derived from groundwater chosen both randomly and on the basis that they may contain VOCs) - 1,1,1,2-tetrachloroethane was not detected in any supplies at a detection limit of 0.2 ppb(1). It was confirmed to be in extracts from the Carrollton water plant in New Orleans which derives its water from the Mississippi River(2). The concentration of 1,1,1,2-tetrachloroethane in a sample collected over 7 days was 0.11 ppb(2). [R61] EFFL: *In a comprehensive survey of wastewater from 4000 industrial and publicly owned treatment works (POTWs) sponsored by the Effluent Guidelines Division of the U.S. EPA, 1,1,1,2-tetrachloroethane was identified in discharges of the following industrial category (frequency of occurrence, median concn in ppb): organics and plastics (1; 27.4), inorganic chemicals (4; 14.8), electronics (1; 272.6)(1). The highest effluent concn was 272.6 ppb in the electronics industry(1). [R62] ATMC: *Field studies were conducted in Phoenix, AZ and Los Angeles and Oakland, CA (USA) to better characterize the atmospheric abundance, fate and human exposure of selected organic chemicals that may be potentially hazardous. Concn, variabilities, and average daily dosages from exposure to the haloethanes, including 1,1,1,2-tetrachloroethane, was determined to be 142 ug/day. Exposure levels in Los Angeles were typically the highest and those in Oakland the lowest. [R63] *RURAL/REMOTE: Not detected in 2 sites in the USA(1). The mean concentrations of 1,1,1,2-tetrachloroethane in marine air at 8 sampling sites over the northern and southern Atlantic Ocean ranged from ND to 1.4 parts/trillion median 0.3 parts/trillion(2). URBAN/SUBURBAN: 602 sites/samples in USA - 2.2 parts/trillion median, 63 parts/trillion maximum(1). SOURCE AREAS: 43 sites/samples in USA - ND in over 75% of samples, 0.071 parts/trillion mean, 3.1 parts/trillion maximum(1). [R64] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- NREC: +Handle with caution in the workplace. [R9, 300] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 70 ug/l [R65] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 1 ug/l [R65] +(ME) MAINE 70 ug/l [R65] +(MN) MINNESOTA 70 ug/l [R65] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R66] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulagated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,1,1,2-tetrachloroethane is included on this list. [R67] RCRA: *U208; As stipulated in 40 CFR 261.33, when 1,1,1,2-Tetrachlroethane, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R68] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EMSLC Method 502.1, Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography; Gas Chromatography Electrolytic Conductivity Detector; detection limit not reported [R69] *EMSLC Method 502.2, Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series; Gas Chromatography Electrolytic Conductivity Detector; detection limit = 0.010 ug/l. [R69] *EMSLC Method 502.2, Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series; Gas Chromatography Photoionization Conductivity Detector; detection limit = 0.050 ug/l. [R69] *EMSLC Method 524.1, Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography/Mass Spectrometry; Gas Chromatography/Mass Spectrometry; detection limit not reported. [R69] *EMSLC Method 524.2, Measurement of Purgeable Organic Compounds in Water by Capillary Column Gas Chromatography/Mass Spectrometry; Capillary Gas Chromatography Mass Spectrometry; detection limit = 0.050 ug/l. [R69] *OSW Method 8021; Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Technique; Capillary Gas Chromatography Electrolytic Conductivity Detector; detection limit = 0.0050 ug/l . [R70] *OSW Method 8240A; Volatile Organics by Gas Chromatography/Mass Spectrometry (GC/MS): Packed Column Technique; Gas Chromatography/Mass Spectrometry; detection limit = 5.0 ug/kg (solid), 5.0 ug/l (liquid). [R70] *OSW Method 8260; Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique; Capillary Gas Chromatography/Mass Spectrometry; detection limit = 0.050 ug/l. [R70] *USEPA; 1600 Series Wastewater Methods. Available from EPA Sample Control Center, VIAR AND Co., 302 N. Lee St., Alexandria, VA 22314; EAD Method 1624, Volatile Organic Compounds by Isotope Dilution GCMS; Gas Chromatography/Mass Spectrometry; detection limit = 10 ug/l (water). [R71] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Studies of 1,1,1,2-Tetrachloroethane in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 237 (1983) NIH Publication No. 83-1793 SO: R1: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 278 R2: The Aldrich Catalog/Handbook of Fine Chemicals 1994-95, Aldrich Chem Co, Milwaukee, WI, pp 1306 (1994) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 88 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R6: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R7: SRI R8: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994. R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R10: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-156 R11: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R12: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 67th ed. Boca Raton, FL: CRC Press, Inc., 1986-87.,p. C-265 R13: Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 606 R15: Dilling WL; Environ Sci Technol 11: 405-9 (1977) R16: Sato A, Nakajima T; Scand J Work Environ Health 13: 81-93 (1987) R17: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-151 R18: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives R19: Bretherick, L. Handbook of Reactive Chemical Hazards. 3rd ed. Boston, MA: Butterworths, 1985. 1236 R20: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997. R21: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2517 R22: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 2162 R23: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3089 R24: NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards Sept. 1986. (Supplement to Morbidity and Mortality Weekly Report 35 No. 15, Sept. 26, 1986) 295 R25: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1992.p. 887-8 R26: 49 CFR 171.2 (7/1/96) R27: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 218 R28: Halebsky M; Ocean Incineration of Toxic Chemical Wastes; pp 175-226 in Toxic and Hazardous Waste Disposal, Vol 4 New and Promising Ultimate Disposal Options; Pojasek RB, ed (1980) R29: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-35 (1981) EPA 68-03-3025 R30: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 172 R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1139 (1999) R32: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 1,1,1,2-Tetrachloroethane (630-20-6) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R33: TRUHAUT R ET AL; ARCH MAL PROF MED TRAV SECUR SOC 35 (6): 593-608 (1974) R34: CHIERUTTINI ME, FRANKLIN CS; BR J PHARMACOL 57 (3): 421 (1976) R35: TRUHAUT R ET AL; EUR J TOXICOL ENVIRON HYG 8 (3): 175-9 (1975) R36: TRUHAUT R ET AL; J EUR TOXICOL 6 (2): 81-4 (1973) R37: Salmon AG et al; Br J Ind Med 42: 305-11 (1985) R38: STORY DL ET AL; TOXICOL IND HEALTH 2 (4): 351-62 (1986) R39: Cluet JL, Boudene C; C R Seances Acad Sci Ser 3; 296 (6): 275-8 (1983) R40: Colacci A et al; J Toxicol Environ Health 26 (4): 485-95 (1989) R41: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 888 R42: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V41 92 (1986) R43: Ogata M, Hasegawa T; Ind Health 19 (2): 71-6 (1981) R44: Buccafusco RJ et al; Bull Environ Contam Toxicol 26 (4): 446-52 (1981) R45: NTP; Carcinogenesis Studies of 1,1,1,2-Tetrachloroethane in F344/N rats and B6C3F1 Mice (Gavage Study); NIH Pub 83-1793 (1983) R46: Arthur D. Little, Inc.; Cell Transformation Assays of 11 Chlorinated Hydrocarbon Analogs. (1983), EPA Document No. 40-8324457, Fiche No. OTS0509392 R47: SRI International; Investigations of the Species Sensitivity and Mechanism of Carcinogenicity of Halogenated Hydrocarbons; Final Report, (1983), EPA Document No. 40+8424225, Fiche No. OTS0509408 R48: Naylor Dana Institute; DNA Repair Tests of 11 Chlorinated Hydrocarbon Analogs. (1983), EPA Document No. 40-8324292, Fiche No. OTS0509403 R49: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 316 R50: YLLNER S; ACTA PHARMACOL TOXICOL 29 (5-6): 471-80 (1971) R51: TRUHAUT R, PHU LICH N; J EUR TOXICOL 6 (4-5): 211-7 (1974) R52: IKEDA M, OHTSUJI H; BRIT J IND MED 29 (1): 99-104 (1972) R53: Nakajima T, Sato A; Toxicol Appl Pharmacol 50 (3): 549-56 (1979) R54: Salmon AG et al; Br J Ind Med 42 (5): 305-11 (1985) R55: (1) Hardie DWF; Kirk-othmer Encyclopedia of Chemical Technology 2nd ed 5: 148-70 (1964) (2) Archer WL; Kirk-othmer Encyclopedia of Chemical Technology 3rd ed 5: 723-42 (1979) R56: (1) Mabey WR et al; in Symp Amer Chem Soc. Div Environ Chem 186th Natl Mtg Washington, DC 23: 359-61 (1983) (2) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) (3) Spence JW, Hanst PL; J Air Pollut Control Fed 28: 250-3 (1978) R57: Jeffers PM et al; Environ Sci Technol 23 (8): 965-9 (1989) R58: (1) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) (2) Lyman WJ et al; Handbook of Chem Property Estimation Methods. NY: McGraw-Hill pp. 5-1 to 5-30 (1982) (3) Barrows ME et al; Dyn Exp Hazard Assess Toxic Chem Ann Arbor MI: Ann Arbor Sci pp. 379-92 (1980) R59: (1) Rao PSC et al; J Environ Qual 14: 376-83 (1985) (2) Lyman WJ et al; Handbook of Chem Property Estimation Methods NY: McGraw-Hill pp. 4-1 to 4-33 (1982) (3) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) R60: (1) Dilling WL; Environ Sci Technol 11: 405-9 (1977) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-1 to 15-34 (1982) (3) Mackay D, Shiu WY; J Phys Chem Ref Data 19: 1175-99 (1981) R61: (1) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) (2) Keith LH et al; pp. 329-73 in Ident Anal Organic Pollut Water Keith LH Ed Ann Arbor, MI: Ann Arbor Press (1976) R62: (1) Shackelford WM et al; Analyt Chim Acta 146: 15-27 (1983) R63: Singh HB et al; Atmos Environ 15 (4): 601-12 (1981) R64: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere. Menlo Park, CA: Atmospheric Science Center SRI International Contract 68-02-3452 (1982) (2) Class T, Ballschmiter K; Chemosphere 15: 413-27 (1986) R65: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R66: 40 CFR 302.4 (7/1/92) R67: 40 CFR 716.120 (7/1/92) R68: 40 CFR 261.33 (7/1/92) R69: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water 500 Series Methods (1988) EPA/600/4-88/039 R70: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R71: USEPA; EMMI. Enviromental Monitoring Methods Index. Version 1.02. EPA-821- B-92-001 (NTIS PB-92-503093, August (1992) RS: 45 Record 261 of 1119 in HSDB (through 2003/06) AN: 4151 UD: 200208 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN- SY: *2,3,7,8-Czterochlorodwubenzo-p-dwuoksyny- (Polish); *Dibenzo(b,e)(1,4)dioxin, 2,3,7,8-tetrachloro-; *Dibenzo-p-dioxin,-2,3,7,8-tetrachloro-; *Dioksyny- (Polish); *Dioxin-; *Dioxine-; *NCI-C03714-; *TCDBD-; *TCDD-; *2,3,7,8-TCDD-; *Tetrachlorodibenzodioxin-; *2,3,7,8-Tetrachlorodibenzo(b,e)(1,4)dioxin; *2,3,7,8-Tetrachlorodibenzo-1,4-dioxin-; *Tetradioxin- RN: 1746-01-6 MF: *C12-H4-Cl4-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *2,3,7,8-Tetrachlorodibenzo-p-dioxin is produced as an unwanted contaminant during the manufacture of chlorobenzenes, chlorophenols and their derivatives such as 2,4,5-trichlorophenoxyacetic acid and 2-(2,4,5-trichlorophenoxy)propionic acid. [R1] *CONVENTIONAL METHODS FOR LAB PREPN ... INVOLVE 2 TYPES OF PROCESSES: (1) CONDENSATION OF POLYCHLOROPHENOL, OR (2) DIRECT HALOGENATION OF PARENT DIBENZO-PARA-DIOXIN OR MONOCHLORO DERIVATIVE. ... CONDENSATION BETWEEN A CATECHOL DIANION AND EITHER AN APPROPRIATE POLYCHLOROBENZENE IN BOILING DIMETHYL SULFOXIDE OR AN APPROPRIATE ORTHO-CHLOROPOLYCHLORONITROBENZENE /MAY BE DONE TO INCREASE YIELD/. [R2] *TETRACHLORODIBENZO-P-DIOXIN IS FORMED IN DISTILLATE /AS A BY-PRODUCT DURING SYNTH OF 2,4,5-TRICHLOROPHENOL/ BY CONDENSATION OF 2 MOLECULES OF SODIUM TRICHLOROPHENATE UNDER INFLUENCE OF HIGHLY EXOTHERMIC DECOMP OF SODIUM-2-HYDROXYETHANOL. [R3] *TCDD CAN BE FORMED BY PYROLYSIS AT 500 DEG C FOR 5 HR OF SODIUM ALPHA-(2,4,5-TRICHLOROPHENOXY)PROPIONATE. [R4] *Prepn by the chlorination of dibenzo-p-dioxin [R5] FORM: *Tetrachlorodibenzo-p-dioxin has been associated with all synthetic compounds derived from 2,4,5-TCP. This includes the widely used herbicide and defoliant 2,4,5-T (2,4,5-trichlorophenoxyacetic acid). ... It is an inadvertant contaminant in herbicide precursors and thus in the herbicides themselves. Thus, it is applied in herbicide formulations, but is not used per se. [R6] MFS: *Eagle-Picher Industries, Inc, Hq, 580 Walnut St, Cincinnati, OH 45202, (513) 721-7010; Specialty Materials Division; Production site: Chemsyn Science Lab, 13605 West 96th Terrace, Lenexa, KS 66215-1297 [R7] OMIN: *DOW CHEM CO SUPPLIED MOST OF 2,4,5-T USED IN DEFOLIATION PROGRAMS DURING VIETNAM WAR IN FORM OF CMPD KNOWN AS AGENT ORANGE, WHICH CONTAINED THE CONTAMINANT TCDD IN AMT IN EXCESS OF 30 PPM. [R8] *Thermal or chemical degradation of chlorophenols can produce ... /Polychlorodibenzoparadioxins/ [R9, p. VA7 5] *2,3,7,8-Tetrachlorodibenzodioxin ... has not been detected in products other than 2,4,5-T and fenoprop [R9, p. VA7 11] *2,3,7,8-Tetrachlorodibenzodioxin has never been detected in any ... chlorophenol ... products derived by chlorination. [R10] *May be produced in the preparation of 2,4,5-trichlorophenol from 1,2,4,5- tetrachlorobenzene and sodium hydroxide [R9, p. VA7 10] *The hydrolysis of one of the chlorine atoms in 1,2,4,5-tetrachlorobenzene with sodium hydroxide in a suitable alcohol solvent produces 2,4,5- trichlorophenol. The reaction must be carried out under extremely restricted conditions to prevent the formation of 2,3,7,8-tetrachlorodibenzodioxin [R11] USE: *RESEARCH CHEMICAL [R12] *TCDD HAS BEEN TESTED FOR USE IN FLAMEPROOFING POLYMERS, EG, POLYESTERS, AND AGAINST INSECTS AND WOOD-DESTROYING FUNGI. IT IS HOPED THAT THESE USES HAVE NEVER BEEN EXPLOITED COMMERCIALLY. [R3] *NOT USED COMMERCIALLY IN USA [R12] PRIE: U.S. PRODUCTION: *(1978) NOT PRODUCED COMMERCIALLY IN USA [R12] *(1982) NOT PRODUCED COMMERCIALLY IN USA [R12] *(1985) Not produced commercially in the USA [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS NEEDLES [R14]; *White crystalline solid [R15, 1218]; +Colorless to white, crystalline solid [Note: Exposure may occur through contact at previously contaminated worksites]. [R16, 298] MP: *305-306 DEG C [R14] MW: *322 [R17] OWPC: *log Kow = 6.8 [R18] SOL: *1.4 G/L IN ORTHO-DICHLOROBENZENE [R19]; *0.72 G/L IN CHLOROBENZENE [R19]; *0.57 G/L IN BENZENE [R19]; *0.37 G/L IN CHLOROFORM [R19]; *0.11 G/L IN ACETONE [R19]; *0.05 G/L IN N-OCTANOL [R19]; *0.01 G/L IN METHANOL [R19]; *0.04 G/L IN LARD OIL [R19]; *Water solubility: 19.3 ng/l [R20] SPEC: *MAX ABSORPTION (CHLOROFORM): 248 NM (E= 92.2); 310 NM (E= 173.6) [R14]; *Intense mass spectral peaks: 322 m/z (100%), 320 m/z (79%), 324 m/z (48%), 257 m/z (25%) [R21]; *Intense mass spectral peaks: 189 m/z [R22] VAP: *7.4x10-10 mm Hg at 25 deg C [R20] OCPP: *Needles, MP 295 deg C; crystals from anisole, MP 320-325 [R5] *Dibenzodioxins occur as 75 different isomers. There are 22 possible TCDD isomers. [R23] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: +UV light (decomposes) [R16, 298] DCMP: */2,3,7,8-Tetrachlorodibenzo-p-dioxin/ begins to decompose at 500 deg C and virtually complete decomposition occurs within 21 seconds at a temp of 800 deg C. [R24] SERI: *Acute exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin results in ... irritation of the eyes, skin, and respiratory tract. [R25] EQUP: *For workers engaged in the decontamination process after an accident, it is recommended that they wear complete throw away equipment to protect the skin and prevent exposure to dust and vapors from the contaminated materials. /NIOSH approved respiration/ should be used if any procedure that may produce inhalation of airborne contaminated material cannot be avoided. [R26, 641] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R27, 1979.8] +Wear appropriate personal protective clothing to prevent skin contact. [R16, 298] +Wear appropriate eye protection to prevent eye contact. [R16, 298] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R16, 298] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R16, 298] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R16, 298] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R16, 298] OPRM: +Contact lenses should not be worn when working with this chemical. [R16, 299] *In case of an accident, that is if the process of synthesis of 2,4,5-trichlorophenol is running out of control and high levels of TCDD are present, contaminated clothing should be immediately removed, avoiding contamination of the skin or other parts of the body. Exposed parts should be washed immediately and repeatedly until medical attention is obtained. [R26, 641] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R27, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R27, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R27, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R27, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R27, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R27, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R27, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R27, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R27, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. +The worker should immediately wash the skin when it becomes contaminated. [R16, 298] +The worker should wash daily at the end of each work shift. [R16, 298] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R16, 298] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R16, 298] SSL: *CHANGED CHEMICALLY WHEN EXPOSED IN ISOOCTANE OR N-OCTANOL TO UV LIGHT [R19] *Tetrachlorodibenzo-p-dioxin is stable under ordinary conditions of storage. [R28, 479] *2,3,7,8-TCDD is considered relatively stable toward heat, acids, and alkalies. [R24] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R27, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R27, 1979.13] STRG: *... Polychlorinated dibenzo-p-dioxins should be protected from light and kept at 4 deg C during transportation and storage. [R29] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R27, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R27, 1979.15] DISP: *Degradation by chemical means are necessary for polychlorophenol formulations because heat stable chlorodioxins are formed during incineration. Ruthenium tetroxide is a powerful oxidizing agent which reacts with a wide range of organic substances, incl those aromatic compounds which are oxidized slowly, or not at all, by permanganate. It may be safely used in soln in water or in organic solvents with no nucleophilic character, such as chloroform, nitromethane or carbon tetrachloride. Studies show that ruthenium tetroxide can be used for detoxification of glassware and artifacts, and for the periodic purging of industrial reactors to counteract the accumulation of polychloro-p-dioxin residues. Preliminary work with TCDD showed that the rate of oxidation was increased at higher temp and that the half-life was less than 15 min in carbon tetrachloride at 70 deg C (TCDD concn= 72 ug/ml carbon tetrachloride ; ruthenium tetroxide= 2X10+3 ug/ml, about 10 equiv). There is no evidence of the nature of fragments formed during oxidation of the polychlorodibenzodioxins. However, the related chlorophenols undergo extensive decomposition to yield chloride ions and no significant levels of organic products. [R30] *Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans could be degraded by ozonation in an alkaline aqueous medium, but no reaction occurred in acid solutions. Degradation rates of at least 99% were observed after the reaction conditions (pH, temperature) had been optimized. The investigated substances with three to eight chlorine atoms had different velocities of reaction depending on their number and configuration following reactions of second order. The selective detection and quantitative determination of polychlorinated dibenzo-p-dioxin and polychlorinated dibenzofuran traces was performed by capillary gas chromatography in combination with a mass selective detector. [R31] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R27, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R27, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R27, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R27, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R27, 1979.17] *Incinerator operating conditions currently considered adequate for complete destruction of 2,3,7,8-TCDD and most other chlorinated organics are a temp of at least 1000 deg C with a dwell time of at least 2 sec. ... The most extensively tested method is incineration, which entails a high-temp oxidation of the dioxin molecules. [R32] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is limited evidence in humans for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. There is sufficient evidence in experimental animals for the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Overall Evaluation: 2,3,7,8-tetrachlorodibenzo-p-dioxin is carcinogenic to humans (Group 1). In making the overall evaluation, the Working Group took into consideration the following supporting evidence: (1) 2,3,7,8-TCDD is a multi-site carcinogen in experimental animals that has been shown by several lines of evidence to act through a mechanism involving the Ah receptor; (2) this receptor is highly conserved in an evolutionary sense and functions the same way in humans as in experimental animals; (3) tissue concentrations are similar in both heavily exposed human populations in which an increased overall cancer risk was observed and in rats exposed to carcinogenic dosage regimens in bioassays. [R33] ANTR: *Persons with recent exposure to polychlorodibenzodioxins ... should have the chemicals removed from their skin as quickly as possible to prevent additional absorption of the compounds. Exposed person should be asked for an exposure history, including onset of exposure, duration of exposure, and type of exposure. Physical examinations, including a thorough examination of the skin, should be given. Routine blood and liver laboratory tests should be carried out. In most situations, however, evidence of exposure and disease relatable to the exposure will be lacking. Because chloracne is the only human effect documented thus far, no other specific abnormality can be considered pathognomonic for exposure. /Polychlorodibenzodioxins/ [R34, 758] MEDS: *There is no need to monitor persons for levels of polychlorodibenzodioxins ... in their blood, serum, or adipose tissue unless they are thought to have been excessively exposed. /Polychlorodibenzodioxins/ [R34, 758] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R27, 1979.23] HTOX: *... 76 CASES OF CHLORACNE /IN WORKERS ARE REPORTED/ FOLLOWING EXPOSURE TO TCDD BETWEEN 1965-1968 IN FACTORY /PRODUCING 2,4,5-T AND PENTACHLORPHENOL/ IN CZECHOSLOVAKIA ... FIFTY-FIVE PATIENTS WERE SUBMITTED TO MEDICAL FOLLOW-UPS FOR OVER 5 YEARS; SOME HAD SYMPTOMS OF PORPHYRIA CUTANEA TARDA, UROPORPHYRINURIA, ABNORMAL LIVER TESTS ... AND LIVER ENLARGEMENT. THE MAJORITY ... SUFFERED ... SEVERE NEURASTHENIA AND DEPRESSIVE SYNDROME. IN 17 SUBJECTS, SIGNS OF PERIPHERAL NEUROPATHY, ESPECIALLY IN LOWER EXTREMITIES, WERE CONFIRMED ... MORE THAN HALF OF THE PATIENTS SHOWED RAISED LEVELS OF BLOOD CHOLESTEROL AND TOTAL LIPIDS. [R35] *Chloracne was found in 52% of 226 workers in a 1979 cross-sectional survey at a plant where 2,4,5-T had been manufactured from 1948 to 1969. Mean duration of residual chloracne was 26 yr, and in 29 subjects, it had been present for 30 yr. A significant increased prevalence of abnormal gamma-glutamyl transpeptidase and higher mean gamma-glutamyl transpeptidase were found in those with chloracne, compared to those without. Although mean triglyceride values were higher in those with chloracne, the difference was not statistically significant. Neurological exam showed statistically significantly higher prevalence of abnormal sensory findings in those with chloracne. Incr prevalence of angina and reported myocardial infarction in those with chloracne was not significant when age adjusted. Incr prevalence of reported sexual dysfunction and decr libido in those with chloracne compared to those without was statistically significant after age adjustment. No differences were found between those with and without chloracne in serum cholesterol, total urinary porphyrins, or in reproductive outcome. [R36] *There is no report of human exposure only to TCDD. Three case control studies have shown relative risks of 5.7 (95% confidence limits, 2.9-11.3) and 5.1 (2.5-10.4) for soft-tissue sarcoma and 6.0 (3.7-9.7) for lymphoma in association with exposure to phenoxyacetic acids or chlorophenols, in which tetrachlorodibenzo-p-dioxin was a likely contaminant. In six of seven cohort studies, 37 deaths from cancer were observed with 33.3 expected in some 869 men exposed to tetrachlorodibenzo-p-dioxin during the manufacture or use of 2,4,5-trichlorophenol and/or 2,4,5-trichlorophenoxyacetic acid. There was an appreciable deficit of deaths from all causes (135 observed, 157.3 expected). Two of the deaths were from lymphomas (both Hodgkin's disease) and two from soft-tissue sarcomas. Three additional cases of soft-tissue sarcoma (and possibly 2 more) have been reported in men assoc with manufacture of 2,4,5-trichlorophenol or 2,4,5-trichlorophenoxyacetic acid, and therefore possibly to tetrachlorodibenzo-p-dioxin. Two of the 3 case-control studies ... gave evidence of an increased risk of soft-tissue sarcoma or lymphoma in assoc with exposure to phenoxyacetic acids not usually contaminated with tetrachlorodibenzo-p-dioxin. [R37] *To determine whether paternal exposure to TCDD or other polychlorinated dioxins might be associated with adverse pregnancy, an interviewer administration questionnaire survey was conducted among wives of Dow Michigan Division employees in Midland, MI area who had been potentially exposed to dioxins. Control group consisted of wives of employees who had no dioxin exposure and whose hire dates were comparable to those of men in exposed group. Total of 737 conceptions, which resulted in 637 live births and 100 stillbirths and spontaneous abortions, were identified as having paternal exposure; 2031 conceptions, resulting in 1785 live births and 246 stillbirths and spontaneous abortions, were identified as having no paternal exposure to any isomer of dioxin. Overall, no statistically significant association was found between any exposure and pregnancy outcome, either before or after stratification by pertinent sets of up to 9 covariables. [R38] *Human keratinocyte line SCC-13, derived from a squamous cell carcinoma of epidermis, was examined for effects on growth and differentiation upon treatment with TCDD. Inhibition of growth was maximal in concn range of 1-100 nM TCDD, but was completely antagonized by addition of hydrocortisone to growth medium. It is concluded that the responses of SCC-13 cells to TCDD depends upon hormonal conditions in culture and that this agent can interfere with cellular responses to normal physiological conditions, thereby altering the differentiating program ordinarily observed. [R39] *... AN INCR IN NUMBER OF PERSONS WITH PRIMARY LIVER CANCER /IS REPORTED/ IN PROPORTION TO ALL CANCER PATIENTS ADMITTED TO HANOI HOSPITALS DURING ... 1962-1968 (791 LIVER CANCER CASES OUT OF 7911 TOTAL CANCER CASES, 10%) AS COMPARED TO PERIOD OF 1955-1961 (159 LIVER CANCER CASES OUT OF 5492 CANCER CASES, 2.9%) WHICH WAS PRIOR TO THE START OF HERBICIDE SPRAYING. ... THIS INCREASE WAS ATTRIBUTED TO EXPOSURE AS A RESULT OF THE SPRAYING OF HERBICIDES CONTAINING TCDD IN SOUTH VIETNAM DURING THE 1960'S (... LIMITATIONS IN REPORTING OF STUDY MAKE IMPOSSIBLE AN ADEQUATE ASSESSMENT OF THE POSSIBLE RELATIONSHIP BETWEEN THE INCIDENCE OF LIVER CANCER AND HERBICIDE SPRAYING IN SOUTH VIETNAM). [R40] *In 1977 several patients were seen with soft tissue sarcomas and previous exposure to phenoxy acids. This clinical observation resulted in a case referent (case control) study being undertaken which showed that exposure to phenoxy acids or chlorophenols, which are chemically related, gave a roughly six fold increase in the risk for this type of tumor. A further case-referent study of soft tissue sarcomas has now been performed to confirm these earlier findings and also to obtain further information on the effects of different phenoxy acids. This new investigation gave an increase of the same magnitude in the risk for soft tissue sarcomas after exposure to phenoxy acids or chlorophenols, but this risk related also to exposure to phenoxy acids free from impurities, such as polychlorinated dibenzodioxins and dibenzofurans. [R41] *A number of men with malignant lymphoma of the histiocytic type and previous exposure to phenoxy acids or chlorophenols were observed and reported in 1979. A matched case-control study has therefore been performed with cases of malignant lymphoma (Hodgkin's disease and non-Hodgkin lymphoma). This study included 169 cases and 338 controls. The results indicate that exposure to phenoxy acids, chlorophenols, and organic solvents may be a causative factor in malignant lymphoma. Combined exposure of these chemicals seemed to increase the risk. [R42] *Chlorinated phenoxyacids were used in Finland since the middle of 1950's and they mainly constituted 2 to 1 mixtures of emulsified esters of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid dissolved in water. Analysis of some old herbicide formulations from the 1960's showed that they contained between 0.1 and 0.9 mg/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). About 500 almost exclusively male workers were involved every year with the spraying, and the annual season lasted from two to eight weeks. Many of the workers complained of irritation of the eyes, respiratory system and the skin as well as fatigue and headache during or after spraying. In a nationwide search for symptoms and signs attributable to phenoxyacids a few cases of possible chloracne emerged, and one case of mild form of chloracne was later diagnosed by a dermatologist. During recent years several epidemiological studies have shown or suggested an association between exposure to chlorinated phenoxyacids and cancer, notably soft-tissure sarcomas and lymphomas. The mortality experience of the Finnish herbicide applicators has recently been reported. This communication supplements previous information with data on cancer morbidity. [R43] *In the light of Swedish studies reporting an association between exposure to phenoxyherbicides or chlorophenols and soft tissue sarcoma, a case control study was undertaken that involved interviewing 82 subjects (cases) with soft tissue sarcoma and 92 controls with other types of cancer. For those potentially exposed to phenoxyherbicides for more than 1 day not in the 5 years before cancer registration, the estimate of relative risk was 1.3, with 90% confidence limits of 0.6-2.5. The comparable relative risk estimate for chlorophenol exposure was 1.5, with 90% confidence limits of 0.5-4.5. [R44] *The most commonly reported symptom related to TCDD exposure in man has been chloracne. The acneform lesions of the skin may develop a few weeks after the exposure and may persist for over a year following the cessation of exposure. Other skin problems which have been reported include hyperpigmentation, hirsutism, increased skin fragility, and vesicular eruptions on exposed areas of the skin. [R45] *INFORMATION CONCERNING EFFECTS OF HERBICIDES, AND ESPECIALLY SO-CALLED 'AGENT ORANGE' ... ON HUMANS IS GIVEN IN NATIONAL ACADEMY OF SCIENCES REPORT (COMMITTEE ON ADVERSE EFFECTS OF HERBICIDES IN VIETNAM, 1974). INTERVIEWS WITH MONTAGNARD PEOPLE PRODUCED REMARKABLY CONSISTENT REPORTS OF CHILD DEATHS, DIARRHEA, VOMITING, SKIN RASHES, FEVER AND ABDOMINAL PAIN FOLLOWING EXPOSURE AFTER 'SPRAY MISSIONS' WITH 'AGENT ORANGE'. [R46] *An evaluation of mortality among industrial employees accidentally exposed to TCDD was conducted. The cohort consisted of 247 workers who had been exposed to TCDD formed in an uncontrolled decomposition reaction at a Badische Soda Fabrick facility in Ludwigshafen, Federal Republic of Germany on March 17, 1953. The cohort was subdivided into three subcohorts: C1 with 69 subjects formed in 1954, C2 with 84 subjects formed in 1983, and C3 with 94 subjects formed in 1987. The vital status of the cohort on December 31, 1987 was determined. Standardized mortality ratios were computed using national mortality rates in the Federal Republic Germany as the reference. Seventy-eight subjects in the total cohort had died as of December 31, 1987. The standardized mortality ratios for all cancer in C1 was moderately, nonsignificantly elevated to 130. The standardized mortality ratio for all cancer in C2 was 238 during the first 20 years of follow-up. No standardized mortality ratios were significantly elevated in C3. When the mortality experience of 114 subjects who developed chloracne was examined, a nonsignificant increase in all cancer mortality for the entire 34 year period was observed (standardized mortality ratio 139). The standardized mortality ratio for all cancer for the chloracne group for the first 20 years of follow-up was 201, a statistically significant increase. This reflected excess mortality from lung cancer and colorectal cancer. In the entire cohort total mortality and all cancer mortality were not significantly elevated, standardized mortality ratios of 95 and 117, respectively. Problems with assessing the health risk of TCDD were discussed. It was concluded that the evaluation does not support a strong association between cancer mortality and TCDD in the BASF workers. [R47] *The effects of TCDD on human embryonic palatal shelves were studied in vitro and compared with results from previous studies on mouse and rat organ cultures. Palatal shelves aged 52, 53 or 54 gestational days were cultured for 4, 3 and 3 days, respectively, to achieve the fusion stage. Cultures were grown in the presence of dimethyl sulfoxide or 5x10(-11), 1x10(-8) or 1x10(-7) molar TCDD dissolved in dimethyl sulfoxide. Labeling with tritiated thymidine was done for 16 hr prior to culture termination. Tissues were evaluated by autoradiography, electron microscopy and immunohistochemistry. The lowest concentration of TCDD had little effect on palatal shelves, with one of four shelves demonstrating inhibition of normal medial cell degeneration. TCDD at 5x10(-8) M inhibited medial cell degeneration in all shelves, and rounded cells covered with short microvilli were observed on medial epithelia. At 1x10(-7) M TCDD, medial epithelia revealed disorganization and debris indicating cytotoxicity. Toxic changes were noted in other epithelia and in mesenchymal cells. Medial cell proliferation was observed with TCDD at two higher concentrations. Control cultures and those exposed to 5x10(-11) M TCDD did not reveal cell proliferation. Growth factor expression was unaffected by TCDD at 5x10(-11) M. At higher levels, medial epithelial growth factor was increased, and levels of transforming growth factor beta2 were decreased in nasal epithelium. Transforming growth factor alpha was decreased in all epithelia, and transforming growth factor beta2 was decreased in nasal epithelium after exposure to 1x10(-7) M TCDD. Although these changes were identical to those noted in rat and mouse shelves, mouse palates responded at lower concentrations. /Results indicate/ that TCDD alters human embryonic palatal shelf proliferation and differentiation similar to that noted in mice but at a decreased sensitivity level. [R48] *A retrospective cohort mortality study was conducted in a cohort of 5,172 chemical workers from 12 facilities located in the United States. Workers had histories of exposure to phenoxy herbicides and chlorophenols contaminated with TCDD. A review of process descriptions and job duties was used along with measurement of serum TCDD levels to document occupational exposure. In this cohort the mortality from several rare cancers previously associated with TCDD contamination was not notable. In a subcohort of 1,520 workers with more than one year of exposure and more than 20 years of latency, soft tissue sarcoma mortality was significantly elevated (standard mortality ratio 922). Respiratory system cancer was also significantly (elevated standard mortality ratio 142) in this subcohort. Mortality due to all cancers combined was significantly elevated both in the cohort (standard mortality ratio 115) and the subcohort (standard mortality ratio 146). Mortality due to all accidents was also significantly elevated in the cohort (standard mortality ratio 128). It was concluded that the excess cancer mortality, especially in the subcohort, is consistent with TCDD being a carcinogen. [R49] *THREE SCIENTISTS WERE POISONED /DURING/ ... PREPN OF TCDD BY HEATING POTASSIUM TRICHLOROPHENATE. TWO ... DEVELOPED TYPICAL CHLORACNE 6 and 8 WK AFTER EXPOSURE ... DELAYED SYMPTOMS, MOST LIKELY DUE TO TCDD, DEVELOPED ABOUT 2 YR /LATER IN 2 SCIENTISTS/; THESE ... INCL PERSONALITY CHANGES, MAINLY LOSS OF ENERGY AND DRIVE, IMPAIRMENTS OF VISION, TASTE AND MUSCULAR COORDINATION, SLEEP DISTURBANCES, GI SYMPTOMS AND HIRSUTISM. HYPERCHOLESTEROLEMIA (IN EXCESS OF 300 MG/100 ML) OCCURRED IN ALL 3 PATIENTS. [R50] *In 1979, rice oil accidentally contaminated with a mixture of polychlorinated dibenzofuran and polychlorinated biphenyls was ingested by a large number of individuals in Taiwan. Placentas obtained from women four years after the exposure had occurred contained several polychlorinated biphenyls congeners known to be present in the rice oil as well as two toxic polychlorinated dibenzofurans congeners: 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran. Placentas from exposed women who had markedly elevated activities of two cytochrome Pl-450 dependent enzymes, arylhydrocarbon hydroxylase and ethoxyresorufin O-deethylase. The average magnitude of enzyme induction was 100-fold, but much interindividual variation was evident. Binding properties of epidermal growth factor to its receptor were not altered by polychlorinated biphenyls-polychlorinated dibenzofuran exposure. However, epidermal growth factor stimulated autophosphorylation of the epidermal growth factor receptor was decreased significantly in placentas from exposed women and this effect was strongly correlated with decreased birth weight. Species comparisons of effects on epidermal growth factor receptor actions and cytochrome p450 isoenzymes, coupled with data on tissue concentrations of polychlorinated dibenzofurans, suggest that humans are more sensitive than rats to some of the biochemical effects of polychlorinated dibenzofurans and TCDD. [R51] *... Conducted a follow-up study of 74 individuals who had been exposed to TCDD 27 years earlier during an accident in a plant producing trichlorophenol. Of the 21 deceased individuals, 7 had cancer, compared with 4.1 expected. Three deaths due to stomach cancer were found, compared with 0.6 expected from regional mortality data. [R15, 1238] *Accidental exposures indicate that TCDD has low toxicity for man as compared with that for certain species (e.g., guinea pig). [R52] *Serum samples from exposed persons in Seveso, Italy, have shown that all children who had serum 2,3,7,8-TCDD levels greater than 11,000 parts per trillion based on lipid content developed chloracne. A 16 year old girl with serum levels of 800 parts per trillion developed chloracne, whereas a 15 year old boy with levels of 10,400 parts per trillion did not. Chloracne was not seen in adults who had serum levels in the range of 1770-9140 parts per trillion. [R34, 757] *Epidemiologic studies have shown an increase, associated with 2,3,7,8-TCDD exposure, in several liver enzymes, but these increases did not exceed what are considered normal values for these enzymes, and they disappeared over several years. [R34, 757] *Other less consistently reported effects from dioxin exposure in humans include /asthenia/, headaches, and pain in the extremities, peripheral neuropathy, ulcers, altered liver function, enzyme induction, altered lipid metabolism, and abnormal urinary porphyrin patterns. Immune system dysfunction and altered T-cell subsets have been reported by some investigators but have not been found by others. /Polychlorodibenzodioxins/ [R34, 757] *All members of a Spanish family (father, mother and six children) developed chloracne. The causative agent was found to be the family's stock of olive oil, which had become contaminated with polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, pentachlorophenol, and hexachlorobenzene. The more highly chlorinated polychlorinated dibenzo-p-dioxins, in particular octachlorodibenzo-p-dioxin, were the predominant congeners in the oil. Three members of the family exhibited either an overt or a sub-clinical disturbance of kidney function. The father also had a chronic respiratory problem. These changes could not be unequivocally attributed to the polychlorinated dibenzo-p-dioxins. Experimental toxicity of the oil was limited to the development of hepatic porphyria in mice. A serum sample taken after the consumption of the oil ceased, contained high levels of the polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans. Extrapolation back to ingested dose was used to validate dosage estimates. The use of toxicity equivalence factors provided estimates of cumulative dosage to produce chloracne as 0.13-0.31 ug 2,3,7,8-tetrachlorodibenzodioxin/kg (using EPA toxicity equivalence factors) or 6.7-16 ug 2,3,7,8-tetrachlorodibenzodioxin/kg (using Nordic/NATO toxicity equivalence factors). This is the first incident in which human toxicity is related primarily to ingestion of polychlorinated dibenzo-p-dioxins and for which estimates of dosage can be made. [R53] NTOX: *HEPATIC CELL NECROSIS PRODUCED BY TCDD IS PROBABLE CAUSE OF DEATH IN RATS, WHILE HEPATIC NECROSIS AND LIVER INSUFFICIENCY ARE MINIMAL IN MICE AND GUINEA PIGS. IN RATS, GUINEA PIGS AND MICE, CHANGES IN WT OF THYMUS APPEARED TO BE MOST SENSITIVE INDICATOR OF TCDD EXPOSURE ... IP INJECTION OF 400 UG/KG BODY WT TCDD IN MONKEYS RESULTED IN HIGH CONCN IN SKIN AND PRODUCED ALOPECIA AND ACNE. [R54] *MOST SIGNIFICANT FINDINGS IN BOTH MICE AND GUINEA PIGS TREATED WITH SUBLETHAL DOSES OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN WERE IN LYMPHOID SYSTEM, RESULTING IN SUPPRESSION OF CELL-MEDIATED IMMUNITY. [R55] *During manufacture of 2,4,5-trichlorophenoxyacetic acid a number of dioxins are formed, the most prevalent of which is TCDD. The concn of TCDD in different batches of Agent Orange varied greatly but averaged about 2 ppm of 2,4,5-T. The LD50 ranges from 0.001 to 0.3 mg/kg after oral admin to various animals. Mutagenicity studies ... gave both positive and negative studies in test systems. [R56] *TCDD was admin to female rats by gavage for 2 consecutive wk at daily doses of 0, 0.125, 0.5 and 2 ug/kg. After treatment females were caged with untreated males. All dams were killed on day 21 of gestation. Their reproductive statuses were recorded and live fetuses were examined for external, visceral, and skeletal malformations. At 2 ug/kg reduction of both maternal wt gain and ovulation rate, incr of pre- and postimplantation loss, and fetal growth retardation were observed. Also, malformed fetuses were observed at this level. /No information on controls is given in the abstract/. [R57] *2,3,7,8-Tetrachlorodibenzo-p-dioxin was given orally to pregnant New Zealand white rabbits on 6-15 day of gestation, in dosages of 0 (control), 0.1, 0.25, 0.5 and 1 ug/kg/day. Severe maternal toxicity and embryotoxicity were evident at 0.25 ug/kg/day dose and higher. Kidney anomalies were observed in treated groups. [R58] *TETRACHLORODIBENZO-P-DIOXIN (TCDD) INCR REVERSION FREQUENCY TO STREPTOMYCIN INDEPENDENCE IN ESCHERICHIA COLI SD-4 AT ... 2 UG/ML. IN SALMONELLA TYPHIMURIUM, FRAMESHIFT MUTATIONS IN STRAIN TA1532, BUT NOT BASE SUBSTITUTIONS IN STRAIN TA1530, WERE INDUCED BY TOXIC CONCENTRATIONS OF TCDD. ... INHIBITION OF MITOSIS AND CHROMOSOMAL ABNORMALITIES WERE OBSERVED IN ENDOSPERM CELLS OF HEMANTHUS KATHERINAE BAKER TREATED WITH 0.2 OR 1.0 UG/L TCDD IN THE PRESENCE OR ABSENCE OF 2,4,5-T. NO CHROMOSOMAL ABERRATIONS WERE OBSERVED IN BONE MARROW CELLS OF MALE RATS TREATED WITH TCDD BY IP INJECTION (5, 10 and 15 UG/KG BODY WT) OR ORALLY (SINGLE DOSE OF 20 UG/KG BODY WT OR 5 CONSECUTIVE DAILY 10 UG/KG BODY WT DOSES). HOWEVER, WHEN RATS OF BOTH SEXES WERE TREATED TWICE WEEKLY WITH TCDD (4 UG/KG OF BODY WT) FOR 13 WEEKS, SIGNIFICANT INCREASE IN NUMBER OF CHROMOSOME ABERRATIONS WAS FOUND. TCDD DID NOT INDUCE DOMINANT LETHAL MUTATIONS IN WISTAR RATS AFTER ORAL ADMIN TO MALES AT DOSES OF 4, 8 OR 12 UG/KG BODY WT/DAY FOR 7 DAYS. [R59] *... AMONG 6 GROUPS OF 10 MALE SPRAGUE-DAWLEY RATS ADMIN 5, 1, 0.5, 0.05, 0.005 OR 0.001 UG TCDD/KG OF DIET FOR 65 WK, 12 ... HAD DIED: 5 and 4 DIED IN THE 2 HIGHER DOSE GROUPS, RESPECTIVELY, and 1 IN 0.5 UG/KG GROUP AND 2 IN 0.005 UG/KG GROUP. DEATH OF 3 RATS ... RECEIVING 5 UG/KG WAS ATTRIBUTED TO APLASTIC ANEMIA; 2 CARCINOMAS OF KIDNEY, 2 CARCINOMAS OF LIVER, 1 CARCINOMA OF SKIN AND 1 ANGIOSARCOMA WERE OBSERVED IN 6 OF 9 REMAINING ... IN RATS THAT WERE STILL ALIVE AT TIME OF REPORTING, 2 ADDNL NEOPLASMS (1 BILE-DUCT CARCINOMA AND 1 ANGIOSARCOMA) WERE DETECTED ... . /NO INFORMATION ON THE CONTROL GROUP IS GIVEN/ [R60] *TREATMENT OF RATS WITH 4X20 UG/KG OF TCDD LED TO 2-3 FOLD INCR IN LIVER MICROSOMAL CYTOCHROME P450 LEVELS CONCOMITANTLY WITH CHANGES IN LIVER MICROSOMAL METAB OF 4-ANDROSTENE-3,17-DIONE, 5ALPHA-ANDROSTANE-3ALPHA, 17BETA-DIOL AND 4-PREGNENE-3,20-DIONE. CHANGES WERE MOST PRONOUNCED IN FEMALE RATS WHERE SOME HYDROXYLASE ACTIVITIES INCREASED 3-5 FOLD. OBSERVED EFFECTS MAY BE RELATED TO ENDOCRINE SYMPTOMS SOMETIMES SEEN AFTER TCDD EXPOSURE. [R61] *FEMALE WISTAR RATS TREATED ORALLY WITH SINGLE DOSE (100 UG/KG) OF TCDD SHOWED BIPHASIC DECLINE IN BODY WT WITH CESSATION OF FOOD AND WATER CONSUMPTION AND URINE PRODUCTION. [R62] *THREE-GENERATION REPRODUCTION STUDY OF RATS WERE GIVEN TCDD IN DIET TO EVALUATE THE EFFECTS OF CHRONIC, LOW LEVEL INGESTION. SPRAGUE-DAWLEY RATS WERE MAINTAINED CONTINUOUSLY ON DIETS PROVIDING DOSE LEVELS OF 0, 0.001, 0.01 OR 0.1 UG TCDD/KG/DAY. AT 0.01 UG TCDD/KG/DAY DECR IN LITTER SIZE, GESTATIONAL AND NEONATAL SURVIVAL AND GROWTH WERE OBSERVED. REPRODUCTIVE CAPACITY OF SPRAGUE-DAWLEY RATS INGESTING TCDD WAS AFFECTED AT DOSE LEVELS OF 0.01 and 0.1 UG TCDD/KG/DAY THROUGH 3 SUCCESSIVE GENERATIONS. SIGNIFICANT DECREASES IN FERTILITY AND NEONATAL SURVIVAL WERE OBSERVED IN F0 GENERATION OF 0.1 UG/DAY GROUP. AT 0.01 UG/DAY FERTILITY WAS SIGNIFICANTLY DECREASED IN F1 AND F2 BUT NOT F0 GENERATIONS. AMONG RATS RECEIVING 0.001 UG TCDD/KG/DAY, NO EFFECT ON FERTILITY, LITTER SIZE AT BIRTH, OR POSTNATAL BODY WT WAS OBSERVED IN ANY GENERATION. [R63] *TCDD produced dose related increase in abnormalities in heart and aortic arches in chick embryos at 0.16 to 31 nmol/egg. [R64] *Tetrachlorodibenzo-p-dioxin at 0.1 mg/l retards development of pike (Esox lucius). [R65] *TCDD was evaluated for its effects on in vitro induction of sister chromatid exchange by alpha-naphthoflavone in Sprague-Dawley rats. Female rats, 9-11 wks old, were given a single oral dose of TCDD at concentrations ranging from 0.3-30 ug/kg in 0.2 ml of corn oil. Blood was withdrawn by cardiac puncture 5 or 6 days post-treatment and cells cultured for 72 hours. A 10 ul aliquot of 20 mM alpha-naphthoflavone in dimethyl sulfoxide was added to appropriate cultures at the beginning of the culture period. No effect on baseline sister chromatid exchange frequency (cultures without alpha-naphthoflavone) was detected in rats exposed to 0-30 ug TCDD/kg, while cultures incubated in the presence of alpha-naphthoflavone had significantly higher sister chromatid exchange frequencies. The potentiating effect of TCDD on sister chromatid exchange induction by alpha-naphthoflavone was dose-dependent between 0 and 3 mg TCDD/kg treatments and plateaued at higher dose levels. TCDD effects on rat liver aryl hydrocarbon hydroxylase activity were dose dependent. The dose response pattern for aryl hydrocarbon hydroxylase activity was similar to that for alpha-naphthoflavone mediated increases in sister chromatid exchange frequency. [R66] *The studies of ... epidermal keratinocytes derived from genotypically segregated newborn haired and hairless HRS/J mice to TCDD exposure in in vitro cultures /were compared/. ... Results suggested that the sensitivity of HRS/J haired and hairless mouse epidermal keratinocyte cultures to TCDD exposure in vitro was very similar. In each type of cell culture, cell proliferation, epidermal transglutaminase activity, cell envelope formation, and keratin staining with Rhodanile blue were stimulated by TCDD exposure in a similar dose-dependent manner. ... Physiologic factors beyond the epidermal cells may be involved in expression of the different responses seen in the skin of mice to TCDD in vivo. [R67] *2,3,7,8-Tetrachlorodibenzo-p-dioxin was given orally to pregnant rats on days 6-15 of gestation, at levels of 0 control, 0.03, 0.125, 0.5, 2.0 and 8.0 ug/kg/day. No adverse effect on the fetuses was noted at the 0.03-ug/kg level, but in the groups given doses of 0.125-2.0 ug/kg, fetal mortality, early and late resorptions and fetal intestinal hemorrhage were observed, with the incidence increasing as the dose increased. There was no evidence of maternal toxicity at 0.03 and 0.125 ug/kg/day, but at 0.5 and 2.0 ug/kg/day there was a decrease in maternal weight gain. Severe maternal toxicity and embryotoxicity were evident at the 8.0 ug/kg/day dose, maternal weight loss and early resorptions occurring in all cases. The results suggest that teratogenic effects attributed earlier to 2,4,5-trichlorophenoxyacetic acid may have been due to 2,3,7,8-tetrachlorodibenzo-p-dioxin, which was present as a contaminant at a level of about 30 ppm in the sample of the herbicide tested. [R68] *The effect of TCDD on the developing embryo and fetus of CF-1 mice has been evaluated. Pregnant CF-1 mice were given TCDD by oral gavage on days 6 through 15 of gestation at dosages of 0, 0.001, 0.01, 0.1, 1, and 3 ug/kg/day. Little or no maternal toxicity was observed at any dosage. Cleft palate and dilated renal pelvis were found at 3.0 ug/kg/day. Cleft palate was found at 1.0 ug/kg/day. No malformations were found at the intermediate dosages of 0.1 or 0.001 ug/kg/day. Teratogenic effects observed, ie, cleft palate and dilated renal pelvis, were comparable to those seen in studies utilizing other strains of mice. The incidence of malformations was not statistically significant at the 0.1 ug/kg/day dosage and below. The experimental non-teratogenic dosage for TCDD in the developing embryo and fetus of CF-1 mice was estimated to be 0.1 ug/kg/day. [R69] *The teratogenic potential of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and TCDD was studied in mice and rats. CD-1-Mice, DBA/2J-mice, and CD-rats were administered technical or analytical grade 2,4,5-trichlorophenoxyacetic acid and TCDD alone or in combination on days 6 through 15 of gestation. Doses ranged up to 150 mg/kg. ... Technical grade 2,4,5-trichlorophenoxyacetic acid at a dose of 150 mg/kg significantly increased fetal mortality in CD-1-mice. Fetal viability in the other mouse strains was not affected by 2,4,5-trichlorophenoxyacetic acid. In rats, 80 mg/kg 2,4,5-trichlorophenoxyacetic acid significantly increased fetal mortality. TCDD did not increase fetal mortality in any animals. Technical grade 2,4,5-trichlorophenoxyacetic acid caused reductions in maternal weight gain in C57B1/6J mice and rats only. 2,4,5-Trichlorophenoxyacetic acid induced significant increases in relative liver weights of all mice strains. TCDD significantly increased maternal relative liver weight only in C57B1/6J mice and DBA/2J-mice. TCDD and 2,4,5-trichlorophenoxyacetic acid induced cleft palates and kidney malformations in all mouse fetuses. 2,4,5-Trichlorophenoxyacetic acid was not teratogenic in rats. TCDD produced kidney malformations in fetal rats. No potentiation of fetal effects occurred when TCDD and 2,4,5-trichlorophenoxyacetic acid were given together. ... [R70] *The potency of TCDD to produce chloracne in the rabbit ear was tested. Threshold levels for the induction of lesions were between 1 ug for the pure compound and 160 ug when the compound was adsorbed onto charcoal. [R71] *Guppies that survived exposure to 0.1 or 10 ug/l tetrachlorodibenzo-p-dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, a highly toxic impurity in the herbicide, 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) for 10 days, showed necrosis of maxillary cartilage and fins. [R72] *In order to test the potential of TCDD as a promoter of hepatocarcinogenesis, rats which had received a single 10 mg/kg dose of diethylnitrosamine following partial hepatectomy were given TCDD (0.14 and 1.4 ug/kg sc once every 2 weeks) for 7 months. Animals which received (a) only a single initiating dose of diethylnitrosamine after partial hepatectomy and no further treatment or (b) TCDD alone with no initiating dose of diethylnitrosamine exhibited relatively few enzyme altered foci and no hepatocellular carcinomas. However, animals initiated with diethylnitrosamine and then given TCDD had a marked increase in enzyme altered foci. At the higher dose of TCDD, hepatocellular carcinomas were present in five of seven rats. By means of three different enzyme markers used to evaluate the phenotypes of the enzyme altered foci, a distinct phenotype heterogeneity of the foci was noted with a shift towards phenotypes exhibiting a greater deviation from normal liver when TCDD was given following diethylnitrosamine partial hepatectomy. Quantitation of the numbers of enzyme altered foci was performed by relating measurements made from two dimensional tissue sections to the numbers of foci per unit volume of liver using relationships established in the field of stereology. The total volume of the liver occupied by the enzyme altered foci, but not their number, increased with the dose of TCDD administered following diethylnitrosamine plus partial hepatectomy. [R73] *Rats were maintained for 2 years on diets supplying 0.1, 0.01 and 0.001 ug TCDD/kg/day, equivalent to 2200, 210 and 22 parts per trillion of TCDD. Ingestion of 0.1 ug/kg/day caused multiple indications of toxicity, including decreased weight gain, increased mortality, slightly decreased erythroid parameters, increased urinary excretion of porphyrins and delta-aminolevulinic acid and abnormal liver function tests. Gross and histopathologic changes were noted in their hepatic, lymphoid, respiratory and vascular tissues. This high dose level caused an increased incidence of hepatocellular carcinomas and squamous cell carcinomas of the lung, hard palate/nasal turbinates or tongue, whereas a reduced incidence of tumors was noted in the pituitary, uterus, mammary gland, pancreas and adrenal. Terminal liver and fat samples from these rats given diets containing 2200 parts per trillion of TCDD contained 24,000 and 8100 parts per trillion of TCDD, respectively. Rats maintained on diets containing 0.01 ug/kg/day (210 parts per trillion ) had a lesser degree of toxicity, limited primarily to increased urinary excretion of porphyrin plus liver and lung lesions. Terminal liver and fat samples contained 5100 and 1700 parts per trillion TCDD, respectively. Ingestion of 0.001 ug/kg/day (22 parts per trillion in the diet) caused no effects considered to be of any toxicologic significance. Terminal liver and fat samples each contained 540 parts per trillion of TCDD. [R74] *... 2,3,7,8-Tetrachlorodibenzo-p-dioxin has been reported to be mutagenic in the yeast Saccharomyces cerevisiae in both in vitro assay with S-9 and the host mediated assay. [R75] *The cmpd TCDD causes hepatocellular damage and porphyria in C57B1/6J mice, among a wide range of toxic effects. ... The effect of TCDD toxicity in iron deficient mice with that in mice receiving a normal diet /were compared/. Porphyria did not develop in the iron deficient animals, and these animals were also protected from hepatocellular damage and certain other toxic effects of TCDD. [R76] *State of the art quantitative risk assessment techniques, including consideration of new time to response data, have been applied to chronic animal bioassay data on the dietary intake of 2,3,7,8-tetrachlorodibenzo-p-dioxin. The nonlinear shapes of the dose response relation for the hepatocellular carcinogenic responses have been estimated. The estimated virtually safe dose for an increase of 1 in a million in the probability of hepatocellular neoplastic nodule and/or carcinoma in a female rat is 0.1 ng/kg/day in the diet. The estimated mean free dose, corresponding to a reduction in the expected amt of time without hepatocellular neoplastic nodule and/or carcinoma proportional to 1 week in 70 yr, is in the range 1-5 ng/kg/day in the diet of a female rat. No species to species extrapolations nor human exposure assessments have been made. [R77] *TCDD has been recognized as a kidney teratogen. This study examines C57BL/6N fetal mouse kidneys from day 14 of gestation through day 17. Pregnant females received a single dose of 0 or 12 ug TCDD/kg by gavage on day 10 of pregnancy. Fetal urinary systems were examined on days 14, 15, 16 (am), 16 (pm), and 17 (pm). The patency of the ureteric lumen was examined by injection of dye into the bladder. TCDD treatment did not delay or prevent breakdown of the ureteric membrane between days 15 and 16. On days 16 through 17, the ureteric lumina of TCDD exposed fetuses were narrow and tortuous when compared to the control lumens. Sections of ureter were observed by light microscopy. On day 15 the lumina of TCDD exposed ureters were occluded by epithelial cells. As a result of hyperplasia of the ureteric luminal epithelium, hydroureter and hydronephrosis became pronounced by day 17. [R78] *Frequencies of sister chromatid exchanges and chromosomal aberrations were examined in peripheral lymphocytes of Rhesus monkeys which had been fed a diet containing 25 parts per trillion 2,3,7,8-tetrachlorodibenzo-p-dioxin for a period of 4 years. When compared to non-exposed control animals, no significant differences were noted for either of these cytogenic endpoints. In addition, there was not a significant difference in sister chromatid exchange response to a challenge dose of mitomycin C in cells from 2,3,7,8-TCDD exposed animals, compared to controls. [R79] *TCDD dissolved in corn oil was administered intragastrically to two groups of 6 to 8 female Sprague-Dawley rats at doses of 0, 40, or 400 ug/kg/day for 3 days each. The animals were killed 6 days after treatment. Relative to controls, the 40 ug/kg dose produced a 4.4-fold increase in hepatic lipid peroxidation and a 4.2-fold increase in aryl hydrocarbon hydroxylase (AHH) activity. This dose also produced a 64% inhibition of glutathione peroxidase (GSH-PX) activity. It also reduced thymus weight by about 80% and caused a 20% loss of body weight. In the kidneys, 400 ug/kg/day of TCDD did not produce lipid peroxidation nor alter glutathione peroxidase activity relative to the contol group. There were no changes in kidney weight. [R80] *2,3,7,8-Tetrachlorodibenzo-p-dioxin tumor incidence is increased by TCDD in female Sprague-Dawley rats but not male rats in chronic carcinogen bioassays. /New/ studies have investigated this finding by evaluating histological and biochemical parameters in a two-stage model for hepatocarcinogenesis in female Sprague-Dawley rats (intact and ovariectomized), using diethylnitrosamine as the initiating agent and TCDD as the promoting agent. Increases in gamma-glutamyl transpeptidase-positive foci were greater in intact female rats than in ovariectomized animals. For example, in intact rats receiving both diethylnitrosamine and TCDD, the percentage of liver occupied by gamma-glutamyl transpeptidase-positive foci was 0.37, compared to 0.08 in ovariectomized rats. Values for intact or ovariectomized rats receiving either diethylnitrosamine or TCDD only were 0.04 or less. Similar results were obtained when using placental glutathione-S-transferase to detect hepatic ... /preneoplatic/ lesions. Cell proliferation data, obtained using bromodeoxyuridine in osmotric minipumps, were consistent with preneoplastic foci data in that the hepatocyte labeling index was increased in diethylnitrosamine/TCDD intact rats but not in diethylnitrosamine/TCDD ovariectomized rats. Analysis of data from individual animals revealed a strong correlation (p < 0.01) between cell proliferation and placental glutathione-S-transferase-positive foci/cu m in liver. These findings did not reflect effects of ovariectomy on TCDD tissue distribution, since livers of ovariectomized rats contained more TCDD than livers of intact rats, although both groups of rats received a dose of 1.4 ug TCDD/kg once every 2 weeks for 30 weeks. Hepatic cytochrome p450d (IA2) was induced approximately 6 to 8-fold in all TCDD-treated groups, and the magnitude of induction was not influenced by ovariectomy. This cytochrome efficiently catalyzes metabolism of 17beta-estradiol to catechol estrogens. Data suggest that ovarian hormones (probably estrogens) play a significant role in the hepatocarcinogenic actions of TCDD. [R81] *Treatment of wild-type Hepa 1c1c7 cells with 1 nM (3)H-17 beta-estradiol resulted in the rapid accumulation of the nuclear estrogen receptor complex whose levels were maximized within 1 hr. Cotreatment of the cells with 10 nM TCDD and (3)H-17 beta-estradiol did not affect the nuclear estrogen receptor levels 1 hr after addition of the radioligand; however, pretreatment of the cells for 1, 6, 24 or 42 hr with 10 nM TCDD prior to the addition of the radiolabeled hormone caused a greater than 50% decrease in nuclear estrogen receptor levels (determined by velocity sedimentation analysis) 1 hr after the addition of (3)H-17 beta-estradiol. In parallel experiments in which 10 nM TCDD was added 6 hr prior to the radiolabeled hormone, TCDD caused a 63% and 74% decrease in immunodetectable cytosolic and nuclear estrogen receptor protein levels, respectively, in the wild-type Hepa 1c1c7 cells. The nuclear estrogen receptor was also detected in two Hepa 1c1c7 mutant (class 1 and class 2) cell lines which have been characterized previously as TCDD non-responsive due to either decreased aryl hydrocarbon receptor levels or a defect in the accumulation of transcriptionally active nuclear aryl hydrocarbon receptor complexes, respectively. Treatment of these mutant cell lines with TCDD and (3)H-17 beta-estradiol caused only a minimum (class 1) or non-detectable (class 2) decrease in nuclear estrogen receptor binding activity or immunodetectable protein levels. These results, coupled with the structure-dependent differences in the activities of TCDD (a strong aryl hydrocarbon receptor agonist) and 2,8-dichlorodibenzo-p-dioxin (a weak aryl hydrocarbon receptor agonist) in this assay system, support a role for the aryl hydrocarbon receptor in the TCDD-mediated decrease of the nuclear estrogen receptor in mouse Hepa 1c1c7 cells. In addition, actinomycin D and cycloheximide both inhibited the TCDD mediated decrease of nuclear estrogen receptor levels in the Hepa 1c1c7 wild-type cells, and these results suggest that TCDD may induce specific gene products which are involved in this process. [R82] *TCDD and retinoic acid are both teratogenic in mice. TCDD is a highly toxic, stable environmental contaminant, while retinoic acid is a naturally occurring form of vitamin A. Exposure to TCDD induces hydronephrosis and cleft palate, and exposure to retinoic acid induces limb defects and cleft palate. Teratology studies previously have shown that the incidence of clefting is higher after exposure to retinoic acid + TCDD than would be observed for the same doses of either compound given alone. This study examines the cellular effects which result in cleft palate, after po administration on gestation day 10 or 12 of retinoic acid + TCDD in corn oil (10 ml/kg total volume). Exposure on gestation day 10 to 6 ug TCDD + 40 mg retinoic acid/kg inhibited early growth of the shelves and clefting was due to a failure of shelves to meet and fuse. This effect on mesenchyme was observed in previous studies to occur after exposure on gestation day 10 to 40 mg/kg retinoic acid alone but not after TCDD alone. After exposure on gestation day 12 to 6 ug TCDD + 80 mg retinoic acid/kg, clefting was due to a failure of shelves to fuse after making contact, because the medial cells differentiated into an oral-like epithelium. This response was observed in previous studies to occur after exposure to TCDD alone, but retinoic acid alone on gestation day 12 resulted in differentiation toward nasal-like cells. The interaction between TCDD and retinoic acid results in retinoic acid-like clefting after exposure on gestation day 10 and TCDD-like clefting after exposure on gestation day 12, and this clefting occurs at higher incidences than would occur after the same levels of either agent alone. After exposure on either gestation day 10 or 12 to retinoic acid + TCDD, the programmed cell death of the medial cells does not occur, and these cells continue to express EGF receptors and to bind 125I-EGF. The effects of retinoic acid and TCDD may involve modulation of the cells responses to embryonic growth and differentiation factors. [R83] *TCDD is a potent cleft palate inducing teratogen in mice. /Studies have investigated/ factors which modify teratogenicity of TCDD in mice. In a series of experiments using JC1-ICR mice, in which exencephaly occurs spontaneously at a low rate, /it was found/ in a litter treated with TCDD at 40 ug/kg at day 12.5 of gestation (VP-day 0) that an exencephalic fetus had a closed palate whereas the remaining non-exencephalic litter mates had cleft palates. This experience prompted /a study to/ examine whether exencephalic fetuses are really resistant to the cleft palate inducing action of TCDD or not. Pregnant JC1:ICR mice were pre-treated with cadmium chloride once at 6 mg/kg at day 7.5 (group A) ip or at 2 mg/kg three times at days 7.5, 8.5, and 9.5 (group B) ip to induce exencephaly in embryos. Then the dams were treated with TCDD at 40 ug/kg at day 12.5 by gavage and fetuses were examined for malformations at day 18.5. In group A, 75% of live fetuses had exencephaly. None of the exencephalic fetuses had cleft palate, whereas all the fetuses without exencephaly had cleft palate. In group B, 29% of live fetuses had exencephaly without any case of cleft palate, whereas 84% of non-exencephalic fetuses had cleft palate. Thus resistance of exencephalic fetuses to the cleft palate inducing action of TCDD was demonstrated in mice. [R84] NTOX: *The interactions of TCDD with hormones and hormone receptors have important implications for TCDD toxicity. Evidence suggests that TCDD modulates receptors for glucocorticoids, prolactin, thyroxine, low density lipids, epidermal growth factor, and estrogens. Estrogen receptor modulation and the animal's physiological responses to this modulation appear to be particularly important effects and can explain much of the toxicity observed in TCDD-treated animals. Susceptibility of different species to TCDD correlates with their steroid glucuronidation capicity. Because of the close interactions and interdependent regulation of hormonal systems, other hormones may have a similar role in TCDD toxicity. [R85] *Prenatal exposure of experimental animals to the environmental contaminant TCDD leads to thymic atrophy and a suppression of cell-mediated immunity that is more severe and persistent than that caused by adult exposure, suggesting that events involved in the maturation of the immune system are particularly sensitive to TCDD. We report here that perinatal TCDD exposure produces an alteration in the lymphocyte stem cell population in the fetus and neonate, as evidenced by a significant reduction in the lymphocyte stem cell-specific enzyme terminal deoxynucleotidyl transferase. After maternal treatment with a single dose of TCDD (10 ug/kg of body weight) on gestational day 14, terminal deoxynucleotidyl transferase biosynthesis and specific mRNA were reduced more than 50% in fetal liver lymphoid cells on gestation day 18. An even more extensive reduction was seen in neonatal bone marrow through postnatal day 18. In contrast, thymic terminal deoxynucleotidyl transferase synthesis appeared to be relatively unaffected on a per cell basis by perinatal TCDD exposure, although the actual number of terminal deoxynucleotidyl transferase-synthesizing thymocytes was diminished due to extensive thymic atrophy. Those effects occurred at concentrations of 1-31 femtogram of TCDD/mg of thymus. Flow cytometric analysis of thymocyte surface marker expression revealed a slight decrease in the percentage of Lyt-2+L3T4+ thymocytes on gestation day 18 and postnatal day 4. This alteration was no longer apparent by postnatal day 11, when marrow terminal deoxynucleotidyl transferase biosynthsis was most suppressed. These results suggest that TCDD-induced thymic atrophy during the perinatal period may be due, in part, to an effect on the prothymocyte. [R86] *TCDD is an extremely toxic chemical pollutant which bioaccumulates in maternal adipose tissue, and is transferred to the developing organism during gestation and lactation. Long-term cognitive deficits have been reported following perinatal exposure to polychlorinated biphenyls, which are structurally and toxicologically similar to TCDD. In the current study, monkeys exposed to TCDD perinatally were later tested in two cognitive paradigms, discrimination-reversal learning and delayed spatial alteration. Discrimination-reversal learning detected effects; whereas delayed spatial alternations, as analyzed, did not. Discrimination-reversal learning consisted of a series of simple spatial reversals, followed by spatial reversals with color and shape as irrelevant cues, then by color reversals and finally by shape reversals. TCDD-exposed monkeys exhibited retarded learning of the shape reversals. The deficit was most pronounced on the first reversal following overtraining. There were no group differences on the spatial or color reversals. However, the number of trials the TCDD-exposed monkeys individually took to learn the spatial reversals was positively correlated with TCDD concentration in body fat. Conversely, the number of trials they took to learn the color reversals was negatively correlated with TCDD in body fat. [R87] *Exposure of neonatal rats to TCDD during the lactation period was studied. Dams, directly exposed to TCDD, and neonates, exposed to TCDD via the milk, showed drastic changes in liver vitamin A content and strong enzyme induction. Neonates seemed to be more sensitive to low level exposure of TCDD, compared to the dams. [R88] *Behavioral effects that were detected in TCDD-exposed monkey offspring included alterations in the social behavior of the mother-infant dyad and of peer groups of the offspring after weaning. Performance on learning tasks was correlated with TCDD concentration in body fat. [R89] *TCDD, an extremely potent mouse teratogen, causes malformations in the kidney and hard palate. TCDD is stored in adipose tissue and mobilized during lactation. The objective of this study was to compare in utero and lactational exposure on the induction and persistence of hydronephrosis. Pregnant C57BL/6N mice were treated po with a single dose of 0, 3, or 12 ug TCDD/kg on gestation day 6. All dams were allowed to litter and each litter was culled to a standard size of 6. Litters were reciprocally cross-fostered on the day of birth, postnatal day 0, resulting in four experimental groups: pups not exposed by either route, pups exposed only in utero, pups exposed only lactationally, and pups exposed by both routes. Pups were sacrificed at weaning (postnatal day 25) and puberty (postnatal day 67). Neither sex nor postnatal day of sacrifice had any significant effect on incidence or severity of hydronephrosis, both of which were greatest for pups receiving dual exposure. Hydronephrotic incidence and severity was essentially the same for gestational vs lactational exposure. Severity of the renal lesion was always greater in the right kidney than in the left. In summary, lactational exposure can both induce or exacerbate exisiting hydronephrosis. The renal lesion appears to persist from weaning through puberty. However, preliminary data suggests that reversal may occur to some extent between gestation day 18 and postnatal day 25. [R90] */It was/ hypothesized that changes in expression of fetal lymphocyte surface antigens after in utero exposure to immunotoxic compounds might be a predictor of impaired immune function observed in neonates. To test this hypothesis TCDD was injected daily sc (0 or 2 ug/kg body weight in corn oil) into C57B1/6N dams from gestational day 6-14. Thymocytes were evaluated from the fetuses on gestation day 17, 18, and 19, postnatally in 4, 5 and 7 week old pups. Fluorescence activated cell sorting was used to quantitate the number of lymphocytes expressing various surface antigens. The total number of fetal thymic cells decreased significantly and the CD8+, suppressor/cytotoxic T cell population increased significantly. These changes returned to normal levels postnatally. Pups from the same F1 population were then tested for selected immune functions at 7, 8, or 10 weeks of age. The cytotoxic T lymphocyte activity in splenocytes was signficantly suppressed at weeks 7 and 8; by week 10, there was no difference as compared to controls. In conclusion, administration of the immunotoxic compound, TCDD, induced a change in cell surface marker expression in prenatal mice that may prove to be an indicator of altered immune function in adult life. [R91] *Perinatal exposure to small amounts of TCDD appears to cause an androgenic deficiency in male rats that from birth into adulthood. The purpose of this study was to determine if male reproductive function in also adversely affected. On day 15 of pregnancy, female rats were dosed orally with TCDD (0.0-1.0 ug/kg), exposing their offspring to TCDD in utero as well as through lactation. Dose-related decreases in testis and epididymis weights were observed in the 32, 49, 63, and 120 day-old offspring. Testicular daily sperm production rate, evaluated on days 49, 63, and 120 also declined in a dose-related fashion which appeared to become less severe with time. Cauda epididymal sperm count and concentration, determined on days 63 and 120, were decreased at doses of TCDD as low as 0.064 ug/kg. Epididymal sperm motility and morphology, however, remained unaltered. When caged with control females, the fertility of TCDD exposed male offspring (measured at 70 and 120 days of age) was not affected. Because male rats normally ejaculate far more sperm than are necessary to impregnate females, the decreases in daily sperm production rate and cauda epididymal sperm reserves caused by perinatal TCDD exposure were not severe enough to impair the ability of these rats to reproduce. [R92] *Following sexual maturation, the reproductive system of male rats is relatively resistant to TCDD. This study was designed to determine the sensitivity of male rats to perinatal TCDD exposure. Female rats were given TCDD (0.0, 0.064, 0.16, 0.40, or 1.0 ug/kg, po) on day 15 of pregnancy, thus exposing their offspring in utero and via lactation. The percentage of live births was slightly decreased (highest dose only), while no effects on maternal weight gain, litter size, or offspring survival were seen. A decrease in body weight seen in day-old pups was maintained into adulthood (typically 10-15% at the highest dose). Of the developmental indices measured (time to pinna detachment, incisor eruption, eye opening, testis descent), only testis descent was delayed. Dose-related decreases in the weights of androgen-dependent organs (seminal vesicles and ventral prostate) were seen on days 32, 49, 63, and 120; plasma testosterone and dihydrotestosterone concentrations were similarly affected. Dose-related decreases in anogenital distances of 1- and 4-day old males also suggest the presence of an androgenic deficiency. Thus, male rats are sensitive to perinatal TCDD exposure; maternal doses as low as 0.16 ug/kg appeared to cause a perinatal androgenic deficiency that persisted into adulthood. [R93] *29 Adult Rhesus and 18 offspring were exposed to relatively low doses of TCDD. There were no clinically significant abnormalities in the immune response of surviving adults. Offspring had increased responses to antigen which correlated with TCDD tissue levels. [R94] *The incidence of ... endometriosis was determined in a colony of rhesus monkeys clinically exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin ... for a period of 4 yr. Ten years after termination of dioxin treatment, the presence of endometriosis was documented by surgical laparoscopy and the severity of disease was assessed. The incidence of endometriosis was directly correlated with dioxin exposure and the severity of disease was dependent upon the dose administered (p < 0.001). Three of the seven animals exposed to 5 parts per trillion dioxin (43%) and 5 of 7 animals exposed to 25 parts per trillion dioxin (71%) had moderate to severe endometriosis. In contrast, the frequency of disease in the control group was 33%, similar to an overall prevalence of 30% in 304 monkeys housed at The Harlow Primate Center with no dioxin exposure. This 15 yr study indicates that latent female reproductive abnormalities may be associated with dioxin exposure in the rhesus. ... [R95] *In the late 1960s a chemical company in southern Missouri, which had produced 2,4,5-trichlorophenoxyacetic acid, ceased production and leased the facilities to another company which produced hexachlorophene and 2,4,5-trichlorophenol. Between Feb and Oct 1971, an estimated 21,500 gallons of contaminated waste oil were removed from this plant for disposal. Much of this material was used for spraying roads and horse arenas for dust control. A number of 57 horses became ill and subsequently died. These horses exhibited extreme weight loss and alopecia. There were 26 known abortions, and many foals, exposed only in utero, died at birth or shortly after. Postmortem examinations showed severe emaciation , hepatic damage, gastric ulcers, atrophy of the spleen, and skin lesions. Many cats and dogs straying in the arena areas died with the same symptoms. [R15, 1219] *Monkeys poisoned by TCDD at a dietary level of 0.5 ppb showed weight loss, blepharitis, loss of fingernails and eyelashes, facial alopecia with acneform eruptions, mild anemia, neutropenia, lymponia, and a decrease in serum cholesterol with increased serum triglycerides. At necropsy, the liver, kidneys, and adrenals showed a relative increase in weight, whereas the thymus was reduced dramatically. There were hyperplastic and metaplastic changes of the sebaceous glands and epithelial hyperplasia of the renal pelvis, stomach, gallbladder, and bile duct. Erythroid elements of the bone marrow were reduced. Female monkeys receiving the same dietary concentration showed reproductive difficulties as they became generally incapacitated. TOXICITY VALUES - TOXV [R15, 1221] *Male Sprague-Dawley rats were treated by oral gavage with 1 umol/kg TCDD dissolved in corn oil and were killed 3 days later. Purification of hepatic microsomal cytochrome p450 showed that 2,3,7,8-tetrachlorodibenzo-p-dioxin remained specifically bound to cytochrome p450 throughout purification. The binding could not be measured spectrally, but 2,3,7,8-tetrachlorodibenzo-p-dioxin inhibited estradiol 2-hydroxylase activity catalyzed by the cytochrome. [R96] *TCDD is a highly potent inducer of cytochrome p450. The role of the induced p450 in TCDD toxicity has been obscure as p450 neither detoxifies TCDD nor activates it to genotoxic or cytoxic metabolites. ... Using a chick embryo model, /results indicate/ that TCDD causes major increases in the reduced form of nicotinamide-adenine dinucleotide phosphate dependent metabolism of arachidonic acid, a predominant cell membrane fatty acid, that it does so with extremely high potency (ED50, 6.3 pmol per egg) and that this metabolism is catalyzed by TCDD-induced cytochrome p450 species. Thus, TCDD treatment increased by six to ten fold the p450 mediated hepatic microsomal metabolism of arachidonic acid to epoxides and monohydroxyeicosatetraenoic acids, products whose diverse biological activities suggest links to TCDD's toxic effects. In contrast only omega and omega-1 hydroxyi arachidonic acid, inactive products, were significantly formed by the controls. These findings open a new perspective on how p450 induction could be related to the diverse toxic effects of TCDD. They lead to the novel hypothesis that TCDD-induced cytochrome p450 metabolizes an endogenous fatty acid to reactive products that mediate or modulate varied manifestations of TCDD toxicity. [R97] *Different halogenated dibenzo-p-dioxins differ greatly in toxicity but, ... a comparison ... the toxicity of the compounds corresponds with their ability to induce delta-aminolevulinic acid synthetase and aryl hydrocarbon hydroxylase. [R28, 479] *Chemical thyroidectomy effectively protected athyroid rats from mortality during 45 days after dosing with 100 ug TCDD/kg, whereas 70-80% of nonthyroidectomized-euthyroid and thyroidectomized-T4 (thyroxine)-maintained-euthyroid rats died within same period of time. There was significant decr in body wt of all TCDD treated groups compared to controls. TCDD significantly reduced feed intake in nonthyroidectomized-euthyroid and thyroidectomized-T4-euthyroid rats, but no altered feed consumption was observable in thyroidectomized-athyroid animals. Data indicate that thyroid hormones play an important role in mediating toxicity of TCDD. [R98] NTXV: *LD50 Dog oral 100-200 ug/kg; [R99] *LD50 Hamster oral 1,157-5,051 ug/kg; [R99] *LD50 Rabbit (mixed) oral 115.0 ug/kg; [R100, 440/5-80-072] *LD50 Rabbit (mixed) dermal 275.0 ug/kg; [R100, 440/5-80-072] *LD50 Guinea pig (female) oral 2.1 ug/kg; [R100, 400/5-80-072] *LD50 Rhesus monkey (female) oral < 70.0 ug/kg; [R101] *LD50 Mouse (male) oral 114.0 ug/kg; [R102] *LD50 Guinea pig oral 0.6 ug/kg; [R103] *LD50 Rat (male) oral 22.0 ug/kg; [R100, 400/5-80-072] *LD50 Rat (female) oral 45.0 ug/kg; [R100, 400/5-80-072] *LD50 Rabbit (mixed) oral 10.0 ug/kg; [R104] ETXV: *LD50 Colinus virginianus oral 0.0150 mg/kg (95% Confidence limit 0.00919-0.0245); [R105] *LD50 Streptopelia risoria oral > 0.810 mg/kg; [R105] NTP: *A bioassay of TCDD for possible carcinogenicity was conducted by applying an acetone suspension of this substance dermally to groups of 30 male and female Swiss-Webster mice 3 days per week for 104 weeks. Similar groups were pretreated with 1 application of 50 ug dimethylbenzanthracene in 0.1 ml acetone 1 week before TCDD administration began. Female mice received 0.005 ug TCDD per application, and the male mice received 0.001 ug TCDD. As vehicle controls, 45 mice of each sex received 0.1 ml acetone three times per week. Thirty animals of each sex were used as untreated controls. ... Mean body weights of dosed and vehicle control groups of the females were less than those of untreated control group thoughout the study and for the males were less than mean body weights of untreated controls during the first 80 weeks. In female mice, the incidence of fibrosarcoma in the integumentary system in groups dosed with TCDD and TCDD following dimethylbenzanthracene was significantly higher than that in the corresponding controls. [R106] *A bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a contaminant in several herbicides, for possible carcinogenicity was conducted by administering the test material by gavage to Osborne-Mendel rats and B6C3F1 mice for 104 weeks. Fifty rats and mice of each sex were administered TCDD suspended in a vehicle of 9:1 corn oil-acetone 2 days per week for 104 weeks at doses of 0.01, 0.05, or 0.5 ug/kg/wk for rats and male mice and 0.04, 0.2, or 2.0 ug/kg/wk for female mice. Seventy-five rats and 75 mice of each sex served as vehicle controls. One untreated control group containing 25 rats and 25 mice of each sex was present in the TCDD treatment room, and one untreated control group containing 25 rats and 25 mice of each sex was present in the vehicle control room. All surviving animals were killed at 105 to 107 weeks. ... In male rats, increased incidences of follicular cell adenomas or carcinomas in the thyroid were dose related and were significantly higher in the mid and high dose groups than in the vehicle controls. In female rats, the incidences of follicular cell adenomas of the thyroid and hepatocellular carcinomas or neoplastic nodules of the liver were dose related, and the incidence of hepatocellular carcinomas in the high dose group was significantly higher (p= 0.001) than that in the vehicle controls. In both male and female mice, incidences of hepatocellular adenomas or carcinomas were dose related and the incidences in the high dose groups were significantly higher than those in the corresponding controls. In female mice, follicular cell adenomas in the thyroid and histocytic lymphomas in the hematopoietic system occurred at dose related incidences, and the incidences of the follicular cell adenomas were significantly higher in the high dose groups than those in the vehicle controls. [R107] POPL: *Exposure to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin) triggered a clinically manifest chronic hepatic porphyria (porphyria cutanea tarda) in patients with hereditary uroporphyrinogen decarboxylase deficiency. Investigations showed that a hereditary disposition was necessary for biochemical and clinical expression of chronic hepatic porphyria after a unique dioxin exposure. [R108] *Prevalence rate ratios for peripheral neuropathy and assoc 95% confidence limits were calculated for subgroups determined by the presence of (i) predisposing factors to neuropathy (alcoholism, diabetes, occupational exposure to neurotoxic agents, etc) or (ii) conditions thought to result from exposure to dioxin TCDD such as chloracne or abnormal serum hepatic enzyme levels. The prevalence rate of peripheral neuropathy among those subjects with predisposing factors and among those with chloracne or abnormal serum hepatic levels was nearly 3 times greater than among those without these manifestations. The results derived from this study may be useful qualitative pointers for identifying subjects at risk in the neurological follow-up. [R109] ADE: *... RATS ... /WERE/ FED (14)C-/TCDD/ ... AT DOSAGES OF 0.45 and 1.3 UG/KG/DAY. ON DAYS 14, 28, and 42 OF TRIAL, TOTAL ACCUM, MAINLY IN LIVER, WAS 5.5, 7.5 and 10 TIMES DAILY INTAKE. [R110] *FOLLOWING SINGLE ORAL ADMIN OF 50 UG/KG BODY WT (14)C-TCDD TO RATS, ALMOST 30% WAS ELIMINATED IN FECES DURING FIRST 48 HR; EXCRETION OF (14)C ACTIVITY VIA FECES AFTER THIS TIME WAS FROM 1-2%/DAY. AFTER ITS ABSORPTION IN THE BODY, MOST OF THE ACTIVITY DERIVED FROM (14)C-TCDD IS LOCALIZED IN LIVER AND FAT: THE LEVEL IN THESE TISSUES IS 10 TIMES THAT IN OTHER TISSUES. A TOTAL OF 53.2% OF THE DOSE WAS ELIMINATED VIA FECES AND 13.2% and 3.2% VIA URINE AND EXPIRED AIR RESPECTIVELY WITHIN 21 DAYS. [R111] *(3)H-TCDD ADMIN BY IP INJECTION TO MALE MICE AT LD50 DOSE (120 UG/KG BODY WT) WAS NOT MEASURABLY CONVERTED TO WATER-SOL PRODUCTS AND WAS ELIMINATED MAINLY IN FECES AND POSSIBLY VIA BILE. TRACES OF TRITIUM ACTIVITY WERE DETECTED IN URINE. LARGE PROPORTION OF ADMIN DOSE PERSISTED UNMETABOLIZED IN LIVER, PARTIALLY CONCENTRATED IN MICROSOMAL FRACTION, 11-20 DAYS AFTER TREATMENT. [R112] *IN FEMALE GUINEA PIGS ADMIN A SINGLE ORAL DOSE OF 2,3,7,8-TCDD ONLY 1/2 OF DOSE WAS ABSORBED. 22 DAYS AFTER DOSING, FAT, LIVER, ADRENALS AND THYMUS CONTAINED 0.75, ... 0.40, ... 0.33, ... and 0.72% ... RESPECTIVELY. [R113] *Radiolabelled TCDD was taken up by mouse livers when injected IP. The proportion of the total dose taken up by the liver was higher in inducible mouse strains than in non-inducible mouse strains. [R114] *... Distribution of (14)C-TCDD in the young following a single oral dose to the mother at the rate of 0.005 mg/kg was consistent with enzyme induction following a single oral dose. TCDD was found in fetuses sampled on gestation days 14, 18, or 21 but at far lower concentrations than in young examined 3, 7, 10, or 14 days after birth. Cross fostering tests indicated that TCDD was excreted in milk, and this accounted for the greater transfer to the neonate. [R28, 482] *Metabolites of TCDD were extracted from bile of TCDD treated dogs and admin by gavage to bile duct cannulated rats and to intact rats. Rapid clearance of TCDD metabolites indicated that bioaccumulation does not occur. Biliary excretion was most important route of elimination; minor route was by kidneys. Enterohepatic circulation was exhibited by intact animals. Results from this study indicate that metabolism is the rate limiting step in elimination from liver. [R115] *The liver concentration of TCDD was measured as a means of following the uptake of this chemical by the intestinal and dermal routes. Accumulation of the (radiolabelled) compound in the liver was found to provide a good and reproducible method of comparing TCDD uptake from different formulations. After oral administration of 14.7 ng TCDD using 50% ethanol as vehicle, 36.7% of the total dose was found in the liver after 24 hr. When the cmpd was administered in a mixture with soil particles, adsorption occurred and only about half of this amount was found in the liver. The liver level also decreased with increasing duration of contact between the soil and the dioxin. Adsorption onto activated carbon almost completely prevented uptake of the cmpd. Similar effects were observed after dermal application of TCDD in the various formulations. The highest liver content, 14.8% of the dose, was found after contact of the pure cmpd with the skin surface. The inhibiting effects of soil and activated carbon were even more pronounced. After incorporation of the dioxin into vaseline (a lipophilic ointment), 1.4% of the dose was found in the liver, wheras, after incorporation into polyethylene glycol 1500 (a hydrophilic ointment) containing 15% water, 14.1% was found in the liver. [R71] *Rats were given a single oral dose of 1.0 ug of (14)C-2,3,7,8-tetrachlorodibenzo-p-dioxin (14)C-TCDD/kg/day, or repeated oral doses of 0.01, 0.1, or 1.0 ug of (14)C-TCDD/kg/day Monday through Friday for 7 weeks. Following a single oral dose of 1.0 ug of (14)C-TCDD/kg, (14)C activity could be detected only in feces, but not in urine. The half-life of (14)C activity in the body was 31 + or - 6 days. Twenty-two days after the single oral dose, concentrations of (14)C activity were located principally in liver and fat. Following repeated oral doses the major route of excretion was via the feces; urine contained 3-18% of the cumulative dose of (14)C activity by 7 weeks. The half-life of (14)C activity in the body of these rats was 23.7 days. Assuming a one compartment open model, 76.2% of steady state concentrations were achieved in the whole body after 7 weeks. (14)C activity in liver and fat approached steady state values at a rate similar to the whole body. Radioactivity in the liver was identified as TCDD by gas chromatography-mass spectrometry and could be extracted from liver tissue with organic solvents. [R116] *The metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was investigated in guinea pigs for 45 days following a single ip injection of tritiated TCDD (0.56 ug/kg). Data were presented only for guinea pigs which exhibited no gross signs of toxicity during the study. Approximately 61% of the administered dose of radioactivity remained in the guinea pig 45 days following exposure; 36% in adipose tissue, 7% in the liver, 7% in the pelt and 7% in skeletal muscle and carcass. Most of the TCDD derived radioactivity in tissues represented unchanged TCDD, but from 4 to 28% was associated with metabolites of TCDD. The urinary and fecal excretion of TCDD derived radioactivity followed apparent first order kinetics, with an elimination half-life of 93.7 +/- 15.5 days. Analysis of urine and bile showed that all the radioactivity represented metabolites of TCDD. In fecal samples, 70 to 90% of the radioactivity represented unmetabolized TCDD. TCDD is primarly eliminated unchanged in the feces of guinea pigs, indicating that the metabolism of TCDD does not play a major role in the ultimate elimination of the toxin from the guinea pig. [R117] *When fed to rats, 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) was stored primarily in the liver. Total retention was dose dependent and varied from 5.5 to 10.0 times daily intake between 14 and 42 days. At steady state, analyses indicated that retention would approximate 10.5 times daily intake. [R118] *The influence of age on dermal absorption and disposition of TCDD and 2,3,4,7,8-pentachlorodibenzofuran was examined in rats. Young, middle aged, or senescent male Fischer-344 rats, 10, 36 and 64, and 96 and 120 weeks old, were administered 0 or 0.1 um/kg 14(C) labeled TCDD or 2,3,4,7,8-pentachlorodibenzofuran topically. The treated areas were covered with stainless steel caps for 3 days. Urine and feces samples were collected during this time and assayed for 14(C) activity. The rats were killed 3 days after application to determine the tissue distribution of TCDD and 2,3,4,7,8-pentachlorodibenzofuran and the amount of each dose absorbed. The greatest amount of TCDD or 2,3,4,7,8-pentachlorodibenzofuran absorption occurred in 10 week old rats. The amount of either compound absorbed was significantly less in 36 and 96 week old rats. Rats that were 120 weeks old revealed a significant increase in 2,3,4,7,8-pentachlorodibenzofuran absorption. Most of the TCDD and 2,3,4,7,8-pentachlorodibenzofuran derived radioactivity was noted in the liver, adipose tissue, skin, and muscle. Less than 2% of the absorbed dose was noted in other tissues. The amounts of TCDD accumulated in the liver, fat, and skin were not affected by age. The liver/fat TCDD ratio was approximately 4:1 in each group. Ten week old rats had significantly higher muscle TCDD concentrations than older rats. Liver 2,3,4,7,8-pentachlorodibenzofuran accumulation was significantly less in 10 week old rats than in older rats. The liver/fat 2,3,4,7,8-pentachlorodibenzofuran ratio generally decreased with age. Skin 2,3,4,7,8-pentachlorodibenzofuran concentrations were significantly higher in 10 day old rats than in older animals. Only small amounts of TCDD and 2,3,4,7,8-pentachlorodibenzofuran were eliminated by the urine or feces. The extent of excretion generally did not vary with age. It was concluded that percutaneous absorption of TCDD and 2,3,4,7,8-pentachlorodibenzofuran decreases in older animals. The tissue distribution of the absorbed doses depends on the compound and tissue. [R119] *The objectives of this study were to examine the pharmacokinetic behavior of (125)I labeled 2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice under TCDD induced and noninduced states, and to further refine the pharmcologically based pharmacokinetic (PB-PK) dioxin model for predicting tissue concentrations under various dosing conditions at environmentally relevant concentrations. Female C57BL/6J-mice were used in this study. The animals were maintained on a diet designed to inhibit 2-iodo-3,7,8-trichlorodibenzo-p-dioxin deiodination. Two days after starting the diet one group of animals was injected intraperitoneally with 0.1 micromole/kilogram of TCDD. Three days later the animals were given intraperitoneally 0.1 nanomole/kilogram 2-iodo-3,7,8-trichlorodibenzo-p-dioxin. The PB-PK model indicated that there was a time delay between tissue elimination of 2-iodo-3,7,8-trichlorodibenzo-p-dioxin and excretion of metabolites from the body. Incorporation of an intermediate compartment for metabolite storage with a first order excretion rate constant of 0.02 per hour gave excellent correspondence to rate observed data. 2-iodo-3,7,8-trichlorodibenzo-p-dioxin offered a convenient ligand for studying the pharmacokinetics of TCDD analogs at noninducing doses. The highest 2-iodo-3,7,8-trichlorodibenzo-p-dioxin derived radioactivity in naive mice was found in the fat while in the pretreated animals the highest concentration was in the liver. The pattern of TCDD distribution in the naive animals mimicked that observed in humans environmentally exposed to low levels of TCDD. These findings suggest that the most important factor responsible for the sequestration of TCDD into the liver at most experimental doses was attributed to enzyme induction and particularly to the increased capacity of the hepatic microsomal TCDD binding protein. The PB-PK model showed that TCDD concentration in the liver was most sensitive to the binding capacity of the hepatic microsomal protein. [R120] *... Inasmuch as 2,4,5-T contains < 0.05 ppm TCDD, treated pasture grasses could have a maximum initial TCDD concentration of 5 parts per trillion. Since the half-life of TCDD on grass is somewhere between 4 hr and 1 wk, the amount of TCDD on grass after 1 month would drop to between < 0.001 and 0.3 parts per trillion. This concentration would not be expected to adversely affect body weight gain or feed consumption. Even the artificially exaggerated feeding level of 24 parts per trillion. TCDD did not adversely affect body weight or feed consumption in beef cattle. [R121] *Male Sprague Dawley rats were given a single, usually lethal, dose of 2,3,7,8-TCDD (125 ug/kg ip in corn oil), or vehicle alone. Twenty-four hours after ip administration of TCDD, the animals received an ip injection of (14)C labeled glucose, and the time course and amount of exhalation of (14)CO2 were monitored for 8 hr continuously and once daily for 20 minutes for the subsequent 5 days. TCDD treatment reduced the amount of (14)CO2 exhaled within 8 hr after the injection of (14)C glucose by 33%, as compared to pair fed controls. Blood levels of radioactivity were affected by TCDD accordingly. No particular organ appeared to act as a sink for the radioactivity not exhaled during these 8 hr by the treated animals. TCDD (125 ug/kg) induced significant changes in the disposition of radioactivity in heart and brown adipose tissue between 25 and 125 minutes after the iv injection in the blood of TCDD treated rats, allowing direct comparison of experiments with iv or ip injection (14)C glucose. The half-lives of radioactivity in the exhaled air and in feces of treated animals were greatly elevated during the 5 days following administration of (14)C glucose. [R122] *Soil environmentally contaminated with TCDD was given by gavage to guinea pigs and rats. The development of a characteristic clinicopathologic syndrome in guinea pigs, the induction of aryl hydrocarbon hydroxylase in rats, and the presence of TCDD in the livers of both species show that TCDD in soil exhibits high biological availability after ingestion. [R123] METB: *THIS STUDY PRESENTS EVIDENCE FOR THE IN VIVO BIOTRANSFORMATION OF TCDD IN THE RAT. THREE MALE RATS WERE IMPLANTED WITH INDWELLING BILE LOOP CANNULAS. THEY WERE THEN GIVEN ORAL DOSES OF 15 UG (14)C-TCDD PER KG. AFTER 2, 4, OR 6 DOSES, THE BILE LOOP OF ONE RAT WAS OPENED AND BILE WAS COLLECTED FOR 24 HR. BILIARY (14)C WAS EXCRETED AT A RATE SIMILAR TO THE EXCRETION OF (14)C IN THE FECES OF RATS FED (14)C-TCDD IN A PREVIOUS STUDY. SELECTIVE SOLVENT EXTRACTION REVEALED THAT THE BILIARY (14)C ACTIVITY WAS DUE TO CMPD MORE POLAR THAN TCDD ITSELF. INCUBATION OF BILE WITH BETA-GLUCURONIDASE RESULTED IN THE EXTRACTION OF MORE (14)C ACTIVITY, IMPLYING THE PRESENCE OF GLUCURONIDE CONJUGATES OF (14)C-TCDD METABOLITES. LIQUID CHROMATOGRAPHY OF BILE HAS REVEALED THE PRESENCE OF AT LEAST 5 DISTINCT RADIOACTIVE PEAKS, NONE OF WHICH WAS DUE TO (14)C-TCDD. THE DATA DID NOT INDICATE EXTENSIVE ENTEROHEPATIC CIRCULATION OF RADIOACTIVITY DERIVED FROM (14)C-TCDD. THESE RESULTS, IN CONJUNCTION WITH THE RESULTS OF PREVIOUS STUDIES, INDICATE THAT TCDD IS SLOWLY METABOLIZED IN THE LIVER TO A VARIETY OF POLAR METABOLITES, WHICH ARE THEN EXCRETED IN THE BILE. [R124] *Mouse liver cytochrome p450 mediated monooxygenase system slowly metabolized TCDD to reactive intermediates that bind to cellular macromolecules in vitro. [R125] *Thin layer and gas chromatographic examination of the bile of dogs which were given tritium labelled TCDD revealed the presence of several polar biotransformation products. The structure of 5 phenolic metabolites was elucidated by combined gas chromatography-mass spectrometry. A metabolic breakdown scheme for TCDD in the dog is proposed /which includes 1,3,7,8-tetrachloro-2-methoxydibenzo-p-dioxin, 2,7,8-trichloro-3-methoxydibenzo-p-dioxin, trichloro-dimethoxydibenzo-p-dioxins, tetrachloro-dimethoxy diphenylether, and 1,2-dichloro-4,5-dimethyoxybenzene/. [R126] *Marked interspecies variability exists in the acute toxicity of TCDD, with the rat having an LD50 about 25 fold greater than the guinea pig. The metabolism of TCDD was examined by incubating hepatocytes isolated from these animals with purified (14)C-TCDD (2.2 uM) for 8 hr. Quantitative differences were observed in the rate of (14)C-TCDD metabolism, with hepatocytes from control rats metabolizing TCDD at a rate 2.8 fold greater than hepatocytes from control guinea pigs. The role of the hepatic cytochrome p450-448 dependent monooxygenase system in the metabolism of TCDD was examined through the use of hepatocytes isolated from animals pretreated with either TCDD (5 ug/kg, ip; 72 hr prior to hepatocyte isolation) or phenobarbital (80 mg/kg, ip x 3 days; 24 hr prior to isolation). The rate of (14)C-TCDD metabolite formation in hepatocytes from TCDD pretreated guinea pigs (0.26 + or - 0.14 pmol/mg cell protein/hr) was unchanged from the control rate (0.25 + or - 0.07), while the rate in hepatocytes from TCDD pretreated rats (2.26 + or - 0.43 pmol/mg cell protein/hr) was 3.2-fold greater than control (0.70 + or - 0.10) and nine times greater than in hepatocytes from TCDD pretreated guinea pigs. In addition, significant differences were observed in the profiles of the metabolites formed by hepatocytes from TCDD-pretreated rats and guinea pigs. On the other hand, phenobarbital pretreatment produced little change in the rate of (14)C-TCDD metabolism in rat hepatocytes (0.98 + or - 0.13 pmol/mg cell protein/hr). [R127] *The in vitro metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin in isolated rat hepatocytes /was investigated/. ... The metabolites were ... identified as 1-hydroxy-2,3,7,8-TCDD and 8-hydroxy-2,3,7-trichlorodibenzo-p-dioxin. [R128] *The major metabolite /of 2,3,7,8-TCDD in dogs/ is 1,3,7,8-tetrachloro-2-hydroxydibenzo-p-dioxin. [R129] *Some animal studies of 2,3,7,8-TCDD have shown that a large proportion of the administered compound persists in an unmetabolized form in the liver, suggesting that toxicity is due to the compound itself and not a metabolite. Other metabolic studies in various species have shown that 2,3,7,8-TCDD gives rise to monohydroxy, dihydroxy, and monomethoxy metabolites. Administration of these metabolites from dogs to guinea pigs showed that the metabolites were at least 100 times less acutely toxic than 2,3,7,8-TCDD itself. [R34, 757] BHL: *(14)C-LABELED TETRACHLORODIBENZO-P-DIOXIN WAS ADMIN BY GAVAGE TO GUINEA PIGS. HALF-LIFE FOR ELIMINATION WAS ESTIMATED TO BE BETWEEN 22 AND 43 DAYS. [R113] *Rats were given a single oral dose of 1.0 ug of (14)C-2,3,7,8-tetrachlorodibenzo-p-dioxin (14)C-TCDD/kg/day, or repeated oral doses of 0.01, 0.1, or 1.0 ug of (14)C-TCDD/kg/day Monday through Friday for 7 weeks. Following a single oral dose of 1.0 ug of (14)C-TCDD/kg, (14)C activity could be detected only in feces, but not in urine. The half-life of (14)C activity in the body was 31 + or - 6 days ... . [R116] *Dioxins are present in milk of dairy cattle following feeding of technical grade pentachlorophenol. A dioxin concentration as high as 85 ug/kg is found in milk after feeding pentachlorophenol for 10 days at 20 mg/kg/day and then for an additional 60 days at 10 mg/kg/day. The elimination half-life of dioxin in milk is approximately 50 days. [R121] *After removal of TCDD from the diet /of rats/, the half-life for elimination was 12 and 15 days for males and females, respectively. [R118] *The half-life of 2,3,7,8-TCDD in humans has been shown in two studies to be 7 years or more; the primary route of elimination was the feces. ... Rates of elimination of 2,3,7,8-TCDD in small animals following a single dose was found to range from 11 days (mouse) to 30 days (guinea pig). [R34, 757] ACTN: *It has been shown by thiobarbituric acid and conjugated diene methods that TCDD induces lipid peroxidation in rats. A 5-6 fold increase in lipid peroxidation occurs within 6 days following admin of 40 ug TCDD/kg body wt/day for 3 days in rats. The toxicity of TCDD may be caused in part by free radical-mediated lipid peroxidation that leads to general cell membrane damage which ultimately produce death. [R130] *The responsiveness of 5 human squamous cell carcinoma lines derived from tumors of epidermis and tongue to TCDD was assessed by measuring induction of cytochrome p450 mediated monooxygenase activity, 7-ethoxycoumarin O-deethylase. In 4 of the squamous cell carcinoma lines the EC50 for this response was approx 1X10(-9) M, whereas in 1 line the EC50 was 1X10-10 M. In each of the less sensitive lines a concn of 1X10(-10) M TCDD elicited less than 5% of the maximal enzyme activity. Specific binding of radiolabeled TCDD was detected in the cytosol fraction from all the squamous cell carcinoma lines. The relative amt of receptor measured in each line correlated with maximally-induced 7-ethoxycoumarin O-deethylase activity. Data indicate that human cell lines derived from target tissue for TCDD toxicity contain the TCDD receptor and show differential sensitivity to TCDD analogous to the murine strain differences in sensitivity regulated by the Ah locus. [R131] *Studies have shown that topical treatment of hairless mice with TCDD induces hyperproliferation and hyperkeratinization in epidermis. This study demonstrated that such TCDD induced morphological changes in skin in vivo are accompanied by incr in activity of epidermal transglutaminase, the enzyme assoc with terminal epidermal differentiation. Thus one mechanism of TCDD in inducing cutaneous changes appears to relate to the stimulation of incr epidermal transglutamine levels. [R132] *Using sucrose density gradient centrifugation in a vertical rotor, three major binding components contained in hepatic cytosols from C57BL/6 mice and Sprague-Dawley rats /have been identified/. Using this preparative method ... after a 3 hr run of 2.4 ml of crude cytosol from 1,4-bis(2-(3,5-dichlorodipyridyloxy))benzene treated C57BL/6 mice (50 mg of protein: 10,000 fmol of Ah receptor) 50 and 75% yields of isolated Ah receptor and carcinogen binding protein (4S binding protein), respectively. A third binding component was recovered from the top fractions of gradients. This large complex was sequentially converted to its subcomponents by lipoprotein lipase, proteinase K, and phospholipases. Only the phospholipases are able to abolish the binding capacity of this light density component for (3)H-2,3,7,8-tetrachlorodibenzo-p-dioxin: hence, phospholipids are the true binders of this radioligand. In vitro, the lipoprotein irreversibly binds many hydrophobic and radioligands (2,3,7,8-TCDD, 3-methylcholanthrene, benzo(a)pyrene, 7,12-dimethylbenz(a)anthracene, and dexamethasone). Using single vertical spin density gradient ultracentrifugation, the major part (80%) of light density component was characterized as a very low density lipoprotein, and a minor part (20%) as a low density lipoprotein. [R133] *TCDD IS A POTENT INDUCER OF HEPATIC AND RENAL MICROSOMAL DRUG METABOLIZING ENZYMES. ... /IT/ CAN SIMULTANEOUSLY ACTIVATE AND SUPPRESS CERTAIN MICROSOME-ASSOCIATED FOREIGN-COMPOUND- AND STEROID-HORMONE-METABOLIZING ENZYME SYSTEMS. IT INCR ACTIVITY OF BOTH RENAL AND HEPATIC GLUTATHIONE-S TRANSFERASE ... IT IS MOST ACTIVE OF CHLORINATED DIBENZO-PARA-DIOXINS IN INDUCING HEPATIC DELTA-AMINOLEVULINIC ACID SYNTHETASE AND ARYL HYDROCARBON HYDROXYLASE ... IN CHICK EMBRYO LIVER PREPN. [R134] *The halogenated aromatic hydrocarbon TCDD is a persistent, widespread, potentially toxic environmental contaminant, which is a potent inducer of aryl hydrocarbon hydroxylase activity in the liver and other tissues. TCDD induces hydroxylase activity by increasing the rate of transcription of the CYP1A1 gene. Activation of CYP1A1 transcription requires the binding of TCDD to an intracellular protein, the Ah receptor, followed by the binding of the liganded receptor to a dioxin-responsive enhancer that is located upstream from the CYP1A1 gene. The liganded receptor recognizes a specific DNA sequence, which is present in multiple copies within the enhancer. The receptor-enhancer interaction occurs within the major groove of the DNA helix. DNA methylation in vitro interferes with the receptor-enhancer interaction and, therefore, has the potential to inhibit the biological response to TCDD. [R135] INTC: *NURSING SPF SWISS-WEBSTER MICE, IN PRESENCE OF 50 UG/KG TCDD TREATED WITH 10, 100, OR 500 UG ENDOTOXIN (ESCHERICIA COLI, LPS) SUFFERED HIGH MORTALITIES, MARKED INCR IN SUSCEPTIBILITY OVER CONTROLS. [R136] *Paw edema formation after subplantar injection of carrageenan was enhanced in rats treated with TCDD. It also enhances dextran-induced paw edema, which follows a time course different from that of carrageenan induced edema and is produced by a different mechanism. [R137] *IN MICE, INCR INCIDENCES IN FREQUENCY OF CLEFT PALATES ... /WERE/ NOTED IN COMBINATION EXPERIMENTS INVOLVING TCDD AND OTHER TERATOGENS SUCH AS 2,4,5-T, DEXAMETHASONE, CYCLOPHOSPHAMIDE AND 6-AMINONICOTINAMIDE, ADMIN AT 'SUB-THRESHOLD' and 'THRESHOLD' DOSES DURING DAYS 6-15 OF PREGNANCY. WHEN 30 MG/KG BODY WT 2,4,5-T, WHICH PRODUCED NO SIGNIFICANT INCR IN INCIDENCE OF CLEFT PALATE COMPARED WITH THAT OF CONTROLS, OR HALF THIS DOSE, WAS COMBINED WITH 2 UG/KG BODY WT TCDD, POTENTIATING EFFECTS WERE OBSERVED. HOWEVER, 1/10 OF TCDD DOSE (0.2 UG/KG BODY WT) INDUCED NO DETECTABLE EFFECT WITH EITHER DOSE OF 2,4,5-T. [R138] *Tumor initiating activity in Sencar mice of 6 monofluoro derivatives of 7,12-dimethylbenz(a)anthracene was determined. Pretreatment with TCDD effectively inhibited tumor initiation with all of monofluoro derivatives of 7,12-dimethylbenz(a)anthracene tested. Results indicated that structural modifications that alter tumor initiating activity do not alter ability of TCDD to inhibit tumorigenesis by 7,12-dimethylbenz(a)anthracene. [R139] *Since 2,3,7,8-tetrachlorodibenzo-p-dioxin is not a mutagen and does not bind appreciably to DNA in vivo, it has been suggested that it is not a complete carcinogen, but rather acts as a tumor promoter, enhancing neoplastic expression in already initiated cells. It has been shown to be a potent tumor promoter in two-stage model of carcinogenesis in rat liver, but has proven ineffective in classical model in mouse skin (using CD-1 AND Swiss-Webster mice). In this study the capacity of TCDD to promote tumor formation in skin of HRS/J hairless (hr/hr) mice and their congeneic, haired (hr/+) littermates was determined. Following application of an initiating dose of a carcinogen 7,12-dimethylbenz(a)anthracene repeated skin application of TCDD produced papillomas in hr/hr mice but not hr/+ mice. In HRS/J hairless mice, tumor promotion by TCDD elicits same incidence and multiplicity of skin papillomas as does the classical tumor promoter, 12-O-tetradecanoylphorbol-13-acetate, but at 1/100th the dose. [R140] *The induction of cleft palate in C57BL/6N mice ... was used to look for potential interactions between two polychlorinated biphenyl congeners and TCDD. Both 2,3,4,5,3',4'-hexachlorobiphenyl and 2,4,5,2',4',5'-hexachlorobiphenyl are of relatively low toxic potency, but their biological properties differ. Pregnant mice were treated with TCDD and either hexachlorobiphenyl on gestation days 10 through 13, and the fetuses examined for the presence of cleft palate and renal abnormalities on gestation day 18. At a dose of TCDD which caused a low level of cleft palate, moderate hydronephrosis was observed. No renal or palatal anomalies were detected after 2,4,5,2',4',5'-hexachlorobiphenyl treatment, and the combination of this isomer with TCDD had no effect on the incidence of TCDD induced cleft palate. 2,3,4,5,3',4'-Hexachlorobiphenyl caused mild renal toxicity, but no cleft palate. However, treatment of pregnant mice with a combination of TCDD and 2,3,4,5,3',4'-hexachlorobiphenyl resulted in a 10 fold increase in the incidence of cleft palate. [R141] *Administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) to 21 day old female Long Evans rats resulted in a dose dependent decrease in uterine and hepatic estrogen receptor levels. At a dose level of 80 ug/kg 2,3,7,8-TCDD, uterine and hepatic estrogen receptor levels were 54 and 41% of values observed in untreated animals. 2,3,7,8-TCDD also antagonized the estrogenicity of estradiol in the 21 day old rat. For example, administration of estradiol (15 ug/kg) resulted in a 194 and 155% increase in cytosolic and uterine estrogen receptor levels and a 42% increase in uterine wet weight 148 hr after treatment. Pretreatment of the rats with 2,3,7,8-TCDD (80 ug/kg) prior to administration of estradiol (15 ug/kg) completely blocked the estrogenic effects of estradiol. In fact, after cotreatment, the uterine and hepatic estrogen receptor levels were 51 and 54% lower than observed in the controls and the uterine wet weight was 20% lower than in the control animals. [R142] *TCDD is one of the most toxic man-made compounds and an extremely potent teratogen in mice. Many of its toxic symptoms resemble those seen during vitamin A deficiency. Vitamin A and its derivatives, such as trans-retinoic acid, are also teratogenic in mice, as well as many other species. Both TCDD and retinoic acid produced cleft palate in susceptible strains of mice. However, while TCDD produces hydronephrosis, retinoic acid does not, and TCDD does not produce limb bud defects while retinoic acid does. To determine whether TCDD and retinoic acid would enhance or antagonize the teratogenic effects of the other compound, C57BL/6N dams were treated po on gestation day 10 or 12 with 10 ml corn oil/kg containing TCDD (0.18 ug/kg), retinoic acid (0-200 mg/kg), or combinations of the two chemicals. Dams were killed on gestation day 18 and toxicity and teratogenicity assessed. Coadministration of TCDD and retinoic acid had no effect on maternal or fetal toxicity beyond what would be expected by either compound alone. Cleft palate was induced by retinoic acid at lower doses on gestation day 10 than on gestation day 12, but by TCDD at lower doses on gestation day 12 than on gestation day 10. Sensitivity to TCDD-induced hydronephrosis was similar on both gestation day 10 and 12. The limb bud defects were only observed when retinoic acid was administered on gestation day 10, not when given on gestation day 12. No other soft tissue or skeletal malformations were related to administration of TCDD or retinoic acid. No effect of TCDD was observed on the incidence or severity of limb bud defects induced by retinoic acid, nor did retinoic acid influence the incidence or severity of hydronephrosis induced by TCDD. However, the incidence of cleft palate was dramatically enhanced by coadministration of the xenobiotic and vitamin. On both gestation day 10 and 12, the dose-response curves for cleft palate induction were parallel, suggestion some similarities in mechanism between the two compounds. However, combination treatment resulted in a synergistic response that varied with the stage of development and was tissue specific. [R143] *At doses as high as 750 to 1000 umol/kg, 2,2',4,4',5,5'-hexachlorobiphenyl did not cause fetal cleft palate, suppress the splenic plaque-forming cell response to sheep red blood cells, or induce hepatic microsomal ethoxyresorufin O-deethylase in C57BL/6J mice. Despite the lack of activity of 2,2',4,4',5,5'-hexachlorobiphenyl in eliciting any of these aryl hydrocarbon receptor-mediated responses, competitive binding studies indicated that 2,2',4,4',5,5'-hexachlorophenyl competitively displaced 2,3,7,8-(3)H TCDD from the murine hepatic cytosolic receptor. Cotreatment of C57BL/6J mice with TCDD (3.7 nmol/kg) and 2,2',4,4',5,5'-hexachlorobiphenyl or 4,4'-diiodo-2,2',5,5'-tetrachlorobiphenyl (400 or 1000 umol/kg) showed that both compounds partially antagonized TCDD-mediated cleft palate and immunotoxicity (ie, suppression of the splenic plaque-forming cell response to sheep red blood cells), and 2,2',4,4',5,5'-hexachlorobiphenyl antagonized TCDD-mediated hepatic microsomal ethoxyresorufin O-deethylase induction. Thus, 2,2',4,4',5,5'-hexachlorobiphenyl and 4,4'-diiodo-2,2'-5,5'-tetrachlorobiphenyl, like the commercial polychlorinated biphenyl mixture Aroclor 1254, were partial antagonists of TCDD action in C57BL/6J mice; however, it was also apparent from the results that Aroclor 1254 was the more effective antagonist at lower doses. Using (3)H TCDD, it was also shown that some of the effects of 2,2',4,4',5,5'-hexachlorobiphenyl on TCDD mediated cleft palate may be due to the decreased levels of TCDD found in the fetal palates after cotreatment with TDCC and 2,2',4,4',5,5'-hexachlorobiphenyl. 4,4'-(125)I2- diiodo-2,2',5,5'-tetrachlorobiphenyl 4,4'-diiodo-2,2',5,5'-tetrachlorobiphenyl of high specific activity (3350 Ci/ mmol) was synthesized and used to investigate the direct binding of this compound to the murine hepatic aryl hydrocarbon receptor or other cytosolic proteins. No direct specific binding was observed between (125)I 4,4'-diiodo-2,2',5,5'-tetrachlorobiphenyl and any cytosolic proteins using a sucrose density gradient assay procedure. These results contrasted with previous studies with Aroclor 1254 that suggested that this mixture acted as a competitive aryl hydrocarbon receptor antagonist. [R144] *Both Aroclor 1254, a commercial polychlorinated biphenyl, and TCDD elicit common aryl hydrocarbon receptor-mediated effects including the induction of aryl hydrocarbon hydroxylase, acytochrome p450-dependent monooxygenase, the inhibition of the T-cell dependent plaque forming cells in response to sheep red blood cells (in C57BL/6 mice) and cleft palate in C57BL/6 mice. However based on ED50 values from dose-response studies with Aroclor 1254 and 2,3,7,8-TCDD, it was apparent that the latter compound is at least 10(5) times more potent. Cotreatment of rat hepatoma H-4-II cells or C57BL/6 mice with ED80-100 dose of 2,3,7,8-TCDD plus various sub-toxic (or effective) doses of Aroclor 1254 clearly shows that the commercial polychlorinated biphenyl can significantly antagonize 2,3,7,8-TCDD-mediated aryl hydrocarbon hydroxylase induction (in vivo and in vitro), immunotoxicity and teratogenicity. In vitro aryl hydrocarbon receptor binding studies suggests that Aroclor 1254 competitively inhibits the aryl hydrocarbon receptor binding of 2,3,7,8-TCDD and this may account for the antagonist activity of the commercial polychlorinated biphenyl. [R145] *Pregnant C57BL/6J mice were treated by oral gavage with either (1) corn oil (10 ml/kg), (2) Aroclor 1254 (244 mg/kg), (3) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (20 ug/kg), (4) Aroclor 1254 (244 mg/kg) followed by TCDD (20 ug/kg), (5) dexamethasone (90 mg/kg), or (6) Aroclor 1254 (244 mg/kg) followed by dexamethasone (90 mg/kg) to study the antagonistic effects of Aroclor 1254 on TCDD. Aroclor 1254 alone was administered on day 9 of pregnancy; corn oil and TCDD were administered on day 10 and dexamethasone was given on day 13. For the mixtures, chemicals were administered one day apart: Aroclor 1254 was given on day 9 and TCDD on day 10; Aroclor 1254 was given on day 12 and dexamethasone on day 13. All chemicals and mixtures were administered in corn oil. Controls were either untreated or treated with corn oil. Each treatment group resulted in ten or more litters. The animals were sacrificed, fetal and maternal weights were recorded, and the number of resorptions and dead and live fetuses were counted. The percent live fetuses and resorptions per litter were not affected by treatments. The percentages of fetuses with hydronephrosis per litter were: untreated (1.3), corn oil (5.7), Aroclor 1254 (33.4), TCDD (87.8), Aroclor 1254 + TCDD (96.0), dexamethasone (3.2), and Aroclor 1254 + dexamethasone (3.7). Both Aroclor 1254 and TCDD caused hydronephrosis and at this dose level Aroclor 1254 did not antagonize the effects of TCDD. Percentages of fetuses with cleft palate per litter were: untreated (1.3), corn oil (0.0), Aroclor 1254 (0.0), TCDD (61.8), Aroclor 1254 + TCDD (8.2), dexamethasone (69.9), and Aroclor 1254 + dexamethasone (85.8). [R146] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,3,7,8-Tetrachlorodibenzodioxin (TCDD) is currently released to the environment primarily through emissions from the incineration of municipal and chemical wastes, in exhaust from automobiles using leaded gasoline, and from the improper disposal of certain chlorinated chemical wastes. If released to the atmosphere, vapor-phase TCDD may be degraded by reaction with hydroxyl radicals and direct photolysis. Particulate-phase TCDD may be physically removed from air by wet and dry deposition. If released to water, TCDD will predominantly be associated with sediments and suspended material. TCDD near the water's surface may experience some photodegradation. Partitioning from the water column to sediment and suspended material will occur. Volatilization from the water column may be important, but adsorption to sediment will limit the overall rate by which TCDD is removed from water. The persistence half-life of TCDD in lakes has been estimated to be in excess of 1.5 yr. Bioconcentration in aquatic organisms has been demonstrated. If released to soil, TCDD is not expected to leach. Photodegradation on terrestrial surfaces may be an important transformation process. Volatilization from soil surfaces during warm conditions may be a major removal mechanism. The persistence half-life of TCDD on soil surfaces may vary from less than 1 yr to 3 yrs, but half-lives in soil interiors may be as long as 12 years. Screening studies have shown that TCDD is generally resistant to biodegradation. The major route of exposure to the general population results from incineration processes and exhausts from leaded gasoline engines. (SRC) NATS: *2,3,7,8-TCDD is not known to occur naturally(1). [R147] ARTS: *2,3,7,8-TCDD is released to the environment in stack emissions from the incineration of municipal refuse and certain chemical wastes, in exhaust from automobiles powered by leaded gasoline, in emissions from wood burning in the presence of chlorine, in accidental fires involving transformers containing PCBs and chlorinated benzenes, and from the improper disposal of certain chlorinated chemical wastes(1). TCDD has been released to the environment as a low level impurity in various pesticides (such as 2,4,5-T and derivatives) which were manufactured from 2,4,5-trichlorophenol(1). [R147] FATE: *TERRESTRIAL FATE: Vertical distribution of TCDD has been monitored in soil at Seveso, Italy down to depth of approx 30 cm at several sites and times in 1976 and 1977. As a rule, the amt of TCDD detected more than 8 cm below the surface were approx 1/10 or less than those detected down to 8 cm. Being only slightly sol in water, its migration in soil may have occurred along with soil colloids and particles to which it may have been bound. No definite conclusions may as yet be drawn as to mechanisms responsible for TCDD vertical movement. Moreover, available data indicate that some soil stabilization of TCDD distribution occurred in 1977 as compared to 1976. [R148] *TERRESTRIAL FATE: Soil adsorption studies and monitoring of various soils contaminated by 2,3,7,8-TCDD have demonstrated that TCDD does not leach. Movement by surface erosion of soil particles or flooding may be possible, however(1). TCDD exposed to sunlight on terrestrial surfaces may be susceptible to photodegradation. Volatilization from soil surfaces during warm, summer months may be a major mechanism by which TCDD is removed from soil. Volatilization during cold, winter months or from soil depths several centimeters below the boundary layer is extremely slow. Various biological screening studies have demonstrated that TCDD is generally resistant to biodegradation. The half-life of TCDD on soil surfaces may vary from less than 1 yr to 3 yrs, but half-lives in soil interiors may be as long as 12 years(1,SRC). [R147] *AQUATIC FATE: Due to its very low water solubility, most of the 2,3,7,8-TCDD occurring in water is expected to be associated with sediments or suspended material. Aquatic sediments may be an important, and ultimate, environmental sink for all global releases of TCDD(1). Two processes which may be able to remove TCDD from water are photolysis and volatilization. The photolysis half-life at the water's surface has been estimated to range from 21 hr in summer to 118 hr in winter; however, these rates will increase significantly as water depth increases. Many bottom sediments may therefore not be susceptible to significant photodegradation. The volatilization half-life from the water column of an environmental pond has been estimated to be 46 days; however, when the effects of adsorption to sediment are considered, the volatilization model predicts an overall volatilization removal half-life of over 50 years. Various biological screening studies have demonstrated that TCDD is generally resistant to biodegradation. The persistence half-life of TCDD in lakes has been estimated to be in excess of 1.5 yr(1). TCDD has been shown to bioconcentrate in aquatic organisms(SRC). [R147] *ATMOSPHERIC FATE: Although 2,3,7,8-TCDD has an extremely low vapor pressure (7.4X10-10 mm Hg at 25 deg C)(1), it has been shown to be volatile(2) and to occur in air in both the gas-phase and particulate-phase(3). Vapor-phase TCDD reacts with photochemically produced hydroxyl radicals in air at an estimated half-life rate of 8.3 days; direct photolysis of gas-phase TCDD may occur at a faster rate than hydroxyl radical reaction. Sufficient data are not currently available to estimate the potential photolysis rate of particulate-phase TCDD. TCDD particulates may be physically removed from the atmosphere by wet and dry deposition. Monitoring data have indicated that TCDD may be transported long distances through the atmosphere. [R149] *TERRESTRIAL FATE: Preliminary results of a ... study on TCDD environmental persistence at Seveso (Milan, Italy) are presented. For this study, the most contaminated territory, Zone A, was divided into areas to fractionate the available TCDD levels in soil into data sets with reduced value spreads. In addition, various time subsets were defined for each area. ... It was estimated that at least 1.2 kg TCDD was present in Zone A shortly after the accident. On average, a considerable portion (23%) of this amount lay on vegetation; TCDD which was not photodegraded or volatilized before the heavy rains of fall 1976, was later washed off and transferred to ground by water action. From this study, mean analytical underestimations affecting Jan 1977 and Mar 1978 contamination map data were on the order of 30 and 24%. All the above figures are considered optimistic. A few years after the accident, mean TCDD half-life in soil appeared to be 9.l yr. ... [R150] BIOD: *A 31 day aquatic model ecosystem study found 14-C labelled TCDD to be very stable to metabolism(1). Screening analyses using 100 microbial strains (which had previously shown the ability to degrade persistent pesticides) determined that only 5 strains showed some ability to degrade TCDD(2). In laboratory studies using aquatic sediments and lake water, TCDD was found to be recalcitrant to microbial attack(3). [R151] ABIO: *... /ONE STUDY REPORTS/ 50% DEGRADATION OF TCDD IN 5 HR; TOTAL AMT DEGRADED WERE INDEPENDENT OF AMT PRESENT. APPLICATION OF TCDD COMBINED WITH FORMULATED 2,4,5-T TO SOIL, GLASS PLATES AND PLANT LEAVES RESULTED IN LOSSES OF 15, 60 and 100% OF APPLIED DOSE AFTER 6 HR EXPOSURE TO SUNLIGHT. ... THESE REPORTS SUGGEST FASTER RATE OF DEGRADATION OF LOW THAN OF HIGHER LEVELS OF TCDD. [R152] *CHLORINATED DIBENZO-PARA-DIOXINS, WHEN DISSOLVED IN METHANOL, ARE DEGRADED BY EXPOSURE TO SUMMER SUNLIGHT OR IRRADIATION WITH AN ULTRA-VIOLET LAMP (300 NM). ... 2,3,7-TRICHLORODIBENZO-PARA-DIOXIN AND SMALL AMOUNTS OF DICHLORODIBENZO-PARA-DIOXIN WERE PRODUCED AS BREAKDOWN PRODUCTS OF TCDD. TCDD WAS PHOTODECOMPOSED ONLY WHEN DISSOLVED IN ORG SOLVENTS. WHEN 0.1 UG/CU M TCDD WAS APPLIED TO A 250 UM LAYER OF SOIL ON GLASS PLATES AND IRRADIATED FOR 96 HR, THERE WAS NO LOSS DUE TO VOLATILIZATION OR PHOTODECOMPOSITION. IRRADIATION OF TCDD IN WATER PRODUCED LITTLE CHANGE AFTER 14 DAYS; HOWEVER IRRADIATION IN AN AQUEOUS SUSPENSION DISPERSED AND STABILIZED BY A SURFACTANT REDUCED THE TCDD CONTENT. [R4] *The half-life for the gas-phase reaction of 2,3,7,8-TCDD with photochemically produced hydroxyl radicals in a typical atmosphere has been estimated to be 8.3 days(1). Based upon photolysis studies for TCDD dissolved in water, the photolysis half-life of TCDD at the water's surface at latitude of 40 deg N has been calculated to be 21, 27, 51 and 118 hrs during summer, spring, fall and winter, respectively(1). Sufficient data are not available to estimate the potential photolysis rate of TCDD adsorbed to airborn particulates in the atmosphere(1). An upper limit photolysis half-life of 58 min (based on quantum yield measurements in hexane) has been estimated for gas-phase TCDD in the atmosphere under summer sunlight conditions; however, the actual environmental rate may be much slower(1). TCDD does not hydrolyze in environmental waters and is not expected to react significantly with photochemically produced singlet oxygen or peroxy radicals in water(2). [R153] *PERSISTENCE ... /WAS OBSERVED/ IN SILTY CLAY LOAM IN HAGERSTOWN AND IN SAND IN LAKELAND, MARYLAND, US, WHICH HAD RECEIVED UP TO 100 MG/KG TCDD. AFTER 1 YR, 71 and 56% ... WAS RECOVERED ... RESPECTIVELY. ... SUBSURFACE INJECTIONS OF A HERBICIDE CONTAINING UNSPECIFIED CONCN OF TCDD RESULTED IN OCCURRENCE OF 15 UG/KG TCDD IN SOIL ... AFTER 282 DAYS AND 2.5 UG/KG TCDD AFTER 3 YEARS. IN ANOTHER PART OF THIS STUDY ... LEVELS OF UP TO 1.5 UG/KG TCDD WERE FOUND IN SOIL 10-12 YEARS AFTER AERIAL SPRAYING OF HERBICIDES CONTAINING TCDD. UNDER RELATIVELY DRY CONDITIONS (UTAH TEST AREA) ... HAS HALF-LIFE OF 330 DAYS; IN MORE MOIST, WARM CONDITIONS (FLORIDA TEST AREA) ... HALF-LIFE ABOUT 190 DAYS. RATE OF DECAY WAS APPROX CONSTANT UP TO 1150 DAYS ... THERE WAS NO INCR IN RATE OF DECAY WHEN SOIL SAMPLES WERE STIRRED AT REGULAR INTERVALS, EXPOSED TO MORE SUNLIGHT OR RECEIVED AN ADDN OF INORGANIC NUTRIENTS. NO APPRECIABLE DOWNWARD MIGRATION OF TCDD OCCURRED EVEN WITH HEAVY ANNUAL RAINFALL (150 CM). ONLY ABOUT 1% OF TCDD INITIALLY DEPOSITED AT DEPTH OF 0-15 CM WAS FOUND BELOW 30 CM AFTER 414-557 DAYS. [R152] BIOC: *SEVERAL ORGANISMS WERE EXPOSED IN MODEL ECOSYSTEM TO (14)C-LABELED 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN FOR UP TO 31 DAYS ... IN AQUATIC ENVIRONMENT. TCDD ACCUM ... WAS DIRECTLY RELATED TO ITS CONCN IN WATER (0.05-1330 NG/L); AVG WERE 2.0 TO 2.6X10+4 (SNAIL, GAMBUSIA AND DAPHNID) and 4 TO 9X10+3 (DUCKWEED, ALGAE AND CATFISH) TIMES CONCN IN WATER, AND EQUILIBRIUM CONCN WERE REACHED IN TISSUES 7-15 DAYS. [R154] *Mean bioconcentration factors (BCF) of 29200 (dry wt) and 5840 (wet wt) were measured for fathead minnows over a 28 day exposure(1); the elimination half-life after exposure was found to be 14.5 days(1). Log BCFs of approximately 3.2 to 3.9 were determined for rainbow trout and fathead minnow in laboratory flow-through studies during 4-5 exposures(2). The following log BCFs have been reported for various aquatic organisms: snails, fish (Gambusia), daphnia 4.3-4.4; duckweed, algae, catfish, 3.6-3.95(3). [R155] KOC: *The rate of 2,3,7,8-TCDD movement in soil plots at Eglin Air Force Base was observed to be very slow over a 10 yr period (1972-1984) as the TCDD dispersed only 10 cm from its initial position(1). Soil cores collected from roadsides in Times Beach, MO in 1985 which had been sprayed with waste oils containing TCDD in the early 1970s indicated that most of the TCDD had remained in the upper 15 cm(2). A mean log Koc of 7.39 was determined for ten contaminated soils from NJ and MO based on TCDD concn in bulk soil and soil leachates(3). Tests conducted by the US Dept of Agric Pesticide Degradation Lab at Beltsville, MD determined that vertical movement of 2,3,7,8-TCDD did not occur in a wide range of soil types(4). [R156] VWS: *The Henry's Law Constant for 2,3,7,8-TCDD can be estimated to be 1.62X10-5 atm cu m/mole at 25 deg C based upon a water solubility of 19.3 ng/l and a vapor pressure of 7.4X10-10 mm Hg(1). This value of Henry's Law Constant suggests that volatilization from environmental waters may be significant, but is probably not rapid(2). Based on this Henry's Law Constant, the volatilization half-life from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be 4.3 days(3,SRC); however, this estimation neglects the potentially significant effect of adsorption(SRC). The volatilization half-life from an environmental pond, which considers the effect of adsorption, can be estimated to be in excess of 50 years(3,SRC); if parameters are introduced into the pond model to exclude the adsorption effects from TCDD's water solubility and log Kow of 7.02(4), the estimated volatilization half-life is reduced to 46 days(3,SRC). [R157] *Based upon microcosm studies and monitoring of soil at the Times Beach, MO contamination site, the following conclusions were reached pertaining to TCDD volatilization from soil: TCDD is volatile; TCDD will volatilize most rapidly during warm summer months, and not appreciably during cold winter months; over 50% of the total applied TCDD volatilized during the first summer at Times Beach(1). Volatilization of TCDD from dry soil surfaces is likely to be faster than from wet soil surfaces(2); TCDD that has been mixed into soil depths beneath the upper surface boundary will volatilize extremely slowly(2). [R158] WATC: *DRINKING WATER: 2,3,7,8-TCDD has not been reported to occur in drinking water(1). [R147] *SURFACE WATER: 2,3,7,8-TCDD has reportedly been detected (no concn reported) in the ecosystems of Lakes Ontario, Huron and Superior(1). TCDD has reportedly been positively detected in 0.2% of 491 USEPA STORET water observation stations(2). [R159] *OTHER WATER: 2,3,7,8-TCDD was not detected in the preliminary analysis of stormwater runoff from 15 US cities as conducted by the USEPA National Urban Runoff Program(1). [R160] EFFL: *Soot samples from six major PCB transformer and capacitor fires in the USA contained 2,3,7,8-TCDD concns of 0.6 to 3.0 ng/g(1). The 2,3,7,8-TCDD concns in flue gases from 3 incineration plants in Germany ranged from < 0.02-0.7 ng/cu m with the TCDD existing at significant levels in both the gas and particulate phases(2). TCDD was detected in fly ash from 3 municipal waste incineration plants and in waste oil from diesel engines(3). Flue gas analysis of 3 industrial boiler sites co-firing with liquid hazardous waste did not find any 2,3,7,8-TCDD(4). Average emission concns of 0.97 and 3.8 ng/cu m were detected in stacks from two municipal incinerators in Belgium which corresponded to emission factors of 0.27 and 0.35 mg/ton of waste burned(5). Analysis of fly ash and cinders from 9 Japanese municipal incinerators detected 2,3,7,8-TCDD levels of 0.1-5.4 ng/g in fly ash and < 0.01-1.3 ng/g in cinders(6). [R161] *A 2,3,7,8-TCDD concn of 60 ppb was detected in oil leachates from a waste dump site in Germany which had been receiving waste oils and liquid chemical wastes(1). 2,3,7,8-TCDD was not detected in auto exhaust from cars using unleaded gas, however, cars using leaded gasoline had emission rates of < 0.05-0.3 ng/24.8 km driven(2); the source of TCDD in these emissions was traced to reactions via the dichloroethane used as a lead scavenger(2). Levels of 2,3,7,8-TCDD occurring in flue gas emissions from various European and US incinerators have been reported to range from 0.05 to 3.5 ng/cu m(3). The discharged wastewater effluent from Dow Chemical into the Tittabawassee River in MI was reported to contain a TCDD level of 0.015 ng/l(3). 2,3,7,8-TCDD concn in sludge from seven pulp and paper mills ranged from not detected (1pg/g) to > 400 pg/g(4). [R162] SEDS: *SUBSEQUENT TO AERIAL SPRAYING OF 2,4,5-T IN PRAN BURI REGION OF VIETNAM, SOIL SAMPLES WERE FOUND TO CONTAIN 1.2 TO 23 UG/KG TCDD. [R163] *Concn of tetrachlorodibenzo-p-dioxin (TCDD) were determined in 6 storm sewer and creek sediment samples from Love Canal chem dump site area in Niagara Falls, NY. Analysis showed concn from 0.9 to 312 ng/g. None was detected in organic rich soil sample from rural New York State area (detection limit, 0.1 ng/g). [R164] *In May and June 1971, waste oil heavily contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (306-356 mg/kg) was sprayed on ground of 3 horse show arenas in rural Missouri in order to control dust. About 7750 l were sprayed on each of 2 arenas; concn ... in soil from 1 was 31.8 to 33 mg/kg. [R163] *Concns of 2,3,7,8-TCDD in most uncontaminated soils are below current analytical detection limits of 0.0002 ng/g(1,2); however, soils from ten urban sites in the US with no obvious source of contamination were found to contain levels up to 0.0094 ng/g(1,2). Soil cores collected from roadsides in Times Beach, MO in 1985 which had been sprayed with waste oils containing TCDD in the early 1970s contained levels of 0.8-196 ppb with the concns decreasing significantly below 15 cm(3). Levels of 4.4 to 382 ng/g were detected in soil at five different sites in MO which had been contaminated by waste oil(4). As of Oct 1984, TCDD had been detected at levels of 1 ppb or greater at 40 of 251 sites in MO during analysis by the USEPA(5). Levels of 0.01-52 ng/g were found in soils from inside the Dow Chemical manufacturing facility in Midland, MI(1). [R165] *Sediment cores taken from the western basin of Lake Ontario contained measurable 2,3,7,8-TCDD levels of 3-13 ng/kg(1). Levels of 0.9-312 ng/g were detected in sediments collected from storm sewers near the Love Canal in NY in 1980(2). TCDD has reportedly been positively detected in 1.3% of 157 USEPA STORET sediment observation stations(3). [R166] ATMC: *Tetrachlorodibenzo-p-dioxin (TCDD) in atmospheric dust was monitored in Seveso area between 1977 and 1979 using dustfall jars and high volume samplers. Apart from sampling site in Subzone A1, sporadic TCDD levels were detected at different times and different sites throughout contaminated area. Variable amt of TCDD were constantly detected at sampling site located in most heavily contaminated subzone. All findings were in range of 0.06-2.1 ng of TCDD/g of dust, for dustfall jar specimens, and 0.17-0.50 ng of TCDD/g of dust, for samples from high volume samplers. [R167] *Ambient air monitoring in the vicinity of a Superfund cleanup site detected 2,3,7,8-TCDD levels on the order of 1.0 pg/cu m(1). Levels of 0.02-0.08 pg/cu m were detected in various ambient air samples from Sweden(2). [R168] FOOD: *2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ... /HAS BEEN/ IDENTIFIED IN SEVERAL COMMERCIAL FATTY ACIDS. [R111] *2,3,7,8-Tetrachlorodibenzo-p-dioxin was not detected in food samples of rough rice, soybeans, crawfish, or bovine fat collected in MO, AR, and LA in 1979-1980(1). [R169] *Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in human fat and milk samples arise from a variety of sources. It is generally assumed that food intake is mainly responsible for the presence of these contaminants in man. Data on levels in food samples are, however, relatively rare. This review reports the levels found in various foodstuffs which are easily obtained in daily life. From the data, it is clear that most animal foodstuffs have already been contaminated by these contaminants even though in very small amounts. However, the plant products are free of most polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans. It is difficult to evaluate the different sources of contamination of food, but municipal solid waste incinerators and chlorophenol industries are likey to be the most important sources. [R170] PFAC: PLANT CONCENTRATIONS: *UPTAKE OF (14)C-LABELED ... 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN FROM NUTRIENT SOLN OR SOIL WAS MEASURED IN OATS AND SOY BEANS. SOLN CONTAINED ... 0.18 MG/L TCDD; SOIL SAMPLES CONTAINED ... 0.06 MG/KG TCDD. AFTER 14 DAYS, SEEDLING OATS AND SOY BEANS CONTAINED (MINUS CONTROL) ... 0.11 and 0.01 MG/KG ... AT MATURITY ... LESS THAN 0.001 and 0.001 MG/KG TCDD, RESPECTIVELY. NO TRANSLOCATION ... WAS OBSERVED AFTER ... APPLICATION TO FOLIAGE. [R152] FISH/SEAFOOD CONCENTRATIONS: *3-4 MO AFTER SPRAYING OF HERBICIDES IN VIETNAM WAS STOPPED, PRAWNS FROM SAIGON RIVER AND FISH FROM DONG NAI RIVER WERE FOUND TO CONTAIN TCDD LEVELS AS HIGH AS 49 and 1020 NG/KG, RESPECTIVELY, AS COMPARED TO LEVELS OF LESS THAN 3 NG/KG IN FISH OBTAINED IN MARKET IN MASS, US. [R163] *Monitoring of various species of fish from the Spring River in MO between 1981 and 1983 detected 2,3,7,8-TCDD levels of < 1.0 to 55 ng/kg(1). TCDD was detected at levels of 2.0-38.5 ppt in seven species of commercial fish (62 total samples) collected from Lake Ontario in 1980(2). TCDD was positively detected in 26 of 36 samples of fish (5 of 6 species) taken from the Lake Michigan-Saginaw River region in 1978 at concns ranging from 4-695 ppt(3). 2,3,7,8-TCDD levels in carp (Cyprinus carpio) from the Petenwell Reservoir on the Wisconsin River range from 65-120 pg/g(4). [R171] ANIMAL CONCENTRATIONS: *FROM AIR FORCE STUDIES IT WOULD APPEAR THAT AFTER AERIAL SPRAYINGS OF HERBICIDES TCDD ACCUM IN LIVERS OF RODENTS, REPTILES, BIRDS AND FISH. ALTHOUGH IT WAS CALCULATED THAT 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN LEVELS IN LIVERS DID NOT EXCEEED HIGHEST LEVEL FOUND IN CONTAMINATED SOIL. IN REVIEWING THESE RESULTS ... /SOME/ CAME TO DIFFERENT CONCLUSIONS. LIVERS OF WILD MICE COLLECTED FROM A ZONE IN FLORIDA TEST AREA CONTAINED AVG LEVEL OF 540 NG/KG ... IN 1973 (MALES AND FEMALES TOGETHER) and 1300 NG/KG (MALES) and 960 NG/KG (FEMALES) IN 1974, COMPARED WITH AVG VALUE IN SOIL OF 340 NG/KG (INITIAL CONCN 10 YR EARLIER WERE ABOUT 2 MG/KG); THESE RESULTS POINT TO CONCN EFFECT IN MOUSE LIVERS. [R154] *IN FLORIDA, AERIAL SPRAYING OF 2,4-D AND 2,4,5-T CONTAINING EST 2-50 G/HA 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN DURING 2-YR PERIOD (1962-1964) RESULTED 10 YR LATER IN DETECTABLE LEVELS OF TCDD IN TISSUES OF WILD MICE (1.3 UG/KG), MEADOW LARKS (1 UG/KG), REPTILES (0.36 UG/KG) AND FISH (0.08 UG/KG). [R163] *Three turtles taken from the St Lawrence River in 1984 and 1985 were found to contain 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of 32-107 pg/g in liver and 232-474 pg/g in fat(1). Tern eggs collected from two sites along the Great Lakes in 1983 were found to contain 2,3,7,8-TCDD levels of 9-47 ng/kg(2). Positive TCDD levels of 8-94 ng/kg were detected in birds (cormorant, great crested grebe, grey heron) taken in the Netherlands in 1983 and 1984(3). [R172] MILK: *2,3,7,8-Tetrachlorodibenzo-p-dioxin found in cow's milk from six locations in Switzerland ranged from below detection limits (0.01 ng/kg) to 0.049 ng/kg(1). The concn of 2,3,7,8-TCDD in human breast milk from various European countries, the US, and Vietnam has been reported to range from below detection limits to 50 pg/g with mean concns on the order of 10 pg/g(2). [R173] *Chlorinated dibenzo-p-dioxin and dibenzofuran were detected in samples of human milk collected in 1973 and 1985 in the South Vietnam and the levels compared to samples taken in 1970 and present day North American samples. In the Vietnam samples from the 3 time periods between one half and two thirds were positive for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Avg levels of the positives on a lipid basis, declined from approx 484 pg/g in 1970, to 121 pg/g in 1973 and then to 12 pg/g in 1985. The latter value is higher but similar to the value of approx 5 pg/gram presently found in samples from in North American milk and much higher than that found in samples from North Vietnam where Agent Orange was not used. The avg body burden of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the nursing mothers from 1970 and 1973 was est to be 3.6 and 0.98 ug, respectively. [R174] OEVC: *2,3,7,8-TCDD has been detected as an impurity in various commercial products as follows: herbicide 2,4,5-T produced prior to 1960 (up to 100 ug/g); 2,4,5-T currently produced (< 0.02 ug/g); Agent Orange in Vietnam before 1970 (0.02-54 ug/g); hexachlorophene (0-0.5 ng/g); 2,4,5-trichlorophenol (up to 6.2 ug/g)(1). [R147] RTEX: *Currently, the major route of exposure of 2,3,7,8-TCDD to the general population results from municipal waste and other incineration processes and from exhausts from automobiles using leaded gasolines(1); food (contaminated fish) can only be considered a secondary route of exposure(1). Occupational exposure occurs through inhalation and dermal contact to fire fighters and cleanup workers involved with PCB transformer fires, to workers involved with incineration operations, and to workers handling pesticides, hexachlorophene, trichlorophenol, or other compounds which may contain small impurities of TCDD(2,SRC). [R175] *IN NITRO, WEST VA, USA, IN 1949 AND IN ITALY, SYMPTOMS THAT SUGGESTED EXPOSURE TO TCDD (ALTHOUGH AGENT WAS NOT IDENTIFIED) WERE OBSERVED IN WORKERS IN 2,4,5-T AND TRICHLOROPHENOL FACTORIES AFTER ACCIDENTAL EXPOSURES. SIMILAR SYMPTOMS WERE OBSERVED IN WORKERS IN 2 TRICHLOROPHENOL FACTORIES IN MITTLE RHINE IN FEDERAL REPUBLIC OF GERMANY IN 1952, IN A 2,4,5-T FACTORY IN USSR AND IN 1 IN MIDLAND, MICH, USA IN 1964. [R176] *OCCUPATIONAL EXPOSURE AND ENVIRONMENTAL CONTAMINATION MAY RESULT FROM FORMATION OF DIOXINS DURING THE SYNTHESIS OF 2,4,5-T, HEXACHLOROPHENE, and /SRP: PURE/ PENTACHLOROPHENOL. [R177] *For 2,4,5-T a Joint Committee of the Food and Agriculture Organization and the World Health Organization has stated (1980) that the "no-effect level" is 3 mg/kg/day and that the ADI for man is 0.003 mg/kg/day when the TCDD content of 2,4,5-T is 0.05 ppm. No similar calculation has been made for hexachlorophene. The USEPA has calculated that, taking into account the cumulative exposure (oral, dermal, and inhalation exposure), a worker would receive 7 mg/kg of 2,4,5-T and 0.0007 ug/kg of TCDD, which is definitely below the "no observable effect level" for TCDD. Whether these values can be accepted as a permissible limit of exposure at the workplace remains, at the moment, a matter of controversy. [R26, 642] *Cleanup workers inside the building in Binghamton, NY which experienced a PCB transformer fire in Feb 1981 were exposed to trace (detection limit not reported) inhalable levels of 2,3,7,8-TCDD two years after the transformer accident(1). A soot sample from inside the Binghamton building was found to contain a 2,3,7,8-TCDD concn of 0.6 ng/g(2). [R178] *At the Diamond Alkali Co, Newark, NJ, workers in the production of the sodium-2,4,5-trichlorophenate had potential exposure to 2,3,7,8-TCDD (a contaminant) while operating the autoclave reaction (20 ug/g), collecting samples from the reactor, operating the dilution/filtration product recovery system (10 ug/g), and operating the anisole still and product recovery system (70 ug/g)(1). Potential exposure to reslurry tank and acidification tank operators was at 20 ug/g. Pre-1967 potential exposure level for production and operator helpers performing formulations and aminizations was 20 ug/g; after 1967 these levels were 1 and 0.5 ug/g, respectively(1). [R179] *Polychlorinated dibenzodioxins and dibenzofurans were isomer-specifically detd by high resolution GC-mass spectrometry in different samples of coffee filter paper. 2,3,7,8-TCDD and tetrachlorodibenzofuran were the most abundant congeners in the lower parts per trillion range. Besides these compounds, several congeners of different alkylated tetrachlorodibenzofurans in distinctly higher concentrations were identified. About 20-35% of TCDD, tetrachlorodibenzofuran, and alkylated tetrachlorodibenzofurans passed from the coffee filter into the coffee extract in a simulated coffee brewing process. The daily intake of these compounds by a coffee drinker is estimated approx 10 pg TCDD equivalent. [R180] */Occupational exposure/ to 2,3,7,8-TCDD may result from steel mill /operations/. [R181] AVDI: *The maximum daily intake of 2,3,7,8-TCDD was estimated for residents of the Great Lakes region who regularly consume fish from the Great Lakes. The intake ranged from 0.39-8.4 ug/day. [R182] BODY: *Analysis of 46 composite samples prepared from 900 adipose tissue specimens detected a mean 2,3,7,8-TCDD concn of 5.0 pg/g with a range of not detected (1.0 pg/g) to 10 pg/g as conducted by the USEPA National Human Adipose Tissue Survey for fiscal year 1982(1). TCDD was detected in 25 of 46 Canadian human adipose tissue samples collected in 1976 at a mean concn of 6.4 pg/g(2). The concn of 2,3,7,8-TCDD in human breast milk from various European countries, the US, and Vietnam has been reported to range from below detection limits to 50 pg/g, with mean concns on the order of 1.0 pg/g(3). [R183] *The Center for Disease Control has reported that the mean serum TCDD level in Vietnam veterans (1967-8) heavily exposed to Agent Orange is 3.8 pg/g as compared to 3.9 pg/g in non-Vietnam veterans(1); serum levels in a group occupationally exposed to TCDD prior to 1970 has been reported to be 30-fold higher(1). 2,3,7,8-TCDD was detected in primapara breast milk fat at 13 parts per trillion avg, 255 samples, from preserved samples collected over a seven year period, 1978-1984, in Osaka prefecture, Japan(2). It was not detected in multipara samples(2). Food is the major source of human residues(3). The level of 2,3,7,8-TCDD in food (133 or 27 parts/quadrillion avg) accounts for the current level in the general population(3). The half-life in humans is 1 or 5 yrs, respectively(3). [R184] *Tetrachlorodibenzo-p-dioxin has been detected at levels ranging from 20 to 173 parts per trillion in adipose tissue from 3 Vietnam veterans who were "heavily exposed" to Agent Orange. Tissue samples from other Vietnam veterans and controls contained levels below 20 part per trillion. [R185] *Chlorinated dibenzo-p-dioxin and dibenzofuran were detected in samples of human milk collected in 1973 and 1985 in the south of Vietnam and the levels compared to samples taken in 1970 and present day North American samples. In the Vietnam samples from the 3 time periods between one half and two thirds were pos for 2,3,7,8-tetrachlorodibenzo-p-dioxin. Avg levels of the positives on a lipid basis, declined from approx 484 pg/gram in 1970, to 121 picograms/gram in 1973 and then to 12 pg/gram in 1985. The latter value is higher but similar to the value of approx 5 pg/gram presently found in samples from in North American milk and much higher than that found in samples from north of Vietnam where Agent Orange was not used. The avg body burden of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the nursing mothers from 1970 and 1973 was est to be 3.6 and 0.98 ug, respectively. [R186] *TCDD were measured in serum specimens from Seveso, Italy, residents, who were potentially highly exposed to the 1976 explosion, and in controls. The residents were chosen so as to represent those who did and did not develop chloracne. Levels of TCDD as high as 56,000 parts per trillion were found in these serum specimens that were collected in 1976. These TCDD levels are the highest ever reported, and yet almost all clinical laboratory tests on these individuals were normal; any abnormal test result was only transitory in nature. These findings are unique in linking clinical histories to TCDD levels following an acute exposure. [R187] *A pilot study was conducted to determine whether patients could be found with elevated dioxin levels in Vietnam at the present time. Detectable levels of TCDD were found in the adipose tissue of eight of nine hospitalized female patients at the Phu San Obstetrical and Gynecological Hospital at Ho Chi Minh City in 1984 and 1985. Patients ranged in age from 22 to 52, and had been selected for study because of probable exposure to phenoxyherbicides. The adipose tissue TCDD values for these patients ranged from 4 to 103 parts per trillion, with a mean of 23 parts per trillion. The levels of TCDD were higher than currently seen levels in the general population of industrialized countries by a factor of about three to four times. The levels were significantly higher than for patients from the north of Vietnam. Agent-Orange was the most probable, and only known TCDD source. However, the existence of levels of polychlorinated dibenzodioxins and polychlorinated dibenzofurans with five through eight chlorines suggest a secondary source such as pentachlorophenol or incineration. In some cases a correlation was determined between a history of herbicide exposure, or lack of known exposure, and TCDD level. A history of nursing after exposure was sometimes associated with relatively lower TCDD tissue levels. With more extensive nursing, it appeared that the levels may be lower than with little or no nursing history in a given patient. [R188] *Review of employment and chemical production records at a Missouri chemical plant and of questionnaires with self-reported occupational exposure to 2,3,7,8-TCDD for 16 Missouri workers has explained the wide diversity of 2,3,7,8-TCDD levels previously reported in the workers adipose tissue (3.5-750 parts per trillion on whole-weight basis). /Data indicate that/ the highest exposures reported to date in the United States occurred in a group of nine production workers who made products contaminated with 2,3,7,8-TCDD. The nine workers had adipose tissue levels with a mean of 246 parts per trillion and a range of 42 to 750 parts per trillion. Seven persons who worked at the same chemical company, but not in the 2,3,7,8-TCDD-contaminated process, had a mean of 8.7 parts per trillion and range of 3.5 to 25.8 parts per trillion. ... Serum levels of 2,3,7,8-TCDD in these individuals /is provided/. The adipose tissue from a subset of four production workers with elevated levels of 2,3,7,8-TCDD and seven Missouri residents with normal 2,3,7,8-TCDD was also analyzed for other isomers of the polychlorinated dibenzodioxins and polychlorinated dibenzofurans. The mean adipose tissue level of 2,3,7,8-TCDD in the subset of production workers was 45 times higher than the mean level in the unexposed Missouri residents, but similar levels of the other polychlorinated dibenzodioxins and polychlorinated dibenzofurans were found in both groups. [R189] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers 2,3,7,8-tetrachlorodibenzo-p-dioxin to be a potential occupational carcinogen. [R16, 298] NREC: *Agent recommended by NIOSH to be treated as a potential human carcinogen. Reduce exposure to lowest feasible concn. [R190] +NIOSH considers 2,3,7,8-tetrachlorodibenzo-p-dioxin to be a potential occupational carcinogen. [R16, 298] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R16, 298] OOPL: *One contaminant produced unintentionally during the manufacture of chlorophenols and phenoxy herbicides is TCDD. The resulting TCDD-containing wastes have been detected at many hazardous waste sites which in recent years have been in the process of remediation. Concerns about worker exposure to TCDD-contaminated soil (dust) during remediation of hazardous waste sites have produced a need for an occupational exposure limit for TCDD. The animal toxicology data and human experience with TCDD are reveiwed, and an occupational exposure limit for TCDD is proposed. The animal data support risk estimations which are based on TCDD as a nongenotoxic carcinogen. Studies on human populations have failed to demonstrate clearly any significant long-term health effects at levels to which humans have been exposed. The data indicate that an 8-hr time-weighted average limit of 2 ng/cu m is appropriate, and the associated risk would be consistent with other carcinogens at their corresponding occupational exposure limits. A preliminary occupational exposure limit of 0.2 ng/cu m (200 pg/cu m) is recommended, however, in light of other sources of exposure because of TCDD's ubiquitousness in the environment, its unclear mechanism of action, and its rather long biological half-life in humans. This limit provides an ample margin of safety to prevent chloracne following repeated, acute exposure, and it addresses those chronic effects of TCDD observed in animal studies as well as those observed after accidental human exposure. The resulting body burden caused by chronic exposure to TCDD at the proposed occupational exposure limit is examined. Its toxicological significance is compared with human tissue data and with other similarly persistent chemicals. [R191] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 2,3,7,8-Tetrachlorodibenzo-p-dioxin is included on this list. [R192] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 0.00003 ug/l [R193] STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 0.000003 ug/l [R193] +(ME) MAINE 0.0000022 ug/l [R193] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. [R194] +The levels that may result in an increase of cancer risk over the lifetime are estimated at 10-5, 10-6, and 10-7. The corresponding recommended criteria ... for consumption of water ... the levels are 2.2x10-6, 2.2x10-7, and 2.2x10-8 ug/l, respectively. [R195] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1 lb or 0.454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R196] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *EPA Method 8280. Sampling procedure for the analysis of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans. For the determination of 2,3,7,8-TCDD, grab and composite samples must be collected in glass containers. Conventional sampling practices must be followed. The bottle must not be prewashed with sample before collection. Composite samples should be collected in glass containers. Sampling equipment must be free of tygon, rubber tubing, other potential sources of contamination which may absorb the target analytes. All samples must be stored at 4 C, extracted within 30 days, and completely analyzed within 45 days of collection. [R197] *Grab samples are collected in clean amber glass bottles of 1 l or 1 quart capacity filled with screw caps lined with Teflon or aluminum foil. All samples must be extracted within 7 days and completely analyzed within 40 days of extraction. /Polychlorinated dibenzo-p-dioxins/ [R198] ALAB: *All aspects of the use of mass spectrometry for identification and quantitation of chlorodibenzo-p-dioxins (incl TCDD) are critically reviewed. [R199] *AREAL Method TO-9. Capillary Gas Chromatography/High Resolution Mass Spectrometry. Detection limit of 1 pg/m3 in air. [R200] *EPA Method 8280. Matrix-specific Extraction, Analyte Specific Clean-up, and High Resolution Capillary Column Gas Chromatography/Low-Resolution Mass Spectrometry (HRGC/LRMS) techniques. These techniques are appropriate for the determination of polychlorinated dibenzodioxins and dibenzofurans including 2,3,7,8-tetrachloro-dibenzo-p-dioxin chemical wastes. For (13)C 12-labeled 2,3,7,8-tetrachlorodibenzo-p-dioxin the method detection limit is 0.13 parts per trillion in fuel oil/sandust. The method performance results included the following: for 2,3,7,8-tetrachlorodibenzo-p-dioxin in sludge the RSD is 4.4 at a spiked analyte level of 5.0 ng/g and the mean percent recovery is 61.7 at a spiked analyte level of 5.0 ng/g. [R201] *EPA Method 613. Gas Chromatography/Mass Spectrometry for the analysis of 2,3,7,8-tetrachlorodibenzo-p-dioxin in industrial and municipal discharges. Under the prescribed conditions, the method has a detection limit of 0.002 ug/l. Precision and method accuracy were found to be directly related to the concentration of the parameter and essentially independent of the sample matrix. [R202] *Clean-up techniques are described for gas chromatography-mass spectrometric measurement of parts per trillion levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in milk, cream, grain, feed, dry plant material, wet plant material, and soil. Sensitivity of 10 parts per trillion TCDD was obtained for most types of samples. [R203] *... Utilizing a DB-225 or DB-17 capillary column and high resolution (10,000 RP) mass spectrometry, baseline resolution has been obtained for this isomer, without recourse to more exotic columns allowing simple quantification of this isomer. A brief investigation has been made into the application of Selected Decomposition Monitoring as a quantitative alternative to high-resolution mass spectrometry on a heavily contaminated environmental sample, and comparisons in sensitivity made with similar samples run using conventional SIM high-resolution and low-resolution mass spectrometry. [R23] *CLP Dioxin Method. USEPA; Contract Laboratory Program, Statement of Work 9/86, Form IFB Series, WA86-K357, USEPA, Washington, DC 20460, August 1987. Capillary Gas Chromatography/Mass Spectrometry. Detection limits of 1 ug/kg in soil and 10 ng/L in water. [R204] *EAD Method 1613. 1600 Series Wastewater Methods. Capillary Gas Chromatography/High Resolution Mass Spectrometry. Detection limits of 1 ng/kg in soil and 10 pg/L in water. [R204] *EMSCL Method 513. Capillary Gas Chromatography/Mass Spectrometry. Detection limit 20 pg/L. [R205] CLAB: *Clean-up techniques are described for gas chromatography-mass spectrometric measurement of part per trillion levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in blood. Sensitivity of 10 part per trillion TCDD was obtained for most types of samples. [R203] *... The competition enzyme linked immunosorbtion assay is able to easily detect 0.5 ng of 2,3,7,8-tetrachlorodibenzo-p-dioxin. [R206] *An analytical method to measure 2,3,7,8-tetrachlorodibenzo-p-dioxin and other 2,3,7,8-tetrachlorodibenzo-p-dioxin isomers in human serum which uses a highly specific cleanup procedure and high-resolution gas chromatography/high resolution mass spectometry was described. The 2,3,7,8-tetrachlorodibenzo-p-dioxin is quantified by the isotope dilution technique with (13)C12-2,3,7,8-tetrachlorodibenzo-p-dioxin as the internal standard. The 1.25 part per quadrillion limit of detection for 200 g samples is more than adequate for determining 2,3,7,8-tetrachlorodibenzo-p-dioxin concentrations in human serum specimens. The method is modified for analyzing 50 g and 10 g serum samples. Analytical accuracy is demonstrated by the results obtained in analyzing spiked samples. The method is shown to be unaffected by a number of potentially interfering cmpd. For 200 g samples containing 25.8 parts per quadrillion of native 2,3,7,8-tetrachlorodibenzo-p-dioxin, a coefficient of variation of 13.0% was observed (n= 20). For 10 g from a pool fortified with 2,3,7,8-tetrachlorodibenzo-p-dioxin (1.9 parts per trillion, n= 22), a coefficient of variation of 15.5% was observed. [R207] *Analytical methods for the determination of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other tetrachlorodibenzo-p-dioxin congeners in human tissue samples, both on a whole weight and lipid basis were developed. Human adipose tissue samples from the anterior abdominal wall were spiked with 24 parts per trillion carbon 13 labelled 2,3,7,8-tetrachlorodibenzo-p-dioxin. After removal of any obvious nonfatty portions, five slices of the tissue sample were independently analyzed for lipids and tetrachlorodibenzo-p-dioxin using an automated mass spectrometry gas chromatography system. Determination of tetrachlorodibenzo-p-dioxin on a whole weight basis was performed on an homogenate of the remaining portion of the adipose tissue sample. Recoveries of 2,3,7,8-tetrachlorodibenzo-p-dioxin were generally greater than 85%. Agreement between duplicate tissue samples was usually within 10%. The precision associated with tetrachlorodibenzo-p-dioxin determination on a whole weight basis was better than on a lipid basis, but the lower precision of the lipid basis procedure was compensated for by analyzing multiple slices of each sample. [R208] *AN ANALYTICAL PROCEDURE HAS BEEN DEVELOPED AND UTILIZED FOR THE DETERMINATION OF APPROXIMATELY 10 TO 100 PARTS PER TRILLION CONCENTRATIONS OF TCDD IN FISH. THE TECHNIQUE INVOLVES DIGESTION AND EXTRACTION OF THE MATRIX FOLLOWED BY A SERIES OF ADSORBENT, AND CHEMICALLY-MODIFIED ABSORBENT, LIQUID COLUMN CHROMATOGRAPHIC CLEAN-UP STEPS ... AND DETECTION BY MULTIPLE ION MODE GAS CHROMATOGRAPHY-MASS SPECTROMETRY. USING 14C-LABELED TCDD AS AN INTERNAL STANDARD AND CARRIER, THE PROCEDURE HAS BEEN VALIDATED FOR RAINBOW TROUT FROM APPROXIMATELY 10 TO 100 PARTS PER TRILLION TCDD. [R209] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: WHO; Environ Health Criteria 88: Polychlorinated Dibenzo-para-dioxins and Dibenzofurans p.262 (1989) YOUNG AL ET AL; US NTIS AD REP AD-A062, 143: 247 (1978). USE IN SOUTH VIETNAM OF AGENT ORANGE, ITS TOXICOLOGY, ENVIRONMENTAL FATE AND HUMAN RISK WERE REVIEWED, INCL NATURE AND QUANTITIES, THEIR HANDLING AND APPLICATION. EMPHASIS WAS PLACED ON HERBICIDE ORANGE AND ITS ASSOC CONTAMINANT TCDD. Young AL et al; Chlorinated Dioxins as Herbicide Contaminants. Environ Sci Technol 17 (11): 530A-40A (1983). A report on studies by the Veterans Administration and other federal agencies concerning chlorinated dioxins as herbicide contaminants, with special focus on veterans of Vietnam, where "Agent Orange" was used. C and E News: June 6 (1983). A special issue concerning dioxin. Kociba RJ, Schwetz BA; Toxicity of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), Drug Metab Rev 13 (3): 387-406 (1982). Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin has been comprehensively examined in multiple acute, subchronic, and chronic studies and some of these results are given. Information is given which is helpful in assessing hazard of exposure to TCDD. Poland A, Knutson JC; 2,3,7,8-Tetrachlorodibenzo-p-dioxin and Related Halogenated Aromatic Hydrocarbons: Examination of the Mechanisms of Toxicity, Annual Rev Pharmacol Toxicol 22: 517-54 (1982). In this review the biochemical and toxic responses produced by halogenated aromatic hydrocarbons (incl TCDD) are examined and efforts to develop a model for their mechanism of action are discussed. DHHS/ATSDR; Toxicological Profile for 2,3,7,8-Tetrachlorodibenzo-p-Dioxin ATSDR/TP-88/23 (1988) USEPA; Ambient Water Quality Criteria Doc: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (1984) EPA 400/5-84-007. USEPA; Health Risk Assessment Approach for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (1985) EPA 600/8-85-013. USEPA; Drinking Water Criteria Document for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (1985) EPA 600/x-84/94-1. Nat'l Research Council Canada; Title (1981) NRCC No. 18574 USEPA; Dioxins (1980) EPA 600/2-80-197 Milby TH; Potential Health Effects Associated with the Use of Phenoxy Herbicides: A Summary of Recent Scientific Literature (1981). USEPA; Health Effects Assessment for 2,3,7,8-Tetrachlorodibenzo-p-dioxin (1984) EPA 540/1-86-044. USEPA; Health Assessment Document for Polychlorinated Dibenzo-p-dioxins (1985) EPA 600/8-84/014F Mabey WR et al; Aquatic Fate Process Data for Organic Priority Pollutants (1981) EPA-440/4/81/014. Fingerhut MA et al; ACS Symp Ser 338: 142-61 (1987). Review of the epidemiology of human exposure to tetrachlorodibenzodioxin. Scientific Review Committee, American Academy of Clinical Toxlcology; J Toxicol Clin Toxicol 23 (2-3): 191-204 (1985). A review with 43 references on documented cases of human exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin and the resulting pathology and on experimental exposure to lab animals. Vet Hum Toxicol 27: 434-8 (1985). A review of the literature on the epidemiology, kinetics, animal toxicity, teratogenicity, human exposure, skin effects and other symptoms of toxicity of the dioxin isomer 2,3,7,8-tetrachlorodibenzo-p-dioxin is presented. Ayres SM et al; Environ Health Perspect 62: 329-35 (1985). A review with 44 references on the carcinogenicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in humans and laboratory animals. Dencker L; Arch Toxicol Suppl 8: 43-60 (1985). A review with 64 references on the role of receptors in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity. Giri AK; Mutat Res 168 (3): 241-8 (1986). A discussion on the mutagenicity and genotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Greenlee WF et al; Rev Biochem Toxicol 8: 1-35 (1987). The studies of mechanisms of skin toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin are described, with particular emphasis on the cellular and molecular targets for the pathological responses observed in interfolicular epidemics. Hatch MC, Stein ZA; Teratog Carcinog Mutagen 6 (3): 185-202 (1986). RRM review Vietnam veterans and 2,3,7,8-tetrachlorodibenzo-p-dioxin. Kimbrough RD, Houk VN; ACS Symp Ser 338: 68-79 (1987). Review tetrachlorodibenzodioxin effect on human health. Poellinger L et al; Mol Mech Steroid Horm Action 755-89 (1985). Comparison of the receptor for 2,3,7,8-tetrachlorodibenzo-p-dioxin with steroid hormone receptors with respect to gene regulation, physiochemical characterization, ligand binding, and interaction with DNA was studied. Fishbein L; Toxicol Ind Health 3 (1): 91-134 (1987). A review of the carcinogenic potential of 2,3,7,8,-tetrachlorodibenzo-p-dioxin and the assumptions underlying risk assessments. Roberts EA et al; Chemosphere 14 (6-7): 661-74 (1985). The Ah receptor and its role in 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity and evidence that a similar receptor system exists in human cells and tissues is discussed. Tarowski S, Yrjanheikki E; Chemosphere 15 (9-12): 1641-8 (1986). A review of 2,3,7,8-tetrachlorodibenzo-p-dioxin ... in human organs and milk in relation to the risk assessment for infants associated with breast feeding. Whitlock JP; Pharmacol Rev 39 (2): 147-61 (1987). The regulation of gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. 56 FR 50903 (10/09/91). Public meeting concerning EPA's scientific reassessment of 2,3,7,8-tetrachloro-p-dioxin. USEPA/OHEA; A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD (Draft) (1988) EPA 600/6-88-007Aa USEPA/OHEA; A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD Appendeces A-F (Draft) (1988) EPA 600/6-88-007Ab USEPA/OHEA; Estimating Exposures to 2,3,7,8-TCDD (Draft) (1988) EPA 600/6-88-05A (Draft) (1988) EPA 600/6-88-005A USEPA/SAB; Report of the Ad Hoc Dioxin Panel of the Science Advisory Board: Review of Draft Documents: "A Cancer Risk-Specific Dose Estimate for 2,3,7,8-TCDD" and "Estimating Exposure to 2,3,7,8-TCDD (1990) EPA-SAB-EC-90-003 Lilienfeld DE, Gallo MA; 2,4-D, 2,4,5-T, and 2,3,7,8-TCDD: An Overview; Epidemiologic Reviews 11: 28-58 (1989). A review A review was presented on the history of the use of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) and included toxicologic and epidemiologic profiles ... . Lijinsky W; Non-genotoxic Environmental Carcinogens; J Environ Sci Health Part C Environ Carcinog Rev 8 (1): 45-88 (1991). Review of rat, mouse, human, guinea pig stomach, liver, kidney, lung tumors /from/ dioxin. A review was provided of the current status of immunotoxicology concentrating on examples of environmental chemicals that produce immunosuppression in humans and animals rather than sensitizers. A discussion was also presented of 2,3,7,8-tetrachlorodibenzo-p-dioxin which typifies the difficulties in using immunotoxicology data in risk assessment. [R210] Safe S, Phil D; Polychlorinated Diphenyls, Dibenzo-p-dioxins, Dibenzofurans, and Related Cmpd: Environmental and Mechanistic Considerations Which Support the Development of Toxic Equivalency Factors; Crit Rev Toxicol 21 (1): 51-88 (1990). Review of human diphenyl ethers and 2,3,7,8-Tetrachlorodibenzo-p-dioxin in-vitro and in-vivo assays. Sheehan DM et al; Workshop on Risk Assessment in Reproductive and Developmental Toxicology Addressing the Assumptions and Identifying the Research Needs; Regul Toxicol Pharmacol 10 (2): 110-22 (1989). A workshop was organized to specifically define the assumptions underlyng the risk assessments for seven specific toxicants, including dioxin. This report is a summary of the workshop discussions. Couture LA et al; A Critical Review of the Developmental Toxicity and Teratogenicity of 2,3,7,8-Tetrachlorodibenzo-p- dioxin: Recent Advances Toward Understanding the Mechanism; Teratology 42 (6); 619-28 (1990) Skene SA et al; Hum Toxicol 8 (3): 173-204 (1989). Polychlorinated Dibenzo-P-Dioxins and Polychlorinated Dibenzofurans The Risk to Human Health A review. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) DHHS/NTP; Carcinogenesis Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Swiss-Webster Mice (Dermal Study) Technical Report Series No. 201 (1982) NIH Publication No. 82-1757 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for 2,3,7,8-tetrachlorodibenzodioxin is in progress. Route: gavage; Species: toxic equivalency factor evaluation, rats. [R211] HIST: *EXPLOSION WHICH PRODUCED CLOUD CONTAINING TCDD WHICH SETTLED OVER SEVESO, ITALY MANY WEEKS PASSED BEFORE PUBLIC WAS ALERTED TO DANGERS, CHILDREN WERE ALREADY SUFFERING FROM CHLORACNE AND MANY ANIMALS HAD DIED. EFFECTS OF TCDD ON PREGNANT WOMEN AND THEIR BABIES SHOW HIGHER INCIDENCE OF SPONTANEOUS ABORTION IN TCDD EXPOSED MOTHERS. OTHER FINDINGS SUGGEST DELETERIOUS EFFECTS ON PERIPHERAL NERVOUS SYSTEM, AS WELL AS LIVER DAMAGE. [R212] *A chemical plant failure 13 miles north of Milan, Italy produced a dangerous contamination of inhabited areas. Environmental specimens were sampled and analyzed to assess distribution of tetrachlorodibenzo-p-dioxin in soil surface layer. On basis of contamination maps, 3 zones were established: Zone A, Zone B, AND Zone R which enclosed the former 2. This report describes the procedure adopted to assess contamination of soil due to 2,3,7,8-tetrachlorodibenzo-p-dioxin. TCDD concn were seen to vary, ranging from less than 0.75 to approx 20X10+3 ug/m sq. TCDD levels were highest in Zone A, while Zones B AND R exhibited lower levels of below 50 and below 5 ug/m sq, respectively. [R213] *TCDD WAS COMPONENT OF PRODUCTS OF EXPLOSION WHICH TOOK PLACE IN 1963 AT PHILIPS DUPHAR 2,4,5-T FACTORY IN NETHERLANDS. ... AN ESTIMATED 30-200 G TCDD WERE RELEASED ... TCDD WAS IDENTIFIED AS PRODUCT OF EXPLOSION WHICH OCCURRED IN COALITE COMPANY'S 2,4,5-TRICHLOROPHENOL FACTORY IN UK IN 1968 ... QUANTITY RELEASED WAS NOT ESTIMATED. ... [R214] *Whether levels of environmental exposure to TCDD were sufficient to produce enzyme induction in man, has been investigated in Seveso, Italy where in July 1976 explosion in a factory spread toxic substances, one of which was TCDD, to the surrounding area. The hepatic microsomal enzyme activity was assessed by estimating urinary d-glucaric acid excretion in children 6-8 yr old. In 31 children, urine samples were collected between August and December 1976; in 67 other children in February 1979. As control, 60 children living in Busto Arsizio (a small industrial town near Milan) and 26 living in Cannero (a non-industrialized village on Lake Maggiore) were chosen. The study concluded that many children living in Seveso area have an increased activity of hepatic microsomal enzymes. [R215] *TETRACHLORODIBENZO-P-DIOXIN (TCDD) ... /WAS/ IDENTIFIED AS CAUSE OF OUTBREAK OF POISONING IN HUMANS ... IN 1971. EXPOSURE WAS RELATED TO THE SPRAYING OF WASTE OIL CONTAMINATED WITH TCDD ON RIDING ARENAS FOR DUST CONTROL. MOST SEVERE EFFECTS OCCURRED IN 6-YR OLD GIRL WHO PLAYED IN ARENA SOIL. HER SYMPTOMS INCL HEADACHE, EPISTAXIS, DIARRHEA, LETHARGY, HEMORRHAGIC CYSTITIS AND FOCAL PYELONEPHRITIS. THREE OTHER CHILDREN AND 1 ADULT WHO WERE FREQUENTLY IN THE ARENA COMPLAINED OF SKIN LESIONS. IN AT LEAST 2 OF CHILDREN, LESIONS DESCRIBED WERE ... CONSISTENT WITH CHLORACNE. INTERMITTENT ARTHRALGIAS IN 2 ADULTS HAVE BEEN ASSOCIATED WITH PREVIOUS EXPOSURE TO THE ARENA. [R216] *LONG TERM FOLLOWUP OF WORKERS EXPOSED TO TCDD AS RESULT OF ACCIDENT IN 1949 AT A 2,4,5-T PRODUCTION PLANT WAS MADE. OF WORKERS PRESENT ON DAY OF REACTOR EXPLOSION, 121 CASES OF CHLORACNE, WERE IDENTIFIED. FOLLOWUP RECORDS ON 121 CHLORACNE VICTIMS 29 YR LATER WERE 100% COMPLETE; 89 WORKERS WERE STILL LIVING AND 32 WERE TRACED BY DEATH RECORDS. NO EXCESS MORTALITY WAS OBSERVED AMONG COHORT WHEN COMPARED TO STD POPULATION FROM MODIFIED LIFE TABLE PROGRAM. NO STATISTICALLY SIGNIFICANT INCR IN DEATH DUE TO CIRCULATORY DISEASES OR MALIGNANT NEOPLASMS WERE FOUND IN TETRACHLORODIBENZO-P-DIOXIN EXPOSED GROUP WHEN COMPARED TO STD POPULATION. HOWEVER, BECAUSE OF SMALL SIZE OF COHORT POPULATION, RESULTS OF THIS STUDY ARE CONSIDERED INCONCLUSIVE. [R217] *Twenty-seven yr after an accident at the Badische Anilin und Soda Fabrik factory in Ludwigshafen on November 17 1953, a mortality study of persons exposed to dioxin in an uncontrolled reaction during trichlorophenol process was undertaken. Follow-up was 100% successful and involved 74 persons. Overall mortality (21 deaths) did not differ in this group from rate expected in 3 external reference populations or from that observed in 2 internal comparison groups, where 18-20 deaths were observed. Of 21 deceased persons, 7 had cancer, compared with 4.1 expected. In addn, 2 other cases of cancer (1 bronchial carcinoma, and 1 carcinoma of prostate) are still alive. Three deaths due to stomach cancer, at ages 64, 66 and 69 yr, were found, compared with 0.6 expected from regional mortality data. One stomach cancer occurred among 148 individuals in the 2 comparison cohorts. [R218] *Ten years after the incident at Coalite Oils and Chemicals Ltd, /in which/ 79 workers developed chloracne due to exposure to tetrachlorodibenzodioxin, a study was undertaken to establish current state of health of affected employees remaining in the company's employment. Half of affected subjects still had minor chloracne. Other than this there was no evidence that they had been adversely affected in any way. [R219] *In the late 1960s a chemical company in southern Missouri, which had produced 2,4,5-trichlorophenoxyacetic acid, ceased production and leased the facilities to another company which produced hexachlorophene and 2,4,5-trichlorophenol. Between Feb and Oct 1971, an estimated 21,500 gallons of contaminated waste oil were removed from this plant for disposal. Much of this material was used for spraying roads and horse arenas for dust control. A number of 57 horses became ill and subsequently died. These horses exhibited extreme weight loss and alopecia. There were 26 known abortions, and many foals, exposed only in utero, died at birth or shortly after. Postmortem examinations showed severe emaciation , hepatic damage, gastric ulcers, atrophy of the spleen, and skin lesions. Many cats and dogs straying in the arena areas died with the same symptoms. 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Report No. IWS-117-116 pp. 52 (1986) R180: Beck H et al; Chemosphere 19 (1-6): 655-60 (1989) R181: Antonsson AB et al; Chemosphere 19 (1-6): 699-704 (1989) R182: Cordle F, Use of Epidemiology in the Regulation of Dioxins in the Food Supply (1983) as cited in USEPA; Drinking Water Criteria Document for 2,3,7,8-Tetrachlorodibenzo-p-dioxin p.IV-3 (1985) EPA 600/x-84/94-1 R183: (1) Stanley JS et al; Chemosphere 15: 1605-12 (1986) (2) Ryan JJ; Chemosphere 15: 1585-93 (1986) (3) DHHS/ATSDR; Toxicological Profile for 2,3,7,8-Tetrachlorodibenzo-p-dioxin ATSDR/TP-88/23 (1988) R184: (1) DHHS/ATSDR; Toxicological Profile for 2,3,7,8-Tetrachlorodibenzo-p-dioxin ATSDR/TP-88/23 (1988) (2) Ogaki J et al; Chemosphere 16: 2047-56 (1987) (3) Byard JL; J Toxicol Environ Health 22: 381-403 (1987) R185: (1) Gross ML et al; Environ Res 33 (1): 261-8 (1984) R186: (1) Schecter et al; Chemosphere 16 (8-9) 2003-16 (1987) R187: Mocarelli P et al; J Toxicol Environ Health 32 (4): 357-66 (1991) R188: Phuong NTN et al; Chemosphere 19 (1-6): 933-6 (1989) R189: Patterson DG Jr et al; Am J Ind Med 16 (2): 135-46 (1989) R190: NIOSH/CDC. NIOSH Recommendations for Occupational Safety and Health Standards 1988, Aug. 1988. (Suppl. to Morbidity and Mortality Wkly. Vol. 37 No. 5-7, Aug. 26, 1988). Atlanta, GA: National Institute for Occupational Safety and Health, CDC, 1988.25 R191: Leung HW et al; Am Ind Hyg Assoc J 49 (9): 466-74 (1988) R192: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R193: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R194: 40 CFR 401.15 (7/1/88) R195: USEPA; Quality Criteria for Water 1986: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (May 1,1986) EPA 440/5-86-001 R196: 40 CFR 302.4 (7/1/92) R197: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R198: USEPA, Health Effects Assessment for 2,3,7,8-Tetrachlorodibenzo-p-dioxin p.3-20 (1984) EPA 540/1-86-044 R199: Mahle NH, Shadoff LA; Biomed Mass Spectrom 9 (2): 45-60 (1982) R200: USEPA/Atmospheric Research and Exposure Laboratory (AREAL); Compendium of Methods for the Determination of Toxic Organic Compounds in Ambient Air (1988) EPA/600/4-89/017 R201: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/Chemical Methods SW846 Methods (1986) R202: 40 CFR 136 (7/1/90) R203: Hummel RA; J Agric Food Chem 25 (5): 1049-53 (1977) R204: USEPA; EMMI. Environmental Monitoring Methods Index. Version 1.02. EPA- 821-B-92-001 (NTIS PB-92-503093). August 1992 R205: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water Supplement 1, 500 Series Methods (1990) EPA/600/4-90/020 R206: Stanker LH et al; Toxicology 45 (3): 229-44 (1987) R207: Patterson DG et al; Anal Chem 59 (15): 2000-5 (1987) R208: Patterson DG; Chemosphere 16 (15): 935-6 (1987) R209: LAMPARSKI LL ET AL; ANAL CHEM 51 (9): 1453-8 (1979) R210: Luster MI et al; Immunotoxicity: Review of Current Status; Annals of Allergy 64 (5): 427-32 (1990) R211: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 R212: BONACCORSI A ET AL; AMBIO 7 (5-6): 234-9 (1978) R213: Di Domenico A et al; Ecotoxicol Environ Safety 4 (3): 298-320 (1980) R214: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V15 54 (1977) R215: Ideo G et al; Clin Chim Acta 120 (3): 273-83 (1982) R216: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V15 84 (1977) R217: ZACK JA, SUSKIND RR; J OCCUP MED 22 (1): 11-4 (1980) R218: Thiess AM et al; Am J Indust Med 3 (2): 179-89 (1982) R219: May G; Br J Ind Med 39 (2): 128-35 (1982) RS: 214 Record 262 of 1119 in HSDB (through 2003/06) AN: 4155 UD: 200205 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GUM-TARA- SY: *NCI-C54364-; *TARA-GUM- RN: 39300-88-4 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DERIVED FROM SEED GUM OF THE TARA TREE [R1] MFS: *NOT PRODUCED COMMERCIALLY IN US [R1] OMIN: *SUGGESTED THAT BECAUSE OF ITS CLOSE BOTANICAL RELATIONSHIP WITH AND SIMILAR CHEM COMPOSITION TO GUAR SEED AND CAROB BEAN MEAL, ITS PURITY AND HARMLESSNESS IN ANIMAL EXPT, TARA SEED MEAL MAY BE USED IN FOOD INDUST AS THICKENING, BINDING AND STABILIZING AGENT. [R2] *MEAL IS 77-78% POLYSACCHARIDE CONSISTING OF GALACTOSE AND MANNOSE- GALACTOMANNAN. RELATIONSHIP BETWEEN MANNOSE AND GALACTOSE 3:1, MANNOSE APPROX 70-80%, GALACTOSE APPROX 20-30%. METAL CONTAMINANTS IN PPM (MG/KG): IRON 30, COPPER 5, ZINC 10, LEAD 5, MERCURY 3. [R2] *MEAL CONSISTS OF 77-78% GALACTOMANNAN, 14-15% MOISTURE, 2.5% FIBER CONTENT (ACID INSOL), 3-4% NITROGEN COMPD, 1.5% MINERALS (ASH), and 1% ETHER SOLUBLE COMPD. [R2] *INCOMPATIBILITIES: MEAL IS VERY COMPATIBLE WITH OTHER THICKENING, BINDING AND STABILIZING AGENTS. BORATES AND BORIC ACID CAUSE GEL FORMATION. ALCOHOL, ACETONE AND OTHER ORGANIC SOLVENTS IN INCR CONCN CAUSE PRECIPITATION. [R2] *SOLUBILITY OF MEAL DEPENDS ON CONTENT OF GALACTOSE, INCR IN GALACTOSE INCREASES SOLUBILITY. DEGRADED BY BACTERIA AND FUNGI AND SEED SPECIFIC ENZYMES- CARUBINASES. 0.2-0.3% P-HYDROXYBENZOIC ACID ESTER AND SODIUM PENTACHLOROPHENOL ARE EFFECTIVE AS PRESERVATIVES. [R2] *GUMS ARE POLYSACCHARIDES WHICH DISPERSE IN COLD OR HOT WATER TO PRODUCE VISCOUS SOLN. THEY IMPART HIGH VISCOSITY EVEN WHEN DISSOLVED AT LOW CONCN. USE: *IN FOOD PRODUCTS *THICKENING AGENT IN FOOD (NON-US USE) [R1] *In ice creams and cosmetics [R3] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Off-white powder [R4] SOL: *DMSO: < 1 mg/ml @ 17 deg C; 95% ethanol: < 1 mg/ml @ 17 deg C; acetone: < 1 mg/ml @ 17 deg C [R5]; *In water, < 1 mg/ml @ 17 deg C [R5] OCPP: *MEAL IS NEUTRAL AND ALMOST ODORLESS [R2] *VISCOSITY O 1% AQ SOLN, PH 3.0-7.5 APPROX 2000-3600 CPS [R2] *MEAL: LIGHT YELLOW-WHITE POWDER [R2] *SOL: 40-60% IN H2O [R2] *When heated to decomposition it emits acrid smoke and irritating fumes [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *PH BELOW 3.0 AND HEATING INCR HYDROLYSIS OF AQ SOLN [R2] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *IN 90-DAY FEEDING EXPT MALE AND FEMALE RATS RECEIVED 0.1, 2, 5% MEAL IN DIET. COMPARED TO CONTROLS NO CHANGES WERE NOTICED IN WELL BEING, BLOOD AND URINE VALUES, GROWTH, WEIGHT, AND MORTALITIES. THERE WERE NO PATHOLOGICAL FINDINGS. [R2] METB: *IN EXPERIMENTS WITH HUMAN GASTRIC AND DUODENAL JUICE THERE WAS NO EVIDENCE THAT TARA SEED MEAL IS DIGESTIBLE OR DEGRADABLE. [R2] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *NATURAL OCCURRENCE: MEAL IS PRODUCT OF ENDOSPERM OF TARA SEEDS, LEGUMINOUS PLANT CAESALPINA SPINOSA L, CULTIVATED IN PERU AND ECUADOR. RELATED TO GUAR SEED AND CAROB BEAN MEAL ALSO DERIVED FROM LEGUMINOUS PLANTS. [R2] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R7] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tara Gum in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 224 (1982) NIH Publication No. 82-1780 SO: R1: SRI R2: BENK E; TARA GRAIN MEAL; RIECHST, AROMEN, KOSMET 27(10) 275 (1977) R3: Department of Health and Human Services USA, National Toxicology Program (NTP). Available from: http://ntp-server.niehs.nih.gov/htdocs/Results_status/ResstatT/10793-E.html as of May, 2000 R4: Department of Health and Human Services USA, National Toxicology Program (NTP). Available from: http://ntp-db.niehs.nih.gov/NTP_Reports/NTP_Chem_H and S/NTP_Chem3/Radian39300- 88-4.txt as of May, 2000 R5: Department of Health and Human Services USA, National Toxicology Program (NTP). Available from: http://ntp-db.niehs.nih.gov/NTP_Reports/NTP_Chem_H and S/NTP_Chem3/Radian39300-88-4. txt as of May, 2000 R6: Sax, N.I. Dangerous Properties of Industrial Materials. Vol 1-3 7th ed. New York, NY: Van Nostrand Reinhold, 1989. 1830 R7: 21 CFR 200-299, 300-499, 820, and 860 (4/1/99) RS: 6 Record 263 of 1119 in HSDB (through 2003/06) AN: 4160 UD: 200303 RD: Reviewed by SRP on 1/29/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BROMODICHLOROMETHANE- SY: *BDCM-; *DICHLOROBROMOMETHANE-; *METHANE,-BROMODICHLORO-; *MONOBROMODICHLOROMETHANE-; *NCI-C55243- RN: 75-27-4 MF: *C-H-Br-Cl2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Treatment of the chlorine analog with slightly more than the stoichiometric quantity of anhydrous aluminum bromide, or with hydrogen bromide in the presence of an aluminum halide catalyst. After replacement of chlorine by bromine, the mixture is washed with cold water to remove the inorganic materials and the product is distilled. [R1] FORM: *98+% grade [R2] MFS: *NO DATA USE: *Chemical reagent/intermediate in organic synthesis. [R3] *Organic synthesis, solvent [R4] *Fire extinguisher fluid ingredient; solvent (fats, waxes, resins); synthesis intermediate; heavy liquid for mineral and salt separations. [R5] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R6] *(1979) NOT PRODUCED COMMERCIALLY IN USA [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Liquid [R7]; *Colorless liquid [R3] BP: *90 deg C [R8] MP: *-57 deg C [R8] MW: *163.83 [R8] DEN: *Specific gravity: 1.980 @ 20 deg C/4 deg C [R8] OWPC: *log Kow= 2.00 [R9] SOL: *Very soluble in ethanol, ethyl ether, and acetone. [R8]; *Water solubility of 4700 ppm at 22 deg C [R10]; *> 10% in acetone [R11, p. V1 838]; *> 10% in benzene [R11, p. V1 838]; *> 10% in ethyl ether [R11, p. V1 838]; *> 10% in ethanol [R11, p. V1 838]; *In water, 3.968X10+3 mg/l @ 30 deg C [R12] SPEC: *Index of refraction: 1.4964 @ 20 deg C/D [R8]; *IR: 18024 (Sadtler Research Laboratories IR Grating Collection) [R11, p. V2 642]; *NMR: 6709 (Sadtler Research Laboratories Spectral Collection) [R11, p. V2 642]; *MASS: 1026 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R11, p. V1 838] VAP: *50 torr at 20 deg C [R13] OCPP: *Dipole moment: 1.31 debyes (in benzene @ 25 deg C) [R14, p. 4-48] *Enthalpy of formation @ 25 deg C: -14.0 kcal/mole (gas); Gibbs (free) energy of formation @ 25 deg C: -10.16 kcal/mole (gas); entropy @ 25 deg C: 75.56 cal/deg.mole (gas) [R14, p. 5-7] *Henry's Law constant= 2.12X10-3 atm-cu m/mol @ 25 deg C [R15] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *NONFLAMMABLE. WILL BURN ON PROLONGED EXPOSURE TO FLAME OR HIGH TEMPERATURE. /CHLOROFORM/ [R16] DCMP: *When heated to decomp it emits very toxic fumes of /hydrogen bromide and hydrogen chloride/. [R17] ODRT: *Odor threshold low: 1680 mg/cu m odor high 1680 mg/cu m. /Bromochloromethane/ [R18] EQUP: *When handling /chloroform/, use safety glasses, self-contained breathing apparatus, protective clothing. Note: PVC and rubber are unsuitable materials for protective clothing. /Chloroform/ [R19, p. 7-1] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Chloroform/ [R20] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. /Chloroform/ [R20] OPRM: *Skin that becomes wet with liquid chloroform should be promptly washed or showered with soap or mild detergent and water to remove any chloroform. Employees who handle chloroform should wash their hands thoroughly with soap and mild detergent and water before eating or smoking. /Chloroform/ [R21, 1981.3] *Where there is any possibility that employees' eyes may be exposed to chloroform, an eye-wash fountain should be provided within the immediate work area for emergency use. /Chloroform/ [R21, 1981.3] *Good industrial hygiene practices recommend that engineering controls be used to reduce environmental concentrations to the permissible level. However, there are some exceptions where respirators may be used to control exposure. Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. /Chloroform/ [R21, 1981.3] *Clothing wet with liquid chloroform should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of chloroform from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the chloroform, the person preforming the operation should be informed of chloroform's hazardous properties. /Chloroform/ [R21, 1981.3] *Non-impervious clothing which becomes wet with liquid chloroform should be removed promptly and not worn until the chloroform is removed ... /Chloroform/ [R21, 1981.3] STRG: +STORE IN COOL, DRY, WELL-VENTILATED LOCATION. SEPARATE FROM STRONG ALKALIS AND STRONG MINERAL ACIDS. /CHLOROFORM/ [R22] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. COLLECT FOR RECLAMATION OR ABSORB IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR MATERIAL. /CHLOROFORM/ [R21, 1981.4] *Do not touch spilled material. Use water spray to reduce vapors. For small spills, take up with absorbent material then flush area with water. For large spills, dike far ahead. /Chloroform/ [R19, p. 8-1] */SRP: In laboratory setting only:/ Absorb on paper and evaporate on a glass dish in hood. Burn the paper. Purify /liquids/ by distillation, then return to supplier. /Chloroform/ [R23] *Oxidation processes are responsible for the removal of organic compounds and precursors of trihalomethanes. Substitution reactions are the source of chlorine incorporation into the organic matter. Disinfectants differ in their abilities to carry out oxidation and substitution reactions, but studies show that chloramines also add chlorine to organic materials by substitution. Before a decision is made to change disinfectants, operating parameters and chemical functions must be taken into account to achieve the best quality drinking water. [R24] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Chloroform is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration, preferably after mixing with another combustible fuel; care must be exercised to assure complete combustion to prevent the formation of phosgene; an acid scrubber is necessary to remove the halo acids produced. /Chloroform/ [R25] *Potential candidate for liquid injection incineration, with a temperature range of 650 to 1600 deg C and a residence time of 0.1 to 2 seconds; for rotary kiln incineration with a temperature of 820 to 1600 deg C and a residence time of seconds for liquids and gases, hours for solids; and for fluidized bed incineration, with a temperature range of 450 to 980 deg C and a residence time of seconds for liquids and gases, longer for solids. /Chloroform/ [R26] *The following wastewater treatment technologies have been investigated for bromodichloromethane. Concentration process: stripping. [R27] *The following wastewater treatment technologies have been investigated for bromodichloromethane. Concentration process: solvent extraction. [R28] *The following wastewater treatment technologies have been investigated for bromodichlorometane. Concentration process: activated carbon. [R29] *The following wastewater treatment technologies have been investigated for bromodichloromethane: Concentration process: resin adsorption [R30] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of bromodichloromethane were available. There is sufficient evidence in experimental animals for the carcinogenicity of bromodichloromethane. Overall evaluation: Bromodichloromethane is possibly carcinogenic to humans (Group 2B). [R31] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on inadequate human data and sufficient evidence of carcinogenicity in two animal species (mice and rats) as shown by increased incidence of kidney tumors and tumors of the large intestine in male and female rats, kidney tumors in male mice, and liver tumors in female mice. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R32] ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with sterile dressings after decontamination ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R33] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the unconscious patient. Positive pre s sure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if hypotensive with a normal fluid volume. Watch for signs of cardiac irritability and fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Halogenated aliphatic hydrocarbons and related compounds/ [R33] HTOX: *Positive correlations between cancer mortality rates and levels of brominated trihalomethanes in drinking water in epidemiological studies have been reported. [R7] *Cultures of human oral carcinoma cells ... were used to assess the toxicity of halomethanes found in drinking water. Cells were incubated for 72 hr in the presence of 100 to 1000 ug/l. After incubation, viable cells were counted, and concentrations causing 50% inhibition of cell growth (ID50) were determined. Linear dose versus response relationship was obtained for bromodichloromethane. ID50 /was/ 405 ug/ml for bromodichloromethane. ... [R34] *Both di- and tri-halogenated methane derivatives have been found to produce increased blood levels of methemoglobin; the greatest increase caused by iodo-, followed by bromo- and chloro- compounds. CNS functional disturbances are reported, including depression of rapid eyemovement sleep, as seen in carbon monoxide exposures. /Di- and tri-halogenated methane derivatives/ [R35] NTOX: *... ORAL LD50 VALUES FOR ADULT FEMALE AND MALE SWISS ICR MICE ARE 900 (RANGE, 811-999) and 450 (RANGE, 326-621) MG/KG /DICHLOROBROMOMETHANE/, RESPECTIVELY. THE DIFFERENCE BETWEEN MALES AND FEMALES IS STATISTICALLY SIGNIFICANT ... ADMIN OF 500 MG/KG PRODUCED SEDATION AND ANESTHESIA THAT LASTED APPROX 4 HR. POSTMORTEM EXAMINATION INDICATED FATTY INFILTRATION OF LIVER, PALE KIDNEYS, AND ADRENAL HEMORRHAGES ... [R36, 188] *BROMODICHLOROMETHANE WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM (TA-100 WITHOUT S-9 MIX) ASSAY. [R36, 188] *IP INJECTIONS /OF BROMODICHLOROMETHANE/ GIVEN OVER 8 WEEKS IN CUMULATIVE DOSE OF 2400 MG/KG DID NOT PRODUCE PULMONARY TUMORS IN STRAIN A/ST MICE, WHICH WERE EXAMINED 24 WEEKS AFTER 1ST INJECTION UNDER CONDITIONS IN WHICH BROMOFORM WAS FOUND TO BE POSITIVE. [R36, 188] *ACUTE TOXICITY OF BROMODICHLOROMETHANE WAS INVESTIGATED IN RATS. SIGNS FOLLOWING SINGLE ORAL DOSE WERE SEDATION, FLACCID MUSCLE TONE, ATAXIA, PILOERECTION, AND PROSTRATION. MALE RATS WERE MORE SUSCEPTIBLE THAN FEMALES TO LETHAL EFFECT, LD50 916 and 969 MG/KG, RESPECTIVELY. [R37] *ACUTE TOXICITY OF BROMODICHLOROMETHANE WAS STUDIED IN MICE FOLLOWING GASTRIC GAVAGE. PATHOLOGICAL CHANGES INCL FATTY INFILTRATION OF LIVER AND SIGNS OF HEMORRHAGE IN KIDNEYS, ADRENALS, LUNG AND BRAIN. MALES WERE MORE SENSITIVE THAN FEMALES. [R38] *Bromodichloromethane was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Bromodichloromethane was tested at doses of 0.01, 0.033, 0.10, 0.33, and 1.0 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Bromodichloromethane was negative in these tests and the highest ineffective dose tested in any Salmonella typhimurium strain was 1.000 mg/plate. Slight clearing of the background bacterial lawn occurred in some cultures at the highest dose. [R39] *Bromodichloromethane is acutely toxic to mice. It was mutagenic in the Salmonella typhimurium TA 100 bacterial test system and carcinogenic in mice with the same qualification for result significance as for dichloromethane ... [R7] *The effects of exposure to a single acute oral dose of bromodichloromethane were studied in the livers of male Wistar rats. Animals received a single 215 mg/kg dose of bromodichloromethane by gastric intubation, while controls received an equivalent volume of the vehicle. Three hours after administration of bromodichloromethane, the modulation of phospholipid metabolism and the accumulation of triacylglycerol were noted in the microsomal membranes. A marked decrease in the synthetic rate of phosphatidylcholine was accompanied by a fall in the microsomal activity of phosphocholine cytidylyltransferase. A decrease in glycerophosphate acyltransferase activity and an enhancement in phosphatidic phosphatase activity seemed to offset each other, and no significant change was noted in the synthetic rate of microsomal triacylglycerol. [R40] *The effects of lifetime exposure to chloroform or bromodichloromethane were studied in Wistar-rats. Haloorganic treatment was initiated with weanlings at 2 ml/l chloroform per liter drinking water or 1.2 ml/l bromodichloromethane per liter drinking water. Concentrations of these halomethanes were halved at 72 weeks because of increasing water intake among the test animals. Animals were weighed regularly and sacrificed when judged to be moribund or when a large tumor was noted. Sections of liver and other organs with grossly observable lesions were examined histologically. Tumor incidence was also analyzed. Treated rats weighed less than unexposed controls at all ages. At about 15 to 17 weeks, females had a higher consumption of water and halomethanes than males. The incidence of neoplastic nodules was significantly increased in females in either treatment group. Treated females also had a high incidence of hepatic adenofibrosis. [R41] *Cultures of ... African green monkey kidney cells were used to assess the toxicity of halomethanes found in drinking water. Cells were incubated for 72 hr in the presence of 100 to 1000 ug/ml. After incubation, viable cells were counted, and concentrations causing 50% inhibition of cell growth (ID50) were determined. Linear dose versus response relationship was obtained for bromodichloromethane. ID50 /was/ 420 ug/ml for bromodichloromethane. ... [R34] *Dichloromethane, bromodichloromethane, bromochloromethane, bromotrichloromethane, and dibromomethane were tested for their mutagenic activity. The Ames test and in vitro cell cultures were used. All substances were positive in the Ames test. In the in vitro test with FAF cells of Chinese hamsters only bromochloromethane produced an increase of the sister chromatid exchange frequency. All tested substances induced an increase in the aberration ratio/cell. The highest ratios were induced by dichloromethane, dibromomethane, bromochloromethane. [R42] *When rats were given bromodichloromethane by gavage in concentrations of 0.0, 0.05, or 0.10 g/kg and mice in concentrations of 0, 0.025, 0.05, 0.075 or 0.15 g/kg ... /males (0, 0.025, 0.05 g/kg) and females (0, 0.075 or 0.15 g/kg)/ ... , respectively, there was clear evidence of carcinogenic activity in F344/N rats as indicated by increased incidence of kidney tubular cell adenomas (Male: 0/50, 1/50, 3/50; Female: 0/50, 1/50, 6/50), kidney tubular cell adenocarcinoma (Male: 0/50, 0/50, 10/50; Female: 0/50, 0/50, 9/50), Large intestine adenomatous polyps (Male: 0/50, 3/50, 33/50; Female: 0/46, 0/50, 6/47). There is clear evidence of carcinogenic activity in B6C3F1 mice as indicated by increased incidence in male mice of kidney adenoma (1/49, 2/50, 6/50) and kidney adenocarcinoma (0/49, 0/50, 4/50) and in female mice of hepatocellular adenoma (1/50, 13/48, 23/50) and hepatocellular carcinoma (2/50, 5/48, 10/50). [R43] *... Under the conditions of these 2 yr gavage studies, there was ... evidence of carcinogenic activity for male and female F344/N rats and B6C3F1 mice as shown by incr incidences of tubular cell adenomas and adenocarcinomas in the kidney and adenocarcinomas and adenomatous polyps in the large intestine in male and female rats, incr incidences of tubular cell adenomas and adenocarcinomas in the kidney of male mice, and incr incidences of hepatocellular adenomas and carcinomas in female mice. [R44] *Bromodichloromethane was tested for carcinogenicity in two-year studies in male and female Fischer 344 rats and B6C3F1 mice by oral gavage, in life-span studies in male and female Wistar rats and in CBA x C57BL/6 hybrid mice by administration in drinking-water. In the gavage studies, bromodichloromethane increased the incidences of adenomatous polyps and adenocarcinomas of the large intestine and of tubule-cell adenomas and adenocarcinomas of the kidney in male and female rats, of tubule-cell adenomas and adenocarcinomas of the kidney in male mice and of hepatocellular adenomas and carcinomas in female mice. When administered in drinking water, it induced neoplastic nodules and adenofibrosis of the liver in rats; no increase in tumor incidence was seen in mice. [R45] *Biochemical and histopathological signs of hepatic damage were observed in rats at dose levels of 150-300 mg/kg bw per day after five days; in mice serum alanine aminotransferase and sorbitol dehydrogenase activities were elevated at a dose level of 150 mg/kg, but no histopathological lesions were observed. In rats, but not in mice, the total hepatic cytochrome P450 levels were decreased. As a sign of kidney damage, serum creatinine and blood urea nitrogen were elevated in rats dosed with 300 mg/kg but not in mice. [R46] *Acetone potentiates the responses /hepatotoxicity/ to ... bromodichloromethane. ... Chlordecone (Kepone) ... exhibits remarkable potentiating properties /hepatotoxicity/ with ... bromodichloromethane ... [R47] NTXV: *LD50 ADULT FEMALE AND MALE SWISS ICR MICE ORAL 900 (RANGE, 811-999) and 450 (RANGE, 326-621) MG/KG; [R36, 188] *LD50 RAT FEMALE ORAL 969 MG/KG; [R37] *LD50 RAT MALE 916 MG/KG; [R37] NTP: *... The 2 yr toxicology and carcinogenesis studies of bromodichloromethane was conducted by admin the chemical in corn oil by gavage, 5 days/wk for 102 wk, to groups of 50 male and 50 female rats at doses of 0, 50, or 100 mg/kg/day; to groups of 50 male mice at doses of 0, 25, or 50 mg/kg/day; and to groups of 50 female mice at doses of 0, 75, or 150 mg/kg/day. The study in male rats was restarted because at 10.5 mo into the original study, a temperature elevation killed 45/50 vehicle control male rats. ... Under the conditions of these 2 yr gavage studies, there was ... evidence of carcinogenic activity for male and female F344/N rats and B6C3F1 mice as shown by incr incidences of tubular cell adenomas and adenocarcinomas in the kidney and adenocarcinomas and adenomatous polyps in the large intestine in male and female rats, incr incidences of tubular cell adenomas and adenocarcinomas in the kidney of male mice, and incr incidences of hepatocellular adenomas and carcinomas in female mice. [R44] +The potential toxicity of bromodichloromethane (BDCM) ... was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the physiologic process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to bromodichloromethane exposure. The dose range-finding study was conducted at concns of 0, 100, 500, 1,000, and 1,500 ppm of bromodichloromethane in the drinking water for 2 wks. Based on decreases in water consumption, concns of 0, 100, 700, and 1,300 ppm (Groups 1, 2, 3, and 4, respectively) were selected for the main study. The main study utilized 2 groups of male rats designated as Group A (non-BrdU treated animals, 10/group in Groups 1-4) AND Group B (BrdU treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4), and three groups of female rats designated as Group A (peri-conception exposure, 10/group in Groups 1-4), Group B (gestational exposure, 13/group in Groups 1-4), AND Group C (peri-conception exposure, BrdU-treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4). Control animals received deionized water, the vehicle. During the treatment period, all animals except one survived to the scheduled necropsy. Body weights and feed and water consumption were decreased at many of the intervals for the 700 and 1,300 ppm dose groups. Body weights were decreased by 5-13% compared to the controls at many of the intervals while feed consumption was decreased 14-47%, and water consumption was decreased by 17-86% at many of the intervals. The overall calculated mean consumption of BDCM for Groups 2-4 was 11, 53, and 88 mg/kg/day, respectively. At necropsy, clinical chemistry and hematology endpoints were unaffected by BDCM treatment except for a 43% incr in the 5'-Nucleotidase in the 1,300 ppm A males, which most likely represents interference with the secretion of bile, and a 14% decr in creatinine in the 100 ppm A males. Necropsy organ weights and organ-to-body weight ratios were comparable to the controls. Gross findings were comparable across all groups. Microscopically, cytoplasmic vacuolization of hepatocytes and individual hepatocyte necrosis were observed in tissues from the 700 and 1,300 ppm A males and the 1,300 ppm B males, indicative of mild liver damage. Hematopoietic cell proliferation in the spleen was observed in tissues from all dosed A males, but this is most likely an indirect change in response to stress... . The Labeling Index (LI) for the liver and kidney from the B males were relatively comparable between treated and control groups, but the LI for the liver and kidneys from the 1300 ppm C females were significantly increased, indicating possible early stimulation of cellular proliferation. There were no treatment-related findings noted in any male and female reproductive parameters. Results of this study indicate that BDCM at doses at and above 700 ppm produced consistent decreases in body weight and food and water consumption in both sexes, but did not result in any male or female reproductive toxicity. From these data, BDCM is taste-aversive and a general toxicant in both sexes at doses at and above 700 ppm. [R48] ADE: *... A SINGLE ORAL DOSE OF 20 MG/KG ... /AS (14)C-BROMODICHLOROMETHANE/ IN RATS IS CLEARED VERY RAPIDLY. ONLY 32% IS RECOVERED FROM GI TRACT AND CARCASS AFTER 3 HR, and 41% AFTER 6 HR. MOST OF CMPD WAS RECOVERED FROM STOMACH. FAT CONTAINED MORE THAN ANY OTHER TISSUE. LESS THAN 1% APPEARED IN URINE. BALANCE ... PROBABLY EXHALED ... [R36, 187] *A 31-DAY RAT-DOSING SEQUENCE WAS USED TO STUDY SOME ASPECTS OF PHYSIOLOGICAL DISTRIBUTION, METABOLISM, STORAGE AND RATE OF ELIMINATION OF BROMODICHLOROMETHANE FROM RAT ADIPOSE AND BLOOD SERUM. FOR THE VOLATILE CMPD, TISSUE LEVELS FLUCTUATED BUT DID NOT INDICATE INCR STORAGE WITH TIME. ADIPOSE TISSUE TO BLOOD SERUM LEVELS NEVER DIFFERED BY MORE THAN A FACTOR OF 3. WITHIN 3-6 DAYS AFTER DOSING WAS TERMINATED, MOST OF THE HALOGENATED CMPD HAD LEFT THE EXAMINED TISSUES. [R49] *Bromodichloromethane may be absorbed readily by inhalation or ingestion, be distributed widely, preferentially to tissues with high lipid content, and be eliminated in part via expired breath. [R50] *Pharmacokinetics and tissue distribution of bromodichloromethane was examined in rats and monkeys. The compound was excreted primarily via the lung either unchanged or as metabolites. [R51] *A study was performed to determine the absorption, distribution and excretion characteristics of bromodichloromethane in mice and rats. Compounds, labeled with carbon-14 were administered by intragastric intubation to male Sprague-Dawley rats and male B6C3F1 mice. The total radioactivity for sampled organs ranged from 3 to 6 percent of the total dose in the rats versus 5 to 14 percent for the mice. The stomach (without contents), nonperfused liver, and kidneys in both rodent species were the organs of highest residual radioactivity levels. In both species the urine contained less than 5 percent of total radiolabel at 8 hours post intubation and less than 10 percent of the total radiolabel at 36 to 48 hours. The majority of the compound in both rats and mice was eliminated through the lung in the expired air within 8 hours. BDCM exhibits limited metabolic activation, which was shown by recovery of a higher percentage of the dose as parent compound. Mice metabolize this compound to a greater extent than rats. [R52] METB: *HALOFORMS ARE METABOLIZED TO CARBON MONOXIDE BY HEPATIC MIXED FUNCTION OXIDASES AND THIS REACTION IS MARKEDLY STIMULATED BY SULFHYDRYL CMPD. MAX STIMULATION OCCURRED AT 0.5 MMOLAR GLUTATHIONE. A MECHANISM FOR CONVERSION OF HALOFORMS TO CARBON MONOXIDE IS PROPOSED. /HALOFORMS/ [R53] *TRIHALOMETHANES (HALOFORMS) WERE METABOLIZED TO CARBON MONOXIDE BY A RAT LIVER MICROSOMAL FRACTION REQUIRING NADPH AND MOLECULAR OXYGEN FOR MAX ACTIVITY. RESULTS SUGGEST HALOFORMS ARE METAB TO CARBON MONOXIDE BY A CYTOCHROME P450 DEPENDENT MIXED-FUNCTION OXIDASE SYSTEM. /TRIHALOMETHANES/ [R54] *ADMIN OF HALOFORMS (TRIHALOMETHANES) TO RATS LED TO SUBSTANTIAL ELEVATIONS IN BLOOD CARBON MONOXIDE LEVELS. SODIUM-PHENOBARBITAL TREATMENT INCR BLOOD CARBON MONOXIDE LEVELS. SKF 525-A SIGNIFICANTLY INHIBITED IN VIVO METAB. THE IN VIVO METAB FOLLOWED THE HALIDE ORDER; THUS, ADMIN OF TRIIODOMETHANE YIELDED THE HIGHEST BLOOD CARBON MONOXIDE LEVELS, WHEREAS TRICHLOROMETHANE YIELDED THE LOWEST LEVELS. /HALOFORMS/ [R55] BHL: *... A SINGLE ORAL DOSE OF 20 MG/KG ... /AS (14)C-BROMODICHLOROMETHANE/ IN RATS IS CLEARED VERY RAPIDLY. ... IN MONKEYS ... THE HALF-LIFE OF A SIMILAR DOSE WAS 4 TO 6 HR ... [R36, 187] INTC: *Pretreatment of Fischer 344 rats with buthionine sulfoximine, which decreased the hepatic glutathione content by 86%, markedly accentuated the hepatic and renal toxicity of bromodichloromethane administered as a single dose (400 mg/kg bw) by gavage. [R56] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Bromodichloromethane's production and use as a chemical intermediate and solvent may result in its release to the environment through various waste streams. The predominant anthropogenic source of bromodichloromethane release to the environment is its inadvertent formation during chlorination treatment processes of water. Bromodichloromethane occurs naturally in ice macroalgae from McMurdo Sound, Antarctic and is subsequently released to sea water. If released to air, an estimated vapor pressure of 17 mm Hg at 25 deg C indicates bromodichloromethane will exist solely as a vapor in the ambient atmosphere. Vapor-phase bromodichloromethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 204. If released to soil, bromodichloromethane is expected to have moderate to very high mobility based upon estimated Kocs of 35-251. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 2.12X10-3 atm-cu m/mole. Bromodichloromethane may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, bromodichloromethane is not expected to adsorb to suspended solids and sediment in water based upon the estimated Kocs. Anaerobic degradation may be an important environmental fate process, with reported removal rates of > 50% in 8 weeks using an anoxic sewage inoculum. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 2 hrs and 5 days, respectively. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to bromodichloromethane may occur through inhalation and dermal contact with this compound at workplaces where bromodichloromethane is produced or used. The general population may be exposed to bromodichloromethane via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with chlorinated water such as swimming pool water, which contains bromodichloromethane. (SRC) NATS: *Bromodichloromethane is biosynthesized and emitted to seawater (and eventually to the atmosphere) by various species of marine macroalgae which are abundant in the various locations of the worlds oceans(1,2). Ice macroalgae from McMurdo Sound, Antarctic were found to contain and release to sea water bromodichloromethane, concns ranging from 0.1 to 50 ng/dm cu(3). Ambient atmospheric samples were collected which confirmed that this area is a source of bromoalkanes to the atmosphere. [R57] ARTS: *Bromodichloromethane's production and use as in organic synthesis and as a solvent(1) may result in its release to the environment through various waste streams(SRC), however, bromodichloromethane is not produced or used on a large commercial-scale indicating that significant releases do not occur from these practices(2). The predominant environmental release of bromodichloromethane results from its inadvertent formation during chlorination treatment processes of drinking, waste, and cooling waters(2,3). The amount of bromodichloromethane which may be produced during chlorination processes depends upon a variety of parameters which include temperature, pH, bromide ion concn of the water, fulvic and humic substance concn, and actual chlorination treatment practices(3). [R58] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), estimated Koc values of 35-251(SRC), determined using various estimation methods(2,5,6), indicate that bromodichloromethane is expected to have very high to moderate mobility in soil(SRC). Volatilization of bromodichloromethane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 2.12X10-3 atm-cu m/mole(3). The potential for volatilization of bromodichloromethane from dry soil surfaces may exist based upon an estimated vapor pressure of 17 mm Hg(SRC), determined from a fragment constant method(4). [R59] *AQUATIC FATE: Based on a classification scheme(1), estimated Koc values of 35-251(SRC), determined from estimation methods(2,9,10), indicate that bromodichloromethane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 2.12X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 2 hrs and 5 days, respectively(SRC). According to a classification scheme(5), an estimated BCF of 7(SRC), from its log Kow of 2.00(8) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation in anoxic environments may occur(11). [R60] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), bromodichloromethane, which has an estimated vapor pressure of 17 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase bromodichloromethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 204(SRC), calculated from its rate constant of 7.9X10-14 cu cm/molecule-sec at 25 deg C determined using a structure estimation method. This relatively persistent tropospheric half-life suggests that a small percentage of the bromodichloromethane present in air will eventually diffuse to the stratosphere where it will be destroyed by photolysis. In addition, long-range global transport is possible. The detection of bromodichloromethane in rainwater(4) indicates that atmospheric removal via washout can occur; however, any bromodichloromethane which is removed by rainfall is likely to revolatilize into the atmosphere. [R61] BIOD: *AEROBIC: Loss of bromodichloromethane was observed to be 51-59% utilizing a static flask screening procedure and 28 days of incubation, which was interpreted as significant biodegradation with gradual adaptation(1). No degradation was noted in aerobic tests in either sterile or seeded conditions using mixed methanogenic bacterial cultures from sewage effluents after 6 weeks(2). [R62] *ANAEROBIC: In anaerobic tests using mixed methanogenic bacterial cultures from sewage effluents, bromodichloromethane was totally degraded within 2 weeks while only 43-50% was lost in sterile controls after 6 weeks(1). Studies conducted under anoxic conditions with denitrifying bacteria found > 50% degradation in bacterial cultures after 8 weeks but no degradation in sterile controls(2). Rapid degradation was observed in a continuous-flow methanogenic fixed-film laboratory-scale column using seeded cultures, but only slow degradation was noted in sterile controls(3). In a groundwater recharge field experiment, bromodichloromethane passed through the biologically active zone (approximate time 0.75 days) with no appreciable degradation(4). Using a continuous-flow biofilm column reactor using primary settled sewage as seed, 50 ug/l bromodichloromethane was degraded to at or below the detection limit of 0.1 ug/l in 120 days(5). Based on a review of the literature, bromodichloromethane biodegrades fast in anaerobic aquatic environments(6). [R63] ABIO: *The rate constant for the vapor-phase reaction of bromodichloromethane with photochemically-produced hydroxyl radicals has been estimated as 7.90X10-14 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 205 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). A base-catalyzed second-order hydrolysis rate constant of 1.2X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 186 and 18 yrs at pH values of 7 and 8, respectively(2). Bromodichloromethane is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). The aqueous hydrolysis half-life of bromodichloromethane at 25 deg C and pH 7 has been estimated to be 137 years(4). Direct photolysis or aquatic oxidation (via peroxy radicals or singlet oxygen) are not environmentally relevant or important fate processes with respect to bromodichloromethane(5). [R64] BIOC: *An estimated BCF of 7 was calculated for bromodichloromethane(SRC), using a log Kow of 2.00(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R65] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for bromodichloromethane can be estimated to be 35(SRC). Bromodichloromethane was observed to have high mobility in laboratory soil column experiments utilizing a sandy soil(3). Relatively high soil mobility was noted during a water infiltration study conducted in the Netherlands along the Rhine River(4). Koc values for bromodichloromethane have been estimated to range from 53-251 based on water solubility and log Kow(5,6). According to a classification scheme(2), these estimated Koc values suggest that bromodichloromethane is expected to have very high to moderate mobility in soil. [R66] VWS: *The Henry's Law constant for bromodichloromethane is as 2.12X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that bromodichloromethane is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 2 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 5 days(SRC). Based on experimentally determined gas transfer rates, the volatilization half-life of bromodichloromethane from rivers and streams has been estimated to range from 33 min to 12 days with a typical half-life of about 35 hours(4). Bromodichloromethane's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of bromodichloromethane from dry soil surfaces may exist(SRC) based upon an estimated vapor pressure of 17 mm Hg(SRC), determined from a fragment constant method(3). Significant volatilization (half-life of about one hour) was observed from laboratory tanks(5). Approximately 50% of applied bromodichloromethane volatilized from soil columns during laboratory studies which monitored transport and fate mechanisms(6). [R67] WATC: *DRINKING WATER: As part of the USEPA Groundwater Supply Survey, bromodichloromethane was positively detected in 445 of 945 USA finished water supplies that use groundwater sources at a median level of about 1.8 ppb(1). Median levels of 9.2-18 ppb were detected in the water supplies of over 80% of the 113 USA cities monitored during the three phases (1976-7) of USEPA National Organic Monitoring Survey(2). A Canadian national survey of 70 drinking water supplies found bromodichloromethane levels of 0-33 ppb with an overall median level of 1.4 ppb(2). In a survey of drinking waters from 12 areas of the world (China, Taiwan, north and south Philippines, Egypt, Indonesia, Australia, England, Brazil, Nicaragua, Venezuela, Peru), bromodichloromethane was found in 9 of the 12 waters at levels ranging from 1.7-10 ppb(3). Positive detections were made in 35 of 40 Michigan drinking water supplies at a median concn of 2.7 ppb(4). Median concn of 5.8 and 12.3 ppb were found in samples collected from Bayonnel Elizabeth, NJ in winter 1981 and spring 1982(5); median concns of 12.5 and 24.3 ppb were found in Los Angeles, CA samples from spring and summer 1984(5). Baseline data on 35 US water utilities showed quarterly concns of 6.9, 10, 5.5, and 4.1 ug/l bromodichloromethane in spring, summer, fall, and winter of 1988, respectively(6), the compound being present as a disinfectant by-product. [R68] *DRINKING WATER: Bromodichloromethane was detected at a concn ranging from 1.04 to 2.09 ug/l in finished drinking water obtained from desalination of seawater for the capital area of the Sultanante of Oman, Egypt(1). Drinking water from Cairo, Egypt sampled during February, March, August, and September 1989 contained bromodichloromethane at avg concns of 45.93, 51.12, 9.98, and 11.22 ug/l, respectively(4). A double distilled water from this sample contained < 0.05 ug/l bromodichloromethane(1). The compound was detected in various municipal water supplies in the US at concns ranging from 1.1 (raw water source - well) to 20.9 ug/l (raw water source - surface)(2). It was detected in finished water from a water-treatment plant at a concn of 20.8 ug/l(2). Reservoir water concns of bromodichloromethane from two water systems in Sardinia, Italy ranged from 0.2 to 30.5 ug/l and from three well systems, 0.1 to 10.3 ug/l(3). Drinking water from 8 cities in Saudi Arabia collected during the summer months of July to October 1989 contained bromodichloromethane at median concns ranging from 0.0 (Buraidah) to 2.75 (Makkah)(5). Concns from various cities in several countries ranged from 0 ppb (Taiwan) to 14 ppb (Osaka Japan)(5). Samples from Los Angeles, CA were 93% positive in winter and 96% positive in spring, while samples from Antioch/Pittsburg, CA were 96% in spring, weighted median concns being 12, 24, and 17 ng/ml, respectively(6). Bromodichloromethane was detected in 76% of US rural surface water supplies, with a mean of 17 ug/l(7). Results of EPA's TEAM study of drinking water are as follows (mean value ug/l): Bayonne-Elizabeth, NJ: fall 1981 - 13.6; summer 1982 - 13.6; winter 1983 - 5.4; Devils Lake, ND: Oct 1982 - 0.21; Greensboro, NC: May 1982 - 7.1; Los Angeles, CA: Feb 1984 - 11; May 1984 - 20; Antioch-Pittsburg, CA: Jun 1984 21; Los Angeles, CA: Feb 1987 - 19; Jul 1987 26; Baltimore, MD: Apr 1987 10(7). [R69] *GROUNDWATER: Bromodichloromethane was one of 27 organic compounds identified in groundwater collected from 315 wells in the area of the Potomac-Raritan-Magothy aquifer system adjacent to the Delaware River(1). Levels of 0.3 ppb have been detected in groundwater from the Netherlands(2). Bromodichloromethane was detected at a concn ranging from 9.2 to 16.7 ug/l in finished drinking water obtained from groundwater for the capital area of the Sultanante of Oman, Egypt(3). An unchlorinated sample contained < 0.05 ug/l bromodichloromethane(3). The compound was not detected in the entire Biscayne Bay aquifer study area (Superfund site) nor well fields, but was detected at 6.1 ug/l in finished water from treatment plants(4). 4 of 1891 groundwater samples from Wisconsin were found to contain bromodichloromethane although the contamination was felt to be due to air contact in a chlorine-containing pumphouse(5). 0.3% of ground water used for preparation of drinking water in the Netherlands contained bromodichloromethane at concns exceeding 0.5 ug/ml(6). [R70] *SURFACE WATER: An analysis of the USEPA STORET Data Base found that bromodichloromethane had been positively detected in 14.0% of 8885 water observation stations at a median concn of 0.1 ug/l(1). Bromodichloromethane was positively detected in 20.9% of 4972 samples collected from 11 stations on the Ohio River during 1980-1 with most concn between 0.1-1.0 ppb(2). Positive identifications were determined at 24 of 204 sites (1-12 ppb) in 14 heavily industrialized river basins in the USA(3). Concns ranging from a trace-25 ng/l and not detected-20 ng/l were reported for 16 stations on the Niagara River and 95 stations on Lake Ontario, respectively, for 1981 monitoring(4). Lake St. Clair - 3 sites > 0.03 ppb; sites 0.10-0.03 ppb; 45 sites < 0.01 ppb; range 0-0.089 ppb(5). Bromodichloromethane was not detected in raw river water prior to processing in a water treatment plant (detection limit= 0.1 ug/l)(6). Preliminary aqueous sample levels of bromodichloromethane in the Potomac River, VA during the spring of 1986 were < 2 ppb(7). Industrial sites on Taiwan's Ho-Chin River did not contain bromodichloromethane; non-potable tap water using this source did contain the compound at 7.28 and 4.83 ug/l(8). Water samples were collected during the summer and fall of 1991 and spring of 1992 at 12 locations on the Mississippi River from New Orleans, LA to Minneapolis, MN and on the Missouri and Ohio Rivers 1.6 km upstream from their confluences with the Mississippi(9). Bromodichloromethane concns ranged from 20 ug/l (3000 km from Head of Passes, LA to 60 ug/l (at Head of Passes, LA)(9). Bromodichloromethane was found in Canadian drinking water collected during winter from a treatment plant (detection limit= 0.1 ug/l), at the following levels: (very low bromide speciation); 3.9 (low bromide speciation) ug/l; 0.7 (moderate bromide speciation)(10). [R71] *SEAWATER: Bromodichloromethane concns of 0.1-1 ng/l have been detected in the North Atlantic while a concn of 0.1 ng/l was detected in the South Atlantic during 1985 monitoring(1). Qualitative detection has been reported for the Narragansett Bay off RI in 1979-80(2). Water samples collected from UK estuaries and offshore in 1992 contained bromodichloromethane at concns ranging from < 10 to 1160 ng/l(3). Possible sources may result from products of water chlorination and industrial effluent(3). Bromodichloromethane was not detected in seawater samples collected from October to November 1990 at the Ariho (industrial region) nor Yoshinga (non-industrial) River mouths in Japan(4). [R72] *RAIN/SNOW: A concn of 0.4 ng/l bromodichloromethane was detected in rain collected in southern Germany in 1985(1). Bromodichloromethane was not detected in rainwater from three different locations in Kobe, Japan from January to December, 1991(2). [R73] *OTHER WATER: A bromodichloromethane concn of 2 ppb was detected in stormwater runoff from Eugene, OR as part of the USEPA Nationwide Urban Runoff Program(1). Bromodichloromethane has been detected in swimming pool water at levels of 6-10 ppb(2) and in swimming pool of the Technical University of Gdansk, Poland at levels ranging from 2.3 to 14.7 ug/cu dm(3). [R74] EFFL: *An analysis of the USEPA STORET Data Base found that bromodichloromethane had been positively detected in 11.0% of 1375 effluent observation stations at a median concn of 5 ug/l(1). Bromodichloromethane was detected in 14 of 63 industrial wastewater discharges in the USA at levels ranging from < 10-100 ppb(2). Three municipal wastewater treatment facilities in Cincinnati, OH were found to be discharging levels as high as 0.2 ppb in 1982(3). Percent occurrence in raw wastewater, septic tank effluents, septic tank sludge, septic tank scum, lift station wastewater, and lagoon cell effluents was (%, no. of samples) 100,2; 100,5; 67,3; 100,3; 100,7; and 86,7 in a Regina, Saskatchewan study (detection limit = 0.02 ppb)(4). The total annual release of bromodichloromethane into Idefjorden, Sweden in effluent water from the pulp mill is 21 kg/a(5). Likewise, bromodichloromethane concn in pulp mill effluent into Jackfish Bay, north shore of Lake Superior ranged from 1.7 ng/l (October 3.3 ng/l) to 3.3 ng/l (August surface water)(6). Bromodichloromethane was found in the bleaching effluents during the processing of hardwood and softwood in Finnish pulp mills at concns of 0.2-0.5 and 0.1-0.5 ug/l, respectively(7). [R75] SEDS: *Bromodichloromethane has been qualitatively detected in soil/sediment/water samples collected from the Love Canal near Niagara Falls, NY(1). It was detected at concns ranging from 3 to 20 ng/l in samples taken on 27 and 28 June, 1988 at 12 stations in the anoxic fjord environment from the Koster trench, Idefjorden, Sweden(2). It was not detected in sediment samples collected from October to November 1990 at the Ariho (industrial region) nor Yoshinga (non-industrial) Rivers in Japan(3). Bromodichloromethane was detected in nearly all samples of soil air in a Douglas Fir forest near Apeldoorn, the Netherlands at a concn of 0.019 ng/l but was not detected in atmospheric air(4). This concn increased with soil depth, suggesting that the soil of the Douglas forest, located in a coastal area, emits bromodichloromethane(4). [R76] ATMC: *SOURCE DOMINATED: A one year monitoring in Finland during 1987 found mean concns of 48 ug/cu cm in industrial air(1). [R77] *URBAN/SUBURBAN: Mean bromodichloromethane levels of 0.76, 1.4, 120, and 180 parts per trillion have been detected in the ambient air of Magnolia (AR), El Dorado (AR), Chapel Hill (NC), and Beaumont (TX), respectively(1). Monitoring of four CA sites between 1982-3 found mean composite concns of 20-100 parts per trillion in ambient air(2). [R78] *INDOOR: Median and maximum concns of 0.055 and 9.0 ug/cu m were found in indoor air samples collected at residences in Greensboro, NC in 1980(4); median and maximum outdoor concns were 0.05 and 0.09 ug/cu cm(1). Indoor data collected from buildings the Netherlands, Germany, Italy, and USA show bromodichloromethane levels of < 1 ug/cu m in dwellings(2). [R79] *RURAL/REMOTE: Atmospheric bromodichloromethane levels ranging from 0.1-1.0 parts per trillion were found in ambient air samples collected from the north and south Atlantic Ocean, the beaches of Bermuda, and southern Germany between 1982-5(1). [R80] FOOD: *In accordance with the USFDA's Total Diet Market Basket Study, an analysis of 39 food items purchased at retail markets (from Elizabeth, NJ, Chapel Hill, NC, Washington, DC) detected bromodichloromethane in one dairy composite (1.2 ppb), in butter (7 ppb), and in two beverages (0.3 and 0.6 ppb); subsequent analysis of cola soft drinks resulted in three positive detections at levels of 2.3, 3.4, and 3.8 ppb(1). An analysis of various soft drinks found cola beverages to ave 0.9-5.9 ppb bromodichloromethane while clear soft drinks had levels of 0.1-0.2 ppb; municipal water supplies from which the soft drinks were manufactured were found to contain up to 20 ppb trihalomethanes(2). Bromodichloromethane was found in the following foods: flavored sparkling water, 12 ng/g; fruit drink, 5 ng/g; carbonated soft drinks, 1-12 ng/g(3). The compound was not detected (detection limit= 12 ppb) in butter purchased from retail outlets located near dry-cleaning establishments(4). Bromodichloromethane was found in grapefruit juice (0.20 ug/kg); reconstituted lemon juice (1.05 ug/kg); reconstituted lime juice (1.00 ug/kg); reconstituted orange juice (0.20-1.27 ug/kg); and in orange drink (0.80 ug/kg)(5). The following foods were also found to contain bromodichloromethane: whey and longhorn cheese process water (2.2 ng/g); gingerale soda (2.3 ng/g); sparkling soda (1.2 ng/g); cola soda (1.2 ng/g); ricotta and mozzarella cheese process waters (3.0-8.3 ng/g); process water for lemon-lime soda, lemon soda, and cola soda - trace; process water for vanilla, chocolate, and butter-pecan ice creams (8.3-14.1 ng/g); vanilla ice cream (2.3 ng/g); chocolate ice cream (0.6 ng/g); and butter pecan ice cream (1.1 ng/g)(6). [R81] PFAC: PLANT CONCENTRATIONS: *Mean bromodichloromethane levels of 7-22 ng/g (dry wt) have been detected in various species of marine algae(1). [R82] FISH/SEAFOOD CONCENTRATIONS: *Bromodichloromethane was not detected in oyster and clam samples collected from October to November 1990 at the Ariho (industrial region) nor Yoshinga (non-industrial) River mouths in Japan(1). [R83] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,266 workers (503 of these are female) are potentially exposed to bromodichloromethane in the US(1). Occupational exposure to bromodichloromethane may occur through inhalation and dermal contact with this compound at workplaces where bromodichloromethane is produced or used(SRC). The compound was monitored for but not detected in the workplace air at a bleaching plant of a softwood and hardwood kraft pulp mill in Finland which was found to be slightly genotoxic(2). The general population is exposed to bromodichloromethane through consumption of contaminated drinking water, beverages, and food products. The contamination is a result of inadvertent formation during chlorination treatment of the drinking water and subsequent use of chlorinated tap water to produce food products. Exposure can also occur through inhalation of background levels in ambient air and through dermal exposure in chlorinated swimming pool water(SRC). [R84] AVDI: *AIR INTAKE: The estimated daily air intake of bromodichloromethane in a study involving 17 subjects from Beaumont, TX and Chapel Hill, NC ranged from below the detection limit (< 1.2 ug/10 cu m) for 9 subjects to 37.1 ug/10 cu m(1); DRINKING WATER INTAKE: Water intake ranged from 15 to 24 ug/1, assuming 10 cu m/d respiration rate and 1 L/d ingestion rate. The percentage intake from air ranged from < 3 to 73. This did not take into account exposure from showering which presumably would increase the proportion due to inhalation(1). FOOD INTAKE: insufficient data(SRC). [R85] BODY: *A bromodichloromethane concn of 14 ng/ml was found in a blood sample from a resident living near the Love Canal near Niagara Falls, NY(1). Bromodichloromethane was not detected in any sample from the USEPA National Human Adipose Tissue Survey for fiscal year 1982(2,5). Bromodichloromethane was detected in 14% of the 1072 blood samples (detection limit= 0.009 ppb) from a nonoccupationally exposed US population(3). Alveolar breath samples of competitive swimmers during a typical 2-hr training period in an indoor facility contained bromodichloromethane(4). The estimated blood/breath coefficient was estimated at 0.01 and 0.12 ug/l for the male and female subjects, respectively (detection limit= 0.39 ug/cu m)(4). Bromodichloromethane was identified in one of eight samples of mother's milk collected from nursing mother's in New Jersey hospitals(5). [R86] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 80 ug/l [R87] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 0.19 ug/l [R87] +(FL) FLORIDA 0.6 ug/l [R87] +(MN) MINNESOTA 6 ug/l [R87] +(NH) NEW HAMPSHIRE 0.60 ug/l [R87] +(WI) WISCONSIN 0.6 ug/l [R87] CWA: +The maximum contaminant level (MCL) set forth by the National Primary Drinking Water Regulations for organic chemicals including total trihalomethanes (the sum of the concentrations of bromodichloromethane, dibromochloromethane, tribromomethane (bromoform) and trichloromethane (chloroform)) is 0.10 mg/l. /Total trihalomethanes/ [R88] +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Halomethanes/ [R89] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R90] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Bromodichloromethane is included on this list. [R91] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determination of halogenated hydrocarbons in water by gas chromatography with time-delayed injection of calibration standard. /Halogenated hydrocarbons/ [R92] *Determination of trihalomethane in drinking water by spectrophotometric method. /Trihalomethanes/ [R93] *EPA Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. Detection limit= 3.0 ug/kg. [R94] *AOB Method VG-001-1. Volatile Organics in Soil Gas - Adsorbent Tube Method. Detection limit= 20.0 ng/l. [R94] *AOB Method VW-001-1. Volatile Organic Compounds (VOCs) in Water by Purge and Trap GC/PID/ELCD. Detection limit= 10.0 ug/l. [R94] *CLP Method LC_VOA. Analysis of Water for Low Concentration Volatile Organic Compounds by Gas Chromatography/Mass Spectroscopy. Detection limit= 1.0 ug/l. [R94] *CLP Method MC_VOA. Analysis of Volatile Organics in Multi-Concentration Water Samples by Gas Chromatography with a Mass Spectrometer. Detection limit= 10.0 ug/l. [R94] *EAD Method 1624. Volatile Organic Compounds by Isotope Dilution GCMS. Detection limit= 10.0 ug/l. [R94] *EMSLC Method 502.1. Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography. Revision 2.0. Detection limit= 0.003 ug/l. [R94] *EMSLC Method 502.2. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. Detection limit= 0.020 ug/l. [R94] *EMSLC Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. Detection limit= 0.500 ug/l. [R94] *EMSLC Method 551. Determination of Chlorination Disinfection Byproducts and Chlorinated Solvents in Drinking Water by Liquid-Liquid Extraction and Gas Chromatography withElectron-Capture Detection. Detection limit= 0.006 ug/l. [R94] *EMSLC Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. Detection limit= 0.100 ug/l. [R94] *EMSLC Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. Detection limit= 2.200 ug/l. [R94] *ODW Method Part 1. Analysis of Trihalomethanes in Drinking Water using the Purge and Trap Method. Detection limit= 0.500 ug/l. [R95] *ODW Method Part 2. Analysis of Trihalomethanes in Drinking Water by Liquid-Liquid Extraction. Detection limit= 0.500 ug/l. [R95] *ODW Method Part 3. Determination of Maximum Total Trihalomethane Potential. [R95] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit= 5.00 ug/l. [R96] *EPA Method SFSAS_7. Determination of Purgeable Organics in Sediment. [R94] *OSW Method 8010. Determination of Halogenated Volatile Organics by Gas Chromatography. Detection limit= 0.002 ug/l. [R96] *OSW Method 8021. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. Detection limit= 0.020 ug/l. [R96] *OSW Method 8260. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit= 0.080 ug/l. [R96] *EPA Method SFSAS_29. Extraction and Analysis of Organics in Biological Tissue. Detection limit= 0.050 mg/kg. [R94] *EPA Method SFSAS_5. Analysis of Fish for Volatile Organics by Purge and Trap Analysis. [R94] CLAB: *GAS CHROMATOGRAPHY-MASS SPECTROMETRY-COMPUTER ANALYSIS WAS USED TO DETERMINE LEVELS OF VOLATILE HALOGENATED HYDROCARBONS INCL BROMODICHLOROMETHANE IN BREATH, BLOOD AND URINE OF THE POPULATION OF OLD LOVE CANAL AREA, NIAGARA, NY. [R97] *CHLORODIBROMOMETHANE WAS DETERMINED IN HUMAN TISSUES BY GAS CHROMATOGRAPHY (OV-101 CAPILLARY WITH TEMP PROGRAMMING AND ELECTRON CAPTURE DETECTION). MEAN RECOVERIES WERE 87%, AND LIMITS OF DETECTION WERE IN THE NG/KG RANGE. [R98] *A method is presented for the analysis of bromodichloromethane, and chlorodibromomethane. Blood samples are warmed and an inert gas is passed through the sample to extract the volatile halocarbons. Tissue samples are macerated in water, then treated the same as for blood samples. A Tenax gas chromatography (GC) cartridge is used to trap the vapors which are then recovered by thermal desorption and analyzed on GC/mass spectrometry. Caution should be exercised in handling the volatile components due to their suspected and proven carcinogenicity. The limits of detection of this method are approximately 3 nanograms/ml for a 10 ml blood sample and 6 nanograms/gram for 5 gram tissue samples. [R99] *Breath samples are collected on Tenax gas chromatography cartridges, dried over calcium-sulfate and analyzed using thermal desorption of volatiles into a gas chromatography/mass spectrometer. Halocarbons for which the method is suitable include bromodichloromethane, and chlorodibromomethane. [R100] *Biological monitoring methods useful for detecting halogenated alkanes and alkenes are described. The most important methods of analysis are gas chromatography with electron capture detection and gas chromatography/mass spectrometry. Solvent extraction, gas stripping and head space techniques may be combined with gas chromatography/mass spectrography for determining volatile halogenated pollutants in biological samples. Descriptions are offered of techniques for determining bromodichloromethane and other volatiles in urine, blood, milk and adipose tissue. [R101] *AN EXTENSIVE STUDY WITH 119 COMPOUNDS INCL BROMODICHLOROMETHANE WAS MADE OF APPLICATIONS OF GAS CHROMATOGRAPHY USING A MICRO ELECTRON CAPTURE DETECTOR. BILE ACIDS WERE AMONG THE SUBSTANCES USED FOR PURPOSES OF DEMONSTRATION. [R102] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Halomethanes (1980) EPA 440/5-80-051. This document reviews the following halomethanes: chloromethane, bromomethane, methylene chloride, bromoform, bromodichloromethane, trichlorofluoromethane, and dichlorodifluoromethane. DHHS/ATSDR; Toxicological Profile for Bromodichloromethane (1989) ATSDR/TP-89/04 DHHS/NTP; Toxicology and Carcinogenesis Studies of Bromodichloromethane in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 321 (1987) NIH Publication No. 88-2537 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for bromodichloromethane is in progress. Route: dosed-water; Species: water disinfection byproducts, rats and mice. [R103, p.22] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for bromodichloromethane. Route: dosed water; Species: water disinfection byproducts rats, and mice. [R103, p.20] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for bromodichloromethane. Route: gavage; Species: water disinfection byproducts rats, and mice. [R103, p.20] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for bromodichloromethane is completed, and the chemical is in review for further evaluation. Route: dosed-water; Species: water disinfection model, mice. [R103, p.21] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for bromodichloromethane is completed, and the chemical is in review for further evaluation. Route: topical; Species: water disinfection model, mice. [R103, p.21] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for bromodichloromethane is in progress. Route: dosed water feed; Species: water disinfection byproducts, rats and mice. [R103, p.22] SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 4(78) 256 R2: CHEMCYCLOPEDIA 1986 p.264 R3: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 231 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V4 573 R5: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 331 R6: SRI R7: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 148 R8: Lide, D.R. (ed.). 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R48: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Bromodichloromethane (CAS No. 75-27-4): Short Term Reproductive and Developmental Toxicity Study When Administered to Sprague-Dawley Rats in the Drinking Water, NTP Study No. RDGT94017 available at http://ntp-server.niehs.nih.gov/htdocs/pub-RDGT0.html as of August 16, 2002 R49: PFAFFENBERGER CD ET AL; INT J ENVIRON ANAL CHEM 8 (1): 55-65 (1980) R50: USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-26 (1980) EPA 440/5-80-051 R51: Smith CC et al; ISS EPA/600/1-85-001 No PB85-152387 (1985) R52: Mink FL et al; Bull Environ Contam Toxicol 37 (5): 752-8 (1986) R53: STEVENS JL, ANDERS MW; BIOCHEM PHARMACOL 28: 3189-94 (1979) R54: AHMED AE ET AL; DRUG METAB DISPOS 5 (2): 198-204 (1977) R55: ANDERS MW ET AL; DRUG METAB DISPOS 6 (5): 556-60 (1978) R56: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1298 (1999) R57: (1) Class T et al; Chemosphere 15: 429-36 (1986) (2) Gschwend PM et al; Science 227: 1033-5 (1985) (3) Sturges WT et al; Tellus 45B: 120-6 (1993) R58: (1) Jackisch PF; Kirk-Othmer Encycl Chem Technol 4th. NY, NY: Wiley-Interscience 4: 560-89 (1992) (2) Perwak J et al; Exposure and Risk Assessment for Trihalomethanes (Chloroform, Bromoform, Bromodichloromethane, Dibromochloromethane) USEPA-440/8- 81-018 p.13 (1980) (3) USEPA; Health and Environmental Effects Profile for Bromochloromethanes ECAO-CIN-P122 (Final Draft) p.12, 21 (1985) R59: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Warner HP et al; Determination of Henry's Law constants of selected priority pollutants. USEPA/600/D-87/229 (NTIS PB87-212684 (1987) (4) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (5) USEPA; Health and Environmental Effects Profile for Bromochloromethanes ECAO-CIN-P122 (Final Draft) p.18-9 (1985) (6) Sabljic A et al; Chemosphere 31: 4489-514 (1995) R60: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Warner HP et al; Determination of Henry's Law constants of selected priority pollutants. USEPA/600/D-87/229 (NTIS PB87-212684 (1987) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) (9) USEPA; Health and Environmental Effects Profile for Bromochloromethanes ECAO-CIN-P122 (Final Draft) p.18-9 (1985) (10) Sabljic A et al; Chemosphere 31: 4489-514 (1995) (11) Rorije E et al; Environ Toxicol Chem 17: 1943-50 (1998) R61: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Class T et al; Chemosphere 15: 429-36 (1986) R62: (1) Tabak HH et al; J Water Pollut Control Fed 53: 1503-18 (1981) (2) Bouwer EJ et al; Environ Sci Technol 15: 596-9 (1981) R63: (1) Bouwer EJ et al; Environ Sci Technol 15: 596-9 (1981) (2) Bouwer EJ, McCarty PL; Appl Environ Microbiol 45: 1295-9 (1983) (3) Bouwer EJ, McCarty PL; Appl Environ Microbiol 45: 1286-94 (1983) (4) Rittman BE et al; Ground Water 18: 236-43 (1980) (5) Cobb GD, Bouwer EJ; Environ Sci Technol 25: 1068-74 (1991) (6) Rorije E et al; Environ Toxicol Chem 17: 1943-50 (1998) R64: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (4) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (5) Mabey WR et al; p.179-82 in Aquatic Fate Process Data for Organic Priority Pollutants USEPA-440/4-81-014 (1981) R65: (1) Sangster J; LOGKOW Databank. Sangster Res. Lab., Montreal Quebec, Canada (1994) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R66: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Wilson JT et al; J Environ Qual 10: 501-6 (1981) (4) Piet GJ et al; Studies Environ Sci 17: 557-64 (1981) (5) USEPA; Health and Environmental Effects Profile for Bromochloromethanes ECAO-CIN-P122 (Final Draft) p.18-9 (1985) (6) Sabljic A et al; Chemosphere 31: 4489-514 (1995) R67: (1) Warner HP et al; Determination of Henry's Law constants of selected priority pollutants. USEPA/600/D-87/229 (NTIS PB87- 212684 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15- 29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (4) Kaczmar SW et al; Environ Toxicol Chem 3: 31-5 (1984) (5) Francois C et al; Trav Soc Pharm Montpellier 39: 49-50 (1979) (6) Wilson JT et al; J Environ Qual 10: 501-6 (1981) R68: (1) Westrick JJ et al; J Amer Water Works Assoc 76: 52-9 (1984) (2) USEPA; Ambient Water Quality Criteria for Halomethanes USEPA-440/5-80-051 p.C-7 (1980) (3) Trussel AR et al; Water Chlorination Environ Impact Health Effects 3: 39-53 (1980) (4) Furlong EAN, Ditri FM; Ecol Modeling 32: 215-25 (1986) (5) Hartwell TD et al; Atmos Environ 11: 2413-24 (1987) (6) Krasner SW et al; J AWWA 81: 41-53 (1989) R69: (1) Badaway MI; Bull Environ Contam Toxicol 48: 157-62 (1992) (2) Bellar TA et al; J Am Water Works Assoc 1974: 703-6 (1974) (3) Contu A et al; Bull Environ Contam Toxicol 44: 805-12 (1990) (4) El-Dib MA, Ali RK; Bull Environ Contam Toxicol 48: 378-86 (1992) (5) Fayad NM, Tawabini BS; Bull Environ Contam Toxicol 46: 305-12 (1991) (6) Hartwell TD et al; Atmos Environ 21: 1995-2004 (1987) (7) Wallace LA; Crit Rev Environ Sci Technol 27: 113-194 (1997) R70: (1) Fusillo TV et al; Groundwater 23: 354-60 (1985) (2) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) (3) Badaway MI; Bull Environ Contam Toxicol 48: 157-62 (1992) (4) Canter LW, Sabatini DA; Inter J Environ Stud 46: 35-57 (1994) (5) Krill RM, Sonzogni WC; J AWWA 78: 70-5 (1986) (6) van Bellen P; Stygologia 5: 199-212 (1990) R71: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Ohio River Valley Sanit Comm; Assessment of Water Quality Conditions. Ohio River Mainstream, Cincinnati, OH (1982) (3) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters USEPA-560/6-77-015a (1977) (4) Kaiser KLE et al; J Great Lakes Res 9: 212-23 (1983) (5) Kaiser KLE, Comba ME; Environ Toxicol Chem 5: 965-76 (1986) (6) Bellar TA et al; J Am Water Works Assoc 1974: 703-6 (1974) (7) Hall LW Jr; Aquat Toxicol 10: 73-99 (1987) (8) Kuo HW et al; Chemosphere 33: 913-20 (1996) (9) Rathbun RE; Sci Total Environ 180: 125-35 (1996) (10) Williams DT et al; Chemosphere 34: 299-316 (1997) R72: (1) Class T et al; Chemosphere 15: 429-36 (1986) (2) Wakeham SG et al; Can J Fish Aquatic Sci 40: 304-21 (1983) (3) Dawes VJ, Waldock MJ Mar Pollut Bull 28: 291-8 (1994) (4) Gotoh M et al; Bull Environ Contam Toxicol 49: 186-91 (1992) R73: (1) Class T et al; Chemosphere 15: 429-36 (1986) (2) Adachi A, Kobayashi T; Bull Environ Contam Toxicol 52: 9-12 (1994) R74: (1) Cole RH et al; J Wat Pollut Control Fed 56: 898-908 (1984) (2) Aggazzotti G, Predieri G; Wat Res 20: 959-63 (1986) (3) Biziuk M et al; Intern J Environ Anal Chem 50: 109-15 (1993) R75: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Perry DL et al; Identification of Organic Compounds in Industrial Effluent Discharges USEPA- 600/4-79-016 p.42-3 (1979) (3) Dunovant VS et al; J Water Pollut Control Fed 58: 886-95 (1986) (4) Virarghavan T, Hasen S; Water Air Soil Pollut 28: 299-308 (1986) (5) Abrahamsson K, Klick S; Chemosphere 18: 2247-56 (1989) (6) Comba ME et al; Environ Toxicol Chem 13: 1065-74 (1994) (7) Juuti S et al; Chemosphere 33: 2431-40 (1996) R76: (1) Hauser TR, Bromberg SM; Environ Monitor Assess 2: 249-72 (1982) (2) Abrahamsson K, Klick S; Chemosphere 18: 2247-56 (1989) (3) Gotoh M et al; Bull Environ Contam Toxicol 49: 186-91 (1992) (4) Hoekstra EJ et al; Environ Sci Technol 32: 3724-9 (1998) R77: (1) Kroneld R; Bull Environ Contam Toxicol 42: 868-72 (1989) R78: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals in the Atmosphere: An Assessment of Available Data. Menlo Park, CA: SRI International (1982) (2) Shikiya J et al; Proc-APCA 77th Annual Mtg Vol 1,84-1.1 (1984) R79: (1) Pellizzari ED et al; Environ Intern 12: 619-23 (1986) (2) Brown SK et al; Indoor Air 4: 123-34 (1994) R80: (1) Class T et al; Chemosphere 15: 429-36 (1986) R81: (1) Entz RC et al; J Agric Food Chem 30: 846-9 (1982) (2) Abdel-Rahman MS; J Appl Toxicol 2: 165-6 (1982) (3) McNeal TP et al; J AOAC Inter 78: 391-7 (1995) (4) Miller LJ, Uhler AD; Bull Environ Contam Toxicol 41: 469-74 (1988) (5) Page BD, Lacroix GM; J AOAC Inter 78: 1416-28 (1995) (6) Uhler AD, Diachenko GW; Bull Environ Contam Toxicol 39: 601-7 (1987) R82: (1) Gschwend PM et al; Science 227: 1033-5 (1985) R83: (1) Gotoh M et al; Bull Environ Contam Toxicol 49: 186-91 (1992) R84: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Rosenberg C et al; Chemosphere 23: 1617-28 (1991) R85: (1) Wallace LA; Crit Rev Environ Sci Technol 27: 113-194 (1997) R86: (1) Barkley J et al; Biomed Mass Spectrom 7: 139-47 (1980) (2) Stanley JS; Broad Scan Analysis of Human Adipose Tissue: Volume II: Volatile Organic Compounds USEPA-560/5-86-036 p.74 (1986) (3) Ashley DL et al; Clin Chem 40: 1401-7 (1994) (4) Lindstrom AB et al; Environ Health Perspec 105: 636-42 (1997) (5) Wallace LA; Crit Rev Environ Sci Technol 27: 113-194 (1997) R87: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R88: 40 CFR 141.12 (7/1/99) R89: 40 CFR 401.15 (7/1/99) R90: 40 CFR 302.4 (7/1/99) R91: 40 CFR 716.120 (7/1/99) R92: Gruber H; GIT Fachz Lab 28 (3): 161-2 165 (1984) R93: Huang JYC, Smith GC; J Am Water Works Assoc 76 (4): 168-71 (1984) R94: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R95: 40 CFR Part 141, Revised July 1993 as cited in USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R96: USEPA/Office of Solid Waste (OSW); Test Methods for Evaluating Solid Waste, Physical/ Chemical Methods, SW-846, 3rd Edition, Final Update II, September (1994) R97: BARKLEY J ET AL; BIOMED MASS SPECTROM 7 (4): 139-47 (1980) R98: ALLES G ET AL; ZENTRALBL BAKTERIOL, MIKROBIOL HYG, ABT 1, ORIG B 174 (3): 238-48 (1981) R99: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 435-44 (1985) R100: Pellizzari ED et al; Environmental Carcinogens Selected Methods of Analysis 7: 413-31 (1985) R101: Fishbein L; Environmental Carcinogens Selected Methods of Analysis 7: 141-68 (1985) R102: BRECHBUEHLER B ET AL; GLASS CAPILLARY CHROMATOGR, INT SYMP, 2ND: 53-72 (1977) R103: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; RS: 83 Record 264 of 1119 in HSDB (through 2003/06) AN: 4161 UD: 200303 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PHENOLPHTHALEIN- SY: *2,2-BIS(P-HYDROXYPHENYL)PHTHALIDE; *3,3-BIS(4-HYDROXYPHENYL)PHTHALIDE; *EUCHESSINA-; *ALPHA-(P-HYDROXYPHENYL)-ALPHA-(4-OXO-2,5-CYCLOHEXADIEN-1-YLIDINE)-O-TOLUIC ACID; *1(3H)-ISOBENZOFURANONE, 3,3-BIS(4-HYDROXYPHENYL)-; *KOPROL-; *LAXIN-; *LAXOGEN-; *LILO-; *PHTHALIMETTEN-; *PURGA-; *PURGOPHEN-; *SPULMAKO-LAX-; *TRILAX- RN: 77-09-8 MF: *C20-H14-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD BY CONDENSING PHENOL WITH PHTHALIC ANHYDRIDE...HUBACHER. [R1] *Interaction of phenol and phthalic anhydride in sulfuric acid. [R2] FORM: *TABLETS NF: 60 and 120 MG [R3, 742] *GRADES: TECHNICAL; PURE REAGENT; NF [R2] *Available in white or yellow forms; the monosodium salt is the most common form sold commercially. [R4] MFS: *Aldrich Chemical Co, Inc, Hq, 1001 W St Paul Ave, Milwaukee, WI 53233, (414) 273-3850. Production site: Milwaukee, WI 53233 [R5] OMIN: *1% ALCOHOLIC SOLN AS INDICATOR IN TITRATIONS... NOT SUITABLE FOR AMMONIA. VERY SENSITIVE TO CO2, AND IN EST CARBONATES LIQ MUST BE BOILED. BORAX CAN BE TITRATED WITH PHENOLPHTHALEIN AS INDICATOR ONLY WHEN GLYCEROL IS PRESENT, BECAUSE COLOR GRADUALLY FADES AWAY AS ACID IS ADDED. USABLE WITH FEW ALKALOIDS. [R1] *DETECTION OF GI BLEEDING...PINK COLORATION FORMS IN AQ PHASE WHEN PHENOLPHTHALEIN AND HYDROGEN PEROXIDE ARE ADDED TO ETHANOL EXTRACT OF FECES. /FORMER USE/ [R6] *COLOR LOSS OF PHENOLPHTHALEIN IN 1% WT/VOL SODIUM CARBONATE AND SATURATED LIME WATER SOLN DUE TO DECOMP TO 2-(4-HYDROXYBENZOYL)BENZOIC ACID AND PHENOL. IDEAL SODIUM CARBONATE CONCN WAS 0.05 N IN BASIC SOLN FOR STORING PHENOLPHTHALEIN SAMPLES AS POSSIBLE EVIDENCE IN CRIMINAL CASES. [R7] USE: *Acid base indicator, laboratory reagent [R2] *Analytical reagent [R4] *MEDICATION *MEDICATION (VET) PRIE: U.S. PRODUCTION: *(1977) PROBABLY LESS THAN 9.08X10+8 G (SALES) [R8] *(1979) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R8] U.S. IMPORTS: *(1977) 5.93X10+7 GRAMS [R8] *(1979) 7.56X10+7 GRAMS [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MINUTE, TRICLINIC CRYSTALS, OFTEN TWINNED; WHITE OR YELLOWISH-WHITE [R1]; *WHITE RHOMBIC NEEDLES [R9]; *Pale yellow powder [R2] ODOR: *ODORLESS [R3, 741] MP: *258-262 DEG C [R1] MW: *318.31 [R1] DEN: *1.299 [R1] DSC: *pKa = 9.7 at 25 deg C [R1] OWPC: *log Kow = 2.41 [R10] SOL: *INSOL IN LIQ PARAFFIN [R11, 90]; *1 G DISSOLVES IN 12 ML ALCOHOL, IN ABOUT 100 ML ETHER; SOL IN DIL SOLUNS OF ALKALI HYDROXIDES AND HOT SOLUTNS OF ALKALI CARBORATES FORMING A RED SOLN [R1]; *SOL IN ETHYL ETHER; VERY SOL IN ACETONE, ETHANOL [R9]; *Water solubility = 400 mg/l at 25 deg C [R12] SPEC: *INDEX OF REFRACTION: 1.635 (ALPHA), 1.673 (GAMMA) [R11, 317]; *MAX ABSORPTION (ALKALI-ALCOHOL): 550 NM (LOG E= 3.90) [R9]; *IR: 1334 (Coblentz Society Spectral Collection) [R13]; *UV: 2188 (Sadtler Research Laboratories Spectral Collection) [R13]; *NMR: 14709 (Sadtler Research Laboratories Spectral Collection) [R13]; *MASS: 2434 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R13]; *UV max (methanol): 205, 229, 276 nm (E 27261.147, 14692.144, 2006.369) [R1] OCPP: *SOLN ARE COLORLESS TO PH 8.5; PINK TO DEEP-RED, ABOVE PH 9 [R1] *Forms an almost colorless solution in neutral or acid solution, pink to deep red in presence of alkali, but colorless in the presence of large amounts of alkali. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R14] SSL: *STABLE IN AIR [R3, 741] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of phenolphthalein. There is sufficient evidence in experimental animals for the carcinogenicity of phenolphthalein. Overall evaluation: Phenolphthalein is possibly carcinogenic to humans (Group 2B) [R15] HTOX: *ONLY OCULAR COMPLICATIONS REPORTED HAVE BEEN EDEMA OF EYELIDS AND CONJUNCTIVAL ECCHYMOSES ACCOMPANYING WIDESPREAD REACTIONS OF SKIN, WHICH MAY BE SEVERE. [R16] *...MAJOR DANGER OF OVERDOSAGE...IS FLUID AND ELECTROLYTE DEFICITS RESULTING FROM EXCESSIVE LAXATIVE EFFECT. HOWEVER, ALLERGIC REACTIONS, INCL FIXED-DRUG ERUPTION, STEVENS-JOHNSON SYNDROME, AND A SYNDROME THAT RESEMBLES LUPUS ERYTHEMATOSUS, HAVE BEEN REPORTED.../DIPHENYLMETHANE DERIVATIVES/ [R17] *PHENOLPHTHALEIN POISONING SHOULD BE TESTED FOR IN ANY CASE OF INTRACTABLE DIARRHEA WHEN OBJECTIVE EVIDENCE OF INTESTINAL MUCOSAL DAMAGE CANNOT BE FOUND. [R18] *Phenolphthalein was used by 236 mother-child pairs during the first trimester and 806 anytime during pregnancy...No evidence was found to associate the use of this drug with major or minor malformations. [R19] *Phenolphthalein that had undergone conjugation, but no unmetabolized phenolphthalein, was excreted into breast milk in concentrations up to 1.0 ug/ml after a single 200-800 mg dose in 22 lactating women. Bowel movements occurred in 16 of the women after the dose, but none of the nursing infants had diarrhea. [R19] *Toxic doses range from 400 mg to 130 g. Doses associated with fatalities have been 1.8 g and 0.65 to 1.3 g. [R20, 1011] *A retrospective study of 172 phenolphthalein ingestions, ranging from 32.5 to 1620 mg... in children indicated that about 20% had no symptoms. Most had minor symptoms that resolved within 24 hours. [R20, 1012] NTOX: *PHENOLPHTHALEIN FED TO MICE FOR 3 GENERATIONS FAILED TO PRODUCE ANY TERATOGENESIS. [R21] *Phenolphthalein was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Phenophthalein was tested at doses of 0.003, 0.01, 0.033, 0.10, 0.22, 0.33, and 1.0 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Phenolphthalein was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 1.0 mg/plate. Some clearing of the background bacterial lawn was exhibited by all doses above 0.10 mg/plate. The highest dose (1.0 mg/plate) caused total clearing in all cultures except for strains TA100 and TA1535 when an activation system was included. [R22] *... Estrogenic in the immature rat. The minimum effective dose per rat causing an increase in uterine glycogen content was 4 mg ... [R23] *... CONCLUSIONS: Under the conditions of these 2 yr feed studies, there was clear evidence of carcinogenic activity of phenolphthalein in male F344/N rats based on markedly increased incidences of benign pheochromocytomas of the adrenal medulla and of renal tubule adenomas and adenomas or carcinomas (combined). There was some evidence of carcinogenic activity of phenolphthalein in female F344/N rats based on the increased incidences of benign pheochromocytomas of the adrenal medulla in the 12,000 ppm group and of benign or malignant pheochromocytomas (combined) in the 12,000 and 25,000 ppm groups. There was clear evidence of carcinogenic activity of phenolphthalein in male B6C3F1 mice based on increased incidences of histiocytic sarcomas and of malignant lymphomas of thymic origin. There was clear evidence of carcinogenic activity of phenolphthalein in female B6C3F1 mice based on increased incidences of histiocytic sarcomas, malignant lymphomas of all types, lymphomas of thymic origin, and benign sex cord stromal tumors of the ovary. [R24] NTP: *... Male and female F344/N rats and B6C3F1 mice were exposed to phenolphthalein (98% to 99% pure) in feed for ... 2 years. ... 2 YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were given 0, 12,000, 25,000, or 50,000 ppm phenolphthalein (equivalent to average daily doses of approximately 500, 1,000, or 2,000 mg phenolphthalein/kg body weight to males and 500, 1,000, or 2,500 mg/kg to females) in feed for 2 yr. 2 YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were given 0, 3,000, 6,000, or 12,000 ppm phenolphthalein (equivalent to average daily doses of approximately 300, 600, or 1,200 mg phenolphthalein/kg body weight to males and 400, 800, or 1,500 mg/kg to females) in feed for 2 yr. CONCLUSIONS: Under the conditions of these 2 yr feed studies, there was clear evidence of carcinogenic activity of phenolphthalein in male F344/N rats based on markedly increased incidences of benign pheochromocytomas of the adrenal medulla and of renal tubule adenomas and adenomas or carcinomas (combined). There was some evidence of carcinogenic activity of phenolphthalein in female F344/N rats based on the increased incidences of benign pheochromocytomas of the adrenal medulla in the 12,000 ppm group and of benign or malignant pheochromocytomas (combined) in the 12,000 and 25,000 ppm groups. There was clear evidence of carcinogenic activity of phenolphthalein in male B6C3F1 mice based on increased incidences of histiocytic sarcomas and of malignant lymphomas of thymic origin. There was clear evidence of carcinogenic activity of phenolphthalein in female B6C3F1 mice based on increased incidences of histiocytic sarcomas, malignant lymphomas of all types, lymphomas of thymic origin, and benign sex cord stromal tumors of the ovary. [R24] +Phenolphthalein administered via feed was tested for its effects on fertility and reproduction in Swiss CD-1 mice according to the Continuous Breeding protocol. A dose-finding study was not conducted; rather based on information available in the literature, 0.1, 0.7, and 3.0% levels were tested in the reproductive study. For F0 evaluation, male and female mice were continuously exposed for a 7 day precohabitation and a 98 day cohabitation period (Task 2). Subsequently, the control and 0.7% groups were used in a cross-over mating trial (Task 3) to determine the sex affected by chemical treatment. The F1 generation from control, 0.1, and 0.7% groups were also evaluated (Task 4). Phenolphthalein with increasing dose and duration of exposure, caused a significant reduction in fertility, with a decr in the number of litters/fertile pair in the 0.7 and 3.0% groups. Parental body weights were not affected by phenolphthalein treatment. The cumulative days to litter values were also increased in the 0.7 and 3% treated animals. In the cross-over mating trial, the treated females mated with control males delivered fewer live pups. There were no adverse effects in the litters from treated males mated with control females. At terminal necropsy, male kidneys were enlarged and right epididymis and testis weights were significantly lower than controls. Sperm morphology and vaginal cytology evaluation (SMVCE) results were parallel to subchronic study results in B6C3F1 mice; both sperm count (Task 3) and incidence of abnormal sperm (Tasks 3 and 4) were adversely affected. Reproductive performance of treated males, however, was similar to the corresponding control males. The middle dose group was chosen for Task 3 crossover in the expectation (based on several previous RACB studies) that use of the high dose would indicate that both sexes were affected. Similar to Task 2 results, fertility declined in F1 mice receiving 0.7% phenolphthalein. The number of live F2 pups/litter decreased as well. Also, in the F1 males in the 0.7% group, testis and epididymis weights were decreased, and the incidence of abnormal sperm was increased. Pathologic lesions in F1 males were similar to those found in the parental males. Thus, phenolphthalein, administered in the feed at concns up to 3.0%, was clearly toxic to murine reproduction in both generations of treated mice. [R25] ADE: *IT ACTS WITHIN 4-8 HR AFTER INGESTION. [R3, 742] */UP TO/...15% OF THERAPEUTIC DOSE...IS ABSORBED AND ELIMINATED BY KIDNEY, MOST OF IT IN CONJUGATED FORM. ... SOME ABSORBED DRUG IS ALSO EXCRETED IN BILE, AND RESULTING ENTEROHEPATIC CYCLE MAY CONTRIBUTE TO PROLONGATION OF CATHARTIC EFFECT. [R17] *BILIARY EXCRETION OF METABOLITES OF...PHENOLPHTHALEIN...IN RATS WAS SHOWN...TO BE INCR BY PRE-TREATMENT WITH HEPATIC-MICROSOMAL-ENZYME INDUCERS, AND TO BE DECR BY ENZYME INHIBITORS AFTER DOSING WITH PARENT COMPD, BUT NO EFFECT WAS OBSERVED AFTER DOSING WITH METABOLITES. [R26] *PHENOLPHTHALEIN GLUCURONIDE (I) EXCRETED MORE RAPIDLY THAN PHENOLPHTHALEIN (II) FOLLOWING IV INJECTION, SUGGESTING THAT UPTAKE OF I FROM BLOOD IMPOSES RATE LIMITATION WHICH OUTWEIGHS THE LACK OF CONJUGATION BEFORE EXCRETION. [R27] *BILIARY EXCRETION RATE OF PHENOLPHTHALEIN GLUCURONIDE (I) AND PHENOLPHTHALEIN (II) BY RATS OVER 1ST 10 MIN APPROX 4 and 7 TIMES GREATER, RESPECTIVELY, AFTER IV THAN IP INJECTION. I AND II EXCRETED @ SIMILAR RATES AFTER IP INJECTION; UPTAKE IS RATE LIMITING PROCESS. [R28] *IN BILE-DUCT-CANNULATED RATS INJECTED WITH (3)H-LABELED PHENOLPHTHALEIN (25 MG/KG, IP) 89% OF (3)H EXCRETED IN BILE IN 3 HR, WHEREAS IN INTACT RATS 4 DAYS REQUIRED FOR ELIMINATION OF 86% IN FECES. DELAYED EXCRETION APPEARS TO BE DUE TO ENTEROHEPATIC CIRCULATION. [R29] *BILIRUBIN COMPETED WITH PHENOLPHTHALEIN TRANSPORT FROM BLOOD TO HEPATIC CELLS AND @ SITE OF GLUCURONYL-CONJUGATE FORMATION, WHEREAS CCL4 PRETREATMENT CAUSED IMPAIRMENT OF TRANSPORT OF CONJUGATED PHENOLPHTHALEIN FROM HEPATIC CELLS TO BILE CANALICULI. [R30] METB: *YIELDS PHENOLPHTHALEIN-BETA-D-GLUCURONIDE IN RAT, IN MOUSE. /FROM TABLE/ [R31] BHL: *CLASSICAL COMPARTMENTAL PHARMACOKINETICS MODEL DEVELOPED TO DESCRIBE SYSTEMIC BLOOD CONCN-TIME PROFILE OF PHENOLPHTHALEIN FOLLOWING SINGLE IV BOLUS INJECTION; USED TO SIMULATE 24-HR TIME COURSE OF BLOOD CONCN. INDICATION THAT LONG T/2 ARE ARTIFACTS OF RECIRCULATION. [R32] ACTN: *WHEN TAKEN ORALLY, IT IS THOUGHT TO BE DISSOLVED BY INTESTINAL JUICES AND BILE AND TO STIMULATE INTESTINAL MUSCULATURE, CHIEFLY THAT OF COLON. [R3, 742] *STUDY INDICATES THAT PHENOLPHTHALEIN AFFECTS INTESTINAL ELECTROLYTE TRANSPORT BY MECHANISMS OTHER THAN INHIBITION OF SODIUM PUMP OR STIMULATION OF SECRETION BY CYCLIC NUCLEOTIDES. [R33] *PHENOLPHTHALEIN INCR INTESTINAL FLUID VOL IN RAT COLON IN SITU, APPARENTLY VIA STIMULATION OF PROSTAGLANDIN E BIOSYNTHESIS IN COLON. [R34] *SUGGESTED THAT LAXATIVE EFFECT OF PHENOLPHTHALEIN WAS CAUSED BY AN INHIBITION OF ABSORPTION AND REABSORPTION FROM SMALL INTESTINE OF SECRETIONS FROM SALIVARY GLANDS, STOMACH, BILE AND INTESTINAL GLANDS. [R35] *WATER ABSORPTION FROM INTESTINES OF 6 PT WITH ILEOSTOMIES AND FROM RATS WAS MEASURED AFTER ADMIN OF PHENOLPHTHALEIN. RESULTS INDICATE THAT SOME LAXATIVE EFFECTS RESULT FROM INHIBITION OF WATER ABSORPTION IN LARGE AND SMALL INTESTINES. [R36] INTC: *PRETREATMENT OF RATS WITH SODIUM METHOTREXATE (1 MG, ORALLY, DAILY FOR 5 DAYS) OR VINCRISTINE SULFATE (0.03 MG/KG, IV, WEEKLY FOR 3 WK) MARKEDLY REDUCED BILIARY EXCRETION OF PHENOLPHTHALEIN (10 MG/KG, IV) INDICATING THAT HEPATIC FUNCTION WAS DECREASED. [R37] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Cathartics; Indicators and Reagents [R38] *...HAS...BEEN WIDELY EMPLOYED AS CATHARTIC. ... /IT/ IS AVAIL...IN NUMEROUS PROPRIETARY PREPN. [R39] *SINCE...LAXATIVE EFFECTS ARE NOT USUALLY PRODUCED IN LESS THAN 6 HR AFTER ORAL ADMIN, THEY ARE OFTEN TAKEN AT BEDTIME, TO PRODUCE THEIR EFFECT NEXT MORNING. BECAUSE OF ADVERSE EFFECTS, USE OF THESE AGENTS SHOULD BE LIMITED TO 10 CONSECUTIVE DAYS. /DIPHENYLMETHANE DERIVATIVES/ [R17] *MEDICATION (VET): HAS BEEN USED AS LAXATIVE [R1] *CATHARTIC DRUG IN LAXATIVES; ACID-BASE INDICATOR [R8] WARN: *PATIENTS SHOULD BE WARNED OF POSSIBLE COLORING OF URINE AND FECES. [R17] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Phenolphthalein's production and use an acid/base indicator, as a laboratory reagent, and its former use as a laxative, may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.7X10-13 mm Hg at 25 deg C indicates phenolphthalein will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase phenolphthalein will be physically removed from the atmosphere by wet and dry deposition. If released to soil, phenolphthalein is expected to have moderate mobility based upon an estimated Koc of 488. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 9.0X10-16 atm-cu m/mole. Volatilization from dry soil surfaces should not be important given the vapor pressure of this compound. If released into water, phenolphthalein is expected to adsorb very little to suspended solids and sediment in water based on the estimated Koc. Biodegradation data for phenolphthalein are not available. Volatilization from water surfaces is not expected to be an important fate process based on its estimated Henry's Law constant. An estimated BCF of 21 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to phenolphthalein may occur through dermal contact with this compound at workplaces where phenolphthalein is produced or used. The general population may be exposed to phenolphthalein via ingestion of and dermal contact with consumer products containing phenolphthalein. (SRC) ARTS: *Phenolphthalein's production and use an acid/base indicator, as a laboratory reagent, and its former use as a laxative(1), may result in its release to the environment through various waste streams(SRC). [R40] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 488(SRC), determined from a log Kow of 2.41(2,SRC) and a regression-derived equation(3), indicates that phenolphthalein is expected to have moderate mobility in soil(SRC). Volatilization of phenolphthalein from moist soil surfaces is not expected to be important(SRC) given an estimated Henry's Law constant of 9.0X10-16 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Phenolphthalein is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 6.7X10-13 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation data for phenolphthalein are not available(SRC). [R41] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 488(SRC), determined from a log Kow of 2.41(2,SRC) and a regression-derived equation(3), indicates that phenolphthalein is expected to adsorb very little to suspended solids and sediment in water(SRC). Phenolphthalein is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 9.0X10-16 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 21(3,SRC), from the log Kow(2,SRC), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data for phenolphthalein are not available(SRC). [R42] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), phenolphthalein, which has an estimated vapor pressure of 6.7X10-13 mm Hg at 25 deg C(2,SRC), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase phenolphthalein may be physically removed from the air by wet and dry deposition(SRC). [R43] ABIO: *The rate constant for the vapor-phase reaction of phenolphthalein with photochemically-produced hydroxyl radicals has been estimated as 8.4X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 4.6 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Phenolphthalein is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). [R44] BIOC: *An estimated BCF of 40 was calculated for phenolphthalein(SRC), using a log Kow of 2.41(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R45] KOC: *The Koc of phenolphthalein is estimated as approximately 488(SRC), using a log Kow of 2.41(1) and a regression-derived equation(2,SRC). According to a classification scheme(3), this estimated Koc value suggests that phenolphthalein is expected to have moderate mobility in soil(SRC). [R46] VWS: *The Henry's Law constant for phenolphthalein is estimated as 9.0X10-16 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that phenolphthalein is expected to be essentially nonvolatile from water surfaces(2,SRC). Phenolphthalein's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces should not occur(SRC). Phenolphthalein is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 6.7X10-13 mm Hg(SRC), determined from a fragment constant method(3). [R47] MILK: *Phenolphthalein, was excreted into breast milk in concentrations up to 1.0 ug/ml after a single 200-800 mg dose in 22 lactating women. [R19] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1946 workers (1408 of these are female) are potentially exposed to phenolphthalein in the US(1). Occupational exposure to phenolphthalein may occur through dermal contact with this compound at workplaces where phenolphthalein is produced or used(SRC). The general population may be exposed to phenolphthalein via ingestion of and dermal contact with consumer products containing phenolphthalein(SRC). [R48] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R49] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SPECTROPHOTOMETRIC DETERMINATION OF PHENOLPHTHALEIN WITH SULFURIC ACID. [R50] *HIGH PRESSURE LIQUID CHROMATOGRAPHY OF PHENOLPHTHALEIN IN ANTHELMINTIC TABLETS. [R51] CLAB: *SPECTROPHOTOMETRIC ASSAY OF PHENOLPHTHALEIN IN INTESTINAL PERFUSATE, SERUM AND URINE. [R52] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the prechronic study for phenolphthalein is completed, and the chemical is in review for further evaluation. Route: dosed feed; Species: transgenic model evaluation II, mice. [R53] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1248 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 895 R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R4: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 682 R5: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 801 R6: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 483 R7: NARAYANASWAMI K ET AL; J INDIAN ACAD FORENSIC SCI 17(2) 92 (1978) R8: SRI R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-202 R10: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 166 R11: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. R12: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 74 R14: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2631 R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 76 410 (2000) R16: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 721 R17: Hardman, J.G., L.E. Limbird, P.B. Molinoff, R.W. Ruddon, A.G. Goodman (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill, 1996. 923 R18: FLEISHER D, AMENT ME; DIARRHEA, RED DIAPERS, AND CHILD ABUSE; CLIN PEDIATR (PHILA) 16(9) 820 (1977) R19: Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams and Wilkins 1994. 683 R20: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. R21: STOCKINGER L; ARZNEIM-FORSCH 15(5) 550 (1965) R22: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R23: Thomas, J.A., K.S. Korach, J.A. McLachlan. Endocrine Toxicology. New York, NY: Raven Press, Ltd., 1985. 25 R24: Toxicology and Carcinogenesis Studies of Phenolphthalein in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 465 (1996) NIH Publication No. 97-3390 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R25: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Phenolphthalein (CAS No. 77-09-8) in CD-1 Swiss Mice, NTP Study No. RACB89066 (June 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R26: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. 436 R27: CLARK AG, COOKE R; J PHARM PHARMACOL 30 (6): 382 (1978) R28: CLARK AG, COOKE R; J PHARM PHARMACOL 30(6) 382 (1978) R29: HIROM PC ET AL; BR J PHARMACOL 56(3) 355 (1976) R30: OHSHIKA H ET AL; SAPPORO IGAKU ZASSHI 48(1) 43 (1979) R31: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-8 R32: COLBURN WA ET AL; DRUG METAB DISPOS 7 (2): 100 (1979) R33: POWELL DW ET AL; GASTROENTEROLOGY 78 (3): 454 (1980) R34: BEUBLER E, JUAN H; EXPERIENTIA 34 (3): 386 (1978) R35: STOCKINGER L; ARZNEIM-FORSCH 15 (5): 550 (1965) R36: SAUNDERS DR ET AL; AM J DIG DIS 23 (OCT): 909 (1978) R37: CAPEL ID ET AL; BIOCHEM PHARMACOL 27 (10): 1413 (1978) R38: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R39: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 1007 R40: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th Ed. NY,NY: Van Nostrand Reinhold Company (1993) R41: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, And Steric Constants. ACS Professional Reference Book. Washington,DC: American Chemical Society (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) R42: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, And Steric Constants. ACS Professional Reference Book. Washington,DC: American Chemical Society (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R43: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R44: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R45: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, And Steric Constants. ACS Prof Reference Book. Washington, DC: American Chemical Society (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R46: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, And Steric Constants. ACS Prof Ref Book. Washington, DC: American Chemical Society (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R47: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) R48: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R49: 21 CFR 200-299, 300-499, 820, and 860 (4/1/97) R50: SUZUKI M ET AL; BUNSEKI KAGAKU 27 (8): 495 (1978) R51: AITZETMUELLER K; HRC CC, J HIGH RESOLUT CHROMATOGR CHROMATOGR COMMUN 1 (4): 220 (1978) R52: MORRIS SM, POWELL DW; ANAL BIOCHEM 95 (2): 465 (1979) R53: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 31 Record 265 of 1119 in HSDB (through 2003/06) AN: 4164 UD: 200301 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALPHA-METHYLBENZYL-ALCOHOL- SY: *BENZENEMETHANOL,-ALPHA-METHYL-; *BENZYL-ALCOHOL,-ALPHA-METHYL-; *ETHANOL,-1-PHENYL-; *FEMA-NUMBER-2685-; *(1-HYDROXYETHYL)BENZENE; *ALPHA-METHYLBENZENEMETHANOL-; *METHYLPHENYLCARBINOL-; *NCI-C55685-; *ALPHA-PHENETHYL-ALCOHOL-; *1-PHENETHYL-ALCOHOL-; *ALPHA-PHENYLETHANOL-; *1-PHENYLETHANOL-; *ALPHA-PHENYLETHYL-ALCOHOL-; *1-PHENYLETHYL-ALCOHOL-; *1-PHENYL-1-HYDROXYETHANE-; *PHENYLMETHYLCARBINOL-; *STYRALLYL-ALCOHOL-; *STYRALYL-ALCOHOL- RN: 98-85-1 MF: *C8-H10-O SHPN: UN 2937; alpha-Methylbenzyl alcohol IMO 6.1; alpha-Methylbenzyl alcohol ASCH: Ethyl benzene, alpha hydroxy (dl); 13323-81-4; Ethyl benzene, alpha hydroxy (l); 1445-91-6; Ethyl benzene, alpha hydroxy (d); 1517-69-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REDUCTION OF ACETOPHENONE; REACTION OF METHYL MAGNESIUM CHLORIDE AND BENZALDEHYDE; OXIDATION OF ETHYLBENZENE [R1] *In the hydroperoxide process, an organic hydroperoxide is used to epoxidize propylene; an organic alcohol is a coproduct. [R2] FORM: *GRADE: FCC [R3] MFS: *Givaudan-Roure Corp, Hq, 100 Delawanna Ave, Clifton, NJ 07014, (201) 365-8000; Specialty Division; Production site: Clifton, NJ 07014 [R4] *International Chemical Group, PO Box 43800, San Ysidro, CA 92173 (619)274-7215. Production Site: La Mesa, CA 91941. [R4] *Lyondell Petrochemical Company, One Houston Center, 1221 McKinney Sutie 1600, PO Box 3646, Houston, TX 77253-3646 (713)652-7200. Production site: Chennelview, TX 77530. [R4] *Penta Manufacturing Company, PO Box 1448, Fairfield, NJ 07007 (201) 740-2300. Production site: East Hanover, NJ 07936 [R4] OMIN: *TWO OPTICALLY ACTIVE ISOMERS EXIST. COMMERCIAL PRODUCT IS RACEMIC FORM. [R5] *REPORTED USES: NON-ALCOHOLIC BEVERAGES 4.6 PPM; ICE CREAM, ICES, ETC 3.8 PPM; CANDY 6.8 PPM; BAKED GOODS 9.0 PPM; GELATINS AND PUDDINGS 4.0 PPM; CHEWING GUM 0.30 PPM. [R5] USE: *PERFUMERY; FLAVORING; DYES; LABORATORY REAGENT [R3] *Methylbenzyl alcohol can be used like benzyl alcohol, and can be employed in stoving enamels. In cellulose nitrate and acetyl cellulose lacquers, methylbenzyl alcohol helps to improve flow and film formation and prevents blushing at relatively high atmospheric humidity levels. It has also proved to be a useful additive in paint-removal agents on account of its dissolution properties and long evaporation time. [R6] PRIE: U.S. PRODUCTION: *(1974) 4.54X10+6 G (CONSUMPTION AS FRAGRANCE) [R1] *(1977) LESS THAN 2.7X10+11 G-UNISOLATED INT [R1] U.S. IMPORTS: *(1977) 1.05X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 6.81X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQ [R3] ODOR: *MILD FLORAL ODOR [R3]; *MILD HYACINTH-GARDENIA ODOR [R5]; *Weak, bitter, almond-like odor [R6] BP: *204 DEG C [R3] MP: *20.7 DEG C [R3] MW: *122.17 [R7] DEN: *1.013 @ 25 deg C [R7] PH: *Neutral [R6] SOL: *Sol in glycerol, mineral oil, alcohol [R3]; *SOL IN MOST ORGANIC SOLVENTS [R5]; *A high solvency for alcohol-soluble cellulose nitrate, cellulose acetate, and cellulose acetobutyrate; for many natural and synthetic resins; and for fats and oils. In contrast to benzyl alcohol, it is miscible with white spirit. [R6]; *In water, 1,950 mg/l @ 25 deg C [R8] SPEC: *MAX ABSORPTION (SULFURIC ACID): 435 NM (LOG E= 4.0) [R9]; *IR: 2:602A (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R10, p. V1 272]; *NMR: 5:1C (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R10, p. V1 272]; *MASS: 4053 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R10, p. V1 272]; *Refractive index = 1.525-1.529 at 20 deg C [R3] OCPP: *CONGEALS BELOW ROOM TEMP [R3] *BP 203 DEG C @ 760 MM HG; DENSITY 1.0129 @ 20 DEG C/4 DEG C; INDEX OF REFRACTION: 1.5272 @ 20 DEG C/D; SPECIFIC OPTICAL ROTATION: +42.9 DEG @ 19 DEG C/D; MAX ABSORPTION (UNDIL SULFURIC ACID): 435 NM (LOG E= 4.0); VERY SOL IN ALC; SOL IN BENZENE, CHLOROFORM /D-FORM/ [R9] *SPECIFIC OPTICAL ROTATION: -45.5 DEG @ 23 DEG C/D (METHANOL, 5%); BP 202-204 DEG C @ 760 MM HG; DENSITY 1.0129; SLIGHTLY SOL IN WATER; VERY SOL IN ALC, ETHER /L-FORM/ [R9] *GLASSY; INSOL IN WATER; SOL IN ALL PROPORTIONS IN ALC, ETHER; INDEX OF REFRACTION: 1.5275 @ 20 DEG C/4 DEG C /DL-FORM/ [R9] *IR: 1830 (National Bureau of Standards Spectral Collection) /Ethyl benzene, alpha-hydroxy (dl)/ [R10, p. V1 614] *MASS: 508 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Ethyl benzene, alpha-hydroxy (dl) [R10, p. V1 614] *MASS: 508 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Ethyl benzene, alpha-hydroxy (l)/ [R10, p. V1 614] *MASS: 508 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Ethyl benzene, alpha-hydroxy (d)/ [R10, p. V1 614] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R11] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R11] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R11] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R11] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R11] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R11] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R11] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R11] NFPA: +Health: 0. 0= Materials that on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R12] +Flammability: 2. 2= Includes materials that must be moderately heated before ignition will occur and includes Class II and IIIA combustible liquids and and solids and semi-solids that readily give off ignitible vapors. Water spray may be used to extinguish fires in these materials because the materials can be cooled below their flash points. [R12] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R12] FLPT: +200 DEG F (93 DEG C) (CLOSED CUP) [R12] FIRP: +"ALCOHOL" FOAM [R12] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R13] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R14] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *Similar threshold conc (0.5%) for conjunctival irritation were noted for phenethyl alcohol in humans and rabbits ... . [R16] NTOX: *Similar threshold conc (0.5%) for conjunctival irritation were noted for phenethyl alcohol in humans and rabbits ... . [R16] NTP: *Toxicology and carcinogenesis studies of a-methylbenzyl alcohol (greater than 99% pure) ... were conducted by administering the chemical in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 yr. ... Doses of 375 and 750 mg/kg a-methylbenzyl alcohol were administered in corn oil by gavage, 5 days/wk for 103 wk, to groups of 50 rats and 50 mice of each sex. ... Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of a-methylbenzyl alcohol for male F344/N rats, as shown by incr incidences of renal tubular cell adenomas and adenomas or adenocarcinomas (combined). There was no evidence of carcinogenic activity for female F344/N rats administered 375 or 750 mg/kg. Renal toxicity ... was observed in dosed rats, and excessive mortality occurred during the last quarter of the studies. Poor survival reduced the sensitivity of the studies for detecting the presence of a carcinogenic response both in chemically exposed groups of male rats and in the high dose group of female rats. There was no evidence of carcinogenic activity of a-methylbenzyl alcohol for male and female B6C3F1 mice administered 375 or 750 mg/kg for 2 yr. [R17] METB: *DEHYDROGENASE PRESENT IN RAT CYTOSOL AND MICROSOMES CONVERTS 1-PHENYLETHANOL INTO ACETOPHENONES. [R18] *...METHYL PHENYLCARBINOL GIVEN TO RATS SHOWS SUBSTRATE STEREOSELECTIVITY IN ITS OWN METABOLISM; WHILE R-(+)-ISOMER IS EXCRETED LARGELY AS GLUCURONIDE, S-(-)-ISOMER UNDERGOES FURTHER OXIDATIVE METABOLISM. [R19] *YIELDS ACETOPHENONE IN RAT. 1-PHENYLETHYL-BETA-D-GLUCURONIDE IN RABBIT. /FROM TABLE/ [R20] *Site directed mutants were constructed in cytochrome p450cam to re-engineer the stereochemistry and coupling of ethylbenzene hydroxylation. The reaction with the wild type enzyme produces one regioisomer 1-phenylethanol with 5% reduced nicotinamide adenine deoxyribonucleic acid product conversion of and a ration of 73:27 for the R and S enantiomers respectively. Ethylbenzene was modeled into the active site of wild type p450cam in a rigid mode and oriented to optimize either pro-R or pro-S hydrogen abstraction. Residues T101, T185 and V247 make extensive contacts with the substrate in the static complexes and were therefore chosen for site directed mutagenesis. Single mutants T101M, V247A and V247M are more stereospecific producing 89, 87 and 82% (R)-1-phenylethanol respectively. The coupling of the reaction is doubled for the single mutants T185L, T185F and V247M. In an effort to engineer incr stereospecificity and coupling into a single catalyst the T101M, T185F and V247M mutants were combined in a multiple mutant of p450cam. This protein hydroxylates ethylbenzene resulting in an R:S ratio of 87:13 for the 1-phenylethanols and 13% coupling of reducing equivalents to product. The catalytic stereospecificity and stoichiometry with T101-T185F-V247M does not represent a summation of changes observed for the single mutants. A portion of the individual effects on substrate recognition produced by the single substitutions is either eliminated or degenerate within the triple mutant. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Alpha-methylbenzyl alcohol's production and use as a dye carrier, in perfumes, flavorings, dyes, and as a laboratory agent may result in its release to the environment through various waste streams. If released to the atmosphere, alpha-methylbenzyl alcohol will mainly exist in the vapor phase based on an estimated vapor pressure of 0.058 mm Hg at 25 deg C. Vapor-phase alpha-methylbenzyl alcohol is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 8 hours. Measured Koc values from < 5-52, with the higher values corresponding to greater organic content in soil, suggest that alpha-methylbenzyl alcohol will have very high mobility in soil. Biodegradation is expected to be a major fate process for this compound in both soil and water. In screening tests, alpha-methylbenzyl alcohol was completely biodegraded under aerobic conditions within 2-3 weeks; a half life of 7 days was measured under anaerobic conditions. Acetophenone was produced as a metabolite under both aerobic and anaerobic conditions. In water, alpha-methylbenzyl alcohol is not expected to adsorb to sediment or suspended matter in the water column. An estimated Henry's Law constant of 2.9X10-7 atm-cu m/mole suggests that this compound will not volatilize from water surfaces. Bioconcentration in aquatic organisms should not occur based on an estimated BCF value of 9. Exposure to alpha-methylbenzyl alcohol may occur occupationally during its production or use in the manufacture of other products. The general population may be exposed to alpha-methylbenzyl alcohol through the ingestion of contaminated drinking water and food or the inhalation of air from new buildings. (SRC) ARTS: *Alpha-methylbenzyl alcohol's production and use as a dye carrier(1), in perfumes, flavorings, dyes, and as a laboratory agent(2) may result in its release to the environment through various waste streams(SRC). [R22] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), measured Koc values of < 5-52, with higher values corresponding to soils with a greater organic content(2), indicate that alpha-methylbenzyl alcohol will have very high mobility in soil(SRC). Biodegradation is expected to be a major fate process for this compound(SRC). Alpha-methylbenzyl alcohol was completely biodegraded within 2-3 weeks under aerobic conditions using an activated sludge inoculum(3). Under anaerobic conditions, this compound had a half-life of 7 days(3). Acetophenone was reported as a major metabolite for both oxygen conditions(3). Volatilization of alpha-methylbenzyl alcohol from either moist surfaces will not be a major fate process(SRC) based on estimated values for Henry's Law constant (2.9X10-7 atm-cu m/mole)(4,SRC). Volatilization from dry soil surfaces should not be significant based on an estimated vapor pressure (0.058 mm Hg)(5,SRC). [R23] *AQUATIC FATE: Based on a recommended classification scheme(1), experimental Koc values of < 5 to 52(2) indicate that alpha-methylbenzyl alcohol will not adsorb to suspended solids and sediment(SRC) in the water column. Biodegradation is expected to be a major fate process for this compound(SRC). Alpha-methylbenzyl alcohol was completely biodegraded within 2-3 weeks under aerobic conditions using an activated sludge inoculum(3). Under anaerobic conditions, this compound had a half-life of 7 days(3). Acetophenone was reported as the major metabolite for both oxygen conditions(3). Retention pond and aerated lagoon systems reported 12 and 17% biodegradation after 260 hours(3) indicating that under some conditions, biodegradation may not occur rapidly(SRC). Alpha-methylbenzyl alcohol should not volatilize from water surfaces based on an estimated Henry's Law constant of 2.9X10-7 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). An estimated BCF value of 9(3,SRC), from a measured water solubility(2), suggests that alpha-methylbenzyl alcohol will not bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(5). [R24] *ATMOSPHERIC FATE: According to a suggested classification scheme(1), an estimated vapor pressure of 0.058 mm Hg at 25 deg C(2,SRC) indicates that alpha-methylbenzyl alcohol will mainly exist in the vapor phase in the ambient atmosphere. Vapor-phase alpha-methylbenzyl alcohol is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 1.1 days(3,SRC). [R25] BIOD: *In an aerobic, sewage die-away screening test alpha-methylbenzyl alcohol (at 6000 ppm) biodegraded rapidly with 78.2% of the theoretical BOD reached in 8-10 days(1). Phenol-adapted cultures grown without alpha-methylbenzyl alcohol, with alpha-methylbenzyl alcohol (at 100 mg/L), and with both phenol and alpha-methylbenzyl alcohol consumed 69, 75, and 320 ul O2, respectively, over a 210 minute period(2). An Arthrobacter strain initially dehydrogenates alpha-methylbenzyl alcohol to acetophenone which is then converted to an ester, producing phenyl acetate which is then hydrolysed to phenol and acetate(3). A Nocardia strain first oxygenates the benzene nucleus to give 3-(1'-hydroxyethyl)-3,5-cyclo-hexadiene-1,2-diol which is then reduced and subjected to extra-diol cleavage(3). This same strain is also able to degrade alpha-methylbenzyl alcohol using the same pathway as described above for Arthrobacter(3). Alpha-methylbenzyl alcohol, inoculated with a mixed microbial culture, was readily biodegraded from 550 ppm to 20 ppm over 32 days(4). Nitrosomonas europaea degraded 2.5% of alpha-methylbenzyl alcohol (initially present at 200 nmol) over a 15 hour period(5). Alpha-methylbenzyl alcohol had a BOD of 1.0 g/g alpha-methylbenzyl alcohol after a 10 day incubation with a sewage inoculum(6). [R26] *Loss of alpha-methylbenzyl alcohol was monitored in four systems. In an aerobic, screening test using an activated sludge inoculum, alpha-methylbenzyl alcohol (at 100 ppm) was nearly completely biodegraded within either 14 or 20 days, depending on the inoculum size(heavy or light, respectively); acetophenone was the major metabolite(1). In an aerobic, retention pond system, 12% biodegradation was measured over 260 hours (alpha-methylbenzyl alcohol initially present at 300 ppm)(1). 17% degradation of alpha-methylbenzyl alcohol (at 300 ppm) was reported in an aerated lagoon system after 240 hours(1). Alpha-methylbenzyl alcohol had a half-life of 7 days under anaerobic conditions using a digester sludge inoculum; acetophenone was formed as a metabolite(1). [R27] ABIO: *The rate constant for the vapor-phase reaction of alpha-methylbenzyl alcohol with photochemically produced hydroxyl radicals has been estimated as 1.2X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 1.1 days at an atmospheric concentration of 2.1X10+5 hydroxyl radicals per cu cm(1,SRC). [R28] BIOC: *An estimated BCF value of 9 was calculated for alpha-methylbenzyl alcohol(SRC), using a measured water solubility of 1950 mg/L at 25 deg C(1) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms will not be an important fate process(SRC). [R29] KOC: *Koc values for alpha-methylbenzyl alcohol were determined for three subsoils: Apison (organic content = 0.11%) had a Koc of 37, Fullerton (organic content = 0.06%) had a Koc of < 5, and Dormont (organic content = 1.2%) had a Koc of 52(1). According to a recommended classification scheme(2), these Koc values suggest that alpha-methylbenzyl alcohol has very high mobility in soil, although increasing organic content will act to reduce mobility slightly(SRC). [R30] VWS: *The Henry's Law constant for alpha-methylbenzyl alcohol is estimated as 2.9X10-7 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that alpha-methylbenzyl alcohol will not volatilize from water surfaces(2,SRC). Volatilization from either dry or moist soil surfaces is not expected to be a major fate process based on estimated values for vapor pressure, 0.058 mm Hg(3,SRC) and Henry's Law constant(1,SRC). [R31] WATC: *SURFACE WATER: Alpha-methylbenzyl alcohol was present in water from the Kanawha River, Nitro, West Virginia (first samples collected in 1959) at a concentration of 17 mg/1000 L water(1). [R32] *DRINKING WATER: Alpha-methylbenzyl alcohol was detected in drinking water in the United States at unreported concentrations(1). [R33] EFFL: *Alpha-methylbenzyl alcohol was detected once in the wastewater from a mechanical products industry(1). Wastewater from a petrochemical company contained alpha-methylbenzyl alcohol at unreported concentrations(2). Alpha-methylbenzyl alcohol was detected in finished water from the Blue Plains Advanced Waste Treatment Plant in Washington, DC in September, 1974(3). [R34] ATMC: *Alpha-methylbenzyl alcohol was present in samples taken of indoor air from residential houses at "low relative abundance"(1). [R35] FOOD: *Alpha-methylbenzyl alcohol was identified in Beaufort cheese in France at unreported concentrations(1). [R36] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 15,990 workers (1959 of these are female) are potentially exposed to alpha-methylbenzyl alcohol in the USA(1). Workers, employed to varnish vehicles with alkyd-, phenol- and polyester varnishes which were dissolved in solvent mixtures, had an average concentration of 1.9 mg alpha-methylbenzyl alcohol/L urine (average over six workplaces, 35 exposed persons)(2). The general population may be exposed to alpha-methylbenzyl alcohol through the ingestion of contaminated drinking water and food or the inhalation of air from new buildings(SRC). [R37] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *alpha-Methylbenzyl alcohol is a food additive permitted for direct addition to food for human consumption as a synthetic flavoring substance and adjuvant in accordance with the following conditions: 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. [R38] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GAS CHROMATOGRAPHIC DETERMINATION OF TRACE IMPURITIES IN BETA-PHENYLETHANOL; DETECTED ON 5% XE-60 USING EITHER FLAME IONIZATION OR ELECTRON CAPTURE DETECTOR. [R39] *Alpha-methylbenzyl alcohol was detected in cheese samples using Freon 11 extraction, silicic acid chromatography followed by CGC/FID. [R40] *Alpha-methylbenzyl alcohol was detected in air samples using thermal desorption/gas chromatography/mass spectrometry. [R41] *Alpha-methylbenzyl alcohol was detected in river water samples using steam distillation, solubility group separations, GC, and infrared spectrometry. [R42] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 369 (1990) NIH Publication No. 90-2824 Tennant RW, Ashby J; Mutat Res 257 (3): 209-28 (1991). Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the U.S. National Toxicology Program. SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V19 253 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 759 R4: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 752 R5: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 348 R6: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA24 488 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-53 R8: Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) R9: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-297 R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R11: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R12: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-71 R13: 49 CFR 171.2 (7/1/96) R14: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 177 R15: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6171 (1988) R16: Marzulli, F.N., H.I. Maibach. Dermatotoxicology 4th ed. New York, NY: Hemisphere Publishing Corp., 1991. 762 R17: DHHS/NTP; Toxicology and Carcinogenesis Studies of a-Methylbenzyl Alcohol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 369 (1990) NIH Publication No. 90-2824 R18: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 444 R19: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 247 R20: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-23 R21: Loida PJ, Sligar SG; Protein Eng 6 (2): 207-12 (1993) R22: (1) Garrison AW, Hill DW; Amer Dyestuff Reporter Feb (1972) (2) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed NY,NY: Van Nostrand Reinhold Co. p. 759 (1991) R23: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (3) Garrison AW; Analytical Studies of Textile Wastes Presented Before the Division of Water, Air, and Waste Chemistry. Amer Chem Soc Div Water Air Waste Chem. Unpubl work (1969) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R24: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (3) Garrison AW; Analytical Studies of Textile Wastes Presented Before the Division of Water, Air, and Waste Chemistry. Amer Chem Soc Div Water Air Waste Chem. Unpubl work (1969) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R25: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R26: (1) Wagner R; Vom Wasser 47: 241-65 (1976) (2) Chambers CW et al; J Water Pollut Control Fed 35: 1517-28 (1963) (3) Fewson CA; In: FEMS Symp 12(Microb Degr Xenobiotics Recalcitrant Compds) pp. 141-79 (1981) (4) Garrison AW, Hill DW; Amer Dyestuff Reporter Feb (1972) (5) Keener WK, Arp DJ; Appl Environ Microbiol 60: 1914-20 (1994) (6) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) R27: (1) Garrison AW; Analytical Studies of Textile Wastes Presented Before the Division of Water, Air, and Waste Chemistry. Amer Chem Soc Div Water Air Waste Chem. Unpubl work (1969) R28: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Hendry DG et al; J Phys Chem Ref Data 3: 944-78 (1974) R29: (1) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R30: (1) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (2) Swann RL et al; Res Rev 85: 23 (1983) R31: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R32: (1) Rosen AA et al; J Water Pollut Contr Fedr 35: 777-82 (1963) R33: (1) Kopfler FC et al; Environ Sci Technol 8: 419-33 (1977) R34: (1) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Degree Survey. Contract No. 68-03-2867. Athens, GA: USEPA Environ Res Lab p. 167 (1982) (2) Well RG et al; Current Practice in GC-MS Analysis of Organics in Water. USEPA-R2-73-277; PB-224-947 (1973) (3) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. Analysis Results for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank Concentrates. USEPA-600/1-84-020A. (NTIS PB85-128221). Columbus, OH: Columbus Labs. Health Eff Res Lab (1984) R35: (1) Kostiainen R; Atmos Environ 29: 693-702 (1995) R36: (1) Dumont JP, Adda J; J Agric Food Chem 26: 364-67 (1978) R37: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Angerer J, Wulf H; Int Arch Occup Environ Health 56: 307-321 (1985) R38: 21 CFR 172.515 (4/1/93) R39: RUDOLF TA ET AL; NOV SORBENTY MOL KHROMATOGR 2 14 (1978) R40: Dumont JP, Adda J; J Agric Food Chem 26: 364-67 (1978) R41: Kostiainen R; Atmos Environ 29: 693-702 (1995) R42: Rosen AA et al; J Water Pollut Control Fedr 35: 777-82 (1963) RS: 33 Record 266 of 1119 in HSDB (through 2003/06) AN: 4165 UD: 200302 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-AMINO-4-NITROPHENOL- SY: *3-AMINO-4-HYDROXYNITROBENZENE-; *CI-76530-; *2-HYDROXY-5-NITROANILINE-; *4-NITRO-2-AMINOFENOL- (CZECH); *P-NITRO-O-AMINOPHENOL-; *4-NITRO-2-AMINOPHENOL-; *PHENOL,-2-AMINO-4-NITRO- RN: 99-57-0 RELT: 2570 [3-NITROANILINE] (METABOLITE); 3101 [INDOMETHACIN] (METABOLIC PRECURSOR) MF: *C6-H6-N2-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The partial reduction of 2,4-dinitrophenol; achieved electrolytically using vanadium or chemically with polysulfide, sodium hydroxulfide, or hydrazine and copper. Alternatively, 2-acetamidophenol or 2-methyl-benzoxazole may be nitrated in sulfuric acid to yield a mixture of 4- and 5-nitro derivatives that are then separated and hydrolyzed with sodium hydroxide. [R1, p. VA2 106] FORM: *2-Amino-4-nitrophenol is available commercially with the following specifications: Purity, 96% (min); ash, 0.1%(max); iron, 100 ppm(mg/kg)(max); lead, 5 ppm (mg/kg)(max); arsenic, 2 ppm(mg/kg)(max). It is available in research quantities at purities from 90- > 99%. [R2] MFS: *MOBAY CHEM CORP, INDUST CHEMS DIV, BUSHY PARK, SC 29401 [R3] *Jos. H. Lowenstein and Sons, 1991 /Trade name: Rodol 42/ [R4] USE: *CHEM INT FOR DYES (EG, CI MORDANT BROWNS 1 AND 33; CI PIGMENT YELLOW 65); COMPONENT OF PERMANENT AND SEMI-PERMANENT HAIR DYE PRODUCTS [R3] *Used in the production of mordant and acid dyes. 2-Amino-4-nitrophenol has limited use as an antioxidant and light stabilizer in butyl rubbers and as a catalyst in the manufacture of hexadiene. [R1, p. VA2 106] *2-Amino-4-nitrophenol is used in hair dyes and as a commodity chemical used in textile dye synthesis. [R1, p. VA17 395] PRIE: U.S. IMPORTS: *(1977) 1.04X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R3] *(1979) 1.35X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORANGE PRISMS (+ WATER) [R5]; *YELLOW-BROWN LEAFLETS CONTAINING WATER OF CRYSTALLIZATION [R6] MP: *145-147 DEG C [R5] MW: *154.13 [R1, p. VA2 106] DSC: *pKa1=3.1; pKa2=7.6 [R7] OWPC: *log Kow = 1.13 [R8] SOL: *SLIGHTLY SOL IN WATER; SOL IN ETHER, HOT BENZENE, METHANOL, ACETIC ACID; VERY SOL IN ALCOHOL [R5]; *SOL IN ACID [R6] SPEC: *IR: 296 (Sadtler Research Laboratories IR Grating Collection) [R9]; *UV: 570 (Sadtler Research Laboratories Spectral Collection) [R9]; *NMR: 2824 (Sadtler Research Laboratories Spectral Collection) [R9] OCPP: *MP: 80-90 DEG C (+ WATER) [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of 2-amino-4-nitrophenol. There is limited evidence in experimental animals for the carcinogenicity of 2-amino-4-nitrophenol. Overall evaluation: 2-Amino-4-nitrophenol is not classifiable as to its carcinogenicity to humans (Group 3). [R10] NTOX: *DOMINANT LETHAL MUTAGENICITY STUDY PERFORMED WITH 2-AMINO-4-NITROPHENOL, USED IN HAIR DYES. 2 MG/KG ADMIN IP 3 TIMES WEEKLY FOR 8 WK TO CHARLES RIVER MALE RATS. NO EVIDENCE OF INCR IN POST IMPLANTATION FETAL LOSS WHICH COULD INDICATE DOMINANT LETHAL EFFECT. [R11] *Groups of 50 male and 50 female B6C3F1 mice, 7 to 8 wk of age, were administered 0, 125 or 250 mg/kg bw 2-amino-4-nitrophenol (98% pure) (impurities unspecified) by gavage in corn oil (10 ml/kg bw) on 5 days a wk for up to 103 wk. The mean body weight of low-dose females was up to 17% greater than that of the controls; the body weights of the other treated groups were comparable with those of vehicle controls. No significant difference in survival was observed at termination of the study in treated and control groups of either sex (males: control, 28/50; low-dose, 29/50 and high-dose, 23/50; females: control, 28/50; low-dose, 31/50; and high-dose, 30/50). The incidence of combined hemangiomas and hemangiosarcomas at all sites in high-dose male mice was significantly higher (5/50) than that in controls (0/50; p < 0.05, Fisher exact test); however, these tumors were not considered to be related to the treatment since their incidence in historical controls at the study laboratory was 16/149 (11 + 10%) and that in all studies of the National Toxicology Program was 101/1743 (6 + 5%) ... . [R12] *Groups of 50 male and 50 female Fischer 344/N rats, 6 wk of age, were administered 0, 125 or 250 mg/kg bw 2-amino-4-nitrophenol (98% pure) (impurities unspecified) by gavage in corn oil (5 ml/kg bw) on 5 days a wk for up to 103 wk. Mean body weights of low-dose and high-dose males were 6 and 10% lower than those of controls, respectively; values for female rats were comparable to those of controls. Survival of high-dose males was significantly lower than that of controls (p < 0.001, Cox and Tarone's method); no significant difference was found for females. Survival at the end of the study was in males, control, 32/50; low-dose, 24/50; high-dose, 10/50, and, in females, control, 25/50, low-dose, 27/50; high-dose, 31/50. Hyperplasia of the renal tubular epithelium was observed only in male rats (control, 1/50; low-dose, 4/48; high-dose, 5/50); the difference was not significant. Renal tubular-cell adenomas were also observed in treated males (control, 0/50; low-dose, 1/48; high-dose, 3/50); among male rats that lived beyond wk 100, when the first renal tubular-cell tumor was observed, the incidence in high-dose animals (3/20) was significantly higher than that in controls (0/39; p = 0.035, Fisher exact test). Two liver-cell neoplastic nodules and one hepatocellular carcinoma were observed in high-dose male rats. The historical incidence of neoplastic nodules or hepatocellular carcinomas at the study laboratory was 3/149 (2 + 3%) and that of renal-cell adenomas, 0/149. In all studies of the National Toxicology Program, renal-cell adenomas occurred in 9/1695 (0.5 + 0.9%) ... . [R12] *During 15-day studies, groups of five Fischer 344/N rats and B6C3F1 mice of each sex received 0, 313, 625, 1250, 2500 or 5000 mg/kg bw 2-amino-4-nitrophenol (purity, 98%) in corn oil by gavage. Reduced survival was observed in all animals that received 2500 or 5000 mg/kg; diarrhea was observed in all treated rats except those receiving the lowest dose ... . [R13] *In 13-wk studies, groups of 10 Fischer 344/N rats and B6C3F1 mice of each sex received 2-amino-4-nitrophenol at doses of 0, 62.5, 125, 250, 500 or 1000 mg/kg bw by gavage in corn oil. Survival was reduced by the highest dose in both species. Diarrhea was observed in rats that received 500 or 1000 mg/kg. Mild to severe mineralization of the renal cortex and mild to severe degeneration of the renal tubular epithelium were observed in male rats that received 500 or 1000 mg/kg and in females that received 1000 mg/kg. Degeneration and necrosis of the renal tubular epithelium, with some indication of regeneration, were observed in mice that received 1000 mg/kg ... . [R13] *2-Amino-4-nitrophenol did not induce mutation in bacteriophage but was mutagenic to Salmonella typhimurium, to the fungus Sordaria brevicollis and at the tk locus in mouse lymphoma L5178Y cells. It induced sister chromatid exchange and chromosomal aberrations in cultured Chinese hamster ovary cells. Neither micronuclei, chromosomal aberrations or dominant lethal effects were induced in rodents exposed in vivo. [R14] NTXV: *LD50 Rat ip 246 mg/kg; [R13] *LD50 Rat oral 2400 mg/kg; [R13] *LD50 Mouse ip 143 mg/kg; [R13] NTP: *Toxicology and carcinogenesis studies were conducted by administering 2-amino-4-nitrophenol (98% pure) in corn oil by gavage, 5 day/wk, to groups of F344/N rats and B6C3F1 mice for 2 yr. ... Rats and mice received 2-amino-4-nitrophenol at doses of 0, 125, or 250 mg/kg. ... Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of 2-amino-4-nitrophenol for male F344/N rats, as shown by increased incidences of renal cortical (tubular cell adenomas). The incidences of renal tubular cell hyperplasia was also increased in male rats exposed to 2-amino-4-nitrophenol. The survival of male rats that received 2-amino-4-nitrophenol was reduced compared with survival of vehicle control male rats. There was no evidence of carcinogenic activity of 2-amino-4-nitrophenol for female F344/N rats or for male or female B6C3F1 mice that received 125 or 250 mg/kg/day. [R15] ADE: *Percutaneous absorption through the skin of Sprague-Dawley rats of each sex was examined following application of two hair dye formulations: formulation 1 contained 1.54% 14C-2-amino-4-nitrophenol; formulation 2 contained 0.77% 14C-2-amino-4-nitrophenol, 1,4-diaminobenzene (1,4-phenylenediamine), 2,4-diaminoanisole, oleic acid and isopropanol and was mixed with equal amt of a 6% hydrogen peroxide soln. After 1 and 5 days, 0.21 and 0.36% of the radiolabel administered in formulation 1 and 1.12 and 1.67% of that administered in formulation 2 had been absorbed (calculated as combined radiolabel in urine, feces, expired air and carcass, without treated skin area). Absorbed material was excreted predominantly in the urine within 24 hr after the initial application ... . [R16] *Five days after oral administration by gavage of 2 ml (14)C-2-amino-4-nitrophenol (0.2% in saline), 68.3% + 9.4 (SD) of the radiolabel had been excreted in the urine and 25.4% + 6.9% in the feces. Within 3 hr, about 4% of the radiolabel was eliminated in the bile. Following subcutaneous injection of the same dose, 89% of the dose was eliminated after 1 day, predominantly in the urine ... (The Working Group noted that metabolites were not identified in the urine, bile or feces in either study.) [R16] *Percutaneous absorption of (14)C-2-amino-4-nitrophenol (specific radioactivity 10 mCi/mmol (65 uCi/mg); purity, 98%) was studied in vitro by partitioning between excised human abdominal skin preparations and water. 2-Amino-4-nitrophenol appeared to bind to skin components ... . [R16] METB: *YIELDS 2,4-DIAMINOPHENOL PROBABLY IN RATS. /FROM TABLE/ [R17] *2-Amino-4-nitrophenol was the predominant metabolite formed enzymatically by nitroreduction following oral administration of 2,4-dinitrophenol (22.5 mg/kg bw) to ICR mice. [R16] BHL: *It had an elimination half-time from the plasma /of ICR mice/ of 46 hr ... . [R16] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Amino-4-nitrophenol's production and subsequent use in the production of mordant and acid dyes for hair coloring and textiles may result in its release to the environment through various waste streams. If released to the atmosphere, 2-amino-4-nitrophenol will exist in both the vapor phase and the particulate phase. In the vapor phase, 2-amino-4-nitrophenol will react with hydroxyl radicals with an estimated half-life of 2 days. It may also react with nitrate radicals. Particulate phase 2-amino-4-nitrophenol may be removed from the atmosphere by wet and dry deposition. In soil, 2-amino-4-nitrophenol may bind strongly to pure mineral soils from pH 3-7. This compound may also bind strongly in the presence of organic matter in the soil, as the aromatic amine should be very reactive. According to a Koc of 98, based on the log Kow, however, 2-amino-4-nitrophenol may be very mobile under high pH conditions where little organic matter is present. Incomplete information is available to determine 2-amino-4-nitrophenol's biodegradability but it was not used as a carbon source by Nocardia v. Direct photolysis of 2-amino-4-nitrophenol may occur on soil surfaces as this compound has UV peaks at 308 and 373. In water, 2-amino-4-nitrophenol is not expected to volatilize from water surfaces or to bioconcentrate in aquatic organisms. It may bind strongly to either pure mineral surfaces depending on the pH or to organic material present in the water column. Exposure to 2-amino-4-nitrophenol may occur occupationally during production or during its use as a hair dye. (SRC) ARTS: *2-Amino-4-nitrophenol's production and subsequent use in the production of mordant and acid dyes(1) for semi permanant and permanant hair coloring and dyeing of leather, nylon, silk, wool, and fur(3), and textiles(2) may result in its release to the environment through various waste streams(SRC). 2-Amino-4-nitrophenol is formed by environmental degradation (reduction) of 2,4-dinitrophenol(3). [R18] FATE: *TERRESTRIAL FATE: The adsorption of 2-amino-4-nitrophenol to TiO2 was measured over the pH range in both high and low ionic strength. There was a rapid increase in adsorption near pKa1 (at pH 3.1), a plateau region of high adsorption near neutral pH and a sharp decrease in adsorption near pKa2 (at pH 7.6)(1). Therefore adsorption to soil may be important from pH 3 to 7. It is possible that the reactive aromatic amino group may cause strong binding of this aniline to humus or soil organic matter(2). An estimated Koc of 98(4,SRC), based on an experimental log Kow(3), indicates that 2-amino-4-nitrophenol will have high mobility in soil(5,SRC), however, this may be possible mainly in mineral soils where organic matter is not present and where the pH is above neutral(SRC). Incomplete information is available regarding the biodegradation potential of 2-amino-4-nitrophenol; however, Nocardia v. failed to utilize this compound as a carbon source under aerobic conditions(6). 2-Amino-4-nitrophenol will not volatilize from moist soil surfaces based on an estimated Henry's Law constant of 2.23X10-12 atm-cu/mole(7,SRC). UV spectra show UV peaks at 373 and 308 indicating that this compound absorbs light at environmental wavelengths; direct photolysis on soil surfaces may be possible(8,SRC). [R19] *AQUATIC FATE: 2-Amino-4-nitrophenol is not expected to volatilize from water surfaces based on an estimated Henry's Law constant of 2.2X10-12 atm-cu/mole(1,SRC). It may adsorb strongly to clay material in the water column as 2-amino-4-nitrophenol has a high measured adsorption to TiO2 in the pH range of 3-7(2). It may also bind strongly to organic matter as the aromatic amino group is indicated as a highly reactive group with an affinity for organic materials(3). An estimated BCF value of 4(5,SRC), based on an experimental log Kow(4), indicates that 2-amino-4-nitrophenol will not bioconcentrate in an aquatic system(SRC). Incomplete information is available regarding the biodegradation potential of 2-amino-4-nitrophenol; however, Nocardia v. failed to utilize this compound as a carbon source under aerobic conditions(6). UV spectra show peaks at 373 and 308, indicating that this compound absorbs light at environmental wavelengths; direct photolysis at water surfaces may be possible(7,SRC). [R20] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of 3.52X10-5 mm Hg at 25 deg C(1,SRC), 2-amino-4-nitrophenol will exist in both the vapor phase and particulate phase in the ambient atmosphere(2,SRC). 2-Amino-4-nitrophenol will degrade in the vapor phase by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 2 days(3,SRC). 2-Amino-4-nitrophenol may also react significantly with nitrate radicals in the atmosphere(4). Particulate phase 2-amino-4-nitrophenol may be removed physically from air by wet and dry deposition(SRC). [R21] BIOD: *2-Amino-4-nitrophenol (0.025% w/v) was not used as a carbon source for Nocardia v. when measured for visible growth over a period of 16 days at 30 deg C(1). [R22] ABIO: *The rate constant for the vapor phase reaction of 2-amino-4-nitrophenol with photochemically produced hydroxyl radicals has been estimated to be 7.25X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life for 2-amino-4-nitrophenol of about 2 days at an atmospheric concentration of 5X10+5 hydroxyl radicals/cu cm (1,SRC). 2-Amino-nitrophenol may react significantly with nitrate radicals in the atmosphere(2). UV spectra show UV peaks at 373 and 308 indicating that this compound absorbs light at environmental wavelengths; direct photolysis may be possible(3,SRC). Two pKa values were measured for 2-amino-4-nitrophenol; pKa1 is 3.1, pKa2 is 7.6(4). Under most environmental pH conditions, 2-amino-4-nitrophenol will exist as an anion. [R23] BIOC: *A BCF of 4 was calculated for 2-amino-4-nitrophenol, using an experimental log Kow of 1.13(1) and a recommended regression-derived equation(2,SRC). This BCF value suggests that 2-amino-4-nitrophenol will not bioconcentrate in aquatic organisms(2,SRC). [R24] KOC: *Based on an experimental log Kow of 1.13(1), the Koc of 2-amino-4-nitrophenol is estimated as approximately 98 using a regression-derived equation(2,SRC). According to a suggested classification scheme, this estimated Koc value suggests that 2-amino-4-nitrophenol has high mobility in soil(3,SRC). The absorption of 2-amino-4-nitrophenol to TiO2(Type P25) was measured under high (0.05 M NaCl) and low (0.001 M NaCl) ionic strength for acidic, neutral, and basic pH conditions(4). There is a rapid increase in adsorption near pKa1 (at pH 3.1), a plateau region of high adsorption near neutral pH and a sharp decrease in adsorption near pKa2 (at pH 7.6)(4). The adsorption of 2-amino-4-nitrophenol to TiO2 was explained by chelate formation between the ligand donor groups and surface-bound Ti(IV) atoms; one proton is consumed for every molecule of aminophenolate anion adsorbed(4). The log value of the surface complex formation constant for 2-amino-4-nitrophenol using 10 g/l TiO2 and at 0.05 M NaCl is 10.9(4). In addition, 4-amino-2-nitrophenol may bind strongly to organic material in the soil; binding may be due to the high reactivity of the aromatic amino group toward humus or soil organic matter(5). [R25] VWS: *The Henry's Law constant for 2-amino-4-nitrophenol is estimated as 2.2X10-12 atm-cu/mole(1,SRC). This indicates that 2-amino-4-nitrophenol will essentially not volatilize from water surfaces(2). [R26] RTEX: *When used as a dye in semi-permanent hair colour products, 2-amino-4-nitrophenol, as the dye component of HC Yellow No. 4, is generally shampooed into the hair, and allowed to remain in contact with the hair and scalp for 30-45 min(1). [R27] *On the basis of a survey conducted in the USA between 1981 and 1983, NIOSH estimated that a total of 20,256 workers, including 17,049 women, were potentially exposed to 2-amino-4-nitrophenol in an estimated 2232 beauty shops(1). [R28] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Amino-4-nitrophenol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 339 (1988) NIH Publication No. 88-2595 SO: R1: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V17 268 (1982) R3: SRI R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 167 (1993) R5: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-428 R6: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 824 R7: Stone AT et al; Environ Sci Technol 27: 895-909 (1993) R8: Bronaugh RL, Congdon ER; J Invest Dermatol 83: 124-27 (1984) R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 53 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 174 (1993) R11: BURNETT C ET AL; J TOXICOL ENVIRON HEALTH 2 (3): 657 (1977) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 169 (1993) R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 171 (1993) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 172 (1993) R15: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Amino-4-Nitrophenol in F344/N Rats and B6C3F1 Mice Technical Report Series No. 339 (1988) NIH Publication No. 88-2595 R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 170 (1993) R17: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. A-46 R18: (1) Ulrich H; Ullmann's Encyclopedia of Industrial Chemistry Elvers B et al (ed), VA2: 106 (1989) (2) Ulrich H; Ullmann's Encyclopedia of Industrial Chemistry Elvers B et al (ed), VA17: 395 (1989) (3) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organizaiton, International Agency for Research on Cancer, 1972- Present 57: 167-176 (1992) R19: (1) Stone AT et al; Environ Sci Technol 27: 895-909 (1993) (2) Adrian P et al; Toxicol Environ Chem 20-21: 109-20 (1989) (3) Bronaugh RL, Congdon ER; J Invest Dermatol 83: 124-27 (1984) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (5) Swann RL et al; Res Rev 85: 23 (1983) (6) Rodriguez-Villanueva J; Microbiol Espan 13: 387-91 (1960) (7) Meylan W, Howard PH; Environ Toxicol Chem 10:1283-93 (1991) (8) Howard PH et al; Investigation of Selected Potential Environmental Contaminants: Nitroaromatics USEPA-560/2-76-010. Research Triangle Park NC: US EPA pp 600 (1976) R20: (1) Meylan W, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Stone AT et al; Environ Sci Technol 27: 895-909 (1993) (3) Adrian P et al; Toxicol Environ Chem 20-21: 109-20 (1989) (4) Bronaugh RL, Congdon ER; J Invest Dermatol 83: 124-27 (1984) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (6) Rodriguez-Villanueva J; Microbiol Espan 13: 387-91 (1960) (7) Howard PH et al; Investigation of Selected Potential Environmental Contaminants: Nitroaromatics, Research Triangle Park,NC: USEPA-560/2-76-010 pp. 600 (1976) R21: (1) Lyman WJ; in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press, p 31 (1985) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (4) Atkinson R; J Phys Chem Ref Data, Monogr 2: 1-216 (1994) R22: (1) Rodriguez-Villanueva J; Microbiol Espan 13: 387-91 (1960) R23: (1) Meylan WM, Howard PH; Chemosphere 26: 213-8 (1993) (2) Atkinson R; J Phys Chem Ref Data, Monogr 2: 1-216 (1994) (3) Howard PH et al; Investigation of Selected Potential Environmental Contaminants: Nitroaromatics. Research Triangle Park,NC: USEPA-560/2-76-010 pp 600 (1976) (4) Stone AT et al; Environ Sci Technol 27: 895-909 (1993) R24: (1) Bronaugh RL, Congdon ER; J Invest Dermatol 83: 124-27 (1984) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) R25: (1) Bronaugh RL, Congdon ER; J Invest Dermatol 83: 124-27 (1984) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Stone AT et al; Environ Sci Technol 27: 895-909 (1993) R26: (1) Meylan W, Howard PH; Environ Toxicol Chem 10:1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 15-15 to 15-29 (1990) R27: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organizaiton, International Agency for Research on Cancer, 1972-Present. 57: 167-176 (1992) R28: (1) IARC; Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organizaiton, International Agency for Research on Cancer, 1972-Present 57: 167-176 (1992) RS: 25 Record 267 of 1119 in HSDB (through 2003/06) AN: 4166 UD: 200211 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIGLYCIDYL-RESORCINOL-ETHER- SY: *ARALDITE-ERE-1359-; *BENZENE, M-BIS(2,3-EPOXYPROPOXY)-; *META-BIS(2,3-EPOXYPROPOXY BENZENE); *1,3-BIS(2,3-EPOXYPROPOXY)BENZENE; *M-BIS(GLYCIDYLOXY)BENZENE; *1,3-DIGLYCIDYLOXYBENZENE-; *NCI-C54966-; *OXIRANE, 2,2'-(1,3-PHENYLENEBIS(OXYMETHYLENE))BIS-; *2,2'-(1,3-PHENYLENEBIS(OXYMETHYLENE))BISOXIRANE; *RDGE-; *RESORCINOL BIS(2,3-EPOXYPROPYL) ETHER; *Resorcinol-diglycidyl-ether-; *RESORCINOL-GLYCIDYL-ETHER- RN: 101-90-6 MF: *C12-H14-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF EXCESS OF EPICHLOROHYDRIN WITH RESORCINOL IN ALKALINE SOLN. [R1, p. V36 182(1985)] MFS: *NOT PRODUCED COMMERCIALLY IN USA [R2] OMIN: *CURED RESINS MADE FROM IT HAVE BEEN REPORTED TO HAVE CHARACTERISTICS WHICH MAKE THEM USEFUL FOR ELECTRICAL, CASTING, TOOLING, ADHESIVE AND LAMINATING APPLICATIONS AND AS COATING FOR METAL AND CERTAIN PAVEMENTS TO INCR TENSILE STRENGTH. [R1, p. V11 126] USE: *Epoxy resins [R3] *CURING AGENT FOR POLYSULFIDE RUBBER [R2] *... AS LIQUID EPOXY RESIN AND AS REACTIVE DILUENT IN PRODN OF OTHER EPOXY RESINS. [R1, p. V36 183(1985)] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R2] *(1979) NOT PRODUCED COMMERCIALLY IN USA [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *STRAW-YELLOW LIQUID [R1, p. V36 182(1985)] ODOR: *SLIGHT PHENOLIC ODOR [R4, 1648] BP: *172 DEG C @ 0.8 MM HG [R1, p. V36 182(1985)] MP: *32 TO 33 DEG C [R4, 1648] MW: *222.2 [R1, p. V36 181(1985)] DEN: *SP GR: 1.21 @ 25 DEG C [R1, p. V36 182(1985)] SOL: *Miscible with most org resins [R3] SPEC: *INDEX OF REFRACTION: 1.541 @ 25 DEG C/D [R1, p. V36 182(1985)] VAP: *VAPOR PRESSURE LOW [R4, 1648] VISC: *500 CENTIPOISES (25 DEG C) [R1, p. V36 182(1985)] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FLPT: *350 DEG F (OPEN CUP) [R5] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R6] SERI: *MODERATELY TO HIGHLY IRRITATING ON SKIN CONTACT. [R4, 1648] *Dermal contact is the usual mode of exposure, but droplets in mist can also attack the eyes and respiratory tract. Glycidyl and diglycidyl ethers tend to be irritants and sensitizing agents. /Glycidyl and diglycidyl ethers/ [R7] *... Instances of eye irritation in workers have been noticed. /Diglycidyl resorcinol/ [R8] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R9, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R9, 1979.11] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R9, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R9, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R9, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R9, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Incineration: It should be atomized into an incinerator and combustion may be improved by mixing with a more flammable solvent (acetone or benzene). [R10] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R9, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R9, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R9, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of diglycidyl resorcinol ether were available. There is sufficient evidence for the carcinogenicity of technical grade of diglycidyl resorcinol ether in experimental animals. Overall evaluation: Diglycidyl resorcinol ether (technical grade) is possibly carcinogenic to humans (Group 2B). [R11] ANTR: */SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R12] */SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R12] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R9, 1979.23] HTOX: *DIGLYCIDYL RESORCINOL ETHER PRODUCES SEVERE BURNS ON CONTACT WITH SKIN, AND SKIN SENSITIZATION HAS OCCURRED IN LIMITED NUMBER OF CASES. [R1, p. V36 185(1985)] *QUESTIONABLE DECREASE IN WHITE COUNT AND SUGGESTION OF APPEARANCE OF ATYPICAL MONOCYTIC CELLS IN PERIPHERAL BLOOD. [R4, 1649] *... SLIGHTLY TOXIC BY INGESTION. MODERATELY TO HIGHLY IRRITATING ON SKIN CONTACT MODERATE RADIOMIMETIC ACTIVITY. [R13] *Dermal contact is the usual mode of exposure, but droplets in mist can also attack the eyes and respiratory tract. Glycidyl and diglycidyl ethers tend to be irritants and sensitizing agents. /Glycidyl and diglycidyl ethers/ [R7] NTOX: *NO EVIDENCE OF TOXICITY IN RATS RECEIVING 50 7-HOUR EXPOSURES TO AIR SATURATED WITH VAPORS. [R4, 1649] *IN MONKEYS, ONCE MONTHLY IV INJECTION OF 100-200 MG/KG BODY WT DIGLYCIDYL RESORCINOL ETHER PRODUCED PROGRESSIVE LOWERING OF LEUCOCYTE COUNT. [R1, p. V36 185(1985)] *... RABBITS WHICH RECEIVED 7.2 G/KG BODY WT BY INHALATION DIED. REPEATED PERCUTANEOUS APPLICATIONS OF UP TO TOTAL OF 1.2 G DIGYLCIDYL RESORCINOL ETHER ALSO CAUSED DEATH IN RABBITS. ... IRRITATION TO EYES AND SKIN ... . [R1, p. V11 127] *NO SKIN TUMORS OCCURRED IN 30 8-WEEK OLD FEMALE SWISS ICR/HA MICE WHICH RECEIVED THRICE WEEKLY SKIN PAINTINGS OF 1% SOLN IN BENZENE (APPROX 0.1 ML SOLN PER APPLICATION) FOR LIFE; MEDIAN SURVIVAL TIME WAS 491 DAYS. [R1, p. V36 184(1985)] *MICE RECEIVING REPEATED APPLICATIONS TO SKIN FOR 1 YR DEVELOP CANCERS, AND RATS SIMILARLY RECEIVING REPEATED SC INJECTIONS DEVELOP SARCOMAS. [R13] *ACUTE TOXICITY. FIRST SIGNS OF INTOXICATION FOLLOWING ORAL ADMIN INCL LACRIMATION AND RESTLESSNESS. THIS IS FOLLOWED BY DYSPNEA, DEPRESSION, AND ATAXIA PRIOR TO DEATH. [R13] *CAUSE OF DEATH: DEPRESSION OF RESPIRATORY CENTER AND SECONDARY SHOCK. [R4, 1649] *Diglycidyl resorcinol ether was tested for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster using a standard protocol approved by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of Diglycidyl resorcinol that resulted in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The test was positive at a dose of 50,000 ppm when administered to males by feeding. [R14] *Rabbits receiving 6 ml/kg died. [R13] *... Under the conditions of these 2-year gavage studies, technical grade diglycidyl resorcinol ether caused hyperkeratosis and hyperplasia of the forestomach in rats and mice. DGRE was carcinogenic for male and female F344/N rats and for male and female B6C3Fl mice, causing both benign and malignant neoplasms of the forestomach. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice; Positive; Female Mice: Positive. [R15] *The occurrence of forestomach hyperkeratosis and epithelial cell proliferation was confirmed in a two week study in rats with doses of 25 mg/kg body weight, but not with 12 mg/kg body weight. [R16] *Diglycidyl resorcinol ether (technical grade) was mutagenic to Salmonella typhimurium and at the tk locus but not the hprt locus of cultured mouse lymphoma cells. It induced chromosomal aberrations in Chinese hamster ovary CHO cells, but did not increase the proportion of micronucleated cells in the bone marrow of treated mice. [R16] *Repeated dose (14 days), subchronic (13 wk) and chronic (2 yr) studies were carried out in succession to evaluate the toxic and carcinogenic effects of diglycidyl resorcinol ether, a liquid spray epoxy resin, in F344/N rats and B6C3F1 mice. Diglycidyl resorcinol ether in corn oil was administered by gavage for 14 consecutive days in the repeated dose study and 5 days/wk in the subchronic and chronic studies. The mortality rate was increased in rats and mice in the repeated dose and subchronic studies. Hyperkeratosis, basal cell hyperplasia and squamous cell papillomas of the forestomach were observed in a few treated rats and mice in the subchronic study. Based on the results of the subchronic study, F344/N rats and B6CF1 mice (50 males and 50 females/species/dose) were administered diglycidyl resorcinol ether (rats-0, 12, 25 and 50 mg/kg body weight, mice-0, 50 and 100 mg/kg body weight) in corn oil by gavage 5 days/wk for 103 wk. The incidence of neoplastic and non-neoplastic changes of the forestomach was increased in rats and mice in the chronic study. Under the conditions of the study, diglycidyl resorcinol ether is considered to be carcinogenic to F344/N rats and B6C3F1 mice. fatty change in the livers of rats and fatty change and necrosis in the livers of mice suggested that a certain amount of DGRE was absorbed and metabolixzed. [R17] *The expression of multiple recessive genes by aberrant mitotic lesions plays a major part in carcinogenesis. These lesions include intragenic mutations as well as chromosomal lesions. An in vitro model for studying carcinogenesis should respond to all these lesions. Mutagenesis studies that target hemizygous loci may not be useful in studying chromosomal mechanisms because lesions incorporating essential genes already missing on the inactive, homologous chromosome may be lethal to the cell. Cells heterozygous at the selectable gene may survive. Using L5178Y mouse cells, we compared the mutagenic responses at the heterozygous tk and hemizygous hprt loci to four chemicals-benzidine dihydrochloride, diglycidylresorcinol ether, nitrofen and p-benzoquinone dioxime. None of the compounds induced clear positive responses at the hprt locus. In contrast, all the compounds induced clear or marginal mutagenic responses at the tk locus. These data are consistent with the expectation that heterozygous loci can detect lesions that are refractory to hemizygous loci. [R18] NTXV: *LD50 Rat oral 2.57 g/kg; [R7] *LD50 Mouse intragastric 0.98 g/kg; [R13] *LD50 Rabbit intragastric 1.24 g/kg; [R13] *LD50 Rat ip 0.178 g/kg; [R13] *LD50 Mouse ip 0.243 g/kg; [R13] *LD50 Mouse oral 980 mg/kg; [R6] *LD50 Rabbit oral 1240 mg/kg; [R6] NTP: *Toxicology and carcinogenesis studies of technical grade diglycidyl resorcinol ether (81 % pure) were conducted by admin the chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 25 or 50 mg/kg and to groups of 50 male and female B6C3F1 mice at doses of 50 or 100 mg/kg. A supplemental study of similar design in male and female rats (0 or 12 mg/kg) was started approximately 12 months later because of high mortality in the 50 mg/kg dose groups. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. ... Under the conditions of these 2-year gavage studies, technical grade diglycidyl resorcinol ether caused hyperkeratosis and hyperplasia of the forestomach in rats and mice. DGRE was carcinogenic for male and female F344/N rats and for male and female B6C3Fl mice, causing both benign and malignant neoplasms of the forestomach. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice; Positive; Female Mice: Positive. [R15] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Oxirane, 2,2'-(1,3-phenylenebis(oxymethylene))bis- is included on this list. [R19] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) DHHS/NTP; Toxicology and Carcinogenesis Studies of Diglycidyl Resorcinol Ether (Technical Grade) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 257 (1986) NIH Publication No. 87-2513 SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R2: SRI R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 965 R4: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1006 R6: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2870 R7: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-411 R8: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 343 R9: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R10: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 276 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1420 (1999) R12: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R13: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2233 R14: Valencia R et al; Environ Mutagen 7: 325-48 (1985) R15: Toxicology and Carcinogenesis Studies of Diglycidyl Resorcinol Ether (Technical Grade) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 257 (1986) NIH Publication No. 87-2513 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1418 (1999) R17: Krishna-Murthy AS et al; Food Chem Toxicol 28 (10): 723-30 (1990) R18: McGregor DB et al; Toxicology in Vitro 10 (5): 643-7 (1996) R19: 40 CFR 716.120 (7/1/2000) RS: 31 Record 268 of 1119 in HSDB (through 2003/06) AN: 4167 UD: 200302 RD: Reviewed by SRP on 2/28/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N-BUTYL-CHLORIDE- SY: *BUTANE,-1-CHLORO-; *BUTYL-CHLORIDE-; *1-CHLOROBUTANE-; *CHLORURE-DE-BUTYLE- (FRENCH); *NCI-C06155-; *N-PROPYLCARBINYL-CHLORIDE- RN: 109-69-3 MF: *C4-H9-Cl SHPN: UN 1127; Butyl chloride IMO 3.2; Butyl chloride STCC: 49 081 15; Butyl chloride ASCH: Butane, 2-chloro (dl); 53178-20-4; Butane, 2-chloro (l); 78-86-4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *IRRADIATION OF ETHYLENE AND HYDROGEN CHLORIDE WITH COBALT 60 [R1] *PREPD FROM N-BUTYL ALC BY HEATING WITH HYDROCHLORIC ACID AND ANHYDROUS ZINC CHLORIDE. [R2] FORM: *GRADES: NF; TECHNICAL. [R3] MFS: *Akzo America, Inc, Hq, Livingstone Ave, Dobbs Ferry, NY 10522-3401, (914) 674-5000; Akzo Chemical Division, 300 S Riverside Plaza, Chicago, IL 60606; Production site: Gallipolis Ferry, WV 25515-1721 [R4] *Union Carbide Corporation, Hq, Old Ridgeway Road, Danbury, CT 06817, (203) 794-2000; Subsidiary, Union Carbide Chemicals and Plastics Co Inc. Specialty Chemicals Division; Production site: South Charleston, WV 25303 [R4] *Albright and Wilson, Americas, Inc, PO ox 26229, Richmond, VA 26229, (804) 550-4300 [R5] USE: *SOLVENT; INT IN SYNTHESIS OF ALKYLATED ANILINES [R1] *Key intermediate for organotin stabilizer [R6] *Reacts with lithium metal in hydrocarbon media, eg, hexane and cyclohexane, to yield n-butyl lithium /the most important organolithium compound/ [R7] *Reacts with magnesium metal in a hydrocarbon solvent to produce di-n-butylmagnesium (DNBM) [R8] *Chain transfer agent in styrene polymerization to reduce the molecular weight of the polymer [R9] *MEDICATION (VET) *BUTYLATING AGENT IN ORGANIC SYNTHESIS [R2] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 4.54X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 4.54X10+6 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQ [R3] ODOR: *Unpleasant [R10, 315] BP: *78.5 deg C @ 760 mm Hg [R2] MP: *-123.1 deg C [R2] MW: *92.57 [R2] CTP: *Critical temperature: 269 deg C [R11] DEN: *0.88098 @ 25 deg C/4 deg C; 0.89197 @ 15 deg C/4 deg C; 0.88648 @ 20 deg C/4 deg C [R12] HTV: *30.39 KJ/mol [R13] OWPC: *log Kow= 2.39 [R10, 315] SOL: *PRACTICALLY INSOL IN WATER (0.066% @ 12 DEG C); MISCIBLE WITH ALC, ETHER [R2] SPEC: *Index of refraction: 1.40223 @ 20 deg C/D [R2]; *IR: 5640 (Coblentz Society Spectral Collection) [R14, p. V1 317]; *NMR: 6763 (Sadtler Research Laboratories Spectral Collection) [R14, p. V1 317]; *MASS: 187 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R14, p. V1 317] VAPD: +3.2 (air= 1) [R15] VAP: *80.1 MM HG @ 20 DEG C [R3] VISC: *0.0045 POISE @ 20 DEG C [R3] OCPP: *1 GAL WEIGHS 7.35 LB; DIPOLE MOMENT: 1.95 [R2] *IR: 19 (Coblentz Society Spectral Collection) /Butane, 2-chloro (dl)/ [R14, p. V1 318] *NMR: 9841 (Sadtler Research Laboratories Spectral Collection) /Butane, 2-chloro (dl)/ [R14, p. V1 318] *MASS: 186 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Butane, 2-chloro (dl)/ [R14, p. V1 318] *MASS: 186 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Butane, 2-chloro (l)/ [R14, p. V1 318] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R16] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R16] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R16] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R16] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R16] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R16] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R16] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R16] FPOT: *FLAMMABLE, DANGEROUS FIRE RISK. [R3] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R15] +Flammability: 3. 3= Includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R15] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R15] FLMT: +LOWER FLAMMABLE LIMIT 1.8 % BY VOLUME; UPPER FLAMMABLE LIMIT 10.1 % BY VOLUME [R15] FLPT: +15 deg F (-9 deg C) (Closed Cup) [R15] AUTO: *860 Deg F (460 Deg C) [R3] FIRP: *To fight fire: Foam, carbon dioxide, dry chemical. [R17] *If material /is/ on fire or involved in /a/ fire do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemial or carbon dioxide. [R18] *If fire becomes uncontrollable or container is exposed to direct flame-consider evacuation of one-third (1/3) mile radius. [R18] EXPL: *Lower explosive limit= 1.9%; Upper explosive limit= 10.1% [R17] *Moderate, when exposed to flame. [R17] DCMP: *Dangerous; when heated to decomposition, emits highly toxic fumes of phosgene. [R17] ODRT: *Odor low: 3.3352 mg/cu m; Odor high: 6.3293 mg/cu m [R19] SERI: *Skin, eye irritant [R17] OPRM: *If material /is/ not on fire and not involved in /a/ fire keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R18] *Avoid breathing vapors. Keep upwind. Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R18] *If material leaking (not on fire) consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R18] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R20] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R21] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R22] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +CLASSIFICATION: D; not classifiable as to human carcinogenicity. BASIS FOR CLASSIFICATION: Based on no human carcinogenicity data and inadequate animal data. HUMAN CARCINOGENICITY DATA: None. ANIMAL CARCINOGENICITY DATA: Inadequate. [R23] HTOX: *TOXIC ON PROLONGED INHALATION. [R3] *WEAKER CENTRAL NERVOUS DEPRESSANT ACTIONS THAN ETHYL CHLORIDE. [R24] NTOX: *NO INCR IN INCIDENCE OF LUNG TUMOR WAS OBSERVED AFTER IP TREATMENT WITH ETHYL BROMIDE, ETHYL IODIDE, AND BUTYL CHLORIDE. [R25] *Minimum autosensitizing doses of butyl chloride following 30 daily oral administrations to rats was 0.0022 mg/kg. [R26] *A closed, inert containment system was used to measure the mutagenicity of haloalkane solvents. This system allowed the avoidance of false negative results that could be caused by vaporization of the solvent and produced mutagenicity data in units of revertants/nmole. Salmonella typhimurium strain TA 1535 was the most efficient detector strain; 1-chlorobutane was negative for mutagenicity. [R27] *n-Butyl chloride was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. n-Butyl chloride was tested at doses of 0, 10, 33, 100, 333, and 666 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, or TA1537) in the presence and absence of Aroclor-induced rat and hamster liver S9. n-Butyl chloride was negative in these tests and the highest ineffective dose level tested in any Salmonella tester strain was 666 ug/plate. [R28] *Dogs tolerate at least 11 mg/kg without toxic effects. [R24] *The role of the chlorinated alkane solvent effect on the inhibition of hepatic triglyceride secretion was investigated using male Swiss-Webster-mice and male Sprague-Dawley-rats. Triglycerides were measured in serum of treated animals or in supernatants of isolated hepatocytes exposed to solvents and tritiated glycerol. Two hours following carbon-tetrachloride injection, triglyceride levels were reduced significantly to 42 percent of control values and to 15 percent by 8 hours. Methylene-chloride caused a more rapid decline in serum triglyceride concentration. Significant dose related decreases in serum triglyceride levels at 2 hours followed the administration of 1-chloropropane, 1-chlorobutane, 1-chloropentane, 1-chlorohexane, 1,2-dichloroethane, 1,3-dichloropropane, 1,4-dichlorobutane, and 1,5-dichloropentane. The shorter chain, less lipid soluble solvents were the more potent at decreasing triglyceride secretion in-vivo. In freshly prepared isolated hepatocyte systems, the relationship between 50 percent inhibitory concentration and lipid solubility was opposite to that observed in vivo. The more lipid soluble solvents were the more potent at decreasing secretion in vitro. It was suggested from this finding that nonspecific solvent effects on membrane integrity may be important in the inhibition of triglyceride secretion. The chlorinated alkane induced development of fatty liver through inhibition of triglyceride secretion may be related to lipid solubility of the chemical rather than to its metabolism to free radicals. [R29] NTXV: *LD50 Rat oral 2.67 g/kg; [R2] ETXV: *LC50 Poecilia reticulata (guppy) 97 ppm/7 days /Conditions of bioassay not specified/; [R10, 316] NTP: *... Carcinogenesis studies of n-butyl chloride (greater than 99.5% pure) ... was conducted by exposing groups of F344/N rats and B6C3F1 mice to n-butyl chloride in corn oil by gavage for ... 2 yr. ... The 2 yr toxicology and carcinogenesis studies of n-butyl chloride were conducted by administering doses of 0, 60, or 120 mg/kg in corn oil by gavage to groups of 50 male and 50 female rats and doses of 0, 500, or 1,000 mg/kg to groups of 50 male and 50 female mice. ... Pheochromocytomas of the adrenal gland occurred at a marginally increased incidence in low dose female rats (1/50; 6/50; 1/49). Hyperplasia was observed in 3/50 vehicle controls, 7/50 low dose females, and 4/49 high dose females. The incidence of pheochromocytomas was low, not dose related, and not seen in male rats, and thus it was not considered to be cmpd related. ... An increased incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was observed in the 500 mg/kg/group of female mice (3/50 vs 9/50), but little effect was seen in the 250 mg/kg group (6/50 vs 8/50). ... An increased incidence of hepatocellular adenomas or carcinomas (combined) was observed in the 500 mg/kg group of female mice (3/50 vs 8/50) but not in the 250 mg/kg (9/50 vs 7/50). ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of n-butyl chloride for male and female F344/N rats at daily doses of 60 or 120 mg/kg, for male B6C3F1 mice at doses of 250, 500, or 1,000 mg/kg, or for female B6C3F1 mice at doses of 250 or 500 mg/kg. Chemical-induced toxicity in high dose rats (primarily females) reduced the sensitivity of the study for determining carcinogenicity. [R30] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): ANTHELMINTIC FOR TREATMENT OF ROUND- AND TAPEWORMS IN DOGS ... [R1] *MEDICATION (VET): Anthelmintic ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Environmental emissions of n-butyl chloride arise from process and fugitive emissions and waste water from its production and use as an alkylating agent and evaporation from its use as a solvent. There is also evidence that it may be formed during chlorination of waste water. n-Butyl chloride has a high vapor pressure and Henry's Law constant. In addition it has a low adsorptivity to soil. Therefore releases to the land or water will partition, to a large extent, to the atmosphere. Limited data suggests that biodegradation is slow. It's rate of hydrolysis is unknown and estimates of its rate from analogous compounds indicate that hydrolysis could not compete with volatilization as a fate process except in groundwater. If released in surface water, the volatilization half-life in a model river and pond are estimated to be 2.9 hr and 34 hr, respectively. In the atmosphere, n-butyl chloride will degrade by reaction with photochemically produced hydroxyl radicals in the atmosphere with a half-life of 7.0 days. Human exposure will be primarily occupational by inhalation and dermal contact. (SRC) ARTS: *n-Butyl chloride is used as a solvent, an alkylating agent, and an antihelmintic medicine(2). It may be released to the environment in emissions or wastewater related to its manufacture and these uses. n-Butyl chloride was formed during the chlorination of leachate obtained from a simulated landfill used to study the codisposal of metal plating sludge with municipal solid waste(1). [R31] FATE: *TERRESTRIAL FATE: n-Butyl chloride has a very high vapor pressure, 100 mm Hg at 25 deg C(1), indicating that volatilization from soil will be rapid and a primary removal process. It has an estimated low adsorptivity to soil (Koc = 93-102)(1-2) and therefore would be mobile in soil. Biodegradation in soil is unknown(SRC). [R32] *AQUATIC FATE: If released in water, n-butyl chloride will be lost rapidly by volatilization. Its estimated volatilization half-life in a model river and pond are 2.9 hr(1-2) and 34 hr(3), respectively. In groundwater, where volatilization may not occur, n-butyl chloride may be lost by hydrolysis. Based upon hydrolysis rates for alkyl chlorides, the half-life is estimated to be between 6 hr and 38 days at neutral pH(4). The half-life at higher pHs will be shorter. Photodegradation, adsorption to sediment, and bioconcentration in fish are not important aquatic fate processes(SRC). [R33] *ATMOSPHERIC FATE: n-Butyl chloride will degrade via reaction with photochemically produced hydroxyl radicals in the atmosphere. The half-life of n-butyl chloride in the atmosphere is estimated to be 7.0 days(1). n-Butyl chloride does not absorb radiation > 290 nm and therefore it will not directly photolyze(2). Due to its water solubility, 1100 mg/l(3), washout by rain should occur. However, n-butyl chloride removed in this manner will revolatilize into the atmosphere(SRC). [R34] *Maximum permissible concentrations in open waters are 0.004 mg/l. [R26] BIOD: *Microbial enzymes and pure cultures have been reported that are capable of degrading n-butyl chloride under aerobic conditions(2). Limited data from screening studies suggest that n-butyl chloride biodegrades slowly under aerobic conditions. When incubated with activated sludges from 3 municipal treatment plants, 2.6% of the n-butyl chloride (500 mg/l) was oxidized after 24 hr(1). At the concentration used, n-butyl chloride was toxic to 1 of the 3 sludges(1). Another screening test using sewage seed and much lower concentrations of n-butyl chloride (1 ppm) resulted in 10% of the theoretical BOD being consumed in 1.4 days(3). [R35] ABIO: *Alkyl halides hydrolyze in water by neutral and base catalyzed reactions to give the corresponding alcohols; no acid catalyzed processes have been reported(2). No rate for neutral hydrolysis of n-butyl chloride is available. Based on extrapolations of hydrolysis rates of analogous compounds determined at higher temperatures and generalizations concerning the relative reactivity of analogs, the hydrolysis half-life of n-butyl chloride at 25 deg C is estimated to lie in the range of 6 hr to 38 days(2). In the atmosphere, n-butyl chloride will react with photchemically produced hydroxyl radicals by H-atom extraction. The estimated rate of reaction is 2.29X10-12 cu cm/molec-sec(3). Assuming a hydroxyl radical concentration of 5X10+5 per cu cm, the half-life of n-butyl chloride in the atmosphere is 7.0 days. n-Butyl chloride does not absorb radiation > 290 nm and therefore it will not directly photolyze(4). The half-life of n-butyl chloride in an eutrophic lake due to the photochemical production of hydroxyl radicals in full summer noon sunlight is 1000 hr(1). Therefore, this reaction would not be a significant degradation route for n-butyl chloride in surface waters(SRC). [R36] BIOC: *Using the log octanol/water partition coefficient for n-butyl chloride, 2.64(1), one estimates a BCF of 60 using a recommended regression equation(2,SRC). Therefore, n-butyl chloride will not bioconcentrate in fish and aquatic organisms(2) [R37] KOC: *Using the water solubility for n-butyl chloride, 1100 mg/l(1), the Koc can be estimated to be 93 and 102 using two recommended regression equations(2,SRC). These estimates indicate that n-butyl chloride will have high mobility in soil(3). [R38] VWS: *Based on a Henry's Law constant of 0.0167 atm-cu m/mol(1), the volatilization of n-butyl chloride from a model river 1 m deep, flowing at 1 m/sec with a 3 m/sec wind is 2.9 hr(2). The volatilization half-life from a model pond is 34 hr(3). Due to its high vapor pressure and Henry's Law constant and low adsorptivity to soil, n-butyl chloride should volatilize rapidly from dry and moist soils(SRC). [R39] EFFL: *In a study of 63 industrial effluents that discharge into surface waters, chlorobutane was found in one effluent at a concentration of < 10 ug/l(1). [R40] ATMC: *SOURCE DOMINATED: n-Butyl chloride was identified, but not quantified, in one of 10 samples of ambient air in the Kanawna Valley, WV(1). Various locations were sampled during three trips. [R41] RTEX: *Exposure to n-butyl chloride is primarily in the workplace. Probable routes occupational exposure are inhalation and dermal contact. (SRC) *NIOSH (NOES Survey 1981-1983) has statistically estimated that 3,201 workers are exposed to n-butyl chloride in the USA(1). [R42] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Specification and dosage requirements for n-butyl chloride are given in detail for the removal of ascarids and hookworms in dogs, puppies, cats, and kittens. [R43] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *The alternating current plasma detector for gas chromatography was shown to be a useful detector for selective organochlorine detection. A standard solution of n-butylchloride (NBC) was chromatographed at an oven temp of 85 deg C and a calibration curve was constructed from the response data. The detection limit was determined to be 1.12 ng/sec and the correlation coefficient was 0.998. [R44] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of n-Butyl Chloride in F344/N Rats and B6C3F1 Mice Technical Report Series No. 312 (1986) NIH Publication No. 86-2568 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 239 R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 184 R4: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 503 R5: United States International Trade Commission. Synthetic Organic Chemicals-United States Production and Sales, 1989. USITC Publication 2338, 1990. Washington, DC: United States International Trade Commission, 1990.p. 15-29 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V12 242 (1980) R7: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V14 467 (1981) R8: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V16 560 (1981) R9: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V21 819 (1983) R10: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. F-88 R12: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 217 R13: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 6-102 R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R15: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-21 R16: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-130 R17: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 576 R18: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.107 R19: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R20: 49 CFR 171.2 (7/1/96) R21: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 122 R22: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3062 (1988) R23: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on 1-Chlorobutane (109-69-3) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R24: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-167 R25: POIRIER LA ET AL; CANCER RES 35 (6): 1411 (1975) R26: Vinogradov GI; Vrach Delo 9: 100-2 (1979) R27: Barber ED, Donish WH; Environ Sci Res 25: 3-18 (1982) R28: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R29: Selan FM, Evans MA; Research Communications in Chemical Pathology and Pharmacology; 55 (2): 249-68 (1987) R30: DHHS/NTP; Toxicology and Carcinogenesis Studies of n-Butyl Chloride in F344/N Rats and B6C3F1 Mice p.10 (1986) Technical Rpt Series No. 312 NIH Pub No. 86-2568 R31: (1) Gould JP et al; pp. 525-39 in Water Chlorination: Environ Impact Health Eff Vol 4 (1983) (2) Hawley CG; The Condensed Chemical Dictionary 10th ed. NY: Van Nostrand Reinhold Co (1981) R32: (1) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 4 (1982) R33: (1) Leighton DTJr, Calo JM; J Chem Eng 26: 382-5 (1981) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 15 (1982) (3) USEPA; EXAMS II (1987) (4) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) R34: (1) Atkinson R et al, Environ Sci Technol 19: 799-828 (1987) (2) Calvert JG, Pitts JN Jr; Photochemistry NY: Wiley pp. 427-30 (1966) (3) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) R35: (1) Gerhold RM, Malaney GW; J Water Pollut Contr Fed 38: 562-79 (1966) (2) Visscher K, Brinkman J; Haz Waste Haz Materials 6: 210-12 (1989) (3) Okey RW, Bogan RH; J Water Pollut Control Fed 37: 692-712 (1965) R36: (1) Haag WR, Hoigne J; Chemosphere 14: 1659-71 (1985) (2) Mabey W, Mill T; J Phys Chem Ref Data 7: 383-415 (1978) (3) Atkinson R et al, Environ Sci Technol 19: 799-828 (1987) (4) Calvert JG, Pitts JN Jr; Photochemistry NY: Wiley pp. 427-30 (1966) R37: (1) Hansch C, Leo AJ; Medchem Project Issue No. 26 Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 5 (1982) R38: (1) Riddick JA et al; Organic Solvents 4th ed. NY: Wiley (1986) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill Chapt 4 (1982) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R39: (1) Leighton DTJr, Calo JM; J Chem Eng 26: 382-5 (1981) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) (3) USEPA; EXAMS II (1987) R40: (1) Perry DL et al; Identification of Organic Compound in Industrial Effluent Discharges USEPA-600/4-79-016, NTIS-PB-294794 (1979) R41: (1) Erickson MD, Pellizzari ED; Analysis of Organic Air Pollutants in the Kanawha Valley, WV and the Shenandoah Valley VA USEPA-903/9-78-007 (1978) R42: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) R43: 21 CFR 520.260(a)-(c) (4/1/90) R44: Costanzo RB, Barry EF; J Chromatogr 467 (2): 373-84 (1989) RS: 30 Record 269 of 1119 in HSDB (through 2003/06) AN: 4168 UD: 200302 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-AMINO-5-NITROPHENOL- SY: *CI-76535-; *2-HYDROXY-4-NITROANILINE-; *5-NITRO-2-AMINOPHENOL-; *PHENOL,-2-AMINO-5-NITRO-; *URSOL-YELLOW-BROWN-A- RN: 121-88-0 MF: *C6-H6-N2-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *NITRATION OF O-ACETAMIDOPHENOL OR 2-METHYLBENZOXAZOLE IN SULFURIC ACID FOLLOWED BY HYDROLYSIS OF THE SEPARATED ISOMERS WITH SODIUM HYDROXIDE [R1] *2-Amino-5-nitrophenol is produced from 2-aminophenol by reaction with acetic anhydride to form 2-methylbenzoxazole, which is nitrated and hydrolysed to form 2-amino-5-nitrophenol. [R2] *2-Amino-5-nitrophenol is prepared from 3-nitro-4-hyroxybenzenesulfonamide using sodium hyposulfite and caustic or zinc and HCl as the reducing agents. It may also be obtained from 2-amino-1-phenol-4-sulfonic acid by treatment with carbon disulfide to give a substituted benzoxazole whose ring is opened to the desired sulfonamide. It may be prepared by the chlorosulfonation of 2-chloronitrobenzene followed by aminolysis and hydrolysis. [R3] *Production of 2-amino-5-nitrophenol is by nitration of benzoxazolone and separation from the 2-amino-4-nitro-phenol isomer after treatment with hydrochloric acid. [R4] FORM: *2-Amino-5-nitrophenol is available commercially with the following specifications: purity, 98% (min); ash, 0.05% (max); iron, 40 ppm (max); lead, 5 ppm (max); arsenic, 2 ppm (max). [R2] MFS: *NOT PRODUCED COMMERCIALLY IN THE US [R1] OMIN: *2-Amino-5-nitrophenol is not produced in commercial quantities in the USA. It is available in research quantities, at purities ranging from 90-99% from Jos. H. Lowenstein and Sons, 1991; TCI America, 1991; Aldrich Chemical Co., 1992; Fluka Chemie AG, 1993. [R2] USE: *2-Amino-5-nitrophenol is used as an intermediate in the manufacture of several azo dyes, including CI Solvent Red 8, which is used for colouring synthetic resins, lacquers, inks and wood stains. It is also used as a dye in semi-permanent hair colouring products to produce red and gold-blond shades. It is used to a limited extent in permanent hair colouring products. [R2] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) 2.33X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 5.95X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Olive-brown, brown to orange crystalline solid [R2]; *Orange needles when recrystallized from water [R3] MP: *207-208 deg C [R3] MW: *154.13 [R2] SOL: *Slightly soluble in water [R2]; *Soluble in ethanol, acetone, and benzene [R2] SPEC: *IR: 21402 (Sadtler Research Laboratories IR Grating Collection) [R5]; *UV: 6008 (Sadtler Research Laboratories Spectral Collection) [R5]; *NMR: 10012 (Sadtler Research Laboratories Spectral Collection) [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of 2-amino-5-nitrophenol. There is limited evidence in experimental animals for the carcinogenicity of 2-amino-5-nitrophenol. Overall evaluation: 2-Amino-5-nitrophenol is not classifiable as to its carcinogenicity to humans (Group 3). [R6] NTOX: *DOMINANT LETHAL MUTAGENICITY STUDY IN RATS WITH CHEMICALS USED IN HAIR DYES. 20 MG/KG OF 2-AMINO-5-NITROPHENOL ADMIN IP 3 TIMES/WK FOR 8 WK TO MALE CHARLES RIVER CD RATS. THERE WAS NO EVIDENCE OF INCR IN POST IMPLANTATION FETAL LOSS. [R7] *Groups of 50 male and 50 female B6C3F1 mice, seven to eight weeks of age, were administered 0, 400 or 800 mg/kg bw 2-amino-5-nitrophenol (98% pure) by gavage in corn oil (10 ml/kg) on five days a week for up to 103 weeks and were killed at 112 weeks of age. The mean body weights of high-dose males were 8-11% lower than those of vehicle controls from week 29 to week 74, whereas those of low-dose males were greater than those of vehicle controls throughout most of the study. The mean body weights of low-dose and high-dose female mice were 5-9 and 8-13% lower than those of vehicle controls from week 69 to the end of the study, respectively. Survival of high-dose males after week 20 and of females after week 22 was reduced compared with that of controls (p < 0.001, Cox and Tarone's test). Survival at termination of the study was: males--control, 31/50; low-dose, 36/50; and high-dose, 12/50; females--control, 37/50; low-dose, 36/50; and high-dose, 10/50. No significant increase in the incidence of tumors was observed in treated groups when compared with controls ... (The Working Group noted the high mortality in the high-dose groups.) [R8] *Groups of 50 male and 50 female Fischer 344/N rats, six to seven weeks of age, were administered 0, 100 or 200 mg/kg bw 2-amino-5-nitrophenol (98% pure) by gavage in corn oil (5 ml/kg) on five days a week for up to 103 weeks and were killed at 111 weeks of age. Mean body weights of male and female high-dose rats were 5-10 and 4-5% lower than those of controls after weeks 33 and 93, respectively. Survival of high-dose males and females after week 75 and that of low-dose males and females after week 99 was significantly lower than that of vehicle controls (p < 0.001, Cox and Tarone's test). Survival at termination was: males--control, 33/50; low-dose, 16/50; and high-dose, 4/50; females--control, 30/50 low-dose, 32/50; and high-dose, 29/50. The incidence of pancreatic acinar-cell adenomas was significantly increased in low-dose (10/50; p = 0.002, incidental tumor test) but not in high-dose (3/49) males in comparison with controls (1/50). One acinar-cell carcinoma was also seen in a low-dose male ... (The Working Group noted the poor survival of treated males.) [R8] *In 13-week studies, groups of 10 Fischer 344/N rats and B6C3F1 mice of each sex received 0, 100, 200, 400, 800 or 1600 mg/kg bw 2-amino-5-nitrophenol by gavage in corn oil. A dose-related reduction in survival was observed in rats. Rats receiving 400-1600 mg/kg and mice receiving 1600 mg/kg had acute or chronic perivasculitis of the vessels of the cecum and colon ... . [R9] *2-Amino-5-nitrophenol induced mutation in bacteriophage, Salmonella typhimurium and at the tk locus in mouse lymphoma L5178Y cells. It also induced sister chromatid exchange and chromosomal aberrations in cultured chinese hamster ovary cells. 2-Amino-5-nitrophenol did not induce dominant lethal mutation in rats exposed in vivo. [R10] NTXV: *The LD50 of 2-amino-5-nitrophenol in rats has been reported to be greater than 4000 mg/kg bw by oral administration and greater than 800 mg/kg bw by ip injection ... ; [R9] NTP: *Toxicology and carcinogenesis studies were conducted by admin 2-amino-5-nitrophenol (98%) by gavage in corn oil 5 day/wk to groups of F344/N rats and B6C3F1 mice of each sex in ... 2 yr studies. In the 2 yr studies, male and female rats were given doses of 0, 100, or 200 mg/kg and male and female mice were given doses of 0, 400, or 800 mg/kg. ... Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity for male F344/N rats that received 100 mg/kg 2-amino-5-nitrophenol, as shown by the increased incidence of acinar cell adenomas of the pancreas. Reduced survival of male F344/N rats that received 200 mg/kg decreased the sensitivity of this group for detecting a carcinogenic response. There was no evidence of carcinogenic activity for female rats that received 100 or 200 mg/kg/day. Marginally increased incidences of preputial or clitoral gland adenomas or carcinomas (combined) occurred in male and female F344/N rats administered 200 mg/kg 2-amino-5-nitrophenol. There was no evidence of carcinogenic activity for B6C3F1 mice that received 400 mg/kg 2-amino-5-nitrophenol; reduced survival of B6C3F1 mice that received 800 mg/kg caused this group to be considered inadequate for detecting a carcinogenic response. [R11] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Amino-5-nitrophenol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 334 (1988) NIH Publication No. 88-2590 SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 177 (1993) R3: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V2 424 (1978) R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA2 106 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 53 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 183 (1993) R7: BURNETT ET AL; J TOXICOL ENVIRON HEALTH 2 (3): 657 (1977) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 179 (1993) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 180 (1993) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 181 (1993) R11: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2-Amino-5-nitrophenol in F344/N Rats and B6C3F1 Mice Technical Report Series No. 334 (1988) NIH Publication No. 88-2590 RS: 11 Record 270 of 1119 in HSDB (through 2003/06) AN: 4169 UD: 200205 RD: Reviewed by SRP on 1/31/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIALLYL-PHTHALATE- SY: *ALLYL-PHTHALATE-; *1,2-BENZENEDICARBOXYLIC-ACID,-DI-2-PROPENYL-ESTER-; *DAPON-R-; *DAPON-35-; *Diallylester-Kyseliny-Ftalove- (Czech); *Di-2-propenyl-1,2-benzenedicarboxylate-; *NCI-C50657-; *PHTHALIC-ACID,-DIALLYL-ESTER-; *O-PHTHALIC-ACID,-DIALLYL-ESTER- RN: 131-17-9 MF: *C14-H14-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The alcohol (butyl, octyl, etc) is esterified with phthalic anhydride in the presence of a catalyst (sulfuric acid or p-toluenesulfonic acid) or non-catalytically at high temp. The esterification is carried out at ordinary pressure or in a vacuum, the water formed during the reaction being eliminated as it is formed by entrainment by a third component (hydrocarbon or usually the alcohol used in the esterification). The hydrocarbon may be benzene, toluene, or cyclohexane. The reaction can be carried out discontinuously or by a continuous method. /Phthalic esters/ [R1] MFS: *ARCO Chemical Co., 3801 West Vester Pike, Newton Square, PA 19073-2387, (610)359-2000. Production site: Channelview, TX 77530 [R2] *NIPA Hardwicke Inc., 3411 Silverside Rd., 104 Halsley Bldg., Wilmington, DE 19810, (302)478-1522. Production site: Elgin, NC 29045 [R2] OMIN: *Diallyl phthalate cmpd show promise of optimizing both flame retardance and contaminated arc resistance in such electrical uses as switches, circuit breakers, stand-off insulators, and TV components. [R3, 57] *Two series of specimens were prepared from a dental heat-cured soft acrylic resin, Vertex Rs, with di-butyl phthalate (DBP) and diallyl phthalate (DAP) as external and internal plasticizers, resp. [R4] *... IN BOAT AND AUTOMOTIVE INDUSTRY ... POLYESTERS ARE DISSOLVED IN STYRENE AND STABILIZED WITH INHIBITOR TO FORM VISCOUS SYRUP-LIKE LIQUID WHICH DOES NOT READILY SOLIDIFY. ... DIALLYL PHTHALATE RESISTS POLYMERIZATION OF THE UNCATALYZED SYRUP. [R5] USE: *Most diallyl phthalate compounds are sold under military specification and are used in critical electrical/electronic applications requiring high reliability under long-term, adverse environmental conditions. A significant application area is in electronic connectors in communications, computer and aerospace systems. Other uses are insulators, potentiometers, and circuit boards. [R3, 57] *Used in industry as a monomer in the processing of thermosetting plastics. [R6, 2350] *PEROXIDE DILUENT IN POLYESTER SPRAY SYSTEMS; DYE CARRIER, EG, IN POLYESTER DYEING; SEALANT, EG, IN INSULATING VARNISHES AND METAL CASTINGS; IMPREGNANT, EG, FOR JEWELRY [R7] *FORMS LOW-PRESSURE LAMINATES WITH VARIOUS FILLERS SUCH AS GLASS CLOTH, PAPER, ETC; PRIMARY PLASTICIZER [R8] *Stabilizer [R9] *Used as a cross linking agent in the production of pourable solid unsaturated polyester resins. [R10, p. VA21 219] PRIE: U.S. PRODUCTION: *The 1977 TSCA inventory listed five companies which manufactured diallyl phthalate, with a total production volume of 11 million pounds. [R11] U.S. IMPORTS: *(1979) 1.82X10+7 G (PRINCPL CUSTMS DISTS) [R7] *(1986) 1.28X10+6 lb [R12] *(1983) 1.76X10+5 lb [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEARLY COLORLESS OILY LIQUID [R8] ODOR: *MILD [R8] BP: *158-165 deg C @ 4 mm Hg [R8] MP: *-70 deg C [R8] MW: *246.26 [R10, p. VA1 435] DEN: *1.120 @ 20 DEG C/20 DEG C [R8] OWPC: *log Kow= 3.23 [R14] SOL: *SOL IN GASOLINE, MINERAL OIL, GLYCERIN, CERTAIN AMINES [R8]; *SOL IN MOST ORG LIQUIDS [R8]; *Water solubility of 182 mg/l at 25 deg C [R15] SPEC: *IR: 15173 (Sadtler Research Laboratories IR Grating Collection) [R16]; *UV: 363 (American Petroleum Institute Collection) [R16]; *NMR: 6707 (Sadtler Research Laboratories Spectral Collection) [R16]; *MASS: 1722 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R16] VAPD: *8.3 (air= 1) [R6, 2345] VAP: *2.4 MM HG @ 150 DEG C [R6, 2345] VISC: *13 CP @ 20 DEG C [R8] OCPP: *Conversion factor: 10.08 mg/cu m= 1 ppm [R6, 2345] *Viscous liquid [R8] *Thermosets: Burns slowly with a phenolic odor and continues to burn slowly after the flame is removed. A yellow flame is produced. No drips are formed. Black smoke is formed with cracks. [R3, 277] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Limiting oxygen index (LOI): 26-36 /for diallyl phthalate/. This is a measure of the minimum concentration of oxygen in an oxygen-nitrogen atmosphere that is necessary to support a flame for at least 3 minutes under specified test conditions. [R3, 268] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R17] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R17] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R17] FLPT: +330 deg F (166 deg C) (Closed cup) [R17] FIRP: +Water or foam may cause frothing. [R17] DCMP: *When heated to decomp it emits acrid smoke and irritating fumes. [R18] POLY: *WILL POLYMERIZE IF NOT INHIBITED; WILL POLYMERIZE WITH HEAT AND CATALYST [R19] EQUP: *Use ... of garments to protect /workmen/ from irritation due to contact with phthalic anhydride /which is used in the manufacturing process of phthalic acid esters/; gloves /should be used/ to prevent contamination of the hand and lower arm. /Phthalic esters/ [R1] *SYNTH OF PHTHALATES REQUIRE GOOD VENTILATION IN ORDER TO /MINIMIZE/ CONTAMINATION OF AIR WITH PHTHALIC ANHYDRIDE OR ALCOHOLS. THERE MAY BE ALSO SOME NEED FOR SKIN PROTECTION. HANDLING MINERAL ACIDS USED AS CATALYSTS REQUIRES ORDINARY PRECAUTIONS. /PHTHALATES/ [R20] OPRM: *Increased /room/ ventilation and /SRP: decreased/ aspiration of vapors and dusts. /Phthalic esters/ [R1] *Avoid contact with skin and eyes. [R21, 597] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Esters and related compounds/ [R22] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... Monitor for shock and treat if necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Esters and related compounds/ [R22] HTOX: *SINCE PHTHALATES ... ARE OF VERY LOW /ACUTE ORAL/ TOXICITY, ONLY HAZARD OF IMPORTANCE IN HANDLING ... CONSISTS OF POSSIBLE EYE, SKIN AND/OR MUCOUS MEMBRANE IRRITATION FROM PHTHALIC ANHYDRIDE, WHICH MAY OCCUR DURING SYNTHESIS OF PHTHALATES. CARELESS HANDLING OF ALCOHOLS MAY CAUSE /CNS DEPRESSION/. /PHTHALATES/ [R20] *Harmful in contact with skin and if swallowed. [R21, 575] *EFFECTS OF VARIOUS PHTHALATE ESTERS ON LECITHIN/CHOLESTEROL ACYLTRANSFERASE ACTIVITY IN MAN STUDIED IN VITRO /IN BLOOD/. ENZYMATIC ACTIVITY WAS STRONGLY REDUCED WITH ALL ESTERS TESTED EXCEPT FOR DIMETHYL PHTHALATE. INHIBITION RATE DEPENDS ON CONCN AND ON CARBON NUMBER OF ALKYL GROUPS OF PHTHALATES. [R23] *Diallyl phthalate appears to be a low human dermal irritant. [R24] NTOX: *... Dermal and mucous membrane effects were investigated. Results revealed no erythema after fifteen 5 hr exposures on shaved rabbit skin. It was also nonirritating to the rabbit eye, with transient conjunctivitis. Application to rabbit skin at 2.8 and 3.8 ml/kg on approximately 14% of the body surface proved lethal, but for a lower level of 1.6 mg/kg over 5% of the surface, animals survived 12 exposures. Autopsies revealed mild skin inflammation, hepatitis, and lung congestion. Results indicate that the allyl ester is so far one of the most toxic phthalate derivatives tested. ... [R24] *RATED 1 ON RABBIT EYES. TESTED EXTERNALLY ON EYES OF RABBITS AND ... RATED NUMERICALLY ON SCALE OF 1-10 ACCORDING TO DEGREE OF INJURY ... AFTER 24 HR /OBSERVATION/ PAYING PARTICULAR ATTENTION TO CONDITION OF CORNEA MOST SEVERE INJURIES HAVE BEEN RATED 10. [R25] *The mutagenic activities of several phthalate esters have been evaluated in an 8-azaguanine resistance assay in Salmonella typhimurium. Three phthalate esters were found to be mutagenic: dimethyl phthalate, diethyl phthalate and di-n-butyl phthalate. A number of other phthalate esters were not found to be mutagenic, including di(2-ethylhexyl) phthalate, di-n-octyl phthalate, diallyl phthalate, diisobutyl phthalate and diisodecyl phthalate. A metabolite of di(2-ethylhexyl)phthalate, 2-ethylhexanol, was also noted to be mutagenic. The mutagenic activity of this agent and others in this series was dose dependent but weak. No dose response curve exceeded more than 3.5 times background at maximally testable concentrations. A liquid suspension histidine reversion assay of dimethyl phthalate showed levels of mutagenic activity similar to that observed in the azaguanine resistance assay. [R26] *... At high doses when injected ip, the esters can act as teratogenic agents ... in rats. These esters also have an effect upon gonads in rats. /also/ the esters may bring about biochemical and pathological changes in the liver of rats when repeatedly administered orally or by ip. /Phthalic acid esters/ [R27] *Generally, the oral acute toxicity of the phthalates decreases with increasing molecular weight. /Alkyl phthalates/ [R28] *... Diallyl phthalate (DAP) is more hepatotoxic to rats than to mice, and demonstrated the same species difference in toxicity for allyl alcohol (AA). The data suggest that the toxicity of diallyl phthalate probably results from allyl alcohol cleaved from diallyl phthalate. To determine if the species difference in susceptibility to hepatotoxicity resulted from differences in the disposition and metabolism of dialyl phthalate, Fischer 344 rats and B6C3F1 mice were given 14(C) diallyl phthalate, 1, 10, or 100 mg/kg po or 10 mg/kg iv, and placed in metabolism cages for 24 hr. In rats, 25-30% of the diallyl phthalate was excreted as carbon dioxide, and 50-70% appeared in the urine within 24 hr. In mice, 6-12% of the diallyl phthalate was excreted as carbon dioxide, and 80-90% was excreted in the urine within 24 hr. Monoallyl phthalate (MAP), allyl alcohol, 3-hydroxypropylmercapturic acid (HPMA), and an unidentified polar metabolite (PM) were found in the urine of rats and mice dosed with diallyl phthalate. The polar metabolite was present in the urine of rats dosed with diallyl phthalate or allyl alcohol, indicating that the compound is a metabolite of allyl alcohol. There was no difference between the species in the quantity of allyl alcohol excrete, but mice excreted more monoallyl phthalate (39 vs 33%), 3-hydroxypropylmercapturic acid (28 vs 17%), and polar metabolite (20 vs 8%) than rats. Because diallyl phthalate is metabolized to allyl alcohol, a potent periportal hepatotoxicant, and because the mouse produced more 3-hydroxypropylmercapturic acid than rats, we postulate that the differential hepatotoxicity of diallyl phthalate is related to the extent of glutathione conjugation with allyl alcohol or acrolein (the active metabolite of allyl alcohol. [R29] *Primary rat hepatocyte cultures were used to compare the effects of some alkylphthalate esters on peroxisomal enzyme activities and morphology. Linear diesters from methyl to n-octyl and their constituent monoesters, and alcohols were compared with the branched chain 2-ethylhexyl derivatives. Studies with diesters indicated that induction of carnitine acetyltransferase required hydrolysis of the diester. The straight chain phthalates had little effect on hepatic peroxisomes compared with the 2-ethylhexyl ester, and hepatocyte cultures provided a rapid means of comparing the peroxisomal effects of different phthalates. /Alkyl phthalate esters/ [R30] NTXV: *LD50 Rat oral 1.7 g/kg /From table/; [R31] *LD50 Rabbit oral 1.7 g/kg /From table/; [R31] *LD50 Rabbit dermal 3.4 mg/kg /From table/; [R32] *LD50 Mouse ip 0.7 g/kg; [R32] ETXV: *EC0 (cell multiplication inhibition test): Uronema parduczi Chatton-Lwoff (protozoa): 22 mg/l; [R33] *EC0 (cell multiplication inhibition test): Pseudomonas putida (bacteria): > 100 mg/L/16 hr; [R33] *EC0 (cell multiplication inhibition test): Microcystis aeruginosa (algae): 0.65 mg/L/8 d; [R33] *EC0 (cell multiplication inhibition test): Scenedesmus quadricauda (green algae): 2.9 mg/L/7 d; [R33] *EC0 (cell multiplication inhibition test): Entosiphon sulcatum (protozoa): 13 mg/L/72 hr; [R33] NTP: *Toxicology and carcinogenesis studies of diallyl phthalate (approximately 99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 0 (vehicle control), 50, or 100 mg/kg 5 days per week for 103 weeks. The diallyl phthalate doses used in the 2 year studies were chosen on the basis of 13 week studies, wherein doses of 200 or 400 mg/kg caused death, reductions in body weight gains, or periportal hepatocellular necrosis and fibrosis in both sexes. Mean body weights and survival of male and female rats administered diallyl phthalate were essentially the same as those of the vehicle controls throughout the 2 year studies, although hepatotoxicity was produced in both sexes by the 100 mg/kg dose. Based on the results of the prechronic studies and the effects on the liver in the 2 year studies, the doses used in the 2 year studies were considered to be adequate for carcinogenicity testing. Male and female rats receiving the 100 mg/kg dose of diallyl phthalate in the 2 year studies developed chronic liver disease characterized by periportal fibrosis, periportal accumulation of pigment, and severe bile duct hyperplasia. Pigment accumulation also occurred at the 50 mg/kg dose in both sexes. Diallylphthalate administration increased the occurrence of mononuclear cell leukemia in female rats (p < 0.05 by trend tests), and the incidence in the 100 mg/kg dose female rats was greater (p < 0.05) than in the vehicle controls by pairwise comparisons (vehicle control, 15/50, 30%; low dose, 15/43, 35%; high dose, 25/49, 51%). An increased occurrence of mononuclear cell leukemia was not observed in male rats receiving diallylphthalate. ... Under the conditions of this study, the administration of diallyl phthalate by gavage in corn oil to male and female F344/N rats for 2 years caused chronic liver disease characterized by periportal fibrosis and pigment accumulation and an increased severity of bile duct hyperplasia. The incidence of mononuclear cell leukemia was significantly increased in female rats receiving 100 mg/kg. Because of the variability in the incidence of this neoplasm in aged Fischer 344 rats and the difficulty in definitively diagnosing this lesion in Fischer 344 rats, this increase was considered to be equivocal evidence of carcinogenicity of diallyl phthalate in female rats. There was no evidence of carcinogenicity in male rats. [R34] *A carcinogenesis bioassay of diallyl phthalate (99% pure) was conducted by administering 0 (vehicle control), 150, or 300 mg/kg diallyl phthalate in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female B6C3F1 mice. Survival rates and mean body weights of dosed mice were not different from those of vehicle controls, and pathological lesions unrelated to proliferative changes were not observed. Therefore, a maximally tolerated dose for the purposes of carcinogenicity testing may not have been achieved. The incidences of lymphoma or either lymphoma and leukemia in dosed male mice were not significantly greater than those in the controls according to pairwise comparisons (p= 0.051 to p=0.096), but the trend tests were statistically significant by either life table or incidental tumor analyses (p= 0.031 to p= 0.045). The incidence of lymphomas in the high do male mice was 12/50 (24%) in comparison with 6/50 (12%) in the controls. Recent historical incidences at the performing laboratory and in the NTP Bioassay Program were 18/120 (15%) and 71/661 (11%), respectively. Since the incidence of high dose male mice with leukemia was not significantly greater than that of concurrent or historical controls at the performing laboratory by pairwise comparisons, this marginal increase was considered only to be equivocally related to diallyl phthalate administration. Increased incidences of squamous cell papillomas, hyperplasia, and inflammatory lesions of the forestomach were observed in diallyl phthalate dosed mice of both sexes in a dose related manner. Because of the numerical elevation of forestomach papillomas in high dose mice of both sexes, the concomitant observation of dose related forestomach hyperplasia, and the rarity of this tumor in corn oil (gavage) control B6C3F1 mice, the development of squamous cell papillomas of the forestomach may have been related to diallyl phthalate administration. Under the conditions of this bioasssay, the development of chronic inflammation and hyperplasia of the forestomach in both male and female B6C3F1 mice was considered to be related to the administration of diallyl phthalate. The development of squamous cell papillomas of the forestomach may also have been related to chemical administration, but the available data are insufficient to indicate a clear cause and effect relationship. An increase in the incidence of male mice with lymphomas was observed, but this increase was considered only to be equivocally related to diallyl phthalate administration. The results of this bioassay, therefore, do not indicate that diallyl phthalate is carcinogenic in B6C3F1 mice, although a maximally tolerated dose may not have been achieved. [R35] ADE: *The phthalic acid esters and/or their metabolites are readily absorbed from the intestinal tract, the intraperitoneal cavity, and the lung. There is also evidence indicating that these esters can be absorbed through the skin. The vehicle can play an important role in the absorption, distribution, and elimination of the ester. /Phthalic acid esters/ [R36] *Absorbed esters of phthalic acid esters (or their metabolites) distribute quite rapidly to various organs and tissues both in animals and humans, especially the liver, kidney, and bile. /Phthalic acid esters/ [R37] *Pharmacokinetic studies have been performed using ingestion, absorption through skin, and injection. Phthalates were readily taken up, distributed, metabolized, and excreted by all three routes of exposure. /Phthalates/ [R28] METB: *MERCAPTURIC ACIDS DETECTED IN URINE OF RATS ADMIN VARIOUS ALLYL ESTERS INDICATING THAT ANIMALS WERE CAPABLE OF SUCH IN VIVO SYNTH. ALLYL ESTERS COULD BE METABOLIZED BY ACYL-OXYGEN FISSION OR ALKYL-OXYGEN FISSION TO YIELD 3-HYDROXYPROPYLMERCAPTURIC ACID OR ALLYLMERCAPTURIC ACID. /ALLYL PHTHALATE ESTERS/ [R38] *The phthalate diesters are rapidly metabolized to the monoester both in the intestine and following absorption. The rate of hydrolysis is greater for the lower molecular weight esters. The monoester may undergo further oxidation of the alcohol side chain, but further hydrolysis is minimal. Suggest that the half hydrolysis of diester substrates is due to the anionic charge of the free carbonyl group inhibiting formation of the enzyme-substrate complex. /Phthalate diesters/ [R39] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Diallyl phthalate's production and use as a cross linking agent in the production of unsaturated polyester resins, and as a plasticizer, may lead to its release to the environment through various waste streams. Based on an estimated vapor pressure of 1.16X10-3 mm Hg at 25 deg C, diallyl phthalate is expected to exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase diallyl phthalate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone molecules with atmospheric half-lives of about 7 and 11 hours respectively. Diallyl phthalate is expected to have low mobility in soil based upon an estimated Koc value of 1,360. Volatilization from dry soil surfaces is not expected based upon the vapor pressure of this compound. Volatilization from moist soil surfaces is not expected based upon the estimated Henry's Law constant of 1.17X10-7 atm-cu m/mole. Biodegradation of diallyl phthalate is expected to occur based upon the Japanese MITI test conducted with an activated sludge inoculum. In water, diallyl phthalate is expected to adsorb to sediment or particulate matter given its estimated Koc value. This compound is not expected to volatilize from water surfaces given its estimated Henry's Law constant. This compound is expected to hydrolyze in aquatic environments with an estimated half-life of about 37 days at pH 8. An estimated BCF value of 168 suggests that the potential for bioconcentration in aquatic organisms may be high. Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where diallyl phthalate is produced or used. (SRC) ARTS: *Diallyl phthalate's production and use as a cross linking agent in the production of unsaturated polyester resins(1), and as a plasticizer(2), may lead to its release to the environment through various waste streams(SRC). [R40] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 1,360(SRC), determined from a measured log Kow of 3.23(2) and a recommended regression-derived equation(3), indicates that diallyl phthalate is expected to have low mobility in soil(SRC). Volatilization of diallyl phthalate is not expected from moist soil surfaces(SRC) given an estimated Henry's Law constant of 1.17X10-7 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Diallyl phthalate is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 1.16X10-3 mm Hg at 25 deg C, determined from a fragment constant estimation method(5,SRC). Diallyl phthalate is expected to biodegrade in the environment based upon the Japanese MITI screening test with an activated sludge inoculum(6). [R41] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 1,360(SRC), determined from a measured log Kow of 3.23(2) and a recommended regression-derived equation(3), indicates that diallyl phthalate is expected to adsorb to suspended solids and sediment in water(SRC). Diallyl phthalate is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 1.17X10-7 atm-cu m/mole(SRC), determined from a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF value of 168(3,SRC), from the measured log Kow(2), suggests that bioconcentration in aquatic organisms is high(SRC). Diallyl phthalate is expected to biodegrade in water based upon the Japanese MITI screening test with an activated sludge inoculum(6). [R42] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diallyl phthalate, which has an estimated vapor pressure of 1.16X10-3 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase diallyl phthalate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone molecules(SRC); the half-life for these reactions in air is estimated to be about 7 and 11 hours respectively(3,SRC). [R43] BIOD: *Using a standard BOD dilution technique and an activated sludge inoculum, a theoretical BOD of 84 percent was observed over a 2 week incubation period for a test at 100 mg/l diallyl phthalate(1). Pure cultures of Pseudomonas acidovorans were found to produce phthalic acid and allyl alcohol from the aerobic degradation of diallyl phthalate(2). [R44] ABIO: *The rate constant for the vapor-phase reaction of diallyl phthalate with photochemically-produced hydroxyl radicals has been estimated as 5.57X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 7 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The rate constant for the vapor-phase reaction of diallyl phthalate with ozone has been estimated as 2.4X10-17 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 11 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(1,SRC). A base-catalyzed second-order rate constant of 0.22 L/mol-sec (SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 1 year and 37 days at pH values of 7 and 8, respectively(2,SRC). The UV spectrum of diallyl phthalate in water was found to have absorbance near 275.5 and 281 nm(3) and is expected to have absorption shoulders which extend beyond 290 nm(SRC). This compound has the potential to photolyze directly, but the kinetics are unknown(SRC). [R45] BIOC: *An estimated BCF value of 168 was calculated for diallyl phthalate(SRC), using a measured log Kow of 3.23(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is high(SRC). [R46] KOC: *The Koc of diallyl phthalate is estimated as approximately 1,360(SRC), using a measured log Kow of 3.23(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that diallyl phthalate is expected to have low mobility in soil(SRC). [R47] VWS: *The Henry's Law constant for diallyl phthalate is estimated as 1.17X10-7 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that diallyl phthalate will be essentially nonvolatile from water surfaces(2,SRC). Diallyl phthalate's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is not expected(SRC). Diallyl phthalate is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 1.16X10-3 mm Hg determined from a fragment constant method(3). [R48] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 8,046 workers (1,658 of these are female) are potentially exposed to diallyl phthalate in the US(1). Occupational exposure may be through inhalation and dermal contact with this compound at workplaces where this compound is produced or used(SRC). [R49] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Phthalate esters/ [R50] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Diallyl phthalate is included on this list. [R51] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Nat'l Research Council Canada; Phthalate Esters in the Aquatic Environment (1980) NRCC No. 17583 USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters (1980) EPA 440/5-80-067 Woodward KN (ed); Phthalate Esters: Toxicity and Metabolism (1988) Phthalate Esters; Environ Health Perspect 45: 1-210 (1982) USEPA/ECAO; Atlas Document for: Phthalate Esters (1980) SO: R1: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 134 R2: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 535 R3: Landrock, A.H. Handbook of Plastics Flammability and Combustion Toxicology. Park Ridge, New Jersey: Noyes Publications, 1983. R4: Andreopoulos AG, Polyzois GL; J Mater Sci Lett 3 (11): 1029-30 (1984) R5: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. 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Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 613 R34: NTP; Toxicology and Carcinogenesis Studies of Diallyl phthalate p.9-10 Report #284 (1985) NIH Pub # 85-2540 R35: NTP; Toxicology and Carcinogenesis Studies of Diallyl phthalate p.5-6 Report #242 (1983) NIH Pub# 83-1798 R36: USEPA; Ambient Water Quality Criteria Doc: Phthalate Esters p.C-12 (1980) EPA 440/5-80-067 R37: USEPA/ECAO; Atlas Document for: Phthalate Esters p.XI-21 (1980) R38: KAYE CM; BIOCHEM J 134 (4): 1093-101 (1973) R39: USEPA/ECAO; Atlas Document for: Phthalate Esters p.XI-5 (1980) R40: (1) Kramer H; Ullmann's Encycl Indust Chem 5th ed Deerfield,FL: VCH Publ A21: 219 (1992) (2) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Reinhold Co., p. 406 (1993) R41: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. 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Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R43: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R44: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Kurane R et al; Agric Biol Chem 41: 2119-23 (1977) R45: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Leyder F, Boulanger P; Bull Environ Contam Toxicol 30: 152-7 (1983) R46: (1) Hansch C, Leo A; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R47: (1) Hansch C, Leo A; Exploring QSAR Fundamentals and Applications in Chemistry and Biology. Washington,DC: Amer Chem Soc (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-8 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R48: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) R49: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R50: 40 CFR 401.15 (7/1/88) R51: 40 CFR 716.120 (7/1/96) RS: 38 Record 271 of 1119 in HSDB (through 2003/06) AN: 4173 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZOFURAN- SY: *BENZO- (B)FURAN; *2,3-BENZOFURAN-; *BENZOFURFURAN-; *COUMARON-; *COUMARONE-; *Cumarone-; *1-OXIDENE- RN: 271-89-6 MF: *C8-H6-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ISOLATION FROM COAL TAR OILS; SYNTH BY HEATING PHENOXYACETALDEHYDE WITH ZINC CHLORIDE AND ACETIC ACID. [R1, 169] *DERIVED FROM CRUDE HEAVY SOLVENT NAPHTHA FRACTION OF COAL TAR LIGHT OIL, OBTAINED AS BYPRODUCT IN COKING OF BITUMINOUS COAL. [R1, 169] *Calcining coumarilic acid with lime. [R2] *From coal tar: coal tar is concentrated and benzofuran is recovered by precipitation as the dibromide or picrate, or by sulfonation in acetic anhydride, followed by the decomposition of the benzofuran derivatives. [R2] *Dehydrogenation and cyclization of 2-ethylphenol. [R2] MFS: *NOT ISOLATED FOR COMMERCIAL PURPOSES [R3] USE: *USED IN MFR OF COUMARONE-INDENE RESINS. [R1, 169] PRIE: U.S. IMPORTS: *(1977) 1.84X10+9 GRAMS [R3] *(1979) 9.08X10+2 GRAMS [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NOT SOLID @ -18 DEG C; OIL [R1, 170]; *COLORLESS, OILY LIQUID [R4] ODOR: *AROMATIC ODOR [R1, 170] BP: *173-175 DEG C @ 760 MM HG [R1, 170] MP: *LESS THAN -18 DEG C [R5] MW: *118.14 [R5] DEN: *1.0913 @ 22.7 DEG C/4 DEG C [R1, 170] OWPC: *log Kow= 2.67(measured) [R6] SOL: *INSOL IN WATER AND AQ ALKALINE SOLN; MISCIBLE WITH BENZENE, PETROLEUM ETHER, ABSOLUTE ALCOHOL, ETHER [R1, 170]; *Soluble in ethanol. [R2] SPEC: *INDEX OF REFRACTION: 1.56897 @ 16.93 DEG C/D; 1.565 @ 22.7 DEG C/D [R1, 170]; *MAX ABSORPTION (ALCOHOL): 245 NM (LOG E= 4.0); 278 NM (LOG E= 3.3); 285 NM (LOG E= 3.3) [R7]; *IR: 6787 (Coblentz Society Spectral Collection) [R8]; *UV: 6-152 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R8]; *NMR: 19610 (Sadtler Research Laboratories Spectral Collection) [R8]; *MASS: 448 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R8] VAP: *0.44 mm Hg at 25 deg C [R9] OCPP: *BP: 62-63 DEG C @ 15 MM HG [R7] *VOLATILE WITH STEAM [R1, 170] *Polymerizes slowly at ambient temperatures, more rapidly with heat, and in the presence of acidic catalyst. Resistant to aqueous alkali. [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- POLY: *SLOWLY POLYMERIZES ON STANDING [R1, 170] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R10, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R10, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R10, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R10, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R10, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R10, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R10, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R10, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R10, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R10, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R10, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R10, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R10, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of benzofuran. There is sufficient evidence in experimental animals for the carcinogenicity of benzofuran. Overall evaluation: Benzofuran is possibly carcinogenic to humans (Group 2B). [R11] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R10, 1979.23] NTOX: *Eighteen chemicals were tested for their mutagenic potential in the L5178Y tk + or - mouse lymphoma cell forward mutation assay. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine, 3 ug/ml. The chemicals were tested at least twice. Significant responses were obtained with benzofuran. [R12] *Groups of 10 male and 10 female Fischer 344/N rats and B6C3F1 mice were administered 0, 31, 63, 125, 250 or 500 mg/kg body weight benzofuran (purity, 99%) in corn oil by gavage on five days per week for 13 weeks. Minimal centrilobular degeneration and necrosis of individual hepatocytes throughout the liver occurred in rats of each sex at the two highest doses and in males at 125 mg/kg body weight. Severe nephropathy with foci of tubular regeneration and dilated tubules occurred in male rats at the two highest doses. Cytoplasmic vacuolization was observed in all animals at the highest dose. Of the mice, 7/10 males at the high dose died, and 7/10 males at 250 mg/kg had nephrosis, with tubular-cell necrosis, inflammation, fibrosis, regeneration and focal mineralization. [R13] *Female CD-1 mice administered benzofuran at 5 mmol/kg body weight (590 mg/kg body weight) in corn oil by gavage for 10 days had liver microsomal p450 levels that were decreased by 70% in comparison with controls, 7-ethoxycoumarin O-deethylase activity increased by 150% and no significant changes in the activities of aniline hydroxylase and aminopyrine N-demethylase. Treatment also increased the activities of microsomal epoxide hydrolase (218% of the control level). UDP-glucuronosyl transferase (237% of control levels), cytosolic glutathione S-transferase (631% of control levels, with 1-chloro-2,4-dinitrobenzene as the substrate) and NADH-quinone reductase (230% of control levels). [R13] *Benzofuran was not mutagenic to Salmonella typhimurium when tested in either the standard plate incorporation assay or in a preincubation protocol in the presence or absence of an exogenous metabolic activation system. [R13] *Benzofuran induced gene mutation at the thymidine kinase locus of L5178Y mouse lymphoma cells in the absence of metabolic activation. It induced sister chromatid exchange and chromosomal aberrations in Chinese hamster ovary cells both in the presence and absence of metabolic activation. [R13] *Groups of 50 male and 50 female Fischer 344/N rats, six to seven weeks of age, were administered benzofuran (purity, 99%) dissolved in corn oil at doses of 0, 30 and 60 mg/kg body weight (males) and 0, 60 or 120 mg/kg body weight (females) by gavage on five days a week for 103 weeks. The numbers of animals that survived to the end of the study were 33/50 male controls, 12/50 at the low dose (p < 0.001) and 18/50 at the high dose (p= 0.003); and 27/50 female controls, 23/50 at the low dose and 25/50 at the high dose. Nephropathy was seen in almost all aged male rats, including controls, but was more severe in treated animals; nephropathy was more frequent and more severe in treated females. The incidences of renal-cell adenocarcinomas were increased in female, but not in male, rats, occurred in 0/50 controls, 1/50 at the low dose and 4/50 at the high dose (p= 0.032, incidental tumor test). This tumor is rare in female rats; the incidence in historical controls at the study laboratory was 1/149 and that in the US National Toxicology Testing Program was 2/2094. [R14] *Groups of 50 male and 50 female B6C3F1 mice, seven to eight weeks of age, were administered benzofuran (purity, 99%) dissolved in corn oil at 0, 60 or 120 mg/kg body weight (males) and 0, 120, or 240 mg/kg body weight (females) by gavage on five days a week for 104 weeks. The numbers of male mice still alive at the end of the experiment were 33/50 controls, 20/50 at the low dose and 28/50 at the high dose; survival or treated females was significantly lower than that of controls (p= 0.005), with 37/50 controls, 19/50 at the low dose and 21/50 at the high dose still alive at the end of the experiment. The incidences of hepatocellular adenomas were increased in treated animals: 4/49 male controls, 24/39 at the low dose (p < 0.001, incidental tumor test) and 34/48 at the high dose (p < 0.001); and 1/50 female controls, 22/48 at the low dose (p < 0.001) and 21/47 at the high dose (p < 0.001). The incidences of hepatoblastoma, which had not been observed in historical controls in the study laboratory, were increased in male animals: 0/49 male controls, 3/39 at the low dose (p= 0.083) and 18/48 at the high dose (p < 0.001); one hepatoblastoma was found in a female at the low dose and in two females at the high dose. The incidence of hepatocellular carcinomas was not increased in treated animals. Male mice had increased incidences of squamous-cell papillomas of the forestomach, which occurred in 2/49 control, 7/39 at the low dose (p= 0.018) and 10/48 at the high dose (p= 0.007); and of squamous-cell carcinomas, seen in 0/49 controls, 4/39 at the low dose (p= 0.05) and 3/48 at the high dose. The combined incidences of forestomach papillomas and carcinomas in males were 2/49 controls, 11/39 at the low dose (p= 0.001) and 13/48 at the high dose (p= 0.001). Squamous-cell papillomas of the forestomach occurred in 2/50 female controls, 8/50 at the low dose (p=0.035) and 5/50 at the high dose; the incidence of carcinomas of the forestomach was not increased in females. Treated animals had increased incidences of pulmonary alveolar-bronchiolar adenomas, which occurred in 4/49 male controls, 7/39 at the low dose and 15/48 at the high dose (p= 0.003); and in 1/50 female controls, 5/48 at the low dose (p= 0.040) and 13/47 at the high dose (p < 0.001). Females had an increased incidence of alveolar-bronchiolar carcinomas, seen in 1/50 controls, 4/48 at the low dose (p= 0.038) and 3/47 at the high dose. The frequency of epithelial hyperplasia of the forestomach was increased in all treated mice except males at the low dose. Bronchiolar epithelial hyperplasia was observed in all treated animals. [R15] *... L5178Y tK+/- mouse lymphoma cell forward mutation assay ... exposed to benzofuran for 4 hr ... then cultured for 2 days before plating in soft agar with or without trifluorothymidine, 3 ug/ml ... /showed/ a significant response. ... [R12] *... Female CD-1 mice were admin ... 5 um/kg of ... benzofuran /by gavage/ ... for 10 days. Animals were /sacrificed/ 1 or 2 days after the last dos; livers were removed and assayed for epoxide hydrolase, glutathione-S-transferase (GST), reduced NADH-quinone-reductase (NADH/QR), glucose-6-phosphate-dehydrogenase (G6PDH), glutathione reductase (GSSG-red), uridine-diphosphate-glucose-dehydrogenase (UDPGDH), aniline hydroxylase, 7-ethoxycoumarin deethylase (ECOD) and cytochrome-c-reductase (cyt-c-red) activities, and cytochrome p450. ... /Benzofuran/ ... significantly enhanced epoxide-hydrolase activity. GST activities were elevated. ... NADH/QR activity was incr by ... benzofuran. ... Benzofuran incr epoxide hydrolase, GST, and NADH/QR activities. Benzofuran decr cytochrome p450 content and elevated ECOD activity. ... [R16] +... Toxicology and carcinogenesis studies were conducted by admin benzofuran (approx 99% pure) in corn oil by gavage to groups of /50 male F344 N rats/ at 30 or 60 mg/kg and 60 or 120 mg/kg /to groups of 50 female F344 N rats for 2 yr/. /Groups of 50 male B6C3F1 mice were dosed/ with 60 or 120 mg/kg and /groups of 50 female B6C3F1 mice were dosed with 120 or 240 mg/kg for 2 yr. ... Under the conditions of these two yr gavage studies, there was no evidence of carcinogenic activity of benzofuran for male F344/N rats receiving doses of 30 or 60 mg/kg/day. There was some evidence of carcinogenic activity of benzofuran for female F344/N rats based on incr incidences of tubular cell adenocarcinomas of the kidney. There was clear evidence of the carcinogenic activity for male and female B6C3F1 mice, based on incr incidences of neoplasms of the liver, lung and forestomach. [R17] NTP: +... Toxicology and carcinogenesis studies were conducted by admin benzofuran (approx 99% pure) in corn oil by gavage to groups of /50 male F344 N rats/ at 30 or 60 mg/kg and 60 or 120 mg/kg /to groups of 50 female F344 N rats for 2 yr/. /Groups of 50 male B6C3F1 mice were dosed/ with 60 or 120 mg/kg and /groups of 50 female B6C3F1 mice were dosed with 120 or 240 mg/kg for 2 yr. ... Under the conditions of these two yr gavage studies, there was no evidence of carcinogenic activity of benzofuran for male F344/N rats receiving doses of 30 or 60 mg/kg/day. There was some evidence of carcinogenic activity of benzofuran for female F344/N rats based on incr incidences of tubular cell adenocarcinomas of the kidney. There was clear evidence of the carcinogenic activity for male and female B6C3F1 mice, based on incr incidences of neoplasms of the liver, lung and forestomach. [R17] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Benzofuran's production and use in the manufacture of coumarone-indene resins may result in its release to the environment through various waste streams. Benzofuran has been detected in exhaust gases from both gasoline and diesel engines, and in emissions from waste incineration. It also has been detected in drinking water, ground water, water effluent, atmospheric samples, in coffee aroma, and in human milk. Benzofuran is a component of coal tar. If released to soil, benzofuran should have low mobility. Volatilization of benzofuran may be important from moist and dry soil surfaces. Insufficient data are available to determine the rate or importance of biodegradation of benzofuran in soil and water. If released to water, benzofuran would adsorb to suspended solids and sediment. Benzofuran would volatilize from water surfaces with estimated half-lives for a model river and model lake of 5 hours and 5 days, respectively. An experimental BCF value of 360 suggests that benzofuran is expected to bioconcentrate in aquatic organisms. If released to the atmosphere, benzofuran will exist as a vapor. Vapor-phase benzofuran is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 10.3 hours. Vapor-phase benzofuran is also degraded in the atmosphere by reaction with ozone with an estimated half-life of about 6.3 days. Although most of the benzofuran released to the atmosphere will exist in the vapor phase, it has been detected as an adsorbed material on airborne dust. Particulate-phase benzofuran may be physically removed from the air by wet and dry deposition. The general population can be exposed to benzofuran through inhalation of vapor and particulates containing the compound that are released in exhausts from combustion processes such as gasoline and diesel engines and waste incineration. (SRC) ARTS: *Benzofuran's production and use in the manufacture of coumarone-indene resins(1) may result in its release to the environment through various waste streams(SRC). [R18] *Benzofuran has been detected in exhaust gases from both gasoline and diesel engines(1,2). Benzofuran has been detected in emissions from waste incineration(3). Benzofuran is a component of coal tar(4). [R19] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 675(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that benzofuran should have low mobility in soil(SRC). Volatilization of benzofuran may be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 5.25X10-4 atm-cu m/mole(SRC), using a recommended regression equation(4) and from dry soil surfaces(SRC) based on an experimental vapor pressure of 0.44 mm Hg(5). Insufficient data are available to determine the rate or importance of biodegradation of benzofuran in soil(SRC). [R20] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 675(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(1), indicates that benzofuran would adsorb to suspended solids and sediment(SRC) in the water. Benzofuran would volatilize from water surfaces based on an estimated Henry's Law constant of 5.25X10-4 atm-cu m/mole(SRC), developed using a fragment constant estimation method(3). Estimated half-lives for a model river and model lake are 5 hours and 5 days, respectively(1,SRC). An experimental BCF value of 360(4) suggests that benzofuran should bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(5). Insufficient data are available to determine the rate or importance of biodegradation of benzofuran in water(SRC). [R21] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), benzofuran, which has an experimental vapor pressure of 0.44 mm Hg at 25 deg C(2), will exist as a vapor in the ambient atmosphere. Vapor-phase benzofuran is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 10.3 hours(3,SRC). Vapor-phase benzofuran is also degraded in the atmosphere by reaction with ozone(4); the half-life for this reaction in air is estimated to be about 6.3 days(4,SRC). Although most of the benzofuran released to the atmosphere will exist in the vapor phase, it has been detected as an adsorbed material on airborne dust(5). Particulate-phase benzofuran may be physically removed from the air by wet and dry deposition(SRC). [R22] ABIO: *The rate constant for the vapor-phase reaction of benzofuran with photochemically produced hydroxyl radicals has been experimentally determined to be 3.73X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 10.3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Benzofuran slowly polymerizes upon standing(2). The rate constant for the vapor-phase reaction of benzofuran with ozone has been experimentally determined to be 1.83X10-18 cu cm/molecule-sec at 25 deg C(3). This corresponds to an atmospheric half-life of about 6.3 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3,SRC). [R23] BIOC: *An estimated BCF value of 62 was calculated for benzofuran(SRC), using an experimental log Kow of 2.67(1) and a recommended regression-derived equation(2). An experimental BCF value of 360 was obtained using guppies(4). According to a recommended classification scheme(3), these BCF values suggest that bioconcentration in aquatic organisms should be an important fate process(SRC). [R24] KOC: *The Koc of benzofuran is estimated as approximately 675(SRC), using an experimental log Kow of 2.67(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that benzofuran should have low mobility in soil(SRC). [R25] VWS: *The Henry's Law constant for benzofuran is estimated as 5.25X10-4 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that benzofuran is expected to volatilize from water surfaces(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 5 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 5 days(2,SRC). Benzofuran's vapor pressure, 0.44 mm Hg(3) and Henry's Law constant(1,SRC) indicate that volatilization from dry and moist soil surfaces may occur(SRC). [R26] WATC: *DRINKING WATER: Trace levels (conc not reported) of benzofuran were detected in raw and treated drinking water samples collected from 15 communities in Iowa and Nebraska(1). [R27] *GROUND WATER: Benzofuran has been qualitatively detected in a contaminated aquifer located near St Louis Park, MN(1); the contamination was the result of leaching from a creosote and wood preserving facility that operated from 1918 to 1982(1). Well waters collected at two coal gasification facility sites in WY contained benzofuran levels of 0.05-111 ppb(2). [R28] EFFL: *Benzofuran has been detected in exhaust gases from both gasoline and diesel engines(1,2). The amount of benzofuran detected in exhaust gases from the combustion of various hydrocarbon fuels ranged from < 0.1 to 2.8 ppm(2). Benzofuran was qualitatively detected in water effluents collected from an advanced treatment facility in Pomona, CA on Sep 25, 1974(3). Aqueous condensate from a coal gasification facility in Morgantown, WV contained a benzofuran conc of 267 ppb(4). [R29] *Benzofuran has been detected in the exhaust of a four-stroke outboard motor(1). [R30] ATMC: *Benzofuran was qualitatively detected in vapor-phase ambient air samples collected in the Kanawha Valley, WV in Sept 1977(1). [R31] FOOD: *Benzofuran has been identified as a component of the aroma produced by coffee roasting(1). [R32] MILK: *Benzofuran was qualitatively detected in 3 of 12 samples of human milk collected from women living in Bayonne, NJ, Jersey City, NJ, Bridgeville, PA, and Baton Rouge, LA(1). [R33] OEVC: *Thermal decomposition of food wrapping materials made from polyvinylidene chloride yielded 60.6-75.2 ug benzofuran/g polymer(1). Benzofurans are emitted by heating coated (painted) steel plates to 350 deg C(2). [R34] RTEX: *The general population can be exposed to benzofuran through inhalation of vapor and particulates containing the compound that are released in exhausts from combustion processes such as gasoline and diesel engines and waste incineration. (SRC) BODY: *Benzofuran was qualitatively detected in 3 of 12 samples of human milk collected from women living in Bayonne, NJ, Jersey City, NJ, Bridgeville, PA, and Baton Rouge, LA(1). [R33] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *The analyte can be extracted from water and gas chromatographed as determined by Athen-ERH or S-Cubed. [R35] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/ATSDR; Toxicological Profile for Benzofuran TP-91/04 (1992) DHHS/NTP; Toxicology and Carcinogenesis Studies of Benzofuran in F344/N Rats and B6C3F1 Mice Technical Report Series No. 370 (1989) NIH Publication No. 90-2825 Miyagawa M et al; Mutat Res 343 (2-3): 157-83 (1995). the in vivo-in vitro replicative DNA synthesis (RDS) test with hepatocytes prepared from male B6C3F1 mice as an early prediction assay for putative nongenotoxic (Ames-negative) mouse hepatocarcinogens. Hazeman JK, Lockhart A; Fundam Appl Toxicol 22 (3): 382-91 (1994). The relationship between the use of maximum tolerated dose and study sensitivity for determining rodent carcinogenicity. Adam W et al; Toxicol Lett 67 (1-3): 41-55 (1993). Genotoxicity studies of benzofuran dioxetanes and epoxides with isolated DNA, bacteria and mammalian cells. Rosenkranz HS, Klopman G; Environ Mol Mutagen 21 (2): 193-206 (1993). Structural relationships between mutagenicity, maximum tolerated dose, and carcinogenicity in rodents. Nendza M, Russom CL; Xenobiotica 21 (2): 147-70 (1991). QSAR modelling of the ERL-D fathead minnow acute toxicity database. Tennant RW, Ashby J; Mutat Res 257 (3): 209-28 (1991). Classification according to chemical structure, mutagenicity to Salmonella and the level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the U.S. National Toxicology Program (NTP). Tennant RW et al; Mol Carcinogen 4 (6): 420-40 (1991). Evidence that toxic injury is not always associated with induction of chemical carcinogenesis. Lijinsky W; J Environ Sci Health Part C Environ Carcinog Rev 8 (1): 45-88 (1990). Non-genotoxic environmental carcinogens /are reviewed/. SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA12 130 R3: SRI R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 320 R5: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-68 R6: Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont CA: Pomona College (1985) R7: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-126 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 209 R9: Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) R10: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 63 438 (1995) R12: McGregor DB et al; Environ Mol Mutagen 11 (1): 91-118 (1988) R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 436 (1995) R14: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 435 (1995) R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 434 (1995) R16: Heine HS et al; Chem Biol Interact 59 (2): 219-30 (1986) R17: Toxicology and Carcinogenesis Studies of Benzofuran in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 370 (1989) NIH Publication No. 90-2825 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R18: (1) Budavari S; The Merck Index - Encyclopedia of Chemicals, Drugs, and Biologicals. Rahway, NJ: Merck and Co Inc pg 169 (1989) R19: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (2) Seizinger DE, Dimitriades B; J Air Pollut Control Assoc 22: 47-51 (1972) (3) Junk GA, Ford CS; Chemosphere 9: 187-230 (1980) (4) McNeil D; Kirk-Othmer Encycl Chem Technol 3rd ed NY: John Wiley and Sons 22: 571 (1983) R20: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont, CA: Pomona College (1985) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) R21: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont, CA: Pomona College (1985) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) DeVoogt P et al; Aquat Toxicol 20: 169-94 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R22: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Chao J et al; J Phys chem Ref data 12: 1033-63 (1983) (3) Atkinson R; J Phys Chem Ref Data Monograph No 1 (1989) (4) Atkinson R et al; Int J Chem Kinet 24: 345-58 (1992) (5) Dmitriev MT et al; Gig Sanit 1984: 44-7 (1984) R23: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) McKillip WJ et al; Ullmann's Encyclopedia of Industrial Chemistry. 5th ed. Gerhartz W (ed). Deerfield Beach, FL: VCH Publishers Vol A12: 119-54 (1985) (3) Atkinson, R et al; Int J Chem Kinet 24: 345-58 (1992) R24: (1) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) DeVoogt P et al; Aquat Toxicol 20: 169-94 (1991) R25: (1) Hansch C, Leo AJ; Medchem Project Issue No 26. Claremont, CA: Pomona College (1985) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R26: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Chao J et al; J Phys Chem Ref Data 12: 1033-63 (1983) R27: (1) Svec HJ et al; Trace Soluble Organic Compounds in Potable Water Supplies ISWRRI-54 (NTIS PB-228-523) Washington DC: Office Water Resources Res (1974) R28: (1) Rostad CE et al; Chemosphere 14: 1023-36 (1985) (2) Pellizzari ED et al; pp 256-74 in ASTM Spec Tech Publ: STP 686 (1979) R29: (1) Hampton CV et al; Environ Sci Technol 16: 287-98 (1982) (2) Seizinger DE, Dimitriades B; J Air Pollut Control Assoc 22: 47-51 (1972) (3) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates Vol 1 USEPA-600/1-84-020A (1984) (4) Pellizzari ED et al; pp. 256-74 in ASTM Spec Tech Publ: STP 686 (1979) R30: (1) Juettner F; Chemosphere 29: 191-20 (1994) R31: (1) Erickson MD, Pellizzari ED; Analysis of Organic Air Pollutants in the Kanawha Valley, WV and the Shenandoah Valley, Va USEPA-903/9-78-007 (1978) R32: (1) SilWar R, Tressl R; Z Lebensm-Unters Forsch 189: 205-11 (1989 R33: (1) Pellizzari ED et al; Bull Environ Contam Toxicol 28: 323-8 (1982) R34: (1) Yasuhara, Morita M; Environ Sci Technol 22: 646-50 (1988) (2) Henricks-Eckerman ML et al; Am Ind Hyg Assoc J 51: 241-44 (1990) R35: USEPA/OST; List of Lists: A Catalog of Analytes and Methods p.77 (1991) OST Pub 21W-4005 RS: 44 Record 272 of 1119 in HSDB (through 2003/06) AN: 4178 UD: 200302 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ERYTHROMYCIN-STEARATE- SY: *ABBOTICINE-; *BRISTAMYCIN-; *DOWMYCIN-E-; *ERATREX-; *ERYPAR-; *ERYTHROCIN-STEARATE-; *ERYTHROMYCIN,-OCTADECANOATE- (SALT); *ERYTHROMYCIN,-STEARATE- (SALT); *ERYTHROMYCIN-STEARIC-ACID-SALT-; *ETHRIL-; *GALLIMYCIN-; *MEBERYT-; *NCI-C55674-; *OE-7-; *PANTOMICINA- RN: 643-22-1 MF: *C37-H67-N-O13.C18-H36-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN OF ERYTHROMCYIN STEARATE (ESTER) IS DESCRIBED IN BOOTH, MURRAY, US PATENT 2,862,921 (1958 TO UPJOHN). [R1, 482] *BY REACTING ERYTHROMYCIN WITH PROPER QUANT OF STEARIC ACID IN ACETONE SOLN AND THEN DILUTING SOLN WITH WATER TO PPT SALT. [R2, 1124] FORM: *ERYTHROMYCIN STEARATE TABLETS, USP (BRISTAMYCIN, ERYTHROCIN STEARATE, ETHRIL), CONTAIN 125, 250, OR 500 MG EACH. [R3, 1224] *ERYTHROMYCIN STEARATE: ...STEARIC ACID SALT OF ERYTHROMYCIN, WITH EXCESS OF STEARIC ACID. IT CONTAINS NOT LESS THAN 55% OF ERYTHROMYCIN. [R2, 1123] MFS: +Abbott Laboratories, Hq, 1400 Sheridan Rd, North Chicago, IL 60064, (800) 323-9065; Chemical and Agricultural Products Division; Chemical Business Unit; Production site: North Chicago, IL 60064 [R4] +The Upjohn Company, Hq, 7000 Portage Rd, Kalamazoo, MI 49001, (616) 323-4000; Fine Chemical Division; Production site: Kalamazoo, MI 49001 [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS [R1, 483]; *WHITE OR SLIGHTLY YELLOW CRYSTALS OR POWDER [R2, 1124] ODOR: *PRACTICALLY ODORLESS [R2, 1124] TAST: *SLIGHTLY BITTER [R2, 1124] MW: *1018.59 PH: *SOLN IS ALKALINE TO LITMUS [R2, 1124] SOL: *SOL IN ALC, ETHER; PRACTICALLY INSOL IN WATER [R1, 483]; *SOL IN METHANOL, CHLOROFORM [R2, 1124] SPEC: *ALCOHOLIC SOLN ARE LEVOROTATORY [R1, 483] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *AMONG ALLERGIC REACTIONS ARE FEVER, EOSINOPHILIA, AND SKIN ERUPTIONS, WHICH MAY OCCUR ALONE OR IN COMBINATION; EACH DISAPPEARS SHORTLY AFTER THERAPY IS STOPPED. ...OFTEN PRODUCES IRRITATIVE EFFECTS. ORAL ADMIN...FREQUENTLY ACCOMPANIED BY EPIGASTRIC DISTRESS, WHICH MAY BE QUITE SEVERE. /ERYTHROMCYIN/ [R3, 1224] *IM INJECTION OF QUANTITIES LARGER THAN 100 MG PRODUCES EXTREMELY SEVERE PAIN THAT PERSISTS FOR HOURS. IV INFUSION OF 1-G DOSES...ALMOST REGULARLY IS FOLLOWED BY THROMBOPHLEBITIS. /ERYTHROMYCIN/ [R3, 1224] *...MILD ELEVATIONS OF THE SGOT /SERUM GLUTAMIC-OXALOACETIC TRANSAMINASE/ WERE ALSO NOTED IN...3 OF 97 PT TREATED WITH ERYTHROMYCIN STEARATE... [R3, 1224] *SEVERE RESP DISTRESS DEVELOPED IN A 60-YR-OLD MAN AFTER INGESTION OF 2 TABLETS OF ERYTHROMYCIN STEARATE. AUTHORS SUGGEST AN ALLERGIC REACTION OF TYPE 1 AND TYPE 3 PARTICIPATED IN COURSE OF CLINICAL PICTURE. [R5] *OTOTOXICITY DUE TO ORAL ERYTHROMYCIN STEARATE DEVELOPED IN 2 PT (17 and 50-YR-OLD) RECEIVING AT LEAST 4 G DAILY. UPON WITHDRAWAL OF THE DRUG, HEARING RETURNED IN BOTH PT. [R6] NTOX: *READILY PRODUCES DIARRHEA AND DEATH IN RABBITS DUE TO OVERGROWTH OF GRAM-NEGATIVE BACTERIA. /ERYTHROMYCIN/ [R7] *CELLULAR DAMAGE PARALLELED KNOWN HEPATOTOXIC POTENTIAL OF THESE AGENTS IN MAN, SUGGESTING POSSIBLE USEFULNESS OF THIS SYSTEM AS AN ADDNL METHOD OF EVALUATING CYTOTOXIC POTENTIAL OF CHEMICALLY RELATED DRUGS [R8] +Erythromycin stearate was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Erythromycin stearate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.300, 1.000, 3.000, 10.000, and 33.000 ug/plate. The highest ineffective dose tested in any S. typhimurium strain was 33.000 ug/plate. [R9] +... Conclusions: Under the conditions of these 2 yr studies, there was no evidence of carcinogenic activity of erythromycin stearate for male or female F344/N rats administered erythromycin stearate in the diet at 5,000 or 10,000 ppm. There was no evidence of carcinogenic activity of erythromycin stearate for male or female B6C3F1 mice administered erythromycin stearate in the diet at 2,500 or 5,000 ppm. ... /Erythromycin stearate/ [R10] NTP: +Toxicology and carcinogenesis studies of erythromycin stearate (USP grade, greater than 96% pure) were conducted by admin ... in feed to groups of F344/N rats and B6C3F1 mice for ... 2 yr studies of erythromycin stearate were conducted by feeding diets containing 0, 5,000 or 10,000 ppm erythromycin stearate to groups of 50 rats of each sex for 103 wk. Diets containing 0, 2,5000 or 5000 ppm were fed to groups of 50 mice of each sex for 103 wk. Conclusions: Under the conditions of these 2 yr studies, there was no evidence of carcinogenic activity of erythromycin stearate for male or female F344/N rats administered erythromycin stearate in the diet at 5,000 or 10,000 ppm. There was no evidence of carcinogenic activity of erythromycin stearate for male or female B6C3F1 mice administered erythromycin stearate in the diet at 2,500 or 5,000 ppm. ... /Erythromycin stearate/ [R10] ADE: *PEAK CONCN IN PLASMA...0.3-0.5 UG/ML 4 HR AFTER ORAL ADMIN OF 250 MG OF BASE AND ARE 0.3-1.9 UG/ML AFTER...500-MG TABLET. VARIOUS ESTERS OF ERYTHROMYCIN HAVE BEEN PREPARED TO...IMPROVE STABILITY AND FACILITATE ABSORPTION. ...CONCN OF ERYTHROMYCIN IN PLASMA ARE LITTLE DIFFERENT IF STEARATE IS GIVEN ORALLY. [R3, 1223] *...DIFFUSES READILY INTO INTRACELLULAR FLUIDS, AND ANTIBACTERIAL ACTIVITY... ACHIEVED AT...ALL SITES EXCEPT BRAIN AND CSF. ...ONE OF FEW ANTIBIOTICS THAT PENETRATES INTO PROSTATIC FLUID, CONCN ARE APPROX 40% OF...PLASMA. EXTENT OF BINDING...TO PLASMA PROTEINS VARIES...PROBABLY EXCEEDS 70% IN ALL.../FORMS OF DRUG/. /ERYTHROMYCIN/ [R3, 1223] *ERYTHROMYCIN BASE IS ADEQUATELY ABSORBED FROM UPPER PART OF SMALL INTESTINE; IT IS INACTIVATED BY GASTRIC JUICE... FOOD IN STOMACH DELAYS ITS ULTIMATE ABSORPTION. /ERYTHROMYCIN/ [R3, 1223] *ERYTHROMYCIN TRAVERSES PLACENTAL BARRIER; AND CONCN OF DRUG IN FETAL PLASMA ARE ABOUT 5-20% OF THOSE IN MATERNAL CIRCULATION. /ERYTHROMYCIN/ [R3, 1223] *ONLY 2-5% OF ORALLY ADMIN ERYTHROMCYIN IS EXCRETED IN ACTIVE FORM IN URINE; FROM 12-15%, AFTER IV INFUSION. WHEN LARGE DOSES...GIVEN BY MOUTH, FECES MAY CONTAIN AS MUCH AS 0.5 MG/G. ...CONCENTRATED IN LIVER AND EXCRETED IN ACTIVE FORM IN BILE, WHICH MAY CONTAIN AS MUCH AS 250 UG/ML WHEN PLASMA CONCN ARE...HIGH. /ERYTHROMYCIN/ [R3, 1223] *...STUDIES, BASED ON BOTH SERUM LEVELS AND URINARY EXCRETION OF ANTIBIOTIC, SHOW THAT ERYTHROMYCIN ESTOLATE IS CONSIDERABLY MORE BIOAVAILABLE THAN ERYTHROMYCIN STEARATE IN NON-FASTING SUBJECTS. [R11] *IT IS INSOL IN WATER AND HENCE IS SUPPOSEDLY DESTROYED TO LESSER EXTENT IN STOMACH /THAN ERYTHROMYCIN/. ... IT IS CLAIMED TO GIVE SAME BLOOD LEVELS AS ORAL ERYTHROMYCIN, BUT THERE IS CONSIDERABLE VARIATION, WHICH IS PARTLY BIOLOGICAL AND PARTLY PHARMACEUTICAL IN CAUSE. [R2, 1124] *ABSORPTION OF ERYTHROMYCIN FROM ENCAPSULATED ENTERIC-COATED DOSAGE FORM OF ERYTHROMYCIN BASE WAS SUPERIOR TO THAT OF ENCAPSULATED ERYTHROMYCIN STEARATE FOLLOWING ORAL DOSES TO VOLUNTEERS. SERUM CONCN...WERE SIGNIFICANTLY HIGHER FROM BASE...AND MEAN AREAS UNDER PLASMA CURVES WERE ALMOST 3-FOLD HIGHER FROM BASE THAN STEARATE. [R12] *ERYTHROMYCIN WAS ABSORBED FROM ERYTHROCIN 8 HR TABLETS CONTAINING 500 MG ERYTHROMYCIN STEARATE. SIGNIFICANT POS CORRELATION WAS OBTAINED BETWEEN STEADY STATE PLASMA AND SALIVA ERYTHROMYCIN LEVELS. [R13] *IN NONFASTING SUBJECTS, MEAN PEAK PLASMA LEVELS FOLLOWING AN ORAL DOSE OF 500 MG STEARATE WAS REACHED MORE RAPIDLY AND WAS TWICE AS HIGH AS THAT OBSERVED IN FASTING SUBJECTS. [R14] *MEAN ORAL BIOAVAIL WAS APPROX 50% COMPARED WITH IV STD. PLASMA LEVELS FOLLOWING 2ND DOSE WERE SUFFICIENT TO INHIBIT MAJORITY OF BACTERIAL PATHOGENS CAUSING ACUTE RESP TRACT INFECTIONS. [R15] METB: *IT IS HYDROLYZED IN SMALL INTESTINE AND IN TISSUES TO YIELD ERYTHROMYCIN. [R2, 1124] ACTN: *...INHIBIT PROTEIN SYNTH BY BINDING TO 50 S RIBOSOMAL SUBUNITS OF SENSITIVE MICROORGANISMS. ... ASSOC BETWEEN ERYTHROMYCIN AND RIBOSOME IS REVERSIBLE BUT TAKES PLACE ONLY WHEN 50 S SUBUNIT IS FREE FROM TRNA MOLECULES BEARING NASCENT PEPTIDE CHAINS. PRODN...OF HIGHLY POLYMERIZED HOMOPEPTIDES IS SUPPRESSED. /ERYTHROMYCIN/ [R3, 1223] *THE NONIONIZED FORM OF THE DRUG IS CONSIDERABLY MORE PERMEABLE TO CELLS, AND THIS PROBABLY EXPLAINS INCREASED ANTIMICROBIAL ACTIVITY THAT IS OBSERVED AT ALKALINE PH. /ERYTHROMYCIN/ [R3, 1223] INTC: *A 77-YR-OLD WOMAN IS REPORTEDLY MAINTAINED ON 7.5 MG OF WARFARIN DAILY IN WHOM THE ADMIN OF ORAL ERYTHROMYCIN STEARATE, 500 MG 4 TIMES A DAY, RESULTED IN A PROTHROMBIN TIME OF 64 SECONDS (CONTROL, 11 SECONDS). [R16] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *ITS ACTIONS AND USES ARE IDENTICAL TO THOSE OF ERYTHROMYCIN. [R2, 1124] *ERYTHROMYCIN MAY BE USEFUL FOR DISSEMINATED GONOCOCCAL DISEASE IN PREGNANT PT WHO IS ALLERGIC TO PENICILLIN... 13 PT...TREATED WITH 500 MG OF ERYTHROMYCIN... STEARATE, GIVEN ORALLY EVERY 6 HR FOR 5 DAYS, SHOWED RAPID CLINICAL AND BACTERIOLOGICAL RESPONSES. [R3, 1225] +ANTIBACTERIAL AGENT +MEDICATION (VET): ANTIBACTERIAL AGENT WARN: *...ERYTHROMYCIN AND ITS DERIV SELDOM CAUSE SERIOUS ADVERSE REACTIONS. [R17] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *TLC ANALYSIS OF MACROLIDE ANTIBIOTICS. FOR THE SEPARATION OF ERYTHROMYCIN ESTERS, CHLOROFORM-ETHANOL-15% AMMONIUM ACETATE PH 7.0 (OR 3.5% AMMONIA) (85:15:1) GAVE BEST RESULTS. [R18] *FLUOROPHOTOMETRIC DETERMINATION OF ERYTHROMYCIN AND ITS DERIVATIVES BY ION PAIR EXTRACTION WITH TETRABROMOSULFONEFLUORESCEIN. [R19] *MICROBIOLOGICAL METHOD FOR ESTIMATING ERYTHROMYCIN AND ITS DERIV WAS VALIDATED. THERE WAS A GRADUAL DECREASE IN ANTIMICROBIAL ACTIVITY AS INCUBATION TEMP INCREASED. THE DATA OBEYED ARRHENIUS EQUATION REQUIREMENTS, ASSURING THE VALIDITY OF THE METHOD. [R20] *DIFFERENTIAL PULSE POLAROGRAPHY WAS USED IN THE DETECTION AND QUANTITATION OF ANTIBIOTICS. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW, WITH APPROX 20 REFERENCES, OF THE BIOAVAILABILITY FROM VARIOUS FORMULATIONS OF ERYTHROMYCIN STEARATE. [R22] DHHS/NTP; Toxicology and Carcinogenesis Studies of Erythromycin sulfate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 338 (1988) NIH Publication No. 89-2594 SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. R2: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R3: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. R4: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 749 R5: ABRAMOV ET AL; ACUTE RESPIRATORY DISTRESS CAUSED BY ERYTHROMYCIN HYPERSENSITIVITY; ARCH INTERN MED 138(JUL) 1156 (1978) R6: VAN MARION ET AL; LANCET 2(JUL) 214 (1978) R7: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 199 R8: DUJOVNE ET AL; TOXICITY OF HEPATOTOXIC DRUGS ON MOUSE LIVER TISSUE CULTURE; ARCH INT PHARMACODYN THER 186(1) 84 (1970) R9: Mortelman K et al; Environ Mutagen 8:1-119 (1986) R10: Toxicology and Carcinogenesis Studies of Erythromycin Stearate in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 338 (1988) NIH Publication No. 89-2594 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R11: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 186 R12: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979. 73 R13: BEREND ET AL; PLASMA AND SALIVA CONCENTRATIONS FOR A NEW FORMULATION OF ERYTHROMYCIN STEARATE; CURR MED RES OPIN 6(2) 118 (1979) R14: MALMBORG A; EFFECT OF FOOD ON ABSORPTION OF ERYTHROMYCIN: STUDY OF TWO DERIVATIVES, THE STEARATE AND THE BASE; J ANTIMICROB CHEMOTHER 5(SEPT) 591 (1979) R15: TRIGGS EJ, ASHLEY JJ; ORAL ADMINISTRATION OF ERYTHROMYCIN STEARATE: EFFECT OF DOSAGE FORM ON PLASMA LEVELS; MED J AUST 2(JUL) 121 (1978) R16: BARTLE WR; POSSIBLE WARFARIN-ERYTHROMYCIN INTERACTION; ARCH INTERN MED 140(JUL) 985 (1980) R17: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 4th ed. Chicago: American Medical Association, 1980. 1258 R18: VANDERHAEGHE H, KERREMANS L; THIN-LAYER CHROMATOGRAPHY OF MACROLIDE ANTIBIOTICS; J CHROMATOGR 193(1) 119 (1980) R19: GOKITA ET AL; FLUOROPHOTOMETRIC DETERMINATION OF ERYTHROMYCIN AND ITS DERIVATIVES BY ION PAIR EXTRACTION WITH TETRABROMOSULFONEFLUORESCEIN; YAKUZAIGAKU 38(2) 82 (1978) R20: KASSEM ET AL; VALIDITY OF BP 1968 MICROBIOLOGICAL METHOD FOR ESTIMATING ERYTHROMYCIN AND ERYTHROMYCIN STEARATE; J DRUG RES 9(1-2) 149 (1977) R21: SIEGERMAN ET AL; DETECTION AND QUANTITATION OF ANTIBIOTICS BY DIFFERENTIAL PULSE POLAROGRAPHY; AUTOM MICROBIOL IMMUNOL, PAP SYMP, 305 (1975) R22: KNOTHE H, DETTE GA; PHARMACOKINETICS OF ERYTHROMYCIN; SCOTT MED J 22(5) 397 (1977) RS: 14 Record 273 of 1119 in HSDB (through 2003/06) AN: 4179 UD: 200302 RD: Reviewed by SRP on 3/11/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: RHODAMINE-6G- SY: *AIZEN-RHODAMINE-6GCP-; *BASIC-RED-1-; *BASIC-RHODAMINE-YELLOW-; *BASIC-RHODAMINIC-YELLOW-; *BENZOIC ACID, O-(6-(ETHYLAMINO)-3-(ETHYLIMINO)-2,7-DIMETHYL-3H-XANTHEN-9-YL)-, ETHYL ESTER, MONOHYDROCHLORIDE; *BENZOIC ACID, 2-(6-(ETHYLAMINO)-3-(ETHYLIMINO)-2,7-DIMETHYL-3H-XANTHEN-9-YL)-, ETHYL ESTER, MONOHYDROCHLORIDE; *CALCOZINE-RED-6G-; *CALCOZINE-RHODAMINE-6GX-; *CI-BASIC-RED-1-; *CI-BASIC-RED-1,-MONOHYDROCHLORIDE-; *CI-45160-; *ELCOZINE-RHODAMINE-6GDN-; *ELJON-PINK-TONER-; *FANAL-PINK-GFK-; *FANAL-RED-25532-; *HELIOSTABLE-BRILLIANT-PINK-B-EXTRA-; *MITSUI-RHODAMINE-6GCP-; *NYCO-LIQUID-RED-GF-; *RED-169-; *RHODAMINE-Y-20-7425-; *RHODAMINE-4GD-; *RHODAMINE-4GH-; *RHODAMINE-5GDN-; *RHODAMINE-5GL-; *RHODAMINE-6GB-; *RHODAMINE-6GBN-; *RHODAMINE-6GCP-; *RHODAMINE-6GD-; *RHODAMINE-6GDN-; *RHODAMINE-6GH-; *RHODAMINE-6GO-; *RHODAMINE-6GX-; *RHODAMINE-6JH-; *RHODAMINE-F5G-CHLORIDE-; *RHODAMINE-6ZH-DN-; *RHODAMINE-6G-EXTRA-; *RHODAMINE-6GDN-EXTRA-; *RHODAMINE-6G-EXTRA-BASE-; *RHODAMINE-F4G-; *RHODAMINE-F5G-; *RHODAMINE-GDN-; *RHODAMINE-6G-LAKE-; *SILOSUPER-PINK-B- RN: 989-38-8 MF: *C28-H30-N2-O3.Cl-H MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CONDENSING OF 3-ETHYLAMINO-P-CRESOL WITH PHTHALIC ANHYDRIDE THEN ESTERIFYING THE PRODUCT WITH ETHANOL AND A MINERAL ACID. [R1] *RHODAMINE 6G IS PREPD COMMERCIALLY BY CONDENSING 3-ETHYLAMINO-4-METHYLPHENOL WITH PHTHALIC ANHYDRIDE, FOLLOWED BY ESTERIFICATION WITH ETHYL CHLORIDE UNDER PRESSURE. [R2] MFS: *Max Marx Color Corporation, Hq, 1200 Grove Street, Irvington, NJ 07111, (202) 373-7801; Production site: Irvington, NJ 07111 [R3] OMIN: *IN WESTERN EUROPE ... MAY PROVISIONALLY BE USED IN COSMETICS WHICH MAY COME INTO CONTACT WITH MUCOUS MEMBRANES. IN JAPAN, RHODAMINE 6G IS USED AS DYE. [R4] USE: *IN WESTERN EUROPE MAY BE PROVISIONALLY USED IN COSMETICS. [R4] *DYE FOR SILK, COTTON, WOOL AND BAST FIBERS; DYE FOR PAPER, LEATHER, AND PLASTICS; COMPONENT OF C.I. SOLVENT RED 36; TRACING AGENT IN WATER POLLUTION STUDIES; ADSORPTION INDICATOR, ESP IN VERY ACID SOLUTIONS [R5] CPAT: *ESSENTIALLY 100% AS A DYE [R5] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 6.81X10+6 G [R5] *(1979) PROBABLY GREATER THAN 4.54X10+6 G [R5] U.S. IMPORTS: *(1977) 2.08X10+7 G (PRINCPL CUSTMS DISTS) [R5] *(1979) 6.91X10+7 G (PRINCPL CUSTMS DISTS) [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *479.06 SOL: *SOL IN WATER AND ETHANOL [R2] SPEC: *MAX ABSORPTION: 535 NM [R2]; *IR: 11293 (Sadtler Research Laboratories Prism Collection) [R6]; *Mass: 5106 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS NBS-63) [R6] OCPP: *CATIONIC [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *VOLATILIZES @ LESS THAN 200 DEG C [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R8] ANTR: *In treatment of eyes contaminated with cationic dyes, first aid measures are aimed at getting rid of dye which has not yet reacted with the tissues. This includes copious irrigation, mechanical removal of particles, and in the case of imbedded colored pencil may necessitate surgical exploration and careful removal of the particles. Solutions of tannin or tannic acid precipitate cationic dyes and render them essentially noninjurious, but this disposes of only that portion of the dye which has not already reacted with the tissues. /It was/ determined experimentally that a 5% to 10% solution of tannin was effective essentially in a prophylactic sense if applied within three minutes following application of powdered basic dyes to the eyes of rabbits, but that the effectiveness of this treatment rapidly diminished after three minutes. Other forms of chemical treatment have been aimed at removing both combined and excess dye. However, studies of the reaction of cationic dyes with cornea in vitro have shown these dyes to bind very tenaciously and to be very difficult to remove from combination with the tissue. ... /Cationic dyes/ [R9, 384] HTOX: *Some important causes of occupational phototoxic or photoallergic reactions /are rhodamine dyes/. /Rhodamine dyes/ [R10] *Two variants have been isolated from the cultured human cell line VA2-B which are resistant in vivo to the mitochondrial specific fluorescent dyes rhodamine 6G and rhodamine 123. Both mutants are cross-resistant to ethidium bromide but are sensitive to both colchicine and chloramphenicol. When either mutant is treated with low levels of rhodamine 6G, mitochondrial associated fluorescence is significantly lower than in wild type cells. Furthermore, when cell cultures are treated with high concentrations of either rhodamine 123 or 6G, and then washed free of the dye, mitochondrial associated rhodamine fluorescence rapidly diminishes in the parental cell line. In hybrid cell fusions between resistant and sensitive cell lines, rhodamine resistance is gradually expressed, reaching maximal expression approximately 11 days after fusion. Cytoplasmic transmission of rhodamine resistance has not been clearly demonstrated in cytoplast-cell fusions, and thus resistance is probably due to a mutation of a nuclear, rather than mitochondrial DNA gene(s). These observations indicate that mitochondria of both rhodamine resistant variants, unlike wild type, have a significantly decreased ability to bind and retain rhodamine, and thus their mitochondrial tramsmembrane electrical potential may be significantly reduced. [R11] NTOX: *16 RATS ... MIXED SAITAMA STRAIN, WEIGHING ABOUT 200 G, RECEIVED REPEATED SC INJECTIONS OF 1 ML OF 0.02% AQ SOLN ... 2-3 TIMES/WK. AFTER 4 MO, INJECTIONS WERE DISCONTINUED FOR 1 MO ... RESUMED, UNTIL TOTAL OF 100 INJECTIONS ... 4/7 RATS THAT SURVIVED FOR 487 DAYS DEVELOPED FIBROSARCOMAS ... . 1 RAT ... SPINDLE CELL SARCOMA OF LIVER ... . [R12] *OF 40 MICE OF BOTH SEXES OF MIXED SAITAMA STRAIN, WEIGHING ABOUT 20 G, FED RICE DIET CONTAINING 0.05, THEN 0.01, THEN 0.02% RHODAMINE 6G, 12 SURVIVED FOR 100 DAYS OR MORE AND 1 FOR 223 DAYS (TOTAL DOSE, 90.6 MG). NONE OF MICE DEVELOPED TUMORS. (WORKING GROUP NOTED HIGH MORTALITY AND SHORT DURATION OF EXPT.) [R13] *... MODERATELY INJURIOUS TO RABBIT EYE. [R9, 381] *COMMERCIAL RHODAMINE DYES 6G AND B INDUCE HIS+ REVERSION MUTATIONS IN SALMONELLA TYPHIMURIUM AND SINGLE-STRAND BREAKS IN CHINESE HAMSTER OVARY CELLS. AROCLOR 1254 INDUCED RAT LIVER HOMOGENATE (S9) IS NECESSARY FOR GENETIC ACTIVITY. FRAMESHIFT AND BASE SUBSTITUTION MUTATIONS NOTED. [R14] *IONIC CHARACTER AND PARTITION COEFFICIENT OF 7 FLUORESCENT XANTHENIC TRACERS (RHODAMINES B, 6G AND WT, SULFORHODAMINES B AND G, URANINE AND EOSINE) WERE DETERMINED. TOXICITY TOWARD DAPHNIA MAGNA AND LEBISTES RETICULATUS WAS SHOWN. A WEAK CORRELATION BETWEEN TOXICITY AND PARTITION COEFFICIENT WAS FOUND. [R15] *IN RAT LIVER MITOCHONDRIA, RHODAMINE 6G BLOCKED ATP-SUPPORTED CALCIUM(+2) ACCUM, BUT NOT THAT DRIVEN BY SUCCINATE OXIDN. CONCN OF GREATER THAN 20 MUMOLE UNCOUPLED RESP AND INHIBITED RESP CALCIUM(+2) UPTAKE. [R16] *F(0)F(1)ATPase activity and ADP translocation were measured on gestation day 12 in embryonic and adult mitochondria of mice following in vivo or in vitro exposure to Rhodamine 6G. ATP synthesis in embryonic mitochondria transplacentally exposed to Rhodamine 6G (0.5 mg/kg/day) given to dams by intraperitoneal injection from gestation day 7 to 10 were inhibited 49%. When isolated mitochondria were treated, dose dependent inhibition was seen: at 5 ug of dye/mg mitochondrial protein, ATP synthesis was inhibited 81% by Rhodamine 6G. When F(0)F(1)ATPase activity was assessed, in vitro Rhodamine 6G exposures at levels up to 8 ug/mg mitochondrial protein resulted in enzyme inhibition, but at 10 ug/mg, ATPase activity was stimulated. Uncoupler stimulated ATPase activity was also inhibited. ADP translocation was decreased by 37.7% by Rhodamine 6G at dye concentrations of 20 ug/mg. Results of in vitro exposure of maternal liver mitochondria were similar to those for embryonic mitochondria, whereas liver from dams exposed in vivo on gestation days 7 to 10 was unaffected on gestation day 12. [R17] *Rhodamine 6G was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation (S9). Rhodamine 6G gave a positive response in the absence of S9 in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y cells; in the presence of S9, rhodamine 6G was negative. Rhodamine 6G induced sister chromatid exchanges (SCEs) and chromosomal aberrations in cultured CHO cells in the presence, but not the absence, of S9. [R18] *Rhodamine 6G is a specific inhibitor of aerobic growth of yeast (Saccharomyces cerevisiae), and isolated rhodamine-6G-resistant mutants have been used to demonstrate extrachromosomal inheritance in yeast. [R19] *Positively charged dyes rhodamine 6G and rhodamine 123 inhibit heartbeat and kill Sprague-Dawley neonatal rat cardiac muscle cells in vitro but the neutral dyes rhodamine B and rhodamine 116 do not. Cationic rhodamine dyes, but not neutral dyes, inhibit oxidative phosphorylation in isolated mitochondria. Differences in the accumulation of rhodamine 123 and rhodamine 6G in cardiac and carcinoma cells were observed. Both dyes selectively inhibit the in vitro growth and in vivo growth. [R20] *At low rhodamine concentrations, ATP dependent calcium ion uptake is blocked (Ki= 3 uM); at concentrations greater than 20 uM, respiration becomes uncoupled and respiration dependent calcium ion uptake is inhibited. Rhodamine 6G inhibited H+ ejection from mitochondria energized with ATP or with succinate and postulated that inhibition sites of rhodamine 6G are on membrane components related to H+ ejection by oxidation/reduction components. Rhodamine 6G has also been found to inhibit the import and processing of matrix catalyzed mitochondrial proteins ... in isolated hepatoma ascites cells or normal hepatocytes (eg, cytochrome b-c1 complex subunits) from male Sprague-Dawley rats at concentrations that did not uncouple mitochondrial respiration. [R20] *Cationic rhodamines (Rh 123 and Rh 6G) can cause developmental toxicity in mice and inhibit embryonic mitochondrial respiration following in vivo or in vitro dye exposure. Rh B, a neutral rhodamine, fails to show such effects at comparable doses. To assess effects of rhodamines on development, F0F1ATPase activity and ADP translocation were measured on gestation day (GD) 12 in embryonic and adult mitochondria. ATP synthesis in embryonic mitochondria transplacentally exposed to Rh 123 (15 mg/kg/day) or Rh 6G (0.5 mg/kg/day) given to dams by ip injection from gestation day 7 to 10 were inhibited 39% and 49%, respectively. When isolated mitochondria were treated, dose-dependent inhibition was seen; at 5 ug of dye/mg mitochondrial protein, ATP synthesis was inhibited 65% and 81% by Rh 123 and Rh 6G, respectively. When F0F1ATPase activity was assessed, in vitro Rh 123 and Rh 6G exposures at levels up to 8 ug/mg mitochondrial protein resulted in enzyme inhibition, but at 10 ug/mg, ATPase activity was stimulated. Uncoupler-stimulate ATPase activity was also inhibited. ADP translocation was decreased by 19.1% and 37.7% by Rh 123 and Rh 6G, respectively, at dye concentrations of 20 ug/mg. Results of in vitro exposure of maternal liver mitochondria were similar to those for embryonic mitochondria, whereas liver from dams exposed in vivo on gestation day 7-10 was unaffected on gestation day 12. In vivo or in vitro treatment with Rh B did not affect any embryonic o maternal parameters. The results support the hypothesis that inhibition of mitochondrial energy metabolism is a mechanism for the developmental toxicity of cationic rhodamines. [R21] *Experiments were carried out to determine whether the mitochondria specific dye rhodamine-6G can affect transmission of cytoplasmic determinants in mammalian cells. When one parental cell type was treated with rhodamine-6G prior to fusion with an untreated partner, the subsequent hybridization frequencies in both intra- and interspecific crosses were not adversely affected even though rhodamine-6G was extremely toxic to the parental cells. Cells lethally treated with rhodamine-6G could be rescued by fusion with cytoplasm alone from untreated cells. [R22] *The effects of cationic and neutral rhodamines on the developing mouse were compared. Sexually mature virgin female CD-1-mice were mated with males of the same strain. Pregnant females were treated ip with rhodamine-123, rhodamine-B, or rhodamine-116 at 15 mg/kg/day. The rhodamines were given alone or combined with 500 mg/kg/day 2-deoxy-D-glucose. Dosing occurred on gestation days seven through ten. Other pregnant mice received rhodamine-6G at 0.5 mg/kg/day. Significant increases were noted in prenatal mortality when given rhodamine-6G either alone or combined with 2-deoxy-D-glucose. Fetal growth was inhibited by treatment with rhodamine-123 or rhodamine-6G with or without 2-deoxy-D-glucose. Little effect was noted on prenatal survival or growth when treated with neutral rhodamines. A high incidence of gross malformation was noted on exposure to rhodamine-6G with or without 2-deoxy-D-glucose. No significant teratogenic effects were noted following treatment with rhodamine-116 or rhodamine-B with or without 2-deoxy-D-glucose or with rhodamine-123 without 2-deoxy-D-glucose. Skeletal malformations were increased in the groups receiving rhodamine-6G plus 2-deoxy-D-glucose, rhodamine-123 plus 2-deoxy-D-glucose, and rhodamine-6G alone. The authors suggest a relationship may exist between the charge on the rhodamine molecule and effects on the conceptus. These effects may have been mediated partly by interference with mitochondrial metabolism. [R23] NTP: *Toxicology and carcinogenesis studies of rhodamine 6G were conducted ... by administering rhodamine 6G (greater than 95% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 2 years. Dietary concentrations selected for the 2 year studies were 0, 120, or 250 ppm rhodamine 6G for rats, 0, 1,000, or 2,000 ppm for male mice, and 0, 500, or 1,000 ppm for female mice. Under the conditions of these 2 year feed studies, there was equivocal evidence of carcinogenic activity for male F344/N rats administered rhodamine 6G, as indicated by a marginally increased incidence of integumentary keratoacanthomas. There was equivocal evidence of carcinogenic activity for female F344/N rats administered rhodamine 6G, as indicated by a marginal increase in pheochromocytomas or malignant pheochromocytomas (combined) of the adrenal gland. There was no evidence of carcinogenic activity for male B6C3F1 mice administered, 1,000 or 2,000 ppm rhodamine 6G in the diet. There was no evidence of carcinogenic activity for female B6C3D1 mice adminsitered 500 or 1,000 ppm rhodamine 6G in the diet. There were no significant nonneoplastic lesions attributed to rhodamine 6G administration to male or female rats or male or female mice. Male and female rats might have been able to tolerate a higher concentration of rhodamine 6G in the feed. [R24] ADE: *RHODAMINE 6G EXHIBITS HIGH PLASMA PROTEIN BINDING. [R12] *Rhodamine 6G and rhodamine B were reported to be excreted in the pancreatic juice in situ after intravenous infusion of 1 mg dye per minute to dogs (strain, age, and sex not specified) followed by the administration of secretin or cholecystokinin-pancreozymin stimulation. The rate of excretion was not reported. [R25] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Some important causes of occupational phototoxic or photoallergic reactions /are rhodamine dyes/. /Rhodaminedyes/ [R10] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Bottled water shall, when a composite of analytical units of equal volume from a sample is examined by the methods described in paragraph (d)(1)(ii) of this section, meet the standards of chemical quality and shall not contain chloride in excess of 250.0 mg/l. /Chloride/ [R26] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Dyes used in lipsticks, including rhodamine 6G, have been separated by thin-layer chromatography and identified by their absorption and fluorescene spectra or determined fluorimetrically. Thin layer chromatography on unactivated, precoated silica, using one solvent system, has been used to separate biological stains, including rhodamine 6G. The separated dyes were then identified by their nuclear magnetic resonance or visible spectra. Also gel permeation chromatography on Sephadex LH-20 resin has been used to separate and identify biological stains, including rhodamine 6G. [R13] *ANALYTICAL SEPARATION OF ROSE BENGAL (I) WAS CARRIED OUT BY HIGH PERFORMANCE LIQ CHROMATOGRAPHY. PREPARATIVE SEPN OF ROSE BENGAL WAS CARRIED OUT WITH PREPAK-500/C18 REVERSE PHASE COLUMN. SIMILARLY RHODAMINE 6G WAS SEPARATED. [R27] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: [DHHS/NTP; Toxicology and Carcinogenesis Studies of Rhodamine 6G (CI Basic Red 1) in F344/N Rats and B6C3F1 Mice (Feed Studies) 1989) Technical Rpt Series No.364 NIH Pub No.89-2819 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V24 665 (1984) R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 234 (1978) R3: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 864 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 235 (1978) R5: SRI R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. VI 268 R7: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 434 R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 71 (1987) R9: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R10: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 148 R11: Wiseman A et al; Somat Cell Mol Genet 11 (6): 541-56 (1986) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 237 (1978) R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 236 (1978) R14: NESTMANN ET AL; CANCER RES 39 (11): 4412 (1979) R15: BENOIT-GUYOD JL ET AL; TOXICOL EUR RES 2 (5): 241-6 (1979) R16: GEAR AR L; J BIOL CHEM 259 (11): 3628 (1974) R17: Ranganathan S, Hood RD; Terat Carc Mut 9 (1): 29-37 (1989) R18: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rhodamine 6G (CI Basic Red 1) in F344/N Rats and B6C3F1 mice (Feed Studies) p.4 (1989) Technical Rpt Series No.364 NIH Pub No. 89-2819 R19: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rhodamine 6G (CI Basic Red 1) in F344/N Rats and B6C3F1 Mice (Feed Studies) p.14 (1989) Technical Rpt Series No.364 NIH Pub No.89-2819 R20: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rhodamine 6G (CI Basic Red 1) in F344/N Rats and B6C3F1 Mice (Feed Studies) p.13 (1989) Technical Rpt Series No.364 NIH Pub No.89-2819 R21: Medoff-Cooper B, Verklan T; Teratogenesis Carcinog Mutagen 9 (1): 29-37 (1989) R22: Ziegler ML, Davidson RL; Somatic Cell Genet 7 (1): 73-88 (1981) R23: Hood RD et al; Teratology 40 (2): 143-50 (1989) R24: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rhodamine 6G (CI Basic Red 1) in F344/N Rats and B6C3F1 Mice (Feed Studies) p.3 (1989) Technical Rpt Series No. 364 NIH Pub No. 89-2819 R25: DHHS/NTP; Toxicology and Carcinogenesis Studies of Rhodamine 6G (CI Basic Red 1) in F344/N Rats and B6C3F1 Mice (Feed Studies) p.13 (1989) Technical Rpt Series No.364 NIH Pub No. 89-2819 R26: 21 CFR 103.35 (4/1/91) R27: PEEPLES WA II, HEITZ JR; CHROMATOGR SCI 12, ISS BIOL/BIOMED APPL LIQ CHROMATOGR 2, 437 (1979) RS: 21 Record 274 of 1119 in HSDB (through 2003/06) AN: 4181 UD: 200301 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-BUTANONE-PEROXIDE- SY: *2-BUTANONE,-PEROXIDE-; *BUTANOX-M-50-; *BUTANOX-M-105-; *BUTANOX-LPT-; *CHALOXYD-MEKP-HA-1-; *CHALOXYD-MEKP-LA-1-; *ETHYL-METHYL-KETONE-PEROXIDE-; *FR-222-; *HI-POINT-180-; *KAYAMEK-A-; *KETONOX-; *Lupersol-Delta-X-; *Lupersol-DDM-; *Lupersol-DEL-; *MEK-PEROXIDE-; *METHYL-ETHYL-KETONE-PEROXIDE-; *NCI-C55447-; *PERMEK-N-; *TRIGONOX-M-50- RN: 1338-23-4 MF: *C8-H16-O4 SHPN: UN 2550; Ethyl methyl ketone peroxide(s) max concn 45% or in soln with not more than 9% by wt active oxygen. UN 3068; Methyl ethyl ketone peroxide(s), not more than 40% in diisobutyl nylonate, with not more than 8.2% available oxygen. UN 2563; Methyl ethyl ketone peroxide(s), 52% or less in solution, not more than 10% available oxygen. IMO 5.2; Methyl ethyl ketone peroxide(s), 52% or less in solution, more than 10% available oxygen. UN 2127; Methyl ethyl ketone peroxide(s), maximum concentration 60% STCC: 49 191 78; Methyl ethyl ketone peroxide (in solution with not more than 9% by weight active oxygen) HAZN: U160; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Reaction of methyl ethyl ketone with hydrogen peroxide (peroxidation) [R1] FORM: *AVAIL AS 60% SOLN IN DIMETHYL PHTHALATE (LUPERSOL DDM) TO SERVE AS CATALYST FOR POLYMERIZING PLASTICS. [R2, p. II-107] *Lupersol DEL /is/ a trade mark for 60% methyl ethyl ketone peroxide in dimethyl phthalate; Lupersol DSW /is/ a proprietary trade name for methyl ethyl ketone. A liq fire resistant peroxide containing 11.5% active oxygen. [R3] *Lupersol Delta-X /is/ ketone peroxide in dimethyl phthalate diluent; Lupersol DNF /is/ ketone peroxide in proprietary diluent. [R4] *Diluents may be any combination of dimethyl phthalate, cyclohexanone peroxide, or diallylphthalate. These diluents provide a stable mixt which under ordinary handling cannot be detonated at room temp. [R5] *Liquid comprising 5-11% active oxygen content in dimethyl phthalate [R1] *Mixed product consisting of dimers (50%), trimers (25%), and monomeric peroxy compounds [R1] MFS: *Akzo America, Inc., Akzo Chemicals, Inc., 300 South Riverside Plaza, Suite 200, Chicago, IL 60606 (312) 906-7500; Production site: Burt, NY 14028 [R6, 745] *Elf Atochem North America, Inc., 2000 Market Street, 21st Floor, Philadelphia, PA 19103-3222, 215-419-7000; Production site: Geneseo, NY 14454 [R6, 475] *The Norac Co., Hq, 405 South Motor Ave., P.O. Box 577, Azusa, CA 91702 (626) 334-2908; Production site: Azusa, CA 91702; West Helena, AR 72390 [R6, 745] *Witco, Corp., One American Lane, Greenwich, CT 06831-2559 (203) 552-2000; Production site: Route 69, Marshall, TX 75670 [R6, 745] USE: *Manufacture of acrylic resins; hardening agent for fiberglass-reinforced plastics. [R7] *MEDICATION *Unsaturated polyester resin crosslinking agent [R1] *Used as a curing agent with polyester resins for adhesives, plastics, lacquers, and fiber glass resin kits for boat and automobile body repair. [R8, 562] CPAT: *CURING AGENT FOR UNSATURATED POLYESTER RESINS, 94%; OTHER USES, 6% (1980). [R9] PRIE: U.S. PRODUCTION: *(1978) 4.09X10+8 G [R9] *(1982) 2.68X10+9 G [R9] *(1985) 4.43X10+8 g. [R10] *(1992) 4,520,000 kg [R11] *(1993) 5,107,000 kg [R12] U.S. IMPORTS: *(1977) AT LEAST 4.54X10+5 G [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R7]; *Colorless liquid [Note: Explosive decomposition occurs at 230 degrees F]. [R13, 208] ODOR: *Typical odor-resembles that of acetone. [R14]; *Fragrant, mint-like, moderately sharp odor [R8, 562] BP: *19 deg C [R15] MW: *176.24 [R16] SOL: *Partially miscible in water; completely miscible with most organic solvents [R14] OCPP: *Strong oxidizing agent [R7] *Has a 10 hour half-life at 105 deg C [R1] *Molecular weights for the monomer, dimers, and trimers are 122.12, 210.22, and 298.34, respectively [R8, 561] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 2-butanone peroxide stem from its toxicologic properties and explosivity. Toxic by all routes (ie, inhalation, ingestion, dermal absorption), exposure to this colorless liquid may occur from its production or use as a curing agent for plastics and polyester resins, and as an initiator in the manufacture of polymers. Effects from exposure may include contact burns to the skin and eyes, hemolytic anemia, shortness-of-breath, or pulmonary edema. OSHA has established a Ceiling limit of 0.7 ppm as a final rule to become effective December 31, 1992. In activities and situations where over-exposure may occur, wear a self-contained breathing apparatus and personal protective clothing. If contact should occur, irrigate exposed eyes with copious amounts of water for at least 30 minutes, and exposed skin for at least 15 minutes. Contaminated clothing and shoes should be removed at the site. 2-Butanone peroxide may be ignited by heat, sparks, or flames; burning rapidly and producing poisonous gases. Containers of this substance may explode from friction, heat, mechanical shock, or contamination (such as from trace amounts of strong acids, bases, metals, metal alloys, salts, sulfur compounds, amines, accelerators, or reducing agents). For fires involving this substance, extinguish with dry chemical, CO2, regular foam, or water (used in flooding quantities for large fires). Fight fire from as far a distance as possible, in an explosion-resistant location. Isolate the area for 1/2 mile in all directions if a tank, rail car, or tank truck is involved. 2-Butanone peroxide should be stored in cool, ventilated areas, away from sunlight, sources of ignition, physical damage, shock, and organic or flammable materials. Smalls spills of this substance should be taken up with a noncombustible absorbent such as vermiculite and placed in a plastic container for immediate disposal. Wet down large spills with water and dike for later disposal. This substance is a good candidate for liquid injection, rotary kiln, or fluidized bed forms of incineration. DOT: +Fire or explosion: May explode from heat or contamination. May ignite combustibles (wood, paper, oil, clothing, etc.). May be ignited by heat, sparks or flames. May burn rapidly with flare-burning effect. Containers may explode when heated. Runoff may create fire or explosion hazard. [R17] +Health: TOXIC; inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns, or death. Contact of vapor or substance with eyes may cause blindness within minutes. Fire may produce irritating, corrosive and/or toxic gases. Toxic fumes or dust may accumulate in confined areas (basement, tanks, hopper/tank cars, etc.). Runoff from fire control or dilution water may cause pollution. [R17] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R17] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R17] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R17] +Fire: Small fires: Water spray or fog is preferred; if water not available use dry chemical, CO2, or regular foam. Large fires: Flood fire area with water from a distance. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Do not move cargo or vehicle if cargo has been exposed to heat. Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R17] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Keep combustibles (wood, paper, oil, etc.) away from spilled material. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Keep substance wet using water spray. Stop leak if you can do it without risk. Small spills: Take up with inert, damp, noncombustible material using clean non-sparking tools and place into loosely covered plastic containers for later disposal. Large spills: Wet down with water and dike for later disposal. Prevent entry into waterways, sewers, basements or confined areas. DO NOT CLEAN-UP OR DISPOSE OF, EXCEPT UNDER SUPERVISION OF A SPECIALIST. [R17] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. Remove material from skin immediately. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R17] FIRP: *In case of fire, water should be applied by the sprinkler system or by hose from a safe distance, preferably with a fog nozzle. Foam may be necessary instead if the peroxide is diluted in a low density flammable solvent. Portable extinguishers should not be used except for very small fires. Peroxides threatened by fire should be wetted from a safe distance for cooling. /Peroxides, Organic and Inorganic/ [R18, p. 104.350] EXPL: *... Shock sensitive peroxide precipitates can be formed if contaminated with acetone ... . [R19, 1611] REAC: *Vigorous decomp can be stimulated by even trace amt of a wide variety of contaminants, such as strong acids, bases, metals, metal alloys and salts, sulfur cmpd, amines, accelerators or reducing agents. This is particularly true of methyl ethyl ketone and benzoyl peroxides, which are intentionally stimulated to decomp @ room temp using small amt of accelerators. [R19, 1613] *Organic materials, heat, flames, sunlight, trace contaminants [Note: A strong oxidizing agent. Pure MEKP is shock sensitive. Commercial product is diluted with 40% dimethyl phthalate, cyclohexane peroxide, or daily phthalate to reduce sensitivity shock]. [R13, 208] SERI: *... Methyl ethyl ketone peroxide ... /is/ extremely irritating and corrosive to the eyes, with risk of blindness ... . [R19, 1613] EQUP: *PROTECTIVE EQUIPMENT ... COMPRISES SAFETY GOGGLES, APRONS OF NON-INFLAMMABLE MATERIAL OR RUBBER (AND NOT PLASTIC, WHICH MAY PRODUCE STATIC ELECTRICITY). RUBBER BOOTS SHOULD BE WORN OVER LEATHER FOOTWEAR. ALL THIS EQUIPMENT SHOULD BE CAREFULLY CLEANED AND AIRED AFTER POSSIBLE CONTAMINATION. /PEROXIDES/ [R20] *Wear appropriate personal protective clothing to prevent skin contact. [R13, 208] *Wear appropriate eye protection to prevent eye contact. [R13, 208] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R13, 208] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R13, 208] *Persons handling peroxides should use safety glasses with side shields, goggles or face shield for eye protection. Emergency eyewash facilities should be provided. Gloves, aprons and other protective clothing as necessary should be used to prevent skin contact. Clothing and equipment that generate static electricity should be avoided. Smoking should be prohibited. /Peroxides, Organic and Inorganic/ [R18, p. 104.350] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *Contact lenses should not be worn when working with this chemical. [R13, 208] *The worker should immediately wash the skin when it becomes contaminated. [R13, 208] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R13, 208] SSL: *UNSTABLE AGENT WHICH LIKE HYDROGEN PEROXIDE RELEASES OXYGEN. [R2, p. II-108] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R22] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R23] CLUP: *Spills should be cleaned up promptly using non-sparking tools and an inert, moist diluent such as vermiculite or sand. Sweepings may be placed in open containers or polyethylene bags and the area washed with water and detergent. Spilled, contaminated, waste or questionable peroxides should be destroyed. /Peroxides, Organic and Inorganic/ [R18, p. 104.350] *Most peroxides can be hydrolyzed by adding them slowly with stirring to about ten times their weight of cold 10% sodium hydroxide solution. The reaction may require several hours. /Peroxides, Organic and Inorganic/ [R18, p. 104.350] *Dilute and drain into the sewer with abundant water. /Hydrogen peroxide/ [R24] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U160, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R25] *A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R26] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Peroxides should be washed promptly from the skin to prevent irritation. In the case of eye contact, the eyes should be flushed immediately with large amounts of water, and medical attention should be obtained. ... Medical attention should also be obtained in case of accidental ingestion. ... /Peroxides, Organic and Inorganic/ [R18, p. 104.350] HTOX: *CONCN SOLN ARE CORROSIVE TO SKIN AND MUCOUS MEMBRANE. [R2, p. II-108] *ALL ... /PEROXIDE CATALYSTS/ ARE DANGEROUS TO SKIN AND IN PARTICULAR TO MUCOUS MEMBRANE OF EYE ... LIQ PEROXIDES CAN BE ABSORBED BY SKIN, PARTICULARLY METHYL ETHYL KETONE PEROXIDE, WHICH CAN CAUSE CERTAIN PHYSIOLOGICAL DISORDERS (HEMOLYTIC ANEMIA). [R20] *13 CASES OF ACUTE POISONING WITH KETONOX WERE DESCRIBED. THE EFFECTS OF POISON RESEMBLED THOSE OBSERVED AFTER POISONING WITH LYES OR ACIDS, WITH VOMITING AND GASTRIC MUCOSA DAMAGE INCLUDING NECROSIS. THE TOXIC ORAL DOSE WAS BETWEEN 50 and 100 ML. [R27] *... Severe eye hazard. [R19, 1611] *Suicidal ingestion of the peroxide of methyl ethyl ketone caused a severe metabolic acidosis, hemolysis, esophageal and gastric necrosis, gastric perforation, and death. [R28] *All 4 peroxides are irritants of the skin and mucous membranes; however, the effects of methyl ethyl ketone (MEK, or 2-butanone) and cyclohexanone peroxides are much greater than those of benzoyl and dicumyl peroxides. The relevance of studies on hemolytic effects of the peroxides to occupational exposure of man is uncertain, and there are no other conclusive reports of systemic toxic effects. [R29] *Fatal massive peripheral zonal hepatic necrosis developed in a 47 yr old man who accidentally ingested a solution of methyl ethyl ketone peroxide in dimethyl phthalate. Such solutions contain about 10% active oxygen. The clinical course was characterized by temporary cardiac arrest, abdominal burns, severe metabolic acidosis, rapid hepatic failure, rhabdomyolysis and respiratory insufficiency. A fatal outcome resulted 4 days afterwards from hepatic coma associated with blood coagulation disorders. Microscopical examination revealed massive periportal hepatic necrosis accompanied by atypical pseudoductular proliferation. The proliferating cells were probably of bile duct origin and exhibited atypia and mitoses. [R30] *This compound ... has a workplace exposure limit of 0.2 ppm (1.5 mg/cu m), which is a ceiling limit and should not be exceeded at any time during the work shift. It is a respiratory tract irritant and a severe eye and skin irritant. The maximum nonirritating strength for skin was 1.5%, for eyes 0.6%. Skin irritation was delayed, with erythema and edema appearing within 2 to 3 days. Eyes washed within 4 sec after exposure resulted in no adverse effects. However, it has been noted that single MEK peroxide exposures to the eye can exacerbate preexisting corneal and limbal disease. [R8, 562] *Human exposure attests to the corrosive nature of this compound, causing chemical burns of the gastrointestinal tract with residual scarring and stricture of the esophagus. Death 2 to 3 days later was due to hepatic failure after ingestion of this material. An oral dose of 50 to 100 ml is toxic and potentially lethal to adults. [R8, 562] *The main toxic effect of most peroxides is irritation of skin, mucous membranes and eyes. Prolonged or intense skin contact or splashes in the eyes may cause severe injury. /Peroxides, Organic and Inorganic/ [R18, p. 104.349] NTOX: *Methyl ethyl ketone peroxide ... /was/ tested by applying two drops of 40% solution in dimethyl phthalate to rabbit eyes, and ... found to cause severe damage, graded 6 on a scale of 0 to 7. (The solvent was not significantly injurious.) At 3% a moderate reaction occurred lasting for two days, followed by rapid improvement. Washing the eyes with water within four seconds after application prevented injury of the eye in all cases. [R31] *On repeated thrice weekly dosing of rats for 7 wk ip and by mouth at one-fifth the LD50, marked evidence of cumulative effect was observed; 2 of 5 rats died from the ip admin, all 5 died by the oral route... Hyperemia of the lungs with petechiae and gross hemorrhages were common and only findings in the lung of rats exposed for 4 hr to methyl ethyl ketone peroxide vapor. In the liver, occasional damage consisting of fatty changes in cells in the central portion of the lobule and incr in number of round cells in the portal spaces; in the kidney, a granula precipitate or cast in the lumina of the convuluted tubules and desquamation of the epithelium of the proximal tubules. [R5] *Embryotoxicity studies were conducted in 3 day old chicken embryos using the air chamber method. The potencies were expressed by the ED50 for the total embryotoxic effect of the chemicals, including deaths and malformations, up to day 14 of the incubation. All nine peroxides including methyl ethyl ketone peroxide caused malformations at a moderate frequency. [R32] *In vitro damage by methyl ethyl ketone peroxide to cytochrome p450 and its associated enzymatic activity was studied. The extent of methyl ethyl ketone peroxide inhibition was different for tetramethylphenylenediamine-peroxidase, NADH-peroxidase, and aminopyrine demethylase. In vitro addition of methyl ethyl ketone peroxide induced production of more thiobarbituric acid reacting substances in liver microsomes from vitamin E deficient rats than from vitamin E supplemented rats. When NADH and/or NADPH were supplied as reductants of methyl ethyl ketone peroxide, the inhibition of aminopyrine demethylase activity and the generation of thiobarbituric acid reacting substances by added methyl ethyl ketone peroxide were markedly reduced. [R33] *Rats fed a vitamin E deficient diet from age 3-10 weeks were either maintained on a vitamin E deficient diet or fed a vitamin E enriched diet for 8 subsequent weeks. The content of vitamin E, endoperoxide derived malonaldehyde, lipofluorescent material and polyunsaturated fatty acids, and the activities of catalase, glutathione reductase, and glutathione peroxidase were then measured in cerebral tissues, with or without intoxication with methyl ethyl ketone peroxide. For this purpose, one half of the animals in each vitamin E group received a ip injection of 5 mg methyl ethyl ketone peroxide per kg of body weight, which was followed 44 hr later, ie, 4 hr before sample collection, by a second ip injection of 15 mg methyl ethyl ketone peroxide per kg of body weight. Despite the fact that the vitamin E concentration was twelve times lower in the brain of vitamin E deficient rats, no significant changes in other cerebral parameters was found between the two groups of animals. In contrast, the activity of selenium glutathione peroxidase was markedly decrease in the liver of 10 week old vitamin E deficient rats. Unexpectedly, acute systemic intoxication with methyl ehtyl ketone peroxide caused only a small, albeit significant, decrease in glutathione reductase activity in the brain of vitamin E sufficient rats, while no significant change in other cerebral parameters was observed in either group of animals. [R34] *A dose of 0.29 umol/egg caused early deaths in 50% of treated eggs /3 day old chicken embryos/ and malformations in 40% of the survivors. The authors classified MEK peroxide as a moderately potent embryo toxin. However, the relevance of these data in relation to humans is unknown. The test method applied solutions directly to the inner membrane, focusing it on the embryo. It is unlikely these data can be accurately extrapolated to humans owing to the direct delivery of the dose. [R8, 562] *Subchronic oral exposures three times a week for 7 weeks at one fifth the LD50 caused all five rats to die. Necropsy revealed mild liver damage with glycogen depletion. These data suggest accumulation of the material in the body. [R8, 562] NTXV: *LD50 Rat oral 6.86 ml/kg; [R35] *LC50 Mouse /inhalation/ 170 ppm/4 hr; [R5] *LC50 Rat /inhalation/ 200 ppm/4 hr; [R5] *LD50 Rat ip 65 mg/kg; [R5] *LD50 Rat oral gavage 484 mg/kg; [R5] POPL: *Individuals with eye, skin, and chronic respiratory diseases /may be/ at an increased risk. /Hydrogen peroxide/ [R36] METB: *The stability of glutathione peroxidase was assessed in vivo via oxidative inactivation by methyl ethyl ketone peroxide. The stability of glutathione peroxidase was compared to other enzymes. Some of the enzymes tested were very stable to methyl ethyl ketone peroxide. Glutathione peroxidase in the absence of glutathione was relatively slowly inactivated. Thus, glutathione peroxidase appears to be a relatively stable enzyme and is well suited to perform its role in peroxide detoxification and prevention of oxidative deterioration of cells. [R37] INTC: *Vitamin E, selenium, vitamin C, and methionine were admin to rats in various combinations by diet and ip injections to rank the individual and combined protective ability of the biological antioxidants at minimum daily requirement levels and at pharmacological levels against lipid peroxidation initiated by 50 mg methyl ethyl ketone peroxide (MEKP)/kg. In vivo lipid peroxidation was monitored throughout a 3 hr period by measuring pentane expired in the breath. Rats fed 30 IU DL-alpha-tocopherol acetate/mg diet significantly decreased pentane production at 20 min by 88% compared to rats fed a vitamin E- and selenium-deficient diet. Rats given 5 ip injections of 180 IU DL-alpha-tocopherol acetate/kg further reduced expired pentane by 83% beyond the protection afforded by dietary vitamin E. Neither additive nor synergistic protection was found when other antioxidants were given in combination with vitamin E. Vitamin E was primary protective antioxidant. Pentane expired by individual rats from various treatment groups strongly correlated with the plasma vitamin E status. [R38] *Male Sprague-Dawley rats were fed 0, 3, 5 or 10 IU of DL-alpha-tocopherol acetate per kg of diet for 12 wk. After 11 weeks they were injected with 3.3 mg of methyl ethyl ketone peroxide (MEKP)/kg body wt and after 12 wk with 13 mg methyl ethyl ketone peroxide/kg body wt 3-4 hr before decapitation. In the absence of vitamin E, rat brain DNA was significantly damaged by the formation of DNA-protein crosslinks and interstrand DNA crosslinks. Adequate dietary vitamin E protected against this damage. 10 IU/kg was the adequate dose. [R39] *In vivo, methyl ethyl ketone peroxide damaged microsomal cytochrome p450 and chytochrome p450 mediated peroxidase in vitamin E-deficient rat liver. Dietary vitamin E treatment of rats protected the microsomal enzymes from peroxide damage. In vivo, adequate levels of vitamin E and of NADH and NADPH are probably necessary to provide important protection to the endoplasmic reticulum during metabolism of methyl ethyl ketone peroxide. [R33] *The tumor promoting effect of methyl ethyl ketone peroxide and the influence of diethyl maleate on this effect, with ultraviolet radiation as the tumor initiator, was studied in hairless albino mutant mice. Four groups of 24 animals were irradiated with ultraviolet light at a daily dose of 2,054 Joules/sq m, 5 days per week. Three weeks after completion of irradiation, the animals received skin applications twice weekly for 25 weeks of either 1 microgram per microliter diethyl maleate in acetone, acetone alone followed by 0.5 microgram per microliter methyl ethyl ketone peroxide in dibutyl phthalate, or dibutyl phthalate alone. Other groups of animals were treated with chemicals without ultraviolet light pretreatment. The animals were killed after 46 weeks and examined for tumors. The great majority of animals with tumors were in the irradiated groups. The highest tumor yield occurred in mice exposed to both dibutyl phthalate and methyl ethyl ketone peroxide after untraviolet light. Dibutyl maleate alone had no measureable effect on the development of tumors. Methyl ethyl ketone peroxide produced an increase in tumor prevalence, but the effect was less marked than in the combined presence of methyl ethyl ketone peroxide and diethyl maleate. [R40] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Butanone peroxide's use in the production of unsaturated polyester resin crosslinking agents, and also its use as a curing agent with polyester resins for adhesives, plastics, lacquers, and fiber glass resin kits for boat and automobile body repair, may result in its release to the environment through various waste streams. 2-Butanone peroxide is a mixture dimers (50%), trimers (25%), and monomer peroxy compounds. If released to air, estimated vapor pressures ranging between 1.4X10-3 and 2X10-3 mm Hg at 25 deg C indicate 2-butanone peroxide will exist solely in the vapor-phase. Vapor-phase 2-butanone peroxide will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-lives for this reaction in air are estimated to range between 1.5 and 2 days. 2-Butanone peroxide may react with organic materials in water or soil since it is a strong oxidizing agent. If released to soil, 2-butanone peroxide's mobility is expected to range from very high, to essentially immobile based upon an estimated Koc range of 10 to 11,000. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant range of 1X10-10 to2X10-8 atm-cu m/mole. If released into water, some portions of the 2-butanone peroxide mixture are expected to adsorb to suspended solids and sediment based upon the higher values of the estimated Koc range. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's range of estimated Henry's Law constants. An estimated BCF of 13 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to 2-butanone peroxide may occur through inhalation and dermal contact with this compound at workplaces where 2-butanone peroxide is produced or used. Consumer exposure may occur during the use of fiber glass resin kits for boat and automobile repair. (SRC) ARTS: *2-Butanone peroxide's use in the production of unsaturated polyester resin crosslinking agents(1), and also its use as a curing agent with polyester resins for adhesives, plastics, lacquers, and fiber glass resin kits for boat and automobile body repair(2), may result in consumer exposure and its release to the environment through various waste streams(SRC). 2-Butanone has been qualitatively detected in ambient air samples collected in the vicinity of a fiberglassing plant(3), which suggests that the compound can be emitted to the atmosphere at sites where it is produced or used in the production of polymers(SRC). [R41] FATE: *TERRESTRIAL FATE: 2-Butanone peroxide is a mixture of dimers (50%), and trimers (25%), and monomer peroxy compounds(5). Based on a classification scheme(1), an estimated Koc range of 10 to 11,000(SRC), determined from a structure estimation method(2), indicates that 2-butanone peroxide's mobility in soil is expected to range from very high, to essentially immobile based upon an estimated Koc range of 10 to 11,000(SRC). Volatilization of 2-butanone peroxide from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant range of 1X10-10 to 2X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(3). 2-Butanone peroxide is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure range of 1.4X10-3 to 2X10-3 mm Hg(SRC), determined from a fragment constant method(4). [R42] *AQUATIC FATE: 2-Butanone peroxide is a mixture dimers (50%), trimers (25%), and monomer peroxy compounds(8). Based on a classification scheme(1), an estimated Koc range of 10 to 11,000(SRC), determined from an estimation method(2), indicates that some portions of 2-butanone peroxide mixture are not expected to adsorb to suspended solids and sediment(SRC), other portions of the mixture are expected to adsorb strongly. 2-Butanone peroxide may react with organic materials in water expected(3) based upon estimated Henry's Law constants ranging between 1X10-10 and 2X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 13(SRC), from an estimated log Kow of 2(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. [R43] *ATMOSPHERIC FATE: 2-Butanone peroxide is a mixture dimers (50%), trimers (25%), and monomer peroxy compounds(4). According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), the 2-butanone peroxide mixture, which has estimated vapor pressures ranging between 1.4X10-3 and 2X10-3 mm Hg at 25 deg C(SRC), determined from a fragment constant method(2), is expected to exist solely in the vapor-phase in the ambient atmosphere. Vapor-phase 2-butanone peroxide is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to range from 1.5 to 2 days(SRC), calculated from its rate constant range of 9X10-12 to 11X10-12 cu cm/molecule-sec at 25 deg C(SRC)determined using a structure estimation method(3). [R44] ABIO: *2-Butanone peroxide is a mixture dimers (50%), trimers (25%), and monomer peroxy compounds(5). The rate constant for the vapor-phase reaction of 2-butanone peroxide with photochemically-produced hydroxyl radicals has been estimated to range between 9X10-12 and 11X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to atmospheric half-lives of approximately 1.5 to 2 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). 2-Butanone peroxide is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(2) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum. Normal heating decomposes 2-butanone peroxide at approximately 120 deg C(3). 2-Butanone peroxide is a strong oxidizing agent and contact with organic materials(4). [R45] BIOC: *An estimated BCF of 13 was calculated for the 2-butanone peroxide mixture(SRC), using an estimated log Kow of 2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. Chemical degradation is expected to be the dominant fate process in water because of reaction with organic matter and therefore, it is doubtful that un-reacted 2-butanone peroxide would be biologically available(SRC). [R46] KOC: *2-Butanone peroxide is a mixture dimers (50%), trimers (25%), and monomer peroxy compounds(3). Using a structure estimation method based on molecular connectivity indices(1), the Koc for 2-butanone peroxide can be estimated to range from 10 to 11,000(SRC). According to a classification scheme(2), this estimated Koc range suggests that some portions of the 2-butanone peroxide mixture are expected to have very high mobility in soil, whereas other portions of the mixture are expected to be essentially immobile. 2-Butanone peroxide is a strong oxidizing agent(3) and may decompose when brought in contact with organic materials(SRC). [R47] VWS: *2-Butanone peroxide is a mixture dimers (50%), trimers (25%), and monomer peroxy compounds(3). The Henry's Law constant for 2-butanone peroxide is estimated as a range of 1X10-10 to 2X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant range indicates that 2-butanone peroxide is expected to be essentially nonvolatile. 2-Butanone peroxide is not expected to volatilize from dry soil surfaces(SRC) based upon estimated vapor pressures ranging between 1.4X10-3 and 2X10-3 mm Hg(SRC), determined from a fragment constant method(2). [R48] ATMC: *SOURCE DOMINATED: 2-Butanone peroxide has been qualitatively detected in ambient air samples collected in the vicinity of a fiberglassing plant(1). [R49] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 16,366 workers are potentially exposed to 2-butanone peroxide in the US(1). Analysis of 35 air samples collected in the working environments of 5 Swedish plants manufacturing reinforced plastics detected 2-butanone peroxide in 13 samples above the detection limit (0.1 mg/cu m) with a maximum concn of 72 mg/cu m(2). Occupational exposure to 2-butanone peroxide may occur through inhalation and dermal contact with this compound at workplaces where 2-butanone peroxide is produced or used(SRC). Consumer exposure may occur during the use of fiber glass resin kits for boat and automobile repair(4). [R50] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: *Vacated 1989 OSHA PEL Ceiling limit 0.7 ppm (5 mg/cu m) is still enforced in some states. [R13, 368] NREC: *Recommended Exposure Limit: Ceiling Value: 0.2 ppm (1.5 mg/cu m). [R13, 208] TLV: *Ceiling limit 0.2 ppm [R51] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R52] RCRA: *U160; As stipulated in 40 CFR 261.33, when 2-butanone peroxide, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R53] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NIOSH Method 3508. Determination of Methyl Ethyl Ketone Peroxide by Visible Absorption Spectrophotometry. [R54] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Anon; Scientific Basis for Swedish Occupational Standards. VI, Arbetarskyddsstyrelsen, Publikationsservice, 171 84 Solna, Sweden, 133p (1985). ... Compilation of consensus reports on the physical, chemical and toxicological properties and methods of determination of potentially hazardous substances. DHHS/NTP; NTP Technical Report on Toxicity Studies of Methyl Ethyl Ketone Peroxide in Dimethyl Phthalate Administered Topically to F344/N Rats and B6C3F1 Mice NTP TOX 18 (1993) NIH Pub No. 93-3341 SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 583 R2: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R3: Gardner, W., E.I. Cooke and R.W.I. Cooke (eds.). Handbook of Chemical Synonyms and Trade Names. 8th ed. Boca Raton, Florida: CRC Press, Inc., 1978. 430 R4: Ash, M. and I. Ash. Encyclopedia of Industrial Chemical Additives. Vols 1, II, III. New York, NY: Chemical Publishing Co., Inc., 1984-1985.,p. V1 386 R5: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.396 R6: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. R7: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 737 R8: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R9: SRI R10: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.268 R11: United States International Trade Commission; Synthetic Organic Chemicals--United States Production and Sales, 1992. USITC. Publication 2720, February 1992. Washington, DC: United States Trade Commission, p. 3-54 (1992) R12: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-54 R13: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R14: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA4 (85) 476 R15: Dixon D, Rissmann E; Physical-Chemical Properties and Categorization of RCRA Wastes According to Votality. US USEPA-450/3-85-007 (NTIS PB85-204527), Springfield, VA: Versar, Inc. p. 35 (1985) R16: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 85/8408 R17: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-147 R18: International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998. R19: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R20: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 145 R21: 49 CFR 171.2 (7/1/96) R22: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 179 R23: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.5185,5186,5186-1 (1988) R24: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 278 R25: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R26: USEPA; Engineering Handbook for Hazardous Waste Incineration p. 3-14 (1981) EPA 68-03-3025 R27: WOJDYLA Z ET AL; ARCH MED SADOWEJ KRYMINOL 29 (3): 199-205 (1979) R28: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 1000 R29: Aringer L; Arbetarskyddsstyrelsen, Publikationsservice, 171 84 Solna, Sweden, 64 pp. (1985) R30: Karhunen PJ et al; Hum Exp Toxicol 9 (3): 197-200 (1990) R31: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 618 R32: Korhonen A et al; Environ Res 33 (1): 54-61 (1984) R33: Ando M, Tappel AL; Chem Biol Interact 55 (3): 317-26 (1985) R34: Chaudiere J et al; Neurotoxicology 9 (2): 173-9 (1988) R35: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 956 R36: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.1 R37: Condell RA, Tappel AL; Arch Biochem Biophys 223 (2): 407-16 (1983) R38: Litov RE et al; Toxicol Appl Pharmacol 59 (1): 96-106 (1981) R39: Summerfield FW, Tappel AL; Mutat Res 126 (2): 113-20 (1984) R40: Logani MK et al; Food Chem Toxicol 22 (11): 879-882 (1984) R41: (1) Ashford RD; Ashford's Dictionary of Industrial Chemicals: Properties, Production, Uses; London, England: Wavelength Publ, Ltd p.583 (1994) (2) Harris RL et al, eds; Patty's Industrial Hygiene and Toxicology. 3rd ed NY, NY: John Wiley and Sons Inc, 3A: 562 (1994) (3) US EPA; Statement of Research Needs for Methyl Ethyl Ketone Peroxide. Contract No. 68-C8-0004 (Task 122). US EPA-ECAO, Cincinnati, OH (1989) R42: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (5) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publ, Ltd p. 583 (1994) R43: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publ, Ltd p. 583 (1994) R44: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publ, Ltd p. 583 (1994) R45: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (3) Manly, TD; Industrial Chemist 32: 271-6 (1956) (4) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary, 13th ed. NY, NY: Van Nostrand Reinhold Co. p. 737 (1997) (5) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publ, Ltd p. 583 (1994) R46: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R47: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed. NY, NY: John Wiley and Sons, Inc. p. 737 (1997) (3) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publ, Ltd p. 583 (1994) R48: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Ashford RD; Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publ, Ltd p. 583 (1994) R49: (1) US EPA; Statement of Research Needs for Methyl Ethyl Ketone Peroxide. Contract No. 68-C8-0004 (Task 122). US EPA-ECAO, Cincinnati, OH (1989) R50: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Bachs A, Runmark S; Inst Vatten-Luftvaardsforsk., Publ. IVL B 836 (1986) (3) Manly, TD; Industrial Chemist 32: 271-6 (1956) (4) Galvin JB, Farr C; Patty's Indust Hyg Toxicol. 4th. Clayton GC, Clayton FE, eds. NY, NY: Wiley IIA: 562 (1993) R51: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 49 R52: 40 CFR 302.4 (7/1/99) R53: 40 CFR 261.33 (7/1/99) R54: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 49 Record 275 of 1119 in HSDB (through 2003/06) AN: 4182 UD: 200302 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HC-BLUE-NO-1- SY: *ETHANOL, 2,2'-((4-(METHYLAMINO)-3-NITROPHENYL)IMINO)BIS-; *ETHANOL, 2,2'-((4-(METHYLAMINO)-3-NITROPHENYL)IMINO)DI-; *HC-BLUE-NUMBER-1- RN: 2784-94-3 MF: *C11-H17-N3-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HC Blue No. 1 was produced commercially by the reaction of 4- fluoro-3-nitrobenzenamine with ethylene oxide to form 2,2-[(4- fluoro-3-nitrophenyl)-imino]bis(ethanol); this intermediate was reacted with methylamine to form HC Blue No. 1. [R1] IMP: *Has been available commercially with purity 95%, with 2-((4- methylamino)-3-nitrophenyl)imino)ethanol (< 5%) as a possible impurity [R2, (1993)] MFS: *NOT CURRENTLY PRODUCED COMMERCIALLY IN US [R3] OMIN: *Not known to be produced or used currently anywhere in the world. Production and use began in the late 1960s and was discontinued in the mid-1980s [R1] *The concentration of HC Blue No. 1 used in hair colouring products ranged from 1-2%. [R1] USE: *Was used exclusively as a dye in semi-permanent hair coloring products. /Former/ [R1] CPAT: *Approximately 20,000-30,000 pounds of HC Blue No. 1 /were/ used annually. [R4] *In the early 1980s, approximately 6-8 tons of HC Blue No. 1 were used annually in the USA, according to industry estimates. [R1] PRIE: U.S. PRODUCTION: *(1975) 4.54X10+6-9.08X10+6 G (CONSUMPTION) [R3] *(1979) NOT PRODUCED COMMERCIALLY IN US [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Dark-blue microcrystals or blue-black amorphous powder [R2, (1993)] MP: *101.5-104 deg C [R2, (1993)] MW: *255.27 OWPC: *Octanol/water partition coefficient = 17.2 [R2, (1993)] SOL: *Slightly soluble in water (0.38% w/w); soluble in ethanol, methanol and acetone [R2, (1993)] SPEC: *Infrared, ultraviolet and nuclear magnetic resonance spectral data have been reported [R2, (1993)] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R5, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R5, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R5, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R5, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R5, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R5, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R5, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R5, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R5, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R5, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R5, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R5, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R5, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R5, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R5, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R5, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R5, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R5, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R5, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. [R6] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R5, 1979.23] NTOX: *Two groups of 48 female B6C3F1 mice, six weeks of age, were fed 0.3% (3000 mg/kg of diet) (ppm) highly purified HC Blue No. 1 or recrystallized, charcoal-filtered commercial HC Blue No. 1 in the diet for 24 months. One group of 48 female mice served as controls. Highly purified HC Blue No. 1 increased the incidences of hepatocellular adenomas (10/46 versus 1/48 controls) and of hepatocellular carcinomas (41/46 versus 2/48 controls), as did commercial HC Blue No. 1 (hepatocellular adenomas: 10/46 versus 1/48 controls; hepatocellular carcinomas: 44/46 versus 2/48 controls). Three additional groups of 24 or 48 females received 0.3% recrystallized, charcoal-filtered commercial HC Blue No. 1 in the diet for nine months followed by 15 months without treatment, for 15 months in the diet followed by nine months without treatment or every other week for 24 months. All three treatment regimens resulted in an increase in the number of mice with benign and malignant hepatocellular tumors. [R7] *Commercial samples of HC Blue No. 1 induced mutation in Salmonella typhimurium and mutations at both the hprt locus of cultured Chinese hamster ovary cells and the tk locus of mouse lymphoma L5178Y cells in contrast, purified samples did not induce mutation in Salmonella typhimurium, Escherichia coli, Saccharomyces cerevisiae, Schizosaccharomyces pombe or Drosophila melanogaster or at the hyrt locus of Chinese hamster V79 cells; a weak resposne was, however, obtained at the tk locus of mouse lymphoma L5178Y cells, The negative result in Salmonella were obtaned at doses of the pruifed material up to 50 fold higher than the effective does needed when commercial HC Blue No. 1 samples were tested. [R8] *Purified and commercial HC Blue No. 1 preparation induced unscheduled DNA synthesis in primary cultures of rat hepatocyte. Purified samples were fund to induce unscheduled DNA synthesis in primary cultures of mouse, Syrian hamster, rabbit and rhesus money hepatocyte. [R8] *Sister chromatid exchange frequency was increased in cultured Chinese hamster ovary cells exposed to purified and commercial HC Blue No. 1 and in primary cultures of mouse hepatocyte exposed to a commercial preparation. Chromosomal aberrations were induced in primary mouse but not rat hepatocyte cultures by commercial HC Blue No. 1. A commercial HC Blue No. 1 preparation increased the frequency of chromosomal aberrations in Chinese hamster ovary cells in vitro in the presence of a metabolic activation system, whereas one study with purified HC Blue No. 1 showed no increase in chromosomal aberrations; however in the latter study, it was tested at a lower concentration and only in the absence of an exogenous metabolic activation system. A commercial HC Blue No. 1 was reported not in induce micronuclei transformation of Syrian hamster embryo cells. [R8] *Purified HC Blue No. 1 induced micronuclei in the bone marrow of female ICR mice exposed in vivo intraperitoneal but did not increase the frequency in the bone marrow of male CBA, male or female CD-1 or male ICR mice. A commercial sample of HC blue No. 1 (97%) did not induce micronuclei in male or female B6C3F1 mice exposed by oral administration. [R9] *Commercial HC Blue No. 1 inhibited gap-junctional intercellular communication in Chinese hamster lung V79 cells a non-cytotoxic doses. [R9] *The compound N-methyl-amino-2-nitro-4-N',N'-bis(2-hydroxyethyl)-aminobenzene was tested for mutagenic activity in the sex-linked recessive lethal test with Drosophila melanogaster, the induction of chromosomal aberrations and sister-chromatid exchanges with Chinese hamster ovary cells in vitro and the micronucleus test with mouse bone-marrow cells in vivo. Consistently negative results were obtained with the 3 tests. The sister chromatid exchange tests gave positive results with prolonged treatments. It is concluded that reliable decisions about mutagenic activity cannot be based on the induction, in vitro, of sister chromatid exchanges alone. [R10] *Commercial HC Blue No. 1 and its analogues HC Red No. 3 and HC Blue No. 2 are all mutagenic in the Ames test but only the HC Blue No. 1 is carcinogenic in animals. A carcinogenicity study in mice was carried out on both a commercial sample of HC Blue No. 1 and a highly purified sample which was negative in a battery of short-term tests for mutagenic activity. Both samples, administered at 0.3% in the diet for up to 24 months, were carcinogenic to mice, inducing hepatocellular carcinomas in greater than or equal to 89% of the mice examined. Therefore the presence of mutagenic impurities is not responsible for the carcinogenicity of commercial HC Blue No. 1. [R11] *In the present study ... the separation of the mutagenic impurities from the nitrophenylenediamine hair dye HC Blue 1 /has been reported/ This was accomplished by bioassay directed HPLC fractionation, using Salmonella strain TA98 and reverse phase HPLC analysis. The mutagenic fraction eluted between 80 and 90% methanol, whereas the HPLC fraction containing the parent compound HC Blue 1 eluted with 30% methanol and was non-mutagenic. 100% of the mutagenic activity applied to the column was recovered in fractions that did not possess the blue color of HC Blue 1. Also, HPLC-purifled HC Blue 1 did not form DNA adducts (32)P-postlabeling) in Salmonella strain TA98. On the other hand, commercial HC Blue 1 and the mutagenic fraction derived from commercial HC Blue 1 (HPLC-isolated) gave similar DNA-adduct profiles that consisted of 7 adducts. DNA adduction was examined concomitantly with mutagenicity and toxicity studies on the HC Blue 1 samples in TA98. The data indicated that, in Salmonella, both the mutagenicity and DNA adduction of commercial HC Blue 1 are due to impurities and not the parent compound. [R12] *The genotoxicity of two nitrophenylenediamine based hair dyes was examined in vitro. Hair color blue number l and hair color blue number 2 were incubated with primary hepatocytes from male Fischer 344 rats, B6C3F1 mice, Syrian hamsters, New Zealand white rabbits, and Rhesus monkeys at concentrations up to 500 ug/ml. The extent of unscheduled DNA synthesis was determined. Hair color blue number 1 induced unscheduled DNA synthesis in hepatocytes of all species. Rat and mouse hepatocytes indicated a stronger response than monkey hepatocytes. Hair color blue number 2 induced a dose dependent increase in unscheduled DNA synthesis in rat, mouse, hamster, and rabbit hepatocytes, but not monkey hepatocytes. The magnitude of the response was always less than that of hair color blue number 1. Hair color blue number 1 has been identified as a carcinogen in a National Toxicology Program (NTP) bioassay. Hair color blue number 2 has been identified as a noncarcinogen by the NTP. The formation of a primary amine from hair color blue number 1 appears to be relatively easier than from hair color blue number 2. [R13] *Blue 1 induced heptocellular carcinomas in B6C3Fl mice whereas the structurally similar nitroaromatic amine HC Blue 2 did not. ... To elucidate the biochemical mechanisms responsible for their different carcinogenic potencies, comparative metabolism and genetic toxicity studies were undertaken. Eighteen-hour urinary recovery of administered radioactivity was equivalent for both compounds following oral gavage (lOO mg/kg) in female B6C3Fl mice. HC Blue 1 yielded 3 major polar metabolite peaks, one of which was susceptible to glucuronidase. In vivo metabolism of HC Blue 2 yielded a single major metabolite peak which was not hydrolyzed by glucuronidase. Metabolism by B6C3Fl mouse hepatocytes yielded metabolite profiles which were qualitatively similar to the profiles observed after in vivo metabolism. HC Blue 1 was metabolized by hepatocytes at approximately twice the rate of HC Blue 2. Cytogenetic evaluations of mouse hepatocytes after in vitro treatment indicated HC Blue 1 was more potent than HC Blue 2 in inducing chromosomal aberrations while both chemicals showed weak activity for inducing sister-chromatid exchanges. Furthermore, in the V79 cell metabolic cooperation assay, HC Blue 1, but not HC Blue 2, inhibited cell-to-cell communication suggesting a on-genotoxic activity may be present for HC Blue 1. ... Qualitative and quantitative differences exist in the metabolism of these compounds and genotoxic as well as nongenotoxic effects may contribute to their different carcinogenic potencies. [R14] *Toxicology and carcinogenesis studies of 2 structurally-related p-phenylelediamines HC Blue No. 1 and HC Blue No. 2 were conducted by administering each chemical in feed for 103 weeks to both sexes of Fischer 344/N rats and B6C3Fl (C57BL/6N x C3H/HEN) mice. Diets containing 0, 1500, or 3000 ppm HC Blue 1 were fed to male and female rats and male mice; female mice received diets with 0, 3000, or 6000 ppm. Diets containing 0, 5000, or 10,000 ppm HC Blue 2 were fed to male rats and mice and the females received diets containing 0, 10,000 or 20,000 ppm. These concentrations were compatible with long-term growth and survival. Substantial differences occurred in the neoplastic and non-neoplastic lesions caused by these structural analogs. HC Blue 2 caused histocytosis in lungs and hyperostosis of the skull in rats and splenic hematopoiesis fibrous osteodystrophy and hyperostosis of the skull in mice. These non-neoplastic lesions were not observed in rats or mice treated with HC Blue 1. In male and female mice HC Blue 1 produced dose-related increases in the incidences of both adenomas and carcinomas of the liver. HC Blue 1 produced a marginally positive trend in hepatocellular nodules and carcinomas in male rats and dose-related increases in hyperplasias and neoplasms of the lungs in female rats. In contrast, there was no evidence of carcinogenicity for HC Blue 2 in either sex of rats or mice despite the fact that it was administered 3-5 times the dose of the HC Blue 1. These 2 nitroaromatic compounds differ only in the methyl vs. 2-hydroxyethyl substituent on the secondary amine of ring carbon 4. [R15] *The hair-dye ingredients HC Blue No. 1 and HC Blue No. 2 were tested for the induction of bacterial mutation using Salmonella typhimuriun strains TA1535, TA1537, TA98 and TA100; and Escherichia coli strains WYP2uvrA-. In addition both dyes were evaluated in the mouse lymphoma L5178Y TK+/- assay for the potential to induce forward mutation. A liver homogenate (S9) prepared from Aroclor 1254-induced male Fischer 344 rats was used for metabolic activation. HC Blue No. 1 was not mutagenic in the Ames assay but was weakly mutagenic in the mouse lymphoma L5178Y TK+/- assay only in the presence of metabolic activation. In contrast, HC Blue No. 2 was a strong mutagen in the Ames assay in tester strain TA98 both in the presence and absence of metabolic activation. A positive response was also noted with HC Blue No. 2 in the mouse lymphoma L5178Y TK+/- assay, both in the presence and absence of metabolic activation. Negative findings from the Ames assay of this study agree with other published results where an identical lot of HC Blue No. 1 was used. With the same lot a weak positive result was observed in the mouse lymphoma L5178Y TK+/- assay however the activation requirements and magnitude of the response were different from that of a lot evaluated by the NTP. In contrast, HC Blue No. 2 appears to be both a bacterial and mammalian cell mutagen independent of lot variability. [R16] *Two hair-dye chemicals, HC Blue No. 1 and HC Blue No. 2, were assessed for the ability to produce chromosome breakage and/or spindle malformation in vivo by evaluating the capacity of these compounds to induce micronuclei in polychromatic erythrocytes of mouse bone marrow. Initial studies were conducted in ICR male and female mice given a single intraperitoneal dose of 1000, 500 or 250 mg/kg body weight and examined for micronucleus induction 24 or 48 hr later. Activity was observed in female mice given 1000 mg/kg of HC Blue No. 1 at the 24 hr harvest time. A questionable response was noted with HC Blue No. 2 in males at the 1000 mg/kg, 24 hr time point. No activity was observed in either sex at the 48 hr harvest time. In a second set of studies, mice from two strains, ICR and CD-l, were administered a single intraperitoneal dose of 1000 mg/kg of each chemical and the one marrow was extracted 24 hr later. HC Blue No. 1 again produced a statistically significant elevation of micronuclei in female ICR mice. No significant effect was observed in CD-l mice of either sex. HC Blue No.2 did no produce any significant elevation of micronuclei in either sex of ICR or CD-1 mice. [R17] +Under the conditions of these feed studies, there was equivocal evidence of carcinogenicity in male F344/N rats, since HC Blue No. 1 caused a marginal increase in the incidence of hepatocellular neoplastic nodules/carcinomas. For female F344/N rats, there was some evidence of carcinogenicity in that HC Blue No. 1 induced increased incidences of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenicity of HC Blue No. 1 for male and female B6C3F1 mice as shown by increased incidences of hepatocellular carcinomas. The incidences of follicular cell adenomas of the thyroid gland were also increased in male mice receiving HC Blue No. 1. [R18] NTP: +oxicology and carcinogenesis studies of HC Blue No. 1 (97% pure), a semipermanent hair dye, were conducted by administering the test chemical in feed for 103 weeks to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex. The dietary concentrations used were 0, 1,500, or 3,000 ppm for rats and male mice and 0, 3,000, or 6,000 ppm for female mice. These concentrations were selected on the basis of results from single-administration gavage studies and 14 day and 13 week feed studies. Under the conditions of these feed studies, there was equivocal evidence of carcinogenicity in male F344/N rats, since HC Blue No. 1 caused a marginal increase in the incidence of hepatocellular neoplastic nodules/carcinomas. For female F344/N rats, there was some evidence of carcinogenicity in that HC Blue No. 1 induced increased incidences of alveolar/bronchiolar neoplasms. There was clear evidence of carcinogenicity of HC Blue No. 1 for male and female B6C3FI mice as shown by increased incidences of hepatocellular carcinomas. The incidences of follicular cell adenomas of the thyroid gland were also increased in male mice receiving HC Blue No. 1. [R18] ADE: *About 85 g of a commercial semi-permanent hair dye formulation containing 1.48% HC Blue No. 1 enriched with 113.6 uCi/mg (ring (14)C labelled HC Blue No. 1 was applied on two occasions to the hair of human volunteers, worked in gently for 5-8 minutes and allowed to remain in contact with the hair and scalp for an additional 30 minutes. On the first occasion, the hair was shaven, and radiolabel accounting for 0.09-0.15% of that applied was detected in the urine over a seven day period; half was excreted in the urine after 18 hours. On the second occasion, the hair was shaven only after 30 days: cumulative absorption was 0.15% on the first day and 0.5% on the 30th day; half of the radiolabel was excreted after 138 hours. [R19] */About 85 g of a commercial semi-permanent hair dye formulation containing 1.48% HC Blue No. 1 enriched with 113.6 uCi/mg (ring (14 C)) labelled HC Blue No. 1/ was applied to the scalp hair of rhesus monkeys and allowed to remain in contact for 30 minutes. Radiolabel accounting for 0.12-0.13% of that applied was detected in urine over a seven day period; half was excreted in the urine after 40 hours. [R19] *Following intraperitoneal or subcutaneous injection of 2.5, 3.5, 4.0, 5.0, or 100 mg/kg body weight HC Blue No. 1 (98% pure, containing four minor components) to adult Fischer rats or rabbits, over 90% was recovered in bile or urine within 6 hours of administration. Following application of about 1 mg/cm sq (250 ug/ml in saline) HC Blue No. 1 to the skin, about 1% of the dose was recovered in the bile and slightly more in the urine of rats and an average of 4.5% of the dose in the rune of rabbits after 48 hours. [R20] METB: *Up to 40% of radiolabel was recovered in the urine of B6C3F1 mice and Fischer 344/N rats after oral administration by gavage of 100 mg/kg body weight (ring-(14)C) Blue No. 1 (29 mCi/mmol (113.6 uCi/mg); 97% pure). HC Blue No.1 administered orally to B6C3F1 mice yielded three metabolites in equal proportions, which were more water soluble than the parent compound; one was a glucuronide of the parent compound. Metabolism of (ring-(14)C) HC Blue No. 1 (200 uM (51 mg)) by hepatocytes isolated from mice and rats yielded profiles similar to those seen in vivo. High-performance liquid chromatography separation showed that HC Blue No.1 is metabolized extensively in mice to five major metabolites. Thermospray liquid chromatography mass spectrometry of these metabolites provided tentative evidence for nitroreduction, N-demethylation and conjugation (glucuronidation of a demethylated product and acetylation). In rats, HC Blue No. 1 produced three metabolites similar to those fund in mice. [R20] *HC BLUE NUMBER 1, A COMPONENT OF HAIR DYE, WAS ABSORBED PERCUTANEOUSLY BY RATS AND RABBITS AFTER APPLICATION OF 250 MUG/ML SOLN. IT WAS ALSO INJECTED IP AND SC. DYE WAS EXCRETED IN URINE AND BILE BUT NO METABOLIC ALTERATION OCCURRED DURING THE IN VIVO TRANSIT. [R21] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A thin-layer chromatographic method with spectrophotometric analysis has been reported for determination in biological fluids. [R2] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of HC Blue No. 1 in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 271 (1985) NIH Publication No. 85-2527 SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 130 (1993) R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 129 R3: SRI R4: National Toxicology Program Technical Report Series No. 271; Toxicology and Carcinogenesis Studies of HC Blue No.1 (CAS No. 2784-94-3) in F344/N Rats and B6C3F1 Mice (Feed Studies); US Department of Health and Human Services Public Health Service National Institutes of Health NIH Publication No. 85-2527 1985 R5: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 140 (1993) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 131 (1993) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 134 (1993) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 135 (1993) R10: Darroudi F et al; Mutat Res 116 (2): 169-78 (1983) R11: Burnett CM, Corbett JF; Food Chem Toxicol 25 (9): 703-7 (1987) R12: Abu-Shakra A et al; Mutat Res 260 (4): 377-85 (1991) R13: Hill LE et al; Mutation Research 241 (2): 145-50 (1990) R14: Kari FW et al; Cell Biol Toxicol 6 (2): 139-56 (1990) R15: Kari FW et al; Toxicology 56 (2): 155-65 (1989) R16: Oberly TJ et al; Mutat Res 241 (2): 151-9 (1990) R17: Parton JW et al; Mutat Res 241 (2): 139-44 (1990) R18: Toxicology and Carcinogenesis Studies of HC Blue No. 1 in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 271 (1985) NIH Publication No.85-2527 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 132 (1993) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V57 133 (1993) R21: FRENKEL EP, BRODY F; ARCH ENVIRON HEALTH 27(6) 401 (1973) RS: 39 Record 276 of 1119 in HSDB (through 2003/06) AN: 4183 UD: 200211 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ALLYL-ISOVALERATE- SY: *BUTANOIC-ACID,-3-METHYL-,-2-PROPENYL-ESTER-; *BUTYRIC-ACID,-3-METHYL-,-ALLYL-ESTER-; *ISOVALERIC-ACID,-ALLYL-ESTER-; *NCI-C54717- RN: 2835-39-4 MF: *C8-H14-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *DIRECT ESTERIFICATION OF ALLYL ALCOHOL WITH ISOVALERIC ACID UNDER AZEOTROPIC CONDITIONS [R1] *SYNTH BY DIRECT ESTERIFICATION IN PRESENCE OF BENZENE. [R2] MFS: +Bell Flavors and Fragrances Inc, Hq, 500 Academy Drive, Northbrook, IL 60062, (312) 291-8300; Production site: Los Angeles, CA 90039 [R3] OMIN: *REPORTED USES: NON-ALCOHOLIC BEVERAGES 8.6 PPM; ICE CREAM, ICES, ETC 18 PPM; CANDY 22 PPM; BAKED GOODS 15-48 PPM; GELATINS AND PUDDINGS 1.0 PPM. [R2] *FLAVOR USEFUL IN: APPLE, CHERRY FRUIT BLENDS [R4] *FEMA NUMBER 2045 [R2] USE: *FRAGRANCE, EG, IN CREAMS AND LOTIONS; FLAVORING AGENT IN FOODS, EG, BAKED GOODS [R1] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1979) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LIQUID [R2] ODOR: *PLEASANT OVER-RIPE FRUIT ODOR [R4] TAST: *APPLE TASTE [R4] BP: *89-90 DEG C [R2] MW: *142.19 SPEC: *INDEX OF REFRACTION: 1.4162 @ 21 DEG C [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of allyl isovalerate were available. There is limited evidence in experimental animals for the carcinogenicity of allyl isovalerate. Overall evaluation: Allyl isovalerate is not classifiable as to its carcinogenicity to humans (Group 3). [R5] NTOX: +Allyl isovalerate (AI) was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of AI that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. All dietary concentrations (1200, 1600, 2000, and 4500 ppm) of AI tested gave negative results. [R6] NTP: +Carcinogenesis studies of allyl isovalerate (96% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and to groups of 50 male and 50 female B6C3F1 mice at doses of 31 or 62 mg/kg. ... Doses were admin five times per wk for 103 wk. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. ... Under the conditions of these studies, allyl isovalerate ... /caused/ mononuclear cell leukemia in male F344/N rats and lymphoma in female B6C3F1 mice. [R7] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *NOT REPORTED FOUND IN NATURE. [R2] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *172.515 [R4] *121.1164 [R2] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW WITH 8 REF ON ALLYL ISOVALERATE INCLUDING TOXICITY, IRRITATION, SENSITIZATION, AND METABOLISM. [R8] DHHS/NTP; Carcinogenesis Studies of Allyl Isovalerate in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 253 (1983) NIH Publication No.83-2509 SO: R1: SRI R2: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 20 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 632 R4: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 257 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1243 (1999) R6: Woodruff RC et al; Environ Mutagen 7:677-702 (1985) R7: DHHS/NTP; Carcinogenesis Studies of Allyl Isovalerate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 253 (1983) NIH Publication No. 83-2509 R8: OPDYKE DL J; FOOD COSMET TOXICOL 17 (SUPPL) 703 (1979) RS: 5 Record 277 of 1119 in HSDB (through 2003/06) AN: 4184 UD: 200303 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,2-BIS(BROMOMETHYL)-1,3-PROPANEDIOL SY: *1,3-DIBROMO-2,2-DIMETHYLOLPROPANE-; *2,2-DIBROMOMETHYL-1,3-PROPANEDIOL-; *DIBROMONEOPENTYL-GLYCOL-; *FR-1138-; *PENTAERYTHRITOL-DIBROMIDE-; *PENTAERYTHRITOL-DIBROMOHYDRIN-; *1,3-PROPANEDIOL, 2,2-BIS(BROMOMETHYL)- RN: 3296-90-0 MF: *C5-H10-Br2-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HYDROBROMINATION OF PENTAERYTHRITOL WITH ANHYDROUS HYDROGEN BROMIDE FOLLOWED BY SOLVENT RECRYSTALLIZATION [R1] MFS: *Albemarle Corporation, 451 Florida Street, Baton Rouge, LA 70801, (225)388-8011; Production site: Magnolia, AR 71753 [R2] USE: *FLAME RETARDANT FOR EPOXY, POLYESTER, AND URETHANE FOAMS; CHEM INT FOR PENTAERYTHRITOL ETHERS; CHEM INT FOR DERIVATIVES USED AS FLAME RETARDANTS [R1] *Used in polyester resin formulations [R3, 655] *Reactive flame retardant [R4] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MP: *111-113 deg C [R5] MW: *261.97 [R6] OWPC: *log Kow= 2.29 [R7] SOL: *In water, 38 g/l @ 25 deg C [R7] OCPP: *61% bromine content; specific gravity=2.20; mp=109 deg C /commercial product/ [R3, 967] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *RATS FED 5 MG FR 1138/KG/DAY HAD NO EFFECTS RELATED TO LIFETIME TREATMENT. RATS FED 100 MG FR 1138/KG/DAY SHOWED DEGENERATIVE CHANGES IN LIVER, EYE, AND POSSIBLY THYROID GLAND; HOWEVER, THERE WAS NO ONCOGENIC RESPONSE, EVEN AT HIGH DOSAGE. [R8] *... CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on increased incidences of neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal vesicle, and the increased incidence of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)- 1,3-propanediol in female F344/N rats based on increased incidences of neoplasms of the oral cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and subcutaneous tissue. [R9] NTP: *Groups of male and female F344/N rats and B6C3FI mice were exposed to technical grade 2,2-bis(bromomethyl)-1,3-propanediol (78.6% pure) in feed for ... 2 years. ... 2 YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 2,500, 5,000, or 10,000 ppm 2,2-bis(bromomethyl)1,3-propanediol in feed for 104 to 105 wk. Groups of 70 males and 60 females received 0 ppm 2,2-bis(bromomethyl)-1,3-propanediol in feed for 104 to 105 weeks. ... Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 100, 200, or 430 mg/kg body weight for males and 115, 230, or 460 mg/kg for females. ... 2 YEAR STUDY IN MICE: Groups of 60 male and 60 female mice received 0, 312, 625, or 1,250 ppm 2,2-bis(bromomethyl)- 1,3-propanediol in feed for 104 to 105 wk. Average daily doses of 2,2-bis(bromomethyl)-1,3-propanediol were 35, 70, or 140 mg/kg (males) and 40, 80, or 170 mg/kg (females). ... CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 2,2-bis-(bromomethyl)-1,3-propanediol (FR-1138) in male F344/N rats based on increased incidences of neoplasms of the skin, subcutaneous tissue, mammary gland, Zymbal's gland, oral cavity, esophagus, forestomach, small and large intestines, mesothelium, urinary bladder, lung, thyroid gland, and seminal vesicle, and the increased incidence of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)- 1,3-propanediol in female F344/N rats based on increased incidences of neoplasms of the oral cavity, esophagus, mammary gland, and thyroid gland. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and kidney. There was clear evidence of carcinogenic activity of 2,2-bis(bromomethyl)-1,3-propanediol in female B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, lung, and subcutaneous tissue. [R9] +2,2-bis(bromomethyl)-1,3-propandiol (BBMP) ... was tested for its effects on reproduction and fertility in CD-1 mice using the RACB protocol. Data from a 2 wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation phase at 0.1, 0.2, and 0.4% in feed. Based on body weights and food consumption, the estimated daily doses were nearly equal to 141, 274, and 589 mg/kg. One middle dose female and one high dose female died during the study from causes considered unrelated to BBMP exposure. Body weight gain for all treated groups was less than in controls; body weight means were reduced for females at the middle and high doses by 6-16%, and for high dose males by approx 10%. At the high dose, the number of litters/pair and the number of pups/litter were reduced by 12% and 44%, respectively. Pup body weight, adjusted for litter size, was reduced by 5% and 8% at the middle and high doses, respectively. Additionally, the cumulative days to deliver each litter was increased at the high dose for all litters; the effect worsened progressively for the first 4 litters. The last litter was reared by the parents until weaning. Although there were significantly fewer pups/litter at the high dose, the survival and growth of those pups to weaning was not affected by parental BBMP consumption. Animals from all dose groups and controls were kept and reared to test fertility of the second generation. While the F1 mice were growing, the control and high dose F0 mice were cross-mated in Task 3. In this crossover mating trial, treated males were unaffected, but treated females were significantly affected: only one-third of the cohabited females delivered a litter; those litters had 30% fewer pups, who were nearly equal to 8% lighter than their control counterparts. Thus, the effects seen during Task 2 were replicated by the treated females during Task 3. After the Task 3 mating, the F0 mice from the control and high dose groups were killed and necropsied. For the treated animals, female body weight was reduced by nearly equal to 18%, and male body weight was reduced by nearly equal to 12%. No organ weights were changed, nor were sperm endpoints or vaginal cyclicity affected. In the Task 4 mating trial, all groups showed equivalent mating and fertility rates. Litters at the high dose were 33% smaller, and the pups weighed 13% less than their controls. These F1 adults were killed and necropsied. Female terminal body weights were reduced by 6% at the low dose, and 18% at the high dose. Also at the high dose, relative liver weights were increased by 9%. For males, body weights at the middle and high doses were reduced by 9% and 25%, respectively. Absolute testis weight was reduced at the high dose by 16%, while relative liver weight was increased by 12%, and epididymal sperm density was reduced by nearly equal to 14%. No changes were seen in estrous cyclicity. This study found that BBMP was both a general toxicant (reduced body weight gain, and lower terminal body weights) as well as a female reproductive toxicant in the parental generation (fewer pups and lighter pups), and affected both sexes in the F1 generation (pup effects, as well as reduced testis weight and epididymal sperm count). BBMP is not a selective reproductive toxicant, as these effects were seen concomitant with the general toxicity. [R10] ADE: *ANAL OF SELECTED TISSUES INDICATED AN INCREASE IN BROMIDE CONTENT IN TISSUES OF RATS INGESTING 100 MG FR 1138/KG/DAY. AT 5 MG FR 1138/KG/DAY, THERE WAS ONLY A MARGINAL INCREASE IN BROMIDE CONTENT OF SOME TISSUES, WITH MOST VALUES IN SAME RANGE AS CONTROLS. [R8] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2,2-Bis(bromomethyl)-1,3-propanediol's production and use as a reactive flame retardant may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.3X10-5 mm Hg at 25 deg C indicates 2,2-bis(bromomethyl)-1,3-propanediol will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2,2-bis(bromomethyl)-1,3-propanediol will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2 days. Particulate-phase 2,2-bis(bromomethyl)-1,3-propanediol will be removed from the atmosphere by wet and dry deposition. If released to soil, 2,2-bis(bromomethyl)-1,3-propanediol is expected to have moderate mobility based upon an estimated Koc of 420. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 4.1X10-9 atm-cu m/mole. No data were located showing the biodegradation of this compound in the environment; however, only 3 to 33% biodegradation of this compound was reported in 28 days in a screening biodegradation test suggesting that biodegradation of this compound in soil and water may be slow. If released into water, 2,2-bis(bromomethyl)-1,3-propanediol may adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. BCF values ranging from 0.8 to 4.8 suggest bioconcentration in aquatic organisms is low. Occupational exposure to 2,2-bis(bromomethyl)-1,3-propanediol may occur through inhalation and dermal contact with this compound at workplaces where 2,2-bis(bromomethyl)-1,3-propanediol is produced or used. (SRC) ARTS: *2,2-Bis(bromomethyl)-1,3-propanediol's production and use as a reactive flame retardant(1) in polyester resin formulations(2) may result in its release to the environment through various waste streams(SRC). [R11] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 420(SRC), determined from a log Kow of 2.29(2) and a regression-derived equation(3), indicates that 2,2-bis(bromomethyl)-1,3-propanediol is expected to have moderate mobility in soil(SRC). Volatilization of 2,2-bis(bromomethyl)-1,3-propanediol from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.1X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(4). 2,2-Bis(bromomethyl)-1,3-propanediol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-5 mm Hg(SRC), determined from a fragment constant method(5). No data were located showing the biodegradation of this compound in soil; however, only 3 to 33% biodegradation of this compound was reported in 28 days in a screening biodegradation test(2) suggesting that biodegradation of this compound in soil may be slow(SRC). [R12] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 420(SRC), determined from a log Kow of 2.29(2) and a regression-derived equation(3), indicates that 2,2-bis(bromomethyl)-1,3-propanediol may adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.1X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), BCF values of 0.8 to 1.1 and < 4.8 in carp(2) suggest that bioconcentration in aquatic organisms is low. No data were located showing the biodegradation of this compound in water; however, only 3 to 33% biodegradation of this compound was reported in 28 days in a screening biodegradation test(2) suggesting that biodegradation of this compound in water may be slow(SRC). [R13] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2,2-bis(bromomethyl)-1,3-propanediol, which has an estimated vapor pressure of 1.3X10-5 mm Hg at 25 deg (SRC), determined from a fragment constant method(2), is expected to exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2,2-bis(bromomethyl)-1,3-propanediol is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2 days(SRC), calculated from its rate constant of 9.0X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Particulate-phase 2,2-bis(bromomethyl)-1,3-propanediol may be removed from the air by wet and dry deposition(SRC). [R14] BIOD: *AEROBIC: 2,2-Bis(bromomethyl)-1,3-propanediol, present at 100 mg/l, reached 3 to 33% of its theoretical BOD in 28 days using an activated sludge inoculum at 30 mg/l in the Japanese MITI test(1). [R15] ABIO: *The rate constant for the vapor-phase reaction of 2,2-bis(bromomethyl)-1,3-propanediol with photochemically-produced hydroxyl radicals has been estimated as 9.0X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). [R16] BIOC: *BCF values of 0.8 to 1.1 and < 4.8 were measured for 2,2-bis(bromomethyl)-1,3-propanediol at concentrations of 3 mg/l and 0.3 mg/l, respectively, in a 6 week study using carp(1). According to a classification scheme(2), these BCF values suggest the potential for bioconcentration in aquatic organisms is low. [R17] KOC: *The Koc of 2,2-bis(bromomethyl)-1,3-propanediol is estimated as 420(SRC), using a log Kow of 2.29(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 2,2-bis(bromomethyl)-1,3-propanediol is expected to have moderate mobility in soil. [R18] VWS: *The Henry's Law constant for 2,2-bis(bromomethyl)-1,3-propanediol is estimated as 4.1X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2,2-bis(bromomethyl)-1,3-propanediol is expected to be essentially nonvolatile from water surfaces(2). 2,2-Bis(bromomethyl)-1,3-propanediol's Henry's Law constant(1) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). 2,2-Bis(bromomethyl)-1,3-propanediol is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.3X10-5 mm Hg(SRC), determined from a fragment constant method(3). [R19] RTEX: *Occupational exposure to 2,2-bis(bromomethyl)-1,3-propanediol may occur through inhalation and dermal contact with this compound at workplaces where 2,2-bis(bromomethyl)-1,3-propanediol is produced or used. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R20] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,3-Propanediol, 2,2-bis(bromomethyl)- is included on this list. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 452 (1996) NIH Publication No. 96-3368 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the laboratory study report in preparation of the two year study for 2,2-bis(bromomethyl)-1,3-propanediol is in progress. Route: aqueous exposure; Species: fish project 1, fish. [R22] SO: R1: SRI R2: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 546 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V19 (96) R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V10 (96) 967 R5: Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals. Based on the CSCL Japan, Ministry of International Trade and Industry, Japan, ISBN 4-89074-101-1 (1992) R6: Howard PH, Neal M; Dictionary of Chemical Names and Synonyms. Ann Arbor,MI: Lewis Pub p. I-764 (1992) R7: Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Ministry of International Trade and Industry, Japan, ISBN 4-89074-101-1 (1992) R8: KEYES DG ET AL; J COMBUST TOXICOL 7(MAY) 77 (1980) R9: Toxicology and Carcinogenesis Studies of 2,2-Bis(Bromomethyl)-1,3-Propanediol in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 452 (1996) NIH Publication No. 96-3368 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R10: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; 2,2-bis(bromomethyl)-1,3-propanediol (CAS #3296-90-0): Reproduction and Fertility Assessment in CD-1 Mice When Administered In Feed, NTP Study No. RACB85043 (January 1986) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R11: (1) Pettigrew A; Kirk-Othmer Encycl Chem Technol, 4th ed, NY, NY: John Wiley and Sons 10: 967 (1996) (2) Selley J; Kirk-Othmer Encycl Chem Technol, 4th ed, NY, NY: John Wiley and Sons 19: 655 (1996) R12: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology-Toxicology and Information Center, ISBN 4-89074-101-1 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R13: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology-Toxicology and Information Center, ISBN 4-89074-101-1 (1992)(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R14: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R15: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals. Based on the CSCL Japan, Japan Chemical Industry Ecology-Toxicology and Information Center, ISBN 4-89074-101-1 (1992) R16: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R17: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan, Japan Chemical Industry Ecology-Toxicology and Information Center, ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R18: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals. Based on the CSCL Japan, Japan Chemical Industry Ecology-Toxicology and Information Center, ISBN 4-89074-101-1 (1992)(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R19: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985) R20: 40 CFR 712.30 (7/1/99) R21: 40 CFR 716.120 (7/1/99) R22: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.22 RS: 22 Record 278 of 1119 in HSDB (through 2003/06) AN: 4185 UD: 200302 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-(1-IODOETHYL)-1,3-DIOXOLANE-4-METHANOL SY: *1,3-DIOXOLANE-4-METHANOL, 2-(1-IODOETHYL)-; *IODOPROPYLIDENE-GLYCEROL-; *NCI-C55469-; *ORGANIDIN- RN: 5634-39-9 MF: *C6-H11-I-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF IODINE AND GLYCEROL [R1] *MANCHEY ET AL, US PATENT 2,872,378 (1959 TO DENVER CHEM MFR). [R2] FORM: *ORGANIDIN... ORAL: ELIXIR 1.2%; SOLN 5%; TABLETS 30 MG. [R3] OMIN: *ISOMERIC MIXT OF 67-75% OF 2-(1-IODOETHYL)-1,3-DIOXOLANE-4-METHANOL OR 2,3-(2-IODOPROPYLIDENEDIOXY)PROPANOL AND 33-25% OF 2-(2-IODOETHYL)-1,3-DIOXOLANE-4-METHANOL OR 2,3-(3-IODOPROPYLIDENEDIOXY)PROPANOL. [R2] USE: +MEDICATION PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] *(1979) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R1] U.S. IMPORTS: *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW LIQ [R2] TAST: *PUNGENT, BITTER AFTERTASTE [R2] MW: *258.07 [R2] DEN: *1.797 [R2] SOL: *SOL IN ETHER, CHLOROFORM, ISOBUTYL ALC, METHYL ACETATE, ETHYL ACETATE, METHYL FORMATE, TETRAHYDROFURAN [R2] SPEC: *INDEX OF REFRACTION: 1.547/D [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: +... Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity for male F344/N rats admin iodinated glycerol, as indicated by increased incidences of mononuclear cell leukemia and follicular cell carcinomas of the thyroid gland. Adenomas of the nasal cavity in two high dose male rats may have been related to the administration of iodinated glycerol. There was no evidence of carcinogenic activity for female F344/N rats administered 62 or 125 mg/kg iodinated glycerol by gavage for 103 wk. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 125 or 250 mg/kg iodinated glycerol by gavage for 103 wk. There was some evidence of carcinogenic activity for female B6C3F1 mice admin iodinated glycerol, as indicated by incr incidences of adenomas of the anterior pituitary gland and neoplasms of the harderian gland. Squamous cell papillomas of the forestomach may have been related to the admin of iodinated glycerol. [R4] NTP: +Toxicology and carcinogenesis studies of iodinated glycerol (Orgarlidin, a complex mixture prepared by the reaction of iodine with glycerol and found to contain 33% 3-iodo-1,2-propanediol as the major component) were conducted because of human exposure to iodinated glycerol as an expectorant and its possible relationship to the formation of alkyl iodides, e.g., methyl iodide, a suspected animal carcinogen. These studies were conducted by giving iodinated glycerol in water by gavage (5 days per week) to groups of F344/N rats and B6C3F1 mice for ... 2 years. ... Two yr studies were conducted by administering 0, 125, or 250 mg/kg iodinated glycerol in deionized water by gavage, 5 days/wk for 103 wk, to groups of 50 male F344/N rats and 50 male B6C3F1 mice. Groups of 50 female F344/N rats and 50 female B6C3F1 mice were admin iodinated glycerol on the same schedule at lower doses of 0, 62 or 125 mg/kg because of the incr severity of kidney and stomach lesions in the 13 wk studies. Conclusions: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity for male F344/N rats admin iodinated glycerol, as indicated by increased incidences of mononuclear cell leukemia and follicular cell carcinomas of the thyroid gland. Adenomas of the nasal cavity in two high dose male rats may have been related to the administration of iodinated glycerol. There was no evidence of carcinogenic activity for female F344/N rats administered 62 or 125 mg/kg iodinated glycerol by gavage for 103 wk. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 125 or 250 mg/kg iodinated glycerol by gavage for 103 wk. There was some evidence of carcinogenic activity for female B6C3F1 mice admin iodinated glycerol, as indicated by incr incidences of adenomas of the anterior pituitary gland and neoplasms of the harderian gland. Squamous cell papillomas of the forestomach may have been related to the admin of iodinated glycerol. [R4] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Expectorants [R5] *...IT IS CLAIMED TO HAVE EXPECTORANT ACTIONS OF IODINE AND GLYCERIN AND DOES NOT CAUSE GASTRIC IRRITATION OR RELEASE INORGANIC IODINE BEFORE ABSORPTION. [R3] WARN: *EFFICACY OF IODINATED GLYCERIN IS QUESTIONABLE... SENSITIVITY REACTIONS OCCUR OCCASIONALLY. THEREFORE, IODINATED GLYCERIN IS CONTRAINDICATED IN PT WHO ARE SENSITIVE TO IODINE. [R3] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Iodinated Glycerol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 340 (1990) NIH Publication No. 90-2596 SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 661 R3: American Medical Association, AMA Department of Drugs, AMA Drug Evaluations. 3rd ed. Littleton, Massachusetts: PSG Publishing Co., Inc., 1977. 658 R4: Toxicology and Carcinogenesis Studies of Iodinated Glycerol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 340 (1990) NIH Publication No. 90-2596 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R5: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) RS: 6 Record 279 of 1119 in HSDB (through 2003/06) AN: 4186 UD: 200208 RD: Reviewed by SRP on 3/2/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: (D)-LIMONENE SY: *Cajeputene-; *CARVENE-; *Cinene-; *CITRENE-; *CYCLOHEXENE, 1-METHYL-4-(1-METHYLETHENYL)-, (R)-; *4-ISOPROPENYL-1-METHYLCYCLOHEXENE-; *Kautschiin-; *D-(+)-LIMONENE; *(+)-R-Limonene; *LIMONENE, (+)-; *P-MENTHA-1,8-DIENE, (R)-(+)-; *(+)-P-MENTHA-1,8-DIENE; *NCI-C55572-; *REFCHOLE- RN: 5989-27-5 RELT: 1809 [LIMONENE] (Mixture) MF: *C10-H16 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *D-LIMONENE MAY BE OBTAINED BY STEAM DISTILLATION OF CITRUS PEELS AND PULP RESULTING FROM PRODN OF JUICE AND COLD-PRESSED OILS, OR FROM DETERPENATION OF CITRUS OILS. IT IS SOMETIMES REDISTILLED. [R1] *ISOLATION OF D-LIMONENE FROM MANDARIN PEEL OIL (CITRUS RETICULATA BLANCO, RUTACEAE). [R2] MFS: *Florida Chemical Co Inc, Hq, PO Box 997, Lake Alfred, FL 33850, (813) 956-1843; Production site: Lake Alfred, FL 33850 [R3] *Hanson Industries, Hq, 99 Wood Ave South, Iselin, NJ 08830, (201) 603-0600; Subsidiary: SCM GLIDCO Organics, 7 St Paul St, Suite 1010, Baltimore, MD 21201; Production site: Jacksonville, FL 32208 [R3] OMIN: *FLAVORS USEFUL IN: CITRUS FLAVOR, ARTIFICIAL ESSENTIAL OILS /FROM TABLE/ [R4] *FEMA NUMBER 2633 (DL-FORM) [R1] USE: *SOLVENT, MFR RESINS [R2] *FRAGRANCE IN COSMETICS (EG, SOAPS AND PERFUMES); FLAVORING AGENT IN FOOD, BEVERAGES AND CHEWING GUM; CHEM INT FOR L-CARVONE, A FRAGRANCE AND FLAVORING AGENT, TERPENE RESIN MFR; SOLVENT; WETTING AND DISPERSING AGENT; PREPN OF SULFURIZED TERPENE LUBE OIL ADDITIVES [R5] *d-Limonene is used to synthesize l-carvone. [R6] CPAT: *(1976) 6.81X10+7 G (CONSUMPTION AS FRAGRANCE) [R5] PRIE: U.S. PRODUCTION: *(1979) MORE THAN 4.5X10+5 G /UNSPECIFIED ISOMER/ [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LIQUID [R2] ODOR: *FRESH, CITRUS ODOR [R4] TAST: *FRESH, CITRUS TASTE [R4] BP: *175.5-176 DEG C @ 763 MM HG [R2] MP: *-74.35 DEG C [R7] MW: *136.23 DEN: *0.8402 @ 25 deg C/4 deg C [R8] OWPC: *log Kow= 4.232 (est) [R9] SOL: *SOL IN ALL PROPORTIONS IN ALCOHOL AND ETHER [R7] SPEC: *INDEX OF REFRACTION: 1.4743 @ 21 DEG C/D; SPECIFIC OPTICAL ROTATION: +123.8 DEG @ 19.5 DEG C/D [R2]; *SPECIFIC OPTICAL ROTATION: +125.6 DEG @ 20 DEG C/D (UNDILUTED); MAX ABSORPTION (ISOOCTANE): 220 NM (LOG E= 2.41), 250 NM (LOG E= 1.36); INDEX OF REFRACTION: 1.4730 @ 20 DEG C/D [R7]; *IR: 10018 (Sadtler Research Laboratories IR Grating Collection) [R10]; *NMR: 2852 (Sadtler Research Laboratories Spectral Collection) [R10]; *MASS: 704 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R10] VAP: *20 mm Hg at 68.2 deg C [R11] OCPP: *Henry's Law constant= 0.380 atm cu m/mole at 25 deg C (calc) [R12] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomp it emits acrid smoke and fumes. [R8] SERI: *CAUTION: SKIN IRRITANT, SENSITIZER. [R2] SSL: *OXIDIZES TO FILM IN AIR /LIMONENE/ [R13] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R15] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of d-limonene. There is sufficient evidence in experimental animals for the carcinogenicity of d-limonene. Overall evaluation: In making its overall evaluation of the carcinogenicity to humans of d-limonene, the Working Group concluded that d-limonene produces renal tubular tumors in male rats by a non-DNA reactive alpha-2-globulin associated response. Therefore, the mechanism by which d-limonene incr the incidence of renal tubular tumors in male rats is not relevant to humans. d-Limonene is not classifiable as to its carcinogenicity to humans (Group 3). [R16] HTOX: *NO TOXIC REACTIONS HAVE BEEN DESCRIBED OTHER THAN MILD LOCAL IRRITATION AND SKIN SENSITIZATION, BUT ALBUMINURIA AND HEMATURIA ARE PROBABLE IF INGESTED IN SUFFICIENT QUANTITY. /LIMONENE/ [R17] *CAUTION: SKIN ... SENSITIZER. [R2] *The toxicokinetics of d-limonene were studied in human volunteers exposed by inhalation (2 hr, work load 50 W) in an exposure chamber on three different occasions. The exposure concn were approximately 10, 225, and 450 mg/cu m d-limonene. The relative pulmonary uptake was high, approximately 70% of the amount supplied. A decrease in vital capacity was observed after exposure to d-limonene at a high exposure level. The subjects did not experience any irritative symptoms or symptoms related to the CNS. [R18] NTOX: *D-LIMONENE ADMIN TO DOGS AT 1.2-3.6 ML/KG/DAY FOR 6 MONTHS CAUSED FREQUENT VOMITING AND NAUSEA AND DECREASE IN BODY WT, BLOOD SUGAR AND CHOLESTEROL. NO SIGNIFICANT CHANGE WAS OBSERVED IN ORGANS EXCEPT IN THE KIDNEY. [R19] *D-LIMONENE, (2869 MG/KG, ORALLY) GIVEN TO PREGNANT RATS FROM DAY 9-15 OF GESTATION, DECREASED BODY WEIGHT GAIN OF THE MOTHERS, AND PROLONGED OSSIFICATION OF FETAL METACARPAL BONE AND PROXIMAL PHALANX. [R20] *D-LIMONENE (1000 MG/KG, ORALLY) GIVEN TO RABBIT DAMS DECR FOOD INTAKE AND BODY WT GAIN AND KILLED 6 OF 21 ANIMALS TESTED; HOWEVER, D-LIMONENE GIVEN AT 250 MG/KG WAS WITHOUT EFFECT. D-LIMONENE HAD NO TERATOGENIC EFFECT IN RABBITS WHEN ADMIN AT 250 MG/KG. [R21] *D-LIMONENE (2363 MG/KG, ORALLY) GIVEN TO MICE FOR 6 DAYS FROM DAY 7-12 OF GESTATION DECR BODY WT GAIN AND INCR INCIDENCE OF ABNORMAL BONE FORMATION IN FETUSES. D-LIMONENE ALSO DECR BODY WT GAIN IN MALE OFFSPRING; HOWEVER, THE TOXICITY OF D-LIMONENE WAS NOT SEVERE. [R22] *The gallstone solubilizer was given to pregnant rats in doses of up to 2869 mg/kg during organogenesis. Although maternal toxicity and fetal growth reduction occured no teratogenicity was found. [R23] *Acute exposure to unleaded gasoline vapors produces nephropathy in male rats characterized by incr protein (hyaline) droplet formation, degenerative changes, and subsequent regeneration in proximal tubular epithelium. This nephropathy has been demostrated following exposure of male, but not female, rats to other petroleum derived hydrocarbons and mixtures ... /including/ d-limonene. [R24, 368] *D-LIMONENE SHOWED CONSTRICTIVE ACTION ON GALLBLADDER IN DOGS WHEN INJECTED IV OR DIRECTLY INTO THE GALLBLADDER. D-LIMONENE ELEVATED PERFUSION PRESSURE OF SPHINCTER OF ODDI IN DOGS WHEN INJECTED IV OR DIRECTLY INTO COMMON BILE DUCT. [R25] *d-Limonene was not mutagenic in four strains of Salmonella typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase the number of trifluorothymidine-resistant cells in the mouse L5178Y/TK + or - assay, and did not induce chromosomal aberrations or sister chromatid exchanges in cultured CHO cells. All assays were conducted in the presence and absence of exogenous metabolic activation. [R26] *Treatment of Chinese hamster ovary cells with d-limonene, in the presence and absence of S9, did not induce sister chromatid exchanges or chromosomal aberrations. [R27] *Inhibition of cholesterol biosynthesis occurred in the small intestine of rats after administration of d-limonene for 7 days, but no significant effect on the secretion of radiolabeled cholesterol into bile and feces was observed. d-Limonene increased the perfusion pressure of the sphincter of Oddi in dogs when injected iv or directly into the common bile duct. d-Limonene has also been used successfully for the postoperative dissolution of retained cholesterol gallstones. [R28] *Naturally occurring compounds belonging to two chemical groups were studied for their capacities to inhibit N-nitrosodiethylamine-induced carcinogenesis in female A/ mice. One group consisted of D-limonene and D-carvone. ... Test compounds were given orally either 15 min or 1 hr prior to N-nitrosodiethylamine. Under these conditions, D-limonene and D-carvone reduced forestomach tumor formation by about 60% and pulmonary adenoma formation by about 35%. [R29] *Adult male and female Sprague Dawley rats were given single oral doses of 0, 0.1, 0.3, 1, or 3 mmol d-limonene/kg (0, 14, 41, 136, or 409 mg/kg) in corn oil. A dose response relationship for acute exacerbation of hyaline droplets by d-limonene treatment was observed. Hyaline droplets were graded according to size, eosinophilic intensity, and the number of tubules loaded with droplets. Control rats received a mean score of 3. At 3 mmol/kg, admin of d-limonene resulted in a score of 10. At 0.1 mmol/kg, no effect on hyaline droplet accumulation was seen in male rats. 24 hr after admin of 3 mmol d-limonene/kg, the renal concentration of d-limonene equivalents was approximately 2.5 times higher in male rats than in female rats. Equilibrium dialysis in the presence or absence of sodium dodecyl sulfate indicated that approximately 40% of the d-limonene equivalents in male rat kidney associated with proteins in a reversible manner, whereas no significant association was observed between d-limonene equivalents and female rat kidney proteins. Gel filtration HPLC indicated that d-limonene in male rat kidney is associated with a protein fraction having a mol wt of approximately 20,000. Using reverse phase HPLC, d-limonene was shown to be associated with alpha-2u-globulin which was identified by amino acid sequencing. The major metabolite associated with alpha-2u-globulin was d-limonene-1,2-oxide. Parent d-limonene was also identified as a minor component in the alpha-2u-globulin fraction. [R30] *ADMIN OF D-LIMONENE FOR 7 DAYSINHIBITED CHOLESTEROL BIOSYNTHESIS IN SMALL INTESTINE OF RATS BUT HAD NO SIGNIFICANT EFFECT ON THE SECRETION OF (14)C-LABELED CHOLESTEROL INTO BILE AND FECES. [R31] *D-LIMONENE SOLUTION INJECTED AS BOLUS INTO BILIARY TRACT OF CATS PRODUCED HEPATOBILIARY TISSUE DAMAGE, DEPENDING ON CONTACT TIME, VOLUME AND FLOW DIRECTION OF THE SOLUTION. [R32] *STUDY OF CHROMATOGRAPHIC DATA OF GLC PROFILES FROM TOTAL PARTICULATE MATTER OF 8 EXPTL CIGARETTES. D-LIMONENE WAS 1 PEAK IDENTIFIED THAT CORRELATED WITH CARCINOGENIC ACTIVITY WHEN PAINTED ON MICE SKIN. D-LIMONENE IS BEST INDICATOR THUS FAR OF TOBACCO SMOKE BIOLOGICAL ACTIVITY. [R33] *The monocyclic monoterpenoid compounds limonene and sobrerol have anticarcinogenic activity when fed during the initiation stage of dimethylbenz(a)anthracene induced rat mammary carcinogenesis. The potential roles of hepatic glutathione-S-transferase and uridine diphosphoglucuronosyl transferase were studied in monoterpene mediated chemoprevention. Diets containing the isoeffective anticarcinogenic terpenes, 5% limonene or 1% sobrerol, elevated hepatic glutathione-S-transferase activity > 2 fold when measured using the general substrate 1-chloro-2,4-dinitrobenzene and 3,4-dichloronitrobenzene for the glutathione-S-transferase dimer 3-3. However, there were no significant changes in hepatic glutathione-S-transferase activity when 1,2-epoxy-3-(p-nitrophenoxy)propane was used. Liver glutathione-S-transferase subunit 3 had the greatest increase followed by 1 and 4 with no change in subunit 2. Both terpene diets significantly increased the activity of the methylcholanthrene inducible and the phenobarbital inducible uridine diphosphoglucuronosyl transferase isozymes. It was proposed that much of the anticarcinogenic activity of these monocyclic monoterpenes during the initiation phase of dimethylbenz(a)anthracene carcinogenesis is mediated through the induction of the hepatic detoxification enzymes glutathione-S-transferase and uridine diphosphoglucuronosyl transferase. [R34] *Themonoterpene d-limonene is a naturally occurring chemical which is the major component in oil of orange. Currently, d-limonene is widely used as a flavor and fragrance and is listed to be generally recognized as safe in food by the Food and Drug Administration, however, d-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to d-limonene causes a significant incidence of renal tubular tumors exclusively in male rats. d-Limonene is not carcinogenic in female rats or male and female mice given much higher dosages. The renal toxicity of d-limonene results from the accumulation of a protein, alpha 2u-globulin, in male rat kidney proximal tubule lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with alpha 2u-globulin. However, none of these proteins, including the mouse equivalent of alpha 2u-globulin, can produce this toxicity, indicating a unique specificity for alpha 2u-globulin. With chronic exposure to d-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensatory cell proliferation. Both d-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in in vitro mutagenicity screens. Therefore, the toxicity related renal cell proliferation is believed to be integrally involved in the carcinogenicity of d-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The data base demonstrates that the tumorigenic activity of d-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of d-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that alph 2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both d-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation. [R35] *The nephrotoxicity of d-limonene was studied in rats and mice. Kidney sections taken from male rats, strain not specified, that had been part of a 91 day oral dosing study of limonene in rats and mice, were examined by light microscopy. The study showed that renal alterations were induced only in male rats. Dose related decreases in absolute weight gain and relative weight gain (expressed as a percentage of the control weight gain) also occurred. The 2400 mg/kg dose killed nine of ten female rats. Kidney sections of male rats showed that limonene caused cytoplasmic basophilia of proximal convoluted tubule cells, tubular hyperplasia or atrophy, fibrosis of Bowman's capsule, and an interstitial fibrolymphocytic response. The severity of the lesions was dose related except in rats given 2400 mg/kg limonene. The severity of the lesions in the 2400 mg/kg group was similar to those seen in rats given 150 mg/kg. Occasional foci of proximal convoluted tubule epithelial cell necrosis degeneration were seen in all treated rats. Granular casts were seen in the outer medulla of animals that survived to the end of the study except for one rat in the 2400 mg/kg group. No hyaline droplet accumulation within the cytoplasm of proximal convoluted tubule epithelial cells was seen. Except for the absence of hyaline droplet formation, the changes induced by limonene are similar to those seen in male rats exposed to decalin. [R36] *The allergenic potential of d-limonene oxidation products was examined. Samples of d-limonene were exposed to air or unexposed in a preliminary experiment. The concn of d-limonene decreased after 8 wk air exposure. Carvone, cis and trans limonene oxide, and cis and trans carveal were the major oxidation products detected. Only slight decomposition was seen in nonexposed d-limonene. Dunkin-Hartley guinea pigs were induced by topical application of (+)-limonene oxide, (R)-(-)-carvone, (-)-carveal, or air exposed d-limonene. (+)-Limonene oxide and (-)-carveal consisted of mixtures of cis and trans isomers of the two compounds. The sensitizing potential of the compounds was assessed by the Freund complete adjuvant test after challenge with (+)-limonene oxide. Other guinea pigs were induced with air exposed d-limonene. The sensitizing potential of air exposed or nonexposed d-limonene, (+)-limonene oxide, or (R)-(-)-carvone was evaluated by the guinea pig maximization test. Air exposed d-limonene was a strong sensitizer in both the Freund complete adjuvant test and guinea pig maximization test. d-Limonene that was not air exposed exhibited no sensitizing potential. (+)-Limonene oxide and R-(-)-carvone, but not (-)-carveal, were potent sensitizers. Air oxidation of d-limonene is necessary for its sensitizing potential. Air oxidation produces potent allergens such as limonene oxide and carvone. [R37] *d-Limonene, a monocyclic monoterpenoid with known insecticidal properties, was assayed (by a standard method of cutaneous exposure) for general lethality effects as well as neurotoxic effects on escape reflex pathways in earthworms, Eisenia fetida (Savigny). Neurotoxicity was assessed by noninvasive electrophysiological techniques involving (a) quantification of the impacts of chronic and acute sublethal exposures on impulse conduction in the worms' medial and lateral giant nerve fiber pathways, (b) determination of whether such effects were generalized or localized within various body regions, and (c) determination of the reversibility of neurotoxic effects. The LD50 value for d-limonene alone was 6.0 ppm, and the LT50 value for exposure to 12.6 ppm was 4.9 hr. Effects on lethality were not synergized significantly by either piperonyl butoxide or sesame oil. Generally, chronic and acute intoxication involved a rapid and predictable cascade of behavioral and morphological symptoms, including increased mucus secretion, writhing, clitellar swelling, and elongation of the body. In addition, chronic d-limonene exposures induced significant weight loss, but there was no effect on median giant nerve fiber and lateral giant nerve fiber conduction velocities, even though abnormal rebounding of median giant nerve fiber impulses and spontaneous lateral giant nerve fiber spiking were often evident. Acute exposures, however, induced significant decreases in conduction velocity in both the median giant nerve fiber and lateral giant nerve fiber, but the effects were regionally specific; for example, lateral giant nerve fiber velocities were significantly reduced in the posterior half of the body but not in the anterior half. The magnitude of conduction velocity decreases was directly related to both concn and duration of exposure. Decreases in conduction velocities after acute exposures were reversed once d-limonene exposure ceased. [R38] *Binding of a chemical to alpha2u-globulin is the limiting step in the development of male rat specific hyaline droplet nephropathy. Mice synthesize mouse urinary protein, a protein which is very similar to alpha2u-globulin, but this protein does not render the mouse sensitive to a similar renal toxicity. The present study was conducted to determine the biochemical basis for mouse resistance to hyaline droplet nephropathy. Male Fischer 344 rats and B6C3F1 mice excreted 12.24 : 0.60 and 14.88 : 0.99 mg of alpha2u-globulin and mouse urinar protein daily, indicating that quantitative differences in protein excretion were not involved in the species specificity of the nephropathy. With d-limonene as a model hyaline droplet inducing agent, both rat and mouse liver microsomes oxidized the terpene to its 1,2-epoxide (the metabolite that binds reversibly to alpha2u-globulin in vivo), demonstrating that metabolic differences do not determine the mouse resistance to this lesion. In spite of the formation of the epoxide intermediate, no binding of (14)C-d-limonene equivalents to mouse kidney proteins was observed. In contrast, about 40% of the d-limonene equivalents in male rat kidney was reversibly bound to renal proteins. The renal reabsorption of alpha2u-globulin and mouse urinary protein was markedly different, as rats reabsorbed about 60% of the total filtered load of alpha2u-globulin, but mouse urinary protein was not reabsorbed by the mouse kidney. In vitr equilibrium saturation binding studies were also conducted. alpha2u-Globulin bound (14)C-d-limonene-1,2-oxide with an apparent Kd of 4 under identical experimental conditions, mouse urinary protein failed to bind the epoxide. These data indicate that two major biochemical differences between alpha2u-globulin and mouse urinary protein contribute to mouse resistance to hyaline droplet nephropathy. Under both in vivo and in vitro conditions, mouse urinary protein does not bind d-limonene-1,2-oxide, the rate limiting step in the development of the nephropathy. However, even if mouse urinary protein did bind the epoxide, the fact that it is not reabsorbed into the mouse kidney precludes its involvement in a syndrome involving renal protein overload. Finally, the absence of an interaction between d-limonene, a model hyaline droplet inducer, and the protein most similar to alpha2u-globulin suggests that no other protein in the alpha2u-globulin superfamily is likely to cause hyaline droplet nephropathy in other species. [R39] *The nephrotoxicity of d-limonene in male rats was attributed to its ability to bind to alpha2microglobulin. Urinary excretion of alpha2-microglobulin and mouse urinary protein, the murine analog to alpha2-microglobulin, by F344 rats and B6C3F1 mice was determined. When normalized to body weight a 250 g rat excreted 50 mg/kg/day alpha2-microglobulin. A 25 g mouse excreted approximately 600 mg/kg/day mouse urinary protein. Liver microsomes from untreated male F344 rats and B6C3F1 mice both oxidized limonene to cis-limonene-1,2-oxide (limonene oxide); however, the amount of limonene oxide formed was less than 1% of the amount of d-limonene metabolized. Mouse liver microsomes formed approximately twice as much limonene oxide as rat liver microsomes. Mouse liver microsomes also formed the trans isomer of limonene oxide. In renal binding experiments, approximately 0.1% of an administered dose of d-limonene was found in male rat kidneys. Of this, approximately 40% was bound to alpha2-microglobulin. The amount of limonene in male rat kidneys was approximately 2.5 times that of female rats. In mice given 500 mg limonene orally, approximately 0.023 and 0.015% of the dose was found in the kidneys of male and female mice, respectively. No binding of d-limonene to kidney proteins was detected. Although d-limonene is metabolized to limonene oxide in mice, mouse urinary protein is sufficiently different from alpha2-microglobulin that limonene oxide does not bind to it. The interaction between limonene oxide and alpha2-microglobulin is very specific. Hyaline droplet neuropathy probably would not occur in all other members of the alpha2-microglobulin family. [R40] *The anticarcinogenic effects of monocyclic monoterpenes such as limonene were demonstrated when given during the initiation phase of 7,12-dimethylbenz(a)anthracene induced mammary cancer in Wistar-Furth rats. The possible mechanisms for this chemoprevention activity including limonene's effects on 7,12-dimethylbenz(a)anthracene-DNA adduct formation and hepatic metabolism of 7,12-dimethylbenz(a)anthracene were investigated. Twenty four hours after carcinogen administration, there were approx 50% decreases in 7,12-dimethylbenz(a)anthracene-DNA adducts found in control animals formed in the liver, spleen, kidney and lung of limonene fed animals. While circulating levels of 7,12-dimethylbenz(a)anthracene and/or its metabolites were not different in control and limonene fed rats, there was a 2.3 fold increase in 7,12-dimethylbenz(a)anthracene and/or 7,12-dimethylbenz(a)anthracene derived metabolites in the urine of the limonene fed animals. Limonene and sobrerol, a hydroxylated monocyclic monoterpenoid with increased chemoprevention activity, modulated cytochrome p-450 and epoxide hydrolyase activity. The 5% limonene diet increased total cytochrome p-450 to the same extent as phenobarbital treatment, while 1% sobrerol (isoeffective in chemoprevention to 5% limonene) did not. However, both 5% limonene and 1% sobrerol diets greatly increased the levels of microsomal epoxide hydrolyase protein and associated hydrating activities towards benzo(a)pyrene 4,5-oxide when compared to control and phenobarbital treatment. These changes also modified the rate and regioselectivity of in vitro microsomal 7,12-dimethylbenz(a)anthracene metabolism when compared to phenobarbital treatment or control. Identification of the specific isoforms of cytochrome p-450 induced by these terpenoids was performed with antibodies to cytochrome p-450 isozymes in Western blot analysis and inhibition studies of microsomal 7,12-dimethylbenz(a)anthracene metabolism. Five per cent limonene was more effective than 1% sobrerol at increasing the levels of members of the cytochrome p-4502B and 2C families but was equally effective at increasing epoxide hydrolyase. Furthermore, both terpenoid diets caused increased formation of the proximate carcinogen, 7,12-dimethylbenz(a)anthracene 3,4-dihydrodiol. [R41] NTXV: *LD50 MICE ORAL 5.6-6.6 G/KG; [R42] *LD50 MICE IP 1.3 G/KG; [R42] NTP: *Two year studies of d-limonene /more than 99% pure/ were conducted by administering 0, 75, or 150 mg/kg d-limonene in corn oil by gavage to groups of 50 F344/N male rats, 5 days per week for 103 weeks; groups of 50 female F344/N rats were administered 0, 300, or 600 mg/kg. Mean body weights of rats dosed with d-limonene were similar to those of vehicle controls throughout the studies. Survival of the high dose female rats after week 39 and of the vehicle control male rats after week 81 was significantly reduced (survival at week 104--male: vehicle control, 29/50; low dose, 33/50; high dose, 40/50; female: 42/50; 40/50; 26/50). The kidney was confirmed as the primary target organ for chemically related lesions. No lesions were observed in female rats. For males, the nonneoplastic lesions included exacerbation of the age-related nephropathy, linear deposits of mineral in the renal medulla and papilla, and focal hyperplasia of the transitional epithelium overlying the renal papilla. Uncommon tubular cell adenomas and adenocarcinomas of the kidney also occurred in dosed male rats, and this effect was supported by a dose-related increased incidence of tubular cell hyperplasia. ... There was clear evidence of carcinogenic activity of d-limonene for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic activity of d-limonene for female F344/N rats that received 300 or 600 mg/kg. [R26] *Groups of 50 male B6C3F1 mice were administered 0, 250, 500 mg/kg, ... /5 days per week for 103 weeks/; groups of 50 female B6C3FI mice were administered 0, 500, or 1000 mg/kg. Mean body weights of dosed and vehicle control male mice were similar throughout the studies. Mean body weights of high dose female mice were notably lower than those of the vehicle controls after week 28. Survival of the low dose group-of male mice was significantly lower than that of vehicle controls at the end of the study (33/50; 24/50; 39/50). No difference in survival was observed between vehicle control and dosed female mice (43/50; 44/50; 43/50). ... No chemically related increases in neoplasms were observed. The incidence of neoplasms of the anterior pituitary gland in high dose female mice was lower than that in vehicle controls (adenomas or carcinomas, combined: vehicle control, 12/49; high dose, 2/48). Cells with an abnormal number of nuclei (8/49; 32/50) and cytomegaly (23/49; 38/50) were observed in the liver of high dose male mice. There was no evidence of carcinogenic activity of d-limonene for male B6C3Fl mice that received 250 or 500 mg/kg. There was no evidence of carcinogenic activity of d-limonene for female B6C3Fl mice that received 500 or 1000 mg/kg. [R26] ADE: *AFTER ORAL ADMIN OF (14)C LABELED D-LIMONENE TO ANIMALS AND MAN, 75-95 AND LESS THAN 10% OF THE RADIOACTIVITY WAS EXCRETED IN THE URINE AND FECES, RESPECTIVELY, WITHIN 2-3 DAYS. [R43] *The toxicokinetics of d-limonene were studied in human volunteers exposed by inhalation (2 hr, work load 50 W) in an exposure chamber on three different occasions. The exposure concn were approximately 10, 225, and 450 mg/cu m d-limonene. The relative pulmonary uptake was high, approximately 70% of the amount supplied. The blood clearance of d-limonene observed in this study, 1.1 l/kg/hr, indicates that d-limonene is metabolized readily. About 1% of the total uptake was eliminated unchanged in the expired air after the end of exposure, while approximately 0.003% was eliminated in the urine. A long half-time in blood was observed in the slow elimination phase, which indicates accumulation in adipose tissues. [R18] METB: *INCUBATION OF D-LIMONENE WITH RAT LIVER MICROSOMES PRODUCED D-LIMONENE-1,2-DIOL AND D-LIMONENE-8,9-DIOL AS METABOLITES AND D-LIMONENE-1,2-EPOXIDE AND D-LIMONENE-8,9-EPOXIDE WERE IDENTIFIED AS INTERMEDIATES. [R44] *AFTER ORAL ADMIN OF (14)C-LABELED D-LIMONENE, 5 NEW METABOLITES WERE ISOLATED FROM DOG AND RAT URINE: 2-HYDROXY-P-MENTH-8-EN-7-OIC ACID, PERILLYLGLYCINE, PERILLYL-BETA-D-GLUCOPYRANOSIDURONIC ACID, P-MENTHA-1,8-DIEN-6-OL, AND PROBABLY P-MENTH-1-ENE-6,8,9-TRIOL. [R43] *THE MAJOR METABOLITE OF D-LIMONENE IN URINE WAS PERILLIC ACID 8,9-DIOL IN RATS AND RABBITS, PERILLYL-BETA-D-GLUCOPYRANOSIDURONIC ACID IN HAMSTERS, P-MENTH-1-ENE-8,9-DIOL IN DOGS, and 8-HYDROXY-P-MENTH-1-ENE-9-YL-BETA-D-GLUCOPYRANOSIDURONIC ACID IN GUINEA PIGS AND MAN. [R43] *Adult male and female Sprague Dawley rats were given single oral doses of 0, 0.1, 0.3, 1, or 3 mmol d-limonene/kg (0, 14, 41, 136, or 409 mg/kg) in corn oil. Gel filtration HPLC indicated that d-limonene in male rat kidney is associated with a protein fraction having a mol wt of approximately 20000. Using reverse phase HPLC, d-limonene was shown to be associated with alpha-2u-globulin which was identified by amino acid sequencing. The major metabolite associated with alpha-2u-globulin was d-limonene-1,2-oxide. Parent d-limonene was also identified as a minor component in the alpha-2u-globulin fraction. [R30] *The major urinary metabolites of d-limonene were identified as perillic acid-8,9-diol in rats and rabbits, perillyl-beta-D-glucopyranosiduronic acid in hamsters, p-menth-l-ene-8,9-diol in dogs, and 8-hydroxy-p-menth-1-ene-9-yl-beta-D-glucopyranosiduronic acid in guinea pigs andhumans. ... Five new metabolites /were isolated/ from dog and rat urine after oral administration of radiolabeled d-limonene: 2-hydroxy-p-menth-8-en-7-oic acid, perillylglycine , perillyl-beta-D-glucopyranosiduronic acid, p-mentha-1,8-diene-6-ol, and probably p-menth-1-ene-6,8,9-triol. [R28] ACTN: *Necrosis and consequent cell regeneration are believed to result in kidney tumorigenesis. Chemicals that have caused kidney tumors in male rats by this mechanism include ... d-limonene. [R24, 190] INTC: *To identify possible hazards of combined exposure to chemicals with the same target organ, a 24 hr single dose experiment was carried out in which the renal toxicity of mercuric chloride, potassium dichromate, d-limonene and hexachloro-1:3-butadiene administered simultaneously was compared with the nephrotoxicity of the individual compounds in 12 wk old male Wistar rats. The dose levels used were based on the results of a range finding study with the individual compounds in the same strain of rats kept under similar experimental conditions, and comprised the 'Minimum Nephrotoxic Effect Level' and the 'No Nephrotoxic Effect Level' of each of the four compunds alone and in combination. A group of vehicle treated rats served as controls. At the 'Minimum Nephrotoxic Effect Level' of the combinations, antagonism of effects was encountered, seen for example as less severely increased activity of gamma-glutamyl transferase in the urine. Synergism of effects was also observed, for example increased severity of renal tubular necrosis, and more markedly increased activity of urinary lysozyme, lactate dehydrogenase, alkaline phosphatase and N-acetyl-beta-glucosaminidase. More importantly, however, at the 'No Nephrotoxic Effect Level' of the combination no signs of impaired renal function or renal damage were observed, suggesting absence of both dose additivity and potentiating interaction at the tested subeffective levels of the individual nephrotoxicants. [R45] *Mouse mammary glands respond to carcinogen stimulus to form mammary lesions in organ culture. In this study it was determined whether the effective chemopreventive agents are active against initiation or the promotion phase of lesion development. Mammary glands were subjected to 24 hr exposure to 2 mg/ml dimethylbenz(a)anthracene followed by a 5 day exposure to 7,12-tetradecanoyl phorbol-13-acetate. This treatment protocol allows the study of initiation and promotion aspects of lesion development. Chemopreventive agents effective when present prior to the carcinogen were considered as anti-initiators, whereas agents effective when present after the dimethylbenz(a)anthracene treatment along with 7,12-tetradecanoyl pherbol-13-acetate were considered as anti-promoters. Within the chemopreventive agents evaluated limonene was an anti-initiator. [R46] *The effects of D-limonene and citrus fruit oils, ie orange oil and lemon oil, on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induced neoplasia of the lungs and forestomach of female A/J mice were investigated. D-Limonene and the citrus fruit oils given orally 1 hr prior to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, also administered orally, inhibited pulmonary adenoma formation and the occurrence of forestomach tumors. In an additional experiment, D-limonene given orally 1 hr prior to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone administered ip again showed pronounced inhibition of pulmonary adenoma formation. [R47] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *(D)-Limonene is both a naturally occurring and a synthetically produced terpene which is used in flavors and fragrances, as a solvent and for numerous other commercial uses. If released to soil, (D)-limonene is expected to exhibit low to slight mobility. It is expected to rapidly volatilize from both dry and moist soil to the atmosphere although strong adsorption to soil may attenuate the rate of this process. If released to water, (D)-limonene may bioconcentrate in fish and aquatic organisms and it may significantly adsorb to sediment and suspended organic matter. It is expected to rapidly volatilize from water to the atmosphere. The estimated half-life for volatilization of (D)-limonene from a model river is 3.4 hr, although adsorption to sediment and suspended organic matter may attenuate the rate of this process. If released to the atmosphere, (D)-limonene is expected to rapidly undergo gas-phase oxidation reactions with photochemically produced hydroxyl radicals, ozone, and at night with nitrate radicals. Calculated half-lives for these processes are 2.3-2.6 hr, 25-26 min and 3.1 min, respectively. Occupational exposure to (D)-limonene may occur by inhalation or dermal contact during its production formulation, transport or use. Exposure to the general population may occur by inhalation due to its presence in the atmosphere as a result of released from natural sources or by ingestion of food in which it is contained. (SRC) NATS: *(D)-Limonene is a naturally occurring compound found in many natural oils including orange, lemon, grapefruit, berry, leaf, caraway, dill, bergamot, peppermint and spearmint oils(1-4). (D)-Limonene emissions to the environment are associated with wax myrtle, sweet acacia, oranges, tomatoes, grasses, and California western gagebrush(5). [R48] ARTS: *(D)-Limonene is used as a flavor and fragrance(1,2). It is also used as a solvent, wetting agent, in resins, and as a monomer and copolymer(2,3). (D)-Limonene may be released to the environment as a fugitive emission during its production, use or transport, and it may also be released to the environment by volatilization during its use as a solvent(SRC). [R49] FATE: *TERRESTRIAL FATE: Based on the solubility of (D)-limonene, 13.8 mg/l at 25 deg C(1) and its estimated log octanol/water partition coefficient of 4.232(2,SRC), soil adsorption coefficients of 1030-4780 can be calculated using appropriate regression equations(3,SRC) indicating that it will display low to slight mobility in soil(4). Its vapor pressure, 20 mm Hg at 68.2 deg C(1) and a calculated Henry's Law constant of 0.380 atm cu m/mole at 25 deg C(5,SRC) indicate that (D)-limonene will rapidly volatilize from both dry and moist soil to the atmosphere although its strong adsorption to soil may attenutae the rate of this process(SRC). [R50] *AQUATIC FATE: Based on the water solubility of (D)-limonene, 13.8 mg/l at 25 deg C(1) and an estimated log octanol/water partition coefficient of 4.232(2,SRC) bioconcentration factors of 246-262 can be calculated using appropriate regression equations(3,SRC) indicating that it may bioconcentrate in fish and aquatic organisms(SRC). Estimated soil adsorption coefficients ranging 1030 to 4780(1,2,3,SRC) indicate that (D)-limonene may significantly adsorb to sediment and suspended organic matter. A calculated Henry's Law constant of 0.380 atm cu m/mole at 25 deg C(4,SRC) suggests that it will rapidly volatilize from water to the atmosphere. The estimated half-life for volatilization of (D)-limonene from a model river 1 m deep flowing at 1 m/sec with a wind speed of 3 m/sec is 3.4 hr(3,SRC), although adsorption to sediment and suspended organic matter may attenuate the rate of this process(SRC). [R51] *ATMOSPHERIC FATE: If released to the atmosphere, (D)-limonene is expected to rapidly undergo gas-phase oxidation reactions with photochemically produced hydroxyl radicals, ozone, and at night with nitrate radicals. Based on experimental rate constants, calculated half-lives for the gas-phase reaction between limonene and photochemically produced hydroxyl radicals range from 2.3-2.6 hr(1,2,3,SRC). For the gas-phase reaction of (D)-limonene with ozone, a half-life ranging from 25-26 min can be calculated(1,4,5,SRC). A calculated half-life, based on an experimentally determined rate constant, for the night-time reaction of (D)-limonene with nitrate radicals of 3.1 min can also be calculated(1,6,SRC). The atmospheric lifetime of (D)-limonene during the daytime was estimated at 0.2-0.8 hr depending on both the local hydroxyl radical and ozone concn(7). [R52] ABIO: *Experimental rate constants for the gas-phase reaction of (D)-limonene with photochemically produced hydroxyl radicals of 1.70X10-10 cu cm/molec-sec at 25 deg C(1), 1.63X10-10 cu cm/molec-sec at 25 deg C(2) and 1.49X10-10 cu cm/molec-sec at 32 deg C(3) correspond to a half-life ranging from 2.3-2.6 hr(SRC) using an average atmospheric hydroxyl radical concn of 5X10+5 molec/cu cm(1). (D)-limonene was classified as group V in a 5 tiered rating system of relative reactivities towards photochemically produced hydroxyl radicals (methane=1, (D)-limonene=18,800), indicating a atmospheric half-life of < 0.24 hr(4). Experimental rate constants for the gas-phase reaction of (D)-limonene with ozone of 6.40X10-16 cu cm/molec-sec at 23 deg C(1,5,6) and 6.5X10-16 cu cm/molec-sec(3) correspond to a half-life ranging from 25-26 min(SRC) using an average atmospheric ozone concn of 7X10-11 molec\cu cm(5). An experimental rate constant for the night time gas phase reaction of (D)-limonene with nitrate radicals of 1.3X10-11 cu cm/molec-sec at 25 deg C(1) corresponds to a half-life of 3.1 min using an average nitrate radical concn of 2.4X10-8 molec/cu cm(7). Photolysis of (D)-limonene in the presence of nitrogen oxides produces formaldehyde, formic acid, carbon monoxide, carbon dioxide, acetaldehyde, peroxyacetyl nitrate and acetone(8). The daytime atmospheric lifetime of (D)-limonene has been estimated at 0.2-0.8 hr depending on both the local hydroxyl radical and ozone concn(8). [R53] BIOC: *Based on the water solubility of (D)-limonene, 13.8 mg/l at 25 deg C(1), and an estimated log octanol/water partition coefficient of 4.232(2,SRC), bioconcentration factors of 246 and 262, respectively, can be calculated using appropriate regression equations(3,SRC). These values indicate that (D)-limonene may bioconcentrate in fish and aquatic organisms(SRC). [R54] KOC: *Based on the water solubility of (D)-limonene, 13.8 mg/l at 25 deg C(1) and an estimated log octanol/water partition coefficient of 4.232(2,SRC), soil adsorption coefficients of 1030 and 4780, respectively, can be calculated using appropriate regression equations(3,SRC). These values indicate that (D)-limonene is expected to display slight to low mobility in soil(4). [R55] VWS: *Based on its vapor pressure, 20 mm Hg at 68.2 deg C(1), (D)-limonene may volatilize rapidly from dry soil to the atmosphere(SRC). A calculated Henry's Law constant of 0.380 atm cu-m/mole(2,SRC) indicates that (D)-limonene will rapidly volatilize from both water and moist soil to the atmosphere(3). The estimated half-life for volatilization of (D)-limonene from a model river 1 m deep flowing at 1 m/sec with a wind speed of 3 m/sec is 3.4 hr (3,SRC). The estimated half-life for volatilization from a model pond which takes into account adsorbtive processes, is 29 days(4,SRC). [R56] ATMC: *URBAN/SUBURBAN: (D)-limonene was detected indoors in an office building, 1987, at a concn ranging from 43-63 ug/cu-m(1). [R57] *RURAL/REMOTE: The average concn of (D)-limonene at a rural site in the Rocky Mts was 0.030 ppb during the day and 0.072 ppb at night, 1982(1). (D)-Limonene was qualitatively identified in air samples obtained at a forest in Germany, 1988(2). [R58] FOOD: *(D)-Limonene is a naturally occurring compound found in many natural oils including orange, lemon, grapefruit, berry, leaf, caraway, dill, bergamot, peppermint and spearmint oils(1,2,3,4). [R59] PFAC: PLANT CONCENTRATIONS: *(D)-Limonene was identified as a volatile constituent of Kiwi fruit flowers(1). [R60] RTEX: *Occupational exposure to (D)-limonene may occur by inhalation or dermal contact during its production, formulation, transport or use. Exposure to the general population may occur by inhalation due to its presence in the atmosphere as a result of its release from natural sources, or by ingestion of food in which it occurs naturally or to which it has been added as a flavor or fragrance. (SRC) *(D)-limonene was detected indoors in an office building, 1987, at a concn ranging from 43-63 ug/cu m(1). [R57] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Synthetic flavoring substances and adjuvants that are generally recognized as safe for their intended use include limonene (d-). [R61] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SILICA GEL TLC AND GC WERE USED FOR IDENTIFICATION OF D-LIMONENE. [R62] *HPLC SEPARATION OF A MIXTURE OF MONOTERPENES, INCLUDING D-LIMONENE. [R63] *Using a dual column GC equipped with two capillary columns coated with heptakis(6-O-methyl-2,3-di-O-pentyl)-beta-cyclodextrin and octakis(6-O-methyl-2,3-di-O-pentyl)-gamma-cyclodextrin, respectively, all important olefinic monoterpene hydrocarbons occurring in essential oils, including alpha-thujene, alpha- and beta-pinene, camphene, sabinene, alpha- and beta-phellandrene, DELTA3-carene and limonene can be resolved into enantiomers. With the chromatographic system described the characteristic enantiomeric composition of these monoterpene hydrocarbons in essential oils can be determined. [R64] *Modified cyclodextrins interact enantioselectively with a great variety of volatile chiral constituents of essential oils by forming diastereomeric inclusion complexes. Capillary gas chromatog. is used for resolving the enantiomers of terpenoid hydrocarbons (camphene, alpha-pinene, limonene, alpha-phellandrene), carbonyl cmpd (carvone, fenchone, menthone, isomenthone, piperitone, camphor, myrtenal), and alcs. (trifluoroacetylated beta-citronellol, myrtenol, trans-pinocarveol, 1-octen-3-ol, and underivatized linalool). The enantiomeric composition of some of these cmpd in a variety of essential oils is investigated. [R65] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Limonene in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 347 (1990) NIH Publication No. 90-2802 SO: R1: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 319 R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 865 R3: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 657 R4: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 283 R5: SRI R6: Royals EE, Horne SE; J Am Chem Soc 73: 5856-5857 (1951) R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-308 R8: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1705 R9: SRC; GEMS; Graphic Exposure Modeling System CLOGP USEPA (1987) R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 815 R11: Riddick JA et al; Organic Solvents NY: Wiley Interscience (1986) R12: SRC; Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) R13: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 514 R14: 49 CFR 171.2 (7/1/96) R15: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3133 (1988) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 73 322 (1999) R17: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-259 R18: Falk-Filipsson A et al; J Toxicol Environ Health 38 (1): 77-88 (1993) R19: TSUJI M ET AL; OYO YAKURI 9 (5): 775 (1975) R20: TSUJI M ET AL; OYO YAKURI 10 (2): 179 (1975) R21: KODAMA R ET AL; OYO YAKURI 13 (6): 885 (1977) R22: KODAMA R ET AL; OYO YAKURI 13 (6): 863 (1977) R23: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986.,p. 342 R24: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. R25: TSUJI M ET AL; OYO YAKURI 10 (2): 187 (1975) R26: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Limonene (gavage Studies) p. 3 (1990) Technical Rpt Series No. 347 NIH Pub No. 90-2802 R27: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Limonene (Gavage Studies) p.13 (1990) Technical Rpt Series No. 347 NIH Pub No. 90-2802 R28: DHHS/NTP; Toxicology and Carcinogenesis Studies of d-Limonene (Gavage Studies) p. 13 (1990) Technical Rpt Series No. 347 NIH Pub No. 90-2802 R29: Wattenberg LW et al; Cancer Res 49 (10): 2689-92 (1989) R30: Lehman-McKeeman LD et al; Toxicol Appl Pharmacol 99 (2): 250-9 (1989) R31: ARIYOSHI T ET AL; OYO YAKURI 18 (1): 195 (1979) R32: SCHENK J ET AL; Z GASTROENTEROL 18 (7): 389 (1980) R33: HO CH ET AL; ANAL CHEM 48 (14): 2223 (1976) R34: Elegbede JA et al; Carcinogenesis 14 (6): 1221-3 (1993) R35: Flamm WG, Lehman-McKeeman LD; Regul Toxicol Pharmacol 13 (1): 70-86 (1991) R36: Kanerva RL, Alden CL; Food Chem Toxicol 25 (5): 355-8 (1987) R37: Karlberg AT et al; Contact Dermatitis 26 (5): 332-40 (1992) R38: Karr LL et al; Pestic Biochem Physiol 36 (2): 175-86 (1990) R39: Lehman-Mckeeman LD, Caudill D; Toxicol Appl Pharmacol 112 (2): 214-21 (1992) R40: Lehman-McKeeman LD et al; Toxicol Lett 53 (1-2): 193-5 (1990) R41: Maltzman TH et al; Carcinogenesis 12 (11): 2081-7 (1991) R42: TSUJI M ET AL; OYO YAKURI 9(3): 387 (1975) R43: KODAMA R ET AL; XENOBIOTICA 6 (6): 377 (1976) R44: WATABE T ET AL; BIOCHEM PHARMACOL 29 (7): 1068 (1980) R45: Jonker D et al; Food Chem Toxicol 31 (1): 45-52 (1993) R46: Mehta RG, Moon RC; Anticancer Res 11 (2): 593-6 (1991) R47: Wattenberg LW, Coccia JB; Carcinogenesis 12 (1): 115-7 (1991) R48: (1) Rogers JAJR; Kirk-Othmer Encycl Chem Tech NY: Wiley 3rd ed. 16: 307-32 (1981) (2) Bauer K et al; pp. 141-50 in Ulmann's Encycl Indust Tech 5th ed. Gerhartz W et al; Eds VCH Publ A11 (1988) (3) Windholz M et al; The Merck Index. Rahway, NJ: Merck and Co Inc 10th ed. (1983) (4) Sax NI, Lewis RJSR; Hawley's Condensed Chemical Dictionary 11th ed. NY: Van Nostrand Reinhold Co pp. 425, 701 (1987) (5) Altshuller AP; Atmos Environ 17: 2131-65 (1983) R49: (1) Rogers JAJR; Kirk Othmer Encycl Chem Tech NY: Wiley 3rd Ed. 16: 307-332 (1981) (2) Sax NI, Lewis RJSR; Hawley's Condensed Chemical Dictionary 11th ed NY: Van Nostrand Reinhold Co pp. 425, 701 (1987) (3) Holohan SF et al; Kirk-Othmer Encycl Chem Tech NY: Wiley 3rd Ed. 12: 852-69 (1980) R50: (1) Riddick JA et al; Organic Solvents NY: Wiley Interscience (1986) (2) GEMS; Graphic Exposure Modeling System CLOGP USEPA (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-1 to 4-33 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) R51: (1) Riddick JA et al; Organic Solvents 4th ed NY: Wiley Interscience (1986) (2)GEMS; Graphic Exposure Modeling System CLOGP USEPA (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-1 to 4-33, 5-1 to 5-30 (1982) (4) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) R52: (1) Atkinson R; Atmos Environ 24A: 1-41 (1990) (2) Mulcahy MFR et al; in Occur Control Photochem Pollut Proc Symp Workshop. SESS, Paper No. IV: 1-7 (1976) (3) Winer AM et al; J Phys Chem: 80: 1635-9 (1976) (4) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (5) Altshuller AP; Atmos Environ 17: 2131-65 (1983) (6) Atkinson R; Chem Rev 85: 69-201 (1985) (8) Altshuller AP; Atmos Environ 17: 2131-65 (1983) R53: (1) Atkinson R; Atmos Environ 24A: 1-41 (1990) (2) Mulcahy MFR et al; in Occur Control Photochem Pollut Proc Symp Workshop. SESS, Paper No. IV: 1-7 (1976) (3) Winer AM et al; J Phys Chem: 80: 1635-9 (1976) (4) Darnall KR et al; Environ Sci Tech 10: 692-6 (1976) (5) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (6) Altshuller AP; Atmos Environ 17: 2131-65 (1983) (7) Atkinson R; Chem Rev 85: 69-201 (1985) (8) Altshuller AP; Atmos Environ 17: 2131-65 (1983) R54: (1) Riddick JA et al; Organic Solvents 4th ed NY: Wiley Interscience (1986) (2)GEMS; Graphic Exposure Modeling System CLOGP USEPA (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 5-1 to 5-30 (1982) R55: (1) Riddick JA et al; Organic Solvents 4th ed NY: Wiley Interscience (1986) (2)GEMS; Graphic Exposure Modeling System CLOGP USEPA (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 4-1 to 4-33 (1982) (4) Swann RL et al; Res Rev 85: 17-28 (1983) R56: (1) Riddick JA et al; Organic Solvents 4th ed NY: Wiley Interscience (1986) (2)Hine J, Mookerjee PK; J Org Chem 40: 292- 8 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 15-15 to 15-29 (1982) (4) USEPA; EXAMS II (1987) R57: (1) Weschler CJ et al; Am Ind Hyg Assoc J 51: 261-8 (1990) R58: (1) Roberts JM et al; Environ Sci Tech 19: 364-9 (1985) (2) Helmig D et al; Chemosphere 19: 1399-1412 (1989) R59: (1) Rogers JAJR; Kirk Othmer Encycl Chem Tech 3rd Ed. NY: Wiley 16: 307-32 (1981) (2) Bauer K et al; pp. 141-250 in Ullmann's Encycl Indust Tech 5th ed. Gerhartz W et al Eds. VCH Publ A11 (1988) (3) Windholz M et al; The Merck Index. Rahway, NJ: Merck and Co Inc 10th ed: (1983) (4) Sax NI, Lewis RJSR; Hawley's Condensed Chemical Dictionary 11th ed NY: Van Nostrand Reinhold Co pp. 701, 425 (1987) R60: (1) Tatsuka K et al; J Agric Food Chem 38: 2176-80 (1990) R61: 21 CFR 182.60 (4/1/91) R62: KUMAR A, SAXENA VK; INDIAN DRUGS 16 (4): 80 (1979) R63: JONES BB, ET AL; J CHROMATOGR 178 (2): 575 (1979) R64: Koenig WA et al; J High Resolut Chromatogr 15 (3): 184-9 (1992) R65: Koenig WA et al; J High Resolut Chromatogr 13 (5): 328-32 (1990) RS: 54 Record 280 of 1119 in HSDB (through 2003/06) AN: 4191 UD: 200211 RD: Reviewed by SRP on 1/31/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORINATED-TRISODIUM-PHOSPHATE- SY: *NCI-C55754-; *PHOSPHORIC-ACID,-TRISODIUM-SALT- (CHLORINATED); *SODIUM-HYPOCHLORITE-PHOSPHATE-; *TRISODIUM-PHOSPHATE,-CHLORINATED- RN: 56802-99-4 RELT: 583 [TRISODIUM PHOSPHATE] (Mixture component); 748 [SODIUM HYPOCHLORITE] (Mixture component) MF: *CL-Na4-O5-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *By reacting sodium phosphate, caustic soda, and sodium hypochlorite. [R1] MFS: *OLIN CORP, OLIN CHEMS GROUP, JOLIET, IL 60434 [R2] *STAUFFER CHEM CO, INDUST CHEM DIV, CHICAGO HEIGHTS, IL 60411, MORRISVILLE, PA 19067, RICHMOND, CA 94804 [R2] OMIN: *Active ingredients: 3.25% Min sodium hypochlorite and 91.75% Min trisodium phosphate dodecahydrate. Inert ingredient, less than 5% NaCl. [R1] *CHLORINATED TRISODIUM PHOSPHATE AT CONCN GREATER THAN OR EQUAL TO 0.2% HAD AN INACTIVATING EFFECT ON TYPE II POLIOVIRUS AND COXSACKIE B-1 AND B-6 ENTEROVIRUSES. [R3] *The use of chlorinated trisodium phosphate is declining. It has been largely replaced by chlorinated isocyanurates in powdered abrasive cleansers and automatic dishwashing detergents to reduce cost, improve performance, or comply with restrictions on the use of phosphates. [R4, p. V4 278] *Crystalline complex of hydrated trisodium phosphate and sodium hypochlorite. Commercial products have 3.5-3.7% available chlorine. They are probably a mixture of phosphate salts, and they contain some sodium chloride. [R4, p. V4 278] *Due to its active chlorine content, chlorinated trisodium phosphate has bleaching and bacterial properties in addition to the fat- and dirt-desolving effect resulting from its high alkalinity. [R5] *It is assumed that chlorinated trisodium phosphate is a mixture of 4(Na3PO4.11H2O).NaCl and 4(Na3PO4.11H2O).NaOCl resulting from the chlorination of crystalline trisodium phosphate. However, it contains free sodium chloride and a mixture of phosphate salts. Commercial material approximates the formula 4(Na3PO4.11H2O).NaOCl, and has a typical chlorine content of ca 4%. [R4, p. V18 688] USE: *Cleaner and bactericide in dairies, food plants, dishwashing compounds, scouring powders. [R1] *Still used in commercial laundries and in disinfectant cleaners. However, it has been largely replaced in powdered abrasive cleansers and automatic dishwashing detergents. [R4, p. V4 278] PRIE: U.S. PRODUCTION: *(1976) 8.63X10+10 to 9.08X10+10 GRAMS [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystalline solid [R1] MW: *238.4 PH: *Approximately 11.8 (1% solution) [R5] SOL: *Approximately 20 wt % at 25 deg C [R4, p. V18 688] OCPP: *Stable under normal storage conditions; in solution has the properties of both trisodium phosphate and sodium hypochlorite. [R1] *A crystalline complex of hydrated trisodium orthophosphate and sodium hypochlorite that releases hypochlorite when mixed with water. Its formula is (Na3PO4.11H20)4.NaOCl. [R4, p. V4 278] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SERI: *IRRITANT TO SKIN AND EYES. [R6] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *STABLE UNDER NORMAL STORAGE CONDITIONS [R6] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *... Under the conditions of these 2 yr studies, there was no evidence of carcinogenicity in either male or female B6C3F1 mice given chlorinated trisodium phosphate by gavage in water for 103 wk at doses of 500 or 1,000 mg. ... The studies in male and female F344/N rats were considered to be inadequate studies of carcinogenicity because the experiments were terminated at 35 wk due to poor survival. [R7] NTP: *Two yr toxicology and carcinogenesis studies of chlorinated trisodium phosphate ... were conducted by administering 0, 500, or 1,000 mg/kg (dose vol: 10 ml/kg) of the chemical in water by gavage, 5 days/wk for 103 wk, to groups of 50 male and 50 female B6C3F1 mice.Groups of mice receiving 250 mg/kg were included in these studies but were removed after 6 mo because of a lack of toxicity in the 500 and 1,000 mg/kg groups. Two yr studies were begun in male and female F344/N rats at doses of 0, 500, 1,000, or 2,000 mg/kg of chlorinated trisodium phosphate in water by gavage (10 ml/kg). The 2,000 mg/kg groups were killed at 15 wk because of poor survival, and the other groups were killed at 35 wk because of toxicity in the 1,000 mg/kg group. ... Under the conditions of these 2 yr studies, there was no evidence of carcinogenicity in either male or female B6C3F1 mice given chlorinated trisodium phosphate by gavage in water for 103 wk at doses of 500 or 1,000 mg. ... The studies in male and female F344/N rats were considered to be inadequate studies of carcinogenicity because the experiments were terminated at 35 wk due to poor survival. [R7] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Chlorinated trisodium phosphate is found on List D. Case No: 4021; Pesticide type: antimicrobial; Case Status: None of the active ingredients in the case are being supported for reregistration by their registrants. All are unsupported, or some are unsupported and some are cancelled. Cases described as "unsupported" generally are being processed for cancellation.; Active ingredient (AI): Chlorinated trisodium phosphate; AI Status: Registrants of the pesticide have not made or honored a commitment to seek reregistration, conduct the necessary studies, or pay the requisite fees, or they have asked EPA to cancel their product registrations. Unless some other interested party supports them, products containing the pesticide will be cancelled. [R8] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorinated trisodium phosphate in B6C3F1 Mice Technical Report Series No. 294 (1986) NIH Publication No. 87-2550 SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1190 R2: SRI R3: SHIROBOKOV VP ET AL; MIKROBIOL ZH (KIEV) 37(3) 368 (1975) R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R5: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA19 484 R6: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 894 R7: Toxicology and Carcinogenesis Studies of Chlorinated Trisodium Phosphate in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 294 (1986) NIH Publication No. 87-2550 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R8: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.300 (Spring, 1998) EPA 738-R-98-002 RS: 9 Record 281 of 1119 in HSDB (through 2003/06) AN: 4195 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIMETHYL-MORPHOLINOPHOSPHORAMIDATE- SY: *DIMETHYL-MORPHOLINOPHOSPHONATE-; *DMMPA-; *NCI-C54740-; *PHOSPHONIC-ACID,-MORPHOLINO-,-DIMETHYL-ESTER-; *PHOSPHONIC-ACID,-4-MORPHOLINYL-,-DIMETHYL-ESTER- RN: 597-25-1 MF: *C6-H14-N-O4-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *NOT PRODUCED COMMERCIALLY IN THE US [R1] USE: *SIMULANT FOR CHEMICAL AGENTS IN STUDYING EFFECTIVENESSS IN CHEMICAL DEFENSE PROCEDURES *PROPOSED ANTICHOLINESTERASE SIMULANT (MILITARY TRAINING) [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *195.18 TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *100 DAYS OF DERMAL APPLICATIONS TO RABBITS WAS WITHOUT EFFECT. THE SAME TREATMENT TO BOTH MALE AND FEMALE RATS DID NOT EFFECT BREEDING. HIGHEST DOSE HAVING NO EFFECT WAS 0.5 G/KG/DAY. [R2] *DMMPA SHOWED VERY LOW TOXICITY WHEN ADMIN ACUTELY TO MICE, and 28 DAYS OF APPLICATION TO SKIN OF RATS AND RABBITS PRODUCED NO EVIDENCE OF DAMAGE TO SKIN. [R3] *IN MICE, RATS AND RABBITS MAXIMUM NONTOXIC DOSE WAS IN NO CASE LESS THAN THE ESTIMATED LD(0) DOSE, INDICATING COMPD WAS REMARKABLY NONTOXIC AND SAFE FOR ACUTE EXPOSURES OF SMALL AMT TO MAN. [R4] +Dimethyl morpholinophosphoramidate was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using a standard protocol approved by the National Toxicology Program. Doses of 0, 100, 333, 1000, 3333, and 10,000 ug/plate were tested in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. These tests were negative and the highest ineffective dose level tested in any Salmonella tester strain was 10,000 ug/plate. [R5] +... Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenicity for male and female F344/N rats given dimethyl morpholinophosphoramidate, as indicated by incr incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for male and female B6C3F1 mice given dimethyl morpholinophosphoramidate at doses of 150 (male), 300 or 600 (female) mg/kg for 2 yr. [R6] NTXV: *LD50 MICE INTRAVENOUS 1717 MG/KG; [R7] NTP: +... In the 2 yr toxicology and carcinogenesis studies, groups of 50 male and 50 female F344/N rats were given dimethylmorpholinophosphoramidate in corn oil by gavage at doses of 0, 150, 300, or 600 mg/kg body weight, 5 days per week for 103 weeks. Groups of 50 male B6C3F1 mice were given dimethylmorpholinophosphoramidate at 0, 150, 300 mg/kg body weight, and groups of 50 female B6C3F1 mice were given dimethylmorpholinophosphoramide at 0, 300, 600 mg/kg body weight on the same schedule. ... Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenicity for male and female F344/N rats given dimethyl morpholinophosphoramidate, as indicated by incr incidences of mononuclear cell leukemia. There was no evidence of carcinogenicity for male and female B6C3F1 mice given dimethyl morpholinophosphoramidate at doses of 150 (male), 300 or 600 (female) mg/kg for 2 yr. [R6] ADE: *DIMETHYLMORPHOLINOPHOSPHORAMIDATE INJECTED INTO RATS WAS NOT ACCUMULATED IN ANY TISSUES AND LEVELS APPROACHING 0 WERE OBSERVED AT 40 HR AFTER INJECTION. URINE LEVELS WERE REDUCED TO 0 BY 4 DAYS AFTER INJECTION. [R8] *URINARY EXCRETION RATE WAS DETERMINED FOR 4, 8, 12 and 24 HR PERIODS FOLLOWING ITS IM INJECTION INTO HUMANS. WHEN DMMPA WAS INJECTED INTO DELTOID MUSCLE, IT COULD BE DETECTED IN URINE FOR 6 DAYS BUT NOT ON THE 7TH DAY. [R9] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *GAS CHROMATOGRAPHIC ASSAY FOR URINARY DIMETHYLMORPHOLINO-PHOSPHORAMIDATE (DMMPA). SENSITIVITY 5 NG DMMPA/L URINE. [R10] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Dimethylmorpholinophosphoramidate in F344/N Rats and B6C3F1 Mice Technical Report Series No. 298 (1986) NIH Publication No. 86-2554 SO: R1: SRI R2: COLEMAN IW; US NTIS, AD REP; ISS AD-A044751, 1977, 78 PP R3: MCNALLY WD, ADIE PA; US NTIS, AD REP; ISS AD-A044065, 1977, 17 PP R4: COLEMAN IW; US NTIS, AD REP; ISS AD-A044988, 1977, 56 PP R5: Zeiger E et al; Environ Mutagen 9:1-110 (1987) R6: Toxicology and Carcinogenesis Studies of Dimethyl Morpholinophosphoramidate in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 298 (1986) NIH Publication No. 86-2554 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R7: CHEYMOL ET AL; THERAPIE 19(5) 1411 (1964) R8: SHAW RK, MCDONALD ML; US NTIS, AD REP; ISS AD-A048358, 1977, 17 PP R9: MCNALLY ET AL; US NTIS, AD REP; ISS AD-A051778, 1978, 17 PP R10: MCNALLY WD, WENNER BJ; US NTIS, AD REP; ISS AD-050201. 1978, 13 PP RS: 6 Record 282 of 1119 in HSDB (through 2003/06) AN: 4200 UD: 200302 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DISPERSE-BLUE-1- SY: *ACETATE-BLUE-6-; *ACETOQUINONE-BLUE-L-; *ACETOQUINONE-BLUE-R-; *ACETYLON-FAST-BLUE-G-; *AMACEL-BLUE-GG-; *AMACEL-PURE-BLUE-B-; *9,10-ANTHRACENEDIONE,-1,4,5,8-TETRAAMINO-; *ANTHRAQUINONE,-1,4,5,8-TETRAAMINO-; *ARTISIL-BLUE-SAP-; *ARTISIL-BLUE-SAP-CONC-; *BRASILAZET-BLUE-GR-; *CELANTHRENE-PURE-BLUE-BRS-; *CELLITON-BLUE-G-; *CELLITON-BLUE-BB-CF-; *CELLITON-BLUE-EXTRA-; *CELLITON-BLUE-GA-CF-; *CI-DISPERSE-BLUE-1-; *CI-SOLVENT-BLUE-18-; *CI-64500-; *CIBACET-SAPPHIRE-BLUE-G-; *CILLA-BLUE-EXTRA-; *DIACELLITON-FAST-BLUE-R-; *DRACET-SAPPHIRE-BLUE-G-; *DURANOL-BRILLIANT-BLUE-CB-; *FENACET-BLUE-G-; *GRASOL-BLUE-2GS-; *KAYALON-FAST-BLUE-BR-; *MICROSETILE-BLUE-EB-; *MIKETON-FAST-BLUE-; *MIKETON-FAST-BLUE-B-; *NACELAN-BLUE-G-; *NCI-C54900-; *NEOSETILE-BLUE-EB-; *NYLOQUINONE-BLUE-2J-; *PERLITON-BLUE-B-; *SERINYL-BLUE-2G-; *SERINYL-BLUE-3G-; *SERINYL-BLUE-3GN-; *SETACYL-BLUE-2GS-; *SETACYL-BLUE-2GS-II-; *SUPRACET-BRILLIANT-BLUE-2GN-; *SUPRACET-DEEP-BLUE-R-; *1,4,5,8-TETRAAMINOANTHRAQUINONE-; *1,4,5,8-TETRAMINOANTHRAQUINONE- RN: 2475-45-8 MF: *C14-H12-N4-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Disperse Blue 1 has been prepared by acylation of 1,5-diaminoanthraquinone with oxalic acid, then nitration in sulfuric acid, followed by hydrolysis and reduction to the tetraamino compound; and by the reduction of mixed 1,5- and 1,8-dinitroanthraquinone to the corresponding diamino compounds, followed by acetylation, nitration, reduction, and hydrolysis. [R1] FORM: *One US distributor markets Disperse Blue 1 with a dye content of approximately 30% ... . [R2] *Commercial preparations of Disperse Blue 1 (approximately 50% 1,4,5,8-tetraaminoanthraquinone, 30% structurally related compounds and 20% water) contain approximately equal amounts of dyestuff and lignosulfonate dispersants (Burnett and Squire, 1986; National Toxicology Program, 1986). [R1] MFS: *Crompton and Knowles Corp., One Station Place, Metro Center, Stamford, CT 06902 (203)353-5400. [R3] OMIN: *CELLITON. TRADEMARK FOR SERIES OF DISPERSE DYESTUFFS CHARACTERIZED BY GOOD FASTNESS TO LIGHT, WASHING, ETC. USED FOR DYEING AND PRINTING ACETATE FIBERS. /CELLITON/ [R4, 174] *ANTHRAQUINONE DYE. DYE WHOSE MOLECULAR STRUCTURE IS BASED ON ANTHRAQUINONE (C6H4(CO)2C6H4). ...BENZENE RING STRUCTURE IS IMPORTANT IN DEVELOPMENT OF COLOR. /ANTHRAQUINONE DYE/ [R4, 64] USE: *DYE FOR SHEEPSKINS, FURS, THERMOPLASTIC RESINS, ACETATE, NYLON AND OTHER SYNTHETIC FIBERS [R5] *Disperse Blue 1 is used in the USA in semipermanent hair color formulations at concentrations of less than 1%. Disperse Blue 1 has been used as a fabric dye for nylon, cellulose acetate and triacetate, polyester, and acrylate fibers. It has also been used for surface dyeing of thermoplastics and as a solvent dye in cellulose acetate plastics. [R1] PRIE: U.S. PRODUCTION: *(1976) PROBABLY GREATER THAN 4.54X10+6 GRAMS [R5] *(1979) NOT PRODUCED COMMERCIALLY IN US [R5] *US production of Disperse Blue 1 was reported to be 159 tons in 1972 ... Separate figures were not reported after 1972, but production of all Disperse Blue dyes was approximately 6030, 9940 and 5740 tons in 1975, 1980 and 1985, respectively. ... [R6] U.S. IMPORTS: *(1977) 3.40X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R5] *(1979) 1.01X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R5] *... approximately 4-6 tons of the material are imported annually (NTP, 1986). [R6] *Approximately 4-6 tons of Disperse Blue 1 are imported annually. [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Blue-black microcrystalline powder [R1] MP: *332 deg C [R1] MW: *268.28 [R1] OWPC: *log P = -0.96 [R2] SOL: *30 ug/l in water at 25 deg C; soluble in acetone, ethanol, and cellosolve; slightly soluble in benzene and linseed oil(Enviro Control, 1981) [R1] SPEC: *Infrared, ultraviolet, and nuclear magnetic resonance spectral data have been reported (National Toxicology Program, 1986); infrared (prism {1477B}; prism-FT {1018A}) spectral data have also been reported by Pouchert (1981, 1985). [R1]; *lambda max is 615 nm, E1=1.8x10-4 [R7] VAP: *1.8X10-8 mm Hg @ 25 deg C [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R9, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R9, 1979.11] SSL: *Degrades at > -20 deg C [R2] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R9, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R9, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R9, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R9, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R9, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R9, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R9, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is sufficient evidence for the carcinogenicity of Disperse Blue 1 in experimental animals. No data were available from studies in humans on the carcinogenicity of Disperse Blue 1. Overall evaluation: Disperse Blue 1 is possibly carcinogenic to humans (Group 2B). [R10] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R9, 1979.23] NTOX: *Mouse: Groups of 50 male and 50 female B6C3F mice, 7 wk of age, were fed diets containing 0, 600, 1200 or 2500 ppm (mg/kg) diet Disperse Blue 1 (commercial grade without lignosulfonate dispersants, containing approximately 50% 1,4,5,8-tetraaminoanthraquinone, 19.5% water and approximately 30% other impurities, mainly an isomer of tetraaminoanthraquinone and a nitrotriaminoanthraquinone isomer) for 104 weeks to give doses in mg/kg bw per day of 0, 112, 239 and 540 in males and 0, 108, 235 and 520 in females. All animals were killed at 112-113 weeks of age. A significant trend to lower survival in higher dose males was observed when early deaths were excluded. The combined incidences of hepatocellular adenomas and carcinomas were increased in treated males (control, 9/50; low-dose, 21/50; mid-dose, 20/50; high-dose, 16/50) and in low-dose females (control, 3/50; low-dose, 13/49; mid-dose, 3/50; high-dose, 4/50). Group incidences did not indicate a dose-response effect, and survival-adjusted trends were not significant. The observed incidences of alveolar/bronchiolar adenomas and carcinomas in male mice were 4/50 in controls, 9/49 in low-dose animals, 5/50 in mid-dose animals and 11/50 in high-dose animals. When adjusted for survival, the increase was dose-related (p = 0.018, incidental tumor test for trend; adjusted rates, 15.0, 27.2, 13.9 and 49.3%, respectively). A high incidence of urinary bladder calculi was observed in mice of each sex. High-dose males and females also had a high incidence of transitional-cell hyperplasia of the bladder ... . [R11] *Rat: Groups of 50 male and 50 female Fischer 344/N rats, 7 wks of age, were fed diets containing 1, 1250, 2500 or 5000 ppm (mg/kg) diet Disperse Blue 1 (commercial grade without lignosulfonate dispersants, containing approximately 50% 1,4,5,8-tetraaminoanthraquinone, 19.5% water and approximately 30% other impurities, mainly an isomer of tetraaminoanthraquinone and a nitrotriaminoanthraquinone isomer) for 103 wks to give doses in mg/kg bw per day of 0, 45, 95 and 217 in males and 0, 56, 111 and 240 in females. All animals were killed at 111-112 wks of age. Survival in high-dose males and females and in mid-dose males was significantly reduced. Dose-related increases in the combined incidences of squamous-cell papillomas and carcinomas, transitional-cell papillomas and carcinomas, and leiomyomas and leiomyosarcomas of the bladder were observed in males and females. In addition, urinary bladder calculi were observed in the groups of rats in which the incidence of bladder tumors was increased ... A dose-related increase in the incidence of pancreatic islet-cell adenomas and carcinomas combined was seen in males: control, 1/49; low-dose, 2/50; mid-dose, 5/50; high-dose, 3/50 (p = 0.042, incidental tumor test for trend ...). [R11] *Disperse Blue 1 (containing 50% lignosulfonate dispersants) was administered to Fischer 344 rats in two short-term and one long-term studies. In one short-term study, it was given either by gavage at 1 g/kg bw for 1-3 days or in the diet at 1% for 4 days, and rats were killed the following day. In the second short-term study, it was given for 4 days, both orally by gavage at 1 g/kg bw at dietary levels of 0.5% commercial dye or 0.25% and 0.5% dye without dispersants. In the long-term study, the dye was administered to rats at dietary levels of 0, 0.01, 0.10 and 1.0% for up to 19 months; interim sacrifices were made for tritiated thymidine autoradiography of the bladder and examination of the principal body organs. Administration by gavage resulted in accumulation of the dye within the renal tubules and nephropathy within 3 days. Dietary dosing with 1% resulted in low-grade hyperplasia of the bladder urothelium, epithelial erosion, with adhesion of dye particles, and submucosal edema after 4 days. At weeks 5, 9 and 17, there was increased DNA synthesis in the urothelium of high-dose rats but no increased labelling in any other group. Bladder lesions were seen only at the 1% level; epithelial erosion with adhering dye particles was seen by day 4, calculi and hyperplasia by week 5 and squamous metaplasia by week 9. The calculi contained more dye in males than in females and more calcium in females than in males. By month 6, dye particles were embedded in the bladder wall, with some evidence of histiocyte accumulation in their vicinity ... . [R12] *Disperse Blue 1 was administered to Fischer 344/N rats and B6C3F mice by oral administration in the diet for 14 days, 13 weeks or 2 years. In the 14-day studies, 2/5 female rats died after receiving 50,000 ppm (mg/kg), and all mice receiving 25,000 ppm or more died. In the 13-week studies, diets containing concentrations up to 20,000 and 20,000 ppm were fed to rats and mice, respectively. No compound-related death occurred in rats, but deaths occurred with 10,000 ppm in mice of each sex. Pathological changes that occurred in rats and mice given diets containing 2500 ppm or more included urinary tract calculi, urinary bladder inflammation, hyperplasia of the urinary bladder transitional epithelium and nephrosis. In the 2-year studies ... lesions related to treatment in rats included renal and urinary bladder calculi, renal casts, hydronephrosis and renal degeneration, renal and urinary bladder epithelial hyperplasia, urinary bladder squamous metaplasia and pigmentation of the urinary bladder and kidney. Lesions in mice that were considered to be related to treatment were inflammation, epithelial hyperplasia, calculi and fibrosis in the urinary bladder, casts in the renal tubular lumina and renal tubular degeneration ... . [R13] *Oral administration of a commercial product (a composite of dyes and base components found in semipermanent hair dyes) containing 0.61% Disperse Blue 1 among other dyes had no effect on fertility, gestation, lactation or viability indices in rats and induced no teratogenicity in rats or rabbits ... . [R13] *Disperse Blue 1 was weakly mutagenic to Salmonella typhimurium TA1537, in the presence and absence of an exogenous metabolic system from Aroclor 1254-induced rat liver; it was not mutagenic to several other strains ... In liquid preincubation assays, it was mutagenic to TA1535, TA97 and TA98 ... . [R13] +s No. 299 (1986) NIH Publication No. 86-2555] ... Under the conditions of these feed studies of C.I. Disperse Blue 1, there was clear evidence of carcinogenicity for male and female F344/N rats as shown by increased occurrence of transitional cell papillomas and carcinomas, of leiomyosarcomas, and of squamous cell papillomas and carcinomas of the urinary bladder. Urinary bladder calculi were observed in the groups of rats in which urinary bladder neoplasms were increased. Positive associations existed between the presence of calculi and transitional cell neoplasms in male and female rats, leiomyomas or leiomyosarcomas (combined) in female rats, and squamous cell neoplasms in male rats. A marginally increased occurrence of pancreatic islet cell adenomas or carcinomas (combined) was observed in male rats exposed to C.I. Disperse Blue 1. There was equivocal evidence of carcinogenicity of C.I. Disperse Blue 1 in male B6C3F1 mice as shown by marginally increased incidences of hepatocellular adenomas or carcinomas (combined) in dosed male mice and a marginally increased occurrence of alveolar/bronchiolar adenomas or carcinomas (combined) in high dose male mice. There was no evidence of carcinogenicity of C.I. Disperse Blue 1 in female B6C3F1 mice. [R14] NTXV: *The oral LD50 value for various dyes, including Disperse Blue 1, in rats ranged from 1.2 to > 6.3 g/kg bw ... ; [R12] NTP: +s No. 299 (1986) NIH Publication No. 86-2555] C.I. Disperse Blue 1 ... was studied as a commercial grade product (minus lingnosulfate dispersants) for toxicity and carcinogenicity in single administration gavage for ... 104 wk. ... All studies used F344/N rats and B6C3F1 mice. ... In the 2 yr studies in rats, groups of 5 animals of each sex were administered the /test cmpd/ at dietary concentrations of 0, 1,250, 2,500, or 5,000 ppm. These dietary concentrations corresponded to 0, 45, 95, and 217 mg/kg/day for males and 0, 56, 111, and 240 mg/kg/day for females. ... In the 2 yr studies in mice, 50 animals of each sex were administered diets containing the /test cmpd/ at 0, 600, 1,200, or 2,500 ppm. The dietary concentrations corresponded to doses of 0, 112, 239, and 540 mg/kg/day for males and 0, 108, 235, and 520 mg/kg/day for females. ... Under the conditions of these feed studies of C.I. Disperse Blue 1, there was clear evidence of carcinogenicity for male and female F344/N rats as shown by increased occurrence of transitional cell papillomas and carcinomas, of leiomyosarcomas, and of squamous cell papillomas and carcinomas of the urinary bladder. Urinary bladder calculi were observed in the groups of rats in which urinary bladder neoplasms were increased. Positive associations existed between the presence of calculi and transitional cell neoplasms in male and female rats, leiomyomas or leiomyosarcomas (combined) in female rats, and squamous cell neoplasms in male rats. A marginally increased occurrence of pancreatic islet cell adenomas or carcinomas (combined) was observed in male rats exposed to C.I. Disperse Blue 1. There was equivocal evidence of carcinogenicity of C.I. Disperse Blue 1 in male B6C3F1 mice as shown by marginally increased incidences of hepatocellular adenomas or carcinomas (combined) in dosed male mice and a marginally increased occurrence of alveolar/bronchiolar adenomas or carcinomas (combined) in high dose male mice. There was no evidence of carcinogenicity of C.I. Disperse Blue 1 in female B6C3F1 mice. [R14] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Disperse Blue 1's production and subsequent use in semipermanent hair color formulations, as a fabric dye for nylon, cellulose acetate and triacetate, polyester, and acrylate fibers and for surface dyeing of thermoplastics and as a solvent dye in cellulose acetate plastics may result in its release to the environment through various waste streams. If released to the atmosphere, Disperse Blue 1 will exist mainly in the particulate phase where it will be removed through both wet and dry deposition. Based on estimated Koc values of 1000 and 30000, Disperse Blue 1 should have low to no mobility in soil. Volatilization from either moist or dry soil surfaces is not expected. Disperse Blue is expected to bind to particulate matter and sediment in the water column based on its estimated Koc values. It is not expected to volatilize from water surfaces based on an estimated Henry's Law constant of 2.1X10-7 atm-cu m/mol. Disperse Blue 1 may bioconcentrate in aquatic organisms given estimated BCF values of 110 and 4500. Exposure to Disperse Blue 1 may occur occupationally during its production or during its use as a hair and fabric dye. (SRC) ARTS: *Disperse Blue 1's production and subsequent use in semipermanent hair color formulations, as a fabric dye for nylon, cellulose acetate and triacetate, polyester, and acrylate fibers and for surface dyeing of thermoplastics and as a solvent dye in cellulose acetate plastics(1) may result in its release to the environment through various waste streams(SRC). [R15] FATE: *TERRESTRIAL FATE: Estimated Koc values of 1000(1,SRC), based on an estimated log Kow(2,SRC), and 30000(1,SRC), based on an experimental water solubility(3), suggest that Disperse Blue 1 will have low to no mobility in soil(4). It may also bind strongly to organic matter in the soil as the aromatic amino group is indicated as a highly reactive group with an affinity for organic matter(5). It is not expected to volatilize from dry or moist soil surfaces based on a vapor pressure of 1.8X10-8 mm Hg(6) and an estimated Henry's Law constant of 2.1X10-7 atm-cu m/mol(7,SRC), respectively. [R16] *AQUATIC FATE: If released to water, Disperse Blue 1 may bind strongly to particulate matter and sediment in the water column given estimated Koc values of 1000(1,SRC), based on an estimated log Kow value(2,SRC), and 30000(1,SRC), based on a measured water solubility(3). It may also bind strongly to organic matter in the water column(SRC) as the aromatic amino group is indicated as a highly reactive group with an affinity for organic matter(4). Estimated BCF values ranging from 110(5,SRC), based on an estimated log Kow(2,SRC), to 4500(5,SRC), based on an experimental water solubility(3), indicate that Disperse Blue 1 may bioconcentrate in an aquatic system(5,SRC). Disperse Blue 1 should not volatilize from water surfaces based on an estimated Henry's Law constant of 2.1X10-7 atm-cu m/mol(6,SRC). [R17] *ATMOSPHERIC FATE: Based on an experimental vapor pressure of 1.8X10-8 mm Hg at 25 deg C(1,SRC), Disperse Blue 1 should exist almost entirely in the particulate phase in the ambient atmosphere(2,SRC). Disperse Blue 1 will degrade in the vapor phase by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 2.8 hours(3,SRC). Particulate phase Disperse Blue 1 may be removed physically from air by wet and dry deposition(SRC). [R18] ABIO: *The rate constant for the vapor phase reaction of Disperse Blue 1 with photochemically produced hydroxyl radicals has been estimated as 1.4X10-10 cu cm/molecule-sec at 25 deg C(1,SRC). This value corresponds to an atmospheric half-life for Disperse Blue 1 of about 3 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals/cu cm (1,SRC). [R19] BIOC: *A BCF of 110 was calculated for Disperse Blue 1, using an estimated log Kow of 2.98(1,SRC) and a recommended regression-derived equation(2,SRC). Based on an experimental water solubility of 0.030 mg/l(3), the BCF of Disperse Blue 1 is estimated as approximately 4466 using a regression-derived equation(2,SRC). These BCF values suggest that Disperse Blue 1 may bioconcentrate in aquatic organisms(2,SRC). [R20] KOC: *Based on an estimated log Kow of 2.98(1,SRC), the Koc of Disperse Blue 1 is estimated as approximately 1000 using a regression-derived equation(2,SRC). Based on an experimental water solubility of 0.030 mg/l(3), the Koc of Disperse Blue 1 is estimated as approximately 30,000 using a regression-derived equation(2,SRC). According to a suggested classification scheme(4), these estimated Koc values suggest that Disperse Blue 1 has low to no mobility in soil(SRC). It may also bind strongly to organic matter in the soil as the aromatic amino group is indicated as a highly reactive group with an affinity for organic matter(5,SRC). [R21] VWS: *The Henry's Law constant for Disperse Blue 1 is estimated as 2.1X10-7 atm-cu m/mole(1,SRC) using an experimental vapor pressure of 1.8X10-8 mm Hg(2) and an experimental water solubility of 0.03 mg/l(3). This suggests that Disperse Blue 1 does not volatilize from water surfaces(1,SRC). [R22] RTEX: *... since Disperse Blue 1 is used in hair dyes, dermal and inhalation exposures may occur among people producing and applying such products. [R6] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 43,520 workers (32,058 of these are female) are potentially exposed to Disperse Blue 1 in the USA(1). [R23] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A method has been described for the spectrophotometric determination of Disperse Blue 1 sorbed on polyethylene terephthalate fibers by dye extraction in mixed solvent systems (Madan and Khan, 1978). [R1] *A polarographic method for the determination of aminoanthraquinones, including 1,4,5,8-tetraaminoanthraquinone, in environmental and biological samples can be used to determine concentrations as low as 0.1-0.5 mg/ml (Popescu and Barbacaru, 1985). [R1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I. Disperse Blue 1 in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 299 (1986) NIH Publication No. 86-2555 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 139 (1990) R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 140 (1990) R3: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994.p. 3-207 R4: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. R5: SRI R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 141 (1990) R7: Kuroiwa S, Ogasawara S; Dispersed State of Dyes and Their Dyeing Properties. VIII. Solubilities of Disperse Dyes in Water. Nippon Kagaku Kaishi. p. 1738-43 (1973) R8: Baughman GL, Perenich TA; Environ Toxic Chem 7: 183-99 (1988) R9: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 145 (1990) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 142 (1990) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 143 (1990) R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 144 (1990) R14: Toxicology and Carcinogenesis Studies of C.I. Disperse Blue 1) in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 299 (1986) NIH Publication No. 86-2555 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: (1) IARC; in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Some Flame Retardants and Textile Chemicals, and Exposures in the Textile Manufacturing Industry. 48: 139 (1990) R16: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Kuroiwa S, Ogasawara S; Nippon Kagaku Kaishi (9): 1738-43 (1973) (4) Swann RL et al; Res Rev 85: 23 (1983) (5) Adrian, P et al; Toxicol Environ Chem 20-21: 109-120 (1989) (6) Baughman GL, Perenich TA; Environ Toxic Chem 7: 183-99 (1988) (7) Meylan W, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) R17: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Kuroiwa S, Ogasawara S; Nippon Kagaku Kaishi (9): 1738-43 (1973) (4) Adrian, P et al; Toxicol Environ Chem 20-21: 109-120 (1989) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (6) Meylan W, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) R18: (1) Baughman GL, Perenich TA; Envir Toxic Chem 7: 183-99 (1988) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 213-8 (1993) R19: (1) Meylan WM, Howard PH; Chemosphere 26: 213-218 (1993) R20: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Kuroiwa S, Ogasawara S; Nippon Kagaku Kaishi (9): 1738-43 (1973) R21: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Kuroiwa S, Ogasawara S; Nippon Kagaku Kaishi (9): 1738-43 (1973) (4) Swann RL et al; Res Rev 85: 23 (1983) (5) Adrian, P et al; Toxicol Environ Chem 20-21: 109-120 (1989) R22: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc p. 15-15 to 15- 29 (1990) (2) Baughman GL, Perenich TA; Environ Toxic Chem 7: 183-99 (1988) (3) Kuroiwa S, Ogasawara S; Nippon Kagaku Kaishi (9): 1738-43 (1973) R23: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) RS: 41 Record 283 of 1119 in HSDB (through 2003/06) AN: 4203 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HC-RED-#3- SY: *ETHANOL, 2-(4-AMINO-2-NITROANILINO)-; *ETHANOL, 2-((4-AMINO-2-NITROPHENYL)AMINO)-; *HC-RED-NO-3- RN: 2871-01-4 MF: *C8-H11-N3-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *NOT PRODUCED COMMERCIALLY IN THE US [R1] USE: *DYE IN SEMI-PERMANENT HAIR DYES [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *197.20 TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of HC Red No. 3. There is inadequate evidence in experimental animals for the carcinogenicity of HC Red No. 3. Overall evaluation: HC Red No. 3 is not classifiable as to its carcinogenicity to humans (Group 3). [R2] NTOX: +... Under the conditions of these 2-year gavage studies of HC Red No. 3, there was no evidence Or carcinogenicity for male or female F344/N rats given 250 or 500 mg/kg per day. There was equivocal evidence of carcinogenicity for male B6C3F1 mice as indicated by an increased incidence of hepatocellular adenomas or carcinomas (combined) in the 250 mg/kg dose group. Poor survival coupled with lack of significant findings rendered the study in female B6C3F1 mice an inadequate study of carcinogenicity. Both sexes of both species may have been able to tolerate higher doses of HC Red No. 3. Therefore, the sensitivity of these studies for detecting carcinogenesis may have been limited. [R3] NTP: +Toxicology and carcinogenesis studies of HC Red No. 3 (97% pure) ... were conducted by admin the chemical in corn oil by gavage for 105 weeks to groups of 50 male and 50 female F344/N rats and for 104 weeks to groups of 50 male and 50 female B6C3F1 mice. The dosage regimen used for rats was 0, 250, or 500 mg/kg per day and for mice, 0, 125. or 250 mg/kg per day. Doses were administered 5 days per week. ... Under the conditions of these 2-year gavage studies of HC Red No. 3, there was no evidence Or carcinogenicity for male or female F344/N rats given 250 or 500 mg/kg per day. There was equivocal evidence of carcinogenicity for male B6C3F1 mice as indicated by an increased incidence of hepatocellular adenomas or carcinomas (combined) in the 250 mg/kg dose group. Poor survival coupled with lack of significant findings rendered the study in female B6C3F1 mice an inadequate study of carcinogenicity. Both sexes of both species may have been able to tolerate higher doses of HC Red No. 3. Therefore, the sensitivity of these studies for detecting carcinogenesis may have been limited. [R3] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of HC Red No. 3 in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 281 (1986) NIH Publication No. 86-2537 SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 57 157 (1993) R3: Toxicology and Carcinogenesis Studies of HC Red No. 3 in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 281 (1986) NIH Publication No. 86-2537 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 RS: 4 Record 284 of 1119 in HSDB (through 2003/06) AN: 4208 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ZEARALENONE- SY: *BENZOXACYCLOTETRADEC-11-EN-1-ONE,-14,16-DIHYDROXY-3-METHYL-7-OXO-,-TRANS-; *1H-2-BENZOXACYCLOTETRADECIN-1,7(8H)-DIONE, 3,4,5,6,9,10-HEXAHYDRO-14,16-DIHYDROXY-3-METHYL-, (S-(E))-; *1H-2-BENZOXACYCLOTETRADECIN-1-ONE, 3,4,5,6,7,8,9,10-OCTAHYDRO-14,16-DIHYDROXY-3-METHYL- 7-OXO-, (E)-; *COMPOUND-F-2-; *FES-; *3,4,5,6,9,10-HEXAHYDRO-14,16-DIHYDROXY-3-METHYL-1H-2-B ENZOXACYCLOTETRADECIN-1,7(8H)-DIONE; *6-(10-HYDROXY-6-OXO-TRANS-1-UNDECENYL)-BETA-RESORCYLIC ACID-N-LACTONE; *6-(10-HYDROXY-6-OXO-TRANS-1-UNDECENYL)-BETA-RESORCYLIC ACID LACTONE; *MYCOTOXIN-F-2-; *NCI-C50226-; *RESORCYLIC ACID, 6-(10-HYDROXY-6-OXO-1-UNDECENYL)-, MU-LACTONE, TRANS-; *F-2-TOXIN-; *TOXIN-F2-; *(-)-ZEARALENONE; *(S)-ZEARALENONE; *TRANS-ZEARALENONE-; *(10S)-ZEARALENONE RN: 17924-92-4 MF: *C18-H22-O5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FERMENTATION OF BACTERIAL CULTURES (GIBBERELLA ZEAE OR ATCC 20273) FOLLOWED BY EXTRACTION AND CRYSTALLIZATION [R1] *SYNTH OF DL-FORM: TAUB ET AL, CHEM COMMUN 1967, 225; NETHERLAND PATENT 68,12148 (1968 TO MERCK AND CO); VLATTAS ET AL, J ORG CHEM 33, 4176 (1968). TOTAL SYNTH AND ABSOLUTE CONFIGURATION: TAUB ET AL, TETRAHEDRON 24, 2443 (1968); GIROTRA, WENDLER, US PATENTS 3,551,455 (1970 TO MERCK AND CO). /DL-FORM/ [R2] MFS: *NOT PRODUCED COMMERCIALLY IN US [R1] OMIN: *ISOLATION OF L-FORM FROM MYCELIA OF FUNGUS GIBBERELLA ZEAE (FUSARIUM GRAMINEARUM): STOB ET AL, NATURE 196, 1318 (1962); ANDREWS, STOB, US PATENT 3,196,019 (1965 TO PURDUE RESEARCH FOUNDATION); HODGE ET AL, US PATENTS 3,239,341/2 (BOTH 1966 TO COMMERCIAL SOLVENTS). [R2] *ZEARALENONE IS ONE OF GROUP OF COMPD KNOWN UNDER MORE GENERAL NAME OF RALS OR RESORCYLIC ACID LACTONES. [R2] *ZEARALENONE WAS NOT DESTROYED @ 80-120 DEG C IN NEUTRAL MEDIUM, BUT WAS @ HIGH TEMP @ PH 11 AND ABOVE. IT IS ALSO DESTROYED BY AQ AMMONIA OR HYDROGEN PEROXIDE. NEITHER OF THESE DETOXIFICATION PROCEDURES IS IN COMMERCIAL USE. [R3] *SEVERAL CLINICAL AND PHYSICAL TREATMENTS WERE INVESTIGATED AS POSSIBLE METHODS FOR DESTROYING ZEARALENONE IN CONTAMINATED CORN. NO TREATMENT USED IN THIS STUDY SIGNIFICANTLY REDUCED ZEARALENONE LEVELS IN WHOLE-KERNEL CORN. [R4] *ZEARALENONE ADMIN ORALLY OR IM FOR 7 CONSECUTIVE DAYS. RESULTS DEMONSTRATE THAT CHICKENS ARE HIGHLY TOLERANT AND THAT ESTROGENIC EFFECTS ARE GREATER WHEN IT IS ADMIN IN MULTIPLE DOSES THAN IN SINGLE DOSE AND IN IM THAN ORALLY. [R5] USE: *CHEMICAL INTERMEDIATE FOR ZERANOL AND ITS 7-HYDROXY EPIMER; VETERINARY ANABOLIC AGENT [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *318.36 [R2] OCPP: *MAX ABSORPTION (METHANOL): 236 NM (E= 29,700), 274 NM (E= 13.909), 316 NM (E= 6020) /L-FORM/ [R2] *MP: 187-189 DEG C /DL-FORM/ [R2] *MP: 123-125 DEG C /L-FORM DIACETATE/ [R2] *CRYSTALS /L-FORM, DL-FORM, AND L-FORM DIACETATE/ [R2] *SOL IN AQ ALKALI, ETHER, BENZENE, ALCOHOLS; PRACTICALLY INSOL IN WATER; SPECIFIC OPTICAL ROTATION: -170.5 DEG @ 25 DEG C/546 (METHANOL, 1%); MP: 164-165 DEG C /L-FORM/ [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of toxins derived from Fusarium graminearum. No data were available on the carcinogenicity to humans of derived from F. crookwellense and F. culmorum. There is limited evidence in experimental animals for the carcinogenicity of zearalenone. ... Overall evaluation: Toxins derived from Fusarium graminearum, F. culmorum and F. crookwellense are not classifiable as to their carcinogenicity to humans (Group 3). [R6] NTOX: *INJECTION OF 30 MUG OF ZEARALENONE/RAT ON 2ND DAY OF LIFE DECR % OF NORMAL PREGNANCIES IN INJECTED FEMALES MATED WITH INTACT MALES FROM 93-33%, WHEREAS INJECTED MALES SIRED 44% NORMAL PREGNANCIES WITH INTACT FEMALES AND 40% NORMAL PREGNANCIES WITH INJECTED FEMALES. [R7] *ADMIN OF ZEARALENONE TO MICE INDUCED INCR IN UTERINE RNA, PROTEIN AND DNA. IN VITRO INCUBATION OF UTERINE TISSUE ISOLATED FROM PRETREATED MICE DEMONSTRATED TEMPORAL ELEVATION OF RNA AND PROTEIN SYNTHESIS. [R8] *ADMIN OF ZEARALENONE TO MICE HAD ACCELERATING EFFECT ON CELLULAR PERMEABILITY TO (14)C-ALPHA-AMINOISOBUTYRIC ACID, (14)C-(3-O-METHYL)-GLUCOSE AND (3)H-URIDINE AND THIS ALTERATION OF UTERINE PERMEABILITY IS PRESUMED TO BE PRIMARY EFFECT OF ZEARALENONE. [R8] *ZEARALENONE IN GELATIN CAPSULES ADMIN TO WHITE LEGHORN CHICKENS IN SINGLE ORAL DOSE OF 15.0 G/KG. ALL CHICKENS SURVIVED 10 DAY EXPT AND HAD SIGNIFICANTLY LESS SERUM CALCIUM BUT SIGNIFICANTLY GREATER SERUM PHOSPHORUS THAN CONTROLS. [R5] *ADDN OF 40 PPM ZEARALENONE TO FOOD OF MALE CHICKS FOR 10 DAYS HAD LITTLE EFFECT ON WT GAIN OR EFFICIENCY OF FOOD CONVERSION, BUT SIGNIFICANTLY INCR WT OF TESTES AND COMB. [R9] *ORAL DOSE OF ZEARALENONE OF 5 MG/KG BODY WT TO RATS RESULTED IN LESS THAN NORMAL WT GAIN, and 25 MG/KG/DAY REDUCED WT GAIN, NUMBER OF CORPORA LUTEA, AND SIZE OF TESTICLES. [R3] *ADMIN OF 25 and 100 PPM OF ZEARALENONE TO HOLSTEIN COWS FOR 42 DAYS RESULTED IN SWOLLEN AND HYPEREMIC EXTERNAL GENITALIA WITHIN 1 WK AFTER TREATMENT BEGAN. [R3] *ZEARALENONE @ CONCN OF 100 PPM CONSUMED BY SWINE FOR 1 WK RESULTED IN DEGENERATIVE LESIONS IN OVARY AND IN MIDPART OF UTERAL HORN. OVULATION WAS SUPPRESSED, AND DEGENERATION OF UTERINE GLANDS IN MUCOSA OF UTERUS CONTRIBUTED TO INFERTILITY. [R3] *UTERUS WT OF GILTS WAS INCR APPRECIABLY BY ADMIN OF 5 MG ORAL ZEARALENONE/DAY; 1 MG/DAY PRODUCED TUMEFACTION OF VULVA. CONSUMPTION BY PREGNANT SWINE OF FEED CONTAMINATED BY ZEARALENONE MAY BE RESPONSIBLE FOR DECR FERTILITY. [R3] *TERATOGENICITY OF ZEARALENONE WAS STUDIED FOLLOWING ORAL ADMIN TO RAT. [R10] *RATS GIVEN ZEARALENONE BY STOMACH TUBE FROM DAY 6-15 AFTER MATING. NO SIGNS OF TOXICITY IN PREGNANT FEMALES...WT LOSS WITH 10 MG/KG BODY WT/DAY, BUT IN FETUSES INCIDENCE OF DELAYED OR ABSENT SKELETON OSSIFICATION INCR WITH INCR DOSAGE [R3] *5 MG OF PURIFIED F-2 TOXIN IM INTO SWINE EACH DAY DURING LAST MO OF PREGNANCY; ENLARGEMENT OF VULVA WAS OBSERVED IN GILT, BUT NOT IN SOW. SOW FARROWED 12 PIGLETS, 3 WERE STILLBORN AND 5 HAD SPLAYLEG; ALL 8 PIGLETS OF GILT HAD SEVERE SPLAYLEG. [R3] *CONSUMPTION BY TURKEY POULTS OF FEED CONTAINING 300 PPM OF ZEARALENONE RESULTED WITHIN 4 DAYS OF ENLARGED VENTS; IN CHICKS IT INCR WT OF BURSA OF FABRICIUS, INCR COMB WT, AND INCR IN NUMBER OF CYSTS IN GENITAL TRACT. [R3] *ZEARALENONE CONSUMED IN RATION DECR OR COMPLETELY INHIBITED FERTILITY OF GANDERS AND TURKEY TOMS, DEPENDING ON AMT CONSUMED; BOTH QUANTITY OF SPERM AND VIABILITY OF SPERMATOZOA WERE REDUCED, AND EPITHELIAL CELLS OF TESTICLES DEGENERATED. [R3] *VULVOVAGINITIS OCCURRED IN PIGS CONSUMING MAIZE INFECTED BY FUSARIUM GRAMINEARUM AND CONTAMINATED WITH ZEARALENONE. [R11] *CHICKENS AND TURKEY POULTS WERE FED ZEARALENONE @ LEVELS OF 0 (CONTROL), 10, 25 (TURKEYS ONLY), 50, 100, 200, 400, and 800 MG/KG DIET FOR 3-WK PERIOD TO EVALUATE ITS TOXICITY. EFFECTS WERE MINIMAL. [R12] *MALE SWINE FED GRAIN CONTAINING 30 PPM F-2 TOXIN. TOXIN INDUCES NOT ONLY THE ESTROGENIC SYNDROME BUT ALSO AFFECTS SPERMATOGENESIS AND SEXUAL MATURATION IS ACCELERATED. [R13] *ZEARALENONE TESTED @ SEVERAL CONCN RANGING 1-500 MUG/PLATE WAS NOT MUTAGENIC TO SALMONELLA TYPHIMURIUM STRAINS TA 1538, TA 98 OR TA 100 @ ANY CONCN. [R14] *ZEARALENONE TESTED FOR MUTAGENICITY BY AMES METHOD DID NOT CAUSE ELEVATION OF THE NUMBER OF REVERTANTS FOR SALMONELLA TYPHIMURIUM TESTER STRAINS AND @ LOW CONCN EXERTS NO MUTAGENIC EFFECTS. [R15] +Pregnant mature gilts were given 0 or 108 mg/day of zearalenone (ZE) mixed in the feed on post-mating days (pmd) 2 to 6, 7 to 10, or 11 to 15. Blood samples were taken on pmd 6, 10, and 15 from control gilts, and from treated gilts on the last day that ZE was consumed. All gilts were killed on pmd 30 to 32. Embryonic survival was reduced in gilts given ZE on pmd 7 to 10. There were no differences in the number of fetuses per gilt in the control, pmd 2 to 6, or pmd 11 to 15 treatment groups. Serum samples from treated gilts on pmd 10 and 15 had lower mean prolactin (PRL) concentration than those from controls. The number of spikes of serum luteinizing hormone (LH) was reduced in gilts treated on pmd 15 compared with controls. The peak of secretion of estradiol-17beta observed in controls at pmd 10 to 14 was absent in treated gilts. [R16] +... Under the conditions of this bioassay, zearalenone was not carcinogenic for F344/N rats of either sex. Zearalenone should be considered carcinogenic in B6C3Fl mice, as evidenced by the incr proportion of male and female mice with pituitary adenomas and by the incr proportion of female mice with hepatocellular adenomas. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Negative; Male Mice: Positive; Female Mice: Positive. [R17] NTP: +A carcinogenesis bioassay of zearalenone ... was conducted by feedmg diets containing 25 or 50 ppm zearalenone to groups of 50 F344/N rats of each sex and 50 or 100 ppm to groups of 50 B6C3Fl mice of each sex for 103 wk. Groups of 50 rats and 50 mice of each sex served as controls. ... Under the conditions of this bioassay, zearalenone was not carcinogenic for F344/N rats of either sex. Zearalenone should be considered carcinogenic in B6C3Fl mice, as evidenced by the incr proportion of male and female mice with pituitary adenomas and by the incr proportion of female mice with hepatocellular adenomas. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Negative; Male Mice: Positive; Female Mice: Positive. [R17] ADE: *WHEN (14)C-LABELED ZEARALENONE ADMIN BY GAVAGE TO WHITE LEGHORN LAYING HENS, 94% OF ADMIN (14)C WAS ELIMINATED VIA EXCRETA WITHIN 72 HR. NO MAJOR RETENTION SITES OF (14)C ACTIVITY WERE FOUND, BUT PERSISTENT LEVELS OF LIPOPHILIC METABOLITES WERE DETECTED IN EGG YOLK. [R18] *ZEARALENONE WITH RADIOACTIVE CARBON WAS ADMIN ORALLY TO RATS AND OF PORTION RECOVERED, 70-80% WAS IN FECES AND 20-30% IN URINE. [R3] *CRYSTALLINE ZEARALENONE IN MIXED FEED WAS ADMIN TO MILK COW AND EWE. EXTRACTS OF MILK ANALYZED REVEALED TRACES OF ZEARALENONE AND BETA-ZEARALENOL IN SOME EXTRACTS OF COW MILK AND IN SOME SHEEP MILK. [R19] *SINGLE EXPOSURE OF LAYING HENS TO FEED CONTAMINATED WITH LOW LEVEL OF ZEARALENONE WOULD PROBABLY RESULT IN MINIMAL HEALTH HAZARD TO HUMANS. HOWEVER, PROLONGED EXPOSURE MIGHT RESULT IN ACCUM OF SIGNIFICANT AMT OF METABOLITE IN EGG YOLK. [R20] METB: *(14)C-LABELED ZEARALENONE ADMIN BY GAVAGE TO WHITE LEGHORN LAYING HENS, ABOUT 94% OF (14)C WAS ELIMINATED VIA EXCRETA WITHIN 72 HR. 1/3 OF DOSE WAS EXCRETED AS UNCHANGED ZEARALENONE, AND ANOTHER 1/3 APPEARED AS POLAR METABOLITE. [R18] *726 MG OF ZEARALENONE ADMIN IN SINGLE DOSE TO PIG, URINE COLLECTED FOR 96 HR THEREAFTER; 7% OF ZEARALENONE ADMIN WAS RECOVERED IN URINE, 40% OF THIS AS ZEARALENOLS. [R3] *THE NONSTEROIDAL ESTROGEN ZEARALENONE WAS METABOLIZED BY LIVER HOMOGENATE INTO ALPHA-ZEARALENOL @ PH 4.5 AND INTO ALPHA-ZEARALENOL AND BETA-ZEARALENOL @ PH 7.4. [R21] *ZEARALENONE WAS REDUCED TO ZEARALENOL IN FEMALE RAT LIVER BY 3ALPHA-HYDROXYSTEROID DEHYDROGENASE. [R22] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *THIN LAYER CHROMATOGRAPHY IN CORN. [R23] *PROCEDURE FOR THE CHROMATOGRAPHIC SEPARATION AND IDENTIFICATION FROM NATURAL PRODUCTS IS DESCRIBED. [R24] *VERSATILE METHOD OF ANALYSIS EMPLOYING OPTIONS OF TLC, GLC AND COMBINATION GAS CHROMATOGRAPHY-MASS SPECTROSCOPY. CHOICE DEPENDS ON WHETHER MIXED FEED OR CLEAN MAIZE SAMPLE IS BEING ANALYZED. [R3] *UTILITY OF HIGH PRESSURE LIQ CHROMATOGRAPHY IN DETECTION OF ZEARALENONE IN FOOD AND FEEDSTUFFS HAS BEEN DEMONSTRATED. RESOLUTION BY HPLC OFFERS ADVANTAGES OVER OTHER METHODS. METHOD CALLED SELECTED ION MONITORING (SIM) HAS BEEN APPLIED IN MIXT USING COMBINATION GC-MS. MOST DEFINITIVE PROCEDURE IS MASS SPECTROSCOPY AND SHOULD BE USED IF POSSIBLE. [R3] *RAPID SCREENING METHOD FOR ZEARALENONE IN CORN. METHOD IS BASED ON MINICOLUMN CHROMATOGRAPHY AND ANALYSIS CAN BE COMPLETED IN ABOUT 10 MIN IN MOST CASES. [R25] *ANALYTICAL METHOD IS DESCRIBED FOR DETERMINATION OF ZEARALENONE (FOOD CONTAMINANTS AND SUSPECTED CARCINOGENS) BY HIGH PERFORMANCE THIN-LAYER CHROMATOGRAPHY. [R26] *HPLC AND FLUORESCENCE DETECTION OF ZEARALENONE IN ANIMAL FEEDS. [R27] CLAB: *SENSITIVE GAS CHROMATOGRAPHIC METHOD FOR QUANTITATIVE ANALYSIS OF ZEARALENONE IN PORCINE BLOOD SERUM IS DESCRIBED. [R28] *A HPLC METHOD USING FLUORESCENCE DETECTION FOR QUANTITATIVE ANALYSIS OF ZEARALENONE IN BLOOD PLASMA IS DESCRIBED. [R29] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Zearalenone in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 235 (1983) NIH Publication No. 83-1791 SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1306 R3: BUR VET MED, FDA, CONF MYCOTOXINS ANIM FEED GRAINS ANIM HEALTH; PB-300 300, (1979) R4: BENNETT GA ET AL; DESTRUCTION OF ZEARALENONE IN CONTAMINATED CORN; J AM OIL CHEM SOC 57(8) 245 (1980) R5: CHI MS ET AL; APPL ENVIRON MICROBIOL 39(5) 1026 (1980) R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 56 431 (1993) R7: RUZSAS C ET AL; DEV ENDOCRINOL 3(HORM BRAIN DEV) 57 (1978) R8: UENO Y, YAGASAKI S; JPN J EXP MED 45(3) 199 (1975) R9: SHERWOOD RF, PEBERDY JF; EFFECTS OF ZEARALENONE ON DEVELOPING MALE CHICK; BRIT POULT SCI 14(1) 127 (1973) R10: RUDDICK JA ET AL; TERATOLOGICAL EVALUATION OF ZEARALENONE ADMIN ORALLY TO RAT; BULL ENVIRON CONTAM TOXICOL 15(6) 678 (1976) R11: AUCOCK HW ET AL; FIELD OUTBREAKS OF HYPERESTROGENISM (VULVOVAGINITIS) IN PIGS CONSUMING MAIZE INFECTED BY FUSARIUM GRAMINEARUM AND CONTAMINATED WITH ZEARALENONE; J S AFR VET ASSOC 51(3) 163 (1980) R12: ALLEN NK ET AL; EFFECTS OF DIETARY ZEARALENONE ON FINISHING BROILER CHICKENS AND YOUNG TURKEY POULTS; POULT SCI 60(1) 124 (1981) R13: ANDRAS V, ANTAL S; FUSARIOTOXICOSES: 6. THE EFFECT OF F-2 TOXIN (ZEARALENONE) ON THE SPERMATOGENESIS OF MALE SWINE; MAGY ALLATORV LAPJA 35(4) 242 (1980) R14: BARTHOLOMEW RM, RYAN DS; LACK OF MUTAGENICITY OF SOME PHYTOESTROGENS ON THE SALMONELLA TYPHIMURIUM MAMMALIAN MICROSOME ASSAY; MUTAT RES 78(4) 317 (1980) R15: INGEROWSKI GH ET AL; MUTAGENICITY STUDIES ON VETERINARY ANABOLIC DRUGS WITH THE SALMONELLA/MICROSOME TEST; MUTAT RES 91(2) 93 (1981) R16: Long GG et al; Am J Vet Res 47:184-187 (1986) R17: Carcinogenesis Bioassay of Zearalenone in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 235 (1983) NIH Publication No. 83-1791 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R18: DAILEY RE ET AL; J AGRIC FOOD CHEM 28(2) 286 (1980) R19: HAGLER WM ET AL; TRANSMISSION OF ZEARALENONE AND ITS METABOLITE INTO RUMINANT MILK; ACTA VET ACAD SCI HUNG 28(2) 209 (1980) R20: DAILEY RE ET AL, J AGRIC FOOD CHEM 28(2) 286 (1980) R21: TASHIRO F ET AL; METABOLISM OF ZEARALENONE IN FEMALE RAT LIVER IN VITRO; MAIKOTOKISHIN (TOKYO) 11: 37 (1980) R22: OLSEN M ET AL; REDUCTION OF ZEARALENONE TO ZEARALENOL IN FEMALE RAT LIVER BY 3ALPHA-HYDROXYSTEROID DEHYDROGENASE; ACTA PHARMACOL TOXICOL 48(2) 157 (1981) R23: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/432 26.124 R24: STOLOFF L; ANALYTICAL METHODS FOR MYCOTOXINS; CLIN TOXICOL 5(4) 465 (1972) R25: HOLADAY CE; RAPID SCREENING METHOD FOR ZEARALENONE IN CORN, WHEAT AND SORGHUM; J AM OIL CHEM SOC 57(6) 491A (1980) R26: LEE KY ET AL; SIMULTANEOUS MULTI-MYCOTOXIN DETERMINATION BY HIGH PERFORMANCE THIN-LAYER CHROMATOGRAPHY; ANAL CHEM 52(6) 837 (1980) R27: COHEN H, LAPOINTE MR; SEPHADEX LH-20 CLEANUP, HIGH PRESSURE LIQUID CHROMATOGRAPHIC ASSAY AND FLUORESCENCE DETECTION OF ZEARALENONE IN ANIMAL FEEDS; J ASSOC OFF ANAL CHEM 63(3) 642 (1980) R28: TRENHOLM HL ET AL; GAS CHROMATOGRAPHIC DETECTION OF MYCOTOXIN ZEARALENONE IN BLOOD SERUM; J ASSOC OFF ANAL CHEM 63(3) 604 (1980) R29: TRENHOLM HL ET AL; HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC METHOD USING FLUORESCENCE DETECTION FOR QUANTITATIVE ANALYSIS OF ZEARALENONE AND ALPHA-ZEARALENOL IN BLOOD PLASMA; J ASSOC OFF ANAL CHEM 64(2) 302 (1981) RS: 17 Record 285 of 1119 in HSDB (through 2003/06) AN: 4212 UD: 200302 RD: Reviewed by SRP on 08/25/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TREMOLITE-ASBESTOS- SY: *ACTINOLITE- (CA2MG5H2(SIO3)8); *ASBESTOS-; *TREMOLITE- RN: 14567-73-8 RELT: 511 [ASBESTOS] (Mixture) MF: *Ca.4H2-O3-Si.5/2Mg SHPN: IMO 9.3; White asbestos UN 2590; White asbestos MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The mineral is mined or quarried with its parent rock. [R1, 186] *Imbedded asbestos fibers are removed from the ore by a repeated series of crushing, fiberizing, screening, aspirating, and grading operations (milling). ... The ore is crushed, dried, and fiberized in a variety of impact mills. The short fiber and granular material is removed by screening the fiberized mass. The oversized fractions are stratified on a screen where the spherical, granular material of high density seeks the screen's surface and the fluffy, low density fiber rises to the top of the bed. At the end of the screen, the fiber is separated from the rock by an aspirating hood. ... Fibers recovered from these primary screening operations are rescreened to removed entrapped granular material and classified into grades by fiber length. ... Conventional asbestos milling uses large quantities of air both for separating the fibers as they are freed from the ore and for dust control. Approx 130 cu m/sec (275,000 cfm) are used to process one metric ton of ore. Preconcentration of ore includes selective grinding, screening, and magnetic techniques. [R2, p. 3(78) 279] *The material from the separating mill was largely unopened bundles of fibers. For many purposes it was necessary to open the fiber by separating the bundles into their constituent fibers, which greatly increases the bulk of the material. In the asbestos textile industry the material is passed through several types of mills which separate the fibers before they are passed into the carding machines in which they undergo the 1st stage of asbestos yarn production . ... /During/ recent years more of the fiber is "opened" at the mills. [R1, 186] FORM: *Typical chemical compositions of tremolite asbestos: Silicon dioxide, 55-60%; Magnesium oxide, 21-26%; Ferrous oxide, 0-4%; Ferric oxide, 0 to 0.5%; Aluminum oxide, 0 to 2.5%; Calcium oxide, 11-13%; Potassium oxide, 0 to 0.6%; Sodium oxide, 0 to 1.5%; AND Water 0.5-2.5%. [R2, p. 3(78) 277] OMIN: *TREMOLITE IS NOT AT PRESENT EXPLOITED AS ASBESTOS MINERAL IN ITS OWN RIGHT. MATERIALS THAT INCL TREMOLITE AS MAJOR COMPONENT ARE ... PRODUCED IN MANY PARTS OF WORLD. THESE INCL MANY INDUSTRIAL POWDERS REFERRED TO AS TALCS OR TREMOLITIC TALCS. [R3] *ACTINOLITE AND TREMOLITE APPEAR TO FORM SOLID SOLN SERIES, REPRESENTING END MEMBERS OF THAT MINERAL GROUP. ... POSSESS CALCIUM IN M4 STRUCTURAL SITE, WITH COMPLETE IRON-MAGNESIUM GRADATIONS IN M1 THROUGH M3 VALENCE SITES. OCCASIONALLY, MANGANESE SUBSTITUTES FOR IRON. [R4] *Tremolite ... /is/ of little commercial value, but may be mixed with true talc (an amorphous magnesium silicate) to make commercial talc. Cosmetic talcs are in general free of fibrous silicates. [R1, 185] *Tremolite is sold as a "fibrous talc". [R5, 1170] USE: *AS ASBESTOS, PARTICULARLY IN ACID RESISTING APPLICATIONS; CERAMICS; PAINT [R5, 1170] *COMPONENT OF CERAMIC WALL TILE; PAINT ADDITIVE, FILLER OR EXTENDER, EG, FOR PLASTICS (AS TREMOLITIC TALC) [R6] *... Used chiefly for insulating refractories in the low to medium temperature range and in fireproof materials. [R2, p. 5(79) 248] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Monoclinic crystals, long and thin columnar to fibrous; gray-white, green, yellow, blue with silky luster [R2, p. 3(78) 274] DEN: *2.9 to 3.2 [R2, p. 3(78) 275] SPEC: *Optical properties: biaxial negative extinction inclined; Index of refraction: 1.61 [R2, p. 3(78) 275] OCPP: *Structure: long, prismatic and fibrous aggregates; veining: slip or mass fiber; essential composition: calcium and magnesium silicate with some water; Mohs hardness: 5.5; cleavage: 110%; Seger cones fusibility; fusible at 4, 1165-1190 deg C; flexibility: generally brittle, sometimes flexible; fiber length: short to long; texture: generally harsh, sometimes soft; acid resistance: fairly resistant to acids; spinnability: generally poor, some are spinnable; specific heat: 887 J/kg deg K (0.212 Btu/lb deg F) [R2, p. 3(78) 274] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Noncombustible. [R5, 1107] DCMP: *Although tremolite fibrils are the lowest in tensile strength of all the common types of asbestos, they exhibit good resitance to chemical attack by both acids and alkalis. [R7] *Asbestos minerals, despite a relatively high fusion temperature, are completely decomposed at temperatures of 1,000 deg C. [R8] *The resistance of the asbestos fibers to attack by reagents other than acid as excellent up to temperatures of approximately 100 deg C with rapid deterioration observed at higher temperatures. /Asbestos cmpd/ [R9] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one piece and close fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R10, 1979.8] +Wear appropriate personal protective clothing to prevent skin contact. /Asbestos/ [R11, 23] +Wear appropriate eye protection to prevent eye contact. /Asbestos/ [R11, 23] +Recommendations for respirator selection: Conditions: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Asbestos/ [R11, 23] +Recommendations for respirator selection: Conditions: Respirators for escape purposes only: Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Asbestos/ [R11, 23] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R10, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R10, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and possibly, respirators may be required. /Chemical Carcinogens/ [R10, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R10, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R10, 1979.11] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. All contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. +Contact lenses should not be worn when working with this chemical. /Asbestos/ [R11, 22] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Asbestos/ [R11, 22] +The worker should wash daily at the end of each work shift. /Asbestos/ [R11, 22] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R12] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R13] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R14] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion proof refrigerator or freezer (depending on chemicophysical properties) ... that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R10, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R10, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R10, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R10, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R10, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium Hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R10, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R10, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: sufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 1: The agent /tremolite/ is carcinogenic to humans. [R15] +A1; Confirmed human carcinogen. /Asbestos, all forms/ [R16, 2002.16] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R10, 1979.23] *Follow up medical examinations for asbestos exposed workers is /based on the following parameters/: Nonsmokers, ex-smokers and smokers who do not inhale: A) No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray, and sputum cytology; B) more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; C) 40 years old and older, at least 20 years from onset of asbestos exposure: Add fecal occult blood testing and an examination of the oral cavity every 6 months. Smokers who inhale: 1) Less than 15 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire, spirometry, chest X-ray and sputum cytology every 4 months. 2) 15-20 years from onset of asbestos exposure: No more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 6 months; more than mild atypical sputum cytopathology: a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months. 3) More than 20 years from onset of asbestos exposure: Less than 40 years old a yearly questionnaire and spirometry; chest X-ray and sputum cytology every 4 months; 40 years old and older: add fecal occult blood testing and an examination of the oral cavity every 6 months. /Asbestos cmpd/ [R17] HTOX: *PLEURAL PLAQUES HAVE BEEN OBSERVED IN AGRICULTURAL WORKERS ENGAGED IN GROWING TOBACCO ON STONY MOUNTAINOUS SOIL IN BULGARIA; ANTHOPHYLLITE, TREMOLITE AND SEPIOLITE HAVE BEEN FOUND IN REGIONS WHERE ENDEMIC PLEURAL CALCIFICATION OCCURS. [R18] *PLEURAL THICKENING, WHICH IS NOT A FEATURE OF OTHER KINDS OF PNEUMOCONIOSIS, OCCURS EARLY AND MAY BE ONLY CHANGE FOLLOWING EXPOSURE TO ASBESTOS. CHARACTERISTIC BILATERAL THICKENING OF THE PLEURA APPEARS AS A THIN LINE A FEW MILLIMETERS WIDE ALONG THE CHEST WALLS IN THE POSTERO-ANTERIOR RADIOGRAPH. LATER, LARGER PLEURAL PLAQUES MAY BE SEEN EXTENDING OVER THE LUNG FIELD FROM THE CHEST WALLS OR ON THE DIAPHRAGM. THE OUTLINE OF THE LEFT CARDIAC BORDER BECOMES ILL-DEFINED, PRODUCING IN SEVERE CASES THE CLASSICAL "SHAGGY" HEART APPEARANCE. ... A STRIKING FEATURE /OF INTERNATIONAL PNEUMOCONIOSIS CLASSIFICATION OF THE RADIOGRAPHIC APPEARANCES SEEN IN ASBESTOS EXPOSED WORKERS/ IN SOME CASES IS CALCIFICATION OF PLEURA. THIS RARELY OCCURS UNDER 20 YEARS FROM THE 1ST EXPOSURE AND MAY OCCUR IN THE ABSENCE OF NAY OTHER CLINICAL FEATURES OR APPARENT DAMAGE TO THE PARENCHYMA OF THE LUNG. PLEURAL CALCIFICATION IS A FEATURE OF ANTHOPHYLLITE EXPOSURE, BUT IS SEEN IN THE OTHER TYPES OF ASBESTOS AS WELL. TALC AND TREMOLITE CAN PRODUCE A SIMILAR EFFECT; EXPOSURES NEED NOT ALWAYS BE OCCUPATIONAL. [R19, 121] *THE FIBROUS VARIETY OF TALC, AS WELL AS THAT OF ITS ASSOC AMPHIBOLES, TREMOLITE AND ANTHOPHYLLITE, CONTAIN FIBERS WHICH ARE CLASSIFIED AS ASBESTOS. FIBROUS TALC HAS BEEN SHOWN TO BE OF GREATER PHYSIOLOGICAL SIGNIFICANCE THAN THE NON-FIBROUS VARIETY IN A NUMBER OF ENVIRONMENTAL AND CLINICAL STUDIES OF WORKERS EXPOSED TO TALC DUSTS. ... ADVANCED FIBROSIS INCIDENCE RATE OF 14.5% /WAS OBSERVED/ IN A STUDY COVERING 221 TREMOLITE TALC MINERS AND MILLERS. THE DUST TO WHICH THESE WORKERS WERE EXPOSED WAS LARGELY FIBROUS AND THIS PHYSICAL CHARACTERISTIC WAS CONSIDERED TO BE RESPONSIBLE FOR PATHOLOGY OF LUNG LESION, PARTICULARLY BECAUSE OF ITS RESEMBELANCE TO ASBESTOSIS. /FIBROUS TALC/ [R20] *As reviewed by NIOSH, most reports are concerned with talc mines in New York state and most of them produced varying amounts of tremolite and anthophyllite. Some talcs were said to also contain serpentines and silica. The number of men involved in the different studies ranged from 6 to 221. Their dust exposure ranged from near 0 to over 800 mppcf, generally higher for millers than miners. With the introduction of wet drilling and other engineering improvements in 1945 the dust exposures generally decreased significantly. However, because of the previous high dust exposures, all of the reports indicated significant deterioration of health of the workers commensurate with the severity and duration of the exposure. These health effects pertained to the resp system and consisted of cough, dyspnea, wheezes, rales, infiltrations in the chext X-ray films, and abdominal lung function tests. /Talc containing asbestos fibers/ [R21, 1986.550] *In a follow-up study of 220 talc workers in a New York State mine producing talc containing tremolite and anthophyllite, 91 deaths were investigated. Of these 91 deaths, 9 were caused by lung cancer, 1 by pleural sarcoma, and 28 by pneumoconiosis or its complications or both. All 28 deaths ascribed to pneumoconiosis and the 10 resp cancer deaths occurred in men who had had their initial exposure prior to the institution of wet mining and other engineering controls in 1945. The proportional mortality from cancer of the lung and pleura was 4 times that of the control population. The authors state, "In the absence of adequate smoking data one cannot assess the role played by smoking in the causation of the pulmonary carcinomas in both series" (talc and asbestos). /Talc containing asbestos fibers/ [R21, 1986.551] *The same cohort /talc workers in New York State mine producing talc containing tremolite and anthophyllite/ was restudied and reported in 1974. It now was composed of 260 talc workers with 108 deaths. There were 13 cancers of the lung and pleura and 29 deaths from pneumoconiosis and complications. ... The differences between observed and expected mortality rates were stated to have been significant in 1950-54 (p < 0.01) but not significant in 1960-64 and 1965-69 (p > 0.05). ... The exposure was predominantly to talc, tremolite, anthophyllite, carbonates, and small amounts of silica. ... Fiber counts made in 1972 showed a range of averages from 3/ml to 36/ml > 5 um. In another mine studied ... and quoted in ... /this cohort report/, controls had been installed at the inception of operations in 1948. Only 1 of 39 workers had chest X-ray changes consistent with pneumoconiosis. This was a 75 yr old man who had worked as a janitor for 11 years. Because of the lack of X-ray evidence of pneumoconiosis in this cohort despite a fiber count that was 2 to 6 times the TLV of 5 fibers/ml > 5 um and a mean exposure of 16.2 years with a range of 11-22 years ... /it was/ concluded that tremolite and anthophyllite were less fibrogenic than chrysotile and amosite at comparable dust exposures. It is reasonable to presume that the tremolite and anthophyllite in the talc was in the usual prismatic, acicular, or fibrous habit and rarely present as asbestos. When the past and recent reports on the health effects of amphibole-containing talc on mine and mill workers are viewed in perspective, there remains no doubt that serious health problems had developed from this kind of dust at exposure levels as were commonly encountered prior to 1945. /Talc containing asbestos fibers/ [R21, 1986.551] *IT IS GENERALLY ACCEPTED THAT SUSTAINED INHALATION OF SIGNIFICANT AMT OF TALC DUSTS, PARTICULARLY THOSE OF INDUSTRIAL OR COMMERCIAL IMPORTANCE SUCH AS THOSE CONTAINING TREMOLITE, SERPENTINE, ANTHOPHYLLITE OR SIMILAR TALCOSE MINERALS CAN PRODUCE SYMPTOMATIC PNEUMOCONIOSIS. ... /ONE THEORY SUGGESTS/ THAT A SYMPTOMATIC PNEUMOCONIOSIS MAY OCCUR FOLLOWING EXPOSURE TO INDUSTRIAL TALCS ADMIXED WITH TREMOLITE, SERPENTINE AND QUARTZ BECAUSE OF THE FIBROGENIC PROPERTIES OF SUCH CONTAMINANTS, BUT THAT THE PURE TALC PROBABLY DOES NOT INDUCE A DISABLING PNEUMOCONIOSIS. IT HAS FURTHER BEEN SUGGESTED THAT TREMOLITE COMPONENT IN THE TALC MIXTURE MAY BE THE CHIEF PATHOGENIC AGENT OF THE CHARACTERISTIC LESIONS SEEN IN TALC PNEUMOCONIOSIS, ALTHOUGH THE ROLE OF PURE TALC AND ANTHOPHYLLITE HAS NOT BEEN ADEQUATELY ASSESSED. /TALC CONTAINING ASBESTOS FIBERS/ [R1, 2141] *TITLE STUDY OF 121 MALE MINERS AND MILLERS EXPOSED TO TALC CONTAINING TREMOLITE SHOWED, IN COMPARISON TO POTASH WORKERS, INCR RESPIRATORY SYMPTOMS, RADIOGRAPHIC ABNORMALITIES, DECR PULMONARY FUNCTIONS, INCR PREVALENCE OF PLEURAL THICKENING, AND PNEUMOCONIOSIS. [R22] *A high incidence of mesothelioma has been attributed to fibrous tremolite in household stucco and whitewash in Turkey. [R23] *SPICULES OF ASBESTOS EASILY PENETRATE THE SKIN, ESP THE FINGERS IN THOSE BAGGING THE FIBER. CHRONIC IRRITATION OF THE DERMIS OCCURS WITH THE FORMATION OF CORNS ... CANCERS OF THE SKIN ARE NOT PRODUCED. /ASBESTOS CMPD/ [R19, 122] *AT PRESENT, IT IS NOT POSSIBLE TO ASSESS WHETHER THERE IS A LEVEL OF EXPOSURE IN HUMANS BELOW WHICH AN INCREASED RISK OF CANCER WOULD NOT OCCUR. /ASBESTOS CMPD/ [R24] *Asbestos fibers are toxic to macrophages, cells responsible for cleaning infectious agents and foreign material from the respiratory tract. /Asbestos cmpd/ [R25] *A study of the largest factory of the company but not limited to retirees, shows a considerably different mortality pattern. All 689 maintenance and production employees on January 1, 1959, who were first employed at least 20 years earlier were followed through 1976. In this group, 274 deaths occurred, whereas 188.19 were expected. Fourteen pleural and 12 peritoneal mesotheliomas accounted for nearly 10% of the deaths, most recurring before age 65. A strong correlation with estimated dust exposure was seen in deaths form asbestosis, but not with the asbestos related malignancies. Gastrointestinal cancer was especially high in the lowest of four dust categories (11 observed versus 3.15 expected) and only elevated slightly in the higher exposure categories. In the highest dust category, the overall cancer was not dramatically increased, but 40% of the deaths were from asbestosis. Individuals in this department tended to die of nonmalignant disease before reaching the age of greatest risk for cancer. /Asbestos cmpd/ [R26] *A retrospective cohort of 40 men occupationally exposed to tremolite in a Montana vermiculite mine was followed from 1963 to 1983. Duration of employment was at least 1 yr. Of the 165 deaths, cause was determined in 163. Compared with the rates of USA white males, the cohort experienced excess mortality from all causes (SMR = 1.17), respiratory cancer (SMR = 2.45), non-malignant respiratory disease (SMR = 2.55) and accidents (SMR = 2.14). There were 4 deaths from malignant mesothelioma (SMR = 2.4%). When compared with Montana death rates, the SMR for respiratory cancer was 3.03. A case-control analysis of the 23 deaths due to respiratory cancer showed a statistically significant linear relationship between relative risk for respiratory cancer and cumulative exposure (p < 0.01). [R27] *In a cross-sectional study of the effects of tremolite exposure, chest radiographs were obtained for 173 present and 80 past employees of a vermiculite mine, and 47 males without known exposure. Workers were stratified into 5 exposure groups based on cumulative exposure expressed as fibers/ml yr. Cumulative exposure ranged from < 10 to > 200 fibers/ml yr with a mean of 65.9 fibers/ml yr for the cohort as a whole. A trend of increasing prevalence of small opacities with increasing exposure was seen (p approx = 0.02). The corresponding trend for prevalence of pleural thickening of the chest wall was less strong (p approx = 0.10). The results of logistic regression analysis showed independent effects of age, smoking, and exposure on the prevalence of small opacities and of age and probably of exposure on pleural thickening. Overall, the data suggest that by retirement age the increase in prevalence of small opacities (greater than or equal to 1/0) lies between 5% and 10% per 100 fibers/ml years. [R28] NTOX: *The ability of asbestiform tremolite and tremolitic talc to cause pleural cancers in hamsters was investigated. Four different dusts were studied: No 72: An asbestiform tremolite consisted of 95% tremolite and contained long thin fibers with parallel sides, having an average diameter of 0.4 um. Many fibers were > 20 um long. No 31: Obtained from a tremolitic talc in western USA and consisted of 90% tremolite. Some particles had parallel sides. Many of the particles resembled acicular fragments rather than fibers. The avg diameter was 0.5 um. No 275: Consisted of 95% tremolite and contained some fiber-shaped particles with parallel sides and roughly shaped acicular fragments. There was a paucity of long thin particles. The average diameter was 0.4 um. FD 14: Consisted of 50% tremolite, 35% talc, 10% antigorite, and 5% chlorite. There were platy and amorphous particles as well as long thick and thin fibers. The avg diameter was 1.6 um. These dusts were injected intrapleurally into groups of hamsters in doses of 25 mg or 10 mg, respectively. No tumors were produced by FD 14 at 25 mg dose level or by No 275 at either the 25 mg or the 10 mg dose. ... No 31 AND No 72 caused pleural cancers. However, fewer animals with cancer were seen in the group injected with No 31 than in the group injected with No 72. ... it was shown that, whereas the asbestos type of tremolite was carcinogenic, the nonasbestos form of tremolite was not carcinogenic. [R21, 1986.552] *ALL COMMERCIAL TYPES OF ASBESTOS HAVE PRODUCED MESOTHELIOMAS IN C/D WISTAR RATS /BY INTRAPLEURAL ADMIN/. /ASBESTOS CMPD/ [R29] *ALL COMMERCIAL FORMS OF ASBESTOS TESTED ARE CARCINOGENIC IN MICE, RATS, HAMSTERS AND RABBITS. ... THE SIZE AND SHAPE OF FIBERS INFLUENCE THE INCIDENCE OF TUMORS; FIBERS LESS THAN 0.5 UM IN DIAMETER ARE MORE ACTIVE IN PRODUCING TUMORS. /ASBESTOS CMPD/ [R30] +... Conclusions: Under the conditions of these feed studies, nonfibrous tremolite was not overly toxic or carcinogenic for male or female F344/N rats, following lifetime ingestion of a diet containing 1% tremolite. [R31] NTP: +A carcinogenesis bioassay of blocky (nonfibrous) tremolite was conducted with male and female F344/N rats. Tremolite was administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. The studies were started in 1978 and ended in 1981. Group sizes were 118 male and female controls and 250 male and female tremolite exposed rats. Litter size was not effected by the administration of tremolite to the dams. The offspring from mothers exposed to tremolite were the same size at birth as the controls but were slightly smaller at weaning and remained so throughout their life. Survival was similar in the exposed and control groups. No toxicity or increase in incidence of neoplasia was observed in the tremolite-exposed animals compared with the concurrent controls. Conclusions: Under the conditions of these feed studies, nonfibrous tremolite was not overly toxic or carcinogenic for male or female F344/N rats, following lifetime ingestion of a diet containing 1% tremolite. [R31] POPL: *Special groups at risk may include neonates and children; however, no data exist on the relative sensitivity to asbestos of infants and children undergoing rapid growth. Concern exists because fibers deposited in the tissues of young may have an extremely long residence time during which malignant changes could occur. In addition, risk could be influenced by differential absorption rates which have not been fully studied at this time. Individuals on kidney dialysis machines may also be at greater risk as fluids, potentially contaminated with asbestos fibers can enter the blood stream directly or, in selected instances, the peritoneal cavity (peritoneal dialysis). An increased risk is also associated with increased exposure to asbestos in water in municipalities such as San Francisco or Seattle where asbestos occurs naturally in water, in cities where there is a interaction between aggressive water and asbestos-cement pipe, or in cities whose water may be contaminated as a result of asbestos operations. /Asbestos cmpd/ [R32] ADE: *Fibers were detected in beverages (beer, wine and soft drinks) and were studied to see if such fibers consumed orally can pass through the intestinal wall and enter the bloodstream. A stock solution was made to contain fibers the same length as those found in beverages (0.5-2) and determined to contain 9.4x10+6 fibers/l. An aliquot (assumed to be 350 ml) was then administered intragastrically to rats (number, species and sex not known). Asbestos fibers were found to accumulate in the omentum surrounding the small intestine, brain and lung. ... counts could not be made on the liver and kidneys. /Asbestos cmpd/ [R33] ACTN: *Animal experimentation ... indicated that the important factor in the carcinogenicity was the dimensionality of the fibers rather than their chemical properties. ... Greatest carcinogenicity was related to fibers that were less than 2.5 cu m in diameter and longer than 10 cu m. /Asbestos cmpd/ [R34] INTC: *Carcinogenesis bioassays of blocky (nonfibrous) tremolite and amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted with male and female Fischer 344 rats. The minerals were administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats starting with the dams of the test animals. One group of amosite rats also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. The offspring from mothers exposed to tremolite ... asbestos were smaller at weaning than those from untreated mothers and remained smaller throughout their life. ... No toxicity or increase in neoplasia was observed in the tremolite-exposed rats compared to the controls. Significant increases (P < 0.5) in the rates of C-cell carcinomas of the thyroid and monocytic leukemia /were noted/ in males. Significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and the positive effect was not observed in the amosite plus preweaning gavage group. [R35] *The relationship between asbestos exposure and smoking indicates a synergistic effect of smoking with regard to lung cancer. Further evaluations indicate that this synergistic effect is close to a multiplicative model. ... The risk of mesothelioma appears to be independent of smoking, and a significantly decreasing trend in risk was observed with the amount smoked in 1 study. /Asbestos cmpd/ [R36] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *TREMOLITE IN METAMORPHOSED CALCAREOUS ROCKS. /FROM TABLE/ [R37] RTEX: *... Fibrous tremolite in household stucco and whitewash ... [R23] *An increased risk is also associated with increased exposure to asbestos in water in municipalities such as San Francisco or Seattle where asbestos occurs naturally in water, in cities where there is an interaction between aggressive water and asbestos cement pipe, or in cities whose water may be contaminated as a result of asbestos operations. /Asbestos cmpd/ [R38] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers asbestos to be a potential occupational carcinogen. /Asbestos/ [R11, 22] OSHA: +The employer shall ensure that no employee is exposed to an airborne concentration of asbestos in excess of 0.1 fiber/cu cm of air as an 8-hr TWA as determined by the method prescribed in Appendix A to this section, or by an equivalent method. /Asbestos/ [R39] NREC: +NIOSH considers asbestos to be a potential occupational carcinogen. /Asbestos/ [R11, 22] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Asbestos/ [R11, 22] TLV: +8 hr Time Weighted Avg (TWA): 0.1 fibers/cc; respirable fibers: length greater than 5 um; aspect ratio greater than or equal to 3:1. /Asbestos, all forms/ [R16, 2002.16] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Asbestos, all forms/ [R16, 2002.6] +A1; Confirmed human carcinogen. /Asbestos, all forms/ [R16, 2002.16] ASTD: *Asbestos has been designated as a hazardous air pollutant under section 112 of the Clean Air Act. [R40] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 7402: Analyte: asbestos fibers (including tremolite); Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25 mm diameter; conductive cassette); Flow rate: 0.5-16 l/min; Vol: min: 400 l at 0.1 fiber/ml; max: 10,000 l; Sample stability: stable. Shipment is routine (securely packed to reduce shock). [R41, p. V1 7402-1] *NIOSH 7400: Analyte: Fibers (including tremolite asbestos); Matrix: air; Sampler: filter (0.8-1.2 um cellulose ester membrane, 25 mm diameter; conductive cowl on cassette); Flow rate: 0.5 to 16 l/min; Minimum vol: 400 l at 0.1 fiber/ml; Maximum vol: 10,000 l; Stability: stable. Shipment is routine (securely packed to reduce shock). [R41, p. V1 7400-1] ALAB: *X-RAY DIFFRACTION TECHNIQUES HAVE BEEN USED TO ESTABLISH PRESENCE OF ASBESTOS ... MINIMUM DETECTION LEVELS OF ... 0.1% FOR TREMOLITE HAVE BEEN REPORTED IN TALC. TECHNIQUES REQUIRE BULK SAMPLES WHICH ARE NOT AVAIL IN MOST ENVIRONMENTAL SITUATIONS. [R42] *METHODS OF CONFIRMING ASBESTOS, INCLUDING TREMOLITE, CAN INCLUDE OPTICAL TESTING USING POLARIZED LIGHT, FIRST ORDER RED OR OTHER RETARDATION PLATES, ANGLES OF EXTINCTION, DISPERSION STAINING. BULK SAMPLES MAY BE ANALYZED BY X-RAY DIFFRACTION OR IR ABSORPTION OF DIFFERENTIAL THERMAL ANALYSIS. [R43] *NIOSH 7402: Analyte: asbestos fibers (including tremolite); Matrix: air; Technique: Transmission electron microscopy (TEM); Range: 100-1300 fibers/sq mm filter area; Precision: 0.28 when 65% of fibers are asbestos; 0.20 when adjusted fiber count is applied to phase-contrast microscope count; Est limit of detection: 1 confirmed asbestos fiber above 95% of expected mean blank value; Interferences: Non-asbestiform amphiboles may interfere in the TEM analysis if the individual particles have aspect ratios greater than 3:1. These interferences can only be eliminated by quantitative zone axis electron diffraction analysis. NIOSH method 7400 (phase-contrast microscopy) is designed for use with this method. [R41, p. V1 7402-1] *NIOSH 7400: Analyte: Fibers (including tremolite asbestos); Matrix: air; Technique: Light microscopy, phase contrast; Range: 100-1300 fibers/sq mm filter area; Precision: 0.10 to 0.12 (based on OSHA regulations for rule A); Est limit of detection: 7 fibers/sq mm filter area. This method gives an index of airborne fibers in workplace atmospheres. Phase contrast microscopy will not differentiate between asbestos and other fibers; use this method in conjunction with electron microscopy (eg, Method 7402) for positive identification. Fibers < about 0.25 um diameter will not be detected by this method. Any other airborne fiber may interfere. Chain-like particles may appear fibrous. High levels of non-fibrous dust particles may obscure fibers in the field of view and increase the detection limit. [R41, p. V1 7400-1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tremolite in F344/N Rats (Feed Studies) Technical Report Series No. 277 (1990) NIH Publication No. 90-2531 U.S. Dept Health and Human Services/Agency for Toxic Substances Disease Registry; Toxicological Profile for Asbestos (Update) (1995) NTIS # PB/95-264305 SO: R1: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 30 (1977) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 25 (1977) R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R6: SRI R7: USEPA, Office of Drinking Water; Criteria Document (Draft): Asbestos p.II-15 (1985) R8: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-3 (1980) EPA 440/5-80-022 R9: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.A-5 (1980) EPA 440/5-80-022 R10: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R11: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R12: 49 CFR 171.2 (7/1/96) R13: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 230 R14: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.9014 (1988) R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 106 (1987) R16: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R17: USDHEW/NCI; Asbestos: An Information Resource P.93 (1978) DHEW Pub No. NIH 79-1681 R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 72 (1977) R19: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R20: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)262 R21: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists R22: GAMBLE JF ET AL; AM REV RESPIR DIS 119 (5): 741-53 (1979) R23: Gilman, A.G., L.S.Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 7th ed. New York: Macmillan Publishing Co., Inc., 1985. 1634 R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 81 (1977) R25: Nat'l Research Council Canada; Effects of Asbestos in the Canadian Environ p.19 (1979) NRCC No. 16452 R26: Enterline PE et al; J Occup Med 14: 897 (1972) as cited in USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-76-77 (1980) EPA 440/5-80-022 R27: McDonald JC et al; Br J Ind Med 43: 436-44 (1986) R28: McDonald JC et al; Br J Ind Med 43: 445-49 (1986) R29: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 45 (1977) R30: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 80 (1977) R31: Toxicology and Carcinogenesis Studies of Tremolite in F344/N Rats (Feed Studies). Technical Report Series No. 277 (1990) NIH Publication No. 90-2531 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R32: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (1989) EPA 440/5-80-022 R33: Cunningham HM, Pontefract RD; J Assoc Off Anal Chem 56: 976 (1973) as cited in USEPA; Office of Drinking Water; Criteria Document (Draft): Asbestos p.III-8 (1985) R34: USEPA; Asbestos Health Assessment Update (Draft) p.9 (1984) EPA-600/8-84-003A R35: McConnell EE et al; Env Hlth Persp 53: 27-44 (1983) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 108 (1987) R37: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 150 R38: USEPA; Ambient Water Quality Criteria Doc: Asbestos p.C-99 (1980) EPA 440/5-80-022 R39: 29 CFR 1910.1001(c) (7/1/98) R40: 40 CFR 61.01 (7/1/88) R41: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R42: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V14 40 (1977) R43: DIXON W; MICROSCOPE 26 (4TH QUARTER): 183-6 (1978) RS: 52 Record 286 of 1119 in HSDB (through 2003/06) AN: 4214 UD: 200211 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CHLORINATED-PARAFFINS- SY: *CERECLOR-; *CERECLOR-S-42-; *CERECLOR-S-52-; *CERECLOR-S-70-; *CERECLOR-30-; *CERECLOR-42-; *CERECLOR-48-; *CERECLOR-52-; *CERECLOR-54-; *CERECLOR-70-; *CERECLOR-50LU-; *CERECLOR-51L-; *CERECLOR-63L-; *CERECLOR-65L-; *CERECLOR-70L-; *CERECLOR-S52-; *CHLORCOSANE-; *CHLOREZ-700-; *CHLOREZ-700HMP-; *CHLOROWAX-S-70-; *CHLOROWAX-50-; *CHLOROWAX-70-; *CHLOROWAX-70-5-; *CHLOROWAX-705-; *CRECLOR-S-45-; *PARAFFIN,-CHLORINATED-; *PARAFFIN-WAXES-AND-HYDROCARBON-WAXES,-CHLORINATED-; *UNICHLOR-50- RN: 63449-39-8 MF: *UVCB ASCH: Chlorinated paraffins: C12, 60% chlorine; 108171-26-2; Chlorinated paraffins: C23, 43% chlorine; 108171-27-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PRODUCED BY PASSING CHLORINE GAS INTO C10-C30 PARAFFINS [R1] FORM: *CHLORINATED PARAFFINS ARE AVAILABLE COMMERCIALLY UNDER FOLLOWING NAMES: CERECLOR (IMPERIAL CHEMICAL INDUSTRIES); CLORAFIN (HERCULES POWDER); CHLOROWAX (DIAMOND ALKALI CO). [R2, 370] *"CHLOROWAX." TRADEMARK FOR SERIES OF LIQUID AND RESINOUS CHLORINATED PARAFFINS CONTAINING FROM 40% TO 70% CL BY WT. [R3, 203] +/Composed of/ chlorinated paraffin waxes and hydrocarbon waxes. [R4] MFS: +Ferro Corp, Hq, One Erieview Plaza, Cleveland, OH 44114, (216) 641-8580; Chemicals Group; Keil Chemical Division, 3000 Sheffield Ave, Hammond, IN 46320 [R5] +ICC Industries, Inc, Hq, 720 5th Ave, New York, NY 10019, (212) 903-1700; Chemical Divisions; Subsidiary: Dover Chemical Corp, PO Box 40, Dover, OH 44622, (216) 343-7711 [R5] +Occidental Petroleum Corp, Hq, 10889 Wilshire Blvd, Suite 1500, Los Angeles, CA 90024, (213) 879-1700; Subsidiary: Occidental Chemical Corp, 5005 LBJ Freeway, Dallas, TX 75244, (214) 404-3800; Electrochemicals, Detergent and Specialty Products Division; Electrochemicals Group; Production site: Deer Park, TX 77536 [R5] +Witco Corp, Hq, 520 Madison Ave, New York, NY 10022-4236, (212) 605-3800; Subsidiary: Continental Carbon Co, 10500 Richmond, Houston, TX 77242-2817, (713) 978-5700; Pearsall Products, PO Box 42817, Houston, TX, 77242-2817; Production site: Phillipsburg, NJ 08865 [R5] OMIN: *RECOMMENDED THAT CHLORINATION OF SOLID PARAFFINS BE CARRIED OUT WITH CAREFUL CONTROL OF COMPONENT ADDN. TO PREVENT MIXING OF PARAFFINS AND CHLORINATED PARAFFINS WITHIN C1 SUPPLY, USE OF HYDRAULIC VALVE AND FLUSHING OF C1 LINE WITH N AFTER TERMINATION OF ADDN IS RECOMMENDED. [R6] USE: *AS SOLVENT FOR DICHLORAMINE-T, DISSOLVING ABOUT 8% [R7] *IN HIGH-PRESSURE LUBRICANTS; AS FLAME RETARDANT IN PLASTICS AND TEXTILES; AS PLASTICIZER FOR POLYVINYL CHLORIDE IN POLYETHYLENE SEALANTS; AND IN DETERGENTS [R3, 650] *IN LUBRICANTS [R2, 141] *EXTREME PRESSURE LUBRICANT ADDITIVE-METAL WORKING INDUST; PLASTICIZER, EG, FOR PLASTICS, PAINTS, RUBBER, ADHESIVES, CAULKS AND SEALANTS; BINDER AND FIRE-RETARDANT IN POLYMERS-EG, PAINTS AND PLASTICS [R1] CPAT: *EXTREME PRESSURE LUBRICANT ADDITIVE, 50%; PLASTICIZER FOR PLASTICS, 22%; PLASTICIZER FOR PAINTS, 9%; PLASTICIZER FOR RUBBER, 8%; PLASTICIZER FOR ADHESIVES, 5%; PLASTICIZER FOR CAULKS AND SEALANTS, 2%; EXPORT AND OTHER, 4% (1980) [R1] +CHEMICAL PROFILE: Chloroparaffins. Lube oil additives, 45%; plastics, including coated fabrics, 20%; rubber, 13%; paint, 9%; adhesives, 4%; caulks and sealants, 2%; miscellaneous, 7%. [R8] +CHEMICAL PROFILE: Chloroparaffins. Demand: 1986: 93 million lb; 1987: 92 million lb; 1991 /projected/: 85 million lb. [R8] PRIE: U.S. PRODUCTION: *(1977) MORE THAN 3.26X10+10 G (C10-C30) [R1] *(1979) MORE THAN 5.13X10+10 G (C10-C30) [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) DATA NOT REPORTED SEPARATELY [R1] *(1979) 3.89X10+9 GRAMS [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *GENERALLY THEY ARE VISCOUS LIQUIDS [R2, 141]; *LIGHT YELLOW TO AMBER, THICK, OILY LIQUID [R7] ODOR: *USUALLY ODORLESS, HOWEVER THOSE WITH HIGH CHLORINE CONTENT (65% OR OVER) HAVE AN ODOR [R2, 141] DEN: *1.00-1.07 [R7] SOL: *INSOL IN WATER; SLIGHTLY SOL IN ALCOHOL; MISCIBLE WITH BENZENE, CHLOROFORM, ETHER, CARBON TETRACHLORIDE [R7]; *INSOL IN GLYCERINE; SOL IN AROMATIC HYDROCARBONS, ALIPHATIC HYDROCARBONS, KETONES, ESTERS, VEGETABLE AND ANIMAL OILS [R2, 141] OCPP: *PRACTICALLY INERT @ ORDINARY TEMP, PARTICULARLY TOWARD ACIDS AND ALKALIS; @ HIGHER TEMP ATTACKED BY ALKALIS AND OXIDIZING AGENTS [R2, 141] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *STABLE IN AIR [R7] *VERY LOW VOLATILITY [R2, 141] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is sufficient evidence for the carcinogenicity of a commercial chlorinated paraffin product of average carbon-chain length C12 and average degree of chlorination 60% in experimental animals. There is limited evidence for the carcinogenicity of a commercial chlorinated paraffin product of average carbon-chain length C23 and average degree of chlorination 43% in experimental animals. No data were available from studies in humans on the carcinogenicity of chlorinated paraffins. Overall evaluation: Chlorinated paraffins of average carbon-chain length C12 and average degree of chlorination approximately 60% are possibly carcinogenic to humans (Group 2B). [R9] HTOX: *CONTACT OF SKIN WITH CHLORINATED PARAFFINS DOES NOT GIVE RISE TO ANY IRRITATION OR SENSITIZATION. [R2, 142] NTOX: *NO INJURY IN TEST ANIMALS SHORT OF DOSES WHICH PRODUCE INTESTINAL OBSTRUCTION. [R10] *...RATS APPEARED TO BE IN NO WAY AFFECTED BY ABSORPTION OF DAILY DOSE OF 1 G OF CHLORINATED PARAFFIN FOR FORTY-TWO DAYS... [R2, 370] +Chlorowax 500C was evaluated for mutagenicity in the Salmonella/microsome preincubation assay using a standard protocol approved by the National Toxicology Program. Chlorowax 500c was tested at doses of 0, 33, 100, 333, 1000, 3333, and 10,000 ug/plate in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Chlorowax 500c was negative in these tests and the highest ineffective dose level tested without formation of a precipitate in any Salmonella tester strain was 333 ug/plate. [R11] +... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male F344/N rats given 1,875 or 3,750 mg/kg per day. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female F344/N rats as shown by an increased incidence of adrenal gland medullary pheochromocytomas. There was clear evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male B6C3F1 mice as shown by an increase in the incidence of malignant lymphomas. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female B6C3F1 mice as shown by a marginal increase in the incidence of hepatocellular neoplasms. [R12] +... Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60% chlorine) for F344/N rats based on increased incidences of hepatocellular neoplasms (primarily neoplastic nodules) in male and female rats, of adenomas or adenocarcinomas (combined) of the kidney tubular cells in male rats, and of follicular cell adenomas or carcinomas (combined) of the thyroid gland in female rats. Mononuclear cell leukemia in dosed male rats may have been related to administration of chlorinated paraffins (C 12, 60% chlorine). There was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60% chlorine) for B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of adenomas or carcinomas (combined) in dosed male and female mice and increased incidences of adenomas and of adenomas or carcinomas (combined) of thyroid gland follicular cells in dosed female mice. [R13] NTP: +Toxicology and carcinogenesis studies of chlorinated paraffins (C23, 43% chlorine) ... were conducted by administering the chemical in corn oil by gavage to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week for 103 wk. Additional groups of 10 rats per sex and dose were examined at 6 and at 12 months. Male rats received doses of 0, 1,875, or 3,750 mg/kg body weight; female rats were given 0, 100, 300, or 900 mg/kg. Male and female mice received 0, 2,500, or 5,000 mg/kg. Doses selected for the 2 yr studies were based on the results from 13 wk studies in which rats of each sex received 0 to 3,750 mg/kg, and mice of each sex, 0 to 7,500 mg/kg. Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male F344/N rats given 1,875 or 3,750 mg/kg per day. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female F344/N rats as shown by an increased incidence of adrenal gland medullary pheochromocytomas. There was clear evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for male B6C3F1 mice as shown by an increase in the incidence of malignant lymphomas. There was equivocal evidence of carcinogenicity of chlorinated paraffins (C23, 43% chlorine) for female B6C3F1 mice as shown by a marginal increase in the incidence of hepatocellular neoplasms. [R12] +Toxicology and carcinogenesis assessments of chlorinated paraffins (C12, 60% chlorine) ... were conducted in male and female F344/N rats and male and female B6C3F1 mice in ... 2 yr studies. Doses used in the 2 yr studies were 0, 312, or 625 mg/kg body weight per day administered by gavage in corn oil five times per week to groups of 70 male and female rats and 0, 125, or 250 mg/kg administered to groups of 50 male and female mice. Ten male and 10 female rats were killed after 6 and 12 months of dosing and examined for toxicity. Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60% chlorine) for F344/N rats based on increased incidences of hepatocellular neoplasms (primarily neoplastic nodules) in male and female rats, of adenomas or adenocarcinomas (combined) of the kidney tubular cells in male rats, and of follicular cell adenomas or carcinomas (combined) of the thyroid gland in female rats. Mononuclear cell leukemia in dosed male rats may have been related to administration of chlorinated paraffins (C 12, 60% chlorine). There was clear evidence of carcinogenicity of chlorinated paraffins (C12, 60% chlorine) for B6C3F1 mice as shown by increased incidences of hepatocellular adenomas and of adenomas or carcinomas (combined) in dosed male and female mice and increased incidences of adenomas and of adenomas or carcinomas (combined) of thyroid gland follicular cells in dosed female mice. [R13] ADE: *FINGERLING RAINBOW TROUT WERE FED DIET FORTIFIED WITH 10 PPM CHLOROWAX 500C FOR UP TO 82 DAYS. CHLORINATED PARAFFIN RESIDUES AS HIGH AS 1.1 PPM (TISSUE BASIS) WERE FOUND. NO GROSS TOXICOLOGICAL EFFECTS WERE NOTED, ALTHOUGH WEIGHT GAIN WAS LESS THAN IN CONTROLS. [R14] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *1. 1= PRACTICALLY NONTOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) ABOVE 15 G/KG, MORE THAN 1 QT (2.2 LB) FOR 70 KG PERSON (150 LB). [R10] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: +Chlorinated paraffins are released to the environment during their production and use in many products as a coating or additive for improved fire retardancy or water repellancy, lubrication, etc. Its form when released will mainly be as the bulk material, coating, emulsion, or incorporated into other materials. Its ability to degrade will depend greatly on the form in which it is dispersed. If released on soil or water it will adsorb to soil, sediment or particulate matter. It would therefore not leach into groundwater. Chlorinated paraffins do not bioconcentrate in fish. If released into the atmosphere on particulate matter, they will be subject to gravitational settling and be degraded by photochemically produced hydroxyl radicals (half-life 15-29 hr). Human exposure to chlorinated paraffins will primarily be from contact with the products containing these chemicals. (SRC) ARTS: +Wastewater and solid waste spills from its production, transport, storage, and use as an extreme pressure lubricant additive in the metal working industry, plastics additive for fire retardants and water repellancy coatings and in rubber, caulks and sealants(1), plasticizer in PVC(3). Discarded components of plastics, coated fabrics, waste oil, leachate from antifouling and marine plants(2). Incinerators would not be as significant a source of chlorinated paraffins as they are of PCB's because chlorinated paraffins decompose at relatively low temperatures (300-400 deg C) whereas the PCB's decompose at 800 deg C or above(2). [R15] FATE: +TERRESTRIAL FATE: When chlorinated paraffins are discarded or released on land they will be strongly adsorbed and would not be expected to leach into groundwater. Biodegradation appears to occur under both aerobic and anaerobic conditions, but the data is poor. There is no experimental estimate for biodegradation under environmental conditions. One would expect radically different degradation rates for bulk materials, emulsions, their films and chemicals embedded in other material. (SRC) +AQUATIC FATE: When chlorinated paraffins are released into water, they would be expected to settle to the bottom of the body of water and adsorb strongly to sediment due to their insolubility. Biodegradation may occur but no environmentally relevant rates are available. (SRC) +ATMOSPHERIC FATE: If chlorinated paraffins are released to the atmosphere, they will most likely be adsorbed on particulate matter and be subject to gravitational settling. Chlorinated paraffins are attacked by photochemically produced hydroxyl radicals and have an estimated half-life of 15 to 29 hr. (SRC) BIOD: +When two chlorinated paraffins each with about 42% chlorine content, Cerelor 42 and Chlorez 700, were added to sediment/sea water/decaying organic mixture and incubated at room temperature, roughly 75% of the chlorinated paraffin was degraded in three weeks (1). Degradation was somewhat greater under anaerobic conditions(1), however inconsistency in the data trends and lack of sensitivity of the analytical measurements suggest that the results are only approximate. Chlorowax 500C and Chlorowax 40 exhibit some biodegradation when combined with a surfactant in a BOD test using an acclimated sewage seed inoculum, while Chlorowax 70 and Exchlor 5C were much more stable under these conditions(2). Due to shortcomings in this study, only qualitative conclusions are justified(2). No degradation products have been identified. [R16] ABIO: +Sunlight appears to catalyze the decomposition of chlorinated paraffins with the evolution of HCl so that it is now customary to add stabilizers to the commercial product during shipment and storage(1). However chlornated paraffins are poor absorbers of UV radiation and were stable when exposed to UV radiation in petroleum ether(3). This contradictory data may be due to impurities in the commercial product or due to attack by photochemically produced radicals rather than photolysis. Traces of hydrochloric acid which is formed during manufacture and must be removed from the molten mixture by purging with air or carbon dioxide will catalyze decomposition, particularly in the presence of iron(1). Photochemically produced hydroxyl radicals abstract hydrogen atoms from the chlorinated paraffins resulting in an estimated half-life of 15.4 and 29.0 hr for the molecules with formula C24H42Cl8 (52% chlorine) and C12H19Cl9 (60% chlorine), respectively(2). Oxygen does not affect the decomposition of chlorinated paraffins and antioxidants are therefore of no use as stabilizing agents(3). [R17] BIOC: +Since chlorinated paraffins are insoluble in water, uptake in fish would be from food or the intake of particulate matter through the gills. Fish will not accumulate chlorinated paraffins Cereclor 42 (42% chlorine) and Chlorez 700 when exposed to these compounds adsorbed on silica(1). No uptake of these preparations from food at levels of 10 and 100 ppm was detectable in a 181 feeding experiment with juvenile Atlantic salmon although some of the dosed fish died(1). [R18] KOC: +No data could be found on the adsorption of chlorinated paraffins to soil. They have extremely high log octanol water partition coefficient (4.4 - > 12.8)(1) and very low solubility in water, lower than the correspondind paraffins because of the solubility- decreasing effects of chlorine substitution; this indicates that the KOC will be extremely high. Therefore chlorinated paraffins would adsorb very strong ly to soil and leaching would be insignificant(SRC). [R19] VWS: +Due to its extremely low vapor pressure and solubility, volatilization for water or soil would not be expected to be a significant loss process (SRC). RTEX: +Exposure to chlorinated paraffins would be primarily dermal to those coming into contact with the many products containing these chemicals (SRC). *...THEIR HANDLING IN FACTORY DOES NOT SEEM TO GIVE RISE TO ANY PROBLEMS. ... HIGHLY CHLORINATED PARAFFIN WAXES (70% CHLORINE) CONTAIN 2-3% CARBON TETRACHLORIDE, WHICH CAN BE RELEASED IN ATMOSPHERE WHEN THESE SUBSTANCES ARE HANDLED IN LIQ FORM OR TREATED WITH CURRENT OF AIR OR STEAM @ HIGH TEMP. [R2, 142] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *COLUMN CHROMATOGRAPHY ON SILICA OR ALUMINA FOLLOWED BY MICROCOULOMETRIC DETERMINATION OF CHLORINE. RECOVERY OF CHLORINATED COMPD FROM SPIKED SAMPLES WAS USUALLY QUANTITATIVE, BUT S- AND N-CONTAINING COMPD INTERFERED WITH DETERMINATION AND WAS NOT SPECIFIC FOR CHLORINATED PARAFFINS. [R20] *MASS SPECTRA OF POSTIVE IONS FROM C20-33 ALKANES AND THEIR CHROMATOGRAPHIC SEPARATED MONO-, DI-, AND TRICHLORO DERIV WERE DETERMINED. [R21] *TECHNICAL CHLORINATED PARAFFINS ARE FOUND TO BE EXTREMELY COMPLEX MIXTURES AND ANALYSIS OF TRACE AMT IS DIFFICULT. A METHOD OF IDENTIFICATION AND DETERMINATION USING GC WITH FLAME IONIZATION DETECTOR IS DESCRIBED. [R22] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: THIS REPORT REVIEWS THE POTENTIAL ENVIRONMENTAL HAZARD FROM COMMERCIAL USE OF CHLORINATED PARAFFINS. INFORMATION ON PHYSICAL AND CHEMICAL PROPERTIES, PRODN, METHODS AND QUANTITIES, USES AND FACTORS AFFECTING ENVIRONMENTAL CONTAMINATION ARE REVIEWED. [R23] DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorinated Parafins (C12, 60% Chlorine) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 308 (1986) NIH Publication No. 86-2564 DHHS/NTP; Toxicology and Carcinogenesis Studies of Chlorinated Parafins (C23, 43% Chlorine) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 305 (1986) NIH Publication No. 86-2561 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) SO: R1: SRI R2: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R3: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. R4: EPA. Toxic Substances Control Act Chemical Substance Inventory. Vol IV Molecular Formula and UVCB Indices p. 131 (1979) R5: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 523 R6: ROZLOVSKII AI ET AL; BEZOP TR PROM-STI (5) 58 (1975) R7: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 910 R8: Kavaler AR; Chemical Marketing Reporter 231 (14): 66 (1987) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 48 69 (1990) R10: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-114 R11: Zeiger E et al; Environ Mutagen 9:1-110 (1987) R12: Toxicology and Carcinogenesis Studies of Chlorinated Paraffins (C23, 43% Chlorine) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 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Technical Report Series No. 308 (1986) NIH Publication No. 86-2564 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R14: LOMBARDO P; J ASSOC OFF ANAL CHEM 58(4) 707 (1975) R15: (1) Kirk-Othmer Enc Chem Technol 3rd 5: 786-91 (1979) (2) Zitko V, Arsenault E; Amer Chem Soc 169th Natl Mtg pp.174-6 (1975) (3) Renberg L et al; Chemosphere 9: 683-91 (1980) R16: (1) Zitko V, Arsenault E; Amer Chem Soc 169th Natl Mtg pp.174-6 (1975) (2) Howard PH et al; Investigation of selected potential environmental contaminants: chlorinated paraffins. pp.109 USEPA-560/2-75-007 (1975) R17: (1) Scheer WG; Chem Indust 54: 203-5 (1944) (2) GEMS Graphic Environmental Modeling System. Fate of Atmospheric Pollutants (FAP) Data Base. Office of Toxic Substances. USEPA (3) Howard PH et al; Investigation of selected potential environmental contaminants: chlorinated paraffins. pp.109 USEPA-560/2-75-007. (1975) R18: (1) Zitko V; Bull Environ Contam Toxicol 12: 406-12 (1974) R19: (1) Renberg L et al; Chemosphere 9: 683-91 (1980) R20: ZITKO V; J CHROMATOGR 81(1) 152 (1973) R21: BORKOWSKA A; MASS SPECTROMETRIC ANALYSIS OF CHLOROPARAFFIN; SB VYS SK CHEM TECHNOL PRAZE TECHNOL PALIV (D33) 323 (1976) R22: PANZEL H ET AL; CHLORINATED PARAFFINS AS ENVIRONMENTAL CHEMICALS. 1. IDENTIFICATION AND DETERMINATION BY IR AND (SUP)(1)H-NMR SPECTROSCOPY AND GAS CHROMATOGRAPHY; FRESENIUS Z ANAL CHEM 271(3) 182 (1974) R23: HOWARD PH ET AL; INVESTIGATION OF SELECTED POTENTIAL ENVIRONMENTAL CONTAMINANTS: CHLORINATED PARAFFINS; US NTIS, PB REP (PB-248634) (1975) RS: 23 Record 287 of 1119 in HSDB (through 2003/06) AN: 4215 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TETRAKIS- (HYDROXYMETHYL)PHOSPHONIUM-SULFATE SY: *BIS- (TETRAKIS(HYDROXYMETHYL)PHOSPHONIUM)SULFATE- (salt); *Pesticide-Code:-129058-; *NCI-C55050-; *OCTAKIS- (HYDROXYMETHYL)PHOSPHONIUM-SULFATE; *PHOSPHONIUM, TETRAKIS(HYDROXYMETHYL)-, SULFATE (2:1) (SALT); *PYROSET-TKO-; *THPS- RN: 55566-30-8 MF: *C4-H12-O4-P.1/2O4-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF FORMALDEHYDE WITH PHOSPHINE IN AQUEOUS SULFURIC ACID [R1] *The salts are produced by the reaction of formaldehyde with phospine in the appropriate aqueous acid. /Tetrakis(hydroxymethyl)phosphonium salts/ [R2, 98] FORM: *Pyroset TKO; Retardol S [R3] MFS: *OCCIDENTAL PETROLEUM CORP, HOOKER CHEM CORP, SUBSID, SPECIALTY CHEMS AND PRODUCTS GROUP, NIAGARA FALLS, NY 14303 [R1] USE: *For Tetrakis(hydroxymethyl)phosphonium sulf (USEPA/OPP Pesticide Code: 129058) ACTIVE products with label matches. /SRP: Registered for use in the U.S. but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses./ [R4] *FLAME RETARDANT FOR TEXTILES, ESPECIALLY COTTON [R1] *Used to flame retard textiles. [R5, 661] *Biocide [R5, 663] PRIE: U.S. PRODUCTION: *(1976) 1.13X10+9 GRAMS (CONSUMPTION) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Crystalline solid [R2, 97] MW: *406.28 [R2, 97] SOL: *Soluble in water [R2, 97] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of /phosphorous oxides and sulfur oxides/. [R6] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of tetrakis(hydroxymethyl)phosphonium salts were available. There is inadequate evidence in experimental animals for the carcinogenicity of tetrakis(hydroxymethyl)phosphonium salts. Overall evaluation: Tetrakis(hydroxymethyl)phosphonium salts are not classifiable as to their carcinogenicity to humans (Group 3). /Tetrakis(hydroxymethyl)phosphonium salts/ [R7] ANTR: */SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R8] */SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R8] NTOX: *0.5% OR 1% SOLUTIONS WERE MUTAGENIC TO V79 HAMSTER LUNG CELLS. UP TO 84 MUTANT COLONIES/106 SURVIVING CELLS WERE FOUND WITH THPS FABRIC EXTRACTS. [R9] *Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPS was available as a 72% aqueous solution and THPC as a 75% aqueous solution. Two yr studies were conducted in F344/N rats by admin 0, 5, 10 mg/kg THPS or 0, 3.75 or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days/wk for 103 or 104 wk. Groups of 49 or 50 B6C3F1 mice were admin 0, 5 or 10 mg/kg THPS (each sex), 0, 7.5 or 15 mg/kg (males) or 0, 15 or 30 mg/kg THPC (females). ... Under the conditions of these 2 year gavage studies, there was no evidence of carcinogenicity of THPS in either sex of F344/N rats or B6C3F1 mice given 5 or 10 mg/kg. There was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg, in male B6C3F1 mice given 7.5 or 15 mg/kg, or in female B6C3F1 mice given 15 or 30 mg/kg. [R10] *In two-year studies, lesions attributed to administration of the sulfate salt in rats included liver cystic degeneration in males and hepatocyte vacuolization in animals of each sex. No lesion was reported in treated mice. [R11] *Tetrakis(hydroxymethyl)phosphonium sulfate was tested for carcinogenicity by oral administration in one strain of mice and one strain of rats. No dose-related increase in the incidence of any tumor was observed, but in males receiving the low dose there was an increased incidence of malignant lymphomas in mice and of mononuclear-cell leukemia in rats. [R12] *During 90 day gavage studies, hepatocyte vacuolar degeneration was seen in rats and mice receiving tetrakis(hydroxymethyl)phosphonium sulfate or chloride. [R11] *In a test for eye irritation ..., an aliquot of 0.1 ml THPS (75%) was introduced to one eye of a New Zealand rabbit. Opacity was observed 24 hr after application and lasted at least for 24 hr. Red coloration of the conjunctiva accompanied by considerable swelling was observed. On the basis of these effects, THPS (75%) is considered to be a severe eye irritant. [R13] *THPS (75%) was assessed for skin sensitization using the Magnusson and Kligman Maximization test ... . 14/20 animals challenged with the test substance were sensitized ... . These data clearly demonstrate a sensitization potential for THPS (75%). [R13] *Groups of ten 5- to 6-wk old F-344/N rats of each sex were admin 0, 5, 10, 20, 40 or 60 mg THPS (obtained from a 72% aqueous soln)/kg bw by gavage 5 days/wk for 13 wk. Three of the male rats that received 60 mg/kg died. Final mean body weights were 5%, 15% and 22% lower than those of the controls for males that received 20, 40, or 60 mg/kg and 9%, 12%, and 19% lower for females that received 20, 40, or 60 mg/kg. Vacuolar degeneration of hepatocytes occurred in all males receiving 10 mg/kg or more, in all females receiving 40 or 60 mg/kg, and in 5/10 females receiving 20 mg/kg. Lymphoid depletion in the spleen was seen in 3 males in the 60 mg/kg group. Bone marrow hypoplasia was diagnosed in 3/10 male and 4/10 female rats in the 60 mg/kg groups. The NOAEL in this study was 3.6 mg/kg bw/day; the LOAEL was 7.1 mg/kg bw/day. [R14] *In a dermal study, daily doses of 25, 250, or 500 mg THPS (75% aqueous soln) were applied to the shaved neck skin of ten (5 females, 5 males) Charles River derived CD rats. The treatment had to be terminated and animals killed after 6 days due to the nature and severity of the skin reaction observed at the application site. [R13] *Three groups of 16 New Zealand white rabbits were admin ... by gavage THPS (75%) at 6, 18, and 60 mg/kg bw/day from day 7-19 of gestation. All animals were killed on day 21. At 60 mg/kg mean body weight gain was significantly lower than that of controls, showing maternal toxicity. Treatment at 60 mg/kg resulted in incr incidence (42/120) of fetuses with eye malformation and some with addnl hydrocephaly or limb/phalangeal reduction defects. An incr incidence of specific skeleton variation was also observed. No adverse effects were noticed in the two lower-dose groups. Charles River CD rats (24 animals/group) were admin by gavage THPS (75%) at 15, 30 and 60 mg/kg bw/day for day 6-15. All animals were killed on day 21. Treatment at gestation onwards, indicating maternal toxicity. No treatment-related effects were observed in dams at the low-dose level. At the high-dose level, the incidence of fetuses showing extra thoraco-lumbar ribs was significantly higher than for controls. At 30 mg/kg only minor signs of maternal toxicity were observed. From these studies a NOAEL of 18 mg/kg bw/day based on maternal toxicity could be derived. No developmental effects were observed in the absence of maternal toxicity. [R15] NTXV: *LD50 Rat oral 248 mg/kg; [R6] *LD50 Rat (male) oral 333 mg/kg bw (72% soln in water) /From table/; [R16] *LC50 Rat inhalation 5.5 mg/l/4 hr (respirable aerosol- nose only); [R16] NTP: *Toxicology and carcinogenesis studies of tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and tetrakis(hydroxymethyl)phosphonium chloride (THPC) were conducted because of the widespread use of these chemicals as flame retardants in cotton fabrics. THPS was available as a 72% aqueous solution and THPC as a 75% aqueous solution. Two yr studies were conducted in F344/N rats by admin 0, 5, 10 mg/kg THPS or 0, 3.75 or 7.5 mg/kg THPC in deionized water by gavage to groups of 49 or 50 animals of each sex, 5 days/wk for 103 or 104 wk. Groups of 49 or 50 B6C3F1 mice were admin 0, 5 or 10 mg/kg THPS (each sex), 0, 7.5 or 15 mg/kg (males) or 0, 15 or 30 mg/kg THPC (females). ... Under the conditions of these 2 year gavage studies, there was no evidence of carcinogenicity of THPS in either sex of F344/N rats or B6C3F1 mice given 5 or 10 mg/kg. There was no evidence of carcinogenicity of THPC in either sex of F344/N rats given 3.75 or 7.5 mg/kg, in male B6C3F1 mice given 7.5 or 15 mg/kg, or in female B6C3F1 mice given 15 or 30 mg/kg. [R10] METB: *A metab study on rats has been conducted using 14C- radiolabelled THPS. THPS was not found in rat urine. However, three metabolites were present, identified as trihydroxymethyl phosphine oxide, bishydroxymethylphosphonic acid and possibly a formaldehyde adduct of the trihydroxy cmpd ... . [R17] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: *New Active Ingredients ... includes pesticide active ingredients initially registered after November 1, 1984, that currently have active product registrations. By law, these newer pesticides are not subject to the reregistration program. They must, however, meet the new safety standard of the FQPA, and will be reviewed on a 15-year cycle under the registration review program. ... Active Ingredient Number: 129058; Tpye of Pesticide: Conventional-Antimicrobial; Use Site: Non-food use; Year: 95. [R18] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and Tetrakis(hydroxymethyl)phosphonium chloride in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 296 (1987) NIH Publication No. 87-2522] SO: R1: SRI R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V48 (1990) R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V13 (1990) 97 R4: U.S. Environmental Protection Agency/Office of Pesticide Program's Chemical Ingredients Database on Tetrakis(hydroxymethyl)phosphonium sulfate (55566-30-8). Available from the Database Query page at http://www.cdpr.ca.gov/docs/epa/epamenu.htm as of May 24, 2001. R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V18 (1996) R6: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3117 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1532 (1999) R8: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R9: EHRLICH K ET AL; J TOXICOL ENVIRON HEALTH 6(2) 259 (1980) R10: Toxicology and Carcinogenesis Studies of Tetrakis(hydroxymethyl)phosphonium sulfate (THPS) and Tetrakis(hydroxymethyl)phosphonium chloride (THPC) in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 296 (1987) NIH Publication No. 87-2552 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1531 (1999) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1530 (1999) R13: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.85 (2000) R14: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.81-82 (2000) R15: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.86 (2000) R16: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate and Tetrakis(hydroxymethyl)Phosphonium Salts p.78 (2000) R17: WHO; Environ Health Criteria 218: Flame Retardants: Tris(2-butoxyethyl) Phosphate, Tris(2-ethylhexyl)Phosphate p.77 (2000) R18: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.395 (Spring, 1998) EPA 738-R-98-002 RS: 15 Record 288 of 1119 in HSDB (through 2003/06) AN: 4218 UD: 200302 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PENTACHLOROANISOLE- SY: *ANISOLE,-2,3,4,5,6-PENTACHLORO-; *BENZENE,-PENTACHLOROMETHOXY-; *ETHER,-METHYL-PENTACHLOROPHENYL-; *METHYL-PENTACHLOROPHENATE-; *METHYL-PENTACHLOROPHENYL-ETHER-; *2,3,4,5,6-PENTACHLOROANISOLE-; *PENTACHLOROMETHOXYBENZENE-; *PENTACHLOROPHENYL-METHYL-ETHER- RN: 1825-21-4 MF: *C7-H3-Cl5-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ADDITION OF SODIUM METHOXIDE IN METHANOL TO A BOILING SOLUTION OF HEXACHLOROBENZENE IN PYRIDINE [R1] FORM: *98% [R2] MFS: *NOT PRODUCED COMMERCIALLY IN THE USA [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R1] *(1979) NOT PRODUCED COMMERCIALLY IN USA [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- TAST: *Oily, muddy [R3] MP: *108-110 deg C [R4] MW: *280.37 [R2] OWPC: *5.45 [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *ADDN OF PENTACHLOROANISOLE TO FEED OF RATS DID NOT APPEAR TO ALTER URINARY AND FECAL PORPHYRIN EXCRETION. [R6] *PENTACHLOROANISOLE WAS MUCH LESS TOXIC THAN PENTACHLOROPHENOL TO TRICHODERMA VIRGATUM, CEPHALOASCUS FRAGRANS AND PENICILLIUM SP, AS WELL AS TO FISH, IN LAB TOXICITY TESTS. [R7] *Pentachloroanisole was evaluated for its mutagenic potential in the L5178Y TK+/TK- mouse lymphoma forward mutation assay using established procedures. Six experiments were conducted: two without metabolic activation and four with metabolic activation. The dose levels tested in these experiments ranged from 0-500 ug/ml. The two experiments without metabolic activation were discarded because no clear mutagenic response was obtained at dose levels where pentachloroanisole did not percipitate. Significant mutagenic responses were obtained in the remaining four experiments. Thus, pentachloroanisole was positive in these tests and the lowest effective dose tested was 31.25 ug/ml. [R8] *Male and female Sprague-Dawley (Spartan) rats were exposed to dietary levels of 60, 200 or 600 ppm purified pentachlorophenol (PCP) or pentachloroanisole (PCA) for 181 days, through mating and pregnancy. The daily intakes of PCP were 0, 4, 13 or 43 mg/kg body weight and of PCA were 0, 4, 12 or 41 mg/kg body weight. Animals exposed to PCP generally consumed more food than control animals during pregnancy. Dams at the high dose level of both compounds showed evidence of toxicity, weighing less on day 0 of gestation and gaining less throughout pregnancy than did the controls. Dams exposed to the high dose of PCP gained less weight during pregnancy (exclusive of the gravid uterus) than control dams. At the 43 mg/kg/day dose level PCP was embryolethal. Fetuses at the lower dose levels of PCP exhibited dose related decreases in body weights. A reduction in crown-rump length and an increase in fetal skeletal variations were seen at 13 mg/kg/day in PCP animals only. An intake of 41 mg PCA/kg/day was associated with a decrease in the number of corpora lutea and in embryolethality. PCA exposure also resulted in reductions in fetal body weight and crown-rump lengths of males at 4 and 41 mg/kg/day. Female fetuses were unaffected. [R9] *Pentachlorophenol (PCP) is a widespread contaminate of soils and ground water throughout North America. Earlier studies have indicated that microbial biodegradation leads to the formation of intermediate metabolites which are more toxic than the parent compound. Microbial degradation is by three general pathways: dechlorination, methylation and oxidation. The relative toxicity of PCP and 25 of its identified intermediates of microbial transformation was evaluated in the static Tetrahymena pyriformis population growth assay. Dechlorination of chlorophenols resulted in a decrease in toxicity because of a decrease in both hydrophobicity and reactivity. Moreover dechlorination of chloroanisoles resulted in a decrease in toxicity due to a decrease in hydrophobicity. Since there was a decrease in reactivity methylation of chlorophenols resulted in a decrease in toxicity. Oxidation of chlorophenols resulted in enhanced toxicity owing to increased reactivity and concomitant decreased hydrophobicity. [R10] +... CONCLUSIONS: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of pentachloroanisole in male F344/N rats based on increased incidences of benign pheochromocytomas of the adrenal medulla. There was equivocal evidence of carcinogenic activity of pentachloroanisole in female F344/N rats based on marginally increased incidences of benign pheochromocytomas of the adrenal medulla. There was some evidence of carcinogenic activity of pentachloroanisole in male B6C3F1 mice based on increased incidences of benign pheochromocytomas of the adrenal medulla and hemangiosarcomas of the liver. There was no evidence of carcinogenic activity of pentachloroanisole in female B6C3F1 mice given doses of 20 or 40 mg/kg~. [R11] NTXV: *LD50 Mouse oral 8.50 mg/kg; [R12] *LD50 Mouse ip 8.40 mg/kg; [R12] NTP: +... Toxicology and carcinogenesis studies were conducted by administering pentachloroanisole (> 99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. ... 2 YEAR STUDIES IN RATS: ... Doses selected for the 2 yr studies were 0, 10, 20, and 40 mg/kg for males and 0, 20, and 40 mg/kg for females. Groups of 70 male and 70 female rats were administered pentachloroanisole in corn oil by gavage 5 days/wk for up to 2 yr. ... 2 YEAR STUDIES IN MICE: ... Doses selected for the 2 yr studies were 0, 20, and 40 mg/kg. Groups of 70 male and 70 female mice were administered pentachloroanisole in corn oil by gavage 5 days/wk for up to 2 years. CONCLUSIONS: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of pentachloroanisole in male F344/N rats based on increased incidences of benign pheochromocytomas of the adrenal medulla. There was equivocal evidence of carcinogenic activity of pentachloroanisole in female F344/N rats based on marginally increased incidences of benign pheochromocytomas of the adrenal medulla. There was some evidence of carcinogenic activity of pentachloroanisole in male B6C3F1 mice based on increased incidences of benign pheochromocytomas of the adrenal medulla and hemangiosarcomas of the liver. There was no evidence of carcinogenic activity of pentachloroanisole in female B6C3F1 mice given doses of 20 or 40 mg/kg~. [R11] ADE: *RELATIVE TISSUE CONCN AND TOTAL BIRD LEVELS OF CHLOROANISOLES IN COMMERCIAL BROILERS REARED ON LITTER REPORTED. ALTHOUGH HIGHEST CONCN OCCURRED IN BONE AND ADIPOSE TISSUE, GREATEST CONTRIBUTION TO WHOLE BIRD LEVELS IN EDIBLE TISSUE WAS PREDOMINANTLY PENTACHLOROANISOLE. [R13] *PENTACHLOROANISOLE (PCA) TAKEN UP RAPIDLY BY RAINBOW TROUT @ 0.025 MG/L IN WATER. AFTER 24 HR, CONCN IN LIVER, BLOOD, FAT AND MUSCLE WERE 16, 6.5, 80, and 1.0 UG/G, RESPECTIVELY; T/2 OF 6.9, 6.3, 23, and 6.3 DAYS, RESPECTIVELY. [R14] *Tissue distribution, excretion and metabolism studies of pentachloroanisole (PCA), an environmental metabolite of pentachlorophenol (PCP), were conducted in the beagle dog and miniature pig following single oral doses (25 mg/kg) of radiolabelled PCA. PCA was readily demethylated by both species, with a half-life of 5-8 min. The resultant PCP was the major metabolite in dogs and pigs. In the dog, an average of 21.9% of the administered radiolabel was excreted in the urine and 62.3% in the feces during a 7 day period. Of the tissues analyzed, an average of 3.2% of the radiolabel remained in the liver, and blood and muscle accounted for averages of 3.0 and 2.3%, respectively, of the dose. Free and conjugated PCP were found in the urine of dogs; no PCA or tetrachlorohydroquinone (TCH) were found. In dog feces, PCP and a trace of polar material were observed; no PCA was excreted in dog feces. In the miniature pig, an average of 25.8% of the administered radiolabel was excreted in the urine and 32.0% in the feces during a 2-wk period. An average of 4.4% of the radiolabel was found in the liver, 8.8% in the blood, 7.1% in the muscle and 6.4% in the fat. In pig urine, PCP and conjugated PCP were the only metabolites observed; no PCA or TCH was found. Pig feces contained a trace of unchanged PCA; PCP and polar metabolites were also found. Since pig tissues retained a sizeable residue 2 wk after a single dose of PCA, various agents were used in an attempt to decrease the tissue level of radiolabel in pigs; anion exchange resin was found to be the most effective. [R15] *Toxicokinetics of pentachloroanisole (PCA) were studied in F344 rat and B6C3F1 mouse of both sexes by gavage at doses of 10, 20 and 40 mg/kg and by iv at 10 mg/kg. PCA was rapidly demethylated to pentachlorophenol (PCP) in both rat and mouse and the resulting PCP plasma concentrations were much higher than that of parent PCA due to the much smaller apparent volume of distribution of PCP. Peak plasma concentrations of PCA and PCP increased with dose in both rat and mouse. Bioavailability of PCA was low in both rat and mouse and was sex independent. The high plasma concentrations and relatively long biological half-life of PCP in both species after both iv and oral dosing with PCA indicate possible bioaccumulation of PCP upon multiple oral administrations of PCA. [R16] *Male Sprague-Dawley rats and New Zealand White rabbits were admin (14)C-labelled pentachloroanisole (PCA) in corn oil by gavage as single doses of 25 mg/kg and were then placed in individual metabolism cages for as long as 4 days. Peak blood level of radioactivity occurred 6 hr after admin of the dose to rats and between 3 and 4 hr in rabbits; the blood elimination half-life ranged from 8 to 15 hr in rats and averaged 6 hr in rabbits. Rats excreted an average of 54.2% of the admin radiolabel in the urine and 32.4% in the feces during the 96 hr following the dose; rabbits excreted an average of 84.2 and 13.1% of the radiolabel in the urine and faces, respectively, during this time. Examination of the metabolites in the rat showed that 60% of the urinary radioactivity was attributable to tetrachlorohydroquinone (TCH), 3% to free pentachlorophenol (PCP) and 29% to conjugated PCP; fecal metabolites were PCP (85.7%), TCH (4.3%) and polar metabolites (10.0%). In the rabbit, 58% of the urinary radioactivity was attributable to TCH, 8% to free PCP and 34% to conjugated PCP. Fecal metabolites consisted of PCP and conjugated material [R17] METB: *PENTACHLOROPHENOL WAS METHYLATED INTO PENTACHLOROANISOLE BY TRICHODERMA VIRGATUM IN LIQUID CULTURES. [R7] *DURING THE DECOMPOSITION OF SODIUM PENTACHLOROPHENOLATE BY ALCALIGENES EUTROPHUS, AEROMONAS HYDROPHILIA VARIETY HYDROPHILIA AND VARIETY ANAEROGENES, AZOTOBACTER CHROOCOCCUM, AZOTOBACTER VINELANDII, FLAVOBACTERIUM AQUATILE, PSEUDOMONAS FLUORESCENS, CYTOPHAGA JOHNSONAE, CORYNEBACTERIUM AQUATICUM, BREVIBACTERIUM TESTACEUUM, AND ARTHROBACTER GLOBIFORMIS THE FOLLOWING /METABOLITES WERE IDENTIFIED/: PENTACHLOROANISOLE, 2,3,4,5-TETRACHLOROANISOLE, 2,3,4,6-TETRACHLOROANISOLE, 2,3,5,6-TETRACHLOROANISOLE, 2,3,4,5-TETRACHLOROPHENOL, 2,3,5,6-TETRACHLOROPHENOL, TETRACHLORORESORCINOL, TETRACHLOROHYDROQUINONE, AND TETRACHLOROACETECHOL DIACETATE, THE PRINCIPAL METABOLITE BEING PENTACHLOROPHENOL ACETATE. UP TO 6.2% OF THE SODIUM PENTACHLOROPHENOLATE WAS RECOVERED AS PENTCHLOROPHENOL ACETATE, WHILE ALL OTHER METABOLITES WERE FOUND IN AMT LESS THAN 1% OF STARTING CMPD. [R18] *Spent sawdust cultures of the Shiitake mushroom (Lentinus edodes) metabolized pentachlorophenol in soil to a significant (p < 0.05) extent with 60.5, 57.3 and 44.4 % disappearance recorded for strains LE2 866 and R26 respectively. Addition of H202 markedly enhanced pentachlorophenol metabolism. Analysis of metabolites by GC/MS showed that pentachloroanisole was a metabolic product. These results suggest that there is potential for commercial application ln bioremediation. [R19] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Pentachloroanisole is not commercially produced but it is an abundant hydrocarbon in the atmosphere. The probable source of pentachloroanisole is the biotic transformation of the widely used biocide, pentachlorophenol (PCP). While pentachloroanisole may be formed from PCP in soil, sediment or wood chips, its conversion is favored by anaerobic conditions. Pentachloroanisole is estimated to have a high Koc, 1490, and therefore is expected to have low mobility in soil. It is estimated to have a high Henry's Law constant, indicating that volatilization may occur from moist soil. Just as pentachloroanisole is formed biotically from PCP, it may also be biotransformed back to PCP. Pentachloroanisole is favored in an aerobic environment and PCP in an anaerobic one. Nevertheless, pentachloroanisole may persist in soil for decades. If released in water, pentachloroanisole will primarily be lost by volatilization; its estimated half-lives for a model river and model lake are 5.7 hr and 6.9 days, respectively. It is stable to hydrolysis and while it may biodegrade into pentachlorophenol, interconversion may occur and reform pentachloroanisole. Pentachloroanisole has a very high measured BCF, however it is metabolized in aquatic organisms (2 experimentally-determined half-lives were 2.2 and 23 days), thus reducing its potential for long term bioconcentration. Pentachloroanisole is present in the atmosphere as the vapor. It reacts with photochemically-produced hydroxyl radicals; the half-life for this reaction is estimated to be 15 days. It may also be physically removed from the air by wet and dry deposition. The general population is exposed to pentachloroanisole in food, especially oils and fats, and in ambient air. Exposure may also occur via dermal contact with soil or wood products that had been treated with pentachlorophenol. (SRC) ARTS: *No commercial production of pentachloroanisole is known(3); its probable source is the biotic transformation of the biocide, pentachlorophenol (PCP) which is widely used as a wood preservative and slimicide in the wood products and leather industries(1-3). Pentachloroanisole's release after being formed in soil or water is believed to be the source of pentachloroanisole in the remote marine atmosphere(1). [R20] *Experiments performed in order to confirm that chlorinated anisoles could be formed in marine air by the action of widely-occurring haloperoxidase enzymes on anisole in the presence of chloride and hydrogen peroxide, failed to produced more highly chlorinated anisoles than dichloroanisole(1). Pentachloroanisole is a metabolite of PCP biodegradation by the fungi, Trichoderma virgatum(4). It was found on softwood chips treated with PCP(4). It is formed during composting of PCP(8). Pentachloroanisole was formed during the biodegradation of PCP in moist soil(3). However only a small percentage of PCP was converted to pentachloroanisole in the absence of molecular oxygen; after 24 days, 51.5% and 5.3% of applied PCP was converted to pentachloroanisole under aerobic and anaerobic conditions, respectively(2). After one vegetation period, 0.09% of the applied radioactivity resulting from the application of C14-PCP to flooded rice soil in a growth chamber was pentachloroanisole(5). In two years of monitoring aerobic and anaerobic sediment following the release of wastewater containing PCP-contaminated fuel oil into a creek, levels of pentachloroanisole did not exceed 10% of total PCP and pentachloroanisole concns(6). However the anaerobic site contained about twice the amount of pentachloroanisole indicating greater conversion. It is also a biodegradation product of pentachloronitrobenzene(7). [R21] *28-30 WK AFTER LAST APPLICATION OF (14)C-LABELED HCB (HEXACHLOROBENZENE) OR PCNB (PENTACHLORONITROBENZENE), PENTACHLOROANISOLE IDENTIFIED AS METABOLITE. [R22] FATE: *DEGRADATION OF PENTACHLOROPHENOL IN SOIL CORRELATED WITH CLAY MINERAL COMPOSITION, FREE IRON CONTENT, PHOSPHATE ABSORPTION COEFFICIENT AND CATION EXCHANGE CAPACITY, HIGHLY CORRELATED WITH SOIL ORG MATTER. PENTACHLOROANISOLE WAS DEGRADATION PRODUCT. [R23] *STUDY OF DEGRADATION OF PENTACHLOROPHENOL (PCP) UNDER AEROBIC AND ANAEROBIC CONDITIONS. PENTACHLOROANISOLE PRESENT IN BOTH AEROBIC AND ANAEROBIC SOILS. [R24] *VERTICAL SOIL DISTRIBUTION OF PENTACHLORONITROBENZENE AND METABOLITES SHOWED PEAK IN PARTS FROM 0-5 CM IN PLOWED SOIL AND FROM 0-20 CM AFTER CULTIVATION. RESIDUAL AMT IN POTATO TUBERS GREATER IN SANDY SOIL THAN IN SOIL WITH MORE HUMUS AND CLAY. [R25] *(14)C-LABELED PENTACHLORONITROBENZENE WAS APPLIED TO SOIL (36.1 KG/HA) UNDER OUTDOOR CONDITIONS AND ONION BULBS WERE PLANTED. AT HARVEST, PENTACHLOROANISOLE OBTAINED FROM ROOT-PEEL EXTRACT. [R26] *EXTENSIVE FISH KILLS IN FRESHWATER LAKE IN DEC 1974 and 1976 DUE TO RELEASE OF WOOD PRESERVATION CHEM INCL PENTACHLOROPHENOL. PENTACHLOROANISOLE, A MAJOR DEGRADATION PRODUCT, APPEARED TO HAVE BEEN FORMED WITHIN LAKE. [R27] *4 SIMULATED LENTIC ENVIRONMENTS USED TO STUDY DEGRADATION OF PCP. PENTACHLOROANISOLE FOUND IN TRACE AMT (2 UG/L) IN AQUARIUM 1, AN OXYGEN RICH EUPHOTIC EPILIMNION; AND AQUARIUM 2, AN OXYGEN RICH EUPHOTIC LITTORAL ZONE. [R28] *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 1490(SRC), derived from a molecular structure estimation method(2), suggests that pentachloroanisole will have low mobility in soil(SRC). Its high estimated Henry's Law constant(3), 1.94X10-3 atm-cu m/mole(SRC), indicates that volatilization may occur from moist soil surfaces(4,SRC). In a rapid infiltration system the mean concns of pentachloroanisole in secondary sewage applied to 250 cm columns of loamy sand and in column effluent were 70 and 40 ng/L, respectively(5), indicating that pentachloroanisole was being retained or transformed(SRC). Microbially mediated interconversion between pentachloroanisole and pentachlorophenol (PCP) may occur in both aerobic and anaerobic soil(6). One investigator reported a 5.6% conversion of pentachloroanisole to PCP after 24 days when aerobically incubated in a silty clay loam soil and a 42.1% conversion when anaerobically incubated(6). PCP is similarly transformed into pentachloroanisole. However, the principal transformations involved are reductive (O-demethylation) in anaerobic soil and oxidative (O-methylation) in aerobic soil(6) thereby favoring pentachloroanisole in an aerobic environment. Nevertheless, pentachloroanisole may persist in soil for decades(7). [R29] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 1490(SRC), determined from molecular structure(2), indicates that pentachloroanisole may adsorb to sediment and particulate matter in the water column(SRC). Pentachloroanisole should readily volatilize from water based on its estimated Henry's Law constant of 1.94X10-3 atm-cu m/mole(SRC), derived from a fragment constant estimation method(3). Estimated half-lives for a model river and model lake are 5.7 hr and 6.9 days, respectively(4,SRC). Pentachloroanisole is stable to hydrolysis and while it may biodegrade into pentachlorophenol, interconversion may occur and reform pentachloroanisole(10). Experimentally-determined BCFs of 9100-20,000(7,8) are very high but the potential for bioconcentration in aquatic organisms will be reduced(6) because pentachloroanisole is metabolized in fish (experimental half-lives 2.2 and 23 days(8,9)). [R30] *ATMOSPHERIC FATE: Atmospheric gas-particle partitioning experiments have shown that pentachloroanisole was present solely in the gas phase(1). Vapor-phase pentachloroanisole is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 15 days(2,SRC). Pentachloroanisole may be physically removed from the air by wet and dry deposition(3,SRC). [R31] BIOD: *O-demethylation of several anisoles can be catalyzed by various anaerobic bacteria(2). Pentachlorophenol (PCP) was formed during the biodegradation of 14C-pentachloroanisole in moist Hagerstown silty clay loam soil under aerobic and anaerobic conditions(1); 5.6% and 42.1% of pentachloroanisole applied to soil and incubated for 24 days was converted to PCP in experiments conducted under aerobic and anaerobic conditions, respectively(1). Pentachloroanisole was formed under similar circumstances when PCP was incubated; more pentachloroanisole was formed under aerobic than under anaerobic conditions. These results indicate that there is interconversion of pentachloroanisole and PCP in both aerobic and anaerobic soil, the principal reactions involved in the degradation are reductive (O-demethylation) in anaerobic soil and oxidative (O-methylation) in aerobic soil(1,2). [R32] ABIO: *Pentachloroanisole is resistant to chemical hydrolysis; it was not hydrolyzed by digestion in acidic or alkaline solutions and it was retained when pulp was cooked(1). [R33] *The rate constant for the vapor-phase reaction of pentachloroanisole with photochemically-produced hydroxyl radicals is estimated as 1.09X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a molecular structure-based estimation method(1,SRC). This corresponds to an atmospheric half-life of 15 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R34] BIOC: *The BCF of Lake Ontario rainbow trout were 15,000 and 20,000 at water concns of 0.9 and 10 ng/L, respectively(1). In another experiment, the BCF of pentachloroanisole in guppies was 9100(2) with an uptake and clearance rate of 1710 mL/g-day and 0.32/day (half-life 2.2 days), respectively(2). The high clearance rate, which may be explained by the metabolic hydrolysis of pentachloroanisole to pentachlorophenol, may be why the BCF of pentachloroanisole is lower than the corresponding chlorinated benzene(2). Another investigator reported a much longer half-life of pentachloroanisole in fish lipid of 23 days(3) which is indicative of a potential for medium term bioaccumulation(6). A BCF of 8200 was estimated for pentachloroanisole(SRC), using an estimated log Kow of 5.45(4,SRC) and a recommended regression-derived equation(5). According to a suggested classification scheme(6), the measured and calculated BCFs are very high(SRC). In assessing bioaccumulation potential one must include the elimination rate(6), which even at the lower of the two available rates would reduce the potential for long term bioaccumulation(SRC). [R35] *Pentachloroanisole levels of 1-2 ng/kg were found in the blood and milk of 3 cows while they were fed technical commercial grade pentachlorophenol (20 mg/kg-day for 10 days and then 10 mg/kg-day for 60 days)(1). [R36] KOC: *Using an estimation method based on molecular connectivity indices(1), the Koc for pentachloroanisole is estimated to be 1490(SRC). According to a suggested classification scheme(2), this Koc value suggests that pentachloroanisole will have low mobility in soil(SRC). During biodegradation studies, pentachloroanisole was largely bound to the humin component of soil(3). [R37] VWS: *The Henry's Law constant for pentachloroanisole is estimated as 1.94X10-3 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that pentachloroanisole will volatilize rapidly from water(2,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as 5.6 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as 6.9 days(1,SRC). For comparison, the Henry's Law constant derived from corresponding air and seawater concn measurements during an ocean cruise, 3.3 pg/cu m and 2.9 ng/cu m, respectively(3) is 2.8 X10-5 atm-cu m/mol(SRC). [R38] WATC: *SURFACE WATER: Lower Fox River, WI, a heavily developed industrial basin with pulp and paper industry contained 0.002-0.02 ug/L and 0.02-0.05 ug/L of pentachloroanisole in water and seston, respectively(1). Pentachloroanisole was detected but not quantified in streams and rivers feeding Lakes Erie, Ontario, Huron, and Michigan, as well as the east and central basins of Lake Ontario(3). It was detected in the River Lee, Great Britain at levels generally < 0.1 ug/L(2). [R39] *SEAWATER: Southern Atlantic Ocean (latitude 52 deg S, longitude 4 deg W; 10 m depth) 2.9 ng/cu m(1). [R40] *SNOW: Brown snow at Chesterfield Inlet, Northwest Territories in the Canadian arctic contained 1442 picograms/l of pentachloroanisole (1230 pg/l in melted snow and 4.3 ng/g in particles)(1). Analysis of air mass trajectories indicates that the source of the pollutant is western China(1). [R41] EFFL: *Pentachloroanisole was detected, not quantified, in secondary wastewater in Phoenix, AZ(1). Wastewater into the Lower Fox River, WI from 15 pulp and/or paper mills and 12 sewage treatment plants contained 0.05-0.38 ug/L of pentachloroanisole(2). [R42] *PENTACHLOROANISOLES IDENTIFIED IN THESE EFFLUENTS. [R43] SEDS: *SEDIMENT: Surficial sediments of Manukau Harbor, New Zealand (5 sites): < 0.1, < 0.1, < 0.1, 0.2, 0.1 ng/g dry wt(1). River and marine sediment from 9 of 12 sites sampled in Osaka, Japan contained pentachloroanisole ranging from 0.7 to 30 ug/kg dry wt with a median of positive samples of 3.5 ug/kg(2). Sediment from 6 estuaries in Japan contained pentachloroanisole levels ranging from not detectable to 1.1 ppb dry wt(3). SOIL: Soil in Japan on which pentachloronitrobenzene was extensively used, contained 0.009 ppm pentachloroanisole(4). Two 0-30 cm soil samples from an uncleaned sawmill in Finland that had been closed for more than 28 yr contained 200 and 806 ng/g pentachloroanisole, while that from two cleaned sawmills contained 3-29 ng/g in the 0-5 cm layer and 3-42 ng/g in the 5-10 cm layer(5,6). [R44] ATMC: *RURAL/REMOTE: Pentachloroanisole is one of the more abundant high molecular weight halocarbons in the remote marine troposphere. Levels of pentachloroanisole in American Samoa in the northern hemisphere were 9.0 picograms/cu m (standard deviation 3.9 picograms/cu m), while those in the southern hemisphere, New Zealand was 2.1 picograms/cu m (standard deviation 0.8 picograms/cu m)(1). It was also detected in the lower troposphere over the southern Indian Ocean in the lower pg/cu m range(4). Air samples collected on a cruise on the Atlantic Ocean between 50 deg N and 50 deg S (22 samples): 1.8 - 40 pg/cu m with a median concn of 8.7 pg/cu m(2). The air samples were collected at a height of 20 m above sea level. Egbert, Ontario, Canada (143 samples between July 1988 and Sept 1989): annual mean 28 pg/cu m, max 130 pg/cu m(3). [R45] FOOD: *Pentachloroanisole was one of the 40 most frequently found organic chemical residue in FDA's Total Diet Study of 1982-1984 and 1984-1985 with 33 and 30 positives among the 1872 individual food samples analyzed (2% incidence)(1). Results from FDA's Adult Total Diet Study in which the typical 14-day diet of a 16-19 yr male was collected throughout the US from market basket composite samples of 12 food groups (fiscal year, average intake (ug/kg body wt-day) are: FY78, 0.001; FY79, 0.001; FY80, 0.002; FY81/82, 0.001(2). Analogous study for infants and toddlers calculated that the intake of pentachloroanisole in ug/kg body wt-day was (fiscal year, average intake - infants, average intake - toddlers): FY78, 0.004, 0.007; FY79, 0.003,0.003; FY80, 0.003, 0.002; FY81/82, 0.002, 0.003(4) The food groups containing pentachloroanisole in the 1980-1982 survey are (class, concn range, average concn, number of positives): potatoes, trace, < 0.0001 ppm, 1; oils and fats, trace-0.004 ppm, 0.0014 ppm, 22; sugar and adjuncts, trace - 0.001 ppm, 0.0001, 2(2). Oils and fats were the only food classes relevant to infants and toddlers that contained pentachloroanisole(4). The food groups containing pentachloroanisole in the 1979-1980 survey was (class, concn range, average concn, number of positives): meat, fish and poultry, trace, < 0.0001 ppm, 1; fruits, 0.001 ppm, 0.001 ppm, 1; oils and fats, trace-0.009 ppm, 0.0012 ppm, 13; sugar and adjuncts, trace, < 0.0001 ppm, 2(3). Pentachloroanisole was detected, but not quantified in commercial fish liver oil from Finland(5). [R46] PFAC: PLANT CONCENTRATIONS: *Pentachloroanisole has been detected in pine needles(1). In fact pine needles have been used as a monitoring tool to establish that pentachloroanisole is a widespread air pollutant(1,2). Levels of pentachloroanisole in Swedish pine needles were twice those found in the rest of Europe, reflecting the past use of pentachlorophenol in Sweden(1). [R47] FISH/SEAFOOD CONCENTRATIONS: *Salmon collected from the Baltic Sea and the Gulf of Bothnia, Finland in 1985 (avg of 3 composite samples) contained 5.7 and 1.7 ng/g of pentachloroanisole, respectively(3). Pike and Burbot (8 composite samples) from Finland: 0.1-0.7 ng/g(3). Trout exposed for 3 months to 0.5% kraft mill effluent (n=9): 1.3 ng/g(3). Fish from the Lower Fox River, WI, a heavily developed industrial basin with pulp and paper industry contained 0.005-0.06 mg/kg pentachloroanisole(4). Neckar River Germany near Rotteweil below industrial discharge (50 samples): mean 0.005 mg/kg (0.12 mg/kg lipid), maximum 0.02 mg/kg (0.53 mg/kg lipid)(1). Mussels and fish collected from different seashore locations or markets in Japan: 11 of 24 samples positive, range of positives 0.1 to 10.7 ppb wet weight(2). The two highest samples were mussels from Osaka (10.7 ppb) and sardines from Wakayama (3.9 ppb)(2). [R48] *Fall run Coho salmon (skin-on filets) obtained from Lake Michigan in 1984 contained < 0.05 mg/kg pentachloroanisole(1). Lake Huron and Lake Superior tributaries and embayments (14 sites, 19 samples): 0.95-33 ng/g fat, median 5.3 ng/g fat(2). Sites around Lake Ontario (15 sites, 21 samples): 0-160 ng/g fat, median 29 ng/g fat(3). The fish with the highest levels were from the Buffalo River, Buffalo, NY(3). Of the bottom feeding and game fish, from each of nearly 400 sites through out the US analyzed between 1986 and 1989, 64% contained pentachloroanisole at a mean (standard deviation) and maximum concn of 10.8 (52.1) and 647 ng/g(4). It was detected, but not quantified in fish at three sites on the Mississippi River in 1979(5). Results of the Biomonitoring Program in which 321 composite fish samples from 112 stations throughout the US were analyzed for organochlorine residues were (collection period, geometric mean residue, maximum concn, % of stations with detectable residues): 1980-81, < 0.01 ppm, 0.07 ppm, 24.3%; 1984, < 0.01 ppm, 0.10 ppm, 30.4%(6). Levels of pentachloroanisole were generally low (< 0.02 ppm) except at stations on the Raritan River, NJ, Cape Fear River, NC, Penobscot River, ME, the Ohio River, Cincinnati, OH, the Mississippi River in Louisiana, and the Willamette River in Oregon(7). Since pentachloroanisole is relatively short-lived in fish, the presence of residues indicates recent inputs of the parent material(7). [R49] *The mean concns of pentachloroanisole in fat of freshwater mussels (Anodonta piscinalis) that had been incubated in cages in situ for 4 weeks at 11 sites in recipient watercourses of the pulp and paper industry in Finland during 1986-1987 (14 sites/years) ranged from 0 to 274 ng/g with a median concn of 23 ng/g(1). Pentachloroanisole was not found in waste liquid or in the water (detection limit 1 ng/L) and therefore the pentachloroanisole is produced as a metabolic product in the mussel or bioaccumulation is very high(1). [R50] ANIMAL CONCENTRATIONS: *The concn of pentachloroanisole in two species of earthworms at an uncleaned sawmill in Finland that had been closed for over 28 yr was 2.6 and 7.5 ug/g fat, while that in a third species at two cleaned sawmills was 0.37 and 1.27 ug/g fat(1,2). [R51] RTEX: *The general population is exposed to pentachloroanisole in food, especially oils and fats, and in ambient air. While not evident in FDA's Total Diet Studies, dietary exposure may occur by eating contaminated fish and fish products such as fish liver oil. Occupational expose, as well as general population exposure, may occur via dermal contact with soil or wood products that had been treated with pentachlorophenol. (SRC) AVDI: *AIR INTAKE (assume mean concn 28 picograms/cu m(1)): 0.56 ng; FOOD INTAKE (assume concn of 0.001 ug/kg(2), 70 kg for adults; 0.002 ug/kg(3), 9.2 kg for infants; and 0.003 ug/kg(3), 13.4 kg for toddlers) 0.07 ug (adults); 0.018 ug (infants); 0.040 ug (toddlers).(SRC) [R52] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GEL PERMEATION CHROMATOGRAPHY USED FOR SAMPLE CLEANUP AND GAS CHROMATOGRAPHY/MASS SPECTROMETRY USED FOR ANALYSIS OF FATHEAD FISH AND WATER. [R53] *ANALYSIS OF VEGETABLE OILS FOR PENTACHLOROANISOLE BY ELECTRON CAPTURE GAS-LIQUID CHROMATOGRAPHY. [R54] *GCMS, fish, limit of quantitation 2.5 ppb [R55] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Pentachloroanisole in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 414 (1993) NIH Publication No. 93-3145 SO: R1: SRI R2: Aldrich Chemical Company; Catalog Handbook of Fine Chemicals p 1092 (1994) R3: Paasivirta J et al; Chemosphere 16: 1231-41 (1987) R4: Schreitmuller J, Ballschmiter K; Environ Sci Technol 29: 207-15 (1995) R5: Opperhuizen A, Voors PI; Chemosphere 16: 953-62 (1987) R6: SIMON N ET AL; INT SYMP CLIN BIOCHEM 145 (1978) R7: CSERJESI AJ, JOHNSON EL; CAN J MICROBIOL 18 (1): 45 (1972) R8: McGregor DB et al; Environ Mutagen 9:143-160 (1987) R9: Welsh JJ et al; Food Chem Toxicol 25 (2): 163-72 (1987) R10: Bryant SE et al; Arch Environ Contam Toxicol 26 (3): 299-303 (1994) R11: Toxicology and Carcinogenesis Studies of Pentachloroanisole in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 414 (1993) NIH Publication No. 93-3145 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R12: Renner G et al; Tox Environ Chem 11 (1): 37-50 (1986) R13: HARPER DB, BALNAVE D; PESTIC SCI 6 (2): 159 (1975) R14: GLICKMAN AH ET AL; TOXICOL APPL PHARMACOL 41 (3): 649 (1977) R15: Ikeda GJ et al; Food Chem Toxicol 33 (5): 409-21 (1995) R16: Yuan JH et al; Xenobiotica 23 (4): 427-38 (1993) R17: Ikeda GJ et al; Food Chem Toxicol 32 (12): 1137-46 (1994) R18: ROTT B ET AL; J AGRIC FOOD CHEM 27 (2): 306 (1979) R19: Okeke BC et al; Biotech Lett 15 (10): 1077-80 (1993) R20: (1) Atlas E et al; Atmos Environ 20: 1217-20 (1986) (2) Schmitt CJ et al; Arch Environ Contam Toxicol 14: 225-60 (1985) (3) Wittlinger R, Ballschmiter K; Fresenius J Anal Chem 336: 193-200 (1990) R21: (1) Walter B, Ballschmiter K; Chemosphere 22: 557-67 (1991) (2) Schmitt CJ et al; Arch Environ Contam Toxicol 14: 225-60 (1985) (3) Murthy NBK et al; J Environ Sci Health B14: 1-14 (1979) (4) Cserjesi AJ, Johnson EL; Can J of Microbiol 18: 45-9 (1972) (5) Weiss UM et al; J Agric Food Chem 30: 1191-4 (1982) (6) Pierce RH Jr et al; in Contaminants and Sediments 2: 43-56, Baker RA, ed, Ann Arbor, MI: Ann Arbor Sci (1980) (7) Ohsawa K et al; J Pestic Sci 9: 339-44 (1984) (8) Behechti A et al; Chemosphere 17: 2433-40 (1988) R22: KORTE F; COMM EUR COMMUNITIES, (REP) EUR, EUR 6388, ENVIRON RES PROGRAMME 205 (1980) R23: KUWATSUKA S, IGARASHI M; SOIL SCI PLANT NUTR (TOKYO) 21 (4): 405 (1975) R24: MURTHY NBK ET AL; J ENVIRON SCI HEALTH B 14 (1): 1 (1979) R25: HANKAWA Y; ANNU REP HIROSHIMA PREF AGRIC EXP STN 40 81 (1978) R26: BEGUM S ET AL; PESTIC BIOCHEM PHYSIOL 11 (1-3): 189 (1979) R27: PIERCE RH JR, VICTOR DM; IN: PENTACHLOROPHENOL. RAO, KR, ED; NY: PLENUM PRESS, 41 PP (1977) R28: BOYLE TP ET AL; BULL ENVIRON CONTAM TOXICOL 24 (1): 177 (1980) R29: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 16 (1982) (5) Bouwer EJ et al; Water Res 15:151-9 (1981) (6) Murthy NBK et al; J Environ Sci Health B14: 1-14 (1979) (7) Palm H et al; Chemosphere 23: 263-7 (1991) R30: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Chapt 15 (1982) (5) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Oliver BG, Niimi AJ; Environ Sci Technol 19: 842-9 (1985) (8) Opperhuizen A, Voors PI; Chemosphere 16: 953-62 (1987) (9) Schmitt CJ et al; Arch Environ Contam Toxicol 14: 225-60 (1985) (10) Murthy NBK et al; J Environ Sci Health B14: 1-14 (1979) R31: (1) Kaupp H, Umlauf G; Atmos Environ 26A: 2259-67 (1992) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Hoff RM et al; Environ Sci Technol 26: 266-75 (1992) R32: (1) Murthy NBK et al; J Environ Sci Health B14: 1-14 (1979) (2) Kuhn EP, Suflita JM; pp. 111-180 in Reactions and Movement of Organic Chemicals in Soils, Soil Science Soc Amer Special Publ No.22, Madison, WI (1989) R33: (1) Cserjesi AJ, Johnson EL; Can J of Microbiol 18: 45-9 (1972) R34: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R35: (1) Oliver BG, Niimi AJ; Environ Sci Technol 19: 842-9 (1985) (2) Opperhuizen A, Voors PI; Chemosphere 16: 953-62 (1987) (3) Schmitt CJ et al; Arch Environ Contam Toxicol 14: 225-60 (1985) (4) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5, Eqn 5-2 (1982) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) R36: (1) Firestone D et al J Agric Food Chem 27: 1171-7 (1979) R37: (1) Meylan WM et al; Environ Sci Technol 28: 459-65 (1992) (2) Swann RL et al; Res Rev 85: 23 (1983) (3) Murthy NBK et al; J Environ Sci Health B14: 1-14 (1979) R38: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. NY: McGraw-Hill Chapt 15 (1982) (3) Schreitmuller J, Ballschmiter K; Environ Sci Technol 29: 207-15 (1995) R39: (1) Peterman PH et al; in Hydrocarbons and halogenated hydrocarbons Aquat Environ, Afgan BK, Mackay D, ed, Plenum Press, NY pp 145-60 (1980) (2) Waggott A; Chem Water Reuse 2: 55-9 (1981) (3) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem Vol 1 Windsor, Ontario, Canada (1983) R40: (1) Schreitmuller J, Ballschmiter K; Environ Sci Technol 29: 207-15 (1995) R41: (1) Welch HE et al; Environ Sci Technol 25:280-6 (1991) R42: (1) Bouwer EJ et al; Water Res 15:151-9 (1981) (2) Peterman PH et al; in Hydrocarbons and halogenated hydrocarbons Aquat Environ, Afgan BK, Mackay D, ed, Pglenum Press, NY pp 145-60 (1980) R43: BURLINGAME AL; ECOTOXICOL ENVIRON SAF 1 (1): 111 (1977) R44: (1) Fox ME et al; Mar Pollut Bull 19:333-6 (1988) (2) Watanabe I et al; Bull Environ Contam Toxicol 35: 272-8 (1985) (3) Watanabe I et al; Arch Environ Contam Toxicol 12: 615-20 (1983) (4) Ohsawa K et al; J Pestic Sci 9: 339-44 (1984) (5) Palm H et al; Chemosphere 23: 263-7 (1991) (6) Knuutinen J et al; Chemosphere 20: 609-23 (1990) R45: (1) Atlas E et al; Atmos Environ 20: 1217-20 (1986) (2) Schreitmuller J, Ballschmiter K; Environ Sci Technol 29: 207-15 (1995) (3) Hoff RM et al; Environ Sci Technol 26: 266-75 (1992) (4) Wittlinger R, Ballschmiter K; Fresenius J Anal Chem 336: 193-200 (1990) R46: (1) Gunderson EL; J Assoc Off Anal Chem 78: 910-21 (1995) (2) Gartrell MJ et al; J Assoc Off Anal Chem 69: 146-61 (1986) (3) Gartrell MJ et al; J Assoc Off Anal Chem 68: 1184-97 (1985) (4) Gartrell MJ et al; J Assoc Off Anal Chem 69: 123-45 (1986) (5) Paasivirta J et al; Chemosphere 16: 1787-90 (1987) R47: (1) Hoff RM et al; Environ Sci Technol 26: 266-75 (1992) (2) Welch HE et al; Environ Sci Technol 25:280-6 (1991) R48: (1) Kypke-Hutter K et al; Z Lebensm Unters Forsch 182: 464-70 (1986) (2) Watanabe I et al; Arch Environ Contam Toxicol 12: 615-20 (1983) (3) Paasivirta J et al; Chemosphere 16: 1231-41 (1987) (4) Peterman PH et al; in Hydrocarbons and halogenated hydrocarbons Aquat Environ, Afgan BK, Mackay D, ed, Pglenum Press, NY pp 145-60 (1980) R49: (1) Great Lakes Water Quality Board; 1987 Report on Great Lakes Water Quality, Appendix B Great Lakes Surveillance, Vol I. Report to International Joint Commission (1989) (2) Jaffe R et al; J Assoc Great Lakes Res 11: 156-162 (1985) (3) Jaffe R, Hites RA; J Great Lakes Res 12: 63-71 (1986) (4) Kuehl DW et al; Chemosphere 29: 523-5 (1994) (5) Kuehl DW et al; Environ Intern 9: 293-9 (1983) (6) Schmitt CJ et al; Arch Environ Contam Toxicol 19: 748-81 (1990) (7) Schmitt CJ et al; Arch Environ Contam Toxicol 14: 225-60 (1985) R50: (1) Herve S et al; Chemosphere 17: 1945-61 (1988) R51: (1) Palm H et al; Chemosphere 23: 263-7 (1991) (2) Knuutinen J et al; Chemosphere 20: 609-23 (1990) R52: (1) Hoff RM et al; Environ Sci Technol 26: 266-75 (1992) (2) Gartrell MJ et al; J Assoc Off Anal Chem 69: 146-61 (1986) (3) Gartrell MJ et al; J Assoc Off Anal Chem 69: 123-45 (1986) R53: KOPPERMAN HL ET AL; ENVIRON IMPACT WATER CHLORINATION, PROC CONF, CONF-751096, 327 (1976) R54: WILLIAMS DT; J ASSOC OFF ANAL CHEM 56 (1): 200 (1973) R55: USEPA; Analytical procedures and quality assurance plan on the determination of xenobiotic chemical contaminants in fish. Duluth, MI: National Environmental Research Lab. USEPA-600-3-90-023 (1990 RS: 43 Record 289 of 1119 in HSDB (through 2003/06) AN: 4227 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-DIRECT-BLUE-15- SY: *AIREDALE-BLUE-D-; *AIZEN-DIRECT-SKY-BLUE-5BH-; *AMANIL-SKY-BLUE-; *ATLANTIC-SKY-BLUE-A-; *ATUL-DIRECT-SKY-BLUE-; *AZINE-SKY-BLUE-5B-; *BELAMINE-SKY-BLUE-A-; *BENZANIL-SKY-BLUE-; *BENZO-SKY-BLUE-S-; *BENZO-SKY-BLUE-A-CF-; *CARTASOL-BLUE-2GF-; *CHLORAMINE-SKY-BLUE-A-; *CHLORAMINE-SKY-BLUE-4B-; *CHROME-LEATHER-PURE-BLUE-; *CI-DIRECT-BLUE-15-; *C.I.-24400-; *CRESOTINE-PURE-BLUE-; *DIACOTTON-SKY-BLUE-5B-; *DIAMINE-BLUE-6B-; *DIAMINE-SKY-BLUE-; *DIAPHTAMINE-PURE-BLUE-; *DIAZOL-PURE-BLUE-4B-; *DIPHENYL-BRILLIANT-BLUE-; *DIPHENYL-SKY-BLUE-6B-; *DIRECT-BLUE-15-; *DIRECT-BLUE-10G-; *DIRECT-BLUE-HH-; *DIRECT-PURE-BLUE-N-; *DIRECT-SKY-BLUE-; *DIRECT-SKY-BLUE-A-; *DIRECT-SKY-BLUE-5B-; *ENIANIL-PURE-BLUE-AN-; *FENAMIN-SKY-BLUE-; *HISPAMIN-SKY-BLUE-3B-; *KAYAKU-DIRECT-SKY-BLUE-5B-; *NAPHTAMINE-BLUE-10G-; *2,7-NAPHTHALENEDISULFONIC ACID, 3,3'-((3,3'-DIMETHOXY(1,1'-BIPHENYL)-4,4'-DIYL)BIS(AZO))BIS(5-AMINO-4-HYDROXY-, TETRASODIU///; *NIAGARA-BLUE-4B-; *NIAGARA-SKY-BLUE-; *NIPPON-DIRECT-SKY-BLUE-; *NITSUI-DIRECT-SKY-BLUE-5B-; *NITTO-DIRECT-SKY-BLUE-5B-; *PHENAMINE-SKY-BLUE-A-; *PONTACYL-SKY-BLUE-4BX-; *PONTAMINE-SKY-BLUE-5BX-; *SHIKISO-DIRECT-SKY-BLUE-5B-; *SKY-BLUE-4B-; *SKY-BLUE-5B-; *TERTRODIRECT-BLUE-F-; *VONDACEL-BLUE-HH- RN: 2429-74-5 MF: *C34-H28-N6-O16-S4.4Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Production: o-dianisidine + H acid (diazotisation/azo coupling) [R1] MFS: *AMERICAN COLOR AND CHEMICAL CORP, CHARLOTTE, NC 28210 [R2] *BASF WYANDOTTE CORP AND PIGMENTS DIV, PARSIPPANY, NJ 07054 [R2] *E I DU PONT DE NEMOURS AND CO, INC, WILMINGTON, DEL 19898 [R2] *MOBAY CHEMICAL CORP, DYESTUFFS DIV, PITTSBURGH, PA 15205 [R2] *TOMS RIVER CHEMICAL CORP, TOMS RIVER, NJ 08753 [R2] *Miles, Inc, One Mellon Center, 500 Grant Street, Pittsburgh, PA 15219-2502 (412) 394-5578. Dyes and Pigments Div Production Site: Bushy Park, SC 29411 [R3] USE: *DYE FOR SILK, WOOL, VISCOSE, LEATHER, PAPER, CELLULOSE FIBERS; BIOLOGICAL STAIN; TINT FOR CINEMATOGRAPHIC FILMS [R2] *Dye (cotton) [R1] CPAT: *ESSENTIALLY 100% AS A DYE [R2] PRIE: U.S. PRODUCTION: *(1977) 2.40X10+8 GRAMS [R2] *(1979) 1.30X10+8 GRAMS (SALES) [R2] U.S. IMPORTS: *(1977) 2.45X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R2] *(1979) 3.40X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *992.80 [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R4, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R4, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R4, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R4, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R4, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R4, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R4, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R4, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R4, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R4, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R4, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R4, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R4, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R4, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R4, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R4, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R4, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R4, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R4, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of CI Direct Blue 15. There is sufficient evidence in experimental animals for the carcinogenicity of CI Direct Blue 15. Overall evaluation: CI Direct Blue 15 is possibly carcinogenic to humans (Group 2B). [R5] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R4, 1979.23] NTOX: *SINGLE IP INJECTION OF AQUEOUS SOLN OF NIAGARA BLUE 4B, 7, 14, OR 20 MG/100 G DURING 8TH DAY OF GESTATION INTO WISTAR RATS CAUSED DOSE-RELATED INCR IN NUMBER OF MALFORMED FETUSES AND INCR IN RESORPTIONS. NIAGARA BLUE 4B PRODUCED MAINLY HYDROCEPHALUS. [R6] *This report introduces a method of detecting chemical-induced morphological transformation of A-31-1-13 BALB/c-3T3 cells. The procedure uses an increased target cell population to assess chemical-induced damage by increasing the initial seeding density and by delaying the initiation time of chemical treatment. ... This assay measured the relative cloning efficiency of chemical treatments in high-density cell cultures. ... From a group of 24 chemicals tested in at least two trials, clear evidence of chemical-induced transformation was detected for 12 chemicals including C.I. Direct Blue 15. ...All positive responses were detected in the absence of an exogenous activation system and exhibited significant activity at two or more consecutive doses. [R7] *Dimethoxybenzidine and dimethylbenzidine are used to synthesize dyes such as C.I. Direct Blue 15 and C.I. Acid Red 114, respectively. These commercially used dyes are metabolically degraded to dimethoxybenzidine or dimethylbenzidine in the intestinal tract of rodents and subsequently dimethoxybenzidine and dimethylbenzidine are absorbed into the blood stream. Animals were exposed to dimethoxybenzidine, dimethylbenzidine, or the dyes in the drinking water. Tumors obtained from control and chemical-treated animals were examines for the presence of activated oncogenes by the NIH 3T3 DNA transfection assay. Activated oncogenes were detected in less than 3% (1/38) of the tumors from control animals whereas 68% (34/50) of the tumors from chemical-treated animals contained detectable oncogenes. Activated oncogenes were detected in both malignant (25/36) and benign (9/14) tumors from the chemically treated animals but only in one of 13 malignant tumors from the control animals. The presence of oncogenes in the chemically induced benign tumors suggests that oncogene activation was an early event in those tumors. Southern blot analysis of transfectant DNA showed that the transforming properties of the chemically induced rat tumor DNAs were due to the transfer of an activated H-ras (31/34) or N-ras (3/34) gene. One spontaneous rat tumor was found to contain an activated H-ras gene. Oligonucleotide hybridization analysis indicated that the H-ras oncogenes from chemical-associated tumors contained mutations at codons 12, 13, or 61 whereas the spontaneously activated H-ras gene contained a point mutation at codon 61. Activation of cellular ras genes by point mutation is an important step in the induction of tumors, at least in rats, by this class of benzidine-derived dyes. Moreover, /on the basis of/ common histogenesis of the normal counterparts of many of the chemically induced neoplasms and histological evidence of varied tissue differentiation in some basal cell neoplasms, it is possible that most or all of the chemically induced neoplasms were derived from a common epidermal progenitor stem cell population. [R8] *The benzidine congener 3,3'-dimethoxybenzidine, and C.I. Direct Blue 15, a prototypical compound of the 3,3'-dimethoxybenzidine derived class of dyes, were evaluated in 13 week studies to characterize the toxicity and established dose levels for subsequent chronic studies. Groups of Fischer 344 rats of each sex were administered either 3,3'-dimethoxybenzidine, or Direct Blue 15, at 1 of 5 concentrations in drinking water for 13 weeks. 3,3'-dimethoxybenzidine concentrations were 0, 0.017, 0.033, 0.063, 0.125, and 0.25% for males and females. For Blue 15, the concentrations were 0.063, 0.125, 0.35, 0.50, and 1.0% for females and 0, 0.125, 0.25, 0.50, 1.0, and 3.0% for male rats. Rats showed dose-related decreases in water consumption and weight gains. All 3,3'-dimethoxybenzidine treated rats and their controls survived the 13 week treatment. There were 7 deaths in the 3% level of male rats treated with Blue 15. Liver and kidney weights were increased in rats treated with both compounds. Target organs for 3,3'-dimethoxybenzidine treated rats were the kidney and thyroid. These lesions were characterized by chronic nephropathy, and increased pigment in the follicular cells of the thyroid. The kidney and liver were identified as target organs for Blue 15 treated rats. In the high-dose rats that died before termination of the study, renal effects were characterized by degeneration and focal necrosis of hepatocytes, fatty metamorphosis, and minimal megalocytosis. Mild chronic nephropathy was the principal histological effect in Blue 15 treated rats surviving to study termination. [R9] *Neoplasms of preputial gland and skin were obtained from Fischer 344 male rats on lifetime drinking water studies of the benzidine congener 3,3'-dimethoxybenzidine, C.I. Direct Blue 15 or C.I. Acid Red 114, bisazobiphenyl dyes derived from 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine. Portions of these well differentiated neoplasms were implanted into the left mammary fat pad of Fischer 344 male recipients. The rate of growth, presence of local invasion and distant metastases, and morphologic features were observed following a 4 serial transplantation. All implants appeared early, grew rapidly, and were histomorphologically similar to the original neoplasms, Metastases from transplants were observed with both preputial gland and skin tumor lines in serial passages. The transplantation results confirm the malignant nature of these neoplasms. [R10] *The arabinose-resistant and Ames assay systems of Salmonella typhimurium were used to evaluate the mutagenic potential of azo dyes and their aromatic amine reduction products. Azo dyes, namely direct black 38, direct blue 15, and direct red 2, were mutagenic in the arabinose-resistant and Ames assays with both hamster and rat liver S9 activation. Both assays gave relatively higher mutagenic responses with hamster S9. Reduction products of these dyes, namely benzidine, o-dianisidine, and o-tolidine, were mutagenic in the Ames assay. Benzidine was weakly mutagenic and o-dianisidine and o-tolidine were nonmutagenic in the arabinose-resistant assay. These results indicate that both arabinose-resistant tester SV50 and Ames tester TA98 were sensitive in detecting mutagenicity of azo dyes. The use of the standard plate protocol with Ames tester TA98 is more efficient than the modified azo dye protocol. In detecting mutagenicity of aromatic amine reduction products. [R11] *Direct Blue 15 (a 3,3'-dimethylbenzidine-based dye), ... /bind/ to albumin, alpha 1-lipoprotein, beta-lipoprotein, and hemopexin. ... Direct Blue 15 /binds/ also to prealbumin and alpha 1-antichymotrypsin, and degraded C3 globulin. Direct Black 38 and Evans Blue bound to numerous additional proteins. [R12] *The metabolism and distribution of Direct Red 2 and Direct Blue 15 were studied in rats. Male Fischer 344 rats were administered 12 mg/kg carbon-14 libeled DR or DB or molar equivalent doses of the corresponding amines, dimethylbenzidine or dimethoxybenzidine, respectively. Urine and feces samples were collected for up to 192 hours after dosing and assayed for carbon-14 activity and metabolites. Selected animals were killed 2 to 72 hours after administration and the tissue distribution of carbon-14 activity was determined. Most of the carbon-14 activity was excreted in the feces, 52.05 to 74.40% of the dose being eliminated. Urinary excretion amounted to 18.79 to 39.66% of the dose. Dimethylbenzidine and dimethoxybenzidine were more extensively metabolized than the corresponding dyes, DR and DB. Urinary metabolites produced by DB included alkaline hydrolyzable conjugates, diacetyldimethoxybenzidine, monoacetyldimethoxybenzidine, and free dimethoxybenzidine. Ninety six percent of the carbon-14 activity, however, was non identifiable water soluble metabolites. The largest amounts of carbon-14 activity derived from both dyes were accumulated and retained in the liver, kidney, and lung. Similar distribution patterns were seen with the free amines. Both dyes accumulate in the liver, a known target organ for rats dosed with benzidine and the site of tumors in rats dosed with benzidine based azo dyes. [R13] +... Conclusions: Under the conditions of these 22 month drinking water studies, there was clear evidence of carcinogenic activity of C.I. Direct Blue 15 (desalted industrial grade) in male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, and small and large intestine. Increased incidences of mononuclear cell leukemia and neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of C.I. Direct Blue 15 in female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, and uterus, and by mononuclear cell leukemia. [R14] NTP: +C.I. Direct Blue l5 is one of five chemicals being evaluated in 2 yr carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. ... Because of the high salt content, the dye was desalted prior to use. The purity was determined to be approximately 50%, with high-performance liquid chromatography indicating one major peak and approximately 35 impurities. Toxicology and carcinogenesis studies were conducted by administering the dye, C.I. Direct Blue 15, in drinking water to groups of F344/N rats of each sex for ... 22 months. Planned as 24 month studies, the 22 month studies were terminated early because of rapidly declining animal survival, which was due primarily to neoplasia. ... 22 Month Studies at study initiation: 70 rats of each sex were given 0 or 2,500 ppm C.I. Direct Blue 15, 45 rats of each sex were given 630 ppm, and 75 rats of each sex were given 1,250 ppm. ... The average amounts of cmpd consumed per day by the six dose groups after week 52 of the studies were estimated to be 45, 90, and 215 mg/kg for male rats and 50, 100, and 200 mg/kg for female rats. Conclusions: Under the conditions of these 22 month drinking water studies, there was clear evidence of carcinogenic activity of C.I. Direct Blue 15 (desalted industrial grade) in male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, and small and large intestine. Increased incidences of mononuclear cell leukemia and neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of C.I. Direct Blue 15 in female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, and uterus, and by mononuclear cell leukemia. [R14] TCAT: ?Acute oral toxicity was evaluated in 5 young adult ChR-CD male rats administered single doses of undiluted direct blue 15 [3,3'-((3,3'-dimethoxy-4,4' 06 biphenylene) bis (azo))bis(5-amino-2,7-naphthalenedisulfonic acid)] by oral gavage at levels of 25,000, 17,000, 11,000, 7,500, or 5,000 mg/kg of body weight. Mortality was observed in both the 25,000 mg/kg and 17,000 mg/kg dose level animals; the approximate lethal dose (ALD) was reported to be 17,000 mg/kg of body weight. Clinical observations included wet perineal area stained with test compound, blue-colored eyes and piloerection day after dosing and entire body stained on second day at the highest dose level. At 5,000 mg/kg and above, there was evidence of test compound in the feces, and weight loss was observed at 7,500 and 11,000 mg/kg on day after dosing. Gross necropsy findings were not reported [R15] ?Direct blue 15 (CAS # 2429-74-5) was evaluated for primary dermal irritation. The test substance was applied at 0.05 ml each of a 10% and 1% solution on the shaved, intact shoulder skin of 10 male albino guinea pigs. It was determined that the test substance produced moderate to no irritation. [R16] ?Direct blue 15 (CAS # 2429-74-5) was evaluated for primary dermal irritation. The test substance was applied to the backs of 78 adult male volunteers under occlusive dressing for 7-days. Dosage levels were not reported. No cases of irritancy occurred. [R17] ?Direct blue 15 (CAS # 2429-74-5) was evaluated for skin corrosion. The test substance was applied to the occluded trunks of 6 albino rabbits at a level of 0.5 ml of a 10% and 1 % solution for 4-hours. No mortality occurred. The test substance was not considered to be corrosive to the skin. [R18] ?Direct blue 15 (CAS # 2429-74-5) was evaluated for dermal sensitization. The test substance was applied to 8 male albino guinea pigs at a level of 0.1 ml of a 1% solution, in a series of 4 sacral intradermal injections, one each week over a 3-week period. Following a 2-week rest period, the test animals were challenged by applying 0.05 ml each of a 10% and a 1% solution on the shaved intact shoulder skin. No sensitization occurred in any of the animals. [R18] ?Direct blue 15 (CAS # 2429-74-5) was evaluated for dermal sensitization. The test substance was applied to the backs of 78 adult male volunteers under occlusive dressing for 7-days. Dosage levels were not reported. Following a 2-week rest period, the test material was re-applied to the same site for 1-week. No cases of contact allergy occurred. [R17] ADE: *Absorption, metabolism and tissue distribution studies were conducted in the rat with (14)C-labeled dyes (12 mg/kg, 62 uCi/kg) and molar equivalent doses of the respective amines were administered. ... A comparison of the metabolism of Direct Blue 15 with its base DiMxBzd, indicated that the base was more extensively metabolized and that most of the (14)C in various extracts was identified in known metabolites. ... Distribution studies conducted with both dyes showed that liver, kidney, and lung accumulated and retained higher levels of (14)C than other tissues (at 72 hours). Peak levels of (14)C, which occurred 8-12 hours after dosing, were significantly higher with Direct Red 2 than Direct Blue 15. Tissue distribution data (72 hour) for rats dosed with the free amines compared with the dyes showed a generally lower but similar distribution pattern. [R19] METB: *The purified azoreductase and nitroreductase of Clostridium perfringens, which have similar electrophoretic properties, both reacted in a Western blot (immunoblot) with a polyclonal antibody raised against the azoreductase. The activity of both enzymes was enhanced by flavin adenine dinucleotide and was inhibited by menadione, o-iodosobenzoic acid, and the antibody against azoreductase. Reduction of the azo dye Direct Blue 15 by the azoreductase was inhibited by nitroaromatic compounds. The apparent Km of the enzyme for reduction of Direct Blue 15 in the presence of 1-nitropyrene was higher than the Km with the azo dye alone, demonstrating competitive inhibition. The data show that the same protein in involved in the reduction of both azo dyes and nitroaromatic compounds. [R20] *The metabolism of a benzidine-based dye, Direct Black 38, a 3,3'-dimethylbenzidine-based dye, Direct Red 2 and a 3,3'-dimethoxybenzidine-based dye, Direct Blue 15 has been studied both in pure cultures of anaerobic bacteria and in bacterial suspensions derived from the intestinal contents of the rat. All of the pure cultures and the rat intestinal bacteria were able to reduce the azo linkages of Direct Black 38, Direct Red 2 and Direct Blue 15 with the subsequent formation of benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine, respectively. ... Results from this study indicate that in vitro anaerobic incubations of rat intestinal microorganisms were able to reduce and cleave the azo bonds of dyes derived from benzidine, 3,3'-dimethylbenzidine and 3,3'-dimethoxybenzidine. [R21] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *C.I. Direct Blue 15's production and use in the dyeing of cotton may result in its release to the environment through various waste streams. The ionic state of C.I. Direct Blue 15 makes this compound essentially non-volatile, therefore this compound will exist solely in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Direct Blue 15 may be physically removed from the air by wet and dry deposition. If released to soil, the retention of C.I. Direct Blue 15 by ion-exchange processes, particularly on clay surfaces, and adsorption at mineral surfaces such as geothite, may slow down or prevent leaching. The volatilization of the dye from soil surfaces to air will not be important as C.I. Direct Blue 15 is an ionic compound. Based on limited data, this compound is expected to be resistant to aerobic biodegradation, however, it should readily biodegrade anaerobically. Complete anaerobic biodegradation of C.I. Direct Blue 15 was reported in 7 days using an activated sludge inoculum. The loss of the dye from water by evaporation is not expected to be an important fate process. Direct Blue 15 is expected to adsorb sediments and particulate matter in water due to ionic processes with adsorption increasing with decreasing pH. Occupational exposure may occur during C.I. Direct Blue 15's production or during its use as a dye. (SRC) ARTS: *C.I. Direct Blue 15's production and use in the dyeing of cotton(1) may result in its release to the environment through various waste streams(SRC). [R22] FATE: *TERRESTRIAL FATE: Due to the ionic nature of C.I. Direct Blue 15, the retention of the dye by ion-exchange processes(1,SRC), particularly on clay surfaces, and adsorption at mineral surfaces such as geothite(2), may slow down or prevent leaching(SRC). Based on limited data, this compound is expected to be resistant to aerobic biodegradation(3), however, it should readily biodegrade anaerobically. Complete anaerobic biodegradation of C.I. Direct Blue 15 was reported in 7 days using an activated sludge inoculum(4). Since ionic compounds normally do not readily volatilize(1), no loss of the dye from soil surfaces is expected to occur due to volatilization(SRC). [R23] *AQUATIC FATE: Sorption to sediment, shown for a structurally similar compound, Direct Blue 14, was dependent on pH with adsorption increasing with decreasing pH(1). The weakly basic amino groups and strongly acidic sulfonate groups, found in both C.I. Direct Blue 14 and C.I. Direct Blue 15, are responsible for sorption mechanisms(1). This compound is expected to be resistant to aerobic biodegradation(2), however, it should readily biodegrade anaerobically. Complete anaerobic biodegradation of C.I. Direct Blue 15 was reported in 7 days using an activated sludge inoculum(3). Since C.I. Direct Blue 15 is an ionic compound, volatilization of the dye from water surfaces will not be important(4,SRC). [R24] *ATMOSPHERIC FATE: The ionic state of C.I. Direct Blue 15 makes this compound essentially non-volatile(1,SRC), therefore this compound should exist in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Direct Blue 15 may be physically removed from the air by wet and dry deposition(SRC). [R25] BIOD: *Using the static test method, C.I. Direct Blue 15, at a concentration of 107 mg/l COD, was not degraded over 41 days with an activated sludge inoculum(1). Adsorption accounted for 6% loss of the dye(1). This compound may be biodegraded anaerobically; a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(2). C.I. Direct Blue 15 at 100 mg/l, incubated with an anaerobic sludge inoculum, was completely degraded in 7 days under anaerobic conditions(3). The main metabolite was 4,4'-diamino-3,3'-dimethoxybiphenyl with a 50% yield(3). [R26] ABIO: *C.I. Direct Blue 15 did not precipitate in water with a calcium concentration of 10-3 M(1). [R27] KOC: *Due to the ionic nature of the dye, the retention of C.I. Direct Blue 15 by ion-exchange processes(1), particularly on clay surfaces and adsorption at mineral surfaces such as geothite(2), may slow down or prevent leaching(SRC). Sorption to sediment, shown for a structurally similar compound, Direct Blue 14, was dependent on pH with adsorption increasing with decreasing pH(3). The weakly basic amino groups and strongly acidic sulfonate groups, found in both C.I. Direct Blue 14 and C.I. Direct Blue 15, are responsible for sorption mechanisms(3). [R28] VWS: *Since C.I. Direct Blue 15 is an ionic compound, volatilization from water and moist soil surfaces will not be important(1,SRC). [R29] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 4,528 workers (201 of these are female) are potentially exposed to C.I. Direct Blue 15 in the USA(1). [R30] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I. Direct Blue 15 in F344/N Rats (Drinking Water Studies) Technical Report Series No. 397 (1992) NIH Publication No. 92-2852 SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 354 R2: SRI R3: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-217 R4: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 57 243 (1993) R6: BEAUDOIN AR; PROC SOC EXP BIOL MED 127 (1): 215 (1968) R7: Matthews EJ et al; Environ Health Perspect 101 (2): 319-45 (1993) R8: Reynolds SH et al; Cancer Res 50 (2): 266-72 (1990) R9: Morgan DL et al; Toxicology 59 (3): 297-310 (1989) R10: Ulland BM et al; Toxicol Pathol 17 (1): 50-6 (1989) R11: Krishna G et al; J Toxicol Environ Health 18 (1): 111-9 (1986) R12: Emmett M et al; Arch Toxicol 57 (2): 130-5 (1985) R13: Bowman MC et al; Proceedings of the third NCI/EPA/NIOSH Collaborative Workshop: Progress on Joint Environmental and Occupational Cancer Studies p.426-36 (1984) R14: Toxicology and Carcinogenesis Studies of C.I. Direct Blue 15 in F344/N Rats (Drinking Water Studies). Technical Report Series No. 397 (1992) NIH Publication No. 92-2852 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: E. I. du Pont de Nemours and Company, Haskell Laboratory for Toxicology and Industrial Medicine; Acute Oral Test (1976), EPA Document No. 878220360, Fiche No. OTS0215029 R16: E I DUPONT DENEMOURS AND CO INC; Primary Skin Irritation and Sensitization Tests on Guinea Pigs; 08/25/75; EPA Doc No. 878220323; Fiche No. OTS0215029 R17: E I DUPONT DENEMOURS AND CO INC; Irritancy and Contact Sensitizing Potential of Dyed Papers With Attached letter; 01/29/69; EPA Doc No. 878220348; Fiche No. OTS0215029 R18: E I DUPONT DENEMOURS AND CO INC; Department of Transportation Skin Corrosion Test on Rabbit Skin; 12/03/74; EPA Doc No. 878220363; Fiche No. OTS0215029 R19: Bowman MC et al; J Anal Toxicol 6 (4): 164-74 (1982) R20: Rafil F, Cerniglia CE; Appl Environ Microbiol 59 (6): 1731-4 (1993) R21: Cerniglia CE et al; Carcinogenesis 3 (11): 1255-60 (1982) R22: (1) Ashford RD; Ashford's Dictionary of Industrial Chemicals: Properties, Production, Uses. London, England: Wavelength Publ, Ltd. p. 354 (1994) R23: (1) Baughman GL, Perenich TA; Amer Dyestuff Repor Feb, p. 19-22 (1988) (2) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) (3) Pagga U, Brown D; Chemosphere 15: 479-91 (1986) (4) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) R24: (1) Weber EJ; Environ Toxicol Chem 10: 609-18 (1991) (2) Pagga U, Brown D; Chemosphere 15: 479-91 (1986) (3) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) (4) Baughman GL, Perenich TA; Amer Dyetuff Report Feb p. 19-22 (1988) R25: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb. 19-22 (1988) R26: (1) Pagga U, Brown D; Chemosphere 15: 479-91 (1986) (2) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) (3) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) R27: (1) Hou M, Baughman GL; Dyes and Pigments 18: 35-46 (1992) R28: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) (2) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) (3) Weber EJ; Environ Toxicol Chem 10: 609-18 (1991) R29: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) R30: (1) NIOSH; National Occupational Exposure Survey (NOES) Cincinnati, OH (1989) RS: 42 Record 290 of 1119 in HSDB (through 2003/06) AN: 4251 UD: 200302 RD: Reviewed by SRP on 9/18/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1-CHLORO-4-(TRIFLUOROMETHYL)BENZENE SY: *BENZENE, 1-CHLORO-4-(TRIFLUOROMETHYL)-; *PARA-CHLOROBENZOTRIFLUORIDE-; *4-CHLOROBENZOTRIFLUORIDE-; *(P-CHLOROPHENYL)TRIFLUOROMETHANE; *PARA-CHLOROTRIFLUOROMETHYLBENZENE-; *4-CHLORO-ALPHA,ALPHA,ALPHA-TRIFLUOROTOLUENE-; *PARA-CHLORO-ALPHA,ALPHA,ALPHA-TRIFLUOROTOLUENE-; *1-Chloro-4-(trimethyl)benzene; *TOLUENE,-P-CHLORO-ALPHA,ALPHA,ALPHA-TRIFLUORO-; *alpha,alpha,alpha-Trifluoro-4-chlorotoluene-; *P-(TRIFLUOROMETHYL)CHLOROBENZENE; *P-TRIFLUOROMETHYLPHENYL-CHLORIDE- RN: 98-56-6 MF: *C7-H4-Cl-F3 SHPN: UN 2234; Chlorobenzotrifluorides IMO 3.3; Chlorobenzotrifluorides MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *p-Chlorobenzotrichloride + hydrogen fluoride (fluorination). [R1] MFS: *Occidental Chemical Corporation, Hq, 5005 LBJ Freeway, Dallas, TX 75244, (972) 404-3800; Specialty Business Group; Production site: Buffalo Ave at 47th Street, Niagara Falls, NY 14303. [R2] USE: *DYE INTERMEDIATE; CHEMICAL INTERMEDIATE; SOLVENT AND DIELECTRIC FLUID [R3] *Key intermediate for the synthesis of dyes, pharmaceuticals, and pesticides. Intermediate for herbicides with a diphenyl ether structure - fluorodifen and acifluorfen - and the insecticide fluvalinate. [R4] CPAT: *ESSENTIALLY 100% AS A CHEMICAL INTERMEDIATE [R5] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R5] *(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R5] U.S. IMPORTS: *(1977) 6.62X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R5] *(1979) 2.90X10+9 GRAMS (PRINCPL CUSTMS DISTS) [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *WATER-WHITE LIQUID [R3] ODOR: *AROMATIC ODOR [R3] BP: *139.3 DEG C [R3] MP: *-33 deg C [R6] MW: *180.6 DEN: *1.3340 g/cu cm at 25 deg C [R6] SPEC: *Index of Refraction = 1.4431 at 30 deg C/D [R6]; *IR: 2:535A (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R7]; *NMR: 4:56C (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R7] VAPD: *6.24 (AIR=1) [R8] VAP: *7.63 mm Hg at 25 deg C [R9] OCPP: *WT/GAL: 11.28 LB @ 15.5 DEG C [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Chlorobenzotrifluorides/ [R10] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Chlorobenzotrifluorides/ [R10] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Chlorobenzotrifluorides/ [R10] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Chlorobenzotrifluorides/ [R10] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Chlorobenzotrifluorides/ [R10] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Chlorobenzotrifluorides/ [R10] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Chlorobenzotrifluorides/ [R10] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Chlorobenzotrifluorides/ [R10] FPOT: *MODERATE FIRE RISK. [R11] NFPA: +Flammability: 2. 2= Liquids which must be moderately heated before ignition will occur and solids that readily give off flammable vapors. Water spray may be used to extinguish the fire because the material can be cooled to below its flash point. /Chlorobenzotrifluoride/ [R12] +Reactivity: 0. 0= Materials which are normally stable even under fire exposure conditions, and which are not reactive with water. Normal fire fighting procedures may be used. /Chlorobenzotrifluoride/ [R12] FLPT: *116 DEG F (CLOSED CUP) [R11] REAC: *Strongly exothermic reaction with sodium dimethylsulfinate. [R13] DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen chloride, hydrogen fluoride/. [R13] SERI: *Mildly toxic by ingestion and inhalation. [R13] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R15] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R16] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *TOXIC BY INGESTION AND INHALATION. [R17] TCAT: ?The ability of p-chlorobenzotrifluoride to induce morphological transformation was evaluated in Balb/3T3 mouse cells (Cell Transformation Assay). Based on preliminary toxicity determinations (exposure time = 72hrs), p-chlorobenzotrifluoride, was tested at concentrations of 0.1, 1.0, 10.0, 20.0 and 40.0nl/ml, resulting in a range of 80% to 50% relative survival. None of the applied concentrations resulted in the induction of any transformed foci, while the positive control (MCA) resulted in 38 transformed foci showing that the sensitivity of the assay was normal. [R18] ?In a two-generation reproduction study, male and female Sprague Dawley rats (F0) (20/sex/group) were orally exposed to 4-(trifluoromethyl)chlorobenzene (TFCB) in corn oil vehicle by gavage at dosage levels of 0, 5, 15 or 45 mg/kg/day for 4 weeks prior to mating one-to-one with animals of the same group, and continuing through one reproduction period until F1 litters had been weaned. Randomly selected F1 pups (20/sex/group) were orally exposed to TFCB by gavage at the same concentration as their parents for 90 days and were then sacrificed. Significant differences between treated and control F0 rats were observed in the following: decreased and/or increased weight gain (high- and mid-dose animals). Significant differences between treated and control F1 rats were observed in the following: weight gain (increased for all treated male groups, decreased for high-dose females), decreased monocytes (females at low-dose), increased serum glutamic-pyruvic transaminase (mid-dose females), increased mean pups/litter (combined sexes of pups for low- and mid-dose groups, female pups of mid-dose group), increased percentage surviving pups and pup weights (all treated groups), decreased erythrocyte counts (low-dose females), decreased mean corpuscular hemoglobin (all treated male groups and high-dose females), increased mean corpuscular volume (high-dose females), and an increase in pathology of the lung including bronchopneumonia, adenomous hyperplasia, and inflammatory cell infiltrates (all treated groups). No significant differences between treated and control F0 rats were observed in the following: mortalities, urinalysis, and dam weights. No significant differences between treated and control F1 rats were observed in the following: mortalities, clinical chemistry values, urinalysis, and absolute or relative organ weights. [R19] ?Mutagenicity of biologic fluids was determined after administration of 50, 167, or 500 mg/kg parachlorobenzotrifluoride by oral gavage over a 2 day period to groups of 7 male CD-1 mice. After collection, neither urine pretreated with beta-glucuronidase, or untreated urine, was mutagenic towards Salmonella typhimurium strains TA1535, TA1537, TA98 or TA100. [R20] ?Parachlorobenzotrifluoride was examined for mutagenic activity in Salmonella typhimurium tester strains TA1535, TA1537, TA1538, TA98, TA100 and in Saccharomyces cerevisiae strain D4 with and without Aroclor induced rat liver S9 fraction metabolic activation. The test article did not cause a mutagenic effect in Salmonella tester strains, or gene conversion in Saccharomyces when administered at concentrations of 0.01, 0.10, 1.0, 5.0 and 10.0 ul/plate in the presence or absence of metabolic activation. Parachlorobenzotrifluoride was reported to be cytotoxic to Salmonella strains TA1535 and TA1537 at a concentration of 10 ul/plate. [R21] ?The frequency of forward mutations was determined at the thymidine kinase (TK) locus of the mouse lymphoma L5178Y cell line exposed in vitro to parachlorobenzotrifluoride with or without Aroclor-induced rat liver S9 fraction metabolic activation. The test article did not cause mutagenic effects in cultures exposed to concentrations of 3.13, 6.25, 12.5, 25.0 or 50 nl/ml in the presence or absence of metabolic activation. In a preliminary cytotoxicity test concentrations greater than 78 nl/ml were toxic to cells, and the percent relative growth after treatment reportedly ranged from 71 to 11% in non activated and from 63 to 30% in activated cultures. [R22] ?The frequency of chromosomal aberrations was evaluated in vitro by exposing Chinese Hamster Ovary cells in the presence and absence of Aroclor-induced rat liver S9 metabolic activation to 4-(trifluoromethyl) chlorobenzene (referred to as compound 38502, purity not reported) at concentrations ranging from 29.99 to 130.00 nl/ml. The nonactivated portion of the study was repeated at concentrations of 29.99 to 80.00 nl/ml due to cytotoxicity observed in the first experiment. No statistically significant (t-test for linear regression, p < 0.05) increase in the frequency of chromosomal aberrations was observed at any dose level. In a separate cytotoxicity test relative cell survivals of 0% and 87.08% were observed at concentrations of 200 and 60 nl/ml, respectively, in the presence of metabolic activation; cell survivals of 0% and 102.87% were observed at these concentrations in the absence of activation. [R23] ?The in vitro transformation efficiency of 4-(trifluoromethyl) chlorobenzene (referred to as compound 38502, purity not reported) was evaluated in Balb/c-3T3 cells at dosages ranging from 10 to 300 ug/ml, in the presence of Aroclor-induced rat liver S9 metabolic activation. No statistically significant (modified t-test, p < 0.05) increase in colony formation was observed at any concentration. The investigators reported that toxicity to cells was apparent at 300 ug/ml. At this level, the compound was found not to be completely soluble. [R24] ?The frequency of chromosomal aberrations in bone marrow cells was investigated in groups of 10 Sprague-Dawley rats (5 male, 5 female) receiving one gavage dose of 0, 0.5, 1.7 or 5.0 ml/kg 4- (trifluoromethyl)chlorobenzene (referred to as compound 38502, purity not reported). Harvest of bone marrow cells was performed at 6, 24 and 48 hours after test article administration. A statistically significant (Chi-square or t-test analysis, p < 0.05) increase in chromosomal aberrations was not observed at any dose level. No mortality was observed at the 5.0 ml/kg level in a separate range finding toxicity study, while a dosage of 10.0 ml/kg resulted in the death of 2 of 5 test animals. [R25] ?Subchronic toxicity was determined in a three month study on groups of 30 Fischer-344 rats (15 male, 15 female) receiving once daily gavage doses of 0, 10, 40, 150, or 500 mg/kg 4-(trifluoromethyl) chlorobenzene (purity 97.77%) in corn oil. No physical signs of toxicity were observed in males or females during the course of treatment. Statistically significant effects in all animals included: initial decrease in mean body weight gain; decreased mean food consumption; initial decrease in efficiency of food utilization; mild proteinuria in males at 500 mg/kg and in females at 150 and 500 mg/kg; reduced urine clarity at 150 and 500 mg/kg; elevated bilirubin at 500 mg/kg; elevated alkaline phosphatase levels in serum at all dose levels in males, and at 500 mg/kg in females; stimulation of hepatic p-nitroanisole-O-demethylase activity at top 3 doses in males, and at 500 mg/kg in females; increased liver weights at all doses in males, and at the three highest doses in females; increased kidney weights in males and females at the two highest doses; increased thyroid weights at the second and fourth dose in females; centrilobular hypertrophy of the liver at the high dose; increased colloid in the thyroid gland. Significant effects observed only in male animals included: decrease in erythrocytes, hemoglobin, packed cell volume, and mean corpuscular volume at 500 mg/kg (decrease in packed cell volume also apparent at 150 mg/kg); dose related decrease in lymphocyte/neutrophil ratio; elevated urea nitrogen at 150 and 500 mg/kg; renal lesions (renal tubular degeneration) at all dose levels. No effects observed exclusively in females were reported. [R26] ?The metabolism of 4-(trifluoromethyl)chlorobenzene (99.0% radiochemically pure) was evaluated after administration of 1 mg/kg by oral gavage to 5 male and 3 female Sprague-Dawley albino rats that had been fasted for 16 hrs prior to dosing. Of the applied label, 3 to 4% was excreted in the feces and 14 to 15% was excreted in the urine over the 4 day test period. The major urinary metabolites were glucuronides of dihydroxybenzotrifluoride and 4- chloro-3-hydroxybenzotrifluoride (each representing 3 to 4% of the applied label), as well as minor amounts of a mercapturic acid conjugate of p-chlorobenzotrifluoride. It was reported that the test substance was rapidly expired unchanged by rats (62-82% of the applied dose) although the time period for expiration was not reported. The test substance was excreted unchanged as the major fecal constituent. Levels of labeled residues in the tissues were low; four days after dosing 1% of the applied label (identified as p-chlorobenzotrifluoride) remained, and was located predominantly in fat tissue. [R27] ?The frequency of sister chromatid exchange (SCE) was determined in L5178Y mouse lymphoma cells exposed in vitro to parachlorobenzotrifluoride (PCBTF) with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article was administered at concentrations of 0.0025, 0.0050, 0.01, 0.02, and 0.04 ul/ml in the presence and absence of activation. In the non-activated assay a statistically significant (t-test, p < 0.01) increase was observed in SCE's/chromosome at all concentrations, and in SCE's/cell at all concentrations except 0.02 ul/ml. In the activated assay a significant (p < 0.01) increase in SCE's/chromosome and SCE's/cell was observed at 0.0025, 0.01 and 0.02 ul/ml. A preliminary cytotoxicity assay was performed in order to determine PCBTF concentrations for the definitive test. [R28] ?Parachlorobenzotrifluoride was examined for DNA modifying activity in a DNA repair deficiency assay using Escherichia coli W3110 polA+ and P3478 polA- tester strains with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. The test article did not induce differential toxicity when administered in volumes of 0.01, 0.10, 1.0, 5.0 and 10.0 ul per plate in the presence or absence of metabolic activation. [R21] POPL: */Individuals who suffer from/ skin, liver, kidney, or chronic respiratory disease, will be at an increased risk if they are exposed to chlorobenzenes. /Chlorobenzenes/ [R29] METB: *When rats were given a single oral dose of 1 mg/kg p-chloro(trifluoromethyl-(14)C) benzotrifluoride 3-4%, and 14-15% of the applied (14)C were excreted in feces and urine, respectively. The major urinary metabolites were glucuronides of dihydroxybenzotrifluoride and 4-chloro-3-hydroxybenzotrifluoride (each representing 3-4% of the applied (14)C), and minor amounts of a mercapturic acid conjugate of p-chlorobenzotrifluoride. p-Chlorobenzotrifluoride itself was rapidly expired by rats (62-82% of the applied dose) and was the major (14)C- labeled residue in feces. Levels of (14)C-labeled residues in tissues were low, but the small amount of radiolabel in the rat carcass 4 days after dosage (1% applied dose) was also identified as p-chlorobenzotrifluoride and was found predominantly in fat. [R30] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1-Chloro-4-(trifluoromethyl)benzene's production and use as an intermediate for dyes, pharmaceuticals, and pesticides, and as a solvent and dielectric fluid may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 7.63 mm Hg at 25 deg C indicates 1-chloro-4-(trifluoromethyl)benzene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1-chloro-4-(trifluoromethyl)benzene will be degraded slowly in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 67 days. If released to soil, 1-chloro-4-(trifluoromethyl)benzene is expected to have slight mobility based upon an estimated Koc of 2,200. Volatilization from moist soil surfaces may be an important fate process based upon an estimated Henry's Law constant of 3.5X10-2 atm-cu m/mole. 1-Chloro-4-(trifluoromethyl)benzene may potentially volatilize from dry soil surfaces based upon its vapor pressure. However, adsorption to soil is expected to attenuate volatilization. 64% degradation occurred over 59 days in an anaerobic screening test, suggesting biodegradation of 1-chloro-4-(trifluoromethyl)benzene may be an important fate process in soil and water under anaerobic conditions. If released into water, 1-chloro-4-(trifluoromethyl)benzene is expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces may be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 4.0 hours and 5.3 days, respectively. However, volatilization is expected to be attenuated by adsorption to suspended solids and sediment in the water column. An estimated BCF of 320 suggests the potential for bioconcentration in aquatic organisms is high. Occupational exposure to 1-chloro-4-(trifluoromethyl)benzene may occur through inhalation and dermal contact with this compound at workplaces where 1-chloro-4-(trifluoromethyl)benzene is produced or used. (SRC) ARTS: *1-Chloro-4-(trifluoromethyl)benzene's production and use as an intermediate for dyes, pharmaceuticals, and pesticides(1), and as a solvent and dielectric fluid(2) may result in its release to the environment through various waste streams(SRC). [R31] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 2,200(SRC), determined from an estimated log Kow of 3.6(2) and a regression-derived equation(3), indicates that 1-chloro-4-(trifluoromethyl)benzene is expected to have slight mobility in soil(SRC). Volatilization of 1-chloro-4-(trifluoromethyl)benzene from moist soil surfaces may be an important fate process(SRC) given an estimated Henry's Law constant of 3.5X10-2 atm-cu m/mole(SRC), using a fragment constant estimation method(4). The potential for volatilization of 1-chloro-4-(trifluoromethyl)benzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 7.63 mm Hg at 25 deg C(5). However, adsorption to soil is expected to attenuate volatilization(SRC). 64% degradation occurred over 59 days in an anaerobic screening test, suggesting biodegradation of 1-chloro-4-(trifluoromethyl)benzene may be important in soil under anaerobic conditions(6). [R32] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 2,200(SRC), determined from an estimated log Kow of 3.6(2) and a regression-derived equation(3), indicates that 1-chloro-4-(trifluoromethyl)benzene is expected to adsorb to suspended solids and sediment in the water column(SRC). 1-Chloro-4-(trifluoromethyl)benzene may volatilize from water surfaces(3) based upon an estimated Henry's Law constant of 3.5X10-2 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Estimated volatilization half-lives for a model river and model lake(3) are 4.0 hours and 5.3 days, respectively(SRC). The volatilization half-life from a model pond 2 m deep is estimated to be about 2.0 days ignoring adsorption(5); when considering maximum adsorption the volatilization half-life increases to 12 days(5). According to a classification scheme(6), an estimated BCF of 320(3), from an estimated log Kow(2), suggests the potential for bioconcentration in aquatic organisms is high(SRC). In an anaerobic screening test using digester sludge, 64% of the originally applied 1-chloro-4-(trifluoromethyl)benzene was degraded in 59 days(7). [R33] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1-chloro-4-(trifluoromethyl)benzene, which has a vapor pressure of 7.63 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1-chloro-4-(trifluoromethyl)benzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 67 days(SRC) from this compound's rate constant for the vapor-phase reaction with photochemically-produced hydroxyl radicals(3). [R34] BIOD: *In an anaerobic screening test with digester sludge, 64% of the 1-chloro-4-(trifluoromethyl)benzene orginally applied was degraded in 59 days(1). [R35] ABIO: *The rate constant for the vapor-phase reaction of 1-chloro-4-(trifluoromethyl)benzene with photochemically-produced hydroxyl radicals has been estimated as 2.4X10-13 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 67 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R36] BIOC: *An estimated BCF of 320 was calculated for 1-chloro-4-(trifluoromethyl)benzene(SRC), using an estimated log Kow of 3.6(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high. [R37] KOC: *The Koc of 1-chloro-4-(trifluoromethyl)benzene is estimated as approximately 2,200(SRC), using an estimated log Kow of 3.6(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1-chloro-4-(trifluoromethyl)benzene is expected to have slight mobility in soil. [R38] VWS: *The Henry's Law constant for 1-chloro-4-(trifluoromethyl)benzene is estimated as 3.5X10-2 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 1-chloro-4-(trifluoromethyl)benzene is expected to volatilize rapidly from water surfaces(2,SRC). Based on this Henry's Law constant, the estimated volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is approximately 4.0 hours(2,SRC). The estimated volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is approximately 5.3 days(2,SRC). The volatilization half-life from a model pond 2 m deep is estimated to be about 2.0 days ignoring adsorption(3); when considering maximum adsorption the volatilization half-life increases to 12 days(3). 1-Chloro-4-(trifluoromethyl)benzene's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 1-chloro-4-(trifluoromethyl)benzene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 7.63 mm Hg at 25 deg C(4). [R39] WATC: *SURFACE WATER: 1-Chloro-4-(trifluoromethyl)benzene was qualitatively detected in water samples obtained in Love Canal, NY, 1980(1). It was qualitatively detected in Lake Ontario water samples(2). [R40] SEDS: *1-Chloro-4-(trifluoromethyl)benzene was qualitatively detected in sediment and soil samples obtained in Love Canal, NY 1980(1). [R41] RTEX: *Occupational exposure to 1-chloro-4-(trifluoromethyl)benzene may occur through inhalation and dermal contact with this compound at workplaces where 1-chloro-4-(trifluoromethyl)benzene is produced or used. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 4-Chlorobenzotrifluoride is included on this list. [R42] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SEVERAL UNKNOWN HALOGENATED CMPD DETECTED IN FISH USING METHOD SIMILAR TO ASSOCIATION OF OFFICIAL ANALYTICAL CHEMISTS MULTIRESIDUE METHOD FOR CHLORINATED PESTICIDES IN FOODS. USING GLC-MASS SPECTOMETRIC DATA AND GLC RETENTION TIME P-CHLOROBENZOTRIFLUORIDE IDENTIFIED. [R43] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Report on Toxicity Studies of p-Chloro-a,a,a-Trifluorotoluene Administered in Corn Oil and a-Cyclodextrin to F344/N Rats and B6C3F1 Mice in 14 Day Comparative Gavage Studies NTP Tox 14 (1992) SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 199 R2: SRI. 1997 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International 1997.. 513 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 264 R4: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 377 R5: SRI R6: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-36 R7: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 262 R8: National Fire Protection Guide. Fire Protection Guide on Hazardous Materials. 10 th ed. Quincy, MA: National Fire Protection Association, 1991.,p. 325M-26 R9: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R10: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-130 R11: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 264 R12: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-25 R13: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 733 R14: 49 CFR 171.2 (7/1/96) R15: IATA. Dangerous Goods Regulations. 39th Ed. Montreal, Canada and Geneva, Switzerland : International Air Transport Association, Dangerous Goods Regulations, 1998. 116 R16: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3123-1 (1988) R17: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 195 R18: Litton Bionetics Inc.; Evaluation of p-Chlorobenzotrifluoride in the In Vitro Transformation of BALB/3T3 Cells Assay, Final Report, (1980), EPA Document No. 40-8052018, Fiche No. OTS0508144 R19: Elars Bioresearch Laboratories, Inc.; Gas Chromatographic Assay PCBTF and Modified 90-Day Gavage and Reproduction Study in Rats - Part II. (1981), EPA Document No. 40-8152022, Fiche No. OTS0508148 R20: Litton Bionetics, Inc.; Mutagenicity Evaluation of Parachlorobenzotrifluoride in a In Vivo/ In Vitro Urine Assay, Final Report, (1979), EPA Document No. 40- 7952013, Fiche No. OTS0508139 R21: Litton Bionetics, Inc.; Mutagenicity Evaluation of Parachlorobenzotrifluoride (PCBTF) in the Ames Salmonella/Microsome Plate Test, Final Report, (1978), EPA Document No. 40-7852007, Fiche No. OTS0508133 R22: Litton Bionetics, Inc.; Mutagenicity Evaluation of Parachlorobenzotrifluoride in the Mouse Lymphoma Forward Mutation Assay, Final Report (1978), EPA Document No. 40-7852009, Fiche No. OTS0508135 R23: Lilly Research Laboratories; Chromosome aberrations in Chinese Hamster Ovary cells, test article compound 38502. (1983), EPA Document No. 40-8452058, Fiche No. OTS0507306 R24: Lilly Research Laboratories; Evaluation of compound #38502 in the Balb/c-3T3 neoplastic transformation assay with an aroclor-induced rat liver microsomal (S9) metabolic activation system. (1983), EPA Document No. 40-8452058, Fiche No. OTS0507306 R25: Microbiological Associates; Activity of compound 38502 (T2025) in the acute in vivo cytogenetics assay in male and female rats, final report. (1983), EPA Document No. 40-8452058, Fiche No. OTS0507306 R26: Lilly Research Laboratories; A subchronic (three-month) toxicity study in Fischer 344 rats given daily gavage doses of 4-chlorobenzotrifluoride (PCBTF). (1983), EPA Document No. 40-8452058, Fiche No. OTS0507306 R27: Zoecon Corp.; Metabolism of p-chlorobenzotrifluoride by rats. (1982), EPA Document No. 40-8352054, Fiche No. OTS0507284 R28: Litton Bionetics; Mutagenicity Evaluation of Parachlorobenzotrifluoride (PCBTF) in the Sister Chromatid Exchange Assay in L5178Y Mouse Lymphoma Cells Final Report (1979), EPA Document No. 40-7952010, Fiche No. OTS0508136 R29: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.1 R30: Quistad GB, Mulholland KM; J Agric Food Chem 31 (3): 585-589 (1983) R31: (1) Siegemund G et al; Ullmann's Encycl Indust Chem. NY,NY: VCH Pub. A11: 377 (1988) (2) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY, NY: Van Nostrand Reinhold Co p.264 (1993) R32: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Vol. 3 NY,NY: Hemisphere Pub Corp (1989) (6) Elanco Prods. Co.; Volatilization rate of p-Chlorobenzotrifluoride from Water. USEPA Doc No. 40-8452058, Fiche No. OTSO507306 (1983) R33: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) USEPA; EXAMS II Computer Simulation (1987) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Elanco Prods Co; Volatilization rate of p-Chlorobenzotrifluoride from Water. USEPA Doc No. 40-8452058, Fiche No. OTSO507306 (1983) R34: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Vol. 3 NY,NY: Hemisphere Pub Corp (1989) (3) Atkinson R; J Chem Phys Ref Data Monograph 1 p. 218 (1989) R35: (1) Elanco Prods. Co.; Volatilization rate of p-Chlorobenzotrifluoride from Water. USEPA Doc No. 40-8452058, Fiche No. OTSO507306 (1983) R36: (1) Atkinson R; J Chem Phys Ref Data Monograph 1 p. 218 (1989) R37: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R38: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R39: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Vol. 3 NY,NY: Hemisphere Pub Corp (1989) R40: (1) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) (2) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem Vol. 1 Windsor, Ontario, Canada (1983) R41: (1) Hauser TR, Bromberg SM; Environ Monit Assess 2: 249-72 (1982) R42: 40 CFR 716.120 (7/1/97) R43: YURAWECZ MP; J ASSOC OFF ANAL CHEM 62 (1): 36 (1979) RS: 37 Record 291 of 1119 in HSDB (through 2003/06) AN: 4252 UD: 200302 RD: Reviewed by SRP on 1/23/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 3,4-DICHLORONITROBENZENE- SY: *BENZENE,-1,2-DICHLORO-4-NITRO-; *3,4-DICHLORONITROBENZEN- (CZECH); *1,2-DICHLORO-4-NITROBENZENE-; *1-NITRO-3,4-DICHLOROBENZENE-; *AI3-03268- (USDA) RN: 99-54-7 MF: *C6-H3-Cl2-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *CHLORINATION OF P-NITROCHLOROBENZENE; NITRATION OF O-DICHLOROBENZENE [R1] MFS: *Du Pont Chemicals, 1007 Market Street, Wilmington, DE 19898, (302) 744-1000; Production site: Deepwater, NJ 08203. [R2] USE: *CHEM INTERMEDIATE FOR HERBICIDES (EG, PROPANIL) AND INSECTICIDES AND DYE INTERMEDIATES [R1] *Reduction of 3,4-dichloronitrobenzene yields 3,4-dichloroaniline, an important agrochemical intermediate. [R3] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 4.54X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] U.S. IMPORTS: *(1977) 1.19X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1978) 2.05X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *NEEDLES FROM ALCOHOL AND CARBON TETRACHLORIDE; LIQUID [R4]; *SOLID [R5] BP: *255-256 DEG C [R4] MP: *43 DEG C [R4] MW: *192.00 [R4] CTP: *Critical temperature: 758 K; Critical pressure: 3.6X10+6 Pa [R6] DEN: *1.4558 @ 75 DEG C/4 DEG C [R4] OWPC: *log Kow= 3.12 [R7] SOL: *SOL IN ETHER, HOT ALCOHOL [R4]; *Water solubility= 121 ppm at 20 deg C [R8] SPEC: *IR: 1218 (Coblentz Society Spectral Collection) [R9]; *UV: 1114 (Sadtler Research Laboratories Spectral Collection) [R9]; *NMR: 687 (Sadtler Research Laboratories Spectral Collection) [R9] VAPD: *6.63 [R10] VAP: *Extrapolated solid state vapor pressure= 0.014 mm Hg at 20 deg C [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *FIRE RISK BY SPONTANEOUS REACTION. [R12] EXPL: *A violent explosion during the plant-scale catalytic hydrogenation of 3,4-dichloronitrobenzene to the aniline (heat of hydrogenation is 523 kJ/mol, 2.72 kJ/g) was traced to thermal decomposition of one of the reaction intermediates, 3,4-dichlorophenylhydroxylamine. [R13] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *The following wastewater treatment technologies have been investigated for nitrobenzene: Activated carbon and stripping. /Nitrobenzene/ [R14] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *3,4-Dichloronitrobenzene, like other nitro and amino aromatics, is responsible for methemoglobin formation in humans. Levels of 10 mg/l of 3,4-dichloronitrobenzene metabolites in human urine may be considered to be warning levels of overexposure. [R15] NTOX: *120 WHITE RATS WERE TESTED FOR 4 MO WITH DAILY INHALATORY EXPOSURE FOR 4 HR @ 10, 3.6, 0.4 MG/CU M. PARTICULARLY @ 10 MG/CU M PERIPHERAL BLOOD PICTURE AND BIOCHEM INDICES WERE ALTERED. @ DAY 80 THERE WAS 10% DECR IN ERYTHROCYTE COUNT, HEMOGLOBIN DECR FROM 15.1 TO 12.2 G%. ... MORPHOLOGICALLY, ONLY THE RATS @ 10 MG/CU M EXPOSURE LEVEL SHOWED NERVE CELLS IN THE BRAIN WHICH HAD HYPERCHROMICALLY STAINED NUCLEI, FREQUENTLY LOCALIZED IN THE SUBCORTICAL GANGLIA. [R16] *RATS WERE FED CONGENERS OF PCB FROM DAYS 8-18 OF GESTATION. GLUTATHIONE S-TRANSFERASE (GS-T) DETERMINED ON SACRIFICED OFFSPRINGS USING THE SUBSTRATE 1,2-DICHLORO-4-NITROBENZENE. RATS EXPOSED PERINATALLY TO 2,4,5-2',4',5'-HEXACHLOROBIPHENYL HAD HIGHER LEVELS OF GS-T THAN CONTROLS. [R17] *Ames mutagenicity assay of 3,4-dichloronitrobenzene using TA98, TA100, TA1530, TA1535, TA1537, TA1538, TA1532, TA1950, TA1975, TA1978, G46, gave positive results. When utilized at high doses the compound produced slight but statistically significant mutagenic activity towards TA1530 in the absence of S9 mice and towards TA100 and TA1538 both in the absence and in the presence of S9 mix, in the plate incorporation assays. It showed weak mutagenic activity towards strains TA100 and TA1538 in fluctuation tests. The number of revertants was slightly enhanced in the presence of fortified S9 fraction. /From table/ [R18] *3,4-Dichloronitrobenzene (DNB) was tested for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster. Using a standard protocol approved by the National Toxicology Program (NTP). Canton-S wild-type males were treated with concentrations of DNB that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. DNB was positive at a dose of 200 ppm when administered to males by injection. [R19] TCAT: ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute oral toxicity. The test substance was administered orally to 10 rats (sex and species not specified) at a dose range of 200-3200 mg/kg body weight. Signs of toxicity included weakness (moderate to very weak), labored respiration, cyanosis, dark eyes, and prostration. Time of death was between 45 minutes and 2 days. The approximate LD50 was determined to be between 1600 and 3200 mg/kg b.w. The test substance was determined to be slightly toxic. [R20] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute intraperitoneal toxicity. The test substance was administered intraperitoneally to 10 rats (sex and species not specified) at a dose range of 200-3200 mg/kg body weight. Signs of toxicity included weakness (moderate to very weak), labored respiration, cyanosis, dark eyes, and prostration. Time of death was between 2 hours and 1 day. The approximate LD50 was determined to be between 400 mg/kg b.w. The test substance was determined to be moderately toxic. [R20] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute oral toxicity. The test substance was administered orally to 10 mice (sex and species not specified) at a dose range of 200-3200 mg/kg body weight. Clinical signs included weakness (normal to very weak), decreased activity, slow respiration, cyanosis, dark eyes, slight tremor, prostration, and yellow-orange urine. Time of death was 1 day. The approximate LD50 was determined to be between 800-1600 mg/kg b.w. The test substance was determined to be slightly toxic. [R20] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute intraperitoneal toxicity. The test substance was administered intraperitoneally to 10 mice (sex and species not specified) at a dose range of 200-3200 mg/kg body weight. Clinical signs included weakness (normal to very weak), decreased activity, slow respiration, cyanosis, dark eyes, slight tremor, prostration, and yellow-orange urine. Time of death was between 4-1/2 hours and 1 day. The approximate LD50 was determined to be between 400-800 mg/kg b.w. The test substance was determined to be moderately toxic. [R20] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for primary dermal irritation. The test substance was applied to the cuff of 3 guinea pigs (sex and strain not specified) at a dose range of 0.25-1.0 g/kg body weight. Clinical signs included slight to moderate edema and erythema with necrosis and hemorrhagic area around treated site. Slight desquamation and scattering with light to heavy eschars at 1 week and light scarring at 2 weeks. The LD50 was determined to be greater than 1.0 g/kg b.w. The test substance was determined to be a moderate skin irritant. [R20] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute oral toxicity. The test substance was administered by oral gavage to Sprague Dawley albino rats. Dose levels and mortality data are as follows: 0.65 (1/3 M, 0/2 F); 0.70 (1/2 M, 1/3 F); 0.80 (2/3 M, 1/3 F); 0.90 g/kg body weight (2/2 M, 2/3 F). The oral LD50 was determined to be 0.80 g/kg b.w. Survival time was 4 to 36 hours. Clinical signs included lethargy soon after dosing, followed by salivation, collapse, and coma. Necropsy findings included pulmonary hyperemia and jaundice-like liver discoloration. [R21] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute dermal toxicity. The test substance was applied to the closely clipped intact skin of albino rabbits and covered to retard evaporation. Dose levels and mortality data are as follows: 0.36 (0/1 M); 0.54 (0/1 F); 0.72 (0/1 M); 0.95 (1/1 F); 1.45 (1/1 M); 2.90 g/kg body weight (1/1 M). The minimum lethal dose by skin absorption was 0.72 to 0.95 g/kg b.w. Survival time was 24-48 hours. The animals gradually became lethargic and lost their appetite. Necropsy findings included liver discoloration and an indication of blood changes with a possible formation of methemoglobin. [R21] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for primary dermal irritation. The test substance was applied undiluted to the intact skin of rabbits (exact dosage not specified). Irritation after 2-hours ranged from mild to moderate redness with very little edema. Redness increased after 24-hours with no change in edema. Two of the animals were free of inflammation in 72-hours. [R21] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for eye irritation. The test substance was instilled undiluted at a dose level of 0.1 ml into the conjunctival sac of the right eye of each of 1 female and 2 male albino rabbits. Signs of irritation included moderate immediate discomfort, lacrimation together with moderate erythema and edema, and a slight cloudiness of the corneal area. A slight degree of inflammation was present in 1 rabbit after 72-hours. All eyes were clear in 5 days. [R21] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for acute inhalation toxicity. The test substance was administered via inhalation to 4 male rats at a saturated concentration for 6-hours. Three animals succumbed during exposure (within 3-4 hours) and the fourth succumbed overnight. Clinical signs included labored breathing developing soon after exposure, severe ocular irritation, excessive salivation, and pawing at the face. Necropsy findings found marked pulmonary congestion sufficient enough to cause death, although skin absorption may have been a contributor. [R21] ?3,4-Dichloronitrobenzene (CAS# 99-54-7) was evaluated for cytotoxicity in Chinese Hamster Ovary (CHO) Cells, clone K1 at dose levels of 0.33, 1.0, 3.3, 10, 33.3, 100, 333, and 1000 ug/ml of volume at concentrations of 0, 1, 2, 5, and 10% metabolic activation. There was complete cytotoxicity at the 1000 ug/ml with all concentrations of activation. The 333 ug/ml level resulted in a 36%, 36%, 34%, 38%, and 18% cell survival at the 0, 1, 2, 5, and 10% concentrations, respectively. The test substance was evaluated in a Preliminary Mutagenicity Screen at dose levels of 100, 120, and 150 ug/ml without metabolic activation; and at dose levels of 50, 150, and 200 ug/ml volume with 1, 2, 5, and 10% concentration of activation. There were no significant increases in the mutation frequencies. The test substance was evaluated in the CHO/HGPRT Mammalian Cell Forward Gene Mutation Assay at dose levels of 25, 50, 125, 200, and 250 ug/ml without activation and with a 5% concentration of activation. There were no statistically significant increases in the mutation frequencies. [R22] ?The ability of 3,4-dichloro-1-nitrobenzene, prepared in chloroform, to cause skin acnegenesis was evaluated in 2 rabbits (sex and strain not reported) administered 0.1 ml the test material on the distal half of the inner aspect of the left ear 5 days/week for 4 weeks. Clinical observations included slight sloughing and roughening. Histopathology was not reported. [R23] ?Nitrated orthene (1,2-dichloro-4-nitrobenzene, CAS# 99-54-7) was administered to rats by gavage at doses of 200, 300, 400, 500, and 600 mg/kg/day on gestation days 6 through 15. At the lowest dose level 2/6 animals died while all animals died at the higher doses. The low dose animals exhibited a 32% weight loss compared to controls in days 6-21 of gestation. One of the surviving animals at the low dose and the 2 that died spontaneously exhibited varying clinical signs of toxicity including respiratory, postural and muscle coordination problems, convulsions and/or seizures, prostration and generally poor health. The animals that died also showed pathological intestinal, liver and stomach signs on postmortem examination. Among the low dosage group fetal body weight was slightly reduced, however, no other fetal abnormalities were noted. This EPA status report only gives a brief summary of the study. [R24] ?Nitrated orthene (1,2-dichloro-4-nitrobenzene, CAS# 99-54-7) was administered to groups of 25 rats by gavage at doses of 10, 30, and 100 mg/kg/day on gestation days 6 through 15. A corn oil (vehicle) control group was also dosed. At gestation day 21 females were sacrificed and implantation sites and fetuses were examined. At the high dose level there was evidence of body weight loss during gestation and urogenital staining. At the middle dose some reduced food consumption and body weight gain was evident for gestation days 6-10. No other statistically significant reproductive or gestational effects were noted. Although there were varied fetal malformations in both treatment and control groups, the distribution and low incidence suggests to the authors that most were not treatment related. There was a statistically significant increase in the incidence of dilated ureters in fetuses from the two highest dose levels according to a linear trend in proportion analysis, although significance was not detected using the Bonferroni inequality correction for comparison of multiple treatments with control. This EPA status report only includes the summary of the study. [R24] METB: *YIELDS S-(2-CHLORO-4-NITROPHENYL)GLUTATHIONE IN RAT AND RABBIT; YIELDS 3,4-DICHLOROANILINE IN RABBIT. /FROM TABLE/ [R25] *RATS WERE GIVEN 25 MG 3,4-DICHLORONITROBENZENE ORALLY FOR 7 DAYS AND ENZYME ACTIVITIES CATALYZING HEPATIC CONJUGATION WITH GLUTATHIONE GSH WERE DETERMINED. [R26] *FOLLOWING ORAL ADMINISTRATION OF 3,4-DICHLORONITROBENZENE TO PIGEONS, ANALYSIS OF EXCREMENT SHOWED THAT DCNB IS MAINLY METABOLIZED BY REDUCTION OF THE NITRO GROUP WITH VERY LITTLE FORMATION OF MERCAPTURIC ACID. [R27] *WHEN THE DRUG METABOLIZING POTENTIALS OF LUNG AND LIVER WERE COMPARED OF 4 TRANSFERASE, THE ACTIVITIES IN THE LUNG WERE GENERALLY LESS THAN THE ACTIVITIES IN THE LIVER. THE ACTIVITY OF GLUTATHIONE S-ARYLTRANSFERASE TOWARD 1,2-DICHLORO-4-NITROBENZENE IN THE LUNG WAS APPROXIMATELY 20% THAT IN THE LIVER. [R28] *Observed that rat liver contains an enzyme that catalyzes the conjugation of glutathione and 3,4-dichloronitrobenzene with loss of the nitro group. [R29] *Female rats were dosed by oral intubation with 3,4-dichloronitrobenzene at 500 mg/kg. Six hr after dosing, liver glutathione had decreased to 56% of controls. Blood glutathione although increased by 18%, was not considered to be significantly changed. The effect on liver glutathione was related to formation of mercapturic acid during metabolism. [R30] *The metabolism of 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dichloro-1-nitrobenzene by Mucor javanicus was investigated, together with 2,4-dichloro-1-nitrobenzene metabolism by other fungi. The main metabolites were the corresponding dichloroanilines, accompanied by a lesser amt of 2,5-dichloro-1-nitrobenzene and 2,6-dichloro-1-nitrobenzene (3- or 4-substituted) from 2,3-dichloro-1-nitrobenzene or 2,4-dichloro-1-nitrobenzene, respectively. Similar metabolic patterns were observed with M griseocyanus, M praini, M hiemalis, or Aspergillus flavus. [R31] INTC: *Kinetic studies of glutathione transferase activites in which nafenopin was mixed with normal rat liver cytosols in the assay system revealed competitive type inhibition toward 3,4-dichloronitrobenzene. [R32] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *3,4-Dichloronitrobenzene's production and use as an intermediate for the production of dyes and pesticides, may result in its release to the environment through various wastestreams. It has an extrapolated vapor pressure of 0.006 mm Hg at 25 deg C and exists solely in the vapor phase in the ambient atmosphere. Vapor-phase 3,4 dichloronitrobenzene is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 321 days. An experimentally determined mean Koc of 339 in four silt loam soils indicates that 3,4-dichloronitrobenzene has moderate mobility in soil. Volatilization from moist soil surfaces is expected based on an estimated Henry's Law constant of 3.2X10-5 atm-cu m/mol. In water, 3,4-dichloronitrobenzene may adsorb to sediment or particulate matter based upon its Koc value. Volatilization from water surfaces is expected based upon its estimated Henry's law constant. Estimated volatilization half-lives for a model river and model lake are 42 and 407 hours respectively. Anaerobic degradation of 3,4 dichloronitrobenzene was observed in industrial waste water treatment facilities and river sediment. 3,4-Dichloronitrobenzene is non-biodegradable under aerobic conditions. Bioconcentration in aquatic organisms is considered high based upon experimental BCF values ranging from 104-130. Occupational exposure may occur through dermal contact or inhalation of dust particles at sites of its commercial use or production. The general population may be exposed to 3,4-dichloronitrobenzene primarily through ingestion of contaminated food sources. (SRC) ARTS: *3,4-Dichloronitrobenzene's use as a an intermediate for the production of dyes and pesticides(1) may result in its release to the environment through various waste streams(SRC). [R33] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an experimentally determined mean Koc value of 393, determined from 4 silt loam soils(2), indicates that 3,4-dichloronitrobenzene will have moderate mobility in soil(SRC). Under conditions of industrial waste treatment plants, microbial sludge populations are capable of reducing influent 3,4-dichloronitrobenzene to 3,4-dichloroaniline(3) and therfore anaerobic biodegradation may take place in soil. [R34] *AQUATIC FATE: Based on a recommended classification scheme(1), an experimentally determined mean Koc value of 339 in four silt loam soils(2) indicates that 3,4-dichloronitrobenzene may adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected based on an estimated Henry's Law constant of 3.2X10-5 atm-cu m/mol developed using a fragment constant estimation method(3). Estimated half-lives for a model river and model lake are 42 and 400 hours, respectively(1,SRC). 3,4-Dichloronitrobenzene has been shown to be biodegradable under conditions of industrial waste treatment plants(4). Anaerobic degradation of 3,4-dichloronitrobenzene in river sediment from the Tsurmi River, Japan was observed over a 100 day inoculation period(5). The degradation of 3,4-dichloronitrobenzene followed first order kinetics with a rate constant of 0.29 days and a half life of 2.4 days and the intermediate metabolites were identified as 3,4-dichloroaniline and 3-chloroaniline(5). Fifty percent anaerobic biodegradation was observed for intitial concns of 0.5X10-6 to 50X10-6 g/l of 3,4-dichloronitrobenzene innoculated in an aquifer slurry over an unspecified time frame(6). 3,4-Dichloronitrobenzene was found to be non-biotransformable under aerobic conditions(6). [R35] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 3,4-dichloronitrobenzene, which has an extrapolated vapor pressure of 0.006 mm Hg at 25 deg C(2,SRC), will exist solely as a vapor in the ambient atmosphere. 3,4-Dichloronitrobenzene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 321 days(3,SRC). [R36] BIOD: *Under conditions of industrial waste treatment plants, microbial sludge populations are capable of reducing influent 3,4-dichloronitrobenzene to 3,4-dichloroaniline(1). Anaerobic degradation of 3,4-dichloronitrobenzene, at a concn of 4X10-6 mols/l, in river sediment from the Tsurmi River, Japan was observed over a 100 day inoculation period(2). The degradation of 3,4-dichloronitrobenzene followed first order kinetics with a rate constant of 0.29 days and a half life of 2.4 days and the intermediate metabolites were identified as 3,4-dichloroaniline and 3-chloroaniline(2). Fifty percent anaerobic biodegradation was observed for intitial concns of 0.5X10-6 to 50X10-6 g/l of 3,4-dichloronitrobenzene innoculated in an aquifer slurry over an unspecified time frame(3). 3,4-Dichloronitrobenzene was found to be non-biotransformable under aerobic conditions(3). [R37] ABIO: *The rate constant for the vapor-phase reaction of 3,4-dichloronitrobenzene with photochemically-produced hydroxyl radicals has been estimated as 5.0X10-14 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 321 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R38] BIOC: *Experimental BCF values of 104-130(1) and 120(2) were obtained from freshwater rainbow trout, Salmo gairdneri. According to a classification scheme(3), these BCF values suggest that bioconcentration in aquatic organisms is high(SRC). [R39] KOC: *Based on a recommended classification scheme(1), an experimentally determined mean Koc value of 393 determined from 4 silt loam soils(2) indicates that 3,4-dichloronitrobenzene will have moderate mobility in soil(SRC). [R40] VWS: *The Henry's Law constant for 3,4-dichloronitrobenzene is estimated as 3.2X10-5 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that 3,4-dichloronitrobenzene is expected to volatilize from water surfaces. Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 42 hours(2,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 400 hours(2,SRC). This Henry' Law constant indicates that volatilization from moist soil surfaces may occur(SRC). [R41] PFAC: FISH/SEAFOOD CONCENTRATIONS: *A 3,4-dichloronitrobenzene concn of 0.085 ppm was detected in a composite sample of edible portions of carp/sucker taken from the Mississippi River at St. Louis (collection date not reported)(1). A 3,4-dichloronitrobenzene concn of 0.03 ppm was detected in a sample of edible portion of buffalo fish taken from the Mississippi River 60 miles south of St. Louis (collection date not reported)(1). 3,4-Dichloronitrobenzene was identified not quantified in fish from the River Main in Germany(2). [R42] RTEX: *3,4-Dichloronitrobenzene is used as a dye and pesticide intermediate(1). Therefore, occupational exposure may occur through dermal contact or inhalation of dust particles at sites of its commercial use or production(SRC). The general population may be exposed to 3,4-dichloronitrobenzene primarily through ingestion of contaminated food sources(SRC). [R43] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 3,4-Dichloronitrobenzene is included on this list. [R44] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R45] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GC-MS quantitative method to determine the concentration of 3,4-dichloronitrobenzene in seawater samples. [R46] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 549 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA17 430 R4: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-40 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 382 R6: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R7: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 6 R8: Eckert JW; Phytopathol 52: 642-9 (1962) R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 168 R10: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 492 R11: Bessarab NA et al; Zh Fiz Khim 47: 1048 (1973) R12: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 380 R13: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 600 R14: USEPA; Management of Hazardous Waste Leachate, EPA Contract No.68-03-2766 p.E-3-E-22 (1982) R15: Linch AL; Am Ind Hyg Assoc J 35: 426-32 (1974) R16: BELIAEV VA ET AL; GIG SANIT 34 (11): 26-9 (1969) R17: LAMARTINIERE CA ET AL; TOXICOL APPL PHARMACOL 51 (2): 233-38 (1979) R18: Gilbert P et al; Arch Environ Contam Toxicol 9: 533-41 (1980) R19: Woodruff RC et al; Environ Mutagen 7: 677-702 (1985) R20: EASTMAN KODAK CO; Letter From Eastman Kodak Company to USEPA Submitting Enclosed Material Safety Data Sheet and Toxicity Report on 1,2-Dichloro-4-Nitrobenzene with Attachments; 09/26/91; EPA Doc. No. 86-920000019; Fiche No. OTS0533585 R21: MONSANTO CO; Initial Submission: Toxicological Investigation of Dichloronitrobenzene with Cover Letter Dated 08/05/92; 04/12/55; EPA Doc. No. 88-920007517; Fiche No. OTS0538600 R22: MONSANTO CO; CHO/HGPRT Mammalian Cell Forward Gene Mutation Assay (Final Report) with Attachment and Cover Letter Dated 11/21/91; 02/18/86; EPA Doc. No. 86-920000156; Fiche No. OTS0534361 R23: EI Dupont De Nemours and Co.; Skin Acnegenesis Using the Dow Modified Method with 3,4-Dichloro-1-Nitrobenzene and 3,4-Dichloroaniline, (1976), EPA Doc. No. 878221303, Fiche No. OTS0215198 R24: Monsanto Company; USEPA Status Report: Nitrated Orthene (1990), EPA Document No. 8EHQ-0590-0972, Fiche No. OTS0524331-1 R25: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. D-20 R26: SUGA T, AKAGI M; CHEM PHARM BULL 18 (1): 115-19 (1970) R27: WIT JG ET AL; BIOCHIM BIOPHYS ACTA 177 (2): 329-35 (1969) R28: GRAM TE ET AL; DRUG METAB DISP: BIOL FATE CHEM 2 (3): 254-8 (1974) R29: Al-Kassab S et al; Biochem J 87: 4-9 (1963) R30: Suga T et al; J Biochem (Tokyo) 59: 209-15 (1966) R31: Hafsah Z et al; Nippon Noyaku Gakkaishi 9 (1): 117-23 (1984) R32: Furukawa K et al; Canc Res 45 (10): 5011-19 (1985) R33: (1) Kuney JH; Chemcyclopedia, Vol 5, Washington DC: Amer Chem Soc p. 64 (1986) R34: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Briggs GC; J Agric Food Chem 29: 1050-9 (1981) (3) Grote A et al; Vom Wasser 60: 191-6 (1983) R35: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Briggs GC; J Agric Food Chem 29: 1050-9 (1981) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Grote A et al; Vom Wasser 60: 191-6 (1983) (5) Susarla S et al; Chemosphere 32: 967-977 (1996) (6) Bosma et al; Org Micropollut Aquat Environ Proc Eur Supp, 6: 184-192 (1990) R36: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R37: (1) Grote A et al; Vom Wasser 60: 191-6 (1983) (2) Susarla S et al; Chemosphere 32: 967-977 (1996) (3) Bosma et al; Org Micropollut Aquat Environ Proc Eur Supp 6: 184-192 (1990) R38: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R39: (1) Sheedy BR et al; Res J WPCF 63: 619-696 (1991) (2) Niimi AJ et al; Environ Toxicol Chem 8: 817-823 (1989) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R40: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Briggs GC; J Agric Food Chem 29: 1050-9 (1981) R41: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R42: (1) Yurawecz MP, Puma BJ; J Assoc Off Anal Chem 66: 1345-52 (1983) (2) Steinwandter H; Fresenius Z Anal Chem 326: 139-41 (1987) R43: (1) Kuney JH; Chemcyclopedia, Volume 5, Washington DC: Amer Chem Soc p. 64 (1986) R44: 40 CFR 716.120 (7/1/95) R45: 40 CFR 712.30 (7/1/95) R46: Gatermann et al; Mar Pollut Bul 30: 221-227 (1995) RS: 30 Record 292 of 1119 in HSDB (through 2003/06) AN: 4263 UD: 200302 RD: Reviewed by SRP on 3/17/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,3-DIOXANE- SY: *1,3-DIOXACYCLOHEXANE-; *meta-Dioxane-; *M-DIOXIN,-DIHYDRO-; *1,3-PROPANEDIOL-FORMAL-; *TRIMETHYLENE-GLYCOL-METHYLENE-ETHER- RN: 505-22-6 MF: *C4-H8-O2 SHPN: IMO 3.2; Dioxane UN 1165; Dioxane STCC: 49 091 55; Dioxane MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 1,3-PROPYLENE GLYCOL AND FORMALDEHYDE [R1] MFS: *Mide Chemical Corp, Hq, 19 Settlers Way, Setauket, NY 11733, (516) 751-9333 [R2] USE: *MONOMER FOR ACETYL RESINS (NO EVIDENCE OF CURRENT USE) [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R1] *(1979) NOT PRODUCED COMMERCIALLY IN USA [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: *105 DEG C AT 755 MM HG [R3] MP: *-42 DEG C [R3] MW: *88.11 [R3] DEN: *1.0342 AT 20 DEG C/4 DEG C [R3] OWPC: *Log Kow= -0.419 (est) [R4] SOL: *SOL IN WATER, ALC, ETHANOL, ACETONE, BENZENE [R3] SPEC: *MAX ABSORPTION (VAPOR): 180 NM (LOG E= 3.8) [R5]; *INDEX OF REFRACTION: 1.4165 AT 20 DEG C/D [R3]; +MASS: 161 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R6] VAP: *Vapor pressure= 39 mm Hg at 25 deg C (estimated) [R7] OCPP: *... Alcohol like odor ... /Dioxane/ [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: HIGHLY FLAMMABLE: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Dioxane/ [R9] +Health: Inhalation or contact with material may irritate or burn skin and eyes. Fire may produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control may cause pollution. /Dioxane/ [R9] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Dioxane/ [R9] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Dioxane/ [R9] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Dioxane/ [R9] +Fire: CAUTION: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Use water spray or fog; do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving Tanks or Car/Trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Dioxane/ [R9] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Dioxane/ [R9] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Dioxane/ [R9] OHAZ: +Strong oxidizers, decarborane, triethynylaluminum. /Dioxane/ [R10, 120] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. /Dioxane/ [R10, 121] +Wear appropriate eye protection to prevent eye contact. /Dioxane/ [R10, 121] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. /Dioxane/ [R10, 121] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.) /Dioxane/ [R10, 121] +Recommendations for respirator selection: Conditions: At the concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Dioxane/ [R10, 121] +Recommendations for respirator selection: Conditions: Respirators for escape purposes only: Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. /Dioxane/ [R10, 121] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. +Contact lenses should not be worn when working with this chemical. /Dioxane/ [R10, 120] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R11] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R12] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R13] STRG: *Dioxane must be stored in tightly closed containers in a cool, dry, well ventilated area away from heat, sparks, open flames, moisture, and strong oxidizers. Storage facilities should be designed to contain spills completely within a surrounding dike and to prevent contamination of workroom air. Dioxane when stored must be checked for peroxide content in accordance with the manufacturer's recommendations. /Dioxane/ [R14] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *An occupational fatality in which a man had been exposed to dioxane for just 1 week /is described/. The 21 year old man, who had a history of heavy beer consumption, had used dioxane to clean a workbench and to keep his hands free of resin-type glue. He kept an uncovered bucket of dioxane between his knees for these purposes. Neither a respirator nor an exhaust ventilation system was employed. After 1 week of dioxane exposure, he was hospitalized with severe epigastric pain and rising blood pressure which reached 220/120 about 3 hours after admission. Within a few hours, he developed severe convulsions followed by unconsciousness and anuria. The anuria lasted 5 days during which time his blood nonprotein nitrogen rose to 181 mg/100 ml compared to a normal value of 15-40 mg/100 ml. His condition continued to deteriorate even after he regained kidney function, and he died on the 6th day of hospitalization. Autopsy findings included centrilobular liver necrosis and necrosis of the renal cortex with extensive interstitial hemorrhage and occassional hyalinization of glomeruli. There were microscopic findings in the brain that were considered to be secondary to anoxia and cerebral edema. /Dioxane/ [R15] *The effects on five volunteers /of a 1 minute exposure to/ inhaled air containing 5,500 ppm dioxane /is described/. Signs and symptoms of exposure included eye irritation, a burning sensation in the nose and throat, and, in three subjects, slight vertigo that disappeared "quickly" after they left the exposure chamber. When the same five subjects were exposed to air containing 1,600 ppm dioxane for 10 minutes, they experienced an immediate slight burning of the eyes with lacrimation, and a slight irritation of the nose and throat. The alcohol-like odor of dioxane, easily noticeable at first, decreased in intensity with continued exposure. Lacrimation and nasal irritation persisted throughout the test. No vertigo was noticed, but one subject complained of an upset stomach after the exposure had been completed. The specifications of the exposure chamber, the purity of the dioxane, and the methods of generating and measuring the dioxane atmospheres were not reported. /Dioxane/ [R16] NTOX: *Results of the mutagenesis testing in Drosophila of 20 coded compounds (including 1,3-dioxane, 94-96% pure) for the National Toxicology Program (NTP) are presented. The chemicals were first assayed in the sex-linked recessive lethal (SLRL) test in an adult feeding experiment. If results were negative, the chemical was retested by injecting adults. ... 1,3-Dioxane was not mutagenic to Drosophila melanogaster /in the sex linked recessive lethal test by either injection or feeding/. [R17] *Effects of nonlethal and lethal doses of dioxane administered intragastrically to an unspecified number of rabbits were reported. Dioxane doses of 0.2 ml/kg in 10 ml water, 1.0 ml/kg in 5 ml water, or 2 ml/kg in 20 ml water were administered as single doses to an unspecified number of rats. Doses of 0.2 ml/kg, repeated at weekly intervals for an unspecified number of weeks, did not appear to affect the rabbits at all; one rabbit received as many as 15 weekly doses of 0.2 ml/kg without effect. A state described as drunkenness was seen with 1 ml doses, but single doses of 2 ml/kg administered to five nonfasting rabbits killed them. The minimal lethal intragastric dose of dioxane was found to be 2.0 ml/kg in 20 ml water. Microscopic changes observed in the kidney and liver were similar to those seen in rabbits given iv injections of dioxane; they were hydropic degeneration of the convoluted tubules of the kidneys and vacuolization of liver cells. /Dioxane/ [R18] *Effects of dioxane administered intraveneously to rabbits were reported. Four rabbits received a single dose of 1, 2, 3, or 5 ml of 80% dioxane diluted with saline to a total volume of 10 ml. Three other rabbits each were given two 5 ml injections of dioxane mixed with 5 ml of saline with an interval of 48 hours between injections. One rabbit, used as a control, received 10 ml of saline. The immediate effect of dioxane injection in all rabbits was violent struggling, which began as soon as the first few drops were injected. With doses of 4 or 5 ml of dioxane, the struggling was followed by convulsions and collapse; then the rabbits returned to normal. The four rabbits given the single doses of 80% dioxane were killed 1 month later. Degeneration of the renal cortices with hemorrhages was observed by microscopic examination. In the rabbit administered the 3 ml dioxane dose, the degenerative changes extended into the medulla, and the liver showed extensive and gross cellular degeneration starting at the periphery of the lobules. No abnormality was found in other organs. The livers of the rabbits given the 1 and 5 ml doses showed no microscopic abnormalities, and areas of cloudy swelling were seen in the liver of the rabbit given 2 ml of dioxane. /Dioxane/ [R19] *The effects of dioxane resulting from its absorption through the skin of rabbits were reported. Undiluted dioxane was applied to a shaved area of the belly which represented approximately 15% of the rabbit's body surface. Dioxane was in contact with the skin of two to four rabbits, used in groups, for 1.7, 3.0, 4.1, and 4.8 hours. A control rabbit was treated with water for 6 hours and another for 7.7 hours. Three rabbits showed evidence of intracutaneous and subcutaneous hemorrhages at the end of exposure. When dioxane was administered to two rabbits for 1.7 hours, unsteadiness and incoordination were noticed in both animals; one died within 24 hours and the other was alive 2 weeks after exposure. When four rabbits were exposed to undiluted dioxane for 3 hours, all showed unsteadiness and incoordination; two died within 3 days, one on the 5th day, and the other was alive 2 weeks after exposure. One rabbit exposed for 4.1 hours and another for 4.8 hours appeared to be in a state of CNS depression with very weak or absent corneal reflexes and both died at the end of exposure. Dioxane caused skin erythema in the two surviving rabbits that cleared in a matter of days with a superficial scaling and without any evidence of permanent damage. /Dioxane/ [R20] *An unspecified number of guinea pigs /were exposed/ to dioxane at concentrations of 1,000, 2,000, 3,000, 10,000, and 30,000 ppm, and observed the duration of exposure in minutes up to a maximum of 8 hours required to produce signs such as nasal irritation, eye irritation, retching movements, changes in respiration, and CNS depression. The composition of the dioxane vapor air mixture was calculated from the quantity of liquid vaporized and the quantity of air contained in, or flowing through, the animal exposure chamber. The calculated composition of the dioxane air mixture was always checked by sorption of the vapor from a measured volume of the mixture by air equilibrated activated charcoal and determination of the gain in weight. Guinea pigs that were exposed at 30,000 ppm for 3 hours developed a state of marked CNS depression during exposure, and the animals died within 2 days. Congestion and edema of the lungs, hyperemia of the surface of the brain, and paleness of the liver were seen in guinea pigs that were killed immediately after the exposure at 30,000 ppm for 30 minutes; patches of congestion in the lung and hyperemia of the surface of the brain occurred in those that were killed 4 or 5 days after the test; and there were no pathologic changes in the animals killed 9 or 10 days after exposure. Congestion of the lung and a few hemorrhagic areas in the mucous membranes of the stomach were seen in the guinea pigs that died within 1 day of exposure at 30,000 ppm dioxane and bronchopneumonia and severe congestion of the surface vessels of the brain in the animal that died 2 days after exposure. Fifteen control animals showed no gross pathologic changes resembling those seen in the exposed animals. /Dioxane/ [R21] METB: *beta-Hydroxyethoxyacetic acid, rather than oxalic acid or diglycolic acid, was the major urinary metabolite of dioxane in rats. Uniformly labeled (14)C dioxane was administered to two rats by oral intubation. Composite 24 hr urine samples were collected and analyzed for metabolites using thin layer ion exchange column chromatography and gas chromatography-mass spectrometry, and by nuclear magnetic resonance spectroscopy. One major and two minor (14)C containing compounds were confirmed by thin layer chromatography. The two minor compounds were identical to (14)C dioxane and (14)C diethylene glycol. The major compound was identified as beta-hydroxyethoxyacetic acid using the other four analytical methods. beta-Hydroxyethoxyacetic acid accounted for approximately 85% of the radioactivity in the urine, with dioxane and diethylene glycol accounting for the remaining 15%. /Dioxane/ [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *No data are available pertaining to either artificial or natural sources of environmental release of 1,3-dioxane. Limited prediction of environmental fate is based entirely on physical properties, chemical structure and analogy to similar compounds since experimental data are not available. If released to the atmosphere, 1,3-dioxane is expected to exist in the gas phase where it will be degraded relatively rapidly (estimated half-life of 2 days) by reaction with photochemically formed hydroxyl radicals. If released to soil, leaching may be possible since 1,3-dioxane is miscible in water. If released to water, volatilization is expected to be slow based on estimated half-lives of 7.2 days, 77.5 days, and 35.5 months from a shallow model river, a model environmental pond, and Lake Zurich, respectively. Aquatic hydrolysis, bioconcentration, and adsorption to sediment are not expected to be important. No data are available pertaining to the biodegradation of 1,3-dioxane in the environment. There are no data available to suggest that the general population of the USA is currently exposed to 1,3-dioxane. (SRC) FATE: *TERRESTRIAL FATE: No experimental data are available pertaining to the chemical or biochemical degradation of 1,3-dioxane in soil. The miscibility of 1,3-dioxane in water(1) suggests that leaching through soil to associated groundwaters may be possible(SRC). [R23] *AQUATIC FATE: No experimental data are available pertaining to the chemical or biochemical degradation of 1,3-dioxane in natural water. The chemical structure of 1,3-dioxane suggests that aqueous hydrolysis will not occur(1,SRC). The miscibility of 1,3-dioxane in water(2) suggest that bioconcentration in aquatic organisms and adsorption to sediments will not be important. Volatilization from environmental waters is expected to be slow based on estimated half-lives of 7.2 days, 77.5 days, and 35.5 months from a shallow model river, a model environmental pond, and Lake Zurich, respectively(1,3,SRC). [R24] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of 39 mm Hg at 25 deg C(1,SRC), 1,3-dioxane can be expected to exist almost entirely in the vapor-phase in the ambient atmosphere(2,SRC). By analogy to 1,4-dioxane, vapor-phase 1,3-dioxane will be degraded relatively rapidly in the atmosphere by reaction with photochemically formed hydroxyl radicals(3,SRC); the half-life for this reaction in average air is approximately 2 days(3,SRC). Due to its miscibility in water(4), physical removal of 1,3-dioxane from the atmosphere via wet deposition may be possible(SRC). [R25] ABIO: *The rate constant for the vapor-phase reaction of 1,3,5-trioxane with photochemically produced hydroxyl radicals has been experimentally measured to be 7.9X10-12 cu cm/molecule-sec at 25 deg C, which corresponds to an atmospheric half-life of about 2 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC); 1,3-dioxane is expected to have a similar rate of reaction with atmospheric hydroxyl radicals because of the structural similartiy(SRC). Ethers are generally resistant to aqueous environmental hydrolysis(2); therefore, 1,3-dioxane is not expected to undergo aqueous hydrolysis in environmental waters(SRC). [R26] BIOC: *Based upon an estimated log Kow of -0.419(1), the BCF for 1,3-dioxane can be estimated to be 0.3 from a recommended regression-derived equation(2,SRC). In addition, 1,3-dioxane has been reported to be miscible in water(3). The estimated BCF and water solubility of 1,3-dioxane indicate that bioconcentration in aquatic organisms is not important(SRC). [R27] KOC: *1,3-Dioxane has been reported to be miscible in water(1); therefore, leaching through soil to associated groundwaters may be possible(SRC). [R28] VWS: *The Henry's Law Constant for 1,4-dioxane has been experimentally measured to be 4.88X10-6 atm cu m/mole at 25 deg C(1); the Henry's Law Constant for 1,3-dioxane is expected to have a similar value(SRC). This value of Henry's Law Constant indicates that volatilization from environmental waters is expected to be relatively slow(2). Based on this Henry's Law Constant, the volatilization half-life from a model river (1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec) can be estimated to be about 7.2 days(2,SRC); the volatilization half-lives from a model environmental pond and from Lake Zurich (Switzerland) can be estimated to be 77.5 days and 35.5 months, respectively(3,SRC). [R29] RTEX: *There are no data available to suggest that the general population of the USA is currently exposed to 1,3-dioxane. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers dioxane to be a potential occupational carcinogen. /Dioxane/ [R10, 120] ATOL: *Dioxane is exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. /Dioxane/ [R30] OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 100 ppm (360 mg/cu m). Skin Designation. /Dioxane/ [R31] +Vacated 1989 OSHA PEL TWA 25 ppm (90 mg/cu m), skin designation, is still enforced in some states. /Dioxane/ [R10, 363] NREC: +Recommended Exposure Limit: 30 Min Ceiling Value: 1 ppm (3.6 mg/cu m). /Dioxane/ [R10, 120] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Dioxane/ [R10, 120] +NIOSH considers dioxane to be a potential occupational carcinogen. /Dioxane/ [R10, 120] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Dioxane is produced, as an intermediate or final product, by process units covered under this subpart. /Dioxane/ [R32] FIFR: *Dioxane is exempted from the requirement of a tolerance when used in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. /Dioxane/ [R30] FDA: *Dioxane is an indirect food additive for use only as a component of adhesives. /Dioxane/ [R33] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NIOSH; Criteria Document: Dioxane p.20-1 (1976) DHEW Pub. NIOSH 77-226 SO: R1: SRI R2: Van, H. and C.A. Deyrup (eds.). OPD Chemical Buyer's Directory 1988. 75th ed. New York, NY: Schnell Publishing Co., Inc. 1988. 709 R3: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-248 R4: USEPA; Graphical Exposure Modeling System (GEMS). CLOGP (1987) R5: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-277 R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 566 R7: USEPA; Graphical Exposure Modeling System R8: NIOSH; Criteria Document: Dioxane p.20-1 (1976) DHEW Pub. NIOSH 77-226 R9: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-127 R10: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R11: 49 CFR 171.2 (7/1/96) R12: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 142 R13: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3072 (1988) R14: NIOSH; Criteria Document: Dioxane p.137 (1977) DHEW Pub. NIOSH 77-226 R15: Johnstone RT; Arch Ind Health 20: 445-7 (1959) as cited in NIOSH; Criteria Document: Dioxane p.24-5 (1977) DHEW Pub. NIOSH 77-226 R16: Yant WP et al; Public Health Rep 45: 2023-32 (1930) as cited in NIOSH; Criteria Document: Dioxane p.20-1 (1977) DHEW Pub. NIOSH 77-226 R17: Zimmering S et al; Environ Mutagen 7: 87-100 (1985) R18: De Navasquez S; J Hyg 35: 540-48 (1935) as cited in NIOSH; Criteria Document: Dioxane p.54 (1977) DHEW Pub. NIOSH 77-226 R19: Fairley A et al; J hyg 34: 486-501 (1934) as cited in NIOSH; Criteria Document: Dioxane p.45 (1977) DHEW Pub. NIOSH 77-226 R20: Nelson N; Med Bull 11: 226-38 (1951) as cited in NIOSH; Criteria Document: Dioxane p.69 (1977) DHEW Pub. NIOSH 77-226 R21: Yant WP et al; Public Health Rep 45: 2023-32 (1930) as cited in NIOSH; Criteria Document: Dioxane p.62-3 (1977) DHEW Pub. NIOSH 77-226 R22: Braun WH, Young JD: Toxicol Appl Pharmacol 38: 643-46 (1976) as cited in NIOSH; Criteria Document: Dioxane p.89-90 (1977) DHEW Pub. NIOSH 77-226 R23: (1) Weast RC; Handbook of Chemistry and Physics 60th Edition p. C-277 (1979) R24: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-16 to 15-29, 7-4 (1982) (2) Weast RC; Handbook of Chemistry and Physics 60th Edition p. C-277 (1979) (3) USEPA; EXAMS II Computer Simulation (1987) R25: (1) USEPA; Graphical Exposure Modeling System (1988) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; J Inter Chem Kinet 19: 799-828 (1987) (4) Weast RC; Handbook of Chemistry and Physics 60th Edition p. C-277 (1979) R26: (1) Atkinson R; Inter J Chem Kinet 19: 799-828 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 7-4 (1982) R27: (1) USEPA; Graphical Exposure Modeling System (GEMS). CLOGP (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-4 (1982) (3) Weast RC; Handbook of Chemistry and Physics. 60th Edition. p. C-277 (1979) R28: (1) Weast RC; Handbook of Chemistry and Physics. 60th Edition. p. C-277 (1979) R29: (1) Park JH et al; Anal Chem 59: 1970-6 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-15 to 15-29 (1982) (3) USEPA; EXAMS II Computer Simulation (1987) R30: 40 CFR 180.1001 (7/1/88) R31: 29 CFR 1910.1000 (7/1/98) R32: 40 CFR 60.489 (7/1/87) R33: 21 CFR 175.105 (4/1/88) RS: 30 Record 293 of 1119 in HSDB (through 2003/06) AN: 4289 UD: 200211 RD: Reviewed by SRP on 02/06/1991 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: EPINEPHRINE- SY: +1-ADRENALIN-; +ADRENALINE-; +ADRENAMINE-; +1,2-BENZENEDIOL, 4-(1-HYDROXY-2-(METHYLAMINO)ETHYL)-, (R)-; +BENZYL ALCOHOL, 3,4-DIHYDROXY-ALPHA-((METHYLAMINO)METHYL)-, (-)-; +3,4-DIHYDROXY-ALPHA-((METHYLAMINO)METHYL)BENZYL ALCOHOL; +1-1-(3,4-DIHYDROXYPHENYL)-2-METHYLAMINOETHANOL; +EPINEFRINA-; +(-)-EPINEPHRINE; +(R)-EPINEPHRINE; +1-EPINEPHRINE-; +EPIRENAMINE-; +GLAUCOSAN-; +GLYCIRENAN-; +HAEMOSTASIN-; +HEKTALIN-; +HEMISINE-; +HEMOSTASIN-; +4-(1-HYDROXY-2-(METHYLAMINO)ETHYL)-1,2-BENZENEDIOL; +INTRANEFRIN-; +KIDOLINE-; +LEVORENIN-; +LYOPHRIN-; +METANEPHRIN-; +METHYLAMINOETHANOLCATECHOL-; +METHYLARTERENOL-; +NEPHRIDINE-; +NIERALINE-; +PARANEPHRIN-; +PRIMATENE-MIST-; +RENAGLADIN-; +RENAGLANDIN-; +RENAGLANDULIN-; +RENALEPTINE-; +SUPRANEPHRANE-; +SUPRANEPHRINE-; +SUPRANOL-; +SUPRARENIN-; +SUPREL-; +SURENINE-; +SUSPHRINE-; +SYMPATHIN-I-; +TAKAMINA-; +VAPONEFRIN-; +VASOCONSTRICTINE-; +VASOCONSTRICTOR-; +VASODRINE- RN: 51-43-4 MF: +C9-H13-N-O3 HAZN: P042; An acute hazardous waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. ASCH: Epinephrine hydrochloride; 55-31-2; Adrenaline; 150-05-0; Epinephrine bitartrate; 51-42-3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +REACTION OF PYROCATECHOL WITH CHLOROACETYL CHLORIDE, FOLLOWED BY REACTION WITH METHYLAMINE, CATALYTIC REDN, AND SEPARATION OF RACEMIC MIXT WITH D-TARTARIC ACID. [R1] +ISOLATION FROM ANIMAL ADRENAL GLANDS. [R2, 567] FORM: +GRADE: USP [R3] +Epinephrine injection is a 1:1000 or a 1:10,000 sterile solution of epinephrine hydrochloride in water, ... aqueous 1:200 suspension of crystalline epinephrine (Sus-phrine), ... epinephrine inhalation is a nonsterile 1% aqueous solution for oral (not nasal) inhalation ... epinephrine nasal solution is a 1:1000 preparation of epinephrine hydrochloride except it is not sterile ... epinephrine bitartrate is available as a 2% ophthalmic solution and as a pressurized aerosol (Medihaler-Epi) ... epinephrine hydrochloride (0.1 to 2%) and epinephrine borate (0.5 to 2.0%) are also available for topical ophthalmic use. [R4, 197] +Epinephrine contains not less than 97.0% and not more than 100.5% of epinephrine, calculated on the dried basis. [R5] +EPINEPHRINE MAY BE GIVEN BY INJECTION, USUALLY SUBCUTANEOUSLY, INHALED AS AEROSOL, OR APPLIED LOCALLY TO MUCOUS MEMBRANES OR ABRADED SURFACES, AS AQUEOUS SOLN. [R4, 197] MFS: +Stansbury Chemical Co, Inc, Hq, 21003 NE 67th St, Redmont, WA 98052, (206) 868-5300; Production site: Seattle, WA 98109 [R6] USE: +Epinephrine may be applied topically to control superficial bleeding from arterioles or capillaries in the skin, mucous membrane, or other tissues. Bleeding from larger vessels is not controllable by topical application of epinephrine. [R7, 626] +Epinephrine has been used to relax uterine musculature and inhibit uterine contractions in premature labor; however the cardiovascular effects and other adverse effects limit the usefullness of the drug for this purpose. Some manufacturers state that epinephrine injection is contraindicated during the second stage of labor. [R7, 626] +MEDICATION +MEDICATION (VET) PRIE: U.S. PRODUCTION: +(1975) PROBABLY GREATER THAN 4.54X10+5 G [R1] +(1979) ND [R1] U.S. IMPORTS: +(1977) 5.58X10+5 G (PRINCPL CUSTMS DISTS) [R1] +(1979) 6.45X10+5 G (PRINCPL CUSTMS DISTS) [R1] +(1983) 5.49X10+7 g [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +LIGHT BROWN OR NEARLY WHITE CRYSTALLINE POWDER. [R3]; +White to nearly white, microcrystalline powder or granules. [R7, 625] ODOR: +ODORLESS [R3] MP: +211-212 DEG C [R2, 567] MW: +183.20 [R2, 567] SOL: +READILY SOL IN AQ SOLUTIONS OF MINERAL ACIDS AND SODIUM HYDROXIDE AND POTASSIUM HYDROXIDE; INSOL IN CHLOROFORM, ETHER, ACETONE, OILS; INSOL IN AQ SOL OF AMMONIA AND OF THE ALKALI CARBONATES. [R2, 567]; +Very slightly sol in alcohol. [R7, 625]; +Water solubility: 1000 mg/l at 25 deg C. [R9] SPEC: +IR: 1566 (Coblentz Society Spectral Collection) [R10]; +UV: 1512 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) [R10]; +MASS: 956 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R10]; +SPECIFIC OPTICAL ROTATION (1 G/20 ML OF 0.5 N HCL, 200 MM TUBE): NOT LESS THAN -50 DEG AND NOT GREATER THAN -53.5 DEG @ 25 DEG C/D. [R2, 567] VAP: +2.93X10-15 mm Hg at 25 deg C (calc). [R11] OCPP: +COMBINES WITH ACIDS FORMING WATER SOL-SALTS; SOLUTIONS UNDERGO OXIDN IN PRESENCE OF OXYGEN ESP IN NEUTRAL OR ALKALINE SOLUTIONS. [R2, 567] +MP 147-154 DEG C; 1 G DISSOLVES IN ABOUT 3 ML WATER; SLIGHTLY SOL IN ALCOHOL. /L-FORM D-BITARTRATE/ [R2, 567] +IR: 7393 (Sadtler Research Laboratories Spectral Collection) /Adrenaline/ [R10] +MASS: 956 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63). /Adrenaline/ [R10] +Henry's Law constant: 7.06X10-19 atm-cu m/mole at 25 deg C (est, SRC) [R12] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: +The major hazards encountered in the use and handling of epinephrine stem from its toxicologic properties. Exposure to this odorless, white-to-light brown, crystalline substance may occur from its production or medical use as a topical hemostat on bleeding surfaces, a cardiac stimulant, bronchodilator, antiglaucoma agent, and to relieve hypersensitivity reactions. Effects from exposure may include anxiety, headache, nausea, palpitations, tremor, myocardial infarction, pulmonary edema, or renal failure. Because of its instability in the presence of light or air, epinephrine should be stored in tight, light-resistant containers. Epinephrine is a good candidate for disposal by fluidized bed, rotary kiln, or liquid injection forms of incineration. SSL: +UNSTABLE ON EXPOSURE TO LIGHT OR AIR, TURNING PINK FROM OXIDATION TO ADRENOCHROME AND THEN BROWN FROM FORMATION OF POLYMERS. [R4, 197] STRG: +Must be stored in tight, light-resistant containers. [R7, 625] +Preserve in tight, light-resistant containers. [R5] DISP: +Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number p042, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R13] +1. A good candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. 2. A good candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. 3. A good candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R14] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: +EPINEPHRINE MAY CAUSE DISTURBING REACTIONS, SUCH AS FEAR, ANXIETY, TENSENESS, RESTLESSNESS, THROBBING HEADACHE, TREMOR, WEAKNESS, DIZZINESS, PALLOR, RESPIRATORY DIFFICULTY, AND PALPITATION. ... MORE SERIOUS REACTIONS INCLUDE CEREBRAL HEMORRHAGE AND CARDIAC ARRHYTHMIAS. ... VENTRICULAR ARRHYTHMIAS MAY FOLLOW ADMIN OF EPINEPHRINE. FIBRILLATION IS PARTICULARLY LIKELY TO OCCUR IF DRUG IS USED UNWISELY DURING ANESTHESIA . [R4, 198] +EPINEPHRINE PRODUCES BROWACHE, HEADACHE, OCULAR IRRITATION AND LACRIMATION IN SOME PATIENTS. REPEATED USE OF EPINEPHRINE MAY CAUSE REACTIVE HYPEREMIA, ALLERGIC CONJUNCTIVITIS, AND CONTACT DERMATITIS. ... CORNEAL EDEMA MAY OCCUR VERY RARELY AFTER LONG-TERM ADMIN. [R15] +Allergy or contact sensitivity develops in many patients ... . This is characterized by itching and burning sensation, epiphora, and hyperemia of conjunctiva and lids. [R16, 394] +Maculopathy from chronic use of epinephrine eyedrops on aphakic glaucomatous eyes was ... /observed/ in fifteen patients (22 eyes), documenting subnormal vision (20/40 to 20/400) while epinephrine eyedrops were being administered, and a significant improvement, almost to normal, in most cases when epinephrine was discontinued. [R16, 396] +Normal human beings have shown no significant changes in the a- and b-waves after injection of 1 mg of epinephrine, ... /during/ ERG /electroretinogram/ studies. [R16, 397] +Minutes after administration of local anesthetic and epinephrine eyedrops the patient felt faint, became pale, trembling and perspiring. These reactions were accompanied by severe headache and probably transient elevation of systemic blood pressure. However, the reactions were transitory. [R16, 398] +In eyes that are aphakic, postcataract extraction cystoid macular edema has been described after the use of epinephrine. [R17, 500] +An excess of granulocytes occurs transiently after the administration of epinephrine. [R17, 226] +An overdose of ... /epinephrine/ can produce ECG signs of myocardial hypoxia (ST segment deviation and ectopic beats) and subendocardial necrosis in humans. [R17, 402] +Epinephrine has no direct effect on cerebral arterioles or cerebral blood flow. However, elevations in cerebral blood flow and oxygen consumption may occur secondary to increased blood pressure. The drug is not a powerful CNS stimulant but may cause restlessness, apprehension, headache, and tremor, probably resulting from peripheral effects. In patients with parkinsonian syndrome, epinephrine increases rigidity and tremor by an unknown mechanism. [R7, 626] +Epinephrine may cause fear, anxiety, tenseness, restlessness, headache, tremor, dizziness, lightheadedness, nervousness, sleeplessness, excitability, and weakness. In patients with parkinsonian syndrome, the drug increases rigidity and tremor. Epinephrine may aggravate or induce psychomotor agitation, disorientation, impaired memory, assaultive behavior, panic, hallucinations, suicidal or homicidal tendencies, and psychosis characterized by clear consciousness with schizophrenic-like thought disorder and paranoid delusions in some patients. Nausea, vomiting, sweating, pallor, respiratory difficulty, or respiratory weakness and apnea may also occur. [R7, 627] +The death of a 7 1/2-month-old girl from the missuse of tetracaine/adrenalin/cocaine solution for wound anesthesia is reported. Ten milliliters of the solution inappropriately came into contact with nasal mucous membranes, causing excessive drug absorption. The patient's death probably was due to cocaine toxicity (post-mortem blood level, 11.9 mg/l). [R18] +Effects of catecholamines on skin necrosis /were examined independently/ of their vasoactive effects. Human breast skin was excised, pinned flat, and incubated at 37 deg C for 6 hours in a buffered salt solution containing catecholamine. At 0.1 and 6 hr the lactate dehydrogenase released from the skin and appearing in the buffer was determined spectrophotometrically. Total tissue lactate dehydrogenase levels were not significantly different at 0.1 or 6 hr. The toxic effect of epinephrine was eliminated by the addition of propranolol or selective beta-2 blockade, but not by alpha- or beta-1 blockade. Therefore, this effect appears to be mediated largely by beta-2 receptors. Similar toxic effects were seen in human breast skin treated with 1:200,000 epinephrine and were blocked with propranolol. ... These studies indicate that addition of catecholamine to ischemic human skin accelerates skin death within 6 hr, but that the toxicity can be reversed with beta-blockade. [R19] NTOX: +LARGE OR REPEATED DOSES OF EPINEPHRINE ... GIVEN TO EXPERIMENTAL ANIMALS LEAD TO DAMAGE TO ARTERIAL WALLS AND MYOCARDIUM, SO SEVERE AS TO CAUSE THE APPEARANCE OF NECROTIC AREAS ... . [R4, 197] +OVERDOSE MAY CAUSE TACHYCARDIA AND FATAL VENTRICULAR FIBRILLATION. /EPINEPHRINE INJECTION/ [R20, p. 16-49] +CATARACTS IN RAT FETUS HAVE BEEN PRODUCED BY GIVING NEAR-LETHAL DOSES OF EPINEPHRINE AT A CRITICAL PERIOD IN PREGNANCY, POSSIBLY AFFECTING THE DEVELOPING LENS BY CONSTRICTING THE HYALOID ARTERIES AND CAUSING ANOXIA. [R16, 397] +... EXPERIMENTS WITH ADRENALIN-INDUCED LIMB DEFECTS IN THE RABBIT. THEY INJECTED 5-50 UG OF ADRENALIN DIRECTLY INTO RABBIT FETUSES AT 18 TO 22 DAYS OF GESTATIONAL AGE AND NOTED HEMORRHAGES, EDEMA AND NECROSIS OF DISTAL EXTREMITIES. [R21] +... DROPPED 20-200 UG OF THIS MATERIAL ON CHORIO-ALLANTOIC MEMBRANE OF CHICK ONCE ON THE 10TH, 11TH OR 12TH DAY AND PRODUCED HEMORRHAGES OF HEAD, SKIN AND EXTREMITIES. ... /OTHERS/ ... ADMINISTERED 5 UG OF EPINEPHRINE TO CHICK EMBRYOS A INTERVALS BETWEEN 24 and 190 HOURS OF INCUBATION. TREATMENT BETWEEN 96 and 126 HOURS PRODUCED OVER 50% AORTIC ARCH ANOMALIES IN THE SURVIVING EMBRYOS. [R21] +In rabbits, daily intravenous injections of near-lethal doses have caused choroidal hemorrhages and exudates, with degenerative changes in the retina, also hemorrhages in the conjunctiva, and opacity of the cornea. [R16, 397] +In monkeys, repeated intravenous injections of epinephrine have produced a central serous chorioetinopathy with angiographic findings similar to those of spontaneous central serous maculopathy in human beings. [R16, 397] +The ERG /electroretinogram/ in rabbits which have been given epinephrine intravenously has shown selective change in the c-wave, suggesting ... a toxic effect on the pigment epithelium of the retina. [R16, 397] +In rats and mice, lens opacities have been seen to appear rapidly, and then to disappear, after systemic administration of very large doses of epinephrine. [R16, 397] +In rabbits a reduction in mitoses in the lens epithelium has been demonstrated from subconjunctival injections. [R16, 398] +In rats given intravenous infusion of epinephrine, the intraocular pressure has been observed ... as rising in association with rising blood pressure, but continuing to rise after the blood pressure had leveled off. [R16, 398] +An experimentally induced glaucoma in rabbits has been /observed/ ... by multiple intravenous injections of epinephrine. [R16, 398] +There is evidence that both epinephrine and carbonic anhydrase inhibitors such as acetazolamide can decrease aqueous humor formation. [R17, 488] +Intravenous infusion of epinephrine into pregnant rabbits elevated maternal blood pressure and caused extensive uterine vasoconstriction, placental cyanosis, and functional cardiovascular alterations in the fetus. The placental cyanosis coincided with, or slightly preceded, the fetal hemodynamic changes. [R17, 212] +Chemically induced predisposition to thrombosis most frequently occurs by induction of platelet aggregation, by an increase of their adhesiveness or by creation of a state of hypercoagulability via an increase or activation of clotting factors. Large doses of epinephrine can affect each of these events. [R17, 394] +Epinephrine and synthetic analogs, particularly the B-adrenergic-receptor agonists, eg, isoproterenol, have positive chronotropic and inotropic effects, and the adverse reactions are related to these pharmacologic effects. In addition to tachycardia, ventricular arrhythmia can occur even at therapeutic doses on rare occasions. An overdose of these drugs can produce ECG signs of myocardial hypoxia (ST segment deviation and ectopic beats) and subendocardial necrosis. [R17, 402] +Epinephrine is reported to affect female reproductive capacity. /From table/ [R17, 455] +Accidental injection of local anesthetics containing epinephrine into a digit can cause distal tissue necrosis. ... /A/ rat foot model was developed to study the possible use of phentolamine or labetalol in protection against tissue necrosis after injection of epinephrine in the extremity. Phentolamine was found to be useful in preventing tissue necrosis after the injection of local anesthetic containing epinephrine in the skin of the rat foot. Labetalol was found to be less effective in preventing tissue necrosis. Phentolamine may be useful in preventing tissue necrosis after the inadvertent injection of epinephrine containing local anesthetics in the digit. [R22] +Effects of catecholamines on skin necrosis /were examined independently/ of their vasoactive effects. Rat abdominal ... skin was excised, pinned flat, and incubated at 37 deg C for 6 hr in a buffered salt solution containing catecholamine. At 0.1 and 6 hr the lactate dehydrogenase released from the skin and appearing in the buffer was determined spectrophotometrically. Rat skin treated with greater than or equal to 1X10(-7) M epinephrine (33 times less than the 1:200,000 used clinically) or greater than or equal to 1X10(-5) M norepinephrine showed a significant increase in the lactate dehydrogenase released at 6 hr versus controls (18.75 + or - 1.25 versus 13.75 + or - 1.25 and 29.25 + or - 2.96 versus 22.00 + or - 1.96 IV, respectively). Total tissue lactate dehydrogenase levels were not significantly different at 0.1 or 6 hr. The toxic effect of epinephrine was eliminated by the addition of propranolol or selective beta 2-blockade, but not by alpha- or beta-1 blockade. Therefore, this effect appears to be mediated largely by beta-2 receptors. These studies indicate that addition of catecholamine to ischemic rat accelerates skin death with 6 hr, but that the toxicity can be reversed with beta-blockade. [R19] +The effects of /epinephrine/ ... were examined during acute hyperkalemia. Six anesthetized dogs were studied every 2 wk, on 18 separate occasions. Hyperkalemia was induced by intravenous infusion of potassium chloride, resulting in plasma potassium concentrations of 9.6 + or - 0.3 mEq/L (mean + or - SEM), bradycardia, and idioventricular rhythm. Dogs were then given slow intravenous injections every 30 min of either saline (controls), /or/ epinephrine. Epinephrine doses were 0.01, 0.1, 1.0, 10 or 100 micrograms/kg. ... At the highest does, ... epinephrine caused clinically important decreases in plasma potassium reducing concentrations to below 7.0 mEq/L. ... Side effects included hypertension and dysrhythmias ... and tachycardia ... . The doses that caused a decrease in plasma potassium also caused an increase in heart rate and there was a correlation between plasma potassium levels and heart rate. ... Increased heart rate could be used as an indicator of therapeutic effect and the magnitude of the increase in heart rate may be helpful in predicting the level of response. [R23] +Effects of a teratogenic dose (5 micrograms) of epinephrine on mean ventricular blood pressure and cardiac output at one and two hours after treating stage 24 /in/ chick embryos were investigated. In this study dysrhythmic epinephrine-treated embryos exhibited reductions in both mean ventricular blood pressure and cardiac output one hour after treatment when compared to control values. Nondysrhythmic epinephrine-treated embryos exhibited elevated mean ventricular blood pressure and no change in cardiac output at one hour after treatment. Mean ventricular blood pressure and cardiac output in recovered dysrhythmic and nondysrhythmic embryos were similar to control values at two hours following epinephrine treatment. Mean ventricular blood pressure and cardiac output measurements were obtained from embryos which were pretreated with metoprolol and then subsequently treated with epinphrine. Pretreating embryos with metoprolol /a beta 1-adrenoreceptor antagonist/ in this study reduced the dysrhythmogenic potential of epinephrihe and also blocked the mean ventricular blood pressure and cardiac output changes observed in embryos treated with epinephrine alone. /Results suggest/ ... that pathogenesis of 1) abnormally absent aortic arches is related to dysrhythmogenesis, reduced mean ventricular blood pressure, and reduced cardiac output, and 2) an abnormally persistent left fourth aortic arch is related to elevated mean ventricular blood pressure in the epinephrine model. [R24] +... Conclusions: Under the conditions of these 2 yr studies, no carcinogenic effects were observed in male or female F344/N rats exposed to aerosols containing 1.5 or 5 mg/cu m l-epinephrine hydrochloride for 2 yr or in B6C3F1 mice exposed to 1.5 or 3 mg/cu m l-epinephrine hydrochloride for 2 yr. However, these studies were considered to be inadequate studies of carcinogenic activity because the concentrations used, which were chosen to represent multiples of therapeutic doses, were considered too low for the animals to have received an adequate systemic challenge from the compound. [R25] NTXV: +LD50 Mouse ip 4 mg/kg; [R2, 567] NTP: +... Toxicology and carcinogenesis studies of epinephrine hydrochloride were conducted by exposing groups of F344/N rats and B6C3Fl mice of each sex to an aerosol containing epinephrine hydrochloride for ... 2 yr. Two yr studies were conducted by exposing groups of 60 rats or each sex to 0, 1.5, or 5 mg/cu m epinephrine hydrochloride, S days/ week for 103 wk. Groups of 60 mice of each sex were exposed to 0, 1.5, or 3 mg/cu m epinephrine hydrochloride, 5 days/wk for 104 wk. Use of these exposure concentrations represented a departure from the usual practice of utilizing doses equivalent to one-half the maximum tolerated dose (MTD) and the MTD for 2 yr carcinogenicity studies. Thus, although the dose levels exceeded maximum human therapeutic use levels (normalized to body weight and surface area), they were less than one-half the MTD. Conclusions: Under the conditions of these 2 yr studies, no carcinogenic effects were observed in male or female F344/N rats exposed to aerosols containing 1.5 or 5 mg/cu m l-epinephrine hydrochloride for 2 yr or in B6C3F1 mice exposed to 1.5 or 3 mg/cu m l-epinephrine hydrochloride for 2 yr. However, these studies were considered to be inadequate studies of carcinogenic activity because the concentrations used, which were chosen to represent multiples of therapeutic doses, were considered too low for the animals to have received an adequate systemic challenge from the compound. [R25] ADE: +EPINEPHRINE IS NOT EFFECTIVE AFTER ORAL ADMIN BECAUSE IT IS RAPIDLY CONJUGATED AND OXIDIZED IN GI MUCOSA AND LIVER. ABSORPTION FROM SC TISSUES OCCURS SLOWLY BECAUSE OF LOCAL VASOCONSTRICTION ... ABSORPTION IS MORE RAPID AFTER IM THAN AFTER SC INJECTION. ... EPINEPHRINE IS RAPIDLY INACTIVATED IN THE BODY. [R26, 150] +THE ORAL INGESTION OF LABELLED EPINEPHRINE BY NORMAL VOLUNTEERS HAS SHOWN THAT 60-70% OF THE TOTAL RADIOACTIVITY IS EXCRETED IN THE URINE WITHIN 72 HOURS. PHENOLIC AMINES MAKE UP 80-85% OF THE URINARY METABOLITES WHILE 15-20% ARE PHENOLIC ACIDS. [R27] +3 groups of 5 greyhounds received 1.5 ug/kg epinephrine 1:200,000 in either lidocaine 0.5%, bupivacaine 0.5% or 0.9% saline. Dogs were anesthetized and 40% of the allocated epinephrine solution was infiltrated beneath the perianal skin and each of the 4 quadrants of the rectal mucosa was injected with the remainder of the solution. Plasma epinephrine, lidocaine, bupivacaine, lactate, glucose and potassium concn were measured at 1, 2, 5, 10 and 30 min following infiltration. Peak plasma epinephrine concn were recorded 2 min following rectal mucosal infiltration in all 3 groups. Plasma epinephrine concn were significantly higher (p < 0.01) in the lidocaine group at 1 and 2 min following infiltration. Both plasma bupivacaine and lidocaine peaked 10 min after infiltration and thereafter tended to decr towards baseline concn. Plasma bupivacaine concn were significantly higher (p < 0.01) than plasma lidocaine concn throughout the study period. There were no significant differences in metabolic or biochemical indices within or between the 3 groups. However, both plasma glucose and lactate concn were elevated and peaked 10 min after infiltration, while plasma potassium concn remained unchanged throughout the study period. Heart rate in the bupivacaine group was significantly reduced at 30 min following infiltration (p < 0.05). There were no significant differences observed in the mean arterial and pulse pressures among the 3 groups. [R28] +Epinephrine is well absorbed after subcutaneous or IM injection; absorption can be hastened by massaging the injection site. Both rapid and prolonged absorption occur after subcutaneous injection of the aqueous suspension. After oral inhalation of epinephrine in the usual dosage, absorption is slight and the effects of the drug are restricted mainly to the respiratory tract. Absorption increases somewhat when larger doses are inhaled, and systemic effects may occur. [R7, 626] +Epinephrine crosses the placenta but not the blood-brain barriers. The drug is distributed into milk. [R7, 626] METB: +BOTH NOREPINEPHRINE AND EPINEPHRINE CAN INITIALLY BE OXIDATIVELY DEAMINATED BY MONOAMINE OXIDASE (MAO) TO 3,4-DIHYDROXYPHENYLGLYCOL ALDEHYDE (DOPGAL) AND THEN EITHER REDUCED TO 3,4-DIHYDROXYPHENYLETHYLENE GLYCOL (DOPEG) OR OXIDIZED TO 3,4-DIHYDROXYMANDELIC ACID (DOMA) ALTERNATIVELY, THEY CAN INITIALLY BE METHYLATED BY CATECHOL-O-METHYLTRANSFERASE (COMT) TO NORMETANEPHRINE AND METANEPHRINE, RESPECTIVELY. MOST OF THE PRODUCTS OF EITHER TYPE OF REACTION ARE THEN METABOLIZED BY THE OTHER ENZYME TO FORM THE MAJOR EXCRETORY PRODUCTS, 3-METHOXY-4-HYDROXYPHENYLETHYLENE GLYCOL (MOPEG OR MHPG) AND 3-METHOXY-4-HYDROXYMANDELIC ACID (VMA). FREE MOPEG IS LARGELY CONVERTED TO VMA. THE GLYCOL AND TO SOME EXTENT, THE O-METHYLATED AMINES AND THE CATECHOLAMINES MAY BE CONJUGATED TO THE CORRESPONDING SULFATES OR GLUCRONIDES. [R4, 107] ACTN: +THE MECHANISM OF RISE IN BLOOD PRESSURE ... IS THREEFOLD: A DIRECT MYOCARDIAL STIMULATION THAT INCREASES THE STRENGTH OF VENTRICULAR CONTRACTION (POSITIVE INOTROPIC ACTION), AN INCREASED HEART RATE (POSITIVE CHRONOTROPIC ACTION), and , MOST IMPORTANT VASOCONSTRICTION IN MANY VASCULAR BEDS, ESPECIALLY IN PRECAPILLARY RESISTANCE VESSELS OF SKIN, MUCOSA, AND KIDNEY, ALONG WITH MARKED CONSTRICTION OF VEINS. [R4, 192] +... EPINEPHRINE HAS A STRIKING THERAPEUTIC EFFECT /IN RESPONSE TO BRONCHIAL SPASM, DUE TO DISEASE, DRUGS OR VARIOUS AUTACOIDS/ AS A PHYSIOLOGICAL ANTAGONIST . THE BENEFICIAL EFFECT OF EPINEPHRINE IN ASTHMA MAY ARISE FROM INHIBITION OF ANTIGEN-INDUCED RELEASE OF INFLAMMATORY MEDIATORS FROM MAST CELLS, AND TO A LESSER EXTENT FROM DIMINUTION OF BRONCHIAL SECRETIONS AND CONGESTION WITHIN THE MUCOSA. INHIBITION OF MAST CELLS SECRETION IS MEDIATED BY BETA-2 ADRENERGIC RECEPTORS < WHILE THE EFFECTS ON THE MUCOSA ARE MEDIATED BY ALPHA RECEPTORS. [R4, 196] +EPINEPHRINE ... /ACTS/ DIRECTLY ON THE EFFECTOR CELLS. [R4, 188] +IT ACTS DIRECTLY ON BETA 1 RECEPTORS OF THE MYOCARDIUM AND OF CELLS OF THE PACEMAKER AND CONDUCTING TISSUES. [R4, 195] +... EPINEPHRINE ... LOWERS INTRAOCULAR PRESSURE ... THE MECHANISM IS NOT CLEAR ... REDUCED PRODUCTION OF AQUEOUS HUMOR DUE TO VASOCONSTRICTION AND ENHANCED OUTFLOW PROBABLY OCCUR ... . [R4, 197] +/Epinephrine stimulates/ plasma coagulation factors. [R29] +The electrophysiologic effects of circulating epinephrine in humans were examined in four study groups of 10 subjects each. In 10 subjects without structural heart disease (Group 1) and in 10 patients with coronary disease or dilated cardiomyopathy (Group 2) epinephrine infusion at 25 and 50 ng/kg body weight per min for 14 min resulted in an elevation of the plasma epinephrine concentration in the physiologic range. In both groups it produced a dose-dependent decrease in the effective refractory period of the atrium, atrioventricular node and ventricle and improvement in atrioventricular node conduction. Epinephrine facilitated the induction of sustained ventricular tachycardia in 3 of the 20 subjects. In Group 3, a beta-adrenergic blocking dose of propranolol was added to the infusion of 50 ng/kg per min of epinephrine. Propranolol not only reversed the effects of epinephrine, but also lengthened these variables compared with baseline values. In group 4, propranolol was administered first, followed by 50 ng/kg per min of epinephrine. Propranolol alone slowed atrioventricular node conduction and mildly prolonged the refractory periods. In the presence of beta-blockade, epinephrine had no effect on atrioventricular node properties but resulted in a lengthening of the atrial and ventricular effective refractory periods. In conclusion, epinephrine in physioloic doses shortens the effective refractory period of the atrium, atrioventricular node and ventricle, improves atrioventricular node conduction and may facilitate the induction of sustained ventricular tachycardia. The overall electrophysiologic effects of epinephrine result from stimulation of beta-receptors. Stimulation of alpha-receptors by epinephrine has no effect on the atrioventricular node but prolongs the effective refractory period of the atrium and ventricle, partially offsetting the shortening of refractory periods mediated by beta-receptor stimulation. [R30] INTC: +PROPRANOLOL BLOCKS THE BRONCHODILATORY ACTION AND REVERSES THE CARDIAC ACTION OF EPINEPHRINE. [R31, 599] +EPINEPHRINE AND OTHER DIRECT-ACTING SYMPATHOMIMETIC AMINES EXERT ENHANCED CARDIOVASCULAR EFFECTS ... IN INDIVIDUALS CONCURRENTLY RECEIVING OR PREVIOUSLY TREATED WITH IMIPRAMINE OR OTHER TRICYCLIC ANTIDEPRESSANTS. [R31, 541] +SYMPATHOMIMETIC AMINES MUST BE USED VERY CAUTIOUSLY IN PATIENTS UNDER GENERAL ANESTHESIA, SINCE HALOGENATED HYDROCARBONS SENSITIZE THE HEART TO THE ARRHYTHMIC ACTION OF CATECHOLAMINES AND RELATED DRUGS. [R26, 169] +THE EFFECTS OF EPINEPHRINE 1/200,000 ADDED TO MG OF EPIDURAL MORPHINE WERE INVESTIGATED IN 3 HEALTHY MALE VOLUNTEERS, DURING 26 HR OBSERVATION SESSIONS. CUTANEOUS HYPALGESIA WAS INTENSE, FASTER IN ONSET, AND LONGER IN DURATION AFTER EPINEPHRINE-MORPHINE THAN AFTER PLAIN MORPHINE. APPARENTLY, EPINEPHRINE 1/200,000 REDUCES MANIFESTATIONS OF CORD AND BRAINSTEM UPTAKE. THE NEED FOR THE REDUCTION OF THE CUSTOMARY DOSE OF EPIDURAL MORPHINE, WHILE EPINEPHRINE IS USED AS AN ADJUVANT, IS DISCUSSED. [R32] +In hypertensive patients, patients with angina, and healthy subjects ... propranolol enhances the pressor response to epinephrine, usually with accompanying bradycardia. [R33, 32] +The hyperglycemic effect of epinephrine administration may necessitate an increase in insulin or oral hypoglycemic dosage. [R33, 155] +In six healthy subjects, protriptyline (60 mg/day for 4 days) pretreatment considerably enhanced the pressor response to epinephrine infusions. [R33, 370] +In four healthy subjects (two receiving phenelzine and two receiving tranylcypromine), the administration of epinephrine did not significantly affect heart rate or blood pressure. [R33, 335] +Epinephrine may produce hypertensive reactions in patients on ... nonselective blockers such as nadolol. [R34] +Administration of intravenous epinephrine to a patient being treated with propranolol may result in a considerable increase systolic and diastolic blood pressure and a marked decrease in heart rate. This interaction has been reported to cause a hypertensive episode resulting in stroke and several cases of cardiac arrhythmias. [R31, p. 11/23] +Local instillation of 8 to 40 ml of lidocaine with 1:100,000 or 1:200,000 epinephrine during dermatologic surgery resulted in 6 cases of hypertension and reflex bradycardia in patients also taking propranolol. One of these patients experienced a cardiac arrest and required intubation and resuscitation. [R31, p. 11/23] +Patients using epinephrine in addition to timolol eyedrops ... had a slight transitory rise of diastolic pressure and slightly more frequent arrythmias. [R16, 399] +Cocaine ... enhanced the effect of epinpherine. [R4, 188] +The effect of ketamine administration on the ventricular arrhythmogenic dose of epinephrine was studied in 4 halothane anesthetized cats. Each cat was anesthetized 4 times, week apart, with halothane (end-tidal concentration, 1.5%) and with halothane (end-tidal concentration, 1.5%) combined with ketamine infusion (50, 100, and 200 micrograms/kg of body weight/min). Epinephrine was infused in progressively increasing doses. The ventricular arrhythmogenic dose of epinephrine (micrograms/kg) was calculated as the product of infusion rate of epinephrine and time of infusion necessary to induce 4 or more ventricular premature depolarizations within 15 sec. The mean (+ or - SD) ventricular arrhythmogenic dose of epinephrine during halothane anesthesia was 1.1 (+ or - 0.30) micrograms/kg. Ketamine infusion significantly (p < 0.01) lowered the ventricular arrhythmogenic dose of epinephrine independently of dose. The dose of epinephrine (micrograms/kg) that induced an ECG change in P-wave configuration was calculated similarly. Less epinephrine was necessary to induce a change in P-wave configuration than was necessary to induce 4 or more ventricular premature depolarizations within 15 sec. Blood samples were collected after 4 hr of ketamine infusion and again immediately after determination of the ventricular arrhythmogenic dose of epinephrine for analysis of plasma ketamine and norketamine concentrations by use of gas chromatography. Plasma ketamine and norketamine concentrations after a 4 hr infusion and immediately after determination of the ventricular arrhythmogenic dose of epinephrine were similar for any given ketamine infusion rate, indicating that steady-state plasma concentrations had been reached for each infusion rate. Blood pressure and heart rate were measured immediately before (base line) and immediately after infusion of the ventricular arrhythmogenic dose of epinephrine. Ketamine infusion significantly (p < 005) lowered base-line blood pressure, but not heart rate. [R35] +/To study the/ effect ... of epinephrine ... on bupivacaine toxicity, toxic doses of bupivacaine were administered to awake spontaneously breathing pigs. Twenty animals were randomized to one of two groups. One group received an infusion of bupivacaine with epinephrine (5 micrograms/ml) at a rate of 2 mg/kg/min; the other received an infusion of plain bupivacaine at the same rate. Bupivacaine infusion was continued until cardiovascular collapse. Following cardiovascular collapse /attempts were made/ to resuscitate the animals via open chest cardiac massage and a standardized resuscitation protocol. The addition of epinephrine to bupivacaine significantly increased blood pressure and systemic vascular resistance but not heart rate or cardiac output early in the bupivacaine infusion. Epinephrine had no effect on the dose of bupivacaine that caused cardiovascular collapse (P= 0.1), on the plasma concentration of bupivacaine at collapse (P= 0.9), or on the ability to resuscitate animals following cardiovascular collapse. The addition of epinephrine decreased the dose of bupivacaine required to initiate cardiac dysrhythmias (p= 0.003). The first dysrhythmia experienced by the epinephrine group was second degree heart block, which contrasts with the premature ventricular and atrial dysrhythmias experienced by the plain group. The dose of bupivacaine that produced seizures was also reduced by the addition of epinephrine (p= 0.006). The addition of epinephrine to bupivacaine did not alter the dose of bupivacaine that caused cardiovascular collapse in awake spontaneously breathing pigs but did decrease the dose of bupivacaine that caused seizures and dysrhythmias. [R36] +Interaction between thiopental and epinephrine in inducing ventricular arrhythmias /was examined/ in dogs. The arrhythmogenic threshold of epinephrine was determined during anesthesia with either halothane alone, thiopental alone, etomidate plus different doses of thiopental, or halothane plus different doses of thiopental. The arrhythmogenic dose and the corresponding plasma concentration of epinephrine during thiopental anesthesia (plasma thiopental concentration: 46-57 micrograms/ml) were 0.77 + or - 0.04 micrograms/kg/min and 10.7 + or - 1.5 ng/ml, respectively. During halothane anesthesia (end-tidal:P 1.3 MAC) they were 2.59 + or - 0.49 micrograms/kg/min and 45.3 + or - 9.2 ng/ml, respectively. The dose-effect relationship for the thiopental action was examined during etomidate plus thiopental and halothane plus thiopental anesthesia. The arrhythmogenic plasma concentration of epinephrine was inversely proportional to the plasma thiopental concentration during both anesthetics. During etomidate plus thiopental anesthesia, at plasma thiopental concentrations of 0, 11.2 + or - 0.83, 20.1 + or - 1.34, and 33.2 + or - 1.95 micrograms/ml, the corresponding epinephrine concentrations were 201.3 + or - 34.4, 142 + or - 19.5, 69.1 + or - 21.2, and 22.7 + or - 4.5 ng/ml. During halothane plus thiopental anesthesia, at plasma thiopental concentrations of 0, 10 + or - 0.86, 18.3 + or - 0.87, and 31.8 + or - 1.05 micrograms/ml, the corresponding epinephrine concentrations were 45.3 + or - 9.2, 34.6 + or - 8.9, 16.2 + or - 1.74, and 15.1 + or - 1.32 micrograms/ml, respectively. These results suggest that thiopental sensitizes the heart to epinephrine in a dose-dependent manner. This sensitizing action of thiopental would in part explain the thiopental potentiation of hydrocarbon anesthetic-epinephrine arrhythmias. [R37] +Intrinsic sympathomimetic activity of pindolol ... /to/ modify its beta-blocking effects on the responses to an adrenaline infusion, /was studied in/ 10 healthy volunteers. ... At an interval of 1-4 weeks each subject received pindolol and atenolol in randomized order before the infusion of adrenaline 0.06 microgram/kg/min. Pindolol prevented hypokalemia and significantly decreased the heart rate during the adrenaline infusion. These effects were not observed after atenolol. The diastolic blood pressure was slightly increased during the infusion of adrenaline after pindolol, whereas it remained unchanged after atenolol. [R38] +Plasma catecholamines where measured in 15 matched controls by radioimmunassay. The data suggest that plasma catecholamines (norepinephrine and epinphrine) were significantly elevated in chronic lead poisoning. Plasma catecholamine elevation may well be important in the clinical finding of hyperactivity and hypertension associated with chronic lead poisoning. [R39] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: +LDLO HUMAN SUBCUTANEOUS 735 UG/KG [R42] THER: +Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Bronchodilator Agents; Mydriatics; Sympathomimetics; Vasoconstrictor Agents [R40] +THE MOST COMMON USES OF EPINEPHRINE ARE TO RELIEVE RESPIRATORY DISTRESS DUE TO BRONCHOSPASM, TO PROVIDE RAPID RELIEF OF HYPERSENSITIVITY REACTIONS TO DRUGS AND OTHER ALLERGENS, AND TO PROLONG THE ACTION OF LOCAL ANESTHETICS. ITS CARDIAC EFFECTS MAY BE OF USE IN RESTORING CARDIAC RHYTHM IN PATIENTS WITH CARDIAC ARREST ... . IT IS ALSO USED AS A TOPICAL HEMOSTATIC ON BLEEDING SURFACES. [R4, 198] +EPINEPHRINE IS USED IN MANY SURGICAL PROCEDURES ON THE NOSE, THROAT, AND LARYNX, TO SHRINK THE MUCOSA AND IMPROVE VISUALIZATION BY LIMITING HEMORRHAGE. [R4, 216] +SYMPATHOMIMETIC AMINES WITH ALPHA-RECEPTOR ACTION CAUSE MARKED VASOCONSTRICTION AND BLANCHING WHEN APPLIED TO NASAL AND PHARYNGEAL MUCOSAL SURFACES. THEY ARE THEREFORE USEFUL IN TREATMENT OF MUCOSAL CONGESTION ACCOMPANYING HAY FEVER, ALLERGIC RHINITIS, ACUTE CORYZA, SINUSITIS, AND OTHER RESPIRATORY CONDITIONS. SHORT DURATION OF ACTION OF ... EPINEPHRINE LIMITS /ITS/ ... VALUE IN SHRINKING NASAL MUCOSA WHEN APPLIED TOPICALLY, AND LONGER ACTING CONGENERS ARE MORE COMMONLY USED IN THESE CONDITIONS. [R26, 168] +UNDER EXCEPTIONAL CIRCUMSTANCES PERIPHERAL VASOCONSTRICTORS MAY BE REQUIRED TO MAINTAIN AN ADEQUATE BLOOD PRESSURE. INFUSIONS OF NOREPINEPHRINE ... AS WELL AS EPINEPHRINE HAVE BEEN EMPLOYED FOR THIS PURPOSE. ... CARE MUST BE TAKEN TO AVOID EXCESSIVE INCREASE IN BLOOD PRESSURE, SINCE THE ADVANTAGES OF IMPROVING CORONARY PERFUSION MAY BE MORE THAN OFFSET BY INCREASED DEMANDS PLACED ON THE MYOCARDIUM; CIRCULATION TO KIDNEYS AND OTHER VITAL ORGANS MAY ALSO BE COMPROMISED. [R26, 169] *EPINEPHRINE IS AN IMPORTANT THERAPEUTIC AGENT IN PATIENTS WITH CARDIAC ARREST. ... EPINEPHRINE AND OTHER ALPHA-ADRENERGIC AGONISTS INCREASE DIASTOLIC PRESSURE AND IMPROVE CORONARY BLOOD FLOW. ... THE OPTIMAL DOSE OF EPINEPHRINE IN PATIENTS WITH CARDIAC ARREST IS NOT KNOWN ... [R4, 215] *ACUTE ASTHMATIC ATTACKS ARE USUALLY RELIEVED WITHIN 3-5 MINUTES AFTER SUBCUTANEOUS INJECTION ... OR AFTER ORAL INHALATION ... . [R26, 170] +MEDICATION (VET): EPINEPHRINE INJECTION (1:1000): ANAPHYLACTOID SHOCK, ALLERGIC REACTIONS, BRONCHIAL ASTHMA, AND AS A TOPICAL HEMOSTAT TO CONTROL EPISTAXIS AND HEMORRHAGE FROM SMALL ARTERIOLES AND CAPILLARIES. EPINEPHRINE IS SOMETIMES SUCCESSFUL IN REINITIATING THE HEART BEAT FOLLOWING CARDIAC ARREST. [R20, p. 16-48] +APPLIED TOPICALLY TO THE EYE, IN OINTMENT OR AS SOLN ... THE OPHTHALMIC PREPARATIONS ARE USED TO DECREASE CONJUNCTIVAL AND SCLERAL INFLAMMATION AND EDEMA AND TO TREAT PRIMARY OPEN-ANGLE GLAUCOMA. /BITARTRATE USP/ [R41] +The main effects of therapeutic parenteral doses of epinephrine are relaxation of smooth muscle of the bronchial tree, cardiac stimulation, and dilation of skeletal muscle vasculature. [R7, 625] +Simultaneous injection of epinephrine with local anesthetics retards the absorption of the anesthetic and increases the duration of anesthesia. [R4, 216] +Epinephrine is a drug of choice to reverse the manifestations of serious acute, hypersensitivity reactions (eg, from food, bee sting, or drug allergy). A sc injection of epinephrine rapidly relieves itching, hives, and swelling of lips, eyelids, annd the tongue. [R4, 217] +MEDICATION (VET): L-FORM: SYMPATHOMIMETIC, VASOCONSTRICTOR, CARDIAC STIMULANT, BRONCHODILATOR; TO COUNTER ALLERGIC REACTIONS, ANESTHESIA, CARDIAC ARREST. [R2, 567] +TO COUNTER ALLERGENIC REACTIONS; TO PROLONG ACTION OF INFILTRATION ANESTHETICS. [R4, 198] +L-FORM AS ADRENERGIC; BRONCHODILATOR; MYDRIATIC, ANTIGLAUCOMA AGENT. [R2, 567] WARN: +A MAJOR LIMITATION OF THERAPY WITH NASAL DECONGESTANTS /ALPHA-ADRENERGIC AGONISTS/ IS THAT LOSS IN EFFICACY AND "REBOUND" HYPEREMIA AND WORSENING SYMPTOMS OFTEN OCCUR WITH CHRONIC USE OR WHEN THE DRUG IS STOPPED. /SYMPATHOMIMETIC AMINES/ [R4, 216] +HYPERTHYROID AND HYPERTENSIVE INDIVIDUALS ARE PARTICULARLY SUSCEPTIBLE TO THE UNTOWARD AND PRESSOR RESPONSES TO EPINEPHRINE. IN PSYCHONEUROTIC INDIVIDUALS, EXISTING SYMPTOMS ARE OFTEN MARKEDLY AGGRAVATED BY THE ADMIN OF EPINEPHRINE. ... VENTRICULAR ARRHYTHMIAS MAY FOLLOW ADMIN OF EPINEPHRINE. FIBRILLATION IS LIKELY TO OCCUR IF THE DRUG IS USED UNWISELY DURING ANESTHESIA. ... PATIENTS WITH LONG-STANDING BRONCHIAL ASTHMA AND SIGNIFICANT DEGREE OF EMPHYSEMA, WHO HAVE REACHED AGE IN WHICH DEGENERATIVE HEART DISEASE IS PREVALENT MUST BE GIVEN EPINEPHRINE ONLY WITH CONSIDERABLE CAUTION. IN PATIENTS SUFFERING FROM SHOCK, THE DRUG MAY ACCENTUATE THE UNDERLYING DISORDERS. ANGINAL PAIN IS READILY INDUCED BY EPINEPHRINE IN PATIENTS WITH ANGINA PECTORIS. [R4, 198] +VET: EPINEPHRINE INJECTION (1:1000): DO NOT USE IN ACUTE HYPOTENSION PRODUCED BY PHENOTHIAZINE DERIVED TRANQUILIZERS, SINCE FURTHER DEPRESSION OF BLOOD PRESSURE CAN OCCUR. DO NOT USE WHEN CYCLOPROPANE OR HALOGENATED ANESTHETICS ARE USED BECAUSE OF POSSIBLE CARDIAC COLLAPSE. DO NOT USE IN TREATMENT OF VASCULAR SHOCK. DO NOT USE IN PATIENTS KNOWN TO BE SENSITIVE TO EPINEPHRINE. ... USE WITH CAUTION IN HYPERTHYROID ANIMALS; ANIMALS BEING TREATED WITH THYROID, DIGITALIS, OR MERCURIAL DIURETICS. DO NOT USE INJECTION IF IT IS BROWN OR CONTAINS A PRECIPITATE. [R20, p. 16-48] +The hyperglycemic effect of epinephrine administration may necessitate an increase in insulin or oral hypoglycemic dosage. [R33, 155] +Epinephrine is contraindicated for parenteral use during the second stage of labor; parenteral administration of the drug to maintain blood pressure during spinal anesthesia for delivery can cause acceleration of fetal heart rate and should not be used in obstetric patients when maternal systolic/diastolic blood pressure exceeds 130/80 mm Hg. [R7, 626] +Epinephrine is contraindicated in patients with shock (other than anaphylactic shock), organic heart disease, or cardiac dilation, as well as most patients with arrhythmias, organic brain damage, or cerebral arteriosclerosis. Epinephrine injection is contraindicated in patients with angle-closure glaucoma. The drug is contraindicated for use during general anesthesia with chloroform, trichloroethylene, or cyclopropane, and should be used cautiously, if at all, with other halogenated hydrocarbon anesthetics such as halothane. In conjunction with local anesthetics, epinephrine is contraindicated for use in fingers, toes, ears, nose, or genitalia. [R7, 627] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: +Epinephrine, (-)-adrenaline is a naturally occurring hormone, which is released from the adrenal medulla and is involved in the regulation of heart rate, blood pressure, and lipid and carbohydrate metabolism. It is also commercially synthesized for medicinal use. Information pertaining to the biodegradation of epinephrine in soil and water was not located in the available literature. Epinephrine is a catecholamine which may dissociate in environmental media in varying proportions that are pH dependent. Ions are not expected to volatilize, nor do they generally adsorb to sediments as strongly as do their neutral counterparts. Volatilization and bioconcentration of epinephrine should not be important environmental fate processes. A low estimated Koc indicates epinephrine should not partition from the water column to organic matter contained in sediments and suspended solids. Epinephrine should be highly mobile in soil and it may leach to ground water. However, epinephrine is unstable in the presence of heat, light, air and alkalies. Rate data for chemical reactions of epinephrine that involve abiotic pathways were not located in the available literature. Nevertheless, epinephrine has the potential to undergo direct photolysis, various photooxidation reactions, and chemical reactions with bases in the environment. If released to the atmosphere as a gas, reactions with photochemically produced hydroxyl radicals may be important (estimated half-life of 3 hours). However, epinephrine is expected to exist almost entirely in the particulate phase in ambient air. The most probable human exposure to exogenous epinephrine would result from oral inhalation or direct injection of medicated solutions containing it and occupational exposure, which may occur through dermal contact or inhalation at workplaces where epinephrine is produced or used. (SRC) NATS: +The principal sympathomimetic hormone produced in most species ... occurs as the l-form in animals and man. [R2, 566] +Epinephrine [(-)-adrenaline] is a naturally occurring hormone, which is released from the adrenal medulla and is involved in the regulation of heart rate, blood pressure, and lipid and carbohydrate metabolism(1). [R43] ARTS: +Epinephrine is commercially synthesized for medicinal use as a sympathomimetic, vasoconstrictor, cardiac stimulant and bronchodilator(1). Epinephrine may be released to the environment via effluents at sites where it is produced or used(SRC). [R43] FATE: +TERRESTRIAL FATE: Information pertaining to the biodegradation of epinephrine in soil was not located in the available literature. Epinephrine is a catecholamine(1) which may dissociate in soil in varying proportions that are pH dependent. Ions are not expected to volatilize, nor do they generally adsorb to particulate matter as strongly as do their neutral counterparts(2). Both estimates of the Henry's Law constant of 7.06X10-19 atm-cu m/mole(3) and the vapor pressure of 2.93X10-15 at 25 deg C indicate that the volatilization of epinephrine from either moist or dry soil surfaces should not be an important fate process(3). An estimated Koc of 98(2) indicates epinephrine should be highly mobile in soil(4); and it may leach to ground water if released to soil. However, epinephrine is unstable in the presence of heat, light, air and alkalies(1). Consequently, epinephrine has the potential to undergo direct photolysis and various photooxidation reactions on sunlit surfaces, and chemical reactions in soil(SRC). [R44] +AQUATIC FATE: Information pertaining to the biodegradation of epinephrine in water was not located in the available literature. Epinephrine is a catecholamine(1) which may dissociate in natural waters in varying proportions that are pH dependent. Ions are not expected to volatilize, nor do they generally adsorb to sediments as strongly as do their neutral counterparts(2). An estimated Henry's Law constant of 7.06X10-19 atm-cu m/mole at 25 deg C(3) indicates that the volatilization of epinephrine from natural bodies of water should not be an important fate process(3). An estimated Koc of 98(2) indicates epinephrine should not partition from the water column to organic matter(4) contained in sediments and suspended solids; and an estimated bioconcentration factor (log BCF) of 1.10(2) indicate that epinephrine should not bioconcentrate among aquatic organisms. Epinephrine is unstable in the presence of heat, light, air and alkalies(1). Consequently, epinephrine has the potential to undergo direct photolysis, various photooxidation reactions, and chemical reactions in aquatic systems(SRC). [R44] +ATMOSPHERIC FATE:Based upon a vapor pressure of 2.93X10-15 mm Hg at 25 deg C, which has been calculated from the water solubility and Henry's Law constant, epinephrine is expected to exist almost entirely in the particulate phase in ambient air(2). However, if released to the atmosphere as a gas, the vapor phase reaction of epinephrine with photochemically produced hydroxyl radicals is likely to be an important fate process. The rate constant for the vapor-phase reaction of epinephrine with photochemically produced hydroxyl radicals has been estimated to be 1.38X10-10 cu cm/molecule-sec at 25 deg C; which corresponds to an atmospheric half-life of about 3 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Epinephrine is unstable in the presence of light(3); therefore, it has the potential to undergo direct photolysis and various photooxidation reactions in ambient air. In addition, epinephrine is susceptible to atmospheric oxidation reactions with nitrate radicals(1). [R45] ABIO: +Epinephrine is unstable in the presence of heat, light, air and alkalies(1). Rate data for chemical reactions of epinephrine that involve abiotic pathways were not located in the available literature. Nevertheless, epinephrine has the potential to undergo direct photolysis, various photooxidation reactions, and chemical reactions in the environment. The rate constant for the vapor-phase reaction of epinephrine with photochemically produced hydroxyl radicals in air has been estimated to be 1.38X10-10 cu cm/molecule-sec at 25 deg C, which corresponds to an atmospheric half-life of about 3 hours at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(2). In addition, epinephrine is susceptible to atmospheric oxidation reactions with nitrate radicals(2). [R46] BIOC: +Based on a water solubility of 1000 mg/L at 25 deg C(1), a bioconcentration factor (log BCF) of 1.10 for epinephrine has been calculated using a recommended regression-derived equation(2,SRC). This BCF values indicates that epinephrine should not bioconcentrate among aquatic organisms(SRC). [R47] KOC: +Based on a water solubility of 1000 mg/L at 25 deg C(1), a Koc for epinephrine of 98 has been calculated using regression-derived equations(2,SRC). This Koc value indicates that epinephrine should be highly mobile in soil(3), and it should not partition from the water column to organic matter contained in sediments and suspended solids(SRC). In addition, epinephrine is a catecholamine(1) which may dissociate in environmental media in varying proportions that are pH dependent. Generally ions do not adsorb to particulate matter as strongly as their neutral counterparts(SRC). [R48] VWS: +Epinephrine is a catecholamine(1) which may dissociate in environmental media in varying proportions that are pH dependent. Ions are not expected to volatilize from water. The Henry's Law constant of 7.06X10-19 atm-cu m/mole at 25 deg C for epinephrine has been estimated using a bond contribution method(2). Based upon this Henry's Law constant, volatilization of epinephrine from natural bodies of water and moist soil should not be an important fate process(3). Based upon a vapor pressure of about 2.93X10-15 mm Hg at 25 deg C, which has been calculated from the water solubility and Henry's Law constant, epinephrine is not expected to evaporate from dry surface(SRC). [R49] MILK: +Epinephrine is distributed into milk. [R7, 626] RTEX: +The most probable route of human exposure to epinephrine is by the oral inhalation or direct injection of medicated solutions containing it(1). [R43] +The most probable human exposure to epinephrine would be occupational exposure, which may occur through dermal contact or inhalation of dust at places where it is produced or used. NIOSH (NOES Survey 1981-1983) has statistically estimated that 18,642 workers are potentially exposed to epinephrine in the USA(1). The most common non-occupational exposure is likely to result from its administration as a clinical drug(SRC). [R50] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CERC: +Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1,000 lb or 454 kg. The toll free telephone number of the NRC is (800) 424-8802; in the Washington metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.6 (see section IV. D.3.b). [R51] RCRA: +P042; As stipulated in 40 CFR 261.33, when epinephrine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to federal and/or state hazardous waste regulations. Also defined as a hazardous waste is any container or inner liner used to hold this waste or any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5(e)). [R52] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: +ADRENALINE WAS DETERMINED IN INJECTIONS CONTAINING PROCAINE IN A 1000-FOLD EXCESS BY REVERSED-PHASE HIGH-PERFORMANCE LIQ CHROMATOGRAPHY USING UV205 DETECTION AND 100 UMOL/DM 3 SULFURIC ACID AS ELUENT WITHOUT ORGANIC SOLVENT COMPONENTS. [R53] CLAB: +AN AUTOMATED ANALYZER USING FLUORESCENCE SPECTROMETRY WAS USED TO DETERMINE ADRENALINE IN BLOOD PLASMA, URINE, AND CEREBROSPINAL FLUID OF HUMANS AND IN PLASMA OF RATS. [R54] +FREE CATECHOLAMINES FROM HUMAN URINE WERE PURIFIED ON A COLUMN OF IMMOBILIZED BORIC ACID, SEPARATED BY ION-PAIR REVERSED-PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY AND DETECTED ELECTROCHEMICALLY. [R55] +INTERLAB DETERMINATIONS OF EPINEPHRINEIN IN PLASMA SAMPLES BY A METHOD INVOLVING LIQUID CHROMATOGRAPHY WITH ELECTROCHEMICAL DETECTION OR A RADIOENZYMIC ASSAY SUGGESTED REAL DIFFERENCES IN CATECHOLAMINE MEASUREMENTS BY THESE 2 METHODS. [R56] +A HIGHLY SENSITIVE AND SIMPLIFIED PROCEDURE FOR SEPARATION AND IDENTIFICATION OF ADRENAL EPINEPHRINEIN IN RATS UTILIZING HIGH-PERFORMANCE REVERSED-PHASE LIQUID CHROMATOGRAPHY IS DESCRIBED. [R57] +HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WAS USED FOR DETERMINING EPINEPHRINE IN RAT TISSUE. [R58] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of l-Epinephrine Hydrochloride in F344/N Rats and B6C3F1 Mice Technical Report Series No. 380 (1990) NIH Publication No. 90-2835 /l-Epinephrine hydrochloride/ SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 466 R4: Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990. R5: USP Convention. The United States Pharmacopeia XXII/National Formulary XVII. Rockville, MD: United States Pharmacopeial Convention, Inc., 1990. 500 R6: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 749 R7: McEvoy, G.K. (ed.). AHFS Drug Information 90. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1990 (Plus Supplements 1990). R8: USITC. IMPORTS OF BENZENOID CHEM AND PROD 1983 p.83 R9: McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 49 R11: Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) R12: Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) R13: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R14: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-9 (1981) EPA 68-03-3025 R15: American Medical Association, Department of Drugs. Drug Evaluations. 6th ed. Chicago, Ill: American Medical Association, 1986. 334 R16: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R17: Doull, J., C.D.Klassen, and M.D. Amdur (eds.). Casarett and Doull's Toxicology. 3rd ed., New York: Macmillan Co., Inc., 1986. R18: Dailey RH; Am Energ Med 17 (2): 159-60 (1988) R19: Burk RW et al; Plast Reconstr Surg 85 (1): 92-9 (1990) R20: Aronson, C.E. (ed.). Veterinary Pharmaceuticals and Biologicals, 1980-1981. Media, Pa.: Harwal Publishing Co., 1980. R21: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 234 R22: Aycock BG; Am Plast Surg 23 (1): 27-30 (1989) R23: Follett DV et al; Anesth Analg 70 (4): 400-6 (1990) R24: Rajala GM et al; Teratology 38 (3): 291-6 (1988) R25: Toxicology and Carcinogenesis Studies of l-Ephedrine Hydrochloride in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report Series No. 380 (1990) NIH Publication No. 90-2835 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R26: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. R27: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-371 R28: Flynn N et al; Can J Anaesth 36 (4): 397-401 (1989) R29: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 210 R30: Morady F et al; J Am Coll Cardiol 11 (6): 1235-44 (1988) R31: Evaluations of Drug Interactions. 2nd ed. and supplements. Washington, DC: American Pharmaceutical Assn., 1976, 1978. R32: BROMAGE PR ET AL; ANESTHESIOLOGY 58 (3): 257 (1983) R33: Hansten P.D. Drug Interactions. 5th ed. Philadelphia: Lea and Febiger, 1985. R34: Knoben, J.E. and P.O. Anderson (eds.) Handbook of Clinical Drug Data. 6th ed. Bethesda, MD: Drug Intelligence Publications, Inc. 1988. 131 R35: Bednarski RM; Am J Vet Res 49 (3): 350-4 (1988) R36: Bernards CM et al; Anesthesiology 71 (5): 711-7 (1989) R37: Hayashi Y et al; Anesthesiology 71 (6): 929-355 (1989) R38: Forfang K, Simonsen S; Eur J Clin Pharmacol 37 (1): 23-7 (1989) R39: deCastro FJ; Vet Hum Toxicol 32 (2): 152-3 (1990) R40: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R41: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 813 R42: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. 83/8209 R43: (1) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) R44: (1) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9, 5-4, 6-3, 15-16 (1982) (3) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (4) Swann RL et al; Res Rev 85: 16-28 (1983) R45: (1) Atkinson R; Intern J Chem Kin 19: 799-828 (1987) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) R46: (1) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) (2) Atkinson R; Intern J Chem Kin 19: 799-828 (1987) R47: (1) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 5-10 (1982) R48: (1) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (3) Swann RL et al; Res Rev 85: 16-28 (1983) R49: (1) McLean JR; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley Interscience 9: 241-9 (1980) (2) Hine J, Mookerjee PK; J Org Chem 40: 292-8 (1975) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-15 to 15-29 (1982) R50: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) R51: 54 FR 33419 (8/14/89) R52: 40 CFR 261.33 (7/1/88) R53: TOROK I ET AL; MAGY KEM FOLY 89 (1): 19 (1983) R54: AIZAWA M ET AL; TOYO SODA KENKYU HOKOKU 27 (1): 13 (1983) R55: SPEEK AJ ET AL; CLIN CHIM ACTA 128 (1): 103 (1983) R56: CAUSON RC ET AL; CLIN CHEM 29 (4): 735 (1983) R57: NAKADA T ET AL; NIPPON HINYOKIKA GAKKAI ZASSHI 73 (11): 1458 (1982) R58: YAMADA K; J PHARMACOL METHOD 9 (1): 1 (1983) RS: 62 Record 294 of 1119 in HSDB (through 2003/06) AN: 4290 UD: 200211 RD: Reviewed by SRP on 9/23/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BUTYROLACTONE- SY: *6480-; *GAMMA-6480-; *GAMMA-BL-; *BLO-; *BUTANOIC-ACID,-4-HYDROXY-,-GAMMA-LACTONE-; *1,2-BUTANOLIDE-; *1,4-BUTANOLIDE-; *4-BUTANOLIDE-; *BUTYRIC-ACID-LACTONE-; *GAMMA-BUTYROLACTONE-; *4-BUTYROLACTONE-; *BUTYRYL-LACTONE-; *4-DEOXYTETRONIC-ACID-; *DIHYDRO-2-FURANONE-; *DIHYDRO-2(3H)-FURANONE; *2(3H)-FURANONE, DIHYDRO-; *4-HYDROXYBUTANOIC-ACID-LACTONE-; *GAMMA-HYDROXYBUTYRIC-ACID-CYCLIC-ESTER-; *GAMMA-HYDROXYBUTYRIC-ACID-LACTONE-; *3-HYDROXYBUTYRIC-ACID-LACTONE-; *4-HYDROXYBUTYRIC-ACID-LACTONE-; *GAMMA-HYDROXYBUTYROLACTONE-; *TETRAHYDRO-2-FURANONE- RN: 96-48-0 MF: *C4-H6-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepd from acetylene and formaldehyde; from ethylene chlorohydrin, or from glutaric acid, or from gamma-hydroxybutyric acid soln, or from tetrahydrofuran, or from vinylacetic acid ... . [R1] *Hydrogenation of maleic anhydride [R2] *Endothermic dehydrogenation of butane-1,4-diol in the gas phase [R3, p. VA4 495] FORM: *Grade: technical [R4] MFS: *ARCO Chemical Co., 3801 West Chester Pike, Newtown Square, PA 19073-2387, (610)359-2000; Production site: Channelview, TX 77530 [R5] *BASF Corp., 3000 Continental Drive-North, Mount Olive, NJ 07828-1234, 973-426-2600; Production site: Geismar, LA 70734 [R5] *International Specialty Products Inc., 1361 Alps Road, Wayne, NJ 07470-3688, 973-628-4000; Production sites: Calvert City, KY 42029; Texas City, TX 77590 [R5] USE: *Intermediate in synth of polyvinylpyrrolidone, DL-methionine, piperidine, phenylbutyric acid, thiobutyric acids; solvent for polyacrylonitrile, cellulose acetate, methyl methacrylate polymers, polystyrene; constituent of paint removers, textile aids, drilling oils [R1] *The main uses of butyrolactone are as an intermediate in the synthesis of N-methylpyrrolidone, pyrrolidone, herbicides, growth regulators, alpha-acetobutyrolactone, the rubber additive thiodibutyric acid, as a solvent for polymers, as a polymerization catalyst, in hairwave compositions, sun lotions, pharmaceuticals, printing inks, as an extractant in the petroleum industry, as a stabilizer for chlorohydrocarbons and phosphorus-based pesticides, and as a nematocide. [R3, p. VA4 495-8] *Gamma-butyrolactone is a chemical solvent used in nail polish removers. [R6] *Solvent for polyacrylonitrile, cellulose acetate, methyl methacrylate polymers, polystyrene. [R1] *Constituent of paint removers, textile aids, drilling oils. [R1] *Used as a co-solvent to remove paint finishes [R7] PRIE: U.S. PRODUCTION: *(1993) 64,607 g [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Oily liquid [R1]; *Colorless [R4] ODOR: *Pleasant odor [R4]; *Faint odor [R3, p. VA4 495] BP: *204 deg C @ 760 mm Hg [R1] MP: *-43.53 deg C [R9] MW: *86.09 [R1] CTP: *Critical temperature: 739 K; Critical pressure: 5.94X10+6 Pa [R10] DEN: *1.1284 @ 16 deg C/0 deg C [R9] HTC: *234 KJ/g @ constant volume or pressure [R3, p. VA4 495] HTV: *-5.5713X10+7 @ 229.78 K [R10] OWPC: *log Kow= -0.64 [R11] SOL: *Miscible with water; sol in methanol, ethanol, acetone, ether, benzene [R1]; *Very soluble in acetone, benzene, ethyl ether, and ethanol. [R9] SPEC: *MAX ABSORPTION (METHANOL): 209 NM (LOG E= 1.63) [R12]; *Index of refraction: 1.4348 @ 25 deg C/D [R1]; *IR: 5996 (Coblentz Society Spectral Collection) [R13, p. V1 650]; *UV: 4-18 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R13, p. V1 650]; *NMR: 63 (Varian Associates NMR Spectra Catalogue) [R13, p. V1 650]; *MASS: 135 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R13, p. V1 650]; *IR: 5530 (Sadtler Research Laboratories Prism Collection) [R13, p. V1 370]; *MASS: 3992 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R13, p. V1 370] SURF: *4.6079X10-2 @ 229.78 K [R10] VAP: *0.45 mm Hg @ 25 deg C [R10] VISC: *1.717X10-3 @ 298.15 K [R10] OCPP: *Density: 1.1441 at 0 deg C/0 deg C; 1.1286 at 15 deg C/0 deg C [R1] *Volatile with steam [R1] *Hydrolyzed by hot alkaline solutions [R1] *Extremely stable at pH 7 [R3, p. VA4 495] *Slightly hygroscopic [R3, p. VA4 495] *VOLATILE WITH STEAM; HYDROLYZED BY HOT ALKALINE SOLN. [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible when exposed to heat or flame ... [R15] NFPA: +Health: 0. 0= Materials which on exposure under fire conditions would offer no health hazard beyond that of ordinary combustible material. [R16] +Flammability: 1. 1= Materials that must be preheated before ignition can occur. Water may cause frothing of liquids ... if it gets below the surface of the liquid and turns to steam. ... water spray gently applied to the surface will cause a frothing which will extinguish the fire. [R16] +Reactivity: 0. 0= Materials which are normally stable even under fire exposure conditions, and which are not reactive with water. Normal fire fighting procedures may be used. [R16] FLPT: *209 DEG F (OPEN CUP) [R14] FIRP: +ALCOHOL FOAM. [R16] *To fight fire, use foam, ... carbon dioxide, dry chemical. [R15] EXPL: *Potentially explosive reaction with butanol + 2,4-dichlorophenol + sodium hydroxide. [R15] REAC: *... Can react with oxidizing materials. [R15] *Potentially explosive reaction with butanol + 2,4-dichlorophenol + sodium hydroxide. [R15] DCMP: *When heated to decomposition it emits acrid and irritating fumes. [R15] EQUP: *Wear rubber gloves, all purpose canister mask and full protective clothing. [R17] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. CLUP: */Lab quantity/. Absorb on paper. Evaporate on a glass or an iron dish in hood. Burn the paper. [R17] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Spray into the furnace. Incineration will become easier by mixing with a more flammable solvent. [R17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 4-butyrolactone. There is evidence suggesting lack of carcinogenicity of 4-butyrolactone in experimental animals. Overall evaluation: 4-Butyrolactone is not classifiable as to its carcinogenicity to humans (Group 3). [R18] HTOX: *TOXIC BY INGESTION. [R19] *The usual symptoms include headache, giddiness, nervousness, blurred vision, weakness, nausea, cramps, diarrhea, and discomfort in the chest. Signs include sweating, miosis, tearing, salivation and other excessive respiratory tract secretion, vomiting, cyanosis, papilledema, uncontrollable muscle twitches followed by muscular weakness, convulsions, coma, loss of reflexes, and loss of sphincter control. The last four signs are seen only in severe cases but do not preclude a favorable outcome if treatment is prompt and energetic. Cardiac arrhythmias, various degrees of heart block, and cardiac arrest may occur ... /Organic phosphorus pesticides/ [R20] NTOX: *... 60 4-WK-OLD C3H MICE OF BOTH SEXES RECEIVED DIET CONTAINING 1000 MG GAMMA-BUTYROLACTONE/KG ... FOR LIFE ... IN C3H MICE, NO INCR IN INCIDENCES OF MAMMARY TUMORS IN FEMALES OR OF HEPATOMAS IN MALES WERE OBSERVED COMPARED WITH THOSE IN 54 MALE AND 61 FEMALE UNTREATED CONTROLS. [R21] *OF 34 NEWBORN XVII/G MICE GIVEN SC INJECTIONS OF 1 UG...ON 1ST, 4TH AND 8TH DAYS OF LIFE, 18 (53%) DEVELOPED LUNG TUMORS (AVG SURVIVAL, 590 DAYS) COMPARED WITH 27/44 (61%) UNTREATED CONTROLS (AVG SURVIVAL, 595 DAYS). [R22] *NO LOCAL TUMORS WERE OBSERVED IN ... 16 FEMALE SWISS-WEBSTER MICE GIVEN 12 SC INJECTIONS OF 0.005 MG ... IN 0.1 ML TRICAPRYLIN THRICE WEEKLY FOR 4 WK; 11 MICE SURVIVED 18 MO. [R22] *NO INCR IN TUMOR INCIDENCE WAS OBSERVED IN GROUP OF 30 FEMALE SWISS ICR/HA MICE PAINTED WITH 0.1 ML OF 10% SOLN IN ACETONE THRICE WEEKLY FOR LIFE; MEAN SURVIVAL TIME WAS 495 DAYS. [R22] *GAMMA-BUTYROLACTONE ADMIN DERMALLY, 10 MG, 3X WEEKLY FOR 292 DAYS TO ICR/HA MICE, PRODUCED 2/30 PAPILLOMAS. CONSIDERED NEGATIVE. /FROM TABLE/ [R23] *SYMPTOMS /IN RAT AND MOUSE/ WERE THOSE OF WEAKNESS, UNCONSCIOUSNESS, AND INCR DEPTH OF RESPIRATION. IT APPEARS TO BE READILY ABSORBED THROUGH GUINEA PIG SKIN WITH SOME IRRITATION PRODUCED. [R24] *GAMMA-BUTYROLACTONE HAS ANESTHETIC PROPERTIES ... . [R25, (1976)] *ANESTHETIC DOSES OF GAMMA-BUTYROLACTONE, WHICH PRODUCE HYPERTHERMIA IN RATS, INCR INITIAL POSITIVITY OF CLICK-EVOKED CORTICAL POTENTIALS. GAMMA-BUTYROLACTONE (400 MG/KG IP) AND ITS METABOLITE, GAMMA-HYDROXYBUTYRIC ACID (750 MG/KG IP) DEPRESSED RESPIRATION. [R26] *IN NORMOXIC RATS GAMMA-BUTYROLACTONE CAUSED MILD METABOLIC ACIDOSIS, AS EVIDENCED BY DECR ARTERIAL PH AND HCO3-CONTENT. IN HYPOXIC ANIMALS GAMMA-BUTYROLACTONE HAD NO EFFECT. [R27] *GAMMA-BUTYROLACTONE (75, 150, 300, and 600 MG/KG, IV) CAUSED DOSE-DEPENDENT CHANGES IN LEVEL OF CONSCIOUSNESS, EEG ACTIVITY, AND RATE OF LOCAL CEREBRAL GLUCOSE UTILIZATION IN RATS. [R28] *@ 600 MG/KG IV IN RATS LOCAL CEREBRAL GLUCOSE UTILIZATION WAS DEPRESSED TO 32 and 58% OF CONTROLS IN GRAY AND WHITE MATTER; ALL 26 GRAY STRUCTURES STUDIED SHOWED SIMILAR DOSE-RESPONSE RELATIONS. GAMMA-BUTYROLACTONE DEPRESSED CEREBRAL ENERGY METAB THROUGHOUT BRAIN. [R28] *LOW DOSES OF GAMMA-BUTYROLACTONE (100 and 200 MG/KG) HAD A BIPHASIC EFFECT ON ACTIVITY. INITIALLY, THE ACTIVITY OF RATS WAS REDUCED, AND THIS REDUCTION WAS THEN FOLLOWED BY A PERIOD OF HYPERACTIVITY. THE INCREASE IN ACTIVITY COULD BE DUE TO A RELEASE OF DOPAMINE. [R29] *IV ADMIN OF 100 MG GAMMA-BUTYROLACTONE PER KG ELEVATED BLOOD PRESSURE AND STIMULATED RESPIRATION IN ANESTHETIZED DOGS, BUT HAD OPPOSITE EFFECTS IN ANESTHETIZED CATS. [R30] *The teratogenic potential of gamma-butyrolactone was studied in rats. Pregnant Sprague-Dawley rats were given 0, 10, 50, 125, 250, or 500 mg/kg gamma-butyrolactone by gavage on days six through 15 of gestation. Each female was observed for signs of intoxication. Body weights were measured daily from days zero through 21 of gestation, and food and water consumption were monitored at 3 day intervals. On day 21, dams were killed and the uteri were removed. The position and number of fetuses in-utero, the number of dead and live fetuses, and fetal and placental weights were recorded. Fetuses were examined for malformations, and dams were necropsied. Four dams, three in the 50 mg/kg group and one in the 125 mg/kg group, died during treatment. Necropsy showed lung edema, hyperemia, and emphysema. Gamma-butyrolactone did not affect maternal body weight or feed and water consumption. Placental weights were significantly reduced in treated animals at all doses. Mean fetal weights were significantly increased in the 50, 125, and 250 mg/kg groups. No other treatment related changes of significance were seen either in the dams of fetuses. Some minor skeletal alterations seen in fetuses did not appear systematically and were not attributed to gamma-butyrolactone. /It was/ noted that the apparent relationship between gamma-butyrolactone exposure and increased fetal weight cannot be explained. [R31] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of y-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats given 225 or 450 mg/kg in corn oil. There was equivocal evidence of carcinogenic activity of y-butyrolactone in male B6C3F1 mice based on marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia in the low-dose group. The sensitivity of the study in male mice to detect a carcinogenic effect was reduced by the low survival of the high dose group associated with f1ghting. There was no evidence of carcinogenic activity of Y-butyrolactone in female B6C3F1 mice given 262 or 525 mg/kg in corn oil. [R32] *gamma-Butyrolactone is an oily liquid, with a melting point of - 44 xC and boiling point of 206 xC. It is used as chemical intermediate, as solvent for polymers, in paint removers, and in drilling oil. gamma-Butyrolactone appears to be readily absorbed through guinea pig skin. In rat, at least 10% of the applied dose penetrated the skin. Data describing the uptake of gamma-butyrolactone from the gastro-intestinal or the respiratory system were not located in the literature. The biological degradation of gamma-butyrolactone in mammals is rapid. It is hydrolysed to gamma-hydroxybutyric acid in the blood and liver. In rats, gamma-hydroxybutyric acid is excreted as CO2. gamma-Butyrolactone has a weak narcotic effect due to its fast metabolic conversion to gamma-hydroxybutyric acid, which has an effect on the central nervous system. gamma-Butyrolactone has a moderate, acute oral toxicity. The oral LD50 of gamma-butyrolactone is in the range of 1540 - 1 800 mg/kg in rat, 800 - 1720 mg/kg in mouse, and 500 -1 690 mg/kg in guinea pig. The symptoms are weakness, unconsciousness, and increased depth of respiration. Rats given more than 700 mg/kg gamma-butyrolactone intragastrically died within a few days of respiratory failure and lung congestion. In Scandinavia some cases of poisoning in children have been reported after ingestion of small amounts (less than 8 ml) of gamma-butyrolactone. The LD50 by skin contact is greater than 5 000 mg/kg. Limited inhalation data from acute exposure were available. In rats, inhalation of a saturated atmosphere (8 hours at 20 xC) indicated a low acute toxic effect of gamma-butyrolactone. gamma-Butyrolactone appears to produce some skin irritation when applied dermally to guinea pigs but not to rabbits. In an experimental study on 200 human volunteers, no primary irritative effect of undiluted y-butyrolactone was found, and there were no indications of a sensitizing action on the skin. Severe irritative effects on the rabbit eye have been reported following instillation of gamma-butyrolactone in the conjunctival sac. The literature offers no evidence of gamma-butyrolactone causing toxic effects following repeated exposure. Doses of 100 - 400 mg/kg were well tolerated and could be given repeatedly by gavage to rats for over 7 months. In a 90-day feeding study with beagles receiving up to 0.8% gamma-butyrolactone in the feed, no symptoms of intoxication or pathological effects were noted. However, a dose of approximately 3 000 mg/kg per day of gamma-butyrolactone in the drinking water to male Sprague-Dawley rats over a period of 4 weeks caused a slight, but significant reduction in weight gain. gamma-Butyrolactone has been tested for genotoxicity in several short-term tests, and discordant results were obtained. A positive response in some of the in vitro assays (sister chromatid exchange, chromosome aberration, and cell transformation) seems to be dependent on addition of an exogenous metabolism system. gamma-Butyrolactone was negative in the UDS, bacterial mutagenicity tests, tests with yeast (mitotic crossing over, mitotic gene conversion, mitotic aneuploidy), and in vivo tests (Drosophila recessive lethals, micronucleus test in mice, and abnormal spermatozoa). gamma-Butyrolactone, given orally (500 - 1000 mg/kg/day) to male rats was shown to reduce gonadal development resulting in significant reduced testicular weights. Foetal weight was significant increased in female rats gavaged with 50, 125, and 250 mg/kg of y-butyrolactone on days 6 to 15 of pregnancy. No differences from unexposed animals in the corpora lutea, total implantations, ratio of dead to live foetuses, resorptions, and pre- and post-implantation losses were noted at doses up to 1000 mg/kg. Furthermore, there were no visceral or skeletal malformations due to gamma-butyrolactone exposure. Doses of 500 - 750 mg/kg given intraperitoneally blocked ovulation in Sprague-Dawley rats. A reduction in the number of rats ovulating was evident at 62.5 mg gamma-butyrolactone/kg. gamma-Butyrolactone was tested for carcinogenicity in mice by oral administration, subcutaneous injection or by skin application, and in rats by subcutaneous administration. All the tests were negative; however, several reports are inadequately documented. From a long-term oral study in rats and mice, there was no evidence of carcinogenic activity of gamma-butyrolactone in rats. There was equivocal evidence of carcinogenic activity of gamma-butyrolactone in male mice (the sensitivity of this part of the study was, however, reduced by a low survival of the high-dose group). There was no evidence of carcinogenic activity of gamma-butyrolactone to female mice. Thus, there is no evidence of carcinogenic effect of gamma-butyrolactone in animals and no data from humans. The critical effects for gamma-butyrolactone appears to be a weak narcotic effect, a moderate, acute oral toxicity, and eye irritation. An effect of gamma-butyrolactone reproduction can not be excluded. [R33] NTXV: *LD50 MOUSE IV 880 MG/KG; [R30] *LD50 MOUSE IP 880 MG/KG; [R30] *LD50 MOUSE ORAL 1260 MG/KG; [R30] *LD50 Rat oral 17.2 ml/kg; [R14] *LD50 Rat oral 1540 mg/kg; [R15] *LD50 Rat ip 1000 mg/kg; [R15] *LD50 Mouse oral 1720 mg/kg; [R15] *LD50 Mouse ip 1100 mg/kg; [R15] *LD50 Mouse oral 9.0 ml/kg; [R34] NTP: *... Toxicology and carcinogenesis studies were conducted by administering Y-butyrolactone (greater than 97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex, 5 days/week for ... 2 years. 2 Year Studies: The doses admin to groups of 50 animals per sex were 0, 112, and 225 mg of y-butyrolactone per kg of body weight for male rats; O, 225, and 450 mg/kg for female rats; and 0, 262, and 525 mg/kg for male and female mice. Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of y-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats given 225 or 450 mg/kg in corn oil. There was equivocal evidence of carcinogenic activity of y-butyrolactone in male B6C3F1 mice based on marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia in the low-dose group. The sensitivity of the study in male mice to detect a carcinogenic effect was reduced by the low survival of the high dose group associated with f1ghting. There was no evidence of carcinogenic activity of Y-butyrolactone in female B6C3F1 mice given 262 or 525 mg/kg in corn oil. [R32] TCAT: ?gamma-Butyrolactone (CAS # 96-48-0) was evaluated for acute inhalation toxicity in Sprague-Dawley rats (5/sex) exposed under dynamic conditions to a mean concentration of 5.1 (range, 4.8-5.3) mg/L in air for 4 hours. Eighty-three percent of particles measured 10 microns or less and ambient gamma-butyrolactone levels were tested 4 times during approximate 1-hour intervals. No control group was tested; quantitative evaluations were based on baseline data. No deaths occurred throughout treatment or 14-day post-exposure observation. Immediately following exposures, rats exhibited pharmacotoxic signs including prostration, lethargy, shallow breathing, limb disuse, and clear discharge from the nose. All animals were hyperactive on Day 2. By Day 7 and again at Day 14, no signs of toxicity remained, save progressive weight loss from Day 2 post-exposure. No treatment-related pathology was identified upon terminal necropsy. [R35] ?Clastogenic activity was evaluated in 3 cultures of RL1 rat liver cells per dose, exposed for 22 hours to gamma-butyrolactone at concentrations of 0, 62.5, 125.0, or 250.0 ug/ml of culture medium. Concentrations were chosen to be approximately 1/4, 1/2, and 1x the GI50 (concentration at which 50% growth inhibition is achieved). Both positive (7,12-dimethylbenzanthracene) and solvent (dimethylsulfoxide) controls were used. No metabolic activation system was used. Cell division was arrested, and at least 280 metaphases from each test concentration were examined. Neither chromosomal nor chromatid aberrations were significantly increased at any test concentration. The proportions of cells showing chromatid aberrations was 0.0%, 0.0%, 0.9%, and 1.1% at 0.0, 62.5, 125.0, and 250.0 ug/ml, respectively. No cells showed chromosomal aberrations. Although the positive control showed 4.6% of cells with chromatid aberrations, no chromosomal aberrations were induced. [R36] ADE: *GAMMA BUTYROLACTONE ... IS ... RAPIDLY HYDROLYSED TO GAMMA HYDROXYBUTYRIC ACID ... IN RATS, (1-(14)C)- OR (4-(14)C)-HYDROXYBUTYRATE GIVEN BY INHALATION IS EXCRETED AS (14)CO2; ABOUT 66% OF ACTIVITY WAS EXCRETED IN 6 HR AND ADDNL 10-20% WITHIN 18 HR. [R25] METB: *... AFTER IV ADMIN TO RATS IT IS CONVERTED RAPIDLY INTO GAMMA-HYDROXYBUTYRIC ACID WHICH CAUSES DEPRESSION OF CNS. IT IS ALSO RAPIDLY HYDROLYZED TO GAMMA-HYDROXYBUTYRIC ACID IN BLOOD AND LIVER. [R25] ACTN: *Reactivity of beta-propiolactone, beta-butyrolactone and gamma-butyrolactone with guanosine, RNA, DNA and 4-(p-nitrobenzyl)pyridine was studied. beta-Propiolactone was 50 to 100 times more reactive with all the nucleophiles than beta-butyrolactone whereas gamma-butyrolactone was completely inactive. The rate of alkylation by lactones was guanosine greater than RNA= denatured DNA greater than double-stranded DNA. The type of the adducts formed were characterized by fluorescence and ultraviolet spectroscopy. Similar alkylation products were formed by the two lactones. The main sites alkylated were N-1 at adenosine, N-3 at cytidine and N-7 at guanosine. The results suggest that the carcinogenic potency of the lactones correlates with their reactivity rather than with specificity of the adducts formed. [R37] *Gamma-butyrolactone in animal studies is rapidly converted to gamma hydroxybutyrate. This may account for the subsequent central nervous system depressant. Gamma-butyrolactone is an anesthetic that causes a selective increase in brain dopamine by antagonizing transmitter release from nerve terminal. It is also an endogenou brain metabolite that may be derived from glutamate through gamma-aminobutyrate. [R6] *The involvement of intranigral gamma-aminobutyric acid (GABA) receptors in the control of generalized non-convulsive epilepsy was investigated in the rat in 3 models of petit mal epilepsy induced by systemic administration of gamma-butyrolactone, pentylenetetrazol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridin 3-ol (THIP). Bilateral intranigral injection of muscimol (2 ng/0.2 uL/side), a gamma-aminobutyric acid receptor agonist, significantly reduced the duration of EEG-recorded spike-and-wave discharges induced by gamma-butyrolactone (100 and 200 mg/kg ip), pentylenetetrazol (20 mg/kg ip) and THIP (7.5 mg/kg ip). This treatment had no effect on the electroencephalographic discharges observed after injection of THIP (10 mg/kg ip). Bilateral injection of muscimol (2 and 4 ng/side) into the substantia nigra did not modify the latency of onset nor the duration of clonic seizures induced by pentylenetetrazol at the dose of 40 mg/kg ip. Bipolar depth electrode recording indicated that intranigral injection of muscimol did not alter nigral electroencephalographic activity. Autoradiography following intranigral injection of [3H]muscimol indicated a diffusion not exceeding 400 microns from the injection site. These results confirm that activation of gamma-aminobutyric acid receptors in the substantia nigra suppresses the occurrence of spike-and-wave discharges in animal models of generalized non-convulsive epilepsy. [R38] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Butyrolactones's production and use as an intermediate in the synthesis of many compounds, constituent in paint removers, in dyeing and printing, and as a nematocide and a stabilizer for chlorohydrocarbons and phosphorus-based pesticides may result in its release to the environment through various waste streams. Butyrolactone is also found naturally in chickpeas and in raw earth almonds. If released to air, a vapor pressure of 0.45 mm Hg at 25 deg C indicates butyrolactone will exist solely as a vapor in the ambient atmosphere. Vapor-phase butyrolactone will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 7 days. If released to soil, butyrolactone is expected to have very high mobility based upon an estimated Koc of 7. Volatilization from moist soil surfaces may occur based upon an estimated Henry's Law constant of 5.3X10-8 atm-cu m/mole. If released into water, butyrolactone is not expected to adsorb to suspended solids and sediment in water based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 3.2 suggests the potential for bioconcentration in aquatic organisms is low. Butyrolactone hydrolysis in neutral aqueous solutions proceeds slowly at room temperatures and more rapidly at acidic conditions and elevated temperatures. Under alkaline conditions, hydrolysis is rapid and irreversible. Occupational exposure to butyrolactone may occur through inhalation and dermal contact with this compound at workplaces where butyrolactone is produced or used. The general population may be exposed to butyrolactone by ingestion of some foods, ingestion of contaminated drinking water, and inhalation. (SRC) NATS: *Butyrolactone is found naturally in raw earth almonds(1) and in chickpeas(2). [R39] ARTS: *Butyrolactone's production and use as an intermediate in the synthesis of many compounds, constituent in paint removers, in dyeing and printing(1), and as a nematocide and a stabilizer for chlorohydrocarbons and phosphorus-based pesticidse(2) may result in its release to the environment through various waste streams(SRC). [R40] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 7(SRC), determined from a structure estimation method(2), indicates that butyrolactone is expected to have very high mobility in soil(SRC). Volatilization of butyrolactone from moist soil surfaces may occur(SRC) given an estimated Henry's Law constant of 5.3X10-8 atm-cu m/mole(3), using a fragment constant estimation method(3). Butyrolactone is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.45 mm Hg(4). [R41] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 7(SRC), determined from an estimation method(2), indicates that butyrolactone is not expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces may occur(3) based upon an estimated Henry's Law constant of 5.3X10-8 atm-cu m/mole(4), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 3.2(SRC), from its log Kow of -0.64(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. [R42] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), butyrolactone, which has a vapor pressure of 0.45 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase butyrolactone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7 days(SRC), calculated from its rate constant of 2X10-12 cu cm/molecule-sec at 25 deg C(3) determined using a structure estimation method(3). [R43] ABIO: *The rate constant for the vapor-phase reaction of butyrolactone with photochemically-produced hydroxyl radicals has been estimated as 2.3X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 7 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Butyrolactone hydrolysis in neutral aqueous solutions proceeds slowly at room temperatures and more rapidly at acidic conditions and elevated temperatures. Under alkaline conditions, hydrolysis is rapid and irreversible(4). [R44] BIOC: *An estimated BCF of 3.2(1) was calculated for butyrolactone, using a log Kow of -0.64(2) and a regression-derived equation(3). According to a classification scheme(4), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R45] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for butyrolactone can be estimated to be 7.1(SRC). According to a classification scheme(2), this estimated Koc value suggests that butyrolactone is expected to have very high mobility in soil. [R46] VWS: *The Henry's Law constant for butyrolactone is estimated as 5.3X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that butyrolactone may volatilize from water surfaces(2). Butyrolactone's Henry's Law constant(1) indicates that volatilization from moist soil surfaces will not occur(SRC). Butyrolactone is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 0.45 mm Hg(3). [R47] WATC: *Butyrolactone has been qualitatively identified in US drinking water supplies(1). [R48] FOOD: *Using a dry method, popcorn contained 22000 ug/kg of butyrolactone(1). Found 0.4% butyrolactone in raw earth almonds and this concentration remained even after 60 minutes of roasting the almonds(2). Butyrolactone has been identified as a constituent of coffee aroma(3), as a volatile flavor component of roasted filberts(4), and as a volatile component of chickpeas(5). [R49] RTEX: *NIOSH (NOES Survey 1981-83) has statistically estimated that 25,089 workers are potentially exposed to butyrolactone in the USA(1). Printer's inks contain solvents of which all are lost to the environment and of which butyrolactone is found at a concentration of 12.7%(2). Occupational exposure to butyrolactone may occur through inhalation and dermal contact with this compound at workplaces where butyrolactone is produced or used. The general population may be exposed to butyrolactone by ingestion of foods in which it occurs naturally, by drinking contaminated water, or by inhalation(SRC). [R50] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *gamma-Butyrolactone is exempted from the requirement of a tolerance when used as a solvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R51] FIFR: *gamma-Butyrolactone is exempted from the requirement of a tolerance when used as a solvent in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R51] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *GAS CHROMATOGRAPHY IN BIOLOGICAL TISSUES. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of gamma-Butyrolactone in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 406 (1992) NIH Publication No. 92-3137 SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 262 R2: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 74th ed. Boca Raton, Fl: CRC Press Inc., 1993-1994.,p. V1 212 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 192 R5: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 500 R6: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1103 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V17 1075 R8: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-171 R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-170 R10: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R11: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 9 R12: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-185 R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R14: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 243 R15: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 545 R16: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-24 R17: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 94 R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 377 (1999) R19: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 193 R20: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 938 R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 234 (1976) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 235 (1976) R23: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 190 R24: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1825 R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 236 R26: BORBELY AA ET AL; SLEEP, PROC EUR CONGR, 1ST 355 (1973) R27: MACMILLAN V; BRAIN RES 146 (1): 177 (1978) R28: WOLFSON LI ET AL; J NEUROCHEM 29 (5): 777 (1977) R29: DAVIES JA; PSYCHOPHARMACOL (BERLIN) 60 (1): 67 (1978) R30: HAMPEL H, HAPKE HJ; ARCH INT PHARMACODYN THER 171 (2): 306 (1968) R31: Kronevi T et al; Pharmacol and Toxicol 62 (1): 57-8 (1988) R32: Toxicology and Carcinogenesis Studies of y-Butyrolactone in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 406 (1992) NIH Publication No. 92-3137 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R33: Larsen J, S derlund E; Nord 29: 25-48 (1993) R34: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 4693 R35: Monsanto Co; Acute Toxicity of Gamma-Butyrolactone Administered by Inhalation to Sprague-Dawley Male and Female Rats (Final Report); 05/02/86; EPA Document No. 88-920000078; Fiche No. OTS0534527 R36: Shell Chem. Co.; The Activity of 27 Coded Compounds in the RL1 Chromosome Assay (1989), EPA Document No. 86-890000950, Fiche No. OTS0520388 R37: Hemminki K; Chem Biol Interact 34 (3): 323-31 (1981) R38: Depaulis A et al; Brain Res 498 (1): 64-72 (1989) R39: (1) Cantalejo MJ; J Agric Food Chem 45: 1853-1860 (1997) (2) Rembold H et al; J Agric Food Chem 37: 659 (1989) R40: (1) Hort EV et al; Kirk-Othmer Encycl Chem Technol, 4th Ed, NY, NY: Wiley-Interscience 1: 212 (1991) (2) Mercker HJ, Kieczka H; Ullmann's Encycl Indust Tech, 5th ed. Gerhartz W et al, eds. VCH Publ A4: 495-8 (1985) R41: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Daubert TE et al; Physical and Thermodynamic Properties of Pure Chemicals NY, NY: Hemisphere Pub Corp (1989) R42: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 9 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) R43: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R44: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (4) Hort EV et al; Kirk-Othmer Encycl Chem Technol, 4th Ed, NY, NY: Wiley-Interscience 1: 212 (1991) R45: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. nn (1995) (1989) (3) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (4) Franke C et al; Chemosphere 29: 1501-14 (1994) R46: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R47: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE et al; Physical and Thermodynamic Properties of Pure Chemicals NY, NY: Hemisphere Pub Corp (1989) R48: (1) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 3 Batch-Liquid Extraction and Analysis of 10 Liter Sample and Analysis of Conc. From Small Vol of Drinking Water, USEPA-600/1-84-020 (NTIS PB85-128247), Columbus, OH (1984) R49: (1) Buttery RG et al; J Agric Food Chem 45: 837-843 (1997) (2) Cantalejo MJ; J Agric Food Chem 45: 1853-1860 (1997) (3) Aeschbacher HU et al; Food Chem Toxic 27: 227-32 (1989) (4) Kinlin TE et al; Food Chem 20: 1021-8 (1972) (5) Rembold H et al; J Agric Food Chem 37: 659 (1989) R50: (1) NIOSH; National Occupational Exposure Survey (NOES) (1989) (2) Rastogi SC; Arch Environ Contam Toxicol 20: 543-547 (1991) R51: 40 CFR 180.1001(d) (7/1/98) RS: 40 Record 295 of 1119 in HSDB (through 2003/06) AN: 4296 UD: 200302 RD: Reviewed by SRP on 9/15/2001 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged to retrieve the Arsenic Compounds record, which has additional information on toxicity and environmental fate of arsenic ions and compounds. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 3-NITRO-4-HYDROXYPHENYLARSONIC-ACID- SY: *3N4HPA-; *AKLOMIX-3-; *ARSONIC ACID, (4-HYDROXY-3-NITROPHENYL)-; *BENZENEARSONIC-ACID,-4-HYDROXY-3-NITRO-; *4-HYDROXY-3-NITROBENZENEARSONIC-ACID-; *4-HYDROXY-3-NITROPHENYLARSONIC-ACID-; *NCI-C56508-; *3-NITRO-; *3-NITRO-10-; *3-NITRO-20-; *3-NITRO-50-; *3-NITRO-80-; *NITRO-ACID-100-PER-CENT-; *2-NITRO-1-HYDROXYBENZENE-4-ARSONIC-ACID-; *3-NITRO-4-HYDROXYBENZENEARSONIC-ACID-; *NITROPHENOLARSONIC-ACID-; *NSC-2101-; *REN-O-SAL-; *RISTAT-; *ROXARSONE- RN: 121-19-7 RELT: 6994 [ARSENIC COMPOUNDS]; 509 [ARSENIC; 7440-38-2] MF: *C6-H6-AS-N-O6 HAZN: D004; A waste containing arsenic may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. /Arsenic/ MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF SODIUM P-HYDROXYPHENYLARSONATE WITH A MIXTURE OF NITRIC AND SULFURIC ACIDS [R1] *Prepd by treating sodium p-hydroxyphenylarsonate with mixt of nitric and sulfuric acids @ 0 deg C: Benda, Bertheim, Ber 44, 3446 (1911); German patent 224,953, CA 5, 156 (1911). [R2] *Phenol + arsenic trioxide (reaction/nitration) [R3] OMIN: *FORMS MONO-, DI-, AND TRISODIUM SALTS. [R4] *APPLICATIONS (VET): DO NOT ADMIN TO DUCKS, GEESE, LAYING HENS, OR DOGS. ... ITS SAFE USE DEMANDS ADEQUATE WATER INTAKE AND NO OTHER SOURCES OF ARSENIC. INCOORDINATION, RICKETS-LIKE APPEARANCE, AND PARALYSIS CAN OCCUR UNDER THESE CONDITIONS. [R5] *APPLICATIONS (VET): FOR MANY YEARS IT HAD BEEN OTC FAVORITE FOR WATER MEDICATION OF CECAL COCCIDIOSIS IN CHICKS. OF VALUE IN IMPROVING PIGMENTATION IN CHICKENS AND TURKEYS. [R5] *IS RECOMMENDED @ 25-50 PPM FOR CHICKENS AND TURKEYS AND @ 25-75 PPM FOR SWINE FOR IMPROVING WT GAIN AND FEED EFFICIENCY. IT IS ALSO RECOMMENDED @ LEVEL OF 200 PPM FOR 5 DAYS FOR CONTROL OF SWINE DYSENTERY. [R6] USE: *ANTIPROTOZOAN AGENT (GROWTH PROMOTER) FOR POULTRY; ANTIBACTERIAL AGENT (GROWTH PROMOTER) FOR POULTRY; REAGENT FOR ZIRCONIUM [R1] *Formerly in mfr arsphenamines; as reagent for zirconium; vet: control of enteric infections; to improve growth and feed efficiency [R2] *Antiprotozoan agent for poultry [R7] *Growth stimulant (pigs, poultry) [R3] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] U.S. IMPORTS: *(1979) 1.92X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Tufts of pale-yellow needles or rhombohedral plates from water [R2]; *Pale-yellow crystals [R8] MW: *263.03 [R2] SOL: *Slightly sol in cold water; freely sol in methanol, ethanol, acetic acid, acetone, alkalies; sol in about 30 parts boiling water; insol in ether, ethyl acetate; sparingly sol in dil mineral acids. [R2] OCPP: *Puffs up and deflagrates on heating [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of /nitrogen oxides and arsenic/. [R9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *ACUTE CLINICAL SIGNS AFTER EXPOSURE TO HIGH LEVELS OF PHENYLARSONIC COMPD INCL INCOORDINATION, INABILITY TO CONTROL BODY AND LIMB MOVEMENTS, AND ATAXIA. AFTER FEW DAYS, SWINE AND POULTRY MAY BECOME PARALYZED. ERYTHEMA IN WHITE SKINNED ANIMALS. [R10, 291] *ARSANILIC ACID AND ITS SODIUM SALT MAY PRODUCE BLINDNESS BUT THIS EFFECT RARELY IS SEEN WITH 3-NITRO-4-HYDROXYPHENYLARSONIC ACID. ORAL ADMIN. [R10, 291] *MAJOR LESIONS NOTED IN SWINE AND POULTRY FROM ORGANIC ARSENICALS ARE NECROSIS OF MYELIN-SUPPORTING CELLS, DEGENERATION OF MYELIN SHEATHS AND AXONS, AND GLIOSIS OF AFFECTED TRACTS. ORAL ADMIN. [R10, 292] *... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of roxarsone for male F344/N rats, as indicated by a marginally incr incidence of adenomas of the exocrine pancreas. There was no evidence of carcinogenic activity for female F344/N rats fed diets containing 50 or 100 ppm roxarsone for 2 yr. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 100 or 200 ppm roxarsone for 2 yr. [R11] *Localized lung hemorrhage was observed in dogs after a single oral dose of 14.2 mg/kg roxarsone in a capsule ... . [R12, p. 105 (2000)] *Hematuria and congested kidneys have been observed in dogs after acute exposure, and tubular degeneration and necrosis have been noted in rats (but not mice) give repeated oral doses of roxarsone (up to 20 mg/kg/day As) ... . However, no renal injury was observed in rats and mice chronically exposed to roxarsone at lower doses (2-10 mg/kg/day As) .. . [R12, p. 111 (2000)] *Several studies in pigs indicate that repeated oral doses of roxarsone (0.87-5.8 mg As/kg/day for 1 mo) can cause significant neurotoxicity ... . The main signs were muscle tremors, partial paralysis, and seizures. Histological exam of the spinal cord revealed a time-dependent degeneration of myeline and axons ... . [R12, p. 116 (2000)] NTXV: *LD50 Rat oral 81 mg/kg; [R9] *LD50 Mouse oral 244 mg/kg; [R9] *LD50 Chicken oral 110 mg/kg; [R9] *LD50 Chicken ip 34 mg/kg; [R9] *LD50 Turkey oral 61 mg/kg; [R9] *LD50 Holtzman rat oral (in water) 44 mg/kg. /From table/; [R12, p. 88 (2000)] *LD50 B6C3F1 female mouse oral (in oil) 69.5 mg/kg. /From table/; [R12, p. 89 (2000)] *LD50 Mongrel dog oral 14.2 mg/kg. /From table/; [R12, p. 89 (2000)] NTP: *... Toxicology and carcinogenesis studies were conducted by admin roxarsone (greater than 99.4% pure) in feed to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 years. ... Dietary concn of roxarsone selected for the 2 yr studies were 0, 50, or 100 ppm for rats and 0, 100, or 200 ppm for mice. Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of roxarsone for male F344/N rats, as indicated by a marginally incr incidence of adenomas of the exocrine pancreas. There was no evidence of carcinogenic activity for female F344/N rats fed diets containing 50 or 100 ppm roxarsone for 2 yr. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 100 or 200 ppm roxarsone for 2 yr. [R11] ADE: *WHEN GIVEN ORALLY, CONSIDERABLE PERCENTAGE IS EXCRETED IN FECES, INDICATING THAT PHENYLARSONIC COMPD ARE POORLY ABSORBED BY INTESTINAL TRACT. THAT PROP WHICH IS ABSORBED, HOWEVER IS APPARENTLY EXCRETED RAPIDLY BY THE KIDNEYS. [R10, 291] *4-WK-OLD CHICKENS FED DAILY RATION WITH 50 PPM ROXARSONE AND SACRIFICIED. PPM ARSENIC IN CONTROLS: KIDNEY 0.05, LIVER 0.08, MUSCLE 0.02, SKIN 0.02; ARSENIC IN TREATED ANIMALS KILLED ON 70TH DAY: KIDNEY 0.64, LIVER 1.26, MUSCLE 0.04, SKIN 0.05. [R10, 293] *IT IS ESTABLISHED THAT ARSANILIC ACID AND ACETYLARSONIC ACID ARE EXCRETED UNCHANGED BY CHICKENS. SIMILAR RESULTS WERE OBTAINED IN STUDIES WITH 3-NITRO-4-HYDROXYBENZENEARSONIC ACID IN CHICKENS. [R10, 291] *There are only a few reports on the excretion of arsenic in the milk of animals. The arsenic level in cow's milk did not incr with the blood concn when the cows were fed methylarsonic acid or dimethylarsinic acid... . However, the milk arsenic levels did incr when cows were fed arsanilic acid or 3-nitro-4-hydroxyphenylarsonic acid (1.6-3.2 mg As/kg bw)... . [R13] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Tolerances for total residues of combined arsenic (calculated as As) in food are established as follows: (a) In edible tissues and in eggs of chickens and turkeys: 0.5 ppm in uncooked muscle tissue; 2 ppm in uncooked edible by-products; and 0.5 ppm in eggs. (b) In edible tissues of swine: 2 ppm in uncooked liver and kidney; 0.5 ppm in uncooked muscle tissue and by-products other than liver and kidney. /Arsenic/ [R14] OSHA: *Permissible Exposure Limit: Table Z-1 8-Hr Time Weighted Avg: 0.5 mg/cu m. /Arsenic, organic cmpd (as As)/ [R15] ASTD: *Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. 3-Nitro-4-hydroxyphenylarsonic acid is included on this list. [R16] *(a) The owner or operator of an existing glass melting furnace subject to the provisions of this subpart shall comply with either paragraph (a)(1) or (a)(2) of this section ... (1) Uncontrolled total arsenic emissions from the glass melting furnace shall be less than 2.5 Mg (2.7 ton) per year, or ... (2) Total arsenic emissions from glass melting furnace shall be conveyed to a control device and reduced by at least 85%. /Total arsenic/ [R17] *(b) The owner or operator of a new or modified glass melting furnace subject to the provisions of this subpart shall comply with either paragraph (b)(1) or (b)(2) of this section ... (1) Uncontrolled total arsenic emissions from the glass melting furnace shall be less than 0.4 Mg (0.44 ton) per year, or ... (2) Total arsenic emissions from glass melting furnace shall be conveyed to a control device and reduced by at least 85%. /Total arsenic/ [R18] *The owner or operator of each copper converter subject to the provisions of this subpart shall reduce inorganic arsenic emissions to the atmosphere by meeting the following design, equipment, work practice, and operational requirements: (1) Install, operate, and maintain a secondary hood system on each copper converter. Each secondary hood system shall consist of a hood enclosure, air curtain fan(s), exhaust system fan(s), and ductwork that conveys the captured emission to a control device ... (2) Optimize the capture of secondary inorganic arsenic emission by operating the copper converter and secondary hood systems at all times ... . /Inorganic arsenic/ [R19] WSTD: FEDERAL DRINKING WATER STANDARDS: +0.05 mg/l /Arsenic/ [R20] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Arsenic and cmpd/ [R21] +For the maximum protection of human health from the potential carcinogenic effects due to exposure of arsenic through ingestion of contaminated water and contaminated aquatic organisms, the ambient water concn should be zero based on the nonthreshold assumption for this chemical. However, zero level may not be attainable at the present time. Therefore, the levels which may result in incremental increase of cancer risk over the lifetime are estimated at 1X10-5, 1X10-6, and 1X10-7. The corresponding criteria are 22 ng/l, 2.2 ng/l, and .22 ng/l, respectively .... For consumption of aquatic organisms only, excluding consumption of water, the levels are 175 ng/ml, 17.5 ng/l, and 1.75 ng/l, respectively. /Arsenic/ [R22] +D004; A solid waste containing arsenic may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R23] FIFR: *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam, dry chemical, or carbon dioxide. /Arsenical cmpd, liquid, NOS/ [R24, 104] *If material involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam, dry chemical, or carbon dioxide. /Arsenical cmpd, solid, NOS/ [R24, 105] FDA: *Roxarsone tablets. ... Conditions of use: growing chickens and growing turkeys ... Indications for use: For increased rate of weight gain, improved feed efficiency, and improved pigmentation. ... Conditions of use: swine ... Indication for use: As an aid in the treatment of swine dysentery (hemorrhagic enteritis or bloody scours). [R25] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SPECTROPHOTOMETRY IN FEEDS; ANALYTICAL CHEMISTRY IN FEEDS. [R26] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/ATSDR; Toxicological Profile for Arsenic (Update) TP-92/02 (1993) DHHS/NTP; Toxicology and Carcinogenesis Studies of Roxarsone in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 345 (1989) NIH Publication No. 89-2800 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1424 R3: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 637 R4: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1072 R5: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 515 R6: CLINICAL AND DIAGNOSTIC VETERINARY TOXICOLOGY, 2ND ED, WB BUCK, P 290 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V3 (1992) 501 R8: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 598 R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1887 R10: CLINICAL AND DIAGNOSTIC VETERINARY TOXICOLOGY, 2ND ED, WB BUCK ET AL, P R11: Toxicology and Carcinogenesis Studies of Roxarsone in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 345 (1989) NIH Publication No. 89-2800 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R12: DHHS/ATSDR; Toxicological Profile for Arsenic R13: WHO; Environ Health Criteria 18: Arsenic p.74 (1981) R14: 21 CFR 556.60 (4/1/2001) R15: 29 CFR 1910.1000 (7/1/2001) R16: Clean Air Act as amended in 1990, Sect. 112 (b) (1) Public Law 101-549 Nov. 15, 1990 R17: 40 CFR 61.162(a) (7/1/2001) R18: 40 CFR 61.162(b) (7/1/2001) R19: 40 CFR 61.172(b) (7/1/2001) R20: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R21: 40 CFR 401.15 (7/1/2001) R22: USEPA; Quality Criteria for Water 1986: Arsenic: Human Health Criteria (May 1, 1986) EPA 440/5-86-001 R23: 40 CFR 261.24 (7/1/2001) R24: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. R25: 21 CFR 520.2088 (4/1/2000) R26: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/713 42.153 RS: 16 Record 296 of 1119 in HSDB (through 2003/06) AN: 4299 UD: 200302 RD: Reviewed by SRP on 1/23/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIMELLITIC-ANHYDRIDE- SY: *ANHYDRIDE-ETHOMID-HT-POLYMER-; *ANHYDRO-TRIMELLIC-ACID-; *ANHYDROTRIMELLITIC-ACID-; *1,2,4-BENZENETRICARBOXYLIC-ACID-ANHYDRIDE-; *1,2,4-BENZENETRICARBOXYLIC-ACID,-CYCLIC-1,2-ANHYDRIDE-; *1,2,4-BENZENETRICARBOXYLIC-ANHYDRIDE-; *4-CARBOXYPHTHALIC-ANHYDRIDE-; *1,3-DIHYDRO-1,3-DIOXO-5-ISOBENZOFURANCARBOXYLIC-ACID-; *1,3-DIOXO-5-PHTHALANCARBOXYLIC-ACID-; *5-ISOBENZOFURANCARBOXYLIC-ACID,-1,3-DIHYDRO-1,3-DIOXO-; *5-PHTHALANACARBOXYLIC-ACID,-1,3-DIOXO-; *TMA-; *TMAN-; *TRIMELLIC-ACID-ANHYDRIDE-; *TRIMELLIC-ACID-1,2-ANHYDRIDE-; *TRIMELLITIC-ACID-ANHYDRIDE-; *TRIMELLITIC-ACID-1,2-ANHYDRIDE-; *TRIMELLITIC-ACID-CYCLIC-1,2-ANHYDRIDE- RN: 552-30-7 MF: *C9-H4-O5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY OXIDATION OF PSEUDOCUMENE TO TRIMELLITIC ACID FOLLOWED BY DEHYDRATION [R1] *PREPARED BY SUBLIMING TRIMELLITIC ACID ABOVE ITS MP; BY HEATING CRUDE TRIMELLITIC ACID WITH V2O5. [R2] *3-Xylene is carbonylated with carbon monoxide in the presence of boron trifluoride and hydrogen fluoride to form 2,4-dimethylbenzaldehyde. 2,4-Dimethylbenzaldehyde is decomplexed from the acids, purified, and oxidized to trimellitic acid. Trimellitic acid is subjected to normal dehydration and purification steps to obtain high quality trimellitic anhydride. [R3, p. V18 1030] MFS: *Amoco Corporation, Hq, 200 East Randolph Drive, Chicago, IL 60601, (312) 856-6111; Production site: Joliet, IL 60434-0941 [R4] USE: *IN PREPN OF RESINS, ADHESIVES, POLYMERS, DYES, PRINTING INKS [R2] *PLASTICIZER FOR POLYVINYLCHLORIDE; HIGH-TEMP PLASTICS; WIRE INSULATION; GASKETS; AUTOMOTIVE UPHOLSTERY [R5] *CHEM INT FOR TRIMELLITATE PLASTICIZERS, POLY(AMIDE-IMIDE) AND POLY(ESTER-IMIDE) RESINS, ALKYD COATING RESINS (PRIMARILY WATER-BASED), DYES AND PRINTING INKS [R1] *The largest amount of trimellitic anhydride is used to make plasticizers for poly(vinyl chloride). ... The anhydride is an important curing agent in the production of epoxy resins. Polyester resins of trimellitic anhydride are widely used as paint resins for water-based and solvent-based coatings. [R6] *Heat-cured epoxy resin curing agent; unsaturated polyester resin comonomer. [R7] *Used as a chemical intermediate for the synthesis of: alkyd resins, water-soluble; 1,4-dichlorophthalazine-6-carboxyl chloride; poly(amide-imide); tri-n-alkyl(C7-C9) trimellitate; tri-n-alkyl(C8-C10) trimellitate; triallyl trimellitate; tri-(2-ethylhexyl) trimellitate; triisooctyl trimellitate; trinonyl trimellitate. [R7] PRIE: U.S. PRODUCTION: *(1977) MORE THAN 2.27X10+6 G-AS ACID CHLORIDE [R1] *(1979) MORE THAN 2.27X10+6 G-AS ACID CHLORIDE [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS [R2]; +Colorless solid. [R8] BP: *390 deg C [R3, p. V18 1026] MP: *161-163.5 DEG C [R2] MW: *192.13 [R9] CTP: *569 deg C at 2968 kPa [R3, p. V18 1026] HTV: *106.2 kJ/mol at 200 deg C; 100.4 kJ/mol at 300 deg C [R3, p. V18 1026] SOL: *SOL AT 25 DEG C: 0.002 G/100 G CARBON TETRACHLORIDE [R2]; *SOL AT 25 DEG C: 0.06 G/100 G PETROLEUM ETHER [R2]; *SOL AT 25 DEG C: 0.4 G/100 G MIXED XYLENES [R2]; *SOL AT 25 DEG C: 15.5 G/100 G DIMETHYL FORMAMIDE [R2]; *SOL AT 25 DEG C: 49.6 G/100 G ACETONE [R2]; *SOL AT 25 DEG C: 21.6 G/100 G ETHYL ACETATE [R2]; *36.5 g/100 g 2-butanone at 25 deg C; 38.4 g/100 g cyclohexanone at 25 deg C; 0.06 g/100 g mineral spirits at 25 deg C [R3, p. V18 1026] SPEC: +IR: 2:919G (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R10]; +NMR: 7:51C (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R10]; +MASS: 1060 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R10] VAPD: *Relative vapor density = 6.6 (air =1) [R3, p. V18 1026] VAP: *1.16X10-9 mm Hg at 25 deg C /from experimentally derived coefficients/ [R11] OCPP: *Boiling point: 240-245 deg C at 14 mm Hg [R2] *Vapor pressure: 4X10-6 mm Hg [R12] *Hydrolyzes in aqueous environment to trimellitic acid. [R13] *Hydrolysis rate constant of trimellitic anhydride at 25 deg C using dimethylacetamide as a solvent: 1X10-4 L/mole-sec [R14] *Trimellitic anhydride reacts with acetic acid and water, and is hygroscopic. [R6] *Boiling point 240-245 deg C at 14 mm Hg [R3, p. V18 1026] *Trimellitic anhydride reacts with atmospheric moisture, even at room temperature, to revert to the acid. [R3, p. V18 1026] *Specific heat 1966 J/ kg K at 204 deg C [R3, p. V18 1026] *Heat of fusion 29.04 kJ/mol at 25 deg C [R3, p. V18 1026] *Vapor pressure of liquid trimellitic anhydride = 2.25 mm Hg at 200 deg C [R3, p. V18 1026] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SERI: *Upper airway irritation (sneezing). [R15] EQUP: *SUGGESTED PROCEDURES FOR MINIMIZING OCCUPATIONAL EXPOSURE TO TRIMELLITIC ANHYDRIDE ARE DISCUSSED. MEASURES FOR HANDLING TRIMELLITIC ANHYDRIDE, SUCH AS PROTECTIVE CLOTHING AND SAFETY GOGGLES ARE DESCRIBED. [R16] +Wear appropriate personal protective clothing to prevent skin contact. [R8] +Wear appropriate eye protection to prevent eye contact. [R8] OPRM: +Contact lenses should not be worn when working with this chemical. [R8] +The worker should immediately wash the skin when it becomes contaminated. [R8] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R8] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R8] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: *... A practical approach that has significantly reduced the incidence of immune disease due to trimellitic anhydride is periodic surveillance of exposed worker populations with serum antibody studies and questionnaires. Workers who have significant levels of antibody, report significant symptoms on questionnaires, or both, are further evaluated to determine the clinical diagnosis and whether any interventions are needed. [R17, 989] HTOX: *When mucosal surfaces are exposed to trimellitic anhydride (as by inhalation) the trimellitic anhydride reacts with autologous proteins in the mucus to form trimellityl-protein complexes. These trimellityl-protein complexes are antigenic, and some workers produce antibodies against them. After re-exposure to trimellitic anhydride and formation of trimellityl complexes, an immune hypersensitivity reaction occurs at the site of exposure. The nature of the hypersensitivity reaction depends on the type of antibody and degree of exposure, ... . Three different immune-mediated syndromes have been described in workers exposed to trimellitic anhydride. ... Asthma-rhinitis is a syndrome of immediate onset asthma and allergic rhinitis that is mediated by immunoglobulin E antibody against trimellityl-protein. Late respiratory systemic syndrome is a hypersensitivity pneumonitis-like syndrome followed by a flulike syndrome 4 to 12 hours after exposure. Pulmonary disease anemia syndrome is characterized by dyspnea, hemoptysis, pulmonary infiltrates, restrictive lung function, and hemolytic anemia. It generally develops only in workers exposed to high levels of trimellitic anhydride fumes, such as those released when resins containing trimellitic anhydride are applied to hot metal. [R17, 988] *PULMONARY EDEMA FROM SPRAYING EPOXY RESINS ON HEATED PIPES HAS BEEN ATTRIBUTED TO FUMES OR DUST OF TMA... WORKERS EXPOSED @ CONCN AVG 1.5 and 2.8 MG/CU M OF TMA SUFFERED EYE, SKIN, NASAL AND THROAT IRRITATION, SHORTNESS OF BREATH, WHEEZING, HEARTBURN, NAUSEA AND HEADACHE. [R12] *A SPECTRUM OF RESP SYMPTOMS ARE DESCRIBED IN WORKERS EXPOSED TO TRIMELLITIC ANHYDRIDE. [R18] *OCCUPATIONAL INHALATION OF TMA APPARENTLY RESULTS IN AN ANTIBODY RESPONSE WITH SPECIFICITY FOR UNIQUE NEW ANTIGENIC DETERMINANTS WHICH ARISE FROM THE COUPLING OF TMA WITH AUTOLOGOUS RESP TRACT PROTEINS. [R19] *WORKERS WITH TRIMELLITIC ANHYDRIDE (TMA) PULMONARY DISEASE-ANEMIA SYNDROME HAD ANTIBODY CONCN COMPARABLE TO THOSE OF WORKERS WITH OTHER TYPES OF IMMUNOLOGIC TMA RESP DISEASE, BUT COWORKERS, WHO APPARENTLY WERE ALSO EXPOSED TO TMA FUMES, COULD NOT BE DISTINGUISHED CLEARLY BY THESE IMMUNOASSAYS. THE INHALATION OF TMA APPEARS TO BE SIGNIFICANT STIMULUS OF SYSTEMIC IMMUNE RESPONSE. [R20] *SPECIFICITY OF ANTIBODIES INDUCED BY INHALATION OF TRIMELLITIC ANHYDRIDE IN MAN WAS STUDIED. [R21] *2 YOUNG MEN EXPOSED @ WORK TO EXPOXY RESIN POWDER CONTAINING TRIMELLITIC ANHYDRIDE HAD HEMOLYTIC ANEMIA AND REPEATED HEMOPTYSES. [R22] *A case of building-related health complaints among 14 full-time employees and 1 part-time employee was investigated with respect to the relationship among frequency of symptoms (involving eyes, nose, sinuses, throat, lung, skeletomuscular system, and central nervous system) and antibodies to human serum albumin conjugates of trimellitic anhydride (TMA). Antibody testing was done by the ELISA procedure. Employees noted the presence or absence of symptoms by filling in questionnaires. Anti-TMA isotypes were found in 12 of 14 full-time employees and were nondetectable in one part-time employee. Anti-TMA-human serum albumin determinations were done in 7 subjects. IgE titers were neg in 3 subjects and pos in 4. IgG antibodies to TMA-human serum albumin were not detected in four subjects and were pos in 3. [R23] *A 50 year old man worked in an area where trimellitic anhydride is flaked and bagged. After working approximately 10 months in this area he developed pruritus of the eyes and nose, lacrimation, nasal congestion, wheeze, and cough almost immediately upon entering the bagging area. This necessitated his being relocated to another area. Results of skin tests and tests in vitro for immunoglobulin E (IgE) against trimellityl-human serum albumin (TM-HSA) were both positive. Even now, when the wind blows trimellitic anhydride from the bagging area to his new work area he develops some symptoms. [R17, 988] *A 35 year old woman worked in an area of a plant where epoxy resin coatings containing trimellitic anhydride were heated. After working approximately 6 months she noticed that she would develop cough, fever, fatigue, malaise, arthralgia, and dyspnea at night. By morning she felt better, took aspirin, and went to work. During a 2 week vacation she had no symptoms. Total titer of antibody against trimellityl-human serum albumin (TM-HSA) was high. When she returned to work the symptoms returned, necessitating her removal from trimellitic anhydride exposure. She no longer has symptoms. [R17, 988] *A 19 year old man worked at a plant that coated hot pipes with a material containing trimellitic anhydride. After 6 weeks he developed cough, dyspnea, fever, malaise, anorexia, nausea, vomiting, and hemoptysis. He had bilateral pulmonary infiltrates and hemolytic anemia. Lung biopsy showed extensive intraalveolar hemorrhage, granular pneumocyte hyperplasia, and interstitial edema. The total antibody titer against trimellityl-human serum albumin (TM-HSA) was very high. The patient received corticosteroids and transfusions in the hospital. Three weeks later all symptoms resolved; he had no further exposure and no symptoms. [R17, 988] *Inhaled trimellic acid anhydride fumes may conjugate with serum albumin or erythrocytes leading to subsequent exposure to a type I (trimellitic acid anhydride-asthma), type II (pulmonary disease-anemia), or type III (hypersensitivity pneumonitis) hypersensitivity reaction. Topical exposure to trimellitic acid anhydride may lead to type IV hypersensitivity reactions resulting in contact dermatitis. Also, reexposure by inhalation may lead to a cell-mediated immune response in the lung, which plays a role in the pathology seen in conjunction with types II and III pulmonary disease. [R24] *Trimellitic anhydride is irritating to the respiratory tract, eyes, and skin. Irritation of the upper respiratory tract can occur immediately upon occupational exposure to a moderately heavy concentration of trimellitic anhydride and is generally accompanied by coughing, sneezing, and nasal discharge. In susceptible workers, repeated inhalation of trimellitic anhydride dust or fume over a period of weeks to years can cause an allergic reaction. [R25] *... 14 Workers employed in the synthesis of trimellitic anhydride. There appear to be three distinct syndromes. The first is rhinitis/asthma which can develop after exposure to trimellitic anhydride for weeks or months. The second syndrome has been termed trimellitic-flu," wherein a sensitization period of weeks or months is required. Wheezing, coughing, and dyspnea begin 4 to 8 hours after the end of a work shift and intensify at 12 hours, usually accompanied by malaise, chills, fever, and muscle and joint pain. These effects seem to be associated with relatively high levels of exposure to trimellitic anhydride. The third syndrome is primarily of an acute irritant nature, typified by sneezing and occasional nose-bleed, cough, dyspnea, and, rarely, wheezing. The symptoms abate after 8 hours. [R25] *Evidence indicates that the allergy results when trimellitic anhydride particles enter the lung and attach or bind to a protein in the blood forming an antigen. Susceptible individuals form one or more types of antibodies specific to the trimellitic anhydride-antigen. When re-exposure to trimellitic anhydride occurs, the antibodies react with the trimellitic anhydride-antigen and an allergic (or sensitization) reaction occurs. [R25] *The results of a 6-year clinical and immunologic study of three groups of workers after trimellitic anhydride control modifications had been instituted at the plant; 29% of workers originally studied developed immunologically induced respiratory disease following repeated exposures to trimellitic anhydride. Subsequent to the original evaluation, trimellitic anhydride exposure control was instituted that resulted in an observable decrease in clinical symptoms and reductions in antibody levels against trimellitic anhydride conjugated to human serum albumin. Workplace air trimellitic anhydride concentrations after institution of exposure controls ranged between < 0.01 and 0.18 mg/cu m in different types of operations; workers exposed at these concentrations did not develop trimellitic anhydride-induced immunologic syndromes or increased specific antibody levels. [R25] *Upper airway irritation (sneezing), bronchoconstriction (sensitization, asthma), pulmonary edema. [R15] NTOX: *INTRABRONCHIAL TRIMELLITIC ANHYDRIDE /ADMIN TO RHESUS MONKEYS/ CAUSED SYSTEMIC AND PULMONARY IMMUNE RESPONSE AGAINST TRIMELLITIC ANHYDRIDE-PROTEIN AND TRIMELLITIC ANHYDRIDE-ERYTHROCYTES. [R26] *Trimellitic anhydride was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Trimellitic anhydride was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 10.000 mg/plate. At this dose, slight clearing of the background bacterial lawn was observed. [R27] *Guinea pigs injected intradermally with a single dose of 0.1 ml of the respiratory sensitizer, trimellitic anhydride, developed high titer antigen specific homocytotropic (immunoglobulin G1 and immunoglobulin E) antibodies. On day 22 after exposure the sensitized animals were then exposed to free trimellitic anhydride or trimellitic anhydride conjugated with protein (guinea pig serum albumin) in inhalation chambers for 15 min with either free trimellitic anhydride (target concentrations of 10 to 50 mg/cu m) or one of three concentrations of trimellitic anhydride with guinea pig serum albumin (0.9 to 2.8 mg/cu m). Only animals pretreated with trimellitic anhydride showed changes in respiration rate which indicated bronchoconstriction. Exposure to the higher concentration of trimellitic anhydride elicited the most severe response in 7 of 8 animals. Similar results were obtained with a second experiment, with atomization of the substances causing slightly more reactions than nebulization. [R28] *Limited animal data are available relative to cutaneous and ocular irritation; a single application of trimellitic anhydride (probably 50% aqueous suspension) to rat skin produced dermatitis, and 100 mg trimellitic anhydride powder applied to rabbit eyes resulted in corneal corrosive lesions and chemical burns of the conjunctiva that did not reverse over 7 days. [R17, 989] NTXV: *LD50 Rat dermal 5.6 g/kg; [R17, 989] TCAT: ?Trimellitic anhydride (CAS# 552-30-7) was evaluated for teratogenicity. The test substance was administered via inhalation to pregnant rats during gestation days 6-15 for 6/hrs/day at a concentration of 500 ug/cu m. Half of the animals were sacrificed for pathological evaluation and the other half were given a single "challenge" exposure of 500 ug/cu m for 6-hours. Pathological findings concluded there was a significant increased in the number of hemorrhagic lung foci and an increased level of trimellitic anhydride (TMA) specific serum antibody in all rats. There were no significant treatment-related differences in litter size, litter viability, variations, or malformations. [R29] ?Trimellitic anhydride (CAS# 552-30-7) was evaluated for teratogenicity. The test substance was administered via inhalation to pregnant guinea pigs during gestation days 6-26 for 6/hrs/day at a concentration of 500 ug/cu m. Half of the animals were sacrificed for pathological evaluation and the other half were given a single "challenge" exposure of 500 ug/cu m for 6-hours. Pathological findings concluded there was a significant increase in the number of hemorrhagic lung foci and an increased level of trimellitic anhydride (TMA) specific serum antibody in 2/7 guinea pigs. There were no significant differences in litter size, litter viability, variations, or malformations. [R29] ?Subchronic inhalation toxicity and sensitization potential were evaluated in groups of 15 rats (sex and strain not reported) exposed to a single 6-hour dose of trimellitic anhydride at a level of 0, 0.3, 1.6, 7.7, 23.9 or 135 micrograms/cu m with a second 6-hour dose to 500 micrograms/cu m 3 weeks later. The method of atmosphere generation and compound concentration measurement was not reported. There were no mortalities or clinical observations reported. Necropsy revealed a dose-dependent increase in hemorrhagic foci in the lungs of treated animals. [R30] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Trimellitic anhydride may be released into the environment in various waste streams from its production and use in the preparation of resins, adhesives, polymers, dyes and printing inks. If released to the atmosphere, trimellitic anhydride is expected to exist almost entirely in the particulate phase in the ambient atmosphere based on an extrapolated vapor pressure of 1.2X10-9 mm Hg at 25 deg C. Particulate-phase trimellitic anhydride may be physically removed from the air by wet and dry deposition. If released to soil, trimellitic anhydride is expected to hydrolyze in moist soils. Adsorption and volatilization from soil are not expected to be important because of hydrolysis. If released into water, trimellitic anhydride is expected to hydrolyze rapidly. Volatilization, adsorption to suspended solids and sediments, biodegradation, and bioconcentration are not expected to be important in aquatic systems because of hydrolysis. Occupational exposure to trimellitic anhydride is expected to occur through inhalation of dust particles or fumes or dermal contact with this compound at workplaces where it is produced or used. (SRC) ARTS: *Trimellitic anhydride's production and use in the preparation of resins, adhesives, polymers, dyes, and printing inks(1) and in automotive upholstery, wire insulation, and gaskets(2) may result in its release to the environment through various waste streams(SRC). [R31] FATE: *TERRESTRIAL FATE: Based upon the hydrolysis of trimellitic anhydride in aqueous environments(1), trimellitic anhydride is expected to hydrolyze in moist soils(SRC). Volatilization from soil surfaces and adsorption to soil are not expected to be important processes because of hydrolysis(SRC). [R32] *AQUATIC FATE: Trimellitic anhydride hydrolyzes rapidly in aqueous environments(1). Volatilization from water surfaces, adsorption to suspended solids and sediments, biodegradation, and bioconcentration are not expected to be important in aquatic systems because of hydrolysis(SRC). [R32] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trimellitic anhydride, which has an extrapolated vapor pressure of 1.2X10-9 mm Hg at 25 deg C(2,SRC), will exist almost entirely in the particulate phase in the ambient atmosphere. Particulate-phase trimellitic anhydride may be physically removed from the air by wet and dry deposition(SRC). [R33] BIOD: *Based upon the hydrolysis of trimellitic anhydride in aqueous environments(1), biodegradation is not expected to be a primary removal process in aquatic systems(SRC). A biodegradation study based on BOD measurements, using an activated sludge seed, and an initial chemical concentration of 100 ppm, reported an 89-101% degree of biodegradation over a period of four weeks(2); however this was probably for trimellitic acid since the anhydride hydrolyzes so rapidly(SRC). [R34] ABIO: *Trimellitic anhydride is not expected to undergo direct photolysis in the environment due to the lack of functional groups to absorb light in the environmental spectrum(SRC). Trimellitic anhydride hydrolyzes in aqueous environments to trimellitic acid(1). Trimellitic anhydride reacts with atmospheric moisture, even at room temperature, to revert to the acid(2). Phthalic anhydride has an observed first-order hydrolysis rate constant of 4.29X10-4 /sec in a 60:40 (v/v) dioxan:water solution at 25 deg C(3), this corresponds to half-life of about 27 minutes(SRC). An aqueous half-life of 1.5 minutes was calculated for phthalic anhydride(SRC) from an observed first-order hydrolysis rate constant of 7.9X10-3 /sec in aqueous solution at 25 deg C(4). Based on the structural similarities to phthalic anhydride, trimellitic anhydride is expected to have a similar hydrolysis rate(SRC). [R35] BIOC: *Based upon the hydrolysis of trimellitic anhydride in aqueous environments(1), bioconcentration is not expected to be an important fate process(SRC). [R32] KOC: *Based upon the hydrolysis of trimellitic anhydride in aqueous environments(1), adsorption to soil and leaching are not expected to be important processes(SRC). [R32] VWS: *Based upon the hydrolysis of trimellitic anhydride in aqueous environments(1), volatilization from water and soil surfaces are not expected to be important processes(SRC). [R32] RTEX: *POTENTIAL OCCUPATIONAL EXPOSURES, TOXICITY, AND PROCEDURES FOR REDUCING EMPLOYEE EXPOSURE TO TRIMELLITIC ANHYDRIDE ARE DISCUSSED. [R36] *Occupational exposure to trimellitic anhydride may occur through inhalation of dusts or fumes or dermal contact with this compound at workplaces where it is produced or used. (SRC) BODY: *Personal breathing zone samples from two workers in a 55-gallon drum manufacturing plant had an 8 hour exposure to trimellitic anhydride of 3.6 mg/cu-m and 1.7 mg/cu-m(1). [R32] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 0.005 ppm (0.04 mg/cu m). [R8] TLV: +Ceiling Limit: 0.04 mg/cu m. [R37] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GAS CHROMATOGRAPHIC DETERMINATION OF TRIMELLITIC ANHYDRIDE (TMA) VIA DIRECT CONVERSION OF TMA TO TRIMETHYL 1,2,4-BENZENETRICARBOXYLATE IN AIR SAMPLES. [R38] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1653 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R4: SRI. 1996 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1996. 957 R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1180 R6: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA5 255 R7: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 917 R8: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 318 R9: U.S. Department of Health, Education and Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances. 1978 edition. Washington, DC: U.S. Government Printing Office, 1979.187 R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 200 R11: Yaws CL; Handbook of Vapor Pressure, Volume 3 - C8 to C28 Compounds, Gulf Publishing Co; Houston, TX p 383 (1994) R12: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values, 4th ed., 1980. Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.415 R13: Letz G et al; Am J Ind Med 12: 407-17 (1987) R14: Kreuz JA et al; J Polymer Sci A15: 2961-3 (1967) R15: Kimbrough, R.D., P. Grandjean, D.D. Rutstein. Clinical Effects of Environmental Chemicals. New York, NY: Hemisphere Publishing Corp., 1989. 30 R16: NATL INST OCCUP SAF HEALTH, CDC, CINCINNATI, OHIO; SUGGESTED PROCEDURES FOR MINIMIZING EMPLOYEE EXPOSURE TO TRIMELLITIC ANHYDRIDE (TMA); DHEW (NIOSH) PUBL (US) 78-121: 5 (1978) R17: Rom, W.N. (ed.). Environmental and Occupational Medicine. 2nd ed. Boston, MA: Little, Brown and Company, 1992. R18: ZEISS ET AL; J ALLERGY CLIN IMMUNOL 60 (2): 96 (1977) R19: ZEISS ET AL; INT ARCH ALLERGY APPL IMMUNOL 61(4) 380 (1980) R20: PATTERSON ET AL; AM REV RESPIR DIS 120 (6): 1259 (1979) R21: ZEISS ET AL; INT ARCH ALLERGY APPL IMMUNOL 61 (4): 380 (1980) R22: AHMAD ET AL; LANCET 2(8138) 328 (1979) R23: Thrasher JD et al; Am J Ind Med 15 (2): 187-95 (1989) R24: Klaassen, C.D., M.O. Amdur, Doull J. (eds.). Casarett and Doull's Toxicology. The Basic Science of Poisons. 5th ed. New York, NY: McGraw-Hill, 1995.,p. 391-2 R25: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1643 R26: PATTERSON ET AL; CLIN IMMUNOL IMMUNOPATHOL 15 (3): 357 (1980) R27: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R28: Botham PA et al; Toxicol Lett 47 (1): 25-39 (1989) R29: AMOCO CORPORATION; Material Safety Data Sheet on Trimellitic Anhydride and Teratological Evaluation Study of Trimellitic Anhydride in Rats and Guinea Pigs with Attachments and Cover Letter Dated 07/19/88; 05/01/88; EPA Doc. No. 89-880000210; Fiche No. OTS0513426-1 R30: Amoco Corporation; Letter from Amoco Corp to USEPA Stating that the Results of the Report Study on Trimellitic Anhydride will be Forwarded Later, (1988), EPA Doc No 89-880000086, Fiche No OTS0513426 R31: (1) Budavari S; The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 12th ed. Whitehouse Station, NJ: Merck and Co Inc p.58 (1996) (2) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY, NY: Van Nostrand Reinhold Co p.359 (1993) R32: (1) Letz G et al; Am J Ind Med 12: 407-17 (1987) R33: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yaws CL; Handbook of Vapor Pressure, Vol. 3, C8 to C28 Compounds. Houston, TX: Gulf Publishing Co., p. 383 (1994) R34: (1) Letz G et al; Am J Ind Med 12: 407-17 (1987) (2) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R35: (1) Letz G et al; Am J Ind Med 12: 407-17 (1987) (2) Kroschwitz JI ed; Kirk-Othmer Encycl Chem Technol 4th ed. NY, NY: John Wiley and Sons 18: 1025-33 (1996) (3) Bunton CA et al; J Chem Soc 1965: 6174-80 (1965) (4) Hawkins MD; J Chem Soc Perkin Trans 2 75: 282-4 (1975) R36: THOMAS AW ET AL; J AM IND HYG ASSOC 39(5) A17-18, A20 (1978) R37: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. 2002.59 R38: PALASSIS J ET AL; AIR SAMPLING AND ANALYSIS OF TRIMELLITIC ANHYDRIDE; AM IND HYG ASSOC J 42(11) 785 (1981) RS: 30 Record 297 of 1119 in HSDB (through 2003/06) AN: 4305 UD: 200205 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: OCHRATOXIN-A- SY: *ALANINE, N-((5-CHLORO-8-HYDROXY-3-METHYL-1-OXO-7-ISOCHROMANYL)CARBONYL)-3-PHENYL-, (-)-; *(R)-N-[(5-CHLORO-3,4-DIHYDRO-8-HYDROXY-3-METHYL-1-OXO-1 H-2-BENZOPYRAN-7-YL)CARBONYL]PHENYLALANIN; *L-PHENYLALANINE, N-((5-CHLORO-3,4-DIHYDRO-8-HYDROXY-3-METHYL-1-OXO-1H-2-BENZOPYRAN-7-YL)CARBONYL)-, (R)- RN: 303-47-9 RELT: 3438 [OCHRATOXIN B]; 3439 [OCHRATOXIN C] MF: *C20-H18-Cl-N-O6 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *TOXIC METABOLITE FROM SPECIES OF ASPERGILLUS AND OTHER MOLDS [R1] *An efficient method for obtaining small amounts of ochratoxin A from fermented wheat has been reported ... . [R2] *Ochratoxin A is produced by inoculating strains of the fungi that produce this compound on autoclaved grains and oilseed. [R3, (1993)] MFS: *Ochratoxin is not produced commercially. [R2] OMIN: *WHILE OCHRATOXIN A IS NOT PRODUCED COMMERCIALLY, IT IS OFFERED FOR SALE IN SMALL QUANTITIES BY ONE FIRM IN ISRAEL. [R4] *OCHRATOXIN A...MAJOR OCHRATOXIN COMPONENT. ... OCHRATOXIN B... LESS TOXIC DECHLORO DERIV OF OCHRATOXIN A. ... OCHRATOXIN C... EQUALLY TOXIC AMORPHOUS ETHYL ESTER OF OCHRATOXIN A... [R5] *PURITY CAN BE DETERMINED BY VISUAL EXAM OF FLUORESCENCE ON CHROMATOGRAMS UNDER UV LIGHT; MICROGRAM QUANTITIES CAN BE DISCERNED UNDER OPTIMUM CONDITIONS. [R6] *AS THESE MOLDS OCCUR WIDELY, SOME TOXINS HAVE BEEN FOUND AS NATURAL CONTAMINANTS ON CORN, PEANUTS, STORAGE GRAINS, COTTONSEED, AND OTHER DECAYING VEGETATION. /OCHRATOXINS/ [R5] *In 1990, a WHO/FAO Joint Expert Committee on Food Additives reviewed the literature on ochratoxin A and recommended a provisional tolerable weekly intake of 112 ng/kg bw ... . [R7] USE: *RESEARCH CHEMICAL [R1] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN US [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM XYLENE [R5] MP: *169 DEG C [R5] MW: *403.8 OWPC: *log Kow = 4.74 [R8] SOL: *AS ACID, SOL IN ORG SOLVENTS (EG. CHLORFORM, ETHANOL, METHANOL) [R4]; *The sodium salt is soluble in water. [R9, p. 310 (1994)] SPEC: *MAX ABSORPTION: 215 NM (E= 910, 1%, 1 CM), 333 NM (E= 150, 1%, 1 CM) @ PH 4; MAX ABSORPTION (ETHANOL): 333 NM (E= 150, 1%, 1 CM), 380 NM (E= 189, 1%, 1 CM) ABOVE PH 9; IN ETHANOL, FLUORESCENCE EMISSION MAX 465 NM [R10]; *SPECIFIC OPTICAL ROTATION: -118 DEG (CHLOROFORM, 1.1%); MAX ABSORPTION (ETHANOL): 215 NM (E= 34,000), 333 NM (E= 2400); MAX ABSORPTION: 213 NM (E= 36,800), 332 NM (E= 6400) [R5] OCPP: *FLUORESCENT IN UV LIGHT, EMITTING GREEN AND BLUE FLUORESCENCE IN ACID AND ALKALINE SOLN [R4] *SODIUM SALT IS SOL IN WATER /OCHRATOXIN A SODIUM SALT/ [R6] *MP: FREQUENTLY REPORTED AS 90 DEG C FROM BENZENE (ONE MOLE OF BENZENE OF CRYSTALLIZATION) [R5] *Partially degraded under normal cooking conditions ... Solutions of ochratoxin A are completely degraded by treatment with an excess of sodium hypochlorite soln ... . [R3, (1993)] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *The lactone group is saponified by alkalis [R2] DCMP: *When heated to decomp, the toxin emits toxic fumes of chlorine and NOx. [R9, p. 310 (1994)] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R11, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R11, 1979.11] SSL: *UNSTABLE TO LIGHT AND AIR; FADING AND DEGRADATION UPON BRIEF EXPOSURE TO LIGHT, ESP @ HIGH HUMIDITY [R6] *ETHANOL SOLN ARE STABLE FOR MORE THAN YR IF KEPT IN DARK AND COLD [R6] *FAIRLY STABLE IN CEREAL PRODUCTS UP TO 35% SURVIVES AUTOCLAVING FOR UP TO 3 HR [R6] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R11, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R11, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R11, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R11, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R11, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R11, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R11, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of ochratoxin A. There is sufficient evidence in experimental animals for the carcinogenicity of ochratoxin A. Overall evaluation: Ochratoxin A is possibly carcinogenic to humans (Group 2B). [R12] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R11, 1979.23] HTOX: *EVIDENCE IS PROVIDED TO SUPPORT HYPOTHESIS THAT OCHRATOXIN A MIGHT BE DISEASE DETERMINANT OF BALKAN (ENDEMIC) NEPHROPATHY. [R13] *Incidence of and mortality from urothelial urinary tract tumors have been correlated with the geographical distribution of Balkan endemic nephropathy in Bulgaria and Yugoslavia. A relatively high frequency of contamination of cereals and bread with ochratoxin A has been reported in an area of Yugoslavia where Balkan endemic nephropathy is present. [R9, p. 310 (1994)] *The occurrence of BEN /Balkan endemic nephropathy/ and of cancer in the populations of 27 villages in Vratza district, Bulgaria, an endemic area for BEN, during the period 1965-74 has been considered in several publications ... The villages were divided into two groups: 15 villages with a high incidence of BEN (populations, 147,321) and 12 villages with a low incidence (population, 120,687). Age-adjusted incidence rates for BEN in the high-incidence villages were reported to be 506 and 315 per 100,000 in women and men, respectively; and the rates for urinary system (kidney and urinary tract) tumors, 104 and 89 per 100,000, respectively. In the same villages, BEN accounted for about 30% of total mortality in women and for over 40% in men, and urinary tract tumors were the most frequent neoplasms recorded, with incidences far higher than those in other parts of Bulgaria and in Europe. A ratio of 28.3 (95% confidence interval [CI], 16.5-47.4) was computed by comparing the urinary tract tumor incidence among the patients with BEN with that in the population of the low-incidence villages. The rate ratio was particularly high for tumors of the renal pelvis and ureter (88.9: 50.0-143.2) among patients with BEN. People in the high-incidence villages not affected by BEN also had increased rates of urinary system tumors in general (4.3; 1.6-11.3) and of tumors of the renal pelvis and ureter in particular (6.7; 2.3-16.4). (The Working Group noted that the statistical analysis was not adequately described and that bias due to better tumor ascertainment among cases of BEN could not be ruled out.) [R14] *A survey of the geographical distribution of BEN /Balkan endemic nephropathy/ and of the incidence of tumors of the urinary system was carried out in central Serbia ... during the period 1970-74. The population of the region was divided into two groups, each of approx 2.6 million people, on the basis of the topographical distribution of BEN. The incidence of urinary system tumors was determined in each of the study groups from cancer registry data. The annual incidence of cancer of the renal pelvis and ureter overall was 39 per 100,000 in counties affected by BEN and 15 per 100,000 in the non-endemic counties, on the basis of 52 and 20 tumor cases, respectively. The incidence of tumors of the renal parenchyma was slightly higher in the endemic than the non-endemic area, but no difference in the incidence of urinary bladder cancer was seen between the two. It was indicated, however, that distinction of the two subpopulations according to endemic area was very crude. This may have led to an underestimate of the true differences in the incidences of urinary system tumors. [R14] *Using records of cases of urinary tract tumor collected over a period of 16 yr (1974-89) at the medical center of the County of Slavonski Brod in Croatia, Sostaric and Vukelic (1991) studied the distribution of these tumors in the areas of the County that were endemic for BEN (population, 10,094) and in the rest of the County (96,306). A total of 67 tumors were recorded in the endemic areas (estimated cumulative incidence, 0.664%) and 126 in the non-endemic area (0.131%). The difference in the recorded relative number of cases was highest for tumors of the renal pelvis (0.287 versus 0.021%) and ureter (0.089 versus 0.013%) and only moderate for bladder cancer (0.228 versus 0.089%). In general, more cases were seen among women that among men in the endemic area. Tumors of the renal parenchyma were not mentioned in this survey. [R14] *In a study carried out in Bulgaria, Petkova-Bocharova and Castegnaro (1985) examined contamination by ochratoxin A of 65 samples of beans, maize or wheat flour from households in an area endemic for BEN /Balkan endemic nephropathy/ and with a high incidence of urinary system tumors and in 65 samples from households in non-endemic areas. None of the samples was visibly mouldy. Samples from high-risk areas were collected from families in which cases of BEN and/or urinary tract tumors had been diagnosed ('affected' households), while samples from nonendemic areas were taken at random. All samples of home-produced beans and maize were taken during February and March 1982 from the 1981 harvest; wheat flour samples were purchased from local shops, which were supplied from central state stocks. Although there was no significant difference between endemic and non-endemic areas in the mean values of ochratoxin A in contaminated samples of beans (range; 25-27 ug/kg in endemic area, 25-50 ug/kg in non-endemic area) and maize (25-35 and 10-25 ug/kg, respectively), a larger proportion of samples from the endemic area were contaminated: [16.7% of beans (95% CI, 4.8-33.9) and 27.3% of maize (11.2-47.4) in endemic areas, and 7.1% of beans and 9.0% of maize in non-endemic areas]. None of the samples of wheat flour analyzed contained measurable amounts of ochratoxin A. In an extension of this survey, Petkova-Bocharova et al. (1991) collected 524 samples of home-produced, home-stored beans and maize from the harvests of 1984-86 and 1989-90. Of these, 298 were taken from 'affected' and 'non-affected' households in the endemic areas of Bulgaria and 226 from non-affected households in non-endemic areas. Overall, significantly more samples from endemic areas than from control areas were contaminated with ochratoxin A (54 versus 12%). [R15] *A study in Bulgaria of the association between BEN /Balkan endemic nephropathy/ and/or urinary system tumors and ochratoxin A content in blood samples taken from 187 subjects living in endemic villages and 125 individuals in non-endemic villages /was reported/. Among 61 patients with BEN and/or urinary system tumors, 14.8% had levels of 1-2 ng/ml and 11.5% had more than 2 ng/ml ochratoxin A in their blood. This proportion was significantly higher than that in a control group of 63 healthy individuals from unaffected families in the endemic villages (7.9 and 3.2%, respectively). The percentage of positive blood samples in the control group was similar to that measured among a random sample of healthy individuals from non-endemic villages (6.2 and 1.5% respectively). Intermediate proportions of positive blood samples were found among healthy individuals from families of patients with either endemic nephropathy and/or a urinary system tumor (9.5 and 6.3%, respectively). (The Working Group noted that no attempt was made by the authors to present separate results for the subgroup of urinary system tumors). Blood samples from 576 people living inside and outside the endemic areas in Bulgaria during 1984, 1986, 1989 and 1990 /were collected/. Overall, a significantly larger proportion of the blood samples from 105 patients with urinary tract tumors and/or BEN (26.7%) contained ochratoxin A than those from 116 healthy people living in villages in the endemic area (12.1%), or from 119 healthy people from non-affected villages in the endemic area (10.9%) or from 125 healthy people living in non-endemic areas of Bulgaria (7.2%); however, the proportion among the patients was not significantly higher than that among 111 healthy relatives of patients with urinary tract tumors and/or BEN living in affected villages (16.2%). [R15] *Mysterious deaths of archaeologists after opening Egyptian tombs have been suspected, but never proved, to be secondary to inhalation of mycotoxin. A case of acute renal failure (ARF) due to inhalation of ochratoxin A /was observed/. /It was/ produced by a mould of the species Aspergillus ochraceus. After working 8 hr in a granary closed for several months, a farmer and his wife suffered respiratory distress; the woman developed non-oliguric ARF and biopsy revealed tubulonecrosis. A strain of Aspergillus ochraceus producing ochratoxin was isolated from the wheat. [R16] *The Penicillium spp and Aspergillus spp associated with 83 samples of foods from Bulgarian households, most of which had a history of Balkan endemic nephropathy, have been defined. Penicillium aurantiogriseum was the most common species of this genus and all isolates tested were acutely nephrotoxic in the rat. Penicillium verrucosum, a species normally associated with ochratoxin A biosynthesis in Europe, was rare and all isolates failed to elaborate ochratoxin A in pure culture. Several isolates of Penicillium citrinum produced abundant citrinin when molding moist shredded wheat, but such had no acute effect on rat kidneys. One apparently unique Penicillium isolate, best assigned to Penicillium solitum, produced ochratoxin A in pure culture. Aspergilli of the flavus and glaucus groups were common but Aspergillus ochraceus was relatively uncommon and no isolate produced more than a trace of ochratoxin A in pure cultures. Beans, maize and other cereals generally contained no detectable ochratoxin A (< 1 ug/kg). One apparently sound maize sample containing 153 ug ochratoxin A/kg did not contain Aspergillus ochraceus but two ochartoxinogenic fungi were isolated, which best conformed to Penicillium viridicatum, and Penicillium griseofulvum. Seeds containing these fungi accounted for most of the ochratoxin A in the whole sample. The natural occurrence of ochratoxin A in food in the region is ascribed mainly to fungi which did not fit the current concept of ochratoxinogenic penicillia, but the low general natural incidence both of ochratoxinogenic fungi and also of ochratoxin A in the present study hardly supports the popular putative epidemiological /relationship/ of ochratoxin A in the highly mosaic distribution of Balkan endemic nephropathy. [R17] *Ochratoxin A (OA) is a mycotoxin produced by certain species of storage fungi of the Penicillium and Aspergillus genera. Toxin production by these fungi is influenced by species and even strain of fungi, time and temperature of incubation, moisture content of substrate and type of substrate. OA has been shown to occur in various grains, cereals and other plant products, animal feeds, meats and human tissues in countries throughout the world. Of interest is the discovery of OA in a high percentage of blood from humans in Germany. OA is acutely toxic to many different animals and in addition to being a nephrotoxin it is a hepatotoxin, a teratogen, a very potent carcinogen, possibly a mutagen and an immunosuppressive agent. OA is rapidly absorbed throughout the entire gastrointestinal tract and distributes itself in the body as a two compartment open model and has a particular high affinity for serum albumin. OA is hydrolyzed by the intestinal microflora into nontoxic compounds (7-carboxy-5-chloro-8-hydroxy-3,4-dihydro-3R-methylisocoumarin (0 alpha) and phenylalanine). It is excreted as either OA, hydroxylated OA or O alpha in both the urine and feces. OA appears to exert its toxic effect by promoting an increased level of lipid peroxidation by inhibition of an amino acylation reaction and possibly by conversion into metabolites that are capable of binding DNA. These in turn cause other secondary effects associated with OA. It would appear that this compound presents a true potential hazard for humans as its occurrence is wide spread and it is highly carcinogenic. [R18] *... The effect of ochratoxin A (OA) on both early and late events during activation of human T lymphocytes /has been investigated/. As early activation parameters ... both charges in intracellular Ca2+ levels and the activity of protein kinase C following the triggering process /were measured/. Results demonstrate that concn of OA that inhibit overall activation had no effect neither on the absolute levels nor on the duration of the Ca2+ response. Furthermore, PKC activity as measured by phosphorylation of two specific cytosolic substrate proteins, was also unaffected. However, when the cells were prestimulated for 48 hr to measure effects on late events in the activation cascade, addition of graded concentrations of ochratoxin A down to 6.4 microns completely inhibited the DNA synthesis. This shows that ochratoxin A is able to block DNA synthesis efficiently even if the activation process has been running for 18 hr in advance. To investigate whether the inhibitory effect on DNA synthesis could be ascribed to inhibition of protein synthesis, /experiments were/ carried out ... to measure protein synthesis both in resting and activated T-cells. In resting T-cells, protein synthesis was nearly abrogated by 12.5 uM ochratoxin A, but only minor effects were observed in stimulated cells. The low impact of ochratoxin A on protein synthesis in activated cells may indicate that other mechanisms than just a general inhibition of protein synthesis are operating. [R19] NTOX: *EACH ANIMAL OF GROUP OF 10 MALE AND 10 FEMALE CBA MICE RECEIVED SC INJECTIONS OF 10 UG...SUSPENDED IN 0.1 ML ARACHIS OIL TWICE WEEKLY FOR 36 WK; NO TUMORS WERE OBSERVED IN 7 SURVIVORS AFTER 81 WK. [R20] *OCHRATOXIN A WAS ADMIN /ORALLY/ @ DOSES OF 100 OR 300 UG/RAT ON 5 DAYS/WK FOR 50 WK TO GROUPS OF 5 MALE AND 5 FEMALE WISTAR RATS; ONLY TUMOR OBSERVED WAS HAMARTOMA OF KIDNEY IN 1/10 RATS RECEIVING HIGHEST DOSE. [R20] *10 FEMALE WISTAR RATS RECEIVED SC INJECTIONS...SUSPENDED IN SUNFLOWER-SEED OIL, @ DOSE OF 2.5 MG/KG BODY WT, INJECTED TWICE WEEKLY FOR 18 WK. AT WK 73 and 87, 2/10 ANIMALS HAD DEVELOPED LOCAL FIBROSARCOMAS; 2/10 CONTROLS INJECTED WITH SUNFLOWER-SEED OIL ALONE ALSO DEVELOPED LOCAL FIBROSARCOMAS @ WK 87. [R21] *NO TUMORS WERE OBSERVED WHEN OCHRATOXIN WAS FED /TO RAINBOW TROUT/ ALONE @ CONCN OF 16, 32, OR 64 UG/KG OF DIET FOR 8 MO. [R20] *OCHRATOXIN A-INDUCED NEPHROPATHY HAS BEEN DEMONSTRATED EXPTL IN PIGS, DOGS, RATS, CHICKENS AND TROUT, AND OCHRATOXIN A IS THOUGHT TO BE CAUSATIVE AGENT IN FIELD CASES OF NEPHROPATHY IN PIGS AND POULTRY. [R21] *PREGNANT MICE GIVEN SINGLE DOSE OF 5 MG/KG BODY WT...BY INTRAPERITONEAL INJECTION ON DAYS 7, 8, 9, 10, 11 OR 12 OF GESTATION SHOWED INCR PRENATAL MORTALITY, DECR FETAL WT AND FETAL MALFORMATIONS. [R21] *OCHRATOXIN A (0.2-3.0 MG/KG, ORAL 14 DAYS) ANOREXIA, WT LOSS, EMESIS, TENESMUS, BLOOD-STAINED MUCUS FROM RECTUM, RECTAL TEMP 107 DEG F, TONSILLITIS, DEHYDRATION AND PROSTRATION IN MALE BEAGLE DOGS. RENAL TOXICITY, GRANULAR CASTS AND NECROTIC RENAL EPITHELIUM. [R22] *SUBLETHAL DOSES OF OCHRATOXIN A GIVEN TO 1-DAY-OLD BABCOCK B-300 COCKERELS PRODUCED SUPPRESSION OF HEMATOPOIESIS IN BONE MARROW AND DEPLETION OF LYMPHOID ELEMENTS FROM SPLEEN AND BURSA OF FABRICIUS. [R23] *SUBLETHAL DOSES OF OCHRATOXIN A GIVEN TO 1-DAY-OLD BABCOCK B-300 COCKERELS RESULTED IN GROWTH SUPPRESSION PROPORTIONAL TO DOSE. VISCERAL GOUT WAS MAJOR FINDING. EXAM REVEALED ACUTE NEPHRITIS, HEPATIC DEGENERATION OR FOCAL NECROSIS, AND ENTERITIS. [R23] *DAILY ADMIN OF OCHRATOXIN A TO RATS IN DOSES OF 0.75 and 2.0 MG/KG CAUSED WEIGHT LOSS, PERSISTENT URINARY HYPOOSMOLALITY AND EXCESSIVE GLUCOSE AND PROTEIN EXCRETION. [R24] *OCHRATOXIN A FED TO BROILER CHICKS FROM HATCHING UNTIL 3 WK OF AGE. SIZE OF LIVER, SPLEEN, PANCREAS, AND PROVENTRICULUS WAS SIGNIFICANTLY ALTERED. LIVER LIPID LEVELS WERE SIGNIFICANTLY DECR. [R25] *OCHRATOXIN A ADMIN TO RATS IN SINGLE OR MULTIPLE ORAL DOSES. SEVERE CATARRHAL OR EROSIVE ENTERITIS OF DUODENUM AND JEJUNUM WITHIN 4 HR OF DOSAGE. AFTER SEVERAL DAILY DOSES, MASSIVE ACIDOPHILIC DEGENERATION, NECROSIS AND DESQUAMATION OF EPITHELIUM IN PROXIMAL TUBULES. [R26] *OCHRATOXIN A ADMIN TO RATS IN SINGLE OR MULTIPLE DOSES. NECROSIS OF CELLS IN GERMINAL CENTERS OF SPLEEN AND LYMPH NODES INDICATED SENSITIVITY OF LYMPHATIC TISSUES. HEPATOTOXICITY LIMITED TO DEPLETION OF HEPATIC GLYCOGEN. [R26] *IN KIDNEY CORTEX SLICES FROM RATS FED OCHRATOXIN A (2 MG/KG/DAY) FOR 2 DAYS, GLUCONEOGENESIS FROM PYRUVATE WAS DECR BY 26%, AND RENAL PHOSPHOENOLPYRUVATE CARBOXYKINASE ACTIVITY LOWERED BY APPROX 55%. [R27] *EFFECTS OF CONTINUOUS FEEDING OF GRADED LEVELS (0.5, 1.0, 2.0 PPM) OCHRATOXIN A FOR 8 WK TO MALE AND FEMALE BROILER CHICKENS INVESTIGATED. DEPRESSION IN BODY WT GAIN OBSERVED IN ALL GROUPS. [R28] *PURE CRYSTALLINE OCHRATOXIN A DISSOLVED IN 0.1 N NAHCO3 WAS GIVEN TO CD-1 MICE @ DOSE LEVELS FROM 3 TO 5 MG/KG BY GAVAGE ON 8TH-10TH OR 15TH-17TH DAYS OF PREGNANCY. WIDESPREAD CEREBRAL NECROSIS IN FETUSES FROM LATTER TREATMENT. [R29] *GRADED DOSES OF OCHRATOXIN A (FROM ASPERGILLUS OCHRACEUS) IN DIET (0-8.0 UG/G) OF BROILER CHICKENS INHIBITED ACTIVITY OF PROTEIN KINASE, INITIATOR ENZYME OF GLYCOGEN PHOSPHORYLASE SYSTEM, IN LIVERS @ ALL DOSES. [R30] *OCHRATOXIN A FED (0-8.0 UG/G) TO BROILER CHICKENS FROM 1 DAY-3 WK OF AGE. IT REDUCED LEUKOCYTE COUNTS AT ALL DOSES; LEUKOCYTOPENIA WAS CHARACTERIZED BY INCR IN CONCN OF HETEROPHILS AND DECR IN CONCN OF LYMPHOCYTES. NUMBER OF MONOCYTES DECR @ 2.0 UG/G AND ABOVE. [R31] *OCHRATOXIN A (0-8 UG/G) IN FEED OF TURKEY POULTS (HATCHING-3 WK OF AGE) RESULTED IN DECR GROWTH RATE, ENLARGED PROVENTRICULUS AND GIZZARD AND REGRESSED THYMUS @ 4 and 8 UG/G. MORTALITY INCR @ 8 MUG/G. LEUKOCYTOPENIA OBSERVED @ 4 and 8 UG/G. [R32] *ORAL ADMIN FOR 5 DAYS, 3 MO OR 2 YR. REDUCED ACTIVITY OF SEVERAL ENZYMES OCCURRED. [R33] *WISTAR RATS GIVEN 4 MG/KG OCHRATOXIN A BY GAVAGE DAILY OVER 4, 6, 8 OR 10 DAYS. DROP IN PLASMA FIBRINOGEN AND DECR IN FACTORS II, VII AND X, AND IN THROMBOCYTE AND MEGAKARYOCYTE COUNT. FALL IN VITAMIN K POOL CAUSES INDIRECT EFFECT SIMILAR TO COUMARIN. [R34] *OCHRATOXIN A IN PROPYLENE GLYCOL INJECTED INTO EMBRYONATING EGGS @ DOSES 0.0005-0.007 MG/EGG. AT DAY 8, SHORT AND TWISTED LIMBS AND NECK, MICROPHTHALMIA, EXENCEPHALY, EVERTED VISCERA, REDUCED BODY SIZE, VENTRICULAR SEPTAL DEFECTS, AORTIC STENOSIS AND DEFORMITY OBSERVED. [R35] *OCHRATOXIN A (5 MG/KG, IP, IN MICE) CAUSED DECR IN HEMOGLOBIN AND IN TOTAL COUNT OF RED BLOOD CELLS. AMONG WHITE BLOOD CELLS, INCR IN SMALL LYMPHOCYTES AND FALL IN COUNT OF NEUTROPHILS, BASOPHILS, AND MONOCYTES. CLOTTING TIME PROLONGED BY MORE THAN 6-FOLD. [R36] *OCHRATOXIN A TREATMENT IN RAT CAUSES DELAY IN SEXUAL MATURATION, VAGINAL OPENING AND FIRST ESTRUS. ALSO CAUSES REDUCTION IN WT OF OVARY, UTERUS AND PITUITARY. APPARENTLY CAUSE OF DELAYED SEXUAL MATURATION IS SUPPRESSED OVARIAN STEROIDOGENESIS. [R37] *ACTIVITIES OF ENZYMES DELTA5-3BETA-HYDROXYSTEROID DEHYDROGENASE AND GLUCOSE-6-PHOSPHATE DEHYDROGENASE INCR IN OCHRATOXIN A TREATED RATS ALONG WITH INCR IN WT AND REDUCTION IN CHOLESTEROL AND ASCORBIC ACID CONTENT OF ADRENAL CORTEX. [R38] *OCHRATOXIN A ADMIN TO RATS 5 MG/KG IP TWICE/WK/15 DAYS, CAUSED ARREST OF ESTROUS CYCLE IN DIESTRUS AND FALL IN OVARIAN DELTA5-3BETA-HYDROXYSTEROID DEHYDROGENASE AND GLUCOSE-6-PHOSPHATE DEHYDROGENASE ACTIVITIES. OVARIAN TOTAL CHOLESTEROL AND ASCORBIC ACID INCREASED. [R39] *ORAL LD50 VALUES DETERMINED IN 24-HR OLD SPRAGUE-DAWLEY RATS FOR OCHRATOXIN A (3.90 MG/KG). COMPARED WITH ORAL LD50 VALUES IN ADULTS, NEONATES SHOWED AN INCREASED SUSCEPTIBILITY. [R40] *OCHRATOXIN A @ 8 MUG/G OF DIET OF CHICKENS FROM 1 DAY TO 3 WK OF AGE RESULTED IN DECR PACKED BLOOD CELL VOL AND HEMOGLOBIN CONCN WITHOUT ALTERING NUMBER OF CIRCULATING ERYTHROCYTES. FE-DEFICIENCY ANEMIA WAS CHARACTERISTIC OF SEVERE OCHRATOXICOSIS IN YOUNG CHICKENS. [R41] *WHEN OCHRATOXIN A WAS SCREENED FOR MUTAGENIC ACTIVITY TO SALMONELLA TYPHIMURIUM STRAINS TA98, TA100, TA1535 AND TA1537, RESULTS WERE NEGATIVE. [R42] *Pregnant SLC:ICR mice were given either a single i.p. injection of 4 mg/kg of ochratoxin A (OA) or an i.v. injection of 5 mg/kg of concanavalin A (CON A) on day 7 of gestation. Untreated females served as controls. The dams were killed at different times from 6 to 72 hours after treatment, and the embryos were dissected and prepared for electron microscopic observation. In the OA-treated embryos, cellular changes were observed from the pre-somite to the 14-somite stage. The changes affected the neural plates and folds, mid-brain, and forebrain. The cellular damage included irregular structure of the neuroepithelium, cytoplasmic inclusions, and piknosis in the surface ectoderm, with the absence of neural crest cells. At the 11 to 13-somite stage (36 hr), the cellular damage disappeared and the neural plate recovered the regular structure of the neuroepithelium, although its height was less than in controls. The CON A treatment produced embryos with extreme elevation of the neural folds in the midbrain and hindbrain and cellular changes that disappeared entirely at the 11 to 13-somite stage (32 hr). [R43] *Pregnant ICR mice were administered a single ip injection of 5 mg/kg ochratoxin A (OA) on day 11 or 13 of gestation. Concentrations of OA in the serum and tissues of treated dams reached maximum levels within 2 hr following injection and rapidly decreased thereafter. The half-life of OA in serum was calculated to be 28.7 hr on day 11 and 23.6 hr on day 13 of gestation. OA concentrations in embryos examined 2 hr after 2 hr maternal injection was low but increased after 48 hr for animals treated on day 11 and 30 hr for animals treated on day 13. Another group of pregnant ICR mice was given ip injections of either 2 or 3 mg/kg OA on day 10 of gestation and sacrificed at 4 hr intervals between 8 and 72 hr following injection. Embryos were removed, and the brains were observed for OA induced cytotoxic effects. This experiment demonstrated that OA increased the incidence of pyknotic cells in the telencephalon 12 hr after injection while peaked between 36 and 48 hr postinjection. The appearance of pyknotic cells correlated with the time when the OA embryonic concentration of OA was highest. Another group of pregnant ICR mice were treated with ip injections of 0.5, 1, 1.5, 2, and 3 mg/kg on day 10 of gestation. Results from this experiment indicated that the cytotoxic effect in the developing brain of ICR mice occurred at 1 mg/kg or higher. [R44] *When administered by gavage, ochratoxin A substantially increased the incidence of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney in male and female rats. Ochratoxin A also increased the incidence and multiplicity of fibroadenomas of the mammary gland in female rats ... . [R9, p. 309 (1994)] *When ochratoxin A was administered in the diet, renal adenomas and carcinomas were observed in male mice, and some hepatocellular carcinomas were observed in female mice in one study. In another study, administration of ochratoxin A in the diet induced hepatomas and renal cell tumors in male mice. [R9, p. 309 (1994)] *A group of 10 male ddy mice (average weight, 26 g) received a diet containing 40 mg/kg ochratoxin A (crystalline) (purity unspecified) for 44 wk. A group of 10 untreated controls were fed the basal diet. All survivors were killed 49 wk after the start of treatment. Hepatic-cell tumors (well-differentiated trabecular adenomas) were found in 5/9 treated mice and in 0/10 of the controls; hyperplastic liver nodules were found in 1/9 treated mice and in 2/10 controls. Solid renal-cell tumors were found in 2/9 treated mice and in 0/10 of the controls; cystic adenomas of the kidney were found in 9/9 treated mice and in 0/10 controls ... (The Working Group noted the small size of the experimental groups.) [R45] *In mice, rats, dogs and pigs, both the acute and chronic effects of ochratoxin A are localized in the kidney, in which it causes necrosis of proximal tubular epithelium ... Ochratoxin A in feed is believed to be the most important agent in the causation of mycotoxic porcine nephropathy ... In beagle dogs, treatment with oral doses of 0.1 or 0.2 mg/kg bw ochratoxin A for 14 days caused necrosis of the lymphoid tissues, of the lymph nodules of the ileum, colon and rectum ... and of the mucosa of the colon ... . [R46] *In isolated hepatoma cells, ochratoxin A inhibited nucleic acid and protein synthesis by competing with phenylalanine at the phenylalanyl-t-RNA-synthetase active site ... Cells entering mitosis after exposure to ochratoxin A show abnormal metaphases and formation of polynucleated cells ... Ochratoxin A, incubated in the presence of fresh renal cortex slices from rats, caused an inhibition of para-aminohippurate uptake, thus altering renal function ... . [R46] *A single ip injection of 2 mg/kg bw to CD-1 mice induced craniofacial malformations when given on day 8 but not when given on day 10 ... Cerebral necrosis occurred in most fetuses of CD-1 or ICR mice treated orally or ip with 3-5 mg/kg bw on days 15-17 of gestation ... . [R47] *In several studies, pregnant Wistar or Sprague-Dawley rats were treated with ochratoxin A on various days during the period of organogenesis. Single oral doses of 6.25, 12.5 and 25 mg/kg bw on day 10 of gestation induced high resorption rates (25, 82 and 78%, respectively). At the highest dose, these was 100% resorption in 6/7 animals ... An abnormal proportion of hemorrhagic fetuses and a significant decrease in fetal body weight, an increase in the resorption rate and a decrease in litter size were noted after total ip or oral doses of 4 or 5 mg/kg bw. ... Furthermore, multiple oral doses of 0.75 mg/kg bw on days 6-15 were embryotoxic and teratogenic: various gross, visceral and skeletal anomalies were induced. ... The effects of single sc injections of 0.5-5 mg/kg bw on one of day 4-10 of gestation were studied. The minimum teratogenic dose in rats was 1.75 mg/kg, which caused decreased fetal weight and various fetal malformation. Higher doses caused fetal resorption. Ochratoxin A was most effective when given on day 5 or day 6 of gestation ... Similar results were obtained in pregnant golden hamsters after single ip injections of 2.5-20 mg/kg bw on one of days 7-10 of gestation; days 8 and 9 were the most critical with regard to malformations. The fetal mortality rate was significantly increased in litters exposed to the highest dose level on days 7, 8 or 9 ... . [R47] *Ochratoxin A had no effect in a Bacillus subtilis rec assay, measuring DNA damage, when tested at 20 and 100 ug/plate ... . [R48] *Ochratoxin A was not mutagenic to Salmonella typhimurium TA1535, TA1537, TA1538, TA98 or TA100 at doses of up to 500 ug/plate, with or without exogenous metabolic activation ... No increase in genetic changes at the ade 2 locus of Saccharomyces cerevisiae was observed after treatment with 50 and 100 ug/plate ochratoxin A, with or without exogenous metabolic activation. ... Ochratoxin A did not induce mutations to 8-azaguanine resistance in C3H mouse mammary carcinoma cells (FM3A) treated with doses of 5 and 10 ug/ml ... . [R48] *Groups of 16 male ddy mice (age unspecified) received a diet containing 50 mg/kg diet ochratoxin A for 0, 5, 10, 15, 20, 25 and 30 weeks, followed by a basal diet for 40 weeks. The experiment was terminated at 70 weeks. The estimated mean cumulative doses of ochratoxin A were 0, 11, 21, 30, 33, 40 and 50 mg/mouse, respectively. Hepatomas were seen in animals fed ochratoxin A in the diet for 20 weeks or more: control 0/15; 20 weeks, 2/14; 25 weeks, 5/15; and 30 weeks, 6/17. Renal-cell tumors (not further specified) were seen in mice fed ochratoxin A in the diet for 15 weeks or more: control, 0/15; 15 weeks, 3/15; 20 weeks, 1/14; 25 weeks, 2/15; and 30 weeks, 4/17. Lung tumors (unspecified) were found in all groups, but the incidence was not related to exposure level ... . [R49] *Two groups of 20 male DDD mice, six weeks of age, received diets containing ochratoxin A at 0 or 25 mg/kg for 70 weeks. Twenty mice exposed to ochratoxin A had renal-cell tumors, designated as cystadenomas (20 tumors) and solid renal-cell tumors (six tumors); no such tumor occurred in controls. The incidence of hyperplastic hepatic nodules was significantly increased: 16/20 in treated mice versus 4/17 in controls, as was that of hepatomas (exhibiting the trabecular structure): 8/20 in treated animals versus 1/17 in controls ... . [R49] *Groups of 50 male and 50 female B6C3F1 mice, three weeks old, received diets containing crude ochratoxin A at 0, 1 or 40 mg/kg for two years. The crude ochratoxin preparation contained 84% ochratoxin A, 7% ochratoxin B and 9% benzene. Both male and female mice in the high-dose group had terminal body weights that were about 40% lower than those of controls, but survival was not decreased after exposure to ochratoxin. The incidence of renal-cell adenomas was significantly increased (26/49) in high-dose male mice that survived 21 months, as none were found in the low-dose and control groups. A significant increase in the incidence of renal- cell carcinomas (14/49) was also found in high-dose male mice that survived at least 20 months, with none in the low-dose or control groups. Nine of the 26 mice with renal-cell adenomas also had renal-cell carcinomas. No renal tumor was observed in female mice. The incidence of hepatocellular tumors was increased in animals of each sex: males - adenomas: 1/50, 5/47 and 6/50 (p = 0.30, Cochran-Armitage test); carcinomas: 0/50, 3/47 and 4/50 (p = 0.03, Cochran-Armitage test); females - adenomas: 0/47, 1/45 and 2/49; carcinomas: 0/47, 1/45 and 5/49 (p = 0.007, Cochran-Armitage test) in control, low-dose and high-dose animals, respectively. The incidences of neoplasms in other tissues were not significantly increased in treated animals compared to controls ... . [R49] *Groups of 80 male and 80 female Fischer 344 rats, 8-10 weeks old, received 0, 21, 70 or 210 ug/kg bw (maximum tolerated dose) ochratoxin A (98% pure) in 5 ml/kg maize oil by gavage on five days per week for 103 weeks. All survivors were killed 104-105 weeks after initiation of exposure. Mean body weights of high-dose rats were generally 4-7% lower than those of vehicle controls. The survival rates of treated and vehicle control female rats were comparable, but the survival of all groups of dosed male rats was decreased. Renal-cell tumors were increased in a dose-related manner in animals of each sex: males - renal-cell adenomas: 1/50, 1/51, 6/51 and 10/50; renal-cell adenocarcinomas: 0/50, 0/51, 16/51 and 30/50; females - renal-cell adenomas: 0/50, 0/51, 1/50 and 5/50; renal-cell adenocarcinomas 0/50, 0/51, 1/50 and 3/50, in control, low-dose, mid-dose and high-dose animals, respectively. Metastasis of the renal-cell tumors occurred in 17 males and one female ... . [R50] *In a medium-term carcinogenicity study, groups of 20 male Fischer 344 rats weighing about 150 g, were kept for one week on a basal diet and were then given ochratoxin A (purity unspecified) at 0 or 50 mg/kg diet for six weeks; one week after initiation of the study, the rats were given a partial hepatectomy, and during weeks 7-9 the animals received 200 mg/kg diet N-2-fluorenylacetamide (purity unspecified). The rats also received carbon tetrachloride (1 ml/kg bw) at the end of week eight. The animals were killed 10 weeks after the start of the experiment. In 14 rats, 0.63 + or - 0.69 hepatic hyperplastic nodules/sq cm were observed (p < 0.02), compared to an average of 0.11 + or - 0.22/sq cm in the 20 rats that received no ochratoxin A. In the same study, groups of 20 male rats were fed the ochratoxin A diets during weeks 3-9 and received the N-2-fluorenylacetamide during the first two weeks and the carbon tetrachloride at week 1; the partial hepatectomy was done at week 4. Sixteen rats had an average of 0.82 + or - 0.54 hepatic hyperplastic nodules/sq cm (p < 0.05) compared with an average of 0.36 + or - 0.43/sq cm in 20 control rats that received similar treatment without exposure to ochratoxin A ... . [R50] *INHIBITORY EFFECT OF OCHRATOXIN A ON CULTURED HEPATOMA CELLS OBSERVED. [R51] *Ochratoxin A is nephrotoxic and has been implicated in the /etiology/ of Balkan endemic nephropathy, a condition that leads to end-stage renal disease and upper urothelial tumors. This cmpd induces renal parenchymal carcinoma in male mice only and is not considered to be a potent carcinogen nor is there experimental evidence of its propensity to cause upper urothelial carcinoma. There is, however evidence that exposure to more than one mycotoxin may be an important factor in the clinical spectrum of Balkan endemic nephropathy. Analgesic nephropathy is clinically different but is also associated with an upper urothelial carcinoma. The combination of urothelial initiation and an acute papillary necrosis in rats produces upper urothelial carcinoma. This two-stage experimental model offers the potential to assess the role of ochratoxin A in Balkan endemic nephropathy associated upper urothelial carcinoma under experimental conditions. [R52] *Ochratoxin A (OTA) is a mycotoxin which contaminates animal feed and human food and is nephrotoxic for all animal species studied so far. It binds to plasma proteins and is transported into target organs, especially the kidney. An attempt to prevent its toxic effects has been made using piroxicam, a non-steroidal anti-inflammatory drug (NSAID). Piroxicam also binds strongly to plasma proteins and /the suggested/ hypothesis is that this drug could stop OTA-binding and transport into target organs, thereby preventing its nephrotoxicity. ... Rats were given/ OTA (289 ug/kg/48 hr for 2 weeks show that piroxicam prevents the enzymuria induced by OTA and increases renal elimination of OTA. In vivo, piroxicam could prove useful in preventing the chronic effects of ochratoxin A, mainly nephrotoxicity, at doses 5 mg/kg/48 hr, which were not found to be nephrotoxic in experimental animals. [R53] *Groups of 80 male and female F344 rats were exposed by gavage to ochratoxin A ... at levels of 21, 70, and 210 ug/kg body weight for up to 2 years. Ochratoxin A induced non-neoplastic renal tubular epithelial changes consisting of cytoplasmic alteration, karyomegaly, degeneration, and cysts. Exposure related renal tubular proliferative lesions included focal hyperplasia, tubular cell adenoma and tubular cell carcinoma. Renal tubular cell adenoma occurred as early as 9 months in 1 high dose male rat, and both adenomas and carcinomas were seen in males by 15 months. At the terminal sacrifice, renal tubular cell tumors were found in both male and female rats, but the response was more pronounced in the males. The incidence of renal tumors high dose rats was the highest of any National Toxicology Program (NTP) study completed to date. In the high dose males approx 1/3 of the renal carcinomas developed metastases. ... [R54] *A disruption of calcium homeostasis leading to a sustained increase in cytosolic calcium levels has been associated with cytotoxicity in response to a variety of agents in different cell types. /It was/ observed that administration of a single high dose or multiple lower doses of the carcinogenic nephrotoxin ochratoxin A (OTA) to rats resulted in an incr of the renal cortex endoplasmic reticulum ATP-dependent calcium pump activity. The incr was vary rapid, being evident within 10 min of OTA admin and remained elevated for at least 6 hr hereafter. The increase in calcium pump activity was inconsistent with previous observations that OTA enhances lipid peroxidation (ethane exhalation) in vivo, a condition known to inhibit the calcium pump. However, no evidence of enhanced lipid peroxidation was observed in the renal cortex, since levels of malondialdehyde and a variety of antioxidant enzymes including catalase, DT-diaphorase, superoxide dismutase, glutathione peroxidase, glutathione reductase and glutathione S-transferase were either unaltered or reduced. In in vitro studies addition OTA to cortex microsomes during calcium uptake inhibited the take process although the effect was reversible. Preincubation of microsomes with NADPH had a profound inhibitory effect on calcium uptake but inclusion of OTA was able to reverse the inhibition. Changes in the rates of microsomal calcium uptake related with changes in the steady-state levels of the phosphorylated Mg2+/Ca(+2)-ATPase intermediate, suggesting that in vivo/in vitro conditions were affecting the rate of enzyme phosphorylation. [R55] *Ochratoxin A (OTA) is a mycotoxin produced by several different fungi with the kidney as the main target. Many studies have suggested that the proximal tubule is an important intrarenal target. The purpose of this study was (1) to show that opossum kidney cells are a suitable model for studying proximal tubule toxicity by monitoring the effects of dome formation and (2) to investigate how the mycotoxin enters proximal tubular cells. Dome formation of OK cell is affected by OTA a biphasic manner: a decr in the dome number (to 0 of control after 50 hr) in the presence of high concn (10-5 mol/l) and stimulation (to 166% of control after 50 hr in the presence of low concn (10-7 mol/l) of the mycotoxin. Furthermore, the uptake across the luminal membrane is mediated by at least three transport systems with high affinity; the L-phenylalanine carrier, the H+-driven dipeptide carrier and the organic anion carrier. For the uptake across the basolateral membrane, only the organic anion carrier could be identified, exerting a low affinity. These findings suggest that (1) filtered OTA is resorbed in the proximal tubule, thus lowering the final urinary excretion, and (2) that OTA may be accumulated in proximal tubular cells. [R56] NTOX: *Ochratoxin A (OTA) is a nephrotoxin which blocks plasma membrane anion conductance in Madin-Darby canine kidney (MDCK) cells. Added to the culture medium, OTA transforms MDCK cells in a manner similar to exposure to alkaline stress. By means of video imaging and microelectrode techniques, /it was/ investigated whether OTA (l umol/l) affects intracellular pH, Cl- or cell volume of MDCK cells acutely exposed to normal (pH norm = 7.4) and alkaline (pH alk = 7.7) conditions. At pH norm, OTA increased Cl by 2.6 +/- 0.4 mmol/l (n = 14, P < 0.05) but had no effect on pH. At pHalk, application of OTA increased Cl by 8.6 +/- 2.6 mmol/l (n = 10, P < 0.05) and raised pH by O.11 +/- 0.03 (n = 8, P < 0.05). The Cl-HCO3 exchange inhibitor DNDS (4,4'-dinitro-stilbene-2,2'-disulfonate; 10 u mol/l eliminated the OTA-induced changes of pH and Cl. OTA did not affect cell volume under both pHnorm and pHalk conditions. /Results conclude/ that the OTA-induced blockade of plasma membrane anion conductance increases Cl without changing cell volume. The driving force of plasma membrane Cl-/HC03 exchange dissipates, leading to a rise of pH when cells are exposed to an acute alkaline load. Thus, OTA interferes with pH and Cl- homeostasis leading to morphological and functional alterations in MDCK cells. [R57] *The nephrotoxin ochratoxin A (OTA) causes a reduction of glomerular filtration rate (GFR) and of para-aminohippuric acid (PAH) clearance. ... Renal plasma flow (RPF), filtration fraction (FF) and total renal vascular resistance (TRVR) /were measured/. Using furosemide, /a study was conducted determining the/ role of tubuloglomerular feedback (TGF) for GFR reduction. Using enalapril and the angiotensin II antagonist DUP 753 ... the role of angiotensin II for GFR reduction /was investigated/. Six days application of 0.5 mg/kg body weight of OTA ip to male Wistar rats leads to RPF reduction from 3.98 +/- 0.18 to 1.97 +/- 0.18 ml/(min g kidney wet weight) and GFR reduction, from 1.08 +/- 0.06 to 0.69 +/- 0.04 ml/(min). FF increased to 130% of control and TRVR to 202% of control (n = 6, P < 0 .05 for both. The application of furosemide (30 mg the reduction of GFR, indicating that TGF is not involved. Pretreatment with OTA and enalapril (0.5 mg/day/kg body weight) blunted the effect of OTA alone significantly (GFR only dropped to 88% of control). Pretreatment with OTA and DUP 753 (20 mg/day/kg body weight) blunted the effect of OTA alone significantly: GFR and RPF only dropped to 89 and 91% of control, respectively. FF and TRVR were no longer different from control. Acute application of DUP 753 (2 mg/kg body weight iv) after pretreatment with OTA blunted the effect of OTA to a lesser extent. /Results of these studies indicate that/: 1) Reduction of para-aminohippuric acid clearance and of GFR is in part due to reduced RPF. 2) The increase in TRVR is at least in part caused by an increase of the efferent resistance. 3) Activation of the TGF is not involved in GFR reduction. 4) The increase in TRVR and the decrease of GFR are mainly mediated by angiotensin II. [R58] *Proximal tubule derived opossum kidney (OK) cells are a suitable model to study proximal tubular protein endocytosis by using fluorescein-isothiocyanate-albumin as substrate. OK cells /were used/ to investigate several steps of the endocytotic process in control cells and in ochratoxin A (OTA) treated cells. OTA is a mycotoxin which causes proteinuria. When OTA was present only during the l5-min period in which uptake was studied it had no effect on albumin endocytosis. Preincubation of OK cells with OTA (l0 umol/l) for 24 hr led to a reduction of transport capacity (Jmax to approx %50 of control) and of apparent affinity (Km to approx 200% of control). Specific binding of albumin to the apical cell surface was reduced also. Maximum binding capacity was reduced to 72% of control. By contrast, endocytotic uptake of the fluid-phase marker dextran was not affected by OTA. Preincubation of OK cells for 24 hr with 10 umol/l of OTA reduced degradation of fluorescein-isothiocyanate-albumin to trichloroacetic acid soluble fluorescence to 59%. ... No difference in endosomal pH (6.13 +/- 0.05 in controls vs 6.04 +/- 0.10 in OTA treated cells). ... [R59] *The possible adverse effects of ochratoxin-A (OTA) on rat testes were investigated using oral doses in the natural contamination range. Male Wistar rats were given 289 ug/kg every 48 hours for 2, 4, 6, or 8 weeks by gastric intubation. This dose level corresponded to a 2 ppm contamination level in feed. The treatment resulted in changes in testicular enzyme activities: alpha-amylase from 1905 to 3190 units/g, alkaline-phosphatase from 259 to 323 units/g, and gamma-glutamyltransferase from 170 to 900 units/g after 8 weeks of treatment. The incr of these enzymes, particularly gamma-qlutamyltransferase, may be connected with an impairment of spermatogenesis and an accumulation of premeiotic germinal cells induced by OTA. Following OTA treatment, a decr was noted for associative stages-I and VII of germinal cells whereas stages XII and XIII increased after OTA treatment. These findings indicated a possible impairment of spermatogenesis. The ... changes /observed/ may be due to an earlier modification of the androgen status as the testosterone level in the testes was 10.4 ug/g of protein after 3 wk of treatment as compared to the 5.3 ug/g in controls. [R60] *The avian kidney has shown a remarkable ability to maintain adequate and even normal function in the face of a mycotoxin challenge. Full evaluation of the nephrotoxicity of a substance must therefore go beyond pathological and ultrastructural documentation and include a complete functional evaluation. To date, only three nephrogenic mycotoxins, citrinin, ochratoxin A, and aflatoxin Bl have been assessed for their ability to alter avian renal function. At non-lethal doses, citrinin appears to have acute reversible effects on the distal portion of the nephron, possibly acting to inhibit water absorption. Ochratoxin A is more potent and less acute than citrinin but less site-specific in that both proximal and distal tubules are damaged, resulting in severe loss of both fluids and electrolytes. Aflatoxin Bl at a dosage and duration which induced hepatotoxicity, concurrently exerted nephrogenic effects such as increased urinary calcium excretion and decreased inorganic phosphate excretion. In commercial broilers aflatoxin Bl has been shown to decr plasma levels of 25-hydroxy vitamin D, l,25-dihydroxy vitamin D and may also decr endogenous parathyroid hormone synthesis and the renal sensitivity to parathyroid hormone. Furthermore, exposure to aflatoxin Bl may cause prolonged alteration in renal function such as reduced glomerular filtration rate. ... [R61] *Three experiments were conducted to study ochratoxin A (OA) toxicity and the effect of supplemental ascorbic acid (AA) in laying hens housed under two environmental temperatures. In experiment 1, 18 hens were divided into three groups of six hens and fed diets containing either 0, 1.7, or 3.1 ppm OA for 14 days. In experiment 2 and 3, 24 hens were randomly assigned to four dietary treatments in six replications. Treatments consisted of a control and three diets containing either 300 ppm AA, 3 ppm OA, or 300 ppm AA plus 3 ppm OA. Treatment diets were fed for 14 days following the feeding of the basal diet for 14 days. The test period temperature was 25 deg C in experiment 1 and 2 and 33 deg C in experiment 3. In experiment 1, feeding OA at 1.7 ppm significantly ... decreased feed intake and increased liver weights and eggshell elasticity. At 3 ppm, OA significantly ... reduced feed intake, body weight change and egg production, and increased shell elasticity. Similar trends were also observed in experiments 2 and 3 when laying hens were fed 3 ppm OA compared with those fed the control diet. An analysis of plasma constituents showed that OA also increased Cl- concn and aspartate transaminase activity and decreased plasma calcium concentrations. Exposing hens to 33 deg C (compared with 25 deg C) appeared to aggravate the negative effects of OA. All the negative effects of OA, apart from body-weight changes, reductions in feed intake, and increases in egg shell elasticity at 33 deg C were either moderated or significantly ... reversed by dietary AA supplementation. ... The results /indicate/ that the detrimental effects of OA in the diet of the laying hen can be counteracted by dietary /administration/ of AA. [R62] *Ochratoxin A (OA) was incorporated in the diets of growing gilts (mean body weight, 20.1 kg) at a concn of 2.5 mg OA/kg of feed and was fed continuously for 35 days. Humoral and cell mediated immunologic measurements were evaluated to determine the effects of OA on immune function in swine. Cutaneous basophil hypersensitivity to phytohemagglutinin (PHA), delayed hypersensitivity to tuberculin, decr stimulation index for lymphoblastogenesis, decr interleukin 2 production, total and isotype immunoglobulin concn, antibody response to chicken RBC, and macrophage activation were used to evaluate immune function. Gilts treated with OA had reduced cutaneous basophil hypersensitivity response to PHA, reduced delayed hypersensitivity to tuberculin, decr stimulation index for lymphoblastogenesis, decr interleukin-2 production when lymphocytes were stimulated with concanavalin A, and decr number and phagocytic activity of macrophages. Differences were not observed for total and isotype immunoglobulin concn, or humoral hemagglutination (chicken RBC) titer. These data indicate that OA may suppress cell mediated immune response in growing swine. [R63] *Primary cultures of hepatocytes derived from untreated rats were incubated in the presence of ochratoxin A for 24 hr. Five different strains of histidine auxotroph Salmonella typhimurium were exposed to conditioned cell culture medium before being tested for mutagenicity. A clear hepatocyte mediated mutagenic response was observed in TA1535, TA1538 and TA100. In addition, peripheral lymphocytes that have been incubated in the presence of conditioned medium derived from ochratoxin A exposed hepatocytes. [R64] *Ochratoxin A (3 mg/kg; OA) was given ip to pregnant mice on day 11 of gestation (day 1 = plug day) and neurochemical changes in brains of their offspring were examined at fetal and adult stages. The weight gain of fetal brains and increments of their DNA content were suppressed. Specific activities of lysosomal enzymes in fetal brains began to incr by the second day after treatment and reach peak activities by the third day. An acidic heat shock like protein with molecular weight of about 30 kD was induced in fetal brains 36 hr after treatment indicative of response to stress such as cell death in developing brains. While at adulthood of OA treated mice tissue weight and DNA content showed 20% reduction in cerebral hemisphere (CH) and 10% reduction in remainder of the brain (RB) without pons-medulla (PM) and cerebellum. Total content of noradrenaline (NA) dopamine (DA) and 5-hydroxytryptamine (5-HT) in treated CH showed about 15% reduction. Total DA content in RB was also reduced to 85% of controls but total content of NA and 5-HT in RB and PM did not change. These results suggest that synaptogenesis of monoamine neurons in the cerebrum is impaired by prenatal treatment with OA and the DA neurons show a slight selective vulnerability to the toxin. [R65] *Ringneck pheasants were fed diets containing 1.25, 2.5 or 5 ppm aflatoxin; 1, 2, or 4 ppm ochratoxin A (OA); or 4, 8, or 16 ppm T-2 toxin. Severe toxin induced mortality was /noted/, during the first to third weeks with 2.50 and 5.00 ppm aflatoxin (92.5% and 97.5%, respectively), compared with the mortality in control pheasants fed no toxin (0%). Slight mortality (less than or equal to 5%) was seen with OA and T-2 toxin. Body weights were significantly decreased by the lowest level (1.25 ppm) of aflatoxin by 2 weeks of age, by the two highest levels of aflatoxins by 1 week of age, and by 16 ppm T-2 toxin by 1 week of age. The feed conversion ratio was increased by 2.50 and 5.00 ppm aflatoxin compared with the feed conversion ratio in controls, although high mortality may have influenced the results. Aflatoxin had no effect on liver weight, but OA increased kidney weight in 3 week old pheasants. Mouth lesions were seen in some of the pheasants fed T-2 toxin. [R66] *During veterinary meat inspection porcine kidneys with macroscopic lesions indicating mycotoxic porcine nephropathy were /studied/. ... About 8 (12%) of the slaughtered pigs showed macroscopic changes in kidneys indicating the disease. Ochratoxin A was found in 35 (41%) kidneys with the highest concn 3.l ng/g. Porcine blood samples (105) were collected at random and ochratoxin A was found in 63 (60%) samples with the highest concn being 122 ng/ml. [R67] *Pregnant mice were treated ip with 3 mg/kg of ochratoxin A on day 10 of gestation. They were allowed to give birth and the offspring were /sacrificed/ at 6 weeks of age for observation. Prenatal exposure to ochratoxin A caused microcephaly in offspring. Their body weight, brain weight, cortical thickness and numerical densities of neurons and synapses in somatosensory and visual cortex were examined. The mice exposed in utero to ochratoxin A showed a significant deficit in brain weight compared to the age matched control, but there was no significant difference in body weight between these two groups. The cortical thickness showed a significant decrease in both somatosensory and visual cortex. Normal control mice had about 66,000 neurons/cu mm, while age matched ochratoxin A treated mice had about 91,000 neurons/cu mm in somatosensory cortex. There was a significant incr in OA treated group, however, there was no significant difference in the numerical density of neurons in visual cortex. On the other hand, there was no significant difference in the numerical density of synapses in both somatosensory and visual cortex. The somatosensory cortex of control mice had about 13,000 synapses per neuron, whereas ochratoxin A treated mice had about 9,400 synapses per neuron. In the visual cortex, no significant difference was seen in synapse to neuron ratios. The discrepancy in the numerical density of neurons and synapse to neuron ratios between the somatosensory and visual cortex might derive from a time difference in cortical neurogenesis. [R68] *Several /studies/ have reported the occurrence of renal and hepatic tumors in mice and rats exposed to ochratoxin A in long term studies. The compound was not mutagenic, however, in various microsomal and mammalian gene mutation assays, either with or without metabolic activation. Contradictory results were obtained for induction of unscheduled DNA synthesis and sister chromatid exchange. /Earlier studies / showed that ochratoxin A causes DNA damage, manifested as single strand breaks in mouse spleen cells and in vivo. These findings, which suggest that ochratoxin A is weakly genotoxic to mammalian cells, prompted /a/ search for DNA adducts using a modified (32)P-postlabelling method, the sensitivity of which was improved by treatment with nuclease P1. DNA was isolated from liver, kidney and spleen excised from mice 24, 48 and 72 hr after oral treatment with ochratoxin A at 0.6, 1.2 and 2.5 mg/kg body weight. Several adducts were found in the DNA of the three organs, the levels varying greatly. After admin of 2.5 mg/kg body weight, 40 adducts per 10(9) nucleotides were found in kidney DNA and 7 adducts per 10(9) nucleotides in liver after 72 hr. The levels of most of the adducts increased from 24 to 72 hr, but those of others diminished after 24 or 48 hr. Adducts were found in spleen only at 24 and 48 hr. These results confirm the genotoxicity of ochratoxin A. [R69] *Ochratoxin A (OA), produced by strains of Aspergillus and Penicillium, at a dose of 20 ug/ml caused nuclear and nucleolar changes characteristic of apoptosis in hamster kidney (HaK) and HeLa cells. However, the morphological and biochemical lesions were not identical in the two cell types. In HaK cells micronuclei formation in prophase and interphase cells predominated but in HeLa cells apoptotic body formation was more prevalent. Indirect immunofluorescence indicated that nucleolar morphology was affected in both cell types with segregation of the fibrillar and granular components of the nucleolus present after 24 hr exposure. (35)S-Methionine incorporation into SDS-PAGE-separated proteins was decr after continuous exposure for 24 hr, but after only 3 hr exposure, the synthesis of three proteins was markedly increased in HaK (approx 39, 90, and 180 kDa) and HeLa (approx 40, 92, and 150 kDa) cells. Enhanced early synthesis of proteins was more pronounced in HaK cells in the G1-phase and in HeLa cells in the S-phase. Internucleosomal DNA breaks, characteristic of apoptosis, were present in Gl and S-phase HaK cells exposed to OA. In contrast, DNA of very high molecular weight was seen in synchronized HeLa cells. The results /show/ that OA may activate different cellular processes involved in the degradation of DNA in HaK and HeLa cells. [R70] *OA is a potent teratogen in all species tested, but its associated pathogenesis and mechanisms remain largely unexplored. At H and H stages 10 and 12, single doses of OA were injected into the air sac of chicken eggs. The LD50 in chick embryos examined at day 8 was 0.0006 and 0.0023 mg/egg respectively. There was a dose-response relationship in terms of viability, weight and malformation rate, with malformed embryos having a lower body weight. The patterns of malformation overlapped in the embryos treated at the two stages and included exencephaly, encephalocele, microcephaly, midline facial cleft, unilateral and bilateral cleft lip and palate, loss of beak or nostrils, everted heart, and omphalocele. Analyses of pathogenesis utilizing vital staining of embryos with Nile blue sulfate or Trypan blue illustrated excessive cell death notable as early as 2.5 hr and extending up to 36 hr after OA injection at stage 12. Preliminary studies directed toward determining OA's mechanism of action have demonstrated that malondialdehyde, the product of lipid peroxidation in the embryos incr significantly 12 hour post-treatment. ... MTT staining showed that the superoxide radical formed in the regions of cell death. Pretreatment with probenecid ... seemed to partially alleviate cell death caused by OA. It appears that intracellular transport of OA and subsequent lipid peroxidation resulting from the generation of free radicals are involved in OA's teratogenicity. [R71] *... With the veratrum alkaloids (the most studied phytotoxins) the mycotoxin Ochratoxin A (OA), ... induces major craniofacial malformations. Single doses of OA admin ip to C57BL/6J mice early on gestational day 7 (2 mg/kg) or 8 (3-4 mg/kg) result in deficiencies in the forebrain and midface. While exencephaly and midfacial clefting are notable malformations resulting from the earlier exposure, synophthalmla is frequently induced at the later treatment time. Vital Nile blue sulfate staining of whole embryos 12 hr post maternal treatment /demonstrates/ that OA causes cell death ln early gastrulation stage embryos (7 days, 12 hr) in a pattern consistent with that of the somitomeres; ie, in 4 circular segments on each side of the anterior midline, thus, affecting the medial half of the anterior neural plate. In contrast, in early somite stage embryos (8 days, 12 hr), the cells that die are at the rim of the cranial neural folds, extending to the anterior midline. OA is known to interfere with protein and RNA (but not DNA) synthesis. If, as would appear likely, it is those cells that are the most active in protein and RNA synthesis that are killed, this model comprehensively illustrates this pattern of activity in early embryos. The pathogenesis of OA-induced craniofacial malformations, including exencephaly, midfacial clefting and synophthalmia appears to be directly related the patterns of cell death observed. [R72] +... Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of ochratoxin A for male F344/N rats as shown by substantially increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney. There was clear evidence of carcinogenic activity for female F344/N rats shown by increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney and by increased incidences and multiplicity of fibroadenomas of the mammary gland. [R73] NTXV: *LD50 Mouse, iv, 30 mg/kg bw; [R46] *LD50 Mouse, ip, 40 mg/kg bw; [R46] *LD50 Dog, oral, 0.2 mg/kg bw; [R74] *LD50 Mouse, oral, 60 mg/kg bw; [R46] *LD50 Pig, oral, 1 mg/kg bw; [R75] NTP: +... Toxicology and carcinogenesis studies were conducted by administering ochratoxin A (98% pure) in corn oil by gavage to groups of F344/N rats of each sex for ... 2 yr. Only rats were studied because ochratoxin A has been shown to be carcinogenic in mice. ... Groups of 80 rats per sex and dose group were administered 0, 21, 70 or 210 ug/kg ochratoxin in corn oil by gavage 5 days/wk for up to 2 yr. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of ochratoxin A for male F344/N rats as shown by substantially increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney. There was clear evidence of carcinogenic activity for female F344/N rats shown by increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney and by increased incidences and multiplicity of fibroadenomas of the mammary gland. [R73] ADE: *RATS INTUBATED DAILY WITH 500 UG OCHRATOXIN A OR FED 250 UG DAILY IN BARLEY. THERE WAS LITTLE ACCUM OF CMPD IN LIVER OR KIDNEYS. AVG TOTAL AMT EXCRETED DAILY IN URINE AND FECES WAS JUST OVER 10% OF ADMIN DOSE. SMALL AMT OF HYDROLYSIS PRODUCT ALSO EXCRETED. [R76] *RATS GIVEN SINGLE IP INJECTION OF 1 MG OCHRATOXIN A LABELLED WITH (14)C. REACHED HIGHEST LEVELS IN SERUM (90%), LIVER (4.5%), AND KIDNEY (4.4%) 30 MIN LATER. WAS EXCRETED PRIMARILY IN URINE AS UNCHANGED TOXIN OR METABOLITES. EXCRETION IN FECES LESS SIGNIFICANT. [R77] *3 HR AFTER ADMIN OF (14)C-LABELED OCHRATOXIN A TO RATS, HIGHEST RADIOACTIVITY FOUND IN STOMACH, FOLLOWED BY KIDNEY, DUODENUM, HEART, LIVER, SPLEEN, LUNG, CECUM, ILEUM, JEJUNUM, THYMUS, MUSCLE AND BRAIN. [R78] *24 HR AFTER ADMIN OF (14)C-LABELED OCHRATOXIN A TO RATS, LEVELS OF RADIOACTIVITY WERE IN THE ORDER FROM HIGHEST TO LOWEST: STOMACH, CECUM, DUODENUM, ILEUM AND LUNG, SPLEEN, JEJUNUM, KIDNEY AND HEART, THYMUS, MUSCLE, BRAIN. [R78] *GOATS GIVEN SINGLE ORAL DOSE OF (3)H-OCHRATOXIN A (0.5 MG/KG). MORE THAN 90% RADIOACTIVITY EXCRETED IN 7 DAYS IN FECES (53%), URINE (38%), MILK (6%), SERUM (2.26%). METABOLITES PRIMARILY FOUND IN URINE AND MILK. [R79] *SINGLE ORAL DOSE OF OCHRATOXIN A GIVEN TO RATS. PATTERNS OF ABSORPTION, TISSUE DISTRIBUTION AND EXCRETION WERE AFFECTED BY ACUTE CATARRHAL ENTERITIS PRODUCED BY OCHRATOXIN A OR OCHRATOXIN ALPHA. OCHRATOXIN A DISTRIBUTED MOSTLY IN KIDNEY. [R80] *In rats, ochratoxin A is absorbed through the stomach wall ... and the jejunum ... It is distributed to most tissues, but mainly to liver, kidneys and muscle ... In rats, it is excreted via the feces and urine ... [R47] *Ochratoxin A was injected into the lumina at various sites of the gastrointestinal tract in rats; the highest concentration in portal blood was observed after injection into the proximal jejunum ... Ruminants do not absorb much ochratoxin A when the concentration in the feed is low because it is hydrolysed rapidly by their ruminal flora ... however, ochratoxin A has been detected in kidney, milk and urine of cows given high doses of ochratoxin A ... . [R81] *In human plasma, ochratoxin A binds in vitro to certain, as yet unidentified macromolecules (relative molecular mass, 20,000) with extremely high affinity, the association constant being 2.3x10+10/mol. ... Saturation of these macromolecules occurs at low levels of ochratoxin A 10-20 ng/ml of serum. ... Ochratoxin A binds to serum albumin in plasma of different animal species ... but at relatively low affinity (up to 1x10+6/mol) in vivo and in vitro. ... Studies of the binding of ochratoxin A to human plasma proteins in vitro showed that only 0.02% of the total concentration of 1x10-9 to 1x10-6 M was unbound; 2% of ochratoxin B, the dechlorinated form of ochratoxin A, was unbound. In monkeys, 0.08% of the toxin remained in the free form ... . [R81] *In rats given ochratoxin A by gavage at levels corresponding to the parts per million range found in contaminated foodstuffs (approx 4 ppm), the compound was found after 24 hr in the following tissues (in decreasing order of concentration): fat, small intestine, testis, kidney, liver, lung, heart, spleen, stomach, muscle and brain. After 48 hr, the concentrations had decreased in all tissues except fat, where increased concentrations were found ... Intravenous administration of 2.5 mg/kg bw to rats resulted after 48 hr in the following distribution (in decreasing order of concentration): thyroid, skin, parotid gland, lung, submaxillary gland, heart, seminal vesicle, kidney, large intestine, testis, liver and lachrymal gland ... A similar distribution pattern of labelled ochratoxin A was found in mice and rats ... . [R81] *Secondary distribution peaks of radiolabel in the intestinal contents and serum of rats and mice after oral or intramuscular administration of 3H-ochratoxin A are a consequence of enterohepatic circulation, since the biliary excretion of ochratoxin A is very efficient ... . [R81] *Japanese quails were fed ochratoxin A at ... 50 ug/quail/day for five wk. At the end of the fifth wk, the quails were sacrificed and /ochratoxin A/ residues in the thigh muscles were /determined/. The residues ranged from 150 ug/kg of muscle to 348 ug/kg of muscle. [R82] *The distribution pattern of orchratoxin A and its non-toxic dechloro-analog ochratoxin B were studied in rats using whole body autoradiography. No prominent difference in distribution patterns was found. ... [R83] *Since there are pathomorphological similarities between porcine mycotoxic nephropathy caused by ochratoxin A and Balkan endemic nephropathy (BEN), it has been suggested that the same etiological agent has a role in BEN. Based on the results from several field and experimental studies carried out on pigs, an appropriate analytical method of monitoring possible human exposure to ochratoxin A was developed. The toxicokinetic properties of the toxin were species specific, although in all the animal species studied (with the exception of fish), as well as in humans, two binding proteins were found in the plasma. The monkey had the longest elimination half-life of the toxin, 510 hr, in contrast to the fish whose elimination half-life was only 0.68 hr. The fish kidney displayed a specific pattern of distribution. In the laying quail, the most prominent observation was the accumulation of labelled ochratoxin A in egg yolk. Generally, (14)C-ochratoxin A was eliminated rapidly from the quail body, but had a long retention time in the circulating blood in the mouse. Although the elimination of ochratoxin A from the body depending on its binding to plasma constituents, the existence of enterohepatic circulation might have been partially responsible for its prolonged retention and elimination from the body of mammals. The toxicokinetic profile of ochratoxin A did not contradict the mycotoxic hypothesis in the etiology of BEN. [R84] *The proximal tubule of the kidney is regarded the main interrenal target of the nephrotoxin 0chratoxin A (OTA). To gain further insight into the importance of the proximal tubule ... /a study was conducted to/ investigate renal p-aminohippurate (PAH), inorganic phosphate, (P) amino acid (AA) and OTA handling in male Wistar rats. The acute application of OTA 1.2 mg/kg did not affect the renal handling of any of the substances investigated. In contrast to the acute effect of OTA on postproximal parts of the nephron application of OTA (0 5 mg/kg day) over 6 days resulted in a dramatic decrease of the transport maximum of PAH (reduction to 15% of control) and to an increase of the apparent affinity of PAH to the organic anion transporter absolute excretion of P was not increased; due to the reduced GFR, the fractional excretion (FE) increased (to 180% of control) FE of the AA was not affected by OTA. Free-flow micropuncture experiments performed in L-homoarginine loaded rats; unmask possible small alterations of the amino acid transport kinetics, revealed that the proximal tubular transport of amino acids is not impaired by OTA. Subchronic exposure of the animals to OTA reduced the excretion of the mycotoxin itself to about 15% of controls /Results indicate/ that the proximal tubule is not the main but one important intrarenal target of subchronically applied OTA. Furthermore the action of OTA on the proximal tubule leads to decreased capacity to eliminate OTA possibly resulting in a self-enhancing effect. [R85] METB: *HYDROXYOCHRATOXIN A WAS ISOLATED AND IDENTIFIED FROM URINE OF RATS AFTER INJECTION WITH OCHRATOXIN A. BY INCUBATING OCHRATOXIN A WITH RAT LIVER MICROSOMES AND NADPH, 1 MAJOR (90%) and 2 MINOR METABOLITES, MORE POLAR THAN OCHRATOXIN A, WERE FORMED. [R86] *SINGLE ORAL OR IV DOSE (2.5 MG/KG) OCHRATOXIN A ADMIN TO HEALTHY ADULT RATS. OCHRATOXIN ALPHA ONLY METABOLITE RECOVERED FROM CECUM AND LARGE INTESTINE. OCHRATOXIN A EXCRETED VIA URINE AND FECES, BOTH AS FREE DRUG AND OCHRATOXIN ALPHA. 5 UNIDENTIFIED METABOLITES IN URINE. [R87] *Ochratoxin A is cleaved into phenylalanine and a less toxic iso-coumarin derivative (ochratoxin alpha) by the microbial flora of the colon ... and by carboxypeptidase A and alpha-chymotrypsin ... . [R47] *When ochratoxin A was incubated with pig, rat or human liver microsomes, (4R)- and (4S)-4-hydroxyochratoxin A were formed, the (4R):(4S) ratios varying with the species ... When 6.6 mg/kg ochratoxin A were administered ip or orally to Wistar rats, 27% ochratoxin alpha, 12% parent cmpd and 1-2% (4R)-4-hydroxyochratoxin A were recovered in the urine after 8 days. Traces of ochratoxin A and ochratoxin alpha were detected in the feces ... . [R48] *The fate of ochratoxin A has been studied in laboratory rodents and in breeding animals. In rats, orally admin ochratoxin A is readily absorbed, and considerable amounts of the toxin are detected in plasma, where maximal concn occur 2-4 hr after admin. Pharmacokinetic analysis of curves of plasma level versus time suggests its distribution in two distinct body compartments. The half-time of the toxin depends on both the dose and the animal species varying from 0.7 hr in fish to 840 hr in monkeys. In plasma, the toxin is bound to albumin, like many acidic compounds. This interaction is competitively inhibited by phenylbutazone, ethylbiscoumacetate and sulfamethoxy-pyridazine and is decr in albumin deficient rats. The hydrolysis of ochratoxin A to an isocoumarin derivative (ochratoxin alpha) is the major metabolic pathway. This detoxication is brought about by animal and bacterial carboxypeptidases and takes place in the rumen and large intestine. 4-Hydroxyochratoxin A is the main hepatic metabolite and its formation appears to be polymorphic like debrisoquine 4-hydroxylation. The ratio of 4-hydroxyochratoxin A to ochratoxin A excreted in urine may be linked to the carcinogenic potential of the toxin, as the metabolite is almost as effective an immunosuppressor as ochratoxin A. After undergoing enterohepatic circulation the toxin and ochratoxin alpha are excreted in feces and urine as various unidentified metabolites. Transport of the mycotoxin in the kidney is mediated by the renal organic anion transport system and renal metabolism may contribute to detoxification. Although dose-dependent placental transfer of ochratoxin A has been described in rodents the toxin does not cross the placenta into fetuses of sows administered a low dose (0.38 mg/kg) orally. Its diffusion into the milk of female rabbits is seen after intravenous administration but in cows given 50 mg of the mycotoxin, barely detectable amounts of ochratoxin alpha were recovered in milk. Ochratoxin A is preferentially distributed in liver, kidney, muscle and fat. The experimental data are in close accordancewith several reports on the spontaneous occurrence of unchanged toxin residues in blood and kidneys of slaughter pigs. [R88] BHL: *Pregnant ICR mice were administered a single ip injection of 5 mg/kg ochratoxin A (OA) on day 11 or 13 of gestation. The half-life of OA in serum was calculated to be 28.7 hr on day 11 and 23.6 hr on day 13 of gestation. [R89] *In rats ... the plasma half-life of ochratoxin A is about 60 hr ... . [R47] *The apparent plasma elimination half-time of ochratoxin A after oral administration at 50 ug/kg bw varied from 0.68 hr in fish to 120 hr in rats and 510 hr in monkeys ... . [R81] ACTN: *For a better understanding of the ochratoxin (OTA) genotoxic effect, OTA-DNA adduct formation and disappearance has been measured using the (32)P post-labelling method after oral admin of 2.5 mg/kg of OTA to mice. In kidney, liver and spleen several modified nucleotides were clearly detected in DNA 24 hr after admin of OTA but their level varied significantly in a tissue and time dependent manner over a 16 day period. Total DNA adducts reached a maximum at 48 hr when 103, 42 and 2.2 adducts per 10(9) nucleotides were found respectively in kidney, liver and spleen indicating that kidney is the main target of the genotoxicity and likely carcinogenicity of OTA. The major adduct differed between kidney and liver. All adducts disappeared in liver and spleen 5 days after compound admin, whereas some adducts persisted for at least 16 days in the kidney. Some adducts were organ specific. The finding that the adducts are not quantitatively and qualitatively the same in the three organs examined is likely due to differences of metabolism in these organs leading to different ultimate carcinogens and may also result from differences in the efficiency of repair processes. [R90] INTC: *ALDRIN CONCN INCR IN LIVER OF NEONATAL RATS DURING 1ST 6 HR AFTER ORAL ADMIN THEN DECR OVER 72 HR TO LESS THAN 0.1% DOSE. ALDRIN AND OCHRATOXIN GIVEN TOGETHER; ALDRIN INCR 1ST 6 HR THEN DECR TO 0.4% DOSE OVER 18 HR. [R91] *DIELDRIN, DETECTED 2 HR AFTER ADMIN OF ALDRIN TO NEONATAL RATS, INCR TO MAX 30% OF INITIAL ALDRIN BY 18 HR. ALDRIN AND OCHRATOXIN GIVEN TOGETHER; DIELDRIN INCR FROM 10% OF ALDRIN DOSE @ 2 HR TO MAX 50% @ 24 HR. [R91] *RAINBOW TROUT FED DIET CONTAINING 20 UG OCHRATOXIN A/KG OF DIET; TOGETHER WITH STERCULIC ACID, DEVELOPED HEPATOMAS (NUMBER UNSPECIFIED). [R20] *2.5 UG/G AFLATOXIN + 2.0 UG/G OCHRATOXIN A FED TO BROILER CHICKS FROM HATCHING UNTIL 3 WK OF AGE. KIDNEY WAS MOST SENSITIVE ORGAN TO COMBINED TOXICITY. GROWTH RATE WAS DECR AND MORTALITY INCR. [R25] *OCHRATOXIN A (0.8 MG) WAS 100% LETHAL IN MICE 24 HR AFTER IP ADMIN. WHEN THIS LD WAS INJECTED IP TOGETHER WITH 0.8 MG OF PHENYLALANINE, 97% OF ANIMALS SURVIVED; 100% SURVIVED WHEN 1 MG PHENYLALANINE WAS INJECTED. [R92] *WHEN OCHRATOXIN A AND CITRININ ARE ADDED SIMULTANEOUSLY TO HEPATOMA TISSUE CULTURE CELLS FROM RATS, INHIBITION OF RNA AND PROTEIN SYNTHESIS OCCURS IMMEDIATELY, AND INHIBITION OF DNA SYNTHESIS AFTER SHORT TIME LAG, SUGGESTING COOPERATIVE EFFECT OF BOTH MYCOTOXINS. [R93] *IN SIMULTANEOUS DOSING EXPT, NEONATAL LD50 VALUE OF OCHRATOXIN A (3.90 MG/KG, ORAL) IN PRESENCE OF 5 MG RUBRATOXIN B/KG WAS APPROX 16 TIMES BELOW THAT FOR OCHRATOXIN A ALONE. NEONATAL LD50 VALUE FOR RUBRATOXIN B DECR APPROX 4-FOLD IN PRESENCE OF 2 MG OCHRATOXIN/KG. [R40] *Ochratoxin A (OTA) ... inhibits protein synthesis by competition with phenylalanine in the phenylalanine-tRNA aminoacylation reaction. ... Lipid peroxidation induced by OTA has been reported indicating that the lesions induced by this mycotoxin could be also related to oxidative pathways. ... The effects of the superoxide dismutase (SOD) and catalase on the nephrotoxicity induced by OTA in rats /was investigated/. The two enzymes (20 mg/kg body weight each) were given to rats by sc injection every 48 hr, 1 hr before gavage by OTA (289 ug/kg bw every 48 hr) for 3 weeks. SOD and catalase prevented most of the nephrotoxic effects induced by ochratoxin A observed as enzymuria proteinuria, creatinemia and incr urinary excretion of OTA. [R94] *Ochratoxin A when admin orally for 45 days to albino Swiss mice ... at a level equivalent to .... 1 ug/kg body weight/day, incr the production of abnormalities in both miotic and meiotic chromosomes as well as in the gross morphology of the sperm head. The sperm count per unit volume of caput epididymal suspension also decr. Vitamin C at a concn ... 10 mg/kg/body weight/day when admin orally concurrently with ochratoxin A significantly minimized the incidence of these abnormalities. The protective effect of vitamin C was most marked in mitotic chromosomes followed by that in meiotic chromosomes and sperm head morphology; the improvement in sperm count was least marked. ... [R95] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ochratoxin A is naturally found in the environment as it is a fungal product produced by Penicillium verrucosum, and by several aspergilli with Aspergillus ochraceus the most important ochratoxin-producing species. If released to the atmosphere, ochratoxin A will exist completely in the particulate phase. The phenol moiety may react with nitrate radicals in the atmosphere. Particulate phase ochratoxin A may be removed from the atmosphere by wet and dry deposition. Based on an estimated Koc of 9000, ochratoxin A should be immobile in soil. Ochratoxin A may photolyze on soil surfaces as it can absorb light at environmental wavelengths. In water, ochratoxin A is not expected to volatilize from water surfaces. It may bind strongly to particulates and organic matter present in the water column based on its estimated Koc value. An estimated BCF value of 2400 suggests that ochratoxin A will bioconcentrate in aquatic organisms. The general population is exposed to ochratoxin A through the consumption of cereals, grains, beans, rice, maize, and pork meat and pork meat products which have been contaminated with this compound. (SRC) NATS: *TOXIC METABOLITES FROM ASPERGILLUS OCHRACEUS WILH: SCOTT, MYOPATHOL MYCOL APPL 25, 213 (1965); A SULPHUREUS AND A MELLEUS: LAI ET AL, APPL MICROBIOL 19, 542 (1970); AND PENICILLIUM VIRIDICATUM WESTLING: VAN WALBEEK ET AL, CAN J MICROBIOL 15, 1281 (1969). /OCHRATOXINS/ [R96] *OCHRATOXIN-PRODUCING FUNGI ARE ENCOMPASSED IN GENERA PENICILLIUM AND ASPERGILLUS; PENICILLIUM STRAINS APPEAR TO BE RESPONSIBLE FOR OCHRATOXIN A FORMATION IN COLDER CLIMATIC AREAS (NORTHERN EUROPE, CANADA), WHEREAS IN TROPICAL AND SUBTROPICAL AREAS ASPERGILLUS OCHRACEOUS GROUP MAY ALSO PRODUCE IT. [R6] *Ochratoxin A is a naturally occurring mycotoxin ... a natural contaminant on corn, peanuts, storage grains, cottonseed, and decaying vegetation ... . [R9, p. 310 (1994)] *There is now general agreement that ochratoxin A is produced by only one species of Penicillium, P. verrucosum ... Among the aspergilli, A. ochraceus is the most important ochratoxin-producing species; however, rare species in the ochraceus group, including A. sclerotiorium, A. melleus, A. alliaceus and A. sulfureous, also produce ochratoxin A ... . [R3, (1993)] *Ochratoxin A is naturally produced by Penicillium verrucosum, and by several aspergilli with Aspergillus ochraceus the most important ochratoxin-producing species(1). [R97] *... Ochratoxin A is a mycotoxin produced by fungi occurring frequently on cereals. Their growth, and the associated toxin production, are closely correlated to the degree of moisture to which they are exposed, which itself is dependent upon weather conditions. ... [R98] FATE: *TERRESTRIAL FATE: An estimated Koc of 9000(1,SRC), based on an experimental log Kow(2), indicates that ochratoxin A will be immobile in soil(3,SRC). Ochratoxin A will not volatilize from moist soil surfaces based on an estimated Henry's Law constant of 3.1X10-17 atm-cu m/mole(4,SRC). It may photolyze on soil surfaces(SRC) as it is able to absorb light at environmental wavelengths(5). [R99] *AQUATIC FATE: Ochratoxin A is not expected to volatilize from water surfaces based on an estimated Henry's Law constant of 3.1X10-17 atm-cu m/mole(1). Given an estimated Koc of 9000(2,SRC), determined from an experimental log Kwo(3), it may bind strongly to particulates and organic matter in the water column. An estimated BCF value of 2400, based on an experimental log Kow(2), suggests that ochratoxin A may bioconcentrate in aquatic organisms(2,3,SRC). [R100] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of 3.3X10-16 mm Hg at 25 deg C(1,SRC), ochratoxin A should exist completely in the particulate phase in the ambient atmosphere(2,SRC). Ochratoxin A may photolyze directly as it absorbs light at environmental wavelengths(3). The phenol moiety of ochratoxin A may react with nitrate radicals in the atmosphere(4). Particulate phase ochratoxin A may be removed physically from air by wet and dry deposition(SRC). [R101] ABIO: *Ochratoxin A absorbs light above 290 nm suggesting that it may photodegrade(1,SRC). The phenol moiety of ochratoxin A may react with nitrate radicals in the atmosphere(2). [R102] BIOC: *A BCF of 2400 was calculated for ochratoxin A, using an experimental log Kow of 4.74(1) and a recommended regression-derived equation(2,SRC). This BCF value suggests that ochratoxin A will bioconcentrate in aquatic organisms(2,SRC). [R103] KOC: *Based on an experimental log Kow of 4.74(1), the Koc of ochratoxin A is estimated as approximately 9000 using a regression-derived equation(2,SRC). According to a suggested classification scheme(3), this Koc value suggests that ochratoxin A is essentially immobile in soil(SRC). [R104] VWS: *The Henry's Law constant for ochratoxin A is estimated as 3.1X10-17 atm-cu m/mole(1,SRC). This value suggests that ochratoxin A will not volatilize from water surfaces(2). [R105] FOOD: *Kidneys from 385 slaughtered pigs were collected in 6 slaughter-houses in various districts of northern Belgium from February to June 1987. 6.3% of kidneys had ochratoxin A present at concentrations from 0.2-0.99 ng/g, 9.1% had ochratoxin A present at concentrations from 1-4.99 ng/g, 1.0% had ochratoxin A present at concentrations from 5-9.99 ng/g, 1.3% had ochratoxin A present at concentrations above 10 ng/g(1). In Denmark, 35% of analyzed porcine kidneys contained ochratoxin A from 2-68 ng/g; Sweden 25% of kidneys from 2-10 ng/g; W.Germany 21% of kidneys from 0.1-1.8 ng/g; Poland 45% of kidneys from 2-23 ng/g; Hungary 39% of kidneys from 5-100 ng/g; Belgium 17.7% of kidneys from 0.2-12 ng/g(1). Ochratoxin A was detected in dried black beans (n=5, 113-136 ug/kg beans), dried white corn (32 ug/kg), cassava flour (32-65 ug/kg), dried Carioquinha beans (94 ug/kg), and dried Rosinha beans (160 ug/kg) from Brazil(2). In the US, ochratoxin A was detected in maize (3 of 293 samples, 80-170 ug/kg), wheat (11 of 577 samples, 10-29 ug/kg), and barley (41 of 309 samples, 10-40 ug/kg)(3). In Canada, ochratoxin A was detected in wheat, hay (7 of 95 samples, 30-6000 ug/kg), grain, forage (5 of 474 samples, 30-4000 ug/kg), cereals (11 of 755 samples, 3-50 ug/kg), and peas, beans (1 of 84 samples, 20 ug/kg)(3). Although ochratoxin A occurs in many commodities all over the world, it has been found primarily in north-temperate barley- and wheat-growing areas(3). [R106] PFAC: PLANT CONCENTRATIONS: *Detected contamination levels in cereals range from 0.03 ppm to 27.5 ppm ... . [R9, p. 311 (1994)] *Although the carryover from barley into beer is possible, one survey of all 130 US breweries did not detect ochratoxin A (up to 10 ug/kg) in beer or malted barley ... The malting process completely degrades the toxin in moderately contaminated barley, but 2-7% of the toxin was carried over to the final product from a heavily contaminated lot ... Up to 28% of added toxin was detected in a final beer product ... . [R9, p. 311 (1994)] *Food: Maize, up to 2.6% of samples analyzed contaminated at concn up to 200 ug/kg. Wheat, up to 2.8% contaminated at up to 115 ug/kg. Barley, up to 12.6% contaminated at up to 3800 ug/kg. Coffee beans, up to 7.1% contaminated at up to 360 ug/kg. Bread, up to 2% contaminated at up to 210 ug/kg. Flour, up to 28.5% contaminated at up to 2900 ug/kg. Rice, contaminated at up to 430 ug/kg. Beans, up to 8.5% contaminated at up to 442 ug/kg. Peas, up to 2.8% contaminated at up to 10 ug/kg. In commodities from Yugoslavia (an area of endemic human nephropathy), up to 8.3% of maize samples were contaminated at concn up to 140 ug/kg; 8.5% of wheat contaminated at up to > 100 ug/kg; and 12.5% of barley contaminated at up to 26 ug/kg. In feed (including barley, wheat, oats, rye, maize, hay) from various countries, up to 57.6% of the samples were contaminated at concn up to 27,500 ug/kg /from table/ [R107] *...HAS BEEN DETECTED IN MOLDY CEREALS (WHEAT, MAIZE, RYE, BARLEY, OATS), BEANS AND PEANUTS (RANGE, 9-27, 500 UG/KG). ...DETECTED IN BARLEY INTENDED FOR BEER PRODN...SOME CARRYOVER...INTO BEER CANNOT BE EXCLUDED. ...ONE SURVEY FAILED TO DETECT ANY...IN BEER AND MALTED BARLEY (SENSITIVITY...10 UG/KG). [R108] ANIMAL CONCENTRATIONS: *Residues of ochratoxin A have been detected in samples of meat from animals slaughtered immediately after consuming contaminated feed. ... It has been detected at levels of 10-920 ug/kg in sausage, ham, and bacon samples ... . [R9, p. 311 (1994)] *When food animals (pigs) are exposed to ochratoxin A-contaminated feed immediately prior to slaughter, a small fraction (< 1%) of the ingested toxin is retained as residues in the tissues. Thus, surveys of meat plants in Denmark and Sweden have revealed that the kidneys of 25-35% of pigs suffering from nephropathy contain residues of ochratoxin A ... . [R109] *In an area of endemic nephropathy, ochratoxin A was found in 28.5% of ham samples at levels of 40-70 ug/kg, 18.5% of bacon samples at levels of 37-200 ug/kg, 13.3% of kulen (specially prepared sausage) samples at levels of 10-460 ug/kg and 12% of sausage samples at levels of 10-920 ug/kg ... . [R109] MILK: */Human milk/ Germany: detected in 4/36 samples at 0.017-0.03 ng/ml. Italy (1989-90): detected in 9/50 samples at 1.7-6.6 ng/ml /from table/ [R7] RTEX: *Its widespread occurrence in food and animal feed results in probably human exposure ... Potential worker exposure exists for all personnel handling and storing grains, nuts, corn, cereals, and animal feeds. [R9, p. 310 (1994)] *Pork products can be a significant human dietary source of ochratoxin A: ochratoxin A occurs at high frequency in the blood of swine produced in several countries ... . [R108] *Human exposure occurs mainly through consumption of contaminated grain and pork products, as confirmed by detection of ochratoxin A in human blood and milk(1). [R110] BODY: */Human milk/ Germany: detected in 4/36 samples at 0.017-0.03 ng/ml. Italy (1989-90): detected in 9/50 samples at 1.7-6.6 ng/ml /from table/ [R7] */Human blood/ Bulgaria (1984-90): detected in 82/576 samples at 1-35 ng/ml. Canada (1988): detected in 63/159 samples at 0.27-35.3 ng/ml. Denmark (1986-88): detected in 78/144 samples at 0.1-13.2 ng/ml. France: detected in approx 18% of samples at 0.1-6 ng/ml. Germany (1977-85): detected in 173/306 samples at 0.1-14.4 ng/ml. Poland: detected in 9/216 samples at 1.3-4.8 ng/ml. Poland (1983-84): detected in 77/1065 samples at 0.10 ng/ml (mean). Sweden (1989): detected in 38/297 samples at 0.3-6.7 ng/ml. Yugoslavia (1980): detected in 42/639 samples at 1-40 ng/ml. Yugoslavia (1981-89): detected in 240/17175 samples at 5-100 ng/ml /from table/ [R7] *Ochratoxin A has been found in blood from individuals in several European countries at levels ranging, e.g., in Sweden from 0.3 to 6 ng/ml. In inhabitants of the Balkans, concentrations of up to 100 ng/ml blood have been found. In Germany, ochratoxin A was detected in human milk in 4 of 36 samples (0.017-0.03 ng/ml); in Italy, ochratoxin A was detected in human milk in 9 of 50 samples (1.7-6.6 ng/ml)(1). [R110] *Ochratoxin A was determined in human serum samples, collected in the south of Italy in November 1992, using ion-pair liquid chromatography and fluorescence detection. The samples were collected from healthy people (65 subjects) as well as from people with different kidney disorders. Five different kinds of kidney disorders were represented: transplanted subjects (13), chronic glomerulonephritis (8), renal calculus or cyst (6), chronic renal failure (13), and subjects treated by dialysis (28). The mean and median concn of ochratoxin A in the healthy group was 0.53 and 0.44 ng/ml serum, respectively. The highest mean concn was found in the group of patients treated by dialysis, 1.4 ng/ml serum. A higher incidence of samples containing > 0.44 ng ochratoxin A/ml serum was found in the dialysis group, compared to the other groups. Comparing the mean concn by Student's t-test, a significant difference was found between the mean concn of the healthy group and of the group of patients treated by dialysis (p < 0.01). No other significant differences were found when comparing the groups two at a time. [R111] *... Analyses of serum samples in European countries revealed that blood from healthy humans was contaminated with ochratoxin A at concn 0.1-14.4 ug/l. The frequency of contamination of human sera indicates continuous widespread exposure. ... [R112] *... In the course of a year 1991 and 1992 about blood donors of the Brno agglomeration in the Czech Republic were examined for ochratoxin A content (OA) in blood serum. ... A mean concn of 0.63 ng OA/l blood serum (0.30 ng geometric mean) was /found/. The assessed continuous mean dietary intake of OA was about 0.74 ng (0.35 ng geometric mean) OA/kg bw/day. The assessed continuous mean contamination of food groups (cereal and meat products) was about 0.65 ug (0.31 ug geometric mean) OA/kg. ... [R113] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *IN BARLEY AND GREEN COFFEE BY THIN LAYER CHROMATOGRAPHY. [R114] *ANALYSIS OF OCHRACTOXINS IN BARLEY USING PARTITION AND THIN LAYER CHROMATOGRAPHY. [R115] *DETERMINATON OF OCHRATOXIN A IN FOODS AND FEEDS BY HIGH-PRESSURE LIQUID CHROMATOGRAPHY. [R116] *METHOD FOR DETERMINATION OF OCHRATOXIN IN FOOD. [R117] *DETERMINATION OF OCHRATOXIN A IN CEREALS BY HIGH PRESSURE LIQUID CHROMATOGRAPHY. [R118] *DETERMINATION OF OCHRATOXIN A IN FLOUR AND BAKERY PRODUCTS. [R119] *DETERMINATION OF MYCOTOXINS BY HIGH PERFORMANCE THIN-LAYER CHROMATOGRAPHY. [R120] *DETERMINATION OF OCHRATOXINS IN MIXED FEEDS AND OTHER FOOD PRODUCTS BY THIN LAYER CHROMATOGRAPHY. [R121] *Cereals: HPLC/UV (limit of detection 1-5 ug/kg); Cereals and coffee: TLC (12 ug/kg); Food and feedstuffs: HPLC/FL (5 ug/kg) or TLC (20 ug/kg); Feedstuffs: TLC (10 ug/kg) or HPLC/FL (1 ug/kg) /from table/ [R109] *DETERMINATION OF OCHRATOXIN A IN PIG'S KIDNEY USING ENZYMIC DIGESTION, DIALYSIS, AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY WITH POSTCOLUMN DERIVATIZATION. [R122] *A liquid chromatographic method for determining ochratoxin A in maize, barley, and kidney was tested in a IUPAC collaborative study. Several high-performance liquid chromatographic methods for various commodities have been proposed and appear to be useful, and a number of enzyme-linked immunosorbent assay methods are valuable for screening and providing semiquantitative data e.g., for cereals and porcene kidney. [R3, (1993)] *AOAC Method 975.38 Ochratoxin A in Green Coffee. Toxin is extd from ground, green coffee beans with CHCl3. Ochratoxin A is entrapped on basic diat. Earth, interferences are removed with hexane and CHCl3, and ochratoxin A is eluted with benzene-HOAc. Ochratoxin A is detd from fluorescent intensity on TLC. [R123, 1208] *AOAC Method 973.37. Ochratoxins in Barley. Thin layer chromatographic method . Detection via UV fluorescence. [R123, p. V2 1207] CLAB: *Methods also have been reported for determining ochratoxins in blood, e.g., by fluorescence with HPLC confirmation ... /ochratoxins/ [R3] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: MUNRO IC ET AL; OCHRATOXIN A. OCCURRENCE AND TOXICITY; J AMER VET MED ASS 163(11) 1269 (1973) REVIEW ARTICLE IN WHICH TOXICOLOGY, BIOCHEMISTRY AND METABOLISM OF OCHRATOXIN A, AND TOXICOSIS AFTER INGESTION OF CONTAMINATED CEREAL AND LEGUME CROPS ARE DISCUSSED. HAYES AW; MYCO TOXINS A REVIEW OF BIOLOGICAL EFFECTS AND THEIR ROLE IN HUMAN DISEASES; CLIN TOXICOL 17(1) 45 (1980). A REVIEW OF BIOLOGICAL EFFECTS OF MYCOTOXINS. 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Washington, DC: Association of Analytical Chemists, 1990 RS: 125 Record 298 of 1119 in HSDB (through 2003/06) AN: 4311 UD: 200302 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIMETHOXANE- SY: *ACETIC-ACID,-2,6-DIMETHYL-M-DIOXAN-4-YL-ESTER-; *ACETOMETHOXAN-; *ACETOMETHOXANE-; *6-ACETOXY-2,4-DIMETHYL-META-DIOXANE-; *6-ACETOXY-2,4-DIMETHYL-1,3-DIOXANE-; *DDOA-; *2,4-DIMETHYL-6-ACETOXY-1,3-DIOXANE-; *2,6-DIMETHYL-META-DIOXAN-4-OL-ACETATE-; *2,6-DIMETHYL-1,3-DIOXAN-4-OL-ACETATE-; *2,4-DIMETHYL-6-M-DIOXANYL-ACETATE-; *2,6-DIMETHYL-META-DIOXAN-4-YL-ACETATE-; *M-DIOXAN-4-OL,-2,6-DIMETHYL-,-ACETATE-; *1,3-DIOXAN-4-OL,-2-6-DIMETHYL-,-ACETATE-; *GIV-GARD-DXN-; *GIV-GARD-DXN-CO- RN: 828-00-2 MF: *C8-H14-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 2,4-DIMETHYL-6-HYDROXY-META-DIOXANE WITH ACETIC ANHYDRIDE IN PYRIDINE [R1] *C.S. Marvel J Org Chem 4, 252 1939); Spath et al., Ber 76, 57 (1943). Description: Am Perfum Cosmet 77, no 12, 32-34 (1962), C.A. 58,8848c (1963). [R2] *CHAFETZ ET AL, US PATENT 3,036,904 (1962 TO TEXACO). [R2] FORM: *PURITY: ...AVAIL IN US AS TECHNICAL GRADE CONTAINING 93% OF PURE CHEM. PREPN: ...WAS PREPARED IN 1943 BY REACTION OF 2,4-DIMETHYL-6-HYDROXY-META-DIOXANE WITH ACETIC ANHYDRIDE IN PYRIDINE. [R3, p. V15 178] MFS: *Givaudan-Roure Corporation, Specialty Dev, 100 Delawanna Avenue, Clifton, NJ 07014, (201) 365-8000. [R4] OMIN: *...ALSO USED TO PREVENT CONTAMINATION OF WATER-BASED PRINTING INKS AND PAINTS. ... DIMETHOXANE WAS RECOMMENDED FOR USE IN COSMETICS IN PAST. IN US...REGISTERED AS ANTIMICROBIAL AGENT 'FOR MFR USE ONLY'. ...IS NOT KNOWN TO OCCUR IN NATURE. [R3, p. V15 178] USE: *Preservative for cutting oil, resin emulsions, water-based paints, cosmetics, inks. Effective range of concn: 0.03-0.1%. Gasoline additive. [R2] *...ANTIMICROBIAL AGENT...USED TO PROTECT AGAINST...SPOILAGE DUE TO BACTERIA, FUNGI AND YEASTS IN...WATER-BASED PAINTS... IT CAN BE USED IN WATER-BASED CUTTING OILS, SPECIALTY TEXTILE CHEM EMULSIONS, DYESTUFFS, FABRIC SOFTENERS, LATEX EMULSIONS, SIZINGS, ADHESIVES, ANTISTATIC LUBRICANTS AND SPINNING EMULSIONS @...500-1500 MG/KG. [R3, p. V15 178] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LIQUID [R2]; *CLEAR YELLOW TO LIGHT AMBER LIQUID [R5] ODOR: *MUSTARD-LIKE ODOR [R2] BP: *74-75 deg C @ 6 mm Hg [R2] MP: *FP: LESS THAN 25 DEG C [R5] MW: *174.19 [R2] DEN: *1.0655 @ 20 DEG C/4 DEG [R2] SOL: *MISCIBLE WITH WATER, MANY ORG SOLVENTS [R2] SPEC: *INDEX OF REFRACTION: 1.430 @ 20 DEG C/D [R2]; *Intense mass spectral peaks: 43 m/z (100%), 45 m/z (33%), 42 m/z (22%), 71 m/z (19%) [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *HYDROLYZES IN AQ SOLN TO PRODUCE ACETIC ACID AND CORRESPONDING FREE ALCOHOL [R3, p. V15 177] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R7] NTOX: */MALE WISTAR RATS GIVEN 1% SOLN IN WATER DAILY FOR 613 DAYS TO GIVE AVG TOTAL DOSE OF 237 G/ANIMAL AND TERRAMYCIN 1 WK BEFORE EXPT STARTED. MALIGNANCIES IN/... 14/25...8 HEPATOMAS...2 LYMPHOSARCOMAS, /CONTROLS 1/, 1 TRANSITIONAL-CELL CARCINOMA OF KIDNEY, 1 LEUKEMIA, 1 EPIDERMOID CARCINOMA OF NECK AND 1 SC FIBROSARCOMA. [R8] *Dimethoxane was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Dimethoxane was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.033, 0.100, 0.333, 1.000, 2.000, 2.150, 3.333, 4.444, 5.500, 5.555, and 6.666 mg/plate. The compound was positive in strain TA100 with and without activation and ineffective in the other strains (TA1535, TA1537, and TA98). The lowest positive dose tested was 3.333 mg/plate in strain TA100 without activation. [R9] *Dimethoxane was reported to be positive for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster. This reference reports on the testing of 53 chemicals, including Dimethoxane, by one or more of 3 different laboratories under contract to the National Toxicology Program (NTP) using a standard protocol approved by the NTP. Canton-S wild-type males were treated with concentrations of the test chemical that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods of 3, 2 and 2 days for analysis. Dimethoxane at a dose of 10,000 ppm when administered to males by injection was positive in this assay. [R10] *Fourteen tumors were found in rats fed 1.2 g/kg /of dimethoxane/ per day for 213 days. The tumors included hepatomas that resembled those found in rats exposed to dioxane. It is not know whether a single sublethal exposure to dimethoxane can lead to tumor formation. [R11] +... Conclusions: Under the conditions of these 2-year corn oil gavage studies, there was no evidence of carcinogenic activity of dimethoxane for male F344/N rats receiving 62.5 or 125 mg/kg or for female F344/N rats receiving 125 or 250 mg/kg per day. There was equivocal evidence of carcinogenic activily of dimethoxane for male B6C3Fl mice, as indicated by an increased incidence of forestomach neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice receiving 250 or 500 mg/kg per day. ... [R12] NTP: +... Toxicology and carcinogenesis studies were conducted by administering commercial grade dimethoxane (80% pure, none of these impurities exceeded 3%) in corn oil gavage to groups of F344/N rats and B6C3F1 mice of each sex one time or 5 days/wk for ... 2 yr. ... Doses selected for the 2 yr studies were 0, 62.5, or 125 mg/kg dimethoxane in corn oil, given by gavage 5 days/wk to groups of 60 male rats; 0, 125, or 250 mg/kg to groups of 60 female rats; and 0, 250, or 500 mg/kg to groups of 58 or 60 mice of each sex. ... Conclusions: Under the conditions of these 2-year corn oil gavage studies, there was no evidence of carcinogenic activity of dimethoxane for male F344/N rats receiving 62.5 or 125 mg/kg or for female F344/N rats receiving 125 or 250 mg/kg per day. There was equivocal evidence of carcinogenic activily of dimethoxane for male B6C3Fl mice, as indicated by an increased incidence of forestomach neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice receiving 250 or 500 mg/kg per day. ... [R12] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dimethoxane will be released to the environment as a result of its use as a bacteriostatic and fungistatic preservative for cutting oil, resin emulsions, water-based paints, cosmetics and inks and as a gasoline additive. It may also be released during its production, transport, formulation, and disposal. If released on soil, dimethoxane would readily leach. Chemicals containing acetal and ester groups are susceptable to chemical hydrolysis, the hydrolysis of the acetal ring being favored under acidic conditions and the ester under alkaline conditions. No hydrolysis rate data are available. Based on limited data, dimethoxane may also biodegrade but no rate data are available. If released in water, dimethoxane would be expected to hydrolyze and possibly biodegrade, rate data in water are also lacking. Volatilization from water, adsorption to sediment, or bioconcentration in aquatic organisms are not expected to be important fate processes in water. In the atmosphere, dimethoxane will react with photochemically-produced hydroxyl radicals, resulting in an estimated atmospheric half-life of 7.9 hr. Since dimethoxane is miscible in water, it should also be washed out by rain. Exposure to dimethoxane would be via dermal contact with products containing this chemical as a preservative both in the workplace and the home. (SRC) ARTS: *Dimethoxane will be released to the environment as a result of its use as a bacteriostatic and fungistatic preservative for cutting oil, resin emulsions, water-based paints, cosmetics and inks and as agasoline additive(1,2). It may also be released during its production, transport, formulation, and disposal(SRC). [R13] FATE: *TERRESTRIAL FATE: If released on soil, dimethoxane would readily leach. Based on limited data, it may biodegrade. Although information on rates are unavailable, dimethoxane may also hydrolyze. Hydrolysis of the ring would be favored under acidic conditions and ester hydrolysis would be favored under alkaline conditions. (SRC) *AQUATIC FATE: If released in water, dimethoxane would be expected to hydrolyze. Hydrolysis of the ring would be favored under acidic conditions and ester hydrolysis would be favored under alkaline conditions. Information on hydrolysis of the acetal-containing ring structure is lacking. The base-catalyzed hydrolytic half-life of the ester linkage is estimated to be 7.4 days at pH 8. Based on the results of a screening test, dimethoxane may also biodegrade. Volatilization from water and adsorption to sediment are not expected to be important fate processes. (SRC) *ATMOSPHERIC FATE: Dimethoxane will react with photochemically-produced hydroxyl radicals in the atmosphere, resulting in an estimated atmospheric half-life of 7.9 hr(1). Since dimethoxane is miscible in water(2), one would expect it to wash out in rain(SRC). [R14] BIOD: *In a 4-week biodegradation screening test (MITI test) using dimethoxane (100 ppm) and an activated sludge inoculum, 76-83% of BOD was removed(1). [R15] ABIO: *Dimethoxane hydrolyzes in water to form active aldehyde-containing compounds plus some acetic acid(1). Acetals, to which dimethoxane is related, are hydrolyzed easily by acid, but are extremely stable under basic conditions(2). The hydrolysis of the ester linkage of dimethoxane is base-catalyzed and the estimated reaction rate is 1.079 L/mol-sec(3). The half-life for the hydrolysis of this moiety of dimethoxane is therefore 74 days at pH 7 and 7.4 days at pH 8(3,SRC). No hydrolysis rates were located for dimethoxane or similar compounds. In the atmosphere, dimethoxane reacts with photochemically-produced hydroxyl radicals with an estimated rate constant of 48.9X10-12 cu cm/molecule-s at 25 deg C(4). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of dimethoxane in the atmosphere would be 7.9 hr(SRC). [R16] BIOC: *Using an estimated log Kow of 0.49(1,SRC), one would estimate a BCF of 1.4 for dimethoxane using a recommended regression equation(2). This would indicate that dimethoxane would not bioconcentrate in aquatic organisms(2). [R17] KOC: *The Koc for dimethoxane estimated from molecular structure is 0.56(1). According to a suggested classification scheme(2), this estimated Koc indicates that dimethoxane would be highly mobile in soil. [R18] VWS: *The Henry's Law constant for dimethoxane estimated from structure activity relationships is 1.24X10-7 atm-cu-m/mol(1). Using this value of the Henry's Law constant, one would estimate a volatilization half-life of 390 days for dimethoxane from a model river 1 m deep with a 1 m/s current and a 3 m/s wind(3,SRC). Therefore dimethoxane would be essentially nonvolatile from water. The vapor pressure of dimethoxane is estimated to be 0.14 mm Hg(3). Considering this and its low adsorptivity to soil, some dimethoxane may volatilize from the soil surface(SRC). [R19] RTEX: *Exposure to dimethoxane would be primarily occupational via dermal contact with products containing this chemical. The general population may be exposed to dimethoxane if they use cosmetics or other products containing this preservative. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,3-Dioxin-4-ol, 2,6 dimethyl-, acetate is included on this list. [R20] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Dimethyl-m-dioxan-4-ol acetate is found on List C. Case No: 3064; Pesticide type: fungicide, antimicrobial; Case Status: RED Approved 06/95; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): Dimethyl-m-dioxan-4-ol acetate; Data Call-in (DCI) Date(s): 03/11/92; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Dimethoxane (Commercial Grade) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 354 (1989) NIH Publication No. 89-2809 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 509 R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R4: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 437 R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 408 R6: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 380 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 62 (1987) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V15 179 (1977) R9: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R10: Woodruff RC et al; Environ Mutagen 7: 677-702 (1985) R11: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-414 R12: Toxicology and Carcinogenesis Studies of Dimethoxane (Commercial Grade) in F344/N Rats and B6C3F1. Technical Report Series No. 354 (1989) NIH Publication No. 89-2809 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R13: (1) Gump W; in Kirk Othmer's Encycl Chem Tech. 3rd ed, NY,NY: Wiley-Interscience 8: 824 (1979) (2) Budavari D et al; The Merck Index 11th ed Rahway, NJ: Merck and Co Inc p. 509 (1989) R14: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (2) Budavari D et al; The Merck Index 11th ed Rahway, NJ: Merck and Co Inc p. 509 (1989) R15: (1) Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. p. 5-21, ISBN 4-89074-101-1 (1992) R16: (1) Gump W; in Kirk Othmer's Encycl Chem Tech. 3rd ed. NY,NY: Wiley-Interscience 8: 824 (1979) (2) Falbe J et al; pp 344-6 in Ullmann's Encycl of Indust Chem A1 NY: VCH Publishers (1987) (3) USEPA; PCGEMS, PCHYDRO (1991) (4) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R17: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5, Eqn 5-2 (1982) R18: (1) Meylan WM et al; Environ Sci Technol 26: 1560-7 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Freed VH, Haque R; Res Rev 52: 89-116 (1974) R19: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) (3) Syracuse Research Corporation; MPBPVP (1995) R20: 40 CFR 716.120 (7/1/92) R21: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.252 (Spring, 1998) EPA 738-R-98-002 RS: 18 Record 299 of 1119 in HSDB (through 2003/06) AN: 4332 UD: 200211 RD: Reviewed by SRP on 9/9/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: VINYLCYCLOHEXENE-DIOXIDE- SY: *CHISSONOX-206-; *CYCLOHEXANE,1,2-EPOXY-4(EPOXY ETHYL); *EP-206-; *1,2-EPOXY-4-(EPOXYETHYL)CYCLOHEXANE; *1-EPOXYETHYL-3,4-EPOXYCYCLOHEXANE-; *3-EPOXYETHYL-7-OXABICYCLOHEPTANE-; *3-(1,2-EPOXYETHYL)-7-OXABICYCLO(4.1.0)HEPTANE; *3-(EPOXYETHYL)-7-OXABICYCLO(4.1.0)HEPTANE; *4-(1,2-EPOXYETHYL)-7-OXABICYCLO(4.1.0)HEPTANE; *4-(EPOXYETHYL)-7-OXABICYCLO(4.1.0)HEPTANE; *ERLA-2270-; *ERLA-2271-; *1-ETHYLENEOXY-3,4-EPOXYCYCLOHEXANE-; *NCI-C60135-; *7-OXABICYCLO(4.1.0)HEPTANE, 3-(EPOXYETHYL)-; *7-OXABICYCLO(4.1.0)HEPTANE, 3-OXIRANYL-; *3-OXIRANYL-7-OXABICYCLO(4.1.0)HEPTANE; *3-OXIRANYL-7-OXABICYCLO(4.1.0)HEPTENE; *UNOX-EPOXIDE-206-; *VINYLCYCLOHEXANE-DIEPOXIDE-; *VINYLCYCLOHEXANE-DIOXIDE-; *VINYLCYCLOHEXENE-DIEPOXIDE-; *4-VINYLCYCLOHEXENE-DIEPOXIDE-; *4-VINYL-1-CYCLOHEXENE-DIEPOXIDE-; *4-VINYL-1,2-CYCLOHEXENE-DIEPOXIDE-; *VINYL-CYCLOHEXENE-DIOXIDE-; *1-VINYL-3-CYCLOHEXENE-DIOXIDE-; *4-VINYLCYCLOHEXENE-DIOXIDE-; *4-VINYL-1-CYCLOHEXENE-DIOXIDE- RN: 106-87-6 MF: *C8-H12-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *ONE GRADE OF 1-EPOXYETHYL-3,4-EPOXYCYCLOHEXENE AVAIL IN US HAS EPOXY EQUIV OF 74-78. ... CAN BE PREPARED BY PERACETIC ACID EPOXIDIZATION OF 4-VINYLCYCLOHEXANE. [R1] OMIN: *IT HAS BEEN PROPOSED FOR USE AS CHEM INTERMEDIATE (EG, FOR CONDENSATION WITH DICARBOXYLIC ACIDS) AND AS MONOMER (EG, FOR PREPN OF POLYGLYCOLS CONTAINING UNREACTED EPOXY GROUPS OR FOR HOMO-POLYMERIZATION TO 3-DIMENSIONAL RESIN). [R1] USE: *POLYMERS; ORGANIC SYNTHESIS [R2] *CHEM INT FOR CONDENSATION WITH DICARBOXYLIC ACIDS. [R3] *... IS USED AS REACTIVE DILUENT FOR OTHER DIEPOXIDES AND FOR EPOXY RESINS DERIVED FROM BISPHENOL-A AND EPICHLOROHYDRIN. [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R2]; +Colorless liquid. [R4, 330] BP: *227 DEG C @ 760 MM HG [R5] MP: *LESS THAN -55 DEG C [R5] MW: *140.18 DEN: *1.0986 @ 20 DEG C/20 DEG C [R5] SOL: *SOL IN WATER [R5] SPEC: *INDEX OF REFRACTION: 1.4787 @ 20 DEG C [R5]; *INFRA-RED EPOXIDE BAND @ 1250 (CM-1) [R6]; *IR: 1455 (National Bureau of Standards Spectral Collection) [R7] VAP: *LESS THAN 0.1 MM HG @ 20 DEG C [R8] VISC: *7.77 CP @ 20 DEG C [R2] OCPP: *SETS TO GLASS @ -55 DEG C [R6] *1 PPM APPROX= 5.73 MG/CU M @ 25 DEG C, 760 MM HG AND 1 MG/L APPROX= 174 PPM @ 25 DEG C, 760 MM HG [R8] *REACTS WITH ACTIVE HYDROGEN COMPD (EG, ALCOHOLS, AMINES) [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Slight, when exposed to heat or flame. [R9] FIRP: *To fight fire: Water, foam, dry chemical. [R9] REAC: +Alcohols, amines, water [Note: Slowly hydrolyzes in water]. [R4, 330] SERI: *STRONG IRRITANT TO SKIN AND TISSUE. [R2] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R4, 330] +Wear appropriate eye protection to prevent eye contact. [R4, 330] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R4, 330] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R4, 330] +Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R4, 330] +Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R4, 330] OPRM: +The worker should immediately wash the skin when it becomes contaminated. [R4, 330] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R4, 330] SSL: *SLOWLY HYDROLYZED IN WATER [R1] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 4-vinylcyclohexene diepoxide. There is sufficient evidence in experimental animals for the carcinogenicity of 4-vinylcyclohexene diepoxide. Overall evaluation: 4-Vinylcyclohexene diepoxide is possibly carcinogenic to humans (Group 2B). [R10] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R11, 2002.60] HTOX: *HUMAN EXPERIENCE INDICATES THAT IT IS MILD TO MODERATE SKIN IRRITANT ... . ONE CASE OF SEVERE VESICULATION OF SKIN OF BOTH FEET WHEN WORKER WORE SHOES PREVIOUSLY CONTAMINATED WITH THIS COMPD. [R12] *TOXIC BY INGESTION AND SKIN ABSORPTION. STRONG IRRITANT TO SKIN AND TISSUE. [R2] *EYE INJURY IS CONSIDERED TO BE DEFINITE HAZARD. IF VAPOR PRESSURE OF 0.1 MM HG AT 20 DEG C IS CORRECT ... RISK BY INHALATION IS CONSIDERED TO BE SLIGHT. BECAUSE OF VERY LIMITED ... DATA AND BECAUSE OF DEMONSTRATED CARCINOGENICITY WHEN ... APPLIED TO SKIN OF MOUSE, EXTREME CAUTION SHOULD BE EXERCISED IN USE OF THIS DIEPOXIDE. [R13] *Allergic contact dermatitis occurred in an electron microscopist after exposure to the cycloaliphatic epoxy, vinyl cyclohexane diepoxide. Cycloaliphatic epoxies are not based on the diglycidyl ether of bisphenol A, presently the epoxy of greatest commercial usage. Latex or polyvinyl chloride gloves did not protect the reported patient from precutaneous absorption and elicitation of allergic dermatitis. [R14] *A study of occupational exposure to sensitizing chemicals was conducted. The study was initiated because of numerous complaints of eye, nasal, skin, and respiratory irritation among workers at an industrial facility. Serum samples were obtained from 31 workers and assayed for immunoglobulin G and immunoglobulin E to an unspecified number of chemicals. An enzyme linked immunosorbent assay technique was used to detect the antibodies. Immunoglobulin G and immunoglobulin E antibodies against four chemicals were found: an aliphatic diisocyanate, 4-vinylcyclohexene-dioxide, trimellitic anhydride, and an unknown substance which was a component of n-octyl-n-decyl-trimellitate. The presence or absence of antibodies could not be correlated with the presence or absence of symptoms; however, the highest incidence of symptoms occurred in workers who were classified as having the highest exposures. It was noted that trimellitic anhydride is not known to be present at the facility. The source of the trimellitic anhydride response is not known. It was concluded that there is no occupational allergic disease in the worker population. The lack of correlation between the antibody responses and symptoms suggests that an immunologic factor is not the cause of the reported symptoms. The symptoms are more likely to be due to irritant nonimmunological reactions. [R15] NTOX: *20 REPEATED SKIN APPLICATIONS TO RABBITS CAUSES SEVERE TO EXTREME IRRITATION. [R8] *REPEATED SKIN APPLICATIONS OF 16 MG OF A COMMERCIAL SAMPLE OF /VINYLCYCLOHEXENE DIOXIDE/ ... IN ACETONE 5 TIMES WEEKLY FOR 12 MO ... SKIN TUMORS IN 11/20 MALE ALBINO MICE; 9 ... SQUAMOUS CELL CARCINOMAS AND/OR SARCOMAS. ... 1/20 and 4/18 C57B1 OR C3H MICE DEVELOPED SKIN TUMORS AFTER ... 10% SOLN IN ACETONE AND TOTAL DOSES OF 70 and 78 MG (CONTROL DATA ... GIVEN FOR NEITHER OF ABOVE STUDIES). [R16] *OF 30 8 WK OLD MALE SWISS ICR/HA MICE PAINTED ON CLIPPED DORSAL SKIN WITH 0.1 MLOF A 10% SOLN /OF VINYLCYCLOHEXENEDIOXIDE/ IN BENZENE THRICE WEEKLY, 14 DEVELOPED SKIN TUMORS; 9 ... HAD SQUAMOUS CELL CARCINOMAS; MEAN SURVIVAL TIME WAS 326 DAYS. AMONG 150 BENZENE-TREATED MICE, SKIN TUMORS ... IN 11, 1 ... SQUAMOUS-CELL ... . [R16] */VINYLCYCLOHEXENE DIOXIDE/ CAUSES ACUTE RESP TRACT IRRITATION AND CONGESTION OF LUNGS. IT PRODUCES REDNESS AND SWELLING COMPATIBLE WITH 1ST DEG BURN ON CLIPPED SKIN OF RABBITS. TREATED RATS SHOWED FOCAL NECROSIS OF THYMUS, AND LEUKOCYTE COUNT FELL BY MORE THAN 60% DURING 1ST 4 DAYS. ... TESTICULAR ATROPHY IN SOME ... ANIMALS ... . [R17] *BACTERIAL PLATE ASSAY SYSTEM USED. STRAINS TA98 AND TA100 OF S TYPHIMURIUM WERE USED. VINYL CYCLOHEXENE DIEPOXIDE WAS MUTAGENIC IN TA100 STRAIN. DOSE-RESPONSE CURVES WERE OBTAINED. MUTAGENICITY WAS NOT AFFECTED BY ADDN OF MICROSOMAL EXTRACT. [R18] *VINYL CMPD OR DERIVED EPOXIDES WERE ASSAYED IN SALMONELLA TYPHIMURIUM/MAMMALIAN MICROSOME SYSTEM. STRAINS TA1535, TA98, AND TA100 WERE USED. 3-EPOXYETHYL-7-OXABICYCLOHEPTANE WAS A MUTAGEN. [R19] *VINYLCYCLOHEXENE DIOXIDE WAS MUTAGENIC IN TA 1535 AND TA 100 BUT NOT IN STRAINS TA 1537 AND TA 98. [R20] *1-Vinyl-3-cyclohexene dioxide was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 1-Vinyl-3-cyclohexene dioxide was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The lowest positive dose tested in any S. typhimurium strain was 0.100 mg/plate. At this dose, the compound was positive in both strain TA100 (without activation and with rat liver S9) and strain TA1535 (under all test conditions). [R21] *Epoxy compounds are alkylating agents. The effects of cytotoxic alkylating agents are similar to those of ionizing radiation in that they are both selectively active against rapidly dividing cells, such as the blood forming elements in the bone marrow, lymphoid tissues, and reproductive organs. /Epoxy Compounds/ [R22] *Repeated intramuscular injections of 400 mg/kg 4-vinyl-1-cyclohexene diepoxide to male Long-Evans rats for 7 days decreased the size of the spleen, thymus, and testis and resulted in enlarged adrenal glands. The leukocyte count fell more than 60%, and the myeloid to erythroid ratio was increased. [R22] *Effects of dermal application of 4-vinyl-1-cyclohexene diepoxide for 14 consecutive days were examined in B6C3F1 mice. The doses applied were 1.25, 2.5, or 5 mg in 0.1 ml of vehicle. The most significant inhibition occurred in the antibody plaque forming cell response to SRBCs, which was suppressed at the 2.5 and 5 mg doses. In addition, there was a decrease in the peripheral lymphocyte count, as well as in vitro inhibition of the lymphoproliferative response to lipopolysaccharide-induced lymphocyte proliferation in the high dose group. No changes were observed in T cell responsiveness at these doses. [R23] *There are only two genetic toxicology studies with 4-vinyl-1-cyclohexene diepoxide in eukaryotic cells. ... Positive results /were reported/ in tests for gene reversion and conversion and mitotic crossing over in Saccharomyces cerevisiae exposed to 4-vinyl-1-cyclohexene diepoxide; Gene mutation induction and anaphase bridge formation /were reported/ in Chinese Hamster V79 cells exposed to 4-vinyl-1-cyclohexene diepoxide. In both of these studies, the exposures were carried out in the absence of S9. [R24] *The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in B6C3F1 mice after a 5 day dermal exposure at doses ranging from 2.5 to 10.0 mg/mouse/day. In addition to evaluation of selected organ weights and hematologic values, the primary antibody responses to sheep erythrocytes, as measured by a plaque forming cell assay, and the lymphoproliferative response to the T cell mitogens, phytohemagglutinin and concanavalin A, were determined. There were no consistent chemical-related effects on body or lymphoid organ weights (ie, spleen, thymus, or mesenteric lymph nodes). Hematologic studies indicated a significant decrease in the leukocyte count at a 4-vinyl-1-cyclohexene diepoxide dose of 10 mg/mouse, which was related to the decreased numbers of circulating lymphocytes. Immune function tests indicated that 4-vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse. This was indicated by a decrease in the lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque forming cell responses in the 5 and 10 mg/mouse groups. Phytohemagglutinin and concanavalin A are plant lectins that produce a nonspecific activation of T cells, stimulating the proliferation of T cells in response to antigens. The antibody response to sheep erythrocytes is more complex and involves maturation of B cells into plasma cells and accessory support by T cells and macrophages. Thus, the current results indicate that 4-vinyl-1-cyclohexene diepoxide can alter T cell proliferation and may have effects on other cell types as well. [R23] *Dermal application of 16 mg 4-vinyl-1-cyclohexene diepoxide, 5 days per week for 12 months, resulted in skin neoplasms in 11/20 exposed male mice. Nine of these animals had squamous cell carcinomas or sarcomas. Ten male and 4 female albino rats were given intraperitoneal injections of 250 mg/kg 4-vinyl-1-cyclohexene diepoxide (5% in arachis oil), 2 days per week for 10 weeks. Seven months after the start of the study, one rat had a mixed cell sarcoma that widely disseminated to the peritoneal cavity; no data were reported for the arachis oil vehicle controls. [R24] *One skin neoplasm and four malignant lymphomas /were noted/ in 16/20 mice surviving a total dermal dose of about 70 mg over a 14 month period. In another study, 4/18 C3H mice developed skin neoplasms when 4-vinyl-1-cyclohexene diepoxide was applied as a 10% solution in acetone for 21 months; the total dose was 78 mg; no data were reported for controls. [R24] *4-Vinyl-1-cyclohexene diepoxide was applied as 0.1 ml of a 10% solution in benzene, 3 days per week. Fourteen of 30 mice developed neoplasms; 9 of these had squamous cell carcinomas of the skin. The mean survival time was 326 days. In controls, 11/150 benzene vehicle control mice and 13/207 untreated control mice had skin neoplasms; one squamous cell carcinoma was seen in the benzene vehicle controls, and one was seen in the untreated controls. [R24] *4-Vinylcyclohexene is present in gases discharged during synthetic rubber production. Chronic treatment of B6C3F1 mice and F-344 rats with 4-vinylcyclohexene by gavage has been shown to induce ovarian tumors in mice but not in rats. Our objective was to understand the mechanism of the species difference in 4-vinylcyclohexene induced ovarian tumors. Since a critical step in the induction of ovarian tumors is destruction of the small oocyte, small oocyte counts obtained from serially sectioned ovaries were used as an index of toxicity. 4-Vinylcyclohexene or its epoxide metabolites (4-vinylcyclohexene diepoxide, 4-vinylcyclohexene-1,2-epoxide, and 4-vinylcyclohexene-7,8-epoxide (in mice only)) were given to 28 day old female mice and rats in corn oil, ip, at doses ranging from 0.07 to 7.4 mmol/kg body wt/day for 30 days. The dose which reduced the small oocyte count to 50% that of control was defined as the ED50. In mice, the ED50 for the reduction in small oocytes by 4-vinylcyclohexene was 2.7 mmol/kg, whereas, no detectable oocyte loss occurred in rats at the highest dose of 4-vinylcyclohexene (7.4 mmol/kg). The potency of the epoxides of 4-vinylcyclohexene was greater than that of 4-vinylcyclohexene in both species. The ED50 for oocyte loss by 4-vinylcyclohexene-1,2-epoxide in mice and rats was 0. and 1.4 mmol/kg, respectively. In mice, 4-vinylcyclohexene-7,8-epoxide had comparable potency to 4-vinylcyclohexene-1,2-epoxide (ED50 = 0.7). 4-Vinylcyclohexene diepoxide was even more potent with ED50 values of 0.2 and 0.4 mmol/kg, in mice and rats, respectively. The dose response of the blood concentration of 4-vinylcyclohexene-1,2-epoxide in mice after 4-vinylcyclohexene showed that doses of 4-vinylcyclohexene which caused minimal toxicity had the lowest blood level of this ovotoxic epoxide. Pretreatment of mice with the cytochrome p450 inhibitor chloramphenicol (200 mg/kg, ip) inhibited 4-vinylcyclohexene epoxidation in vivo and in vitro and partially protected mice from 4-vinylcyclohexene toxicity. Thus it appears that metabolism of 4-vinylcyclohexene to epoxides and their subsequent destruction of oocytes are critical steps in 4-vinylcyclohexene induced ovarian tumors. Rats may be resistant to ovarian tumor induction by 4-vinylcyclohexene because the amt of 4-vinylcyclohexene converted to epoxides is insufficient to produce oocyte destruction. [R25] *Thedermal toxicity and carcinogenicity of 4-vinyl-1-cyclohexene diepoxide were studied in rats and mice. 4-Vinyl-1-cyclohexene diepoxide was applied dermally to Fischer F 344/N rats at doses of 15 or 30 mg or to B6C3F1 mice at doses of 2.5, 5, or 10 mg for up to 103 wk. In rats, two of ten males given 30 mg 4-vinyl-1-cyclohexene diepoxide had squamous cell carcinomas after 15 mo. Males given 15 and 30 mg 4-vinyl-1-cyclohexene diepoxide had dermal acanthosis. One 30 mg female had forestomach squamous cell carcinoma. After 103 wk, final body wt of 30 mg dose rats were decreased by 11 to 14%. Female rats given 15 or 30 mg 4-vinyl-1-cyclohexene diepoxide had significantly reduced survival. 4-Vinyl-1-cyclohexene diepoxide significantly increased the incidence of dermal squamous cell carcinomas and basal cell adenomas in male and female rats and squamous cell papillomas in male rats. The squamous cell carcinomas metastasized to the lungs and other organs in a few rats. In mice, 5 or 10 mg 4-vinyl-1-cyclohexene diepoxide induced squamous cell papillomas and carcinomas after 15 mo. The incidence of sebaceous gland hyperplasia, acanthosis, and other nonneoplastic lesions was increased. A few female mice given 10 mg 4-vinyl-1-cyclohexene diepoxide had granular cell ovarian tumors. In the 103 wk study, 5 and 10 mg 4-vinyl-1-cyclohexene diepoxide significantly reduced body wt and survival. All male mice given 10 mg 4-vinyl-1-cyclohexene diepoxide became moribund and were killed during wk 83. All 10 mg female mice were killed during wk 84. 4-Vinyl-1-cyclohexene diepoxide significantly increased the incidence of dermal squamous cell carcinomas and basal cell adenomas in males and females andsquamous cell papillomas in male mice. The incidences of acanthosis, hyperkeratosis, and necrotizing skin inflammation were increased. Female mice given 5 or 10 mg 4-vinyl-1-cyclohexene diepoxide had increased incidences of benign or malignant ovarian granular cell tumors and benign mixed tumors. Female mice given 5 mg had a significantly increased incidence of alveolar and bronchiolar adenomas or carcinomas. It was concluded that 4-vinyl-1-cyclohexene diepoxide is carcinogenic to rats and mice of both sexes. [R26] *Theoral and dermal subchronic toxicity of 4-vinyl-1-cyclohexene diepoxide was studied in rats and mice. B6C3F1 mice were administered 0.625, 1.25, 2.5, 5.0, or 1O mg/ml and F344/N rats were administered 3.75, 7.5, 15, 30, or 60 mg/ml 4-vinyl-1-cyclohexene diepoxide topically 5 days/wk for 13 wk. Other groups of rats and mice were given 62.5, 125, 250, 500, or 1000 mg/kg 4-vinyl-1-cyclohexene diepoxide by gavage daily 5 days/wk for 13 wk. The animals were observed for clinical sign of toxicity. After 13 wk surviving animals were killed and necropsied. Blood samples were collected to determine standard hematologic parameters. In the dermal study, all treated rats survived. 4-Vinyl-1-cyclohexene diepoxide decreased body wt by 9 to 14%. Acanthosis, parakeratosis, and sebaceous gland hyperplasia were induced by 30 or 60 mg/ml 4-vinyl-1-cyclohexene diepoxide. Male rats receiving 30 or 60 mg/ml 4-vinyl-1-cyclohexene diepoxide had significantly decreased thymus wt. All treated mice survived. Acanthosis was seen in 10 mg/ml male mice. Hyperkeratosis was seen in all mice given 5 or 10 mg/ml 4-vinyl-1-cyclohexene diepoxide. Female mice given 5 or 10 mg/ml 4-vinyl-1-cyclohexene diepoxide had atrophied ovaries. In the gavage study, three male rats and six females given 1000 mg/kg 4-vinyl-1-cyclohexene diepoxide died of treatment related causes. Body wt were slightly decreased by the 500 and 1000 mg/kg doses. The 500 and 1000 mg/kg doses caused burrowing behavior and the 250, 500, and 1000 mg/kg doses excessive salivation. The 500 and 1000 mg/kg doses increased liver and kidney wt. Forestomach hyperplasia and hyperkeratosis and renal tubular cell degeneration and necrosis were the major histopathological findings. In mice, the 500 and 1000 mg/kg doses slightly decreased body wt. All doses except 62.5 mg/kg caused forestomach diffuse hyperplasia and hyperkeratosis. 4-Vinyl-1-cyclohexene diepoxide at 250 to 1000 mg/kg induced testicular germinal epithelial degeneration in male mice. The 1000 mg/kg dose induced diffuse atrophy of the ovaries and moderate uterine atrophy in females. It was suggested that 4-vinyl-1-cyclohexene diepoxide is a direct irritant at the site of contact as indicated by the occurrence of stomach and skin lesions following oral and dermal exposure. 4-Vinyl-1-cyclohexene diepoxide also demonstrates species an exposure route dependent toxicity. [R27] *A review was presented of data for eight chemicals for which either ovarian toxicity or carcinogenicity, or both, have been documented in recent studies in the NTP. In most cases, ovarian atrophy was commonly found after 90 days of exposure, and ovarian hyperplasia and neoplasia after longer periods. Ovarian lesions in mice exposed by inhalation to 1,3-butadiene included loss of follicles, tubular hyperplasia, atrophy and a variety of tumors. Benign granulosa cell tumors predominated although one granulosa cell tumor was malignant. A dimer of 1,3-butadiene, 4-vinylcyclohexene, administered to mice by gavage, produced ovarian hyperplasia and neoplasia after 2 yr of exposure. A potential metabolic product of 4-vinylcyclohexene, vinylcyclohexene diepoxide, produced ovarian atrophy, tubular hyperplasia and neoplasia by 65 wk. [R28] NTXV: *LD50 Rat oral 2.8 g/kg; [R12] *LD50 Rabbit dermal 0.06 ml/kg; [R12] *LD50 Rat oral 2130 mg/kg; [R9] *LC50 Rat oral inhalation 800 ppm/4 hr; [R9] *LD50 Rabbit dermal 620 mg/kg; [R9] NTP: *Two-year studies were conducted by administrating 4-vinyl-1- cyclohexene diepoxide in acetone by dermal application, 5 days per week to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for 103 weeks. None of the doses selected had produced ulceration of skin in 13 week studies. ... In general, the body weights and survival were lower in mid and high dose groups than in vehicle controls. The survival was lower in exposed groups, primarily because of neoplasms (survival at week 105 male rats: vehicle control, 7/50; low dose, 8/50; high dose, 4/50; female rats: 27/50; 23/50; 15/50; male mice; vehicle control 38/50; low dose, 35/50; mid dose, 4/50; high dose, 0/50; female mice; 30/50; 15/50; 0/50). All high dose male mice died by week 83; the 10 surviving high dose female mice were killed during week 85. ... Acanthosis and sebaceous gland hypertrophy of skin from the scapula or back were observed at substantially increased incidences in exposed male and female rats. Squamous cell papillomas in male rats and squamous cell carcinomas in male and female rats were observed only in exposed rats (squamous cell carcinomas--male: vehicle control 0/50; low dose 33/50; high dose, 36/50; female: 0/50; 16/50). The incidences of basal celladenomas or carcinomas (combined) were increased (male: 0/50; 1/50; 6/50; female: 0/50; 3/50; 4/50). ... For exposed mice, acanthosis, hyperkeratosis, and necrotizing inflammation of the skin were observed over the scapula or back. Squamous cell carcinomas were found only in exposed mice (male: vehicle control, 0/50; low dose, 14/50; mid dose, 39/50; high dose, 42/50; female: 0/50; 6/50; 37/50; 41/50). ... Follicular atrophy and tubular hyperplasia of the ovary in female mice were increased (atrophy: 12/50; 43/49; 42/49; 47/50; tubular hyperplasia: 5/50; 35/49; 34/50). Mid and high dose females had benign or malignant granulosa cell tumors (0/50; 0/49; 7/49; 12/50) and benign mixed tumors (0/50; 0/49; 11/49; 6/50). The combined incidences of luteomas, granulosa cell tumors benign mixed tumors, or malignant granulosa cell tumors in mid and high dose female mice were increased (1/50; 0/49; 17/49; 18/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in exposed female mice were marginally increased (4/50; 9/50; 11/50; 7/50). ... Under the conditions of these 2 year dermal studies, there was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female F344/N rats as shown by squamous cell and basal cell neoplasms of the skin. There was clear evidence of carcinogenic activity of 4-vinyl-1- cyclohexene diepoxide for male and female B6C3F1 mice, as shown by squamous cell carcinomas of the skin in males and squamous cell carcinomas of the skin and ovarian neoplasms in females; increased incidences of lung neoplasms in females may also have been related to chemical application. [R22] *The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in male B6C3F1 mice after a 5 day dermal exposure at doses ranging from 2.5 to 10 mg/mouse/day. 4-Vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse, as indicated by a decrease in peripheral lymphocytes and the in vitro lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque-forming-cell response in the 5 and 10 mg/mouse groups. [R29] *4-Vinyl-1-cyclohexene diepoxide was mutagenic in Salmonella typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation; the compound was equivocally mutagenic in strain TA1537 without S9 but gave a positive response in the presence of activation. 4-Vinyl-1-cyclohexene diepoxide induced resistance to trifluorothymidine in mouse L5178Y/TK cells without exogenous metabolic activation; it was not tested with activation. 4-Vinyl-1-cyclohexene diepoxide induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the presence and absence of exogenous metabolic activation. [R22] ADE: *4-Vinyl-1-cyclohexene diepoxide is absorbed by rodents exposed dermally orally, or by inhalation. ... Rats and mice received 0.1 ml and 0.01 ml, respectively, of dose mixtures containing 500 mg/ml (200 uc/ml) [ethylene-(14)C] 4-vinyl-1-cyclohexene diepoxide in acetone. The preliminary results indicate that 30% of the dose applied to the skin is absorbed over a 24 hr period for both rats and mice; only 1%-3% of the dose remained on the skin at the site of application. By 24 hr, 70%-80% of the absorbed dose had been eliminated from the body, virtually all in the urine. The radioactivity remaining in the body was distributed over a number of tissues, with no tissue containing more than 1% of the applied dose. The liver, muscle, and adipose tissue, however, contained 0.5%-1.6% and 1.2%-2.9% of the absorbed dose in rat and mouse tissue, respectively. Tissue to blood ratios ranged from 0.3 to 1.5 in rats and from 0.8 to 2.8 in mice. [R30] METB: *In vitro studies with rabbit liver microsomal preparations showed that 4-vinyl-1-cyclohexene diepoxide can be metabolized to monoepoxymonoglycols, 1,2-hydroxy-4-vinylcyclohexane oxide, and 4-(1',2'-dihydroxyethyl)-1-cyclohexane oxide. Formation of these products is catalyzed by epoxide hydrolase. Conjugation with glutathione is another pathway for metabolism of 4-vinyl-1- cyclohexene. Depletion of reduced glutathione /was reported/ in the liver of mice given ip injections of 500 mg/kg 4-vinyl-1-cyclohexene diepoxide. [R23] *Carcinogenicity studies have shown that chronic administration of 4-vinylcyclohexene will induce ovarian tumors in B6C3F1 mice but not F-344 rats. This occurs because the blood level of the ovotoxic 4-vinylcyclohexene metabolite, 4-vinylcyclohexene-1,2-epoxide, is dramatically higher in 4-vinylcyclohexene treated female mice compared with rats. This species difference in 4-vinylcyclohexene epoxidation is also reflected in the rate of 4-vinylcyclohexene metabolism by hepatic microsomes (female mouse greater than female rat). The present study assessed the ability of microsomes obtained from human liver to metabolize 4-vinylcyclohexene to epoxides since humans are exposed to 4-vinylcyclohexene in certain occupational settings. The production of 4-vinylcyclohexene-1,2-epoxide and 4-vinylcyclohexene-7,8-epoxide from 4-vinylcyclohexene (1 mM) by human hepatic microsomes was linear with respect to microsomal protein concentration (0.25-1.0 mg/ml) and incubation time (5-20 min). 4-Vinylcyclohexene-1,2-epoxide was the major metabolite, while the rate 4-vinylcyclohexene-7,8-epoxide formation was about 6 fold lower and in some cases was below the limit of detection. There was no dramatic difference in the rate of 4-vinylcyclohexene epoxidation by hepatic microsomes obtained from male and female humans. The rate of 4-vinylcyclohexene-1,2-epoxide formation by female human hepatic microsomes was 0.71 + or - 0.35 nmol/mg microsomal protein/min (n = 4). This is 13 and 2 fold lower than the rate of 4-vinylcyclohexene-1,2-epoxide formation by female mouse and rat hepatic microsomes, respectively. [R31] *4-Vinylcyclohexene is a chemical to which humans are exposed in the rubber industry. A chronic carcinogenicity bioassay conducted by the NTP showed that oral administration of 4-vinylcyclohexene induced tumors in the ovaries of mice but not in those of rats. The hypothesis tested was that the species and organ specificity of 4-vinylcyclohexene toxicity was due to differences in the disposition of 4-vinylcyclohexene between the female rat and mouse. Therefore, the disposition of a single oral dose of 400 mg/kg (14)C 4-vinylcyclohexene was studied in female B6C3F1 mice and Fischer 344 rats. Mice eliminated greater than 95% of the dose in 24 hr, whereas rats required 48 hr to eliminate greater than 95% of the dose. The major routes of excretion of (14)C 4-vinylcyclohexene derived radioactivity were in the urine (50-60%) and expired air (30-40%). No evidence was obtained to indicate that the ovaries of either species retained 4-vinylcyclohexene as a parent cmpd or as radioactive equivalents. A dramatic difference was observed between the rat and mouse in the appearance of a monoepoxide of 4-vinylcyclohexene in blood from 0.5 to 6 hr after 4-vinylcyclohexene administration (800 mg/kg, ip). 4-Vinylcyclohexene-1,2-epoxide was present in the blood of mice with the highest concentration at 2 hr (41 nmol/ml). The blood concentration of 4-vinylcyclohexene-1,2-epoxide in rats was less than 2.5 nmol/ml at all times examined. 4-Vinylcyclohexene-7,8-epoxide was not present in the blood of either species at the level of detection. These findings were supported by in vitro studies of 4-vinylcyclohexene epoxidation by liver microsomes. The rate of epoxidation of 4-vinylcyclohexene (1 mM) to 4-vinylcyclohexene-1,2-epoxide was 6.5 fold greater in mouse liver microsomes than that in rat liver microsomes. The species difference in the rate of epoxide formation by the liver may be an important factor in the species difference in susceptibility to 4-vinylcyclohexene induced ovarian tumors. [R32] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers vinyl cyclohexene to be a potential occupational carcinogen. [R4, 330] OSHA: +Vacated 1989 OSHA PEL TWA 10 ppm (60 mg/cu m), skin designation, is still enforced in some states. [R4, 373] NREC: +NIOSH considers vinyl cyclohexene to be a potential occupational carcinogen. [R4, 330] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R4, 330] +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (60 mg/cu m), skin. [R4, 330] TLV: +8 hr Time Weighted Avg (TWA): 0.1 ppm, skin. [R11, 2002.60] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R11, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. [R11, 2002.60] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R33] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determination of vinyl cyclohexene dioxide using GC and IR spectroscopy. [R1] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) NTP TR No 362; Route: skin paint; Species: rats and mice. NTIS No PB90219957/AS. [R34] SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 142 (1976) R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1216 R3: SRI R4: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R5: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 73rd ed. Boca Raton, FL: CRC Press Inc., 1992-1993.,p. 3-195 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 141 (1976) R7: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 479 R8: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. 1652 R9: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2729 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 60 370 (1994) R11: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R12: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.627 R13: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)407 R14: Dannaker CJ; J of Occupational Medicine 30 (8): 641-3 (1988) R15: Patterson R et al; International Archives of Allergy and Applied Immunology 85 (4): 467-71 (1988) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 143 (1976) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 144 (1976) R18: WADE MJ ET AL; MUTAT RES 66 (4): 367 (1979) R19: SIMMON VF, BADEN JM; MUTAT RES 78 (3): 227 (1980) R20: EL-TANTAWY MA, HAMMOCK BD; MUTAT RES 79 (1): 59 (1980) R21: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R22: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinyl-1-Cyclohexene diepoxide in F344/N Rat and B6C3F1 Mice (Dermal Studies) p.4 (1989) Technical Rpt Series No. 362 NIH Pub No. 90-2817 R23: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinyl-1-Cyclohexene diepoxide in F344/N Rat and B6C3F1 Mice (Dermal Studies) p.13 (1989) Technical Rpt Series No. 362 NIH Pub No. 90-2817 R24: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinyl-1-Cyclohexene diepoxide in F344/N Rat and B6C3F1 Mice (Dermal Studies) p.14 (1989) Technical Rpt Series No. 362 NIH Pub No. 90-2817 R25: Smith BJ et al; Toxicol Appl Pharmacol 105 (3): 372-81 (1990) R26: Chhabra RS et al; Fundamental and Applied Toxicology 14 (4): 752-63 (1990) R27: Chhabra RS et al; Fundamental and Applied Toxicology 14 (4): 745-51 (1990) R28: Maronpot RR; Environmental Health Perspectives 73: 125-30 (1987) R29: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinyl-1-Cyclohexene diepoxide in F344/N Rat and B6C3F1 Mice (Dermal Studies) p.5 (1989) Technical Rpt Series No. 362 NIH Pub No. 90-2817 R30: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinyl-1-Cyclohexene diepoxide in F344/N Rat and B6C3F1 Mice (Dermal Studies) p.12 (1989) Technical Rpt Series No. 362 NIH Pub No. 90-2817 R31: Smith BJ, Sipes IG; Toxicol Appl Pharmacol 109 (2): 367-71 (1991) R32: Smith BJ et al; Toxicol Appl Pharmacol 105 (3): 364-71 (1990) R33: 40 CFR 712.30 (7/1/91) R34: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.27 RS: 38 Record 300 of 1119 in HSDB (through 2003/06) AN: 4333 UD: 200201 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 3,4-DIHYDROCOUMARIN- SY: *1,2-BENZODIHYDROPYRONE-; *2H-1-BENZOPYRAN-2-ONE,-3,4-DIHYDRO-; *2-CHROMANONE-; *CHROMAN,-2-OXO-; *COUMARIN,-3,4-DIHYDRO-; *DIHYDROCOUMARIN-; *HYDROCINNAMIC-ACID,-O-HYDROXY-,-DELTA-LACTONE-; *HYDROCOUMARIN-; *MELILOTIC-LACTONE-; *MELILOTIN-; *MELILOTINE-; *MELILOTOL-; *USAF-DO-12- RN: 119-84-6 RELT: 1623 [COUMARIN] (Analog) MF: *C9-H8-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *HYDROGENATION OF COUMARIN IN THE PRESENCE OF AN ACTIVE RANEY CATALYST [R1] MFS: *Elan Chemical Co, Hq, 268 Doremus Ave, Newark, NJ 07105, (201) 344-8014 [R2] *Givaudan-Roure Corp, Hq, 100 Delawanna Ave, Clifton, NJ 07014, (201) 365-8000; Chemicals Division; Production site: Clifton, NJ 07014 [R2] *Penta Manufacturing Company, Hqr, P.O. Box 1448, Fairfield, NJ 07007, (201)740-2300; Manufacturing site: East Hanover, NJ 07936 [R2] OMIN: *REGULATORY STATUS OF DIRECT FOOD ADDITIVES: LIMITATIONS; DIHYDROCOUMARIN, SYNTHETIC FLAVOR. [R3] *REPORTED USES: NON-ALCOHOLIC BEVERAGES, 7.8 PPM; ICE CREAM, ICES, ETC, 21 PPM; CANDY, 44 PPM; BAKED GOODS, 28 PPM; GELATINS AND PUDDINGS, 10 PPM; CHEWING GUM, 78 PPM. REGULATORY STATUS: FDA STATUS NOT FULLY DEFINED; FEMA NO 2381. [R4] *USEFUL IN VANILLA, BUTTER, CREAM SODA, TOBACCO FLAVORS [R5] *BY REDUCTION OF COUMARIN UNDER PRESSURE IN PRESENCE OF NICKEL @ 160-200 DEG C (TETRALIN GESELLSCHAFT, GERMAN PATENT 355,650) OR IN PRESENCE OF PALLADIUM-BARIUM SULFATE IN ALCOHOLIC SOLN (PAAL AND SCHIEDEWITZ, BER DTSCH CHEM GES, 63, 775, 1930). [R4] USE: *FRAGRANCE IN COSMETICS AND DETERGENTS; FLAVORING AGENT IN FOODS AND BEVERAGES [R1] *...used in perfumery industry for its haylike odor. [R6] *It has GRAS status and can be used as a food flavor ingredient with a sweet carmel-like taste. [R6] *...in woodruff-type flavor compositions. [R7] PRIE: U.S. PRODUCTION: *(1974) 4.5X10+6 G-MAX CONSUMPTION AS FRAGRANCE [R1] *(1979) PROBABLY GREATER THAN 1.36X10+6 GRAMS [R1] *The U.S. market is estimated at 50 tons/yr. [R6] U.S. IMPORTS: *(1977) 2.00X10+5 GRAMS (PRINCPL CUSTMS DISTS) [R1] *(1979) 2.25X10+5 GRAMS (PRINCPL CUSTMS DISTS) [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LEAFLETS [R8]; *WHITE TO LIGHT YELLOW, OILY LIQUID [R9]; *Colorless crystals [R7] ODOR: *Sweet - herbal [R7]; *ODOR SIMILAR TO COUMARIN @ ROOM TEMP OR REMINISCENT OF NITROBENZENE @ HIGHER TEMP [R4] TAST: *SWEET THEN BITTER [R5]; *BURNING [R4] BP: *272 DEG C [R10] MP: *25 DEG C [R10] MW: *148.16 [R10] DEN: *1.169 @ 18 DEG C [R11] SOL: *INSOL IN WATER, SLIGHTLY SOL IN ETHER AND CARBON TETRACHLORIDE [R11]; *1:2.5-3.5 IN 70% ALCOHOL [R4]; *Soluble in chloroform. [R9] SPEC: *INDEX OF REFRACTION: 1.5563 @ 20 DEG C/D; MAX ABSORPTION (ALCOHOL): 266 NM (LOG E= 2.85), 273 NM (LOG E= 2.86), 312 NM (LOG E= 1.02) [R8]; *IR: 973 (Coblentz Society Spectral Collection) [R12]; *UV: 3578 (Sadtler Research Laboratories Spectral Collection) [R12]; *NMR: 6884 (Sadtler Research Laboratories Spectral Collection) [R12]; *MASS: 852 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R12] OCPP: *CONGEALING POINT: 23-23.6 DEG C [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FLPT: *130 DEG C [R4] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *TECHNIQUE WAS DEVELOPED FOR DETERMINING SENSITIZING POTENTIAL OF COSMETIC PRODUCTS IN ALBINO GUINEA PIG. COMPD TESTED INCL DIHYDROCOUMARIN. [R13] +Results from two Salmonella typhimurium gene mutation tests with or without S9 were negative. [R14] +... CONCLUSIONS: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of 3,4-dihydrocoumarin in male F344/N rats based on increased incidences of renal tubule adenomas and focal hyperplasia. The transitional cell carcinomas in two 600 mg/kg males may also have been chemical related. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in female F344/N rats receiving 150, 300, or 600 mg/kg. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in male B6C3FI mice receiving 200, 400, or 800 mg/kg. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). [R15] NTXV: *LD50 Rat oral 1460 mg/kg; [R16] NTP: +Toxicity and carcinogenicity studies were conducted by administering 3,4-dihydrocoumarin (99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. ... 2 YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 200, 400 or 800 mg/kg body weight. ... 2 YEAR STUDY IN RATS: Groups of 60 male and female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 150, 300, or 600 mg/kg body weight. ... CONCLUSIONS: Under the conditions of these 2 yr gavage studies, there was some evidence of carcinogenic activity of 3,4-dihydrocoumarin in male F344/N rats based on increased incidences of renal tubule adenomas and focal hyperplasia. The transitional cell carcinomas in two 600 mg/kg males may also have been chemical related. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in female F344/N rats receiving 150, 300, or 600 mg/kg. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in male B6C3FI mice receiving 200, 400, or 800 mg/kg. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). [R15] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *REPORTED FOUND IN MELILOTUS OFFICINALIS (PHIPSON, CHEM NEWS, 32, 25, 1875), FROM WHICH IT MAY BE EXTRACTED BY WATER DISTILLATION. [R4] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: REVIEW WITH 9 REFERENCES ON IRRITATION, SENSITIZATION AND TOXICITY OF DIHYDROCOUMARIN. [R17] DHHS/NTP; Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 423 (1993) NIH Publication No. 93-3154 SO: R1: SRI R2: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 624 R3: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. 833 R4: Fenaroli's Handbook of Flavor Ingredients. Volume 2. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. 132 R5: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 266 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V7 655 R7: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA11 209 R8: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-256 R9: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 131 R10: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-78 R11: Lide. CRC Hdbk Chem Phys. 75th ed. p 3-78. 1994 R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 450 R13: BRULOS MF ET AL; J SOC COSMET CHEM 28(JUL) 357-365 (1977) R14: DHHS/NTP; Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 423 p. 17 (1993) NIH Publication No. 93-3154 R15: Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 423 (1993) NIH Publication No. 93-3154 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R16: DHHS/NTP; Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 423 p. 16 (1993) NIH Publication No. 93-3154 R17: OPDYKE DL J; FOOD COSMET TOXICOL 12(4) 521 (1974) RS: 9 Record 301 of 1119 in HSDB (through 2003/06) AN: 4334 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: CURCUMIN- SY: *CI-NATURAL-YELLOW-3-; *CI-75300-; *1,6-HEPTADIENE-3,5-DIONE, 1,7-BIS(4-HYDROXY-3-METHOXYPHENYL)- RN: 458-37-7 MF: *C21-H20-O6 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OCCURS NATURALLY IN THE ROOT OF THE HERB CURCUMA LONGA (TURMERIC); ISOLATION BY STEAM DISTILLATION [R1] *ESSENTIAL OIL OF C LONGA...IS OBTAINED BY STEAM DISTILLATION, WITH YIELDS RANGING BETWEEN 1.3 and 5.5%. ... OIL CONTAINS, IN ADDITION TO TUMERONE, FREE ACIDS, CINEOL, BORNEOL, ZINGERONE, PHELLANDRENE, and 3-4% COLORING MATTER (CURCUMIN). /ESSENTIAL OIL OF CURCUMA LONGA/ [R2, 482] *STIEGLITZ, HORN, GERMAN PATENT 859,145 (1952 TO HOECHST). [R3] FORM: *DERIVATIVES: TINCTURE (20% IN 60% ETHANOL), FLUID EXTRACT, AND OLEORESIN. /DERIV OF TURMERIC/ [R2, 482] MFS: *EASTMAN KODAK CO, EASTMAN ORGANIC CHEMS, ROCHESTER, NY 14650 [R1] OMIN: *COLORING MATTER FROM ROOT OF CURCUMA LONGA L, ZINGIBERACEAE. ... HAS ANTI-INFLAMMATORY ACTIVITY. [R3] *CURCUMA LONGA...IS ORIGINALLY FROM SOUTH ASIA AND IS WIDESPREAD THROUGHOUT INDIA, MALAYSIA, CEYLON AND JAPAN. IT IS PERENNIAL HERB WHOSE RHIZOME YIELDS... CLIMBING STALKS WITH LEAVES ONLY OR WITH LEAVES AND FLOWERS. REPRODUCTION OCCURS THROUGH SPLITTING OF RHIZOME. PARTS OF PLANT USED: RHIZOME (DRIED RHIZOME AS IS OR AFTER PREVIOUSLY BOILING IN WATER). /CURCUMA LONGA/ [R2, 481] *TURMERIC YIELDS ABOUT 5% VOLATILE OIL... OIL CONTAINS ALC, TURMEROL, AND KETONE, CURCUMONE. ABOUT 59%...CONSISTS OF MIXT OF ALICYCLIC SESQUITERPENE KETONE, TURMERONE, C15H22O, AND AROMATIC KETONE, ARTURMERONE C15H20O. OTHER ORGANIC COMPD INCL D-ALPHA-PHELLANDRENE, D-SABINENE, ZINGIBERENE, CINEOLE AND BORNEOL. /TURMERIC/ [R4, 118] *CURCUMIN ASSISTS IN IDENTIFICATION OF TURMERIC STARCH. YELLOW, PASTY MASSES OF STARCH BECOME REDDISH-BROWN WITH SODIUM, POTASSIUM, AND AMMONIUM HYDROXIDES; CRIMSON WITH CONCENTRATED SULFURIC ACID. [R4, 119] *CURCUMIN SHOWED BACTERIOSTATIC ACTIVITY AGAINST STAPHYLOCOCCUS. [R5] *IT WAS EFFECTIVE AS AN ANTIINFLAMMATORY AGENT IN INFLAMMATION INDUCED BY CARRAGEENIN AND FORMALIN IN RATS. [R6] *DRIED PRODUCT IS USED IN FORMULATION OF CURRIES. DERIV...IN FORMULATION OF COMPOUNDED OILS AND CONCENTRATES TO FLAVOR FOOD PRODUCTS, PARTICULARLY BOUILLONS, SOUPS, PRECOOKED BEANS, AND SAUCES. FINELY GROUND DRIED PRODUCT OFTEN USED FOR SAME...ALSO AS COLORING IN MUSTARD. COLORING DUE TO CURCUMIN. /PLANT EXTRACTS/ [R2, 482] *REPORTED USES: TURMERIC...GELATINS AND PUDDINGS 0.05 PPM, CONDIMENTS 760 PPM, SOUPS 30-50 PPM, MEATS 200 PPM, PICKLES 690 PPM. TURMERIC EXTRACT... NON-ALCOHOLIC BEVERAGES 0.78 PPM, CONDIMENTS 59 PPM, SOUPS 30-40 PPM, MEATS 43 PPM, PICKLES 40 PPM. /TURMERIC AND TURMERIC EXTRACT/ [R2, 482] *REPORTED USES: TURMERIC OLEORESIN /IN/...CONDIMENTS 640 PPM, MEATS 20-100 PPM, PICKLES 200 PPM. /TURMERIC OLEORESIN/ REGULATORY STATUS: GRAS (I), (II). /TURMERIC AND DERIV/ [R2, 482] *CURCUMIN GAVE GOOD SENSITIVITY AS DETECTION AGENT FOR ALKALI METAL CATIONS BY PAPER CHROMATOGRAPHY. [R7] *A METHOD IS PRESENTED FOR DETERMINING BORON IN SHELLFISH USING A BORON-CURCUMIN COMPLEX. [R8] USE: *FOR PREPARING CURCUMA PAPER, PH RANGE 8-9; IN DETECTION OF BORON [R3] *DYE; ANALYTICAL REAGENT; FOOD DYE; BIOLOGICAL STAIN; ACID-BASE INDICATOR [R9] *DYEING COTTON, WOOL, SILK; COLORING OILS AND WAXES [R10] *FLAVORING AND COLORING AGENT IN FOOD-AS TURMERIC; BORON INDICATOR; STAIN IN MICROSCOPY; ALKALI INDICATOR; COLORING AGENT FOR OILS, WAXES, AND TEXTILES [R1] PRIE: U.S. PRODUCTION: *(1976) 6.4X10+8 G-MIN USE IN FOODS-AS TURMERIC [R1] *(1979) ND [R1] U.S. IMPORTS: *(1977) 1.12X10+9 GRAMS AS TUMERIC [R1] *(1979) 1.54X10+9 GRAMS AS TUMERIC [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *ORANGE-YELLOW, CRYSTAL POWDER; GIVES BROWNISH-RED COLOR WITH ALKALI; LIGHT-YELLOW COLOR WITH ACIDS [R3]; *NEEDLES [R9]; *ORANGE YELLOW PRISMS, RHOMBIC PRISMS FROM METHANOL [R11] MP: *183 DEG C [R3] MW: *368.37 [R3] SOL: *INSOL IN WATER, ETHER; SOL IN ALC, GLACIAL ACETIC ACID [R3]; *SLIGHTLY SOL IN ACETONE, BENZENE; SOL IN ALKALI; SLIGHTLY SOL IN CARBON DISULFIDE; INSOL IN PETROLEUM ETHER [R11] SPEC: *MAX ABSORPTION (DIOXANE): 265 NM (LOG E= 4.18); 420 NM (LOG E= 4.77) [R11]; +IR: 13460 (Sadtler Research Laboratories Prism Collection) [R12]; +UV: 6-924 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R12] OCPP: *ESTER VALUE: 9.8; ESTER VALUE (AFTER ACETYLATION) 36.6; KETONES (CALCULATED AS TURMERONE): 53% /ESSENTIAL OIL OF C LONGA/ [R2, 482] *SPICY, FRESH ODOR REMINISCENT OF SWEET ORANGE AND GINGER; SLIGHTLY PUNGENT, BITTER FLAVOR /CURCUMA LONGA EXTRACTS/ [R2, 482] *SLIGHTLY FLUORESCENT [R4, 118] *SPECIFIC GRAVITY: 0.9348 AT 15 DEG C /ESSENTIAL OILOF CURCUMA LONGA/ [R2, 482] *DARK RED; INSOL IN OIL DILL, VEGETABLE OIL; SOL IN OIL CLOVE; PARTLY SOL IN PROPYLENE GLYCOL, OIL CASSIA /TURMERIC/ [R13] *INDEX OF REFRACTION: 1.5118 @ 20 DEG C/D; SPECIFIC 0PTICAL ROTATION: +14 DEG 4 MIN; SOL: 1:0.6 IN 90% ETHANOL /ESSENTIAL OIL OF CURCUMA LONGA/ [R2, 482] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *ORANGE-YELLOW TURMERIC WILL HOLD SHADE BETTER THAN LEMON-YELLOW WHEN EXPOSED DIRECTLY OR INDIRECTLY TO SUNLIGHT /TURMERIC/ [R4, 118] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *100 MG/KG OF CURCUMIN ADMIN ORALLY FOR 6 CONSECUTIVE DAYS PRODUCED GASTRIC ULCERATION IN ALBINO RATS DUE TO REDUCTION IN THE MUCIN CONTENT OF GASTRIC JUICE. [R14] +Curcumin was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Curcumin was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.001, 0.003, 0.010, 0.033, 0.100, 0.333, 1.000, and 3.333 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 3.333 mg/plate. Precipitate was observed in many of the cultures at this dose as well as some clearing of the background bacterial lawn. [R15] +... CONCLUSIONS: Under the conditions of these 2 year feed studies, there was no evidence of carcinogenic activity of turmeric oleoresin in male F344/N rats administered 2,000, 10,000, or 50,000 ppm. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female F344/N rats based on increased incidences of clitoral gland adenomas in the exposed groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in male B6C3F1 mice based on a marginally increased incidence of hepatocellular adenoma at the 10,000 ppm level, and the occurrence of carcinomas of the small intestine in the 2,000 and 10,000 ppm groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female B6C3F1 mice based on an increased incidence of hepatocellular adenomas in the 10,000 ppm group. /Turmeric Oleoresin, major component 79%-85% curcumin/ [R16] NTP: +... Toxicity and carcinogenicity studies were conducted by administering turmeric oleoresin in feed to groups of male and female F344/N rats and B6C3F1 mice for ... 2 yr. ... 2 YEAR STUDY IN RATS: ... Groups of 60 male and 60 female F344/N rats were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 104 (males) or 103 (females) wk, which were estimated to deliver average daily doses of 80, 460, or 2,000 mg/kg to males and 90, 440, or 2,400 mg/kg to females. ... 2 YEAR STUDY IN MICE: ... Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 103 weeks, which were estimated to deliver average daily doses of 220, 520, or 6,000 mg/kg to males and 320,1,620, or 8,400 mg/kg to females. ... CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of turmeric oleoresin in male F344/N rats administered 2,000, 10,000, or 50,000 ppm. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female F344/N rats based on increased incidences of clitoral gland adenomas in the exposed groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in male B6C3F1 mice based on a marginally increased incidence of hepatocellular adenoma at the 10,000 ppm level, and the occurrence of carcinomas of the small intestine in the 2,000 and 10,000 ppm groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female B6C3F1 mice based on an increased incidence of hepatocellular adenomas in the 10,000 ppm group. /Turmeric Oleoresin, major component 79%-85% curcumin/ [R16] ADE: *ORAL AND IP DOSES OF (3)H-CURCUMIN LED TO FECAL EXCRETION OF MOST OF RADIOACTIVITY. IV AND IP DOSES WERE WELL EXCRETED IN BILE OF CANNULATED RATS. [R17] *WHEN ADMIN ORALLY IN DOSE OF 1 G/KG, CURCUMIN WAS EXCRETED IN FECES TO ABOUT 75%, WHILE NEGLIGIBLE AMT APPEARED IN URINE. MEASUREMENT OF BLOOD PLASMA LEVELS AND BILIARY EXCRETION SHOWED THAT CURCUMIN WAS POORLY ABSORBED FROM THE GUT. [R18] METB: *IV AND IP DOSES OF (3)H-CURCUMIN EXCRETED IN BILE OF CANNULATED RATS. MAJOR METAB WERE GLUCURONIDES OF TETRAHYDROCURCUMIN AND HEXAHYDROCURCUMIN. MINOR METAB WAS DIHYDROFERULIC ACID TOGETHER WITH TRACES OF FERULIC ACID. [R17] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *COLORIMETRY. 44.121; 44.141. FILTH IN TURMERIC, ANALYTICAL CHEMISTRY. /TURMERIC/ [R19] *THIN-LAYER CHROMATOGRAPHIC METHOD AND CONDITIONS FOR DETECTION OF CURCUMIN ARE PRESENTED. [R20] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Turmeric Oleoresin in F344/N Rats and B6C3F1 Mice Technical Report Series No. 427 (1993) NIH Publication No. 93-3158 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for curcumin. Route: dosed feed; Species: prevention 4, mice. [R21] SO: R1: SRI R2: Fenaroli's Handbook of Flavor Ingredients. Volume 1. Edited, translated, and revised by T.E. Furia and N. Bellanca. 2nd ed. Cleveland: The Chemical Rubber Co., 1975. R3: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 348 R4: Merory, J. Food Flavorings: Composition, Manufacture, and Use. 2nd ed. Westport, Conn.: Avi Publishing Co., 1968. R5: LUTOMSKI ET AL; PLANTA MED 26(1) 9 (1974) R6: GHATAK N, BASU N; SODIUM CURCUMINATE AS AN EFFECTIVE ANTIINFLAMMATORY AGENT; INDIAN J EXP BIOL 10(3) 235 (1972) R7: NASI JC; USE OF CURCUMIN FOR IDENTIFICATION OF ALKALI METALS CATIONS; CIENTIFICA 5(3) 241 (1977) R8: DREW RW; SIMPLIFIED SPECTROPHOTOMETRIC CURCUMIN METHOD FOR THE DETERMINATION OF BORON IN MARINE SHELLFISH; J FISH RES BOARD CAN; 32(6) 813 (1975) R9: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 243 R10: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. VI-197 R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-258 R12: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 463 R13: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 247 R14: GUPTA ET AL; INDIAN J MED RES 71(MAY) 806 (1980) R15: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R16: Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (Major Component 79%-85% Curcumin in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 427 (1993) NIH Publication No. 93-3158 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R17: HOLDER ET AL; XENOBIOTICA 8(12) 761 (1978) R18: WAHLSTROM B, BLENNOW G; ACTA PHARMACOL TOXICOL 43(2) 86 (1978) R19: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982.p. 13/230 14.154 R20: KARIG F; RAPID IDENTIFICATION OF CURCUMA RHIZOMES WITH THE TAS (THERMOMICROSEPARATION AND APPLICATION) PROCESS; DTSCH APOTH-ZTG 115(10) 325 (1975) R21: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.20 RS: 13 Record 302 of 1119 in HSDB (through 2003/06) AN: 4336 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HC-YELLOW-#4- SY: *HC-YELLOW-NO-4-; *PHENOL, 2-(BIS(2-HYDROXYETHYL)AMINO)-5-NITRO- RN: 52551-67-4 MF: *C10-H14-N2-O5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *NOT PRODUCED COMMERCIALLY IN THE US [R1] USE: *DYE IN SEMI-PERMANENT HAIR DYE FORMULATIONS [R1] CPAT: *ESSENTIALLY 100% AS HAIR DYE INGREDIENT [R1] PRIE: U.S. PRODUCTION: *(1976) PROBABLY LESS THAN 2.3X10+6 GRAMS [R1] *(1979) NOT PRODUCED COMMERCIALLY IN US [R1] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *242.23 REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 4-Vinyl-1-cyclohexene diepoxide in F344/N Rats and B6C3F1 Mice (Dermal Studies) Technical Report Series No. 362 (1989) NIH Publication No 90-2817 SO: R1: SRI RS: 2 Record 303 of 1119 in HSDB (through 2003/06) AN: 4340 UD: 200302 RD: Reviewed by SRP on 1/26/2002 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged to retrieve the Titanium Compounds record, which has additional information on toxicity and environmental fate of titanium ions and compounds. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TITANOCENE-DICHLORIDE- SY: *BIS- (CYCLOPENTADIENYL)TITANIUM-DICHLORIDE; *BIS(ETA(5)-CYCLOPENTADIENYL)TITANIUM DICHLORIDE; *BISCYCLOPENTADIENYLTITANIUM- (IV)-DICHLORIDE; *BIS(PI-CYCLOPENTADIENYL)TITANIUM DICHLORIDE; *DICHLOROBIS- (CYCLOPENTADIENYL)TITANIUM; *DICHLOROBIS(ETA(5)-CYCLOPENTADIENYL)TITANIUM; *Dichlorobis(eta5-2,4-cyclopentadien-1-yl)titanium; *DICHLOROBIS(PI-CYCLOPENTADIENYL)TITANIUM; *Dichlorobis(eta(sup 5)-2,4-cyclopentadien-1-yltitanium); *DICHLORODICYCLOPENTADIENYLTITANIUM-; *DICHLORODI-PI-CYCLOPENTADIENYLTITANIUM-; *DICHLOROTITANOCENE-; *DICYCLOPENTADIENYLDICHLOROTITANIUM-; *DICYCLOPENTADIENYLTITANIUM-DICHLORIDE-; *TITANIUM, DICHLOROBIS(ETA(5)-2,4-CYCLOPENTADIEN-1-YL)-; *Titanium, dichlorobis(eta5-2,4-cyclopentadien-1-yl)- (9CI); *TITANIUM,-DICHLORODI-PI-CYCLOPENTADIENYL-; *Titanium-ferrocene-; *TITANOCENE- RN: 1271-19-8 RELT: 7000 [TITANIUM COMPOUNDS] MF: *C10-H10-Cl2-Ti MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Dicyclopentadiene + titanium tetrachloride (complex formation) [R1] MFS: *Boulder Scientific Co., 598 3rd Street, P.O. Box 548, Mead, CO 80542, (303) 442- 1199; Production site: Mead, CO 80542 [R2] *Strem Chemicals Inc., 7 Mulliken Way, Newburyport, MA 01950-4-98, (800) 647-8736; Production site: Newburyport, MA 01950-4098 [R2] USE: *RESEARCH CHEMICAL [R3] *Catalyst; with aluminum alkyls as Ziegler-Natta polymerization catalyst [R4, 1618] *Used as an experimental cancer chemotherapeutic agent [R5] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R3] *(1979) NOT PRODUCED COMMERCIALLY IN USA [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Bright red acicular crystals from toluene [R4, 1618]; *Reddish-orange crystalline solid [R5] MP: *289 deg C +/- 2 deg [R4, 14931618] MW: *248.96 [R4, 1618] DEN: *1.60 [R4, 1618] SOL: *Moderately sol in toluene, chloroform, alc, other hydroxylic solvents; sparingly sol in water, petroleum ether, benzene, ether, carbon disulfide, carbon tetrachloride [R4, 1618] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits toxic fumes of /hydrogen chloride/. [R6] SERI: *... IRRITANT TO SKIN AND MUCOUS MEMBRANES. [R7] SSL: *STABLE IN DRY AIR; SLOWLY HYDROLYZED IN MOIST AIR [R7] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *TOXIC BY INHALATION ... [R7] NTOX: *Peripheral blood parameters (hematocrit, counts of red blood cells, reticulocytes, white blood cells and platelets, differential blood count) were analyzed after single injections of the cytostatic agents titanocene dichloride; (ED90, 40 mg/kg; LD10, 60 mg/kg) and cisplatin (ED90, 10 mg/kg). Whereas cisplatin depressed the number of reticulocytes and polychromatophilic erythrocytes to near zero level, titanocene dichloride did not obviously affect the supply of young erythrocytes from bone marrow; red blood cell count and hematocrit values were never reduced after application either of titanocene dichloride or of cisplatin. In the case of leukocytes, white blood cells count did not leave the normal range after treatment with titanocene dichloride, whereas a diminution under control values was observed after application of cisplatin. Finally, the number of circulating platelets transiently decreased beneath control range as well after application of titanocene dichloride as of cisplatin. The results indicate an only slight myelotoxicity induced by titanocene dichloride, the platelets being the only cells affected in a reversible manner. Thus, myelosuppression by titanocene dichloride is apparently even less pronounced than in the case of cisplatin. [R8] *The pattern of organ toxicity after single injections of the antitumor agent titanocene dichloride in ED90 (40 mg/kg) and LD10 (60 mg/kg) doses to female mice was investigated by analyzing various blood chemical parameters and the composition of urine at intervals between 30 min and 16 days after administration. Whereas the serum levels of electrolytes, blood urea nitrogen, creatinine, total bilirubin and cholesterol did not alter, marked and simultaneous increase in serum concentrations of the enzymes gultamate dehydrogenase, glutamine-oxaloacetic transaminase and glutamic-pyruvic transaminase occurred pointing to cellular damage within liver parenchyma; these lesions were apparently reversible within 8 and 16 days after application of titanocene dichloride even at the LD10 dose. Moreover, glucose concentration decreased immediately after titanocene dichloride administration, obviously stimulating a regulative output of glucagon and cortisol; these effects were also reversible within 4 to 8 days after titanocene dichloride administration. No hints to nephrotoxicity induced by titanocene dichloride became manifest in the present study. [R9] *The effect of a single application of toxicologically equivalent doses of the cytostatically active metal complexes titanocene dichloride, upon the morphologic appearance and the functional behavior of the kidneys was analyzed in mice by use of light and electron microscopy, by determination of blood retention values and by urine analysis. The dichlorides of titanium caused only slight morphologic alterations such as increased vacuolation in the proximal tubular cells even after administration of LD50 doses; severe pathologic injuries within the kidneys were always lacking. [R10] *The teratogenic and embryotoxic effects of the antitumor agent titanocene dichloride were investigated after application of single doses of titanocene dichloride (30 or 60 mg/kg) to pregnant mice on days 8, 10, 12, 14, or 16 of gestation. The fetuses were removed on day 18 by caesarian section and examined for external, internal and skeletal malformations as well as for toxic phenomena. The most striking result was the occurrence of cleft palate in numerous fetuses (10% of the fetuses, 30 mg/kg; 40-50%; 60 mg/kg) after titanocene dichloride application on days 10 and 12. Besides the additional appearance of costal malformations in some fetuses, no other malformations were recognizable. On the other hand, the embryotoxic influence titanocene dichloride was significant and caused diminution of the number of live fetuses per litter, marked and dose dependent reduction of mean fetal body weight after titanocene dichloride application on day 8 through day 16 and distinct retardation of skeletal ossification. [R11] *... Toxicology and carcinogenesis studies were conducted by administering titanocene dichloride (greater than 98% pure) in corn oil by gavage to groups of F344/N rats for ... 2 yr. ... The doses selected for the 2 yr studies in rats /were/ O, 25, and 50 mg/kg. ... Under the conditions of these 2 yr gavage studies, there was equivocal evidence of carcinogenic activity of titanocene dichloride in male F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas, squamous cell carcinoma, and basosquamous tumor benign. There was equivocal evidence of carcinogenic activity of titanocene dichloride in female F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas. [R12] NTXV: *LD50 Rat ip 25 mg/kg; [R6] *LD50 Mouse ip 60 mg/kg; [R6] *LD50 Mouse iv 180 mg/kg; [R6] NTP: *... Toxicology and carcinogenesis studies were conducted by administering titanocene dichloride (greater than 98% pure) in corn oil by gavage to groups of F344/N rats for ... 2 yr. ... The doses selected for the 2 yr studies in rats /were/ O, 25, and 50 mg/kg. ... Under the conditions of these 2 yr gavage studies, there was equivocal evidence of carcinogenic activity of titanocene dichloride in male F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas, squamous cell carcinoma, and basosquamous tumor benign. There was equivocal evidence of carcinogenic activity of titanocene dichloride in female F344/N rats based on a marginal increase in the incidence of forestomach squamous cell papillomas. [R12] ADE: *In the present study, the subcellular distribution of titanium in the liver of mice was determined 24 and 48 hr after application of a therapeutic (ED100; ED = effective dose) and a toxic (LD25; LD= lethal dose) dose (60 and 80 mg/kg, respectively) of the antitumor agent titanocene dichloride by electron spectroscopic imaging at the ultrastructural level. At 24 hr titanium was mainly accumulated in the cytoplasm of endothelial and Kupffer cells, lining the hepatic sinusoids. Titanium was detected in the nucleoli and the euchromatin of liver cells, packaged as granules together with phosphorus and oxygen. One day later titanium was still present in cytoplasmic inclusions within endothelial and Kupffer cells, whereas in hepatocyte nucleoli only a few deposits of titanium were observed at 48 hr. At this time titanium was mainly accumulated in the form of highly condensed granules in the euchromatin and the perinucleolar heterochromatin. It was found in the cytoplasm of liver cells, incorporated into cytoplasmic inclusion bodies which probably respresent lysosomes. Sometimes these inclusions were situated near bile canaliculi and occasionally extruded their content into the lumen of bile capillaries. This observation suggests a mainly biliary elimination of titanium containing metabolites. These results confirm electron spectroscopic imaging to be an appropriate method for determining the subcellular distribution of light and medium weight elements within biological tissues. Insights into the cellular mode of action of titanocene complexes or titanocene metabolites can be deduced from the findings of the present study. [R13] *The passage of titaniun containing metabolites across the placenta into the embryonal compartment was investigated by analyzing the titanium content in embryos/fetuses at various intervals between 1 hr and 24 hr after treatment of pregnant mice with single doses of the antitumor agent titanocene dichloride (60 mg/kg) on days 10, 12, 14 or 16 of gestation. After treatment on days 10, 12 or 14, the titanium concentrations were not elevated in comparison to untreated embryos. Only on day 16, beyond the end of organogenesis, small amounts of titanium were detectable in the fetal compartment 4-24 hr after substance application, exceeding the control values by ranging between 2 and 3. These results explain the absence of histologic lesions in developing embryonal organs and the lack of multiple teratogenic effects in new-borns after application of therapeutic doses of titanocene dichloride to pregnant mice during the embryonal organogenesis. [R14] *The pharmacokinetics and organ distribution of titanium were analyzed at various intervals up to 96 hr after a single ip injection of a therapeutic dose of the antitumor agent titanocene dichloride (60 mg/kg). Highest organ concentrations were found in the liver and the intestine where 80-90 mg titanium/kg dry weight were accumulated at 24 and 48 hr, corresponding to liver/blood and intestine/blood ratios of 8-9. [R15] *The serum concentrations of cortisol, aldosterone, progesterone and catecholamines were determined 30 min, 1, 2, 4, 8, 24 and 48 hr after application of single doses of titanocene dichloride (60 mg/kg) to non-pregnant and to pregnant mice (treatment on day 10 of gestation). Titanocene dichloride induced 5-6 fold increases in serum cortisol concentration of pregnant as well as of non-pregnant mice within 1-2 hr after substance application. The serum levels of aldosterone, progesterone and catecholamines were not influenced by treatment with titanocene dichloride. It is supposed that the augmentation of cortisol in the serum is due to a rapid release of cortisol from the suprarenal glands after application of titanocene dichloride thus mediating indirectly the induction of cleft palate in mice. [R16] ACTN: *Dichloro-bis(etanidazole 5-cyclopentadienyl)titanium(IV) and some related complexes were compared with cis-dichlorodiammineplatinum(II) in rats for acute anti-inflammatory activity against carrageenan paw edema, anti-arthritic activity against developing and established adjuvant induced polyarthritis, immunosuppressant activity in a local graft versus host assay, irritant effects at sites of administration (paw, skin, peritoneum) and nephro- and gastro-toxicities. These titanium complexes, like cisplatin and its hydrolysis products, in vivo exhibited both anti-inflammatory and anti-arthritic activity as well as immunosuppressant effects. Nephro- and gastro-toxicity were much less severe than in rats given platinum complexes. In vitro they selectively inhibited (3)H-thymidine incorporation by isolated thymocytes and prevented the germination of radish seeds. When given intraperitoneally, the anti-inflammatory activity may partly be due to a counter-irritant phenomenon since the titanium derivatives elicited an acute peritoneal effusion if they were injected towards the omentum. However, when injected subcutaneously or applied in dimethylformamide or dimethylsulfoxide to the skin, they manifested both anti-inflammatory and anti-arthritic activity without irritancy or much local skin damage. They might therefore have the potential of being useful drugs, especially if released slowly. [R17] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Titanocene Dichloride in F344/N Rats (Gavage Studies) Technical Report Series No. 399 NIH Publication No. 91-2854 (1991) SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 294 R2: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 479 R3: SRI R4: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R5: Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley and Sons. New York, N.Y. (2001).,p. V2 688 R6: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1138 R7: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1160 R8: Kopj-Maier P, Gerlach S; Anticancer Res 6 (2): 235-40 (1986) R9: Kopf-Maier P, Gerlach S; J Cancer Res Clin Oncol 111 (3): 243-7 (1986) R10: Kopf-Maier P, Funke-Kaiser P; Toxicol 38 (1): 81-90 (1986) R11: Kopf-Maier Erkensuwick P; Toxicol 33 (2): 171-81 (1984) R12: Toxicology and Carcinogenesis Studies of Titanocene Dichloride in F344/N Rats (Gavage Studies). Technical Report Series No. 399 (1991) NIH Publication No. 91-2854 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R13: Kopf-Maier P, Martin R; Virchows Arch 57 (4): 213-22 (1989) R14: Kopf-Maier P et al; Toxicol 48 (3): 253-60 (1988) R15: Kopf-Maier P et al; Toxicol 51 (2-3): 291-8 (1988) R16: Kopf-Maier P; Toxicol 37 (1-2): 111-6 (1985) R17: Fairlie DP et al; Chem Biol Interact 61 (3): 277-91 (1987) RS: 16 Record 304 of 1119 in HSDB (through 2003/06) AN: 4346 UD: 200302 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-CHLOROBENZALMALONONITRILE- SY: *(O-CHLOROBENZAL)MALONONITRILE; *O-CHLOROBENZYLIDENE-MALONITRILE-; *Ortho-chlorobenzylidene-malononitrile-; *2-CHLOROBENZYLIDENE-MALONONITRILE-; *2-CHLOROBMN-; *CS-; *CS- (LACRIMATOR); *BETA,BETA-DICYANO-O-CHLOROSTYRENE-; *MALONONITRILE, (O-CHLOROBENZYLIDENE)-; *NCI-C55118-; *OCBM-; *PROPANEDINITRILE, ((2-CHLOROPHENYL)METHYLENE)-; *USAF-KF-11- RN: 2698-41-1 RELT: 2523 [MALONONITRILE] (Metabolite) MF: *C10-H5-Cl-N2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *o-Chlorobenzaldehyde + malononitrile (carbonyl condesation) [R1] *Prepn: B.B. Corson, R.W. Stoughton, J Am Chem Soc 50: 2825 (1928) [R2] FORM: *Available both unground and ground with 5% silica aerogel or treated Cab-O-Sil. [R3] USE: *IT IS USED PRIMARILY AS AN INCAPACITATING AGENT, BOTH BY MILITARY AND LAW ENFORCEMENT PERSONNEL. IT CAN BE DISSEMINATED IN BURNING GRENADES AND WEAPON-FIRED PROJECTILES, AS AN AEROSOL FROM THE FINELY DIVIDED SOLID CHEMICAL, OR FROM A SOLUTION OF THE CHEMICAL DISSOLVED IN METHYLENE CHLORIDE OR ACETONE. [R4, 1991.275] *Riot control agent. [R2] *... lachrymatory chemical used for self-defense devices. [R5] *CS is a sensory irritant whose moderate degree of toxicity has led to its use as a riot/adversary control agent. Major exposure symptoms include eye irritation, conjunctivitis, excess lacrimation, blepharospasm, burning sensation in the nose and throat, chest tightness, sneezing and coughing, stinging or burning sensations on the exposed skin and possible skin sensitization. [R4, 1991.277] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystalline solid [R2] ODOR: *Pepper-like odor. [R6, 62] BP: *310-315 deg C [R2] MP: *95-96 deg C [R2] MW: *188.62 [R2] SOL: *Sparingly soluble in water [R4, 1991.275]; *Soluble in acetone, dioxane, methylene chloride, ethyl acetate, benzene; sparingly soluble in water [R2] VAP: *3.4X10-5 mm Hg at 20 deg C [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of 2-chlorobenzalmalononitrile stem from its toxicologic properties. Toxic primarily by inhalation and dermal contact, exposure to this pepper-smelling, white crystalline substance may occur from its production or use as an incapacitating agent by military and law enforcement personnel. Effects from exposure may include lacrimation, headache, contact burns to the eyes and skin, bronchospasm, laryngospasm, hypersensitivity reactions, and pulmonary edema. Some effects may be delayed. OSHA has established a Ceiling exposure limit of 0.4 mg/cu m for this substance. If contact should occur, irrigate exposed eyes with copious amounts of tepid water for at least 15 minutes, and wash exposed skin thoroughly with soap and water. REAC: *Strong oxidizers. [R6, 62] *The finely powdered nitrile is a significant dust explosion hazard. [R7] DCMP: *When heated to decomposition it emits very toxic fumes of /hydrogen chloride, nitrogen oxides and cyanides./ [R8] SERI: *A human skin, eye irritant. [R8] *Human volunteers experienced greater ocular and respiratory irritation from 0.9 u than from 60 u particles. However, with the larger particles the ocular irritation predominated and required a longer recovery time than with the smaller particles. [R9, 209] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R6, 62] *Wear appropriate eye protection to prevent eye contact. [R6, 62] *Any supplied-air respirator with a full facepiece. Recommendations for respirator selection. Max concn for use: 2 mg/cu m: Respirator Classes: Any supplied-air respirator operated in a continuous flow mode. Eye protection needed. Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern and having a high-efficiency particulate filter. Any self-contained breathing apparatus with a full facepiece. [R6, 62] *Recommendations for respirator selection. Condition: Emergency or planned entry into unknown concn or IDLH conditions: Respirator Classes: Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator with a full face piece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. [R6, 62] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Classes: Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted canister providing protection against the compound of concern and having a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. [R6, 62] OPRM: *The worker should immediately wash the skin when it becomes contaminated. [R6, 62] *The worker should wash daily at the end of each work shift. [R6, 62] *Work clothing that becomes wet or significantly contaminated should be removed or replaced. [R6, 62] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R6, 62] *Contact lenses should not be worn when working with this chemical. [R6, 62] *All nitriles should be handled under carefully controlled conditions and only by personnel having a thorough understanding and knowledge of safe handling techniques. Because of the nature of nitrile cmpd and the lack of complete toxicity data on many nitriles, care should be exercised in handling these cmpd to avoid inhalation of the vapors, ingestion, and contact with the skin. /Nitriles/ [R10] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. CLUP: *1. VENTILATE AREA OF SPILL. 2. FOR SMALL QUANTITIES, SWEEP ONTO PAPER OR OTHER SUITABLE MATERIAL, PLACE IN APPROPRIATE CONTAINER AND BURN IN SAFE PLACE (SUCH AS FUME HOOD). LARGE QUANTITIES MAY BE RECLAIMED; HOWEVER, IF THIS IS NOT PRACTICAL, DISSOLVE IN FLAMMABLE SOLVENT (SUCH AS ALCOHOL) AND ATOMIZE IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. 3. DECONTAMINATE AREA OF SPILL: (A) BY WASHING WITH A 5% SOLUTION OF SODIUM HYDROXIDE IN 50/50 ETHYL ALCOHOL/WATER; OR (B) BY ADDING FLAKE SODIUM HYDROXIDE TO A SOLUTION OR SLURRY OF THE SPILL IN ISOPROPYL ALCOHOL; OR (C) BY COVERING THE SPILL WITH A 10% SOLUTION OF SODIUM HYDROXIDE IN 50/50 ISOPROPYL ALCOHOL/WATER AND LETTING STAND 20 MINUTES BEFORE FLUSHING WITH WATER. [R11] *CHEMICAL DISPOSAL METHOD FOR CS WAS DEVELOPED. THE RECOMMENDED REACTION IS AQ ALKALINE HYDROLYSIS OF CS TO O-CHLOROBENZALDEHYDE. [R12] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *1. BY MAKING PACKAGES OF O-CHLOROBENZYLIDENE MALONONITRILE IN PAPER OR OTHER FLAMMABLE MATERIAL AND BURNING IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. 2. BY DISSOLVING O-CHLOROBENZYLIDENE MALONONITRILE IN FLAMMABLE SOLVENT (SUCH AS ALCOHOL) AND ATOMIZING IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. 3. BY MIXING SOLID WITH 5 PARTS OF 10% SOLUTION OF MONOETHANOLAMINE IN WATER CONTAINING 0.3% OF NONIONIC DETERGENT. 4. BY STIRRING 1 LB OF SOLID FOR 2 HOURS IN 1 GALLON OF A 5-15% SOLUTION OF SODIUM HYDROXIDE IN ETHYLENE GLYCOL, ETHYL ALCOHOL, OR METHYL ALCOHOL. [R11] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Rapid support of respiration and circulation is essential to successful treatment of cyanide intoxication. Massive cyanide overdoses have survived with only good supportive care. Immediate attention should be directed toward assisted ventilation, administration of 100% oxygen, insertion of intravenous lines, and institution of cardiac monitoring. Obtain an arterial blood gas immediately and correct any severe metabolic acidosis (pH below 7.15). Oxygen (100%) should be used routinely in moderate or severely symptomatic patients even in the presence of a normal pO2, since 100% O2 increases O2 delivery, may reactivate cyanide-inhibited mitochondrial enzymes, and potentiates the effect of thiosulfate. Avoid mouth to mouth resuscitation during CPR in order to prevent self poisoning. /Cyanides/ [R13] *Amyl nitrite perles are designed to produce 3% to 5% methemoglobinemia while an iv line is established for iv sodium nitrite. As a temporizing measure, the patient inhales the vapors until the sodium nitrite is ready. Because of the variability in methemoglobin production and the potential for cardiovascular collapse, this step may be omitted if sodium nitrite is readily available and the patient is not in extremes. Adequate ventilation and oxygenation are more important than administration of amyl nitrite. One perle (0.2 ml) is crushed and inhaled for 30 seconds every minute until iv nitrite is given. Sodium nitrite (3% solution), as 10 ml of a 3% solution (eg, 300 mg), is administered iv slowly over 4 minutes to produce a 20% methemoglobin level in adults. Children should receive 0.33 ml of the 3% solution per kilogram initially at an infusion rate of 2.5 ml/min, up to a maximum of 10 ml. Administer sodium nitrite doses to children on the basis of body weight, since fatal methemoglobinemia has occurred in children. /Cyanides/ [R13] HTOX: *... HUMAN VOLUNTEERS /WERE EXPOSED/ TO CS AEROSOLS DISPERSED FROM A 10% SOLUTION IN METHYLENE CHLORIDE, OR FROM PURE MOLTEN COMPOUND. ... 3 OF 4 MEN EXPOSED FOR 90 MINUTES AT 1.5 MG/CU M CS DEVELOPED HEADACHES, and 1 ... DEVELOPED SLIGHT EYE AND NOSE IRRITATION. TWO ... EXPERIENCED HEADACHE FOR 24 HR FOLLOWING EXPOSURE. ... INCREASING TEMPERATURE AND RELATIVE HUMIDITY AS WELL AS HYPERVENTILATION CAUSED DECREASE IN TOLERANCE TIME TO CS EFFECTS. MAJOR EXPOSURE SYMPTOMS WERE EYE IRRITATION, CONJUNCTIVITIS, LACRIMATION AND SKIN BURNING. [R4, 1991.276] *TWENTY FIVE OF 28 WORKERS IN A CHEMICAL PLANT MANUFACTURING ORTHO-CHLOROBENZYLIDENE MALONONITRILE GAVE A HISTORY OF DERMATITIS INVOLVING THE ARMS AND NECK. TWO OF 25 WORKERS SHOWED POSITIVE PATCH TEST REACTIONS WHEN TESTED TO A 1:1000 DILUTION OF ORTHO-CHLOROBENZYLIDENE MALONONITRILE IN OLIVE OIL. [R14] *PULMONARY EDEMA COMPLICATED BY PNEUMONIA, HEART FAILURE AND HEPATOCELLULAR DAMAGE WERE OBSERVED IN A 43 YR OLD MALE EXPOSED TO CS TEAR GAS. [R15] *A 4 MO OLD MALE INFANT DEVELOPED PNEUMONITIS FOLLOWING A PROLONGED EXPOSURE TO TEAR GAS. THE PAIENT HAD A PERSISTENT LEUKOCYTOSIS (WHITE BLOOD CELL COUNT 20000 TO 30000/CU MM) WITH A PREDOMINANCE OF LYMPHOCYTES ON PERIPHERAL BLOOD SMEAR. [R16] *Major exposure symptoms include eye irritation, conjunctivitis, excess lacrimation, blepharospasm, burning sensation in the nose and throat, chest tightness, sneezing and coughing, stinging or burning sensations on the exposed skin and possible skin sensitization. [R4, 1991.277] *... A SIGNIFICANT SKIN SENSITIZING POTENTIAL TO CS EXISTS IN INDUSTRY WHERE THIS CHEMICAL IS HANDLED. THE RESULTING DERMATITIS INVOLVES MAINLY THE ARMS AND NECKS. [R4, 1991.277] *Poison by ingestion, intraperitoneal, and intravenous routes. Moderately toxic by inhalation. Human systemic effects by inhalation: conjunctiva irritation, cough, and unspecified respiratory system effects. A human skin and eye irritant. [R8] *Contact dermatitis was reported in 25/28 workers in a US chemical plant manufacturing CS. [R17, 226] NTOX: *THE LETHAL CONCENTRATION OF 2-CHLOROBENZALMALONONITRILE TO RAINBOW TROUT WAS MORE THAN 0.1 MG/L FOR AN EXPOSURE PERIOD OF LESS THAN 1 WK. [R18] *IN ACUTE EXPOSURES OF RATS TO 2-CHLOROBENZALMALONONITRILE, BOTH THE CORTICAL AND MEDULLARY REGIONS OF THE ADRENAL GLANDS SHOWED SIGNIFICANT CYTOCHEMICAL CHANGES. IP INJECTIONS OF 10 MG/KG AND 20 MG/KG PRODUCED INCREASE IN PERIODIC ACID-SCHIFF, SUDANOPHILIC AND ALKALINE PHOSPHATASE REACTIONS. [R19] *A DOSE-DEPENDENT INHIBITION OF CYTOCHROME OXIDASE, PYRUVATE DEHYDROGENASE COMPLEX, SUCCINATE DEHYDROGENASE, LACTATE DEHYDROGENASE, MALATE DEHYDROGENASE, AND GLUTAMATE DEHYDROGENASE WAS OBSERVED IN RATS ADMINISTERED 10 MG/KG AND 20 MG/KG, IP. IT ALSO HAS A STIMULATING EFFECT ON THE LACTIC ACID FORMATION IN RAT BRAIN DURING GLYCOLYSIS. [R20] *DAILY DOSES OF 8 and 16 MG/KG FOR 10 DAYS TO MICE SUPPRESSED THE HUMORAL IMMUNE RESPONSE TO SHEEP RED BLOOD CELLS. IN ADDITION TO THE DIRECT EFFECT, INCREASED CORTICOSTERONE LEVELS AT 16 MG/KG MAY BE INSTRUMENTAL IN BRINGING ABOUT IMMUNOSUPPRESSION. [R21] *MUTAGENICITY OF O-CHLOROBENZYLIDENE MALONONITRILE WAS TESTED IN AMES SALMONELLA/MICROSOME ASSAY WITH STRAINS TA 1535, TA 1537, TA 1538, TA 98, AND TA 100. WITHOUT PREINCUBATION DOUBLING OF REVERTANTS WAS SEEN IN STRAIN TA 100 AT CONCENTRATIONS OF 1000 and 2000 UG/PLATE. A SLIGHT INCREASE OCCURRED WITH PREINCUBATION IN TA 100 AT CONCENTRATIONS OF 100 and 500 UG. [R22] *FOLLOWING EXPOSURE TO 150 MG/CU M O-CHLOROBENZYLIDENE MALONONITRILE FOR 2 HR, 2 ANIMALS (HAMSTERS) OUT OF 240 DIED OF BRONCHOPNEUMONIA. EXPOSURE OF 106 HAMSTERS AND 120 RATS TO 480 MG/CU M RESULTED IN THE DEATHS OF 31 HAMSTERS AND 9 RATS. ANIMALS THAT DIED WITHIN 48 HR OF EXPOSURE HAD MODERATELY SEVERE PULMONARY CONGESTION, HEMORRHAGES AND OCCASIONALLY EDEMA. ACUTE RENAL CORTICAL AND MEDULLARY TUBULAR NECROSIS WAS A COMMON FINDING. IN SOME RATS THERE WAS MIDZONAL HEPATOCELLULAR NECROSIS. [R23] *PYROTECHNICALLY GENERATED (GRENADE) O-CHLOROBENZYLIDENE MALONONITRILE WAS GIVEN BY INHALATION TO CATS IN CONCN BETWEEN 460 AND 1040 MG/CU M FOR 1 HR. RESP DEPRESSION, POSSIBLY REFLEX IN NATURE, REGULARLY OCCURRED WHEN THE MATERIAL WAS GIVEN VIA THE UPPER RESP TRACT, AND RESP STIMULATION OCCURRED WHEN IT WAS GIVEN VIA TRACHEAL CANNULA. [R24] *O-CHLOROBENZYLIDENE MALONONITRILE PRODUCED A 50% DEPRESSION OF RESP RATE IN MICE AFTER A 1 MIN EXPOSURE. [R25] *RABBIT EYES WERE CONTAMINATED WITH CS IN SOLN (0.5 TO 10% IN POLYETHYLENE GLYCOL 300), AS A SOLID (0.5 TO 5 MG), AND AS A PYROTECHNICALLY GENERATED SMOKE (15 MIN EXPOSURE TO 6 G/CU M). CS CAUSED LACRIMATION, BLEPHARITIS AND CONJUNCTIVAL IRRITATION BY ALL THE METHODS OF CONTAMINATION, THE SEVERITY AND DURATION OF WHICH INCR WITH THE AMT OF MATERIAL APPLIED. [R26] *NO INCR IN LUNG TUMORS WAS OBSERVED IN MICE OR RATS EXPOSED TO CT'S OF 50 AND 500 MG O-CHLOROBENZYLIDENEMALONONITRILE MIN/CU M 5 DAYS A WEEK FOR 4 WEEKS. EXPOSURE CONCN WERE ABOUT 21 MG/CU M, AND TOTAL CT'S WERE, THUS, 1000 AND 10000 MG MIN/CU M. [R27] *PREGNANT RATS AND RABBITS WERE EXPOSED TO O-CHLOROBENZYLIDENE MALONONITRILE AEROSOLS AT 6, 20, AND 60 MG/CU M FOR 5 MIN ON DAYS 6-15 AND 6-18 OF PREGNANCY, RESPECTIVELY, AND RATS WERE INJECTED IP AT 20 MG/KG ON DAYS 6, 8, 10, 12, OR 14 OF PREGNANCY, BUT IT WAS NOT EMBRYOLETHAL OR TERATOGENIC AND THERE WAS NO EFFECT ON THE NUMBER OF IMPLANTATIONS OR LITTERS PRODUCED. [R28] *CS was found to bind to nuclear proteins but not to DNA in rats. In a study in which Sprague Dawley rats were administered an intraperitoneal injection of 13 mg/kg of CS with a (14)C-label at the benzylic carbon, very little radioactivity was found in liver DNA 8 or 75 hours after the animals were dosed. However, a considerable amount of radioactivity was observed in nuclear proteins isolated from liver and kidney at these times. The binding to protein may have occurred between the carbons at the double bond in CS and the sulfhydryl groups of proteins. Additionally, the binding could have occurred between o-chlorobenzaldehyde (a hydrolysis product) and the amino groups of proteins. [R29] *Results of bacterial mutagenicity assays with CS were generally negative, although there have been reports of equivocal to weakly positive responses observed in Salmonella strain TA100 in the absence of S9 activation and in TA97 with S9. Administration of CS in feed did not result in an increase in sex-linked recessive lethal mutations in germ cells of male Drosophila. In mammalian cell cultures, positive results were reported for gene mutation induction in L5178Y mouse lymphoma cells, and cytogenetic tests conducted by the National Toxicology Program in Chinese hamster ovary cells were positive for induction of sister chromatid exchanges and chromosomal aberrations in the presence and absence of S9. However, no increase /was observed/ in micronucleated polychromatic erythrocytes in the bone marrow of mice administered CS either by intraperitoneal injection or orally. [R29] *The responses in Salmonella gene mutation tests with 94% o-chlorobenzalmalononitrile (with 5% Cab-O-Sil colloidal silica; 1% hexamethyldisilizane) were equivocal in one laboratory for strain TA100 in the absence of exogenous metabolic activation (S9) and equivocal in another laboratory for TA97 with (S9); in all other strains tested. 94% o-Chlorobenzalmalononitrile (with 5% Cab-O-Sil colloidal silica; 1% hexamethyldisilizane) was clearly negative with or without (S9). 94% o-Chlorobenzalmalononitrile (with 5% Cab-O-Sil colloidal silica; 1% hexamethyldisilizane) induced trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells in the absence of (S9); it was not tested with (S9). 94% o-Chlorobenzalmalononitrile (with 5% Cab-O-Sil colloidal silica; 1% hexamethyldisilizane) induced both sister chromatid exchanges and chromosomal aberrations in CHO cells with and without S(9). [R30] *STRUCTURE-ACTIVITY RELATIONSHIPS WERE QUALITATIVELY AND QUANTITIVELY EXAMINED FOR 56 COMPOUNDS (EG DERIVATIVES OF PROPIONITRILE, ACRYLONITRILE, AND CYSTEAMINE) WHICH CAUSED DUODENAL ULCER AND/OR ADRENOCORTICAL NECROSIS IN RATS. ULCEROGENIC ACTIVITY WAS MOST INTENSE IN THE CARBONITRILES ATTACHED TO 2 OR 3-C BACKBONES. [R31] *Animals that died within 48 hours after inhalation exposure showed extreme congestion, marked congestion of the alveolar capillaries and intrapulmonary veins, interpulmonary and intrapulmonary hemorrhage, and excessive secretions in the bronchioles. [R4, 1991.275] *... Long-term repeated exposures in rodents may result in non-neoplastic toxic changes in the respiratory epithelium of the nasal passages. [R4, 1991.275] *... Mice, rats and guinea pigs /were exposed/ to CS for 1 hr per day, 5 days per week, for up to 120 days. Animals were then observed for 6 months and the survivors were sacrificed. Exposure concn were approximately 0.3, 30 and 200 ug/l. Exposure of the highest group was stopped after 3-5 exposures, because of high mortality. A few pathological changes were observed that showed a relationship with exposure, mostly chronic inflammatory changes in the lungs, especially in the guinea pigs. There was no evidence of a tumorigenic response to CS, although the study was too short to exclude the possibility that CS had tumorigenic potential. The authors concluded that 30 ug/l could be considered a no-adverse-effect concn for CS. [R17, 225] *... Rats and hamsters /were exposed/ to a single dose of CS of either 28,800 mg min/cu m or 18,000 mg min/cu m, the animals being observed for up to 32 months. The procedure had no effect on survival and no other test-material-related effects were observed. [R17, 225] NTXV: *LD50 Rat iv 28 mg/kg; [R32] *LD50 Rat ip 48 mg/kg; [R32] *LD50 Rat (male) oral 1366 mg/kg; [R33] *LD50 Rat (female) oral 1284 mg/kg; [R33] *LD50 Guinea pig (female) 212 mg/kg /From table/; [R17, 225] *LD50 Rabbit (female) 27 mg/kg /From table/; [R17, 225] ETXV: *LC50 Rainbow trout 1.28 mg/l/12 hr. /Conditions of bioassay not specified/; [R34] *LC50 RAINBOW TROUT > 0.1 MG/L < 1 WK; [R18] NTP: *Toxicology and carcinogenesis studies were conducted by exposing 50 F344/N rats and 50 B6C3F1 mice of each sex to ... (94% o-chlorobenzalmalononitrile) /by inhalation/. ... Exposure concentrations for the 2 yr studies were 0, 0.075, 0.25, or 0.75 mg/cu m for 6 hr/day, 5 days/wk for 105 wk for groups of 50 rats of each sex. Groups of 50 mice of each sex were exposed to 0, 0.75, or 1.5 mg/cu m on the same schedule. ... Under the conclusions of these inhalation studies, there was no evidence of carcinogenic activity ... for male or female F344/N rats exposed to 0.075, 0.25, or 0.75 mg/cu m for 2 yr. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 0.75 or 1.5 mg/cu m in air for up to 2 yr. [R35] *Toxicology and carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years, to a CS2 (94% o-chlorobenzalmalonitrile [CS]; 5% Cab-O-Sil colloidal silica; 1% hexamethyldissilizane), aerosol. ... No compound-related clinical signs were observed. No significant differences in survival were seen for any group of rats or mice of either sex. ... Compound-related nonneoplastic lesions occurred in the nasal passage of exposed rats and mice. In exposed rats, hyperplasia and squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium with ciliated columnar and/or squamous metaplasia were observed. Focal chronic inflammation and proliferation of the periosteum of the turbinate bones were increased slightly in rats at the top exposure concentration. Suppurative inflammation with hyperplasia and squamous metaplasia of the respiratory epithelium occurred in exposed mice. The were no compound-related increased incidences of neoplasms in rats or mice. ... In exposed female mice, there were pronounced decreases in the incidences of adenomas of the pituitary pars distalis (control, 13/47; 0.75 mg/cu m, 5/46; 1.5 mg/cu m, 1/46) and decreased incidences of malignant lymphomas (21/50; 12/50; 8/50). [R30] ADE: *... Rats exposed to CS aerosols at concn of 14-245 mg/cu m for 5 min absorbed measurable quantities of the compound. Both CS and a reduction product, 2-chlorobenzyl malononitrile, were detected in the blood. [R17, 222] METB: *... METABOLITE IN BLOOD OF CATS AND RATS, TO WHICH CS, O-CHLOROBENZYLIDENE MALONONITRILE, HAD BEEN ADMINISTERED, HAS ... BEEN /IDENTIFIED/ ... AS O-CHLOROBENZYLMALONONITRILE. REDUCTION OF THE BENZYLIDENE DOUBLE BOND, WHICH OCCURS IN THE ERYTHROCYTE CYTOPLASM, IS ASSOCIATED WITH THE DETOXIFICATION OF CS. [R36] *IN RABBITS ADMINISTERED IV DOSES 2 REACTIONS TAKE PLACE HYDROLYSIS AND REDUCTION. O-CHLOROBENZALDEHYDE AND MALONONITRILE ARE PRODUCTS OF HYDROLYSIS AND O-CHLOROBENZYL MALONONITRILE IS PRODUCT OF REDUCTION. BIOTRANSFORMATION TAKES PLACE MAINLY IN THE BLOOD, BUT LIVER, IN CONTRAST TO KIDNEYS, IS ALSO IMPORTANT IN THE TRANSFORMATION. O-CHLOROBENZYLIDENE MALONONITRILE AND ITS BASIC METABOLITES, O-CHLOROBENZALDEHYDE AND O-CHLOROBENZYL MALONONITRILE HAVE SHORT HALF-LIVES IN THE BLOOD. [R37] *MICE RECEIVED O-CHLOROBENZYLIDENE MALONONITRILE BY IP INJECTION (0.5 LD50) OR BY AEROSOL EXPOSURE (20000 MG/MIN/CU M). INCREASED EXCRETION OF THIOCYANATE IN THE URINE WAS OBSERVED, INDICATING A TRANSFORMATION OF CS TO CYANIDE IN VIVO. [R38] *The fate of (3)H-ring labeled, (14(C-cyanide labeled, and (14C=C) side chain-labeled CS was studied in Porton rats given intraperitoneal or gavage doses ranging from 0.08 to 159 umol/kg. In most cases, the largest proportion (44%-100%) of the dose was eliminated in the urine. The major urinary metabolites identified were 2-chlorohippuric acid, 1-O-(2-chlorobenzyl)glucuronic acid, 2-chlorobenzyl cysteine, and 2-chlorobenzoic acid. Minor metabolites identified included 2-chlorobenzyl alcohol and 2-chlorophenyl-2-cyanopropionate. [R29] *... Six male volunteers /were exposed/ to CS at concn of 0.5-1.5 mg/cu m for 90 min. Neither CS nor 2-chlorobenzaldehyde was detected in the blood of those persons, and only in one was a trace of 2-chlorobenzyl malononitrile detected. [R17, 223] ACTN: *2-CHLOROBENZYLIDENEMALONONITRILE HAS 2 DISTINCT ... /MECHANISMS/ OF TOXICITY IN MICE; ONE, OF SHORT TERM DURATION, WHICH IS THE MORE TOXIC OF THE TWO, INVOLVES LIBERATION OF CYANIDE WITHIN THE BODY, AND IS REVERSED BY SODIUM THIOSULFATE; THE OTHER IS OF LONG-TERM DURATION, THE MECHANISM OF WHICH HAS NOT BEEN DETERMINED. [R39] *The high toxicity of CS when given by the intraperitoneal or intravenous routes was due to its rapid metabolism, which leads to high levels of cyanide and thiocyanate in the urine. [R40] *Many of the changes seen in the lungs with CS smoke are similar in quality to those produced by other irritant smokes. The lethality of CS is probably dependent on two main factors: its alkylating properties and its cyanogenic potential. On the first point, CS reacts with glutathione, and also lipoic acid and cysteine, and ... the alkylating properties of the molecule are major determinants of the toxicity of CS after intravenous administration. There is also evidence that cyanide contributes to the toxicity of CS. [R17, 225] INTC: *When CS is applied in a solvent, its effect on the cornea is very much influenced by the nature of the solvent, less injury resulting from solutions in trichloroethane or tri(2-ethylhexyl)phosphate than in methylene dichloride, corn oil, or polyethylene glycol 300. [R9, 210] *The toxic mechanism of nitriles and the effect of metabolic modifiers in mice were studied in relation to their physicochemical properties. All the test nitriles liberated cyanide both in vivo and in vitro, with the exception of benzonitrile, although the extent of liberation and the effect of carbon tetrachloride pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into 3 groups. In group 1, acute toxicity was greatly reduced by carbon tetrachloride pretreatment, in group 2, toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher at death in the brains of mice given group 1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. The relation between log (1/LD50) and log p for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear. For most nitriles, the in vitro metabolism was inhibited when the incubation mixture contained either SKF-525A, carbon monoxide, or microsomes from mice treated with carbon tetrachloride. When mice were dosed with ethyl alcohol, metabolic enhancement of nitriles was seen compared with the control. However, ethyl alcohol, when added to the incubation mixture, inhibited the in vitro metabolism of nitriles. /Nitriles/ [R41] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *2-Chlorobenzalmalononitrile's production and use as a riot control agent may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 3.4X10-5 mm Hg at 20 deg C indicates 2-chlorobenzalmalononitrile will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2-chlorobenzalmalononitrile will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 110 hrs. Particulate-phase 2-chlorobenzalmalononitrile will be removed from the atmosphere by wet and dry deposition. If released to soil, 2-chlorobenzalmalononitrile is expected to have low mobility based upon an estimated Koc of 1700. Analysis of snow samples near a detonation of a 2-chlorobenzalmalononitrile tear gas grenade in a Norwegian forest found detectable levels (0.3 ug) in snow 70 meters from the detonation site 29 days after the detonation. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 1.0X10-8 atm-cu m/mole. 2-Chlorobenzalmalononitrile will not volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 2-chlorobenzalmalononitrile is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. An estimated BCF of 30 suggests the potential for bioconcentration in aquatic organisms is low. If released to water or soil, the major degradation process is expected to be hydrolysis. Aqueous hydrolysis experiments in seawater have determined hydrolysis half-lives of 281.7 min at 0 deg C and 14.5 min at 25 deg C. However, actual environmental degradation rates may be much slower because the rate at which 2-chlorobenzalmalononitrile dissolves in water can be very slow. 2-Chlorobenzalmalononitrile released to water could float and travel for considerable distances before it dissolves. Occupational exposure to 2-chlorobenzalmalononitrile may occur through dermal contact with this compound at workplaces where 2-chlorobenzalmalononitrile is produced or used. Exposure to the general population may occur due to its use as a riot control agent through eye and dermal contact. (SRC) ARTS: *2-Chlorobenzalmalononitrile's production and use as a riot control agent(1) may result in its release to the environment through various waste streams(SRC). [R42] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a structure estimation method(2), indicates that 2-chlorobenzalmalononitrile is expected to have low mobility in soil(SRC). 2-Chlorobenzalmalononitrile was applied to snow surfaces in a Norwegian forest; more than 10% remained after 28 days(5). 2-Chlorobenzalmalononitrile was found in Norwegian snow samples 70 m downwind and for as long as 29 days following the detonation of a grenade containing this compound(5). Dusts or powders of 2-chlorobenzalmalononitrile that have settled to the ground after its use as a riot control agent can remain active for as long as 5 days(6); if the compound was formulated with a silicone water repellent, it may persist for as long as 45 days(6). Volatilization of 2- chlorobenzalmalononitrile from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.0X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(3). The major degradation process for 2-chlorobenzalmalononitrile in moist soil is expected to be hydrolysis(SRC); half-lives of 281.7 min at 0 deg C and 14.5 min at 25 deg C have been determined(7). Actual environmental degradation rates may be much slower because the rate at which 2-chlorobenzalmalononitrile dissolves in water can be very slow(7). 2-Chlorobenzalmalononitrile is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 3.4X10-5 mm Hg(4). [R43] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from an estimation method(2), indicates that 2-chlorobenzalmalononitrile is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 1.0X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). 2-Chlorobenzalmalononitrile is expected to hydrolyze in aquatic environments forming 2-chlorobenzaldehyde. Aqueous hydrolysis experiments in seawater have determined hydrolysis half-lives of 281.7 min at 0 deg C and 14.5 min at 25 deg C(8). However, actual environmental degradation rates may be much slower because the rate at which 2-chlorobenzalmalononitrile dissolves in water can be very slow(8). 2-Chlorobenzalmalononitrile released to water could float and travel for considerable distances before it dissolves(8); once it is dissolved, hydrolysis will proceed rapidly. Bioconcentration is not expected when 2-chlorobenzalmalononitrile is present in the dissolved form as hydrolysis will occur so rapidly(SRC). According to a classification scheme(5), an estimated BCF of 30(SRC), from an estimated log Kow of 2.76(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low. Aquatic volatilization and adsorption to sediment are not expected to be environmentally important(SRC). [R44] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 2-chlorobenzalmalononitrile, which has a vapor pressure of 3.4X10-5 mm Hg at 20 deg C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase 2-chlorobenzalmalononitrile is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 110 hrs(SRC), calculated from its rate constant of 3.5X10-12 cu cm/molecule-sec at 25 deg C(3) determined using a structure estimation method(3). Particulate-phase 2-chlorobenzalmalononitrile may be removed from the air by wet and dry deposition(SRC). 2-Chlorobenzalmalononitrile when dissolved in water is susceptible to rapid hydrolysis; half-lives range from 281.7-14.5 minutes at 0-25 deg C(4). Therefore, dissolution of the compound into clouds or rain will contribute to its atmospheric removal(SRC). [R45] ABIO: *The rate constant for the vapor-phase reaction of 2-chlorobenzalmalononitrile with photochemically-produced hydroxyl radicals has been estimated as 3.5X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 110 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The first-order hydrolysis rate constants of 2-chlorobenzalmalononitrile in seawater at 0, 15, and 25 deg C were experimentally determined to be 4.10X-5, 2.30X10-4, and 7.97X10-4 per sec, respectively(2); these rate constants correspond to respective half-lives of 281.7, 50.2, and 14.5 minutes(SRC). However, the degradation rate in water may be much longer than the hydrolysis rates would suggest(2); 2-chlorobenzalmalononitrile is produced as fine particles whose size and surface coatings greatly affect the rate at which it dissolves in water(2). 2-Chlorobenzalmalononitrile released to water could float and travel for considerable distances before it dissolves(2). Once it is dissolved, hydrolysis will proceed rapidly(2). o-Chlorobenzaldehyde was detected as a hydrolysis product(2). [R46] BIOC: *An estimated BCF of 30 was calculated for 2-chlorobenzalmalononitrile(SRC), using an estimated log Kow of 2.76(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R47] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 2-chlorobenzalmalononitrile can be estimated to be 1700(SRC). According to a classification scheme(2), this estimated Koc value suggests that 2-chlorobenzalmalononitrile is expected to have low mobility in soil. [R48] VWS: *The Henry's Law constant for 2-chlorobenzalmalononitrile is estimated as 1.0X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that 2-chlorobenzalmalononitrile is expected to be essentially nonvolatile from water surfaces(2). 2-Chlorobenzalmalononitrile's Henry's Law constant(1) indicates that volatilization from moist soil surfaces will not occur(SRC). 2-Chlorobenzalmalononitrile is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 3.4X10-5 mm Hg(3). [R49] RTEX: *Occupational exposure to 2-chlorobenzalmalononitrile may occur through dermal contact with this compound at workplaces where 2-chlorobenzalmalononitrile is produced or used. Exposure to the general population may occur through eye and dermal contact due to its use as a riot control agent. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *2 mg/cu m [R6, 62] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.05 ppm (0.4 mg/cu m). [R50] *Vacated 1989 OSHA PEL Ceiling limit 0.05 ppm (0.4 mg/cu m), skin designation, is still enforced in some states. [R6, 361] NREC: *Recommended Exposure Limit: Ceiling value: 0.05 ppm (0.4 mg/cu m), skin [R6, 62] TLV: *Ceiling Limit 0.05 ppm, skin [R51] *A4. A4= Not classifiable as a human carcinogen. [R51] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 304. Analyte: 2-Chlorobenzylidene malononitrile. Matrix: Air. Procedure: Filter/sorbent collection, extraction with 20% methylene chloride in hexane. Flow rate: 1.5 l/min. Sample size: 90 liters. [R52] *NIOSH Method: 304. Analyte: o-Chlorobenzylidene malononitrile. Matrix: Air. Procedure: Filter/sorbent collection, extraction with 20% methylene chloride in hexane. Flow Rate: 1.5 l/min. Sample Size: 90 liters. [R53] ALAB: *CAN BE EXTRACTED FROM CHEMICAL PROTECTION SPRAYS WITH METHANOL. ANALYSIS IS BY GC/MS. [R54] *REVERSED-PHASE HPLC IS DESCRIBED. A CONCENTRATION OF 1-10 NG CAN BE DETECTED AT 313 NM. [R55] *NIOSH Method: 304. Analyte: o-Chlorobenzylidene malononitrile. Matrix: Air. Procedure: HPLC. Method Evaluation: Method was validated over the range of 0.1472 to 0.819 mg/cu m using a 90 liter sample. Method detection limit: 0.3 ug/sample. Precision (CVt): 0.102. Interferences: No specific interferences. [R53] CLAB: *CONCENTRATIONS OF 2-CHLOROBENZALMALONONITRILE AND ITS METABOLITES WERE DETERMINED IN BLOOD BY GC. [R37] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: JONES G RN; CS (2,CHLOROBENZYLIDENE MALONONITRILE) AND ITS CHEMICAL RELATIVES; NATURE (LOND) 235 (5336): 257 (1972). THIS REVIEW ARTICLE SURVEYS THE PRINCIPAL ASPECTS OF THE CHEMICAL PROPERTIES OF BENZYLIDENE MALONONITRILES AND THEIR EFFECTS ON THE INTERACTIONS WITH LIVING ORGANISMS (HUMAN AND ANIMAL). Kaplita PV and Smith RP; Toxicol Appl Pharmacol 84 (3): 533-540 (1986). Pathways for the bioactivation of aliphatic nitriles to free cyanide in mice. DHHS/NTP; Toxicology and Carcinogenesis Studies of CS (94% o-Chlorobenzalmalononitrile) in F344/N Rats and B6C3F1 Mice (Inhalation Studies)Technical Report Series No. 377 (1990) NIH Publication No. 90-2832 SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 197 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 354 R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 254 R4: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R5: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V15 (95) 943 R6: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R7: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 815 R8: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 734 R9: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. R10: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1447 R11: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R12: BROOKS ME ET AL; US NTIS, AD REPORT AD-A033469 (1976) R13: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 833 R14: SHMUNES E, TAYLOR JS; ARCH DERMATOL 107 (2): 212 (1973) R15: KRAPF R, THALMANN H; SCHWEIZ MED WOCHENSCHR 111 (52): 2056 (1981) R16: PARK S, GIAMMONA ST; AM J DIS CHILD 123 (3): 245 (1972) R17: Marrs, T.C., Maynard, R.L., Sidell, F.R.; Chemical Warfare Agents. Toxicology and Treatment. John Wiley and Sons, New York, NY. (1996). R18: ABRAM FSH, WILSON P; WATER RES 13 (7): 631 (1979) R19: CHOWDHURY AR ET AL; MIKROSKOPIE 35 (7-8): 183 (1979) R20: DUBE SN; INDIAN J EXP BIOL 18 (1): 80 (1980) R21: NAGARKATTI M ET AL; TOXICOL LETT 8 (1-2): 73 (1981) R22: VON DAENIKEN A ET AL; ARCH TOXICOL 49 (1): 15 (1981) R23: BALLANTYNE B, CALLAWAY S; MED SCI LAW 12 (1): 43 (1972) R24: BRIMBLECOMBE RW ET AL; BRIT J PHARMACOL 44 (3): 561 (1972) R25: BALLANTYNE B ET AL; CURR APPROACHES TOXICOL: 129 (1977) R26: BALLANTYNE B ET AL; ARCH TOXICOL 32 (3): 149 (1974) R27: MCNAMARA BP ET AL; CS. US NAT TECH INFORM SERV, AD REPORT NO 770365/5GA (1973) R28: UPSHALL DG; TOXICOL APPL PHARMACOL 24 (1): 45 (1973) R29: DHHS/NTP; Toxicology and Carcinogenesis Studies of CS (94% o-Chlorobenzalmalononitrile) in F344/N Rats and B6C3F1 Mice p.14 (1990) Technical Rpt Series No. 377 NIH Pub No. 90-2832 R30: DHHS/NTP; Toxicology and Carcinogenesis Studies of CS (94% o-Chlorobenzalmalononitrile) in F344/N Rats and B6C3F1 Mice p.3 (1990) Technical Rpt Series No. 377 NIH Pub No. 90-2832 R31: SZABO S ET AL; J PHARMACOL EXP THER 223 (1): 68 (1982) R32: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 328 R33: DHHS/NTP; Toxicology and Carcinogenesis Studies of CS (94% o-Chlorobenzalmalononitrile) in F344/N Rats and B6C3F1 Mice p.13 (1990) Technical Rpt Series No. 377 NIH Pub No. 90-2832 R34: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 361 R35: DHHS/NTP; Toxicology and Carcinogenesis Studies of CS2 (94% o-Chlorobenzalmalononitrile) in F344/N Rats and B6C3F1 Mice p.3 (1990) Technical Rpt Series No. 377 NIH Pub No. 90-2832 R36: The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975. 338 R37: PARADOWSKI M; POL J PHARMACOL PHARM 31 (6): 563 (1979) R38: FRANKENBERG L, SORBO B; ARCH TOXIKOL 31 (2): 99 (1973) R39: JONES GR N, ISRAEL MS; NATURE (LONDON) 228 (5278): 1315 (1970) R40: Lunn, G., E.B. Sansone. Destruction of Hazardous Chemicals in the Laboratory. New York, NY: John Wiley and Sons, Inc. 1994. 275 R41: Tanii H; Juzen Igakkai Zasshi 94 (4): 664-77 (1985) R42: (1) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co., p. 354 (1996) R43: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Budavari S, ed; The Merck Index. 12th ed. Station, NJ: Merck and Co., p. 354 (1996) (5) Johnsen BA, Blanch JH; pp. 22-30 in Proc First World Congress, Med Soc Hyg Chem Warfare Toxicol Eval Part 22 (1984) (6) Harris BL et al; Kirk-Othmer Encycl Chem Technol 3rd ed. NY, NY: John Wiley and Sons 5: 401 (1979) (7) Demek MM et al; Behavior of Chemical Agents in Seawater. Edgewood Arsenal Technical Report EATR 4417. Task 1B662706A09501. Edgewood Arsenal, MD: Dept of the Army (1970) R44: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Demek MM et al; Behavior of Chemical Agents in Seawater. Edgewood Arsenal Technical Report EATR 4417. Task 1B662706A09501. Edgewood Arsenal, MD: Dept of the Army (1970) R45: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co., Inc., p. 354 (1996) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Demek MM et al; Behavior of Chemical Agents in Seawater. Edgewood Arsenal Technical Report EATR 4417. Task 1B662706A09501. Edgewood Arsenal, MD: Dept of the Army (1970) R46: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Demek MM et al; Behavior of Chemical Agents in Seawater. Edgewood Arsenal Technical Report EATR 4417. Task 1B662706A09501. Edgewood Arsenal, MD: Dept of the Army (1970) R47: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R48: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Johnsen BA, Blanch JH; pp. 22-30 in Proc First World Congress, Med Soc Hyg Chem Warfare Toxicol Eval Part 22 (1984) R49: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co., p. 354 (1996) R50: 29 CFR 1910.1000 (7/1/99) R51: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. 25 R52: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.304 R53: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V5 304-1 R54: NOWICKI J; J FORENSIC SCI 27 (3): 704 (1982) R55: RAGHUVEERAN CD, MALHOTRA RC; J CHROMATOGR 240 (1): 243 (1982) RS: 47 Record 305 of 1119 in HSDB (through 2003/06) AN: 4347 UD: 200302 RD: Reviewed by SRP on 9/14/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYLENEDIANILINE-DIHYDROCHLORIDE- SY: *ANILINE,-4,4'-METHYLENEDI-,-DIHYDROCHLORIDE-; *BENZENAMINE,-4,4'-METHYLENEDI-,-DIHYDROCHLORIDE-; *4,4'-METHYLENEDIANILINE-DIHYDROCHLORIDE-; *NCI-C54604- RN: 13552-44-8 MF: *C13-H14-N2.2Cl-H MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- IMP: *Assay of a commercial sample indicated a minimum content of 99% aromatic amine; this would contain approximately 3% isomeric amines and traces of aniline. [R1] OMIN: *Available as the free amine in bulk quantities. [R1] USE: *... As a research chemical ... . [R2, p. 251 (1994)] *Over 90% of the 4,4'-methylenedianiline produced in the USA is used as a closed system intermediate in the production of 4,4'-methylenediphenyl diisocyanate which is used for the manufacture of elastomers such as spandex fibers. /4,4'-Methylenedianiline/ [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *crystalline solid [R2, p. 251 (1994)] MP: *288 deg C [R1] MW: *271.21 [R4] SOL: *soluble in water [R2, p. 251 (1994)] SPEC: *Sadtler Research Lab Spectra - UV: 19954; IR: 42877 (prism), 23877 (grating); NMR: 14566 (C-13) [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *It is combustible when exposed to heat or flame. /4,4'-Methylenedianiline/ [R2, p. 251 (1994)] DCMP: *When heated to decomp /temperature unspecified/ , it emits toxic fumes of aniline and NOx. /4,4'-Methylenedianiline/ [R2, p. 251 (1994)] +When heated to decomposition ... emits toxic fumes of /nitrogen oxides and hydrogen chloride/. [R5] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R6, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R6, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R6, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R6, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R6, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R6, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R6, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R6, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R6, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R6, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R6, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R6, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R6, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Sufficient evidence of carcinogenicity in animals. Overall evaluation: Group 2B: The agent is possibly carcinogenic to humans. /data lumped for 4,4'-methylenedianiline and its dihydrochloride/ [R7] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R6, 1979.23] HTOX: *SEVERE HEPATOTOXIC EFFECTS OF EXPOSURES...ARE...DOCUMENTED...IN...DESCRIPTION OF 84 PERSONS AFFECTED IN 'EPPING JAUNDICE' OUTBREAK, WHICH FOLLOWED ACCIDENTAL CONTAMINATION OF FLOUR USED.../IN/ BREAD. HEPATOCELLULAR DAMAGE WAS MIRRORED BY RAISED SGOT AND SGPT LEVELS BUT NORMAL SERUM ALKALINE PHOSPHATASE... /4,4'-METHYLENEDIANILINE/ [R8] *...MINIMALLY IRRITATING TO RESP SYSTEM @ 0.5 TO 1 PPM, BUT PAINFULLY IRRITATING TO EYES @ 4 PPM. /4,4'-METHYLENEDIANILINE/ [R9] *TWO REPORTS OF ACUTE HEPATITIS IN HUMANS FROM INDUST MDA /METHYLENEDIANILINE/ EXPOSURES... IN 1 OF THESE REPORTS...12 OUT OF 100...EXPERIENCED FEBRILE ILLNESS ASSOC WITH JAUNDICE. ... HANDS OF WORKERS WERE IN MDA SEVERAL HR/DAY. ... CLINICAL PATTERN...INCL...RIGHT-UPPER QUADRANT PAIN...AND CHILLS... ALL...RECOVERED... /METHYLENEDIANILINE/ [R9] NTOX: */P,P'-METHYLENEDIANILINE ADMIN TO 24 MALE RATS/...@ NEAR MAX TOLERATED DOSE BY GASTRIC INTUBATION IN ARACHIS OIL 5 DAYS/WK FOR 121 DAYS (TOTAL DOSE, 3.3 G/KG BODY WT). ...19...ALIVE AT 12 MO, 17 AT 18 MO AND 12 AT 2 YR. ALL...HAD CIRRHOSIS OF LIVER... /4,4'-METHYLENEDIANILINE/ [R10] */P,P'-METHYLENEDIANILINE ADMIN TO 24 MALE RATS/...@ NEAR MAX TOLERATED DOSE BY GASTRIC INTUBATION IN ARACHIS OIL 5 DAYS/WK FOR 121 DAYS (TOTAL DOSE, 3.3 G/KG BODY WT). ... TWO BENIGN HEPATOMAS @ 792 and 947 DAYS, AS WELL AS A VARIETY OF MISCELLANEOUS TUMORS /WERE FOUND/. /4,4'-METHYLENEDIANILINE/ [R10] *...INTRAGASTRIC DOSING...CONTINUED FOR ABOUT 18 MO (TOTAL DOSE, 6 G/KG BODY WT). 2 LIVER TUMORS, 1 INTESTINAL TUMOR, 1 PITUITARY TUMOR AND 2 SUBCUTANEOUS FIBROMAS WERE FOUND. .../USE OF OTHER SUBSTANCES DEMONSTRATED/ THAT THESE RATS WERE SUSCEPTIBLE TO LIVER CARCINOGENS. /4,4'-METHYLENEDIANILINE/ [R10] *...GROUPS OF 25 MALE AND 25 FEMALE WISTAR RATS /INJECTED/ WITH SC DOSES OF 30-50 MG.../KG BODY WT IN PHYSIOLOGIC SALINE @ 1 TO 3 WK INTERVALS OVER A PERIOD OF 700 DAYS (AVG TOTAL DOSE, 1.4 G/KG BODY WT). MEAN SURVIVAL TIME WAS 970 DAYS IN MALES AND 1060 IN...FEMALE/S/, COMPARED WITH 1007...IN CONTROLS. /4,4'-METHYLENEDIANILINE/ [R8] */MALE AND FEMALE WISTAR RATS RECEIVED SC DOSES OF 30-50 MG 4,4'-DIAMINODIPHENYLMETHANE/KG BODY WT OVER 700 DAYS (AVG TOTAL DOSE 1.4 G/KG BODY WT)/...33 MALIGNANT TUMORS...IN TREATED... COMPARED WITH...16 MALIGNANT...IN EQUAL NUMBER OF CONTROLS. FOUR HEPATOMAS...IN TREATED RATS. EXACT INCIDENCE OF TUMOR TYPES...NOT RECORDED. /4,4'-METHYLENEDIANILINE/ [R8] */IT/...HAS BEEN FOUND TO CAUSE BLINDNESS IN CATS... A SINGLE NEAR-LETHAL DOSE OF 100 MG/KG PRODUCED SELECTIVE ATROPHY OF RODS, CONES, AND NUCLEI IN OUTER GRANULAR LAYER. /4,4'-METHYLENEDIANILINE/ [R11] *...LIVER CIRRHOSIS IN RATS WITHIN 5 MO AFTER 7 IMPLANTATIONS SC OF ABOUT 125 MG.../KG. ...SINGLE ORAL DOSES OF 10 MG/KG CAUSED BOTH LIVER AND KIDNEY DAMAGE; CHRONIC ORAL ADMIN OF 3 MG/KG CAUSED...BLOOD DAMAGE. /4,4'-METHYLENEDIANILINE/ [R9] *METHYLENEDIANILINE CAUSED CHOLESTASIS AND HEPATIC NECROSIS IN ANIMALS. /METHYLENEDIANILINE/ [R12] *WHEN ADMIN ORALLY TO 16 RATS IN 4-5 DOSES OF 20 MG, 4,4'-DIAMINODIPHENYLMETHANE INDUCED HEPATOMAS AND KIDNEY TUMORS IN 1 RAT, ADENOCARCINOMA OF UTERUS IN ANOTHER, AND LIVER LESIONS IN MOST OF THOSE TREATED. /4,4'-DIAMINODIPHENYLMETHANE/ [R13] *4,4'-DIAMINODIPHENYLMETHANE @ 0.083 G/KG ORALLY WAS INJURIOUS TO LIVER AND SPLEEN OF RATS. /4,4'-DIAMINODIPHENYLMETHANE/ [R14] *600, 250, 200, 50, 20, and 8 MG/KG GIVEN BY STOMACH TUBE TO RATS CAUSED HEPATOMEGALY AND NECROTIZING CHOLANGITIS. AT THE HIGHER DOSES (200-600 MG), IT INDUCED PARAPORTAL NECROSIS OF LIVER PARENCHYMA AND LOSS OF GLYCOGEN. [R15] *SUB-CHRONIC (6 WK) AND CHRONIC (16 WK) PERIODS OF ORAL ADMIN OF 8 MG/KG CAUSED LIVER DAMAGE IN RATS, WITH FORMATION OF HYPERPLASTIC NODULES, ADENOMA-LIKE BILE DUCT PROLIFERATION AND CIRRHOSIS-LIKE CHANGES. IN 2 ANIMALS IT CAUSED HEMANGIOMAS OF THE LIVER. [R16] *When administered in the drinking water, 4,4'-methylenedianiline dihydrochloride increased the incidences of thyroid follicular cell carcinomas and neoplastic nodules of the liver in male rats; follicular cell and C-cell adenomas of the thyroid gland in female rats; thyroid follicular cell adenomas and hepatocellular carcinomas in mice of both sexes, adrenal pheochromocytomas in male mice; and hepatocellular adenomas and malignant lymphomas in female mice ... . [R2, p. 250 (1994)] *In a study in rats in which 4,4'-methylenedianiline was administered orally in conjunction with a known carcinogen /SRP: Not specified/, the incidence of thyroid tumors was greater than that produced by the carcinogen alone ... . /4,4'-methylenedianiline/ [R2, p. 251 (1994)] *Groups of 50 male and 50 female B6C3F1 mice, 12 wk of age, were given 0.015% (150 ppm, mg/l) or 0.03% (300 ppm, mg/l) 4,4'-methylenedianiline dihydrochloride (98.6% pure) in the drinking-water for 103 wk, followed by 1 wk without treatment prior to terminal sacrifice. Groups of 50 male and 50 female mice receiving drinking-water adjusted with 0.1 N HCl to pH 3.7 (equivalent to the pH of the 0.03% 4,4-methylenedianiline dihydrochloride soln) served as controls. Survival at termination of the study was 40/50 (80%) control, 39/50 (78%) low-dose and 32/50 (64%) high-dose males and 40/50 (80%) control, 38/50 (76%) low-dose and 37/50 (74%) high-dose females. An increased incidence of follicular-cell adenomas of the thyroid was observed in high-dose animals: 0/47 control, 3/49 (6%) low-dose and 16/49 (33%) high-dose males (p < 0.001) and 0/50 control, 1/47 (2%) low-dose and 13/50 (26%) high-dose females (p < 0.001). In addition, a dose-related incidence of thyroid-gland follicular-cell hyperplasia was observed in both males and females, and 2/50 high-dose females developed thyroid follicular-cell carcinomas. An increased incidence of hepatocellular adenomas occurred in females: 3/50 (6%) controls, 9/50 (18%) low-dose and 12/50 (24%) high-dose animals (P = 0.01, Fisher exact and Cochran-Armitage trend tests), but not in males. Increased incidences of hepatocellular carcinomas were observed in treated males (10/49 (20%) controls, 33/50 (66%; p < 0.001) low-dose and 29/50 (58%; p < 0.001) high-dose animals) and in treated females (1/50 (2%) controls, 6/50 (12%) low-dose and 11/50 (22%; p = 0.002, Fisher exact and Cochran-Armitage trend tests) high-dose animals)... . [R17] *A group of 20 female Sprague-Dawley rats, 40 days old, received 30 mg (max tolerated dose) 4,4'-methylenedianiline dihydrochloride (purity unspecified) in 1 ml sesame oil by gastric intubation every 3 days for 30 days (total dose, 300 mg/rat) and were observed for a further 9 months. A group of 140 female rats receiving sesame oil alone served as negative controls and a group of 40 females receiving single doses of 18 mg 7,12-dimethylbenz(a)anthracene (DMBA) served as positive controls. Survival after 9 months was 14/20 in the 4,4'-methylenedianiline dihydrochloride-treated group, 127/140 in the negative-control group and 19/40 in the DMBA-treated group. Mammary lesions were found in 5/132 negative controls (three carcinomas, one fibroadenoma, five hyperplasias), 29/29 DMBA-treated (75 carcinomas, ten fibroadenomas, 47 hyperplasias) and 1/14 4,4'-methylenedianiline dihydrochloride-treated (one hyperplasia) animals ... (The Working Group noted the limited duration of the study, the small number of test animals, which were of one sex only, and the fact that this study was aimed principally at examining use of the mammary gland in female Sprague-Dawley rats as a tool for identifying chemical carcinogens.) [R17] *Groups of 50 male and 50 female Fischer 344/N rats, 6 wk old, were given 0.015% (150 ppm, mg/l) or 0.03% (300 ppm, mg/l) 4,4'-methylenedianiline dihydrochloride (98.6% pure) in the drinking-water for 103 wk, followed by 1 wk without treatment, after which time the animals were sacrificed. Groups of 50 males and 50 females receiving drinking-water adjusted with 0.1 N HCl to the pH 3.7 (equivalent to the pH of the 0.03% 4,4'-methylenedianiline dihydrochloride soln) served as controls. There was no significant effect on survival in males or females. The incidences of thyroid follicular-cell carcinomas in high-dose animals were significantly increased over those in controls: 0/49 control, 0/47 low-dose and 7/48 high-dose males (p < 0.012, life-table test) and 0/47 control, 2/47 low-dose and 17/48 high-dose females (p < 0.001). A significant increase in the incidence of liver neoplastic nodules was also observed in male rats: 1/50 controls, 12/50 low-dose (p = 0.002) and 25/50 high-dose (p < 0.001) animals, and a statistically nonsignificant increase in these lesions was seen in treated females: 4/50 controls, 8/50 low-dose and 8/50 high-dose ... . [R18] *Increased weights of adrenal gland, uterus and thyroid gland were observed in ovariectomized female Sprague-Dawley rats given 14 daily doses of 150 mg/kg bw 4,4'-methylenedianiline dihydrochloride by gavage. Thyroid weights nearly doubled during the dosing period ... . [R19] *IN INTACT SODIUM PENTOBARBITAL 50 MG/KG IP-ANESTHETIZED RATS, THE INCR CORTICOSTERONE SECRETION IN RESPONSE TO SURGICAL STRESS CAUSED BY ADRENAL VEIN CANNULATION WAS MARKEDLY 50-60% DEPRESSED FOLLOWING THE IV INJECTION OF 4,4'-METHYLENEDIANILINE-2HCL 100 MG/KG. A LOW SECRETION RATE OF CORTICOSTERONE PERSISTED FOR THIRTY MIN THEREAFTER. IN HYPOPHYSECTOMIZED RATS, THE IV INFUSION OF ADRENOCORTICOTROPIC HORMONE 0.396 MILLIUNITS/MIN FOR 60 MIN WAS ALSO MARKEDLY 50-70% DEPRESSED BY THE INJECTION OF 4,4'-METHYLENEDIANILINE-2HCL. THE EFFECTS OF THE DRUG ON CORTICOSTERONE SECRETION ARE PROBABLY DUE TO A DIRECT ACTION ON THE ADRENAL CORTEX. [R20] *The ability of a three exposure mouse bone marrow micronucleus test to detect genotoxic chemicals was evaluated. Twenty five known rodent carcinogens and 24 compounds noncarcinogenic to rodents were tested. They were adiministered to male B6C3Fl-mice using three daily exposures by intraperitoneal injection at concentrations equal to 25, 50, or 100% of the maximally tolerated dose. 24 hours after the last injection, the femoral bone marrow was removed and assayed for micronucleated polychromatic erythrocytes. A significant elevation in polychromatic erythrocytes micronuclei frequency above that of the solvent control was judged to be a positive response. Among the carcinogens, 4,4 -methylenedianine showed positive responses. +Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by admin this chemical in the drinking water of F344/N rats and B6C3F1 mice. ... Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly incr incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R21] NTP: +Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by admin this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 weeks. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0. lN HCl to the pH (3.7) of the 300 ppm formulation served as controls. ... Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly incr incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R21] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *Using ultravilet detection, the limit of detection (LOD) for 4 aromatic diamines was < 2 ug/L while the limit of quantitation (LOQ) was 6 ug/L. For electrochemical detection, the LOD was < 0.3 ug/L and the LOQ was < 0.9 ug/L. /Aromatic diamines/ [R22] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Carcinogenesis Studies of 4,4-Methylenedianiline Dihydrochloride in F344/N Rats and B6C3F1 Mice (Drinking Water Studies) Technical Report Series No. 248 (1983) NIH Publication No. 83-2504 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) Anonymous; 4,4'-Methylenedianiline and Its Dihydrochloride; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans: Some Chemicals Used in Plastics and Elastomers, International Agency for Research on Cancer, Lyon, France, 39 347-65 (1986) SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 349 (1986) R2: DHHS/NIEHS; Seventh Annual Rpt on Carcinogens Summary R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 350 (1986) R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8212 R5: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2232 R6: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 66 (1987) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 83 (1974) R9: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values, 4th ed., 1980. Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.278 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 82 (1974) R11: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 357 R12: MCGILL DB, MOTTO JD; N ENGL J MED 291 (AUG 8): 278 (1974) R13: SCHOENTAL R; NATURE (LONDON) 219 (5159): 1162 (1968) R14: PLUDRO G ET AL; ACTA POL PHARM 26 (4): 353 (1969) R15: GOHLKE R; SCHMIDT P; INT ARCH ARBEITSMED 32 (3): 217 (1974) R16: GOHLKE P; Z GESAMTE HYG IHRE GRENZGEB 24 (3): 159 (1978) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 353 (1986) R18: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 354 (1986) R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V39 355 (1986) R20: HARADA Y; TOHOKU J EXP MED 91 (4): 315 (1967) R21: Carcinogenesis Studies of 4,4'-Methylenedianiline Dihydrochloride in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 248 (1983) NIH Publication No. 83-2504 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R22: Neumeister CE; Appl Occup Environ Hyg 6:953-8 (1991) RS: 34 Record 306 of 1119 in HSDB (through 2003/06) AN: 4348 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-ORANGE-G- SY: *ACIDAL-FAST-ORANGE-; *ACID-FAST-ORANGE-G-; *ACID-FAST-ORANGE-EGG-; *ACID-LEATHER-ORANGE-KG-; *ACID-LEATHER-ORANGE-PGW-; *ACID-LIGHT-ORANGE-G-; *ACID-LIGHT-ORANGE-J-; *ACID-LIGHT-ORANGE-JA-EXPORT-; *ACID-LIGHT-ORANGE-SX-; *ACID-ORANGE-G-; *ACID-ORANGE-10-; *ACID-ORANGE-2G-; *ACID-ORANGE-GG-; *ACILAN-ORANGE-GX-; *APOCID-ORANGE-2G-; *ATUL-ACID-CRYSTAL-ORANGE-G-; *BRASILAN-ORANGE-2G-; *BUCACID-FAST-ORANGE-G-; *CALCOCID-FAST-LIGHT-ORANGE-2G-; *CERTICOL-ORANGE-GS-; *CETIL-LIGHT-ORANGE-GG-; *C.I.-ACID-ORANGE-10-; *C.I.-ACID-ORANGE-10,-DISODIUM-SALT-; *C.I.-FOOD-ORANGE-4-; *CI-ORANGE-G-; *CI-27-; *CI-16230-; *COLACID-ORANGE-G-; *CRYSTAL-ORANGE-2G-; *ENIACID-LIGHT-ORANGE-G-; *ERIO-FAST-ORANGE-AS-; *FAST-LIGHT-ORANGE-GA-; *FAST-LIGHT-ORANGE-GA-CF-; *FAST-ORANGE-G-; *HEXACOL-ORANGE-GG-CRYSTALS-; *HIDACID-FAST-ORANGE-2G-; *HISPACID-FAST-ORANGE-2G-; *7-HYDROXY-8-(PHENYLAZO)-1,3-NAPHTHALENEDISULFONIC ACID, DISODIUM SALT; *7-HYDROXY-8-(PHENYLAZO)-1,3-NAPHTHALENEDISULPHONIC ACID, DISODIUM SALT; *INK-ORANGE-JSN-; *INTRACID-FAST-ORANGE-G-; *JAVA-ORANGE-2G-; *KITON-FAST-ORANGE-G-; *1,3-NAPHTHALENEDISULFONIC ACID, 7-HYDROXY-8-(PHENYLAZO)-, DISODIUM SALT; *NAPHTHALENE-FAST-ORANGE-2G-; *NAPHTHALENE-FAST-ORANGE-2GS-; *NCI-C53838-; *ORANGE-G-; *ORANGE-#10-; *1370-ORANGE-; *1-PHENYLAZO-2-NAPHTHOL-6,8-DISULFONIC-ACID,-DISODIUM-SALT-; *1-PHENYLAZO-2-NAPHTHOL-6,8-DISULPHONIC-ACID,-DISODIUM-SALT- RN: 1936-15-8 MF: *C16-H10-N2-O7-S2.2Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Orange G is an anionic monoazo dye that is made by coupling diazotized aniline to G acid (2-naphthol-6,8-disulfonic acid) and converting the coupling product to the disodium salt. [R1] FORM: *SPECIFICATIONS FOR ORANGE G ARE GIVEN BY THE BRITISH STANDARDS INSTITUTION (1960), TOGETHER WITH APPROPRIATE ANALYTICAL METHODS: THE PRODUCTS MUST CONTAIN A MINIMUM OF 85% OF THE COLOR... [R2] USE: *Orange G dyes wool directly and silk from either a formic acid or sulfuric acid bath. Wool and silk can be printed directly. Non-textile industrial uses include dyeing paper, staining wood, and coloring inks and copying pencils. Fully chromed leather is dyed a dull orange. [R3] *Orange G is an important biological stain that is used widely as a background or contrast stain for a number of important nuclear stains such as Hematoxylin, Safranin O, Crystal Violet, Methyl Green and Basic Fuchsin. It is an excellent plasma stain and an important component of one of the stain solutions used in the Papanicolaou method for detecting vaginal, cervical, and uterine cancer. [R3] *ITS USE IN COSMETICS WAS REPORTED TO BE PERMITTED IN THE FEDERAL REPUBLIC OF GERMANY... [R4] *IN THE US, THIS COLOR WAS USED AS A DRUG AND COSMETIC COLORANT UNTIL OCTOBER 1966, WHEN ITS USE FOR THESE APPLICATIONS WAS CANCELLED. [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOWISH-RED CRYSTALS OR LEAFLETS [R2] MW: *452.38 [R5] DSC: *pKa = approx. 11.5 at room temperature in water [R6] SOL: *GENERALLY INSOL IN ORGANIC SOLVENTS, BUT SLIGHTLY SOL IN ETHANOL AND CELLOSOLVE [R2]; *Solubility in water = 80 mg/ml, in ethanol = 3 mg/ml, in methyl Cellosolve(monomethyl ether of ethylene glycol) = 40 mg/ml. [R3] SPEC: *MAX ABSORPTION (0.02 N AMMONIUM ACETATE SOLN): 474 NM [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Inadequate evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R7] NTOX: *NO LIVER TUMOR OCCURRED IN A GROUP OF 20 MICE (SEX AND STRAIN UNSPECIFIED) WHICH RECEIVED WEEKLY DOSES OF 15-20 MG ORANGE G FOR LIFE, GIVEN OVER 5 DAYS A WK, IN THE FORM OF A SOLN IN TAP-WATER ADDED TO 20 G BROWN BREAD. THE LAST SURVIVING MOUSE DIED 538 DAYS AFTER THE START OF THE TREATMENT... [R8] *MALE AND FEMALE MICE OF A TYPE B HETEROZYGOUS STRAIN WERE ADMIN 1 MG ORANGE G/ANIMALS (AS A 2% SOLN IN WATER ADDED TO THE LAB DIET) DAILY FOR 500-700 DAYS. TUMORS DEVELOPED IN 12/113 MALES AND IN 15/78 FEMALES, INCLUDING 8 LYMPHOMAS, 5 MAMMARY TUMORS, 10 LUNG TUMORS, 2 ENDOTHELIOMAS AND 2 PAPILLOMAS OF THE STOMACH. OF THE CONTROLS, 7/109 MALES AND 11/59 FEMALES DEVELOPED A TOTAL OF 18 TUMORS, INCLUDING 8 LYMPHOMAS, 6 MAMMARY TUMORS, 3 LUNG TUMORS AND 1 PAPILLOMA OF THE FORESTOMACH. OF THE TREATED MICE, 70 MALES AND 59 FEMALES WERE ALIVE @ 400 DAYS, COMPARED WITH 92 MALES AND 51 FEMALE CONTROL MICE. THE LAST TREATED MOUSE DIED @ 712 DAYS, COMPARED WITH 684 DAYS IN THE CONTROL GROUP... [R9] *NO TUMORS WERE OBSERVED AFTER ORAL ADMIN OF 200 MG ORANGE G/KG OF DIET TO 10 RATS (SEX AND STRAIN UNSPECIFIED) FOR 245 DAYS, OR 1000 MG ORANGE G/KG OF DIET TO 75 RATS FOR 400 DAYS... [R10] *ADMIN OF LEVELS OF 2500, 5000, 10,000, 20,000 OR 50,000 MG ORANGE G/KG OF DIET TO GROUPS OF 10 ALBINO RATS FOR 90 DAYS CAUSED ENLARGEMENT OF SPLEEN... ADMIN OF A DIET CONTAINING 50 MG ORANGE G/KG OF DIET (APPROX EQUIV TO 2.5 MG/KG BODY WT/DAY) FOR 15 WK TO CFE RATS HAD NO EFFECT ON BEHAVIOR, GROWTH RATE, FOOD OR WATER CONSUMPTION, BLOOD AND URINE ANALYSES, ORGAN WT OR HISTOPATHOLOGY... [R10] *HEINZ BODIES ARE FORMED IN RED BLOOD CELLS OF RATS FED DIETS CONTAINING 9000 MG/KG OF DIET... [R10] *ORANGE G ADMIN IN THE DIET TO GROUPS OF 5 MALE AND FEMALE FERRETS AT CONCN PROVIDING INTAKES OF 0, 1.5, 15 and 150 MG/KG PER DAY FOR 12 MO. THE HEMOLYTIC ANEMIA PRODUCED BY THIS COLORING IN OTHER SPECIES WAS NOT SEEN IN THE FERRET. [R11] *AT DOSAGE LEVELS OF 25 OR 250 MG/KG/DAY FOR 112 DAYS, HEINZ BODIES WERE FOUND IN THE ERYTHROCYTES, ALONG WITH ANEMIA, RETICULOCYTOSIS, SPLENOMEGALY, AND AT THE HIGHEST LEVEL ONLY, A HISTOLOGICAL DEMONSTRABLE INCR IN SPLENIC IRON. [R12] *ORANGE G SHOWED A SIGNIFICANT INCREASE IN CHROMOSOME DAMAGE, CLASTOGENIC ACTIVITY, WHEN CHINESE HAMSTER CELLS WHERE INCUBATED FOR 5 HR AT 20 UMOL. [R13] *ORANGE G WAS STUDIED FOR ITS ABILITY TO CAUSE DNA DAMAGE AND MUTATIONS IN ESCHERICHIA COLI WITH AND WITHOUT RAT-LIVER MICROSOMAL ACTIVATION. IT DID NOT INDUCE ANY DETECTABLE EFFECTS. [R14] *ORANGE G WAS TESTED FOR BACTERIAL MUTAGENICITY WITH SALMONELLA TYPHIMURIUM TA1538 USING SOFT-AGAR OVERLAY METHOD AND WAS FOUND NOT TO BE MUTAGENIC. [R15] *Orange G, a m monoazo dye was evaluated with in vivo cytogenetic assays to determine its genotoxicity. Swiss albino male mice were exposed to Orange G through ip injections. Bone marrow cells isolated from femora were analyzed for sister chromatid exchanges (SCE) and chromosome aberrations ... the incidence of SCEs and chromosome aberrations were significantly higher than controls at certain concn. Twenty-five mg/kg of Orange G was found to be the minimum effective dose for the induction of both SCEs and chromosome aberrations. Orange G is thus found to be clastogenic and genotoxic in vivo in mice. [R16] *An evaluation was conducted that tested 27 chemicals for their mutagenic potential in the L5178Y tk+/tkmouse lymphoma cell forward mutation assay. Cultures were exposed to the chemicals for 4 hr, then cultured for 2 days before plating in soft agar with or without trifluorothymidine (TFT), at 3 ug/ml ... Of the 27 chemicals evaluated, ten were not mutagenic in the assay. Of the remaining 17 which were mutagenic, phenazopyridine-hydrochloride ... acid-orange-10 ... and solvent yellow-14 ... required S9 mix. [R17] +Under these conditions, there was no evidence of carcinogenicity for male and female F344/N rats or for male and female B6C3Fl mice. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative [R18] NTP: +Carcinogenesis studies of 80% pure C.I. Acid Orange 10 (a monoazo textile dye) were conducted by feeding to-groups of 50 male and 50 female F344/N rats diets containing 1,000 or 3,000 ppm C.I. Acid Orange 10 for 103 weeks. Groups of 50 male and 50 female B6C3Fl mice were fed diets containing 3,000 or 6,000 ppm for 103 weeks. Groups of 90 male and 90 female untreated rats and 50 male and 50 female untreated mice served as controls. ... Under these conditions, there was no evidence of carcinogenicity for male and female F344/N rats or for male and female B6C3Fl mice. ... Levels of Evidence of Carcinogenicity: Male Rats: Negative; Female Rats: Negative; Male Mice: Negative; Female Mice: Negative [R18] METB: *OF 500 MG/KG BODY WT ORANGE G FED TO RABBITS, 40% IS EXCRETED IN THE URINE AS PARA-AMINOPHENOL, 3% AS ORTHO-AMINOPHENOL AND 0.6% AS FREE ANILINE... IN THE URINE OF RATS GIVEN SINGLE ORAL DOSES OF 250 MG/KG BODY WT, 61% APPEARS AS PARA-AMINOPHENOL, AND ANILINE IS FOUND IN FECES. NO UNCHANGED DYE IS FOUND IN EITHER THE URINE OR THE FECES... [R10] *THE URINE OF HUMANS GIVEN 20 MG/KG BODY WEIGHT ORANGE G CONTAINED 95% AS PARA-AMINOPHENOL, 0.5% AS ANILINE AND 1.3% AS UNCHANGED COLOR... [R8] *THE AZO LINKAGE OF ORANGE G IS REDUCED BY BACTERIA PRESENT IN RAT FECES AND BY RAT-LIVER HOMOGENATES... [R10] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Orange G's production and use in the staining of paper and wood, the dyeing of textiles and leather, its use in inks and colored pencils and as a biological stain, and former use in cosmetics may result in its release to the environment through various waste streams. If released to the atmosphere, Orange G will exist solely in the particulate phase in the ambient atmosphere based on an estimated vapor pressure of 2.5X10-20 mm Hg at 25 deg C. Particulate-phase Orange G may be physically removed from the air by wet and dry deposition. An estimated Koc of 0 suggests that Orange G will have very high mobility in soil; however, its ionic nature may result in ion-exchange processes with clay that would retard leaching. Volatilization from dry and moist soil surfaces is not expected to be a major fate process for this compound. Orange G is expected to be resistant to aerobic biodegradation; it may be biodegraded anaerobically as a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines. Orange G is not expected to volatilize from water surfaces. It may adsorb to sediments and particulate matter in water. It may undergo photosensitized photodegradation in water containing humic material. Orange G should not bioconcentrate in aquatic organisms based on an estimated bioconcentration factor of 0. Occupational exposure to Orange G may occur during its production and use as a dye and stain. (SRC) ARTS: *Orange G's production and use in the staining of paper and wood, the dyeing of textiles and leather, its use in inks and colored pencils and as a biological stain(1), and former use in cosmetics(1) may result in its release to the environment through various waste streams(SRC). [R19] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 0(SRC), determined from an estimated log Kow(2,SRC) and a recommended regression-derived equation(3), indicates that Orange G will have very high mobility in soil(SRC); however, its ionic nature may result in ion-exchange processes with clay that would retard leaching(8). Orange G is expected to be resistant to aerobic biodegradation(4); it may be biodegraded anaerobically as a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(5). Since Orange G is an ionic compound, volatilization from moist soil surfaces will not be important(8). Volatilization of Orange G is not expected to be important from dry soil surfaces(SRC) based on its estimated vapor pressure(6,SRC). Orange G is not expected to be susceptible to direct photolysis on soil surfaces based on its absorption of light at wavelengths > 290 nm(SRC) (absorption max = 474 nm)(7). [R20] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 0(SRC), determined from an estimated log Kow(2,SRC) and a recommended regression-derived equation(1), indicates that Orange G is not expected to adsorb to suspended solids and sediment in the water(SRC). However, its ionic nature may result in ion-exchange porcesses with clay particles resulting in increased adsorption to sediment and particulate material(6). Orange G is expected to be resistant to aerobic biodegradation(3); it may biodegrade anaerobically as a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(4). In a humic acid solution, Orange G showed enhanced photodegradation as compared to a distilled water solution, indicating that Orange G is photosensitized in the presence of humics(5). Since Orange G is an ionic compound, volatilization from moist soil surfaces will not be important(6). An estimated BCF value of 0(1,SRC), from an estimated log Kow(2,SRC), suggests that Orange G will not bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(7). [R21] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), Orange G, which has an estimated vapor pressure of 2.5X10-20 mm Hg at 25 deg C(2), exists solely in the particulate phase in the ambient atmosphere. Particulate-phase Orange G may be physically removed from the air by wet and dry deposition(SRC). [R22] BIOD: *Using a culture medium containing glucose, peptone, meat extract, and mineral salts and a sewage inoculum, Orange G at 2.5X10-4 mol/l showed an 11% decrease in concentration over 24 hours(1). Screened raw wastewater containing Orange G was then passed through three pilot-scale activated sludge biological treatment systems, each having a retention time of 0.28 days; Orange G passed through the activated sludge process substantially untreated and did not adsorb to the sludge(2). This compound may be biodegraded anaerobically; a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(3). [R23] ABIO: *Orange G did not precipitate in water with a calcium concentration of 10-3 M(1). Orange G, added to distilled water and subjected to photolysis, had half-lives of 340 and 32 hours for the protonated and dissociated forms, respectively(2). These half-lives decreased to 44 and 1.8 hours for the protonated and dissociated forms, respectively, when Orange G was added to a humic solution (5 mg/l total organic carbon) and the solution was subjected to photolysis(2). These results suggest that photodegradation of Orange G is photosensitized in the presence of humics, although concentrations of photochemical oxidant produced during this experiment were considerably greater than those normally seen in the natural environment(2). [R24] BIOC: *An estimated BCF value of 0 was calculated for Orange G(SRC), using an estimated log Kow of -4.56(1,SRC) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration of Orange G in aquatic organisms will not be an important fate process(SRC). [R25] KOC: *The Koc of Orange G is estimated as approximately 0(SRC), using an estimated log Kow of -4.56(1,SRC) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that Orange G has very high mobility in soil(SRC). The ionic nature of Orange G may result in ion-exchange processes with clay that would retard leaching(4). [R26] VWS: *Since Orange G is an ionic compound, volatilization from moist soil surfaces will not be important(1). [R27] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 27,557 workers (12,180 of these are female) are potentially exposed to Orange G in the USA(1). [R28] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *IDENTIFICATION OF WATER-SOLUBLE COLORS IN FOOD USING THIN-LAYER CHROMATOGRAPHY. [R29] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I Acid Orange 10 in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 211 (1987) NIH Publication No. 88-1767 SO: R1: Green,FJ; The Sigma-Aldrich Handbook of Stains, Dyes, and Indicators. Aldrich Chemical Company, Inc.: Milwaukee, WI p. 539 (1990) R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 181 (1975) R3: Green,FJ; The Sigma-Aldrich Handbook of Stains, Dyes, and Indicators. Aldrich Chemical Company, Inc: Milwaukee, WI p. 539 (1990) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 182 (1975) R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8209 R6: Haag WR, Mill T; Environ Toxicol Chem 6: 359-69 (1987) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 69 (1987) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 185 (1975) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 183 (1975) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V8 184 (1975) R11: BRANTOM PG ET AL; FOOD COSMET TOXICOL 15 (5): 379 (1977) R12: GAUNT IF ET AL; FOOD COSMET TOXICOL 11 (3): 367 (1973) R13: AU W, HSU TC; ENVIRON MUTAGENESIS 1: 27 (1979) R14: HAVELAND-SMITH RB, COMBES RD; FOOD COSMET TOXICOL 18: 215 (1980) R15: GARNER R, NUTMAN CA; MUTAT RES 44: 9 (1977) R16: Giri et al; Toxicol Lett 44 (3): 253-61 (1988) R17: McGregor DB et al; Environ and Molecular Mutagen 17 (3): 196-219 (1991) R18: Carcinogenesis Studies of C.I. Acid Orange 10 in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 211 (1987) NIH Publication No. 88-1767 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R19: (1) IARC; Monographs in the Evaluation of Carcinogenic Risk of Chemicals to Man 8: 182 (1975) R20: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Shaul GM et al; Chemosphere 22: 107-19 (1991) (5) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) (6) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Col I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) (7) IARC; Monographs in the Evaluation of Carcinogenic Risk of Chemicals to Man. 8:182 (1975) (8) Baughman GL, Perenich TA; Amer Dyestuff Report Fe, pp. 19-22 (1988) R21: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Shaul GM et al; Chemosphere 22: 107-19 (1991) (4) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) (5) Haag WR, Mill T; Environ Toxicol Chem 6:359-69 (1987) (6) Baughman GL, Perenich TA; Amer Dyestuff Report Fe, pp. 19-22 (1988) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) R22: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R23: (1) Ogawa T et al; Sen'i Gakkaishi 30: 153-9 (1974) (2) Shaul GM et al; Chemosphere 22: 107-19 (1991) (3) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) R24: (1) Hou M, Baughman GL; Dyes and Pigments 18: 35-46 (1992) (2) Haag WR, Mill T; Environ Toxicol Chem 6:359-69 (1987) R25: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R26: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Baughman GL, Perenich TA; Amer Dyestuff Report Fe, pp. 19-22 (1988) R27: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Fe, pp. 19-22 (1988) R28: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R29: CROSBY NT; IARC SCI PUBL 40: 337 (1981) RS: 21 Record 307 of 1119 in HSDB (through 2003/06) AN: 4349 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 11-AMINOUNDECANOIC-ACID- SY: *AMINOUNDECANOIC-ACID-; *NCI-C50613-; *UNDECANOIC-ACID,-11-AMINO- RN: 2432-99-7 MF: *C11-H23-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +Four step processes: Step 1, castor oil reacts with methyl alcohol to form methyl ricinoleate; Step 2, pyrolysis of this ester at 450-500 deg C to form 10-undecylenate; Step 3, hydrolysis to form 10-undecylenic acid; Step 4, bromination by hydrogen bromide in the presence of peroxides to form 11-bromoundecanoic acid which is then converted to 11-aminoundecanoic acid [R1] OMIN: +Industrial manufacture of /Nylon 11 and 11-aminoundecanoic acid/ is primarily carried out in France where the /Nylon 11/ polymer is known as Rilsan [R2] USE: +Initiator for type 11 Nylons [R3] PRIE: U.S. PRODUCTION: +(1986) ND U.S. IMPORTS: +(1986) ND U.S. EXPORTS: +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *201.35 [R4] SPEC: +IR: 2:308C (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R5]; +NMR: 3:7A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R5] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R6] NTOX: *CARCINOGENESIS BIOASSAY OF 11-AMINOUNDECANOIC ACID WAS CARRIED OUT BY ADMIN DIETS CONTAINING 7500 OR 15,000 PPM TO F344 RATS AND B6C3F1 MICE FOR 104 WEEKS (RATS) OR 103 WEEKS (MICE). RESULTS WERE NEGATIVE IN MICE BUT POSITIVE IN RATS. [R7] NTP: +A carcinogenesis bioassay of 11-aminoundecanoic acid was carried out by administering diets containing 7,500 or 15,000 ppm 11-aminoundecanoic acid to F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of either sex were administered the test chemical for 104 wk (rats) or 103 wk (mice). Controls consisted of 50 untreated rats and 50 untreated mice of each sex. ... Under the conditions of this bioassay, 11-aminoundecanoic acid was carcinogenic for male F344 rats, inducing neoplastic nodules in the liver and transitional cell carcinomas of the urinary bladder. The test chemical was not carcinogenic for female F344 rats. No clear evidence was found for the carcinogenicity of 11-aminoundecanoic acid in B6C3F1 mice of either sex, although the incr in malignant lymphoma in male mice may have been associated with administration of 11-aminoundecanoic acid. [R8] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 11-Aminoundecanoic Acid in F344/N Rats and B6C3F1 Mice (Feed Study) Technical Report Series No. 216 (1982) NIH Publication No. 82-1772 SO: R1: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V5 p.6 R2: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V18 p.363 R3: CONSIDINE. CHEMICAL AND PROCESS TECHNOL ENCYC 1974 p.787 R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8207 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 408 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 57 (1987) R7: CARCINOGENESIS BIOASSAY OF 11-AMINOUNDECANOIC ACID (CAS NUMBER 2432-99-7) IN F344 RATS AND B6C3F1 MICE (FEED STUDY); REPORT; ISS NIH/PUB-82-1772, NTP-80-34; ORDER NUMBER PB82-225640, 125 PP (1982) R8: DHHS/NTP; Carcinogenesis Bioassay of 11-Aminoundecanoic Acid in F344 Rats and B6C3F1 Mice p.vii (1982) Technical Rpt Series No. 216 NIH Pub No. (NIH) 82-1772 RS: 5 Record 308 of 1119 in HSDB (through 2003/06) AN: 4353 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MALONALDEHYDE- SY: *MALONDIALDEHYDE-; *MALONIC-ALDEHYDE-; *MALONIC-DIALDEHYDE-; *MALONODIALDEHYDE-; *MALONYLDIALDEHYDE-; *NCI-C54842-; *PROPANEDIAL-; *1,3-PROPANEDIAL-; *1,3-PROPANEDIALDEHYDE-; *1,3-Propanedione- RN: 542-78-9 MF: *C3-H4-O2 ASCH: Malonaldehyde, sodium salt; 24382-04-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *FREE MALONALDEHYDE CAN BE GENERATED FROM/ITS BIS(DIALKYL)ACETALS (eg 1,1,3,3-TETRAETHOXYPROPANE)/BY ACID-CATALYZED HYDROLYSIS WITH DILUTE HYDROCHLORIC ACID OR SHAKING THEM WITH ACID DOWEX 50 ION-EXCHANGE RESIN [R1] MFS: *NO COMMERCIAL PRODUCTION [R1] USE: *RESEARCH COMPOUND [R1] PRIE: U.S. PRODUCTION: *NO COMMERCIAL PRODUCTION [R1] U.S. IMPORTS: *(1986) ND U.S. EXPORTS: *(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Solid (needles) [R2, 190] MW: *72.07 [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: *Proteins [Note: Pure compound is stable under neutral conditions, but not under acidic conditions]. [R2, 190] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R4] EQUP: *Wear appropriate personal protective clothing to prevent skin contact. [R2, 190] *Wear appropriate eye protection to prevent eye contact. [R2, 190] *Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R2, 190] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R2, 190] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. [R2, 190] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. [R2, 190] OPRM: *Contact lenses should not be worn when working with this chemical. [R2, 191] *The worker should immediately wash the skin when it becomes contaminated. [R2, 190] *The worker should wash daily at the end of each work shift. [R2, 190] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R2, 190] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R2, 190] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: No epidemiological data relevant to the carcinogenicity of malonaldehyde were available. There is limited evidence in experimental animals for the carcinogenicity of malonaldehyde. Overall evaluation: Malonaldehyde is not classifiable as to its carcinogenicity to humans (Group 3) [R5] HTOX: *Malonaldehyde reacts with DNA to form an adduct with 2'-deoxyguanosine with has been characterized as 3-(2-deoxy-beta-D-erythro-pentofuranosy)pyrimido(1,2-alpha)purin-10(3H)-one (M1G-dR). This adduct is present at quantifiable levels in DNA from many human tissues. [R6] NTOX: *DESPITE ITS LOW UPTAKE AND RAPID OXIDATION TO CARBON DIOXIDE, TREATMENT OF PRIMARY RAT SKIN FIBROBLAST CULTURES WITH 1X10-3 MOLAR (14)C-MALONALDEHYDE FOR 24 HR PRODUCED A LATENT INHIBITION OF (14)C-LABELED GLUCOSE OXIDATION. [R7] *EXPOSURE OF PRIMARY RAT SKIN FIBROBLAST CULTURES TO 1X10(-3) AND 1X10(-4) MOLAR MALONALDEHYDE GAVE DOSE-DEPENDENT PRODUCTION OF MICRONUCLEI. CHROMOSOMAL ABERRATIONS WERE PRODUCED IN 14 AND 34% OF METAPHASES, RESPECTIVELY. AT 24 HR, THE CORRESPONDING FREQUENCIES WERE 46 AND 52%. DOSE-DEPENDENT INCREASES IN ANEUPLOIDY WERE SEEN AT GREATER THAN OR EQUAL TO 1X10(-4) MOLAR MALONALDEHYDE. [R8] *MALONDIALDEHYDE, THE MOST STUDIED PRODUCT OF LIPID PEROXIDATION, WAS INVESTIGATED FOR POSSIBLE INHIBITORY EFFECTS ON ALDH FOR RAT LIVER MITOCHONDRIA. MALONDIALDEHYDE WAS A POTENT INHIBITOR OF THE ENZYME. THE ENZYME WAS EQUALLY SENSITIVE TO INHIBITION WHEN INTACT MITOCHONDRIAL PREPARATIONS WERE COMPARED WITH DISRUPTED MITOCHONDRIA. EXTENT OF INHIBITION DEPENDED ON MALONDIALDEHYDE CONCN AND TIME OF INCUBATION; HIGH CONCN COMPLETELY AND IRREVERSIBLY INHIBITED LOW KM MITOCHONDRIAL ALDH. THE RATE OF ALDH INACTIVATION WAS BIPHASIC, WITH RAPID AND SLOWER RATES BOTH DEPENDENT ON MALONDIALDEHYDE CONCN. [R9] *RAW AND COOKED MEAT WITH 30% FAT HAD HIGHER MALONALDEHYDE LEVELS THAN THE MEAT WITH 10% FAT. MALONALDEHYDE VALUES WERE HIGHER IN THE COOKED PATTIES THAN IN THE RAW. AMES TEST REVERTANT NUMBERS WERE HIGHER FOR THE EXTRACT FROM PATTIES COOKED TO 95 DEG C AT 218 DEG C THAN THOSE COOKED TO 83 DEG C AT 175 DEG C. REVERTANT NUMBERS WERE NOT DIFFERENT FOR PATTIES AT THE TWO DIFFERENT FAT LEVELS. GENERALLY THE LOWER COOKING TEMPERATURE RESULTED IN LOWER COOKING LOSSES, LOWER MALONALDEHYDE LEVELS, AND REVERTANT NUMBERS THAN DID THE HIGHER TEMPERATURES. [R10] *IN E COLI H/R30, HAVING ACTIVE DNA-REPAIR SYSTEMS, MALONDIALDEHYDE IS MUTAGENIC. THE HS30 AND NG30 DERIVATIVES, HOWEVER, ARE NOT MUTABLE BY MALONDIALDEHYDE. LETHAL ACTION ON THEM, HOWEVER, IS INCREASED. [R11] *MDA PREPARED BY CHROMATOGRAPHIC PURIFICATION OF THE SODIUM SALT, SUBLIMATION OF THE FREE ACID, AND BASIC HYDROLYSIS OF BETA-(P-NITROPHENOXY)ACROLEIN INDUCED APPROX 5 REVERTANTS/MUMOL IN SALMONELLA TYPHIMURIUM HIS D 3052. [R12] *WHEN MALONDIALDEHYDE WAS SCREENED FOR GENETIC MOSAICS OF DROSOPHILA MELANOGASTER AND BY THE MULLER-5 TEST FOR SEX-LINKED RECESSIVE LETHAL MUTATIONS, IT WAS FOUND TO BE A WEAK MUTAGEN; IT INDUCED POINT MUTATIONS AND CHROMOSOME EXCHANGES AT LOW FREQUENCY, BUT FAILED TO INDUCE DETECTABLE SEX-LINKED LETHALITY. [R13] *WHEN MALONALDEHYDE AS THE SODIUM ENOL SALT WAS ADMIN IN THE DRINKING WATER TO 8-WK-OLD FEMALE SWISS MICE AT LEVELS CALCULATED TO PROVIDE 2, 10, 50, 250, OR 500 UG/G BODY WT/DAY, THOSE THAT RECEIVED 500 UG/G BODY WT/DAY GAINED MORE SLOWLY AND LOST WT AFTER 50 DAYS. ALL LEVELS INDUCED IRREGULARITIES (ANISOKARYOSIS, HYPERCHROMICITY, VESICULATION) OF HEPATIC NUCLEI. PANCREATIC LESIONS CONSISTING PRIMARILY OF ATROPHY OF THE EXOCRINE CELLS WITH LOSS OF ZYMOGEN GRANULATION OCCURRED IN ANIMALS WHICH RECEIVED 500 UG/G BODY WT/DAY. MILD DYSPLASIA OF THE URINARY BLADDER EPITHELIUM WAS FOUND IN ALL TREATMENT GROUPS. [R14] *MALONALDEHYDE WAS ADMIN IN THE DRINKING WATER OF GROUPS OF 50 FEMALE SWISS MICE FOR 12 MO AT LEVELS OF 0.1, 1, AND 10 UG/G BODY WT/DAY WITH 100 CONTROLS. THE HIGHEST DOSE WAS ASSOC WITH INCR MORTALITY (28% VERSUS 12-14%). MORE LIVER LESIONS, WHICH INCLUDED ANISOKARYOSIS, CHANGES IN CYTOPLASMIC VOLUME WITH ARCHITECTURAL DERANGEMENTS, NECROSIS, AND NEOPLASTIC CHANGES (NODULAR HYPERPLASIA, HEPATOMA, AND HEMANGIOMA) WERE OBSERVED IN THE THREE TREATMENT GROUPS THAN IN CONTROLS. THERE WAS NO SIGNIFICANT INCR IN SPECIFIC NEOPLASMS IN THE TREATED GROUPS, BUT THE INCIDENCE OF TOTAL NEOPLASMS AND NEOPLASTIC LESIONS WAS DOSE-DEPENDENT (4%, 8%, AND 12%, RESPECTIVELY). THERE WAS ONLY 1 HEMANGIOMA AMONG THE CONTROLS (1%). THREE ANIMALS (6%) GIVEN THE HIGHEST DOSE DEVELOPED STOMACH NEOPLASMS. [R15] *... Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats administered malonaldehyde, sodium salt, as shown by the increased incidences of follicular cell adenomas or carcinomas (combined) of the thyroid gland. Pancreatic islet cell adenomas were also observed at an increased incidence in low dose male rats. There was no evidence of carcinogenic activity for B6C3F1 mice administered 60 or 120 mg/kg malonaldehyde, sodium salt, in distilled water by gavage 5 days per week for 2 yr. /Malonaldehyde, sodium salt/ [R16] *Malonaldehyde, given in the drinking water, induced morphological changes in the liver and mild dysplasia at all doses tested (2-500 mg/kg body weight per day) in female ICR mice; pancreatic damage was observed at doses of 500 mg/kg body weight per day. [R6] *Malonaldehyde induced mutation in bacteria that were either DNA repair competent or were sensitive to oxidative DNA damage. It had been suggested previously that all or part of the activity might be attributable to impurities, which occur as a result of malonaldehyde instability. However, specially purified or specially synthesized malonaldehyde continued to show mutagenic activity in S. typhimurium his D3052. [R17] *... Malonaldehyde induced somatic mutations but not sex-linked recessive lethal mutations /in Drosophila melanogaster/. [R17] *Malonaldehyde induced dose-dependent increases in sister chromatid exchanges but did not produce chromosomal aberrations in Chinese hamster ovary cells, but did induce chromosomal aberrations and micronuclei in rat primary skin fibroblasts. [R17] *At concentrations of malonaldehyde which produce reversion to histidine prototrophy in Salmonella typhimurium (TA100), characteristic adducts were found in bacterial DNA. The adducts were formed in a dose-dependent manner. [R17] NTXV: *LD50 Mouse oral 606 mg/kg; [R4] *LD50 Rat oral 632 mg/kg; [R4] NTP: *... 2 yr studies of malonaldehyde, sodium salt, were conducted by exposing groups of 50 F344/N rats of each sex at doses of 0, 50, or 100 mg/kg, administered 5 days per week for 103 weeks. Doses of 0, 60, or 120 mg/kg were administered in the same schedule to groups of 50 male and 50 female B6C3F1 mice. Conclusions: Under the conditions of these 2 yr gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats administered malonaldehyde, sodium salt, as shown by the increased incidences of follicular cell adenomas or carcinomas (combined) of the thyroid gland. Pancreatic islet cell adenomas were also observed at an increased incidence in low dose male rats. There was no evidence of carcinogenic activity for B6C3F1 mice administered 60 or 120 mg/kg malonaldehyde, sodium salt, in distilled water by gavage 5 days per week for 2 yr. /Malonaldehyde, sodium salt/ [R16] ADE: *IN PRIMARY RAT SKIN FIBROBLAST CULTURES GROWN IN A MEDIUM CONTAINING 1X10(-5), 1X10(-4), OR 1X10(-3) MOLAR OF 1,3-(14)C MALONALDEHYDE, THERE WAS A LIMITED, CONCENTRATION-DEPENDENT UPTAKE OF MALONALDEHYDE BY 24 HR (APPROXIMATELY 4% AT ALL CONCENTRATIONS). 83-89% OF THE (14)C WAS OXIDIZED TO (14)CO2 BY 24 HR AND APPROXIMATELY 5% WAS RECOVERED IN THE MAJOR LIPIDS. LIMITED CELLULAR UPTAKE OF MALONALDEHYDE MAY EXPLAIN THE TOLERANCE OF CELLS GROWN IN CULTURE TO RELATIVELY HIGH CONCENTRATIONS. [R7] *TWELVE HOURS AFTER INTUBATION WITH 1,3-(14)C MALONALDEHYDE, MALE WISTAR RATS SHOWED 60-70%, 5-15% AND 9-17% OF ADMINISTERED RADIOACTIVITY IN EXPIRED CARBON DIOXIDE, FECES AND URINE, RESPECTIVELY. IN VITRO EXPERIMENTS SHOWED METABOLISM TO BE PRIMARILY IN MITOCHONDRIA VIA REACTIONS INVOLVING OXYGEN UTILIZATION AND (14)CO2 PRODUCTION. THE APPARENT KM AND VMAX WERE 0.5 MMOL AND 9.3 NMOL/MIN/MG PROTEIN FOR OXYGEN UPTAKE, RESPECTIVELY, AND 2.0 MMOL AND 2.4 NMOL/MIN/MG PROTEIN FOR (14)CO2 PRODUCTION. [R18] METB: *THIOBARBITURIC ACID-REACTING MATERIAL PRODUCED DURING ENZYMIC MICROSOMAL LIPID PEROXIDATION WAS IDENTIFIED AS MALONALDEHYDE. PHOSPHOLIPID ARACHIDONATE WAS ESTABLISHED AS THE MAJOR SOURCE OF THE MALONALDEHYDE PRODUCED IN THE REACTION. [R19] *(14)C-ACETATE APPEARED TO BE THE MAJOR ACCUMULATING METABOLITE IN RAT LIVER MITOCHONDRIAL PREPARATIONS FOLLOWING A 120-MINUTE INCUBATION WITH (14)C-MALONALDEHYDE. A PROBABLE BIOCHEMICAL ROUTE FOR MALONALDEHYDE METABOLISM INVOLVES OXIDATION OF MALONALDEHYDE BY MITOCHONDRIAL ALDEHYDE DEHYDROGENASE FOLLOWED BY DECARBOXYLATION TO PRODUCE CARBON DIOXIDE AND ACETATE. [R18] *Two aldehyde dehydrogenases in the rat-liver cytosol fraction account for virtually all of the metabolizing activity for malonaldehyde. [R6] *After oral administration of malonaldehyde (158 mg/kg body weight) to rats, increased quantities of formaldehyde, acetaldehyde, acetone and malonaldehyde itself were found in the urine. Additionally, methyl ethyl ketone, not found in control rats, was present in the urine of the animals that had received malonaldehyde. [R6] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *MALONALDEHYDE HAS BEEN DETECTED IN LIPID-PEROXIDIZING MICROSOMES AND IS FOUND IN ANIMAL TISSUE AS AN END-PRODUCT OF LIPID PEROXIDATION. IT IS ALSO A SIDE-PRODUCT OF PROSTAGLANDIN AND THROMBOXANE BIOSYNTHESIS. MALONALDEHYDE HAS BEEN DETECTED IN THE LEAVES OF PEA AND COTTON PLANTS. [R20] ARTS: +CONCENTRATIONS OF FREE MALONALDEHYDE IN COMMERCIAL SAMPLES OF REFINED GROUND NUT OILS RANGED FROM 0.04-0.14 mg/kg, AND THE LEVEL IN SUNFLOWER OIL WAS 0.08 mg/kg. THE TOTAL MALONALDEHYDE (FREE AND BOUND) CONCENTRATIONS WERE 0.53-4.36 mg/kg IN GROUND NUT OILS AND 0.98 mg/kg IN SUNFLOWER OIL. INCREASED LEVELS OF MALONALDEHYDE HAVE BEEN FOUND IN HAMBURGER, CHICKEN AND BEEF AS A RESULT OF COOKING UNDER A VARIETY OF CONDITIONS (eg, MICROWAVE, FRYING, BAKING AND BOILING) [R1] FOOD: *MALONALDEHYDE IS FOUND IN MANY FOODSTUFFS AND IS PRESENT AT GENERALLY HIGH LEVELS IN RANCID FOODS. IT HAS BEEN DETECTED IN FISH MEAT, FISH OIL, RANCID SALMON OIL, RANCID NUTS, RANCID FLOUR, ORANGE JUICE ESSENCE, VEGETABLE OIL, FATS, FRESH FROZEN GREEN BEANS, MILK, MILK FAT, RYE BREAD, AND IN RAW, CURED AND COOKED MEATS. [R20] PFAC: PLANT CONCENTRATIONS: *MALONALDEHYDE HAS BEEN DETECTED IN THE LEAVES OF PEA AND COTTON PLANTS. [R20] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers malonaldehyde to be a potential occupational carcinogen. [R2, 190] NREC: *NIOSH considers maloaldehyde to be a potential occupational carcinogen. [R2, 190] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concn. [R2, 190] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *PROCEDURE INVOLVES EXTRACTING THE SAMPLE WITH TRICHLORACETIC ACID, HEATING THE EXTRACT WITH THIOBARBITURIC ACID, SEPARATING THE THIOBARBITURIC ACID-MALONALDEHYDE COMPLEX ON A UBONDPAK(18)C COLUMN, AND MEASURING ABSORBANCE USING A 546-NM INTERFERENCE FILTER. METHOD IS SPECIFIC FOR MALONALDEHYDE IN SEVERAL FOOD AND FEED SAMPLES. A COEFFICIENT OF VARIABILITY OF 7.0% WAS OBTAINED FOR SAMPLES CONTAINING 1-2 UG OF MALONALDEHYDE PER GRAM. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Malonaldehyde, Sodium Salt (3-Hydroxy-2-propenal, sodium salt) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 331 (1988) NIH Publication No. 88-1792 /Malonaldehyde, sodium salt/ SO: R1: IARC MONOGRAPHS 1972-PRESENT V36 p.164 R2: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R3: Howard PH, Neal M; Dictionary of Chemical Names and Synonyms. Boca Raton, FL: Lewis Publishers, p. I-466 (1992) R4: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2789 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1045 (1999) R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1040 (1999) R7: BIRD RP, DRAPER HH; LIPIDS 17 (8): 519 (1982) R8: BIRD RP, DRAPER HH; MUTAT RES 101 (3): 237 (1982) R9: HJELLE JJ ET AL; TOXICOL LETT 14 (1-2): 35 (1982) R10: GODWIN SL MC; DISS ABSTR INT B 1982 42 (11): 4347 (1981) R11: YONEI S, FURUI H; MUTAT RES 88: 23 (1981) R12: BASU AK, MARNETT LJ; CARCINOGENESIS 4 (3): 331 (1983) R13: SZABAD J ET AL; MUTAT RES 113 (2): 117 (1983) R14: SIU GM ET AL; J TOXICOL ENVIRON HEALTH 11 (1): 105 (1983) R15: BIRD RP ET AL; J TOXICOL ENVIRON HEALTH 10 (6): 897 (1982) R16: Toxicology and Carcinogenesis Studies of Malonaldehyde, Sodium Salt (3-Hydroxy-2-propenal, Sodium Salt) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 331 (1988) NIH Publication No. 88-1792 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1041 (1999) R18: SIU GM, DRAPER HH; LIPIDS 17 (5): 349 (1982) R19: NIEHAUS WG JR, SAMUELSSON B; EUR J BIOCHEM 6 (1): 126 (1968) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V36 164 R21: BIRD RP ET AL; DETERMINATION OF MALONALDEHYDE IN BIOLOGICAL MATERIALS BY HIGH-PRESSURE LIQUID CHROMATOGRAPHY; ANAL BIOCHEM 128(1) 240 (1983) RS: 20 Record 309 of 1119 in HSDB (through 2003/06) AN: 4356 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-PIGMENT-RED-23- SY: *ALKALI-RESISTANT-RED-DARK-; *CALCOTONE-RED-3B-; *CARNATION-RED-TONER-B-; *CI-12355-; *CONGO-RED-R-138-; *FENALAC-RED-FKB-EXTRA-; *MALTA-RED-X-2284-; *NAPHTHOL-RED-B-; *NAPHTHOL-RED-DEEP-10459-; *NAPHTHOL-RED-D-TONER-35-6001-; *2-NAPTHALENECARBOXAMIDE, 3-HYDROXY-4-((2-METHOXY-5-NITROPHENYL)AZO)-N -(3-NITROPHENYL)-; *NCI-C60377-; *PIGMENT-RED-23-; *PIGMENT-RED-BH-; *RUBESCENCE-RED-MT-21-; *SANYO-FAST-RED-10B-; *SAPONA-RED-LAKE-RL-6280-; *SEGNALE-LIGHT-RUBINE-RG-; *TEXTILE-RED-WD-263- RN: 6471-49-4 MF: *C24-H17-N5-O7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +Coupling of 5-nitro-2-methoxyaniline with Naphthol AS-BS [R1] MFS: +EI duPont de Nemours and Co, Inc, Chemicals and Pigments Dept, DuPont Bldg, Wilmington, DE 19898, (302)774-1000 [R2, p.89] +Galaxie Chemical Corp, 26 Piercy St, Paterson, NJ 07524, (201)279-0558 [R2, p.89] +Harshaw/Filtrol Partnership, 30100 Chagrin Blvd, Cleveland, OH 44124, (216)292-9200 [R2, p.89] +Keystone Color Works, Inc, 151 W. Gray Ave, York, PA 17403, (717)854-9541 [R2, p.89] +Sun Chemical Corp, Pigment Div, 411 Sun Ave, Cincinnati, OH 45232, (212)986-5500 [R2, p.89] +Indol Color Co, Inc, 1029 Newark Ave, Elizabeth, NJ 07201, (201)242-1300 [R2, p.89] +Paul Ulrich and Co, 1 Railroad Ave, Hastings-on-Hudson, NY 10706, (914)478-2000 [R2, p.89] USE: *IN PAINTS, INKS, PLASTICS, RUBBER, TEXTILE PRINTING [R3] +Paints, printing inks and linoleum, also textile printing, rubber, plastics, alkyd resin enamels, lacquers, emulsion paints, paper [R4] PRIE: U.S. PRODUCTION: +(1984) 4.77X10+7 g [R2, p.85] U.S. IMPORTS: +(1986) ND U.S. EXPORTS: +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *487.46 [R5] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: +... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of C.I. Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence of renal tubule cell neoplasms. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in female F344 rats fed diets containing 10,000, 25,000, or 50,000 ppm. Mononuclear cell leukemia occurred with a decreased incidence in male and female rats receiving C.I. Pigment Red 23. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3F1 mice fed diets containing 10,000, 25,000 or 50,000 ppm. [R6] NTP: +... Toxicology and carcinogenicity studies were conducted by feeding groups of rats and mice diets containing C.I. Pigment Red 23 (greater than 96% pure) for ... 2 years. ... Doses of 0, 10,000, 25,000, or 50,000 ppm were selected for the 2 yr studies. ... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of carcinogenic activity of C.I. Pigment Red 23 in male F344 rats as evidenced by a marginally increased incidence of renal tubule cell neoplasms. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in female F344 rats fed diets containing 10,000, 25,000, or 50,000 ppm. Mononuclear cell leukemia occurred with a decreased incidence in male and female rats receiving C.I. Pigment Red 23. There was no evidence of carcinogenic activity of C.I. Pigment Red 23 in male and female B6C3F1 mice fed diets containing 10,000, 25,000 or 50,000 ppm. [R6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I. Pigment Red 23 in F344/N Rats and B6C3F1 Mice Technical Report Series No. 411 (1992) NIH Publication No. 93-3142 SO: R1: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V17 p.840 R2: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 R3: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. VI-180 R4: Soc Dyers and Colourists; Color Index 3rd ed 1971 V3 p.3303 R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8209 R6: Toxicology and Carcinogenesis Studies of C.I. Pigment Red 23 in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 411 (1992) NIH Publication No. 93-3142 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 RS: 5 Record 310 of 1119 in HSDB (through 2003/06) AN: 4357 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-PIGMENT-RED-3- SY: *ACCOSPERSE-TOLUIDINE-RED-XL-; *ADC-TOLUIDINE-RED-B-; *D-AND-C-RED-NO-35-; *CALCOTONE-TOLUIDINE-RED-YP-; *CARNELIO-HELIO-RED-; *CHROMATEX-RED-J-; *CI-12120-; *CP-TOLUIDINE-TONER-A-2989-; *DAINICHI-PERMANENT-RED-4-R-; *DEEP-FASTONA-RED-; *DUPLEX-TOLUIDINE-RED-L-20-3140-; *ELJON-FAST-SCARLET-PV-EXTRA-; *ENIALIT-LIGHT-RED-RL-; *FASTONA-RED-B-; *FASTONA-SCARLET-YS-; *FAST-RED-A- (PIGMENT); *GRAPHTOL-RED-A-4RL-; *HANSA-RED-B-; *HELIO-FAST-RED-BN-; *HISPALIT-FAST-SCARLET-RN-; *INDEPENDENCE-RED-; *IRGALITE-FAST-RED-P4R-; *ISOL-FAST-RED-HB-; *KROMON-HELIO-FAST-RED-; *LAKE-RED-4R-; *LITHOL-FAST-SCARLET-RN-; *LUTETIA-FAST-SCARLET-RF-; *MONOLITE-FAST-SCARLET-CA-; *2-NAPHTHALENOL, 1-((4-METHYL-2-NITROPHENYL)AZO)-; *NCI-C60366-; *NO-2-FORTHFAST-SCARLET-; *ORALITH-RED-P4R-; *PERMANENT-RED-4R-; *PIGMENT-SCARLET-R-; *PIGMENT-SCARLET- (RUSSIAN); *POLYMO-RED-FGN-; *RECOLITE-FAST-RED-RBL-; *SCARLET-PIGMENT-RN-; *SEGNALE-LIGHT-RED-B-; *SIEGLE-RED-1-; *SILOGOMMA-RED-RLL-; *SILOSOL-RED-RBN-; *SYMULER-FAST-SCARLET-4R-; *SYTON-FAST-SCARLET-RB-; *TERTROPIGMENT-RED-HAB-; *TOLUIDINE-RED-; *TOLUIDINE-RED-10451-; *VERSAL-SCARLET-PRNL-; *VERSAL-SCARLET-RNL-; *VULCAFOR-SCARLET-A- RN: 2425-85-6 MF: *C17-H13-N3-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +Coupling of 2-nitro-4-methylaniline with 2-napthol [R1, V840] MFS: +BASF Wyandotte Corp, 491 Columbus Ave, Holland, MI 49423, (616)3922391 [R2, p.89] +Ciba-Geigy Corp, 444 Saw Mill River Rd, Ardsley, NY 10502, (914)478-3131 [R2, p.89] +Flint Ink Corp, Cal/Inc Div, 1404-4th St, Berkeley, CA 94710, (415)525-1188 [R2, p.89] +Harshaw/Filtrol Partnership, 30100 Chagrin Blvd, Cleveland, OH 44124, (216)292-9200 [R2, p.89] +Keystone Color Works, Inc, 151 W. Gay Ave, York, PA 17403, (717)854-9541 [R2, p.89] +Hilton Davis Chemical Co, 2235 Langdon Farm Rd, Cincinnati, OH 45237, (513)841-4000 [R2, p.89] +Sun Chemical Corp, Pigment Div, 411 Sun Ave, Cincinnati, OH 45232, (212)986-5500 [R2, p.89] +Paul Ulrich and Co, Inc, 1 Railroad Ave, Hastings-on-Hudson, NY 10706, (914)478-2000 [R2, p.89] USE: *USED IN MFR OF PAINTS, INKS, PLASTICS, RUBBER, TEXTILE PRINTING [R3] +One of the most widely used of all red pigments on account of the bright scarlet hue, high tinctorial strength, good fastness to acids, alkalis and to light and economy. Some limitation is improved by the relatively poor fastness to organic solvents. Widely used in paints, printing inks, emulsion paints and distempers. Other uses are in synthetic resin lacquers and leather finishes, inks for foil and tinplate printing, paper coating and dyeing, wallpaper, linoleum, carbon papers, typewriter ribbons and student-grade artist materials. Rubber with good strength and fastness to vulcanisation but limited by solubility in rubber; celluloid, cellulose acetate, P/F, U/F, styrene and protein plastics but suffers from migration in some cases. Cement, because of fastness to lime. Textile printing for "print on" style with Aniline Black [R4] +Component of some tracer munitions [R1, V19] PRIE: U.S. PRODUCTION: +(1984) 4.40X10+8 g [R2, p.970] U.S. IMPORTS: +(1983) 3.58X10+6 g [R5] U.S. EXPORTS: +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *307.33 [R6] SOL: *INSOLUBLE [R3] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of CI Pigment Red 3. There is limited evidence in experimental animals for the carcinogenicity of CI Pigment Red 3. Overall evaluation: CI Pigment Red 3 cannot be classified as to its carcinogenicity to humans (Group 3). [R7] HTOX: *EIGHT PT SUFFERING FROM PIGMENTED CONTACT DERMATITIS CAUSED BY THE COMMERCIAL BRILLIANT LAKE RED R WERE PATCH TESTED WITH PURIFIED SUDAN I AND ITS SEVERAL CHEMICAL ANALOGS. NEGATIVE PATCH TESTS WERE OBTAINED WITH TOLUIDINE RED. [R8] NTOX: +... Conclusions: Under the conditions of these 2 yr feed studies, there was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male F344/N rats as exhibited by increased incidences of benign pheochromocytomas of the adrenal gland. The marginal increase in the incidences of squamous cell papillomas of the skin and Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in female F344/N rats as indicated by the increased incidence of hepatocellular adenomas. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male B6C3F1 mice as exhibited by the increased incidences of tubule adenomas of the renal cortex and follicular cell adenomas of the thyroid gland. There was no evidence of carcinogenic activity of C.I. Pigment Red 3 in female B6C3F1 mice that received 12,500, 25,000, or 50,000 ppm. [R9] NTP: +... Toxicology and carcinogenicity studies were conducted by feeding groups of F344/N rats and B6C3F1 mice of each sex diets containing C.I. Pigment Red 3 (97% pure) for ... 2 years. ... 2 Year Studies: Doses selected for the 2 year feed studies were 0, 6,000, 12,500, and 25,000 ppm for rats and 0, 12,500, 25,000, and 50,000 ppm for mice. ... Conclusions: Under the conditions of these 2 yr feed studies, there was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male F344/N rats as exhibited by increased incidences of benign pheochromocytomas of the adrenal gland. The marginal increase in the incidences of squamous cell papillomas of the skin and Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in female F344/N rats as indicated by the increased incidence of hepatocellular adenomas. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male B6C3F1 mice as exhibited by the increased incidences of tubule adenomas of the renal cortex and follicular cell adenomas of the thyroid gland. There was no evidence of carcinogenic activity of C.I. Pigment Red 3 in female B6C3F1 mice that received 12,500, 25,000, or 50,000 ppm. [R9] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *EXTRACTION OF COLORED HOUSEHOLD GLOSS PAINT FRAGMENTS WITH DICHLOROMETHANE AND CHROMATOGRAPHY OF THE EXTRACT ON SILICA GEL PLATES WITH CHLOROBENZENE-TOLUENE-1,2-DICHLOROETHANE (1:1:1), PROVIDES GOOD DISCRIMINATION BETWEEN VISUALLY SIMILAR RED, ORANGE, YELLOW, DARK BLUE, PURPLE, AND BROWN PAINTS. [R10] *THE FAT-SOL TAR DYE FOR COSMETIC PRODUCTS, CI 12120, WAS SEPARATED ON A LICHROSORB SI 100 COLUMN BY AN ISOCRATIC ELUTION TECHNIQUE. THE ELUENT WAS MONITORED BY A WAVELENGTH TUNABLE DETECTOR, SUITABLE SOLVENT SYSTEM WAS CHLOROFORM-N-HEXANE. THE RECOVERIES FROM WAX BASE OF LIPSTICKS WAS IN THE RANGE OF 91.9-97.0%. [R11] CLAB: *1-(2-NITRO-4-METHYLPHENYLAZO)-2-NAPHTHOL WAS EXTRACTED FROM ORGANS WITH CHLOROFORM, SEPARATED FROM FATS ON ALUMINUM OXIDE COLUMNS, ELUTED WITH CHLOROFORM, EVAPORATED, AND CHROMATOGRAPHED ON SILICA GEL KSK. CHLOROFORM WAS THE MOBILE PHASE. EXTRACTION OF PIGMENTS FROM ORGAN WAS 100%. [R12] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I. Pigment Red 3 in F344/N Rats and B6C3F1 Mice(Feed Studies) Technical Report Series No. 407 (1992) NIH Publication No. 92-3138 SO: R1: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT R2: USITC. SYN ORG CHEM-U.S. PROD/SALES 1984 R3: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. VI-185 R4: Soc Dyers and Colourists; Color Index 3rd ed 1971 V3 p.3299 R5: USITC. IMPORTS OF BENZENOID CHEM AND PROD 1983 p.73 R6: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8209 R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 57 264 (1993) R8: KGZUKA T ET AL; PIGMENTED CONTACT DERMATITIS FROM AZO DYES: 1. CROSS-SENSITIVITY IN HUMANS; CONTACT DERMATITIS 6(5) 330 (1980) R9: Toxicology and Carcinogenesis Studies of _C.I. Pigment Red 3 in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 407 (1992) NIH Publication No. 92-3138 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R10: HOME JM ET AL; THE DISCRIMINATION OF MODERN HOUSEHOLD PAINTS USING THIN LAYER CHROMATOGRAPHY; J FORENSIC SCI SOC 22(2) 147 (1982) R11: OHNISHI S ET AL; CHROMATOGRAPHIC ANALYSIS OF TAR DYES IN COSMETIC PRODUCTS. PART 3; BUNSEKI KAGAKU 26(12) 814 (1977) R12: VLADIMIRSKAYA AI ET AL; METHOD FOR THE DETERMINATION OF SOME AZO PIGMENTS IN INTERNAL-ORGAN TISSUES OF ANIMALS; GIG SANIT 4: 54 (1976) RS: 9 Record 311 of 1119 in HSDB (through 2003/06) AN: 4359 UD: 200303 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: GLYCOL- (POLYSORBATE80) SY: *ARMOTAN-PMO-20-; *ATLOX-1087-; *ATOLOX-8916TF-; *CAPMUL-POE-O-; *CRILLET-4-; *DREWMULSE-POE-SMO-; *DURFAX-80-; *EMSORB-6900-; *GLYCOSPERSE-O-20-; *GLYCOSPERSE-O-20X-; *GLYCOSPERSE-O-20-VEG-; *LIPOSORB-O-20-; *MO-55F-; *MONTANOX-80-; *NCI-C60286-; *NIKKOL-TO-; *POLYOXYETHYLENE-SORBITAN-MONOOLEATE-; *POLYSORBATE-80-; *POLYSORBATE-80-BPC-; *POLYSORBATE-80,-USP-; *PROTASORB-O-20-; *ROMULGIN-O-; *SORBIMACROGOL-OLEATE-300-; *SORBITAN, MONO-9-OCTADECENOATE, POLY(OXY-1,2-ETHANEDIYL) DERIVS, (Z)-; *SORBITAN,-MONOOLEATE,-POLYOXYETHYLENE-DERIVS-; *SORBON-T-80-; *SVO-9-; *TO-10-; *TWEEN-80-; *TWEEN-81- RN: 9005-65-6 MF: *UNKNOWN MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *AN OLEATE ESTER OF SORBITOL AND ITS ANHYDRIDES COPOLYMERIZED WITH APPROX 20 MOLES OF ETHYLENE OXIDE FOR EACH MOLE OF SORBITOL AND SORBITOL ANHYDRIDES. [R1] *.../PREPARED BY/ STARTING WITH SORBITOL BY (1) ELIMINATION OF WATER FORMING SORBITAN (A CYCLIC SORBITOL ANHYDRIDE); (2) PARTIAL ESTERIFICATION OF SORBITAN WITH FATTY ACID SUCH AS OLEIC OR STEARIC ACID YIELDING HEXITAN ESTER KNOWN COMMERCIALLY AS SPAN; and (3) CHEMICAL ADDITION OF ETHYLENE OXIDE YIELDING A TWEEN (THE POLYOXYETHYLENE DERIVATIVE). /POLYSORBATES/ [R2, 1252] OMIN: *ESCHERICHIA COLI K-12 WAS CULTURED IN A MINIMAL MEDIUM WITH 0.005% VOL/VOL POLYSORBATE 80. ALTHOUGH E COLI NORMALLY GROWS IN A CULTURE IN A DISPERSED STATE, AGGREGATION OCCURRED. COMPARISONS OF THE PROLIFERATION OF THE MICROORGANISMS IN CONTROL CULTURES (NO AGGREGATION) TO THE POLYSORBATE 80 CULTURES INDICATED A STATISTICALLY VALID INCR IN GROWTH RATE IN THE LATTER. [R3] *BECAUSE OF THEIR HYDROPHILIC AND LYOPHILIC CHARACTERISTICS, THESE NONIONIC SURFACTANTS ARE VERY USEFUL AS EMULSIFYING AGENTS IN PHARMACEUTICALS, COSMETICS, AND OTHER TYPES OF PRODUCTS. POLYSORBATE 80 IS AN INGREDIENT IN COAL TAR OINTMENT AND SOLUTION. [R2, 1251] *WHEREAS ONLY 10% OF THE RATS GIVEN IV INJECTIONS OF 106 WALKER TUMOR CELLS DEVELOPED METASTATIC TUMORS, ANIMALS GIVEN, WITH THE 1 ML CELL SUSPENSION, TWEEN 80 (1%) SHOWED 40% INCIDENCE OF METASTASIS. [R4] USE: *USP GRADE IS USED AS EMULSIFIER AND DISPERSING AGENT FOR MEDICINAL PRODUCTS DESIGNED FOR INTERNAL USE; PHARMACEUTIC AID (SURFACTANT) [R1] +Defoamer and emulsifier in foods [R5] +Neutrilizer for quaternary ammonium compounds /in testing disinfectants/ [R6] PRIE: U.S. PRODUCTION: +(1986) ND U.S. IMPORTS: +(1986) ND U.S. EXPORTS: +(1986) ND CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *AMBER COLORED LIQUID [R1] DEN: *1.06-1.10 [R1] PH: *PH OF 5% AQ SOLN BETWEEN 5 and 7 [R1] SOL: *VERY SOL IN WATER; SOL IN ALCOHOL, COTTONSEED OIL, CORN OIL, ETHYL ACETATE, METHANOL, TOLUENE; INSOL IN MINERAL OIL [R1] VISC: *270-430 CENTISTOKES [R1] OCPP: *LEMON TO AMBER COLORED, OILY LIQUID; VERY SOL IN WATER PRODUCING AN ODORLESS AND NEARLY COLORLESS SOLN /USP/ [R2, 1252] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FLPT: *GREATER THAN 300 DEG F [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *UNINTENTIONALLY ADMINISTERED TO A 4-MONTH /OLD/ INFANT AT DAILY DOSE OF 19.2 G/KG FOR 2 CONSECUTIVE DAYS. THE PATIENT PASSED 6 LOOSE STOOLS BUT SHOWED NO OTHER EVIDENCE OF INTOXICATION. [R8] *TWEEN 80 DID NOT CAUSE IRRITATION TO HUMAN SKIN. [R9] NTOX: *...USP GRADE OF THIS COMPOUND INJECTED INTO CORNEAS OF RABBITS PROVOKED NECROSIS, WITH LIPOGENESIS IN ADJACENT SURVIVING CELLS... [R10] *10-20 DAY OLD MALE RAT PUPS WHOSE DAMS RECEIVED CHRONIC DOSES OF TWEEN 80 (1.25 ML/L) VIA DRINKING WATER EXHIBITED AN ENHANCEMENT IN THEIR EXPLORATORY AND LOCOMOTOR ACTIVITY DURING THE DIURNAL PERIOD OF THE DAY. [R11] *COMMERCIAL IV AMIODARONE AND POLYSORBATE 80 CAUSED A 60% DROP IN MEAN BLOOD PRESSURE AND LEFT VENTRICULAR MAXIMUM DP/DT FOR AT LEAST 30 MINUTES IN DOGS. THESE EFFECTS WERE NOT OBSERVED WITH IV AMIODARONE AND ETHANOL. HYPOTENSION WAS NOT PRINCIPALLY DUE TO PERIPHERAL VASODILATION. IN DOGS, THE DILUENT POLYSORBATE 80 WAS THE MAJOR CAUSE OF THE HYPOTENSIVE ACTION OF COMMERCIAL IV AMIODARONE. [R12] *THE LACTATE DEHYDROGENASE ACTIVITY AND THE POTASSIUM LEVEL INCREASED SIGNIFICANTLY WHEN COMPARED TO THE CONTROLS WHEN DOG KIDNEYS WERE PERFUSED WITH POLYSORBATE 80 ALONE OR WITH ONE OF THE PHTHALATE PLASTICIZERS. KIDNEY WEIGHT WAS ALSO INCREASED. [R13] +... Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of polysorbate 80 in male F344/N rats based pheochromocytomas of the adrenal medulla. There was no evidence of carcinogenic activity for polysorbate 80 in female F344/N rats or in male or female B6C3F1 mice given 25,000 or 50,000 ppm. [R14] NTP: +... Toxicity and carcinogenicity studies were conducted by administering polysorbate 80 (which met all compendial specifications) in feed to groups of F344/N rats and B6C3F1 mice of each sex for ... 2 years. ... 2 Yr Studies: Doses for the 2 yr studies ... groups of 60 rats and 60 mice of each sex received diets containing 0, 25,000 or 50,000 polysorbate 80 for up to 103 wk. Conclusions: Under the conditions of these 2 yr feed studies, there was equivocal evidence of polysorbate 80 in male F344/N rats based pheochromocytomas of the adrenal medulla. There was no evidence of carcinogenic activity for polysorbate 80 in female F344/N rats or in male or female B6C3F1 mice given 25,000 or 50,000 ppm. [R14] +... Timed-mated Sprague-Dawley-derived (CD(R)) rats (25/group) were exposed to 0, 500 or 5,000 mg/kg/day of polyoxyethylene sorbitan monooleate (TW80). Aqueous solns were delivered by gavage in a volume of 5 ml/kg of body weight on gestational days (gd) 6-15. ... All treated females survived to scheduled necropsy and 19-23 pregnancies/group were confirmed. No dose-related signs of toxicity were observed for individual animals during the in-life phase of the study or at scheduled necropsy. Avg maternal body weight (gestational days 0, 3, 6, 9, 12, 15, 18, or 20) did not differ among treatment groups, nor was there a treatment related change in maternal weight gain during treatment or gestation (absolute or corrected). There were no treatment-related effects upon the following maternal organ weights: gravid weight (absolute), kidney weight (absolute or relative), and heart weight (absolute or relative). Relative maternal liver weight (% body weight on gestational day 20 or % corrected body weight) was elevated in both olyoxyethylene sorbitan monooleate groups and absolute liver weight was elevated at 500 mg/kg/day. Maternal food intake was comparable across groups during the pre- and post-treatment periods, but was decreased by 14% during the first 3 days of treatment at 5,000 mg/kg/day relative to the vehicle control group. Maternal relative water intake was comparable among treatment groups throughout gestation. No differences among groups were noted for the number of corpora lutea/dam, the number of implantation sites/dam or the % preimplantation loss/litter. No adverse effects were noted on the growth, viability or morphological development of the conceptuses. In conclusion, the maternal LOAEL was 500 mg/kg/day (based upon an incr in maternal relative liver weight). No definitive adverse effects of olyoxyethylene sorbitan monooleate upon prenatal development were noted in this study. Thus, the developmental NOAEL was > 5,000 mg/kg/day. [R15] ADE: *SEE POLYOXYETHYLENE (20) SORBITAN MONOSTEARATE. IN THE BOWEL THE FATTY ACID IS SPLIT OFF AND ABSORBED, AND THE REST IS ELIMINATED IN FECES. /POLYOXYETHYLENE (20) SORBITAN MONOSTEARATE/ [R8] ACTN: *TWEEN 80 (2.4 MUG/ML PERFUSION FLUID) SHOWED A CORONARY VASODILATORY EFFECT AND INCR THE CARDIAC OUTPUT IN ISOLATED GUINEA PIG AND RABBIT HEARTS, BUT DID NOT ALTER THE FREQUENCY OR AMPLITUDE OF MYOCARDIAL CONTRACTION. IF THE CONCN OF THE SURFACTANT WAS INCR FROM 0.7 TO 4 MUG/ML, THERE WAS A DOSE-RELATED INCR IN THE CORONARY OUTPUT AND AT HIGHER DOSES A SLIGHT DECR IN THE AMPLITUDE OF CONTRACTION AND AN INCR IN THE HEART RATE WERE SEEN. TWEEN 80 (0.25 MG/40 ML) DECR BOTH THE AMPLITUDE OF THE PENDULAR MOVEMENTS AND THE TONICITY IN GUINEA PIG ILEUM, BUT HAD NO EFFECT IN RABBIT ILEUM. [R16] INTC: *EFFECT OF POLYSORBATE 80 ON THE BIOAVAILABILITY AND DISTRIBUTION OF METHOTREXATE (MTX) WAS STUDIED IN NMRI AND PORTON MICE FOLLOWING ORAL ADMINISTRATION. IN THESE TWO STRAINS OF MICE CONCENTRATIONS OF MTX WERE INCREASED IN VARIOUS ORGANS BY THIS NONIONIC SURFACTANT. [R17] *TWEEN 80 POTENTIATED THE ANTITUMOR EFFECTS OF DAUNOMYCIN BOTH IN RATS WITH EHRLICH ASCITES TUMOR AND IN ISOLATED TUMOR CELLS. AT THE SUBCELLULAR LEVEL, TWEEN 80 INCR BINDING OF DAUNOMYCIN TO THE NUCLEUS AND MITOCHONDRIA. [R18] *IN CULTURES OF CHINESE HAMSTER CELL LINES RESISTANT TO ACTINOMYCIN D AND DAUNOMYCIN, TREATMENT WITH THE NONIONIC SURFACTANT TWEEN 80 POTENTIATED THE EFFECTS OF THE 2 ANTIBIOTICS IN GROWTH STUDIES AND ENHANCED UPTAKE. [R19] *ADRIAMYCIN IN A 10% TWEEN 80 AQ SOLN INJECTED IV INTO SARCOMA-BEARING MICE HAD HIGHER ANTITUMOR ACTIVITY AND PRODUCED HIGHER ADRIAMYCIN LEVELS IN THE SPLEEN, LUNG, AND KIDNEY THAN DID ADRIAMYCIN GIVEN ALONE. [R20] *POLYSORBATE 80 ANTAGONIZED THE ACTIVITY OF FENTICLOR AGAINST EXPONENTIAL PHASE CULTURES OF STAPHYLOCOCCUS AUREUS, PROTEUS VULGARIS, AND ESCHERICHIA COLI. [R21] *THE GI ABSORPTION OF VIRGINIAMYCIN AND OF A MIXT OF THE FACTORS M AND S (CONSTITUENTS OF VIRGINIAMYCIN) IN RATS, WAS ENHANCED WHEN POLYSORBATE 80 WAS ADMIN SIMULTANEOUSLY. [R22] *POLYMYXIN B (3-30 UNITS/ML) AND POLYSORBATE 80 (0.0001-0.25%, VOL/VOL) ACTED SYNERGISTICALLY AGAINST PSEUDOMONAS AERUGINOSA WITH RESPECT TO LEAKAGE, DEATH, AND LYSIS. [R23] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *1. 1= PRACTICALLY NONTOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) ABOVE 15 G/KG, MORE THAN 1 QUART (2.2 LB) FOR 70 KG PERSON (150 LB). [R8] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *MID /MEAT INSPECTION DIVISION OF US DEPT OF AGRICULTURE/. LIMITATIONS: TO EMULSIFY SHORTENINGS SOLD IN UNITS NOT EXCEEDING 6 POUNDS OR 1 GALLON FLUID CONTENT, 1% ALONE; WITH POLYSORBATE 60 OR SORBITAN MONOSTEARATE, TOTAL ADDITIVES 1% MAXIMUM. [R24, 922] FDA: *172.515 [R25] *121.1009. LIMITATIONS: 1. EMULSIFIER IN ICE CREAM, FROZEN CUSTARD, ICE MILK, FRUIT SHERBET, AND NONSTANDARDIZED FROZEN DESSERT, ALONE OR WITH POLYOXYETHYLENE (20) SORBITAN TRISTEARATE, TOTAL ADDITIVE(S) 0.10% MAXIMUM. 2. EMULSIFIER IN SHORTENINGS AND EDIBLE OILS FOR USE IN NONSTANDARDIZED BAKED GOODS, BAKING MIXES, ICINGS, FILLINGS, AND TOPPINGS AND IN FRYING OF FOODS, ALONE, 1.0% MAXIMUM; WITH POLYSORBATE 60, TOTAL ADDITIVES, 1.0% MAXIMUM. 3. IN YEAST-DEFOAMER FORMULATIONS, 4% MAXIMUM OF FINISHED YEAST DEFOAMER, OR OF THE YEAST FROM SUCH USE. [R24, p. 921] *121.1009. LIMITATIONS: 4. SOLUBILIZING AND DISPERSING AGENT IN PICKLES AND PICKLE PRODUCTS, UP TO 0.05%. 5. SOLUBILIZING AND DISPERSING AGENT FOR FAT-SOL VITAMINS IN VITAMIN-MINERAL PREPARATIONS, INTAKE FROM RECOMMENDED DAILY DOSE 300 MG MAXIMUM; IN VITAMIN A PREPARATIONS CONTAINING MORE THAN 30,000 UNITS/DOSE, DAILY INTAKE 500 MG MAXIMUM. 6. SURFACTANT IN PRODUCTION OF COARSE CRYSTAL SODIUM CHLORIDE, UP TO 10 PPM IN FINISHED SALT. 7. EMULSIFIER FOR EDIBLE FATS AND OILS IN SPECIAL DIETARY FOODS, DAILY INGESTION NOT TO EXCEED 360 MG. [R24, 921] *121.1009. LIMITATIONS: 8. EMULSIFIER IN WHIPPED, VEGETABLE OIL TOPPING, ALONE OR WITH SORBITAN MONOSTEARATE, POLYSORBATE 60, and /OR POLYOXYETHYLENE(20)SORBITAN TRISTEARATE; TOTAL ADDITIVE(S), 0.4%. 9. WETTING AGENT IN SCALD WATER FOR POULTRY DEFEATHERING, FOLLOWED BY POTABLE WATER RINSE; 0.0175% MAXIMUM IN SCALD WATER. 10. SOLUBILIZING AND DISPERSING AGENT FOR DILL OIL IN CANNED, SPICED GREEN BEANS, UP TO 0.003%. 11. DISPERSING AGENT IN GELATIN DESSERTS AND IN GELATIN DESSERT MIXES, UP TO 0.082%; PRODUCT SPECIFICATIONS APPLY. [R24, 921] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Polysorbate 80 in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 415 (1992) NIH Publication No. 92-3146 SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 985 R2: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. R3: LEVINSON RS ET AL; EFFECT OF POLYSORBATE 80 ON ESCHERICHIA COLI CULTURES; CAN J PHARM SCI 13(APR) 48 (1978) R4: KIRICUTA I ET AL; INFLUENCE OF SOME SURFACE-ACTIVE AGENTS ON WALKER TUMOR CELLS METASTASES; REV ROUM EMBRYOL CYTOL, SER CYTOL 8(2) 29 (1971) R5: MERCK INDEX 10TH ED 1983 p.1095 R6: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V7 p.798 R7: National Fire Protection Association. Fire Protection Guide on Hazardous Materials. 7th ed. Boston, Mass.: National Fire Protection Association, 1978. 208 R8: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-181 R9: GAKENHEIMER WC, LUDWIG KG; PHYSIOLOGICAL SAFETY OF TWEEN 20 AND TWEEN 80 AS COSMETIC SURFACTANTS; PARFUEM KOSMET 54(2) 43 (1973) R10: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 848 R11: BRUBAKER CM ET AL; EFFECT OF TWEEN 80 ON EXPLORATORY BEHAVIOR AND LOCOMOTOR ACTIVITY IN RATS; LIFE SCI 30(23) 1965 (1982) R12: GOUGH WB ET AL; HYPOTENSIVE ACTION OF COMMERCIAL INTRAVENOUS AMIODARONE AND POLYSORBATE 80 IN DOGS; J CARDIOVASC PHARMACOL 4(3) 375 (1982) R13: OLSEN PR ET AL; NEPHROTOXICITY OF PLASTICIZERS INVESTIGATED BY 48 HOUR HYPOTHERM PERFUSION OF DOG KIDNEYS; SCAND J UROL NEPHROL 16(2) 187 (1982) R14: Toxicology and Carcinogenesis Studies of Polysorbate 80 in F344/N Rats and B6C3F1 Mice (Feed Studies). Technical Report Series No. 415 (1992) NIH Publication No. 92-3146 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Developmental Toxicology of Polyoxyethylene Sorbitan Monooleate (CAS #9005-65-6) in Sprague-Dawley CD(R) Rats, NTP Study No. TER91009 (October 1992) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R16: CORREIA DA SILVA AC, PAIVA MQ; PHARMACODYNAMIC ACTIVITY OF THE "TWEENS"; AN FAC FARM PORTO 30 141 (1970) R17: AZIN MN ET AL; EFFECTS OF POLYSORBATE 80 ON THE ABSORPTION AND DISTRIBUTION OF ORAL METHOTREXATE (MTX) IN MICE; CANCER CHEMOTHER PHARMACOL 9(3) 161 (1982) R18: BOSSA R ET AL; POTENTIATION OF THE ANTITUMOR ACTIVITY OF DAUNOMYCIN BY TWEEN 80. IN VIVO AND IN VITRO STUDIES ON EHRLICH ASCITES TUMORS; G ITAL CHEMIOTER 20(1-4) 55 (1973) R19: RIEHM H, BIEDLER JL; POTENTIATION OF DRUG EFFECT BY TWEEN 80 IN CHINESE HAMSTER CELLS RESISTANT TO ACTINOMYCIN D AND DAUNOMYCIN; CANCER RES 32(6) 1195 (1972) R20: CASAZZA AM ET AL; ENHANCEMENT OF THE ANTITUMOR ACTIVITY OF ADRIAMYCIN BY TWEEN 80; TUMORI 64(2) 115 (1978) R21: RICHARDS RM E, HARDIE MP; EFFECT OF POLYSORBATE 80 AND PHENYLETHANOL ON THE ANTIBACTERIAL ACTIVITY OF FENTICLOR; J PHARM PHARMACOL 24(SUPPL) 90P (1972) R22: FILS F; EFFECT OF POLYSORBATE 80 ON THE RESORPTION OF VIRGINIAMYCIN; J PHARM BELG 27(5) 543 (1972) R23: BROWN MR W, WINSLEY BE; SYNERGISM BETWEEN POLYMYXIN AND POLYSORBATE 80 AGAINST PSEUDOMONAS AERUGINOSA; J GEN MICROBIOL 68(PT 3) 367 (1971) R24: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Cleveland: The Chemical Rubber Co., 1972. R25: Furia, T.E. (ed.). CRC Handbook of Food Additives. 2nd ed. Volume 2. Boca Raton, Florida: CRC Press, Inc., 1980. 299 RS: 16 Record 312 of 1119 in HSDB (through 2003/06) AN: 4361 UD: 200302 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N-(HYDROXYMETHYL)ACRYLAMIDE SY: *ACRYLAMIDE, N-(HYDROXYMETHYL)-; *N-(HYDROXYMETHYL)-2-PROPENAMIDE; *N-METHANOLACRYLAMIDE-; *N-METHYLOLACRYLAMIDE-; *MONOMETHYLOLACRYLAMIDE-; *NCI-C60333-; *2-PROPENAMIDE, N-(HYDROXYMETHYL)-; *URAMINE-T-80- RN: 924-42-5 MF: *C4-H7-N-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Acrylamide + formaldehyde (hydroxymethylation) [R1] MFS: *Cytec Industries, Inc., Specialty Chemicals, Polymer Additives, Five Garret Mountain Plaza, West Patterson, NJ 07424, (973) 357-3100; Production site: Wallingford, CT 06493 [R2] *National Starch and Chemical Company, 10 Finderne, Bridgewater, NJ 08807-3300, (908) 685-5000; Production site: Salisbury, NC 28145-0399 [R2] USE: *PROPOSED FOR USE IN SUNSCREEN PREPARATIONS *Reactive comonomer (vinyl acetate, styrene-butadiene resins); starch modifier [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *101.11 [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *AMONG 4 FIBER DRUMS OF THIS CHEMICAL /N-HYDROXYMETHYLACRYLAMIDE/, 2 OF WHICH HAD NEVER BEEN OPENED, EXCESSIVE HEAT, SMOKE, CRACKLING AND SMALL FLAME WERE NOTED. VERY SMALL AMOUNTS OF CONTAMINANT ARE BELIEVED TO HAVE CATALYZED THIS POLYMERIZATION REACTION, BUT STORAGE IN EXCESSIVELY HEATED AREAS CAN ALSO START THE REACTION. [R3] *May undergo spontaneous combustion in storage. [R4] TOXC: *When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [R4] REAC: *Excessive heat, smoke, flames, and cracking noise were emitted from stored fibre drums of the monomer, some unopened. Polymerization may have been initiated by minor contaminants (perhaps as vapors), and/or by excessively warm storage conditions. [R5] DCMP: *When heated to decomposition it emits toxic fumes of /nitrogen oxides/. [R4] SSL: *May undergo spontaneous combustion in storage. [R4] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist respirations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Activated charcoal is not effective ... . Do not attempt to neutralize because of exothermic reaction. Cover skin burns with dry, sterile dressings after decontamination ... . /Organic acids and related compounds/ [R6, p. 152-3] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Early intubation, at the first sign of upper airway obstruction, may be necessary. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors if patient is hypotensive with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Organic acids and related compounds/ [R6, 153] NTOX: *NEUROTOXICITY OF ACRYLAMIDE AND RELATED COMPD AND ITS EFFECT ON THE TESTIS AFTER REPEATED ORAL DOSES WERE STUDIED IN MICE. N-HYDROXYMETHYLACRYLAMIDE WAS AMONG THOSE COMPOUNDS PRODUCING TESTICULAR ATROPHY. HISTOLOGICAL CHANGES PRODUCED WERE DEGENERATION OF THE EPITHELIAL CELLS OF THE SEMINIFEROUS TUBULES WITH INTERSTITIAL CELLS BEING NORMAL. IT ALSO CAUSED NEUROPATHY AS ASSESSED BY ROTAROD PERFORMANCE TEST. [R7] *N-HYDROXYMETHYLACRYLAMIDE AT A CONCN OF 1800 PPM (DAILY INTAKE 27 MG/RAT) FOR 1 WK AND THEREAFTER 900 PPM (DAILY INTAKE 18.6 MG/RAT) PRODUCED SLIGHT ATAXIA IN MALE PORTON RATS AFTER 5 WK. OVER THE NEXT 2 WK, IN ADDN TO THE DOSING VIA THE DIET, 4 IP DOSES OF N-HYDROXYMETHYLACRYLAMIDE (50 MG/KG) WERE GIVEN. THE DISABILITY BECAME MODERATE AT 7 WK. [R8] *... Conclusions: Under the conditions of these 2 year studies, there was no evidence of carcinogenic activity of N-methylolacrylamide for male or female F344/N rats receiving doses of 6 or 12 mg/kg/day by aqueous gavage. There was clear evidence of carcinogenic activity of N-methylolacrylamide for male B6C3Fl mice, based on increased incidences of neoplasms of the Harderian gland, liver, and lung. There was clear evidence of carcinogenic activity of N-methylolacrylamide for female B6C3Fl mice, based on increased incidences of neoplasms of the Harderian gland, liver, lung, and ovary. [R9] NTXV: *LD50 Rat oral 474 mg/kg; [R4] *LD50 Rat ip 563 mg/kg; [R4] *LD50 Mouse oral 420 mg/kg; [R4] NTP: *... Toxicology and carcinogenesis studies were conducted by administering N-methylolacrylamide (98% pure) in water by gavage to groups of F344/N rats and B6C3Fl mice of each sex for ... 2 yr. ... Two yr studies were conducted by administering 0, 6, or 12 mg/kg N-methylolacrylamide in water by gavage, 5 days/wk for 103 wk, to groups of 50 rats of each sex. Groups of 50 mice of each sex were administered 0, 25, or 50 mg/kg on the same schedule. ... Conclusions: Under the conditions of these 2 year studies, there was no evidence of carcinogenic activity of N-methylolacrylamide for male or female F344/N rats receiving doses of 6 or 12 mg/kg/day by aqueous gavage. There was clear evidence of carcinogenic activity of N-methylolacrylamide for male B6C3Fl mice, based on increased incidences of neoplasms of the Harderian gland, liver, and lung. There was clear evidence of carcinogenic activity of N-methylolacrylamide for female B6C3Fl mice, based on increased incidences of neoplasms of the Harderian gland, liver, lung, and ovary. [R9] *N'(Hydroxymethyl)-acrylamide (HACR) was evaluated for reproductive toxicity, neurotoxicity, and dominant lethal effects using a modified Reproductive Assessment by Continuous Breeding (RACB) Protocol in CD-1 (Swiss) mice. ... During the continuous breeding phase, exposure to HACR at doses ranging from 11.1±0.57 mg/kg/day in the low-dose group males (60 ppm in water), to 113.4±15.86 mg/kg/day in the high-dose group females (360 ppm in water), for 27 wks of cohabitation, significantly affected measures of reproductive competence, including a 26% decr in the number of live pups/litter at 360 ppm and an increased inter-birth interval at all doses. However, the mean number of litters/pair, the proportion of pups born alive, or adjusted live pup weight were not affected. In a modified dominant lethal test. HACR-treated F0 males were mated to nontreated females. Significantly more early resorptions were detected at 180 ppm (/about/ 30-40 mg/kg/day) and higher, and fewer pups were born at 360 ppm (/about/ 80 mg/kg/day), indicating an effect of HACR on male reproduction. However, the crossover mating trial indicated no significant affect of 360 ppm HACR on any indices of fertility or mating and did not clearly indicate the affected sex, even though the number of pups/litter was reduced by 1.5 pups on the avg when sires were HACR treated (control x control, 10.6±1.0 vs. HACR male x control female, 9.1±0.9). Clinically, no dose-related signs were noted in F0 HACR- treated mice. F0 body weight and feed consumption during the initial weeks of HACR exposure were not adversely affected by treatment. HACR produced only slight changes in grip strength: in forelimbs of females after 12 wks (360 ppm) and 27 wks (180 and 360 ppm) of treatment. Trends towards reduced grip strength were also observed in the hind limbs of females and forelimbs of males after 12 wks of dosing. At necropsy of F0 adults, HACR (360 ppm) caused a 14% decr in testicular weight from controls, a 7% reduction in the total number of spermatids, and a 14% reduction in the concn of epididymal spermatozoa. No other dose-related trends in reproductive or somatic organ or body weights were noted for males and none for females. Estrual cycle characteristics were normal. No treatment-related reproductive, neural, or somatic organ histopathology was observed in either sex. In the second generation (F1) growth phase. HACR at dose levels of > or =60 ppm in water did not adversely affect preweaning growth or survival of the F1 generation. However, after weaning, dose-related decreases in body weight occurred in the face of increased water and feed consumption between 82±10 and 110±10 days of age in the F1 generation, more so in males than in females. Calculated exposure averaged between 15.6±0.61 and 188.8±11.3 mg/kg/day for adult F1 males and females at 60 and 360 ppm, respectively. No treatment related clinical signs were noted. In the F1 mating trial, HACR at > or =60 ppm had slight effects on the reproductive competence of the F1 generation. HACR caused a 18%-55% reduction in the number of live F2 pups/litter at > or =60 ppm and reduced dam weight by 5%-9% at > or =60 ppm. HACR clearly decreased forelimb and hind limb grip strength of males and hind limbs of females for Weeks 3-10 at most doses, with the forelimb of females being affected only at Week 10. There were significant treatment affects on male body weight, so that any decreases in reproductive organ weight when adjusted for body size were not significant. The exception was the seminal vesicles at 360 ppm, which were relatively smaller than for controls. Sperm parameters significantly affected by HACR were limited to the epididymal spermatozoa concns at 360 ppm (reduced by 13%): Spermatid counts (/mg of testicular weight) were non-significantly decreased (8%), and testicular histopathology was not markedly different from controls. In F1 females, terminal body weight was not reduced, AND HACR had no affect on reproductive organ weight, vaginal cytology, or histopathology. In summary, exposure to HACR in water at dose levels as high as 360 ppm (/about/ 115 mg/kg/day), for up to 27 wks, resulted in moderate reproductive toxicity--decreased pups/litter at 360 ppm in F0 mice and at 60, 180, and 360 ppm in F1 mice, longer inter-litter interval in F0 females at 60, 180, and 360 ppm, and increased postimplantation loss (dominant lethal effect at 180 and 360 ppm) for untreated females mated to F0 males, in the absence of any clear-cut systemic toxicity in F0 mice. F1 mice had lowered body weights and increased liver and kidney/adrenal weight at all doses. Testicular toxicity was present in F0 animals at 360 ppm as indicated by decreased weight. Histopathology was not evident. F1 animals were more susceptible than F0 animals to the neuromuscular effects of HACR at all doses: HACR consistently decreased grip strength in both limbs of both sexes in F1 animals during post-weaning development, as opposed to sporadic effects in the hind limbs and forelimbs of F0 animals: more often in females. Neurotoxicity and litter effects were present in both F0 AND F1 animals at doses lower than for currently or previously described testicular effects. The F1 generation, exposed from the time of gametogenesis, was more susceptible to neurotoxic and reproductive effects than were the F0 animals. We were not able to separate reproductive effects from testicular toxicity, although early resorptions occurred at a lower dose (180 ppm) than decreased testicular weight (360 ppm). Testicular effects were observed in F0 males at doses that did not cause neurotoxicity. Thus, these data indicate that HACR does affect reproductive performance of either F0 or F1 mice under the conditions used in Tasks 2-4 of this study (at doses < or =120 mg/kg/day). HACR had dominant lethal effects, which reduced live litter size by 26% in the F0 mice and by as much as 55% for the F1 mice at the high dose. The reduced number of pups/litter was equivalent in pairs fed HACR to those after exposed males were mated to nontreated females in the dominant lethal test. Thus, the dominant lethal effects may account for all of the F0 reproductive toxicity. [R10] ADE: *N-HYDROXYMETHYLACRYLAMIDE IV INJECTED INTO RATS @ 140 MG/KG WAS DISTRIBUTED THROUGHOUT THE TOTAL BODY WATER WITHIN A FEW MIN. BREAKDOWN OF N-HYDROXYMETHYLACRYLAMIDE TO ACRYLAMIDE WAS NEGLIGIBLE IN VITRO AND IN VIVO. IT CAUSED A RAPID DECR IN LIVER GLUTATHIONE IN VIVO AND GLUTATHIONE CONJUGATES WERE EXCRETED IN THE BILE. [R11] METB: *IN VITRO BIOTRANSFORMATION OF ACRYLAMIDE AND 10 RELATED CMPDS IN THE HEPATIC ENZYME SYSTEM OF THE MOUSE WERE STUDIED. ALL ANALOGS STUDIED WERE METABOLIZED BY HEPATIC GLUTATHIONE S-TRANSFERASE. [R12] ACTN: *AFTER A DOSE OF 100 MG/KG OF ACRYLAMIDE NO NEUROLOGICAL SIGNS OF NEUROPATHY HAD YET APPEARED, BUT RETROGRADE BUILDUP OF PROTEIN LABEL WAS SIGNIFICANTLY REDUCED FOR THE LONG INTERVAL. TO TEST THE SPECIFICITY OF ACRYLAMIDE ON THE RETROGRADE TRANSPORT DEFECT N-HYROXYMETHYLACRYLAMIDE WAS STUDIED. IT DID NOT INFLUENCE THE TRANSPORT. [R13] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of N-Methyloacrylamide in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 352 (1989) NIH Publication No. 89-2807 SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 591 R2: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 749 R3: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-100 R4: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1878 R5: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 459 R6: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R7: HASHIMOTO K ET AL; ARCH TOXICOL 47 (3): 179 (1981) R8: EDWARDS PM; BR J IND MED 32 (1): 31 (1975) R9: Toxicology and Carcinogenesis Studies of N-Methyloacrylamide in F344/N Rats and B6C3F1 Mice. Technical Report Series No. 352 (1989) NIH Publication No. 89-2807 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R10: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of N-Methylolacrylamide (CAS No. 924-42-5) in CD-1 Swiss Mice, NTP Study No. RACB90017 (January 1993) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 8, 2002 R11: EDWARDS PM; BIOCHEM PHARMACOL 24 (13-14): 1277 (1975) R12: TANII H, HASHIMOTO K; ARCH TOXICOL 48 (2-3): 157 (1981) R13: JAKOBSEN J, SIDENIUS P; J NEUROCHEM 40 (2): 447 (1983) RS: 16 Record 313 of 1119 in HSDB (through 2003/06) AN: 4363 UD: 200208 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,4-DIAMINOPHENOL-DIHYDROCHLORIDE- SY: *ACROL-; *AMIDOL-; *NCI-C60026-; *PHENOL,-2,4-DIAMINO-,-DIHYDROCHLORIDE- RN: 137-09-7 MF: *C6-H8-N2-O.2CL-H MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY INTERACTION OF DINITROPHENOL WITH IRON AND HYDROCHLORIC ACID. [R1] MFS: +United-Guardian, Inc, PO Box 2500, Smithtown, NY 11787, (516) 273-0900; Guardian Chemical Division; Eastern Chemical Division, Department St, PO Box 2500, Smithtown, NY 11787; Production site: Hauppauge, NY 11787 [R2] USE: *AS PHOTOGRAPHIC DEVELOPER; IN FUR AND HAIR DYEING; IN TEST FOR FORMALDEHYDE AND AMMONIA [R3] *ANALYTICAL REAGENT [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *GRAYISH-WHITE CRYSTALS [R1]; *NEEDLES [R4] MP: *205 DEG C [R3] MW: *197.08 [R5] SOL: *27.5 G/100 ML WATER @ 15 DEG C; SLIGHTLY SOL IN ALCOHOL [R3]; *SLIGHTLY SOL IN ETHER [R4] SPEC: +MAX ABSORPTION (WATER, PH 3): 235 NM (LOG E= 3.6) SHOULDER; 280 NM (LOG E= 3.3); SADTLER REF NUMBER: 6766 (IR, PRISM); 1896 (UV) [R4]; +IR: 8488 (Sadtler Research Laboratories IR Grating Collection) [R6]; +UV: 2-68 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R6] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *SEE PHENYLENEDIAMINE. PRODUCES SEVERE LOCAL REACTIONS AND SYSTEMIC EFFECTS FROM PERCUTANEOUS ABSORPTION AND FROM INGESTION. LOCAL ACTIONS INCLUDE SEVERE DERMATITIS AND URTICARIA; IN THE EYE, CHEMOSIS, LACRIMATION, EXOPHTHALMOS, OPHTHALMIA, AND EVEN PERMANENT BLINDNESS. SYSTEMIC ACTIONS INCLUDE ASTHMA, GASTRITIS (REGARDLESS OF PORTAL OF ENTRY), RISE IN BLOOD PRESSURE, TRANSUDATION INTO SEROUS CAVITIES, VERTIGO, TREMORS CONVULSIONS, AND COMA. /PHENYLENEDIAMINE/ [R7] NTOX: *2,4-DIAMINOPHENOL DIHYDROCHLORIDE HAS BEEN TESTED BY IRRIGATING A RABBIT EYE WITH 0.02 MOLAR (PH 5.3) AQUEOUS SOLUTION FOR 10 MINUTES, AFTER REMOVAL OF THE CORNEAL EPITHELIUM TO FACILITATE PENETRATION. THIS PRODUCED DARK BROWN STAINING OF THE CORNEAL STROMA, PERMANENT CORNEAL OPACIFICATION, AND VASCULARIZATION. [R8] +2,4-Diaminophenol dihydrochloride was evaluated for its mutagenic potential in the L5178Y TK+/TK- mouse lymphoma forward mutation assay using established procedures. Three experiments were conducted without metabolic activation. The dose levels tested in these experiments ranged from 0-4 ug/ml. Results from one experiment were discarded; however, significant mutagenic responses were obtained in the remaining two. Thus, 2,4-Diaminophenol dihyrochloride was positive in these tests and the lowest effective dose tested was 2 ug/ml. [R9] +... Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male or female F344/N rats that received 12.5 or 25 mg/kg. There was some evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male B6C3F1 mice based on incr incidences of renal tubule adenomas; there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in female B6C3F1 mice that received 19 or 38 mg/kg. [R10] NTP: +... Toxicology and carcinogenesis studies were conducted by administering 2,4-diaminophenol dihydrochloride (greater than 97% pure) in corn oil by gavage to F344/N rats and B6C3F1 mice for ... 2 years. ... 2 Yr Studies: The 2 yr studies were conducted by administering 2,4-diaminophenol dihydrochloride in corn oil by gavage to groups of 60 male and 60 female F344/N rats and B6C3F1 mice. ... Rats received doses of 0, 12.5, or 25 mg/kg; mice received doses of 0, 19, or 38 mg/kg. Conclusions: Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male or female F344/N rats that received 12.5 or 25 mg/kg. There was some evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in male B6C3F1 mice based on incr incidences of renal tubule adenomas; there was no evidence of carcinogenic activity of 2,4-diaminophenol dihydrochloride in female B6C3F1 mice that received 19 or 38 mg/kg. [R10] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of 2,4-Diaminophenol Dihydrochloride in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 401 (1992) NIH Publication No. 92-2856 SO: R1: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 266 R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 552 R3: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 391 R4: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-430 R5: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8212 R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 59 R7: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-141 R8: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 357 R9: McGregor DB et al; Environ Mutagen 9:143-160 (1987) R10: Toxicology and Carcinogenesis Studies of 2,4-Diaminophenol Dihydrochloride in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 401 (1992) NIH Publication No. 92-2856 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 RS: 7 Record 314 of 1119 in HSDB (through 2003/06) AN: 4379 UD: 200302 RD: Reviewed by SRP on 5/7/1998 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SULFAMETHIZOLE- SY: *2-(P-AMINOBENZENESULFONAMIDO)-5-METHYLTHIADIAZOLE; *4-AMINO-N-(5-METHYL-1,3,4-THIADIAZOL-2-YL)BENZENESULFONAMIDE; *AYERLUCIL-; *BENZENESULFONAMIDE, 4-AMINO-N-(5-METHYL-1,3,4-THIADIAZOL-2-YL)-; *FAMET-; *LUCOSIL-; *METHAZOL-; *2-METHYL-5-SULFANILAMIDO-1,3,4-THIADIAZOLE-; *5-METHYL-2-SULFANILAMIDO-1,3,4-THIADIAZOLE-; *N(1)-(5-METHYL-1,3,4-THIADIAZOL-2-YL)SULFANILAMIDE; *MICROSUL-; *RENASUL-; *RP-2145-; *RUFOL-; *SALIMOL-; *SULFA-GRAM-; *SULFAMETHIZOL-; *SULFANILAMIDE, N(1)-(5-METHYL-1,3,4-THIADIAZOL-2-YL)-; *SULFANILAMIDE, N(SUP 1)-(5-METHYL-1,3,4-THIADIAZOL-2-YL)-; *2-SULFANILAMIDO-5-METHYL-1,3,4-THIADIAZOLE-; *SULFAPYELON-; *SULFSTAT-; *SULFURINE-; *SULPHAMETHIZOLE-; *TETRACID-; *THIDICUR-; *THIOSULFIL-; *ULTRASUL-; *UROCYDAL-; *URODIATON-; *UROLUCOSIL-; *UROSULFIN-; *UROZ-; *VK-53- RN: 144-82-1 MF: *C9-H10-N4-O2-S2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by reaction of acetaldehyde thiosemicarbazone with p-acetylaminobenzenesulfonyl chloride in pyridine. [R1] FORM: *MARKETED AS A 4% AQUEOUS SOLN, PH 7.3-7.4. /SODIUM SALT/ [R2] *SULFAMETHIZOLE IS AVAILABLE IN TABLETS CONTAINING 250, 500, OR 1000 MG AND IN SUSPENSIONS OF 250 MG/5 ML OR 500 MG/5 ML. [R3, 1111] *Thiosnifil-A (Ayerst), Proklar (O'Neal, Jones and Feldman), component of Azotrex (Bristol), and component of Suladyne (Reid-Provident). [R1] MFS: *Cytec Industries, Five Garret Mountain Plaza, West Paterson, NJ 07424, (201)357-3100. Production site: Process Chemicals, Fine Chemicals, Contract Bound Brook, NJ 08805 [R4] USE: *MEDICATION *MEDICATION (VET) CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM WATER [R5]; *Colorless crystal [R1] MP: *208 DEG C [R5] MW: *270.34 [R5] DSC: *pKa= 5.45 [R5] OWPC: *log Kow= 0.54 [R6] SOL: *1 G DISSOLVES IN: 4000 ML WATER @ PH 6.5, 5 ML WATER @ PH 7.5, 40 G METHANOL, 30 G ETHANOL, 10 G ACETONE, 1370 G ETHER, 2800 G CHLOROFORM; PRACTICALLY INSOL IN BENZENE [R5]; *In water, 105 mg/l at 37 deg C. [R7] OCPP: *PH OF 20% SOLN 7.5 /SODIUM SALT/ [R2] *The electronic absorption spectra of the Cu(II), Ni(II) and Co(II) chelates of the Schiff bases synthesized from 5-bromo-salicylaldehyde and sulfamethoxypyridazine, sulfamethizole and sulfafurazole (sulfisoxazole) were studied in dimethyl sulfoxide solution. All the chelates showed an intense charge transfer absorption band at the blue end of the visible region. The stereochemical characteristics of the chelates were illustrated by means of the absorptions caused by the d-d transitions. The Ni(II) and Co(II) chelates are 6 coordinated in all cases. [R8] *The Cu(II), Co(II) and Ni(II) chelates of the Schiff bases formed from 5-bromo-salicylaldehyde and sulfamethizole, sulfamethoxypyridazine and sulfafurazole(sulfisoxazole) were synthesized and an atomic absorption spectrometric method for the determination of the metal content of the chelates is described. The stoichiometry was found to be 1:1 for all compounds. The metal content determined by the described method agreed with theoretical values. Structure analysis by infrared spectrometry and x-ray diffraction is also included. Thermostability of these Schiff bases was investigated using a thermogravimetric method. Decomposition began at 200-290DGC for the Schiff bases, while chelates began to decompose at 60-120DG. Stable oxides were formed by all chelated at 530-800DG. The orders and the activation energies of some decomposition reactions were calculated for the chelates on the basis of the thermograms. [R9] *The formation and stability of copper, cobalt and nickel chelates of the Schiff bases synthesized from the 5-bromo derivatives of salicylaldehyde, sulfamethoxypyridazine, sulfamethizole and sulfisoxazole (sulfafurazole) were studied in an absolute ethanol-acetone (70:30 v/v) solution. [R10] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits very toxic fumes of nitroxides and sulfoxides. [R11] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *Sulfamethiazole was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Sulfamethiazole was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.001, 0.003, 0.0033, 0.010, 0.033, 0.100, 0.200, and 0.333 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 0.333 mg/plate. [R12] *Previous work has demonstrated that hydrazine after formylation to its corresponding hydrazone may be activated both in vivo and in vitro to a methylating intermediate resulting in the formation of O6-methyl- and N7-methylguanines in DNA. Incubation of calf thymus DNA with the hydrazine derivative, hydralazine, and formaldehyde resulted in the production of N7-methylguanine and two aberrant bases in DNA. These bases were separated by strong cation-exchange high-performance liquid chromatographic fractionation of neutral thermal hydrolysates. Administration of hydralazine to rats resulted in the formation of N7-methylguanine in liver DNA, but the two unknown bases observed in the in vitro experiment could not be demonstrated in vivo. In contrast to hydrazine, administration of hydralazine resulted in the methylation of DNA only at doses approaching the LD50, suggesting that formylation does not represent a significant mechanism for hydralazine toxicity in the system described. Hydralazine in combination with formaldehyde resulted in the formation of triazolophthaiazine, a metabolite which has been characterized in man. The ability of 17 other hydrazine derivatives to alkylate liver DNA was determined after single administration to young adult male Sprague-Dawley rats of C57BL6 mice. Quantifiable amounts of N7-methylguanine were measured in liver DNA from animals treated with 10 of the 17 compounds. In 3 of the 10 cases quantifiable amounts of O6-methylguanine were also measured. Methylation of liver DNA guanine was obtained with hydrazine, hydralazine, procarbazine, isoniazid, phenylhydrazine, nialamide, nitrofurazone, maleic hydrazide, sulfomethoxypyridazine, and sulfomethiazole and two hydrazine-formaldehyde polymerization products, formalazine and tetraformyltrisazine. [R13] *The effect of tolbutamide (TB) on the urinary excretion of sulfamethizole (SMZ) under constant infusion of sulfamethizole at 100 mg/h was studied. Intravenous administration of tolbutamide (50 mg/kg) caused a decrease in the urinary excretion rate of sulfamethizole but an increase in the unbound concentration of sulfamethizole in plasma decreased rapidly after tolbutamide injection and then increased gradually to a level higher than the control. The slope of the terminal phase of the unbound concentration of tolbutamide in plasma in the presence of sulfamethizole was significantly smaller than that of tolbutamide alone. The analysis using the perfusion limited model showed that the elimination kinetics of sulfamethizole in the presence of tolbutamide could be described by the mutual displacement of plasma protein binding of both drugs and the competitive inhibition of the tubular secretion of sulfamethizole by the unbound concentration of tolbutamide in renal vein. Further the inhibitor constant was in good agreement with that for the in vitro uptake by renal cortex slices. [R14] *A quantitative analytical method for studying renal handling of drugs in dogs with mild renal impairment is described. Renal damage was induced experimentally by pretreatment with mercuric chloride or neomycin. Analytical results of renal handling in those animals indicated a reduction in maximum transport of secretion, while the affinity of drugs to secretion site and reabsorption showed slight or no change. These results were consistent qualitatively with other renal function test values which demonstrated the state of glomerular or proximal renal tubular function. Evidence for the applicability of the proposed analytical method for quantitative validation of functional changes in the nephron in renally impaired animals, as well as the precise determination of the site of damage, was demonstrated. This work holds considerable promise for the study of dosage adjustments in patients with renal disease. [R15] *The active transport of drugs in isolated renal tubules was investigated in New Zealand rabbits. Rabbits were killed and renal tubules were isolated. Tubule suspensions were incubated for 30 min. with various concentrations of sulfamethizole, phenolsulfonphthalein (PSP), sulfamethoxazole, sulfanilamide, and iodopyracet (IP). Samples were centrifuged and supernatants were assayed for drug concentrations. Tubule water concentrations were determined. The effects of iodopyracet on drug uptake were determined. The uptake of phenolsulfonphthalein and sulfamethizole proceeded against the concentration gradient of the drugs, with a dependency on drug concentration in the medium and uptake inhibition by iodopyracet. Tubular uptake of sulfamethoxazole was slightly inhibited by iodopyracet and no inhibition of sulfanilamide uptake by iodopyracet was detected. The concentration dependency of sulfamethoxazole almost completely disappeared in the presence of mercuric-chloride. Nephrotoxic antibiotics inhibited sulfamethizole uptake by tubules, with the most potent being neomycin. The authors conclude that the isolated renal tubule preparation is a simple method for detecting nephrotoxicity of drugs. [R16] *Previous work has demonstrated that hydrazine after formylation to its corresponding hydrazone may be activated both in vivo and in vitro to a methylating intermediate resulting in the formation of O6-methyl- and N7-methylguanines in DNA. Incubation of calf thymus DNA with the hydrazine derivative, hydralazine, and formaldehyde resulted in the production of N7-methylguanine and two aberrant bases in DNA. These bases were separated by strong cation-exchange high-performance liquid chromatographic fractionation of neutral thermalhydrolysates. Administration of hydralazine to rats resulted in the formation of N7-methylguanine in liver DNA, but the two unknown bases observed in the in vitro experiment could not be demonstrated in vivo. in contrast to hydrazine, administration of hydralazine resulted in the methylation of DNA only at doses approaching the LD50, suggesting that formylation does not represent a significant mechanism for hydralazine toxicity in the system described. Hydralazine in combination with formaldehyde resulted in the formation of triazolophthalazine, a metabolite which has been characterized in man. The ability of 17 other hydrazine derivatives to alkylate liver DNA was determined after single administration to young adult male Sprague-Dawley rats or C57BL6 mice. Quantifiable amounts of N7-methylguanine were measured in liver DNA from animals treated with 10 of the 17 compounds. In 3 of the 10 cases quantifiable amounts of O6-methylguanine were also measured. Methylation of liver DNA guanine was obtained with hydrazine, hydralazine, procarbazine, isoniazid, phenylhydrazine, nialamide, nitrofurazone, maleic hydrazide, sulfomethoxypridazine, and sulfamethiazole and two hydrazine-formaldehyde polymerization products, formalazine and tetraformyltrisazine. [R17] NTXV: *LD50 Rat oral 3500 mg/kg; [R11] ADE: *APPROXIMATELY 90% OF SULFAMETHIZOLE IS EXCRETED BY KIDNEYS IN ACTIVE FORM... [R18] *SULFAMETHIZOLE...IS A RAPIDLY ELIMINATED SULFONAMIDE; CONCENTRATIONS OF DRUG IN BLOOD ARE THUS LOW AFTER ADMIN OF CONVENTIONAL DOSES. [R3, 1111] *...FOR SHORT-ACTING SULFONAMIDES...SULFAMETHIZOLE, CLEARANCE RATIOS OF N4-ACETATES WERE LESS THAN FOR PARENT COMPOUNDS. BOTH UNCHANGED DRUGS AND N4-ACETATES WERE ACTIVELY SECRETED BY PROXIMAL TUBULES, AND IT IS SUGGESTED THAT ELIMINATION BY TUBULAR SECRETION...MAY EXPLAIN RAPID EXCRETION OF THESE HIGHLY PROTEIN-BOUND DRUGS. [R19] *SERUM LEVELS OF...SULFAMETHIZOLE...WERE CONSIDERABLY REDUCED FOLLOWING ORAL DOSES TO RESTING SUBJECTS COMPARED WITH THOSE UNDERGOING INTENSIVE EXERCISE, AND THIS RESULT APPEARED TO BE CONSISTENT WITH DELAYED ABSORPTION DURING REST AND SUPPRESSED RENAL EXCRETION DURING EXERCISE. [R20] *RENAL CLEARANCE VALUES OF METABOLITE N4-ACETYLSULFONAMIDES ARE 6-20 TIMES HIGHER THAN THEIR PARENT COMPD. RENAL CLEARANCE IS DEPENDENT ON URINE FLOW. SULFAMETHIZOLE IS ACETYLATED VERY LITTLE. [R21] *RENAL CLEARANCE RATIO OF SULFAMETHIZOLE IN DOGS WAS HIGHER THAN ITS CORRESPONDING ACETATE. AFFINITY OF SULFAMETHIZOLE N4-GLUCURONIDE TO THE PLASMA PROTEINS WAS LOWER THAN THAT OF SULFAMETHIZOLE, THE CLEARANCE RATIO OF THE GLUCURONIDE WAS LOWER. [R22] *IN RABBITS EXCRETION RATIO OF SULFAMETHIZOLE 0.4 MG/KG IV WAS LITTLE OR NOT AFFECTED BY MODIFICATION OF THE URINARY PH, IT EXHIBITED AN EXCRETION PATTERN WHICH WAS DEPENDENT ON ITS PLASMA LEVEL. [R23] *IV INFUSED IN RABBITS SULFAMETHIZOLE'S CLEARANCE, CORRECTED FOR PROTEIN BINDING, SHOWED NET SECRETION IN TUBULES. [R24] *Approximately 43-72% of a single oral dose of sulfamethizole may be recovered in the urine intact and as metabolites within 4 hours; approximately 84-97% of the dose is excreted within 10 hours. [R25] *SULFONAMIDES ARE ELIMINATED FROM BODY PARTLY AS SUCH AND PARTLY AS METABOLIC PRODUCTS. LARGEST FRACTION IS EXCRETED IN URINE, AND HALF LIFE ... IS THUS DEPENDENT ON RENAL FUNCTION. SMALL AMT ARE ELIMINATED IN FECES AND IN BILE, MILK, AND OTHER SECRETIONS. /SULFONAMIDES/ [R26, 1059] *ALL SULFONAMIDES ARE BOUND IN VARYING DEGREE TO PLASMA PROTEINS, PARTICULARLY TO ALBUMIN. EXTENT ... IS DETERMINED BY HYDROPHOBICITY ... AND ITS PKA ... IN GENERAL, SULFONAMIDE IS BOUND TO SOMEWHAT GREATER EXTENT IN ACETYLATED THAN IN FREE FORM. /SULFONAMIDES/ [R26, 1059] *SULFONAMIDES ARE DISTRIBUTED THROUGHOUT ALL TISSUES OF BODY. ... READILY ENTER PLEURAL, PERITONEAL, SYNOVIAL, OCULAR, AND SIMILAR BODY FLUIDS, AND MAY REACH CONCN THAT ARE 50-80% OF SIMULTANEOUSLY DETERMINED BLOOD CONCN. ... ATTAIN CEREBROSPINAL FLUID CONCN THAT ARE EFFECTIVE IN MENINGEAL INFECTIONS. /SULFONAMIDES/ [R26, 1059] *SULFONAMIDES READILY PASS THROUGH PLACENTA AND REACH FETAL CIRCULATION. EQUILIBRIUM BETWEEN MATERNAL AND FETAL BLOOD IS USUALLY ESTABLISHED WITHIN 3 HR AFTER SINGLE ORAL DOSE. CONCN ATTAINED IN FETAL TISSUES ARE SUFFICIENT TO CAUSE BOTH ANTIBACTERIAL AND TOXIC EFFECTS. /SULFONAMIDES/ [R26, 1059] *... THIS CLASS OF DRUGS IS RAPIDLY AND ADEQUATELY ABSORBED FROM GI TRACT. INDEED, AGENT CAN OFTEN BE FOUND IN URINE WITHIN 30 MIN AFTER ITS ORAL INGESTION. SMALL INTESTINE IS MAJOR SITE OF ABSORPTION, BUT SOME OF DRUG IS ABSORBED FROM STOMACH. /SULFONAMIDES/ [R26, 1059] *Sulfamethizole-loaded Eudragit RL-100 microspheres were prepared by the emulsification-solvent evaporation technique with a view to characterize the factors influencing in vitro drug release. The cross flow of solvent and solute inside the microspheres did not influence drug release, which was dependent on the pH of the dissolution media. Significant drug-polymer adsorption-type interaction occurred in dissolution media having pH 7.4 leading to retarded drug release. Increase in ionic strength decreased the adsorption of the drug onto the polymer and consequently increased the drug release in pH 7.4. [R27] *The preparation and evaluation of sustained-release lipid granules of sulfamethizole, using hydrogenated castor oil (Cutina HR) and polyethylene glycol 4000 (PEG 4000) in various formulations, are described. Data from particle size analysis and dissolution data shows that the drug release rates increase with increasing amounts of PEG 4000 added to the formulation up to a certain percentage. No increase beyond this point was noticed. The drug release rates were mostly zero order and modified Hixon-Crowell kinetics. [R28] *The release of sulfamethizole (I) from an oral sustained-action tablet coated with poly(methylmethacrylate) was determined in 8 volunteers, 7 male, one female, aged 26 to 50. Based on urinary excretion rates, the in vivo data support the in vitro dissolution data. An overall excretion rate of 32.6 mg/hr was obtained. The blood levels of intact drug were determined and found to be satisfactory, although it was concluded that a faster releasing dosage form would be more appropriate. [R29] *The preparation of freeze dried solid dispersion formulations of dicumarol (I) or sulfamethizole (II) in defatted milk is presented, and bioequivalency of reconstituted preparations was investigated compared to capsules containing pure drug in 4 healthy subjects. Plasma dicumarol levels showed the freeze dried formulation to be superior to capsules of pure drug. Solubility of dicumarol increased in the presence of casein. Urinary sulfamethizole data failed to show a difference between dosage forms in rates or extent of excretion. No solubility differences were noted for sulfamethizole in the presence of casein. [R30] *The production of an inert matrix type sustained release tablet of sulfamethizole using poly(methylmethacrylate) as the sustaining polymer in 13 different formulations is described. Release and dissolution profiles were determined and the experimental results were fitted to several different kinetic equations using a computer program. [R31] *The preparation of matrix sustained release sulfamethizole granules employing poly(methyl methacylate) and cellulose acetate phthalate and the effects of various adjuvants on the release profile are described. This type of sustained release was suitable for high values of release rate in contrast to inert matrix type tablets. [R32] *Propantheline bromide, salicylamide and sulfamethizole tablets were used as models to evaluate automated flow injection analysis as a method for studying dissolution. In each case, the automated system, with the appropriate chemistry manifold coupled to the rotating basket apparatus, achieved adequate monitoring and a dissolution profile was provided by computer. [R33] *A renal clearance method based on a computer analysis after administration of a single dose of drug was examined for its applicability in dogs and humans, utilizing sulfamethizole, sulfanilamide, cephalexin and ampicillin as test drugs. Secretion and reabsorption of the drugs in the nephron was analyzed and the utility of the method was demonstrated. Kinetic evaluations of the drugs in rabbits, dogs and humans were compared, and it was suggested that canine renal handling may provide useful information when considering appropriate therapeutic doses in humans. [R34] *The use of ethylcellulose microcapsules possessing a reservoir system to achieve the sustained release of sulfamethizole (I) or fluorouracil (II) was examined in vitro. A comparison of the release patterns of sulfamethizole and fluorouracil from the matrices and the microcapsules with the dissolution patterns of the drug powders is presented. [R35] *Four healthy volunteers received sulfamethizole (I), 250 mg, tablets or enteric coated microcapsules, and urine was collected at appropriate intervals up to 12 hr for sulfamethizole assay. Release rates of the sulfamethizole from the microcapsules in vitro were much slower than dissolution rates of sulfamethizole from tablets. The urinary excretion of sulfamethizole following oral administration of the microcapsules in humans was sustained over that of the tablets. Pharmacokinetic analyses indicated sustained absorption following the administration of the microcapsules. The extent of bioavailability was only slightly decreased following administration of the microcapsules. [R36] *A comparative study between in vivo drug dissolution calculated by deconvolution, and absorption rates calculated by the multicompartment model method, was made in rabbits, using sulfadimethoxine, sulfadiazine, sulfisoxazole, sulfathiazole (I) and sulfamethizole (II) whose solubilities ranged from 0.001 to 0.1%. The semilogarithmic plots of undissolved vs time for the in vivo dissolution process, and of unabsorbed vs time for the absorption process were biphasic with convex descending times course curves for the large particle sizes of low solubility drugs. For the high solubility drugs, sulfathiazole and sulfamethizole, the undissolved time course was a single line and the unabsorbed time course was biphasic with a concave descending curve. The rate constants of in vivo dissolution correlated well with those of absorption at a constant ratio for each drug during the initial linear portions (2-5 hr); thereafter, this correlation disappeared. For 2 of the low solubility drugs, there was a good particle size dependent correlation between in vitro and in vivo dissolution rates; this ceased with increasing solubility. [R37] *The release of drug from agar beads was studied, using sulfamethizole as the test drug. Preparation of the drug impregnated beads is included. In vitro results showed that the release rate of drug from dry beads was slightly smaller than that from undried beads and much smaller than the dissolution rate of the drug from pure drug powder. Sustained but complete release of drug was observed. Effects of pH on release profiles are also discussed. [R38] METB: *SULFONAMIDES UNDERGO METABOLIC ALTERATIONS TO VARYING EXTENT IN TISSUES, ESP IN LIVER. BOTH ACETYLATION AND OXIDATION OCCUR. ... IN NEARLY ALL SPECIES, MAJOR METABOLIC DERIVATIVE IS N4-ACETYLATED SULFONAMIDE. /SULFONAMIDES/ [R26, 1059] ACTN: *SULFONAMIDES ARE STRUCTURAL ANALOGS AND COMPETITIVE ANTAGONISTS OF PARA-AMINOBENZOIC ACID (PABA), AND THUS PREVENT NORMAL BACTERIAL UTILIZATION OF PABA FOR THE SYNTHESIS OF FOLIC ACID (PTEROYLGLUTAMIC ACID, PGA). /SULFONAMIDES/ [R26, 1058] *...SULFONAMIDES ARE COMPETITIVE INHIBITORS OF BACTERIAL ENZYME RESPONSIBLE FOR THE CORPORATION OF PABA /PARA-AMINOBENZOIC ACID/ INTO DIHYDROPTEROIC ACID, THE IMMEDIATE PRECURSOR OF FOLIC ACID. SENSITIVE MICROORGANISMS ARE THOSE THAT MUST SYNTHESIZE THEIR OWN PGA /PTEROYLGLUTAMIC ACID/. /SULFONAMIDES/ [R26, 1058] INTC: *SULFAMETHIZOLE WAS REMOVED MORE SLOWLY FROM BLOOD PLASMA AFTER SIMULTANEOUS ADMIN. [R39] *SULFAMETHIZOLE INCR T/2 AND DECR MEAN METABOLIC CLEARANCE, IT WAS SUGGESTED THAT IT INHIBITS HEPATIC METABOLISM OF DIPHENYLHYDANTON, TOLBUTAMIDE, AND WARFARIN. [R40] *These medications /coumarin- or indandione-derivative anticoagulants; hydantoin anticonvulsants or oral antidiabetic agents/ may be displaced from protein binding sites and/or their metabolism may be inhibited by some sulfonamides, resulting in increased or prolonged effects and/or toxicity; dosage adjustments may be necessary during and after sulfonamide therapy. /Sulfonamides/ [R41, 2695] *Concurrent use of bone marrow depressants with sulfonamides may increase the leukopenic and/or thrombocytopenic effects; if concurrent use is required, close observation for myelotoxic effects should be considered. /Sulfonamides/ [R41, 2695] *Concurrent long-term use of sulfonamides /with estrogen-containing, oral contraceptives/ may result in increased incidence of breakthrough bleeding and pregnancy. /Sulfonamides/ [R41, 2695] *Concurrent use /of cyclosporine/ with sulfonamides may increase the metabolism of cyclosporine, resulting in decreased plasma concentration and potential transplant rejection, and additive nephrotoxicity; plasma cyclosporine concentrations and renal function should be monitored. /Sulfonamides/ [R41, 2695] *Concurrent use /of hemolytics/ with sulfonamides may increase the potential for toxic side effects. /Sulfonamides/ [R41, 2695] *Concurrent use /of hepatotoxic medications/ with sulfonamides may result in an increased incidence of hepatotoxicity; patients, especially those on prolonged administration or those with a history of liver disease, should be carefully monitored. /Sulfonamides/ [R41, 2695] *In acid urine, methenamine breaks down into formaldehyde, which may form an insoluble precipitate with certain sulfonamides, especially those that are less soluble in urine, and may also increase the danger of crystalluria; concurrent use is not recommended. /Sulfonamides/ [R41, 2695] *The effects of methotrexate may be potentiated during concurrent use with sulfonamides because of displacement from plasma protein binding sites; phenylbutazone and sulfinpyrazone may displace sulfonamides from plasma protein binding sites, increasing sulfonamide concentrations. /Sulfonamides/ [R41, 2695] *Since bacteriostatic drugs may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations where a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy. /Sulfonamides/ [R41, 2695] *The extended Hildebrand approach for predicting the solubility of sulfamethizole in a solvent mixture consisting of 1,4-dioxane (dioxane) and water and a quantitative equation for predicting solubilities of this drug are described. The solubility of this drug was determined at 25DGC. [R42] *To predict quantitatively drug interaction kinetics from the single-drug clearance studies, we examined the effect of iodopyracet (IOD) on sulfamethizole (SMZ) excretion in rabbits. Even though the decline of systemic iodopyracet plasma concentration was linear, the renal clearance of sulfamethizole decreased significantly in the presence of iodopyracet. The results could be described by a perfusion model incorporated with the competitive inhibition for tubular secretion. For iodopyracet with a high extraction ratio, it was suggested that a heavy load of the drug was supplied to the sites of secretion and caused the saturation of transport systems, even though the renal excretion kinetics were apparently linear in respect to the systemic circulation. These facts indicated that a linear relationship between the concentrations in the systemic circulation and at the sites of tubular secretion can not always be presumed. Consequently, sulfamethizole-iodopyracet interaction study stressed the importance of the drug concentrations at the sites of interaction for quantitative elucidation of drug-drug interactions. [R43] *Formation of triazene derivatives from sodium nitrite and sulfanilamide, sulfamethizole or sulfamethoxazole in acidic solution containing saliva or canned vegetable juice was studied using reverse-phase high-performance liquid chromatography with ultraviolet light detection at 365 nm. At the optimal pH of 3.2-3.7, the mean yield of the triazene formed by reaction of sulfanilamide and nitrite in saliva was 28.8%, calculated on the nitrite content, and there was a high positive correlation (r = 0.993) between the nitrite concentration in the saliva and the triazene yield. In contrast, at the optimal pH values for triazene formation from sulfamethizole and sulfamethoxazole (3.0-3.5 and 2.5-2.9 respectively), triazene yields were much lower, accounting for only 0.9 and 1.0%, respectively, of the nitrite present. Triazene formation was partly inhibited int he presence of vegetable juice. [R44] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents /SRP: Antibacterial/ [R45] *MEDICATION (VET): ANTIBACTERIAL [R5] *Sulfonamides are indicated in the treatment of chancroid caused by Hemophilus ducreyi. However, other agents such as erythromycin and ceftriaxone, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in the treatment of endocervical and urethral infections caused by Chlamydia trachomatis. However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in the treatment of neonatal inclusion conjunctivitis caused by chlamydia trachomatis. However, other agents, such as erythromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated as adjunctive therapy in the treatment of chloroquine-resistant Plasmodium falciparum. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in the prophylaxis of meningitis caused by susceptible strains of Neisseria meningitidis. However, other agents, such as rifampin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in the treatment of nocardiosis caused by Nocardia asteroides. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in combination with other antibacterials in the treatment of otitis media caused by susceptible strains of H. influenza, streptococci, and pneumococci. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfisoxazole is indicated in the prophylaxis of rheumatic fever associated with group A beta-hemolytic streptococcal infections. However, other agents, such as penicillin, are considered to be first line agents. /NOT included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in combination with pyrimethamine in the treatment of toxoplasmosis caused by Toxoplasma gondii. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in the treatment of ocular trachoma caused by Chlamydia trachomatis. However, other agents, such as doxycycline and azithromycin, are considered to be first line agents. /Sulfonamides; Included in US product labeling/ [R41, 2693] *Sulfonamides are indicated in the treatment of acute, uncomplicated urinary tract infections caused by susceptible bacteria. Because sulfamethizole produces low plasma levels and is rapidly eliminated, it is recommended only for use in urinary tract infections, not systemic infections. Sulfadiazine is not recommended for the treatment of urinary tract infections because of its relatively lower urine solubility and the increased chance of crystalluria; other, more soluble agents, such as sulfisoxazole, are generally preferred. /Included in US product labeling/ [R41, 2693] *Sulfonamides are used in the treatment of lymphogranuloma venereum caused by Chlamydia species. However, other agents, such as doxycycline and erythromycin, are considered to be first line agents. /Sulfonamides; NOT included in US product labeling/ [R41, 2693] *Background: Patients receiving interferon-alpha often experience symptoms such as upper abdominal discomfort, anorexia, and nausea, which suggest a delay in gastric emptying. Reduction of the dosages of interferon-alpha or even interruption of the treatment is sometimes required because of these symptoms. The present study was designed to investigate the effect of interferon-alpha on gastric emptying and to evaluate the effects of cisapride on gastric emptying and to evaluate the effects of cisapride on gastric emptying and upper abdominal symptoms during interferon-alpha therapy. Methods: Gastric emptying in 14 patients with chronic hepatitis C was estimated by the sulfamethizole capsule method before and 1 and 2 weeks after the beginning of interferon-alpha (6 million U/day) therapy. Results: Before therapy none of the patients complained of upper abdominal symptoms, and all had normal gastric emptying. Interferon treatment delayed gastric emptying in 12 of the patients and induced discomfort and anorexia in 9 of the patients. The administration of cisapride reversed the delayed gastric emptying in six of seven patients and relieved abdominal discomfort and anorexia. Conclusions: These findings indicate that interferon-alpha delays gastric emptying and suggest that cisapride administration corrects the delayed gastric emptying and relieves the abdominal symptoms associated with interferon-alpha therapy. [R46] *Two dogs with systemic nocardiosis are presented and the pathobiology, diagnosis, and treatment of nocardial infections are discussed. Both dogs had nonspecific respiratory signs and depression. The diagnosis was made by isolation of the organism only after surgical drainage was established and appropriate tissues were cultured. The response to surgical drainage and antimicrobial therapy was dramatic in both dogs, but one dog experienced a drug reaction to trimethoprim-potentiated sulfonamide. Although systemic nocardial infections traditionally have had a grave prognosis, through early diagnosis, surgical intervention, and the use of newer, safe and synergistically acting antimicrobials, the prognosis has improved. This article reviews current human and veterinary literature regarding the microbiology, pathogenesis, and treatment of nocardiosis and reports on the successful treatment of systemic nocardiosis in two dogs. [R47] *Fifty-six patients receiving remission induction treatment for acute leukemia were studied in a randomized trial comparing ciprofloxacin with trimethoprim-sulfamethoxazole plus colistin for prevention of infections. Both groups received amphotericin B for antifungal prophylaxis. Six major infections occurred in 28 patients receiving ciprofloxacin, and 11 major infections occurred in 28 patients receiving trimethoprim-sulfamethoxazole plus colistin. No infections caused by gram-negative bacilli were seen in the ciprofloxacin group (p less than 0.02). Ciprofloxacin prevented colonization with resistant gram-negative bacilli, but 12 resistant colonizing strains were isolated from 10 patients receiving trimethoprim-sulfamethoxazole plus colistin (p less than 0.010. Ciprofloxacin was better tolerated: 23 of 28 patients were highly compliant to the drug, compared with 15 of 28 patients in the trimethoprim-sulfamethoxazole group (p less than 0.05). These results suggest that ciprofloxacin is a promising drug for the prevention of infection in patients with granulocytopenia. [R48] *The efficacy of a combination of 80 mg nitroxoline, 40 mg pyridoxine hydrochloride, and 80 mg sulfamethizole (Nicene) was evaluated in 12 patients with symptomatic lower urinary tract infection in a 14 day study. A cur rate (sterile urine) of 92% was found after 7 days of therapy. The bacterial count of one patient was initially reduced by 50% after 7 days, but returned to the pretreatment value after 14 days of therapy. [R49] *The efficacy of Nicene (nitroxoline, combination, sulfamethizole; I) in the treatment of uncomplicated urinary tract infections (UTI) was studied in 23 patients with symptoms of acute urinary tract infections treated with oral Nicene table at a dose of 2 tablets in the morning, one at midday and 2 in the evening for 14 days. In 21 patients there was an excellent response to Nicene therapy. Two patients with group B streptococci infections in the urine did not respond to medication. It was concluded that Nicene is effective in eliminating organisms frequently encountered in urinary tract infections. [R50] *A quantitative analytical method for studying renal handling of drugs in dogs with mild renal impairment is described. Renal damage was induced experimentally by pretreatment with mercuric chloride or neomycin. Analytical results of renal handling in those animals indicated a reduction in maximum transport of secretion, while the affinity of drugs to secretion site and reabsorption showed slight or no change. These results were consistent qualitatively with other renal function test values which demonstrated the state of glomerular or proximal renal tubular function. Evidence for the applicability of the proposed analytical method for quantitative validation of functional changes in the nephron in renally impaired animals, as well as the precise determination of the site of damage, was demonstrated. This work holds considerable promise for the study of dosage adjustments in patients with renal disease. [R15] *The bacterial sensitivity of 9 antibacterial agents was assessed in a 26 month study in spinal cord injury patients; the agents studied were: Nicene (nitroxoline, combination, sulfamethizole), gentamicin (I), kanamycin, carbenicillin, ampicillin, a cephalosporin, co-trimoxazole (trimethoprim, combination, sulfamethoxazole), nalidix acid, and nitrofurantoin. Overall, klebsiella was cultured most frequently, followed by proteus and coliforms. Although the number of organisms observed in each species fluctuated over the study period, there was no evidence of any species developing resistance. Nicene and I were 80.5% and 80.6%, respectively, effective against the cultured bacteria. These 2 products were both significantly more effective against the cultured bacteria than any other drug tested. [R51] *A multicenter study was undertaken in 1,284 patients with bacteriuria in a randomized double-blind fashion in order to compare sulfamethizole (I) with trimethoprim (II) and the combination sulfadiazine-trimethoprim (co-trimazine; III) in the treatment of acute urinary tract infection in general practice. The patients were treated with one g of sulfamethizole twice daily, 400 mg of trimethoprim twice daily, or co-trimazine (sulfadiazine 810 mg plus trimethoprim 120 mg) twice daily. Patients received instructions about dosage and follow-up examination as well as a dip-slide. There were 965 patients with bacteriuria who completed the 2 week follow-up. Results showed that 68.5% of those treated with sulfamethizole, 78.9% of those treated with trimethoprim and 83.6% of those treated with co-trimazine had sterile urine at the time of the 2 week follow-up. Skin reactions were most common with trimethoprim (4.1%) and co-trimazine (3.2%). Skin reactions with sulfamethizole were recorded in only 1.4% of the patients. Gastrointestinal side-effects and other side-effects occurred with nearly equal frequency in the 3 treatment groups. Although not statistically significant, the results show a consistent trend towards superiority of co-trimazine over trimethoprim alone and a superiority of trimethoprim over sulfamethizole. It was concluded that the rapidly excreted sulfonamides are the preparations of choice since over 70% of the patients with urinary tract infections had sterile urine after treatment. [R52] WARN: *SULFONAMIDES SHOULD NOT BE GIVEN TO PREGNANT WOMEN NEAR TERM... /SULFONAMIDES/ [R26, 1062] *AN UNTOWARD REACTION INCR LIKELIHOOD OF SEVERE RESPONSE TO SUBSEQUENT ADMIN OF A MEMBER OF THIS CLASS OF DRUGS. /SULFONAMIDES/ [R3, 1113] *...ADEQUATE FLUID INTAKE SHOULD BE MAINTAINED. [R18] *POTENTIAL ADVERSE EFFECTS ON FETUS: May cause jaundice and kernicterus in fetus. POTENTIAL SIDE EFFECTS ON BREAST-FED INFANT: Excreted in low concentrations. Cited by U.S. Pharmacopeia Dispensing Information to be contraindicated in first 2 months of life because of risk of kernicterus, but American Academy of Pediatrics considers safe for breast-feeding. Sulfonamides may cause hemolytic anemia in G6PD /glucose 6-phosphate dehydrogenase/ deficient infants. COMMENTS: Trimethoprimsulfamethoxazole may interfere with folic acid metabolism. FDA Category: C (C = Studies in laboratory animals have revealed adverse effects on the fetus (teratogenic, embryocidal, etc.) but there are no controlled studies in pregnant women. The benefits from use of the drug in pregnant women may be acceptable despite its potential risks, or there are no laboratory animal studies or adequate studies in pregnant women.) /Sulfonamides/ /from table II/ [R53] *Sulfonamides should not be used in the treatment of Group A beta-hemolytic streptococcal tonsillopharyngitis since they may not eradicate streptococci and therefore may not prevent sequelae such as rheumatic fever. /Sulfonamides/ [R41, 2693] *Sulfonamides are also not effective in treating rickettsial, viral, tuberculous, actinomycotic, fungal, or mycoplasmal infections. they are also not effective in the treatment of shigellosis. /Sulfonamides/ [R41, 2693] *Except as concurrent adjunctive therapy with pyrimethamine in the treatment of congenital toxoplasmosis, use of sulfonamides is contraindicated in infants up to 2 months of age. Sulfonamides compete for bilirubin binding sites on plasma albumin, increasing the risk of kernicterus in the newborn. Also, because the acetyltransferase system is not fully developed in the newborn, increased blood concentrations of the free sulfonamide can further increase the risk of kernicterus. /Sulfonamides/ [R41, 2694] *Elderly patients may be at increased risk of severe side/adverse effects. Severe skin reactions, generalized bone marrow depression, and decreased platelet count (with or without purpura) are the most frequently reported severe side/adverse effects in the elderly. An increased incidence of thrombocytopenia with purpura has been reported in elderly patients who are receiving diuretics, primarily thiazides, concurrently with sulfamethoxazole. The potential for these problems should also be considered for elderly patients taking other sulfonamide medications. /Sulfonamides/ [R41, 2694] *The leukopenic and thrombocytopenic effects of sulfonamides may result in an increased incidence of certain microbial infections, delayed healing, and gingival bleeding. If leukopenia or thrombocytopenia occurs, dental work should be deferred until blood counts have returned to normal. Patients should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks. /Sulfonamides/ [R41, 2694] *Patients with acquired immunodeficiency syndrome (AIDS) may have a greater incidence of side/adverse effects, especially rash, fever, and leukopenia, than do non-AIDS patients. /Sulfonamides/ [R41, 2695] *Effects...acute and reversible myopia; most common ocular side effect, conjunctivitis, optic neuritis, photosensitivity [R54] *EFFECT UPON EYE MOST COMMONLY PRODUCED BY SYSTEMICALLY ADMIN SULFONAMIDE DRUGS HAS BEEN ACUTE AND COMPLETELY REVERSIBLE MYOPIA. /SULFONAMIDES/ [R55] *DRUG ERUPTIONS OCCUR MOST OFTEN AFTER FIRST WK OF THERAPY ... FEVER, MALAISE, AND PRURITUS ARE FREQUENTLY PRESENT SIMULTANEOUSLY. ... SYNDROME SIMILAR TO SERUM SICKNESS ... FEVER, JOINT PAIN, URTICARIAL ERUPTIONS, CONJUNCTIVITIS, BRONCHOSPASM, AND LEUKOPENIA ARE OUTSTANDING FEATURES. ... DRUG FEVER ... /SULFONAMIDES/ [R26, 1062] *Fatalities have occurred, although rarely, due to severe reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Therapy should be discontinued at the first appearance of skin rash or any serious side/adverse effects. /Sulfonamides/ [R41, 2695] *The sulfonamides readily cross the placenta to the fetus during all stages of gestation. Equilibrium with maternal blood is usually established 2-3 hr., with fetal levels averaging 70-90% of maternal. Significant levels may persist in the newborn for several days after birth when given near term. The primary danger of sulfonamide administration during pregnancy is manifested when these agents are given close to delivery. Toxicities that may be observed in the newborn include jaundice, hemolytic anemia and, theoretically, kernicterus. /Sulfonamides/ [R56, 795] *PRIMARY FACTOR RESPONSIBLE FOR RENAL DAMAGE...PRODUCED BY OLDER SULFONAMIDES IS FORMATION AND DEPOSITION OF CRYSTALLINE AGGREGATES IN KIDNEYS... URETERS, OR BLADDER... ANURIA AND DEATH MAY OCCUR IN PT IN WHOM NO...CRYSTALLURIA OR HEMATURIA CAN BE DETECTED AND IN WHOM LESION FOUND...IS TUBULAR NECROSIS... /SULFONAMIDES/ [R3, 1113] *FOCAL OR DIFFUSE NECROSIS OF LIVER DUE TO DIRECT DRUG TOXICITY OR SENSITIZATION OCCURS IN LESS THAN 0.1% OF PT. HEADACHE, NAUSEA, VOMITING, FEVER, HEPATOMEGALY, JAUNDICE...USUALLY APPEAR 3 TO 5 DAYS AFTER SULFONAMIDE ADMIN IS STARTED AND SYNDROME MAY PROGRESS TO ACUTE YELLOW ATROPHY AND DEATH. /SULFONAMIDES/ [R26, 1062] *AGRANULOCYTOSIS...CAN FOLLOW USE OF...SULFONAMIDES. ... COMPLETE SUPPRESSION OF BONE-MARROW ACTIVITY WITH PROFOUND ANEMIA, GRANULOCYTOPENIA AND THROMBOCYTOPENIA IS EXTREMELY RARE OCCURRENCE WITH SULFONAMIDE THERAPY. /SULFONAMIDES/ [R26, 1062] *DEVELOPMENT OF ACUTE HEMOLYTIC ANEMIA IN ABSENCE OF DEFICIENCY OF GLUCOSE-6-PHOSPHATE DEHYDROGENASE MAY NOT BE DEPENDENT ON DOSAGE OR CONCN OF DRUG IN PLASMA. NAUSEA, FEVER, VERTIGO, JAUNDICE, PALLOR, HEPATOSPLENOMEGALY, AND SHOCK MAY DEVELOP SUDDENLY. ... ACUTE RENAL TUBULAR NECROSIS MAY FOLLOW HEMOGLOBINURIA. /SULFONAMIDES/ [R3, 1113] *HYPERSENSITIVITY REACTIONS. AMONG SKIN AND MUCOUS MEMBRANE MANIFESTATIONS...ARE MORBILLIFORM, SCARLATINAL, URTICARIAL, ERYSIPELOID, PEMPHIGOID, PURPURIC, AND PETECHIAL RASHES; AND ERYTHEMA NODOSUM, ERYTHEMA MULTIFORME OF STEVENS-JOHNSON TYPE... /SULFONAMIDES/ [R26, 1062] *AMONG OTHER UNTOWARD EFFECTS...ARE GOITER AND HYPOTHYROIDISM, ARTHRITIS, AND VARIOUS NEUROPSYCHIATRIC DISTURBANCES. ... PERIPHERAL NEURITIS IS VERY RARE. ANOREXIA, NAUSEA, AND VOMITING OCCUR IN 1-2% OF PERSONS RECEIVING SULFONAMIDES... /SULFONAMIDES/ [R3, 1114] *...sulfonamide excretion into breast milk apparently does not pose a significant risk for the healthy, full-term neonate. Exposure to sulfonamides via breast milk should be avoided in ill, stressed, or premature infants and in infants with hyperbilirubinemia or glucose-6-phosphate dehydrogenase deficiency./Sulfonamides/ [R56, 797] *AMONG THE SKIN AND MUCOUS MEMBRANE MANIFESTATIONS ATTRIBUTED TO SENSITIZATION TO SULFONAMIDE ARE...BEHCET'S SYNDROME, EXFOLIATIVE DERMATITIS, AND PHOTOSENSITIVITY. ...SERUM SICKNESS MAY APPEAR ... FEVER, JOINT PAIN, URTICARIAL ERUPTIONS, CONJUNCTIVITIS, BRONCHOSPASM, AND LEUKOPENIA ARE OUTSTANDING FEATURES. /SULFONAMIDES/ [R26, 1062] *DRUG FEVER IS A COMMON MANIFESTATION OF SULFONAMIDE TREATMENT. ...GENERALLY SUDDEN IN ONSET... HEADACHE, CHILLS, MALAISE, PRURITUS, AND SKIN RASH MAY ACCOMPANY THE FEVER. ...CROSS-SENSITIVITY BETWEEN DIFFERENT SULFONAMIDES DOES OCCUR... /SULFONAMIDES/ [R26, 1062] *Eleven hundred cases of drug induced liver disease have been reported in Denmark from 1978 to 1987, including 52 fatal cases. Approximately 100 new cases have been reported every year since 1987. The definition and classification of drug induced liver disease are presented together with a review of the most common patho-anatomical pictures and pathogenic mechanisms, followed by a description of symptoms and paraclinical abnormalities for each of the ten most common drugs causing serious liver disease. Individual cases of liver disease caused by paracetamol, sulfamethizole and androgenic steroid hormones are presented. Guidelines to minimize the risk of liver disease when using halothane, disulfiram or methotrexate are mentioned. Finally there are some proposals for diminishing the number of and the severity of drug induced liver disease. [R57] *Computed tomography (CT) of the brain was performed in a random sample of a total of 195 men and 211 male alcoholic patients admitted for the first time during a period of two years from the same geographically limited area of Greater Stockholm as the sample. The same medical, social and neuroradiological methods were used for examination of the alcoholic inpatients as for the random controls. Laboratory tests were performed, including liver and pancreatic tests. Toxicological screening was performed and the consumption of hepatotoxic drugs was also investigated and the following were the types of drugs used: antiarrhythmics, antiepileptics, antiphlogistics, mixed analgesics, barbiturates, sulfonamides, benzodiazepines, clomethiazole and phenolthiazine derivatives, all of which are metabolized by the liver. The group of male alcoholic inpatients and the random sample were then subdivided with respect to alcohol consumption and use of hepatotoxic drugs: Group IA, men from the random sample with low or moderate alcohol consumption and no use of hepatotoxic drugs; IB, men from the random sample with low or moderate alcohol consumption with use of hepatotoxic drugs; IIA, alcoholic inpatients with use of alcohol and no drugs; IIB, alcoholic inpatients with use of alcohol and drugs. Group IIB was found to have a higher incidence of cortical and subcortical changes than group IA. Group IB had a higher incidence of subcortical changes than group IA, and they differed only in drug use. Group IIB and IIA only differed in drug use, and IIB had a higher incidence of brain damage except for anterior horn index and wide cerebellar sulci indicating vermian atrophy. Significantly higher serum (S) levels of bilirubin, gamma-glutamyl transpeptidase (GGT), asparate aminotransferase (ASAT), alanine amino-transferase (ALAT), creatine kinase (CK), lactate dehydrogenase (LD) and amylase were found in IIB. The results indicate that drug use influences the incidence of cortical and subcortical aberrations, except anterior horn index. It is concluded that the groups with alcohol abuse who used hepatotoxic drugs showed a picture of cortical changes (wide transport sulci and clear-cut or high-grade cortical changes) and also of subcortical aberrations, expressed as an increased widening of the third ventricle. [R58] *Trimethoprim-sulfamethoxazole reaction simulating Pneumocystis carinii pneumonia. [R59] *Between September 1976 and May 1989, 12 cases of uveitis attributed to the systemic use of sulfonamide derivatives were reported to the National Registry of Drug-Induced Ocular Side Effects and the US Food and Drug Administration. We evaluated these reports in addition to one case previously reported in the literature and one patient seen at the Uveitis Clinic, Oregon Health Sciences University, Portland. The patients' median age was 34 yr. Twelve of 14 patients were treated with trimethoprim-sulfamethoxazole. All patients for whom the location of the eye disease was specified presented with an iritis. Six reports included a description of ocular symmetry, with all patients having bilateral inflammation. Of the nine patients for whom data on the duration of drug use was available, seven experience adverse effects within 8 days of beginning trimethoprim-sulfamethoxazole therapy and four showed effects within 24 hr. Three patients had histories of rechallenge with trimethoprim-sulfimethoxazole, and in each case acute iritis recurred within 24 hr of reinstitution of therapy. Five patients had additional evidence of an adverse reaction manifested as Stevens-Johnson syndrome, erythema multiforme, diffuse macular or vesicular rashes, stomatitis, glossitis, conjunctival and scleral injection, and granulomatous hepatitis. The consistent presentation including bilateral, anterior inflammation and the recurrence with rechallenge strongly indicate a cause-effect relationship. Although uveitis secondary to sulfonamides is a rarely diagnosed clinical event, recognition of the distinct presentation of this entity is important in the differential diagnosis of uveitis. [R60] *As a third year medical student, I was hospitalized for approximately one month with Toxic Epidermal Necrolysis (TEN). Consequently, I have developed an insight into the role of patient as well as that of medical care giver. My experience prompted an intense interest in this particular adverse drug reaction and research into treatment recommendations. Treatment has changed in recent years and this resulted in significantly improved survival. Steroids, once commonly used, are now considered contraindicated. Because of the wide variety of medications which may be associated with this adverse reaction, it is essential to be familiar with the clinical presentation of toxic epidermal necrolysis, as well as the initial steps in treatment. [R61] *Fatal hemolytic anemia occurred in a 71 yr old man after trimethoprim-sulfamethoxazole was given for presume cystitis. Administration of this combination has previously caused multiple hematologic reactions by affecting folic acid metabolism. Megaloblastic anemia and neutropenia have been produced by both of these agents, while sulfamethoxazole alone has induced acute hemolytic anemia in patients with hereditary deficiency of glucose-6-phosphate dehydrogenase. Although hematologic complications of trimethoprim-sulfamethoxazole treatment usually follow long-term or high-dose therapy, acute reactions apparently may occur at lower doses as well. [R62] *Dermatoses ascribed to allergies to chlorambucil (I) therapy, 8-14 mg/day for 3-6 wk, are reported in 3 non-Hodgkins lymphoma patients, aged 58-72 yr. Other therapy included furosemide (frusemide), allopurinol, metoprolol,, diazepam, sulfamethizole and ibuprofen. Cases were confirmed by exclusion of other drugs, rechallenge, skin testing and histology. In one patient, withdrawal of chlorambucil led to resolution of the eruption. In the second, both discontinuing chlorambucil and therapy with prednisone (II), 50 mg/day in a tapering dose, plus topical measures were necessary to clear the rash. The third patient died of erythema multiforme, despite therapy with prednisone at 100 mg/day. [R63] *Fever, lypotension, pulmonary infiltrates, and hypoxemia developed upon re-exposure to trimethoprim-sulfamethoxazole in 2 patients with the Acquired Immunodeficiency Syndrome. This reaction can mimic sepsis or the clinical worsening of underlying pulmonary opportunistic infection. The literature concerning adverse pulmonary effects of trimethoprim-sulfamethoxazole is reviewed. [R64] *The porphyrias are a group of diseases which may be complicated by acute neurological crises having serious morbidity and a high rate of mortality. We report a case of acute porphyria in which an acute neurological crisis, resulting in loss of laryngeal function, precipitated life-threatening aspiration pneumonia. [R65] *The data on 211 patients using Co-trimoxazole (sulfamethoxazole-trimethoprim) and 127 patients using sulfamethizole during pregnancy were studied to determine teratogenic potential. There was no evidence of harm resulting from the use of Co-trimoxazole or sulfamethizole in pregnancy for any of the parameters studied here. In view of the high risk of hyperbilirubinemia associated with prematurity, it was suggested that alternate therapy for highly protein bound sulfonamides be administered in the wk prior to delivery or at mid-term in women who exhibit evidence of premature labor. [R66] *CASE REPORT OF A 50-YR-OLD MAN WITH RENAL DYSFUNCTION WHO DEVELOPED OXIDANT HEMOLYSIS WHILE ON SULFAMETHIZOLE THERAPY IS DESCRIBED. [R67] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R68] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HPLC WAS USED FOR THE IDENTIFICATION AND DETERMINATION OF SULFISOXAZOLE IN TABLET, LIQUID AND OINTMENT DOSAGE FORMS. [R69] *HIGH-PRESSURE LIQ CHROMATOGRAPHY WAS USED FOR THE SEPARATION AND DETECTION OF SULFANILAMIDES IN PHARMACEUTICAL PREPN. [R70] *QUALITATIVE ANALYSIS OF 14 SULFA DRUGS AND THEIR INDIVIDUAL QUANTITATIVE DETERMINATIONS WERE PERFORMED BY GAS-LIQUID CHROMATOGRAPHY. [R71] *THE RATE OF EXTRACTIVE ALKYLATION OF 24 STRUCTURALLY RELATED SULFONAMIDES WAS STUDIED WITH RESPECT TO THE ALKYLATING AGENT AND ORGANIC SOLVENT. [R72] *A THIN-LAYER CHROMATOGRAPHIC SYSTEM WAS USED FOR THE SEPARATION OF A SERIES OF SULFONAMIDES. [R73] *15 SULFONAMIDES WERE SEPARATED BY THIN-LAYER CHROMATOGRAPHY. [R74] *10 SULFA DRUGS EG SULFAMETHIZOLE WERE SEPARATED AND IDENTIFIED BY THIN-LAYER CHROMATOGRAPHY. [R75] *AOAC 983.31. Sulfonamide Residues in Animal Tissues. 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Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990 RS: 65 Record 315 of 1119 in HSDB (through 2003/06) AN: 4481 UD: 200303 RD: Reviewed by SRP on 5/6/2000 NT: This record contains information for barium in its zero valence state only. For general toxicology and environmental fate of barium ion and barium compounds, refer to the BARIUM COMPOUNDS record; for compound-specific information, refer to the appropriate individual records, e.g., barium sulfate, barium chloride, etc. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BARIUM,-ELEMENTAL- SY: *Bario- (Spanish); *BARIUM-; *Baryum- (French) RN: 7440-39-3 RELT: 6934 [BARIUM COMPOUNDS] MF: *Ba SHPN: UN 1400; Barium, non-pyrophoric IMO 4.3; Barium, non-pyrophoric HAZN: D005; A waste containing barium may (or may not) be characterized a hazardous waste following testing for reactivity as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *... CAN BE EXTRACTED BY HEATING BARIUM OXIDES WITH ALUMINUM IN VACUO AT ABOUT 1200 DEG C AND CONDENSING BARIUM VAPOR IN THE COOL END OF TUBE; OR WITH FERROSILICON AT TEMP ABOUT 50 DEG C HIGHER. LEAD-BARIUM-CALCIUM ALLOYS CAN BE PREPD BY ELECTROLYSIS OF FUSED CHLORIDES IN CELL WITH MOLTEN LEAD AS THE CATHODE. [R1, 61] *... Barium metal is produced commercially by the reduction of barium oxide with a less reactive, nonvolatile element (usually aluminum). [R2, p. V3 903] *To obtain the pure metal, barium oxide as starting material is reduced with ... silicon under vacuum at 1050 deg C. The barium obtained (96-98.5%) is purified by vacuum distillation (99.5%). [R3] IMP: *Impurities: Calcium, magnesium, and alkali metal compounds [R2, p. V3 905] FORM: *Grades: technical; pure; forms: rods, wire, powder [R4] *Commercial barium typically has a min purity of 99.5% [R2, p. V3 906] *Barium-cadmium cmpd: powder grade; barium-cadmium-organic phosphorus cmpd: liq grades, liq and solid grades; barium-cadmium-zinc-organic phosphorus cmpd: liq grade, liq and solid grades; barium-zinc cmpd: powder and liq grades, liq and solid grades [R5] OMIN: *Production of ultra pure barium metal has been investigated on a lab scale. Redistillations, zone recrystallization, and combinations of these techniques have been studied. Impurity levels of less than 100 ppm have been attained. [R2, p. V3 906] USE: *Carrier for radium; alloys of barium with aluminum or magnesium are used as getters in electronic tubes; emissions from (140)Ba contribute to fission products of uranium rods. [R6] *Emissions from (133)Barium and (137m)Ba are used as std in gamma-spectrometry. [R6] *Deoxidizer for copper; Fray's metal; lubricant for anode rotors in X-ray tubes; spark-plug alloys. [R4] *Used as a component in various proprietary nodularizing and deoxidizing alloys [R2, p. V3 907] *USED EXTENSIVELY IN MANUFACTURE OF ALLOYS FOR SUCH PRODUCTS AS NICKEL BARIUM PARTS USED IN IGNITION EQUIPMENT FOR AUTOMOBILES AND IN MANUFACTURE OF LITHOPONE, GLASS, CERAMICS, AND TELEVISION PICTURE TUBES. [R7] *As heat stabilizer for plastics. [R2, p. V3 907] *The largest end use of barium is as a "getter" to remove the last traces of gases from vacuum and television picture tubes. It is also used to improve performance of lead alloy grids of acid batteries, as a component of grey and ductile irons, and in the manufacture of steel, copper and other metals. [R8] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Yellowish-white, slightly lustrous lumps; body-centered cubic structure [R6]; *Silver-white [R4] BP: *1897 deg C [R9, p. 4-42] MP: *727 deg C [R9, p. 4-42] MW: *137.327 [R9, p. 4-42] DEN: *3.62 g/cu cm [R9, p. 4-42] SOL: *Reacts with water; slightly soluble in ethanol [R9, p. 4-42] SURF: *224 dynes/cm (liq form of barium) at 720 deg C in argon atmosphere as determined by bubbler pressure method [R10, p. F-20] VAP: *1 Pa, 638 deg C; 10 Pa, 765 deg C; 100 Pa, 912 deg C; 1 kPa, 1115 deg C; 10 kPa, 1413 deg C; 100 kPa, 1897 deg C [R9, p. 6-61] OCPP: *Somewhat malleable; electromotive force (aq) barium(2+)/barium= -2.91 Volts [R6] *Gives green color in flame [R4] *It has a distinctive property of absorbing gases. [R11] *The stable isotopes 130, 132, 134, 135, 136, 137, and 138 are known. [R6] *Alkaline-earth element of atomic number 56, Group IIA of Periodic Table; extrudable and machinable [R4] *NATURALLY OCCURRING BARIUM IS A MIXTURE OF SEVEN STABLE ISOTOPES. THIRTEEN OTHER RADIOACTIVE ISOTOPES ARE KNOWN TO EXIST. [R10, p. B-9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Produce flammable gases on contact with water. May ignite on contact with water or moist air. Some react vigorously or explosively on contact with water. May be ignited by heat, sparks or flames. May re-ignite after fire is extinguished. Some are transported in highly flammable liquids. Runoff may create fire or explosion hazard. [R12] +Health: Inhalation or contact with vapors, substance, or decomposition products may cause severe injury or death. May produce corrosive solutions on contact with water. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire may cause pollution. [R12] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate the area before entry. [R12] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. [R12] +Evacuation: ... Consider initial downwind evacuation for at least 250 meters (800 feet). If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R12] +Fire: DO NOT USE WATER OR FOAM. Small fires: Dry chemical, soda ash, lime or sand. Large fires: Dry sand, dry chemical, soda ash or lime or withdraw from area and let fire burn. Move containers from fire area if you can do it without risk. Magnesium fires: DRY sand, sodium chloride powder, graphite powder or Met-L-X powder. Lithium fires: DRY sand, sodium chloride powder, graphite powder, copper powder or Lith-X powder. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R12] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch or walk through spilled material. Stop leak if you can do it without risk. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. DO NOT GET WATER on spilled substance or inside containers. Small spills: Cover with DRY earth, DRY sand, or other non-combustible material followed with plastic sheet to minimize spreading or contact with rain. Dike for later disposal; do not apply water unless directed to do so. Powder spills: Cover powder spill with plastic sheet or tarp to minimize spreading and keep powder dry. DO NOT CLEAN-UP OR DISPOSE OF, EXCEPT UNDER SUPERVISION OF A SPECIALIST. [R12] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, wipe from skin immediately; flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R12] FPOT: *FLAMMABLE (PYROPHORIC) AT ROOM TEMP IN POWDER FORM. [R13] FIRP: *If material on fire or involved in fire: Do not use water. Use graphite, soda ash, powdered sodium chloride, or suitable dry powder. If fire is massive, back off, protect surroundings, and let burn. Keep run-off water out of sewers and water sources. [R14] EXPL: *... Explosive in the form of dust when exposed to heat or flame or by chem reaction. [R15] REAC: *WHEN HEATED TO ABOUT 200 DEG C IN HYDROGEN, BARIUM REACTS VIOLENTLY, FORMING BARIUM HYDRIDE (BAH2). [R13] *BARIUM REACTS VIOLENTLY WITH ACIDS. A VIOLENT REACTION OCCURRED WHEN SMALL CHUNKS OF BARIUM WERE CLEANED BY SUBMERGING IN CHEMICALLY PURE CARBON TETRACHLORIDE. ... MIXT OF FINELY DIVIDED BARIUM METAL AND ... HALOGENATED HYDROCARBONS POSSESS EXPLOSIVE CAPABILITY. SPECIFICALLY, IMPACT SENSITIVE TESTS HAVE SHOWN THAT GRANULAR BARIUM IN CONTACT WITH MONOFLUOROTRICHLOROMETHANE, TRICHLOROTRIFLUORETHANE, CARBON TETRACHLORIDE, TRICHLOROETHYLENE, OR TETRACHLOROETHYLENE CAN DETONATE. [R16] *BARIUM RAOUDKT DECINOISES WATER. THE HEAT OF REACTION IS SUFFICENT THAT THE EVOLVED HYDROGEN MAY IGNITE. [R16] *THE FREE METAL PRESENTS ... EXPLOSION HAZARD IF EXPOSED TO MOIST AIR OWING TO LIBERATION OF HYDROGEN. [R11] *REACTS IN COLD WATER WITH EVOLUTION OF HYDROGEN GAS [R10, p. B-73] *EXTREMELY REACTIVE; REACTS READILY WITH AMMONIA, HALOGENS, OXYGEN AND MOST ACIDS [R13] EQUP: *Wear rubber gloves, rubber protective clothing and apron, goggles, and gas-filter mask. [R17] OPRM: *TO KEEP DUST CONCN BELOW RECOMMENDED LEVELS, PROCESSES SHOULD BE ENCLOSED AND/OR EXHAUST VENTILATION INSTALLED. [R18] *ADEQUATE WASHING AND ... SANITARY FACILITIES SHOULD BE PROVIDED ... AND RIGOROUS PERSONAL HYGIENE MEASURES SHOULD BE ENCOURAGED. SMOKING AND CONSUMPTION OF FOOD AND BEVERAGES IN WORKSHOPS SHOULD BE PROHIBITED. FLOORS IN WORKSHOPS SHOULD BE MADE OF IMPERMEABLE MATERIALS AND FREQUENTLY WASHED DOWN. [R18] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of igniton away. Keep material out of water sources and sewers. Do not use water. Cover all suspected material with dry sand or earth to prevent ignition until material can be permanently disposed of. [R14] *Personnel protection: Keep upwind. Avoid breathing dusts, and fumes from burning material. [R14] SSL: *THE FREE ELEMENT OXIDIZES READILY IN MOIST AIR. [R19] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R20] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R21] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R22] STRG: *STORE UNDER INERT GAS, PETROLEUM, OR OXYGEN FREE LIQUID. [R13] *... Packaged in argon filled plastic bags inside argon filled steel containers. [R23, p. 3(78) 460] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. RADL: *OF ISOTOPES OF BARIUM, (140)BA HAS LONGEST HALF-LIFE AND CONTRIBUTES 10% OF TOTAL FISSION PRODUCTS AT 10 DAYS AFTER NUCLEAR FALL-OUT, BUT AT 60 DAYS ITS CONTRIBUTION ... /WILL BE/ 2% OF TOTAL ACTIVITY. [R1, 62] *THIRTEEN ... RADIOACTIVE ISOTOPES ARE KNOWN TO EXIST. [R10, p. B-9] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: +IDENTIFICATION: Barium is a yellowish white soft metal that is strongly electropositive. In nature barium occurs in a combined state, the principal forms being barite (barium sulfate) and witherite (barium carbonate). Barium is also present in small quantities in igneous rocks such as feldspar and micas. It may also be found as a natural component of fossil fuel and is present in the air, water and soil. HUMAN EXPOSURE: Exposure to barium can occur through the air, water or food. Another souce of barium is nuclear fallout. The average person accumulates 91% of barium in bones. Trace quantities are found in various tissues such as the aorta, brain, heart, kidney, spleen, pancreas and lung. Total barium in human beings tends to increase with age and the levels in the body depend on the geographical location of the individual. Barium has also been found in all samples of stillborn babies, suggesting it can cross the placenta. Inhaled barium can be absorbed through the lung or directly from the nasal membrane into the blood. Barium is eliminated in the urine and feces, the rates varying with the route of administration. Within 24 hr approximately 20% of the barium dose, injected into humans was eliminated in the feces and approxinately 5% in the urine. Plasma barium is almost eliminated from the blood stream within 24 hr. ANIMAL/PLANT STUDIES: In general, barium does not accumulate in common plants in sufficient quantities to be toxic to animals. Large quantities of barium (as high as 1260 mg/kg) accumulated in legumes, alfalfa and soybeans. The elimination of ingested barium in animals occurs mainly in the feces rather than in the urine. An estimated of the biological half-life for barium in the rat is 90-120 days. The acute effects of barium ingestion in animals includes salivation, nausea, diarrhea, tachycardia, hypokalaemia, twitching, flacid paralysis of skeletal muscle, respiratory muscle paralysis and ventricular fibrillation may lead to death. Various studies have demonstrated the detremental effect of barium upon ventricular automaticity and pacemaker current in the heart. IV barium injections to anesthetized dogs indicated that these acute effects were due to prompt and substantial hypokalemia. Barium causes mild skin and eye irritation. No conclusive association was found between the level of barium in the drinking water and the incidence of congenital malformations. There is no evidence that barium is carcinogenic. Rats given 10 or 100 mg barium/l in their drinking water for 16 months experienced hypertension, but at a level of 1 mg/l did not induce any blood pressure changes. Analysis of myocardial function at 16 months (100 mg barium/l) revealed significantly altered cardiac contractility and excitability, myocardial metabolic disturbances and hypersensitivity of the cardiovascular system to sodium pentobarbital. Barium posesses chemical and physiological properties that allow it to compete with and replace calcium, particularly those relating to the release of adrenal catecholamines and neurotransmitters such as acetylcholine and norepinephrine. Barium affects the development of germinating bacterial spores and has a variety of specific effects on different microorganisms including the inhibition of cellular processes. Little information is available on the effects of barium on aquatic organisms. There were no effects on survival of fish following exposure for 30 days. However, in a 21 day study, impairment of reproduction and reduction in growth in daphnids. Marine plants as well as invertebrates may actively accumulate barium from sea water. [R24] CARC: *WEIGHT OF EVIDENCE CHARACTERIZATION: Under EPA's 1986 Guidelines for Carcinogen Risk Assessment, barium would be classified as Group D, not classifiable as to human carcinogenicity. Although adequate chronic oral exposure studies in rats and mice have not demonstrated carcinogenic effects, the lack of adequate inhalation studies precludes assessing the carcinogenic potential of inhaled barium. Under the Proposed Guidelines for Carcinogenic Risk Assessment, barium is considered not likely to be carcinogenic to humans following oral exposure and its carcinogenic potential cannot be determined following inhalation exposure. Basis - Oral exposure studies in rats and mice ... did not find significant increases in tumor incidence following chronic exposure. In the 1994 NTP rat study /National Toxicology Program Technical Report Series #432 on Barium Chloride Dihydrate (10326-27-9)/, statistically significant negative trends in the incidence of leukemia, adrenal tumors, and mammary gland tumors were observed. The design of the rat and mouse NTP studies was adequate to assess carcinogenicity. These studies used an adequate number of animals per group, exposed animals for 2 years, tested several dosage levels, and examined an extensive number of tissues. The inhalation exposure and intratracheal studies ... are inadequate for subchronic exposure carcinogenicity evaluation because of several deficiencies in the design and reporting ... HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Oral Exposure - Sufficient; Inhalation Studies - Inadequate. [R25] +A4; Not classifiable as a human carcinogen. /Barium and soluble cmpd, as Ba/ [R26, 2002.16] MEDS: *Consideration should be given to the skin, eye, heart, and lung in any placement or periodic examination. [R27] *... Individuals with pulmonary diseases /should be protected from exposure/. [R17] HTOX: *The rapid onset of reflex paralysis was reported in a chrome-plating worker following the inhalation of barium powder. Complete recovery occurred during the 5-day period that followed exposure. [R28] *Several hundred cases of acute or subacute barium poisoning occurred in the Kiating district of China, where table salt contained a large amt of barium (up to 26%). The victims suffered sudden attacks of paralysis, ranging from mild to severe, paraesthesia, and cardiac symptoms, but recovery was usually rapid ... . [R28] *BARIUM IS NOT CONSIDERED TO BE AN INDUSTRIAL HEALTH HAZARD ... . [R7] *The prolonged contact of barium containing contraceptive devices with cervical cells presented a potential cancer risk in susceptible individuals. [R29] TCAT: ?Acute toxicity was evaluated in a bioassay of mice L-cells exposed to a test water medium containing lead, silver, arsenic, barium, cadmium, and chromium had EC50 values (50% reduction in protein synthesis) were 0.5 mg/l, lead; 0.5 mg/l, silver; 0.5 mg/l, arsenic; 0.1 mg/l, cadmium; 0.1 mg/l, barium; 0.2 mg/l, chromium. No other observations were reported. [R30] POPL: *... Those individuals with pulmonary diseases. [R17] ADE: *In young rats given an ip dose of carrier-free (140)barium, 18.4% (average of four rats) of the dose had been recovered in the GI tract and feces 4 hr after dosing and 5.8% in urine. After 24 hr, the corresponding values in three rats were 2..7 and 6.6%. thus, there was a change from an initial rapid clearance to a slower phase. [R31] *Using barium, it was shown that absorption from the gastrointestinal tract of the rat was rapid and complete. The form of the curves of stomach, small intestine, and large intestine suggested a period of excretion by way of the gastrointestinal tract that followed the period of absorption and reached its maximum at about 48 hr. This excretion into the gastrointestinal tract was confirmed by other studies in which barium was administered by the intravenous route. Storage in bone increased for about 48 hr following oral administration and then decreased far more slowly than storage in other tissues. From the sixth day onward nearly all the barium remaining in the body was in the bone ... The uptake into bone decreases with age of the animal. [R32] *Study of rats injected intraperitoneally with barium indicated that excretion was most rapid during the first 4 hr and reached 7% in the urine and 20% in the feces in 24 hr ... . Experiments in dogs showed that barium can be actively reabsorbed by the kidney tubules. Its clearance was correlated with calcium clearance. Protein binding of barium averaged 54% and was of the same order of magnitude as that of other alkaline earths. [R32] ACTN: *Barium stimulates striated, cardiac, and smooth muscle, regardless of innervation. It is antagonistic to all muscle depressants, no matter whether they act primarily on nerve or muscle. Initial stimulation of contraction leads to vasoconstriction through direct action on arterial muscle, peristalsis through action on smooth muscle, tremors and cramps through action on the skeletal muscles, and various arrhythmias through action on the heart. If the dose is sufficient, stimulation is followed by weakness and eventually by paralysis of the different kinds of muscle. Some effects such as hypertension, violent tremors, and convulsions are uncommon following ingestion of barium carbonate. They are more likely to follow absorption of more soluble barium compounds. If death does occur, it is caused by failure of muscular contraction leading to respiratory failure or cardiovascular collapse. [R32] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: *Barium metal does not occur free in nature ... . [R23, p. 3(78) 457] RTEX: *Ingestion or inhalation of dust or fume, skin or eye contact. [R27] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TLV: +8 hr Time Weighted Avg (TWA): 0.5 mg/cu m. /Barium and soluble cmpds, as Ba/ [R26, 2002.16] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Barium and soluble cmpd, as Ba/ [R26, 2002.6] +A4; Not classifiable as a human carcinogen. /Barium and soluble cmpd, as Ba/ [R26, 2002.16] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 2000 ug/l [R33] FEDERAL DRINKING WATER GUIDELINES: +EPA 2000 ug/l [R33] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 1000 ug/l [R33] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 1,500 ug/l [R33] +(ME) MAINE 1500 ug/l [R33] +(MN) MINNESOTA 2000 ug/l [R33] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). /Barium/ [R34] RCRA: *D005; A solid waste containing barium may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. [R35] *D005; A solid waste containing barium may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. /Barium/ [R35] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology and Carcinogenesis Studies of Barium Chloride Dihydrate in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). Technical Report Series No. 432 (1994) NIH Publication No. 94-3163 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 SO: R1: Browning, E. Toxicity of Industrial Metals. 2nd ed. New York: Appleton-Century-Crofts, 1969. R2: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present. R3: Seiler, H.G., H. Sigel and A. Sigel (eds.). Handbook on the Toxicity of Inorganic Compounds. New York, NY: Marcel Dekker, Inc. 1988. 97 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 112 R5: Kuney, J.H. and J.N. Nullican (eds.) Chemcyclopedia. Washington, DC: American Chemical Society, 1988. 271 R6: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 165 R7: Venugopal, B. and T.D. Luckey. Metal Toxicity in Mammals, 2. New York: Plenum Press, 1978. 63 R8: USEPA; Drinking Water Criteria Document for Barium (Draft) p.II-7 (1985) TR-540-60F R9: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999. R10: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989. R11: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 1926 R12: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-138 R13: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 117 R14: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 120 R15: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 3456 R16: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 491-27 R17: ITII. Toxic and Hazarous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1982. 57 R18: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 244 R19: Friberg, L., Nordberg, G.F., Kessler, E. and Vouk, V.B. (eds). Handbook of the Toxicology of Metals. 2nd ed. Vols I, II.: Amsterdam: Elsevier Science Publishers B.V., 1986.,p. V2 85 R20: 49 CFR 171.2 (7/1/99) R21: IATA. Dangerous Goods Regulations. 40th Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 1999. 114 R22: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.4332 (1998) R23: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R24: Environmental Health Criteria 107 Barium. pp.13-19 (1990) by the International Programme on Chemical Safety (IPCS) under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation and the World Health Organization. R25: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) for Barium and compounds (7440-39-3) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of August 10, 1998 R26: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R27: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 105 R28: WHO; Environ Health Criteria 107: Barium p.90 (1990) R29: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 926 R30: U.S, Department of the Army; The Development of a Test for the Probability of Water Treated by Direct Reuse System (Contract No. DADA-17-73-C-3013) (Final Report), (1980), EPA Doc. 40-8069226, Fiche No. OTS0517889 R31: WHO; Environ Health Criteria 107: Barium p.62 (1990) R32: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 498 R33: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R34: 40 CFR 302.4 (7/1/99) R35: 40 CFR 261.24 (7/1/99) RS: 30 Record 316 of 1119 in HSDB (through 2003/06) AN: 4503 UD: 200303 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-HYDROXY-4-METHOXYBENZOPHENONE- SY: *ADVASTAB-45-; *BENZOPHENONE,-2-HYDROXY-4-METHOXY-; *CYASORB-UV-9-; *METHANONE, (2-HYDROXY-4-METHOXYPHENYL)PHENYL-; *4-METHOXY-2-HYDROXYBENZOPHENONE-; *MOB-; *MOD-; *NCI-C60957-; *NSC-7778-; *ONGROSTAB-HMB-; *OXYBENZONE-; *SPECTRA-SORB-UV-9-; *SYNTASE-62-; *UF-3-; *USAF-CY-9-; *UVINUL-M-40-; *UVINUL-9- RN: 131-57-7 MF: *C14-H12-O3 ASCH: Benzophenone, 2-hydroxy-4'-methoxy; 18733-07-8; Benzophenone, 2-hydroxy-5-methoxy; 14770-96-8 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN: KONIG, V KOSTANECKI, BER 39, 4027 (1906); HARDY, FORSTER, US PATENT 2,773,903 (1956 TO AM CYANAMID); STANLEY ET AL, US PATENTS 2,861,104/5 and 3,073,866 (1958 and 1963, ALL TO GENERAL ANILINE AND FILM). [R1] *BENZOIC ACID IS CONDENSED WITH RESORCINOL MONOMETHYL ETHER BY HEATING IN PRESENCE OF ZNCL2, POLYPHOSPHORIC ACID (103% H3PO4 EQUIVALENT), US PATENT 3,073,866. [R2] MFS: +American Cyanamid Company, Hq, One Cyanamid Plaza, Wayne, NJ 07470, (201) 831-2000; Chemical Products Division; Production site: Marietta, OH 45750; Fine Chemicals Department (address same as Hq); Production site: Willow Island, WV 26190 [R3] +Neville-Synthese Organics, Inc, Hq, 2800 Neville Rd, Pittsburgh, PA 15225-1496, (412) 331-4200; Production site: Neville Island, PA 15225 [R3] OMIN: *A SUNSCREEN. IT HAS HIGH MOLAR ABSORPTIVITY, AND IT ABSORBS IN BOTH LONG AND SHORT ULTRAVIOLET SPECTRUM. THEREFORE, IT SERVES NOT ONLY TO PREVENT SUNBURN BUT ALSO TO PROTECT AGAINST PHOTODYNAMIC, PHOTOSENSITIZING, AND PHOTOTOTOXIC EFFECTS OF VARIOUS DRUGS. CONTACT WITH THE EYES SHOULD BE AVOIDED. AT PRESENT, OXYBENZONE IS MARKETED IN COMBINATION WITH ITS 2'-HYDROXY-DERIVATIVE, DIOXYBENZONE. [R2] *UVINUL /IS A/ TRADEMARK FOR ULTRAVIOLET LIGHT ABSORBERS. ...EFFECTIVE IN RANGE OF 200-400 MILLIMICRONS. THEY DO NOT DARKEN OR DECOMPOSE UPON PROLONGED EXPOSURE TO AN INTENSE ULTRAVIOLET SOURCE. THE ABSORBED ENERGY IS NOT RE-EMITTED IN THE VISIBLE SPECTRUM. TYPICAL APPLICATIONS INCLUDE PROTECTION OF PLASTICS, OILS, COSMETICS, PAPER, WOOD, AND LEATHER. /UVINUL/ [R4] USE: *SUNSCREEN AGENT [R1] *A PHOTOSTABILIZER FOR SYNTHETIC RESINS [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS FROM ISOPROPANOL [R1] MP: *66 DEG C [R1] MW: *228.26 [R6] SOL: *READILY SOL IN MOST ORGANIC SOLVENTS [R1]; *PRACTICALLY INSOL IN WATER; FREELY SOL IN ALCOHOL AND TOLUENE [R2] SPEC: +IR: 8476 (Sadtler Research Laboratories IR Grating Collection) [R7]; +UV: 5-408 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R7]; +NMR: 3204 (Sadtler Research Laboratories Spectral Collection) [R7]; +MASS: 1618 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R7] OCPP: *WHITE TO OFF-WHITE POWDER /USP/ [R2] +UV: 939 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) /Benzophenone, 2-hydroxy-4'-methoxy/ [R7] +MASS: 1532 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /Benzophenone, 2-hydroxy-4'-methoxy/ [R7] +UV: 1120 (Absorption Spectra in the UV and visible Regions, Academic Press, New York) /Benzophenone, 2-hydroxy-5-methoxy/ [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *A 42-YR OLD WOMAN WHO HAD A RECURRENCY OF SUNLIGHT PROVOKED EXZEMATOUS ERUPTIONS WAS TESTED BY PHOTOPATCH-TESTING USING ACTIVE INGREDIENTS OF SUNSCREEN FORMULATIONS. THE TEST REVEALED PHOTOSENSITIVITY TO THE UV-BLOCKING AGENT 2-HYDROXY-4-METHOXYBENZOPHENONE. [R8] *2-HYDROXY-4-METHOXYBENZOPHENONE WAS EVALUATED FOR PULP IRRITATION. IT DID NOT CAUSE SIGNIFICANT INFLAMMATION. [R9] NTOX: *2-HYDROXY-4-METHOXYBENZOPHENONE...HAS BEEN TESTED FOR TOXICITY ON RABBITS AND BEEN FOUND TO BE ESSENTIALLY NONIRRITATING TO THE SKIN AND EYES. [R5] *THE MUTAGENICITY OF 2-HYDROXY-4-METHOXYBENZOPHENONE, A SUNSCREEN AGENT, WAS TESTED IN SALMONELLA TYPHIMURIUM STRAINS TA100, TA98, TA1535, TA1537 AND TA1538. RESULTS WERE NEGATIVE. [R10] *2-HYDROXY-4-METHOXYBENZOPHENONE (MOB) WAS FED TO RATS AT CONCENTRATIONS OF 0.02%, 0.1%, 0.5% and 1% FOR 90 DAYS. IN FEMALES AND MALES GROWTH WAS DEPRESSED AT THE 2 HIGHEST LEVELS. FEMALES FED 0.5% OR 1% FOR 6 WK HAD LOWERED HEMOGLOBIN LEVEL AND LEUKOCYTOSIS, WITH INCR IN LYMPHOCYTES AND A DECR IN NEUTROPHILS. AFTER 12 WK, ANEMIA AND LYMPHOCYTOSIS, WITH A REDN IN GRANULOCYTES, WERE ESTABLISHED. 1% CAUSED DEGENERATIVE NEPHROSIS IN THE KIDNEYS OF BOTH SEXES. [R11] NTP: +2-Hydroxy-4-methoxybenzophenone, (HMBP) ... was tested for its effects on fertility and reproduction in Swiss CD-1 mice according to the Continuous Breeding protocol. It was administered via feed. Based on results of a dose-finding study, 1.25, 2.5, and 5.0% (w/w) were chosen to investigate effects on fertility and reproduction. Male and female mice were continuously exposed for a 7 day precohabitation and a 98 day cohabitation period (Task 2). The feed consumption in 2.5 and 5.0% groups was consistently higher but the F0 body weights were consistently lower. These findings suggest that HMBP may be adversely affecting metab or the digestive process in Swiss mice. In the 2.5 and 5.0% HMBP groups, the number of live pups/litter was significantly reduced. The F1 generation from control, 2.5 and 5.0% groups were weaned for second generation studies. During lactation and nursing of F1 pups, pup survival was significantly below the control value in the 2.5 and 5.0% groups. HMBP had minimal effects on fertility in the F1 generation but F2 pup weights were significantly reduced. Based on the results of the present study, it is concluded that HMBP causes systemic toxicity but has minimal effects on fertility and reproduction at these doses. [R12] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *GAS AND HIGH PRESSURE LIQUID CHROMATOGRAPHIC PROCEDURES WERE USED TO DETERMINE 19 FAT- AND WATER-SOL ACTIVE INGREDIENTS IN SUNSCREEN PREPARATIONS. [R13] *UV SPECTRA OF SUNSCREEN PREPARATIONS USING 7% PADIMATE O AND 3% OXYBENZONE WERE RECORDED IN ISOPROPYL ALC SOLN AND AS IS IN THE FORM OF THIN FILM DEPOSITED BETWEEN 2 CLEAN, EMPTY, MATCHED CELLS. BY TRANSPOSING THE UV SPECTRUM OVER THAT RECORDED IN ISOPROPYL ALC SOLN ACTUALLY TRANSMITTED ENERGY WAS CALCULATED. WHEN ERYTHEMAL RESULTS WERE COMPARED, SAMPLE DETERMINED BY DIRECT METHOD WAS APPROX 3 TIMES MORE EFFICIENT AND 5 TIMES BETTER IN UV ABSORPTION REGION THAN THAT DETERMINED IN ISOPROPYL ALC SOLN. [R14] *GAS CHROMATOGRAPHY RETENTION TIMES OF DIFFERENT UV ABSORBING AGENTS USED IN SUNSCREEN PREPARATIONS ARE COMPILED AS AN AID TO THEIR IDENTIFICATION IN COMMERCIAL SAMPLES. THE ACCURACY OF THIS METHOD IS 85-80%. [R15] *A HIGH PRESSURE LIQUID CHROMATOGRAPHIC METHOD IS PRESENTED FOR DETERMINING SOME HYDROXY-SUBSTITUTED AROMATIC COMPOUNDS. [R16] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of 2-Hydroxy-4-methoxybenzophenone Administered Topically and in Dosed Feed to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 21 NIH Publication No. 93-3344 (1992) SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 901 R2: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 727 R3: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 700 R4: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 907 R5: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 569 R6: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8111 R7: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 247 R8: HOLZLE E, PLEWIG G; PHOTOALLERGIC CONTACT DERMATITIS BY BENZOPHENONE CONTAINING SUNSCREENING PREPARATIONS; HAUTARZT 33(7) 391 (1982) R9: STANLEY HR ET AL; COMPATABILITY OF VARIOUS MATERIALS WITH ORAL TISSUES. II. PULP RESPONSES TO COMPOSITE INGREDIENTS; J DENT RES 58(5) 1507 (1979) R10: BONIN AM ET AL; UV-ABSORBING AND OTHER SUN-PROTECTING SUBSTANCES: GENOTOXICITY OF 2-ETHYLHEXYL P-METHOXYCINNAMATE; MUTAT RES 105: 303 (1982) R11: LEWERENZ HJ ET AL; ACUTE AND SUBACUTE TOXICITY STUDIES OF THE UV ABSORBER MOB IN RATS; FOOD COSMET TOXICOL 10(1) 41 (1972) R12: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; 2-Hydroxy-4-Methoxybenzophenone (CAS No. 131-57-7): Reproductive Toxicity in CD-1 Swiss Mice; Dose 1.25, 2.5 and 5% in Feed, NTP Study No. RACB88076 (December 1990) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R13: EIDEN F, TITTEL C; ANALYSIS OF SUN PROTECTION PREPARATIONS; DTSCH APOTH-ZTG 121(35) 1874 (1981) R14: CUMPELIK BM; SUNSCREENS AT SKIN APPLICATION LEVELS: DIRECT SPECTROPHOTOMETRIC EVALUATION; J SOC COSMET CHEM 31(7) 361 (1980) R15: CUMPELIK BM; GLC ANALYSIS OF MULTIPLE ABSORBER SUNSCREENS; COSMET TOILETRIES 97(5) 67 (1982) R16: CHIAVARI G ET AL; HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY OF SOME HYDROXY-SUBSTITUTED AROMATIC COMPOUNDS; J CHROMATOGR 249(2) 385 (1982) RS: 10 Record 317 of 1119 in HSDB (through 2003/06) AN: 4505 UD: 200303 RD: Reviewed by SRP on 1/23/1997 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 9-AMINOACRIDINE-HYDROCHLORIDE- SY: *ACRAMINE-YELLOW-; *9-ACRIDINAMINE,-MONOHYDROCHLORIDE-; *ACRIDINE,-9-AMINO,-HYDROCHLORIDE-; *ACRIDINE,-9-AMINO-,-MONOHYDROCHLORIDE-; *AMINACRINE-HYDROCHLORIDE-; *AMINOACRIDINE-HYDROCHLORIDE-; *5-AMINOACRIDINE-HYDROCHLORIDE-; *9-AMINOACRIDINE-MONOHYDROCHLORIDE-; *MONACRIN-; *MONACRIN-HYDROCHLORIDE-; *NSC-7571- RN: 134-50-9 MF: *C13-H10-N2.Cl-H ASCH: 9-Aminoacridine; 90-45-9 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared from 9-chloroacridine which is obtained by heating N-phenylanthranilic acid with PCl5; A. Albert, B. Ritchie, Org Syn coll vol III, 53 (1955) /9-aminoacridine/ [R1] OMIN: *USED AS REFERENCE COMPD IN THE VISCOMETRIC ANALYSIS OF CLOSED CIRCULAR DNA COMBINED WITH SPECTROPHOTOMETRIC AND FLUOROMETRIC STUDIES TO CHARACTERIZE THE MODE OF DNA BINDING OF ANTITRYPANOSOMAL AND ANTITUMOR COMPOUNDS. [R2] USE: *USED EXPERIMENTALLY AS A PROBE FOR BIOLOGICAL MEMBRANES AND DNA +MEDICATION (VET) *MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW CRYSTALS [R1] ODOR: *ODORLESS [R3] TAST: *BITTER TASTE [R3] MW: *230.71 [R4] PH: *0.2% SOLN BETWEEN 5 and 6.5 [R3] SOL: *1 G SOL IN 300 ML WATER AND 150 ML ALCOHOL; SOL IN GLYCERIN [R3] SPEC: +IR: 3:1400 (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R5]; +NMR: 9:114A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R5] OCPP: *NEUTRAL REACTION; ONE OF THE MOST HIGHLY FLUORESCENT SUBSTANCES; 1 G DISSOLVED IN 300 ML WATER FORMS A FAINT YELLOW SOLN WITH BLUISH-VIOLET FLUORESCENCE [R1] *IR: 7591 (Sadtler Research Laboratories Prism Collection) /9-Aminoacridine/ [R5] *UV: 2125 (Sadtler Research Laboratories Spectral Collection) /9-Aminoacridine/ [R5] *NMR: 11293 (Sadtler Research Laboratories Spectral Collection) /9-Aminoacridine/ [R5] *log Kow= 3.0 /9-aminoacridine/ [R6] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *...MODERATELY INJURIOUS TO RABBIT EYES. [R7] *IN FIBROBLAST CELL LINES FROM RAINBOW TROUT GONAD, BLUEGILL FRY AND STEELHEAD EMBRYO INCUBATED IN PRESENCE OF 8 MUTAGENS (INCL 9-AMINOACRIDINE) AT VARIOUS CONCN FOR 72 HR, THE NUMBER OF CELLS CONTINUED TO DECLINE IN DIRECT PROPORTION TO AMT OF CHEM IN MEDIA. THIS REPRESENTED INCR TOXICITY AS CONCN OF MUTAGEN INCR. THIS RESPONSE WAS THE RESULT OF TREATED CELLS NOT DIVIDING, WHILE UNTREATED CONTROLS CONTINUED TO REPLICATE. BLUEGILL FRY CELLS WERE MOST SUSCEPTIBLE TO TOXIC EFFECT. [R8] *TESTICULAR CELLS OF MALE MICE WERE ISOLATED, AND INCORPORATION OF TRITIUM LABELED THYMIDINE INTO DNA OF CELLS WAS ESTIMATED AFTER EXPOSURE TO VARIOUS CHEMICAL MUTAGENS. NORMAL SEMICONSERVATIVE DNA SYNTH WAS SUPPRESSED BY ADDN OF HYDROXYUREA WHICH WAS USED AS CONTROL. 8/13 TEST CHEM STIMULATED UNSCHEDULED DNA SYNTHESIS. 9-AMINOACRIDINE AND THE REMAINING 4 TEST CHEM DID NOT INDUCE UNSCHEDULED DNA SYNTHESIS, EVEN WHEN INCUBATION PERIODS WITH CELLS WERE PROLONGED, AND CONCN OF COMPD INCR TO BEGINNING OF TOXIC EFFECTS. [R9] NTP: +9-Aminoacridine hydrochloride (9AH) ... was tested for its effects on reproduction and fertility in CD-1 mice using the NTP Report # RACB protocol. Data from a two wk dose-range-finding study (Task 1) were used to set exposure concns for the Task 2 continuous cohabitation study at 0.025, 0.05, and 0.1% in feed. Based on body weights and food consumption data, the estimated daily doses were nearly equal to 31, 66, and 145 mg/kg. One male and 2 female control mice, and one female in the middle dose group, died during the 18 wk Task 2 cohabitation phase. While the male mice in the high dose group gained less weight than controls, only high dose female mean body weights were significantly lower than control means during the study, by nearly equal to 10%. While 9AH consumption did not alter the number of litters/pair, the number of pups/litter or their viability, the pup weight adjusted for body weight was reduced by 9% in the high dose group. This pup weight reduction may be related to the reduced postpartum dam weights. In the absence of changes in F0 fertility parameters, Task 3 was not conducted, and the last litter from the control, middle, and high dose groups was reared by their dams. Approx 2/3rds of the pups in the high dose group died before /postnatal day/ 14, and pup weight at all times until weaning was reduced by nearly equal to 30%. Pup survival and weight gain in the middle dose group were not changed. The increased morbidity at the high dose left insufficient pups to evaluate for fertility effects. Thus, Task 4 was performed using controls and middle dose group mice. During the Task 4 mating trial, 9AH had no effect on the number of pups/litter, or their viability or weight. Thus, there was no adverse reproductive effect noted in the second generation at 0.05% 9AH. After the F2 pups were delivered and evaluated, the F1 adults were killed and necropsied. While female body weights at the middle dose were not changed, liver weight was increased by nearly equal to 30%, and adjusted kidney weights were reduced by nearly equal to 10%. For treated males, body weight was reduced by nearly equal to 10%, while adjusted liver weight was increased by nearly equal to 25%. Sperm indices at necropsy were unchanged, as was estrous cycle length. Thus, 9AH induced some developmental toxicity, in the form of reduced F1 pup weight, at the same dose that also reduced dam weight, and at doses > those that increased F1 liver weight. No changes in other fertility indices were observed. These data suggest that , for 9AH, the hepatic effects are > any reproductive effects. Developmental toxicity could not be separated from the general toxicity. [R10] ACTN: *IN PRESENCE OF 9-AMINOACRIDINE-HCL, BACTERIOPHAGE P22 OF SALMONELLA TYPHIMURIUM WAS KILLED ON IRRADIATION WITH VISIBLE LIGHT; NEITHER THE COMPD NOR THE LIGHT ALONE INACTIVATED THE PHAGE. THE ACRIDINE INDUCED DAMAGE IN THE PHAGES BY 4 INDEPENDENT MODES: 1) FROM SHIFT MUTAGENESIS DURING PHAGE DNA REPLICATION; 2) ACRIDINE-SENSITIZED PHYTOTOXICITY TO PHAGE PARTICLES; 3) ACRIDINE-SENSITIZED PHOTOMUTAGENESIS; AND 4) INTERFERENCE WITH VIRUS ASSEMBLY. KINETIC ANALYSIS OF FORMATION AND PHOTOINACTIVATION OF COMPLEX BETWEEN 9-AMINOACRIDINE-HCL AND P22 INDICATED THAT ACRIDINES BOUND TO DNA BACKBONE AND INTERCALATED BETWEEN THE BASIS COULD MEDIATE LETHAL DAMAGE TO DNA-INJECTION PROTEINS. [R11] *INFLUENCE OF SELF-COMPLEMENTARY OLIGODEOXYNUCLEOTIDES ON CHEMICAL SHIFTS OF PROTONS OF MUTAGENIC 9-AMINOACRIDINE WAS MEASURED. UPFIELD SHIFTS INDICATIVE OF INTERCALATIVE BINDING ARE FOUND IN CASES OF DG-DC, DC-DG AND DA-DT-DG-DC-DA-DT BUT NOT IN DA-DT. GEOMETRIES FOR COMPLEXES ARE COMPATIBLE WITH CHEMICAL-SHIFT DATA AND X-RAY STRUCTURE OF COMPLEX BETWEEN RI5C-RG AND 9-AMINOACRIDINE DETERMINED BY SAKORE ET AL CAN BE IDENTIFIED USING RECENT THEORETICAL ESTIMATES OF SHIFTS INDUCED BY NUCLEOTIDE BASES. [R12] *INTERACTIONS OF 9-AMINOACRIDINE-HCL WITH IONIC CHANNELS WERE STUDIED IN INTERNALLY PERFUSED SQUID AXONS. KINETICS OF BLOCK OF SODIUM CHANNELS WITH 9-AMINOACRIDINE-HCL VARIED DEPENDING ON VOLTAGE-CLAMP PULSES AND THE STATE OF GATING MACHINERY OFF SODIUM CHANNELS. IN AN AXON WITH INTACT H GATE, THE BLOCK EXHIBITED FREQUENCY- AND VOLTAGE-DEPENDENT CHARACTERISTICS. IT ALSO BLOCKED POTASSIUM CHANNELS. [R13] *EFFECT OF SEQUENCE ON BINDING TO DNA WAS INVESTIGATED BY STUDYING ITS INTERACTION WITH DEOXYDINUCLEOSIDE PHOSPHATES OF DIFFERENT SEQUENCES USING PNMR. SIMPLEST MODEL THAT FITS THE DATA INCL 1) DIMERIZATION OF 9-AMINOACRIDINE AND 2) A MIXTURE OF 1:1 and 2:1 (DINUCLEOSIDE PHOSPHATE/9-AMINOACRIDINE) COMPLEXES. THE 1:1 COMPLEXES SEEM TO INVOLVE INTERACTION OF THE RING NITROGEN WITH THE BACKBONE PHOSPHATE AND STACKING OF ONE OR BOTH CHROMOPHORES ON THE ACRIDINE; PREFERENCE IN BINDING WAS OBSERVED FOR ALTERNATING (PURINE-PYRIMIDINE OR PYRIMIDINE-PURINE) OVER NON-ALTERNATING (PURINE-PURINE) DINUCLEOSIDE PHOSPHATES. THE 2:1 COMPLEXES INVOLVE INTERCALATION OF ACRIDINE BETWEEN 2 COMPLEMENTARY DINUCLEOSIDE PHOSPHATE STRANDS WITH WEAK SEQUENCE PREFERENCES IN BINDING. STEREOCHEMISTRY OF INTERACTION DIFFERS BETWEEN NON-ALTERNATING PURINE-PURINE SEQUENCES AND ALTERNATING PYRIMIDINE-PURINE OR PURINE-PYRIMIDINE SEQUENCES IN HAVING 9-AMINOACRIDINE STACKED WITH PURINES OF 1 STRAND RATHER THAN STRADDLING PURINES ON OPPOSITE STRANDS. DIFFERENCES IN STEREOCHEMISTRY COULD POSSIBLY BE DETERMINING FACTOR IN FRAMESHIFT SEQUENCE SPECIFICITY. [R14] *9-AMINOACRIDINE STRONGLY INHIBITED IN VITRO THE DNA-PRIMED RNA POLYMERASE OF ESCHERICHIA COLI. AMT BOUND TO DNA INCR WITH INCR INHIBITION, A STAGE WAS REACHED WHERE INCR IN CONCN STILL CAUSED AN INCR IN INHIBITION, WITH PRACTICALLY NO INCR IN AMT BOUND TO DNA. PLOTS OF RECIPROCAL RATES AGAINST RECIPROCAL OF DNA CONCN WERE LINEAR AND HAD A COMMON INTERCEPT WHEN 9-AMINOACRIDINE-HCL WAS PRESENT. SIMILAR RELATIONS WERE OBTAINED WHEN RECIPROCAL CONCN OF NUCLEOSIDE TRIPHOSPHATES WAS PLOTTED. OBSERVATIONS WERE INTERPRETED KINETICALLY IN TERMS OF COMPETITIVE INHIBITION OF THE ENZYME BY 9-AMINOACRIDINE HYDROCHLORIDE AND OF A KINETIC ROLE OF DNA ANALOGOUS TO ACTIVATION. THE INHIBITOR MOLECULES PROBABLY OCCUPY THE NUCLEOSIDE TRIPHOSPHATE SUBSTRATE OR THE BASES OF DNA, WHEN THESE BECOME ACCESSIBLE DURING COPYING PROCESS. [R15] *INCREASING CONCN (0 TO 600 UMOL) OF 9-AMINOACRIDINE GRADUALLY AND COMPLETELY INHIBITED THE TRANSCRIPTION OF CALF THYMUS DNA BY ISOLATED RAT LIVER RNA POLYMERASES I AND II. COMPLETION OF STRONG BINDING TO DNA TEMPLATE WAS NOT ALWAYS ASSOC WITH TOTAL ENZYME INHIBITION ATTAINABLE AT HIGHER CONCN. THIS INDICATES THAT INHIBITORY ACTION MAY INVOLVE ADDNL MECHANISMS OTHER THAN INTERCALATION INTO DNA. EVIDENCE IS PRESENTED FOR THE FIRST TIME THAT AMINOACRIDINES INTERFERE WITH ACTIVITY OF ISOLATED EUKARYOTIC DNA-DEPENDENT RNA POLYMERASES. [R16] INTC: *STUDY WAS DESIGNED TO TEST POSSIBILITY THAT ETHIONINE MIGHT ACT AS INHIBITOR OF CERTAIN DNA METHYLATION REACTIONS, INCL METHYLATION OF ADENINE RESIDUES WHICH IS ASSOC WITH PRODUCT OF ESCHERICHIA COLI DAM+ GENE AND PLAYS IMPORTANT PART IN MISMATCH REPAIR. IT WAS REASONED THAT INHIBITION OF GENE PRODUCT EQUIVALENT TO THE DAM+ GENE PRODUCT BY ETHIONINE IN SALMONELLA TYPHIMURIUM MIGHT MAKE THE CELLS PHENOTYPICALLY DAM-, IN WHICH CASE THEY SHOULD RESEMBLE THE ESCHERICHIA COLI DAM MUTANTS IN BEING HYPERMUTABLE BY 2-AMINOPURINE AND 9-AMINOACRIDINE. RESULTS SHOW THAT ETHIONINE DOES SLIGHTLY ENHANCE YIELD OF TRP+ REVERTANTS OBTAINED FROM BASE-PAIR SUBSTITUTION SALMONELLA TYPHIMURIUM STRAIN TRPE8 FOLLOWING TREATMENT WITH 2-AMINOPURINE, BUT THAT IT EXERTS VERY POWERFUL ANTIMUTAGENIC EFFECT IN CELLS OF STRAIN TA1537 TREATED WITH FRAMESHIFT MUTAGEN 9-AMINOACRIDINE. [R17] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-Infective Agents, Local; Fluorescent Dyes; Indicators and Reagents; Mutagens [R18] *AMINACRINE HYDROCHLORIDE EXERTS GERMICICAL ACTIONS AGAINST BOTH GRAM-POSITIVE AND GRAM NEGATIVE BACTERIA AND AGAINST FUNGI AND TRICHOMONADS. IT IS NOT INACTIVATED BY PUS, SECRETIONS, OR BODY FLUIDS. IN THE TREATMENT OF VAGINAL CANDIDIASIS, TRICHOMONIASIS, OR HAEMOPHILUS INFECTIONS ... [R19] *ITS PRINCIPAL USE IS IN THE TREATMENT OF INFECTIONS OF VAGINA AND EXOCERVIX, SUCH AS MONILIASIS, TRICHOMONAL VAGINITIS...OR AS PROPHYLACTIC AGENT IN VARIOUS GYNECOLOGICAL PROCEDURES. IN ADDITION, IT FINDS USE IN TREATMENT OF TINEA VERSICOLOR. IT HAS ALSO BEEN USED IN TREATMENT OF MASTITIS. [R3] *EXPTL USE: EVIDENCE IS PRESENTED TO SUPPORT USE AS A SAFE AND EFFECTIVE SURGICAL IRRIGANT IN DENTISTRY. AVAIL LITERATURE CONFIRMS THAT IT IS A POTENT ANTIMICROBIAL AGENT, EFFECTIVE AGAINST WIDE RANGE OF MICROORGANISMS COMMONLY FOUND IN SEPTIC WOUNDS AND CAUSING MINIMAL TISSUE IRRITATION. ITS USE FOR ROUTINE ROOT CANAL IRRIGATION AND AS ANTISEPTIC IN MANAGEMENT OF MAXILLOFACIA ABSCESSES IS RECOMMENDED. [R20] +MEDICATION (VET): Antiseptic [R1] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Exposure was primarily via the dermal route from topical antiseptics and vaginal creams containing the broad spectrum antimicrobial chemical. [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 72 R2: BRAITHWAITE AW, BAGULEY BC; EXISTENCE OF AN EXTENDED SERIES OF ANTITUMOR COMPOUNDS WHICH BIND TO DEOXYRIBONUCLEIC ACID BY NONINTERCALATIVE MEANS; BIOCHEMISTRY 19: 1101 (1980) R3: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1102 R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8107 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 40 R6: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 108 R7: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 431 R8: KOCAN RM ET AL; IN VITRO TOXICITY OF EIGHT MUTAGENS/CARCINOGENS FOR THREE FISH CELL LINES; BULL ENVIRON CONTAM TOXICOL 23(1-2) 269 (1979) R9: BEIKIRCH H; INDUCTION OF UNSCHEDULED DNA SYNTHESIS BY CHEMICAL MUTAGENS IN TESTICULAR CELLS OF THE MOUSE IN VITRO; ARCH TOXICOL 37: 195 (1977) R10: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproduction and Fertility Assessment of 9-Aminoacridine Hydrochloride (CAS# 134-50-9) in CD-1 Mice When Administered in Feed, NTP Study No. RACB84042 (December 1985) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R11: LOECHLER E ET AL; THE USE OF SALMONELLA BACTERIOPHAGE P22 TO STUDY THE MULTIPLE MECHANISMS OF ACRIDINE-INDUCED DAMAGE; NATO CONF SER 1, 5A(IN VITRO TOXIC TEST ENVIRON AGENTS: CURR FUTURE POSSIBILITIES, PT A) 79 (1983) R12: REUBEN J ET AL; STRUCTURE OF MUTAGEN NUCLEIC ACID COMPLEXES IN SOLUTION: PROTON CHEMICAL SHIFTS IN 9-AMINOACRIDINE COMPLEXES WITH DG-DC, DC-DG, AND DA-DT-DG-DC-DA-DT; BIOCHEMISTRY 17(14) 2915 (1978) R13: YEH JZ; DYNAMICS OF 9-AMINOACRIDINE BLOCK OF SODIUM CHANNELS IN SQUID AXONS; J GEN PHYSIOL 73(1) 1 (1979) R14: YOUNG PR, KALLENBACH NR; BINDING OF 9-AMINOACRIDINE TO DEOXYDINUCLEOSIDE PHOSPHATES OF DEFINED SEQUENCE: PREFERENCES AND STEREOCHEMISTRY; J MOL BIOL 145(4) 785 (1981) R15: ANICHOLSON BH, PEACOCKE AR; THE INHIBITION OF RIBONUCLEIC ACID POLYMERASE BY ACRIDINES; BIOCHEM J 100: 50 (1966) R16: ZONCHEDDU A ET AL; INHIBITION OF ISOLATED RAT LIVER RNA POLYMERASES I AND II BY AMINOACRIDINES; EXPERIENTIA 36: 1151 (1980) R17: PODGER DM ET AL; ETHIONINE ABOLISHES MUTAGENESIS BY 9-AMINOACRIDINE (BUT NOT BY 2-AMINOPURINE) IN SALMONELLA PLATE TESTS; MUTAT RES 119(2) 113 (1983) R18: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R19: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 980 R20: SCHMITZ JP; 9-AMINOACRIDINE--ITS PRESENT STATUS AND CURRENT RECOMMENDATIONS FOR USE AS A SURGICAL AND ENDODONTIC IRRIGANT IN DENTISTRY; ORAL SURG 50(3) 273 (1980) R21: Department of Health and Human Services/National Toxicology Program; 9-Aminoacridine Hydrochloride: Reproduction and Fertility assessment in CD-1 Mice When Admin in Feed NTP 86-022 (1985) RS: 17 Record 318 of 1119 in HSDB (through 2003/06) AN: 5012 UD: 200303 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ETHYLENE-GLYCOL- SY: *ATHYLENGLYKOL- (GERMAN); *1,2-DIHYDROXYETHANE-; *Dowtherm-; *Dowtherm-Sr-1-; *1,2-ETHANDIOL-; *ETHANE-1,2-DIOL-; *ETHYLENE-ALCOHOL-; *ETHYLENE-DIHYDRATE-; *Fridex-; *GLYCOL-; *2-HYDROXYETHANOL-; *Lutrol-9-; *MACROGOL-400-BPC-; *MEG-; *MONOETHYLENE-GLYCOL-; *NCI-C00920-; *Norkool-; *Ramp-; *Tescol-; *Ucar-17- RN: 107-21-1 MF: *C2-H6-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPD ON LARGE SCALE BY HYDRATION OF ETHYLENE OXIDE. [R1] *(1) AIR OXIDATION OF ETHYLENE FOLLOWED BY HYDRATION OF THE ETHYLENE OXIDE FORMED (2) ACETOXYLATION, (3) FROM CARBON MONOXIDE AND HYDROGEN (SYNTHESIS GAS) FROM COAL GASIFICATION, (4) OXIRANE PROCESS. [R2] *Two methods are presently used for the production of ethylene glycol: one uses ethylene chlorohydrin as an intermediate; a second, more recent innovation, uses the reaction of ethylene with oxygen and water. [R3] FORM: *Grades or purity: Industrial grade: Low-conductivity grade. [R4] MFS: *BASF Corporation, 3000 Continental Drive-North, Mount Olive, NJ 07828-1234 (201)426-2600. Consumer Products and Life Science Division. Automotive Products. Production Site: Geismar, LA 70734. [R5, 590] *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48640, (517) 636-1000; Production site: Plaquemine, LA 70764 [R5, 590] *Eastman Kodak Company, Hq, 343 State St, Rochester, NY 14650, (716) 724-4000; Eastman Chemical Products, Inc, PO Box 431, Kingsport, TN 37662; Texas Eastman Company Division; Production site: Longview, TX 75607 [R5, 590] *Formosa Plastics Corporation USA, 9 Peach Tree Road, Livingston, NJ 07039 (201) 992-2090. Production Site: Point Comfort, TX 77978 [R5, 590] *Hoechst Celanese Corporation, Hq, Route 202-206 North, Somerville, NJ 08876, (201) 231-2000; Hoechst Celanese Chemical Group, Inc, 1601 West LBJ Freeway, Dallas, TX 75381-9005; Production site: Clear Lake, TX 77058 [R5, 591] *Huntsman Corporation, 2000 Eagle Gate Tower, Salt Lake City, UT 84111 (801)532-5200. Production Site: 6001 Highway 366, Port Neches, TX 77651 [R5, 590] *Shell Oil Company, Hq, One Shell Plaza, PO Box 2463, Houston, TX 77252-2463, (713) 241-6161; Shell Chemical Company, division (address same as Hq); Production site: Geismar, LA 70734 [R5, 590] *Sun Company, Inc., 1801 Market Street, Philadelphia, PA 19103 (215)977-3451. Production Site: Brandenburg, KY 40108 [R5, 590] *Union Carbide Corporation, Hq, Old Ridgebury Road, Danbury, CT 06817; (203) 794-2000; Industrial Chemicals Division; Industrial Chemicals Division; Production sites: Taft, LA 70057; Seadrift, TX 77983 [R5, 590] *Occidental Petroleum Corporation, Hq, 10889 Wilshire Blvd, Suite 1500, Los Angeles, CA 90024, (213) 879-1700; Petrochemicals Division, Occidental Tower, 5005 LBJ Freeway, Dallas, TX 75244 (214)404-3800. Production Site: Bayport, TX 77000 [R5, 590] *PD Glycol, Hq, Gulf States Road, Beaumont, TX 77707, (409) 838-4521; Production site: Beaumont, TX 77704 [R5, 590] OMIN: *29th highest-volume chemical produced in the US (1985) [R6] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R7] *Antifreeze in cooling and heating systems; in hydraulic brake fluids; indust humectant; ingredient of electrolytic condensers (where it serves as solvent for boric acid and borates). Solvent in the paint and plastics industries. In the formulation of printers' inks, stamp pad inks, and inks for ball-point pens. Softening agent for cellophane. Stabilizer for soybean foam used to extinguish oil and gasoline fires. In the synthesis of safety explosives, glyoxal, unsaturated ester type alkyd resins, plasticizers, elastomers, synthetic fibers (Terylene, Dacron) and synthetic waxes. [R8] *VEHICLE FOR PHARMACEUTICAL PREPN, FOOD EXTRACTS AND FLAVORING ESSENCES; COMPONENT OF SKIN LOTIONS, ADDED TO VARIOUS POWDERS; SUBSTITUTE FOR GLYCERIN [R9, 595] *Coolant and antifreeze; asphalt-emulsion paints; heat-transfer agent; low-pressure laminates, brake fluids; glycol diacetate; polyester fibers and films, low-freezing dynamite; solvent, extractant for various purposes, solvent mixture for cellulose esters and ethers, especially cellophane; cosmetics (up to 5%), lacquers, alkyd resins, printing inks, wood stains, adhesives; leather dyeing, textile processing, tobacco; ingredient of deicing fluid for airport runways; humectant; ballpoint pen inks; foam stabilizer. [R2] CPAT: *CHEMICAL PROFILE: Ethylene glycol. Uses: 1993: Antifreeze, 42%; polyester fiber, 27%; PET bottles and other packaging materials, 12.5%; PET film, 6%; miscellaneous industrial and PET resin uses, 12.5%. [R10] *CHEMICAL PROFILE: Ethylene glycol. Demand: 1992: 7.4 billion pounds; 1993: 7.5 billion pounds; 1997: 8 billion pounds. (Includes exports, which producers place at 2.2 billion pounds, but not imports, which total 400 million pounds.) [R10] *Polyester: fibers, 30%; polyester: plastics, film, bottles, 20%; antifreeze, 40%; miscellaneous, 10% (1984) /Estimate/ [R11] *CHEMICAL PROFILE: Ethylene Glycol. Antifreeze, 43%; polyester fiber, 26%; exports, 12%; PET bottles, 7%; PET film, 4%; miscellaneous industrial and PET resin uses, 8% (1986). [R12] *CHEMICAL PROFILE: Ethylene glycol. Demand: 1986: 4.7 billion lb; 1987: 4.8 billion lb; 1991 /projected/: 5.2 billion lb. (Includes exports. In addition, 346 million lb were imported in 1986.) [R12] *CHEMICAL PROFILE: Ethylene glycol. Antifreeze, 39%; polyester fiber, 26%; exports, 12%; PET bottles, 9%; PET film, 5%; miscellaneous industrial and PET resin uses, 9% (1989). [R13] *CHEMICAL PROFILE: Ethylene glycol. Demand: 1989: 5.1 billion lb; 1990 /projected/: 5.2 billion lb; 1994 /projected/: 5.6 billion lb. (Includes exports, but not imports, which totaled 370 million lb last year.) [R13] PRIE: U.S. PRODUCTION: *(1981) 1.84X10+12 G [R14] *(1977) 1.67X10+12 G [R15] *(1982) 1.96X10+12 G [R15] *(1983) 4,424,515,000 lb [R16] *(1985) 1.89X10+12 g [R17] *(1990) 5.07 billion lb [R18] *(1991) 4.81 billion lb [R19] *(1992) 5.13 billion lb [R20] *(1993) 5.23 billion lb [R20] U.S. IMPORTS: *(1977) 2.93X10+10 G [R15] *(1982) 1.70X10+10 G [R15] *(1985) 1.30X10+11 g [R21] U.S. EXPORTS: *(1978) 5.68X10+10 G [R15] *(1983) 3.16X10+10 G [R15] *(1985) 2.70X10+11 g [R22] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +Clear, colorless, syrupy, liquid [Note: A solid below 9 degrees F]. [R23, 136] ODOR: +Odorless. [R23, 136] TAST: *SWEET TASTE [R2] BP: *197.6 DEG C @ 760 MM HG [R24] MP: *-13 DEG C [R24] MW: *62.07 [R24] DEN: *1.1088 @ 20 DEG C/4 DEG C [R24] HTC: *-7259 BTU/LB= -4033 CAL/G= -168.9X10+5 J/KG [R4] HTV: *191 cal/g; 344 BTU/lb @ 760 mm Hg [R25] OWPC: *Log Kow= -1.36 [R26] SOL: *MISCIBLE WITH WATER, LOWER ALIPHATIC ALCOHOLS, GLYCEROL, ACETIC ACID, ACETONE AND SIMILAR KETONES, ALDEHYDES, PYRIDINE, SIMILAR COAL TAR BASES [R1]; *SLIGHTLY SOL IN ETHER (1:200); PRACTICALLY INSOL IN BENZENE AND ITS HOMOLOGS, CHLORINATED HYDROCARBONS, PETROLEUM ETHER, OILS [R1] SPEC: *INDEX OF REFRACTION: 1.43312 @ 20 DEG C/D; 1.43063 @ 25 DEG C/D [R8]; *IR: 299 (Sadtler Research Laboratories IR Grating Collection) [R27]; *NMR: 6406 (Sadtler Research Laboratories Spectral Collection) [R27]; *MASS: 44 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R27]; *Intense mass spectral peaks: 33 m/z, 43 m/z, 62 m/z [R28] SURF: *48.4 DYNES/CM @ 20 DEG C [R1] VAPD: *2.14 (Air= 1) [R29] VAP: *0.092 mm Hg @ 25 deg C /from experimentally determined coefficients/ [R30] VISC: *26 CP @ 15 DEG C; 21 CP @ 20 DEG C; 17.3 CP @ 25 DEG C [R1] OCPP: *% IN SATURATED AIR: 0.017 @ 25 DEG C; 1 PPM IS EQUIV TO 2.54 MG/CU M; 1 MG/L IS EQUIV TO 365.0 PPM @ 25 DEG C, 760 MM HG [R31, 3818] *SPECIFIC HEAT @ 20 DEG C: 0.561 CAL/G/DEG C [R1] *Saturation concn in air: Less than 0.34 g/cu m at 20 deg C, 0.65 g/cu m at 30 deg C. [R32, 646] *Ratio of specific heats of vapor (gas): 1.095. [R4] *HEAT OF SOLN -6.5 CAL/G OF SOLN @ 17 DEG C WHEN 37 PARTS MIXED WITH 63 PARTS WATER (WT/WT) [R1] *HYGROSCOPIC, ABSORBS TWICE ITS WT OF WATER @ 100% RELATIVE HUMIDITY [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and breathing protection is needed. [R33, p. 325-50] +Flammability: 1. 1= Materials that must be preheated before ignition will occur, such as class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R33, p. 325-50] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R33, p. 325-50] FLMT: +LOWER 3.2% BY VOL [R33, p. 325-50] FLPT: +111 DEG C (CLOSED CUP) [R33, p. 325-50] *116 deg C (closed cup) /Commercial material/ [R34] AUTO: +748 DEG F (398 DEG C) [R33, p. 325-50] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use "alcohol" foam, dry chemical or carbon dioxide. Keep run-off water out of sewers and water sources. [R35] REAC: *Contact of aq ethylene glycol soln with DC-energized silvered copper wires causes ignition of the latter. Bare copper or nickel- or tin-plated wires were inert and silver-plated wire can be made by adding benzotriazole as a metal deactivator to the coolant soln. This problem of electrical connector fires in aircraft has been studied in detail to identify the significant factors. [R36, 304] *A mixture of phosphorus(V) sulfide, ethylene glycol, and hexane in a mantle-heated flask spontaneously overheated and exploded at an internal temperature of about 180 deg C. It had been intended to maintain the reaction temp at 60 deg C, but since alcoholysis of the sulfide is exothermic, presence of the heating mantle prevented the dissipation of heat, and the reaction accelerated continuously until explosive decomposition occurred. [R36, 1441] *Mixing of equal weights /of ethylene glycol and potassium dichromate/ at ambient temp uneventful, but at 100 deg C an exotherm of 170 deg C occurs. [R36, 1075] +Mixing ethylene glycol and chlorosulfonic acid in a closed container caused the temp and pressure to incr. [R33, p. 491-81] +Mixing ethylene glycol and oleum in a closed container caused the temp and pressure to incr. [R33, p. 491-82] +Strong oxidizers, chromium trioxide, potassium permanganate, sodium peroxide (Note: hygroscopic (i.e., absorbs moisture from the air)). [R23, 136] ODRT: *Odor index: 3 at 20 deg C [R32, 646] SERI: *Liquid is irritating to eyes and skin; Vapors are nonirritating to the eyes and throat. [R4] EQUP: */Breakthrough times greater than one hour reported by (normally) two or more testers for natural rubber (nat Rub), neoprene (neop), nitrile rubber (nitrile), polyethlene (PE), and polyvinyl chloride (PVC). Some data suggesting breakthrough times of approximately an hour or more for neoprene/natural rubber (Neop/Nat Rub) and polyvinyl alcohol (PVA). No data for butyl rubber (Butyl) Neoprene/styrene-butadiene (Neop/SBR), nitrile rubber/polyvinyl chloride (Nitrile/PVC), chlorinated polyethylene (CPE), polyurethane (PU), styrene-butadiene rubber (SBR), and viton. [R37] +Wear appropriate personal protective clothing to prevent skin contact. [R23, 136] +Wear appropriate eye protection to prevent eye contact. [R23, 136] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to top leak if without undue personnel hazard. [R35] *Personnel protection: Keep upwind. Avoid breathing vapors. ... Avoid bodily contact with the material. [R35] +Contact lenses should not be worn when working with this chemical. [R23, 137] +The worker should immediately wash the skin when it becomes contaminated. [R23, 136] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R23, 136] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R23, 136] STRG: *Temperature: Ambient [R4] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +A4; Not classifiable as a human carcinogen. [R38] ANTR: *Presence of ethanol will therefore inhibit formation of toxic metabolites from methanol and ethylene glycol. [R39] *Treatment should include gastric lavage for removal of residual ethylene glycol, correction of dehydration and shock, and management of fluid balance in the presence of pulmonary edema, which might be due to the toxic effects of ethylene glycol metabolites or the sodium overload. In addition, hypocalcemia should be corrected with calcium chloride, depending on serum calcium levels. The mainstay of treatment, however, is correction of the metabolic acidosis, which often requires massive doses of sodium bicarbonate administration (as much as 1000 to 2000 ml); such obligatory sodium administration requires early institution of hemodialysis. [R40, 697] *Ethylene glycol has long been recognized as a potentially lethal poison and remains available today as automotive antifreeze and windsheld deicer fluids. Ethylene glycol is rapidly absorbed from the gastrointestinal tract, with peak levels measured one to four hours after ingestion. Metabolism of the parent compound and the production of several organic acids are responsible for the metabolic acidosis observed in ethylene glycol poisoning. Target organ cellular damage is seen in the kidney, brain, myocardium, pancreas, and blood vessel walls. Renal tubular deposition of calcium oxalate crystals is felt to be responsible for the development of the severe renal injury which may accompany ethylene glycol ingestion. The clinical course is quite varied and includes inebriation, hematuria, cardiorespiratory compromise, and neurologic effects. Prompt diagnosis and initiation of treatment, including ethanol therapy and hemodialysis, is necessary to ameliorate the effects of ethylene glycol ingestion. Two cases of ethylene glycol poisoning, one accidental and one intentional, are reviewed. [R41] *We report the cases of two patients who developed cranial nerve palsies after drinking ethylene glycol. A 33-year-old man developed multiple cranial nerve deficits nine days after the ingestion of ethylene glycol in a suicide attempt. Clinical findings included profound bilateral cranial nerve VII palsies and severe dysfunction of cranial nerves IX and X. The neuropathy occurred despite treatment with hemodialysis. The dysphagia completely cleared within two weeks, but at six months a severe bilateral cranial nerve VII dysfunction persisted. A 22-year-old man undergoing hemodialysis for ethylene glycol-induced renal failure developed bilateral cranial nerve VII dysfunction 14 days after ingestion. At a three month follow-up, the patient demonstrated only moderate functional recovery. The etiology of the cranial nerve deficits is unknown but may be related to oxalate crystal deposition of ethylene glycnl-induced pyridoxine dysfunction. [R42] MEDS: *Ethylene glycol is a toxic chemical found in antifreeze and heat exchangers. Standard therapy for ethylene glycol intoxication in administration of ethanol to inhibit its metabolism by alcohol dehydrogenase. Studies indicate 1,3-butylene glycol binds to alcohol dehydrogenase more efficiently than ethylene glycol and is orally less toxic than ethylene glycol or ethanol. Male rats were divided into 5 groups of 6 animals. Groups received by oral intubation a single dose of ethylene glycol (32 mmole/kg), 1,3-butylene glycol (39 mmole/kg) initially and every 6 hr up to 72 hr, ethanol (39 mmole/kg) initially and every 6 hr up to 72 hr, or ethylene glycol initially and then either 1,3-butylene glycol or ethanol every 6 hr up to 72 hr. Administration of ethanol produced hepatotoxicity and pulmonary pathology as indicated by changes in clinical chemistry, urinalysis, and histopathology, while 1,3-butylene glycol did not. Neither ethanol nor 1,3-butylene glycol produced any apparent nephrotoxicity. Ethanol produced ataxia, lethargy and central nervous system depression while 1,3-butylene glycol did not. 1,3-butylene glycol produced a higher concentration of urinary ethylene glycol indicating a better inhibition of alcohol dehydrogenase metabolism of ethylene glycol. Ethanol produced a higher ethylene glycol blood concentration than 1,3-butylene glycol. Ethanol's higher ethylene glycol blood concentration may be partially attributed to dehydration and a decreased urine output as well as inhibition of alcohol dehydrogenase metabolism. Ethanol produced mortality in all animals prior to 72 hr. The ethylene glycol/ ethanol combination produced mortality more quickly due to additive toxicity of the combination. Lack of any significant toxicity produced by 1,3-butylene glycol and the production of significant toxicities by ethanol indicates that 1,3-butylene glycol is potentially a better antidote than ethanol. [R43] *Potentially fatal ethylene glycol intoxication in an adult with normal renal function was treated with 4-methylpyrazole administered three hours after the incident occurred. The plasma ethylene glycol concentration was 3.5 g 1-1 on admission. The metabolic acidosis present on admission resolved within four hours, and the subsequent clinical course was uneventful. The apparent plasma half-life of ethylene glycol was 16 hr and the mean renal and plasma clearances of ethylene glycol were 24 and 25 ml/min, respectively. These results support the hypothesis that complete blockade of hepatic metabolism of ethylene glycol is achieved by 4-methylpyrazole. The only side-effect observed as a result of treatment was a transient slight increase in serum transaminase activity. [R44] HTOX: *... FATAL CASE /DESCRIBED/ IN WHICH 1/4 TO 1/2 PINT OF ANTIFREEZE SOLN WAS INGESTED; ACUTE MENINGOENCEPHALITIS FOLLOWED BY ANURIA. DEATH FROM RENAL FAILURE RESULTED AFTER 12 DAYS. [R31, 3802] *In a study with human volunteers exposed 22 to 20 hr/day at mean daily concentrations of ethylene glycol ranging from 1.4 to 27 ppm for about 4 weeks, there were some complaints of throat irritation, mild headache, and low backache, but on the whole, the exposure was very well tolerated. The complaints became marked when the concentration of ethylene glycol within the exposure chamber was raised above 56 mg/cu m for part of a day. The most common complaint was irritation of the upper respiratory tract. ... Concentrations of about 80 ppm or more were intolerable, with a burning sensation along the trachea and a burning cough. The irritative phenomena became common when the concentration was raised to about 60 ppm. [R45] *... Poisoning in children from ingestion of ethylene glycol /is described. Dosage and age of children are not stated/. Ophthalmoscopically papilledema was evident, with indistinct borders to the optic nerve head and dark dilated retinal veins, owing to cerebral edema and very high cerebrospinal fluid pressure. [R46, 416] *A most unusual type of intoxication affecting eye movement occurred in a group of women working in the presence of vapor from ethylene glycol that was heated in open containers. Of 38 women exposed, nine were subject to attacks of unconsciousness of five to ten minutes' duration, occurring 2 or 3 times a wk while at work. These patients, and an additional 5 who were exposed but not subject to attacks of unconsciousness, had nystagmus, usually horizontal, but definitely rotatory in 2 cases. The nystagmus appeared to be of supranuclear origin with participation of the vestibular nuclei. The attacks ceased on discontinuing exposure. [R46, 417] *MEDULLA OBLONGATA SHOWED TOXIC CHANGES IN NERVE CELLS SIMILAR TO THOSE OF ANOXIA AS ALSO DID THOSE OF THE THALAMUS WITH PERIVASCULAR EDEMA, LEUKOCYTIC INFILTRATION, AND CRYSTALS, SIMILAR TO THOSE PRESENT IN SOME OF WALLS OF VESSELS. THE CORTEX ALSO SHOWED INJURY OF THE GANGLION CELLS, AND THE CEREBELLUM LEUKOCYTIC INFILTRATION, AND EOSINOPHILS IN THE PLASMA. [R9, 599] *THOSE WHO DIE FROM UREMIA /RESULTING FROM ETHYLENE GLYCOL EXPOSURE/ EXHIBIT MARKED RENAL PATHOLOGY, INCL DESTRUCTION OF EPITHELIAL CELLS, INTERSTITIAL EDEMA, FOCAL HEMORRHAGIC NECROSIS IN THE CORTEX, EXTENSIVE HYDROPIC DEGENERATION, NUMEROUS CELLULAR CASTS, AND OXALATE CRYSTALS IN CONVOLUTED TUBULES. [R47] *REPORTED CASE OF 19-YR-OLD MAN WHO DEVELOPED HEAVY CRYSTALLURIA, FOUND TO BE CALCIUM OXALATE MONOHYDRATE, AFTER INGESTING ETHYLENE GLYCOL. [R48] *Constitutes a hazard when ingested, eg, drinking antifreeze fluid. Transient stimulation of CNS followed by depression, vomiting, drowsiness, coma, respiratory failure, convulsions, and renal damage, which may proceed to anuria, uremia, and death. [R8] *Ingestion of ethylene glycol can result in intoxication, resembling that due to alcohol with ataxia, drowsiness, and slurred speech, possibly stupor, coma, convulsions, and death. [R49] *Although oxalate normally is a minor metabolic product of ethylene glycol metabolism, urinary oxalate crystals are a common, but not invariable, feature of ethylene glycol intoxication. There are two forms of urinary calcium oxalate crystals: the octahedral or tent-shaped form of the dihydrate crystals, and the prism or dumbell-shaped monohydrate. The latter form is stable under normal physiologic conditions; the dihydrate form appears only during high urinary calcium and oxalate concentrations, as seen in ethylene glycol poisoning. The dihydrate form can transform into the monohydrate form. [R50, 807] *... Humans /exposed/ to vapor or spray of ethylene glycol for 4 weeks at a concentration of 17 mg/cu m produced no ill effects. [R31, 3823] *Inhalation is not generally associated with toxicity, although cases of chronic poisoning with nystagmus and recurrent attacks of unconsciousness have been reported in factory workers exposed to vapors of ethylene glycol. [R40, 695] *We describe a case of 2 siblings aged 2 1/2 and 3 1/2 yrs accidentally poisoned by ethylene glycol ingestion. We found estimating the level of ethylene glycol in plasma by calculation of osmolar gap too insensitive to be of value and advocate the availability of a specific method. In our study only one of the 2 children had a toxic level of ethylene glycol but assay by conventional assay and by proton magnetic resonance spectroscopy of toxic metabolites viz glycolate, glyoxylate and oxalate showed both to be excreting grossly elevated levels. This indicates the desirability of assaying the toxic metabolites of the glycol as well as the parent compound in assessing ingestions. [R51] *The authors report the case of a man 49 years of age with near-fatal ethylene glycol poisoning. Detection of calcium oxalate monohydrate crystals in the urine was the only real-time confirmation of the diagnosis. The case illustrates that, if the toxin has already been metabolized, familiarity with the appearance and significance of this unusual form of calcium oxalate crystal may be the key to an accurate diagnosis. [R52] *A 6 month-old girl was hospital on three occasions for irritability, vomiting, acidosis, and hypotonia. During the third hospitalization hyperglycinemia a urinary glycolic acid were detected. Ethylene glycol was discovered in the infant's blood and bottled formula. Clinicians must consider ethylene glycol intoxication as a cause of recurrent infantile metabolic acidosis. [R53] *A case of intentional ethylene glycol poisoning presenting as an inborn error of metabolism is reported in a 6 month-old female infant who was hospitalized on 3 occasions; during the third hospitalization, ethylene glycol was discovered in the infant's blood and bottled formula. It was concluded that ethylene glycol intoxication must be considered as a cause of recurrent infantile metabolic acidosis. [R54] NTOX: *... RATS /WERE MAINTAINED/ FOR 2 YR ON DIETS CONTAINING 1 and 2% OF ETHYLENE GLYCOL. SHORTENED LIFE SPAN, CALCIUM OXALATE BLADDER STONES, SEVERE RENAL INJURY PARTICULARLY OF TUBULES, AND CENTROLOBULAR DEGENERATION OF LIVER AT BOTH LEVELS /WERE DETECTED/. [R31, 3820] *RATS /WERE ADMIN SC/ DAILY DOSES OF 4 ML OF ETHYLENE GLYCOL DILUTED WITH WATER. PROGRESSIVE HEMOLYTIC ANEMIA AND VARIETY OF CHANGES IN THE LEUKOCYTES WERE SEEN. OTHER FINDINGS INCL RENAL LESIONS, CHANGES IN LIVER AND SPLEEN, AND IRON DEPOSITS IN ALL ORGANS. ... /ETHYLENE GLYCOL WAS GIVEN/ (DOSE NOT STATED) PARENTERALLY TO MICE ... /IN WHICH/ A HEMOLYTIC EFFECT /WAS OBSERVED/, BUT /IT WAS/ CONCLUDED THAT DEATH WAS DUE TO ... /CNS DEPRESSANT/ EFFECT AND TO RENAL INSUFFICIENCY, NOT TO THE HEMOLYTIC EFFECT. [R31, 3823] *THE CONSTANT SYMPTOMS /OF ETHYLENE GLYCOL INTOXICATION IN DOGS AND CATS/ ARE DEPRESSION, ATAXIA AND COMA, BUT POLYDIPSIA, VOMITING AND CONVULSIONS MAY OCCUR. MOST CHARACTERISTIC POST MORTEM FINDING IS PRESENCE OF BIREFRINGENT POLARIZING CRYSTALS OF CALCIUM OXALATE IN RENAL TUBULES AND BLOOD VESSELS OF BRAIN; KIDNEY MAY CONTAIN OVER 6% OF CALCIUM OXALATE ON DRY-WT BASIS. [R55] */ETHYLENE GLYCOL-TREATED/ PIGS SHOWED MUSCULAR FLACCIDITY, ABDOMINAL DISTENSION, STERNAL RECUMBENCY AND DEATH; MOST OF INTERNAL ORGANS WERE EDEMATOUS, WITH CALCIUM OXALATE CRYSTALS IN KIDNEY. POULTRY SHOWED DROWSINESS, ATAXIA, DYSPNEA AND TORTICOLLIS WITH RUFFLED FEATHERS AND WATERY DROPPINGS. THERE WERE OXALATE CRYSTALS IN KIDNEYS. [R55] *THE EFFECT OF SPLASH CONTACT OF ETHYLENE GLYCOL WITH THE EYE HAS BEEN FOUND WITHOUT EXCEPTION IN TESTS ON RABBITS TO RESULT IN IMMEDIATE MODERATE SYMPTOMS OF DISCOMFORT WITH MILD TEMPORARY CONJUNCTIVAL REACTION, BUT NO SIGNIFICANT CORNEAL DAMAGE. [R46, 417] *... /ETHYLENE GLYCOL/ INHALATION STUDIES ON RATS AND MICE EXPOSED 8 HR/DAY FOR 16 WK TO CONCN RANGING FROM 0.35 TO 3.49 MG/LITER. AT HIGH LEVELS, THIS PERHAPS CONSISTED OF BOTH VAPORS AND MIST (DROPLETS). NO INJURIOUS EFFECTS WERE REPORTED. [R56] *... Mice and rats /were gavaged/ on days 6 through 15 with doses of up to 3,000 and 5,000 mg/kg respectively. At dose levels of 750 mg in the mice and 1250 mg/kg in rats increased defects were found. They consisted of cleft palates, facial defects, neural tube closure defects and other visceral and skeletal anomalies. [R57] *ACUTE OCULAR TOXICITY OF VARIOUS CONCN OF ETHYLENE GLYCOL IN NORMAL AND IRRITATED RABBIT EYES WAS EVALUATED. NORMAL AND IRRITATED EYES RESPONDED SIMILARLY SO THAT MAX NONDAMAGING CONCN WAS 5%. [R58] *0.05 ML OF ETHYLENE GLYCOL CAUSED NO MALFORMATIONS IN SURVIVING CHICK EMBRYOS AFTER INJECTION INTO AIR CHAMBER EITHER PRIOR TO OR ON THE FOURTH DAY OF INCUBATION, OR AFTER INJECTION INTO YOLK SAC ON THE FOURTH DAY OF INCUBATION. [R59] *ETHYLENE GLYCOL WAS ADMIN ORALLY TO MALE RATS (2 ML/KG FOR 6 DAYS). DECR OBSERVED IN CALCIUM AND PHOSPHORUS OF BONE, SERUM CALCIUM, URINARY PHOSPHORUS AND CITRIC ACID. SERUM PHOSPHORUS, ALKALINE PHOSPHATASE ACTIVITY AND URINARY CALCIUM AND HYDROXYPROLINE WERE INCR. BONE DEMINERALIZATION IS AN ATTEMPT TO MAINTAIN SERUM CALCIUM CONCN. THE HYPERPHOSPHATEMIA OBSERVED AFTER ETHYLENE GLYCOL ADMIN WAS RESULT OF NEPHROTOXIC EFFECT OF THE GLYCOL. [R60] *No significant mutagenic activity was observed using the Ames test in the Salmonella typhimurium (TA1538, TA98, TA1537, AND TA100) mutagenicity with or without microsomal activation. Concn ranged from 10 ug to 100 mg/ml for all compounds tested. [R61] *Tests performed on lamprey larvae at 5.0 ppm, conducted for a 24-hr period at water temperature of 55 deg F, indicated no effect. [R62] *... Rat /were maintained/ for 2 years on diets containing 1 and 2 percent ethylene glycol. The findings were those of shortened life span, calcium oxalate bladder stones, severe renal injury, particularly of the tubules, and centrolobular degeneration of the liver at both levels. [R31, 3820] *... Three rhesus monkeys /were used in / ... 3 year feeding studies. The two males were fed a diet containing 0.2 percent ethylene glycol, which equates to an average daily dose between 0.02 and 0.07 g/kg. The one female was fed a diet containing 0.5 percent, which equates to an average daily dose between 0.14 and 0.17 g/kg. No adverse effects were observed and no oxalate crystals were found in the urine. [R31, 3822] *... The median lethal concentration for ethylene glycol was 7.5 percent when given to chickens in their drinking water for 2 weeks. Those fed 27.9 g/l or more developed renal oxalosis. Those fed less than 27.9 g/l developed no adverse effects. [R31, 3822] *... One drop of ethylene glycol (0.05 ml) /was placed onto rabbit eyes/ every 10 min for 6 hr (36 applications). ... A concentration of ethylene glycol of 4 percent in a balanced salt solution caused mild conjunctival redness, mild chemosis, minor flare, and iritis. A concentration of 0.4 percent caused no detectable effects beyond those seen with the control balanced salt solution. [R31, 3823] *Levels of 265 mg/cu m caused no ocular damage to the eyes of chimpanzees; however, rabbits and rats developed severe eye irritation, edema of the lids, and some corneal opacity when exposed several days to 12 mg/cu m. [R31, 3823] *... Four chimpanzees were exposed for 28 days to saturated vapors of ethylene glycol (256 mg/cu m) at 5 psi in an atmosphere consisting of 68 percent oxygen and 32 percent nitrogen, and observed only minor depression of the white blood cell count 2 weeks after termination of exposure. [R31, 3825] *... No chemically related tumors /were found/ when ethylene glycol was injected into Fischer rats subcutaneously twice a week for 52 weeks, then held for 18 months for examination. [R31, 3826] *An effort was made to determine a no observed effect level for the developmental toxicity of ethylene-glycol when given by gavage to mated CD-1-mice and CD-rats. Dams were given ethylene glycol on gestation days six to 15. Rats were dosed with 0, 150, 500, 1,000, or 2,500 mg/kg/day. Mice were dosed with 0, 150, 500, or 1,500 mg/kg/day. Rats and mice were killed on gestation days 21 or 18, respectively. Maternal liver, kidney, and gravid uterine weights were determined at necropsy. Live and dead fetuses and resorption sites were recorded. Live fetuses from both species were studied for variations and malformations. Liver and kidney weights were increased in animals receiving 2,500 mg/kg/day. Relative liver weights were also increased at l,OOO mg/kg/day. Reduced body weights, duplicated or missing ribs, centra, and arches, and poor ossification were also observed in rat fetuses at l,OOO mg/kg/day. In mice, there was no apparent treatment related maternal toxicity. In mouse fetuses, effects were noted at 1,500 mg/kg/day and included reduced body weights, fused ribs and arches, poor ossification in thoracic and lumbar centra, and increased occurrence of an extra (fourteenth) rib. At 500 mg/kg/day, small reductions in fetal weight and increased rates of fourteenth ribs were noted. The authors conclude that the no observed effect levels for developmental toxicity are 500 mg/kg/day for rats and 150 mg/kg/day for mice, suggesting that the mice are more susceptible than rats to the teratogenic effect of ethylene glycol. The no observed effect levels determined in this study are consistent with those reported for whole body aerosol exposure. The mouse appears to be the most developmentally susceptible species among rats, rabbits, and mice. [R63] *Ethylene glycol was given orally in 6 crossbred male cow calves a 12 ml/kg b wt for 2 days continuously to develop acute nephrotoxicity and monitor blood chemicals profile in affected calves. Progressive depression, hypersalivation, ataxia, incoordination, staggering gait grinding of teeth, recumbency, coma, convulsions and death were prominent symptoms in affected calves. Respiration and pulse rates were increased whereas body temperature and rumen movements were low. Haematological investigations revealed increase in total erythrocyte count, platelets count and packed cell volume till death and total leukocyte count up to day 3 which decreased on day 4 and 5. These calves revealed azotaemia, reduction in calcium, chloride and potassium and rise in sodium and AST, ALT and alkaline phosphatase enzymes activity. [R64] *Ethylene glycol has a wide variety of industrial uses, but its most common consumer use is as an antifreeze and a deicing fluid. Therefore, skin contact is considered the most common exposure route for people. Because of this, ethylene glycol was evaluated for its skin penetration characteristics using an established in vitro technique. Full-thickness skin preparations from female CD-l mice and female human abdominal skin were used. Skin preparations were placed in a dynamic, flow-through design skin penetration apparatus. (l4C) ethylene glycol was applied undiluted or as a 50% aqueous solution (antifreeze use concentration) at a target dosage of 22-28 mg ethylene glycol/cu m of skin surface in an "infinite dose" manner. The time course of 14C penetration was measured for 6 hr. The lag times before steady-state rates of penetration were attained were three times longer for human skin (3 hr) than that for mouse skin (1 hr). For mouse skin, the steady-state rate of penetration for undiluted ethylene glycol (0.52 mg/cu cm/hr) was approximately twice that of the 50% aqueous ethylene glycol solution (0.22 mg/cu cm/hr), while the permeability constants (kp) were about the same hr). For human skin, the steadystate rate of penetration for undiluted ethyl glycol (0.013 Mg/cu cm/hr) was again approximately twice that of the 50 aqueous ethylene glycol solution (0.007 mg/cu cm/hr), while the permeability constants (kp) were again approximately the same (0.1be half for cutaneous exposure to 50% water solutions of ethylene glycol than for similar cutaneous exposure to undiluted ethylene glycol for both mice and humans. When these results are compared between species, the steady-state rates of penetration and permeability constants values of both the undiluted ethylene glycol and the 50% aqueous solution of ethylene glycol were 30-40 times less for human skin than those for mouse skin. In previous studies, ethylene glycol has been shown to cause maternal and developmental toxicity after repeated oral and, to a lesser extent, repeated inhalation exposures, but not after repeated dermal applications. Therefore, because the permeability of ethylene glycol through human skin is significantly less than that through mouse skin, it is highly unlikely that ethylene glycol would be toxic to humans if exposure was by the dermal route. [R65] *We describe an 18 year old man with acute renal failure due to inadvertent ingestion of antifreeze that contained ethylene glycol. A relatively small amount of ethylene glycol was ingested, but nausea and vomiting were observed soon after ingestion. During admission to a local hospital, consciousness became impaired and generalized convulsion was noted. He was transferred to our hospital because of rapid deterioration of renal function. Emergency hemodialysis was begun. The patient underwent one treatment session of hemodialysis each day, for a total of 8 hemodialytic sessions before his renal function recovered. Examination of the renal biopsy specimen revealed degeneration of the renal tubular epithelium and presence of intratubular calcium oxalate crystals. The clinical features of the patient were mild except for acute renal failure. These findings suggest that even a small amount of ethylene glycol will have toxic effects on the kidney. [R66] *A study was conducted with ethylene-glycol aerosol to determine whether inhalation will result in developmental toxicity in mice. Mated female CD-l-albino-mice were placed in chambers and whole body or nose only exposed at up to 2,100 mg/cu m or 2,500 mg/cu m ethylene glycol, respectively, for 6 hours per day from gestation days six through 15. All mice were killed on gestation days 18 for determinations of the morphological and reproductive effects of ethylene glycol exposure. Live fetuses were studied for structural alterations. Whole body exposure of mice to ethylene glycol aerosol at 2,100 mg/cu m resulted in maternal and developmental toxicity, including teratogenicity, and was consistent with findings from earlier studies. Exposure of mice to ethylene glycol aerosol during organogenesis by nose only procedures produced minimal maternal toxicity and developmental toxicity at 2,500 mg/cu m. One skeletal malformation, fused ribs, was also increased in incidence in this group. Nose only exposure to ethylene glycol at 1,000 mg/cu m resulted only in increased maternal absolute kidney weight. Whole body exposure to 2,100 mg/cu m ethylene glycol aerosol produced maternal toxicity and developmental toxicity including skeletal malformations and variations. The no observed adverse effect level for maternal toxicity from ethylene glycol via nose only exposure was 500 mg/cu m. The no observed effect level for development toxicity, including teratogenicity, was l,OOO mg/cu m in mice under the conditions of this study. [R67] *Ethylene glycol is a major industrial chemical, shown to be teratogenic at high doses by gavage in rodents. Since one route of industrial exposure is to the aerosol at high concentrations, timed-pregnant CD rats and CD-l mice were exposed, whole-body, to a respirable aerosol of ethylene glycol (mass median aerodynamic diameter, 2.3 microns) on gestational days 6 through 15 for 6 I-r per day at target exposure concentrations of 0, 150, 1000, or 2500 mg/cu m (analytical concentrations of 0, 119 + or - 13, 888 + or - 149, and 2090 + or - 244 mg/cu m, respectively), with 25 plug-positive animals per species per group. Clinical observations and maternal body weights were documented throughout gestation for both species. Maternal food and water consumption was measured in rats only throughout gestation. At scheduled necropsy (gestational days 21 for rats, gestational days 18 for mice), maternal animals were evaluated for body weight, liver weight, kidney weight, gravid uterine weight, number of ovarian corpora lutea, and status of implantation sites, ie, resorptions, dead fetuses, live fetuses. Fetuses were dissected from the uterus, counted, weighed, sexed, and examined for external, visceral, and skeletal malformations and variations. All rat dams survived to scheduled termination. Minimal maternal toxicity was indicated by a significant increase in absolute and relative liver weight at 2500 mg/cu m. Food and water consumption, maternal body weights and weight gain, and maternal organ weights (other than liver) were unaffected by exposure. Gestational parameters were unaffected by exposure, including pre- and post-implantation loss, livefetuses/litter, sex ratio, and fetal body weight/litter. There was no treatment-related increase in the incidence of any individual malformation, in the incidence of pooled external, visceral, or skeletal malformations, or in the incidence of total malformations by fetus or by litter. There were no increases in the incidence of external or visceral variations. Evidence of fetotoxicity, expressed as reduced ossification in the humerus, the zygomatic arch, and the metatarsals and proximal phalanges of the hind-limb, was observed at 1000 and 2500 mg/cu m. All mouse dams survived to scheduled termination. One dam at 2500 mg/cu m was carrying a totally resorbed litter at termination. Maternal toxicity was observed at 1000 and 2500 mg/cu m, expressed as reduced body weight and weight gain during and after the exposure period, and reduced gravid uterine weight. (Maternal effects may have been due, in part or whole, to effects on the conceptuses; below. [R68] *Pregnant CD-l-mice were exposed to ethylene-glycol by occluded cutaneous application to evaluate developmental toxicity and to differentiate the effects of cutaneous absorption from oral ingestion as it contributes to developmental toxicity. Mice were exposed to ethylene glycol on gestational days six through 15 for 6 hours per day at levels of 0, 404, 1677 or 3,549 mg/kg per day cutaneously, or at 3,000 mg/kg per day by gavage (positive control gavage group, or PCGG). Each group consisted of 30 dams. Dams were examined daily for water consumption and clinical signs. At gestational day 18, all mice were asphyxiated; maternal uterus, liver and kidneys were weighed and examined and corpora lutea and implantation sites were recorded. Fetuses were weighed, sexed and examined for structural anomalies. Cutaneously exposed mice exhibited no maternal toxicity, no difference in implantation loss or fetal body weight per litter, no increase in incidence of fetal malformation, no treatment related increase in water intake and no significant changes in liver, kidney or uterine weights. Positive control gavage group mice experienced eight maternal deaths, increased incidence of hypoactivity, cold extremities, hunched posture, urogenital discharge, abortions and increased water intake. A reduction in fetal body weights per litter, and an increase in total fetal malformations, including external, visceral and skeletal variations and increased maternal renal pathology were seen. The authors conclude that cutaneous ethylene glycol doses of up to 3,54 mg/kg per day were essentially without maternal or developmental effects in mice. 107-21-1 [R69] *Ethylene glycol and the derivative ethylene glycol monoethyl ether are widely used industrial solvents. Ethylene glycol is used primarily in antifreeze products, while ethylene glycol monoethyl ether has many uses including as a solvent for lacquers and varnish removers and in dye baths. The principal health hazard is from ingestion or dermal absorption. No reports describe the effect of these solvents on human reproduction, however both have been shown to cause developmental defects in animals The role of maternal toxicity in these findings is unknown. In the present study, the embryotoxicity of ethylene glycol and ethylene glycol monoethyl ether was evaluated using in vitro culture of post-implantation rat embryos. The embryos were explanted on day 10.5 of gestation and cultured for 40 hours in heat-inactivated rat serum to which 5.0 to 25.0 ul/ml ethylene glycol or 1.0 to 15.0 ul/ml ethylene glycol monoethyl ether was added. The actual concentration in the culture medium was determined by gas chromatography. The results showed that both compounds were embryotoxic in a dose-dependent manner. A no-effect level was established for each solvent. The minimum embryotoxic level of ethylene glycol was 14.2 + or - 1.5 ul/ml (253.6 + or - 27.3 umol/ml. Crown-rump length was normal, however, the protein content of the embryos was reduced and the embryos appeared edematous. The minimum embryotoxic level of ethylene glycol monoethyl ether was 7.3 + or - 0.2 ul/ml (75.5 + or - 2.3 umol/ml). Embryonic growth and development were retarded. To assess the potential risk of these solvents to the human embryo, culture serum levels found to be embryotoxic may be compared to reported human blood levels. The level in postmortem blood in fatal cases of ethylene glycol poisoning usually falls within the range 0.1 - 2.7 ul/ml (1.6 - 48.3 umol/ml). These levels are significantly lower than the concentrations found to be embryotoxic in the present study. No data could be found for ethylene glycol monoethyl ether. [R70] *Artificially inseminated New Zealand white rabbits were administered ethylene glycol by gavage on Gestational Days 6 through 19 at doses of 0, 100, 500, 1000, or 2000 mg/kg/day, with 23-24 inseminated animals per group. Clinical signs were recorded and water consumption was measured daily; does were weighted on gestation days 0, 6-19, 25, and 30. At necropsy (gestation day 30), maternal liver, kidney, and gravid uterine weights were recorded. Histopathologic examination was performed on kidneys from 10 does/dose and for all unscheduled deaths. Ovarian corpora lutea were counted and uterine implantation sites (total sites, resorptions, dead and live fetuses) were recorded. All live fetuses were weighted, sexed, and examined for external, visceral, and skeletal malformations and variations. Ethylene glycol resulted in profound maternal toxicity at 2000 mg/kg/day (42% mortality; three early deliveries and one spontaneous abortion) associated with renal pathology and unaccompanied by any other indicators of maternal toxicity. Renal lesions at 2000 mg/kg/day involved the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis, and tubular dilatation and degeneration. No dose-related maternal toxicity occurred at 100-1000 mg/kg/day. There was no indication of developmental toxicity at any dose tested, including no effects on pre- or postimplantation loss, number of fetuses, fetal body weight, or sex ratio (% male fetuses) per litter, and no evidence of teratogenicity. The "no observable adverse effect level" (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the no observable adverse effect level for developmental toxicity was at least 2000 mg/kg/day in this study. The sensitivity of New Zealand white rabbits relative to that of Sprague-Dawley rats and Swiss mice for maternal and developmental toxicity from gavage administration of ethylene glycol during organogenesis can be determined for maternal toxicity:rabbits > mice > rats and for developmental toxicity, mice \ rats \ rabbits. [R71] *The effects of maternal exposure to ethylene-glycol on the developmental stages of the offspring skeleton were examined in rats. Sperm positive CD-rats were dosed by gavage with 2500 mg/kg per day ethylene-glycol on gestational days six through 15. Dams and fetuses or pups were sacrificed on gestational days 18 or 20 or postnatal days one, four, 14, 21, or 63 for assessment of skeletal malformations and degree of ossification of rapidly developing skeletal districts. Regions of the skeleton that were examined included the sternum, carpals, tarsals, phalanges, and vertebral centra. No differences were observed in the gestational day of delivery between controls and ethylene-glycol treated rats. While treatment with ethylene-glycol was associated with a significant decrease in fetal weights per litter, no reduction in pup body weights on postnatal days four to 63 was noted. Ethylene-glycol treatment was also associated with a significant increase in the percentage of fetuses and pups with skeletal malformations per litter at all time points except postnatal day 63. Reduced ossification values (percentages of total ossification, sternebrae ossified, and vertebral centra ossified) were obtained for ethylene-glycol exposed pups on postnatal days one to 21, but not on day 63. /It was/ concluded that some perinatal abnormalities of the skeleton may be transient due to remodeling in the postnatal period. [R72] +... Conclusions: Under the conditions of these 2 year feed studies, there was no evidence of carcinogenic activity of ethylene glycol in male B6C3F1 mice receiving 6,250, 12,500, or 25,000 ppm, or in female B6C3F1 mice receiving 12,500, 25,000, or 50,000 ppm. ... [R73] NTXV: *LD50 Rat oral 6.14 g/kg /From table/; [R31, 3821] *LD50 Mouse oral 14.6 g/kg /From table/; [R31, 3821] *LD50 Guinea pig oral 8.20 g/kg /From table/; [R31, 3821] *LD50 Dog oral > 8.81 g/kg /From table/; [R31, 3821] *LD50 Mouse ip 5.8 g/kg; [R31, 3822] *LD50 Mouse sc 10.0 g/kg; [R31, 3823] ETXV: *LD50 Carassius auratus (goldfish) > 5,000 mg/l/24 hr modified ASTM D 1345; [R32, 647] *LC50 Guppies (Poecilia reticulata) 49,300 ppm/7 days /Conditions of bioassay not specified/; [R32, 647] *LC50 Rainbow trout 18500 mg/l/96 hr /Conditions of bioassay not specified/; [R74] *LC50 Rainbow trout 41000 mg/l/96 hr at 20 deg C /Conditions of bioassay not specified/; [R75] *LC50 Brown shrimp (Crangon crangon) given > 100 mg/l/48 hr aerated salt water; [R76] *LC50 Goldfish given 5000 mg/l/24 hr at 20 deg C static conditions; [R77] *Toxicity threshold (cell multiplication inhibition test): Bacteria (Pseudomonas putida): 10,000 mg/l; [R32, 647] *Toxicity threshold (cell multiplication inhibition test): Protozoa (Entosiphon sulcatum) and (Uronema parduczi Chatton-Lwoff) > 10,000 mg/l; [R32, 647] *Algae (Chlorella pyrenoidosa) 180,0000 mg/l toxic; [R32, 647] *Toxicity threshold (cell multiplication inhibition test): Algae (Microcystis aeruginosa) 2,000 mg/l; Green algae (Scenedesmus quandricauda) > 10,000 mg/l; [R32, 647] NTP: +... Toxicology an carcinogenesis studies were conducted by administering ethylene glycol (greater than 99% pure) in feed to male and female B6C3F1 mice ... for 2 yr. ...2 Year Studies: Groups of 60 mice received diets containing ethylene glycol for up to 103 weeks (males: 0, 6,250, 12,500, or 25,000 ppm; females: 0, 12,500, 25,000, or 50,000 ppm). These concentrations correspond to daily doses of approximately 1,500, 3,000, or 6,000 mg/kg body weight for male mice and 3,000, 6,000, or 12,000 mg/kg for females. Conclusions: Under the conditions of these 2 year feed studies, there was no evidence of carcinogenic activity of ethylene glycol in male B6C3F1 mice receiving 6,250, 12,500, or 25,000 ppm, or in female B6C3F1 mice receiving 12,500, 25,000, or 50,000 ppm. ... [R73] +Ethylene Glycol (EG) ... was tested for reproductive toxicity in Swiss CD-1 mice using the RACB protocol. It was part of a large structure-activity series of glycol ethers and congeners evaluated using this design, generating data on compounds for which there were few or no reproductive data in the open literature. Food and water consumption, body weight and clinical sign data from Task 1 were used to set levels for the Task 2 at 0.0, 0.25%, 0.50%, and 1.0% EG in drinking water. Based on water consumption data collected during Task 2, these concns produced calculated EG consumptions of approx 400, 850, and 1700 mg/kg/day. There was no EG-related depression of body weight during the cohabitation phase of the study. For the cohabitation phase, the total number of litters/pair was reduced by 9% at the high dose, and the mean number of pups/litter was reduced by nearly equal to 5%. Pup weight (both absolute and adjusted for litter size) was also reduced at the middle and top doses by 3% and 7%, respectively. The relatively small degree of change in pup number contributed to the decision not to conduct a Task 3 crossover mating to determine the affected sex. Thus, the F0 mice were killed at the end of the cohabitation phase (Task 2), and discarded without necropsy. It was noted during the nursing period that selected high-dose F1's had abnormal facial development. Selected affected animals were necropsied at weaning, and their skeletons stained with Alizarin Red S. Rib/vertebral and facial bone abnormalities were noted in the treated skeletons, and were absent from the controls. The remaining mice from the control and high dose groups were evaluated by an F1 mating trial at 74 ± 10 days of age. There were no significant effects of EG consumption on the number or viability of F2 pups. Pup weight adjusted for litter size was reduced by 5%, a change of borderline significance (p=0.064). After the F2 litters were born, the F1 adults were killed and necropsied. Terminal body weight was not changed, but there was a nearly equal to 8.5% reduction in brain weight in both sexes, and a 9% reduction in relative liver weight for females. These data show that EG, at sufficient doses, can reduce litter size and pup weight without affecting F0 body weight. Of potentially more interest, however, were the skeletal terata induced by 1% EG consumption. [R78] +Ethylene Glycol (EG) ... was tested for reproductive toxicity in Swiss CD-1 mice using the RACB protocol. ... This study used a higher top dose, and incorporated a crossover mating, and an evaluation of all dose levels in F1's. Based on the data from the previous study, doses for this study were set at 0.0, 0.5%, 1.0%, and 1.5% EG in drinking water for approx 21 wks. Based on water consumption data collected during this study, these concns produced calculated EG consumptions of nearly equal to 850, 1800, and 2800 mg/kg/day. Body weight was not affected during the Task 2 cohabitation phase. While the number of litters/pair was unchanged, the number of pups/litter was reduced by nearly equal to 15% at the top dose, and the pup weight adjusted for litter size was reduced by 3%, 7%, and 10% (low to high doses, respectively). After the last litter was delivered and reared to weaning, the control and 1.5% EG F0 mice were cross-mated in Task 3 to determine the affected sex. While the number of pups/litter was the same as controls, the adjusted pup weight was 9% lower than controls in the control male x 1.5% EG female group. After the last Task 3 litter was delivered, the females were subject to vaginal lavage for 7 days, and then all control and 1.5% EG mice were necropsied. While female body weight was unchanged by 1.5% EG consumption, male body weight was reduced by 9%; organ weights were unaffected. Sperm motility at 1.5%EG was reduced by 15%, and the frequency of abnormal sperm rose from 5% (controls) to 8% (1.5%EG). Estrous cycle length was unaffected by EG exposure. No treatment-related microscopic lesions were seen in tissues of the 1.5% EG females. Renal tubule lesions were noted in 60% of male mice, concomitant with the presence of crystals presumed to be oxalate. Serum total calcium levels were the same across all dose groups. All offspring from the last litter of F1's were reared and dosed until mating at /postnatal day/ 74±10. Dosing continued through the wk of mating, and until sacrifice. There were no effects on the indices of mating and fertility, and the number of pups/litter was unchanged, but pup weight adjusted for litter size was reduced by 5, 5, and 6% in the low, middle, and high doses, respectively. All dose groups of F1 mice were killed and necropsied after vaginal lavage. Female body weight and weights of liver and kidney were not affected at any dose level, and male body weights were not different across dose groups. Absolute testis weight was reduced by 12%, 15%, and 15% as dose increased, and adjusted right epididymis weight was reduced by 9 and 11% in the middle and top dose groups, respectively. Sperm count was reduced by 23%, 18%, and 17% as dose increased; only the first two were significant. The % motile sperm was reduced by 3 and 12% in the middle and top dose groups, respectively. Estrous cycle length and characteristics were unchanged. Total serum calcium was measured in all dose groups, and was not changed by EG exposure. Microscopically, there was a greater incidence and severity of testicular damage in the 1.5%EG males, but neither sex showed signs of renal damage or regeneration. This study repeated the findings of facial structural abnormalities (cleft palate and ablepheron). These were seen in the middle and top dose groups, and were also seen in Task 3 only in pups born to EG-exposed dams. This repeat ethylene glycol study used a higher top dose to confirm the reproductive and developmental toxicities caused by EG in Swiss mice. These were seen in the presence of a 9% change in body weight only in F0 males. [R79] +... Ethylene glycol (EG) (O, 750, 1500, and 3000 mg/kg/day, po) in distilled water was administered in a volume of 10 ml per kilogram of body weight on gestational days (gd) 6 through 15. Females were weighed and observed during daily treatment for clinical signs of toxicity. At sacrifice on gestational days 17, a total of 23-25 dams (i.e., confirmed-pregnant females) per treatment group were evaluated. The gravid uterus of each dam was weighed, and the status of uterine implantation sites were recorded (i.e., number of resorptions, dead fetuses, and live fetuses). All live fetuses were weighed, sexed, and examined for external, visceral, and skeletal malformations. No unscheduled maternal deaths occurred during this investigation, nor were any distinctive clinical signs associated with ethylene glycol treatment other than piloerection and maternal body weight loss. Maternal body weight on gestational days O and 6 (i.e., prior to the initiation of treatment) did not differ significantly among treatment groups. On gestational days 11, 15, and 17, maternal body weight was decreased across treatment groups in a dose-related manner, and both the mid-and high-dose groups were significantly below vehicle controls. Maternal weight gain during the treatment period, as well as maternal weight gain for the entire gestational period, was negatively associated with dose (i.e., weight gain decreased with increasing dose) and was significantly below vehicle controls for both the mid-and high-dose ethylene glycol groups. When gravid uterine weight was subtracted from total gestational weight gain, none of the ethylene glycol-treated groups were significantly different from vehicle controls with regard to absolute maternal weight gain, but a dose-related downward trend in absolute weight gain was observed as dosage increased. A significant dose-related reduction in gravid uterine weight was observed, which was significantly below vehicle controls for both the mid-and high-dose groups, and appeared to account for the corresponding reductions in maternal body weight on dg 17. Maternal liver weight (g) displayed a statistically significant dose-related decrease, and both the mid- and high-dose groups were significantly below vehicle controls by pairwise comparison. No significant differences among dose groups were observed for relative maternal liver weight (% body weight). Indices of reproductive competence prior to the initiation of treatment on dg 6 revealed a preexisting difference among dose groups; i.e., statistically significant differences were observed for the number of corpora lutea per dam and number of implantation sites per dam, but not for percent preimplantation loss. Specifically, dams in the mid-dose group (1500 mg/kg/day ethylene glycol) had a lower average number of corpora lutea and a corresponding decrease in the number of implantation sites per litter as compared to vehicle control dams. Viability of implanted embryos was significantly affected in the high-dose group (19.86% resorptions per litter) when compared to vehicle controls (8.74% resorptions per litter). A significant dose-related trend toward an increased proportion of litters with one or more resorptions per litter was also observed. The incidence of "dead" fetuses (i.e., fetuses weighing greater than 0.3 g, having discernible digits and exhibiting no vital signs at uterine dissection on gestational days 17) was decreased in dose-related manner and the mid- and high-dose ethylene glycol groups were significantly below vehicle controls on this measure. The proportion of litters with one or more dead fetuses was significantly below vehicle controls for the mid-dose group. In summarizing post-implantation mortality (i.e., resorptions plus dead fetuses), the percent nonlive implants per litter exhibited a dose-related increase as dosage increased, but none of the individual treatment groups were significantly different from vehicle control by pairwise comparison. Similarly, the proportion of litters with one or more nonlive implants exhibited a dose-related upward trend as dosage increased, but no significant differences were observed between individual treatment groups and vehicle control. When the outcome of pregnancy was considered as a whole (i.e., accounting for all resorp-tions, dead fetuses and malformed live fetuses from all confirmed-pregnant dams), there was a significant increase in the percent of conceptuses per litter which were adversely affected during the post-implantation phase of gestation; this increase reached statistical significance for both the mid- and high-dose groups. The percent of adversely affected implants per litter exhibited a significant dose-relate trend and occurred with the following incidence for the vehicle control through high-dose groups, respectively: 11.17%, 19.65%, 50.67%, and 64.41%. The percent of litters containing one or more affected implants also increased with dose, i.e., 72.0%, 83.3%, 95.7%, and 100.0%, respectively; the increases for this parameter were statistically higher than vehicle controls for both the mid-and the high-dose groups. Statistical evaluation of litters containing at least one live fetus (herein referred to as "live litters"), revealed a significant dose-relate reduction in the number of live fetuses per live litter which was significantly below vehicle controls at the highest dose of ethylene glycol (3000 mg/kg/day). No treatment-relate effect was observed on the percentage of live male fetuses per litter. Average live fetal body weight per live litter was negatively associated with dose and was statistically below vehicle controls for all doses tested, with males and females being equally affected on this measure. The percentage of malformed live fetuses per live litter was positively associated with dose and displayed the following incidence for the vehicle control through high-dose groups, respectively: 0.25%, 10.00%, 37.77%, and 56.54%. The percentage of malformed live fetuses per live litter was statistically higher than vehicle controls for all ethylene glycol-treated groups. When incidence of malformations was analyzed by fetal sex, male fetuses exhibited an increased incidence of malformations at all ethylene glycol doses, but female fetuses exhibited an increase only in the mid-and high-dose groups. However, the absence of a significant dose x sex interaction in a dose (4) x replicate (2) x sex (2) ANOVA design with sex as a repeated measure, indicated that no robust sex-selective effect was observed with regard to the incidence of malformed live fetuses. The proportion of live litters containing at least one malformed live fetus also increased with dose and displayed an incidence of 4.00%, 66.67%, 81. 82%, and 95.65% in the vehicle control through high-dose respectively. The proportion of live litters with malformed live fetuses was significantly elevated in all ethylene glycol-treated groups relative to the vehicle control group. A diversity of gross, visceral, and skeletal malformations were observed with the most characteristic malformations involving craniofacial and skeletal dysmorphogenesis. Report Date: July 23, 1984 [R80] +Ethylene glycol (EG) ... was administered by gavage to pregnant CD rats (F0 generation) on gestational days (gd) 6 through 20 at doses of 0, 250, 1250 or 2250 mg/kg/day (i.e., 0, 4. 20 or 36 mmol/kg/day, respectively). The offspring (F1 generation) were fostered to untreated mothers on postnatal day (gd) 1 and evaluated for postnatal growth and viability, developmental landmarks, sexual maturation, locomotor activity and performance of a complex learning task. Maternal body weight (gd 20) and weight gain during treatment and gestation were negatively influenced by 2250 mg ethylene glycol/kg/day, but similar effects were not found at lower doses. The gestational period was significantly longer in dams exposed to 1250 or 2250 mg/kg/day ethylene glycol. On pnd 1, absolute and relative maternal kidney weights and postpartum uterine weight were decreased in the high- dose group. No differences among groups were noted on pnd 1 for maternal body weight, maternal liver weight, or number of implantation sites per dam. Evidence of treatment-related renal pathology was noted in 27% (4/15) of females examined in the mid- dose group and in 33% (5/15) of females examined in the high-dose group, as compared to a 0% (0/18) incidence of similar lesions in the control group. Per the study protocol, no other maternal organs were examined microscopically. Live litter size and neonatal pup body weight were decreased, and cumulative mortality of offspring through pnd 4 (expressed as a percent of implantation sites) was increased in the high-dose group. There was no effect of treatment on the age of incisor eruption or development of external genitalia (i.e., vaginal opening or testes descent). While there was an initial difference between groups in the percentage of pups per litter with wire grasping skills on pnd 9 (9%, 18%, 40% and 37% for control through high-dose groups, respectively), by pnd 10, the control group contained 70% pups per litter with wire grasping skills, and no differences among groups were noted on pnd 10-15. Thus, no adverse effects of prenatal ethylene glycol upon postnatal acquisition of wire grasping skills were observed. There were no statistically significant effects of treatment on exploratory behavior (preweaning) or performance on a visual discrimination task (~12-24 weeks of age). A significant increase in skeletal malformations was observed on pnd 22 for pups in the 2250 mg EG/kg/day group. Hydrocephalus was observed in the 250 and 2250 mg/kg/day groups, but not at 1250 mg/kg/day, suggesting that the incidence was related to treatment only at the high dose. Relative kidney weights tended to be lower than controls on pnd 63 at the mid- and high-dose levels. However, no treatment-related pathology was noted upon microscopic examination of the liver or kidneys collected from F1 pups at scheduled sacrifices on pnd 4, 22 or 63. In summary, administration of ethylene glycol (EG) to timed-mated CD rats on gd 6 through 20 resulted in no observed toxicity at 250 mg/kg/day. At 1250 mg/kg/day, the gestational period was lengthened, and maternal renal pathology was noted, but no adverse developmental effects were observed. At 2250 mg/kg/day, reduction of maternal body weight, weight gain, kidney weight and postpartum uterine weight were observed. In addition, gestation was lengthened and maternal renal pathology was present. Developmental toxicity at 2250 mg/kg/day included reduced pup body weight, reduced viability and increased malformation incidence (primarily hydrocephaly and abnormalities of the axial skeleton), but adverse effects upon other indices of postnatal development were not observed. [R81] +Artificially-inseminated New Zealand White (NZW) rabbits were administered ethylene glycol by gavage on gestational days (gd) 6 through 19 at doses of 0, 100, 500, 1000 or 2000 mg/kg/day , with 23-24 inseminated animals per group. Clinical signs were recorded daily during treatment and on gestational days 25 and 30 (animals were observed at least once daily throughout the study); maternal body weights were recorded on gestational days 0, 6-19, 25 and 30 and maternal water consumption was measured daily. At necropsy (gestational days 30), maternal body weight, liver weight, kidney weight and gravid uterine weight were recorded. ... Ethylene glycol administered by gavage to pregnant New Zealand White rabbits during major organogenesis resulted in profound maternal toxicity (42% mortality; three early deliveries and one spontaneous abortion) at 2000 mg/kg/day associated with renal pathology and unaccompanied by any other indicators of maternal toxicity such as effects on periodic maternal body weights or weight change or on water consumption. At necropsy, there were no significant effects on gravid uterine weight, liver or kidney weights. The kidney lesion at 2000 mg/kg/day was limited to the cortical renal tubules and included intraluminal oxalate crystals, epithelial necrosis and tubular dilatation and renal tubular degeneration. There was no dose-related maternal toxicity at 100-1000 mg/kg/day . There was no indication of developmental toxicity including no effects on pre- or post implantation loss, the number of fetuses per litter, fetal body weight per litter or sex ratio (% male fetuses per litter), and no evidence of teratogenicity based on evaluation of external, visceral including craniofacial, skeletal or total malformations or variations at any dose tested. These dose levels include a dose which resulted in severe maternal toxicity (2000 mg/kg/day ) and doses which produced no observable maternal toxicity (100-1000 mg/kg/day ). The No Observable Adverse Effect Level (NOAEL) for maternal toxicity was therefore 1000 mg/kg/day and the NOAEL for developmental toxicity was at least 2000 mg/kg/day under the conditions of this study. The sensitivity of New Zealand White rabbits relative to CD(R) rats and CD(R)-I mice previously evaluated for maternal and developmental toxicity from gavage administration of ethylene glycol during organogenesis can be determined for maternal toxicity: rabbits more sensitive than mice, mice more sensitive than rats, and for developmental toxicity: mice more sensitive than rats, and rats more sensitive than rabbits. [R82] +Ethylene glycol (EG) ... was administered by gavage to sperm positive CD(R) rats (7 per group for two doses and seven sacrifice times; i.e., 14 groups) on gestational days (gd) 6 through 15 at doses of 0 or 2500 mg/kg/day . Subsequently, two groups of dams were killed on gd 18 or 20, and fetal skeletons were double-stained and examined for degree of ossification in selected regions as well as for skeletal malformations. Other groups of dams were allowed to deliver their litters which were fostered to untreated dams on postnatal day (pnd) 1. Pups were sacrificed by litter on postnatal day 1, 4, 14, 21 or 63. Pup skeletons were double-stained and examined for degree of ossification and skeletal malformations. Maternal body weight after initiation of dosing and weight gain during gestation were significantly below controls in the gd 18 and postnatal day 1 ethylene glycol groups. Corrected maternal weight gain was reduced in the gd 18 ethylene glycol group only. Gd 20 and postnatal day 63 ethylene glycol groups had significantly decreased weight gain during treatment. ... Fetal weights per litter were significantly decreased with ethylene glycol treatment in the gd 18 and 20 groups. There was no increase in % resorptions per litter in ethylene glycol treated dams sacrificed on gd 18 or 20. No significant effects of treatment were seen for pup body weight in any of the individual or combined postnatal groups except that body weight on postnatal day 1 for all postnatal ethylene glycol groups combined was significantly below controls. Number of live pups per litter were significantly lower on postnatal day 1 in the postnatal day 1 ethylene glycol group only. Percent fetuses/pups with skeletal malformations per litter were significantly increased in all ethylene glycol groups except for the postnatal day 63 group, with a predominance of axial skeletal defects. Percent total ossification, percent sternebrae ossified and percent vertebral central ossified were significantly reduced in the ethylene glycol groups but were not significantly different when co-varied by body weight on gd 18, 20 or postnatal day 63. All were significantly lower than controls in the postnatal day 1 through postnatal day 21 groups. There was no effect of dose or body weight on ossification of fore or hind limb digits. In conclusion, ethylene glycol treatment caused developmental delays and apparent malformations in the perinatal rat skeleton which were resolved by postnatal day 63. [R83] TCAT: ?Acute oral toxicity was evaluated in 3 groups of 10 male Holzman Sprague-Dawley rats administered ethylene glycol (diluted in corn oil) by gavage at dose levels of 50, 500 and 5000 mg/kg of body weight. No mortalities were observed and the LD50 was estimated to be > 5000 mg/kg. Clinical observations included depression, labored breathing, emaciation and alopecia (gross necropsy not reported). [R84] ?Acute oral toxicity was evaluated in 5 groups of 2 male Holzman Sprague-Dawley rats administered ethylene glycol (diluted in corn oil) by gavage at dose levels of 316, 1000, 3160, 10000 and 31600 mg/kg of body weight. Observed mortalities included both rats at the 31600 mg/kg dose level. The LD50 value was estimated to be 17800 mg/kg using the Litchfield and Wicoxon method. Clinical observations included depression, rapid respiration and hunching (gross necropsy not conducted). [R85] ?Ethylene glycol (CAS No. 107-21-1) was tested for acute toxicity. Rabbits treated by gavage 7 times at 0.1 and 0.5 g/kg developed slight kidney damage, and death in 3 weeks, respectively. Death was also produced after 6 treatments at 1.0 g/kg (at 7 days) and 2 treatments at 2.0 g/kg (at 24 hours). There was severe kidney damage in all animals that died. [R86] ?Ethylene glycol (CAS No. 107-21-1) was tested for acute toxicity. Rabbits treated by subcutaneous injection 7 times at 0.1 and 0.5 g/kg developed slight kidney damage, and death in 3 weeks, respectively. Death was also produced after 3 injections at 1.0 g/kg (at 3 days) and 2 injections at 2.0 g/kg. No effects were noted after a single injection at 0.5 or 1.0 g/kg. There was severe kidney damage in all animals that died. [R86] ?Teratogenicity was evaluated in groups of 30 pregnant CD-1 mice administered ethylene glycol by gavage at doses of 0, 50, 150, 500, and 1500 mg/kg on days 6-15 of gestation. Surviving mice were sacrificed on gestation day 18. Maternal mortality was observed in 1 mouse in the control group, 2 at 50 mg/kg, 3 at 500 mg/kg, and in 2 mice at 1500 mg/kg. Signs of maternal toxicity included: labored respiration (500 mg/kg); hypoactivity, red urogenital discharge, and a hunched posture (50, 500 and 1500 mg/kg); ataxia (50 and 1500 mg/kg); and ocular discharge and slight reductions in body weights (1500 mg/kg). Examination of the uteri revealed slight increases in early resorptions and non-viable implants/litter at 1500 mg/kg. Significantly reduced fetal body weights and increased fetal skeletal malformations were observed at 1500 mg/kg. The NOEL for ethylene glycol was determined to be 1500 mg/kg/day for maternal toxicity and 150 mg/kg/day for developmental toxicity. [R87] ?Reproductive toxicity was evaluated in groups of 10 pregnant Charles River CD female mice receiving ethylene glycol via oral gavage at a single dose level of 10 ml/kg body weight on gestation days 7 through 14. Maternal mortality, clinical observations or gross necropsy were not reported. There was a significant reduction (p < 0.05) in the number of live pups per litter, reduced survival, and reduced birth weight among treated offspring. [R88] ?Ethylene Glycol (CAS# 107-21-1) was administered by gavage at dose levels of 150, 500, 1000 and 2500 mg/kg/day to groups of 25 pregnant CD (Sprague-Dawley) rats for gestational days 6 through 15. Dams were sacrificed at gestational day 21 and evaluated for organ and body weights, and status of implantations. Fetuses were counted, weighed, sexed and examined for external, visceral and skeletal abnormalities and some were sectioned for examination of craniofacial abnormalities. A water (vehicle) control group was similarly treated. At the highest dose level there were maternal toxicity effects including reduced gestational and terminal body weight and weight changes, increased water consumption and increased relative kidney weight. Increased relative liver weights were also observed in all levels except the 500 mg/kg, so the authors conclude that this was not an effect of chemical treatment. Fetotoxic effects included skeletal malformations at the two highest dose levels and gastroschisis at the highest level. A variety of statistical tests were used to analyze the results. The authors derive a "no observable effect level" (NOEL) for maternal toxicity of 1000 mg/kg day and 500 mg/kg/day for developmental toxicity. [R89] ?Ethylene glycol (CAS# 107-21-1) was administered by gavage to groups of 25 CD (Sprague-Dawley) rats on gestation days 6 through 15 at dosages of 0, 150, 500, 1000, 2500 mg/kg/day. Rats were sacrificed at gestation day 21 and evaluated for organ and body weights and status of implantations as well as histological examination of kidneys. Fetuses were counted, weighed, sexed and examined for external and visceral abnormalities as well as craniofacial malformations and skeletal abnormalities. Fetotoxicity and teratogenicity was evidenced at the two highest doses with regard to reduced fetal body weights, and at the highest dose with increased malformations including gastroschisis, umbilical hernia, hydrocephaly, lateral ventrical dilation with tissue depression, and skeletal malformations especially in the thoracic region. Some increased variation and malformations in the thoracic region were also evident at the 1000 mg/kg level. Relative liver relative weight was also increased at this level. Maternal body weight changes were significantly reduced while absolute and relative kidney weight and relative liver weight were increased at the highest dose level. Other maternal and gestational parameters were unaffected by treatment. A variety of statistical tests were used to analyze the data. The authors conclude that there is a "no observable effect level" (NOEL) for maternal toxicity at 1000 mg/kg and a NOEL for developmental toxicity at 500 mg/kg. [R90] ?Ethylene glycol (107-21-1) was evaluated for developmental toxicity in groups of 25 pregnant Sprague-Dawley rats administered the test substance by oral gavage on days 6-15 of gestation at doses of 0, 150, 500, 1000 or 2500 mg/kg/day. Animals were sacrificed on day 21 of gestation. Animals at 2500 mg/kg/day showed significantly reduced maternal body weight and body weight gains, significantly increased water consumption, increased absolute and relative kidney weights, and increased relative liver weights. Rats at 1000 mg/kg/day showed increased relative liver weights. Significantly reduced fetal body weights per litter were observed at 1000 and 2500 mg/kg/day. There was a significant increase in gastroschisis, hydrocephaly, lateral ventricle dilation with tissue depression, fetal atelectasis and umbilical hernia. A significant increase in skeletal malformations and skeletal variations was observed in fetuses at 1000 and 2500 mg/kg/day. The level of significance for all cases was p < 0.05. The authors concluded that the NOEL for developmental toxicity was 500 mg/kg/day. [R91] ?Ethylene glycol (107-21-1) was evaluated for reproductive toxicity in groups of male and female CD-1 mice administered the test substance at dose levels of 0 (38 pairs), 0.25 (20 pairs) mice, 0.5 (18 pairs), and 1.0% (20 pairs) in the drinking water. Mice were exposed to the test substance for 1 week prior to breeding. Breeding pairs were then exposed for 14 weeks. Mice were monitored for fertility, number of live and dead pups, average pup weight, and sex ratio. Mice exposed to the test substance showed a significantly decreased number of litters per pair, number of live pups per pair, and live pup weight (p < 0.05). Pups in the 1% dose group showed a significantly increased number of facial deformities. Pups with facial deformities also showed significantly abnormal skeletons. Offspring assessed for reproductive success showed decreased mating and fertility index values and decreased male pup weight while other reproductive parameters such as female pup weight, number of live pups, and sex ratio were not affected. [R92] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 23 to 25 female CD-1 mice administered the test substance by gavage at dose levels of 0 (25 mice), 750 (24 mice), 1500 (23 mice) and 3000 mg/kg/day (23 mice) on days 6-15 of gestation. Animals were sacrificed on day 17 of gestation. Maternal body weight and body weight gain were decreased in a dose-related manner in all treatment groups during exposure. There was a statistically higher percentage of malformed live fetuses in all treated groups (10.00%, 37.77%, and 56.5%, respectively) when compared to controls (0.25%). There was a statistically higher percentage of litters with at least one malformed live fetus in all treated groups (66.67%, 81.82% and 95.65%, respectively) when compared to controls (4.00%). Among the various visceral and skeletal malformation observed, those involving craniofacial and skeletal dysmorphogenesis were most characteristic. Since there were developmental effects at all dose levels, no NOEL was established. [R93] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female Sprague-Dawley rats administered the test substance by gavage at dose levels of 0, 150, 500, 1000 or 2500 mg/kg/day on days 6-15 of gestation. Animals were sacrificed on day 21 of gestation. Maternal animals at 2500 mg/kg/day showed significantly reduced body weights and body weight gains, increased water consumption, reduced gravid uterine weight, increased absolute and relative kidney weights and increased relative liver weights. Fetal body weights at 1000 and 2500 were significantly reduced. Fetuses at 2500 mg/kg/day showed an increased incidence of external, visceral, and skeletal malformations. An increased incidence of gastroschisis was observed at 2500 mg/kg/day. An increased incidence of skeletal malformations primarily involving the thoracic region were observed at 1000 and 2500 mg/kg/day. The level of significance for all cases was p < 0.05. The authors conclude that the NOEL for developmental toxicity is 500 mg/kg/day. [R94] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 27 to 29 female CD rats administered the test substance by gavage at dose levels of 0 (28 rats), 1250 (28 rats), 2500 (29 rats), and 5000 (27 rats) mg/kg/day on days 6-15 of gestation. Maternal animals at all dose levels showed statistically decreased weight gain during exposure. Animals were sacrificed on day 20 of gestation. The rats at 2500 and 5000 mg/kg/day showed a significantly increased number of resorptions, reduced number of live fetuses, decreased fetal body weight per litter (p < 0.05), and number of malformed fetuses per litter (p < 0.05) when compared to controls. Malformations involving varying degrees of skeletal dysplasia and clefts of the face, lip or palate were the most characteristic. [R95] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female Sprague-Dawley rats administered the test substance by gavage at dose levels of 0, 150, 500, 1000 or 2500 mg/kg/day on days 6-15 of gestation. Animals were sacrificed on day 21 of gestation. Maternal animals at 2500 mg/kg/day showed significantly reduced body weights and body weight gains, increased water consumption, reduced gravid uterine weight, increased absolute and relative kidney weights and increased relative liver weights. Fetal body weights at 1000 and 2500 were significantly reduced. Fetuses at 2500 mg/kg/day showed an increased incidence of external, visceral, and skeletal malformations. An increased incidence of gastroschisis was observed at 2500 mg/kg/day. An increased incidence of skeletal malformations primarily involving the thoracic region were observed at 1000 and 2500 mg/kg/day. The level of significance for all cases was p < 0.05. The authors conclude that the NOEL for developmental toxicity is 500 mg/kg/day. [R96] ?Teratogenicity was evaluated in groups of 30 restrained pregnant CD-1 albino mice administered occluded 0.1 ml doses of 0, 127 (404), 527 (1677), and 1115 (3549) mg/ml (mg/kg) ethylene glycol applied to shaved skin 6 hrs/day or (positive control) 3000 mg/kg/day ethylene glycol by gavage gestation days (GD) 6-15. In the positive control group were 8 maternal mortalities. Abortions or early deliveries for negative control, low, mid, high, and positive control dose groups were 3, 1, 5, 4, and 5; fully resorbed litters were 2, 6, 6, 4, and 1, respectively. Dermally dosed dams had no clinical signs except those due to restraint, no skin lesions were at dosing sites. Surviving positive control dams showed hypoactivity, cold extremities, hunched posture, urogenital discharge, and abortion. Body weights and weight gains were comparable in all groups, except high dose and positive control dams had gestational weight minus gravid uterine weight increased relative to controls. Water consumption increased in positive controls during treatment. Gross necropsies were unremarkable, but kidney damage observed on microscopic examination in positive control dams affected 3 high dose dams. There were no treatment-related differences among groups in number of corpora lutea/dam, total, nonviable or viable implantations/litter, or fetal sex ratio. Incidence of late resorptions and dead fetuses was reduced in the low dose group. Fetal body weights were reduced only in positive controls. Many fetal malformations and variations were found in positive controls, not in dermally treated dams. High dose fetuses had poorly ossified parietal skull bones and unossified intermediate hindlimb phalanges. [R97] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of female 30 CD-1 mice administered the test substance by occluded cutaneous application of 0%, 12.5 %, 50.0%, or 100% solutions at a constant dose volume of 0.1 ml on days 6-15 of gestation (a positive control received 3000 mg/kg/day by gavage which produced both maternal and developmental toxicity). Maternal animals (excluding the positive controls) showed no observable signs toxicity. The only indication of developmental toxicity was an increased incidence of poorly ossified parietal skull bones and unossified intermediate phalanges of the hindlimb in the 100% group. [R98] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 30 female CD-1 mice administered the test substance by occluded cutaneous application of 0%, 12.5 %, 50.0%, or 100% solutions at a constant dose volume of 0.1 ml on days 6-15 of gestation (a positive control received 3000 mg/kg/day by gavage which produced both maternal and developmental toxicity). Maternal animals (excluding the positive controls) showed no observable signs toxicity. The only indication of developmental toxicity was an increased incidence of poorly ossified parietal skull bones and unossified intermediate phalanges of the hindlimb in the 100% group. [R99] ?Teratogenicity was evaluated in pregnant CD rats (25/group) exposed to ethylene glycol by inhalation at nominal concentrations of 0, 60, 400 or 1000 ppm for 6 hrs/day on gestation days (GD) 6-15. There were significant differences observed between treated and control animals in the following: increased absolute and relative maternal liver weights (high-dose group), reduced ossification in the fetal humorous, zygomatic arch, and metatarsals and proximal phalanges of the hindlimb (mid- and high-dose groups). There were no significant differences observed between treated and control animals in the following: maternal mortality, food and water consumption, maternal body weights, weight gain and organ weights (other than liver), reproductive parameters including pre- and postimplantation loss, live fetuses/litter, sex ratio and fetal body weight/litter, incidence of any individual fetal malformation, or total external, visceral or skeletal malformations by fetus or litter, and incidence of external or visceral variations. [R100] ?Teratogenicity was evaluated in pregnant CD-1 mice (25/group) exposed to ethylene glycol by inhalation at nominal concentrations of 0, 60, 400 or 1000 ppm for 6 hrs/day on gestation days (GD) 6-15. There were significant differences observed between treated and control animals in the following: decreased maternal body weights, weight gain and gravid uterine weight (mid- and high-dose groups), increase in non-viable implantations/litter, reduction in viable implantations/litter, total fetal body weights/litter, increased incidence of individual and total external, visceral and skeletal fetal malformations and total malformations including malformations in the head (exencephaly), cleft palate, foreshortened and abnormal face, vertebral fusion, fused, forked or missing ribs, and abnormal facial bones. There were no significant differences observed between treated and control animals in the following: maternal mortality, and organ weights (except gravid uterus). [R100] ?Teratogenicity was evaluated in groups of 30 pregnant CD-1 albino mice dosed by inhalation 6 hrs/day gestation days (GD) 6-15 at total ethylene glycol concentrations generated as an aerosol and measured by gas chromatography at (nose-only, restrained) 0 (water), 250-360, 570-779, or 969-2505 mg/m3, aerosol of particle size 1.0 um MMAD +/- 4.2 GSD, or (whole-body, unrestrained, positive control) 0 (water) or 2008 mg/m3, aerosol of particle size 7.5 um MMAD +/- 1.6 GSD. Groups of 5 dams either nose- or whole-body exposed to top doses GD 6 showed whole-body exposed dams had > 1000 more mg/kg extractable ethylene glycol deposited on fur. Nose-exposed maternal mortalities (2 and 6 in 0 and high dose groups, respectively) were believed to be dosing errors. Early deliveries (total resorptions) for negative control, low, mid, high, and whole body dose groups were 3, 3, (2), (1), 1, and 1. Maternal signs of clinical toxicity (other than restraint-induced in nose-only groups) were wet fur in both high dose groups. Treatment increased water consumption in low dose and whole-body dams. Dam weights and weight gains were unaffected. Absolute (mid and high dose) and relative (high dose) dam kidney weights increased. The number of corpora lutea/dam, total or viable implants/litter, and sex ratio were unaffected. Nonviable implants/litter increased in whole-body treated group. Fetal weights were reduced in both high-dose groups. There was no treatment-related effect on soft tissue anomalies in fetuses, but skeletal effects were seen both high dose groups. [R101] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 30 female CD-1 mice administered the test substance by nose only exposure for 6 hours per day on days 6 through 15 of gestation at concentrations of 0, 500, 1000 or 2500 mg/cu m. Additional groups were exposed to the test substance by whole body exposure at concentrations of 0 or 2100 mg/cu m. Animals were sacrificed on day 18 of gestation. Two females in the 0 nose-only control and 3 in the 2500 mg/cu m nose-only died due to apparent asphyxiation or drowning caused by improper insertion of the nose-only inhalation device. Body weight and body weight gain were not affected in any of the exposure groups. The 2100 mg/cu m whole-body exposure group showed an increased incidence of skeletal malformation, total malformations, and skeletal variations. Fused ribs were seen at 2500 mg/cu m nose-only. Extra ribs were seen at 2500 mg/cu m nose-only and 2100 mg/cu m whole body exposures. The level of significance for all cases was p < 0.05. The NOEL for developmental toxicity and teratology was determined to be 1000 mg/cu m. [R102] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female CD-1 mice administered the test substance by inhalation for 6 hours/day on days 6 to 15 of gestation at concentrations of 0, 150, 1000, or 2500 mg/cu m. Animals were sacrificed on day 18 of gestation. Maternal animals at 100 and 2500 mg/cu m showed reduced body weight, body weight gain, and gravid uterine weight. A reduced number of viable implantations per litter and increased non-viable implantations were seen at 1000 and 2500 mg/cu m. Fetal body weights were also reduced at 100 and 2500 mg/cu m. There was an increased incidence of total external, visceral, and skeletal malformations at 1000 and 2500 mg/cu m. These malformations included exencephaly, cleft palate, foreshortened and abnormal face, abnormal facial bones, vertebral fusions, and fused, forked and missing ribs. The level of significance for all cases was p < 0.05. The NOEL (maternal and fetal) was 150 mg/cu m. [R103] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female CD-1 rats administered the test substance by inhalation for 6 hours/day on days 6 to 15 of gestation at concentrations of 0, 150, 1000, or 2500 mg/cu m. Animals were sacrificed on day 21 of gestation. Maternal animals at 2500 mg/cu m showed a significant increase in absolute and relative liver weight. Reproductive parameters such as postimplantaion loss, live fetuses per litter, sex ratio and fetal body weights were unaffected by exposure to the test substance. The incidence of total external, total visceral, total skeletal, and total malformations were unaffected by exposure. Rats at 100 and 2500 mg/cu m showed reduced ossification of the humerus, zygomatic arch, and metatarsals and proximal phalanges of the hindlimb. The level of significance for all cases was p < 0.05. [R103] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female CD-1 rats administered the test substance by inhalation for 6 hours/day on days 6 to 15 of gestation at concentrations of 0, 150, 1000, or 2500 mg/cu m. Animals were sacrificed on day 21 of gestation. Maternal animals at 2500 mg/cu m showed a significant increase in absolute and relative liver weight. Reproductive parameters such as postimplantaion loss, live fetuses per litter, sex ratio and fetal body weights were unaffected by exposure to the test substance. The incidence of total external, total visceral, total skeletal, and total malformations were unaffected by exposure. Rats at 100 and 2500 mg/cu m showed reduced ossification of the humerus, zygomatic arch, and metatarsals and proximal phalanges of the hindlimb. The level of significance for all cases was p < 0.05. [R104] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female CD-1 mice administered the test substance by inhalation for 6 hours/day on days 6 to 15 of gestation at concentrations of 0, 150, 1000, or 2500 mg/cu m. Animals were sacrificed on day 18 of gestation. Maternal animals at 100 and 2500 mg/cu m showed reduced body weight and body weight gain and reduced gravid uterine weight. A reduced number of viable implantations per litter and increased non-viable implantations were seen at 1000 and 2500 mg/cu m. Fetal body weights were also reduced at 100 and 2500 mg/cu m. There was an increased incidence of total external, visceral, and skeletal malformations at 1000 and 2500 mg/cu m. These malformations included exencephaly, cleft palate, foreshortened and abnormal face, abnormal facial bones, vertebral fusions, and fused, forked and missing ribs. The level of significance for all cases was p < 0.05. The NOEL (maternal and fetal) was 150 mg/cu m. [R105] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 30 female CD-1 mice administered the test substance by nose only exposure for 6 hour per day on days 6 through 15 of gestation at concentrations of 0, 500, 1000 or 2500 mg/cu m. Two additional groups were exposed to the test substance by whole body exposure at concentrations of 0 or 2100 mg/cu m. Animals were sacrificed on day 18 of gestation. Two females in the 0 mg/cu m nose-only control and 3 in the 2500 mg/cu m nose-only died due to apparent asphixiation or drowning caused by improper insertion of the nose-only inhalation device. Body weight and body weight gain were not affected in any of the dose groups. The 2100 mg/cu m whole-body exposure group showed an increased incidence of skeletal malformations, total malformations, and skeletal variations. Fused ribs were seen at 2500 mg/cu m nose-only. Extra ribs were seen at 2500 mg/cu m nose-only and 2100 mg/cu m whole body exposures. The level of significance for all cases was p < 0.05. The NOEL for developmental toxicity and teratology was determined to be 1000 mg/cu m. [R106] TCAT: ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female CD-1 rats administered the test substance by inhalation for 6 hours/day on days 6 to 15 of gestation at concentrations of 0, 150, 1000, or 2500 mg/cu m. Animals were sacrificed on day 21 of gestation. Maternal animals at 2500 mg/cu m showed a significant increase in absolute and relative liver weight. Reproductive parameters such as postimplantaion loss, live fetuses per litter, sex ratio and fetal body weights were unaffected by exposure to the test substance. The incidence of total external, total visceral, total skeletal, and total malformations were unaffected by exposure. Rats at 100 and 2500 mg/cu m showed reduced ossification of the humerus, zygomatic arch, and metatarsals and proximal phalanges of the hindlimb. The level of significance for all cases was p < 0.05. [R107] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 25 female CD-1 mice administered the test substance by inhalation for 6 hours/day on days 6 to 15 of gestation at concentrations of 0, 150, 1000, or 2500 mg/cu m. Animals were sacrificed on day 18 of gestation. Maternal animals at 100 and 2500 mg/cu m showed reduced body weight and body weight gain and reduced gravid uterine weight. A reduced number of viable implantations per litter and increased non-viable implantations were seen at 1000 and 2500 mg/cu m. Fetal body weights were also reduced at 100 and 2500 mg/cu m. There was an increased incidence of total external, visceral, and skeletal malformations at 1000 and 2500 mg/cu m. These malformations included exencephaly, cleft palate, foreshortened and abnormal face, abnormal facial bones, vertebral fusions, and fused, forked and missing ribs. The level of significance for all cases was p < 0.05. The NOEL (maternal and fetal) was 150 mg/cu m. [R107] ?Ethylene glycol (107-21-1) was evaluated for teratogenicity in groups of 30 female CD-1 mice administered the test substance by nose only exposure for 6 hours per day on days 6 through 15 of gestation at concentrations of 0, 500, 1000 or 2500 mg/cu m. Two additional groups were exposed to the test substance by whole body exposure at concentrations of 0 or 2100 mg/cu m. Animals were sacrificed on day 18 of gestation. Two females in the 0 mg/cu m nose-only control and 3 in the 2500 mg/cu m nose-only died due to apparent asphixiation or drowning caused by improper insertion of the nose-only inhalation device. Body weight and body weight gain were not affected in any of the dose groups. The 2100 mg/cu m whole-body exposure group showed an increased incidence of skeletal malformations, total malformations, and skeletal variations. Fused ribs were seen at 2500 mg/cu m nose-only. Extra ribs were seen at 2500 mg/cu m nose-only and 2100 mg/cu m whole body exposures. The level of significance for all cases was p < 0.05. The NOEL for developmental toxicity and teratology was determined to be 1000 mg/cu m. [R108] ADE: *DURING 4 HR FOLLOWING IV DOSE OF (14)C-ETHYLENE GLYCOL, URINARY EXCRETION OF (14)C WAS MORE RAPID FROM RATS (38%) THAN FROM RHESUS MONKEYS (10%), BUT EXCRETION IN EXPIRED AIR WAS SIMILAR (ABOUT 5%). SOME (14)C ENTERED BODY CARBON POOL. ORAL DOSE WAS ALSO MORE RAPIDLY EXCRETED BY RATS. [R109] *STUDY OF RENAL CLEARANCE OF ETHYLENE GLYCOL SUGGESTS THAT GLOMERULAR FILTRATION AND PASSIVE REABSORPTION ARE MAIN MECHANISMS INVOLVED IN RENAL EXCRETION OF ETHYLENE GLYCOL. [R56] *IN RABBIT, MAJOR END-PRODUCT OF METAB OF (14)C-ETHYLENE GLYCOL IS RESP CARBON DIOXIDE (60% OF DOSE IN 3 DAYS), AND METABOLITES EXCRETED IN URINE ARE UNCHANGED ETHYLENE GLYCOL (10%) AND OXALIC ACID (0.1%). [R110, 214] *THE PROPORTION OF ADMINISTERED (14)C (AS ETHYLENE GLYCOL) EXCRETED IN URINE OF RATS VARIED WITH DOSAGE, BEING 21% @ DOSE OF 0.1 G/KG AND 78% @ DOSE OF 7.5 G/KG. DISTRIBUTION OF RADIOACTIVITY 24 HR AFTER ADMIN ... TO RATS WAS HIGHEST IN BONES (2-10%); HIGHEST IN MUSCLE OF RABBITS (3.4%), ALTHOUGH LIVER CONTAINED 1.4 AND BONE 1.7% OF DOSE. [R111] *A DOSE-DEPENDENT CHANGE WAS OBSERVED IN DISPOSITION OF (14)C-LABELED ETHYLENE GLYCOL AFTER IV ADMIN OF 20, 200, 1000, and 2000 MG/KG TO FISCHER 344 RATS. PART OF THE DOSE WAS EXPIRED AS CARBON DIOXIDE AND DECR FROM 39% AT 20 and 200 MG/KG TO 26% AT 1000 and 2000 MG/KG, WHILE URINARY EXCRETION OF RADIOCARBON INCR FROM 35 TO 56%. AS DOSE INCREASED FROM 20 TO 2,000 MG/KG INCR IN URINARY (14)C WAS ALMOST ENTIRELY ATTRIBUTABLE TO (14)C-GLYCOLATE, WHICH COMPRISED 20% OF DOSE IN 24 HR AT TWO HIGHER DOSE LEVELS AND ONLY 2% AT LOWER DOSES. BLOOD CLEARANCE OF (14)C OCCURRED IN INITIAL RAPID PHASE (HALF-LIFE, 3-5 HR), WHEN PLASMA COMPRISED PREDOMINANTLY OF ETHYLENE GLYCOL, THAT PERSISTED FOR 12 HR AT 20 MG/KG AND 30 HR AT 2000 MG/KG ADMINISTERED IV TO FISCHER 344 RATS. [R112] *DOGS ADMIN 5 ML OF ETHYLENE GLYCOL ORALLY HAD 7.2-9.1 PPM OXALATE IN RENAL TISSUE AND 10-100 PPM IN URINE 8 HR AFTER ADMIN. HIPPURATE WAS 40-90 PPM IN URINE. CONCENTRATION OF ETHYLENE GLYCOL WAS 10-100 PPM IN RENAL TISSUE AND 5,300-27,000 PPM IN URINE. [R113] *Investigator drank ethylene glycol with 100 ml of water on separate occasions and collected his urine after each trial to quantify ethylene glycol and oxalic levels. 24-31% of the ethylene glycol was excreted in the urine in unchanged form within 24 to 36 hr, while urinary oxalic acid levels were elevated for 8 to 12 days. No oxalate crystals were found in the urine and no impairment of health from these doses was reported. [R114] *... Rats /were exposed/ (nose only) to (14)C-ethylene glycol vapor at a concentration of 32 ug/l for 30 min. Approximately 61 percent of the amount inhaled was deposited, largely in the nasopharyngeal region. The total amount retained was calculated to be equivalent to 0.9 + or - 0.3 g/kg for the males and 0.6 + or - 0.05 for the females. Blood levels of radioactivity were relatively constant for the first 6 hr post exposure, then declined by apparent first order kinetics with a half life of 53 hr. The predominant routes of elimination of the radioactivity were via the expired air and the urine, 55 to 70 percent at (14)CO2 and 14 to 26 percent, respectively, of the initial body burden. [R31, 3824] *Ethylene glycol is rapidly absorbed orally but not by lung or dermal routes. [R50, 805] METB: *IN OXIDATIVE METAB OF ETHYLENE GLYCOL IN MAMMALS, SPECIES VARIATIONS OCCUR WHICH EXPLAIN ... DIFFERENCES IN TOXICITY. GLYCOL IS OXIDIZED BY MAJOR PATHWAY INTO CARBON DIOXIDE, AND BY MINOR PATHWAY TO ... OXALIC ACID. EXTENT OF FORMATION OF OXALIC ACID IS DEPENDENT ON DOSE LEVEL, BUT HAS ... BEEN SHOWN TO VARY WITH SPECIES ... [R110, 118] *INITIAL STEPS IN OXIDATION OF ETHYLENE GLYCOL TO DIALDEHYDE (GLYOXAL) AND TO GLYOXYLIC ACID SEEM TO BE MEDIATED BY ALC DEHYDROGENASE; DECARBOXYLATION OF GLYOXYLIC ACID YIELDS CARBON DIOXIDE AND FORMIC ACID. GLYOXYLIC ACID IS ALSO OXIDIZED TO OXALIC ACID. [R47] *Rabbits and rats were given doses of 0.1-2.0 g/kg /of (14)C-ethylene glycol/. Rabbits received the doses orally or by subcutaneous injection, rats were given subcutaneous injections. In rabbits and rats, approximately 20% to 30% of the (14)C label from ethylene glycol (14)C was eliminated in the urine. Metabolites found in the 24-hr urine incl unchanged ethylene glycol (6.0 to 15.1%) and a trace of oxalic acid (0.1% [R115] *Excretion and tissue distribution in rats following iv dosing with 139 mg/kg of ethylene glycol-(14)C showed that 46.5% of (14)C was excreted in the urine by 24 hr. 14.4% was removed in expired air as (14)C carbon dioxide, 5% was in blood, 8.5% in 4.9% in brain, and 13.3% in carcass. A similar study in Rhesus monkeys yielded comparable data. [R116] *Oxalate is produced in vivo following the ingestion of ethylene glycol. [R117] *IN RABBIT, MAJOR END-PRODUCT OF METAB OF (14)C-ETHYLENE GLYCOL IS RESP CARBON DIOXIDE (60% OF DOSE IN 3 DAYS), AND METABOLITES EXCRETED IN URINE ARE UNCHANGED ETHYLENE GLYCOL (10%) AND OXALIC ACID (0.1%). ... GLYCOLALDEHYDE, GLYCOLLIC ACID AND GLYOXYLIC ACID ARE INTERMEDIATES IN CONVERSION TO CARBON DIOXIDE. [R110, 214] *Dogs that were admin 5 ml of ethylene glycol orally had extremely high levels (40-90 ppm) of hippurate in their urine. [R113] *Ethylene glycol is metabolised more rapidly than methanol, via alcohol dehydrogenase to glycolaldehyde which is rapidly metabolised to glycolate, the metabolite mainly responsible for the metabolic acidosis in ethylene glycol poisoning. Glycolate is metabolised by various pathways, including one to oxalate which rapidly precipitates with calcium in various tissues and in the urine. Ethylene glycol toxicity is complex and not fully understood, but is mainly due to the severe metabolic acidosis caused by glycolate and to the calcium oxalate precipitation. The clinical course in both poisonings is initially characterised by the development of metabolic acidosis following a latent period, which is more pronounced in methanol poisoning and is the time taken for alcohols to be metabolised to their toxic metabolites. [R118] *... Ethylene glycol is metabolized at a moderate rate to glycoaldehyde. Glycoaldehyde, however, is apparently metabolized nearly instantaneously to glycolic acid and glyoxal. Glyoxal, too, is rapidly metabolized while glycolic acid is slowly degraded. Glyoxylic acid, because it has not been hound in the urine, is also broken down rapidly, apparently to a large extent to carbon dioxide and water via the formic acid route. Its other metabolites are considered to be minor. [R31, 3828] *The liver oxidizes ethylene glycol primarily to glycolaldehyde, glycolate, and then glyoxylate. The metabolism of glyoxylate follows several pathways that depend on the cofactors thiamine and pyridoxine. The oxidation of ethylene glycol to glyoxylate and subsequently to oxalate requires the conversion of NAD to NADH. The altered NAD/NADH ratio shifts pyruvate to lactate and thereby helps produce lactic acidosis. The acidic metabolites are more toxic than the parent compound. The order of toxicity appears to be glyoxalate > glycolaldehyde > ethylene glycol. [R50, 805] *The ability of ethylene-glycol to be oxidized by microsomes was investigated using liver microsomes isolated from male Sprague-Dawley-rats. The oxidation of ethylene-glycol to produce formaldehyde was NADPH dependent and carbon-monoxide sensitive. Aniline, p-nitrophenol, pyrazole, 4-methylpyrazole, tryptamine, cimetidine, and micronazole inhibited the production of formaldehyde. Ethylene-glycol was oxidized at rates which were about twice those found with control microsomes in microsomes isolated from rats treated with pyrazole or 4-methylpyrazole to induce cytochrome p450IIEl. Formaldehyde production was inhibited by antibody raised against the pyrazole induced p450IIEl in microsomes from pyrazole treated rats. Hydrogen-peroxide itself did not oxidize ethylene-glycol to formaldehyde. However, stimulation of catalase or glutathione plus glutathione-peroxidase through added hydrogen-peroxide inhibited the microsomal reaction in the presence of NADPH. Formaldehyde production was also inhibited by desferrioxamine, EDTA and DTPA. Findings suggested that the oxidant derived from hydrogen-peroxide and iron and responsible for the production of formaldehyde from ethylene-glycol was not superoxide, hydroxyl radical, or lipid hydroperoxide. The authors suggest that ethylene-glycol is oxidized to formaldehyde by an oxidant derived from hydrogen-peroxide and nonheme iron, and that cytochrome p450 may function to generate the hydrogen-peroxide and to catalyze reduction of the nonheme iron. [R119] *Coma with grave metabolic acidosis, increased anion and osmolal gap, oxalate crystals in urine sediment and increased ultrasound density of the renal parenchyma are essential clues to the diagnosis of ethylene glycol poisoning. Envelope-like dihydrate calcium oxalate crystals are usually found in the sediment of these patients. We describe a patient with needle and cigar-shaped monohydrate calcium oxalate crystals in urinary sediment, but no detectable ethylene glycol in blood tests taken upon arrival at hospital 12 hours after ingestion. The patient was treated with alkali and hemodialysis, and recovered without any sequelae. Monohydrate calcium oxalate crystals were an essential clue for diagnosis of ethylene glycol poisoning in this patient. [R120] *Glycol ethers and glycol ether acetates are dehydrogenated to alkoxyacetic acid congeners which may serve as biological indicators of exposure. The ethereal bond may also be cut in an oxidation reaction catalyzed by the mixed function oxidase. In case of ethylene glycol, the eventual endproduct is oxalic acid. Urinary oxalic acid and alkoxyacetic acid excretion together was found to relate to the decrease of the succinate dehydrogenase activity as an indicator of renal mitochondrial effects. The excretion of ammonia by exposed workers was doubled as compared to controls. The excretion of chloride was found to be smaller in the exposed than in controls. The excretion of calcium and glycosaminoglycans among exposed workers were similar compared to controls. [R121] ACTN: *... Ethylene glycol produces central nervous system depression. ... The glycol probably causes the initial CNS depression; oxalate and the other intermediates seem to be responsible for nephrotoxicity. Formic acid produces the metabolic acidosis of ethylene glycol poisoning ... [R47] *Prognosis is excellent in both pisonings provided that there is early treatment with alkali to combat acidosis, ethanol as an antimetabolite, an haemodialysis to remove the alcohols and their toxic metabolites. [R39] *Previous studies have shown that the onset of ethylene glycol induced developmental toxicity corresponds with a dose-dependent shift in ethylene glycol metabolism, leading to accumulation of a weak acid metabolite, glycolic acid, and a resultant metabolic acidosis. To determine if glycolic acid accumulation is responsible for developmental toxicity, the effects of glycolic acid vs parent ethylene glycol were compared in whole embryo culture. Day 10.5 rat embryos were cultured for 46 hr in media containing 0.5, 2.5, 12.5, 25 or 50 mM ethylene glycol (all pH 7.5) or with glycolic acid at these same concentrations (pH 7.5-4.3). These concentrations reflected peak maternal plasma levels observed at a no observed effect levels dose ( 11 mM ethylene glycol, less than 2 mM glycolic acid), low observed effect level dose (21 mM ethylene glycol, 2 mM glycolic acid) or dose causing malformations (43 mM ethylene glycol, 13 mM glycolic acid), ethylene glycol up to 50 mM and glycolic acid at less than or equal to 2.5 mM were essentially without effect, while 12.5 mM glycolic acid significantly inhibited embryo growth, protein content and morphology score. Higher glycolic acid levels were lethal. Dysmorphogenesis mainly of the craniofacial region, was found in 70% of the 12.5 mM glycolic acid embryos vs 0% in controls. To determine the role of reduced pH in vitro, a second experiment was conducted in which embryos were cultured in 12.5 mM glycolic acid (pH 6.7), 12.5 mM sodium glycolate (pH 7.4) or in control medium (pH 7.4 or 6.71. Glycolate at pH 7.4 and control medium at pH 6.7 affected growth and development, although to a lesser extent than glycolic acid at pH 6.7. These results support the hypothesis that ethylene glycol developmental toxicity requires a shift in metabolism leading to high levels of glycolic acid, which then acts both intrinsically and via induction of metabolic acidosis. [R122] INTC: *... THE RELATION BETWEEN VITAMIN B6 AND MAGNESIUM WITH METAB OF ETHYLENE GLYCOL ... /WAS EXAMINED AND IT WAS/ CONCLUDED THAT VITAMIN B6 HAS MARKED EFFECT IN ACCELERATING ITS OXIDATION AND THAT DEFICIENCY OF /THIS/ VITAMIN IS ASSOCIATED WITH INHIBITION OF /ETHYLENE GLYCOL'S/ OXIDATION TO CARBON DIOXIDE. MAGNESIUM HAS A DIFFERENT MECHANISM OF ACTION IN PROVIDING GREATER DEGREE OF RESISTANCE TO CHRONIC TOXICITY OF ETHYLENE GLYCOL, POSSIBLY BY ALTERING SOLVENT CHARACTERISTICS OF URINE AND THUS PREVENTING RENAL DEPOSITION OF CALCIUM OXALATE. [R9, 596] *... /IT HAS BEEN/ DEMONSTRATED THAT HUMAN LIVER ALCOHOL DEHYDROGENASE BIOTRANSFORMED ETHYLENE GLYCOL AS WELL AS ETHANOL, METHANOL, AND OTHER ALCOHOLS. ETHANOL, WHICH IS MUCH BETTER SUBSTRATE FOR ALC DEHYDROGENASE THAN IS ETHYLENE GLYCOL, IS THUS A POTENT COMPETITIVE INHIBITOR OF ETHYLENE GLYCOL METABOLISM. [R123] *The combination of a lethal dose of ethylene glycol and pyrazole (as alcohol dehydrogenase inhibitor) produced 0% mortality in Wistar rats compared to 100% when only ethylene glycol was given. This expt suggests that ethylene glycol, per se, was not toxic, but the possible metabolic products were toxic. [R124] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *The appropriate minimum lethal dose is 1-1.5 ml/kg or approximately 100 ml in an adult. [R50, 805] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Ethylene glycol's production and use in numerous manufactured products may result in its release to the environment through various waste streams. If released to the atmosphere, ethylene glycol will mainly exist in the vapor phase in the ambient atmosphere based on a vapor pressure determined from experimentally derived coeeficients of 0.092 mm Hg at 25 deg C. Vapor-phase ethylene glycol is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 50 hours. An estimated Koc of 4 suggests that ethylene glycol will have very high mobility in soil. Biodegradation in both soil and water is expected to be a major fate process for this compound. Aerobic biodegradation is essentially complete in < 1-4 days although 100% theoretical biological oxygen demand may not be realized for several weeks. Under anaerobic conditions, ethylene glycol at 30 mg-C/l, with added glucose, was completely biodegraded within 7 days. Ethylene glycol is not expected to volatilize from moist soil or water surfaces based on an experimental Henry's Law constant of 6.0X10-8 atm-cu m/mole. It is not expected to bioconcentrate in aquatic organisms based on measured bioconcentration factors of 0.21-0.61 and 10 for crawfish and fish, respectively. Human exposure appears to be primarily from contact with antifreeze solutions, although industrial exposure during manufacture and use may also occur. (SRC) ARTS: *Ethylene glycol's production and use in numerous manufactured products(1) may result in its release to the environment through various waste streams(SRC). [R125] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 4(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that ethylene glycol will have very high mobility in soil(SRC). Percent adsorption to 4 soils (two clay and two sandy clay soils) ranged from 0-0.5%(4). Biodegradation of ethylene glycol in soil is expected to be a major fate process; complete biodegradation was shown in one soil within 2 days and 97% biodegradation in 12 days was reported for a second soil(5). Ethylene glycol at 100 ppm and 1000 ppm required 6 and 8 days, respectively, for complete biodegradation using a Mississippi soil inoculum(5). Biodegradation of aircraft deicing fluid components, containing ethylene glycol, was studied at 8 deg C using a soil collected from the side of an airport runway(6). Complete disappearance was reported in 29 days; 63% of the theoretical carbon dioxide was recovered after 34 days indicating that substantial mineralization was taking place(6). Volatilization of ethylene glycol will not be important from moist soil surfaces(SRC) given an experimental Henry's Law constant of 6.0X10-8 atm-cu m/mole(7) or from dry soil surfaces(SRC) based on a vapor pressure of 0.092 mm Hg(SRC) determined from experimentally-derived coefficients(8). [R126] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 4(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(1), indicates that ethylene glycol will not adsorb to suspended solids and sediment in the water(SRC). Both aerobic and anaerobic biodegradation of ethylene glycol in water are expected to be major fate processes; aerobic degradation is essentially complete in < 1-4 days although 100% theoretical biological oxygen demand may not be realized for several weeks(3-13). [R127] *AQUATIC FATE: In a river die-away test, degradation was complete within 3 days at 20 deg C and 5-14 days at 8 deg C(1). An initial ethylene glycol concentration of 111 ppm was biodegraded by 7, 48, 78, and 100% in 2, 3, 4, and 6 days, respectively, using a groundwater inoculum(2). Under anaerobic conditions, ethylene glycol at 30 mg-C/l, with added glucose, was completely biodegraded within 7 days(3). Ethylene glycol is not expected to volatilize from water surfaces based on an experimental Henry's Law constant of 6.0X10-8 atm-cu m/mole(4). A bioconcentration factor of 10 was reported for ethylene glycol in fish (Golden ide); algae (Chlorella fusca) had a bioconcentration factor of 190(5). Crawfish had measured BCF values from 0.21 to 0.61(6). [R128] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ethylene glycol, which has a vapor pressure of 0.092 mm Hg at 25 deg C, determined from experimentally-derived coefficients(2), will exist as a vapor in the ambient atmosphere. Vapor-phase ethylene glycol is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 50 hours(3,SRC). [R129] BIOD: *BIOLOGICAL OXYGEN DEMAND 0.47 G OXYGEN/G ETHYLENE GLYCOL; CHEMICAL OXYGEN DEMAND 1.29 G OXYGEN/G ETHYLENE GLYCOL. [R130] *There is a large body of information confirming the biodegradability of ethylene glycol in aerobic systems using activated sludge, sewage, and soil inocula. Degradation was essentially complete in < 1-4 days although 100% theoretical biological oxygen demand may not be realized for several weeks(1-10). In a river die-away test, degradation was completed in 3 days at 20 deg C and 5-14 days at 8 deg C(11). [R131] *With ethylene glycol at 100 mg/L, 83-96% of the theoretical BOD was reached within 14 days using activated sludge as an inoculum(1). In the BOD20 screening test 51, 80, 85, and 97% of the ethylene glycol was biooxidized in 5, 10, 15, and 20 days, respectively(2). In the OECD 301D screening test, 44, 83, and 96% of the ethylene glycol was biooxidized in 5, 15, and 28 days, respectively(2). 100% of the ethylene glycol added to Texas soil (sandy silt loam) at 100 ppm was biodegraded in 2 days; Mississippi soil (sandy loam) containing 100 ppm ethylene glycol showed 90, 95, and 97% biodegradation in 3, 4, and 12 days, respectively(3). An initial ethylene glycol concentration of 111 ppm was biodegraded by 7, 48, 78, and 100% in 2, 3, 4, and 6 days, respectively, using a groundwater inoculum(3). Ethylene glycol at 100 ppm and 1000 ppm required 6 and 8 days, respectively, for complete biodegradation using a Mississippi soil inoculum(3). Biodegradation of aircraft deicing fluid components, containing ethylene glycol, was studied at 8 deg C using a sandy loam soil collected from the side of an airport runway; corrected biodegradation rates of ethylene glycol ranged from 18.9-20.3 mg/kg/day, complete disappearance was reported in 29 days(4). Biodegradation resulted in mineralization of the parent compound as 63% of the theoretical carbon dioxide was recovered after 34 days(4). [R132] *Under anaerobic conditions, ethylene glycol at 30 mg-C/l was completely biodegraded within 7 days; glucose was added to this culture at 15 mg-C/l(1). Dilute organic wastes (13 lb COD/day/1000 cu ft), containing ethylene glycol at 135 mg/l were added to an anaerobic lagoon resulting in an effluent concentration of 30 mg/l ethylene glycol; anaerobic lagoons receiving concentrated wastes (22 and 48 lb COD/day/1000 cu ft) with ethylene glycol at 755 mg/l resulted in effluent ethylene glycol concentrations of 155 and 190 mg/l, respectively(2). [R133] ABIO: *The rate constant for the vapor-phase reaction of ethylene glycol with photochemically produced hydroxyl radicals has been experimentally determined as 7.7X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 50 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). Photooxidation in aqueous systems will not be significant(2,3). Glycols are known to be resistant to hydrolysis(4). [R134] BIOC: *The bioconcentration factor for ethylene glycol in fish (Golden ide) was reported to be 10 after 3 days of exposure(1). In algae (Chlorella fusca), the bioconcentration factor was 190 after 1 day(1). Crawfish were exposed to ethylene glycol at three concentrations (50 ug/ml, 200 ug/ml, and 1000 ug/ml) for 61 days and then transferred to clean water for 67 days; BCF values of 0.21 to 0.61 were recorded. Crawfish were able to completely eliminate the accumulated ethylene glycol within 5 days for animals exposed to 50 ug/ml and 6 days for those exposed to 200 and 1000 ug/ml ethylene glycol(2). This compound's extremely low octanol/water partition coefficient (log P = -1.36(3)) suggests that ethylene glycol will not bioconcentrate in fish(SRC). [R135] KOC: *Percent adsorption to 4 soils (two clay and two sandy clay soils) ranged from 0-0.5% indicating that this compound is not readily adsorbed to these soils and should have high mobility(1). Desorption was almost complete at the end of a 4 hour experiment using the same soils and a montmorillonite sample(1). Leaching experiments with undisturbed soil cores of sandy till showed that 14C-labelled ethylene glycol closely followed the movement of water when chloride was used as a tracer; no adsorption was observed for this compound onto subhorizons of sandy till, clayey till, and melt water sand(2). The Koc of ethylene glycol is estimated as approximately 4(SRC), using an experimental log Kow of -1.36(3) and a regression-derived equation(4,SRC). According to a recommended classification scheme(5), this estimated Koc value suggests that ethylene glycol has very high mobility in soil(SRC). [R136] VWS: *An experimental Henry's Law constant for ethylene glycol of 6.0X10-8 atm-cu m/mole(1) indicates that this compound should not volatilize from water surfaces(3,SRC). Ethylene glycol's vapor pressure of 0.092 mm Hg at 25 deg C(SRC), from experimentally derived coefficients(2), indicates that volatilization from dry soil surfaces is possible. Volatilization from moist soil surfaces is not expected based on the Henry's Law constant for this compound(1). [R137] EFFL: *Ethylene glycol is released during the production of polyethylene terephthalate(1). Ethylene glycol is primarily emitted by the synthetic organic chemical manufacturing industry(2). Ethylene glycol was measured in 7 formulations of paints, primers, and varnishes, making up 26-80.6% by weight of the VOC present in the coating formulation(3). This compound was also measured in one formulation of automobile antifreeze at 95.01% by weight of the VOC present(3). Ethylene glycol was detected, but not quantified in chemical effluent in Brandenburg, KY(4). [R138] ATMC: *SOURCE DOMINATED: Ethylene glycol was detected in emissions from water-borne architectural coatings; organic gas emissions from these coatings contained 44%, by weight, ethylene glycol(1). Emissions from industrial adhesives, based on composite samples of primers, lacquers, and enamels, contained 0.2%, by weight, ethylene glycol(1). Regionwide emission totals for ethylene glycol in the Los Angeles, CA region were 10X10+3 kg/day(2). [R139] *PERSONAL AIR: 15 minute air samples were taken from the inside of trucks being used to spray ethylene glycol on bridge surfaces; concentrations of ethylene glycol aerosol ranged from < 0.05 to 2.33 mg/cu m; concentrations of ethylene glycol vapor ranged from < 0.05 to 3.36 mg/cu m(1). [R140] RTEX: *CONTACT WITH SKIN AND EYES IS MOST LIKELY TO OCCUR IN INDUST HANDLING. INHALATION MAY BE A PROBLEM IF MATERIAL IS HANDLED HOT OR IF A MIST IS GENERATED BY VIOLENT AGITATION. SWALLOWING IS NOT LIKELY TO BE AN INDUST PROBLEM UNLESS MATERIAL IS STORED IN UNMARKED OR MISLABELED CONTAINERS. [R31, 3818] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1,133,792 workers (352,752 of these are female) are potentially exposed to ethylene glycol in the USA(1). Humans are exposed to ethylene glycol probably primarily from contact with antifreeze and coolants containing ethylene glycol(SRC). [R141] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Ethylene glycol is exempted from the requirement of a tolerance when used as a antifreeze or deactivator for all pesticides used before crop emerges from soil and in herbicides before or after crop emerges in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R142] *Ethylene glycol as a component of pesticide formulations is exempt from the requirement of a tolerance when used in foliar applications to peanut plants. [R143] OSHA: +Vacated 1989 OSHA PEL Ceiling value 50 ppm (125 mg/cu m) is still enforced in some states. [R23, 364] NREC: +NIOSH questioned whether the OSHA PEL proposed for ethylene glycol [ceiling 50 ppm] is adequate to protect workers from recognized health hazards. [R23, 136] TLV: +Ceiling Limit: 100 mg/cu m. /Aerosol only/ [R38] +A4; Not classifiable as a human carcinogen. [R38] ASTD: +Listed as a hazardous air pollutant (HAP) generally known or suspected to cause serious health problems. The Clean Air Act, as amended in 1990, directs EPA to set standards requiring major sources to sharply reduce routine emissions of toxic pollutants. EPA is required to establish and phase in specific performance based standards for all air emission sources that emit one or more of the listed pollutants. Ethylene glycol is included on this list. [R144] WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 7000 ug/l [R145] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 5500 ug/l [R145] +(FL) FLORIDA 14,000 ug/l [R145] +(MA) MASSACHUSETTS 14,000 ug/l [R145] +(ME) MAINE 5500 ug/l [R145] +(MN) MINNESOTA 10000 ug/l [R145] +(NC) NORTH CAROLINA 7000 ug/l [R145] +(NH) NEW HAMPSHIRE 7000 ug/l [R145] +(NJ) NEW JERSEY 290 ug/l [R145] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 5000 lb or 2270 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R146] FIFR: *Ethylene glycol is exempted from the requirement of a tolerance when used as a antifreeze or deactivator for all pesticides used before crop emerges from soil and in herbicides before or after crop emerges in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R142] *Ethylene glycol as a component of pesticide formulations is exempt from the requirement of a tolerance when used in foliar applications to peanut plants. [R143] +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Ethylene glycol is found on List D. Case No: 4033; Pesticide type: insecticide, fungicide, antimicrobial; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Ethylene glycol; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R7] FDA: *Ethylene glycol is an indirect food additive for use only as a component of adhesives. [R147] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH 5500: Analyte: Ethylene glycol; Matrix: air; Sampler: filter + sorbent (glass fiber filter + silica gel, 520 mg/20 mg); Flow rate: 0.2 l/min; Vol: min: 0.3 l; max: 60 l; Sample stability: greater than or equal to 15 days @ 25 deg C. [R148] ALAB: *NIOSH 5500: Analyte: Ethylene glycol; Matrix: air; Technique: gas chromatography, flame ionization detector; Desorption: 1 ml 2:98 (2-propanol:water); stand 5 min; Range: 0.02 to 1 mg per sample; Precision: relative std deviation: 0.060 (filters); 0.080 (silica gel); Est limit of detection: 4 ug per sample; Interferences: A ghosting phenomenon ... caused little or no error in measurements when samples were analyzed with standards at similar concn. [R148] *By direct injection- gas chromatography of samples at concn of at least 5 mg/l. Confirmatory analysis by a Porapak R column at 170 deg C is recommended. [R149] *Isothermal gas chromatography with flame ionization detection was used to detect residual ethylene oxide, ethylene chlorohydrin, and ethylene glycol in soft rubber catheters sterilized with ethylene oxide. Catheter samples were extracted by shaking with CS2, and the extract was analyzed on a 3% Carbowax 20M on 80-100 mesh Chromosorb 101 column, using nitrogen as the carrier gas. Ten replicate injections of a mixed standard solns gave relative standard deviations 1.91, 1.23, and 4.74% for ethylene oxide, ethylene chlorohydrin , and ethylene glycol, resp. A linear response was obtained with concns ranging from 1.0 to 7.9 ug ethylene oxide, 14.0 to 88.0 ug ethylene chlorohydrin, and 31.0 to 98.5 ug ethylene glycol. The proposed method detected as little as 0.5, 5.0, and 16.5 ng ethylene oxide, ethylene chlorohydrin, and ethylene glycol, respectively. [R150] *Method 8430. Analysis of Bis(2-chloroethyl)Ether Hydrolysis Products by Direct Aqueous Injection. [R151] *EAD Method 1666. Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by Isotope Dilution GC/MS. Detection Limit = 200 mg/l. [R152] *EAD Method 1671. Volatile Organic Compounds Specific to the Pharmaceutical Manufacturing Industry by GC/FID. Detection Limit = 100 mg/l. [R152] *Method 8015B. Non-Halogenated Organics Using GC/FID. [R151] CLAB: *DETERMINED BY DIRECT INJECTION OF BLOOD AND URINE /SAMPLES/ ONTO POLAR COLUMN IN GAS CHROMATOGRAPH EQUIPPED WITH FLAME IONIZATION DETECTOR. /IN ADDITION/, TISSUE AND STOMACH CONTENT SAMPLES ARE TREATED FIRST WITH 1.2 N PERCHLORIC ACID TO PRECIPITATE PROTEIN AND PREPARE THEM FOR GLC ANALYSIS. [R153] *APPLICATION OF ULTRAFILTRATION TO SAMPLE PREPN IN DETECTION AND QUANTIFICATION OF ETHYLENE GLYCOL IN BLOOD PLASMA BY GAS CHROMATOGRAPHY IS DESCRIBED. AFTER ADDITION OT THE BUTYLENE GLYCOL INTERNAL STANDARD AND ULTRAFILTRATION, THE SAMPLE IS DIRECTLY INJECTED, OBVIATING THE NEED FUR FURTHER DILUTION. [R154] *A simultaneous detection of ethylene and ethylene chlorohydrin, which are formed during steriliztion of bone and dura mater with ethylene oxide, was reported. The ethylene glycol and ethylene chlorohydrin residues. [R155] *Thin layer chromatography methods were developed to detect the presence of ethylene of glycol, diethylene glycol, polyethylene glycol, propylene glycol, and trimethylene glycol in glycerol. A preliminary separation was achieved on silica gel G layers using Me2CO-5N NH40H-CHCl3 (9:1:1, vol/vol). Total separation of all the constituents was obtained by 2-dimensional chromatography using the same solvent system and EtOAc-MeCN-(9:1, vol/vol) as the sec solvent system. A similar method for complete separation consisted of multiple development using EtOAc-MeCN (9:1, vol/vol) or Me2CO-CHC13-HOAc (3:6:1, vol/vol). Chromic acid-Sulfuric acid spraying reagent was used for detection of all glycols and glycerol and Dragendorff's reagent for detection of polyethylene glycol. The detection limit was 0.5% of the contaminant. [R156] *A modification of the technique for using the DuPont Automated Clin Analyzer triglyceride procedure is presented for screening serum samples for ethylene glycol. The modification involves adding 100 uL buffered ATP magnesium sulfate soln and 50 uL glycerol kinase soln to 100 uL patient's sample just before analysis. The modification makes the procedure faster, easier, and more economical to perform ethylene glycol screening. [R157] *Gas chromatography workplace air monitoring, Toxicant monitoring workplace air, Poison monitoring workplace air; Air analysis Toxic gas and vapor monitoring in, automated gas chromatography system for; Alarm devices For toxic gases and vapors in workplace air, gas chromatography system in; Automation Of gas chromatography system for toxic gas and vapor monitoring in workplace air; Chromatographs With photoionization defector, for toxic gases and vapors in workplace air Gas. [R158] *Ethylene glycol in plasma, urine, or dialysis fluid is analyzed as the phenylboronate derivation by mixing with methylene cyanide/acidified 2,2-dimethoxypropane containing phenylboronic acid. After centrifugation, a portion of the supernatant is analyzed directly by gas-liquid chromatography using a 3% OV-101 column at 150 degree and flame-ionization detection. Propane-1,3-diol is used as a reactive internal standard. The limit of accurate measurement is greater than or equal to 0.1 g/l and the linear range extends up to 5.0 g/l. No sources of interference have been identified. [R159] *Alkoxyacetate ions were extracted from 200 ul urine into methylene chloride, with tetrabutylammonium acting as counter ion, and derivatized with pentafluorobenzyl bromide in a single step. After separation of the methylene chloride phase, evaporation, and dissolution of the residues in hexane the esters were analyzed by fused silica capillary column gas chromatography and electron capture detection. The esters formed were stable for greater than or equal to 2 wk at room temp. The limit of quantification was apprx 2 uM (corresponding to an injected amount of 2 pg) for methoxyacetic acid and ethoxyacetic acid in urine. The corresponding values for butoxyacetic acid were 4 uM and 5 pg, resp. The detector response was linear ltoreq 80 uM and the formation of deriv at least up to 1 mM. The method error may be reduced by using a second alkoxyacetic acid deriv, ethoxyacetic acid, butoxyacetic acid, or 2-pentoxyacetic acid, as an internal standard. The sensitivity, stability, reduced number of extractions and small volumes of reagents and sample needed make the present method useful in biomonitoring of occupational exposure to ethylene glycol ethers. [R160] *A simple procedure for the detection of ethylene glycol in blood by capillary gas chromatography was developed. The proteins are precipitated by the addition of perchloric acid which includes the internal standard 1,2-butanediol. The extract is neutralized and the solution is directly injected. The assay is linear and the precision, expressed as coefficient of variation, is 4-11% (within run). The detection limit is apprx 0.05 g/l. The method also seems applicable for the detection of ethylene glycol in urine. [R161] *Ethylene glycol was detected in 1 ml of blood or tissue homogenate after mixing with 1.5 g anhydrous sodium sulfate and esterification with n-butylboronic acid (2 ml of 0.2% soln in Me2CO containing 1 g 1,3-butanediol as internal standard) for 15 s. The supernatant of the reaction mixture (1-2 uL) was injected into gas chromatography column with alkali-FID. The method is suitable for the detection of 0.5-5 g ethylene glycol/l in blood or liver with relative standard deviation ltoreg 10 or ltoreq 15%, resp. This simple and fast (15-min) method is suitable for toxicol emergency analyses. [R162] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: BALAZS T ET AL; MONOGR APPL TOXICOL 1 (NEPHROTOXICITY) p.487-97 (1982). A REVIEW ON THE NEPHROTOXICITY OF ETHYLENE GLYCOL. 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Cleveland: CRC Press, Inc., 1975. 163 R154: CUMMINGS KC, JATLOW PI; J ANAL TOXICOL 6 (6): 324-6 (1982) R155: Wu NM, Malinin TI; J Anal Toxicol II (2) 63-6 (1987) R156: Thakkar RA; J Oil Technol Assoc India (Bombay) 20 (3) 47-51 (1988) R157: Ochs ML et al; Clin Chem 34 (7) 1507-8 (1988) R158: Adams M, Collins M; Anal Proc (London) 25 (6) 190-1 (1988) R159: Flanagan RJ et al; Ann Clin Biochem 24 (1) 80-4 (1987) R160: Johanson G; Arch Toxicol 63 (2) 107-11 (1989) R161: Jonson JA et al; J Anal Toxicol 13 (1) 25-6 (1989) R162: Bogusz M et al; Z Rechtsmed 96 (1) 23-6 (1986) RS: 165 Record 319 of 1119 in HSDB (through 2003/06) AN: 5031 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-DIRECT-BLACK-38- SY: *AHCO-DIRECT-BLACK-GX-; *AIREDALE-BLACK-ED-; *AIZEN-DIRECT-DEEP-BLACK-EH-; *AMANIL-BLACK-GL-; *AMANIL-BLACK-WD-; *APOMINE-BLACK-GK-; *ATLANTIC-BLACK-C-; *ATUL-DIRECT-BLACK-E-; *AZINE-DEEP-BLACK-EW-; *AZOCARD-BLACK-EW-; *AZOMINE-BLACK-EWO-; *BELAMINE-BLACK-GX-; *BENCIDAL-BLACK-E-; *BENZANIL-BLACK-E-; *BENZO-LEATHER-BLACK-E-; *META-BLACK-; *BLACK-2EMBL-; *BRASILAMINA-BLACK-GN-; *BRILLIANT-CHROME-LEATHER-BLACK-H-; *CALCOMINE-BLACK-; *CARBIDE-BLACK-E-; *CHLORAMINE-BLACK-C-; *CHLORAZOL-BLACK-E- (BIOLOGICALSTAIN); *CHROME-LEATHER-BLACK-E-; *CI-DIRECT-BLACK-38-; *C.I.-DIRECT-BLACK-38,-DISODIUM-SALT-; *C.I.-30235-; *COIR-DEEP-BLACK-C-; *COLUMBUS-BLACK-EP-; *CORANIL-DIRECT-BLACK-F-; *DIACOTTON-DEEP-BLACK-; *DIAMINE-DEEP-BLACK-EC-; *DIAPHTAMINE-BLACK-V-; *DIAZINE-BLACK-E-; *DIAZOL-BLACK-2V-; *DIPHENYL-DEEP-BLACK-G-; *DIRECT-BLACK-A-; *DIRECT-BLACK-E-; *DIRECT-BLACK-META-; *DIRECT-BLACK-N-; *DIRECT-BLACK-Z-; *DIRECT-BLACK-3-; *DIRECT-BLACK-38-; *DIRECT-BLACK-BRN-; *DIRECT-BLACK-CX-; *DIRECT-BLACK-CXR-; *DIRECT-BLACK-EW-; *DIRECT-BLACK-EX-; *DIRECT-BLACK-FR-; *DIRECT-BLACK-GAC-; *DIRECT-BLACK-GW-; *DIRECT-BLACK-GX-; *DIRECT-BLACK-GXR-; *DIRECT-BLACK-JET-; *DIRECT-BLACK-METHYL-; *DIRECT-BLACK-RX-; *DIRECT-BLACK-SD-; *DIRECT-BLACK-WS-; *Disodium 4-amino-3-((4'-((2,4-diaminophenyl)azo)(1,1'-biphenyl)-4-azo)-5- hydroxy-6-(phenylazo)naphthalene-2,7-disulphonate; *ENIANIL-BLACK-CN-; *ERIE-BLACK-B-; *FENAMIN-BLACK-E-; *FIBRE-BLACK-VF-; *FORMALINE-BLACK-C-; *FORMIC-BLACK-C-; *HISPAMIN-BLACK-EF-; *INTERCHEM-DIRECT-BLACK-Z-; *KAYAKU-DIRECT-DEEP-BLACK-S-; *KAYAKU-DIRECT-DEEP-BLACK-EX-; *KAYAKU-DIRECT-DEEP-BLACK-GX-; *KAYAKU-DIRECT-LEATHER-BLACK-EX-; *KAYAKU-DIRECT-SPECIAL-BLACK-AAX-; *LURAZOL-BLACK-BA-; *MITSUL-DIRECT-BLACK-EX-; *MITSUL-DIRECT-BLACK-GX-; *2,7-NAPHTHALENEDISULFONIC ACID, 4-AMINO-3-((4'-((2,4-DIAMINOPHENYL)AZO)(1,1'-BIPHENYL)-4-YL)AZO)--5-HYDROXY-6-(P HENYLAZO)-, DISODIUM SALT; *NCI-C54557-; *NIPPON-DEEP-BLACK-; *NIPPON-DEEP-BLACK-GX-; *NSC-47756-; *NSC-8679-; *PAPER-BLACK-T-; *PAPER-BLACK-BA-; *PAPER-DEEP-BLACK-C-; *PARAMINE-BLACK-B-; *PHENAMINE-BLACK-E-; *SANDOPEL-BLACK-EX-; *TELON-FAST-BLACK-E-; *TERTRODIRECT-BLACK-E-; *TETRAZO-DEEP-BLACK-G-; *UNION-BLACK-EM- RN: 1937-37-7 MF: *C34-H27-N9-O7-S2.2Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Direct Black 38 is prepared commercially by: (1) coupling diazotized benzidine with 1 mol H-acid (8-amino-1-naphthol-3,6-disulphonic acid) under acid conditions, (2) reacting the resulting product with 1 mol diazotized aniline under alkaline conditions, (3) coupling this intermediate with meta-phenylenediamine, and (4) neutralization with sodium hydroxide. [R1] IMP: *The benzidine content of six US-produced samples of Direct Black 38 ranged from 2-20 mg/kg...In another study, the benzidine content of a Direct Black 38 sample was found to be < 0.1 mg/kg, but 150 mg/kg 4-aminobiphenyl and 9200 mg/kg 2,4-diaminoazobenzene (the hydrochloride of which is chrysoidine, were present. [R2] MFS: *Ciba Geigy Corp, 444 Saw Mill River Road, Ardsley, NY 10502-2699 (914) 479-5000 [R3] OMIN: *"PARAMINE" /IS/ TRADEMARK /OF ARKANSAS CO, INC/ FOR CATIONIC FINISHING AGENT FOR TEXTILES ... /PARAMINE/ [R4] *"PONTAMINE" /IS/ TRADEMARK /OF DU PONT DE NEMOURS, EI AND CO/ FOR SERIES OF DYES AND DEVELOPERS FOR TEXTILE FIBERS, PAPER AND LEATHER. /PONTAMINE/ [R5] *The commercial material is a reaction product and is not to be regarded as a single substance. [R1] *The manufacture and testing of Direct Black 38 do not conform to rigid chemical specifications, and its composition varies in order to meet the shade and intensity requirements of each customer. USE: *Direct Black 38 can be used to: (1) dye cellulose, wool, silk, bast, and hog's hair; (2) print cellulose, wool and silk; (3) dye leather, plastics, vegetable-ivory buttons and wood flour used as a resin filler; (4) stain wool, silk, acetate, nylon, wood and biological materials, and (5) produce aqueous inks. It has reportedly been used in hair dyes. [R1] PRIE: U.S. PRODUCTION: *374 thousand kg in 1978 [R1] U.S. IMPORTS: *95 thousand kg in 1980 [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Grey-black powder [R6] MW: *783.0 [R1] SOL: *Soluble in water; moderately soluble in ethanol and ethylene glycol monoethyl ether; insoluble in other organic solvents. [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: +Red fuming nitric acid. /Benzidine based dyes/ [R8, 26] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R9, 1979.8] +Wear appropriate personal protective clothing to prevent skin contact. /Benzidine based dyes/ [R8, 26] +Wear appropriate eye protection to prevent eye contact. /Benzidine based dyes/ [R8, 26] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. /Benzidine based dyes/ [R8, 27] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.) /Benzidine based dyes/ [R8, 27] +Recommendations for respirator selection: Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Benzidine based dyes/ [R8, 27] +Recommendations for respirator selection: Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Benzidine based dyes/ [R8, 27] OPRM: *The most effective control of Direct Black 38, Direct Brown 95, and Direct Blue 6, where feasible, is at the source of contamination by enclosure of the operation and/or local exhaust ventilation. If feasible, the process or operation should be enclosed with a slight vacuum so that any leakage will result in the flow of air into the enclosure. The next most effective means of control would be a well-designed local exhaust ventilation system that physically encloses the process as much as possible, with sufficient capture velocity to keep the contaminant from entering the work atmosphere. To ensure that ventilation equipment is working properly, effectiveness (eg, air velocity static pressure, or air volume) should be checked at least every three months. System effectiveness should be checked soon after any change in production, process, or control that might result in significant increases in airborne exposures to Direct black 38, Direct Brown 95, and Direct Blue 6. ... Exposure to Direct Black 38, Direct Brown 95, and Direct Blue 6 should not be controlled with the use of respirators except during the time period necessary to install or implement engineering or work practice controls, or in work situation in which engineering and work practice controls are technically not feasible, or for maintenance, or for operations that require entry into tanks or closed vessels or in emergencies. [R10, 699] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R9, 1979.11] +Contact lenses should not be worn when working with this chemical. /Benzidine based dyes/ [R8, 27] +The worker should wash daily at the end of each work shift. /Benzidine based dyes/ [R8, 27] +The worker should immediately wash the skin when it becomes contaminated. /Benzidine based dyes/ [R8, 27] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Benzidine based dyes/ [R8, 27] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Benzidine based dyes/ [R8, 27] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R9, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R9, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R9, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R9, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R9, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R9, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R9, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) No data for evidence in animals. Overall summary evaluation of carcinogenic risk to humans is Group 2A: The agent is probably carcinogenic to humans. /From table; Benzidine-based dyes/ [R11] MEDS: *Urine cytology surveillance has proved useful in evaluating tumors in dyestuff plant workers. The system consists of two-stage tests: periodic urine cytology, followed by, in suspicious cases, urological examinations. /Benzidine/ [R12] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R9, 1979.23] HTOX: *A strong association relating human exposure to benzidine based dyes with the subsequent development of bladder tumors was presented after a case-control mortality study of 200 bladder cancer patients in Japan. The patients were found to have been predominantly kimono painters and dyers. The kimono painters had a habit of forming a point on their brushes by drawing the brush between their lips, which allowed for ingestion of the dyes. Several other case-control mortality studies indicate an increased risk of developing bladder cancer in the textile and leather industries, both large users of direct dyes. However, only a few references have been made concerning benzidine-derived dyestuffs. In Russia, a medical study concerning the early detection of bladder tumors among textile dyers using benzidine-derived dyes revealed an unusual incidence of bladder lesions, some of which were suggested as being of a precancerous nature. The greatest number of such lesions were found in those workers with the highest potential exposure to these dyes. /Benzidine-based dyes/ [R10, 698] NTOX: *DIRECT BLACK 38 WAS CARCINOGENIC IN FISCHER 344 RATS FED 190-3000 PPM. HEPATOCELLULAR CARCINOMAS AND NEOPLASTIC NODULES IN LIVER. [R13] *DIRECT BLACK 38 WAS MUTAGENIC ON TESTER STRAINS OF SALMONELLA TYPHIMURIUM AFTER METAB ACTIVATION WITH MOUSE LIVER S9 FRACTIONS. [R14] *A group of 60 ICR mice (sex unspecified), 14 wk old, received 3000 mg/l Direct Black 38 in their drinking water for 55-60 wk, at which time the 59 surviving animals were killed. Hepatocellular carcinomas were found in 46/59 mice, and mammary carcinomas in 20/59; 9 animals developed both types of tumors. A further 40 mice were given the same concentration of Direct Black 38 in drinking water, and 2 mice were killed every two weeks starting from the 16th week of treatment. The first liver tumor occurred in a mouse killed 20 wk after the start of treatment. No liver or mammary tumor was reported to occur in a group of 20 untreated controls. [R15] *A group of 12 Wistar rats were administered 100 mg/l commercial Direct Black 38 (Direct Deep Black EX; benzidine free, as shown by high-performance liquid chromatography) in their drinking water. When the 8 rats still alive at 60 wk were killed, no tumor was observed. Of 15 rats administered 500 mg/l Direct Black 38, 13 carcinomas of the liver and 2 adenocarcinomas of the colon were observed in 6 animals. In addition, 9 survivors developed hyperplasia of the bladder mucosa, and 8, hyperplasia of the liver. No tumor was observed in a control group of 9 rats. [R15] *A group of 20 male and 25 female rats were given 500 mg/l Direct Black 38 in their drinking water (0.04%) for 14 months, at which time 4 males and 2 females were still alive. One of the females had breast cancer (pathological designation not specified); no other neoplasm was noted. [R15] *Bladder implantation: Two groups of 50 female dd mice (20 g) received either a paraffin wax pellet (20 mg) containing 10% Direct Black 38 or a wax pellet alone implanted in the bladder. After 40 wk, when the surviving animals were killed, one bladder carcinoma was observed among the 21 mice still alive. In the control group, one bladder carcinoma was observed in 36 surviving mice. [R15] *Studies in which rats were fed diets containing 190-3000 mg/kg Direct Black 38 and mice 750-12,500 mg/kg for 13 wk resulted in a series of dose and substance related changes, seen when all animals were killed at the end of treatment. In rats, portal fibrosis and multifocal necrosis of the liver were observed; lymphoid depletion in spleen, and thymus and myeloid depletion of the bone marrow were also seen. Other effects included hemosiderosis of the spleen and intersitial hemorrhage and seminiferous tubular degeneration in the testis. Biliary hyperplasia was seen with doses of 750 mg/kg and above. In mice, diffuse hepatocellular degeneration, biliary hyperplasia and pigment deposition in the liver, haemosiderosis of the spleen and kidney, and pigment deposition in the thyroid were observed. [R15] *Wistar rats were injected subcutaneously on days 7, 8, and 9 of pregnancy with 10 mg (about 40 mg/kg bw per day) Direct Black 38 (Chlorazol black E, biological stain quality). Three of the 16 dams died and 4 resorbed completely, but no malformations were observed in the 70 fetuses that survived to term. [R16] *The genotoxicity of Direct Black 38, a benzidine derived azo dye, was studied in rats. Male Wistar rats were given 0, 10, 100, 500, or 1000 mg/kg Direct Black 38 orally dissolved in water or corn oil. The exposure times were 12, 24, or 36 hr. Genotoxicity was evaluated by measuring unscheduled DNA synthesis in the liver and induction of micronuclei in bone marrow taken from the femur. The percentage of hepatocytes in the S-phase was also determined. Direct Black 38 at 10 and 100 mg/kg in water after 12 hr exposure had no effect on unscheduled DNA synthesis, whereas the 500 and 1000 mg/kg doses caused an induction of unscheduled DNA synthesis. After 36 hr exposure, a dose dependent induction of unscheduled DNA synthesis occurred. Direct Black 38 in corn oil caused a dose dependent induction of unscheduled DNA synthesis at both 12 and 36 hr. Direct Black 38 had no effects on S-phase hepatocytes. Direct Black 38 in water showed a weak dose dependent induction of bone marrow micronuclei after 36 hr exposure. The response was statistically significant at 500 and 1000 mg/kg. When Direct Black 38 was dispersed in corn oil, the only induction of micronuclei was noted at 1000 mg/kg. It was concluded that the observed induction of liver unscheduled DNA synthesis due to Direct Black 38 with no indication of an increase in S-phases indicates that its carcinogenic effects on the liver are primarily due to a genotoxic effect. Direct Black 38 metabolites might also be reactive in tissues distal to the liver. [R17] *The mutagenic potentials of the azo dyes, direct black 38, direct blue 15, and direct red 2, and their aromatic amine reduction products were tested employing the Ames test and the arabinose resistant assay of Salmonella typhimurium. S9 fractions were prepared from the livers of Sprague-Dawley rats and Syrian golden hamsters, and Salmonella typhimurium strains (TA-98) and (SV-50) were used in the mutagenicity tests. All three azo dyes tested were mutagenic in both the Ames and arabinose resistant assays; however the Ames test yielded relatively higher mutagenic responses than the arabinose resistant assay. Relatively higher mutagenic responses were observed with hamster S9 than with rat S9 in both assays. Direct black 38 produced higher mutagenic responses in both assays than the other two dyes. The reduction products, benzidine, o-dianisidine, and o-tolidine were all mutagenic in the Ames test. In the arabinose resistant assay, benzidine was only weakly mutagenic, and o-dianisidine and o-tolidine were nonmutagenic. It was concluded that both the Ames test and arabinose resistant assay are sensitive in testing the mutagenicity of azo dyes, but the Ames test is more efficient than the arabinose resistant assay in detecting mutagenicity of the aromatic amine reduction products of these dyes. [R18] *The mutagenic activities of Direct Black 38 and four of its identified metabolites, benzidine, monoacetylbenzidine, 4-aminobiphenyl and 4-acetylaminobiphenyl in Salmonella typhimurium (TA-98) were examined. The assays were conducted without exogenous activation, with S9 prepared from Aroclor induced rats, with hamster S9, and with hamster S9 supplemented with a source of reducing equivalents. Hamster S9 activation produced the highest mutagenic activities, rat S9 somewhat lower responses and none of the tested compounds displayed any appreciable mutagenic activity without exogenous activation. All previously identified metabolites of Direct Black 38 were highly mutagenic in Salmonella typhimurium (TA-98) and all could contribute to the genotoxicity of the azo dye. As hamster S9 produced the highest mutagenic responses with Direct Black 38 and metabolites, this system was used to test the mutagenicities of the extracts from the incubations conducted with human intestinal microflora. Human intestinal microflora rapidly reduced the azo linkages of Direct Black 38 with a corresponding increase in mutagenicity. This increase in mutagenicity appeared to be due to the formation of benzidine, 4-aminobiphenyl and their acetylated derivatives which were then metabolically activated to mutagens by hamster liver S9. In addition, although 1,2,4-triaminobenzene formation was not determined, this aromatic amine was likely produced when Direct Black 38 was reduced and could have contributed to the overall mutagenicity of the microbial extracts. [R19] *The activity of benzidine and three structurally related carcinogens in an in vivo/in vitro rat liver assay for unscheduled DNA synthesis is described. The first three of these chemicals, benzidine, 4-aminobiphenyl and Direct Black 38 have been reported as positive in this assay by other investigators, albeit the data reported for 4-aminobiphenyl were limited. The fourth compound, 3,3'-dichlorobenzidine has not been studied in this assay before. Each compound gave a clear positive response under conditions of routine testing. [R20] *In mice and rats, prenatal exposure to the dye Congo red permanently reduces the number of germ cells in male and female offspring. In the current investigation, nine dyes structurally related to Congo red were examined for developmental testicular toxicity. Only benzidine based dyes altered testicular development and caused hypospermatogenesis in mice during adulthood. Dimethyl- and dimethoxy-benzidine-based dyes were without effect. Pregnant mice were dosed orally on days 8-12 of gestation with a benzidinedimethlybenzidine-, or a dimethoxybenzidine-based dye and the testes of 45 to 50 day old male offspring were examined. The testes of postpubertal male offspring exposed to the benzidine based dyes, Congo red, diamine blue, and Chlorazol Black E, were small and contained some tubules completely devoid of germ cells, but the dimethlybenzidine based dyes, trypan blue, Evans blue, and benzopurpurin 4B, and the dimethoxybenzidine based dye, Chicago sky blue, did not alter testicular development in this manner. Azoic diazo component 48, a dimethoxybenzidine congener, and two other diazo dyes, naphthol blue black and Sudan III, were also without effect on the germ cells. Experiments with Chlorazol Black E indicate that the period of susceptibility in the male fetus is limited to the period of primordial germ cell migration and division. When Chlorazol Black E was administered on days 8-10 of gestation it reduced testis weight after puberty by 30%, while treatment after day 13 did not affect testicular function. The structure-activity relationship of the dyes for developmental toxicity following oral administration differs considerably from that produced by maternal ip administration. [R21] NTP: *Thirteen wk subchronic toxicity studies of Direct Black 38 ... was conducted by administering the test /cmpd/ in feed to Fischer 344 rats and B6C3F1 mice. Groups of 10 rats and 10 mice of each sex were administered /the test cmpd/ at one of five concentrations for 13 wk and then necropsied, beginning the second day after the end of the dosing period. The concentrations used for the rats were 190, 375, 750, 1,500 and 3,000 ppm. The concentrations used for the mice were 750, 1,500, 3,000, 6,000, and 12,500 ppm. ... Matched controls consisted of groups of 10 untreated rats and 10 untreated mice of each sex. ... It is concluded that under the conditions of /this/ 13 wk subchronic toxicity study, ... Direct Black 38 /was/ carcinogenic in male and female Fischer 344 rats. /Direct Black 38/ was not carcinogenic for B6C3F1 mice in the 13 wk subchronic toxicity study. [R22] TCAT: ?The mutagenicity of Erie brilliant black s (EBB) was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Based on preliminary bacterial toxicity determinations, EBB was tested for mutagenicity at concentrations up to 400 ug/plate using the plate incorporation method. EBB caused a positive response in bacterial tester strains TA1538 and TA98 with activation. EBB did not cause a positive response in any of the other bacterial tester strains, either with or without metabolic activation. [R23] ?Acute oral toxicity was evaluated in groups (size not reported) of fasted Sprague-Dawley rats (mixed male and female) administered a single dose of Erie Black as a 20% w/v corn oil suspension by oral gavage at a level of 1262, 3024, 7096, 7962, 8934, or 10020 mg/kg body weight. Corresponding mortality rates were 0, 0, 33, 50, 83 and 100%. The LD50 value was calculated to be 7600 mg/kg with a confidence interval of 6666 to 8664 mg/kg. Clinical observations included blackish diarrhea, dark urine, atonia, loss of the righting reflex, debility, ataxia, tremors and convulsions. Necropsy observations included deep coloration of the gastrointestinal tract and enlarged adrenals. [R24] ?Acute oral toxicity was evaluated in groups of 2 fasted New Zealand albino rabbits (mixed male and female) administered a single dose of Erie Black as a 20% w/v corn oil suspension by oral gavage at a level of 317, 632, 1262, or 3024 mg/kg body weight. Mortality was observed in all animals in the 2 highest dose groups and the MLD (minimum lethal dose) was calculated to be 632 mg/kg. Clinical observations included blackened urine and feces and emaciation. Necropsy observations included deep coloration of the gastrointestinal tract, sloughing of the gastric mucous, renal congestion, coloration of the peritoneum, an accumulation of serous fluid in the pleural cavity and a purplish-black coloration of the kidneys. [R24] ?Acute oral toxicity was evaluated in groups of male and female Sprague Dawley albino rats (6 animals/group) administered single doses of Erie Black GX00 Conc (direct black 38) as a 20% w/v corn oil suspension by oral gavage at levels of 1262 (2 animals), 5024, 7096, 7962, 8934 and 10020 mg/kg of body weight. Mortality was observed in 2 animals in the 7096 mg/kg dose group, 3 in the 7962 mg/kg dose group, 5 in the 8934 mg/kg dose group and all 6 animals in the highest dose group. The LD50 was calculated to be 7600 mg/kg (6666 to 8664 mg/kg) by the Litchfield and Wilcoxon method. Clinical observations included diarrhea, dark-colored urine, atonia, loss of the righting reflex, debility, ataxia, tremors, clonic convulsions and malaise. Gross necropsy revealed deep coloration of the gastrointestinal tract and its contents in decedents, and enlarged adrenals in 3 survivors. [R25] ?Acute oral toxicity was evaluated in groups of New Zealand albino rabbits (1 female and 1 male/group) administered single doses of Erie Black GX00 Conc as a 20% w/v corn oil suspension by oral gavage at levels of 317, 632, 1262 and 5024 mg/kg of body weight. Mortality (100%) was observed in the 1262 and 5024 mg/kg dose groups. The MLD was reported to be between 632 and 1262 mg/kg. Clinical observations included a blackish coloration of the urine and feces, emaciation and malaise. Gross necropsy revealed a deep coloration of the gastrointestinal tract and its contents with slight sloughing of the gastric mucosa in decedents, and a purplish-black coloration of the kidneys in survivors. [R26] ?Acute dermal toxicity was evaluated in groups of male and female New Zealand albino rabbits exposed to a single occluded dose of Erie Black as a thin corn oil paste to either abraded or intact skin at a level of 2000, 4000, or 8000 mg/kg body weight for 24 hours. Mortality was not observed in any animal and the LD50 was determined to be greater than 8000 mg/kg. Clinical observations included darkened urine in some of the animals with abraded skin and a deep crimson stain on the skin of all treated animals. Necropsy observations included serous fluid in the peritoneal cavity of 1 animal and in the pleural cavity of another. [R24] ?Acute inhalation toxicity was evaluated in 10 Sprague-Dawley rats (mixed male and female) exposed to a concentrated atmosphere of Erie Black dust for 1 hour. The method of test atmosphere generation was not reported. Mortality was observed in 1 animal 14 days after exposure and an LC50 value was not reported. Clinical observations included weakness and emaciation in the decedent and normal activity and weight gain in the other animals. Because of advanced autolysis, a gross necropsy was not performed on the decedent. Examination of the remaining animals revealed pulmonary abscess in 1 animal and kidney damage in another. [R24] ?Acute inhalation toxicity was evaluated in 10 male and female Sprague-Dawley albino rats exposed to a concentrated atmosphere of Erie Black GX00 Conc dust at a flow concentration of approximately 180 mg/liter for 1 hour. Particle size ranged from < 2 microns to > 20 microns (90% < 5 microns). Mortality was observed in 1 animal; an LC50 value was not reported. Clinical observations included emaciation and weakness in the decedent; others appeared normal. Gross necropsy revealed a pulmonary abscess in 1 survivor and kidney damage in another; autolysis prevented necropsy of the decedent. [R27] ?C.I. Direct Black 38 (CAS# 1937-37-7) was evaluated for developmental toxicity. Ninety- five, 31, 25, 44, 24, and 25 pregnant dams were administered 0, 100, 150, 200, 300, and 400 mg/kg/day of the test material, respectively, on days 6-15 of gestation (the method of administration was not reported). Four of 44, 2/24, and 2/25 dams died at 200, 300, and 400 mg/kg/day, respectively. At 150 and 400 mg/kg/day significantly (p < 0.05) increased weight gains were observed during pregnancy. The increase in average liver weight significantly (p < 0.001) increased at all doses tested except 400 mg/kg/day. There was a significant (p < 0.02) increase in percent resorptions at 100 mg/kg/day or above. In addition, the number of live fetuses was significantly (p < 0.01) reduced at 400 mg/kg/day. Significant (p < 0.01) decreases of average fetal weights were reported at all doses tested. All dose levels caused a significant (p < 0.01) increase in the average percent of malformed fetuses. Skeletal malformations were significantly (p < 0.01) increased at all doses except 150 mg/kg/day. Malformed centra were significantly (p < 0.05) increased at 200 mg/kg/day and above. Fused arches and ribs were significantly (p < 0.05) increased at 200 and 400 mg/kg/day. External malformations were significantly (p < 0.05) increased at 200 mg/kg/day and above as were visceral malformations at 300 mg/kg/day and above. Cleft palate and tail malformations were significantly increased at 300 and 400 mg/kg/day. Lesions in the left cardiac ventricle were significantly increased at 300 mg/kg/day. [R28] ADE: *Urine samples of 18 workers in a small scale unit manufacturing Direct Black 38 were /determined/ by high-pressure liquid chromatography for the presence of benzidine and mono and diacetyl benzidine. Acetylated metabolites were found in all the urine samples, and benzidine was found in all except two. Two workers excreted very high levels of benzidine and its metabolites in their urine. This study highlights the potential risk of bladder cancer in such units of developing countries where manufacture of benzidine based dyes is yet to be regulated. [R29] *The time course of dermal absorption of two azo dyes was investigated in rats and rabbits. A benzidine derived dye, CI Direct Black 38 and a related dye CI Direct Black 19 which contained a p-phenylenediamine moiety instead of benzidine, were employed. Specific pathogen free male New Zealand white rabbits and male Fischer 344 rats were shaved on the left dorsum and radiolabeled dye was applied to a 2 centimeter by 2 centimeter area. ... Radioactivity from CI Direct Black 38 treated rats appeared in urine and feces in negligible quantities. Cumulative excretion of radioactivity at 144 hours was 0.05% of the total dermal dose in the urine and 0.16% in the feces. Cumulative excretion of radioactivity from CI Direct Black 38 dosed rabbits was higher at 144 hours: 3.12% of total dermal dose in urine and 5.12 in feces. At 144 hours excretion of radioactivity from CI Direct Black 38 dosed animals of both species was still increasing. ... CI Direct Black 38 is less stable on rabbit skin under experimental conditions than CI Direct Black 19, although differences in skin permeability and microflora may be partially responsible [R30] METB: *SINGLE DOSE (100 MG/KG) OF PURIFIED DIRECT BLACK 38 ADMIN TO HAMSTERS REVEALED BY URINE ASSAY HIGH LEVELS OF BENZIDINE, MONOACETYLBENZIDINE, DIACETYLBENZIDINE, 4-AMINOBIPHENYL, AND ALKALINE HYDROLYZABLE CONJUGATES OF BENZIDINE AND 4-AMINOBIPHENYL DURING 1ST 8 HR OF EXCRETION [R31] *DIRECT BLACK 38 WAS SHOWN TO BE METABOLIZED IN ANIMALS TO HUMAN CARCINOGEN BENZIDINE. [R32] *Caution is also indicated by preliminary results from the NIOSH field studies showing that humans working with these same dyes /Direct Black 38, Direct Brown 95, and Direct Blue 6/ also excrete higher than expected levels of benzidine in their urine. Both laboratory and field studies indicate that these benzidine derived dyes can be metabolized to benzidine, which is present in the urine of animals and humans. Based on the data from the short-term study, National Cancer Institute scientists believe that a cancer causing potential exists on exposure to the benzidine derived dyes, most likely through the mechanism of metabolic conversion of the dyes to benzidine in the animal system. [R33] *Benzidine and monoacetylbenzidine were found in the urine of rats and mice on the course of 13-week subchronic toxicity studies with Direct Black 38. Analysis of 24-hour urine samples 4 and 12 weeks (rats) and 3 and 11 weeks (mice) later showed a clear-cut relationship between the concentration of dyestuff in the food consumed and the amount of benzidine excreted. Mice biotransformed considerably more dye to benzidine than did rats. [R16] *Rhesus monkeys excreted an average of 1.25% benzidine plus monoacetylbenzidine of the benzidine moiety in the Direct Black 38 in the urine after receiving two different doses by gavage, whereas gavage with pure benzidine yielded 1.45%. [R16] *Following oral administration of a single dose of 10 mg/kg body weight Direct Black 38 to Syrian golden hamsters, 10.7 ug benzidine, 535 ug monoacetylbenzidine, 27.6 ug diacetylbenzidine [see IARC, 1978], 1.5 ug 4-aminobiphenyl and, as alkaline hydrolyzable conjugates, 328.5 ug benzidine and 6.3 ug 4-aminobiphenyl, were identified in the urine by parallel electron capture gas chromatography and high performance liquid chromatography. Peak excretion occurred between 0-8 and 8-16 hours. These results indicate that a total of 10% of the dye is metabolized to benzidine and its metabolic follow up products. [R16] *The role of the rat intestinal flora in the azo reduction of some benzidine based dyes was studied in vitro and in vivo. The formation of benzidine was measured after anaerobic incubation of direct black 38, direct blue 6 and direct brown 95 in the presence of cecal bacteria in vitro. Benzidine was absorbed from the intestinal tract much better than the parent compounds. Oral administration of direct black 38 or direct brown 95 to Wistar rats results in the urinary excretion of mutagens. After oral administration of these dyes to germ free Wistar rats no mutagenicity was observed in urine. The present results show that after oral administration, reduction by the intestinal flora should be considered as the first essential step in the biotoxification of benzidine based dyes. [R34] *Metabolism of the benzidine based dye Direct Black 38 was examined by using a semicontinuous culture system that simulates the lumen of the human large intestine. The system was inoculated with freshly voided feces, and an active flora was maintained. Within 7 days after exposure to the dye, the following metabolites were isolated and identified by gas chromatography-mass spectrometry: benzidine, 4-aminobiphenyl, monoacetylbenzidine, and acetylaminobiphenyl. Benzidine reached its peak level after 24 hr, accounting for 39.1% of the added dye. Its level began to decline, and by day 7 the predominant metabolite was acetylaminobiphenyl, which accounted for 51.1% of the parent compound. [R35] *Six azodyes derived from benzidine, o-tolidine or o-dianisidine were separately administered orally by gavage to rats. Urine was collected over a 24 hr period. ... All six dyes, direct black 38, direct brown 95, direct blue 6, Congo red, trypan blue and Chicago sky blue were found to be reduced, N-acetylated and N-conjugated. However, no N,N-diacetylated metabolites were detected. After administration of the same dyes via injection into the hepatic portal vein, bile was collected over a 3 hr period by cannulation of the bile duct. Urine was withdrawn from the bladder by syringe at the end of the three hours. Both body fluids were analyzed for reduction products which were found only in the case of direct black 38, direct brown 95 and direct blue 6. Of the six dyes examined only the three direct dyes were mutagenic to S. typhimurium strains TA98 and TA1538 in the absence of flavin mononucleotide. The same three dyes were also substrates for rat liver microsomal azoreductase enzymes whereas Congo red, trypan blue and Chicago sky blue were shown to be inactive. [R36] *The ability of rat liver microsomes from phenobarbitone pretreated animals to reduce the azo groups of amaranth, sunset yellow,congo red, trypan blue, chloramine sky blue FF and direct black 38 was measured spectrophotometrically in vitro. The dyes amaranth and sunset yellow acted as positive controls. Of the dyes derived from benzidine or its congeners, only direct black 38 was reduced to an appreciable extent; the rate of reduction was 10% of that for amaranth. The dyes were tested for mutagenicity in the Salmonella/microsome assay, the only active compound being direct black 38. ... Mutagenic activity and azo-reduction of direct black 38 wad independent of the presence of oxygen. [R37] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *C.I. Direct Black 38's production and use as a dye for cellulose, wool, silk, bast, hog's hair, and leather, plastics, and wood flour used as a resin filler, and to produce aqueous inks may result in its release to the environment through various waste streams. If released to the atmosphere, C.I. Direct Black 38 exists solely in the particulate phase in the ambient atmosphere due to its ionic nature. Particulate-phase C.I. Direct Black 38 may be physically removed from the air by wet and dry deposition. An estimated Koc of 300 suggests that C.I. Direct Black 38 will have moderate mobility in soil although its ionic nature may result in ion-exchange processes with clay that would retard leaching. Volatilization from dry and moist soil surfaces is not expected to be a major fate process for this compound. Based on limited data this compound may biodegrade in both soil and water with the formation of benzidine and related products. C.I. Direct Black 38 may biodegrade anaerobically as a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines. C.I. Direct Black 38 is not expected to volatilize from water surfaces or to adsorb to sediments or particulate matter in water. This compound is not expected to bioconcentrate in aquatic organisms based on an estimated bioconcentration factor of 20. It has been detected in the workplace air of both textile- and paper-dyeing facilities. The most likely routes of occupational exposure to the dye are inhalation and dermal contact. (SRC) NATS: *CI Direct Black 38 has not been reported to occur naturally(1). [R38] ARTS: *C.I. Direct Black 38's production and use as a dye for cellulose, wool, silk, bast, and hog's hair, used to print cellulose, wool and silk, to dye leather, plastics, vegetable-ivory buttons and wood flour used as a resin filler, to stain wool, silk, acetate, nylon, wood and biological materials, and to produce aqueous inks(1) may result in its release to the environment through various waste streams(SRC). It has also reportedly been used in hair dyes(1). [R38] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 300(SRC), determined from an estimated log Kow of 2.0(2,SRC) and a recommended regression-derived equation(3), indicates that C.I. Direct Black 38 will have moderate mobility in soil(SRC). Due to the ionic nature of the dye(4), the retention of the dye by ion-exchange processes, particularly on clay surfaces and adsorption at mineral surfaces such as geothite(5), may slow down or prevent leaching(SRC). Volatilization of C.I. Direct Black 38 is not expected to be important from dry soil surfaces(SRC) based on its estimated vapor pressure(6,SRC). Since ionic compounds normally do not evaporate, no loss of the dye from soil is expected to occur due to evaporation(SRC). C.I. Direct Black 38 was found to biodegrade in a soil with the formation of benzidine products, although no data on the rate of biodegradation was provided(7). These results indicate that complete mineralization of the dye is a slow process, although the rate of the process leading to cleavage of the azo group producing benzidine products may be faster(7). C.I. Direct Black 38 may be readily biodegraded anaerobically as a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(8). [R39] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 300(SRC), determined from an estimated log Kow of 2.0(2,SRC) and a recommended regression-derived equation(1), indicates that C.I. Direct Black 38 is not expected to adsorb to suspended solids and sediment in the water(SRC). C.I. Direct Black 38 was found to biodegrade in a river water with the formation of benzidine products, although no data on the rate of biodegradation was provided(3). A 5-day BOD value, 8% of the theoretical value, was determined(4). These results indicate that complete mineralization of the dye is a slow process, although the rate of the process leading to cleavage of the azo group producing benzidine products may be faster(3). C.I. Direct Black 38 may be biodegraded anaerobically; a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(5). Since the dye is an ionic compound(6), evaporation of the dye from water will not be important. An estimated BCF value of 20(1,SRC), from an estimated log Kow(2,SRC), suggests that C.I. Direct Black 38 will not bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(7). [R40] *ATMOSPHERIC FATE: The ionic state of C.I. Direct Black 38 makes this compound essentially nonvolatile(1,SRC); therefore this compound should exist solely in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Direct Black 38 may be physically removed from the air by wet and dry deposition(SRC). [R41] BIOD: *A 5-day BOD value of 8% of the theoretical value has been determined for this dye(2). C.I. Direct Black 38 biodegraded to benzidine in both river water and soil(1). Benzidine did not degrade further in over 9 days(1). This compound may be biodegraded anaerobically; a wide variety of anaerobic bacteria have the ability to cleave the azo linkage to produce aromatic amines(3). [R42] BIOC: *An estimated BCF value of 20 was calculated for C.I. Direct Black 38(SRC), using an estimated log Kow of 2(1,SRC) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration of C.I. Direct Black 38 in aquatic organisms will not be an important fate process(SRC). [R43] KOC: *The Koc of C.I. Direct Black 38 is estimated as approximately 300(SRC), using an estimated log Kow of 2(1,SRC) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that C.I. Direct Black 38 has moderate mobility in soil(SRC). Due to the ionic nature of the dye, the retention of C.I. Direct Black 38 by ion-exchange porcesses(4), particularly on clay surfaces and adsorption at mineral surfaces such as goethite(5), may slow down or prevent leaching(SRC). [R44] VWS: *As C.I. Direct Black 38 is an ionic compound(1), volatilization from water and soil surfaces will not be important(SRC). [R38] RTEX: *Two probable routes of exposure to C.I. Direct Black 38 for workers are inhalation exposure of the powder during manufacture, packing and shipping, and dermal exposure of the solution and powder during manufacture and use(SRC). Since the dye is used for painting kimonos in Japan, occupational oral exposure to this dye has resulted from the painters' practice of moistening their brushes with their tongues(1). C.I. Direct Black 38 has been measured at airborne particulate levels of 1.6-5.1 mg/cu m in the workplace of a paper-dyeing facility in the United States. It was also detected at unspecified levels in the workplace air of a textile-dyeing facility in the US(1). [R38] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 10,542 workers (5,820 are female) are potentially exposed to C.I. Direct Black 38 in the USA(1). [R45] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers benzidine based dyes to be potential occupational carcinogens. /Benzidine based dyes/ [R8, 26] NREC: *NIOSH recommends that three widely used benzidine derived dyes, Direct Black 38, Direct Blue 6, and Direct Brown 95, be handled in the workplace as if they were human carcinogens. [R46] +NIOSH considers benzidine based dyes to be potential occupational carcinogens. /Benzidine based dyes/ [R8, 26] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Benzidine based dyes/ [R8, 26] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2,7-Naphthalenedisulfonic acid, 4-amino-3-((4'-((2,4-diaminophenyl)azo) (1,1'biphenyl)-4-yl)azo) 5-hydroxy-6-(phenylazo)-, disodium salt is included on this list. [R47] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 325. Analyte: CI Direct Black 38. Matrix: Air. Procedure: Filter collection, sodium hydrosulfite reduction. Flow Rate: 1.5 to 2.0 l/min. Sample Size: 500 liters. /From table/ [R48] *NIOSH Method 5013. Analyte: CI Direct Black 38. Matrix: Air. Sampler: Filter (5 um polytetrafluoroethylene membrane). Flow Rate: 1 to 3 l/min: Sample Size: 500 liters. Shipment: Keep samples dry and cool; protect from light. Sample Stability: Greater than or equal to 7 day @ 25 deg C in the dark. /From table/ [R49] ALAB: *NIOSH Method 5013. Analyte: Benzidine, o-tolidine, o-dianisidine. Matrix: Air. Procedure: High performance liquid chromatography, ultra violet detection. For benzidine, o-tolidine, o-dianisidine this method has an estimated detection limit of 3 ug benzidine/sample. The precision/RSD is 0.04 to 0.08 and the recovery is 100.3%. Applicability: The working range is ca 0.06 to 8 mg/cu m for a 250 liter air sample. Interferences: Aniline, azobenzene, p-aminophenol, p-phenylenediamine or p-nitroaniline do not interfere in the measurement when present in equimolar amounts. [R50] *Direct dyes such as Direct Black 38 are reportedly distinguished from basic and disperse dyes by their pH-dependent chromatographic behavior on cellulose acetate. Direct Black 38 in air is determined by gravimetric method. Limit of detection is not given. [R51] CLAB: *METABOLITES OF AZO DYE AND PIGMENT WERE DETERMINED IN HAMSTER AND HUMAN URINE BY TWO CHROMATOGRAPHIC PROCEDURES. [R52] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.21. NTP TR No 108; Route: oral in feed; Species: rats and mice. NTIS No PB280204/AS. King's College London, Monitoring and Assessment Research Center; The Health Effects of Aromatic Amines A Review 1986. U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) Uziel M et al; DNA Adduct Formation by 12 Chemicals with Populations Potentially Suitable for Molecular Epidmiological Studies; Mutat Res 277 (1): 35-90 (1992). SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 295 (1982) R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V17 268 (1982) R3: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1993. USITC Publication 2810, Nov. 1994. Washington, D.C.,p. 3-217 R4: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 874 R5: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 708 R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 296 (1982) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V20 296 (1982) R8: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R9: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R10: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 58 (1987) R12: Yamaguchi N et al; Am J Ind Med 3 (2): 139-48 (1982) R13: DHEW/NCI; 13-WEEK SUBCHRONIC TOXICITY STUDIES OF DIRECT BLUE 6, DIRECT BLACK 38, AND DIRECT BROWN 95 DYES; DHEW (NIH) PUBLICATION No. 78-1358 (1978) R14: LAZEAR EJ ET AL; TOXICOL LETT 4 (6): 519 (1979) R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 299 (1982) R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 301 (1982) R17: Beije B; Mutation Research 187 (4): 227-34 (1987) R18: Krishna G et al; J Toxicol Environ Health 18 (1): 111-9 (1986) R19: Cerniglia CE et al; Mutation Research 175 (1): 11-16 (1986) R20: Ashby J, Mohammed R; Mutagenesis 3 (1): 69-71 (1988) R21: Gray LE Jr, Ostby JS; Fund Appl Toxicol 20 (2): 177-183 (1993) R22: DHEW/NCI; 13 Week Subchronic Toxicity Studies of Direct Blue 6, Direct Black 38, and Direct Brown 95 Dyes p.vii (1978) Technical Rpt Series No. 108 DHEW Pub No. (NIH) 78-1358 R23: International Business Machines; Detection of Mutagenic Azo Dye Urinary Metabolites with the Salmonella/Microsome Assay. (1982), EPA Document No. 878210279, Fiche No. OTS0205901 R24: Scientific Associates; Toxicity Tests on 5105.200 Erie Black GX00 Conc. (1963), EPA Document No. 878212460, Fiche No. OTS0206237-5 R25: Scientific Associates; Certificate of Analysis - Toxicity Tests on Erie Black GX00 Conc. (1963), EPA Document No. 878221041, Fiche No. OTS0215154 R26: Scientific Associates; Certificate of Analysis - Toxicity Tests on Erie Black GX00 Conc. (1963), EPA Document No 878221041, Fiche No. OTS0215154 R27: Scientific Associates; Toxicity Tests on Erie Black GX00 Conc., (1963), EPA Document No. 878221041, Fiche No. OTS0215154 R28: ROHM AND HAAS CO; Teratogenic potential of environmental agents: Direct Black 38 (Report No. 79RN-1026); 12/31/79, EPA 88- 920005530, Fiche No. OTS0544784 R29: Dewan A et al; Archives of Environmental Health 43 (4): 269-72 (1988) R30: Aldrich FD et al; J Toxicol Environ Health 18 (3): 347-355 (1986) R31: NONY CR ET AL; J ANAL TOXICOL 4 (3): 132 (1980) R32: VAN DUUREN BL; J ENVIRON PATHOL TOXICOL 3(4) 237 (1980) R33: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. 710 R34: Bos RP et al; Toxicology 40 (2): 207-13 (1986) R35: Manning BW et al; Appl Environ Microbiol 50 (1): 10-15 (1985) R36: Kennelly JC et al; Carcinogenesis 3 (8): 947-51 (1982) R37: Martin CN, Kennelly JC; Carcinogenesis 2 (4): 307-12 (1981) R38: (1) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29, IARC, Lyon, France pp. 295-310 (1982) R39: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Shaul GM et al; Chemosphere 22: 107-19 (1991) (4) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29, IARC, Lyon, France pp. 295-310 (1982) (5) Evans LJ; Environ Sci Technol 23: 1046-56 (1989) (6) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (7) Yoshida O et al; pp. 227-31 in Decomposition of Toxic and Nontoxic Organic Compounds in Soil, Overcash, MR (ed.) Ann Arbor Sci Publ Ann Arbor, MI (1981) (8) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) R40: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Yoshida O et al; pp. 227-31 in Decomposition of Toxic and Nontoxic Organic Compounds in Soil, Overcash, MR (ed.) Ann Arbor Sci Publ Ann Arbor, MI (1981) (4) Stafford W, Northup HJ; Am Dyestuff Reporter 44: 355-9 (1955) (5) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) (6) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29, IARC, Lyon, France pp. 295-310 (1982) (7) Franke C et al; Chemosphere 29: 1501-14 (1994) R41: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) R42: (1) Yoshida, O et al; pp. 227-31 in Decomposition of Toxic and Nontoxic Organic Compounds in soil, Overcash, MR Ed. Ann Arbor Sci Publ Ann Arbor, MI (1981) (2) Stafford W, Northup HJ; Am Dyestuff Reporter 44: 355-9 (1955) (3) Chung KT et al; Crit Rev Microbiol 18: 175-90 (1992) R43: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R44: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Shaul GM et al; Chemosphere 22: 107-19 (1991) (4) IARC; IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 29, IARC, Lyon, France pp. 295-310 (1982) (5) Evans LJ; Environ Sci Technol 23: 1046-56 (1989) R45: (1) NIOSH; National Occupational Exposure Survey (NOES) Cincinnati, OH (1989) R46: NIOSH; Current Intelligence Bulletin (Reprints-Bulletins 19 thru 30), Sept 1979 No. 24 - Direct Blue 6, Direct Black 38, Direct Brown 95 - Benzidine Derived Dyes p.1 (1978) R47: 40 CFR 716.120 (7/1/94) R48: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V6 325-1 R49: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5013-1 R50: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R51: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 298 (1982) R52: NONY CR, BOWMAN MC; J CHROMATOGR SCI 18 (2): 64 (1980) RS: 69 Record 320 of 1119 in HSDB (through 2003/06) AN: 5082 UD: 200302 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-DIRECT-BROWN-95- SY: *AIZEN-PRIMULA-BROWN-BRLH-; *AMANIL-SUPRA-BROWN-LBL-; *ATLANTIC-FAST-BROWN-BRL-; *ATLANTIC-RESIN-FAST-BROWN-BRL-; *BELAMINE-FAST-BROWN-BRLL-; *BENZANIL-SUPRA-BROWN-BRLL-; *BROWN-4EMBL-; *CALCODUR-BROWN-BRL-; *CHLORAMINE-FAST-BROWN-BRL-; *CHLORANTINE-FAST-BROWN-BRLL-; *CHROME-LEATHER-BROWN-BRLL-; *CI-30145-; *CUPRATE(2-),(5-((4'-((2,6-DIHYDROXY-3-((2-HYDROXY-5-SULFOPHENYL) AZO)PHENYL)AZO)(1,1'-BIPHENYL)-4-YL)AZO)-2-HYDROXYBENZOATO(4-)), DISODIUM; *CUPROFIX-BROWN-GL-; *DERMA-FAST-BROWN-W-GL-; *DIALUMINOUS-BROWN-BRS-; *DIAPHTHAMINE-LIGHT-BROWN-BRLL-; *DIAZINE-FAST-BROWN-RSL-; *DIAZOL-LIGHT-BROWN-BRN-; *DICOREL-BROWN-LMR-; *DIPHENYL-FAST-BROWN-BRL-; *Direct-Brown-95-; *DIRECT-FAST-BROWN-BRL-; *DIRECT-SUPRA-LIGHT-BROWN-ML-; *DURAZOL-BROWN-BR-; *DUROFAST-BROWN-BRL-; *ELIAMINA-LIGHT-BROWN-BRL-; *ENIANIL-LIGHT-BROWN-BRL-; *FASTOLITE-BROWN-BRL-; *FASTUSOL-BROWN-LBRSA-; *FENALUZ-BROWN-BRL-; *HELION-BROWN-BRSL-; *Ismafast-Brown-Brsl-; *KAYARUS-SUPRA-BROWN-BRS-; *KCA-LIGHT-FAST-BROWN-; *NCI-C54568-; *PARANOL-FAST-BROWN-BRL-; *PEERAMINE-FAST-BROWN-BRL-; *PONTAMINE-FAST-BROWN-BRL-; *PONTAMINE-FAST-BROWN-NP-; *PYRAZOL-FAST-BROWN-BRL-; *PYRAZOLINE-BROWN-BRL-; *SATURN-BROWN-LBR-; *SIRIUS-SUPRA-BROWN-BRS-; *SOLANTINE-BROWN-BRL-; *SOLAR-BROWN-PL-; *SOLEX-BROWN-R-; *SOLIUS-LIGHT-BROWN-BRLL-; *SOLIUS-LIGHT-BROWN-BRS-; *SUMILIGHT-SUPRA-BROWN-BRS-; *SUPRAZO-BROWN-BRL-; *SUPREXCEL-BROWN-BRL-; *TERTRODIRECT-FAST-BROWN-BR-; *TETRAMINE-FAST-BROWN-BRDN-EXTRA-; *TRIANTINE-LIGHT-BROWN-BRS- RN: 16071-86-6 RELT: 948 [BENZIDINE] MF: *C31-H18-Cu-N6-O9-S-Na2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *COUPLING OF BENZIDINE TO SALICYLIC ACID, THEN COUPLING TO THE COPPER COMPLEX OF 2-AMINO-1-PHENOL-4-SULFONIC ACID PREVIOUSLY COUPLED TO RESORCINOL. [R1] MFS: *FABRICOLOR INC, PATERSON, NJ 07505 [R2] USE: *DYE FOR COLORING AND PRINTING CELLULOSE AND SILK; DYE FOR COTTON, WOOL, NYLON, LEATHER, PAPER, AND PLASTICS. [R2] *Direct Brown 95: Dyeing or staining silk, cotton, acetate, cellulose, wood, nylon, leather, paper, and certain plastics. [R3, 710] CPAT: *ESSENTIALLY 100% AS A DYE [R2] PRIE: U.S. PRODUCTION: *(1976) 2.70X10+8 G [R2] *(1978) 3.45X10+7 G [R2] *Direct Brown 95 showed an increased production to 300,000 kg in 1976, which was up from 200,000 kg in 1975 and 150,000 kg in 1974. [R3, 710] U.S. IMPORTS: *(1977) 7.25X10+6 G (PRINCPL CUSTMS DISTS) [R2] *(1979) 1.01X10+7 G (PRINCPL CUSTMS DISTS) [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *762.15 [R4] SOL: *Sol in water; slightly sol in ethanol; insol in acetone. [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- REAC: +Red fuming nitric acid. /Benzidine based dyes/ [R6, 26] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R7, 1979.8] +Wear appropriate personal protective clothing to prevent skin contact. /Benzidine based dyes/ [R6, 26] +Wear appropriate eye protection to prevent eye contact. /Benzidine based dyes/ [R6, 26] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. /Benzidine based dyes/ [R6, 27] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. (Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.) /Benzidine based dyes/ [R6, 27] +Recommendations for respirator selection: Condition: At concentrations above the NIOSH REL, or where there is no REL, at any detectable concentration: Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure-mode. Any supplied-air respirator that has a full facepiece and is operated in a pressure-demand or other positive-pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive-pressure mode. /Benzidine based dyes/ [R6, 27] +Recommendations for respirator selection: Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator with a high-efficiency particulate filter. Any appropriate escape-type, self-contained breathing apparatus. /Benzidine based dyes/ [R6, 27] OPRM: *STUDIES SHOWED CANCER-CAUSING POTENTIAL EXISTS UPON EXPOSURE TO THESE DYES THROUGH MECHANISM OF METABOLIC CONVERSION TO BENZIDINE. GUIDELINES ARE GIVEN FOR MINIMIZING EMPLOYEE EXPOSURES. [R8] *The most effective control of Direct Black 38, Direct Brown 95, and Direct Blue 6, where feasible, is at the source of contamination by enclosure of the operation and/or local exhaust ventilation. If feasible, the process or operation should be enclosed with a slight vacuum so that any leakage will result in the flow of air into the enclosure. The next most effective means of control would be a well designed local exhaust ventilation system that physically encloses the process as much as possible, with sufficient capture velocity to keep the contaminant from entering the work atmosphere. To ensure that ventilation equipment is working properly, effectiveness (eg, air velocity, static pressure, or air volume) should be checked at least every three months. System effectiveness should be checked soon after any change in production, process, or control that might result in significant increases in airborne exposures to Direct Black 38, Direct Brown 95, and Direct Blue 6. ... Exposure to Direct Black 38, Direct Brown 95, and Direct Blue 6 should not be controlled with the use of respirators except during the time period necessary to install or implement engineering or work practice controls, or in work situation in which engineering and work practice controls are technically not feasible, or for maintenance, or for operations that require entry into tanks or closed vessels or in emergencies. [R3, 711] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R7, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R7, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R7, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R7, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R7, 1979.11] +Contact lenses should not be worn when working with this chemical. /Benzidine based dyes/ [R6, 27] +The worker should wash daily at the end of each work shift. /Benzidine based dyes/ [R6, 27] +The worker should immediately wash the skin when it becomes contaminated. /Benzidine based dyes/ [R6, 27] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Benzidine based dyes/ [R6, 27] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Benzidine based dyes/ [R6, 27] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R7, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R7, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R7, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R7, 1979.15] DISP: *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R7, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R7, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R7, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R7, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R7, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Classification of carcinogenicity: 1) evidence in humans: inadequate; 2) No data for evidence in animals. Overall summary evaluation of carcinogenic risk to humans is Group 2A: The agent is probably carcinogenic to humans. /From table; Benzidine-based dyes/ [R9] MEDS: *Urine cytology surveillance has proved useful in evaluating tumors in dyestuff plant workers. The system consists of two-stage tests: periodic urine cytology, followed by, in suspicious cases, urological examinations. [R10] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R7, 1979.23] HTOX: *An epidemiological study of silk dyers and painters who had multiple exposure to benzidine based and other dyes indicated that those exposures were strongly associated with the occurrence of bladder cancer. /Benzidine based dyes/ [R11] *A strong association relating human exposure to benzidine based dyes with the subsequent development of bladder tumors was presented after a case control mortality study of 200 bladder cancer patients in Japan. The patients were found to have been predominantly kimono painters and dyers. The kimono painters had a habit of forming a point on their brushes by drawing the brush between their lips, which allowed for ingestion of the dyes. Several other case control mortality studies indicate an increased risk of developing bladder cancer in the textile and leather industries, both large users of direct dyes. However, only a few references have been made concerning benzidine derived dyestuffs. In Russia, a medical study concerning the early detection of bladder tumors among textile dyers using benzidine derived dyes revealed an unusual incidence of bladder lesions, some of which were suggested as being of a precancerous nature. The greatest number of such lesions were found in those workers with the highest potential exposure to these dyes. /Benzidine based dyes/ [R3, 711] *Most organic azo dyes are potential skin sensitizers, the most important of which are paraphenylenediamine and its analogs. Water soluble azo dyes are more likely to cause clinical sensitization than insoluble dyes. Beauticians exposed to paraphenylenediamine derivatives in hair dyes, workers dyeing texitle resins, and photographic film developers exposed to color developing solutions not infrequently become sensitized to azo dyes. In addition to allergic eczematous contact dermatitis, color developing solutions have caused lichen planus like eruptions. /Organic dyes/ [R3, 147] NTOX: *Groups of 10 male and 10 female Fischer 344 rats, 6 weeks old, were fed a diet containing 0, 190, 375, 750, 1500 or 3000 mg/kg (ppm) Direct Brown 95 and 1.3% corn oil. Surviving rats were killed at 13 weeks. All male and female animals administered 1500 or 3000 mg/kg Direct Brown 95 died prior to termination of the studies; male rats survived for less than 5 weeks, females given the high dose less than 6 weeks on the study, and females fed 1500 mg/kg about 12 weeks; 2 males receiving 750 mg/kg Direct Brown 95 also died prior to the end of the study. Among male rats, basophilic foci or foci of cellular alteration were seen in 2/9 animals given 3000 mg/kg in 7/8 given 1500 mg/kg and in 8/10 given 750 mg/kg. In female animals, 4/8 given the 1500 mg/kg dose exhibited neoplastic nodules, and 1 of these showed a hepatocellular carcinoma; basophilic foci or foci of cellular alteration in the liver were seen in 3/8 females given 3000 mg/kg, 6/8 given 1500 mg/kg and 3/10 given 750 mg/kg. No other relevant findings in relation to neoplastic development were seen in these animals. [R12, (1982(] *Groups of 10 male B6C3F1 mice, 6-7 weeks of age, were fed a diet containing 750, 1500, 3000, 6000, or 12500 mg/kg (ppm) Direct Brown 95 and 1.3% corn oil. Groups of 10 female B6C3F1 mice, 6-7 weeks of age, were fed similar diets containing 350, 750, 1500, 3000 or 6000 mg/kg of the dye. Control diets contained corn oil in amounts equal to that in the diets of groups given the highest doses. The compound was administered for 13 weeks, when all animals were killed. The only suggestive neoplastic lesion observed was foci of basophilic cellular alteration in one male mouse administered 12,500 mg/kg Direct Brown 95. The Working Group noted the short duration of the experiment, the limited number of animals tested, and the impurity of the compound used. Other samples of the compound may have different impurities. [R12, (1982)] *Studies in which rats were fed diets containing 190-3000 mg/kg Direct Brown 95 and mice 375-12,500 mg/kg for 13 weeks resulted in a series of dose and substance related changes seen when all animals were killed at the end of treatment. In rats, biliary hyperplasia and portal fibrosis were observed in the liver; lymphoid depletion in spleen and thymus, lymphoid necrosis in lymph nodes and myeloid depletion in the bone marrow were also seen. Other effects included subacute glomerulonephritis, interstitial hemorrhage and degeneration of germinal epithelium of the testes, and some extramedullary hematopoiesis in the liver. Biliary hyperplasia was seen in all animals given 375 mg/kg or more. In mice, pigment deposition in the liver and hemosiderosis of the spleen were observed. [R13] NTP: *Thirteen wk subchronic toxicity study of ... Direct Brown 95 was conducted by administering the test /cmpd/ in feed to Fischer 344 rats and B6C3F1 mice. Groups of 10 rats and 10 mice of each sex were administered /the test cmpd/ at one of five concentrations for 13 wk and then necropsied, beginning the second day after the end of the dosing period. The concentrations used for the rats were 190, 375, 750, 1,500, and 3,000 ppm. The concentrations used for the male mice were 750, 1,500, 3,000, 6,000, and 12,500 ppm; concentrations of used for the female mice were 375, 750, 1,500, 3,000, and 6,000 ppm. It was concluded that under the conditions of this 13 wk subchronic toxicity studies, ... Direct Brown 95 was carcinogenic in female rats; /the cmpd/ induced hepatocellular carcinomas and neoplastic nodules in the liver. /The test cmpd/ was not carcinogenic for B6C3F1 mice in the 13 wk subchronic toxicity studies. [R14] METB: *Benzidine derived azo dyes may be degraded metabolically in the gut or liver in man to free benzidine or monoacetylbenzidine. /Benzidine derived azo dyes/ [R15] *Rhesus monkeys excreted an average of 1.25% benzidine plus monoacetylbenzidine of the benzidine moiety in Direct Brown 95 in the urine after receiving two different doses by gavage, whereas gavage with pure benzidine yielded 1.45%. [R15] *Caution is also indicated by preliminary results from the NIOSH field studies showing that humans working with these same dyes /Direct Black 38, Direct Brown 95, and Direct Blue 6/ also excrete higher than expected levels of benzidine in their urine. Both laboratory and field studies indicate that these benzidine derived dyes can be metabolized to benzidine, which is present in the urine of animals and humans. [R3, 710] *Environmental and urine samples were collected at six factories where workers were potentially exposed to benzidine based dyes (two benzidine based dye manufacturers, two textile dyeing plants, a leather tanning and dyeing plant and a mill where paper was dyed). Monoacetylbenzidine was detected in the urine of 2/8 workers at one of the dye manufacturing plants at levels of 3 and 7 ppb. At the second factory, 4 workers exposed to average levels of 7.9, 5.2, 11.7 and 17.4 mg total particulate/cu m had corresponding urinary concentrations of 52, 11, 10 and 112 ppb benzidine; 590, 248 and 22 ppb monoacetylbenzidine were detected in urine samples containing 112, 52 and 11 ppb benzidine. Traces of diacetylbenzidine, ortho-tolidine and ortho-dianisidine were also detected. Benzidine was not detected in the urine of workers from the other facilities. Minute levels of impurities in the dyestuffs could not account for the quantity of benzidine and its derivatives that were found in the urine samples. [R15] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *The National Occupational Hazard Survey (NOHS), conducted between 1972 and 1974 by the National Institute for Occupational Safety and Health, indicates that workers are occupationally exposed to Direct Black 38, Direct Brown 95, and Direct Blue 6 in a variety of industries, including: paper and allied products, petroleum and related industries, rubber and plastic products, leather and leather products, instrumentation and measuring devices, and banking. In addition, the textile industry accounts for a substantial occupational exposure. It is estimated that 25% of the benzidine-derived azo dyes are applied to textiles, 40% to paper, 15% to leather, and the remainder to other diverse applications. ... In the general population, unspecified exposure levels to the three dyes are thought to occur through the use of retail packaged dyes for home dyeing and for home and school use in art and craft projects such as tie-dyeing or batik. [R3, 709] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: +NIOSH considers benzidine based dyes to be a potential occupational carcinogen. /Benzidine based dyes/ [R6, 26] NREC: *NIOSH recommends that three widely used benzidine-derived dyes, Direct Black 38, Direct Blue 6, and Direct Brown 95, be handled in the workplace as if they were human carcinogens. [R16] +NIOSH considers benzidine based dyes to be potential occupational carcinogens. /Benzidine based dyes/ [R6, 26] +NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Benzidine based dyes/ [R6, 26] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Cuprate (2-), (5-((4"-((2,6-dihydroxy-3-((2-hydroxy-5-sulfophenyl)azo) (1,1'-biphenyl)-4-yl)azo)-2-hydroxybenzoato(4-)-, disodium is included on this list. [R17] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 325. Analyte: CI Direct Brown 95. Matrix: Air. Procedure: Filter collection, sodium hydrosulfite reduction. Flow Rate: 1.5 to 2.0 l/min. Sample Size: 500 liters. /From table/ [R18] *NIOSH Method 5013. Analyte: CI Direct Brown 95. Matrix: Air. Sampler: Filter (5 um polytetrafluoroethylene membrane). Flow Rate: 1 to 3 l/min: Sample Size: 500 liters. Shipment: Keep samples dry and cool; protect from light. Sample Stability: Greater than or equal to 7 day @ 25 deg C in the dark. /From table/ [R19] ALAB: *Direct dyes such as Direct Brown 95 are reportedly distinguished from basic and disperse dyes by their pH dependent chromatographic behaviour on cellulose acetate, and separated from each other by chromatography on silica gel. Direct dyes can be collected from air with a glass fiber filter and analysed gravimetrically. (This method will detect all dye particles.) For more specific identification, the filter may be extracted with an appropriate solvent and scanned in a spectrometer from 400-700 nm for comparison with scans of bulk dye sample solutions. Direct Brown 95 may be as an impurity in reactive dyes by thin-layer chromatography. Several eluent systems for separating Direct Brown 95 from Reactive Brown 9 were studied by this method; the most successful were 6:9:5 n-butyl acetate:pyridine:water and 4:2:1:3 n-propanol:isobutanol:ethyl acetate:water. [R12, (1982)] *NIOSH Method 5013. Analyte: CI Direct Brown 95. Matrix: Air. Procedure: High performance liquid chromatography, ultra violet detection. Estimated level of detection: Not determined. The precision/RSD is 6.7% and the recovery is 78.5%. Applicability: The working range is 48.6 to 485 ug/cu m for a 500 liter air sample. Interferences: Aniline, azobenzene, p-aminophenol, p-phenylenediamine or p-nitroaniline do not interfere in the measurement when present in equimolar amounts. /From table/ [R19] *NIOSH Method 325. Analyte: CI Direct Brown 95. Matrix: Air. Procedure: High performance liquid chromatography, ultra violet detector. Method Evaluation: Method was validated over the range of 48.6 to 485.2 ug/cu m using a 500 liter sample. Method detection limit: 3.8 ng (benzidine). Precision (CVt): 0.07. Interferences: No specific interferences. /From table/ [R18] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.22. NTP TR No 108; Route: oral in feed; Species: rats and mice. NTIS No PB280204/AS. King's College London, Monitoring and Assessment Research Center; The Health Effects of Aromatic Amines A Review 1986. Uziel M et al; DNA Adduct Formation by 12 Chemicals with Populations Potentially Suitable for Molecular Epidmiological Studies; Mutat Res 277 (1): 35-90 (1992). SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 415 (1978) R2: SRI R3: Zenz, C. Occupational Medicine-Principles and Practical Applications. 2nd ed. St. Louis, MO: Mosby-Yearbook, Inc, 1988. R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety and Health. Registry of Toxic Effects of Chemical Substances 1979 edition. Volumes 1 and 2. Washington, DC: U.S. Government Printing Office, 1980.p. V1 446 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 322 (1982) R6: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R7: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R8: DIRECT BLACK 38, DIRECT BLUE 6, AND DIRECT BROWN 95 BENZIDINE-DERIVED DYES, DHEW (NIOSH) PUBLICATION (US), 78-148, 11 (1978) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 58 (1987) R10: Yamaguchi N et al; Am J Ind Med 3 (2): 139-48 (1982) R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 327 (1982) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 324 R13: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 325 (1982) R14: DHEW/NCI; 13 Week Subchronic Toxicity Studies of Direct Blue 6, Direct Black 38, and Direct Brown 95 Dyes for Possible Carcinogenicity p.vi (1978) Technical Rpt Series No. 108 DHEW Pub No. (NIH) 78-1358 R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V29 326 (1982) R16: NIOSH; Current Intelligence Bulletin (Reprints-Bulletins 19 thru 30), Sept 1979 No. 24 - Direct Blue 6, Direct Black 38, Direct Brown 95 - Benzidine Derived Dyes p.1 (1978) R17: 40 CFR 716.120 (7/1/91) R18: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present.p. V6 325-1 R19: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984.p. 5013-1 RS: 37 Record 321 of 1119 in HSDB (through 2003/06) AN: 5104 UD: 200302 RD: Reviewed by SRP on 1/31/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N-METHYL-N'-NITRO-N-NITROSOGUANIDINE- SY: *GUANIDINE,-N-METHYL-N'-NITRO-N-NITROSO-; *GUANIDINE,-1-METHYL-3-NITRO-1-NITROSO-; *METHYLNITRONITROSOGUANIDINE-; *1-Methyl-3-nitro-1-nitrosoguanidine-; *N-METHYL-N-NITROSO-N'-NITROGUANIDINE-; *1-METHYL-1-NITROSO-3-NITROGUANIDINE-; *N-METHYL-N-NITROSONITROGUANIDIN- (GERMAN); *N-METHYLO-N'-NITRO-N-NITROZOGUANIDYNY- (Polish); *N-METYLO-N'-NITRO-N-NITROZOGUANIDYNY- (Polish); *MNG-; *MNNG-; *NCI-C01423-; *NG-; *N'-NITRO-N-NITROSO-N-METHYLGUANIDINE-; *N-NITROSO-N-METHYLNITROGUANIDINE-; *N-NITROSO-N'-NITRO-N-METHYLGUANIDINE-; *1-NITROSO-3-NITRO-1-METHYLGUANIDINE-; *NSC-9369- RN: 70-25-7 MF: *C2-H5-N5-O3 STCC: 49 167 23; N-Methyl-N'-Nitro-N-Nitrosoguanidine HAZN: U163; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *NITROSATION OF N-METHYL-N'-NITROGUANIDINE [R1] *Preparation: A.F. McKay, G.F. Wright, J Am Chem Soc 69, 3028 (1947) [R2] MFS: *NOT PRODUCED COMMERCIALLY IN USA [R3] USE: *Experimentally as a carcinogen and mutagen. Formerly used in preparation of diazomethane. [R2] *... N-nitroso compounds are produced primarily as research chemicals and not for commercial purposes. /N-Nitroso compounds/ [R4] PRIE: U.S. PRODUCTION: *(1977) NOT PRODUCED COMMERCIALLY IN USA [R3] *(1982) NOT PRODUCED COMMERCIALLY IN USA [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW TO PINK CRYSTALS [R5]; *Yellow crystals from methanol. [R2] MP: *118-123.5 DEG C (WITH DECOMPOSITION) [R5] MW: *147.12 [R6] SOL: *SLIGHTLY SOL IN WATER (LESS THAN 0.5%); SOL IN POLAR ORG SOLVENTS (OFTEN ACCOMPANIED BY DECOMPOSITION) [R5]; *Soluble in DMSO. [R7] SPEC: *MAX ABSORPTION: 275 NM (LOG E = 4.26); 306 NM (LOG E = 3.18); (IN METHANOL) 402 NM (LOG E = 2.29) [R5] OCPP: *At acid pH slowly releases nitrous acid to give N-methyl-N'-nitroguanidine; it is converted by concentrated aqueous alkali hydroxide to diazomethane; reactions with several nucleophiles are known, especially with amines [R1] *Reacts with aq KOH to form diazomethane: a.f. McKay, J Am Chem Soc 70, 1974 (1948); reacts at acid pH to give methylnitroguanidine. [R2] *Pure N-methyl-N'-nitro-N-nitrosoguanidine is sensitive to light, changing to orange and green colors. [R5] *Half-life at pH 8 is about 200 hours; at pH 7 (phosphate buffer) and 37 deg C the half-life is 170 hours. [R5] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FIRP: *Flood with water [R8] EXPL: *An explosive sensitive to heat or impact. [R9] *... this material will detonate under high impact, and a sample exploded when melted in a sealed capillary tube. [R10] REAC: *Reacts with aqueous potassium hydroxide to form diazomethane. [R2] *Reacts at acid pH to give methylnitroguanidine. [R2] DCMP: *When heated to decomposition it emits very toxic fumes of ... /nitrogen oxides/. [R9] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent ... Safety pipettes ... for all pipetting. ... In animal laboratory ... protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators ... when working with particulates or gases, and disposable plastic aprons ... gowns ... /should be/ of distinctive color. /Chemical carcinogens/ [R11, 1979.8] *Wear boots, protective gloves, and goggles. [R8] *Wear nitrile rubber gloves, protective laboratory coat, self-contained breathing apparatus, eye protection and protective shoes. /Nitrosamines/ [R12] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide additional protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synthesis and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used. ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of admin volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt is begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres for chem such as nitrosamines. Methods ... should ... where possible, be simple and sensitive. ... /Chemical carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. ... Contaminated cleaning materials should not be re-used. ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access should be ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical carcinogens/ [R11, 1979.11] *Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Keep material dry. [R8] SSL: *PURE CMPD IS SENSITIVE TO LIGHT, CHANGING TO ORANGE AND GREEN COLORS; DEGRADATION PRODUCTS ARISING FROM PROLONGED OR INADEQUATE STORAGE INCLUDE N-METHYL-N'-NITROGUANIDINE, N-NITROGUANIDINE, NITROCYANAMIDE AND GUANIDINE; MORE STABLE THAN COMPARABLE ALKYL-NITROSOUREAS AND ALKYLNITROSOURETHANES; AT ROOM TEMP, T/2 AT PH 8 IS ABOUT 200 HR; AT PH 7.0 (PHOSPHATE BUFFER) and 37 DEG C, T/2 IS 170 HR; TAP WATER DECOMPOSES MNNG MUCH MORE RAPIDLY THAN DOES DEIONIZED WATER [R5] *Although the crude product from the aqueous nitrosation is pyrophoric, recrystallized material is stable (though powerfully mutagenic). [R10] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R11, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R11, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired. ... Facilities for dispensing ... should be contiguous to storage area. /Chemical carcinogens/ [R11, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms. ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal. ... The plastic bag should be sealed immediately. ... The sealed bag should be labelled properly. ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated. ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical carcinogens/ [R11, 1979.15] *Decontamination of N-nitrosamine contaminated glassware /was described/. /N-nitrosamines/ [R13, 1982.27] *Nitrosamine residues generated in laboratory research or accidental spills in research laboratories and diluted to concn of 10 mg/l or less are rapidly reduced to innocuous amines, ammonia, or alcohols by aluminum-nickel alloy powder and aqueous alkali. The method is applicable to a variety of media (water, mineral oil, olive oil, dimethylsulfoxide, soln of agar gel) but is not recommended for use with nitrosamines in acetone or dichloromethane because reactions are slow and incomplete. After the reduced reaction mixture is filtered, the liquid is disposed of by pouring it over sufficient absorbent material to convert it to a solid waste for incineration. /Nitrosamines/ [R14] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U163, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R15] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R16] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical carcinogens/ [R11, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": Total destruction ... by incineration may be only feasable method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable. ... Most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn of 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R11, 1979.16] *N-Methyl-N'-nitro-N-nitrosoguanidine is slowly hydrolyzed in water but is rapidly destroyed by 10% thiosulfate solution. ... The treatment of MNNG and related nitrosamines, such as N-nitrosomethyl- and N-nitrosoethylurea, with alkali should be avoided, or carried out with extreme care, because the very toxic gaseous diazomethane is produced. [R11, 1979.17] *BECAUSE N-NITROSODIETHYLAMINE IS CHEMICALLY STABLE UNDER USUAL CONDITIONS, DISPOSAL IS BEST CARRIED OUT BY INCINERATION. FOR INCINERATION OF LIQ WASTES, SOLN SHOULD BE NEUTRALIZED IF NECESSARY, FILTERED TO REMOVE SOLIDS, AND PUT IN CLOSED POLYETHYLENE CONTAINERS FOR TRANSPORT. ALL EQUIPMENT SHOULD BE THOROUGHLY RINSED WITH SOLVENT, WHICH SHOULD THEN BE ADDED TO LIQ WASTE FOR INCINERATION. GREAT CARE SHOULD BE EXERCISED TO PREVENT CONTAMINATION OF OUTSIDE OF SOLVENT CONTAINER. IF POSSIBLE, SOLID WASTES SHOULD BE INCINERATED; IF THIS IS NOT POSSIBLE, SOLID WASTES FROM REACTION MIXT THAT MAY CONTAIN N-NITROSODIETHYLAMINE SHOULD BE EXTRACTED AND EXTRACTS ADDED TO LIQ WASTE. ... ANY RAGS, PAPER, AND SUCH THAT MAY BE CONTAMINATED SHOULD BE INCINERATED. CONTAMINATED SOLID MATERIALS SHOULD BE ENCLOSED IN SEALED PLASTIC BAGS THAT ARE LABELED CANCER-SUSPECT AGENT AND WITH NAME AND AMT OF CARCINOGEN. BAGS SHOULD BE STORED IN WELL-VENTILATED AREA UNTIL THEY ARE INCINERATED. /N-NITROSODIETHYLAMINE, ALSO APPLICABLE TO OTHER ALKYLNITROSAMINES/ [R17] *Destruction of N-nitrosamines in lab wastes using denitrosation with hydrobromic acid /was described/. /N-Nitrosamines/ [R13, 1982.15] *Destruction of N-nitrosamines in lab wastes using potassium permanganate /was described/. /N-Nitrosamines/ [R13, 1982.23] *Decontamination of N-nitrosamine contaminated glassware /was described/. /N-Nitrosamines/ [R13, 1982.27] *Undiluted N-nitrosamines: Estimate the amount of N-nitrosamines to be destroyed and calculate the volume of hydrobromic acid solution required for their destruction. Add twice the quantity of hydrobromic acid solution calculated. Allow to react at room temperature for at least 2 hr. Check for completion of destruction. Add excess of alkali to prevent re-formation of N-nitrosamines. /N-Nitrosamines/ [R13, 1982.18] *Although previously published methods for the destruction of nitrosamines also degrade nitrosamides, the products in the latter case may be carcinogenic or otherwise harmful. This report gives safe methods of destruction of 5 representative nitrosamides: N-nitroso-N-methylurea, N-nitroso-N-ethylurea, N-nitroso-N-methylurethane, N-nitroso-N-ethylurethane and N-nitro-N'-nitro-N-methylguanidine. [R18] *(1) Oxidation by potassium permanganate in sulfuric acid (KMnO4 in H2SO4). The products of the reaction have not been determined. Degradation efficiency was > 99.5%. (2) Reaction with sulfamic acid in hydrochloric acid solution (HCl). The strong hydrochloric acid causes displacement of the nitroso group. The nitrosyl chloride formed reacts with the sulfamic acid to form nitrogen and H2SO4. This reaction prevents any reformation of the nitrosamide. The products of the reaction are the corresponding amides produced by simple removal of the nitroso group. Degradation efficiency was > 99.5%. (3) Reaction with iron filings in HCl solution. The strong HCl causes displacement of the nitroso group. The nitrosyl chloride formed is reduced by the iron filings in the acid to ammonia. This reaction prevents any reformation of the nitrosamide. The products of the reaction are the corresponding amides produced by simple removal of the nitroso group except for N-methyl-N'-nitro-N-nitrosoguanidine and N-ethyl-N'-nitro-N-nitrosoguanidine, where reductive removal of the nitro group causes the major products to be methylguanidine and ethylguanidine, respectively. Degradation efficiency was > 99%. (4) Reaction with sodium bicarbonate solution (NaHCO3). This weak base causes a slow, base-mediated decomposition. The rate of reaction is sufficiently slow so that any diazoalkanes that are formed react with the solvent before escaping from the solution. The products of the reaction have not been definitely identified ... Degradation efficiency was > 99.99% for N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea, N-methyl-N-nitrosourethane, and N-ethyl-N-nitrosourethane. The method is not suitable for N-methyl-N'-nitro-N-nitrosoguanidine, N-ethyl-N'-nitro-N-nitrosoguanidine, or N-methyl-N-nitroso-p-toluenesulfonamide. (5) Reaction with NaHCO3 solution, then nickel-aluminum (Ni-Al) alloy and sodium carbonate (Na2CO3) solution, then potassium hydroxide (KOH) solution. The slow incr in pH of the solution produced by sequential addition of the bases causes a slow degradation of the nitrosamide. The degradation rate is sufficiently slow so that any diazoalkanes that are formed have time to react with the solvent before escaping from the solution. The products from this reaction have been discussed. Degradation efficiency was > 99.9%. /Nitrosamides/ [R19] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Inadequate evidence of carcinogenicity in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2A: The agent is probably carcinogenic to humans. [R20] ANTR: *For immediate first aid: Ensure that adequate decontamination has been carried out. If victim is not breathing, start artificial respiration, preferably with a demand-valve resuscitator, bag-valve-mask device, or pocket mask as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep victim quiet and maintain normal body temperature. Obtain medical attention. /Nitrates, nitrites, and related compounds/ [R21] *For basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... Anticipate seizures and treat as necessary ... For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... /Nitrates, nitrites, and related compounds/ [R21] MEDS: *PRECAUTIONS FOR "CARCINOGENS": ... In relation specifically to cancer hazards, there are at present no health monitoring methods that may ensure the early detection of preneoplastic lesions or lesions which may prelude them. Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning additional tests that might become useful or mandatory. /Chemical carcinogens/ [R11, 1979.23] HTOX: *CULTURED HUMAN LYMPHOCYTES EXPOSED TO MNNG INDUCED RESISTANCE TO 6-THIOGUANINE. /FROM TABLE/ [R22] *HUMAN OSTEOSARCOMA CLONAL CELLS TRANSFORMED IN VITRO BY MNNG PRODUCED TUMORS OR TUMOR NODULES WHEN INOCULATED INTO NUDE MICE. WHEN TRANSPLANTED INTO ATS-TREATED HAMSTERS, THE CELLS TRANSFORMED AT 0.01 UG/ML MNNG PRODUCED TUMORS, BUT MNNG (0.1 UG/ML) TRANSFORMED CELLS DID NOT. THE CONTROL CELL LINE (NON-PRODUCER HUMAN OSTEOSARCOMA CELLS TRANSFORMED BY KRISTEN MURINE SARCOMA VIRUS) WAS NEG IN MICE AND HAMSTERS. [R23] *MNNG TREATMENT OF HUMAN PERIPHERAL BLOOD MONONUCLEAR CELLS INCREASES FREQUENCY OF LYMPHOCYTE TRANSFORMATION INTO PERMANENTLY PROLIFERATING LINES WHICH ARE DOSE DEPENDENT AND DO NOT OCCUR IN PRESENCE OF AUTOLOGOUS HUMAN SERUM. 38/42 LINES PRODUCED EPSTEIN-BARR VIRUS ANTIGENS. [R24] *A single exposure of cultured human endometrial stromal cells to 0.5 to 4.0 mug/l MNNG resulted in morphological evidence of toxicity and reductions in growth rates, plating efficiency, and saturation density as compared to solvent-treated control cells. Cytotoxicity was reduced after additional exposures. Following repetitive treatments with MNNG, cells developed enhanced growth potential, the capacity to form macroscopic colonies in soft agar, and elevated gamma-glutamyltranspeptidase activity. MNNG treated cells displayed atypical morphology characterized by irregularities in cell and nuclear size and shape, large bizarre nucleoli, incr nuclear:cytoplasmic ratios, and cellular crowding. The cells were progressing towards preneoplastic and perhaps neoplastic transformation in vitro. [R25] *Fibroblast cell strains were obtained from skin biopsies taken from patients with adenomatoses of the colon and rectum (ACR), and their relatives. A total of 50 different fibroblast strains were tested for their frequencies of sister chromatid exchange in vitro. These strains included nine from patients with the Gardner syndrome, 21 from patients with non-Gardner ACR, and 20 cell strains from healthy relatives who were not at an increased risk for ACR. In 23 strains, the sister chromatid exchange frequencies after in vitro exposure to N-methyl-N'-nitro-N-nitroso-guanidine (MNNG) were also determined. Both with and without MNNG induction, sister chromatid exchange values in the Gardner strains were found to be significantly higher than in the control strains (p < 0.02 and p < 0.03, respectively). Non-Gardner ACR strains differed only slightly from controls, thus making the difference between the control group and the pooled Gardner + non-Gardner ACR group not significant. In all groups, there was a significant increase in sister chromatid exchange after MNNG exposure, and those strains which had low sister chromatid exchange values spontaneously, also tended to have relatively moderate sister chromatid exchange values after MNNG induction. There was no significant difference between the ratios of SCE values with and without MNNG exposure in the different groups. [R26] *Induction of 6-thioguanine (YG) resistance by chem mutagens was exam in P3 cells, a line of cells derived from a human epithelial teratocarcinoma cell clone which have a stable diploid karyotype with 46(XX) chromosomes, including a translocation between chromosomes 15 and 20. Efficient recovery of TG-resistant mutants induced by the direct-acting mutagens N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), ... the TG-resistant mutant cells induced by MNNG maintained their resistant phenotype 4-6 wk after isolation. This mutant phenotype was assoc with a > 10-fold reduction in hypoxanthine-guanine phosphoribosyl transferase (HGPRT) activity relative to that of the parental P3 cell line, which catalyzed the formation of 4.6 pmol inosine-5'-monophosphate/min/mug protein. ... Thus, P3 cells can be useful for the study of mutagenesis at the HGPRT locus by direct-acting chem mutagens, as well as by chems activated in a cell-mediated assay. [R27] *N-methyl-N'-nitro-N-nitrosoguanidine, aflatoxin B1, benzopyrene, dinitrosopiperazine and 2-acetylaminofluorene, are all powerful carcinogens and sister chromatid exchange inducers. The sister chromatid exchange changes of the workers of long term exposure to those chemicals for 2 yr was reported. The sister chromatid exchange value detected in the exposure in first yr approximated to that of the 2nd yr and both were significantly higher than that of normal controls. The fact that the peripheral lymphocytes from exposed and normal controls are of the same sensitivity to mitomycin C verified that the chromosomes of lymphocytes from exposed have a normal stability. Although the variations of chromosomal stability in the exposed with normal DNA repair system do not occur in a given period of time, the long term exposure to carcinogenic environments can result in the damage of chromosomal DNA and the increase of sister chromatid exchange value. [R28] *Lymphocytes from passive smokers, and patients with FA, /Fanconi anemia/, Alz, /Alzheimer's Disease/, or FPC, /Familial polyposis coli/ were studied for sister chromatid exchanges in cultures treated with MMC, 4NQO, or MNNG. Fanconi anemia lymphocytes were also studied for cell cycle. Mean SCE frequencies in FPC or normal cells. Kinetics, and CAs after completion of 1, 2, or 3 more divisions in MMC-treated cultures. The results can be summarized as follows: (1) lymphocytes from passive smokers showed a slightly higher induction of sister chromatid exchanges than nonsmokers when exposed to MMC. (2) FA cells had about 1.4 times higher frequencies of sister chromatid exchanges than normal cells in both MMC-treated and untreated cultures while they showed several times higher frequencies of CAs in both cultures. Analysis of cell cycle kinetics by the sister chromatid differential staining method revealed that MMC treatements of FA and normal cells let to a clearly dose-related delay in cell turnover times, the duration of delay being much longer in FA than in normal cells. (3) Alz cells showed about 1.5 times higher induction of sister chromatid exchanges in MMC-treated cultures whereas they had only 10% as much sister chromatid exchanges as controls when exposed to 4NQO. Familial polyposis coli cells showed no significant difference in the induction of sister chromatid exchanges in untreated cultures and cultures treated with MMC, 4NQO, and MNNG. [R29] *Description and analysis of 3 cases of glioblastoma in laboratory workers whose work involved physical and chemical mutagenesis techniques. Literature survey of the epidemiology of gliobastoma in the general population and in various workplaces, and of animal and in-vitro experiments on the mutagenic and carcinogenic effects of nitroso compounds. Detailed study of 1-methyl-3-nitro-1-nitrosoguanidine, a substance handled by the 3 victims of the disease, which could therefore be one of its important causing agents. [R30] *... Health hazards ... related to the consumption of water containing large concentrations of nitrate (or nitrite) ... /include/ potential formation of carcinogenic nitrosamines. /Nitrosamines/ [R31, 416] *Human cells (VH10 or Hep G2) and hamster cells V79 were exposed to different concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and the level of DNA lesions was evaluated by the DNA unwinding technique, alkaline elution of DNA and the comet assay. All three methods were able to detect the effects of N-methyl-N'-nitro-N-nitrosoguanidine but with a clear difference in sensitivity. At low concentrations of N-methyl-N'-nitro-N-nitrosoguanidine the most sensitive method appeared to be the comet assay. After the short-term treatment the comet assay was able to detect the lesions induced by N-methyl-N'-nitro-N-nitrosoguanidine at approximately 0.1 ug/ml, alkaline elution of DNA at 1 ug/ml and DNA unwinding at 1-2 ug/ml. N-methyl-N'-nitro-N-nitrosoguanidine treated VH10 cells, human lymphocytes and V79 cells were also tested cytogenetically, confirming that N-methyl-N'-nitro-N-nitrosoguanidine induced chromosomal aberrations at concentrations > 1 ug/ml in VH10 cells (short-term treatment): > 0.2 ug/ml in V79 cells (long-term treatment) and > 8 ug/ml in human lymphocytes (long-term treatment). In some experiments we tried to increase the level of N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA breaks with help of DNA repair inhibitors cytosine arabinoside (Ara C) and hydroxyurea (HU) which were applied either after or during N-methyl-N'-nitro-N-nitrosoguanidine treatment. ... results showed that the level of N-methyl-N'-nitro-N-nitrosoguanidine-induced lesions was increased by simultaneous treatment of cells with N-methyl-N'-nitro-N-nitrosoguanidine and cytosine arabinoside and hydroxyurea. 2 x 10(-5) M cytosine arabinoside and 2 x 10(-3) M hydroxyurea were as effective as 10-times higher concentrations of inhibitors. cytosine arabinoside and hydroxyurea increased the level of N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA breaks mainly in combination with lower concentrations of N-methyl-N'-nitro-N-nitrosoguanidine (< 2 ug/ml). Rejoining of DNA breaks was observed in human cells VH10 and Hep G2 as well as in Chinese hamster cells V79 damaged by both lower and higher N-methyl-N'-nitro-N-nitrosoguanidine-concentrations. All methods showed that N-methyl-N'-nitro-N-nitrosoguanidine-induced DNA breaks had been gradually rejoined. [R32] NTOX: *SINGLE DOSE OF 125 MG/KG BODY WT MNNG GIVEN BY INTRAGASTRIC INTUBATION AS SUSPENSION IN 30% AQ ALCOHOL TO 6 MALE C3H MICE INDUCED 3 SQUAMOUS CELL CARCINOMAS AND 1 PAPILLOMA OF STOMACH IN 3 MICE WITHIN 11 TO 21 MO. ADENOMAS IN SMALL BOWEL AND LIVER WERE FOUND IN 1 OTHER MOUSE; SPONTANEOUS INCIDENCE OF GI TUMORS IS CONSIDERED EXTREMELY RARE IN THIS SPECIES (SCHOENTAL AND BENSTED, 1969). CONTINUOUS ADMIN OF 50 MG/L IN DRINKING-WATER FOR 10 MONTHS TO DD/I STRAIN MICE DID NOT INDUCE GASTRIC TUMORS BUT GAVE RISE TO LEIOMYOSARCOMAS IN THE WALLS OF GASTRIC CYSTS, NEONATALLY GRAFTED INTO THE SC TISSUES IN 5/26 MICE. [R33] *CONTINUOUS ADMIN TO MALE WISTAR RATS ... IN DRINKING WATER AT CONCN OF 33, 83 and 167 MG/L, FOR ... 6-12 MO, INDUCED MALIGNANT TUMORS OF GLANDULAR STOMACH IN HIGH REGULARITY, WITH TUMOR INCIDENCE OF 70% AND ABOVE. MALIGNANCIES WERE FOUND MAINLY IN PYLORUS AND IN ANTRUM REGION. ... TUMORS /WERE CLASSIFIED/ AS ADENOMAS AND ADENOCARCINOMAS WITH FEW LEIOMYOSARCOMAS AND SIGNET-RING CELL CARCINOMAS. ADDNL MALIGNANT TUMORS, ESP AT HIGH MNNG CONCN WERE OBSERVED IN DUODENUM, JEJUNUM AND MESENTERY ... WITH PAPILLOMAS IN FORESTOMACH AND LIVER TUMORS. [R34] *SINGLE DOSE OF 50 OR 250 MG/KG BODY WT GIVEN IN SALINE OR 250 MG/KG BODY WT GIVEN IN OLIVE OIL TO GROUPS OF 11 OR 12 ACI RATS RESULTED IN TUMOR INCIDENCES OF 10-45% and 66-70%, RESPECTIVELY. AN EFFECTIVE NUMBER OF 51 ANIMALS SURVIVING LONGER THAN 300 DAYS WAS EVALUATED. MALIGNANT TUMORS IN THE GLANDULAR AND FORESTOMACH WERE SEEN ONLY AT HIGHER DOSE LEVEL, WHILE PAPILLOMAS OF FORESTOMACH OCCURRED IN BOTH GROUPS. ... [R35] *... CONTINUOUS TREATMENT OF 26 MALE GOLDEN HAMSTERS WITH CONCN OF 83 MG/L MNNG IN DRINKING WATER PRODUCED MALIGNANCIES WITHIN 6-10 MO. 20 FIBROSARCOMAS OF PYLORIC REGION OF GLANDULAR STOMACH, ORIGINATING FROM SUBMUCOSA WERE FOUND. IN ANIMALS DYING AFTER 260 DAYS 3 ADENOCARCINOMAS AND 2 FIBROSARCOMAS WERE FOUND IN DUODENUM. [R35] *ADMIN IN DRINKING-WATER OF 167 MG/L ... TO 10 MALE RABBITS FOR 15 MO PRODUCED SQUAMOUS CELL CARCINOMAS IN TRACHEOBRONCHIAL REGION IN 3 ... LIVING LONGER THAN 15 MO. NO TUMORS WERE FOUND IN GLANDULAR STOMACH, BUT ABNORMAL EPITHELIAL GROWTH WAS OBSERVED. ADENOCARCINOMA OF DUODENUM WAS ... FOUND. TRACHEOBRONCHIAL TUMORS MAY HAVE ARISEN FROM ASPIRATION ... DURING DRINKING. [R35] *Four Mongrel dogs received 167 mg/l ... in drinking water for 1 month, and then a reduced concentration of 87 mg/l for 14 months. Treatment was stopped at this time (... 463 days), and animals ... observed until death. All dogs developed adenocarcinomas of the stomach. Tumors were localized mainly in cardiac portion and in antrum. ... Spindle cell sarcomas and hemangioblastomas were found in small intestine. The latent period of tumor production was 518 to 1045 days. [R36] *IN 6/6 and 8/10 BDII RATS GIVEN 5 SC INJECTIONS OF 90 OR 45 MG/KG BODY WT/WK IN OIL ... FIBROSARCOMAS AND POLYMORPHIC SARCOMAS DEVELOPED AT SITE OF INJECTION AFTER 180-360 DAYS (DRUCKREYET AL, 1966). WEEKLY SC INJECTIONS OF 10 OR 25 MG ... IN 0.5% AQ SOLN TO 2 GROUPS OF 12 WISTAR RATS GAVE RISE MAINLY TO LOCAL FIBROSARCOMAS AND ... RHABDOMYOSARCOMAS IN 33% and 50% OF ANIMALS, RESPECTIVELY, WITHIN 300-360 and 170-333 DAYS. [R36] *... OF 154 ACI X SPRAGUE-DAWLEY RATS RECEIVING SINGLE SC DOSE OF 2, 10 OR 100 UG/RAT AT BIRTH, TUMORS DEVELOPED IN 15/46 RATS SURVIVING FOR LONGER THAN 1 YR. TUMORS WERE MAINLY ADENOCARCINOMAS AND FIBRO- AND MYOSARCOMAS OF SMALL INTESTINE. OTHER SITES ... /WHERE/ MALIGNANCIES WERE FOUND WERE STOMACH, LIVER, PERITONEUM, UTERUS AND OVARY. ... INCIDENCES WERE 2/10, 1/12, and 12/24 AT THE 3 LEVELS, RESPECTIVELY. [R36] *TREATMENT OF SKIN 3 TIMES WEEKLY WITH 0.05 ML OF 0.15%, 0.3% and 0.5% SOLN ... IN ACETONE FOR 5 MO INDUCED 6 PAPILLOMAS, 17 FIBROSARCOMAS, 8 MIXED TUMORS (COMPOSED OF BOTH SQUAMOUS CELL CARCINOMAS AND FIBROSARCOMAS) and 7 SQUAMOUS CELL CARCINOMAS AT SITE OF APPLICATION IN 28 ICR MICE. ... NO LOCAL TUMORS ... IN CONTROLS. [R36] *IN 12 CFW AND 12 C3H MALE MICE GIVEN 2 TO 3 /IP/ DOSES OF APPROX 100 MG/KG BODY WT WITHIN 6 TO 10 MONTHS, 4 BENIGN AND MALIGNANT TUMORS OF CECUM, ILEUM AND JEJUNUM AND 1 ADRENAL CORTICAL TUMOR WERE OBSERVED IN ANIMALS DYING AFTER 13 TO 16 MONTHS. ... IN 12 MALE RATS A SINGLE /IP/ DOSE OF APPROX 60 MG/KG BODY WT FOLLOWED BY 2 TO 3 DOSES OF 10-25 MG/KG BODY WT WITHIN 11 MONTHS LED TO DEVELOPMENT OF 5 MALIGNANT TUMORS IN STOMACH, JEJUNUM AND CECUM AFTER 12 TO 19 MONTHS. IN SUCKLING ACI X SPRAGUE-DAWLEY RATS A SINGLE DOSE OF 600 UG/RAT RESULTED IN PAPILLOMAS, CARCINOMAS AND SARCOMAS OF STOMACH AND SMALL INTESTINE AND FEW TUMORS AT OTHER SITES IN 53% OF 38 ANIMALS SURVIVING LONGER THAN 1 YR. ... DAILY RECTAL INFUSION FOR 32 DAYS OF 0.5 ML OF 0.25% AQ SOLN (TOTAL DOSE, 40 MG/RAT) OF MNNG INDUCED 1 OR MORE ADENOMATOUS POLYPS AND POLYPOID CARCINOMAS IN COLON AND RECTUM IN 7/9 RATS LIVING LONGER THAN 30 WK. [R37] *MNNG INDUCED GLY- + THY- + HYPOX- TYPE OF MUTATION (MAINLY) IN CHINESE HAMSTER CHO/PRO-K1 CELLS; IN CHO/PRO- CELLS IT INDUCED REVERSION TO PROTOTROPHY; AND IN V79 CELLS IT INDUCED RESISTANCE TO 8-AZAGUANINE AND ITS REVERSION. /FROM TABLE/ [R22] *A CELL LINE FROM NORMAL BEAGLE EMBRYO WAS TREATED IN VITRO WITH VARIOUS LEVELS OF MNNG OR DIMETHYL SULFOXIDE (CONTROL). TREATED CELLS UNDERWENT MORPHOLOGIC ALTERATIONS IN VITRO. ONE LINE GREW ON LIQ GROWTH MEDIUM ABOVE AN AGAR BASE AND PRODUCED SC TUMORS WHEN INJECTED INTO NIH NUDE MICE. [R38] *RAT TRACHEAL EPITHELIAL CELLS WERE TRANSFORMED IN VITRO BY BEING EXPOSED TWICE (AT DAYS 3 and 6) TO 0, 0.001, 1.0 OR 10.0 UG MNNG/ML OF MEDIUM. THE RESULTING CELL LINES WERE CARCINOGEN-DOSE-DEPENDENT. SOME CELL LINES PRODUCED PALPABLE TUMORS IN IMMUNOSUPPRESSED RECIPIENTS. [R39] *MALIGNANT TRANSFORMATION WAS INDUCED BY MNNG IN SYNCHRONIZED CULTURES OF C3H/10T1/2CL8 LINE OF MOUSE FIBROBLASTS. MORPHOLOGICALLY TRANSFORMED COLONIES FROM MNNG-TREATED DISHES WERE CLONED, CULTURED, AND INJECTED INTO X-IRRADIATED SYNGENEIC MICE. MNNG TREATED CELL LINES PRODUCED SARCOMAS, BUT UNTREATED CELLS DID NOT. [R40] *BALB/3T3 CELLS TRANSFORMED IN CULTURE BY MNNG MULTIPLIED IN MEDIUM SUPPLEMENTED WITH 2% CALF SERUM OR 10% AGAMMA NEWBORN CALF SERUM. CELLS MULTIPLIED WELL IN 10% AGAMMA SERUM AND PRODUCED HIGH INCIDENCE OF TUMORS IN X-IRRADIATED WEANLING MICE. [R41] *BREAKDOWN OF DNA IN SYNCHRONOUS, ONCOGENICALLY TRANSFORMABLE FIBROBLASTS OF C3H/10T1/2 MOUSE CELL LINES (TREATED WITH 10-20% LETHAL DOSE MNNG FOR 2 HR) WAS EASILY DETECTED AND DOSE DEPENDENT. REPAIR WAS NOT COMPLETE 48 HR AFTER TREATMENT. [R42] *EPITHELIAL-LIKE CELLS FROM LIVER OF 10 DAY-8 WK OLD BD RATS WERE CULTURED AND TREATED 1 OR 4 WK WITH MNNG. 61 NEWBORN SYNGENEIC RATS WERE INJECTED WITH 1.5-2X10+6 TREATED CELLS OR 1.5-5X10+6 CONTROL CELLS FOR 38 WK. TREATED CELLS PRODUCED 30 TUMORS WHICH INCL 8 CARCINOMAS, 9 CARCINOSARCOMAS AND 13 FIBROSARCOMAS. CONTROL CELLS PRODUCED EPITHELIAL AND MESENCHYMAL TUMORS, ALTHOUGH MESENCHYMAL TYPE APPEARED AT LOWER FREQUENCY. OBSERVATION OF MESENCHYMAL TUMORS WAS ATTRIBUTED TO PRESENCE OF A MIXED POPULATION OF EPITHELIAL AND MESENCHYMAL CELLS IN ORIGINAL CULTURE. [R43] *MNNG INDUCED MORPHOLOGICAL ALTERATIONS IN GUINEA PIG FETAL CELLS SHORTLY AFTER TREATMENT. CELL TRANSFORMATION DID NOT OCCUR FOR APPROX 4 MO AND DID NOT UNIFORMLY APPEAR SIMULTANEOUSLY WITH CAPACITY OF TRANSFORMED CELLS TO GROW AS TUMORS IN IRRADIATED SYNGENEIC NEWBORN GUINEA PIGS. [R44] *... Pregnant mice ... /were admin/ dose levels of 40 to 80 mg/kg ... as single IP injection on day 7, 8, 9, 10, 11 or 12. Hydrocephalus, cleft palate, micrognathia and reduction defects of the extremities were found in fetus. The highest incidence of hyrocephalus was found in the group treated on day 10 with 60 mg/kg. At 80 mg/kg approx 1/3 of mothers died. [R45] *Although N-nitrosamines are rapidly and fairly evenly distributed throughout the bodies of rats after injection, the acute toxic damage they produce is more severe in the liver than elsewhere, and tumors following chronic exposure are confined mainly to the liver and kidney. /N-nitrosamines/ [R46] *In a study to determine whether acute gastric ulcers are predisposed to carcinogenesis by the oral carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) it was found that repeated stress ulceration, produced by restraint and cold water immersion, protected the rat stomachs from the carcinogenic effect of MNNG. Thus none of the rats subjected to the repeated stress procedure developed any stomach tumor despite taking MNNG in drinking water for 12 months. For comparison, in a control group of 42 rats taking MNNG only, stomach tumors were found in 26 rats (62%). The mechanism of this is obscure; increased vagal activity and hyperacidity are suggested explanations. [R47] *Four species of nonhuman primates (Macaca mulatta, M fascicularis, Cercopithecus aethiops, and Galago crassicaudatus) were used for testing the carcinogenicity of a wide variety of chemicals. Nitroso cmpd except nitrosodiemthylamine, induced tumors in monkeys. The latent period for tumor induction was related to the chronic dosage of the carcinogen. [R48] *Recurrent exposures (17 administrations in 37 days) to the direct-acting mutagens N-methyl-N-nitrosourea and N-ethyl-N-nitrosourea and a chronic exposure (38 days) to the metabolism-requiring mutagen dimethylnitrosamine markedly increased the frequency of somatic mutations in a double heterozygous chlorophyll mutant of Nicotiana tabacum, whereas exposure to MNNG was ineffective. [R49] *A battery of short-term tests used to predict carcinogenesis must be both sensitive (correctly identifying carcinogens) and specific (correctly identifying noncarcinogens). A publication of results in 4 short-term tests for 70 noncarcinogens tested under the aegis of the National Toxicol Program (NTP) indicates that the battery of short-term tests lacked specificity. These results were analyzed using the carcinogen prediction and battery selection procedure and it was calculated that the specificity of the NTP battery is indeed very low, ie, 0.50. Using published data from NTP, the GeneTox program of EPA, and the collaborative study of the WHO International Program on Chemical Safety, an alternate battery was constructed that has fewer false positives; this battery has a specificity of 0.80. Thus, the lack of specificity of the original NTP battery does not imply that no set of short-term tests is able to predict carcinogenicity accurately. [R50] *Adult fish of 2 different inbred strains (HO4C and HB32C) of Oryzias latipes that were established in this lab were exposed for 2 hr to an aq soln of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) at 20-100 ppm. The acute toxicity and carcinogenicity of MNNG differed between 2 inbred strains. Almost no tumors were in strain HO4C fish, although these fish were sensitive to the acute toxicity of MNNG, with the median LD being 28 ppm at 48 hr after the treatment. Most MNNG-induced tumors were considered amelanotic melanomas on the basis of histological findings and a positive dopa reaction in selected samples. By the technique of transplantation of tumor tissue into the eye chamber and ip cavity of fish of the syngeneic strain, serial transplantation of the tumor was successful. Tumor transplantation into 1 of the allogeneic strains (HO5) was also successful. The tumors have now been serially grown in the eye chambers in syngeneic fish for > 14 generations. [R51] *45% or more of 20 male rats treated with N-methyl-N'-nitro-N-nitrosoguanidine, at an equimolar concn in drinking water developed neoplasms of the glandular stomach. There was some shortening of life span in these animals. An additional group of 20 male rats was given an identical treatment with N-methyl-N'-nitro-N-nitrosoguanidine in water, but prepared fresh on alternate days, rather than once a week, to minimize decomposition. These animals died more rapidly than did the previous group and had a higher incidence of neoplasms of the glandular stomach. The neoplasms seen in this organ were usually adenomas or adenocarcinomas, but there were a few hemangiosarcomas and neurosarcomas. ... [R52] *The acute toxicity of N-nitrosocimetidine, the nitrosated derivatived of the histamine H2-receptor blocking agent cimetidine, was compared with the toxicities of three structurally related nitroso-compounds known to be potent carcinogens, namely N-methyl-N'-nitro-N-nitrosoguanidine, and N-methyl-N-nitrosourea ... . The acute toxicity of each compound was investigated in 6-week-old female fischer-344 rats by estimating the median lethal doses via three different routes of administration, and by estimating the sequence of histopathological alterations induced. According to median lethalities, all three known carcinogens were substantially more toxic than nitrosocimetidine whether administered by the intravenous, intraperitioneal, or oral routes. ... Sequential histological assessment indicated that the three known carcinogens induced specific pathological alterations mainly in organs which were also known to be targets for their carcinogenic activity. ... [R53] *Normal regeneration of the amputated forelimb of the Japanese newt, Cynops pyrrhogaster and regeneration after a single intraperitioneal injection of three potent mutagenic/carcinogenic agents was investigated. Three dose levels of each agent and controls were tested for teratogenicity in this newt model with the following chemicals: N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4-nitro-quinoline-uryl)-3-(5-nitrofuryl)acrylamide. These chemicals were administered at 10 days (late dedifferentiation stage), 20 days (late bud stage), and 30 days (early digits stage) after amputation at the mid forelimb. A total of 628 newts, with 16-20 animals per group, were used. Normal forelimb regeneration in Cynops pyrrhogaster closely paralleled that reported for other species. A variety of deformities, including syndactyly, polydactyly, oligodactyly, brachydactyly, and digital branching, were occasionally observed in control regenerating forelimbs, with syndactyly occurring at highest incidence (17.5%). All three mutagens at all tested dose levels enhanced the incidence of teratogenic changes, though increases were not always statistically significant. MNNG, particularly when administered at the time of initial chondrogenesis (20 days, late bud stage), was especially teratogenic. The type of forelimb deformity was not mutagen-specific in this experiment. ... [R54] *The induction of mutations in Chinese hamster ovary (CHO) cells pretreated every 6 hr with 0.01 mug/ml N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 72 hr (a total of 13 treatments) was linear up to 0.5 mug/ml MNNG; but above this dose, there was a substantial decrease in mutation induction. The induction of mutations in control cells was linear with the dose. Thus, pretreatment of chinese hamster ovary cells does not induce a measureable increase in the ability of these cells to repair premutagenic alkylation damage after low MNNG challenge doses. [R55] *The effects of selected chem teratogens on sister-chromatid exchange (SCE) frequencies and cell replication kinetics (CRK) in pregnant mice and their fetuses were investigated. Maternal and fetal cells were analyzed for SCE and classified as to whether they had gone through 1(M1), 2(M2), or 3 or more (M3+) cell cycles for quantifying cell replication kinetics and est avg generation time (AGT). ... MNNG /N-methyl-N'-nitro-N-nitrosoguanidine/ did not induce any increase in SCE in either maternal or fetal cells. Chi-square analysis of the relative numbers of M1, M2, and M3+ cells revealed significant heterogeneity among test chem doses in both maternal and fetal cells ... A significant linear relation between ACT and test chem dose was noted /for/ MNNG in fetal cells. Although significant, the effects of MNNG, on AGT were small, with increases in AGT of only 1 hr or less at the highest doses tested. Avg generation time was consistently lower in fetal cells as compared with maternal cells (overall mean AGT from solvent controls was 8.6 hr for fetal cells and 11.6 hr for maternal cells). Thus, SCE induction and cell replication inhibition can occur independently, and the assessment of SCE and CRK in maternal and fetal cells may be a promising approach to the identification of teratogenic agents. [R56] *To determine whether chronic gastric ulcers in the rat are predisposed to tumor formation when exposed to a usually noncarcinogenic dose of the carcinogen, N-Methyl-N'-nitro-N-nitosoguanidine (MNNG). Two groups of rats were prepared: one subjected to a standard ulcer-producing operation, the other as control. Both groups were given oral MNNG (100 mg/l as drinking water) for 12 weeks, the carcinogen was then stopped and replaced with tap water, and the experiment terminated at 52 weeks. Results showed that low dose of carcinogen (200 mg) did not induce tumor formation in any of the normal rats. In the presence of a chronic gastric ulcer, only intestinal net metaplasia and hyperplastic glandular nodules were observed, but there were no gastric tumors. It is conclude that the presence of a chronic gastric ulcer did not increase the likelihood of gastric tumor formation in rats treated with a noncarcinogenic dose of the carcinogen MNNG. [R57] *Nuclear toxicity of several known carcinogens and fecal fractions obtained from 10 healthy individuals was investigated in the colonic nuclear aberration (NA) assay using an intrarectal administration. Two known colon carcinogens, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and DMAB, and a carcinogen of organs other than the colon, benzo(a)pyrene, induced nuclear aberration in a dose-related manner. Chromatographic fractions of feces from 10 donors were tested for their ability to produce nuclear aberration. The methylene chloride fraction for several was active and yielded a significantly positive response which was dose-related. Thus, the feces of some healthy individuals contain compounds which damage colonic nuclei in a similar manner to that seen with some known carcinogens. [R58] *Following chronic oral administration of hot water and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 4 of 30 Wistar rats developed sarcoma of the esophagus. Six animals had tumors of the stomach, the liver and in the jejunum. One malignant tumor of the mediastinum was observed. The relatively short tumor induction time may be caused by the combined action of thermal injury and subsequently administered carcinogen. Organotropy of MNNG is changed and malignanacies not only developed in the glandular stomach but also at the site of thermal injury to the esophagus. [R59] *Cells derived from rainbow trout gonad (RTG-2) and bluegill fry tissues (BF-2) were used as model cell systems to measure cytotoxicity and genotoxicity following exposure to Puget Sound sediment extracts, benzo(a)pyrene and MNNG (N-methyl-N'-nitro-N-nitrosoguanidine). Sediment was collected from several sites withing Puget Sound (Wasington USA) known to be contaminated with compounds such as polycyclic aromatic hydrocarbons, polychlorinated biphenyls, chlorinated hydrocarbons and heavy metals. Each of the sediment samples was extracted with organic solvents and added to cultures of the 2 model cell systems in DMSO (dimethyl sulfoxide). Following exposure the cultures were evaluated for cell death, mitotic inhibition, stimulatory effects and chromosomal damage. These cell cultures responded to the sediment extracts much as they did to known mutagenic/carcinogenic chemicals which were used as model compounds. [R60] *Ultra-acute 4 hr algal interaction experiments on the genotoxic activity of N-methyl-N'-nitro-N-nitrosoguanidine were undertaken with Selenastrum capricornutum. Genotoxic activity was determined with the SOS Chromotest on each pre-exposure test solution and on each post-exposure supernatant and algal cell extract. Test concn of N-methyl-N'-nitro-N-nitrosoguanidine was 0.1 mg/l. No genotoxic activity change was observed for algal exposure to N-methyl-N'-nitro-N-nitrosoguanidine with or without S9 activation. [R61] *The cytotoxic activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was determined in cell culture by using a P388 (mouse leukemia) cell growth rate inhibition assay. Expt were conducted at a cell density of 10+6 cells/ml, pH 7.4 and 37 C with either the initial concn or incubation time varied. The ED50 for MNNG was 4.1 uM at 15 min exposure. MNNG activity was affected by cell culture medium. The activity of 7.5 uM MNNG over time against cells in phosphate-buffered saline appears to be greater than that against cells in Fisher's medium containing 10% (vol/vol) donor horse serum. A kinetic model was developed to calculate the concn of MNNG that is converted to active methylating species within the cell during the assay incubation period. By use of measured values for initial drug concn, incubation time, and cell vol, as well as extracellular and intracellular chemical activation rate constant, the intracellular concn, which represents the cumulative intracellular reaction products formed during the incubation period, was calculated and related to cytotoxicity. The intracellular concn ED50 for MNNG was between 140 and 180 uM, and was independent of extracellular sulfhydryl concn. [R62] *An example of an agent that produces ... /teratogenicity/ is ... N-methyl-N'- nitro-N-nitrosoguanidine, an alkylating agent that induces replication-dependent mutations and inhibition of DNA synthesis. When administered on days 7 to 12 of gestation, a spectrum of malformations involving the brain, palate, vertebral column, ribs, and limbs is produced. Limb defects are prominent, but not unique, with exposure on day 10 or 11. Teratogenicity predominates under these exposure conditions, but embryolethality is elevated at all dose levels. [R63] *Three different developmental stages of embryonated eggs of Oryzias latipes were exposed to 2-hr pulses of a number of different concentrations of MNU, MNNG, and DENA. Lethality and teratogenic endpoints were assessed through 24 h posthatch. MNU (greater than or equal to 2.5 mM) and MNNG (greater than or equal to 0.75 mM) exposure at the multicell stage was lethal, but the same exposure during early organogenesis was largely teratogenic. Four days before hatching, embryos were very resistant to MNU and proceeded to hatch normally; 7.5 mM MNU was required to significantly reduce the percent normal hatch. Effects of DENA were equivocal and only seen at the multicell stage. In order to differentiate between potential changes in chorion permeability, and toxicity per cell, the same three stages were exposed to a series of radiolabeled compounds of varying hydrophobicity, and apparent uptake measured. There were no differences in uptake rate or equilibrium concentration between any of the compounds at the different stages. These results suggest that, as in mammals, certain stages of development are more susceptible than others, and that these differences are a result of embryo sensitivity rather than chemical bioavailability. The most sensitive indicator of exposure was posthatch inflation of the swimbladder. Other terata included pericardial edema, anisophthalmia, and partial rupture of the chorion. [R64] *Gastric carcinomas in rats have been selectively induced by N-methyl-N'-nitro-N-nitrosoguanidine. Similar models for the induction of gastric carcinomas in other species by using N-methyl-N'-nitro-N-nitrosoguanidine and its ethyl derivative N-ethyl-N'-nitro-N-nitrosoguanidine have been established. The susceptibility to gastric carcinogenesis, the histologic types of gastric carcinomas induced, and their biological behavior depend on the mode of treatment, species, strain and/or sex. The organ specificity of N-methyl-N'-nitro-N-nitrosoguanidine correlates well with the level of DNA methylation in target and non-target tissues following oral administration in rats. The high concentration of methylated DNA bases in the stomach mucosa appears to result from thiol-mediated acceleration of the decomposition of N-methyl-N'-nitro-N-nitrosoguanidine. Experimental gastric carcinogenesis is markedly modified by various factors and agents, including bile reflux, bile acids, sodium chloride, and ulceration, indicating that both host and environmental factors contribute significantly to gastric carcinogenesis by chemical carcinogens [R65] NTOX: *The response of the filamentous fungus Aspergillus nidulans to low, non-killing, doses of the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine was investigated. Such treatment causes a substantial induction of DNA alkyltransferase activity, with the specific activity in treated cells increasing up to one hundred fold. Fluorography reveals the two main inducible species as proteins of 18.5 kDa and 21 kDa, both of which have activity primarily against O6-methylguanine lesions. In addition, two other alkyltransferase proteins can also be detected. One, of MW 16 kDa, is expressed in non-treated cells, but is not induced to the same extent as the 18.5 and 21 kDa proteins. The other, a protein of 19.5 kDa, is highly inducible and can only be detected i treated cells. Unlike the other three proteins, it acts primarily against methyl phosphotriester lesions. This is the first instance in which an methyl phosphotriester alkyltransferase has been detected in a eukaryotic organism and, coupled with the high level of induction of the O6-methylguanine alkyltransferase enzymes, this indicates that a control system similar to the bacterial adaptive response may be present in filamentous fungi. [R66] *The ada gene of Escherichia coli encodes O6-methylguanine-DNA methyltransferase, which serves as a positive regulator of the adaptive response to alkylating agents and as a DNA repair enzyme. The gene which can make an ada-deficient strain of Escherichia coli resistant to the cell-killing and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine has been cloned from Salmonella typhimurium TA1538. DNA sequence analysis indicated that the gene potentially encoded a protein with a calculated molecular weight of 39,217. Since the nucleotide sequence of the cloned gene shows 70% similarity to the ada gene of Escherichia coli and there is an ada box-like sequence (5'-GAATTAAAACGCA-3') in the promoter region, we tentatively refer to this cloned DNA as the adaST gene. The gene encodes Cys-68 and Cys-320, which are potential acceptor sites for the methyl group from the damaged DNA. The multicopy plasmid carrying the adaST gene significantly reduced the frequency of mutation induced by N-methyl-N'-nitro-N-nitrosoguanidine both in Escherichia coli and in Salmonella typhimurium. The AdaST protein encoded by the plasmid increased expression of the ada'-lacZ chromosome fusion about 5-fold when an Escherichia coli strain carrying both the fusion operon and the plasmid was exposed to a low concentration of N-methyl-N'-nitro-N-nitrosoguanidine, whereas the Escherichia coli Ada protein encoded by a low-copy-number plasmid increased it about 40-fold under the same conditions. The low ability of AdaST to function as a positive regulator could account for the apparent lack of an adaptive response to alkylation damage in Salmonella typhimurium. [R67] *The hormonal aspect of N-methyl-N'-nitro-N-nitrosoguanidine is discussed in relation to its carcinogenic potency for the gastric epithelium. The action of N-methyl-N'-nitro-N-nitrosoguanidine, as assessed in terms of a) the affinities for both the glucocorticoid receptor and androgen receptor of mouse, b) the effects on th turnover of hydrocortisone and dihydrotestosterone in the glandular stomach of mouse, c) the induction of ornithine decarboxylase in the same tissue, and d) the interfering effect on the hydrocortisone - linked acceleration of water turnover at the whole body level of a mouse, points to the steroid-mimetic nature of the carcinogen. It is suggested that N-methyl-N'-nitro-N-nitrosoguanidine may behave like an androgen antagonist on the one hand, and like a chimera between glucocorticoid agonist and glycocorticoid antagonist on the other hand. The proposition that a chemical carcinogen may have an interplay with the steroid and thyroid hormone receptor superfamily in the induction of malignant transformation is reviewed in the light of recent progress of steroid receptor biology. [R68] *Admin of MNNG in drinking water induces tumors, mainly adenocarcinomas in glandular stomach of rats. The sensitivities of different strains of rats to gastrocarcinogenesis induced by MNNG vary: Wistar and ACI strains are sensitive, whereas the Buffalo strain is resistant. The gene(s) controlling resistance to MNNG is autosomal in the Buffalo strain and is inherited dominantly by F1 AND F2 hybrids. In both strains and their hybrids, the incidence of gastric tumors was higher in males than in females. [R69] *The effects of ... N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) on epithelia of human fetal trachea and bronchiolar epithelia of human fetal lung /was/ studied /in/ organ-cultured explants. In epithelium of human fetal trachea, 34 um N-methyl-N'-nitro-N'nitrosoguanidine induced hyperplasia, metaplasia, and dysplasia. ... In glandular epithelium of human fetal trachea, 34 um N-methyl-N'-nitro-N'nitrosoguanidine induced hyperplasia and metaplasia ... [R70] *Five direct-acting alkylating agents were examined qualitatively and quantitatively for their ability to produce developmental toxicity i rodent postimplantation embryos. These agents were structurally related and were capable of donating either a methyl (methylnitrosourea, MNU; methylnitronitrosoguanidine, MNNG; methyl methanesulfonate, MMS) or ethyl (ethylnitrosourea, ENU; ethyl methanesulfonate, EMS) group to nucleophiles. These agents' reactivities were known to differ. In day 10 rat embryos in vitro a single, 2 hr exposure was shown to be sufficient to elicit dose-dependent increases in embryo lethality and malformations. Qualitatively, the patterns of embryo malformations reported in treated embryos paralleled those observed in in vivo studies, especially in regard to adverse effects on central nervous system and craniofacial systems. Quantitatively, the order of potency of these agents in vitro was: methylnitronitrosoguanidine greater than methylnitrosourea greater than ethylnitrosourea greater than methyl methanesulfonate greater than ethyl methanesulfonate. In vivo studies reported a different order of potency. In vitro, methylating agents were consistently more potent than ethylating agents. Other chemical properties such as nucleophilic reactivity or half-life under physiological conditions could not explain observed potency relationships. [R71] *O6-Methylguanine (O6MeG) is important in induction of chromosome aberrations (abs), with the unusual property that new abs are produced in the second cycle after treatment: cells lacking repair by O6-alkylguanine DNA-alkyltransferase (AGT) have more abs at the second division (M2) than at the first (M1). These second-cycle abs are likely caused by attempted correction by mismatch repair (MMR) of O6-methylguanine:T mispairs, since we previously showed that mismatch repair-deficient human cells (MT1 lymphoblasts) treated with SN-1 methylating agents do not produce new abs at M2 and are resistant to killing. Her we used mismatch repair-deficient rodent cells to examine ab induction by alkylators and by incorporated 6-thioguanine (6-tG) which produces mispairs. BrdUrd labeling was used to identify cells at first, second and third metaphase after treatment (M1, M2 and M3). mismatch repair-deficient Chinese hamster Clone B cells were 10-fold more resistant to ab induction by methyl nitrosourea and 1-methyl-3-nitro-1-nitrosoguanidine compared to their mismatch repair-proficient parent cells, CHO MT+. Both cell lines express O6-alkylguanine DNA-alkyltransferase and can remove the methyl group from O6-methylguanine. Clone B has twice the O6-alkylguanine DNA-alkyltransferase activity of CHO MT+, but inhibition of O6-alkylguanine DNA-alkyltransferase with O6-benzylguanine did not change ab induction, indicating that methylation tolerance of Clone B cells was due to defective mismatch repair and not to increased repair of O6-methylguanine. ... [R72] *Administration of N-methyl-N'-nitro-N-nitrosoguanidine, a glandular stomach carcinogen, at the concentration of 100 mug/ml in drinking water for 8 days induced the appearance of a MHC class II-associated invariant chain in the target organ of stomach pyloric mucosa of male Lewis rats. The up-regulation of the MHC class II-associated invariant chain was revealed by fluorescent differential display analysis, reverse transcription PCR, Northern blot, and histochemical staining. The appearance of MHC class II and MHC class I was also demonstrated by reverse transcription PCR and Northern blot. The results suggest the involvement of MHC controlled immune reactions in chemically-induced stomach carcinogenesis. [R73] *The modifying effects of Chelidonium majis L. (Papaveraceae) herb extract (CH), an analgesic traditionally prescribed for gastric and duodenal ulcer patients, on gastric tumor development were studied in rats given N-methyl-N'-nitro-N-nitrosoguanidine(MNNG). Sixty-four male 6-week-old Wistar rats were used. Group1 rats were initially given N-methyl-N'-nitro-N-nitrosoguanidine (200 mg/kg bw) by gavage at days 0 and 14 as well as saturated sodium chloride solution (S-NaCl, 1 ml per rat) every 3 days during weeks 0-3 (six times), and then placed on basal diet containing 0.1 or 0.2% Chelidonium majis L. herb extract for 16 weeks from week 4. Rats of Group 2 and 3 were treated with N-methyl-N'-nitro-N-nitrosoguanidine together with S-NaCl or saline (0.9% NaCl, 1 ml per rat), respectively, timed as in Group 1 but without further treatment. All surviving animals were killed at week 20 and histopathologically investigated. In the glandular stomach, the number of preneoplastic pepsinogen 1 altered pyloric glands (PAPGs) in the N-methyl-N'-nitro-N-nitrosoguanidine + S-NaCl+:Chelidonium majis L. herb extract (0.1%) group (Group 1) was significantly smaller than in the N-methyl-N'-nitro-N-nitrosoguanidine + S-NaCl group (Group 2) (P < 0.02). The incidences of forestomach neoplastic lesions (papillomas and squamous cell carcinomas) also showed a tendency to decrease with the Chelidonium majis L. herb extract treatment. ... Chelidonium majis L. herb extract exerts inhibitory effects on glandular stomach carcinogenesis in the rat. ... [R74] *... to increase the understanding of the factors responsible for causing human colon cancer, a technique was developed to detect genotoxic effects of chemicals in human colon cells. ... the method is based on the measurement of DNA damage in primary cells freshly isolated from human colon biopsies with the single cell ... ('Comet Assay'). 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3-methyl-3H-imidazo[4,5f]quinoline (IQ), N-methyl-N-nitro-N-nitrosoguanidine (MNNG), dinitrosocaffeidine (DNC), lithocholic acid (LCA), hydrogen peroxide (H2O2) and benzo[a]pyrene (B[a]P) were investigated for their genotoxic and cytotoxic effects following 30 min incubation with colon cells of human, and for comparative purposes also of the rat colon. The nitrosamides (N-methyl-N-nitro-N-nitrosoguanidine, dinitrosocaffeidine) were very genotoxic in human colon cells. N-methyl-N-nitro-N-nitrosoguanidine was more genotoxic in human than in rat colon cells. In contrast, the rat colon carcinogens 2-Amino-1-methyl-6-phenylimidazo[4,5-]pyridine and 2-amino-3-methyl-3H-imidazo[4,5f]quinoline were not genotoxic in human colon cells. 2-Amino-1-methyl-6-phenylimidazo[4,5-]pyridine did induce DNA damage in rat colon cells, which correlates to its capacity of inducing tumors in this animal tissue. lithocholic acid was toxic (rat > human) and concomitantly caused DNA damage in higher concentrations. The widespread contaminant benzo[a]pyrene was not genotoxic in colon cells of either species using this system. hydrogen peroxide was found to be a potent genotoxic agent to both rat and human colon cells (human > rat). In summary, those compounds chosen as representatives of endogenously formed risk factors (N-methyl-N-nitro-N-nitrosoguanidine, hydrogen peroxide, lithocholic acid) have a higher toxic and/or genotoxic potency in human colon tissue than in rat colon. They are also more effective in this system than the contaminants tested so far (benzo[a]pyrene, 2-Amino-1-methyl-6-phenylimidazo[4,5-]pyridine, 2-amino-3-methyl-3H-imidazo[4,5f]quinoline). ... [R75] *Recently, we designed a fast and simple method to obtain nuclei for the alkaline SCG /(single-cell gel)/ assay and we tested it with mouse liver, lung, kidney, spleen, and bone marrow. Instead of isolating organ cells by trypsinization, we homogenized tissue and isolated the nuclei. ... The nuclei ... were used for the assay. To evaluate the validity of this method, we tested the genotoxicity in mouse organs of 11 chemical mutagens with different modes of action. Mice were sacrificed 3 or 24 hr after administration of each mutagen. Treatment with three alkylating agents (MMS, EMS, and MNNG), a DNA crosslinking agent (MMC), two aromatic amines (2-AAF and phenacetin), a polycyclic aromatic hydrocarbon (B(a)P), and two inorganic chemicals (KBrO3 and K2CrO4) increased migration of the DNA from mouse organs. 5-FU (a base analog) and colchicine (a spindle poison) treatment produced negative results in all /organs/ studied. ... [R76] *An enzyme O6-methylguanine-DNA methyltransferase (MGMT) catalyzes transfer of a methyl group from O6-methylguanine and O4-methylthymine of alkylated DNA to its own molecule, thereby repairing the pre-mutagenic lesions in a single step reaction. ... /the authors/ developed mouse embryonic stem (ES) cell lines deficient in the methyltransferase. Quantitative immunoblot analysis and enzyme assay revealed that O6-methylguanine-DNA methyltransferase-/- cells, in which both alleles were disrupted, contained no methyltransferase protein while cells with one intact allele (O6-methylguanine-DNA methyltransferase+/-) contained about half the amount of protein carried by the parental O6-methylguanine-DNA methyltransferase+/+ cells. O6-methylguanine-DNA methyltransferase -/- cells have an extremely high degree of sensitivity to simple alkylating agents, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU), whereas O6-methylguanine-DNA methyltransferase+/- cells are slightly more sensitive to these agents, as compared with findings from normal cells. A high frequency of mutation was induced in O6-methylguanine-DNA methyltransferase-/- cells on exposure to a relatively low dose of N-methyl-N'-nitro-nitrosoguanidine. [R77] *Monofunctional alkylating agents like methyl methanesulfonate (MMS) and N-methyl-N'-nitro-nitrosoguanidine (MNNG) are potent inducers of cellular stress leading to chromosomal aberrations, point mutations, and cell killing. ... these agents induce a specific cellular stress response program which includes the activation of Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPKs), p38 mitogen-activated protein kinase, and the upstream kinase SEK1/MKK4 and which depends on the reaction mechanism of the alkylating agent ... [R78] *To determine the relationship between neoplastic transformation and increased genetic instability, spontaneous and induced mutation rates were compared in a nontumorigenic, immortalized human bronchial epithelial cell line (NL20) and a tumorigenic cell lie (NL20T) spontaneously derived from the NL20 line. Using the hypoxanthine phosphoribosyltransferase (HPRT) locus as a marker for determining mutation rate, fluctuation analysis was utilized to evaluate the spontaneous mutation rate. Induced mutation rates were determined for each cell line after N-methyl-N'-nitro-N-nitrosoguanidine exposure. Both the spontaneous and induced mutation rates were noted to be significantly higher in the nontumorigenic NL20 cell line, These findings suggest that increasing genetic instability, as measured by spontaneous or induced mutation rate in the HPRT locus, does not correlate with tumorigenicity in these cells. [R79] *Single-cell gel electrophoresis assays (comet assays) are described in which DNA damage is assessed in mouse skin keratinocytes treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and beta-propiolactone (BPL) either in vitro or in vivo. ... A series of experiments was conducted in which control and N-methyl-N'-nitro-N-nitrosoguanidine-treated cells were exposed to a range of alkaline DNA-unwinding times (0.3-18 hr) followed by measurement of the three comet tail parameters (length, DNA content, and their product, tail moment). Each of these parameters increased with increasing time of unwinding such that the tails observed for N-methyl-N'-nitro-N-nitrosoguanidine-treated cells with 0.3 hr of DNA unwinding were similar in length to the tails of control cells exposed to an 8 hr DNA-unwinding time. ... DNA-unwinding time is a critical parameter of the comet assay and ... it may require optimization for each tissue/cell type studied. ... agents that uniquely affect chromosomal protein superstructure may increase comet tail length/DNA content in the absence of chemically induced DNA damage. Thus, there may be two discrete classes of chemical interaction with chromosomal DNA that yield identical comet assay results, but which have different implications for the genetic toxicity of the test agent. Similar effects were observed for rat hepatocytes or mouse lymphoma cells exposed to an 18 hr DNA-unwinding time, but no comet tails were produced by exposure of cells to the lysis conditions (pH 10.0) for 18 hr. [R80] *Japanese medaka (Oryzias latipes) and channel catfish (Ictalurus punctatus) were investigated for carcinogenic response following a 28-day, 3 x/wk pulse exposure to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Five-week-old medaka were exposed to concentrations of 0, 0.5, and 1.0 mg/l, and 5-mo-old catfish at concentrations of 0, 0.1, and 0.5 mg/l. In medaka, a total of 19 tumors including 2 branchioblastomas, 6 thyroid follicular adenomas and 1 adenocarcinoma, and 11 subcutaneous fibrosarcomas were observed in 16 of 96 N-methyl-N'-nitro-N-nitrosoguanidine-exposed fish. In catfish, a total of 37 tumors including 4 squamous cell carcinomas and 16 papillomas, 3 lipomas, 1 fibroma, 1 osteosarcoma, 4 branchioblastomas, 6 thymic epithelial tumors, and 2 generalized lymphosarcomas were observed in 34 of 172 N-methyl-N'-nitro-N-nitrosoguanidine-exposed fish. The induction of neoplasms in medaka was primarily in the gill, thyroid, and subcutis of the cervical and trunk regions, whereas in catfish skin, thymus, oro-pharynx, and hemopoietic tissues were also commonly affected. In both species, the neoplastic response was considered to be related to direct exposure of the tissues to N-methyl-N'-nitro-N-nitrosoguanidine. ... The results ... suggest species-specific differences in carcinogenic response following N-methyl-N'-nitro-N-nitrosoguanidine exposure. [R81] *An early and immediate response of cells upon irradiation with UV light and various other forms of genotoxic stress is the induction of the proto-oncogenes c-fos and c-jun. To address the questions of whether (a) methylating agents that are powerful carcinogens are effective in induction of fos and jun mRNAs, (b) induction is affected by the repair capacity of the cells, and (c) induction is accompanied by genotoxic effects, the levels of c-fos, c-jun, junB and junD mRNA were analyzed in isogenic Chinese hamster cell lines deficient (phenotypically Mex-) and proficient (Mex+) for the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) after treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and methyl methanesulfonate (MMS). Both methylating agents were very effective in inducing fos and jun mRNAs, although they differ markedly in their potency to induce O6-methylguanine in DNA. Most responsive were c-fos and c-jun (up to 80-fold increases in mRNA level) whereas junB (up to ninefold) and junD (up to twofold) displayed an intermediate and weak response, respectively. No difference in the dose-dependence of induction of these mRNAs was observed between Mex- and Mex+ cells indicating that the critical genotoxic and mutagenic lesion induced by N-methyl-N'-nitro-N-nitrosoguanidine, i.e. O6-methylguanine, which is rapidly repaired by O6-methylguanine-DNA methyltransferase, does not act as a trigger for this response. Induction of fos and jun mRNAs by N-methyl-N'-nitro-N-nitrosoguanidine and methyl methanesulfonate was accompanied by a dose-dependent increase in the activity of the transcription factor AP-1. To induce fos and jun mRNAs as well as AP-1, doses of N-methyl-N'-nitro-N-nitrosoguanidine were required which were more than 50-fold higher than those inducing gene mutations, recombination events (SCEs) and reproductive cell death, and fivefold higher than those inducing chromosomal aberrations in Mex cells. Therefore, the immediate induction of fos and jun mRNAs and AP-1 in Mex- cells upon their exposure to N-methyl-N'-nitro-N-nitrosoguanidine appears not to be essential for the generation of N-methyl-N'-nitro-N-nitrosoguanidine-induced mutagenic and genotoxic effects, which is possibly due to the high genotoxic potential of non-repaired O6-methylguanine. However, for methyl methanesulfonate and UV light, which was included in this study for comparison, c-fos, c-jun, junB and junD mRNA as well as AP-1 induction paralleled the dose-response for induction of cell killing effects, recombination and chromosomal breakage indicating that increased expression of Fos and Jun is related to the generation of methyl methanesulfonate and UV-induced genetic changes. These data are in line with a model according to which the induced c-Fos and Jun proteins are involved in defense against UV radiation and other DNA damaging agents. [R82] *Two biochemical strategies using nick translation-type of incubation and terminal transferase-catalyzed reaction were used to assess single-(SSB) and double-strand (DSB) breaks in DNA of permeabilized neurons isolated from young, adult, and old rat cerebral cortex. Both single-strand breaks and double-strand breaks accumulate with age. On prior treatment of neuronal cells with 1mM glutamate or 50 uM N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), more extensive damage was seen at all ages, with the old neurons suffering maximal damage. When neuronal DNA was subjected to agarose electrophoresis, increasingly diffused bands were seen with age in normally aging neurons. However, a typical nucleosomal ladder, characteristic of apoptosis, was seen only when the cells were exposed to either glutamate or N-methyl-N'-nitro-N-nitrosoguanidine irrespective of the age of the neurons. Furthermore, this apoptotic fragmentation of DNA was prevented by prior treatment of the cells with either cycloheximide or aurintricarboxylic acid, indicating that both glutamate and N-methyl-N'-nitro-N-nitrosoguanidine induce programmed cell death. Fluorescence microscopic observation of glutamate- and N-methyl-N'-nitro-N-nitrosoguanidine-treated neurons after acridine orange staining revealed a high degree of staining and marked condensation of nuclear DNA. On the other hand, no such phenomenon was observed in normally aging neurons either histologically or in biochemical assays of damage. ... both glutamate and N-methyl-N'-nitro-N-nitrosoguanidine induce programmed cell death in neurons independent of age and ... accumulation of DNA damage in naturally aging neurons occurs through a process other than that of apoptosis. [R83] *Metallothionein (MT) has been proposed to play an important role in heavy metal detoxication and in the scavenging of free radicals. Effects of metallothionein on the cytotoxicity of cadmium (Cd), tert-butylhydroperoxide (t-BHP) and N-methyl-N-nitro-N-nitrosoguanidine (MNNG) were examined using primary hepatocyte cultures from control (C57BL/6J) and metallothionein-I and II knock-out (metallothionein-null) mice. Compared to control hepatocytes, metallothionein-null hepatocytes had minimal cadmium-binding proteins (metallothionein equivalents), but cellular glutathione concentration was similar to the control hepatocytes. Metallothionein-null hepatocytes were more sensitive than controls to the cytotoxic effects of cadmium (50-300 uM) and tert-butylhydroperoxide (125-500 uM), as indicated by the levels of lactate dehydrogenase released into the medium. Cadmium and tert-butylhydroperoxide also produced more lipid peroxidation in metallothionein-null hepatocytes than in control cells, as demonstrated by the abundance of thiobarbituric acid-reactive substances. However, metallothionein-null hepatocytes were equally sensitive as controls to the cytotoxicity of N-methyl-N'-nitro-N-nitrosoguanidine (0.5 - 2.0 mM), suggesting that metallothionein does not protect against N-methyl-N'-nitro-N-nitrosoguanidine-induced cytotoxicity. These results support the hypothesis that constitutive metallothionein levels affect the sensitivity of mammalian cells to cadmium and oxidative stress. [R84] NTOX: *Many N-nitrosamines are teratogenic, mutagenic, and carcinogenic. Evidence from experimental animals suggests that, as carcinogens, they are /effective by all routes of administration/. However, some are capable of inducing tumors after a single dose, and they are also capable of inducing tumors in certain organs and tissues regardless of the route of administration, ie, they are systemic carcinogens. /N-nitrosamines/ [R85] NTXV: *Median lethal values rat(female) iv 140.5 mg/kg body weight, 113.0-174.7 mg/kg 95% confidence limits /from table/; [R86] *Median lethal values rat(female) ip 113.9 mg/kg body weight, 86.4-150.1 mg/kg 95% confidence limits /from table/; [R87] *Median lethal values rat(female) peroral 377.5 mg/kg body weight, 288.3-494.4 mg/kg 95% confidence limits /from table/; [R86] ADE: *... Nitrosamines ... can presumably cross the placenta since they are capable of inducing neoplasma in the offspring if administered to rats in late pregnancy. /Nitrosamines/ [R88] METB: *AFTER ORAL ADMIN OF MNNG ABOUT 90% IS EXCRETED IN URINE, MOSTLY AS N-METHYL-N'-NITRO-GUANIDINE IN FIRST 9 HR. THERE IS EVIDENCE THAT DENITROSATION OF MNNG IS EFFECTED BY ENZYMES OCCURRING IN STOMACH, LIVER AND KIDNEY. ... [R37] *Following an oral dose of (14)C-labeled N-methyl-N'-nitro-N-nitrosoguanidine, most of the radioactivity was excreted in the urine within 24 hrs and less than 3 percent in the feces. Less than 3 percent of the radioactivity remained in the body as acid-insoluble materials at 24 to 48 hrs. [R89] *The product(s) of metabolism of N-nitrosamines are thought to be responsible for the mutagenicity and/or carcinogenicity of many of these compounds. One hypothesis is that these active intermediates alkylate DNA at specific sites. Although the liver appears to be the major site of decomposition, other organs, such as kidney and lung, possess varying capacity to metabolize nitrosamines. The relative metabolic activity of different organs toward the same compound varies among species. /Nitrosamines/ [R88] *... Reduction of nitrate to nitrite /in the gastrointestinal tract/ permits the formation of highly carcinogenic nitrosamines by reaction with secondary amines from the diet. /Nitrosamines/ [R31, 33] ACTN: *IN VITRO AND IN VIVO, MNNG CAUSES METHYLATION OF NUCLEIC ACIDS, FORMING MAINLY 7-METHYLGUANINE WITH SMALLER AMT OF 3-METHYLADENINE, 1-METHYLADENINE, 3-METHYLCYTOSINE AND (6)O-METHYLGUANINE. ... MNNG CAN MODIFY PROTEINS BY TRANSFERRING ITS NITROGUANIDINE RESIDUE, EG, BY CONVERTING LYSINE INTO NITROHOMOARGININE. CYTOCHROME C THUS MODIFIED NO LONGER ACTS AS AN ELECTRON ACCEPTOR. HISTONES FROM ASCITES TUMOR CELLS CONTAINED NITROHOMOARGININE AFTER MNNG TREATMENT. [R37] *Chronic administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in drinking water causes a high incidence of carcinomas of the glandular stomach in rats. ... Following a single oral dose of (14)C-methyl-MNNG (80 mg/l; 2.5 mg/kg bw), the extent of DNA methylation in the glandular stomach was 9 and 21 times higher than in forestomach and oesophagus, respectively. These differences were found to correlate with regional variations in the concentration of cellular thiols, which are known to accelerate the heterolytic decomposition of MNNG. When (14)C-methyl-MNNG was given intragastrically together with the thiol blocking agent, N-ethylmaleimide, covalent binding of (14)C radioactivity to forestomach, glandular stomach and duodenum was almost completely abolished. [R90] *The cytotoxic mechanisms of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was investigated in synchronized 10T1/2 cells, using colony-forming ability as a measure of toxicity. MNNG causes dose-dependent redn in the ability of 10T1/2 cells to produce colonies of > 50 cells after 2 wk in culture. ... MNNG treatment produces toxicity that is maximal when 10T1/2 cells are exposed during the S phase and the effect is potentiated by caffeine. MNNG treatment delays DNA replication and this delay is reversed by caffeine. MNNG-treated /10T1/2/ cells are not made permeable to trypan blue, but are blocked in their ability to proliferate. MNNG produces toxicity mainly by preventing chromosome replication /in 10T1/2 cells/. [R91] *N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), which alkylates many positions in DNA including the O6 position of guanine, efficiently induces intrachromosomal homologous recombination in mouse L-cells. To investigate the role of O6-methylguanine in the induction of homologous recombination in human cells, three cell strains containing duplicated copies of the Herpes simplex virus I thymidine kinase (Htk) gene and three cell strains containing duplicated copies of the gene coding for hydromycin phoshotransferase (hyg) were treated with N-methyl-N'-nitro-N-nitrosoguanidine. Neither the Herpes simplex virus I thymidine kinase genes nor the hygromycin phosphotransferase genes code for a functional enzyme because each contains an insertion mutation at a unique site. ... These cell strains differ in their level of O6-alkylguanine-DNA alkyltransferase (AGT), which specifically removes the methyl group from the O6 position of guanine. Generation of a functional Herpes simplex virus I thymidine kinase or hygromycin phosphotransferase gene has been shown to require intrachromosomal homologous recombination between the two mutant Herpes simplex virus I thymidine kinase genes or the two mutant hygromycin phosphotransferase genes. In all six cell strains, N-methyl-N'-nitro-N-nitrosoguanidine induced a dose-dependent increase in the frequency of homologous recombination. In each set, there was an inverse correlation between the frequency of N-methyl-N'-nitro-N-nitrosoguanidine-induced recombination and the level of O6-alkylguanine-DNA alkyltransferase activity. To further study the role of O6-methylguanine in the induction of homologous recombination, we used O6-benzylguanine to inactivate O6-alkylguanine-DNA alkyltransferase in two additional human cell strains containing the hygromycin phosphotransferase recombination substrate. After depletion of O6-alkylguanine-DNA alkyltransferase activity by O6-benzylguanine, both cell strains showed a significantly elevated level of N-methyl-N'-nitro-N-nitrosoguanidine-induced homologous recombination. ... O6-methylguanine is the principal lesion responsible for the induction of homologous recombination in these human cells by this methylating agent. [R92] INTC: *WHEN SYRIAN HAMSTER EMBRYO CELLS WERE PRETREATED WITH WEAK CHEM CARCINOGEN, METHYL AND ETHYL METHANE SULFONATE OR WITH X-IRRADIATION, THE FREQUENCY OF TRANSFORMATION (CRISSCROSSING OF CELLS NOT SEEN IN CONTROL) RESULTING FROM MNNG TREATMENT WAS INCREASED. [R93] *The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) was found to incr the incidence of phenotypic alterations induced by direct-acting MNNG in human endometrial stromal cells. Following MNNG treatment, changes in saturation density, gamma-glutamyltranspeptidase expression, morphology, and growth in selective media were enhanced in cell cultures subjected to continuous TPA exposure as compared to cultures receiving ethanol vehicle. [R94] *Inbred male F344 rats were pretreated with MNNG then given BHA, BHT AND NaCl and combinations of these antioxidants with NaCl. The study revealed that BHA AND NaCl but not BHT exert promoting activity on MNNG-induced forestomach carcinogenesis in rats and that, when BHA AND BHT were given with NaCl, promotion was more marked, suggesting a synergistic effect on tumor promotion. [R95] *Mega-ascorbate intake in diet was more beneficial in alleviating development of gastric cancer in rats when it was commenced after middle of long-term experimental period (initiation of adenomatous hyperplasia but no appearance of malignant lesions) rather than from the beginning of MNNG drinking. A remarkable effect of mega-ascorbate intake was to reinforce surrounding connective tissues to retard the malignant growth. [R96] *Hydroxyurea (HU) protected KB (human oral carcinoma) cells specifically against the toxic effect of MNNG. [R97] *Mitomycin C AND 4-nitroquinoline-N-oxide are two mutagens which can induce the SOS DNA repair system in Escherichia coli. Induction of the adaptive response repair pathway by prior cultivation in low concentrations of MNNG reduced both mutagenic and lethal effects of subsequent challenge with mitomycin C but not 4-nitroquinoline-N-oxide. [R98] *Effect of chronic ulcers by formalin on the development of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was studied in a large number of rats and the following results were obtained. After ulcer was formed in the anterior wall of the fundic region of the glandular stomach of male Wistar rats by formalin, 83 mg/l of MNNG was administrated in drinking water for 30 wk (group I). As control groups, rats received MNNG alone (group II), ulcer formation alone (group III) or no treatment (group IV). Adenocarcinoma was found within the ulcers in 7 of the 131 effective numbers of animals (5.3%) in group I (p= 0.30 between group I and II) but not in the fundic region of the stomach in rats of 3 control groups. The incidence of adenocarcinomas of atypical glands were higher in active ulcer than in healing or healed ulcers (p < 0.05) at the end of the experiments. Immature regenerative glands, downward hyperplasia of regenerative glands or ectopic glands were also observed in higher incidence in the former groups (p < 0.05). The labeling index of 3H-thymidine in adenocarcinomas was highest of lesions investigated and regenerative glands or adenomatous hyperplasia had higher indices than normal gastric mucosa. These findings suggest that the existence of chronic formalin ulcer in the stomach fundus may promote carcinogenesis of the mucosa by MNNG since rapid cell division occurs in the regenerating mucosa near the margin of chronic ulcer. [R99] *Rats were inoculated with or accidentally colonized by Pseudomonas aeruginosa after oral MNNG treatment. In three serial experiments Pseudomonas aeruginosa-positive, MNNG-treated rats consistently showed a significantly higher incidence of gastric tumors than Pseudomonas aeruginosa-negative, MNNG-treated animals. The total incidence of gastric tumors was 40% (34/86) in the former, and only 11% (7/61) in the latter. The development of tumors in the small intestine was not likely to be influenced by Pseudomonas aeruginosa colonization. Thus, Pseudomonas aeruginosa in the gut plays a promoting role in gastric tumorigenesis in rats orally administered with MNNG. [R100] *Factors which control the process of DNA amplification were investigated using a simian virus 40 (SV40)-transformed Chinese hamster cell line (CO60) as a model system. Addition of ethanol to the culture media (0-2% vol/vol) inhibited amplification induced by the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine or by gamma-irradiation in a dose-dependent fashion. In the case of N-methyl-N'-nitro-N-nitrosoguanidine induction (50 uM), the highest concn of ethanol (2% vol/vol) tested reduced SV40 amplification from about 20-fold to < 2-fold. Significant inhibition of amplification is achieved with nearly nontoxic concn of ethanol (1% vol/vol) without direct interference with the inducer. [R101] *The effects of 6-hydroxydopamine on inhibition by tetragastrin of gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in inbred Wistar rats. Groups of male rats (n = 25 to 30) received sc injections of tetragastrin (1 mg/kg every other day) in depot form, ip injections of 6-hydroxydopamine (42 mg/kg twice within 24 hr and 105 mg/kg every 2 wk), or injections of both compounds after 25 wk of per os treatment with 100 ug/ml MNNG. Gastric cancers were found in all 18 control (olive oil) rats treated first with MNNG, the avg number of cancers per rat being 1.6 + or - 0.2. At 52 wk, prolonged admin of tetragastrin or 6-hydroxydopamine had significantly reduced the incidence and the number of adenocarcinomas. At 52 wk, the incidence was 10/16 (62%, p < 0.02) with 0.8 cancers/rat (p < 0.05) for tetragastrin and 8/14 (57%, p < 0.01) with 0.6 cancers/rat (p < 0.01) for 6-hydroxydopamine. Combined admin of tetragastrin and 6-hydroxydopamine significantly (p < 0.05) enhanced the inhibitory effects of tetragastrin or 6-hydroxydopamine on gastric carcinogenesis. Incidence of gastric tumors was only 3/18 (17%, p < 0.001 compared to olive oil group) with 0.3 cancers/rat (p < 0.001). [R102] *N-methyl-N'-nitro-N-nitrosoguanidine, an alkylating agent, is a potent teratogen. In this study, the effect of cobalt chloride, a DNA repair inhibitor, on the teratogenicity of N-methyl-N'-nitro-N-nitrosoguanidine was investigated. 60 mg/kg of N-methyl-N'-nitro-N-nitrosoguanidine ip and 10 mg/kg of cobalt chloride iv were administrated in Jcl:ICR mice on day 10 of gestation. To elucidate the interaction of cobalt chloride to the N-methyl-N'-nitro-N-nitrosoguanidine teratogenicity, a combined administration of both agents was given to pregnant mice in the same manner. Fetuses were examined for malformations on day 18. N-methyl-N'-nitro-N-nitrosoguanidine induced a significant reduction on body weight compared to the saline administrated group. The combined administration of cobalt chloride did not inhibit the reduction of body weight caused by N-methyl-N'-nitro-N-nitrosoguanidine. The incidence of malformed fetuses were 51.6% in the N-methyl-N'-nitro-N-nitrosoguanidine administrated group, and 34.8% in the N-methyl-N'-nitro-N-nitrosoguanidine + cobalt chloride. Cobalt chloride administration made the incidence of malformed fetuses tend to reduce, however there were no significant differences between these two groups. Among the external malformations induced by N-methyl-N'-nitro-N-nitrosoguanidine, cleft palate, which had a high incidence rate, was reduced by cobalt chloride (N-methyl-N'-nitro-N-nitrosoguanidine:45.2%, N-methyl-N'-nitro-N-nitrosoguanidine + cobalt chloride:26.0%). The results suggest that the combined administration of cobalt chloride interferes with N-methyl-N'-nitro-N-nitrosoguanidine teratogenicity. [R103] *The effects of vasoactive intestinal peptide on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were investigated in Wistar rats given vasoactive intestinal peptide every other day for 27 wk after oral administration of N-methyl-N'-nitro-N-nitrosoguanidine for 25 wk. In week 52, administration of vasoactive intestinal peptide caused a significant increase in the incidence of gastric cancers, but did not influence their histological appearance. Vasoactive intestinal peptide significantly increased the labeling indices of the antral mucosa. Finding indicates that vasoactive intestinal peptide enhances gastric carcinogenesis, and that this effect may be related to its effect in increasing cell proliferation of the antral epithelial cells. [R104] *The effect of oral administration of L-phenylalanine on the incidence and histology of gastric adenocarcinomas induced by N-methyl-N'-nitro-N-nitrosoguanidine was investigated in inbred Wistar rats. Oral administration of 6% phenylalanine after 25 wk of treatment with the carcinogen significantly reduced the incidence and number of adenocarcinomas of the glandular stomach at experimental week 52. Oral administration of high dose phenylalanine significantly increased the basal serum gastrin level and significantly decreased the norepinephrine concentration in the antral portion of the gastric wall, as well as the labelling indices of antral mucosa. These findings indicate that orally administered phenylalanine inhibits the development of gastric cancers. [R105] *A 3 x 3 factorial experiment was conducted to examine how dietary fiber (wheat bran) and fat (lard) interactively affect the genesis of N-methyl-N'-nitro-N-nitrosoguanidine induced colon cancer in rats. Groups of 30 male 4 week old Wistar rats were fed ad libitum one of nine experimental diets containing either 15 (low), 27.5 (medium), or 40% (high) energy as fat in combination with 0.7 (low), 2.2 (medium), or 3.8 g (high) fiber/100 kcal for a period of 37 wk. After 4 wk, each rat received a total of five weekly intrarectal instillations of 6 mg N-methyl-N'-nitro-N-nitrosoguanidine/kg. The highest colon carcinoma incidence and the highest total number of carcinomas of the colon were observed in the animals fed the medium-fat/medium-fiber diet. The highest number of polyps and a relatively high polyp incidence occurred in the animals on the high-fat/low-fiber diet. An enhancing effect of fat on both the tumor incidence and tumor multiplicity was clearly present for the low-fiber diets, whereas fat had no effect when the fiber content of the diet was high. In general, the results showed a nonlinear dose-response relationship for fiber and fat. These results indicate that both dietary fiber and fat affect colon carcinogenesis in a complex, interactive manner. [R106] *Teratogenic to subteratogenic doses of MNNG /N-methyl-N'-nitro-N-nitrosoguanidine/ ... were administered to pregnant mice together with caffeine (12.5, 25, or 50 mg/kg) on day 11 of gestation. Fetuses were examinied for gross malformations on day 18 of gestation. ... The teratogenicity of /MNNG was not/ significantly potentiated by the caffeine. ... [R107] *The effects of ethanol on the incidence and histology of gastric cancers induced by N-methyl-N'-nitro-N-nitrosoguanidine were investigated in Wistar rats. Rats received alternate-day ip injections of 2.5 ml/kg body wt of 20% ethanol in 0.9% NaCl solution after 20 wk of oral treatment with N-methyl-N'-nitro-N-nitrosoguanidine. Prolonged administration of ethanol resulted in a significant incr in the incidence and number of gastric cancers of the glandular stomach in wk 52. However, it had no influence on the histological types of the gastric cancers. Furthermore, it caused a significant incr in the labelling index of the epithelial cells of the antrum in wk 52. [R108] *Ultraviolet irradiation can systematically enhance subsequent skin cancer induction by benzo(a)pyrene, methylcholanthrene, or UV radiation. The present study was designed to determine whether UVB irradiation influences host susceptibility to the alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine. Female C3H/HeJ mice were exposed dorsally to UVB radiation from banks of 6 Westinghouse FS40 sun lamps. The mice received a total UV dose of approximately 8.1 sq m over a 15 wk period. After termination of UVB treatments, ventral tumors were induced by 4 applications of 30 umol of N-methyl-N'-nitro-N-nitrosoguanidine at 8-day intervals. At 20 wk after the first N-methyl-N'-nitro-N-nitrosoguanidine treatment, UVB-irradiated mice had 7-fold more N-methyl-N'-nitro-N-nitrosoguanidine-induced, ventral tumors than did the unirradiated control mice (p = 0.026, Wilcoxon rank sum test). Ventral application of N-methyl-N'-nitro-N-nitrosoguanidine after cessation of dorsal UVB exposure, but before UV tumor appearance, did not influence photocarcinogenesis. These results demonstrate that UV irradiation can systemically decrease host resistance to tumor induction by the methylating agent, N-methyl-N'-nitro-N-nitrosoguanidine. [R109] *MNNG and methyl methanesulfonate (MMS) are directly active alkylating agents that methylate cellular macromolecules by SN1 AND SN2 mechanisms, respectively. They produce similar types of alkylation products in DNA and similar level of total alkylations on a molar basis, but strikingly different proportions of alkylations of ring oxygen atoms of purines and pyrimidines. MNNG produces toxicity mainly by preventing chromosome replication and MMS produces toxicity mainly by damaging cell membranes. [R91] *The purpose of this study was to investigate the effect of long-term misoprostol administration, at non-antisecretory doses, on N-methyl-N'-nitro-N-nitrosoguanidine induced gastric carcinogenesis. The incidence of gastric carcinomas and precancerous lesions was evaluated in 50 male 250 g Sprague Dawley rats after 52 wk of continuous oral administration of N-methyl-N'-nitro-N-nitrosoguanidine (120 mg/l; n = 20), N-methyl-N'-nitro-N-nitrosoguanidine plus misoprostol (2 mg/kg/day; n = 20) or tap water (n = 10) (experiment 1), and in 30 rats treated with N-methyl-N'-nitro-N-nitrosoguanidine for 30 wk followed by tap water (n = 15) or by misoprostol (n = 15) for 22 wk; a third group (n = 10) received tap water only for 52 wk (experiment 2). After sacrifice, gastric mucosal lesions were macroscopically evaluated and their histology obtained. N-methyl-N'-nitro-N-nitrosoguanidine consumption was comparable in all groups (6.5 +/- 1.1 mg/rat/day). Misoprostol consumption was 180 +/- 0.25 mg/kg/day/rat. In experiment 1 the incidence of gastric carcinomas was 60% in the N-methyl-N'-nitro-N-nitrosoguanidine group and 25% in the group treated with N-methyl-N'-nitro-N-nitrosoguanidine plus misoprostol (p < 0.05). Cytotoxic and hyperplastic gastric mucosal lesions were also significantly reduced by misoprostol. In experiment 2 the incidence of carcinomas was 31% and 38.6% respectively. Misoprostol significantly decreased the incidence of gastric cancer formation when given from the beginning of the experiment. By contrast, when administered after 30 wk of N-methyl-N'-nitro-N-nitrosoguanidine treatment it did not interfere with experimental gastric cancer formation. Exogenous prostaglandins are able to prevent the early N-methyl-N'-nitro-N-nitrosoguanidine-induced gastric mucosal lesions, thus interfering with gastric carcinogenesis. [R110] *The combined effects of low doses of hepatocarcinogens, nitroso compounds, and carcinogenesis modifiers (antioxidants) were studied in rats. Male F344 rats were pretreated sequentially with N-diethylnitrosamine, N-methylnitrosourea, and dihydroxy-di-N-propylnitrosamine or untreated. They were then administered combinations of the antioxidants butylated hydroxyanisole, catechol, propyl gallate, or tert-butyl hydroquinone, the hepatocarcinogens 2-acetylaminofluorene, dimethylnitrosamine, 3'-methyl-4-dimethylaminoazobenzene, phenobarbital, or thioacetanide, or the nitrosamines dibutylnitrosamine , N-butyl-N-(4-hydroxybutyl)nitrosamine , N-ethyl-N-hydroxyethylnitrosamine or N-methyl-N'-nitro-N-nitrosoguanidine in their diet or drinking water for up to 20 wk. Doses ranged up to 1000 ppm and were generally below the known effective levels of the individual chemicals. The rats were killed after 20 wk and necropsied. The hepatocarcinogens in combination with the nitroso compounds generally had a synergistic effect on induction of hyperplastic nodules an hepatocellular carcinomas. The effects were similar in DMD pretreated and nonpretreated rats although the incidences of hepatocellular carcinomas were lower in the nonDMD group. Combined administration of the hepatocarcinogens, nitroso compounds, and antioxidants caused significant reductions in the incidence of hyperplastic nodules and hepatocellular carcinomas. Nitroso compounds + antioxidants significantly increased the incidence of urinary bladder tumors in both N-diethylnitrosamine, N-methylnitrosourea, and dihydroxy-di-N-propylnitrosamine treated and untreated groups. Rats given nitroso compounds + hepatocarcinogens showed a trend toward increased bladder tumorigenesis. Nitroso compounds + antioxidants caused an additive increase in the incidence of pepsinogen-isozyme-1 altered pyloric glands in both N-diethylnitrosamine, N-methylnitrosourea, and dihydroxy-di-N-propylnitrosamine pretreated and untreated rats. Esophageal and forestomach papillomas were significantly increased in pretreated rats given nitroso compounds and antioxidants, respectively. No synergistic effects were observed in these organs. The authors conclude that combinations of various compounds even at low doses can exert organ dependent effects throughout the body. [R111] *A heat-resistant factor in ethanol extracts of the fungus Craterellus cornucopioides completely inhibited the mutagenicity of aflatoxin B1, benzo[a]pyrene, the acridine half mustard ICR-191 and 2-nitrofluorene in a forward-mutation system using Salmonella typhimurium TM677 (screening for 8-azaguanine resistance). There was no inhibitory effect on the mutagenic activity of 4-nitroquinoline-N-oxide, methyl methanesulfonate or N-methyl-N'-nitro-N-nitrosoguanidine. Experiments performed to elucidate the mechanism of the antimutagenic effect showed that neither an alteration of cell viability nor an interference with the excision-repair and the inducible SOS-repair system was involved. The conceivable mechanisms for the antimutagenicity of the ethanol extract include direct chemical interaction with the mutagen and/or inhibition of the activation process in the case of the promutagens. The antimutagenic activity of Craterellus cornucopioides is not unique among mushroom species. The ethanol extracts of 6 other mushrooms showed a similar antimutagenic activity. [R112] *The effect of human cytomegalovirus (HCMV) infection on the frequency of mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) locus was studied in Chinese hamster lung V79 cells. When V79 cells were infected with human cytomegalovirus (strain AD169) at multiplicities of 0.1 to 50 plaque forming units (PFU) per cell the presumptive mutation frequency, as determined by the number of 6-thioguanine-resistant (TGr) colonies, was increased up to 16.8-fold (P < 0.005), depending on the multiplicity of infection. ... Infection of V79 cells with human cytomegalovirus also increased their sensitivity to mutation with N-methyl-N'-nitro-N-nitrosoguanidine, giving a synergistic enhancement of the mutation frequency. These results indicate that human cytomegalovirus infection has the capacity to induce mutations in the cellular genome and increase the sensitivity of infected cells to mutation by genotoxic chemicals. [R113] *The ability of neighboring normal cells to inhibit proliferation of transformed cells is regarded as the classical mode of intercellular control of potential tumor cells. This mechanism, however, only controls the pool size of transformed cells, but does not impair their survival. ... cells transformed by biological agents are subject to a novel control system: transforming growth factor beta (TGF-beta) induces normal cells to release factors that mediate apoptosis specifically in transformed cells. Here we show that cells transformed by chemical carcinogens are also subject to this dominant control mechanism. The number of foci induced by methylcholanthrene, N-methyl-N'-nitro-N-nitrosoguanidine or quercetin was significantly reduced when the cultures were treated with transforming growth factor beta. Established lines of chemically transformed cells proved to be sensitive to induction of apoptosis by neighboring normal cells in the presence of transforming growth factor beta. This finding demonstrates that sensitivity to induction of apoptosis is a general feature of transformed cells, irrespective of the transforming agent. ... [R114] *The effect of a purified, high protein diet on enhanced gastric carcinogenesis induced by oral administration of NaCl was investigated in Wistar rats. Rats were fed on a purified diet with an equalized caloric content, containing 8% NaCl and 25% casein (normal protein diet), or 50% casein (high protein diet) after oral treatment with N-methyl-N'-nitro-N-nitrosoguanidine for 25 weeks. In week 52, oral administration of NaCl had significantly increased the incidence and size of gastric cancer in rats fed a normal protein diet. However, NaCl had no significant effect on gastric carcinogenesis in rats fed a high protein diet. Oral administration of NaCl also caused a significant increase in tissue norepinephrine concentrations in the antral portion of the gastric wall, and increased the labeling indices of the antral epithelial cells of rats fed on a normal protein diet. However, in rats fed a high protein diet, administration of NaCl had no significant influence on these two parameters. These findings indicate that a high protein diet attenuates enhanced gastric carcinogenesis induced by the administration of NaCl, and that this effect may be related to its ability to decrease norepinephrine concentrations in the gastric wall, which subsequently decreases the proliferation of antral epithelial cells. [R115] *The effects of prolonged administration of aminoguanidine on gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), the ornithine decarboxylase activity of the gastric wall, and the labeling index of the gastric mucosa were investigated in inbred Wistar rats. ... Prolonged administration of aminoguanidine at 25.0 mg/kg body weight, but not at 12.5 mg/kg body weight, significantly increased the incidence of gastric cancers in experimental week 52. However, it did not influence the histologic types of gastric cancers. Aminoguanidine at 25.0 mg/kg body weight also significantly increased the ornithine decarboxylase activity of the antral portion of the gastric wall and the labeling index of the antral epithelial cells. ... aminoguanidine enhances gastric carcinogenesis and ... its effect may be related to increased proliferation of antral epithelial cells. [R116] *There are divergent opinions on the effect of ethanol in the carcinogenesis of gastroduodenal tumors. The effect of the synchronous application of 11% ethanol or wine (11% ethanol) and N-methyl-N'-nitro-N-nitrosoguanidine (100 ug/ml, MNNG) in a drinking solution on the incidence of gastroduodenal tumors was evaluated. Sixty outbred male Wistar rats were distributed among three groups. The animals drank N-methyl-N'-nitro-N-nitrosoguanidine and ethanol or wine for six months and consumed the same quantity of N-methyl-N'-nitro-N-nitrosoguanidine. Then they consumed a normal diet until the 13th month, when the experiment was terminated. The stomach and duodenum were examined histologically. In the stomach, 15 tumors (2 squamous papillomas, 4 squamous carcinomas, 1 sarcoma, and 8 adenocarcinomas) and 4 cases of dysplasia were found; in the duodenum, there were four cases of adenocarcinoma. There were 6 cases of multiple tumors. Incidence of forestomach tumors did not differ among the groups, whereas the incidence of glandular stomach carcinoma and duodenal carcinoma was significantly lower in the groups treated with 11% ethanol or wine than in the control group. N-methyl-N'-nitro-N-nitrosoguanidine was not inactivated by ethanol in the drinking solutions. ... the inhibitory effect on gastroduodenal carcinogenesis is the result of 11% ethanol ingestion and its protective action on the mucosa and not of the wine's nonethanol components. [R117] INTC: *Dehydroepiandrosterone (DHEA) and its sulfate conjugate are the major circulating steroids in human plasma. ... In animal studies, dehydroepiandrosterone is chemopreventive toward both spontaneous and chemically induced cancers. A potential concern for long-term usage of dehydroepiandrosterone in humans is the finding that dehydroepiandrosterone is hepatocarcinogenic in rats. The human health risk has been thought to be minimal, however, as the mechanism of dehydroepiandrosterone hepatocarcinogenesis is assumed to be due to its properties as a peroxisome proliferator, a class of compounds to which humans are relatively insensitive. Recently, we have found dehydroepiandrosterone to be a potent promoter of aflatoxin B1-initiation as well as a complete hepatocarcinogen in the rainbow trout, a species which is also insensitive to peroxisome proliferators. ... to determine the initiator- and tissue-specificity of dehydroepiandrosterone promotion, we examined the effects of dehydroepiandrosterone on N-methyl-N'-nitro-nitrosoguanidine (MNNG)-initiated carcinogenesis. Trout fry were initiated by a bath exposure (30 min at 35 ppm) to N-methyl-N'-nitro-N-nitrosoguanidine and then fed dehydroepiandrosterone at levels of 0, 55, 111, 222,444,or 888 ppm for 7 months. dehydroepiandrosterone increased liver tumor incidence, multiplicity, and size in a dose-dependent manner. The liver tumor incidence ranged from 0 in the N-methyl-N'-nitro-N-nitrosoguanidine-initiated trout fed this level of dehydroepiandrosterone was 41%. The kidney tumor incidence was also enhanced two- and threefold over initiated controls by 111 and 888 ppm dehydroepiandrosterone, respectively. In contrast, the total number of stomach and swim bladder tumors was reduced by dehydroepiandrosterone treatment. This study demonstrates differential effects of dehydroepiandrosterone on N-methyl-N'-nitro-N-nitrosoguanidine-initiated carcinogenesis in liver, kidney, stomach, and swim bladder. [R118] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *No evidence was found that N-methyl-N'-nitro-N-nitrosoguanidine is produced commercially. It is used as a research chemical and may be released to the environment with laboratory waste. In air, an estimated vapor pressure of 1.2X10-4 mm Hg at 25 deg C indicates N-methyl-N'-nitro-N-nitrosoguanidine is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase N-methyl-N'-nitro-N-nitrosoguanidine will be physically removed from the atmosphere by wet and dry deposition. N-Methyl-N'-nitro-N-nitrosoguanidine absorbs light in the environmental spectrum indicating this compound may be susceptible to direct photolysis. In soil, an estimated Koc of 7.5 suggests N-methyl-N'-nitro-N-nitrosoguanidine will have very high mobility. An estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole indicates that this compound is not expected to volatilize from moist soil surfaces. This compound's estimated vapor pressure indicates N-methyl-N'-nitro-N-nitrosoguanidine is not expected to volatilize from dry soil surfaces. Hydrolysis is expected to be an important process in moist soil. In water, the estimated Koc of 7.5 indicates that N-methyl-N'-nitro-N-nitrosoguanidine is not expected to adsorb to suspended solids and sediment in the water column. N-Methyl-N'-nitro-N-nitrosoguanidine is not expected to volatilize from water surfaces based on its estimated Henry's Law constant. An estimated BCF of 0.11 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is expected to be an important process based upon an estimated half-life of 27 hours at pH 7 and 25 deg C. Occupational exposure to N-methyl-N'-nitro-N-nitrosoguanidine may occur through inhalation of dust particles and dermal contact with this compound at workplaces where N-methyl-N'-nitro-N-nitrosoguanidine is used as a research chemical. (SRC) ARTS: *No evidence was found that N-methyl-N'-nitro-N-nitrosoguanidine is produced commercially except as a research chemical(1). [R119] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 7.5(SRC), determined from an estimated log Kow(2,SRC) and a recommended regression-derived equation(3), indicates that N-methyl-N'-nitro-N-nitrosoguanidine is expected to have very high mobility in soil(SRC). Volatilization of N-methyl-N'-nitro-N-nitrosoguanidine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(4). N-Methyl-N'-nitro-N-nitrosoguanidine is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 1.2X10-4 mm Hg(SRC), determined from a fragment constant method(6). Hydrolysis is expected to be an important process in moist soil(SRC) based upon a neutral hydrolysis half-life of 27 hours at 25 deg C(5). [R120] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 7.5(SRC), determined from an estimated log Kow of -0.92(2,SRC) and a recommended regression-derived equation(3), indicates that N-methyl-N'-nitro-N-nitrosoguanidine is not expected to adsorb to suspended solids and sediment in water(SRC). N-Methyl-N'-nitro-N-nitrosoguanidine is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 1.2X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 0.11(3,SRC), from an estimated log Kow(2,SRC), suggests that bioconcentration in aquatic organisms is low(SRC). Hydrolysis is expected to be an important process(SRC) based upon a hydrolysis half-life of 27 hours at pH 7 and 25 deg C(6,SRC). [R121] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), N-methyl-N'-nitro-N-nitrosoguanidine, which has an estimated vapor pressure of 1.2X10-4 mm Hg at 25 deg C(2,SRC), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase N-methyl-N'-nitro-N-nitrosoguanidine may be physically removed from the air by wet and dry deposition(SRC). [R122] ABIO: *Nitrosamines are rapidly decomposed by photolysis and do not persist for a significant time in water illuminated in sunlight. Thus, it is unlikely that they will be present in high (greater than 1 mg/l) concentrations in surface waters. However, in the absence of light they can be expected to persist. /Nitrosamines/ [R123] *N-Methyl-N'-nitro-N-nitrosoguanidine absorbs light in the environmental spectrum and therefore may be susceptible to direct photolysis(1). A neutral first-order hydrolysis rate constant of 2.7X10-2 /hour was measured for N-methyl-N'-nitro-N-nitrosoguanidine at 25 deg C(2); this corresponds to a half-life of about 27 hours at pH 7(2,SRC). [R124] BIOC: *An estimated BCF of 0.11 was calculated for N-methyl-N'-nitro-N-nitrosoguanidine(SRC), using an estimated log Kow of -0.92(1,SRC) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF suggests that bioconcentration in aquatic organisms is low(SRC). [R125] KOC: *The Koc of N-methyl-N'-nitro-N-nitrosoguanidine is estimated as approximately 7.5(SRC), using an estimated log Kow of -0.92(1,SRC) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that N-Methyl-N'-nitro-N-nitrosoguanidine is expected to have very high mobility in soil(SRC). [R126] VWS: *The Henry's Law constant for N-methyl-N'-nitro-N-nitrosoguanidine is estimated as 1.2X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that N-methyl-N'-nitro-N-nitrosoguanidine is expected to be essentially nonvolatile from water surfaces(2,SRC). N-Methyl-N'-nitro-N-nitrosoguanidine's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). N-Methyl-N'-nitro-N-nitrosoguanidine is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 1.2X10-4 mm Hg(SRC), determined from a fragment constant estimation method(3). [R127] RTEX: *NO EVIDENCE WAS FOUND ... THAT THERE IS ANY HUMAN EXPOSURE /TO MNNG/ EXCEPT FOR THAT OF RESEARCHERS ENGAGED IN STUDY OF ITS BIOLOGICAL PROPERITES. [R1] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 522 workers are potentially exposed to N-methyl-N'-nitro-N-nitrosoguanidine in the US(1). Occupational exposure to N-methyl-N'-nitro-N-nitrosoguanidine may occur through inhalation of dust particles and dermal contact with this compound at workplaces where N-methyl-N'-nitro-N-nitrosoguanidine is used as a research chemical(SRC). [R128] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Nitrosamines/ [R129] +The levels for nitrosamines through ingestion of contaminated water and contaminated aquatic organisms ... which may result in incremental increase of cancer risk over the lifetime are estimated at 1X10-5, 1X10-6, and 1X10-7. The corresponding criteria are 8.0 ng/l, 0.8 ng/l, and 0.08 ng/l, respectively. For consumption of aquatic organisms only, excluding consumption of water, the levels are 12,400 ng/l, 1,240 ng/l, and 124 ng/l, respectively. /Nitrosamines/ [R130] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 10 lb or 4.54 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R131] RCRA: *U163; As stipulated in 40 CFR 261.33, when N-methyl-N'-nitro-N-nitrosoguanidine, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R132] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Volatile N-nitrosamines were confirmed in foods at concentrations of less than 10 ug/kg by full scan low resolution mass spectrometry. Concn from 1 ug/kg in foods to 2-5 ug/kg in fried commercial bacon were detected. /N-Nitrosamines/ [R133] *Determination of nonvolatile N-nitriso cmpds in biological fluids by liquid chromatography with postcolumn photohydrolysis detection. [R134] CLAB: *METHOD FOR ANALYZING NITROSAMINES IN AQ SOLN AND IN BIOLOGICAL FLUIDS (BLOOD PLASMA AND RAT LIVER MICROSOMAL PREPN) IS PRESENTED. SCHEME IS A 3 MODULAR COMPONENT SYSTEM. FLUOROMETRIC ANALYSIS IMPROVED SENSITIVITY TO 4 NG/ML. /NITROSAMINES/ [R135] *A gas chromatographic method coupled with a thermal energy analyzer was developed for the quantitative analysis of nitrosamines in the urine of workers and bottle-fed babies. /Nitrosamines/ [R136] *Determination of nonvolatile N-nitroso cmpds in biological fluids by liquid chromatography with postcolumn photohydrolysis detection. [R137] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology Review: Archiv Fuer Tosikologie 28: 135 (1971) Toxicology Review: Basic Life Sciences 24: 129 (1983) Toxicology Review: Nutrition and Cancer 3: 109 (1981) USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.A-1 (1980) EPA-440/5-80-064 WHO; Environ Health Criteria 5: Nitrates, Nitrites, and N-Nitroso Compounds (1978) USEPA; Environmental Assessment of Atmospheric Nitrosamines, MTR-7512, Contract No 68-02-1495 (1976) U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) Dangerous Prop Ind Mater Rep 5 (4): 59-65 (1985). A review of methylnitronitrosoguanidine toxicological safety and health hazards SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 184 (1974) R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1041 R3: SRI R4: USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.A-1 (1980) EPA-440/5-80-064 R5: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 183 (1974) R6: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1308 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-174 R8: Bureau of Explosives; Emergency Handling of Haz Matl in Surface Trans p.345 (1981) R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2274 R10: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 289 R11: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R12: Armour, M.A. Hazardous Laboratory Chemicals Disposal Guide. Boca Raton, FL: CRC Press Inc., 1991. 256 R13: Castegnaro, M., G. Eisenbrand, G. Ellen, L. Keefer, D. Klein, E.B. Sansone, D. Spincer, G. Telling, K. Webb, and W. Davis (eds.). Laboratory Decontamination and Destruction of Carcinogens in Laboratory Wastes: Some N-Nitrosamines. IARC Publications No. 43. Lyon, France: International Agency for Research on Cancer R14: Lunn G et al; Carcinogenesis (London) 4 (3): 315-19 (1983) R15: 40 CFR 240-280, 300-306, 702-799 (7/1/91) R16: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-14 (1981) EPA 68-03-3025 R17: National Research Council. Prudent Practices for Handling Hazardous Chemicals in Laboratories. Washington, DC: National Academy Press, 1981. 55 R18: Castegnaro M et al; International Agency for Research on Cancer: 65 (1983) R19: Lunn, G., E.B. Sansone. Destruction of Hazardous Chemicals in the Laboratory. New York, NY: John Wiley and Sons, Inc. 1994. 279 R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 66 (1987) R21: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 252 R22: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 124 R23: RHIM JS ET AL; INT J CANCER 19 (4): 505-10 (1977) R24: HENDERSON EE ET AL; CANCER RES 35 (2): 358-63 (1975) R25: Dorman BH et al; Cancer Res 43 (7): 3348-57 (1983) R26: Heim S; Clin Genet 27 (1): 51-8 (1985) R27: Huberman E et al; Mutat Res 130 (2): 127-37 (1984) R28: Li G et al; Bull Hunan Med Coll 10 (2): 129-33 (1985) R29: Morimoto K, et al; Basic Life Sci 29: 801-11 (1984) R30: Pleven C et al; Journal de Toxicologie Medicale 4 (3): 249-56 (1984) R31: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. R32: Slame nov'a D et al; Mutat Res 383 (3): 243-52 (1997) R33: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 185 (1974) R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 186 (1974) R35: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 187 (1974) R36: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 188 (1974) R37: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V4 189 (1974) R38: RHIM JS ET AL; INT J CANCER 22 (4): 441-6 (1978) R39: STEELE VE ET AL; INT J CANCER 20 (2): 234-8 (1977) R40: BERTRAM JS, HEIDELBERGER C; CANCER RES 34 (3): 526-37 (1974) R41: OSHIRO Y, DI PAOLO JA; J CELL PHYSIOL 83 (2): 193-202 (1974) R42: PETERSON AR ET AL; CANCER RES 34 (7): 1592-9 (1974) R43: MONTESANO R ET AL; INT J CANCER 16 (4): 550-8 (1975) R44: EVANS CH, DI PAOLO JA; CANCER RES 35 (4): 1035-44 (1975) R45: Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986. 382 R46: USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.C-41 (1980) EPA-440/5-80-064 R47: Siu KF, Wong J; Dig Surg 3 (4): 297-300 (1986) R48: Adamson RH, Sieber SM; US Environ Prot Agency p.129-56 EPA-600/9-83-008 (1983) R49: Briza J et al; Biol Plant 27 (1): 22-7 (1985) R50: Ennever FK, Rosenkranz HS; Environ Mutagen 8 (6): 849-65 (1986) R51: Hyodo-Taguchi Y, Matsudaira H; J Natl Cancer Inst 73 (5): 1219-27 (1984) R52: Linjinsky W, Reuber MD; Cancer Res 44 (2): 447-9 (1984) R53: Ogiu T et al; Toxicol Pathol 14 (4): 395-403 (1986) R54: Pfeiffer CJ et al; Teratogenesis Carcinog Mutagen 5 (3): 137-47 (1985) R55: Schwartz JL, Samson L; Mutat Res 119 (3-4): 393-7 (1983) R56: Sharma RK et al; Mutat Res 158 (3): 217-31 (1985) R57: Siu KF et al; J Surg Res 41 (1): 58-64 (1986) R58: Suzuki K, Bruce WR; Mutat Res 141 (1): 35-9 (1984) R59: Yioris N et al; Oncology 41 (1): 36-8 (1984) R60: Kocan RM et al; Aquat Toxicol 6 (3): 165-78 (1985) R61: Harwood M et al; Aquat Toxicol 14 (3): 263-76 (1989) R62: Weinkam RJ, Dolan ME; Chem Res Toxicol 2 (3): 157-61 (1989) R63: Amdur, M.O., J. 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Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Ellington JJ; Hydrolysis Rate Constants for Enhancing Property-Activity Relationships. Report 1989, USEPA/60073-89/063, PB89-220479 (1989) (6) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) R121: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Ellington JJ; Hydrolysis Rate Constants for Enhancing Property-Activity Relationships. Report 1989, USEPA/60073-89/063, NTIS PB89-220479 (1989) R122: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) R123: USEPA; Ambient Water Quality Criteria Doc: Nitrosamines p.C-7 (1980) EPA-440/5-80-064 R124: (1) IARC; Some Aromatic Amines, hydrazine and related substances, N-nitroso compounds and miscellaneous alkylating agents V4: 183-95 (1974) (2) Ellington JJ; Hydrolysis Rate Constants for Enhancing Property-Activity Relationships. Report 1989, USEPA/60073-89/063, NTIS PB89-220479 (1989) R125: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R126: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R127: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) R128: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R129: 40 CFR 401.15 (7/1/91) R130: USEPA; Quality Criteria for Water 1986: Nitrosamines (May 1, 1986) EPA 440/5-86-001 R131: 40 CFR 302.4 (7/1/96) R132: 40 CFR 261.33 (7/1/96) R133: Hotchkiss JH et al; J Assoc Off Anal Chem 63 (1): 74-9 (1980) R134: Shuker DE G et al; Anal Chem 55 (13): 2152-5 (1983) R135: MUSSON DG, STERNSON LA; J PHARM SCI 68 (9): 1159-62 (1979) R136: Airoldi L et al; J Chromatogr 276 (2): 402-7 (1983) R137: Shuker DEG, Tannenbaum ST; Anal Chem 55 (13): 2152-5 (1983) RS: 141 Record 322 of 1119 in HSDB (through 2003/06) AN: 5153 UD: 200205 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SAFFLOWER-OIL- RN: 8001-23-8 MF: +UVCB MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *SAFFLOWER SEEDS ARE PRESSED MECHANICALLY AND THE OIL RECOVERED BY SOLVENT EXTRACTION WITH HEXANE, AND REFINED BY TREATMENT WITH CAUSTIC SODA [R1] *MILLING AND EXTRACTION PROCEDURES: WINTER, J AM OIL CHEM SOC 27, 82 (1950). PURIFICATION AND STABILIZATION: FREEDMAN, SHAPIRO, US PATENT 2,978,381 (1961). [R2] FORM: +Fatty acids present as glycerides: Palmitic 6.4%, stearic 3.1%, arachidic 0.2%, oleic 13.4%, linoleic 76.6-79.0%, unolenic 0.04-0.13% [R3] +Contains 78% linoleic acid (unsaturated fatty acids) [R4] MFS: *CARGILL, INC, MINNEAPOLIS, MN 55440 [R1] *KAY CORP, PVO INTERNATIONAL INC, SUBSIDIARY, LOS ANGELES, CA 90022, RICHMOND, CA 94804 [R1] *SAFEWAY STORES, INC, BROOKSIDE DIVISION, DENISON, TX [R1] +Agro Ingredients Inc, 602 E Algonquin Rd, Des Plaines, IL 60016, (312)298-4000 [R5] +PVO International Inc, 416 Div St, Boonton, NJ 07005, (201)334-2902 [R5] +Pacific Anchor Chem Co, 6055 E Washington Blvd, Los Angeles, CA 90040, (213)725-1800 [R5] +Welch, Holme and Clark Co I nc, 1000 S 4 St, Harrison, NJ 07029, (201)482-7612 [R5] +Alnor Oil Co Inc, PO Box 699, Valley Stream, NY 11582, (516)561-6146 [R6] OMIN: */SAFFLOWER IS/ EDIBLE DRYING OIL, INTERMEDIATE BETWEEN SOYBEAN AND LINSEED OIL. [R2] *SAFFLOWER CONTAINS 2 COLORING MATTERS... SAFFLOWER-YELLOW, C24-H30-O15 IS YELLOW...PRESENT FROM 25-30%; IT IS SOL IN WATER AND IN ALC. CARTHAMIN, C21-H22-011, A GLUCOSIDE, IS...SAFFLOR-RED, FROM 0.3-0.6%. CARTHAMIN IS DARK-RED, GRANULAR POWDER WITH GREEN LUSTER; SLIGHTLY SOL IN WATER. /SAFFLOWER/ [R7] *SEPARATION AND PURIFICATION OF TRIGLYCERIDE HYDROPEROXIDES FROM OXIDIZED SAFFLOWER OIL WERE DONE BY SILICA GEL COLUMN CHROMATOGRAPHY AND TLC. METHOD USEFUL FOR STUDIES ON TOXICITY OF OXIDIZED LIPID. [R8] *...WHEN USED IN DIET IN LIEU OF MORE ANIMAL FATS AND OILS, BLOOD CHOLESTEROL IS NOT ELEVATED TO THE EXTENT AS WITH THE MORE SATURATED LIPIDS. THERE IS SOME EVIDENCE THAT IT MAY ALSO PARTIALLY SUPPRESS THE HYPERCHOLESTEREMIC EFFECT OF SATURATED FATS. [R9] *TO /SUPPRESS HYPERCHOLESTEREMIC EFFECT OF SATURATED FATS/... APPROX 3 TIMES AS MUCH SAFFLOWER OIL AS DIETARY SATURATED FAT MUST BE INGESTED. THUS, UNLESS SATURATED FAT INTAKE IS GREATLY REDUCED, ADDITION OF SAFFLOWER OIL MARKEDLY INCR CALORIC INTAKE. [R9] *IT IS PROBABLY BETTER SIMPLY TO REDUCE FAT INTAKE IN DIET...AND TO USE POLYUNSATURATED OILS IN COOKING WHERE FAT OR OIL CANNOT BE ELIMINATED /THAN TO UTILIZE SAFFLOWER OIL/. THERE IS NO GOOD EVIDENCE THAT SAFFLOWER...IS SUPERIOR TO OTHER POLYUNSATURATED OILS MARKETED AS ORDINARY FOOD ITEMS. [R9] *SOURCE OF LINOLEIC (70-79%) AND LINOLENIC (0.04-0.13%) ACIDS IN TREATMENT OF DERMATOSES IN DOGS. [R10] *DIETARY SUPPLEMENT IN HYPERCHOLESTEREMIA (AND POSSIBLE PROPHYLAXIS AND TREATMENT OF ATHEROSCLEROSIS). [R2] +High-oleic safflower oil is now commercially available [R11] USE: *AS LINSEED OIL IN PAINTS; FOR SALAD OIL BLENDS, IN HYDROGENATED STATE AS SHORTENING; DIETARY SUPPLEMENT [R2] *ALKYD RESINS; PAINTS; VARNISHES; DIETETIC FOODS; MARGARINE [R12] *EDIBLE OIL FOR SALAD AND COOKING OILS AND IN MFR OF MARGARINE AND SHORTENING; CHEM INT IN MFR OF COSMETICS, EG, SUNTAN LOTIONS; POLYUNSATURATED FAT FEED SUPPLEMENT FOR COWS [R1] +MEDICATION +MEDICATION (VET) CPAT: *FOOD USES: SALAD AND COOKING OILS, 73%; MARGARINE, 24%; AND SHORTENING, 3% (1977) [R1] PRIE: U.S. PRODUCTION: *(1977) 1.68X10+10 GRAMS (CONSUMPTION) [R1] *(1979) ND [R1] +(1987) ND U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] +(1987) ND U.S. EXPORTS: *(1977) 1.0X10+7 G OIL EQUIV OF SAFFLOWER SEED [R1] *(1978) 1.8X10+7 G OIL EQUIV OF SAFFLOWER SEED [R1] +(1985) 1.48X10+10 g /safflower seed oil, unmixed/ [R13] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *STRAW-COLORED LIQ [R12] DEN: *0.9211-0.9215 @ 25/25 DEG C [R2] SOL: *SOL IN THE USUAL OIL AND FAT SOLVENTS [R2] SPEC: *INDEX OF REFRACTION 1.472-1.475 @ 25 DEG C/D, 1.4690-1.4692 @ 40 DEG C/D [R2] OCPP: *TITER: 15-18%; ACID VALUE 1.0-9.7; SAPONIFICATION VALUE 188-194; IODINE VALUE 100-150; THIOCYANOGEN VALUE 82.5-86.0; REICHERT-MEISSL VALUE BELOW 0.5; HYDROXYL VALUE 2.9-6.0; UNSAPONIFIABLE BELOW 1.5% [R2] *POLYUNSATURATED OIL [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- SSL: *THICKENS AND BECOMES RANCID ON PROLONGED EXPOSURE TO AIR [R2] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *ESSENTIAL FATTY ACID SUPPLEMENTATION WITH ORAL SAFFLOWER OIL 1 G/KG/DAY (WITH ADDED VIT E OR PLACEBO) PRODUCED NO SIGNIFICANT CHANGE IN SWEAT CHLORIDE CONCN (MEQ/ML) IN CHILDREN WITH CYSTIC FIBROSIS, OR IN SWEAT RATE (G/MIN/SQ M). [R14] NTOX: *THE EFFECT OF FEEDING RABBITS DIETS CONTAINING HIGH CONCN OF SAFFLOWER OIL. [R15] *DEGREE OF SAFFLOWER OIL AUTOOXIDATION WAS PARALLEL TO DEGREE OF LIPASE, PEPSIN, PAPAIN, AND CYTOCHROME C INACTIVATION IN VITRO BY THE AUTOOXIDIZED OIL. FRACTION OF LOW MOL WT COMPD ISOLATED FROM AUTOOXIDIZED OIL DOMINANTLY INACTIVATED ENZYME ACTIVITY AND WAS HIGHLY TOXIC TO MICE. [R16] *AUTOOXIDIZED SAFFLOWER OIL INTRAGASTRICALLY 1 ML/DAY TO WEANLING MALE RATS FOR 3 DAYS, 3 WK OR 3 MO DECR BODY GROWTH AND INCR LIVER WT. GAVE CHANGES IN ENDOPLASMIC RETICULUM AND INCR IN MICROBODIES IN LIVER CELLS OF 3-DAY RATS. SGOT AND SGPT LEVELS WERE INCR. [R17] *AUTOOXIDIZED SAFFLOWER OIL INTRAGASTRICALLY TO RATS 1 ML/DAY FOR 3 DAYS, 3 WK OR 3 MO: PLASMA TRIGLYCERIDE LEVEL INCR IN LIVERS OF THOSE TREATED 3 DAYS, BUT DECR IN 3-MO ANIMALS. A DECR INCORPORATION INTO CHOLESTEROL SHOWN. INCORPORATION INTO LIVER FATTY ACID: 3 DAY INCR, 3 MO DECR. [R17] *RAT DIET CONTAINED EITHER 20% ADDED LARD OR SAFFLOWER OIL, SUBSEQUENTLY GIVEN (14)C-LABELED SODIUM ACETATE 50 MUCI OF ACTIVITY/ML. SAFFLOWER OIL RATS SHOWED BLOOD LIPID AND CHOLESTEROL LEVELS 15-30% LOWER THAN SATURATED FAT RATS; TOTAL BLOOD LIPID RADIOACTIVITY WAS SAME. [R18] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *LITHIUM INHIBITS PROSTAGLANDIN SYNTHESIS BY BLOCKING DGLA MOBILIZATION. LINOLEIC ACID (OF SAFFLOWER OIL) GIVEN TO RAISE DGLA (LINOLEIC ACID METABOLITE) LEVELS IN LITHIUM-POISONED PT: EFFECTIVE IN REMITTING NEUROTOXICITY, AND ALSO EFFECTIVE IN A PT WITH FAMILIAL TREMOR. [R19] *DOSE: ORAL, SUPPOSEDLY 75 ML OF 65% EMULSION IN DIVIDED DOSES. ...WITH RESPECT TO REQUIRED /3:1/ RATIO OF SAFFLOWER OIL TO DIETARY SATURATED FAT. [R9] *IN DIABETIC OR OBESE PT, CALORIC CONTENT SHOULD BE BORNE IN MIND AND IN DIABETICS INSULIN DOSAGE SHOULD BE ADJUSTED ACCORDINGLY. (FOR EXAMPLE, 90 ML DOSE SAFFLOWER OIL...PROVIDES ABOUT 540 CALORIES). PERIODIC LIVER FUNCTION TESTS SHOULD BE PERFORMED IN ALL PT RECEIVING UNSATURATED FATTY ACIDS FOR PROLONGED PERIODS. [R20] +MEDICATION (VET): TREATMENT OF DERMATOSES IN DOGS [R10] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Comparative Toxicology Studies of Corn Oil, Safflower Oil, and Tricaprylin in Male F344/N Rats as Vehicles for Gavage Tech Rpt No. 426 NIH Pub No. 94-3157 (1994) SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1077 R3: MERCK INDEX 10TH ED 1983 p.8174 R4: SAX. HAWLEY'S CONDENSED CHEM DICTNRY 11TH ED 1987 p.1022 R5: CHEMICALWEEK BUYERS' GUIDE '86 p.440 R6: OPD CHEMICAL BUYERS DIRECTORY 1987 p.612 R7: Merory, J. Food Flavorings: Composition, Manufacture, and Use. 2nd ed. Westport, Conn.: Avi Publishing Co., 1968. 108 R8: SOHDE ET AL; AGRIC BIOL CHEM 37(8) 1979 (1973) R9: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 797 R10: Rossoff, I.S. Handbook of Veterinary Drugs. New York: Springer Publishing Company, 1974. 518 R11: KIRK-OTHMER ENCYC CHEM TECH 3RD ED 1978-PRESENT V9 p.800 R12: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 761 R13: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1985 p.2-68 R14: LLOYD-STILL ET AL; PEDIATRICS 64(JULY 1979) 50 R15: KENNEDY ET AL; FAT INDUCED HYPERTENSION IN RABBITS PART 2 THE EFFECT OF FEEDING DIETS CONTAINING HIGH CONCN OF SAFFLOWER OIL AND PALM OIL; PROC NUTR SOC 37(3) 98A (1978) R16: YOSHIOKA ET AL; YUKAGAKU 21(12) 881 (1972) R17: NAKAMURA ET AL; LIPIDS 8(10) 566 (1973) R18: PAWAR SS, TIDWELL HC; AM J PHYSIOL 213(6) 1350 (1967) R19: LIEB J; PROSTAGLANDINS MED 4(4) 275 (1980) R20: American Hospital Formulary Service. Volumes I and II. Washington, DC: American Society of Hospital Pharmacists, to 1984.,p. 24:06 RS: 9 Record 323 of 1119 in HSDB (through 2003/06) AN: 5179 UD: 200302 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: O-BENZYL-P-CHLOROPHENOL- SY: *BENZYLCHLOROPHENOL-; *ORTHO-BENZYL-PARA-CHLOROPHENOL-; *2-BENZYL-4-CHLOROPHENOL-; *BIO-CLAVE-; *P-CHLORO-O-BENZYLPHENOL-; *4-CHLORO-2-BENZYLPHENOL-; *5-CHLORO-2-HYDROXYDIPHENYLMETHANE-; *CHLOROPHENE-; *CHLOROPHENE,-USAN-; *4-CHLORO-ALPHA-PHENYL-ORTHO-CRESOL-; *4-CHLORO-2-(PHENYLMETHYL)PHENOL; *CLOROFENE-; *CLOROPHENE-; *O-CRESOL,-4-CHLORO-ALPHA-PHENYL-; *KETOLIN-H-; *NEOSABENYL-; *ORTHOBENZYL-P-CHLOROPHENOL-; *ORTHOBENZYLPARACHLOROPHENOL-; *PHENOL, 4-CHLORO-2-(PHENYLMETHYL)-; *SANTOPHEN-; *SANTOPHEN-1-; *SANTOPHEN-L-GERMICIDE-; *SEPTIPHENE- RN: 120-32-1 MF: *C13-H11-CL-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF SODIUM OR POTASSIUM PHENOXIDE AND BENZYL CHLORIDE FOLLOWED BY CHLORINATION OF THE RESULTING O-BENZYLPHENOL; REACTION OF P-CHLOROPHENOL AND BENZYL CHLORIDE [R1] *KLARMANN ET AL, J AM CHEM SOC 54, 3315 (1932); KLARMANN, GATE, US PATENT 1,967,825 (TO LEHN AND FINK); FROM NA OR K PHENOXIDE AND BENZYL CHLORIDE FOLLOWED BY CHLORINATION OF RESULTING O-BENZYLPHENOL: KAISER, GERMAN PATENT 703,955 (1941 TO DEUTSCHE HYDRIERWERKE). [R2] MFS: *Dow Chemical USA, Hq, 2020 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Main Street, Midland, MI 48667 [R3] USE: *ACTIVE PRINCIPLE OR ENHANCING AGENT FOR DISINFECTANTS [R4, 376] *GERMICIDE IN DISINFECTANT SOLUTIONS AND SOAP FORMULATIONS [R1] *o-Benzyl-p-chlorophenol is produced as a fungicide. [R3] *Fungicide, herbicide, antimicrobial [R5] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] *(1979) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R1] *Annual production averages less than 4.5X10+6 kg. [R6] U.S. IMPORTS: *(1977) ND [R1] *(1979) ND [R1] U.S. EXPORTS: *(1977) ND [R1] *(1979) ND [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *CRYSTALS [R2]; *WHITE TO LIGHT TAN OR PINK FLAKES [R4, 135] ODOR: *SLIGHTLY PHENOLIC [R4, 135] BP: *160-162 DEG C @ 3.5 MM HG [R2] MP: *48.5 DEG C [R2] MW: *218.69 [R2] CORR: *NONCORROSIVE TO MOST METALS [R4, 135] DEN: *1.186-1.190 @ 55 DEG/15.5 DEG C [R2] OWPC: *log P = 3.6 [R6] SOL: *INSOL IN WATER; HIGHLY SOL IN ALCOHOL AND OTHER ORG SOLVENT [R4, 135]; *Water solubility = 149 mg/L @ 25 deg C [R6] SPEC: *Intense mass spectral peaks: 140 m/z, 183 m/z, 218 m/z [R7] VAP: *Vapor pressure = 1.87X10-7 kPa [R6] OCPP: *CRYSTALLIZING POINT 45 DEG C MIN; DISPERSIBLE IN AQ MEDIA WITH AID OF SOAPS OR SYNTH DISPERSING AGENTS [R4, 135] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *IN FORMULATIONS OF 10% OR MORE, IT IS A PRIMARY SKIN IRRITANT. ... ONLY MILD SKIN IRRITATION AFTER PROLONGED CONTACT WITH USE DILUTIONS (0.03%). [R8] *SYMPTOMATOLOGY: 1. BURNING PAIN IN MOUTH AND THROAT. WHITE NECROTIC LESIONS IN MOUTH, ESOPHAGUS AND STOMACH. ABDOMINAL PAIN, VOMITING...AND BLOODY DIARRHEA. 2. PALLOR, SWEATING, WEAKNESS, HEADACHE, DIZZINESS, TINNITUS. /PHENOL/ [R8] *SYMPTOMATOLOGY: 3. SHOCK: WEAK IRREGULAR PULSE, HYPOTENSION, SHALLOW RESPIRATIONS, CYANOSIS, PALLOR, AND PROFOUND FALL IN BODY TEMP. 4. POSSIBLY FLEETING EXCITEMENT (DELIRIUM), FOLLOWED BY UNCONSCIOUSNESS. CONVULSIONS ARE RARELY SEEN EXCEPT IN CHILDREN. /PHENOL/ [R8] *SYMPTOMATOLOGY: 5. STERTOROUS BREATHING, MUCOUS RALES, RHONCHI, FROTHING AT NOSE AND MOUTH...PULMONARY EDEMA ARE SOMETIMES SEEN. CHARACTERISTIC ODOR OF PHENOL ON BREATH. 6. SCANTY, DARK-COLORED OR "SMOKY" URINE. /PHENOL/ [R8] *SYMPTOMATOLOGY: 6. IF DEATH DOES NOT OCCUR PROMPTLY, MODERATELY SEVERE RENAL INSUFFICIENCY MAY APPEAR. 7. DEATH FROM RESPIRATORY, CIRCULATORY OR CARDIAC FAILURE. /PHENOL/ [R8] *SYMPTOMATOLOGY: 8. IF SPILLED ON SKIN, PAIN IS FOLLOWED PROMPTLY BY NUMBNESS. THE SKIN BECOMES BLANCHED, AND A DRY OPAQUE ESCHAR FORMS OVER THE BURN. WHEN THE ESCHAR SLOUGHS OFF, A BROWN STAIN REMAINS. /PHENOL/ [R8] *INCR IN NEONATES EXCHANGE TRANSFUSIONS FOR IDIOPATHIC HYPERBILIRUBINEMIA COINCIDED WITH INCR CONCN OF PHENOLIC DISINFECTANT DETERGENT USED FOR CLEANING BASSINETS AND MATTRESSES. AFTER USE OF PHENOLIC CMPD WAS DISCONTINUED, EPIDEMIC OF HYPERBILIRUBINEMIA CEASED. [R9] *A cleaning woman who mixed a commercial solution of this disinfectant with hypochlorite bleach suffered a severe attack of porphyrea cutanea tarda, probably because of polychlorinated phenolic derivatives generated in the mixture ... . [R8] *...P-TERTIARYAMYLPHENOL, AND O-BENZYL-P-CHLOROPHENOL...EMPLOYED AS HOSPITAL DISINFECTANTS. LATTER...PLUS ORTHOCHLOROPHENOL ARE COMBINED IN DETERGENT DISINFECTANT, VESTAL LPH, WHICH HAS BEEN IMPLICATED IN EPIDEMICS OF NEONATAL HYPERBILIRUBINEMIA. [R10] NTOX: *POISONED ANIMALS EXHIBIT DIARRHEA, LASSITUDE, RAPID BREATHING, DYSPNEA, COLLAPSE, AND DEATH. [R8] *MICE EXPOSED TO COMPD CONTAINING O-PHENYLPHENOL, O-BENZYL-P-CHLOROPHENOL AND P-TERT-AMYLPHENOL DEVELOPED CONSIDERABLE DEPRESSION OF ABILITY TO GENERATE PLAQUE-FORMING CELLS IN RESPONSE TO SHEEP ERYTHROCYTES IN VITRO AFTER 4 WK EXPOSURE. [R11] *o-Benzyl-p-chlorophenol was found to be negative when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). o-Benzyl-p-chlorophenol was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.300, 1.000, 3.000, 3.300, 10.000, 33.000, 66.000, and 100.000 ug/plate. The highest ineffective dose tested in any S typhimurium strain was 100.000 ug/plate. At this dose, slight clearing of the background bacterial lawn occurred. The highest dose tested without metabolic activation was 33.000 ug/plate and at this dose, total clearing of the background lawn occurred. [R12] *o-Benzyl-p-chlorophenol was evaluated for its potential as a sensitizing agent for allergic contact hypersensitivity in mice. Female B6C3F1 mice were sensitized with 1.0, 3.0 and 10.0% o-benzyl-p-chlorophenol and challenged with 20% o-benzyl-p-chlorophenol. Doses of o-benzyl-p-chlorophenol were selected from assays for primary irritancy. Mice received 20 ul by direct dermal application, 5 days, to sites prepared by shaving, dermabrading and, in some mice, with intradermal injection of Freund's complete adjuvant. The rest period was 7 days. Measurement of the contact hypersensitivity response by radioisotopic assay two days after challenge and mouse ear swelling test one and two days after challenge. Mice demonstrated statistically significant dose dependent hypersensitivity response /to this cmpd/ with or without adjuvant pretreatment. [R13] *... The prechronic toxicity of o-benzyl-p-chlorophenol was evaluated in male and female F344 rats and B6C3F1 mice. Treatment was by gavage in corn oil. /The cmpd/ was slightly toxic after acute oral exposure, with high mortality at 4000 and 2000 mg/kg in rats and mice. Exposure to 12 oral doses of o-benzyl-p-chlorophenol at 1000, 500, 250, 125, 62.5 or 0 mg/kg/bw resulted in dose related cecal dilatation and nephrosis in both rats and mice. Doses for the subchronic studies were based on the results of the 2 wk studies. Ten animals were treated per dose per sex. Rats received 480, 240, 120, 60, 30 or 0 mg o-benzyl-p-chlorophenol/kg. Mice were treated with 1000, 800, 650, 500 or 0 mg o-benzyl-p-chlorophenol/kg. Animals were dosed 5 days/wk for 13 wk. Clinical signs related to dosing included urogenital staining in rats and rough oily haircoats in mice. No effects on growth rate were seen in rats, but growth was retarded at the higher doses used in mice. Kidney weights increased in rats, and liver weights increased in mice. A decr in thymus weight accompanied by a depletion of thymic lymphocytes (rats) or thymic necrosis (mice) occurred only in high dose animals. In both species, the kidney was the major target organ. In rats, there was an incr in the incidence and severity of nephropathy and renal tubule regeneration. No effects of /cmpd/ exposure in rats were /noted/ in a broad spectrum of hematology or urinalysis parameters. Minor decr in blood urea nitrogen, creatinine, and alanine amino transferase were detected in male and female rats. There was no biologically significant neurobehavioral effects in rats or immunotoxic effects in mice due to this /chemical/ exposure. ... The kidney is the major target for /this agent/. [R14] NTP: +Groups of 80 male and 80 female F344/N rats were administered o-benzyl-p-chlorophenol in corn oil by gavage 5 days/wk for 103 wk. The doses were 0, 30, 60 or 120 mg/kg body weight for male rats and 0, 60, 120 or 240 mg/kg body weight for female rats. ... Under the conditions of these 2 yr gavage studies, there was no evidence of carcinogenic activity of o-benzyl-p-chlorophenol in male F344/N rats receiving 30, 60 or 120 mg/kg body weight. There was equivocal evidence of carcinogenic activity of o-benzyl-p-chlorophenol in female F344/N rats based on the occurrence of two rare renal transitional cell carcinomas. Groups of 70 male and 70 female B6C3F1 mice were administered o-benzyl-p-chlorophenol in corn oil by gavage at doses of 0, 120, 240 or 480 mg/kg body weight 5 days/wk for 103 wk. There was some evidence of carcinogenic activity of o-benzyl-p-chlorophenol in male B6C3F1 mice based on increased incidence of renal tubule adenoma and renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of o-benzyl-p-chlorophenol in female B6C3F1 mice receiving 120, 240 or 480 mg/kg body weight. [R15] +Groups of 50 male and 50 female Swiss CD-1 mice were topically exposed to o-benzyl-p-chlorophenol (BCP) to study its effect as an initiator, promoter, and complete carcinogen. A number of control groups were included in these studies as a reference for the responses of the mouse skin to (BCP). ... Results in the Study of BCP as a Complete Carcinogen: BCP acted as an irritant when tested as a complete carcinogen using a single initiating dose of 10 mg BCP followed by repetitive applications of 0.1, 1.0, or 3.0 mg BCP for up to 52 wk, and many mice developed cutaneous lesions of scaling/crusts and ulceration. During the course of the study, a single papilloma was first observed after 12 wk in one 0.1 mg BCP male mouse. One 3.0 mg BCP female was observed with a papilloma at week 10, and three 0.1 mg BCP females were observed with papillomas between weeks 22 and 27. No mice administered BCP/BCP had papillomas at the end of the study, and no malignant cutaneous epithelial tumors were observed at the application sites on any BCP/BCP treated mice. Thus, in the present study, BCP was not a complete carcinogen. [R16] +Groups of 50 male and 50 female Swiss CD-1 mice were topically exposed to o-benzyl-p-chlorophenol (BCP) to study its effect as an initiator, promoter, and complete carcinogen. A number of control groups were included in these studies as a reference for the responses of the mouse skin to (BCP). ... Results in the Study of BCP as an Initiator: One vehicle control (acetone/acetone) male mouse had developed crusts at the site of application at necropsy, but no male or female controls had developed papillomas. Mice administered BCP/TPA developed application site lesions including scaling/crusts, ulceration, and irritation; the incidences of these lesions were similar to those in the initiator/promoter control (DMBA/TPA) groups. After 22 wk papillomas were observed in 12/50 male mice administered BCP/TPA. After 12 wk papillomas were observed in 7/50 female mice administered BCP/TPA. However, the incidences of papillomas in mice administered BCP/TPA were lower than those in mice administered TPA/TPA (males, 40/50; females 48/50). Although the incidences of papillomas in mice administered BCP as an initiator were significantly greater than those in vehicle controls, the incidences were not significantly different from those in TPA/TPA mice. Thus, in the present study, BCP did not demonstrate initiating potential. [R17] +Groups of 50 male and 50 female Swiss CD-1 mice were topically exposed to o-benzyl-p-chlorophenol (BCP) to study its effect as an initiator, promoter, and complete carcinogen. A number of control groups were included in these studies as a reference for the responses of the mouse skin to (BCP). ... Results in the Study of BCP as a Promoter: During the course of the study, incidences of scaling and/or crusts, ulceration, and irritation were observed at the site of application in DMBA/BCP male and female mice, and the incidences were dose related. Incidences of scaling and/or crusts, ulceration, and irritation in 3.0 mg BCP mice were similar to the incidences of these lesions in initiator/promoter (DMBA/TPA) group, but much higher than the incidences of these lesions in the initiator control (DMBA/acetone) group. A dose-related increased incidence of papillomas was observed in males (DMBA/acetone, 8/50; DMBA/0.1 mg BCP, 3/50; DMBA/1.0 mg BCP, 5/50; and DMBA/3.0 mg BCP, 14/50) and females (2/50, 6/50, 6/50, 18/50). The incidence of papillomas in DMBA/3.0 mg BCP females was significantly greater (p < 0.001) than that in DMBA/acetone females; the incidence of papillomas in DMBA/3.0 mg BCP males was marginally increased (p=0.077). No acetone/acetone mice developed papillomas. Although a higher percentage of DMBA/3.0 mg BCP mice developed papillomas over the course of the study than did DMBA/acetone controls, the time it took for half of the number of responding animals to develop papillomas was similar between DMBA/acetone groups and DMBA/3.0 mg BCP groups (DMBA/acetone males, wk 38; DMBA/acetone females, wk 34; DMBA/3.0 mg BCP females, wk 37). However, the time to appearance of the first papilloma was shorter in DMBA/3.0 mg BCP mice (males, wk 18; females, 10) than DMBA/acetone mice (males, wk 26; females, wk 27). BCP was considered to have promotion potential because the incidences of papillomas were greater than those in DMBA/acetone (initiator control) mice and because topical exposure to BCP alone caused no significant incr incidences of papillomas. However, the incidences of papillomas in DMBA/3.0 mg BCP mice (males, 14/50; females, 18/50) were much less than the incidences in DMBA/TPA (promoter control) mice (males, 40/50; females, 48/50); thus BCP was classified as a weak promoter. Conclusions: Under the conditions of this 1 yr mouse skin initiation/promotion study in swiss (CD-1) mice, o-benzyl-p-chlorophenol was a cutaneous irritant and a weak skin tumor promoter relative to strong promoters such as TPA. BCP had no activity as an initiator or as a complete carcinogen. [R17] ADE: *PERCUTANEOUS ABSORPTION DEMONSTRATED IN RABBITS. [R8] *Male rats given an oral dose of 69 mg/kg or 206 mg/kg (14)C labeled o-benzyl-p-chlorophenol. By 120 hr post dose, rats rapidly eliminated and extensively metabolized /this cmpd/. Expired carbon dioxide accounted for less than 0.05% of the radioactivity after either dose. Both urine and feces were major routes of excretion, with about half the dose remained eliminated by each route. Only 0.28 to 0.30 % of the dose remained within the body 5 days after dosing, about half this radioactivity was associated with the liver and kidney. Excretion of o-benzyl-p-chlorophenol was biphasic with an initial rapid alpha phase with a half life of 8 to 9 hr and slightly slower beta phase estimated to have a half life of 52 to 140 hr. A major portion of the metabolites of /this cmpd/ in the urine are excreted as conjugates at both low and high dose levels, while sulfate and glucuronide conjugates accounting for the majority if the metabolic radioactivity. Unchanged /cmpd/ was found as well as two metabolites with modified benzyl rings. ... [R18] BHL: *Male rats given an oral dose of 69 mg/kg or 206 mg/kg (14)C labeled o-benzyl-p-chlorophenol. ... Excretion of o-benzyl-p-chlorophenol was biphasic with an initial rapid alpha phase with a half life of 8 to 9 hr and slightly slower beta phase estimated to have a half life of 52 to 140 hr. ... [R18] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3. 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT FOR 70 KG PERSON (150 LB). [R8] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *o-Benzyl-p-chlorophenol's production and former use as a hospital disinfectant and as a fungicide could have resulted in its release to the environment through various waste streams. o-Benzyl-p-chlorophenol is rapidly transformed in aquatic and terrestrial environments through biodegradation and/or photodegradation; in soil, an experimental Koc of 2050 indicates only slight mobility. In the atmosphere, o-benzyl-p-chlorophenol degrades readily by reaction with photochemically produced hydroxyl radicals (estimated half-life of about 20 hours). Hydrolysis and volatilization are insignificant fate processes for this compound. o-Benzyl-p-chlorophenol has a low potential to bioconcentrate and is rapidly metabolized and excreted in fish. Exposure to o-benzyl-p-chlorophenol may occur occupationally during production or during its use as a disinfectant or as a fungicide and a small segment of the population may be exposed through ingestion of contaminated fish or drinking water. (SRC) ARTS: *o-Benzyl-p-chlorophenol was a hospital disinfectant which had widespread low level discharge to the environment through municipal waste treatment facilities(1,2). The primary routes of disposal of o-benzyl-p-chlorophenol were through domestic sewage into natural water with or without intermediate waste treatment or into natural water directly(2). o-Benzyl-p-chlorophenol's use as a fungicide(3) will result in its release to the environment(SRC). [R19] FATE: *TERRESTRIAL FATE: Various aqueous biodegradation screening studies have demonstrated that o-benzyl-p-chlorophenol biodegrades rapidly(1-4); thus biodegradation is expected to be the major degradation process within soil systems. An experimental Koc value of 2050 indicates that o-benzyl-p-chlorophenol has only slight mobility in soil(1). Hydrolysis of o-benzyl-p-chlorophenol was experimentally shown not to occur for this compound for a variety of pH and temperature conditions(1). Volatilization rates for o-benzyl-p-chlorophenol are very slow(1). [R20] *AQUATIC FATE: Various aqueous biodegradation screening studies have demonstrated that o-benzyl-p-chlorophenol biodegrades rapidly(1-4). In river die-away studies using non-acclimated river water(1,2) o-benzyl-p-chlorophenol biodegrades with a half-life of 0.21 to 1.04 days. Photolysis of o-benzyl-p-chlorophenol in natural water gave a half life of 0.7 days(1). An experimental Koc of 2050(1) suggests that o-benzyl-p-chlorophenol should partition from the water column to suspended sediments. Hydrolysis of o-benzyl-p-chlorophenol was experimentally shown not to occur under a variety of pH and temperature conditions(1). Bioconcentration and volatilization from water surfaces are not expected to be important fate processes(1). [R21] *ATMOSPHERIC FATE: Based on an estimated vapor pressure of 5X10-5 mm Hg at 25 deg C(1,SRC), o-benzyl-p-chlorophenol can exist in both the vapor phase and particulate phase in the ambient atmosphere(2,SRC). It will degrade rapidly in the vapor phase by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 20 hours(3,SRC). Particulate phase o-benzyl-p-chlorophenol may be removed physically from air by wet and dry deposition(SRC). [R22] BIOD: *Biodegradation rate constants and half-lives of 0.21 to 1.04/days and < 1 to 3 days, respectively, were reported in river die away studies using unacclimated river water containing 0.1 mg/l o-benzyl-p-chlorophenol(1). Sewage containing 0.5 mg/l o-benzyl-p-chlorophenol had a biodegradation rate and half-life for this compound of 0.42 to 2.07/days and 1 to 2 days, respectively. Activated sludge with an initial concentration of 0.5 mg/l o-benzyl-p-chlorophenol had a biodegradation rate constant of 3.88/days and a half life of 0.18 days as measured by DOC loss(1). Ultimate biodegradation to CO2 and H2O using acclimated sewage and 20-30 mg/l o-benzyl-p-chlorophenol, took slightly longer with a half-life of 7 to 23 days(1). o-Benzyl-p-chlorophenol undergoes rapid biodegradation after a short acclimation period in river water; o-benzyl-p-chlorophenol at a concentration of 0.1 mg/l was 78% degraded aerobically after 8 days; first respike (0.1 mg/l) on day 8 with 90% removal after 2 days; second respike of 0.1 mg/l on day 10 with 100% removal by day 13(2). o-Benzyl-p-chlorophenol, 0.5 mg/l, added to natural domestic sewage was substantially gone within one day; respiked (1.0 mg/l) with nearly 100% removal within one day(2). Acclimated activated sludge mixed liquor in a semicontinuous activated sludge unit (o-benzyl-p-chlorophenol concentration, 2.0 mg/l) gave complete removal of DOC (dissolved organic carbon) in 24 hours. Sludge from a semicontinuous activated sludge unit was used as inoculum (o-benzyl-p-chlorophenol, 20 mg/l); there was a one week lag period followed by CO2 evolution at 60% of the theoretical within 27 days(2). CO2 evolution was used as a test method in this experiment to ensure that degradation was due to microbial action(2). [R23] *In an aerobic, closed bottle screening test containing 10 mg/l of o-benzyl-p-chlorophenol and using activated sludge, 69% of the theoretical BOD was degraded over 28 days(1). Using activated sludge from a communal clarification plant in the presence of 28, 100, and 500 mg/L o- benzyl-p-chlorophenol, theoretical BOD removal after 1 day of incubation was 60, 78, and 15%, respectively, after 2 days incubation was 88, 80, and 15%, respectively, and after 5 days incubation was 95, 65, and 28%, respectively, using the Sapromat test method(2). Using industrial activated sludge in the presence of 10, 28, and 100 mg/l o-benzyl-p-chlorophenol, theoretical BOD removal after 1 day of incubation was 100, 66, and 40%, respectively, after 2 days incubation was 90, 100, and 53%, respectively, and after 5 days incubation was 92, 88, and 58% degradation, respectively, using the Sapromat test method(2). [R24] ABIO: *Rates of hydrolysis for o-benzyl-p-chlorophenol were calculated for pH values of 5, 7, and 9 and at both 25 and 50 deg C. For these conditions the rate constant for hydrolysis was < 0.005/days(1); therefore hydrolysis of this compound is not expected to occur in the environment(1). Photolysis of o-benzyl-p-chlorophenol in natural water was measured in quartz tubes exposed to sunlight from 0.25 to 9 days giving a rate constant of 0.95/days with a half life of 0.7 days. The rate constant for the vapor-phase reaction of o-benzyl-p-chlorophenol with photochemically produced hydroxyl radicals has been estimated to be 1.8X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 21 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(2,SRC). [R25] BIOC: *A BCF value of 75 was measured for bluegill sunfish(1). Bluegill sunfish (Lepomis machrochirus) were exposed to 0.057 mg/l o-benzyl-p-chlorophenol for a period of 96 hours followed by a depuration period of 96 hours to determine the ability of the fish to metabolize and eliminate o-benzyl-p-chlorophenol. Depuration rate constants were from 4.67 to 6.94/days with a half-life of 0.14 days(1). The rate constant of o-benzyl-p-chlorophenol uptake in fish ranged from 11.8 to 13.8/days with a half-life of 0.06 days. These BCF value suggests that bioconcentration in aquatic organisms is not an important fate process(SRC). [R26] KOC: *An experimentally determined Koc of 2050 was obtained by equilibrating aqueous solutions of o-benzyl-p-chlorophenol (at concentrations ranging from 0.5 to 10 mg/l) with four different soils, with organic carbon contents ranging from 0.41 to 1.97%, and then analyzing both soil and water phases for o-benzyl-p-chlorophenol(1). According to a suggested classification scheme(2), these Koc values indicate that o-benzyl-p-chlorophenol is essentially immobile in soil(SRC). [R27] VWS: *The Henry's Law constant for o-benzyl-p-chlorophenol was estimated as 9.96X10-9 atm-cu m/mole using a structure estimation method(1,SRC). This value of Henry's Law constant indicates that the compound is essentially non-volatile. Therefore, volatilization from water or moist soil is not an important environmental fate process(SRC). [R28] WATC: *o-Benzyl-p-chlorophenol was detected in surface waters in the United States (18 sites, 54 samples, 2 positive samples, mean positive = 16.5 ug/l, geometric mean concentration = < 0.11 ug/l, detection limit = 0.11 ug/l)(1). Only two samples had measurable concentrations of o-benzyl-p-chlorophenol, the Illinois River, 0.12 ug/l, and the Delaware Bay, 0.21 ug/l. [R26] EFFL: *Influent and effluent samples from 11 municipal sewage treatment plants in St. Louis, MO and Dayton, OH, were obtained during November, 1978 and August, 1981 respectively. Influent concentrations averaged 14.8 ug/l o-benzyl-p-chlorophenol with a range of concentrations from < 0.1 to 115 ug/l. Effluent concentrations averaged 0.8 ug/l o-benzyl-p-chlorophenol with a range of concentrations from < 0.1 to 28 ug/l. Sludge concentrations were an average of 23 mg/kg o-benzyl-p-chlorophenol with a range of concentrations from 13 to 30 mg/kg(1). Municipal wastewater was monitored in Vancouver, BC from June through August 1983; o-benzyl-p-chlorophenol was qualitatively detected in both wastewater and sludge base/neutral extracts(2). o-Benzyl-p-chlorophenol was detected at a rurally located treatment plant in New Jersey and at an unreported date; there were no industrial contributors to this waste site(3). [R29] RTEX: *Occupational exposure to o-benzyl-chlorophenol occurred during its use as a hospital disinfectant(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 216,335 workers are potentially exposed to o-benzyl-p-chlorophenol in the USA(2). [R30] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble in 51 FR 41329. [R31] *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 2-benzyl-4-chlorophenol is included on this list. [R32] FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. 2-Benzyl-4-chlorophenol is found on List B. Case No: 2045; Pesticide type: fungicide, antimicrobial; Case Status: RED Approved 09/95; OPP has made a decision that some/all uses of the pesticide are eligible for reregistration, as reflected in a Reregistration Eligibility Decision (RED) document.; Active ingredient (AI): 2-Benzyl-4-chlorophenol; Data Call-in (DCI) Date(s): 06/10/91, 11/15/96; AI Status: OPP has completed a Reregistration Eligibility Decision (RED) document for the case/AI. [R33] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *THIN-LAYER CHROMATOGRAPHY ON SILICA GEL 60 F254 WITH PHME-MECO2 (4:1) OR ETHYL ACETATE-METHANOL-10% AMMONIUM HYDROXIDE (65:30:5) WAS USED TO SEPARATE 38 PRESERVATIVES USED IN COSMETICS. THE CMPD WERE IDENTIFIED BY COLOR REACTIONS WITH 12 SPRAY REAGENT SYSTEMS. [R34] *MIXT OF 22 BACTERICIDES WERE SEPARATED BY PROGRAMMED-TEMP GAS CHROMATOGRAPHY BETWEEN 100 and 300 DEG C USING COLUMNS WITH 10% SILICONE RUBBER W-982 ON CHROMOSORB W (DMCS, 60-80 MESH) AS STATIONARY PHASE AND FLAME IONIZATION DETECTOR. [R35] CLAB: *DETERMINATION OF 3 GERMICIDAL PHENOLS IN SERUM OF INFANTS WITH HYPERBILIRUBINEMIA BY HPLC. CHLOROPHENE WAS AMONG GERMICIDAL AGENTS DETERMINED BY HIGH PRESSURE LIQUID CHROMATOGRAPHY. [R36] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of o-Benzyl-p-chlorophenol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 424 (1994) NIH Publication No. 94-3155 SO: R1: SRI R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 376 R3: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 800 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R5: USEPA/OPP; Status of Pesticides in Reregistration and Special Review p.121 (Mar, 1992) EPA 700-R-92-004 R6: Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983) R7: Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985.344 R8: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-193 R9: WYSOWSKI DK ET AL; PEDIATRICS 61(2) 165 (1978) R10: Gilman, A. G., L. S. Goodman, and A. Gilman. (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 6th ed. New York: Macmillan Publishing Co., Inc. 1980. 969 R11: LA VIA MF ET AL; DRUG CHEM TOXICOL 2(1-2) 167 (1979) R12: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R13: Stern ML et al; Drug Chem Toxicol 14 (3): 231-42 (1991) R14: Birnbaum LS et al; Fundam Appl Toxicol 7 (4): 615-25 (1986) R15: Toxicology and Carcinogenesis Studies of o-Benzyl-p-chlorophenol in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 424 (1994) NIH Publication No. 94-3155 U.S. Department of Health and Human Services, National Toxicology Program, Research Triangle Park, NC 27709 R16: One Year Initiation/Promotion Study of o-Benzyl-p-chlorophenol in Swiss CD-1 Mice (Mouse Study) Technical Report Series No. 444 (1995) NIH Publication No. 95-3157 U.S. Department of Health and Human Services, National Toxicology Program, Research Triangle Park, NC 27709 R17: One Year Initiation/Promotion Study of o-Benzyl-p-chlorophenol in Swiss CD-1 Mice (Mouse Study) Technical Report Series No. 444 (1995) NIH Publication No. 95-3157 U.S. Department of Health and Human Services, National Toxicology Program, Research Triangle Park, NC 27709 R18: Ridley WP et al; J Toxicol Environ Health 18 (2): 267-83 (1986) R19: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983)(2) Swisher RD, Gledhill WE; Appl Microbiol 26: 394-8 (1973) (2) Rogers IH et al; Water Pollut Res J Canada 21: 187-204 (1986) (3) SRI International; 1994 Directory of Chemical Producers in the USA. p.800 (1994) R20: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983) (2) Swisher RD, Gledhill WE; Appl Microbiol 26: 394-8 (1973) (3) Dewaart J, Vandermost MM; Int Biodetermination 22: 113-20 (1986) (4) Pauli O, Franke G; pp 52-60 in Biodeter Mater. Proc Int Biodeter Symp 2nd (1971) R21: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983)(2) Swisher RD, Gledhill WE; Appl Microbiol 26: 394-8 (1973)(3) Dewaart J, Vandermost MM; Int Biodetermination 22: 113-20 (1986) (4) Pauli O, Franke G; pp 52-60 in Biodeter Mater. Proc Int Biodeter Symp 2nd (1971) R22: (1) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton, FL: CRC Press (1985) (2) Bidleman TF; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R23: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983) (2) Swisher RD, Gledhill WE; Appl Microbiol 26: 394-8 (1974) R24: (1) Dewaart J, Vandermost MM; Int Biodetermination 22: 113-20 (1986) (2) Pauli O, Franke G; pp 52-60 in Biodeter Mater. Proc Int Biodeter Symp 2nd (1971) R25: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-55 (1983) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) R26: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983) R27: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983) (2) Swann RL et al; Res Rev 85: 23(1983) R28: (1) Meylan W, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods Washington, DC: Amer Chem Soc p. 15-15 to 15-29 (1990) R29: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983)(2) Rogers IH, et al; Water Pollut Res J Canada 21: 187-204 (1986) (3) Clark LB, et al; Res J WPCF 63: 104-13 (1991) R30: (1) Werner FA et al; Arch Environ Contam Toxicol 12: 569-75 (1983) (2) NIOSH; National Occupational Exposure Survey (NOES) (1983) R31: 40 CFR 712.30 (7/1/94) R32: 40 CFR 716.120 (7/1/94) R33: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.161 (Spring, 1998) EPA 738-R-98-002 R34: SCHMAHL HJ ET AL; FRESENIUS' Z ANAL CHEM 304(5) 398 (1980) R35: KOENIG H; FRESENIUS' Z ANAL CHEM 266(2) 119 (1973) R36: NEEDHAM LL ET AL; DETERMINATION OF THREE GERMICIDAL PHENOLS IN SERUM OF INFANTS WITH HYPERBILIRUBINEMIA; CLIN CHIM ACTA 107(3 NOV 6) 261 (1980) RS: 35 Record 324 of 1119 in HSDB (through 2003/06) AN: 5180 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-ACID-RED-114- SY: *ACID-LEATHER-RED-BG-; *ACID-RED-114-; *BENZYL-FAST-RED-BG-; *BENZYL-RED-BR-; *CI-ACID-RED-114-; *C.I.-ACID-RED-114,-DISODIUM-SALT-; *C.I.-23635-; *ERIONYL-RED-RS-; *FENAFOR-RED-PB-; *FOLAN-RED-B-; *KAYANOL-MILLING-RED-RS-; *LEATHER-FAST-RED-B-; *MIDLON-RED-PRS-; *MILLING-FAST-RED-B-; *MILLING-RED-B-; *MILLING-RED-BB-; *MILLING-RED-SWB-; *1,3-NAPHTHALENEDISULFONIC ACID, 8-((3,3'-DIMETHYL-4'-((4-(((4-METHYLPHENYL)SULFONYL)OXY)PHENYL)AZO)(1,1'- BIPHENYL)-4-YL)AZO)-7-HYDROXY-, DISODIUM SALT; *POLAR-RED-RS-; *SULPHONOL-RED-R-; *SUMINOL-MILLING-RED-RS-; *SUPRANOL-FAST-RED-GG-; *SUPRANOL-RED-R-; *SUPRANOL-RED-PBX-CF-; *TELON-FAST-RED-GG-; *TERTRACID-MILLING-RED-B-; *VONDAMOL-FAST-RED-RS- RN: 6459-94-5 MF: *C37-H30-N4-O10-S3.2Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepared by coupling one mole each of phenol and G acid (2-naphthol-6,8-disulfonic acid) to one mole of tetraazotized o-tolidine and finally esterifying the phenol-hydroxy function with p-tolylsulfonyl chloride. [R1] *...Is manufactured by coupling bisdiazotized 3,3'-dimethylbenzidine with one equivalent of G acid; the monoazo compound obtained is further coupled with phenol to yield the disazo dye, the p-hydroxyl group of which is subsequently esterified with toluenesulfonic acid to improve the fastness properties and pH stability. [R2] MFS: *AMERICAN COLOR AND CHEMICAL COMPANY, CHARLOTTE, NC 28232 [R3] *ATLANTIC CHEMICAL INDUSTRIES, INC, ATLANTIC CHEMICAL CORP, SUBSID, NUTLEY, NJ 07110 [R3] *CROMPTON AND KNOWLES CORP, DYES AND CHEMICALS DIV, READING, PA 19603 [R3] *TOMS RIVER CHEMICAL CORP, TOMS RIVER, NJ 08753 [R3] USE: *DYE FOR WOOL, SILK, JUTE FIBERS, LEATHER, PRINTING ON WOOL AND SILK [R3] *Dye (wool, silk, polyamide) [R4] *Acid Red 114 dyes wool (from a weak acid bath), silk (from either a neutral or acetic acid bath), jute and chromed leather. Wool and silk are printed directly. [R1] PRIE: U.S. PRODUCTION: *(1977) 1.09X10+8 GRAMS [R3] *(1979) 1.73X10+8 GRAMS [R3] *117 tons in 1975 [R5] U.S. IMPORTS: *(1977) 1.10X10+7 GRAMS (PRINCPL CUSTMS DISTS) [R3] *(1980) 6.51X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Deep-maroon powder [R1] MW: *830.82 [R4] SOL: *Soluble in water and very slightly soluble in ethanol. [R1] SPEC: *Absorption max = 532 (365) nm in ethanol [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of CI Acid Red 114. There is sufficient evidence in experimental animals for the carcinogenicity of CI Acid Red 114. Overall evaluation: CI Acid Red 114 is possibly carcinogenic to humans (Group 2B). [R6] NTOX: *Acid Red 114 (AR 114) was evaluated for the induction of sex-linked recessive lethal mutations in Drosophila melanogaster by the National Toxicology Program. Canton-S wild-type males were treated with concentrations of AR 114 that result in approximately 30% mortality. Following treatment, males were mated individually to 3 harems of Basc virgin females to produce 3 broods for analysis. The concentrations of AR 114 tested by injection (1500 ppm) and feeding (50,000 ppm) were negative in this assay. [R7] *Five textile azo dyes viz CI acid violet 17 CI acid green 16, CI acid red 85, CI acid red 114 and C I direct green 6, were tested for bacterial mutagenicity with Salmonella typhimurium TA98 and TA100 strains using a plate incorporation assay. After testing over a concentration range of 1 uq to 500 ug with and without metabolic activation the dyes showed no mutagenicity or toxicity. [R8] *This report introduces an improved method of detecting chemical-induced morphological transformation of A-31-1-13 BALB/c-3T3 cells. The new procedure uses an increased target cell population to assess chemical-induced damage by increasing the initial seeding density and by delaying the initiation time of chemical treatment. Furthermore, a newly developed co-culture clonal survival assay was used to select chemical doses for the transformation assay. This assay measured the relative cloning efficiency (RCE) of chemical treatments in high-density cell cultures. In addition, transformation assay sensitivity was enhanced through the use of improved methods to solubilize many chemicals. From a group of 24 chemicals tested in at least two trials, clear evidence of chemical-induced transformation was detected for 12 chemicals (aphidicolin, barium chloride-2H20, 5-bromo-2'-deoxyuridine, CI direct blue 15, trans-cinnamaldehyde, cytosine arabinoside, diphenylnitrosamine, manganese sulfate-H20, 2-mercaptobenzimidazole, mezerein, riddelliine, and 2,6-xylidine); 2 chemicals had equivocal activity [CI direct blue 218 and mono(2-ethylhexyl)phthalate], 9 chemicals were inactive [carisoprodol, chloramphenicol sodium succinate, 4-chloro-2-nitroaniline, CI acid red 114, isobutyraldehyde, mono(2-ethylhexyl)adipate, sodium fluoride, and 12-o-tetradecanoylpharbol-l3-acetate), and 1 chemical had an indeterminate response (2,6-dinitrotoluene). All positive responses were detected in the absence of an exogenous activation system and exhibited significant activity at two or more consecutive doses. This report also presents a mathematical method that uses t-statistics for rank-ordering the potency of chemical-induced transformation responses. This model detects sensitivity differences in experiments used to evaluate chemical-induced transformation. Furthermore, it provides a method to estimate a chemical's transformation response in terms of the historical behavior of the assay, as well as its future activity. The most active of the 24 chemicals was mezerein, and the least active chemical was diphenylnitrosamine. [R9] *C-I-Acid-Red-114, 3,3 -dimethoxybenzidine, C-I-Direct-Blue-15, and 3,3'-dimethylbenzidine-dihydrochloride were administered orally in drinking water to studies were conducted, one for 9 months and one for 15 months using doses of O, 30, 70, or 150 ppm of each compound. Determinations were made regarding body and organ weights and feed consumption. Results of the 15 month study indicated that 3,3'-dimethylbenzidine-dihydrochloride was clearly carcinogenic for both sexes of rats. Chemically related neoplastic lesions were noted in the skin, Zymbal's gland, preputial gland, clitoral gland, liver, oral cavity, large and small intestines, and lung following exposure for the l5 month study. Nonneoplastic lesions related to exposure included: cystic degeneration and foci of alteration in the liver; exacerbation of nephropathy; and hyperplasia of Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Average daily water consumption dropped slightly with increased 3,3'-dimethylbenzidine-dihydrochloride dose in female rats. Mean body weights of both sexes decreased with increasing dose in the 15 month study. [R10] *Retrospective characterization of morphological and stereological features of altered hepatocellular foci in hematoxylin and eosin stained sections was performed on 6 conventional 2 yr carcinogenicity studies conducted in Fischer 344 (F344) rats by the National Toxicology Program. In 3 of these studies where there was clear evidence of hepatocarcinogenicity [l-amino-2,4-dibromoanthraquinone, CI Acid Red 114, methyl carbamate], there was greater morphological variability in altered hepatocellular foci than in the studies of chemicals that were not hepatocarcinogenic [4-hydroxyacetanilide, epinephrine, dimethoxane]. In addition to having the expected types of altered hepatocellular foci, rats treated with 1-amino-2,4-dibromoanthraquinone, CI Acid Red 114, and methyl carbamate had atypical basophilic altered hepatocellular foci. [R11] *Neoplasms of preputial gland and skin were obtained from Fischer 344 male rats on lifetime drinking water studies of the benzidine congener 3,3'-dimethoxybenzidine, CI Direct Blue 15 or CI Acid Red 114, bisazobiphenyl dyes derived from 3,3'-dimethoxybenzidine and 3,3'-dimethylbenzidine. Portions of these well differentiated neoplasms were implanted into the left mammary fat pad of Fischer 344 male recipients. The rate of growth, presence of local invasion and distant metastases, and morphologic features were observed following 4 serial transplantations. All implants appeared early, grew rapidly, and were histomorphologically similar to the original neoplasms. Metastases from transplants were observed with both preputial gland and skin tumor lines in serial passages. The transplantation results confirm the malignant nature of these neoplasms. [R12] +... Conclusions: Under the conditions of these 2 yr drinking water studies, there was clear evidence of carcinogenlc activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. [R13] NTP: +Toxicology and carcinogenesis studies were conducted by admin desalted, industrial grade C.I Acid Red 114 in drinking water to groups of F344/N rats of each sex for ... 2 years. ... 2 Yr studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high dose groups, 45 in the low dose groups, and 75 in the mid dose groups. ... The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Conclusions: Under the conditions of these 2 yr drinking water studies, there was clear evidence of carcinogenlc activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. [R13] TCAT: ?The mutagenicity of acid red 114 was evaluated in Salmonella tester strains TA98, TA100, TA1535, TA1537 and TA1538, both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. Acid red 114 was tested at concentrations of 20, 100, 500, 2500 and 5000 ug/plate. No mutagenicity was observed without added metabolic activation or in tester strains TA1535 and TA1537 with activation. Acid red 114 caused a positive response at 250 ug/plate (TA98) and 500-1000 ug/plate (TA1538) with activation. Inconsistent results were obtained in tester strain TA100. [R14] ?C. I. acid red 114 was examined for mutagenic activity in Salmonella typhimurium tester strains TA100, TA1535, TA1537, TA1538, TA98 and E. coli WP2uvrA. The test article was administered to cells at concentrations ranging from 4 to 10,000 ug/plate both with and without metabolic activation provided by Aroclor-induced rat liver S9 fraction. A small reproducible mutagenic effect was observed in TA1538 in activated and non-activated assays; the effect was dose dependent between 100 and 2500 ug/plate in activated assays. Small reproducible increases in the number of revertant colonies (up to 2.1 fold) were also observed in TA98 both with and without activation. Doses up to 10,000 ug/plate were reported to be non-toxic in a preliminary toxicity test. [R15] ?C.I. acid red 114, disodium salt (CAS # 6459-94-5) was evaluated for subchronic oral toxicity and carcinogenicity. The test substance was administered in the drinking water of male and female F344/N rats (number not reported) for 13-days (doses of 0, 10,000, 20,000, and 30,000 ppm); 13-weeks (doses of 0, 600, 1200, 2500, 5000, 10,000 ppm); and 9 or 15 months, or 2 years [doses of 0, 70 (males only), 150, 300, and 600 (females only) ppm]. It was concluded that there was evidence of carcinogenic activity. No further information was submitted [R16] ?C.I. acid red 114, disodium salt (CAS # 6459-94-5) was evaluated for carcinogenicity. The test substance was administered in the drinking water of male and female F344/N rats (number not reported) for 13-days (doses of 0, 10,000, 20,000, and 30,000 ppm); 13-weeks (doses of 0, 600, 1200, 2500, 5000, 10,000 ppm); and 9 or 15 months, or 2 years [doses of 0, 70 (males only), 150, 300, and 600 (females only) ppm]. It was concluded that there was evidence of carcinogenic activity. No further information was submitted [R16] ?C.I. acid red 114, disodium salt (CAS # 6459-94-5) was evaluated for mutagenicity in an in vitro mammalian point mutation assay. The test substance was determined to be nonmutagenic using the Chinese hamster V79 cell. No further information was submitted. [R17] ?C.I. acid red 114, disodium salt (CAS # 6459-94-5) was evaluated for mutagenicity in the Ames test. The test substance was determined to be positive using Salmonella typhimurium strains TA1538 and TA98. No further information was submitted. [R17] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *C.I. Acid Red 114's production and use in the dyeing of wool, silk, jute, chromed leather, and polyamide, may result in its release to the environment through various waste streams. The ionic nature of C.I. Acid Red 114 makes this compound non-volatile; therefore this compound is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Acid Red 114 may be physically removed from the air by wet and dry deposition. If released to soil, the retention of C.I. Acid Red 114 by ion-exchange processes, particularly on clay surfaces, and adsorption at mineral surfaces such as geothite, may slow down or prevent leaching. The volatilization of the dye from soil surfaces to air will not be important as C.I. Acid Red 114 is an ionic compound. Based on limited data, this compound is expected to readily biodegrade anaerobically. Complete anaerobic biodegradation of C.I. Acid Red 114 was reported in 7 days using an activated sludge inoculum; major metabolites were 4,4'-diamino-3,3'-dimethylbiphenyl and 4-methylbenzenesulphonic acid-(4'-aminophenyl) ester. The loss of this dye from water by evaporation should not be important. It is expected to adsorb to sediments and particulate matter in the water with adsorption increasing with decreasing pH. Occupational exposure may occur during C.I. Acid Red's production or during its use as a dye. (SRC) ARTS: *C.I. Acid Red 114's production and use in the dyeing of wool, silk, jute, chromed leather(1), and polyamide(2), may result in its release to the environment through various waste streams(SRC). [R18] FATE: *TERRESTRIAL FATE: Due to the ionic nature of C.I. Acid Red 114, the retention of the dye by ion-exchange processes(1,SRC), particularly on clay surfaces, and adsorption at mineral surfaces such as geothite(2,SRC), may slow down or prevent leaching(SRC). Based on limited data, this compound is expected to readily biodegrade anaerobically(SRC). Complete anaerobic biodegradation of C.I. Acid Red 114 was reported in 7 days using an activated sludge inoculum; major metabolites were 4,4'-diamino-3,3'-dimethylbiphenyl and 4-methylbenzenesulphonic acid-(4'-aminophenyl) ester(3). Since ionic compounds normally do not readily volatilize(1), no loss of the dye from soil surfaces is expected to occur due to volatilization(SRC). [R19] *AQUATIC FATE: Due to the ionic nature of C.I. Acid Red 114, the retention of the dye by ion-exchange processes(1,SRC), particularly on clay surfaces, and adsorption at mineral surfaces such as geothite(2,SRC), may cause this compound to adsorb to sediment and particulate matter in water(SRC). Complete anaerobic biodegradation of C.I. Acid Red 114 was reported in 7 days using an activated sludge inoculum; major metabolites were 4,4'-diamino-3,3'-dimethylbiphenyl and 4-methylbenzenesulphonic acid-(4'-aminophenyl) ester(3). Since C.I. Acid Red 114 is an ionic compound, volatilization of the dye from water surfaces will not be important(1,SRC). Measured BCF values of 42-76 and 52-84, respectively, measured in orange-red killifish exposed to either 0.2 or 0.02 mg/l C.I. Acid Red 114(4), indicate that C.I. Acid Red 114 may bioconcentrate in aquatic organisms(SRC), according to a recommended classification scheme(5). [R20] *ATMOSPHERIC FATE: The ionic state of C.I. Acid Red 114 makes this compound essentially non-volatile(1,SRC), therefore this compound is expected to exist in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Acid Red 114 may be physically removed from the air by wet and dry deposition(SRC). [R21] BIOD: *Several laboratories studying the anaerobic degradation of C.I. Acid Red 114 obtained results of 33-90% degradation within 42 days using a sludge inoculum; some loss may be due to adsorption onto the sludge(1). C.I. Acid Red 114 at 100 mg/l, incubated with an anaerobic sludge inoculum, was completely degraded in 7 days under anaerobic conditions(2). The main metabolites were 4,4'-diamino-3,3'-dimethylbiphenyl and 4-methylbenzenesulphonic acid-(4'-aminophenyl) ester(2). [R22] ABIO: *C.I. Acid Red 114 showed a light precipitate in water with a calcium concentration of 10-3 M(1). [R23] BIOC: *Carp exposed to either 0.2 or 0.02 mg/l C.I. Acid Red 114 had measured BCF values of 42-76 and 52-84, respectively(1). According to a recommended classification scheme(2), these BCF values indicate that bioconcentration of C.I. Acid Red 114 in aquatic organisms may be a somewhat important fate process(SRC). [R24] KOC: *Due to the ionic nature of the dye, the retention of C.I. Acid Red 114 by ion-exchange processes(1,SRC), particularly on clay surfaces and adsorption at mineral surfaces such as geothite(2,SRC), may slow down or prevent leaching(SRC). It was noted during a biodegradation experiment that C.I. Acid Red 114 tended to adsorb onto sludge(3). [R25] VWS: *Since C.I. Acid Red is an ionic compound, volatilzation from water and moist soil surfaces will not be important(1,SRC). [R21] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 13,795 workers (90 of these are female) are potentially exposed to C.I. Acid Red 114 in the USA(1). [R26] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 in F344/N Rats (Drinking Water Studies) Technical Report Series No. 405 (1991) NIH Publication No. 92-3136 SO: R1: Green FJ; The Sigma-Aldrich Handbook of Stains, Dyes, and Indicators. Aldrich Chemical Company, Inc: Milwaukee, WI p. 38 (1990) R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA3 268 R3: SRI R4: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 30 R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V3 399 (1978) R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 57 255 (1993) R7: Woodruff RC et al; Environ Mutagen 7: 677-702 (1985) R8: Kaur A et al; J Of Environ Biol 14 (4): 327-33 (1993) R9: Matthews EJ et al; Environ Health Perspect 101 (2): 319-45 (1993) R10: Morgan DL et al; J of the Amer Coll of Toxicol 10 (2): 255-67 (1991) R11: Harada T et al; Toxicol Pathol 17 (4 Pt 1): 690-706 (1989) R12: Ulland BM et al; Toxico1 Pathol 17 (1 Pt 1): 50-6 (1989) R13: Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 in F344/N Rats (Drinking Water Studies). Technical Report Series No. 405 (1991) NIH Publication No. 92-3136 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R14: BASF Corporation; Appendix II: Report on Salmonella Microsome Mutation Test (Acid Red 114). (1982), EPA Document No. 40-8229019, Fiche No. OTS0507287 R15: Pharma Research Toxicology; C.I. Acid Red 114: Study of the mutagenic potential in strains of Salmonella typhimurium (Ames Test) and Escherichia Coli (1984), EPA Document No. 868600075, Fiche No. OTS0510225 R16: U S EPA; USEPA Submission Summary: C I Acid Red 114 With Cover Letter Dated 06/18/91; 05/21/91; Old Doc. No. 8EHQ-0491-1226; Fiche No. OTS0529774-1 R17: ETAD; Executive Summary on the ETAD Project T 2015 Toxicological Testing of Major Colorants, With Attachments and Cover Letter Dated June 3, 1988; 04/15/88; EPA Doc No. FYI-AX-0688-0621; Fiche No. OTS0000621 R18: (1) Green FJ; The Sigma-Aldrich Handbook of Stains, Dyes, and Indicators. Aldrich Chemical Company, Inc: Milwaukee, WI p. 38 (1990) (2) Ashford RD; Ashford's Dictionary of Industrial Chemicals: Properties, Production, Uses. London, England: Wavelength Publ, Ltd. p. 30 (1994) R19: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) (2) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) (3) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) R20: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) (2) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) (3) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) (4) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R21: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) R22: (1) Brown D, Laboureur P; Chemosphere 12: 397-404 (1983) (2) Brown D, Hamburger B; Chemosphere 16: 1539-53 (1987) R23: (1) Hou M, Baughman GL; Dyes and Pigments 18: 35-46 (1992) R24: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology-Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R25: (1) Baughman GL, Perenich TA; Amer Dyestuff Report Feb p. 19-22 (1988) (2) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) (3) Brown D, Laboureur P; Chemosphere 12: 397-404 (1983) R26: (1) NIOSH; National Occupational Exposure Survey (NOES) Cincinnati, OH (1989) RS: 24 Record 325 of 1119 in HSDB (through 2003/06) AN: 5186 UD: 200302 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: O-NITROANISOLE- SY: *ANISOLE,-O-NITRO-; *BENZENE,-1-METHOXY-2-NITRO-; *1-METHOXY-2-NITROBENZENE-; *2-METHOXYNITROBENZENE-; *2-METHOXY-1-NITROBENZENE-; *2-NITROANISOLE-; *1-NITRO-2-METHOXYBENZENE-; *O-NITROPHENYL-METHYL-ETHER- RN: 91-23-6 MF: *C7-H7-N-O3 SHPN: UN 2730; Nitroanisole IMO 6.1; Nitroanisole ASCH: 3-Nitroanisole; 555-03-3; 4-Nitroanisole; 100-17-4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *From o-nitrophenol by methylation or from o-nitrochlorobenzene by action of methanol and caustic soda [R1] FORM: *GRADE: TECHNICAL. [R1] MFS: *MONSANTO CO, MONSANTO CHEM INTERMEDIATES CO, ST LOUIS, MO 63177 [R2] USE: *ORGANIC SYNTHESIS; INTERMEDIATE FOR PHARMACEUTICALS, DYES [R1] *CHEM INT FOR DYE INTERMEDIATES, EG, O-ANISIDINE [R2] PRIE: U.S. PRODUCTION: *(1977) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R2] *(1978) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R2] U.S. IMPORTS: *(1976) 3.19X10+8 G (PRINCPL CUSTMS DISTS) [R2] *(1978) 2.46X10+8 G (PRINCPL CUSTMS DISTS) [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS TO YELLOWISH LIQUID [R3]; *LIGHT REDDISH OR AMBER LIQUID [R1] BP: *277 DEG C [R3] MP: *9.4 DEG C [R3] MW: *153.13 [R3] DEN: *1.254 @ 20 DEG C/4 DEG C [R3] OWPC: *Log Kow = 1.73 [R4] SOL: *INSOL IN WATER; SOL IN ALCOHOL, ETHER [R3]; *Water solubility = 1690 mg/L at 30 deg C [R5]; *Liquid molar volume = 0.123068 cu m/kmol [R6] SPEC: *INDEX OF REFRACTION: 1.5620 @ 20 DEG C/D [R3]; *MAX ABSORPTION (CYCLOHEXANE): 249 NM (LOG E= 3.53); 304 NM (LOG E= 3.40) [R7]; *IR: 5864 (Sadtler Research Laboratories Prism Collection) [R8]; *UV: 1643 (Sadtler Research Laboratories Spectral Collection) [R8]; *NMR: 1887 (Sadtler Research Laboratories Spectral Collection) [R8]; *MASS: 4169 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R8] SURF: *4.7471X10-2 N/m @ melting point [R6] VAP: *Vapor pressure = 3.6x10-3 mm Hg at 25 deg C [R9] VISC: *Liquid viscosity = 3.9768X10-3 @ melting point [R6] OCPP: *CRYSTALLIZING POINT: 9.6 DEG C [R10] *IR: 15184 (Sadtler Research Laboratories Prism Collection) /3-Nitroanisole/ [R8] *UV: 6-111 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) /3-Nitroanisole/ [R8] *NMR: 17156 (Sadtler Research Laboratories Spectral Collection) /3-Nitroanisole/ [R8] *MASS: 498 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /3-Nitroanisole/ [R8] *IR: 8421 (Sadtler Research Laboratories IR Grating Collection) /4-Nitroanisole/ [R8] *UV: 1644 (Sadtler Research Laboratories Spectral Collection) /4-Nitroanisole/ [R8] *NMR: 3185 (Sadtler Research Laboratories Spectral Collection) /4-Nitroanisole/ [R8] *MASS: 497 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) /4-Nitroanisole/ [R8] *Liquid molar volume = 0.123068 cu m/kmol [R6] *Boiling point range: 268-271 deg C [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: Highly toxic, may be fatal if inhaled, swallowed or absorbed through skin. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R11] +Fire or explosion: Combustible material: may burn but does not ignite readily. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R11] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. [R11] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R11] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R11] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Water spray, fog or regular foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R11] +Spill or leak: Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Cover with plastic sheet to prevent spreading . Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. [R11] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R11] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Use foam, dry chemical, or carbon dioxide. Keep run-off water out of sewers and water sources. /Nitroanisole/ [R12] EXPL: *In the preparation of 2,2'-dimethoxyazoxybenzene, solvent ethanol was distilled out of the mixture of 2-nitroanisole, zinc and sodium hydroxide before reaction was complete. The exothermic reaction continued unmoderated, and finally exploded. [R13] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. /Nitroanisole/ [R12] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R14] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R15] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R16] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of 2-nitroanisole. There is sufficient evidence in experimental animals for the carcinogenicity of 2-nitroanisole. Overall evaluation: 2-Nitroanisole is possibly carcinogenic to humans (Group 2B). [R17] NTOX: *O-NITROANISOLE WAS MUTAGENIC FOR BOTH STRAINS OF SALMONELLA TYPHIMURIUM TA98 AND TA100. [R18] *Nineteen nitro compounds, including o-nitroanisole, were evaluated for mutagenicity, using a modification of the standard Salmonella typhimurium mutagenicity assay. A preincubation protocol was used which incorporated flavin mononucleotide (FMN) to facilitate nitro reduction. Results were compared with those by the standard plate test. For o-nitroanisole, the standard plate assay gave a clear positive response while the modified preincubation assay did not. [R19] NTP: *Toxicology and carcinogenesis studies were conducted by feeding groups of 60 F344 rats of each sex diets containing 0, 222, 666 or 2,000 ppm of o-nitroanisole and groups of 60 B6C3F1 mice of each sex diets containing 0, 666, 2,000 or 6,000 ppm o-nitroanisole for 103 wk. Under the conditions of these feed studies there was clear evidence of the carcinogenic activity of o-nitroanisole in male and female F344 rats that received diets containing 6,000 or 18,000 ppm for 6 mo based on incr incidences of benign and malignant neoplasms of the urinary bladder, transitional cell neoplasms of the kidney, and benign and malignant neoplasms of the large intestine. There was a chem related incr incidence of mononuclear cell leukemia in male and female rats receiving diets containing 222, 666 or 2,000 ppm o-nitroanisole for 2 yr. Marginally incr incidences of uncommon renal tubule neoplasms in male rats and forestomach neoplasms in male and female rats were considered uncertain findings. There was clear evidence of the carcinogenic activity of o-nitroanisole in male B6C3F1 mice based on incr incidences of benign and malignant hepatocellular neoplasms. There was some evidence of the carcinogenic activity of o-nitroanisole in female B6C3F1 mice based on incr incidences of hepatocellular adenomas. [R20] METB: *YIELDS O-NITROPHENOL IN RABBITS. /FROM TABLE/ [R21] *OXIDATIVE AND CONJUGATIVE METABOLISM OF P-NITROANISOLE AND P-NITROPHENOL IN ISOLATED RAT LIVER CELLS. [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *o-Nitroanisole's production and use in organic synthesis, and in the manufacture of dyes and pharmaceuticals may result in its release to the environment through various waste streams. o-Nitroanisole has been detected in drinking water. If released to soil, o-nitroanisole will have moderate mobility. Volatilization of o-nitroanisole will not be important from moist soil surfaces based on the estimated Henry's Law constant of 4.3X10-7. Volatilization of o-nitroanisole is not important from dry soil surfaces either based on an estimated vapor pressure of 3.6X10-3 mm Hg. Biodegradation of o-nitroanisole will not be an important fate process in soil based on two biodegradation studies. If released to water, o-nitroanisole may adsorb to suspended solids and sediment. o-Nitroanisole may volatilize very slowlyfrom water surfaces with estimated half-lives for a model river and model lake of about 105 days and 772 days, respectively. Bioconcentration and biodegradation of o-nitroanisole will not be important fate processes in water. If released to the atmosphere, o-nitroanisole will exist in the vapor phase in the ambient atmosphere. Vapor-phase o-nitroanisole is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 109 hours. (SRC) ARTS: *o-Nitroanisole's production and use in organic synthesis, and in the manufacture of dyes and pharmaceuticals(1) may result in its release to the environment through various waste streams(SRC). [R23] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 200(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that o-nitroanisole will have moderate mobility in soil(SRC). Volatilization of o-nitroanisole will not be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 4.3X10-7 atm-cu m/mole(SRC), calculated from experimental values for vapor pressure(5) and water solubility(6). Volatilization will not be important from dry soil surfaces either(SRC), based on an estimated vapor pressure of 3.6X10-3 mm Hg(5). Biodegradation of o-nitroanisole will not be an important fate process in soil based on the lack of degradation in two biodegradation studies(7,8). [R24] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 200(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates little adsorption of o-nitroanisole may adsorb to suspended solids and sediment(SRC). o-Nitroanisole may volatilize very slowly from water surfaces based on an estimated Henry's Law constant of 4.3X10-7 atm-cu m/mole(SRC), calculated from experimental values of vapor pressure(4) and water solubility(5). Estimated half-lives for a model river and model lake are 105 days and 772 days, respectively(3,SRC). Bioconcentration and biodegradation of o-nitroanisole will not be important fate processes in water(6). [R25] *ATMOSPHERIC FATE: According to a suggested classification scheme(1), an experimental vapor pressure of 3.6X10-3 mm Hg at 25 deg C(2) indicates that o-nitroanisole will exist in the vapor phase in the ambient atmosphere. Vapor-phase o-nitroanisole is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 109 hours(3,SRC). [R26] BIOD: *Greater than 64 days were required to degrade o-nitroanisole by a soil microflora inoculum from a Niagara silt loam in a mineral salts medium(1). A two week biodegradation study using 30 mg/l sludge and a o-nitroanisole concentration of 100 mg/L gave a 0% theoretical BOD(2). [R27] ABIO: *The rate constant for the vapor-phase reaction of o-nitroanisole with photochemically produced hydroxyl radicals has been estimated as 3.5X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 109 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R28] BIOC: *An estimated BCF value of 12 was calculated for o-nitroanisole(SRC), using an experimental log Kow of 1.73(1) and a recommended regression-derived equation(2). According to a recommended classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms will not be an important fate process(SRC). Bioconcentration factors of 1.4-2.3 and 2.7-5.2 were obtained during an 8 week bioconcentration study using carp and o-nitroanisole concentrations of 50 and 5 ug/L, respectively(4). [R29] KOC: *The Koc of o-nitroanisole is estimated as approximately 200(SRC), using an experimental log Kow of 1.73(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that o-nitroanisole has medium mobility in soil(SRC). [R30] VWS: *The Henry's Law constant for o-nitroanisole is estimated as 4.3X10-7 atm-cu m/mole(SRC) from its experimental values for vapor pressure, 3.6X10-3 mm Hg(1), and water solubility, 1690 mg/l(2). This value indicates that o-nitroanisole will not volatilize from water surfaces very rapidly(3,SRC). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec) is estimated as approximately 105 days(3,SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec) is estimated as approximately 772 days(3,SRC). Volatilization of o-nitroanisole will not be important from moist soil surfaces based on the estimated Henry's Law constant of 4.3X10-7(1,2,SRC). Volatilization of o-nitroanisole is not important from dry soil surfaces either based on an estimated vapor pressure of 3.6X10-3 mm Hg(1). [R31] WATC: *DRINKING WATER: o-Nitroanisole has been qualitatively detected in drinking water(1). [R32] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of o-Nitroanisole in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 416 (1993) NIH Publication No. 93-3147 Advisory Committee on Existing Chemicals of Environmental Relevance (BUA). o-Nitroanisole (1-methoxy-2-nitrobenzene). S. Hirzel Verlag, Stuttgart Germany 1993. This document reviews the currently available data on the environmental behavior of o-nitroanisole along with ecotoxic effects and toxicological data. ... SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 824 R2: SRI R3: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1042 R4: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 30 R5: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 1325 R6: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R7: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-168 R8: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 92 R9: Yaws CL; Handbook of Vapor Pressure. Volume 2-C5 to C7 Compounds. Gulf Publishing Co: Houston, TX 391 pp (1994) R10: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 613 R11: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-152 R12: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 770 R13: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 710 R14: 49 CFR 171.2 (7/1/96) R15: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 185 R16: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.6183 (1988) R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 65 378 (1996) R18: CHIU CW ET AL; MUTAT RES 58: 11 (1978) R19: Dellarco VL, Prival MJ; Environ Mol Mutagen 13 (2): 116-27 (1989) R20: DHHS/NTP; Toxicology and Carcinogenesis Studies of o-Nitroanisole in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 416 (1993) NIH Publication No. 93-3147 R21: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. N-12 R22: MOLDEUS P ET AL; ACTA PHARMACOL TOXICOL 39 (1): 17 (1976) R23: (1) Lewis RJSR; Hawley's Condensed Chemical Dictionary 12th ed. New York, NY: Van Nostrand Rheinhold Co (1993) R24: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 30 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Yaws CL; Handbook of Vapor Pressure. Volume 2-C5 to C7 Compounds. Gulf Publishing Co: Houston, TX pp 391 (1994) (6) Riddick JA et al; Organic Solvents: Physical Properties and Methods of Purification. Techniques of Chemistry 4th ed. New York, NY: Wiley-Interscience pp 1325 (1986) (7) Alexander M, Lustigman BK; J Agr Food Chem 14: 410-13 (1966) (8) Chemicals Inspection and Testing Institute Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center ISBN 4-89074-101-1 (1992) R25: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 30 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Yaws CL; Handbook of Vapor Pressure. Volume 2-C5 to C7 Compounds. Gulf Publishing Co: Houston, TX pp 391 (1994) (5) Riddick JA et al; Organic Solvents: Physical Properties and Methods of Purification. Techniques of Chemistry 4th ed. New York, NY: Wiley-Interscience pp 1325 (1986) (6) Chemicals Inspection and Testing Institute Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center ISBN 4-89074-101-1 (1992) R26: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yaws CL; Handbook of Vapor Pressure. Volume 2-C5 to C7 Compounds. Gulf Publishing Co: Houston, TX pp 391 (1994A) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R27: (1) Alexander M, Lustigman BK; J Agr Food Chem 14: 410-13 (1966) (2) Chemicals Inspection and Testing Institute Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center ISBN 4-89074-101-1 (1992) R28: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R29: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 30 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Chemicals Inspection and Testing Institute Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center ISBN 4-89074-101-1 (1992) R30: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 30 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R31: (1) Yaws CL; Handbook of Vapor Pressure. Volume 2-C5 to C7 Compounds. Gulf Publishing Co: Houston, TX pp 391 (1994) (2) Riddick JA et al; Organic Solvents: Physical Properties and Methods of Purification. Techniques of Chemistry 4th ed. New York, NY: Wiley-Interscience pp 1325 (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R32: (1) Kool HJ et al; Crit Rev Env Control 12: 307-57 (1982) RS: 25 Record 326 of 1119 in HSDB (through 2003/06) AN: 5227 UD: 200302 RD: Reviewed by SRP on 9/29/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: HYDROXYACETIC-ACID- SY: *ACETIC-ACID,-HYDROXY-; *GLYCOLIC-ACID-; *ALPHA-HYDROXYACETIC-ACID-; *HYDROXYETHANOIC-ACID- RN: 79-14-1 MF: *C2-H4-O3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *MADE BY ACTION OF SODIUM HYDROXIDE ON MONOCHLOROACETIC ACID; ALSO BY ELECTROLYTIC REDN OF OXALIC ACID. [R1] *Under high pressure, 30.4-91.2 MPa (300-900 atm), formaldehyde reacts with carbon monoxide and water in the presence of an acidic catalyst to form hydroxyacetic acid. Reaction temperature depends on the acid in use: 160-200 deg C for sulfuric, hydrochloric, or phosphoric acid; 20-60 deg C for hydrofluoric acid [R2, p. V13 91] *Hydrolysis of glyconitrile with an acid (eg phosphite or sulfite) at 100-150 deg C [R2, p. V13 91] *Water hydrolysis of trichloroethylene under pressure at 150 deg C; treating glycine with nitric acid; oxidation of hexoses, isoamyl benzoate, and 5-oxodigluconic acid [R2, p. V5 747] *Hydroxyacetic acid is produced commercially in the United States (Du Pont) by treating trioxymethylene with carbon monoxide and water in the presence of acid catalysts at > 30 MPa. [R3, p. VA13 513] FORM: *GRADES: TECHNICAL, 70% SOLN; PURE CRYSTALS. AVAIL COMMERCIALLY AS 70% SOLN. [R4] *Available commercially as either a 57% (Hoechst) or a 70% (Du Pont) aqueous solution [R3, p. VA13 513] MFS: *Du Pont, Hq, 1007 Market Street, Wilmington, DE 19898, (302) 774-1000, (800) 441-7515; Du Pont Chemicals; Production site: Belle, WV 25015 [R5] *Eastman Kodak Company, Hq, 343 State Street Rochester, NY 14650 (716) 724-4000 (800) 225-5352; Laboratory and Research Products [R5] OMIN: *ALUMINUM MAGNESIUM GLYCOLATE SHOWED GOOD ANTACID PROPERTIES. THEY BUFFER GASTRIC JUICE IN OPTIMUM PH RANGE FOR LONGER TIME THAN KNOWN EXHISTING ANTACIDS. [R6] *CONSTITUENT OF SUGAR CANE. [R1] USE: +The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R7] *IN PH CONTROL [R1] *WHEREVER CHEAP ORG ACID IS NEEDED: IN MFR OF ADHESIVES, DECONTAMINATION CLEANING, DYEING, IN PICKLING, CLEANING AND CHEM MILLING OF METALS [R8] *BREAKING OF PETROLEUM EMULSIONS; CHELATING AGENT FOR IRON [R4] *Soldering compounds; adhesives [R4] *Biodegradable polymer; water well cleaning; masonary; textiles; detergents; dairy sanitation [R2, p. V13 91] *Hydroxyacetic acid (glycolic acid) is used in textile dyeing, printing, and creaseproofing. The fact that it can form a chelate with calcium(II) ions makes it well-suited to hide deliming in the leather industry, as well as to inclusion in alum and chrome mordants and in fur-processing operations. The compound has little tendency to cause corrosion, and this characteristic, coupled with its bactericidal properties, makes it suitable for incorporation into acidic cleansing agents. It is especially well-adapted to cleansing operations involving milk containers, milk-processing equipment, and drinking fountains, as well as rust and scale removal in heat exchangers and pipelines. Glycolic acid inhibits the growth of iron-oxidizing bacteria. The use of glycolic acid eliminates the need for simultaneous addition of chelating agents and bactericides. The effectiveness of glycolic acid as a complexing agent also contributes to its use in copper polishes, as an etching agent for lithographic plates, and in the preparation of electropolishing and galvanizing baths. [R3, p. VA13 513] *Hydroxyacetic acid is produced commercially in the United States as an intermediate in the manufacture of ethylene glycol [R2, p. V13 91] *AMIDES AND/OR AMMONIUM SALTS OF ALPHA- AND BETA-HYDROXYACIDS OR ALPHA-KETOACIDS ARE USEFUL FOR TREATING DANDRUFF AND ACNE. [R9] +MEDICATION CPAT: *Total annual consumption worldwide is ca. 2000-3000 t of solution [R3, p. VA13 513] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS CRYSTALS [R4]; *RHOMBIC NEEDLES FROM WATER; LEAVES FROM ETHANOL [R10] ODOR: *ODORLESS [R1] BP: *100 deg C (decomposes) [R3, p. VA13 509] MP: *80 DEG C [R1] MW: *76.1 CORR: *The compound has little tendency to cause corrosion. [R3, p. VA13 513] DEN: *1.49 at 25 deg C [R3, p. VA13 509] DSC: *Ka= 1.48X10-4 @ 25 DEG C [R1]; *PKA 3.83 [R11, 1803] OWPC: *Log Kow= -1.11 [R12] PH: *AQ SOLN: 2.5 (0.5%); 2.33 (1.0%); 2.16 (2.0%); 1.91 (5.0%); 1.73 (10.0%) [R1] SOL: *SOL IN WATER, METHANOL, ALCOHOL, ACETONE, ACETIC ACID [R1]; *SOL IN ETHER [R1] SPEC: *IR: 6254 (Coblentz Society Spectral Collection) [R13]; *NMR: 6411 (Sadtler Research Laboratories Spectral Collection) [R13]; *MASS: 24 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R13] VAP: *8.1 mm Hg at 80 deg C [R14] OCPP: *HYGROSCOPIC; DELIQUESCENT [R1] *ODOR LIKE BURNT SUGAR; SP GRAVITY: 1.27; MP: 10 DEG C /70% SOLN/ [R4] *LIGHT, STRAW-COLORED LIQUID /70% SOLN/ [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits acrid fumes. [R15] SERI: *MILD IRRITANT TO SKIN, MUCOUS MEMBRANES. [R8] *IT PRODUCES VERY SEVERE BURNS OF SKIN OR EYE IN 70% TECHNICAL SOLN. [R11, 1803] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *MILD IRRITANT TO SKIN, MUCOUS MEMBRANES. [R8] *IT PRODUCES VERY SEVERE BURNS OF SKIN OR EYE IN 70% TECHNICAL SOLN. @ 20% REACTION IS GREATLY REDUCED. [R11, 1803] *MODERATELY TOXIC BY INGESTION. [R16] *Ethylene glycol intoxication produces a severe metabolic acidosis with an increased anion gap. ... Three patients with this intoxication /were examined/ to identify the organic acids that cause acidemia in humans and to determine how effectively these acids can be removed during dialysis. All patients had markedly elevated glycolic acid levels of more than 7 meq/l and two patients had lactic acidosis with lactic acid levels of greater than 5.0 meq/l. Hemodialysis clearance of glycolic acid was 105 ml/min and 159 meq was removed in 3 hours. After hemodialysis using a bicarbonate dialysate the mean anion gap decreased from 34 to 23 meq/l; the mean serum bicarbonate concentration increased from 5.5 to 20 meq/l. Therefore glycolic and lactic acids are important in the acidosis caused by ethylene glycol intoxication in humans. Hemodialysis treatment with a bicarbonate dialysate is an efficient method for removing glycolic acid and resolving acidemia. [R17] NTOX: *OXALATE CRYSTALS WERE ... PRESENT IN RENAL TUBULES OF ... /RATS/ RECEIVING ... GLYCOLIC ACID. ... A NUMBER OF ANIMALS DIED WITHIN 8 HR OF RECEIVING 5-6 G/KG BODY WT ... RENAL TUBULAR PATHOLOGY WAS NOT ALWAYS ACCOMPANIED BY CRYSTAL FORMATION ... CYTOTOXICITY, RATHER THAN ... MECHANICAL OBSTRUCTION, ... RESPONSIBLE FOR RENAL FAILURE. [R18, 704] *... SEVERE METABOLIC ACIDOSIS PRODUCED ... IN DOG AND PIGTAIL MONKEY. ... ACCUMULATION OF METABOLITE GLYCOLIC ACID AFTER ETHYLENE GLYCOL ADMIN IS SUFFICIENT TO ACCOUNT FOR METABOLIC ACIDOSIS THAT DEVELOPS. CONTRIBUTION OF OTHER POSSIBLE METABOLITES WAS CONSIDERED NEGLIGIBLE. [R19] *TESTED BY DROPPING ON RABBIT EYES, IT HAS CAUSED MODERATELY SEVERE INJURY, GRADED 7 ON SCALE OF 1 TO 10 AFTER 24 HR ... . [R20] *GLYCOLATE PERTURBS LIPID METABOLISM IN ALL MAJOR TISSUES OF MICE, ACTIVATES PEROXISOMAL PATHWAY FOR BETA-OXIDATION OF FATTY ACIDS IN LIVER, AND PRODUCES AN ASSOC COMPENSATORY MOBILIZATION OF LIPIDS IN PERIPHERAL TISSUES. [R21] *IP INJECTION OF GLYCOLATE (1 G/KG) INTO RATS 1 HR BEFORE SACRIFICE INCR RATIO OF NAD TO NADH IN LIVER. THIS EFFECT MAY PARTIALLY EXPLAIN ITS METABOLIC EFFECTS AND TOXICITY. [R22] *GLYCOLATE WAS LEAST TOXIC OF THE 3 CMPD IN MICE, RATS AND RABBITS. NEUROMUSCULAR INHIBITION INDUCED APPEARED TO RESULT FROM AN INCR IN CNS GLYCINE LEVEL. [R23] *Dichloroacetate and trichloroacetate are major by-products of drinking water chlorination. Recent experiments have shown that both of these compounds produce hepatic tumors in B6C3Fl mice. There was evidence that these effects may be associated with cytotoxic effects and/or peroxisomal proliferation. Therefore, in the present study the in vitro cytotoxicity of monochloroacetate, dichloroacetate, trichloroacetate, and a metabolite glycolate was determined in hepatocyte suspensions prepared from naive and clofibric acid-pretreated male Sprague-Dawley rats and B6C3Fl mice. Cytotoxic responses measured by release of lactic dehydrogenase and/or trypan blue exclusion were only observed with high concentrations (5.0 mM) of monochloroacetate and glycolate in hepatocytes from naive animals (p = 0.025 and 0.008 respectively, Sprague-Dawley rat; p = 0.033 and 0.001 respectlvely, B6C3Fl mouse). The cytotoxic responses to both compounds were observed much earlier and at much lower concentrations in hepatocytes taken from mice and rats that had been pretreated with clofibric acid (p = 0.001 Sprague-Dawley rat and B6C3F1 mouse). Dichloroacetate and trichloroacetate produced no evidence of cytotoxicity in hepatocytes from naive or clofibric acid-pretreated animals of either species at concentrations up to 5.0 mM. Increasing concentrations of monochloroacetate and glycolate resulted in dose-related depletion of intracellular reduced glutathione that closely paralleled the cytotoxic responses. Only glycolate (0.25-5.0 mM) produced increased intracellular oxidized glutathione. Neither dichloroacetate nor trichloroacetate was found to alter cellular glutathione status in hepatocytes isolated fron either Sprague-Dawley rats or B6C3Fl mice. It was concluded from these in vitro observations that dichloroacetate and trichloroacetate are not highly cytotoxic to hepatocytes. Moreover the rates of their conversion to monochloroacetate or glycolate may be insufficient to induce cytotoxic effects in hepatocytes in vivo. [R24] NTXV: *LD50 Rat oral 1,950 mg/kg; [R15] *LD50 Guinea pig oral 1,920 mg/kg; [R15] ADE: *URINARY EXCRETION OF (14)C ACCOUNTED FOR 37-52% OF (14)C-LABELLED GLYCOLIC ACID WITHIN 96 HR OF ORAL ADMIN OF 500 MG/KG DOSES TO RHESUS MONKEYS. [R25] *Ethylene glycol toxicity results from its metabolism to glycolic acid and other toxic metabolites. The accumulation of glycolate and the elimination kinetics of ethylene glycol and its metabolites are not well understood, so studies with male Sprague-Dawley rats and mixed breed dogs have been carried out. Ethylene glycol was administered by gavage to rats and dogs which were placed in metabolic cages for urine and blood sample collection at timed intervals. The peak plasma level of ethylene glycol occurred at 2 hr after dosing and that of glycolate between 4-6 hr. The rate of ethylene glycol elimination was somewhat faster in rats with a half-life of 1.7 hr compared to 3.4 hr in dogs. The maximum plasma level of glycolate was greater in rats although the pattern of accumulation was similar to that in dogs. Glycolate disappeared from the plasma at the same time as ethylene glycol, suggesting a slower rate of elimination of the metabolite than that of ethylene glycol. Renal excretion of ethylene glycol was an important route for its elimination accounting for 20-30% of the dose. Renal excretion of glycolate represented about 5% of the dose. Ethylene glycol induced an immediate, but short lived diuresis compared to that in control rats. Minimal clinical effects (mild acidosis with no sedation) were noted at these doses of ethylene glycol (1-2 g/kg) in both rats and dogs. The results indicate that the toxicokinetics of ethylene glycol and glycolate were similar in both species. [R26] *Ethylene glycol (I) and glycolate (glycolic acid) pharmacokinetics were studied in 2 adult patients who had ingested antifreeze; therapy with intravenous ethyl alcohol (II) was also discussed. The patients had maximal ethylene glycol concentrations of 40.9 and 56.9 mmol/l respectlvely. Both patients survived but with prolonged renal failure. Glycolic acid was the major cause of the metabolic acidosis in both cases; lactate levels were only slightly elevated. Kinetic calculations showed that both ethylene glycol and glycolate were distributed in total body water with plasma half-lives of 8.4 and 7.0 hr respectively. The half-life of ethylene glycol was increased more than 10 fold by ethyl alcohol treatment alone. Calcium oxalate monohydrate crystalluria was dominant in both cases but in one was preceded by a short period with mainly dihydrate excretion; crystalluria was not present upon admission. It was suggested that repetitive urine microscopy in search of needle or envelope shaped crystals should be performed when ethylene glycol intoxication is suspected. [R27] *The pharmacokinetics and metabolism of diethylene-glycol and ethylene-glycol were studied in rats. Male Sprague-Dawley-rats were given O to 17.5 ml/kg (14)C-labeled diethylene glycol or O to 5 ml/kg ethylene glycol by gavage. Expired air, urine, and feces were collected at periodic intervals for up to 126 hr and analyzed for (14)C- activity. Urine volume and pH were measured in some rats. The rats were killed after 126 hr to determine the tissue distribution of diethylene glycol derived radioactivity. Urine samples were analyzed for diethylene glycol and ethylene glycol metabolites. The urine was the major elimination pathway 84% of the 1O ml/kg diethylene glycol dose and 94.5% of the 5 ml/kg ethylene glycol dose being excreted by this route. Rats given 1, 5, and 1O ml/kg diethylene glycol eliminated diethylene glycol in their urine with halflives of 6, 6, and 12 hr assuming first order kinetics. More detailed analysis showed that 6, 9, and 18 hr after dosing with 1, 5, and 1O ml/kg diethylene glycol elimination of (14)C activity followed zero order kinetics then changed to first order kinetics with a halflife of 3 hr. Rats dosed with 3 and 5 ml/kg ethylene glycol excreted unchanged ethylene glycol in their urine with halflives of 4.5 and 4.1 hr respectively. One percent or less of the diethylene glycol doses was found in the carcass and organs. The largest amounts occurred in the liver muscle fat and skin. Sixty two to 67% of the diethylene glycol dose was excreted as unchanged diethylene glycol and 16 to 31% as 2-hydroxyethoxyacetic-acid. Sixty two to 67% of the ethylene glycol dose was excreted as unchanged ethylene glycol and 28.7% as glycolic-acid. Urine volume increased and pH increased with the increasing diethylene glycol and ethylene glycol doses. /It was/ concluded that 2-hydroxyethoxyacetic-acid and glycolic-acid are the primary urinary metabolites of diethylene glycol and ethylene glycol. [R28] METB: *... CAN BE CONVERTED TO GLYCINE THROUGH INTERMEDIATE OXIDATION TO GLYOXYLIC ACID. [R11, 1804] *Ethylene glycol is oxidized by alcohol dehydrogenase to glycolaldehyde and further to glycolic acid by cytosolic aldehyde oxidase. Glycolic acid is further oxidized via glyoxylic acid to oxalic acid by glycolic acid oxidase. [R18, 703] INTC: *GLYCOLIC ACID, A DEPRESSANT ANTAGONIZING THE CONVULSANT ACTION OF STRYCHNINE IN SPINAL CORD OF CATS. /GLYCOLIC ACID/ [R29] *GLYCOLATE POTENTIATED SODIUM 4-HYDROXYBUTYRATE HYPNOTIC ACTIVITY AND HAD SYNERGISTIC ACTION WITH NICOTINAMIDE IN INDUCING HYPOTHERMIA IN MICE, RATS, AND RABBITS. [R23] *Hepatic oxidases were studied in rat and monkey liver homogenates and subcellular fractions for their ability to provide hydrogen peroxide for the catalase-dependent peroxidation of methanol. Urate oxidase and glycolate oxidase were the most active hepatic hydrogen peroxide-generating enzymes in the rat, while much less active preparations were obtained from monkey liver. Supplimentation of solubilized hepatic microbodies, a particulate cell fraction containing catalase and oxidases, previously termed peroxosomes, or cell sap from either species with an exogenous hydrogen peroxide generating system stimulated methanol oxidation above rates obtained when uric acid or glycolic acid was used to enhance methanol oxidation. [R30] *Glycollate was used as the inducer of oxalate hyperoxaluria in rats. The increase in lipid peroxidation and superoxide dismutase activity, associated with a decrease in catalase activity and glutathione level, are the salient features observed in tissues of hyperoxaluric rats. [R31] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Keratolytic Agents [R32] *When they are absorbed, humectants help the skin retain moisture; examples include ... glycolic acid. [R33] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ NATS: */Hydroxyacetic acid/ occurs naturally in sugar cane syrup [R34] ARTS: *Hydroxyacetic acid can be found in the spent sulfite liquor from pulp processing [R2, p. V13 91] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FIFR: +As the federal pesticide law FIFRA directs, EPA is conducting a comprehensive review of older pesticides to consider their health and environmental effects and make decisions about their future use. Under this pesticide reregistration program, EPA examines health and safety data for pesticide active ingredients initially registered before November 1, 1984, and determines whether they are eligible for reregistration. In addition, all pesticides must meet the new safety standard of the Food Quality Protection Act of 1996. Pesticides for which EPA had not issued Registration Standards prior to the effective date of FIFRA, as amended in 1988, were divided into three lists based upon their potential for human exposure and other factors, with List B containing pesticides of greater concern and List D pesticides of less concern. Glycolic acid is found on List D. Case No: 4045; Pesticide type: antimicrobial; Case Status: No products containing the pesticide are actively registered ... The case /is characterized/ as "cancelled." Under FIFRA, pesticide producers may voluntarily cancel their registered products. EPA also may cancel pesticide registrations if registrants fail to pay required fees or make/meet certain reregistration commitments, or if EPA reaches findings of unreasonable adverse effects.; Active ingredient (AI): Glycolic acid; AI Status: The active ingredient is no longer contained in any registered pesticide products ... "cancelled." [R7] FDA: *Hydroxyacetic acid is an indirect food additive for use as a component of adhesives. [R35] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SEPARATIONS AND DETERMINATIONS OF ORGANIC ACIDS IN PULP WASTE WATER BY LIQUID CHROMATOGRAPHY USING A HEAT DETECTOR. [R36] *Comparison of ion chromatographic methods for the determination of organic and inorganic acids in precipitation samples; Ion gas chromatography [R37] CLAB: *Colorimetric and gas chromatographic procedures for glycolic acid in serum: the major toxic metabolite of ethylene glycol; colorimetry, gas chromatography [R38] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for glycolic acid. Route: topical; Species: mice. [R39] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 707 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R4: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 620 R5: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 665 R6: JAIN PK ET AL; INDIAN DRUGS 15 (8): 158 (1978) R7: USEPA/OPP; Status of Pesticides in Registration, Reregistration and Special Review p.314 (Spring, 1998) EPA 738-R-98-002 R8: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 583 R9: YU RJ ET AL; TREATMENT OF ACNE AND DANDRUFF; US PATENT NUMBER 4105782 08/08/78 R10: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 71st ed. Boca Raton, FL: CRC Press Inc., 1990-1991.,p. 3-262 R11: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R12: Hansch, C. and A. Leo. The Log P Database. Claremont, CA: Pomona College, 1987. R13: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 672 R14: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R15: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1482 R16: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 454 R17: Gabow PA et al; Ann Intern Med 105 (1): 16-20 (1986) R18: Amdur, M.O., J. Doull, C.D. Klaasen (eds). Casarett and Doull's Toxicology. 4th ed. New York, NY: Pergamon Press, 1991. R19: Doull, J., C.D. Klaassen, and M. D. Amdur (eds.). Casarett and Doull's Toxicology. 2nd ed. New York: Macmillan Publishing Co., 1980. 482 R20: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 529 R21: CRANE D ET AL; BIOCHEM INT 1 (2): 133 (1980) R22: THURET F ET AL; AGRESSOLOGIE 12 (3): 183 (1971) R23: LABORIT H ET AL; AGRESSOLOGIE 12 (3): 187 (1971) R24: Bruschi SA, Bull RJ; FUNDAM AND APPL TOXICOL 21 (3): 366-375 (1993) R25: MCCHESNEY EW ET AL; FOOD COSMET TOXICOL 10 (5): 655 (1972) R26: Hewlett TP et al; Vet Hum Toxicol 31 (2): 116-20 (1989) R27: Jacobsen D et al; Am J Med 84: 145-52 (Jan) (1988) R28: Lenk W et al; Xenobiotica 19 (9): 961-79 (1989) R29: BANNA NR; IRCS LIBR COMPEND 1 (5): 7.10.7 (1973) R30: GOODMAN JI ET AL; MOL PHARMACOL 4 (5): 492 (1968) R31: Sumathi R et al; Pharmacol Res 27 (4): 309-18 (1993) R32: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R33: American Medical Association, Council on Drugs. AMA Drug Evaluations Annual 1994. Chicago, IL: American Medical Association, 1994. 1224 R34: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 547 R35: 21 CFR 175.105 (4/1/93) R36: KABEYA H ET AL; NIPPON KAGAKU KAISHI ISS 11, 1910 (1975) R37: Cheam V; Analyst 117: 1137-44 (1992) R38: Fraser AD, MacNeil W; J Toxicol Clin Toxicol 31:397-405 (1993) R39: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 24 Record 327 of 1119 in HSDB (through 2003/06) AN: 5233 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4,4'-DICHLORODIPHENYL-SULFONE- SY: *BENZENE, 1,1'-SULFONYLBIS(4-CHLORO-; *BIS(P-CHLOROPHENYL) SULFONE; *BIS(4-CHLOROPHENYL) SULFONE; *4-CHLORO-1-(4-CHLOROPHENYLSULFONYL)BENZENE; *4-CHLOROPHENYL-SULFONE-; *P,P'-DICHLORODIPHENYL-SULFONE-; *4,4'-DICHLORODIPHENYL-SULPHONE-; *SULFONE, BIS(P-CHLOROPHENYL) RN: 80-07-9 MF: *C12-H8-CL2-O2-S CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- MW: *287.16 SPEC: +IR: 2:1003 H (Aldrich Library of Infrared Spectra, Aldrich Chemical Co, Milwaukee, WI) [R1, p. V1 424]; +NMR: 10:24A (Aldrich Library of Mass Spectra, Aldrich Chemical Co, Milwaukee, WI) [R1, p. V1 424]; +MASS: 4769 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R1, p. V1 424]; +IR: 18067 (Sadtler Research Laboratories IR Grating Collection) [R1, p. V2 101]; +UV: 1356 (Sadtler Research Laboratories Spectral Collection) [R1, p. V2 101]; +NMR: 9042 (Sadtler Research Laboratories Spectral Collection) [R1, p. V2 101] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the technical report on 4,4'-dichlorodiphenyl sulfone is in the galley/camera ready copy stage of development. Route: dosed-feed; Species: rats and mice. NTP TR No 501. [R2] SO: R1: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985. R2: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 2 Record 328 of 1119 in HSDB (through 2003/06) AN: 5279 UD: 200302 RD: Reviewed by SRP on 5/16/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PHENOTHIAZINE- SY: *AFI-TIAZIN-; *AGRAZINE-; *ANTIVERM-; *BIVERM-; *CONTAVERM-; *DIBENZOPARATHIAZINE-; *DIBENZOTHIAZINE-; *DIBENZO-1,4-THIAZINE-; *EARLY-BIRD-WORMER-; *ENT-38-; *FEENO-; *FENOTHIAZINE- (DUTCH); *FENOVERM-; *FENTIAZIN-; *HELMETINA-; *LETHELMIN-; *NEMAZENE-; *NEMAZINE-; *NEXARBOL-; *ORIMON-; *PADOPHENE-; *PENTHAZINE-; *PHENEGIC-; *PHENOSAN-; *10H-PHENOTHIAZINE-; *PHENOVERM-; *PHENOVIS-; *PHENOXUR-; *PHENTHIAZINE-; *PHENZEEN-; *RECONOX-; *SOUFRAMINE-; *THIODIFENYLAMINE- (DUTCH); *THIODIPHENYLAMINE-; *THIODIPHENYLAMIN- (GERMAN); *TIODIFENILAMINA- (ITALIAN); *VERMITIN-; *WURM-THIONAL-; *XL-50- RN: 92-84-2 MF: *C12-H9-N-S MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...BY FUSING DIPHENYLAMINE WITH SULFUR; IMPROVED YIELDS WITH IODINE AS CATALYST. [R1, 1152] FORM: *DISPERSIBLE POWDERS (36%). [R2, 403] *GRADES: TECHNICAL; NF. [R3] MFS: *Zeneca Inc, Hq, 1800 Concord Pike, Wilmington, DE 19897 (302) 886-3000. Zeneca Specialties, New Murphy Road and Concord Pike, Wilmington, DE 19897 (302) 886-3000. Production site: PO Box 152, 7910 Mt Joy Road, Mount Pleasant, TN 38474 [R4] OMIN: *PURIFICATION: VIERLING, US PATENT 2,887,482 (1959); RIGBY, US PATENT 3,000,887 (1961 TO SHELL OIL). [R1, 1152] */OXIDATION/...CAN BE PREVENTED BY ADMIXTURE OF 0.3-1.0% METHENAMINE. [R1, 1152] *...PARENT OF NUMBER OF DYESTUFFS INCL METHYLENE BLUE, THIAZINE DYES AND THIAMINE BLUE. [R5, 1676] *INTRODUCED IN 1925, IT WAS ONE OF EARLIEST ORG INSECTICIDES. ACTION: ORAL INSECTICIDE AND ANTHELMINTIC. FED IN SALT OR MINERAL SUPPLEMENT TO CONTROL HORN FLY AND FACE FLY LARVAE AND TO REMOVE AND CONTROL CERTAIN INTERNAL PARASITES. [R6] *STOMACH POISON MODERATELY SELECTIVE IN ACTION AND WITH SOME CONTACT INSECTICIDAL PROPERTIES. ...CONCLUDED THAT TOXICITY WAS ASSOC WITH FORMATION OF LEUCOTHIONOL CONJUGATE IN HEMOLYMPH WHICH INHIBITS RESP ENZYMES. OXIDATION PRODUCTS REPORTED TO BE FUNGICIDAL. PHYTOTOXICITY LOW... [R2, 402] *It is used now primarily in continuous low-level feeding programs for ruminants and, because of the development of mixtures with other drugs for a broader spectrum, it remains widely used in horses. [R7, 803] USE: *MFR OF DYES; PARENT CMPD FOR CHLORPROMAZINE AND RELATED ANTIPSYCHOTIC DRUGS; POLYMERIZATION INHIBITOR; ANTIOXIDANT [R3] *Used in control of insects that breed in manure [R7, 1094] *Synthesis of promethazine hydrochloride [R8, p. V13 134] *Polymerization inhibitor for chloroprene [R9] *Antioxidant for epichlorohydrin elastomers [R8, p. V8 577] *Oxidation inhibitor for organic ester lubricating oils [R8, p. V14 497] *Antioxidant for ethylene oxide polymers [R8, p. V18 623] +MEDICATION (VET) +MEDICATION *Antioxidant for THF polymers [R8, p. V18 652] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *YELLOW, RHOMBIC LEAFLETS OR DIAMOND-SHAPED PLATES FROM TOLUENE OR BUTANOL [R1, 1152]; *YELLOW PRISMS FROM ALCOHOL [R10]; *GRAYISH-GREEN TO GREENISH YELLOW POWDER, GRANULES OR FLAKES [R3]; *Grayish-green to greenish-yellow solid. [insecticide] [R11] ODOR: *SLIGHT ODOR [R3] TAST: *TASTELESS [R3] BP: *371 DEG C @ 760 MM HG [R1, 1152] MP: *185.1 DEG C [R1, 1152] MW: *199.28 [R12] DSC: *pKa = 2.52 [R13] OWPC: *log Kow = 4.15 [R14] SOL: *FREELY SOL IN BENZENE; SOL IN ETHER AND IN HOT ACETIC ACID; SLIGHTLY SOL IN ALCOHOL AND IN MINERAL OILS; PRACTICALLY INSOL IN PETROLEUM ETHER, CHLOROFORM [R1, 1152]; *VERY SOL IN ACETONE [R15]; *Water solubilty = 1.59 mg/l at 25 deg C [R16] SPEC: *MAX ABSORPTION (METHANOL): 254 NM (LOG E= 4.5), 285 NM (LOG E= 3.1), 318 NM (LOG E= 3.6) [R17]; *Intense mass spectral peaks: 199 m/z (100%), 167 m/z (55%), 200 m/z (21%), 198 m/z (20%) [R18]; *IR: 2199 (Coblentz Society Spectral Collection) [R19]; *UV: 122 (Sadtler Research Laboratories Spectral Collection) [R19]; *NMR: 9237 (Sadtler Research Laboratories Spectral Collection) [R19]; *MASS: 162 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R19] OCPP: *SUBLIMES @ 130 DEG C @ 1 MM HG [R1, 1157] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *ALTHOUGH PHENOTHIAZINE OXIDIZES FAIRLY EASILY WHEN IT IS EXPOSED TO AIR, RISK OF FIRE IS NOT HIGH. [R5, 1676] TOXC: *...IF INVOLVED IN FIRE, PHENOTHIAZINE PRODUCES HIGHLY TOXIC SULFUR AND NITROGEN OXIDES, WHICH ARE DANGEROUS LUNG IRRITANTS. [R5, 1676] SERI: *Employee, with skin irritation characterized by itching and reddening, developed a tolerance within a 1- to 4-week period following initial exposure. [R20] EQUP: +Wear appropriate personal protective clothing to prevent skin contact. [R21, 249] *Wear butyl rubber gloves, full protective clothing, self-contained breathing apparatus, and protective shoes. [R22] OPRM: *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *MAIN PRECAUTIONS MUST BE DIRECTED @ PREVENTING ACCIDENTAL INGESTION OF MATERIAL DURING MFR AND USE. ... PROCESSES SHOULD BE ENCLOSED AND LOCAL EXHAUST VENTILATION SHOULD BE APPLIED WHERE DUST WOULD OTHERWISE ESCAPE... FIRE PRECAUTIONS SHOULD BE PROVIDED... [R5, 1677] +The worker should immediately wash the skin when it becomes contaminated. [R21, 249] +The worker should wash daily at the end of each work shift. [R21, 249] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R21, 249] +Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. [R21, 249] +Contact lenses should not be worn when working with this chemical. [R21, 249] SSL: *READILY OXIDIZED BY SUNLIGHT OR WHEN IN PRESENCE OF FINELY DIVIDED INERT CARRIER, ACQUIRING GREENISH-BROWN TINT [R23] *SENSITIVE TO AIR AND LIGHT [R24] *DARKENS TO DEEP OLIVE-GREEN ON EXPOSURE TO LIGHT [R2, 402] *It is stable when dry but easily oxidizes when wet. [R7, 803] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: */Protect/ from exposure personnel developing photosensitization. /Protect/ from exposure those individuals with diseases of blood skin, liver, and kidneys. [R22] HTOX: *In human beings, photosensitization of the skin has been noted, but keratitis has been reported only among workers handling the compound, and in this instance the nature of the keratitis has not been described, and it is not clear whether it is due to mechanical irritation by crystals of the substance or from hydrogen sulfide liberated in its manufacture [R25] *OVERDOSAGE (AND ACCIDENTAL EXPOSURES) HAVE CAUSED HEMOLYTIC ANEMIA, TOXIC HEPATITIS, SKIN PHOTOSENSITIZATION, AND INTENSE PRURITUS BUT APPARENTLY NOT CENTRAL NERVOUS DEPRESSION. [R26] *Average or large oral doses of phenothiazine may cause hepatotoxicity, hemolytic anemia, abdominal cramps, and tachycardia. Gastrointestinal and skin irritation, renal damage, skin photosensitization, and pruritus have also been reported. [R20] *PHENOTHIAZINE ITSELF HAS HARMFUL IRRITANT PROPERTIES, AND INDUSTRIAL EXPOSURE MAY PRODUCE SKIN LESIONS AND PHOTOSENSITIZATION INCL PHOTOSENSITIZED KERATITIS. [R5, 1676] *Workers exposed to 15 to 48 mg/cu m of phenothiazine dust during pulverizing and packaging operations developed pinkish-red colored hair, brown fingernails, and skin irritation. Employee, with skin irritation characterized by itching and reddening, developed a tolerance within a 1- to 4-week period following initial exposure. The hair and fingernail colorations are due to a dyeing effect because toenails covered by shoes and hair covered by hats failed to exhibit the discolorations. The color change was said to intensify with increased or prolonged phenothiazine exposure; these discolorations apparently resolve without sequelae after cessation of exposure. [R20] *No systemic toxicities, other than photosensitization, have been reported in phenothiazine workers exposed at concentrations sufficient to produce hair and fingernail discoloration. [R20] *WORKERS EXPOSED TO PHENOTHIAZINE DURING FIELD TESTING IN ORCHARDS FOR CONTROL OF CODDLING MOTHS COMPLAINED OF INTENSE PRURITUS WITH IRRITATION AND REDDENING OF THE SKIN. THESE SYMPTOMS WERE ATTRIBUTED TO DIRECT PERCUTANEOUS ABSORPTION THROUGH THE SKIN, WITH SOME POSSIBLE CONTRIBUTION BY INGESTION OR PULMONARY ABSORPTION AFTER INHALATION OF THE SPRAY. [R20] *Photosensitization with direct sunlight is a result of an oxidation reduction reaction between two metabolites of phenothiazine. The sensitizing dose is less than 0.75 gram, as two individuals given three doses of 0.25 gram each became photosensitive to ultraviolet light. [R20] NTOX: *TOXIC SIGNS SEEN IN HORSE INCL ANOREXIA, DULLNESS, WEAKNESS OF HIND LEGS AND STAGGERING, HEMOLYSIS OF RED BLOOD CELLS LEADING TO ANEMIA, JAUNDICE AND HEMOGLOBINURIA, WEAK RAPID PULSE, DYSPNEA, COLIC AND PROSTRATION. ONE OF ITS MOST IMPORTANT EFFECTS IN HORSE IS TO CAUSE HEMOLYSIS OF RED BLOOD CELLS (VIDE INFRA) and .../INVESTIGATORS/ HAVE ENDEAVORED TO CORRELATE THEIR FINDINGS WITH REGARD TO INHIBITORY EFFECT...ON VARIOUS ENZYME SYSTEMS WITH THIS HEMOLYTIC ACTION. [R27, 99] *DEATH FROM PHENOTHIAZINE POISONING IN PIG IS UNCOMMON. TOXIC SYMPTOMS INCL... MARKED INCOORDINATION WITH EVIDENCE OF OTHER NERVOUS DERANGEMENTS, and , LATER, POSTERIOR PARALYSIS, PROSTRATION AND COMA. CORNEAL OPACITY...SEEN AND MAY CAUSE TEMPORARY BLINDNESS. AFFECTED ANIMALS USUALLY RECOVER WITHIN FEW DAYS... IN CATTLE, PARTICULARLY CALVES, AND IN OTHER RUMINANTS, IT IS MORE USUAL FOR TOXIC EFFECTS TO TAKE FORM OF PHOTOSENSITIZATION KERATITIS. /ALSO/...OBSERVED IN KIDS. ...BLOOD DYSCRASIAS AND CHANGES IN ENDOCRINE ORGANS OBSERVED IN EXPTL POISONED SHEEP AND CATTLE. ...MAY BE CARCINOGENIC IN SHEEP. [R27, 99] *The effects on the eyes of pigs and cattle are particularly well known in New Zealand. The corneal edema or clouding and the interference with vision usually come on in 12 to 36 hours, but clear within a few days or a week. The keratitis has been observed also in sheep and birds, but sheep are said to be less susceptible because in sheep the photosensitizing agent, identified as phenothiazine sulfoxide, is more rapidly converted to an inactive derivative than in the other animals. [R25] *Phenothiazine was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program (NTP). Phenothiazine was tested at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate in as many as 5 Salmonella typhimurium (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9. The highest ineffective dose tested in any S. typhimurium strain was 10.000 mg/plate. Precipitate was present in all cultures above 0.333 mg/plate. [R28] *Phenothiazine toxicity can be avoided in most instances by administering smaller doses of the drug to animals that are heavily parasitized and in poor condition. Not all worms will be eliminated by the smaller dose, but with improved condition of the animal, a larger dose can be given to remove the remaining worms. [R7, 805] */IT IS BELIEVED THAT/...IT IS NOT PHENOTHIAZINE ITSELF, BUT DIPHENYLAMINE, PRESENT AS IMPURITY IN CRUDE PREPN, THAT IS RESPONSIBLE FOR BILIRUBINEMIA AND DELAY IN CLOTTING OBSERVED... CLAIMS THAT PURE DRUG DOES NOT HAVE THESE EFFECTS. [R27, 99] NTXV: *LD50 Rat oral 5000 mg/kg; [R20] ADE: *BECAUSE OF ITS LOW SOLUBILITY, RATE OF ITS ABSORPTION FROM GI TRACT IS DEPENDENT ON PARTICLE SIZE. MICRONIZED FORM OF DRUG IS ABSORBED RAPIDLY. [R5, 1676] *...ABOUT 30-50% OF ORAL DOSE PASSES THROUGH ALIMENTARY TRACT UNCHANGED. SOME PHENOTHIAZINE IS CONVERTED WITHIN GUT TO SOL DERIV...WHICH ARE ABSORBED INTO PORTAL VENOUS SYSTEM. ...DERIV ARE SECRETED IN URINE AND ARE RESPONSIBLE FOR ITS RED COLOR WHEN EXPOSED TO AIR. THEY ALSO APPEAR IN BILE AND IN MILK OF LACTATING ANIMALS. URINARY AND FECAL EXCRETION OF PHENOTHIAZINE OR ITS DERIV ACCOUNTS FOR 80% OF ORAL DOSE IN SHEEP; FATE OF REMAINING 20% IS UNKNOWN. [R27, 198] *URINARY AND FECAL EXCRETION OF PHENOTHIAZINE OR ITS DERIV ACCOUNTS FOR 80% OF ORAL DOSE IN SHEEP; FATE OF REMAINING 20% IS UNKNOWN. [R29] *ABSORBED BY SKIN. [R30] *... Phenothiazine was readily absorbed from the alimentary tract, with the free drug and reddish oxidation products appearing in the urine. [R20] METB: *SOME PHENOTHIAZINE IS CONVERTED WITHIN GUT TO SOL DERIV, MAINLY PHENOTHIAZINE SULFATE... [R29] *YIELDS 3-HYDROXYPHENOTHIAZINE IN DOGS. /FROM TABLE/ [R31] *THE ANTHELMINTIC, PHENOTHIAZINE, WAS OXIDIZED TO SULFOXIDE BY ENZYMES OF THE PROGLOTTIDS OF THE CESTODE, MONIEZIA EXPANSA AND CYTOSOL OF INTESTINAL EPITHELIAL CELLS OF THE NEMATODE ASCARIS SUUM. ENZYMES IN THESE TISSUES ALSO DECR SULFOXIDES TO THIOETHERS IN ABSENCE OF O. [R32] *RAT, MOUSE, AND GERBIL EXCRETED THE MAJORITY OF PHENOTHIAZINE IN CONJUGATED FORM. THE RAT, MOUSE, AND GERBIL PRODUCED LEUCOPHENOTHIAZONE SULFATE AS MAJOR METABOLITE, RELYING MORE ON C-OXIDATION PATHS THAN THE HAMSTER WHICH EXCRETED LARGE AMT OF PHENOTHIAZINE N-GLUCURONIDE. [R33] INTC: *PREVIOUS DRENCHING WITH CARBON TETRACHLORIDE MAY ALSO SERVE TO INCR ITS TOXICITY. [R27, 98] *ANTIOXIDANTS, EG PHENOTHIAZINE, INHIBITED THE MUTAGENICITY OF BENZO(A)PYRENE AND SOME OF ITS DERIVATIVES TOWARDS SALMONELLA TYPHIMURIUM STRAIN TA98; THIS INHIBITION WAS CONCN DEPENDENT. [R34] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3. PROBABLY LIES NEAR BORDERLINE BETWEEN TOXICITY CLASSES 3 and 4. 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT FOR 70 KG PERSON (150 LB). 4= VERY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 50-500 MG/KG BETWEEN 1 TEASPOON AND 1 OZ FOR 70 KG PERSON (150 LB). [R26] THER: +Antibiotics, Macrolide; Antiprotozoal Agents [R35] *AT ONE TIME EMPLOYED IN HUMAN MEDICINE AS ANTHELMINTIC AND URINARY ANTISEPTIC. [R26] +MEDICATION (VET): ...EMPLOYED IN...VET MEDICINE FOR PINWORM, THREADWORM AND ROUNDWORM INFESTATIONS. IT HAS ALSO BEEN USED AS URINARY ANTISEPTIC... [R36] +MEDICATION (VET): IT IS STILL OF VALUE FOR TREATMENT OF HELMINTHIASIS IN SHEEP AND OTHER DOMESTIC ANIMALS. [R37] +ANTHELMINTIC AGENT [R1, 1152] +MEDICATION (VET): INSECTICIDE [R1, 1152] +MEDICATION (VET): Control horn fly and face fly larvae and to remove certain pinternal parasites [R38] +MEDICATION (VET): against intestinal nematodes of ruminants and horses [R8, p. V23 746] WARN: *VET: ...ANIMALS.../HAVE/ DIED AFTER RECEIVING...THERAPEUTIC DOSE, WHEREAS OTHERS HAVE SURVIVED MANY TIMES THIS AMT. ...VARIATION IN TOXICITY...ADEQUACY OR OTHERWISE OF DIET, AND PARTICULARLY ITS PROTEIN CONTENT, IS IMPORTANT FACTOR. DEHYDRATION IS ANOTHER, MORTALITY IN LAMBS BEING HIGHEST UNDER DROUGHT CONDITIONS. SUSCEPTIBILITY TO TOXIC EFFECTS...CONSIDERED...GREATEST IN HORSE, LESS SO IN DOG AND PIG, WHILE RUMINANTS AND BIRDS APPEAR...RESISTANT. ...TOXIC EFFECTS... MORE FREQUENTLY IN CATTLE THAN IN SHEEP AND GOATS. YOUNG AND DEBILITATED ANIMALS...MORE SUSCEPTIBLE... DIGESTIVE DISTURBANCES...PROMOTE ABSORPTION... [R29] *Use of the drug in weak animals, particularly those that are anemic and emaciated, is strictly contraindicated. Animals known to be constipated should not be treated with phenothiazine, since retention of the drug in the digestive tract and resulting absorption of greater than normal quantities is likely to lead to drug poisoning. Use of phenothiazine in pregnancy is contraindicated only during the last month of gestation. [R7, 805] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Phenothiazine's production and use as an insecticide, medication/anthelmintic, polymerization inhibitor, an antioxidant and in the manufacture of promethazine hydrochloride, pharmaceuticals, dyes, chloropromazine and related antipsychotic drugs may result in its release to the environment through various waste streams. Phenothiazine has been detected in the Niagara River, in river sediments near Niagara Falls, and in industrial effluent. If released to soil, phenothiazine will have slight mobility. Volatilization of phenothiazine will not be important from moist or dry soil surfaces. The adsorptivity of phenothiazine is expected to be sensitive to pH since phenothiazine is a base with a pKa of 2.52. According to a MITI biodegradation study, biodegradation of phenothiazine will not be an important fate process in soil or water. If released to water, phenothiazine will adsorb to suspended solids and sediment. Phenothiazine will be essentially non-volatile from water surfaces. Experimental BCF values of 127-660 and 180-528 suggest that phenothiazine will bioconcentrate in aquatic organisms. If released to the atmosphere phenothiazine will exist as both vapor and particulate. Vapor-phase phenothiazine is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals with an estimated half-life of about 2 hours. Particulate-phase phenothiazine may be physically removed from the air by dry deposition. Occupational exposure to phenothiazine can occur through dermal contact and ingestion. (SRC) ARTS: *Phenothiazine's production and use as an insecticide(1,3), medication(3,10), anthelmintic agent(3), polymerization inhibitor(4,5), an antioxidant(4,6-9) and in the manufacture of promethazine hydrochloride(2), pharmaceuticals(3), dyes(4), chloropromazine and related antipsychotic drugs(4) may result in its release to the environment through various waste streams(SRC). [R39] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 4300(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that phenothiazine will have slight mobility in soil(SRC). Volatilization of phenothiazine will not be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 2.8X10-8 atm-cu m/mole(4,SRC), or from dry soil surfaces(SRC) based on an estimated vapor pressure of 8.9X10-7 mm Hg(5,SRC). The adsorptivity of phenothiazine is expected to be sensitive to pH since phenothiazine is a base with a pKa of 2.52(6). According to a MITI biodegradation study(7), biodegradation of phenothiazine will not be an important fate process in soil(SRC). [R40] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 4300(SRC), determined from an experimental log Kow(2) and a recommended regression-derived equation(3), indicates that phenothiazine would adsorb to suspended solids and sediment(SRC). Phenothiazine would be essentially non-volatile from water surfaces based on an estimated Henry's Law constant of 2.8X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4,SRC). Experimental BCF values of 127-660 and 180-528(6) suggest that phenothiazine will bioconcentrate in aquatic organisms(SRC) according to a recommended classification scheme(5). According to a MITI biodegradation study(6), biodegradation of phenothiazine will not be an important fate process in water(SRC). [R41] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), phenothiazine, which has an estimated vapor pressure of 8.9X10-7 mm Hg at 25 deg C(2,SRC) will exist as both vapor and particulate in the ambient atmosphere. Vapor-phase phenothiazine is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 2 hours(3,SRC). Particulate-phase phenothiazine may be physically removed from the air by dry deposition(SRC). [R42] BIOD: *A four-week biodegradation study using 30 mg/l sludge and a phenothiazine concentration of 100 mg/l gave a theoretical BOD of 0%(1). [R43] ABIO: *The rate constant for the vapor-phase reaction of phenothiazine with photochemically produced hydroxyl radicals has been estimated as 1.8X10-10 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 2 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R44] BIOC: *An estimated BCF value of 840 was calculated for phenothiazine(SRC), using an experimental log Kow of 4.15(1) and a recommended regression-derived equation(2). An eight-week bioconcentration study using carp and phenothiazine concentrations of 20 and 2 ug/l gave BCF values of 127-660 and 180-528, respectively(4). According to a classification scheme(3), these BCF values suggest that bioconcentration in aquatic organisms is high(SRC). [R45] KOC: *The Koc of phenothiazine is estimated as approximately 4300(SRC), using an experimental log Kow of 4.15(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that phenothiazine has slight mobility in soil(SRC). The adsorptivity of phenothiazine is expected to be sensitive to pH since phenothiazine is a base with a pKa of 2.52(4). [R46] VWS: *The Henry's Law constant for phenothiazine is estimated as 2.8X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that phenothiazine will be essentially nonvolatile from water surfaces(2,SRC). Phenothiazine's estimated vapor pressure, 8.9X10-7 mm Hg(3,SRC) and Henry's Law constant(1,SRC) indicate that volatilization from dry and moist soil will not occur(SRC). [R47] WATC: *SURFACE WATER: Phenothiazine has been qualitatively identified in the Niagara River(1). [R48] EFFL: *Phenothiazine has been identified in the effluent from the organics and plastics industry (551 ng/ul extract) and the rubber processing industry (29441 ng/ul extract)(1). [R49] SEDS: *Phenothiazine has been identified in Gill Creek, near Niagara Falls, at a maximum sediment concentration of 80 ppm(1). [R50] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 59,591 workers (3,840 of these are female) are potentially exposed to phenothiazine in the USA(1). [R51] *Occupational exposure to phenothiazine can occur through dermal contact and ingestion(1). [R52] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *While petitions for tolerances for negligible residues are pending and until action is completed on the petitions, an interim tolerance of 2 ppm is established for residues of phenothiazine in or on the following raw agricultural commodity(ies): meat, fat, and meat byproducts of cattle. [R53] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 5 mg/cu m, skin. [R21, 248] TLV: +8 hr Time Weighted Avg (TWA): 5 mg/cu m, skin. [R54, 2002.47] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R54, 2002.6] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Phenothiazine is included on this list. [R55] FIFR: *While petitions for tolerances for negligible residues are pending and until action is completed on the petitions, an interim tolerance of 2 ppm is established for residues of phenothiazine in or on the following raw agricultural commodity(ies): meat, fat, and meat byproducts of cattle. [R53] FDA: *Phenothiazine for use only as a polymerization-control agent is an indirect food additive for use as a component of adhesives. [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *IN FEEDS BY SPECTROPHOTOMETRY. [R57, p. 13/710 42.128] *GAS CHROMATOGRAPHIC METHOD PRESENTED. [R57, p. 13/659 38.185] *Method 1625 W and S. Semivolatile Organic Compounds by Isotope Dilution GCMS. Capillary Gas Chromatography with Low Resolution Mass Spectrometry. Minimum level = 20 ug/l (Water). [R58] *PMD-PFI Determination of Phenothiazine by IR Spectrometry. Infrared Spectrometry with no detection limit reported. [R59] *PMD-TLC Thin-layer Chromatographic System for Identification of Pesticides. Thin layer chromatography with no detection limit reported. [R59] CLAB: *HPLC DETERMINATION OF PHENOTHIAZINE RESIDUES IN SHEEP TISSUES. [R60] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R2: Spencer, E.Y. Guide to the Chemicals Used in Crop Protection. 6th ed. Publication 1093, Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1973. R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 895 R4: SRI. 1995 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1995 808 R5: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. R6: Farm Chemicals Handbook 1984. Willoughby, Ohio: Meister Publishing Co., 1984.,p. C-177 R7: Booth, N.H., L.E. McDonald (eds.). Veterinary Pharmacology and Therapeutics. 5th ed. Ames, Iowa: Iowa State University Press, 1982. R8: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R9: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 75 R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 64th ed. Boca Raton, Florida: CRC Press Inc., 1983-84.,p. C-439 R11: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 94-116. Washington, D.C.: U.S. Government Printing Office, June 1994. 248 R12: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 85/8307 R13: Sangster J; LogKow Databank. A Databank of Evaluated Octanol-Water Partition Coefficients on microcomputer diskette. Montreal, Quebec Canada. Sangster Research Labs (1994) R14: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 97 R15: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 75th ed. Boca Raton, Fl: CRC Press Inc., 1994-1995.,p. 3-260 R16: Yalkowsky SH, Dannenfelser RM; Aquasol Database of Aqueous Solubility. Version 5 (1992) R17: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-433 R18: Hites, R.A. Handbook of Mass Spectra of Environmental Contaminants. Boca Raton, FL: CRC Press Inc., 1985. 42 R19: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 74 R20: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1209 R21: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R22: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 407 R23: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1046 R24: Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969. 93 R25: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 721 R26: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-390 R27: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. R28: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R29: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.98 R30: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. 797 R31: Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976.,p. P-9 R32: DOUGH PG C, BUCHANAN LL; XENOBIOTICA 9 (11): 675 (1979) R33: MITCHELL SC; COMP BIOCHEM PHYSIOL C 67C (2): 199 (1980) R34: SULLIVAN ET AL; POLYNUCL AROMAT HYDROCARBONS: CHEM BIOL EFF, INT SYMP, 4TH; 163 (1980) R35: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R36: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values, 4th ed., 1980. Cincinnati, Ohio: American Conference of Governmmental Industrial Hygienists, Inc., 1980.329 R37: Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975. 1178 R38: Farm Chemicals Handbook 1986. Willoughby, Ohio: Meister Publishing Co., 1986.,p. C-182 R39: (1) Booth NH, McDonald LE; Veterinary Pharmacology and Therapeutics. 5th ed. Ames, IA: Iowa State University Press, pg 1094 (1982) (2) Houlihan WJ, Bennett GB; Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: John Wiley and Sons Vol 13: 122-42 (1981) (3) Budavari S; The Merck Index - Encycl Chems, Drugs, and Biologicals. Rahway, NJ: Merck and Co Inc pg 1152 (1989) (4) Lewis RJSr; Hawley's Condensed Chemical Dictionary. 12th ed. NY,NY: Van Nostrand Rheinhold Co pg 895 (1993) (5) Stewart CAJr; Kirk-Othmer Encycl Chem Tech 4th ed. NY,NY: John Wiley and Sons Vol 6: 70-78 (1993) (6) Vandenberg EJ; Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: John Wiley and Sons Vol 8: 568-82 (1979) (7) Booser ER; Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: John Wiley and Sons Vol 14: 477-526 (1981) (8) Braun DB, Delong DJ; Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: John Wiley and Sons Vol 18: 616-32 (1982) (9) Dreyfus P, Dreyfus MP; Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: John Wiley and Sons Vol 18: 645-70 (1982) (10) Petrick DM, Dougherty RD; Kirk-Othmer Encycl Chem Tech 3rd ed. NY,NY: John Wiley and Sons Vol 23: 742-53 (1983) R40: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 97 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (6) Sangster J; LogKow Databank. A Databank of Evaluated Octanol-Water Partition Coefficients on microcomputer diskette. Montreal, Quebec Canada. Sangster Research Labs (1994) (7) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R41: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Profess Ref Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 97 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R42: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R43: (1) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R44: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R45: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 97 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R46: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Professional Reference Book. Heller SR (consult ed) Washington, DC: Amer Chem Soc pg 97 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Sangster J; LogKow Databank. A Databank of Evaluated Octanol-Water Partition Coefficients on microcomputer diskette. Montreal, Quebec Canada. Sangster Research Labs (1994) R47: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton, FL: CRC Press (1985) R48: (1) Great Lakes Water Quality Board; An Inventory of Chemical Substances Identified in the Great Lakes Ecosystem. Volume I - Summary. Report to the Great Lakes Water Quality Board. Windsor, Ontario December 195 pp. (1983) R49: (1) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Decree Survey. Contract No 68-03-2867 Athens, GA USEPA Env Res Lab pg 167 (1982) R50: (1) Elder VA et al; Environ Sci Technol 15: 1237-43 (1981) R51: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R52: (1) Parmeggiani L; Encycl Occup Health and Safety 3rd ed Geneva, Switzerland: International Labour Office pg. 1676 (1983) R53: 40 CFR 180.319 (7/1/94) R54: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R55: 40 CFR 716.120 (7/1/94) R56: 21 CFR 175.105 (4/1/93) R57: Association of Official Analytical Chemists. Official Methods of Analysis. 10th ed. and supplements. Washington, DC: Association of Official Analytical Chemists, 1965. New editions through 13th ed. plus supplements, 1982. R58: USEPA; EMMI Environmental Monitoring Methods Index Version 2.0. EPA-821-B-92-001 (NTIS PB-92-503093) (1995) R59: USEPA; Manual of Chemical Methods for Pesticides and Devices, 2nd ed. USEPA Office of Pesticide Programs Analytical Chemistry Research Branch, Beltsville, MD 20270. AOAC R60: BLACKMAN GL ET AL; J ASSOC OFF ANAL CHEM 63 (5): 988 (1980) RS: 36 Record 329 of 1119 in HSDB (through 2003/06) AN: 5345 UD: 200302 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: N,N'-DIPHENYLGUANIDINE- SY: *ACCELERATOR-D-; *DENAX-; *DFG-; *SYM-DIPHENYLGUANIDINE-; *1,3-DIPHENYLGUANIDINE-; *DPG-; *GUANIDINE,-N,N'-DIPHENYL-; *GUANIDINE,-1,3-DIPHENYL-; *MELANILINE-; *NCI-C60924-; *USAF-EK-1270-; *VULCAFOR-DPG-; *VULKACIT-D-; *VULKACITE-D-; *VULKAZIT- RN: 102-06-7 MF: *C13-H13-N3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *NAUNTON J, SOC CHEM IND (LONDON) 45: 376T (1926); MACHOLDT-ERDNISS, BER 91: 1992 (1958); FERRIS, SCHUTZ, J ORG CHEM 28: 71 (1963). [R1] *TREATMENT OF ANILINE WITH CYANOGEN CHLORIDE. [R2] *REACTION OF CYANOGEN CHLORIDE WITH AN AQUEOUS SOLN OF ANILINE FOLLOWED BY NEUTRALIZATION WITH SODIUM HYDROXIDE; REACTION OF N,N-DIPHENYLTHIOUREA WITH AMMONIUM HYDROXIDE IN THE PRESENCE OF A CATALYST, EG, POTASSIUM HYDROXIDE AND LEAD OXIDE [R3] MFS: *AMERICAN CYANAMID CO, CHEM PRODUCTS DIV, LINDEN, NJ 07037 [R3] OMIN: *THE CONCN OF DIPHENYLGUANIDINE EXTRACTED WITH WATER FROM THIOKOL SEALANTS WERE LOWER THAN THE MAX PERMISSIBLE ONES FOR WARM-BLOODED ANIMALS WHEN THE SEALANT SURFACE/WATER VOLUME RATIO WAS 1/2000. [R4] *PROMOTED LETTUCE SEED GERMINATION. [R5] USE: *PRIMARY MATERIAL FOR STANDARDIZING ACIDS; FREE BASE AND PHTHALATE AS ACCELERATORS FOR VULCANIZATION OF RUBBER [R1] *VULCANIZATION ACCELERATOR FOR NATURAL AND SYNTHETIC RUBBERS [R3] *ACTIVATOR FOR OTHER RUBBER ACCELERATORS [R3] *PRIMARY STANDARD FOR ACIDS [R3] PRIE: U.S. PRODUCTION: *(1979) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R3] *(1981) PROBABLY GREATER THAN 4.54X10+5 GRAMS [R3] U.S. IMPORTS: *(1979) 1.76X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R3] *(1981) 8.88X10+8 GRAMS (PRINCPL CUSTMS DISTS) [R3] U.S. EXPORTS: *(1979) ND [R3] *(1981) ND [R3] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MONOCLINIC NEEDLES [R6]; *WHITE POWDER [R2] ODOR: *SLIGHT ODOR [R2] TAST: *BITTER TASTE [R2] BP: *170 DEG C [R6] MP: *150 DEG C [R1] MW: *211.29 DEN: *1.13 DEG C/4 DEG C [R6] PH: *AQ SOLN IS STRONGLY ALKALINE [R1] SOL: *SPARINGLY SOL IN WATER; SOL IN ALC, CHLOROFORM, HOT BENZENE, HOT TOLUENE; READILY SOL IN DIL MINERAL ACIDS [R1] SPEC: *MAXIMUM ABSORPTION (ALCOHOL): 251 NM (LOG E= 4.4), 286 NM SHOULDER (LOG E= 1.1) [R6]; +IR: 8143 (Sadtler Research Laboratories IR Grating Collection) [R7]; +UV: 396 (Sadtler Research Laboratories Spectral Collection) [R7]; +NMR: 97 (Sadtler Research Laboratories Spectral Collection) [R7] OCPP: *DECOMP ABOVE 170 DEG C [R2] *MORE SOLUBLE IN CRUDE SWEAT THAN IN WATER [R8] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *RUBBER ADDITIVES SUCH AS DIPHENYLQUANIDINE MAY CAUSE DERMATITIS IN STRETCH GARMENTS. [R9] *OCCUPATIONAL ALLERGIC DERMATOSIS WAS OBSERVED IN RUBBER WORKERS AND WAS CAUSED BY RUBBER ADDITIVES SUCH AS DIPHENYLGUANIDINE. [R10] *STEROID METABOLISM WAS REDUCED IN PATIENTS WITH SECONDARY AMENORRHEA. PATHOGENETIC ROUTES OF THESE DISORDERS IN WORKERS CONTACTING CHEM ARE DIVERSE. [R11] *IRRITANT. [R1] NTOX: *TOXIC EFFECTS INCL INCR LEVELS OF TRIGLYCERIDES AND CHOLESTEROL ESTERS IN LIVER AND FREE FATTY ACIDS IN BLOOD PLASMA AND DECR OF SAME IN THE PLASMA. [R12] *WHEN FED TO ADULT RATS AS 1% EMULSION WITH AQ-STARCH SUSPENSION OR TO 2-WK-OLD RATS AS SUPPLEMENT IN MILK AND SUNFLOWER OIL, PRODUCED RAPIDLY UNSTEADY WALK, FLABBINESS, SPASMODIC JERKING OF LIMBS, TENSING OF BODY MUSCLES. DEATH OCCURRED ON 1ST OR 2ND DAY. [R13] *PREGNANT MICE OF ICR-JCL STRAIN WERE GIVEN ORAL DOSES IN 0.5% CARBOXYMETHYL CELLULOSE SUSPENSION IN DOSES OF 0.25, 1.0, OR 4.0 MG/KG OF BODY WT/DAY THROUGHOUT PREGNANCY. NO DETRIMENTAL EFFECTS ON DEVELOPMENT OF FETUSES IN DOSES OF 4 MG/KG OR LESS. [R14] *PREGNANT MICE OF ICR-JCL STRAIN WERE GIVEN ORAL DOSES IN 0.5% CARBOXYMETHYL CELLULOSE SUSPENSION IN DOSE OF 10.0 MG/KG OF BODY WT/DAY THROUGHOUT PREGNANCY. DISTURBANCES IN IMPLANTATION WERE SEEN IN THE MOTHERS. [R14] +1,3-Diphenylguanidine was found to be positive when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 1,3-Diphenylquanidine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at does of 0.001, 0.003, 0.010, 0.033, 0.100, 0.333, 1.000, 3.333, 6.666, and 10.000 mg/plate. The lowest positive dose tested was 0.001 mg/plate in strain TA100 with 10% hamster liver S-9. The doubling dose was 0.033 mg/plate also in strain TA100 with hamster liver activation. [R15] ADE: *A CHRONIC EXPERIMENT WITH RABBITS ESTABLISHED THAT DIPHENYLGUANIDINE AFTER ENTERING THE BLOOD IS SORBED BY ALL BODY TISSUES WITH ITS PREDOMINANT LOCATION IN THE KIDNEYS AND LIVER. [R16] INTC: *A MATHEMATICAL DESIGN TO STUDY COMBINED TOXIC EFFECTS OF RUBBER INGREDIENTS THIRAM AND DIPHENYLGUANIDINE DERIVATIVE REVEALED ONLY MILD TOXICITY. [R17] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *A THIN LAYER CHROMATOGRAPHIC METHOD WAS DEVELOPED FOR DETERMINING DIPHENYLGUANIDINE IN URINE, BLOOD AND TISSUES OF INTERNAL ORGANS OF HUMANS AND ANIMALS. [R16] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Report on Toxicity Studies of 1.3-Diphenylguanidine Administered in Feed to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 42 NIH Publication No. 95-3993 (1995) SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 444 R2: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 317 R3: SRI R4: KOROLEV AA ET AL; GIG PRIMEN POLIM MATER STROIT MATER VSES SOVESHCH 1ST: 168 (1973) R5: KEFFORD NP ET AL; ENHANCEMENT OF LETTUCE SEED GERMINATION BY SOME UREA DERIVATIVES; PLANTA 67(1) 103 (1965) R6: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-323 R7: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 675 R8: ITO M ET AL; ATCH IKA DAIGAKU IGAKKAI ZASSHI 7(3) 183 (1979) R9: BAUER M; THE ENVIRONMENT AND THE WOMAN; WOMAN PHYSICIAN 27(1) 16 (1972) R10: SOMOV BA ET AL; PROPHYLAXIS OF OCCUPATIONAL DERMATOSIS OF WORKERS IN THE RUBBER INDUSTRY; VESTN DERMATOL VENEROL 5: 68 (1976) R11: TITOVA EY; PATHOGENESIS OF SECONDARY AMENORRHEA IN INDUSTRIAL RUBBER PRODUCTS PLANT WORKERS; GIG TR SOSTOYANIE SPETSIFICHESKIKH FUNKTS RAB NEFTEKHIM KHIM PROM-STI 67 (1974) R12: PITSIN DG ET AL; EFFECT OF DIPHENYLGUANIDINE ON LIPID FRACTION LEVEL IN LIVER AND PLASMA OF RATS DURING ACUTE AND SUBACUTE POISONING; FARMAKOL TOKSIKOL (MOSCOW) 35(3) 360 (1972) R13: VLASYUK MG; GIG PRIMEN TOKSIKOL PESTITS KLIN OTRAVL 9: 363 (1971) R14: YASUDA Y ET AL; J ENVIRON PATH TOXICOL 4: 451 (1980) R15: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R16: KAZARINOVA NF ET AL; GIG SANIT 4: 63 (1975) R17: SHCHUMSKAYA NI ET AL; KAUCH REZINA 12: 41 (1981) RS: 7 Record 330 of 1119 in HSDB (through 2003/06) AN: 5408 UD: 200211 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2,4,7-TRINITRO-9H-FLUOREN-9-ONE- SY: *FLUOREN-9-ONE,-2,4,7-TRINITRO-; *9H-FLUOREN-9-ONE,-2,4,7-TRINITRO-; *TNF-; *2,4,7-TRINITROFLUORENONE-; *2,4,7-TRINITROFLUOREN-9-ONE- RN: 129-79-3 MF: *C13-H5-N3-O7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *...FROM NITRATION OF FLUORENONE: SCHMIDT, BAUER, BER 38, 3758 (1905); ORCHIN ET AL, J AM CHEM SOC 69, 1225 (1947); BY NITRATION OF 2,5-DINITROFLUORENONE: RAY, FRANCIS, J ORG CHEM 8, 58 (1943). [R1] USE: *FORMS CHARGE-TRANSFER COMPLEXES WITH AROMATIC HYDROCARBONS AND AMINES [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE YELLOW NEEDLES FROM ACETIC ACID OR BENZENE [R2] MP: *175.2-176 DEG C [R1] MW: *315.19 [R1] SOL: *SLIGHTLY SOL IN WATER; VERY SOL IN ACETONE, BENZENE, CHLOROFORM [R2] SPEC: +MAX ABSORPTION (ACETIC ACID): 350 NM (LOG E= 3.9) SHOULDER; 380 NM (LOG E= 3.5) SHOULDER [R2]; +IR: 3518 (Sadtler Research Laboratories Prism Collection) [R3]; +UV: 1093 (Sadtler Research Laboratories Spectral Collection) [R3]; +MASS: 2394 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R3] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *2,4,7-TRINITRO-9-FLUORENONE INDUCED BOTH FRAMESHIFT MUTATIONS AND BASE-PAIR SUBSTITUTIONS IN SALMONELLA TYPHIMURIUM STRAINS TA100, TA98, TA1537 AND TA1538. COMPARISONS OF MUTAGENIC POTENCY SUGGEST IMPORTANCE OF CARBONYL GROUP SUBSTITUTED AT THE CARBON-9 POSITION OF MUTAGENIC DERIV. [R4] *NITRATED DERIVATIVES OF FLUORENE ARE POTENT FRAMESHIFT-TYPE MUTAGENS. REDN OF NITRO FUNCTION IS REQUIRED FOR EXPRESSION OF MUTAGENICITY. HYDROXYLAMINES ARE PRESUMED KEY INTERMEDIATES, WHICH FOLLOWING ESTERIFICATION TO ELECTROPHILS ARE CAPABLE OF FORMING ADDUCTS WITH CELLULAR DNA. [R5] *2,4,7-TRINITRO-9H-FLUOREN-9-ONE IS MUTAGENIC IN SALMONELLA TYPHIMURIUM/MICROSOMAL ASSAY WITH AND WITHOUT S9 METABOLISM. IT IS PRIMARILY A FRAMESHIFT MUTAGEN. IT IS ALSO MUTAGENIC IN MOUSE LYMPHOMA ASSAY AND CHINESE HAMSTER OVARY CELLS. [R6] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *HPLC DETERMINATION OF 2,4,7-TRINITRO-9-FLUORENONE IN AIR. [R7] *2,4,7-TRINITRO-9-FLUORENONE WAS DETERMINED IN WORKPLACE ENVIRONMENTAL SAMPLES BY HPLC. [R8] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Technical Rpt on Toxicity Studies of Trinitrofluorenone Admin by Dermal Application and Dosed Feed to F344/N Rats and B6C3F1 Mice NTP Tox 13 (1992) SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1248 R2: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-308 R3: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 640 R4: LEVIN DE ET AL; MUTAT RES 63(1) 1 (1979) R5: MCCOY EC ET AL; MUTAT RES 90(1) 11 (1981) R6: BURRELL AD ET AL; MUTAGEN 3(3) 360 (1981) R7: BAGON DA, PURNELL CJ; DETERMINATION OF 2,4,7-TRINITRO-9-FLUORENONE (TNF) IN AIR BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY; J HIGH RESOLUT CHROMATOGR CHROMATOGR COMMUN 4(11) 586 (1981) R8: SEYMOUR MJ; DETERMINATION OF 2,4,7-TRINITRO-9-FLUORENONE IN WORKPLACE ENVIRONMENTAL SAMPLES USING HIGH PERFORMANCE LIQUID CHROMATOGR 236(2) 530 (1982) RS: 4 Record 331 of 1119 in HSDB (through 2003/06) AN: 5410 UD: 200303 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,3-DIPHENYL-1-TRIAZENE- SY: *ANILINE, N-(PHENYLAZO)-; *ANILINOAZOBENZENE-; *BENZENEAZOANILIDE-; *BENZENEAZOANILINE-; *CELLOFOR- (CZECH); *DAAB-; *DIAZOAMINOBENZEN- (CZECH); *DIAZOAMINOBENZENE-; *P-DIAZOAMINOBENZENE-; *DIAZOAMINOBENZOL- (GERMAN); *DIAZOBENZENEANILIDE-; *1,3-DIPHENYLTRIAZENE-; *1-TRIAZENE,-1,3-DIPHENYL-; *TRIAZENE,-1,3-DIPHENYL- RN: 136-35-6 MF: *C12-H11-N3 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY DIAZOTIZING ANILINE DISSOLVED IN HYDROCHLORIC ACID WITH SODIUM NITRITE AND THEN ADDING A CONCENTRATED SOLUTION OF SODIUM ACETATE: HARTMAN, DICKEY, ORG SYN COLL VOL II 163 (1943). [R1] *INTERACTION OF NITROUS ACID AND AN ALCOHOLIC SOLUTION OF ANILINE. [R2] OMIN: *1,3-DIPHENYL-1-TRIAZENE WAS THE MOST ACTIVE OF TWELVE 1,3-DIARYLTRIAZENES TESTED POSTEMERGENCE AT 6 KG/HA AGAINST AMARANTHUS RETROFLEXUS, ARTEMISIA VULGARIS AND OTHER COMMON WEEDS. [R3] USE: *ORGANIC SYNTHESIS; DYES; INSECTICIDE [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *GOLDEN-YELLOW, SMALL CRYSTALS [R1] MP: *98 DEG C [R1] MW: *197.11 SOL: *INSOLUBLE IN WATER; FREELY SOLUBLE IN BENZENE, ETHER, HOT ALCOHOL [R1] SPEC: +IR: 20997 (Sadtler Research Laboratories Prism Collection) [R4]; +UV: 3-342 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EXPL: *EXPLODES WHEN HEATED TO 150 DEG C. [R1] *A MIXTURE /OF 1,3-DIPHENYLTRIAZENE AND ACETIC ANHYDRIDE/ EXPLODED WITH EXTRAORDINARY VIOLENCE ON WARMING. [R5] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on diazoaminobenzene is scheduled for peer review. Route: topical; Species: rats and mice. [R6] SO: R1: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 394 R2: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 269 R3: MAZZA M, PAGANI G; PHYTOTOXIC ACTIVITY OF TRIAZENE DERIVATIVES. V. 1,3-DIARYLTRIAZENE DERIVATIVES; FARMACO, ED SCI 39(6) 482 (1974) R4: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 544 R5: Bretherick, L. Handbook of Reactive Chemical Hazards. 2nd ed. Boston MA: Butterworths, 1979. 710 R6: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 3 Record 332 of 1119 in HSDB (through 2003/06) AN: 5449 UD: 200211 RD: Reviewed by SRP on 12/01/1989 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: VINYLSTYRENE- SY: *BENZENE,-DIETHENYL-; *BENZENE,-DIVINYL-; *DIETHENYLBENZENE-; *DIVINYLBENZENE-; *DVB-; *DVB-22-; *DVB-27-; *DVB-55-; *DVB-80-; *DVB-100- RN: 1321-74-0 MF: *C10-H10 ASCH: o-Divinylbenzene; 91-14-5; m-Divinylbenzene; 108-57-6; p-Divinylbenzene; 105-06-6 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Diethylbenzene is recovered as a splitstream from an ethylbenzene alkylation unit. This splitstream contains o-, m- and p-diethylbenzene isomers in relative concn of 1:6:3. After removal of other impurities, eg, propyl- and butylbenzenes, the isomer mixture is used as a feedstock for divinylbenzene manufacture. Dehydrogenation of diethylbenzene is carried out in a manner analogous to ethylbenzene dehydrogenation. Temperatures ... greater than 600 deg C and superheated dilution steam are used over typical iron oxide dehydrogenation catalysts. Under these conditions, a mixture of light by-products, ie, benzene, toluene, xylenes, ethylbenzene, styrene, diethylbenzene, vinyltoluene, and ethyltoluene are produced. o-Diethylbenzene is converted to naphthalene which must be removed. Unreacted diethylbenzene and partially converted ethylvinylbenzene are recycled to the dehydrogenation reactor. The product is recovered as a mixture of divinylbenzene and ethylvinylbenzene. [R1, p. 21(83) 796] *Product finishing occurs in a series of 3 columns. Light by-products are removed overhead in the 1st column with recycleable ethylvinylbenzene and unreacted diethylbenzene. The lights are taken overhead in the 2nd column and they are separated from the recycleables. Product DVB mixtures are taken as an overhead product in the 3rd column, and napthalene and tar are rejected as a bottoms product. The high reactivity of the unsaturated components requires very low operating pressures and temperatures as well as the use of in-process polymerization inhibitors. The final product is inhibited with TBC and sulfur. [R1, p. 21(83) 798] IMP: *THE COMMERCIAL FORM /OF VINYLSTYRENE/ CONTAINS THE 3 ISOMERIC FORMS TOGETHER WITH ETHYLVINYLBENZENE AND DIETHYLBENZENE. [R2, 436] FORM: *The commercial grade of divinylbenzene ... contains all three isomeric forms, but the meta isomer predominates. [R3] *USUALLY, INHIBITORS ARE ADDED TO DIVINYLBENZENE TO PREVENT THE AUTOPOLYMERIZATION, WHICH OCCURS READILY AT ELEVATED TEMP FOR THE META AND PARA ISOMERS. [R4, 3323] *Typical chemical analysis of divinylbenzene: polymer, 100 ppm; aldehydes as CHO, 40 ppm; peroxides as hydrogen peroxide, 5 ppm; sulfur as S, 20 ppm; TBC, 1000 ppm; total unsaturation (as ethylvinylbenzene), 83.3 wt%; m-divinylbenzene, 17.1 wt%; p-divinylbenzene, 8.2 wt%; total divinylbenzene, 25.3 wt%; m-ethylvinylbenzene, 23.1 wt%; p-ethylvinylbenzene, 10 wt%. [R1, p. 21(83) 799] *Typical chemical analysis of divinylbenzene: polymer, 100 ppm; aldehydes as CHO, 40 ppm; peroxides as hydrogen peroxide, 5 ppm; sulfur as S, 230 ppm; TBC, 1000 ppm; total unsaturation (as ethylvinylbenzene), 149.4 wt%; m-divinylbenzene, 36.4 wt%; p-divinylbenzene, 18.6 wt%; total divinylbenzene, 55.0 wt%; m-ethylvinylbenzene, 25 wt%; p-ethylvinylbenzene, 13 wt%. [R1, p. 21(83) 799] *Typical chemical analysis of divinylbenzene: sulfur as S, 240 ppm; TBC, 1200- 1500 pm; total unsaturation (as ethylvinylbenzene), 177.3 wt%; m-divinylbenzene, 60.3 wt%; p-divinylbenzene, 21.6 wt%; total divinylbenzene, 81.9 wt%; m-ethylvinylbenzene, 6.7 wt%; p-ethylvinylbenzene, 6.8 wt%. [R1, p. 21(83) 799] *DICHLOROVOS EMULSION CONCN ARE DESCRIBED WHICH CONTAIN STYRENE OR STILBENE DERIVATIVES AS STABILIZERS. THE FORMULATION CONSISTS OF DICHLOROVOS 40 STYRENE 18 VINYLSTYRENE (MIXTURE OF M- AND P-DIVINYLBENZENE) 10 4,4'-DIMETHOXYSTILBENE 2 AND POLYETHYLENE GLYCOL MONOOLEATE 30%. [R5] MFS: +DOW Chemical USA, Hq, 2020 Dow Ctr, Midland, MI 48674, (517) 636-1000; Production site: Main St, Midland, MI 48667 [R6] OMIN: *A SLOW-RELEASE INSECTICIDAL FUMIGATION DEVICE IS OBTAINED BY IMPREGNATING PLATES MADE OF HIGH-DENSITY POROUS MATERIAL WITH DICHLOROVOS. A 360 G POROUS ALUMINA PLATE IS IMPREGNATED WITH A MIXTURE OF DICHLOROVOS 20, DIETHYL PHTHALATE 18, 4-METHOXYSYTRENE 0.4 AND VINYLSTYRENE (MIXTURE OF M- AND P-DIVINYLBENZENE) 1.6 G. [R7] *Divinylbenzene is a specialty monomer which is of unique value because of its bifunctionality. The presence of 2 reactive vinyl groups accounts for its strong propensity for cross-linking with itself and other monomers. ... Its real commercial value is that in a copolymer with styrene. Small quantities of DVB markedly modify linear styrene polymers. The cross-linking results in resins with reduced solubility in most solvents, increased heat-distortion temperatures, increased surface hardness, and improved impact and tensil strengths. Since the amount of DVB included in the copolymer is small, the appearance and optical and electrical properties are much like those of styrene homopolymer. [R1, p. 21(83) 796] *Dow is the largest producer of DVB mixtures and has established the standard commercial grades; however, new producers have sought to match those grades. In addn to DVB-55, American Hoechst offers DVB-27 AND DVB-80. The -27 and -80 designates the approximate content of divinylbenzene. [R1, p. 21(83) 797] USE: *POLYMERIZATION MONOMER FOR SPECIAL SYNTHETIC RUBBERS, DRYING OILS, ION-EXCHANGE RESINS, CASTING RESINS, POLYESTERS [R2, 437] *MONOMER FOR STYRENE-VINYLSTYRENE ION-EXCHANGE RESINS [R8] *MONOMER AND CROSSLINKING AGENT FOR ACRYLIC POLYMERS [R8] *MONOMER FOR CHOLESTYRAMINE RESIN (CARDIOVASCULAR AGENT) [R8] *Its uses as a monomer or polymer are extensive. The monomer is utilized as an insecticide stabilizer, as an ion exchange resin, as a cross-linking agent in water purification and decolonization, as a sustained release agent, and as a dental filling component, applications for which patents are avail. In biology, it has been applied as an experimental clotting agent for sustained life research. [R4, 3323] *Used in the manufacture of soft contact lenses. [R1, p. 6(79) 731] *Used in the manufacture of cholestyramine resin which is used as a drug to increase lipoprotein catabolism [R1, p. 4(78) 913] *The world market for DVB as 100 wt% DVB was 3000-4000 metric tons in 1981. By far the largest use was as a copolymer with styrene in ion-exhange resins. These resins are used primarily in home water softeners as well as for municipal and industrial water conditioning. [R1, p. 21(83) 798] *Tetrafilcon A, which is used in making the Aquaflex and Aosoft contact lenses has, in addn to its main ingredients 2-hydroxyethyl methacrylate (about 82%) and vinylpyrrolidinone (about 15%), small amounts of methyl methacrylate (about 2%), and divinylbenzene (about 0.5%) as the cross-linking agent. [R1, p. 6(79) 731] *The bile sequestering quaternary ammonium salt anion-exchange resin, cholestyramine is a high mol wt ... copolymer of styrene, which bears a quaternary ammonium moiety, with 2% of divinylbenzene. [R1, p. 4(78) 913] PRIE: U.S. PRODUCTION: *(1979) PROBABLY GREATER THAN 4.54X10+6 G [R8] *(1981) PROBABLY GREATER THAN 4.54X10+6 G [R8] *Production of these resins /ion-exchange resins containing DVB/ is estimated to increase 5-10% per year. Other markets show little growth, although research at the University of Akron indicates future increased use of thermoplastic elastomers containing DVB as the heart of a radial or star-configuration block copolymer. [R1, p. 21(83) 799] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: +Pale, straw-colored liquid. [R9, 124] MW: *130.19 [R10] OWPC: *Log Kow= 3.59 (estimated). [R11] SOL: *Water sol of 50 ppm. [R12] VAP: *6.58x10-1 mm Hg. [R13] OCPP: *BP: 76 deg C at 14 mm Hg; Density, 0.9325 at 22 deg C/4 deg C; Index of refraction, 1.5767 at 20 deg C; sol in acetone, benzene. /o-Divinylbenzene/ [R10] *BP: 121 deg C at 76 mm Hg; MP: -52.3 deg C; Density, 0.9294 at 20 deg C/4 deg C; Index of refraction, 1.5760 at 20 deg C; sol in acetone, benzene. /m-Divinylbenzene/ [R10] *BP: 95-6 deg C at 18 mm Hg; MP: 31 deg C; Density, 0.913 at 40 deg C; Index of refraction, 1.5835 at 25 deg C; sol in acetone, benzene. /p-Divinylbenzene/ [R10] *WATER-WHITE LIQ; EASILY POLYMERIZED; VISCOSITY, 109 CP AT 20 DEG C. /PURE M-DIVINYLBENZENE/ [R2, 436] *VAPOR DENSITY (AIR= 1), 4.48; VAPOR PRESSURE, 1 MM HG AT 32.7 DEG C; CONVERSION FACTOR, 5.3 MG/CU M IS EQUIV TO 1 PPM. /M-DIVINYLBENZENE/ [R4, 3257] *MW, 130.08; Index of refraction, 1.5326 at 25 deg C/D; Viscosity, 0.883 cp at 25 deg C; surface tension, 30.55 dynes/cm at 25 deg C; Density, 0.8979 g/cu cm at 20 deg C; BP, 180 deg C (calculated); Critical pressure, 2.45 MPa and critical temperature, 348 deg C (each calculated); Latent heat of vaporization, 320.49 J/g at boiling point; Solubility, 0.0065% in water at 25 deg C; Soluble in acetone, carbon tetrachloride, benzene, ethanol. [R1, p. 21(83) 798] *MW, 130.18; Index of refraction, 1.5585 at 25 deg C/D; Viscosity, 1.007 cp at 25 deg C; surface tension, 32.10 dynes/cm at 25 deg C; Density, 0.9162 g/cu cm at 20 deg C; BP, 195 deg C (calculated); Freezing point, -45 deg C; Critical pressure, 2.45 MPa and critical temperature, 369 deg C (each calculated); Latent heat of vaporization, 350.62 J/g at boiling point; Solubility, 0.0052% in water at 25 deg C; Soluble in acetone, carbon tetrachloride, benzene, ethanol. [R1, p. 21(83) 798] *PALE STRAW COLORED LIQ /DIVINYLBENZENE 55%/ [R2, 436] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of vinylstyrene stem from its toxicologic properties and flammability. Toxic primarily via inhalation and skin contact, exposure to this pale straw-colored liquid may occur from its use as a copolymer with styrene in ion-exchange resins, and as a monomer and crosslinking agent in the manufacture of special synthetic rubbers, drying oils, casting resins, and polyesters. Effects from exposure may include skin, eye, and respiratory tract irritation. OSHA has extablished a time weighted average (TWA) limit of 10 ppm as a final rule to become effective December 31, 1992. Engineering controls should be used to maintain airborne levels of vinylstyrene at or below the permissible limit. In activities and situations where over-exposure may occur, wear chemical protective clothing and a self-contained breathing apparatus. Vinylstyrene will ignite if moderately heated, and may polymerize in the heat of a fire. For fires involving vinylstyrene, extinguish with dry chemical, CO2, foam, water spray or fog. Fight such fires from a safe distance or protected location. Vinylstyrene should be stored in cool, dry, well-ventilated locations, away from sources of ignition and physical damage. Build dikes to prevent any spilled vinylstyrene from entering water sources and sewers. Before implementing land disposal of vinylstyrene waste, consul t with environmental regulatory agencies for guidance. NFPA: +Health: 1. 1= Materials that, on exposure, would cause irritation, but only minor residual injury, including those requiring the use of an approved air-purifying respirator. These materials are only slightly hazardous to health and only breathing protection is needed. [R14] +Flammability: 2. 2= Liquids which must be moderately heated before ignition will occur and solids that readily give off flammable vapors. Water spray may be used to extinguish the fire because the material can be cooled to below its flash point. [R14] +Reactivity: 2. 2= Materials which in themselves are normally unstable and readily undergo violent chemical change but do not detonate. ... Also ... materials which may react violently with water or ... may form potentially explosive mixtures with water. [R14] FLMT: +0.7% (lower); 6.2% (upper) [R14] FLPT: +169 deg F (76 deg C) (open cup) [R14] *57 deg C (Cleveland open-cup) /DVB-22/ [R1, p. 21(83) 798] *74 deg C (Cleveland open-cup) /DVB-55/ [R1, p. 21(83) 798] FIRP: *If material on fire or involved in fire, use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Use foam, dry chemical, or carbon dioxide. /Divinyl benzene (combustible liquid, flammable liquid not otherwise specified)/ [R15] EXPL: *Lower, 1.1%; Upper, 6.2% in air. /DVB-22/ [R1, p. 21(83) 798] *Explosive limit in air is equal to or greater than 1.1% (could not be measured at 130 deg C). /DVB-55/ [R1, p. 21(83) 798] POLY: *... Autopolymerization ... occurs readily at elevated temperatures for the meta and the para isomers. /m- and p-Divinylbenzene/ [R4, 3323] ODRT: *As with other styrene monomers, the odor can be detected by humans at levels below dangerous concn, ie, 10-60 ppm. [R1, p. 21(83) 799] SERI: *Above 100 ppm, eye and nasal irritation may occur. [R1, p. 21(83) 799] *Skin ... /irritant/. [R16] *DIVINYLBENZENE IS MODERATELY IRRITANT TO THE EYES AND RESPIRATORY SYSTEM, AND TO A LESSER DEGREE TO THE SKIN. [R4, 3323] EQUP: *Wear appropriate chemical protective gloves, boots and goggles. /Divinyl benzene (flammable liquid, combustible liquid, not otherwise specified)/ [R15] +Wear appropriate personal protective clothing to prevent skin contact. [R9, 124] +Wear appropriate eye protection to prevent eye contact. [R9, 124] +Eyewash fountains should be provided in areas where there is any possibility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. [R9, 124] +Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] [R9, 124] OPRM: *Eyes and skin should be protected, and respiratory equipment should be used above the irritant level. [R4, 3323] *If material not on fire and not involved in fire, keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. Avoid bodily contact with the material. /Divinyl benzene (combustible liquid, flammable liquid, not otherwise specified)/ [R15] *If material not on fire and not involved in fire ... build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. /Divinyl benzene (combustible liquid, flammable liquid, not otherwise specified)/ [R15] +Contact lenses should not be worn when working with this chemical. [R9, 125] +The worker should immediately wash the skin when it becomes contaminated. [R9, 124] +Work clothing that becomes wet or significantly contaminated should be removed and replaced. [R9, 124] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. STRG: *IF UNINHIBITED, STORE AT BELOW 90 DEG F. [R2, 437] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Incineration in a furnace equipped with after-burner and scrubber. [R16] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *MILD IRRITATION HAS BEEN OBSERVED IN WORKERS ACUTELY EXPOSED BY INHALATION, AS WELL AS FROM SKIN AND EYE CONTACT. [R3] *... THE TOXICITY OF DIVINYLBENZENE APPEARS TO RESEMBLE THAT OF STYRENE. [R4, 3323] NTOX: *... SKIN BURNS MAY RESULT /IN RATS/ FROM REPEATED OR PROLONGED CONTACT WITH THE LIQ. AN ACUTE INHALATION STUDY WITH RATS SHOWED NO EFFECTS FROM SINGLE 7-HR EXPOSURE AT 351 PPM. [R3] *Divinylbenzene admin orally to rats at 2.5 ml/animal in a 1:1 ratio in olive oil produced 5 deaths in 10 rats. /From table/ [R4, 3321] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Vinylstyrene is produced as a mixture of isomers which is primarily used for its reduced solubility, increased heat distortion temperatures, added surface hardness and improved impact and tensile strengths, in the formulation of polymers with styrenes. Hence vinylstyrene may be released to the environment via manufacturing effluents and at sites where vinylstyrene is used. Sufficient data are not available to predict the importance of biodegradation and chemical degradation of vinylstyrene in the environment. A calculated Koc indicates a low to slight mobility class for vinylstyrene in soils. In aquatic systems, vinylstyrene may partition from the water column to organic matter contained in sediments and suspended solids. Vinylstyrene is not expected to bioconcentrate in aquatic systems. An estimated Henry's Law constant of 2.253X10-3 atm-cu m/mole at 25 deg C suggests volatilization of vinylstyrene from environmental waters will be rapid. The volatilization half-lives from a model river and a model pond, the latter considers the effect of adsorption, have been estimated to be 4 hr and 14 days, respectively. Vinylstyrene is expected to exist entirely in the vapor phase in ambient air. Reactions with photochemically produced hydroxyl radicals (estimated half-life of 7 hr) and ozone (estimated half-life of 6.5 hr) in the atmosphere are likely to be important fate processes. The most probable human exposure would be occupational exposure, which may occur through dermal contact or inhalation at places where vinylstyrene is produced or used. (SRC) ARTS: *Vinylstyrene is commercially produced as a mixture of isomers(2), primarily for use in the manufacture of ion-exchange resins(3). Vinylstyrene is most commonly employed as a co-polymer with styrene(1), but is also employed with methyl acrylate(3). Formulations with small amounts of vinylstyrene possess reduced solubility in most solvents, increased heat distortion temperatures, added surface hardness and improved impact and tensile strengths; yet, still maintain the optical and electrical properties and the appearance of the homopolymer, styrene(1). Ion-exchange resins with vinylstyrene are predominantly used in water treatment processes such as softening and deionization, and chemical processes including sugar purification, pharmaceutical manufacture and uranium processing(3). Vinylstyrene is also added to styrene-butadiene rubber for its swelling, shrinkage and extrusion properties(3). Therefore, vinylstyrene is released to the environment via effluents where it is produced and used. Vinylstyrene was identified as a stack emission from waste incinerators(4). The combustion of propane in the presence of HCl emitted vinylstyrene in the flue gases(5). [R17] *The combustion of propane in the presence of HCl emitted vinylstyrene in the flue gases(1). [R18] FATE: *TERRESTRIAL FATE: Sufficient data are not available to predict the importance of biodegradation and chemical degradation of vinylstyrene in soils(SRC). A calculated Koc range of 510 to 2150(1) indicates a low to slight mobility class for vinylstyrene in soils(2). [R19] *AQUATIC FATE: Sufficient data are not available to predict the importance of biodegradation and chemical degradation in aquatic systems. Vinylstyrene is not expected to bioconcentrate in aquatic systems. An estimated Koc indicates vinylstyrene will absorb to organic carbon(2) and may partition from the water column to organic matter contained in sediments and suspended solids. A Henry's Law constant of 2.253X10-3 atm-cu m/mole at 25 deg C(3) suggests volatilization of vinylstyrene from environmental waters will be rapid(1). Based on this Henry's Law Constant, the volatilization half-life from a model river has been estimated to be 4 hr(1,SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be about 14 day(3,SRC). [R20] *ATMOSPHERIC FATE: Based upon a vapor pressure of 6.58X10-1 mm Hg, extrapolated using the Clausius-Clapeyron equation to 25 deg C from 1.53 mm Hg at 40 deg C(1), vinylstyrene is expected to exist entirely in the vapor phase in ambient air(2). In the atmosphere, reactions with photochemically produced hydroxyl radicals and ozone are likely to be important fate processes(SRC). The rate constant for the vapor-phase reaction of vinylstyrene with photochemically produced hydroxyl radicals has been estimated to be 5.4403X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 7 hr at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(3). The rate constant for the vapor-phase reaction of vinylstyrene with ozone has been estimated to be 4.2X10-17 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 6.5 hr at an atmospheric concn of 7X10+11 molecules per cu cm(3). [R21] BIOD: *Data regarding the biodegradation of vinylstyrene in either soil or aquatic systems were not available. (SRC) ABIO: *Data regarding chemical degradation of vinylstyrene in the environment were not available. However, reactions with photochemically produced hydroxyl radicals and ozone in the atmosphere are likely to be more important fate processes(SRC). The rate constant for the vapor-phase reaction of vinylstyrene with photochemically produced hydroxyl radicals has been estimated to be 5.4403X10-11 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 7 hr at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of vinylstyrene with ozone has been estimated to be 4.2X10-17 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 6.5 hr at an atmospheric concn of 7X10+11 molecules per cu cm(1). [R22] BIOC: *Based on a water solubility of 50 ppm(1) and an estimated log kow of 3.59(2), a range for log BCF between 1.83 and 2.50 has been calculated(3), which indicates vinylstyrene is not expected to bioconcentrate in aquatic systems(SRC). [R23] KOC: *Based on a water solubility of 50 ppm(1) and an estimated log kow of 3.59(2), the Koc of vinylstyrene has been calculated using various regression equations to range from 510 to 2150(3), which indicates slight to low mobility for vinylstyrene in soils(4). [R24] VWS: *Based upon a water solubility of 50 ppm(1) and a vapor pressure of 6.58X10-1 mm Hg for mixtures or pure isomers extrapolated using the Clausius-clapeyron equation to 25 deg C from 1.53 mm Hg at 40 deg C(1), the Henry's Law Constant for vinylstyrene has been calculated to be 2.253X10-3 atm-cu m/mole(SRC). This value of Henry's Law Constant indicates volatilization of vinylstyrene from environmental waters may be rapid(2). The volatilization half-life from a model river (1 meter deep flowing 1 m/sec with wind speed of 3 m/sec) has been estimated to be 4 hr(2,SRC). The volatilization half-life from a model pond, which considers the effect of adsorption, has been estimated to be 14 days(3,SRC). [R25] WATC: *DRINKING WATER: Vinylstyrene was detected in trace quantities in 4 of 18 drinking water concentrates from the cities of Cincinnati, Miami, New Orleans, Ottuma (IA), Philadelphia and Seattle(1). A chemical analysis of tap water from three municipal water plants using bank filtered Rhine (Netherlands) water reported vinylstyrene at maximum concentrations of 30 ng/l(2,3). [R26] *GROUND WATER: A study identified the effects of dune soil on the removal and modification of organic compounds present in the water of the river Rhine (Netherlands)(1,2). A chemical analysis of tap water from three municipal water plants using bank filtrated Rhine (Netherlands) water reported vinylstyrene at maximum concentrations of 30 ng/l (1,2). [R27] EFFL: *Vinylstyrene was identified as a stack emission from waste incinerators(1). Vinylstyrene was detected in 1 of 63 industrial wastewater effluents at a concn less than 10 ug/l(2). The combustion of propane in the presence of HCl emitted vinylstyrene in the flue gases(3). [R28] RTEX: *Vinylstyrene is used in the formulation of polymers with styrenes(1). The most probable human exposure would be occupational exposure, which may occur through dermal contact or inhalation at places where vinylstyrene is produced or used(SRC). [R29] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: +Vacated 1989 OSHA PEL TWA 10 ppm (50 mg/cu m) is still enforced in some states. [R9, 363] NREC: +Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 10 ppm (50 mg/cu m). [R9, 124] TLV: +8 hr Time Weighted Avg (TWA): 10 ppm. [R30, 2002.30] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R30, 2002.6] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for divinylbenzene. Route: inhalation; Species: rats and mice. [R31] SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. R3: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.228 R4: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. R5: ARIES R; FR DEMANDE PATENT NO 2108829 06/30/72 R6: SRI. 1988 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1988.. 532 R7: ARIES R; FR DEMANDE PATENT NO 2108927 06/30/72 R8: SRI R9: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R10: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-114 R11: CLOGP; PCGEMS Graphical Exposure Modeling System USEPA(1986) R12: Santodonato J et al; Invest Selected Potential Environ Contam: Styrene, Ethyl benzene, and Related Cmpd EPA560/11-80/018 p.57,69 (1980) R13: Santodonato J et al; Invest Selected Potential Environ Contam: Styrene, Ethyl Benzene Related Cmpd EPA-560/11-80018 p.57, 69 (1980) R14: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-46 R15: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.280 R16: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 395 R17: (1) Lewis PJ et al; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley-Interscience 21 770-801 (1983) (2) SRI International; Directory of Chemical Producers in the US p. 787 (1988) (3) Santodonato J et al; Invest Selected Potential Environ Contam Styrene, Ethyl Benzene and Related Cmpds USEPA-560/11-80/018 p. 57, 69 (1980) (4) Junk GA, Ford CS; Chemosphere 9: 187-230 (1980) (5) Eklund G et al; Chemosphere 16: 161-6 (1987) R18: (1) Eklund G et al; Chemosphere 16: 161-6 (1987) R19: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY:McGraw-Hill p. 4-9 (1982) (2) Swann RL et al; Res Rev 85: 16-28 (1983) R20: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9, 5-4, 15-15 to 15-29 (1982) (2) Swann RL et al; Res Rev 85: 16-28 (1983) (3) USEPA; EXAMS II Computer Simulation (1987) R21: (1) Santodonato J et al; Invest Selected Potential Environ Contam: Styrene, Ethyl Benzene and Related Cmpds USEPA-560/11-80/018 p. 57, 69 (1980) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R et al; Environ Sci Technol 21: 64-72 (1987) R22: (1) Atkinson R et al; Environ Sci Technol 21: 64-72 (1987) R23: (1) Santodonato J et al; Invest Selected Potential Environ Contam: Styrene, Ethyl Benzene and Related Cmpds USEPA-560/11-80/018 p. 57, 69 (1980) (2) CLOGP; PCGEMS Graphical Exposure Modeling System. USEPA (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) R24: (1) Santodonato J et al; Invest Selected Potential Environ Contam: Styrene, Ethyl Benzene and Related Cmpds USEPA-560/11-80/018 p. 57, 69 (1980) (2) CLOGP; PCGEMS Graphical Exposure Modeling System. USEPA (1986) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 4-9 (1982) (4) Swann RL et al; Res Rev 85: 16-28 (1983) R25: (1) Santodonato J et al; Invest Selected Potential Environ Contam: Styrene, Ethyl Benzene and Related Cmpds USEPA-560/11-80/018 p. 57, 69 (1980) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-1 to 15-29 (1982) (3) USEPA; EXAMS II Computer Simulation (1987) R26: (1) Lucas SV; GC/MS Anal Org Drink Water Concn and Adv Waste Treat Concn. Vol USEPA 600/1-84-020B (NTIS PB85-128239) p. 18 (1984) (2) Piet GJ, Morra CF; pp. 608-20 in Oxidation Techniques in Drinking Water Treatment. Kuehn IW, Sontheime H Eds. USEPA-570/9-79-020 (NTIS PB-301 313) p. 608-20 (1979) (3) Piet GJ, Morra CF; pp. 31-42 in Artificial Ground Water Recharge (Water Resources Engineering Series) Huisman L, Olsthorn TN Eds. (1983) R27: (1) Piet GJ, Morra CF; pp. 608-20 in Oxidation Techniques in Drinking Water Treatment. Kuehn IW, Sontheimer H Eds. USEPA-570/9-79-020 (NTIS PB-301 313) p. 608-20 (1979) (2) Piet GJ, Morra CF; pp. 31-42 in Artificial Ground Water Recharge (Water Resources Engineering Series) Huisman L, Olsthorn TN Eds (1983) R28: (1) Junk GA, Ford CS; Chemosphere 9: 187-230 (1980) (2) Perry DL et al; Ident of Org Compounds in Ind Effluent discharges. USEPA-600/4-79-016 (NTIS PB-294794) p. 42 (1979) (3) Eklund G et al; Chemosphere 16: 161-6 (1987) R29: (1) Lewis PJ et al; Kirk-Othmer Encycl Chem Tech 3rd NY: Wiley-Interscience 21 770-801 (1983) R30: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R31: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 32 Record 333 of 1119 in HSDB (through 2003/06) AN: 5476 UD: 200302 RD: Reviewed by SRP on 1/23/1997 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: C.I.-FOOD-BLUE-3- SY: *ACID-BLUE-V-; *ACID-BLUE-1-; *ACID-BRIGHT-AZURE-Z-; *ACID-BRILLIANT-BLUE-Z-; *ACID-BRILLIANT-SKY-BLUE-Z-; *ACID-LEATHER-BLUE-V-; *AIZEN-BRILLIANT-ACID-PURE-BLUE-VH-; *ALPHAZURINE-2G-; *AMACID-BLUE-V-; *1085-BLUE-; *BLUE-URS-; *BLUE-VRS-; *BRILLIANT-ACID-BLUE-A-EXPORT-; *BRILLIANT-ACID-BLUE-V-EXTRA-; *BRILLIANT-ACID-BLUE-VS-; *BRILLIANT-BLUE-GS-; *BUCACID-PATENT-BLUE-VF-; *CARMINE-BLUE-VF-; *C.I.-ACID-BLUE-1-; *C.I.-ACID-BLUE-1,-SODIUM-SALT-; *C.I.-42045-; *DISULFINE-BLUE-VN-; *DISULPHINE-BLUE-VN-; *DISULPHINE-BLUE-VN-150-; *DISULPHINE-VN-; *EDICOL-SUPRA-BLUE-VR-; *ERIOGLAUCINE-SUPRA-; *ETHANAMINIUM, N-(4-((4-(DIETHYLAMINO)PHENYL)(2,4-DISULFOPHENYL)METHYLENE)-2,5-CYCLOHEXADIEN-1 -YLIDENE)-N-ETHYL-, HYDROXIDE, INNER SALT, SODIUM SALT; *FENAZO-BLUE-XF-; *FOOD-BLUE-3-; *HEXACOL-BLUE-VRS-; *HIDACID-BLUE-V-; *KITON-PURE-BLUE-V-; *KITON-PURE-BLUE-V-FQ-; *LEATHER-BLUE-G-; *MERANTINE-BLUE-VF-; *PATENT-BLUE-; *PATENT-BLUE-V-; *PATENT-BLUE-VF-; *PATENT-BLUE-VF-CF-; *PATENT-BLUE-VF-SPECIAL-; *PATENT-BLUE-VIOLET-; *PATENT-BLUE-VS-; *PONTACYL-BRILLIANT-BLUE-V-; *SODIUM-BLUE-VRS-; *SODIUM-PATENT-BLUE-V-; *SULFAN-BLUE-; *SULPHAN-BLUE-; *SUMITOMO-PATENT-PURE-BLUE-VX-; *TERTRACID-CARMINE-BLUE-V-; *XYLENE-BLUE-VS- RN: 129-17-9 MF: *C27-H32-N2-O6-S2.Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *BY CONDENSING 4-FORMYLBENZENE-1,3-DISULFONIC ACID WITH DIETHYLANILINE [R1] *Disodium benzaldehyde-2,4-disulphonate + N,N-diethylaniline (carbonyl condensation/oxidation) [R2] FORM: *A grade of C.I. Acid Blue 1 produced in the UK has the following specifications: dye content, 82% min.; volatile matter (at 135 deg C), 6% max.; water-insoluble matter, 0.2% max.; subsidiary dye content, 5% max.; sodium chloride and sulfate, 10% max.; arsenic, 1 mg/kg; lead, 10 mg/kg; copper, 10 mg/kg; chromium, 20 mg/kg. [R3] OMIN: *PHYSICOCHEMICAL DATA FOR PATENT BLUE VIOLET (PATENT BLUE V) DYE IN VARIOUS AQ AND ORGANIC SOLVENTS. [R4] *OFFICIAL IN THE BRITISH PHARMACEUTICAL CODEX. A STOCK SOLN CONTAINING 0.06% GIVES A SUITABLE BLUE COLOR IN A CONCN OF 15 ML/L. TO OBTAIN A GREEN STOCK SOLN MIX 0.3% SULPHAN BLUE WITH 0.3% TARTRAZINE IN WATER. [R5] *BLUE VRS WAS USED IN THE PAST AS A FOOD DYE; HOWEVER, IT DOES NOT APPEAR ON ANY CURRENT LISTS OF DYES PERMITTED FOR USE IN FOOD IN US, JAPAN OR EUROPEAN ECONOMIC COMMUNITIES. IT IS PROVISIONALLY ACCEPTED FOR USE IN COSMETICS IN WHICH IT DOES NOT COME INTO CONTACT WITH MUCOUS MEMBRANES. [R6] *STUDY WAS CONDUCTED TO SUGGEST ADDITIONAL INDICATOR SUBSTANCES FOR THE TECHNIQUE OF ANGIOGRAPHY OF THE RETINAL AND CHOROIDAL VASCULATURES. CONCLUSION WAS THAT PATENT BLUE VF IS PROMISING SINCE ITS LD50 EXCEEDS 1000 MG/KG. [R7] USE: *COLORING MEDICINAL PRODUCTS [R1] *USED TO DYE WOOL, SILK, LEATHER, JUTE; TO STAIN PAPER, TO COLOR PHENOL-FORMALDEHYDE RESINS, MILLED SOAPS; TO COLOR INKS AND METHYLATED SPIRIT WASH, MASS COLORATION OF CASEIN; AS A BIOLOGICAL STAIN; HEAVY METAL SALTS OF THE FREE ACID ARE USED AS PIGMENTS; ALUMINUM SALTS USED TO COLOR PHARMACEUTICALS [R8] *FOOD DYE (REPORTED NON-U.S. USE) [R9] *Used to dye wool directly and silk from either a sulfuric acid or acetic acid bath. It dyes fully chromed leather a bright blue, prints wool and silk directly. [R10, p. 553 (1990)] PRIE: U.S. PRODUCTION: *(1978) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R9] *(1981) NOT PRODUCED COMMERCIALLY IN U.S. [R9] U.S. IMPORTS: *(1979) 3.98X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R9] *(1981) 4.49X10+6 GRAMS (PRINCPL CUSTMS DISTS) [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *VIOLET POWDER [R1]; *Dark bluish-green powder [R10, p. 553 (1990)] MW: *566.67 [R1] SOL: *ONE G DISSOLVES IN 20 ML WATER @ 20 DEG C; PARTLY SOL IN ALCOHOL [R1]; *30 mg/ml in water; 30 mg/ml in 2-methoxyethanol; 7 mg/ml in ethanol [R10, p. 533 (1990)] SPEC: *Minor absorption peak at 410 nm and major peak at 635 nm, in water. [R10, p. 553 (1990)] OCPP: *A 2% AQ SOLN SHOWED A DEPRESSION OF SURFACE TENSION OF WATER OF 38.5% @ 37 DEG C [R11] *DILUTE AQ SOLN ARE BLUE AND TURN YELLOW UPON ADDITION OF CONCN HYDROCHLORIC ACID; IN ABSENCE OF STRONG ACID OR CAUSTIC THE BLUE COLOR IS STABLE OVER WIDE PH RANGE [R1] *C.I. Acid Blue 1 displays acid-base-indicator properties, turning orange in the presence of concentrated hydrochloric acid and deep blue when sodium hydroxide is added. [R10, p. 553 (1990)] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Limited evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 3: The agent is not classifiable as to its carcinogenicity to humans. [R12] HTOX: *DRUG HYPERSENSITIVITY ON PATIENTS BEING TESTED BY SKIN-PRICK AND RECEIVING LYMPHOGRAM. [R13] *A CASE OF AN ALLERGIC REACTION TO PATENT BLUE VIOLET DYE USED FOR THE PURPOSE OF LYMPHANGIOGRAPHY IS REPORTED. SYMPTOMS WERE URTICARIAL REACTION, EDEMA OF THE EYELIDS AND LIPS, AND HYPOTENSION. [R14] *Immediate reactions to patent blue dye /is presented/. [R15] *sensitivity to patent blue dye during skin prick testing and lymphography. A retrospective and prospective study. [R16] */It was noted that/ a few minutes after sc injection of patent blue dye, two patients developed acute uticaria with a characteristic blue green hue. [R17] *allergic reaction to the food dye patent blue. [R18] *Allergic reactions during lymphography are uncommon, usually minor and difficult to attribute to a single agent because of the common practice of mixing patent blue dye and local anaesthetic before injection. A case is presented where injection of patent blue dye alone was followed by a generalized urticaria, swelling and constriction in the throat and difficulty breathing. [R19] NTOX: *GROUP OF 10 MALE AND 10 FEMALE 5-WK-OLD WISTAR RATS RECEIVED WEEKLY SC INJECTIONS OF 0.5 ML OF 4% SOLN OF BLUE VRS (PURITY NOT GIVEN) IN ISOTONIC SALINE FOR 45 WK (TOTAL DOSE 900 MG). ... 2 FEMALES DEVELOPED RHABDOMYOSARCOMAS IN AREA OF INJECTION SITE. IN 20 CONTROL ANIMALS /8 ALIVE @ 71 WK/, NO INJECTION-SITE TUMORS SEEN. [R20] *SHELL OR CARWORTH FARM E ALBINO RATS OF BOTH SEXES, WEIGHING 100-150 G, WERE GIVEN TWICE WEEKLY SC INJECTIONS OF EITHER 0.5 ML OF 2% SOLN (20 RATS) OR 1 ML OF 1% AQ SOLN (65 RATS) OF BLUE VRS (82% PURE) FOR 55 OR 72 WK, RESPECTIVELY. 6 OUT OF 19 and 8/60 RATS DEVELOPED SARCOMAS AT SITE OF REPEATED INJECTIONS. [R20] *TWENTY RATS RECEIVED TWICE WEEKLY SC INJECTIONS OF 0.5% ML OF A 2% AQ SOLN OF THE DYE FOR 65 WK, BUT INJECTIONS WERE DISTRIBUTED AMONG 4 SC SITES IN TURN (DORSAL TO THE SCAPULAE AND IN THE LUMBAR REGION). AT 81 WK, NO SARCOMAS OBSERVED IN THESE RATS AT ANY OF THE INJECTION SITES. [R21] *...20 MALE AND 20 FEMALE 10-WK-OLD WISTAR RATS RECEIVED WEEKLY INJECTIONS OF 0.4 ML OF 4% ...(FOOD GRADE) IN 0.9% SALINE INTO POSTERIOR THIGH MUSCLES OF THE RIGHT LEG. ...5/19 MALES AND 9/18 FEMALES DEVELOPED RHABDOMYOSARCOMAS @ INJECTION SITE. ... METASTASES OCCURRED IN LYMPH NODES, LUNGS AND LIVER. /NONE/ IN CONTROLS. [R21] *SULFAN BLUE WAS FOUND TO BE THE MOST VALUABLE DYE TESTED FOR VISUALIZATION IN PRIMARY IRRITATION STUDIES USING GUINEA PIGS, MICE AND RABBITS. NO ADVERSE EFFECTS WERE OBSERVED AFTER 10 TIMES THE CLINICAL DOSE OR DAILY TREATMENT WITH THE RECOMMENDED DOSE FOR 5 DAYS. [R22] *IN ACUTE TOXICITY STUDIES, MICE AND RATS TOLERATED SINGLE ORAL DOSES OF 5 and 10 G/KG, RESPECTIVELY OF BLUE VRS SODIUM WITHOUT ANY ILL EFFECTS. IN RATS GIVEN DIETARY LEVELS OF 0.3, 0.75, 1.5, OR 3.0 BLUE VRS FOR 90 DAYS, GROWTH WAS RETARDED IN MALES AT THE 1.5 and 3.0 LEVELS AND FEMALES AT THE 3 LEVEL SHOWED AN INCR IN THE INCIDENCE OF FATTY LIVER. [R23] *TWICE WEEKLY SC INJECTIONS OF THE FOOD COLORING SURFACTANT, BLUE VRS TO RATS ELICITED A DERANGED CONNECTIVE TISSUE REPAIR WITH CONTINUED PROLIFERATION OF FIBROBLASTS AND EXTENSIVE COLLAGEN DEPOSITION. SUCH SURFACTANTS GAVE RISE TO LOCAL SARCOMATA ONLY AFTER APPROXIMATELY 47 WEEKS. [R24] *NO MUTAGENICITY WAS DETECTED WITH THE SINGLE SAMPLE OF PATENT BLUE V TESTED WITH SALMONELLA TYPHIMURIUM. [R25] *PATENT BLUE V HAS PROVEN NON-MUTAGENIC AND INCAPABLE OF INDUCING NON-SPECIFIC DNA DAMAGE WITH OR WITHOUT MICROSOMES IN SEVERAL SYSTEMS. [R26] *Sulfan blue was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Sulfan blue was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The compound was positive in strain TA98 with activation. The lowest positive dose tested was 0.333 mg/plate in strain TA98 with 10% hamster liver S-9. [R27] *Three widely used dyes, acridine orange, blue VRS and fast green FCF were admin to male mice ... to /examine/ the induction of gross chromosomal anomalies using the micronucleus test. All three cmpd were shown to be clastogenic. [R28] *Liposomes produced from phosphatidylcholine and cholesterol and containing Parent Blue V has been injected endolymphatically in the rabbit. The lymph nodes stained dark blue and retained this color until termination of the /study/ after 28 days. No toxic effects were observed histologically. The liposomes were deposited within the macrophages in a fine granular pattern. ... [R29] *Patent blue 4 was of low acute oral toxicity in rats and mice. Although a 13 wk feeding study in dogs suggested a mild effect on the kidneys and gall bladder, a lifetime feeding study in mice using higher doses found only reduced growth and slight effects on the blood. Patent Blue V had no adverse effects on the reproduction of rats or mice treated orally. There was ... no evidence of carcinogenicity in mice given repeated oral doses. No genotoxic activity was demonstrated in a range of screening assays including a test for chromosomal damage in mice and Ames tests for mutagenicity in bacteria. ... [R30] ACTN: *IT IS OF SOME INTEREST THAT SEVERAL DYES RELATED TO PARAROSANILINE, WHICH INCLUDES BLUE VRS, EXHIBIT GENOTOXICITY AND THAT THIS ACTIVITY IS CORRELATED WITH THE PRESENCE OF A SUBSTITUTED OR UNSUBSTITUTED AMINO GROUP AT THE R3 POSITION PARA TO THE N+ AMINO GROUP. THUS PATENT BLUE IS INACTIVE. THIS DYE INSTEAD HAS SULFONIC GROUPS IN THIS POSITION WHICH MAY INTERFERE WITH ACTIVATION AT THE N+ ATOM. [R26] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Dyes [R31] *EXPTL USE: THE BLUE TEST IS DESIGNED TO REVEAL EDEMA OF TOTAL OR PARTIAL LYMPHATIC ORIGIN. INTOLERANCE TO THE DYE INJECTED IS RARE, THOUGH SOMETIMES SEVERE, AND USERS SHOULD BY AWARE OF THE POSSIBILITY. [R32] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *C.I. Acid Blue 1's production and use as a dye, a biological stain and to color medicinal products may result in its release to the environment through various waste streams. The ionic state of C.I. Acid Blue 1 makes this compound essentially non-volatile, therefore C.I. Acid Blue 1 should exist solely in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Acid Blue 1 may be physically removed from the air, mainly by wet deposition. An estimated Koc of 15 suggests that C.I. Acid Blue 1 will have very high mobility in soil although its ionic nature may result in ion-exchange processes with clay that would retard leaching. The volatilization of the dye from moist soil surfaces to air will not be important as C.I. Acid Blue 1 is an ionic compound. It may adsorb to clay sediments and particulate matter in the water due to ion-exchange processes. The loss of the dye from water surfaces by volatilization should not be important due to its ionic nature. The potential for bioconcentration in aquatic organisms should be low based on an estimated BCF value of 2. Occupational exposure may be through inhalation of dusts and dermal contact with this compound at workplaces where C.I. Acid Blue 1 is produced or used. The general population may be exposed to C.I. Acid Blue 1 via ingestion of pharmaceuticals and dermal contact with products containing C.I. Acid Blue 1. (SRC) ARTS: *C.I. Acid Blue 1's production and use as a dye for wool, silk, leather, and jute, as a paper stain, to color phenol-formaldehyde resins, milled soaps, inks, and casein, as a biological stain(1) and to color medicinal products(2) may result in its release to the environment through various waste streams(SRC). [R33] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 15(SRC), determined from a measured water solubility(2) and a recommended regression-derived equation(3), indicates that C.I. Acid Blue 1 will have very high mobility in soil(SRC). Due to the ionic nature of C.I. Acid Blue 1, the retention of the dye by ion-exchange processes(4,SRC), particularly on clay surfaces, and adsorption at mineral surfaces such as geothite(5,SRC), may slow down or prevent leaching(SRC). As C.I. Acid Blue 1 is an ionic compound, volatilization of this compound will not be important from moist soil surfaces(4,SRC). [R34] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 15(SRC), determined from a measured water solubility(2) and a recommended regression-derived equation(1), indicates that C.I. Acid Blue 1 should not adsorb to suspended solids and sediment in water(SRC). However, due to the ionic nature of C.I. Acid Blue 1, the retention of the dye by ion-exchange processes(3,SRC), particularly on clay surfaces, and adsorption at mineral surfaces such as geothite(4,SRC), may lead to increased adsorption on some surfaces(SRC). As C.I. Acid Blue 1 is an ionic compound, volatilization from water surfaces is not expected(3,SRC). According to a classification scheme(5), an estimated BCF value of 2(1,SRC), from a measured water solubility(2), suggests that bioconcentration in aquatic organisms is low(SRC). [R35] *ATMOSPHERIC FATE: The ionic state of C.I. Acid Blue 1 makes this compound essentially non-volatile(1,SRC); therefore, this compound should exist in the particulate phase in the ambient atmosphere. Particulate-phase C.I. Acid Blue 1 may be physically removed from the air, mainly by wet deposition(SRC). [R36] BIOC: *An estimated BCF value of 2 was calculated for C.I. Acid Blue 1(SRC), using a measured water solubility of 30,000 mg/l(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R37] KOC: *The Koc of C.I. Acid Blue 1 is estimated as approximately 15(SRC), using a measured water solubility of 30,000 mg/l(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that C.I. Acid Blue 1 has very high mobility in soil(SRC). Due to the ionic nature of the dye, the retention of C.I. Acid Blue 1 by ion-exchange processes(4,SRC), particularly on clay surfaces and adsorption at mineral surfaces such as geothite(5,SRC), may slow down or prevent leaching(SRC). [R38] VWS: *Since C.I. Acid Blue 1 is an ionic compound, volatilization from water and moist soil surfaces will not be important(1,SRC). [R36] WATC: *THE OCCURRENCE AND FATE OF TRIPHENYLMETHANE BLUE DYES INCLUDING PATENT BLUE V DYE IN THE AQUATIC ENVIRONMENT WERE STUDIED. [R39] EFFL: *CI ACID BLUE DYE (ORIGINATING FROM GERMICIDE BLOCKS IN TOILET RESERVOIRS) RECOVERED FROM FILTERED SEWAGE. [R40] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 62,878 workers (9626 of these are female) are potentially exposed to C.I. Acid Blue 1 in the US(1). Occupational exposure may be through inhalation of dusts and dermal contact with this compound at workplaces where C.I. Acid Blue 1 is produced or used(2,SRC). The general population may be exposed to C.I. Acid Blue 1 via ingestion of pharmaceuticals and dermal contact with products containing C.I. Acid Blue 1(SRC). [R41] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *RECOVERY OF CI ACID BLUE DYE ORIGINATING FROM GERMICIDE BLOCKS IN TOILET RESERVOIRS FROM FILTERED SEWAGE AND RECOVERIES OF SAME SUGGEST A METHOD FOR SEPARATION @ A SAMPLING SITE FOR TRANSPORTATION TO AND ANALYSIS IN THE LABORATORY. [R42] ALAB: *THE PURITY OF BATCHES OF COMMERCIAL DYES, INCL BLUE VRS, HAS BEEN EVALUATED BY THIN-LAYER CHROMATOGRAPHY AND NUCLEAR MAGNETIC RESONANCE SPECTROMETRY. [R20] *COLORED PAPER NAPKINS AND TOILET PAPER WERE EXTRACTED AND PATENT BLUE V WAS DETECTED BY CHROMATOGRAPHY AND SPECTROPHOTOMETRY. [R43] *IDENTIFICATION OF FOOD DYES VIA THIN-LAYER, PAPER AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. 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Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 168 (1978) R7: LUTTY GA; TOXICOL APPL PHARMACOL 44 (2): 225 (1978) R8: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 165 (1978) R9: SRI R10: Green FJ; The Sigma-Aldrich Handbook of Stains, Dyes and Indicators. Milwaukee, Wisconsin: Aldrich Chemical Company, Inc. R11: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V16 164 (1978) R12: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 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February (1988) (4) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R36: (1) Baughman GL, Perenich TA; Amer Dyestuff Reporter p. 19-22. February (1988) R37: (1) Green FJ; The Sigma-Aldrich Handbook of Stains, Dyes and Indicators. Milwaukee, Wisconsin: Aldrich Chemical Company, Inc. p. 553 (1990) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R38: (1) Green FJ; The Sigma-Aldrich Handbook of Stains, Dyes and Indicators. Milwaukee, Wisconsin: Aldrich Chemical Company, Inc. p. 553 (1990) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) (4) Baughman GL, Perenich TA; Amer Dyestuff Reporter p. 19-22. February (1988) (5) Evans, LJ; Environ Sci Technol 23: 1046-56 (1989) R39: RICHARDSON ML; ECOTOXICOL ENVIRON SAF 5 (4): 424 (1981) R40: GARDINER J; TR-89: 21 (1978) R41: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Schulte PA et al; in Carcinogenic Mutagenic Responses to Aromatic Amines and Nitroarenes. Proc Inter Confer Carcinogenic Mugenic N-Substitute Aryl Compd 3: 23-85 (1988) R42: GARDINER J; ANALYSIS OF RELATIVELY NONPOLAR ORGANIC COMPOUNDS IN SEWAGE EFFLUENTS USING AMBERLITE XAD-2; TECH REP TR-WATER RES CENT (MEDMENHAM, ENGLAND); TR-89: 21 (1978) R43: MULLOR JB ET AL; REV FAC ING QUIM (UNIV NAC LITORAL) 207 (1979) R44: PUTTEMANS ML ET AL; J ASSOC OFF ANAL CHEM 65 (3): 730 (1982) RS: 23 Record 334 of 1119 in HSDB (through 2003/06) AN: 5543 UD: 200211 RD: Reviewed by SRP on 9/23/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIISOBUTYLAMINE- SY: *AMINE,-DIISOBUTYL-; *BIS(BETA-METHYLPROPYL)AMINE; *N,N-BIS(2-METHYLPROPYL)AMINE; *1-PROPANAMINE, 2-METHYL-N-(2-METHYLPROPYL)- RN: 110-96-3 MF: *C8-H19-N MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *Air Products and Chemicals, Inc., Chemicals group, Industrial Chemicals Division, 7201 Hamilton Blvd., Allentown, PA 18195-1501 (610) 481-4911; Production site: Pace, FL 32571 [R1] *Celanese Ltd., Chemicals Division, 1601 West LBJ Blvd., Dallas, TX 75234 (972) 443-4000; Production site: Bucks, AL 36512 [R1] USE: *As an intermediate [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Water-white liquid [R2] ODOR: *Amine odor [R2] BP: *139.6 deg C [R3, p. 3-269] MP: *-73.5 deg C [R3, p. 3-269] MW: *129.25 [R3, p. 3-296] DEN: *0.745 @ 20 deg C [R2] DSC: *pKa= 10.91 @ 21 deg C [R4] SOL: *Sol in ethanol, ether, acetone, benzene [R3, p. 3-269]; *In water, 2,200 mg/l @ 25 deg C. [R5] SPEC: *Index of refraction: 1.4090 @ 20 deg C/D; Sadtler reference number: 2246 (IR, Prism) [R3, p. 3-269]; *IR: 1632 (Coblentz Society Spectral Collection) [R6]; *NMR: 136 (Sadtler Research Laboratories Spectral Collection) [R6]; *MASS: 582 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R6] VAP: *7.27 mm Hg @ 25 deg C [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. [R8] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. [R8] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. [R8] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. [R8] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R8] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. [R8] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. [R8] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R8] FPOT: *FLAMMABLE, MODERATE FIRE RISK [R9] *A dangerous fire hazard when exposed to heat or flame ... [R10] NFPA: *Health: 3. 3= Materials that, on short exposure, could cause serious temporary or residual injury, including those requiring protection from all bodily contact. Fire fighters may enter the area only if they are protected from all contact with the material. Full protective clothing, including self-contained breathing apparatus, coat, pants, gloves, boots and bands around legs, arms, and waist, should be provided. No skin surface should be exposed. [R11] *Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R11] *Reactivity: 0. 0= This degree includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R11] FLPT: *29 DEG C (85 DEG F) (CLOSED CUP) [R11] FIRP: *Alcohol foam. Water may be ineffective. [R11] *To fight fire, use alcohol foam, carbon dioxide, dry chemical. [R10] REAC: *... Can react vigorously with oxidizing materials. [R10] DCMP: *When heated to decomposition it emits toxic fumes of nitroxides. [R10] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patent can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . /Organic bases/amines and related cmpds/ [R12] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconsious or has severe pulmonary edema. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W TKO /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's of hypovolemia are present. Watch for signs of fluid overload. Administer 1% solution methylene blue if patient is symptomatic with severe hypoxia, cyanosis, and cardiac compromise not responding to oxygen. DIRECT PHYSICIAN ORDER ONLY ... . Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. If patient is unresponsive to these measures, vasopressors may be helpful. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Organic bases/amines and related cmpds/ [R12] NTOX: *MORTALITY RATE OF 75 PPM INHALED BY RATS FOR 4 HR WAS 4/6; NO DEATHS OCCURRED WHEN INHALING SATURATED VAPOR FOR 50 MIN. /FROM TABLE/ [R13] *Diisobutylamine was found to be negative when tested for mutagenicity using the Salmonella/ microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Diisobutylamine was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest ineffective dose tested in any S. typhimurium strain was 10.000 mg/plate. [R14] NTXV: *LD50 Rat oral 258 mg/kg; [R10] *LD50 Mouse oral 629 mg/kg; [R10] *LD50 Guinea pig oral 620 mg/kg; [R10] *LD50 Rabbit dermal 0.25 ml/kg; [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Diisobutylamine's production and use as a chemical intermediate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 7.27 mm Hg at 25 deg C indicates diisobutylamine will exist solely as a vapor in the ambient atmosphere. Vapor-phase diisobutylamine will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 4 hours. If released to soil, diisobutylamine is expected to have low mobility based upon an estimated Koc of 640. The pKa of diisobutylamine is 10.91, indicating that this compound will exist in the protonated form in the environment and cations generally adsorb more strongly than their neutral counterparts. Volatilization from moist soil surfaces is not expected to be an important fate process because the cation is not expected to volatilize. Diisobutylamine may volatilize from dry soil surfaces based upon its vapor pressure. 63 to 87% of the theoretical BOD was achieved for diisobutylamine using activated sludges over a 4 week incubation period. If released into water, diisobutylamine is expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Volatilization from water surfaces is not expected to be an important fate process since this compound is expected to exist in the protonated form at environmental pH. An estimated BCF of 21 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to diisobutylamine may occur through inhalation and dermal contact with this compound at workplaces where diisobutylamine is produced or used. (SRC) ARTS: *Diisobutylamine's production and use as a chemical intermediate(1), may result in its release to the environment through various waste streams(SRC). [R15] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 640(SRC) from an estimated log Kow of 2.63(2) and a regression derived equation(3) indicates that diisobutylamine is expected to have low mobility in soil(SRC). A pKa value of 10.91(4) indicates that the protonated form of diisobutylamine will be the dominant species in moist soil surfaces and cations generally adsorb strongly to soils. Volatilization of diisobutylamine from moist soil surfaces is not expected to be an important fate process since the cation will not volatilize. Diisobutylamine may volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 7.27 mm Hg at 25 deg C(5). 63 to 87% of the theoretical BOD was achieved for diisobutylamine using activated sludges over a 4 week incubation period(6), which suggests that biodegradation in soil is expected to be important(SRC). [R16] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 640(SRC) from an estimated log Kow of 2.63(2) and a regression derived equation(3) indicates that diisobutylamine is expected to adsorb to suspended solids and sediment in water(SRC). A pKa value of 10.91(4) indicates that the protonated form of diisobutylamine will be the predominant species in water. Volatilization from water surfaces is not expected to be an important fate process(SRC) since the protonated form will not volatilize. According to a classification scheme(5), an estimated BCF of 21(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). 63 to 87% of the theoretical BOD was achieved for diisobutylamine using activated sludges over a 4 week incubation period(7), which suggests that biodegradation in water is expected to be important(SRC). [R17] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), diisobutylamine, which has a vapor pressure of 7.27 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase diisobutylamine is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 4 hours(SRC), from its rate constant of 9X10-11 cu cm/molecule-sec at 25 deg C(3). Diisobutylamine is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum(SRC). [R18] BIOD: *63 to 87% of the theoretical BOD was achieved for diisobutylamine using activated sludges over a 4 week incubation period(1). [R19] ABIO: *The rate constant for the vapor-phase reaction of diisobutylamine with photochemically-produced hydroxyl radicals has been estimated as 9X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Diisobutylamine will exist predominantly in the protonated form in the environment based on a pKa value of 10.91(2). Diisobutylamine is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum(SRC). [R20] BIOC: *An estimated BCF of 21 was calculated for diisobutylamine(SRC), using an estimated log Kow of 2.63(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R21] KOC: *The Koc of diisobutylamine was estimated as 640(SRC), using an estimated log Kow of 2.63(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that diisobutylamine is expected to have low mobility in soil(SRC). The pKa of diisobutylamine is 10.91(4), indicating that the protonated form will be the predominant species in moist soils and cations are expected to adsorb strongly to soil surfaces. [R22] VWS: *With a pKa of 10.91(1), diisobutylamine will exist predominantly in its protonated form in the environment and the protonated form of diisobutylamine will not volatilize from water or moist soil surfaces(2). Diisobutylamine may volatilize from dry soil surfaces(SRC) based on its vapor pressure of 7.27 mm Hg at 25 deg C(3). [R23] FOOD: *Diisobutylamine was detected in miso at a concn of 0.007 ppm(1). [R24] RTEX: *Occupational exposure to diisobutylamine may occur through inhalation and dermal contact with this compound at workplaces where diisobutylamine is produced or used. (SRC) MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *A SIMPLE AND SELECTIVE GAS CHROMATOGRAPHIC METHOD WAS ESTABLISHED FOR DETERMINING NATURALLY OCCURRING SECONDARY AMINES (POSSIBLE CARCINOGENS). SECONDARY AMINES SEPARATED FROM FOODS BY EXTRACTION WITH DICHLOROMETHANE AND REEXTRACTION WITH HYDROCHLORIC ACID WERE READILY CONVERTED INTO THE CORRESPONDING SULFONAMIDES. GAS CHROMATOGRAPHY WAS CARRIED OUT WITH A CAPILLARY COATED WITH OV-101 AND A FLAME PHOTOMETRIC DETECTOR. [R25] *DETERMINATION OF TRACE ALIPHATIC AMINES IN WATER WITH 2,4-DINITROPHENYLAMINE DERIVATIVES BY GAS CHROMATOGRAPHY MASS SPECTROMETRY. [R26] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 557 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 405 R3: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999. R4: Perrin DD; Dissociation constants of organic bases in aqueous solution. IUPAC Chem Data Ser, Buttersworth, London (1965) R5: Chemicals Inspection and Testing Institute; Biodegradation and bioaccumulation data of existing chemicals based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 560 R7: Yaws CL; Handbook of Vapor Pressure. Vol 3: C8-C28 Compounds. Houston,TX: Gulf Pub Co (1994) R8: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-132 R9: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 298 R10: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1250 R11: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-40 R12: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 168 R13: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 1105 R14: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R15: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th ed. NY, NY: Van Nostrand Reinhold Co., p. 371 (1993) R16: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser. Butterworth, London (1965) (5) Yaws CL; Handbook of Vapor Pressure Vol 2. C5 to C8 Compounds. Houston, TX: Gulf Publ Co: (1994) (6) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R17: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser. Butterworth, London (1965) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-672 (1999) (7) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R18: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Yaws CL; Handbook of Vapor Pressure Vol 2. C5 to C8 Compounds. Houston,TX: Gulf Publ Co (1994) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R19: (1) Chemicals Inspection and Testing Institute. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) R20: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser. Butterworth, London (1965) R21: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-672 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R22: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-23 (1983) (4) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser. Butterworth, London (1965) R23: (1) Perrin DD; Dissociation Constants of Organic Bases in Aqueous Solution. IUPAC Chem Data Ser. Butterworth, London (1965) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Yaws CL; Handbook of Vapor Pressure Vol 2. C5 to C8 Compounds. Houston,TX: Gulf Publ Co (1994) R24: (1) Hamano T et al; Agric Biol Chem 45: 2237-43 (1981) R25: HAMANO T ET AL; AGRIC BIOL CHEM 45 (10): 2237 (1981) R26: KOGA M ET AL; BUNSEKI KAGAKU 30 (11): 745 (1981) RS: 23 Record 335 of 1119 in HSDB (through 2003/06) AN: 5547 UD: 200303 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIGLYCOL-DIACETATE- SY: *ETHANOL, 2,2'-[1,2-ETHANEDIYLBIS(OXY)]BIS-, DIACETAT; *ETHANOL,-2,2'-ETHYLENEDIOXYDI-,-DIACETATE-; *2,2'-(ETHYLENEDIOXY)DI(ETHYL ACETATE); *TRIETHYLENE-GLYCOL,-DIACETATE-; *TRIGLYCOL,-DIACETATE- RN: 111-21-7 MF: *C10-H18-O6 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Triethylene glycol + acetic anhydride (acetylation). [R1] MFS: *EASTMAN KODAK CO, TENNESSEE EASTMAN CO DIV, KINGSPORT, TN 37662 [R2] *UNION CARBIDE CORP, SOLVENTS AND COATING MATERIALS DIV, SOUTH CHARLESTON, WV 25303 [R2] OMIN: *Though the toxicity data available /from animal studies/ ... suggest that this material should pose no significant health hazard, it would seem prudent to follow generally accepted good industrial hygiene practices in the handling of triethylene glycol diacetate. [R3] USE: *PLASTICIZER [R4] *PLASTICIZER FOR CELLULOSE ACETATE AND NITRATE RESINS [R2] *PLASTICIZER FOR CELLULOSE ACETATE BUTYRATE RESINS [R2] *PLASTICIZER FOR ETHYL CELLULOSE RESINS [R2] *PLASTICIZER FOR POLYMETHYL METHACRYLATE RESINS [R2] PRIE: U.S. PRODUCTION: *(1980) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R2] *(1982) PROBABLY GREATER THAN 2.27X10+6 GRAMS [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *COLORLESS LIQUID [R4] BP: *286 deg C [R5] MP: *-50 deg C [R5] MW: *234.25 [R5] DEN: *1.112 AT 25 DEG C [R4] SOL: *MISCIBLE WITH ALCOHOL, ETHER [R4]; *Very soluble in water, ethyl ether, and ethanol. [R5] SPEC: *INDEX OF REFRACTION: 1.437 AT 25 DEG C [R6]; *IR: 22925 (Sadtler Research Laboratories IR Grating Collection) [R7]; *NMR: 12765 (Sadtler Research Laboratories Spectral Collection) [R7] OCPP: *Saponification value: 480 mg KOH/g. [R1] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- NFPA: +Health: 0. 0= Materials that, on exposure under fire conditions, offer no hazard beyond that of ordinary combustible material. [R8] +Flammability: 1. 1= Includes materials that must be preheated before ignition will occur, such as Class IIIB combustible liquids and solids and semi-solids whose flash point exceeds 200 deg F (93.4 deg C), as well as most ordinary combustible materials. Water may cause frothing if it sinks below the surface of the burning liquid and turns to steam. However, a water fog that is gently applied to the surface of the liquid will cause a frothing which will extinguish the fire. [R8] +Reactivity: 0. 0= Includes materials that are normally stable, even under fire exposure conditions, and that do not react with water. Normal fire fighting procedures may be used. [R8] FLPT: +345 DEG F (174 DEG C) (OPEN CUP) [R8] FIRP: +"ALCOHOL" FOAM. WATER OR FOAM MAY CAUSE FROTHING. [R8] DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R9] SSL: *LOW DEGREE OF VOLATILITY [R3] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *IT IS...LOW IN SINGLE-DOSE TOXICITY WHEN INJECTED IP, SINCE THE LD50 FOR RATS IS 1.41 ML/KG. ...EYE CONTACT SHOULD GIVE RISE TO NO SIGNIFICANT IRRITATION NOR IS IT LIKELY TO BE ABSORBED THROUGH THE SKIN IN TOXIC AMOUNTS... [R3] *A SINGLE 8-HR EXPOSURE OF RATS TO ESSENTIALLY SATURATED VAPORS GENERATED AT APPROX 20 DEG C RESULTED IN NO SIGNIFICANT ADVERSE EFFECTS. [R3] *Triethylene glycol and two of its derivatives were evaluated for reproductive toxicity in a continuous breeding protocol with Swiss CD-1 mice. Triethylene glycol (TEG: 0, 0.3, 1.5, and 3%), triethylene glycol diacetate (TGD: 0, 0.75, 1.5, and 3%), and triethylene glycol dimethyl ether (triethylene glycol dimethyl ether: 0, 0.25, 0.5, and 1%) were administered in drinking water to breeding pairs (20 pairs per treatment groups, 40 control pairs) during a 98-day cohabitation period. Reproductive function was assessed by the number of litters per pair, live pups per litter, proportion of pups born alive, and pup weight. There were no apparent effects on reproductive function in the animals receiving triethylene glycol or triethylene glycol diacetate at doses up to 3% in the drinking water (representing 6.78 or 5.45 g/kg, respectively). However, some developmental toxicity was demonstrated for both triethylene glycol and triethylene glycol diacetate. Continuous exposure of dams to 1.5 or 3% triethylene glycol significantly reduced live pup weight at birth compared to control and 0.3% triethylene glycol significantly reduced live pup weight at birth compared to control and 0.3% triethylene glycol. while exposure to 3% triethylene glycol diacetate during lactation significantly (but reversibly) reduced pup body weights on Postnatal Days 14 and 21. In contrast, triethylene glycol dimethyl ether was toxic to the reproductive system as evidenced by decreases at the highest does (1% triethylene glycol dimethyl ether; 1.47 g/kg) in the proportion of pairs that produced at least one litter, live pups per litter, and proportion of pups born alive, with dose-related trends seen in the latter two parameters. A crossover mating trial showed that triethylene glycol dimethyl ether was more toxic to the female than the male reproductive system. These data indicate that triethylene glycol dimethyl ether (1.47 g/kg) is a reproductive toxicant in Swiss mice while reproductive toxicity was not demonstrated in mice receiving triethylene glycol or triethylene glycol diacetate (at doses up to 6.78 or 5.45 g/kg, respectively). [R10] NTP: +Triethylene glycol diacetate (TGDA) was tested in the Reproductive Assessment by Continuous Breedng (RACB) protocol using Swiss CD-1 mice, ... Data gathered on body weights, clinical signs, and food and water consumption during the Task 1 dose-range-finding study were used to select concns for the continuous breeding phase (Task 2) of 0.0, 0.75%, 1.5%, and 3% /weight/volume/ in drinking water. These concns produced calculated consumption estimates of nearly equal to 1.31, 2.62, and 5.25 g/kg/day. Continuous exposure of adult F0 mice to these concns of TGD had no effect on the number of litters/pair, or the number or weight of live pups/litter. The proportion of pups born alive was not affected by these concns of TGDA. Since no effects were observed in Task 2, Task 3, which determines the effected sex, was not conducted. The last litter from Task 2 was nursed until weaning, and then given water containing TGDA at the same concn as their parents. Only the control and 3% TGDA groups were assessed in a second generation. Although viability was not adversely affected, pups nursed by dams receiving 3% TGDA weighed between 15 and 25% less than their controls at /postnatal day/ 14 and 21. These differences in body weight had disappeared by the time of Task 4 mating at nearly equal to /postnatal day/ 74. In the second generation mating trial, there were no treatment-related effects on mating or fertility indices, or on the number of F2 pups, their viability, or weight adjusted for litter size. After the F2 litters were delivered and evaluated, the F1 adults were killed and necropsied. There were no TGDA-related differences in body weight for either sex. In males and females, relative kidney weight was increased by nearly equal to 6-8%. No other treatment-related effects were found. Epididymal sperm concn, motility, and morphology were unaffected by 3% TGDA consumption. These data show that triethylene glycol diacetate had no detectable reproductive toxicity in Swiss mice at exposure levels that altered kidney weights and neonatal development. [R11] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Triethylene glycol, diacetate's production and use as a plasticizer may result in its release to the environment through various waste streams. If released to air, triethylene glycol, diacetate is expected to exist solely as a vapor in the ambient atmosphere based upon an estimated vapor pressure of 4.1X10-3 mm Hg at 25 deg C. Vapor-phase triethylene glycol, diacetate will be readily degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated half-life of 12 hours. If released to soil, an estimated Koc of 20 suggests that triethylene glycol, diacetate is expected to have very high mobility. Volatilization from wet and dry soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 2.7X10-13 atm-cu m/mol and this compound's estimated vapor pressure, respectively. If released into water, this compound is not expected to adsorb to suspended solids and sediment in the water column based upon its estimated Koc. Triethylene glycol, diacetate is not expected to volatilize from water surfaces based on the estimated Henry's Law constant. An estimated BCF of 0.46 suggests the potential for bioconcentration in aquatic organisms is low. Estimated hydrolysis half-lives of 150 and 15 days at pHs 7 and 8, respectively, indicate that hydrolysis is expected to be a slow process. Biodegradation of triethylene glycol, diacetate may be important, based upon 100% biodegradation of 2-(2-butoxyethoxy)ethyl acetate, a structurally similar compound. Occupational exposure to triethylene glycol, diacetate may occur through dermal contact with this compound at workplaces where triethylene glycol, diacetate is produced or used. (SRC) ARTS: *Triethylene glycol, diacetate's production and use as a plasticizer(1) may result in its release to the environment through various waste streams(SRC). [R12] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 20(SRC), determined from an estimated log Kow of -0.14(2,SRC) and a regression-derived equation(3), indicates that triethylene glycol, diacetate is expected to have very high mobility in soil(SRC). Volatilization of triethylene glycol, diacetate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.7X10-13 atm-cu m/mole(SRC), using a fragment constant estimation method(4). Triethylene glycol, diacetate is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 4.1X10-3 mm Hg(SRC), determined from a fragment constant method(5). Biodegradation of triethylene glycol, diacetate may be important(SRC), based upon 100% biodegradation of 2-(2-butoxyethoxy)ethyl acetate(6), a structurally similar compound. [R13] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 20(SRC), determined from an estimated log Kow of -0.14(2,SRC) and a regression-derived equation(3), indicates that triethylene glycol, diacetate is not expected to adsorb to suspended solids and sediment in water(SRC). Triethylene glycol, diacetate is not expected to volatilize from water surfaces(3,SRC) based on an estimated Henry's Law constant of 2.7X10-13 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 0.46(3,SRC), from an estimated log Kow(2,SRC), suggests that bioconcentration in aquatic organisms is low(SRC). Estimated hydrolysis half-lives of 150 and 15 days at pHs 7 and 8, respectively(6), suggest that hydrolysis is expected to be a slow process(SRC). Biodegradation of triethylene glycol, diacetate may be important(SRC), based upon 100% biodegradation of 2-(2-butoxyethoxy)ethyl acetate(7), a structurally similar compound. [R14] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), triethylene glycol, diacetate, which has an estimated vapor pressure of 4.1X10-3 mm Hg at 25 deg C(2,SRC), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase triethylene glycol, diacetate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 12 hours(3,SRC). [R15] BIOD: *Biodegradation data were not available for triethylene glycol, diacetate(SRC). However 2-(2-butoxyethoxy)ethyl acetate degraded 100% in an unspecified biodegradability test(1). [R16] ABIO: *The rate constant for the vapor-phase reaction of triethylene glycol, diacetate with photochemically-produced hydroxyl radicals has been estimated as 3.2X10-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 12 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). A base-catalyzed second-order hydrolysis rate constant of 0.53 L/mol-sec (SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 150 and 15 days at pH values of 7 and 8, respectively(2,SRC). [R17] BIOC: *An estimated BCF of 0.46 was calculated for triethylene glycol, diacetate(SRC), using an estimated log Kow of -0.14(1,SRC) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests that bioconcentration in aquatic organisms is low(SRC). [R18] KOC: *The Koc of triethylene glycol, diacetate is estimated as approximately 20(SRC), using a measured log Kow of -0.14(1) and a regression-derived equation(2,SRC). According to a classification scheme(3), this estimated Koc value suggests that triethylene glycol, diacetate is expected to have very high mobility in soil(SRC). [R19] VWS: *The Henry's Law constant for triethylene glycol, diacetate is estimated as 2.7X10-13 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that triethylene glycol, diacetate is expected to be essentially nonvolatile from water surfaces(2,SRC). Triethylene glycol, diacetate's Henry's Law constant(1,SRC) indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Triethylene glycol, diacetate is not expected to volatilize from dry soil surfaces based on an estimated vapor pressure of 4.1X10-3 mm Hg(SRC), determined from a fragment constant method(3). [R20] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 4,322 workers (356 of these are female) are potentially exposed to triethylene glycol, diacetate in the US(1). Occupational exposure to triethylene glycol, diacetate may occur through dermal contact with this compound at workplaces where triethylene glycol, diacetate is produced or used(SRC). [R21] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Triethylene glcol diacetate is exempted from the requirement of a tolerance when used as a solvent (limit: for use on beef cattle only) in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R22] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Triethylene glycol diacetate is included on this list. [R23] FIFR: *Triethylene glcol diacetate is exempted from the requirement of a tolerance when used as a solvent (limit: for use on beef cattle only) in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to animals. [R22] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Reel JR et al; Report (NTP 86-039): 190 (1985). Triethylene glycol diacetate: Reproduction and fertility assessment in CD-1 mice when administered in the drinking water. SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 911 R2: SRI R3: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 2909 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1175 R5: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-158 R6: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 882 R7: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 395 R8: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-89 R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1548 R10: Bossert NL et al; Fundam Appl Toxicol 18 (4): 602-8 (1992) R11: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Triethylene Glycol Diacetate (CAS #111-21-7): Reproduction and Fertility Assessment in CD-1 Mice When Administered in Drinking Water, NTP Study No. RACB84116 (January 1986) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R12: (1) Lewis RJ Jr; Hawley's Condensed Chemical Dictionary 12th ed NY,NY: Van Nostrand Reinhold Co p. 1175 (1993) R13: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE (eds), Boca Raton,FL: CRC Press (1985) (6) Riemenschneider W; Ullmann's Encycl Indust Chem, NY,NY: VCH Publ A9: 578 (1987) R14: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (7) Riemenschneider W; Ullmann's Encycl Indust Chem, NY,NY: VCH Publ A9: 578 (1987) R15: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R16: (1) Riemenschneider W; Ullmann's Encycl Indust Chem, NY,NY: VCH Publ A9: 578 (1987) R17: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park,CA: SRI International (1987) R18: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R19: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R20: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE(eds), Boca Raton,FL: CRC Press (1985) R21: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R22: 40 CFR 180.1001(e) (7/1/97) R23: 40 CFR 716.120 (7/1/97) RS: 21 Record 336 of 1119 in HSDB (through 2003/06) AN: 5572 UD: 200302 RD: Reviewed by SRP on 5/20/1999 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-OLEATE- SY: *EMEREST-2801-; *EMERY,-OLEIC-ACID-ESTER-; *EMERY-OLEIC-ACID-ESTER-2301-; *METHYL-CIS-9-OCTADECENOATE-; *METHYL (Z)-9-OCTADECENOATE; *METHYL-9-OCTADECENOATE-; *CIS-OCTADEC-9-ENOIC-ACID-; *9-OCTADECENOIC ACID(CIS), METHYL ESTER; *9-OCTADECENOIC ACID (Z)-, METHYL ESTER; *OLEIC-ACID,-METHYL-ESTER-; *OLEIC-ACID,-METHYL-ESTER,-CIS- RN: 112-62-9 MF: *C19-H36-O2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Esterification of oleic acid; vacuum fractional distillation; solvent crystallization. [R1] *REACTION OF TRIGLYCERIDES, EG, OLIVE OIL, WITH EXCESS METHANOL AND A CATALYST FOLLOWED BY FRACTIONAL DISTILLATION; REACTION OF OLEIC ACID WITH METHANOL IN THE PRESENCE OF SULFURIC ACID [R2] FORM: *Grades: Technical; Purified 99+% [R1] MFS: *GEO Specialty Chemicals, Hq, 9129 Southern Pine Blvd., Charlotte, NC 28273, (800) 243-6535; Production site: Cedartown, GA 30125 [R3] *Henkel Corporation, Hq, The Triad, Suite 200, 2200 Renaissance Boulevard, Gulph Mills, PA 19406 (215) 270-8100; Chemicals Group, 5051 Estecreek Drive, Cincinnati, OH 45232 (513) 530-7300, Production sites: Cincinnati, OH 45202; City of Commerce, CA 90040 [R3] *Stepan Company, Hq, 22 West Frontage Rd., Northfield, IL 60093, (800) 745-STEP [R3] *Unichema North America, Hq, 4650 South Racine Ave, Chicago, IL 60609 (993) 376-9000; Production site: Chicago, IL 60609 [R3] *Witco Corporation, Hq, 520 Madison Ave, New York, NY 10022-4236 (212) 605-3800; Oleochemicals Group, 755 Crossover Lane, Memphis, TN 38117-4907 (901) 684-7000; Production sites: Chicago, IL 60638; Newark, NJ 07105 [R3] USE: *Intermediate for detergents, emulsifiers, wetting agents, stabilizers, textiles treatment, plasticizers for duplicating inks, rubbers, waxes, chromatographic reference standard [R1] *CHEM INT-EG, FOR ALKANOLAMIDES, FATTY ALCOHOLS AND ACIDS [R2] *EMULSIFIER/EMOLLIENT FOR COSMETICS [R2] *LUBRICANT FOR LEATHER [R2] *PLASTICIZER AND SOFTENER FOR NATURAL AND SYNTHETIC RUBBERS [R2] *The C19 dicarboxylic acids are obtained from oleic acid and/or methyl oleate by three routes ... . [R4, p. V7 625] *Intermediate in the production of drying oils [R4, p. V8 140] *In the production of oleonitrile [R5] *Used in the epoxidation of fatty oils and esters in the Repeated- resin process [R4, p. V9 260] *... In synthesis of cephalosporinS [R6] PRIE: U.S. PRODUCTION: *(1979) PROBABLY GREATER THAN 6.81X10+6 GRAMS [R2] *(1981) PROBABLY GREATER THAN 1.14X10+7 GRAMS [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless to amber clear liquid [R1] ODOR: *Faint fatty odor [R1] BP: *218.5 deg C @ 20 mm Hg [R7] MP: *-19.9 deg C [R7] MW: *296.49 [R7] DEN: *0.8739 @ 20 deg C [R7] HTC: *At constant volume, delta Ec = -2837.3 kcal/mol at 25 deg C [R8] HTV: *20.17 kcal/mol at 1 torr [R8] OWPC: *log Kow= 7.45 [R9] SOL: *Insol in water; miscible with ethyl alcohol, ether; sol in chloroform [R7] SPEC: *MAX ABSORPTION (ALCOHOL): 230 NM (LOG E= 3.5); INDEX OF REFRACTION: 1.4522 AT 20 DEG C; SADTLER REFERENCE NUMBER: 917 (IR, PRISM) [R10]; *IR: 4792 (Coblentz Society Spectral Collection) [R11]; *NMR: 71 (Sadtler Research Laboratories Spectral Collection) [R11]; *MASS: 1894 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R11] SURF: *31.3 dyne/cm at 25 deg C; 25.4 dyne/cm at 100 deg C; 19.1 dyne/cm at 180 deg C [R8] VAP: *6.29X10-6 at 25 deg C [R12] VISC: *Viscosity coefficients = 4.88, 2.62, and 1.64 cP at 30, 60, and 90 deg C, respectively [R8] OCPP: *Boiling point - 217 deg C at 16 torr (decomposes) [R8] *Standard heat of formation = -173.91 kcal/mol at 25 deg C [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition it emits acrid smoke and irritating fumes. [R13] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *0.05 ML OF 10% EMULSION OF OLEIC ACID IN NACL SOLN OR 0.05 ML OF 10% SOLN OF SODIUM OLEATE ADJUSTED WITH HCL TO PH 7.2 INJECTED INTO CORNEAS OF RABBITS CAUSED EYES TO BECOME INFLAMED WITHIN FEW HR AND TO DEVELOP CORNEAL ABSCESS WITHIN FEW DAYS. ... METHYL OLEATE ALSO PRODUCED NECROSIS AND LIPOGENESIS WHEN TESTED IN SAME WAY. [R14] *METHYL OLEATE WAS TESTED FOR CARCINOGENICITY BY ORAL AND SC ADMIN IN ST/A MICE OF BOTH SEXES, BUT A POSITIVE EFFECT COULD NOT BE ASSESSED. [R15] *METHYL OLEATE PROMOTED SKIN TUMOR FORMATION IN MICE. THE RELATION OF MOLECULAR CONFIGURATION AND CARCINOGENICITY OF FATTY ACIDS IS DISCUSSED. [R16] *GROWTH OF THE CRICKET, CRYLLODES SIGILLATUS, WAS SHOWN TO BE INHIBITED BY FATTY ACIDS AND SOME FATTY ACID METHYL ESTERS. THE ROUTE OF ENTRY APPEARED TO BE THROUGH THE CUTICLE OF THE TARSI. METHYL OLEATE SIGNIFICANTLY RETARDED GROWTH, AND RESULTED IN LOWER SURVIVAL. [R17] *Methyl oleate was found to be negative when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Methyl oleate was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.100, 0.333, 1.000, 3.333, and 10.000 mg/plate. The highest negative dose tested in any S. typhimurium strain was 10.000 mg/plate. Slight clearing of the background bacterial lawn occurred at the high dose in cultures without activation. [R18] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methyl oleate's production and use as a synthetic intermediate may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 6.3X10-6 mm Hg at 25 deg C indicates methyl oleate will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase methyl oleate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 7.5 hours. Vapor-phase methyl oleate will also be degraded in the atmosphere by reaction with ozone; the half-life for this reaction is estimated to be 2.1 hours. Particulate-phase methyl oleate will be removed from the atmosphere by wet and dry deposition. If released to soil, methyl oleate is expected to have no mobility based upon an estimated Koc of 62,000. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 0.014 atm-cu m/mole. However, adsorption to soil is expected to attenuate volatilization. Methyl oleate is expected to rapidly biodegrade in aerobic soils as suggested by the rapid biodegradation of structurally similar long-chain fatty acid esters. If released into water, methyl oleate is expected to adsorb to suspended solids and sediment in the water column based upon the estimated Koc. Methyl oleate is expected to rapidly biodegrade in aerobic waters as suggested by the rapid biodegradation of structurally similar long-chain fatty acid esters. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 5 hours and 7 days, respectively. However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column. The volatilization half-life from a model pond is estimated to be about 61 hours ignoring adsorption; when considering maximum adsorption the volatilization half-life increases to 18 months. An estimated BCF of 490 suggests the potential for bioconcentration in aquatic organisms is moderate. An estimated base-catalyzed second-order hydrolysis rate constant of 0.011 L/mole-sec corresponds to half-lives of 2 years and 74 days at pH values of 7 and 8, respectively. Occupational exposure to methyl oleate may occur through inhalation and dermal contact with this compound at workplaces where methyl oleate is produced or used. (SRC) ARTS: *Methyl oleate's production and use as a synthetic intermediate(1) may result in its release to the environment through various waste streams. [R19] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 62,000(SRC), determined from a structure estimation method(2), indicates that methyl oleate is expected to be immobile in soil(SRC). Volatilization of methyl oleate from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 0.014 atm-cu m/mole(SRC), using a fragment constant estimation method(3). However, adsorption to soil is expected to attenuate volatilization(SRC). Methyl oleate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 6.3X10-6 mm Hg(4). Methyl oleate is expected to rapidly biodegrade in aerobic soils as suggested by the rapid biodegradation of structurally similar long-chain fatty acid esters(5-7). [R20] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 62,000(SRC), determined from a structure estimation method(2), indicates that methyl oleate is expected to adsorb to suspended solids and sediment in water(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 0.014 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). Volatilization half-lives for a model river and model lake are 5 hours and 7 days, respectively(SRC), using an estimation method(3). However, volatilization from water surfaces is expected to be attenuated by adsorption to suspended solids and sediment in the water column(SRC). The volatilization half-life from a model pond is estimated to be about 61 hours ignoring adsorption; when considering maximum adsorption the volatilization half-life increases to 18 months(5). According to a classification scheme(6), an estimated BCF of 490 from its log Kow of 7.45(12) and a regression-derived equation suggests the potential for bioconcentration in aquatic organisms is moderate. Methyl oleate is expected to rapidly biodegrade in aerobic soils as suggested by the rapid biodegradation of structurally similar long-chain fatty acid esters(8-10). An estimated base-catalyzed second-order hydrolysis rate constant of 0.011 L/mole-sec(9,SRC) corresponds to half-lives of 2 years and 70 days at pH values of 7 and 8, respectively(11). [R21] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methyl oleate, which has a vapor pressure of 6.3X10-6 mm Hg at 25 deg C(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase methyl oleate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 7.5 hours(SRC) from its estimated rate constant of 7.4X10-11 cu cm/molecule-sec at 25 deg C(3). Vapor-phase methyl oleate is also degraded in the atmosphere by reaction with ozone(SRC); the half-life for this reaction in air is estimated to be 2.1 hours(SRC) from its estimated rate constant of 1.3X10-16 cu cm/molecule-sec at 25 deg C(3). Particulate-phase methyl oleate may be removed from the air by wet and dry deposition(SRC). [R22] BIOD: *AEROBIC: By analogy to chemically similar long chain fatty acid esters that were rapidly degraded by mixed sewage sludge(1-3), methyl oleate is expected to rapidly biodegrade under aerobic conditions(SRC). [R23] ABIO: *The rate constant for the vapor-phase reaction of methyl oleate with photochemically-produced hydroxyl radicals has been estimated as 7.4E-11 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 7.5 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of methyl oleate with ozone has been estimated as 1.3X10-16 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 2 hours at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). A base-catalyzed second-order hydrolysis rate constant of 0.11 L/mole-sec(SRC) was estimated using a structure estimation method(3); this corresponds to half-lives of 2 years and 70 days at pH values of 7 and 8, respectively(3). The predicted near-surface half-life for the photosensitized oxidation of methyl oleate in near suface waters in the Southern US is 1100 hrs(4). Methyl oleate is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum(5). [R24] BIOC: *An estimated BCF of 490 was calculated for methyl oleate(SRC) using a log Kow of 7.45(1) and a regression-derived equation(2). According to a classification scheme(3), the estimated BCF suggests the potential for bioconcentration in aquatic organisms is moderate. [R25] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for methyl oleate can be estimated to be about 62,000(SRC). According to a classification scheme(2), this estimated Koc value suggests that methyl oleate is expected to be immobile in soil. [R26] VWS: *The Henry's Law constant for methyl oleate is estimated as 0.014 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that methyl oleate is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as approximately 5 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as approximately 7 days(SRC). The volatilization half-life from a model pond 2 m deep is estimated to be about 61 hours ignoring adsorption; when considering maximum adsorption the volatilization half-life increases to 18 months(3). Methyl oleate's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). Methyl oleate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 6.3X10-6 mm Hg(4). [R27] WATC: *SURFACE WATER: Methyl oleate was detected in trace quantities in samples from the River Lee, in the UK(1). [R28] EFFL: *Methyl oleate was identified in 3 of 3 New Jersey POTW effluents, date not provided, at a estimated concentration of 0.3-18 ppb(1). It was detected in 13 of 13 effluents samples from an olive oil production plant, Spain, at 520-77721 ug/l(2). It was qualitatively detected in the effluent of a pulp and paper mill in Finland(3). [R29] SEDS: *SOIL: Methyl oleate was qualitatively detected in soil samples from Southern Alberta, Canada, in strata associated with the Mazama volcano eruption which occurred approximately 7000 years ago(1). [R30] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 35,946 workers (1,256 of these are female) are potentially exposed to methyl oleate in the US(1). Occupational exposure to methyl oleate may occur through inhalation and dermal contact with this compound at workplaces where methyl oleate is produced or used(SRC). [R31] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *Methyl oleate is exempted from the requirement of a tolerance when used as a surfacant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R32] FIFR: *Methyl oleate is exempted from the requirement of a tolerance when used as a surfacant in accordance with good agricultural practice as inert (or occasionally active) ingredients in pesticide formulations applied to growing crops only. [R32] FDA: *Methyl oleate is an indirect food additive for use only as a component of adhesives. [R33] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *DETERMINATION OF METHYL OLEATE IN FATS AND OILS BY GAS CHROMATOGRAPHY. [R34] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 775 R2: SRI R3: SRI. 1998 Directory of Chemical Producers -United States of America. SRI International, Menlo Park, CA. 1998.. 755 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. R5: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V9 317 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V3 56 R7: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-228 R8: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 424 R9: Krop HB et al; Chemosphere 34: 107-19 (1997) R10: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-404 R11: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 943 R12: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R13: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 2532 R14: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. 765 R15: KLAER HW ET AL; ACTA PATHOL MICROBIOL SCAND SECT A PATHOL 83 (5): 550 (1975) R16: ARFFMANN E, GLAVIND J; ACTA PATHOL MICROBIOL SCAND, SECT A 82A (1): 127 (1974) R17: MCFARLANE JE, HENNEBERRY GO; J INSECT PHYSIOL 11 (9): 1247 (1965) R18: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R19: (1) Lewis RJ; Hawley's Condensed Chemical Dictionary. 12th Ed. NY,NY: Van Nostrand Reinhold Company (1993) R20: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY,NY: Hemisphere Pub Corp (1989) (5) Malaney GW, Gerhold RM; Proc 17th Ind Waste Conf Purdue Univ Ext Ser 112: 249-57 (1962) (6) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (7) Freitag D et al; Environmental Hazard Profile - Test Results as Related to Structures and Translation into the Environment: QSAR in Environmental Toxicology pp. 111-136 (1984) R21: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) USEPA; EXAMS II Computer Simulation (1987) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Malaney GW, Gerhold RM; Proc 17th Ind Waste Conf Purdue Univ Ext Ser 112: 249-57 (1962) (9) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (10) Freitag D et al; Environmental Hazard Profile - Test Results as Related to Structures and Translation into the Environment: QSAR in Environmental Toxicology pp. 111-136 (1984) (11) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (12) Krop HB et al; Chemisophere 34: 107-19 (1997) R22: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R23: (1) Malaney GW, Gerhold RM; Proc 17th Ind Waste Conf Purdue Univ Ext Ser 112: 249-57 (1962) (2) Kawasaki M; Ecotox Environ Safety 4: 444-54 (1980) (3) Freitag D et al; Environmental Hazard Profile - Test Results as Related to Structures and Translation into the Environment: QSAR in Environmental Toxicology pp. 111-136 (1984) R24: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Kwok ESC et al; Environ Sci Technol 30: 329-34 (1996) (3) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (4) Zepp RG, Baughmann GL; pp. 237-63 in Aquatic Pollutants. Hutzinger O et al Eds. Oxford: Pergamon Press (1978) (5) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R25: (1) Krop HB et al; Chemosphere 34: 107-19 (1997) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R26: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R27: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington,DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) USEPA; EXAMS II Computer Simulation (1987) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY,NY: Hemisphere Pub Corp (1989) R28: (1) Waggott A; Chem Water Reuse 2: 55-9 (1981) R29: (1) Clark LB et al; Res J WPCF 63: 104-13 (1991) (2) Crespo RS, Alvares-Buyilla PA; Org Micropollut Aquat Environ, Proc Eur Supp 6: 511-17 (1990) (3) Koistinen J et al; Chemosphere 37: 219-35 (1998) R30: (1) Dormaar JF; Can J Earth Sci 20: 859-65 (1983) R31: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R32: 40 CFR 180.1001(d) (7/1/97) R33: 21 CFR 175.105 (4/1/97) R34: BANNON CD ET AL; J CHROMATOGR 247 (1): 71 (1982) RS: 23 Record 337 of 1119 in HSDB (through 2003/06) AN: 5613 UD: 200303 RD: Reviewed by SRP on 5/10/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYLACRYLONITRILE- SY: *2-CYANOPROPENE-; *2-CYANOPROPENE-1-; *ISOPROPENE-CYANIDE-; *ISOPROPENYLNITRILE-; *METHACRYLONITRILE-; *ALPHA-METHACRYLONITRILE-; *ALPHA-METHYLACRYLONITRILE-; *2-METHYLACRYLONITRILE-; *2-METHYLPROPENENITRILE-; *2-METHYL-2-PROPENENITRILE-; *2-PROPENENITRILE,-2-METHYL-; *USAF-ST-40- RN: 126-98-7 MF: *C4-H5-N SHPN: UN 3079; Methacrylonitrile, inhibited IMO 3.0; Methacrylonitrile, inhibited HAZN: U152; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Vapor-phase catalytic oxidation of methallylamine; dehydration of methacrylamide; from isopropylene oxide and ammonia. [R1, 1015] IMP: *Product may be stabilized with 50 ppm the monoethyl ether of hydroquinone. [R2] USE: *In prepn of homopolymers and copolymers; as an intermediate in prepn of acids, amides, amines, esters, nitriles [R1, 751] *Vinyl nitrile monomer, copolymer with styrene, butadiene, etc, elastomers, coatings, plastics [R3] *MONOMER FOR POLYMETHACRYLONITRILE [R4] PRIE: U.S. PRODUCTION: *(1979) PROBABLY GREATER THAN 4.54X10+6 G [R4] *(1981) PROBABLY GREATER THAN 2.27X10+6 G [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid. [R5, 198] ODOR: *Odor-like bitter almonds. [R5, 198] BP: *90.3 deg C @ 760 mm Hg [R1, 1015] MP: *-35.8 deg C [R1, 1015] MW: *67.09 [R6] DEN: *0.8001 @ 20 deg C/4 deg C [R1, 1015] HTV: *31.8 kJ/mol @ BP [R7] OWPC: *log Kow = 0.68 [R8] SOL: *Miscible with acetone, octane, toluene @ 20-25 deg C [R1, 1015]; *Sol in alcohol, ether [R6]; *In water, 2.54X10+4 mg/l @ 25 deg C [R9] SPEC: *Index of refraction: 1.4007 @ 20 deg C/D; 1.3954 @ 30 deg C/D [R1, 1015]; *Absorptivity in aqueous phase: 1.563X10+3 @ 215 nm; absorptivity in gas phase: 7.624X10+3 @ 197.8 nm [R10]; *MAX ABSORPTION (ALCOHOL): 215 NM (LOG E= 2.83); SADTLER REF NUMBER: 14000 (IR, PRISM); V97 (NMR) [R11]; *IR: COB 4346 (Coblentz Society Spectral Collection) [R12]; *UV: OES 4-16 (Organic Electronic Spectral Data, Phillips et al, John Wiley and Sons, New York) [R12]; *NMR: 97 (Varian Associates NMR Spectra Catalogue) [R12]; *MS: NIST 35004 (NIST/EPA/MSDC Mass Spectral Database 1990 Version) [R12] SURF: *24.4 dynes/cm @ 20 deg C [R1, 1015] VAPD: *2.31 (Air= 1) [R2] VAP: *71.2 mm Hg @ 25 deg C [R13] VISC: *0.392 cP @ 20 deg C [R1, 1015] OCPP: *DENSITY OF SATURATED AIR: 1.17 (AIR= 1) [R14] *VAP: 40 mm Hg @ 13 deg C; 65 mm Hg @ 25 deg C; 100 mm Hg @ 33 deg C [R2] *Saturated concn: 208 g/cu m @ 20 deg C, 318 g/cu m @ 30 deg C [R2] *Heat of polymerization = 64.0 kJ/mol; aqueous azeotrope = 84% water [R7] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- HAZS: *The major hazards encountered in the use and handling of methylacrylonitrile stem from its toxicologic properties and flammability. Toxic by all routes (ie, inhalation, ingestion, and dermal absorption), exposure to this bitter-almond-smelling, colorless liquid may occur from its use as a copolymer with styrene and butadiene; as an intermediate in the preparation of acids, amides, amines, esters, and nitriles; and in elastomers, coatings, and plastics. Effects from exposure may include contact burns to the skin and eyes, nausea, headache, tachycardia, CNS depression, convulsions, asphyxiation, coma, and death. OSHA has established a time-weighted average (TWA) limit of 1 ppm, with an indication that skin contact is to be avoided. In activities and situations where over-exposure may occur, wear a positive pressure self-contained breathing apparatus, and chemical protective clothing which is specifically recommended by the shipper or manufacturer. If contact should occur, immediately flush exposed eyes and skin with running water for at least 15 minutes. Contaminated clothing and shoes should be removed and left at the site. Methylacrylonitrile is extremely flammable (flash point: 13 deg C, open cup), capable of ignition by heat, sparks, or flames. Its heavier-than-air vapor may travel to a source of ignition and flash back, or accumulate to explosive concentrations in confined spaces such as sewers. Because of its tendency to polymerize violently, containers of methylacrylonitrile may explode in the heat of a fire. For fires involving this substance, extinguish with dry chemical, CO2, water spray, fog, or alcohol-resistant foam. If a tank, rail car, or tank truck is involved in the fire, isolate for 1/2 mile in all directions. Dike fire control waterfor later disposal and do not scatter the material. Take up small spills of methylacrylonitrile with sand or other noncombustible absorbent and place into containers for later disposal. Dike far ahead of large spills for later disposal. Methylacrylonitrile is a potential candidate for liquid injection, rotary kiln, or fluidized bed forms of incineration. DOT: +Health: Toxic; may be fatal if inhaled, ingested or absorbed through skin. Inhalation or contact with some of these materials will irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Methacrylonitrile, inhibited/ [R15] +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion and poison hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Methacrylonitrile, inhibited/ [R15] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 100 to 200 meters (330 to 660 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Methacrylonitrile, inhibited/ [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. /Methacrylonitrile, inhibited/ [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Methacrylonitrile, inhibited/ [R15] +Fire: CAUTION: All these products have a very low flash point. Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Methacrylonitrile, inhibited/ [R15] +Spill or leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Small spills: Absorb with earth, sand or other non-combustible material and transfer to containers for later disposal. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Methacrylonitrile, inhibited/ [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Methacrylonitrile, inhibited/ [R15] FPOT: *METHACRYLONITRILE EVOLVES FLAMMABLE CONCENTRATIONS OF VAPOR AT TEMPERATURES DOWN TO 12.8 DEG C. THUS, AT ROOM TEMPERATURES, FLAMMABLE ... CONCENTRATIONS ARE LIABLE TO BE PRESENT IN ABSENCE OF PRECAUTIONS. THE NORMAL DANGERS ASSOCIATED WITH FIRE ... ARE INTENSIFIED BY THE LETHAL NATURE OF THE FUMES AND VAPORS EVOLVED. [R16, 36] *A dangerous fire hazard when exposed to heat, flame, or sparks. [R17, 2173] NFPA: +Health: 2. 2= Materials that, on intense or continued (but not chronic) exposure, could cause temporary incapacitation or possible residual injury, including those requiring the use of respiratory protective equipment that has an independent air supply. These materials are hazardous to health, but areas may be entered freely if personnel are provided with full-face mask self-contained breathing apparatus that provides complete eye protection. [R18] +Flammability: 3. 3= This degree includes Class IB and IC flammable liquids and materials that can be easily ignited under almost all normal temperature conditions. Water may be ineffective in controlling or extinguishing fires in such materials. [R18] +Reactivity: 2. 2= This degree includes materials that are normally unstable and readily undergo violent chemical change, but are not capable of detonation. This includes materials that can undergo chemical change with rapid release of energy at normal temperatures and pressures and materials that can undergo violent chemical changes at elevated temperatures and pressures. This also includes materials that may react violently with water or that may form potentially explosive mixtures with water. In advanced or massive fires involving these materials, fire fighting should be done from a safe distance or from a protected location. [R18] FLMT: +Lower flammable limit: 2%; upper flammable limit: 6.8% [R18] FLPT: *13 Deg C (55 Deg F) open cup [R19] EXPL: *THE DOMINANT HAZARD IS ... EXPLOSION DUE ... TO ... TENDENCY TO POLYMERIZE VIOLENTLY. [R16, 36] REAC: *Strong acids, strong oxidizers, alkali, light. [Note: Polymerization may occur due to elevated temperature, visible light, or contact with a concentrated alkali.] [R5, 199] DCMP: *When heated to decomposition it emits toxic fumes of /nitrogen oxides and cyanides/. [R17, 2174] ODRT: *... IT SHOULD BE NOTED THAT METHACRYLONITRILE CANNOT BE DETECTED BY ITS SMELL EVEN AT CONCENTRATIONS WHICH ARE ALREADY DANGEROUS FOR HUMANS. [R20] *An odor threshold of 2.1 ppm has been reported. [R21, 1991.935] SERI: *LACRIMATOR [R19] *An eye irritant. [R17, 2173] *It is only mildly irritating to the eyes and skin. [R21, 1991.936] EQUP: *SUITABLE RESP PROTECTIVE EQUIPMENT, PROTECTIVE CLOTHING AND FIRE-FIGHTING EQUIPMENT SHOULD BE AVAILABLE FOR AN EMERGENCY. [R16, 37] *Wear appropriate personal protective clothing to prevent skin contact. [R5, 198] *Wear appropriate eye protection to prevent eye contact. [R5, 198] OPRM: *Contact lenses should not be worn when working with this chemical. [R5, 199] *The worker should immediately wash the skin when it becomes contaminated. [R5, 198] *Work clothing that becomes wet should be immediately removed due to its flammability hazard. [R5, 198] *... IT SHOULD BE NOTED THAT METHACRYLONITRILE CANNOT BE DETECTED BY ITS SMELL EVEN AT CONCENTRATIONS WHICH ARE ALREADY DANGEROUS FOR HUMANS. HENCE SPECIAL ATTENTION MUST BE GIVEN TO VENTILATION AND ESTIMATIONS OF THE AMT OF POISON PRESENT MUST BE CARRIED OUT FREQUENTLY. [R20] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. [R22] *All nitriles should be handled under carefully controlled conditions and only by personnel having a thorough understanding and knowledge of safe handling techniques. Because of the nature of nitrile cmpd and the lack of complete toxicity data on many nitriles, care should be exercised in handling these cmpd to avoid inhalation of the vapors, ingestion, and contact with the skin. /Nitriles/ [R22] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R23] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R24] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R25] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste numbers D003, P030, and U152 must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R26] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R27] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Severe acute inhalations should be treated like cyanide poisoning. The first priority is to establish adequate ventilation (100% oxygen) and circulation, since cyanide antidotes are theoretically useful but clinically unproven in acrylonitrile poisoning. /Acrylonitrile/ [R28] *Contaminated clothing should be removed and placed in a sealed container. Attendents should use plastic gloves and should discard them after use since acrylonitrile may penetrate rubber, gloves, and leather. The usual decontamination measures (... lavage, charcoal) may be effective within the first 1 to 2 hours postingestion, but should not delay the use of nitrites and thiosulfate in significantly symptomatic patients. /Acrylonitrile/ [R28] *Sodium nitrite and sodium thiosulfate have been recommended as antidotes, although their efficacy in human toxicity is unproven. Most exposures will not require an antidote, but the Lilly cyanide kit theoretically may be useful in severe exposures. /Acrylonitrile/ [R28] *Symptomatic management especially of respiration is the mainstay of treatment. Moderately to severely exposed patients should have an evaluation of liver function. /Acrylonitrile/ [R28] *Rapid support of respiration and circulation is essential to successful treatment of cyanide intoxication. Massive cyanide overdoses have survived with only good supportive care. Immediate attention should be directed toward assisted ventilation, administration of 100% oxygen, insertion of intravenous lines, and institution of cardiac monitoring. Obtain an arterial blood gas immediately and correct any severe metabolic acidosis (pH below 7.15). Oxygen (100%) should be used routinely in moderate or severely symptomatic patients even in the presence of a normal pO2, since 100% O2 increases O2 delivery, may reactivate cyanide-inhibited mitochondrial enzymes, and potentiates the effect of thiosulfate. Avoid mouth to mouth resuscitation during CPR in order to prevent self poisoning. /Cyanides/ [R28] *Amyl nitrite perles are designed to produce 3% to 5% methemoglobinemia while an iv line is established for iv sodium nitrite. As a temporizing measure, the patient inhales the vapors until the sodium nitrite is ready. Because of the variability in methemoglobin production and the potential for cardiovascular collapse, this step may be omitted if sodium nitrite is readily available and the patient is not in extremis. Adequate ventilation and oxygenation are more important than administration of amyl nitrite. One perle ... is crushed and inhaled ... until iv nitrite is given. Sodium nitrite ... is administered iv slowly ... to produce a 20% methemoglobin level in adults. Administer sodium nitrite doses to children on the basis of body weight, since fatal methemoglobinemia has occurred in children. /Cyanides/ [R28] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Administer amyl nitrite ampules as per protocol and physician order ... . Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Cyanide and related compounds/ [R29] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Administer cyanide antidote kit as per protocol and physician order ... . Monitor and treat cardiac arrhythmias if necessary ... . Consider vasopressors to treat hypotension without signs of hypovolemia ... . Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Cyanide and related compounds/ [R29] HTOX: *LACRIMATOR, INSIDIOUS POISON, DELAYED SKIN REACTION. [R19] *TOXIC BY INGESTION, INHALATION, AND SKIN ABSORPTION. [R3] NTOX: *LC50 VALUES FOR METHYLACRYLONITRILE OF 630 PPM FOR A 1 HR EXPOSURE AND 400 PPM FOR A 4 HR EXPOSURE WERE CALCULATED. THE ANIMALS DIED IN ASPHYXIA AND NO GROSS CHANGES WERE SEEN AT NECROPSY. [R21, 1991.935] *... INHALATION OF 50-100 PPM FOR 3 TO 7 HR WAS LETHAL /TO DOGS/. DEATH OF THE DOGS WAS PRECEDED BY VOMITING, DIARRHEA, AND CONVULSIONS. [R21, 1991.935] *IN A SHORT TERM, REPEATED INHALATION EXPOSURE BIOASSAY, RATS WERE EXPOSED 7 HR/DAY, 5 DAYS/WK, FOR A TOTAL OF 9 DAYS TO 20, 50 and 110 PPM METHYLACRYLONITRILE. ON THE 1ST DAY, 2 OF 12 RATS DIED @ 110 PPM. ... DOGS WERE EXPOSED ON SAME SCHEDULE FOR 8 DAYS @ 20 PPM. ANIMALS VOMITED ON 1ST DAY AND SUFFERED A 20% WT LOSS BY END OF 8TH DAY. NO GROSS OR MICROSCOPIC LESIONS WERE SEEN ON NECROPSY. [R21, 1991.935] *IN A SUBCHRONIC STUDY, RATS WERE EXPOSED 7 HR/DAY, 5 DAYS/WK FOR A TOTAL OF 91 DAYS ... 7 MALE RATS DIED ON FIRST DAY @ 109.3 PPM; 1 ... ON SECOND DAY @ 52.6 PPM. ... WEIGHT GAINS WERE DEPRESSED AND LIVER WT INCR @ 109.3 and 52.9 PPM. IT WAS CONCLUDED THAT FEMALE RATS WERE MORE RESISTANT THAN MALES AND THAT NOEL WAS BETWEEN 19.3 and 52.9 PPM FOR RATS. [R21, 1991.935] *BEAGLE DOGS WERE EXPOSED FOR 90 DAYS ... /7 HR/DAY, 5 DAYS/WK/. CNS TOXICITY, MANIFEST IN CONVULSIONS AND LOSS OF MOTOR CONTROL IN HIND LIMBS WAS SEEN IN 2 OF 3 DOGS @ 13.5 PPM ... MICROSCOPIC BRAIN LESIONS WERE DETECTED IN 1 ... /DOG/. DIARRHEA WAS NOTED ON 5TH DAY. AT 8.8 PPM, THERE WAS A TRANSITORY ELEVATION OF SERUM TRANSAMINASE VALUES AT 21ST DAY. [R21, 1991.936] *Approx LD50 for mice exposed 1 hr was 630 ppm (1700 mg/cu m); for 4 hr it was about 400 ppm. None out of 6 mice was killed by 8 hr exposure to 75 ppm. Animals showed resp paralysis and convulsions. [R14] */Oral/ ... LD50 in mice /found/ to be 20-25 mg/kg and in rats 25-50 mg/kg. Symptoms were those of weakness, tremors, cyanosis, and convulsions. ... It was absorbed readily through guinea pig skin with no skin irritation. It was not a skin sensitizer in this species. [R14] *A DROP OF LIQ APPLIED TO RABBIT EYE CAUSED IMMEDIATE BLEPHAROSPASM AND ... IRRITATION ... . [R30] *ACUTE TOXICITY OF ALIPHATIC NITRILES WAS STUDIED IN MICE. METHACRYLONITRILE WAS ONE OF THOSE STUDIED. TOXICITY DECREASED AS THE NUMBER OF CARBON ATOMS IN THE ALKYL CHAIN INCREASED. SUBACUTE TOXIC SYMPTOMS, EG, CONVULSIONS, ON THE OTHER HAND, WERE MORE INTENSIFIED AS THE NUMBER OF CARBON ATOMS INCREASED. THE TOXICITY OF THE COMPOUNDS STUDIED WAS NOT RELATED TO THE RELEASE OF CYANIDE FROM THE MOLECULE, BUT WAS DUE TO THE INTACT MOLECULE ITSELF EXCEPT FOR ACRYLONITRILE. [R31] *Methacrylonitrile was tested for mutagenicity in the Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. Methacrylonitrile was tested over a wide range of doses (0, 100, 333, 1000, 3333, and 6666 ug/plate) in five Salmonella typhimurium strains (TA97, TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor-induced rat or hamster liver S9. Methacrylonitrile was negative in these tests and the highest ineffective dose level tested in all five Salmonella tester strains was 3333 ug/plate. The 10,000 ug/plate dose level caused clearing of the background lawn in strain TA100 without activation and in strain TA1537 in the presence of rat liver S9. [R32] *The interaction of 2(14)C methyl-2,3 (14)C acrylonitrile with the components of blood and its deposition in male Sprague Dawley rats has been investigated. Following an oral administration of 100 mg/kg (0.5 LD50, 8 uCurie/kg), the rats excreted 43% of the (14)C in the urine, 15% in the feces and 2.5% in the expired air as (14)CO2 in 5 days. Hydrogen cyanide was not detectable. The red blood cells retained significant amounts of radioactivity for more than five days after administration, whereas the (14)C activity in plasma declined sharply. More than 50% of the radioactivity in erythrocytes was detected as covalently bound to cytoplasmic (hemoglobin) and membrane proteins. A small amount of radioactivity was also found in the heme fraction. About 13% of the total dose administered was recovered as thiocyanate in the plasma and the urine. These results suggest that the toxicity of 2(14)C methyl-2,3 (14)C acrylonitrile may be attributable to the whole molecule and not entirely to the in vivo liberation of cyanide. [R33] *STRUCTURE-ACTIVITY RELATIONSHIPS WERE QUALITATIVELY AND QUANTITIVELY EXAMINED FOR 56 COMPOUNDS (EG DERIVATIVES OF PROPIONITRILE, ACRYLONITRILE, AND CYSTEAMINE) WHICH CAUSED DUODENAL ULCER AND/OR ADRENOCORTICAL NECROSIS IN RATS. ULCEROGENIC ACTIVITY WAS MOST INTENSE IN THE CARBONITRILES ATTACHED TO 2 OR 3-C BACKBONES. [R34] NTXV: *LD50 Rat oral 25-50 mg/kg; [R21, 1991.935] *LD50 Rabbit dermal 0.32-0.35 mg/kg bw; [R21, 1991.935] *LD50 Mouse oral 20 to 25 mg/kg; [R21, 1991.935] *LC50 Rat inhalation 328 ppm/4 hr; [R17, 2173] *LD50 Rabbit oral 16 mg/kg; [R17, 2173] *LC50 Mouse inhalation 36 ppm/4 hr; [R17, 2173] *LC50 Rabbit inhalation 37 ppm/4 hr; [R17, 2173] *LD50 Rat skin 2080 mg/kg; [R17, 2173] *LC50 Guinea pig inhalation 88 ppm/4 hr; [R17, 2173] *Approx LD50 for mice exposed 1 hr was 630 ppm (1700 mg/cu m); for 4 hr it was about 400 ppm; [R14] *LC50 VALUES FOR METHYLACRYLONITRILE OF 630 PPM FOR A 1 HR EXPOSURE AND 400 PPM FOR A 4 HR EXPOSURE WERE CALCULATED; [R21, 1991.935] *Approx LD50 for mice exposed 1 hr was 630 ppm (1700 mg/cu m); for 4 hr it was about 400 ppm; [R14] NTP: +The potential reproductive toxicity of methacrylonitrile in Sprague-Dawley rats was evaluated using the Reproductive Assessment by Continuous Breeding (RACB) protocol. Based on decreased body weights and feed consumption, increased water consumption, and mortality noted during Task 1, dose levels for the continuous breeding phase for this study were set at 2, 7, and 20 mg/kg in deionized water by oral gavage. Exposure to methacrylonitrile by gavage (20 rats/sex/group) did not affect the reproductive performance of F0 rats (Task 2) or F1 rats (Task 4) where only the controls and high-dose groups were evaluated. In Task 4, estrous cyclicity of the F1 animals was not affected by methacrylonitrile admin. Slight but consistent decr (3-6%) were noted in the 20 mg/kg F0 male body weights, although none of these reached statistical significance. F0 female body weights were unchanged. Body weights of the F1 20 mg/kg males and females were consistently less (6-10%) than controls and were occasionally statistically significant. Daily mean feed consumption was decreased by 8-11% in the 20 mg/kg F1 males; F0 male and female and F1 female feed consumption values were unchanged. No treatment-related changes were noted in hematology or clinical chemistry parameters for either the F0 or F1 animals. At necropsy, no differences were noted in F0 or F1 animals absolute organ weights; however, relative liver weight was increased in the 20 mg/kg males and females from both generations by /about/ 12% when compared to controls. No treatment-related gross or microscopic lesions were observed in either the F0 or F1 animals. The % normal sperm was decreased slightly (by /about/ 1%) in the 2 and 20 mg/kg F0 males while no differences were seen in F0 epididymal sperm density. In the F1 generation, epididymal sperm density was decreased by 19% at 20 mg/kg but epididymal sperm morphology was unchanged. F0 AND F1 sperm motion parameters and testicular spermatid head counts were unchanged. Results of this study show that methacrylonitrile is not a selective reproductive toxicant, because the decr in epididymal sperm density occurred concomitant with those doses that reduced body weight. The no-observable-adverse-effect level (NOAEL) in this study was 7 mg/kg. The /about/ 1% change in epididymal sperm abnormalities at 2 and 20 mg/kg is believed to be "noise" and not a treatment-related response because the historical control range of % abnormal sperm is 0.1-1.4% in this lab. A max tolerated dose (MTD) was reached in this study based on the decr in F0 AND F1 body weight and incr in relative liver weights. Methacrylonitrile may be a slight developmental toxicant in males at 20 mg/kg based on the decreased epididymal sperm density in the F1 males. [R35] ADE: *... READILY ABSORBED THROUGH SKIN. [R21, 1991.936] *FOLLOWING ADMINISTRATION OF A SINGLE DOSE OF 50 MG/KG IP TO RATS, METHACRYLONITRILE WAS SLOWLY ELIMINATED IN THE URINE AND WAS NO LONGER DETECTABLE AFTER 4-5 DAYS. FREE HYDROGEN CYANIDE WAS DETECTABLE ONLY ON THE FIRST DAY IN THE URINE AND BOUND HYDROGEN CYANIDE ONLY THE FIRST 2 DAYS AFTER TREATMENT. DISTRIBUTION IN THE ORGANS OF UNCHANGED METHACRYLONITRILE AND HYDROGEN CYANIDE WAS STUDIED. [R36] METB: *FOLLOWING ADMINISTRATION OF A SINGLE DOSE OF 50 MG/KG IP TO RATS, METHACRYLONITRILE WAS SLOWLY ELIMINATED IN THE URINE AND WAS NO LONGER DETECTABLE AFTER 4-5 DAYS. FREE HYDROGEN CYANIDE WAS DETECTABLE ONLY ON THE FIRST DAY IN THE URINE AND BOUND HYDROGEN CYANIDE ONLY THE FIRST 2 DAYS AFTER TREATMENT. DISTRIBUTION IN THE ORGANS OF UNCHANGED METHACRYLONITRILE AND HYDROGEN CYANIDE WAS STUDIED. [R36] INTC: *Antidotes for acute toxicity of methacrylonitrile were studied in rats. Male Wistar rats were exposed for 30 minutes to methacrylonitrile at lethal concentrations from 3180 to 5700 ppm. Animals were removed to plain air. Some exposed to 3180 or 3210 ppm were injected with unusual cyanide antidotes 4-dimethylaminophenol at 10 mg/kg plus 500 mg/kg sodium thiosulfate. Some exposed to 3500 to 5700 ppm were given N-acetyl-cysteine at 200 mg/kg, an acrylonitrile antidote. Clinical effects observed in animals not given the antidotes were compared with those of comparable doses of acrylonitrile. Animals intoxicated with acrylonitrile showed marked salivation, flow of tears, diarrhea, and convulsions with death occurring in 3 to 4 hours. Animal intoxicated with methacrylonitrile showed rapid unconsciousness with convulsions and lethality by 1 hr, suggesting metabolically formed cyanide. While all animals not given antidotes died, those given the cyanide antidotes all survived. N-acetyl-cysteine caused surival of all animals through exposure to 4340 ppm. At higher doses some deaths occurred but the majority survived. ... Acute toxicity of methacrylonitrile is predominantly caused by metabolically formed cyanide. N-acetyl-cysteine, which reacts directly with alpha, beta unsaturated nitrites, is an effective antidote, as it is against acrylonitrile. [R37] *WHEN SODIUM THIOSULFATE WAS GIVEN IN MULTIPLE INJECTIONS, IT PROTECTED MICE AGAINST DEATH BY PROPIONITRILE. [R38] *The toxic mechanism of nitriles (including propionitrile) and the effect of metabolic modifiers in mice were studied in relation to their physicochemical properties. All the test nitriles liberated cyanide both in vivo and in vitro, with the exception of benzonitrile, although the extent of liberation and the effect of carbon tetrachloride pretreatment on the mortality of animals differed among nitriles. From these results, test compounds were tentatively divided into 3 groups. In group 1, acute toxicity was greatly reduced by carbon tetrachloride pretreatment, in group 2, toxicity was not significantly changed or was somewhat enhanced, and in group 3, benzonitrile only, toxicity was clearly enhanced. The amount of cyanide was higher at death in the brains of mice given group 1 compounds, the level being comparable to that found in mice killed by dosing with potassium cyanide. The relation between log (1/LD50) and log p for the compounds in group 1 fitted a parabolic plot, while that for compounds in group 2 was linear. For most nitriles, the in vitro metabolism was inhibited when the incubation mixture contained either SKF-525A, carbon monoxide, or microsomes from mice treated with carbon tetrachloride. When mice were closed with ethyl alcohol, metabolic enhancement of nitriles was seen compared with the control. However, ethyl alcohol, when added to the incubation mixture, inhibited the in vitro metabolism of nitriles. [R39] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methylacrylonitrile's production and use in polymers and coatings may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 71.2 mm Hg at 25 deg C indicates methylacrylonitrile will exist solely as a vapor in the ambient atmosphere. Vapor-phase methylacrylonitrile will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone; the half-life for these reactions in air are estimated to be 46 hours and 33 days, respectively. If released to soil, methylacrylonitrile is expected to have high mobility based upon an estimated Koc of 56. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 2.47X10-4 atm-cu m/mole. Methylacrylonitrile may volatilize from dry soil surfaces based upon its vapor pressure. Microorganisms hydrolyze nitriles predominately to ammonia and carboxylic acids. A bacterium isolated from soil was able to utilize methylacrylonitrile as a sole source of carbon and nitrogen, therefore biodegradation may be important for this compound. If released into water, methylacrylonitrile is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3 hours and 4 days, respectively. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur based on the negligible hydrolysis of acrylonitrile between pH 4 and 10. Occupational exposure to methylacrylonitrile may occur through inhalation and dermal contact with this compound at workplaces where methylacrylonitrile is produced or used. (SRC) ARTS: *Methylacrylonitrile's production and use in polymers and coatings(1,2) may result in its release to the environment through various waste streams(SRC). [R40] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 56(SRC), determined from a measured log Kow of 0.68(2) and a regression-derived equation(3), indicates that methylacrylonitrile is expected to have high mobility in soil(SRC). Volatilization of methylacrylonitrile from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 2.47X10-4 atm-cu m/mole(SRC) derived from its vapor pressure, 71.2 mm Hg(4), and water solubility, 2.54X10+4 mg/l(5). The potential for volatilization of methylacrylonitrile from dry soil surfaces may exist(SRC) based upon its vapor pressure(4). Microorganisms hydrolyze nitriles predominately to ammonia and carboxylic acids(6). A bacterium isolated from soil (Pseudomonas putida) was able to utilize methylacrylonitrile as a sole source of carbon and nitrogen(7); therefore, biodegradation may be an important fate process for this compound(SRC). [R41] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 56(SRC), determined from a measured log Kow of 0.68(2) and a regression-derived equation(3), indicates that methylacrylonitrile is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 2.47X10-4 atm-cu m/mole(SRC) derived from its vapor pressure, 71.2 mm Hg(4), and water solubility, 2.54X10+4 mg/l(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3 hours and 4 days, respectively(SRC). According to a classification scheme(6), an estimated BCF of 3(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Microorganisms hydrolyze nitriles predominately to ammonia and carboxylic acids(8). A bacterium isolated from soil (Pseudomonas putida) was able to utilize methylacrylonitrile as a sole source of carbon and nitrogen(9); therefore, biodegradation may be an important fate process for this compound(SRC). [R42] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), methylacrylonitrile, which has a vapor pressure of 71.2 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase methylacrylonitrile is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 46 hours(SRC), calculated from its rate constant of 8.36X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). The rate constant for the vapor-phase reaction of methylacrylonitrile with ozone is 3.52X10-19 cu cm/molecule-sec (temperature unspecified)(4). This corresponds to an atmospheric half-life of about 33 days(SRC) at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(5). [R43] BIOD: *Microorganisms hydrolyze nitriles predominately to ammonia and carboxylic acids(1). A bacterium isolated from soil (Pseudomonas putida) was able to utilize methylacrylonitrile as a sole source of carbon and nitrogen(2). In another study, a mixed microbial culture, isolated from an environment contaminated with organic cyanides and PCBs, utilized methylacrylonitrile as the sole source of carbon and nitrogen(1). The mixed microbial culture was grown for 48 hrs at pH 7 with 1 g/l of methylacrylonitrile; the final pH and ammonia concn were determined to be 8.17 and 40.9 umol/ml, respectively(1). [R44] ABIO: *The rate constant for the vapor-phase reaction of methylacrylonitrile with photochemically-produced hydroxyl radicals has been estimated as 8.36X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 46 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of methylacrylonitrile with ozone is 3.52X10-19 cu cm/molecule-sec (temperature unspecified)(2). This corresponds to an atmospheric half-life of about 33 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). Methylacrylonitrile is not expected to undergo hydrolysis in the environment based on the negligible hydrolysis of acrylonitrile between pH 4 and 10(4) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R45] BIOC: *An estimated BCF of 3 was calculated for methylacrylonitrile(SRC), using a log Kow of 0.68(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R46] KOC: *The Koc of methylacrylonitrile is estimated as 56(SRC), using a measured log Kow of 0.68(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that methylacrylonitrile is expected to have high mobility in soil(SRC). [R47] VWS: *The Henry's Law constant for methylacrylonitrile is estimated as 2.47X10-4 atm-cu m/mole(SRC) based upon its vapor pressure, 71.2 mm Hg(1), and water solubility, 2.54X10+4 mg/l(2). This Henry's Law constant indicates that methylacrylonitrile is expected to volatilize from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 3 hours (SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4 days(SRC). Methylacrylonitrile's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of methylacrylonitrile from dry soil surfaces may exist(SRC) based upon a vapor pressure of 71.2 mm Hg(1). [R48] WATC: *SURFACE WATERS: Methylacrylonitrile was qualitatively detected in only 1 surface water sample collected from 204 sites near heavily industrialized areas across the US(1). [R49] EFFL: *Trace amounts of methylacrylonitrile (concn or detection limit not reported) were detected in an aqueous process effluent from a coal gasification facility in Gillette, WY(1). [R50] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 213 workers are potentially exposed to methylacrylonitrile in the US(1). Occupational exposure to methylacrylonitrile may occur through inhalation and dermal contact with this compound at workplaces where methylacrylonitrile is produced or used(SRC). [R51] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- NREC: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1 ppm (3 mg/cu m). [R5, 198] TLV: *8 hr Time Weighted Avg (TWA) 1 ppm, skin [R52, 47] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R52, 6] WSTD: STATE DRINKING WATER GUIDELINES: +(FL) FLORIDA 50 ug/l [R53] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R54] *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Methylacrylonitrile is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 500 lbs. [R55] RCRA: *U152; As stipulated in 40 CFR 261.33, when methylacrylonitrile, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R56] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *OSW Method 8240B-S,W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). Detection limit = 100 ug/l. [R57] *EPA Method 1624-S. Volatile Organic Compounds by Isotope Dilution GC/MS. Detection limit unspecified. [R57] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit unspecified. [R57] *OSW Method 8260B. Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. Detection limit unspecified. Detection limit unspecified. [R57] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Kaplita PV and Smith RP; Toxicol Appl Pharmacol 84 (3): 533-540 (1986). Pathways for the bioactivation of aliphatic nitriles to free cyanide in mice. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that methacrylonitrile is on the list of post peer review technical reports in progress. Route: gavage; Species: rats and mice. NTP TR No 497. [R58] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. R2: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 3rd ed. New York, NY: Van Nostrand Reinhold Co., 1996. 1227 R3: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 751 R4: SRI R5: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. R6: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-289 R7: Riddick, J.A., W.B. Bunger, Sakano T.K. Techniques of Chemistry 4th ed., Volume II. Organic Solvents. New York, NY: John Wiley and Sons., 1985. 597 R8: Tanii H, Hashimoto K; Arch Toxicol 55: 47-54 (1984) R9: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R10: Munshi H et al; Atmos Environ 23: 1971-76 (1989) R11: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-465 R12: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V5 4527 R13: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R14: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. 3140 R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-131P R16: International Labour Office. Encyclopedia of Occupational Health and Safety. Volumes I and II. New York: McGraw-Hill Book Co., 1971. R17: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R18: Fire Protection Guide to Hazardous Materials. 12 ed. Quincy, MA: National Fire Protection Association, 1997.,p. 325-65 R19: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 935 R20: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. 75 R21: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R22: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1447 R23: 49 CFR 171.2 (7/1/2000) R24: IATA. Dangerous Goods Regulations. 41st Ed.Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2000. 184 R25: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3250 (1998) R26: 40 CFR 240-280, 300-306, 702-799 (7/1/91) R27: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-14 (1981) EPA 68-03-3025 R28: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1487 R29: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 388 R30: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 590 R31: YOSHIKAWA H; IGAKU TO SEIBUTSUGAKU 77 (1): 1 (1968) R32: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R33: Cavazos R Jr et al; J Appl Toxicol 9 (1): 53-7 (1989) R34: SZABO S ET AL; J PHARMACOL EXP THER 223 (1): 68 (1982) R35: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Reproductive Toxicity of Methacrylonitrile (CAS No. 126-98-7) Administered in Diet to Sprague-Dawley Rats, NTP Study No. RACB94019 (May 16, 1997) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RT0.html as of August 14, 2002 R36: HAGUENOER JM ET AL; BULL SOC PHARM LILLE 32 (2-3): 185 (1976) R37: Peter H, Bolt HM; Internat Arch Occupat Environ Hlth 55 (2): 175-7 (1985) R38: WILLHITE CC, SMITH RP; TOXICOL APPL PHARMACOL 59 (3): 589-602 (1981) R39: Tanii H; Juzen Igakkai Zasshi 94 (4): 664-77 (1985) R40: (1) Budavari S, ed; The Merck Index. 12th ed. Whitehouse Station, NJ: Merck and Co Inc, p. 1015 (1996) (2) Sax NI, Lewis RJ Sr, eds; Hawley's Condensed Chemical Dictionary. 11th ed. NY, NY: Van Nostrand Reinhold Co, p. 751 (1987) R41: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Tanii H, Hashimoto K; Arch Toxicol 55: 47-54 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (6) Chapatwala KD et al; Environ Toxicol Chem 11: 1145-51 (1992) (7) Nawaz MS et al; Appl Environ Microbiol 55: 2267-74 (1989) R42: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Tanii H, Hashimoto K; Arch Toxicol 55: 47-54 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (5) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (8) Chapatwala KD et al; Environ Toxicol Chem 11: 1145-51 (1992) (9) Nawaz MS et al; Appl Environ Microbiol 55: 2267-74 (1989) R43: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (4) Munshi H et al; Atmos Environ 23: 1971-76 (1989) (5) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) R44: (1) Chapatwala KD et al; Environ Toxicol Chem 11: 1145-51 (1992) (2) Nawaz MS et al; Appl Environ Microbiol 55: 2267-74 (1989) R45: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Going J et al; Environ Monitoring Near Industrial Sites Acrylonitrile. USEPA-560/6-79-003 (1979) (3) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R46: (1) Tanii H, Hashimoto K; Arch Toxicol 55: 47-54 (1984) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R47: (1) Tanii H, Hashimoto K; Arch Toxicol 55: 47-54 (1984) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R48: (1) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals: Data Compilation. Design Inst Phys Prop Data, Amer Inst Chem Eng NY, NY: Hemisphere Pub Corp 5 Vol (1989) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R49: (1) Ewing BB et al; Monitoring to Detect Previously Unrecognized Pollutants in Surface Waters USEPA-560/6-77-015 (1977) R50: (1) Pellizzari ED et al; pp. 256-74 in ASTM Spec Tech Publ STP 686 (1979) R51: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R52: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. 2000. R53: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R54: 40 CFR 302.4 (7/1/2000) R55: 40 CFR 355 (7/1/2000) R56: 40 CFR 261.33 (7/1/2000) R57: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R58: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 55 Record 338 of 1119 in HSDB (through 2003/06) AN: 6002 UD: 200302 RD: Reviewed by SRP on 02/06/1991 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-METHYLANILINE-HYDROCHLORIDE- SY: *1-AMINO-2-METHYLBENZENE-HYDROCHLORIDE-; *2-AMINO-1-METHYLBENZENE-HYDROCHLORIDE-; *ORTHO-AMINOTOLUENE-HYDROCHLORIDE-; *2-AMINOTOLUENE-HYDROCHLORIDE-; *BENZENAMINE,-2-METHYL-,-HYDROCHLORIDE-; *1-METHYL-2-AMINOBENZENE-HYDROCHLORIDE-; *2-METHYL-1-AMINOBENZENE-HYDROCHLORIDE-; *O-METHYLANILINE-HYDROCHLORIDE-; *O-METHYLBENZENAMINE-HYDROCHLORIDE-; *2-METHYLBENZENAMINE-HYDROCHLORIDE-; *NCI-C02335-; *TOLUENE,-2-AMINO,-HYDROCHLORIDE-; *O-TOLUIDINE,-HYDROCHLORIDE-; *2-TOLUIDINE-HYDROCHLORIDE-; *O-TOLUIDINIUM-CHLORIDE-; *O-TOLYLAMINE-HYDROCHLORIDE- RN: 636-21-5 RELT: 2042 [2-AMINOTOLUENE] (Analog) MF: *C7-H9-N.Cl-H HAZN: U222; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *REACTION OF 2-METHYLANILINE WITH HYDROCHLORIC ACID. [R1] FORM: *Commercial derivatives and uses: triphenylmethane dyes; safranine colors; ... Basic Red 9; Acid Green 25. [R2] MFS: *AMERICAN CYANAMID CO, CHEM PRODUCTS DIV, BOUNDBROOK, NJ 08805 [R1] OMIN: *Commercial production of ortho-toluidine hydrochloride was last reported in the USA in 1975. One USA company is believed to produce this chemical currently /1982/ [R3] *Imports of /ortho-toluidine/ hydrochloride were last reported in 1975, when one thousand kg were imported. [R3] USE: *INTERMEDIATE IN MANUFACTURE OF DYES [R4, p. V16 353] CPAT: *ESSENTIALLY 100% AS A CHEM INT FOR DYES. [R1] PRIE: U.S. IMPORTS: *(1974) 2.19X10+4 kg [R5] *(1975) 1.0X10+3 kg [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *MONOCLINIC PRISMS FROM COLD WATER; RHOMBIC PYRAMIDS FROM HOT WATER [R7] BP: *242.2 DEG C [R7] MP: *215 DEG C [R7] MW: *143.62 [R7] SOL: *VERY SOL IN WATER; SOL IN ALCOHOL [R7]; *INSOL IN ETHER, INSOL IN BENZENE [R8] SPEC: *MAX ABSORPTION (METHANOL): 284 NM, 266 NM, 258 NM [R4, p. V16 351]; *IR: 6330 (Sadtler Research Laboratories Prism Collection) [R9]; *UV: 1740 (Sadtler Research Laboratories Spectral Collection) [R9]; *NMR: 10946 (Sadtler Research Laboratories Spectral Collection) [R9]; *MASS: 783 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomp it emits very toxic fumes of /hydrogen chloride and nitrogen oxides/. [R10] EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R11, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R11, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R11, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R11, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R11, 1979.13] CLUP: *1. VENTILATE AREA OF SPILL OR LEAK. 2. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR HOOD DUCTWORK. BURN PAPER IN SUITABLE LOCATION AWAY FROM COMBUSTIBLE MATERIALS. /O-TOLUIDINE/ [R12] *2. LARGE QUANTITIES CAN BE COLLECTED AND ATOMIZED IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH APPROPRIATE EFFLUENT GAS CLEANING DEVICE. /O-TOLUIDINE/ [R12] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R11, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U222, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R13] *BY ABSORBING IT IN VERMICULITE, DRY SAND, EARTH OR SIMILAR MATERIAL AND DISPOSING IN SECURED SANITARY LANDFILL. /O-TOLUIDINE/ [R12] *Controlled incineration (oxides of nitrogen are removed from the effluent gas by scrubbers and/or thermal devices). /Toluidine/ [R14] *A potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R15] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R11, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R11, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R11, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *The Human Health Assessment Group in EPA's Office of Health and Environmental Assessment has evaluated o-toluidine hydrochloride for carcinogenicity. According to their analysis, the weight-of-evidence for o-toluidine hydrochloride is group B2, which is based on inadequate evidence in humans and sufficient evidence in animals. As a group B2 chemical, o-toluidine hydrochloride is considered to be probably carcinogenic to humans. [R16] *Classification of carcinogenicity: 1) evidence in humans: insufficient; 2) evidence in animals: sufficient. Overall summary evaluation of carcinogenic risk to humans is Group 2B: The agent is possibly carcinogenic to humans. /From table; ortho-Toluidine/ [R17] +A3; Confirmed animal carcinogen with unknown relevance to humans. /o-Toluidine/ [R18, 2002.58] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R11, 1979.23] HTOX: *CLINICAL SIGNS OF INTOXICATION INCL PHYSIOLOGICAL AND PSYCHICAL DISTURBANCES AND MARKED IRRITATION OF KIDNEYS AND BLADDER. ACUTE POISONING ... MAY BE ACCOMPANIED BY METHEMOGLOBINEMIA AND HEMATURIA. /O-TOLUIDINE/ [R4, p. V16 358] *Toxic effects of toluidines in humans ... include ... headache, difficulty in breathing. /Toluidines/ [R19, 2593] *Cause-specific mortality of 906 workers first employed during 1922-1970 in a dyestuff factory in northern Italy ... a marked excess of bladder cancer was observed (36 observed vs 1.23 expected deaths). The mean latent period was 25 yr. The excess was higher among those with a longer duration of exposure. ... Mortality from bladder cancer was very much higher among those exposed in benzidine and naphthylamines manufacture than among those only exposed in use or intermittent contact. ... There is evidence that o-toluidine ... should be implicated in such excess mortality. Caution in handling ... is suggested. /2-Aminotoluene/ [R20] *... BLADDER TUMORS /REPORTED/ IN WORKERS ENGAGED ON PRODN OF O-TOLUIDINE AND/OR P-TOLUIDINE IN USSR IN 1960'S. CONCN RANGE OF ORTHO- ... MEASURED IN AIR ... WAS 0.5-28.6 MG/CU M. TWO CASES OF BLADDER TUMORS (PAPILLOMAS) ... FOUND WHEN 75/81 ... WORKERS EXAM CYSTOSCOPICALLY. /O-TOLUIDINE/ [R4, p. V16 359] *... /CASE REPORTS OF EPIDEMIOLOGICAL STUDIES INVOLVING/ OCCUPATIONAL EXPOSURE ... TO TOLUIDINES ... /IS/ SUGGESTIVE OF CARCINOGENIC EFFECT ... /TOLUIDINES / [R4, p. V16 360] NTOX: *... MALE AND FEMALE CHARLES RIVER (HA/ICR) CG-1 MICE GIVEN ORTHO-TOLUIDINE (PROBABLY AS HYDROCHLORIDE) AT TWO DOSE LEVELS IN DIET DEVELOPED VASCULAR TUMORS. [R4, p. V16 356] *... FEEDING ... (PROBABLY AS HYDROCHLORIDE) TO 50 MALE CHARLES RIVER (SPRAGUE-DAWLEY DERIVED) CD RATS AT 2 DOSE LEVELS ... FOR 2 YR INCR ... SUBCUTANEOUS FIBROMAS AND FIBROSARCOMAS TO 83% FROM 16% THAT OCCURRED SPONTANEOUSLY IN 111 CONTROL RATS. URINARY BLADDER CANCERS AND HEPATOMAS WERE ALSO PRESENT IN TREATED ANIMALS. [R4, p. V16 357] *ORTHO-TOLUIDINE DID NOT INDUCE REVERSE MUTATIONS IN SALMONELLA TYPHIMURIUM TA 1535, TA 1537, TA 1538, TA 98 OR TA 100 IN PRESENCE OR ABSENCE OF RAT LIVER PREPARATION. /O-TOLUIDINE/ [R4, p. V16 358] *Toluidines were especially toxic to blue-green algae /PR-6 (Agmemellum quadruplicatum) and 17A (Coccochloris elabens)/ /Toluidines/ [R21] *... Male and female F344 rats were fed diets containing ... o-toluidine hydrochloride. ... The rats, from 6 wk to 2 yr old, were given ... 2 dose levels, the estimated maximum tolerated dose and one-half that dose. ... Dose-dependent incidences of splenic sarcomas and fibrosis were seen, with the highest incidences in male rats. Fibrosis occurred in the splenic parenchyma and/or the capsule. Fatty infiltration was seen in the spleen. Sarcomas appeared to arise in the splenic red pulp or splenic capsule, usually in association with areas of parenchymal and capsular fibrosis and pigmentation. Larger tumors metastasized to the peritoneal cavity and abdominal organs. In some rats there was marked osseous metaplasia when the primary tumor metastasized to peritoneal surfaces. Less common splenic neoplasms included hemangiosarcoma and hemangiopericytoma. [R22] *o-Toluidine hydrochloride and one of its metabolites, o-nitrosotoluene, were administered in the diet (0.028 mol/kg diet) to 2 groups of 30 male F-344 rats for 72 wk. o-Nitrosotoluene induced significantly more tumors of the bladder (16/30 rats) and liver (20/30) than did o-toluidine hydrochloride (bladder, 4/30; liver 3/30). Both compounds induced comparable numbers of peritoneal tumors and fibroma of the skin and spleen. o-Toluidine hydrochloride induced more mammary tumors (13/30) than did o-nitrosotoluene (3/30). N-Oxidation is important in the induction of bladder and liver tumors by these single ring compounds but that other mechanisms could be involved in the induction of peritoneal, skin, spleen and mammary tumors. [R23] *Tests for in-vivo genotoxic activity in B6C3F1 mice were performed using three pairs of structurally similar carcinogenic/noncarcinogenic chemicals. These pairs included o-toluidine hydrochloride and o-anthranilic acid, 4-chloro-phenyledediamine and 4-nitro-o-phenylenediamine, and 3-(chloromethyl)pyridine hydrochloride and 2-(chloromethyl)pyridine hydrochloride. Bone marrow cells from the mice given intraperitoneal injections of up to the maximum tolerated doses were evaluated for chromosomal aberration, sister chromatid exchange, and micronucleus induction. No increase in the frequency of chromosomal aberrations or micronuclei was caused by o-anthranilic acid and o-toluidine hydrochloride. The frequency of sister chromatid exchanges in two successive trials was increased by o-toluidine hydrochloride, while o-anthranilic acid had a positive effect on sister chromatid exchanges in two of three trials. Both 2-(chloromethyl)pyridine hydrochloride and 3-(chloromethyl)pyridine hydrochloride were negative for all three endpoints. Assays for chromosomal aberration and micronuclei each distinguished between 4-chloro-o-phenylenediamine and its noncarcinogenic companion, 4-nitro-o-phenylenediamine. A few cells with very large numbers of aberrations were produced by 4-chloro-o-phenylenediamine in the aberration test, rather than an even distribution of damage among cells. [R24] +... Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R25] NTXV: *LD50 Mouse oral 1100 mg/kg; [R26] *LD50 Rat oral 2951 mg/kg; [R19, 2594] *LD50 Rat ip 150 mg/kg; [R19, 2594] *LD50 Mouse ip 113 mg/kg; [R19, 2594] *LD50 Rat oral 0.94 g/kg. /2-Methylaniline/; [R27] NTP: +A bioassay of o-toluidine hydrochloride for possible carcinogenicity was conducted by admin the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex and 50 mice of each sex were admin o-toluidine hydrochloride at one of several doses, either 3,000 or 6,000 ppm for rats and either 1,000 or 3,000 ppm for the mice, for 101 to 104 wk. Matched controls consisted of 20 untreated rats of each sex and 20 untreated mice of each sex. All surviving rats and mice were /sacrificed/ at the end of admin of the test chemical. ... Under the conditions of this bioassay, o-toluidine hydrochloride was carcinogenic in both male and female F344 rats and B6C3F1 mice, producing a significant increased incidence of one or more types of neoplasms. ... Evidence of Carcinogenicity: Male Rats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R25] ADE: *Following a single dose (400 mg/kg sc) of o-(methyl-(14)C-toluidine ... to male F344 rats, 56% of the (14)C was recovered in the 24 hr urine, 2.4% in the feces and 1% as exhaled (14)CO2. After 48 hr, 83.9% of the (14)C appeared in the urine, 3.3% in the feces and 1.4% was exhaled. /2-Aminotoluene/ [R28] *Via the respiratory tract and skin. /2-Aminotoluene/ [R4, p. V16 358] METB: *One of /the/ metabolites /is/ o-nitrosotoluene. [R23] ACTN: *N-oxidation is important in the induction of bladder and liver tumors by the single ring compounds /o-toluidine hydrochloride and o-nitrosotoluidine/ but ... other mechanisms could be involved in the induction of peritoneal, skin, spleen, and mammary tumors. [R23] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ BIOD: *Thirty-eight process wastewaters and 37 organic substances identified in the wastewater of the Kashima petrochemical complex were subjected to the activated sludge degradability test. The test used the activated sludge of the Fukashiba industrial wastewater treatment plant, which was acclimatized to the wastewater and organic substances. Water in the test container was sampled during aeration at 0 hr and 24 hr later. After 1 day of acclimation, 100 mg/l of 2-methylaniline resulted in a chemical oxygen demand (Mn) of 92% and 83% total organic carbon. /2-methylaniline/ [R29] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: +Permissible Exposure Limit: Table Z-1 8-hr Time-Weighted Avg: 5 ppm (22 mg/cu m). Skin Designation. /o-Toluidine/ [R30] TLV: +8 hr Time Weighted Avg (TWA): 0.5 ppm, skin. /N-Methyl aniline/ [R18, 2002.40] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /N-Methyl aniline/ [R18, 2002.6] +8 hr Time Weighted Avg (TWA): 2 ppm, skin. /o-Toluidine/ [R18, 2002.58] +Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /o-Toluidine/ [R18, 2002.6] +A3; Confirmed animal carcinogen with unknown relevance to humans. /o-Toluidine/ [R18, 2002.58] +Biological Exposure Index (BEI): Determinant: methemoglobin in blood; Sampling Time: during or end of shift; BEI: 1.5% of hemoglobin. The determinant may be present in biological specimens collected from subjects who have not been occupationally exposed, at a concentration which could affect interpretation of the result. Such background concentrations are incorporated in the BEI value. The determinant is nonspecific, since it is also observed after exposure to other chemicals. The biological determinant is an indicator of exposure to the chemical, but the quantitative interpretation of the measurement is ambiguous. These determinants should be used as a screening test if a quantitative test is not practical or as a confirmatory test if the quantitative test is not specific and the origin of the determinant is in question. /Methemoglobin inducers/ [R18, 2002.91] OOPL: *USSR (1980): 0.7 ppm ceiling limit; Czechoslavakia (1976): 1.1 ppm: Italy (1975) AND East Germany (1973): 2.2 ppm; West Germany (1983): 5 ppm. /o-Toluidine/ [R31] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Toluidines are produced, as an intermediate or final product, by process units covered under this subpart. /Toluidines/ [R32] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R33] RCRA: *U222; As stipulated in 40 CFR 261.33, when o-toluidine hydrochloride, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R34] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determined in amounts greater than 1 mg by atomic absorption spectrophotometry of the copper-amine complex /Primary amines/ [R4, p. V16 355] *Thin-layer chromatography has been used to separate aromatic amines ... especially from their isomers, on films impregnated with 1,1'-disulphostilbene and visualization by ultraviolet light /and/ ... on silica gel using ... different solvents. /Aromatic amines/ [R4, p. V16 355] *Column chromatography on anion exchange resin ... /has been/ used to separate aromatic amines /Aromatic amines/ [R4, p. V16 356] *... Gel permeation chromatography ... used to separate aromatic amines /aromatic amines/ [R4, p. V16 356] *... Gas chromatography on barium chloride ... used for separation /nitrogen- substituted benzene compounds/ [R4, p. V16 356] *Gas chromatography with electron-capture detection is used for determination of ortho-Toluidine hydrochloride in water. This method has a detection limit of 2-3 mg/l. [R4, p. V27 163] *Gas chromatography with flame ionization detection is used for determination of ortho-toluidine hydrochloride in air samples. [R4, p. V27 163] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHEW/NCI; Bioassay of o-Toluidine Hydrochloride for Possible Carcinogenicity (1979) Technical Rpt Series No. 153 DHEW Pub No. (NIH) 79-1709 U.S. Department of Health and Human Services/National Toxicology Program; 9th Report on Carcinogens. National Institute of Environmental Health Sciences, Research Triangle Park, NC. (2000) DHHS/NTP; NTP Technical Report on Comparative Toxicity Studies of o-Nitrotoluene and o-Toluidine Hydrochloride Administered in Feed to Male F344/N Rats. Toxicity Rpt Series No. 44 NIH Publication No. 96-3936 (1996) SO: R1: SRI R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. 2:317 R3: IARC MONOGRAPHS 1972-PRESENT V27 p.158 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R5: US International Trade Commission; Imports of Benzenoid Chemicals and Products, 1984, p.28 (1976a) as cited in IARC MONOGRAPHS 1972-Present Vol. 16 p. 352 R6: US International Trade Commission; Imports of Benzoid Chemicals and Products, 1975; p.27 (1977b) as cited in IARC MONOGRAPHS 1972-Present Vol. 16 p.352 R7: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 69th ed. Boca Raton, FL: CRC Press Inc., 1988-1989.,p. C-525 R8: Weast, R.C. (ed.). Handbook of Chemistry and Physics. 60th ed. Boca Raton, Florida: CRC Press Inc., 1979.,p. C-519 R9: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 379 R10: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3199 R11: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R12: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R13: 40 CFR 240-280, 300-306, 702-799 (7/1/89) R14: USEPA; Engineering Handbook for Hazardous Waste Incineration p.2-10 (1981) EPA 68-03-3025 R15: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-16 (1981) EPA 68-03-3025 R16: USEPA; Methodology for Evaluating Potential Carcinogenicity in Support of Reportable Quantity Adjustments Pursuant to Cercla Section 102 (Final) p. 42 (1988) EPA/600/8-89/053 R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 72 (1987) R18: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R19: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R20: Rubino GF et al; Environ Res 27 (2): 241-54 (1982) R21: Winters K et al; Cons Int Explor Mer 171 (Pet Hydrocarbons Mar Environ): 166:174 (1977) R22: Goodman, DG et al; J Natl Cancer Inst 37(1): 265-74 (1984) R23: Hecht SS et al; Cancer Lett 16 (1): 103-8 (1982) R24: McFee AF et al; Environ and Molecular Mutagenesis 14 (4): 207-20 (1989) R25: Bioassay of o-Toluidine Hydrochloride for Possible Carcinogenicity (1979) Technical Rpt Series No. 153 DHEW Pub No. (NIH) 79-1709, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R26: NIOSH; Current Awareness Listing (1984) R27: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1502 R28: Son OS et al; Xenobiotica 10 (7-8): 457-68 (1980) R29: Matsui S et al; Water Sci Technol 20 (10): 201-10 (1989) R30: 29 CFR 1910.1000 (7/1/98) R31: American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values and Biological Exposure Indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 1986.586 R32: 40 CFR 60.489 (7/1/89) R33: 54 FR 33419 (8/14/89) R34: 40 CFR 261.33 (7/1/88) RS: 37 Record 339 of 1119 in HSDB (through 2003/06) AN: 6003 UD: 200301 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TOLUENE-DIISOCYANATE- SY: *BENZENE,-1,3-DIISOCYANATOMETHYL-; *DESMODUR-T100-; *DIISOCYANATOMETHYLBENZENE-; *DIISOCYANATOTOLUENE-; *HYLENE-T-; *ISOCYANIC-ACID,-METHYL-M-PHENYLENE-ESTER-; *METHYL-M-PHENYLENE-DIISOCYANATE-; *METHYLPHENYLENE-ISOCYANATE-; *METHYL-M-PHENYLENE-ISOCYANATE-; *MONDUR-TD-; *MONDUR-TD-80-; *RUBINATE-TDI-; *RUBINATE-TDI-80/20-; *TDI-; *TOLUENE-1,3-DIISOCYANATE-; *TOLYLENE-DIISOCYANATE-; *TOLYLENE-ISOCYANATE-; *U223- RN: 26471-62-5 RELT: 874 [2,4-TOLUENE DIISOCYANATE] (Mixture Component); 5272 [2,6-TOLUENE DIISOCYANATE] (Mixture Component) MF: *C9-H6-N2-O2 SHPN: UN 2078; Toluene diisocyanate IMO 6.1; Toluene diisocyanate STCC: 49 215 75; Toluene diisocyanate HAZN: U223; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *NITRATION OF TOLUENE, FOLLOWED BY REDUCTION TO DIAMINE, REACTION WITH PHOSGENE, PURIFICATION, AND RECOVERY OF COPRODUCT HYDROGEN CHLORIDE. [R1] *From toluene diamine by reaction with carbonyl chloride (phosgene) [R2, 1016] *2,4/2,6-Diaminotoluene + phosgene (phosgenation) [R3, 895] FORM: *The most common grade is a mixed isomer product containing 80% 2,4- and 20% 2,6-isomers. A second grade containing 65% 2,4- and 35% 2,6-isomers is also available as well as the pure 2,4-isomer. [R3, 691] MFS: *BASF Corporation, Hq, 3000 Continental Dr. - North, Mount Oilve, NJ 07828-1234, (973) 426-2600, Polymers Division, Urethanes; Production site: Geismar, LA 70734 /2,4/2,6-Toluene diisocyanate (mixed)/ [R4] *Bayer Corp., Hq, 100 Bayer Rd., Pittsburgh, PA 15219-2502, (412) 777-2000, Polyurethane Division; Production sites: Baytown, TX 77521; New Martinsville, WV 26155 /2,4/2,6-Toluene diisocyanate (mixed)/ [R4] *Dow Chemical, USA, Hq, 2030 Dow Center, Midland, MI 48674, (517) 636-1000; Production site: Freeport, TX 77541 /2,4/2,6-Toluene diisocyanate (mixed)/ [R4] *Huntsman ICI Chemicals LLC, 500 Huntsman Way, Salt Lake City, UT 84108, (801) 584-5700; Production site: Geismar, LA 70734 /2,4/2,6-Toluene diisocyanate (mixed)/ [R4] *Lyondell Chemical Company, 1221 McKinney St., Suite 700, Houston, TX 77010, (713) 652-7200; Production site: Lake Charles, LA 70602 /2,4/2,6-Toluene diisocyanate (mixed)/ [R4] OMIN: *Diisocyanates used in the polyurethane industry pose a possible threat to workers exposed to them. A method for generating low concn was developed using tetrafluoroethylene Teflon permeation tubes. The tubes were prepared by sealing in clean spaghetti tubing with solid tetrafluoroethylene Teflon rod held in place with crimped aluminum Swagelok ferrules. Using a commercially avail air bath capable of maintaining a temp within 0.05 deg K, the permeation tubes were kept at 303, 323 and 343 deg K toluene diisocyanate was swept from the thermostated chamber with dry nitrogen and further diluted with clean dry air to the desired concn. Permeation rates for the thick wall tube were 2.14 ng/min/cm at 303 deg K, 10.66 at 323 deg K and 42.84 at 343 deg K. For the thin wall tube, the permeation rates were 8.30 ng/min/cm at 303 deg K, 45.39 at 323 deg K and 179.62 at 343 deg K. /Diisocyanates/ [R5] *MITSUBISHI CHEM CO IS DEVELOPING A PROCESS TO PRODUCE TDI BY CARBONYLATING DINITROTOLUENE IN THE PRESENCE OF AN ALCOHOL-PRODUCING URETHANE THAT DECOMPOSES TO TDI AND THE ALCOHOL (THE ALCOHOL AND CARBON DIOXIDE CAN BE RECYCLED). [R6] *METHOD OF PURIFICATION: DISTILLATION TO REMOVE HYDROCHLORIC ACID. [R7] USE: *Used as a monomer in the preparation of polyurethane foams, elastomers and coatings, as a cross-linking agent for nylon-6, and as a hardener in polyurethane adhesives and finishes. [R8] *Polyurethane elastomers made from toluene diisocyanates are used in coated fabrics and clay-pipe seals. [R8] *Polyurethane coatings made from toluene diisocyanates are used in floor finishes, wood finishes and sealers, and in coatings for aircraft, tank trucks, truck trailers and truck fleets. [R8] *... used as hardener in the production of polyurethane. [R9] *Moisture-cured polyurethane varnish (interior woodwork, flooring) [R3, 895] *Adhesives; coatings manufacture; elastomers; flexible foam; rigid foam [R10] *Used principally in polyurethanes as flexible foams for upholstery and other types of padding. [R11] CPAT: *90% FLEXIBLE FOAMS-MOLDED FLEXIBLE; 5% COATINGS; 3% ELASTOMERS; 2% OTHER (1984 EST) /FOR 80:20 MIX OF 2,4-2,6 ISOMER/ [R6] *CHEMICAL PROFILE: Toluene Diisocyanate. Flexible urethane foams, 65%; (furniture, 28%; transportation, 16%; carpet underlay, 9%; bedding, 6%; other foam uses, 6%; ) exports, 22%; rigid foams, 5%; polyurethane coatings, 4%; elastomers, 2%; miscellaneous non-foam uses, 2%. [R12] *CHEMICAL PROFILE: Toluene diisocyanate. Demand: 1986: 650 million lb; 1987: 695 million lb; 1991 /projected/: 720 million lb (Includes exports, imports are negligible). [R12] *80% 2,4:20% 2,6 MIXT REPRESENTS OVER 95% OF INDUSTRIAL USAGE ... . [R13, 1991.1580] *Flexible urethane foams, 90% (furniture, 32%; transportation, 30%; carpet underlay, 10%; bedding, 10%; packaging, 8%; other foam uses, 10%); polyurethane coatings, 4%; cast elastomers, 2%; sealants, 2%; miscellaneous, including polyurethane fibers, 2%. [R14] *(1998) 940 million pounds; (1999) 960 million pounds; (2003) 1.1 billion pounds. [R14] PRIE: U.S. PRODUCTION: *(1984) 3.32X10+11 g /80:20 MIX OF 2,4-2,6 ISOMERS/ [R15] *Worldwide production capacities for toluene diisocyanates in 1987 were reported as (thousand tons): western hemisphere, 356; eastern Europe, 46; western Europe, 380; and Japan and the Far East, 88. Worldwide production capaciites in 1993 were reported as (thousand tons): North America, 485; Europe, 530; Pacific region, 308; and Latin America, 102.5. [R16] U.S. IMPORTS: *(1983) 2.00X10+9 g /FOR 2,4 (AND 2,6) TDI/ [R17] *(1983) 8.94X10+8 g /FOR TDI (UNMIXED)/ [R17] *(1983) 2.00X10+7 g /2,4 TDI DIMER/ [R17] *Negligible [R14] U.S. EXPORTS: *(1984) 6.27x10+10 g /TOLUENE DIISOCYANATES/ [R18] *(1998) 289 million. Average annual exports during the 1993-1998 period amounted to 288 million pounds. [R14] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Clear colorless to pale yellow liquid. [R19] ODOR: *Pungent odor [R19] BP: *251 deg C [R20] MP: *11-14 deg C (freezing point) [R21] MW: *174.16 [R16] DEN: *1.22 + or - 0.01 g/ml at 25 deg C [R20] SPEC: *Index of refraction: 1.5666 at 25 deg C (80:20 mix); 1.5663 at 25 deg C (65:35 mixture) [R21] VAP: *2.30X10-2 mm Hg @ 25 deg C [R22] OCPP: *VAPOR PRESSURE: 0.5 MM @ 25 DEG C /80% 2,4:20% 2,6/ [R23] *MISCIBLE WITH ALCOHOL, ETHER, ACETONE /80% 2,4:20% 2,6/ [R23] *MISCIBLE WITH CARBON TETRACHLORIDE /80% 2,4:20% 2,6/ [R23] *MISCIBLE WITH BENZENE, KEROSENE /80% 2,4:20% 2,6/ [R23] *SPECIFIC GRAVITY: 1.22 @ 25 DEG C; BP: 250 DEG C; FP: 11.3-13.5 DEG C /80% 2,4:20% 2,6/ [R13, 1991.1581] *Hydroxyl radical reaction rate constant= 7.07X10-12 cu cm/molecule-sec @ 25 deg C [R24] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Combustible material: may burn but does not ignite readily. Substance will react with water (some violently) releasing flammable, toxic or corrosive gases and runoff. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapors may travel to source of ignition and flash back. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated or if contaminated with water. [R25] +Health: TOXIC; inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns, or death. Reaction with water or moist air will release toxic, corrosive or flammable gases. Reaction with water may generate much heat which will increase the concentration of fumes in the air. Fire will produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R25] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R25] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R25] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R25] +Fire: Note: Most foams will react with the material and release corrosive/toxic gases. Small fires: CO2, dry chemical, dry sand, alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. FOR CHLOROSILANES, DO NOT USE WATER; use AFFF alcohol-resistant medium expansion foam. Move containers from fire area if you can do it without risk. Use water spray or fog; do not use straight streams. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R25] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. A vapor suppressing foam may be used to reduce vapors. FOR CHLOROSILANES, use AFFF alcohol-resistant medium expansion foam to reduce vapors. DO NOT GET WATER on spilled substance or inside containers. Use water spray to reduce vapors or divert vapor cloud drift. Avoid allowing water runoff to contact spilled material. Prevent entry into waterways, sewers, basements or confined areas. Small spills: Cover with DRY earth, DRY sand, or other non-combustible material followed with plastic sheet to minimize spreading or contact with rain. Use clean non-sparking tools to collect material and place it into loosely covered plastic containers for later disposal. [R25] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R25] FPOT: *DUE TO ITS HIGH FLASH POINT, TOLUENE DIISOCYANATE OFFERS NO SERIOUS RISK OF FIRE ... . [R26, 103] *Combustible when exposed to heat or flame. [R27] FLPT: *270 DEG F CLOSED CUP /80% 2,4:20% 2,6/ [R23] FIRP: *FIREFIGHTERS MUST BE PROTECTED AGAINST DIISOCYANATE VAPORS AND /NITROGEN DIOXIDE/ BY COMPLETE PROTECTIVE EQUIPMENT (..., RUBBER GLOVES, ETC). /DIISOCYANATES/ [R26, 103] *Firemen must be equipped with self-contained breathing apparatus. /Isocyanates/ [R28, 1162] *If material on fire or involved in fire: Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use "alcohol" foam, dry chemical, or carbon dioxide. Use water spray to knock-down vapors. [R19] *To fight fire, use dry chemical, /carbon dioxide/. [R29] TOXC: *Toxic oxides of nitrogen are produced during combustion of this material. [R19] EXPL: *Explosive in the form of vapor when exposed to heat or flame. [R29] REAC: *It can react with aniline. The heat of this reaction may be sufficient to ignite surrounding combustibles and the material itself. [R19] *Strong oxidizers, water, acids, bases and amines (may cause foam and splatter); alcohols. [Note: Reacts slowly with water to form carbon dioxide and polyureas.] /Toluene 2,4-diisocyanate/ [R30] *0.9-9.5 vol % in air. Reacts violently with amines, alcohols, bases and warm water, causing explosion hazards. /2,4-Toluene diisocyanate/ [R31] DCMP: *WHEN HEATED TO DECOMPOSITION, IT EMITS HIGHLY TOXIC FUMES OF /NITROGEN OXIDES/. [R29] POLY: *Potentially violent polymerization reaction with bases or acyl chlorides. [R29] ODRT: *Odor recognition in air: 2.10 ppm (purity) [R32] *TOLUENE DIISOCYANATE HAS MARKED CHARACTERISTIC ODOR WHICH ALLOWS IT TO BE DETECTED READILY. YET @ MAX RECOMMENDED CONCN (0.02 PPM) THE POISON CANNOT BE DETECTED BY ITS SMELL. [R26, 102] SERI: *AS A VAPOR ... /TOLUENE DIISOCYANATE/ IS A POWERFUL IRRITANT TO EYES, SKIN, RESPIRATORY TRACT. [R33] *Capable of producing severe dermatitis and bronchial spasm. [R29] EQUP: *... Provide the workers with protective clothing, gloves and goggles. Respiratory protection may be provided by masks incorporating a prefilter, but the best form of protection in work carried on in a high concn of isocyanates is air-supplied breathing apparatus. /Isocyanates/ [R28, 1162] *PRECAUTIONS FOR "CARCINOGENS": ... dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R34, 1979.8] *Three commercial air-purifying respirators for protection against toluene diisocyanate vapors were evaluated. The Willson R-21 AND Survivair, organic vapor cartridges, and the disposable, valveless 3M-8711 were the three respirators evaluated. Each respirator/cartridge was tested three times at 0.2 ppm toluene diisocyanate concn for 40 hr and once for 20 hr or more at concn > 1.5 ppm toluene diisocyanate. All cartridges/respirators had the capacity to provide the required protection against toluene diisocyanate vapors. Additional considerations in the respirator selection process included the training and experience of the respirator user, the enforcement of the respirator program, fit of the respirator, knowledge of toluene diisocyanate concn onsite, presence of other solvents or chemicals in the air which may adversely affect the capacity of the respirator for toluene diisocyanate, and the high odor threshold of toluene diisocyanate that makes it impossible for the user to receive advance warning of a leak. [R35] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R34, 1979.8] *Wear appropriate personal protective clothing to prevent skin contact. /Toluene 2,4-diisocyanate/ [R30] *Wear appropriate eye protection to prevent eye contact. /Toluene 2,4-diisocyanate/ [R30] *Eyewash fountains should be provided in areas where there is any possbility that workers could be exposed to the substance; this is irrespective of the recommendation involving the wearing of eye protection. /Toluene 2,4-diisocyanate/ [R30] *Facilities for quickly drenching the body should be provided within the immediate work area for emergency use where there is a possibility of exposure. [Note: It is intended that these facilities provide a sufficient quantity or flow of water to quickly remove the substance from any body areas likely to be exposed. The actual determination of what constitutes an adequate quick drench facility depends on the specific circumstances. In certain instances, a deluge shower should be readily available, whereas in others, the availability of water from a sink or hose could be considered adequate.] /Toluene 2,4-diisocyanate/ [R30] *Recommendations for respirator selection. Condition: At concentrations above the NIOSH REL, or where there is no REL at any detectable concentration. Respirator Class(es): Any self-contained breathing apparatus that has a full facepiece and is operated in a pressure-demand or other positive pressure mode. Any supplied-air respirator that has a full facepiece and is operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. /Toluene 2,4-diisocyanate/ [R30] *Recommendations for respirator selection. Condition: Escape from suddenly occurring respiratory hazards: Respirator Class(es): Any air-purifying, full-facepiece respirator (gas mask) with a chin-style, front- or back-mounted organic vapor canister. Any appropriate escape-type, self-contained breathing apparatus. /Toluene 2,4-diisocyanate/ [R30] OPRM: *VENTILATION SHOULD BE ADEQUATE ... OUTDOOR SPRAYING OPERATIONS SHOULD BE SHIELDED ... IF POLYURETHANE PRODUCTS ARE HEATED ... PROTECTION AGAINST ISOCYANATES THUS RELEASED IS NECESSARY. /ISOCYANATES/ [R36] *The sanitary facilities ... /for/ workers must incl showers. /Isocyanates/ [R28, 1162] *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R19] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. Do not handle broken packages unless wearing appropriate personnel protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R19] *Evacuation: If material leaking (not on fire), consider evacuation from downwind area based on amount of material spilled, location and weather conditions. [R19] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R34, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R34, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R34, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R34, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R34, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R34, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. ... /Chemical Carcinogens/ [R34, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R34, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R34, 1979.11] *Contact lenses should not be worn when working with this chemical. /Toluene 2,4-diisocyanate/ [R30] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. /Toluene 2,4-diisocyanate/ [R30] *The worker should wash daily at the end of each work shift. /Toluene 2,4-diisocyanate/ [R30] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Toluene 2,4-diisocyanate/ [R30] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Toluene 2,4-diisocyanate/ [R30] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R37] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R38] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R39] STRG: *Store separated from amines, alcohols, bases and acids. [R31] *Storage temp: 75-100 deg F [R40] *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practicable to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R34, 1979.13] *Storage in polyethylene containers is hazardous due to absorption of water through the plastic. [R29] CLUP: *AQUEOUS SOLUTIONS CONTAINING 10-20% (WT) OF A NONIONIC SURFACTANT, ARKOPAL-N100, WAS A USEFUL DECONTAMINATING AGENT FOR TOLYLENE DIISOCYANATE (TDI). THE SOLUTION CAN BE SPRAYED DIRECTLY ON SPILLS AS A LIQUID OR MAY BE APPLIED IN THE FORM OF A FOAM WHICH CAN BE GENERATED IN SUITABLE FIRE EXTINGUISHING EQUIPMENT. SOLID DECONTAMINANT FORMULATIONS WERE ALSO DEVELOPED WHICH CAN BE USED FOR GROUND SPILLS OF TDI. [R41] *Spillage: Neutralize with special mixt (50% water, 45% alc, 5% concn ammonia water), collect leaking liq in sealable containers (extra personal protection: self-contained breathing apparatus). [R31] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R34, 1979.15] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U223, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R42] *Toluene diisocyanate is a waste chemical stream constituent which may be subjected to ultimate disposal by controlled incineration. Controlled incineration: Oxides of nitrogen are removed from the effluent gas by scrubbers and/or thermal devices. [R43] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids. A potential candidate for liquid injection incineration at a temperature range of 650 to 1600 deg C and a residence time of 0.1 to 2 seconds. A potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids. [R44] *This compound should be susceptible to removal from waste water by air stripping. [R45] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... Summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R34, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R34, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R34, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as sat soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R34, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R34, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence for the carcinogenicity of toluene diisocyanates in humans. There is sufficient evidence for the carcinogenicity of toluene diisocyanates in experimental animals. Overall evaluation: Toluene diisocyanates are possibly carcinogenic to humans (Group 2B). /Toluene diisocyanates/ [R46] ANTR: *Noncardiogenic pulmonary edema and bronchospasm are the most immediate serious clinical consequences of isocyanate exposure. Markedly symptomatic patients should receive oxygen, ventilatory support, and an intravenous line. Treatment for asthma includes inhaled sympathomimetics (salbutamol, metaproterenol), intravenous theophylline, parenteral sympathomimetics (epinephrine, terbutaline), and steroids. /Isocyanates/ [R47, 881] *Copiously irrigate contaminated skin and eyes with saline. Few medical data are available to guide gut decontamination. Activated charcoal (1 g/kg) and a cathartic (sorbitol, magnesium citrate) may be useful for ingestions. /Isocyanates/ [R47, 881] *Most treatment is symptomatic. Mydriatics, systemic analgesics, and topical antibiotics (Sulamyd) may be used for corneal abrasions. There is no effective therapy for sensitized workers, and these people should be moved to a work site devoid of exposure to isocyanates. /Isocyanates/ [R47, 881] *Any employee who begins to experience shortness of breath during a shift should be removed from work immediately and should not return to work until pulmonary function tests have returned to base line. As is the case with asthma of any type, pulmonary function recovery may lag behind symptom recovery and take up to eight weeks to return to normal. If sensitized, the individual should not return to work in a TDI area or work with any other isocyanate. [R2, 1020] MEDS: *A SCREENING PROGRAM WAS UNDERTAKEN AT A RESEARCH AND DEVELOPMENT FACILITY OF A LARGE TOLUENE-DIISOCYANATE (TDI) MANUFACTURING CORPORATION. THE PURPOSE WAS TO DETERMINE THE OCCURRENCE OF ANTIBODIES TO TDI IN SELECTED WORKER POPULATIONS. NO TOLYL-REACTIVE IMMUNOGLOBULIN-E ANTIBODIES WERE DETECTED IN SERA WHEN WORKERS WERE EXPOSED ONLY TO AMBIENT TDI CONCN. WORKERS HAD ACUTE EXPOSURES TO TDI AS A RESULT OF SPILLS OR SPLASHES. ANTIBODY RESPONSES DEVELOPED IN 3 OF 4 INDIVIDUALS WHOSE ACUTE EXPOSURES WERE ACCOMPANIED BY IMMEDIATE RESPIRATORY SYMPTOMATOLOGY AND A DECREASED FORCED EXPIRATORY VOLUME. AN ANTIBODY RESPONSE DEVELOPED IN 1 OF 9 WORKERS AND IMMEDIATE RESPIRATORY SYMPTOMS, BUT NO SPIROMETRIC CHANGES UPON ACUTE TDI EXPOSURE. ROUTINE SEROLOGIC SCREENING OF WORKERS FOR TOLYL-REACTIVE ANTIBODIES MAY BE OF VALUE IN CONFIRMING SUSPECTED ISOCYANATE EXPOSURE AND IN PROVIDING AN EARLY WARNING OF DEVELOPING TDI HYPERSENSITIVITY. [R48] *MEDICAL EVALUATIONS OF 15 WORKERS WERE MADE TO DETERMINE THE HEALTH EFFECTS OF EXPOSURE TO TDI, PHOSGENE AND TDA. THE FOLLOWING STEPS WERE RECOMMENDED: THE ENTIRE FACTORY POPULATION SHOULD BE SURVEYED PERIODICALLY FOR SYMPTOMS OF LOWER RESPIRATORY TRACT DISEASES AND LUNG FUNCTION ABNORMALITIES THAT MAY BE CAUSED BY CHEMICAL EXPOSURE; TDI EXPOSURE SHOULD BE ENDED FOR SENSITIZED WORKERS OR FOR THOSE WITH EXCESSIVE DECLINE IN LUNG FUNCTION. [R49] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R34, 1979.23] *Comprehensive preplacement medical examinations should be given to each employee. The examination should include a pulmonary function test including FEV1, FVC, and FEV1/FVC, a history of diisocyanate exposure, smoking history, and history of respiratory conditions. The medical data obtained in the pre-placement examination can be used as a base line for periodic examination. Periodic examinations may be useful in detecting a reduction in lung function. Lung function tests, pulmonary history, and pulmonary physical exam should be repeated at least annually. All medical records, including pulmonary function and related medical tests, should be maintained for 30 years. [R2, 1019] HTOX: *TOLUENE DIISOCYANATE (TDI) SENSITIVITY ACCOMPANIED BY NONSPECIFIC BRONCHIAL HYPERRESPONSIVENESS OCCURS IN 5% OF OCCUPATIONALLY EXPOSED WORKERS. THE CASE OF A 32 YR OLD WORKER FOLLOWED LONGITUDINALLY AFTER REMOVAL FROM ISOCYANATE EXPOSURE IS REPORTED. TDI REACTIVITY WAS LOST 11 MONTHS AFTER REMOVAL FROM EXPOSURE AND NONSPECIFIC BRONCHIAL HYPERRESPONSIVENESS RESOLVED AFTER 17 MONTHS. IMMUNOPHARMACOLOGIC RESULTS SHOW THAT THE WORKER'S INITIAL DECREASED ABILITY OF LYMPHOCYTES TO PRODUCE CYCLIC-AMP RETURNED TO NEAR NORMAL AFTER 2 YR. IMMUNOGLOBULIN-E ANTIBODIES TO A HUMAN SERUM ALBUMIN TOLYL MONOISOCYANATE CONJUGATE WERE STILL PRESENT AT THIS TIME. [R50] *ACCIDENTAL SPLASH ... IN EYES OF WORKMEN HAS CAUSED KERATITIS AND CONJUNCTIVITIS. ONE CASE ... DESCRIBES "UNUSUAL AMT OF PHOTOPHOBIA AND BLEPHAROSPASM" ... SECOND CASE ... INVOLVED SEVERE IRIDOCYCLITIS AND SECONDARY GLAUCOMA. [R51] *WORKERS EXPOSED ... DEVELOPED IRRITATION OF EYES, IRRITATION OR DRYNESS OF THROAT AND/OR TIGHTNESS OF CHEST. EXPOSURE TO LEVELS AS LOW AS 0.014 MG/CU M (0.002 PPM) CAN RESULT IN CHRONIC LOSS OF PULMONARY FUNCTION. MORE ACUTE, ASTHMATIC TYPE OF BRONCHITIS IS ... TYPICAL, FRANK ASTHMA MAY OCCUR. [R52] *RESP SYMPTOMS ... IMPROVE ... AFTER REMOVAL FROM /OCCUPATIONAL/ EXPOSURE, BUT ... RE-EXPOSURE TO EVEN MINIMAL CONCN ... PRODUCED RECURRENCE OF ... SYMPTOMS. HYPERSENSITIVITY ... ARISES AFTER ... INHALATION, AND IT HAS BEEN RELATED TO IMMUNOLOGICAL CHANGES ... AND TO ALTERED BETA-ADRENERGIC FUNCTION. [R52] *Toluene diisocyanates are potent respiratory irritants and sensitizers, even at low airborne concentrations. Chronic bronchitis, chronic restrictive pulmonary disease and hypersensitivity pneumonitis have also been described among toluene diisocyanate exposed people. /Toluene diisocyanates/ [R53] *... DOSE-RESPONSE RELATIONSHIP OF ACUTE PULMONARY FUNCTION CHANGES AMONG 112 WORKERS EXPOSED ... TO 0.0035-0.06 MG/CU M (0.0005-0.009 PPM). 2-YR FOLLOW-UP EXAM OF 57 OF WORKERS DISCLOSED DECR IN PULMONARY FUNCTION ... RELATED TO EXPOSURE LEVELS, CONTROLLING FOR AGE, MO EMPLOYED, SMOKING ... AND PHYSIQUE. [R52] *A series of workers with exposure to and respiratory symptoms from toluene diisocyanate was compared with a group of exposed, asymptomatic workers and with normal controls using immunologic and clinical evaluations. Improved understanding of toluene diisocyanate-induced respiratory disease may best be achieved by categorizing the symptomatic workers into at least 3 and possibly 4 groups: immunologic asthma; pre-existing chronic respiratory disease exacerbated or unaffected by toluene diisocyanate; asthma coincidental with exposure, and possibly respiratory disease secondary to toxic or inflammatory mechanisms. [R54] *Subjects exposed to 0.0010 to 0.0015 ppm of toluene diisocyanate demonstrated a normal age and smoking-related rate of decline in forced expiratory volume in 1 sec and no evidence that it was related to isocyanate exposures. [R55] *Twelve subjects were studied with inhalation challenge testing to toluene diisocyanate because of suspected asthma based on a consistent clinical and occupational history. In 7 cases, asthma was documented by a positive inhalation challenge to low levels of toluene diisocyanate. 6 of the 7 reactors had persistent respiratory symptoms and required daily treatment even though they had been removed from isocyanate exposure for intervals as long as 12 yr (mean 4.5 yr). These 6 reactors had either dual (4 cases) or late bronchospasm (2 cases) to < 20 ppb and all had a positive methacholine or cold air challenge prior to study. The 1 reactor with a negative methacholine challenge had a positive (immediate) bronchospastic response to a challenge performed one wk after removal from isocyanate exposure. 5 workers had a negative challenge, 2 of whom had persistent respiratory symptoms and positive methacholine challenges at the time of inhalation testing. ... Respiratory symptoms may persist following long-term removal from occupational exposure and are associated with nonspecific bronchial hyperreactivity. The sensitivity may also persist for a long time even in the absence of any additional occupational exposure. Long-term prospective studies of symptomatic isocyanate workers are needed to fully define the extent of this problem. [R56] *Two workers who developed asthmatic symptoms were studied with inhalation provocation tests using ... toluene diisocyanate. Subjects did not show asthmatic reations to TDI challenge. [R57] *Amine induced asthma was studied in polyurethane foam workers. A total of 12 subjects, occupationally exposed to polyurethane foams, who complained of wheezing and breathlessness at work were tested. Subjects were given 20 to 2000 ug methacholine. Forced expiratory volume in 1 sec was measured. Subjects were challenged with 0.01 ppm toluene diisocyanate for 15 min in an atmosphere chamber. Forced expiratory volume in 1 sec was measured. Positive tests were considered as a 15% fall in forced expiratory volume in 1 sec. High sensitivity to methacholine was seen in ten subjects with a 15% fall in forced expiratory volume in 1 sec at < 1000 ug; normal subjects responded at 2000 ug. All subjects reacted to toluene diisocyanate. [R58] *... Humans are exposed to high concentrations of diisocyanates in polyurethane industries. Toxic symptoms are acute inflammation with lachrymation, rhinitis, soreness and burning in the throat and upper part of the chest, and coughing. Fire fighters are particularly prone to these clinical symptoms. The toxic limit value for toluene diisocyanate is 0.005 ppm. Exposure to diisocyanates can cause asthma. [R59] *The respiratory status of factory workers exposed continously to isocyanates over 10 yr was studied. A total of 80 workers in two facilities that manufactured fixtures used in the interiors of cars were examined and underwent spirometry before and after work. Of these, 12 were comparisons not exposed to toluene diisocyanate. Subjects included those previously examined in 1971. Ventilatory capacity tests were performed inlcuding forced expiratory volume in 1 sec and forced vital capacity testing. Annual decrements were calculated. The mean average concn of toluene diisocyanate was not more than 0.0033 ppm respectively. Subjects who had been studied previously had a mean forced vital capacity of 104.6% and a mean forced expiratory volume in 1 sec of 107% of predicted values. Three subjects with significant obstruction in the lung function tests were smokers. The comparisons in facility 1 had a significantly lower % of the predicted forced fital capacity and forced expiratory volume than the exposed population. Most of the data from 1971 for annual decrement calculations were not reliable. A 10% decrement in forced vital capacity and forced expiratory volume in 1 sec was indicative of significant postshift decline and would indicate the presence of isocyanate asthma or hypersensitivity; no subject at either facility met the criteria. [R60] *The mechanism by which late asthmatic reactions are induced by toluene diisocyanate, a low molecular weight chemical that causes occupational asthma in exposed subjects, is unknown. An investigation was conducted to determine whether early and late asthmatic reactions induced by toluene diisocyanate are associated with changes in airway responsiveness to methacholine and airway inflammation as determined by bronchoalveolar lavage. Forced expiratory volume in 1 sec was measured before and at regular intervals after exposure to toluene diisocyanate and dose-response curves to methacholine and bronchoalveolar lavage at 8 hr after toluene diisocyanate /were performed/ in a group of 6 subjects with late asthmatic reactions and in 6 subjects with only early asthmatic reactions. The same procedure was followed 2 hr after toluene diisocyanate in a group of 6 subjects with previously documented late asthmatic reactions and in a group of 6 subjects without any previously documented asthmatic reaction after toluene diisocyanate. In subjects with late asthmatic reactions, neutrophils were increased at both 2 hr and 8 hr and eosinophils and airway responsiveness were increased only at 8 hr. By contrast, neutrophils, eosinophils and airway responsiveness were not increased at 8 hr after toluene diisocyanate in subjects with an early asthmatic reaction or at 2 hr after toluene diisocyanate in normal control subjects. These results suggest that late asthmatic reactions to toluene diisocyanate, and the associated incr in airway responsiveness may be caused by airway inflammation. [R61] *Technical grade toluene diisocyanate induced chromosome aberrations after a 24 hr treatment in the absence of metabolic activation in human whole blood lymphocyte cultures. [R9] *To determine whether late asthmatic reactions and the associated incr in airway induced by toluene diisocyanate are linked to airway inflammation, inhibition by prednisone was investigated. Ten "sensitized" subjects were studied in 2 sets of experiments. In the first set, each subject was given no treatment and was studied before and for 8 hr after exposure to toluene diisocyanate. In the second set, 2-4 wk later, each subject was studied before treatment and then during treatment with prednisone (50 mg once a day for 3 days, orally), both before and after exposure to toluene diisocyanate. To assess late asthmatic reactions to toluene diisocyanate FEV1 /was measured/ immediately before and after exposure, then hourly for 8 hr. To assess changes in airway responsiveness, a /measurement was made of/ the provocation dose (mg) of methacholine causing a 20% decr in FEV1 (PD20FEV1) before and 8 hr after exposure to toluene diisocyanate. When the subjects received no prednisione treatment, toluene diisocyanate caused late asthmatic reactions and increased airway responsiveness. By contrast, when the subjects received prednisone, toluene diisocyanate caused no late asthmatic reaction or increased airway responsiveness. Prednisone did not change baseline airway caliber or airway responsiveness. These results suggest that late asthmatic reactions and the associated incr in airway responsiveness induced by toluene diisocyanate in "sensitized" subjects may depend on the development of a steroid-responsive acute inflammatory reaction within the airways. [R62] *Case reports of keratophathy in polyurethane production workers were examined. The experimental production of similar conditions was studied in cats and a monkey. A male polyurethane worker complained of blurred vision which improved over weekends away from work. The only significant finding on exam of the eyes was subepithelial corneal vesicles of 30-50 micrometers in diameter. A second patient, a female worker from the same facility, also complained of attacks of blurred vision. Slit lamp exam showed deep or subepithelial vacuolization only in the palpebral aperture. ... Corneas were normal between 3 day and 2 wk. Exposure to toluene diisocyanate did not result in the clinical appearance of the eye resembling that of the workers. [R63] *Symptoms and lung function of workers exposed to isocyanates in polyurethane foam factories were studied. A group of 67 workers was examined for toluene-diisocyanate ... exposure. Measurements were made by samples obtained from subject carried pumps. Interviews were also conducted for information of symptoms involving the nose, eyes, upper airways, and lung. Another group of 56 nonexposed workers was determined by spirometry and nitrogen wash out prior to the work shift. The exposed workers were examined again immediately after work. The variables studied were forced expired vital capacity and forced expired volume in 1 sec. ... The highest exposure group was foaming machine workers, with a day mean exposure of 0.023 mg/cu m. Nonsmokers showed an increased frequency of symptoms involving the nose, throat, and dyspnea. Smokers had no significant incr. Smokers of the exposed group reported coughing. Only smokers reported symptoms classified as chronic bronchitis, with frequency independent of exposure. Decreased forced expired vital capacity and forced expired volume were observed in the exposed group. This group also showed increased expired vital capacity. Lung function impairment was restricted to smokers. Spirometric and nitrogen washout variables did not change significantly during the work shift. Decreasing spirometric values with increased exposure was seen in smokers. Conclusions indicate that mean exposure of 0.01 mg/cu m/day to isocyanates may give an increased frequency of symptoms in nonsmokers. [R64] *A survey of the incidence of occupational asthma in a steel coating factory was conducted. The survey was prompted by 2 male employees developing symptoms suggestive of occupational asthma. The cohort consisted of 221 males employed in the coating shop. A respiratory questionnaire was administered. Spirometric tests were conducted. Peak expiratory flow rate studies were performed on 50 subjects. 21 subjects reported symptoms of occupational asthma. 63 had other work related symptoms and 58 had respiratory symptoms unrelated to work. The mean length of employment of the subjects with asthmatic symptoms was 7.7 years. All symptomatic subjects had significantly reduced 1 sec forced expiratory volumes, compared to asymptomatic workers. 21% of the peak expiratory flow rates were indicative of work related asthma. 2 symptomatic subjects were administered inhalation challenge tests with toluene diisocyanate after it was discovered that one of the coatings that had been used for 8 yr released toluene diisocyanate during the coating process. Both subjects showed decreases in forced expiratory volumes of at least 15% below the baseline values. Environmental sampling for toluene diisocyanate indicated concns ranging from below 0.001-0.026 ppm. The coating containing toluene diisocyanate was removed from the process. A follow-up survey conducted 1 yr later showed that 17 of the symptomatic subjects had become asymptomatic or improved. [R65] *The presence of different thresholds on bronchial reactivity to toluene diisocyanate was tested in 20 spray painters employed in the furniture industry and affected by TDI induced asthma. Bronchial provocation tests failed to demonstrate nonspecific hyperreactivity to methacholine. Exposure of the workers to toluene diisocyanate in concns ranging from 0.02-0.25 ppm demonstrated the occurrence of low, moderate and high thresholds of airways response to toluene diisocyanate in 9, 7 and 4 patients, respectively. There was no association between the toluene diisocyanate response threshold and the positive response pattern to the lower range of toluene diisocyanate levels, but 6 of the 9 patients with low threshold of response to toluene diisocyanate and 6 of the 11 patients with moderate or high thresholds had nonspecific bronchial hyperreactivity. The response to toluene diisocyanate also was not associated with the duration of the asthmatic condition, smoking, cessation of work or nonspecific response to methacholine. The pattern of response was not dose dependent in 10 of 13 patients who had two positive bronchial provocation tests with different levels of toluene diisocyanate, although dual responses were recorded in 3 patients who had late reactions at low concns of toluene diisocyanate. The value of forced expiratory volume in 1 sec, recorded during immediate reactions, showed a dose response relationship, in that it declined by 28.4% at lower toluene diisocyanate levels as compared to 38.3% following inhalation of higher doses of the cmpd; no such association was established for the late reaction to toluene diisocyanate. The results conclude that patients who are sensitive to toluene diisocyanate may have different thresholds of response to the agent. [R66] *Respiratory variables were measured in workers exposed to toluene diisocyanate in Canada. Exposure and effect relationships were studied. Results from 95 isocyanate workers were compared with unexposed workers. Exposed workers were grouped according to production areas based on isocyanate concns measured. Individual monitors were worn to identify exposure for some workers. Symptoms and history of respiratory illness were compared through questionnaires. Pulmonary function tests included forced vital capacity, forced expiratory volume in 1 sec, and forced expiratory flow at 50% and 75% of vital capacity. Pulmonary function was measured at the beginning and end of work shifts on Monday, Wednesday, AND Friday of a work week. Regression analysis of exposure concn and other variables was attempted. When comparisons were adjusted for smoking habits, exposed workers had a significantly lower family history of respiratory complaints. Isocyanate workers had slightly lower base line lung function than comparisons, but had significantly higher declines in pulmonary function over the work week. A 5% or greater decline over a day occurred in 44 percent of exposed but only 22% of comparison workers. Foam line and finishing area workers had greatest declines in forced vital capacity and forced expiratory volume in 1 sec. It was concluded that although regression analysis does not show an exposure/effect relationship, an all or none effect may be operating with acute and chronic compartments. However, sample size may have been insufficient. [R67] *Toluene diisocyanate may produce a true hemorrhagic syndrome affecting the bone marrow and producing primarily thrombocyte series suppression. [R28, 303] *All workers develop eye, nose, and throat irritation at 0.5 ppm. Sensitized individuals may manifest symptoms at levels as low as 0.02 ppm. [R47, 880] *A worker developed toluene diisocyanate induced asthma in 1974. On reassessment, 11 yr after leaving the chemical plant where toluene diisocyanate was produced, he had no respiratory symptoms and normal bronchial reactivity in response to methacholine, and showed no reaction when challenged with a subirritant concn of toluene diisocyanate. He developed asthma within 5 months of returning to the workplace. Repeat challenge testing showed bronchial hyperreactivity to methacholine and to the specific sensitizing agent, toluene diisocyanate. This clinical pattern could be due to underlying toluene diisocyanate sensitivity with resolution and reappearance of hyperresponsiveness to methacholine and toluene diisocyanate reactivity associated with workplace toluene diisocyanate exposure. Alternatively, this worker may have developed sensitization to toluene diisocyanate anew. [R68] *An investigation of the persistence of isocyanate induced asthma in workers with negligible occupational exposure was carried out. Six asthmatic workers, proven to be toluene diisocyanate sensitive by inhalation challenge testing in a longitudinal study of respiratory health risks associated with polyurethane foam production, were examined. The subjects were followed for 5 yr during which they completed a respiratory symptom questionnaire annually. Pulmonary function and responsiveness to methacholine challenge were measured annually. toluene diisocyanate concn in their breathing zones were measured. After the original survey the six subjects were transferred to areas thought to have negligible toluene diisocyanate exposures. None of the subjects had respiratory or asthmatic complaints before they started work in polyurethane production. The respiratory symptoms of the subjects did not improve during the follow-up period. All 6 had bronchial hyperresponsiveness to methacholine that did not resolve over time. Three subjects demonstrated deficits in 1 sec forced expiratory volume of > 15% on one of the testing days during the follow-up period. The need for less or additional asthma therapy of the subjects could not be predicted. The mean time weighted average toluene diisocyanate exposure experienced by the subjects was 0.64 ppb; < 5% of the OSHA standard of 20 ppb. It was concluded that although the outcome of isocyanate induced asthma cannot be predicted, the asthmatic symptoms of these workers have persisted despite the negligible toluene diisocyanate exposures. [R69] *The prevention of airway inflammation caused by toluene diisocyanate by prednisone was studied. Healthy toluene diisocyanate sensitive individuals were exposed to 0.018 ppm toluene diisocyanate in a test chamber. Bronchoalveolar lavage fluid was collected with a flexible fiberoptic bronchoscope. The lavage fluid was spun in a cytocentrifuge and stained with May/Grunwald/Giemsa for differential cell count. The total cell count was performed on resuspended cell pellets. A late asthmatic response was characterized by the occurrence of < 20% of free expiratory volume in 1 second. The airway responsiveness was assessed by the reaction to methacholine. The cumulative dose of methacholine that produced a 20% decr in forced expiratory volume in 1 sec was used to measure airway responsiveness. Five subjects who received no prednisone treatment developed a late or dual asthmatic reaction. The albumin concn and total number of cells increased in subjects that were given no prednisone compared to controls. There was a significant incr in the number of neutrophils and a small incr in eosinophilia. There was no significant difference in the counts of other cell types. Results suggest that toluene diisocyanate induce late asthmatic reactions causing airway inflammation and that prednisone inhibits these reactions. [R70] *Thirty factory workers whose annual exposure to toluene diisocyanate amounted to 280 hr were examined. Seven of them had been removed from their jobs for presenting respiratory symptomatology and a further 5 were removed for presenting bronchial asthma. Their medical histories were consulted and further measures were taken such as a radiological thorax study, total immunoglobulin-E, toluene diisocyanate, diphenylmethane diisocyanate and hexamethylene diisocyanate RAST, a basal spirometric study and finally a provocation test. The Rast proved negative in every case. In the spirometric study carried out on the provocation test, 4 cases showed a significant decr in the forced expiratory volume in 1 second over 20% and over 40% in the FMEF AND PEFR. There was no connection between the 4 patients who presented an elevated total immunoglobulin-E and the four who presented a positive provocation test. The provocation test proved negative in five of the seven patients removed from their places of work. Two of the four workers who responded positively to the provocation test remained in their places of work during the toluene diisocyanate foam test without showing any symptoms. The patients who presented symptoms did not appear to present bronchial obstruction during the provocation test. Nonetheless, patients who seemingly had not shown any symptoms presented what appeared to be bronchial obstruction. [R71] *The nature of neurohumoral regulation was studied in 125 healthy workers, aged 20-40 yr, with different length of service and toluene diisocyanate exposure levels. Adrenal gland activity and some haematological parameters were determined. Neurohumoral regulation of adaptation processes in toluene diisocyanate exposed persons seemed to display some cyclicity, somehow related to the length of service. Two early regulatory phases (service up to 3 yr) had common features unrelated to the exposure levels, while after 3 yr of employment some dissimilarities evolved which did depend on the toluene diisocyanate exposure levels. [R72] *Sensitized subjects may develop symptoms of asthma after exposure to isocyanates in their place of work. After challenge with isocyanates in the lab, sensitized subjects develop immediate, late and dual asthmatic reactions. Toluene diisocyanate might cause late asthmatic reactions and incr bronchial responsiveness by causing an acute inflammatory reaction in the airways, and that airway inflammation may be responsible for persistence of occupational asthma induced by isocyanates. To test these hypotheses, sensitized subjects were examined during asthmatic reactions induced by exposure to toluene diisocyanate in the lab. It was observed that late and dual, but not early, asthmatic reactions are associated with a transient incr of bronchial responsiveness which is associated with an acute inflammatory reaction of the airways characterized by an incr of neutrophils followed by eosinophils, by an incr of leukotriene B4 and albumin in bronchoalveolar lavage fluid, and that all these effects are inhibited by steroids. Longitudinal studies suggest that the majority of subjects with occupational asthma continue to have persistent asthma months and yrs after the cessation of exposure, and the results of our studies combined with the results of studies performed by others suggest that the persistence of asthma may be related to the persistence of airway inflammation. [R73] HTOX: *A shortened protocol was developed for the epidemiological measurement of bronchial responsiveness to methacholine without compromising sensitivity, power, precision or safety, and without distorting the numerical value of the PD20.FEV1 (the cumulative dose from a doubling incremental sequence which provokes a 20% decrement in forced expiratory volume in 1 second). It was used in a survey of 254 polyurethane workers (83% of the eligible workforce) exposed occupationally to toluene diisocyanate. The mean duration of each test proved to be 38 min, it was well tolerated and 64 workers (25%) proved to be reactors. PD20.FEV1 appeared to be distributed unimodally. It was significantly correlated with questionnaire records of shortness of breath, chest tightness, and wheeze; and with pre-shift forced expiratory volume in 1 sec and FEF25-75. Even the reactors requiring the highest dose of 640 cumulative inhalation units (1 unit = one 8.9 ul inhalation of methacholine 1 mg/ml) to generate a PD20 measurement reported significantly more wheeze than the non-reactors. This indicates that the test had clinical meaning throughout its dose range of 0.3-640 units. No correlation was found between PD20 and individual changes in ventilatory function across the working shift, but mean shift changes were negligible and not statistically significant. PD20 was also found to be unrelated to age, sex, race, smoking, cough and atopy. [R74] *Among the painters handling polyurethane varnish in two furniture manufacturing factories with high toluene diisocyanate exposure (0.79 mg/cu m and 0.31 mg/cu m), 26.3% and 15% subjects, respectively displayed asthmatic symptoms, lung function loss, and an increment in mast cell degranulation percentage specific to toluene diisocyanate. Some cases of toluene diisocyanate linked contact dermatitis were also found among them, being elucidated by positive patch testing to toluene diisocyanate. However, the previous abnormalities could not be verified among the painters from another factory with toluene diisocyanate concn below the TLV of it (0.11 mg/cu m). It was concluded that both pulmonary hypersensitivity and contact sensitization to toluene diisocyanate had occurred in some of the painters included in this study, and that the immunologic effects of toluene diisocyanate was concn dependent. [R75] *The importance of airways inflammation for the development of bronchial hyperresponsiveness and for exacerbation of asthma was investigated in subjects with occupational asthma. Subjects sensitized to isocyanates, a small molecular weight cmpd that causes occupational asthma were examined. Studies in asthmatic subjects sensitized to toluene diisocyanate demonstrated that late, but not early, asthmatic reactions induced by toluene diisocyanate were associated with an acute incr in bronchial responsiveness, and with a marked infiltration of neutrophils and a slight infiltration of eosinophils into the airways, both prevented by steroids. As the late asthmatic reactions and the incr in responsiveness induced by toluene diisocyanate were prevented by steroids, but not by indomethacin, it was speculated that cell membrane phospholipid metabolites, which are inhibited by steroids but not by indomethacin, may be involved in toluene diisocyanate induced hyperresponsiveness. The results of these studies suggest that bronchial hyperresponsiveness and exacerbation of asthma may be related to inflammation of the airways and that cell membrane phospholipid metabolites may be involved. [R76] *A study of individuals with occupational asthma induced by toluene diisocyanate was conducted. This was a follow-up of 35 patients, 25 males, with a history of isocyanate sensitization. They had 3-41 yrs' occupational exposure to isocyanate cmpds. The subjects had been diagnosed with isocyanate asthma on the basis of their response to bronchial challenge with toluene diisocyanate. They were examined an average of 11 mo after diagnosis. They underwent bronchial challenge with toluene diisocyanate and methacholine. Forced expiratory volumes in 1 sec were measured. Symptoms reported by the subjects were recorded. Twenty seven subjects were still asthmatic at follow-up as shown by a positive reaction to toluene diisocyanate challenge. They showed a deterioration in their forced expiratory volumes in 1 sec and response to methacholine similar to that seen at diagnosis. 77% of these subjects continued to have recurring attacks of dyspnea, wheezing, and cough which required medication. Twenty two of the asthma subjects had been removed from exposure. Subjects who recovered (did not react to toluene diisocyanate at the follow-up exam) showed an improvement in their forced expiratory volumes in 1 sec and a reduced response to methacholine. At the time of diagnosis they tended to have an immediate or dual asthmatic reaction and were younger than the other subjects. The asthmatic subjects had dual or late reactions at diagnosis. It was concluded that respiratory symptoms, isocyanate sensitization, and airway hyperresponsiveness may persist for some time after exposure to toluene diisocyanate has ended. [R77] *Six workers with occupational asthma due to toluene diisocyanate were studied. For each worker a detailed clinical and occupational history was taken, and lung function measurement and skin intradermal tests for common allergens were carried out. Methacholine inhalation challenge was performed before toluene diisocyanate inhalation, and 8 hr after toluene diisocyanate inhalation. Methacholine challenge was within normal limits when performed before toluene diisocyanate inhalation, but went into the asthmatic range after toluene diisocyanate inhalation. These cases provide evidence that asthma can be induced by toluene diisocyanate in the absence of airway hyperresponsiveness. They further demonstrate that an isolated negative methacholine inhalation test cannot be used to exclude sensitization to toluene diisocyanate. Screening and follow-up studies on workers exposed on toluene diisocyanate require serial measurements of airway responsiveness and of variable air-flow obstruction. [R78] *The clinical findings and the results of inhalation challenge with toluene diisocyanate and methacholine in 113 subjects with a history of exposure to toluene diisocyanate and work-related respiratory symptoms are reported. Only some of the subjects (40.7%) had isocyanate asthma, diagnosed by a positive toluene diisocyanate inhalation challenge. Most reactors had a dual (30.4%) or a late (41.3%) response. The interval between the last occupational exposure and the specific challenge was significantly shorter in reactors, and among this group the number of immediate reactions to toluene diisocyanate decr progressively with an incr interval. The reactors had a significantly higher proportion of positive responses to methacholine and a significantly lower mean PD(1)(5) FEV(1) (provocative dose of methacholine which provoked a 15% decrease in forced expiratory volume in 1 sec): reactors 557:g, SEM 92.3; non-reactors 1346:g, SEM 128, P < .01. Methacholine challenge could not identify subjects with isocyanate asthma. [R79] *Toluene diisocyanate is commonly used as the 2,4 and 2,6 isomers. NIOSH has estimated that 50,000 to 100,000 workers in the U.S. are regularly exposed to diisocyanates. As of 1977, 49,996 were estimated to be exposed to toluene diisocyanate alone. Methods for measuring diisocyanate exposures were considered. The current American Conference of Governmental Industrial Hygienists' recommended standard is 0.005 ppm time weighted average and 0.02 ppm peak for four 15 min periods/day. Results of exposure measurements taken in industry were summarized. Health effects of diisocyanates were discussed. In laboratory animals, toluene diisocyanate has caused inflammation and necrosis when applied directly to the skin, conjunctivitis when applied to the eyes, and rhinitis, laryngitis, tracheitis, bronchitis, and pneumonia when inhaled. Diisocyanates are potent pulmonary sensitizers capable of causing isocyanate asthma in humans. They can induce nonspecific airways disease and hypersensitivity pneumonitis after either acute or chronic exposure. [R80] *A 46 yr old man who had worked in a paint processing plast for over 29 yr was admitted to our hospital with complaints of nocturnal dyspnea and dry cough. A chest X-ray film showed diffuse granular shadows in bilateral lungs. Pulmonary function tests revealed reduction of diffusing capacity and restrictive impairments. Hypersensitivity pneumonitis due to isocyanates was speculated from his occupational history and clinical course. Positive skin tests against toluene diisocyanate-human serum albumin and diphenylmethane diisocyanate-human serum albumin, precipitating antibody against toluene diisocyanate-human serum albumin, and negative lymphocyte stimulating tests of peripheral blood and bronchoalveolar lavage fluid were also noticed. Environmental provocation test was positive. Histological findings of transbronchial lung biopsy specimens showed diffuse alveolitis and Masson body, but no granulomas. According to these results, the patient was diagnosed as hypersensitivity pneumonitis due to toluene diisocyanate. Type III allergy of Gell-Coombs seems to participate in this case. The granulomatous lesion is seen less frequently in isocyanate related hypersensitivity pneumonitis than in hypersensitivity pneumonitis induced by organic dusts, which suggests the difference in immunological and histological reactions between both types of hypersensitivity pneumonitis. [R81] *Pulmonary function tests were done and compared to current and past potential exposure levels of toluene diisocyanate for 57 toluene diisocyanate manufacturing workers and 89 workers not exposed to toluene diisocyanate or other known respiratory hazards. The average toluene diisocyanate plant experience was 4.1 yr (standard deviation= 2.8). Routine industrial hygiene measurements have shown toluene diisocyanate exposure below a time-weighted average of 0.005 ppm and a short-term exposure level of 0.02 ppm. A certified industrial hygienist ranked department and job classification by level of potential exposure to toluene diisocyanate (none, low, moderate, and high). A questionnaire was administered to determine the prevalence of respiratory symptoms and smoking habits. Using backward regression analysis, cumulative pack-yrs of cigarette smoking and prevalence of lower respiratory symptoms were statistically significant predictors of a standardized forced expiratory volume at 1 sec; however, toluene diisocyanate exposure, whether classified as current, highest career level, cumulative, or cumulative highest-to-date, was not associated with a decline in forced expiratory volume. [R82] *Fifty seven polyurethane foam manufacturing workers and 24 reference workers were followed for 4 yr to clarify the effects on pulmonary function of working in polyurethane foam factories with exposure to toluene diisocyanate. No significant differences in the average annual losses of pulmonary function for 4 yr were observed among the 28 polyurethane foam workers whose toluene diisocyanate exposure levels were very low (mean = 0.1 ppb, group L), the remaining 29 polyurethane foam workers with mean toluene diisocyanate exposure of 5.7 ppb (group H), and the reference workers. However, 15 polyurethane foam workers in group H who had experienced peak exposure excursions to 30 ppb or above with a mean concn of 8.2 ppb showed significantly larger average annual losses in % maximal mid-expiratory flow, forced expiratory volume in 1 sec ratio to vital capacity, and forced expiratory flow at 25% of forced vital capacity than expected, and significantly larger average annual losses in some obstructive pulmonary function indices than those of the 14 remaining polyurethane foam workers in group H whose peak exposure excursion levels were 3-14 ppb with a mean time-weighted average of 1.7 ppb, group L, and the reference workers. These findings suggest that the peak exposure excursion level of toluene diisocyanate might be important in inducing obstructive pulmonary function changes in the polyurethane foam workers rather than the TWA exposure levels, though further comparative studies of the AAL in those who are exposed to different peak exposure excursion levels but the same mean exposure levels are necessary. From the standpoint of prevention, the proposition that peak exposure excursion levels exceeding 20 ppb should be avoided is reasonable. [R83] *To evaluate the morphologic basis of the different outcomes of toluene diisocyanate asthma after quitting occupational exposure, 10 patients with toluene diisocyanate asthma were examined who showed, at diagnosis, a positive toluene diisocyanate challenge test and nonspecific bronchial hyperresponsiveness to methacholine. After diagnosis, all patients ceased work and a 4-40 mo follow-up was obtained with 3-8 determinations of the cumulative dose producing a 15% fall in forced expiratory volume in 1 sec to methacholine in each patient. Bronchoalveolar lavage and biopsy of bronchial mucosa were performed 3-39 mo after cessation of work, in the absence of acute exacerbations of the disease. Total cell count in bronchoalveolar lavage fluid was moderately increased in 4 of 10 patients, eosinophils were increased in 5 of 10 patients, and neutrophils were increased in 8 of 10 patients. Mucosal biopsy specimens of main or lobar bronchi were available in 8 of 10 patients; epithelial damage and thickening of basement membrane was observed in almost all patients, as well as a mild to moderate inflammatory reaction in the submucosa, mainly represented by lymphocytes, eosinophils, and neutrophils. No relationship was observed between the cellularity of bronchoalveolar lavage and the degree of nonspecific bronchial hyperresponsiveness at the time of bronchoalveolar lavage; mean values of total cells and differential count were not different between patients with presence or absence of the different histologic findings. Mucosal biopsy and bronchoalveolar lavage were performed also in 4 subjects exposed to dusts without respiratory symptoms or nonspecific bronchial hyperresponsiveness; similar findings were obtained except for the absence of eosinophils in bronchoalveolar lavage and a lesser degree of basement membrane thickening and inflammatory reaction in the submucosa. The study of the changes in nonspecific bronchial hyperresponsiveness after quitting exposure showed that 5 of 10 patients had a significant improvement in nonspecific bronchial hyperresponsiveness to methacholine, as evaluated by a positive significant linear regression between months of work cessation and forced expiratory volume in 1 sec of methacholine; only 1 of these 5 patients had an increased number of eosinophils in bronchoalveolar lavage fluid. By contrast, 4 of the 5 patients with persistent nonspecific bronchial hyperresponsiveness after quitting exposure had an increased number of eosinophil in bronchoalveolar lavage. It is suggested that persistent nonspecific bronchial hyperresponsiveness in toluene diisocyanate asthma after cessation of work may be related to an inflammatory reaction in which eosinophil infiltration seems to be a major determinant. [R84] *The effect of cessation of exposure to toluene diisocyanate was studied in 6 patients with toluene diisocyanate induced asthma, proved by a positive inhalation challenge with toluene diisocyanate. Bronchial challenges with toluene diisocyanate and methacholine were performed, and lobar bronchial biopsies were taken at diagnosis and 6 mo later, after cessation of exposure. Biopsies from four nonasthmatic control subjects were also examined. At diagnosis, asthmatic subjects had thickened reticular basement membrane (p < 0.05) and increased numbers of mononuclear cells (p < 0.05) and eosinophils (p < 0.05) in the lamina propria when compared with control subjects. Electron microscopy showed degranulation of eosinophils and mast cells in asthmatics. Six months after cessation of exposure, the thickness of reticular basement membrane was significantly reduced compared with that at diagnosis (p < 0.05), and it decr to values similar to those of control biopsies. Inflammatory cell numbers in bronchial mucosa of asthmatic subjects did not change significantly 6 mo after removal from exposure, and degranulation of eosinophils and mast cells was still present. At the end of the study, airway hyperresponsiveness to methacholine and/or sensitivity to toluene diisocyanate persisted in most of the asthmatic patients despite the cessation of exposure and the disappearance of asthmatic symptoms. In conclusion, in patients with occupational asthma induced by toluene diisocyanate, the avoidance of exposure to the sensitizing agent for 6 mo is able to reverse the reticular basement membrane thickening in the bronchial mucosa, but the inflammatory cell infiltrate, the specific sensitivity to toluene diisocyanate, and the nonspecific airway hyperreactivity may persist. [R85] *Forty-three workers exposed to low levels of toluene diisocyanate during the process of producing polyurethane forms were examined immunologically for immunoglobulin-G, A, M, AND E and serum enzyme activities such as serum angiotensin converting enzyme, serum lysozyme and glycylproline dipeptidyl aminopeptidase. Air concn of toluene diisocyanate was annually measured in various places of work during the past 5 yr from 1979-1983. The results obtained in the present study were as follows. The air concn of toluene diisocyanate at all places of work was below the permissible concn level of 0.02 ppm throughout the study period. Subjective symptoms and abnormal findings on chest X-ray considered directly related to toluene diisocyanate exposure were no observed. No remarkable abnormal findings in blood cell counts and in serum biochemical studies could be seen in any of the workers. The serum immunoglobulin-G levels in workers directly exposed to toluene diisocyanate were significantly higher (p < 0.05) than those in workers indirectly exposed to toluene diisocyanate and in non-exposed workers. In the study of serum enzymatic activity, serum lysozyme activity in workers exposed directly to toluene diisocyanate was significantly higher (p < 0.01) than those in workers indirectly exposed to toluene diisocyanate and in non-exposed workers. [R86] *A case of building related health complaints was investigated with respect to the relationship among frequency of symptoms, antibodies to albumin conjugates of formaldehyde, toluene diisocyanate, and trimellitic anhydride, and volatile organic chemicals. The indoor air concn of volatile organic chemicals, formaldehyde, toluene diisocyanate and trimellitic anhydride did not exceed Fed-OSHA AND ACGIH permissible standards. However, formaldehyde concn ranged between 0.05 and 0.08 ppm. The reported symptoms were multiple, involving the eyes, nose, sinuses, throat, lungs, skeletomuscular system and CNS. Anti-formaldehyde, toluene diisocyanate, and trimellitic anhydride isotypes were found in 12 of 14 full-time employees and were nondetectable in one part-time employee. The data suggest that a synergistic immunological response to airborne chemicals may be occurring in these subjects. In conclusion, immunological monitoring of affected individuals where chemicals are suspected may prove to be useful in future investigations of building related illness. [R87] *Diisocyanate inhalation tests (maximal concn, 20 ppb; exposure time, 1-2 hr) were performed using toluene diisocyanate (TDI, n=15) and diphenylmethane diisocyanate (MDI, n=7) as well as methacholine challenges in 19 workers who had a clinical history of toluene diisocyanate/diphenylmethane diisocyanate induced asthma. Additionally volunteers were tested who had no previous contact with diisocyanates: 10 healthy individuals with a negative methacholine test and 14 patients with asthma and a positive methacholine test were exposed to toluene diisocyanate. In all, 1 of the normal volunteers and 3 of the patients with asthma unrelated to diisocyanates showed a positive airway reaction to toluene diisocyanate, and 13 of the 19 diisocyanate workers displayed a positive result in the toluene diisocyanate/diphenylmethane diisocyanate inhalation test; however, only 6 of these 13 individuals reacted to methacholine. Furthermore, 3 of the 6 patients with a negative toluene diisocyanate/diphenylmethane diisocyanate challenge test demonstrated a significant response to methacholine. It was concluded that bronchial hyperreactivity as evaluated by the methacholine challenge test is not closely related to isocyanate induced bronchoconstriction and, therefore, the metacholine challenge is only of limited diagnostic value in patients with suspected isocyanate induced asthma. [R88] *An outbreak of occupational asthma due to toluene diisocyanate among industrial workers was described. 4 employees at a velcro/like tape manufacturing factory in Taipei, Taiwan were seen in an outpatient clinic complaining of cough, shortness of breath, and wheezing. The symptoms became worse at night and improved after long holidays. The patients' job involved applying an adhesive to the tape. 38 of 45 employees were interviewed by questionnaire and given pulmonary function tests. The pulmonary function tests were given during a workday, after a 10 day holiday, and 5 mo after control measures such as process isolation, improved ventilation, and substitution for toluene diisocyanate were instituted. Industrial hygiene sampling for toluene diisocyanate was conducted. 14 workers had symptoms of asthma or asthmatic bronchitis. The highest attack rate occurred in workers employed in the tape processing area where the adhesive was applied. Workers in the tape processing area also showed the greatest decr in 1 sec forced expiratory volume and forced vital capacity over the workday. Mean toluene diisocyanate concn ranged from 0.012-0.047 ppm, the highest occurring in the tape processing area and the lowest in the weaving area. The prevalence of asthmatic symptoms was significantly correlated with toluene diisocyanate concn. The forced expiratory volume in 1 sec and forced vital capacity values were significantly improved after the 10 day holiday and 5 mo after the control methods were instituted. No asthmatic symptoms were reported after 5 mo. It was concluded that toluene diisocyanate was responsible for the outbreak and improving the work environment was effective in reducing exposure to toluene diisocyanate. [R89] *A 41 yr old automobile paint sprayer showed the clinical features of hypersensitivity pneumonitis 1 wk after he had begun to work with paint materials containing toluene diisocyanate. His symptoms began 6 to 8 hr after exposure to the agent and spontaneously disappeared by the next morning. He had diffuse, fine reticulonodular shadows on a chest roentgenogram and a restrictive impairment of pulmonary function. Immunoglobulin G antibody to toluene diisocyanate-human serum albumin was present in bronchoalveolar lavage fluid and sera: IgA antibody was present only in bronchoalveolar lavage fluid. Also, the patient had sensitized bronchoalveolar lymphocytes to toluene diisocyanate-human serum albumin. The histologic findings suggested hypersensitivity pneumonitis. The results of bronchoalveolar lavage, which was repeated on 4 separate occasions, showed lymphocytosis and a predominance of suppresser cytotoxic T cells. The findings from serial determinations of humoral antibodies showed no changes consistent with the results of clinical and laboratory studies. In contrast, blastogenic responses of bronchoalveolar lymphocytes to toluene diisocyanate markedly decr, and the patient showed clinical improvement despite continued exposure to the agent. [R90] HTOX: *Preliminary studies suggest that pulmonary hypersensitivity and contact sensitivity to toluene diisocyanate may be diagnosed by determination of toluene diisocyanate-specific antibodies and by a rat mast cell degranulation test, respectively. [R91] *... Patients with toluene diisocyanate induced asthma suggest that a short period of exposure and a short duration of symptoms before diagnosis, followed by complete cessation of exposure, are likely to lead to improvement of the symptoms and lung function. A decrease only of the exposure led to deterioration of lung function, and long exposure and duration of symptoms were unfavourable prognostically. [R92] *A study of the occurrence of serum immunoglobulin-E and immunoglobulin-G antibodies in workers with isocyanate induced asthma was conducted. The study group consisted of 62 workers (58 males) being evaluated for occupational asthma. 39 had been exposed to hexamethylene diisocyanate, 17 to diphenylmethane diisocyanate, and 6 to toluene diisocyanate. The subjects completed a respiratory and occupational questionnaire. Spirometric tests were administered. Skin prick tests were performed with 15 common inhalant allergens and toluene diisocyanate, hexamethylene diisocyanate, and diphenylmethane diisocyanate human serum albumin conjugates. Blood samples were collected and assayed for specific serum immunoglobulin-G and immunoglobulin-E antibodies to hexamethylene diisocyanate, diphenylmethane diisocyanate, and toluene diisocyanate. Specific inhalation challenges were conducted with hexamethylene diisocyanate, diphenylmethane diisocyanate, and toluene diisocyanate. Specific inhalation challenge with toluene diisocyanate, hexamethylene diisocyanate, or diphenylmethane diisocyanate induced significant bronchoconstriction in half of the subjects, late reactions being the most common. 20 subjects had significantly elevated immunoglobulin-G concn and 9 had significantly elevated immunoglobulin-G plus immunoglobulin-E concn. 6 of 12 subjects with elevated immunoglobulin-E and immunoglobulin-G antibodies had positive skin prick tests for hexamethylene diisocyanate and one was sensitized to diphenylmethane diisocyanate. It was concluded that an association between isocyanate specific antibodies and the results of specific inhalation challenge tests has been established. This suggests that isocyanate induced asthma may involve an immunological mechanism. [R93] *The influence of cyclophosphamide induced granulocyte depletion on toluene diisocyanate related changes in airway reactivity and pathology was assessed in guinea pigs. Twelve cyclophosphamide-treated and 12 control animals comprising each group were studied physiologically before and 2 hr after a single 10 min exposure to 3 ppm of toluene diisocyanate. Reactivity was determined in intact unanesthetized animals by measuring specific airway conductance before and during iv acetylcholine infusion. After testing, tracheal tissue for light microscopic examination was obtained from 3 hyperreactive guinea pigs in each exposed group and compared with tissue from treated and control animals (n= 3 each) that had not been toluene diisocyanate exposed. Cyclophosphamide treatment caused substantial decr in both circulating and airway granulocyte counts. However, the incidence and degree of bronchial hyperreactivity that occurred 2 hr post-toluene diisocyanate was similar in the untreated and treated groups. Results indicate that toluene diisocyanate induced bronchial hyperreactivity 1) occurs shortly after a brief high concn exposure and 2) appears independent of circulating or airway granulocyte counts. [R94] *The effects of toluene diisocyanate on T-cell subpopulations and circulating lymphocytes in 10 persons (5 males)): 19-50 yr old, with toluene diisocyanate induced occupational asthma were examined. 5 subjects revealed early and late asthmatic reactions to toluene diisocyanate (dual responders) and 5 revealed late asthmatic reactions (late responders). Subjects underwent inhalation challenge with 0.005-0.015 ppm toluene diisocyanate or filtered air for 10-30 min on 2 occasions. 1 sec forced expiratory volumes were measured before and at periodic intervals between 30 min and 24 hr after challenge. Venous blood samples were drawn 30 min and 8, 24, 48, and 72 hr after toluene diisocyanate. Total and differential leukocyte counts and T-cell subpopulations were determined. The 5 dual responders demonstrated forced expiratory volume in 1 sec decreased indicative of early and late asthmatic reactions and the five late responders demonstrated forced expiratory volume in 1 sec decr indicative of a late asthmatic reaction. Toluene diisocyanate challenge did not affect the number of circulating erythrocytes and leukocytes. The % of eosinophils was significantly increased 24 hr after challenge and sustained for up to 48 hr. The % of neutrophils, lymphocytes, and monocytes were not altered by toluene diisocyanate. Among the T-lymphocyte subpopulation, the proportion of CD8(+) lymphocytes was significantly increased 8 hr after toluene diisocyanate challenge. The incr was more pronounced in the late responders. An addnl incr in CD8(+) lymphocytes occurred 48 hr post exposure in 7 subjects but was unrelated to responder type. The number of CD4(+) cells did not change. This resulted in a decr in the CD4(+)/CD8(+) ratio 8 and 48 hr after toluene diisocyanate challenge. It was concluded that toluene diisocyanate induced late asthmatic reactions are associated with an incr in the number of suppressor/cytotoxic lymphocytes and eosinophils in peripheral blood. [R95] *Serum immunoglobulin-G and immunoglobulin-E to isocyanate haptenized human serum albumin (HSA) were estimated by ELISA in 55 isocyanate workers who underwent isocyanate inhalation challenge studies in Montreal, Canada. The challenges were negative in 29 workers and positive in 26 workers. Isocyanate antibodies were estimated by ELISA index. The mean immunoglobulin-G indices were found to be significantly higher in the challenge-positive workers, and there was a similar trend for the immunoglobulin-E indices. Antibody specificities for toluene diisocyanate-human serum albumin, diphenylmethane diisocyanate-human serum albumin, and hexamethylene diisocyanate-human serum albumin were determined by inhibition studies with a variety of isocyanate haptenized carriers. The other isocyanate substituted carriers were either noninhibitory or caused only partial inhibition as contrasted with the complete inhibition achieved by human serum albumin conjugated to the isocyanate to which the worker was exposed. We interpret these specificity studies as indicating that the inhalation of isocyanates results in production of antibody that recognizes new antigenic determinants that develop from the coupling of isocyanates to homologous proteins. [R96] *Light and electron microscopic structure of lobar bronchial biopsies were examined of 9 subjects with occupational asthma induced by toluene diisocyanate and of 4 control nonasthmatic subjects who had never been exposed to toluene diisocyanate. Inflammatory cell numbers were separately assessed in the intact epithelium, in the more superficial layer of the submucosa, and in the total submucosa. Asthmatic subjects had an increased number of inflammatory cells in the airway mucosa compared with control subjects. Eosinophils were significantly increased in all compartments, CD45-positive cells were significantly increased in the epithelium and in the more superficial layer of the submucosa, and mast cells were significantly increased only in epithelium. By electron microscopy eosinophils and mast cells appeare degranulated only in asthmatic patients. In the areas of epithelium that appeared intact by light microscopy, electron microscopy showed that, although the intercellular spaces between columnar cells were similar in asthmatic and control groups, the intercellular spaces between basal cells were significantly wider in patients with asthma. Patients with toluene diisocyanate induced asthma also had a thicker subepithelial reticular layer, where immunohistochemistry showed the presence of collagen III. In conclusion, in patients with asthma induced by toluene diisocyanate, the airway mucosa shows pathologic features, such as inflammatory cell infiltrate and thickening of subepithelial collagen, similar to those described in atopic asthma. [R97] *Serum neutrophil chemotactic activity, which is associated with mast cell or basophil activation, was quantitated to determine if mast cell or basophil mediators are released during bronchoprovocation-inhalation challenge with subirritant levels of toluene diisocyanate. 4 subjects with suspected toluene diisocyanate induced asthma and 4 mite-sensitive subjects with asthma who served as a comparison group were studied. Neutrophil chemotactic activity was measured in a multiwell, microchemotaxis chamber. Blood samples were collected, and forced expiratory volume in 1 sec measurements were performed before challenge and at regular intervals during the subsequent 24 hr. 3 of 4 workers clinically sensitive to toluene diisocyanate reacted to a subirritant toluene diisocyanate exposure. There was no incr in neutrophil chemotactic activity during placebo challenges. Neutrophil chemotactic activity increased in the 3 toluene diisocyanate sensitive workers during early and late asthmatic reactions in quantities proportional to the forced expiratory volume in 1 sec decline. No incr in neutrophil chemotactic activity was found during toluene diisocyanate exposures in the toluene diisocyanate negative worker. Gel filtration analysis demonstrated the main neutrophil chemotactic activity fraction eluted with macromolecules of an estimated molecular weight > 440,000 daltons. This characteristic is compatible with neutrophil chemotactic factor of basophil or mast cell origin. The kinetics of neutrophil chemotactic activity release were similar in mite- and toluene diisocyanate induced asthmatic reactions. A high correlation (r= 0.97; p= 0.0006) was obtained between the % decr in forced expiratory volume in 1 sec during early asthmatic reactions and % incr in neutrophil chemotactic activity. These observations support the hypothesis that activation of mast cells or basophils is associated with toluene diisocyanate induced early and late asthmatic reaction. [R98] *The beta-adrenoceptors on intact peripheral blood lymphocytes were studied in 21 allergic asthmatics, 11 toluene diisocyanate asthmatics and 17 normal subjects with radioligand binding assay technique. The airway responsiveness to methacholine provocation test was determined. The results indicated that beta-adrenoceptor Bmax values in allergic and toluene diisocyanate asthmatics were reduced but the affinity between receptor and ligand was increased; there was a positive correlation between the values of Bmax and forced expiratory volume in 1 sec, V25/Pr in both asthmatic groups, a positive correlation between the values of Bmax and PC20 in allergic asthmatics. The beta-adrenoceptor responsiveness was remarkably reduced in allergic asthmatics. [R99] *Leukotriene B4 release from the lungs of sensitized subjects during asthmatic reactions induced by toluene diisocyanate was investigated. 3 groups of toluene diisocyanate sensitized subjects were examined, 1 after no exposure to toluene diisocyanate, the second 8 hr after an exposure to toluene diisocyanate that caused an early asthmatic reaction, and the third 8 hr after an exposure to toluene diisocyanate that caused a late asthmatic reaction. Bronchoalveolar lavage fluid was analysed by reverse-phase HPLC and by specific radioimmunoassay. The mean concn of leukotriene B4 was higher (0.31 + or - 0.09 (standard error) ng/ml, range 0.15-0.51) in bronchoalveolar lavage fluid of sensitized subjects who developed a late asthmatic reaction than in bronchoalveolar lavage fluid of subjects who developed an early asthmatic reaction (0.05 + or - 0.04 ng/ml, range 0-0.224), and no leukotriene B4 was detectable in the control subjects. Bronchoalveolar lavage was also performed 8 hr after toluene diisocyanate exposure on 4 toluene diisocyanate sensitized late-dual reactors who were on steroid treatment. In this group of subjects no leukotriene B4 was detectable. These results suggest that leukotriene B4 may be involved in late asthmatic reactions induced by toluene diisocyanate. [R100] NTOX: *THE POSSIBILITY OF DERMAL EXPOSURES TO TOLUENE DIISOCYANATE RESULTING IN PULMONARY SENSITIVITY WAS INVESTIGATED USING GUINEA PIGS AS AN ANIMAL MODEL. TOLUENE DIISOCYANATE (1-100% CONCN) WAS APPLIED TO DORSAL SITES ON GUINEA PIGS, WHERE SKIN SENSITIVITY TO TDI WAS APPARENT BY THE 7TH DAY. AFTER 14 DAYS, ANIMALS WERE ADDNL EVALUATED FOR TDI SENSITIVITY BY SEROLOGIC ANALYSIS AND BRONCHIAL PROVOCATION CHALLENGE. ANTIBODIES TO TOLUENE DIISOCYANATE WERE DETECTED USING PASSIVE CUTANEOUS ANAPHYLAXIS, DOUBLE DIFFUSION IN GEL, AND RADIOLABELED ANTIGEN BINDING ASSAYS. ANTIBODIES WERE SPECIFIC FOR TOLUENE DIISOCYANATE. THE DEVELOPMENT OF RESPIRATORY HYPERSENSITIVITY AS A RESULT OF DERMAL CONTACT WITH TOLUENE DIISOCYANATE EMPHASIZES THE IMPORTANCE OF CAREFUL WORKPLACE PRACTICES AND SUGGESTS REEVALUATION OF THE ROLE OF INHALATION AND/OR DERMAL CONTACT IN CAUSING PULMONARY SENSITIZATION OF WORKERS. [R101] *TOLUENE DIISOCYANATE WAS MUTAGENIC IN SALMONELLA TYPHIMURIUM STRAINS TA1538 AND TA98 AFTER METABOLIC ACTIVATION. [R102] *GROUPS OF MALE AND FEMALE RATS AND MICE WERE EXPOSED TO 0.05 and 0.15 PPM OF 2,4/2,6-TOLUENE-DIISOCYANATE (80/20) BY INHALATION FOR 6 HR/DAY, 5 DAYS/WEEK FOR 2 YR. TYPE AND INCIDENCE OF TUMORS AND THE NUMBER OF TUMOR-BEARING ANIMALS OF EITHER SPECIES DID NOT INDICATE ANY CARCINOGENIC EFFECT. HEMATOLOGY, BIOCHEMISTRY, URINALYSIS, AND CYTOGENICITY STUDIES DID NOT REVEAL ANY UNTOWARD EFFECT. INCREASED MORTALITY (FEMALES ONLY), REDUCED WEIGHT GAIN AND SIGNS OF IRRITATION IN THE UPPER AND LOWER RESPIRATORY TRACT RESULTED FROM EXPOSURE TO TOLUENE DIISOCYANATE IN THE MOUSE STUDY WITH THE HIGHEST INCIDENCE IN THE 0.15 PPM EXPOSURE LEVEL. [R103] *EXPOSURE BY INHALATION TO 70 MG/CU M (10 PPM) ... 2,6-TDI OR 65/35 MIXT FOR 6 HR/DAY FOR 3-5 DAYS WAS LETHAL TO RATS; EXPOSURE TO 35 MG/CU M (5 PPM) OF MIXT FOR 4 DAYS KILLED 65% OF RATS. [R104] *LC50 FOLLOWING EXPOSURE ... FOR 14 DAYS WAS: MOUSE, 70 MG/CU M ... GUINEA PIG, 90 MG/CU M ... AND RAT, 100 MG/CU M ... LC50 FOLLOWING EXPOSURE FOR 7 DAYS WAS 80 MG/CU M ... IN RABBITS. ... MICE, RATS AND GUINEA PIGS EXHIBITED LACRIMATION, SALIVATION, RESTLESSNESS AND HYPERACTIVITY. [R104] *ACUTE 6-HR INHALATION STUDIES IN RATS, CONCN OF 4200 MG/CU M ... WAS LETHAL, WHEREAS 420 MG/CU M ... WAS NOT. ANIMALS THAT DIED SHOWED ACUTE PULMONARY CONGESTION AND EDEMA. [R104] *FOLLOWING EXPOSURE BY INHALATION ... TO 0.7 MG/CU M (0.1 PPM) ... FOR 6-HR ... 1 DAY/WK FOR 38 WK, OR ... 6 HR/DAY ON 5 DAYS/WK FOR ... 58 EXPOSURES, RAT SHOWED PROLIFERATION OF FIBROUS TISSUE ... OF BRONCHIOLES AS WELL AS PNEUMONITIS, TRACHEITIS AND BRONCHITIS. IN RABBITS AND GUINEA PIGS, NO PROLIFERATION ... . [R104] *ACUTE SKIN ABSORPTION TESTS ... ON RABBITS PRODUCED SEVERE LOCAL IRRITATION BUT FAILED TO KILL, EVEN WITH DOSES AS HIGH AS 16 G/KG BODY WT ... NO ANATOMICAL INJURY TO INTESTINAL ORGANS. [R104] *TEST APPLICATION OF DROP OF META AND PARA TOLUENEDIISOCYANATES ON RABBIT EYES CAUSED IMMEDIATE PAIN, LACRIMATION, SWELLING OF LIDS, AND CONJUNCTIVAL REACTION. HOWEVER, CORNEAL EPITHELIUM WAS ONLY MILDLY DAMAGED ... /MIXT OF 2,4- and 2,6-ISOMERS/ [R51] *EXPOSURE OF GUINEA PIGS BY INHALATION TO 14-35 MG/CU M (2-5 PPM) ... IN AIR ... 6 HR/DAY FOR 3 DAYS RENDERED THEM MORE SENSITIVE WHEN 3 WK LATER THEY WERE EXPOSED TO 0.14 MG/CU M (0.02 PPM) FOR 5 HR, AS SHOWN BY MORE PRONOUNCED REDN OF BREATH RATE ... COMPARED WITH ANIMALS ... NOT ... PREVIOUSLY EXPOSED. [R104] *Groups of 120 male and 120 female CD-1 mice, 3-4 wk old, were exposed to 0, 0.05, or 0.15 ppm (0, 0.36 or 1.07 mg/cu m) production grade toluene diisocyanate (approx 80% 2,4 isomer and 20% 2,6 isomer) in an inhalation chamber for 6 hr/day on 5 days/wk for 104 wk. There was a significant reduction in body weight in the high-dose group /sex not stated/ and a significant incr in mortality in both high and low-dose females by the termination of the study. No such effect was seen in males. Neither the types of tumor observed nor their incidences were dose-related, and both corresponded to those seen in historical controls for this strain of mice. However, dose-related pathological changes were observed in the nasal cavity (chronic or necrotic rhinitis), together with changes in the lower respiratory tract (interstitial pneumonia, catarrhal bronchitis) in both groups. [R105] *Groups of 126 male and 126 female Sprague Dawley CD rats, 6-9 wk old, were exposed to 0, 0.05 or 0.15 ppm (0, 0.36 or 1.07 mg/cu m) production-grade toluene diisocyanate (approx 80% 2,4 isomer and 20% 2,6 isomer) in an inhalation chamber for 6 hr/day on 5 days/wk for 108 wk or 110 wk. A significant reduction in weight gain was observed during the first 12 wk of the study among the high-dose animals of each sex, but body wt gain was similar in all groups thereafter. No significant difference in mortality between treated and control groups of either sex was reported. Tumor incidences and types were reported to be similar in control and treated groups. [R106] *Rats receiving up to 240 mg/kg toluene diisocyanate by gavage daily on 5 days/wk for 13 wk were found to suffer from mild to moderate bronchopneumonia. [R107] *In dogs, a correlation has been made between immunological and respiratory responses to toluene diisocyanate. Dogs exposed once every second wk for 41 wk to 1 mg/kg toluene diisocyanate delivered as an aerosol intratracheally developed a systemic immune response to toluene diisocyanate conjugated with dog serum albumin as well as immediate-type airway responses. [R108] *The toluene diisocyanate induced delayed type hypersensitivity reaction in the ear of male mice was investigated and compared with the picryl chloride induced one. The results obtained were as follows: 1) When 1% toluene diisocyanate soln (20 ul/ear) as a challenging concn was used for 7 wk old ICR mice, distinct ear swelling was observed in every group sensitized with various concns (1-5%, 100 ul/animal) of toluene diisocyanate solution, and the swelling rate was the same or higher than that of picryl chloride induced delayed type hypersensitivity. 2) 5, 7 and 13 wk old ICR mice showed a similar high response in TDI induced delayed type hypersensitivity, whereas the reactivity of 16 wk old ICR mice was significantly lower than that of the above mentioned younger mice. 3) In both toluene diisocyanate and picryl chloride induced delayed type hypersensitivity reaction, ICR AND BALB/c mice showed a similar high response, whereas the reactivity of ddY mice was significantly lower. The effects of dexamethasone and indomethacin were investigated with the toluene diisocyanate induced delayed type hypersensitivity model. The delayed type hypersensitivity reaction was suppressed significantly by both drugs, but the suppressive effects of dexamethasone were higher than that of indomethacin. All the above results indicate that the toluene diisocyanate induced delayed type hypersensitivity model in mice taking dye leakage as an index may be useful for evaluation of drugs for disorders derived from delayed type hypersensitivity reactions. [R109] *Exposing guinea pigs to toluene diisocyanate causes an acute incr in airway responsiveness to inhaled acetylcholine. The mechanism of this incr in airway responsiveness is unknown. Capsaicin-sensitive afferent nerves and the tachykinins they release upon activation are important in controlling bronchomotor tone in guinea pigs. To determine whether tachykinins are important in toluene diisocyanate induced airway hyperresponsiveness, the effects of tachykinin depletion were studied using capsaicin, and competitive tachykinin antagonism, using (D-Argl, D-Pro2, D-Trp7.9, Leull) substance P, on toluene diisocyanate induced airway hyperresponsiveness. In 9 of 9 untreated animals, toluene diisocyanate exposure caused a large and significant incr in airway responsiveness to acetylcholine. The mean concn of acetylcholine required to decrease specific airway conductance by 50% below baseline (the PD50) was 1.51% before toluene diisocyanate exposure and 0.17% after toluene diisocyanate exposure (p < 0.0005). Capsaicin treatment had no effect on the PD50 but prevented the toluene diisocyanate induced incr in airway responsiveness in 10 of 12 animals. (The PD50 was 1.03% before toluene diisocyanate and 1.27% after toluene diisocyanate exposure.) Treatment with the tachykinin antagonist (D-Argl, D-Pro2, D-Trp7.9, Leull) substance P also abolished the toluene diisocyanate induced incr in airway responsiveness in all 5 animals treated. Although toluene diisocyanate exposure also caused airway edema, the effect of capsaicin treatment on toluene diisocyanate induced hyperresponsiveness did not result from prevention of airway edema. Toluene diisocyanate exposure caused a marked incr in tracheal extravasation of iv administered Evans blue dye that was not prevented by capsaicin treatment. [R110] *The changes in airway responsiveness to increasing doses of an acetylcholine aerosol in anesthetized and ventilated guinea pigs 2, 6, or 24 hr after exposure to air or 1 ppm toluene diisocyanate were examined. Pulmonary resistance after the animals inhaled a buffered saline aerosol was used as baseline and was similar for air and groups. The concn of acetylcholine calculated to cause a 200% incr in pulmonary resistance was significantly lower for animals studied at 2 hr (0.68%) or at 6 hr (0.77%), but not at 24 hr (2.39%), after than for air animals (3.07%). The incr in airway responsiveness in the exposed animals was associated with histologic changes in the trachea and intrapulmonary airways. Exposure to 2 ppm caused a patchy loss of cilia, shedding of epithelial cells into the airway lumen, and an influx of inflammatory cells into the trachea and other airways. In the lamina propria of the trachea, the concn of extravascular polymorphonuclear leukocytes was 13 to 26-fold greater in animals studied 2 or 6 hr after exposure to 2 ppm toluene diisocyanate or at 2 hr after 1 ppm toluene diisocyanate than in animals exposed to air. The concn of polymorphonuclear leukocytes in the epithelium was significantly increased only in animals examined 2 hr after 2 ppm toluene diisocyanate. Exposure to toluene diisocyanate also caused an influx of eosinophils into the tracheal mucosa. This influx occurred later and was more persistent than the influx of polymorphonuclear leukocytes. These results indicate that a single exposure to toluene diisocyanate can cause an incr in airway responsiveness that is associated with epithelial injury and acute airway inflammation. [R111] *The effect of exposure to toluene diisocyanate vapor on pulmonary performance was studied in guinea pigs. Female English smooth haired guinea pigs were exposed to 1.4 ppm toluene diisocyanate vapor or air for 3 hr/day for 4 days, or to 0.02 ppm toluene diisocyanate for 6 hr/day for 70 days. Pulmonary performance was evaluated by the ventilatory response of the animals to 10% carbon dioxide. Serum antibodies to toluene diisocyanate were measured on days 22 and 50 and toluene diisocyanate pulmonary hypersensitivity was measured on days 37 and 38. Lung tissue histopathology was evaluated in all animals on day 50 following toluene diisocyanate exposure. Pulmonary response to 10% carbon dioxide diminished by 30-50% following toluene diisocyanate exposures at 1.4 ppm up to day 14. The ventilatory response showed recovery during the next 5 wk. In contrast, animals exposed to 0.02 ppm toluene diisocyanate daily for 70 days showed no change in ventilatory response, nor did control animals that were not exposed to toluene diisocyanate. Antibodies were detected on day 22 and pulmonary hypersensitivity to toluene diisocyanate was found in all animals exposed to 1.4 ppm toluene diisocyanate. No antibodies to toluene diisocyanate nor pulmonary hypersensitivity were detected in animals exposed to 0.02 ppm toluene diisocyanate or in control animals. Lung tissue on day 50 in the 1.4 ppm toluene diisocyanate exposed animals showed multifocal subchronic interstitial inflammation, localized pleural thickening, and peripheral lymphoid hyperplasia. No apparent abnormalities were observed in lung tissue of the 0.02 ppm exposed group. Exposure to 1.4 or 0.02 ppm toluene diisocyanate resulted in measurable and no apparent pulmonary toxicity in guinea pigs, respectively. The 10% carbon dioxide challenge provide several advantages for measuring pulmonary function. [R112] *Groups of 50 F344/N rats of each sex and 50 B6C3F1 mice of each sex were gavaged with corn oil or a mixture of toluene diisocyanate in corn oil for 5 days/wk for 105 or 106 wk. Female rats and mice were given doses of 60 or 120 mg/kg bw, while male rats received 30 or 60 mg/kg, and male mice received 120 or 240 mg/kg. The toluene diisocyanate reacted with the moisture in the corn oil vehicle resulting in doses that were 10% to 23% below the target dose concn. The chemical product used was commercial grade toluene diisocyanate, which was an 80%-20% mixture of the 2,4- and 2,6-isomers. Chemical disposition and metab studies were conducted with each of the radiolabelled toluene diisocyanate isomers in male rats. Absorption of both of the toluene diisocyanate isomers occurred, with the highest concn found in the stomach, cecum, large intestine, and bladder. Excretion occurred via the feces and urine. The major metabolic products from the metab of 2,4-toluene diisocyanate were shown to be identical with those from the metab of the carcinogen, 2,4-diaminotoluene, whereas the metab of the 2,6-toluene diisocyanate isomer yielded one major product, identified as 2,6-bis(acetylamino)toluene. Greater than 10% depression in body weight gain occurred in all dosed groups of rats throughout most of the study. The major non-neoplastic lesions that were observed in both sexes of the toluene diisocyanate exposed rats were dose related incr in acute broncho-pneumonia, characterized as chemical pneumonitis, with incidences as high as 50%. In mice mean body weight gain was depressed in dosed male and in high dose females. The principle non-neoplastic lesion in mice that was attributed to chemical treatment was cytomegaly of the kidney tubular epithelium in males. Survival in all groups of dosed rats was significantly lower than in controls. A dose-dependent pattern of mortality did not commence until 70 wk of exposure, demonstrating that toluene diisocyanate elicited a cumulative toxic response. There was also significantly lower survival in high dose male, but not female mice, by comparison to controls. Despite the reduction of power and sensitivity in the rat studies caused by early mortality, statistically significant incr in tumor incidences were observed in many different target organs. Toluene diisocyanate was carcinogenic in F344/N rats, causing sc fibromas and fibrosarcomas in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland tumors in females. [R113] *Toluene diisocyanate is a causative agent in occupational asthma. Through an oral catheter toluene diisocyanate, 0.03 ul, dissolved in 0.02 ml olive oil, was superfused on the tracheobronchial mucosa of anaesthetized guinea pigs. Toluene diisocyanate induced plasma exudation into both airway tissue and lumen (peak effect: 5 hr; duration approx 17 hr). Light microscopy exams demonstrated that the epithelium was not disrupted by this process (and that microvessels are abundant just beneath the epithelium). At days 6 and 21 after exposure to toluene diisocyanate PAS-positive cells were increased, but no other histological alterations were found. Also, the occurrence of peptide containing nerve fibers was not altered by toluene diisocyanate. After toluene diisocyanate exposure the airway smooth muscle tone was elevated as examined in vitro at base-line and at concn response to carbachol. The largest incr in tone were recorded 21 days after exposure to toluene diisocyanate. The abnormally large tone was not associated with an increased thickness of the smooth muscle layer nor was it associated with reduced effects of either beta 2-agonist (terbutaline) or xanthine (theophylline) relaxants. It is concluded that toluene diisocyanate induced plasma exudation into guinea pig airways for 17 hr without disrupting the epithelial lining and without causing major changes in the airway peptidergic innervation. Both the airway tone, and the number of mucous cells, are increased for at least 3 wk after exposure to toluene diisocyanate. [R114] *Toluene diisocyanate was mutagenic in Salmonella typhimurium strains TA98 AND TA100 in the presence (but not the absence) of Aroclor 1254-induced male Sprague Dawley rat or male Syrian hamster liver S9; it was not mutagenic in strains TA 1535 or 1537. [R115] *Toluene diisocyanates induced respiratory epithelial inflammation, metaplasia and necrosis in mice at the lowest concentration tested (0.71 mg/cu m) after the shortest exposure period studied (6 hr per day for four days). The reaction became more severe when the exposure period was extended to 9 or 14 days. No effects were observed in the olfactory epithelium, trachea or lungs. /Toluene diisocyanates/ [R92] *In vitro tracheal hyperreactivity to carbachol was induced in mice by cutaneous application of toluene diisocyanates (isomeric composition not indicated), followed by nasal toluene diisocyanate challenge; this was not accompanied by an elevation of toluene diisocyanate specific IgE. The reaction could be transferred to naive recipient mice by transfusion of lymphoid cells from sensitized mice. /Toluene diisocyanates/ [R92] *Inhalation exposure of guinea pigs to toluene diisocyanates (3 hr per day on five consecutive days) led to sensitization (antibody formation, pulmonary reactiveness to toluene diisocyanate albumin conjugate), at exposure levels > or = to 0.14 mg/cu m. /Toluene diisocyanates/ [R92] *When guinea pigs were sensitized to toluene diisocyanates by daily instillations for one week on the nasal mucosa and further exposed nasally once a week for four weeks, pulmonary alveolitis, characterized by infiltration of mononuclear cells and eosinophils, was observed. Vasculitis was not found, and fibrosis was negligible, but small nonnecrotizing granulomas, containing epithelioid histiocytes, multinucleated giant cells, lymphocytes and eosinophils were also observed. The histological picture was thus reminiscent of the hypersensitivity pneumonitis described in humans after exposure to toluene diisocyanates. /Toluene diisocyanates/ [R92] *Epithelial injury and inflammation are involved in airway hyperresponsiveness and asthma induced by toluene diisocyanate. In that isocyanates are insoluble and highly reactive compounds, bronchial epithelial cells may represent the most important target cells of their toxic effect. /The authors/ hypothesized that damage to airway epithelium by toluene diisocyanate may result in the release of metabolites of arachidonic acid, which are known to promote inflammation and to alter epithelial cell function and airway smooth muscle responsiveness. To test this hypothesis /the authors/ examined eicosanoid products in the culture media of bronchial epithelial cells exposed in vitro to 8 and 18 ppb toluene diisocyanate. Epithelial cells derived from human bronchi obtained at surgery were cultured to confluency on collagen-coated microporous membranes. Those cells, which expressed differentiated characteristics of epithelial cells (they showed keratin-containing filaments and had a cobblestone appearance), were alternatively exposed to toluene diisocyanate or air for 30 min in a specially designed in vitro chamber. The production of metabolites of arachidonic acid was assessed by measuring the release of immunoreactive products into the cell medium at the end of the exposure and during a 2 hr period after exposure. This method revealed a predominant isocyanate induced release of immunoreactive 15-hydroxyeicosatetraenoic acid. Release rate of this cmpd tended to be dose-related and was associated with cell damage as assessed by the release of lactate dehydrogenase in the medium. [R116] *IV administered endotoxin inhibits the polymorphonuclear leukocyte dependent airway edema produced in guinea pigs exposed to toluene diisocyanate. Tumor necrosis factor is produced in vivo by peripheral blood monocytes and tissue macrophages stimulated with endotoxin and has been shown to activate polymorphonuclear leukocyte's and vascular endothelial cells. To determine whether the inhibition of airway edema is mediated by tumor necrosis factor, guinea pigs were treated with iv saline or 75,000 U/kg recombinant human tumor necrosis factor 1.5 hr before exposure to air or 3 ppm toluene diisocyanate for 1 hr. Animals were then injected iv with 50 mg/kg Evans blue dye as a marker of protein extravasation. Saline-treated animals exposed to toluene diisocyanate had a significant incr in tracheal Evans blue dye extravasation (85 + or - 6.5 ug dye/g trachea, mean + or - standard error) compared with saline-treated animals exposed to air (31.3 + or - 2.5, P < 0.001). The tracheal extravasation of Evans blue dye was significantly inhibited (P < 0.05) in toluene diisocyanate exposed animals treated with tumor necrosis factor (64.7 + or - 7.5). Neither heat-inactivated tumor necrosis factor (104.9 + or - 9.5) nor tumor necrosis factor neutralized with a monoclonal antibody against tumor necrosis factor (99.7 + or - 17.9) inhibited toluene diisocyanate induced airway edema. In addition, treatment with 15,000 U/kg (99.9 + or - 21.3) or 150,000 U/kg (103.2 + or - 17.6) interleukin 1, a monokine also produced in response to endotoxin, did not prevent airway edema. These results suggest that tumor necrosis factor released in response to endotoxin mediates endotoxin's inhibition of a polymorphonuclear leukocyte dependent airway edema. [R117] *Isocyanates are an important cause of occupational asthma. The mechanism of isocyanate induced asthma is still unknown. To determine whether toluene diisocyanate stimulates the 'efferent' function of peripheral endings of capsaicin-sensitive sensory nerves, we investigated the effect of toluene diisocyanate in the rat isolated urinary bladder, a preparation in which the action of capsaicin has been well characterized. Toluene diisocyanate (0.03 mM) produced a concn dependent contraction of the bladder strips. It maximal effect was @ 50% of the response to capsaicin (1 uM). Previous exposure of the strips to capsaicin followed by washing out produced complete unresponsiveness, both to the first exposure to toluene diisocyanate and to a second exposure of capsaicin. Further, the response to both toluene diisocyanate and capsaicin was completely prevented by extrinsic bladder denervation, achieved by bilateral removal of pelvic ganglia (72 hr before). Repeated exposure of the rat bladder to toluene diisocyanate reduced the capsaicin-evoked release of calcitonin gene-related peptide like immunoreactivity (CGRP-LI), taken as biochemical marker of activation of these sensory nerves. These experiments provide the first evidence that toluene diisocyanate activates directly or indirectly the efferent function of capsaicin-sensitive primary sensory nerves. [R118] NTXV: *LC50 Rat inhalation 56.96 mg/cu m/1 hr; [R119] *LC50 Rat inhalation 98.96 + or - 8.6 mg/cu m/4 hr; [R119] *LC50 Rat (male) inhalation 348.88 mg/cu m/4 hr; [R119] *LC50 Rat (female) inhalation 356 mg/cu m/4 hr; [R119] *LC50 Mouse inhalation 69.1 + or - 9.96 mg/cu m/4 hr; [R119] *LC50 Rabbit inhalation 78.32 mg/cu m/4 hr; [R119] *LC50 Guinea pig inhalation 90.4 + or - 19.2 mg/cu m/4 hr; [R119] *LD50 Rat oral 3060 mg/kg; [R119] *LD50 Mouse oral 1950 mg/kg; [R29] NTP: *Groups of 50 female F344/N rats and 50 female B6C3F1 mice were administered commercial grade toluene diisocyanate (80% 2,4- and 20% 2,6-) in corn oil by gavage at doses of 60 or 120 mg/kg body weight, 5 days per week for 105 or 106 weeks. Groups of 50 male F344/N rats received 30 or 60 mg/kg and groups of 50 male B6C3F1 mice received 120 or 240 mg/kg on the same schedule. Dosage analyses of toluene diisocyanate indicated that the chemical had reacted in the corn oil vehicle, resulting in actual gavage concentrations 77% to 90% of theoretical values. Groups of 50 rats and 50 mice of each sex received corn oil only and served as vehicle controls. Survival in all groups of dosed rats in the 2-year studies was shorter (P less than or equal to 0.005) than that of the controls; depressions in mean body weight gain relative to controls were greater than 10% in all dosed rat groups throughout most of the study. A dose-dependent pattern of cumulative toxicity began at 70 weeks and culminated in excessive mortality, indicating the estimated maximum tolerated dose had been exceeded for rats. Acute bronchopneumonia occurred at increased incidences in groups of dosed male and female rats (males: control, 2/50; low dose, 6/50; high dose, 14/50; females: 1/50, 10/50, 25/49). /Results indicated that/ commercial grade toluene diisocyanate in corn oil was carcinogenic for F344/N rats, causing subcutaneous fibromas and fibrosarcomas (combined) in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland fibroadenomas in females. Toluene diisocyanate was not carcinogenic for male B6C3F1 mice. TDI was carcinogenic for female B6C3F1 mice, causing hemangiomas or hemangiosarcomas (combined), as well as hepatocellular adenomas. [R115] POPL: *Occupations with the potential of having exposure to isocyanate products /including toluene diisocyanate/ include diisocyanate workers, polyurethane manufacturing workers, upholstery workers, spray painters, coating workers, plastic film makers, plastic molders, and rubber workers. [R120, 510] ADE: *The toxicokinetics of 2,4- and 2,6-toluenediisocyanates in 11 chronically exposed workers at two flexible foam polyurethane production plants have been reported. The toluene diisocyanate, concentrations in air varied between 0.4 and 4 ug/cu m in one plant and in the other between 10 and 120 ug/cu m. In one of the plants, the plasma 2,4-toluene diamine levels were 0.4-1 ug/mL before a 4-5 week holiday and 0.2-0.5 ug/mL afterwards. The corresponding plasma levels of 2,6-toluene diamine were 2-6 and 0.5-2 ug/mL, respectively. In the other plant, the plasma 2,4 toluene diamine concentrations were 2-23 ng/mL before the holiday and 0.5-6 ng/mL afterwards and those of 2,6-toluene diamine were 7-24 ng/mL before and 3-6 ng/mL afterwards. The plasma concentrations of 2,4-toluene diamine were, 2-24 ng/mL before a 12 day holiday, and 1-14 ng/mL afterwards. The corresponding values for plasma 2,6-toluene diamine were 12-29 and 8-17 ng/mL, respectively The urinary elimination rates for 2,4-toluene diamine before the, holiday were 0.04-0.54 and 0.02-0.18 ug/hr afterwards. The corresponding values for 2,6-toluene diamine were 0.18-0.76 ug/hr before and 0.09-0.27 ug/hr after the holiday. The half life in urine ranged from 5.8 to 11 days for 2,4 and 2.6 toluene diamines. The differences in exposure were reflected by the plasma toluene diamine concentrations. The mean half life in plasma was 21 (range, 14-34) days for 2,4-toluene diamine and 21 (16-26) days for 2,6-toluene diamine, The study showed that the half life in plasma of chronically exposed workers for 2,4- and 2,6-toluene diamine was twice as long as for volunteers with short term exposure. An indication of a two phase elimination pattern in urine was found. The first phase was related to the more recent exposure and the second, much slower one was probably related to release of toluene diamines in urine from toluene diisocyanate adducts in the body. [R121] *Two men were exposed to toluene diisocyanate atmospheres at three different air concn (ca 25, 50 and 70 ug/cu m). The toluene diisocyanate atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-cu m stainless-steel test chamber. The effective exposure period was 4 hr. The isomeric composition of the air in the test chamber was 30% 2,4-toluene diisocyanate and 70% 2,6-toluene diisocyanate. The concn of toluene diisocyanate in air of the test chamber was determined by an HPLC method using the 9-(N-methyl-amino-methyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. Following the hydrolysis of plasma and urine, the related amines, 2,4-toluenediamine and 2,6-toluenediamine, were determined as pentafluoropropionic anhydride derivatives by capillary gas chromatography using selected ion monitoring in the electron impact mode. In plasma, 2,4- and 2,6-toluenediamine showed a rapid-phase elimination half-time of ca 2-5 hr, and that for the slow phase was greater than 6 days. A connection was observed between concn of 2,4- and 2,6-toluene diisocyanate in air and the levels of 2,4- and 2,6-toluenediamine in plasma. The cumulated amount of 2,4-toluenediamine excreted in the urine over 24 hr was ca 15%-19% of the estimated inhaled dose of 2,4-toluene diisocyanate, and that of 2,6-toluenediamine was ca 17%-23% of the inhaled dose of 2,6-toluene diisocyanate. A connection was found between the cumulated (24 hr) urinary excretion of 2,4- and 2,6-toluenediamine and the air concn of 2,4- and 2,6-toluene diisocyanate in the test chamber. [R122] *Five men were exposed to toluene diisocyanate atmospheres for 7.5 hr. The toluene diisocyanate atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8 cu m stainless steel test chamber. The mean air concn of toluene diisocyanate was ca 40 ug/cu m, which corresponds to the TLV of Sweden. The inhaled doses of 2,4- and 2,6-toluene diisocyanate were ca 120 ug. Toluene diisocyanate in the test chamber air was determined by an HPLC method using the 9-(N-methylaminomethyl)-anthracene reagent and by a continuous monitoring filter-tape instrument. After hydrolysis of plasma and urine, the related amines, 2,4- and 2,6-toluenediamine 2,4-, and 2,6-TDA), were determined as pentafluoropropionic anhydride derivatives by capillary gas-chromatography using selected ion monitoring in the electron-impact mode. The urinary elimination of the toluenediamines showed a possible biphasic pattern, with rapid first phases for 2,4-toluenediamine (mean half-life for the concn in urine, 1.9 hr) and for 2,6-toluenediamine (mean half-life for the concn in urine, 1.6 hr). The cumulative amount of 2,4-toluenediamine excreted in urine within 28 hr ranged from 8% to 14% of the estimated dose of 2,4-toluene diisocyanate, and the cumulative amount of 2,6-toluenediamine in urine ranged from 14%-18% of the 2,6-toluene diisocyanate dose. The average urinary level of 2,4-toluenediamine was 5 ug/l in the 6-8 hr sample (range 2.8-9.6 ug/l), and the corresponding value fo 2,6-toluenediamine was 8.6 ug/l (range, 5.6-16.6 ug/l). Biological monitoring of exposure to 2,4- and 2,6-toluene diisocyanate by analysis of 2,4- and 2,6-toluenediamine in urine is feasible. [R123] *Inhalation of toluene diisocyanate results in toxic responses ranging from pulmonary irritation to immunological sensitization. The use of radioactively labeled isocyanate has made it possible to follow the initial uptake of the cmpd into the bloodstream independent of the final fate of the isocyanate. This study shows that the rate of uptake into the blood is linear during exposure to concn ranging from 0.00005-0.146 ppm and that the uptake continues to incr slightly postexposure. It also demonstrates that the radioactivity clears from the bloodstream to a level corresponding to approximately a 100 nM concn of tolyl group after 72 hr and persists at a nanomolar level even 2 wk following the exposure. The initial rate of (14)C uptake is also a linear function of the concn of toluene diisocyanate when expressed either as concn (ppm) or as concn multiplied by duration of exposure (ppm.hr). This is discussed in comparison with the toxic responses as a function of both ppm and ppm.hr. Finally, the inclusion of the data on methyl isocyanate indicates that the uptake into arterial blood is a function of exposure concn, independent of isocyanate structure. [R124] METB: *A technique for detecting urinary amine metabolites in rats exposed to toluene diisocyanate was evaluated. Skin tissue of rats was exposed to 40% toluene-2,4-diisocyanate soln in di-n-butyl-ether liquid. Rats were exposed daily for 3 hr on 4 consecutive days. Urine was collected in metabolic cages for 18 hr after the last exposure. Chromatographic techniques were used for nitrogen selective detection of non-derivatized amines. An autolinear temperature programmer was employed to analyze derivatized amine. The identity of the amine was confirmed by gas chromatography/mass spectrometry. A linear correlation was found between toluene-2,4-diamine added to urine and peak height. Peak height and recovery from the non hydrolyzed and from the hydrolyzed urine was about 85 and 70%, respectively. No free toluene-2,4-diamine or free toluene-2,4-diisocyanate was detected in the urine of rats exposed to toluene-2,4-diamine in hydrolyzed urine was 1.5 ug/ml. Gas chromatography/mass spectrometry confirmed the identity of the amine. /This/ highly sensitive technique tested is easy to apply and is effective for trace assays of amines. [R125] *It has been previously shown that tachykinin depletion or antagonism prevented the incr in airway responsiveness to inhaled acetylcholine caused by exposure to toluene diisocyanate in awake guinea pigs. To insure that the effects of tachykinins were not limited to the extrathoracic airways and were not dependent on effects of toluene diisocyanate on baseline airway caliber, airway responsiveness to acetylcholine inhaled through tracheostomy in anesthetized and ventilated guinea pigs that were exposed to toluene diisocyanate or air after treatment with the tachykinin antagonist spantide, the tachykinin metab inhibitor phosphoramidon, or the vehicles for each drug were determined. When these drugs were administered before and during toluene diisocyanate exposure, spantide significantly inhibited the toluene diisocyanate induced incr in acetylcholine responsiveness and phosphoramidon significantly potentiated this effect, whereas neither drug altered acetylcholine responsiveness in air exposed animals. To determine whether tachykinins were exerting their effect primarily during toluene diisocyanate exposure or during the subsequent acetylcholine challenge, the effect of each drug on acetylcholine responsiveness was also examined when the drugs were given after toluene diisocyanate exposure. At that time, spantide did not inhibit toluene diisocyanate induced acetylcholine hyperresponsiveness and phosphoramidon did not potentiate it. Neither drug nor toluene diisocyanate increased pulmonary resistance measured through a tracheostomy in these anesthetized and ventilated animals. These results suggest that the toluene diisocyanate induced incr in acetylcholine responsiveness is mediated by release of tachykinins into the intrathoracic airways during exposure to toluene diisocyanate. [R126] *The major metabolites of toluene diisocyanates in both animals and humans are toluene diamines and their acetylated products. /Toluene diisocyanates/ [R121] ACTN: *To investigate the role of pharmacological mechanisms in toluene diisocyanate induced occupational asthma, the effects of toluene diisocyanate on rat trachea ring and lung parenchymal strip were studied in vitro. The most prominent effect observed was a stimulation of metacholine induced contraction of the tracheal ring by 1M toluene diisocyanate (added in dimethyl sulfoxide). The results were less pronounced when toluene diisocyanate was added from a stock solution prepared in water, which is possibly due to copolymerisation. It is concluded that the pharmacological effect of toluene diisocyanate may result from an autonomic imbalance between cholinergic and B-adrenergic neural control. [R127] *To determine the importance of airway inflammation for the development of late asthmatic reactions, we examined sensitized subjects during late asthmatic reactions induced by exposure to toluene diisocyanate in the lab. Late asthmatic reactions are associated with a transient incr of bronchial responsiveness and, at the same time, with an incr of neutrophils followed by eosinophils, and of leukotriene B4 and albumin in bronchoalveolar lavage fluid. Late asthmatic reactions, increased bronchial responsiveness, and incr of neutrophils, eosinophils, leukotriene B4, and albumin concn in bronchoalveolar lavage induced by exposure to toluene diisocyanate are all prevented by pretreatment with prednisone but not with the nonsteroidal anti-inflammatory agent indomethacin. Aerosolized steroids (beclomethasone and dexamethasone isonicotinate) completely inhibit late asthmatic reactions induced by toluene diisocyanate, whereas theophylline has a partial, and verapamil, ketotifen, and cromolyn have no protective effect. These results suggest that late asthmatic reactions induced by toluene diisocyanate may be caused by airway inflammation, and that anti-inflammatory steroids should be recommended in the prophylaxis of toluene diisocyanate asthma. [R128] *The in vivo exposure to an asthmogenic stimulus, toluene diisocyanate, causes airway epithelial damage associated with inflammation and increased bronchial hyperresponsiveness. The latter mechanisms might partly be mediated by the release of eicosanoids from bronchial epithelial cells. Previously it has been demonstrated that the in vitro exposure of bronchial epithelial cells to toluene diisocyanate results in the release of immunoreactive 15-hydroxyeicosatetraenoic acid, a product of activation of the 15-lipoxygenase pathway with inflammatory properties. Present study shows that toluene diisocyanate induced release of 15-hydroxyeicosatetraenoic acid from epithelial cells can be prevented by nedocromil sodium, an anti-asthmatic drug with anti-inflammatory properties. This mode of action of the compound may explain its clinical effectiveness in asthma. [R129] *To determine whether early and/or late asthmatic responses induced by toluene diisocyanate are caused by a reflex mechanism involving stimulation of muscarinic receptors, we studied the effect of the muscarinic antagonist atropine on early and late airway response induced by toluene diisocyanate. A preliminary study was conducted in asthmatics to assess whether the selected dose of atropine provided adequate muscarinic blockade. On different days we measured the provocation dose (in mg) of carbachol causing a 15% decr in forced expiratory volume in 1 seC (PD15FEV1) without and with atropine premedication (0.008 or 0.012 mg/kg sc atropine 30 or 90 min before carbachol challenge test). 0.008 to 0.012 mg/kg sc atropine increased the PD15FEV1 carbachol by 6 to 10 fold, inducing a consistent and prolonged decr in nonspecific bronchial hyperresponsiveness to cholinergic agent. 10 Subjects with a history of sensitization to toluene diisocyanate were then examined in 2 sets of experiments. In the first set of experiments, the subjects were studied before and after exposure to toluene diisocyanate (0.04 ppm; 30 min) after no treatment. In the second set of experiments, carried out 1-2 wk later, the same procedure was repeated after treatment with atropine (0.008-0.012 mg/kg atropine sulfate admin sc 30 min before toluene diisocyanate challenge, and then at 90 min intervals after toluene diisocyanate exposure); all patients showed symptoms of atropine effect (dryness of mouth, cycloplegia, increased heart rate). [R130] *Toluene diisocyanate (TDI) has ... been found to suppress the incr of intracellular cyclic adenosine monophosphate (cAMP) by the beta-agonist isoproterenol in peripheral blood lymphocytes indicative of a pharmacologic mechanism of action. Research data suggest that isocyanates may cause nonspecific inhibition of a variety of membrane receptors and enzyme systems. Both immunologic and nonimmunologic mechanisms appear to be involved. Although much research has been directed toward the mechanism of isocyanate-induced disease, the complete pathophysiology remains unknown. [R120, 947] INTC: *The effects of methacholine inhalation on airway responsiveness in toluene diisocyanate induced asthma were studied in six workers with a history of sensitivity to toluene diisocyanate. Symptoms among subjects included shortness of breath, wheezing, cough, and chest tightness at work, during the evening, or at night. A detailed cllnical and occupational history was taken for each subject, and lung function measurement and skin intradermal tests for common allergens were conducted. Airway responsiveness to methacholine was assessed before subjects were exposed for 30 minutes to 0.02 part per million toluene diisocyanate in an exposure chamber. Eight hours after toluene diisocyanate inhalation, airway responsiveness to methacholine was again determined. Forced expiratory volume was the measure of airway responsiveness. Although methacholine challenge was within normal limits when performed before toluene diisocyanate inhalation, the challenge went into the asthmatic range after toluene diisocyanate inhalation. Airway responsiveness increased significantly 8 hours after toluene diisocyanate challenge in the subjects and was accompanied by a decrease in forced expiratory volume. The late asthmatic reaction began between 3 and 5 hours asthma can be induced by toluene diisocyanate in the absence of airway responsiveness. [R131] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Toluene diisocyanate's production and use in adhesives, coatings manufacture, elastomers, and inflexible and rigid foams may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 2.3X10-2 mm Hg at 25 deg C indicates toluene diisocyanate will exist solely as a vapor in the ambient atmosphere. Vapor-phase toluene diisocyanate will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 2.7 days. Atmospheric degradation may also occur through contact with clouds, fog or rain. If released to moist soil, toluene diisocyanate is not expected to leach or adsorb to solids due to its rapid degradation reaction with water. In one experiment simulating a spill, 5.5% of the original material remained after 24 hours and in a field situation; the concn of toluene diisocyanate had declined to the ppm level in 12 weeks. If released to water, toluene diisocyanate is not expected to leach or adsorp to solids due to its rapid degradation reaction with water. If released into water in a spill situation, a crust forms around the liquid toluene diisocyanate mixture and < 0.5% of the original material remains after 35 days. Low concentrations of toluene diisocyanate hydrolyze in the aqueous environment in approximately a day. It is not expected to bioconcentrate in aquatic organisms. Occupational exposure to toluene diisocyanate may occur through inhalation and dermal contact with this compound at workplaces where toluene diisocyanate is produced or used. The general population may be exposed to toluene diisocyanate via use of consumer products containing this compound. (SRC) NATS: *2,4- and 2,6-Toluene diisocyanate, the components of commercial TDI are not known to occur as natural products(1). [R132] ARTS: *Levels of 100-17,700 ug/cu m toluene diisocyanate were reported in samples from the stack exhaust of a polyurethane foam production plant. [R133] *Toluene diisocyanate's production and use in adhesives, coatings manufacture, elastomers, and inflexible and rigid foams(1) may result in its release to the environment through various waste streams(SRC). [R134] FATE: *TERRESTRIAL FATE: Toluene diisocyanate reacts readily with compounds containing active hydrogens, such as water, acids, and alcohols(1); therefore, volatilization from moist soil surfaces is not expected to be an important environmental fate process. In one experiment simulating a spill, 5.5% of the original material remained after 24 hours and in a field situation; the concn of toluene diisocyanate had declined to the ppm level in 12 weeks(2). Toluene diisocyanate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 2.3X10-2 mm Hg(3). [R135] *AQUATIC FATE: Toluene diisocyanate reacts readily with compounds containing active hydrogens, such as water, acids, and alcohols(1); therefore, volatilization from water and moist soil surfaces is not expected to be an important environmental fate process. In one experiment simulating a spill, 5.5% of the original material remained after 24 hours and in a field situation; the concn of toluene diisocyanate had declined to the ppm level in 12 weeks(2). Likewise, bioconcentration in aquatic organisms is not expected to be an important environmental fate process(SRC). [R136] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), toluene diisocyanate, which has a vapor pressure of 2.3X10-2 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase toluene diisocyanate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 2.7 days(SRC), calculated from its rate constant of 7.07X10-12 cu cm/molecule-sec at 25 deg C(3). Atmospheric degradation may also occur through contact with clouds, fog or rain. [R137] BIOD: *Toluene diisocyanates are expected to be hydrolyzed much more rapidly than they are attacked by microorganisms. The resulting toluene diamines are subject to a wide variety of biochemical transformations. [R138] ABIO: *The rate constant for the vapor-phase reaction of toluene diisocyanate with photochemically-produced hydroxyl radicals is 7.07X10-12 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 2.7 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). [R139] *Toluene diisocyanate reacts readily with compounds containing active hydrogens, such as water, acids, and alcohols(1). Contact with bases may cause uncontrollable polymerization with rapid evolution of heat(1). In concentrated solutions, hydrolysis of one of the isocyanate groups to the amine is followed by rapid reaction of the amine with an isocyanate group on another molecule leading to dimers, oligimers, and polymers(1). In one experiment the hydrolysis product yield was 20% diamine and 80% polyurea(2). When 50 ppm of toluene diisocyanate was added to model river and seawater systems, the concn fell to 0.1 ppm or less at the end of 1 day(3). [R140] *Gas phase loss of toluene diisocyanate was originally thought to be due to reaction of toluene diisocyanate with water vapor(1). One early work showed that the % disappearance of toluene diisocyanate in air depended almost solely on the water vapor concn, increasing 3.2%/unit incr in absolute humidity (g water/kg dry air), so that at 15g water/kg dry air, a 50% reduction in toluene diisocyanate was obtained(1). These reductions were obtained after 8 sec and did not differ appreciably after 75 sec(1). More recent work contradicted these earlier findings and a program was instituted to study the gas-phase reactions between toluene diisocyanate and water using a room sized environmental chamber(2). They found that over a relative humidity range of 7-70%, the loss rate of toluene diisocyanate was independent of humidity and no toluenediamine or toluene diisocyanate-urea products could be detected(2). No evidence of gas phase reaction between water and toluene diisocyanate could be detected. The loss of toluene diisocyanate was due to adsorption to the chamber walls(2). [R141] *Subsequent experiments were performed in the environmental chamber to assess the importance of toluene diisocyanate's photolysis, reaction with free radicals, and adsorption onto particulate matter as atmospheric removal processes(1). The loss rate of toluene diisocyanate in irradiated clean air was first order with a half-life of 3.3 hr(1). By using a free radical scavenger, it was shown that free-radicals and not photolysis was responsible for the removal. The half-life is consistent with the reaction with photochemically generated hydroxyl radicals(1). The addition of a urban surrogate hydrocarbon mixture (polluted urban air), did not significantly alter removal rates(1). The concn of hydroxyl radicals generally increases in polluted air resulting in shorter half-lives which were not observed in the above study(SRC). [R142] *Ten days after a spill of 13 tons of toluene diisocyanate onto swampy, wet forest soil, toluene diisocyanate and toluenediamines were found in the soil(1,2). The toluene diisocyanate solidified and the area was covered with sand. The soil concn of toluene diisocyanate and toluenediamine combined declined from the parts per thousand to parts per million range between 10 days and 12 wk after the spill(2). No toluene diisocyanate was detected in a connecting brook 10 days after the spill(2). After 6 years only toluene diisocyanate-derived polyureas were found at the site(1). In a simulated spill, 5 kg of toluene diisocyanate in a container was covered with 50 kg of sand and 5 kg of water at ambient temperatures and samples taken from the top and bottom of the sand pile. After 24 hr, 5.5% of the toluene diisocyanate remained unreacted and after 8 days 3.5% remained(2). The reaction product was largely polyureas(2). [R136] BIOC: *Toluene diisocyanate reacts readily with compounds containing active hydrogens, such as water, acids, and alcohols(1); therefore, bioconcentration in aquatic organisms is not expected to be an important environmental fate process(SRC). [R143] KOC: *Toluene diisocyanate reacts readily with compounds containing active hydrogens, such as water, acids, and alcohols(1); therefore, adsorption to soils and sediments is not expected to be an important environmental fate process(SRC). [R143] VWS: *Toluene diisocyanate reacts readily with compounds containing active hydrogens, such as water, acids, and alcohols(1); therefore, volatilization from water and moist soil surfaces is not expected to be an important environmental fate process(SRC). Toluene diisocyanate is not expected to volatilize from dry soil surfaces(SRC) based upon a vapor pressure of 2.3X10-2 mm Hg(2). [R144] EFFL: *Toluene diisocyanate has been reported in waste water from furniture manufacturing in the concn range of 0.1-4.1 ppm(1). However the colorometric method used did not distinguish between the diisocyanate or the corresponding amine(1). In view of toluene diisocyanate's rapid reactivity with water(1), it is probable that the chemical detected was the corresponding amine(SRC). Stack exhaust from a polyurethane foam production plant were reported to contain 100-17,700 ug/cu m of toluene diisocyanate(1). [R143] SEDS: *Ten days after an accident resulting in the spillage of 13 tons of toluene diisocyanate from a lorry on a swampy wet forest area, toluene diisocyanate and toluenediamine were /found/ in the soil. After six yr, only toluene diisocyanate-derived polyureas were found in soil samples taken at the same site. [R133] OEVC: *Toluene diisocyanate monomer has been found in a urethane foam fabric coating in concn of < 200 mk/kg. [R145] RTEX: *... Reported 42 accepted or established cases of toluene diisocyanate intoxication and 73 questionable or disputed cases, among workers in 14 plants in MA between 1957 and 1962. In 14 of the accepted cases the avg toluene diisocyanate vapor concn found in the workroom was about 0.03 ppm, with very few samples showing more than 0.05 ppm; in 11 cases the avg concn was 0.015 ppm; in 9 cases levels below 0.01 ppm were found; in the remainder measurements ... could not be made. All plants, where avg exposures exceeded 0.01 ppm (some exposure values were as high as 1.2 ppm), had workers with related resp illness, but no such illnesses were reported in plants where avg exposures were 0.007 ppm or lower. /Toluene diisocyanate/ [R13, 1991.1582] *Pulmonary function tests were done and compared to current and past potential exposure levels of toluene diisocyanate (TDI) for 57 TDI manufacturing workers and 89 workers not exposed to TDI or other known respiratory hazards. The avg TDI plant experience at Texas Operations of Dow Chemical USA was 4.1 + or - 2.8 yr. Routine industrial hygiene measurements have shown TDI exposure below a time weighted avg of 0.005 ppm and a short term exposure of 0.02 ppm. Ranking was made of department and job classification by level of potential exposure to TDI (none, n= 10; moderate, n= 14; and high, n= 33). TDI exposure, whether classified as current, highest career level, cumulative or cumulative highest to date, was not associated with a decline of forced expiratory volume. [R82] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 38,881 workers (4,723 of these are female) are potentially exposed to toluene diisocyanate in the US(1). Occupational exposure to toluene diisocyanate may occur through inhalation and dermal contact with this compound at workplaces where toluene diisocyanate is produced or used(SRC). The general population may be exposed to toluene diisocyanate via use of consumer products containing this compound(SRC). [R146] *In a Finnish study, toluene diisocyanate vapor concentrations ranged from 25-80 ug/cu m for pouring, 14-44 ug/cu m for paper stripping, and 1-8 ug/cu m for cutting(1). Personal monitors measured 9-34 ug/cu m and 5-30 ug/cu m of the 2,4-isomer for pouring and paper stripping, respectively(1). While 2,4-toluene diisocyanate constitutes 80% of toluene diisocyanate, and 2,6-toluene diisocyanate 20%, the 2,4-isomer is more reactive so that the concentration of the 2,6-isomer is higher in workplace air(1). The percentage of 2,4-toluene diisocyanate to total toluene diisocyanate measured with the personal monitors ranged from 29 to 69%(1). Toluene diisocyanate levels of 1.3-2.8 ppb were detected in air inside a Swedish factory manufacturing polyurethanes(2). [R147] *Mean concn ranges of toluene diisocyanate reported in ambient workplace air were 0.7-710 ug/cu m in toluene diisocyanate production, not detected-1490 ug/cu m during polyurethane foam production, 70-140 mg/cu m during elastomer production, 13-1050 ug/cu m during polyurethane foam use, 10-710 ug/cu m during polyurethane spray paint use, and < 1-740 ug/cu m during the production of polyurethane-coated wire(1). Mean concn in personal samples ranged from not detected-540 ug/cu m during polyurethane foam production and 2-1220 ug/cu m during polyurethane spray foam use(1). Additionally, mean concn of toluene diisocyanate released from insulation in a ship's hold was reported to be 120-150 ug/cu m and that released from coated fabric in a workplace 2-10 ug/cu m(1). During the outdoor application of toluene diisocyanate foam to a 40 ft diameter storage tanks, the mean atmospheric toluene diisocyanate concentration downwind from the spray gun was 0.3 ppm at 8 ft, 0.02 ppm at 40 ft, and 0.002 ppm at 150 ft(2). Toluene diisocyanate was not detected more than 8 ft upwind of the spray gun(2). Air samples taken within two ft of the foam surface immediately after spraying had ceased was found to be 0.03 ppm(2). Mean TDI concentrations near the pumping equipment during material transfer was 0.02 ppm(2). [R148] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers 2,4-toluene diisocyanate to be a potential occupational carcinogen. /2,4-Toluene diisocyanate/ [R30] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Toluene diisocyanates (mixture) is produced, as an intermediate or a final product, by process units covered under this subpart. [R149] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R150] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Benzene, 1-3-diisocyanatomethyl- is included on this list. [R151] RCRA: *U223; As stipulated in 40 CFR 261.33, when toluene diisocyanate (R,T), as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). [R152] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *THE RESPONSE OF A DUNLOP/ICI CONTINUOUS TDI MONITOR WAS EVALUATED USING THE NIOSH MODIFIED MARCALI SPECTROPHOTOMETRIC METHOD AS THE REFERENCE PROCEDURE. [R153] *AN ANALYTICAL METHOD FOR THE CALIBRATION OF A CONTINUOUS 701 MONITOR USING A DIFFUSION CELL TO GENERATE CONSTANT CONCN OF TDI IS DESCRIBED. APPLICATION TO OCCUPATIONAL EXPOSURE MONITORING IS DISCUSSED. [R154] *Matrix: Air. Procedure: Draw air through impinger containing aq acid or through tube containing glass wool coated with N-para-nitrobenzenyl-N-propylamine or through impinger containing ethanol. /From table/ [R155] *Matrix: Polymer. Procedure: Extract (ortho-dichlorobenzene) /From table/ [R155] *EPA Method 8020. For the analysis of solid waste, a representative sample (solid or liquid) is collected in a standard 40 ml glass screw cap VOA vial equipped with a Teflon faced silicone septum. Sample agitation, as well as contamination of the sample with air, must be avoided. Two vials are filled per sample location, then placed in separate plastic bags for shipment and storage. /Toluene/ [R156] *A solvent free sampling method for airborne toluene diisocyanate was described. Air samples were collected on quartz fiber filters impregnated with 1-(2-methoxyphenyl)piperazine. When the samples were collected on the 1-(2-methoxyphenyl)piperazine coated fibers, the collected toluene diisocyanate concn were not affected by changes in relative humidity. [R157] ALAB: *DETERMINATION OF TOLUENE DIISOCYANATE WORKING ATMOSPHERES BY HPLC USING UV OR FLUORESCENCE DETECTION. THE DETECTION LIMIT IS APPROX 1X10-4 MG/CU M. [R158] *DETERMINATION OF TOLUENE DIISOCYANATE (TDI) IN AIR BY LC. MAX SENSITIVITY IS OBSERVED AT AN EXCITATION WAVELENGTH OF 226 NM AND USING A 300-NM CUT-OFF EMISSION FILTER. A DETECTION LIMIT OF 0.4 PPB FOR TDI CAN BE ACHIEVED WITH A 1 L AIR SAMPLE. [R159] *GASES IN THE ATMOSPHERE ARE MONITORED WITH CHEMICALLY-COATED QUARTZ PIEZOELECTRIC CRYSTALS; THE METHOD IS DEMONSTRATED IN THE USE OF POLYETHYLENE GLYCOL FOR TOLUENE DIISOCYANATE DETERMINATION. A MICROPROCESSOR IS USED TO CONTROL THE GAS SAMPLE FLOW THROUGH THE DETECTOR HEAD AS WELL AS THE DATA ACQUISITION. THE THEORETICAL DETECTION LIMIT IS APPROX 0.006 PPM. [R160] *TOLUENE DIISOCYANATE ... DETERMINED IN ... ATMOSPHERE BY TLC. [R161] *Matrix: Air. Sample preparation: Draw air through impinger containing aq acid; diazotize (NaNO2/NaBr); decompose excess nitrous acid; react with N-(1-naphthyl)-ethylenediamine. Procedure: colorimetric. Limit of detection: 50 ug/cu m. /From table/ [R155] *Matrix: Air. Sample preparation: Draw air through tube containing glass wool coated with N-para-nitrobenzyl-N-propylamine; extract (dichloromethane). Procedure: HPLC/UV. Limit of detection: 4 ug/cu m. /From table/ [R155] *Matrix: Air. Sample preparation: Draw air through impinger containing ethanol. Procedure: HPLC/UV. Limit of detection: 1-5 ug/cu m, /From table/ [R155] *Matrix: Air. Sample preparation: Draw air through impinger containing aq acid; neutralize; extract (chloroform or toluene); react with trifluoroacetic anhydride or heptafluorobutyric anhydride. Procedure: GC/ECD. Limit of detection: 1-5 ug/cu m. /From table/ [R155] *Matrix: Polymer. Sample preparation: Extract (ortho-dichlorobenzene). Procedure: GC/FID. Limit of detection: 5 ug/g. /From table/ [R155] *An electrochemical detection for TDI in air, using 1-(2-methoxyphenyl)piperazine as the electrogenic reagent, was significantly more sensitive than high-performance liq chromatography-uv detection methods. [R162] *A reversed-phase HPLC using a 1-(2-pyridyl)piperazine reagent was described for the determination of TDI in air. [R163] *A passive monitor for toluene diisocyanate which utilizes microporous Teflon diffusion membranes and a 0.5% sulfuric acid absorbing medium was evaluated. The collection rate of toluene diisocyanate is proportional to exposure dose from 10 to at least 300 ppb.hr, and response is equivalent for 2,4- and 2,6-toluene diisocyanate. Collection rate is independent of humidity and normal atmospheric pressure variations, while temperature causes a decrease of 1.0% per deg C. Negative interference caused by ambient nitrogen dioxide is eliminated by addition of sulfamic acid to the collecting medium. N-Ethylmorpholine is a positive interferent. Field testing of the sampler against a reference impinger technique indicated a positive bias when toluene diisocyanate is aerosolized. [R164] *A solvent free sampling method for airborne toluene diisocyanate was described. Air samples were collected on quartz fiber filters impregnated with 1-(2-methoxyphenyl)piperazine. Toluene diisocyanate in the samples reacted with 1-(2-methoxyphenyl)piperazine to form urea derivatives which after dissolution in methanol were analyzed by reversed or normal phase HPLC. When reversed phase HPLC was used, a C18 bonded phase column was utilized. A cyano amino bonded phase column was used with normal phase HPLC. An ultraviolet detector set at a wavelength 250 nanometers was also used. Detection limits for a 15 liter air sample based on a 5 mm peak height were 0.02 to 0.04 mg/cu m, corresponding to 0.5 to 1 nanograms of toluene diisocyanate injected. The method was used to sample laboratory generated toluene diisocyanate containing atmospheres over the relative humidity range 11 to 75% and temperature range 20 to 50 deg C. In the study of the effects of humidity, samples were also collected with gas bubblers and silica gel tubes for comparison purposes. toluene diisocyanate concn in the collected samples increased linearly with incr temperature. When the samples were collected on the 1-(2-methoxyphenyl)piperazine coated fibers the collected toluene diisocyanate concn were not affected by changes in relative humidity. Collection efficiency of the bubblers and silica gel tubes decr for humidities in excess of 45%. It was concluded that the 1-(2-methoxyphenyl)piperazine impregnated quartz fiber filter method for toluene diisocyanate sampling is convenient and efficient, and that collection efficiency does not appear to be affected by humidity. [R157] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Santodonato J et al; Report ISB SRC-TR-85-189 Order No PB86-180213/gar (1985) Davies RJ; Clinics in Immunology and Allergy 4 (1): 103-23 (1984) Respiratory Hypersensitivity To Diisocyanates Kay S; Food and Chemical Toxicology 23 (3): 411-13. (1985) Toluene diisocyanate and Lung Function. Toluene diisocyanate; Safety Practitioner 3 (5): 32-3 (1985). 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V19 309 (1979) R162: Warwick CJ et al; Analyst 106 (June): 676-85 (1981) R163: Goldberg PA et al; J Chromatogr 212 (1): 93-104 (1981) R164: Rando RJ et al; Am Ind Hyg Assoc J 50 (1): 8-14 (1989) RS: 185 Record 340 of 1119 in HSDB (through 2003/06) AN: 6094 UD: 200302 RD: SRP Review on 6/15/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRIXYLYL-PHOSPHATE- SY: *COALITE-NTP-; *IVVIOL-3-; *PHENOL,-DIMETHYL-,-PHOSPHATE- (3:1); *PHOSPHORIC-ACID,-TRIXYLYL-ESTER-; *REOFOS-95-; *Tri-dimethyl-phenyl-phosphate-; *TRIXYLENYL-PHOSPHATE-; *XYLENOL,-PHOSPHATE- (3:1); *XYLYL-PHOSPHATE- RN: 25155-23-1 MF: *C24-H27-O4-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: +... /Trixylyl and tritolyl phosphates/ differ only in the fraction (as defined by boiling range) of tar acids used as raw materials. ... As commercial products both are made by the interaction of phosphorus oxychloride on mixtures containing phenol and all isomers of cresol, xylenol, and some higher molecular wt tar acids. The resultant products are internal mixtures, as the reactivities of the isomers differ in their readiness to esterify. /Trixylyl and tritolyl phosphates/ [R1, 128] MFS: *FMC Corporation, Hq, 200 E Randolph Dr, Chicago, IL 60601, (312) 861-6000; Chemical Products Group, 2000 Market St, Philadelphia, PA 19103; Production site: Nitro, WV 25143 [R2] OMIN: *The bulk of the hydrolysis products from two commercial flame retardants, Fyrquell 220 AND Kronitex TXP, were xylenols which occurred in the following order of abundance: 2,5- > 2,3- > 3,5- > 2,4- > 3,4-xylenol. [R3] *... A) ARYL PHOSPHATES ... NOT SUITABLE FOR PLASTICS IN CONTACT WITH FOODSTUFFS; C) ... SHOULD NOT BE USED IN ARTICLES INTENDED FOR WEAR DIRECTLY ON SKIN OR ARTICLES ... HANDLED BY CHILDREN. /ARYL PHOSPHATES/ [R1, 131] USE: *The only commercial products found to contain trixylyl phosphate are Phosflex 41-P and Kronitex TXP, which are generally employed as flame-retardants and plasticizers ... . [R4] *The only commercial products found to contain trixylyl phosphate are Phosflex 41-P and Kronitex TXP, which are generally employed as ... hydraulic fluids. [R5] PRIE: U.S. IMPORTS: *(1978) 4.10X10+7 G (PRINCIPAL CUSTOMS DISTRICTS) [R6] *(1980) 1.00X10+7 G (PRINCIPAL CUSTOMS DISTRICTS) [R6] *(1983) 9.9X10+3 lb [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Liquid [R8] BP: *243-265 deg C at 10 mm Hg [R8] MW: *410.45 DEN: *1.155 [R8] OWPC: *log Kow= 5.63 [R9] SOL: *0.002% by wt in water at 85 deg C [R8]; *0.89 ppm at 25 deg C [R9] SPEC: *Index of refraction 1.5535 [R8] VAP: *5.15X10-8 mm Hg at 30 deg C [R10] OCPP: *Henry's Law Constant: 3.13X10-8 atm-cu m/mole (est) [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *WHEN HEATED TO DECOMP, CAN EMIT HIGHLY TOXIC FUMES OF /PHOSPHORUS OXIDES/. [R12] EQUP: *Protective gloves and clothing were developed in order to reduce the hazard of industrial use of triaryl phosphate. ... /Triaryl phosphate/ [R13] *Respiratory protection (supplied-air respirator with full facepiece or self-contained breathing apparatus) should be available where these compounds are manufactured or used and should be worn in case of emergency and overexposure. /Phosphorus compounds/ [R14] OPRM: *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *Triaryl phosphates ... include mixed isomers of triphenyl phosphate, tricresyl phosphate, trixylenyl phosphate, and ... /others/. Of these, the ortho isomer of tricresyl phosphate ... is by far the most toxic. /Triaryl phosphates/ [R15] NTOX: *RATS WERE GIVEN TRIXYLYL PHOSPHATE AT 0.1 TO 54 G/KG, IP. INCREASING DOSAGE CAUSED WEIGHT LOSS. THE SYMPTOMS OF INTOXICATION WERE ATAXIA, FINE TREMOR, AND ABNORMAL TIMIDITY. HISTOLOGICALLY, AN UNSPECIFIC INTOXICATION WAS DEMONSTRATED WITH INCREASED EOSINOPHILIA, NECROSIS OF ISOLATED CELLS, NUCLEAR PYKNOSIS, AND ATROPHY ESPECIALLY OF THE HEART, KIDNEYS, LIVER, AND SKELETAL MUSCLES. ALTERATIONS IN LUNG TISSUE WERE CHARACTERIZED BY BROADENING OF THE SEPTA AND MARKED FILLING OF THE SEPTAL VESSELS. DOSES > 1 G/KG WERE TOXIC, AND > 10 G/KG WERE LETHAL. [R16] *Trixylenyl phosphate, mixed isomers, was tested for mutagenicity in the Salmonella/microsome preincubation assay using a protocol approved by the National Toxicology Program. Trixylenyl phosphate, mixed isomers were tested over a wide range of doses (0, 100, 333, 1000, 3333, and 10,000 ug/plate) in four Salmonella typhimurium strains (TA98, TA100, TA1535, and TA1537) in the presence and absence of Aroclor induced rat or hamster liver S9. Trixylenyl phosphate, mixed isomers were negative in these tests and the highest ineffective dose level tested (not causing formation of a precipitate) in any Salmonella tester strain was 333 ug/plate. [R17] *THREE COMMERCIALTRIARYL PHOSPHATES, PILABRAC 521, REOFOS 95 /TRIXYLYL PHOSPHATE/ AND REOLUB HYD 46, WERE TESTED FOR ACUTE TOXICITY AGAINST THE BRACKISH WATER HARPACTICOID NITOCRA SPINIPES BROECK (CRUSTACEA) AND THE ZEBRA FISH, BRACHYDANIO RERIO. THE 96 HR LC50 VALUES RANGED FORM 0.27 TO 1.75 MG/L, WITH PLIABRAC 521 AS THE MOST TOXIC AND REOLUB HYD 46 AS THE LEAST TOXIC. LOW TO MODERATE ACCUMULATION OF TRIARYL PHOSPHATES WAS OBSERVED. FOR THE VARIOUS TRIARYL PHOSPHATES, A DIETARY ACCUMULATION OF 0.06 TO O.6 FROM FOOD TO MINNOW, PHOXINUS PHOXINUS, WAS OBSERVED. THE MOST HYDROPHILIC COMPOUNDS WERE READILY CLEARED FROM FISH WHEN THE FISH WERE PLACED IN CLEAN WATER, WHEREAS THE MOST LIPOHILIC ONES WERE STILL DETECTABLE, ALBEIT IN LOW CONCENTRATIONS, IN THE FISH AFTER A 2 WEEK DEPURATION PERIOD. A ROTARY FLOW BEHAVIORAL STUDY DID NOT REVEAL ANY EFFECTS ON SWIMMING PERFORMANCE IN THE BLEAK, BUT REPRODUCTION WAS AFFECTED AS A RESULT OF LONG-TERM (163 DAY) EXPOSURE OF MINNOWS TO SUBACUTE CONCENTRATIONS OF PLIABRAC 521. [R18] *RELATION BETWEEN THE TOXIC EFFECT OF TRIARYL PHOSPHATES AND THEIR CHEMICAL STRUCTURE WAS DETERMINED. WHEN INJECTED SC INTO GUINEA PIGS, THE NEUROPARALYTIC EFFECT OF TRIARYL PHOSPHATES DECREASED IN THE FOLLOWING ORDER: TRICRESYL PHOSPHATE WITH 37% O-ISOMERS, DIPHENYL CRESYL PHOSPHATE, PLASTICIZER G (SYNTHESIZED FROM TRICRESOL AND PHENOL), TRICRESYL PHOSPHATE WITH 2% O-ISOMERS, AND TRIXYLENYL PHOSPHATE. /TRIARYL PHOSPHATES/ [R19] *EXPERIMENTAL POISONINGS INDUCED BY VARIOUS DOSES OF TRIARYL PHOSPHATES WAS STUDIED. WHEN ADMIN TO GUINEA PIGS AT 0.6-2.1 G/SPECIMEN/DAY, TRIXYLENYL PHOSPHATE CAUSED DISTURBANCES IN THE NEUROMUSCULAR FUNCTION, ESPECIALLY OF THE LIMBS; A DOSE-EFFECT RELATION WAS OBSERVED. AT 2.1 G/KG/DAY THE PREPN CAUSED SEVERE POISONING SYMPTOMS. TRICRESYL PHOSPHATE CAUSED DAMAGES TO MYELIN MEMBRANES IN THE NERVOUS SYSTEM, DEGENERATION OF THE AXIAL CYLINDERS IN SOME PARTS OF THE NERVOUS SYSTEM, MUSCLE DYSTROPHY, AND DEGENERATION OF TESTICLES. TRIXYLENYL PHOSPHATE HAD SIMILAR EFFECTS. /TRIARYL PHOSPHATES/ [R20] TCAT: ?The mutagenicity of dimethyl phenyl phosphate was evaluated in Salmonella tester strains TA98, TA100, TA1535 and TA1537 (Ames Test), both in the presence and absence of added metabolic activation by Aroclor-induced rat liver S9 fraction. The compound was tested at concentrations of 2, 6, 18, 54 and 162 ug/0.1 ml in DMSO solvent. Dimethyl phenol phosphate did not cause a positive response in any of the tester strains with or without metabolic activation. [R21] INTC: *4,4'-DIAMINODIPHENYL DISULFIDE WAS 1 OF 5 ANTIOXIDANTS STUDIED FOR THE PROTECTION OF POISONING BY AROMATIC ESTERS OF PHOSPHORIC ACID (H3PO4). WHEN IT WAS INJECTED SC INTO GUINEA PIGS OR RATS IN COMBINATION WITH TRIXYLENYL PHOSPHATE, IT SHOWED THE GREATEST PROTECTIVE ACTION AGAINST THE INHIBITORY EFFECTS OF AROMATIC ESTERS ON THE ACTIVITY OF CHOLINESTERASE. /AROMATIC ESTERS OF PHOSPHORIC ACID/ [R22] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Trixylyl phosphates are released into the environment via effluents at sites where they are produced or used as a flame-retardant, plasticizer or hydraulic fluid. Based upon estimated Koc values for the commercial product TXP, a mixture primarily composed of trixylyl phosphates, trixylyl phosphates are expected to be slightly mobile to immobile in soil. Limited data suggest trixylyl phosphates may be biodegradable. Volatilization from soil and water are not expected to be important fate processes. Trixylyl phosphates have a potential for bioconcentration within aquatic systems. Trixylyl phosphates may undergo some adsorption to humic materials, thereby partitioning from the water column to sediments and suspended material. If released to the atmosphere, trixylyl phosphates are expected to exist almost entirely in the particulate phase. However any portion of trixylyl phosphate that exists in the vapor phase is expected to rapidly degrade in an average ambient atmosphere by reaction with photochemically produced hydroxyl radicals (estimated half-life from 5 to 12 hr). Occupational exposure to trixylyl phosphates may occur through inhalation and dermal contact at sites of commercial manufacture and use as a flame-retardant, plasticizer or hydraulic fluid. (SRC) ARTS: +Trixylyl phosphate's use in commercial flame retardant-plasticizer and hydraulic fluid products such as Phosflex 41-P and Kronitex TXP(1-2) could results in releases to the environment through waste stream effluents at sites of usage and production(SRC). [R23] FATE: *TERRESTRIAL FATE: Based upon estimated Koc values for the commercial product TXP, a mixture primarily composed of trixylyl phosphate isomers, trixylyl phosphate is expected to be slightly mobile to immobile in soil. Limited data for TXP suggest trixylyl phosphate may be biodegradable. Volatilization from soil is not expected to be an important fate process. (SRC) *AQUATIC FATE: Trixylyl phosphates may be stable to degradation in waters having slightly acidic and neutral pHs; however, decomposition of trixylyl phosphate may occur in alkaline waters. Volatilization from water does not appear to be an important environmental fate process. BCF values for TXP, a mixture primarily composed of isomers of trixylyl phosphates, suggest trixylyl phosphates have a potential for bioconcentration in aquatic systems. Based upon estimated Koc values for TXP, trixylyl phosphates should undergo some adsorption to humic materials, thereby partitioning from the water column to sediments and suspended material. (SRC) *Based upon a vapor pressure of 5.15X10-8 mm Hg at 30 deg C for TXP(1), a commercial product containing isomers of trixylyl phosphates and triethylphenyl-phosphate isomers, trixylyl phosphates are expected to exist almost entirely in the particulate phase in the ambient atmosphere(2). However any portion of trixylyl phosphate that exists in the vapor phase is expected to rapidly degrade in an average ambient atmosphere by reaction with photochemically produced hydroxyl radicals at an estimated half-life rate between 5 and 12 hr(3). [R24] BIOD: *Kronitex TXP is a commercial product primarily consisting of the 2,5-, 3,4-, 3,5- and/or the 2,4-isomers of trixylyl phosphates along with mixes of xylenyl phosphates or xylenyl/ethylphenyl phosphates(2). A 65% and 13% loss of TXP was attributed to biodegradation by an activated sludge at addition rates of 3 and 13 mg/l/day over durations of 14 and 25 weeks, respectively. The degradation of specific isomers within the mixture was not quantified(1). In general the biodegradability of triaryl phosphates decreases with increasing number and size of substituent groups to the phenolic ring(1,3). Based upon the limited evidence pertaining to TXP(1), trixylyl phosphates may be susceptible to biodegradation(1). [R25] ABIO: +The rate constants for vapor-phase reactions of the various isomers of trixylyl phosphates with photochemically produced hydroxyl radicals have been estimated to range from 79.718X10-12 to 31.897X10-12 cu cm/molecule-sec at 25 deg C which correspond to atmospheric half-lives of between 5 and 12 hr at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1). Triaryl phosphates are generally stable to hydrolysis at neutral pH's and undergo moderate hydrolysis in acidic solutions(2). Triaryl phosphates will degrade in natural waters under alkaline conditions to apparently stable, water soluble, anionic diesters such as diaryl phosphates(2). No persistence data specific to trixylyl phosphates were available, however based on data pertaining to triphenyl- and tricresyl-phosphates(2), trixylyl phosphates may be expected to hydrolyze in natural alkaline waters. Under slightly acid conditions trixylyl phosphates might hydrolyse at extremely slow rates(2). [R26] BIOC: +Based upon a water solubility at 25 deg C of 0.89 ppm and a log Kow of 5.63 for Kronitex TXP(2), a commercial product consisting primarily of trixylyl phosphate isomers(1), estimated bioconcentration factor's (BCF) of 660 and 11,189, respectively, can be calculated from recommended regression-derived equations(3). These BCF values for TXP suggest trixylyl phosphates have a potential for bioconcentration. [R27] KOC: +Based upon a water solubility at 25 deg C of 0.89 ppm and a log Kow of and 5.63 for Kronitex TXP(2), a commercial product consisting primarily of trixylyl phosphate isomers(1), the Koc for trixylyl phosphates can be expected to approximate the estimated range of TXP's at 4654 to 27,525. These Koc values, derived from various regression equations(3), suggest that trixylyl phosphates will be slightly mobile to immobile in soil(4). [R28] VWS: +Based upon a water solubility of 0.89 ppm(1) and a vapor pressure of 5.15X10-8 mm Hg at 30 deg C(2), the Henry's Law Constant for TXP can be estimated to be 3.13X10-8 atm-cu m/mole(3). Based upon this value of Henry's Law Constant for TXP, volatilization of trixylyl phosphates from soil and water should not be environmentally important(3). [R29] RTEX: *Occupational exposure to trixylyl phosphates may occur through dermal contact or inhalation at sites where the commercial products containing trixylyl phosphates are produced or used. (SRC) *Foods sometimes become contaminated with aryl/alkyl phosphates by diffusion from phosphate treated packaging materials. Food samples also become contaminated during analysis through laboratory reagents that contain these esters, eg, bulk alcohols and organic solvents. /Aryl and alkyl phosphates/ [R30] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. Phenol, dimethyl-, phosphate (3:1) is included on this list. [R31] *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, use, and exposure to EPA as cited in the preamble of the 51 FR 41329. [R32] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 7905. Analyte: Phosphorus. Matrix: Air. Sampler: Solid sorbent tube (Tenax Gas chromatography, 100 mg/50 mg). Flow Rate: 0.01 to 0.2 l/min: Sample Size: 12 liters. Shipment: Routine. Sample Stability; 94% recovery after 7 days at 25 deg C. /Phosphorus/ [R33, p. 7905-1] *NIOSH Method 7300. Analyte: Phosphorus. Matrix: Air. Sampler: Filter (0.8 um cellulose ester membrane) Flow Rate: 1 to 4 l/min: Sample Size: 500 liters. Shipment: Routine. Sample Stability; Stable. /Phosphorus/ [R33, p. 7300-1] ALAB: *The retention times for most industrial phosphates fall into a 12-40 min range using the chromatographic conditions described in "Pesticides Analytical Manual I 1982". Several of them have complex eluting patterns. The procedures described in this report deal with the ability to identify these late-eluting compounds rapidly. By using known analytical characteristics such as Florisil recoveries and tabulated retention data, phosphate esters can be identified as soon as they appear on food sample chromatograms. Retention values for trixylyl phosphate are given. The gas chromatographs were Tracor 222's or 560's equipped with 1.8 m X 2 or 4 mm inner diameter glass columns and flame photometric or nitrogen/phosphorus detectors (phosphorus selective). Based on 10% full scale deflection, the avg limit of detection for the 15 phosphates tested was 0.03 ug. The procedure is applicable to a variety of food and food products, such as meats, dairy products, fruits and root vegetables as well as food containers, lid or package liners, and individual-product wrappings. [R30] *Phosphorus was determined by a continuous flow method using fluorescence quenching of Rhodamine 6G with molybdophosphate. /Phosphorus/ [R34] *Phosphorus and organic carbon was simultaneously determined in wastewater using flame ionization and photometric detectors. /Phosphorus/ [R35] *Phosphorus was determined in natural waters by direct current plasma atomic emission spectrometry. /Phosphorus/ [R36] *Proton-induced x-ray emission analysis constitutes a method for trace element analysis characterized by multielement capability, detection limits in the low ppm-range, and size resolution approximating a millimicron. /Phosphorus/ [R37] *Microamounts of phosphorus in wastewater were determined by high-speed liquid chromatography. /Phosphorus/ [R38] *Fly ash particle sizes are compared using scanning electron microscopy and x-ray elemental analysis. /Phosphorus/ [R39] *The sample is collected and extracted. A 1 ml aliquot of the decant from the first or second 10 ml portion is placed in a beaker. A 5 ml volume of concentrated nitric acid is added and the mixture evaporated to 1 ml in a fume hood. A 2 ml volume of water is added and the mixture transferred to a test tube. A 1 ml volume of 1M ammonium nitrate and 2 ml of 0.5M ammonium molybdate are added. The solution is heated to boiling and the formation of a yellow precipitate of ammonium phosphomolybdate indicates phosphate. /Phosphate/ [R40] *A range of 1 to 20 mg/l of phosphoric acid as phosphate may be determined colorimetrically. A 35 ml aliquot or less of sample is placed in a 50 ml volumetric flask. A 10 ml volume of vanadate-molybdate reagent is added and the volume taken to mark with distilled water. The treated sample is left to develop for 10 min, then the absorbance determined at 400 nm using a suitable spectrophotometer with matched 1 cm cells. A blank determination must also be made. The phosphate is determined using a calibration curve. /Phosphate/ [R41] *NIOSH Method 7905. Analyte: Phosphorus. Matrix: Air. Procedure: Gas chromatography, phosphorus flame photometric detector. For phosphorus this method has an estimated detection limit of 0.005 ug/sample. The precision/RSD is 0.024 at 0.6 to 2.4 ug/sample and the recovery is not given. Applicability: The working range is 0.04 to 0.18 mg/cu m (0.008 to 0.16 ppm) for a 12-liter air sample. Interferences: None identified. /Phosphorus/ [R33, p. 7905-1] *NIOSH Method 7300. Analyte: Phosphorus. Matrix: Air. Procedure: Inductively coupled argon plasma. For phosphorus this method has an estimated detection limit of 1 ug/sample. The precision/RSD and the recovery are not given. Applicability: The working range of this method is 0.005 to 2.0 mg/cu m in a 500-liter air sample. Interferences: Spectral interferences. /Phosphorus/ [R33, p. 7300-1] *Method 4500-Phosphorus C. Vanadomolybdophosphoric Acid Colorimetric Method. This method determines the total phosphorus in natural waters and wastewaters following a digestion procedure to release phosphorus as orthophosphate. The method is based on the formation of yellow vanadomolybdo- phosphoric acid upon the addition of ammonium molybdate and vanadium to ortho- phosphate solution. This method is most useful for routine analysis in the range of 1 to 20 mg phosphorus/l. Minimum detectable concentration is 200 ug phosphorus/l in 1-cm spectrometer cells. Positive interference is caused by silica and arsenate. Negative interference is caused by arsenate, fluoride, thorium, bismuth, sulfide, thiosulfate, thiocyanate or excess molybdate. /Phosphorus/ [R42, p. 4-173 (1989)] *Method 4500-Phosphorus D. Stannous Chloride Method. This method determines total phosphorus in natural waters and wastewaters following a digestion procedure to release phosphorus as orthophosphate. The method is based upon the reduction of molybdophosphoric acid by stannous chloride to intensely colored molybdenum blue. This method is most suited for the concentration range of 0.01-6 mg phosphorus/l. The minimum detectable concentration is 3 ug phosphorus/l. The sensitivity at 0.3010 absorbance is 10 ug phosphorus/l for an absorbance change of 0.009. Positive interference is caused by silica and arsenate. Negative interference is caused by arsenate, fluoride, thorium, bismuth, sulfide, thiosulfate, thiocyanate, or excess molybdate. /Phosphorus/ [R42, p. 4-175 (1989)] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- SO: R1: Lefaux, R. Practical Toxicology of Plastics. Cleveland: CRC Press Inc., 1968. R2: SRI. 1989 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1989.. 883 R3: Nobile ER et al; Bull Environ Contam Toxicol 25 (5): 755-61 (1980) R4: SRC; Gray AD et al; Technical Support Document for Aryl Phosphates, Test Rules Devel Branch. Existing Chem Assess Div. Off Toxic Substances pp. 516 (1988) R5: SRC; Howard PH, Deo PG; Bull Environ Contam Toxicol 22: 337-44 (1979) R6: SRI R7: USTIC. IMPORTS OF BENZENOID CHEM AND PROD p.30 (1983) R8: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 1179 R9: SRC; Saeger VW et al; Environ Sci Tehnol 13: 840-4 (1979) R10: SRC; Gray AD et al; Technical Support Document for Aryl Phosphates Test Rules Devel Branch. Existing Chem Assess Div. Off Toxic Substances pp. 516 (1988) R11: SRC; Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-15 to 15-29 (1982) R12: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 2120 R13: Levina EN et al; Vopr Gig Tr, Profpatol Toksikol Proizvod Ispolz Fosfororg Plastif 16-8 (1973) R14: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1684 R15: Clarke, M. L., D. G. Harvey and D. J. Humphreys. Veterinary Toxicology. 2nd ed. London: Bailliere Tindall, 1981. 186 R16: RIESS W, WALTHER G; BEITR GERICHTL MED 41: 123-32 (1983) R17: Zeiger E et al; Environ Mutagen 9: 1-110 (1987) R18: BENGTSSON BE ET AL; ENVIRON TOXICOL CHEM 5 (9): 853-61 (1986) R19: DVORKIN EA; VOPR GIG TR, PROFPATOL TOKSIKOL PROIZVOD ISPOLZ FOSFORORG PLASTIF P.80-2 (1973) R20: ZILBER YD ET AL; VOPR GIG TR, PROFPATOL TOKSIKOL PROIZVOD ISPOLZ FOSFORORG PLASTIF P.77-80 (1973) R21: CIBA-GEIGY Limited; Salmonella/Mammalian-Microsome Mutagenicity Test With TK 10 509 (Reofos 95). (1978), EPA Document No. 40-8442159, Fiche No. OTS0507280 R22: IVANOV KI ET AL; TEOR PRAKT ZHIDKOFAZN OKISLENIYA, (MATER VSES KONF OKISLENIYU ORG SOEDIN ZHIDK FAZE) (2): 229-32 (1974) R23: (1) Gray AD et al; Technical Support Document for Aryl Phosphates, Test Rules Devel Branch. Existing Chem Assess Div. Off Toxic Substances pp. 516 (1988) (2) Howard PH, Deo PG; Bull Environ Contam Toxicol 22: 337-44 (1979) R24: (1) Gray AD et al; Technical Support Document for Aryl Phosphates Test Rules Devel Branch. Existing Chem Assess Div. Off Toxic Substances pp. 516 (1988) (2) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (3) Atkinson R; J Inter Chem Kinet 19: 799-828 (1987) R25: (1) Saeger VW et al; Environ Sci Technol 13: 840-4 (1979) (2) Nobile ER et al; Bull Environ Contam Toxicol 25: 755-61 (1980) (3) Howard PH, Deo PG; Bull Environ Contam Toxicol 22: 337-44 (1979) R26: (1) Atkinson R; J Inter Chem Kinet 19: 799-828 (1987) (2) Howard PH, Deo PG; Bull Environ Contam Toxicol 22: 337-44 (1979) R27: (1) Nobile ER et al; Bull Environ Contam Toxicol 25: 755-61 (1980) (2) Saeger VW et al; Environ Sci Tehnol 13: 840-4 (1979) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 2-14, 5-4, 5-10 (1982) R28: (1) Nobile ER et al; Bull Environ Contam Toxicol 25: 755-61 (1980) (2) Saeger VW et al; Environ Sci Tehnol 13: 840-4 (1979) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill pp. 2-14, 4-9 (1982) (4) Swann RL et al; Res Rev 85: 16-28 (1983) R29: (1) Saeger VW et al; Environ Sci Tehnol 13: 840-4 (1979) (2) Gray AD et al; Technical Support Document for Aryl Phosphates Test Rules Devel Branch Existing Chem Assess Div. Off Toxic Substances pp. 516 (1988) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods NY: McGraw-Hill p. 15-15 to 15-29 (1982) R30: Daft JL; Bull Environ Contam Toxicol 29 (2): 221-7 (1982) R31: 40 CFR 716.120 (7/1/90) R32: 40 CFR 712.30 (7/1/90) R33: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R34: Motomizu S et al; Bunseki Kagaku 33 (2): 116-9 (1984) R35: Nakajima K; Water Res 18 (5): 555-9 (1984) R36: Urasa IT; Anal Chem 56 (6): 904-8 (1984) R37: Malmquist KG et al; Scanning Electron Microsc (4): 1815-26 (1983) R38: Sakurai N et al; Fresenius' Z Anal Chem 314 (7): 634-7 (1983) R39: Kaufherr N, Lichtman D; Environ Sci Technol 18 (7): 544-7 (1984) R40: Welcher FJ, Hahn RB; Semimicro Qual Anal 458 pp (1955) as cited in Environment Canada; Tech Info for Problem Spills: Phosphoric acid (Draft) p.82 (1981) R41: AWWA; Standard Methods for the Examination of Water and Wastewater, 15 ed (1981) as cited in Environment Canada; Tech Info for Problem Spills: Phosphoric acid (Draft) p.83 (1981) R42: Franson MA, ed; Standard Methods for the Examination of Water and Wastewater, 17th ed RS: 27 Record 341 of 1119 in HSDB (through 2003/06) AN: 6141 UD: 200211 RD: Reviewed by SRP on 5/11/1995 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-2-MERCAPTOBENZOTHIAZOLE- SY: *2-BENZOTHIAZOLETHIOL,-SODIUM-DERIV-; *Benzothiazolethiol,-sodium-salt-; *2-BENZOTHIAZOLETHIOL,-SODIUM-SALT-; *2(3H)-BENZOTHIAZOLETHIONE, SODIUM SALT; *DUODEX-; *2-MERCAPTO-BENZOTHIAZOLE,-SODIUM-; *2-MERCAPTOBENZOTHIAZOLE-SODIUM-DERIV-; *MERCAPTOBENZOTHIAZOLE-SODIUM-SALT-; *2-MERCAPTOBENZOTHIAZOLE-SODIUM-SALT-; *NACAP-; *NaMBT-; *SODIUM-2-BENZOTHIAZOLETHIOATE-; *SODIUM-BENZOTHIAZOLETHIOLATE-; *SODIUM-2-BENZOTHIAZOLETHIOLATE-; *Sodium 2(3H)-benzothiazolethionate; *SODIUM, (2-BENZOTHIAZOLYLTHIO)-; *Sodium-MBT-; *SODIUM-MERCAPTOBENZOTHIAZOLATE-; *SODIUM-2-MERCAPTOBENZOTHIAZOLATE-; *SODIUM-MERCAPTOBENZOTHIAZOLE- RN: 2492-26-4 RELT: 4025 [MERCAPTOBENZOTHIAZOLE] (Analog) MF: *C7-H5-N-S2.Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *...COMBINATION OF THE SODIUM SALTS OF MERCAPTOBENZOTHIAZOLE AND DIMETHYLDITHIOCARBAMIC ACID (EG, VANCIDE 51)...ARE MARKETED AS COMMERCIAL FUNGICIDES AND BACTERICIDES. [R1] *NUODEX 84 CONTAINS THE SODIUM SALT /OF MERCAPTOBENZOTHIAZOLE/ FOR USE IN WATER-BASE ADHESIVES, PAPER SIZINGS, ETC. [R2] *NACAP contains 50% sodium mercaptobenzothiazole. [R3] *50% aqueous solution grade. [R4] MFS: *The BFGoodrich Company, Hq, 3925 Embassy Parkway, Akron, OH 44313, (216) 374-2000; BFGoodrich Chemical Group; Production site: Henry, IL 61537 [R5] *Monsanto Company, Chemical Group, Hq, 800 North Lindbergh Blvd, St. Louis, MO 63167, (314) 694-1000; Production site: Nitro, WV 25143 [R5] *Uniroyal Chemical Co., Inc., Hq, World Headquaters, Middlebury, CT 06749, (203) 573-2000; Production site: Geismar, LA 70734 [R5] OMIN: *Monsanto states that its 1982 production volume within the U.S. /was/ 40 million lb. [R6] *Uniroyal produces between 5 and 25 million lb per yr on a dry weight basis. [R7] *BF Goodrich manufactured sodium mercaptobenzothiazole in the range of 1 to 10 million lb in 1982. [R8] USE: *CORROSION INHIBITOR FOR NONFERROUS METALS; ANTIFREEZE, PAPER MILL SYSTEMS /50% AQUEOUS SOLN/ [R9] *FUNGICIDE [R10] *THE SODIUM SALT /OF MERCAPTOBENZOTHIAZOLE/ (EG, NACAP, 50% SOLN) IS A CORROSION INHIBITOR IN ANTIFREEZE, COOLANTS AND OTHER AQUEOUS SYSTEMS WHERE CORROSION IS A PROBLEM, PARTICULARLY WITH COPPER AND BRASS. [R1] *The predominant use of sodium mercaptobenzothiazole is as an intermediate in the manufacture of natural and synthetic rubber vulcanization accelerators. [R11] *Used to thermally stabilize methyl methacrylate copolymers, acrylonitrile polymers, polyester fibers, anion exchange resins, polyoxyphenylene, and silicon fluids. [R11] *Used as a preservative in latex paint and on wood. [R11] *Has applications as a metal chelator. [R11] *Has been found to be useful in electroplating silver, nickel, and cobalt. [R11] *Used in the separation of sulfide ore from copper ore. [R11] *Used in the dyeing of textiles. [R11] *Used in transmission fluids. [R11] *Prevents discoloration of freeze dried bananas. [R12] CPAT: *32 million lb in the manufacture of rubber vulcanization accelerator, 4 million lb as corrosion inhibitors in aqueous cooling systems, and 4 million lb for the use of mercaptobenzothiazole. [R13] PRIE: U.S. PRODUCTION: *1982- Estimated to be 40 million lb [R14] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *LIGHT-AMBER LIQUID /50% AQUEOUS SOLN/ [R9] MW: *189.23 CORR: *Not corrosive to metals as a 50% aq soln. [R15] DEN: *DENSITY 10.5 LB/GAL (50% AQ SOLN) [R9] OWPC: *As an ionic salt the partition coefficient is expected to be neg. [R6] PH: *Alkaline as a 50% aq solution [R15] SOL: *Sol in water. [R6] VAP: *Presumably extremely low, /however/, in the presence of moisture the salt will hydrolyze to give mercaptobenzothiazole which will have a higher, but still very low vapor pressure. [R16] VISC: *Sodium mercaptobenzothiazole in motor oil soln maintains a uniform viscosity over a large temp range. [R17] OCPP: *Specific gravity of a 50% aq soln: 1.25 @ 25/15 deg C. [R6] *Sodium mercaptobenzothiazole will dissociate into ions in aq solution. The anion complexes readily with a wide range of metal ions; this is believed to be the basis for its activity as an anti-corrosion agent. Below pH 7 the anion is protonated and forms insoluble mercaptobenzothiazole. [R18] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Nonflammable as a 50% aqueous solution. [R19] SERI: *Mercaptobenzothiazole, the protonated form of sodium mercaptobenzothiazole, is well known as a skin sensitizer and accounts for numerous cases of allergic contact dermatitis. [R20] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *NACAP CAUSED VESICULATIONS AND ERYTHEMATOUS LESIONS IN HUMAN PATCH TESTS... [R1] NTOX: *Daily oral admin to two hybrid strains of mice of 100 mg/kg of mercaptobenzothiazole in 0.5% gelatin failed to cause a significant increase in tumors after 18 months of treatment. /Mercaptobenzothiazole/ [R21] *A drop in blood glucose in rabbits 5 hr after ip injection of mercaptobenzothiazole at a dose of 100 mg/kg was observed. [R22] *Male mice treated daily for one week with ip injections of mercaptobenzothiazole at one-fourth and one-eight the LD50 (110 and 55 mg/kg, respectively) showed no signs of overt toxicity after one week. Microscopic exam of various tissues, however, revealed serious damage to liver of mice receiving the 110 mg/kg dose. Tissues from mice receiving the 55 mg/kg dose were not examined microscopically. /Mercaptobenzothiazole/ [R23] ETXV: *LC50 Salmo gairdneri (Rainbow trout) 2.0 (1.6-2.4) mg/l 24-hr; [R24] *LC50 Salmo gairdneri (Rainbow trout) 1.8 (1.3-2.4) mg/l 48-hr and 96-hr; [R25] *LC50 Lepomis macrochirus (bluegill) 5.7 (4.6-7.1) mg/l 24-hr; [R24] *LC50 Lepomis macrochirus (bluegill) 4.5 (3.9-5.2) mg/l 48-hr; [R24] *LC50 Lepomis macrochirus (bluegill) 3.8 (3.2-4.4) mg/l 96-hr; [R26] *LC50 Daphnia magna 44 (32-60) mg/l 24-hr; [R24] *LC50 Daphnia magna 19 (15-24) mg/l 48-hr; [R24] *EC50 Selenastrum capricornutum 2.0 (0.4-15) mg/l 24-hr; [R24] *EC50 Selenastrum capricornutum 1.0 (0.3-30) mg/l 48-hr; [R27] *EC50 Selenastru capriornutum 0.4 (0.1-2.0) mg/l 72-hr; [R28] *EC50 Selenastrum capricornutum 0.4 (0.2-1.0) mg/l 96-hr; [R24] ADE: *The percutaneous absorption of mercaptobenzothiazole in aqueous soln was studied in guinea pigs. [14C]-labeled mercaptobenzothiazole (about 11 mg/kg body weight) was applied to the shaved skin of the test animals ... Radioactivity in the tissues and excreta was monitored for up to 48 hr. At 48 hr the following distribution of radioactivity (percent of applied dose) was observed following application to intact (abraded) skin: blood: 0.08 (0.17); internal organs: 0.02 (0.05); GI contents: 0.02 (0.03); feces: 0.46 (1.92); urine: 8.39 (34.58); skin (at application site): 12.13 (7.29); coverings and washings: 60.97 (39.10) /from table/. Max rate of absorption was observed at 3 to 6 hours after application as measured by radioactivity in the urine. [R29] *The tissue distribution and excretion of mercaptobenzothiazole was studied in guinea pigs injected sc with [14C]-labeled aqueous soln of mercaptobenzothiazole (5 mg/kg). Max values of radioactivity were observed in tissues at 15 min after injection, and thereafter the radioactivity decr rapidly with time. At 1 hr afr dosing highest values of radioactivity were observed in kidney, liver, and thyroid. At 48 hr the highest values were observed in the thyroid. Excretion of the cmpd appeared to be rapid. At 6 hr after dosing 92.6% of the applied dose had been recovered in urine. [R30] METB: *...Rats... were dosed ip with 35S-mercapto-labelled 2-mercaptobenzothiazole. Analysis of urinary metabolites indicated that mercaptobenzothiazole underwent conjugation with glutathione and with glucuronic acid. Radiolabelled inorg sulfate was also identified in urine. /Mercaptobenzothiazole/ [R31] *At an in vitro concn of 1mM mercaptobenzothiazole caused a slow inhibition of the hexose monophosphate pathway and a moderate stimulation of the tricarboxylic acid cycle of Ehrlich ascites tumor cells./Mercaptobenzothiazole/ [R32] ACTN: *In in vitro studies mercaptobenzothiazole (MBT) (5x10-6 M) inhibited dopamine-beta-hydroxylase (an enzyme involved in the synthesis of norepinephrine) activity by 47%. In in vivo studies MBT (200 mg/kg, ip) lowered norepinephrine levels of mouse brain by 40% at 1 hr after injection; possibly by chelation of cupric ions necessary for dopamine-beta-hydroxylase activity./Mercaptobenzothiazole/ [R33] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ MINF: *3. 3= MODERATELY TOXIC: PROBABLE ORAL LETHAL DOSE (HUMAN) 0.5-5 G/KG, BETWEEN 1 OZ AND 1 PINT (OR 1 LB) FOR 70 KG PERSON (150 LB). [R1] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ARTS: *Mercaptobenzothiazole compounds enter the environment through plant effluents and emissions associated with their manufacture, use, and end product processing and through the degradation and wear of end products, such as tire dust. /Mercaptobenzothiazole/ [R34] *Substantial releases will occur when mercaptobenzothiazole leach from the est 12 million lb of vulcanization accelerators that are deposited as tire dust along the nation's highways. Releases will asooccur as a result of disposal of waste radiator coolants from automobiles and industrial cooling systems. [R35] FATE: *Sodium mercaptobenzothiazole will partition into aq compartments. Being nonvolatile, it will not partition to the atmosphere. [R34] *Below pH 7 sodium mercaptobenzothiazole will be protonated to form insoluble mercaptobenzothiazole. If iron is present sodium mercaptobenzothiazole will be reduced to benzothiazole. [R34] *In aqueous solution sodium mercaptobenzothiazole is not oxidized even @ temp of 100 deg C, nor is it readily hydrolyzed. [R34] *In a weak alkaline or neutral soln the mercaptobenzothiazole anion can readily complex with various metal ions, such as Cu+2 or Zn+2, and form insoluble relatively undissociable salts. [R34] BIOD: *Sodium mercaptobenzothiazole should be readily biodegradable at concentration below toxic limits. [R36] BIOC: *It is unlikely that sodium mercaptobenzothiazole will bioconcentrate, since substitution of the mercapto group on benzothiazole should reduce its partition coefficient ... The fact that sodium mercaptobenzothiazole is a salt will even further reduce the partition coefficient and thus its tendency to bioaccumulate. [R36] RTEX: *Consumers are expected to be exposed to sodium mercaptobenzothiazole through its use as: a corrosion inhibitor in automobile antifreeze solution, a thermal stabilizer in silicon fluids, a preservative in latex paint and on wood, and a component of agricultural pesticides. [R37] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NTP TR No 332; Route: oral,gavage ; Species: rats and mice. NTIS No PB88245154/AS. [R38] SO: R1: Gosselin, R.E., H.C. Hodge, R.P. Smith, and M.N. Gleason. Clinical Toxicology of Commercial Products. 4th ed. Baltimore: Williams and Wilkins, 1976.,p. II-202 R2: Farm Chemicals Handbook 1994. Willoughby, OH: Meister, 1994.,p. C-228 R3: NIH/EPA; SANSS (1984) R4: Kuney JH; Chemcyclopedia 95, Washington DC: American Chemical Society (1995) R5: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 890 R6: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.2 (1983) R7: ITC/USEPA; Information Review #351 (Draft) Sodium Mercatobenzothiazole p.2 (1983) R8: ITC/USEPA; Informaton Review #351 (Draft) Sodium Mercaptobenzothiazole p.2 (1983) R9: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1060 R10: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 923 R11: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.4 (1983) R12: Mellor JD, Irving AR; Bull Inst Int Froid 9: 225-32 (1969) as cited in ITC/USEPA; Information Review #351 (Draft) Sodium mercaptobenzothiazole p.4 (1983) R13: Monsanto; Unpublished information on the production, uses, toxicity, environmental releases, and aquatic toxicity of MBT and sodium MBT (7/16/82) as cited in ITC/USEPA; Information Review #351 (Draft Addendum) Sodium Mercaptobenzothiazole (1983) R14: Monsanto; Unpublished information on the production, uses, toxicity, environmental releases, and aquatic toxicity of MBT and sodium MBT (7/16/82) as cited in ITC/USEPA; Information Review #351 (Draft Addendum) Sodium Mercaptobenzothiazole p.3 (1983) R15: Uniroyal; Product Safety Data Sheet on Sodium mercaptobenzothiazole dated 5/15/75 as cited in ITC/USEPA; Information Review #351 (Draft) Sodium mercaptobenzothiazole p.2 (1983) R16: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.1 (1983) R17: ITC/USEPA; Information Review #352 (Draft) Sodium Mercaptobenzothiazole p.2 (1983) R18: Santodonato J et al; Investigation of Selected Potential Environmental Contaminants: Mercaptobenzothiazoles (1976) Final Report, EPA Contract No 68-01-3128 as cited in ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.2 (1983) R19: Uniroyal; Product Safety Data Sheet on NaMBT dated 5/15/75 as cited in ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.2 (1983) R20: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.11 (1983) R21: Innes JRM et al; J Natl Cancer Inst 42(6): 1101-1114 (1969) as cited in ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.7 (1983) R22: Chiba T; Yakugasku Zasshi 89: 1138-43 (1976) as cited in ITC/USEPA; Information Review #351-A (Draft) Mercaptobenzothiazole p.12 (1983) R23: Guess WL, O'Leary RK; Tox App Pharmacol 14: 221-31 (1969) as cited in ITC/USEPA; Information Review #351-A (Draft) Mercaptobenzothiazole p.15 (1983) R24: ITC/USEPA; Information Review #351 (Draft; Addendum-A) Sodium Mercaptobenzothiazole (1983) R25: ITC/USEPA; Information Review #351 (Draft; Addendum-A) Sodium Mercaptobenzotiazole (1983) R26: ITC/USEPA; Information Review #351 (Draft; Addendum-A) Sodium Mrcaptobenzothiazole (1983) R27: ITC/USEPA; nformation Review #351 (Draft; Addendum-A) Sodium Mercaptobenzothiazole (1983) R28: ITC/USEPA; Information Review#351 (Draft; Addendum-A) Sodium Mercaptobenzothiazole (1983) R29: Nagamatsu K et al; Eisei Kagaku 25: 59-65 (1979) as cited in ITC/USEPA; Information Reiew 351-A (Draft) Mercaptobenzothiazole p.7 (1983) R30: Nagamatsu K et al; Eisei Kagaku 25: 59-65 (1979) as cited in ITC/USEPA; Information Review #351-A (Draft) Mercaptobenzothiazole p.10 (1983) R31: Colucci DF, Buyske DA; Biochem Pharmacol 14: 457-46 (1965) as cited in ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.6 (1983) R32: Grasseti DR et al; J Med Chem 13: 273-6 (1970) as cited in ITC/USEPA; Information Review #351-A (Draft) Mercaptobenzothiazole p.11 (1983) R33: Johnson GA et al; J Pharm Pharmacol 22: 710-712 (1970) as cited in ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.7 (1983) R34: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.12 (1983) R35: ITC/USEPA; Information Review #351 (Draft Addendum) Sodium Mercaptobenzothiazole (1983) R36: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.13 (1983) R37: ITC/USEPA; Information Review #351 (Draft) Sodium Mercaptobenzothiazole p.5 (1983) R38: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/22/92; p.24 RS: 16 Record 342 of 1119 in HSDB (through 2003/06) AN: 6192 UD: 200208 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: MAGENTA- SY: *AIZEN-MAGENTA-; *ANILINE-RED-; *ASTRA-FUCHSINE-B-; *BASIC-FUCHSIN-; *BASIC-FUCHSINE-; *BASIC-MAGENTA-; *BASIC-MAGENTA-E-200-; *BENZENAMINE, 4-((4-AMINOPHENYL)(4-IMINO-2,5-CYCLOHEXADIEN-1-YLIDENE) METHYL)-2-METHYL-, MONOHYDROCHLORIDE; *CALCOZINE-FUCHSINE-HO-; *CALCOZINE-MAGENTA-RIN-; *CALCOZINE-MAGENTA-XX-; *CERISE-B-; *CI-BASIC-VIOLET-14-; *CI-BASIC-VIOLET-14,-MONOHYDROCHLORIDE-; *CI-42510-; *DIABASIC-MAGENTA-; *DIAMOND-FUCHSINE-; *FUCHSINE-; *FUCHSINE-A-; *FUCHSINE-G-; *FUCHSINE-N-; *FUCHSINE-Y-; *FUCHSINE-CS-; *FUCHSINE-HO-; *FUCHSINE-RTN-; *MAGENTA-E-; *MAGENTA-G-; *MAGENTA-I-; *MAGENTA-S-; *MAGENTA-DP-; *MAGENTA-PN-; *MAGENTA-POWDER-N-; *MAGENTA-SUPERTINE-; *ORIENT-BASIC-MAGENTA-; *12418-RED-; *ROSANILINE-; *ROSANILINE-CHLORIDE-; *ROSANILINIUM-CHLORIDE-; *ROSANILINIUM-HYDROCHLORIDE- RN: 632-99-5 MF: *C20-H19-N3.CL-H MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *OXIDATION OF A MIXTURE OF ANILINE, O(AND P)-TOLUIDINE AND THEIR HYDROCHLORIDES WITH NITROBENZENE, OR A MIXTURE OF NITROBENZENE AND O-NITROTOLUENE, IN PRESENCE OF FERROUS CHLORIDE, FERROUS OXIDE AND ZINC CHLORIDE, FOLLOWED BY NEUTRALIZATION TO THE FREE BASE /MAGENTA BASE/ [R1] +FISCHER, FISCHER; ANN 194(276) 290 (1878); BER 13: 2204 (1880); MICHAELS, GRAMICK; J AM CHEM SOC 67: 1212 (1943). /MAGENTA BASE/ [R2] FORM: *A SYNTHETIC ROSANILINE DYESTUFF, A MIXTURE OF ROSANILINE AND PARAROSANILINE HYDROCHLORIDES...GRADE NF. [R3] *MAGENTA IS A MIXTURE OF THREE CLOSELY RELATED 4,4',4"-TRIAMINOTRIARYL-METHANE DYES IN THE FORM OF THEIR MONOHYDROCHLORIDE SALTS. [R4, p. V4 57] *MAGENTA, AS COMMMERCIAL MATERIAL, IS MIXTURE OF...MAGENTA I, PARA-MAGENTA, AND SMALL AMT OF MAGENTA II. MAGENTA...AVAILABLE IN US AS BASIC FUCHSIN NF... /CONTAINING/ A MAX LIMIT OF 8 PPM OF ARSENIC AND 30 PPM OF LEAD (AMERICAN PHARMACEUTICAL ASSOC, 1970). [R4, p. V4 59] MFS: *DYE SPECIALTIES, INC, JERSEY CITY, NJ 07306 /MAGENTA BASE/ [R1] OMIN: *THE GRADE OF MAGENTA USED IN MEDICINE, BASIC FUCHSIN, NF, IS APPROVED FOR USE IN CARBOL-FUCHSIN SOLUTION, NF, AN ANTIFUNGAL AGENT CONTAINING PHENOL AND RESORCINOL. [R4, p. V4 60] *BASIC FUCHSIN...IS STILL MARKETED IN MIXT CONTAINING 0.3% BASIC FUCHSIN FOR TREATMENT OF TINEA PEDIS AND TINEA CAPITIS. [R5] USE: *ANTIFUNGAL AGENT [R2] *AS DYE OR DYE INTERMEDIATE IN COLORING TEXTILE FIBERS, FABRICS, PAPER PRODUCTS, COTTON AND WOOL, JUTE FIBERS, CHINA CLAY PRODUCTS AND LEATHER; IN PRINTING INKS, AS A FILTER DYE IN PHOTOGRAPHY; BIOLOGICAL STAIN; LAB REAGENT, IN THIN-LAYER CHROMATOGRAPHY [R4, p. V4 60] *DYE FOR OILS, FATS, WAXES (ESPECIALLY FOR POLISHES), CARBON PAPERS AND BALL POINT PEN INKS /MAGENTA BASE/ [R1] CPAT: *ESSENTIALLY 100% AS A DYE /MAGENTA BASE/ [R1] PRIE: U.S. PRODUCTION: *(1972) PROBABLY GREATER THAN 4.5X10+5 GRAMS /MAGENTA BASE/ [R1] *(1975) PROBABLY GREATER THAN 4.5X10+5 GRAMS /MAGENTA BASE/ [R1] U.S. IMPORTS: *(1972) ND /MAGENTA BASE/ [R1] *(1975) ND /MAGENTA BASE/ [R1] U.S. EXPORTS: *(1972) ND /MAGENTA BASE/ [R1] *(1975) ND /MAGENTA BASE/ [R1] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *METALLIC GREEN LUSTROUS CRYSTALS [R2] MW: *337.88 [R6] SOL: *2.65 PARTS DISSOLVE IN 1000 PARTS WATER; SOL IN ALCOHOL WITH A CARMINE RED COLOR; PRACTICALLY INSOL IN ETHER [R2] SPEC: +MAX ABSORPTION (ETHANOL): 543 NM (E= 93,000) [R4, p. V4 59] OCPP: *DECOMPOSES @ 186 DEG C /MAGENTA BASE/ [R2] +DECOMPOSES ABOVE 200 DEG C [R4, p. V4 59] *BROWNISH-RED CRYSTALS /MAGENTA BASE/ [R2] *SLIGHTLY SOL IN WATER; SOL IN ALCOHOL, ACIDS /MAGENTA BASE/ [R2] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- OPRM: *1. COMPETENT ENGINEERING... 2. ADEQUATE VENTILATION; 3. DAILY CHANGES OF FRESHLY LAUNDERED CLOTHING...AND SHOWER BATH...@ END OF...WORK PERIOD; 4. ...MEDICAL DEPT FOR INSPECTION @ END OF...SHIFT; 5. INDIVIDUALS SHOWING GROSS EVIDENCE OF CYANOSIS...KEPT UNDER OBSERVATION. /AROMATIC AMINO COMPD/ [R7, 2130] *6. WORKMEN SHOULD NEVER BE PERMITTED TO ENTER A VESSEL... UNTIL DEGREE OF ATMOSPHERIC CONCN HAS BEEN QUANT EST BY PLANT HYGIENIST; 7. COMPLETE PHYSICAL EXAM INCL HEMOGLOBIN DETERMINATIONS, RED, WHITE, AND DIFFERENTIAL COUNTS, AND COMPLETE URINALYSIS, EVERY 6 MO OR OFTENER. /AROMATIC AMINO COMPD/ [R7, 2131] SSL: *EASILY REDUCED TO COLORLESS LEUCO-BASES [R4, p. V4 59] CLUP: *ADSORPTION OF ORGANIC COMPOUNDS IN WASTEWATER BY AN ACTIVATED CLAY WAS STUDIED. THE MIXTURE OF ORGANIC COMPOUNDS, KAOLIN (AS SUSPENDED SOLIDS 100 PPM), AND ACTIVATED CLAY (0.8-5.0 G/L) WAS STIRRED FOR 2 HR AND THE SUSPENSION WAS FLOCCULATED WITH AL2(SO4)3 AND AN ANIONIC FLOCCULANT (4 PPM). COD REMOVALS WERE: POLY(VINYL ALCOHOL) 92.7, METHYLENE BLUE 97.7, AND FUCHSINE 96.9%. [R8] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of magenta. There is inadequate evidence in humans for the carcinogenicity of CI Basic Red 9. There is sufficient evidence that the manufacture of magenta entails exposures that are carcinogenic. There is sufficient evidence in experimental animals for the carcinogenicity of CI Basic Red 9. There is inadequate evidence in experimental animals for the carcinogenicity of magenta. Overall evaluation: The manufacture of magenta entails exposures that are carcinogenic (Group 1). CI Basic Red 9 is possibly carcinogenic to humans (Group 2B). Magenta containing CI Basic Red 9 is possibly carcinogenic to humans (Group 2B). [R9] HTOX: *...IN A SURVEY OF THE BRITISH CHEMICAL INDUSTRY...THERE WAS A HIGHLY SIGNIFICANT RISK OF CONTRACTING BLADDER CANCER AMONG MEN ENGAGED IN MANUFACTURING, BUT NOT IN PURIFYING OR USING, MAGENTA. OF 85 MEN KNOWN TO HAVE BEEN ENGAGED IN MANUFACTURING MAGENTA, BUT NOT EXPOSED TO 1- OR 2-NAPHTHYLAMINE OR BENZIDINE, THERE WERE 5 CASES OF BLADDER CANCER. THREE OF THESE WERE RECORDED AS DYING OF BLADDER CANCER, WHEREAS ONLY 0.13 CASES WOULD HAVE BEEN EXPECTED (RELATIVE RISK= 23.0; P LESS THAN 0.005). [R4, p. V4 62] *THE MFR OF MAGENTA HAS CARRIED A CARCINOGENIC SUBSTANCES REGULATIONS 1967, BUT THERE APPEARS TO BE NO FIRM EVIDENCE THAT MAGENTA ITSELF IS CARCINOGENIC. [R10] NTOX: *...GAVE 12 MG MAGENTA IN ARACHIS OIL PER WEEK TO 60 STOCK MICE BY GASTRIC INSTILLATION FOR 52 WEEKS (TOTAL DOSE, 624 MG). ... SEVEN OF THE 60 MICE WERE EXAMINED BEFORE WK 50, COMPARED WITH 2 OF 60 CONTROL; and 14 MICE IN THE TEST GROUP WERE EXAMINED BETWEEN WEEKS 50 and 90, COMPARED WITH 16 MICE IN THE CONTROL GROUP. FOUR LYMPHOMAS AND 1 HEPATOMA WERE FOUND IN THE 21 TEST ANIMALS, and 5 LYMPHOMAS WERE FOUND IN 18 CONTROLS. ... MANY MICE DIED FROM ECTROMELIA. [R4, p. V4 61] *...INJECTED 10 MG PARA-MAGENTA AS 1% SOLN SC WEEKLY...INTO 20 BD III RATS. FIRST LOCAL SARCOMA...@ 300 DAYS, AFTER TOTAL DOSE OF 370 MG OF DYE. TOTAL OF 7 SARCOMAS...IN 12 RATS SURVIVING AFTER APPEARANCE OF FIRST TUMOR, COMPARED TO SPONTANEOUS INCIDENCE OF SARCOMAS IN THESE RATS OF LESS THAN 5%. [R4, p. V4 62] *FUCHSINE WAS POSITIVE IN THE REC ASSAY WITH BACILLUS SUBTILIS STRAINS. [R11] *NO TUMORS COULD BE FOUND IN RATS INTRAGASTRICALLY ADMIN MAGENTA, TWICE WEEKLY FOR LIFE. [R12] *FUCHSIN WAS NOT TOXIC TO THE FISH, CARASSIUS AURATUS, AT CONCN UP TO 20 MG/L. [R13] *GROUPS OF SYRIAN GOLDEN HAMSTERS WERE TREATED WITH MAGENTA (400 MG/KG), INTRAGASTRICALLY, TWICE WEEKLY FOR LIFE. NO TUMORS WERE ASSOCIATED WITH THE TREATMENTS. [R14] *THE BACTERIOLOGICAL STAIN, BASIC FUCHSIN CI 42500-42510, WAS MUTAGENIC IN FRAMESHIFT MUTATION DETECTOR STRAINS TA98 and /OR TA1538 AND REQUIRED METABOLIC ACTIVATION. [R15] *IN CHINESE HAMSTER OVARY CELLS TREATED WITH 20 UMOL BASIC FUCHSIN FOR 5 HR, THE NUMBER OF BREAKS PER METAPHASE WAS 0.18; HOWEVER, THIS WAS NOT A SIGNIFICANT INCREASE. THE SIGNIFICANT VALUE FOR THE NUMBER OF CHROMOSOME BREAKS PER METAPHASE BY SOME WATER-SOLUBLE DYES WAS 0.32. [R16] +Basic violet 14 was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). Basic violet 14 was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 0.030, 0.100, 0.160, 0.300, 0.330, 0.670, 1.000, 3.300, 10.000, 33.000, 100.000, 333.000, and 1000.000 ug/plate. The compound was positive in strains TA100 and TA98 with activation. The lowest positive dose tested was 33.000 ug/plate in strain TA100 with rat liver S-9. Precipitate was observed in cultures at the 2 highest dose levels. [R17] ADE: *...GAVE 12 MG MAGENTA IN ARACHIS OIL TO 60 STOCK MICE BY GASTRIC INSTILLATION FOR 52 WEEKS (TOTAL DOSE, 624 MG). DYE WAS FOUND TO HAVE STAINED THE TISSUES AT AUTOPSY. [R4, p. V4 61] *CATIONIC DYES ARE WELL KNOWN TO BIND TO NUCLEIC ACIDS. /CATIONIC DYES/ [R18, 437] *CATIONIC DYES APPEAR TO HAVE SPECIAL ATTRIBUTE OF NITROGEN ATOM WHICH IS PART OF RESONANT SYSTEM RESPONSIBLE FOR COLOR, AND WHICH APPEARS TO BE ASSOC WITH PROPENSITY TO VERY STRONG BINDING TO CARBOXYL GROUPS OF CORNEAL MUCOPROTEINS. /CATIONIC DYES/ [R18, 436] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ EFFL: +IT MAY BE PRESENT IN THE WASTE STREAMS FROM PLANTS WHERE IT IS MADE OR USED. [R4, p. V4 61] RTEX: *...IT IS NOT POSSIBLE TO INDICATE WHETHER INDUSTRIAL BLADDER CANCER FOUND IN MAGENTA WORKERS IS ATTRIBUTABLE TO EXPOSURE TO MAGENTA ITSELF, OR TO ONE OR MORE OF ITS ASSOCIATED INTERMEDIATES AND IMPURITIES. [R4, p. V4 63] *THERE WAS HIGHLY SIGNIFICANT RISK OF CONTRACTING BLADDER CANCER AMONG MEN ENGAGED IN MANUFACTURING, BUT NOT IN PURIFYING OR USING, MAGENTA. ... IT IS KNOWN...THAT THE MODERN PROCESS FOR MANUFACTURING MAGENTA INVOLVES THE REPLACEMENT OF ANILINE BY ORTHO-TOLUIDINE, AND...THAT ORTHO-TOLUIDINE MAY BE IMPLICATED IN THE ETIOLOGY OF THE MAGENTA TUMORS. [R4, p. V4 62] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *SPECTROPHOTOMETRIC METHODS ARE DESCRIBED...BUT ABSORPTION MAXIMA DIFFER SLIGHTLY FOR THE INDIVIDUAL COMPONENTS OF MAGENTA. ...DETERMINATION IN PHARMACEUTICAL PREPN...DESCRIBED BY SUKHLITSKAYA YM, AND BELEVITCH NA; FUCHSIN DETERMINATION IN DRUGS; APTECHN DELO 12: 75 (1963). [R4, p. V4 61] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: A REVIEW AND DISCUSSION WITH 14 REFERENCES ON THE CANCER RISK OF MAGENTA AND RELATED DYES IN LAB USE. [R19] SO: R1: SRI R2: The Merck Index. 9th ed. Rahway, New Jersey: Merck and Co., Inc., 1976. 1071 R3: Hawley, G.G. The Condensed Chemical Dictionary. 9th ed. New York: Van Nostrand Reinhold Co., 1977. 399 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work). R5: Goodman, L.S., and A. Gilman. (eds.) The Pharmacological Basis of Therapeutics. 5th ed. New York: Macmillan Publishing Co., Inc., 1975. 1012 R6: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8209 R7: Patty, F. (ed.). Industrial Hygiene and Toxicology: Volume II: Toxicology. 2nd ed. New York: Interscience Publishers, 1963. R8: YOKOTA F ET AL; ADVANCED WASTEWATER TREATMENT BY ACTIVATED CLAY; AICHI-KEN KOGYO SHIDOSHO HOKOKU 16: 74 (1980) R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 57 230 (1993) R10: Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976. 488 R11: FUJITA H ET AL; MUTAGENICITY OF DYES IN THE MICROBIAL SYSTEM; TOKYO TORITSU EISEI KENKYUSHO KENKYU NEMPO 27-2: 153 (1976) R12: KETKAR MB, MOHR U; THE CHRONIC EFFECTS OF MAGENTA, PARAMAGENTA AND PHENYL-BETA-NAPHTHYLAMINE IN RATS AFTER INTRAGASTRIC ADMINISTRATION; CANCER LETT (SHANNON, IREL) 16(2) 203 (1982) R13: GHISOTTI F, COLOMBO G; TOXICOLOGICAL ANALYSIS OF WATER-SOLUBLE SYNTHETIC ORGANIC DYES IN AQUATIC ANIMALS; ECOLOGIA 2(4) 32 (1972) R14: GREEN U ET AL; A COMPARATIVE STUDY OF THE CHRONIC EFFECTS OF MAGENTA, PARAMAGENTA, AND PHENYL-BETA-NAPHTHYLAMINE IN SYRIAN GOLDEN HAMSTERS; J CANCER RES CLIN ONCOL 95(1) 51 (1979) R15: BONIN AM ET AL; MUTAGENICITY OF ARYLMETHANE DYES IN SALMONELLA TYPHIMURIUM; MUTAT RES 89(1) 21 (1981) R16: AU W, HSU TC; STUDIES ON THE CLASTOGENIC EFFECTS OF BIOLOGIC STAINS AND DYES; ENVIRON MUTAGEN 1(1) 27 (1979) R17: Mortelmans K et al; Environ Mutagen 8:1-119 (1986) R18: Grant, W. M. Toxicology of the Eye. 2nd ed. Springfield, Illinois: Charles C. Thomas, 1974. R19: HOWE JR; IS THERE A CANCER RISK IN THE LABORATORY USE OF MAGENTA AND RELATED DYES?; LAB PRACT 26(2) 87 (1977) RS: 13 Record 343 of 1119 in HSDB (through 2003/06) AN: 6193 UD: 200201 RD: Reviewed by SRP on 1/31/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 2-METHYL-1-NITROANTHRAQUINONE- SY: *9,10-ANTHRACENEDIONE,-2-METHYL-1-NITRO-; *ANTHRAQUINONE,-2-METHYL-1-NITRO-; *1-N-2-MA- (RUSSIAN); *2-METHYL-1-NITRO-9,10-ANTHRACENEDIONE-; *NCI-C01923-; *1-NITRO-2-METHYLANTHRAQUINONE-; *Violet-Cibacet-2R- RN: 129-15-7 MF: *C15-H9-N-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *PREPN: ...BY NITRATION OF 2-METHYLANTHRAQUINONE WITH A MIXT OF NITRIC AND SULFURIC ACIDS. [R1] OMIN: *2-Methyl-1-nitroanthraquinone is no longer used by the dye industry in the United States and has not been produced commercially in this country since 1970. [R2] USE: *DYE INTERMEDIATE; MFR 1-AMINO-2-METHYLANTHRAQUINONE [R1] *2-METHYL-1-NITROANTHRAQUINONE CAN BE OXIDIZED TO 1-NITRO-2-ANTHRAQUINONECARBOXYLIC ACID, WHICH CAN BE USED TO PREPARE 5 DYES; ONLY 2 OF THESE HAVE BEEN PRODUCED COMMERCIALLY IN US IN RECENT YR: VAT BROWN 31.28%, LAST PRODUCED BY ONE COMPANY IN 1974. [R1] *In the past, 2-methyl-1-nitroanthraquinone served as an intermediate in the manufacture of certain wool dyes of the alizarin series and of anthraquinone vat dyes such as CI Vat Red 39. [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *PALE-YELLOW NEEDLES [R3] MP: *270-271 DEG C [R3] MW: *267.25 [R4] SOL: *INSOL IN WATER AND HOT ETHANOL; SLIGHTLY SOL IN HOT DIETHYL ETHER, HOT BENZENE, HOT ACETIC ACID AND CHLOROFORM; SOL IN NITROBENZENE [R3] SPEC: *IR: 4628 (Coblentz Society Spectral Collection) [R5]; *MASS: 4709 (National Bureau of Standards EPA-NIH Mass Spectra Data Base, NSRDS-NBS-63) [R5] OCPP: *NITRO GROUP MAY BE REPLACED BY A VARIETY OF SUBSTITUENTS; EASILY REDUCED TO AMINO GROUP [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R6, 1979.8] OPRM: *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R6, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R6, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R6, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R6, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R6, 1979.11] SHIP: +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R6, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R6, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R6, 1979.13] CLUP: *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R6, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R6, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R6, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R6, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R6, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R6, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *No data are available in humans. Sufficient evidence of carcinogenicity in animals. OVERALL EVALUATION: Group 2B: The agent is possibly carcinogenic to humans. [R7] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R6, 1979.23] HTOX: *Carcinogenic determination: human indefinite [R3] *Chronic neurotoxic effects include vision disturbances. /From table; Quinones/ [R8] NTOX: *GROUPS OF 50 MALE AND 50 FEMALE B6C3F1 MICE, 6 WK OF AGE, WERE FED DIETS CONTAINING 300 OR 600 MG/KG 2-METHYL-1-NITROANTHRAQUINONE (IMPURITIES UNSPECIFIED). ... NONE OF THE MICE IN EITHER OF TREATED GROUPS SURVIVED LONGER THAN 338 DAYS. SC HEMANGIOSARCOMAS DEVELOPED IN MAJORITY OF TREATED MICE AT THE TWO DOSE LEVELS (88/90 MALES AND 79/82 FEMALES); FOUR OF THESE TUMORS METASTASIZED TO THE LUNG. MESENTERIC HEMANGIOSARCOMAS...OBSERVED IN 6 MALE AND 8 FEMALE MICE. 1 HEMANGIOSARCOMA OF SPLEEN OCCURRED AMONG 49 MALE CONTROLS; NO HEMANGIOSARCOMA AT ANY SITE OCCURRED IN 48 FEMALE CONTROLS. (THE WORKING GROUP NOTED THAT NO ATTEMPT WAS MADE TO MEASURE PURITY OF TESTED MATERIAL OR TO CHARACTERIZE IT.) [R9] *GROUPS OF 50 MALE AND 50 FEMALE FISCHER 344 RATS, 6 WK OF AGE WERE FED DIETS CONTAINING 600 OR 1200 MG/KG 2-METHYL-1-NITROANTHRAQUINONE (IMPURITIES UNSPECIFIED) FOR 78 WK AND...OBSERVED FOR ADDITIONAL 31 WK. ... BY END OF STUDY, 60, 70 and 54% OF MALES AND 44, 80 and 58% OF FEMALES WERE STILL ALIVE IN CONTROL, LOW-DOSE AND HIGH-DOSE GROUPS, RESPECTIVELY. INCR IN INCIDENCE OF HEPATOCELLULAR CARCINOMAS WAS OBSERVED ONLY IN MALES: 1/48 CONTROLS, 5/48 LOW-DOSE AND 9/49 HIGH-DOSE ANIMALS... FIBROMAS OF SC TISSUE WERE OBSERVED IN BOTH MALE AND FEMALE RATS: IN MALES- 3/48 CONTROLS, 10/49 LOW-DOSE... and 34/49 HIGH-DOSE ANIMALS...IN FEMALES- 1/50, 0/50 and 13/49...RESPECTIVELY. SC HEMANGIOSARCOMAS OCCURRED IN 3 HIGH-DOSE MALE RATS. (WORKING GROUP NOTED THAT NO ATTEMPT WAS MADE TO MEASURE PURITY OF TESTED MATERIAL OR TO CHARACTERIZE IT.) [R9] *2-METHYL-1-NITROANTHRAQUINONE (PURITY UNSPECIFIED) INDUCED REVERSE MUTATION IN SALMONELLA TYPHIMURIUM STRAINS TA1537, TA1538, TA98 AND TA100, WITH OR WITHOUT A LIVER ACTIVATION SYSTEM FROM AROCLOR 1254-INDUCED RATS. [R10] *IN A SIX-WK SUBCHRONIC TOXICITY FEEDING STUDY WITH UP TO 5% 2-METHYL-1-NITROANTHRAQUINONE IN THE DIET, MALE AND FEMALE RATS THAT RECEIVED 0.15% SHOWED REDN IN WEIGHT GAIN OF 14% and 3%, RESPECTIVELY. IN A CHRONIC STUDY IN RATS WITH 0.06 OR 0.12% IN THE DIET, HYPERPLASIA OF THE LYMPHOID TISSUE AND BASAL CELLS OF STOMACH AS WELL AS INFLAMMATORY CHANGES OF THE STOMACH WERE REPORTED. [R10] *Carcinogenic determination: animal positive [R3] *2-Methyl-1-nitroanthraquinone was found to be positive when tested for mutagenicity using the Salmonella/microsome preincubation assay, using the standard protocol approved by the National Toxicology Program (NTP). 2-Methyl-1-nitroanthraquinone was tested in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat and hamster liver S-9, at doses of 1.000, 3.000, 10.000, 33.000, 100.000, 333.000, and 1000.000 ug/plate. The compound was positive in strains TA100, TA98, and TA1537 both with and without activation and in strain TA1535 only with activation. The lowest positive dose tested was 3.000 ug/plate in strain TA1537 with metabolic activation. Precipitate was observed in cultures tested at the 2 highest dose levels. [R11] *Acute neurotoxic effects reported in animals include convulsions; medullary paralysis. /From table; Quinones/ [R8] NTP: +A bioassay of 2-methyl-1-nitroanthraquinone for possible carcinogenicity was conducted using Fischer 344 rats. /The cmpd/ was administered in the feed at two concentrations to groups of 50 male and 50 female animals. The high and low dietary concentrations were 0.12 and 0.06%, respectively, for the male and female rats. After a 78 wk treatment period, observation of the rats continued for an additional 31 wk. Fifty rats of each sex were placed on test as controls. Survival in both male and female rats was adequate for a meaningful statistical analysis of late developing tumors; however, there was a significant positive association between incr dosage and elevated mortality in female rats. Hepatocellular carcinomas and neoplastic nodules of the liver occurred in both the male and female treated rats. A statistically significant association between incr dosage and elevated incidence of hepatocellular carcinomas was indicated by the Cochran-Armitage test for the males (1/48, 5/48, and 9/49 in control, low dose, and high dose, respectively); however the Fisher exact tests supported these results only for the high dose males. The incidence of neoplastic nodules was statistically significant in the male rats (0/48, 2/48, and 6/49 in control, low dose, and high dose, respectively,) as indicated by the Cochran-Armitage test and supported by the Fisher exact test fir the high dose group, When those rats having hepatocellular carcinomas or neoplastic nodules of the liver were combined and evaluated simultaneously, the Cochran-Armitage tests indicated statistically significant associations between increased dosages and elevated tumor incidences in both males and females. This was supported by the Fisher exact tests for males and not for females. The incidences of one tumor type, subcutaneous fibroma, were found to be statistically significant in both male and female rats. No other tumors occurred in treated animals in statistically significant incidences when compared to controls. Squamous cell papillomas and squamous cell carcinomas of the forestomach were observed only in high dose rats. Although the incidences of these gastric tumors were not statistically significant, historical data indicate that these tumors are rare in Fischer 344 rats. The occurrence of these tumors in high dose rats, together with the frequent occurrence of nonneoplastic proliferative lesions of the forestomach in treated rats, indicates that the occurrence of these tumors was related to admin of 2-methyl-1-nitroanthraquinone. An incr incidence of bladder tumors (papillomas, transitional cell papillomas, and sarcomas) was observed among female rats. Under the conditions of this bioassay, the results indicate that orally administered 2-methyl-1-nitroanthraquinone is carcinogenic in male Fischer 344 rats, producing hepatocellular carcinomas. Incr incidences of subcutaneous fibromas in both male and female Fischer 344 rats were also associated with the administration of the cmpd. Tumors of the forestomach and bladder in these animals may also have been related to the administration of the test chemical. MaleRats: Positive; Female Rats: Positive; Male Mice: Positive; Female Mice: Positive. [R12] METB: *Quinones (ie, 6,12-dione) have been shown to undergo oxidation-reduction cycles involving quinone, hydroquinone, and molecular oxygen, resulting in the formation of oxygen radicals and semiquinone radicals. /Quinones/ [R13] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ RTEX: *Most likely to be via dermal contact [R14] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Not approved for use in food, drugs or cosmetics [R14] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Weisburger EK; Bioassay Program for Carcinogenic Hazards of Cancer Chemotherapeutic Agents; Cancer 40: 1935-49 (1977). Route: oral in feed; Species: mice. Bioassay of 2-Methyl-1-Nitroanthraquinone for Possible Carcinogenicity (1978) Technical Rpt Series No. 29 DHEW Pub No. (NIH) 78-829 U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014. SO: R1: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 206 (1982) R2: US Dept of Health, Education, and Welfare; Bioassay of 2-Methyl-1-Nitroanthraquinone for Possible Carcinogenicity. NCI/NIH; Bethesda, MD NCI-CG-TR-29. PB277-439. (1978) R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 205 (1982) R4: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 83/8209 R5: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 108 R6: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. S7 66 (1987) R8: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985. 129 R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 207 (1982) R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V27 208 (1982) R11: Mortelmans K et al; Environ Mutagen 8: 1-119 (1986) R12: Bioassay of 2-Methyl-1-Nitroanthraquinone for Possible Carcinogenicity (1978) Technical Rpt Series No. 29 DHEW Pub No. (NIH) 78-829, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014 R13: Dean, J.H., M.I. Luster, A.E. Munson, I. Kimber. Immunotoxicology and Immunopharmacology. 2nd ed. New York, NY: Raven Press, Ltd., 1994. 577 R14: USCPSC; Toxicological Profiles: Anthraquinone Dyes p.98 (October 1981) CPSC-C-81-1110 RS: 27 Record 344 of 1119 in HSDB (through 2003/06) AN: 6293 UD: 200303 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DICHLOROPROPENE- SY: *ALPHA-CHLOROALLYL-CHLORIDE-; *1-Propene,-dichloro- RN: 26952-23-8 RELT: 6298 [DICHLOROPROPANE-DICHLOROPROPENE MIXTURE] (MIXTURE); 6175 [1,2-DICHLOROPROPENE] (Mixture Component ); 5222 [2,3-DICHLORO-1-PROPENE] (Mixture Component); 1109 [1,3-DICHLOROPROPENE] (Mixture Component ); 1503 [CIS-1,3-DICHLOROPROPENE] (Mixture Component); 1504 [TRANS-1,3-DICHLOROPROPENE] (Mixture Component) MF: *C3-H4-Cl2 SHPN: UN 2047; Dichloropropenes IMO 3.3; Dichloropropenes STCC: 49 092 55; Dichloropropene ASCH: Propylene, 1,2-dichloro (cis); 6923-20-2; Propylene, 1,2-dichloro (trans); 7069-38-7 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *MADE BY THE HIGH TEMPERATURE CHLORINATION OF XYLENE TO YIELD ALLYL CHLORIDE AS A PRIMARY PRODUCT. THE 1,3-DICHLOROPROPENE IS SEPARATED FROM THE HEAVY ENDS AFTER REMOVAL OF ALLYL CHLORIDE AS AN OVERHEAD PRODUCT IN DISTILLATION. [R1] IMP: *OTHER CHLORINATED HYDROCARBONS MAY BE PRESENT AS IMPURITIES AND STABILIZERS. THESE INCLUDE CHLOROPICRIN, ISOMERS OF DICHLOROPROPANE, DICHLOROPROPENE AND EPICHLOROHYDRIN. [R2] OMIN: *Production of ... DD mixture has been discontinued by the Dow Chemical Co [R3] *DICHLOROPROPENE WILL REPLACE MANY FORMER USES OF ETHYLENE DIBROMIDE [R4] USE: *Various mixtures of dichloropropenes are used as fumigants applied to the soil before crops are planted. [R5, p. III-141] *Preplant for nematode, disease, insect control on a variety of crops. [R6] *USED ALONE OR IN COMBINATION WITH CHLOROPICRIN, METHYL ISOTHIOCYANATE, AND METHYL BROMIDE FOR SOIL TREATMENT BEFORE PLANTING OF MANY CROPS. MAJOR SPECIFIC USE SITES INCLUDE COTTON, POTATOES, SUGAR BEETS, TOBACCO, AND VEGETABLE CROPS. [R7] *Oil and fat solvent [R8] PRIE: U.S. PRODUCTION: *(1983) 1.63X10+10 G (CONSUMPTION) [R9] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R10] MW: *110.98 [R11] SOL: *In water, 2.7X10+3 mg/l at 20 deg C [R12] VAP: *24 mm Hg at 25 deg C [R13] OCPP: *Heavier than water. Vapors are heavier than air. It weighs 10.2 lb/gal [R10] *IR: 13903 (Sadtler Research Laboratories Prism Collection) /Propylene, 1,2-dichloro (cis)/ [R14] *MASS: 347 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Propylene, 1,2-dichloro (cis)/ [R14] *IR: 23674 (Sadtler Research Laboratories Prism Collection) /Propylene, 1,2-dichloro (trans)/ [R14] *MASS: 347 (Atlas of Mass Spectral Data, John Wiley and Sons, New York) /Propylene, 1,2-dichloro (trans)/ [R14] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Flammable/combustible materials. May be ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances desigmnated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Dichloropropenes/ [R15] +Health: May cause toxic effects if inhaled or ingested/swallowed. Contact with substance may cause severe burns to skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Dichloropropenes/ [R15] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Dichloropropenes/ [R15] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing is recommended for fire situations only; it is not effective in spill situations. /Dichloropropenes/ [R15] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Dichloropropenes/ [R15] +Fire: Some of these materials may react violently with water. Small fires: Dry chemical, CO2, water spray or alcohol-resistant foam. Large fires: Water spray, fog or alcohol-resistant foam. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Do not get water inside containers. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Dichloropropenes/ [R15] +Spill or Leak: Fully encapsulating, vapor protective clothing should be worn for spills and leaks with no fire. ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb with earth, sand or other non-combustible material and transfer to containers (except for Hydrazine). Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Dichloropropenes/ [R15] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Dichloropropenes/ [R15] FPOT: *Flammable liquid. [R16] FIRP: *If material on fire or involved in fire: Do not entinguish fire unless flow can be stopped or safely confined. Use water in flooding quantities as fog. Do not extinguish fire unless flow can be stopped. Use water in flooding quantities as fog. Solid streams of water may spread fire. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. [R17] *Personnel protection: ... Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R17] TOXC: *When heated to decomposition it emits toxic vapors of /hydrogen chloride/. [R18] DCMP: *When heated to decomposition it emits toxic vapors of /hydrogen chloride/. [R18] SERI: *Odor and intense irritation of eyes, skin, and resp mucosa. [R5, p. III-141] *IRRITATION OF EYES AND UPPER RESP MUCOSA APPEARS PROMPTLY AFTER EXPOSURE TO CONCN VAPORS. LACRIMATION IS PROMINENT. ... SEVERE SKIN IRRITATION WITH MARKED INFLAMMATORY RESPONSE OF EPIDERMIS AND UNDERLYING TISSUES /FROM DERMAL EXPOSURES/. /DICHLOROPROPENES/ [R5, p. III-142] *Dichloropropene is strongly irritating to the skin, eyes, and respiratory tract. [R19] EQUP: *Wear boots, appropriate chemical protective gloves, boots and goggles. [R10] *Wear positive pressure self-contained breathing apparatus when fighting fires involving this material. [R10] *Chemical Protective Clothing Material Vendor Ratings: "Fair" or "poor" ratings were given by less than three vendors. "Good" and "fair" ratings, with "fair" predominating, were given by several vendors for butyl, natural rubber, neoprene and nitrile materials used in occupational exposure to dichloropropenes. [R20] OPRM: *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. Use water spray to knock-down vapors. [R17] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. [R17] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R21] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R22] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R23] CLUP: *Environmental considerations: Land spill: Dig a pit, pond, lagoon, or holding area to contain liquid or solid material. /SRP: If time permits, pits, ponds, lagoons, soak holes, or holding areas should be sealed with an impermeable flexible membrane liner./ Dike surface flow using soil, sand bags, foamed polyurethane, or foamed concrete. Absorb bulk liquid with fly ash, cement powder, sawdust, or commercial sorbents. Apply fluorocarbon-water foam to diminish vapor and fire hazard. [R17] *Environmental considerations: Water spill: Use natural deep water pockets, excavated lagoons, or sand bag barriers to trap material at bottom. Remove trapped material with suction hoses. Use mechanical dredges or lifts to remove immobilized masses of pollutants and precipitates. [R17] *Environmental considerations: Air spills: Apply water spray or mist to knock down vapors. Combustion products include corrosive or toxic vapors. [R17] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *IDENTIFICATION: The technical mixture of dichloropropenes and dichloropropane is a clear amber liquid with a pungent odor. It is soluble in halogenated solvents, esters, and ketones. It was widely used as a soil nematocide before planting. HUMAN EXPOSURE: Dichloropropane-Dichloropropene mixture is no longer widely used and, thus, exposure of the general population via air, water, and food is unlikely. One case of acute fatal poisoning has been reported following accidental ingestion. Several cases of contact dermatitis and skin sensitization have been reported. ANIMAL STUDIES: The acute toxicity of dichloropropane-dichloropropene mixture for laboratory animals is moderate to high. Acute exposure results in clinical signs associated with central nervous system depression. It is a severe eye and skin irritant and it is a moderate dermal sensitizer. In a long-term study on rats fed diets containing up to 120 mg of the mixture per kg for 2 years, no toxic or carcinogenic effects were seen. No metabolic studies have been carried out on dichloropropane-dichloropropene mixture. The two major components, 1,2-dichloropropene and 1,2-dichloropropane, are rapidly eliminated, primarily in the urine and, to a lesser extent, via expired air. The components of the mixture are metabolized by oxidative and conjunction pathways. The major urinary metabolites are mercapturic acids. [R24] ANTR: *1. FLUSH contaminating fumigants from the skin and eyse with copious amounts of water or saline for at least 15 minutes. Some fumigants are corrosive to the cornea and may cause BLINDNESS. Specialized medical treatment should be obtained promptly following removal of toxicant by copious flushing with clean water. Skin contamination may cause BLISTERING and deep chemical burns. Absorption of some fumigants across the skin may be sufficient to cause systemic poisoning in the absence of fumigant inhalation. For all these reasons, decontamination of eyes and skin must must be IMMEDIATE and THROUGH. 2. REMOVE victims of fumigant inhalation to FRESH AIR immediately. Even though initial symptoms and signs are mild, keep the victim quiet, in a semi-reclining position. Minimum pohysical activity limits the likehood ofpulmonary edema. 3. If victim is not breathing, clear the airway of secretions and RESUSCITATE with positive poressure oxygen apparatus. If this is not available, use chest compression to sustain respiration. If victim is pulseless, employ cardiac resuscitation. 4. If PULMONARY EDEMA is evident, there are several measures avilable to sustain life. Medical judgement must be relied upon, however, in the management of each case. The following procedures are generally recommended: A. Put the victim in a SITTING position with a backrest. B. Use intermittent and/or continuous positive pressure OXYGEN to relieve hypoxemia. ... Slowly administer FUROSEMIDE, 40 mg, or SODIUM ETHACRYNATE, 50 mg, to reduce venous load by inducing diuresis. ... Morphine in small doses (5-10 mg), slowly, iv to allay anxiety and promote deeper respiratory excursions. Administer AMINOPHYLLINE (0.25-0.50 gm) slowly, iv. ... Digitalization may be considered, but there is a serious risk of arrhythmias in an anoxic and toxic myocardium. TRACHEOSTOMY may be necessary in some cases to facilitate aspiration of large amounts of pulmonary edema fluid. Epinephrine, atorpine, and expectorants are generally not helpful, and may complicate treatment. I. Watch for RECURRENT PULMONARY EDEMA, even up to 2 weeks after the initial episode. Limit victim's physical activity for at least 4 weeks. Severe physical weakness usually indicates persistent pulmonary injury. Serial pulmonary function testing may be useful in assessing recovery. 5. Combat SHOCK by placing victim in the Trendelenburg position and administering plasma, whole blood, and/or electrolyte and glucose solutions intravenously, with great care, to avoid pulmonary edema. Central venous pressure should be monitored continously. Vasopressor amines must be given with great caution, because of the irritability of the myocardium. 6. Control CONVULSIONS. Seizures are most likely to occur in poisonings by methyl bromide, hydrogen cyanide, acrylonitrile, phosphine, and carbon disulfide. ... /Fumigant poisoning/ [R25] *7. If a FUMIGANT LIQUID OR SOLID has been INGESTED less than several hours prior to treatment, quantities remaining in the stomach must be removed as effectively as possible by gastric intubation, aspiration, and lavage, after all possible precautions have been taken to protect the respiratory tract from aspirated gasric contents. A. Put in place a cuffed ENDOTRACHEAL TUBE prior to gastric intubation. Administer OXYGEN, using a mechanical ventilator if respiration is depressed. B. Lavage the stomach with a slurry of ACTIVATED CHARCOAL in saline or water. Leave a volume of the slurry in the stomach with an appropriate dose of sorbitol as cathartic ... . C. If treatment is delayed and if the patient remains fully alert, adminsiter activated charcoal and sorbitol orally. ... Repeated administration of charcoal at half or more the initial dosage every 2-4 hours may be beneficial. D. Do not given vegetable or animal fats or oils, which enhance gastrointestinal absorption of many of the fumigant compounds. 8. Intravenous infusions of GLUCOSE are valuable in limiting the heptotoxicity of many substances. Monitor central venous presure to avoid precipitating, or aggravating, pulmonary edema by fluid overlaod. The victim should be watched closely for indications of delayed or recurrent pulmonary edema, and for bronchophenumonia. Fluid balance should be monitored, and urine sediment should be checked regularly for indications of tubular injury. Measure serum alkaline phosphatase, LDH, ALT, AST, and bilirubin to assess liver injury. 9. HEMOPERFUSION OVER ACTIVATED CHARCOAL has been used in managing a case of carbon tetrachloride poisoning with apparent success. ... 10. EXTRACORPOREAL HEMODIALYSIS may be needed to regulate extracellular fluid composition if renal failure supervenes. It is probably not very effective in removing lipophilic fumigant compounds from blood, but is, of course, effective in controlling extracellular fluid composition if renal failure occurs. /Fumigant poisoning/ [R25] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . Cover skin burns with dry sterile dressings after decontamination ... . /Dichloropropane, dichloropropene, and related compounds/ [R26, 297] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in severe respiratory distress. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Consider drug therapy for pulmonary edema ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Dichloropropane, dichloropropene, and related compounds/ [R26, 298] *Stabilization: Treatment is largely supportive. Watch for respiratory depression and arrhythmias. Obtain arterial blood gases. Administer oxygen if there is evidence of altered mental status or dyspnea. Treat hypotension with volume expansion and vasopression. Use lidocaine or beta-blockers for ventricular arrhythmias. Skin: Remove contaminated clothing. Wash affected area with soap and copious amounts or water. Eye: Irrigate the eye for 15-20 min. Obtain a consultation if symptoms persist. Oral: Most of the halogenated solvents ingested in quantities of 1-2 swallows may be partially removed by ipecac-induced emesis if admin within a few hr to a patient who has not lost the gag reflex, is not seizing, is not markedly lethargic, or is not in coma. Observe the patient in the upright position to lessen the possibility of aspiration. Activated charcoal is probably ineffective. Inhalation: Move from the contaminated area. Provide a source of oxygen and prepare for mechanical ventilation. If the patient is unconscious and the pulse is absent, initiate CPR measures. Enhancement of Elimination: Maintain good ventilation. Hemodialysis or hemoperfusion are not likely to be useful because of the high lipophilic properties of these solvents. Antidote: N-acetylcysteine may restore depleted glutathione stores, but no adequate clinical studies are available to validate this possible treatment. Supportive Care: Watch for cardiac dysrhythmias, aspiration pneumonitis, hepatotoxicity, and hypoxic encephalopathy. Monitor for arrhythmia for at least 24 hr and for hepatorenal failure for about 3 days. Obtain a chest x-ray, arterial blood gas, EKG, serum creatinine, and hepatic aminotransferase. Check electrolyte imbalance daily. Treat renal failure with dialysis and hepatic failure with fresh frozen plasma, vitamin K, a low-protein diet, neomycin, and lactulose. Watch fluid and electrolyte balance. /Halogenated hydrocarbons/ [R27] HTOX: *Symptomatology: 1A) Inhalation, high vapor concn: gasping, refusal to breathe, coughing, substernal pain, and extreme respiratory distress at vapor concn over 1500 ppm. Irritation of eyes and upper respiratory mucosa appears promptly after exposure to concentrated vapors. Lacrimation and headache are prominent. Coma may occur rapidly. B) Inhalation, low vapor concn: central nervous depression and moderate irritation of respiratory system. Headache is frequent. 2) Dermal: severe skin irritation with marked inflammatory response of epidermis and underlying tissues. 3) Oral: acute gastrointestinal distress with pulmonary congestion and edema. Central nervous depression, perhaps even in the absence of impaired oxygen uptake. 4) By any route, possible late injuries to liver, kidneys and heart. 5) After inhalation exposures, malaise, headache, chest and abdominal discomfort and irritability have been reported to persist for several weeks and perhaps for several years. [R5, p. III-142] *THREE CASES REPORTED OF ADVERSE REACTION TO SOIL FUMIGANT D-D. FOLLOWING REPEATED APPLICATION, THE PATIENTS (ALL FARMERS) NOTED ERYTHEMATOUS, ITCHING ERUPTION FOLLOWING DIRECT CONTACT WITH SOLN. PATCH TESTS WITH 1% D-D MIXTURE IN ACETONE AS WELL AS WITH INDIVIDUAL COMPONENTS GAVE POS RESULTS ONLY IN 1 PATIENT. ALLERGIC PATIENT ALSO HAD POSITIVE PATCH TEST WITH DICHLOROPROPENE ALONE. [R28] *Intense irritation of eyes, skin, and resp mucosa. [R5, p. III-141] *Bronchospasm may result from inhalation of high concentrations. Liver, kidney, and cardiac toxicity is probably similar to that produced by carbon tetrachloride. /Dichloropropene and dichloropropane/ [R19] NTOX: *Dichloropropenes are highly toxic to mammals by ingestion and inhalation and moderately toxic by skin absorption. ... A mixture of dichloropropenes dissolved in propylene glycol proved lethal when applied for 24 hr under cuff on intact rabbit skin at a dose of 0.5 g/kg. In continued exposures, inhalation is the chief hazard. The symptoms abate promptly after respiratory exposure ceases. In animals, visceral lesions of liver, heart and kidney have been described. Unsaturation of aliphatic propyl derivatives predisposes to greater hepatic damage and higher acute toxicity. [R5, p. III-141] *IN A SERIES OF ALLYLIC CHLOROOLEFINS AND THEIR NON-ALLYLIC ISOMERS, THE SIGNIFICANCE OF THE ALLYLIC STRUCTURE AND THE INFLUENCE OF METHYL AND CHLORINE SUBSTITUENTS ON THE DIRECT MUTAGENIC ACTIVITY IN SALMONELLA TYPIMURIUM (TA100) WAS TESTED. THE DIRECT MUTAGENIC POTENTIALS CORRELATE WELL WITH THE ALKYLATING ACTIVITIES AS MEASURED IN THE NITROBENZYL-PYRIDINE (NBP) TEST. DICHLOROPROPENES WERE MORE DIRECTLY MUTAGENIC THAN ALLYL CHLORIDE. [R29] *The transforming ability of 6 epoxides of structurally related chloroalkenes was determined with a quantitative Syrian hamster embryo cell model. The epoxides used were cis-1-chloropropene oxide, trans-1-chloropropene oxide, cis-1,3-dichloropropene oxide, trans-1,3-dichloropropene oxide, trichloroethylene oxide, and tetrachloroethylene oxide. All six epoxides induced morphologic transformation of Syrian hamster embryo cells and caused cell lethality as reflected in the reduced cloning efficiency; in all instances, transformation was observed with < 25% toxicity. The potency of the various epoxides was influenced by the difference in stability of the compounds. The results with cis-1,3-chloropropene oxide, trans-1-chloropropene oxide, trichloroethylene oxide, and tetrachloroethylene oxide were consistent with a linear dose response. The transformation results reflect the carcinogenicity of the parental chloroalkenes tested thus far. If the epoxides are metabolic intermediates of the chloropropene parent chloropropenes, the epoxides are probably proximate carcinogens. [R30] *The subchronic reproductive toxicity of DD, a mixture of 1,3-dichloropropene and 1,2-dichloropropane, was studied in rats. Wistar rats were exposed by inhalation to 0, 10, 30, or 90 ppm DD 6 hr daily 5 days a wk for 10 wk. Selected male rats from each exposure group were mated with unexposed virgin females during wk 3, 5, 8, and 10 of exposure. On the 12th day after mating, each female was killed and examined for numbers of corpora lutea, uterine implantation, and resorption sites. After the 10 wk exposure period, selected females from each exposure group were mated with unexposed males. Gestation lengths were recorded. After delivery, the number of live and dead pups was recorded on postnatal days 0, 1, and 4. The litters were weighed on postnatal days one and four. Other animals were killed 10 to 22 hr, 5 wk, or 7 wk after exposure ended and necropsied. Semen samples were examined for sperm abnormalities. Vaginal smears were taken and stained to evaluate estrus cycle activity. DD exerted no adverse effects on sperm morphology or estrus cycling activity. None of the measured reproductive parameters were affected by DD. Kidney and liver weights were slightly increased in rats of either sex exposed to 90 ppm DD. No other treatment related gross or histopathologic changes were seen. [R31] *Rats, guinea pigs, and rabbits were exposed to 1 or 3 ppm of Dichloropropene, 7 hr per day for 125 to 130 days over a 180 day period. Hematological studies were run midway and near the end of the study. No changes which could be attributed to the treatment were seen in hematocrit, white blood cell, hemoglobin, or differential count. The only effects ... described which could be attributed to treatment were cloudy swelling of renal tubular epithelium in male rats and an increase in liver/body ratio in female rats. Some rats were also allowed a 3 mo recovery period. After this time, no changes attributable to treatment were observed. /Dichloropropene/ [R32] *Dichloropropene was mutagenic to Salmonella typhimurium TA 1535 AND TA 100 but not the TA 1978, TA 1538, or TA 98. Mutagenicity was the same with or without the addition of liver microsomal fraction. /Dichloropropene/ [R33] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dichloropropenes' production and use as soil fumigants, in organic synthesis, and occurrence as impurities in some pesticide formulations result in their direct release to the environment. If released to air, a vapor pressure of 24 mm Hg at 25 deg C indicates dichloropropene will exist solely as a vapor in the ambient atmosphere. Vapor-phase dichloropropene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 3 days. The half-life for the reaction in air with ozone is estimated to be 49 days. Dichloropropene is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). If released to soil, dichloropropene is expected to have high mobility based upon an estimated Koc of 59. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 1.3X10-3 atm-cu m/mole. Dichloropropene may volatilize from dry soil surfaces based upon its vapor pressure. The biochemical half-life for the pesticide dichloropropene in soil has been reported to be 16 days. If released into water, dichloropropene is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1 hr and 4 days, respectively. Using distilled river water, a hydrolysis half-life of 11 days at a temperature range of 15 to 25 deg C has been reported for the pesticide formulation. An estimated BCF of 7 suggests the potential for bioconcentration in aquatic organisms is low. Occupational exposure to dichloropropenes may occur through inhalation and dermal contact with these compounds at workplaces where dichloropropenes are produced or used. Monitoring data indicate that the general population may be exposed to dichloropropenes via inhalation of ambient air in the immediate vicinity during application of dichloropropene-based pesticides. (SRC) ARTS: *... Dichloropropenes can enter the aquatic environment as a discharge from industrial effluents, by runoff from agricultural land, and from municipal effluents. [R34] *Dichloropropenes' production and use as soil fumigants(1), in organic synthesis(2), and occurrence as impurities in some pesticide formulations(3) result in their direct release to the environment(SRC). [R35] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 59(SRC), determined from a water solubility of 2,700 mg/l(2) and a regression-derived equation(3), indicates that dichloropropene is expected to have high mobility in soil(SRC). Volatilization of dichloropropene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 1.3X10-3 atm-cu m/mole(SRC), using a fragment constant estimation method(4). The potential for volatilization of dichloropropene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 24 mm Hg(5). The biochemical half-life for the pesticide dichloropropene in soil has been reported to be 16 days(6). [R36] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 68(SRC), determined from a water solubility of 2,700 mg/l(2) and a regression-derived equation(3), indicates that dichloropropene is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces may occur(3) based upon an estimated Henry's Law constant of 1.3X10-3 atm-cu m/mole(SRC), derived from its vapor pressure, 24 mm Hg(4), and water solubility, 2,700 mg/l(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1 and 101 hours, respectively(SRC). Using distilled river water, a hydrolysis half-life of 11 days at a temperature range of 15 to 25 deg C has been reported for the pesticide formulation(7). According to a classification scheme(5), an estimated BCF of 18(SRC), from an estimated log Kow 2.53(SRC) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R37] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dichloropropene, which has a vapor pressure of 24 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase dichloropropene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 3 days(SRC), calculated from its rate constant of 3.9X10-12 cu cm/molecule-sec at 25 deg C(SRC) determined using a structure estimation method(3). Dichloropropene is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm). [R38] BIOD: *Soil-water cultures converted dichloropropene to 3-chloroallyl alcohol. Further studies with a Pseudomonad indicated that the trans-3-chloroallyl alcohol was converted to the trans-3-chloroacrylic acid and then to formylacetic acid. The latter is then decarboxylated. [R39] *AEROBIC: The biochemical half-life for the pesticide dichloropropene in soil has been reported to be 16 days(1). [R40] ABIO: *Dichloropropenes have been shown to undergo photochemical formation of free radicals. [R41] *The rate constant for the vapor-phase reaction of dichloropropene with photochemically-produced hydroxyl radicals has been estimated as 4X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half- life of about 32 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of dichloropropene with ozone molecules has been estimated as 0.023X10-17 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to atmospheric half-life of about 49 days at an atmospheric concentration of 7X10+11 hydroxyl radicals per cu cm(2). Dichloropropenes have been shown to undergo photochemical formation of free radicals(3). Using distilled river water, a hydrolysis half-life of 11 days at a temperature range of 15 to 25 deg C has been reported, with 2-3% CO2 production noted after 7 days for the pesticide formulation(4). [R42] BIOC: *An estimated BCF of 7 was calculated for dichloropropene(SRC), using a water solubility of 2,700 mg/l(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R43] KOC: *The Koc of dichloropropene is estimated as 59(SRC), using a water solubility of 2,700 mg/l(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that dichloropropene is expected to have high mobility in soil. [R44] VWS: *In the nonaquatic environment, movement of dichloropropene and dichloropropane in the soil results from diffusion in the vapor phase, as these cmpd tend to establish an equilibrium between concn in vapor, water, and adsorbing phases. [R45] *The Henry's Law constant for dichloropropene is estimated as 1.3X10-3 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that dichloropropene is expected to volatilize from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1 hour(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 4 days(SRC). Dichloropropene's Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of dichloropropene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 24 mm Hg(3). [R46] WATC: *GROUNDWATER: Samples from municipal wells in areas of CA where Telone or D-D has been applied for over 15 yr (54 wells in 5 counties, 65-1200 ft deep): not detected at a quantitation limit of 0.1 ppb(1). Dichloropropene was detected in one of seventeen wells in New York at a concentration range of 18-140 ug/l(2). [R47] *DRINKING WATER: Dichloropropene has been identified in New Orleans drinking water(1). Dichloropropene was detected at unreported concentrations in Philadelphia drinking water by GC/MS analysis(2). [R48] EFFL: *Effluent concentrations reported in the USEPA's STORET data base, 1980-1982 (153 samples) 0% pos(1). Dichloropropenes were identified at 1 site in industrial effluent entering the St. Clair River - Sarnia, Ontario(2). Of 63 industrial effluents analyzed, 1 contained concn < 10 ppb of dichloropropene(3). Dichloropropene has been detected in wastewater from organic chemical manufacturing/plastics (79 ppb, mean)(6). National Urban Runoff Program in which 86 samples from 19 cities throughout the US were analyzed reported that dichloropropene was detected only in Eugene, OR 1-2 ppb, 2% frequency of detection nationwide(4). cis-1,3-Dichloropropene was detected in 1 out of 5 municipal landfill leachate samples in WI, concn 18 ppb, but not detected in 6 municipal landfill leachates in MN(5). [R49] *Dichloropropene was detected at a concentration range of 0.05-0.183 mg/l in a mixed locational sample of industrial landfill leachate(1). [R50] ATMC: *RURAL/REMOTE: Dichloropropene was tested for but not detected in 7 samples from the Grand Canyon, AZ(1). [R51] *URBAN/SUBURBAN: 2 of 11 samples from Baton Rouge, LA were pos for dichloropropene, with concns of trace and 2.2 parts per trillion, isomer not specified(1). [R52] *SOURCE DOMINATED: Dichloropropene was detected in 16 US samples at a concn of 7.3 parts per median, 570 parts per trillion max for all dichloropropene isomers(1). [R51] FOOD: *Dichloropropene was detected in one of eight human mother's milk samples at an unreported concentration(1). Dichloropropene was detected at a maximum concentration of 160 ug/cu m and a mean concentration of 24 ug/cu m at 4 different sweet potato/sugar beet crop sites in California(2). [R53] PFAC: FISH/SEAFOOD CONCENTRATIONS: *Biota concentrations for dichloropropene as reported in the USEPA's STORET data base from 1980-1982 were 0% positive for 35 samples(1). [R54] MILK: *Dichloropropene was detected in one of 8 samples of mother's milk from 4 urban areas in the US but the isomer was not specified(1). [R55] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 158 workers are potentially exposed to dichloropropene in the US(1). The NOES Survey does not include farm workers. Occupational exposure to dichloropropene may occur through inhalation and dermal contact with this compound at workplaces where dichloropropenes are produced or used(SRC). Monitoring data indicate that the general population may be exposed to dichloropropene via inhalation of ambient air in the immediate vicinity during application of dichloropropene-based pesticides(SRC). [R56] BODY: *Dichloropropene was detected in one of 8 samples of mother's milk from 4 urban areas in the US but the isomer was not specified(1). [R55] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Dichloropropene is produced, as an intermediate or a final product, by process units covered under this subpart. [R57] WSTD: STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 87 ug/l [R58] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. [R59] +Dichloropropene is designated as a hazardous substance under section 311(b)(2)(A) of the Federal Water Pollution Control Act and further regulated by the Clean Water Act Amendments of 1977 and 1978. These regulations apply to discharges of this substance. This designation includes any isomers and hydrates, as well as any solutions and mixtures containing this substance. [R60] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 100 lb or 45.4 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). [R61] TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1-Propene, dichloro- is included on this list. [R62] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Absorptive pads of charcoal cloth were developed and tested for monitoring the deposition of volatile toxic materials on skin. The dosimeters can retain over 60% of volatile deposits such as dichloropropene droplets over an 8 hr workday. Evaporation from liquid deposits and vapor adsorption onto the dosimeters are factors which can complicate the interpretation of exposure data. Evaporation was inversely proportional to the log of the deposit size (volume), vapor pressure, and the air humidity. Vapor adsorption was proportional to the vapor concn exposure duration, and the log of air velocity. A procedure for estimating the initial size of the liquid deposit from retained mass involves an equation requiring knowledge of the retention efficiency and vapor adsorption. The accuracy and precision of the charcoal cloth dosimeter are optimal in situations involving possible dermal exposure to toxic materials with low to moderate volatility or with low vapor concn. For 1,3-dichloropropene on charcoal cloth the total loss was 33.7%; long term loss, 7.2%; mean retention, 63.5%; and total recovery, 96.6%. Retention efficiency at 80% humidity, wind velocity of 570 fpm, and dose of 3 ul/l was 65.4% observed (67.1% expected) and at a dose of 10 ul/l, 50.8% observed (62.1% expected). [R63] ALAB: *EPA Method 8240. Gas Chromatography/Mass Spectrometry for the determination of volatile organics. This method can be used to quantify most volatile organic compounds including dichloropropene, that have boiling points below 200 deg C and are insoluble or slightly soluble in water. The detection limit is not given. Precision and method accuracy were found to be directly related to the concentration of the analyte and essentially independent of the sample matrix. [R64] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Telone II ((Technical-Grade 1,3-Dichlorpropene Containing 1.0% Epichlorhydrin as a Stabilizer) in F344/N Rats and B6C3F1 Mice (Gavage Studies) Report #269 (1985) NIH Pub# 85-2525 Dangerous Prop Ind Mater Rep 6 (4): 63-70 (1986). Reviews dichloropropene safety, toxicology and health hazards. SO: R1: Sittig, M. (ed.) Pesticide Manufacturing and Toxic Materials Control Encyclopedia. park Ridge, NJ: Noyes Data Corporation. 1980. 291 R2: OSTERLOH JD ET AL; ARCH ENVIRON HEALTH 39 (4): 271-275 (1984) R3: Farm Chemicals Handbook 1991. Willoughby, OH: Meister, 1991.,p. C-253 R4: USEPA; PRELIMINARY QUANTITATIVE USAGE ANALYSIS OF DICHLOROPROPENE (1984) R5: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984. R6: Farm Chemicals Handbook 1992. Willoughby, OH: Meister Publishing Co., 1992.,p. C-113 R7: HORTLOFF RC; PRELIMINARY QUANTITIATIVE USAGE ANALYSIS OF DICHLOROPROPENE (1984) R8: USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-1 (1980) R9: HORTLOFF RC; PRELIMINARY QUANTITATIVE USAGE ANALYSIS OF DICHLOROPROPENE (1984) R10: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, D.C.: Assoc. of American Railroads, Hazardous Materials Systems (BOE), 1987.246 R11: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 484 R12: Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) R13: Weinjnen PHC et al; Sorption of Pesticides by Aquifer Materials: Batch Experiments. Bilthoven, Netherlands: Natl Inst Pub Health Environ Prot. Report RIVM-72862004. NTIS PB90-248295 (1989) R14: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 183 R15: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-132 R16: Roytech/SOCMA Suspect Chemicals Source Book. 4th ed. Burlingame, CA: Roytech Publications, 1985.,p. IV-284 R17: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 358 R18: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1124 R19: Morgan DP; Recognition and Management of Pesticide Poisonings. 4th ed. p.134 EPA 540/9-88-001. Washington, DC: U.S. Government Printing Office, March 1989 R20: ACGIH; Guidelines Select of Chem Protect Clothing Volume #1 Field Guide p.49 (1983) R21: 49 CFR 171.2 (7/1/2000) R22: IATA. Dangerous Goods Regulations. 42nd Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2001. 149 R23: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3330 (1998) R24: World Health Organization/International Programme on Chemical Safety. Environmental Health Criteria 146 1,3-Dichloropropene, 1,2-Dichloropropane and Mixtures. pp. 167-170 (1993) R25: Morgan DP; Recognition and Management of Pesticide Poisonings. 4th ed. p.138 EPA 540/9-88-001. Washington, DC: U.S. Government Printing Office, March 1989 R26: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R27: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1439 R28: NATER JP, GOOSKENS VHJ; CONTACT DERMATITIS 2 (4): 227-9 (1976) R29: NEUDECKER T ET AL; BIOCHEM PHARMACOL 29 (19): 2611-8 (1980) R30: Dipaolo JA, Doniger J; J Natl Cancer Inst 69 (2): 531-34 (1982) R31: Linnett SL et al; Fundam and Appl Toxicol 10 (2): 214-23 (1988) R32: USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.C-19 (1980) R33: USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.C-20 (1980) R34: Dowty B; Science 87: 75 (1975) as cited in USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-5 (1980) R35: (1) Farm Chemicals Handbook 2001. Willoughby, Ohio: Meister p. C 137 (2001) (2) Lewis RJ Sr, ed; Hawley's Condensed Chemical Dictionary. 13th ed p. 367 (1997) (3) Zebarth BJ et al; Water Qual Res J Canada 33: 31-50 (1998) R36: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ AZ, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-5 (1990) (4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (5) Weinjnen PHC et al; Sorption of Pesticides by Aquifer Materials: Batch Experiments. Bilthoven, Netherlands: Natl Inst Pub Health Environ Prot. Report RIVM-72862004. NTIS PB90-248295 (1989) (6) Jury WA et al; J Environ Qual 16: 422-8 (1987) R37: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ Az, College of Pharmacy (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Weinjnen PHC et al; Sorption of Pesticides by Aquifer Materials: Batch Experiments. Bilthoven, Netherlands: National Institute of public Health and Environmental Protection. Report RIVM-72862004. NTIS PB90-248295 (1989) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) Canton JH et al; Catch-up operation on old pesticides: an integration. Bilthoven, The Netherlands: Rijkinst Volksgezodh Milieuhyg RIVM-678801002. NTIS PB92-105063. pp. 149 (1991) R38: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Weinjnen PHC et al; Sorption of Pesticides by Aquifer Materials: Batch Experiments. Bilthoven, Netherlands: Natl Inst Pub Health Environ Prot. Report RIVM-72862004. NTIS PB90-248295 (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R39: Menzie, C. M. Metabolism of Pesticides, An Update. U.S. Department of the Interior, Fish, Wild-life Service, Special Scientific Report - Wildlife No. 184, Washington, DC: U.S. Government Printing Office, l974.134 R40: (1) Jury WA et al; J Environ Qual 16: 422-8 (1987) R41: Richerzhagen T; J Phys Chem 77: 1819 (1973) as cited in USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-1 (1980) R42: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Atkinson R, Carter WPL; Chem Revies 84: 437-70 (1984) (3) Richerzhagen T; J Phys Chem 77: 1819 (1973) as cited in USEPA; Ambient WaterQuality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-1 (1980) (4) Canton JH et al; Catch-up operation on old pesticides: an integration. Bilthoven, The Netherlands: Rijkinst Volksgezodh Milieuhyg RIVM-678801002. NTIS PB92-105063. pp. 149 (1991) R43: (1) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ AZ, College of Pharmacy (1992) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R44: (1) Yalkowsky SH, Dannenfelser RM; The AQUASOL dATAbASE of Aqueous Solubility. Fifth Ed, Tucson, AZ: Univ AZ, College of Pharmacy (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-5 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R45: Leistra M; J Agric Food Chem 18: 1124 (1970) as cited in USEPA; Ambient Water Quality Criteria Doc: Dichloropropanes/Dichloropropenes (Draft) p.A-3 (1980) R46: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Weinjnen PHC et al; Sorption of Pesticides by Aquifer Materials: Batch Experiments. Bilthoven, Netherlands: Natl Inst Pub Health Environ Prot. Report RIVM-72862004. NTIS PB90-248295 (1989) R47: (1) Maddy KT et al; Bull Environ Contam Toxicol 29: 354-9 (1982) (2) USEPA; Pesticides in Groundwater Database. USEPA Off Pest Programs. Prevention Pesticides and Toxic Substances. (H7507C) USEPA-734-12-92-001 (1992) R48: (1) Dowty B et al; Science 187: 75-7 (1975) (2) Suffet IH et al; Water Research 14: 853-867 (1980) R49: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) (2) Konasewich D et al; Status Report on Org and Heavy Metal Contam in the Lakes Erie, Michigan, Huron and Superior Basins, Great Lake Water Quality Board (1978) (3) Perry DL et al; Identification of Organic Compounds in Industrial Effluent Discharges, USEPA-600/4-79-016 (1979) (4) Cole RH et al; J Water Pollut Control Fed 56: 898-908 (1984) (5) Sabel GV, Clark TP; Waste Manag Res 2: 119-30 (1984) (6) USEPA; Treatability Manual I.12.14-1 to I.12.14-5 USEPA-600/282-001A (1981) R50: (1) Brown KW, Donnelly KC; Hazardous Waste and Hazardous Materials 5: 1-30 (1988) R51: (1) Brodzinsky R, Singh NB; Volatile Org Chem in the Atmos USEPA-600/53-83-021 (1982) R52: (1) Pellizzari ED et al; Formulation of Prelim Assess of Halogenated Organ Compounds in Man and Environ Media USEPA-560/13-79-006 (1979) R53: (1) Erickson MD et al; Acquisition and Chemical Analysis of Mother's Milk for Selected Toxic Substances USEPA-560/13-80-029 (1980) (2) Baker LW et al; Environ Sci Technol 30: 1365-1368 (1996) R54: (1) Staples CA et al; Environ Toxicol Chem 4: 131-42 (1985) R55: (1) Pellizzari ED et al; Environ Contam Toxicol 28: 322-8 (1982) R56: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R57: 40 CFR 60.489 (7/1/2000) R58: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R59: 40 CFR 401.15 (7/1/2000) R60: 40 CFR 116.4 (7/1/2000) R61: 40 CFR 302.4 (7/1/2000) R62: 40 CFR 716.120 (7/1/2000) R63: Cohen BM, Popendorf W; Am Ind Hyg Assoc J 50 (4): 216-23 (1989) R64: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) RS: 55 Record 345 of 1119 in HSDB (through 2003/06) AN: 6313 UD: 200303 RD: Reviewed by SRP on 9/24/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PENTAERYTHRITOL-TETRANITRATE- SY: *Angicap-; *Angitet-; *Antora-; *Arcotrate-; *Baritrate-; *2,2-Bisdihydroxymethyl-1,3-propanediol-tetranitrate-; *2,2-Bis(hydroxymethyl)-1,3-propanediol tetranitrate; *2,2-Bis((nitrooxy)methyl)-1,3-propanediol dinitrate (ester); *Cardiacap-; *CHOT-; *Deltrate-20-; *Dilcoran-80-; *1,3-Dinitrato-2,2-bis(nitratomethyl)propane; *Dipentrate-; *EL-PETN-; *Erinit-; *Extex-; *Hasethrol-; *Kaytrate-; *Lentrat-; *Lowetrate-; *Martrate-45-; *Metranil-; *Mycardol-; *Myotrate-"10"-; *NCI-C55743-; *Neo-corovas-; *Neopentanetetrayl-nitrate-; *Niperyt-; *Niperyth-; *Nitropenta-; *Nitropentaerythrite-; *Nitropentaerythritol-; *Nitropenton-; *Pencard-; *Pentaerythrite-tetranitrate-; *Pentaerythritol,-tetranitrate-; *Pentaerythritol-tetranitrate,-diluted-; *Pentaerythrityl-tetranitrate-; *Pentafin-; *Pentanitrine-; *Pentanitrol-; *Pentestan-80-; *Pentetrate-unicelles-; *Penthrit-; *Penthrite-; *Pentitrate-; *Pentral-80-; *Pentrate-; *Pentriol-; *Pentrite-; *Pentryate-; *Pentryate-80-; *Pergitral-; *Peridex-; *Peridex-LA-; *Peritrate-; *Perityl-; *PET-; *PETN-; *Prevangor-; *1,3-Propanediol, 2,2-bis((nitrooxy)methyl)-, dinitrate (ester); *Quintrate-; *Rythritol-; *SDM-No-23-; *SDM-No-35-; *Subicard-; *Tanipent-; *TEN-; *Tentrate-20-; *Terpate-; *Tetranitropentaerythrite-; *Tetrasule-; *Tranite-D-lay-; *Vasitol-; *Vaso-80-; *Vasodiatol-; *Vasolat-; *Vaso-80-unicelies-; *XTX-8003- RN: 78-11-5 MF: *C5-H8-N4-O12 SHPN: UN 0411; Pentaerythrite tetranitrate, with not less than 7% wax, by weight. UN 0150; Pentaerythrite tetranitrate, desensitized with 15% or more phlegmatizer, by weight; Pentaerythrite tetranitrate, wetted with not less than 25% water, by weight. UN 0150; Pentaerythrite tetranitrate, wetted with not less than 25% water, by weight. HAZN: D003; A waste containing pentaerythritol tetranitrate may (or may not) be characterized a hazardous waste following testing for the reactivity characteristics as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Generally manufactured by the reaction of pentaerythritol with nitric acid. ... [R1] FORM: *For medicinal purposes it is dil with an inert ingredient, usually lactose, to prevent accidental explosions. [R2] *Available in ... 20 and 40 mg tablets for sublingual use and in 30, 45, 60 ... mg sustained-release capsules. [R3] *The drug is diluted with ... mannitol, or other suitable inert excipients to permit safe handling. ... Capsules, extended-release: 30 mg Duotrate Plateau Caps, Marion; 45 mg Duotrate-45 Plateau Caps, Marion; 80 mg Peritrate SR, Parke-Davis; Tablets: 10 mg Peritrate, Parke-Davis; 20 mg Peritrate (scored), Parke-Davis; 40 mg Peritrate (scored), Parke-Davis; Tablets, extended-release: 80 mg Peritrate SA, Parke-Davis; Pentaerythritol tetranitrate is also commercially available in combination with ethaverine and sedatives. [R2] OMIN: *In a mixture with TNT it is used for loading small caliber projectiles and grenades as well as booster charges. [R4] USE: *Mainly in the manuf of detonating fuse (Primacord), a waterproof textile filled with powdered PETN. [R2] *Demolition explosive; blasting caps [R5] *MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Tetragonal holohedra from acetone + alcohol [R2]; *White crystalline [R5]; *Prisms (acetone-alcohol) [R6] ODOR: *Faint, mild odor [R7] BP: *180 deg C at 50 mm Hg [R4] MP: *140 deg C [R2] MW: *316.15 [R2] DEN: *1.773 at 20 deg C/4 deg C [R2] OWPC: *log Kow= 1.61(est) [R8] SOL: *Sparingly sol in alcohol, ether [R2]; *Sol in benzene [R6]; *4.3 mg/100 g water (25 deg C); 25.4 g/100 g acetone (20 deg C); slightly sol in most organic solvents. [R4]; *Water solubility of 43 mg/l at 25 deg C(measured) [R9] SPEC: *IR: 5115 (Coblentz Society Spectral Collection) [R10]; *MASS: 233 (Aldermaston, Eight Peak Index of Mass Spectra, UK) [R10] VAP: *Vapor pressure of 1.035X10-10 mm Hg at 25 deg C(exp) [R11] OCPP: *Does not reduce Fehling's soln (difference from erythritol tetranitrate) [R2] *White to ivory colored powder; a faint, mild odor. /Diluted pentaerythritol tetranitrate/ [R7] *The Henry's Law constant for PETN can be estimated to be approximately 1.2X10-11 atm-cu m/mole at 25 deg C. [R9] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EXPL: *Explodes on percussion; more sensitive to shock than TNT. [R2] *... Detonates at 210 deg C. [R5] REAC: *Pentaerythrityl tetranitrate may explode when heated strongly, even when dissolved. [R12] DCMP: *Decomposes above 150 deg C [R5] OHAZ: *... The undiluted compound may explode upon percussion or on exposure to heat. [R13] SERI: *Patch tests in 20 persons gave no evidence of skin irritation ... . [R4] OPRM: *... The controls and good housekeeping necessary to prevent explosions from this shock-sensitive material should be adequate to prevent injurious effects in workers. [R4] SSL: *Although PETN safely withstands storage for 18 mo at 65 deg C, continued storage has marked effects of instability; the presence of as little as 0.01% free acid or alkali in PETN markedly accelerates its deterioration. It is the least stable of the standard military bursting charge explosives. [R4] *Loss of potency is accelerated by exposure to heat and moisture. [R14] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R15] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R16] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R17] STRG: *Store below 40 deg C (104 deg F), preferably between 15 and 30 deg C (59 and 86 deg F), unless otherwise specified by manufacturer. Store in a tight container. [R14] *Store in a cool place in a airtight container. Protect from light. [R13] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number D003, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R18] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Initial attention should be directed toward improving oxygen delivery with assisted ventilation, if necessary, and 100% oxygen while intravenous methylene blue is prepared. Institute cardiac monitoring, especially in patients with coronary artery or pulmonary disease. Hypotension should respond to Trendelenburg's position and intravenous fluids. Otherwise, dopamine may be needed. ... Use syrup of ipecac for alert patients and lavage for obtunded patients who ingest methemoglobin forming agents and present within 2-4 hours of ingestion. ... Exchange transfusion and/or the transfusion of packed red blood cells may be useful for methylene blue failures or for patients with known G6PD or NADPH methemoglobin reductase deficiencies. The inherent risks of the large blood volumes required in adults limit the applicability of this method. The usual dose of methylne blue is 1-2 mg/kg (25-50 mg/sq m) of a 1% solution (10 mg/ml) intravenously over 5 minutes. ... The same dose may be repeated within 1 hour if symptoms of hypoxia fail to subside. The administration of ascorbic acid (100-500 mg twice daily either orally or intravenously) is harmless but probably has a minor effect on increasing methemoglobin reduction. /Methemoglobin forming agents/ [R19] HTOX: *Patch tests in 20 persons gave no evidence of skin irritation or sensitization. Although some cases of mild illness and dermatitis have been attributed to contact with PETN in ordnance plants, it is apparent that PETN is relatively nontoxic ... . [R4] *Individuals taking the drug may experience headache and episodes of dizziness and weakness from postural hypotension ... . Rarely severe responses are encountered, consisting of nausea, vomiting, weakness, pallor, sweating and collapse, but no reports of death were found. [R3] *Symptomatology 1. A prompt fall in blood pressure. 2. A roaring sound in the ears, a headache which is persistent and throbbing, with associated vertigo, a generalized tingling sensation, palpitations, and visual disturbances. 3. The skin is flushed and perspiring, later cold and cyanotic. 4. Nausea and vomiting. The ingestion of nitrites may also cause colic and diarrhea. 5. Syncope, esp when attempting to stand upright. 6. Methemoglobinemia, with attendant cyanosis and anoxia. 7. Hyperpnea; later dyspnea and slow breathing. 8. The pulse may be slow, dicrotic, and intermittent. 9. Incr intraocular tension and intracranial pressure. 10. Collapse and coma, followed by clonic convulsions. 11. Death due to circulatory collapse. /Nitrite/ [R3] *... In tests on patients with open angle glaucoma and white eyes subject to angle closure glauocoma produced no elevation of intraocular pressure when an ordinary amount of drug was given by mouth as in the treatment of angina pectoris. [R20] *A 63 year old man who had taken pentaerythritol tetranitrate and glyceryl trinitrate for 8 years developed extensive erythroderma due to the drugs. The condition regressed when the drugs were withdrawn but reappeared after separate challenge doses of each drug. [R13] *Cutaneous sensitivity to PETN has been reported in humans and appears to be a common effect of exposure to all organic nitrates. [R21] *Toxicity associated with organic nitrate exposure is generally secondary to cardiovascular effects. Symptoms of headache /in munitions workers/ and weakness, dizziness, and other manifestations of cerebral ischemia associated with postural hypotension may develop. [R21] NTOX: *The daily oral admin of 2 mg/kg for 1 yr caused no effects on growth, hematology, or pathology in rats. [R4] *Pentaerythritol mononitrate was reported to induce gene mutations in the Escherichia coli bacteriophage T4B, but the completely denitrated metabolite pentaerythritol was negative when tested for gene reversion in Escherichia coli and Salmonella typhimurium at doses up to 5 mg/plate. [R21] *Pentaerythritol PETN was reported to be negative for induction of mitotic recombination when tested in Saccharomyces cerevisiae D3. [R21] NTP: *In 2 year feed studies to 5% of the diet, the 2 year studies were conducted by administering 0, 25,000, or 50,000 ppm pentaerythritol tetranitrate: D-lactose monohydrate 1:4, in feed for 104 weeks to groups of 50 male rats and for 103 weeks to groups of 49 or 50 mice of each sex. Groups of 50 female rats were given feed containing 0, 6,200, or 12,500 ppm pentaerythritol tetranitrate: D-lactose monohydrate 1:4, for 104 weeks. Mean body weights of high dose male rats were 2%-9% lower than those of controls throughout the study; body weights of all groups of female rats were similar. No significant differences in survival were observed between any groups of rats of either sex ... . Mean body weights of dosed and control mice were similar. The survival of both groups of dosed male mice was significantly greater than that of the controls ... . No significant differences in survival were observed between any groups of female mice ... . No nonneoplastic lesions were attributed to pentaerythritol tetranitrate: D-lactose monohydrate 1:4, administered in rats or mice. Neoplasms of the Zymbal gland occurred in dosed male (control, 0/49; low dose, 3/45; high dose, 2/41) and dosed female (0/36; 1/37; 3/35) rats. The historical incidence of these neoplasms is 1% + or - 2% in untreated males and 0.6% + or - 1% in females. ... At no site was a significantly increased incidence of neoplasms observed in dosed male or female mice. [R22] *Pentaerythritol tetranitrate was found not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with or without exogenous metabolic activation (S9). [R23] *When testedfor cytogenetic effects in cultured Chinese hamster ovary cells, pentaerytyritol tetranitrate induced sister chromatid exchanges in the presence and absence of metabolic activation; no induction of chromosomal aberrations was observed in Chinese hamster ovary cells with or without activation. [R23] ADE: *During the first 4 hr after ... /pentaerythritol tetranitrate/ admin /in man/ ... there were significant blood levels of pentaerythritol dinitrate. [R24, 173] *Absorbed slowly from intestines and lungs, not appreciably through skin. [R3] *Following oral admin of (14)Carbon labeled pentaerythritol tetranitrate in one study in fasting subjects, 60% and 50% of a 20 mg and 40 mg dose, respectively, were absorbed. Following oral admin of the drug in a tablet form, the onset of hemodynamic effects is about 20-60 min and the duration of action is 4-5 hr. [R25] *Pentaerythritol tetranitrate is absorbed from the gastro-intestinal tract, and to some extent from the oral mucosa. It has been reported to be absorbed through intact skin. [R13] *In 15 healthy men given 20 or 40 mg of radioactive pentaerythritol tetranitrate, radioactivity was detected in the blood within 15 minutes, with peak concentrations 4 to 8 hours after the dose. The tetranitrate and trinitrate were not detected in the blood; pentaerythritol and pentaerythritol mononitrate were the principal metabolites, with traces of the dinitrate. Of the 20 mg and 40 mg doses 32 and 41% respectively were eliminated in the feces partly as unchanged tetranitrate. About 60% of the 20 mg dose and 50% of the 40 mg dose were recovered in the urine in 48 hours, chiefly as pentaerythritol and the mononitrate. The proportion of pentaerythritol to mononitrate after the 20 mg dose was 1:1 compared with 1:3 after the 40 mg dose, possibly indicating a limiting rate of deesterification of the mononitrate. [R13] METB: *Rapid de-esterfication of pentaerythritol tetranitrate after po dosing to man resulted in measurable serum levels of pentaerythritol, pentaerythritol pentaerythritol mononitrate, and small amt of the dinitrate, but no unchanged drug. The kinetics of urinary excretion of pentaerythritol tetranitrate were first-order and dose-dependent. The ratio of mononitrate to pentaerythritol excreted in urine was 3:1 from a 40 mg dose and 1:1 from a 20 mg dose, suggesting a limited capacity for conversion of pentaerythritol mononitrate into pentaerythritol. [R24, 446] *The main metabolites were found to be pentaerythritol and the mononitrate ester; unchanged drug was recovered from feces only, suggesting a partial hydrolysis mediated by the intestinal microflora to be necessary prior to absorption /in man/. [R26] *Pentaerythritol tetranitrate is metabolized primarily to ... pentaerythritol trinitrate (pertrinitrol) ... . The trinitrate, dinitrate, and mononitrate metabolites may undergo glucuronide conjugation. The plasma half-life of pentaerythritol trinitrate, which is therapeutically active, is about 10 min. The other metabolites are inactive. [R7] ACTN: *The nitrates reduce myocardial oxygen requirements through their effects on the systemic circulation. Their systemic actions include (1) a reduction in venous tone, which leads to pooling of blood in peripheral veins, decr venous return, and reduced ventricular volume and myocardial tension (preload); and (2) a decr in peripheral vascular resistance, which reduces arterial blood pressure and ventricular outflow resistance (afterload). /Nitrates/ [R27] *Antianginal or cardiac load reducing agent: Antianginal or cardiac load reducing agent: /Mechanism of action/ not specifically known but thought to cause a reduction of myocardial oxygen demand. This is attributed to a reduction in left ventricular preload and afterload because of venous (predominantly) and arterial dilation with a more efficient redistribution of blood flow within the myocardium. Antihypertensive: Peripheral vasodilation. /Nitrates (systemic)/ [R28] INTC: *The chronic admin of long acting nitrates had been reported to produce tolerance, thus decr the therapeutic effect of subsequently admin nitroglycerin. ... A pharmacologic study of ten patients demonstrated that a partial tolerance to nitroglycerin developed after as little as one week of pentaerythritol tetranitrate therapy. /Nitroglycerin interactions/ [R29] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Vasodilator Agents [R30] *Pentaerythritol tetranitrate is admin orally. The drug should be admin at least 30 min before or 1 hr after meals. Dosage must be carefully adjusted according to the patient's requirements and response. For the long-term prophylactic management of angina pectoris, the usual initial dosage ... is 10-20 mg 3 or 4 times daily. If necessary, dosage is incr gradually up to 40 mg 4 times daily. Alternatively, 30-80 mg of the drug in an extended release preparation may be admin every 12 hr. [R7] *FDA has classified the oral forms of pentaerythritol tetranitrate as possibly effective in the prophylaxis of angina pectoris, but not in the treatment of acute attacks. This classification requires the submission of adequate and well controlled studies in order to provide substantial evidence of effectiveness. [R28] *Congestive heart failure (treatment). ... Regular oral pentaerythritol tetranitrate is also being used for treatment of congestive heart failure, whether or not it is associated with acute myocardial infarction. [R28] *Vasodivalator [R2] WARN: *Transient headache and nausea may accompany its use. ... Medical authorities state that the sustained release forms are poorly effective. It is not absorbed sublingually. Since absorption by the oral route is erratic, efficacy is unpredictable. /Pentaerythritol tetranitrate, diluted/ [R31] *... Elderly patients may be more sensitive to the hypotensive effects. In addition, elderly patients are more likely to have age related renal function impairment, which may require caution in patients receiving nitrates. /Nitrates (systemic)/ [R32] *Nitrate therapy should be discontinued if blurred vision or dry mouth continues or is severe. /Nitrates (systemic)/ [R33] *The /pentaerythritol/ tetranitrate is much longer acting than nitroglycerin but is slower in onset of action. Hence it is used in the prophylaxis of attacks of angina pectoris but not in the management of the acute attack. It is no better than a placebo as a routine chronic prophylactic in angina pectoris; tolerance develops with chronic use. /Pentaerythritol tetranitrate, diluted/ [R31] TOLR: *... Those taking the drug orally may develop cross tolerance to the vasodilating effects of sublingual nitroglycerin. [R3] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Pentaerythritol tetranitrate (PETN) is released to the environemnt as a munitions pollutant. If released to soil, PETN may adsorb to soil. No data were located which suggest biodegradation is an important fate process of PETN in soil or water. If released to water, volatilization and bioconcentration in aquatic organisms are not expected to be environmentally important removal processes. Stepwise hydrolysis to pentaerythritol and nitrate ion may be a possible fate process of PETN in natural waters; however, no experimental data directly applicable to environmental conditions (pH 5-9) were located. If released to the atmosphere, vapor-phase PETN is expected to degrade by reaction with photochemically produced hydroxyl radicals (estimated half-life of 21 days). Exposure of the general public to PETN is expected to be through oral ingestion during its use as a drug. In occupational settings, workers may be exposed to PETN through inhalation of dust and through eye and skin contact. (SRC) ARTS: *Pentaerythritol tetranitrate (PETN) is a military munitions pollutant(1). [R34] FATE: *TERRESTRIAL FATE: An estimated Koc range of 179 to 1,720(SRC) suggests low to medium mobility in soil(1,SRC); therefore, some pentaerythritol tetranitrate (PETN) may adsorb to soil. No data were located which suggest biodegradation is an important terrestrial fate process of PETN(SRC). [R35] *AQUATIC FATE: An estimated Koc range of 179 to 1,720(SRC) suggests low to medium mobility in sediment(1,SRC); therefore, some leaching may occur. Volatilization of pentaerythritol tetranitrate (PETN) will not be an important aquatic fate process based on a low Henry's Law constant. Stepwise hydrolysis to pentaerythritol and nitrate ion may be a possible fate process of PETN in natural waters(2); however, no experimental data directly applicable to environmental conditions (pH 5-9) were located(SRC). [R36] *ATMOSPHERIC FATE: Based on experimental vapor pressure of 1.035X10-10 mm Hg at 25 deg C(2), pentaerythritol tetranitrate (PETN) will exist almost entirely in the particulate phase in the ambient atmosphere(1). Vapor phase PETN is degraded in the ambient atmosphere by reaction with photochemically formed hydroxyl radaicls; the half-life for this reaction in air can be estimated to be about 21 days(3,SRC). [R37] ABIO: *The rate constant for the vapor-phase reaction of pentaerythritol tetranitrate (PETN) with photochemically produced hydroxyl radicals can be estimated to be 7.78X10-13 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 21 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). [R38] BIOC: *Based on a measured water solubility of 43 mg/L at 25 deg C(2), the BCF for pentaerythritol tetranitrate (PETN) can be estimated to be about 74 from a regression derived equation(1). Thus, bioconcentration should not be important in aquatic organism (SRC). [R39] KOC: *Based on a measured water solubility of 43 mg/l at 25 deg C(3) and an estimated log Kow of 1.61(5), the Koc for pentaerythritol tetranitrate (PETN) can be estimated to be approximately 552 and 179, respectively, from regression derived equations(3). The Koc for PETN can also be estimated to be about 1,720 using a chemical structure estimation method(1). According to a suggested classification scheme(4), PETN will have low to medium mobility in soil. [R40] VWS: *The Henry's Law constant for pentaerythritol tetranitrate (PETN) can be estimated to be approximately 1.2X10-11 atm-cu m/mole at 25 deg C based on an experimental water solubility of 43 mg/l at 25 deg C(1) and an experimental vapor pressure of 1.035X10-10 mm Hg at 25 deg C(3). This value of Henry's Law constant indicates that PETN is essentially nonvolatile from water(2). [R41] RTEX: *The general public may be exposed to pentaerythritol tetranitrate (PETN) by ingestion of capsules, tablets or sedatives during its use as a drug. Workers may be exposed by inhalation of dust or through eye and skin contact. (SRC) *Munitions workers are likely to be exposed. [R3] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 10,773 workers are potentially exposed to pentaerythritol tetranitrate (PETN) in the USA(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 2,650 workers are potentially exposed to PETN in the USA(2). [R42] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- RCRA: *D003; A solid waste containing pentaerythritol tetranitrate may become characterized as a hazardous waste when subjected to testing for reactivity as stipulated in 40 CFR 261.23, and if so characterized, must be managed as a hazardous waste. [R43] FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R44] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determination of pentaerythrityl tetranitrate in drugs by using spectrophotometric method. [R12] *Pentaerythrityl tetranitrate and meprobamate in drugs are determined by infared spectroscopic method. [R12] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Pentaerythritol Tetranitrate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 365 (1989) NIH Publication No. 89-2820 SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. VI 799 (1978) R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1127 R3: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-213 R4: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 4195 R5: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 882 R6: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992.,p. 3-362 R7: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992). 1022 R8: CLOGP; GEMS-Graphic Exposure Modeling System CLOGP USEPA (1986) R9: Rinkenback WH; Kirk-Othmer Encycl Chem Tech. 2nd NY: Wiley 8: 608 (1965) R10: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V2 10 R11: Lindner V; Kirk-Othmer Encycl Chem Tech 3rd ed. NY: Wiley 9: 561-620 (1980) R12: Association of Official Analytical Chemists. Official Methods of Analysis. 15th ed. and Supplements. Washington, DC: Association of Analytical Chemists, 1990,p. VI 528 R13: Reynolds, J.E.F., Prasad, A.B. (eds.) Martindale-The Extra Pharmacopoeia. 28th ed. London: The Pharmaceutical Press, 1982. 1630 R14: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.IB p.2032 (1992) R15: 49 CFR 171.2 (7/1/96) R16: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 193 R17: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.1107,1125-1 (1988) R18: 40 CFR 240-280, 300-306, 702-799 (7/1/91) R19: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 845 R20: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 707 R21: DHHS/NTP; Toxicology and Carcinogenesis Studies of Pentaerythritol Tetranitratewith 80% d-Lactose Monohydrate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 365 p.15 (1989) Pub No. 89-2820 R22: DHHS/NTP; Toxicology and Carcinogenesis Studies of Pentaerythritol Tetranitratewith 80% d-Lactose Monohydrate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 365 p.3-4 (1989) Pub No. 89-2820 R23: DHHS/NTP; Toxicology and Carcinogenesis Studies of Pentaerythritol Tetranitratewith 80% d-Lactose Monohydrate in F344/N Rats and B6C3F1 Mice (Feed Studies) Technical Report Series No. 365 p.3 (1989) Pub No. 89-2820 R24: The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972. R25: American Hospital Formulary Service-Drug Information 85. Bethesda, MD: American Society Hospital Pharmacists, 1985. (Plus supplements A AND B, 1985). 694 R26: Testa, B. and P. Jenner. Drug Metabolism: Chemical and Biochemical Aspects. New York: Marcel Dekker, Inc., 1976. 141 R27: American Medical Association. AMA Drug Evaluations Annual 1991. Chicago, IL: American Medical Association, 1991. 527 R28: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.IB p.2025 (1992) R29: Hansten, P.D. Drug Interactions. 4th ed. Philadelphia: Lea and Febiger, 1979. 10 R30: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R31: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 794 R32: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.IB p.2026 (1992) R33: US Pharmacopeial Convention; US Pharmacopeia Dispensing Information (USP DI); Drug Information for the Health Care Professional 12th ed, V.IB p.2027 (1992) R34: (1) Burrows D, Dacre JC; U.S. Army Medical Bioengineering Research and Development Lab TR-7503 (1975) R35: (1) Swann RL et al; Res Rev 85: 17-28 (1983) R36: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Burrows D, Dacre JC; U.S. Army Medical Bioengineering Research and Development Lab TR-7503 (1975) R37: (1) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (2) Lindner V; Kirk-Othmer Encycl Chem Tech 3rd ed. NY: Wiley 9: 561-620 (1980) (3) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) R38: (1) Atkinson R; Int J Chem Kinet 19: 799-828 (1987) R39: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-15 to 15-32 (1990) (2) Rinkenback WH; Kirk-Othmer Encycl Chem Tech. 2nd NY: Wiley 8: 608 (1965) R40: (1) Meylan WM et al; Molecular Topology/Fragment Contribution Method for Predicting Soil Sorption Coefficients. SETAC Mtg Seattle, WA Nov 4-6 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-15 to 15-32 (1990) (3) Rinkenback WH; Kirk-Othmer Encycl Chem Tech. 2nd NY: Wiley 8: 608 (1965) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) CLOGP; GEMS-Graphic Exposure Modeling System CLOGP USEPA (1986) R41: (1) Rinkenback WH; Kirk-Othmer Encycl Chem Tech. 2nd NY: Wiley 8: 608 (1965) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-15 to 15-32 (1990) (3) Lindner V; Kirk-Othmer Encycl Chem Tech 3rd ed NY, NY: Wiley 9: 561-620 (1980) R42: (1) NIOSH; National Occupational Hazard Survey (NOHS) (1974) (2) NIOSH; National Occupational Exposure Survey (NOES) (1983) R43: 40 CFR 261.23 (7/1/91) R44: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91 RS: 31 Record 346 of 1119 in HSDB (through 2003/06) AN: 6315 UD: 200302 RD: Reviewed by SRP on 9/14/1995 NT: This HSDB drug record is no longer being updated. For more current information consult ChemIDPlus at http://chem.sis.nlm.nih.gov/chemidplus/ or MEDLINEPlus at http://medlineplus.gov/. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: PENICILLIN-VK- SY: *Antibiocin-; *Arcacil-; *Arcasin-; *Aspin-VK-; *Betapen-VK-; *Calciopen-K-; *V-cil-k-; *V-Cillin-K-; *Cliacil-; *Compocillin-VK-; *Distakaps-V-K-; *Distaquaine-V-K-; *Dov-k-; *Dowpen-V-K-; *DQV-K-; *Icipen-; *Isocillin-; *Ispenoral-; *Kavepenin-; *Ledercillin-VK-; *Megacillin-oral-; *Monopotassium (2S,5R,6R)-3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia- 1-azabicyclo[3.2.0]heptane-2-carboxylat; *Oracil-VK-; *Orapen-; *Ospeneff-; *Pedipen-; *Penagen-; *Penapar-VK-; *Pencompren-; *Penicillin-V-Potassium-; *Penicillin-Potassium-Phenoxymethyl-; *Penicillin-V-Potassium-Salt-; *Pen-v-k-powder-; *Pen-Vee-K-; *Pen-vee-k-powder-; *Penvikal-; *Pfizerpen-VK-; *D-alpha-Phenoxymethylpenicillinate-K-salt-; *Phenoxymethylpenicillin-potassium-; *Potassium-penicillin-V-; *Potassium-penicillin-V-salt-; *Potassium-phenoxymethylpenicillin-; *PVK-; *Qidpen-VK-; *Robicillin-VK-; *Rocillin-VK-; *Roscopenin-; *SK-Penicillin-VK-; *Stabillin-VK-syrup-62.5-; *Stabillin-VK-syrup-125-; *Sumapen-VK-; *Suspen-; *4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-(( phenoxyacetyl)amino)-, monopotassium salt, (2S-(2alpha,5alpha,6beta))-; *4-Thia-1-azabicyclo(3.2.0)heptane-2-carboxylic acid, 3,3-dimethyl-7-oxo-6-(2 -phenoxyacetamido)-, monopotassium salt; *Uticillin-VK-; *Vepen-; *VK- RN: 132-98-9 RELT: 6314 [PENICILLIN V] (analog) MF: *C16-H18-N2-O5-S.K MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *... tablets 250 and 500 mg [R1] *Penicillin V potassium powder for oral solution should be reconstituted at the time of dispensing by adding the amount of water specified on the bottle to provide a solution containing 125 or 250 mg of penicillin V per 5 ml. The water should be added to the powder for oral solution in 2 portions and the solution agitated vigorously immediately after each addition. [R2, p. 8:12.16 153] MFS: *Bristol-Myers Co, 345 Park Ave, 5th Floor, New York, NY 10154 (212)546-4000. Production Site: Bio/Chem Division, Syracuse, NY 13221-4755 [R3] *Eli Lilly and Co., Lilly Corporate Center, Indianapolis, IN 46285, (317) 276-2000. Production Site: Animal Health Products, Lafayette, IN 47902 [R3] OMIN: *... each mg of penicillin V potassium has a potency of 1380-1610 USP penicillin V units. Although potency of penicillin ... V potassium is generally expressed in terms of the weight of penicillin V, potency of the drugs may be expressed in terms of USP penicillin V units. For labeling purposes, each mg of penicillin V contained in ... penicillin V potassium preparations is considered equivalent to 1695 penicillin V units. However, the manufacturers state that potency of penicillin V potassium preparations containing 125, 250, or 500 mg of penicillin V is approximately equivalent to 200,000, 400,000, or 800,000 penicillin V units, respectively. Each 250 mg of penicillin V as the potassium salt contains 0.7 mEq of potassium. [R2, p. 8:12.16 152] USE: *MEDICATION *MEDICATION (VET) PRIE: U.S. PRODUCTION: *(1985) /Data not reported/ [R4] U.S. IMPORTS: *(1985) 3.44X10+7 g /Penicillins, NSPF/ [R5] U.S. EXPORTS: *(1985) 1.28X10+9 g /Penicillins, NSPF/ [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White, colorless crystalline powder [R7] ODOR: *Odorless [R8] MW: *388.51 [R9] DSC: *pKa= 2.73 [R7] PH: *5-7.5 in solution [R2, p. 8:12.16 152] SOL: *Very sol in water; 1 g in about 150 ml alcohol [R7] SPEC: *Specific optical rotation: +223 deg at 25 deg C/D (c= 0.2) [R10] OCPP: *White, odorless, crystalline powder; very slightly soluble in water; soluble in alcohol and acetone; insoluble in fixed oils, pH of saturated solution is 2.5-4.0, decomposes at 120 deg C /penicillin V/ [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- STRG: *Commercially available ... penicillin V potassium tablets and powders for oral suspension or solution should be stored in tight containers at 15-30 deg C. Following reconstitution, penicillin V potassium oral solutions should be refrigerated at 2-8 deg C and any unused solution should be discarded after 14 days. [R2, p. 8:12.16 152] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- HTOX: *A double blind, randomized study was undertaken in 52 children to compare the bacteriological efficacy and safety of oral sultamicillin (iosylate (I) to those of oral penicillin V potassium (II) in the treatment of childhood streptococcal pharyngitis for a period of 10 days. The dosage was determined by age and weight: patients under 5 yr were given 125 mg/dose and patients over 20 kg, 375 mg/dose. Recolonization did not occur in the II group. Adverse effects were self-limited. One child receiving II developed an elevated serum transaminase level. [R12] *Two patients (aged 24 and 34 yr) with penicillin V potassium induced anaphylaxis experienced cardiac disorders immediately after 5 ml of 1:10,000 epinephrine chloride (I) admin by slow IV. Within sec after the injection, ventricular premature beats and apparent accelerated idioventricular rhythm occurred in one patient and possible ventricular tachycardia occurred in the other. It was concluded that patients during anaphylaxis should be monitored and the potential hazards of admin I by IV route in this clinical setting should be emphasized. [R13] *However, seizures, myoclonus, and problems with mentation and level of consciousness have been reported, particularly with penicillins. Most often this toxicity is seen in the setting of renal failure, which may allow drug accumulation. The precise mechanism responsible for these neurologic side effects is unclear, but it is known that direct application of penicillin to the brain is associated with seizures. /Penicillins/ [R14, 934] *In an epidemiologic study from Sweden, about half the cases of pseudomembranous colitis were associated with penicillins, about one third with cephalosporins, and about 14 percent with lincosamides (mostly clindamycin), reflecting the more frequent use of the penicillins and cephalosporins. The clustering of cases in some studies has suggested possible nosocomial transmission of C. difficile. /Penicillins and cephalosporins/ [R14, 940] *Penicillins, which are cleared by both filtration and secretion /by the kidneys/, also accumulate in renal failure if dosages are not adjusted. The acylureidopenicillins are about 60-75 percent excreted by tubular secretion. This secretory mechanism is saturable, and at higher concn nonrenal elimination pathways may become important in their clearance. Thus, the half-lives of these drugs are dose dependent. /Penicillins/ [R14, 941] *Glomerulonephritis caused by drug allergy is usually seen as part of a serum sickness. Deposition of antigen-antibody complexes occurs nonspecifically along the glomeruli. The nephrotic syndrome has occurred with drug allergy but is rarely associated with antimicrobials, except for penicillin. /Penicillins/ [R14, 946] *Adverse cutaneous reactions to penicillins include morbilliform, macular, urticaria, Stevens-Johnson exfoliation, and angioedema/anaphylaxis. /Penicillins; from table/ [R14, 948] *Hemolytic anemia is probably most frequently associated with the penicillins and the cephalosporins. ... A Coombs-positive reaction with or without hemolysis occurs with the penicillins. Specific IgG antibodies that react with penicillin-red blood cell complexes can be identified. This occurs in less than 1 percent of patients treated with penicillins. Coombs antibody is present in from 5-25 percent of patients treated with a cephalosporin, with rats depending on the particular cmpd studied. These antibodies are caused by binding of the cephalosporin with the red blood cell as well as by nonselective adsorption of plasma proteins such as immunoglobulins, complement, albumin, and fibrinogen to the red cell membrane. Hemolysis rarely occurs despite the frequency with which these antibodies are expressed ... . /Penicillins and cephalosporins/ [R14, 949] *Drug-related immunologic destruction of granulocytes usually develops after the second wk of therapy but may be delayed and occur weeks or months into a course of therapy. It is characterized by a sudden fall in the peripheral neutrophil count; fever may be present. Absolute neutropenia can be severe and may place the patient at increased risk of infection. ... Drug-induced neutropenia may be due to antibodies to the neutrophil. ... The neutropenia seen with prolonged high-dose therapy with penicillins and cephalosporins is of uncertain etiology, but it may not have an immunologic basis as rechallenge is not associated with an accelerated recurrence of the neutropenia and the neutrophil count may fall more slowly. /Penicillins and cephalosporins/ [R14, 949] *An antibody-induced immune thrombocytopenia has been described with the penicillins and cephalosporins. These are reversed quickly when the particular drug is discontinued. /Penicillins and cephalosporins/ [R14, 950] *It has been estimated that up to 10 percent of patients treated with a penicillin will experience a hypersensitivity reaction to the drug. This figure may be up to 40 percent in those who have a prior history of an adverse reaction to penicillin. These reactions may vary from a minor rash to fatal anaphylaxis. In one series, 0.04 to 0.2 percent of all acute allergic reactions to penicillin were severe, and 0.001 percent of these had a fatal outcome. /Penicillins/ [R14, 952] *Anaphylaxis presents clinically as the acute onset of peripheral vascular collapse and shock. This may begin minutes after contact with the precipitating allergen. It is the most feared and serious of the allergic reactions and carries with it a significant risk of death. Skin and mucosal lesions, including urticaria and angioedema, may immediately precede the onset of anaphylaxis. Nausea, vomiting, diarrhea, and bronchospasm may occur as part of the acute reaction to the drug. These end-organ responses are initiated by the release of histamine, serotonin, bradykinin and other vasoactive substances released by the basophils and mast cells. ... Penicillins, cephalosporins, and sulfonamides are the antimicrobials most often associated with anaphylactic reactions. /Penicillins and cephalosporins/ [R14, 953] *Most experience with desensitization techniques has been with penicillin. Skin testing before initiating therapy may help indicate the likelihood of a persisting allergy. A commercial skin test called PrePen is available for penicillin but it must be combined with a test for the minor penicillin determinants because these may also mediate anaphylaxis. Even with a negative response to these skin tests, desensitization may be the safest way to administer penicillin or a related drug in a patient with a clear history of acute penicillin allergy. /Penicillins/ [R14, 955] *Cross-reactivity between the cephalosporins and the penicillins occurs and may reflect the structural similarities (beta-lactam ring) of these classes of drugs. Up to 20 percent, but probably closer to 5-10 percent, of patients who are allergic to penicillin will be allergic to the cephalosporins. /Penicillins and cephalosporins/ [R14, 955] *Serum sickness is a rare complication of antimicrobial therapy, caused by a delayed hypersensitivity reaction. It usually begins approx 7-10 days after the initiation of therapy. ... The rash associated with serum sickness may include urticaria and angioneurotic edema. Palpable skin lesions consistent with a vasculitis are often present and are very suggestive of the diagnosis. This IgG-mediated toxicity also may cause GI signs, pericarditis, myocarditis, polyneuritis, and rarely, myelitis. ... Fever is common, and red blood cell casts in the urine confirm the presence of a vasculitis. The offending drug should be stopped and avoided in the future. The penicillins ... are most frequently associated with serum sickness ... . /Penicillins/ [R14, 955] *Erythema nodosum, distinguished by the presence of painful subcutaneous nodules predominately over the lower legs, has a prolonged course and is associated with systemic signs. An Arthus or mixed form of allergic reaction is suggested. ... Penicillins are associated with erythema nodosum reactions, as well as various viral and bacterial infections. /Penicillins/ [R14, 956] *Drug fever is a common sign of drug allergy. It may occur alone or in combination with other signs of allergy, such as rash. Fever may precede the development of other more serious signs of drug allergy, such as serum sickness. The penicillins and cephalosporins lead the list of antimicrobial agents associated with drug fever. The mechanism of drug fever is uncertain. /Penicillins and cephalosporins/ [R14, 957] *Electrolyte abnormalities may occur with antimicrobials that contain large salt loads. The penicillins may cause sodium overload with subsequent fluid retention. This may be very significant clinically, especially in the patient with underlying cardiac disease. Carbenicillin, for example, contains 4.7 mEq of sodium per gram of drug. When the dosage is 20 to 30 g/day, this drug may make a significant contribution to sodium metabolism ... . /Penicillins/ [R14, 957] *Another side effect resulting from the electrolyte content of the penicillin salt is the rapid rise in serum potassium that may occur with a large iv bolus of the potassium salt of crystallin penicillin. Cardiac arrest has been precipitated by the rapid infusion of very large doses of aqueous penicillin potassium. In renal failure, the use of potassium penicillin is usually best avoided; even slow infusions here may result in rises of serum potassium to toxic levels. Using the sodium salt avoid this potentially severe side effect. /Penicillins/ [R14, 958] *Hypokalemia may occur during penicillin therapy owing to competition of the penicillin at the distal renal tubule and excessive potassium excretion. /Penicillins/ [R14, 958] *The GI complication of most concern is the development of pseudomembranous enterocolitis. Although this may begin without prior GI complaints, diarrhea in a patient on antimicrobial therapy must be followed closely. The acute development of fever and pain in a patient with copious diarrhea and bloody or mucous stools strongly suggests this diagnosis. Pseudomembranous enterocolitis is diagnosed when proctoscopic examination discloses pseudomembranes (small, yellow-white plaques) along the colonic mucosa. ... Various causes have been proposed, and multiple factors appear to be important. However, much data suggest that an alteration in bowel flora induced by the offending antimicrobial may allow the emergence of resistant organisms such as Clostridium difficile. Such organisms can produce cytotoxic substances that affect mucosal function and integrity. Overgrowth of staphylococci may be seen in the stool in some cases, and a toxin has been isolated from the staphylococci that is capable of causing tissue destruction and cell damage. /Antimicrobial agents/ [R14, 938] *Although pseudomembranous colitis is most often associated with oral therapy, parenteral exposure also may be a predisposing factor. Most cases occur during parenteral exposure also may be a predisposing factor. Most cases occur during a course of antimicrobial therapy, often a week or two after therapy begins. However, cases have occurred up to 4 wk after discontinuation of an antimicrobial agent. /Antimicrobial agents/ [R14, 939] *Antimicrobial agents frequently affect the hematopoietic system. These effects may be due to direct effects on stem cells in the bone marrow or on the formed cells in the blood stream. Thus, suppression of each of the three cell lines can occur independently or in combination. ... Most often suppression is reversible when the offending drug is discontinued. /Antimicrobial agents/ [R14, 948] *Hematologic toxicity may include aplastic anemia and effects on the erythrocyte (RBC) which may include peripheral destruction - hemolysis due to immune mechanisms and to RBC abnormalities, and marrow suppression; effects on the leukocytes which may include antibody-mediated peripheral destruction and marrow suppression; and effects on the platelets which may include peripheral destruction, marrow suppression, and platelet dysfunction. /Antimicrobial agents; from table/ [R14, 948] *Immunotoxic reactions include systemic: anaphylactic shock, serum sickness/vasculitis, and fever/eosinophilia; hematologic: hemolytic anemia, agranulocytosis, and thrombocytopenia; hepatic: hepatitis; renal: interstitial nephritis; respiratory: asthma and eosinophilic pneumonia; autoimmune reactions: SLE syndrome; and skin: maculopapular/maculovesicular rash, contact dermatitis, fixed drug eruptions, erythema multiforme, Stevens-Johnson syndrome, and phototoxicity/photoallergy. /Antimicrobial agents; from table/ [R14, 953] *GI side effects of penicillins include diarrhea, epigastric/abdominal pain, and stomatitis/glossitis. /Penicillins; from table/ [R14, 939] *Reversible, nonspecific liver enzyme elevations occur in from 1-4 percent of patients treated with the various penicillins, notably with the ureidepenicillins, carbenicillin, ticarcillin, and oxacillin, as well as with the new beta-lactams imipenem and aztreonam. Nonspecific mild elevations may also occur with many antimicrobials ... . /Antimicrobials, esp penicillins/ [R14, 940] *Platelet dysfunction has been described with penicillins and is concn related. The penicillins, especially carbenicillin and ticarcillin, bind to adenosine diphosphate receptor sites on the platelet and can interfere with platelet aggregation. This effect is reversible, unlike the effect of aspirin on platelets. With very-high-dose therapy, significant bleeding may occur. /Penicillins/ [R14, 950] *Acute neurotoxic effects of penicillin include visual, auditory hallucinations; encephalopathy; muscle hyperirritability; convulsions; and myoclonus. /Penicillins; from table/ [R15] NTOX: +DHHS/NTP; Toxicology and Carcinogenesis Studies of Penicillin VK in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 336 (1988) NIH Publication No. 88-2592 Acute neurotoxic effects of penicillin include visual, auditory hallucinations; encepalopathy; muscle hyperirritability; convulsions; and myoclonus. /Penicillins; from table/ +... Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of penicillin VK for F344/N rats or for B6C3F1 mice administered 500 or 1,000 mg/kg penicillin VK in corn oil gavage, 5 days per week for 2 years. ... Decreased survival of low and high dose male rats and of high dose female rats reduced the sensitivity of the studies for determining the presence or absence of a carcinogenic response in this species. [R16] NTP: +... Doses selected for F344/N rats and B6C3F1 mice in the 2 yr studies were 0, 500, or 1,000 mg/kg. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of penicillin VK for F344/N rats or for B6C3F1 mice administered 500 or 1,000 mg/kg penicillin VK in corn oil gavage, 5 days per week for 2 years. ... Decreased survival of low and high dose male rats and of high dose female rats reduced the sensitivity of the studies for determining the presence or absence of a carcinogenic response in this species. [R16] ADE: *A dose of 1,000,000 units of the acid gives peak plasma levels of about 2 to 3 ug/ml, but the potassium salt will provide levels of 4.5 to 9 ug/ml. [R7] *Penicillin VK provides faster and higher blood levels of antibiotic than Penicillin V. [R8] BHL: *The half-life is 0.5 to 0.6 hr. [R7] ACTN: *The penicillins and their metabolites are potent immunogens because of their ability to combine with proteins and act as haptens for acute antibody-mediated reactions. The most frequent (about 95 percent) or "major" determinant of penicillin allergy is the penicilloyl determinant produced by opening the beta-lactam ring of the penicillin. This allows linkage of the penicillin to protein at the amide group. "Minor" determinants (less frequent) are the other metabolites formed, including native penicillin and penicilloic acids. /Penicillins/ [R14, 953] *Bactericidal; inhibit bacterial cell wall synthesis. Action is dependent on the ability of penicillins to reach and bind penicillin-binding proteins (PBPs) located on the inner membrane of the bacterial cell wall. Penicillin-binding proteins (which include transpeptidases, carboxypeptidases, and endopeptidases) are enzymes that are involved in the terminal stages of assembling the bacterial cell wall and in reshaping the cell wall during growth and division. Penicillins bind to, and inactivate, penicillin-binding proteins, resulting in the weakening of the bacterial cell wall and lysis. /Penicillins/ [R17, 2150] INTC: *Mixing penicillins with aminoglycosides in vitro has resulted in substantial mutual inactivation; if these groups of antibacterials are to be administered concurrently, they should be administered at separate sites at least 1 hour apart. /Penicillins/ [R17, 2152] *Concurrent of /methotrexate/ with penicillins has resulted in decreased clearance of methotrexate and in methotrexate toxicity; this is thought to be due to competition for renal tubular secretion; patients should be closely monitored; leucovorin doses may need to be increased and administered for longer periods of time. /Penicillins/ [R17, 2152] *Since bacteriostatic drugs /Chloramphenicol, erythromycins, sulfonamides, or tetracyclines/ may interfere with the bactericidal effect of penicillins in the treatment of meningitis or in other situations in which a rapid bactericidal effect is necessary, it is best to avoid concurrent therapy; however, chloramphenicol and ampicillin are sometimes administered concurrently to pediatric patients. /Penicillins/ [R17, 2152] *Probenecid decreases renal tubular secretion of penicillins when used concurrently; this effect results in increased and prolonged serum concentrations, prolonged elimination half-life, and increased risk of toxicity. Penicillins and probenecid are often used concurrently to treat sexually transmitted diseases or other infections in which high and/or prolonged antibiotic serum and tissue concentrations are required. /Penicillins/ [R17, 2152] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Penicillins [R18] *Penicillin V /is/ indicated in the treatment of acute otitis media caused by susceptible organisms. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of bacterial pharyngitis cuased by susceptible organisms. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of sinusitis caused by susceptible organisms. /Included in US product labeling/ [R17, 2150] *Amoxicillin and penicillin V are used in the treatment of early Lyme disease, caused by Borrelia burgdorferi. Amoxicillin in combination with probenecid, and penicillin G (parenteral) are used to treat more advanced stages of Lyme disease, including mild neurological manifestations, cardiac manifestations, and arthritis. /Included in US product labeling/ [R17, 2150] *... Penicillin V /is/ indicated in the treatment of actinomycosis caused by Actinomyces sp. /Included in US product labeling; Not included in Canadian product labeling/ [R17, 2149] *Penicillin V ... /is/ indicated in the treatment of bronchitis caused by susceptible organisms. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of sinusitis caused by susceptible organisms. /Included in US product labeling/ [R17, 2150] *Penicillin V ... /is/ indicated in the treatment of rat-bite fever caused by Streptobacillus moniliformis or Spirillum minor. /Included in US product labeling; Not included in Canadian product labeling/ [R17, 6314] *Penicillin V ... /is/ indicated in the prophylaxis of rheumatic fever caused by group A streptococci. /Included in US product labeling/ [R17, 2150] *Penicillin V ... /is/ indicated in the treatment of scarlet fever caused by group A streptococci. /Included in US product labeling/ [R17, 2150] *Penicillin V /is/ indicated in the prophylaxis of diphtheria, caused by Corynebacterium diphtheria, as an adjunct to antitoxin. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the prophylaxis of bacterial endocarditis caused by susceptible organisms. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of erysipelas caused by susceptible strains of group A streptococci. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of erysipeloid, including endocarditis and septicemia, caused by Erysipelothrix rhusiopathiae. /Included in US product labeling; Not included in Canadian product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of acute, necrotizing, ulcerative gingivitis, also called Vincent's angina or "trench mouth," a pharyngeal and tonsillar infection caused by anaerobes and spirochetes. /Included in US product labeling/ [R17, 2149] *Penicillin V /is/ indicated in the treatment of infections caused by Pasteurella multocida. /Included in US product labeling; Not included in Canadian product labeling/ [R17, 2149] *MEDICATION (VET): Antibacterial [R19] WARN: *Penicillins are distributed into breast milk, some in low concentrations. Although significant problems in humans have not been documented, the use of penicillins by nursing mothers may lead to sensitization, diarrhea, candidiasis, and skin rash in the infant. /Penicillins/ [R17, 2151] *Many penicillins have been used in pediatric patients and no pediatrics-specific problems have been documented to date. However, the incompletely developed renal function of neonates and young infants may delay the excretion of renally eliminated penicillins. /Penicillins/ [R17, 2151] *Penicillins have been used in geriatric patients and no geriatrics-specific problems have been documented to date. However, elderly patients are more likely to have age-related renal function impairment, which may require an adjustment in dosage in patients receiving penicillins. /Penicillins/ [R17, 2151] *Prolonged use of penicillins may lead to the development of oral candidiasis. /Penicillins/ [R17, 2151] *Side/Adverse Effects: Those indicating need for medial attention: Incidence less frequent: Allergic reactions, specifically anaphylaxis (fast or irregular breathing; puffiness or swelling around face; shortness of breath; sudden, severe decrease in blood pressure), exfoliative dermatitis (red, scaly skin), serum sickness-like reactions (skin rash; joint pain, fever), skin rash, hives, or itching. Incidence rare: Hepatotoxicity (fever, nausea and vomiting, yellow eyes or skin); interstitial nephritis (fever, possibly decreased urine output, skin rash); leukopenia or neutropenia (sore throat and fever); mental disturbances (anxiety, confusion, agitation or combativeness, depression, seizures, hallucinations, or expressed fear of impending death) pain at site of injection; platelet dysfunction or thrombocytopenia (unusual bleeding or bruising); Clostridium difficile colitis (severe abdominal or stomach cramps and pain; abdominal tenderness; watery and severe diarrhea, which may also be bloody; fever); seizures. /Penicillins/ [R17, 2153] *Side/Adverse Effects: Those indicating need for medical attention only if they continue or are bothersome: Incidence more frequent: Gastrointestinal reactions (mild diarrhea, nausea or vomiting); headache; oral candidiasis (sore mouth or tongue, white patches in mouth and/or on tongue); vaginal candidiasis (vaginal itching and discharge). /Penicillins/ [R17, 2153] *Concurrent of /methotrexate/ with penicillins has resulted in decreased clearance of methotrexate and in methotrexate toxicity; this is thought to be due to competition for renal tubular secretion; patients should be closely monitored; leucovorin doses may need to be increased and administered for longer periods of time. /Penicillins/ [R17, 2152] *Probenecid decreases renal tubular secretion of penicillins when used concurrently; this effect results in increased and prolonged serum concentrations, prolonged elimination half-life, and increased risk of toxicity. Penicillins and probenecid are often used concurrently to treat sexually transmitted diseases or other infections in which high and/or prolonged antibiotic serum and tissue concentrations are required. /Penicillins/ [R17, 2152] *Potential Adverse Effects on Fetus: None known. Potential Side Effects on Breast-fed Infant: Significant problems not documented, but may lead to sensitization, diarrhea, candidiasis, or skin rash in infant. Comments: Fetal serum levels 20%-50% of maternal. FDA Category: B (B = Studies in laboratory animals have not demonstrated a fetal risk, but there are no controlled studies in pregnant women; nor animal studies have shown an adverse effect (other than a decrease in fertility), but controlled studies in pregnant women have not demonstrated a risk to the fetus in the first trimester and there is no evidence of a risk in later trimesters.) /Penicillin; from Table II/ [R20] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R21] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; Toxicology and Carcinogenesis Studies of Penicillin VK in F344/N Rats and B6C3F1 Mice (Gavage Studies) Technical Report Series No. 336 (1988) NIH Publication No. 88-2592. SO: R1: American Medical Association, AMA Department of Drugs. AMA Drug Evaluations. 5th ed. Chicago: American Medical Association, 1983. 1593 R2: American Hospital Formulary Service-Drug Information 85. Bethesda, MD: American Society Hospital Pharmacists, 1985. (Plus supplements A AND B, 1985). R3: SRI. 1994 Directory of Chemical Producers -United States of America. Menlo Park, CA: SRI International, 1994.. 741 R4: USITC. SYN ORG CHEM-U.S. PROD/SALES 1985 p.102 R5: BUREAU OF THE CENSUS. U.S. IMPORTS FOR CONSUMPTION AND GENERAL IMPORTS 1985 p.1-561 R6: BUREAU OF THE CENSUS. U.S. EXPORTS, SCHEDULE E, 1985 p.2-98 R7: Osol, A. (ed.). Remington's Pharmaceutical Sciences. 16th ed. Easton, Pennsylvania: Mack Publishing Co., 1980. 1142 R8: Osol A, Hoover JE et al (eds); Remington's Pharmaceutical Sciences. 14th ed. Easton, PA: Mack Publishing Co., p. 1230 (1975) R9: U.S. Department of Health and Human Services, Public Health Service, Center for Disease Control, National Institute for Occupational Safety Health. Registry of Toxic Effects of Chemical Substances (RTECS). National Library of Medicine's current MEDLARS file.p. 86/8510 R10: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 1125 R11: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 896 R12: Arnoff SC et al; J Antimicrob Chemother 14 (Sept): 261-5 (1984) R13: Sullivan TJ; J Am Med Assoc 248 (Nov 5): 2161-2 (1982) R14: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. R15: O'Donoghue, J.L. (ed.). Neurotoxicity of Industrial and Commercial Chemicals. Volume I. Boca Raton, FL: CRC Press, Inc., 1985. 123 R16: Toxicology and Carcinogenesis Studies of Penicillin VK in F344/N Rats and B6C3F1 Mice (Gavage Studies). Technical Report Series No. 336 (1988) NIH Publication No. 88-2592 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R17: USP Convention. USPDI - Drug Information for the Health Care Professional. 15 th ed. Volume 1. Rockville, MD: United States Pharmacopeial Convention, Inc., 1995. (Plus updates.) R18: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R19: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 1125 R20: Stockton DL, Paller AS; J Am Acad Dermatol 23 (1):87-103 (1990) R21: 21 CFR 200-299, 300-499, 820, and 860 (4/1/93) RS: 33 Record 347 of 1119 in HSDB (through 2003/06) AN: 6361 UD: 200211 RD: Reviewed by SRP on 9/15/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: TRANS-1,2-DICHLOROETHYLENE- SY: *sym-Dichloroethylene-; *Ethylene,-1,2-dichloro-,- RN: 156-60-5 RELT: 149 [1,2-DICHLOROETHYLENE] (Mixture); 6878 [DICHLOROETHYLENE] (Mixture) MF: *C2H2Cl2 STCC: 49 091 45; Dichloroethylene HAZN: U079; A toxic waste when a discarded commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or manufacturing chemical intermediate. /1,2-Dichloroethylene/ MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Bordner, US patent 2,504,919 (1950 to Du Pont). Prepn of trans-form: Adler, US patent 2,440,997 (1948 to Stockholms Superfosfot Fabriks Aktiebolag). Separation of ... trans-form by fractional distillation: ... Truce, Barney, J Org Chem 27, 128 (1962). [R1] *1,1,2-trichloroethane is dehydrochlorinated at 500 deg C to produce cis- and trans-dichloroethylene [R2] FORM: *AI3-28786 MFS: *Schumacher, 1969 Palomar Oaks Way, Carlsbad, CA 92009-1307, (800) 545-9242; Production site: Carlsbad, CA 92009 [R3] OMIN: *Trans-isomer is more widely used in industry than either the cis-isomer or the commercial mixture [R4] *Addition of a hot liquid to the cold solvent caused sudden emission of sufficient vapor to cause a flame to flash back 12 m from a fire. Although the bulk of the solvent did not ignite, various items of paper and wood in the room were ignited by the transient flame. /1,2-Dichloroethylene/ [R5] *Cis and trans isomers of 1,2-dichloroethylene have had use as solvents and chem intermediate. Neither of isomers has developed wide industrial usage in the USA partly because of their flammability. [R6] USE: *Used as a solvent for waxes, resins and acetylcellulose. It is also used in the extraction of rubber, as a refrigerant, in the manufacture of pharmaceuticals and artificial pearls and in the extraction of oils and fats from fish and meat. /1,2-Dichloroethylene/ [R7, 322] *Solvent for fats, phenols, camphor, etc; retard fermentation; rubber manufacturing; refrigerant; additive to dye and lacquer solutions; low-temperature solvent for heat-sensitive substances (eg, caffeine); constituent of perfumes, thermoplastics; used in organic synthesis and medicine /cis and trans isomers/ [R8, p. V1 755] CPAT: *In applications where dichloroethylenes could be used as solvents and for low temperature extraction processes, they have been replaced by methylene chloride. /Dichloroethylenes/ [R9, 299] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless, light liquid [R9, 297] ODOR: *Sweetish [R9, 297] BP: *48.7 deg C at 760 mm Hg [R10] MP: *-49.8 deg C [R10] MW: *96.94 [R10] CTP: *Critical temperature = 516.7 K; criticial pressure = 5510 kPa [R9, 297] DEN: *1.2565 @ 20 deg C/4 deg C [R10] HTV: *73.7 cal/g at bp [R11] OWPC: *log Kow = 2.06 [R12] SOL: *Soluble in benzene and chloroform. [R13]; *Soluble in alcohol, ether, and acetone [R10]; *In water, 4.52X10+3 mg/l @ 25 deg C [R14]; *water: 0.63 g/100 g at 25 deg C [R15] SPEC: *Index of refraction: 1.4454 @ 20 deg C [R10]; *IR: 3646 (Sadtler Research Laboratories Prism Collection) [R16]; *NMR: 6742 (Sadtler Research Laboratories Spectral Collection) [R16]; *MASS: NIST 19681 (NIST/EPA/MCDC Mass Spectral Database 1990 version); WILEY 203 (Atlas of Mass Spectral Data, John Wiley and Sons, NY) [R16] SURF: *25X10-3 N/m @ 20 deg C [R9, 297] VAPD: *3.67 g/l at bp at 760 mm Hg [R11] VAP: *3.31X10+2 mm Hg @ 25 deg C [R17] VISC: *0.41 cP @ 20 deg C [R11] OCPP: *Specific heat: 0.270 cal/g at 20 deg C [R11] *Residue on evaporation: 0.0007% by weight maximum [R11] *Vapor pressure = 35.3 mPa at 20 deg C [R18] *Partition coefficients at 37 deg C for trans-1,2-dichloroethylene into blood = 58; into oil = 189. [R19] *Vapor pressure: 395 mm Hg at 30 deg C [R11] *Henry's Law constant= 9.28X10-3 atm-cu m/mole @ 24 deg C [R20] *Hydroxyl radical reaction rate constant = 2.34X10-12 cu cm/molecule-sec @ 25 deg C [R21] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *FLAMMABLE, DANGEROUS FIRE HAZARD. /1,2-DICHLOROETHYLENE/ [R22] *FLAMMABLE, DANGEROUS FIRE HAZARD. /sym-Dichloroethylene/ [R22, 6361] *Dangerous fire hazard when exposed to heat, flame or oxidizers. [R23] *Reaction with solid caustic alkalies or their concentrated solns produces chloracetylene gas, that ignites spontaneously in air. [R23] FLPT: *36 deg F [R23] AUTO: *860 deg F (460 deg C) /1,2-Dichloroethylene/ [R24, 1981.2] FIRP: */Use/ dry chemical, foam or carbon dioxide /1,2-Dichloroethylene/ [R25] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Keep run-off water out of sewers and water sources. /1,2-Dichloroethylene/ [R26] TOXC: *Phosgene and hydrogen chloride fumes may form in fires. /1,2-Dichloroethylene/ [R25] *... Carbon monoxide may be released in a fire involving 1,2-dichloroethylene. /1,2-Dichloroethylene/ [R24, 1981.2] EXPL: *Lower 9.7%; upper 12.8% /1,2-Dichloroethylene/ [R27] *Containers may explode in fire. [R25] *Moderate explosion hazard in the form of vapor when exposed to flame. [R23] REAC: *May release explosive chloroacetylene by the contact with copper or copper alloys. /1,2-Dichloroethylene/ [R28] *Reacts with strong oxidizers. /1,2-Dichloroethylene/ [R7, 322] *Violent reaction with difluoromethylene dihypofluorite. Forms shock-sensitive explosive mixtures with dinitrogen tetraoxide. Reaction with solid caustic alkalies or their concentrated solns produces chloracetylene gas, that ignites spontaneously in air. Reacts violently with /dinitrogen oxide, potassium hydroxide, sodium, sodium hydroxide/. ... Can react vigorously with oxidizing materials. [R23] DCMP: *Decomposes slowly on exposure to air, light and moisture. /1,2-Dichloroethylene/ [R22, 335] *When heated to decomposition it emits toxic fumes of /hydrogen chlorine/. [R23] ODRT: *Odor low: 0.3357 mg/cu m; Odor high 1975.00 ppm [R29] SERI: *This liquid can act as a primary irritant producing dermatitis and irritation of mucous membranes. /1,2-Dichloroethylene/ [R7, 322] *1,2-Dichloroethylene is an eye irritant. /1,2-Dichloroethylene/ [R24, 1981.2] *A skin and eye irritant. ... Dermatitis may result from defatting action on skin. [R23] EQUP: *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent any reasonable probability of eye contact. /1,2-Dichloroethylene/ [R7, 322] *RUBBER GLOVES; SAFETY GOGGLES; AIR SUPPLY MASK OR SELF-CONTAINED BREATHING APPARATUS. /1,2-DICHLOROETHYLENE/ [R25] *The following types of respirators should be selected under the prescribed concentrations: 1000 ppm: 1. Any powered air-purifying respirator with organic vapor cartridge(s), 2. Any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s); 4000 ppm: 1. Any supplied-air respirator operated in a continuous flow mode, 2. Any air-purifying full facepiece respirator (gas mask) with a chin-style or front- or back-mounted organic vapor canister, 3. Any self-contained breathing apparatus with a full facepiece, 4. Any supplied-air respirator with a full facepiece; Emergency or planned entry in unknown concentration or IDLH conditions: 1. Any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode, 2. Any supplied-air respirator with a full face piece and operated in pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. Escape: 1. Any air-purifying full facepiece respirator (gas mask) with a chin-style or front- or back-mounted organic vapor canister, 2. Any appropriate escape-type self-contained breathing apparatus. /1,2-dichloroethylene/ [R30] *Employees should be provided with and required to use impervious clothing, gloves, face-shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent any possibility of skin contact with 1,2-dichloroethylene. Employees should be provided with and required to use splash-proof goggles where there is any possibility of liquid 1,2-dichloroethylene contacting the eyes. /1,2-Dichloroethylene/ [R24, 1981.2] OPRM: *... Employees should wash promptly when skin is wet or contaminated. Remove clothing promptly if wet or contaminated to avoid flammability hazard. /1,2-Dichloroethylene/ [R7, 322] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. /1,2-Dichloroethylene/ [R24, 1981.2] *In addition to respirator selection, a complete respiratory protection program should be instituted which includes regular training, maintenance, inspection, cleaning, and evaluation. /1,2-Dichloroethylene/ [R24, 1981.2] *Clothing contaminated with liquid 1,2-dichloroethylene should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of 1,2-dichloroethylene from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the 1,2-dichloroethylene, the person performing the operation should be informed of 1,2-dichloroethylene's hazardous properties. Non-impervious clothing which becomes contaminated with liquid 1,2-dichloroethylene should be removed immediately and not reworn until the 1,2-dichloroethylene is removed from the clothing. /1,2-Dichloroethylene/ [R24, 1981.2] *Skin that becomes contaminated with liquid 1,2-dichloroethylene should be immediately washed or showered with soap or mild detergent and water to remove any 1,2-dichloroethylene. /1,2-Dichloroethylene/ [R24, 1981.2] *Contact lenses should not be worn when working with this chemical. /1,2-Dichloroethylene/ [R30] *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *It material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Attempt to stop leak if without undue personnel hazard. /1,2-Dichloroethylene/ [R26] *Personnel protection: Keep upwind. Avoid breathing vapors. ... Do not handle broken packages unless wearing appropriate personal protective equipment. /1,2-Dichloroethylene/ [R26] SSL: *GRADUALLY DECOMPOSED BY AIR, LIGHT AND MOISTURE, FORMING HCl; /SRP: POTENTIAL PHOSGENE FORMATION/ /1,2-DICHLOROETHYLENE/ [R31] CLUP: *1. REMOVE ALL IGNITION SOURCES. 2. VENTILATE AREA OF SPILL OR LEAK. 3. FOR SMALL QUANTITIES, ABSORB ON PAPER TOWELS. EVAPORATE IN SAFE PLACE (SUCH AS A FUME HOOD). ALLOW SUFFICIENT TIME FOR EVAPORATING VAPORS TO COMPLETELY CLEAR THE HOOD DUCTWORK. BURN PAPER IN SUITABLE LOCATION ... 3. 1,2-DICHLOROETHYLENE SHOULD NOT BE ALLOWED TO ENTER CONFINED SPACE, SUCH AS SEWER, BECAUSE OF POSSIBILITY OF EXPLOSION. SEWERS DESIGNED TO PRECLUDE FORMATION OF EXPLOSIVE CONCN OF 1,2-DICHLOROETHYLENE VAPORS ARE PERMITTED. /1,2-DICHLOROETHYLENE/ [R24, 1981.2] DISP: *Generators of waste (equal to or greater than 100 kg/mo) containing this contaminant, EPA hazardous waste number U079, must conform with USEPA regulations in storage, transportation, treatment and disposal of waste. [R32] *Incineration, preferably after mixing with another combustible fuel. Care must be exercised to assure complete combustion to prevent the formation of phosgene. An acid scrubber is necessary to remove the halo acids produced. /1,2-Dichloroethylene/ [R7, 323] *1,2-DICHLOROETHYLENE MAY BE DISPOSED OF BY ATOMIZING IN SUITABLE COMBUSTION CHAMBER EQUIPPED WITH AN APPROPRIATE EFFLUENT GAS CLEANING DEVICE. /1,2-DICHLOROETHYLENE/ [R24, 1981.2] *A potential candidate for rotary kiln incineration at a temperature range of 820 to 1,600 deg C and residence times of seconds for liquids and gases, and hours for solids; Also, a potential candidate for fluidized bed incineration at a temperature range of 450 to 980 deg C and residence times of seconds for liquids and gases, and longer for solids; Also a potential candidate for liquid injection incineration at a temperature range of 650 to 1,600 deg C and a residence time of 0.1 to 2 seconds. [R33] *This compound should be susceptible to removal from wastewater by air stripping. /1,2-Dichloroethylene/ [R34] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *If this chemical gets into the eyes, irrigate immediately. If this chemical contacts the skin, wash with soap promptly. If a person breathes in large amounts of this chemical, move the exposed person to fresh air at once and perform artificial respiration. ... /1,2-Dichloroethylene/ [R7, 322] MEDS: *Employees should be screened for history of certain medical conditions which might place the employee at increased risk from 1,2-dichloroethylene exposure. Liver disease: The importance of /the liver/ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Chronic respiratory disease: In persons with impaired pulmonary function, expecially those with obstructive airway disease, the breathing of 1,2-dichloroethylene might cause exacerbation of symptoms due to its irritant properties. Any employee developing the above listed conditions should be referred for further medical examination. /1,2-dichloroethylene/ [R24, 1981.1] HTOX: *INHALATION CAUSES NAUSEA, VOMITING, WEAKNESS, TREMOR, EPIGASTRIC CRAMPS, CENTRAL NERVOUS DEPRESSION. CONTACT WITH LIQ CAUSES IRRITATION OF EYES AND (ON PROLONGED CONTACT) SKIN. INGESTION CAUSES SLIGHT DEPRESSION TO DEEP ... /SRP: CNS DEPRESSION/. /1,2-DICHLOROETHYLENE/ [R25] *TOXIC BY INGESTION, INHALATION AND SKIN CONTACT; IRRITANT AND ... /SRP: CNS DEPRESSANT/ IN HIGH CONCN. /1,2-DICHLOROETHYLENE/ [R22, 335] *The trans-isomer is twice as toxic as the cis-isomer. [R35] *1,2-DCE has been used as a general anesthetic in humans. Exposure to the trans-isomer at 2200 ppm caused burning of the eyes, vertigo, and nausea. [R36, 1991.430] NTOX: *Some but not all dogs narcotized by inhaling the vapor have been observed to develop delicate superficial corneal turbidity. The first observation of corneal disturbance was made on three dogs repeatedly exposed to dichloroethylene by evaporation of 10-15 cc in a chamber of 0.115 cu m volume. Haziness was observed in both corneas of one dog after the second exposure and slight haziness of one eye of another dog after fourteen exposures, but no ocular disturbance was found in the third dog. A more detailed study subsequently showed that the corneal haziness occuring in dogs was attributable to many fine gray flecks in the endothelium, and that this usually cleared in twenty-four hours, or forty-eight hours at the most. /1,2-Dichloroethylene/ [R37] *... /CATS AND RABBITS REPEATEDLY EXPOSED TO TRANS-ISOMER @ CONCN OF 0.16-0.19% IN AIR/ SHOWED LOSS OF APPETITE AND SOME RESP IRRITATION BUT NO HISTOPATHOLOGICAL CHANGES IN ORGANS. [R38, 4192] *THE MUTAGENICITY OF SEVERAL CHLORINATED ETHYLENES WAS TESTED ON ESCHERICHIA COLI STRAIN K-12 IN CULTURE MEDIUM CONTAINING MOUSE LIVER MICROSOMES METABOLIC ACTIVATION SYSTEM. 1,2-TRANS-DICHLOROETHYLENE WAS NOT MUTAGENIC. [R39] *TRANS-1,2-DICHLOROETHYLENE WAS NOT MUTAGENIC IN TESTS USING SALMONELLA TYPHIMURIUM STRAINS IN VITRO WITHOUT METABOLIC ACTIVATION AND IN VIVO WITH METABOLIC ACTIVATION (HOST-MEDIATED ASSAY), OR IN A CYTOGENETIC ANALYSIS OF BONE MARROW CELLS FROM FEMALE ICR MICE AFTER SINGLE AND REPEATED IP APPLICATIONS (5/DAY) 6, 24 AND 48 HR FOLLOWING THE LAST APPLICATION. [R40] *ONE DOG NARCOTIZED WITH ... VAPOR WHILE EYES WERE PROTECTED FROM DIRECT CONTACT WAS FOUND TO HAVE NO GROSS CORNEAL TURBIDITY, BUT SLIGHT DISTURBANCE OF CORNEAL ENDOTHELIUM AND SLIGHT STROMAL EDEMA WERE FOUND MICROSCOPICALLY. /1,2-DICHLOROETHYLENE/ [R37] *AT 16,000 PPM /RATS/ ... WERE ANESTHETIZED IN 8 MIN AND WERE KILLED IN 4 HR. ... TRANS ISOMER /IS/ ... TWICE AS TOXIC AND ANESTHETIC AS CIS ISOMER ... EFFECT OF INHALATION IS ... /SRP: CNS DEPRESSION/. ... DISTURBANCE OF EQUILIBRIUM AND PROSTRATION OCCUR IN APPROX SAME LENGTH OF TIME FROM SIMILAR CONCN OF CIS AND TRANS ISOMERS. [R38, p. 4191-2] *Cis- and trans-1,2-dichloroethylene were tested for mutagenic effects in a diploid strain (D7) of the yeast Saccharomyces cerevisiae in suspension tests with and without a mammalian microsomal activation system, a S9 mouse liver fraction, and by an in vivo intrasanguineous host-mediated assay. ... Both isomers exhibited dose-dependent toxicity, and survival was lower with metabolic activation than without. In the host-mediated assay, only the cis-isomer showed evidence of mutagenic activity with significant increases in convertants at the tip locus and revertants at the ilv locus. Such mutagenic activity was found after acute and chronic doses and in liver, kidney, and lung tissue. [R41] *Trans-1,2-dichloroethylene (DCE) was administered to male and female CD-1 mice. Following an acute LD50 determination (2122 mg/kg in males and 2391 mg/kg in females) and a 14-day range-finding study, a 90-day drinking water study was performed using levels of DCE calculated to deliver approximately 1/100, 1/10, and 1/5 the LD50. Various toxicological assessments were made, including body and organ weights, hematology, serum chemistries, and hepatic microsomal activities. Few alterations were observed in either sex following 90 days of exposure. The most noteworthy changes occurred in the males exposed to the highest level of DCE. where there was a significant decrease in glutathione levels, and in the females exposed to all three DCE levels, where there was a significant decrease in aniline hydroxylase activity. [R42] *The developmental toxicity of trans-1,2-dichloroethylene a component of certain Freon cleaning agents, was examined in pregnant rats. trans-1,2-dichloroethylene was admin by inhalation 6 hr daily on days 7-16 of gestation (the day copulation was confirmed was termed Day 1 of gestation) at exposure levels of 0, 2000, 6000, or 12,000 ppm. The offspring were then examined on Day 22 of gestation. Overt maternal toxicity was expressed as a significant reduction in weight gain at 12,000 ppm and in feed consumption at 6000 and 12,000 ppm. During the exposure period, lacrimation and stained periocular hair, and signs of ocular irritation, were observed in all groups. In addition, increased incidence of alopecia, lethargy, and salivation were observed in the high dose dams. ... The mean combined and female fetal weights were significantly reduced in the litters of dams exposed to the highest concentration 12,000 ppm of trans-1,2-dichloroethylene. Marginal effects on feed consumption, unaccompanied by other changes and reflective of the pattern seen at higher doses, were seen at 2000 ppm. Thus, marginal maternal toxicity was seen at 2000 ppm and exposures to 6000 ppm trans-1,2-dichloroethylene or caused frank maternal toxicity while the fetus was affected only at 12,000 ppm. Therefore, trans-1,2-dichloroethylene is not considered to be uniquely toxic to the rat conceptus. [R43] *Inhalation studies were performed ... on both mature female SPF Wistar rats, weighing about 180-200g, and mature female NMRI mice, weighing about 20g. Both animals were given either a single 8 hr exposure at 200 ppm trans-1,2-DCE or an 8 hr inhalation dose at 200 ppm over 5 consecutive days for 1 or 2 wk. Histopathological organ changes were observed after single or repetitive doses of trans-1,2-DCE at 200 ppm including slight to severe fatty degeneration of the hepatic lobules and Kupffer cells over the controls. [R36, 1991.429] NTXV: *LC50 Mouse inhalation 21,723 ppm/6 hr; [R36, 1991.429] *LD50 Rat oral 1235 mg/kg; [R23] *LD50 Rat ip 7411 mg/kg; [R23] *LD5 Mouse oral 2122 mg/kg; [R23] *LD50 Mouse ip 4019 mg/kg; [R23] ETXV: *LC50 Lepomis machrochirus (bluegill) 135,000 ug/l/96 hr in a static unmeasured bioassay; [R44] ADE: *DICHLOROETHYLENE IS LARGELY EXCRETED THROUGH THE LUNGS. /1,2-DICHLOROETHYLENE/ [R36, 1991.429] METB: *Metabolism of trans-1,2-dichloroethylene in perfused rat liver produced detectable amounts of dichloroethanol and dichloroacetic acid. [R45] *The major initial metabolites of chlorinated ethylenes in hepatocyte suspensions isolated from phenobarbital-treated rats were studied. The initial products of trans-1,2-dichloroethylene from cytochrome p450 in hepatic microsomes are rapidly and extensively metabolized in the hepatocyte, where the Phase II enzymes are present. Trichloroethylene and tetrachloroethylene in the X systems are identical. The abilities of chlorinated ethylenes to induce unscheduled DNA synthesis was assessed in isolated hepatocytes using a method which does not require the blocking of semi-conservative DNA synthesis. Trans-1,2-dichloroethylene did not induce unscheduled DNA synthesis. [R46] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *trans-1,2-Dichloroethylene's production and use as a solvent may result in its release to the environment through various waste streams. Under anaerobic conditions, that may exist in landfills or sediment, trans-1,2-dichloroethylene may be formed by reductive dehalogenation of trichloroethylene facilitated by microorganisms. If released to air, a vapor pressure of 331 mm Hg at 25 deg C indicates trans-1,2-dichloroethylene will exist solely as a vapor in the ambient atmosphere. Vapor-phase trans-1,2-dichloroethylene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 6.9 days. If released to soil, trans-1,2-dichloroethylene is expected to have moderate mobility based upon an estimated Koc of 330. Volatilization from moist soil surfaces is expected to be an important fate process based upon a Henry's Law constant of 9.4X10-3 atm-cu m/mole. trans-1,2-Dichloroethylene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, trans-1,2-dichloroethylene is expected to adsorb to suspended solids and sediment based upon the estimated Koc. trans-1,2-Dichloroethylene slowly biodegrades in environment under anaerobic conditions. Under anaerobic conditions, 73% of trans-1,2-dichloroethylene was lost in 6 months with the accompanying formation of vinyl chloride. trans-1,2-Dichloroethylene is not expected to biodegrade under aerobic conditions. trans-1,2-Dichloroethylene, present at 2.3 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum (concn not specified) and the Japanese MITI test. No biodegradation occurred in a river die-away test. Volatilization from water surfaces is expected to be an important fate process based upon this compound's Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.1 and 94 hours, respectively. An estimated BCF of 8 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected since chlorinated ethylenes hydrolyze very slowly at environmental conditions. Occupational exposure to trans-1,2-dichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where trans-1,2-dichloroethylene is produced or used. Monitoring data indicate that the general population may be exposed to trans-1,2-dichloroethylene via drinking water. trans-1,2-Dichloroethylene widely detected in groundwater at concns ranging from not detected to 2,277 ug/l. (SRC) ARTS: *trans-1,2-Dichloroethylene's production and use as a solvent(1) may result in its release to the environment through various waste streams(SRC). Under anaerobic conditions, that may exist in landfills or sediment, trans-1,2-dichloroethylene may be formed by reductive dehalogenation of trichloroethylene facilitated by microorganisms(2). [R47] FATE: *Waste water treatment: Evaporation from water @ 25 deg C of 1 ppm solution was 50% after 24 min and 90% after 83 min; measured half-life for evaporation from 1 ppm aqueous solution @ 25 deg C, still air, and an avg depth of 6.5 cm was 24 min. [R8, p. V1 756] *Aquatic and Atmospheric Fate: ... Photodissociation is /not/ a significant fate for trans-1,2-dichloroethylene in the aquatic or atmospheric environment. ... Oxidation and hydrolysis in the aquatic environment is not significant for this compound. [R48, p. 51-1] *Aquatic Fate: Volatilization ... is a major transport process for removal of trans-1,2-dichloroethylene from aquatic systems. [R48, p. 51-1] *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a log Kow of 2.09(2) and a regression-derived equation(3), indicates that trans-1,2-dichloroethylene is expected to have moderate mobility in soil(SRC). Volatilization of trans-1,2-dichloroethylene from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 9.4X10-3 atm-cu m/mole(4). The potential for volatilization of trans-1,2-dichloroethylene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 331 mm Hg(5). trans-1,2-Dichloroethylene slowly biodegrades in soil under anaerobic conditions(SRC). Biodegradation of trans-1,2-dichloroethylene was studied in microcosms prepared from uncontaminated organic sediment from the Everglades and allowed to sit to insure oxygen depletion(6). Under these anoxic conditions, 73% of the chemical was lost in 6 months with the accompanying formation of vinyl chloride(6). trans-1,2-Dichloroethylene is not expected to biodegrade under aerobic conditions(SRC). trans-1,2-Dichloroethylene, present at 2.3 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum (concn not specified) and the Japanese MITI test(7). No biodegradation occurred in a river die-away test(8). [R49] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 330(SRC), determined from a log Kow of 2.09(2) and a regression-derived equation(3), indicates that trans-1,2-dichloroethylene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a Henry's Law constant of 9.4X10-3 atm-cu m/mole(4). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.1 and 94 hours, respectively(SRC). According to a classification scheme(5), an estimated BCF of 8(SRC), from its log Kow(2) and a regression-derived equation(6), suggests the potential for bioconcentration in aquatic organisms is low(SRC). trans-1,2-Dichloroethylene slowly biodegrades in water under anaerobic conditions(SRC). Biodegradation of trans-1,2-dichloroethylene was studied in microcosms prepared from uncontaminated organic sediment from the Everglades and allowed to sit to insure oxygen depletion(7). Under these anoxic conditions, 73% of the chemical was lost in 6 months with the accompanying formation of vinyl chloride(7). trans-1,2-Dichloroethylene is not expected to biodegrade under aerobic conditions(SRC). trans-1,2- Dichloroethylene, present at 2.3 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum (concn not specified) and the Japanese MITI test(8). No biodegradation occurred in a river die-away test(9). [R50] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), trans-1,2-dichloroethylene, which has a vapor pressure of 330 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase trans-1,2-dichloroethylene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 6.9 days(SRC), calculated from its rate constant of 2.3X10-12 cu cm/molecule-sec at 25 deg C(3). [R51] BIOD: *AEROBIC: trans-1,2- Dichloroethylene, present at 2.3 mg/l, reached 0% of its theoretical BOD in 4 weeks using an activated sludge inoculum (concn not specified) and the Japanese MITI test(1). trans-1,2-Dichloroethylene was recalcitrant in shake flask tests modified to accommodate volatile chemicals(2,3). The concns examined in this studies ranged from 0.80 to 25 ppm(2,3). A 21 day acclimation period and the addition of a lactose co-metabolite did not alter the biodegradability(2,3). Similarly no biodegradation occurred in a river die-away test(3). Thus trans-1,2-dichloroethylene is not expected to biodegrade under aerobic conditions(SRC). However, some degradation was obtained in a biodegradability screen test using a wastewater inoculum and 5 ppm, of trans-1,2-dichloroethylene(4). 67% of the chemical was lost in 7 days, whereas the 33% loss due to volatilization occurred in 10 days(4). The inoculum in this study may have contained a facultative methanotroph capable of degrading dichloroethylenes(5). [R52] *ANAEROBIC: When trans-1,2-Dichloroethylene was incubated with aquifer material obtained adjacent to a landfill site in a serum bottle at 17 deg C, at least 16 wk of incubation were required before disappearance began relative to autoclaved controls(1). After 40 wk, the average concn was reduced to 18% of controls and vinyl chloride was identified as a degradation product(1). Another investigator found that when trans-1,2-dichloroethylene was incubated anaerobically using an inoculum from a municipal waste digester in order to simulate conditions in a landfill, vinyl chloride appeared within 6 weeks(2). Biodegradation of trans-1,2-dichloroethylene was studied in microcosms prepared from uncontaminated organic sediment from the Everglades and allowed to sit to insure oxygen depletion. Under these anoxic conditions, 73% of the chemical was lost in 6 months with the accompanying formation of vinyl chloride(3). [R53] ABIO: *The rate constant for the vapor-phase reaction of trans-1,2-dichloroethylene with photochemically-produced hydroxyl radicals is 2.3X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 6.9 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). The rate constant for the vapor-phase reaction of trans-1,2-dichloroethylene with ozone has been estimated as 3.6X10-20 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(2). This corresponds to an atmospheric half-life of about 320 days at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(3). Hydrolysis is not expected since chlorinated ethylenes hydrolyze very slowly at environmental conditions(4). trans-1,2-Dichloroethylene is not expected to directly photolyze due to the lack of absorption in the environmental UV spectrum (> 290 nm)(SRC). [R54] BIOC: *An estimated BCF of 8 was calculated for trans-1,2-dichloroethylene(SRC), using a log Kow of 2.1(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC). [R55] KOC: *The Koc of trans-1,2-dichloroethylene is estimated as 330(SRC), using a log Kow of 2.1(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that trans-1,2-dichloroethylene is expected to have moderate mobility in soil(SRC). [R56] VWS: *... the experimental half-life of volatilization of 1 mg/liter trans-1,2-dichloroethylene from water to be 22 minutes when stirred at 200 rpm at approximately 25 degrees C in an open container. Removal of 90% of the /cmpd/ required 89 minutes. [R48, p. 51-5] *The Henry's Law constant for trans-1,2-dichloroethylene is 9.4X10-3 atm-cu m/mole(1). This Henry's Law constant indicates that trans-1,2-dichloroethylene is expected to volatilize rapidly from water surfaces(2). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(2) is estimated as 1.1 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(2) is estimated as 94 hours(SRC). trans-1,2-Dichloroethylene's Henry's Law constant(1) indicates that volatilization from moist soil surfaces may occur(SRC). The volatilization half-life in an open beaker containing 1 ppm of trans-1,2-dichloroethylene at a solution depth of 6.5 cm under continuous stirring (200 rpm) was 24 min(3). The potential for volatilization of trans-1,2-dichloroethylene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 330 mm Hg(4). [R57] WATC: *GROUNDWATER: As part of the National Water-Quality Assessment Program of the USGS, the VOC concns were determined for untreated, ambient groundwater from the conterminous United States; the survey was conducted between 1985 and 1995 from 2,948 wells; the range of trans-1,2-dichloroethylene concns in this survey were between 0.2 ug/l to 20 ug/l in urban areas (detection frequency, 4.7%), and 0.2 ug/l to 9 ug/l in rural areas (detection frequency, 0.4%)(1). 4.6% of the 315 wells sampled from the outcrop area of the Potomac-Raritan-Mogothy aquifer system adjacent to the Delaware River contained trans-1,2-dichloroethylene(2). The chemical was absent from wells down dip of the outcrop area(2). trans-1,2-Dichloroethylene was detected in 4 groundwater samples in Montgomery County, MO in 1983(3); the mean and range of concns were 158 ppb and 27-320 ppb, respectively(3). The range of avg concns of trans-1,2-dichloroethylene from the Biscayne aquifer in Miami, FL between Nov 1982 and March 1983 was 0.25-28 ppb for 12 samples (total) from 6 geographical areas defined within the study site(4). trans-1,2-Dichloroethylene was detected in 29 of 35 groundwater samples from Southington, CT in 1980 at a mean and max concn of 16 ppb and 50,000 ppb, respectively(5). trans-1,2-Dichloroethylene was detected in 76 of 6,264 ambient groundwater samples in the National Contaminant Occurrence Database (NCOD); the mean trans-1,2-dichloroethylene concn was 5.14 +/- 7.80 ug/l (range, 0.2-41 ug/l)(6). [R58] *GROUNDWATER: The concns of trans-1,2-dichloroethylene in landfill leachates ranges from 1.6 to 88 ug/l(1). The occurrence of organic priority pollutants originating from leachate at a landfill adjacent to a wetlands in Orange County, FL was compared to a prior one-year study(2). The concn of trans-1,2-dichloroethylene in groundwater during the first year (1989-1990) of the study was 0.14 ug/l, while in the second year, the concn was 6.22 ug/l in one sample(2). A site study of a western Connecticut manufacturing plant that used large quantities of high quality trichloroethylene for degreasing found that 7 of 9 monitoring wells around the plant contained 1.2 to 320.9 ppb of trans-1,2-dichloroethylene(3). [R59] *SURFACE WATER: The occurrence of organic priority pollutants orginating from leachate at a landfill adjacent to a wetlands in Orange County, FL was compared to a prior one-year study(1). The concn of trans-1,2-dichloroethylene in surface water during the first year (1989-1990) of the study was 0.14 ug/l(1). The avg concn of trans-1,2-dichloroethylene in the influent at the Calumet and West-southwest waste water treatment plants in Illinois were 1.43 and 1.77 ug/l, respectively(2). trans-1,2-Dichloroethylene was detected in 9 of 2,245 ambient surface water (eg, other) samples in the National Contaminant Occurrence Database (NCOD); the mean trans-1,2-dichloroethylene concn was 4.17 +/- 8.66 ug/l (range, 0.2-27 ug/l)(3). [R60] *DRINKING WATER: trans-1,2-Dichloroethylene was detected at 31 of 1,548 Public Water Systems (PWS) derived from surface water in the National Contaminant Occurrence Database (NCOD)(1); the avg concn for all PWS systems was 2,277 +/- 15,090 ug/l (range, 0.1 - 100,100 ug/l)(1). trans-1,2-Dichloroethylene was detected at 1 of 107 Public Water Systems (PWS) derived from ground water under the direct influence of surface water in the National Contaminant Occurrence Database (NCOD)(1); the concn at this PWS systems was 1.3 ug/l(1). trans-1,2-Dichloroethylene was detected at 92 of 10,094 Public Water Systems (PWS) derived from surface water in the National Contaminant Occurrence Database (NCOD)(1); the avg concn for all PWS systems was 3.74 +/- 7.26 ug/l (range, 0.11 - 61 ug/l)(1). Water quality testing in the NCOD was performed at many points in the system, including the intake and at various points in the treatment and distribution systems, as well as at the point where the drinking water can be labeled finished(1). [R61] EFFL: *In a comprehensive survey of wastewater from 4000 industrial and publicly owned treatment works (POTWs) sponsored by the Effluent Guidelines Division of the U.S. EPA, trans-1,2-dichloroethylene was identified in discharges of the following industrial category (frequency of occurrence; median concn in ppb): iron and steel mfg (2; 2265.9), organics and plastics (3; 14.6), inorganic chemicals (2; 3.9), rubber processing (2; 19.0), auto and other laundries (1; 60.6), explosives (1; 3.9), electronics (7; 140.7), mechanical products (2; 13.7), transportation equipment (1; 29.3), publicly owned treatment works (63; 16.3)(1). The highest effluent concn was 3013 ppb in the iron and steel mfg industry(1). [R62] *In another survey of the industrial occurrences of trans-1,2-dichloroethylene, 4 industries had wastewater discharges of > 0.1 kg/day. These (industry (mean conc (ppb); Max conc (ppb))) were: metal finishing (260; 1700), photographic equipment/supplies (-; 2200), nonferrous metal mfg (75; 260), rubber processing (150; 290)(3). The concn of trans-1,2-dichloroethylene in 3 sewage treatment effluents ranged from 31 to 43 ppb(2). While effluent from the Los Angeles City, Orange County and San Diego County contained < 10 ppb of trans-1,2-dichloroethylene, sludge from two of the plants contained 145 and 44 ppb of the chemical(6). At the Valley of the Drums waste site near Louisville, KY, water samples contained trace amounts to 75 ppb of trans-1,2-dichloroethylene, while some sediment samples contained trace amounts of the chemical(4). In the National Urban Runoff Program in which samples of runoff were collected from 19 cities (51 catchments) in the U.S., trans-1,2-dichloroethylene was detected in Eugene, OR and Little Rock, AK (5% of the samples) at levels of 1-3 ppb(5). In a four city study (Cincinnati, St. Louis, Atlanta, and Hartford) to determine the major source type of priority pollutants in tap water and publicly owned treatment work (POTW) influents, it was found that 43%, 38%, and 28% of commercial sources, industrial sources, and POTW influents contained trans-1,2-dichloroethylene(1). The average level of the industrial sources was between 10 and 100 ppb while the others were < 10 ppb(1). [R63] SEDS: *trans-1,2-Dichloroethylene has been detected, not quantified, in sediment/soil/water samples at the Love Canal(1). [R64] ATMC: *SOURCE AREAS: Edison NJ - 930 parts/trillion trans-1,2-dichloroethylene(1). Air samples were collected from methane vents at 2 sanitary landfills in Long Island, NY (sampling date unspecified)(2); the max concn of trans-1,2-dichloroethylene was 75,600 ppb in these samples(2). The max concn of trans-1,2-dichloroethylene ws 59,000 ppb from 20 Class II landfills in California (sampling date not specified)(2). [R65] *URBAN/SUBURBAN: The concn of trans-1,2-dichloroethylene in air at Edison, NJ (sampling date not specified) was 0.93 ppb(1). [R66] PFAC: FISH/SEAFOOD CONCENTRATIONS: *The concn of trans-1,2-dichloroethylene in fish tissue taken from Port Defiance, Commencement Bay (Tacoma, WA) was 0.04 ppm(1). The concn of trans-1,2-dichloroethylene in fish tissue from the Storet Database was 0.132 ppm(1). [R67] OEVC: *Primary sludges from three publicly owned treatment works treating municipal and industrial wastes contained 22, 1540, and 1317 ppb of trans-1,2-dichloroethylene(1). [R68] RTEX: *Occupational exposure to trans-1,2-dichloroethylene may occur through inhalation and dermal contact with this compound at workplaces where trans-1,2-dichloroethylene is produced or used. Monitoring data indicate that the general population may be exposed to trans-1,2-dichloroethylene via drinking water. (SRC) AVDI: *WATER INTAKE: Assume 0 to 2,277 ug/l(1), 0 to 4,554 ug trans-1,2-dichloroethylene(SRC). [R61] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *Recommended Exposure Limit: 10 Hr Time-Weighted Avg: 1000 ppm. /1,2-Dichloroethylene/ [R69] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 200 ppm (790 mg/cu m). /1,2-Dichloroethylene/ [R70] TLV: *8 hr Time Weighted Avg (TWA) 200 ppm [R71, 2001.26] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R71, 2001.6] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 100 ug/l [R72] FEDERAL DRINKING WATER GUIDELINES: +EPA 100 ug/l [R72] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 10 ug/l [R72] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 70 ug/l [R72] +(ME) MAINE 70 ug/l [R72] +(MN) MINNESOTA 100 ug/l [R72] +(WA) WASHINGTON 60 ug/l [R72] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Federal Water Pollution Control Act and is subject to effluent limitations. /Dichloroethylenes (1,1-, and 1,2-dichloroethylene)/ [R73] RCRA: *U079; As stipulated in 40 CFR 261.33, when 1,2-dichloroethylene, as a commercial chemical product or manufacturing chemical intermediate or an off-specification commercial chemical product or a manufacturing chemical intermediate, becomes a waste, it must be managed according to Federal and/or State hazardous waste regulations. Also defined as a hazardous waste is any residue, contaminated soil, water, or other debris resulting from the cleanup of a spill, into water or on dry land, of this waste. Generators of small quantities of this waste may qualify for partial exclusion from hazardous waste regulations (40 CFR 261.5). /1,2-Dichloroethylene/ [R74] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *NIOSH Method 1003. Calibrate each personal sampling pump with sampler in line. Break ends of sampler (solid sorbent tube) and attach sampler to personal sampling pump with flexible tubing. Sample at flow rate of 0.01 to 0.2 liter/min for total sample of 3 liter. /1,2-Dichloroethylene/ [R75] *OSW Method 5021. Volatile Organic Compounds in Soils and Other Solid Matrices Using Equilibrium Headspace Analysis. This is a general purpose method for the preparation of volatile organic compounds (VOCs) in soils/sediments and solid wastes for determination by gas chromatography/mass spectrometry (GC/MS). [R76] *OSW Method 5041. Protocol for Desorption of Sorbent Cartridges from Volatile Organic Sampling Train (VOST): Wide-Bore Capillary GC/MS Technique. [R76] ALAB: *NIOSH Method 1003. Analyte: 1,2-Dichloroethylene; Technique: Gas Chromatography, FID; Range: 475 to 1915 mg/cu m; Matrix: air; Precision: 0.052. /1,2-Dichloroethylene/ [R75] *OSW Method 31. Sampling Method for Volatile Organic Compounds. This method is used to determine volatile organic compounds in gaseous emissions from a wide variety of stationary sources including hazardous waste incinerators to an upper concentration limit of 1.5 ppm. This method is used to quantify volatile organic compounds that have a boiling point between -15 and 121 degrees C. It is not applicable to polar water-soluble and reactive volatile organic compounds. Detection limit = 0.1 ug/cu m. [R76] *APHA Method 6200-B. Volatile Organics in Water by Gas Chromatograph/Mass Spectrometric Purge and Trap Packed-Column Technique. This method is useful for the determination of purgeable organics in industrial and municipal wastes. Detection limit = 0.2 ug/l. [R77, p. 6-24] *APHA Method 6200-C. Volatile Organics in Water by Gas Chromatograph/Mass Spectrometric Purge and Trap Packed-Column Technique. This method is useful for the determination of purgeable organics in industrial and municipal wastes. Detection limit = 0.015 ug/l. [R77, p. 6-26] *EPA Method LC_VOA. Analysis of Water for Low Concentration Volatile Organic Compounds by Gas Chromatography/Mass Spectroscopy. This method is applicable to drinking water and well water, and ground water sources around Superfund sites. Detection limit = 1 ug/l. [R76] *EPA Method 502.1. Volatile Halogenated Organic Compounds in Water by Purge and Trap Gas Chromatography. Revision 2.0. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. Detection limit = 0.002 ug/l. [R76] *EPA Method 502.2-ELCD. Volatile Organic Compounds in Water by Purge and Trap Capillary Column Gas Chromatography with Photoionization and Electrolytic Conductivity Detectors in Series. Revision 2.0. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. Detection limit = 0.06 ug/l. [R76] *EPA Method 502.2-PID. This method is applicable to finished drinking water, raw source water, or drinking water in any treatment stage. Detection limit = 0.05 ug/l. [R76] *EPA Method 524.1. Measurement of Purgeable Organic Compounds in Water by Packed Column Gas Chromatography and Mass Spectrometry. Revision 3.0. This method is applicable to finished drinking water, raw source water, and drinking water in any treatment stage. Detection limit = 0.2 ug/l. [R76] *EPA Method 524.2. This method is applicable to surface water, ground water, and drinking water in any treatment stage. Detection limit = 0.06 ug/l. [R76] *EPA Method 601. Purgeable Halocarbons in Wastewater by Gas Chromatography with Electrolytic Conductivity Detection. This method is applicable to municipal and industrial discharges as provided under 40 CFR 136.1. Detection limit = 0.1 ug/l. [R76] *EPA Method 624. Protocol for the Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater. This method is applicable to the determination of purgeable organics in industrial and municipal discharges. Detection limit = 1.6 ug/l. [R76] *EPA Method 624-S. Analysis of Purgeable Organic Priority Pollutants in Industrial and Municipal Wastewater Treatment Sludge. This method is used for qualitative and quantitative analysis of purgeable (volatile) organic compounds in municipal and industrial wastewater treatment sludges. Detection limit = 1.6 ug/l. [R76] *OSW Method 8240B-W. Determination of Volatile Organics Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). This method is applicable to various type of samples, regardless of water content, including ground water, aqueous sludge, caustic liquors, acid liquors, waste solvents, and oily waste. Detection limit = 5.0 ug/l. [R76] *OSW Method 5032. Determination of Pentamidine Isethionate by High Performance Liquid Chromatography with Fluorescence Detection. This method is applicable to air samples. Detection limit unspecified. [R76] *OSW Method 8010B. Determination of Halogenated Volatile Organics by Gas Chromatography. This method is applicable to various volatile halogenated organic compounds. Detection limit = 0.002 ug/l. [R76] *OSW Method 8021A-FID. Analysis of Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Column Technique. This Method is applicable to ground water, aqueous sludges, caustic liquors, acid liquors, waste, solvents, oily wastes, mousses, tars, fibrous wastes, polymeric emulsions, filter cakes, spent carbons, spent catalysts, soils, and sediments. Detection limit = 0.06 ug/l. [R76] *OSW Method 8021A-PID. Halogenated and Aromatic Volatiles By Gas Chromatography using Electrolytic Conductivity and Photoionization Detectors in Series: Capillary Technique. Detection limit = 0.05 ug/l. [R76] *OSW Method 8240B. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS). This method is applicable to various types of samples regardless of water content, including ground water, aqueous sludges, caustic liquors, acid liquors, waste solvents, oily waste, mousses, tars, fibrous wastes, polymeric emulsions, filter cakes, spent carbons, spent catalysts, soils, and sediments. Detection limit = 5 ug/kg. [R76] *OSW Method 8260A. Determination of Volatile Organic Compounds by Gas Chromatography/Mass Spectrometry (GC/MS): Capillary Column Technique. This method is applicable to nearly all types of samples, regardless of water content, including ground water, aqueous sludges, caustic liquors, acid liquors, waste solvents, oily wastes, mousses, tars, fibrous wastes, polymeric emulsions, filter cakes, spent carbons, spent catalysts, soils, and sediments. Detection limit = 0.06 ug/l. [R76] *OSW Method 8260B. This method is used to determine volatile organic compounds in a variety of solid waste matrices. It is applicable to nearly all types of samples, regardless of water content, including various air sampling trapping media, ground and surface waters, aqueous sludges, caustic liquors, acid liquors, waste solvents, oily wastes, mousses, tars, fibrous wastes, polymeric emulsions, filter cakes, spent carbons, spent catalysts, soils, and sediments. Detection limit unspecified. [R76] *OSW Method 5041. Analysis of Sorbent Cartridges From Volatile Organic Sampling Train by using the Wide-Bore Capillary Column Technique. This method is applicable to the analysis of non-polar organic compounds with boiling points between 30 C and 100, and many compounds which boil above 100 C. Detection limit unspecified. [R76] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Ambient Water Quality Criteria Doc: Dichloroethylenes (1980) EPA 440/5-80-041] Rev Environ Contam Toxicol 106: 103-12 (1988). A review article on the pharmacokinetics of trans-1,2-dichloroethylene. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that short term toxicity study on 1,2-trans-dichloroethylene is scheduled for peer review. Route: microencapsulation in feed; Species: rats and mice. NTP TR No 55. [R78] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 17 R2: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984. 733 R3: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 549 R4: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-62 R5: Bretherick, L. Handbook of Reactive Chemical Hazards. 4th ed. Boston, MA: Butterworth-Heinemann Ltd., 1990 238 R6: Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley and Sons. New York, N.Y. (2001). 214 R7: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. R8: Verschueren, K. Handbook of Environmental Data on Organic Chemicals. Volumes 1-2. 4th ed. John Wiley and Sons. New York, NY. 2001 R9: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 (1986) R10: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-163 R11: Flick, E.W. (ed.). Industrial Solvents Handbook 4 th ed. Noyes Data Corporation., Park Ridge, NJ., 1991. 143 R12: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 4 R13: Weast, R.C. (ed.) Handbook of Chemistry and Physics. 67th ed. Boca Raton, FL: CRC Press, Inc., 1986-87.,p. C-272 R14: Horvath AL et al; J Phys Chem Ref Data 28: 395-627 (1999) R15: Flick, E.W. Industrial Solvents Handbook. 3rd ed. Park Ridge, NJ: Noyes Publications, 1985. 116 R16: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V3 2764 R17: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. 98 R18: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V6 37 R19: Sato A, Nakajima T; Scand J Work Environ Health 13: 81-93 (1987) R20: Gossett JM; Environ Sci Tech 21: 202-6 (1987) R21: Kwok ESC, Atkinson R: Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) R22: Hawley, G.G. The Condensed Chemical Dictionary. 10th ed. New York: Van Nostrand Reinhold Co., 1981. R23: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 38 R24: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. R25: U.S. Coast Guard, Department of Transportation. CHRIS - Hazardous Chemical Data. Volume II. Washington, D.C.: U.S. Government Printing Office, 1984-5. R26: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 354 R27: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1079 R28: ITII. Toxic and Hazardous Industrial Chemicals Safety Manual. Tokyo, Japan: The International Technical Information Institute, 1988. 165 R29: Ruth JH; Am Ind Hyg Assoc J 47: A-142-51 (1986) R30: NIOSH. Pocket Guide to Chemical Hazards. 5th Printing/Revision. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, Sept. 1985.99 R31: The Merck Index. 10th ed. Rahway, New Jersey: Merck Co., Inc., 1983. 14 R32: 40 CFR 240-280, 300-306, 702-799 (7/1/2000) R33: USEPA; Engineering Handbook for Hazardous Waste Incineration p.3-12 (1981) EPA 68-03-3025 R34: USEPA/ORD; Innovative and Alternative Technology Assessment Manual 3-5, 3-11-3-12 (1980) EPA 430/9-78-009 R35: Verschueren, K. Handbook of Environmental Data of Organic Chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Co., 1983. 489 R36: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH R37: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 325 R38: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R39: GREIM H ET AL; LEBERSCHAEDEN VINYLCHLORID: VINYLCHLORID-KR, (WISS TAG), 2ND: 1-36 (1977) R40: CERNA M, KYPENOVA H; MUTAT RES 46 (3): 214-5 (1977) R41: Bronzetti G et al; Teratog, Carcinog Mutagen 4 (4): 365-75 (1984) R42: Barnes DW et al; Drug Chem Toxicol 8 (5): 373-92 (1985) R43: Hurtt ME et al; Fundam Appl Toxicol 20 (2): 225-30 (1993) R44: USEPA; Ambient Water Quality Criteria Doc: Dichloroethylenes p.B-5 (1980) EPA 440/5-80-041 R45: USEPA/ODW; Suggested No Adverse Response Level for Trans-1,2-Dichloroethylene p.4 (1981) R46: Costa AK, Ivanetich KM; Carcinogenisis (London) 5 (12): 1629-36 (1984) R47: (1) Verschueren, K. Handbook of Environmental Data on Organic Chemicals. 4th ed. NY, NY: John Wiley and Sons 1: 755 (2001) (2) Fiorenza S et al; pp. 277-86 in Bioremediation of Chlorinated Polycyclic Aromatic Hydrocarbon Compounds. Hinchee RE, ed. Boca Raton, FL: Lewis Pub (1994) R48: Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. Water-Related Environmental Fate of 129 Priority Pollutants. Volume I. EPA-440/4 79-029a. Washington, DC: U.S. Environmental Protection Agency, December 1979. R49: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Gossett JM; Environ Sci Tech 21: 202-6 (1987) (5) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci. Pub p. 98 (1984) (6) Barrio-Lage G et al; Environ Sci Technol 20: 96-9 (1986) (7) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. trans-1,2-Dichloroethylene (156-60-5) and cis-1,2-Dichloroethylene (156-59-2). Available from the Database Query page at http://www.citi.or.jp/citi/owa/search_cas as of Apr 18, 2001. (8) Mudder TI; Diss Abstra Int B 42: 1804 (1981) R50: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Gossett JM; Environ Sci Tech 21: 202-6 (1987) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) (6) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (7) Barrio-Lage G et al; Environ Sci Technol 20: 96-9 (1986) (8) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. trans-1,2-Dichloroethylene (156-60-5) and cis-1,2-Dichloroethylene (156-59-2). Available from the Database Query page at http://www.citi.or.jp/citi/owa/search_cas as of Apr 18, 2001. (9) Mudder TI; Diss Abstra Int B 42: 1804 (1981) R51: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Pub p. 98 (1984) (3) Kwok ESC, Atkinson R: Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) R52: (1) CITI; Biodegradation and Bioaccumulation Data of Existing Chemicals. trans-1,2-Dichloroethylene (156-60-5) and cis-1,2-Dichloroethylene (156-59-2). Available from the Database Query page at http://www.citi.or.jp/citi/owa/search_cas as of Apr 18, 2001. (2) Mudder TI, Musterman JL; PP. 52-3 in Preprints. Div Environ Chem Amer Chem Soc, Sept . Kansas City, MO (1982) (3) Mudder TI; Diss Abstra Int B 42: 1804 (1981) (4) Tabak HH et al: J Water Pollut Contr Fed 53: 1503-18 (1981) (5) Fogel MM et al; Appli Environ Microbiol 51: 720-4 (1986) R53: (1) Wilson BH et al; Environ Sci Technol 20: 997-1002 (1986) (2) Hallen RT et al; in ACS Div Environ Chem 192nd Natl Mtg 26: 344-6 (1986) (3) Barrio-Lage G et al; Environ Sci Technol 20: 96-9 (1986) R54: (1) Kwok ESC, Atkinson R: Estimation of hydroxyl radical reaction rate constants for gas-phase organic compounds using a structure-reactivity relationship: an update. Riverside, CA: Univ CA, Statewide Air Pollut Res Ctr. CMA Contract No. ARC-8.0-OR (1994) (2) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (3) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (4) Callahan MA et al; Water related fate of 129 priority pollutants. Vol II. Washington DC: USEPA, Off Plan Stnds, Off Water Waste Management. USEPA 440/4-79-029b (1979) R55: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R56: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R57: (1) Gossett JM; Environ Sci Tech 21: 202-6 (1987) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Dilling WL et al; Environ Sci Technol 9:833-8 (1975) (4) Boublik T et al; The vapor pressures of pure substances. Vol. 17. Amsterdam, Netherlands: Elsevier Sci Pub p. 98 (1984) R58: (1) Squillace PJ et al; Environ Sci Technol 33: 4176-87 (1999) (2) Fusillo TV et al; Ground Water 23:354-60 (1985) (3) Dever RJ; J Am Water Works Assoc 78:82-6 (1986) (4) Singh UP, Orban JE; Water Resource Bull 23: 879-88 (1987) (5) Hall DW; pp. 190-7 in Hazard Wastes Environ Emerg Manage Prev Cleanup Control Int Conf Exhib (1984) (6) USEPA; National Contaminant Occurrence Database. trans-1,2-Dichloroethylene. Available from the Database Query page at http://www.epa.gov/ncod/ as of Apr 12, 2001. R59: (1) Christensen TH et al; Crit Rev Env Sci Technol 24: 119-202 (1994) (2) Chen CS, Zoltek J; Chemosphere 31: 3455-3464 (1995) (3) Stuart JD; Organics Transported Thru Selected Geological Media. NTIS PB83-224246 Comm Univ Storrs Inst of Water Res pp. 37 (1983) R60: (1) Chen CS, Zoltek J; Chemosphere 31: 3455-3464 (1995) (2) Namkung E, Rittmann BE; J WPCF 59: 670-8 (1987) (3) USEPA; National Contaminant Occurrence Database. trans-1,2-Dichloroethylene. Available from the Database Query page at http://www.epa.gov/ncod/ as of Apr 12, 2001. R61: (1) USEPA; National Contaminant Occurrence Database. trans-1,2-Dichloroethylene. Available from the Database Query page at http://www.epa.gov/ncod/ as of Apr 12, 2001. R62: (1) Shackelford WM et al; Analyt Chim Acta 146: 15-27 (1983) R63: (1) Levins P et al; Sources of Toxic Pollutants in Influents to Sewage Treatment Plants p.118 (1981) USEPA-440/4-81-008 NTIS PB81-219685 (2) Lao RC et al; pp.107-18 in Analytical Techniques in Environmental Chemistry II Albaiges J ed NY: Pergamon Press (1982) (3) USEPA; Treatability Manual - Vol I (1980) USEPA-600/8-80-042 (4) Stonebraker RD, Smith AJ Jr; pp.1-10 in Control Hazard Mater Spills, Proc Natl Conf Nashville, TN (1980) (5) Cole RH et al; J Water Pollut Control Fed 56: 898-908 (1984) (6) Young DR; Ann Rep South Calif Coastal Water Res Proj p.103-12 (1978) R64: (1) Hauser TR et al; EPA's Monitoring Program AT Love Canal 1980 Env Monit Assess 2:249-72 (1982) R65: (1) Brodzinsky R, Singh HB; Volatile Organic Chemicals In The Atmosphere Menlo Park, CA: SRI International 198 pp. (1982) (2) Lipsky D, Jacot B; Hazardous emissions from sanitary landfills. Proc 78th Ann Meet Air Pollut Control Assoc, Detroit, MI: June 16-21 (1985) R66: (1) USEPA; Volatile organic chemicals in the atmosphere: An assessment of available data. Menlo Park, CA: SRI Int USEPA-600/3-83-027A p. 198 (1982) R67: (1) Nicola RM, Bachflower R; J Environ Health 49:342-7 (1987) R68: (1) Feiler HD et al; pp.53-7 in Natl Conf Munic Ind Sludge Util Disposal, Silver Spring, MD (1980) R69: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 98 R70: 29 CFR 1910.1000 (7/1/2000) R71: American Conference of Governmental Industrial Hygienists. TLVs and BEIs. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2001. Cincinnati, OH. R72: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R73: 40 CFR 401.15 (7/1/2000) R74: 40 CFR 261.33 (7/1/2000) R75: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R76: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R77: American Public Health Association, American Water Works Association, Warer Environment Federation. M.A.H. Franson (ed.); Standard Methods for the Examination of Water and Wastewater 20th ed., Washington, D.C. 1998. R78: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.23 RS: 67 Record 348 of 1119 in HSDB (through 2003/06) AN: 6370 UD: 200303 RD: Reviewed by SRP on 5/7/1998 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: SODIUM-SELENATE- SY: *A13-10625-; *Caswell-No-791-; *Disodium-selenate-; *EPA-Pesticide-Chemical-Code-072002-; *Natriumseleniat- (German); *Selenic-acid,-disodium-salt-; *Selenic-acid- (H2SeO4),-disodium-salt; *Sodium-selenate- RN: 13410-01-0 RELT: 6909 [SELENIUM COMPOUNDS] MF: *H2-O4-Se.2Na MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *AC Industries Inc, Sattiva Chemical Co Div, 26 Sixth St, Suite 603A, Stamford, CT 06905, (203) 348-8002 [R1] *Brand-Nu Laboratories Inc, PO Box 895, 30 Maynard St, Meriden, CT 06450, (203) 235-7989 [R1] USE: *Insecticide in some horticultural applications [R2] *MEDICATION (VET) CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White crystals /Decahydrate/ [R2] MW: *188.94 [R2] DEN: *3.098 [R3] OCPP: *Very soluble in water /Decahydrate/ [R2] *Density = 1.603-1.620 /Decahydrate/ [R4] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DCMP: *When heated to decomposition, it emits fumes of /selenium and disodium oxide/. [R5] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Recycling: As the price of selenium is very high, recovery of it by processing selenium-containing waste is economical. For example, selenium refineries are equipped with wet scrubbers that employ an approx 50% soln of hydrobromic acid containing free bromine. The acid fumes are adsorbed in a lime and soda bed, and the selenium separated from the hydrobromic acid soln by distillation is recycled. Otherwise, solid or sludgy selenium-containing wastes from the manufacture or repair of xerox drums or from paint production are disposed of in special dumps. Recommendable methods: Chemical reduction, solidification and landfill. Not recommendable methods: Thermal destruction and discharge to sewer. Peer review: Reduction with SO2 /sulfur dioxide/ to SE /selenium/ metal. Do not use metal and acids to reduce disodium selenate as this will produce toxic gaseous hydrogen selenide. (Peer-review conclusions of an IRPTC expert consultation (May 1985)) [R6] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- MEDS: *The following medical procedures should be made available to each employee who is exposed to selenium and its inorganic compounds at potentially hazardous levels: 1. Initial Medical Examination: A complete history and physical examination: The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Persons with a history of asthma, allergies, or known sensitization to selenium, or with a history of other chronic respiratory disease, gastrointestinal disturbances, disorders of liver or kidneys or recurrent dermatitis would be expected to be at increased risk from exposure. Examination of the eyes, respiratory system, liver, kidneys, and blood should be stressed. The skin should be examined for evidence of chronic disorders. Special consideration should be given to women of childbearing age since the possibility that selenium may be teratogenic might place these women in a high risk group. Urinalysis: Proper function of the kidneys is necessary to validate levels of selenium in the urine. A urinalysis should be obtained to include at a minimum specific gravity, albumin, glucose, and a microscopic /examination of/ centrifuged sediment. Liver function tests: Selenium causes liver damage and tumors in animals. A profile of liver function should be obtained by using a medically acceptable array of biochemical tests. The aforementioned medical examinations should be repeated on an annual basis. /Selenium and its inorganic compounds/ [R7] HTOX: *The ingestion of 22 mg of sodium selenate per kilogram produced minimal toxicity despite a substantial rise in the blood level. [R8] *The gastric absorption of selenium as ... selenates ... is rapid. /Selenates/ [R9] *Selenate is the least toxic inorganic selenium form ... /Selenate salts/ [R8] NTOX: *Groups of about 100 male and female weanling Long-Evans rats were given 2 mg/l selenium as ... sodium selenate in drinking-water (equal to about 4.5 mg/kg of diet) until they were 1 yr of age when the dose was raised to 3 mg/l. A group of 105 controls received no selenium in drinking-water. After 58 days ... male rats receiving 2 mg/l sodium selenite were transferred to sodium selenate, since 50% of the animals had died; surviving animals in this group were killed after 596 days and no tumors observed. Thirty tumors were reported in the 48 selenate-treated rats examined histologically (62.5%); 20 of these tumors were malignant (41.7%). ... Of the 65 control rats examined, 20 had tumors (30.8%) 11 of which were malignant (16.9%). ... an evaluation of results was not possible because not all autopsied animals were examined histologically and because treated animals lived longer than controls ... (avg lifespan of control males and females was 813 and 814 days and that of treated animals 847 and 929 days, respectively). [R10] *... accumulates in plants which are thus rendered toxic to many pests, and also to mammals. Highly toxic by all routes. ... causes degenerative lesions in liver, kidneys, heart, spleen, stomach, bowel, and lungs. [R11] *Long-term Exposure: Prolonged exposure to ... sodium selenate ... may cause paleness, coated tongue, stomach disorders, nervousness, metallic taste and a garlic odor of the breath. Fluid in the abdominal cavity, damage to the liver and spleen, and anemia have been reported in animals. [R7] *Oral intake of selenium compounds leads to restricted food intake and marked loss of weight. Weight loss also occurred in an experiment involving subcutaneous administration, even though food intake was increased above the control level ... . In spite of this difference, the rats showed many changes found in the other studies, including both atrophy and hypertrophy of liver lobes. [R12] *Rats receiving selenium compounds (generally sodium selenite) in their diets show acute, subacute, and chronic pathologic pictures entirely similar to those seen in rats fed poisonous field-grown grain... . Rats that received selenium (as sodium selenate) at a dietary level of 100 ppm ate little food and all died in 8-16 days; those receiving 50 ppm all died in 10-97 days. A dietary level of 15 ppm was tolerated for 72 days or more, but food intake was about half of normal. All rats survived a dietary level of 7.5 ppm (about 0.37 mg/kg/day) for 6 months, and their growth was normal. /Selenium compd/ [R12] NTP: +The potential toxicity of sodium selenate was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to use a known toxic compound in a truncated test. This design extended previous studies by addressing both reproduction and development. Sodium Selenate at dose levels of 0, 7.5, 15.0, and 30.0 ppm was administered in the drinking water over a 30-day period. One group of male (10/group) and 3 groups of female rats designated as Group A (peri-conception exposure, 10/group), Group B (gestational exposure, 13/group), AND Group C (vaginal cytology, 10/group) were used for each dose level. Control animals received deionized water, the vehicle. Weekly absolute body weights and feed and water consumption values decreased with increasing dose. Water consumption decreased in all groups and was dramatically reduced in the 30 ppm group by approx 70-80% compared to the controls. The majority of the 30 ppm females appeared thin during cageside observations on SD 7-30. Mortality was observed only in the 30 ppm group, especially just prior to or during parturition of the Group B females. The avg calculated consumption of sodium selenate for Groups 2-4, was 0.5, 0.8 and 1.1 mg/kg/day, respectively. Final body weights at necropsy for the 15 and 30 ppm males were 12% and 20%, respectively, lower than controls. Changes in relative organ weights (absolute organ weight/ body weight) were noted in the 15 and 30 ppm groups but they were attributed to the decr in body weight, since animal size effects organ size... . Sperm endpoints were generally unchanged. No treatment-related microscopic lesions were noted in the right kidney, liver, spleen, left testis, or left epididymis. Group A females (treated before, during, and after mating) in the 30 ppm group had significantly fewer implants/litter and corpora lutea when compared to controls. The number live fetuses/litter were also slightly decreased. Because of the large reductions in fluid intake, it is believed that changes in reproductive parameters were the result of dehydration. For the 30 ppm Group B gestationally-exposed females, there was a decr in the number of live pups/litter (68% of control value), adjusted live pup weight (44% of control value), and the proportion of pups born alive (58% of control value). The avg gestation length increased by 5% when compared to controls. The adjusted live pup weight was decreased during lactation for the 15 and 30 ppm females. Pup survival was reduced by 21% for the 15 ppm females, but was not statistically significant (due to high standard error, low sample size, and lack of dose response) when compared to the control group. Pup survival at 30 ppm was decreased by 73% when compared to the control group. These effects cannot be separated from dehydration, as indicated by the decreased water consumption and weekly mean absolute body weights in these groups. Treatment-related gross lesions were observed in 15 and 30 ppm Group B females. These included pale and small adrenals, thickened stomach walls, stomach adhesions involving abdominal organs, enlarged and small kidneys, enlarged spleen, and implantation sites with nodular material. Evaluation of the Group C female vaginal cytology data revealed that the estrous cycle in the 7.5 and 15.0 ppm Group C females was comparable to the controls. The 30 ppm Group C females spent less time in estrus than the controls, and there was a 22% incr in cycle length. Results of this study indicated that sodium selenate produced toxicity at 15 and 30 ppm, which had more restricted water consumption but also greater sodium selenate intake, than at 7.5 ppm. Reproductive toxicity was noted in both Group A AND B females at 30 ppm based on increased gestation length and decreased number of live pups, live pup weight, proportion of pups born alive, number of implants and corpora lutea/litter, and pup survival. However, the toxicity of sodium selenate could not be separated from the effects due to reduced water consumption. Sodium selenate produced only minor effects on male reproductive function. Based on decreased weekly mean absolute body weights, and feed and water consumption values, a max tolerated dose was reached at 15 ppm. The no-observable-adverse-effect-level (NOAEL) was not determined in females because there were decreased absolute body weights at 7.5 ppm. In this study, sodium selenate was not a selective reproductive toxicant, as it caused body weight decreases at doses below those that affected reproduction. [R13] ADE: *Selenium is excreted chiefly in the urine but about 3-10% is metabolized and excreted by the lungs, and there is some fecal excretion even when sodium selenate is administered subcutaneously ... . When sodium selenite is administered in the same way, 17-52% is exhaled within 8 hr ... . [R12] ACTN: *The effects of sodium selenite and sodium selenate on DNA and RNA synthesis have been examined using intact HeLa cells, isolated nuclei and extracted polymerases. Selenate had no effect on any of the systems examined. Selenite inhibited DNA synthesis in intact cells and in isolated nuclei, and to a limited extent also inhibited DNA polymerase alpha. Selenite also inhibited RNA synthesis in intact cells and alpha-amanitin resistant RNA synthesis in isolated nuclei (ie, synthesis catalyzed by RNA polymerase I and III). It had no effect on alpha-amanitin sensitive synthesis (catalyzed by RNA polymerase II) at concentrations up to 500 uM. However, transcription of exogenous DNA by extracted RNA polymerase II (as well as by polymerase I and II) was inhibited by selenite. [R14] INTC: *The chemopreventive efficacies of selenate, selenite, selenium dioxide, selenomethionine and selenocystine were examined during the promotion phase of carcinogenesis in the 7,12-dimethylbenz(a)anthracene-induced mammary tumor model in rats. Each agent was added to the diet of a final concentration of 3 ppm selenium. In general, there was no significant difference in the potency of these five selenium compounds in inhibiting the development of mammary tumors. The interaction of vitamin E (500 ppm) with either selenite or selenomethionine was further characterized in a second carcinogenesis study. Results of this experiment suggested that vitamin E enhanced the protective effect of selenite but not that of selenomethionine. In an attempt to explore the synergistic mechanism of selenium and vitamin E, the effects of these two agents on mitogen induced blastogenesis and natural killer cytotoxic activity were also investigated. No consistent changes in these in vitro immune functions were detected resulting from supranutritional feeding of either selenite or vitamin E or both. ... /Selenite/ [R15] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *MEDICATION (VET): Sodium selenate has been admin to prevent exudative diathesis in chicks, white muscle disease in sheep and infertility in ewes. It is reported to prevent pneumonia in premature lambs and calves and to control hepatitis in swine. [R16] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ KOC: *No sorption of sodium selenate was observed in 10 of 11 soils; a log Kd value of 0.958 was determined in Kula soil(pH 5.9, 6.62% TOC, 73.7% sand, 25.4% silt, 0.9% clay)(1). [R17] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.2 mg/cu m. /Selenium compounds, as Se/ [R18] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 50 ug/l /Selenium/ [R19] STATE DRINKING WATER STANDARDS: +(AZ) ARIZONA 10 ug/l /Selenium/ [R19] +(NY) NEW YORK 10 ug/l /Selenium/ [R19] STATE DRINKING WATER GUIDELINES: +(AZ) ARIZONA 45 ug/l /Selenium/ [R19] +(CT) CONNECTICUT 10 ug/l /Selenium/ [R19] +(ME) MAINE 10 ug/l /Selenium/ [R19] +(MN) MINNESOTA 30 ug/l /Selenium/ [R19] CERC: *Releases of CERCLA hazardous substances are subject to the release reporting requirement of CERCLA section 103, codified at 40 CFR part 302, in addition to the requirements of 40 CFR part 355. Sodium selenate is an extremely hazardous substance (EHS) subject to reporting requirements when stored in amounts in excess of its threshold planning quantity (TPQ) of 100/10,000 lbs. [R20] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: DHHS/NTP; NTP Toxicity Studies of Sodium Selenate and Sodium Selenite Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Toxicity Rpt Series No. 38 NIH Publication No. 94-3387 (1994) SO: R1: Van, H. and C.A. Deyrup (eds.). OPD Chemical Buyer's Directory 1988. 75th ed. New York, NY: Schnell Publishing Co., Inc. 1988. 592 R2: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 1482 R3: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 1254 R4: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 1068 R5: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1427 R6: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 277 R7: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981.1 R8: Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997. 1607 R9: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 2130 R10: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 251 (1975) R11: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-129 R12: Hayes, W.J., Jr., E.R. Laws, Jr., (eds.). Handbook of Pesticide Toxicology. Volume 2. Classes of Pesticides. New York, NY: Academic Press, Inc., 1991. 558 R13: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Sodium Selenate (CAS No. 13410-01-0): Administered to Sprague-Dawley Rats in the Drinking Water Short Term Reproductive and Developmental Toxicity Study, NTP Study No. RDGT94011 (May 1, 1996) available at http://ntp-server.niehs.nih.gov/htdocs/pub-RDGT0.html as of August 16, 2002 R14: Frenkel GD; Toxicol Lett 25 (2): 219-23 (1985) R15: Ip C, White G; Carcinogenesis 8 (12): 1763-6 (1987 R16: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V9 248 (1975) R17: (1) Buchter B et al; Soil Sci 148: 370-9 (1989) R18: 29 CFR 1910.1000 (7/1/98) R19: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R20: 40 CFR 355 (7/1/97) RS: 20 Record 349 of 1119 in HSDB (through 2003/06) AN: 6503 UD: 200301 RD: Reviewed by SRP on 1/26/2002 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 4-VINYLTOLUENE- SY: *Benzene,-1-Ethenyl-4-methyl-; *P-METHYL-STYRENE-; *4-Methylstyrene-; *1-p-Tolylethene-; *p-Vinyltoluene- RN: 622-97-9 RELT: 1035 [VINYL TOLUENE] MF: *C6-H10 SHPN: UN 2618; Vinyl toluenes (mixed isomers), inhibited IMO 3.3; Vinyl toluenes (mixed isomers), inhibited MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *4-Methylstyrene /4-vinyltoluene/ is commercially produced by the catalytic dehydrogenation of 4-ethyltoluene [R1, p. VA13 256] *Toluene + acetaldehyde (Mobil process) [R2] IMP: *3% meta-vinyltoluene, 0.2% ortho-vinyltoluene [R3] FORM: *A formulation of approx 97 wt% para-vinyltoluene and 3% meta-vinyltoluene [R3] *A commercial vinyltoluene mixture of meta- and para-vinyltoluene, usually with 56-60% meta, 40-45% para, and 1% ortho. [R4] MFS: *Deltech Corp., 16 South Jefferson Rd., Whippany, NJ 07981, (973) 428-5311; Production site: Baton Rouge, LA 70800 [R5] OMIN: *A plant for the alkylation of toluene to 4-ethyltoluene by the Mobil Process was opened in 1982 by Hoechst (now Hoechst-Celanese) in Baton Rouge, LA; the plant has an annual capacity of 16,000 tons of 4-methylsytrene /4- vinyltoluene/ and was purchased by Deltech in 1989 [R1, p. VA13 257] *Vinyltoluene, comprising a mixture of about 33% para- and 67% meta- methylstyrene, was marketed for about 30 yr by Dow Chemical and also by Cosden [R6] USE: *Use in mixtures with other vinyltoluene isomers (3-vinyltoluene) as monomers for producing poly(vinyltoluene) [R1, p. VA13 256] *Used as a monomer in the production polyester resins [R7] *Co-polymerized with isobutylene to produce synthetic elastomers [R8] *Reactive monomer; used in the coatings industry as a modifier for drying oils and oil-modified alkyds; used as a replacement for styrene in unsaturated polyester resins; used as a copolymer with styrene to increase the operating temperature range of paints, coatings and varnishes. /Vinyltoluene/ [R9] PRIE: U.S. PRODUCTION: *NO DATA (1992) [R10] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: *172.8 deg C [R11] MP: *-34.1 deg C [R11] MW: *118.18 [R11] CTP: *Critical temperature = 665 K; critical pressure = 3.36X10+06 Pa [R12] DEN: *0.9173 @ 25 deg C/4 deg C [R11] HTC: *-4.8229X10+09 J/kmol [R12] HTV: *6.20X10+07 J/kmol @ 25 deg C [R12] OWPC: *log Kow= 3.35 [R13] SOL: *Soluble in benzene [R11]; *In water, 89 mg/l @ 25 deg C [R14] SPEC: *Index of refraction: 1.5420 at 20 deg C [R11]; *IR: 21205 (Sadtler Research Laboratories Prism Collection) [R15]; *UV: 8303 (Sadtler Research Laboratories Spectral Collection) [R15]; *MASS: 69765 (NIST/EPA/MSDC Mass Spectral Database, 1990 version) [R15] SURF: *0.043227 Newtons/m @ 239.02 K [R12] VAP: *1.81 mm Hg @ 25 deg C [R16] VISC: *0.0020986 Pa-s (liquid) @ 239.02 K [R12] OCPP: *Liquid molar volume = 0.129067 cu m/kmol; heat of formation = 1.1464X10+08 J/kmol [R12] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Fire or explosion: Highly flammable: Will be easily ignited by heat, sparks or flames. Vapors may form explosive mixtures with air. Vapors may travel to source of ignition and flash back. Most vapors are heavier than air. They will spread along ground and collect in low or confined areas (sewers, basements, tanks). Vapor explosion hazard indoors, outdoors or in sewers. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Runoff to sewer may create fire or explosion hazard. Containers may explode when heated. Many liquids are lighter than water. /Vinyltoluene, inhibited/ [R17] +Health: May cause toxic effects if inhaled or absorbed through skin. Inhalation or contact with material may irritate or burn skin and eyes. Fire will produce irritating, corrosive and/or toxic gases. Vapors may cause dizziness or suffocation. Runoff from fire control or dilution water may cause pollution. /Vinyltoluene, inhibited/ [R17] +Public safety: Call Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 50 to 100 meters (160 to 330 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate closed spaces before entering. /Vinyltoluene, inhibited/ [R17] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Structural firefighters' protective clothing will only provide limited protection. /Vinyltoluene, inhibited/ [R17] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, isolate for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Vinyltoluene, inhibited/ [R17] +Fire: Caution: All these products have a very low flash point: Use of water spray when fighting fire may be inefficient. Small fires: Dry chemical, CO2, water spray or regular foam. Large fires: Water spray, fog or regular foam. Do not use straight streams. Move containers from fire area if you can do it without risk. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. Always stay away from tanks engulfed in fire. For massive fire, use unmanned hose holders or monitor nozzles; if this is impossible, withdraw from area and let fire burn. /Vinyltoluene, inhibited/ [R17] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). All equipment used when handling the product must be grounded. Do not touch or walk through spilled material. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. A vapor suppressing foam may be used to reduce vapors. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. Use clean non-sparking tools to collect absorbed material. Large spills: Dike far ahead of liquid spill for later disposal. Water spray may reduce vapor; but may not prevent ignition in closed spaces. /Vinyltoluene, inhibited/ [R17] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. Wash skin with soap and water. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Vinyltoluene, inhibited/ [R17] REAC: *Incompatible with oxidizing agents, catalysts for vinyl polymerization, such as peroxides, strong acids, aluminum chloride. /Vinyl toluene/ [R18] SERI: *Slightly toxic by skin contact. [R19] EQUP: *Respirator selection, upper limit devices recommended by ACGIH. At concn up to 500 ppm, use any chemical cartridge respirator with organic vapor cartridge(s) or any supplied air respirator or any self-contained breathing apparatus. For concn up to 1000 ppm, use any powered air-purifying respirator with organic vapor cartridge(s) or any chemical cartridge respirator with a full facepiece and organic vapor cartridge(s). For concn up to 1250 ppm, use any supplied-air respirator operated in a continuous flow mode. For concn up to 2500 ppm, use any air-purifying full facepiece respirator (gas mask) with a chin-style or front- or back-mounted organic vapor canister or any self-contained breathing apparatus with a full facepiece or any supplied-air respirator with a full facepiece. For concn up to 5000 ppm, use any supplied-air respirator with a full facepiece and operated in a pressure-demand or other positive pressure mode. For emergency or planned entry in unknown concentrations or IDLH conditions, use any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode or any supplied-air respirator with a full facepiece and operated in a pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode. For escape conditions, use any air-purifying full facepiece respirator (gas mask) with a chin-style or front- or back-mounted organic vapor canister or any appropriate escape-type self-contained breathing apparatus. /Vinyl toluene/ [R20] OPRM: *Wear appropriate clothing to prevent repeated or prolonged skin contact. Wear eye protection to prevent ... eye contact. Employees should wash promptly when skin is wet or contaminated. Remove nonimpervious clothing promptly if wet or contaminated. /Vinyl toluene/ [R21] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R22] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R23] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R24] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *If vinyl toluene gets into the eyes, wash eyes immediately with large amounts of water, lifting the lower and upper lids occasionally. Get medical attention as soon as possible. Contact lenses should not be worn when working with this chemical. /Vinyl toluene/ [R25] *If vinyl toluene gets in the skin, promptly flush the contaminated skin with water. If vinyl toluene soaks through the clothing, remove the clothing immediately and flush the skin with water. When there is skin irritation, get medical attention. /Vinyl toluene/ [R25] *If a person breathes in large amounts of vinyl toluene, move the exposed person to fresh air at once. If breathing has stopped, perform artificial respiration. Keep the affected person warm and at rest. Get medical attention as soon as possible. /Vinyl toluene/ [R25] *If vinyl toluene has been swallowed, do not induce vomiting. Get medical attention immediately. /Vinyl toluene/ [R25] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool. Administer activated charcoal ... . /Aromatic hydrocarbons and related compounds/ [R26, p. 181-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious or in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Aromatic hydrocarbons and related compounds/ [R26, 182] MEDS: *Employees should be screened for history of certain medical conditions which might place the employee at increased risk from vinyl toluene exposure. Kidney disease: Although vinyl toluene is not known as a kidney toxin in humans, the importance of this organ in the elimination of toxic substances justifies special consideration in those with possible impairment of renal function. Chronic respiratory disease: In persons with impaired pulmonary function, especially those with obstructive airway disease, the breathing of vinyl toluene might cause exacerbation of symptoms due to its irritant properties or ... bronchospasm. Liver disease: Although vinyl toluene is not known as a liver toxin in humans, the importance of this organ in the biotransformation and detoxification of foreign substances should be considered before exposing persons with impaired liver function. Skin disease: Vinyl toluene is a defatting agent and can cause dermatitis on prolonged exposure. Persons with pre-existing skin disorders may be more susceptible to the effects of this agent. /Vinyl toluene/ [R25] HTOX: *VINYLTOLUENE (40% PARA-, 60% META-ISOMERS) WAS TESTED FOR POTENTIAL TO INDUCE CHROMOSOME ABERRATIONS AND SISTER CHROMATID EXCHANGE IN PHYTOHEMAGGLUTININ-STIMULATED HUMAN LYMPHOCYTES CULTURED FOR 48 HR (ABERRATION ANALYSIS) OR 72 HR (SISTER CHROMATID EXCHANGE ANALYSIS). THE TREATMENTS WERE CARRIED OUT 24 HR (ABERRATIONS) OR 48 HR (SISTER CHROMATID EXCHANGE) BEFORE HARVEST. THE TOXICITY OF VINYLTOLUENE WAS SIMILAR TO THAT OF STYRENE. CHROMOSOME ABERRATIONS WERE OBSERVED IN CELLS TREATED WITH 0.33 TO 4.00 MMOLAR VINYLTOLUENE. LIKE STYRENE, VINYLTOLUENE IS CONVERTED IN VITRO TO REACTIVE METABOLITES, PRESUMABLY EPOXIDES. /VINYL TOLUENE/ [R27] *... In human lymphocytes exposed in whole blood cultures, vinyl toluene induced both sister chromatid exchange and chromosomal aberrations in a dose-dependent manner, in the absence of exogenous metabolic activation. The induction of sister chromatid exchange was dependent on the number of erythrocytes present. Significant increases in the frequencies of sister chromatid exchange were observed in human lymphocytes exposed in whole blood cultures to ortho, meta and para isomer. The strongest responses were seen with the meta and para isomers, which are the dominant species in vinyl toluene. [R28] NTOX: *VINYLTOLUENE (72% PARA AND 28% ORTHO ISOMERS) EXHIBITED A /CNS DEPRESSANT/ EFFECT ... DURING EXPOSURE OF MICE, RATS, GUINEA PIGS, AND RABBITS BY VARIOUS ROUTES (ORAL, INHALATION, AND SKIN). DURING REPEATED EXPOSURE FOR 1 MO VINYLTOLUENE HAD SOME EFFECT ON THE CNS OF MICE, AND DURING CHRONIC INHALATION AT 0.03 MG/L IT CAUSED REDN IN WT OF MICE AND SYMPTOMS OF INTOXICATION IN THE OFFSPRING OF GUINEA PIGS. THE LIQUID FORM IRRITATED THE SKIN AND MUCOUS MEMBRANES OF EYES. /VINYL TOLUENE/ [R29] *The single oral rat LD50 of a meta- and para-isomer mixture was 4 g/kg. When animals received 92 to 100 seven- to eight-hour inhalation exposures of the mixture at 1250 ppm, there was an increase in renal and hepatic weights and fatty degeneration of the liver. Some mortality occurred in exposed rats, but all guinea pigs, rabbits, and monkeys survived. Similar exposures at 600 ppm were well tolerated, and all animals appeared normal as judged by body weight gain, hematology, organ weight, gross and microscopic examination of tissues, blood urea nitrogen, and the results of qualitative urinanalyses. [R30] *Groups of 60 male and 60 female Swiss mice, six weeks old, were administered 0 (control), 10, 50, or 250 mg/kg body weight vinyl toluene (purity, > 99%; 96.8% para isomer and 3% meta isomer) by gastric intubation in olive oil once a day on five days a week for 78 weeks. The study was terminated at 83 weeks, when the survival rate was reduced to less than 50% in at least one group. There was no treatment-related effect on survival of female mice or on body weight in mice of either sex; survival of male mice was reduced in treated groups, but /it was/ concluded that both the chemical and amyloidosis were causal factors in the increased mortality (survival data not provided). There was no significant treatment-related increase in either the percentage of mice with malignant tumors or with benign and malignant tumors combined or in the number of malignant tumors per mouse. [R31] *Groups of 60 or 90 male and 60 or 90 female Sprague Dawley rats, six weeks old, were administered 10, 50, 250, or 500 mg/kg body weight vinyl toluene (purity, > 99%; 96.8% para isomer and 3% meta isomer) by gastric intubation in olive oil once a day on five days a week for 108 weeks. Control groups of 60 male and 60 female rats received olive oil alone. Five rats from the 500 mg/kg group were killed at 54 and 107 weeks. The study was terminated at 123 weeks when the survival rate was reduced to less than 50% in at least one group. Survival of male rats receiving 250 and 500 mg/kg body weight was reduced (exact data not provided). There was no treatment-related effect on survival in female rats or on body weights of male or female rats and no treatment-related increase in either the percentage of rats with malignant tumors or with benign and malignant tumors combined nor in the number of malignant tumors per rat. [R31] NTXV: *LD50 Rat single oral para-isomer mixture 4 g/kg; [R30] *LD50 Rat oral 2255 mg/kg; [R19] *LD50 Rat ip 2324 mg/kg; [R19] *LD50 Mouse oral 1072 mg/kg; [R19] *LD50 Mouse ip 581 mg/kg; [R19] *LD50 Mouse iv 280 mg/kg; [R19] *LD50 Dog oral > 5 g/kg; [R19] *LD50 Rabbit skin > 5 g/kg; [R19] NTP: *Two yr toxicology and carcinogenesis studies were conducted by exposing groups of 50 F344/N rats of each sex to 0, 100 or 300 ppm vinyl toluene by inhalation, 6 hr/day, 5 days/wk for 103 wk. Groups of 50 B6C3F1 mice were exposed to 0, 10 or 25 ppm on the same schedule. Under the conditions of these 2 yr studies, there was no evidence of carcinogenicity for male or female F344/N rats and no evidence of carcinogenicity in male or female B6C3F1 mice. [R32] TCAT: ?para-Methyl styrene (CAS # 622-97-9) was evaluated for clastogenicity in male Sprague-Dawley rats (5/dose group) given doses of 0 (Methocel K4M vehicle control), 0.134, 0.045, 0.0134, or 0.006 gm/mL daily for 5 days. Two high-dose rats died during dosing and were replaced. Treatment-associated clinical signs included slight oral discharge and decrease activity among several high dose animals, slight nasal discharge in 1 mid-dose rat, and decreased activity in 1 low-dose rat. Blood levels of para-methylstyrene correlated to doses administered. No significant (Chi square analysis, p < 0.001) increased numbers of total aberrant cells, including those with chromosome breaks, chromatid breaks, exchanges, fragments, or pulverized contents, were observed in any treated group relative to controls. [R33] METB: *After ortho-, meta- and para-vinyl toluenes were injected intraperitoneally into male albino Wistar rats, 11 urinary metabolites were distinguished /para-vinylbenzoic acid, para-vinylbenzoyl glycine, vinyltoluene-7,8-oxide, para-methylphenyl acetaldehyde, para-methylphenylacetic acid, para-methylphenylacetyl glycine, para-methylphenylethylene glycol, para-methylmandelic acid, para-methylbenzoic acid, para-methylphenylglyoxylic acid, para-methylbenzoyl glycine/. The main metabolites were similar to the corresponding styrene metabolites and included ethylene glycol, mandelic acid, glyoxylic acid derivatives and N-acetylcysteine and glucuronide conjugates. Over 90% of the recovered metabolites were excreted within 24 hours. N-Acetylcysteine derivatives substituted at carbon 8 greatly exceeded (> 80%) those substituted at carbon 9 in Sprague Dawley rats, in spite of steric hindrance by the methyl group. [R34] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *4-Vinyltoluene's production and use as an specialty monomer in the production of styrene polymers may result in its release to the environment through various waste streams. If released to air, a vapor pressure of 1.8 mm Hg at 25 deg C indicates 4-vinyltoluene will exist solely as a vapor in the ambient atmosphere. Vapor-phase 4-vinyltoluene will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone; the half-lives for these reactions in air are estimated to be 12 and 13 hrs, respectively. 4-Vinyltoluene absorbs light in the environmental UV spectrum and has the potential for direct photolysis. If released to soil, 4-vinyltoluene is expected to have low mobility based upon an estimated Koc of 840. Volatilization from moist soil surfaces is expected to be an important fate process based upon an estimated Henry's Law constant of 3.2X10-3 atm-cu m/mole. 4-Vinyltoluene may volatilize from dry soil surfaces based upon its vapor pressure. If released into water, 4-vinyltoluene is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively. An estimated BCF of 32 for goldfish suggests the potential for bioconcentration in aquatic organisms is moderate. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to 4-vinyltoluene may occur through inhalation and dermal contact with this compound at workplaces where 4-vinyltoluene is produced or used. (SRC) ARTS: *4-Vinyltoluene's production and use as an specialty monomer in the production of styrene polymers(1) may result in its release to the environment through various waste streams(SRC). The removal of lead from gasoline and its subsequent replacement with aromatic compounds has caused an increased release of compounds such as vinyltoluenes to the atmosphere via fossil fuel combustion(2). Gasoline combustion in motorboats also releases 4-vinyltoluene to water(3). [R35] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 840(SRC), determined from a structure estimation method(2), indicates that 4-vinyltoluene is expected to have low mobility in soil(SRC). Volatilization of 4-vinyltoluene from moist soil surfaces is expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.2X10-3 atm-cu m/mole(SRC), based upon its vapor pressure, 1.8 mm Hg(3) and water solubility(4). The potential for volatilization of 4-vinyltoluene from dry soil surfaces may exist(SRC) based upon its vapor pressure(3). [R36] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 840(SRC), determined from a structure estimation method(2), indicates that 4-vinyltoluene is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon an estimated Henry's Law constant of 3.2X10-3 atm-cu m/mole(SRC), derived from its vapor pressure, 1.8 mm Hg(4), and its water solubility(5). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 3 hrs and 4 days, respectively(SRC). According to a classification scheme(6), a BCF of 32 for goldfish(7), suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). [R37] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 4-vinyltoluene, which has a vapor pressure of 1.8 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere(SRC). Vapor-phase 4-vinyltoluene is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals and ozone(SRC); the half-life for these reactions in air are estimated to be 12 hrs (rate constants = 3.2X10-11 cu cm/molecule-sec)(3) and 13 hrs (rate constant = 2.1X10-17 cu cm/molecule-sec)(4), respectively, at 25 deg C(SRC). 4-Vinyltoluene in methanol weakly adsorbs UV light in the environmentally significant range (wavelengths > 290 nm)(5). Hence, 4-vinyltoluene has the potential for direct photolysis in the environment(SRC). [R38] ABIO: *The rate constant for the vapor-phase reaction of 4-vinyltoluene with photochemically-produced hydroxyl radicals has been estimated as 3.2X10-11 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 12 hrs at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). The rate constant for the vapor-phase reaction of 4-vinyltoluene with ozone has been estimated as 2.1X10-17 cu cm/molecule-sec at 25 deg C(SRC) that was derived using a structure estimation method(1). This corresponds to an atmospheric half-life of about 13 hrs at an atmospheric concentration of 7X10+11 ozone molecules per cu cm(2). 4-Vinyltoluene is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(3). 4-Vinyltoluene in methanol weakly adsorbs UV light in the environmentally significant range (wavelengths > 290 nm)(4). Hence, 4-vinyltoluene has the potential for direct photolysis in the environment(SRC). [R39] BIOC: *A BCF of 32 in goldfish was measured for 4-vinyltoluene(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is moderate(SRC). [R40] KOC: *Using a structure estimation method based on molecular connectivity indices(1), the Koc for 4-vinyltoluene can be estimated to be 840(SRC). According to a classification scheme(2), this estimated Koc value suggests that 4-vinyltoluene is expected to have low mobility in soil(SRC). [R41] VWS: *The Henry's Law constant for 4-vinyltoluene is estimated as 3.2X10-3 atm-cu m/mole(SRC) derived from its vapor pressure, 1.8 mm Hg(1), and water solubility, 89 mg/l(2). This Henry's Law constant indicates that 4-vinyltoluene is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 3 hrs(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4 days(SRC). 4-Vinyltoluene's estimated Henry's Law constant indicates that volatilization from moist soil surfaces may occur(SRC). The potential for volatilization of 4-vinyltoluene from dry soil surfaces may exist(SRC) based upon a vapor pressure of 1.8 mm Hg(1). [R42] WATC: *DRINKING WATER: 4-Vinyltoluene was listed as a contaminant found in drinking water for a survey of US cities including Pomona, CA, Escondido, CA, Lake Tahoe, CA, and Orange Co, CA, Dallas, TX, Washington, DC, Cincinnati, OH, Philadelphia, PA, Miami, FL, New Orleans, LA, Ottumwa, IA, and Seattle, WA(1). [R43] EFFL: *Motorboats emitted 4-vinyltoluene to canal water; concn were not reported(1). The removal of lead from gasoline and its subsequent replacement with aromatic compounds has caused an increased release of compounds such as vinyltoluenes to the atmosphere via fossil fuel combustion(2). [R44] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 5,274 workers (377 of these are female) are potentially exposed to 4-vinyltoluene in the US(1). Occupational exposure to 4-vinyltoluene may occur through inhalation and dermal contact with this compound at workplaces where 4-vinyltoluene is produced or used(SRC). [R45] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *NIOSH Method 1501. Hydrocarbons, Aromatic. Matrix: Air, Gas Chromatography, Flame Ionization Detection; estimated limit of detection of 0.001-0.01 mg per sample /Vinyltoluene/ [R46] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Health and Environmental Effects Profile for Methyl Styrenes (1987) ECAO-CIN-G006 O'Donoghue JL; p.127-37 in Neurotoxicity of Industrial and Commercial Chemicals; O'Donoghue JL, ed (1985). The toxic effects of toluene and styrene in humans and in experimental animals were reviewed. DHHS/NTP; Toxicology and Carcinogenesis Studies of Vinyl toluene (Mixed Isomers) in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 375 (1990) NIH Publication No. 90-2830 SO: R1: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present. R2: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 596 R3: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V22 (1997) 988 R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 374 (1994) R5: SRI International. 2000 Directory of Chemical Producers -- United States. SRI Consulting, Menlo Park: CA 2000 751 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 3rd ed., Volumes 1-26. New York, NY: John Wiley and Sons, 1978-1984.,p. V23 270 R7: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V7 (1993) 29 R8: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V8 (1993) 938 R9: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 375 (1994) R10: United States International Trade Commission. Synthetic Organic Chemicals - United States Production and Sales, 1992. USITC Publication 2720, Feb. 1994 Washington, D.C.: United States Trade Commission, 1994.p. 3-16 R11: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-47 R12: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R13: Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984) R14: Yaws C, Yang HC; Pollut Engin 22: 70-5 (1990) R15: Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994.,p. V1 960 R16: Boublik, T., Fried, V., and Hala, E., The Vapour Pressures of Pure Substances. Second Revised Edition. Amsterdam: Elsevier, 1984. 704 R17: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-130 R18: NIOSH. Pocket Guide to Chemical Hazards. 2nd Printing. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, February 1987.236 R19: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 3383 R20: NIOSH. Pocket Guide to Chemical Hazards. 2nd Printing. DHHS (NIOSH) Publ. No. 85-114. Washington, D.C.: U.S. Dept. of Health and Human Services, NIOSH/Supt. of Documents, GPO, February 1987.p. 188-189 R21: Sittig, M. Handbook of Toxic and Hazardous Chemicals and Carcinogens, 1985. 2nd ed. Park Ridge, NJ: Noyes Data Corporation, 1985. 926 R22: 49 CFR 171.2 (7/1/2000) R23: IATA. Dangerous Goods Regulations. 42nd Ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Regulations, 2001. 241 R24: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.3392 (1998) R25: Mackison, F. W., R. S. Stricoff, and L. J. Partridge, Jr. (eds.). NIOSH/OSHA - Occupational Health Guidelines for Chemical Hazards. DHHS(NIOSH) Publication No. 81-123 (3 VOLS). Washington, DC: U.S. Government Printing Office, Jan. 1981. R26: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. R27: NORPPA H; CARCINOGENESIS (LOND) 2 (3): 237-42 (1981) R28: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 382 (1994) R29: KRYNSKAYA IL ET AL; GIG SANIT 34 (9): 40-5 (1969) R30: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1717 R31: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 378 (1994) R32: DHHS/NTP; Toxicology and Carcinogenesis Studies of Vinyl toluene (Mixed Isomers) in F344/N Rats and B6C3F1 Mice (Inhalation Studies) Technical Report Series No. 375 (1990) NIH Publication No. 90-2830 R33: Mobil Oil Corp; Metaphase Analysis of Rat Bone Marrow Cells Treated In Vivo with para-Methylstyrene; 10/30/81; EPA Doc No. 40-8258107; Fiche No. OTS0514320 R34: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V60 380 (1994) R35: (1) Chen SS; Kirk-Othmer Encycl Chem Tech 4th ed. NY, NY: John Wiley and Sons 22: 988 (1997) (2) Grosjean D; Sci Total Environ 46: 41-59 (1985) (3) Juttner F; Z Wasser-Abwasser-Forrsch 21: 36-9 (1988) R36: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Boublik T et al; The Vapor Pressures of Pure Substances. Amsterdam, The Netherlands: Elsevier, pp. 704-5 (1984) (4) Yaws C, Yang HC; Pollut Engin 22: 70-5 (1990) R37: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 15-1 to 15-29 (1990) (4) Boublik T et al; The Vapor Pressures of Pure Substances. Amsterdam, The Netherlands: Elsevier, pp. 704-5 (1984) (5) Yaws C, Yang HC; Pollut Engin 22: 70-5 (1990) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984) R38: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Boublik T et al; The Vapor Pressures of Pure Substances. Amsterdam, The Netherlands: Elsevier, pp. 704-5 (1984) (3) Atkinson R; Int J Chem Kinetics 19:799-828 (1987) (4) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (5) Sadtler Res Lab; Sadtler Standard UV spectra No. 8303 (NA) R39: (1) Atkinson R; Int J Chem Kinetics 19:799-828 (1987) (2) Atkinson R, Carter WPL; Chem Rev 84: 437-70 (1984) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) (4) Sadtler Res Lab; Sadtler Standard UV spectra No. 8303 (NA--) R40: (1) Ogata M et al; Bull Environ Contam Toxicol 33: 561-7 (1984) (2) Franke C et al; Chemosphere 29: 1501-14 (1994) R41: (1) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (2) Swann RL et al; Res Rev 85: 17-28 (1983) R42: (1) Boublik T et al; The Vapor Pressures of Pure Substances. Amsterdam, The Netherlands: Elsevier pp. 704-5 (1984) (2) Yaws C, Yang HC; Pollut Engin 22: 70-5 (1990) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R43: (1) Lucas SV; GC/MS Anal of Org in Drinking Water Concentrates and Advanced Treatment Concentrates Vol 1 USEPA-600/1-84-020A (NTIS PB85-128239) p. 397 (1984) R44: (1) Juttner F; Z Wasser-Abwasser-Forrsch 21: 36-9 (1988) (2) Grosjean D; Sci Total Environ 46: 41-59 (1985) R45: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R46: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. RS: 38 Record 350 of 1119 in HSDB (through 2003/06) AN: 6515 UD: 200303 RD: Reviewed by SRP on 11/30/1992 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: ZIDOVUDINE- SY: *3'-Azido-3'-deoxythymidine-; *Azidothymidine-; *AZT-; *BW-A509U-; *Retrovir- RN: 30516-87-1 MF: *C10-H13-N5-O4 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- FORM: *Oral capsules, 100 mg, Retrovir; Burroughs Wellcome; solution, 50 mg/5 ml, Retrovir syrup, Burroughs Wellcome; parenteral injection for iv infusion, 10 mg/ml, Retrovir iv Infusion, Burroughs Wellcome. [R1, 401] MFS: *Burroughs Wellcome Co, Hq, 3030 Cornwallis Rd, Research Triangle Park, NC 27709, (919) 248-3000; Production site: Greenville, NC 27834 [R1, 401] USE: +MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White to off-white crystalline solid [R1, 392]; *Needles from petroleum ether [R2, 1597] ODOR: *Odorless [R1, 392] MP: *106-112 deg C [R2, p. 15f97] MW: *267.24 [R2, 1597] SOL: *20 mg/ml in water and 71 mg/ml in alc @ 25 deg C [R1, 392] OCPP: *Zidovudine is a thymidine analog which differs structurally from thymidine in that zidovudine contains a 3'-azide group rather than a 3'-hydroxyl group. [R1, 392] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- STRG: *Commercially available zidovudine ... Should be stored @ 15-25 deg C and protected from heat, light and moisture. [R1, 392] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: There is inadequate evidence in humans for the carcinogenicity of zidovudine. There is sufficient evidence in experimental animals for the carcinogenicity of zidovudine. Overall evaluation: Zidovudine is possibly carcinogenic to humans (Group 2B). [R3] ANTR: *If acute overdosage of zidovudine occurs, supportive and symptomatic treatment should be initiated and the patient should be observed carefully. ... The stomach /should/ be emptied by inducing emesis and ... activated charcoal/should be/ administered to prevent further absorption of unrecovered drug. [R1, 399] HTOX: *Myalgia has been reported in 8% of patients receiving zidovudine, and ... using usual oral dosages of the drug, occurred more frequently in treated patients than in those receiving placebo. Severe, necrotizing myopathy, which generally affected the legs, and a polymyositis like syndrome have been reported occasionally. ... Pigmentation of fingernails and toenails has been reported occasionally in patients receiving zidovudine. [R1, 398] *Increases in liver function test results, including AST (SGOT), LDH, and alkaline phosphatase concentrations, have occurred in several patients within 2-3 weeks after initiating zidovudine therapy; serum concentrations of these enzymes returned to pretreatment values when therapy with the drug was withheld and did not increase when therapy was restarted. Acute cholestatic hepatitis, which recurred on rechallenge, has been reported in at least one patient. [R1, 398] *Anemia (hemoglobin concentration less than 7.5 g/dl) has occurred in 30% and granulocytopenia (granulocyte count less than 750/cu mm) in 47% of patients with pretreatment helper/inducer (CD4+, T4+) T-cell counts of 200/cu mm or less, but these hematologic effects have occurred in only 3 and 10%, respectively, of patients with pretreatment counts greater than 200/cu mm. A decrease in hematocrit of greater than 10% may also occur. [R1, 397] *Headache, which may be severe, has been reported in up to 50% of patients receiving zidovudine, and asthenia has been reported in about 20%. Malaise, somnolence, paresthesia, dizziness, agitation, restlessness, and insomnia have been reported in up to 8% of patients, most frequently in those who received high dosage of the drug ... Using usual oral dosages of zidovudine, severe headache and insomnia occurred more frequently in treated patients than in those receiving placebo. [R1, 397] *Nausea has been reported in about 50%, GI/abdominal pain in 20%, diarrhea in 12%, and dyspepsia, anorexia, and vomiting in 5-11% of patients receiving usual dosages of zidovudine. ... Using usual oral dosage of zidovudine, nausea was the only adverse GI effect that occurred more frequently in treated patients than in those receiving placebo. Constipation, dysphagia, edema of the tongue, eructation, flatulence, bleeding gums, rectal hemorrhage, and mouth ulcer have been reported in less than 5% of patients receiving zidovudine, but a causal relationship to the drug has not been definitely established. In asymptomatic HIV infected patients receiving low dose (100 mg 5 times daily) zidovudine therapy, nausea was reported in about 3% of patients. ... To reduce the risk of esophageal irritation and ulceration, patients should be advised to swallow zidovudine capsules while in an upright position and with adequate amounts of fluid (eg, at least 120 ml of water). [R1, 398] *Lymphadenopathy and non-Hodgkin's lymphoma have been reported in patients receiving zidovudine, although the possible contribution of the drug to their development remains to be elucidated. [R1, 399] *Zidovudine therapy has been used throughout pregnancy in several women with HIV infections without evidence of teratogenicity or harm to the fetus. ... [R1, 399] *Acute overdosages of zidovudine (up to 50 g) have been reported in both adults and children. There were no fatalities as a result of these overdosages and all patients recovered without permanent sequelae. The only consistent finding was spontaneous or induced nausea and vomiting. Although adverse hematologic effects, including anemia and a decrease in hemoglobin, occurred in a few patients following zidovudine overdosage, these effects were mild and transient and there was no evidence of prolonged bone marrow toxicity attributable to acute zidovudine overdosage. Acute overdosage of zidovudine (10-40 g) alone or in conjunction with overdosage of a bonzodiazepine and/or barbiturate has resulted in mild ataxia, lethargia, and fatigue. A single tonic-clonic (grand mal) seizure occurred in an adult who ingested 36 g of zidovudine in a single dose. In another adult who inadvertently received 2.5 g (33 mg/kg) of zidovudine daily for 16 days, there was an increase in serum concentrations of aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) and alanine aminotransferase (serum glutamic-pyruvic transaminase), but no evidence of bone marrow toxicity. [R1, 399] *Zidovudine caused dose related structural chromosomal abnormalities at concentrations of 3 ug/ml and higher in an in vitro cytogenetic study in cultured human lymphocytes, but not at the lowest concentrations tested (0.3 and 1 ug/ml). [R1, 399] *For several human cell lines, zidovudine had little effect on cell growth except at concentrations greater than 50 ug/ml; human fibroblasts and lymphocytes generally showed little inhibition of growth except at very high concentrations of the drug. However, one human T-cell line was susceptible to the cytotoxic effect of zidovudine, and the ID50 (concentration of the drug required to produce 50% inhibition of cell growth) was 5 ug/ml. In a colony forming unit assay designed to assess the toxicity of the drug for human bone marrow, zidovudine exhibited a direct, dose dependent inhibitory effect on erythroid and myeloid function in vitro; the ID50 of the drug was estimated to be less than 1.25 ug/ml. About 20% of human lympohocyte cultures tested have been susceptible to zidovudine concentrations of 5 ug/ml or less. [R1, 393] *Zidovudine induced depletion of normal pyrimidine pools may contribute to the bone marrow toxicity reported during therapy with the drug. [R1, 393] *The expanding indications for zidovudine treatment make it important to elucidate the safety and toxicity of this drug for pregnant women and their fetuses. Pediatricians and obstetricians at the (Acquired Immunodeficiency Syndrome Clinical Trials Units reported information about pregnant women infected with the human immunodeficiency virus who were continuing their pregnancies and had received, or were receiving, zidovudine during gestation. Reports of 43 women were received from 17 institutions. Doses of zidovudine ranged from 300 to 1200 mg/day and 24 women took the drug for at least two trimesters. There were two reported instances of maternal toxicity (one gastrointestinal and one hematologic). No teratogenic abnormalities occurred in the 12 infants with first-trimester exposure to zidovudine. All the infants, including two sets of twins, were born alive. The 38 singleton infants born at term for whom birth weights were reported had a mean birth weight of 3287 + or - 670 g; two cases of intrauterine growth retardation were reported among the infants delivered at term. Hemoglobin values, which were available for 31 newborns, ranged from 7.0 to 12.4 mmol/l (11.2 to 20 g/dl); 3 of the 7 newborns with hemoglobin values of less than 8.4 mmol/l (13.5 g/dl) were born prematurely. ... Zidovudine was well tolerated by the pregnant women and was apparently not associated with malformations in the newborns, premature birth, or fetal distress. No pattern of hematologic toxicity was observed in the newborns, but the anemia and growth retardation seen in a minority of the infants could, in part, have resulted from their mothers' treatment with zidovudine. [R4] NTOX: *Zidovudine was carcinogenic at concentrations of 0.5 ug/ml and higher in an in vitro mammalian cell transformation assay. ... Long-term studies in animals have revealed some evidence of carcinogenic potential at oral dosages estimated as being comparable to 3-24 times the usual human maintenance dosage. Approximately 12% of female mice receiving the highest oral dosages (ie, 120 mg/kg daily initially and then 40 mg/kg daily) ... developed vaginal neoplasms after 19 months of drug administration. One animal receiving an intermediate dosage (60 mg/kg daily and then 30 mg/kg daily) developed vaginal squamous cell papilloma late in the study, but no vaginal neoplasms were observed in mice receiving the lowest dosage studies. A similar study in rats also demonstrated the development of nonmetastisizing vaginal squamous cell carcinoma in animals receiving the highest oral dosages (ie, 600 mg/kg daily initially and then 300 mg/kg daily) after 20 months of drug administration; no vaginal neoplasms occurred in rats receiving low or intermediate study dosages. There were no other drug related neoplasms observed in either sex of either species studied. [R1, 399] *Reproduction studies in rats and rabbits using oral zidovudine in doses up to 20 times the usual human dose have not revealed evidence of teratogenicity. However, the incidence of fetal resorptions was increased in rats given 7 or 20 times the usual human dose and rabbits given 20 times the usual human dose of zidovudine. [R1, 399] *There was no evidence that zidovudine affected fertility when the drug was given orally to male and female rats in doses up to 20 times the usual human dose. [R1, 399] *Zidovudine was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. However, in a mammalian mutagenicity assay using L5178Y/TK + or - mouse lymphoma cells, zidovudine was weakly mutagenic in the presence of metabolic activation at concentrations of 1000 ug/ml and higher and was also weakly mutagenic in the absence of metabolic activation at concentrations of 4000 and 5000 ug/ml ... In an in vivo cytogenetic study in rats given a single IV dose of 37.5-300 mg/kg, there were no drug related structural or numerical chromosomal alterations despite plasma concentrations of up to 453 ug/ml at 5 minutes dosing. [R1, 399] *Zidovudine inhibits HIV 1 replication in AIDS. A limiting side effect is zidovudine induced toxic myopathy. Molecular changes in a rat model of zidovudine induced toxic myopathy in vivo helped define pathogenetic molecular, biochemical, and ultrastructural toxic events in skeletal muscle and supported clinical and in vitro findings. After 35 days of zidovudine treatment, selective changes in rat striated muscle were localized ultrastructurally to mitochondria, and included swelling, cristae disruption, and myelin figures. Decreased muscle mitochondrial DNA, mitochondrial RNA, and decreased mitochondrial polypeptide synthesis in vitro were found in parallel. Mitochondrial molecular changes occurred in absence of altered abundance of cytosolic glyceraldehyde-3-phosphate dehydrogenase, or sarcomeric mitochondrial creatine kinase mRNAs. Quadriceps mitochondrial DNA polymerase gamma activity was similar in both zidovudine treated and control rats. In vivo findings with rats support the hypothesis that zidovudine induced inhibition of mitochondrial DNA replication has an effect of depressing the abundance of striated muscle mitochondrial DNA, mitochondrial RNA, and mitochondrial polypeptide synthesis. This experimental approach may be useful to examine mitochondrial or toxic myopathies. [R5] *The long term effect was studied of continued zidovudine exposure in mice on hematopoiesis, as determined by peripheral blood indices, assays of erythroid colony forming unit-erythroid and burst forming unit-erythroid, myeloid colony forming unit-granulocyte macrophage, megakaryocyte colony forming unit-megakaryocytes, and plasma titers of erythropoietin, granulocyte macrophage colony stimulating factor, megakaryocyte colony stimulating factor, and tumor necrosis factor alpha. Dose escalation of zidovudine (0.1, 1.0, and 2.5 mg/ml) induced a dose dependent decrease in hematocrit, white blood cells, and platelets. High dose drug, ie, greater than 1.0 mg/ml, reduced marrow colony forming unit erythroid; splenic colony forming unit-erythroid was increased after 1 week, then declined. Burst forming unit-erythroid was increased at weeks 1 and 2, then declined to control levels. Splenic burst forming unit-erythroid rose during the examination period that was dose dependent. Femoral colony forming unit granulocyte macrophage was cyclic, ie, low dose drug, 0.1 mg/ml, was increased gradually, then declined; higher doses of 1.0 and 2.5 mg/ml were lower until week 5, then were above controls. Splenic colony forming unit-granulocyte macrophage was increased initially at week 2 (1.0 mg/ml), then declined; the higher dose (2.5 mg/ml) increased initially, then declined below controls (week 6). Femoral colony forming unit-megakaryocyte was increased after low dose drug and inhibited after high dose (2.5 mg/ml). Splenic colony-forming unit-megakaryocyte was reduced initially, followed by an increase at week 4. Plasma titer of erythropoietin was elevated, proportional to dose escalation of drug, and inversely proportional to the hematocrit. No difference was observed in plasma levels of granulocyte macrophage colony stimulating factor, megakaryocyte colony stimulating factor, or tumor necrosis factor-alpha. This study demonstrates that zidovudine induced anemia results from: (i) inadequate numbers of bone marrow derived, erythropoietin dependent hematopoietic progenitors, ie, colony forming unit-erythroid; and (ii) a shift in erythropoietin responsive progenitors from bone marrow to spleen capable of responding to obligatory growth factors. [R6] *Groups of 20 female Wistar rats ... were given three oral doses of 100 mg zidovudine/kg at 5 hr intervals on gestation day 10 (total dose = 300 mg/kg). Control rats received three oral doses of the vehicle, distilled water. This design approximated that of an earlier study that reported 38% postnatal mortality among the offspring of Wistar rats given zidovudine. In the study reported here, no adverse effects were noted on maternal body weight, food consumption, reproductive capacity, or hematology. Similarly, no effects on growth or survival of the offspring were noted. Hematology and clinical chemistry values were comparable between offspring of treated and control dams, and no treatment related gross or histopathologic lesions were noted in the weanling rats. The mean concentration of zidovudine in embryonal homogenates, collected 30 min after administration of the third dose to the dam on gestation day 10, was 21.1 micrograms/g tissue. This value is approximately 1/3 of the mean drug plasma concentration (62.6 micrograms/ml) measured in the dams at the same time point. The dramatic difference in results in the two studies may be related to differences in Wistar rats from two different sources or to other unknown factors associated with the design and conduct of the studies. The results of the current study were consistent with other preclinical studies on the reproductive toxicity of zidovudine in rats and rabbits. [R7] *To examine the mechanism of mitochondrial myocytotoxicity caused by long term administration of zidovudine in human immunodeficiency virus positive patients, the effect of zidovudine was examined in vitro on human muscle in tissue culture and in vivo in rats treated with daily intraperitoneal injections of zidovudine at doses equivalent to the total daily dose used in acquired immunodeficiency syndrome patients. After 19 days, the zidovudine treated myotubes in tissue culture exhibited abnormal mitochondria characterized by proliferation (mean + or - standard deviation, 27.5 + or - 8 mitochondria/16 sq microns surface area, compared with 12.8 + or - 4 in the control cultures (p < 0.001), enlarged size, abnormal cristae and electron dense deposits in their matrix. The changes were partially reversible after zidovudine withdrawal. Rats treated with zidovudine developed weight loss, 100 fold elevation of creatine kinase, and increased serum lactate and glucose. In tissues, zidovudine had its highest concentration in the skeletal muscle and the heart. Skeletal and heart muscles from the treated animals, but not the controls, showed enlarged mitochondria with disorganized or absent cristae and electron dense deposits in their matrix. Study of the mitochondrial functions assessed by evaluating stimulated oxygen consumption rate, enzymatic activities of electron transport chain and coupling state of oxidative phosphorylation (respiratory control ratio) revealed a decrease in rotenone sensitive reduced nicotinamide adenine dinucleotide cytochrome C reductase (complex I + III) and an uncoupling effect demonstrated by decreased respiratory control ratio. It was concluded that zidovudine, a DNA chain terminator, is a muscle mitochondrial toxin that affects the oxidation phosphorylation coupling and the activity of complex I and III of the mitochondrial respiratory chain. [R8] *The effects of zidovudine on parameters of the reproductive and hematopoietic systems of male rats were evaluated and compared to those of the controls. Young male Wistar rats were divided into three groups. The control rats (Group 1) received no drug. Zidovudine was administered via drinking water to rats in Groups 2 and 3 (0.1 mg/ml Group 2, and 1.0 mg/ml Group 3) for 4 weeks. Daily water intake and weekly body weight were monitored. Serum luteinizing hormone, follicle stimulating hormone, testosterone, prolactin and intratesticular testosterone levels were determined by specific radioimmunoassays. Serum zidovudine was measured by high performance liquid chromatography. Bone marrow toxicity was monitored by colony forming units of erythroid and granulocyte macrophage assays. The body weight of all rats increased 2 fold in four weeks, and no significant differences were observed between control and treated groups. Ventral prostate weight decreased significantly (p < 0.05) by 32% in Group 2 and 27% in Group 3 rats, compared to the control group. Seminal vesicle weight decreased by 20% in Group 2 (NS) and 30% in Group 3 (p < 0.05) rats. No significant differences were observed in testes weight or in the intratesticular sperm count between control and zidovudine treated groups. Serum testosterone levels (ng/ml) decreased significantly in Group 2 rats (2.8 + or - 0.4 in control to 1.7 + or - 0.2, p < 0.05) but recovered (2.6 + or - 0.5) in Group 3 when compared to Group 1 (control). Serum luteinizing hormone and prolactin levels showed a significant increase (p < 0.05) in Group 3 compared to control or Group 2 rats. Serum follicle stimulating hormone and intratesticular testosterone levels showed no significant change. A significant (p < 0.05) dose dependent decrease in colony forming units of erythroid and in colony forming units of granulocyte-macrophage was observed in zidovudine treated rats compared to controls. These results demonstrate that the effects of zidovudine on the reproductive system in the male rat are more subtle and complex, compared to its significant effects on bone marrow. This suggests that important interactions may exist between the endocrine and hematopoietic systems. [R9] *The ability of vitamin E (alpha-tocopherol) to stimulate erythroid progenitor cells was investigated in an attempt to identify ways to ameliorate zidovudine induced anemia. In vitro, alpha-tocopherol acid succinate, upon incubation with murine bone marrow cells at concentrations of up to 4 micrograms/ml, caused a dose dependent increase in erythroid colony forming unit derived colonies. This increase was equivalent to the effect demonstrated by 50 mU of recombinant human erythropoietin or 200 U of recombinant interleukin-3. For in vivo studies, anemia was produced in CD-1 male mice by administering zidovudine in drinking water (1.5 mg/ml). Treatment with vitamin E (50 mg/kg body weight) or erythropoietin (0.4 U per mouse) was initiated 24 hr later and continued for five consecutive days. Seventh day bone marrow cells from femurs were assayed for erythroid colony forming unit derived colonies. Both vitamin E and erythropoietin significantly increased the number of erythroid colony forming unit derived colonies by 75% and 86% of control, respectively, indicating that these agents were approximately similar in protecting the bone marrow from zidovudine induced toxicity. [R10] *Chronic exposure of H9 cells to 25 microM zidovudine causes a 2 to 3 fold increase in thymidine kinase activity. The present study compared thymidine and zidovudine anabolism in H9 and H9-zidovudine cells. After a 3.5 hr incubation with 10 microM thymidine or zidovudine, the total intracellular accumulations of zidovudine (48.7 microM in H9 cells and 32.8 microM in H9-zidovudine cells) were 46.4% of thymidine accumulation. Other major differences between thymidine and zidovudine anabolism were: (i) the majority of thymidine (84-87%) was incorporated into DNA compared to less than 1% of zidovudine; and (ii) whereas distribution of thymidine in the nucleotides was thymidine triphosphate greater than thymidine monophosphate greater than thymidine diphosphate, zidovudine distributed was zidovudine monophosphate much greater than zidovudine triphosphate much greater than zidovudine diphosphate. Because of the poor substrate activity of zidovudine monophosphate for thymidylate kinase (thymidine monophosphate kinase), most of the zidovudine (95-98%) remained as zodovudine monophosphate. Thymidine monophosphate kinase activities with thymidine monophosphate as substrate were 47.6 + or - 20.3 and 91.4 + or - 28.8 pmol/mg protein/min in H9 and H9-zidovudine cells, respectively. 5'-Nucleotidase activities with thymidine monophosphate as substrate were 428.9 + or - 37.8 and 255.9 + or - 28.7 pmol/mg protein/min in H9 and H9-zidovudine cells, respectively. Activities of these enzymes with zidovudine monophosphate as a substrate were very low. Despite an increase in thymidine kinase and thymidine monophosphate kinase, and a decrease in 5'-nucleotidase activities, the total intracellular accumulations of thymidine and zidovudine were reduced significantly (p < 0.05) to 67.5% in H9-zidovudine cells. Thymidine transport (0.66 to 0.68 pmol/sec/1 X 10+6 cells) was similar in both the cell lines. The severe reductions of thymidine salvage caused by chronic exposure of cells to zidovudine, if it occurs in AIDS patients on zidovudine chemotherapy, may explain some of the long term clinical toxicities of the drug. [R11] *Zidovudine toxicity to the bone marrow is a major hindrance to its widespread clinical application in the treatment of the acquired immunodeficiency syndrome. The prediction of a mathematical model that cytotoxicity to the host can be reduced when the frequency of drug administration is an integer multiple of the target cell average cycle time (ca 7 hr in murine bone marrow cells) was verified. In vivo experiments in mice were reported showing that a 7 hr frequency of zidovudine administration is significantly less toxic than other frequencies when peripheral blood parameters and the proportion of bone marrow cells arrested at the S-phase gate of the DNA content distribution are considered. [R12] *Feline leukemia virus infection of cats is a model for the acquired immunodeficiency syndrome in humans. The toxicity of zidovudine was evaluated in SPF cats experimentally infected with feline leukemia virus. At initiation of the zidovudine study, all cats were antibody positive for feline leukemia virus antigens but clinically asymptomatic. Four cats were also viremic. Thirteen, 6 to 10 mo old cats were divided into five dosage groups and given zidovudine orally at 0, 7.5, 15, 30, or 60 mg/kg daily in three equally divided doses for 32 to 34 days. Titers of circulating virus antigen remained constant; however, three of six cats receiving the higher doses of zidovudine (greater than or equal to 30 mg/kg) showed an increase in antibody titers to feline leukemia virus. Administration of zidovudine resulted in a progressive anemia, dependent upon dose and time. Macrocytes were observed prior to the development of anemia and were also found in several nonanemic cats. Repeated measures regression analyses indicated that an increased dose of zidovudine was associated with decreased packed cell volume, red blood cell count, and hemoglobin. As determined from the packed cell volume, the analyses indicate that anemia is induced only by the two highest doses of zidovudine. The regression model indicates that daily doses of 60 and 30 mg/kg are expected to induce anemia by day 4 and day 13, respectively. Progressive absolute neutropenia was observed in the greater than or equal to 30 mg/kg groups. Histopathologic lesions consisted of marked bone marrow hypercellularity in cats given greater than or equal to 30 mg/kg zidovudine and splenic extramedullary hematopoiesis in cats given greater than or equal to 15 mg/kg. Thus, oral toxicity of zidovudine in the cat is manifested by a dose related anemia and neutropenia as observed in humans. [R13] +... CONCLUSIONS: Under the conditions of these 2 yr gavage studies there was equivocal evidence of carcinogenic activity of AZT in male mice based on incr incidences of renal tubule and harderian gland neoplasms in groups receiving AZT ... . There was clear evidence of carcinogenic activity of AZT in female mice based on incr incidences of squamous cell neoplasms of the vagina in groups that received AZT. ... [R14] NTXV: *LD50 Rat iv > 750 mg/kg; [R1, 399] *LD50 Mice iv > 3000 mg/kg; [R1, 399] NTP: +... Groups of 95 male and 95 female B6C3F1 mice received AZT in 0.5% methylcellulose by gavage at daily doses of 0, 30, 60 or 120 mg/kg body wt, admin as two equal doses at least 6 hr apart, 5 days/wk for 105 wk. Each group of 95 animals was composed of a core group of 50 animals for evaluation of a carcinogenic response, a group of 30 animals for evaluation of hematology and bone marrow cellularity, and a group of 15 animals from which blood was drawn for determination of plasma AZT concn at week 54. ... CONCLUSIONS: Under the conditions of these 2 yr gavage studies there was equivocal evidence of carcinogenic activity of AZT in male mice based on incr incidences of renal tubule and harderian gland neoplasms in groups receiving AZT ... . There was clear evidence of carcinogenic activity of AZT in female mice based on incr incidences of squamous cell neoplasms of the vagina in groups that received AZT. ... [R14] +... In the present study, timed-mated CD-1(R) mice were dosed by gavage with 3'-azido-3'-deoxythymidine (0, 100, 200, or 400 mg/kg/day) plus 2', 3'-Dideoxycytidine (0, 200, or 500 mg/kg/day) on gestational days (gd) 6 through 15. The vehicle was 0.5% aqueous methylcellulose. Total daily doses were divided (a.m. and p.m., each with a volume of 10 ml/kg body weight (wt.)). The oral route corresponds to one of the commonly used routes in human patients. Timed-mated mice (24-25/group) were monitored at regular intervals for clinical signs of toxicity, feed intake, and body wt. ... For 3'-azido-3'-deoxythymidine alone, there were no maternal deaths or remarkable clinical signs. Downward trends for maternal body wt., wt. gain and gravid uterine wt. were noted. Liver wt. (absolute or relative) was unaffected. Average daily feed intake (gestational days 9 to 12) was transiently decreased at the high dose. Prenatal mortality (resorptions or late fetal deaths) was equivalent among groups. Fetal body wt. was reduced by 10% (significant) in the low- and high-dose groups, and by 6% (nonsignificant) in the mid-dose group. Fetal morphological anomalies were not dose-related. For 2', 3'-Dideoxycytidine alone, maternal mortality (4%) was noted at the high dose, but otherwise clinical observations were unremarkable. Maternal body wt., wt. gain, gravid uterine and liver wts. were unaffected. There were no consistent treatment-related changes in maternal feed intake. Prenatal mortality or fetal morphological anomalies were unaffected, but fetal body wt. was reduced by 13% (significant) at the high dose. For endpoints with a significant p value in the overall (12-group) model, 3'-Azido-3'-deoxythymidine/2', 3'-dideoxycytidine combinations were compared to their constituent doses. Differences between each drug combination and its constituent doses are summarized below, excluding two parameters (maternal feed intake and percent male fetuses) that failed to show a consistent pattern of treatment-related effects. At 100 3'-Azido-3'-deoxythymidine/200 2', 3'-dideoxycytidine, maternal body wt. change (gestational days 9 to 12) was lower than for either constituent dose. Incidences of resorptions, adversely affected implants, and skeletal malformations were higher, and body weight was lower than for 2', 3'-dideoxycytidine alone. The incidence of skeletal variations was higher than for either constituent dose. At 100 3'-azido-3'-deoxythymidine/500 2', 3'-ddeoxycytidine, maternal body wt. (gestational days 15, 17) and wt. change (gestational days 9 to 12, 15 to 17, 0 to 17) were lower than for 3'-azido-3'-deoxythymidine alone. Maternal wt. gain (gestational days 12 to 15 and 6 to 15) and gravid uterine wt. were lower and relative liver wt. was higher than for either constituent dose. The incidence of adversely affected implants was higher and fetal body wt. was lower than for either constituent dose. Incidences of external, visceral or skeletal malformations, as well as all variations, were higher than for either treatment alone. At 200 3'-azido-3'-deoxythymidine/200 2', 3'-dideoxycytidine, several parameters were lower than for 2', 3'-dideoxycytidine alone: maternal body wt. (gestational days 17), wt. change (gestational days 12 to 15, 6 to 15, 0 to 17), and gravid uterine wt. Fetal body wt. was lower than for either treatment alone. Incidences of morphological anomalies were not affected. At 200 3'-azido-3'-deoxythymidine/500 2', 3'-Dideoxycytidine, maternal body wt. (gestational days 17), wt. gain (gestational days 12 to 15, 15 to 17, 6 to 15, 0 to 17), and gravid uterine wt. were lower and relative liver wt. was higher than for either treatment alone. Percent adversely affected implantation sites, incidences of malformations (external, visceral, skeletal), and variations (external, visceral) were higher and fetal body wt. was lower than for either treatment alone. At 400 3'-azido-3'-deoxythymidine/200 2', 3'-Dideoxycytidine, maternal wt. gain (gestational days 9 to 12, 12 to 15, 6 to 15, 0 to 17) and gravid uterine wt. were lower, and relative liver wt. and percent adversely affected implants were higher than for 2', 3'-Dideoxycytidine alone. Fetal body wt. was lower than for either treatment alone. External malformations were higher than for 3'-azido-3'-deoxythymidine alone, and skeletal malformations were higher than for 2', 3'-Dideoxycytidine alone. The overall incidence of fetal malformations was higher, but visceral variations were less frequent than for either dose alone. At 400 3'-azido-3'-deoxythymidine/500 2', 3'-Dideoxycytidine, maternal body wt. (gestational days 15, 17), wt. change (gestational days 12 to 15, 15 to 17, 6 to 15, 0 to 17) and gravid uterine wt. were lower, and relative liver wt. was higher than for either dose alone. Incidences of resorptions, adversely affected implants, malformations (external, visceral, skeletal), and variations (external, visceral) were higher and fetal body wt. was lower than for either drug alone. Maternal and developmental endpoints were analyzed for three-way (3'-azido-3'-deoxythymidine*DDC*REP) and two-way (3'-azido-3'-deoxythymidine*2', 3'-Dideoxycytidine) interactions. When a significant two-way interaction occurred, the six groups receiving 3'-azido-3'-deoxythymidine plus 2', 3'-dideoxycytidine were analyzed individually. Specific dose combinations yielding non-additive responses (i.e., synergism, potentiation or antagonism) were identified, and their component doses were compared to the vehicle control group (0 3'-Azido-3'-deoxythymidine/0 2', 3'-dideoxycytidine). Significant two-way interactions (3'-Azido-3'-deoxythymidine*2', 3'-Dideoxycytidine) were observed for maternal body wt. change (gestational days 15 to 17), relative feed intake (gestational days 9 to 12 and 15 to 17), gravid uterine wt., and maternal relative (but not absolute) liver wt. Each parameter showed a statistically significant drug interaction at 400 3'-azido-3'-deoxythymidine/500 2', 3'-dideoxycytidine. This drug combination significantly decreased maternal body wt. change (gestational days 15 to 17) and gravid uterine wt. even though neither of these doses alone affected either parameter (potentiation). Maternal relative liver wt. was increased by each of these doses alone, and a synergistic response was found for the drug combination. For the measurement period (gestational days 9 to 12) in which 400 3'-azido-3'-deoxythymidine decreased maternal relative feed intake, the combination produced no change (antagonism). For the period (gestational days 15 to 17) in which 400 3'-azido-3'-deoxythymidine or 500 2', 3'-dideoxycytidine did not change maternal relative feed intake, the combination produced an increase. Two-way interactions (3'-Azido-3'-deoxythymidine*DDC) were significant for fetal body wt., as well as the incidences of resorptions, malformations (external, skeletal, visceral or all types), and variations (external, visceral or all types). At 400 3'-Azido-3'-deoxythymidine/500 2', 3'-dideoxycytidine the incidence of resorptions was significantly increased, even though each of these doses alone had no effect. Fetal body weight was reduced by the high dose of 3'-Azido-3'-deoxythymidine or 2', 3'-dideoxycytidine alone, and two dose combinations showed potentiation (200 3'-Azido-3'-deoxythymidine/500 2', 3'-dideoxycytidine) or synergism (400 3'-Azido-3'-deoxythymidine/500 2', 3'-dideoxycytidine). 3'-Azido-3'-deoxythymidine (any dose) combined with 500 2', 3'-dideoxycytidine significantly increased the incidences of fetal morphological anomalies, even though each dose alone generally had no effect. Malformations included anasarca (generalized edema), micrognathia (small lower jaw), cleft palate, ectrodactyly (reduced or absent digit), short tail, micromelia (small or shortened limb), anal atresia (no anal opening), hydrocephaly and various rib anomalies. For female fetuses, the incidence of malformations at 400 3'-Azido-3'-deoxythymidine or 200 2', 3'-dideoxycytidine did not differ significantly from controls, but was elevated for the combination (potentiation). In summary, co-administration of 3'-Azido-3'-deoxythymidine and 2', 3'-dideoxycytidine to CD-1(R) mice during major organogenesis resulted in significant drug interactions. Low dose combinations, specifically 100 or 200 mg/kg/day 3'-Azido-3'-deoxythymidine combined with 200 mg/kg/day 2', 3'-dideoxycytidine, were not associated with statistically significant non-additive drug interactions, but did occasionally result in effects that exceeded those of 3'-Azido-3'-deoxythymidine and/or 2', 3'-dideoxycytidine alone. In contrast, synergism or potentiation of adverse developmental effects were found when 100, 200 or 400 mg/kg/day 3'-Azido-3'-deoxythymidine was combined with 500 mg/kg/day 2', 3'-dideoxycytidine, and when 400 mg/kg/day 3'-Azido-3'-deoxythymidine was combined with 200 mg/kg/day 2', 3'-dideoxycytidine. 1 2', 3'-dideoxycytidine is a commonly used synonym for 2'3'-dideoxycytidine. In the present report, the abbreviation 2', 3'-dideoxycytidine refers to the main effect for 2', 3'-dideoxycytidine treatment in the experimental design, and is used in this context to report statistical results. Report Date: February 14, 2002 [R15] +... 3'-Azido-3'-deoxythymidine ... was selected for immunotoxicity studies /using female B6C3F1 mice/ ... Oral administration of AZT at 50, 125, 250 and 500 mg/kg/day for 180 days significantly decreased body weight and rate of weight gain at the 500 mg/kg dose level when the 5 studies are combined. A significant dose-dependent increase in relative spleen weight was seen, reaching 31% at the 500 mg/kg dose. These studies confirmed the significant decreases in the erythroid elements seen in other animal and clinical studies. These significant effects were observed at all dose levels for erythrocyte number (28%), hemoglobin (10%), mean corpuscular volume (30%), mean corpuscular hemoglobin (24%) and mean corpuscular hemoglobin concentration (4%) resulting in a NOAEL with these parameters of below 50 mg/kg. The percent reticulocytes were significantly increased at all dose levels from 20% to 95%. The leukocyte number was significantly decreased only at the high dose by 21%. In evaluating the bone marrow, no alteration was seen in the CFU-E (colony-forming units-erythrocytes); however, there were increases in CFU-GM (colony-forming units-granulocytes/monocytes) and CFU-M (colony-forming units-macrophage). ... In the immune parameters evaluated, no alteration was seen in the T-dependent antibody-forming cell response to s-RBC; however, a significant decrease was observed with the serum IgM antibody titer up to 16%. When expressed as lytic units per spleen, the cytotoxic T lymphocyte cell response showed a significant dose-dependent decrease up to 66%. Significant high dose decreases were also observed in the natural killer cell number and in the number of CD4+ spleen cells. In conclusion, adverse toxicological effects are present in mice treated with AZT for 180 days as seen in a decrease of body weight at the high dose and a significant decrease in the erythroid elements at all doses. Increases were seen in the CFU-GM (colony-forming units-granulocytes/monocytes) and CFU-M (colony-forming units-macrophage). Adverse immunotoxicological effects are present in mice treated with AZT for 180 days as seen in a decrease in the serum sRBC titer, cytotoxic T lymphocyte response, and absolute T helper cells and NK cells, resulting in NOAEL of below 125 mg/kg, 50 mg/kg and 250 mg/kg, respectively. Information on these immune alterations could be beneficial when using AZT in the treatment of AIDS patients [R16] ADE: *The plasma half life of zidovudine in adults averages approximately 1 hour (range: 0.8-1.9 hours) following oral administration and 1.1 hours (range: 0.5-2.9 hours) following iv administration. Following iv administration of zidovudine in adults or children, plasma concentrations of the drug appear to decline in a biphasic manner. Half-life in adults is less than 10 minutes in the initial phase and 1 hour in the terminal phase. Following iv administration over 1 hour of a single 80, 120, or 160 mg/sq m dose in children 1-13 years of age with symptomatic HIV infections, the alpha half life of zidovudine averaged 0.16-0.25 hours and the beta half live averaged 1-1.7 hours. [R1, 395] *In one study in adults with impaired renal function (creatinine clearances ranging from 6-31 ml/minute) without HIV infections beta half life of zidovudine averaged 1.4 hours and was similar to that reported for adults with HIV infections who had normal renal function. However, the beta half life of glucuronide in these adults with impaired renal function averaged 8 hours and was considerably prolonged compared with that reported for adults with HIV infections who had normal renal function. In one study in adults with hemophilia and HIV infections who had elevated serum concentrations of aspartate aminotransferase (serum glutamic-oxaloacetic transaminase), alanine aminotransferase (serum glutamic-pyruvic transaminase), pharmacokinetics of zidovudine after a single 300 mg oral dose showed considerable interindividual variation. [R1, 395] *Following oral administration of zidovudine in patients with HIV infections, 63-95% of the dose is excreted in urine; approximately 14-18% of the dose is excreted as unchanged zidovudine and 72-74% is excreted as zidovudine 5'-O-glucuronide within 6 hours. Following iv administration of the drug in adults or children with HIV infections, approximately 18-29% of the dose is excreted in urine as unchanged drug and 45-60% is excreted as zidovudine 5'-O-glucuronide within 6 hours. [R1, 395] *Zidovudine and zidovudine 5'-O-glucuronide are eliminated principally in urine via both glomerular filtration and tubular secretion. In a limited number of adults, total body clearance of zidovudine has averaged 22-27 ml/minute per kg and renal clearance of the drug has averaged 4-6 ml/minute per kg. In children 6 months through 12 years of age, total body clearance of zidovudine averaged 30.9 ml/min/kg. Preliminary data suggest that zidovudine clearance may be reduced in children younger than 1 month of age. [R1, 395] *Zidovudine is rapidly metabolized via glucuronidation in the liver to zidovudine 5'-O-glucuronide (GAZT); the metabolite has an apparent elimination half life of 1 hour (range: 0.6-1.7 hours). Zidovudine 5'-O-glucuronide does not appear to have antiviral activity against HIV. [R1, 395] *There is limited information on the distribution of zidovudine into body tissue or fluids, but the drug appears to be widely distributed. The apparent volume of distribution of the drug in adults with HIV infections is 1.4-1.6 liter/kg. In children 1-13 years of age with symptomatic HIV infections, the volume of distribution of zidovudine at steady state ranges from 22-64 l/sq m. [R1, 394] *Zidovudine is 34-38% bound to plasma proteins. [R1, 394] *The ratio of CSF/plasma concentrations of zidovudine reported in ... adults or children with HIV infections who received oral or iv therapy with the drug has generally ranged from 0.15-0.98. In an adult who received an oral zidovudine dosage of 2 mg/kg every 8 hours, the CSF concentration of the drug 1.8 hours after a dose was about 0.04 ug/ml and the ratio of CSF/plasma concentration was 0.15. [R1, 394] *Zidovudine and its glucuronide metabolite cross the human placenta and are distributed into cord and amniotic fluid as well as fetal liver, muscle, and CNS tissue. Concentrations of the drug and its metabolite in fetal blood, amniotic fluid, and fetal muscle tissue are similar to those in maternal blood; only very low concentrations are distributed into fetal CNS tissue. The ratio of the glucuronide metabolite to zidovudine is higher in maternal blood than in fetal blood. It is not known whether zidovudine is distributed into milk in humans, but the drug is distributed into milk in mice. [R1, 394] *Zidovudine is rapidly absorbed from the GI tract, with peak serum concentrations of the drug generally occurring within 0.4-1.5 hours. Following oral administration, the drug is well absorbed, ... and the drug appears to undergo first pass metabolism. In both adults and children, about 65% (range: 50-76%) of an oral dose reaches systemic circulation as unchanged drug. ... Food and/or milk did not appear to substantially affect GI absorption of zidovudine. ... Results of an unpublished study indicate that the rate of absorption and peak plasma concentrations of zidovudine may be decreased substantially if the drug is taken with a high fat meal. [R1, 394] *In adults with human immunodeficiency virus (HIV; formerly HTLV-III/LAV) infections who received an oral zidovudine dosage of 250 mg (3-5.4 mg/kg) every 4 hours, steady state serum concentrations of the drug 1.5 hours after dosing averaged 0.62 ug/ml and steady state tough serum concentrations averaged 0.16 ug/ ml. Zidovudine appears to have dose independent pharmacokinetics over the oral dosage range of 2 mg/kg every 8 hours to 15 mg/kg every 4 hours or the iv dosage range of 1 mg/kg every 8 hours to 7.5 mg/kg every 4 hours. ... The area under the plasma concentration-time curve was similar following administration of either dosage form of the drug. /Oral solution or capsules/. [R1, 394] *Following iv infusion over 1 hour of a single 2.5 or 5 mg/kg dose of zidovudine in adults with HIV infections, peak plasma concentrations of the drug immediately following completion of the infusion ranged from 1.07-1.6 or 1.6-2.7 ug/ml, respectively. In children 14 months to 12 years of age with symptomatic HIV infections who received a single 80 mg/sq m dose of zidovudine given by iv infusion over 1 hour, peak plasma concentrations of the drug averaged 1.58 ug/ml; plasma concentrations were less than 0.27 ug/ml within an hour following completion of the infusion. When these children received continuous iv infusion of zidovudine in a dosage of 0.5, 0.9, 1.4, or 1.8 mg/kg per hour, steady state plasma concentrations of the drug averaged 0.51, 0.75, 0.83, or 1.2 ug/ml, respectively. In children 6 months through 12 years of age, zidovudine appears to have dose independent pharmacokinetics over the oral dosage range of 90-240 mg/sq m every 6 hours or the iv dosage range of 80-160 mg/sq m every 6 hours. [R1, 394] *Following iv dosages of 2.5 or 5 mg/kg every 4 hours, CSF concentrations 2-4 hours after dosing were about 0.1-0.13 or 0.23-0.37 ug/ml, respectively, and the CSF/plasma ratio was 0.2-0.5 or 0.64-0.73, respectively. Studies in rats indicate that, although zidovudine readily distributes into CSF, distribution of the drug into brain interstitial fluid may be minimal. Studies in patients with HIV infections receiving 200 mg oral doses of zidovudine every 4 hours indicate that the drug is distributed into semen; ... the ratio of semen/plasma concentration ranges from 1.3-20. There is no evidence to date that presence of zidovudine in semen decreases infectivity of the semen. [R1, 394] *Absorption of 0.01, 0.1, and 1.0 mM zidovudine in 4 segments of rat intestine was examined. Drug disappearance followed first-order kinetics throughout the gastrointestinal tract at all concentrations. Intrinsic absorptivity was greater in the upper gastrointestinal tract than in lower portions, possibly due to differences in surface area. Zidovudine absorption was enhanced by mixed micelles, indicating paracellular transport. [R17] *To examine the effects of continuous ambulatory peritoneal dialysis on zidovudine pharmacokinetics, a study was conducted in 5 HIV seronegative men (ages 37-62 yr) undergoing continuous ambulatory peritoneal dialysis due to end stage renal disease who received a single 200 mg oral dose of zidovudine all other medications were withheld for the duration of the study. Zidovudine pharmacokinetics displayed wide interpatient variability. Peak serum concentrations ranged from 0.3-47.8 muM, total body clearance ranged from 66-3176 ml/min/1.73 sq m, and volume of distribution from 16-825 l. Less than 1% of the administered dose was recovered from the peritoneal dialysate with a net clearance rate of 5 ml/min. It was concluded that the effect of continuous ambulatory peritoneal dialysis on zidovudine disposition was negligible, and subsequent variability in zidovudine pharmacokinetics results from extensive renal dysfunction and, to a lesser extent, from interpatient variability in zidovudine glucuronidation. [R18] *The metabolism and pharmacodynamics of zidovudine in 5 patients with chronic renal failure or end stage renal disease are reported. Serum levels of zidovudine were measured after a single oral dose of 100 mg in a patient with chronic renal failure who had discontinued the drug for one wk. The clearance of zidovudine was delayed, with a 4 hr trough level of 0.43 mcg/ml as compared with 0.16 in control patients. Three other patients with end stage renal disease undergoing hemodialysis 3 times/wk and a fourth with chronic renal failure were studied. Trough levels in serum were measured over an 8 mo period, during which the patients took 100 mg of oral zidovudine 3 times/day. The trough levels of zidovudine remained at the optimal therapeutic concentration throughout the study period. It was concluded that the current maintenance dosage of 100 mg 3 times/day is adequate and well tolerated in both chronic renal failure and end stage renal disease. [R19] *The release of zidovudine from sustained action suppository formulations containing 10 and 20% drug and regular release suppositories was studied in vitro and rectal absorption of 10 mg/kg suppositories was studied in rats who also received 3 mg/kg drug after oral solution and iv dosing. The suppository containing 20% drug showed faster release in vitro than the lower dose suppository. In rats the drug was absorbed rapidly from the conventional suppository, reaching the maximum concentration in 30 min, and was eliminated within 3 hr. The sustained action suppository, however, maintained constant plasma levels above one muM for more than 6 hr. The mean area under the concentration-time curve was 6.07, 5.29, 12.38, and 7.3 muM hr for iv, oral, conventional suppositories, and sustained action suppositories, respectively. It was concluded that suppositories can be a useful alternative dosage form of zidovudine. [R20] *To investigate the distribution of azidothymidine and its inactive metabolite 5'-glucuronide azidothymidine in the mother, fetus, and amniotic fluid, 12 near term pregnant baboons were given oral azidothymidine (21 mg/kg/day in four divided doses every 6 hours, equivalent to the usual nonpregnant human dose of 1500 mg/day). Specimens of maternal blood, fetal arterial blood obtained by percutaneous umbilical cord blood sampling, and amniotic fluid were obtained after from one to 17 doses of azidothymidine. Azidothymidine levels were measured by radioimmunoassay with the INCSTAR commercial radioimmunoassay kit and using Escherichia coli beta-glucuronidase for determination of 5'-glucuronide azidothymidine levels. Paired analyses revealed significant concentration gradients between amniotic fluid, fetal serum, and maternal serum for both azidothymidine (p < 0.019) and 5'-glucuronide azidothymidine (p < 0.002). The amniotic fluid 5'-glucuronide azidothymidine level increased with increasing doses of azidothymidine despite the fact that the maternal azidothymidine and 5'-glucuronide azidothymidine concentrations were unchanged. This accumulation of amniotic fluid 5'-glucuronide azidothymidine may provide a functional drug reservoir and contribute to the higher fetal concentrations of the medication and its metabolite. Alternatively, the higher fetal levels may represent slower clearance in the fetus than in the mother. [R21] *Six patients who were HIV positive and who had requested termination of pregnancy were selected to study the passage of zidovudine through the placenta. After the patients had been warned about the procedure and given consent, 1 g of zidovudine was given in five doses of 200 mg each orally. Ethical Committee consent had been obtained. At a mean age of 17.5 weeks of amenorrhoea, samples were taken from the mothers' blood, from the amniotic fluid and from the fetal blood between one and two hours and forty five minutes after the last dose of zidovudine had been taken. Pregnancy was terminated immediately after the amniotic fluid had been obtained. The levels of zidovudine and its metabolite glucuronide were carried out using HPLC. The concentrations of the drug in the liquor and in the fetal blood were higher or equaled those found in the maternal blood. This makes it likely that the half life elimination was longer and the metabolism of the product slower when it had been metabolised to glucuronide. This study does not concern the teratogenic effect or the toxicity for the fetus. The drug remains contraindicated in pregnancy. There is no proposal at present to use it to lessen transmission of the virus from the mother to the fetus. [R22] *The transfer of zidovudine across human placenta was studied using an in vitro perfusion system with independent maternal and fetal circulations. Zidovudine is transferred toward the fetus more rapidly than L-glucose (transfer index 1.5), a water soluble molecule smaller than zidovudine (267 vs 180 Da) that passively diffuses across the placenta. The transfer rate is proportional to the concentration in the maternal perfusate over a range of 0.03-300 uM. Transfer rate in the reverse direction, toward the maternal perfusate, also exceeds that of L-glucose and fails to show saturability. These observations are consistent with simple diffusion. The partition of zidovudine and glucose between perfusion buffer and octanol is 1.04 and 0.013, respectively, indicating that zidovudine is more lipophilic and providing a reasonable explanation for the more rapid transfer. Zidovudine is extensively metabolized by the placenta to more polar and as yet unidentified metabolites that are not released into the perfusate. The possibility that the placental accumulation of such metabolite(s) may exert an antiviral action and may also affect placental function must be considered. [R23] METB: *The mechanisms of intestinal mucosal transport and metabolism of zidovudine and other thymidine analogs were studied. No zidovudine metabolites appeared in any part of the gastrointestinal tract. Other thymidine analogs were rapidly metabolized in the upper gastrointestinal tract, but not in the colon. [R17] BHL: *The value for half-life of zidovudine is 1-2 hr. [R24] ACTN: *Zidovudine triphosphate can bind to and inhibit some mammalian cellular DNA polymerases, particularly beta- and gamma- polymerases, in vitro. However, zidovudine triphosphate appears to have a much greater affinity for viral RNA-directed DNA polymerase than for mammalian DNA polymerases, and chain termination of host cellular DNA has not been demonstrated. /Zidovudine triphosphate/ [R1, 393] *The antiretroviral activity of zidovudine appears to depend on intracellular conversion of the drug zidovudine triphosphate. Zidovudine is converted to zidovudine monophosphate by cellular thymidine kinase; the monophosphate is phosphorylated to zidovudine diphosphate via cellular thymidylate kinase and then to the tirphosphate via other cellular enzymes. ... Conversion of the drug to the active triphosphate derivative occurs in both virus infected and uninfected cells. ... Zidovudine triphosphate appears to compete with thymidine triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA. Following incorporation of zidovudine triphosphate into the viral DNA chain instead of thymidine triphosphate, DNA synthesis is prematurely terminated. In addition, zidovudine monophosphate competively inhibits thymidylate kinase, resulting in decreased formation of thymidine triphosphate. ... /The drug/ facilitates binding of zidovudine triphosphate to the enzyme /and/ appears to decrease 2'-deoxycytidine trihosphate concentrations. [R1, 393] *Antibacterial action of zidovudine appears to result from premature termination of bacterial DNA synthesis secondary to incorporation of phosphorylated zidovudine in the bacterial DNA chain. In vitro exposure of susceptible bacteria to the drug results in bacterial elongation and death secondary to cell lysis. ... The antibacterial action appears to depend on conversion of zidovudine to the active phosphorylated form via bacterial enzymes rather than via host enzymes. Zidovudine monophosphate, diphosphate, and triphosphate exhibit antibacterial activity in vitro with the triphosphate being most active and the monophosphate being least active. Susceptibility of bacteria to zidovudine appears to depend in large part on the presence of bacterial thymidine kinase. ... Organisms lacking thymidine kinase ... have been resistant to zidovudine, while those with relatively high concentrations of the enzyme ... have been highly susceptible to the drug; in addition, mutants resistant to the drug have had relatively low concentrations of the enzyme. The antibacterial activity of zidovudine also appears to depend in part on other factors such as permeability of the organism to the drug. [R1, 393] *Zidovudine appears to alter mucleoside metabolism within host cells, resulting in decreased levels of thymidine triphosphate, 2'-deoxycytidine triphosphate, and several other deoxynucleoside triphosphates. [R1, 393] INTC: *Concomitant use of probenecid may produce substantially higher and prolonged serum concentrations of zidovudine. [R1, 400] *In at least one study, concomitant use of acetaminophen reportedly resulted in an increased risk of granulocytopenia in patients receiving zidovudine; this potentiation of hematologic toxicity appeared to correlate with the duration of acetaminophen use. [R1, 400] *In one study in a limited number of patients who received zidovudine concomitantly with an antituberculosis regimen of isoniazid and rifampin (with or without ethambutol) or a regimen of isoniazid, ethambutol, and pyrazinamide for 12 weeks, mild to moderate decreases in leukocyte counts occurred more frequently in the group that received concomitant therapy than in a control group that received zidovudine alone; however, there was no statistical difference between the groups in other reported adverse effects. [R1, 400] *Acyclovir has been used concomitantly with zidovudine ... without evidence of increased toxicity; however, neurotoxicity (profound drowsiness and lethargy), which recurred on rechallenge, has been reported in at least one patient with acquired immunodeficiency syndrome (AIDS) during concomitant therapy with the drugs. Neurotoxicity was evident within 30-60 days after initiation of IV acyclovir therapy, persisted with some improvement when acyclovir was administered orally, and resolved following discontinuance of acyclovir in this patient. [R1, 399] *Combined use of /ganciclovir and zidovudine/ increases the risk of hematologic toxicity and may result in additive or synergistic myelotoxic effects. In several studies in patients with AIDS and cytomegalovirus infections, profound, intolerable myelosuppression, evidenced principally as severe neutropenia, occurred in all patients receiving ganciclovir (5 mg/kg iv 1-4 times daily) concomitantly with zidovudine (200 mg orally every 4 hours); anemia also occurred in many of these patients. Severe hematologic toxicity, which required a reduction in zidovudine dosage, also occurred in more than 80% of patients receiving ganciclovir (5 mg/kg iv 1-2 times daily) concomitantly with zidovudine (100 mg orally every 4 hours). [R1, 399] *The antiviral drug zidovudine and the analgesic and antipyretic agent acetaminophen are both biotransformed in the liver of humans to ether glucuronides. A previous clinical trial of zidovudine suggested the potential for a clinically significant interaction between acetaminophen and zidovudine, probably based upon competing hepatic metabolism. To study the mechanism of this potential competition between acetaminophen and zidovudine as substrates for uridine diphosphoglucuronyltransferase, enzyme kinetic studies were performed using rat liver microsome preparations. Cross inhibition studies demonstrated that acetaminophen glucuronidation was competitively inhibited by zidovudine, while zidovudine glucuronidation was slightly inhibited by acetaminophen in a noncompetitive interaction. [R25] *Pharmacokinetic parameters for methadone and zidovudine, alone and in combination, were determined in 14 HIV infected individuals including nine former intravenous drug users who were receiving methadone maintenance therapy. The serum levels of methadone were measured prior to and after initiation of zidovudine treatment, with each patient serving as his or her own control. Concurrent administration of zidovudine did not alter either the peak methadone concentration or the area under the methadone concentration-time curve. Serum and urine zidovudine and zidovudine-glucuronide concentrations were measured by both high pressure liquid chromatography and radioimmunoassay, and pharmacokinetic parameters determined at least twice in each of nine methadone maintained former intavenous drug use patients initiating zidovudine therapy. These parameters were compared to those for zidovudine in a group of five control patients who were neither receiving methadone nor had a history of iv drug use. The serum zidovudine levels were significantly higher in the methadone patients, with a 43% increase (p < 0.05) over the mean area under the curve of 7.68 microM hr observed in the control patients. Furthermore the methadone patients could be divided into two groups based on their zidovudine area under the curve: four patients whose zidovudine area under the curve averaged twofold higher than the control group, and five patients whose zidovudine area under the curve were equal to control. No significant differences were found between the control and methadone groups for zidovudine bioavailability or Tmax, serum half-life, glucuronidation, or urinary excretion. Methadone also did not affect zidovudine glucuronidation in an in vitro assay using human hepatic microsomes. [R26] *The effects of dideoxycytidine on the pharmacokinetics of zidovudine were studied in monkeys who received 20 mg/kg intragastric zidovudine in the absence and presence of an intravenous infusion of dideoxycytidine designed to produce steady state dideoxycytidine plasma levels of 1.77 ug/ml for 30 min. The mean apparent clearance of zidovudine was 1.4 and 1.78 l/hr/kg in the absence and presence of dideoxycytidine, respectively. The mean area under the curve (AUC) for its major glucuronide metabolite was 36.69 ug hr/ml in the absence of dideoxycytidine and 28.81 ug hr/ml in the presence of dideoxycytidine. No statistically significant differences were found in these and other pharmacokinetic parameters in the absence and presence of dideoxycytidine. This was attributed to the primary metabolic and renal elimination pathways of zidovudine and dideoxycytidine, respectively. It was concluded that dideoxycytidine does not significantly alter the pharmacokinetics of zidovudine and its major glucuronide metabolite. [R27] *The drug zidovudine, a synthetic thymidine analog, has been used in the treatment of acquired immunodeficiency syndrome. Clinical use of zidovudine has induced hematopoietic toxicity manifested by anemia, neutropenia, frequent thrombocytopenia, and overall bone marrow suppression. The monovalent cation lithium has been shown to be an effective agent capable of modulating several aspects of hematopoiesis such as the induction of neutrophilia, thrombopoiesis, and protection against suppression of hematopoietic progenitor stem cells following exposure to anticancer drugs and/or radiation in the treatment of malignant disease. The results of studies designed to evaluate the effectiveness of lithium in reversing and/or protecting against either murine or human bone marrow derived hematopoietic progenitors, ie (colony forming unit-granulocyte-macrophage, colony forming unit-magakaryocyte, and burst forming unit-erythroid) when co-cultured in the presence of zidovudine in vitro were reported. Lithium chloride reversed zidovudine toxicity to either murine or human derived colony forming unit-granulocyte-macrophage and colony forming unit-magakaryocyte that was optimal at a concentration of 1 mM (p < 0.05). However, the addition of lithium failed to influence zidovudine toxicity toward either murine or human burst forming unit-erythroid. In summary, these results support the scant clinical studies that have described the presence of neutrophilia and/or thrombopoiesis in zidovudine treated acquired immunodeficiency syndrome patients receiving lithium. In addition, these data further confirm the need for more detailed evaluation of lithium as an adjuvant agent to reduce the hematopoietic toxicity associated with the use of antiviral therapy in HIV infected patients. [R28] *A pharmacokinetic evaluation of a potential drug interaction between zidovudine and dideoxycytidine was conducted in monkeys. Each of six animals received 20 mg/kg of zidovudine intragastrically in the absence and presence of an intravenous steady state dosage regimen of dideoxycytidine. The regimen was designed to produce a steady state dideoxycytidine plasma concentration of 1.77 micrograms/ml for 30 min. Plasma and urine samples were analyzed for zidovudine, its major glucuronide metabolite, and dideoxycytidine by HPLC techniques. Pharmacokinetic parameters for zidovudine and the glucuronide metabolite of zidovudine were calculated by non-compartmental methods. The mean apparent clearance of zidovudine was 1.40 and 1.78 l/hr/kg in the absence and presence of dideoxycytidine, respectively. The mean area under the curve for the glucuronide metabolite of zidovudine was 36.39 micrograms hr/ml in the absence of dideoxycytidine and 28.81 micrograms hr/ml in the presence of dideoxycytidine. No statistical differences were found in these and other pharmacokinetic parameters in the absence and presence of dideoxycytidine. The absence of an effect on zidovudine's pharmacokinetics by dideoxycytidine is attributed to the primary metabolic and renal elimination pathways for zidovudine and dideoxycytidine, respectively. The results of this study provide a rational basis to design combined zidovudine dideoxycytidine treatment regimens in AIDS patients. [R29] *Zidovudine, the antiviral drug used in the treatment of acquired immunodeficiency syndrome, produces some toxicity to the hematopoietic system. Although several hematopoietic growth factors are currently undergoing clinical trials to evaluate their ability to modulate antiviral toxicity, there are scant data which support their ability to ameliorate zidovudine toxicity on hematopoietic progenitor cells when combined in vitro. The results of studies designed to evaluate in vitro the capacity of the cytokine interleukin-3, in dose escalation fashion, to modulate zidovudine toxicity on normal human marrow derived granulocyte/erythroid/macrophage/megakaryocyte colony forming units, colony forming units-granulocyte/macrophage and erythroid burst forming units are described. Colony formation for each progenitor was increased in the presence of interleukin-3 compared to cultures plated in its absence. In the presence of zidovudine (ID50 dose, used for each progenitor), interleukin-3 reduced zidovudine toxicity, with the most significant response observed for granulocyte/erythroid/macrophage/megakaryocyte colony forming units, indicating interleukin-3 may exert an effect on early, less differentiated hematopoietic progenitors. These studies indicate interleukin-3 may be an effective agent in reversing the hematopoietic toxicity associated with zidovudine; however, further in vivo studies are required before clinical use of interleukin-3 is advocated. [R30] *The pharmacokinetic basis of a drug interaction between AZT and 2',3'-dideoxyinosine was investigated in normal monkeys. Five animals received 20 mg/kg of AZT intragastrically in the absence and presence of 2',3'-dideoxyinosine. 2',3'-Dideoxyinosine was administered intravenously to produce steady state 2',3'-dideoxyinosine plasma concentrations for 30 min. Plasma and urine samples were analyzed for AZT, its major glucuronide metabolite, and 2',3'-dideoxyinosine by high performance liquid chromatography. Resultant AZT and glucuronide metabolite of AZT concentration data were analyzed by noncompartmental methods. Statistical analysis indicated no differences in AZT's apparent total clearance, apparent volume of distribution at steady state, and elimination half-life due to 2',3'- dideoxyinosine, however, the mean apparent total clearance decreased from 2.92 to 1.67 l/hr/kg, and the mean apparent volume of distribution at steady state decreased from 5.79 to 3.43 l/kg in the presence of 2',3'-dideoxyinosine. Incomplete urine collections in most animals prevented conclusions from being made about 2',3'-dideoxyinosine's effect on renal elimination parameters. Nonetheless, the urinary glucuronide metabolite of AZT/AZT ratio, a parameter not influenced by incomplete urine collection, was significantly reduced in the presence of 2',3'-dideoxyinosine. Although additional studies will be useful to characterize the full importance of the interaction, there is evidence to suggest that both renal and metabolic elimination of AZT and renal elimination of glucuronide metabolite of AZT may be inhibited by 2',3-dideoxyinosine. [R31] *In uncontrolled trials, granulocyte macrophage colony stimulating factor also appears to reduce toxicity from zidovudine, ganciclovir, alpha-interferon, and antineoplastic therapy. In a placebo controlled trial, erythropoietin decreased transfusion requirements and corrected anemia in the majority of patients receiving zidovudine. Combined granulocyte colony stimulating factor and erythropoietin treatment corrected both anemia and leukopenia and reduced zidovudine toxicity. [R32] *The systemic availability of oral zidovudine has been studied in 13 patients with the acquired immunodeficiency syndrome dosed either fasting or with breakfast. The mean peak plasma concentration and area under the curve of zidovudine were significantly 2.8 and 1.4 times higher in fasting patients than in those treated during meal. In both conditions the mean half-life was about 1.5 hr and the period of plasma zidovudine concentrations greater than 1 umol/l was 2 hr. It is concluded that if zidovudine is taken on an empty stomach, high peak plasma concentrations and decreased variation in pharmacological parameters may be expected. Whether or not this will influence toxicity and efficacy remains to be shown. [R33] *Drug interactions occur primarily between zidovudine and other agents that undergo hepatic glucuronidation (eg, probenecid, sulfamethoxazole) resulting in decreased zidovudine clearance. [R24] *OBJECTIVE: To assess the toxicity, efficacy, and pharmacology of combined zidovudine and ganciclovir therapy in patients with the acquired immunodeficiency syndrome and serious cytomegalovirus disease. DESIGN: Prospective, phase I multicenter trial (ACTG 004) with patients grouped by previous study drug history. SETTING: Three university based acquired immunodeficiency syndrome Clinical Trials Units sponsored by the National Institute of Allergy and Infectious Diseases. PATIENTS: Forty-one patients with acquired immunodeficiency syndrome related cytomegalovirus disease. Previous therapy with either zidovudine or ganciclovir was allowed. INTERVENTIONS: Patients were treated with zidovudine, 600 to 1200 mg/day; or, if on ganciclovir maintenance, ganciclovir, 5 mg/kg body weight; blood was sampled for pharmacokinetic studies. The other drug was then administered to the patient with blood sampling and, finally, the two drugs in combination were given. Patients were continued on both drug therapies with dose reduction of zidovudine only for grade 3 or 4 toxicity. MEASUREMENTS AND MAIN RESULTS: Forty patients were eligible. Hematologic toxicity was frequent, with 9 of the 10 patients requiring dose reductions for grade 3 or 4 toxicity at zidovudine doses of 1200 mg/day. With zidovudine doses of 600 mg/day, 82% experienced such hematologic toxicity. Median survival was 6 mo; 10 patients developed intercurrent infection and 19, progressive cytomegalovirus disease. Pharmacokinetic variables (alpha and beta half-lives, volume of distribution, clearance) were not affected in combination therapy. CONCLUSION: The combination of zidovudine and ganciclovir is poorly tolerated in patients with acquired immunodeficiency syndrome and serious cytomegalovirus disease, with 82% developing severe to life-threatening hematologic toxicity. Such toxicity is not a result of pharmacologic interactions, drug metabolism, or excretion. [R34] *The effect of probenecid on the disposition of AZT was investigated in a pilot study in two healthy volunteers. The pharmacokinetics of AZT were examined after a single oral dose of 200 mg with and without probenecid coadministration in a balanced crossover study. Administration of 500 mg probenecid every 6 hr prior to and during AZT dosing resulted in an increase in the average area under the curve for AZT from 89 micrograms min/ml (control) to 191 micrograms min/ml during probenecid treatment. This was manifested by a corresponding decrease in total clearance/F, which is attributed to the inhibitory effect of probenecid on the glucuronidation and renal excretion of AZT. Average renal clearance and total clearance/F of AZT decreased from 4.76 and 28.7 to 2.98 and 14.1 ml/min/kg during control and probenecid treatment, respectively. AZT glucuronidation was affected to a greater extent than its renal excretion, as reflected by the decreased ratio of the glucuronide metabolite of AZT/AZT urinary recoveries. The terminal half-life of AZT was slightly longer during probenecid administration. That only a small change in the half-life occurred indicates that probenecid also reduced the volume of distribution of AZT. The renal clearance of the glucuronide metabolite of AZT decreased from an average of 11.3 ml/min/kg (control) to 2.63 ml/min/kg during probenecid treatment, resulting in a greater than 3.5 fold increase in area under the curve for the glucronide metabolite of AZT. Probenecid did not affect the blood/plasma distribution or the plasma protein binding of AZT. These preliminary findings suggest that it may be possible to maintain effective plasma AZT concentrations in AIDS patients receiving a reduced daily dose, in combination with probenecid. [R35] *In vitro, trimethoprim and zidovudine have exhibited synergistic antibacterial activity in vitro against some gram-negative bacteria (ie, Citrobacter, Enterobacter, Escherichia, Klebsiella, Proteus, Providencia, Salmonella, Shigella). [R1, 400] *In vitro, ribavirin antagonizes the antiviral activity of zidovudine against HIV. This antagonism appears to result from inhibition of zidovudine phosphorylation by ribavirin and/or phosphorylated ribavirin, possibly secondary to a ribavirin-induced increase in deoxythymidine triphosphate (dTTP) concentrations and a subsequent feedback inhibition of thymidine kinase. Increased dTTP concentration might also interfere with the interaction of zidovudine triphosphate with HIV RNA-directed DNA polymerase (reverse transcriptase). [R1, 400] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: +Anti-HIV Agents; Antimetabolites; Antimetabolites, Antineoplastic; Reverse Transcriptase Inhibitors [R36] *Zidovudine is designated an orphan drug by the US Food and Drug Administration (FDA) for use in the management of human immunodeficiency virus (HIV; formerly HTLV-III/LAV) infections. [R1, 395] *The antiviral activity of zidovudine and interferon alpha-2a is synergistic in vitro against HIV. ... Clinical studies employing combined therapy with the drugs are under way. ... Human mononuclear cells from peripheral blood did not appear to be affected substantially in vitro by the combination /of drugs/. Zidovudine and interferon alpha have had an additive inhibitory effect on Epstein-Barr virus-induced transformation of human lymphocytes in vitro. [R1, 400] *2',3'-Dideoxythymidine /and/ ribaviran currently being evaluated in patients with HIV infection may adversely affect erythrocyte and/or leukocyte number or function, and concomitant use of these agents with zidovudine may increase the risk of hematologic toxicity. In addition, in vitro studies indicate that some nucleoside antiviral agents that affect DNA replication (eg, ribavirin) may antagonize the in vitro activity of zidovudine against HIV. Concomitant use of /zidovidine and/ nucleoside antiviral agents that affect DNA replication ... should be avoided. [R1, 400] *A synergistic virustatic effect has been reported during combined use of zidovudine and ampligen (a mismatched polymer of double stranded RNA) in vitro. [R1, 400] *In vitro studies have shown that zidovudine and interferon synergistically inhibit the replication of the human immunodeficiency virus type 1 in peripheral blood mononuclear cells at concentrations achievable in patients. Interferon alfa can cause lesions to regress in patients with acquired immunodeficiency syndrome related Kaposi's sarcoma. Although zidovudine has no significant effect on the regression of these lesions, it does have antiviral activity in these patients as manifested by a decline in serum human immunodeficiency virus type I antigen. However, when used separately, the two drugs can have serious side effects in some patients. In addition, the development of zidovudine resistant strains has been noted in patients with advanced human immunodeficiency virus type I disease receiving zidovudine for nine mo or longer. Three in vivo trials have been initiated to assess possible advantages of combination therapy with zidovudine and interferon alfa in patients with acquired immunodeficiency syndrome related Kaposi's sarcoma. The incidence of serious adverse reactions, therapeutic efficacy, and the rate of emergence of zidovudine resistant strains of human immunodeficiency virus type I were evaluated. Preliminary results indicate that combination therapy with interferon alfa and zidovudine can safely be administered to patients with acquired immunodeficiency syndrome related Kaposi's sarcoma in doses that elicit antitumor and antiviral responses and discourage the potential emergence of zidovudine resistant human immunodeficiency virus type I strains. [R37] *Zidovudine 1500 mg/day was previously prescribed only to adult human immunodeficiency virus infected patients who had developed AIDS or AIDS related complex. However, results obtained from recently completed studies indicate that a lower daily dose (500 mg) appears to be equivalent. In addition, zidovudine therapy appears to be beneficial to asymptomatic human immunodeficiency infected patients with CD4+ counts less than 500/cu mm. [R24] *Immunosuppression due to human immunodeficiency virus type 1 infection has led to a marked increase in Pneumocystis carinii pneumonia. Zidovudine appears to have a synergistic benefit in further reducing the attack rate of Pneumocystis carinii pneumonia when used with aerosolized pentamidine. [R38] +Medication: Anti-infective agent [R39] WARN: *Patients should be evaluated at least every 1 or 2 weeks during the first month of zidovudine therapy. ... Blood cell counts and indices of anemia ... should be performed prior to initiation of zidovudine therapy to established baseline values and should then be monitored during therapy with the drug. Patients with advanced symptomatic HIV infections or low baseline values for blood cell counts and indices of anemia should be monitored frequently (at least every 2 weeks); however, less frequent monitoring (once monthly for the first 3 months and then, if stable, once every 3 months generally is sufficient in patients with asymptomatic or early symptomatic HIV infections. If anemia and/or granulocytopenia occurs, interruption of zidovudine therapy and/or dosage adjustment may be necessary. Blood transfusions may also be necessary. Zidovudine should be used with extreme caution in patients who have comprised bone marrow function as evidenced by a hemoglobin concentration less than 9.5 g/dl or a granulocyte count less than 1000/cu mm. [R1, 398] *Because serious myopathy or myositis has been reported in individuals who have received long term zidovudine therapy, patients should be questioned during routine visits about symptoms such as myalgia, loss of muscle mass, weight loss, and proximal muscle weakness. Elevations in serum concentrations of muscle enzymes (eg, creatine kinase, LDH) may occur weeks before symptoms of myopathy and ... serum creatine kinase concentrations /should/ be determined every 3 months in patients who have received zidovudine for 6-12 months or longer ... . Interruption of zidovudine therapy or, preferably, dosage reduction should be considered in patients who develop myopathy during therapy with the drug. If symptoms of myopathy persist following discontinuance of zidovudine therapy, the drug probably should be reinstated since the myopathy may be related to the HIV infection. [R1, 398] *Drugs that are nephrotoxic, cytotoxic, or myelosuppressive (eg, amphotericin B, co-trimoxazole, dapsone, doxorubicin, flucytosine, interferon, pentamidine, vinblastine, vincristine) should be used with caution during zidovudine therapy since concomitant use of these drugs may increase the risk of toxicity. [R1, 400] *Decreased plasma phenytoin concentrations have been reported in some patients receiving concomitant zidovudine and, in at least one patient, an increased phenytoin concentration was reported. Because many patients with advanced HIV infections have CNS conditions that may predispose to seizure activity phenytoin concentrations should be monitored carefully in patients receiving zidovudine. [R1, 400] *Drugs that could interfere with renal excretion or hepatic blood flow may decrease zidovudine clearance and increase the risk of toxicity. [R1, 400] *It is not known whether zidovudine is distributed into milk in humans. Because of the potential for serious adverse reactions to zidovudine in nursing infants if the drug were distributed into milk, nursing should be discontinued in women who are receiving zidovudine. [R1, 399] *It is not known whether zidovudine can cause fetal harm when administered to pregnant women, and the drug should be used during pregnancy only when clearly needed. [R1, 399] *Concomitant use of /zidovidine and/ nucleoside antiviral agents that affect DNA replication ... should be avoided. [R1, 400] TOLR: *Organisms lacking thymidine kinase ... have been resistant to zidovudine, while those with relatively high concentrations of the enzyme ... have been highly susceptible to the drug; in addition, mutants resistant to the drug have had relatively low concentrations of the enzyme. The antibacterial activity of zidovudine also appears to depend in part on other factors such as permeability of the organism to the drug. [R1, 393] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ MILK: *Zidovudine ... is distributed into milk in mice. [R1, 394] BODY: *Zidovudine ... is distributed into milk in mice. [R1, 394] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- FDA: *Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended; 21 U.S.C. 321-392). [R40] *Zidovudine, used as a anti-infective agent, was approved by FDA for marketing in the United States on 3/19/87. [R39] *The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed drug products, incl zidovudine, approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /From the Prescription Drug Product List/ [R41] *Zidovudine is designated an orphan drug by the US Food and Drug Administration (FDA) for use in the management of human immunodeficiency virus (HIV; formerly HTLV-III/LAV) infections. Zidovudine currently is labeled by the FDA for the management of HIV infections in certain adults with an absolute helper/inducer (CD4+, T4+) T-cell count from peripheral blood of 500/cu mm or less at the time therapy with the drug is initiated and who are asymptomatic, have early symptomatic HIV infections, or have advanced symptomatic infections (eg, acquired immunodeficiency syndrome AIDS or advanced AIDS related complex ARC). Zidovudine also is labeled by the FDA for the management of HIV infections in children 3 months of age or older who have HIV related symptoms or who are asymptomatic but have abnormal laboratory values indicating substantial HIV related immunosuppression. [R1, 395] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- CLAB: *A sensitive high performance liquid chromatographic (HPLC) assay was established to analyze levels of ... zidovudine in serum, milk and tissue extracts. After methanol precipitation, serum samples could be injected directly into the HPLC apparatus, whereas tissue extracts required further clarification. Recovery of /zidovudine/ was virtually complete. Isocratic elution with a mobile phase consisting of 6% acetonitrile and 0.1M ammonium acetate, pH adjusted to 4.5 with glacial acetic acid, resulted in good resolution /of the drug/ and its metabolites; retention times for /zidovudine/ and the internal standard, p-nitrophenol, were 20 and 37 min, respectively. ... [R42] *A simple and rapid reversed phase HPLC method is described for the determination of zidovudine and its major metabolite, zidovudine 5'-O-glucuronide ... in human serum. ... [R43] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Toxicology and Carcinogenesis Studies of AZT and AZT/a-Interferon A/D in B6C3F1 Mice Technical Report Series No. 469 (1999) NIH Publication No. 99-3959 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for AZT. Route: in utero; Species: transplacental carcinogenic study, mice. [R44] SO: R1: McEvoy, G.K. (ed.). American Hospital Formulary Service - Drug Information 92. Bethesda, MD: American Society of Hospital Pharmacists, Inc., 1992 (Plus Supplements 1992). R2: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. R3: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 76 114 (2000) R4: Sperling RS et al; N Engl J Med 326 (13): 857-61 (1992) R5: Lewis W et al; J Clin Invest 89 (4): 1354-60 (1992) R6: Gallicchio VS, Hughes NK; Proc Soc Exp Biol Med 199 (4): 459-65 (1992) R7: Greene JA et al; Fundam Appl Toxicol 15 (1): 201-6 (1990) R8: Lamperth L et al; Lab Invest 65 (6): 742-51 (1991) R9: Sikka SC et al; Biochem Pharmacol 42 (6): 1293-7 (1991) R10: Gogu SR et al; Exp Hematol 19 (7): 649-52 (1991) R11: Agarwal RP, Mian AM; Biochem Pharmacol 42 (4): 905-11 (1991) R12: Agur Z et al; Exp Hematol 19 (5): 364-8 (1991) R13: Haschek WM et al; Fundam Appl Toxicol 14 (4): 764-75 (1990) R14: Toxicology and Carcinogenesis Studies of AZT and AZT/a-Interferon A/D in B6C3F1 Mice p.8 Technical Report Series No. 469 (1999) NIH Publication No. 99-3959 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Final Study Report Developmental Toxicity Evaluation of 3'-Azido-3'-deoxythymidine (AZT; CAS No. 30516-87-1) and 2', 3'-Dideoxycytidine (ddC; CAS No. 7481-89-2) Administered by Gavage to Swiss Albino (CD-1(R)) Mice on Gestational Days 6-15, NTP Study No. TER97001 (February 14, 2002) available at http://ntp-server.niehs.nih.gov/htdocs/pub-TT0.html as of August 16, 2002 R16: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; The Immunotoxicity of 3'-Azido-3'-deoxythymidine (AZT) (CAS No. 30516-87-1) in Female B6C3F1, NTP Study No. IMM96003 available at http://ntp-server.niehs.nih.gov/htdocs/pub-IT0.html as of August 15, 2002 R17: Park GB, Mitra AK; Pharm Res 9 (Mar): 326-31 (1992) R18: Kremer D et al; Pharmacotherapy 12 (1): 56-60 (1992) R19: Paoli I et al; N Engl J Med 326 (Mar 19): 839-40 (1992) R20: Kawaguchi T et al; Int J Pharm 77 (Oct 31): 71-4 (1991) R21: Hankins GD et al; Am J Obstet Gynecol 163 (3): 728-32 (1990) R22: Gillet JY et al; J Gynecol Obstet Biol Reprod (Paris) 19 (2): 177-80 (1990) R23: Liebes L et al; J Infect Dis 161 (2): 203-7 (1990) R24: Morse GD et al; DICP 24 (7-8): 754-60 (1990) R25: Ameer B et al; Drug Chem Toxicol 15 (2): 161-75 (1992) R26: Schwartz EL et al; J Acquir Immune Defic Syndr 5 (6): 619-26 (1992) R27: Qian M et al; Pharm Res 9 (Feb): 224-7 (1992) R28: Gallicchio VS, Hughes NK; J Intern Med 231 (3): 219-26 (1992) R29: Qian MX et al; Pharm Res 9 (2): 224-7 (1992) R30: Gallicchio VS, Hughes NK; Int J Cell Cloning 10 (2): 99-104 (1992) R31: Gallo JM et al; AIDS Res Hum Retroviruses 8 (2): 277-83 (1992) R32: Miles SA; Cancer Invest 9 (2): 229-38 (1991) R33: Lotterer E et al; Eur J Clin Pharmacol 40 (3) 305-8 (1991) R34: Hochster H et al; Ann Intern Med 113 (2): 111-7 (1990) R35: Hedaya MA et al; Pharm Res 7 (4): 411-7 (1990) R36: National Library of Medicine's Medical Subject Headings online file (MeSH, 1999) R37: Fischl MA; Am J Med 90 (4A): 2S-7S (1991) R38: Montgomery AB; Semin Respir Infect 4 (4): 311-7 (1989) R39: U.S. Department of Health and Human Services. Public Health Service. FDA. Drug Utilization in the United States: 1989. Eleventh Annual Review. p.11 (April, 1991) R40: 21 CFR 200-299, 300-499, 820, and 860 (4/1/91 R41: DHHS/FDA; Approved Drug Products with Therapeutic Equivalence Evaluations 12th edition p.3-286 (1992) R42: Ruprecht RM et al; J Chromatogr 528 (2): 371-83 (1990 R43: Kamali F, Rawlins MD; J Chromatogr 530: 474-9 (1990) R44: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 92 Record 351 of 1119 in HSDB (through 2003/06) AN: 6758 UD: 200302 RD: Reviewed by SRP on 1/20/2001 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: 1,2-DICHLORO-1,1-DIFLUOROETHANE- SY: *HCFC-132b- RN: 1649-08-7 MF: *C2-H2-Cl2-F2 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *The most important commercial method of manufacturing HCFCs is the successive replacement of chlorine by fluorine using HF. /HCFCs/ [R1, 507] MFS: *PCR Inc, Hq, PO Box 1466, Gainesville, FL 32602; (904) 376-8246, Production site: Gainesville, FL 32601 [R2] OMIN: *1,2-Dichloro-1,1-difluoroethane is not produced in commodity quantities. [R3] *... /The use of chlorofluorocarbons for aerosol sprays/ was prohibited in 1979 except for a few specialized items, because of their depleting effect on stratospheric ozone. /Chlorofluorocarbons/ [R4] USE: *1,2-Dichloro-1,1- difluoroethane is a potential substitute for some ozone depleting chlorofluorocarbons and a model for other 1,1,1,2-tetrahaloethanes under consideration as chlorofluorocarbon substitutes. [R5] *Mechanical vapor compression systems use fluorocarbons for refrigeration and air conditioning and account for ... majority of refrigeration capability in us. ... fluorocarbons are used as refrigerants in home appliances, mobile air conditioning units, retail food refrigeration systems and ... chillers. /Fluorocarbons/ [R6, 1196] PRIE: U.S. PRODUCTION: *(1984) 1.36X10+11 g (EST) /CFC-13, -113, -114, -115, FLUORINATED MONOMERS AND SPECIALITIES/ [R7] U.S. IMPORTS: *(1984) GREATER THAN 4.54X10+9 g (EST) /UNCLASSIFIED FLUOROCARBONS/ [R7] U.S. EXPORTS: *(1984) RANGE FROM 1.82X10+10 g TO 2.27X10+10 g (EST) /UNCLASSIFIED FLUOROCARBONS/ [R7] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless [R3] BP: *46.8 deg C @ 760 mm Hg [R8] MP: *-101.2 deg C [R8] MW: *134.94 [R8] CTP: *Critial temperature: 222 deg C [R1, 506] DEN: *1.4163 g/cu cm @ 20 deg C [R8] SOL: *In water, 850 mg/l @ 24 deg C [R9] SPEC: *1.36193 @ 20 deg C/D [R8] VAP: *340 mm Hg @ 25 deg C [R10] OCPP: *Hydroxyl radical rate constant= 1.6X10-14 cu cm/molecule-sec @ 25 deg C [R11] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Nonflammable [R3] TOXC: *ALL FLUOROCARBONS WILL UNDERGO THERMAL DECOMPOSITION WHEN EXPOSED TO FLAME OR RED-HOT METAL. DECOMPOSITION PRODUCTS OF THE CHLOROFLUOROCARBONS WILL INCLUDE HYDROFLUORIC AND HYDROCHLORIC ACID ALONG WITH SMALLER AMOUNTS OF PHOSGENE AND CARBONYL FLUORIDE. THE LAST COMPOUND IS VERY UNSTABLE TO HYDROLYSIS AND QUICKLY CHANGES TO HYDROFLUORIC ACID AND CARBON DIOXIDE IN THE PRESENCE OF MOISTURE. /FLUOROCARBONS/ [R12] *IN CONTACT WITH OPEN FLAME OR VERY HOT SURFACE FLUOROCARBONS MAY DECOMP INTO HIGHLY IRRITANT AND TOXIC GASES: CHLORINE, HYDROGEN FLUORIDE OR CHLORIDE, AND EVEN PHOSGENE. /FLUOROCARBON REFRIGERANT AND PROPELLANTS/ [R13] *UNDER CERTAIN CONDITIONS, FLUOROCARBON VAPORS MAY DECOMPOSE ON CONTACT WITH FLAMES OR HOT SURFACES, CREATING THE POTENTIAL HAZARD OF INHALATION OF TOXIC DECOMPOSITION PRODUCTS. /FLUOROCARBONS/ [R6, 1195] REAC: *Dangerous ... on contact with acid or acid fumes, they emit highly toxic fumes. /Fluorides/ [R14, 541] *DANGEROUS ... ON CONTACT WITH ACIDS OR ACID FUMES THEY EVOLVE HIGHLY TOXIC CHLORIDE FUMES. /CHLORIDES/ [R14, 966] DCMP: *When heated to decomp it emits very toxic fumes of /hydrogen chloride and hydrogen fluoride/. [R15] *UNDER CERTAIN CONDITIONS, FLUOROCARBON VAPORS MAY DECOMPOSE ON CONTACT WITH FLAMES OR HOT SURFACES, CREATING THE POTENTIAL HAZARD OF INHALATION OF TOXIC DECOMPOSITION PRODUCTS. /FLUOROCARBONS/ [R6, 1195] EQUP: *Many of the fluorocarbons are good solvents of skin oil, so protective ointment should be used. /Fluorocarbons/ [R16, 499] *NEOPRENE GLOVES, PROTECTIVE CLOTHING, AND EYE PROTECTION MINIMIZE RISK OF TOPICAL CONTACT. DEGREASING EFFECT ON SKIN CAN BE TREATED WITH LANOLIN OINTMENT. /FLUOROCARBONS/ [R6, 1198] *FORCED AIR VENTILATION @ LEVEL OF VAPOR CONCN TOGETHER WITH USE OF INDIVIDUAL BREATHING DEVICES WITH INDEPENDENT AIR SUPPLY WILL MINIMIZE RISK OF INHALATION. LIFELINES SHOULD BE WORN WHEN ENTERING TANKS OR OTHER CONFINED SPACES. /FLUOROCARBONS/ [R6, 1195] OPRM: *SUFFICIENT EXHAUST AND GENERAL VENTILATION SHOULD BE PROVIDED TO KEEP VAPOR CONCN BELOW RECOMMENDED LEVELS. /FLUOROCARBONS/ [R17] *INHALATION OF FLUOROCARBON VAPORS SHOULD BE AVOIDED. /FLUOROCARBONS/ [R6, 1195] *Forced air ventilation at the level of vapor concentration together with the use of individual breathing devices with independent air supply will minimize the risk of inhalation. Lifelines should be worn when entering tanks or other confined spaces. /Fluorocarbons/ [R6, 1195] *Enclosure of process materials and isolation of reaction vessels and proper design and operation of filling heads for packaging and shipping /are administrative controls that may be instituted to limit occupational exposure to fluorocarbons during manufacture, packaging, and use/. /Fluorocarbons/ [R6, 1195] *FILLING AREAS SHOULD BE MONITORED TO ENSURE ... AMBIENT CONCN OF FLUOROCARBONS DOES NOT EXCEED 1000 PPM ... INHALATION OF FLUOROCARBON VAPORS SHOULD BE AVOIDED ... IF INHALATION OCCURS, EPINEPHRINE OR OTHER SYMPATHOMIMETIC AMINES AND ADRENERGIC ACTIVATORS SHOULD NOT BE ADMIN SINCE THEY WILL FURTHER SENSITIZE HEART TO DEVELOPMENT OF ARRHYTHMIAS. /FLUOROCARBONS/ [R6, 1195] *APPEARANCE OF TOXIC DECOMP PRODUCTS SERVES AS WARNING OF OCCURRENCE OF THERMAL DECOMP AND DETECTION OF SHARP ACRID ODOR WARNS OF PRESENCE ... HALIDE LAMPS OR ELECTRONIC LEAK DETECTORS MAY ALSO BE USED. ADEQUATE VENTILATION ALSO AVOIDS PROBLEM OF TOXIC DECOMPOSITION PRODUCTS. /FLUOROCARBONS/ [R18] *Eye washer and instant shower facilities should be located near the work areas where spills and splash hazards exist. /Fluorocarbons/ [R16, 499] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Because of recent discovery of potential ozone decomposition in the stratosphere by fluorotrichloromethane, this material should be released to the environment only as a last resort. Waste material should be /recovered and/ returned to the vendor, or to licensed waste disposal company. [R19] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *... Emergency treatment is supportive and includes decontamination, oxygen, and any specific therapy required in a particular case such as antiarrhythmics or anticonvulsants. A few patients may require intermittent positive-pressure ventilation, dialysis, or treatment for hepatic failure. /Solvent abuse/ [R20, 1259] *... In persons who are intoxicated with fluorocarbons, steps can be taken to lessen the risk of arrhythmias. ... Before evaluation at the hospital, patients should be advised to avoid strenuous exercise. In the hospital, patients can be placed in a quiet, nonthreatening environment and sedated if necessary. If hypoxic, oxygen should be administered and metabolic abnormalities corrected. Sympathomimetic drugs should be avoided. Ventricular arrhythmias are best treated with beta-blocking agents. /Fluorocarbons/ [R20, 81] *Patients with fluorohydrocarbon poisoning should not be given epinephrine (Adrenalin) or similar drugs because of the tendency of fluorohydrocarbon to induce cardiac arrhythmia, including ventricular fibrillation. /Fluorohydrocarbons/ [R16, 498] *Victims of Freon inhalation require management for hypoxic, CNS anesthetic, and cardiac symptoms. Patients must be removed from the exposure environment, and high-flow supplemental oxygen should be utilized. The respiratory system should be evaluated for injury, aspiration, or pulmonary edema and treated appropriately. CNS findings should be treated supportively. A calm environment with no physical exertion is imperative to avoid increasing endogenous adrenergic levels. Exogenous adrenergic drugs must not be used to avoid inducing sensitized myocardial dysrhythmias. Atropine is ineffective in treating bradyarrhythmias. For ventricular dysrhythmias, diphenylhydantoin and countershock may be effective. Cryogenic dermal injuries should be treated by water bath rewarming at 40 to 42 deg C until vasodilatory flush has returned. Elevation of the limb and standard frostbite management with late surgical debridement should be utilized. Ocular exposure requires irrigation and slit-lamp evaluation for injury. /Freons/ [R20, 1282] *... IF INHALATION OCCURS, EPINEPHRINE OR OTHER SYMPATHOMIMETIC AMINES AND ADRENERGIC ACTIVATORS SHOULD NOT BE ADMIN SINCE THEY WILL FURTHER SENSITIZE HEART TO DEVELOPMENT OF ARRHYTHMIAS. /FLUOROCARBONS/ [R6, 1195] HTOX: *EXCESSIVE SKIN CONTACT WITH LIQ FLUOROCARBONS SHOULD BE MINIMIZED TO PREVENT DEFATTING OF SKIN ... /FLUOROCARBONS/ [R17] *FLUOROCARBON VAPORS ARE 4 TO 5 TIMES HEAVIER THAN AIR. THUS HIGH CONCN TEND TO ACCUMULATE IN LOW-LYING AREAS, RESULTING IN HAZARD OF INHALATION OF CONCENTRATED VAPORS, WHICH MAY BE FATAL. /FLUOROCARBONS/ [R6, 1195] *UNDER CERTAIN CONDITIONS, FLUOROCARBON VAPORS MAY DECOMPOSE ON CONTACT WITH FLAMES OR HOT SURFACES, CREATING POTENTIAL HAZARD OF INHALATION OF TOXIC DECOMPOSITION PRODUCTS. /FLUOROCARBONS/ [R6, 1195] *CLINICAL PATHOLOGISTS EXPOSED TO FLUOROCARBONS IN THE PREPN OF FROZEN TISSUE SECTIONS HAVE BEEN SEEN TO DEVELOP CORONARY HEART DISEASE. /FLUOROCARBONS/ [R6, 1209] *There is ... evidence that the atmospheric concentrations of chlorofluorocarbons deplete ozone in the stratosphere. A reduction in ozone concentration will result in increased transmission of solar ultraviolet radiation through the stratosphere. Many significant adverse effects of such an increase in exposure to this radiation have been identified. ... One of the most well defined human health effects resulting from stratospheric ozone depletion is an increase in the frequency of skin cancer expected as a result of even small increases in UV-B radiation (280-320 nm) reaching the earths's surface. /Chlorofluorocarbons/ [R21] *Freons are toxic to humans by several mechanisms. Inhaled fluorocarbons sensitized the myocardium to catecholamines, frequently resulting in lethal ventricular arrhythmias. Because they are gases heavier than air, fluorocarbons can displace atmospheric oxygen, thus resulting in asphyxiation. These compounds also have a central nervous system (CNS) anesthetic effect analogous to a structurally similar general anesthetic, halothane. Pressurized refrigerant or liquid fluorocarbons with a low boiling point have a cyrogenic effect on exposed tissues, causing frostbite, laryngeal or pulmonary edema, and gastrointestinal perforation. Certain fluorocarbons degrade at high temperatures into toxic products of chlorine, hydrofluoric acid, or phosgene gases. /Freons/ [R20, 1281] *MANUFACTURING PROCESSES USE HYDROFLUORIC ACID FROM FLUOROSPAR IN PRODUCTION OF ALL FLUOROCARBONS. SOME PROCESSES USE CARBON TETRACHLORIDE FROM CARBON DISULFIDE, OR AS CO-PRODUCT OF PERCHLOROETHYLENE AND CHLORINATION OF PROPYLENE, OR CHLOROFORM FROM CHLORINATION OF METHANOL. THE MAJOR HAZARDS RELATE PRIMARILY TO THE INADVERTENT RELEASE OF HYDROFLUORIC ACID OR CARBON TETRACHLORIDE, RATHER THAN TO THE MANUFACTURED FLUOROCARBONS. /FLUOROCARBONS/ [R6, 1194] NTOX: *It is not mutagenic in Salmonella typhimurium. In animal experiments, adverse effects have been seen at high concentrations. [R22] *Its approximate oral lethal dose in rats in 25,000 mg/kg and its approximate lethal concentration 110,000 mg/cu m. Its main action is weak anesthesia at or near the lethal concentration. It is not mutagenic in Salmonella typhimurium. In animal experiments, adverse effects have been seen at high concentrations. [R22] *A single dose of HCFC 132b (2 g/kg) /was applied/ under an occluding dressing to the shaved skin of five male and five female Wistar rats, there were no deaths. The clinical signs observed were decr respiratory rate, decr startle rate, altered locomotor activity, restlessness and vocalization. Three male and four female rats had swollen or slightly swollen livers on autopsy. [R23, p. 50 (1992)] *One drop (approx 0.05 ml) each of 100% HCFC 132b and a 10% solution in propylene glycol was applied and slightly rubbed in to the shaved intact shoulder skin of 10 male albino guinea-pigs, but the area was not occluded. The pure compound produced only mild irritation in one animal only. No irritation was induced by the 10% solution. [R23, p. 60 (1992)] *Groups of 20 male and 20 female Crl:CDBR rats were exposed to 0, 3, 11, and 27 g/cu m (6 hr/day, 5 days/week) for 13 weeks. Male rats exposed at all concn of HCFC 132b showed bile duct proliferation and disruption of spermatogenesis with cell debris in the epididymides at the two higher concn. Other effects included incr in liver/body weight ratio in males at all concn and in females at the two higher concn. Elevation of serum alkaline phosphatase activity was found in both sexes exposed to 11 or 27 g/cu m. During the study, all groups exposed to HCFC 132b showed reduced food consumption and body weight gain. In the two highest exposure groups there were depressions in the absolute but not relative brain and testes weights. Other organ weight changes were also seen (slight incr in heart, lung, and kidney weights). The biological significance of these weight changes is not clear since there were no accompanying histological findings. During exposure to 27 g/cu m, rats showed CNS depression as indicated by decr activity and low responsiveness to sound. [R23, p. 52-53 (1992)] *When 20 male Crl:CDBR rats were exposed to 55 g/cu m (6 hr/day, 5 days/week) for 2 weeks, reduction in body weight gain, irregular respiration and CNS depression (lethargy, poor coordination, occasional tremors and prostration) were seen. The CNS effects disappeared within 30 min after each exposure. Pathological exam of rats sacrificed immediately after the tenth exposure showed thymic atrophy and spermatogenesis arrest, but these changes were not present in rats sacrificed 14 days after exposure ceased. [R23, p. 52 (1992)] *A series of sacral intradermal injections of HCFC 132b was given (once per week at 7-day intervals) over a 3-week period to groups of nine male albino guinea-pigs (0.1 ml of a 1% solution in dimethyl phthalate). Fourteen days after the last application, the animals were challenged with either 1 drop (0.05 ml) of undiluted liquid or a 19% solution of test material in propylene glycol on the shaved skin. No evidence of sensitization was observed. [R23, p. 61 (1992)] */G/roups of seven or eight pregnant rats were exposed to 3, 11, or 28 g/cu m for 6 hr/day on days 6-15 of gestation. Maternal and fetal body weights were reduced at all exposure levels. The number of resorptions was incr in the 11- and 27-g/cu m exposure groups. [R23, p. 65 (1992)] *HCFC 132b was reported to produce cardiac sensitization in beagle dogs in response to an intravenous adrenaline challenge at exposure levels of 27 g/cu m or more. [R23, p. 83 (1992)] NTXV: *Its approximate oral lethal dose in rats is 25,000 mg/kg and its approximate lethal concentration is 110,000 mg/cu m; [R22] *LC50 Mouse 269 g/cu m /from table/; [R23, p. 46 (1992)] ADE: *... MAIN FACTOR AFFECTING FATE OF FLUOROCARBONS IS BODY FAT, WHERE THEY ARE CONCENTRATED AND SLOWLY RELEASED INTO BLOOD @ CONCN THAT SHOULD NOT CAUSE ANY RISK OF CARDIAC SENSITIZATION. /FLUOROCARBONS/ [R24] *THERE IS A SIGNIFICANT ACCUMULATION OF FLUOROCARBONS IN BRAIN, LIVER AND LUNG COMPARED TO BLOOD LEVELS, SIGNIFYING A TISSUE DISTRIBUTION OF FLUOROCARBONS SIMILAR TO THAT OF CHLOROFORM. /FLUOROCARBONS/ [R6, 1203] *Absorption of fluorocarbons is much lower after oral ingestion (35-48 times) than after inhalation. ... The lung generally has the highest fluorocarbon concentrations on autopsy. /Fluorocarbons/ [R25] *Although fluorocarbons cause cardiac sensitization in certain animal species, rapid elimination prevents the development of cardiotoxic concentrations from aerosol bronchodilator use except at exceedingly high doses (12 to 24 doses in 2 minutes). /Fluorocarbons/ [R25] *FLUOROCARBON COMPOUNDS ARE LIPID-SOLUBLE AND THUS ARE GENERALLY WELL ABSORBED THROUGH LUNG. ABSORPTION AFTER INGESTION IS 35 TO 48 TIMES LOWER THAN AFTER INHALATION. ... FLUOROCARBONS ARE ELIMINATED BY WAY OF LUNG. /FLUOROCARBON COMPOUNDS/ [R26] METB: *... It is expected that /HCFCs/ would be metabolized by a cytochrome P-450-dependent monooxygenase liver enzyme to give reactive metabolic products. /HCFCs/ [R23, p. 36 (1992)] *In a metabolism study using intraperitoneal admin of HCFC 132b to rats, 2-chloro-2,2-difluoroethylglucuronide, chlorodifluoroacetaldehyde (hydrated and conjugated) and chlorodifluoroacetic acid were identified in the urine. Formation and excretion of chlorodifluoroacetic acid were incr after repeated injection of the animals with HCFC 132b. In vitro experiments using rat liver microsomes suggested the involvement of cytochrome P-450 IIEI in the initial hydroxylation step. No evidence for covalent binding of fluorinated metabolites to liver proteins has been observed. [R23, p. 13 (1992)] *The chlorofluorocarbon substitute 1,1,1,2-tetrafluoroethane (HFC-134a) is subject to metabolism by cytochrome p450 in hepatic microsomes from rat, rabbit, and human. In rat and rabbit, the p450 form 2E1 is a predominant low-KM, high-rate catalyst of HFC-134a biotranformation and is prominently involved in the metabolism of other tetrahaloalkanes of greater toxicity than HFC-134a (e.g. 1,2-dichloro-1,1-difluoroethane (HCFC-132b)). In this study, we determined that the human ortholog of p450 2E1 plays a role of similar importance in the metabolism of HFC-134a. In human hepatic microsomes from 12 individuals, preparations from subjects with relatively high p450 2E1 levels were shown to metabolize HFC-134a at rates 5- to 10-fold greater than microsomes of individuals with lower levels of this enzyme; the increased rate of metabolism of HFC-134a was specifically linked to increased expression of p450 2E1. The primary evidence for the conclusion is drawn from studies using mechanism-based inactivation of p450 2E1 by diethyldithiocarbamate, competitive inhibition of HFC-134a oxidation by p-nitrophenol (a high-affinity substrate for p450 2E1), strong positive correlations of rates of HFC-134a defluorination with p-nitrophenol hydroxylation in the study population, and correlation of p450 2E1 levels with rates of halocarbon oxidation. Thus, our findings support the conclusion that human metabolism of HFC-134a is qualitatively similar to that of the species (rat and rabbit) used for toxicological assessment of this halocarbon. Although hazard from HFC-134a exposure is not anticipated in most humans (based on toxicological evaluation in laboratory animals), our results suggest that HFC-134a exposure should be minimized for individuals with chemical exposure histories commensurate with elevation of p450 2E1 (i.e. frequent contact with agents such as ethanol, trichloroethylene, or pyridine). Furthermore, these findings suggest that toxicity assessment of certain other haloethanes currently under consideration as replacements for chlorofluorocarbons should be considered in animals with elevated p450 2E1. [R27] *1-Fluoro-1,1,2-trichloroethane (HCFC-131a), 1,2-dichloro-1,1-difluoroethane (HCFC-132b), and 1,1,1-trifluoro-2-chloroethane (HCFC-133a) were chosen as models for comparative metabolism studies on 1,1,1,2-tetrahaloethanes, which are under consideration as replacements for ozone-depleting chlorofluorocarbons (CFCs). Male Fischer 344 rats were given 10 mmol/kg ip 1-fluoro-1,1,2-trichloroethane or 1,2-dichloro-1,1-difluoroethane or exposed by inhalation to 1% 1,1,1-trifluoro-2-chloroethane for 2 hr. Urine collected in the first 24 hr after exposure was analyzed by 19F NMR and GC/MS and with a fluoride-selective ion electrode for the formation of fluorine-containing metabolites. Metabolites of 1-fluoro-1,1,2-trichloroethane included 2,2-dichloro-2-fluoroethyl glucuronide, 2,2-dichloro-2-fluoroethyl sulfate, dichlorofluoroacetic acid, and inorganic fluoride. Metabolites of 1,2-dichloro-1,1-difluoroethane were characterized as 2-chloro-2,2-difluoroethyl glucuronide, 2-chloro-2,2-difluoroethyl sulfate, chlorodifluoroacetic acid, chlorodifluoroacetaldehyde hydrate, chlorodifluoroacetaldehyde-urea adduct, and inorganic fluoride. 1,1,1-Trifluoro-2-chloroethane was metabolized to 2,2,2-trifluoroethyl glucuronide, trifluoroacetic acid, trifluoroacetaldehyde hydrate, trifluoroacetaldehyde-urea adduct, inorganic fluoride, and a minor, unidentified metabolite. With 1-Fluoro-1,1,2-trichloroethane and 1,2-dichloro-1,1-difluoroethane, glucuronide conjugates of 2,2,2-trihaloethanols were the major urinary metabolites, whereas with 1,1,1-trifluoro-2-chloroethane, a trifluoroacetaldehyde-urea adduct was the major urinary metabolite. Analysis of metabolite distribution in vivo indicated that aldehydic metabolites increased as fluorine substitution increased in the order 1-Fluoro-1,1,2-trichloroethane < 1,2-dichloro-1,1-difluoroethane < 1,1,1-trifluoro-2-chloroethane. With NADPH-fortified rat liver microsomes, 1,1,1-trifluoro-2-chloroethane and 1,2-dichloro-1,1-difluoroethane were biotransformed to trifluoroacetaldehyde and chlorodifluoroacetaldehyde, respectively, whereas 1-Fluoro-1,1,2-trichloroethane was converted to dichlorofluoroacetic acid. No covalently bound metabolites of 1-Fluoro-1,1,2-trichloroethane and 1,1,1-trifluoro-2-chloroethane metabolites were detected by 19F NMR spectroscopy. The nature of the identified organic fluorine-containing metabolites indicates that cytochrome p450-dependent oxidation predominates in the metabolism of these 1,1,1,2-tetrahaloethanes. The generation of fluoride from the fluorodihalomethyl group (-CFX2) apparently arises from a separate dehalogenation pathway. [R28] *The chlorofluorocarbon substitute 1,2-dichloro-1,1-difluorethane (HCFC-132b) undergoes oxidative metabolism in rats to give a range of metabolites, including chlorodifluoroacetaldehyde ... . The present experiments were undertaken after studies to characterize an unidentified metabolite of HCFC-132b revealed that chloro-difluoroacetaldehyde was toxic in vivo: rats given chlorodifluoracetaldehyde died showing signs of cholinergic stimulation. Because some fluoroketones are known inhibitors of hydrolases, including acetylcholinesterase, the inhibitory effects of chlorodifluoracetaldehyde on acetylcholinesterase (electric eel and human erythrocyte), on pseudocholinesterase (horse serum), on carboxylesterase (pig liver), and on alpha-chymotrypsin (bovine pancreas) were studied. In aqueous solution, the ratio chlorodifluoroacetaldehyde:chlorodifluoroacetaldehyde hydrate, as determined by 1H nuclear magnetic resonance spectroscopy, was 1:157. Chlorodifluoroacetaldehyde was a slow-binding inhibitor of both acetylcholinesterase, of pseudo cholinesterase, and of carboxylesterase; the Ki values, corrected for the aldehyde:hydrate ratio, were 150 nM, 1.7 nM, 3.7 nM, and 23 pM, respectively, as determined by final velocity of the progress curves; the kappaon values were 9.1 104, and 9.2taldehyde did not inhibit alpha-chymotrypsin. Acetaldehyde and trichloroacetaldehyde were classical competitive inhibitors of acetylcholinesterase. These results show that hydrochlorofluorocarbon metabolites may exert significant biological effects. [R29] *1,2-Dichloro-1,1-difluoroethane (HCFC-132b) is a potential substitute for some ozone-depleting chlorofluorocarbons and a model for other 1,1,1,2-tetrahaloethanes under consideration as chlorofluorocarbon substitutes. Male Fischer 344 rats were given 10 mmol/kg 1,2-Dichloro-1,1-difluoroethane dissolved in corn oil by intraperitoneal injection. An NMR assay for convalent binding of 1,2-Dichloro-1,1-difluoroethane metabolites to liver proteins was negative, whereas binding was observed in halothane-treated rats. Total urinary metabolites excreted by rat given 1,2-Dichloro-1,1-difluoroethane during the first 24 hr amounted to 1.8 : 0.1% of the injected dose, as determined by 19F NMR. During the first 6 h, metabolites of 1,2-Dichloro-1,1-difluoroethane corresponding to 2-chloro-2,2-difluoroethyl glucuronide, unknown metabolite A, chlorodifluoroacetic acid, and chlorodifluoroacetaldehyde hydrate (both free and conjugated (unknown metabolite B)) were excreted in urine in the approximate ratio 100:9:3:7, respectively. Metabolite A is apparently an O-conjugate of 2-chloro-2,2-difluoroethanol; unconjugated 2-chloro-2,2-difluoroethanol was not detected in urine. The 19F NMR spectrum of metabolite B indicates the formation of a hemiacetal of chlorodifluoroacetaldehyde. Repeated exposure of rats of 1,2-Dichloro-1,1-difluoroethane significantly increased both the rate of chlorodifluoroacetic acid excretion and the relative fraction of the HCFC-132 dose excreted as chlorodifluoroacetic acid in urine. Incubation of 1,2-Dichloro-1,1-difluoroethane with rat hepatic microsomes yielded chlorodifluoroacetaldehyde hydrate as the only fluorinated product. The in vivo metabolism of 1,2-Dichloro-1,1-difluoroethane was increased in microsomes from pyridine-treated rats as compared with control rats, and 1,2-Dichloro-1,1-difluoroethane metabolism was inhibited by p-nitrophenol, indicating that the cytochrome p450 isoform IIE1 is largely responsible for the initial hydroxylation of 1,2-Dichloro-1,1-difluoroethane. [R30] *Human subjects were exposed by inhalation to 250, 500, and 1000 ppm 1,1-dichloro-1-fluoroethane (HCFC-141b) for 4 hr, and urine samples were collected from 0-4, 4-12, and 12-24 hr for metabolite analysis. 'OF nuclear magnetic resonance spectroscopic analysis of urine samples from exposed subjects showed that 2,2-dichloro-2-fluoroethyl glucuronide and dichlorofluoroacetic acid were the major and minor metabolites, respectively, of 1,1-dichloro-1-fluoroethane. Urinary 2,2-dichloro-2-fluoroethyl glucuronide was hydrolyzed to 2,2-dichloro-2-fluoroethanol by incubation with beta-glucuronidase, and the released 2,2-dichloro-2-fluoroethanol was quantified by gas chromatography/mass spectrometry. Concentrations of 2,2-dichloro-2-fluoroethanol were highest in the urine samples collected 4-12 hr after exposure, but 2,2-dichloro-2-fluoroethanol was also detected in the samples collected 0-4 and 12-24 hr after exposure. Exposure concentration-dependent excretion of 2,2-dichloro-2-fluoroethanol, obtained by hydrolysis of 2,2-dichloro-2-fluoroethyl glucuronide, was observed in seven of the eight subjects studied. In conclusion, 1,1-dichloro-1-fluoroethane is metabolized in human subjects to 2,2-dichloro-2-fluoroethanol, which is conjugated with glucuronic acid and excreted as its glucuronide in urine in a time- and exposure concentration-dependent manner. [R31] INTC: *IF INHALATION OCCURS, EPINEPHRINE OR OTHER SYMPATHOMIMETIC AMINES AND ADRENERGIC ACTIVATORS SHOULD NOT BE ADMIN SINCE THEY WILL FURTHER SENSITIZE HEART TO DEVELOPMENT OF ARRHYTHMIAS. /FLUOROCARBONS/ [R6, 1195] *... THE COMBINATION OF FLUOROCARBON WITH A SYMPATHOMIMETIC BRONCHODILATOR IS POTENTIALLY DANGEROUS FOR THE TREATMENT OF BRONCHIAL ASTHMA. FOR THE SAME REASON, SYMPATHOMIMETIC DRUGS ARE CONTRAINDICATED IN CARDIAC RESUSCITATION OF PATIENTS SUFFERING FROM FLUOROCARBON POISONING. /FLUOROCARBON POISONING/ [R6, 1183] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *1,2-Dichloro-1,1-difluoroethane is an anthropogenic compound which may be released to the environment as a fugitive emission during its production or use. However, no information was found as to whether it 1,2-dichloro-1,1-difluoroethane is presently in commercial use. If released to air, a vapor pressure of 340 mm Hg at 25 deg C indicates 1,2-dichloro-1,1-difluoroethane will exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichloro-1,1-difluoroethane will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is about 1,000 days. 1,2-Dichloro-1,1-difluoroethane has a water solubility of 850 mg/l and may be removed from the air by rain. If released to soil, 1,2-dichloro-1,1-difluoroethane is expected to have high mobility based upon an estimated Koc of 107. Volatilization from moist soil surfaces is an important fate process based upon an estimated Henry's Law constant of 0.071 atm-cu m/mole. 1,2-Dichloro-1,1-difluoroethane may volatilize from dry soil surfaces based upon its vapor pressure. Its biodegradability in soil and water in not known. If released into water, 1,2-dichloro-1,1-difluoroethane is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization from water surfaces is expected to be an important fate process based upon this compound's estimated Henry's Law constant. Estimated volatilization half-lives for a model river and model lake are 1.2 hours and 4.6 days, respectively. An estimated BCF of 14 suggests the potential for bioconcentration in aquatic organisms is low. (SRC) FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 107(SRC), determined from a water solubility of 850 mg/l(2) and a regression-derived equation(3), indicates that 1,2-dichloro-1,1-difluoroethane is expected to have high mobility in soil(SRC). Volatilization of 1,2-dichloro-1,1-difluoroethane from moist soil surfaces is expected to be an important fate process(SRC) given a Henry's Law constant of 0.071 atm-cu m/mole(SRC), based upon its vapor pressure, 340 mm Hg(4), and water solubility(2). The potential for volatilization of 1,2-dichloro-1,1-difluoroethane from dry soil surfaces may exist(SRC) based upon its vapor pressure(4). [R32] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 107(SRC), determined from a water solubility of 850 mg/l(2) and a regression-derived equation(3), indicates that 1,2-dichloro-1,1-difluoroethane is not expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is expected(3) based upon a an estimated Henry's Law constant of 0.0710 atm-cu m/mole calculated from its vapor pressure, 340 mm Hg(4), and water solubility(2). Using this Henry's Law constant and an estimation method(3), volatilization half-lives for a model river and model lake are 1.2 hours and 4.6 days, respectively(SRC). According to a classification scheme(5), a BCF of 14(SRC), estimated from its water solubility and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low. [R33] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), 1,2-dichloro-1,1-difluoroethane, which has a vapor pressure of 340 mm Hg at 25 deg C(2), is expected to exist solely as a vapor in the ambient atmosphere. Vapor-phase 1,2-dichloro-1,1-difluoroethane is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is about 1,000 days(SRC), calculated from its rate constant of 1.6X10-14 cu cm/molecule-sec at 25 deg C(3). The water solubility of 1,2-dichloro-1,1-difluoroethane of 850 mg/l at 24 deg C(4), indicates that it may undergo atmospheric removal by wet deposition processes; however, any removed by this process is expected to rapidly revolatilize to the atmosphere(SRC). [R34] ABIO: *The rate constant for the vapor-phase reaction of 1,2-dichloro-1,1-difluoroethane with photochemically-produced hydroxyl radicals is 1.6X10-14 cu cm/molecule-sec at 25 deg C(1). This corresponds to an atmospheric half-life of about 1,000 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(SRC). A base-catalyzed second-order hydrolysis rate constant of 9,4X10-5 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 2300 years and 230 years at pH values of 7 and 8, respectively(2). 1,2-Dichloro-1,1-difluoroethane is not expected to undergo direct photolysis due to the lack of absorption in the environmental UV spectrum (> 290 nm)(3). [R35] BIOC: *An estimated BCF of 14 was calculated for 1,2-dichloro-1,1-difluoroethane(SRC), using a mwater solubility of 850 mg/l(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. [R36] KOC: *The Koc of 1,2-dichloro-1,1-difluoroethane is estimated as 107(SRC), using a water solubility of 850 mg/l(1)and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that 1,2-dichloro-1,1-difluoroethane is expected to have high mobility in soil. [R37] VWS: *The Henry's Law constant for 1,2-dichloro-1,1-difluoroethane is estimated as 0.0710 atm-cu m/mole(SRC) based upon its vapor pressure, 340 mm Hg(1), and water solubility, 850 mg/l(2). This Henry's Law constant indicates that 1,2-dichloro-1,1-difluoroethane is expected to volatilize rapidly from water surfaces(3). Based on this Henry's Law constant, the volatilization half-life from a model river (1 m deep, flowing 1 m/sec, wind velocity of 3 m/sec)(3) is estimated as 1.2 hours(SRC). The volatilization half-life from a model lake (1 m deep, flowing 0.05 m/sec, wind velocity of 0.5 m/sec)(3) is estimated as 4.6 days(SRC). 1,2-Dichloro-1,1-difluoroethane's estimated Henry's Law constant(1,2) indicates that volatilization from moist soil surfaces may occur(SRC). 1,2-Dichloro-1,1-difluoroethane would be expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1). [R38] RTEX: *Occupational exposure to 1,2-dichloro-1,1-difluoroethane may occur through inhalation and dermal contact with this compound at workplaces where 1,2-dichloro-1,1-difluoroethane is produced or used. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- TSCA: *Pursuant to section 8(d) of TSCA, EPA promulgated a model Health and Safety Data Reporting Rule. The section 8(d) model rule requires manufacturers, importers, and processors of listed chemical substances and mixtures to submit to EPA copies and lists of unpublished health and safety studies. 1,2-dichloro-1,1-difluoroethane is included on this list. [R39] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Determination of 1,1,1,2-tetrafluoroethane purity by gas chromatography with flame ionization detection. [R40] *GAS CHROMATOGRAPHIC METHOD FOR DETERMINING FLUOROCARBONS IN AIR IS DESCRIBED. CONCN IN AIR ARE DETERMINED DIRECTLY. /FLUOROCARBONS/ [R41] *A GAS CHROMATOGRAPHIC PROCEDURE FOR DETERMINING ATMOSPHERIC LEVELS OF FLUOROCARBONS IS DESCRIBED. COLUMN IS TEMP PROGRAMMED TO SEPARATE HALOGENATED COMPONENTS WHILE MAINTAINING SHORT RETENTION TIMES FOR EACH COMPONENT. FREON 113 INCL. /FLUOROCARBONS/ [R42] *GAS CHROMATOGRAPHIC METHOD FOR MEASURING HALOCARBONS IN AMBIENT AIR SAMPLES IS PRESENTED. /HALOCARBONS/ [R43] *FLUOROCARBONS IN AIR OF WORKING AREA AND IN EXHALED AIR CAN BE ANALYZED BY IR SPECTROMETRY. /FLUOROCARBONS/ [R44] *GAS CHROMATOGRAPHIC METHOD IS PRESENTED FOR FREONS. /FREONS/ [R45] CLAB: *GAS CHROMATOGRAPHIC METHOD FOR DETERMINING FLUOROCARBONS IS DESCRIBED. CONCN IN BODY FLUIDS ARE DETERMINED BY MEANS OF HEAD SPACE ANALYSIS. /FLUOROCARBONS/ [R41] *FLUOROCARBON DETERMINATION IN BLOOD: GAS CHROMATOGRAPHY WITH ELECTRON CAPTURE DETECTION. /FLUOROCARBONS/ [R46] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Zakhari S, Aviado DM; Cardiovascular Toxicology of Aerosol Propellants, Refrigerants and Related Solvents; Target Organ Toxicology Series: Cardiovascular Toxicology, XII+ 388 pages; Raven Press: New York, NY 281-326 (1982). Review of the toxicology of aerosol propellants, refrigerants and related solvents on the cardiovascular system of humans. ... The lifetimes of halohydrocarbons in air is presented. /Halohydrocarbons/ [R47] Anders MW; Metabolism and Toxicity of Hydrochlorofluorocarbons: Current Knowledge and Needs for the Future; Environmental Health Perspectives 96: 185-191 (1991). The metabolism and toxicity of hydrochlorofluorocarbons (HCFCs), potential replacements for ozone depleting chlorofluorocarbons, were reviewed. Bucher JR; NTP Technical Report on Renal Toxicity Studies of Selected Halogenated Ethanes Administered by Gavage to F344/N Rats; National Toxicology Program, Research Triangle Park, North Carolina, Toxicity Report Series No. 45, NIH Publication No. 96-3935, 63: 43 1996. A renal toxicity appraisal of commercial halogenated ethanes, was conducted in male F344/N-rats, to elucidate structure activity relationships in hyaline droplet nephropathy induction. Longstretch J et al; Journal of Photochemistry and Photobiology B Biology 46 (1-3): 20-39 (1998). The health risks associated with ozone depletion will principally be those due to increased ultraviolet B (UV-B) radiation in the environment, ie, increased damage to the eyes, the immune system, and the skin. Some new risks may also be introduced with the increased use of alternatives to the ozone-depleting substances (ODSs). SO: R1: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V11 (94) R2: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 561 R3: European Chemical Industry Ecology and Toxicology Center; 1,2-Dichloro-1,1-difluoroethane (HPA-132b) p15 (1990) R4: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 266 R5: Harris JW, Anders MW; Chem Res Toxicol 4 (2): 180-6 (1991) R6: Clayton, G.D., F.E. Clayton (eds.) Patty's Industrial Hygiene and Toxicology. Volumes 2A, 2B, 2C, 2D, 2E, 2F: Toxicology. 4th ed. New York, NY: John Wiley and Sons Inc., 1993-1994. R7: CHEMICAL PRODUCTS SYNOPSIS: FLUOROCARBONS (1984) R8: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000,p. 3-154 R9: Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) R10: Kubota H et al; Inter J Therm 10: 629-637 (1989) R11: Atkinson R et al; J Chem Phys Ref Data 21: 1125-69 (1992) R12: International Labour Office. Encyclopaedia of Occupational Health and Safety. 4th edition, Volumes 1-4 1998. Geneva, Switzerland: International Labour Office, 1998.,p. 104.185 R13: Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-159 R14: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. R15: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. 1098 R16: Zenz, C., O.B. Dickerson, E.P. Horvath. Occupational Medicine. 3rd ed. St. Louis, MO., 1994 R17: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 897 R18: Clayton, G. D. and F. E. Clayton (eds.). Patty's Industrial Hygiene and Toxicology: Volume 2A, 2B, 2C: Toxicology. 3rd ed. New York: John Wiley Sons, 1981-1982. 3101 R19: United Nations. Treatment and Disposal Methods for Waste Chemicals (IRPTC File). Data Profile Series No. 5. Geneva, Switzerland: United Nations Environmental Programme, Dec. 1985. 207 R20: Haddad, L.M., Clinical Management of Poisoning and Drug Overdose. 2nd ed. Philadelphia, PA: W.B. Saunders Co., 1990. R21: WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.95 (1990) R22: European Chemical Industry Ecology and Toxicology Center; 1,2-Dichloro-1,1-difluoroethane (HPA-132b) p.15 (1990) R23: WHO; Environmental Health Criteria 139: Partially Halogenated Chlorofluorocarbons R24: National Research Council. Drinking Water and Health Volume 1. Washington, DC: National Academy Press, 1977. 781 R25: Ellenhorn, M.J. and D.G. Barceloux. Medical Toxicology - Diagnosis and Treatment of Human Poisoning. New York, NY: Elsevier Science Publishing Co., Inc. 1988. 884 R26: National Research Council. Drinking Water and Health. Volume 3. Washington, DC: National Academy Press, 1980. 101 R27: Surbrook S E JR, Olson MJ; Drug Metab Dispos 20 (4): 518-24 (1992) R28: Yin H et al; Chemical Research in Toxicology 8 (2): 262-8 (1995) R29: Yin H et al; Chem Res Toxicol 6 (5): 630-4 (1993) R30: Harris JW et al; Chem Res Toxicol 4 (2): 180-6 () R31: Tong Z et al; Drug Metabolism and Disposition 26 (7): 711-3 (1998) R32: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (4) Kubota H et al; Inter J Therm 10: 629-637 (1989) R33: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9, 5-5, 15-1 to 15-29 (1990) (4) Kubota H et al; Inter J Therm 10: 629-637 (1989) (5) Franke C et al; Chemosphere 29: 1501-14 (1994) R34: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Kubota H et al; Inter J Therm 10: 629-637 (1989) (3) Atkinson R et al; J Chem Phys Ref Data 21: 1125-69 (1992) (4) Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) R35: (1) Atkinson R et al; J Chem Phys Ref Data 21: 1125-69 (1992) (2) Mill T et al; Environmental Fate and Exposure Studies Development of a PC-SAR for Hydrolysis: Esters, Alkyl Halides and Epoxides. EPA Contract No. 68-02-4254. Menlo Park, CA: SRI International (1987) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc p. 8-13 (1990) R36: (1) Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc p. 5-5 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R37: (1) Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 17-28 (1983) R38: (1) Kubota H et al; Inter J Therm 10: 629-637 (1989) (2) Horvath et al; J Phys Chem Ref Data 28: 395-507 (1999) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) R39: 40 CFR 716.120 (7/1/2000) R40: Gehring DG et al; J Chromatogr Sci 30 (7): 280-4 (1992) R41: RAUWS ET AL; J PHARM PHARMACOL 25 (9): 718-22 (1973) R42: RASMUSSEN ET AL; J AIR POLLUT CONTROL ASSOC 27 (6): 579-81 (1977) R43: LILLIAN ET AL; J ENVIRON SCI HEALTH A-11 (12): 687-710 (1976) R44: TRIEBIG G, BURKHARDT K; INT ARCH OCCUP ENVIRON HEALTH 42 (2): 129-36 (1979) R45: CHIOU WL, NIAZI S; RES COMMUN CHEM PATHOL PHARMACOL 6 (2): 481-98 (1973) R46: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 175 R47: USEPA/ORD; Comments on the Lifetimes of Organic Molecules in Air. EPA-600/9-80-003 (1980) RS: 44 Record 352 of 1119 in HSDB (through 2003/06) AN: 6762 UD: 200201 RD: Reviewed by SRP on 9/14/2000 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: METHYL-PHOSPHONIC-ACID- RN: 993-13-5 RELT: 6459 [PHOSPHONOTHIOIC ACID, METHYL-,S-(2-(BIS(1-METHYLETHYL)AMINO)ETHYL) O-ETHYL ESTER] (Precursor); 6764 [SOMAN] (Precursor); 6382 [SARIN] (Precursor) MF: *C-H5-O3-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MFS: *Johnson Metthey, Inc., 460 Swedeford Rd., Wayne, PA 19087, (610) 971-3000; Production site: Ward Hill, MA 01835-8099 [R1] OMIN: *Methyl phosphonic acid is a degradation product of the nerve agents sarin, soman, and VX. [R2] USE: *Organic synthesis [R3] *Used in the production of lubricant additives and for treating textiles. [R4] *Chemical warfare simulant [R5] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *White solid [R3] BP: *Decomposes [R6] MP: *108.5 deg C [R6] DSC: *pKa1= 2.12; pKa2= 7.29 [R7] SOL: *Soluble in ethanol and ethyl ether; insoluble in benzene [R6]; *In water, > 20,000 mg/l (no temperature reported) [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- EQUP: *Respiratory protection (supplied-air respirator with full facepiece or self-contained breathing apparatus) should be available where these compounds are manufactured or used and should be worn in case of emergency and overexposure. /Phosphorus compounds/ [R9] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *Four genotoxic rat carcinogens, previously reported as negative in the standard hepatocyte/DNA repair assay, were studied in hepatocyte cultures derived from the livers of rats pretreated with the hepatic mixed function oxidase inducers, Aroclor and 3-methylcholanthrene. Cytembena and dimethyl hydrogen phosphite induced positive dose dependent DNA repair responses in Aroclor and 3-methylcholanthrene pretreated cultures, while 2,4-, 2,6-toluene diisocyanate, and ziram were negative for unschedule synthesis in cultures from both pretreatments. The results from this study indicate that pretreatment with hepatic mixed function oxidase inducers lowers the false negative detection rate of various genotoxic rat carcinogens and other organ specific genotopins and significantly increases the sensitivity of the in vitro rat hepatocyte/DNA repair assay. [R10] *The development of lung neoplasms following chronic dimethyl hydrogen phosphite administration was studied in rodents. Male Fischer 344 rats and B6C3F1 mice of both sexes received dimethyl hydrogen phosphite by oral gavage in doses of 0, 100, or 200 mg/kg body weight 5 days a week for 103 weeks, while female rats received dimethyl hydrogen phosphite via the same route in doses of 0, 50, or 100 mg/kg for an identical period of time. A dose related toxicity was observed in the lungs of dimethyl hydrogen phosphite treated male and female rats. Lung lesions were most prevalent among high dose male rats, which received twice the dimethyl hydrogen phosphite dose administered to high dose female rats. These pulmonary lesions included alevolar epithelial hyperplasia, chemically related pneumonia, alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, and squamous cell carcinoma. Dimethyl hydrogen phosphite administration also caused the development of neoplastic and non neoplastic lesions in the forestomachs of male rats, with a similar but less pronounced effect being noted in female rats. The non neoplastic lesions associated with dimethyl hydrogen phosphite administration included mineralization of the cerebellum in male rats and focal calcification of the testes in male mice. The authors conclude that evidence of dimethyl hydrogen phosphite carcinogenicity is clear in male rats and equivocal in female rats, while no evidence exists to support dimethyl hydrogen phosphite carcinogenicity in mice of either sex. [R11] *Pathological and biochemical effects induced by dimethyl hydrogen phosphite were studied in rats. Male Fischer 344 rats were administered 0 or 200 mg/kg dimethylhydrogen phosphite by oral gavage for 4, 5, or 6 wk. Some animals were treated for 4 wk and maintained for 1 or 2 wk of recovery. No overt signs of toxicity were seen in any animals. The weights of the forestomachs of treated rats were significantly increased. The other organ weights were not significantly affected by dimethyl hydrogen phosphite. Forestomach weights of rats treated for 4 wk returned to the control value after 1 wk of recovery. Epithelial hyperplasia, hyperkeratosis, subepithelial inflammation, and edema were seen in the forestomachs of rats given dimethyl hydrogen phosphite for 6 wk. No treatment related changes were seen in the glandular stomach or lungs. Serum angiotensin converting enzyme activity was increased in all treated rats. Angiotensin converting enzyme activity in rats treated for 4 wk decreased to near the control value after 2 wk recovery. The nonprotein sulfhydryl content of the forestomach was increased and carboxylesterase activity in the forestomach and lungs was reduced in rats given dimethyl hydrogen phosphite for 6 wk. In rats given a single oral or iv dose of 1000 mg/kg dimethyl hydrogen phosphite, and killed 0.5 to 8 hr later, nonprotein sulfhydryl content was significantly reduced in that dimethyl hydrogen phosphite, a known forestomach carcinogen for Fischer 344 rats, induces early and possibly preneoplastic changes in the forestomach. [R12] *Dimethyl hydrogen phosphite, an intermediate in the production of insecticides or herbicides, was administered by oral gavage for 2 yr to male Fischer 344/N rats and male and female B6C3F1 mice at doses of 0, 100, or 200 mg/kg and to female Fischer 344/N rats at doses of 0, 50 or 100 mg/kg. Dose related toxicity was seen in the lungs of treated male and female rats. The lung lesions were most prevalent in the high dose male rat group which received a dose twice that given to the high dose female rats. Lung lesions included alveolar epithelial hyperplasia, chemically related pneumonia, alveolar-bronchiolar adenoma, alveolar-bronchiolar carcinoma, and squamous cell carcinoma. Dimethyl hydrogen phosphite also caused neoplastic and nonneoplastic lesions of the forestomach in male rats; a similar but less pronounced effect was observed in female rats. Nonneoplastic lesions associated with administration of dimethyl hydrogen phosphite included mineralization of the cerebellum in male rat and focal calcification of the testis in male mice. Under the conditions of this study, there was clear evidence for carcinogenicity for male rats, equivocal evidence for carcinogenicity in female rats, and no evidence for carcinogenicity in either male or female mice. Dimethyl hydrogen phosphite caused the highest incidence of lung tumors in the male rat of all chemicals studied to date in the National Cancer Institute-National Toxicology Program Carcinogenesis Testing Program. [R13] *In a chronic study by the National Toxicology Program, dimethyl hydrogen phosphite caused neoplastic and nonneoplastic changes in the lungs and forestomach of F344/N rats following gavage administration for 2 years. The current investigation was designed to study the effect of a short term exposure on a series of biochemical systems in target and nontarget tissues which may be involved in the metabolism and/or the manifestation of dimethyl hydrogen phosphite toxicity. Rats were treated daily with a dose similar to that used in the NTP study (200 mg/kg) for 4, 5, or 6 weeks. Two groups of animals were also treated for 4 weeks and then treatment was discontinued and the rats were allowed to recover for 1 or 2 weeks. An equal number of animals was treated similarly with the vehicle and used as control. The microsomal and soluble fractions were separated from liver, lungs kidneys, forestomach, and glandular stomach from the 6 week treatment group. Another group of rats treated for 6 weeks was prepared for pathology examination of the lungs, forestomach, and glandular stomach. There was a significant increase in the weight of the forestomach of rats treated for 4, 5, or 6 weeks relative to control animals, while no significant difference was observed in the weight of liver, lungs, kidneys, and glandular stomach. The forestomach weight of rats treated for 4 weeks returned to the control value after 1 week of recovery. Microscopic examination of the forestomach of rats treated for 6 weeks revealed a thickened stratified squamous epithelium characterized by hyperplasia, hyperkeratosis, and subepithelial inflammation and edema. There were no microscopic changes in the lungs or glandular stomach of animals treated for 6 weeks. The activity of angiotensin converting enzyme in the serum of rats treated for 4, 5, or 6 weeks was significantly increased over that of control animals. The activity of this enzyme returned to near levels seen in the control animals after 1 week of recovery following 4 weeks of treatment. No treatment related effect was observed in the activities of the microsomal p-nitroanisole demethylase, soluble glutathione S-transferase, and soluble superoxide dismutase in the five tissues studied. There was a significant increase in the level of nonprotein soluble sulfhydryls in the forestomach but in no other tissue of rats treated for 6 weeks. Also the activity of soluble carboxylesterase was significantly reduced in the lungs and forestomach, but not in any other tissue of the 6 week treated rats. [R14] METB: *For the verification of the use of chemical warfare agents (CWA), sarin, soman and VX, a simple rapid and accurate method which allows us to simultaneously determine their degradation products, isopropyl methylphosphonic acid (IPMPA), pinacolyl methylphosphonic acid (PMPA), ethyl methylphosphonic acid (EMPA) and methylphosphonic acid (MPA), in human serum, was explored by indirect photometric detection ion chromatography (IPD-IC) which employs an anion-exchange column. IC analysis was performed after sample preparation with an Ag+-form cation-exchange resin cartridge, and the four methylphosphonic acids could be separated well. The proposed conditions are as follows: eluent, 0.5 mM phthalic acid-0.1 mM Tris (hydroxymethyl) aminomethane-5% acetonitrile; flow-rate, 1.0 ml/min; temperature, 50 degrees C; UV detector, 266 nm. All four methylphosphonic acids were eluted within 30 min with hardly any disturbance by impurities in the serum. Linear calibration curves were obtained for methylphosphonic acid, ethyl methylphosphonic acid and isopropyl methylphosphonic acid in the concentration range from 50 ng/ml to 1 ug/ml and for pinacolyl methylphosphonic acid from 100 ng/ml to 1 ug/ml. The relative standard deviation for the methylphosphonic acids ranged from 3.8 to 6.9% at 500 ng/ml and the detection limits were 40 ng/ml for methylphosphonic acid, ethyl methylphosphonic acid and isopropyl methylphosphonic acid and 80 ng/ml for pinacolyl methylphosphonic acid. The method would be suitable for analysis of human serum samples. [R15] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Methylphosphonic acid's production and use as a chemical warfare simulant may result in its release to the environment through various waste streams. It is also a degradation product of the nerve agents sarin, soman, and VX. A pKa of 2.12 indicates methylphosphonic acid will exist almost entirely in the dissociated form in the ambient environment. Since dissociated compounds are not volatile, methylphosphonic acid will only exist in the particulate phase in the atmosphere. Particulate phase methylphosphonic acid will be removed from the atmosphere by wet and dry deposition. If released to soil, methylphosphonic acid is expected to have very high mobility based upon an estimated Koc of 1. Dissociated methylphosphonic acid is not expected to volatilize from moist soil surfaces. Some microorganisms and bacterial cells have been shown to cleave the C-P bond producing methane gas; however, this occurs only when the C-P compound is the sole phosphorus source. Most soil environments are not characterized by a lack of phosphorus; therefore, biodegradation in soil may not be an important removal process. If released into water, methylphosphonic acid is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Biodegradation in water to methane gas may be an important removal process if methylphosphonic acid is the sole phosphorus source especially in marine water where there is a low phosphorus content. Volatilization of the dissociated form from water surfaces will not occur. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to occur due to the lack of hydrolyzable functional groups. Occupational exposure to methylphosphonic acid may occur through inhalation and dermal contact with this compound at workplaces where methylphosphonic acid is produced or used. (SRC) ARTS: *Methylphosphonic acid may be released to the environment during its production and use as a chemical warfare simulant(1). Methylphosphonic acid is a degradation product of the nerve agents sarin (GB), soman(2), and VX(3). It is also a degradation product of the two pesticides, O,O-bis(2,4,5-trichlorophenyl)methylphosphonate(4) and mecarphon (no longer being produced)(2) and O-ethyl S-2 diisopropyl-aminoethylmethyl-phosphonothioate(1). Methylphosphonic acid is a degradation product of the flame retardants dimethyl methyl phosphonate, Fyrol 58 and Antiblaze 19(5). Another source of methyl phosphonic acid in the environment may be methylphospholane dichloride(5). Therefore, methyl phosphonic acid may be released to the environment in waste streams during the production and use of these compounds(1,5). [R16] FATE: *TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from a structure estimation method(2), indicates that methyl phosphonic acid is expected to have very high mobility in soil(SRC). In soils with high metal content, methyl phosphonic acid may adsorb to metal oxide surfaces(3,4). Methyl phosphonic acid is expected to exist in the dissociated form in the environment based on its pKa of 2.12(5). Dissociated methyl phosphonic acid will not volatilize from moist or dry soils(SRC). Some microorganisms and bacterial cells have been shown to cleave the C-P bond producing methane gas(6-8); however, this occurs only when the C-P compound is the sole phosphorus source. Most soil environments are not characterized by a lack of phosphorus(7); therefore, biodegradation in soil may not be an important removal process(SRC). [R17] *AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1(SRC), determined from an estimation method(2), indicates that methylphosphonic acid is not expected to adsorb to suspended solids and sediment(SRC). A pKa of 2.12(3) indicates methyl phosphonic acid will exist almost entirely in the dissociated form at pH values of 5 to 9. Therefore volatilization from water surfaces is not expected to be an important fate process(SRC). The half-life for the OH radical reaction with methyl phosphonic acid in water can be estimated to be approximately 18 years based on an experimental rate constant of 1.2X10+8 /Mole/sec(4) and an average OH concn of 1X10-17(5). According to a classification scheme(6), an estimated BCF of 3(SRC), from an estimated log Kow of -0.70(7) and a regression-derived equation(8), suggests the potential for bioconcentration in aquatic organisms is low. Biodegradation in water to methane gas may be an important removal process if methyl phosphonic acid is the sole phosphorus source especially in marine water where there is a low phosphorus content(9). [R18] *ATMOSPHERIC FATE: A pKa of 2.12(1) indicates methyl phosphonic acid will exist almost entirely in the dissociated form in the ambient environment. Since dissociated compounds are not volatile, methyl phosphonic acid will only exist in the particulate phase in the atmosphere. Particulate phase methyl phosphonic acid will be removed from the atmosphere by wet and dry deposition(SRC). Based on its high water solubility, 2.0X10+4 mg/l(2), wet deposition will be an important atmospheric removal process(SRC). [R19] BIOD: *Methyl phosphonic acid is expected to be resistant to biodegradation under environmental conditions(1-3). Compounds containing the C-P bond resist cleavage during metabolism in mammals and higher plants(4). In pure culture studies, the microorganism, Pseudomonas testosteroni, has been shown to cleave the C-P bond(5) and some bacterial cells were also shown to cleave the C-P bond(6,7); however, this occurs only when the C-P compound is the sole phosphorus source. Based on a pure culture study, the predominant degradation product of Escherichia coli growth on methyl phosphonic acid is methane gas(8). [R20] ABIO: *The resistance of methyl phosphonic acid to hydrolysis, photolysis, and thermal decomposition has been thoroughly substantiated in the literature(1-5). Methyl phosphonic acid in the ionized form can be oxidized to phosphoric acid when treated with ozone in an aqueous medium(6-7). The half-life for the OH radical reaction with methyl phosphonic acid in water can be estimated to be approximately 18 years based on an experimental rate constant of 1.2X10+8 /Mole/sec(8) and an average OH concn of 1X10-17(9). Oxidation of methyl phosphonic acid in basic solution has been shown to occur by a photochemically initiated reaction(10). Methylphosphonic acid is not expected to undergo hydrolysis in the environment due to the lack of hydrolyzable functional groups(11) nor to directly photolyze due to the lack of absorption in the environmental UV spectrum(> 290 nm). [R21] BIOC: *An estimated BCF of 3 was calculated for methyl phosphonic acid(SRC), using an estimated log Kow of -0.70(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low. Furthermore, methyl phosphonic acid will be highly dissociated under environmental conditions (pH 5-9) based on its pKa values (pKa1 of 2.12 and pKa2 of 7.29(4)) and methyl phosphonic acid in the dissociated form will not bioconcentrate in aquatic organisms(SRC). [R22] KOC: *The adsorption of methylphosphonic acid onto solid silt particles in a river sample was negligible(1). Based on a classification scheme(2), an estimated Koc value of 1(SRC), determined from a structure estimation method(3), indicates that methyl phosphonic acid is expected to have very high mobility in soil(SRC). In soils with high metal content, methyl phosphonic acid may adsorb to metal oxide surfaces(4,5). Methyl phosphonic acid is expected to exist in the dissociated form in the environment based on its pKa1 of 2.12 and pKa2 of 7.29(6). Dissociated methyl phosphonic acid is expected to be highly mobile in soil environments(SRC). [R23] VWS: *A pKa of 2.12(1) indicates methyl phosphonic acid will exist almost entirely in the dissociated form at pH values of 5 to 9. Therefore volatilization from water surfaces is not expected to be an important fate process(SRC). [R24] WATC: *SURFACE WATER: Compounds containing the phosphorus-methyl linkage expressed as methyl phosphonic acid were quantitatively reported at concn ranging from 0.35-1.23 ug/l in samples taken from the river Rhine, Netherlands and at concn of 0.21 and 0.25 ug/l in two samples from the river Muese, Netherlands in the period of August, 1975 to April, 1978(1). The analytical method first hydrolyzed the sample so that all compounds containing the P-CH3 bond would be converted to methyl phosphonic acid and then the methyl phosphonic acid was esterifed to trimethyl methylphosphonate for analytical detection(1). In the same study, concn of P-CH3 bond expressed as methyl phosphonic acid were reported at concn of 0.25 ug/l and 0.5 ug/l in Maarsseveen Lake and Viagtwedde Lake, respectively(1). [R25] *SURFACE WATER: The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.09 ug/l in water from the river Meuse (Dinant, Belgium) in April, 1980(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.39 ug/l in industrially polluted water from the river Schelde (Helchin, Belgium) in April, 1980 and 0.17 ug/l in water from the river Renkajoki (Renko, Finland) sampled on April 22, 1980(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.11 ug/l in water from the River Bow (Canada), sampled 60 km from the glacier source on May 13, 1980(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.31 ug/l in industrial polluted water from the river South Saskatchewan, sampled at 450 km from the source and 250 km from Calgary (Canada) on May 21, 1980(1). [R26] *SURFACE WATER: The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.45 ug/l in surface water in the Federal Republic of Germany. The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.29 ug/l in industrially polluted surface water from the river Tervajoki sampled at Janankala (Finland) on May 5, 1980(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.18 ug/l in water from the Lake of Maarseveen (The Netherlands) on August 4, 1980. The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to range from 0.21-2.65 ug/l in industrial polluted water from the river Rhine, sampled at Bergambacnt (The Netherlands) in the period of 1979-1980(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.02 ug/l in water from the lake Gittsjon (Sweden) beneath the ice on April 11, 1980(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 0.30 ug/l in water from the river Ume (Gimonas, Sweden) on April 21, 1980(1). [R26] EFFL: *The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 11.0 ug/l in industrial polluted waste water in the Federal Republic of Germany(1). The concn of P-CH3 bond expressed as methyl phosphonic acid was reported to be 2.4 ug/l in drainage water from an industrial waste deposit near Davamyran (Sweden) on March 26, 1980 and treated waste water from an industrial waste deposit in Kansas City (USA)(1). [R26] RTEX: *Occupational exposure to methylphosphonic acid may occur through inhalation and dermal contact with this compound at workplaces(SRC) where methylphosphonic acid is produced or used as a chemical warfare simulant(1). [R27] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: WHO; Diseases Caused by Phosphorus and Its Toxic Compounds; Early Detection of Occupational Diseases pg 53-62 (1986). Review of diseases and health related effects resulting from exposure to phosphorus or phosphorus cmpd. /Phosphorus or phosphorus cmpd/ SO: R1: SRI. 1999 Directory of Chemical Producers -United States. Menlo Park, CA. SRI Consulting 1999.. 750 R2: Schiff LJ et al; pp. 329-44 in Ion Chromatographic Analysis of Environmental Pollutants 2. Sawicki E et al, eds. Ann Arbor, MI: Ann Arbor Press (1979) R3: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 747 R4: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. VA19 (91) 560 R5: Williams RT et al; Environmental Fate and Effects of Tributyl phosphate and Methylphosphonic Acid. CRDEC-CR-87103 (1987) R6: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 79th ed. Boca Raton, FL: CRC Press Inc., 1998-1999.,p. 3-261 R7: Serjeant, E.P., Dempsey B.; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23, 1979. New York, New York: Pergamon Press, Inc.12 R8: Rosenblatt DH et al; Problem Definition Studies on Potential Environmental Pollutants II U.S. Army Medical Bioeng Res Devel Lab Fort Detrick . Frederick, MD AD AO30428 pp. 7, C1-C7 (1975) R9: International Labour Office. Encyclopedia of Occupational Health and Safety. Vols. I and II. Geneva, Switzerland: International Labour Office, 1983. 1684 R10: Shaddock JG et al; Mutagenesis 5 (4): 387-92 (1990) R11: Dunnick JK et al; Cancer Research 46: 264-70 (1986) R12: Nomeir AA, Uraih LC; Fundamental and Applied Toxicology 10 (1): 114-24 (1988) R13: Dunnick JK et al; Cancer Res 46 (1): 264-70 (1986) R14: Nomeir AA, Uraih LC; Fundam Appl Toxicol 10 (1): 114-24 (1988) R15: Katagi M et al; J Chromatogr B Biomed Sci Appl 698 (1-2): 81-8 (1997) R16: (1) Williams RT et al; Environmental Fate and Effects of Tributyl phosphate and Methylphosphonic Acid. CRDEC-CR-87103 (1987) (2) Verweij A et al; Science 204: 616-8 (1979) (3) Schiff LJ et al; pp. 329-44 in Ion Chromatographic Analysis of Environmental Pollutants 2. Sawicki E et al, eds. Ann Arbor, MI: Ann Arbor Press (1979) (4) Vasu K, Roy NK; Agric Biol Chem 49: 307-10 (1985) (5) Verweij A et al; Chemosphere 11: 985-90 (1982) R17: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Smirnov VV et al; Zh Obshchei Khimii 38: 1197 (1967) (4) Daughton CG et al; Appl Environ Microbiol 37: 605-9 (1979) (5) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press, Inc. p. 12 (1979) (6) Daughton CG et al; Appl Environ Microbiol 37: 605-9 (1979) (7) Schowanek D, Verstraete W; Appl Environ Microbiol 56: 895-903 (1990) (8) Osamura N et al; J Ferment Bioeng 71: 128-30 (1991) R18: (1) Swann RL et al; Res Rev 85: 17-28 (1983) (2) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (3) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press, Inc. p. 12 (1979) (4) Mill T, Gould CW; Environ Sci Technol 13: 205-8 (1979) (5) Mill T et al; Science 207: 886-7 (1980) (6) Franke C et al; Chemosphere 29: 1501-14 (1994) (7) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (8) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (9) Cordeiro ML et al; J Amer Chem Soc 108: 332-4 (1986) R19: (1) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press, Inc. p. 12 (1979) (2) Rosenblatt DH et al; Problem Definition Studies on Potential Environmental Pollutants II U.S. Army Medical Bioeng Res Devel Lab Fort Detrick. Frederick, MD AD AO30428 pp. 7, C1-C7 (1975) R20: (1) Verweij A et al; Science 204: 616-8 (1979) (2) Williams RT et al; Environmental Fate and Effects of Tributyl Phosphate and Methylphosphonic Acid. CRDEC-CR-87103 (1987) (3) Verweij A et al; Chemosphere 8: 115-24 (1979) (4) Menn JJ, McBain JB; Research Reviews 53: 35 (1974) (5) Daughton CG et al; Appl Environ Microbiol 37: 605-9 (1979) (6) Schowanek D, Verstraete W; Appl Environ Microbiol 56: 895-903 (1990) (7) Osamura N et al; J Ferment Bioeng 71: 128-30 (1991) (8) Cordeiro ML et al; J Amer Chem Soc 108: 332-4 (1986) R21: (1) Verweij A et al; Science 204: 616-8 (1979) (2) Williams RT et al; Environmental Fate and Effects of Tributyl Phosphate and Methylphosphonic Acid. CRDEC-CR-87103 (1987) (3) Vasu K, Roy NK; Agric Biol Chem 49: 307-10 (1985) (4) Verweij A et al; Chemosphere 8: 115-24 (1979) (5) Povstugar VI et al; Zh Strukt Khim 18: 701-7 (1977) (6) Smirnov VV et al; Zh Obshchei Khimii 37: 2783-4 (1967) (7) Smirnov VV et al; Zh Obshchei Khimii 38: 1197 (1967) (8) Mill T, Gould CW; Environ Sci Technol 13: 205-8 (1979) (9) Mill T et al; Science 207: 886-7 (1980) (10) Mill T, Gould CW; Environ Sci Technol 13: 205-8 (1979) (11) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990) R22: (1) Meylan WM, Howard PH; J Pharm Sci 84: 83-92 (1995) (2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) (4) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press, Inc. p. 12 (1979) R23: (1) Verweij A et al; Science 204: 616-8 (1979) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Meylan WM et al; Environ Sci Technol 26: 1560-67 (1992) (4) Smirnov VV et al; Zh Obshchei Khimii 38: 1197 (1967) (5) Daughton CG et al; Appl Environ Microbiol 37: 605-9 (1979) (6) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press, Inc. p. 12 (1979) R24: (1) Serjeant EP, Dempsey B; Ionisation Constants of Organic Acids in Aqueous Solution. International Union of Pure and Applied Chemistry (IUPAC). IUPAC Chemical Data Series No. 23. NY, NY: Pergamon Press, Inc. p. 12 (1979) R25: (1) Verweij A et al; Chemosphere 8: 115-24 (1979) R26: (1) Verweij A et al; Chemosphere 11: 985-90 (1982) R27: (1) Williams RT et al; Environmental Fate and Effects of Tributyl phosphate and Methylphosphonic Acid. CRDEC-CR-87103 (1987) RS: 30 Record 353 of 1119 in HSDB (through 2003/06) AN: 6809 UD: 200303 RD: Reviewed by SRP on 3/11/1993 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BENZOPHENONE- SY: *benzoylbenzene-; *diphenylketone-; *Diphenylmethanone-; *alpha-oxodiphenylmethane-; *phenyl-ketone- RN: 119-61-9 MF: *C13-H10-O MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepd by the Friedel-Crafts ketone synthesis from benzene and benzoyl chloride in the presence of aluminum chloride; by decarboxylation of o-benzoylbenzoic acid in the presence of copper catalyst. [R1] FORM: *Free from chlorine; also food chemicals codex [R2] MFS: *The Upjohn Co, Hq, 7000 Portage Rd. Kalamazoo, MI 49001; (616) 323-4000; Fine Chemicals Division, 410 Sackett Point Rd, North Haven, CT 06473. [R3, p. 3-4] *Parke-Davis Division of Warner Lambert, 188 Howard Ave, Holland, MI 49424, (616) 392-2375 [R3, p. 7-3] *MTM (Americas) Inc, Hq, MTM Chemicals, Inc, 8720 Red Oak Blvd, Suite 426, Charlotte, NC 28217, (704) 529-1575; Production site: Rock Hill, SC 29731 /Benzophenone (technical)/ [R4] OMIN: *Purification: crystallization from alcohol [R2] USE: *Fixative for heavy perfumes, such as geranium new-mown hay, especially when used in soaps. In the manufacture of antihistamines, hypnotics, insecticides. [R1] *Organic synthesis; derivatives are used as ultraviolet absorbers; flavoring; polymerization inhibitor for styrene. [R2] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Orthorhombic bisphenoidal prisms from alcohol or ether [R1]; *White prisms [R2] ODOR: *Geranium-like odor [R1]; *Rose-like odor [R2] BP: *305.4 deg C at 760 mm Hg [R1] MP: *48.5 deg C [R1] MW: *182.21 [R1] DEN: *1.1108 at 18 deg C/4 deg C [R1] HTV: *23.86 cal/g= 99.83 J/g= 18,191 J/mol [R5, p. 5-89] SOL: *Insol in water; 1 g dissolves in 7.5 ml alcohol, 6 ml ether; sol in chloroform [R1]; *Sol in acetone and benzene [R5, p. 3-107] SPEC: *Index of refraction: 1.5975 at 45.2 deg C/D [R1]; *IR 6051: (Coblentz Society Spectral Collection) [R6]; *UV 659: (Sadtler Reserach Laboratories Spectral Collection) [R6]; *NMR 153: (Sadtler Research Laboratories Spectral Collection) [R6]; *Mass 1239: (Atlas of Mass Spectral Data, John Wiley and Sons, New York) [R6] SURF: *45.1 dyne/cm at 20 deg C [R5, p. 6-118] VAP: *1 mm Hg at 108.2 deg C [R5, p. 6-81] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Combustible [R2] *Fire Hazard: Slight, when heated. [R7] REAC: *Oxidizers [R7] DCMP: *When heated to decomp it emits acrid and irritating fumes. [R7] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- NTOX: *Benzophenone was admin in the diet to rats at target dose levels of 20 mg/kg body weight for 90 days and 100 or 500 mg/kg body weight for 28 days. Body weights and food consumption were measured weekly; hematology, clinical chemistry and urinalysis values were obtained at 4 wk and at the end of the study. Gross and microscopic pathological examinations were conducted and organ weights were recorded. Treatment related changes occurred in erythrocyte count, hemoglobin, hematocrit, bilirubin, total protein and albumin at the mid and high dose levels, although all changes did not occur in both groups on both sexes. There were indications of incr absolute and relative liver and kidney weights in the mid and high dose groups, but this was not statistically consistent for absoulte kidney weights. Histopathology of the liver in the mid and high dose groups showed hepatocellular enlargement with an associated clumping of cytoplasmic basophilic material around the central vein. A no-effect level was demonstrated at 20 mg/kg/day for 90 days of admin. This would be an equivalent to an intake of 1200 mg/day for a 60 kg human. On the basis of the possible average daily intake of 0.33 mg/day, a safety factor of greater than 3600 is demonstrated. The safety factor based on the more realistic per capita consumption of 0.32 ug/day would be approx 3.7 million. [R8] *The lethal and sublethal effects of six monosubstituted derivatives of benzene were measured by using the 7 day test with fathead minnow larvae. The LC50s for larvae were compared to those derived from the acute test. The larvae were more sensitive than juvenile fish, yet the toxicity order /of the six monosubstituted derivatives of benzene/ was the same for both life stages, that is, butylphenylether > benzophenone > toluene = benzene > nitrobenzene > aniline. ... [R9] NTXV: *LC50 Pimephales promelas (fathead minnow) 15.3 mg/l/96 hr (confidence limit 14.4-16.3 mg/l), flow-through bioassay with measured concentrations, 25.3 deg C, dissolved oxygen 6.9 mg/l, hardness 47.9 mg/l calcium carbonate, alkalinity 34.0 mg/l calcium carbonate, and pH 7.72; [R10] *EC50 Pimephales promelas (fathead minnow) 15.3 mg/l/96 hr (confidence limit 14.4-16.3 mg/l), flow-through bioassay with measured concentrations, 25.3 deg C, dissolved oxygen 6.9 mg/l, hardness 47.9 mg/l calcium carbonate, alkalinity 34.0 mg/l calcium carbonate, and pH 7.72. Effect: loss of equilibrium; [R10] ADE: *... The percutaneous absorption of the fragrances benzyl acetate and five other benzyl derivatives (benzyl alcohol, benzyl benzoate, benzamide, benzoin and benzophenone) was determined in vivo in monkeys. Absorption through occluded skin was high for all cmpd (approx 70% of the applied dose in 24 hr) and no significant differences between the values for the different cmpd were observed. No correlations were seen between skin penetration of these cmpd and their octanol-water partition coefficients. Under unoccluded conditions skin penetration of the fragrances was reduced and there was great variability between cmpd, presumably because of variations in the rates of evaporation from the site of application. [R11] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Benzophenone is released to the environment in waste streams resulting from its production and use and in emissions from coal, refuse, and fuel oil combustion. Vapor phase benzophenone in the ambient atmosphere is expected to degrade by reaction with photochemically produced hydroxyl radicals (estimated half-life of 5.4 days). If released to soil, benzophenone is expected to have low to medium soil mobility (Kocs of 430 and 517); leaching will be important and adsorption may take place. One aerobic screening study suggests that microbial degradation may be an important fate process of benzophenone in soil and water. Furthermore, one soil column study concludes that anaerobic conditions may inhibit biotic activity. If released to water, photooxidation (half-life of 91 days), photolysis (half-life of greater than 100 days), hydrolysis, and bioconcentration in fish will not be important. Volatilization will be slow; estimated half-life of 26 days from a model river. Benzophenone may adsorb from the water column to sediment and suspended material and biodegradation in water may occur. Exposure of the general population to benzophenone may occur via inhalation of smoke from a residential fuel oil burner, ingestion of contaminated drinking water, dermal contact with soaps and perfumes in which it is used as a fixative, or ingestion or inhalation of antihistamines and hypnotics. Workers may be exposed to benzophenone via dermal contact and inhalation of dust. (SRC) ARTS: *Benzophenone may be released to the environment in emissions from coal(1), refuse(1), and fuel oil combustion(2). Benzophenone will be released to the environment in waste streams during its production and use(3-7). [R12] FATE: *Kocs of 430(1) and 517(2) indicate that benzophenone will have low to medium soil mobility category(4). Leaching in soil should be important(SRC); benzophenone has been detected in groundwater samples(8-12). One aerobic screening study using sewage inoculum (12 %BODT in 5 days(3)) suggests that benzophenone may biodegrade in soil(SRC). Biodegradatio was observed (no rates given) in soil column studies(5-6); Photolysis on soil surfaces will not be important (half-life of greater than 100 days in water(7)). [R13] *The estimated Henry's Law constant for benzophenone of 1.94X10-6 atm-cu m/mole at 25 deg C(1) suggests that volatilization may be slow, but important from shallow rivers(2); estimated half-life of 26 days from a model river(2,SRC). Bioconcentration in aquatic organisms will not be important based on an estimated BCF range of 70-90(SRC). Photolysis will not be important (half-life of greater than 100 days in water(3)). The aquatic oxidation half-life of 91 days(7,SRC) indicates that oxidation in water is slow. Kocs of 430(4) and 517(5) indicate that benzophenone may adsorb to sediment and suspended material(SRC). One aerobic screening study using sewage inoculum (12 %BODT in 5 days(6)) suggests that benzophenone may biodegrade in water(SRC). [R14] *ATMOSPHERIC FATE: Based on an extrapolated vapor pressure of 0.0033 mm Hg at 25 deg C(2) for the super cooled liquid, a vapor pressure of 0.0019 mm Hg at 25 deg C can be estimated for benzophenone after converting to the solid phase(SRC). Based on this vapor pressure value, benzophenone should exist almost entirely in the vapor phase in the ambient atmosphere(1). Vapor phase benzophenone is degraded in the ambient atmosphere by reaction with photochemically formed hydroxyl radicals; the half-life for this reaction in air can be estimated to be about 5.4 days(3,SRC). The photolysis half-life of greater than 100 days in water(4) suggests that photolysis will not be important in the ambient atmosphere(SRC). [R15] BIOD: *Benzophenone exhibited 12% BODT over an incubation period of 5 days in an aerobic screening study using sewage inoculum(1). According to one study, microbial degradation was considered to be insignificant when feed solutions containing 5.8X10-5, 1.3X10-4, 1.1X10-4, and 2X10-3 ppm benzophenone were treated in soil columns and 15, 41, 45, and 40% removal was observed, respectively(2). However, an increase in column effluent concn of benzophenone was observed when mercuric chloride was added to the feed solution indicating that some biodegradation took place in the soil column(2). In another soil column study, anaerobic conditions were simulated by flooding the column; anaerobic conditions inhibited biotic activity(3). [R16] ABIO: *The rate constant for the vapor phase reaction of benzophenone with photochemically produced hydroxyl radicals can be estimated to be 2.99X10-12 cu cm/molecule-sec at 25 deg C which corresponds to an atmospheric half-life of about 5.4 days at an atmospheric concn of 5X10+5 hydroxyl radicals per cu cm(1,SRC). The aquatic oxidation rate for benzophenone has been experimentally determined to be 8.8X10+9 L/mol-s(2). Based on this rate and a hydroxyl radical concn of 1X10-17 mol/L in water under continuous sunlight(3), the half-life for the aquatic oxidation of benzophenone can be estimated to be 91 days(SRC). Ketones are generally resistent to hydrolysis(4); therefore, hydrolysis is not expected to be important(SRC). The photolysis half-life for benzophenone in water was determined to be greater than 100 days at a concn of 2.8X10-5 mol/L(5). [R17] BIOC: *Based on an experimental log Kow of 3.18(2) and two regression derived equations(1), the BCF range for benzophenone can be estimated to be 70-90(SRC). This BCF range suggests that benzophenone will not bioconcentrate in aquatic organisms(SRC). [R18] KOC: *The Kd for benzophenone was measured to be 2.71 on a red earth soil from Australia with an organic matter content of 1.09%(1); therefore, the Koc for benzophenone is about 430(SRC). The average Koc value from three soils was measured to be 517(3). Based on a suggested classification scheme(2), these Koc values indicate that benzophenone will have low to medium soil mobility(SRC). [R19] VWS: *The Henry's Law constant for benzophenone can be estimated to be 1.94X10-6 atm-cu m/mole at 25 deg C based on a structure activity relationship(2). According to a suggested classification scheme(1), this value of Henry's Law constant indicates that volatilization of benzophenone from water will not be rapid, but possibly important in shallow rivers. The volatilization half-life of benzophenone from a model river 1 m deep flowing 1 m/sec with a wind velocity of 3 m/sec can be estimated to be approximately 26 days based on the Henry's Law constant(1,SRC). [R20] WATC: *GROUNDWATER: Benzophenone was identified at a concn in the range of 10-100 ng/L in a groundwater well near Zagreb in Northern Croatia, Yugoslavia(1). Benzophenone was detected at an average concn of 0.86 ug/L in two groundwater wells adjacent to infiltration basins at Ft. Devens, MA during November 1978 and April 1981; the basin influent was measured to contain 5.17 ug/L benzophenone(2,4). Benzophenone concns in groundwaters from Ft. Devens, MA, Boulder, CO, and Phoenix, AZ were measured to be 1.4, 2.13, and 0.05 ug/L, respectively, in wells adjacent to rapid infiltration sites(3). Benzophenone was detected in groundwaters from the Netherlands; the highest reported concn was 0.03 ug/L(5). [R21] *SURFACE WATER: Benzophenone was qualitatively detected in Baltic Sea water(1) and water from Hamilton Harbour, Bermuda(2). [R22] *DRINKING WATER: Benzophenone was detected at a concn of 8.8 ppb in tap water from Kitakyushu Municipal Institute in Kitakyushu, Japan(1). [R23] EFFL: *Benzophenone was identified at a concn greater than 1,000 ng/L in industrial wastewater discharged into the Sava River in Northern Croatia, Yugoslavia(1). Benzophenone was qualitatively identified in effluents from three Illinois Publicly Owned Treatment Works (POTWs)(2). Benzophenone was found at a concn of 1 ppb in effluent from a New Jersey POTW facility(4). Benzophenone has been detected in wastewater effluents from the Paint and Ink industry at a concn of 367 ng/uL extract, the Pharmaceutical industry at a concn of 44 ng/uL extract, and the Mechanical Products industry at a concn of 6 ng/uL extract(5). Benzophenone was qualitatively identified in smoke from a residential oil burner(6) and effluent from a textile plant(3). Benzophenone was qualitatively found in wastewater at the Iona treatment plant in Vancouver, British Columbia(7). [R24] ATMC: *Benzophenone was qualitatively identified in air samples from a 45-year-old spruce forest in Germany on January 11, 1988 at a height of 1 m(1). [R25] RTEX: *Exposure of the general population to benzophenone may occur via inhalation of smoke from a residential fuel oil burner(1), ingestion of contaminated drinking water(2,SRC), dermal contact with soaps and perfumes in which it is used as a fixative(3,SRC), or ingestion or inhalation of antihistamines and hypnotics(3,SRC). Workers may be exposed to benzophenone via dermal contact and inhalation of dust(SRC). [R26] *NIOSH (NOHS Survey 1972-1974) has statistically estimated that 240,940 workers are potentially exposed to benzophenone in the USA(1). NIOSH (NOES Survey 1981-1983) has statistically estimated that 19,898 workers are potentially exposed to benzophenone in the USA(2). [R27] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- OOPL: +Workplace Environmental Exposure Level (WEEL): 8-hr Time-weighted Average (TWA) 5 mg/cu m. [R28] ASTD: *This action promulgates standards of performance for equipment leaks of Volatile Organic Compounds (VOC) in the Synthetic Organic Chemical Manufacturing Industry (SOCMI). The intended effect of these standards is to require all newly constructed, modified, and reconstructed SOCMI process units to use the best demonstrated system of continuous emission reduction for equipment leaks of VOC, considering costs, non air quality health and environmental impact and energy requirements. Benzophenone is produced, as an intermediate or a final product, by process units covered under this subpart. [R29] FDA: *Benzophenone is a food additive permitted for direct addition to food for human consumption, as long as 1) the quantity added to food does not exceed the amount reasonably required to accomplish its intended physical, nutritive, or other technical effect in food, and 2) when intended for use in or on food it is of appropriate food grade and is prepared and handled as a food ingredient. Synthetic flavoring substances and adjuvants /incl benzophenone/ may be safely used in foods. [R30] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that two year study is in progress for benzophenone. Route: dosed feed; Species: rats and mice. [R31] SO: R1: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 171 R2: Sax, N.I. and R.J. Lewis, Sr. (eds.). Hawley's Condensed Chemical Dictionary. 11th ed. New York: Van Nostrand Reinhold Co., 1987. 132 R3: United States International Trade Commission. Synthetic Organic Chemicals-United States Production and Sales, 1989. USITC Publication 2338, 1990. Washington, DC: United States International Trade Commission, 1990. R4: SRI. 1992 Directory of Chemical Producers-United States of America. Menlo Park, CA: SRI International, 1992. 482 R5: Lide, D.R. (ed). CRC Handbook of Chemistry and Physics. 72nd ed. Boca Raton, FL: CRC Press, 1991-1992. R6: Weast, R.C. and M.J. Astle. CRC Handbook of Data on Organic Compounds. Volumes I and II. Boca Raton, FL: CRC Press Inc. 1985.,p. V1 241 R7: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 382 R8: Burdock GA et al; Food Chem Toxicol 29 (11): 741-50 (1991) R9: Marchini S et al; Environ Toxicol Chem 11 (2): 187-96 (1992) R10: Brooke, L.T., D.J. Call, D.T. Geiger and C.E. Northcott (eds.). Acute Toxicities of Organic Chemicals to Fathead Minnows (Pimephales Promelas). Superior, WI: Center for Lake Superior Environmental Studies Univ. of Wisconsin Superior, 1984.392 R11: Bronaugh RL et al; Food Chem Toxicol 28 (5): 369-73 (1990) R12: (1) Graedel TE et al; Atmospheric Chemical Compounds NY: Academic Press p. 275 (1986) (2) Leary JA et al; Environ Health Perspectives 73: 223-34 (1987) (3) Ahel M; Bull Environ Contam 47: 586-93 (1991) (4) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (5) Gordon AW, Gordon M; Trans Ky Acad Sci 42: 149-57 (1981) (6) Clark LB et al; Res J WPCF 63: 104-13 (1991) (7) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Decree Survey USEPA-68-03-2867 (1982) R13: (1) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (2) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (3) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (4) Swann RL et al; Res Rev 85: 17-28 (1983) (5) Hutchins SR et al; Environ Tox Chem 2: 195-216 (1983) (6) Hutchins SR et al; Appl Environ Microb 48: 1046-8 (1984) (7) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol.I Boca Raton, FL CRC Press p. 201 (1985) (8) Ahel M; Bull Environ Contam 47 586-93 (1991) (9) Bedient PB et al; J Environ Eng 109: 485-501 (1983) (10) Hutchins SR and Ward CH; J Hydro 67: 223-33 (1984) (11) Hutchins SR et al; Water Res 18: 1025-36 (1984) (12) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) R14: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-15 to 15-32 (1990) (3) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol.I Boca Raton, FL CRC Press p. 201 (1985) (4) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (5) Southworth GR, Keller JL; Water Air Soil Poll 28: 239-48 (1986) (6) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (7) Buxton GV et al; J Phys Chem Ref Data 17: 517-882 (1988) R15: (1) Eisenreich SJ et al; Environ Sci Technol 15: 30-8 (1981) (2) Daubert TE, Danner RP; Physical and Thermodynamic Properties of Pure Chemicals Supplement 1 NY: Hemisphere Pub Corp (1991) (3) Atkinson R; Environ Toxicol Chem 7: 435-42 (1988) (4) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol.I Boca Raton, FL CRC Press p. 201 (1985) R16: (1) Dore M et al; Trib Cebedeau 28: 3-11 (1975) (2) Hutchins SR et al; Environ Tox Chem 2: 195-216 (1983) (3) Hutchins SR et al; Appl Environ Microb 48: 1046-8 (1984) R17: (1) Atkinson R; Environ Toxicol Chem 7: 435-42 (1988) (2) Buxton GV et al; J Phys Chem Ref Data 17: 517-882 (1988) (3) Mill T et al; Science 207: 886-7 (1980) (4) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 7-4,5 (1990) (5) Neely WB, Blau GE; Environmental Exposure from Chemicals Vol.I Boca Raton, FL CRC Press p. 201 (1985) R18: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) Hansch C, Leo AJ; Medchem Project Issue No.26 Claremont, CA: Pomona College (1985) R19: (1) Briggs GG; J Agric Food Chem 29: 1050-9 (1981) (2) Swann RL et al; Res Rev 85: 17-28 (1983) (3) Southworth GR and Keller JL; Water Air Soil Poll 28: 239-48 (1986) R20: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 7-4, 7-5, 15-15 to 15-32 (1990) (2) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) R21: (1) Ahel M; Bull Environ Contam 47: 586-93 (1991) (2) Bedient PB et al; J Environ Eng 109: 485-501 (1983) (3) Hutchins SR AND Ward CH; J Hydro 67: 223-33 (1984) (4) Hutchins SR et al; Water Res 18: 1025-36 (1984) (5) Zoeteman BCJ et al; Sci Total Environ 21: 187-202 (1981) R22: (1) Ehrhardt M et al; Marine Chemistry 11: 449-61 (1982) (2) Ehrhardt M; Marine Chem 22: 85-94 (1987) R23: (1) Shinohara R et al; Water Res 15: 535-42 (1981) R24: (1) Ahel M; Bull Environ Contam 47: 586-93 (1991) (2) Ellis DD et al; Arch Environ Contam Toxicol 11: 373-82 (1982) (3) Gordon AW, Gordon M; Trans Ky Acad Sci 42: 149-57 (1981) (4) Clark LB et al; Res J WPCF 63: 104-13 (1991) (5) Bursey JT, Pellizzari ED; Analysis of Industrial Wastewater for Organic Pollutants in Consent Decree Survey USEPA-68-03-2867 (1982) (6) Leary JA et al; Environ Health Perspectives 73: 223-34 (1987) (7) Rogers IH et al; Water Poll Res J Canada 21: 187-204 (1986) R25: (1) Helmig D et al; Chemosphere 19: 1399-1412 (1989) R26: (1) Shinohara R et al; Water Res 15: 535-42 (1981) (2) Leary JA et al; Environ Health Perspectives 73: 223-34 (1987) (3) Budavari S et al; The Merck Index 11th ed. Rahway, NJ: Merck and Co Inc p. 171 (1989) R27: (1) NIOSH National Occupational Hazard Survey (NOHS) (1974) (2) NIOSH National Occupational Exposure Survey (NOES) (1983) R28: American Industrial Hygiene Association. The AIHA 1999 Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. American Industrial Hygiene Association. Fairfax, VA 1999.39 R29: 40 CFR 60.489 (7/1/91) R30: 21 CFR 172.515 (4/1/91) R31: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.21 RS: 24 Record 354 of 1119 in HSDB (through 2003/06) AN: 6862 UD: 200303 RD: Reviewed by SRP 11/1/1994 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DIBROMOACETONITRILE- SY: *Acetonitrile,-dibromo-; *Dibromoacetonitrile- RN: 3252-43-5 MF: *C2-H-Br2-N CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- BP: *67-69 deg C at 24 mm Hg [R1] MW: *198.84 [R1] DEN: *2.296 g/cu cm at 25 deg C [R1] SPEC: *Refractive Index = 1.5393 20/D [R1] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: +Evaluation: No epidemiological data relevant to the carcinogenicity of dibromoacetonitrile were available. There is inadequate evidence in experimental animals for the carcinogenicity of dibromoacetonitrile. Overall evaluation: Dibromoacetonitrile is not classifiable as to its carcinogenicity to humans (Group 3). [R2] HTOX: +Chlorinated and brominated haloacetonitriles (HAN) ... produced DNA strand breaks in cultured human lymphoblastic (CCRF-CEM) cells. /Information pertaining to dose and duration of exposure not specified/. /Chlorinated and brominated haloacetonitriles/ [R3] NTOX: *In a screening assay based on the enhanced induction of lung tumors, groups of 40 female strain A/J mice, 10 weeks old, were given 10 mg/kg body weight ... dibromoacetonitrile, ... in 10% Emulfor by oral gavage three times per week for eight weeks. A group of 40 animals given 10% Emulfor only served as controls. Survival at the end of the study ( at nine months of age) was: control, 31/40; ... dibromoacetonitrile-treated, 31/40 ... . The numbers of animals with lung tumors and the average number of tumors per animal were: control, 3/31 and 0.1; ... dibromoacetonitrile-treated, 5/31 and 0.19. [R4] *Nitriles have been shown to be potent inducers of aneuploidy in yeast and Drosophila test systems. Haloacetonitriles are by products of water chlorination that have been shown to be mutagenic and carcinogenic following topical application. ... Dichloroacetonitrile, but not dibromoacetonitrile is an effective inducer of aneuploidy in oocytes of Drosophila melanogaster. Following inhalation exposure of ZESTE adult females, dichloroactonitrile (8.6 ppm) induced highly significant increments in the frequencies of sex chromosome loss and gain. Sodium cyanide was also found to be a highly effective inducer of germline aneuploidy, suggesting that cyanide toxicity may contribute to potency of nitriles as inducers of aneuploidy. [R5] *In a screening study, Long-Evans rats were administered dibromoacetonitrile in tricaprylin by gavage at 50 mg/kg body weight daily on gestation days 7-21. The litters were culled on postnatal day 6 (to six to eight pups) and again at weaning, when litters were reduced to four pups, which were retained until 41 or 42 days of age. Four of the 26 dams treated with dibromoacetonitrile died. There was a significant decrease in maternal weight gain during the period of treatment. Litter weight at the time of birth was lower than in the controls, and weight gain to lactation day 4 was significantly decreased. There was no significant effect on the percentages of pregnant females or resorptions and no effect on neonatal survival after birth. [R6] *Dibromoacetonitrile was not mutagenic in either Salmonella typhimurium or Drosophila melanogaster. Sister chromatid exchange was induced in Chinese hamster ovary cells and DNA strand breaks in human lymphoblast cell lines. In mice dosed for five days, neither micronuclei in bone marrow nor abnormal sperm morphology was induced. [R7] *The haloacetonitrile dibromoacetonitrile (DBAN) is a direct-acting genotoxic agent that has been detected in drinking water. In a time course study, male Sprague-Dawley rats were treated with DBAN (75 mg/kg PO), and /sacrificed/ at 0.5, 1, 2 and 4 hr after treatment. In a dose response study, animals were treated orally with various doses of DBAN (25, 50, 75 and 100 mg/kg) and /sacrificed/ at one-half hour after treatment. Control animals received 1 ml/kg PO of the vehicle dimethyl sulfoxide (DMSO). In both experiments blood and organs were collected and stored at -80 deg C until the time of analysis. At 0.5 hr after treatment a single oral dose of DBAN caused a significant decrease of glutathione (GSH) concentrations in liver (54% of control) and stomach (6% of control). Hepatic GSH depletion was maximal at 0.5 hr and rebound to the control levels by 4 hr. In contrast gastric GSH concentrations remained low at all time points. DBAN caused an insignificant change in both kidney and blood GSH levels. DBAN significantly inhibited glutathione-S-transferase (GST) activity in liver and stomach. Hepatic GST inhibition was maximal (34% of control) at 2 hr and minimal (80% of control) at 4 hr. Meanwhile in the stomach, GST activity was inhibited at 1 hr (60% of control) and remained low at all times after treatment. Both GSH depletion and GST inhibition were dose-dependent. This study indicates that GSH and GST play an important role In the metabolism and detoxification of DBAN in rats. The prolonged depletion of GSH and inhibition of GST In the gastrointestinal tissues suggest that the GI tract is a major target for DBAN toxicity. [R8] *... Dibromoacetonitrile (in corn oil) was administered by gavage to male and female CD rats for 14 or 90 days at levels of 23, 45, 90 and 180 mg/kg/day or 6, 23 and 45 mg/kg/day, respectively. Mortality was 100% at 180 mg/kg and 40% (males) and 20% (females) at 90 mg/kg/day. Compound related mortality was 10% (males) and 5% (females) at 45 mg/kg and 0% (males) and 10% (females) at 23 mg/kg during the 90 day study. No consistent, significant, adverse compound related effects on any of the parameters evaluated were evident. Possible target organs might be spleen, thymus and liver. The no-observed adverse-effect level (NOAEL) for 14 days was 45 mg/kg/day and for 90 days was 23 mg/kg/day. ... [R9] */In this study/ dichloroacetonitile, but not dibromoacetonitrile, is an effective inducer of aneuploidy in oocytes of Drosophila melanogaster. Following inhalation exposure of ZESTE adult females, dichloroacetonitrile (8.6 ppm) induced highly significant increments in the frequencies of sex chromosome loss and gain. Sodium cyanide was also found to be a highly effective inducer of germline aneuploidy, suggesting that cyanide toxicity may contribute to potency of nitriles as inducers of aneuploidy. [R10] *... The alkylating potential of the haloacetonitriles to react with the electrophile trapping agent 4-(p-nitrobenzyl)pyridine followed the order dibromoacetonitrile greater than bromochloroacetonitrile greater than chloroacetonitrile greater than dichloroacetonitrile greater than trichloroacetonitrile. ... Administered orally to rats, the haloacetonitriles were metabolized to cyanide and excreted in the urine as thiocyanate. The extent of thiocyanate excretion was chloroacetonitrile greater than bromochloroacetonitrile greater than dichloroacetonitrile greater than dibromoacetonitrile much greater than trichloroacetonitrile. Haloacetonitriles inhibited in vitro microsomal dimethylnitrosamine demethylase activity. The most potent inhibitors were dibromoacetonitrile and bromochloroacetonitrile, with a Ki = 3-4 x 10(-5) M; the next potent were dichloroacetonitrile and trichloroacetonitrile, with Ki = 2 x 10(-4) M; and least potent inhibitor was chloroacetonitrile, with Ki 9 x 10(-2). ... None of the haloacetonitriles initiated gamma-glutamyltranspeptidase (GGT) foci when assayed for tumor initiating activity in rat liver foci. [R11] *Induction of mitotic chromosome loss could be demonstrated for ... dibromoacetonitrile ... only when /combined/ with subacute concentrations of propionitrile, which is a strong inducer of chromosomal malsegregation. /Dibromoacetonitrile/ did not induce mitotic chromosome loss when applied in pure form. ... Dibromoacetonitrile ... when applied in pure form also induced mitotic recombination. Respiratory deficiency was induced, in the absence of propionitrile by ... dibromoacetonitrile. [R12] NTXV: *LD50 Mouse (male) oral 289 mg/kg; [R9] *LD50 Mouse (female) oral 303 mg/kg; [R9] *LD50 Rat (male) oral 245 mg/kg; [R9] *LD50 Rat (female) oral 361 mg/kg; [R9] *LD50 Mouse iv 56 mg/kg; [R13] NTP: +The potential toxicity of dibromoacetonitrile (DBAN) was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to dibromoacetonitrile exposure. The dose-range finding study initially used concns of 250-2,000 ppm. This study was suspended after 4 days due to sharp reductions in fluid intake. The second dose-range finding study was conducted at concns of 0, 7, 20, 70, and 200 ppm of DBAN in the drinking water for 2 wks. Based on a slight dose-related decr in mean body weight and a decr in water consumption, concns of 0, 15, 50, and 150 ppm were selected for the main study, which utilized 1 group of male rats (10/dose level) and 2 groups of female rats designated as Group A (peri-conception exposure, 10/dose level) AND Group B (gestational exposure, 13/dose level). Control animals received deionized water, the vehicle. During the treatment period, all animals survived to the scheduled necropsy and there were no clinical signs of general toxicity noted at any dose level. Over the course of the study, water consumption was decreased in the 50 ppm males and B females by 15-32% while water consumption was decreased by 28-49% at most of the intervals in all 150 ppm groups. The overall average calculated consumption of DBAN for Groups 2-4 was 1.7, 4.5, and 9.9 mg/kg/day, respectively. Male and female mean absolute body weights, clinical observations, and gross findings were comparable across dose groups, as were male organ weights, organ-to-body weight ratios, and clinical chemistry and hematology endpoints. Male feed consumption in the 150 ppm group was reduced by 11-18% at the first two measurement intervals only. There were no treatment-related reproductive effects in the males or females. Results of this study indicate that DBAN treatment reduced water consumption in the 50 and 150 ppm dose levels in males and females in the absence of reproductive toxicity. A max tolerated dose in both males and females was achieved at 50 ppm DBAN based on a > 20% reduction in water consumption. From these data, DBAN may be a taste-aversive at 50 or 150 ppm in male and female rats, but is not a reproductive toxicant in males or females at dose levels up to 150 ppm DBAN. [R14] ACTN: */In this study/ dichloroacetonitile, but not dibromoacetonitrile, is an effective inducer of aneuploidy in oocytes of Drosophila melanogaster. Following inhalation exposure of ZESTE adult females, dichloroacetonitrile (8.6 ppm) induced highly significant increments in the frequencies of sex chromosome loss and gain. Sodium cyanide was also found to be a highly effective inducer of germline aneuploidy, suggesting that cyanide toxicity may contribute to potency of nitriles as inducers of aneuploidy. [R10] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dibromoacetonitrile is a byproduct of the chlorination of water. It is very mobile in soil and if released on land it is expected to leach. It may hydrolyze in moist, alkaline soils. If released in water, dibromoacetonitrile will be lost through hydrolysis. Hydrolysis will be faster in alkaline waters and in the presence of chlorine. Roughly 5 and 20% of dibromoacetonitrile is lost in 10 days at pH 6 and 8, respectively. Volatilization losses are expected to be minimal and bioconcentration in aquatic organisms should not occur. In the atmosphere, dibromoacetonitrile reacts extremely slowly with photochemically-produced hydroxyl radicals (half-life 696 days). Exposure to dichloroacetonitrile will be primarily via ingestion of and dermal contact with drinking water. (SRC) ARTS: *... Haloacetonitriles are by products of water chlorination. ... /Haloacetonitriles/ [R5] *Dibromoacetonitrile is formed during the chlorination of water(1,2). In experiments performed at an Evansville, IN treatment plant, dibromoacetonitrile was only found in water treated with chlorine and not in raw water or water treated with liquid or gaseous chlorine dioxide(1). The source of bromine wasn't stated. However, chlorinated waters containing inorganic bromide may lead to brominated organics(3). In addition, the bromine may occur as an impurity in the chlorinating agent. [R15] FATE: *TERRESTRIAL FATE: Dibromoacetonitrile is very mobile in soil and if released on soil will leach. It is subject to base-catalyzed hydrolysis and therefore may hydrolyze in alkaline soil. No information was found concerning its biodegradability in soil. (SRC) *AQUATIC FATE: If released in water, dibromoacetonitrile will hydrolyze. Hydrolysis will be faster in alkaline waters and in the presence of residual chlorine from water chlorination(1,2). Roughly 5 and 20% of dichloroacetonitrile is lost in 10 days at pH 6 and 8, respectively(1). Volatilization losses are expected to be minimal. Dichloroacetonitrile is not expected to adsorb to sediment. Its biodegradability in water is unknown(SRC). [R16] *ATMOSPHERIC FATE: In the atmosphere, dibromoacetonitrile reacts with photochemically-produced hydroxyl radicals. This reaction is estimated to be very slow; the resulting half-life of dibromoacetonitrile is 696 days. (SRC) ABIO: *The estimated vapor pressure of dibromoacetonitrile at 25 deg C is 0.30 mmHg(1), indicating that dibromoacetonitrile will be present in the atmosphere in the vapor phase(2). In the atmosphere, dibromoacetonitrile reacts with photochemically-produced hydroxyl radicals with a rate constant of 0.0231X10-12 cu cm/molecule-s(3). Assuming a hydroxyl radical concn of 5X10+5 radicals/cu cm, the half-life of dichloroacetonitrile in the atmosphere would be 696 days(SRC). Dibromoacetonitrile hydrolyzes by a base-catalyzed reaction(4,5). The reaction is also catalyzed by chlorine that may be present in water from chlorination (eg, drinking water, waste water effluent)(4,5). The concn of dibromoacetonitrile in buffered water declined over the course of 10 days with 95%, 89%, and 81% remaining at pH 6, 7, and 8, respectively(5). The concn in of dibromoacetonitrile in tap water was generally 20-50% of that at the treatment plants indicating that hydrolysis occurred during transport(6). [R17] BIOC: *The log Kow for dibromoacetonitrile estimated from molecular structure is 0.47(1). Using this value of log Kow, one estimates a BCF of 1.34 using a recommended regression equation(2). This indicates that dibromoacetonitrile will not bioconcentrate in aquatic organisms(SRC). [R18] KOC: *The Koc for dibromoacetonitrile estimated from molecular structure is 12.8(1). According to a suggested classification scheme(2), this estimated Koc suggests that dibromoacetonitrile would be very highly mobile in soil and would leach(SRC). [R19] VWS: *The Henry's Law constant for dibromoacetonitrile estimated from structure activity relationships is 4.06X10-7 atm-cu-m/mol(1). Using this value for the Henry's Law constant, one can estimate a volatilization half-life for dibromoacetonitrile of 127 days in a model river 1 m deep flowing at 1 m/s with a wind speed of 3 m/s(2,SRC). [R20] WATC: *Ten chlorinated drinking water samples from diverse locations in southern Ontario, Canada were found to contain dihaloacetonitriles (DHAN). All samples contained CHCl2CN (range 0.3-8.1 ppb) and some samples contained CHBrClCN (range not detected to 1.8 ppb). [R21] *DRINKING WATER: In a study of 35 water utilities across the U.S. by the EPA and State of California Department of Health Services, the quarterly median concns of dibromoacetonitrile from the spring of 1988 through the winter of 1989 were 0.54, 0.48, 0.51, and 0.46 ug/L(1). The quarterly dibromoacetonitrile concns in the facility with the highest bromide level (2.8-3.0 ppm) from the summer of 1988 through the winter of 1989 were 5.9, 6.7, and 6.0 ug/L(1). Another facility with seasonal changes in bromide level, 0.41 to 0.79 ppm, had quarterly dibromoacetonitrile levels ranging from 4.6 to 11 ug/L(1). The concn of dibromoacetonitrile in two water treatment plants using chlorine treatment was 0.41 and 5.8 ug/L(2). The concns of dibromoacetonitrile in the same plants using a combination of chlorination and ozonation were 0.79 and 5.3 ug/L(2). In a survey of 14 treated drinking water supplies of varied sources in England, dibromoacetonitrile was detected in 8 supplies(3). [R22] *DRINKING WATER: The concn of dibromoacetonitrile in 6 Dutch treatment plants that chlorinated their water and distributed water from these plants was < 0.04- 0.81 ug/L and < 0.04-0.70 ug/L, respectively, while it was absent in three plants that did not use chlorine(1). The concn in tap water was generally 20-50% of that at the treatment plants indicating that hydrolysis occurred during transport(1). [R23] RTEX: *The general population is exposure to dibromoacetonitrile through the ingestion of and dermal contact with drinking water. (SRC) EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER GUIDELINES: +EPA 20 ug/l [R24] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Method EMSLC No. 551. Determination of chlorination disinfectation byproducts and chlorinated solvents in drinking water by liquid-liquid extraction and gas chromatolgraphy with electron capture detection. GC with electron capture detection. Method detection limit 0.34 ug/L. [R25] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: Bull RJ; Fundam Appl Toxicol 5 (6 Part 1): 1065-74 (1985). Evaluation of mutagenic and carcinogenic properties of brominated and chlorinated acetonitriles byproducts of chlorination. Fu LJ et al; Regul Toxicol Pharmacol 11 (3): 213-9 (1990). Prediction of the developmental toxicity hazard potential of halogenated drinking water disinfection by-products tested by the in vitro Hydra assay. Mantovani A; Ann Ist Super Sanita 29 (2): 317-26 (1993). Reproductive risks from contaminants in drinking water. TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for dibromoacetonitrile. Route: dosed water feed; Species: water disinfection byproducts, rats and mice. [R26] SO: R1: Lide; CRC Hdbk Chem and Phys 75th ed p. 3-10 1994 R2: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V71 1371 (1999) R3: Daniel FB et al; Fundam Appl Toxicol 6 (3): 447-53 (1986) R4: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V52 277 (1991) R5: Osgood C, Sterling D; Mutat Res 261 (2): 85-91 (1991) R6: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V52 283 (1991) R7: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V52 285 (1991) R8: Ahmed AE et al; J Biochem Toxicol 6 (2): 115-22 (1991) R9: Hayes JR et al; Environ Health Perspect 69: 183-202 (1986) R10: Osgood C, Sterling D; Mutat Res 261(2) 85-91 (1991) R11: Lin EL et al; Environ Health Perspect 69: 67-71 (1986) R12: Zimmerman FK, Mohr A; Mutat Res 270 (2): 151-66 (1992) R13: Sax, N.I. Dangerous Properties of Industrial Materials. 6th ed. New York, NY: Van Nostrand Reinhold, 1984. 910 R14: Department of Health and Human Services/National Institute of Environmental Health Sciences, National Toxicology Program; Dibromoacetonitrile: Short-Term Reproductive and Developmental Toxicity Study when Administered to Sprague-Dawley Rats in the Drinking Water (CAS No: 3252-43-5), NTP Study No. RDGT94014 available at http://ntp-server.niehs.nih.gov/htdocs/pub-RDGT0.html as of August 16, 2002 R15: (1) Richardson SD et al; Environ Sci Technol 28: 592-9 (1994) (2) Peters RJ et al; Water Res 24: 797-800 (1990) (3) Oliver BG; Environ Sci Technol 17: 80-3 (1983) R16: (1) Oliver BG; Environ Sci Technol 17: 80-3 (1983) (2) Peters RJB et al; Environ Sci Technol 24:81-6 (1990) R17: (1) Lyman WJ; in Environmental Exposure from Chemicals. Vol I., chapt 2, Neeley WB, Blau GE (eds) Boca Raton FL: CRC Press Inc (1985) (2) Bidelman T; Environ Sci Technol 22: 361-7 (1988) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-9 (1993) (4) Peters RJB et al; Environ Sci Technol 24: 81-6 (1990) (5) Oliver BG; Environ Sci Technol 17: 80-3 (1983) (6) Peters RJ et al; Water Res 24: 797-800 (1990) R18: (1) Meylan WM, Howard PH; Group Contribution Method for Estimating Octanol-Water Partition Coefficients. SETAC Meeting Cincinnati, OH. Nov 8-12, (1992) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 5, Eqn 5.2 (1982) R19: (1) Meylan WM et al; Environ Sci Technol 26:1560-7 (1992) (2) Swann RL et al; Res Rev 85:17-28 (1983) R20: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods, NY: McGraw-Hill Chapt 15 (1982) R21: Oliver BG; Environ Sci Technol 17 (2): 80-3 (1983) R22: (1) Krasner SW et al; J Amer Water Works Assoc 81: 41-53 (1989) (2) Jacangelo JG et al; J Amer Water Works Assoc 81:74-84 (1989) (3) Fielding M et al; Organic micropollutants in drinking water TR-159. Medmenham, England: Water Resources Center (1981) R23: (1) Peters RJ et al; Water Res 24: 797-800 (1990) R24: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R25: USEPA/Office of Drinking Water (ODW); Methods for the Determination of Organic Compounds in Drinking Water Supplement 1, 500 Series Methods (1990) EPA/600/4-90/020 R26: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/10/2001; p.20 RS: 23 Record 355 of 1119 in HSDB (through 2003/06) AN: 6894 UD: 200302 RD: Reviewed by SRP on 9/19/1996 ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: DICHLOROACETIC-ACID- RN: 79-43-6 MF: +C2-H2-Cl2-O2 SHPN: UN 1764; Dichloroacetic acid IMO 8.2; Dichloroacetic acid MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Acetic acid + chlorine (alpha chlorination; byproduct of chloroacetic acid production) [R1] *Derivation: Chlorination of acetic acid in presence of iodine. [R2, 377] *The most cost-effective production method is the hydrolysis of dichloroacetyl chloride...98% dichloroacetic acid can be obtained in 90% yield by hydrolysis of pentachloroethane with 88-99% sulfuric acid or by oxidation of 1,1-dichloroacetone with nitric acid and air. Extremely pure dichloroacetic acid can be produced by hydrolysis of the methyl ester, which is readily available by esterification of crude dichloroacetic acid...dichloroacetic acid and ethyl dichloroacetate can be obtained by catalytic dechlorination of trichloroacetic acid or ethyl trichloroacetate with hydrogen over a palladium catalyst. [R3] USE: *Used as a chemical intermediate in the synthesis of dichlormid. [R1] +Intermediate [R2, 376] *Dichloroacetic acid is used as a test reagent for analytical measurements during fiber manufacture and as a medicinal disinfectant (substitute for formalin). Dichloroacetic acid, particularly in the form of its esters, is an important intermediate in organic synthesis. It is a reactive starting material for the production of glyoxylic acid, dialkoxy and diaroxy acids, and sulfonamides. [R3] +MEDICATION CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Colorless liquid [R1] ODOR: *Pungent odor [R4] BP: *193-194 deg C [R4] MP: *13.5 deg C [R5] MW: *128.95 [R4] CORR: *Highly corrosive liquid that gives off acidic vapors. [R3] DEN: *1.563 @ 20 deg C/4 deg C [R4] DSC: *pKa= 1.26 [R6] OWPC: *log Kow = 0.92 [R7] SOL: *Miscible with water, alcohol, and ether [R4]; *Miscible with water in any proportion. Dichloroacetic acid is readily soluble in the usual organic solvents, such as alcohols, ketones, hydrocarbons, and chlorinated hydrocarbons. [R3] SPEC: *1.4659 @ 22 deg C [R4] VAP: *0.179 mm Hg at 25 deg C, from experimentally-derived coefficients [R8] OCPP: *Apparently occurs in two crystalline forms, mp 9.7 deg C and -4 deg C. [R4] *Liquid molar volume = 0.083010 cu m/kmol; Heat of fusion at melting point = 1.2343X10+7 J/kmol [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC; inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. [R9] +Fire or explosion: Combustible material: may burn but does not ignite readily. When heated, vapors may form explosive mixtures with air: indoors, outdoors, and sewers explosion hazards. Those substances designated with a "P" may polymerize explosively when heated or involved in a fire. Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. Runoff may pollute waterways. Substance may be transported in a molten form. [R9] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. [R9] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY; it is not effective in spill situations. [R9] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. [R9] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. [R9] +Spill or leak: Eliminate all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINER. [R9] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. [R9] FIRP: *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Use water in flooding quantities as fog. Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. [R10] EQUP: *Personnel protection: ... Wear appropriate chemical protective gloves, boots and goggles. [R10] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R11, 1979.8] OPRM: *If material not on fire and not involved in fire: Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Neutralize spilled material with crushed limestone, soda ash, or lime. [R10] *Personnel protection: Avoid breathing vapors. Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. Wash away any material which may have contacted the body with copious amounts of water or soap and water. If contact with the material anticipated, wear appropriate chemical protective equipment. [R10] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R11, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R11, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R11, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R11, 1979.11] SHIP: +No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R12] +The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R13] +The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R14] +PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R11, 1979.13] +PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R11, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R11, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R11, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R11, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R11, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R11, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R11, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- CARC: *Evaluation: There is inadequate evidence in humans for the carcinogenicity of dichloroacetic acid. There is limited evidence in experimental animals for the carcinogenicity of dichloroacetic acid. Overall evaluation: Dichloroacetic acid is not classifiable as to its carcinogenicity to humans (Group 3). [R15] *CLASSIFICATION: B2; probable human carcinogen. BASIS FOR CLASSIFICATION: Based on a lack of human carcinogenicity data and increased incidence of hepatocellular adenomas and carcinomas in male and female mice. Hyperplastic liver nodules, which are expected to progress into hepatocellular adenomas and carcinomas, were increased in both rats and mice. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Sufficient. [R16] MEDS: *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R11, 1979.23] HTOX: *The neurotoxic effects of dichloroacetic acid observed repeatedly in experimental animals have rarely been documented in clinical trails. Drowsiness is a fairly frequent side effect of dichloroacetic acid and has been observed in healthy volunteers, adults with type I diabetes and patients with lactic acidosis. A patient with homozygous familial hypercholesterolemia who received single doses of 50 mg/kg body weigh dichloroacetic acid daily for four months developed reversible peripheral neuropathy characterized by loss of reflexes and muscle weakness; the effect subsided several weeks after cessation of administration of dichloroacetic acid. [R17] NTOX: *The compound was tested externally on the eyes of rabbits, and, according to the degree of injury observed after 24 hours, rated on a scale of 1 to 10. The most severely injurious substances have been rated 10. Dichloroacetic acid rated 10 on rabbit eyes. [R18] *A group of 26 male B6C3F1 mice, four weeks of age, received drinking water containing 5 g/l dichloroacetic acid (purity, > 99%) neutralized with sodium hydroxide to a pH of 6.5-7.5. A control group of 27 mice received drinking water containing 2 g/l sodium chloride. Both groups were kept for 61 weeks, at which time they were killed and necropsied. Two of 22 control mice had hepatic adenomas and none had hepatic carcinomas, whereas 25/26 mice that received dichloroacetic acid had hepatic adenomas and 21/26 had hepatocellular carcinomas (p < 0.01); Fisher's exact test. [R19] *Groups of male and female B6C3F1 mice, 37 days old, received dichloroacetic acid in drinking water neutralized to pH 6.8-7.2 with sodium hydroxide) for up to 52 weeks, at which time the experiment was terminated. A group of 11 male mice received a dose of 1 g/l for 52 weeks, 24 male mice received 2.0 g/l for 52 weeks, and a further group of 11 males received 2.0 g/l for 37 weeks and then water alone until week 52. Two groups of 35 and 11 male control mice were kept until the end of the experiment. Groups of 10 female mice received either 0 or 2.0 g/l dichloroacetic acid for 52 weeks. Livers and kidneys were weighted and examined macroscopically. Microscopic examination was undertaken only of lesions found in the livers of 35 male control mice, the 11 male mice treated with 2.0 g/l dichloroacetic acid for 37 weeks and other groups (numbers unspecified) chosen at random. The lesions were classified histologically as hyperplastic nodules, adenomas or hepatocellular carcinomas. The incidences of these lesions were increased in mice receiving 2 g/l dichloroacetic acid. Only hyperplastic nodules and adenomas were found in mice treated for 37 weeks, and only hyperplastic nodules were observed in 3/10 treated female mice (no further details reported). Other pathological signs seen at 37 or 52 weeks in males and females treated with dichloroacetic acid included cytomegaly, massive accumulation of glycogen and focal necrotic lesions. [R20] *Groups of 50 male B6C3F1 mice, four weeks old, were given 0.05, 0.5, or 5 g/l dichloroacetic acid (purity, > 99%; adjusted to pH 6.8-7.2 by the addition of 10 N sodium hydroxide) in the drinking water. A control group of 50 mice was given drinking water containing 2 g/l sodium chloride. In a second experiment, groups of 50 male B6C3F1 mice were given drinking water containing either 3.5 g/l dichloroacetic acid or 1.5 g/l acetic acid (control group) in order to examine the metabolic appropriateness of an alternative control group. Interim kills of five mice were made in all treatment groups at four, 15, 30, and 45 weeks, except i the group given 3.5 g/l dichloroacetic acid. After 60 weeks of treatment, nine mice treated with 2 g/l saline or with 0.05 or 0.5 g/l dichloroacetic acid and 3- mice given 5.0 g/l dichloroacetic acid were killed. The remaining animals were killed at 75 weeks. In the second experiment, 12 mice receiving 3.5 g/l dichloroacetic acid and 10 mice given acetic acid were killed at 60 weeks. (The fate of the remaining mice in these two groups is not described) Drinking water intake and final body weight were lower in the groups receiving 3.5 or 5.0 g/l dichloroacetic acid than among their respective controls; there was no difference in survival. Proliferative lesions of the liver were classified as hyperplastic nodules, hepatocellular adenomas or hepatocellular carcinomas; the prevalence of the two tumors types was reported only as percentages on the basis of the number of animals examined. Hyperplastic nodules occurred mainly among animals receiving dichloroacetic acid; the prevalence rates (presented graphically) at 60 weeks were 58% among those given 3.5 g/l and 83% for those given 5.0 g/l. Hepatocellular carcinomas were first observed at 30 weeks in mice at 3.5 g/l. At 60 weeks, the group given 5.0 g/l dichloroacetic acid had prevalences of 80% hepatic adenomas and 83% hepatocellular carcinomas (p < 0.001). In contrast, the prevalences of hepatic adenomas and carcinomas (combined) were 11.1% in the group given 0.5 g/l dichloroacetic acid and 24.1% in that given 0.05% g/l; these values were not significantly different from that in the saline controls (7.1%). No liver tumors were found in 10 controls given acetic acid and killed at 60 weeks. [R21] *A group of 33 male B6C3F1 mice (initially two groups of 23 and 10 mice but analyzed as one), four weeks of age, received 0.5 g/l dichloroacetic acid (purity, > 95%; impurities unspecified; pH adjusted to 6.8-7.2 with 10 N sodium hydroxide) in distilled drinking water (pooled estimated mean dose, 88 mg/kg body weight per day) for 104 weeks; 33 control mice received distilled water only. Five mice per group were killed at 30 weeks and a further five in the control group at 60 weeks, for interim evaluation. Three control mice and four treated mice died before week 104. Of the animals killed at week 104, 15/24 treated mice and 2/20 controls had hepatocellular carcinomas (p= 0.001, Fisher's exact test); 10/24 treated mice and 1/20 control mice had hepatocellular adenomas (p= 0.005); and 18/24 treated mice and 3/20 controls had carcinomas or adenomas (p= 0.001). Two treated mice had hyperplastic liver modules; 8/24 treated mice and 1/20 controls had hepatocellular necrosis, and 22/24 treated mice and 1/20 controls had cytomegaly. [R22] *Exposure of male and female Sprague-Dawley rats to dichloroacetic acid at target doses of 10-600 mg/kg body weight per day in the drinking water for 14 days resulted in reduced weight gain only in the group given the highest dose. Treatment also increased urinary excretion of ammonia and changed the activities of enzymes of ammoniagenesis, indicating renal compensation for an acid load. [R23] *Male Sprague Dawley rats administered dichloroacetic acid in the drinking water for 90 days at concentrations providing daily doses of about 4, 35 or 350 mg/kg body weight had decreased body weights. Animals given the high dose also showed histological and biochemical signs of liver and kidney damage and increased hepatic peroxisomal beta-oxidation activity. [R23] *Male Sprague Dawley rats were given dichloroacetic acid in the drinking water at a concentration of 80.5 mmol/l (10 g/l) to provide an approximate intake of 1100 mg/kg body weight per day. After 90 days, body weights were decreased, and there was an 11% increase in liver weight and a 34% decrease in testicular weight; histopathological changes were seen in the liver and lung. [R23] *Ocular toxicity was observed in beagle dogs (which are susceptible to drug induced cataract formation) that were treated for 13 weeks with an approximate dose of 1100 mg/kg body weight dichloroacetic acid in the drinking water. No similar organ specific effect has been seen in other studies or in other species. [R23] *Exposure of male and female B6C3F1 mice to dichloroacetic acid at 1000 and 2000 mg/l in drinking water for up to 52 weeks induced severe cytomegaly associated with extensive accumulation of glycogen, the effects progressing to multiple focal areas of necrosis, regenerative cell division and hepatomegaly. [R23] *Induction of peroxisome proliferation has been repeatedly associated with the chronic toxicity and carcinogenicity of dichloroacetic acid to the liver. It can induce peroxisome proliferation in the livers of both mice and rats, as indicated by increased activities of palmitoyl coenzyme A oxidase and carnitine acetyl transferase, the appearance of a peroxisome proliferation associated protein and increased volume-density of peroxisomes after exposure to dichloroacetic acid for 14 days. [R24] *Dichloroacetic acid and its metabolites accumulate in rat fetuses after treatment of the dam. The main effect of maternal doses of 140-2400 mg/kg body weight per day on days 6-15 of gestation was altered development of the heart and major vessels and less frequently, the kidneys and the orbits of the eyes. [R24] *Long term administration of dichloroacetic acid orally at up to 72 mg/kg body weight per day to dogs and 80.5 mmol/l (10 g/l) in drinking water to rats (calculated dose, 1100 mg/kg body weight per day) for 90 days induced testicular toxicity in both species, with degeneration of the seminiferous epithelium. Earlier studies in rats, including one with a similar dose (1100 mg/kg body weight per day for seven days), showed normal testicular histopathology and sperm production. In male Long-Evans rats given 0, 31.3, 62.5, or 125 mg/kg body weight per dy by gavage for 10 weeks, toxic effects were seen on the male reproductive accessory organs (preputial glands and epididymes) and sperm at 31.3 or 62.5 mg/kg body weight, whereas toxic effects on the testis and a reduction in late-step spermatid head count were observed only in the group given the highest dose. The number of viable implants on day 14 of gestation after an overnight mating with unexposed controls was decreased only in group at the high dose. [R24] *Dichloroacetic acid did not induce differential toxicity in DNA repair-deficient strains of Salmonella typhimurium but did induce prophage in Escherichia coli in one study. It was metagenic to Salmonella typhimurium TA100 and TA98 in single studies. Most of the mutations in 400 revertants of dichloroacetic acid treated Salmonella typhimurium TA100 cultures were GA AT transitions. [R24] *DNA strand breaks were not induced in mammalian cells in vitro in the absence of an exogenous metabolic activation system, but contradictory results were obtained in vivo. No effect was seen in either mouse or rat hepatic cells after single or repeated dosing, and no effects were observed in epithelial cells from spleen, stomach or duodenum after a single dose. [R25] *A group of 110 male B6C3F1 mice, eight weeks of age, were administered dichloroacetic acid, neutralized with sodium hydroxide, at a concentration of 0.5% in their drinking water for up to 76 weeks. Of two concurrent control groups, each consisting of 50 male mice, one was untreated and the other received corn oil at a dose of 10 ml/kg body; 10 mice in each group were killed at 76 weeks and the remainder at 96, 103, and 134 weeks (numbers not stated). At death, liver tumors measuring > or = 0.5 cm in diameter were taken for histological examination and for oncogene analysis. At the time of the terminal kill, there were 24 untreated controls, 32 corn oil controls and 89 treated animals. The number so hepatocellular adenomas per mouse in these three groups were 0.9 = or + 0.06 (8%), 0.13 = or + 0.06 (13%) and 4.98 = or + 0.38 (93%). the corresponding numbers of hepatocellular carcinomas were 0.09 = or + 0.06 (85), 0.12 = or + 0.06 (12%) and 1.73 = or + 0.17 (74%). /It was noted/ numerous foci of cellular alteration (presumed preneoplasic lesions) in the livers of treated mice but only rare foci in the livers of controls. No neoplasms related to treatment were found at other sites. The frequency of mutations in codon 61 of H-ras was not significantly different in the hepatocellular tumors from 64 treated mice (62%) and in those from 74 combined historical and concurrent controls (69%); however, the spectra of these mutations showed a significant decrease in AAA and an increase in CTA in the treated mice in comparison with the controls. No other H-ras mutations were found, and only one K-ras mutation was detected in tumors from the treated and concurrent control groups. [R25] *... The ability of dichloroacetic acid to elicit a lipid peroxidative response in liver was ... investigated in male Fischer 344 rats and male B6C3F1 mice after administration of a single oral dose of 100-2000 mg/kg body weight in water. A dose dependent response was induced up to 300 mg/kg body weight dichloroacetic acid in both species. A further increase to 1000 mg/kg body weight resulted in only minimal increases in the lipid peroxidative response in mice and in a decreased response in rats. [R26] *A major class of disinfection by-products found in drinking water are the haloacetic acids. Haloacetic acids can be formed by a variety of processes, e.g. chloroacetic acids can be formed during chlorination and bromoacetic acids can be by-products of ozonation. Both dichloro- and tricholoroacetic acids have been reported to be teratogenic. There is little information regarding the developmental toxicity of bromoacetates and no structure-activity analysis of haloacetates. Therefore, 3-6 somite CD-1 mouse embryos were exposed to acetic acid (AA), or mono(M), di(D), and tri(T) substituted chloro(C) or bromo(B)-acetic acids(A) (e.g. DCA = dichloroacetic acid) in whole embryo culture and the morphological effects were evaluated. Conceptuses exposed to these agents for 24 hours exhibited malformations. Neural tube defects ranged from prosencephalic hypoplasia to non-closure throughout the cranial region. Other craniofacial defects included optic, otic and pharyngeal arch dysmorphogenesis. Benchmark concentrations (BC) for a 5% increase in NTDs for the studied chemicals in order of increasing potency are DCA (2452 uM) less than AA (1888 uM) less than TBA (1403 uM) less than TCA (1336 uM) less than DBA (162 uM) less than MCA (91.5 uM) less than MBA (2.68 uM). Quantitative structure-activity relationships were derived from these data and other (iodo(I) and fluoro(F)) haloacetic acid data not presented (MIA, MFA, DFA, TFA). The best regression was derived by excluding acetic acid (n = 10) and relating log(1/BC) to Elumo and pKa with r = 0.96, adj r2 = 0.90. These studies indicate that all of the haloacetates can directly alter development and there is a wide range of concentrations that produce dysmorphogenesis. [R27] *Preimplantation embryos up to the 8 cell stage of development use lactate and pyruvate but not glucose or Krebs cycle intermediates to support growth, development, and cleavage. The dominant effect of dichloroacetic acid (DCA) is the irreversible stimulation of pyruvate dehydrogenase (PDH) activity, thus accelerating the oxidative metabolism of pyruvate and lactate. To test the hypothesis that early induction of oxidative metabolism in 2 cell murine embryos accelerates preimplantation embryo cleavage rates, female B6C3Fl mice at 6 to 8 weeks of age were superovulated with pregnant mare serum gonadotropin (PMSG) and human chorionic gonadotropin (hCG) and mated. All 2 cell stage embryos were randomly assigned to culture media with or without 130 ug/ml DCA. The developmental stage of all embryos was then noted every 24 hours for a total of 72 hours. Chi-square analysis and the method of average rank sum were used to compare the distribution of embryos at each observation point. At 24 hours, DCA-exposed embryos had achieved an advanced stage of growth and development relative to controls (average rank sum, P = 0.026; chi-square distribution, P = 0.047). Subsequently, at 48 and 72 hours, neither the average rank sum nor the chi-square distribution was different. /Results/ suggest that DCA accelerates early growth and development of murine embryos before implantation, possibly through the early induction of oxidative metabolism. [R28] *... Previous studies revealed teratogenic effects, particularly heart malformations, at high doses (900-2,400 mg/kg /dichloroacetic acid (DCA)/ given on days 6-15 of pregnancy). In a series of three studies, groups of 7-10 Long-Evans rats were dosed with 1,900 mg/kg of DCA on days 6-8, 9-11, or 12-15; with 2,400 mg/kg on days 10, 11, 12, or 13; and with 3,500 mg/kg on days 9, 10, 11, 12, or 13, in an attempt to determine the most sensitive period and further characterize the heart defect. In a fourth study, six dams were treated with 1,900 mg/kg of DCA days 6-15 of pregnancy, and 56 fetuses were harvested for light microscopy of the heart. Eight control fetuses from four litters were also examined. No heart malformations were seen in the groups treated with 1,900 mg/kg DCA days 6-8 but were present in the group treated on days 9-11 and 12-15, with the higher incidence occurring on days 12-15. Single doses of 2,400 mg/kg DCA given on days 10, 11, 12, or 13 resulted in a much lower incidence of cardiac malformations, which occurred only on days 10 and 12. The high dose of DCA (3,500 mg/kg) did not increase the incidence of heart defects but showed that dosing on day 9 as well as on days 10 and 12 would produce the defect. The defects seen were characterized as high interventricular septal defects (H-IVSD). Light microscopy showed that the defect was caudal to the semilunar valves, with the anterior right wall of the aorta communicating with the right ventricle. Another aspect of the defect is at the level of the semilunar valves, with the right cusp or sinus of Valsalva in communication with the right ventricle. The defects are discussed more fully and methods for further study suggested. [R29] *Dichloroacetic acid (DCA) is a by-product of the chlorine disinfection of water containing natural organic material. It may be found in finished drinking water at levels comparable to the trihalomethanes (5-200 ppb). Previous investigations in this laboratory showed that DCA given to pregnant Long-Evans rats on gestation days 6-15 (plug=0) at 140, 400, 900, 1400 or 2400 mg/kg/day caused malformations principally in the cardiovascular system. Since a no observed adverse effect level (NOAEL) was not demonstrated, we did an additional study using a lower dose of 14 mg/kg and repeated two other doses, 140 and 400 mg/kg. No animals died during treatment, but as seen in the previous study, maternal weight gain was reduced at 140 and 400 mg/kg/day. The relative weights of liver, spleen and kidney were increased at all dose levels. Mean fetal weight and length were decreased in the groups treated with 400 mg/kg DCA but not in controls and the lower dose groups. The patterns of malformations seen in this study were similar to those observed in the preceding study with a defect between the ascending aorta and right ventricle being predominate. The incidence of the defect was significantly increased only at the 400 mg/kg dose level, but total soft tissue malformations were significantly elevated at 140 mg/kg. We conclude that the 14 mg/kg dose of DCA is a NOAEL for developmental toxicity in the rat. [R30] *Halogenated acetic acids are major disinfection by products of water chlorination and ozonation. Limited data in experimental animals indicate that repeated doses of dichloroacetic acid (DCA) or single doses of dibromoacetic acid (DBAA) cause testicular damage. In the present study, spermatotoxic effects were investigated in rats given oral doses of 0, 10, 30, 90, or 270 mg DBAA/kg/day for 14 days. In rats dosed with 270 mg/kg/day, there were marked effects on epididymal sperm motility and morphology including the flagellar fusion of 2 or more sperm. Testis weight, epididymis weight, and testicular sperm head counts were mildly reduced relative to control, whereas epididymal sperm counts were substantially decreased. Histologic changes in the testis included retention of Step 19 spermatids in Stages IX to XII, abnormal development of late spermatids, and the formation of atypical structures resembling residual bodies that were observed predominantly in Stages X to XIV and I of the cycle of the seminiferous epithelium. At the dosage of 90 mg/kg/day, effects on spermiation, spermatid development, epididymal sperm counts, sperm motility, and sperm morphology were less severe than at the higher dosage. Reduced caput sperm counts and mild effects on spermiation also occurred at 30 and 10 mg/kg/day. These studies indicate that subchronic exposure to DBAA has the potential to affect reproductive outcome in the rat. Compared to previous studies of DCA (12), DBAA, on a molar basis, appears to be a stronger testicular toxicant than the dichloro analog. [R31] *... The objective of the present study was to examine the toxic effects of monochloroacetic acid (MCA), dichloroacetic acid (DCA), and trichloroacetic acid(TCA) in a 90 day subchronic study in rats via oral exposure by drinking water. Chloroacetic acid solutions were prepared at concentrations which provided an approximate intake of 1/4 the LD50 dose per day: MCA, 1.9 mM; DCA, 80.5 mM; TCA, 45.8 mM. Control rats received distilled water only. After 90 days, major organs were removed, fixed, paraffin embedded, and stained. Light microscopic examination of the major organs revealed variable degrees of alterations in the lung and liver of all three treated groups. In the liver, morphological changes were predominantly localized to the portal triads, which were mildly to moderately enlarged with random bile duct proliferation, extension of portal veins, fibrosis, edema, and occasional foci of inflammation. In the lungs, minimal alterations were observed as foci of perivascular inflammation on small pulmonary veins. Morphological changes in the testes and brain were seen only in the DCA treated group. Tests were atrophic with few spermatocytes and no mature spermatozoa. Focal vacuolation and gliosis were present in the forebrain and brainstem. The results of these studies indicate that,relative to their respective LD50 values, DCA given at 80.5 mM is more toxic than TCA given at 45.8 mM and MCA at 1.9 mM is least toxic. [R32] *Spontaneous apoptosis in hepatocytes of male B6C3F1 mice that received dichloroacetic acid (DCA) in their drinking water for 5-30 days (28-58 days of life) was examined as part of ongoing studies to determine the molecular basis of the hepatocarcinogenicity of this nongenotoxic water chlorination by-product. DCA at 0.5 and 5.0 g/liter, significantly reduced apoptosis relative to untreated controls in a dose dependent fashion. Regression analysis indicated that apoptosis declined over the 30-day period in the livers of control, age paired animals receiving no drug. Animals receiving low dose DCA exhibited a similar, although quantitatively depressed, trend line, whereas animals receiving high-dose DCA showed maximal depression of apoptosis at 5 days, which was sustained throughout the course of the 30 day period. These studies suggest that DCA has the ability to down regulate apoptosis in murine liver. When taken together with previous data demonstrating DCA dependent decrease in labeling index in these same livers, these data further support the hypothesis that the carcinogenic mechanism of DCA may involve suppression of the ability of the liver to remove initiated cells by apoptosis rather than by induction of selective proliferation of initiated cells. [R33] *... The incidence of proliferative lesions, hyperplastic nodules and altered hepatic foci, in male Fischer F344 rat liver, /was investigated/ to determine their preneoplastic potential during dichloroacetic acid (DCA) induced hepatocarcinogenesis. Immunohistochemical and image analysis methods were used to detect the expression of 6 histochemical markers of neoplastic cells; p21 ras, p39 c-jun, p55 c-fos, aldehyde dehydrogenase (ALDH), glutathione s-transferase (GST-p), and alpha fetoprotein (AFP) during DCA-induced hepatocarcinogenesis. Our results were consistent with our previous data and suggested that the hyperplastic nodules, rather than altered hepatic foci, is a putative preneoplastic lesion during DCA induced hepatocarcinogenesis in the male F344 rat. [R34] *Dichloroacetic (DCA) and trichloroacetic (TCA) acids ... increase the incidence of tumors in B6C3Fl mice by 6- and 3-fold respectively. In order to understand better the mechanism by which these two compounds induce liver tumors, the incidence and spectrum of mutations in the K- and H-ras proto-oncogenes in these tumors were analyzed. DNA from spontaneous, DCA- and TCA-induced liver tumors from B6C3Fl male mice was evaluated for point mutations in exons 1, 2 and 3 of the two genes by single-stranded conformation polymorphism. Results demonstrated a similar incidence of mutations for exon 2 of H-ras in spontaneous carcinomas (58%), and in carcinomas induced by DCA 3.5 g/l (50%), 1.0 g/l (48%) and TCA 4.5 g/l (45%). Only four samples showed mutations in the other exons of H-ras or in K-ras. Sequence analysis of spontaneous tumor samples with second exon H-ras mutations revealed a change in codon 61 from CAA to AAA in 80% and CAA to CGA in 20% of tumors. In contrast, tumors with H-ras mutations from DCA-treated mice revealed a H-61 change from CAA to AAA in 21% at 3.5 g/l and 16% at 1.0 g/l. CAA to CGA was observed in 50% of tumors from mice given DCA 3.5 or 1.0 g/l, and CAA to CTA was present in 29% and 34% of the two dosage groups respectively. Interestingly, TCA showed the same mutational spectrum as the spontaneous liver tumors. The data indicates that induction of liver carcinoma by DCA and TCA involves activation of the H-ras protooncogene at a frequency similar to that observed in spontaneous tumors. However, the mechanism(s) for inducing hepatocellular carcinoma does not appear to be identical for DCA and TCA. [R35] NTOX: *Dichloroacetic acid (DCA) is a complete hepatocarcinogen and tumor promoter in the male B6C3F1 mouse. Published reports indicate that the compound is non-genotoxic. This study examines possible non-genotoxic (epigenetic) mechanisms by which DCA elicits its carcinogenic response. Correlative biochemical, pathologic and morphometric techniques are used to characterize and quantify the acute, short-term response of hepatocytes in the male B6C3F1 mouse to drinking water containing DCA. Cellularity, (3)H-thymidine incorporation, DNA concentration, nuclear size, and binuclearity are evaluated in terms of level of exposure (0, 0.5 and 5 g/l) and length of exposure to DCA. The dose-related alterations in hepatocytes of animals exposed to DCA for 30 days or less indicate that short-term exposure to DCA results in inhibition of mitoses, alterations in cellular metabolism and a shift in ploidy class. Thus, DCA carcinogenesis may involve cellular adaptations, development of drug resistance and selection of phenotypically altered cells with a growth advantage. [R36] ADE: *The toxicokinetics of dichloroacetic acid were investigated in male Fischer 344 rats during 48 hour after oral administration of 28.2 or 282 mg/kg body weight (14)C dichloroacetic acid. The percentage of radiolabel excreted in the urine increased from 12.7% at the lower dose to 35.2% at the high dose. Unmetabolized dichloroacetic acid comprised > 20% of the urinary radiolabel at the high dose and < 1% at the low dose. The percentage of the dose excreted as carbon dioxide decreased from 34.4% at the lower dose to 25% at the higher. Significant percentages of the administered dose were retained in the liver (4.9%-7.9%), muscle (4.5-9.9%), skin 3.3-4.5%) and intestines 1.0-1.7%). [R26] METB: *Dichloroacetic acid is metabolized by both oxidative and reductive pathways. Both pathways lead ultimately to oxalate and carbon dioxide, glycolate and glyoxylate being probably intermediate metabolites in the reductive pathway. Reductive dechlorination of dichloroacetic acid to monochloroacetate, followed by glutathione conjugation to give thiodiacetic acid as the ultimate metabolite, has also been demonstrated. Oxalic, glycolic and thiodiacetic acids are the major urinary metabolites of dichloroacetic acid in both rats and mice. The metabolic reactions possibly involve free-radical intermediates. [R26] *Both humans and rodents metabolize dichloroacetic acid to glyoxylate by oxidative dechlorination; the plasma half-life of the parent compound is 0.5-2 hours. A significantly greater percentage of the dose is excreted in the urine of rodents (about 20-30%), however, than by humans, Since only a negligible percentage of administered radiolabel is bound to plasma proteins or taken up by erythrocyte, dichloroacetic acid and its metabolites may be distributed to other tissues, although there is no direct evidence for this suggestion. Administration of repeated doses results in a marked decrease in the clearance of dichloroacetic acid from human plasma, but similar inhibition by dichloroacetic acid of its own metabolism has not been reported in rodents. [R17] *Dichloroacetic acid (DCA) arises from the chlorination of drinking water and the metabolism of trichloroethylene (TRI) and is used therapeutically. The toxicity of TRI exposure is dependent on metabolism, and DCA has been proposed to be one contributor to this toxicity. Beyond the identification of some metabolites of DCA and some pharmacokinetic studies, little is known about the tissue distribution and enzymology of DCA metabolism. ... Data /is presented/ that indicate that DCA degradation occurs primarily in the cytosol. Low molecular weight components of cytosol are required for the reaction, including nicotinamide cofactor and glutathione (GSH). GSH plays a role in the removal of DCA from cytosol, although not through transferase mediated conjugation. In rat cytosol, the KM is approximately 0.3 mM, and the apparent Vmax approximates 12 nmoles/min/mg cytosolic protein. These results set DCA apart from other chlorinated compounds that are metabolized by the cytochrome P450 enzyme family. [R37] *The disposition of dichloroacetic acid (DCA) was investigated in Fischer 344 rats over the 48 h after oral gavage of 282 mg/kg of 1- or 2-(14)C-DCA (1-DCA or 2-DCA) and 28.2 mg/kg of 2-DCA. DCA was absorbed quickly, and the major route of disposition was through exhalation of carbon dioxide and elimination in the urine. The disposition of 1- and 2-DCA at 282 mg/kg were similar. With 2-DCA, the disposition differed with dose in that the percentage of the dose expired as carbon dioxide decreased from 34.4% (28.2 mg/kg) to 25.0% (282 mg/kg), while the percentage of the radioactivity excreted in the urine increased from 12.7 to 35.2%. This percentage increase in the urinary excretion was mostly attributable to the presence of unmetabolized DCA, which comprised more than 20% at the higher dose and less than 1% at the lower dose. The major urinary metabolites were glycolic acid, glyoxylic acid, and oxalic acid. DCA and its metabolites accumulated in the tissues and were eliminated slowly. After 48 hr, 36.4%, 26.2%, and 20.8% of the dose was retained in the tissues of rats administered 28.2 and 282 mg/kg of 2-DCA and 282 mg/kg of 1-DCA, respectively. Of the organs examined, the liver(4.9-7.9% of dose) and muscle (4.5-9.9%) contained the most radioactivity, followed by skin (3.3-4.5%), blood (1.4-2.6%), and intestines (1.0-1.7%). One metabolite, glyoxylic acid, which is mutagenic, might be responsible for or contribute to the carcinogenicity of DCA. [R38] BHL: *Both humans and rodents metabolize dichloroacetic acid to glyoxylate by oxidative dechlorination; the plasma half-life of the parent compound is 0.5-2 hours. ... [R17] ACTN: *The frequency and mutation spectra of protooncogene activation in hepatocellular neoplasms induced by tetrachloroethylene, trichloroethylene and dichloroacetic acid were examined to /determine/ the molecular basis for their carcinogenicity. H-ras codon 61 activation was not significantly different among dichloroacetic acid- and trichloroethylene-induced and combined historical and concurrent control hepatocellular tumors (62%, 51% and 69% respectively). The mutation spectra of H-ras codon 61 mutations showed a significant decrease in AAA and increase in CTA mutations for dichloroacetic acid- and trichloroethylene induced tumors when compared to combined controls. The H-ras codon 61 mutation frequency for tetrachloroethylene induced tumors was significantly lower (24%) than that of combined controls and also that of the two other chemicals. Mutations at codons 13 and 117 plus a second exon insert contributed 4% to the total H-ras frequencies for trichloroethylene and tetrachloroethylene. There was also a higher incidence of K-ras activation (13%) in tetrachloroethylene induced tumors than in the other chemically induced or control tumors. Four liver tumors were found to contain insertions of additional bases within the second exon of K- or H-ras. These findings suggest that exposure to dichloroacetic acid, trichloroethylene and tetrachloroethylene provides a selective growth advantage to spontaneously occurring mutations in codon 61 of H-ras and, at the same time, is responsible for a small number of unique molecular lesions suggestive of either a random genotoxic mode of action or a non-specific result of secondary DNA damage. However, the absence of ras activation in many of the liver neoplasms suggests that alternative mechanisms are also important in B6C3F1 mouse hepatocarcinogenesis. [R39] INTC: *Dichloro and trichloroacetic acids (DCA and TCA) and chloroform are formed during chlorination disinfection of drinking water. The effects of DCA and TCA treatment on CHCI3 toxicity were assessed in these studies. Male and female rats were gavaged with DCA or TCA (0.92 and 2.45 mmol/kg administered 3 times over 24 hr). Three hours after the last dose CHCI3 was injected ip (0.75 mg/kg). Male rats experienced some weight loss (15%) and slight increases of ALT and BUN, but there were no effects of either DCA or TCA on any of these responses. In females, CHCI3 increased plasma ALT and this response was greater (up to threefold) in the DCA group, compared to saline controls. Similarly, BUN was increased by CHCL3 and this was more severe (up to threefold) in both the DCA and TCA pretreated groups. These results show that CHCI3 toxicity is increased by DCA and TCA, and this effect is gender-specific, occurring only in females. DCA increases both liver and kidney toxicity, whereas TCA affects only kidney toxicity. [R40] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ THER: *Exptl Ther: The pharmacological and toxic effects of dichloroacetic acid in humans have been studied extensively owing to the potential use of this chloroacetic acid for the treatment of various disorders. /It has been considered for use in the treatment of lactic acidosis, diabetes mellitus, hyperlipoproteinemia and several other disorders; however, it has never been marketed for any of these purposes./ Dichloroacetic acid lowers blood sugar levels in animals and humans with diabetes mellitus by stimulating peripheral glucose use and inhibiting gluconeogenesis. In addition, long term administration of dichloroacetic acid reduces plasma triglyceride and cholesterol levels ( a particularly important effect in patients with congenital hypercholesterolemia, who have no cholesterol receptors), and it facilitates oxidation of lactate by activating pyruvate dehydrogenase in patients with acquired and congenital forms of acetic acidosis. Its capacity to activate pyruvate dehydrogenase also made dichloroacetic acid a candidate for use in the treatment of conditions involving myocardial ischemia, because when oxygen delivery to heart muscle is limited, a shift from fatty acid to carbohydrate oxidation may increased the ration of ATP production; oxygen consumption. [R17] +Caustic; keratolytic; topical astringent [R4] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Dichloroacetic acid's production and use as an intermediate, in pharmaceuticals, and as a medical disinfectant may result in its release to the environment through various waste streams. Dichloroacetic acid is also produced as a by-product during the chlorination and ozonation of drinking water. If released to the atmosphere, dichloroacetic acid will exist solely in the vapor phase in the ambient atmosphere, based on a measured vapor pressure of 0.179 mm Hg at 25 deg C. Vapor-phase dichloroacetic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals with an estimated half-life of about 22 days. An estimated Koc value of 75 suggests that dichloroacetic acid will have high mobility in soil. Volatilization from moist soil surfaces is not expected to occur based on an estimated Henry's Law constant of 6.8X10-8 atm-cu m/mole. Volatilization from dry soil surfaces is not expected given the vapor pressure of this compound. Dichloroacetic acid is expected to aerobically biodegrade in both soil and water, although it may require a short acclimation period. 14 and 8% degradation was reported for river water and seawater samples, respectively, after 3 days incubation; in aqueous screening studies, 97% of the added dichloroacetic acid was degraded in 14 days using an activated sludge inoculum. Aerobic degradation may proceed via dehalogenation with the loss of chlorine. In water, dichloroacetic acid is not expected to adsorb to sediment or particulate matter based on its Koc value. This compound will not volatilize from water surfaces given its estimated Henry's Law constant. Bioconcentration in aquatic organisms is expected to be low based on an estimated BCF value of 3. The general population may be exposed to dichloroacetic acid through dermal contact and ingestion of treated drinking water. Occupational exposure is expected through both respiratory and dermal routes. (SRC) ARTS: *Dichloroacetic acid's production and use as an intermediate, in pharmaceuticals(1), and as a medical disinfectant(2) may result in its release to the environment through various waste streams(SRC). Dichloroacetic acid is produced as a by-product during the chlorination and ozonation of drinking water(3). [R41] FATE: *TERRESTRIAL FATE: Based on a recommended classification scheme(1), an estimated Koc value of 75(SRC), determined from an measured log Kow(2) and a recommended regression-derived equation(3), indicates that dichloroacetic acid will have high mobility in soil(SRC). Dichloroacetic acid may readily biodegrade in aerobic soil following a short acclimation period(SRC). 14 and 8% degradation was reported for river water and seawater samples, respectively, after 3 days incubation(4); in aqueous screening studies, 97% of the added dichloroacetic acid was degraded in 14 days using an activated sludge inoculum(5). Pure culture experiments show that aerobic degradation occurs via dehalogenation with the loss of chlorine(6). Under environmental pH conditions, dichloroacetic acid should exist mainly as the anion(SRC), based on its pKa value(7). Volatilization of dichloroacetic acid is not exepcted to be important from moist soil surfaces(SRC) given an estimated Henry's Law constant of 6.8X10-8 atm-cu m/mole(SRC), using a fragment constant estimation method(8). Volatilization from dry soil surfaces(SRC) is not expected based on a measured vapor pressure of 0.179 mm Hg(SRC), from experimentally-derived coefficients(9). [R42] *AQUATIC FATE: Based on a recommended classification scheme(1), an estimated Koc value of 75(SRC), determined from a measured log Kow(2) and a recommended regression-derived equation(1), indicates that dichloroacetic acid should not adsorb to suspended solids and sediment in water(SRC). 14 and 8% degradation was reported for river water and seawater samples, respectively, after 3 days incubation(3); in aqueous screening studies, 97% of the added dichloroacetic acid was degraded in 14 days using an activated sludge inoculum(4). Pure culture experiments show that aerobic degradation occurs via dehalogenation with the loss of chlorine(5). Under environmental pH conditions, dichloroacetic acid should exist mainly as the anion(SRC), based on its pKa value(6). Dichloroacetic acid is not expected to volatilize from water surfaces(1,SRC) given an estimated Henry's Law constant of 6.8X10-8 atm-cu m/mole(SRC), developed using a fragment constant estimation method(7). According to a classification scheme(8), an estimated BCF value of 3(1,SRC), from a measured log Kow(2), suggests that bioconcentration in aquatic organisms is low(SRC). Dichloroacetic acid may be photolyzed in aqueous solutions(6). [R43] *ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), dichloroacetic acid, which has a measured vapor pressure of 0.179 mm Hg at 25 deg C(2,SRC), from experimentally-derived coefficients, will exist solely as a vapor in the ambient atmosphere. Vapor-phase dichloroacetic acid is degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be about 22 days(3,SRC). [R44] BIOD: *The biodegradability of dichloroacetic acid, at 10 ppm, was measured in both river water and seawater using the cultivation method; 14 and 8% degradation was reported for river water and seawater, respectively, after 3 days incubation(1). Based on these results, this compound was determined to be difficult to degrade(1). 0, 27, and 68% of the theoretical BOD in a BOD test was reached in 2, 5, and 10 days, respectively, following inoculation with sewage(2). Dichloroacetic acid was not biodegraded during a 5 day BOD test using a sewage inoculum(3). Dichloroacetic acid at 20 mg/l was > 95% degraded in a 20 day BOD test; in a second screening test, this compound was 83% degraded after 30 days(4). At 100 mg/l, dichloroacetic acid was 97% degraded in 14 days using an activated sludge inoculum(5). Pure culture experiments show that aerobic degradation occurs via dehalogenation(6). [R45] ABIO: *The rate constant for the vapor-phase reaction of dichloroacetic acid with photochemically-produced hydroxyl radicals has been estimated as 7.3X10-12 cu cm/molecule-sec at 25 deg C(SRC) using a structure estimation method(1,SRC). This corresponds to an atmospheric half-life of about 22 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1,SRC). Aqueous solutions of ferric ions and dichloroacetic acid were photolyzed by light with wavelengths greater than 300 nm; dichloroacetic acid was photolyzed at a rate of 2X10-7 eins/sec-ml(2). Based on a measured pKa of 1.26(2), dichloroacetic acid is expected to mainly exist as an anion at environmental pH values(SRC). [R46] BIOC: *An estimated BCF value of 3 was calculated for dichloroacetic acid(SRC), using a measured log Kow of 0.92(1) and a recommended regression-derived equation(2). According to a classification scheme(3), this BCF value suggests that bioconcentration in aquatic organisms is low(SRC). [R47] KOC: *The Koc of dichloroacetic acid is estimated as approximately 75(SRC), using a measured log Kow of 0.92(1) and a regression-derived equation(2,SRC). According to a recommended classification scheme(3), this estimated Koc value suggests that dichloroacetic acid has high mobility in soil(SRC). [R48] VWS: *The Henry's Law constant for dichloroacetic acid is estimated as 6.8X10-8 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This value indicates that dichloroacetic acid will be essentially nonvolatile from water surfaces(2,SRC). Dichloroacetic acid's value for vapor pressure, 0.179 mm Hg(SRC), from experimentally-derived coefficients(3), indicates that volatilization from dry soil surfaces may be significant(SRC). Volatilization from moist soil surfaces is not expected(SRC) based on the Henry's Law constant(1,SRC) for this compound. [R49] WATC: *DRINKING WATER: Water sampled from 6 full-scale treatment drinking water plants from 1983 to 1984 contained dichloroacetic acid at concns ranging from 8 to 79 ug/l(1). During a survey of drinking waters at water treatment plants treating lowland river water in England, dichloroacetic acid was detected at unreported concns(2). Water samples collected from 35 drinking water treatment facilities during 1988 contained dichloroacetic acid at concns ranging from 5.0 to 7.3 ug/l(3). Tap water from Japan contained dichloroacetic acid at concns of 2.8 to 10.9 ug/l during 1987 to 1988(4). 20 drinking water samples collected in The Netherlands contained dichloroacetic acid ranging from < 0.1 ug/l(below detection) to 3.0 ug/l; dichloroacetic acid was found only in drinking water prepared from surface waters and not from water prepared from groundwater sources(5). Tap water collected near 2 Massachusetts water treatment plants immediately following treatment contained dichloroacetic acid at concns ranging from 63.1 to 133 ug/l(6). [R50] *DRINKING WATER: Dichloroacetic acid was measured as a disinfection by-product at two water treatment plants(1). After chlorine treatment, concns of dichloroacetic acid ranged from 9.4 to 23 ug/l; after both ozone and chlorine treatment, concns of dichloroacetic acid ranged from 4.7 to 21 ug/l(1). Drinking water samples collected from Cincinnati, OH (in 1978 and 1980), Miami, FL (in 1976), Philadelphia, PA (in 1976), Ottumwa, IA (in 1976), and Seattle, WA (in 1976) contained dichloroacetic acid at unreported concns(2). [R51] *SURFACE WATER: Water samples collected from the Pols and Mur Rivers in Austria are impacted by effluent of pulp mills(1). Concns of dichloroacetic acid on the Pols river ranged from < 3 to 522 ug/l during 1989 to 1990; concns of dichloroacetic acid on the Mur River ranged from < 3 to 17 ug/l during the same time period(1). [R52] EFFL: *Dichloroacetic acid was detected in the spent chlorination liquor from the bleaching of sulphite pulp at concns ranging from 0.2 to 0.5 g/ton pulp(1). Kraft pulp mill bleach plant effluents contained dichloroacetic acid from 12-20 g/ton pulp(2). Dichloroacetic acid was measured in the flue gases from the municipal incinerator at Boras, Sweden at concns from 1.3 to 5.7 ug/cu m(3). Effluent from a Pomona, CA advanced waste treatment plant contained dichloroacetic acid at unreported concns(4). [R53] RTEX: *NIOSH (NOES Survey 1981-1983) has statistically estimated that 1592 workers (579 of these are female) are potentially exposed to dichloroacetic acid in the USA(1). Possible routes of exposure include both inhalation and dermal contact(SRC). The general population may be exposed to dichloroacetic acid via the ingestion of drinking water containing dichloroacetic acid(2,SRC). [R54] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 60 ug/l /Haloacetic acids/ [R55] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- ALAB: *Dichloroacetic acid was measured in treated drinking water via capillary GC/ECD following adsorption onto a Dowex-1-chloride resin. Detection limit = 0.1 ug/l. [R56] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for dichloroacetic acid. Route: dosed water; Species: water disinfection model, mice. [R57] +The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that prechronic study is in progress for dichloroacetic acid. Route: topical; Species: water disinfection model, mice. [R57] SO: R1: Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994. 281 R2: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 12th ed. New York, NY: Van Nostrand Rheinhold Co., 1993 R3: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA6 543 R4: Budavari, S. (ed.). The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals. Rahway, NJ: Merck and Co., Inc., 1989. 481 R5: Lide, D.R. (ed.). CRC Handbook of Chemistry and Physics. 76th ed. Boca Raton, FL: CRC Press Inc., 1995-1996.,p. 3-7 R6: Maruthamuthu P, Huie RE; Chemosphere 30: 2199-207 (1995) R7: Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995. 4 R8: Daubert, T.E., R.P. Danner. Physical and Thermodynamic Properties of Pure Chemicals Data Compilation. Washington, D.C.: Taylor and Francis, 1989. R9: U.S. Department of Transportation. 2000 Emergency Response Guidebook. RSPA P 5800.8 Edition. Washington, D.C: U.S. Government Printing Office, 2000,p. G-153 R10: Association of American Railroads. Emergency Handling of Hazardous Materials in Surface Transportation. Washington, DC: Association of American Railroads, Bureau of Explosives, 1994. 346 R11: Montesano, R., H. Bartsch, E.Boyland, G. Della Porta, L. Fishbein, R. A. Griesemer, A.B. Swan, L. Tomatis, and W. Davis (eds.). Handling Chemical Carcinogens in the Laboratory: Problems of Safety. IARC Scientific Publications No. 33. Lyon, France: International Agency for Research on Cancer R12: 49 CFR 171.2 (7/1/96) R13: IATA. Dangerous Goods Regulations. 38th ed. Montreal, Canada and Geneva, Switzerland: International Air Transport Association, Dangerous Goods Board, January, 1997. 135 R14: IMDG; International Maritime Dangerous Goods Code; International Maritime Organization p.8150 (1988) R15: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. 63 286 (1995) R16: U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) on Dichloroacetic Acid (79-43-6) Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March 15, 2000 R17: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 280 (1995) R18: Grant, W.M. Toxicology of the Eye. 3rd ed. Springfield, IL: Charles C. Thomas Publisher, 1986. 1029 R19: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 275 (1995) R20: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 276 (1995) R21: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 276-7 (1995) R22: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 277 (1995) R23: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 281 (1995) R24: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 282 (1995) R25: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 284 (1995) R26: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V63 278 (1995) R27: Rogers EH et al; Teratol 51 (3):195 (1995) R28: Penzias AS, et al; 42 (9):1077-80 (1993) R29: Epstein DL et al; Teratol 46 (3):225-35 (1992) R30: Randall JL et al; Teratol 43 (5): 454 (1991) R31: Linder RE et al; Reprod Toxicol 8 (3): 251-9 (1994) R32: Bhat HK et al; Fundam Appl Toxicol 17 (2) 240-53 (1991) R33: Snyder RD, et al; Cancer Res 55 (17): 3702-5 (1995) R34: Richmond RE et al; Cancer Lett 92 (1): 67-76 (1995) R35: Ferreria-Gonzalez, et al; Carcinogenesis 16 (3): 495-500 (1995) R36: Carter JH et al; Toxicol Lett 81 (1):55-71 (1991) R37: Lipscomb JC, et al; Drug Metab Dispos 23 (11): 1202-5 (1995) R38: Lin E LC, et al; J Toxicol Environ Health 38 (1): 19-32 (1993) R39: Anna CH, et al; Carcinogenesis 15 (10): 2255-61 (1994) R40: Davis ME; J Toxicol Environ Health 37 (1): 139-48 (1992) R41: (1) Hawley GG; Condensed Chemical Dictionary 10th ed Van Nostrand Reinhold NY p. 377 (1981) (2) Koenig G et al; Ullmann's Encycl Indust Chem. NY,NY: VCH Publishers VA6: 544 (1986) (3) Krasner SW et al; J Amer Water Works Assoc 81: 41-53 (1989) R42: (1) Swann RL et al; Res Rev 85: 23 (1983) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Amer Chem Soc, Washington,DC. p. 4 (1995) (3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (4) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (5) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Hirsch P, Alexander M; Canadian J Microbiol 6: 241-49 (1990) (7) Maruthamuthu P, Huie RE; Chemosphere 30: 2199-207 (1995) (8) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (9) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds, NY,NY: Design Inst Phys Prop Data, Am Inst Phys Prop Data (1989) R43: (1) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9, 5-4, 5-10, 15-1 to 15-29 (1990) (2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Amer Chem Soc, Washington, DC. p. 4 (1995) (3) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (4) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (5) Hirsch P, Alexander M; Canadian J Microbiol 6: 241-49 (1990) (6) Maruthamuthu P, Huie RE; Chemosphere 30: 2199-207 (1995) (7) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (8) Franke C et al; Chemosphere 29: 1501-14 (1994) R44: (1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988) (2) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds, NY,NY: Design Inst Phys Prop Data, Am Inst Phys Prop Data (1989) (3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) R45: (1) Kondo M et al; Eisei Kagaku 34: 188-95 (1988) (2) Dias FF, Alexander M; Appl Microbiol 22: 1114-18 (1971) (3) Heukelekian H, Rand MC; J Water Pollut Contr Assoc 29: 1040-53 (1955) (4) Popp KH; GWP, Gaswasserfach: Wasser/Abwasser 126: 286-92 (1985) (5) Chemicals Inspection and Testing Institute; Biodegradation and Bioaccumulation Data of Existing Chemicals Based on the CSCL Japan. Japan Chemical Industry Ecology - Toxicology and Information Center. ISBN 4-89074-101-1 (1992) (6) Hirsch P, Alexander M; Canadian J Microbiol 6: 241-49 (1990) R46: (1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993) (2) Maruthamuthu P, Huie RE; Chemosphere 30: 2199-207 (1995) R47: (1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Amer Chem Soc, Washington, DC. p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 5-4, 5-10 (1990) (3) Franke C et al; Chemosphere 29: 1501-14 (1994) R48: (1) Hansch C et al; In: Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Amer Chem Soc, Washington, DC. p. 4 (1995) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 4-9 (1990) (3) Swann RL et al; Res Rev 85: 23 (1983) R49: (1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991) (2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington DC: Amer Chem Soc pp. 15-1 to 15-29 (1990) (3) Daubert TE, Danner RP; Data Compilation, Tables of Properties of Pure Compounds, Design Inst for Phys Prop Data, Am Inst for Phys Prop Data, NY,NY (1989) R50: (1) Singer PC, Chang SD; J Amer Water Works Assoc 81: 61-5 (1989) (2) Fielding M et al; Organic Micropollutants in Drinking Water. TR-159. Medmanham, Eng. Water Res Cent (1981) (3) Krasner SW et al; J Amer Water Works Assoc 81: 41-53 (1989) (4) Ohura T et al; Eisei Kenkyo 11: 153-5 (1987) (5) Peters RJB et al; Wat Res 25: 473-77 (1991) (6) Uden PC, Miller JW; J Amer Water Works Assoc 75: 524-7 (1983) R51: (1) Jacangelo JG et al; J Amer Wat Works Assoc 81: 74-84 (1989) (2) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. Analysis Results for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank Concentrates. USEPA-600/1-84-020A (NTIS PB85-128221). Columbus, OH: Columbus Labs. Health Eff Res Lab (1984) R52: (1) Geist S et al; Determination of Chloroacetic Acids in Surface Water. Org Micropollut Aquat Environ, Proc Eur Supp, 6th, pp. 393-97 (1990) R53: (1) Carlberg GE, et al; Sci Total Environ 48: 157-67 (1986) (2) Lindstrom K, Osterberg F; Environ Sci Technol 20: 133-138 (1986) (3) Mowrer J, Nordin J; Chemosphere 16: 1181-92 (1987) (4) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. Analysis Results for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank Concentrates. USEPA-600/1-84-020A (NTIS PB85-128221). Columbus, OH: Columbus Labs. Health Eff Res Lab (1984) R54: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Lucas SV; GC/MS Analysis of Organics in Drinking Water Concentrates and Advanced Waste Treatment Concentrates: Vol 1. Analysis Results for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank Concentrates. USEPA-600/1-84-020A (NTIS PB85-128221). Columbus, OH: Columbus Labs. Health Eff Res Lab (1984) R55: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R56: Hargesheimer EE, Satchwill T; Aqua (London) 38: 345-51 (1989) R57: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.20 RS: 84 Record 356 of 1119 in HSDB (through 2003/06) AN: 6933 UD: 200302 RD: Reviewed by SRP on 5/6/2000 NT: This record contains general information for nickel ions and compounds, including statements in the literature referenced to nickel compounds, nickel salts, etc. For compound-specific information, refer to the appropriate individual records as listed in the RELATED HSDB RECORDS field; for information on the metal itself, refer to the NICKEL, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: NICKEL-COMPOUNDS- RN: NO CAS RN RELT: 1096 [NICKEL, ELEMENTAL; 7440-02-0]; 1664 [NICKEL OXIDE]; 1827 [NICKEL HYDROXIDE]; 1662 [NICKEL CARBONATE]; 6154 [BASIC NICKEL(II) CARBONATE]; 1826 [NICKEL FLUORIDE]; 860 [NICKEL CHLORIDE]; 1828 [NICKEL IODIDE]; 1829 [NICKEL NITRATE]; 1190 [NICKEL PERCHLORATE]; 1114 [NICKEL SULFATE]; 1241 [NICKEL AMMONIUM SULFATE]; 2965 [TRINICKEL DISULFIDE]; 1663 [NICKEL CARBONYL]; 1191 [NICKEL FORMATE]; 1029 [NICKEL ACETATE]; 1309 [NICKEL (2+) NTA]; 2950 [NICKEL, BIS(DIBUTYLDITHIOCARBAMATO)-]; 1185 [NICKEL CYANIDE] ASCH: Nickel ion (2+); 14701-22-5 MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- USE: *The primary uses for nickel compounds, aside from nickel refining and electroplating, are in steel making, catalysts, storage batteries, specialty chemicals, and specialty ceramics. [R1] *The major uses of nickel include the production of steel and various alloys and electroplating; it is also used in nickel-cadmium batteries, fuel cells, specialty ceramics, magnets, specialty chemicals, electronic circuitry, filters for gases, preparation of colored glass, as a hydrogenation catalyst in industrial and laboratory processes, in various pigments and for color stabilization of color copy paper. Nickel plating is used for car bumpers and trim and other consumer products. [R2] CPAT: *TOTAL USA CONSUMPTION IN 1973 OF NICKEL SULFATE AND OTHER NICKEL SALTS WAS REPORTED TO BE 3.3 MILLION KG. [R3] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- TOXC: *Toxic gases and vapors (such as nickel carbonyl) may be released in a fire involving nickel ... /Nickel and sol nickel cmpd/ [R4, 1981.3] REAC: *Incompatibilities: Strong acids /Nickel, metal and sol compounds (as Ni)/ [R5, 1985.172] *Reacts vigorously or explosively with aniline, hydrogen sulfide , flammable solvents, hydrazine, and metal powders (especially zinc, aluminum, and magnesium). /Nickel/ [R6] DCMP: *Toxic gases and vapors (such as nickel carbonyl) may be released ... in the decomp of nickel cmpd. /Nickel and sol nickel cmpd/ [R4, 1981.3] SERI: *EYE IRRITATION IN WORKERS EXPOSED TO AEROSOLS FROM NICKEL ELECTROLYSIS TANKS HAS BEEN REPORTED. /NICKEL AND COMPOUNDS/ [R7, 1986.422] EQUP: *Respirator selection: Upper limit devices recommended by NIOSH: > at any detectable concn: any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode or any supplied-air respirator with a full facepiece and operated in a pressure-demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure-demand or other positive pressure mode; escape: any air-purifying full facepiece respirator with a high-efficiency particulate filter; any appropriate escape-type self-contained breathing apparatus /Nickel, metal and sol compounds (as Ni)/ [R5, 1985.173] *Respiratory protection for dust, mist, or fume of nickel metal and soluble compounds is as follows: 10 mg/cu m or less: any fume respirator, high efficiency particulate respirator, supplied air respirator, or any self-contained breathing apparatus; 50 mg/cu m or less: a high efficiency particulate filter respirator with a full facepiece, any supplied-air respirator with a full facepiece, helmet or hood or any self-contained breathing apparatus with a full facepiece; 1000 mg/cu m or less: a powered air-purifying respirator with a high efficiency filter or a type-C supplied-air respirator operated in pressure-demand, positive pressure or continous flow mode; 2000 mg/cu m or less: a type-C supplied-air respirator with a full facepiece operated in a pressure-demand or other positive pressure mode or with full facepiece, helmet, or hood operated in a continuous-flow mode; > 2000 mg/cu m or entry and escape from unknown concn: a self-contained breathing apparatus with a full facepiece operated in pressure demand or other positive pressure mode or a combination respirator which includes a type-C supplied-air respirator. /Nickel metal and soluble compounds, dust, mist, or fume/ [R4, 1981.7] *If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. ... Employees should be provided with and required to use impervious clothing, gloves, face shields (eight-inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with powdered nickel or solid or liquids containing sol nickel cmpd. /Nickel metal and sol nickel cmpd/ [R4, 1981.3] *Use goggles, barrier shields, and other devices as necessary for personal protection; use polyvinyl chloride, not rubber, for gloves. /Nickel/ [R8] *PRECAUTIONS FOR "CARCINOGENS": ... Dispensers of liq detergent /should be available./ ... Safety pipettes should be used for all pipetting. ... In animal laboratory, personnel should ... wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. ... Gowns ... /should be/ of distinctive color, this is a reminder that they are not to be worn outside the laboratory. /Chemical Carcinogens/ [R9, 1979.8] OPRM: *Stringent requirements for warning labels and signs ... employee instruction, work practices, sanitation, environmental monitoring, and record keeping are recommended ... where employees are exposed to nickel cmpd. /Nickel and compounds/ [R10, 1439] *Skin that becomes contaminated with metallic nickel or sol nickel cmpd should be promptly washed or showered with soap or mild detergent and water to remove any metallic nickel or sol nickel cmpd. Eating and smoking should not be permitted in areas where solids or liquids containing sol nickel cmpd are handled, processed, or stored. Employees who handle powdered metallic nickel or solids or liquids containing sol nickel cmpd should wash their hands thoroughly with soap or mild detergent before eating, smoking, or using toilet facilities. Areas in which exposure to nickel metal and sol nickel cmpd may occur should be identified by signs or appropriate means, and access to these areas should be limited to authorized persons. /Nickel or sol nickel cmpd/ [R4, 1981.3] *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. ... If employees' clothing becomes contaminated with powdered metallic nickel or solid sol nickel cmpd, employees should change into uncontaminated clothing before leaving the work premises. Clothing contaminated with metallic or sol nickel cmpd should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of metallic nickel or sol nickel cmpd from the clothing. If the clothing is to be laundered or otherwise cleaned to remove metallic nickel or sol nickel cmpd, the person performing the operation should be informed of these substances's hazardous properties. Non-pervious clothing which becomes contaminated with metallic or sol nickel cmpd should be removed promptly and not reworn until the nickel or sol nickel cmpd are removed from the clothing. /Nickel or sol nickel cmpd/ [R4, 1981.3] *WORKERS WHO DEVELOP NICKEL DERMATITIS SHOULD BE REMOVED FROM CONTACT AND SHOULD NOT BE ALLOWED TO RESUME WORK UNTIL CONDITION HAS DISAPPEARED. EVEN THEN, WORKER SHOULD RECEIVE CLOSE MEDICAL SUPERVISION TO DETECT EARLIEST SIGN OF RECURRENCE. /NICKEL AND NICKEL CMPD/ [R11] *Full body protective clothing is advisable, as is the use of barrier creams to prevent skin sensitization and dermatitis. Employees should wash promptly when skin is wet or contaminated. Work clothing should be changed daily if it is possible that clothing is contaminated. Remove nonimpervious clothing promptly if wet or contaminated. /Nickel and soluble compounds/ [R12] *PERSONS ... REQUIRED TO WORK WITH ... NICKEL SALTS SHOULD BE PROVIDED WITH ADEQUATE WASHING FACILITIES AND INSTRUCTED CONCERNING NECESSITY OF AVOIDING CONTACT WITH MATERIALS IN QUESTION. ... /NICKEL/ [R10, 1439] *SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. *SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. Quality assurance to ascertain the completeness of the cleaning procedures should be implemented before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at end of shift, but should remain at employee's place of work for cleaning. *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *The worker should immediately wash the skin when it becomes contaminated. /Nickel metal and other compounds, as Ni/ [R13, 225] *The worker should wash daily at the end of each work shift. /Nickel metal and other compounds, as Ni/ [R13, 225] *Work clothing that becomes wet or significantly contaminated should be removed and replaced. /Nickel metal and other compounds, as Ni/ [R13, 225] *Workers whose clothing may have become contaminated should change into uncontaminated clothing before leaving the work premises. /Nickel metal and other compounds, as Ni/ [R13, 225] *PRECAUTIONS FOR "CARCINOGENS": Smoking, drinking, eating, storage of food or of food and beverage containers or utensils, and the application of cosmetics should be prohibited in any laboratory. All personnel should remove gloves, if worn, after completion of procedures in which carcinogens have been used. They should ... wash ... hands, preferably using dispensers of liq detergent, and rinse ... thoroughly. Consideration should be given to appropriate methods for cleaning the skin, depending on nature of the contaminant. No standard procedure can be recommended, but the use of organic solvents should be avoided. Safety pipettes should be used for all pipetting. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": In animal laboratory, personnel should remove their outdoor clothes and wear protective suits (preferably disposable, one-piece and close-fitting at ankles and wrists), gloves, hair covering and overshoes. ... Clothing should be changed daily but ... discarded immediately if obvious contamination occurs ... /also,/ workers should shower immediately. In chemical laboratory, gloves and gowns should always be worn ... however, gloves should not be assumed to provide full protection. Carefully fitted masks or respirators may be necessary when working with particulates or gases, and disposable plastic aprons might provide addnl protection. If gowns are of distinctive color, this is a reminder that they should not be worn outside of lab. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": ... Operations connected with synth and purification ... should be carried out under well-ventilated hood. Analytical procedures ... should be carried out with care and vapors evolved during ... procedures should be removed. ... Expert advice should be obtained before existing fume cupboards are used ... and when new fume cupboards are installed. It is desirable that there be means for decreasing the rate of air extraction, so that carcinogenic powders can be handled without ... powder being blown around the hood. Glove boxes should be kept under negative air pressure. Air changes should be adequate, so that concn of vapors of volatile carcinogens will not occur. /Chemical Carcinogens/ [R9, 1979.8] *PRECAUTIONS FOR "CARCINOGENS": Vertical laminar-flow biological safety cabinets may be used for containment of in vitro procedures ... provided that the exhaust air flow is sufficient to provide an inward air flow at the face opening of the cabinet, and contaminated air plenums that are under positive pressure are leak-tight. Horizontal laminar-flow hoods or safety cabinets, where filtered air is blown across the working area towards the operator, should never be used ... Each cabinet or fume cupboard to be used ... should be tested before work is begun (eg, with fume bomb) and label fixed to it, giving date of test and avg air-flow measured. This test should be repeated periodically and after any structural changes. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": Principles that apply to chem or biochem lab also apply to microbiological and cell-culture labs ... Special consideration should be given to route of admin. ... Safest method of administering volatile carcinogen is by injection of a soln. Admin by topical application, gavage, or intratracheal instillation should be performed under hood. If chem will be exhaled, animals should be kept under hood during this period. Inhalation exposure requires special equipment. ... Unless specifically required, routes of admin other than in the diet should be used. Mixing of carcinogen in diet should be carried out in sealed mixers under fume hood, from which the exhaust is fitted with an efficient particulate filter. Techniques for cleaning mixer and hood should be devised before expt begun. When mixing diets, special protective clothing and, possibly, respirators may be required. /Chemical Carcinogens/ [R9, 1979.9] *PRECAUTIONS FOR "CARCINOGENS": When ... admin in diet or applied to skin, animals should be kept in cages with solid bottoms and sides and fitted with a filter top. When volatile carcinogens are given, filter tops should not be used. Cages which have been used to house animals that received carcinogens should be decontaminated. Cage-cleaning facilities should be installed in area in which carcinogens are being used, to avoid moving of ... contaminated /cages/. It is difficult to ensure that cages are decontaminated, and monitoring methods are necessary. Situations may exist in which the use of disposable cages should be recommended, depending on type and amt of carcinogen and efficiency with which it can be removed. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": To eliminate risk that ... contamination in lab could build up during conduct of expt, periodic checks should be carried out on lab atmospheres, surfaces, such as walls, floors and benches, and ... interior of fume hoods and airducts. As well as regular monitoring, check must be carried out after cleaning-up of spillage. Sensitive methods are required when testing lab atmospheres. ... Methods ... should ... where possible, be simple and sensitive. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Rooms in which obvious contamination has occurred, such as spillage, should be decontaminated by lab personnel engaged in expt. Design of expt should ... avoid contamination of permanent equipment. ... Procedures should ensure that maintenance workers are not exposed to carcinogens. ... Particular care should be taken to avoid contamination of drains or ventilation ducts. In cleaning labs, procedures should be used which do not produce aerosols or dispersal of dust, ie, wet mop or vacuum cleaner equipped with high-efficiency particulate filter on exhaust, which are avail commercially, should be used. Sweeping, brushing and use of dry dusters or mops should be prohibited. Grossly contaminated cleaning materials should not be re-used ... If gowns or towels are contaminated, they should not be sent to laundry, but ... decontaminated or burnt, to avoid any hazard to laundry personnel. /Chemical Carcinogens/ [R9, 1979.10] *PRECAUTIONS FOR "CARCINOGENS": Doors leading into areas where carcinogens are used ... should be marked distinctively with appropriate labels. Access ... limited to persons involved in expt. ... A prominently displayed notice should give the name of the Scientific Investigator or other person who can advise in an emergency and who can inform others (such as firemen) on the handling of carcinogenic substances. /Chemical Carcinogens/ [R9, 1979.11] SHIP: *PRECAUTIONS FOR "CARCINOGENS": Procurement ... of unduly large amt ... should be avoided. To avoid spilling, carcinogens should be transported in securely sealed glass bottles or ampoules, which should themselves be placed inside strong screw-cap or snap-top container that will not open when dropped and will resist attack from the carcinogen. Both bottle and the outside container should be appropriately labelled. ... National post offices, railway companies, road haulage companies and airlines have regulations governing transport of hazardous materials. These authorities should be consulted before ... material is shipped. /Chemical Carcinogens/ [R9, 1979.13] *PRECAUTIONS FOR "CARCINOGENS": When no regulations exist, the following procedure must be adopted. The carcinogen should be enclosed in a securely sealed, watertight container (primary container), which should be enclosed in a second, unbreakable, leakproof container that will withstand chem attack from the carcinogen (secondary container). The space between primary and secondary container should be filled with absorbent material, which would withstand chem attack from the carcinogen and is sufficient to absorb the entire contents of the primary container in the event of breakage or leakage. Each secondary container should then be enclosed in a strong outer box. The space between the secondary container and the outer box should be filled with an appropriate quantity of shock-absorbent material. Sender should use fastest and most secure form of transport and notify recipient of its departure. If parcel is not received when expected, carrier should be informed so that immediate effort can be made to find it. Traffic schedules should be consulted to avoid ... arrival on weekend or holiday ... /Chemical Carcinogens/ [R9, 1979.13] STRG: *PRECAUTIONS FOR "CARCINOGENS": Storage site should be as close as practical to lab in which carcinogens are to be used, so that only small quantities required for ... expt need to be carried. Carcinogens should be kept in only one section of cupboard, an explosion-proof refrigerator or freezer (depending on chemicophysical properties ...) that bears appropriate label. An inventory ... should be kept, showing quantity of carcinogen and date it was acquired ... Facilities for dispensing ... should be contiguous to storage area. /Chemical Carcinogens/ [R9, 1979.13] CLUP: *1. VENTILATE AREA OF SPILL. 2. COLLECT SPILLED MATERIAL IN THE MOST CONVENIENT AND SAFE MANNER FOR RECLAMATION. LIQ CONTAINING NICKEL SHOULD BE ABSORBED IN VERMICULITE, DRY SAND, EARTH, OR A SIMILAR MATERIAL. /NICKEL AND SOL NICKEL COMPOUNDS/ [R4, 1981.4] *PRECAUTIONS FOR "CARCINOGENS": A high-efficiency particulate arrestor (HEPA) or charcoal filters can be used to minimize amt of carcinogen in exhausted air ventilated safety cabinets, lab hoods, glove boxes or animal rooms ... Filter housing that is designed so that used filters can be transferred into plastic bag without contaminating maintenance staff is avail commercially. Filters should be placed in plastic bags immediately after removal ... The plastic bag should be sealed immediately ... The sealed bag should be labelled properly ... Waste liquids ... should be placed or collected in proper containers for disposal. The lid should be secured and the bottles properly labelled. Once filled, bottles should be placed in plastic bag, so that outer surface ... is not contaminated ... The plastic bag should also be sealed and labelled. ... Broken glassware ... should be decontaminated by solvent extraction, by chemical destruction, or in specially designed incinerators. /Chemical Carcinogens/ [R9, 1979.15] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *Chemical Treatability of Nickel; Concentration Process: Biological Treatment; Chemical Classification: Metal; Scale of Study: Full Scale; Type of Wastewater Used: Domestic Wastewater; Results of Study: 0-33% reduction achieved; (Survey of municipal wastewater treatment plant). [R14] *Chemical Treatability of Nickel; Concentration Process: Biological Treatment; Chemical Classification: Metal; Scale of Study: Continuous Flow, Pilot Scale; Type of Wastewater Used: Domestic Wastewater; Results of Study: 28-42% reduction; (Activated sludge process). [R14] *Chemical Treatability of Nickel; Concentration Process: Biological Treatment; Chemical Classification: Metal; Scale of Study: Continuous Flow, Full Scale; Type of Wastewater Used: Domestic Wastewater; Results of Study: 30% reduction; (Activated sludge process). [R15] *Chemical Treatability of Nickel; Concentration Process: Biological Treatment; Chemical Classification: Metal; Scale of Study: Pilot Scale; Type of Wastewater Used: Domestic Wastewater; Results of Study: 28% reduction; (Activated sludge process). [R15] *Chemical Treatability of Nickel; Concentration Process: Chemical Precipitation; Chemical Classification: Metal; Scale of Study: Pilot Scale; Type of Wastewater Used: Synthetic Wastewater; Results of Study: 25% reduction with aluminum; (3 coagulants used: 220 ppm of aluminum @ pH= 6.4. 40 ppm of ferric chloride @ pH= 6.2, 415 ppm of lime @ pH= 11.5. Chemical coagulation was followed by dual media filtration). [R16] *Chemical Treatability of Nickel; Concentration Process: Chemical Precipitation; Chemical Classification: Metal; Scale of Study: Laboratory Scale, Continuous Flow; Type of Wastewater Used: Synthetic Wastewater; Results of Study: 100% reduction with lime; (lime dose of 50 ppm added). [R16] *Chemical Treatability of Nickel; Concentration Process: Chemical Precipitation; Chemical Classification: Metal; Scale of Study: Pilot Scale; Type of Wastewater Used: Domestic Wastewater + Pure Compound; Results of Study: 5ppm @ 4 gpm @ pH= 7.0. Iron system-10% reduction; low lime system-94% reduction; high lime system-97% reduction; (3 coagulant systems were used: Iron system used 45 ppm as Fe of Fe2(SO4)3 @ pH= 6.0. Low lime system used 20 ppm as Fe of Fe2(SO4)3 and 260 ppm of CaO @ pH= 10.0. High lime system used 600 ppm of CaO @ pH= 11.5. Chemical coagulation was followed by multimedia filtration). [R16] *Chemical Treatability of Nickel; Concentration Process: Reverse Osmosis; Chemical Classification: Metal; Scale of Study: Batch Flow; Type of Wastewater Used: Pure Compound; Results of Study: Each with C-PEI membrane and effluent character of 12.5 ppm; 92.8% reduction @ pH= 8.0, 97.6% reduction @ pH= 11.0. (C-PEI) membrane operated @ 600 psig and room temperature). [R17] *Chemical Treatability of Nickel; Concentration Process: Activated Carbon; Chemical Classification: Metal; Scale of Study: Laboratory Scale, Isotherm Test; Type of Wastewater Used: Pure Compound; Results of Study: 0 ppm carbon dose, 0 % removal; 500 ppm carbon dose, 4% removal; 1000 ppm carbon dose, 5% removal; 5000 ppm carbon dose, 10.5% removal; 10,000 ppm carbon dose, 52% removal; (24 hr contact time, test chemical used was NiCl2). [R18] *PRECAUTIONS FOR "CARCINOGENS": There is no universal method of disposal that has been proved satisfactory for all carcinogenic compounds and specific methods of chem destruction ... published have not been tested on all kinds of carcinogen-containing waste. ... summary of avail methods and recommendations ... /given/ must be treated as guide only. /Chemical Carcinogens/ [R9, 1979.14] *PRECAUTIONS FOR "CARCINOGENS": ... Incineration may be only feasible method for disposal of contaminated laboratory waste from biological expt. However, not all incinerators are suitable for this purpose. The most efficient type ... is probably the gas-fired type, in which a first-stage combustion with a less than stoichiometric air:fuel ratio is followed by a second stage with excess air. Some ... are designed to accept ... aqueous and organic-solvent solutions, otherwise it is necessary ... to absorb soln onto suitable combustible material, such as sawdust. Alternatively, chem destruction may be used, esp when small quantities ... are to be destroyed in laboratory. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": HEPA (high-efficiency particulate arrestor) filters ... can be disposed of by incineration. For spent charcoal filters, the adsorbed material can be stripped off at high temp and carcinogenic wastes generated by this treatment conducted to and burned in an incinerator. ... LIQUID WASTE: ... Disposal should be carried out by incineration at temp that ... ensure complete combustion. SOLID WASTE: Carcasses of lab animals, cage litter and misc solid wastes ... should be disposed of by incineration at temp high enough to ensure destruction of chem carcinogens or their metabolites. /Chemical Carcinogens/ [R9, 1979.15] *PRECAUTIONS FOR "CARCINOGENS": ... Small quantities of ... some carcinogens can be destroyed using chem reactions ... but no general rules can be given. ... As a general technique ... treatment with sodium dichromate in strong sulfuric acid can be used. The time necessary for destruction ... is seldom known ... but 1-2 days is generally considered sufficient when freshly prepd reagent is used. ... Carcinogens that are easily oxidizable can be destroyed with milder oxidative agents, such as saturated soln of potassium permanganate in acetone, which appears to be a suitable agent for destruction of hydrazines or of compounds containing isolated carbon-carbon double bonds. Concn or 50% aqueous sodium hypochlorite can also be used as an oxidizing agent. /Chemical Carcinogens/ [R9, 1979.16] *PRECAUTIONS FOR "CARCINOGENS": Carcinogens that are alkylating, arylating or acylating agents per se can be destroyed by reaction with appropriate nucleophiles, such as water, hydroxyl ions, ammonia, thiols and thiosulfate. The reactivity of various alkylating agents varies greatly ... and is also influenced by sol of agent in the reaction medium. To facilitate the complete reaction, it is suggested that the agents be dissolved in ethanol or similar solvents. ... No method should be applied ... until it has been thoroughly tested for its effectiveness and safety on material to be inactivated. For example, in case of destruction of alkylating agents, it is possible to detect residual compounds by reaction with 4(4-nitrobenzyl)-pyridine. /Chemical Carcinogens/ [R9, 1979.17] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *Nickel can be absorbed in human beings and animals via inhalation or ingestion, or percutaneously. Respiratory absorption with secondary gastrointestinal absorption of nickel (insoluble and soluble) is the major route of entry during occupational exposure. A significant quantity of inhaled material is swallowed following mucociliary clearance from the respiratory tract. ... Percutaneous absorption is negligible, quantitatively, but is important in the pathogenesis of contact hypersensitivity. Absorption is related to the solubility of the compound, following the general relationships nickel carbonyl > soluble nickel compounds > insoluble nickel compounds. ... Nickel is transported in the blood, principally bound to albumin. Gastrointestinal absorption of nickel is variable and depends on the composition of the diet. ... All body secretions are potential routes of excretion including urine, bile, sweat, tears, milk, and mucociliary fluid. Non-absorbed nickel is eliminated in the feces. ... Following parenteral administration of nickel salts, the highest nickel accumulation occurs in the kidney, endocrine glands, lung and liver: high concentrations are also observed in the brain following administration of nickel carbonyl. ... Nickel is essential for the catalytic activity of some plant and bacterial enzymes. Slow weight gain, anemia, and decreased viability of offspring have been described in some animal species after dietary deprivation of nickel. The most acutely toxic nickel compound is nickel carbonyl, the lung being the target organ; pulmonary edema may occur within 4 hr following exposure. ... contact allergy to nickel is very common in human beings ... Metallic nickel and a very large number of nickel compounds have been tested for carcinogenicity by parenteral routes of administration; with few exceptions, they caused local tumors. Only nickel subsulfide has been shown convincingly to cause cancer after inhalation exposure. ... In terms of human health, nickel carbonyl is the most acutely toxic nickel compound. ... Cases of nickel poisoning have also been reported in patients dialysed with nickel-contaminated dialysate and in electroplaters who accidently ingested water contaminated with nickel sulfate and nickel chloride. Chronic effects such as rhinitis, sinusitis, nasal septal perforations and asthma have been reported in nickel refinery and nickel plating workers. ... Nickel contact hypersensitivity has been documented extensively in both the general population and in a number of occupations in which workers were exposed to soluble nickel compounds. ... Nephrotoxic effects, such as renal edema with hyperemia and parenchymatous degeneration, have been reported in cases of accidental industrial exposure to nickel carbonyl. Transient nephrotoxic effects have been recorded after accidental ingestion of nickel salts. Very high risks of lung and nasal cancer have been reported in nickel refinery workers employed in the high-temperature roasting of sulfide ores, involving substantial exposure to nickel subsulfide, oxide and, perhaps, sulfate. [R19] CARC: *Evaluation: There is sufficient evidence in humans for the carcinogenicity of nickel sulfate, and of the combinations of nickel sulfides and oxides encountered in the nickel refining industry. There is inadequate evidence in humans for the carcinogenicity of metallic nickel and nickel alloys. There is sufficient evidence in experimental animals for the carcinogenicity of metallic nickel, nickel monoxides, nickel hydroxides and crystalline nickel sulfides. There is limited evidence in experimental animals for the carcinogenicity of nickel alloys, nickelocene, nickel carbonyl, nickel salts, nickel arsenides, nickel antimonide, nickel selenides and nickel telluride. There is inadequate evidence in experimental animals for the carcinogenicity of nickel trioxide, amorphous nickel sulfide and nickel titanate. The Working Group made the overall evaluation on nickel compounds as a group on the basis of the combined results of epidemiological studies, carcinogenicity studies in experimental animals, and several types of other relevant data, supported by the underlying concept that nickel compounds can generate nickel ions at critical sites in their target cells. Overall evaluation: Nickel compounds are carcinogenic to humans (Group 1). Metallic nickel is possibly carcinogenic to humans (Group 2B). [R20] *A1. A1= Confirmed human carcinogen. /Nickel, insoluble compounds, as Ni/ [R21, 51] ANTR: *DIETHYLDITHIOCARBAMATE TRIHYDRATE (DITHIOCARB), A METAL BINDING AGENT, HAS BEEN USED SUCCESSFULLY TO TREAT ACUTE POISONING. /NICKEL/ [R22] */BAL/ is ... useful for treatment of poisoning by compounds of ...nickel. /Nickel compounds/ [R23] *A number of chelating agents have been assessed for their ability to prevent the systemic toxicity associated with nickel exposure, including diethyldithiocarbamate (DDC, a metabolite of disulfiram or Antabuse). /Nickel/ [R24] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilation if necessary. Administer oxygen by nonrebreather mask at 10 t0 15 L/min. Monitor for shock and treat if necessary ... . Monitor for pulmonary edema and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . /Nickel and related compounds/ [R25, p. 371-2] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Consider drug therapy for pulmonary edema ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Consider vasopressors for hypotension with a normal fluid volume. Watch for signs of fluid overload ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Nickel and related compounds/ [R25, 372] MEDS: *... NIOSH RECOMMENDS THAT WORKERS EXPOSED TO NICKEL AND INORG NICKEL COMPOUNDS SHOULD HAVE INITIAL MEDICAL EXAM, INCL (A) COMPREHENSIVE MEDICAL AND WORK HISTORIES WITH EMPHASIS ON SKIN CONDITIONS, ALLERGIES, UPPER AND LOWER RESP TRACT ILLNESSES, AND SMOKING; (B) COMPLETE PHYS EXAM WITH PARTICULAR ATTENTION TO UPPER RESP TRACT AND SKIN; (C) SPECIFIC CLINICAL TESTS SUCH AS CHEST X-RAY, PULMONARY FUNCTION TESTS, and , IF INDICATED, SPUTUM CYTOLOGY AND URINE NICKEL ANALYSIS; and (D) JUDGEMENT OF EMPLOYEE'S ABILITY TO USE POS OR NEG PRESSURE RESPIRATORS ...(E) PERIODIC MEDICAL EXAM ... PERFORMED AT LEAST ANNUALLY, INCL SAME PHYS EXAM AND CLINICAL TESTS; (F) EMPLOYEES WITH MED CONDITIONS SUCH AS DERMATITIS ... MUST BE COUNSELED ON POTENTIAL HEALTH RISK; (G) APPROPRIATE MEDICAL SERVICES ... AVAIL TO EMPLOYEES SUFFERING ADVERSE HEALTH EFFECTS FROM ... EXPOSURE TO NICKEL; (I) MEDICAL RECORDS ... MAINTAINED FOR AT LEAST 40 YR AFTER LAST OCCUPATIONAL EXPOSURE TO NICKEL. /NICKEL AND NICKEL COMPOUNDS/ [R10, 1439] *Employment physical examinations should evaluate any history of skin allergies or asthma, other exposures to nickel or other suspect carcinogens, smoking history, and the respiratory tract. Lung function should be studied and chest x-rays periodically evaluated. Special attention should be given to the nasal sinuses and skin. Note also that measurement of urinary nickel levels for several days after acute exposures may be helpful. /Nickel and soluble compounds/ [R26] *Complete Blood Count: Nickel has been shown to cause hematological changes, which can be assessed by performing a complete blood count. /Nickel/ [R27, 1786] *The assessment of nickel exposure can be accomplished through measurement of nickel. ... Blood Reference Ranges: Normal - less than 2 ug/l; Exposed - not established; Toxic - not established. ... Serum or Plasma Reference Ranges: Normal - less than 4 ug/l; Exposed - levels of 3 to 11 ug/l have been seen in refinery workers without overt clinical effects; Toxic - not established. ... Urine Reference Ranges: Normal - average approx 2.0 ug/l; Exposed - Nickel (nickel metal, nickel oxide, nickel carbonate, nickel sulfide, and sulfitic ores) concentrations in urine that have been found to corelate with workplace air concentrations are as follows: ... Urinary levels of 30-50 ug/l have been found to correlate with an air level of 0.5 mg/cu m. Urinary levels of approx 12 ug/l have been found to ccorrelate with an air level of 0.05 mg/cu m.; Toxic - greater than 400 ug/l. /Nickel/ [R27, 1785] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. /Nickel/ [R27, 1787] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. /Nickel/ [R27, 1787] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. /Nickel/ [R27, 1787] *Sputum Cytology: Sputum cytology along with chest radiographs have been the standard procedures for detecting early lung cancer in asymptomatic patients. Sputum cytology has been found to be useful for detection of central tumors, especially squamous carcinomas. /Nickel/ [R27, 1787] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; Thermography. /Nickel/ [R27, 1788] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. /Nickel/ [R27, 1788] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell Assessment ... Visual Assessment ... Facial and Trigeminal Nerve Assessment ... Vestibular Assessment ... Hearing Assessment. /Nickel/ [R27, 1788] *PRECAUTIONS FOR "CARCINOGENS": Whenever medical surveillance is indicated, in particular when exposure to a carcinogen has occurred, ad hoc decisions should be taken concerning ... /cytogenetic and/or other/ tests that might become useful or mandatory. /Chemical Carcinogens/ [R9, 1979.23] HTOX: *... Nickel ... has been known to cause both irritation and bronchial asthma. /Nickel/ [R28, 461] *Nickel and its salts are among the commonest causes of metal allergic contact dermatitis and ... the most common of all causes of human skin sensitization. /Nickel/ [R28, 827] *... immunoallergological studies on some ... revealed humoral and cell-mediated immunity to ... nickel. /Nickel/ [R28, 452] *EXPOSURE TO INDUSTRIAL NICKEL DUST CAUSES NICKEL DERMATITIS. SENSITIVITY TO NICKEL MAY BE EXHIBITED FROM SKIN CONTACT ... DIVALENT NICKEL IONS CAN PENETRATE SKIN AT SWEAT-DUCT AND HAIR FOLLICLE OSTIA, AND BIND WITH KERATIN. CONTACT DERMATITIS THUS RESULTS FROM PERMEABILITY OF ... DERMIS AND EPIDERMIS TO NICKEL. /NICKEL DUST AND SALTS/ [R29, 292] *"NICKEL ITCH", WHICH IS VARIABLE IN NATURE, USUALLY BEGINS WITH SENSATION OF BURNING AND ITCHING IN HAND, FOLLOWED BY ERYTHEMA AND NODULAR ERUPTION ON WEB OF FINGERS, WRISTS AND FOREARMS. NODULES MAY BECOME PUSTULES OR MAY ULCERATE. /NICKEL SALTS/ [R30, 1829] *PARTLY BECAUSE OF LOCAL ASTRINGENT AND IRRITANT ACTIONS, NICKEL SALTS ACT AS EMETICS WHEN SWALLOWED (BUT ALSO BY OTHER ROUTES). AS WITH OTHER IRRITANT- EMETICS, THE ORAL LETHAL DOSE IS PRESUMED TO VARY WIDELY. ABSORPTION FROM BOWEL IS POOR AND SYSTEMIC POISONING IS RARE. SYSTEMIC EFFECTS INCL CAPILLARY DAMAGE (ESPECIALLY IN BRAIN AND ADRENALS), RENAL INJURY, MYOCARDIAL WEAKNESS, AND CENTRAL NERVOUS DEPRESSION. /NICKEL SALTS/ [R31] *A nickel plated water heater in a dialysis unit was believed to be responsible for contaminating dialysis fluid, which resulted in mild signs of intoxication in 23 pt. At plasma nickel levels of 3 mg/l, nausea, vomiting, weakness, headache and palpitations occurred; they regressed over 3 to 13 hr. /Nickel salts/ [R31] *An incr incidence of lung and nasal cavity cancers has been noted among workmen in nickel smelters and refineries. /Nickel dust and compounds/ [R31] *It has been estimated that 5% of all eczema can be linked to contact with nickel containing cmpd. /Nickel and nickel compounds/ [R32, 266] *... Incr in lung cancer among nickel workers has been reported from several different countries incl suggestions of incr risks to laryngeal cancer in nickel refinery workers in Norway and gastric carcinoma and soft tissue sarcoma from the Soviet Union. Six cases of renal cancer have been reported among Canadian and Norwegian workers employed in electrolytic refining of nickel. /The investigator/ ... has been able to detect early cytologic changes in sputum of exposed workers prior to chest X-ray or clinical indicators of resp tract cancers. /Nickel and nickel cmpd/ [R32, 610] *The organs which are affected by exposure to nickel, metal and sol cmpd (as Ni) are nasal cavities, lung, skin. /Nickel, metal and sol compounds (as Ni)/ [R5, 1985.173] *IN NICKEL PLATING INDUSTRY, EXPOSURE TO NICKEL-CONTAINING VAPORS HAS BEEN REPORTED TO BE ASSOC WITH ASTHMA. SYMPTOMS WERE ATTRIBUTED TO HYPERSENSITIVITY TO NICKEL OF NON-OCCUPATIONAL ORIGIN. PNEUMOCONIOSIS HAS BEEN REPORTED AMONG WORKERS EXPOSED TO NICKEL DUST ... EFFECTS ON NASAL MEMBRANE WERE NOTED IN WORKERS EXPOSED TO NICKEL AEROSOLS IN AN ELECTROLYSIS SHOP. /NICKEL VAPORS AND DUST/ [R33, p. V2 473] *WORKERS EMPLOYED IN NICKEL PLATING HAVE DEVELOPED CONJUNCTIVITIS AND EPIPHORA WHEN VENTILATION WAS POOR. /NICKEL PLATING CMPD/ [R34] *The avg latency period for the induction of ... /lung and nasal passage/ cancers appears to be about 25 yr (range 4 to 51 yr). /Nickel and sol cmpd/ [R35] *NICKEL AS INDUSTRIAL INHALANT WAS FIRST SUSPECTED AS CARCINOGEN IN BRONCHI IN 1933, ESTABLISHED BOTH EPIDEMIOLOGICALLY AND EXPERIMENTALLY; FIRST AS CARCINOGEN IN NASAL CAVITY IN 1933, ESTABLISHED EPIDEMIOLOGICALLY BUT NEGATIVE RESULTS EXPERIMENTALLY. /FROM TABLE, NICKEL/ [R36] *THE TOXICITY /TO HUMANS/ OF NICKEL OR NICKEL SALTS THROUGH ORAL INTAKE IS LOW ... NICKEL SALTS EXERT THEIR ACTION MAINLY BY GASTROINTESTINAL IRRITATION. /NICKEL OR NICKEL SALTS/ [R37] *LOW ABSORPTION FROM GI TRACT CAUSES NICKEL CMPD TO BE ESSENTIALLY NONTOXIC AFTER INGESTION. AFTER INHALATION CERTAIN NICKEL CMPD ARE EXTREMELY POTENT CARCINOGENS. [R38] *Based on data concerning the death of a patient given human serum albumin which was suspected of being contaminated with nickel, it is recommended that the maximum permissible level of Ni be 5 ug/l for common iv solutions containing albumins or amino acids. Also, it is recommended that the maximum permissible amount of Ni administered to infants, children, and adults as a contaminant in iv fluids should not exceed 0.5 ug/kg/day. /Soluble nickel cmpd/ [R39] *In a cross-sectional study, 38 production workers exposed to nickel (Ni) and 35 exposed to cobalt (Co) were examined for the content of Ni and cobalt in hair, serum concentration levels of immunoglobulins, and serum proteins. Age matched healthy males without exposure to Ni or cobalt were selected as controls. No information was provided on dose or duration of exposure. The respective geometric mean values of Ni and cobalt in the hair of Ni exposed workers were 216.75 and 3.31 ug/g and in cobalt exposed workers were 34.5 and 96.8 ug/g, respectively. these values were significantly higher than respective control values (Ni: 3.31 ug/g, cobalt: 0.38 ug/g). Tests for serum immunoglobulins revealed that nickel workers differed from controls by exhibiting significantly elevated IgG (p < 0.005), IgA (p < 0.01), and IgM (p < 0.005) levels and that cobalt workers differed from controls by a significant elevation of IgA level (p < 0.05). Both workers exposed to Ni or to cobalt exhibited a significant drop in IgE level (0.001 < p < 0.05). There was a significant elevation (p,0.001, p < 0.005) in the concentration of the serum proteins, alpha-one-antitrypsin, alpha-two-macroglobulin, ceruloplasmin, and lysozyme, in exposed workers when compared to controls. /Soluble nickel cmpd/ [R40] *BLACK PATIENT READILY ACQUIRE ALLERGIC CONTACT DERMATITIS FROM NICKEL. SUCH DERMATITIS IS OFTEN COMPLICATED BY HYPERPIGMENTATION AND LICHENIFICATION UNLESS TREATED EARLY AND VIGOROUSLY WITH SYSTEMIC CORTICOSTEROIDS. /NICKEL/ [R41] *EPIDEMIOLOGICAL STUDIES CONCLUSIVELY DEMONSTRATE AN EXCESS RISK OF CANCER OF THE NASAL CAVITY AND LUNG IN WORKERS IN NICKEL REFINERIES. IT IS LIKELY THAT NICKEL IN SOME FORM(S) IS CARCINOGENIC TO MAN. /NICKEL AND NICKEL CMPD/ [R42] *Nickel dermatitis, "nickel itch," consititutes the most common affliction among nickel platers. It has two components, a simple dermatitis localized to the area of contact and a chronic eczema or a neurodermatitis without apparent connection to such contact. /Nickel salts/ [R43] *Pregnancy complications, ... increased occurence of birth defects (primarily cardiovascular and musculoskeletal) have been reported ... [R28, 994] *Sensitization is only known to occur after dermal exposure to nickel, whereas provocation can take place after exposure of the skin and after ingestion of nickel. The clinical manifestations of nickel associated allergic contact dermatitis comprise both primary and secondary eruptions. The primary eruptions usually appear at the site of sensitization, and the secondary eruptions will frequently be more or less generalized, often symmetrical, maculopapular vesicules of the pompholyx type eczema, which affects the flexures of the elbows, the sides of the neck, the axillae, the eyelids, and the genital area. A vesicular hand eczema can also develop. /Nickel/ [R44] *... Adverse health effects from occupational exposure to nickel have been reported. Increased risk of cancer of the lung ... /and/ Nasal sinus ... Increased risk of laryngeal ... /and/ gastric cancer ... Increased risk of sarcoma ... Chronic irritation of the upper respiratory tract ... Pulmonary irritation and ... fibrosis ... Pneumoconiosis ... Bronchial asthma ... Increased susceptibility of respiratory infections ... Allergic contact dermatitis ... Acute toxic effects from exposure to nickel carbonyl ... /Reported health effects from occupational exposure to nickel and nickel compounds/ [R45, 563] *Many are human carcinogens by inhalation. Nickel and many of its compounds are poisons and carcinogens. ... Ingestion of large doses ... of nickel compounds has been shown to cause intestinal disorders, convulsions, and asphyxia. ... The most common effect resulting from exposure to nickel compounds is the development of "nickel itch." /Nickel and cmpd/ [R46] *Allergic reaction as well as urticarial and eczematous dermatitis in nickel-sensitive persons can be produced by implanted prostheses and other surgical devices made from nickel-containing alloys ... Nickel sensitivity /was found/ in 11 out of 85 patients following hip prosthesis implantation. Three of the patients had had previous implants ... described 4 patients with a history of metal intolerance, who developed dermatitis following surgical wound closure with disposable skin clips (nickel content about 10%). Two positive reactions were reported ... in 85 patch-tested patients, who had undergone hip arthroplasty. /Nickel-containing alloys/ [R44] *It has been estimated that 5% of all eczema can be linked to contact with nickel containing cmpd. /Nickel/ [R32, 266] *Nickel-induced toxicity depends on the route of exposure and the solubility of the nickel compound. The major route of toxic nickel exposure is via pulmonary absorption. Gastrointestinal and dermal absorption of nickel compounds is significantly less important, although dermal exposure can lead to nickel sensitivity and contact sensitivity. ... Kidney and lung are the primary organs for the accumulation of nickel. Absorbed nickel can also be measured in the blood, where it is mostly protein bound. [R24] *Nickel has both embryotoxic and teratogenic effects in animals. It can directly affect the developing embryo or fetus and indirectly alters the maternal hormone balance by inducing hyperglycemia. Maternal exposure can result in decreased implantation frequency, increased early and late resorption and increased frequency of stillborn fetuses. Exposure to nickel during organogenesis can also result in a variety of teratogenic effects, such as exoencephaly, eye malformations, and skeletal abnormalities. [R24] *The chronic effects of exposures to Ni compounds primarily affect the immune system and the respiratory tract. [R47] *50 patients with chronic fatigue syndrome and 73 controls were patch tested with 8 metal allergens. We found an overrepresentation of allergies among the chronic fatigue syndrome patients, which was not significant. However, allergy to nickel occurred in 36% of patients in the chronic fatigue syndrome group and in 19% of subjects in the control group (p < 0.05). The high frequency of nickel allergy was more noteworthy in females in the chronic fatigue syndrome group than among female controls (52% and 24%, respectively, p < 0.05). [R48] NTOX: *... NICKEL SALTS CAUSE INJURY OR DESTRUCTION OF ALPHA CELLS OF PANCREAS, and ... TO A LESS EXTENT, DAMAGE TO BETA CELLS. /NICKEL SALTS/ [R49] *BY ORAL ADMIN LARGE DOSES OF NICKEL SALTS CAUSE ACUTE GASTRO-INTESTINAL IRRITATION, WITH VOMITING AND DIARRHEA. LETHAL DOSE VARIES WITH THE SPECIES. ... IN ... INVESTIGATIONS, 6-12 MG OF NICKEL PER KG BODY WT DAILY FOR 100-200 DAYS OF CHLORIDE AND SULFATE IN THE FORM OF THE ACETATE, CAUSED NO SIGNIFICANT INJURY. BY SUBCUTANEOUS OR INTRAVENOUS INJECTION ... NERVOUS SYMPTOMS ... OCCUR: TREMOR, CHOREA-LIKE MOVEMENTS AND FINALLY PARALYSIS; CONVULSIONS ARE RARE IN DOGS AND DEATH IS DUE TO HEART FAILURE. /NICKEL SALTS/ [R50] *TOXICITY STUDIES HAVE DEMONSTRATED THAT ... NICKEL SALTS HAVE RELATIVELY LOW TOXICITY IN VARIOUS SPECIES OF ANIMALS WHEN ADMIN ORALLY. ... PARENTERAL INJECTIONS OF NICKEL SALTS ARE MUCH MORE TOXIC. MAJOR SIGNS OF ACUTE NICKEL TOXICITY CONSIST OF HYPERGLYCEMIA AND GI AND CNS EFFECTS. /NICKEL SALTS/ [R51, 287] *NICKEL SALTS ARE HIGHLY TOXIC WHEN ADMIN IV OR SC. GASTROENTERITIS, TREMORS, AND PARALYSIS OCCUR IN DOGS AND GUINEA PIGS IMMEDIATELY FOLLOWING IV ADMIN OF SUBLETHAL DOSES; HYPERGLYCEMIA DEVELOPS, BUT CAN BE PREVENTED BY ADMIN OF INSULIN. LOCALIZATION OF INJECTED NICKEL SALTS IN PITUITARY GLAND AND SUBSEQUENT DECREASED SERUM LEVEL OF PROLACTIN SUGGEST THAT DIVALENT NICKEL EXERTS A DIRECT SPECIFIC INHIBITORY ACTION ON PROLACTIN-SECRETING CELLS IN ANTERIOR PITUITARY. /NICKEL SALTS/ [R29, 295] *There is evidence in lab animals that nickel exposure results in altered resistance to virus and bacteria. A direct effect on macrophage function has also been attributed to nickel. /Nickel compounds/ [R32, 276] *IN LABORATORY ANIMALS, INHALATION OF NICKEL CMPD WITH LOW SOLUBILITY CAUSES INFLAMMATORY REACTIONS IN NASAL MUCOSA AND IN LUNG. /NICKEL SALTS/ [R33, p. V2 462] *... RATS /WERE GIVEN/ NICKEL SALT IN DRINKING WATER (5 MG NI/LITER) FOR 3 GENERATIONS AND NOTED AN INCR MORTALITY AMONG NEWBORNS IN ALL 3 GENERATIONS AND AN INCR NUMBER OF RUNTS. IN THIRD GENERATION MORE FEMALES THAN MALES WERE BORN. /NICKEL SALTS/ [R33, p. V2 475] *... Nickel in drinking water to rats for 7 mo before pregnancy and during pregnancy and some incr of preimplantation mortality was found. Some cases of malformed fetuses were noted. /Nickel salts/ [R52] *DNA LESIONS OBSERVED IN KIDNEY NUCLEI ISOLATED FROM RATS 20 HR AFTER IP INJECTION. DOSE-DEPENDENT, NICKEL-INDUCED DNA CROSSLINKS AND DNA SINGLE STRAND BREAKS WERE DETECTED USING ALKALINE ELUTION TECHNIQUE. DNA DAMAGE IS DISCUSSED RELATIVE TO CARCINOGENICITY OF NICKEL CMPD. [R53] *Although water soluble nickel salts have not been shown to initiate carcinogenesis in rodents, the soluble nickel salts are evidently effective as cancer promotors following initiation of tumorigenesis by aromatic hydrocarbons and nitrosoamines. Growing evidence suggest that the nickel(III)/nickel(II) redox couple facilitates oxygen free radical reactions, which may represent one of the molecular mechanisms for genotoxicity and carcinogenicity of nickel cmpds. /Soluble nickel cmpd/ [R54] *Coliphage T1 was more sensitive than its host bacterium, Escherichia coli B, to nickel. A five hr exposure to 100 ppm Ni in nutrient broth did not adversely affect T1, whereas 10 and 20 ppm Ni extended the lag phase of growth of E coli B, and no growth occurred with 40 or more ppm Ni. Ni (5 ppm) enhanced the survival (after 4 wk) of T1 in sea or simulated estuarine water but was toxic (ie reduced viral infectivity) in lake water; 50 ppm Ni was not toxic to T1 in sea water, was moderately toxic in estuarine water, but was highly toxic in lake water; and 100 ppm Ni was toxic in all systems, with the sequence of loss in viral infectivity being lake > estuarine > sea water. Ni (100 ppm) was not toxic to T1 in nutrient broth, even after 3 weeks of exposure, probably because of the protective effect of the organic compounds in the broth. /Soluble nickel cmpd/ [R55] *The survival of some eubacteria, an actinomycete, and yeasts after acute and chronic exposure to nickel in lake, simulated estuarine and sea waters; and the influence of environmental factors on Ni toxicity were determined. Ni toxicity to microbes in marine systems was reduced by increasing the salinity, decreasing the temperature, and incorporation of simulated sediment. The toxicity of Ni to microbes in fresh water was reduced by increasing the pH, increasing the hardness, and incorporation of suspended particulates. Chronic toxicity studies indicated that fresh waters were more sensitive than marine waters to Ni pollution, as microbial survival was greater in marine waters stressed with equivalent concentrations of Ni. /Soluble nickel cmpd/ [R56] *Plasma and pancreatic cation alterations were investigated in rats subjected to chronic oral nickel ingestion. Decreases in sodium and potassium, significant in the former, were observed in plasma, while calcium and magnesium were unchanged. Calcium and zinc levels in total pancreatic tissue were higher than in the controls. /Soluble nickel cmpd/ [R57] *Eggs, alevins, swim up fry, and 8 month old Atlantic salmon (Salmo salar) were exposed to concentrations of ... nickel in soft water. ... The maximum acceptable toxicant concentration (MATC) was approximately ... 50 ug Ni/l. ... Ni affected the hatching process, delayed hatching, and increased mortality of embryos. /Soluble nickel cmpd/ [R58] *... IN PROPER CONCN ... /NICKEL/ CAN ACTIVATE PANCREATIC RIBONUCLEASE AND DESOXYRIBONUCLEASE I AND CAN REPLACE ZINC IN CARBOXYPEPTIDASE AND CARBONIC ANHYDRASE ... INHIBITION OF RNA POLYMERASE AND ATPASE ARE OF PARTICULAR SIGNIFICANCE ... /SOLUBLE NICKEL CMPD/ [R30, 1836] *Phytotoxicity causes visible symptoms (interveinal chlorosis of young leaves) at about 50-100 mg/kg dry leaves. These levels are phytotoxic for grasses, legumes, and leafy vegetables. ... No health effect or nickel bioaccumulation in voles fed sludge fertilized soybeans containing 30 ppm nickel; this is the Ni level in soybean grain when yield is significantly reduced. /Soluble nickel cmpd/ [R59] *Maximum acceptable nickel concn from partial and complete life cycle toxicity test with fathead minnow is 380-730 ug/l, from embryo larval and early juvenile 380-730 ug/l. /From table/ /Soluble nickel cmpd/ [R60] *Aquatic plants can extract nickel from water and concentrate it to a high degree (1x10+3-1x10+4 mg/kg dry weight). Laboratory experiments showed that planktonic algae and aquatic macrophytes had 50% reductions in growth rates when exposed to aqueous nickel in the range 0.5-2.0 mg/l. /Soluble nickel cmpd/ [R61] *The effect of nickel(2+) on the release of amylase from rat parotids, insulin from mouse pancreatic islets, and growth hormone from bovine pituitary slices were investigated. In all these secretory systems, Ni(2+) inhibited release evoked by a variety of stimuli both physiological and pharmacological. ... Results suggest that this inhibitory action of Ni(2+) does not arise through an effect on energy metabolism or cyclic AMP metabolism. /Soluble nickel cmpd/ [R62] *A study involving three experiments was done to ascertain whether the beneficial effect of nickel on hematopoiesis in moderately iron deficient rats was due to physiologic and/or pharmacologic mechanisms. Female Sprague-Dawley rats were fed nickel supplements ranging from 0 to 100 micrograms/g in iron low (15 micrograms iron(3+)/g), iron adequate (65 micrograms iron(3+)/g), or iron luxuriant (100 micrograms iron(3+)/g) diets. The basal diet contained from 2 ng (experiment 3) to 36 ng (experiment 1) of nickel/g. At 10 weeks, both nickel deficiency and toxicity (100 micrograms/g diet) tended to depress hematopoiesis and markedly altered femur and liver trace element content in marginally iron deficient rats. The alterations included elevated copper, iron and nickel, and depressed calcium and manganese in femurs. The pharmacologic action of nickel was indicated by the finding that high dietary nickel (5, 10, 20, or 50 micrograms/g) apparently stimulated hematopoiesis in marginally iron deprived rats to a greater extent than dietary levels of nickel (0.1, 0.5, or 1.0 micrograms/g) considered adequate for nutritional needs. High dietary nickel also elevated the iron content in liver of marginally iron adequate rats. The findings indicate that nickel influences iron metabolism at physiologic, pharmacologic, and toxic levels of intake. They also indicate that many previously reported signs of nickel deprivation, including effects on hematopoiesis, may have been misinterpreted and might be manifestations of pharmacologic actions of nickel. /Soluble nickel cmpd/ [R63] *The DNA damaging effect of ionic nickel was studied in Chinese hamster ovary cells using several chromatin isolation methods in combination with SDS-polyacrylamide gel electrophoresis. DNA from nickel treated cells consistently had more (35S)-methionine radioactivity than did DNA from untreated cells. This radioactivity was resistant to ribonuclease but sensitive to protease. Differential extraction using denaturing agents and high ionic strength followed by SDS-polyacrylamide gel electrophoresis revealed that most of the tightly bound proteins were nonhistone chromosomal proteins, and possibly histone 1. The enhancement of DNA protein binding from nickel treated cells was disrupted by SDS, suggesting that nickel ions do not function as classical bifunctional crosslinking agents. /Soluble nickel cmpd/ [R64] *Nickel treatment of a liver epithelial cell line (T51B) in vitro selectively induced cytokeratin filament accumulation in a juxtanuclear location as the cells rounded up. After removal of nickel, vimentin filaments remained attached to the cell periphery as the cells spread out again, but the cytokeratin filaments remained aggregated in a perinuclear position without reestablishing all peripheral connections. /Soluble nickel cmpd/ [R65] *The Potential of ammonium chloride, sodium butyrate, sodium propionate, and the heavy metals nickel, zinc, and copper to interfere with methanogenesis of Methanospirillum hungatei, Methanosarcina barkeri, Methanobacterium thermoautotrophicum, and Methanobacterium formicicum at pH 6.5 was studied. All strains were sensitive to copper (1-5 mg/l) and zinc (1-10 mg/l) but resistant to nickel. /Soluble nickel cmpd/ [R66] *Nickel dusts and several specific cmpd are carcinogenic in animals after inhalation or parenteral admin, but not by ingestion or skin contact. /Nickel dust and compounds/ [R31] *... Nickel also affects the hypothalamus of animals. Nickel salts specifically inhibited the release of prolactin in vivo (in the rat) and in vitro from bovine pituitary. /Nickel salts/ [R67] ETXV: *LC50 Channa punctatus 306.9 mg/l/96-hr /Conditions of bioassay not specified/ /Nickel ion/; [R68] *LC50 Daphnia magna 0.13 mg/l/3 weeks /Conditions of bioassay not specified/ /Nickel ion/; [R69] *LC50 Acroneuria lycoria 4 mg/l/96 hr /Conditions of bioassay not specified/ /Nickel ion/; [R69] *LC50 Artemia salina 163.0 mg/l/48 hr /Conditions of bioassay not specified/ /Nickel ion/; [R70] POPL: *... OF INTEREST TO EMERGING ROLE OF WOMEN IN INDUSTRY, NICKEL CAN APPARENTLY CROSS ... PLACENTA, FOR NICKEL HAS BEEN FOUND IN HUMAN FETAL TISSUE AND IN CORD SERUM WHERE AVG CONCN FROM 12 NEWBORNS WAS 0.3 TO 12 UG/DL (RANGE 0.17 TO 0.49), AND WAS IDENTICAL WITH THAT IN MOTHER'S SERUM IMMEDIATELY AFTER DELIVERY. /NICKEL SALTS/ [R30, 1834] ADE: *... RETAINED ESP BY LUNG, 38% OF ITS UPTAKE BEING PRESENT AFTER 72 HR, WHILE THE BRAIN, WITH 16.7%, ALSO RETAINED LARGER AMT THAN OTHER TISSUES. /NICKEL/ [R50] *INGESTED NICKEL IS EXCRETED PRIMARILY IN FECES, WHEREAS PARENTERALLY ADMIN NICKEL IS EXCRETED MOSTLY IN URINE. [R51, 288] *APPROX 50% OF INHALED NICKEL DUST IS DEPOSITED ON BRONCHIAL MUCOSA AND SWEPT UPWARD IN MUCUS TO BE SWALLOWED, ABOUT 25% IS EXHALED, AND REST IS DEPOSITED IN THE PULMONARY PARENCHYMA. ... IV INJECTED NICKEL SALTS DISAPPEAR QUICKLY FROM BLOOD, INDICATING WIDESPREAD DISTRIBUTION IN TISSUES. IN SPITE OF FIRMLY CHELATED NICKEL IN HUMAN TISSUES, RETENTION OF NEWLY ACQUIRED NICKEL IN TISSUES IS TRANSIENT AND POOR. ... UNDER CERTAIN PATHOLOGICAL CONDITIONS ... INCR AMT OF NICKEL ARE FOUND IN BLOOD ... EXCRETION OF INGESTED NICKEL CMPD IS MAINLY FECAL, WITH ONLY ABOUT 10% IN URINE; THIS ... IS NOTED ... IN DOGS AND HUMANS. EXCRETION OF ABSORBED NICKEL AND IV ADMIN NICKEL CMPD IS PRIMARILY URINARY (ABOUT 60%) AND REST FECAL, PRESUMABLY FROM BILE, WHICH INDICATES AN ENTEROHEPATIC TRANSFER. /NICKEL CMPD/ [R29, 291] *... OF INTEREST TO EMERGING ROLE OF WOMEN IN INDUSTRY, NICKEL CAN APPARENTLY CROSS ... PLACENTA, FOR NICKEL HAS BEEN FOUND IN HUMAN FETAL TISSUE AND IN CORD SERUM WHERE AVG CONCN FROM 12 NEWBORNS WAS 0.3 TO 12 UG/DL (RANGE 0.17 TO 0.49), AND WAS IDENTICAL WITH THAT IN MOTHER'S SERUM IMMEDIATELY AFTER DELIVERY. /NICKEL SALTS/ [R30, 1834] *ABSORPTION FROM BOWEL IS POOR ... /NICKEL SALTS/ [R31] *Therapeutic or normal level of nickel in human blood was determined: 0.011 mg%, 0.11 ug/ml. /Nickel/ [R71] *Nickel is only sparsely absorbed from the GI tract. It is transported in the plasma bound to serum albumin and multiple small organic ligands, amino acids, or polypeptides. /Soluble nickel cmpd/ [R72] *Nickel admin parenterally to animals is rapidly distributed to kidney, pituitary, lung, skin, adrenal, and ovary and testis. /Nickel salts/ [R72] *IN ANIMAL EXPT ABOUT 90% OF INGESTED NICKEL WAS RECOVERED IN FECES, MEANING THAT ABOUT 10% MIGHT HAVE BEEN ABSORBED. ... 10 PERSONS WITH AVG FECAL ELIMINATION OF ... 258 UG/DAY HAD A CORRESPONDING URINARY EXCRETION OF 2.6 UG/DAY. ... THESE DATA INDICATE THAT ABSORPTION IS LESS THAN 10% IN HUMAN ... /NICKEL SALTS/ [R33, p. V2 467] *WHEN SINGLE OR REPEATED IV INJECTIONS OF SOL NICKEL SALTS WERE GIVEN TO RABBITS, HIGHEST CONCN WAS FOUND IN KIDNEY. PITUITARY GLAND, LIVER AND LUNG ALSO CONTAINED RELATIVELY LARGE AMT OF NICKEL. IN RATS GIVEN INTRATRACHEAL INJECTIONS OF SOL NICKEL SALTS, CONCN PATTERN WAS SIMILAR, WITH EXCEPTION THAT PITUITARY GLAND WAS NOT AS RICH ... /SOL NICKEL SALTS/ [R33, p. V2 468] *Following parenteral admin of nickel salts in experimental animals, nickel is cleared rapidly from plasma and excreted predominantly in the urine. ... Only a few percent of an injected dose is excreted via the GI tract in the rat. Experiments on rabbits indicate that biliary excretion is the principal excretion mechanism for the GI tract. ... In human beings nickel is excreted via urine, saliva and sweat ... /Nickel salts/ [R33, p. V2 469] *BOTH SERUM NICKEL AND URINARY NICKEL SEEM TO BE GOOD INDICATORS OF ... EXPOSURE. ... PERSONS LIVING IN VICINITY OF LARGE NICKEL MINE HAD AVG SERUM CONCN OF 4.6 UG/L AND EXCRETED 7.9 UG/DAY. THE CORRESPONDING VALUES IN NON-EXPOSED POPULATION WERE 2.6 UG/L AND 2.6 UG/L. IN WORKERS IN NICKEL REFINERY A SIGNIFICANT CORRELATION WAS FOUND BETWEEN LEVELS OF NICKEL IN URINE AND PLASMA. IN 3 GROUPS OF WORKERS WITH AVG PLASMA LEVELS OF 6.4, 7.2 and 11.9 UG/L, RESPECTIVELY, THE CORRESPONDING MEAN URINARY CONCN OF NICKEL WERE 44.6, 65.0 and 129.2 UG/L. [R33, p. V2 470] *ABSORPTION OF NICKEL IS SMALL FROM ORDINARY DIETS. EXCRETION IS PRIMARILY THROUGH FECES; HOWEVER SIGNIFICANT AMT CAN BE LOST IN SWEAT. /NICKEL/ [R73] *NICKEL IS PRESENT IN LUNG, LIVER, KIDNEY, AND INTESTINE OF MOST STILLBORN INFANTS. CONCN IN LUNG INCR WITH AGE. IN RATS BONES ACCUMULATE A MAJOR PORTION OF INCR INTAKE. ... NICKEL HAS BEEN FOUND IN BILE. /NICKEL/ [R22] *Tissue distribution of nickel (II) after parenteral administration generally leads to highest accumulation in kidneys, endocrine glands, lung, and liver, with only slight uptake into bone, and little retention in soft or mineral tissue. /Divalent nickel salts/ [R74] *Nickel concn were determined in roots and green parts of Cannabis sativa, Phleum pratense, Lyninus luteus, Zea mays, Cucumis sativus, and Avena sativa at Ni concn in soil of 2.5-50 ppm. Avena sativa and Lyninus luteus were most sensitive (> or = 5 ppm) and Cannabis sativa and Zea mays were least sensitive to Ni. Ni concn in roots are usually several fold higher than in green parts. Monocotyledons accumulated less Ni than dicotyledons. Zea mays had the highest ratio of root to leaf concns of Ni. Apparently, corn has a very efficient barrier against heavy metals between root and leaf. /Soluble nickel cmpd/ [R75] *AFTER ACUTE OR CHRONIC EXPOSURE OF RATS ... BY INHALATION, INCR IN NICKEL OCCUR PREDOMINANTLY IN MICROSOMAL AND SUPERNATANT FRACTIONS OF LUNG AND LIVER. AFTER CHRONIC EXPOSURE, INCR AMT OF NI ARE ALSO OBSERVED IN NUCLEAR AND MITOCHONDRIAL FRACTION OF THE LUNG. /NICKEL AND NICKEL CMPD/ [R76] *SIGNIFICANT UPTAKE AND ACCUM OCCURRED IN 20, 40, and 80 MG NICKEL/L IN 96 HR EXPT. MUSSELS SECRETED BYSSAL THREADS IN CONCN OF 20 MG NI/L, BUT NOT IN HIGHER CONCN. /NICKEL AND NICKEL CMPD/ [R77] *Metallic nickel oxide and nonsoluable salts are only very slowly (within tens of years) cleared from the mucous membranes of the respiratory tract. Soluable nickel salts are rapidly cleared and excreted in the urine. /Nickel/ [R45, 145] *An important factor for retention in the lung is the solubility of the nickel compounds. Insoluble forms, such as nickel oxide and metallic nickel, seem to be retained in the lung for a longer time, whereas the more soluble nickel salts are absorbed. They are also solubilized in the fluids and mucus cleared from the lung by the mucociliary mechanisms into the alimentary tract. [R78] *Nickel is poorly absorbed from ordinary diets and is eliminated mainly in the feces. This has been shown in a nickel balance study on dogs ... in which the nickel intake in the food was equal to the output in the urine and feces. The results also indicated than an avg of 90% ... of the amt of nickel ingested ... was eliminated in the feces. In rats, even at very high intakes of nickel (approx 14.5 mg) from different sources, over periods of 4, 8, 12, and 16 days, nickel was absorbed poorly (0.15 mg, i.e., 1%) and was eliminated mainly in the feces (13.9 mg = 96%). Levels of retained nickel avg 0.5 mg (range: 0.29-0.8 mg), i.e., 3.5% ... . /Nickel/ [R79] BHL: *For the first 50 hr after exposure, the biological half-life of nickel in rat plasma was 6.3 hr, and in rabbit plasma it was 7.5 hr. /Nickel salts/ [R33, p. V2 469] *On the basis of nickel values in air, plasma and urine in four nickel platers during one working week ... /the investigators/, assuming a one-compartment model, computed the biological half-life for nickel in plasma to range from 20 to 34 hr and in urine from 17 to 39 hr. /Nickel/ [R33, p. V2 469] *The kinetics of sol Ni2+ cmpd admin to rats and rabbits by parenteral routes confirm to a two-compartment model; the biological half-life for injected (63)Ni2+ in rats is approx 10 hr. /Nickel(2+) sol compounds/ [R80, 458] ACTN: *... NICKEL SALTS CAUSE INJURY OR DESTRUCTION OF ALPHA CELLS OF PANCREAS, and ... TO A LESS EXTENT, DAMAGE TO BETA CELLS. /NICKEL SALTS/ [R49] *... HAS INDIRECT EFFECTS ON MANY BODY ENZYME SYSTEMS, AND ON PIGMENTATION. /NICKEL/ [R81] *DIVALENT NICKEL IONS CAN PENETRATE SKIN AT SWEAT-DUCT AND HAIR FOLLICLE OSTIA, AND BIND WITH KERATIN. CONTACT DERMATITIS THUS RESULTS FROM PERMEABILITY OF ... DERMIS AND EPIDERMIS TO NICKEL. /NICKEL SALTS/ [R29, 292] *LOCALIZATION OF INJECTED NICKEL SALTS IN PITUITARY GLAND AND SUBSEQUENT DECREASED SERUM LEVEL OF PROLACTIN SUGGEST THAT DIVALENT NICKEL EXERTS A DIRECT SPECIFIC INHIBITORY ACTION ON PROLACTIN-SECRETING CELLS IN ANTERIOR PITUITARY. /NICKEL SALTS/ [R29, 295] *... NICKEL CMPD FORM COMPLEXES WITH SERUM PROTEINS OR ULTRAFILTRABLE MOLECULES ... THESE ... COMPLEXES ADSORB TO SURFACE OF CELL AND ENTER ... BY ENDOCYTOSIS. WITHIN CELL, LYSOSOMAL PROTEINASES HYDROLYZE CARRIER PROTEIN TO RELEASE ELECTROPHILIC METAL ION. NICKEL IONS THEN BIND WITH NUCLEIC ACIDS AND ... CELLULAR CONSTITUENTS. [R29, 296] *... /NICKEL/ CAN ACTIVATE PANCREATIC RIBONUCLEASE AND DESOXYRIBONUCLEASE I AND CAN REPLACE ZINC IN CARBOXYPEPTIDASE AND CARBONIC ANHYDRASE ... INHIBITION OF RNA POLYMERASE AND ATPASE ARE OF PARTICULAR SIGNIFICANCE ... /NICKEL/ [R30, 1836] *The intracellular distribution and binding of nickel is not well understood. Ultrafiltrable ligands seem to be of major importance in transport in serum and bile and urinary excretion as well as intracellular binding. The ligands are not well characterized, but ... /the investigator/ suggests that cysteine, histidine, and aspartic acid form nickel complexes either singly or as nickel-ligand species. In vivo binding with metallothionein has been demonstrated, but nickel at best induces metallothionein synthesis in liver or kidney only slightly. /Soluble nickel cmpd/ [R72] *The mechanisms of nickel toxicity are not well understood, but studies ... suggest that acute Ni2+ toxicity in rats is assoc with lipid peroxidation in target organs. The chemical reactions whereby Ni2+ induces lipid peroxidation in vivo have not yet been explained, however, ... proposed the following four possible mechanisms: i.) An indirect mechanism owing to Ni2+ displacement of iron and copper from intracellular binding sites; ii) An indirect mechanism, by which Ni2+ inhibits cellular defences against peroxidative damage, mediated by catalase, superoxide dismutase, glutathione peroxidase, aldehyde dehydrogenase, or other enzymes that protect against free-radical injury or that metabolize products of lipid peroxidation; iii) Generation of oxygen-free radicals by the redox couple ... iv) Ni2+ may accelerate the degradation of lipid hydroperoxides to form lipid-oxygen radicals, propagating autocatalytic peroxidation of polyenoic fatty acids /Nickel/ [R82] *... In the presence of certain peptides, the Ni3+/Ni2+ redox couple can participate in dioxygen radical reactions in vitro. As chemical promoters of cancer appear to have the capacity to stimulate phagocytic cells to produce dioxygen radicals, which may damage DNA, proteins and lipids, and as metal ions catalyze processes involving molecular oxygen, this observed effect of nickel may have implications for nickel carcinogenesis. /Nickel ions/ [R83] *The activity of the DNA repair protein O6-alkylguanine-DNA-alkyltransferase was found to be strongly inhibited by a number of metal ions. However, other metals or metallic compounds which are known to be carcinogenic (such as compounds containing arsenic, lead, nickel, or chromium) did not interfere with DNA repair by this protein. [R84] *The parent wild strain Neurospora crassa Em 529a and 3 nickel(2) resistant Neurospora crassa mutants excreted pyruvic acid into the culture medium in nickel(2) ... toxicities. The excretion is progressive with growth inhibition and is abolished by magnanese(2) in all strains and by iron(3) partially in the Em strain but not in Neurospora crassa NiR1. Pyruvate, citric acid, and malic acid supplementation reverse growth inhibition caused by excess nickel (2), but with concomitant suppression of nickel(2) accumulation. Apparently, one of the features of nickel(2) toxicity in Neurospora crassa is a derangement in carbohydrate metabolism at step(s) beyond pyruvate. [R85] *In vitro studies have shown nickel to be an activator of several enzymes. Nickel stabilizes RNA and DNA against thermal denaturation and may have a role in membrane structure or metabolism. [R86] *Nickel readily crosses the cell membrane via Ca2+ channels and competes with Ca2+ for specific receptors. [R87] INTC: *... SOL NICKEL SALTS IN DRINKING WATER PRODUCED ADVERSE EFFECTS ON RAT REPRODUCTION WHEN CHROMIUM WAS ADDED TO DIET IN TRACE AMT. /NICKEL SALTS/ [R30, 1829] *An interaction of nickel with copper and zinc is suspected since anemia-induced nickel deficiency is only partially corrected with nickel supplementation in rats receiving low dietary copper and zinc. /Nickel/ [R72] *Certain oral medications (eg, disulfiram (tetraethylthiuram disulfide) used for aversion therapy of alcoholism) can cause incr nickel concn in blood and urine by enhancing its gastrointestinal uptake. /Nickel/ [R80, 457] *Co-administration of high doses of vitamin C to ... weanling rats offset the effects of oral nickel exposure on growth rate, and the activity of certain enzymes, such as liver and kidney succinic dehydrogenase and liver glutamic-oxaloacetic transaminase. /Soluble nickel cmpd/ [R88] *Divalent nickel appears to antagonize the digoxin induced arrhythmias in the rat, rabbit, and guinea pig in both intact, as well as, isolated hearts, ... by either binding competitively with calcium ion at cell membranes or provoking an increase in malic and oxaloacetic acid activity. /Soluble nickel cmpd/ [R89] *Chlorine-nickel (Cl-Ni) temperature interactions were studied in rainbow trout (Salmo gairdneri). Mortality in chlorine-nickel test groups was significantly greater than predicted by an additive interaction. chlorine-nickel treatment groups with high chlorine concn, regardless of the level of Ni, had higher mortality rates than chlorine-nickel treatment groups with low chlorine concn. Chlorine-nickel treatment groups with low chlorine concn, regardless of Ni concn, showed greater percentage mortality than treatment groups with either Ni or chlorine alone. When chlorine and Ni were combined, the chlorine concn was the key factor in determining mortality, even at sublethal levels of chlorine for the concn tested. Temperature did not influence toxicity as strongly as either chlorine or Ni concn. The presence of 0.018 ppm total residual chlorine significantly increased Ni accumulation in tissues from fish exposed to chlorine and Ni, when compared with tissue samples from fish under similar exposure conditions in the absence of chlorine. The increased Ni concn may be attributed to an increase in the permeability of the gill to Ni during chlorine exposures. /Soluble nickel cmpd/ [R90] *Suggested that iron might affect nickel absorption. Using isolated intestinal segments of rats in an in vitro test system, they found that nickel ions had their own transport system located in the proximal part of the intestine, thus making it likely that iron nutrition could affect nickel absorption ... Found that the transfer of nickel from the mucosal to the serosal side was elevated in iron-deficient intestinal segments. [R91] PHCY: ------------------PHARMACOLOGY CATEGORY (USE CODE ZPHC)------------------ BION: *Nickel deficiency has been reported in ... birds; deficiency is unlikely in humans taking a conventional diet; the margin between required and toxic concn is wide. /Nickel/ [R92] *Pathological signs of nickel deficiency have been produced in chickens, rats and swine. Retarded growth, anemia and decr enzyme activities are among the signs seen in rat. /Nickel/ [R33, p. V2 471] *In vitro studies have shown nickel to be an activator of several enzymes. Nickel stabilizes RNA and DNA against thermal denaturation and may have a role in membrane structure or metabolism. /Nickel/ [R86] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Nickel's use in the production of steel and various alloys, in electroplating, nickel-cadmium batteries, fuel cells, electronic circuitry and miscellaneous other applications, may result in its release to the environment through various waste streams. Approximately 0.009% of the earth's crust is nickel. Estimated worldwide atmospheric emissions of nickel from natural sources include (% of total emissions) windblown dust: 9.3%; volcanoes: 4.9% and vegetation: 1.6%. Nickel compounds are expected to exist in the particulate phase in the ambient atmosphere. An exception is nickel carbonyl which is expected to exist entirely in the vapor phase. Particulate-phase nickel will be removed from the atmosphere by wet and dry deposition. If released to soil, soluble nickel compounds such as nickel chlorides and nickel nitrate, will tend to migrate more than the insoluble compounds such as nickel oxides and nickel sulfides. Volatilization from moist and dry soil surfaces is not expected to be an important fate process based upon the low vapor pressures for most nickel compounds. An exception is nickel carbonyl which is expected to volatilize from moist and dry soil surfaces. If released into water, nickel compounds are expected to adsorb to suspended solids and sediment in water. Due to their low vapor pressure and ionic form, volatilization from water surfaces is not expected to be an important fate process for most nickel compounds. An exception is nickel carbonyl which is expected to volatilize from water surfaces. BCFs ranging from 40-100 suggest that the potential for bioconcentration in aquatic organisms is low to moderate. Occupational exposure to nickel and nickel compounds may occur through inhalation of dust particles and fumes and dermal contact with this compound at workplaces where nickel is produced or used. Cigarette smoking increases exposure to nickel. The general population may be exposed to nickel and nickel compounds via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and other products containing nickel and nickel compounds. (SRC) NATS: *Found in many ores as sulfides, arsenides, antimonides and oxides or silicates; chief sources incl chalcopyrite ... pyrrhotite, pentlandite ((Fe,Ni)S8) and garnierite (3(Mg,Ni)O.-2SiO2.2H2O); other ores incl niccolite ... and millerite (NiS). [R93] *NICKEL ... IS IN SEAWATER AT 2-5 PPB. ... NICKEL OCCURS IN VERY MINOR QUANTITIES IN ALL TYPES OF COAL ... [R29, 289] *NICKEL CONSTITUTES 0.03% OF THE PARTICULATE MATTER SUSPENDED IN ATMOSPHERE. [R94] *Natural sources of airborne particles that contain nickel include soil, sea, volcanoes, forest fires, and vegetation. /Nickel and nickel cmpd/ [R95] *Average concn of nickel in the earth's crust is 60-90 mg/kg. /Nickel and nickel cmpd/ [R96] *Approximately 0.009% of the earth's crust is nickel(1). The largest economic reserves are located in Canada, Cuba and Russia(2). An estimated 8X10+08 tons of nickel are present in seabed nodules, which contain approximately 1% nickel(2). As of 1992, approximately 50% of nickel comes from sulfide deposits mined in Canada, Russia and Finland(2). The other economically-significant source of nickel is found in lateritic ores, in the form of oxides and silicates, which are found in regions that are, or which were once tropical or subtropical for extended periods(2). Ni(II) is the most common oxidation state(3). Estimated worldwide atmospheric emissions of nickel from natural sources include (% of total emissions) windblown dust: 9.3%; volcanoes: 4.9% and vegetation: 1.6%(1). [R97] ARTS: *Cigarette smoking can contribute significantly to man's daily nickel intake by inhalation and nickel from this source probably exceeds the amount absorbed by breathing ambient air. /Nickel and cmpd/ [R98] *Regular gasoline contains 0.001-0.07 mg/kg Ni; Premium gasoline contains 0.003-1.5 mg/kg Ni; Low-lead contains 0.03-2.0 mg/kg Ni. /Nickel and cmpd/ [R99] *Crude oil (Canadian): 0.4-35 mg/kg of Ni; Crude oil (Venezuelan): 2-45 mg/kg of Ni; Heavy fuel oil (Canadian): 3-72 mg/kg of Ni; Light fuel oil: < 0.05-0.09 mg/kg of Ni; Diesel oil: < 0.05-0.06 mg/kg of Ni. /Nickel and cmpd/ [R100] *NICKEL SALTS ARE CONSIDERED AN INDUSTRIAL HEALTH HAZARD BECAUSE MANY NICKEL COMPOUNDS ARE RELEASED INTO THE ATMOSPHERE DURING MINING, SMELTING, AND REFINING OPERATIONS. /NICKEL SALTS/ [R29, 290] *The extraction, processing and use of nickel compounds may result in their release to the environment through various waste streams(SRC). There are over 237,000 nickel compounds(1). Estimated worldwide atmospheric emissions of nickel from artificial sources include (% of total emissions) residual and fuel oil combustion: 52%, nickel mining and refining: 14%; incineration: 10%; steel production: 2.3%; gasoline and diesel fuel combustion: 1.8%; nickel alloy production: 1.4%; coal combustion: 1.3%(1). [R101] FATE: *AQUATIC FATE: The mobility of nickel in the aquatic environment is controlled largely by the capability of various sorbents to scavenge it from solution. Although data are limited, it appears that in pristine environments, hydrous oxides of iron and manganese control nickel's mobility via co-precipitation and sorption. In polluted environments, the more prevalent organic material will keep nickel soluble. In reducing environments, insoluble nickel sulfide may be formed. Although nickel is bioaccumulated, the concn factors are such as to suggest that partitioning into the biota is not a dominant fate process. Nickel is one of the most mobile of the heavy metals in the aquatic environment. /Nickel and nickel cmpd/ [R102, p. 15-6] *ATMOSPHERIC FATE: The atmosphere is a major conduit for nickel as particulate matter. Contributions to atmospheric loading come from both natural sources and anthropogenic activity, with input from both stationary and mobile sources. Various dry and wet precipitation processes remove particulate matter as wash out or fallout from the atmosphere with transfer to soils and waters. Soil borne nickel may enter waters by surface runoff or by percolation into ground water. Once nickel is in surface and ground water systems, physical and chemical interactions (complexation, precipitation/dissolution, adsorption/desorption, and oxidation/reduction) occur that will determine its fate and that of its constituents. /Nickel and cmpd/ [R103] *TERRESTRIAL FATE: In general, the mobility of nickel compounds that are soluble in water, such as nickel chlorides and nickel nitrate, will tend to be greater than the mobility of insoluble compounds such as nickel oxides and nickel sulfides(1,SRC). At pH values less than 6.5 the soluble nickel compounds predominate(2), increasing the mobility of nickel. Organic substances and sulphate ion can increase the mobility of nickel through the formation of complexes(3). In polluted environments, the presence of EDTA, a common substitute for polyphosphates, will tend to increase the mobility of nickel and nickel compounds through the formation of complexes(4). The majority of nickel compounds are not expected to volatilize from moist or dry soil surfaces, based on their low vapor pressures(5). One notable exception is nickel carbonyl which is expected to volatilize from moist and dry soil surfaces based on its estimated Henry's Law constant(SRC) and vapor pressure(5). However nickel carbonyl is unstable under normal atmospheric conditions(2). [R104] *AQUATIC FATE: Nickel compounds that are soluble in water such as nickel chlorides and nickel nitrate, are generally more mobile than insoluble nickel compounds such as nickel oxides and nickel sulfides(SRC). At pH levels less than 6.5 the soluble compounds predominate(1). Approximately half of the nickel in river water is in the ionic form while the other half forms complexes with organic material(1). In polluted environments the presence of EDTA, a common substitute for polyphosphates, will tend to increase the mobility of nickel and nickel compounds through the formation of complexes(2). The majority of nickel compounds are not expected to volatilize from water surfaces based on their low vapor pressures(3). One notable exception is nickel carbonyl which is expected to volatilize from water surfaces based on its estimated Henry's Law constant(SRC). However, nickel carbonyl is unstable under normal atmospheric conditions(1). If released into water, nickel compounds are expected to adsorb to sediment and suspended solids in water(4,5). [R105] *ATMOSPHERIC FATE: Nickel compounds, which generally have low vapor pressures(1), are expected to exist in the particulate phase in the ambient atmosphere. One exception is nickel carbonyl which is expected to exist entirely in the vapor phase(1). However, nickel carbonyl is unstable under normal atmospheric conditions(2). Nickel compounds in the particulate-phase may be removed from the air by wet and dry deposition(SRC). [R106] BIOC: *Six strains of algae and one Euglena sp were tested for their ability to bioaccumulate (63)Ni. The cyanobacteria tested were more sensitive to Ni toxicity than the green algae or the Euglena sp. The concentration factor for Ni was determined under a variety of conditions and in the range 0-3.0x10+3. The effect of environmental variables on Ni uptake was examined, and a striking pH effect for bioaccumulation was observed, with most of the algae strains accumulating Ni optimally at approximate pH= 8.0. /Nickel and nickel cmpd/ [R107] *Fish can accumulate Ni from food and water. Levels up to 13 mg/kg were measured in pike and pickerel. /Nickel and nickel cmpd/ [R69] *Although aquatic organisms may accumulate Ni from their surroundings, there is little evidence for significant biomagnification of Ni levels along food chains. /Nickel and nickel cmpd/ [R69] *Aquatic plants can extract nickel from water and concentrate it to ... (10+3 to 10+4 mg/kg dry weight). /Nickel and nickel cmpd/ [R69] *... No ... nickel bioaccumulation in voles fed sludge-fertilized soybeans containing 30 ppm nickel ... /Nickel and nickel cmpd/ [R59] *Water-soluble nickel compounds, such as the chloride and sulfate compounds, are poorly absorbed by most living organisms(1). The uptake of nickel by plants depends upon the extractable nickel content of a soil which is a function of physical, chemical and biological factors of the soil environment(1). High nickel concns have been found in jack beans and soybeans, Seberetia acuminata (tree native to New Caledonia), oatmeal, wheat bran, dried beans, and soya products(1). Reported BCFs for nickel range from 100 for fresh water plants, 550-2000 for seaweeds, < 20-8000 for marine phytopklankton and 2,000-40,000 for algae(2) suggests the potential for bioconcentration ranges from moderate to very high(SRC). [R108] *Higher nickel concns have been observed in shellfish and crustacea than in fish(1). Reported BCFs for nickel range from 40 for fresh water fish, 50 for skipjack tuna and 100 for marine fish(2). The bioconcentration of nickel in a mussel (L. marginalis) and fish (C. carpio) was found to be concentration-dependent(3). Higher concns of nickel in fish that are bottom feeders has been observed(4). [R109] KOC: *In general, water-soluble nickel compounds, such as nickel chlorides and nickel nitrate, may travel more easily through soil than the insoluble nickel compounds such as nickel oxides and nickel sulfides(1,SRC). Adsorption experiments conducted on a mixture of low concns of nickel, cadmium, cobalt and zinc, in soils with varying pH's, clay content and organic carbon content, indicated nickel was more mobile than cadmium, less mobile than cobalt and had approximately the same mobility as zinc(2). The mobility of nickel in acid soils relative to other heavy metals was reported to be as follows (in decreasing mobility): cadmium > nickel > zinc > manganese > copper > lead > mercury(2). Another study found the following relationship among the mobility, based on measured distribution coefficients, for heavy metals in nine soils at two pH levels (increasing mobility); pH = 4.5: lead, copper, zinc, nickel, cadmium/chromium; pH = 6.5: lead, copper/zinc, cadmium, nickel, chromium(3). Organic substances and sulphate can increase the mobility of nickel through the formation of complexes(2). Conversely, acid-volatile sulfide can decrease the mobility of nickel through the formation of insoluble sulfide complexes(4). The presence of dissolved organic carbon has been shown to increase the mobility of nickel in groundwater environments(5). Very high mobility for nickel was observed in 5 sandy sediments with low organic carbon content(4). [R110] VWS: *No evidence was found to suggest that volatilization of nickel compounds occurs from the aquatic environment. [R102, p. 15-2] *In general, nickel compounds are not expected to volatilize from water surfaces based on their low vapor pressures(1). One notable exception is nickel carbonyl(1) which is expected to volatilize based on an estimated Henry's Law constant. However, nickel carbonyl is unstable under normal atmospheric conditions, persisting forapproximately 60 seconds at 23 degress C(2). [R111] WATC: *Municipal tap water Hartford, Connecticut 1.1 ug/l nickel; tap water Sudbury, Ontario 200 ug/l. /Nickel and soluble cmpd/ [R112] *GROUNDWATER: Nickel was detected in groundwater samples collected from an aquifer contaminated by leachate from a municipal landfill near North Bay, Ontario at 0.060-0.10 mg/l(1). [R113] *DRINKING WATER: Typical concns of nickel found in drinking water are less than 20 ug/l although higher concns may be found due to the presence of nickel in pipe materials and fixtures(1). The range and mean (std error) of 59 potable water samples collected from 32 primary schools in Riyadh, Saudi Arabia was 0.42 - 129.09 and 11.79 (21.70)(2). [R114] *SURFACE WATER: Typical concns of nickel in seawater range from 0.1-0.5 ug/l, mainly as Ni 2+ and as chloro- and carbonato-complexes; concns increase with depth(1). [R115] *SURFACE WATER: Nickel concns in fresh water typically avg 15-20 ug/l(1). Mean nickel concns measured in water samples collected on 25 Nov 1986 in 11 locations from a lake in Illinois that received industrial and municipal wastewater discharges and agricultural runoff range from below detection (detection limit = 0.007 mg/l) to 0.010 mg/l(2). Dissolved nickel concn measured in samples collected between 1980-84 from a polluted estuary of the UK (Mersey) ranged from 1 to 16 ug/l(3). Nickel concns in suspended solids collected from a heavily polluted harbor of Lake Ontario between April and September 1986 ranged from 12-102 ug/g(4). [R116] *RAIN/SNOW/FOG: Nickel concn in arctic snow varies from 20-300 uk/kg(1). Mean nickel concns measured in precipitation collected from southwest Ontario, Sudbury Ontario (mining/smelting area), Delaware, northwest Ontario and Bermuda were 0.9, 0.5-17, 0.79, 0.7 and 0.17 ug/l respectively; the latter two sites were considered remote areas(2). [R117] EFFL: *Nickel (unfiltered, total) was detected in 103 of 322 samples of raw wastewater samples (20 of 37 plants) collected from 37 Ontario municipal wastewater treatment plants between January 1987 and July 1987 at concns ranging from 20-1469.9 ug/l and a geometric mean concn of 38.8; the detection limit was 10 ug/l(1). In the same survey, nickel (unfiltered, total) was detected in 10 of 48 samples of primary effluent(4 of 7 plants) at concns ranging from below the detection limit (10 ug/l) to 140 ug/l at a geometric mean concn of 8.7 ug/l, and in secondary effluent in 171 of 267 samples (24 of 28 plants) ranging from below the detection limit (10 ug/l) to 900 ug/l at a geometric mean concn of 22.1 ug/l(1). [R118] SEDS: *Commercial fertilizers add little Ni to soil, but sewage-derived fertilizer from industrial areas may contain 1000 mg/kg (dry weight) or more. /Nickel and nickel cmpd/ [R69] *Aerial fallout from a nickel smelter at Port Colborne, Ontario, Canada, resulted in accumulation of nickel ranging from 600 to 6455 mg/kg in the organic soil of a farm. /Nickel and nickel cmpd/ [R119] *Uncontaminated agricultural soils in Canada generally contain less than 30 mg Ni/kg. Soils derived from serpentine rock may contain up to 25,000 mg Ni/kg, although a more typical value is 1000 mg/kg. Accumulations of Ni in soil exceeding 1000 mg/kg occur within 1-2 km of large Nickel smelters. /Nickel and nickel cmpd/ [R120] *The use of irrigation water that contains the upper limit of the acceptable concn of nickel as recommended by NAS and NAE (1972) is equivalent to an accumulation of 100 ppm of Ni in the upper 15 cm of soil. ... the phytotoxic level of Ni in soil ranges from 50 to 200 ppm. /Nickel and nickel cmpd/ [R121, 286] *SOIL: Nickel was detected in soil samples collected from four areas of the Chukotka arctic region at mean concns (std errors; number of observations) ranging from 2.3 (0.3; 12) to 209 (42; 36) ppm(1). Typical concns of nickel in US soils range from < 5-150 mg/kg (dry weight)(2). Nickel was detected in soil samples collected from three areas in Sudbury, Ontario that were contaminated by nickel and copper mining and smelting operations at concns ranging from 23-2,149 mg/kg with mean concns ranging from 210-580 mg/kg (dry weight)(3). Nickel was detected in soil samples collected from four sites in the US, adjacent to heavily traveled roadways, at concns ranging from 3-47 mg/kg(4). [R122] *SEDIMENT: Mean nickel concns measured in sediment samples collected on 4 December 1986 from 11 locations in an Illinois lake that received industrial and municipal wastewater discharges and agricultural runoff ranged from below detection (detection limit = 6.80 mg/kg) to 28.3 mg/kg (dry weight)(1). The mean nickel concn (std error) measured in sediment samples collected between 11-16 February 1990 from 13 locations in an industrialized harbor of Ireland ranged from 11.50 mg/kg (0.75) to 15.77 mg/kg (0.47)(2). Nickel concns in samples of suspended solids collected from a heavily polluted harbor of Lake Ontario between April and September 1986 ranged from 12-102 ug/g(3). Nickel was detected in non-polluted sediments of the Great Lakes, Puget Sound and Yaquina Bay at < 20, 13 and 14.5 mg/kg, respectively(4). Nickel was detected in three sediment samples collected from each of 10 lakes located at various distances from the Sudbury copper and smelting area of Ontario as follows (distance(km) - mean(ug/g dry weight) - std error): 10-4490-230, 10-4390-115, 10-2500-150, 30-444-25, 35-495-75, 35-1080-25, 35-205-25, 40-255-30, 40-300-25, 180-17.5-5.3(5). [R123] ATMC: *Typical average levels of airborne nickel are: 0.00001-0.003 ug/cu m in remote areas; 0.003-0.03 ug/cu m in urban areas having no metallurgical industry; 0.07-0.77 ug/cu m in nickel processing areas. /Nickel and cmpd/ [R124] *URBAN/SUBURBAN: Avg nickel concns in non-urban areas is 6 ng/cu m; in urban areas the avg nickel concn is 17 ng/cu m in the summer and 25 ng/cu m in the winter(1). [R115] *RURAL/REMOTE: Avg annual nickel concns of arctic air samples collected between 1979 and 1984 from three locations in Canada ranged from 0.14-0.45 ng/cu m(1). [R125] *SOURCE DOMINATED: Concns of nickel as high as 120-170 ng/cu m have been found in some urban areas(1). Avg nickel concn was 1.2 ug/cu m near a nickel refinery in West Virginia(1). [R115] FOOD: *The nickel content, in ppm wet weight, was determined for various classes of food in the US diet. Grains/grain products: wheat flour, all purpose (0.54); corn, fresh frozen (0.70); rice, polished American (0.47). Fruits: apples (0.08); bananas (0.34); pears (0.20). Vegetables: potatoes, raw (0.56); tomatoes, fresh (0.02); celery, fresh (0.37). Meats: pork, chops (0.02); lamb, chops (not detected); beef, round (not detected). /Nickel and nickel cmpd/ [R126] *Nickel content was determined for the edible parts of crops grown on the soil of a farm located one kilometer from a nickel smelter and in direct line with the prevailing winds. Nickel (mg/kg dry weight) ranged from 80 to 280 in beet roots, 76 to 400 in cabbage heads, 15 to 395 in celery tops, 22 to 130 in lettuce tops, and 24 to 140 in radish roots. /Nickel and nickel cmpd/ [R119] *A 2,300 calorie diet with 100 g fat, 100 g protein, and 250 g carbohydrate could have a nickel content varying from 3-10 to 700-900 ug. /Nickel and nickel cmpd/ [R127] *Concentrations of nickel in various foods include: up to 6.5 ug/g in cereal foodstuffs, up to 2.6 ug/g in vegetables, and up to 7.6 ug/g in tea. /Nickel and nickel cmpd/ [R128] *The avg concn (mg/kg) of nickel in various foods were reported as follows: wheat - 0.19-0.34, rye - 0.12, potatoes - 0.05-0.26, fruit - 0.08, cocoa - 15.1, tea - 5.25, and coffee - 0.77(1); oat, precooked - 2.35, rice, American, polished - 0.47, spinach - 2.4-4.6, peas - 2.25, clams, fresh - 0.58, shrimp, fresh-frozen - 0.03; haddock - 0.05, pork chop - 0.02, whole egg - 0.03, orange pekoe tea - 7.6, beer - 0.01, salt - 0.35, sugar - 0.03 and cinnamon - 0.74(2). [R129] *Nickel concns measured in vegetables, fruits and herbs grown in a remote location of the UK were reported as follows (all ug/g, fresh weight): vegetables - ranged from 0.01-0.14, maximum concns detected in carrots and onions; fruits - 0.008 ug/g; cereals - 0.02-0.04; herbs - 0.04-0.08(1). Nickel concns measured in vegetables, fruits and herbs grown approximately 30 m from a roadway (London Orbital Motorway) with daily traffic volume of 120,000 vehicles/day were reported as follows(all ug/g, fresh weight): vegetables - < detection-0.0.09; strawberry - 0.003 ug/g; herbs - 0.06-0.105(1). Avg concns of nickel found in Japanese shellfish ranged from 0.5-2.2 mg/kg; 1-13 ppb typically is found in bovine meat(2). [R130] PFAC: PLANT CONCENTRATIONS: *Concentrations of ... Ni ... in leaf and root tissue of Typha latifolia grown in a series of solution cultures containing 10-150 ug g/l Ni ... were correlated with concentrations of the same metals in the growth medium. In contrast to plants growing in contaminated wetlands near Sudbury, Ontario (Canada), plants grown in solution culture were unable to minimize entry of ... Ni into leaf tissue. Leaves of Typha latifolia accumulated 467 + or - 50 ug g/l Ni and did not show toxic symptoms ... Thus, T latifolia would appear to have internal ... Ni tolerance mechanisms. /Nickel and nickel cmpd/ [R131] *Concn of nickel in plant leaves: range: 0.1-1.0 ppm dry wt; toxic: > 50-200 ppm dry wt (From table) /Nickel and nickel cmpd/ [R121, 312] *In grains, fresh-weight values ranged from 0-6.45 ug/g, in vegetables and fruits from 0-2.59 ug/g. /Nickel and nickel cmpd/ [R33, p. V2 465] *Nickel has been found in plants grown in lateritic soils at concns up to 100 ppm(1). Nickel concns measured in 26 mushroom species collected from remote areas of Latin American forests between 1967-81 ranged from 1.36 - 38.10 ppm with a mean of 7.95 ppm (dry weight)(2). [R132] FISH/SEAFOOD CONCENTRATIONS: */Daily intake/ in seafood /ranges from/ 0.3-1.7 ug/g. /Nickel and nickel cmpd/ [R33, p. V2 465] *Up to 1.7 ug/g of nickel found in fish. /Nickel and nickel cmpd/ [R133] *The nickel content, in ppm wet weight, was determined for seafood in US diet. Oysters, fresh (1.50); Clams, fresh (0.58); shrimp (0.03); Crabmeat, canned (0.03); Swordfish, frozen (0.02); Salmon (1.70). [R134] *Mean nickel concns in samples of 6 species of fish collected between 24 September and 4 November 1996 from an Illinois lake that received industrial and municipal wastewater discharges and agricultural runoff, ranged from non-detectable to approximately 1.70 mg/kg (n=26-27 for each species)(1). The mean nickel concn (std error) measured in mussels (Mytilus edulis L.) collected between 11-16 February 1990 from 13 locations in an industrialized harbor of Ireland ranged from 6.17 mg/kg (0.93) to 11.67 mg/kg (0.44)(2). The mean nickel concn measured in samples of American oysters (Crassostrea virginica) collected between August 1984 and June 1985 from the San Andres Lagoon in Mexico, which is reportedly not impacted by industrial pollution, ranged from 2.0-4.5 ppm; the maximum concn found was 12.0 ppm(3). Nickel was detected in muscle tissue of lake trout and grayling collected from four arctic lakes in Alaska at geometric mean concns ranging from 0.07-0.45 and 0.12-0.33 ug/g (dry weight), respectively(4). [R135] OEVC: *In cigarettes ... an average nickel content of 2.2 and 2.3 ug/cigarette /was found/. /Nickel and nickel cmpd/ [R33, p. V2 465] RTEX: *HIGHEST RISK OF MORTALITY FROM CANCER OF RESP TRACT IS FOUND AMONG NICKEL MINE WORKERS INVOLVED IN ROASTING, SMELTING, AND ELECTROLYSIS. [R29, 296] *EPIDEMIOLOGICAL STUDIES CONCLUSIVELY DEMONSTRATE AN EXCESS OF CANCER OF THE NASAL CAVITY AND LUNG IN WORKERS IN NICKEL REFINERIES. IT IS LIKELY THAT NICKEL IN SOME FORM IS CARCINOGENIC TO MAN. /NICKEL/ [R42] *THE INDUSTRIAL MOND PROCESS WAS DEVELOPED IN WALES FOR PRODUCTION OF PURE NICKEL AND REQUIRED MIXTURE OF NICKEL OXIDE AND CARBON MONOXIDE TO MAKE NICKEL CARBONYL. IT IS THIS PROCESS WHICH HAS BEEN THE GREATEST CAUSE OF INDUSTRIAL ILLNESS ASSOCIATED WITH NICKEL EXPOSURE. [R136] *The toxicologically important routes of entry for nickel, metal and sol compounds (as Ni) are inhalation, skin absorption, ingestion, and skin and/or eye contact. /Nickel and nickel cmpd/ [R5, 1985.173] *The route by which most people in the general population receive the largest portion of daily nickel intake is through food. /Nickel and nickel cmpd/ [R137] *Metallic nickel or soluble nickel compounds can affect the body if they are inhaled or if they come in contact with eyes or skin. They also can affect the body if they are swallowed. /Nickel and nickel compounds/ [R4, 1981.1] *SOL NICKEL SALTS ... PRESENT EXPOSURE POTENTIAL FROM THEIR USE IN ELECTROPLATING BATHS AND IN PREPN OF NICKEL CATALYSTS. NICKEL DERMATITIS, "NICKEL ITCH", CONSTITUTES MOST COMMON AFFECTION AMONG NICKEL PLATERS. ... HEAT AROUND NICKEL PLATING BATHS IS CONSIDERED TO BE A PREDISPOSING FACTOR. /NICKEL SALTS/ [R30, 1822] *Occupational exposures to nickel and its cmpd occur in (1) mining and comminution of nickel containing ores; (2) nickel refining and smelting; (3) nickel electroplating; (4) producing and using nickel catalysts; (5) fabricating parts and structures by welding, flame spraying, cutting, grinding, and polishing of nickel containing alloys; (6) manufacturing nickel cadmium batteries; (7) constructing nickel molds in glass bottle factories; (8) spraying nickel containing paints (eg, yellow nickel titanate pigment); and (9) recycling or disposal of nickel containing products. /Nickel and compounds/ [R80, 455] *IN NICKEL PLATING INDUSTRY, EXPOSURE TO NICKEL-CONTAINING MISTS HAS BEEN REPORTED TO BE ASSOC WITH ASTHMA. SYMPTOMS WERE ATTRIBUTED TO HYPERSENSITIVITY TO NICKEL. ... EFFECTS ON NASAL MEMBRANE WERE NOTED IN WORKERS EXPOSED TO NICKEL AEROSOLS IN AN ELECTROLYSIS SHOP. /NICKEL SALTS/ [R138] *Occupational groups such as nickel workers and other workers handling nickel comprise the individuals at the highest risk. Women, particularly housewives, are at special risk to nickel induced skin disorders because of the greater than average contact with nickel containing materials. Approximately 47 million individuals, comprising the smoking population of the United States, are potentially at risk for possible co-factor effects of nickel in adverse effects on the respiratory track. /Nickel and nickel cmpd/ [R139] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 507,681 workers (19,673 of these are female) are potentially exposed to nickel and nickel compounds in the US(1). Occupational exposure to nickel and nickel compounds may occur through inhalation of dust particles and fumes and dermal contact with this compound at workplaces where nickel and nickel compounds are produced or used(SRC). Exposure to nickel and nickel compounds is common for workers in industrial operations that involve nickel or nickel compounds, such as mining, smelting, welding, casting, spray painting and grinding(2). The general population may be exposed to nickel and nickel compounds via inhalation of ambient air, ingestion of food and drinking water, and dermal contact with this compound and other products containing nickel and nickel compounds(SRC). [R140] AVDI: *The average daily oral intake of nickel has been reported to be 300 to 600 ug/day. /Nickel and nickel cmpd/ [R141] *The highest level of nickel observed in water was 75 ug/l. Average drinking water levels are about 5 ug/l. A typical consumption of 2 liters daily would yield an additional intake of 10 ug of nickel, of which 1 ug would be expected to be absorbed. /Nickel and nickel cmpd/ [R142] *Average daily nickel intake from food in institutionalized children 9-12 years of age from 28 US cities was 451 ug/l. /Nickel and nickel cmpd/ [R143] *Nickel content of nine institutional diets in the US would result in an avg Ni intake of 165 ug/day. /Nickel and nickel cmpd/ [R144] *Nickel may be inhaled by urban residents at a rate of about 2-14 ug/day. /Nickel and nickel cmpd/ [R145] *In a ... study of nickel content of diets prepared in university or hospital kitchens in the US, ... /the investigators/ found nickel intake to avg 165 (SD +/- 11) ug/day or 75 +/- 10 ug/1000 cal. [R32, 610] *Average nickel intake for American adults is 300-600 ug/day. /Nickel and nickel cmpd/ [R146] */Daily intake/ in seafood /ranges from/ 0.3-1.7 ug/g. /Nickel and nickel cmpd/ [R33, p. V2 465] *Estimates of the avg daily intake of nickel range from 0.14 to 0.6 mg/day(1). Diet is the source of approximately 83-94% of the body burden of nickel(2). The inhalation of nickel in urban areas is reported to range between 0.2 to 1.0 ug/day, with an avg rate of 0.4 ug/day; in rural areas the range is 0.1-0.4 ug/day with an avg of 0.2 ug/day(1). Smoking cigarettes can increase the intake of nickel by 4 ug/day per pack of cigarettes smoked(1). [R147] BODY: *... Mean serum levels of 2.6 ... and 3.1 ug/l ... in persons living in Connecticut ... In newborns, the serum concn of nickel were similar to those of mothers, ie an avg of 3 ug/l ... In whole blood, a level of 4.8 ug/l has been reported. ... Avg nickel concn /was/ ... 0.22 ug/l in hair. ... Hair values were 0.6 and 1 ug/g in men and women ... /Nickel and nickel cmpd/ [R33, p. V2 470] *Nickel concn in specimens from healthy, nonexposed adults: Whole blood: 0.34 + or - 0.28 ug/l; Serum: 0.28 + or - 0.24 ug/l; Urine (spot collection): 2.0 + or - 1.5 ug/l; Urine (24 hr collection): 2.2 + or - 1.2 ug/l; Feces (3 day collection): 14.2 + or - 2.7 ug/g dry wt /From table/ /Nickel and nickel cmpd/ [R80, 463] *Usually, Ni is found at low levels (< 0.1 mg/kg, wet weight) in most human tissues and body fluids. The average population has 3-7 ug Ni/l of whole blood, 1-5 ug Ni/l in blood serum, and 1-5 ug Ni/l in urine. Perspiration contains 52 + or - 36 ug Ni/l. /Nickel and nickel cmpd/ [R148] *In 24 hr urine: reference range (conventional): 2.6 ug + or - 1.3 (1 SD) (male); 2.2 + or - 0.8 ug/dl (female); 8-800 ug/l (refinery workers); reference range (international recommended): 44.2 + or - 22.1 nmol/d (1 SD) (male); 37.4 + or - 13.6 (female); 136-13,600 nmol/l (refinery workers); In feces: reference range (conventional): 260 + or - 120 ug/d (1 SD) (adult); reference range (international recommended): 4.4 + or - 2.1 umol/d (1 SD) (adult) /Nickel and nickel cmpd/ [R149] *In 24 hr urine: reference range (conventional): 100-2500 ug/l; reference range (international recommended): 1700-42500 nmol/l. [R149] *In hair: reference range (conventional): 0.24 ug + or - 0.09 ug/kg and 0.19 + or - 0.04 ug/kg (adult); reference range (international recommended): 4.1 + or - 1.5 ug/kg and 3.2 + or - 0.7 ug/kg (adult) /Nickel and nickel cmpd/ [R149] *... Serum nickel was found to be 2.6 + or - 0.9 ug/l (range: 0.8 to 5.2) and mean excretion of nickel in urine of 2.6 + or - 1.4 ug/day (range: 0.5 to 6.4). ... Serum nickel measured in persons living in Sudbury, Ontario, which is in the vicinity of a large nickel mine, showed concn of 4.6 + or - 1.4 ug/l (range: 2.0 to 3.7) and urinary concn were 7.9 + or - 3.7 ug/day (range: 2.3 to 15.7). Generally, fetal nickel is about 100 times urine nickel concn. /Nickel and nickel cmpd/ [R32, 610] *Normal level of nickel in human blood: 0.011 mg%, 0.11 ug/ml. /Nickel/ [R150] *NICKEL HAS BEEN FOUND IN HUMAN FETAL TISSUE AND IN CORD SERUM WHERE AVG CONCN FROM 12 NEWBORNS WAS 0.3 TO 12 UG/DL (RANGE 0.17 TO 0.49), AND WAS IDENTICAL WITH THAT IN MOTHER'S SERUM IMMEDIATELY AFTER DELIVERY. /NICKEL SALTS/ [R30, 1834] *The avg body burden of nickel in healthy adults is 7.3 ug/kg body weight(1). The range and avg nickel concns in whole blood, serum, urine (24-hour collection) and feces (72-hour collection) of non-exposed, healthy adults are: < 0.05-1.05 ug/l, 0.34 ug/l; < 0.05-1.08 ug/l, 0.28 ug/l; 0.7-5.2 ug/l, 2.2 ug/l, and 10.8-18.6 ug/g, 14.2 ug/g (dry weight)(1). The following mean, median, and ranges of nickel concns in various body tissues were found in non-occupationally exposed individuals (wet weight; number of observations indicated in parentheses): lung - 18, 12, 7-46 (9); thyroid - 20,24, 7-32 (8); adrenal - 26, 24, 13-56 (10); kidney - 9, 7, 3-25 (10); heart - 8, 6, 1-14 (9); liver - 10, 8, 2-21 (10); brain - 8, 8, 5-11 (7); spleen - 7, 4, 1-15 (10); pancreas - 8, 6, 9-19 (10)(2). [R151] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *NIOSH considers nickel to be a potential occupational carcinogen. [R13, 224] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1 mg/cu m. /Nickel, soluble cmpd, as Ni/ [R152] *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 1 mg/cu m. /Nickel, metal and insoluble cmpd, as Ni/ [R152] NREC: *NIOSH considers nickel metal and other compounds (as Ni) to be a potential occupational carcinogen. /Nickel metal and other compounds (as Ni)/ [R13, 224] *NIOSH usually recommends that occupational exposures to carcinogens be limited to the lowest feasible concentration. /Nickel metal and other compounds (as Ni)/ [R13, 224] *Recommended Exposure Limit: 10 Hr TWA 0.015 mg/cu m. /Nickel metal and other compounds (as Ni)/ [R13, 224] TLV: *8 hr Time Weighted Avg (TWA) 0.1 mg/cu m, inhalable fraction. A4. A4= Not classifiable as a human carcinogen. /Nickel, soluble compounds, as Ni/ [R21, 51] *8 hr Time Weighted Avg (TWA) 0.2 mg/cu m, inhalable fraction. A1. A1= Confirmed human carcinogen. /Nickel, insoluble compounds, as Ni/ [R21, 51] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R21, 6] OOPL: *Max allowable concn (MAC) USSR 0.5 mg/cu m /Nickel, nickel oxide and nickel sulfides as dust/ [R10, 1438] *Max allowable concn (MAX) USSR 0.005 mg/cu m as Ni /Nickel salts and aerosols/ [R10, 1438] *Other recommendations: 0.05 ppm, Australia (1978), Belgium (1978), and the Netherlands (1978); 0.001 ppm, Finland (1975), Italy (1978), Japan (1978), Poland (1976), Sweden (1978), and Yugoslavia (1971); 0.002 ppm, Romania (1975); and 0.00007 ppm, USSR (1977). Italy and Sweden retained the carcinogenic designation. [R7, 1986.424] *1 ug nickel/deciliter blood and 70 ug/g creatine urine are suggested as the maximum permissable values. ... /Nickel and nickel cmpd/ [R153] CWA: +Toxic pollutant designated pursuant to section 307(a)(1) of the Clean Water Act and is subject to effluent limitations. /Nickel and compounds/ [R154] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Analyte: nickel; matrix: air; procedure: filter collection, acid digestion, graphite furnace /Nickel and nickel cmpd/ [R155, p. V7 298-1] *Measurements to determine employee exposure are best taken so that the avg 8-hr exposure is based on a single 8-hr sample or on two 4-hr samples. Several short-time interval samples (up to 30 min) may also be used to determine the avg exposure level. Air samples should be taken in the employee's breathing zone (air that would most nearly represent that inhaled by the employee). /Nickel metal and sol nickel compounds/ [R4, 1981.3] *Sampling and analyses may be performed by collection on a cellulose membrane filter followed by treatment with nitric and perchloric acids, solution in nitric acid ... /Nickel metal and soluble nickel compound/ [R4, 1981.3] *Analyte: Nickel; Matrix: air; Sampler: filter (0.8-um cellulose membrane); Flow rate: 1-4 l/min; Vol: min: 5 l, max: 1000 l; Stability: stable /Nickel and nickel cmpd/ [R156, p. V1 7300-1] *Analyte: Nickel; Specimen: Blood or tissue; Vol: 10 ml blood, or 1 g tissue; Preservative: Heparin for blood, none for tissue; Controls: collect 3 blood specimens from unexposed workers; Stability: not established /Nickel and nickel cmpd/ [R156, p. V1 8005-1] *Analyte: Nickel; Specimen: urine; Vol: 50-200 ml in polyethylene bottle; Preservative: 5 ml conc HNO3 added after collection; Controls: collect at least 3 urine specimens from unexposed workers; Stability: not established /Nickel and nickel cmpd/ [R156, p. V1 8310-1] *Analyte: Nickel; Matrix: air; Sampler: filter (0.8 um cellulose ester membrane); Flow rate: 1 l/min; Vol: min: 10 l, max: 400 l; Stability: At least 1 yr at 25 deg C /Welding and brazing fumes/ [R156, p. V2 7200-1] *NIOSH Method 7200. Analyte: Nickel. Matrix: Air. Sampler: Filter (0.8 um cellulose ester membrane). Flow Rate: 1 l/min. Sample Size: 100 liters. Shipment: Routine. Sample Stability: Stable at least 1 year @ 25 deg C. /Nickel/ [R156, p. 7200-1] *NIOSH Method 8005. Analyte: Nickel. Specimen: Blood or tissue. Volume: 10 ml (blood) or 1 g (tissue). Preservative: Heparin (blood); none for tissue. Shipment: Frozen for blood and "wet" tissue; routine for "dry" tissue. Sample Stability: Not established. /Nickel/ [R156, p. 8005-1] *NIOSH Method 8310. Analyte: Nickel. Specimen: Urine. Volume: 50 to 200 ml in polyethylene bottle. Preservative: 5.0 ml conc nitric acid added after collection. Shipment: Frozen in dry ice. Sample Stability: Not established. /Nickel/ [R156, p. 8310-1] *NIOSH Method 7300. Analyte: Nickel. Matrix: Air. Sampler: Filter (0.8 um, cellulose ester membrane). Flow Rate: 1 to 4 l/min. Sample Size: 500 liters. Shipment: Routine. Sample Stability: Stable. /Nickel/ [R156, p. 7300-1] *NIOSH Method 173. Analyte: Nickel. Matrix: Air. Procedure: Filter collection, acid digestion. Flow Rate: 1.5 l/min. Sample Size: 10 ml. /Nickel/ [R155, p. V5 173-1] *NIOSH Method S206. Analyte: Nickel. Matrix: Air. Procedure: Filter collection, acid digestion. Flow Rate: 1.5 l/min. Sample Size: 90 liters. /Nickel/ [R155, p. V3 S206-1] *NIOSH Method 298. Analyte: Nickel. Matrix: Air. Procedure: Filter collection, acid digestion. Flow Rate: 1.5 to 2.5 l/min. Sample Size: 400 liters. /Nickel/ [R155, p. V7 298-1] ALAB: *ATOMIC ABSORPTION SPECTROPHOTOMETRY ... FOR NICKEL IN BOTH AIR AND WATER: SACHDEV SL, WEST PW; ENVIRON SCI TECHNOL 4: 749 (1970). DIMETHYLGLYOXIME METHOD FOR COLORIMETRIC DETERMINATION OF TRACES OF NICKEL ... SANDELL EB; COLORIMETRIC DETERMINATION OF TRACES OF METALS, 3RD ED, 665 (1959), INTERSCIENCE, NY. /TOTAL NICKEL/ [R157] *DUST FILTER SAMPLE WAS PLACED ON A FLAT POLISHED QUARTZ GLASS AND IRRADIATED WITH PRIMARY X-RAY BEAM TO ANALYZE THE DUST. NICKEL AND OTHER METALS WERE DETERMINED. /TOTAL NICKEL/ [R158] *Analyte: nickel; matrix: air; procedure: AAS; range: 0.447-2.075 mg/cu m; precision (coefficient of variation): 0.057 /Total nickel/ [R155, p. V3 S206-1] *Analyte: trace metals (incl nickel); matrix: air; procedure: AAS; range: 0.5-5.0 ug/ml; 21-210 ug/cu m; precision: 3% RSD (analytical) /Trace metals/ [R155, p. V5 173-1] *MATRIX: AIR: ATOMIC ABSORPTION WITH HEATED GRAPHITE ATOMIZING ROD, TUBE OR FURNACE; RANGE: 0.005-0.030 MG/CU M (METHOD IS PROPOSED). /TOTAL NICKEL/ [R155, p. V5 298-1] *Analyte: nickel; matrix: air; procedure: AAS; range: 0.57-30.7 ug/cu m; precision: 0.075 /Total nickel/ [R155, p. V7 298-1] *Analyte: Nickel; Matrix: air; Procedure: X-ray fluorescence; Range: 0.02 - 0.14 mg/cu m; Est LOD: 2 ug each metal/samp; Precision: 0.071; Interferences: Controlled with wavelength dispersive fluorescence, more severe with energy dispersive systems, cobalt in fumes requires different ratio standard element /Total nickel/ [R156, p. V2 7200-1] *NIOSH Method 7300. Analyte: Nickel; Matrix: air; Procedure: inductively coupled argon plasma, atomic emission spectroscopy; Wavelength: 231.6 nm; Range: 2.5-1000 ug/sample; Precision: at 2.5 ug/filter: 0.027, at 1000 ug/filter: 0.020; Interferences: spectral, minimized by wavelength selection, interelement and background correction /Total nickel/ [R159] *NIOSH 8005. Determination of Elements in Blood or Tissue Samples by Inductively Coupled Argon Plasma - Atomic Emission Spectroscopy (ICP-AES). This method is for monitoring the tissue of workers exposed to several metals simultaneously. This is a simultaneous multielemental analysis, but is not compound specific. The reported detection limit is 0.2 ug/g. [R159] *NICKEL ANALYSIS DEVICE IS COMPRISED OF A FIRST AUTOMATIC MEASURING SYSTEM, A SECOND AUTOMATIC MEASURING SYSTEM, AND A COLORIMETRIC MEASUREMENT SYSTEM. /TOTAL NICKEL/ [R160] *METHOD HAS BEEN APPLIED TO DETERMINE NICKEL @ PERCENTAGE LEVEL IN ALLOY AND @ TRACE LEVELS IN TEA AND FAT SAMPLES. /TOTAL NICKEL/ [R161] *A RAPID ELECTROTHERMAL ATOMIC ABSORPTION PROCEDURE FOR ANALYSIS OF METAL CONTENT OF SEWAGE SLUDGE IS PRESENTED. /TOTAL NICKEL/ [R162] *The Parr bomb technique is found to be the preferred acid digestion method for multi-elemental analysis by simultaneous inductively coupled plasma atomic emission spectroscopy when compared with microwave and hot plate methods for many environmental and biological specimens, but especially for the latter. One digestion alone often did not produce quantitative results compared with a sequential digestion scheme. The digestions were then refined to be as similar as possible for the various substrates studied. The use of modified k values was demonstrated to provide accuracy and had to be used for inductively coupled plasma atomic emission spectroscopy spectrometers where background corrections were performed first for fixed channels. /Total nickel/ [R163] *EPA Method 7520: Nickel (Atomic Absorption, Direct Aspiration) Method 7520 is applicable for the determination of metals in solution by atomic absorption spectrometry. Preliminary treatment of waste water, ground water, EP extracts, and industrial waste is always necessary because of the complexity and variability of sample matrix. After aspiration and atomization of the sample in a flame, a light beam from a hollow cathode lamp or an electrodeless discharge lamp is directed through the flame into a monochromator and onto a detector that measures the amount of absorbed light. ... The light energy absorbed by the flame is a measure of the concentration of that metal in the sample. The performance characteristics for an aqueous sample free of interferences are: optimum concentration range of 0.3-5 mg/l with a wavelength of 232.0 nm, a sensitivity of 0.15 mg/l, and a detection limit of 0.04 mg/l. /Total nickel/ [R164] *Direct Aspiration Atomic Absorption Spectrometry is used for the determination of nickel. Using air-acetylene as the flame gas at a wavelength of 232.0 nm, the detection limit is 0.02 mg/l, with a sensitivity of 0.15 mg/l, at an optimum concentration range of 0.3-10 mg/l. /Total nickel/ [R165] *Method 3114 C. Electrothermal Atomization Atomic Absorption Spectrometry for the determination of micro quantities of selected elements including nickel in water and wastewater samples. Using an electrically heated atomizer or graphite furnace, at a wavelength of 232.0 nm, the estimated detection limit for nickel is 1 ug/l at an optimum concentration range of 5 to 100 ug/l. These values may vary with the chemical form of the nickel being determined, sample composition, or instrumental conditions. Pyrolytically coated tubes are used to minimize the chemical interaction with nickel to form the refractory carbide at high atomization temperatures. Elements that form carbides are barium, molybdenum. nickel, titanium, vanadium, and silicon. /Total nickel/ [R166] *Method 3120. Emission Spectroscopy for the determination of nickel in water and wastewater samples using an inductively coupled plasma source. The exact choice of emission line is related to sample matrix and instrumentation. A typically used emission line for nickel in water is a wavelength of 231.60 nm, with an estimated detection limit of 15 ug/l. /Total nickel/ [R167] *EPA Method 200.7: An Inductively Coupled Plasma - Atomic Emission Spectrophotmetric method for the determination of dissolved, suspended, or total elements in drinking water, surface water, and domestic and industrial waste waters, is described. Nickel is analyzed at a wavelength of 231.604 nm and has an estimated detection limit of 15 ug/l. /Total nickel/ [R168] *DETERMINATION OF NICKEL IN RAT LUNG BY ATOMIC ABSORPTION SPECTROPHOTOMETRY. /TOTAL NICKEL/ [R169] *A method capable of speciation of metallic nickel, nickel(+2) and nickel oxides in atmospheric monitoring is described. [R170] *DOE MS410. Determination of Nickel (Ni2+) in Aqueous Samples using the Indicator Strip Based Colorimetric Test. This field screening method is applicable to waste water samples containing nickel. The reported detection limit is 5 ug/ml. [R171] *OSW 6020. Inductively Coupled Plasma with Mass Spectrometry. This method is applicable to water and waste samples. Prior to analysis for total values, samples must be digested using appropriate sample preparation methods (such as OSW Methods 3005A, 3010A, 3015, 3020A, 3040, or 3050A). The reported detection limit is 0.03 ug/l. [R171] *OSW 7000A. Atomic Absorption By FLAA. This method is used for the analysis of drinking water, surface water, saline waters, and domestic and industrial wastes. Drinking water free of particulates may be analyzed directly. Ground water, other aqueous samples, EP extracts, industrial wastes, soils, sludges, sediments and other solid wastes require digestion by Methods 3005-3050 prior to analysis for both total and acid leachable metals. When analyzing for dissolved metals, acid digestion is not necessary for samples that have been filtered and preserved. The reported detection limit is 0.04 mg/l. [R171] *SFSAS_14. Analysis of Fish for Metals. This method is applicable to the determination of metals in fish tissue. For sample preparation refer to method SFSAS_FT-PREP. Group I: Samples are digested by a dry ashing process. For samples being tested for Be, Cd, Cr, Cu, Pb, Ni, Ag, Tl, and Zn. The detection limit is not provided. [R171] *OSW 3031. Acid Digestion of Oils for Metals Analysis by FLAA or ICP-AES. This method is applicable to the digestion of oils, oil sludges, tars, waxes, paints, paint sludges, and other viscous petroleum products for the analysis of 16 metals by FLAA or ICP-AES. The detection limit is not provided. [R171] CLAB: *NANOGRAM QUANTITIES OF NICKEL IN URINE AND BLOOD CAN BE DETERMINED BY PULSE POLAROGRAPHY. /TOTAL NICKEL/ [R172] *FLAMELESS ATOMIC ABSORPTION HAS BEEN USED FOR ANALYSIS OF NICKEL IN SMALL TISSUE (61 TO 662 MG WET WT) SAMPLES WHERE NICKEL CONCN WERE OF ... 4 TO 30 UG/100 G TISSUE: TORJUSSEN W ET AL, CLIN CHEM 23: 1018 (1977). /TOTAL NICKEL/ [R30, 1824] *AN IMPROVED CHELATION EXTRACTION METHOD USING FURILDOXIME FOR NICKEL ANALYSIS IN SERUM AND URINE BY ELECTROTHERMAL ATOMIC ABSORPTION HAS BEEN REPORTED ... MIKAC-DEVIC D ET AL, CLIN CHEM 23: 948 (1977). /TOTAL NICKEL/ [R30, 1824] *Analyte: Nickel; Matrix: blood or tissue; Procedure: Inductively-coupled argon plasma-atomic emission spectroscopy; Wavelength: 231.6 nm; Range: 10 to 10,000 ug/100 g blood, 2 to 2000 ug/g tissue; Est LOD: 1 ug/100 g blood, 0.2 ug/g tissue; Precision: 16; Interferences: spectral, minimized by wavelength selection /Total nickel/ [R156, p. V1 8005-1] *Analyte: Nickel; Matrix: urine; Procedure: Inductively-coupled argon-plasma, atomic emission spectroscopy; Extraction media: polydithiocarbamate resin; Wavelength: 231.6 nm; Range: 0.25-200 ug/samp; Est LOD: 0.1 ug/samp; Precision: 0.42; Interferences: spectral, minimized by wavelength selection /Total nickel/ [R156, p. V1 8310-1] *Analyte: nickel; matrix: urine; range: < 5 ug/g creatinine (normal value), 70 ug/g creatinine (tentative max permissible value) /Total nickel/ [R32, 909] *Analyte: nickel; matrix: plasma; range: < 1 ug/100 ml (normal value), 1 ug/100 ml (tentative max permissible value) /Total nickel/ [R32, 909] *FLAMELESS ATOMIC ABSORPTION HAS BEEN USED FOR ANALYSIS OF NICKEL IN SMALL TISSUE (61 TO 662 MG WET WT) SAMPLES WHERE NICKEL CONCN WERE OF ... 4 TO 30 UG/100 G TISSUE. /NICKEL/ [R30, 1824] *AN IMPROVED CHELATION EXTRACTION METHOD USING FURILDOXIME FOR NICKEL ANALYSIS IN SERUM AND URINE BY ELECTROTHERMAL ATOMIC ABSORPTION HAS BEEN REPORTED ... . /NICKEL/ [R30, 1824] *NIOSH Method: 8005. Analyte: Nickel. Matrix: Blood or tissue. Procedure: Inductively coupled argon plasma, atomic emission spectroscopy. For nickel this method has an estimated detection limit of 1 ug/100 g blood; 0.2 ug/g tissue. The precision/RSD is 16 and the recovery is 86%. The working range is 10 to 10,000 ug/100 g blood; 2 to 2,000 ug/g tissue for a 10 ml (blood) or 1 g (tissue) sample. Applicability: This method is useful for monitoring the blood of workers exposed to several metals simultaneously. Interferences: No specific interferences. /Nickel/ [R156, p. 8005-1] *NIOSH Method 8310. Analyte: Nickel. Specimen: Urine. Procedure: Inductively coupled argon plasma, atomic emission spectroscopy. For nickel this method has an estimated detection limit of 0.1 ug/sample. The precision/RSD is 0.42 and the recovery is 80%. The working range is 0.25 to 200 ug/sample. Applicability: This method measures urine concentrations of metals. Interferences: Spectral interferences. /Nickel/ [R156, p. 8310-1] *TYPE C PROCEDURE (C= ELEGANT AND PRECISE, USING REQUIRED EQUIPMENT) FOR SERUM, URINE, WHOLE BLOOD AND TISSUES; SPECTROMETER, ATOMIC ABSORPTION. CADMIUM AND GOLD SALTS CAN CAUSE SLIGHT INHIBITION OF ATOMIC ABSORPTION OF NICKEL WHEN THEIR CONCN EXCEED 10 and 25 UG/100 ML, RESPECTIVELY. /NICKEL/ [R173] *Electrothermal atomic absorption spectrophotometry with Zeeman background correction provides an accurate, sensitive, and practical routine mehtod for analysis of nickel concentrations in body fluids and tissues of human subjects to monitor environmetal, occupational, or iatrogenic exposures to nickel compounds. /Total nickel/ [R174] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: NIOSH; Criteria Document: Inorganic Nickel (1977) DHEW Pub NIOSH 77-164 Nat'l Research Council Canada; Nickel (1981) NRCC No. 18568 DHHS/ATSDR; Toxicological Profile for Nickel (Draft) (10/87) NAS; Report of the Committee on Med and Envir Poll: Nickel (1975) NTP; Chem Selection Profile: Nickel Chloride (1979) USEPA; Ambient Water Quality Criteria Doc: Nickel (1980) EPA 400/5-80-060 USEPA; Health Assessment Document: Nickel (1983) EPA 600/8-83-012 Longstaff E et al; IARC Sci Pub 53: 235-43 (1984). Epidemiological studies of workers exposed to nickel ores free of sulfur and workers exposed to metallic nickel and its alloys in the steel industry and in an aircraft engine manufacturing facility have not shown any connection between exposure and deaths from cancer. In experiments in which rodents were exposed to metallic nickel dust, nickel carbonyl, nickel subsulfide, and nickel oxide, only nickel subsulfide has been found to be definitely carcinogenic. Nickel cmpds do not all have the same biological potential. Nickel and nickel oxide should not be considered carcinogenic for risk assessment purposes. Santodonato J et al; Monograph on Human Exposure to Chemicals in the Workplace: Nickel Report No SRC-TR-84-673 (1985). 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NY, NY: Weinheim (1991) (2) Barrie LA et al; Atmos Environ 21: 1133-5 (1987) R118: (1) Canviro Consultants; Thirty Seven Municipal Water Pollution Control Plants Pilot Monitoring Study V1 Interim Report (1988) R119: USEPA; Health Assessment Document: Nickel p.29 (1983) USEPA 600/8-83-012 R120: Nat Research Council Canada; Effects of Nickel in the Canadian Envir p.28 (1981) NRCC No. 18568 R121: Brown, K.W., G. B. Evans, Jr., B.D. Frentrup (eds.). Hazardous Waste Land Treatment. Boston, MA: Butterworth Publishers, 1983. R122: (1) Alexeeva-Popova NV et al; Sci Total Environ 106/161: 643-652 (1995) (2) Breckenridge RP, Crockett AB; Determination of Background concns of Inorganics in Soil and Sediments at Hazardous Waste Sites. USEPA/540/S-96/500 pp.8-10 (1995) (3) Adamo P et al; Environ Poll 91: 11-19 (1996) (4) Amrhein C et al; Environ Sci Technol 26: 703-709 (1992) R123: (1) Kohler CC et al; Levels of PCBs and Trace Elements in Crab Orchard Lake Sediment, Benthos, Zooplanton and Fish p.54 (1990) PB 90-195652 (2) Berrow SD; Mar Pollut Bull 22: 467-9 (1991) (3) Mayer T, Manning PG; J Great Lakes Res 16: 299-318 (1990) (4) Breckenridge RP, Crockett AB; Determination of Background concns of Inorganics in Soil and Sediments at Hazardous Waste Sites. pp.8-10 USEPA/540/S-96/500 (1995) (5) Bradley RW, Morros JR; Water Air Soil Pollution 27: 341-354 (1986) R124: Nat'l Research Council Canada; Effects of Nickel in the Canadian Envir p.27 (1981) NRCC No. 18568 R125: (1) Barrie LA, Hoff RM; Atmos Environ 19: 1995-2010 (1985) R126: USEPA; Health Assessment Document: Nickel p.27 (1983) USEPA 600/8-83-012 R127: Schroeder HA et al; J Chronic Dis 15: 51-65 (1962) as cited in NIOSH; Criteria Document: Inorganic Nickel p.192 (1977) DHEW Pub. NIOSH 77-164 R128: NAS; Report of the Committe on Med and Envir Poll: Nickel (1975) as cited in NTP; Chem Selection Profile: Nickel Chloride p.2 (1979) R129: (1) Weigert P; pp.449-468 in Metals and Their Compounds in the Environment. Merian E, ed. NY, NY: Weinheim (1991) (2) ATSDR; Toxicological Profile for Nickel. ATSDR/TP-88/19 pp. 77 (1988) R130: (1) Ward NI, Savage JM; Sci Tot Environ 147: 309-319 (1994) (2) Sunderman FW Jr, Oskarsson A; pp. 1101-1126 in Metals and Their Compounds in the Environment; Merian E, ed. NY, NY: Weinheim (1991) R131: Taylor GJ, Crowder AA; Can J Bot 61 (7): 1825-30 (1983) R132: (1) Antonsen DH; Kirk-Othmer Encycl Chem Technol 4th ed NY, NY: John Wiley and Sons 17: 35 (1992) (2) Michelot F et al; Arch Environ Contam Toxicol 36: 256-63 (1999) R133: NAS; Report of the Committee on Med and Envir Poll: Nickel (1975) as cited in NTP; Chem Selection Profile: Nickel Chloride p.2 (1979) R134: USEPA; Health Assessment Document: Nickel p.27 (1983) EPA 600/8-83-012 R135: (1) Kohler CC et al; Levels of PCBs and Trace Elements in Crab Orchard Lake Sediment, Benthos, Zooplanton and Fish, NTIS PB 90-195652 p. 54 (1990) (2) Berrow SD; Mar Pollut Bull 22: 467-9 (1991) (3) Vazquez F et al; Bull Environ Contam Toxicol 45: 907-914 (1990) (4) Allen-Gil SM et al; Environ Toxicol Chem 16: 733-41 (1997) R136: Hamilton, A., and H. L. Hardy. Industrial Toxicology. 3rd ed. Acton, Mass.: Publishing Sciences Group, Inc., 1974. 151 R137: USEPA; Ambient Water Quality Criteria Document: Nickel p.C-130 (1980) EPA 400/5-80-060 R138: Friberg, L., G.R. Nordberg, and V.B. Vouk. Handbook on the Toxicology of Metals. New York: Elsevier North Holland, 1979. 549 R139: USEPA; Ambient Water Quality Criteria Doc: Nickel p.C-130 (1980) EPA 400/5-80-060 R140: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) (2) Sunderman FW Jr, Oskarsson A; pp. 1101-1126 in Metals and Their Compounds in the Environment; Merian E, ed. NY, NY: Weinheim (1991) R141: 48 FR 45502 (10/05/83) R142: USEPA; Ambient Water Quality Criteria Doc: Nickel p.C-130 (1980) USEPA 400/5-80-060 R143: Murthy GD et al; Envir Sci Tech 7: 1042 (1973) R144: Myron DR et al; Am J Clin Nutr 31: 527 (1978) R145: NAS; Report of the Committee on Med and Envir Poll; Nickel (1975) as cited in NTP; Chem Selection Profile: Nickel Chloride p.2 (1979) R146: Schroeder HA et al; J Chronic Dis 15: 51-65 (1962) R147: (1) Sunderman FW Jr, Oskarsson A; pp. 1101-1126 in Metals and Their Compounds in the Environment; Merian E, ed. NY, NY: Weinheim (1991) (2) ATSDR; Toxicological Profile for Nickel. ATSDR/TP-88/19. pp. 1-70 (1988) R148: Nat'l Research Council Canada; Effects of Nickel in the Canadian Environment p.29 (1981) NRCC 18568 R149: Tietz, N.W. (ed.). Clinical Guide to Laboratory Tests. Philadelphia, PA: W.B. Saunders Co., 1983. 358 R150: Winek CL; Drug and Chemical Blood-Level Data Nickel (1985) R151: (1) Sunderman FW Jr, Oskarsson A; pp. 1101-1126 in Metals and Their Compounds in the Environment. Merian E, ed. NY, NY: Weinheim (1991) (2) ATSDR; Toxicological Profile for Nickel. ATSDR/TP-88/19 pp. 1-70 (1988) R152: 29 CFR 1910.1000 (7/1/99) R153: Lauwerys Rh; Industrial Chemicals Exposure: Guidelines for Biological Monitoring, Biomedical Publications, Davis, CA p.135 (1983) R154: 40 CFR 401.15 (7/1/99) R155: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R156: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R157: IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work).p. V11 86 (1976) R158: FREITAG K ET AL; GES KERNENERGIEVERWERT SCHIFFBAU SCHIFFAHRT (BER), ISS GUSS 79/E/9 (1979) R159: U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. 4th ed. Methods A-Z AND Supplements. Washington, DC: U.S. Government Printing Office, Aug 1994. R160: YEE TB; GOVT REPORTS ANNOUNCEMENTS AND INDEX (GRA and I) (3) (1981) R161: BARRATT RS ET AL; ANALYTICA CHIMICA ACTA (59): 59 (1972) R162: CARRONDO MJ T ET AL; ANAL CHIM ACTA 106 (2): 309 (1979) R163: Que Hee SS, Boyle Jr; Anal Chem 60 (10): 1033-42 (1988) R164: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R165: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p. 154 (1985) R166: Franson MA, ed; Standard Methods for the Examination of Water and Wastewater, 17th ed p.3-32 (1989) R167: Franson MA, ed; Standard Methods for the Examination of Water and Wastewater, 17th ed p.3-53 (1989) R168: 40 CFR 136 (7/1/87) R169: KAPLAN P ET AL; ARCH ENVIRON HEALTH 27 (6): 387 (1973) R170: Wu TG, Wong JL; Anal Chim Acta 235: 457-60 (1990) R171: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) R172: NIEBOER E ET AL; ANN CLIN LAB SCI 8 (6): 497 (1978) R173: Sunshine, Irving (ed.) Methodology for Analytical Toxicology. Cleveland: CRC Press, Inc., 1975. 275 R174: Sunderman FW; Govt Reports Announcements and Index 5 (1988) RS: 154 Record 357 of 1119 in HSDB (through 2003/06) AN: 6934 UD: 200301 RD: Reviewed by SRP on 5/6/2000 NT: This record contains general information for barium ions and compounds, including statements in the literature referenced to barium compounds, barium salts, etc. For compound-specific information, refer to the appropriate individual records as listed in the RELATED HSDB RECORDS field; for information on the metal itself, refer to the BARIUM, ELEMENTAL record. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: BARIUM-COMPOUNDS- RN: NO CAS RN RELT: 4481 [BARIUM, ELEMENTAL; 7440-39-3]; 1605 [BARIUM HYDROXIDE]; 396 [BARIUM PEROXIDE]; 950 [BARIUM CARBONATE]; 2633 [BARIUM CHLORIDE]; 405 [BARIUM CHLORATE]; 401 [BARIUM NITRATE]; 5041 [BARIUM SULFATE]; 397 [BARIUM PERMANGANATE]; 5523 [BARIUM LITHOL RED]; 403 [BARIUM CYANIDE] SHPN: UN 1564; Barium compounds, not otherwise specified IMO 6.1; Barium compounds, not otherwise specified HAZN: D005; A waste containing barium may or may not be characterized as a hazardous waste following testing by the Toxicity Characteristic Leaching Procedure as prescribed by the Resource Conservation and Recovery Act (RCRA) regulations. /Barium/ MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- OMIN: *RADIOACTIVE IONS ARE REMOVED FROM WASTE WATER BY MIXT OF BARIUM SALT AND FERROCYANIDE. [R1] USE: *Barium compounds are used commercially as pigments and in the manufacture of rubber goods, photographic paper, x-ray contrast material, brick and ceramic products, glass, plastic, pyrotechnics, oil additives, and steel. /Barium cmpd/ [R2] CPAT: *(1992) U.S. consumption of barite: 637,000 tons [R3] PRIE: U.S. PRODUCTION: *(1992) 316,000 tons /Barite/ [R3] *(1998) 476,000 tons [R4] U.S. IMPORTS: *(1986) 3,604,738 lb /Barium cmpd/ [R5] *(1998) 21,300 tons /Barite/ [R4] U.S. EXPORTS: *(1988) 574,808 lb /Barium cmpd/ [R6] *(1998) 14,700 tons /Barite/ [R4] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- OCPP: *Soln of barium salts yield a white precipitate with 2 N sulfuric acid. This precipitate is insol in hydrochloric acid and in nitric acid. /These/ salts impart a yellowish green color to a nonluminous flame, which appears blue when viewed through green glass. /Soluble barium salts/ [R7] *NATURALLY OCCURRING BARIUM IS A MIXTURE OF SEVEN STABLE ISOTOPES. THIRTEEN OTHER RADIOACTIVE ISOTOPES ARE KNOWN TO EXIST. [R8] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- DOT: +Health: TOXIC, inhalation, ingestion, or skin contact with material may cause severe injury or death. Contact with molten substance may cause severe burns to skin and eyes. Avoid any skin contact. Effects of contact or inhalation may be delayed. Fire may produce irritating, corrosive and/or toxic gases. Runoff from fire control or dilution water may be corrosive and/or toxic and cause pollution. /Barium cmpd, nos/ [R9] +Fire or explosion: Non-combustible, substance itself does not burn but may decompose upon heating to produce corrosive and/or toxic fumes. Some are oxidizers and may ignite combustibles (wood, paper, oil, clothing, etc.). Contact with metals may evolve flammable hydrogen gas. Containers may explode when heated. /Barium cmpd, nos/ [R9] +Public safety: CALL Emergency Response Telephone Number. ... Isolate spill or leak area immediately for at least 25 to 50 meters (80 to 160 feet) in all directions. Keep unauthorized personnel away. Stay upwind. Keep out of low areas. Ventilate enclosed areas. /Barium cmpd, nos/ [R9] +Protective clothing: Wear positive pressure self-contained breathing apparatus (SCBA). Wear chemical protective clothing which is specifically recommended by the manufacturer. It may provide little or no thermal protection. Structural firefighters' protective clothing provides limited protection in fire situations ONLY, it is not effective in spill situations. /Barium cmpd, nos/ [R9] +Evacuation: ... Fire: If tank, rail car or tank truck is involved in a fire, ISOLATE for 800 meters (1/2 mile) in all directions; also, consider initial evacuation for 800 meters (1/2 mile) in all directions. /Barium cmpd, nos/ [R9] +Fire: Small fires: Dry chemical, CO2 or water spray. Large fires: Dry chemical, CO2, alcohol-resistant foam or water spray. Move containers from fire area if you can do it without risk. Dike fire control water for later disposal; do not scatter the material. Fire involving tanks or car/trailer loads: Fight fire from maximum distance or use unmanned hose holders or monitor nozzles. Do not get water inside containers. Cool containers with flooding quantities of water until well after fire is out. Withdraw immediately in case of rising sound from venting safety devices or discoloration of tank. ALWAYS stay away from tanks engulfed in fire. /Barium cmpd, nos/ [R9] +Spill or leak: ELIMINATE all ignition sources (no smoking, flares, sparks or flames in immediate area). Do not touch damaged containers or spilled material unless wearing appropriate protective clothing. Stop leak if you can do it without risk. Prevent entry into waterways, sewers, basements or confined areas. Absorb or cover with dry earth, sand or other non-combustible material and transfer to containers. DO NOT GET WATER INSIDE CONTAINERS. /Barium cmpd, nos/ [R9] +First aid: Move victim to fresh air. Call 911 or emergency medical service. Apply artificial respiration if victim is not breathing. Do not use mouth-to-mouth method if victim ingested or inhaled the substance; induce artificial respiration with the aid of a pocket mask equipped with a one-way valve or other proper respiratory medical device. Administer oxygen if breathing is difficult. Remove and isolate contaminated clothing and shoes. In case of contact with substance, immediately flush skin or eyes with running water for at least 20 minutes. For minor skin contact, avoid spreading material on unaffected skin. Keep victim warm and quiet. Effects of exposure (inhalation, ingestion or skin contact) to substance may be delayed. Ensure that medical personnel are aware of the material(s) involved, and take precautions to protect themselves. /Barium cmpd, nos/ [R9] FIRP: *Large amt of water should be used on adjacent fires. /Soluble barium cmpd (as barium)/ [R10, 1981.2] *Self-contained breathing apparatus with a full facepiece operated in pressure demand or other positive pressure mode. /Soluble barium cmpd (as barium)/ [R10, 1981.6] *If material on fire or involved in fire: Extinguish fire using agent suitable for type of surrounding fire. (Material itself does not burn or burns with difficulty.) Cool all affected containers with flooding quantities of water. Apply water from as far a distance as possible. Use foam, dry chemical, or carbon dioxide. Keep run-off water out of sewers and water sources. /Barium compounds, NOS/ [R11] REAC: *Barium is divalent and combines readily with oxygen, nitrogen, hydrogen, ammonia, water, halogens, and sulfides, generating large amounts of heat. /Barium cmpd/ [R12] SERI: *Soluble barium compounds may cause local irritation of the eyes, nose, throat, bronchial tubes, and skin. /Soluble barium cmpd (as barium)/ [R10, 1981.1] EQUP: *Respirators may be used when engineering and work practice controls are not technically feasible, when such controls are in the process of being installed, or when they fail and need to be supplemented. Respirators may also be used for operations which require entry into tanks or closed vessels, and in emergency situations. If the use of respirators is necessary, the only respirators permitted are those that have been approved by the Mine Safety and Health Administration (formerly Mining Enforcement and Safety Administration) or by the National Institute for Occupational Safety and Health. /Soluble barium cmpd (as barium)/ [R10, 1981.3] *Employees should be provided with and required to use impervious clothing, gloves, face shields (eight inch minimum), and other appropriate protective clothing necessary to prevent repeated or prolonged skin contact with barium carbonate, barium chloride, barium nitrate, or liq containing these cmpd. ... Employees should be provided with and required to use dust and splash proof safety goggles where barium carbonate, barium chloride, barium nitrate, or liq containing these cmpd may contact the eyes. [R10, 1981.3] *Respiratory Protection for Soluble Barium Compounds (as Barium) as follows: Condition Minimum Respiratory Protection Required Above 0.5 mg/cu m; 2.5 mg/cu m or less: Any dust and mist respirator, except single use. 5 mg/cu m or less: Any dust and mist respirator, except single use or quarter mask respirator. Any fume respirator or high efficiency particulate filter respirator. Any supplied air respirator. Any self-contained breathing apparatus. 25 mg/cu m or less: A high efficiency particulate filter respirator with a full facepiece. Any supplied air respirator with a full facepiece, helmet, or hood. Any self-contained breathing apparatus with a full facepiece. 250 mg/cu m or less: A Type C supplied air respirator operated in pressure demand or other positive pressure mode or with a full facepiece, helmet, or hood operated in continuous flow mode. A powered air purifying respirator with a high efficiency particulate filter. Greater than 250 mg/cu m or entry and escape from unknown concentrations: Self-contained breathing apparatus with a full facepiece operated in pressure demand or other positive pressure mode. A combination respirator which includes a Type C supplied air respirator with a full facepiece operated in pressure demand or other positive pressure or continuous flow mode and an auxiliary self-contained breathing apparatus operated in pressure demand or other positive pressure mode. ... Escape: A high efficiency particulate filter respirator. Any escape self contained breathing apparatus. /Soluble barium cmpd (as barium)/ [R10, 1981.6] */NIOSH approved respirators,/ or goggles may be needed where amounts of significant soluble or alkaline forms are encountered, as well as protective clothing. RESPIRATOR SELECTION (max concn): 2.5 mg/cu m use dust mask and mist respirator, except single use respirators; 5 mg/cu m use dust mask and mist respirator, except single use and quarter mask respirators, or use fume or high efficiency particulate respirator, or a supplied air respirator, or a self-contained breathing apparatus; 25 mg/cu m use a high efficiency particulate respirator with a full facepiece, or a supplied air respirator with a full facepiece, helmet or hood, or use a self-contained breathing apparatus with a full facepiece; 250 mg/cu m use a Type C supplied air respirator with full facepiece operated in pressure demand or other positive pressure mode or with full facepiece, helmet, or hood operated in continuous flow mode, or use a powered air purifying respirator with high efficiency filter; at escape levels use a high efficiency particulate respirator or a self-contained breathing apparatus. /Soluble or alkaline barium compounds/ [R13, 106] *Respirator selection: Upper limit devices recommended by OSHA: 5 mg/cu m: any dust and mist respirator except single use and quarter mask respirators or any supplied air respirator or any self-contained breathing apparatus; 12.5 mg/cu m: any powered air purifying respirator with a dust and mist filter or any supplied air respirator operated in a continuous flow mode; 25 mg/cu m: any air purifying full facepiece respirator with a high efficiency particulate filter or any powered air purifying respirator with a tight fitting facepiece and a high efficiency particulate filter or any supplied air respirator with a tight fitting facepiece operated in a continuous flow mode or any self-contained breathing apparatus with a full facepiece or any supplied air respirator with a full facepiece; 250 mg/cu m: any supplied air respirator with a full facepiece and operated in a pressure demand or other positive pressure mode; Emergency or planned entry in unknown concn or IDLH conditions: any self-contained breathing apparatus with a full facepiece and operated in a pressure-demand or other positive pressure mode or any supplied air respirator with a full facepiece and operated in a pressure demand or other positive pressure mode in combination with an auxiliary self-contained breathing apparatus operated in pressure demand or other positive pressure mode; Escape: any air purifying full facepiece respirator with a high efficiency particulate filter or any appropriate escape-type self-contained breathing apparatus /Barium soluble compounds, as Ba/ [R14] OPRM: *If employees' clothing has had any possibility of being contaminated with barium carbonate, barium chloride, barium nitrate ... or liq containing these cmpd, employees should change into uncontaminated clothing before leaving the work premises. ... Clothing contaminated with barium carbonate, barium chloride, barium nitrate ... should be placed in closed containers for storage until it can be discarded or until provision is made for the removal of contaminant from the clothing. If the clothing is to be laundered or otherwise cleaned to remove the contaminant, the person performing the operation should be informed of contaminant's hazardous properties. ... Non-impervious clothing which becomes contaminated with barium carbonate, barium chloride, barium nitrate ... should be removed promptly and not reworn until the contaminant is removed from the clothing. /Soluble barium cmpd/ [R10, 1981.3] *Skin that becomes contaminated with barium carbonate, barium chloride, or barium nitrate should be promptly washed or showered to remove any contaminant. In the case of barium carbonate, employees should use soap or mild detergent and water for washing purposes. /Soluble barium cmpd/ [R10, 1981.3] *Eating and smoking should not be permitted in areas where solid barium carbonate, barium chloride, barium nitrate ... or liq containing these cmpd are handled, processed, or stored. Employees who handle barium carbonate, barium chloride, barium nitrate ... or liq containing these cmpd should wash their hands thoroughly before eating, smoking, or using toilet facilities. In the case of barium carbonate, employees should use soap or mild detergent and water for washing purposes. /Soluble barium cmpd/ [R10, 1981.4] *TO KEEP DUST CONCN BELOW RECOMMENDED LEVELS, PROCESSES SHOULD BE ENCLOSED AND/OR EXHAUST VENTILATION INSTALLED. ADEQUATE WASHING AND OTHER SANITARY FACILITIES SHOULD BE PROVIDED ... AND RIGOROUS PERSONAL HYGIENE MEASURES SHOULD BE ENCOURAGED. SMOKING AND CONSUMPTION OF FOOD AND BEVERAGES IN WORKSHOPS SHOULD BE PROHIBITED. FLOORS IN WORKSHOPS SHOULD BE MADE OF IMPERMEABLE MATERIALS AND FREQUENTLY WASHED DOWN. /BARIUM AND COMPOUNDS/ [R15] *Contact lenses should not be worn when working with this chemical. /Sol barium cmpd, as Ba/ [R14] *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. *If material not on fire and not involved in fire: Keep sparks, flames, and other sources of ignition away. Keep material out of water sources and sewers. Build dikes to contain flow as necessary. Do not use water. /Barium compounds, NOS/ [R11] *Personnel protection: Avoid breathing vapors. Keep upwind. ... Avoid bodily contact with the material. ... Do not handle broken packages unless wearing appropriate personal protective equipment. /Barium compounds, NOS/ [R11] *... EFFORTS SHOULD ... BE MADE TO REDUCE ATMOSPHERIC CONCN OF BARITE DUST TO A MINIMUM. /BARITE DUST/ [R15] SSL: *The free element oxidizes readily in moist air ... . /Barium/ [R12] SHIP: *No person may /transport,/ offer or accept a hazardous material for transportation in commerce unless that person is registered in conformance ... and the hazardous material is properly classed, described, packaged, marked, labeled, and in condition for shipment as required or authorized by ... /the hazardous materials regulations (49 CFR 171-177)./ [R16] *The International Air Transport Association (IATA) Dangerous Goods Regulations are published by the IATA Dangerous Goods Board pursuant to IATA Resolutions 618 and 619 and constitute a manual of industry carrier regulations to be followed by all IATA Member airlines when transporting hazardous materials. [R17] *The International Maritime Dangerous Goods Code lays down basic principles for transporting hazardous chemicals. Detailed recommendations for individual substances and a number of recommendations for good practice are included in the classes dealing with such substances. A general index of technical names has also been compiled. This index should always be consulted when attempting to locate the appropriate procedures to be used when shipping any substance or article. [R18] CLUP: *If soluble barium compounds are spilled, the following steps should be taken: 1. Ventilate area of spill. 2. Collect spilled material in the most convenient and safe manner and deposit in sealed containers for reclamation or for disposal in a secured sanitary landfill. Liquid containing soluble barium compounds should be absorbed in vermiculite, dry sand, earth, or a similar material. /Soluble barium compounds (as barium)/ [R10, 1981.5] *The European Community guidelines regard sol barium salts as moderately dangerous for water quality (LD50 5-50 mg/kg) and their removal may be accomplished by diluted sulfuric acid and subsequent neutralization. /Sol barium salts/ [R19, 100] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. *... Ion exchange, lime softening and reverse osmosis are effective to remove barium from drinking water. Conventional coagulation/filtration processes are not effective to remove barium from drinking water. /Barium ion/ [R20] TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- TOXS: *Like calcium, barium accumulates in bone. It is deposited preferentially in the most active areas of bone growth, primarily at the periosteal surfaces. Other factors important in absorption and deposition include age and dietary restrictions. ... Inhaled barium can be absorbed through the lung or directly from the nasal membrane into the bloodstream. ... Insoluble compounds, such as barium sulfate, accumulate in the lungs and are cleared slowly by ciliary action. Barium is eliminated in the urine and in the feces, the rates varying with the route of administration. ... Barium possesses chemical and physiological properties that allow it to compete with and replace calcium in processes mediated normally by calcium, particularly those relating to the release of adrenal catecholamines and neurotransmitters, such as acetylcholine and noradrenaline. ... Barium doses as low as 0.2-0.5 mg/kg body weight, generally resulting from the ingestion of barium chloride or carbonate, have been found to lead to toxic effects in adult humans. Clinical features of barium poisoning include acute gastroenteritis, loss of deep reflexes with onset of muscular paralysis and progressive muscular paralysis. The muscular paralysis appears to be related to severe hypokalemia. ... Baritosis has been observed in individuals occupationally exposed to barium compounds. ... There is no evidence that barium is carcinogenic. [R21] CARC: *WEIGHT OF EVIDENCE CHARACTERIZATION: Under EPA's 1986 Guidelines for Carcinogen Risk Assessment, barium would be classified as Group D, not classifiable as to human carcinogenicity. Although adequate chronic oral exposure studies in rats and mice have not demonstrated carcinogenic effects, the lack of adequate inhalation studies precludes assessing the carcinogenic potential of inhaled barium. Under the Proposed Guidelines for Carcinogenic Risk Assessment, barium is considered not likely to be carcinogenic to humans following oral exposure and its carcinogenic potential cannot be determined following inhalation exposure. Basis - Oral exposure studies in rats and mice ... did not find significant increases in tumor incidence following chronic exposure. In the 1994 NTP rat study /National Toxicology Program Technical Report Series #432 on Barium Chloride Dihydrate (10326-27-9)/, statistically significant negative trends in the incidence of leukemia, adrenal tumors, and mammary gland tumors were observed. The design of the rat and mouse NTP studies was adequate to assess carcinogenicity. These studies used an adequate number of animals per group, exposed animals for 2 years, tested several dosage levels, and examined an extensive number of tissues. The inhalation exposure and intratracheal studies ... are inadequate for subchronic exposure carcinogenicity evaluation because of several deficiencies in the design and reporting ... HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Oral Exposure - Sufficient; Inhalation Studies - Inadequate. /Barium and Compounds/ [R22] ANTR: *Treatment generally consists of iv infusion of potassium carbonate or lactate and/or oral admin of sodium sulfate to precipitate the barium as barium sulfate ... . /Barium/ [R23] *Magnesium sulfate administered ... may prevent severe barium poisoning by precipitating insoluble barium sulfate. [R24, 1545] *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if necessary. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Do not attempt to neutralize because of exothermic reaction. Cover skin burns with dry sterile dressings after decontamination ... . /Barium and related compounds/ [R25, 338] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious. Monitor cardiac rhythm and treat arrhythmias if necessary ... . Start an IV with lactated Ringer's /SRP: "To keep open", minimal flow rate/. Watch for signs of fluid overload. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Barium and related compounds/ [R25, 339] MEDS: *Initial Medical Examination: A complete history and physical examination: The purpose is to detect existing conditions that might place the exposed employee at increased risk, and to establish a baseline for future health monitoring. Examination of the heart, lung, and nervous system should be stressed. The skin should be examined for chronic disorders. 14"X17" chest roentgenogram: Soluble barium compounds cause human lung damage. Surveillance of the lung is indicated. FVC (Forced Vital Capacity) and FEV1 (Forced Expiratory Volume) (1 sec): Soluble barium compounds are respiratory irritants. Persons with impaired pulmonary function may be at increased risk from exposure. Periodic surveillance is indicated. Electrocardiogram: Barium compounds may cause cardiac arrhythmias and may have a direct effect on the cardiac muscle. Periodic surveillance of the heart is indicated. Periodic Medical Examination: The aforementioned medical examinations should be repeated on an annual basis, except that an x-ray is necessary only when indicated by the results of pulmonary function testing, or by signs and symptoms of respiratory disease. /Soluble barium compounds (as barium)/ [R10, 1981.1] *Consideration should be given to the skin, eye, heart, and lung in any placement or periodic examination. /Barium and cmpd/ [R13, 105] *The assessment of barium exposure can be accomplished through measurement of barium. However, the literature search did not reveal reports of blood levels that correlated with exposure levels or the onset of adverse clinical effects ... Blood Reference Ranges: Normal - not established; Exposed - not established; Toxic - not established. Serum or Plasma Reference Ranges: Normal - not established; Exposed - not established; Toxic - not established. Urine Reference Ranges: Normal - not established; Exposed - not established; Toxic - not established. /Barium/ [R26, 350] *Urine Albumin: Albuminuria has been shown to be a specific marker of glomerular dysfunction. Tubular damage, however, can also result in increased levels of albumin in the urine. /Barium/ [R26, 351] *Urinary Beta-2-Microglobulin and/or Retinal Binding Protein: Measurements for the presence of either of these low molecular weight proteins are useful in detection of early impairment of proximal tubular function. However, beta-2-microglobulin is unstable at urinary pH less than 6, and may degrade in the bladder prior to collection and subsequent neutralization of the urine sample. Measurement of retinal /SRP: retinol/ binding protein appears to be a better marker for early tubular dysfunction due to its stability in the urine subsequent to collection and analysis. However, retinal /SRP: retinol/ binding protein is produced in the liver and not a constitutive protein of the kidney, so that its presence in the kidney provides only indirect evidence of tubular damage. /Barium/ [R26, 351] *Urinary Alpha and Pi Isoenzymes of Glutathione S-Transferase: Radio-immunological and Elisa techniques have been developed for quantitation of and isoenzymes of glutathione S-transferase, which are constitutive proteins in the kidney." The isoenzyme is located only in the proximal tubule, while the isoenzyme is located in the distal convoluted tubule, the loop of Henle, and the collecting ducts of the kidney. Damage to epithelial cell membranes can result in the increased excretion of these isoenzymes in the urine. This test for assessing renal tubular damage appears to have many advantages over other available tests, such as: (1) the and isoenzymes are constitutive proteins in the kidney; (2) these isoenzymes are stable in the urine; (3) the test is simple and reproducible; and (4) due to selective localization of the isoenzymes, differential diagnosis of specific tubular damage is possible. In addition, increased levels of these isoenzymes were seen in patients previously exposed to nephrotoxicants where'conventional tests for kidney function were normal, indicating a high degree of sensitivity. /Barium/ [R26, 351] *Urinary Enzyme N-Acetylglucosaminidase: This lysosomal enzyme has shown promise in assessment of subclinical nephrotoxic injury. This enzyme is not normally filtered at the glomerulus due to its high molecular weight. In the absence of glomerular injury, this enzyme will be detected in the urine as a result of leakage or exocytosis from damaged, stimulated, or exfoliated renal cells. The sensitivity of measurement for this enzyme has not been thoroughly studied, but it's usefulness has shown some promise. However, this enzyme is unstable at urinary pH greater than 8, which could diminish the sensitivity of the measurement due to enzyme degradation. /Barium/ [R26, 352] *Routine Urinalysis: Performing a routine urinalysis including parameters such as specific gravity, glucose, and microscopic examination may be useful for assessing renal toxicity. /Barium/ [R26, 352] *Respiratory Symptom Questionnaires: Questionnaires have been published by the American Thoracic Society and the British Medical Research Council. These questionnaires have been found to be useful in identification of people with chronic bronchitis, however certain pulmonary function tests such as FEV1 have been found to be better predictors of chronic airflow obstruction. /Barium/ [R26, 352] *Evaluation of Central Nervous System Effects: Evaluation of CNS effects can be performed through neuropsychological assessment, which consists of a clinical interview and administration of standardized personality and neuropsychological tests. The areas that the neuropsychology test batteries focus on include the domains of memory and attention; visuoperceptual, visual scanning, visuospatial, and visual memory; and motor speed and reaction time. There is limited data on which components of the test batteries are best indicators of early CNS effects. /Barium/ [R26, 353] *Evaluation of Cranial Neuropathies: Evaluation of cranial nerve damage, as evidenced by symptoms such as loss of balance, visual function, smell, taste, or sensation on the face, can be accomplished through a physical examination focusing on tests such as: Smell Assessment ... Visual Assessment ... Facial and Trigeminal Nerve Assessment ... Vestibular Assessment ... Hearing Assessment. /Barium/ [R26, 354] *Chest Radiography: This test is widely used for assessing pulmonary disease. Chest radiographs have been found to be useful for detection of early lung cancer in asymptomatic people, especially for detection of peripheral tumors such as adenocarcinomas. However, even though OSHA mandates this test for exposure to some toxicants such as asbestos, there are conflicting views on its efficacy in detection of pulmonary disease. /Barium/ [R26, 352] *Pulmonary Function Tests: The tests that have been found to be practical for population monitoring include: Spirometry and expiratory flow-volume curves; Determination of lung volumes; Diffusing capacity for carbon monoxide; Single-breath nitrogen washout; Inhalation challenge tests; Serial measurements of peak expiratory flow; Exercise testing. /Barium/ [R26, 353] *Evaluation of Peripheral Neuropathy: Nerve conduction study; Electromyography; Quantitative sensory testing; and Thermography. /Barium/ [R26, 353] *Measurement of Serum Potassium Levels: Monitoring of these levels may be helpful in diagnosing and monitoring hypokalemia, which can be caused by barium compounds. /Barium/ [R26, 351] HTOX: *INGESTION OF GRAM QUANTITIES OF SOL BARIUM SALTS MAY BE FATAL, WITH DEATH RESULTING FROM CARDIAC ARREST. MUSCLE TREMORS ARE FREQUENT. RESPIRATORY FAILURE AND CONVULSIONS FOLLOWED BY PARALYSIS OF EXTREMITIES MAY ALSO OCCUR. ... BARIUM CAUSES INCR IN CELL-MEMBRANE RESISTANCE, A PROLONGATION OF ACTION POTENTIALS, AND DEPOLARIZATION OF SMOOTH AND SKELETAL MUSCLE. IT HAS BEEN PROPOSED THAT THESE CHANGES ARE DUE TO BARIUM INDUCED DECR IN POTASSIUM CONDUCTANCE ... . /SOL BARIUM SALTS/ [R27] *SOMETIMES DANGEROUS BECAUSE OF SOLUBLE BARIUM IMPURITIES. OTHERWISE INERT AND INSOLUBLE. /BARIUM SALTS, INSOLUBLE/ [R28] *BARIUM SALTS THAT ARE SOL IN WATER OR ACID ARE POISONOUS WHEN SWALLOWED, CAUSING SEVERE IRRITATION OF GI TRACT, PROSTRATION, PARALYSIS AND CONVULSIONS. /SOLUBLE BARIUM SALTS/ [R29] *... Human poisonings by soluble barium salts are uncommon ... . The acid soluble barium salts ... are highly toxic ... . For most of acid soluble salts of barium the lethal dose for adults appears to lie between 1 and 15 g. Death occurs within few hr or few days. ... Barium ion stimulates smooth, striated and cardiac muscle; result is violent peristalsis, arterial hypertension, muscle twitching and disturbances in cardiac action. Motor disorders incl stiffness and immobility of limbs and sometimes of the trunk, leg cramps, twitching of facial muscles, and paralysis of tongue and pharynx with attendant loss or impairment of speech and deglutition. CNS may be first stimulated and then depressed. Ventricular tachyarrhythmias (incl ventricular fibrillation) and transient asystole have been observed. Kidney damage has been described as a late complication, probably as result of circulatory insufficiency. /Sol barium salts/ [R30, p. III-61] *SYMPTOMATOLOGY: 1. EXCESSIVE SALIVATION, VOMITING, SEVERE ABDOMINAL PAIN AND VIOLENT PURGING WITH WATERY AND BLOODY STOOLS. 2. SLOW AND OFTEN IRREGULAR PULSE DUE TO VENTRICULAR PREMATURE CONTRACTIONS AND TRANSIENT ELEVATION IN ARTERIAL BLOOD PRESSURE. 3. TINNITUS, GIDDINESS AND VERTIGO. 4. MUSCLE TWITCHING, PROGRESSING TO CONVULSIONS AND/OR PARALYSIS. 5. DILATED PUPILS WITH IMPAIRED ACCOMMODATION. 6. CONFUSION AND INCR SOMNOLENCE, WITHOUT COMA. 7. COLLAPSE AND DEATH FROM RESP FAILURE, APPARENTLY DUE TO FLACCID PARALYSIS OF RESP MUSCLES. 8. CARDIAC ARREST AFTER PERIODS OF VENTRICULAR TACHYCARDIA AND FIBRILLATION. /SOLUBLE BARIUM CMPD/ [R30, p. III-62] *ACCIDENTAL POISONING FROM INGESTION OF SOL BARIUM SALTS HAS RESULTED IN GASTROENTERITIS, MUSCULAR PARALYSIS, DECR PULSE RATE, AND VENTRICULAR FIBRILLATION AND EXTRASYSTOLES. POTASSIUM DEFICIENCY OCCURS IN ACUTE POISONING ... DIGITALIS-LIKE TOXICITY, MUSCLE STIMULATION, AND CNS EFFECTS HAVE BEEN CONFIRMED ... . /SOL BARIUM SALTS/ [R31, 624] *In the Chinese province of Szechuan, an endemic condition resembling familial periodic paralysis (pa-ping) has been described, which eventually turned out to be food poisoning from the very high proportion of barium in the table salt mined there. /Soluble barium cmpd/ [R32, p. V2 90] *Threshold of a toxic dose in adult humans is about 0.2-0.5 g barium; lethal in untreated cases is 3-4 g barium (LD50 about 66 mg/kg). These figures apply to the portion absorbed from the gut. /Soluble barium cmpd/ [R32, p. V2 90] *The organs which are affected by exposure to barium sol cmpd, as Ba are heart, CNS, skin, resp system, eyes. /Soluble barium cmpd, as Ba/ [R14] *Potential symptoms as a result of exposure /to barium sol cmpd, as Ba/: Upper resp irritation; GI; muscle spasm; slow pulse, extrasystoles; hypokalemia; irritation of eyes; skin burns. /Sol barium cmpd, as Ba/ [R14] *Symptoms of acute barium toxicity in humans after oral ingestion are ... pronounced stimulation of cardiac, smooth, or striated muscle. Effects on the cardiovascular system include premature ectopic ventricular contractions, leading progressively to tachycardia, ventricular fibrillation and death. Hypertension is also common, stemming from increased cardiac contractility and/or increased peripheral resistance (arteriolar constriction). Hypokalemia occurs as a result of abnormal potassium permeability. Gastrointestinal abnormalities include salivation and diarrhea. Skeletal muscles are initially stimulated, but later enter a state of flaccid paralysis. /Barium ion/ [R33] *Symptoms of acute barium toxicity in humans after oral ingestion ... reflect pronounced stimulation of cardiac, smooth or striated muscle. Effects on the cardiovascular system include premature ectopic ventricular contractions, leading progressively to tachycardia, ventricular fibrillation and death. hypertension is also common, stemming from increased cardiac contractility and/or increased peripheral resistance (arteriolar constriction). Hypokalemia occurs as a result of abnormal potassium permeability. Gastrointestinal abnormalities include salivation and diarrhea. Skeletal muscles are initially stimulated, but later enter a state of flaccid paralysis. /Barium ion/ [R33] *Barium poisoning results in a rapid onset of gastrointestinal symptoms, paralysis, cardiac dysrhythmias, hypertension, and often severe hypokalemia. The acute syndrome can be fatal. /Barium/ [R24, 1543] *Within 1 or 2 hours after ingestion of the poison /barium/, patients experience tingling around the mouth, diarrhea, vomiting, and colicky abdominal pain. Arterial hypertension is usually observed. In 2 to 3 hours the tingling moves from the face to the hands, pupillary reactions are impaired, muscle stretch reflexes become depressed, muscle twitching is noticeable, and flaccid weakness begins to spread through the muscles of the upper and lower extremities. In some cases, complete flaccid quadriplegia develops within a few hours; in others, paralysis becomes severe on the second day of illness. Sensation is always preserved despite subjective paresthesias. In most cases symptoms abate by 24 hours and patients can be ambulatory within 48 hours. In some patients muscle paralysis and weakness can persist for more than a week. ... Long-term prognosis is favorable, but the acute syndrome, which can also include cardiac dysrhythmia, can be fatal and must be treated promptly. Death may ensue in a few hours from cardiac arrest or respiratory paralysis, unless vigorous therapy is administered with intravenous potassium. /Barium/ [R24, 1545] *It is important to recognize soluble barium salts as potentially dangerous materials when ingested, since they are rapidly absorbed from the gastrointestinal system and are fatal to humans in amounts less than 1 g. /Soluble barium salts/ [R34] *There are three stages of barium poisoning: a) acute gastroenteritis; b) loss of deep reflexes with onset of muscular paralysis; and c) progressive muscular paralysis. The muscular paralysis seems to be related to severe hypokalemia ... In most cases, recovery is rapid and uneventful. /Barium/ [R23] *... Workers exposed to finely ground barium salts develop baritosis consisting of a mixture of very fine punctate and annular lesions and some slightly larger nodular lesions ... Cardiac activity disturbances noted in 31/60 workers exposed to barium salts for 3-22 yr possibly reflect the effect of barium on cell potassium levels. /Barium/ [R35] *At a mineral processing plant/ ... Barium workers had a significantly higher incidence of hypertension than did non- barium workers (58% versus 20%). Barium exposure resulting from the grinding and mixing of several grades of barium-containing ore ("baryte process") ranged from 0.8 to 1.92 mg/m3, with a mean of 1.07 mg/m3. /Barium/ [R35] *The prevalence of dental caries was reported to be significantly lower in 39 children residing in a community supplied with drinking water containing high barium concn (8-10 mg/l) than in 36 children from a similar community with drinking water concn of < 3.0 mg/l ... ./Barium/ [R36] *Barium poisoning results in a rapid onset of gastrointestinal symptoms, paralysis, cardiac dysrhythmias, hypertension, and often severe hypokalemia. The acute syndrome can be fatal. [R24, 1543] *Clinical toxicity of barium poisoning: Gastrointestinal: salivation, nausea, vomiting, severe abdominal pain, watery diarrhea, increased peristalsis; Nervous system: mydriasis, anxiety, circumoral and peripheral paresthesias, diminished deep tendon reflexes, headache, confusion, seizure; Respiratory: respiratory failure, ... Cardiac: ... hypertension, premature ventricular contractions, asystole, ... Muscle: ... myalgias, rigidity, cramps, dysarthria ... /From table/ [R24, 1543] *The toxicity of barium compounds depends on their solubility. [R37] *Maximum contaminant levels (MCLs) for inorganic chemicals in drinking water /for/ Barium /is/ 1.0 mg/l /due to/ recognized toxic effects on heart, blood vessels, and nerves from accidental perimental, and therapeutic ingestion. /from table/ [R38] NTOX: *BARIUM PRODUCES STRONG VASOCONSTRICTION BY DIRECT STIMULATION OF ARTERIAL MUSCLE, VIOLENT STIMULATION OF SMOOTH MUSCLE (PERISTALSIS), AND STIMULATION FOLLOWED BY PARALYSIS OF CNS. HEMATOPOIESIS IS REPORTED STIMULATED IN RABBITS; TOXIC DOSES ARE HEMOLYTIC. /SOL BARIUM CMPD/ [R39] *CLINICAL SIGNS FOLLOWING INGESTION OF TOXIC DOSE OF BARIUM ... IN POULTRY /ARE/ DARKENING OF COMB, DISTRESSED APPEARANCE AND INCOORDINATION OF MOVEMENT; IN OTHER SPECIES, SALIVATION, VOMITING AND DEFECATION, WITH TWITCHING, TREMORS AND MOTOR WEAKNESS, FOLLOWED BY PARALYSIS OF SKELETAL MUSCLES IN SEVERE CASES. AFTER IV INJECTION, GASTROINTESTINAL SIGNS ARE LESS MARKED, THE MOST DISTINCTIVE FEATURE BEING SLOWING OF HEART. DEATH IS CAUSED BY EXTREME DIGITALIS-LIKE ACTION OF BARIUM ION ON THE HEART. /SOL BARIUM CMPD/ [R40] *The cardiomyopathies in dogs and guinea pigs included ectopic ventricular contractions, ventricular tachycardia and finally, ventricular fibrillation. The non-cardiac effects were salivation, diarrhea, hypertension, skeletal muscle paralysis, and resp paralysis. /Sol barium cmpd/ [R32, p. V2 92] *The effect of barium on the central nervous system was studied by examining the electroshock thresholds for convulsions prior to and following barium administration. Male albino Swiss Webster mice (20 to 25 g) exhibited increased convulsive electroshock sensitivity when tested 0.5 hr after intraperitoneal barium administration (6.6 and 20 mg/kg) and decreased sensitivity when tested after 24 hr (2, 6.6, and 20 mg/kg). /Barium ion/ [R41] */It was/ found that one week old chickens (male and female) could tolerate barium concentrations (hydroxide or acetate salt) up to 1,000 ppm in their diets for three weeks without apparent ill effects. Assuming that 1 ppm barium in food equals 0.125 mg barium/day for 21 days, the estimated total barium dosage was 2,625 mg/kg. A slight depression of growth was seen at 2,000 ppm (5,250 mg/kg total) and 4,000 ppm (10,500 mg/kg total), but no increase in mortality was apparent. More than half of the chickens receiving 8,000 ppm (21,000 mg/kg total) barium during the feeding period died. All chickens receiving 16,000 ppm and 32,000 ppm barium died after an average of seven days (14,000 mg/g total) and five days (20,000 mg/kg total), respectively. /Barium/ [R42] *Ingestion of soluble barium compounds in doses exceeding 0.2 to 0.3 mg/kg body weight causes acute intoxication with symptoms and signs, including gastroenteritis, muscular paralysis, slow pulse rate, extrasystoles, and marked hypokalemia. This hypokalemia is believed to be the cause for skeletal muscle paralysis, which can progress to involve respiratory muscles. ... Muscle cramping and twitching may occur, and small amounts of barium in cerebrospinal fluid lead to convulsions. Marked hypertension due to smooth muscle spasms in arterioles occurs. /Barium compounds/ [R34] *Exposure to barium may occur in connection with welding. ... Various commonly used welding electrodes using barium compounds as fluxes in are welding were studied. They examined five welders working in a 12 X 4 X 3 m tent with natural ventilation for a 3 hour period, with actual fume generation taking 30% of this time. Analyses revealed that fumes from a cored wire electrode with barium fluoride flux contain more than 16% barium (soluble in water). Stick electrodes with barium carbonate flux produced fumes with 15% to 30% barium in readily soluble form. Urine samples for barium analysis taken at the end of the 3 hour exposure and the next morning resulted in elevated barium levels, averaging 120 ug Ba/L and 48 ug Ba/L, respectively. /Barium compounds/ [R34] *At a mineral processing plant/ ... Barium workers had a significantly higher incidence of hypertension than did non- barium workers (58% versus 20%). Barium exposure resulting from the grinding and mixing of several grades of barium-containing ore ("baryte process") ranged from 0.8 to 1.92 mg/m3, with a mean of 1.07 mg/m3. /Barium/ [R43] *... Investigated the toxic effect on the growth of Eurasian water milfoil Myriophyllum spicatum. Root weight was the most sensitive parameter measured and showed a 50% reduction, relative to controls, at a barium concn of 41.2 mg/l. /Barium/ [R44] */Ionic barium/ ... like Ca+2, spontaneously changes the membrane potential of Paramecium caudatum, making it resemble the long-lasting potential found in cardiac muscle fibres and smooth muscle cells. Upon replacement of calcium ions with barium ions, the normal swimming behavior of Paramecium multimicronucleatum in an essential mineral soln (200 umol Ca+2/l) changed into continuous avoidance reactions ... . /Barium/ [R43] *The production of aflatoxins by Aspergillus is affected by the barium ion (Ba+2) ... . /Barium/ [R45] *The divalent barium ion may cause dissociation of the polyribosome-mRNA complex in Paramecium aurelia and a marked decr in the amt of monoribosomes ... . /Barium/ [R45] *Barium inhibits the lipolytic activity of the intact cells of Mycobacterium rubrum and is a potent inhibitor for Actinomyces streptomycin ... The barium ion (Ba +2) has been shown to inhibit the dehydrogenase activities of resting cells of Proteus vulgaris ... and to inhibit flocculation in Saccharomyces cerevisiae ... . /Barium/ [R45] *... The highest concn of barium tolerated by cultures of Chlorella vulgaris without affecting growth was 4 mg/l and the lowest inhibitory concn was 8 mg/l. Problems with the precipitation of barium from the culture soln as the sulfate suggested ... that the above results might have been artificially high ... Barium inhibited calcification of the freshwater green alga Gloeotaenium at a concn of 50 mg/l. /Barium/ [R45] *... Exposed water fleas (Daphnia magna) in a 48-hr test to various concn of barium and calculated the NOAEL to be 68 mg/l. In contrast ... reported 48-hr and 21-day LC50 values of 14.5 and 13.5 mg/l, respectively. The also measured the reproductive performance of the daphnids during the 21-day tests and reported 16% impairment of reproduction at 5.8 mg barium/l and 50% impairment at 8.9 mg/l. In the same study, a reduction in avg weight was also observed. /Barium/ [R44] *The toxic effects of ionic barium (Ba+2) and other divalent cations to Paramecium has been found to incr in alkaline and decr in acid solutions. The effect was most noticeable at the isoelectric point of the cell surface ... An incr in Ba+2 concn incr the staining of Escherischia coli and Shigella ellipsoideus with the anionic fluorochrome, uranin ... . /Barium/ [R45] POPL: *Persons with impaired pulmonary function may be at increased risk from /inhalation/ exposure. /Soluble barium compounds (as barium)/ [R10, 1981.1] *Several groups warrant special consideration because of potential increased sensitivity to barium. These groups are: a) children, individuals who have a low food intake or individuals consuming milk (in all cases evidence exists for increased barium absorption), b) individuals with cardiovascular disease or hypertension, and c)individuals suffering from nervous or muscular disorders. Populations exposed to high natural levels of barium in drinking water are also likely to be at greater risk. /Soluble barium cmpd/ [R46] *Patients receiving drugs such as acetazolamide ... or thiazide diuretics have incr urinary potassium excretion ... and would be at higher risk of potassium deficiency due to barium toxicity. Patients subject to X-ray studies of the GI tract have shown occasional incr in serum protein-bound iodine ... . /Barium/ [R47] *Occupational exposure to soluble barium cmpd has been reported for workers exposed to welding fumes ... The wiring used in arc welding processes was shown to contain 20-40% soluble barium cmpd, and fumes produced during these processes contained 25% barium. Urine analysis of workers revealed barium concn ranging from 31 to 234 ug/l after 3 hr of exposure ... The level in the urine of controls ranged from 1.8 to 4.7 ug/l. /Barium/ [R47] ADE: *SOLUBLE SALTS ARE RAPIDLY ABSORBED FROM THE ALIMENTARY CANAL. THE BARIUM ION IS FOUND IN MOST TISSUES AFTER ABSORPTION, INCLUDING BONE; DISAPPEARS FROM ALL BUT BONE IN FEW DAYS BEING EXCRETED BY LARGE BOWEL, EVEN AFTER PARENTERAL ADMINISTRATION, AND TO SOME EXTENT BY KIDNEYS. /SOLUBLE BARIUM SALTS/ [R48] *The digestive system is extremely permeable to barium /ion/, allowing for rapid transfer to and from the blood stream. The /barium ion/ is transported in the plasma and disappears from the blood completely within 24 hr. ... In feces, 20% of barium is excreted in 24 hr ... / and / in urine 7% ... is excreted in 24 hr ... . /Soluble barium salts/ [R49, 230] *... ABOUT 2/3 OF BARIUM PRESENT IS TO BE FOUND IN SOFT TISSUES. ... ABSORPTION OF NATURALLY OCCURRING BARIUM IN FOOD IS ONLY ABOUT 2% OF TOTAL DIETARY BARIUM CONTENT, BECAUSE BARIUM OCCURS IN BOUND OR INSOLUBLE FORMS. /BARIUM/ [R50, 64] *There is no incr total accumulation of barium with age in humans, except in the lung and aorta. Since barium is found in newborn young, barium ions cross the mammary and placental barriers; the concn in infant tissues is higher than in adult tissue. /Barium ions/ [R50, 65] *THE SOLUBLE COMPOUNDS ONCE ABSORBED ARE TRANSPORTED BY THE PLASMA. /BARIUM SOLUBLE SALTS/ [R51] *... A STUDY OF THE METABOLISM OF (140)-BARIUM IN RATS SHOWED 24 HOUR URINARY AND FECAL EXCRETIONS TO BE 7 AND 20% RESPECTIVELY; BARIUM WAS IRREVERSIBLY DEPOSITED IN THE SKELETON IN TRACE AMT. /BARIUM SALTS/ [R52] *The sol compounds of barium are absorbed, and small amt are accumulated in the skeleton. The lung has an average concn of 1 ppm (dry wt). The kidney, spleen, muscle, heart, brain, and liver concn are 0.10, 0.08, 0.05, /0.04, 0.03/, and 0.03, respectively. Although some barium is excreted in urine, it is reabsorbed by the renal tubules. The major route of excretion is the feces. /Soluble barium salts/ [R31, 623] *Soluble forms of barium are readily absorbed from all segments of the respiratory tract. /Soluble barium salts/ [R32, p. V2 87] *After intravenous injection of (133)barium ion into beagle dogs, specific activity was highest in the sternum, followed by sacrum and coccyx, vertebre, ribs, humerus, and femur. In the skull, mandible, radius, ulna, and tibia-fibula, the specific activity was less than whole body specific activity. /Barium ion/ [R32, p. V2 88] *In normal humans in a state of barium equilibrium (with virtually all of the intake occurring orally), about 91% of total output was found in feces, 6% in sweat and 3% in urine. Intravenously injected soluble barium ion in a healthy man was excreted through ... feces and urine, in a ratio ranging from 3:1, and to 9:1 ... . About 75% of the dose was cleared from the body in 3 days and an addnl 10-20% during the following 7 to 42 days. The pattern of total excretion fitted a 3 compartment exponential function with biological half-time of 3.6, 34.2 and 1033 days, respectively. ... Barium excretion at 3 to 6 hr after admin of sol salt was also measured in saliva and seminal fluid of a healthy man, yielding values of 0.22-0.33% and 0.81% of dose, respectively. ... /Soluble barium salts/ [R32, p. V2 89] *... In lactating cows, excretion in milk during first 8 days after dosing was 0.6% of dose after oral and 10% of dose after iv admin. /Soluble barium salts/ [R32, p. V2 89] *Barium forms a protein adduct in serum and is deposited in bone up to 65%. /Barium ion/ [R19, 99] *Barium is absorbed via the nasal mucosal membrane, lung, and gastrointestinal tract. Soluble barium salts are absorbed most readily (3% to 11% of barium chloride), but even the less soluble carbonate and sulfate salts of barium are absorbed (45% and 85% of absorbed barium chloride dose, respectively). ... Absorbed barium is distributed via the plasma to soft tissues and to bone and maximum concn are achieved within three hours after dosing. It may also cross the placenta and reach the fetus in mammals. /Barium ion/ [R53] *Retention of barium after exposure is primarily due to skeletal deposition which occurs preferentially in active areas of bone growth (tibia ends) and on bone surfaces. /Barium ion/ [R54] *Based on autopsy data, barium levels in human bone are relatively constant and do not appear to increase with age, ranging from an average value of 7.0 ppm in bone at age 0 to 3 months to an average of 8.5 ppm at age 33 to 74 years. /Barium cmpd/ [R55] *A healthy 60 year old man was given (133)barium in a single intravenous injection. Urinary and fecal excretion in the first eight days after administration was approximately 85% of the injected dose and the ratio of total fecal to total urinary excretion was 9:1 from day 8 to day 28. Barium excretion in the saliva and seminal fluid six hr after administration was 0.22% and 0.81% of the administered dose. /Barium cmpd/ [R56] *The skeletal accretion rates /were calculated/ after (140)barium and (45)calcium were injected intramuscularly into three children (two girls and one boy of ages 1 month, 1.5 years and 5 months, weighing 4.3 kg, 12.9 kg, and 6.9 kg, respectively) and intravenously into an adult female (25 years old and 60 kg). Whole skeletal accretion rates calculated from (140)barium and (45)calcium data were approximately 0.7 and 0.4 g calcium/day, respectively, for children and 0.57 and 0.47 g calcium/day, respectively, for the adult. The accretion rate in spongy bone (data obtained from the five-month old boy) was about twice that of compact bone (0.0233 and 0.0126 g calcium per day/g calcium of bone sample, respectively). /Barium/ [R57] *Two pairs of mature lactating Redpoll X Ayrshire cows (weight not indicated) received tracer amounts of (140)barium orally, followed by an intravenous injection one to two months later. Excretion in milk during the first eight days after administration was approximately 0.6% of the oral dose and 10% of the intravenous dose. Fecal and urinary excretion rates over the same period were about 98% and 1.1%, respectively, of the oral dose and 37% and 3.4% of the intravenous dose. /Barium cmpd/ [R58] *... Observed that on day 24 after the exposure of male Sprague-Dawley rats (275 g) by nasal intubation to combustion products from diesel fuel containing a barium-based additive in soln (vehicle not specified), more than 85% of the admin dose was found in the bone, indicating significant absorption in the respiratory tract. /Barium/ [R59] *The absorption of ingested barium depends on factors such as the presence of food in the intestine, the sulfate content in the food, the age of the animal, and the location of the barium in the GI tract. /Barium/ [R60] *... Two males /human/ fed controlled diets for 80 wk absorbed between 2 and 6% of the barium content in their diet, based on urinary elimination. Elimination via the GI tract was not given. /Barium/ [R61] *... Beyond 100 days the disappearance of barium from bone was similar for both soluble and poorly soluble compounds, the half-life being 460 days. /Barium/ [R62] *In healthy human beings in a state of barium equilibrium (virtually all of the intake occurring by mouth), approx 91% of the total output was found in the feces, 6% in sweat, and 3% in urine ... . /Barium/ [R63] *Within 24 hr, 20% of an ingested dose (solubility not specified) appeared in the feces and 5-7% was excreted in the urine ... Furthermore, barium that had been absorbed and transported by the plasma was found to have been almost entirely cleared from the bloodstream within 24 hr ... . /Barium/ [R63] *... Barium is inc into the bone matrix in much the same way as calcium ... This means that the major part of the body burden will be in the skeleton. Soft tissues generally have low concn of barium, an exception being pigmented areas of the eye ... Barium is inc into the bone, esp in young animals that are still growing. In mature animals, 60-80% of the barium initially deposited is removed from the femur during the first 14 days after exposure ... The uptake of barium into bone decr with the age of the animal. No detrimental effects on the integrity of the bone have been seen. /Barium/ [R61] *Barium deposition appears to occur preferentially in the most active areas of bone growth ... although research indicates that the preferential uptake of barium is localized primarily in the periosteal, endosteal, and tabular surfaces of the bone ... . /Unspecified barium cmpd/ [R61] *... Barium has been identified in all samples taken from stillborn babies and children up to 1 yr of age, implying that barium can cross the placental barrier and be transported in the maternal milk. /Barium/ [R62] *In the USA, barium in the tooth enamel of people under 20 years of age has been found to avg 4.2 mg/kg dry weight ... /another study/ reported a mean barium concn of 22 mg/kg (a range of 0.8 to 432 mg/kg) in the teeth of people less than 20 yr old from 13 countries. /Barium/ [R64] *In the USA, the highest concn /of barium/ in soft tissues /of humans/ was found in the large intestine, muscle, and lung. The median values were approx 0.15 mg/kg wet weight ... In the liver and kidney, the median concn were < 0.003 and approx 0.1 mg/kg wet weight, respectively. /Barium/ [R65] *... The standard man ... of 70 kg contains approx 22 mg of barium ... A major part of the element is concentrated in the bone (nearly 91%), the remainder being in soft tissues such as the aorta, brain, heart, kidney, spleen, pancreas, and lung ... In human beings there is no incr of total barium with age, except in the aorta and lung ... barium deposition in the bone occurred preferentially in the active sites of bone growth. /Barium/ [R66] *... The excretion via the feces and the urine was measured for 10 days in a healthy 60-yr-old man given an iv injection of (133)barium. The barium elimination 3-6 hr after administration was measured in saliva and seminal fluid, yielding values of 0.22-0.33 and 0.81% of the dose, respectively. The percentage of the injected dose eliminated via the feces and the urine was 20% after 24 hr, 70% after 3 days, and 85% after 10 days. The ratio of fecal to urinary barium was 9.0 after 8 days. /Barium/ [R63] METB: *In a metabolic study ... admin ip injections of (140)barium and (45)calcium to young rats. The results indicated that there was no difference in the metabolism of the two cations. Barium was transferred more rapidly than calcium from the exchangeable to the non-exchangeable fractions of bone, but these differences were not significant. /Barium/ [R63] BHL: *... Beyond 100 days the disappearance of barium from bone was similar for both soluble and poorly soluble compounds, the half-life being 460 days. /Barium/ [R62] *The biological half-time for barium in the bone of mice seems to be 100 days ... . /Barium/ [R62] *An estimate of the biological half-life for barium in the rat is 90-120 days. /Barium/ [R67] *The biologic half-life /in plasma/ is short (less than 24 hours). /Soluble barium salts/ [R51] *The half-life of barium in bone has been estimated to be 50 days. /Barium ion/ [R19, 99] *... (140)barium ... has a half-life of ... 12.8 days ... . /Barium/ [R68] *Peak serum barium levels appear within 2 hr in overdose. Normal barium levels do not exceed 0.4 ug/ml. After overdose, barium levels fall quickly with an elimination half-life of 3 hr. /Barium ion/ [R69] ACTN: *The mode of release of neurotransmitter by barium is distinct from that by calcium ... Barium can evoke the release of transmitter without previous depolarization. Another characteristic of the barium-evoked release is that it is persistent, while release by calcium is transitory and terminated by membrane repolarization. /Barium/ [R70] *Barium mimics this action /of calcium/ and can evoke the release of (1) acetylcholine from the neuromuscular junction ... (2) acetylcholine from the sympathetic ganglia ... (3) noradrenaline from the sympathetic nerve terminals ... and (4) catecholamines from the adrenal medulla ... . /Barium/ [R70] *Barium blocks the passive potassium conductance of muscle. the membrane potential remains normal at first, owing to the basal activity of the sodium-potassium pump. Since barium inhibits passive efflux and influx of potassium equally, basal sodium-potassium pumping results in a net uptake of potassium. Because the mass of skeletal muscle is very large (about 40 percent of body weight) the shift of extracellular potassium into muscle soon lowers the plasma potassium concentration. As the plasma potassium concentration falls, barium blockade of potassium permeability becomes more effective and the ionic diffusion potential is increasingly dominated by the sodium conductance, which exerts a depolarizing influence on the membrane potential. At the same time the falling concentration of plasma potassium rapidly shuts off the sodium-potassium pump, so that the membrane potential is now determined by the ionic diffusion potential, which has fallen to less than -60 mV. At this membrane potential the muscle is inexcitable and paralysis ensues. /Barium/ [R24, 1545] *BARIUM CAUSES INCR IN CELL-MEMBRANE RESISTANCE, A PROLONGATION OF ACTION POTENTIALS, AND DEPOLARIZATION OF SMOOTH AND SKELETAL MUSCLE. IT HAS BEEN PROPOSED THAT THESE CHANGES ARE DUE TO BARIUM INDUCED DECR IN POTASSIUM CONDUCTANCE. THERE IS EVIDENCE THAT BARIUM IONS MAY BE SUBSTITUTED FOR SODIUM IONS TO PRODUCE ACTION POTENTIALS IN MAMMALIAN B AND C FIBERS. IN THESE FIBERS, ACTION POTENTIALS ARE REMARKABLY PROLONGED IN ISOTONIC BARIUM SOLN. IN MAMMALIAN A FIBERS, BARIUM CANNOT BE SUBSTITUTED FOR SODIUM, AND ISOTONIC BARIUM SOLN RESULTS IN CONDUCTION BLOCK. BARIUM HAS ... BEEN SHOWN TO RELEASE ACETYLCHOLINE FROM CHOLINERGIC NERVES AND CATECHOLAMINES FROM ADRENAL MEDULLA. THESE ACTIONS ON NEUROTRANSMITTER RELEASE ARE DUE TO ABILITY OF BARIUM TO SUBSTITUE FOR CALCIUM IN NEUROSECRETORY PROCESS. /SOLUBLE BARIUM SALTS/ [R27] *Most of the toxic effects of barium ion appear to follow from its effects on potassium fluxes in excitable cells (nerve, skeletal muscle, smooth muscle, heart). Exposure of such cells to barium ion results in a rapid decrease in potassium permeability and efflux. This leads to a decreased resting membrane potential, with resulting hyperirritability and increased activity. In the heart, extra-nodal cells may begin to depolarize spontaneously (leading to premature ventricular contractions), and abnormalities in the ECG become evident. Because potassium uptake by cells is stimulated by barium ion, there follows a large net flux of potassium from extracellular fluid into cells, resulting in marked hypokalemia. /Barium ion/ [R71] *Barium possesses chemical and physiological properties that allow it to compete with and replace calcium in processes mediated normally by calcium, particularly those relating to the release of adrenal catecholamines and neurotransmitters, such as acetylcholine and noradrenaline. /Barium/ [R72] *An important biological action of barium is the blockade of potassium efflux from cells. The addition of barium (0.8 mmol/l) to cell medium resulted in an incr in the release of noradrenalin from cat spleen tissue ... When potassium efflux is blocked by barium, depolarization is prolonged. This allows for greater cellular influx of calcium during depolarization and accounts for the enhanced effect of nerve stimulation in the presence of barium ... . /Barium/ [R73] *Barium can also affect calcium metabolism by blocking its efflux from cells. Concn of 0.3 mmol/l inhibited by 41% the ATPase-mediated extrusion of calcium in bovine adrenomedullary plasma membrane preparations ... Owing to its ability to block calcium efflux from cells, barium may have widespread effects in secretory tissues and, possibly, in certain muscle tissues. In frog sartorious muscle, barium (0.01 mmol/l) inhibited potassium uptake and efflux symmetrically ... . /Barium/ [R73] *... Studied the electrophysiological action of barium in chick embryo atria and compared it to that of calcium. The ability of barium to evoke an action potential decr during ontogeny, but barium was more potent that calcium in generating an action potential. Based on these findings, the author suggested that barium can enter the cell by the same mechanism as calcium. /Barium/ [R73] *Barium stimulates striated, cardiac, and smooth muscle, regardless of innervation. It is antagonistic to all muscle depressants, no matter whether they act primarily on nerve or muscle. Initial stimulation of contraction leads to vasoconstriction through direct action on arterial muscle, peristalsis through action on smooth muscle, tremors and cramps through action on the skeletal muscles, and various arrhythmias through action on the heart. If the dose is sufficient, stimulation is followed by weakness and eventually by paralysis of the different kinds of muscle. Some effects such as hypertension, violent tremors, and convulsions are uncommon following ingestion of barium carbonate. They are more likely to follow absorption of more soluble barium compounds. If death does occur, it is caused by failure of muscular contraction leading to respiratory failure or cardiovascular collapse. [R74] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ENVS: *Barium is a naturally occurring element found in the earth's crust that enters the environment through the weathering of rocks and minerals. The principal barium minerals are barytes (barium sulfate) and witherite (barium carbonate). The production and use of various barium compounds in pyrotechnic devices, ceramics, paints, enamels, optical glasses and as a getter to remove traces of gas from vacuum and television tubes may result in its release to the environment through various waste streams. Barium has been detected in air effluent particulate matter from coal power plants and waste incinerators. Particulate phase barium is expected to be physically removed from the air by wet and dry deposition. Soluble barium compounds, such as barium nitrate, barium cyanide, barium permanganate, and barium chloride, are expected to be mobile in the environment. Barium has been detected in surface water, groundwater, drinking water and sediment. Soluble barium compounds are expected to bioconcentrate in aquatic organisms with bioconcentration factors of 100, 120 and 260 reported in marine animals, plankton and brown algae, respectively. Soluble barium can react with sulfates and carbonates in water forming insoluble barium sulfate and barium carbonate salts. Occupational exposure may be through inhalation of airborne dust and dermal contact with this compound at metal ore refining facilities and other workplaces where barium compounds are produced and used. The general population may be exposed to barium from inhalation of ambient air and the ingestion of drinking water and food. (SRC) NATS: *... IT ... OCCURS IN ZINC OR IRON ORES. THE EARTH'S CRUST CONTAINS 450 PPM ... AND SEAWATER CONTAINS ABOUT 0.03 PPM. /BARIUM CMPD/ [R50, 63] *Ores of barite and witherite are found in Georgia, Missouri, Arkansas, Kentucky, California, Nevada, Canada, Mexico. [R75] *Barium is a naturally occurring element found in the earth's crust(1) that enters the environment through the weathering of rocks and minerals(SRC). The principal barium minerals are barites (barium sulfate) and witherite (barium carbonate)(1). [R76] *NATURALLY OCCURRING BARIUM IS A MIXTURE OF SEVEN STABLE ISOTOPES. [R8] ARTS: *Barium is emitted into the atmosphere mainly by the industrial processes involved in the mining, refining, and production of barium and barium based chemicals and as a result of combustion of coal and oil. /Barium cmpd/ [R77] *The production and use of various barium compounds in pyrotechnique devices, ceramics, paints, enamels, optical glasses and as a getter to remove traces of gas from vacuum and television tubes(1,2) may result in its release to the environment through various waste streams(SRC). Particulate emissions from the industrial production of barium compounds include an estimated 820 metric tons per year from uncontrolled kilns during the processing of barite ore and 8 metric tons per year from black ash rotary kilns during the production of barium hydroxide(3). [R78] FATE: *TERRESTRIAL FATE: Soluble barium compounds such as barium nitrate, barium cyanide, barium permanganate, and barium chloride(1), are expected to be mobile in the environment(SRC). Adsorption of 26 elements including barium were studied in a sandy soil and sandy loam at concns closely corresponding to field conditions(2). It was determined that the solubility and mobility of barium was greater in the sandy soil and increased with decreasing pH and decreasing organic matter content(2). Barium can react with metal oxides and hydroxides in soils thus limiting its mobility and increasing adsorption(3). Barium mobility decreases in soils with high sulfate and calcium carbonate content(3). [R79] *AQUATIC FATE: Soluble barium compounds such as barium nitrate, barium cyanide, barium permanganate, and barium chloride(1), are expected to bioconcentrate in aquatic organisms(SRC). Bioconcentration factors of 100, 120 and 260 were reported in marine animals, plankton and brown algae, respectively(2). In waters with a high sulfate or carbonate content, soluble barium can react with sulfates and carbonates in water forming insoluble barium sulfate and barium carbonate salts(2). [R80] *ATMOSPHERIC FATE: Barium compounds are expected to exist in the particulate phase in the ambient atmosphere. Particulate-phase barium may be physically removed from the air by wet and dry deposition. (SRC) ABIO: *Soluble barium compounds such as barium nitrate, barium cyanide, barium permanganate, and barium chloride, can react with sulfates and carbonates in water forming insoluble barium sulfate and barium carbonate salts(1). [R81] BIOC: *Marine animals concentrate the element 7-100 times, and marine plants 1000 times from seawater. ... Soybeans and tomatoes also accumulate soil barium 2-20 times. /Barium cmpd/ [R32, p. V2 86] *Soluble barium compounds such as barium nitrate, barium cyanide, barium permanganate, and barium chloride(1), are expected to bioconcentrate in aquatic organisms(SRC). Bioconcentration factors of 100, 120 and 260 were reported in marine animals, plankton and brown algae, respectively(2). [R80] KOC: *Adsorption of barium was measured in a sandy soil and a sandy loam soil at concn levels closely corresponding to those to be expected for field conditions. In general, sludge solutions appeared to incr the mobility of elements in a soil. This is due to a combination of complexation by dissolved organic cmpd, high background concn and high ionic strengths of the soil solution. /Barium cmpd/ [R82] *Soluble barium compounds such as barium nitrate, barium cyanide, barium permanganate, and barium chloride(1), are expected to be mobile in the environment(SRC). Adsorption of 26 elements including barium were studied in a sandy soil and sandy loam at concns closely corresponding field conditions(2). It was determined that the solubility and mobility of barium was greater in the sandy soil and increased with decreasing pH and decreasing organic matter content(2). Barium can react with metal oxides and hydroxides in soils thus limiting its mobility and increasing adsorption(3). Barium mobility decreases in soils with high sulfate and calcium carbonate content(3). [R83] VWS: *Barium is not expected to volatilize from moist soils, dry soils or water surfaces. (SRC) WATC: *Seawater: Concn of the element in seawater is 6 ug/l ... . /Total barium/ [R32, p. V2 86] *Concn of the element ... in fresh water 7-15000 (avg 50) ug/l. Municipal waters in Sweden ranged 1-20 ug barium/l and in the USA 1.7-8000 (avg 43) ug barium/l. /Total barium/ [R32, p. V2 86] *Surface water: Barium is found in waste streams from a large number of manufacturing plants in quantities that seldom exceed the normal levels found in soil. Background levels for soil range from 100-3000 ppm barium. /Total barium/ [R84] *Seawater: Barium 2 ug/l as barium(2+) /Barium ion/ [R85] *SURFACE WATER: ... Occurs naturally in almost all (99.4%) surface waters examined, in concn of 2 to 340 ug/l, with an average of 43 ug/l ... /from a 1967 report/. The drainage basins with low mean concn of barium (15 ug/l) occur in the western Great Lakes, and the highest mean concn of 90 ug/l is in the southwestern drainage basins of the lower Mississippi Valley. ... In stream water and most groundwater, only traces of the element are present. /Total barium/ [R49, 229] *DRINKING WATER: The average concn of barium in USA drinking water is 28.6 ug/l (range, 1 to 172 ug/l (NAS, 1977)). The drinking water of many communities in Illinois, Kentucky, Pennsylvania, AND New Mexico contains concentrations of barium that may be 10 times higher than the drinking water standard. The source of these supplies is usually well water. /Total barium/ [R86] *The Illinois Environmental Protection Agency has identified 16 cities and 3 sub-divisions in Northern Illinois that have drinking water sources containing 1.1 to 10.0 mg/l barium. These affected water supplies are from deep rock and drift wells. /Total barium/ [R87] *There are limited survey data on the occurrence of barium in drinking water. Most supplies contain less than 200 ug/l of barium. Currently 60 ground water supplies and 1 surface water supply exceeds 1000 ug/l. /Total barium/ [R88] *GROUNDWATER: Barium was detected at a concn of 120 ug/l in groundwater at the Galloway Ponds Superfund Site in Gallaway, TN(1). Barium was detected at a median concns of 0.53 and 0.20 mg/l in groundwater near a landfill in Porto Alegre, Brazil(2). Barium was detected in groundwater at various locations in Denver, CO at concns of 18-594 ug/l(3). Barium was detected in groundwater at the Idaho National Engineering Laboratory in southeastern Idaho at concns of 17-140 ug/l(4). Barium was detected at median levels of 7-1,160 ug/l in 92 municipal groundwaters in Italy(5). [R89] *DRINKING WATER: Barium was detected at concns of 17-180 ug/l in residential drinking water wells near the Gallaway Ponds Superfund Site in Gallaway, TN(1). Barium was detected at median levels of 7-660 ug/l in 60 different brands of bottled water and 13-140 ug/l in 39 treated drinking water supplies in Italy(2). Barium has been detected in almost all drinking water supplies sampled in the US with concns ranging from 2-380 ug/l(3). [R90] *SURFACE WATER: Barium was detected in surface water at a hazardous waste site in Gallaway, TN at concns of 30-250 ug/l(1) and a hazardous waste site in NJ at a concn of 2.6 ug/l(2). Barium was detected at concns of 70 and 80 ug/l in a creek near a landfill in Porto Alegre, Brazil(3). Barium was detected at concns of 55-59 ug/l in the Mississippi River near St. Francisville, LA and at concns of 24-31 ug/l in the Tangipahoa River near Robert, LA(4). Barium was detected at a mean concn of 21 ug/l in Lake Superior in 1983(5). [R91] *RAIN/SNOW/FOG: Barium was detected in rainwater samples obtained from Finland, Norway and Russia at median concns of 0.47-1.07 ug/l(1). [R92] EFFL: *The max concn of soluble barium in the exhaust of diesel engines was estimated as 12,000 mg/cu m(1). Barium was detected at concns of less than 700 to 1,120 ug/g in the ash of a hazardous waste incinerator located in Mississippi(2). Sewage sludges commonly contain barium concns of 150-4,000 ppm(3). Barium was detected in the fly ash of a hazardous waste incinerator in Switzerland at concns of 0.1-0.4 g/kg(4). Barium was detected at concns of 193-5,870 ug/cu m in the emissions of 2 coal burning power plants(5). Barium was detected at concns of 550-1,400 ug/g in the ash from an urban waste incinerator in Barcelona, Spain(6). Barium was detected at concns of 0.27-2.6 mg/l in the leachate of a municipal landfill in Canada(7). [R93] SEDS: *Agricultural soils contain barium ion in the range of several ug/g. [R32, p. V2 86] *Background levels for soil range from 100-3000 ppm barium. /Total barium/ [R84] *SOIL: Barium was detected at concns of 39-130 mg/kg in surface soil at the Gallaway Ponds Superfund Site in Gallaway, TN(1). Barium was detected at a concn of 73 ug/kg in soil of a hazardous waste site in NJ(2). Barium was detected at a max concn of 1,300 mg/kg in soil of a hazardous waste site in KS(3). Dust samples collected from residential areas of India contained barium at 285-641 ug/g, and dust samples from industrial areas of India contained barium at concns of 811-9,380 ug/g(4). Barium concns of 7.25-52.5 mg/kg were detected in soil of Hafr Al Batin, Kuwait following a series of fires at nearby oilfields(5). Mean concns of 53.95, 45.29 and 45.17 mg/kg were measured in soils of Boston, MA, Providence, RI and Springfield, MA, respectively(6). The mean concn of barium in a variety of surface soils commonly found in the US was in the range of 265-835 mg/kg, depending on soil type(7). [R94] *SEDIMENT: Barium was detected at concns of 55-150 mg/kg in sediment from the Gallaway Ponds Superfund Site in Gallaway, TN(1). Barium was detected at concns of 1,180-53,900 mg/kg in cutting and drilling sediment from offshore oil drilling facilities in the Santa Maria Basin, CA(2). Barium was also detected at concns of 736 and 923 mg/kg in suspended sediment and surficial sediment, respectively near oil drilling field sites while concns of 687 and 869 mg/kg were measured far from the sites(2). Barium was detected at concns of 63-253 mg/kg in a pristine lagoon in Fiji(3). Barium was detected at concns of 20-60 mg/kg in 5 harbors in Lake Erie and at concns of greater than 60 mg/kg in 11 harbors in Lake Erie(4). Barium was detected in sediment off the coast of Saudi Arabia at concns of 7.11-67.23 mg/kg(5). [R95] ATMC: *In urban air, the avg concn of barium was 5 (range 0-1500) ng/cu m in 18 USA cities. /Total barium/ [R32, p. V2 86] *Barium was detected at mean concns of 0.16-0.50 ng/cu m in air samples from the Canadian Arctic(1). Barium was detected at mean concns of 8.4-34 pg/cu m in air samples from the South Pole from Dec 1974-Feb 1975(2). Barium concns in air samples from urban areas of North America range from 0.0002 ug/cu m to 0.028 ug/cu m, with a mean concn of 0.012 ug/cu m(3). [R96] FOOD: *Barium content of edible crops ranges from about 10 ug/g in wheat and corn grain to 3-4 mg/g in brazil nuts. ... In milk were 45-136; in wheat flour, 1300; and in oatmeal, 2320-8290. /Total barium/ [R32, p. V2 86] *Barium was detected in Brazil nuts at concns of 3,000-4,000 ppm(1). Barium was detected in corn from Georgia, Missouri and Wisconsin at concns of 5-150 ppm while the concns in lima beans, soybeans, cabbage and tomatoes was reported as 7-1,500 ppm(1). Barium was detected in onions at a mean concn of 114 ug/kg(2). [R97] PFAC: PLANT CONCENTRATIONS: *... Sol salts of barium are found in the accumulator plant Aragalus lamberti. Barium accumulation in plants is unusual except when the barium concn exceeds calcium and mangnesium concn in the soil ... . /Total barium/ [R84] *Barium content of dry tobacco leaves was found as 88-293 ug/g ... more recent measurements yielded 24-170 (avg 105) ug/g. /Total barium/ [R32, p. V2 87] *Barium was detected in the leaves of corn plants at a mean concn of 3 ug/g(1). [R98] FISH/SEAFOOD CONCENTRATIONS: *Barium was detected at concns of 0.01-0.08 ug/g in tuna caught off the coast of Newfoundland, Canada(1). Barium was detected at a concn of 0.1 ug/g in bluegill sunfish from the San Joaquin River, CA(2). Barium was detected in crayfish from Louisiana at concns of 0.62-12.14 mg/kg(3). [R99] ANIMAL CONCENTRATIONS: *... MAMMALIAN EYES CONTAIN BARIUM IN PIGMENTED PART IN CONCN VARYING FROM 206-1110 UG/G WET TISSUE. /TOTAL BARIUM/ [R50, 63] *Toads living near a coal combustion plant had barium concns of 83.8 ppm, while toads from a pristine site had barium concns of 27.3 ppm(1). Barium concns of 11 and 15 ppm were detected in Lessser snow geese from Wrangel Island, Russia(2). Barium was detected in sea urchins from coastal areas of Saudi Arabia at concns of 0-17.38 mg/kg(3). [R100] MILK: *Barium content ... in milk ... 45-136 ug/g ... . /Total barium/ [R32, p. V2 86] RTEX: *Small numbers of people are known to be consuming well waters in Illinois, Kentucky, Pennsylvania, AND New Mexico that are at, or exceed by 10 times, the standard for barium. /Total barium/ [R49, 231] *Poisoning may occur in industry, from accidental use of soluble barium salt in X-ray procedures, from ingestion of certain rodenticides and pesticides that contain barium salts ... . Certain firework powders also contain soluble barium salts. /Soluble barium salts/ [R27] *Ingestion or inhalation of dust or fume, skin or eye contact. /Barium and cmpd/ [R13, 105] *The toxicologically important routes of entry for barium sol cmpd, as Ba are inhalation, ingestion, and skin and/or eye contact. /Barium sol cmpd, as Ba/ [R14] *Food represents a primary source of barium for the general population. /Total barium/ [R101] *NIOSH (NOES Survey 1981-1983) has statistically estimated that 554,784 workers (129,535 of these are female) are potentially exposed to barium and barium compounds in the US(1). Occupational exposure to barium may occur through inhalation and dermal contact with this compound at workplaces where barium is produced or used(SRC). The general population may be exposed to barium via inhalation of ambient air, ingestion of food and drinking water(SRC). [R102] AVDI: *AVG DAILY BARIUM INTAKE OF HUMAN ADULT IS ABOUT 1.3 MG (0.65-1.7 MG) ... . /TOTAL BARIUM/ [R50, 64] *In an American hospital diet, the avg daily intake of barium was estimated as 375 ug, while in the diet of the general population it may be as high as 1.33 mg. ... Estimated ... typical dietary barium intake originated 25% from milk, 25% from flour, 25% from potatoes, and 25% from misc high barium foods consumed in minor quantities, esp nuts. /Total barium/ [R32, p. V2 87] *The AVDI of barium was estimated as 1,250 ug(1). [R81] BODY: *The pigmented parts of the eye (iris, sclera, and esp the choroid) are the strongest accumulators of circulating barium with concn reaching the 0.1 mg/g (wet wt) level. /Total barium/ [R32, p. V2 88] *... Normal levels for barium in various organs of unexposed persons /have been published/. Total amt in skeleton of a 70 kg American adult was estimated at 2 ug/g or about 90% of total body barium (Ba). Other organs with measurable levels incl eye (330 ng/g), lungs (160 ng/g), connective tissue (125 ng/g), skin (50 ng/g), adipose tissue (36 ng/g). In other internal organs, barium concn were slight. Among various parts of the eye, choroid had highest ... level, reaching ... 10 ug/g in man. Normal human blood contains 0.08-0.4 mg Ba/l; most or all is in the plasma fraction. /Total barium/ [R32, p. V2 89] *... Avg values are found: Bone 4.1-29 ug Ba/g; blood 41-95 ug Ba/g; kidney 1.3-20 ug Ba/g; liver 0.2-10 ug Ba/g; spleen 0.6-12 ug Ba/g. Assuming an avg of 70 kg as human body wt, the barium content has been estimated to be 16 mg. /Total barium/ [R19, 99] *... HUMAN ADULT BODY CONTAINS ABOUT 22 MG BARIUM, 66% OF IT PRESENT IN BONES. /TOTAL BARIUM/ [R50, 63] *Dental enamel of the first bicuspids of humans less than 20 years of age was analyzed for 66 minor inorganic elements by spark source mass spectroscopy. Teeth were from 24 communities located in 16 states in the USA. Mean barium concentration was 4.2 + or - 0.60 ug/g (mg/kg) dry weight. /Total barium/ [R103] *Humans: Total body burden: 22 mg barium (90% in bone); levels in bone and aorta incr with age. Kidney: 0.04-1.0 mg Ba/kg; Liver: 0.04-1.0 mg Ba/kg; Muscle: 0.09 mg Ba/kg; Bone: 3-70 mg Ba/kg; Hair: 0.55-4.0 mg Ba/kg; Nails: 7.5 mg Ba/kg; iris (eye): 206-1100 mg Ba/kg (possible function in vision); Blood: 0.068 mg Ba/l. /Total barium/ [R104] *Based on autopsy data, barium levels in human bone are relatively constant and do not appear to increase with age, ranging from an average value of 7.0 ppm in bone at age 0 to 3 months to an average of 8.5 ppm at age 33 to 74 years. /Total barium/ [R105] *The total barium content for a 70 kg adult male was estimated as 22,000 ug(1). [R81] *Normal levels of barium in hair are generally 1-2 mg/kg ... . /Barium/ [R62] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- IDLH: *50 mg/cu m /Barium (sol cmpd as Ba)/ [R106] OSHA: *Permissible Exposure Limit: Table Z-1 8-hr Time Weighted Avg: 0.5 mg/cu m. /Barium, soluble compounds, as Ba/ [R107] TLV: *8 hr Time Weighted Avg (TWA) 0.5 mg/cu m /Barium and soluble cmpds, as Ba/ [R108, 18] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. /Barium and soluble cmpd, as Ba/ [R108, 6] *A4. A4= Not classifiable as a human carcinogen. /Barium and soluble cmpd, as Ba/ [R108, 18] WSTD: FEDERAL DRINKING WATER STANDARDS: +EPA 2000 ug/l /Barium/ [R109] FEDERAL DRINKING WATER GUIDELINES: +EPA 2000 ug/l /Barium/ [R109] STATE DRINKING WATER STANDARDS: +(CA) CALIFORNIA 1000 ug/l [R109] CERC: *Persons in charge of vessels or facilities are required to notify the National Response Center (NRC) immediately, when there is a release of this designated hazardous substance, in an amount equal to or greater than its reportable quantity of 1000 lb or 454 kg. The toll free number of the NRC is (800) 424-8802; In the Washington D.C. metropolitan area (202) 426-2675. The rule for determining when notification is required is stated in 40 CFR 302.4 (section IV. D.3.b). /Barium/ [R110] RCRA: *D005; A solid waste containing barium may or may not become characterized as a hazardous waste when subjected to the Toxicity Characteristic Leaching Procedure listed in 40 CFR 261.24, and if so characterized, must be managed as a hazardous waste. /Barium/ [R111] MAM: --------MONITORING AND ANALYSIS METHODS CATEGORY (USE CODE ZMAM)--------- SAMP: *Measurements to determine employee exposure are best taken so that the avg 8 hr exposure is based on a single 8 hr sample or on two 4 hr samples. Several short time interval samples (up to 30 min) may also be used to determine the avg exposure level. Air samples should be taken in the employee's breathing zone. ... Sampling ... may be performed by collection on a cellulose membrane filter followed by leaching in hot water, solution of sample in acid ... . /Barium and barium cmpd/ [R10, 1981.3] *NIOSH 173: Analyte: barium; Matrix: air; Procedure: filter collection, acid digestion. /Barium and Ba cmpd/ [R112, p. V5 173-1] *NIOSH 351: Analyte: barium; Matrix: air; Procedure: filter collection. /Barium and Ba cmpd/ [R112, p. V7 351-1] *NIOSH 7056: Analyte: barium ion; Matrix: air; Sampler: filter (0.8 um cellulose ester membrane); Flow rate: 1-4 l/min; Vol: min: 50 l, max: 2000 l; Sample stability: stable. /Barium and Ba cmpd/ [R113, p. V1 7056-1] *NIOSH 8310: Analyte: barium; Specimen: urine; Vol: 50-200 ml in polyethylene bottle; Preservative: 5 ml concn nitric acid added after collection; Controls: collect at least 3 urine specimens from unexposed workers; Shipment: frozen in dry ice; Stability: not established. /Barium and Ba cmpd/ [R113, p. V1 8310-1] *Cryogenic impact grinding technique for powdering whole fish for metal determinations was evaluated. /Total barium/ [R114] ALAB: *NIOSH 7056: Technique: atomic absorption, flame; Extraction: hot water leach, 10 ml, 10 min, twice; concentrated hydrochloric acid, 3 drops; evaporate to dryness; Wavelength: 553.6 nm; Range: 0.025 to 0.2 mg/sample; Precision (Sr): 0.025 @ 0.043 to 0.18 mg/sample; Est LOD: 0.002 mg/sample; Interferences: ionization of barium in the flame is controlled by addition of sodium chloride to samples and standards. Calcium, at > 0.1%, gives a positive interference unless background correction is used. /Total barium/ [R113, p. V1 7056-1] *NIOSH 173: Analyte: barium; Matrix: air; Procedure: filter collection, acid digestion, atomic absorption spectrophotometry; Range: 1-25 ug/l, 42-1050 ug/cu m; Precision: 3% relative standard deviation (analytical); Sensitivity: 0.4 ug/ml with soln detection limit of 0.008 ug/ml. /Total barium/ [R112, p. V5 173-1] *NIOSH 351: Analyte: barium; Matrix: air; Procedure: filter collection, inductively coupled plasma-atomic emission spectroscopy (ICP-AES); Range: 5-2000 ug/cu m; Wavelength: 455.4 nm; Interferences: none /Total barium/ [R112, p. V7 351-1] *Determination of barium with conventional analytical reagents is unsatisfactory for micro-quantities. Modern procedures ... /incl/ neutron activation analysis, limit of detection about 1 ug/g: Sowden EM AND Stitch R; Biochem J 67: 104-9 (1957); atomic absorption spectrophotometry, limit of detection about 0.01 ug/g: Edelbeck L AND West PW; Anal Chem Acta 52: 447-53 (1970) and emission spectrography, limit of detection about 0.0001 ug/g: Mauras Y AND Allain P; Anal Chim Acta 110: 271-7 (1979). /Total barium/ [R32, p. V2 85] *Traces of barium in mineral containing water was determined by selective retention on ion exchange papers and x-ray fluorescence spectrometry. /Total barium/ [R115] *Barium in sea water was determined by graphite furnace atomic absorption spectrometry after preconcentration and separation by solvent extraction. /Total barium/ [R116] *EPA Method 200.7: An Inductively Coupled Plasma - Atomic Emission Spectrophotmetric method for the determination of dissolved, suspended, or total elements in drinking water, surface water, and domestic and industrial wastewaters, is described. Barium is analyzed at a wavelength of 455.403 um nm and has an estimated detection limit of 2 ug/l. /Total barium/ [R117] *EPA Method 7080: Total Barium (Atomic Absorption, Direct Aspiration) Method 7080 is applicable for the determination of metals in solution by atomic absorption spectrometry. Preliminary treatment of waste water, ground water, extraction procedure extracts, and industrial waste is always necessary because of the complexity and variability of sample matrix. After aspiration and atomization of the sample in a flame, a light beam from a hollow cathode lamp or an electrodeless discharge lamp is directed through the flame into a monochromator and onto a detector that measures the amount of light absorbed. ... The light energy absorbed by the flame is a measure of the concentration of that metal in the sample. The performance characteristics for an aqueous sample free of interferences are: optimum concentration range of 1-20 mg/l with a wavelength of 553.6 um, a sensitivity of 0.4 mg/l, and a detection limit of 0.1 mg/l. /Total barium/ [R118] *Method 304: Electrothermal Atomization Atomic Absorption Spectrometry for the determination of micro quantities of selected elements including barium in water and wastewater samples. Using an electrically heated atomizer or graphite furnace, at a wavelength of 553.6 nm, the extimated detection limit is 2 ug/l at an optimum concentration range of 10-200 ug/l. These values may vary with the chemical form of the barium being determined, sample composition, or instrumental conditions. /Total barium (from table)/ [R119] *Barium in water sediments and coal fly ashes was determined by spectroscopic emission using powder samples on a flat carbon electrode. /Total barium/ [R120] *NIOSH Method 7056. Determination of Barium by Flame Atomic Absorption. Detection limit 0.001 mg/cu m. [R121] *EPA OSW Method 0060. Determination of Metals in Stack Emissions. No detection limit. [R121] *EPA OSW Method 3005. Acid Digestion of Waters for Total Recoverable or Dissolved Metals for Analysis by FLAA or ICP Spectroscopy. No detection limit. [R121] *EPA OSW Method 3005A. Acid Digestion of Sediments, Sludges, and Soils. No detection limit. [R121] *EPA OSW Method 3005B.Acid Digestion of Sediments, Sludges, and Soils for Metals Analysis by FLAA/ICP or GFAA/ICPMS. No detection limit. [R121] *EPA OSW Method 3051. Microwave Assisted Acid Digestion of Sediments, Sludges, Soils, and Oils. No detection limit. [R121] *EPA OSW Method 3052. Microwave Assisted Acid Digestion of Siliceous and Organically Based Matrices Including Ash, Biological Tissue, Oil, Oil Contaminated Soil, Sediment, Sludge, and Soil for Metals Analysis by FLAAS, CVAAS, GFAAS, ICP-AES, ICP-MS, and Other Techniques. No detection limit. [R121] *EPA OSW Method 3010A. Acid Digestion of Aqueous Samples and Extracts for Total Metals for Analysis by FLAA or ICP Spectrometry. No detection limit. [R121] *EPA OSW Method 3015. Microwave Assisted Acid Digestion of Aqueous Samples and Extracts. No detection limit. [R121] *EPA OSW Method 6010. Inductively Coupled Plasma-Atomic Emission Spectroscopy. Detection limit 2 ug/l. [R121] *EPA OSW Method 6020. Inductively Coupled Plasma with Mass Spectrometry. Detection limit 0.02 ug/l. [R121] *EPA OSW Method 3031. Acid Digestion of Oils for Metals Analysis by FLAA or ICP-AES. No detection limit. [R121] *EPA OSW Method 3040A. Dissolution Procedure for Oils, Greases, and Waxes. No detection limit. [R121] *EPA OSW Method 7080A. Barium by Direct Aspiration Atomic Absorption. Detection limit 0.1 mg/l. [R121] *EPA OSW Method 7081. Barium by Graphite Furnace Atomic Absorption. Detection limit 2 ug/l. [R121] CLAB: *NIOSH 8310: Analyte: barium; Specimen: urine; Vol: 50-200 ml in polyethylene bottle; Preservative: 5 ml concn nitric acid added after collection; Controls: collect at least 3 urine specimens from unexposed workers; Shipment: frozen in dry ice; Stability: not established; Technique: inductively coupled argon plasma, atomic emission spectroscopy; Extraction media: polydithiocarbamate resin; Wavelength: 455.4 nm; Range: 0.25 to 200 ug/sample; Precision (Sr): 0.11; Est LOD: 0.1 ug/sample; Interferences: spectral interferences are the primary interferences encountered in inductively coupled plasma-atomic emission spectroscopy analysis. These are minimized by judicious wavelentgh selection and interelement correction factors. Background corrections are also made. /Total barium/ [R113, p. V1 8310-1] *Determination of barium with conventional analytical reagents is unsatisfactory for micro-quantities. Modern procedures ... /incl/ neutron activation analysis, limit of detection about 1 ug/g: Sowden EM AND Stitch R; Biochem J 67: 104-9 (1957); atomic absorption spectrophotometry, limit of detection about 0.01 ug/g: Edelbeck L AND West PW; Anal Chem Acta 52: 447-53 (1970) and emission spectrography, limit of detection about 0.0001 ug/g: Mauras Y AND Allain P; Anal Chim Acta 110: 271-7 (1979). Several of these are specifically adapted for assay in biological material. /Total barium/ [R32, p. V2 85] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- RPTS: USEPA; Drinking Water Criteria Document for Barium (Draft) (1985) TR-540-60F Health Advisories for Legionella and Seven Inorganics (1987) PB87-235586 Nat'l Research Council Canada; Data Sheets on Selected Toxic Elements (1982) NRCC No. 19252 DHHS/ATSDR; Toxicological Profile for Barium (1992) ATSDR/TP-91/03 U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) for Barium and compounds (7440-39-3) Toxicological Review in Adobe PDF. Available from: http://www.epa.gov/ngispgm3/iris on the Substance File List as of March, 1998. Toxicology and Carcinogenesis Studies of Barium Chloride Dihydrate in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 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USEPA/ROD/R04-86/013, NTIS PB87-189080 (1987) (2) Lanciotti E et al; Bull Environ Contam Toxicol 43: 833-37 (1989) (3) Agency For Toxic Substances and Disease Registry; Toxicological Profile For Barium. TP-91/03 (1992) R91: (1) USEPA; Superfund Record of Decision Gallaway Ponds Site Gallaway, TN. EPA/ROD/R04-86/013, PB87-189080 (1987) (2) USEPA; Superfund Record of Decision Gallaway Ponds Site Gallaway, TN. EPA/ROD/R02-86/031, PB87-188470 (1987) (3) Kuajara O et al; Water Environ Res 69: 1170-77 (1997) (4) Horowitz AJ et al; Environ Sci Technol 30: 954-63 (1996) (5) Great Lakes Water Quality Board; 1987 Report on the Great Lakes Water Quality. Appendix B. Great Lakes Survelliance, Vol 1. Report to the International Joint Commission (1989) R92: (1) Reimann C et al; Atmos Environ 31: 159-70 (1997) R93: (1) Agency For Toxic Substances and Disease Registry; Toxicological Profile For Barium. TP-91/03 (1992) (2) Buchholz BA, Landsberger S; J Air Waste Manage Assoc 45: 579-590 (1995) (3) Breckenridge PP, Crockett AB; Determination of Background Concentrations of Inorganics in Soils and Sediments at Hazardous Waste Sites. USEPA/540/S-96/500 (1995) (4) Pluss A, Ferrel RE; Haz Waste Haz Mat 8: 275-92 (1991) (5) Ondov JM et al; Atmos Environ 23: 2193-2204 (1989) (6) Fernandez MA et al; Environ Sci Technol 26: 1040-47 (1992) (7) Barker JF et al; J Contam Hydrol 1: 171-89 (1986) R94: (1) USEPA; Superfund Record of Decision Gallaway Ponds Site Gallaway, TN. USEPA/ROD/R02-86/031, PB87-188470 (1987) (2) USEPA; Superfund Record of Decision Lang Property, Pemberton Township, NJ EPA/ROD/R04-86/013, PB87-189080 (1987) (3) USEPA; Superfund Record of Decision Doepke Disposal (Holliday), KS USEPA/ROD/R07-89/032, PB90-162645 (1990) (4) Chutke NL et al; Sci Total Environ 164: 185-194 (1995) (5) Sadiq M et al; Bull Environ Contam Toxicol 49: 633-39 (1992) (6) Bradley LJ et al; J Soil Contam 3: 349-61 (1994) (7) Breckenridge PP, Crockett AB; Determination of Background Concentrations of Inorganics in Soils and Sediments at Hazardous Waste Sites. USEPA/540/S-96/500 (1995) R95: (1) USEPA; Superfund Record of Decision Gallaway Ponds Site Gallaway, TN. USEPA/ROD/R02-86/031, PB87-188470 (1987) (2) Phillips C et al; Environ Contam Toxicol 17: 1653-61 (1998) (3) Morrison RJ et al; Mar Pollut Bull 34: 353-56 (1997) (4) Great Lakes Water Quality Board; 1987 Report on the Great Lakes Water Quality. Appendix B. Great Lakes Surveillance, Vol 1. Report to the International Joint Commission (1989) (5) Sadiq M et al; Bull Environ Contam Toxicol 57: 964-71 (1996) R96: (1) Barrie LA, Hoff RM; Atmos Environ 19: 1995-2010 (1985) (2) Maehnaut W et al; J Geophys Res 84: 2421-31 (1979) (3) Agency For Toxic Substances and Disease Registry; Toxicological Profile For Barium. TP-91/03 (1992) R97: (1) Agency For Toxic Substances and Disease Registry; Toxicological Profile For Barium. TP-91/03 (1992) (2) Bibak A et al; J Agric Food Chem 46: 3139-45 (1998) R98: (1) Raven KP, Loeppert RH; J Environ Qual 26: 551-57 (1997) R99: (1) Hellou J et al; Chemosphere 24: 211-18 (1992) (2) Nakamoto RJ, Hassler TJ; Arch Environ Contam Toxicol 22: 88-98 (1992) (3) Madden JD et al; J Food Safety 12: 1-15 (1991) R100: (1) Hopkins WA et al; Arch Environ Contam Toxicol 35: 325-29 (1998) (2) Hui A et al; Arch Environ Contam Toxicol 34: 197-203 (1998) (3) Sadiq M et al; Bull Environ Contam Toxicol 57: 964-71 (1996) R101: USEPA; Drinking Water Criteria Document for Barium (Draft) p. I-1 (1985) TR-540-60F R102: (1) NIOSH; National Occupational Exposure Survey (NOES) (1983) R103: Losee FL et al; Caries Res 8: 123-34 (1974) as cited in USEPA; Drinking Water Criteria Document for Barium (Draft) p.III-34 (1985) TR-540-60F R104: Nat'l Research Council Canada; Data Sheets on Selected Toxic Elements p.11 (1982) NRCC No. 19252 R105: Sowden EM, Stitch SR; Biochem J 67: 104-9 (1957) as cited in USEPA; Health Advisories for Legionella and Seven Inorganics p.3 (1987) R106: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 24 R107: 29 CFR 1910.1000 (7/1/99) R108: American Conference of Governmental Industrial Hygienists. Threshold Limit Values (TLVs) for Chemical Substances and Physical Agents Biological Exposure Indices for 1999. Cincinnati, OH: ACGIH, 1999. R109: USEPA/Office of Water; Federal-State Toxicology and Risk Analysis Committee (FSTRAC). Summary of State and Federal Drinking Water Standards and Guidelines (11/93) R110: 40 CFR 302.4 (7/1/99) R111: 40 CFR 261.24 (7/1/99) R112: U.S. Department of Health, Education Welfare, Public Health Service. Center for Disease Control, National Institute for Occupational Safety Health. NIOSH Manual of Analytical Methods. 2nd ed. Volumes 1-7. Washington, DC: U.S. Government Printing Office, 1977-present. R113: U.S. Department of Health and Human Services, Public Health Service. Centers for Disease Control, National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods, 3rd ed. Volumes 1 and 2 with 1985 supplement, and revisions. Washington, DC: U.S. Government Printing Office, February 1984. R114: May TW, Kaiser ML; J Assoc Off Chem 67 (3): 589-93 (1984) R115: Clechet P, Eschalier G; Anal Chim Acta 156: 295-9 (1984) R116: Sugiyama M et al; Bunseki Kagaku 33 (4): E123-9 (1984) R117: 40 CFR 136 (7/1/88) R118: USEPA; Test Methods for Evaluating Solid Waste SW-846 (1986) R119: Franson MA (Ed); Standard Methods for the Examination of Water and Wastewater p.174 (1985) R120: Sun D et al; Huanjing Huaxue 3 (2): 65-72 (1984) R121: USEPA; EMMI. EPA's Environmental Monitoring Methods Index. Version 1.1. PC# 4082. Rockville, MD: Government Institutes (1997) RS: 113 Record 358 of 1119 in HSDB (through 2003/06) AN: 6935 UD: 200206 RD: Reviewed by SRP on 1/26/2002 NT: This record contains information specific to the title compound. Users with an interest in this substance are strongly encouraged to retrieve the Indium Compounds record, which has additional information on toxicity and environmental fate of indium ions and compounds. ID: ------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)------------- PN: INDIUM-PHOSPHIDE- RN: 22398-80-7 RELT: 6995 [INDIUM COMPOUNDS] MF: *In-P MANF: ---------MANUFACTURING/USE INFORMATION CATEGORY (USE CODE ZMAN)---------- MMFG: *Prepd from white phosphorus and indium iodide at 400 deg C: Thiel, Koelsch, Z. Anorg. Chem. 66, 319(1910) [R1] *Prepd from phosphorus vapor and heated indium metal: Jandelli, Gazz. Chim. Ital. 71, 58 (1941) [R1] *Synthesis in zone melting furnace at 1010 deg C from a non-stoichiometric melt: Minden, Sylvania Technologist 11, no. 1, 18 (Jan. 1958) [R1] *Indium phosphide is prepared by direct combination of the high-purity elements at high temperature [R2] *Indium phosphide is obtained by thermal decomposition of a mixture of a trialkyl indium compound and phosphine. [R2] MFS: *Apache Chems., Inc., P.O. Box 126, Seward, IL 61077; Production site: Seward, IL [R3] OMIN: *It is predicted that indium phosphide containing materials will replace the silicon used in microchips. [R4] USE: *Electronic grade in semiconductor devices, injection lasers, and experimental solar cells [R5] *Indium is finding increased use...in semiconductors such as indium phosphide for laser diodes used in fiber optic communication systems. [R6] CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)-------- COFO: *Black, cubic crystals [R7, 463] MP: *1070 deg C [R1] MW: *145.79 [R1] DEN: *4.81 g/cu cm [R7, p. 4-63] SOL: *Slightly soluble in mineral acids [R5] OCPP: *Dielectric constant: 10.8; Energy gap: 1.3 eV at 25 deg C; electron mobility: approx 4600 sq cm/volt-sec [R1] *Standard molar enthalpy (heat) of formation at 298.15 deg K=-88.7 kJ/mol; Standard molar Gibbs energy of formation at 298.15 deg K= -77.0 kJ/mol; Standard molar entropy at 298.15 deg K=59.8 J/mol-K; Molar heat capacity at constant pressure at 298.15 deg C=45.4 J/mol-K [R7, p. 5-20] *BP: 2000 deg C; mp: 156.6 deg C; density: 7.31 @ 20 deg C. Insoluble in hot or cold water; soluble in acids; very slightly soluble in sodium hydroxide. /Indium/ [R8] *Soft, silvery-white, malleable and ductile metal. Has plastic properties at cryogenic temps. /Indium/ [R9, 1918] SAFE: --------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)--------------- FPOT: *Flammable in the form of dust when exposed to heat or flame. [R9, 1919] *Mixtures with sulfur ignite when heated. [R9, 1919] EXPL: *Explosive reaction with dinitrogen tetraoxide + acetonitrile. Violent reaction with mercury(II) bromide at 350 deg C. [R9, 1919] REAC: *Reacts with halogens, S, Se, Te, As, P on heating. Dissolves in Hg /mercury/. [R9, 1918] *Explosive reaction with dinitrogen tetraoxide + acetonitrile. Violent reaction with mercury(II) bromide at 350 deg C. Mixtures with sulfur ignite when heated. [R9, 1919] SERI: *The soluble salts are very irritating to the eyes. [R8] OPRM: *SRP: The scientific literature for the use of contact lenses in industry is conflicting. The benefit or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place. SSL: *Stable in dry air. Slowly oxidized in moist air. [R9, 1918] DISP: *SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices. TOXB: ----------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOB)----------- ANTR: *Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/ [R10] *Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/ [R10] HTOX: *Workers exposed to indium compounds during the production of indium complained of tooth decay, pains in joints and bones, nervous and gastrointestinal disorders, heart pains, and general debility. [R8] NTOX: *... Conclusions: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of indium phosphide in male and female F344/N rats based on incr incidences of benign and malignant neoplasms of the lung. Incr incidences of pheochromocytoma of the adrenal medulla in males and females were also considered exposure related. Marginal incr in incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. There was clear evidence of carcinogenic activity of indium phosphide in male B6C3F1 mice based on incr incidences of malignant neoplasms of the lung and benign and malignant neoplasms of the liver. Marginal incr in incidences of adenoma and carcinoma of the small intestine may have been related to exposure to indium phosphide. There was clear evidence of carcinogenic activity of indium phosphide in female B6C3F1 mice based on incr incidences of benign and malignant neoplasms of the lung. Incr incidences of liver neoplasms were also considered exposure related. [R11] *Groups of 10 male and 10 female /F344/N/ rats were exposed to aerosols of indium phosphide with a mass median aerodynamic diameter of approx 1.2 um at concn of 0, 1, 3, 10, 30 or 100 mg/cu m by inhalation /6 hr day/5 days/wk (weeks 1-4 and weeks 10-14) or 7 days/wk (weeks 5-9). One male in the 100 mg/cu m group died before the end of the study. Body weight gains of all males were less than those of chamber controls. As a result of the indium phosphide exposure, the lungs of all exposed rats had a gray to black discoloration and were significantly enlarged, weighing 2.7-4.4 fold more than those of chamber controls. Indium phosphide particles were observed throughout the respiratory tract and in the lung associated lymphnodes. ... Inflammatory and proliferative lesions occurred in the lungs of all exposed groups of rats and consisted of alveolar proteinosis, chronic inflammation, interstitial fibrosis and alveolar epithelial hyperplasia. Pulmonary inflammation was attended by incr leukocyte and neutrophil counts in the blood. ... Indium phosphide caused inflammation at the base of the epiglottis of the larynx and hyperplasia of the bronchial and mediastinal lymph nodes. ... Indium phosphide ... induced a microcytic erythrocytosis consistent with bone marrow hyperplasia and hematopoietic cell proliferaation in the spleen. Hepatocellular necrosis was suggested by incr serum activities of alanine aminotransferase and sorbitol dehydrogenase in all groups of males and in 10 mg/cu m or greater females and was confirmed microscopically in 100 mg/cu m males and females. [R11] *Groups of 10 male and 10 female /B6C3f1) mice were exposed to aerosols of indium phosphide with a mass median aerodynamic diameter of approx 1.2 um at concn of 0, 1, 3, 10, 30 or 100 mg/cu m by inhalation /6 hr day/5 days/wk (weeks 1-4 and weeks 10-14) or 7 days/wk (weeks 5-9). Although the effects of indium phosphide exposure were similar in rats and mice, mice were more severely affected in that all males and females in the 100 mg/cu m groups either died or were removed moribund during the study. One male and three females in the 30 mg/cu m group were also removed before the end of the study. In general body weight gains were significantly less in males and females exposed to 3 mg/cu m or greater compared to chamber controls. Mice exposed to 30 or 100 mg/cu m were lethargic and experienced rapid, shallow breathing. /In mice/ the lungs were discolored and enlarged 2.6 -4.1 fold greater than chamber controls due to exposure induced alveolar proteinosis. Indium phosphide particles were observed in the nose, trachea, and lymph nodes of some exposed males and females. Alveolar proteinosis, chronic active inflammation, interstitial fibrosis, and alveolar epithelial hyperplasia were observed. ... Hyperplasia in the bronchial lymph nodes and squamous metaplasia, necrosis and suppurative inflammation of the larynx were observed in some exposed males and females. Exposure to indium phosphide induced a microcytic erythrocytosis which was consistent with the observed hematopoietic cell proliferation in the spleen. [R12] *Genetic Toxicology: No significant incr in the frequencies of micronucleated normochromatic erythrocytes were noted in peripheral blood samples of male or female mice exposed to indium phosphide for 14 wk. ... There was a significant incr in micronucleated polychromatic erythrocytes in 30 mg/cu m male mice, there was no incr in female mice, and the percentage of polychromatic erythrocytes was not altered in males or females. [R13] NTP: *... 2 Yr Study in Rats: Groups of 60 male and 60 female /F344/N/ rats were exposed to particulate aerosols of indium phosphide at concn of 0, 0.03, 0.1 or 0.3 mg/cu m/6 hr day/5 days/wk for 22 wk (0.1 and 0.3 mg/cu m groups) or 105 wk (0 and 0.03 mg/cum groups). Animals in the 0.1 and 0.3 mg/cu m group were maintained on filtered air from exposure termination at wk 21 until the end of the studies. 2 Yr Study in Mice: Groups of 60 male and female /B6C3F1/ mice were exposed to particulate aerosols of indium phosphide at concn of 0, 0.03, 0.1 or 0.3 mg/cu m 6 hr/day/5 days/wk for 21 wk (0.1 and 0.3 mg/cu m groups) or 105 wk (0 and 0.3 mg/cu m groups). Animals in the 0.1 and 0.3 mg/cu m groups were maintained on filtered air from exposure termination at wk 21 until the end of the studies. Conclusions: Under the conditions of these 2 yr inhalation studies, there was clear evidence of carcinogenic activity of indium phosphide in male and female F344/N rats based on incr incidences of benign and malignant neoplasms of the lung. Incr incidences of pheochromocytoma of the adrenal medulla in males and females were also considered exposure related. Marginal incr in incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. There was clear evidence of carcinogenic activity of indium phosphide in male B6C3F1 mice based on incr incidences of malignant neoplasms of the lung and benign and malignant neoplasms of the liver. Marginal incr in incidences of adenoma and carcinoma of the small intestine may have been related to exposure to indium phosphide. There was clear evidence of carcinogenic activity of indium phosphide in female B6C3F1 mice based on incr incidences of benign and malignant neoplasms of the lung. Incr incidences of liver neoplasms were also considered exposure related. [R11] ADE: *The absorption of indium phosphide particles (2 um in diameter) following admin by oral gavage or ip injection of single doses of 0, 1,000, 3,000 or 5,000 mg/kg indium phosphide to male ICR mice, which were observed for up to 14 days /was evaluated/. Absorption from the gastrointestinal tract was minimal in less than 0.125 ug indium/ml of serum was detected at all doses. Following ip injection, there was a dose related incr in indium concn in serum (0.13, 0.6 and 1.75 ug/ml). After a dose of 5,000 mg/kg, indium was detected primarily in the liver and lungs (approx 150 ug/g tissue), with some being detected in the kidneys and testes (less than 20 ug/g tissue). [R14] *The distribution of indium phosphide particles (1.73 um diameter) in male F344 rats following a single oral dose, 14 days of oral dosing, or a single intratracheal instillation of 10 mg/kg indium phosphide. Indium phosphide was poorly absorbed from the intestinal tract in both oral studies, with most being excreted in the feces. Less than 0.23% of the admin dose was excreted in the urine over a 10 day recovery period. Absorbed indium was evenly distributed among the major organs, although less than 0.67% of the dose was retained in tissues or urine following 24 hr in both oral studies, indicating that the indium was not accumulating in the bodies of rats following multiple dosing. The urinary elimination half time was determined to be about 321 hr. Intratracheal admin of indium phosphide, the majority of the tissue indium was in the lungs and less than 0.36% of the dose being evenly distributed to the other major organs. [R15] ENEX: -----ENVIRONMENTAL FATE/EXPOSURE POTENTIAL CATEGORY (USE CODE ZENE)------ ARTS: *GALLIUM, INDIUM, PHOSPHORUS, AND ARSENIC ARE BASE MATERIALS IN SEMICONDUCTOR MFR. WASTE OCCURS AS SLURRY AND AS COMPD DISSOLVED IN AQ, ALK, AND ACIDIC SOLN. A GAS WASTE SLUDGE RECOVERY AND TREATMENT SYSTEM IS DISCUSSED. /INDIUM/ [R16] EXSR: -------EXPOSURE STANDARDS AND REGULATIONS CATEGORY (USE CODE ZEXS)------- ATOL: *No data. NREC: *Recommended Exposure Limit: 10 hr Time Weighted Avg: 0.1 mg/cu m. /Indium/ [R17] TLV: *8 hr Time Weighted Avg (TWA): 0.1 mg/cu m. /Indium and compounds, as In/ [R18, 2002.36] *Excursion Limit Recommendation: Excursions in worker exposure levels may exceed three times the TLV-TWA for no more than a total of 30 min during a work day, and under no circumstances should they exceed five times the TLV-TWA, provided that the TLV-TWA is not exceeded. [R18, 2002.6] TSCA: *Section 8(a) of TSCA requires manufacturers of this chemical substance to report preliminary assessment information concerned with production, exposure, and use to EPA as cited in the preamble in 51 FR 41329. [R19] REFS: -------------ADDITIONAL REFERENCES CATEGORY (USE CODE ZREF)-------------- TEST: *The NTP Toxicology Research and Testing Program releases a Management Status Report on a quarterly basis. This report gives the status of chemicals studied, under study, or proposed for study by NTP. The 07/11/2001 issue indicates that the technical report on indium phosphide is in the galley/camera ready copy stage of development. Route: inhalation; Species: rats and mice. NTP TR No 499. [R20] SO: R1: Budavari, S. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 1996. 851 R2: Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present.,p. VA14 (1989) 163 R3: SRI; 1984 Directory of Chemical Producers, SRI International: Menlo Park, CA (1984) R4: Chemistry and Industry (London). Liverpool chips in first. Chem Ind 11: 403 (1983) R5: Lewis, R.J., Sr (Ed.). Hawley's Condensed Chemical Dictionary. 13th ed. New York, NY: John Wiley and Sons, Inc. 1997. 608 R6: Kirk-Othmer Encyclopedia of Chemical Technology. 4th ed. Volumes 1: New York, NY. John Wiley and Sons, 1991-Present.,p. V14 (1995) 158 R7: Lide, DR (ed.). CRC Handbook of Chemistry and Physics. 81st Edition. CRC Press LLC, Boca Raton: FL 2000 R8: American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.797 R9: Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996. R10: Bronstein, A.C., P.L. Currance; Emergency Care for Hazardous Materials Exposure. 2nd ed. St. Louis, MO. Mosby Lifeline. 1994. 139 R11: Toxicology and Carcinogenesis Studies of Indium Phosphide in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.8-10 Technical Report Series No. 499 (2001) NIH Publication No. 01-4433 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R12: Toxicology and Carcinogenesis Studies of Indium Phosphide in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.7-8 Technical Report Series No. 499 (2001) NIH Publication No. 01-4433 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R13: Toxicology and Carcinogenesis Studies of Indium Phosphide in F344/N Rats and B6C3F1 Mice (Inhalation Studies) p.9-10 Technical Report Series No. 499 (2001) NIH Publication No. 01-4433 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R14: Kabe I, et al; J Occupat Health 38: 6-12 (1996) as cited in: Toxicol Environ Health 43: 483-94 (1994) as cited in: Toxicology and Carcinogenesis Studies of Indium phosphide in F344/N Rats and B6C3F1 Mice p.18 Technical Report Series No. 499 (2001) NIH Publication No. 01-4433 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R15: Zheng W, et al; J Toxicol Environ Health 43: 483-94 (1994) as cited in: Toxicology and Carcinogenesis Studies of Indium phosphide in F344/N Rats and B6C3F1 Mice p.18 Technical Report Series No. 499 (2001) NIH Publication No. 01-4433 U.S. Department of Health and Human Services, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 R16: DAMICO FA ET AL; MID ATL IND WASTE CONF (PROC) 11: 157 (1979) R17: NIOSH. NIOSH Pocket Guide to Chemical Hazards. DHHS (NIOSH) Publication No. 97-140. Washington, D.C. U.S. Government Printing Office, 1997. 172 R18: American Conference of Governmental Industrial Hygienists. TLVs and BEIs: Threshold limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices for 2002. Cincinnati, OH. R19: 40 CFR 712.30 (7/1/2001) R20: NTP; Division of Toxicology Research and Testing; Management Status Report; 07/11/2001; p.24 RS: 20 Record 359 of 1119 in IRIS (through 2003/06) AN: 10 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0010-tr.pdf UD: 199901 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Barium-and-Compounds- SY: 7440-39-3; BARIUM-; UN-1399-; UN-1400-; UN-1854- RN: 7440-39-3 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199901 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Barium and Compounds CASRN -- 7440-39-3 Last Revised -- 01/21/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ---------------------------------------------------- --------------- No Adverse Effect** NOAELs: 10 and 7.3 mg/L 3 1 7E-2 NOAEL (adjusted): mg/kg-day Subchronic human study and 0.21 mg/kg-day community exposure study LOAEL: None Wones et al., 1990; Brenniman and Levy, 1984 Increased kidney weight NOAEL: 65 mg/kg-day LOAEL: 115 mg/kg-day Subchronic rat study NTP, 1994 Increased kidney weight*** NOAEL: 45 mg/kg-day LOAEL: 75 mg/kg-day Chronic rat study NTP, 1994 ------------------------------------------------------------------------ *Conversion Factors and Assumptions: Wones et al. (1990): 10 mg Ba/L drinking water concentration was multiplied by the actual water consumption rate of 1.5 L/day and divided by the 70 kg reference body weight. NOAEL (adjusted) = 10 mg/L x 1.5 L/day x 1/70 kg = 0.21 mg/kg-day. Brenniman and Levy (1984): 7.3 mg Ba/L drinking water concentration was multiplied by the reference water consumption rate of 2 L/day and divided by the 70 kg reference body weight. NOAEL (adjusted) = 7.3 mg/L x 2 L/day x 1/70 kg = 0.21 mg/kg-day. NTP (1994) subchronic and chronic studies: as estimated by authors. **Previous investigations in research animals (both acute and chronic) have demonstrated the potential for hypertension to develop as a result of high barium exposures. Based on these reports, lower dose human studies were conducted to examine potential effects on blood pressure, electrocardiographic events, serum and urinary markers of toxicity following barium exposure. Although no evidence of barium-induced toxicity was identified in humans, these studies have identified a dose at which no adverse effects were observed. That dose, along with the kidney effects in experimental animals, serves as the basis for derivation of the reference dose and is consistent with EPA's RfD methodology. ***Based on 15-month interim evaluation. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Brenniman, GR; Levy, PS. (1984) Epidemiological study of barium in Illinois drinking water supplies. In: Advances in modern toxicology, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 231-249. National Toxicology Program (NTP). (1994) Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (Drinking Water Studies). NTP TR 432. National Toxicological Program, Research Triangle Park, NC. NIH Pub. No. 94-3163. NTIS Pub PB94-214178. Wones, RG; Stadler, BL; Frohman, LA. (1990) Lack of effect of drinking water barium on cardiovascular risk factor. Environ Health Perspect 85:355-359. No single study is appropriate as the basis for a lifetime RfD for barium. The RfD is based on a weight-of-evidence approach that focuses on four co-principal studies: the Wones et al. (1990) experimental study in humans, the Brenniman and Levy (1984) epidemiologic study, and the subchronic and chronic rat studies that employed adequate diets and investigated both cardiovascular and renal endpoints (NTP, 1994). The McCauley et al. (1985) study of unilaterally nephrectomized rats was used to support the identification of the kidney as a co-critical target. The identification of hypertension as a health endpoint of concern is supported by findings of hypertensive effects in humans who ingested acutely high doses of barium compounds, in workers who inhaled dusts of barium ores and barium carbonate, in experimental animals given barium intravenously, and in rats exposed to barium in drinking water while on restricted diets. Based on these findings, lower dose human studies were conducted to examine the potential effects on blood pressure in humans, and both blood pressure and kidney function in animals. Although the experimental study by Wones et al. (1990) together with the epidemiological study by Brenniman and Levy (1984) did not report any significant effects on blood pressure, they establish a NOAEL in humans of 0.21 mg Ba/kg-day. The animal data suggest that the kidney may also be a sensitive target for ingested barium from low level exposure (McCauley et al., 1985; NTP, 1984; Schroeder and Mitchener, 1975a); neither of the human studies investigated sensitive renal endpoints. Therefore, 0.21 mg Ba/kg-day is used as the basis to derive the RfD. The use of a NOAEL from human studies increases the confidence in the Agency's judgement in the derivation of the RfD, which is defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a life time. Wones et al. (1990) administered barium (as barium chloride) in the drinking water of 11 healthy male volunteers (mean age of 39.5 years). None of the subjects was taking any medications and none had hypertension, diabetes, or cardiovascular disease. Barium concentrations in the drinking water consumed by the subjects prior to the study were known to be very low. The subjects were given 1.5 L/day of distilled water containing various levels of barium chloride. No barium was added for the first 2 weeks, which served as a control period; 5 ppm barium (0.11 mg Ba/kg-day using 70 kg reference weight) was added for the next 4 weeks and 10 ppm barium (0.21 mg Ba/kg-day) was added for the last 4 weeks of the study. Diets were controlled in order to mimic American dietary practices (barium content of the diet was not determined, but the authors mentioned that a typical hospital diet provides 0.75 mg Ba/day, or 0.011 mg Ba/kg-day using 70 kg reference weight). All beverages and food were provided, and subjects were instructed to consume only what was provided. The subjects were instructed to keep their level of exercise constant and to abstain from alcohol, and smokers were told to smoke consistently throughout the study. Systolic and diastolic blood pressures (measured in the morning and evening) were not significantly affected by barium exposure. Blood was collected at the beginning and periodically, particularly as four consecutive daily samples at the end of each of the three study periods. No significant alterations in serum calcium levels were observed (9.11, 9.23, and 9.23 mg/dL at the 0, 5, and 10 ppm exposure levels, respectively). When the serum calcium levels were "normalized" for differences in albumin levels, a significant increase (p = 0.01) was observed (8.86, 9.03, and 9.01, respectively). This type of adjustment has been considered unreliable (Sutton and Dirks, 1986). The study authors attributed the increase in adjusted serum calcium levels to a slight decrease in serum albumin. The increase in serum calcium levels was considered borderline and not clinically significant. No significant changes were observed in plasma total cholesterol, triglyceride, LDL or HDL cholesterol, LDL:HDL ratio, and apolipoproteins A1, A2, and B; in serum glucose, albumin, and potassium levels; or in urinary levels of sodium, potassium, vanillymandelic [sic] acid or metanephrines. Electrocardiograms (measured for 24 h on 2 consecutive days at the end of each study period) revealed no changes in cardiac cycle intervals including the QT interval; the study authors noted that the lack of shortening of the QT interval provided evidence that the slight increase in serum calcium was not clinically significant. In addition, no significant arrhythmias, increase in ventricular irritability, or apparent conduction problems were seen with barium exposure. The NOAEL of 0.21 mg Ba/kg-day can be determined from the 10 ppm barium exposure regime that was used for the last 4 weeks of the study. Brenniman and Levy (1984) reported a retrospective epidemiology study of two communities, McHenry and West Dundee, IL, which had similar demographic and socioeconomic characteristics and a 70-fold difference in barium concentrations in drinking water. The mean concentration in McHenry's drinking water was 0.1 mg Ba/L, whereas the mean concentration in West Dundee's drinking water was 7.3 mg Ba/L. The levels of other minerals in the drinking water of the two communities were stated to be similar. Subjects were selected randomly from a pool that included every person 18 years of age or older in a random sample of blocks within each community. All subjects underwent three blood pressure measurements (taken over a 20-min period with a calibrated electronic blood pressure apparatus) and responded to a health questionnaire that included such variables as sex, age, weight, height, smoking habits, family history, occupation, medication, and physician-diagnosed heart disease, stroke, and renal disease. Data were analyzed using the signed ranked test for age-specific rates, the weighted Z test for prevalence rates, and analysis of variance for blood pressures. No significant differences in mean systolic or diastolic blood pressures, or in rates of hypertension, heart disease, stroke, or kidney disease were found for men or women of the two communities. A more controlled study was conducted on a subpopulation of the McHenry and West Dundee subjects who did not have home water softeners, were not taking medication for hypertension, and had lived in the study community for more than 10 years. No significant differences were observed between the mean systolic or diastolic blood pressures for men or women of these subpopulations in the low-barium (0.1 mg Ba/L, 0.0029 mg Ba/kg-day assuming water ingestion of 2 L/day and 70 kg weight) and elevated-barium communities (7.3 mg Ba/L, 0.21 mg Ba/kg-day). Thus, the dosage associated with the elevated barium levels, 0.21 mg Ba/kg-day, is a NOAEL. In subchronic and chronic studies conducted by NTP (1994), groups of male and female F344/N rats were exposed to barium chloride dihydrate in drinking water for 13 weeks or 2 years. The barium chloride concentrations tested were 0, 125, 500, 1,000, 2,000, and 4,000 ppm (0, 10, 65, 110, and 200 mg Ba/kg-day for males and 0, 10, 35, 65, 115, and 180 mg Ba/kg-day for females; the study authors estimated doses using water consumption and body weight data) in the subchronic study (10 rats/sex/group) and 0, 500, 1,250, and 2,500 ppm (0, 15, 30, and 60 mg Ba/kg-day for males and 0, 15, 45, and 75 mg Ba/kg-day for females) in the chronic study (60/sex/group). The animals were fed an NIH-07 diet; barium content of the diet was not reported. Neurobehavioral and cardiovascular assessments were conducted as part of the subchronic study. In the subchronic study, chemical-related deaths were limited to 3 males and 1 female in the 4,000 ppm group; the cause of death was not evident on histological examination. In rats receiving 4,000 ppm barium chloride, there were significant decreases in water consumption (30% relative to that of controls) and body weight gain (final body weights increased 13% in males and 8% in females). Toxicologically significant organ weight changes consisted of increased absolute and relative kidney weights in female rats at 2,000 and 4,000 ppm and increased relative kidney weights in male rats at 4,000 ppm. Serum phosphorus levels were significantly elevated in female rats at 500 ppm and in male rats at 2,000 ppm, but the increase did not appear to be dose-related. The NTP (1994) concluded that the elevated values probably were due to an artifact from hemolysis of the collected blood samples. No other chemical-related or biologically significant changes in serum electrolytes or hematology values were seen. Minimal to mild focal to multifocal areas of dilatation of the renal proximal convoluted tubules were observed in 3/10 male and 3/10 female rats exposed to 4,000 ppm; crystals were not present in the kidney tubules. Lymphoid depletions in the spleen and thymus were observed in the rats receiving 4,000 ppm that died during the study. No other histological changes were observed. Neurobehavioral assessments were conducted at days 0, 45, and 90. At day 90, statistically significant decreases in the magnitude of undifferentiated motor activity were observed in both sexes of rats receiving 4,000 ppm. Marginal decreases were observed in all other barium-exposed groups except the 1,000 ppm females. No significant or dose-related changes were observed in the other neurobehavioral endpoints (thermal sensitivity judged by a tail flick latency test, startle-response to acoustic and air-puff stimuli, forelimb or hindlimb grip strength, or hindlimb foot splay). The neurobehavioral effects were attributed to the general condition of the high-dose animals (Dietz et al., 1992). Cardiovascular studies in the rats revealed no barium-associated differences in heart rate, systolic blood pressure, or electrocardiogram. Thus, 4,000 ppm of barium in the drinking water (200 mg Ba/kg-day for males and 180 mg Ba/kg-day for females) constitutes a subchronic FEL for mortality in rats. Renal histopathological lesions were seen at this dose level but were not severe. Detection of glomerular effects, however, would have required electron microscopy or urinalysis, neither of which was performed. Glomerular effects were seen during electron microscopic examination in unilaterally nephrectomized rats given 1,000 ppm barium (150 mg Ba/kg-day) through the drinking water in a study by McCauley et al. (1985). The next lower dose level in the NTP (1994) study, 2,000 ppm (110 mg Ba/kg-day for males and 115 mg Ba/kg-day for females), may be a subchronic LOAEL for renal effects in females based on the increased absolute and relative kidney weight changes. The subchronic NOAEL would be 1,000 ppm (65 mg Ba/kg-day for both sexes). In the chronic portion of the NTP (1994) study, there were no significant increases in mortality in the barium-exposed rats. Mean body weights were slightly lower in male rats receiving 2,500 ppm (5% lower than controls) and in female rats receiving 1,250 or 2,500 ppm (6% and 11% lower, respectively, than controls). Water consumption was decreased in a dose-related manner; at 2,500 ppm consumption was 22% and 25% lower than controls in the males and females, respectively. Barium exposure did not result in toxicologically significant alterations in hematologic or clinical chemistry parameters (assessed after 15 mo of exposure). Toxicologically significant alterations in organ weights (measured at the 15-mo interim evaluation) were limited to a statistically significant (p 0.01) increase in relative kidney weights in female rats at 2,500 ppm. Chemical-related kidney lesions were not observed in rats; the only potential indication of renal toxicity was the increased relative kidney weight seen in the females at 2,500 ppm. In addition, there were no chemical-related histological changes in any other organs or tissues. Thus, the highest exposure level tested in this study, 2,500 ppm barium in drinking water (60 mg Ba/kg-day for males and 75 mg Ba/kg-day for females), may be a chronic NOAEL or LOAEL for rats, depending on interpretation of the increased relative kidney weight in females. When considered together with the results in the 13-week NTP (1994) study in rats, in which increased relative and absolute kidney weights were seen in female rats receiving 2,000 ppm barium in drinking water (115 mg Ba/kg-day), and kidney lesions and greater increases in relative and absolute kidney weights were seen in female rats at 4,000 ppm (180 mg Ba/kg-day), the increased relative kidney weight in females in the 2-year study is suggestive of potential renal effects. Therefore, 2,500 ppm (75 mg Ba/kg-day) is designated a chronic LOAEL and 1,250 ppm (45 mg Ba/kg-day) a chronic NOAEL for female rats for renal effects in the NTP (1994) study. McCauley et al. (1985) reported histological, electron microscopic, electrocardiograph, and blood pressure studies in rats given barium in their drinking water for various durations and fed Purina rat chow (contributing significant barium intake) or Tekland rat chow (insignificant barium intake). In the histology studies, groups of 10-12 male or female CD Sprague-Dawley rats received 0, 1, 10, 100, or 250 ppm barium (as barium chloride) in drinking water and Purina rat chow containing 12 ppm barium for 36, 46, or 68 weeks (not all concentrations or both sexes tested for each duration). The authors reported that no significant differences in food or water intake or body weight were observed, but did not report the actual data. They stated that rats that received 10 ppm of barium in the drinking water ingested 1.5 mg Ba/kg-day from water and 1 mg Ba/kg-day from the Purina diet. This barium intake was used to estimate total barium intake for the other exposure levels. Thus, the estimated total barium intakes were 1, 1.15, 2.5, 16, and 38.5 mg/kg-day for the 0, 1, 10, 100, and 250 ppm concentrations for all exposure regimens. Histological evaluations of an extensive number of tissues, including gastrointestinal tract, liver, heart, adrenal gland, brain, respiratory tract, spleen, thymus, kidneys, ovaries, and testes, did not reveal barium-related lesions. No alterations in hematocrit levels were observed. In the electrocardiographic study, CD Sprague-Dawley rats (10-11/group, sex not specified) were given drinking water containing 0 or 250 ppm of barium (as barium chloride) for 5 mo and Purina rat chow (estimated intakes of 1 and 38.5 mg Ba/kg-day, based on the estimates for the histology study). Data were obtained at 0, 4, and 60 min after an intravenous injection of 0.5 microg/kg of l-norepinephrine (NE). Barium induced a significant enhancement of NE-induced bradycardia compared with controls 4 min after NE administration, but by 60 min, the heart rates of controls were still depressed, whereas those of barium-exposed animals were approaching normal. No significant alterations in the PR, QS, QT, and ST interval durations or peak amplitudes were observed. The toxicological significance of these findings is uncertain. In the blood pressure study, CD Sprague-Dawley rats (6/group, sex was not specified) were fed Tekland rat chow (0.5 microg Ba/kg-day) and administered barium in drinking water for 16 weeks. Normotensive rats received 0, 3, 10, 30, or 100 ppm barium in drinking water or in 0.9% sodium chloride solution as drinking water. Unilaterally nephrectomized rats received 1, 10, 100, or 1,000 ppm barium in regular drinking water or in 0.9% sodium chloride as drinking water. Using data from the histology study, the doses corresponding to 0, 1, 3, 10, 30, 100, and 1,000 ppm were estimated to be 0, 0.15, 0.45, 1.5, 4.5, 15, and 150 mg Ba/kg-day, respectively. All of these groups showed fluctuations of blood pressure but no hypertension. Dahl salt-sensitive rats, exposed to 1, 10, 100, or 1,000 ppm barium in 0.9% sodium chloride for 16 weeks, had a transiently elevated blood pressure (approximately 150-160 mm Hg) during the first 1-2 weeks of exposure to 1 or 10 ppm barium. This response was considered to be a normal reaction to 0.9% sodium chloride in the drinking water for this strain of rat. Blood pressure during the remaining period of exposure to 1 or 10 ppm barium or during the entire period of exposure to 100 or 1,000 ppm barium was not indicative of hypertension. No hypertension was seen in Dahl salt-resistant rats given the same exposures. Thus, there was no indication that barium contributed to hypertension, but further interpretation of the results is problematic because of the lack of 0 ppm barium/0.9% sodium chloride control groups. Electron microscopic examination of kidneys in all the rats in the blood pressure studies demonstrated no histopathologic changes in arteriolar vessel walls or in tubules of the nephrons. However, structural changes in glomeruli (fused podocyte processes and thickening of the capillary basement membrane, and myelin figures in Bowman's space) were observed in the 1,000 ppm groups. These changes are indicative of damage to the glomerulus that would be evidenced as inefficient glomerular filtration, including proteinuria. Two groups of unilaterally nephrectomized rats (barium administered in drinking water or in 0.9% sodium chloride) and the Dahl salt-sensitive and salt-resistant rats (barium administered in 0.9% sodium chloride) were exposed to 1,000 ppm. Normal CD Sprague-Dawley rats were not tested at this exposure level. No glomerular effects were seen at the next-lower exposure level, 100 ppm, in any group of rats, including normal CD Sprague-Dawley rats that received barium in regular drinking water. Thus, the study by McCauley et al. (1985) detected no adverse effect of barium on blood pressure at drinking water exposure levels up to 1,000 ppm (150 mg Ba/kg-day), the highest level tested. The only effect seen was glomerular damage in all groups of rats (unilaterally nephrectomized rats, Dahl salt-sensitive rats and Dahl salt-resistant rats) that received 1,000 ppm of barium in drinking water (150 mg Ba/kg-day). The NOAEL for glomerular effects in this study is 100 ppm (15 mg Ba/kg-day) in both unilaterally nephrectomized and intact rats. The McCauley et al. (1985) study is the only study that examined the kidney for glomerular effects and also measured blood pressure. The applicability of dose-response data from renal toxicity studies in unilaterally nephrectomized rats to intact rats or humans is uncertain, however, because removal of renal tissue may affect sensitivity of the remaining tissue to nephrotoxins. A reduction in renal mass, such as that produced by partial nephrectomy, results in compensatory adaptation of the remnant kidney tissue and associated changes in cellular metabolism and function that may affect the sensitivity of the animal to nephrotoxicity. These changes include cellular hypertrophy and increased transport activity in the proximal and distal tubule, changes in renal metabolism, and increased renal plasma flow and glomerular filtration rate (Zalups et al., 1987). Increased, decreased, or no change in susceptibility to nephrotoxicity has been demonstrated in rats that have undergone unilateral or three-quarter nephrectomy, depending on the chemical (Zalups and Lash, 1990; Zalups et al., 1988). At present, it is not possible to reliably predict which chemicals are likely to be more or less toxic or to have no change in toxicity to unilaterally nephrectomized rats. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 3. An uncertainty factor of 1 is assigned to account for some database deficiencies and 3 for lack of potential differences between adults and children and adequate developmental toxicity studies. The RfD for barium is based on four principal studies. Two human studies (Brenniman and Levy, 1984; Wones et al., 1990) identified no effects in adults. Two well-designed rat studies (NTP, 1994) identified NOAELs and LOAELs for renal effects following subchronic or chronic exposure. The results of the NTP (1994) subchronic study suggest that under these test conditions renal effects may be a sensitive endpoint. However, a similar relationship may not occur following chronic exposure or in humans. Animal studies (Perry et al., 1983, 1985, 1989) suggest that a marginally adequate diet, particularly one with inadequate calcium levels, may increase sensitivity to barium-induced hypertension. The Brenniman and Levy (1984) study examined more than 2,000 men and women; it is likely that a wide range of dietary variability, including low calcium intakes, was represented in this population. Additionally, it is likely that this population includes individuals who may be unusually susceptible to the toxicity of barium. Dog and rat pharmacokinetic studies (Taylor et al., 1962; Cuddihy and Griffith, 1972) suggest that gastrointestinal absorption of barium may be higher in young animals than in older animals. Brenniman and Levy (1984) examined 18- to 75+-year-old residents living in the community for more than 10 years. It is likely that this study included adult residents who were exposed to elevated barium levels as young children, but it may not account for all of the uncertainty. The barium database consists of subchronic and chronic toxicity studies in three species (humans, rats, mice) and a marginally adequate one-generation reproductive/developmental toxicity study. This rat and mouse study (Dietz et al., 1992) gave no indication that developmental or reproductive endpoints are more sensitive than other endpoints; interpretation of the study results is limited by very low pregnancy rates in all groups, including controls, and by examination of a small number of developmental endpoints. MF = 1 ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) The WHO (1990) reported several published estimates of dietary and drinking water intake of barium by humans. The range of daily dietary intake was 300-1,770 microg Ba/day, with wide variations. This is equivalent to 4-25 microg (0.004-0.025 mg) Ba/kg-day, assuming a 70 kg adult body weight. The WHO (1990) also reported levels of barium in U.S. drinking water of 1-20 microg/L. This is equivalent to an intake of 0.03-0.60 microg Ba/kg-day, assuming a consumption rate of 2 L/day and 70 kg adult body weight. The range from these two sources combined is 0.004-0.026 mg Ba/kg-day. NTP (1994) also examined the subchronic and chronic toxicity of barium in mice. In these studies, groups of male and female B6C3F1 mice received 0, 125, 500, 1,000, 2,000, or 4,000 ppm (13-week duration) or 0, 500, 1,250, or 2,500 ppm (2 years) barium (as barium chloride dihydrate) in the drinking water. The animals were fed a NIH-07 diet; barium content not reported. Increased mortality was observed in the subchronic and chronic studies at the highest doses tested (4,000 or 2,500 ppm, respectively). Chemical-related nephropathy was also observed at these doses. The nephropathy was characterized as tubule dilatation, renal tubule atrophy, tubule cell regeneration, and the presence of crystals primarily in the lumen of the renal tubules. Other adverse effects observed in the high-dose animals were attributed to debilitation of the animals. Thus, these studies identify FELs for nephropathy and mortality of 4,000 ppm (450 and 495 mg Ba/kg-day for males and females) and 2,500 ppm (160 and 200 mg Ba/kg-day) in mice receiving barium in drinking water for a subchronic or chronic duration. The NOAELs were 2,000 ppm (205 and 200 mg Ba/kg-day) and 1,250 ppm (75 and 90 mg Ba/kg-day), respectively. In a study by Tardiff et al. (1980), male and female Charles River rats were exposed to 0, 10, 50, or 250 ppm barium (as barium chloride) in drinking water for 4, 8, or 13 weeks. The rats were fed Tekland diet pellets (baseline dose of 0.5 microg Ba/kg-day). No significant alterations in survival, organ weights, hematologic and serum clinical chemistry parameters, and gross or histopathologic appearance of major tissues (liver, kidney, spleen, heart, brain, muscle, femur, and adrenal glands) were observed. This study identifies a subchronic NOAEL of 250 ppm (38.1 and 45.7 mg Ba/kg-day for males and females). Perry et al. (1983, 1985, 1989) exposed female weanling Long-Evans rats to 0, 1, 10, or 100 ppm barium (as barium chloride) in drinking water for 1, 4, or 16 mo. The drinking water was fortified with five essential metals (molybdenum, cobalt, copper, manganese, and zinc). The rats were fed a rye-based diet with low trace metal content (1.5 ppm barium). After 8 mo of exposure to 10 ppm, there was a significant increase in systolic blood pressure (6 mm Hg), which remained significantly elevated (4 mm Hg) through 16 mo. In the 100 ppm group, systolic blood pressure was elevated at 1 mo (12 mm Hg) and continued through 16 mo (16 mm Hg). No effects were observed at 1 ppm. Exposure to 100 ppm also resulted in reductions in ATP and phosphocreatinine levels in the myocardium, depressed cardiac contraction rates, and depressed excitability. This study identifies a NOAEL of 1 ppm (0.17 mg Ba/kg-day) and LOAEL of 10 ppm (0.82 mg Ba/kg-day) for hypertension in rats maintained on low-mineral-content diets. The differences in the cardiovascular outcome of the Perry et al. (1983, 1985, 1989) study as compared with the NTP (1994) and McCauley et al. (1985) studies may have been confounded by differences in diet composition. Rats in the Perry et al. (1983, 1985, 1989) study were maintained on a rye-based diet that contained low levels of several elements compared to standard laboratory chow (e.g., Purina chow), including calcium (3,800 vs. 12,000 ppm) and potassium (7,600 vs. 8,200 ppm). Animals maintained on diets low in calcium and/or potassium may be more sensitive to the cardiovascular effects of barium. The calcium content of the above rye-based diet is below the minimum requirement according to the NRC (1995); the potassium content is not. Acute effects of barium on the cardiovascular system are modified by calcium and potassium. Barium has been shown to be a calcium agonist (Perry et al., 1989; Brenniman et al., 1981; Shanbaky et al., 1978; U.S. EPA, 1990; WHO, 1990). Potassium alleviates the cardiac effects and skeletal muscle effects associated with acute barium poisoning (Gould et al., 1973; Roza and Berman, 1971; Diengott et al., 1964; U.S. EPA, 1990; WHO, 1990). Perry and Erlanger (1982) observed that rats maintained on the rye-based diet and exposed to cadmium developed hypertension, whereas rats maintained on standard chow and exposed to cadmium did not. In view of a possible association between the barium-induced cardiovascular effects and calcium and potassium intake, the applicability of dose-response data from the Perry et al. (1983) study to RfD derivation is not considered appropriate. Schroeder and Mitchner (1975a,b) exposed groups of male and female Long-Evans rats and Charles River CD mice to 0 or 5 ppm barium (as barium acetate) in drinking water from weaning to natural death. No adverse alterations in lifespan, growth, or histopathology of the heart, lungs, kidneys, liver, and spleen were observed in either species. A significant reduction in longevity (defined as mean lifespan of the last surviving five animals) was observed in the male mice. The incidence of proteinuria in male rats exposed to barium for 152 days (173 days of age) was significantly higher than in controls; proteinuria was assessed by dipstick method and the magnitude was not reported. Other clinical chemistry alterations observed in the rats included an increase in serum cholesterol concentrations in females (measured at age 532 and 773 days) and a non-age-related alteration in serum glucose levels in males; the study authors attached no toxicological significance to these serum chemistry results. Thus, these studies identify a LOAEL of 5 ppm (0.61 mg Ba/kg-day) for renal glomerular damage, evidenced as proteinuria in male rats maintained on low mineral diets, and a NOAEL of 5 ppm (1.2 mg Ba/kg-day) in similarly exposed mice. A health survey of workers at a Sherwin Williams plant concluded that workers exposed to inhaled barium ores and barium carbonate during grinding and mixing operations for at least 5 years had a significantly higher incidence of hypertension (7/12 or 58%) as compared with workers who never worked in barium processes (5/25 or 20%) (NIOSH, 1982). Demographic characteristics and smoking histories for the two groups were similar. No statistically significant differences in mean beta2-microglobulin or prevalence of workers with elevated serum creatinine, blood urea nitrogen (BUN) values, or urine protein levels were observed between the two groups. No significant differences in mean blood lead levels or the number of workers with blood lead levels of > 39 microg/dL were found. Although the results of this study suggest an association between exposure to barium and hypertension, the results should be interpreted cautiously because a small number of workers were examined, it appears that blood pressure was only measured once, and the workers were exposed to a number of other chemicals, including lead, which is associated with an increase in blood pressure. This study also compared the health status of current workers exposed to barium ores with those in each of four other job areas; these comparisons revealed no differences in blood pressure or renal parameters. Intentional or accidental ingestion of barium compounds causes gastroenteritis, hypokalemia, hypertension, cardiac arrhythmias, and skeletal muscle paralysis. Potassium infusion is used clinically to reverse many of the toxic effects, but does not reverse the hypertension (Diengott et al., 1964; Gould et al., 1973; U.S. EPA, 1990; WHO, 1990). Intravenous infusion of barium chloride into anesthetized dogs or guinea pigs resulted in increased blood pressure and cardiac arrhythmias (Hicks et al., 1986; Roza and Berman, 1971). The study in dogs also reported skeletal muscle flaccidity and paralysis (Roza and Berman, 1971). In the dog study, determination of plasma potassium concentrations revealed severe hypokalemia, apparently resulting from enhanced movement of potassium into cells. The hypertension did not appear to be mediated through the renin-angiotensin system because it was not prevented by bilateral nephrectomy of the dogs. Simultaneous infusion of potassium into the dogs abolished the cardiac effects and the skeletal muscle flaccidity but did not affect hypertension. Data on the reproductive and developmental toxicity of barium compounds are limited. In a study by Dietz et al. (1992), no significant alterations in gestation length, pup survival, or occurrence of external abnormalities were observed in Fischer 344/N rats or B6C3F1 mice exposed to 0, 500 (mice only), 1,000, 2,000, or 4,000 (rats only) ppm barium (as barium chloride dihydrate) in drinking water for 60 (males) or 30 (females) days. Decreases in average litter sizes (not statistically significant in rats) were observed in the 4,000 ppm rat group and 1,000 ppm mouse group. No alterations in epididymal sperm counts, sperm motility, sperm morphology, testicular or epididymal weights, or vaginal cytology were observed in the F0 rats or mice. Low pregnancy rates were observed in all groups (40% in controls to 65% in 4,000 ppm in rats and 55% in controls to 55%-70% in barium-treated groups of mice). The results of this study suggest that oral exposure to barium chloride does not result in reproductive toxicity; however, the results should be interpreted cautiously because of the below-normal pregnancy rates in all groups. Tarasenko et al. (1977) conducted oral and inhalation developmental toxicity studies, but the poor reporting of the study design and results and the lack of statistical analysis of data limit the usefulness of these studies in assessing the developmental toxicity of barium. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=38 CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Database -- Medium. RfD -- Medium. The overall confidence in this RfD assessment is medium. Confidence in the principal studies is medium. In the human studies, LOAELs for cardiovascular effects and kidney disease were not identified. The subchronic and chronic animal studies using adequate diets (NTP, 1994; McCauley et al., 1985) provide information regarding NOAELs and LOAELs for renal effects of barium, but cardiovascular effects did not occur in these studies. The lack of cardiovascular measurements (heart rate, blood pressure, or electrocardiogram recordings) in the chronic animal studies that used adequate diets (NTP, 1994) reduces the confidence. Confidence in the database is medium because of the existence of subchronic and chronic human studies, subchronic and chronic animal studies in more than one species, and a reproductive/developmental study in rats and mice. Medium confidence in the RfD follows. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=41 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 1998. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=50. Other EPA Documentation -- None Agency Consensus Date -- 2/18/1998 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 199803 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Barium and Compounds CASRN --7440-39-3 Last Revised -- 03/30/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: NOT VERIFIABLE status indicates that the available data do not meet the minimum database requirements according to the current Agency methods document for RfCs (U.S. EPA, 1994). This status does not preclude the use of information in cited references for assessment by others. SURC: ___I.B.1. INHALATION RfC SUMMARY An RfC for barium is not recommended at this time. The human and animal inhalation and intratracheal studies suggest that the respiratory system is a target of barium toxicity. The data also suggest that systemic effects, such as hypertension, may occur following inhalation exposure. The human studies cannot be used to derive an RfC for barium because exposure concentrations were not reported. Although the NIOSH (1982) study measured barium breathing zone levels for some groups of workers, the barium exposure levels were not measured in the group of workers with the increased incidence of hypertension. The deficient reporting of the methods and results (in particular, the lack of information on the aerosol generation, number of animals tested, incidence data, and statistical analysis) of the only animal subchronic/chronic inhalation study (Tarasenko et al., 1977) precludes deriving an RfC for barium from animal data. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Several human studies have investigated the toxicity of inhaled barium compounds. Exposure to insoluble forms of barium such as barium sulfate and barite ore results in baritosis (Pendergrass and Greening, 1953; Seaton et al., 1986; Doig, 1976). Although profuse opacities are observed on the radiographs, no alterations in lung function, abnormal physical findings, or increases in the incidence of subjective symptoms have been reported. It appears that the accumulation of barium sulfate in the lungs will diminish upon termination of barium exposure. Barium exposure levels resulting in baritosis have not been reported. NIOSH (1982) reported an increased incidence of hypertension in workers exposed to an unspecified concentration of barium. Although the results of this study are consistent with the suggestion of hypertension following oral exposure to barium compounds, the results of the NIOSH (1982) study should be interpreted cautiously because it is likely that the workers were also exposed to other metals, including lead, which has a known hypertensive effect. Inhalation toxicity data in animals are limited to inhalation exposure and intratracheal administration studies by Tarasenko et al. (1977) and an intratracheal administration study by Uchiyama et al. (1995). In the Tarasenko et al. (1977) inhalation study, a number of adverse effects were reported in rats exposed to 5.20 mg/m3 barium carbonate (3.6 mg/m3 barium) 4 h/day, 6 days/week for 4 mo. The effects included alterations in some hematological and serum chemistry parameters, perivascular and peribronchial sclerosis with collagenation in the lungs, and increases in arterial pressure. It does not appear that statistical analysis of the data was performed, and incidence data for the lung effects were not reported. No adverse effects were observed in the rats exposed to 1.15 mg/m3 barium carbonate (0.80 mg/m3 barium). The finding of lung lesions following exposure to barium carbonate was confirmed by an intratracheal administration study conducted by Tarasenko et al. (1977). In this study, fibrous pneumonia and necrosis of the mucous membrane of the large bronchi was observed 9 mo after animals received an intratracheal dose of 50 mg barium carbonate (35 mg barium). As with the inhalation study, the results of this study were poorly reported. Uchiyama et al. (1995) also found pulmonary effects (bronchopneumonia, bronchitis, or bronchiolitis) in rabbits intratracheally administered a suspension containing 85% barium sulfate. Although studies conducted by Tarasenko et al. (1977) suggest that inhalation exposure to barium carbonate may result in reproductive effects, confidence in these studies is very low because of poor reporting of study design and results. Thus, the potential of barium to induce developmental and/or reproductive effects following inhalation exposure has not been adequately assessed. Human Studies The database on the toxicity of inhaled barium compounds in humans consists primarily of studies of occupational exposure to barium sulfate or barite ore or to unspecified soluble barium compounds. Several case reports (for example, Pendergrass and Greening, 1953; Seaton et al., 1986) and a prospective study conducted by Doig (1976) have reported baritosis in barium-exposed workers. Baritosis is considered a benign pneumoconiosis resulting from the inhalation of barite ore or barium sulfate. The most outstanding feature of baritosis is the intense radiopacity of the discrete opacities, which are usually profusely disseminated throughout the lung fields; in some cases the opacities may be so numerous that they appear confluent. The Third Conference of Experts on Pneumoconiosis (ACGIH, 1992) noted that barium sulfate produced a noncollagenous type of pneumoconiosis that has a minimal stromal reaction and consists mainly of reticulin fibers, intact alveolar architecture, and potentially reversible lesions. The available human data on baritosis suggest that the accumulation of barium in the lungs does not result in medical disability or symptomatology. A decline in the profusion and opacity density, suggesting a decrease in the amount of accumulated barium in the lung, has been observed several years after termination of barium exposure. Studies by NIOSH (1982) and Zschiesche et al. (1992) on soluble barium compounds did not include radiography; these studies focused on the potential for barium to induce systemic effects (e.g., increases in blood pressure, kidney effects, EKG alterations). Doig (1976) conducted a prospective study on workers at a barite grinding facility. During the initial investigation in 1947, 5 workers employed for more than 3.5 years were examined. No evidence of baritosis was observed in any of the workers. In 1961, 8 workers (aged 26-45 years, mean of 32 years) employed for 3.5-18 years (mean of 9 years) were examined (1 of these workers was also examined in 1947). Seven of the workers reported no respiratory symptoms; 1 worker reported a slight occasional cough. No abnormal findings were observed during the physical examination of 7 of the workers; crepitations dispelled by cough were observed in 1 worker (not the same worker reporting an occasional cough). Pneumoconiosis was detected in the radiographs of 7 workers. Three other workers employed for 1 mo to 1 year were also examined in 1961. Two of these workers reported having slight coughs, but no abnormal findings were observed during the physical examination and the chest radiographs were normal. At this time, dust concentrations ranging from 2,734 to 11,365 particles per cubic mL were measured using a thermal precipitator; the concentration of barium in the dust was not measured. Barite samples were analyzed for quartz, silica, and iron content. No quartz was detected, and the total silica and total iron (as Fe2O3) concentrations were 0.07%-1.96% and 0.03%-0.89%, respectively. Ten of the 11 workers examined in 1961 were reexamined in 1963 (18 mo later). Two new cases of pneumoconiosis were diagnosed. Thus, 9 of 10 workers exposed to barium sulfate for 1.5 to 19.5 years (mean of 8.2 years) had well-marked baritosis. Three of these workers reported a slight or occasional cough and none had dyspnea. Among the 9 workers with baritosis, 3 did not smoke, 4 smoked 1 pack/day, and 2 smoked > 1 pack/day. In six of the seven workers with previously diagnosed baritosis, no significant changes in the degree of pneumoconiosis were observed; an increase in the number of opacities was observed in the seventh worker. Spirometric lung function tests (vital capacity, flow rate, and forced expiratory volume) were performed in five workers. For three of these workers, the results of the lung function tests were similar to predicted normal values (89%-119% of predicted values). Lung function was below normal in the other two workers (70%-85% of predicted values). It is questionable whether the impaired lung function was related to barium exposure. One of the two workers was an alcoholic and heavy smoker and the other had a fibrotic right middle lung lobe that probably resulted from a childhood illness. In 1964, the barite grinding facility closed. Follow-up examinations were performed in 1966, 1969, and 1973 on five of the workers. Termination from barium exposure resulted in a decline in the profusion and density of opacities. In 1966, there was slight clearing of opacities; by 1973, there was a marked decrease in profusion and density. No significant changes in lung function were observed during this 10-year period. NIOSH (1982) conducted a health survey of past and present workers at the Sherwin Williams Company's Coffeyville, KS, facility. Work performed at the facility included grinding, blending, and mixing of mineral ores. At the time of the study, four processes were in operation: "ozide process," which involved blending several grades of zinc oxide; "ozark process," which involved bagging very pure zinc oxide powder; "bayrite process;" which involved grinding and mixing several grades of barium-containing ores; and "sher-tone process," which involved mixing inert clays with animal tallow. A medical evaluation was performed on 61 current workers (91% participation) and 35 laid-off or retired workers (27% participation). Information on demographics, frequency of various symptoms occurring during the past 2 mo, chemical exposure, occupational history, smoking history, and histories of renal disease, allergies, and hypertension were obtained from directed questionnaires. In addition, spot urine and blood samples and blood pressure measurements were taken. Exposures to barium, lead, cadmium, and zinc were estimated from 27 personal samples collected over a 2-day period. In the seven personal breathing zone samples collected from the bayrite area, the levels of soluble barium ranged from 87.3 to 1,920.0 microg/m3 (mean of 1,068.5 microg/m3), lead levels ranged from not detected to 15.0 microg/m3 (mean of 12.2 microg/m3, excluding the two detect samples), zinc levels ranged from 22.4 to 132.0 microg/m3 (mean of 72 microg/m3), and all seven samples had no detectable levels of cadmium. Soluble barium was also detected in breathing zone samples in the ozark area (10.6-1,397.0 microg/m3; mean of 196.1 microg/m3), ozide area (11.6-99.5 microg/m3; mean of 46.8 microg/m3), and sher-tone area (114.3-167.5 microg/m3; mean of 70.45 microg/m3). Two approaches were used to analyze the results of the health survey. In the first approach, the workers were divided into five groups on the basis of current job assignments. Fourteen of the 61 current workers worked in the bayrite area. No statistically significant increases among the different groups of workers were observed in the incidence of subjective symptoms (e.g., headache, cough, nausea), or differences in mean blood lead levels, number of workers with blood lead levels of greater than 39 microg/dL, mean free erythrocyte protoporphyrin (FEP) levels, mean hematocrit levels, mean serum creatinine levels, number of workers with serum creatinine levels of greater than 1.5 mg/dL, number of workers with BUN levels of greater than 20 mg/dL, blood pressure, or mean urine cadmium levels. In the second approach, the workers were divided into seven groups on the basis of past job assignments. One group consisted of 12 workers working in barium process areas (bayrite process and other processes no longer in operation at the facility that involved exposure to barium ores and barium carbonate) for at least 5 years; barium exposure levels were not reported for this group. The results of the health survey for the barium-exposed workers were compared with 25 workers who stated that they had never worked in barium process areas. No statistically significant differences between the groups were observed in mean age, number of years employed, number of current or past smokers, prevalence of subjective symptoms, mean FEP levels, mean hematocrit levels, mean urine cadmium levels, mean beta2-microglobulin levels, or the prevalence of workers with elevated serum creatinine, BUN, or urine protein levels. The number of workers with elevated blood pressure (defined as systolic pressure 140 mm Hg or diastolic pressure 90 mm Hg, or taking medication for hypertension) was significantly higher (p = 0.029) in the barium-exposed group (7/12, 58%) than in the comparison group (5/25, 20%). The number of workers in the barium group with blood lead levels of > 39 microg/dL was lower than in the comparison group (0% versus 28%); however, the authors determined the difference not to be statistically significant (p = 0.072). Additionally, there was no significant difference between mean blood lead levels in the barium-exposed workers (24 microg/dL) and the comparison group (32 microg/dL). Although the results of this study suggest an association between exposure to barium and hypertension, the results should be interpreted cautiously because only a small number of workers were examined, it appears that blood pressure was only measured once, and the workers were exposed to a number of other chemicals, including lead, which is associated with an increase in blood pressure. The health effects associated with occupational exposure to barium during arc welding with barium-containing stick electrodes and flux-cored wires were investigated by Zschiesche et al. (1992). A group of 18 healthy welders not using barium-containing consumables in the past 10 days were divided into three groups: group A (n = 8, mean age of 30.4 years) performed arc welding with barium-containing stick electrodes, group B (n = 5, mean age of 43.6 years) performed arc welding with barium-containing self-shielded flux-cored wires, and group C (n = 5, mean age of 32.0 years) performed arc welding with barium-containing self-shielded flux- cored wires using welding guns with built-in ventilation systems. All welders performed welding with barium-free consumables on Thursday and Friday of the first week of the study. Barium-containing consumables were used during week 2 of the study and on Monday of week 3. The subjects welded for an average of 4 h per day. The average barium concentrations in the breathing zones were 4.4 (range of 0.1-22.7), 2.0 (0.3-6.0), and 0.3 (0.1-1.5) mg/m3 for groups A, B, and C, respectively. No exposure-related subjective symptoms of health or neurological signs were found. No significant differences between pre and postshift EKG, pulse rate, whole blood pH, base excess and standard bicarbonate, and plasma concentrations of sodium, magnesium, and total and ionized calcium were observed. During week 2, decreases in plasma potassium concentrations were observed in groups A and C; the levels returned to the normal range under continuation of barium exposure and were not statistically different from levels during week 1 (no barium exposure). This drop in serum potassium levels was not observed in group B, which had a barium exposure level similar to group A. Animal Studies Data on the toxicity of barium compounds in animals following inhalation exposure is limited to a subchronic study conducted by Tarasenko et al. (1977). In this study, male albino rats (strain and number of animals per group not reported) were exposed to 0, 1.15, or 5.20 mg/m3 barium carbonate (0, 0.80, or 3.6 mg Ba/m3) 4 h/day, 6 days/week for 4 mo. No information on aerosol generation or the size distribution of the particles was reported. In the introduction section of the paper, the authors state, "we have demonstrated by electron microscopy that the size of almost 80% of the dust particles is less than 2 microm"; however, it is not known if this statement refers to the aerosols generated for this study. The following endpoints were used to assess toxicity: body weight gain, arterial pressure, hematological (hemoglobin, leukocytes, and thrombocytes) and serum chemistry (glucose, phosphorus, total protein, alkaline phosphatase, and cholinesterase) parameters, urine calcium levels, bromosulfophthalein test of liver function, electrocardiogram measurement, and histological examination (tissues examined were not listed). The authors noted that no alterations were observed in the rats exposed to 1.15 mg/m3 barium carbonate. In the 5.20 mg/m3 group, a number of alterations were reported; however, it does not appear that the data were statistically analyzed. The alterations included a 21% decrease in body weight gain, a 32% increase in arterial pressure, altered hematological parameters (decreases in hemoglobin and thrombocyte levels and increases in leukocyte levels), altered serum chemistry parameters (decreased sugar and total protein levels, increased phosphorus levels, decreased alkaline phosphatase activity, and increased cholinesterase activity), increased calcium levels in the urine, impaired liver function, and histological alterations in the heart, liver, kidneys, and lungs. No alterations in the EKG readings were reported. However, when the rats were administered proserine, the EKG reading suggested disturbances in heart conductivity. The authors noted that the heart, liver, and kidneys "had a character of mild protein ('granular') dystrophy." In the lungs, the histological alterations consisted of moderate perivascular and peribronchial sclerosis with focal thickening of the intraalveolar septa and collagenation. No incidence data were provided. In another study conducted by Tarasenko et al. (1977), animals (it appears that albino rats and rabbits were tested; number of animals not specified) were administered an intratracheal dose of 50 mg barium carbonate (35 mg barium). Three months after administration, sclerotic changes were observed in the lungs. The severity of the sclerosis progressed. At 9 mo, fibrous pneumonia with necrosis of mucous membranes of the large bronchi was observed. Uchiyama et al. (1995) administered a single intratracheal dose of 0.015, 0.3, or 0.6 mL/kg of Ba147 to rabbits. Ba147 is a preparation containing 85% barium sulfate. No treatment-related effects on pulmonary ventilation (measured 1 day, 3 days, and 1, 2, and 4 weeks after dosing), levels of blood gases (measured at the same time as pulmonary ventilation), or lung weights were observed. Soft X-rays of the lungs revealed dose-related shadows. Bronchopneumonia, bronchitis, or bronchiolitis was observed in 28 of 36 animals during the first week after dosing. Thereafter, the alterations were not observed. No further details of this study were available because the study was published in a Japanese-language journal; information on the study was obtained from an English abstract. Information on the reproductive/developmental toxicity of inhaled barium compounds is limited to a series of studies conducted by Tarasenko et al. (1977). The results of these studies were described in general terms and no data were provided. The poor reporting of the study design and results and the lack of statistical analysis of the data limit the usefulness of the data for assessing the reproductive/developmental toxicity of barium. Exposure of male rats to 22.6 mg/m3 barium carbonate (15.7 mg Ba/m3) for one cycle of spermatogenesis (daily exposure duration and frequency of exposure were not reported) resulted in decreases in the number of spermatozoids, percentage of motile forms and time of motility, osmotic resistance of spermatozoids, increases in the number of ducts with desquamated epithelium, and a reduced number of ducts with 12th stage meiosis (Tarasenko et al., 1977). Similar results were observed in rats exposed to 5.2 mg/m3 barium carbonate (3.6 mg Ba/m3) 4 h/day, 6 days/week for 4 mo. Tarasenko et al. (1977) also reported that a shortening of the mean duration of estrous cycle and an alteration in the proportion of mature and dying ovarian follicles were observed in rats exposed to 13.4 mg/m3 barium carbonate (9.3 mg Ba/m3) for 4 mo (duration of daily exposure or frequency of exposure was not reported), as compared to a control group. These effects were not observed in rats exposed to 3.1 mg/m3 (2.2 mg Ba/m3). The authors also noted that rats in the 13.4 mg/m3 group gave birth to underdeveloped offspring that showed considerable mortality and slow increases in body weight during the first two months of life. The authors did not state whether the barium carbonate-exposed females were mated to exposed or unexposed males. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) Not applicable. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) Not applicable. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=38 CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Not applicable. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=45 EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 1998. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Barium and Compounds (CAS No. 7440-39-3) in support of summary information on IRIS (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=50. Agency Consensus Date -- 2/18/1998 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 199803 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Barium and Compounds CASRN -- 7440-39-3 Last Revised -- 03/30/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under EPA's 1986 Guidelines for Carcinogen Risk Assessment, barium would be classified as Group D, not classifiable as to human carcinogenicity. Although adequate chronic oral exposure studies in rats and mice have not demonstrated carcinogenic effects, the lack of adequate inhalation studies precludes assessing the carcinogenic potential of inhaled barium. Under the Proposed Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 1996), barium is considered not likely to be carcinogenic to humans following oral exposure and its carcinogenic potential cannot be determined following inhalation exposure. Basis -- Oral exposure studies in rats and mice (NTP, 1994; McCauley et al., 1985; Schroeder and Mitchener, 1975a,b) did not find significant increases in tumor incidence following chronic exposure. In the NTP (1994) rat study, statistically significant negative trends in the incidence of leukemia, adrenal tumors, and mammary gland tumors were observed. The design of the rat and mouse NTP (1994) studies was adequate to assess carcinogenicity. These studies used an adequate number of animals per group, exposed animals for 2 years, tested several dosage levels, and examined an extensive number of tissues. The inhalation exposure and intratracheal studies conducted by Tarasenko et al. (1977) are inadequate for carcinogenicity evaluation because of several deficiencies in the design and reporting, including single or subchronic exposure duration, inadequate reporting of aerosol generation methodology, inferior reporting of study results (including the apparent lack of statistical analysis), and the use of only one sex (males). These studies were designed to be toxicity studies, and it is not known if the investigators looked for tumors. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. The only available human carcinogenicity data are two topical application studies conducted by Ayre (1966) and Ayre and LeGuerrier (1967). These studies involved a single topical application of barium chloride to the cervix of one woman. In a study to determine the safety of components of intrauterine contraceptive devices, a single topical application of 1.25 mM barium chloride was applied to the squamocolumnar junctional area of the cervix of a woman with no known history of abnormal cervical cytology results (Ayre, 1966; Ayre and LeGuerrier, 1967). A cervical cell scraping was performed 48 h after application. The topical application of barium chloride and cervical cell scraping was repeated four times at intervals of 4-6 weeks. A number of cell transformations resembling severe premalignant dysplasia were observed; the transformed cells were described as bizarre, multinucleated cells with profoundly altered nuclear chromatin. One to three weeks after barium chloride application, these cellular alterations were no longer observed. In another study (Ayre, 1966; Ayre and LeGuerrier, 1967), 1.25 mM barium chloride was mixed with equal amounts of 70% DMSO and a single topical application of the mixture was applied to the squamocolumnar junctional area of the cervix. It is assumed that only one subject was used, and it was not reported whether this was the same woman previously tested. Cervical scrapings were performed after 48 h, 72 h, and twice weekly for an unspecified amount of time. The cell transformations were similar to extreme dysplasia; in addition, spindle cells and cells with marked hyperchromatism with multiple chromatin bundles and enlarged irregular nucleated forms were observed. Cell transformations were also observed in deeper layers of the squamous epithelium. The authors noted that the transformed cells resembled cell findings of cancer in situ. Sixteen days after topical application, the cell transformations were not observed in the deeper layers of the epithelium, but were still present in superficial and intermediate areas. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Oral Exposure. Sufficient. Four animal studies evaluated the carcinogenicity of barium (NTP, 1994; McCauley et al., 1985; Schroeder and Mitchener, 1975a,b) in rats and mice. The design of NTP (1994) rat and mouse studies was adequate for carcinogenicity evaluation. In a chronic study conducted by NTP (1994), male and female B6C3F1 mice (60 animals/dose group/sex) received barium chloride dihydrate in drinking water at concentrations of 0, 500, 1,250, or 2,500 ppm for 103 weeks (males) and 104 weeks (females). The authors estimated the daily doses for the treated groups using measured water consumption and body weights as 30, 75, and 160 mg Ba/kg-day for males, and 40, 90, and 200 mg Ba/kg-day for females. The animals were fed an NIH-07 mash diet; the barium content of the diet was not reported. At the 15-mo interim evaluation, venous blood was collected from all mice for hematology and clinical chemistry. In addition, a limited number of mice (9, 10, 10, and 10 males and 10, 7, 10, and 6 females from the 0, 500, 1,250, and 2,500 ppm groups, respectively) were sacrificed at 15 mo. The remaining animals continued on the study until they were moribund, died naturally, or were sacrificed at the end of the study. Necropsy and complete histopathological examinations were performed on all animals. Body weights were monitored and organ weights were determined at 15 mo. At 2,500 ppm, the percent probabilities of survival for mice at the end of study (65% for males and 26% for females) were significantly lower than those of the controls (89% males; 76% females). The reduction in survival became apparent in females at week 15 and in males at week 65, and was attributed to chemical-related renal lesions. Survival was not significantly lower relative to controls at the lower dosage levels. In male and female high-dose mice, the final mean body weights were 8% and 12% lower, respectively, than those of the corresponding control groups. Water consumption was not affected by barium. At the 15-mo interim evaluation, the absolute and relative spleen weights of the female mice that received 2,500 ppm were significantly lower than those of the controls, and the absolute and relative thymus weights of high-dose male mice that received 2,500 ppm were marginally lower than those of the controls. Determination of hematology and clinical chemistry parameters (e.g., phosphorus, calcium, and urea nitrogen) at the 15-mo interim evaluation showed no significant differences between control and exposed mice. The incidence of nephropathy at the end of the study was significantly increased in mice receiving 2,500 ppm. There were no other chemical-related noncarcinogenic histological changes. The incidence of neoplasms in the barium-exposed mice was not significantly higher than in control mice. In the 2,500 ppm female mice, the incidence of several neoplasms was significantly lower than in the controls; the authors attributed this finding to the marked reduction in survival in the barium-exposed animals. In the same chronic study (NTP, 1994), male and female F344/N rats (60 animals/dose group/sex) received drinking water containing 0, 500, 1,250, or 2,500 ppm barium chloride dihydrate for 104 weeks (males) or 105 weeks (females). The authors estimated daily doses for the treated groups using measured water consumption and body weights as 15, 30, and 60 mg Ba/kg-day for males, and 15, 45, and 75 mg Ba/kg-day for females. The animals were fed an NIH-07 mash diet; the barium content of the diet was not reported. For a 15-mo interim evaluation, venous blood was collected from all rats for hematology and clinical chemistry. In addition, a limited number of rats (10 from each group) were sacrificed at 15 mo. The remaining animals stayed on the study until they were moribund, died naturally, or were terminally sacrificed. Necropsy and complete histopathological examinations were performed on all animals. Body weights were monitored throughout the study, and organ weights were determined in the animals killed at 15 mo. A marginally increased survival of exposed male groups (percent probability of survival: 62%, 58%, and 67% for the 500, 1,250, and 2,500 ppm groups, respectively) compared with that of the male controls (44%) was observed. Survival of the females was not significantly affected. For male rats receiving 2,500 ppm the final mean body weights were 5% lower than for controls. The final mean body weights of females receiving 1,250 and 2,500 ppm were 6% and 11% lower, respectively, than those of controls. Water consumption was decreased in a dose-related manner; at the highest exposure level the decrease, relative to controls, was 22% in males and 25% in females. Absolute and relative organ weights, determined only at the 15-mo interim evaluation, were not affected in the males. In the females, a decrease in the absolute liver weight and an increase in the relative kidney weights occurred at 2,500 ppm. Body weights in the females at 15 mo were decreased by 9% at 2,500 ppm in comparison with controls, whereas kidney weights in this group were slightly increased relative to those of controls. Determination of hematology values and clinical chemistry values (e.g., phosphorus, calcium, and urea nitrogen) at the 15-mo interim evaluation showed no significant differences between control and exposed rats. No chemical-related noncarcinogenic histological changes were observed in any organs or tissues. No statistically significant increases in the incidence of neoplasms were observed in the barium-exposed rats. Significant negative trends were observed in the incidence of mononuclear cell leukemia in male rats (35/50, 25/50, 26/50, and 15/50 in 0, 500, 1,250, and 2,500 ppm groups, respectively), benign and malignant adrenal medulla pheochromocytoma in male rats (13/49, 11/50, 12/49, and 6/50, respectively), and mammary gland neoplasms (fibroadenoma, adenoma, or carcinoma) in female rats (17/50, 21/50, 13/50, 11/50, respectively). Additionally, the incidences of mononuclear cell leukemia in the male rats exposed to 500, 1,250, and 2,500 ppm and adrenal medulla pheochromocytoma in male rats exposed to 2,500 ppm were significantly lower than the incidences in the controls. In a study by McCauley et al. (1985), CD Sprague-Dawley rats were fed Purina rat chow containing 12 ppm barium. The three exposure regimens were as follows: (1) male CD Sprague-Dawley rats (12/group) were exposed to 0, 1, 10, 100, or 250 ppm barium (barium chloride) in drinking water for 36 weeks; (2) female CD Sprague-Dawley rats (12/group) were exposed to 0 or 250 ppm for 46 weeks; and (3) male CD Sprague-Dawley rats (10/group) were exposed to 0, 1, 10, or 100 ppm barium in drinking water for 68 weeks. The authors reported that no significant differences in food or water intake or body weight were observed, but did not report the actual data. They stated that rats that received 10 ppm of barium in the drinking water ingested 1.5 mg Ba/kg-day from water and 1 mg Ba/kg-day from the Purina diet. This barium intake was used to estimate total barium intake for the other exposure levels. Thus, the estimated total barium intakes were 1, 1.15, 2.5, 16, and 38.5 mg/kg-day for the 0, 1, 10, 100, and 250 ppm concentrations for all exposure regimens. The authors did not comment on whether there were any effects on survival. Histological evaluations of an extensive number of tissues, including gastrointestinal tract, liver, heart, adrenal gland, brain, respiratory tract, spleen, thymus, kidneys, ovaries, and testes, did not reveal barium-related lesions. No alterations in hematocrit levels were observed. A retinal lesion (focal absence of the outer layers of the retina) was observed in 5/12 males exposed to 100 ppm but 0/11 males exposed to 250 ppm for 36 weeks, 7/12 females exposed to 250 ppm for 46 weeks, 1/10 male controls exposed for 68 weeks, and 2/10 males in each of the 1, 10, and 100 ppm groups exposed for 68 weeks. Because this lesion does not appear to be dose or duration-related, its relationship to barium exposure is uncertain. No significant increases in the incidence of neoplasms were observed in the barium-exposed rats, but the study is shorter than lifetime and would have missed late-developing tumors. Schroeder and Mitchener (1975a) exposed Long-Evans rats (52/sex/group) to 0 or 5 ppm barium (barium acetate) in drinking water from weaning to natural death. Dosages from drinking water were 0.61 mg Ba/kg-day for males and 0.67 mg Ba/kg-day for females based on reference body weights and water intake from U.S. EPA (1988). The diet was characterized as a "low- metal" diet and included 60% rye flour, 30% dried skim milk, 9% corn oil, 1% iodized chloride, and assorted vitamins; the barium content was not reported. Barium had no significant effect on the growth of males, but increased the growth of older females. The life span of the rats was not significantly affected. The incidence of proteinuria in males exposed to barium for approximately 152 days (at 173 days of age) was significantly (p < 0.05) higher than in controls; proteinuria was assessed by a dipstick method and the magnitude was not reported. Female rats at 532 and 773 days of age had higher (p < 0.001) serum cholesterol concentrations than did controls tested at 516 and 769 days of age. Serum glucose levels for males at these ages were also different from controls but did not follow an age-related pattern. The authors attached no biological or toxicological significance to these serum chemistry results. Histopathology of heart, lung, kidney, liver, and spleen did not reveal alterations. No significant increases in the number of gross tumors were observed in the barium-exposed male (8/30) or female (15/33) rats as compared to the controls (4/26 and 17/24 for males and females, respectively). Schroeder and Mitchener (1975b) exposed white mice of the Charles River CD strain (36-54/sex) to 0 or 5 ppm of barium (as barium acetate) in drinking water for their lifetimes. Dosages from drinking water were 1.18 mg Ba/kg-day for males and 1.20 mg Ba/kg-day for females (U.S. EPA, 1988). The diet was characterized as a "low metal" diet and included 60% rye flour, 30% dried skim milk, 9% corn oil, 1% iodized chloride, and assorted vitamins; the barium content of the diet was not reported. Growth and body weights were not affected by the barium treatment. Histology of the heart, lung, liver, kidney, and spleen was normal. In males, longevity (defined as the mean life span of the last surviving 5 animals of each sex in each treatment group) was significantly (p 0.025) reduced; longevity of the barium-treated males was 815 days as compared with 920 days for the controls. The mean life span, however, was not affected. The incidences of lymphoma leukemia and lung tumors in the male (7/37 and 4/37, respectively) and female (5/21 and 3/21) mice exposed to barium were not significantly different from the incidences in the control mice (3/38 and 3/47 for lymphoma leukemia in males and females, respectively, and 5/38 and 9/47 for lung tumors). Inhalation Studies. Inadequate. The carcinogenic potential of barium following inhalation exposure has not been adequately tested. The inhalation toxicity/carcinogenicity database is limited to a single subchronic inhalation study conducted by Tarasenko et al. (1977). This study was not designed to assess carcinogenicity; the duration was too short (4 mo) and the study design and results were poorly reported. Tarasenko et al. (1977) also conducted an intratracheal administration study. Although this single-exposure study was not designed to assess carcinogenicity, it provides some information on the progression of lesions 3, 6, and 9 mo postexposure. In the Tarasenko et al. (1977) inhalation study, male albino rats (strain and number of animals per group not reported) were exposed to 0, 1.15, or 5.20 mg/m3 barium carbonate (0, 0.80, or 3.6 mg Ba/m3) 4 h/day, 6 days/week for 4 mo. No information on aerosol generation or the size distribution of the particles was reported. In the introduction section of the paper, the authors state, "we have demonstrated by electron microscopy that the size of almost 80% of the dust particles is less than 2 microm"; however, it is not known if this statement refers to the aerosols generated for this study. The following endpoints were used to assess toxicity: body weight gain, arterial pressure, hematological (hemoglobin, leukocytes, and thrombocytes) and serum chemistry (glucose, phosphorus, total protein, alkaline phosphatase, and cholinesterase) parameters, urine calcium levels, bromosulfophthalein test of liver function, electrocardiogram measurement, and histological examination (tissues examined were not listed). The authors noted that no alterations were observed in the rats exposed to 1.15 mg/m3 barium carbonate. In the 5.20 mg/m3 group, a number of alterations were reported; however, it does not appear that the data were statistically analyzed. The alterations included a 21% decrease in body weight gain, a 32% increase in arterial pressure, altered hematological parameters (decreases in hemoglobin and thrombocyte levels and increases in leukocyte levels), altered serum chemistry parameters (decreased sugar and total protein levels, increased phosphorus levels, decreased alkaline phosphatase activity, and increased cholinesterase activity), increased calcium levels in the urine, impaired liver function, and histological alterations in the heart, liver, kidneys, and lungs. No alterations in the EKG readings were reported. However, when the rats were administered proserine, the EKG reading suggested disturbances in heart conductivity. The authors noted that the heart, liver, and kidneys "had a character of mild protein ('granular') dystrophy." In the lungs, the histological alterations consisted of moderate perivascular and peribronchial sclerosis with focal thickening of the intraalveolar septa and collagenation. No incidence data were provided. The presence of neoplasms was not reported; it is unclear whether the investigators looked for neoplasms. This study was not designed to assess carcinogenicity; in particular, the exposure duration was too short. In another study conducted by Tarasenko et al. (1977), animals (species and number not specified) were administered an intratracheal dose of 50 mg barium carbonate (35 mg barium). Three months after administration, sclerotic changes were observed in the lungs. The severity of the sclerosis progressed. At 9 mo, fibrous pneumonia with necrosis of mucous membranes of the large bronchi was observed. Although this study was not designed to assess carcinogenicity, the findings of the study suggest that the fibrogenic lesions progress over time. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY There is a limited amount of information available on the genotoxicity of barium compounds. No in vivo studies have been conducted. Most in vitro studies have found that barium chloride and barium nitrate did not induce gene mutations in bacterial assays with or without metabolic activation. Ames assays with Salmonella typhimurium strains TA1535, TA1538, TA1537, TA97, TA98, and TA100 with or without metabolic activation (Monaco et al., 1990, 1991; NTP, 1994), rec assays with Bacillus subtilis strains H17 and H45 (Nishioka, 1975; Kanematsu et al., 1980), and a microscreen assay with Escherichia coli (Rossman et al., 1991) with metabolic activation have produced negative results with barium chloride. Negative results have also been observed for barium nitrate in the rec assay using B. subtilis strains H17 and H45 (Kanematsu et al., 1980). Barium chloride induced gene mutations in L5178Y mouse lymphoma cells with metabolic activation, but not in the absence of metabolic activation (NTP, 1994). Neither barium acetate nor barium chloride decreased the fidelity of DNA synthesis in avian myeloblastosis virus DNA polymerase (Sirover and Loeb, 1976). In mammalian cells, barium chloride did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without activation (NTP, 1994). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not applicable. The results of the oral carcinogenicity study suggest that barium is not likely to be carcinogenic to humans. SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Not applicable. DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Not applicable. ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Not applicable. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Not applicable. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not applicable. The inhalation database is inadequate to determine the qualitative and quantitative cancer risk for barium. SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Not applicable. DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Not applicable. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) Not applicable. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Not applicable. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated and incorporated in finalization of this IRIS summary. A record of these comments in included as an appendix to the Toxicological Review of Barium and Compounds (CAS No. 7440-39-3) in support of summary information on IRIS (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0010-tr.pdf#page=50. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 2/18/1998 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199803 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Barium and Compounds CASRN -- 7440-39-3 Last Revised -- 03/30/1998 SORD: __VI.A. ORAL RfD REFERENCES Brenniman, GR; Levy, PS. (1984) Epidemiological study of barium in Illinois drinking water supplies. In: Advances in modern toxicology, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 231-249. Brenniman, GR; Kojola, WH; Levy, PS; et al. (1981) High barium levels in public drinking water and its association with elevated blood pressure. Arch Environ Health 36(1):28-32. Cuddihy, RG; Griffith, WC. (1972) A biological model describing tissue distribution and whole-body retention of barium and lanthanum in beagle dogs after inhalation and gavage. Health Phys 23:621-633. Diengott, D; Rozsa, O; Levy, N; et al. (1964) Hypokalemia in barium poisoning. Lancet 2:343-344. Dietz, DD; Elwell, MR; Davis, WE, Jr.; et al. (1992) Subchronic toxicity of barium chloride dihydrate administered to rats and mice in the drinking water. Fundam Appl Toxicol 19:527-537. Gould, DB; Sorrell, MR; Lupariello, AD. (1973) Barium sulfide poisoning, some factors contributing to survival. Arch Intern Med 132(6):891-894. Hicks, R; Caldas, LQ; Dare, PR; et al. (1986) Cardiotoxic and bronchoconstrictor effects of industrial metal fumes containing barium. Arch Toxicol Suppl 9:416-420. McCauley, PT; Douglas, BH; Laurie, RD; et al. (1985) Investigations into the effect of drinking water barium on rats. In: Inorganics in drinking water and cardiovascular disease, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 197-210. National Institute for Occupational Safety and Health (NIOSH). (1982) Health hazard evaluation report: Sherwin Williams Company, Coffeyville, Kansas. National Institute for Occupational Safety and Health, Centers for Disease Control, Cincinnati, OH. NIOSH Report No. HETA/81-356-1183. National Research Council (NRC). (1995) Nutrient requirements of laboratory animals. Washington, DC: National Academy Press, p. 13. National Toxicology Program (NTP). (1994) Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). NTP TR 432. National Toxicological Program, Research Triangle Park, NC. NIH Pub. No. 94-3163. NTIS Pub PB94-214178. Perry, Jr., HM; Erlanger, MW. (1982) Effect of diet on increases in systolic pressure induced in rats by chronic cadmium feeding. J Nutr 112(10):1983-1989. Perry, HM; Kopp, SJ; Erlanger, MW; et al. (1983) Cardiovascular effects of chronic barium ingestion. In: Trace substances in environmental health, XVII, Hemphill, DD, ed. Proc. Univ. Missouri's 17th Ann. Conf. on Trace Substances in Environmental Health. University of Missouri Press, Columbia, MO. pp. 155-164. Perry, HM; Perry, EF; Erlanger, MW; et al. (1985) Barium-induced hypertension. In: Inorganic in drinking water and cardiovascular disease. Ch. XX. Adv Mod Environ Toxicol 9:221-279. Perry, HM, Jr.; Koop, SJ; Perry, EF; et al. (1989) Hypertension and associated cardiovascular abnormalities induced by chronic barium feeding. J Toxicol Environ Health 28(3):373-388. Roza, O; Berman, LB. (1971) The pathophysiology of barium: hypokalemic and cardiovascular effects. J Pharmacol Exp Ther 177(2):433-439. Schroeder, H; Mitchener, M. (1975a) Life-term studies in rats: effects of aluminum, barium, beryllium and tungsten. J Nutr 105:421-427. Schroeder, H; Mitchener, M. (1975b) Life-term effects of mercury, methyl mercury and nine other trace metals on mice. J Nutr 105:452-458. Shanbaky, IO; Borowitz, JL; Kessler, WV. (1978) Mechanisms of cadmium- and barium-induced adrenal catecholamine release. Toxicol Appl Pharmacol 44(1):99-105. Sutton, RAL; Dirks, JH. (1986) Calcium and magnesium: renal handling and disorders of metabolism. In: The kidney, third ed. Brenner, BM; Rector, Jr., FC, eds. Philadelphia: W.B. Saunders Company, pp. 551-552. Tarasenko, NY; Pronin, OA; Silayev, AA. (1977) Barium compounds as industrial poisons (an experimental study). J Hyg Epid Microbiol Immun 21(4):361-373. Tardiff, RG; Robinson, M; Ulmer, NS. (1980) Subchronic oral toxicity of BaCl2 in rats. J Environ Pathol Toxicol 4:267-275. Taylor, DM; Pligh, PH; Duggan, MH. (1962) The absorption of calcium, strontium, barium and radium from the gastrointestinal tract of the rat. Biochem J 83:25-29. U.S. Environmental Protection Agency. (1990) Drinking water criteria document on barium. Criteria and Standards Division, Office of Drinking Water, Washington, DC. NTIS PB 91-142869. U.S. Environmental Protection Agency. (1998) Toxicological review of barium and compounds in support of summary information on the Integrated Risk Information System (IRIS). Available online from National Center for Environmental Assessment, http://www.epa.gov/iris. Wones, RG; Stadler, BL; Frohman, LA. (1990) Lack of effect of drinking water barium on cardiovascular risk factor. Environ Health Perspect 85:355-359. World Health Organization (WHO). (1990) Environmental Health Criteria 107: Barium. Sponsored by United Nations Environment Programme, International Labour Organisation, and World Health Organization. Zalups, RK; Lash, LH. (1990) Advances in understanding the renal transport and toxicity of mercury. J Toxicol Environ Health 42(1):1-44. Zalups, RK; Klotzbach, JM; Diamond, GL. (1987) Enhanced accumulation of injected inorganic mercury in renal outer medulla after unilateral nephrectomy. Toxicol Appl Pharmacol 89(2):226-236. Zalups, RK; Gelein, RM; Morrow, PE; et al. (1988) Nephrotoxicity of uranyl fluoride in uninephrectomized and sham-operated rats. Toxicol Appl Pharmacol 94(1):11-22. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES American Conference of Governmental Industrial Hygienists (ACGIH). (1992) Documentation of threshold limit values for chemical substances. ACGIH, Cincinnati, OH. Doig, AT. (1976) Baritosis: a benign pneumoconiosis. Thorax 31:30-39. National Institute for Occupational Safety and Health (NIOSH). (1982) Health hazard evaluation report No. 81-356-1183, Sherwin Williams Company, Coffeyville, Kansas. U.S. Department of Health and Human Services, NIOSH, Health Evaluation and Technical Assistance Branch, Cincinnati, OH. Pendergrass, EP; Greening, RR. (1953) Baritosis: report of a case. Arch Indust Hyg Occup Med 7:44-48. Seaton, A; Ruckley, VA; Addison, J, et al. (1986) Silicosis in barium miners. Thorax 41:591-595. Tarasenko, NYu; Pronin, OA; Silayev, AA. (1977) Barium compounds as industrial poisons (an experimental study). J Hyg Epidemol Microbiol Immunol 21:361-373. Uchiyama, K; Nakajima, I; Hayashi, T, et al. (1995) Influence of a barium sulfate preparation (BA147) on lungs of rabbits following single dose intratracheal administration. Oyo Yakuri. 50(2):123-134. [Japanese; English abstract from TOXLINE database]. U.S. Environmental Protection Agency. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, Research Triangle Park, NC. EPA/600/8-90/066F. Zschiesche, W; Schaller, KH; Weltle, D. (1992) Exposure to soluble barium compounds: an interventional study in arc welders. Int Arch Occup Environ Health 64(1):13-23. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Ayre, JE. (1966) Human cell-dysplasia following barium. Industr Med Surg 35(5):393-399. Ayre, JE; Le Guerrier, J. (1967) Some (regressive) effects of DMSO dexamethasone upon cervical cells in cervical dysplasia and carcinoma in situ. Ann NY Acad Sci 141:414-422. Kanematsu, N; Hara, M; Kada, T. (1980) Rec assay and mutagenicity studies on metal compounds. Mutat Res 77(2):109-116. McCauley, PT; Douglas, BH; Laurie, RD; et al. (1985) Investigations into the effect of drinking water barium on rats. In: Inorganics in drinking water and cardiovascular disease, Calabrese, EJ, ed. Princeton, NJ: Princeton Scientific Publications, pp. 197-210. Monaco, M; Dominici, R; Barisano, P; et al. (1990) Studio dell'attivata mutagena del bario cloruro in Salmonella typhimurium. Med Lav 81(1):54-64. [Italian with English abstract]. Monaco, M; Dominici, R; Barisano, P; et al. (1991) Valutazione della presunta attivita mutagena del bario nitrato. Med Lav 82(5):439-445. [Italian with English abstract]. National Toxicology Program (NTP). (1994) Technical report on the toxicology and carcinogenesis studies of barium chloride dihydrate (CAS No. 10326-27-9) in F344/N rats and B6C3F1 mice (drinking water studies). NTP TR 432. National Toxicological Program, Research Triangle Park, NC. NIH Pub. No. 94-3163. NTIS Pub PB94-214178. Nishioka, H. (1975) Mutagenic activities of metal compounds in bacteria. Mutat Res 31(3):185-190. Rossman, TG; Molina, M; Meyer, L; et al. (1991) Performance of 133 compounds in the lambda prophage induction endpoint of the Microscreen assay and a comparison with S. typhimurium mutagenicity and rodent carcinogenicity assays. Mutat Res 260(4):349-367. Schroeder, H; Mitchener, M. (1975a) Life-term studies in rats: effects of aluminum, barium, beryllium and tungsten. J Nutr 105:421-427. Schroeder, H; Mitchener, M. (1975b) Life-term effects of mercury, methyl mercury and nine other trace metals on mice. J Nutr 105:452-458. Sirover, MA; Loeb, LA. (1976) Infidelity of DNA synthesis in vitro: screening for potential metal mutagens or carcinogens. Science 194:1434-1436. Tarasenko, NYu; Pronin, OA; Silayev, AA. (1977) Barium compounds as industrial poisons (an experimental study). J Hyg Epid Microbiol Immunol 21:361-373. U.S. Environmental Protection Agency. (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34003. U.S. Environmental Protection Agency. (1988) Recommendations for and documentation of biological values for use in risk assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/6-87/008; NTIS PB88-179874. U.S. Environmental Protection Agency. (1996) Proposed guidelines for carcinogen risk assessment. Federal Register 61(79):17959-18011. U.S. Environmental Protection Agency. (1998) Toxicological review of barium and compounds in support of summary information on the Integrated Risk Information System (IRIS). Available online from National Center for Environmental Assessment, http://www.epa.gov/iris. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Barium and Compounds CASRN -- 7440-39-3 Last Revised -- 01/21/1999 Date Section Description ---------------------------------------------------------------------------- 09/30/1987 IV. Regulatory Action section added 03/01/1988 I.A.1. Dose conversion clarified 03/01/1988 I.A.3. Text changed 03/01/1988 I.A.7. Secondary contact changed 06/30/1988 I.A.7. Contacts switched 08/01/1989 VI. Bibliography on-line 06/01/1990 IV.F.1. EPA contact changed 07/01/1990 I.A. Withdrawn; new RfD verified (in preparation) 07/01/1990 VI. Bibliography withdrawn 08/01/1990 I.A. Oral RfD summary replaced; RfD changed 08/01/1990 VI. Bibliography replaced 12/01/1991 I.B. Inhalation RfC now under review 01/01/1992 IV. Regulatory actions updated 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 03/30/1998 I.A. Oral RfD Assessment 03/30/1998 I.B. Inhalation RfC Assessment 03/30/1998 II. Carcinogenicity Assessment 01/21/1999 I.A. Minor revisions to RfD Assessment, revised critical effect ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 360 of 1119 in IRIS (through 2003/06) AN: 14 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199302 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Di(2-ethylhexyl)phthalate (DEHP) SY: *BIS(2-ETHYLHEXYL)PHTHALATE; 117-81-7; BEHP-; BIS(2-ETHYLHEXYL)-1,2-BENZENE-DICARBOXYLATE; BISOFLEX-81-; BISOFLEX-DOP-; COMPOUND-889-; DAF-68-; DEHP-; DI(2-ETHYLHEXYL)ORTHOPHTHALATE; DI(2-ETHYLHEXYL)PHTHALATE; DIOCTYL-PHTHALATE-; DI-SEC-OCTYL-PHTHALATE-; DOP-; ERGOPLAST-FDO-; ETHYLHEXYL-PHTHALATE-; 2-ETHYLHEXYL-PHTHALATE-; EVIPLAST-80-; EVIPLAST-81-; FLEXIMEL-; FLEXOL-DOP-; FLEXOL-PLASTICIZER-DOP-; GOOD-RITE-GP-264-; HATCOL-DOP-; HERCOFLEX-260-; KODAFLEX-DOP-; MOLLAN-O-; NCI--C52733-; NUOPLAZ-DOP-; OCTOIL-; OCTYL-PHTHALATE-; PALATINOL-AH-; PHTHALIC ACID, BIS(2-ETHYLHEXYL) ESTER; PHTHALIC-ACID,-DIOCTYL-ESTER-; PITTSBURGH-PX-138-; PLATINOL-DOP-; RC-PLASTICIZER-DOP-; RCRA-WASTE-NUMBER-U028-; REOMOL-D-79P-; REOMOL-DOP-; SICOL-150-; STAFLEX-DOP-; TRUFLEX-DOP-; VESTINOL-AH-; VINICIZER-80-; WITCIZER-312- RN: 117-81-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199105 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Di(2-ethylhexyl)phthalate (DEHP) CASRN -- 117-81-7 Primary Synonym -- Bis(2-ethylhexyl)phthalate Last Revised -- 05/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Increased relative NOAEL: none 1000 1 2E-2 liver weight mg/kg/day LOAEL: 0.04% of diet Guinea Pig Sub- (19 mg/kg bw/day) chronic-to-Chronic Oral Bioassay Carpenter et al., 1953 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Carpenter, C.P., C.S. Weil and H.F. Smyth. 1953. Chronic oral toxicity of di(2-ethylhexyl)phthalate for rats and guinea pigs. Arch. Indust. Hyg. Occup. Med. 8: 219-226. The following numbers of guinea pigs were fed diets containing DEHP for a period of 1 year: 24 males and 23 females consumed feed containing 0.13% DEHP; 23 males and 23 females consumed feed containing 0.04% DEHP; and 24 males and 22 females were fed the control diet. These dietary levels corresponded to 64 or 19 mg/kg bw/day based on measured food consumption. No treatment-related effects were observed on mortality, body weight, kidney weight, or gross pathology and histopathology of kidney, liver, lung, spleen, or testes. Statistically significant increases in relative liver weights were observed in both groups of treated females (64 and 19 mg/kg bw/day). Groups of 32 male and 32 female Sherman rats were maintained for 2 years on diets containing either 0.04, 0.13 or 0.4% DEHP (equivalent to 20, 60, and about 195 mg/kg bw/day based on measured food consumption). An F1 group of 80 animals was fed the 0.04% diet for 1 year. Mortality in the F1 treated and control groups was high; 46.2 and 42.7%, respectively, survived to 1 year. There was, however, no effect of treatment on either parental or F1 group mortality, life expectancy, hematology, or histopathology of organs. Both parental and F1 rats receiving the 0.4% DEHP diet were retarded in growth and had increased kidney and liver weights. It appears that guinea pigs offer the more sensitive animal model for DEHP toxicity. A LOAEL in this species is determined to be 19 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- Factors of 10 each were used for interspecies variation and for protection of sensitive human subpopulations. An additional factor of 10 was used since the guinea pig exposure was longer than subchronic but less than lifetime, and because, while the RfD is set on a LOAEL, the effect observed was considered to be minimally adverse. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Dietary levels of 0, 0.01, 0.1, and 0.3% DEHP (greater than 99% pure) were administered to male and female CD-1 mice that were examined for adverse fertility and reproductive effects using a continuous breeding protocol. DEHP was a reproductive toxicant in both sexes significantly decreasing fertility and the proportion of pups born alive per litter at the 0.3% level, and inducing damage to the seminiferous tubules. DEHP has been observed to be both fetotoxic and teratogenic (Singhe, 1972; Shiot and Nishimura, 1982). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The study by Carpenter et al. (1953) utilized sufficient numbers of guinea pigs and measured multiple endpoints. The fact that there were only two concentrations of DEHP tested precludes a rating higher than medium. Since there are corroborating chronic animal bioassays, the data base is likewise rated medium. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD The RfD has been reviewed by the RfD Work Group. Documentation may be found in the meeting notes of 01/22/1986. Other EPA Documentation -- None Agency Work Group Review -- 01/22/1986 Verification Date -- 01/22/1986 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Di(2-ethylhexyl)phthalate (DEHP) CASRN -- 117-81-7 Primary Synonym -- Bis(2-ethylhexyl)phthalate NORC: Not available at this time. ============================================================================ UDCA: 199302 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Di(2-ethylhexyl)phthalate (DEHP) CASRN -- 117-81-7 Primary Synonym -- Bis(2-ethylhexyl)phthalate Last Revised -- 02/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen. Basis -- Orally administered DEHP produced significant dose-related increases in liver tumor responses in rats and mice of both sexes. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Thiess et al. (1978) conducted a mortality study of 221 DEHP production workers exposed to unknown concentrations of DEHP for 3 months to 24 years. Workers were followed for a minimum of 5 to 10 years (mean follow-up time was 11.5 years). Eight deaths were reported in the exposed population. Deaths attributable to pancreatic carcinoma (1 case) and uremia (1 case in which the workers also had urethral and bladder papillomas) were significantly elevated in workers exposed for >15 years when compared to the corresponding age groups in the general population. The study is limited by a short follow-up period and unquantified worker exposure. Results are considered inadequate for evidence of a causal association. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. In an NTP (1982) study, 50 male and 50 female fisher 344 rats per group were fed diets containing 0, 6000 or 12,000 ppm DEHP for 103 weeks. Similarly, groups of 50 male and 50 female B6C3F1 mice were given 0, 3000 or 6000 ppm DEHP in the diet for 103 weeks. Animals were killed and examined histologically when morbund or after 105 weeks. No clinical signs of toxicity were observed in either rats or mice. A statistically significant increase in the incidence of hepatocellular carcinomas and combined incidence of carcinomas and adenoma were observed in female rats and both sexes of mice. The combined incidence of neoplastic nodules and hepatocellular carcinomas was statistically significantly increased in the high-dose male rats. A positive dose response trend was also noted. Carpenter et al. (1953) found no malignant tumors in treated groups of 32 male and 32 female Sherman rats. Animals were given 400, 1300 or 4000 ppm DEHP in the diet for 1 year and reduced to a maximum of 8 males and 8 females and treated for another year. Controls, F1 and 4000 ppm groups were sacrificed after being maintained on control or 4000 ppm diets for 1 year. Only 40 to 47% of the animals in each group, including F1 animals, survived 1 year. Thus, an insufficient number of animals were available for a lifetime evaluation. Carpenter et al. (1953) did not find a carcinogenic effect in guinea pigs and dogs exposed to 1300 or 4000 ppm DEHP. Both guinea pigs and dogs were terminated after 1 year of exposure. The treatment and survival periods for these animals were considerably below their lifetimes. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Studies indicate that DEHP is not a direct acting mutagen in either a forward mutation assay in Salmonella typhimurium (Seed, 1982) or the rec assay in Bacillus subtilis (Tomita et al., 1982). DEHP did not induce mutations in a modified reverse mutation plate incorporation assay in Salmonella strains TA100 and TA98 at concentrations up to 1000 ug/plate in the presence or absence of S9 hepatic homogenate (Kozumbo et al., 1982). MEHP, the monoester form of DEHP and a metabolite is positive in the rec assay and in the reverse mutation assay in Salmonella. In the absence of exogenous metabolism MEHP produced chromosomal aberrations and sister chromatid exchanges in V79 cells. Both DEHP and MEHP induced chromosomal aberrations and morphological transformation in cultured fetal Syrian hamster cells exposed in utero (Tomita et al., 1982). Chromosomal effects were not found in CHO mammalian cells (Phillips et al., 1982) exposed to DEHP. DEHP was weakly positive with metabolic activation in only one of several studies testing for mutagenic activity at the thymidine kinase locus in L5178Y mouse lymphoma cells (Ashby et al., 1985). DEHP is a potent inducer of hepatic peroxisomal enzyme activity (Ganning et al., 1984). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 1.4E-2/mg/kg/day Drinking Water Unit Risk -- 4.0E-7 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 3E+2 ug/L E-5 (1 in 100,000) 3E+1 ug/L E-6 (1 in 1,000,000) 3E+0 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- Mouse/B6C3Fl, male Test Animals -- hepatocellular carcinoma and adenoma Route -- diet Reference -- NTP, 1982 ------- Dose -------- Admin- Human istered Equivalent Tumor (ppm) (mg/kg)/day Incidence -------- ----------- --------- 0 0 14/50 3000 32 25/48 6000 65 29/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) In this study powdered rodent meal was provided in such a way that measured food consumption could include significant waste and spillage rather than true food intake. For this reason a standard food consumption rate of 13% mouse body weight was used in the dose conversion. DEHP is hydrolyzed to monoesters including MEHP (Pollack et al., 1985; Lhuguenot et al., 1985; Kluwe, 1982). Although several species of animals have been determined to excrete glucuronide conjugates of monoethylhexyl phthalate (MEHP) upon exposure to DEHP, rats do not (Tanaka et al., 1975; Williams and Blanchfield, 1975; Albro et al., 1982). Slope factors based on combined hepatocellular carcinoma and neoplastic nodule incidences were 4.5E-3/mg/kg/day for female rats, 3.2E-3/mg/kg/day for male rats. A slope factor based on hepatocellular adenomas or carcinomas in female mice is 1.0E-2/mg/kg/day. The unit risk should not be used if the water concentration exceeds 4E+4 ug/L, since above this concentration the slope factor may differ from that stated. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) An adequate number of animals was observed and a statistically significant increase in incidence of liver tumors was seen in both sexes and were dose dependent in both sexes of mice and female rats. A potential source of variability in the NTP study is the possibility of feed scattering. The above calculations are based on standard food consumption rates for mice (13% of body weight) and rats (5% of body weight). ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1988 The values in the 1988 Drinking Water Criteria Document for Phthalic Acid Esters (External Review Draft) have received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 08/26/1987, 10/07/1987 Verification Date -- 10/07/1987 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199005 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Di(2-ethylhexyl)phthalate (DEHP) CASRN -- 117-81-7 Primary Synonym -- Bis(2-ethylhexyl)phthalate Last Revised -- 05/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Carpenter, C.P., C.S. Weil and H.F. Smyth. 1953. Chronic oral toxicity of di(2-ethylhexyl)phthalate for rats and guinea pigs. Arch. Indust. Hyg. Occup. Med. 8: 219-226. NTP (National Toxicology Program). 1984. Di(2-ethylhexyl)phthalate: Reproduction and fertility assessment in CD-1 mice when administered by gavage. Final Report. NTP-84-079. NTP, Research Triangle Park, NC. Shiota, K. and H. Nishimura. 1982. Teratogenicity of di-2-ethylhexyl phthalate and di-n-butyl phthalate in mice. Environ. Health Perspect. 45(0): 65-70. Singhe, A.R., W.H. Lawrence and J. Autian. 1972. Teratogenicity of phthalate esters in rats. J. Pharmacol. Sci. 61: 51. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Albro, P.W., J.T. Corbett, J.L. Schroeder, et al. 1982. Pharmacokinetics, interactions with macromolecules and species differences in metabolism of DEHP. Environ. Health Perspect. 45: 19-25. Ashby, J., F.J. de Serres, M. Draper, et al. 1985. Evaluation of short-term tests for carcinogens. Report of the International Programme on Chemical Safety's Collaborative Study on In Vitro Assays. Elsevier Science Publishers, Amsterdam. Carpenter, C.P., C.S. Weil and H.F. Smith, Jr. 1953. Chronic oral toxicity of di-(2-ethylhexyl)phthalate for rats, guinea pigs and dogs. AMA Arch. Ind. Hyg. Occup. Med. 8: 219-226. Ganning, A.E., V. Brunk and G. Dallner. 1984. Phthalate esters and their effect on the liver. Hepatology. 4(3): 541-547. Kluwe, W.M. 1982. Overview of phthalate ester pharmacokinetics in mammalian species. Environ. Health Perspect. 45: 3-10. Kozumbo, W.J., R. Kroll and R.J. Rubin. 1982. Assessment of the mutagenicity of phthalate esters. Environ. Health Perspect. 45: 103-109. Lhuguenot, J.C., A.M. Mitchell, G. Milner, E.A. Lock and C.R. Elcombe. 1985. The metabolism of di-(2-ethylhexyl)phthalate (DEHP) and mono-(2-ethylhexyl)phthalate (MEHP) in rats: In vivo and in vitro dose and time dependency of metabolism. Toxicol. Appl. Pharmacol. 80: 11-22. NTP (National Toxicology Program). 1982. Carcinogenesis bioassay of di-(2-ethylhexyl)phthalate (CAS No. 117-81-7) in F344 rats and B6C3F, mice (feed study). NTP Tech. Rep. Ser. TR No. 217, NTP, Research Triangle Park, NC. Phillips, B.J., T.E.B. James and S.D. Gangolli. 1982. Genotoxicity studies of di-(2-ethylhexyl)phthalate and its metabolites in CHO cells. Mutat. Res. 102: 297-304. Pollack, G.M., R.C. Li, J.C. Ermer and D.D. Shen. 1985. Effects of route of administration and repetitive dosing on the disposition kinetics of di-(2-ethylhexyl)phthalate and its mono-de-esterified metabolite in rats. Toxicol. Appl. Pharmacol. 79: 246-256. Seed, J.L. 1982. Mutagenic activity of phthalate esters in bacterial liquid suspension assays. Environ. Health Perspect. 45: 111-114. Tanaka, A., T. Adachi, T. Takahashi and T. Yamaha. 1975. Biochemical studies on phthalic esters. I. Elimination, distribution and metabolism of di-(2-ethylhexyl)phthalate in rats. Toxicology. 4: 253-264. Thiess, A.M., R. Frentzel-Beyme and R. Wieland. 1978. Mortality study in workers exposed to di-(2-ethylhexyl)phthalate (DOP). In: Moglichkerten und Grenzen des Biological Monitoring. Arbeitsmedizinische Probleme des Dienstleistungsqewerbes. Arbeitsmedizinische kolloquium [Possibilities and Limits of Biological Monitoring. Problems of Occupational Medicine in Small Industries. Colloquim in Occupational Medicine], Frankfurt/M., May 1978. Stuttgart, A.W. Gentner, p. 155-164. (Ger.) Tomita, I., Y. Nakamura, N. Aoki and N. Inui. 1982. Mutagenic/carcinogenic potential of DEHP and MEHP. Environ. Health Perspect. 45: 119-125. Williams, D.T. and B.J. Blanchfield. 1975. The retention, distribution, excretion and metabolism of dibutylphthalate-7-14C in the rat. J. Agric. Food Chem. 23: 854-857. U.S. EPA. 1988. Drinking Water Criteria Document for Phthalic Acid Esters. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. (External Review Draft). ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Di(2-ethylhexyl)phthalate (DEHP) CASRN -- 117-81-7 Primary Synonym -- Bis(2-ethylhexyl)phthalate ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.2. Text added to paragraph 1 09/07/1988 II. Carcinogen summary on-line 02/01/1989 II.A.2. Study description revised 02/01/1989 II.D.3. Primary contact's phone number corrected 07/01/1989 VI. Bibliography on-line 08/01/1989 I.A.4. Text revised 05/01/1990 II.A.4. Text revised 05/01/1990 VI.C. Kozumbo et al., 1982 citation added 05/01/1991 I.A.2. Corrected principal study title 05/01/1991 I.A.2. 2nd para, line 3 units corrected from g/kg to mg/kg 08/01/1991 II.D.3. Primary and secondary contacts changed 08/01/1991 IV.F.1. EPA contact changed 09/01/1991 All Primary name changed from Bis(2-ethylhexyl)phthalate 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 02/01/1993 II.D.3. Primary contact changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 05/04/1998 I.A.4. NTP, 1984 citation added for clarification. 12/10/1998 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 361 of 1119 in IRIS (through 2003/06) AN: 15 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199210 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Bromomethane- SY: *METHYL-BROMIDE-; 74-83-9; BROM-O-GAS-; CURAFUME-; DOWFUME-MC-2-SOIL-FUMIGANT-; DOWFUME-MC-33-; EDCO-; EMBAFUME-; HALON-1001-; HALTOX-; ISCOBROME-; KAYAFUME-; MB-; MBX-; MEBR-; METAFUME-; METHANE,-BROMO-; METHOGAS-; MONOBROMOMETHANE-; PESTMASTER-; PROFUME-; R40B1-; ROTOX-; TERABOL-; TERR-O-GAS-100-; ZYTOX- RN: 74-83-9 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199107 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Bromomethane CASRN -- 74-83-9 Primary Synonym -- Methyl bromide Last Revised -- 07/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Epithelial hyperplasia NOAEL: 1.4 mg/kg/day 1000 1 1.4E-3 of the forestomach mg/kg/day LOAEL: 7.1 mg/kg/day Rat Subchronic Gavage Study Danse et al., 1984 ---------------------------------------------------------------------------- *Conversion Factors: doses adjusted for gavage schedule (5 days/week) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Danse, L.H.J.C., F.L. van Velsen and C.A. van der Heijden. 1984. Methylbromide: Carcinogenic effects in the rat forestomach. Toxicol. Appl. Pharmacol. 72: 262-271. Treatment of groups of 10 male and 10 female Wistar rats by gavage 5 days/week for 13 weeks with bromomethane at 0, 0.4, 2, 10, or 50 mg/kg resulted in severe hyperplasia of the stratified squamous epithelium in the forestomach at a dose of 50 mg/kg/day and slight epithelial hyperplasia in the forestomach at a dose of 10 mg/kg/day (Danse et al., 1984). At the 50 mg/kg/day dose level, decreased food consumption, body weight gain and anemia were observed in the male rats. Slight pulmonary atelectasis was observed, at the two higher dose levels, in both male and female rats; however, the investigators stated that the possible inhalation of bromomethane-containing oil during the gastric intubation procedure might have been responsible for this effect. No neurotoxic effects were observed at any dose level tested. Renal histopathology was not evaluated. Adverse effects were not observed at 0.4 or 2 mg/kg. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF includes the standard uncertainty factors for interspecies and intrahuman variability and a factor of 10 for extrapolation to lifetime exposure from an intermediate exposure duration. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) The current RfD is based on the Danse et al. (1984) study, which uses the preferred oral route of exposure for deriving an oral RfD. The previous oral RfD (4E-4 mg/kg/day) was based on the inhalation studies by Irish et al. (1940). Inhalation studies are inappropriate for oral risk assessment extrapolation for bromomethane because portal-of-entry effects are observed for both the inhalation route (lung pathology) and oral route (stomach hyperplasia). In addition, neurological effects reported after inhalation exposures have not been reported after oral exposures. Beagle dogs of either sex were fed methyl bromide fumigated food ad libitum for 1 year so that groups of four dogs each ingested approximately 35, 75, or 150 mg/kg/day of bromide, or adjusting for molecular weight, 41.6, 89.1, or 178.2 mg/kg/day of methyl bromide, assuming all the bromide was present as methyl bromide (Rosenblum et al., 1960). The control group consisted of three male and three female dogs fed only dog chow, ad libitum. The dogs ingesting 178.2 mg/kg/day methyl bromide gained more weight than the controls or the two lower treatment groups; they also became lethargic and displayed excessive salivation and occasional diarrhea. Methyl bromide was reported to have no effect on hematological values, urinalysis, blood chemistry (including BUN levels) or mortality rate. Mild chronic renal inflammation was reported in two dogs in the high-dose group and in one dog in the control group. Mild hepatic focal inflammation was reported in three dogs in the high-dose group, two dogs in the low-dose group and one dog in the control group. No other histological lesions were reported. No adverse developmental effects were observed in the fetuses of Wistar rats exposed to 20 ppm (78 mg/cu.m) or 70 ppm (272 mg/cu.m) of bromomethane for 7 hours/day on days 1-19 of gestation (Hardin et al., 1981; Sikov et al., 1980). Exposure to 20 ppm (78 mg/cu.m) or 70 ppm (272 mg/cu.m) for 7 hours/day, 5 days/week for 3 weeks prior to mating, and gestation, did not result in developmental toxicity in the offspring. No maternal toxic effects were observed. Bromomethane was highly toxic to pregnant New Zealand White rabbits exposed to 70 ppm (272 mg/cu.m) for 7 hours/day, 5 days/week on days 1 to 15 of gestation; 24/25 rabbits died by day 30 of gestation (Hardin et al., 1981; Sikov et al., 1980). No adverse developmental effects were observed in the one remaining litter or in a group of rabbits exposed to 20 ppm (78 mg/cu.m) of bromomethane for 7 hours/day, 5 days/week on days 1 to 30 of gestation. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The study by Danse et al. (1984) used the preferred route of administration for derivation of an oral RfD. The study was adequately conducted, and the determination of epithelial hyperplasia of the forestomach was independently confirmed. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington DC. U.S. EPA. 1987. Drinking Water Health Advisory for Bromomethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington DC. Agency Work Group Review -- 12/02/1985, 02/05/1986, 09/29/1986, 04/15/1987, 05/26/1988 Verification Date -- 05/26/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Bromomethane conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199210 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Bromomethane CASRN -- 74-83-9 Primary Synonym -- Methyl bromide Last Revised -- 10/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Degenerative and NOAEL: None 100 1 5E-3 proliferative lesions mg/cu.m of the olfactory LOAEL: 11.7 mg/cu.m (3 ppm) epithelium of the LOAEL(ADJ): 2.08 mg/cu.m nasal cavity LOAEL(HEC): 0.48 mg/cu.m Rat 29-month Inhalation Study Reuzel et al., 1987, 1991 ---------------------------------------------------------------------------- *Conversion Factors: MW = 94.95. Assuming 25 degrees C and 760 mmHg, LOAEL(mg/cu.m) = 3 ppm x 94.95/24.45 = 11.7 mg/cu.m. LOAEL(ADJ) = 11.7 x 6 hours/24 hours x 5 days/7 days = 2.08 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in the extrathoracic region. MVa (chronic, female Wistar rats) = 0.30 cu.m/day, MVh = 20 cu.m/day, Sa(ET) = 11.6 sq. cm., Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa)/(MVh/Sh) = 0.23. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 0.48 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Reuzel, P.G.J., C.F. Kuper, H.C. Dreef-van der Meulen and V.M.H. Hollanders. 1987. Chronic (29-month) inhalation toxicity and carcinogenicity study of methyl bromide in rats. Report No. V86.469/221044. Netherlands Organization for Applied Scientific Research, Division for Nutrition and Food Research, TNO. EPA/OTS Document No. 86-8700001202. Reuzel, P.G.J., H.C. Dreef-van der Meulen, V.M.H. Hollanders, C.F. Kuper, V.J. Feron and C.A. van der Heijden. 1991. Chronic inhalation toxicity and carcinogenicity study of methyl bromide in Wistar rats. Fd. Chem. Toxic. 29(1): 31-39. A series of inhalation toxicity studies of bromomethane were conducted under the sponsorship of the National Institute of Public Health and Environmental Hygiene of the Netherlands. In a chronic inhalation study conducted by Reuzel et al. (1987, 1991), 50 male and 60 female Wistar rats were exposed to 0, 3, 30, or 90 ppm (0, 11.7, 117, or 350 mg/cu.m, respectively) 98.8 % pure bromomethane 6 hours/day, 5 days/week (duration-adjusted concentrations are 0, 2.08, 20.9, or 62.5 mg/cu.m, respectively) for up to 29 months. Three satellite groups of 10 animals/sex/exposure level were sacrificed at 14, 53, and 105 weeks of exposure. Animals were observed daily, and body weight was recorded weekly for the first 12 weeks and monthly thereafter. Hematology, clinical chemistry, and urinalyses were conducted at 12-14 weeks and 52-53 weeks in the satellite groups. Eleven organs were weighed at necropsy, and approximately 36 tissues, including the lungs with trachea and larynx; 6 cross-sections of the nose; heart; brain; and adrenal glands were examined histopathologically. The test atmosphere was measured by gas chromatography every 30 minutes during exposure. Males and females exposed to 90 ppm exhibited decreased body weight gains; no treatment-related changes in hematological, biochemical, or urine parameters were observed. A significant concentration-related decrease in relative kidney weights was reported in the 30- and 90-ppm males. A decrease in mean absolute brain weight was reported to occur in the 90-ppm females at weeks 53 and 105, but there was no change in relative brain weight or in brain histology. Microscopic evaluation revealed that the nose, the heart, and the esophagus and forestomach were the principle targets of bromomethane toxicity in this study. Very slight to moderate hyperplastic changes in the basal cells accompanied by degeneration in the olfactory epithelium in the dorso-medial part of the nasal cavity were observed in all exposed groups of both sexes at 29 months of exposure. At the lowest concentration, the lesion is described as very slight. These changes were concentration-related in both incidence and severity and were statistically significant at 29 months. Incidence of basal cell hyperplasia in control, 3-, 30-, and 90-ppm groups were 4/46, 13/48, 23/49, and 31/48 in males and 9/58, 19/58, 25/59, and 42/59 in females, respectively. Slight increases in incidence of basal cell hyperplasia in the 30- and 90-ppm groups (n=7-10) at 53 and 105 weeks were not statistically significant. Lesions in the heart were statistically significant in the males (cartilaginous metaplasia and thrombus), and the females (myocardial degeneration and thrombus) exposed to 90 ppm. The authors attributed part of the increased mortality in the high-concentration animals to the cardiac lesions. A statistically significant increase in hyperkeratosis of the esophagus was observed in the 90-ppm males after 29 months of exposure. Slight increases in forestomach lesions were not statistically significant. No effects were observed in the tracheobronchial or pulmonary regions of the respiratory tract. No other exposure-related effects were noted. Based on these results, a LOAEL of 3 ppm (HEC = 0.48 mg/cu.m) for nasal effects is established. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- The uncertainty factor of 100 reflects a factor of 10 for intraspecies uncertainty, a factor of 3 for the use of a LOAEL for a mild effects and a factor of 3 for interspecies extrapolation because dosimetric adjustments have been applied. The factors of 3 represent operational application of a geometric half of the standard factor of 10, rounded to a single significant figure. As a result, multiplication of two factors of 3 results in a composite factor of 10. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) NTP conducted a 13-week subchronic study in B6C3F1 mice and F344 rats and a 6-week target organ study (Eustis et al., 1988; NTP, 1990). A chronic study on the toxicology and carcinogenesis of bromomethane following inhalation exposure to B6C3F1 mice was also conducted (NTP, 1990). In the 13-week study, 18 rats/sex/group were exposed to target concentrations of 0, 30, 60, or 120 ppm (0, 117, 233, or 466 mg/cu.m, respectively) bromomethane 6 hours/day, 5 days/week (duration-adjusted concentrations are 0, 20.9, 41.6, and 83.2 mg/cu.m, respectively). Mice (18-27/sex/group) were exposed to 0, 10, 20, 40, 80, or 120 ppm (0, 38.8, 77.6, 155, 311, or 466 mg/cu.m, respectively) bromomethane 6 hours/day, 5 days/week (duration-adjusted concentrations are 0, 6.93, 13.9, 27.7, 55.5, or 83.2 mg/cu.m, respectively). Hematological parameters were measured and organ weights were determined for the adrenals (rats only), brain, heart, kidney, lung, spleen (rats only), testis, and thymus (mice only). Pseudocholinesterase activity was measured in the mice only. Neurobehavioral testing was conducted on 8 rats and 8 mice/sex/group at weeks 0, 6, and 12, and neuromorphological studies were conducted on 4 rats/sex from the control and 120-ppm group and on 4 mice/sex for each concentration. Histopathological examination of approximately 40 tissues from control and 120-ppm animals were carried out, including lungs, bronchi, and nasal turbinates. Exposure-related changes seen in the mice were a significant (58%) body weight gain reduction and a 17% increase in mortality in mice exposed to 120 ppm bromomethane. Mice exposed to this level exhibited severe curling and crossing of the hindlimbs and twitching of the forelimbs; these effects were more severe in the males. Hematological parameters that were found to be statistically significantly different from control values in mice included decreased mean cell hemoglobin, decreased mean cell count, and increased erythrocyte count in males exposed to 40, 80, and 120 ppm; and increased hemoglobin in males exposed to 120 ppm. No exposure-related effects were seen upon histopathological examination. In the rats there was no increase in mortality, but the males exposed to 120 ppm and the females exposed to 60 and 120 ppm bromomethane exhibited significant decreases in body weight gain. Mild neurobehavioral effects were noted in the high-concentration rats of both sexes. Females exposed to 120 ppm were found to have significantly lower hematocrit, hemoglobin, and erythrocytes counts, but the males did not exhibit these changes. The only exposure-related effect noted at histopathological examination was an increase in the incidence of olfactory epithelial dysplasia and cysts in the rats of both sexes exposed to 120 ppm [LOAEL(HEC) = 12 mg/cu.m]. Based on these results a NOAEL of 80 ppm [NOAEL(HEC) = 8 mg/cu.m] for nasal olfactory epithelial changes in rats is established. Because no significant target organ toxicity was noted in the 14-day or 13-week studies, a special 6-week target organ toxicity study at a near lethal concentration was conducted in F344 rats and B6C3F1 mice (Eustis et al., 1988; NTP, 1990). Groups of 5 animals/sex were exposed to 0 or 160 ppm (621 mg/cu.m) bromomethane 6 hours/day for either 3 consecutive days (rats), or 5 days/week over 2 weeks (rats and mice) or 6 weeks (rats). Fifteen mice/sex/dose were exposed to 0 or 160 ppm (621 mg/cu.m) 6 hours/day, 5 days/week, for 6 weeks. Endpoints studied included clinical observations, mortality, body and organ weights, hematology, clinical chemistry, urinalysis, gross pathology, and histopathology of a standard set of tissues, including the lungs and nasal turbinates. The female rats were the only group to demonstrate more than 50% survival, with mice being more sensitive than rats (mortality exceeded 50% after 6-8 exposures in both the male and female mice and after 14 exposures in the male rats). Because of the high mortality, the male and female mice and male rats were killed after 10, 8, or 14 exposures, respectively. Neurological signs exhibited by both rats and mice, but to a lesser extent in the rats, included lethargy and curling and crossing of hindlimbs, forelimb twitching, and tremors. Decreases in body weight gain were observed in the exposed animals as compared to controls (18% in the mice and 32% in the rats). The mean organ weights of most organs were significantly reduced in both species. Notable hematological effects were seen mostly in the female mice and included decreased RBC and increased WBC counts. Target organs affected by exposure to 160 ppm bromomethane were the brain, kidney, nasal cavity, heart, adrenal gland, liver, and testes. Species differences were noted in the responses of these organs. For example, neuronal necrosis in the cerebral cortex, hippocampus, and thalamus of the brain were seen in the rats whereas neuronal necrosis was seen predominantly in the internal granular layer of the cerebellum of the mice. Nephrosis, characterized by degeneration, necrosis, and sloughing of the epithelium of the cortical convoluted tubules was seen in all of the exposed mice and was considered by the authors to be partially responsible for the increase in mortality, but these lesions were not observed in the rats. Degeneration and atrophy of the seminiferous tubules was observed in several of the exposed rats and mice, but was less severe in the mice. Olfactory epithelial degeneration was observed in the rats of both sexes, and this was seen to a lesser degree in the male mice, with only one female mouse exhibiting this lesion. Myocardial degeneration was seen in rats of both sexes, and to a lesser degree in the male mice. Atrophy of the inner zone of the adrenal cortex was observed in the female mice, and cytoplasmic vacuolation of the adrenal cortex was seen in rats. In the chronic study (NTP, 1990), a total of 86 mice/sex/concentration were exposed to 0, 10, 33, or 100 ppm (0, 38.8, 128, or 388 mg/cu.m, respectively) bromomethane 6 hours/day, 5 days/week (duration-adjusted concentrations are 0, 6.93, 22.9, or 69.3 mg/cu.m, respectively). Exposures to 10 and 33 ppm were for 103 weeks, with interim sacrifices at 6 and 11 months. Exposure to 100 ppm produced 47% mortality in the males and 10% mortality in the females by 20 weeks, so exposure was discontinued in this group at this time and the surviving animals were observed for an additional 84 weeks, except for the females scheduled for the 15-month sacrifice. The endpoints studied were the same as those described for the 6-week target organ toxicity study in addition to neurobehavioral assessments in 16 mice/sex/group and neuropathological examination on 3-8 animals/sex/group at 20 weeks and 6, 15, and 24 months. Body weights were significantly depressed in the animals exposed to 100 ppm (33% in the males and 31% in the females) beginning at week 11 and persisting until study termination. Significant body weight changes were not observed in the lower exposure groups. Because of the reduced body weight in the 100-ppm animals, organ weight changes were difficult to interpret, but reduced absolute and relative thymus weights were observed in both the males and females exposed to 100 ppm bromomethane. Clinical signs of toxicity observed almost exclusively in the 100-ppm animals that persisted throughout the 103 weeks included tremors, abnormal posture, and limb paralysis. Functional neurobehavioral changes consisting of hypoactivity, a heightened startle response, and higher hindlimb grip scores and hot plate latency were observed in both sexes exposed to 100 ppm at various times during exposure, but were more pronounced in the males. The target organs of toxicity identified in this study were the brain, bone (sternum), heart, and nose, with lesions in these organs occurring more frequently in the males. In the brain, there was a statistically significant increase in the incidence of cerebellar degeneration in the animals exposed to 100 ppm. Cerebral degeneration was also observed in these animals, but the incidence of this lesion was statistically significant in the males only. Because this lesion was observed more frequently in the animals that died prior to study termination, it may have contributed to the early mortality in this group. Dysplasia of the sternal bone marrow was observed at a statistically significantly increased rate in both the males and the females exposed to 100 ppm, but because it was observed more frequently in the animals that survived to study termination than in those that died early, it was not considered to be a contributing factor to the death of these animals. Myocardial degeneration and chronic cardiomyopathy were also observed at a statistically higher incidence in both males and females exposed to 100 ppm bromomethane, and occurred at a higher incidence in those animals dying early. Finally, a statistically significant increase in the incidence of olfactory epithelial necrosis and metaplasia was seen in the nasal cavities of both the male and female mice exposed to 100 ppm. Necrosis was seen only in the animals dying early, whereas metaplasia was exhibited mainly in those animals surviving until study termination. Histopathological changes in other organs were observed and considered to be secondary to stress and weight loss rather than a direct toxic effect of bromomethane. Animals exposed to lower concentrations did not exhibit significant increases in any of the lesions described above. Based on the results of this study, a NOAEL of 33 ppm (HEC = 4.4 mg/cu.m for respiratory effects and 23 mg/cu.m for extrarespiratory effects) and a LOAEL of 100 ppm (HEC = 13 mg/cu.m for respiratory effects and 69 mg/cu.m for extrarespiratory effects) are established based on toxicity in multiple organs. Male Fischer 344 rats (10/group) were exposed to 0, 90, 175, 250, or 325 ppm (0, 350, 680, 971, or 1,262 mg/cu.m, respectively) bromomethane (99.9% pure) 6 hours/day for 5 days (Hurtt et al., 1987). The brain, nasal cavity, liver, kidney, adrenal glands, testes, and epididymides were examined histopathologically. The lungs were not examined. Three animals exposed to 325 ppm died after the fourth exposure. Diarrhea, hemoglobinuria, gait disturbances, convulsions and hepatocellular degeneration were observed in animals exposed to 250 ppm or greater; vacuolar degeneration of the zona fasciculata of the adrenal gland and cerebellar granule cell degeneration were observed in rats exposed at 175 ppm and greater. Minor alterations in testicular histology and cerebrocortical degeneration were observed in the 350-ppm exposure group. A concentration-dependent degeneration of the nasal olfactory sensory cells was observed in rats exposed to 175 ppm bromomethane or greater. This degeneration affected 50-80% of the olfactory mucosa, and was characterized by complete or partial destruction of the olfactory epithelium at the higher concentrations. Small foci of hepatocellular coagulative necrosis were observed in animals exposed to the two highest concentrations. No exposure-related lesions were noted in the kidneys. In a subsequent study, Hurtt et al. (1988) investigated the ability and time-course of the olfactory epithelium to regenerate following acute exposure to bromomethane. Male Fischer 344 rats were exposed to 0 (n=5) or 200 ppm (n=40) 99.9% pure bromomethane (777 mg/cu.m) 6 hours/day for 1-5 days. Five animals/group were killed after 1, 3, or 5 days of exposure and 1, 2, 3, 5, or 10 weeks after cessation of treatment. In a companion study, 6 animals/group were exposed to 0, 90, or 200 ppm (0, 350, or 777 mg/cu.m) bromomethane for 6 hours and olfactory function was studied by determining the effects of bromomethane on the ability of food-deprived animals to locate buried food pellets. Additional animals similarly exposed were killed at various times following the single 6-hour exposure to assess the state of morphological regeneration at the time of functional recovery. Only the nasal cavities were examined histopathologically in these studies. No clinical signs of toxicity were observed in the exposed animals. Extensive destruction of the olfactory epithelium, characterized by epithelial disruption, fragmentation, and exfoliation, was evident after a single 6-hour exposure to 90 or 200 ppm, with the most severe effects observed in the sustentacular and mature sensory cells, and the basal cell remaining intact. Regeneration of the olfactory epithelium, characterized at first by replacement with a squamous cell layer that increased in thickness, began by the third day of exposure and was essentially complete by 10 weeks after the last exposure. It is important to note that regeneration began even though exposure to bromomethane was still ongoing. Olfactory function was impaired in animals exposed to 200 ppm bromomethane, but not 90 ppm. Recovery of this function was evident by 4-6 days after exposure, which preceded morphological regeneration. Similar results were obtained by Hastings (1990). In this study, rats were exposed to 200 ppm (777 mg/cu.m) bromomethane 4 hours/day 2 days/week for 2 weeks. Prior to exposure, rats were food-deprived and trained to find buried food pellets. Morphological as well as biochemical (carnosine content in the olfactory bulb, which is an indication of the integrity of the olfactory primary sensory neurons) studies were performed as well to assess the integrity of the olfactory epithelium. Extensive damage to the olfactory epithelium was seen, as evidenced by both morphological analysis and decreased carnosine content after a single 4-hour exposure. Olfactory function was also impaired after 4 hours, as evidenced by the inability of the rats to find the buried food pellets. However, olfactory function began to return after the second week of exposure and the animals performed as well as their controls by the end of the exposure period whereas regeneration of the olfactory epithelium, as indicated by morphological and biochemical analysis was not complete until 30 days from the start of exposure. The most common signs of acute intoxication with bromomethane in humans are neurotoxic in nature and include headache, dizziness, fainting, apathy, weakness, tiredness, giddiness, delirium, stupor, psychosis, loss of memory, mental confusion, speech impairment, visual effects, limb numbness, tremors, muscle twitching, paralysis, ataxia, seizures, convulsions, and unconscious. Several studies have been conducted on the longer-term effects of occupational exposure to bromomethane. None of these studies can serve as the basis for the derivation of an RfC for bromomethane because of concurrent exposures to other chemicals, inadequate quantitation of exposure levels and/or durations, and other deficits in study design. In a cross-sectional occupational study conducted by Anger et al. (1986), soil and structural fumigators underwent a neurological examination. The exposure group was blinded to the physician giving the examination. Most of the structural fumigators used both bromomethane (MB) and sulfuryl fluoride (SF). The formation of the study groups was based on the estimated time devoted to bromomethane and sulfuryl fluoride fumigation activities, and estimated length of time in the occupation. Four groups were formed: the MB group (n=32) consisted of structural fumigators using MB 80% or more of the time and soil fumigators using the mixture MB and chloropicrin; the SF group (n=24) consisted of structural fumigators who used SF 80% or more of the time; group COMB (n=18) consisted of workers using both MB and SF 40-60% of the time, the reference group (Group R, n=29) consisted of those workers who were not directly exposed to fumigants, but worked in the fumigation industry. The workers in the exposed groups had been in the profession for 1 or more years and had fumigated a house or field within the last 50 days. More symptoms were reported in the exposed groups than in the reference population: 78-83% and 41% respectively showed symptoms. The difference was significant for the MB and COMB groups when compared to Group R. The MB group did not perform as well as referents on several behavioral tests, including tests of cognitive function, reflexes, sensory and visual effects. Although this study suggests mild neurological effects of exposure to methyl bromide, it is difficult to draw any conclusions between exposure and effect because of the confounding factors. The exposed and reference groups were not well matched for age; use of prescription medication, alcohol, or illegal drugs within 2 days of the testing; education; or ethnic group. In addition, participation in the study was voluntary and no information is provided on the use of personal protective equipment in these groups. Herzstein and Cullen (1990) reported on 4 cases of bromomethane toxicity at a nursery following the removal of polyethylene sheets covering soil fumigated with 98% bromomethane and 2% chloropicrin. Four workers involved in removing the tarp wore no respiratory protection, and had no training in the handling or hazards of bromomethane. On the second day, all four workers noted fatigue and lightheadedness. After arriving home, three of the workers developed severe coughing, chest tightness, nausea, vomiting, headaches, and tremulousness during the night. Three workers were found to have either ataxia, tremor, or both. Blood bromide levels were not performed. The symptoms continued to improve without treatment. Upper- and lower-extremity paresthesias and reduced hand dexterity were reported in two workers at 3 weeks post-exposure. There were no long-term adverse effects after 18 months of follow-up. The first reported study on the effects of short-term and repeated exposure to bromomethane in experimental animals was conducted by Irish et al. (1940). In the first set of experiments, rats and rabbits were exposed once to 420-50,000 mg/cu.m bromomethane for varying lengths of time. Concentrations of bromomethane greater than or equal to 10,000 mg/cu.m were lethal to 100% of the animals within 6-132 minutes. Deaths also occurred at 6-36 hours after exposure to concentrations less than 10,000 mg/cu.m. Clinical signs observed in rats exposed to less than 10,000 mg/cu.m included roughening of the fur, hunching of the back, drowsiness, heavy breathing, and lacrimation. Nasal irritation and lacrimation were observed, in addition to the signs mentioned above, at higher concentrations. Rabbits did not exhibit these signs. However, in rats exposed to greater than 1000 mg/cu.m for 20 hours, a hyperexcitable state was observed, whereas rabbits exposed to the same concentration exhibited paralysis. Evidence of pulmonary irritation (congestion and edema) was found (predominantly in the rat) following exposures to 1,000-20,000 mg/cu.m. In subsequent studies, rats (n=135), rabbits (n=104), guinea pigs (n=98) and female rhesus monkeys (n=13) were exposed to 0, 17, 33, 66, 100, or 220 ppm (0, 66, 128, 256, 388, or 853 mg/cu.m, respectively) 7-8 hours/day, 5 days/week for 6 months or until the majority exhibited severe reactions or died. The frank-effect-levels (increased mortality) were 100 ppm for rats, guinea pigs, and monkeys and 133 ppm for rabbits (Irish et al., 1940). Rabbits and monkeys exhibited paralysis after exposure to 66 ppm whereas rats and guinea pigs exhibited no adverse effects. Pulmonary damage was still seen in rabbits exposed to 33 ppm, but the monkeys appeared normal. None of the species exhibited adverse effects following repeated exposure to 17 ppm (66 mg/cu.m; Irish et al. 1940). The brain and heart also appeared to be target organs following inhalation exposure to bromomethane in a study conducted by Kato et al. (1986). Male Sprague-Dawley rats (10-12/group) were exposed to 150 ppm (583 mg/cu.m) bromomethane (purity unspecified) 4 hours/day, 5 days/week for 11 weeks (duration-adjusted to 69.3 mg/cu.m). Focal necrosis and fibrosis of coronary ventricles and papillary muscle disorders were observed in the exposed animals. In the same study, male Sprague-Dawley rats (10-12/group) were exposed to 0, 200, 300, or 400 ppm (0, 777, 1,165, or 1,553 mg/cu.m) 4 hours/day, 5 days/week for 6 weeks (duration-adjusted concentrations are 0, 92.5, 139, and 185 mg/cu.m, respectively). Focal necrosis and fibrosis of coronary ventricles and papillary muscle were observed in all exposed animals. Neurological dysfunction (ataxia, paralysis) were reported at levels at and exceeding 300 ppm; necrosis in the bilateral regions of the dorso-external cortex of the cerebral hemisphere was observed in animals exposed at 400 ppm. Testicular atrophy with suppression of spermatogenesis was apparent in 6 of the 8 the animals exposed to 400 ppm. Although the lungs appeared to be one of the tissues examined histopathologically, respiratory effects were not addressed in the descriptions of either experiment. Neurobehavioral effects of bromomethane inhalation were studied in rats and rabbits by Anger et al. (1981). In one set of experiments, Sprague-Dawley rats and New Zealand white rabbits were exposed to 0 (n=2) or 65 ppm (252 mg/cu.m, n=6) 7.5 hours/day, 4 days/week for 4 weeks. Neurobehavioral testing, consisting of conduction velocity in the sciatic and ulnar nerves (rats and rabbits), eye-blink reflex (rabbits), open field activity (rats), and grip/coordination (rats) were conducted weekly. Exposed rabbits exhibited depressed body weight gain as compared with the controls, and signs of hind limb paralysis were evident during the last week of exposure. Statistically significant decreases in the eyeblink reflex magnitude and in nerve conduction velocity were also observed in the exposed rabbits. In contrast, no effects on weight gain, grip/coordination, or nerve conduction velocity were observed in the rats exposed to 65 ppm for 4 weeks. The LOAEL for neurological effects in rabbits and the NOAEL for rats is 65 ppm. In another experiment that was performed as part of this study, Sprague-Dawley rats were exposed to 0 or 55 ppm (214 mg/cu.m) bromomethane 6 hour/day, 5 day/week for 36 weeks. Neurobehavioral tests (conduction velocity in the sciatic and ulnar nerves, open-field activity, and grip/coordination) conducted at 25- to 30-day intervals did not reveal any exposure-related effects. In a subsequent study performed by this group (Russo et al., 1984) that was designed to assess the neurotoxic effects of bromomethane in rabbits following longer-term exposure at lower concentration, male New Zealand white rabbits were exposed to 0 (n=2) or 26.6 ppm (103 mg/cu.m, n=6) 99% pure bromomethane 7.5 hours/day, 4 days/week for 8 months (Russo et al., 1984). Exposure concentrations were monitored every 12 minutes by an infrared analyzer. Neurobehavioral tests examined the latency rates of the sciatic and ulnar nerves and the amplitude of the eyeblink reflex of the orbicularis oculi muscle. No other parameters, including respiratory effects, were monitored. No exposure-related neurological effects were observed [NOAEL(HEC) = 23 mg/cu.m]. As part of this study, the animals exposed to 252 mg/cu.m bromomethane for 4 weeks (previously discussed; Anger et al., 1981) were allowed to recover for 6-8 weeks and the neurological tests were repeated. The animals demonstrated partial, but not complete recovery within the 6-week period. Therefore rabbits, which are sensitive to the neurotoxic effects of high-level exposure to bromomethane, can tolerate long-term low-level exposure to bromomethane, and appear to be able to recover from severe neurological effects after cessation of exposure. Morrissey et al. (1988), using data obtained from the 13-week NTP (1990) study in rats and mice, evaluated testis, epididymis, and cauda epididymis weights; caudal sperm motility and count; sperm head morphology; average estrous cycle length; and relative frequency of different estrous stages to assess the potential reproductive effects of bromomethane. In mice, they found that inhalation exposure to bromomethane resulted in an increase in the relative weights of the epididymis and testis, a decrease in sperm density, and an increase in the percentage of abnormal sperm. In the rats, a decrease in absolute cauda epididymis and absolute and relative epididymis weights, an increase in relative testis weight, and a decrease in sperm motility occurred as a result of subchronic inhalation exposure to bromomethane. No effects on estrous cycle length were noted. This study is an evaluation of a screening method for reproductive toxicants and was applied to 50 subchronic studies carried out by the NTP. The exposure levels at which these effects were found were not specified. Male Fischer 344 rats (75/group) were exposed to 0 or 200 ppm bromomethane (777 mg/cu.m) 6 hours/day for 5 consecutive days and sacrificed on various days beginning on day 1 of exposure through 68 days after termination of exposure. Plasma testosterone and testicular glutathione levels were depressed, but returned to control levels within 3 days after exposure had ended. No effects on spermatogenesis, sperm quality, or testicular weight or histology were noted (Hurtt and Working, 1988). Female Wistar rats (n=39-45) were exposed to 0, 20, or 70 ppm (0, 78, or 272 mg/cu.m, respectively) bromomethane 7 hours/day, 5 days/ week for 3 weeks, mated and exposed during gestational days 1-19. The study design included groups at each exposure level exposed pregestationally, during gestation, and both, as well as a control. At gestational day 21, litters were evaluated for fetotoxicity and live fetuses were examined for external, visceral (about 1/2 of fetuses), and skeletal abnormalities. Maternal organ weights for liver, kidney, and lung, and histopathology on 8 animals/group on ovaries, uterus, kidney, lung, and trachea were performed. No mortality or change in organ weights were observed and body weight was decreased during gestation but was not different than controls at full term. Histological effects observed in the lung and kidney were not clearly exposure-related due to the small sample size and high control incidence. There was no effect on pregnancy rate or fetal size. There were 31-38 litters/group examined and no effect on embryotoxicity, fetal viability, or fecundity measures was observed. There was no increase in malformations. The NOAEL for reproductive toxicity (changes in fertility rate) and maternal and fetal toxicity in rats is 70 ppm (Sikov et al., 1981; Hardin et al., 1981). Female New Zealand white rabbits (25/group) were exposed to 0, 20, or 70 ppm (0, 78, or 272 mg/cu.m, respectively) bromomethane 7 hours/day, 5 days/week for 3 weeks during gestational days 1-24. Evaluation of developmental effects was the same as in the rat study except that all fetuses were evaluated for visceral abnormalities. In the 70-ppm group, severe neurotoxic effects occurred and 24/25 animals died. No effects on body weight, organ weight, or histology were observed in maternal animals exposed to 20 ppm. There was no effect on pregnancy rate or fetal size. There were 13 litters in the group exposed to 20 ppm examined and no effect on embryotoxicity, fetal viability, or fecundity measures was observed. There was no increase in malformations. The NOAEL for maternal and fetal toxicity in rabbits is 20 ppm (Sikov et al., 1981; Hardin et al., 1981). Breslin et al. (1990) performed a developmental study in rabbits in which New Zealand rabbits (26/group) were exposed to 0, 20, 40, or 80 ppm (0, 78, 155, or 311 mg/cu.m, respectively) methyl bromide 6 hours/day on gestation days 6-19. Maternal toxicity at 80 ppm included reduced body weight and weight gain. Clinical signs of central nervous system toxicity were observed at 80 ppm. There was no effect on pre- or postimplantation loss, litter size, or fetal body weights. There was an increase in agenesis of the gall bladder and fused sternebrae at 80 ppm. The NOAEL for maternal toxicity and developmental effects in this study is 40 ppm [NOAEL(HEC) = 155 mg/cu.m]. American Biogenics Corporation (1986) conducted a two-generation reproduction study in Sprague-Dawley rats. Groups of 25 rats/sex/dose were exposed by inhalation to methyl bromide vapor at 0, 3, 30, or 90 ppm (0, 12, 117, or 350 mg/cu.m) 6 hours/day, 5 days/week during the premating, gestation, and lactation periods for 2 generations. In F0 male rats, exposure at 90 ppm caused statistically significant decreases in body weight gain during the premating period, final body weight, and total weight gain. No treatment-related changes in reproductive organs were noted. Also, no adverse effects were found on the progeny and reproductive parameters examined. In second generation (F1) animals, no adverse effects were found on body weights, histopathology of reproductive organs, or reproductive parameters measured. However, a statistically significant concentration-related reduction in body weights at 28 days was noted in F2 males and females at 30 ppm and 90 ppm. Although significant changes were seen in some of the mean organ weights and organ-to-body weight ratios in F0, F1, and F2 generation animals, no histopathology changes were seen in these organs. Therefore, the biological significance of these findings if any is not clear. Under the conditions of the study, exposure to methyl bromide did not affect fertility in rats but decreased the body weights of parental rats and reduced the growth of neonatal rats. The NOAEL and LOAEL for these effects were 30 and 90 ppm for adult rats and 3 and 30 ppm for neonates, respectively. Medinsky et al. (1985) and Bond et al. (1985) conducted a series of experiments to assess the uptake, distribution, and excretion of bromomethane in rats following inhalation exposure. In one experiment, F344 rats were exposed to 1.6, 9, 170, or 310 ppm (6, 35, 660, or 1,203 mg/cu.m) radiolabeled bromomethane (nose-only) for 6 hours (Medinsky et al., 1985), and in the other, F344 rats were exposed to 9 ppm radiolabeled bromomethane for 6 hours (Bond et al., 1985). The percentage of total volume of inhaled radiolabeled bromomethane that was absorbed decreased in a concentration-related manner from 48+/-2% at the two lower concentrations to 27+/-4% at the highest concentration, which indicates that uptake of bromomethane is a saturable process. In both studies, inhaled bromomethane was distributed quickly throughout the body, and the highest concentrations were found in the lung, adrenal, kidney, liver, and nasal turbinates. By 65-66 hours after exposure, 75% of the radiolabel had been eliminated. The amount of bromomethane eliminated was linearly related to the amount absorbed (Medinsky et al., 1985). Excretion of bromomethane and its metabolites does not appear to be a concentration dependent (i.e., saturable) process, once absorbed. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- High RfC -- High The Reuzel et al. (1987, 1991) chronic study was well conducted, used an appropriate number of animals and exposure levels, and included thorough histopathological examination of the respiratory tract; however, it is given a medium confidence rating because it did not identify a NOAEL. The LOAEL identified in this study is supported by the effects seen in rats in the subchronic NTP (1990) study and mice in the chronic NTP (1990) study, as well as in subacute and subchronic studies in rats (Hastings, 1990; Hurtt et al., 1987, 1988). The data base is given a high confidence rating because there is a chronic inhalation study in two species supported by subchronic inhalation studies in several species, and because data are available on the developmental and reproductive effects of bromomethane as well as its pharmacokinetics following inhalation exposure. Based on the confidence in the data base and study, high confidence in the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in an existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1986, 1987 Agency Work Group Review -- 10/13/1988, 09/19/1989, 08/15/1991, 12/10/1991 Verification Date -- 12/10/1991 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Bromomethane conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199008 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Bromomethane CASRN -- 74-83-9 Primary Synonym -- Methyl bromide Last Revised -- 08/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- Inadequate human and animal data: a single mortality study from which direct exposure associations could not be deduced and studies in several animal species with too few animals, too brief exposure or observation time for adequate power. Bromomethane has shown genotoxicity. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. A prospective mortality study was reported for a population of 3579 white male chemical workers. The men, employed between 1935 and 1976, were potentially exposed to 1,2-dibromo-3-chloropropane, 2,3-dibromopropyl phosphate, polybrominated biphenyls, DDT, and several brominated organic and inorganic compounds (Wong et al., 1984). Overall mortality for the cohort, as well as for several subgroups, was less than expected. Of the 665 men exposed to methyl bromides (the only common exposure to organic bromides), two died from testicular cancer, as compared with 0.11 expected. This finding may be noteworthy as testicular cancer is usually associated with a low mortality rate. Therefore, there could be more cancer cases than there appear to be based on mortality. The authors noted that it was difficult to draw definitive conclusions as to causality because of the lack of exposure information and the likelihood that exposure was to many brominated compounds. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. Bromomethane was administered by gavage to groups of 10 male and female Wistar rats (Danse et al., 1984). Animals were administered doses of 0, 0.4, 2, 10, or 50 mg/kg/day bromomethane in arachis oil 5 days/week for 13 weeks, at which time the experiment was terminated. There was an apparent dose-related increase in diffuse hyperplasia of the forestomach. The authors reported a forestomach papilloma incidence of 2/10 in the high-dose males and forestomach carcinoma incidences of 7/10 and 6/10 in the high-dose males and females, respectively. These results were subsequently questioned (U.S. EPA, 1985; Schatzow, 1984). A panel of NTP scientists reevaluated the histological slides and concluded that the lesions were hyperplasia and inflammation rather than neoplasia. Rosenblum et al. (1960) reported a 1-year study in which beagle dogs (4/treatment group, 6/control) were provided diets fumigated to residue levels of 0, 35, 75, or 150 ppm bromomethane. No tumors were observed at any dose level; however, there was no indication that the dogs were examined for tumors. In addition, 1-year observation is considered to be inadequate by the EPA for tumor induction in dogs. In an earlier study (Irish et al., 1940) small numbers of rats, guinea pigs, rabbits and monkeys were exposed by inhalation to bromomethane at doses ranging from 0.065 to 0.85 mg/L air. Exposures were for 7.5 to 8 hours/day, 5 days/week for up to 6 months. The authors reported that the highest dose produced acutely toxic effects in all species, but no tumors were observed at any dose level. The short duration of exposure and observation are considered inadequate by the EPA. Bromomethane is currently on test at NTP. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Bromomethane has been shown to produce mutations in Salmonella strains sensitive to alkylating agents and to E. coli both with and without the addition of a metabolic activation system (Voogd et al., 1982; Moriya et al., 1983; Kramers et al.,1985; Djalali-Behzad et al., 1981). Bromomethane was also mutagenic in a modification of the standard Salmonella assay employing vapor phase exposure (Simmon and Tardiff, 1978; Simmon, 1978, 1981; Simmon et al., 1977). Bromomethane was observed to be mutagenic for Drosophila and for mouse lymphoma cells (Voogd et al., 1982; Kramers et al., 1985). Bromomethane is structurally related to bromoethane which, when tested in mice and rats of both sexes, has shown clear evidence of carcinogenicity in some cases and equivocal in others. NTP (1988) conducted an inhalation bioassay on bromoethane, and the results were recently released in a draft report. Groups of F344/N rats (50/sex) and B6C3F1 mice (50/sex) were exposed to 0, 100, 200 or 400 ppm bromoethane 6 hours/day for 5 days/week. A statistically significant increase in uterine adenomas, adenocarcinomas, or squamous cell carcinomas was observed in female mice exposed to 200 and 400 ppm, indicating clear evidence of carcinogenic activity. Equivocal evidence of carcinogenic activity was reported for male and female rats and male mice. While alveolar/bronchiolar adenomas or carcinomas and pheochromocytomas were observed in male rats, the incidences were not dose-related and were within the historical ranges for NTP studies. Granular cell tumors of the brain were also observed in male rats and, although not statistically significant, the incidence was higher than historical incidence in either the study lab or NTP studies. The incidence of alveolar/bronchiolar neoplasms in exposed male mice was marginally greater than control or historical incidence. An increased incidence of gliomas in exposed female rats was significant by the trend test; however, the incidence was not significantly greater when compared with the controls in the study and the controls used in NTP stuides. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985, 1986, 1987 The Health and Environmental Effects Profile for Methyl Bromide and the Health Effects Assessment for Bromoethane received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 02/01/1989, 03/01/1989 Verification Date -- 03/01/1989 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Bromomethane conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199204 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Bromomethane CASRN -- 74-83-9 Primary Synonym -- Methyl bromide Last Revised -- 04/01/1992 SORD: __VI.A. ORAL RfD REFERENCES Danse, L.H.J.C., F.L. van Velsen and C.A. van der Heijden. 1984. Methylbromide: Carcinogenic effects in the rat forestomach. Toxicol. Appl. Pharmacol. 72: 262-271. Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier. 1981. Testing of selected workplace chemicals for teratogenic potential. Scand. J. Work Environ. Health. 7: 66-75. Irish, D.D., E.M. Adams, H.C. Spencer and V.K. Rowe. 1940. The response attending exposure of laboratory animals to vapors of methyl bromide. J. Ind. Hyg. Toxicol. 22: 218-230. Rosenblum, I., A.A. Stein, and G. Eisinger. 1960. Chronic ingestion by dogs of methyl bromide-fumigated food. Arch. Environ. Health. 1: 316-323. Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery and D.W. Phelps. 1980. Teratologic assessment of butylene oxide, styrene oxide and methyl bromide. NTIS PB 81-16851. 87 p. U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington DC. U.S. EPA. 1987. Drinking Water Health Advisory for Bromomethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES American Biogenics Corporation. 1986. Two-generation reproduction study via inhalation in albino rats using methyl bromide. Final Report. American Biogenics Corporation Study 450-1525, OTS 0515364, sponsored by the Methyl Bromide Panel. Anger, W.K., J.V. Setzer, J.M. Russo, W.S. Brightwell, R.G. Wait and B.L. Johnson. Neurobehavioral effects of methyl bromide inhalation exposures. Scand. J. Work Environ. Health. 7(Suppl. 4): 40-47. Anger, W.K., L. Moody, J. Burg, W.S. Brightwell, B.J. Taylor, J.M. Russo, et al. 1986. Neurobehavioral evaluation of soil and structural fumigators using methyl bromide and sulfuryl fluoride. Neurotoxicology. 7(3): 137-156. Bond, J.A., J.S. Dutcher, M.A. Medinsky, R.F. Henderson and L.S. Birnbaum. 1985. Disposition of [14C]methyl bromide in rats after inhalation. Toxicol. Appl. Pharmacol. 78: 259-267. Breslin, W.J., C.L. Zablotny, G.J. Brabley and L.G. Lomax. 1990. Methylbromide inhalation teratology study in New Zealand white rabbits. Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI. Study No. K-000681-033. OTS Number 8EHQ-1189-0844 S. Eustis, S.L., S.B. Haber, R.T. Drew and R.S.H. Yang. 1988. Toxicology and pathology of methyl bromide in F344 rats and B6C3F1 mice following repeated inhalation exposure. Fund. Appl. Toxicol. 11: 594-610. Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier. 1981. Testing of selected workplace chemicals for teratogenic potential. Scand. J. Environ. Health. 7(Suppl. 4): 66-75. Hastings, L. 1990. Sensory neurotoxicology: Use of the olfactory system in the assessment of toxicity. Neurotoxicol. Teratol. 12: 455-459. Herzstein, J. and M.R. Cullen. 1990. Methyl bromide intoxication in four field-workers during removal of soil fumigation sheets. Am. J. Ind. Med. 17: 321-326. Hurtt, M.E. and P.K. Working. 1988. Evaluation of spermatogenesis and sperm quality in the rat following acute inhalation exposure to methyl bromide. Fund. Appl. Toxicol. 10(3): 490-498. Hurtt, M.E., K.T. Morgan and P.K. Working. 1987. Histopathology of acute toxic responses in selected tissues from rats exposed by inhalation to methyl bromide. Fund. Appl. Toxicol. 9: 352-365. Hurtt, M.E., D.A. Thomas, P.K. Working, T.M. Monticello and K.T. Morgan. 1988. Degeneration and regeneration of the olfactory epithelium following inhalation exposure to methyl bromide: Pathology, cell kinetics, and olfactory function. Toxicol. Appl. Pharmacol. 94: 311-328. Irish, D.D., E.M. Adams, H.C. Spencer and V.K. Rowe. 1940. The response attending exposure of laboratory animals to vapors of methyl bromide. J. Ind. Hyg. Toxicol. 22(6): 218-230. Kato, N., S. Morinobu and S. Ishizu. 1986. Subacute inhalation experiment for methyl bromide in rats. Indust. Health. 24: 87-103. Medinsky, M.A., J.S. Dutcher, J.A. Bond, R.F. Henderson, J.L Mauderly, M.B. Snipes, et al. 1985. Uptake and excretion of [14C]methyl bromide as influenced by exposure concentration. Toxicol. Appl. Pharmacol. 78: 215-225. Morrissey, R.E., B.A. Schwetz, J.C. Lamb IV, M.D. Ross, J.L. Teague and R.W. Morris. 1988. Evaluation of rodent sperm, vaginal cytology, and reproductive weight data from National Toxicology Program 13-week studies. Fund. Appl. Toxicol. 11: 343-358. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of methyl bromide (CAS No. 74-83-9) in B6C3F1 mice (inhalation studies). NTP TR 385, NIH Publication No. 91-2840. Peer Review Draft. Reuzel, P.G.J., C.F. Kuper, H.C. Dreef-van der Meulen and V.M.H. Hollanders. 1987. Chronic (29-month) inhalation toxicity and carcinogenicity study of methyl bromide in rats. Report No. V86.469/221044. Netherlands Organization for Applied Scientific Research, Division for Nutrition and Food Research, TNO. EPA/OTS Document No. 86-8700001202. Reuzel, P.G.J., H.C. Dreef-van der Meulen, V.M.H. Hollanders, C.F. Kuper, V.J. Feron and C.A. van der Heijden. 1991. Chronic inhalation toxicity and carcinogenicity study of methyl bromide in Wistar rats. Fd. Chem. Toxic. 29(1): 31-39. Russo, J.M., W.K. Anger, J.V. Setzer and W.S. Brightwell. 1984. Neurobehavioral assessment of chronic low-level methyl bromide exposure in the rabbit. J. Toxicol. Environ. Health. 14: 247-255. Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery and D.W. Phelps. 1981. Teratologic assessment of butylene oxide, styrene oxide and methyl bromide. Battelle Pacific Northwest Laboratory, Richland, WA, for the National Institute for Occupational Safety and Health, Cincinnati, OH. U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide. Final Draft. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1987. Health Effects Assessment for Bromomethane. Final Draft. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Danse, L.H.D.C., F.L. van Velsen and C.A. Van der Heijden. 1984. Methylbromide: Carcinogenic effects in the rat forestomach. Toxicol. Appl. Pharmacol. 72: 262-271. Djalali-Behzad, G., S. Hussain, S. Osterman-Golker and D. Segerback. 1981. Estimation of genetic risks of alkylating agents. VI. Exposure of mice and bacteria to methyl bromide. Mutat. Res. 84(1): 1-10. Irish, D.D., E.M. Adams, H.C. Spencer and V.K. Rowe. 1940. The response attending exposure of laboratory animals to vapors of methyl bromide. J. Ind. Hyg. Toxicol. 22: 218-230. Kramers, P.G.N, C.E. Voogd, A.G.A.C. Knaap and C.A. Van der Heijden. 1985. Mutagenicity of methyl bromide in a series of short-term tests. Mutat. Res. 155(1-2): 41-47. Moriya, M., T. Ohta, K. Watanabe, T. Miyazawa, K. Kato and Y. Shirasu. 1983. Further mutagenicity studies on pesticides in bacterial reversion assay systems. Mutat. Res. 116(3-4): 185-216. NTP (National Toxicology Program). 1988. NTP technical report on the toxicology and carcinogenesis studies of bromomethane (CAS No. 74-96-4) in F344/N rats and B6C3F1 mice (inhalation studies). NIH Publication No. 89-2818. Peer Review Date: October 3, 1988. Rosenblum, I., A.A. Stein and G. Eisinger. 1960. Chronic ingestion by dogs of methyl bromide-fumigated food. Arch. Environ. Health. 1: 316-323. Schatzow, S. 1984. Memorandum to D. Clay, November 9, 1984. FXI-OTS-1184-0327. Supplement, Sequence D. Simmon, V.F. 1978. Structural correlations of carcinogenic and mutagenic alkyl halides. FDA Publ(US); (FDA-78-1046): 163-171. Simmon, V.F. 1981. Applications of the Salmonella/Microsome Assay. Short-Term Tests. Chem. Carcinog. p.\120-126. Simmon, V.F. and R.G. Tardiff. 1978. The mutagenic activity of halogenated compounds found in chlorinated drinking water. Water Chlorination: Environ. Impact Health Eff. Proc. Conf. 2: 417-431. Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. Dev. Toxicol. Environ. Sci. 2: 249-258. U.S. EPA. 1985. Chemical Hazard Information Profile. Draft Report. Methyl Bromide. Rev. Feb. 20, 1985. U.S. EPA, OTS, Washington, DC. U.S. EPA. 1986. Health and Environmental Effects Profile for Methyl Bromide. Final Draft. ECAO-CIN-P182, June, 1986. U.S. EPA. 1987. Health Effects Assessment for Bromoethane. Final Draft. ECAO-CIN-H090. June, 1987. Voogd, C.E., A.G.A.C. Knaap, C.A. Van der Heijden and P.G. Kramers. 1982. Genotoxicity of methylbromide in short-term assay systems. Mutat. Res. 97: 233. Wong, O., W. Brocker, H.V. Davis and G.S. Nagle. 1984. Mortality of workers potentially exposed to organic and inorganic brominated chemicals, DBCP, TRIS, PBB, and DDT. Br. J. Ind. Med. 41: 15-24. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Bromomethane CASRN -- 74-83-9 Primary Synonym -- Methyl bromide ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/30/1987 I.A.1. MF changed to UF -- no change in RfD 09/30/1987 I.A.2. Text changes 09/30/1987 I.A.3. Text changes 09/30/1987 I.A.4. Study descriptions added 09/30/1987 I.A.5. Text change 09/30/1987 I.A.6. Secondary contact changed 03/01/1988 I.A.1. Critical effect added 06/30/1988 I.A. Withdrawn; new RfD verified (in preparation) 09/26/1988 I.A. Oral RfD summary replaced 05/01/1989 II. Carcinogen assessment now under review 06/01/1989 II. Carcinogen summary on-line 06/01/1989 VI. Bibliography on-line 08/01/1989 VI.A. Oral RfD references added 10/01/1989 I.B. Inhalation RfD now under review 06/01/1990 I.A.2. Dosing clarified 06/01/1990 IV.F.1. EPA contact changed 08/01/1990 I.A. Text edited 08/01/1990 II. Text edited 08/01/1990 III.A. Health Advisory on-line 08/01/1990 VI.D. Health Advisory references added 07/01/1991 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 I.B. Inhalation RfC summary on-line 04/01/1992 VI.B. Inhalation RfC references added 05/01/1992 I.B.6. Deleted incorrect work group review date 10/01/1992 I.B.1. 'NOAEL' corrected to LOAEL 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 362 of 1119 in IRIS (through 2003/06) AN: 25 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0025-tr.pdf UD: 200110 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Chloroform- SY: 67-66-3; FORMYL-TRICHLORIDE-; FREON-20-; METHANE-TRICHLORIDE-; METHANE,-TRICHLORO-; METHENYL-CHLORIDE-; METHENYL-TRICHLORIDE-; METHYL-TRICHLORIDE-; NCI-CO2686-; R-20-; TCM-; TRICHLOROFORM-; TRICHLOROMETHANE- RN: 67-66-3 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200110 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chloroform CASRN -- 67-66-3 Last Revised -- 10/19/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: Traditional Approach. For comparison purposes, an RfD was developed using the traditional NOAEL/LOAEL approach. The results of this method are provided below. This is the same approach and RfD result reported on IRIS (01/13/87). SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Moderate/marked fatty cyst formation NOEL: none 1000 1 1E-2 in liver and elevated mg/kg/day SGPT LOAEL: 15 mg/kg/day Dog, Chronic Oral (converted to 12.9 Bioassay mg/kg/day) Heywood et al., 1979 ---------------------------------------------------------------------------- *Conversion Factors: 15 mg/kg/day x 6 days/7 days = 12.9 mg/kg/day PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Heywood, R; Sortwell, RJ; Noel, PRB; et al. (1979) Safety evaluation of toothpaste containing chloroform: III. Long-term study in beagle dogs. J Environ Pathol Toxicol 2:835-851. Heywood et al. (1979) exposed groups of eight male and eight female beagle dogs to doses of 15 or 30 mg chloroform/kg/day. The chemical was given orally in a toothpaste base in gelatin capsules, 6 days/week for 7.5 years. This was followed by a 20- to 24-week recovery period. Eight dogs of each sex served as an untreated group and a final group of 16 dogs (8/sex) received an alternative nonchloroform toothpaste (vehicle control). Four male dogs (one each from the low- and high-dose chloroform groups, the vehicle control group, and the untreated control group) and seven female dogs (four from the vehicle control group and three from the untreated control group) died during the study. In the low-dose group, levels of serum glutamate-pyruvate transaminase (SGPT, also known as alanine aminotransferase) were increased by an average of about 40% compared with control, with the effects being statistically significant from week 130 through week 364. In the high-dose group, SGPT levels tended to average about twice those in the control group, and the differences were statistically significant from week 6 throughout treatment. After 14 weeks of recovery, SGPT levels remained significantly increased in the high-dose group, but not in the low-dose group, when compared with the controls. After 19 weeks of recovery, SGPT levels were not significantly increased in either treated group when compared with the controls. The authors concluded that the increases in SGPT levels were likely the result of minimal liver damage. Serum alkaline phosphatase (SAP) and SGPT levels were also moderately increased (not statistically significant) in the treated dogs at the end of the treatment period when compared with the controls. Microscopic examinations were conducted on the major organs. The most prominent microscopic effect observed in the liver was the presence of "fatty cysts," which were described as aggregations of vacuolated histiocytes. The fatty cysts were observed in the control and treated dogs, but were larger and more numerous (i.e., higher incidence of cysts rated as "moderate or marked," as opposed to "occasional or minimal") in the treated dogs than in the control dogs at both doses. The prevalence of moderate or marked fatty cysts was 1/27 in control animals, 9/15 in low dose animals, and 13/15 in high dose animals. Nodules of altered hepatocytes were observed in both treated and control animals, and therefore were not considered related to treatment. No other treatment-related nonneoplastic or neoplastic lesions were reported for the liver, gall bladder, cardiovascular system, reproductive system, or urinary system. A NOAEL was not identified in this study. However, a LOAEL of 15 mg/kg/day was identified, based on elevated SGPT levels and increased incidence and severity of fatty cysts (U.S. EPA, 1998a). BENCHMARK DOSE (BMD) APPROACH Selection of Data Sets for Modeling The following data sets were selected for BMD modeling: - Incidence of fatty cysts in liver and SGPT levels of dogs (Heywood et al., 1979) - Histological evidence of renal cytotoxicity in male rats exposed via drinking water (Hard et al., 2000) - Increased labeling index in kidney of female mice exposed via drinking water (Larson et al., 1994b) - Increased labeling index in liver of female rats exposed via gavage in corn oil (Larson et al., 1995b) These studies were chosen because they all provide quantitative dose-response data for sensitive indicators of chloroform toxicity. BMD Modeling of Selected Data Sets The detailed results of the BMD model fitting are presented in Appendix B of the Toxicological Review of Chloroform. Within a data set, the preferred model was selected based on the quality of the model fit to the data. As seen, the kidney LI data set from Larson et al. (1994b) could not be adequately described by any of the continuous models. This is because even though the response was statistically significant, the magnitude of the response was small in comparison to normal variability, and the data did not form a smooth dose-response relationship (tending to first increase and then decrease as dose increased). The liver and kidney LI data sets from Larson et al. (1995b) were reasonably well fit by the Hill equation, with BMD values of 64-75 mg/kg/day. However, the software was not able to estimate a benchmark dose limit (BMDL) value in either case. The data sets from the studies by Hard et al. (2000) and by Heywood et al. (1979) were adequately fit by one or more of the dichotomous models, with the best fit being given by the log-logistic and the quantal-linear models, respectively. The preferred BMD of 70 mg/kg/day based on the renal cytotoxicity data of Hard et al. (2000) is similar to the BMD values derived for the LI data from Larson et al (1995b), but is significantly higher than the preferred BMD based on the incidence of fatty cysts in dogs (1.7 mg/kg/day) reported by Heywood et al. (1979). The basis for this marked difference in BMD between studies is not known, but the data suggest that liver toxicity in the dog is a more sensitive endpoint of chloroform toxicity than renal or liver cytotoxicity in rodents. Calculation of the BMD-Based RfD Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Moderate/marked fatty cyst formation BMDL10: 1.2 mg/kg/day 1000 1 1E-2 in liver and elevated (converted to 1.0 mg/kg/day SGPT mg/kg/day) Dog, Chronic Oral Bioassay Heywood et al., 1979 ---------------------------------------------------------------------------- The BMDL10 provided in the table represents the 95% confidence lower bound on the dose associated with a 10% extra risk based on the prevalence of animals with moderate to marked fatty cysts in liver and elevated SGPT. The value of the BMDL10 was calculated from the data of Heywood et al. (1979) using EPA's BMDS software Version 1.2. The value derived from the BMD modeling (1.2 mg/kg/day) was adjusted by a factor of 6/7 to account for exposure 6 days per week. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100 In the benchmark dose approach, an uncertainty factor (UF) of 10 was used to account for interspecies extrapolation, and a UF of 10 was used to protect sensitive subpopulations. In the NOAEL/LOAEL approach, an additional factor of 10 was used to account for extrapolation from a LOAEL to a NOAEL (total UF = 1,000). No additional factors were required to account for extrapolation from short term to long term (the study duration was 7.5 years) or to account for limitations in the database. MF = 1 No additional modifying factors (MFs) were considered necessary because there are no substantial concerns or limitations in the derivation of the RfD that are not accounted for in the UFs described above. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) In general, the NOAEL/LOAEL approach for derivation of an RfD is subject to a number of limitations, most of which are addressed by use of the BMD approach (U.S. EPA, 1995). Thus, the RfD based on the BMD approach is generally preferred, unless there are insufficient dose-response data to support derivation of a reliable BMD. In this case, the dose-response data set from the critical study (Heywood et al., 1979) is composed of only two doses plus a control group. This is considered to be a limitation, as the shape of the dose-response curve is difficult to define with only three values, especially when the lowest dose yields a response that is well above the benchmark response. Nevertheless, the data do yield curve fits of adequate quality, so the results of the BMD approach are considered preferable to the NOAEL/LOAEL approach. Note that, in this particular case, the two approaches (NOAEL/LOAEL and benchmark) yield equal RfD values. This is consistent, albeit coincidental, with the results from the default LOAEL/NOAEL method. Many other studies in animals support the conclusion that the liver and/or the kidney are the key target organs for chloroform-induced toxicity. Most of these studies have been performed in rats and mice, and most yield LOAEL values that are substantially higher than those observed in dogs. In a study conducted by Palmer et al. (1979), in which rats were administered daily oral doses of 60 mg chloroform/kg/day in a toothpaste vehicle, treatment-related effects included a decrease in plasma but not erythrocyte, cholinesterase in females, a decrease in liver weight in females, and a marginal but consistent and progressive retardation in weight gain in both sexes. The authors stated that although minor histological changes in the liver were noted, there was no evidence of severe fatty infiltration, fibrosis, or bile duct abnormalities in the livers of treated animals. The authors concluded that there was no evidence of treatment-related toxic effects in the liver. However, the "minor histopathological" changes in the liver were not described and the presence of any fatty infiltration that would be designated as less than severe was not reported. Therefore, these results could not be compared to those reported in the dog study. The LOAEL for this study was 60 mg/kg/day. A slight (2%-3% vs. 7%-8%) increase in moderate to severe fatty degeneration of the liver was seen in ICI mice given 60 mg but not 17 mg chloroform/kg/day in a toothpaste vehicle for 80 weeks (Roe et al., 1979). However, no effects were evident when the incidences of fatty and nonfatty liver degeneration were combined in the ICI or three other mice strains. No other noncancer effects attributable to chloroform were noted. A NOAEL of 17 mg/kg/day and a LOAEL of 60 mg/kg/day were identified from this study. No treatment-related noncancer effects were noted in rats administered chloroform in drinking water for 23 months at time-weighted average doses up to 160 mg/kg/day (Jorgenson et al., 1982, 1985). However, subsequent review of the histopathology slides from this study revealed evidence that chloroform produced a moderate to low level of renal proximal tubule injury associated with cell turnover indicative of cytotoxicity (Hard et al., 2000). These changes were noted in the high-dose (160 mg/kg) group males as early as 12 months but were increased in grade by 18 months. Similar changes were found in the mid-dose males (81 mg/kg), although at a lower grade, in the 18-month and 2-year dose groups. These changes were not seen in controls or the low-dose group. Therefore, the identified NOAEL for noncancer effects for this study is 38 mg chloroform/kg/day, with the LOAEL at 81 mg/kg/day. In mice exposed to chloroform in drinking water, mortality within the first 3 weeks was significantly increased in the two highest dose groups, 130 and 263 mg/kg/day, but was comparable with controls after that time (Jorgenson et al., 1982). Early mortality and behavioral effects (e.g., lassitude, lack of vigor) were apparently related to reduced water consumption among some treated mice in the two highest dose groups. A significant increase in liver fat in mice was noted at doses of 65 mg/kg/day and higher at 3 months, but only at doses of 130 and 263 mg/kg/day by 6 months. Liver fat content was not reported for any later time points or at terminal sacrifice; therefore, the relevance of this observation as an adverse effect rather than an adaptive response could not be assessed. No increased incidence of liver tumors was reported, and the presence or absence of nonneoplastic histopathological alterations was not described. These data indicate that doses of 130 to 263 mg/kg/day may produce adverse effects in mice; however, these effects may be secondary to decreased water consumption. Reproductive/developmental toxicity studies were also considered in the selection of the critical study/effect for the reference dose in the event the fetus represented a more sensitive population. These included studies in rats (Thompson et al., 1974), in rabbits (Thompson et al., 1974), and in mice (NTP, 1988). In the developmental studies in rabbits and rats, no treatment-related effects were noted when chloroform was administered by gavage in corn oil during gestation at doses of 50 mg/kg/day or less (Thompson et al., 1974). In the rabbit study, a clear dose-response was absent and the effects noted in offspring of dams administered chloroform at doses up to 50 mg/kg/day (the highest dose tested) on days 6 to 18 of gestation were not considered to be treatment-related (Thompson et al., 1974). In rats, the only effect noted was a significant reduction in fetal weight found only in offspring of dams given chloroform at the highest dose tested, 126 mg/kg/day, on days 6 to 15 of gestation (Thompson et al., 1974). No fetal effects attributed to chloroform treatment were noted in this rat study for the lower dose groups (up to 50 mg/kg/day during gestation). A NOAEL of 50 mg/kg/day was identified for both studies. In a two-generation reproductive study in mice, no significant effects were seen in any reproductive parameter assessed in either the parental or the F1 generations at doses up to 41 mg/kg/day administered by gavage in corn oil (NTP, 1988). Systemic toxicity was not evaluated in the parental generation. However, increased liver weights and liver lesions, described as mild to moderate degeneration of centrilobular hepatocytes accompanied by single-cell necrosis, were noted in F1 females, but not males, exposed both in utero and postnatally at a dose of 41 mg/kg/day. Postnatal exposure in the F1 generation began at postnatal day 22 and continued until the birth of the F2 generation (mice were mated at 64 to 84 days of age). The F1 offspring in the two lower dose groups, 6.6 and 16 mg/kg/day, were not evaluated histopathologically; therefore, no NOAEL or LOAEL could be definitively established for this study. A dose of 41 mg/kg/day may represent the LOAEL; however, the amount of in utero exposure was not estimated, nor was the contribution of in utero exposure to liver toxicity assessed. Because quantitative data were available only for the control and high-dose groups, the study was not selected for benchmark modeling. In the reproductive/developmental studies, both maternal toxicity and effects on the fetus or offspring occurred at doses higher than those that produced evidence of liver toxicity in the dog study. Therefore, these were not used as the critical study for derivation of the RfD. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0025-tr.pdf#page=55 CORD: ___I.A.5. CONFIDENCE IN THE ORAL RFD Study -- Medium Database -- Medium RfD -- Medium The overall confidence in this RfD assessment is medium. The database on noncancer effects in animals is extensive, and data are adequate to derive reliable dose-response curves for key endpoints. Confidence is not rated higher because data in humans are limited, and extrapolation from animals to humans (with an attendant uncertainty factor of 10) is required. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0025-tr.pdf#page=74 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2001 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA (2001). To review this appendix, exit to the toxicological review, Appendix A - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0025-tr.pdf#page=95 Other EPA Documentation -- U.S. EPA, 1994, 1997, 1998a-c, 2001 Agency Consensus Date -- 7/27/2001 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 200110 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Chloroform CASRN -- 67-66-3 Last Revised -- 10/19/2001 NORC: Not available at this time ============================================================================ UDCA: 200110 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chloroform CASRN -- 67-66-3 Last Revised -- 10/19/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under the 1986 U.S. EPA Guidelines for Carcinogen Risk Assessment, chloroform has been classified as Group B2, probable human carcinogen, based on "sufficient evidence" of carcinogenicity in animals (U.S. EPA, 1998a). Under the Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996; U.S. EPA, 1999), chloroform is likely to be carcinogenic to humans by all routes of exposure under high-exposure conditions that lead to cytotoxicity and regenerative hyperplasia in susceptible tissues (U.S. EPA, 1998a,b). Chloroform is not likely to be carcinogenic to humans by any route of exposure under exposure conditions that do not cause cytotoxicity and cell regeneration. This weight-of-evidence conclusion is based on: 1) observations in animals exposed by both oral and inhalation pathways which indicate that sustained or repeated cytotoxicity with secondary regenerative hyperplasia precedes, and is probably required for, hepatic and renal neoplasia; 2) there are no epidemiological data specific to chloroform and, at most, equivocal epidemiological data related to drinking water exposures that cannot necessarily be attributed to chloroform amongst multiple other disinfection byproducts; and 3) genotoxicity data on chloroform are essentially negative, although there are some scattered positive results that generally have limitations such as excessively high dose or with confounding factors. Thus, the weight-of-evidence of the genotoxicity data on chloroform supports a conclusion that chloroform is not strongly mutagenic, and that genotoxicity is not likely to be the predominant mode of action underlying the carcinogenic potential of chloroform. Although no cancer data exist for exposures via the dermal pathway, the weight-of-evidence conclusion is considered to be applicable to this pathway as well, because chloroform absorbed through the skin and into the blood is expected to be metabolized and to cause toxicity in much the same way as chloroform absorbed by other exposure routes. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0025-tr.pdf#page=74 , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0025-tr.pdf#page=55 HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. There are no epidemiological data attributing cancer to exposure to chloroform per se. Although there are some equivocal epidemiological data relating a weak association of drinking water exposures to bladder, rectal and colon cancer (Morris et al. 1992 ; McGeehin et al., 1993; Vena et al. 1993; Morris, 1995; King and Marrett, 1996; Doyle et al., 1997; Freedman et al., 1997; Cantor et al, 1998; Hildesheim et al., 1998), these studies can not attribute to chloroform among multiple other disinfection byproducts (DBPs) (SAB, 2000, ATSDR, 1997; IPCS, 2000). Morris et al. (1992) did a meta-analysis that pooled the relative risks from ten cancer epidemiology studies in which there was a presumed exposure to chlorinated water and its byproducts and estimated that approximately 10,000 cases of rectal and bladder cancer cases per year could be associated with exposure to DBPs in chlorinated water in the United States. Later, Poole (1997) reviewed the studies available to Morris et al. (1992) plus three additional studies (McGeehin et al., 1993; Vena et al., 1993; and King and Marrett, 1996). Poole (1997) observed that there was considerable heterogeneity among the data and that there was evidence of publication bias within the body of literature. In addition, Poole found that the aggregate estimates reported by Morris et al. were sensitive to small changes in the analysis (e.g., addition or deletion of a single study). Based on the observations, Poole recommended that the cancer epidemiology data considered in the Morris evaluation should not be combined into a single summary estimate and that the data had limited utility for risk assessment purposes. Based on the available cancer epidemiology database, bladder cancer studies provide the strongest evidence for an association between exposure to chlorinated water and cancer. Based on the studies of Cantor et al. (1985), McGeehin et al. (1993), King and Marrett (1996), Freedman et al. (1997), and Cantor et al. (1998), EPA calculated that the population attributable risk (the fraction of a disease that could be eliminated if the exposure of concern were eliminated) for bladder cancer ranged from 2% to 17% (U.S. EPA, 1998c). However, these calculations are based on a number of assumptions, including the assumption that there is a cause-effect relationship between exposure to chlorinated drinking water and increased risk of bladder cancer. This assumption is subject to considerable uncertainty, especially because findings are not consistent within or between studies. Evaluation of these studies by application of standard criteria for establishing causality from epidemiological observations (strength of association, consistency of findings, specificity of association, temporal sequence, dose-response relation, biological plausibility) has led EPA to conclude that the current data are insufficient to establish a causal relationship between exposure to chloroform and increased risk of cancer (U.S. EPA, 1998a). Moreover, if, in the future, the weight-of-evidence does reach a point where a causal link is established between exposure to chlorinated water and increased risk of bladder or other types of cancer, it could not be concluded from epidemiological studies of this type that chloroform per se is carcinogenic in humans, as chlorinated water contains numerous disinfection byproducts besides chloroform that are potentially carcinogenic (U.S. EPA, 1998a). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Adequate. At high doses, chloroform has been reported to be carcinogenic in several chronic animal bioassays, with significant increases in the incidence of liver tumors in male and female mice and significant increases in the incidence of kidney tumors in male rats and mice (U.S. EPA, 1994, 1998c). When examining the biology of the tumor production, the occurrence of tumors is demonstrably species-, strain-, and gender-specific, and has only been observed under dose conditions that caused cytotoxicity and regenerative cell proliferation in the target organ. In a gavage bioassay (NCI, 1976), Osborne-Mendel rats and B6C3F1 mice were treated with chloroform in corn oil 5 times/week for 78 weeks (50 animals per sex per dose group). Male rats received 90 or 125 mg/kg/day; females initially were treated with 125 or 250 mg/kg/day for 22 weeks and 90 or 180 mg/kg/day thereafter. A decrease in survival rate and weight gain was evident for all treated rats. A significant increase in kidney epithelial tumors was observed in male rats (0% in controls, 8% in the low dose and 24% in the high dose groups). Male mice received 100 or 200 mg/kg/day, raised to 150 or 300 mg/kg/day at 18 weeks; females were dosed with 200 or 400 mg/kg/day, raised to 250 or 500 mg/kg/day. Survival rates and weight gains were comparable for all groups except high dose female mice which had a decreased survival. In mice, highly significant increases in hepatocellular carcinomas were observed in both sexes (98% and 95% for males and females at the high dose; 36% and 80% for males and females at the low dose as compared with 6% of both matched and colony control males , 0% in matched control females and 1% in colony control females). Nodular hyperplasia of the liver was observed in many low dose male mice that had not developed hepatocellular carcinoma. Hepatomas have also developed in female strain A mice and NLC mice gavaged with chloroform (Eschenbrenner and Miller, 1945; Rudali, 1967). Jorgenson et al. (1985) administered chloroform (pesticide quality and distilled) in drinking water to male Osborne-Mendel rats and female B6C3F1 mice at concentrations of 200, 400, 900, and 1,800 mg/L for 104 weeks. These concentrations were reported by the author to correspond to 19, 38, 81, and 160 mg/kg/day for rats and 34, 65, 130, and 263 mg/kg/day for mice. The combined benign and malignant renal tumor incidence in male rats was 2%, 2%, 2%, 5%, 6% and 14% for the control, matched control, 19, 38, 81, and 160 mg/kg/day groups, respectively. A significant increase in renal tumors (14%) in rats was observed in the highest dose group (160 mg/kg/day). A reevaluation of the histopathology of the slides (Hard et al., 2000), found evidence of persistent cytotoxicity and regenerative hyperplasia in all rats of the highest dose group. Similar changes were also observed in rats at 81 mg/kg/day, but at a much lower incidence and grade. Thus, the histopathology reexamination provides evidence supporting chronic renal tubule injury as the mode of action underlying the renal tumor response. The liver tumor incidence in female mice was not significantly increased. Chloroform administered in toothpaste was not carcinogenic to male C57B1, CBA, CF-1, or female ICI mice or to beagle dogs. Male ICI mice administered 60 mg/kg/day were found to have an increased incidence of kidney epithelial tumors (Roe et al., 1979; Heywood et al., 1979). A pulmonary tumor bioassay in strain A/St mice was negative, as was one in which newborn C57X DBA2/F1 mice were treated s.c. on days 1 to 8 of life (Theiss et al., 1977; Roe et al., 1968). Matsushima (1994) exposed F344 rats (50/sex/group) and BDF1 mice (50/sex/group) to chloroform vapor 6 hours/day, 5 days/week for 104 weeks. Rats were exposed to concentrations of 0, 10, 30, or 90 ppm, and mice were exposed to 0, 5, 30, or 90 ppm. In order to avoid short- term lethality, mice in the two highest groups (30 and 90 ppm) were initially exposed to a lower levels for 2-6 weeks before the long-term exposure. The time-weighted average (TWA) for the 30 ppm group was 29.1 ppm and for the 90 ppm group was 85.7 ppm (U.S. EPA, 1998a). Statistically significant increases in the incidence of overall renal cell adenoma and renal cell carcinoma were observed in male mice in the 30 (7/50) and 90 (12/48) ppm groups, when compared to controls (0/50). The overall incidence rates of renal cell carcinoma were statistically significantly increased in males in the 90-ppm group (11/48) when compared to controls (0/50). There were no statistically significant findings reported for female mice in any exposure groups. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Mutagenicity Many studies have investigated the mutagenic potential of chloroform. However, there are several reasons these studies must be reviewed carefully and interpreted cautiously. For example, chloroform is relatively volatile, so test systems not designed to prevent chloroform escape to the air may yield unreliable results. Earlier studies in which appropriate P450-based metabolic activation systems were absent are also likely to be unreliable. Further, some older studies that used ethanol as a solvent or preservative for chloroform may be confounded by formation of ethyl or diethyl carbonate, which are potent alkylating agents. Another important issue is that studies that focused on clastogenicity endpoints using excessively high doses may be confounded by severe cytotoxicity, causing lysosomal or other releases (Brusick, 1986). In Vitro Studies Two investigators reported DNA binding in studies with calf thymus DNA in the presence of exogenous activation (DiRenzo et al., 1982; Colacci et al., 1991). The study by DiRenzo et al. (1982) used ethanol as a solvent, suggesting that ethyl carbonate formation might be a problem. In the study by Colacci et al. (1991), addition of SKF-525A inhibited DNA binding, suggesting that binding was mediated by a cytochrome P-450 mediated pathway, as would be expected for chloroform. In interpreting these studies, it is important to remember that cell-free systems may not always be a good model for intact cellular processes. Gene mutation studies in Salmonella typhimurium and E. coli (Ames assay), including tests done under conditions designed to reduce evaporation, are mostly negative, with or without activation with microsomes from liver or kidney of rats or mice (Rapson et al., 1980; San Agustin and Lim-Sylianco, 1978; Van Abbe et al., 1982; Uehleke et al., 1977; Gocke et al., 1981; Roland-Arjona et al., 1991; Le Curieux et al., 1995; Kirkland et al., 1981; Simmon et al., 1977). However, four studies have showed positive results in bacteria. Varma et al. (1988) reported that chloroform caused mutagenicity in five strains of S. typhimurium, but the response was noted only at the lowest dose tested, and all higher doses were not different from control. This unusual pattern casts some doubt on these results. San Agustin and Lim-Sylianco (1997) reported that chloroform caused DNA damage in Bacillus subtilis, and Wecher and Scher (1982) reported that chloroform caused mutations in Photobacterium phosphoreum. However, neither study reported the exposure concentrations that caused these effects, so the relevance of these reports is uncertain. In addition, the studies by Varma et al. (1988) and Wecher and Scher (1982) each used ethanol as a diluent, raising the possibility that the positive effect might be related to ethyl carbonate formation rather than to chloroform. The majority of results reported for S. typhimurium and E. coli exposed to the vapor phase were also negative (Van Abbe et al., 1982; Pegram et al., 1997; Simmon, 1977; Sasaki et al., 1998). Pegram et al. (1997) reported that chloroform was weakly positive at vapor concentrations greater than 19,200 ppm (about 770 mg/L in the aqueous phase). Employing physiologically based pharmacokinetic models, the authors estimated the oral doses needed to produce the effect would exceed 2,000 mg/kg (approximately twice the LD50). Tests of genotoxicity are also mainly negative in fungi (Gualandi, 1984; Mehta and von Borstel, 1981; Kassinova et al., 1981; Jagannath et al., 1981). However, chloroform was shown to induce intrachromosomal recombination in Saccharomyces cerevisiae at concentrations of 6,400 mg/L (Callen et al., 1980) or 750 mg/L (Brennan and Schiestl, 1998). In the Brennan and Schiestl study, addition of N-acetylcysteine reduced chloroform-induced toxicity and recombination, suggesting a free radical may have been involved. Chromosome malsegregation was also reported in Aspergillus nidulans (Crebelli et al., 1988), but only at concentrations above 1,600 mg/L. In all three of these positive studies, doses that caused positive results also caused cell death, indicating that exposures were directly toxic to the test cells. Studies in intact mammalian cells are mainly negative (Larson et al., 1994a; Perocco and Prodi, 1981; Butterworth et al., 1989; Kirkland et al., 1981; White et al., 1979; Sturrock, 1977), although positive results have been reported in a few systems. Increased sister chromatid exchange was reported in human lymphocytes at a concentration of about 1,200 mg/L without exogenous activation (Morimoto and Koizumi, 1983), and at a lower concentration (12 mg/L) with exogenous activation (Sobti, 1984). In the study by Sobti, the increase was quite small (less than 50%), and there was an increase in the number of cells that did not exclude dye. This suggests that the exposure levels that caused the mutagenic effect may have been directly toxic to the cells. In addition, ethanol was used as a dose vehicle. Mitchell et al. (1988) did not detect an increase in mutation in mouse lymphoma cells at an exposure level of 2,100 mg/L in the absence of exogenous activation, but did detect an effect at a concentration of 59 mg/L with exogenous activation. In Vivo Studies A number of different endpoints of chloroform genotoxicity have been measured in intact animals exposed to chloroform either orally or by inhalation. In studies of DNA binding in liver and kidney of mice and rats, negative results have been reported at doses of 742 mg/kg, 119 mg/kg, and 48 mg/kg (Diaz-Gomez and Castro, 1980; Reitz et al., 1982; Pereira et al., 1982). However, positive results have been reported at doses as low as 2.9 mg/kg (Colacci et al., 1991). But, in the study by Colacci et al. (1991), no significant difference in binding was noted between multiple tissues (liver, kidney, lung, and stomach), and there was no increase in binding with phenobarital pretreatment. This suggests the binding may not have been related to chloroform metabolism. Studies based on signs of DNA damage or repair have been uniformly negative (Larson et al., 1994a; Potter et al., 1996; Reitz et al., 1982; Mirsalis et al., 1982). However, studies based on various signs of chromosomal abnormalities have been mixed, with some studies reporting negative findings at doses of 371 mg/kg and 800 mg/kg (Shelby and Witt, 1995; Topham, 1980), while other studies report positive results at doses as low as 1.2 mg/kg (Fujie et al., 1990). However, the positive result at low dose in the study by Fujie et al. (1990) was observed following intraperitoneal exposure, and positive results following oral exposure were not observed until a dose level of 119 mg/kg. Morimoto and Koizumi (1983) observed an increase in the frequency of sister chromatid exchange in bone marrow cells at a dose of 50 mg/kg/day, but at 200 mg/kg/day, all of the mice died. As discussed before, mutagenicity results observed following highly toxic doses may have been confounded by cytotoxic responses and should be viewed as being of uncertain relevance. Several studies have reported negative findings for the micronucleus test in rats and mice (Gocke et al., 1981; Salamone et al., 1981; Le Curieux, 1995), but several other studies have detected positive results, mainly at exposure levels of 400-600 mg/kg (San Agustin and Lim-Sylianco, 1982; Robbiano et al., 1998; Sasaki et al., 1998; Shelby and Witt, 1995). This suggests that chloroform may be clastogenic, but it is important to note that these doses are well above the level that causes cytotoxicity in liver and kidney in most oral exposure studies in rodents. Butterworth et al. (1998) did not detect an increase in mutation frequency in male mice exposed by inhalation at an exposure level of 90 ppm, even though this exposure did cause an increase in tumors in the study by Nagano et al. (1998). Increased incidence of sperm head abnormalities was reported in mice exposed at 400 ppm (Land et al., 1981), but was not observed in mice exposed to 371 mg/kg intraperitoneally (Topham, 1980). In Drosophila melanogaster larvae exposed to chloroform vapor, gene mutation (Gocke et al., 1981) and mitotic recombination tests (Vogel and Nivard, 1993) were both negative. Grasshopper embryos (Melanoplus sanguinipes) did not display mitotic arrest at vapor concentrations of 30,000 ppm, but an effect was seen at 150,000 ppm (Liang et al., 1983). San Agustin and Lim-Syllianco (1981) reported a single positive and negative result for host- mediated mutagenicity in Salmonella typhimurium, but exposure levels were not reported in either case. On the basis of the in vitro and in vivo studies reviewed above, even though a role of mutagenicity cannot be completely ruled out, the majority of available studies are negative, and many of the positive studies have limitations (excessive doses or other confounding factors). Thus, the weight-of-evidence supports the conclusion that chloroform is not strongly mutagenic, and that genotoxicity is not likely to be the predominant mode of action underlying the carcinogenic potential of chloroform. This conclusion is supported by a number of other groups who have reviewed and evaluated the available data on chloroform genotoxicity, including the International Commission for Protection against Environmental Mutagens and Carcinogens (Lohman et al., 1992), ILSI (1997), Health Canada (2000), and WHO (1998). Mode of Action 1. Summary of Postulated Mode of Action Studies in animals reveal that chloroform can cause an increased incidence of kidney tumors in male rats and an increased incidence of liver tumors in male and female mice. Available data suggest that tumors are produced only at dose levels that result in cytotoxicity. These induced tumor responses are postulated to be secondary to sustained or repeated cytotoxicity and secondary regenerative hyperplasia. Chloroform's carcinogenic effects in rodent liver and kidney are attributed to oxidative metabolism-mediated cytotoxicity in the target organs. Although chloroform undergoes both oxidative and reductive cytochrome P450-mediated metabolism, it is the oxidative (CYP2E1) metabolic pathway that predominates at low chloroform exposures. This oxidative pathway produces highly tissue-reactive metabolites (in particular phosgene) that lead to tissue injury and cell death. It is likely that the electrophilic metabolite phosgene causes cellular toxicity by reaction with tissue proteins and cellular macromolecules as well as phospholipids, glutathione, free cysteine, histidine, methionine, and tyrosine. The liver and kidney tumors induced by chloroform depend on persistent cytotoxic and regenerative cell proliferation responses. The persistent cell proliferation presumably would lead to higher probabilities of cell mutation and subsequent cancer. The weight of the evidence indicates that a mutagenic mode of action via DNA reactivity is not a significant component of the chloroform carcinogenic process. 2. Identification of key events There are essentially three key steps in the sequence of events that lead to chloroform-induced tumorigenesis in the liver and kidneys of rodents. The first step is oxidative metabolism of chloroform in the target organs, kidney and liver. Numerous binding and metabolism studies (as described in ILSI, 1997, and U.S. EPA, 1998a) provide support that chloroform is metabolized by the oxidative cytochrome P450 (CYP2E1) pathway. This conclusion is supported by the study of Constan et al. (1999) in Sv/129 wild type, Sv/129 CYP2E1 null, and B6C3F1 mice. In the wild type of each strain, exposure to 90 ppm chloroform for 6 hours per day for 4 consecutive days resulted in severe hepatic and renal lesions along with increased cell proliferation. With the same exposure, neither the cytotoxicity nor cell proliferation occurred in the CYP2E1 null mouse or in the wild type of either strains treated with the P450 inhibitor ABT. Available evidence indicates that metabolism by CYP2E1 predominates at low exposures and is rate-limiting to chloroform's carcinogenic potential. Reductive metabolism, if it occurs, can lead to free radicals and tissue damage, but this pathway is absent or minor under normal physiological conditions. The next key step is the resultant cytotoxicity and cell death caused by the oxidative metabolites (with phosgene as the significant toxic intermediate). Regenerative cell proliferation follows the hepatotoxicity and nephrotoxicity as measured by labeling index in mouse kidney and liver and rat kidney from chloroform-treated animals. This increase in cell division is responsible for the increased probability of cancer. 3. Strength, consistency, specificity of association There are numerous cases where exposure to chloroform causes an increase in cytotoxicity (as evidenced by histopathological evaluation and/or increased labeling index) without any observable increase in cancer incidence. These data indicate that chloroform exposures that are adequate to cause cytotoxicity and regenerative cell proliferation do not always lead to cancer. However, there are no cases where a tumorogenic response has been observed in which evidence of cell regeneration is not also observed at the same or lower dose as that which caused an increase in tumors. This consistency of evidence (i.e., cell regeneration is detected in all cases of tumorigenicity) is strong evidence supporting the conclusion that cell regeneration is a mandatory precursor for tumorigenicity. Evidence for a link between sustained cytotoxicity/regenerative hyperplasia and cancer is strongest in the kidney. In male Osborne-Mendel rats exposed to chloroform in water for 2 years (Jorgenson et al., 1985), a statistically significant increase in renal tumors was observed at a concentration of 1,800 ppm (160 mg/kg/day). A re-analysis of the histopathological slides from this study (Hard et al., 2000) revealed evidence for sustained cytotoxicity and cell proliferation in the kidney at exposures of 900 ppm (81 mg/kg/day) or higher. Likewise, in BDF1 mice exposed to chloroform by inhalation at 5, 30, or 90 ppm for 6 hours/day, 5 days/week (Nagano et al., 1998), increased incidence of renal tumors was observed in male mice at the two higher doses, whereas females showed no significant tumor response. Templin et al. (1998) duplicated this exposure regimen in order to study whether the treatment caused cytotoxicity and regenerative hyperplasia. These authors observed cytotoxicity and hyperplasia in the kidneys of male mice exposed to 30 or 90 ppm throughout a 90-day exposure period, but not in females. This observation is consistent with the hypothesis that sustained cytotoxicity and regenerative hyperplasia are key events in the neoplastic response of the kidney to chloroform. Available data also indicate that cytotoxicity and regenerative hyperplasia are required for liver cancer, although the strength of this conclusion is somewhat limited because most of the observations are based on short-term rather than long-term histological or labeling index measurements. For example, in the B6C3F1 mouse, corn oil gavage (bolus dosing) at the same doses that resulted in liver tumors in the study by NCI (1976) also caused hepatic cytolethality and a cell proliferative response at both 4 days and 3 weeks (Larson et al., 1994b,c). Similarly, exposure of female B6C3F1 mice to chloroform in drinking water at levels that did not induce liver tumors (Jorgenson et al., 1985) also did not induce hepatic cytolethality or cell proliferation at 4 days or 3 weeks (Larson et al., 1994b). This consistency of the data (i.e., evidence of cytolethality and/or regenerative hyperplasia is always observed in cases of increased liver tumors) supports the conclusion that this liver cancer also occurs via a mode of action involving regenerative hyperplasia. 4. Dose-response relationship Chloroform-induced liver tumors in mice are only seen after bolus corn oil dosing. Mouse liver tumors are not found following administration by other routes (drinking water and inhalation). Rat liver tumors are not induced by chloroform following either drinking water or corn oil gavage administration. Kidney tumors are found in mice exposed to chloroform via inhalation or toothpaste preparations, and in rats when exposed via drinking water or corn oil gavage. Kidney and liver tumors develop only at doses that cause persistent cytotoxicity and regenerative proliferation, regardless of route of exposure or dosing regime. The overall dose-response for the cytotoxicity and cell proliferation responses is nonlinear. All key events and tumor effects depend on the dose-rate as shown by the difference in oil gavage versus drinking water administration (ILSI, 1997; U.S. EPA, 1998a). 5. Temporal relationship As noted above, there is very strong evidence from short-term and long-term histological and labeling index studies in mice and rats that cytotoxicity and cell proliferation always precede the occurrence of increased kidney or liver tumor effects in long-term bioassays. For example, a re-evaluation of serial sacrifice data from the chloroform 2-year drinking water bioassay in Osborne-Mendel rats revealed a linkage between toxicity in the renal tubules and tumor development and showed that renal toxicity preceded tumor development (Hard and Wolf, 1999; Hard et al., 2000). 6. Biological plausibility and coherence The theory that sustained cell proliferation to replace cells killed by toxicity, viral, or other insults such as physical abrasion of tissues can be a significant risk factor for cancer is plausible and generally accepted (Correa, 1996). It is logical to deduce that sustained cytotoxicity and regenerative cell proliferation may result in a greater likelihood of mutations being perpetuated with the possibility of more of these resulting in uncontrolled growth. It may also be that continuous stimulus of proliferation by growth factors involved in inflammatory responses increases the probability that damaged cells may slip through cell cycle check points carrying DNA alterations that would otherwise be repaired. Current views of cancer processes support both these possibilities. There are no data on chloroform that allow the events that occur during cell proliferation to be directly observed. A high proliferation rate alone is not assumed to cause cancer; tissues with naturally high rates of turnover do not necessarily have high rates of cancer and tissue toxicity in animal studies does not invariably lead to cancer. Nevertheless, regenerative proliferation associated with persistent cytotoxicity appears to be a risk factor of consequence. 7. Role of genotoxicity As noted above, the question whether chloroform or a metabolite is mutagenic has been tested extensively across different phylogenetic orders (i.e., bacterial, eukaryotic, and mammalian systems). Predominately negative results are reported in all test systems, with no pattern of mutagenicity seen in any one system considered to be a competent predictor. Positive results appear sporadically in the database, but they generally have problems with high dose or other confounding issues. ILSI (1997) considered results from 40 tests by the quantitative weight-of-evidence method for heterogeneous genetic toxicology databases from the International Commission for Protection against Environmental Mutagens and Carcinogens (ICEMC) (Lohman et al., 1992). This method scores relative DNA reactivity, with a maximum positive score being +100 and maximum negative -100. The maximum positive score obtained among 100 chemical databases has been +49.7 (triazaquone) and the maximum negative has been -27.7. The score for chloroform was -14.3. Testing of chloroform in the p53 heterozygous knockout mouse shows no tumor effect (Gollapudi et al., 1999). Heterozygous p53 males were dosed up to 140 mg/kg and females up to 240 mg/kg via corn oil gavage for 13 weeks. This model is known to respond most effectively to mutagenic carcinogens. Products of oxidative and reductive metabolism of chloroform are highly reactive. Such species are unstable and will likely react with cytoplasmic molecules before reaching nuclear DNA. Such reactive species (e.g., phosgene) have not been evaluated separately for genetic toxicity, and because of reactivity, would not be amenable to study and would not likely be able to transport from the cellular site of production to the nucleus. Comparative examination of both oxidative and reductive metabolism for structural analogues and chloroform has revealed that carbon tetrachloride, which is largely metabolized to a free radical via the reductive pathway, results in cell toxicity, not mutagenicity. Moreover, chloroform and carbon tetrachloride show very different patterns of liver toxicity (i.e., carbon tetrachloride's toxicity is more consistent with free radical production and chloroform's is not). For methylene chloride, glutathione conjugation results in mutagenic metabolites. When rat glutathione transferase gene copies are introduced into Salmonella, bromodichloromethane produces mutagenic metabolites; the fact that chloroform in this system did so only marginally and only at high toxic doses (Pegram et al., 1997) supports a conclusion that the reductive pathway does not contribute to chloroform's toxicity or carcinogenicity. In initiation-promotion studies, chloroform at the highest test dose of the drinking water bioassay does not promote development of hepatic lesions in rats or two strains of mice, nor does it initiate or act as a cocarcinogen. Administered in oil, chloroform was a promoter in the rat liver in initiation-promotion protocols. These results are more consistent with the postulated mode of action than with any mutagenic potential. 8. Effects on children The central questions asked in a mode of action analysis are, 1) whether the standard assumption that a mode of action observed in animals is relevant to humans holds true in a particular case, and 2) what the nature of the mode of action implies about the shape of the dose response relationship. In the case of chloroform the conclusions have been that the rodent mode of action can be assumed to be relevant to humans and that a nonlinear approach is most appropriate. The next question is whether the data lead one to anticipate similarities or differences in response by sex or age. Ideally, one would have adequate data to compare each of the key events of chloroform toxicity and subsequent carcinogenicity in tissues of adults with those of the developing fetus and young. This kind of information is currently not to be found. In the absence of data on the fetus and young specific to chloroform, an evaluation is made as to whether a cogent biological rationale exists for determining that the postulated mode of action is applicable to children (EPA, 1999). There is no suggestion from available studies of chloroform to indicate that children or fetuses would be qualitatively more sensitive to its effects than adults. The developing organism would not be expected to be particularly sensitive to cytotoxic agents at minimally toxic levels because cell division is proceeding rapidly and repair capacity at the molecular and cellular level is high. This is reflected by the relatively low incidence of spontaneous tumors in developing and young organisms. Moreover, the reproductive and developmental studies available, while they have limitations, show that fetal effects are seen only at doses at which maternal toxicity is evident. Research would be needed to further explore whether there are circumstances in which this relationship does not hold. Research would also be needed to discover whether there is some other mode of action, not seen in rodents, that might be possible. Presently, there are no clues from in vivo or in vitro studies as to what alternative mode of action might be considered. In keeping with traditional toxicologic evaluations, chloroform has been tested in lifetime studies with high level doses to provide maximal opportunities for toxicologic effects to manifest themselves in multiple tissues and organs through multiple mechanisms. In the absence of data to the contrary, this approach is considered to provide evidence for lack of potential for significant response, other than those noted, even for sensitive individuals and life stages. The mode of action analyzed as well as all other potential modes of action identified required that chloroform be metabolized by cytochrome P450 (CYP2E1) (SAB (2000), p.2). When this is considered along with the comparison of this enzyme activity between adults and the young there is confidence in assuming similarity in response among life stages. Further research on the processes of cell injury, death and regeneration would increase this confidence by addressing any uncertainty about potential quantitative similarity. The literature does not reveal any such quantitative data at present. Given the above, it is reasonable to assume that: 1) The reactive metabolite inside the cell should have similar effects by reacting with and disrupting macromolecules in the cells of fetuses, children and adults, 2) Cell necrosis and reparative replication are not likely to be qualitatively different in various stages in life, 3) Cancer risk to the fetus or children would be a function of cytotoxic injury, like in adults, and protecting these life stages from sufficient cytotoxicity to elicit this response should protect against cancer risks. Further research would be needed to assess whether there are significant quantitative differences between life stages which have not yet been elucidated. It can be noted that if data indicated that it were appropriate to apply a linear approach to part of a lifetime, such as the first 3 years of life, the resulting risk would be represented by a small increment of the total dose per body weight over a lifetime since most of a 70 year life is at an adult body weight. When this total is divided by 70 years to derive the lifetime average daily dose, the small increment of early dose does not significantly increase risk. 9. Conclusion regarding cancer mode of action The weight of the evidence supports the conclusion that chloroform-induced tumors in liver and kidney are produced only at dose levels that result in repeated or sustained cytotoxicity and regenerative cell proliferation. A wide range of evidence across different species, sexes, and routes of exposure implicates oxidative CYP2E1 metabolism leading to persistent cytotoxicity and regenerative cell proliferation as events that precede and are associated with tumor formation. The cytochrome P450 oxidative metabolism that leads to oxidative damage and ensuing cell growth, involving basic tissue responses to cellular toxicity and death, is common to humans and rodents. No data exist indicating that the mode of action observed in rodents is not also likely to apply to humans. Available data on the mutagenic potential of chloroform are mixed, but the majority of tests are negative, and some of the positive results are observed only at extreme exposure conditions. Thus, the weight of the evidence indicates that chloroform is not a strong mutagen and that neither chloroform nor its metabolites readily bind to DNA. On the basis of these results and the results of studies that evaluated other endpoints of mutagenicity, it seems likely that even though a role for mutagenicity cannot be excluded with certainty, chloroform does not produce carcinogenic effects primarily by a specific genotoxic mechanism. The proposed dose-response relationship for chloroform tumorigenesis by the cytotoxicity-regenerative hyperplasia mode of action will be nonlinear, as it is dependent on biochemical and histopathological events that are nonlinear. The dose-response assessment would ideally be based on use of phosgene dosimetry because it marks the rate-limiting step of oxidative metabolism. The toxicokinetic modeling to support this phosgene approach is not currently available, so the dose-response assessment is based on the tumor precursor event of cytotoxicity to project a level of exposure that will be protective against the key event of regenerative hyperplasia. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE In accord with proposed EPA guidelines for cancer risk assessment (U.S. EPA, 1996), the method used to characterize and quantify cancer risk from a chemical depends on what is known about the mode of action of carcinogenicity and the shape of the cancer dose-response curve for that chemical. A default assumption of linearity is appropriate when evidence supports a mode of action of gene mutation due to DNA reactivity, or another mode of action that is anticipated to be linear. The linear approach is used as a matter of policy if the mode of action of carcinogenicity is not understood. Alternatively, an assumption of nonlinearity is appropriate when there is no evidence for linearity and sufficient evidence to support an assumption of nonlinearity. In this case, the carcinogenicity may be a secondary effect of toxicity that itself is a threshold phenomenon (U.S. EPA, 1996). In the case of chloroform, the mode of action of carcinogenicity is reasonably well understood. Available data indicate that chloroform is not strongly mutagenic and chloroform is not expected to produce rodent tumors via a mutagenic mode of action (ILSI, 1997). Rather, there is good evidence that carcinogenic responses observed in animals are associated with regenerative hyperplasia that occurs in response to cytolethality (ILSI, 1997; U.S. EPA, 1998a,b). Because cytolethality occurs only at exposure levels above some critical dose level, a nonlinear approach is considered the most appropriate method for characterizing the cancer risk from chloroform. The Proposed Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 1996) state that when the mode-of-action analysis based on available data indicates that "the carcinogenic response is secondary to another toxicity that has a threshold, the margin-of-exposure analysis performed for toxicity is the same as is done for a noncancer endpoint, and an RfD for that toxicity may be considered in the cancer assessment." For chloroform, available evidence indicates that chloroform-induced carcinogenicity is secondary to cytotoxicity and regenerative hyperplasia; hence, the Agency relies on a nonlinear dose-response approach and the use of a margin-of-exposure analysis for cancer risk. The Agency has also chosen not to rely on a mathematical model to estimate a point of departure for cancer risk estimate, because the mode of action indicates that cytotoxicity is the critical effect and the reference dose value is considered protective for this effect. RfD and Margin of Exposure For more discussion of margin of exposure (MOE), see the Toxicological Review for Chloroform. Based on the kidney tumor of the drinking water study (Jorgenson et al., 1985), a point of departure (Pdp or LED10) of 23 mg/kg/day can be calculated using quantitative modeling of tumor dose-response data. Comparing the Pdp to the RfD of 0.01 mg/kg/day leads to a MOE of 2,000, which is considered large. Thus, in this case, the RfD for noncancer effect is also considered adequately protective of public health for cancer effects by the oral route, on the basis of the nonlinear dose response for chloroform and the mode of action for both cancer and noncancer effects having a common link through cytotoxicity. As discussed above, the RfD for noncancer effects is derived from the most sensitive endpoint in the most sensitive species. The RfD is based on fatty cysts formation (fat accumulation) in the liver and elevation of SGPT in dogs (Heywood et al., 1979). Hepatic fat accumulation and elevated SGPT are considered early signs of impaired liver function resulting from chloroform-induced cytotoxicity. This effect occurs at doses at or below those that cause increased labeling index, morphological changes, or cellular necrosis, so protection against this effect is believed to protect against cytolethality and regenerative hyperplasia. Accordingly, the RfD of 0.01 mg/kg/day presented in Section I.A.1 can be considered protective against increased risk of cancer. SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES A dose of 0.01 mg/kg/day (equal to the RfD) can be considered protective against cancer risk ____II.B.1.1. Oral Slope Factor -- Not applicable (see text). ____II.B.1.2. Drinking Water Unit Risk -- Not applicable (see text). DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Dose-response data used to derive the RfD for chloroform are presented in Section I.A.2. ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Because chloroform is a volatile chemical, exposure to chloroform in drinking water may occur not only via direct ingestion, but also by inhalation of chloroform released from household uses of water (showering, cooking, washing, etc.) into indoor air. Therefore, assessments of cancer and noncancer health effects from chloroform in water should account for exposures by all pathways, including oral, inhalation, and dermal. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Confidence in the cancer assessment for chloroform is rated as medium. This is based on a strong database in animals that supports the conclusion that cancer does not occur without antecedent cytotoxicity and regenerative hyperplasia, leading in turn to the conclusion that cancer risk is negligible at doses that do not result in cytotoxicity. Confidence in this conclusion is tempered by absence of direct studies in humans and by the finding that there are some positive results in studies on the mutagenicity of chloroform, even though the weight-of-evidence indicates that chloroform is not a strong mutagen and that a mutagenic mode of action is not likely to account for the cancer responses observed in animals. EPA is currently revising its guidelines for cancer risk assessment. Among other issues, EPA is looking closely at how to assess whether a postulated mode of action in adults is applicable to children. When the guidelines are final, EPA will consider their impact on existing health assessments on IRIS. __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE NOTE: The following evaluation of cancer risk from chloroform inhalation was developed in 1987 and does not incorporate newer data or the 1996 or 1999 draft cancer assessment guidelines. EPA is currently working to revise the assessment for inhalation exposure. ___II.C.1. SUMMARY OF RISK ESTIMATES ____II.C.1.1. Inhalation Unit Risk -- 2.3E-5 per (ug/cm3). ____II.C.1.2. Extrapolation Method -- Linearized multistage procedure, extra risk. Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) 4E+0 ug/cm3 E-5 (1 in 100,000) 4E-1 ug/cm3 E-6 (1 in 1,000,000) 4E-2 ug/cm3 ___II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure Tumor Type -- hepatocellular carcinoma Test Animals -- mouse, B6C3F1, female Route -- oral, gavage Reference -- NCI, 1976 DOSE Human Tumor Administered Equivalent Incidence (mg/kg/day) (mg/kg/day) Female 0 0 0/20 238 9.9 36/45 477 19.9 39/41 Male 0 0 1/18 138 6.2 18/50 277 12.5 44/45 ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) This inhalation quantitative risk estimate is based on data from a gavage study. Above doses are TWA; body weights at the end of the assay were 35 g for males and 28 g for females. Vehicle control animals were run concurrently and housed with test animals. All treated animals experienced decreased body weight gain. Survival was reduced in high-dose males and in all treated females. Experimental data for this compound support complete absorption of orally administered chloroform under conditions of this assay. There are no apparent species differences in this regard. Extrapolation of metabolism-dependent carcinogenic responses from mice to humans on the basis of body surface area is supported by experimental data. The incidence data for both male and female mice were used to derive slope factors of 3.3E-2 and 2.0E-1 per (mg/kg)/day, respectively. The unit risk was prepared by taking a geometric mean of the slope factor and assuming 100% for low doses of chloroform in air. The unit risk should not be used if the air concentration exceeds 400 ug/m3, because above this concentration the unit risk may not be appropriate. ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Adequate numbers of animals were treated and observed. Risk estimates derived from male rat kidney tumor data (2.4E-2) (NCI, 1976) and studies by Roe et al. (1979) (1.0E-1) are generally supportive of the risk estimate. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2001 (oral carcinogenicity assessment); U.S. EPA, 1985, 1987 (inhalation carcinogenicity assessment). This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of comments on the oral carcinogenicity assessment is included in an appendix to U.S. EPA (2001). To review this appendix, exit to the toxicological review, Appendix A - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0025-tr.pdf#page=95 RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date (oral carcinogenicity assessment) - 7/27/2001 Verification Date (inhalation carcinogenicity assessment) - 8/26/1987 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 200110 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Chloroform CASRN -- 67-66-3 Last Revised -- 10/19/2001 SORD: __VI.A. ORAL RFD REFERENCES Golden, RJ; Holm, SE; Robinson, DE; et al. (1997) Chloroform mode of action: implications for cancer risk assessment. Reg Toxicol Pharmacol 26:142-155. Hard, GC; Boorman, GA; Wolf, DC. (2000) Re-evaluation of the 2-year chloroform drinking water carcinogenicity bioassay in Osborne-Mendel rats supports chronic renal tubule injury as the mode of action underlying renal tumor response. Toxicol Sci 53:237-244. Heywood, R; Sortwell, RJ; Noel, PRB; et al. (1979) Safety evaluation of toothpaste containing chloroform: III. Long-term study in beagle dogs. J Environ Pathol Toxicol 2:835-851. Jorgenson, TA; Meierhenry, EF; Rushbrook, CJ; et al. (1985) Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice. Fundam Appl Toxicol 5:760-769. Jorgenson, TA; Rushbrook, CJ; Jones DCL. (1982) Dose-response study of chloroform carcinogenesis in the mouse and rat: Status report. Environ Health Perspect 46:141-149. Larson, JL; Sprankle, CS; Butterworth, BE. (1994a) Lack of chloroform-induced DNA repair in vitro and in vivo in hepatocytes of female B6C3F1 mice. Environ Mol Mutagen 23:132-136. Larson, JL; Wolf, DC; Butterworth, BE. (1994b) Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3F1 mice. Comparison of administration by gavage in corn oil vs. ad libitum in drinking water. Fundam Appl Toxicol 22:90-102. Nagano, K; Nishizawa, T; Yamamoto, S; et al. (1998) Inhalation carcinogenesis studies of six halogenated hydrocarbons in rats and mice. In: Advances in the prevention of occupational respiratory diseases. Chiyotani, K; Hosoda, Y; Aizawa, Y, eds. Elsevier Science B.V. National Toxicology Program (NTP). (1988) Chloroform reproduction and fertility assessment in CD-1 mice when administered by gavage. Report by Environmental Health Research and Testing, Inc., Lexington, KY to National Toxicology Program, NTP- 89-018. NTIS PB89-148639. Palmer, AK; Street, AE; Roe, FJC; et al. (1979) Safety evaluation of toothpaste containing chloroform: II. Long-term studies in rats. J Environ Pathol Toxicol 2:821-833. Pereira, MA; Lin, LC; Lippitt, JM; et al. (1982) Trihalomethanes as initiators and promoters of carcinogenesis. Environ Health Perspect 46:151-156. Reitz, RH; Fox, TR; Quast, JF. (1982) Mechanistic considerations for carcinogenic risk estimation: Chloroform. Environ Health Perspect 45:163-168. Roe, FJ; Palmer, AK; Worden, AN; et al. (1979) Safety evaluation of toothpaste containing chloroform: I. Long-term studies in mice. J Environ Pathol Toxicol 2:799-819. Salamone, MF; Heddle, JA; Katz, M. (1981) Mutagenic activity of 41 compounds in the in vivo micronucleus assay. In: Evaluation of short-term tests for carcinogens: Report of the international collaborative program. Prog Mutat Res 1:686-697. Templin, MV; Constan, AA; Wolf, DC; et al. (1998) Patterns of chloroform-induced regenerative cell proliferation in BDF1 mice correlate with organ specificity and dose-response of tumor formation. Carcinogenesis 19(1):187-193. Thompson, DJ; Warner, SD; Robinson, VB. (1974) Teratology studies on orally administered chloroform in the rat and rabbit. Toxicol Appl Pharmacol 29:348-357. Tsuchimoto, T; Matter, BE. (1981) Activity of coded compounds in the micronucleus test. In: evaluation of short-term test for carcinogens: report of the international collaborative program. Arch Toxicol 46:89-98. U.S. Environmental Protection Agency (U.S. EPA). (1994) Final draft for the drinking water criteria document on trihalomethanes. Prepared for Health and Ecological Criteria Division, Office of Science and Technology, Washington, DC. Under EPA Contract No. 68-C2-0139 by Clement International Corporation. April 8, 1994. U.S. EPA. (1995) Use of the benchmark dose approach in health risk assessment. EPA/630/R-94/007. U.S. EPA. (1997) Summary of new data on trihalomethanes (THMS) for the notice of availability. Draft. U.S. EPA. (1998a) Benchmark modeling of studies related to RfDs for trihalomethanes: Chloroform, bromodichloromethane, dibromochloromethane, and bromoform. Draft. Prepared by ICF Kaiser International. Washington, DC: Office of Water, Health Effects Criteria Division. June, 1998. U.S. EPA. (1998b) National primary drinking water regulations: disinfectants and disinfection byproducts. Notice of data availability; proposed rule. 40 CFR Parts 141-142:15674. U.S. EPA. (1998c) Health risk assessment/characterization of the drinking water disinfection byproduct chloroform. Prepared for Health and Ecological Criteria Division, Office of Science and Technology, Washington, DC. Prepared by Toxicology Excellence for Risk Assessment, Cincinnati, OH, under Purchase Order No. 8W-0767-NTLX. November 4, 1998. U.S. EPA. (2001) Toxicological review of chloroform in support of summary information on IRIS. Available online at www.epa.gov/IRIS. Back to top ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RFC REFERENCES Not applicable. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES ATSDR 1997. Toxicological Profile for Chloroform (Update). Agency for Toxic Substances and Disease Registry. Atlanta, GA. Brennan, RJ; Schiestl, RH. (1998) Chloroform and carbon tetrachloride induce intrachromosomal recombination and oxidative free radicals in Saccharomyces cerevisiae. Mutat Res 397:271-278. Butterworth, BE; Templin, MV; Constan, AA; et al. (1998) Long-term mutagenicity studies with chloroform and dimethylnitrosamine in female lacl transgenic B6C3F1 mice. Environ Mol Mutagen 31:248-256. Butterworth, B; Smith-Oliver, T; Earle, L; et al. (1989) Use of primary cultures of human hepatocytes in toxicology studies. Cancer Res 49:1075-108. Callen, DF; Wolf, CR; Philpot, RM. (1980) Cytochrome P-450 mediated genetic activity and cytotoxicity of seven halogenated aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutat Res 77:55-63. Cantor, KP; Hoover, R; Hartge, RP; et al. (1985) Drinking water source and bladder cancer: case-control study. In: Water chlorination chemistry, environmental impact and health effects. Vol. 5. Jolley, RL; Bull, RJ; Davis, WP; et al., eds. Chelsea MI: Lewis Publishers, Inc., pp. 145-152. Cantor, KP; Lunch, CF; Hildesheim, M; et al. (1998) Drinking water source and chlorination byproducts. I. Risk of bladder cancer. Epidemiology 9:21-28. Colacci, A; Bartolie, S; Bonora, B; et al. (1991) Chloroform bioactivation leading to nucleic acids binding. Tumori 77:285-290. Constan, AA; Sprankle, CS; Peters, JM; et al. (1999) Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. Toxicol Appl Pharmacol 160:120-126. Correa, P. (1996) Morphology and natural history of cancer precursors. In: Cancer epidemiology and prevention. Schottenfield, D; Fraumeni, JF, eds. New York: Oxford University Press. Crebelli, R; Benigni, R; Franekic, J; et al. (1988) Induction of chromosomes malsegregation by halogenated organic solvents in Aspergillus nidulans: unspecific or specific mechanism? Mutat Res 101:401-411. Diaz-Gomez, MI; Castro, JA. (1980) Covalent binding of chloroform metabolites to nuclear proteins: No evidence for binding to nucleic acids. Cancer Lett 9:213-218. DiRenzo, AB; Gandolfi, AJ; Sipes, IG. (1982) Microsomal bioactivation and covalent binding of aliphatic halides to DNA. Tox Lett 11:243-252. Doyle, TJ; Sheng, W; Cerhan, JR; et al. (1997) The association of drinking water source and chlorination by-products with cancer incidence among postmenopausal women in Iowa: a prospective cohort study. Am J Public Health 87:7. Eschenbrenner, AB; Miller, E. (1945) Induction of hepatomas in mice by repeated oral administration of chloroform, with observations on sex differences. J Natl Cancer Inst 5:251-255. Freedman, M; Cantor, KP; Lee, NL; et al. (1997) Bladder cancer and drinking water: a population-based case-control study in Washington County, Maryland (United States). Cancer Causes Control 8:738-744. Fujie, K; Aoki, T; Wada, M. (1990) Acute and subacute cytogenetic effects of the trihalomethanes on rat bone marrow cells in vivo. Mutat Res 242:111-119. Gocke, E; King, MT; Eckhardt, K; et al. (1981) Mutagenicity of cosmetics ingredients licensed by the European communities. Mutat Res 90:91-109. Gollapudi, BB; Yano, BL; Day, SJ; et al. (1999) Response of the transgenic P53+/- mouse 26-week carcinogenicity assay to chloroform. SOT, 1999 Annual Meeting, The Toxicologists, Abstract #1740, p. 369. Gualandi, G. (1984) Genotoxicity of the free-radical producers CCl4 and lipoperoxidation in Aspergillus nidulans. Mutat Res 136:109-114. Hard, GC; Wolf, DC. (1999) Re-evaluation of the chloroform 2-year drinking water bioassay in Osborne Mendel rats indicates that sustained renal tubule injury is associated with renal tumor development. Toxicol Sci 48 (1-S): Abstr 140, 30. Heywood, R; Sortwell, RJ; Noel, PRB; et al. (1979) Safety evaluation of toothpaste containing chloroform: III. Long-term study in beagle dogs. J Environ Pathol Toxicol 2:835-851. Hildesheim, ME; Cantor, KP; Lynch, CF; Dosemeci, M; Lubin, J; Alavanja, M; Craun, GF. (1998) Drinking water sources and chlorination byproducts: risk of colon and rectal cancers. Epidemiology 9(1):29-35. International Life Sciences Institute (ILSI). (1997) An evaluation of EPA's proposed guidelines for carcinogen risk assessment using chloroform and dichloroacetate as case studies: report of an expert panel. Washington, DC: ILSI Health and Environmental Sciences Institute. November, 1997. IPCS. (2000) International Programme on Chemical Safety. Environmental Health Criteria 216. Disinfectants and Disinfectant Byproducts. Geneva: WHO. Jagannath, DR; Vultaggio, DM; Brusick, DJ. (1981) Genetic activity of forty-two coded compounds in the mitotic gene conversion assay using saccharomyces cerevisiae strain D4. In: Evaluation of short-term tests for carcinogens; Report of the International Collaborative Program. Jorgenson, TA; Meierhenry, EF; Rushbrook, CJ; et al. (1985) Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice. Fundam Appl Toxicol 5:760-769. Kassinova, GV; Kovaltsova, SV; Marfin, SV; et al. (1981) Activity of 40 coded compounds in differential inhibition and mitotic crossing-over assays in yeast. Environmental Health Criteria 163. King, WD; Marrett, LD. (1996) Case control study of water sources and bladder cancer. Cancer Causes Control 7:596-604. Kirkland, DJ; Smith, KL; Van Abbe, NJ. (1981) Failure of chloroform to induce chromosome damage or sister chromatid exchanges in cultured human lymphocytes and failure to induce reversion in Escherichia coli. Food Cosmet Toxicol 19:651-656. Land, PC; Owen, EL; Linde, HW. (1981) Morphologic changes in mouse spermatozoa after exposure to inhalational anesthetics during early spermatogenesis. Anesthesiology 54:53-56. Larson, JL; Sprankle, CS; Butterworth, BE. (1994a) Lack of chloroform-induced DNA repair in vitro and in vivo in hepatocytes of female B6C3F1 mice. Environ Mol Mutagen 23:132-136. Larson, JL; Wolf, DC; Butterworth, BE. (1994b) Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3F1 mice. Comparison of administration by gavage in corn oil vs. ad libitum in drinking water. Fundam Appl Toxicol 22:90-102. Larson, JL; Wolf, DC; Butterworth, BE. (1994c) Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage. Fundam Appl Toxicol 23:537-543. LeCurieux, F; Gauthier, L; Erb, F; et al. (1995) Use of the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test to study the genotoxicity of four trihalomethanes. Mutagenesis 10:333-341 (as cited in U.S. EPA, 1998a). Liang, JC; Hsu, TC; Henry, JE. (1983) Cytogenetic assays for mitotic poisoning: The grasshopper embryo system for volatile liquids. Mutat Res 113:467-479 (as cited in U.S. EPA, 1994). Lohman, PHM; Mendelsohn, ML; Moore, DH II; et al. (1992) A method for comparing and combining short-term genotoxicity test data: the basic system. Mutat Res 266:7-25. Matsushima, T. (1994) Inhalation carcinogenesis study of chloroform. Letter summary from T. Matsushima (Japan Bioassay Laboratory) to A. Chiu (U.S. EPA), August 1994. McGeehin, MA; et al. (1993) Case-control study of bladder cancer and water disinfection methods in Colorado. Am J Epidemiol 138:492-501. Mehta, RD; Von Borstel, RC. (1981) Mutagenic activity of forty two encoded compounds in the haploid yeast reversion assay, strain XV18514C. In: Evaluation of short-term tests for carcinogens: Report of the International Collaborative Program. Prog Mutat Res 1:414-423. Mirsalis, J; Tyson, K; Butterworth, B. (1982) Detection of genotoxic carcinogens in the vivo-in vitro hepatocyte DNA repair assay. Environ Mutagen 4:553-562. Mitchell, A; Myhr, B; Rudd, C; et al. (1988) Evaluation of the L5178Y mouse lymphoma cell mutagenesis assay: Intra-laboratory results for sixty-three coded chemicals tested at SRI International. Environ Mol Mutagen 12(Suppl 13):37-101. Morimoto, K; Koizumi, A. (1983) Trihalomethanes induce sister chromatid exchanges in human lymphocytes in vitro and mouse bone marrow cells in vivo. Environ Res 32:72-79. Morris, RD; Audet, AM; et al. (1992). "Chlorination, chlorination byproducts, and cancer: a meta-analysis". Am J Public Health 82:955-63. National Academy of Sciences (NAS). (1987) Drinking water and health. Washington, DC: National Academy of Sciences. National Cancer Institute (NCI). (1976) Report on carcinogenesis bioassay of chloroform. Bethesda, MD: National Cancer Institute. Pegram, RA; Andersen, ME; Warren, SH; et al. (1997) Glutathione S-transferase mediated mutagenicity of trihalomethanes in Salmonella typhimurium: contrasting results with bromodichloromethane and chloroform. Toxicol Appl Pharmacol 144:183-188. Periera, MA; Lin, LC; Lippitt, JM; et al. (1982) Trihalomethanes as initiators and promoters of carcinogenesis. Environ Health Perspect 46:151-156. Perocco, P; Prodi, G. (1981) DNA damage by haloalkanes in human lymphocytes cultured in vitro. Cancer Lett 13:213-218. Poole, C (1997). Analytical meta analysis of epidemiological studies of chlorinated drinking water and cancer. Quantitative review of re-analysis of the work published by Morris et al., Am J Public Health 1992. 82:955-963. National Center for Environmental Assessment, Office of Research and Development, EPA, September 30, 1997 Potter, CL; Chang, LW; DeAngelo, AB; et al. (1996) Effects of four trihalomethanes on DNA strand breaks, renal hyaline droplet formation and serum testosterone in male F-344 rats. Cancer Lett 106:235-242 (as cited in U.S. EPA, 1998b). Rapson, WH; Nazar, MA; Butsky, W. (1980) Mutagenicity produced by aqueous chlorination of organic compounds. Bull Environ Contam Toxicol 24:590-596 (as cited in U.S. EPA, 1994). Reitz, RH; Fox, TR; Quast, JF. (1982) Mechanistic considerations for carcinogenic risk estimation: Chloroform. Environ Health Perspect 45:163-168. Ries, LAG; Smith, MA; Gurney, JG; Linet, M; Tamara, T; Young, JL; Bunin, GR, eds. (1999) Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. National Cancer Institute, SEER Program, NIH Pub. 99-4649. Bethesda, MD.Ref. VI.C. References. Robbiano, L; Meretoe, E; Migliazza Morando, A; et al. (1998) Increased frequency of micronucleated kidney cells in rats exposed to halogenated anaesthetics. Mutat Res 413:1-6. Roe, FJC; Carter, RL; Mitchley, BCV. (1968) Test of chloroform and AS-hydroxyquinoline for carcinogenicity using newborn mice. Br Emp Campgn 46:13. Roe, FJC; Palmer, AK; Worden, AN; et al. (1979) Safety evaluation of toothpaste containing chloroform: I. Long-term studies in mice. J Environ Pathol Toxicol 2:799-819. Roldlan-Arjona, T; Garcia-Pedrajas, MD; Luque-Romero, FL; et al. (1991) An association between mutagenicity of the ARA test of Salmonella typhimurium and carcinogenicity in rodents for 16 halogenated aliphatic hydrocarbons. Mutagen 6(3):199-205 Rudali, G. (1967) A propos de l'activate oncogene de quelques hydrocarbures halogens utilises en therapeutique. Springer Verlag 7:138-143. SAB, 2000. Science Advisory Board Review Report. See http://www.epa.gov/sab/fiscal00.htm. Salamone, MF; Heddle, JA; Katz, M. (1981) Mutagenic activity of 41 compounds in the in vivo micronucleus assay, in: Evaluation of short-term tests for carcinogens: report of the International Collaborative Program. Prog Mutat Res 1:686-697. San Agustin, J; Lim-Sylianco, CY. (1978) Mutagenic and clastogenic effects of chloroform. Bull Phil Biochem Soc 1:17-23. Sasaki, TM; Suzuki, K; Noda, T; et al. (1998) Mutagenicity study of carbon tetrachloride and chloroform with microbial mutagenicity test and rat liver micronucleus test. Abstract. P-018. J Toxicol Sci 23 (suppl. II):305. Shelby, MD; Witt, KL. (1995) Comparison of results from mouse bone marrow chromosome aberration and micronucleus tests. Environ Mol Mutagen 25:302-313 (as cited in U.S. EPA, 1998a). Simmon, VF; Kauhanen, K; Tardiff, RG. (1977) Mutagenic activity of chemicals identified in drinking water. In: Progress in genetic toxicology. Scott, D; Bridges, DA; Sobels, eds. Elsevier/North Holland: Biomedical Press, pp. 249-258. Sobti, RC. (1984) Sister chromatid exchange induction potential of the halogenated hydrocarbons produced during water chlorination. Chromo Info Serv 37:17-19. Sturrock, J. (1977) Lack of mutagenic effects of halothene or chloroform on cultured cells using the azaguanine test system. Br J Anaesth 49:207-210. Templin, MV; Constan, AA; Wolf, DC; et al. (1998) Patterns of chloroform-induced regenerative cell proliferation in BDF1 mice correlate with organ specificity and dose-response of tumor formation. Carcinogenesis 19(1):187-193. Theiss, JC; Stoner, GD; Shimkin, MB. (1977) Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice. Cancer Res 37:2717-2720. Topham, JC. (1980) Do induced sperm-head abnormalities in mice specifically identify mammalian mutagens rather than carcinogens? Mutat Res 74:379-387. Uehleke, H; Werner, T; Greim, H; et al. (1977) Metabolic activation of haloalkanes and tests in vitro for mutagenicity. Xenobiotica 7:393-400. U.S. EPA. (U.S. Environmental Protection Agency). (1994) Final draft for the drinking water criteria document on trihalomethanes. Prepared for Health and Ecological Criteria Division, Office of Science and Technology, Washington, DC. Under EPA Contract No. 68-C2-0139 by Clement International Corporation. April 8, 1994. U.S. EPA. (1996) Proposed guidelines for carcinogen risk assessment. Federal Register 61(79):17960-18011. U.S. EPA. (1998a) Health risk assessment/characterization of the drinking water disinfection byproduct chloroform. Prepared for Health and Ecological Criteria Division, Office of Science and Technology, Washington, DC, by Toxicology Excellence for Risk Assessment, Cincinnati, OH, under Purchase Order No. 8W-0767-NTLX. November 4, 1998. U.S. EPA. (1998b) National primary drinking water regulations: disinfectants and disinfection byproducts. Notice of data availability; proposed rule. 40 CFR Parts 141-142:15674. U.S. EPA. (1998c) National primary drinking water regulations: disinfectants and disinfection byproducts. Final Rule. Federal Register 63(241):69406-69407. Wed. Dec. 16, 1998. U.S. EPA. (1999) Guidelines for Carcinogenic Risk Assessment. Review Draft. July 1999. US Environmental Protection Agency, Risk Assessment Forum. U.S. EPA. (2001) Toxicological review of chloroform in support of summary information on IRIS. Available online at http://www.epa.gov/IRIS. Van Abbe, NJ; Green, TJ; Richold, M. (1982) Bacterial mutagenicity studies on chloroform in vitro. Food Chem Toxicol 20:557-561. Varma, MM; Ampy, FR; Verma, K; et al. (1988) In vitro mutagenicity of water contaminants in complex mixtures. J Appl Toxicol 8:243-248. Vena, JE; Graham, S; Freudenheim, JO; et al. (1993). Drinking water, fluid intake, and bladder cancer in Western New York. Archives of Environmental Health. 48:(3). Vogel, EW; Nivard, MJM. (1993) Performance of 181 chemicals in a Drosophila assay predominantly monitoring interchromosomal mitotic recombination. Mutagenesis 8:57-81. Wecher, RA; Scher, S. (1982) Bioassay procedures for identifying genotoxic agents using light- emitting bacteria as indicator organisms. In: Luminescent assays: perspectives in endocrinology and clinical chemistry. Seno M, Pazzagli M, eds. New York: Raven Press, pp. 109-113. White, AE; Takehisa, S; Eger, EI; et al. (1979) Sister chromatid exchanges induced by inhaled anesthetics. Anesthesiology 50:426-430 (as cited in U.S. EPA, 1994). World Health Organization (WHO). (1998) Guidelines for drinking-water quality. Second edition. Addendum to Volume 2. Health criteria and other supporting information. Chloroform. Geneva: World Health Organization, pp. 255-275. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Chloroform CASRN -- 67-66-3 Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. Dose conversion clarified 03/01/1988 I.A.2. LOAEL and RfD in text corrected 03/01/1988 I.A.4. Text revised 03/01/1988 I.A.5. Text revised 06/30/1988 II. Carcinogen summary on-line 06/30/1988 I.A.7. Primary contact changed 10/01/1989 I.B. Inhalation RfD now under review 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 02/01/1991 II.C.3. Information on extrapolation process included 02/01/1991 II.C.4. Text edited 03/01/1991 II.D.3. Primary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 07/01/1992 I.A. Clarify Schwetz citation 07/01/1992 VI.C. Oral RfD references on-line 07/01/1992 VI.C. Carcinogenicity assessment references on-line 09/01/1992 I.A.7. Primary contact changed 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III.,IV.,V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/10/1998 I.B. This chemical is being reassessed under the IRIS program 10/19/2001 I.A., VI Oral RfD and references updated 10/19/2001 II.B., VI Oral carcinogenicty assessment and references updated 01/08/2002 II.C.1 Corrected typographical error in units in inhalation unit risk. 03/26/2002 Tox. Review Corrected list of external peer reviewers. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 363 of 1119 in IRIS (through 2003/06) AN: 28 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0028-tr.pdf UD: 199809 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Chromium(III), insoluble salts SY: 16065-83-1; 7440-47-3; CHROMIC-ION-; CHROMIUM-; CHROMIUM- (III); CHROMIUM (III) ION; CHROMIUM,-ION- RN: 16065-83-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199809 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chromium(III), insoluble salts CASRN -- 16065-83-1 Last Revised -- 09/03/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ------------------ ------------------------------ -- -- --- No effects observed NOAEL: 5% Cr2O3 in diet 5 100 10 1.5E+0 days/week for 600 mg/kg-day feedings (1,800 g/kg bw average total dose) NOAEL(ADJ): 1,468 mg/kg-day LOAEL: none LOAEL(ADJ): none Rat chronic feeding study Ivankovic and Preussman, 1975 ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- 1,800 g Cr2O3/kg bw x 1,000 mg/g x 0.6849 g Cr/g Cr2O3/600 feeding days x 5 feeding days/7 days = 1,468 mg/kg-day. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Ivankovic, S; Preussmann, R. (1975) Absence of toxic and carcinogenic effects after administration of high doses of chromic oxide pigment in subacute and long-term feeding experiments in rats. Food Cosmet Toxicol 13:347-351. Groups of 60 male and female rats were fed chromic oxide (Cr2O3) baked in bread at dietary levels of 0, 1%, 2%, or 5%, 5 days/week for 600 feedings (840 total days). The primary purpose of this study was to assess the carcinogenic potential of Cr2O3. Body weight and food consumption were monitored. The average total amounts of ingested Cr2O3 were given as 360, 720, and 1,800 g/kg bw for the 1%, 2%, and 5% treatment groups, respectively. The animals were maintained on control diets following termination of exposure until they became moribund or died. All major organs were examined histologically. Other toxicologic parameters were not mentioned explicitly, but may have included some or all of those described for the accompanying subchronic study (see below). No effects due to Cr2O3 treatment were observed at any dose level. Ivankovic and Preussmann (1975) also treated rats (both sexes, 12-19 rats/group) at dietary levels of 0, 2%, or 5% Cr2O3 in bread, 5 days/week for 90 days. Food consumption and body weight were monitored. Toxicologic parameters included serum protein, bilirubin, hematology, urinalysis, organ weights, and histopathology. The only effects observed were reductions (12%-37%) in the absolute weights of the livers and spleens of animals in the high-dose group. Organ weights relative to body weight were not reported. The high dose is equivalent to 1,400 mg/kg-day (dose converted using reported data). Other subchronic oral studies show no indication of adverse effects attributable to trivalent chromium compounds, but dose levels were considerably lower. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100. The factor of 100 represents two 10-fold decreases in mg/kg bw-day dose that account for both the expected interhuman and interspecies variability to the toxicity of the chemical in lieu of specific data. MF = 10. An additional 10-fold modifying factor is applied to reflect database deficiencies including the lack of a study in a nonrodent mammal, lack of unequivocal data evaluating reproductive impacts, and the concern regarding potential reproductive effects raised by the study of Elbetieha and Al-Hamood (1997). The value of the modifying factor has not been changed from the previous IRIS entry. The study of Elbetieha and Al-Hamood (1997) provides strong support for the use of a 10-fold modifying factor to reflect uncertainty regarding potential reproductive effects of Cr(III). The following additional uncertainties relate to the NOAEL derived from the Ivankovic and Preussman (1975) study: 1) the effects observed in the 90-day study were not explicitly addressed in the 2-year study; 2) the effect of the vehicle (baked bread) on absorption of chromium is uncertain, and the relevance of this dosing regimen to exposures in the environment is unclear; 3) animals were allowed to die naturally after feeding stopped (2 years) and only then was histology performed. Application of the 100-fold uncertainty factor and 10-fold modifying factor to the adjusted NOAEL of 1,468 mg/kg-day gives the reference dose of 1.5 mg/kg-day. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) This RfD is limited to metallic chromium (III) of insoluble salts. Examples of insoluble salts include chromic III oxide (Cr2O3) and chromium (III) sulfate (Cr2[SO4]3). Trivalent chromium is an essential element that potentiates insulin action in peripheral tissue and is essential for lipid, protein, and fat metabolism in animals and human beings. Chromium deficiency causes changes in the metabolism of glucose and lipids and may be associated with maturity-onset diabetes, cardiovascular diseases, and nervous system disorders (Anderson, 1993, 1995). The National Research Council has identified an estimated safe and adequate daily dietary intake (ESADDI) for chromium of 50-200 ug/d (NRC, 1989), corresponding to 0.71-2.9 ug/kg/d for a 70 kg adult. FDA has selected a Reference Daily Intake for chromium of 120 ug/d (DHHS, 1995). Very limited data suggest that Cr(III) may have respiratory effects on humans (see Section I.B). No data on chronic or subchronic effects of inhaled Cr(III) in animals can be found. Adequate developmental toxicity data do not exist, and there are inadequate data on reproductive effects. Elbetieha and Al-Hamood (1997) reported impacts on fertility following high doses (2,000-5,000 ppm in the drinking water) of chromium chloride in mice; however, many of the observed effects did not occur in a clear dose-dependent fashion. The authors did not indicate the amount of water ingested by the animals, and only stated that water ingestion was reduced in the treatment groups relative to the controls. Zahid et al. (1990) fed mice trivalent chromium at concentrations of 100, 200, and 400 ppm for 35 days in food and reported ambiguous levels of degeneration in the outermost cellular layers of the seminiferous tubules, reduced spermatogonia per tubule, reduced sperm count, and increased percentage of morphologically abnormal sperms at all dose levels. Serious questions have been raised regarding the design and conduct of this study (Finley et al., 1993; NTP, 1996a,b, 1997). The methods utilized by Zahid et al. were considered to be insufficient to identify spermatogonia, likely generated nonreproducible counts of epididymal sperm, and resulted in the biologically implausible conclusion of reduction in spermatogonia numbers concurrent with unchanged spermatocyte and spermatid numbers. Additional questions have been raised with regard to the groupings of animals used and the statistical analysis of the data. The uncertainties preclude the use of the Elbetieha and Al-Hamood (1997) and Zahid et al. (1990) studies in the risk assessment for trivalent chromium. The 1998 IRIS assessment updates the previous RfD of 1E+0 mg/kg-day. For more details on other Hazard Identification Issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=29 CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Database -- Low RfD -- Low The overall confidence in this RfD assessment is low. The principal study is rated low because of the lack of explicit detail on study protocol and results. Low confidence in the database reflects the lack of high-dose supporting data. The low confidence in the RfD reflects the foregoing, but also reflects the lack of an observed effect level. Thus, the RfD, as given, should be considered conservative, since the MF addresses only those factors that might lower the RfD. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=33 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Trivalent Chromium in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=46. Other EPA Documentation -- U.S. EPA, 1984 Agency Consensus Date -- 04/28/1998 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Chromium(III), insoluble salts, conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (fax), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 199808 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Chromium(III), insoluble salts CASRN -- 16065-83-1 Last Revised -- 09/03/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Not available. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Not available. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) Not available. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) Data are considered to be inadequate for development of an RfC due to the lack of a relevant toxicity study addressing respiratory effects of Cr(III). Data from animal studies have identified the respiratory tract as the primary target of chromium toxicity following inhalation of hexavalent chromium and these data have been used for development of an RfC for hexavalent chromium particulates. However, these data do not demonstrate that the effects observed following inhalation of hexavalent chromium particulates are relevant to inhalation of trivalent chromium, and these data are considered to be inappropriate for development of an RfC for trivalent chromium. The following discussion of issues related to development of an RfC for Cr(III) has been added in 1998. Occupational exposure to trivalent chromium and other chromium compounds by inhalation has been studied in the chromate manufacturing and ferrochromium industries; however, exposures all include mixed exposures to both Cr(III) and Cr(VI). A number of epidemiological studies have demonstrated an association between inhalation of Cr(VI) and noncarcinogenic endpoints, including upper respiratory irritation and atrophy, changes in lung function, and renal toxicity. These studies have been used to support the development of an RfC for chromic acid mists (VI) and soluble chromates (VI). Data addressing exposures to Cr(III) alone are not available, and the occupational studies are considered to be unsuitable for development of an RfC for Cr(III). Several animal studies have been performed to assess the carcinogenic potential of Cr(III) by inhalation, either by natural routes, intrapleural injection, or intrabronchial implantation (Baetjer et al., 1959; Hueper and Payne, 1962; Levy and Venitt, 1975; Levy and Martin, 1983). These studies did not provide detailed reports of noncarcinogenic effects associated with inhalation exposure to Cr(III). Data from subchronic animal studies identify the respiratory tract as the primary target of chromium toxicity following inhalation. Johansson et al. (1986) exposed rabbits to aerosols of hexavalent (0.9 mg/m3 Na2CrO4) or trivalent (0.6 mg/m3 Cr(NO3)3) chromium for 5 days/week, 6 hours/day for 4 to 6 weeks. The number of macrophages obtained from the lungs of the rabbits exposed to Cr(VI) was significantly increased. While the numbers of macrophages from rabbits exposed to Cr(III) were not increased, striking morphological changes were observed, including round dark chromium-rich inclusions in the cytoplasm, an increased number of cells with a smooth inactive cell surface, enlarged Golgi apparatus, and a tendency toward elongated cell shape. The macrophages from rabbits exposed to Cr(VI) showed less marked morphological changes than those exposed to Cr(III). This study did not focus on endpoints that are considered suitable for development of an RfC for Cr(III). Johansson et al. (1980) exposed groups of four rabbits to chromium dust at concentrations of 3.1 mg/m3 and 0.6 mg/m3 for 5 days/week, 6 hours/day for 4 weeks. Macrophages collected from rabbits exposed to the higher concentration of chromium phagocytized significantly more chromium particles than the controls, though the number of nonviable macrophages was less than 3%. This study utilized small groups and did not focus on endpoints that are considered to be suitable for development of an RfC for Cr(III). Akatsuka and Fairhall (1934) exposed cats to chromium carbonate dust and found no effects in terms of gross or microscopic pathology upon termination of the experiment. Only two cats were exposed, however, and neither the doses nor the durations of exposure were precisely defined; therefore, these data cannot be used in quantitative risk assessment. For more details on other Hazard Identification Issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=29. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Not available. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=33. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 1998 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Chromium(III), insoluble salts, conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Trivalent Chromium in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=46. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 199809 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chromium(III), insoluble salts CASRN -- 16065-83-1 Last Revised -- 09/03/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY The following discussion of issues related to potential Cr(III) carcinogenicity has been updated in 1998. WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Applying the criteria for evaluating the overall weight of evidence for carcinogenicity to humans outlined in EPA's guidelines for carcinogen risk assessment (U.S. EPA, 1986), trivalent chromium is most appropriately designated a Group D -- Not classified as to its human carcinogenicity. Using the Proposed Guidelines for Carcinogen Risk Assessment (EPA, 1996), there are inadequate data to determine the potential carcinogenicity of trivalent chromium, as discussed below. However, the classification of hexavalent chromium as a known human carcinogen raises a concern for the carcinogenic potential of trivalent chromium. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=33 , For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=29 HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Occupational exposure to trivalent chromium and other chromium compounds by inhalation has been studied in the chromate manufacturing and ferrochromium industries; however, exposures all include mixed exposures to both Cr(III) and Cr(VI). The Cr(VI) species is the likely etiological agent in reports of excess cancer risk in chromium workers. Data addressing exposures to Cr(III) alone are not available, and data are inadequate for an evaluation of human carcinogen potential. Two oral studies located in the available literature (Schroeder et al., 1965; Ivankovic and Preussman, 1975) reported negative results for rats and mice. Several animal studies have been performed to assess the carcinogenic potential of Cr(III) by inhalation. These studies have not found an increased incidence of lung tumors following exposure either by natural routes, intrapleural injection, or intrabronchial implantation (Baetjer et al., 1959; Hueper and Payne, 1962; Levy and Venitt, 1975; Levy and Martin, 1983). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA The data from oral and inhalation exposures of animals to trivalent chromium do not support determination of the carcinogenicity of trivalent chromium. IARC (1990) concluded that animal data are inadequate for the evaluation of the carcinogenicity of Cr(III) compounds. Furthermore, although there is sufficient evidence of respiratory carcinogenicity associated with exposure to chromium, the relative contributions of Cr(III), Cr(VI), metallic chromium, or soluble versus insoluble chromium to carcinogenicity cannot be elucidated. In general, trivalent chromium was not mutagenic in bacterial assays when tested with or without a mammalian activation system (Venitt and Levy, 1974; Petrilli and Deflora, 1977, 1978a,b). In one study, trivalent chromium was mutagenic in Baccillus subtilis, but this activity was low compared with compounds of hexavalent chromium (Nakamuro et al., 1978). Taken together, these studies do not provide adequate data to support determination of the carcinogenicity of Cr(III), and a quantitative estimate of potential Cr(III) carcinogenicity has not been generated. ------------------------------------------------------------------------ CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Trivalent Chromium in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0028-tr.pdf#page=46 RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Not available. Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Chromium(III), insoluble salts, conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199809 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Chromium(III), insoluble salts CASRN -- 16065-83-1 Last Revised -- 09/03/1998 SORD: __VI.A. ORAL RfD REFERENCES Anderson, RA. (1993) Recent advances in the clinical and biochemical effects of chromium deficiency. Prog Clin Biol Res 380:221-234. Anderson, RA. (1995) Chromium and parenteral nutrition. Nutr 11(1 suppl.):83-86. Elbetieha, A; Al-Hamood, MH. (1997) Long-term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility. Toxicology 116:19-47. Finley, BL; Johnson, EM; Holson, JF. (1993) Comment on "Comparative effects of trivalent and hexavalent chromium on spermatogenesis of the mouse." Toxicol Env Chem 39:133-137. Ivankovic, S; Preussman, R. (1975) Absence of toxic and carcinogenic effects after administration of high doses of chromic oxide pigment in subacute and long-term feeding experiments in rats. Food Cosmet Toxicol 13(3):347-351. National Research Council (NRC). (1989) Recommended dietary allowances. 10th ed. Washington, DC: National Academy of Sciences, 241-243. National Toxicology Program (NTP). (1996a) Final report. Potassium dichromate (hexavalent): The effects of potassium dichromate on Sprague-Dawley rats when administered in the diet. December 13, 1996. NTP. (1996b) Final report. Potassium dichromate (hexavalent): the effects of potassium dichromate in BALB/c mice when administered in the diet. November 27, 1996. NTP. (1997) Final report. Potassium dichromate (hexavalent): reproductive assessment by continuous breeding when administered to BALB/c mice in the diet. February 18, 1997. U.S. Department of Health and Human Services (DHHS), Food and Drug Administration. (1995, Dec. 28) Food labeling: reference daily intakes, final rule. 21 CFR Part 101. Federal Register 60(249):67164-67175. U.S. Environmental Protection Agency (EPA). (1984) Health effects assessment for trivalent chromium. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA, for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. (1998) Toxicological review of trivalent chromium. Available online at http://www.epa.gov/iris. Zahid, ZR; Al-Hakkak, ZS; Kadhim, AHH; et al. (1990) Comparative effects of trivalent and hexavalent chromium on spermatogenesis of the mouse. Toxicol Environ Chem 25:131-136. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Akatsuka, K; Fairhall, J. (1934) The toxicology of chromium. J Ind Hyg 16:1-24 (cited in U.S. EPA, 1983b). Baetjer, AM; Lowney, JF; Steffee, H; et al. (1959) Effect of chromium on incidence of lung tumors in mice and rats. Arch Ind Health 20:124-135 (cited in U.S. EPA, 1983b). Hueper, WC; Payne, WW. (1962) Experimental studies in metal carcinogenesis--chromium, nickel, iron, arsenic. Arch Environ Health 5:445-462 (cited in U.S. EPA, 1983b). Johansson, A; Lundborg, M; Hellstrom, P; et al. (1980) Effect of iron, cobalt, and chromium dust on rabbit alveolar macrophages: a comparison with the effects of nickel dust. Environ Res 21:165-176. Levy, LS; Venitt, S. (1975) Carcinogenic and mutagenic activity of chromium-containing materials. Br J Cancer 32:254-255 (cited in U.S. EPA, 1983b). Levy, LS; Martin, PA. (1983) The effects of a range of chromium-containing materials on rat lung. Dye Color Manufacturers Association. U.S. EPA. (1989) Interim methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066F. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066F. U.S. EPA. (1998) Toxicological review of trivalent chromium. Available online at http://www.epa.gov/iris/. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Akatsuka, K; Fairhall, J. (1934) The toxicology of chromium. J Ind Hyg 16:1-24 (cited in U.S. EPA, 1983b). Baetjer, AM; Lowney, JF; Steffee, H; et al. (1959) Effect of chromium on incidence of lung tumors in mice and rats. Arch Ind Health 20:124-135 (cited in U.S. EPA, 1983b). Hueper, WC; Payne, WW. (1962) Experimental studies in metal carcinogenesis--chromium, nickel, iron, arsenic. Arch Environ Health 5:445-462 (cited in U.S. EPA, 1983b). International Agency for Research on Cancer (IARC). (1990) IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans: some metals and metallic compounds. Lyon, France: World Health Organization, IARC. Ivankovic, S; Preussman, R. (1975) Absence of toxic and carcinogenic effects after administration of high doses of chromic oxide pigment in subacute and long-term feeding experiments in rats. Food Cosmet Toxicol 13(3):347-351. Lees, PSJ; Gibb, HJ; Rooney, BC. (1995) Derivation of exposure-response relationship for chromium from historic exposure data. 11th International Symposium of Epidemiology in Occupational Health, the Netherlands, September 1995. Levy, LS; Venitt, S. (1975) Carcinogenic and mutagenic activity of chromium-containing materials. Br J Cancer 32:254-255. Levy, LS; Martin, PA. (1983) The effects of a range of chromium-containing materials on rat lung. Dye Color Manufacturers Association. Nakamuro, K; Yoshikawa, K; Sayato, Y; et al. (1978) Comparative studies of chromosomal aberration and mutagenicity of trivalent and hexavalent chromium. Mutat Res 58:175-181. Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagenicity of hexavalent chromium on Salmonella typhinurium. Appl Environ Microbiol 33:805-809. Petrilli, FL; DeFlora, S. (1978a) Oxidation of inactive trivalent chromium to the mutagenic hexavalent form. Mutat Res 58:167-178. Petrilli, FL; DeFlora, S. (1978b) Metabolic deactivation of hexavalent chromium mutagenicity. Mutat Res 54:139-147. Schroeder, HA; Balassa, JJ; Vinton, WH, Jr. (1965) Chromium, cadmium and lead in rats: effects on lifespan, tumors, and tissue levels. J Nutr 86:51-66. U.S. EPA. (1984) Health effects assessment for trivalent chromium. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA, for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. (1986, Sept. 24) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34003. U.S. EPA. (1996, April 23) Proposed guidelines for carcinogen risk assessment. Federal Register 61(79):17960-18011. U.S. EPA. (1998) Toxicological review of trivalent chromium. Available online at http://www.epa.gov/iris/. Venitt, S; Levy, LS. (1974) Mutagenicity of chromates in bacteria and its relevance to chromate carcinogenesis. Nature 250:493-495. ============================================================================ HIST: _VII. REVISION HISTORY Chromium(III), insoluble salts CASRN -- 16065-83-1 Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. Critical effect added 03/01/1988 III.A. Health Advisory added 08/01/1989 VI. Bibliography on-line 08/01/1990 IV.F.1. EPA contact changed 10/01/1990 I.B. Inhalation RfC now under review 11/01/1990 III.A. Full Health Advisory summary added 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 05/01/1992 II. Carcinogenicity assessment now under review 09/01/1994 File File name changed to include "insoluble salts" 08/01/1995 I.B., II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 09/03/1998 I., II., VI. Revised RfD, RfC, carcinogenicity sections, refs. 12/03/2002 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 364 of 1119 in IRIS (through 2003/06) AN: 35 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199502 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Decabromodiphenyl-ether- (DBDPE) SY: 1163-19-5; BENZENE, 1,1'-OXYBIS(2,3,4,5,6-PENTABROMO-; BERKFLAM-B-10E-; BR-55N-; BROMKAL-83-10DE-; BROMKAL-82-ODE-; DBDPE-; DBDPO-; DE-83R-; DECABROMOBIPHENYL-ETHER-; DECABROMOBIPHENYL-OXIDE-; DECABROMODIPHENYL-ETHER-; DECABROMODIPHENYL-OXIDE-; DECABROMOPHENYL-ETHER-; ETHER, BIS(PENTABROMOPHENYL); ETHER,-DECABROMODIPHENYL-; FR-300-; FR-300BA-; FRP-53-; NCI-C55287-; PENTABROMOPHENYL-ETHER-; SAYTEX-102-; SAYTEX-102E-; TARDEX-100- RN: 1163-19-5 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199502 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Decabromodiphenyl ether (DBDPE) CASRN -- 1163-19-5 Last Revised -- 02/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- No adverse effects NOEL: 1.0 mg/kg/day 100 1 1E-2 observed mg/kg/day LOAEL: none Rat Chronic Oral Bioassay Kociba et al., 1975 Liver enlargement NOEL: 8 mg/kg/day Rat Subchronic LOAEL: 80 mg/kg/day Oral Bioassay Norris et al., 1973, 1975 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Kociba, R.J., L.O. Frauson, C.G. Humiston, et al. 1975. Results of a two-year dietary feeding study with decabromodiphenyl oxide (DBDPO) in rats. J. Combust. Toxicol. 2: 267-285. Norris, J.M., J.W. Ehrmantraut, C.L. Gibbons, et al. 1973. Toxicological and environmental factors involved in the selection of decadibromophenyl oxide as a fire retardant chemical. Appl. Polym. Symp. 22: 195-219. Norris, J.M., R.J. Kociba, B.A. Schwetz, et al. 1975. Toxicology of octabromobiphenyl and decabromodiphenyl oxide. Environ. Health Perspect. 11: 153-161. Kociba et al. (1975) treated Sprague-Dawley (Spartan) rats (25/sex/dose) with daily doses (in the diet) of 0.0, 0.01, 0.1, and 1.0 mg decabromodiphenyl ether (oxide)/kg bw for 2 years. Parameters examined were hematology, clinical chemistry, food consumption, organ weight, body weight, and incidence of histopathologic lesions. No significant differences between treatment and control groups were found. The NOEL for this study was 1.0 mg/kg/day. Norris et al. (1973, 1975) reported on earlier stages of the same study. Supporting data are reported by Norris et al. (1973, 1975) in a 30-day oral study, in which male rats were administered decabromodiphenyl ether (DBDPE) at dietary concentrations of 0, 0.01, 0.1, or 1.0%. These concentrations correspond to doses of 0, 8, 80, or 800 mg/kg/day. A NOEL for enlarged livers of 8 mg/kg/day was established. This short-term-to-subchronic NOEL is close to the chronic NOEL of 1.0 mg/kg/day when adjusted by a factor of 10 to account for the uncertainty in extrapolating subchronic dose to chronic dose. The chemical analysis of the DBDPE used in these studies was reported as follows (Kociba et al., 1975): DBDPE, 77.4%; nonabromodiphenyl ether (NBDPE), 21.8%; and octabromodiphenyl ether (OBDPE), 0.8%. The presence of OBDPE in this mixture has an uncertain effect on the toxicity of DBDPE, since information on the mechanism of toxicity of DBDPE is lacking. An RfD of 0.00062 mg/kg/day has been proposed for OBDPE based on its liver enzyme reducing capabilities (U.S. EPA, 1984). No RfD has been proposed for NBDPE because of lack of data. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The 100-fold factor reflects both the expected intra- and interspecies variability to the toxicity of this chemical in lieu of specific data. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Absorption and subsequent toxicity of this compound may be highly dependent on the relative proportions of water and oils in the diet because of the chemical's physical properties (low aqueous solubility and varied crystal size). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The principal study was well-conducted with a sufficient number of animals and toxicity parameters, but lacked an adequate dose range. The supporting in-house study, which established the LOAEL, was very short in duration. Since no other data pertaining to the chronic toxicity of DBDPE were found in the available literature, confidence in the data base is rated low. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1984 The ADI in the 1984 Health and Environmental Effects Profile has received an Agency review with the help of two external scientists. Other EPA Documentation -- None Agency Work Group Review -- 10/09/1985 Verification Date -- 10/09/1985 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Decabromodiphenyl ether (DBDPE) CASRN -- 1163-19-5 NORC: Not available at this time. ============================================================================ UDCA: 199001 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Decabromodiphenyl ether (DBDPE) CASRN -- 1163-19-5 Last Revised -- 01/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Based on no human data and limited evidence of carcinogenicity in animals; namely, significantly increased incidences of neoplastic liver nodules in male and female rats and increased incidences of hepatocellular adenomas or carcinomas (combined) in male mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. Groups of 50 male and 50 female F344-N rats and 50 male and 50 female B6C3F1 mice were given diets containing 0, 25,000, or 50,000 ppm commercial-grade compound (94-97% pure) for 103 weeks. Average daily dosages estimated from food consumption data were 1120 and 2240 mg/kg for low- and high-dose male rats; 1200 and 2550 mg/kg for low- and high-dose female rats; 3200 and 6650 mg/kg for low- and high-dose male mice; and 3760 and 7780 mg/kg for low- and high-dose female mice (NTP, 1985). Rats and mice were maintained without treatment for an additional 1 and 0-1 weeks, respectively, and then sacrificed. Survival of the low-dose male rats was significantly lower than controls after week 102; however, since no reduced survival was observed in any other group and the decrease was observed so late in the study, the authors concluded that the effect on survival may not have been compound related. The incidences of liver neoplastic nodules in low- and high-dose male rats (7/50 and 15/49, respectively) and high-dose female rats (9/50) were significantly greater than in controls (1/50 in both males and females). Incidences of hepatocellular carcinoma alone (1/50, control males; 1/50, low-dose males; 1/49, high-dose males; 0/50, control females; 2/49, low-dose females; 0/50, high-dose females) were not significantly increased in the treated groups compared to controls. A dose-related trend for mononuclear cell leukemia was observed in treated male rats; however, because of the high incidence in control animals, this was not considered to be biologically significant. No evidence of carcinogenicity was observed in female mice, although there was some indication that cancer incidence had increased in male mice. Hepatocellular adenomas or carcinomas (combined) occurred at a significantly increased incidence in low-dose male mice (control, 8/50; low dose, 22/50; high dose, 18/50) after correction for survival. The incidence of hepatocellular carcinomas alone was not significant in either the low- or high-dose male mice. Treatment-related effects on body weight or clinical signs of toxicity or survival were not observed in any dose group. A high mortality of control male mice during the first year of the study, presumably due to fighting weakens the evidence of carcinogenicity in male mice. Thyroid gland follicular cell adenomas or carcinomas (combined) also occurred in treated male mice, but the increases were not significant (control, 0/50; low dose, 4/50; high dose, 3/50). The incidence of follicular cell hyperplasia in male mice was significantly increased. Group of 25 male and 25 female Sprague-Dawley rats were given decabromodiphenyl oxide in the diet at dose levels of 0, 0.01, 0.1, or 1.0 mg/kg/day for 2 years (Kociba et al., 1975; Norris et al., 1973, 1975). The sample used contained 77.4% decabromodiphenyl oxide, 21.8% nonabromodiphenyl oxide and 0.8% octabromodiphenyl oxide. Histological examinations conducted on rats that died during the study and on those sacrificed at termination (day 702 for males and day 735 for females) did not reveal any treatment-related neoplastic effects as indicated by numbers of rats that developed tumors, total numbers of tumors, specific types of tumors or combined male and female data. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The commercial-grade compound used in the NTP (1985) carcinogenicity study was not mutagenic in Salmonella typhimurium strains TA1535, TA1537, TA98, or TA100 with or without rat or hamster liver enzyme preparations (NTP, 1985). Doses ranged from 100 to 10,000 /g/plate. Mutagenicity was not detected in the mouse lymphoma L5178Y/TK+/-assay with or without rat liver enzyme preparations at doses of 7 to 10 /g/mL (NTP, 1985). Sister chromatid exchanges or chromosomal aberrations were not induced in Chinese hamster ovary cells treated in vivo at doses of 50 to 500 /g/mL with or without rat liver enzyme preparations (NTP, 1985). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987 The 1987 Health and Environmental Effects Profile for Decabromodiphenyl Oxide has received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 05/04/1989 Verification Date -- 05/04/1989 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 198912 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Decabromodiphenyl ether (DBDPE) CASRN -- 1163-19-5 Last Revised -- 12/01/1989 SORD: __VI.A. ORAL RfD REFERENCES Kociba, R.J., L.O. Frauson, C.G. Humiston, et al. 1975. Results of a two-year dietary feeding study with decabromodiphenyl oxide (DBDPO) in rats. J. Combust. Toxicol. 2: 267-285. Norris, J.M., J.W. Ehrmantraut, C.L. Gibbons, et al. 1973. Toxicological and environmental factors involved in the selection of decadibromophenyl oxide as a fire retardant chemical. Appl. Polym. Symp. 22: 195-219. Norris, J.M., R.J. Kociba, B.A. Schwetz, et al. 1975. Toxicology of octabromobiphenyl and decabromodiphenyl oxide. Environ. Health Perspect. 11: 153-161. U.S. EPA. 1984. Health and Environmental Effects Profile for Brominated Biphenyl Ethers. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Kociba, R.J., L.O. Frauson, C.G. Huniston, et al. 1975. Results of a two-year dietary feeding study with decabromodiphenyl oxide (DBDPO) in rats. J. Combust. Toxicol. 2(4): 267-285. Norris, J.M., J.W. Ehrmantraut, C.L. Gibbons, et al. 1973. Toxicological and environmental factors involved in the selection of decabromodiphenyl oxide as a fire retardant chemical. App. Polym. Symp. 22: 195-219. Norris, J.M. R.J. Kociba, B.A. Schwetz, et al. 1975. Toxicology of octabromodiphenyl and decabromodiphenyl oxide. Environ. Health Perspect. 11: 153-161. NTP (National Toxicology Program). 1985. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide in F344/N Rats and B6C3F1 Mice (Feed Studies). NTP-TR-309, NIH-85-2565. U.S. EPA. 1987. Health and Environmental Effects Profile for Decabromodiphenyl Oxide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste, Washington, DC. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Decabromodiphenyl ether (DBDPE) CASRN -- 1163-19-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.4. Text clarified 03/01/1988 I.A.6. Verification date changed 08/01/1989 II. Carcinogen assessment now under review 08/01/1989 VI. Bibliography on-line 12/01/1989 I.A.2. Corrected Norris et al. 1975 citation 12/01/1989 II. Carcinogen assessment on-line 12/01/1989 VI.C. Carcinogen references added 01/01/1990 II.A.3. Doses corrected 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 02/01/1995 I.A.7. Secondary contact's name changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 02/05/2003 I.A., I.B., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 365 of 1119 in IRIS (through 2003/06) AN: 39 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0039-tr.pdf UD: 200208 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,1-Dichloroethylene- (1,1-DCE) SY: *VINYLIDENE-CHLORIDE-; 1,1-DICHLOROETHENE-; 1,1-DCE-; DICHLOROETHENE,-1,1-; ETHYLENE,-1,1-DICHLORO-; NCI-C54262-; RCRA-WASTE-NUMBER-U078-; SCONATEX-; UN-1303-; VINYLIDENE-DICHLORIDE-; VINYLIDINE-CHLORIDE-; CHLORURE-DE-VINYLIDENE-; VDC- RN: 75-35-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200208 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,1-Dichloroethylene (1,1-DCE) CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 08/13/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: This summary replaces the summary dated 04/01/1989. This RfD differs from the previous EPA value of 0.009 mg/kg-day. The previous EPA evaluation used the same study but considered the lowest exposure of 9 mg/kg-day in female rats as a LOAEL for minimal hepatocellular fatty change and minimal hepatocellular swelling and applied a total uncertainty factor (UF) of 1000 (10 for LOAEL-to-NOAEL extrapolation, 10 for interspecies extrapolation, and 10 for human variability). EPA no longer considers hepatocellular swelling, in the absence of other effects such as increased liver enzymes in the serum, as biologically significant in this bioassay. The increased incidence of midzonal fatty change at 9 mg/kg-day in female rats is not statistically significant. The NOAEL in this bioassay is 9 mg/kg-day. In addition, the present evaluation uses benchmark dose (BMD) methodology and calculates a BMDL10 for midzonal fatty change in female rats. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ------------------------- ------------------------ ---------------- Liver toxicity NOAEL: 9 mg/kg-day (fatty change) Rat chronic drinking LOAEL: 14 mg/kg-day water study BMDL10: 4.6 mg/kg-day 100 1 5E-2 mg/kg-day Quast et al. (1983) ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- The authors provided the exposure data from the bioassay based on measured drinking water consumption. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Quast et al. (1983) conducted a 2-year chronic toxicity and carcinogenicity study of 1,1-DCE in Sprague-Dawley rats (6-7 weeks old). The control group comprised 80 rats of each sex, and each exposed group comprised 48 rats of each sex. The 1,1-DCE was incorporated in the drinking water of the rats at nominal concentrations of 0, 50, 100, or 200 ppm. The time-weighted average exposure over the 2-year period was 7, 10, or 20 mg/kg-day for males and 9, 14, or 30 mg/kg-day for females. Rampy et al. (1977) also reported some of the data. Humiston et al. (1978) reported more detailed data. No significant differences were observed among the groups in appearance and demeanor, mortality, body weight, food consumption, water consumption, hematology, urinalysis, clinical chemistry determinations, organ weights, or organ to body weight ratios. After 1 year on study, there was no depletion of the nonprotein sulfhydryl levels in the liver or the kidneys (Rampy et al., 1977). The only treatment-related effect observed in rats was minimal hepatocellular midzonal fatty change and hepatocellular swelling. At the termination of the study, male rats showed increased incidence of minimal hepatocellular fatty change (control, 14/80; 50 ppm, 5/48; 100 ppm, 13/48; 200 ppm, 19/47) and minimal hepatocellular swelling (control, 0/80; 50 ppm, 1/48; 100 ppm, 2/48; 200 ppm, 3/47). The changes were statistically significant (p<0.05) only in the 200 ppm group. At the termination of the study, female rats showed an increased incidence of minimal hepatocellular fatty change (control, 10/80; 50 ppm, 12/48; 100 ppm, 14/48; 200 ppm, 22/48; statistically significant [p<0.05] at 100 and 200 ppm) and minimal hepatocellular swelling (control, 3/80; 50 ppm, 7/48; 100 ppm, 11/48; 200 ppm, 20/48; statistically significant [p<0.05] in all groups). No exposure-related neoplastic changes occurred at any exposure. No hepatocellular necrosis was evident at any exposure. Based on the minimal nature of the hepatocellular swelling reported by the authors and no change in liver weight, no change in clinical chemistry measurements diagnostic for liver damage, and no other indication of abnormal liver function, the hepatocellular swelling is not considered biologically significant or an adverse effect in this study. The statistically significant hepatocellular midzonal fatty change, however, is considered a minimal adverse effect in this study. Accordingly, the NOAEL in male rats is 10 mg/kg-day and the LOAEL is 20 mg/kg-day; the NOAEL in female rats is 9 mg/kg-day and the LOAEL is 14 mg/kg-day. A BMD analysis was conducted for the results in female rats. In female rats, the BMD10 is 6.6 mg/kg-day and the BMDL10 is 4.6 mg/kg-day. A three-generation study by Nitschke et al. (1983), described in Section I.A.4, corroborated the results of Quast et al. (1983). The National Toxicology Program conducted 104-week chronic toxicity and carcinogenicity studies of 1,1-DCE in male and female F344 rats (200 of each sex, 9 weeks old) by gavage in corn oil at 0, 1, or 5 mg/kg-day (NTP, 1982). There were no significant differences in survival, clinical signs, or body weight as compared with controls for any group, suggesting that the maximum tolerated dose was not achieved. The results of histopathological examination indicated chronic renal inflammation in male rats (26/50, 24/48, 43/48) and female rats (3/49, 6/49, 9/44). The increase was statistically significant only in males. As this lesion commonly occurs in male rats (Kluwe et al., 1984, 1990), it is not considered biologically significant in this study. The NOAEL in this study 5 is mg/kg-day (the highest exposure tested). NTP also conducted 104-week chronic toxicity and carcinogenicity studies of 1,1-DCE in male and female B6C3F1 mice (50 of each sex in each group, 9 weeks old) by gavage in corn oil at 0, 2, or 10 mg/kg (NTP, 1982). There were no significant differences in survival, clinical signs, or body weight in any group. The only noncancer effect observed by histopathological examination was necrosis of the liver (male: 1/46; 3/46; 7/49; female: 0/47; 4/49; 1/49). The effect was not statistically significant at either exposure (p=0.6 and 0.06 at the mid- and high-exposure levels in males using a two-tailed test, respectively). In male and female mice the NOAEL is 10 mg/kg-day (the highest exposure tested). The BMD10 is 7.8 mg/kg-day and the BMDL10 is 4.1 mg/kg-day. This study was not used to derive the RfD because the gavage route of exposure will affect the pharmacokinetics of 1,1-DCE and the exposure-response relationship. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100 The critical effect is liver toxicity (fatty change) in rats, with a BMDL10 of 4.6 mg/kg-day. Although this minimal effect might not be considered adverse - as there is no evidence of a functional change in the liver in rats exposed and glutathione levels are not reduced in this bioassay - the BMDL10 was used to derive the RfD, because limiting exposure to the BMDL10 will protect the liver from more serious damage (fatty liver or necrosis) that could compromise liver function. Individual UFs of 10 each were used for interspecies extrapolation and intraspecies variability because there were no applicable data to justify departure from the default values. Derivation of the RfD from the BMDL10 for the minimal fatty change in the liver does not require an effect-level extrapolation. This conclusion is based on the minimal nature of the fatty change and its questionable biological significance because of the absence of any observable functional deficit in the liver. A subchronic-to-chronic extrapolation factor was not applied because the study exposed the animals for 2 years. A database UF is not applied because the database is considered complete. A number of long-term bioassays in rodents by the oral or inhalation route show that liver toxicity is the critical effect. There is no chronic bioassay in a nonrodent mammal. However, there are 90-day bioassays in several species (rats, mice, dogs, guinea pigs, rabbits, and monkeys) that suggest similar exposure-response relationships across species. Therefore, the lack of a chronic bioassay in a nonrodent mammal is not considered a data gap. There are no focused studies on neurotoxicity, but there is no indication from chronic, reproductive, and developmental bioassays in rats and mice by oral or inhalation exposure that neurotoxicity in an important toxic endpoint. No long-term studies have evaluated immunotoxicity in laboratory animals by any route of exposure. The existing bioassays, however, provide no suggestion that immunotoxicity is a critical effect. EPA does not consider these data gaps compelling enough to require application of a database UF. MF = 1. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) NTP (1982) conducted a study in male and female F344 rats (10 of each sex, 9 weeks old) administered 1,1-DCE by gavage in corn oil at 0, 5, 15, 40, 100, or 250 mg/kg. Animals were exposed five times per week for 13 weeks. Representative tissues from animals receiving 250 mg/kg and from control animals were examined microscopically. Livers from all groups were examined. Three female rats receiving 250 mg/kg died during the first week of the study. No other rats died. The mean body weight was depressed 13% for male rats receiving 250 mg/kg as compared with controls. Mean body weight in other groups was comparable. Only the liver showed effects attributed to 1,1-DCE. At 250 mg/kg, the three female rats that died showed severe centrilobular necrosis. Minimal to moderate hepatocytomegaly was seen in the rest of the rats at 250 mg/kg. Minimal to mild hepatocytomegaly was seen in 6/10 male rats and 3/10 female rats that received 100 mg/kg. No biologically significant changes were observed in rats that received 40 mg/kg or less. The NOAEL in this study is 40 mg/kg (equivalent to 28.5 mg/kg-day); the LOAEL is 100 mg/kg (equivalent to 71.4 mg/kg-day). NTP (1982) conducted a study in male and female B6C3F1 mice (10 of each sex, 9 weeks old) administered 1,1-DCE by gavage in corn oil at 0, 5, 15, 40, 100, or 250 mg/kg. Animals were exposed five times per week for 13 weeks. Representative tissues from mice receiving 100 and 250 mg/kg and from control animals were examined microscopically. Livers from all groups were also examined. Survival was 20/20, 19/20, 19/20, 19/20, 15/20, and 1/20 at 0, 5, 15, 40, 100, and 250 mg/kg, respectively. At 100 mg/kg there was a decrease in mean body weight in males (14%) but not in females. No change in mean body weight was observed at lower exposures. Only the liver showed effects attributed to 1,1-DCE. Centrilobular necrosis of the liver was observed in 5/10 males and 5/10 females that received 250 mg/kg and 2/10 males and 2/10 females that received 100 mg/kg. No biologically significant changes in the liver occurred in mice receiving 40 mg/kg or less. The NOAEL in this study is 40 mg/kg (adjusted to a continuous daily exposure of 28.6 mg/kg-day); the LOAEL is 100 mg/kg (adjusted to a continuous daily exposure of 71.4 mg/kg-day). Quast et al. (1983) conducted a study in beagle dogs (four per group, 8 months old) administered 1,1-DCE by gavage in peanut oil at 0, 6.25, 12.5, or 25 mg/kg-day for 97 days. No significant differences were observed among groups in appearance and demeanor, mortality, body weight, food consumption, hematology, urinalysis, clinical chemistry determinations, organ weights, and organ-to-body-weight ratios. No exposure-related gross or histopathological changes were present in tissues. There was no depletion of the nonprotein sulfhydryl levels in the liver or kidneys. The NOAEL in this study is 25 mg/kg-day (the highest exposure tested). REPRODUCTIVE AND DEVELOPMENTAL STUDIES Nitschke et al. (1983) evaluated the reproductive and developmental toxicity of 1,1-DCE in Sprague-Dawley rats. Three generations of the test animals were exposed to drinking water containing nominal 1,1-DCE concentrations of 0 (initially 15 males and 30 females), 50, 100, or 200 ppm (initially 10 males and 20 females at each exposure). The authors provided no information on water consumption. This study was a companion study to Quast et al. (1983) and used the same concentrations of 1,1-DCE in drinking water; in Quast et al. (1983) the average exposure to females was 9, 14, or 30 mg/kg-day. After 100 days of exposure, the rats were mated. In this three-generation study, there were no biologically significant changes in fertility index, in average number of pups per litter, in average body weight of pups, or in pup survival at any exposure. Neonatal survival was decreased from concurrent control values in the f2 and f3a litters of dams ingesting 1,1-DCE from drinking water. The survival indices, however, were within the range of control values for this strain of rats in this laboratory. The authors attributed the decreased survival index in f2 to increased litter size at birth in dams exposed to 1,1-DCE. The apparent effect seen in the f3a litters was not repeated in subsequent matings of the same adults to produce either the f3b or the f3c litters. The authors attributed the decreased survival in the f3a litters as being due to chance. Histopathological examination of tissues of rats exposed to 1,1-DCE in the drinking water in utero, during lactation, and postweaning revealed slight hepatocellular fatty change and an accentuated hepatic lobular pattern of a reversible nature in the adult rats (data not reported, but the observation is consistent with that reported by Quast et al. [1983] in a chronic bioassay). These effects were observed in the 100 and 200 ppm groups in the F1 generation and in all groups of the F2 generation. The authors did not present incidence data and did not report statistical analysis. Exposure to 1,1-DCE in drinking water at concentrations causing mild, dose-related changes in the liver did not affect the reproductive capacity of rats through three generations that produced six sets of litters. The NOAEL for reproductive and developmental toxicity in this study is 200 ppm for exposure to 1,1-DCE in drinking water (the highest exposure tested and about 30 mg/kg-day). Murray et al. (1979) evaluated the developmental toxicity of 1,1-DCE administered in drinking water at 0 (27 animals) or 200 ppm (26 animals) to pregnant Sprague-Dawley rats (body weight 250 g). Rats were exposed on gestation days 6-15 at 40 mg/kg-day. No teratogenic effects were seen in the embryos using standard techniques for soft and hard tissue examination, and there was no evidence of toxicity to the dams or their offspring. The NOAEL for developmental toxicity in this study is 40 mg/kg-day (the highest exposure tested). Dawson et al. (1993) evaluated the ability of 1,1-DCE administered in drinking water at 110 ppm or 0.15 ppm to female Sprague-Dawley rats (body weight 250 g) to induce fetal cardiac changes. Rats were administered 110 ppm 1,1-DCE for 61 days before mating or for 48 days before mating and for 20 days during gestation. Other rats were administered 0.15 ppm 1,1-DCE for 82 days before mating or for 56 days before mating and for 20 days during gestation. The dams were killed on gestational day 22 and the gravid uterus was removed and examined. There was no effect on maternal weight gain, average resorption sites (sites where development began but resorption later occurred), or average implantation sites (sites that did not appear to develop beyond implantation and contained a metrial gland only). No increase in the incidence of cardiac changes occurred when dams were exposed only before mating. There was, however, a statistically significant increase (p<0.01) in the percent of fetuses with cardiac changes (atrial septal, mitral valve, and aortic valve changes) when the dams were exposed before mating and during gestation. The incidence was control, 7/232 (3%); 0.15 ppm, 14/121 (12%); and 110 ppm, 24/184 (13%). This statistical analysis was based on total occurrence of affected fetuses. Because the exposure was to the dam and not to individual fetuses, a nested statistical analysis is preferred. Such an analysis takes into account the correlation among fetuses within a litter and the possible nesting of effects within litters. This analysis has not been conducted because all the necessary data are not available. The author provided additional data to resolve typographical errors in the exposure information for each group and to clarify the number of affected litters and number of fetuses per litter affected (letter from Brenda Dawson, University of Auckland, New Zealand, to Robert Benson, U.S. EPA, January 24, 2001). The exposure to dams before and during pregnancy was 0, 0.02, or 18 mg/kg-day in the control, 0.15 ppm, and 110 ppm groups, respectively. The number of affected litters was 5/21 (24%), 8/11 (73%), and 13/17 (76%). The mean number of affected fetuses per litter for affected litters only was 1.40 (13% of the fetuses in the litter), 1.75 (16% of the fetuses in the litter), and 1.85 (17% of the fetuses in the litter). The mean number of affected fetuses per litter for all litters was 0.33 (3% of the fetuses in the litter), 1.27 (12% of the fetuses in the litter), and 1.41 (13% of the fetuses in the litter). Dawson et al. (1993) did a much more thorough evaluation of alterations in cardiac development than is done in standard developmental toxicity testing protocols. There is no experience with the background rates or the functional significance of such alterations from other studies or laboratories. The incidence of alterations in control fetuses (3% of all fetuses, 24% of all litters, and 1.40 affected fetuses per affected litter) suggests a high background incidence. The authors reported that examinations were done blind to the treatment group, so the data are presumed not to be affected by observer bias. There is no demonstrated exposure-response relationship in Dawson et al. (1993). A 900-fold increase in exposure did not produce a significant, increase in response in any measure of effect. The cardiac changes are of questionable biological significance, as there were no biologically significant effects reported on growth and survival in the three-generation study (Nitschke et al., 1983). No cardiac effects were reported in a prenatal developmental study (Murray et al., 1979); however, in this study exposure to 1,1-DCE did not occur throughout pregnancy. The pharmacokinetics of 1,1-DCE make it biologically implausible that the cardiac changes were causally associated with exposure to 1,1-DCE. The exposures used in Dawson et al. (1993) are below the level of saturation of CYP2E1 in the rat liver. Essentially all of the 1,1-DCE administered to the dams will be metabolized in the liver and will react with glutathione or macromolecules in the liver. (See the discussion and references in Section 3.) Therefore, it is extremely unlikely that any significant amount of 1,1-DCE or any toxic metabolite will be in the fetal compartment. CYP2E1 is not expressed in fetal liver but begins to be expressed shortly after birth (Cresteil, 1998). EPA is not aware of any information on the expression of CYP2E1 in fetal cardiac tissue. Cardiac tissue, however, is not generally considered to be a tissue with significant potential for metabolism of xenobiotics. For these reasons EPA cannot conclude that the cardiac changes are caused by exposure to 1,1-DCE. It would be helpful if more definitive studies with a greater range of exposures were conducted to determine the cause and biological significance of the cardiac changes apparently associated with exposure to 1,1-DCE during the period of cardiac organogenesis. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=42. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Database -- Medium RfD -- Medium The overall confidence in this RfD assessment is medium. The principal study (Quast, 1983) was well conducted, with an adequate number of animals and appropriate evaluation of a wide variety of endpoints. This study is supported by an additional bioassay in rats (NTP, 1982) and a three-generation reproductive and developmental study showing consistent effects in the liver. A three-generation reproductive study and several bioassays show that reproductive and developmental toxicity are not critical effects. One developmental study, however, shows variations in cardiac morphology that have appear to have little or no physiological consequence. There are no focused studies on neurotoxicity, but there are no indications from chronic, reproductive, or developmental bioassays in rats and mice by oral or inhalation exposure that neurotoxicity is an important toxic endpoint. No long-term studies have evaluated immunotoxicity in laboratory animals by any route of exposure. The existing bioassays, however, provide no suggestion that immunotoxicity is a critical effect. Accordingly, the database is given a medium confidence, but no additional UF is considered necessary. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=47. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- Toxicological Review of 1,1-Dichloroethylene (2002) This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of 1,1-Dichloroethylene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=61. Other EPA Documentation -- This assessment replaces previous assessments (U.S. EPA, 1985a,b). Agency Consensus Date -- 06/07/2002 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 200208 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,1-Dichloroethylene (1,1-DCE) CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 08/13/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: Note: The previous EPA evaluation did not derive an RfC. SURC: ___I.B.1. Inhalation RfC Summary Critical Effect Experimental Doses* UF MF RfC ------------------- ------------------- ---- --- ---- Liver toxicity NOAEL HEC: 17.7 mg/m3 (fatty change) LOAEL HEC: 53.2 mg/m3 BMCL10HEC: 6.9 mg/m3 30 1 2E-1 mg/m3 Rat chronic inhalation study Quast et al. (1986) ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- The NOAEL from the chronic bioassay is 25 ppm, where the exposure was for 6 hrs/day, 5 days/wk. The conversion factor is 1 ppm = 3.97 mg/m3. The human equivalent concentration (HEC) was calculated using the equation for a category 3 gas (U.S. EPA, 1994). The blood:gas partition coefficient in the rat is 5 (D'Souza and Andersen, 1988). No useable data are available on the blood:gas coefficient in humans. Accordingly the default value of 1 is used for the ratio of these coefficients. NOAELHEC = NOAEL adj x (Hb/g)A/(Hb/g)H = 25 ppm x 6/24 x 5/7 x 1 x 3.97 = 17.7 mg/m3 BMCLHEC = BMCL adj x (Hb/g)A/(Hb/g)H = 9.8 ppm x 6/24 x 5/7 x 1 x 3.97 = 6.9 mg/m3 PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Quast et al. (1986) and Rampy et al. (1977) reported results from studies that exposed male and female Sprague-Dawley rats (Spartan substrain, 86 animals/group) to 1,1-DCE by inhalation 6 hrs/day, 5 days/wk, for up to 18 months. Interim sacrifices occurred at 1, 6, and 12 months. Rats were exposed to 1,1-DCE concentrations of 10 ppm and 40 ppm for the first 5 weeks of the study. Because of the absence of observable treatment-related effects among rats sacrificed after 1 month of exposure, the concentrations were increased to 25 and 75 ppm. Exposures were continued at these concentrations through the 18th month of the study. The surviving animals were then held without exposure to 1,1-DCE until 24 months. Cytogenetic evaluations were performed on a separate group of animals (four/sex) exposed to 0, 25, or 75 ppm for 6 months. A separate 90-day study using 20 rats/sex/treatment group was conducted at 0, 25, and 75 ppm, with an interim sacrifice of 8 rats/group at 30 days. There were no exposure-related changes in mortality, appearance and demeanor, body weight, clinical chemistry determinations, hematologic evaluations, urinalysis, or cytogenetic evaluation of bone marrow preparations. Minimal hepatocellular fatty change in the midzonal region of the hepatic lobule was observed in both male and female rats in the 25 ppm and 75 ppm groups at the 6-month interim sacrifice (male: control, 0/5; 25 ppm, 1/5; 75 ppm, 4/5; female: control, 0/5; 25 ppm, 2/5; 75 ppm, 4/5). The fatty change was also observed at the 12-month sacrifice, but there was no indication of progression of severity (male: control, 0/5; 25 ppm, 3/5; 75 ppm, 5/5; female: control, 0/5; 25 ppm, 5/5; 75 ppm, 5/5). At the 18-month sacrifice the incidence of this change was no longer increased in male rats (control, 0/27; 25 ppm, 0/25; 75 ppm, 1/27). However, the change persisted in female rats (control, 0/16; 25 ppm, 6/29; 75 ppm, 7/20). The effect was statistically significant (p<0.05) only at the higher exposure. During the last 6 months of the study, after exposure had been discontinued, this effect was no longer discernible (male: control, 0/46; 25 ppm, 1/47; 75 ppm, 0/51; female: control, 0/49; 25 ppm, 0/46; 75 ppm, 1/48). Although the incidences of several tumors and/or tumor types were found to be statistically increased or decreased compared with controls, none of these differences were judged to be attributable to 1,1-DCE. The tumor incidence data for both control and treated rats in this study were comparable to historical control data for the Sprague-Dawley rats (Spartan substrain) used by this laboratory for several studies of similar design and duration. Although the minimal hepatocellular midzonal fatty change was reversible and did not result in altered organ weight, clinical chemistry changes diagnostic for liver damage, or any obvious decrement in liver function, the fatty change in liver is considered a minimal adverse effect. Accordingly, the NOAEL in male rats in this study is 75 ppm (the highest exposure tested). The NOAEL for female rats in this study is 25 ppm; the LOAEL is 75 ppm. A benchmark dose analysis was conducted. In female rats the BMC10 is 15.1 ppm and the BMCL10 is 9.8 ppm, equivalent to 1.8 ppm adjusted for continuous exposure (9.8 ppm x 6/24 x 5/7). UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 30. The critical effect is liver toxicity (fatty change) in rats with a BMCL10HEC of 6.9 mg/m3. Although this minimal effect might not be considered adverse - as there is no evidence of a functional change in the liver in rats exposed at this level and glutathione levels are not reduced - it is used to derive the RfC, because limiting exposure to this level will protect the liver from more serious damage (fatty liver or necrosis) that could compromise liver function. The total UF is 30 and the modifying factor is 1. A UF of 3 is used for interspecies extrapolation because a dosimetric adjustment was used. There is some suggestion that the effects in the kidney of male mice might occur at an exposure lower than the level that produced effects in the liver of rats. Thus, there is some uncertainty as to whether the most sensitive species has been used to derive the RfC. A UF of 10 is used for intraspecies variability because there were no applicable data to depart from the default value. Derivation of the RfD from the BMDL10 for the minimum fatty change in the liver does not require an effect-level extrapolation. This conclusion is based on the minimal nature of the fatty change and its questionable biological significance because of the absence of any observable functional deficit in the liver. Although the animals were exposed for 18 months, rather than the full lifetime, there was no indication that the fatty change was progressing. In contrast, the evidence indicated the fatty change was decreasing in incidence with continued exposure. EPA, therefore, did not apply a subchronic-to-chronic extrapolation factor. A database UF is not applied because the database is considered complete. A number of long-term bioassays in rodents by the oral or inhalation route show that liver toxicity is the critical effect. There is no chronic bioassay in a nonrodent mammal. However, there are 90-day bioassays in several species (rats, mice, dogs, guinea pigs, rabbits, and monkeys) that suggest similar exposure-response relationships across species. Therefore, the lack of a chronic bioassay in a nonrodent mammal is not considered a data gap. There are no focused studies on neurotoxicity, but there are no indications from chronic, reproductive, and developmental bioassays in rats and mice by oral or inhalation exposure that neurotoxicity is an important toxic endpoint. No long-term studies have evaluated immunotoxicity in laboratory animals by any route of exposure. The existing bioassays, however, provide no suggestion that immunotoxicity is a critical effect. EPA does not consider these data gaps compelling enough to require application of a database UF. MF = 1. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) Prendergast et al. (1967) evaluated the toxicity of 1,1-DCE in Long-Evans or Sprague-Dawley rats, Hartley guinea pigs, beagle dogs, New Zealand albino rabbits, and squirrel monkeys. The test animals (15 rats/group, 15 guinea pigs/group, 3 rabbits/group, 2 dogs/group, or 3 or 9 monkeys/group) were exposed continuously for 90 days to 1,1-DCE vapors at 189 ± 6.2, 101 ± 4.4, 61 ± 5.7, or 20 ± 2.1 mg/m3. The concurrent controls included 304 rats, 314 guinea pigs, 48 rabbits, 34 dogs, and 57 monkeys. The age of the animals was not specified. The exposed animals were evaluated for visible signs of toxicity, mortality, and hematologic, biochemical, pathologic, and body weight changes. There was apparent exposure-related mortality in guinea pigs and monkeys. In guinea pigs the mortality was 2/314, 2/45, 3/15, 3/15, and 7/15 and in monkeys it was 1/57, 1/21, 0/9, 2/3, and 3/9 in the 0, 20, 61, 101, or 189 mg/m3 exposure groups, respectively. The guinea pigs died between days 3 to 9 of exposure; the monkeys died on days 26, 39, 47, 60, and 64 of exposure. There were no visible signs of toxicity in any surviving animals. At the highest exposure in monkeys, but not in guinea pigs, there was some histopathological evidence of liver damage (see below). In guinea pigs at the highest exposure, there was an increase in serum glutamic-pyruvic transaminase and liver alkaline transaminase (see below). Because visible signs of toxicity were not observed and only minor liver damage is apparent in this study, the mortality data in guinea pigs and monkeys are given no weight. Varying degrees of growth depression were found in all exposures, but were significant in all species only at 189 mg/m3. The test animals exhibited no significant hematologic alterations, and serum urea nitrogen levels were within control limits in all exposures in which determinations were made. Significant elevations of serum glutamic-pyruvic transaminase and liver alkaline phosphatase activities were found in rats (a threefold and 1.75-fold increase, respectively) and guinea pigs (sevenfold and 2.4-fold increase, respectively) exposed to 189 mg/m3 (other species not tested) but not at 20 mg/m3 (enzyme levels at intermediate exposures not tested). Histopathological examination of liver from dogs, monkeys, and rats revealed damage at 189 mg/m3 (other species not examined). The effects observed included fatty metamorphosis, focal necrosis, hemosiderosis deposition, lymphocytic infiltration, bile duct proliferation, and fibrosis. The changes were most severe in dogs. Sections of kidney from all rats showed nuclear hypertrophy of the tubular epithelium. No detectable liver or kidney damage was observed in any species exposed to 101 mg/m3 or less. The NOAEL in this study is 101 mg/m3 (equivalent to 25 ppm); the LOAEL is 189 mg/m3 (equivalent to 47 ppm). Short et al. (1977) evaluated developmental toxicity of 1,1-DCE administered by inhalation to pregnant CD-1 rats (Charles River). Animals were exposed to 0 (58 animals), 15 ppm (18 animals), 57 ppm (20 animals), 300 ppm (18 animals), or 449 ppm (18 animals) for 22-23 hours/day on gestation days 6 to 16. Dams were sacrificed on gestation day 20. Maternal toxicity was exhibited as severe maternal weight loss (> 28 grams/dam) at 15 ppm and higher and by maternal mortality at 57 ppm and higher. There was a statistically significant increase in the mean number of fetuses per litter with hydrocephalus at 15 and 57 ppm, with malaligned sternebrae at 15 ppm, and with unossified sternebrae at 57 ppm. Because of the severe maternal toxicity at 15 ppm (60 mg/m3) and higher, this study is not useful for evaluating developmental toxicity. Short et al. (1977) evaluated developmental toxicity of 1,1-DCE administered by inhalation to pregnant CD-1 mice (Charles River). Animals were exposed to 0 (65 animals), 15 ppm (23 animals), 30 ppm (19 animals), 57 ppm (21 animals), 144 ppm (18 animals), or 300 ppm (15 animals) for 22-23 hrs/day on gestation days 6 to 16. Dams were sacrificed on gestation day 17. At 30 ppm and higher there was maternal toxicity, as shown by statistically significant decreases in maternal weight gain. At 144 and 300 ppm there was an increase in maternal mortality. At 30 ppm and higher there was severe fetal toxicity, with complete early resorption of the litters. At 15 ppm there was no evidence of maternal toxicity, no decrease in fetal body weight, and no decrease in the percentage of viable fetuses. At 15 ppm, there was an increase in the mean number of fetuses per litter with hydrocephalus, occluded nasal passages, micropthalmia, cleft palate, small liver, and hydronephrosis. None of these changes, however, were statistically significant when compared to controls. Also at 15 ppm there was a statistically significant increase in the mean number of fetuses with an unossified incus and with incompletely ossified sternebrae. This study provides evidence of fetal toxicity at 15 ppm, the only exposure without significant maternal toxicity. In this study the LOAEL for developmental toxicity is 15 ppm (60 mg/m3), the lowest exposure tested. Short et al. (1977) also evaluated developmental neurotoxicity of 1,1-DCE administered by inhalation to CD-1 rats (Charles River). Pregnant rats were exposed to 0 (24 animals), 56 ppm (20 animals), or 283 ppm (19 animals) for 22-23 hrs/day on gestation days 8 to 20. Maternal toxicity was observed at both exposures, as shown by weight loss of 7 g per dam at 56 ppm and 15 grams per dam at 283 ppm. There was complete resorption of three litters at 283 ppm. There was a statistically significant decrease in average pup weight as compared to control at both exposures on post-natal day 1. The difference in pup weight between control and exposed groups decreased with time and disappeared by postnatal day 21. There was no evidence of developmental neurotoxicity at either exposure in pups tested at various times from postnatal day 1 to day 21 in a battery of behavioral tasks, including surface righting, pivoting, auditory startle, bar holding, righting in air, visual placing, swimming ability, physical maturation, and activity. This study shows evidence of maternal and fetal toxicity at both exposures but no evidence of developmental neurotoxicity at either exposure. Accordingly, the NOAEL for developmental neurotoxicity in this study is 283 ppm (1124 mg/m3), the highest exposure tested. Murray et al. (1979) evaluated developmental toxicity of 1,1-DCE administered by inhalation to pregnant Sprague-Dawley rats (body weight 250 g). Animals were exposed to 0 (20 or 47 animals), 20 ppm (44 animals), 80 ppm (30 animals), or 160 ppm (30 animals) for 7 hrs/day on gestation days 6-15. At 20 ppm there was no maternal toxicity and no effect on embryonal or fetal development. At 80 and 160 ppm, there was toxicity to the dams (statistically significant depression in weight gain at gestation day 6-9, more severe at 160 ppm). At 80 and 160 ppm, there were also statistically significant increased incidences of wavy ribs and delayed ossification of the skull, which are regarded as embryotoxic effects. Both effects were more severe at 160 ppm. No teratogenic effects were seen at any exposure. The NOAEL for developmental toxicity in this study is 20 ppm; the LOAEL is 80 ppm. Under the Guidelines for Developmental Toxicity (U.S. EPA, 1994), these values are not adjusted to continuous exposure. Murray et al. (1979) evaluated the developmental toxicity of 1,1-DCE administered by inhalation to New Zealand white rabbits (body weight 3.4-4.7 kg). Animals were exposed to 0 (16 animals), 80 ppm (22 animals), or 160 ppm (18 animals) for 7 hrs/day on gestation days 6-18. At 80 ppm there was no maternal toxicity and no effect on embryonal or fetal development. Toxicity to both the dams and their developing embryos was observed at 160 ppm. There was a marked increase in the incidence of resorptions per litter (0.3 ± 0.6 vs. 2.7 ± 3.9). A significant change occurred in the incidence of several minor skeletal variations in their offspring, including an increase in the occurrence of 13 pairs of ribs and a increased incidence of delayed ossification of the fifth sternebra (data not reported). No teratogenic effects were seen at any exposure. The NOAEL for developmental toxicity in this study is 80 ppm; the LOAEL is 160 ppm. Under the Guidelines for Developmental Toxicity (U.S. EPA, 1991), these values are not adjusted to continuous exposure. See also studies showing liver toxicity and the reproductive and developmental studies summarized in the RfD section. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=42. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Database -- Medium RfC -- Medium The overall confidence in this RfC assessment is medium. The principal study (Quast, 1986) was a well-conducted inhalation bioassay with adequate numbers of animals and appropriate evaluation of a wide variety of endpoints. The result is supported by several other 90-day inhalation studies in a variety of species (Prendergast et al. 1967). These inhalation studies are supported by an additional bioassay in rats and a 90-day study in dogs, both by the oral route of exposure showing NOAELs (see the summary of these studies in the RfD section). There is no evidence from the inhalation bioassays that the respiratory tract is a target tissue of low-dose exposure. Several studies by the inhalation route of exposure show that developmental toxicity is not a critical effect. A three-generation reproductive study by the oral route of exposure showed no significant reproductive effects, and several bioassays showed no developmental toxicity. However, one developmental study by the oral route of exposure shows variations in cardiac morphology that appear to have little or no physiological consequence. There are no focused studies on neurotoxicity, but no indication from chronic, reproductive, and developmental bioassays in rats and mice by oral or inhalation exposure that neurotoxicity is an important toxic endpoint. No long-term studies have evaluated immunotoxicity in laboratory animals by any route of exposure. The existing bioassays, however, provide no suggestion that immunotoxicity is a critical effect. Accordingly, the database is given medium confidence, but no additional UF is considered necessary. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=47. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- Toxicological Review of 1,1-Dichloroethylene (2002) This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of 1,1-Dichloroethylene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=61. Other EPA Documentation -- None. Agency Consensus Date -- 06/07/2002 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ============================================================================ UDCA: 200208 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,1-Dichloroethylene (1,1-DCE) CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 08/13/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY This IRIS summary replaces the summary dated 03/31/1987. The assessment of carcinogenicity by the inhalation route of exposure under the draft revised guidelines for carcinogen risk assessment (U.S. EPA, 1999) differs from the previous EPA evaluation (U.S. EPA, 1985a, b). EPA's previous evaluation considered the incidence of kidney adenocarcinomas (Maltoni et al., 1985) as providing sufficient evidence of carcinogenicity to justify deriving an inhalation unit risk for quantifying the potential human cancer risk. As noted in Sections 4.4.3 and 4.6 of the Toxicological Review of 1,1-Dichloroethylene, the new data suggesting that the kidney adenocarcinomas could be a sex- and species-specific response reduce the weight of evidence for carcinogenicity by the inhalation route of exposure. Accordingly, the present evaluation does not derive an inhalation unit risk. This conclusion is consistent with the evaluation by the International Agency for Research on Cancer (IARC) (IARC, 1999). In addition, this assessment of carcinogenicity by the oral route of exposure under the draft revised guidelines for carcinogen risk assessment (U.S. EPA, 1999) differs from the previous EPA evaluation (U.S. EPA, 1985a, b). The previous EPA evaluation derived an oral slope factor from the highest of four slope factors calculated from two studies (NTP, 1982; Quast et al., 1983) that did not show statistically significant increases in tumor incidence attributable to oral exposure. The highest slope factor was based on the adrenal pheochromocytomas in male rats (NTP, 1982). Under the 1999 draft revised guidelines for carcinogen risk assessment, EPA emphasizes the importance of using data that show a statistically significant increase in tumor incidence for calculating a slope factor. As there is no statistically or biologically significant increase in tumor incidence at any site in the relevant oral bioassays, the present evaluation characterizes the weight of evidence as inadequate and accordingly does not derive an oral slope factor. This conclusion is consistent with the evaluation by IARC (1999). WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under the 1986 cancer guidelines (U.S. EPA, 1986), 1,1-DCE is assigned to Group C, possible human carcinogen. Under the draft revised guidelines for carcinogen risk assessment (U.S. EPA, 1999), EPA concludes 1,1-DCE exhibits suggestive evidence of carcinogenicity but not sufficient evidence to assess human carcinogenic potential following inhalation exposure in studies in rodents. Male mice developed kidney tumors at one exposure in a lifetime bioassay, a finding tempered by the absence of similar results in female mice or male or female rats and by the enzymatic differences (i.e., CYP2E1) between male mice and female mice, male and female rats, and human kidney cells. Limited evidence of genotoxicity has been reported in bacterial systems with metabolic activation. The data for 1,1-DCE are inadequate for an assessment of human carcinogenic potential by the oral route, based on the absence of statistically or biologically significant tumors in limited bioassays in rats and mice balanced against the suggestive evidence in male mice in a single bioassay by inhalation and the limited evidence of genotoxicity. The human epidemiological results on the carcinogenicity of 1,1-DCE are too limited to draw useful conclusions. EPA concludes that the results of kidney tumors in one sex and one exposure in a single species of rodents are too limited to support an exposure-response assessment. Bioassays for cancer by the oral route of exposure have been conducted in rats (Maltoni et al., 1985; NTP, 1982; Ponomarkov and Tomatis, 1980; Quast et al., 1983) mice (NTP, 1982), and trout (Hendricks et al., 1995). Some of these bioassays were conducted at an exposure below the maximum tolerated dose. The bioassay conducted by Maltoni et al. (1985) exposed the animals for only 1 year. The bioassay conducted in rats by Quast et al. (1983) and the bioassay conducted in mice by NTP (1982) were well conducted and both showed some toxicity in the liver at the highest exposure. Neither of these bioassays provides any significant evidence that 1,1-DCE is a carcinogen by the oral route of exposure. The genotoxicity studies are incomplete, but most studies in mammalian cells indicate a lack of genotoxicity. Bioassays for cancer by the inhalation route of exposure have been conducted in rats (Lee et al., 1977, 1978; Viola and Caputo, 1977; Hong et al., 1981; Maltoni et al., 1985; Quast et al., 1986; Cotti et al., 1988), mice (Lee et al., 1977, 1978; Hong et al., 1981; Maltoni et al., 1985), and hamsters (Maltoni et al., 1985). None of these bioassays was conducted by a protocol that meets current standards. The major defects in most of these bioassays include exposure of the animals for 1 year and exposure at less than the maximum tolerated dose. The only bioassay that showed some evidence of carcinogenicity was the study in Swiss-Webster mice (Maltoni et al., 1985). This study was conducted at or near the maximum tolerated dose, as animals exposed at 50 ppm died after a few exposures. Although the animals were exposed for only 1 year and then observed until natural death, this study showed an increased incidence of kidney adenocarcinomas in male mice at 25 ppm but not at 10 ppm. The incidence of mammary carcinomas in female mice and pulmonary adenomas in male and female mice did not increase with increased exposure. The responses were actually lower at 25 ppm than at 10 ppm, but survival and other toxicities were comparable. There is evidence that the induction of kidney adenocarcinomas is a sex- and species-specific response related to the expression of CYP2E1 in the kidney of male mice (Speerschneider and Dekant, 1995; Amet et al., 1997; Cummings et al., 2000). The data presented by these researchers, however, are not sufficient to justify a conclusion that the kidney tumors in male mice have no relevance for a human health risk assessment. This conclusion is made with the knowledge that compounds similar in structure to 1,1-DCE (e.g., tetrachloroethylene, trichloroethylene, and 1,2-dichloroethylene) produce varying degrees of kidney tumors in animal bioassays. The genotoxicity studies are incomplete, but most studies in mammalian cells indicate a lack of genotoxicity. Accordingly, EPA concludes that the data on the increased incidence of kidney adenocarcinomas in male mice (Maltoni et al., 1985) provide suggestive evidence of carcinogenicity by the inhalation route of exposure. EPA also concludes, considering the evidence of a potential sex- and species-specific response, that the results of this bioassay showing an increase in tumors in one sex and one exposure in a single species of rodents are too limited to support an exposure-response assessment. 1,1-DCE causes gene mutations in microorganisms in the presence of an exogenous activation system. Although most tests with mammalian cells show no evidence of genetic toxicity, the test battery is incomplete because it lacks an in vivo test for chromosomal damage in the mouse lymphoma system. There are a number of uncertainties in the assessment of the carcinogenicity of 1,1-DCE. As noted above, many of the bioassays by the inhalation route of exposure were not conducted at the maximum tolerated dose or for the full lifetime of the animals. EPA has acknowledged this uncertainty in the weight-of-evidence classification. In addition, our knowledge of the metabolic pathways for 1,1-DCE in the human is incomplete. Although it is likely that the initial oxidation of 1,1-DCE in humans occurs via CYP2E1, there could be other CYP isoforms that could activate 1,1-DCE. Thus, there is some potential for a species-specific carcinogenic response in humans similar to the apparent sex- and species-specific response observed by Maltoni et al. (1985) in the kidney of male mice. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=47. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=42. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Ott et al. (1976) investigated the health records of 138 employees occupationally exposed to 1,1-DCE in processes not involving vinyl chloride. The individuals included in the study had worked in experimental or pilot plant polymerization operations, in a monomer production process as tankcar loaders, or in a production plant that manufactured a monofilament fiber. Time-weighted-average concentrations (8 hours) of 1,1-DCE in the workplace were estimated from job descriptions and the results of industrial hygiene sampling. The subjects were grouped into three exposure categories: less than 10 ppm, 10-24 ppm, and greater than 25 ppm. The researchers estimated career exposure by taking into account average duration of employment. Results of the most recent health inventory for individuals in the cohort were compared with findings of matched controls. Analysis of mortalities among the cohort indicated no statistically significant findings. Overall, there were no significant differences between the exposed cohort and the controls in hematology and clinical chemistry parameters. Based on power considerations, this study is inadequate for assessing cancer risk in humans. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA ORAL Rats Ponomarkov and Tomatis (1980) treated 24 female BD IV rats by gavage with 1,1-DCE dissolved in olive oil (150 mg/kg body weight) on the 17th day of gestation. Their offspring (81 males and 80 females) were treated weekly with 1,1-DCE at 50 mg/kg body weight by gavage from the time of weaning for 120 weeks or until the animal was moribund. A control group of offspring (49 males and 47 females) received only olive oil. Liver and meningeal tumors were more frequently observed in treated than in untreated animals, but the difference was not statistically significant. The total number of tumor-bearing animals was not statistically different between treated and untreated animals. NTP (1982) conducted chronic toxicity and carcinogenicity studies of 1,1-DCE for 104 weeks in male and female F344 rats (200 of each sex, 9 weeks old) by gavage in corn oil at 0, 1, or 5 mg/kg-day. No significant differences were observed in survival, clinical signs, or body weight as compared with controls for any group, suggesting that the maximum tolerated dose was not achieved. All of the increased tumor incidences that were statistically significant by the Fisher exact test or by the Cochran-Armitage linear trend test (adrenal pheochromocytoma, pancreatic islet cell adenoma or carcinoma, and subcutaneous fibroma in males and pituitary adenoma in females) were not significant when life-table analyses were used. This difference occurs because life table analyses adjust for intercurrent mortality, and thus minimize the impact of animals dying before the onset of late-appearing tumor. This adjustment was particularly critical for the analyses of tumor incidences in male rats, because 12 controls and 10 low-dose animals were accidentally killed during week 82 of the study. Accordingly, NTP concluded that no increased incidence of tumors was found at any site in these bioassays. Under the conditions of this bioassay, 1,1-DCE administered by gavage was not carcinogenic for F344 rats. Quast et al. (1983) conducted a 2-year chronic toxicity and carcinogenicity study of 1,1-DCE in Sprague-Dawley rats (6-7 weeks old). There were 80 of each sex rats in the control group and 48 rats of each sex in each exposed group. The 1,1-DCE was incorporated in the drinking water of the rats at nominal concentrations of 0, 50, 100, or 200 ppm. The time-weighted-average exposure over the 2-year period was 7, 10, or 20 mg/kg-day for males and 9, 14, or 30 mg/kg-day for females. No significant differences were found among the groups in appearance and demeanor, mortality, body weight, food consumption, water consumption, hematology, urinalysis, clinical chemistry determinations, organ weights, or organ-to-body-weight ratios. The only treatment-related effect observed in rats was a minimal amount of midzonal fatty change and hepatocellular swelling. No exposure-related neoplastic changes occurred at any exposure. Maltoni et al. (1985) conducted a carcinogenicity and toxicity study of 1,1-DCE in Sprague-Dawley rats. Animals (9 or 10 weeks old) were exposed by gavage in olive oil to 0, 0.5, 5, 10, or 20 mg/kg, 4-5 days/wk for 52 weeks. There were two control groups, one with 150 animals (75 of each sex) and the other with 200 animals (100 of each sex). The exposed groups had 100 animals (50 of each sex). Following the 52-week exposure, animals were observed until spontaneous death (total duration 147 weeks). Body weight was measured every 2 weeks during the 52 week exposure and every 8 weeks thereafter. Full necropsy and histopathological examination were performed. No biologically significant changes were observed in mortality or body weight. There were no biologically significant noncancer or cancer effects in any organ. Mice NTP (1982) conducted 104 weeks of chronic toxicity and carcinogenicity studies on 1,1-DCE in male and female B6C3F1 mice (200 of each sex, 9 weeks old) by gavage in corn oil at 0, 2, or 10 mg/kg. No significant differences in survival, clinical signs, or body weight were in any group, suggesting that the maximum tolerated dose was not achieved. The only observed significant increase (p<0.05) in tumor incidence occurred in low-dose females for lymphoma (2/48, 9/49, 6/50) and for lymphoma or leukemia (7/48, 15/49, 7/50). These increases were not considered to be related to 1,1-DCE administration because similar effects were not found in the high-dose females or in males. Under the conditions of this bioassay, 1,1-DCE administered by gavage was not carcinogenic for B6C3F1 mice. Trout Hendricks et al. (1995) conducted an 18-month carcinogenicity study of 1,1-DCE in rainbow trout (8 weeks old) at 4 mg/kg-day. Tissues examined for neoplasms included liver, kidney, spleen, gill, gonads, thymus, thyroid, heart, stomach, pyloric ceca, duodenum, rectum, pancreas, and swimbladder. 1,1-DCE produced no neoplasms and no increase in liver weight. There was no evidence of any other chronic toxic effects. INHALATION Rats Lee et al. (1977, 1978) exposed 2-month-old Charles River CD rats (36 males and 35 females) to 55 ppm 1,1-DCE for 6 hrs/day, 5 days/wk, for 12 months. No significant changes were observed in survival, body weight, hematology, clinical blood chemistry, pulmonary macrophage count, cytogenetic analysis of bone marrow, x-ray examination of extremities, collagen contents in liver and lung, serum aminolevulinic acid (ALA) synthetase, urinary ALA level, and serum alpha-fetoprotein. A mild to markedly severe focal, disseminated vacuolization was observed in livers of most of the rats. No hemangiosarcomas were found in the liver or lung. The incidence of hemangiosarcomas in mesenteric lymph node or subcutaneous tissue was 2/36 in males and 0/35 in females. Viola and Caputo (1977) exposed 2-month-old Sprague-Dawley rats (30 males and 30 females per group) to 0, 75 ppm, or 100 ppm 1,1-DCE for 22-24 months (hours of daily exposure not reported). The incidence of tumors observed at necropsy (males and females combined) was 15/60; 10/36 and 20/60 at 0, 75 ppm, and 100 ppm, respectively. The tumors observed were classified as subcutaneous fibromas or abdominal lymphomas. The histopathological results from this study have not been published. No other data are reported for this study. Viola and Caputo (1977) also exposed 2-month-old albino Wistar rats (37 males and 37 females) to 1,1-DCE for 4 hrs/day, 5 days/wk, for 12 months. The exposure was at 200 ppm for the first 6 months and at 100 ppm for the rest of the study. A control group of 60 animals received air only. The incidence of tumors (described as reticulum cell sarcomas of a nonsincytial type, primarily in the abdominal cavity) was 15/60 and 17/74 in control and exposed groups, respectively. No other data are reported from this study. Hong et al. (1981) evaluated mortality and tumor incidence in rats exposed to 1,1-DCE. Groups of 2-month-old CD rats of both sexes were exposed to 0 or 55 ppm 1,1-DCE 6 hrs/day, 4 days/wk for 1 month (four of each sex), 3 months (four of each sex), 6 months (four of each sex), or 10 months (16 of each sex). Following exposure, all animals were observed for an additional 12 months. In rats exposed for 10 months, there was an increase in mortality following the 12-month observation period (67% in exposed, 41% in controls). There was no significant increase in tumors at any site for any exposure period. Maltoni et al. (1985) conducted a carcinogenicity and toxicity study of 1,1-DCE in Sprague-Dawley rats. Animals (16 weeks old) were exposed by inhalation to 0, 10, 25, 50, 100, or 150 ppm for 4 hrs/day, 4-5 days/wk for 52 weeks. The control group had 200 animals (100 of each sex); the 10, 25, 50, and 100 ppm groups had 60 animals (30 of each sex), and the 150 ppm group had 120 animals (60 of each sex). Following the 52-week exposure, animals were observed until spontaneous death (total duration 137 weeks). Body weight was measured every 2 weeks during the 52-week exposure and every 8 weeks thereafter. Full necropsy and histopathological examination were performed. No biologically significant changes were seen in mortality or body weight. There were no biologically significant noncancer effects in any organ in either sex and no increase in tumors in males at any site. There was a statistically significant increase (p<0.05) in each treatment group as compared with controls in the number of females with mammary fibromas and fibroadenomas. The incidence was 44/56 (78.6%), 24/24 (100% ), 20/20 (100%), 21/22 (95.4%), 21/23 (91.3%), and 38/43 (88.4%) in the control, 10, 25, 50, 100, and 150 ppm groups, respectively. The latency time and the number of tumors per tumor-bearing animal were similar among all groups. The incidence of mammary carcinoma in exposed groups was consistently less than that of controls. The incidence was 16/56 (28.6%), 5/24 (20.8%), 4/20 (20%), 1/21 (4.5%), 3/21 (13.0%), and 9/38 (20.9%) in the control, 10, 25, 50, 100, and 150 ppm groups, respectively. Quast et al. (1986) and Rampy et al. (1977) reported results from studies that exposed male and female Sprague-Dawley rats (Spartan substrain, 86 animals/group) to 1,1-DCE by inhalation 6 hrs/day, 5 days/wk, for up to 18 months. Interim sacrifices occurred at 1, 6, and 12 months. Rats were exposed to 1,1-DCE concentrations of 10 ppm and 40 ppm for the first 5 weeks of the study. Based on the absence of observable treatment-related effects among rats sacrificed after 1 month of exposure, the concentrations were increased to 25 and 75 ppm. Exposures were continued at these concentrations through the 18th month of the study. The surviving animals were then held without exposure to 1,1-DCE until 24 months. Cytogenetic evaluations were performed on a separate group of animals (four per sex) exposed to 0, 25, or 75 ppm for 6 months. There were no exposure-related changes in mortality, appearance and demeanor, body weight, clinical chemistry determinations, hematologic evaluations, urinalysis, or cytogenetic evaluation of bone marrow preparations. Although the incidences of several tumors and/or tumor types were found to be statistically increased or decreased as compared with controls, none of these differences were judged to be attributable to 1,1-DCE. The tumor incidence data for both control and treated rats in this study were comparable to historical control data for the Sprague-Dawley rats (Spartan substrain) used by this laboratory for several studies of similar design and duration. Cotti et al. (1988) exposed Sprague-Dawley rats to 1,1-DCE at 0 or 100 ppm for 4-7 hrs/day, 5 days/wk. The exposures were to 13-week-old females for 104 weeks (60 control animals and 54 exposed animals) and to 12-day embryos for 15 or 104 weeks (158 males and 149 females as controls, 60 males and 60 females exposed for 15 weeks, and 62 males and 61 females exposed for 104 weeks). Animals were observed until spontaneous death. In males and females exposed for 104 weeks and in male offspring exposed for 15 weeks, a slight decrease in body weight (data not reported) was observed. An increased percentage of rats bearing malignant tumors (30.9% vs. 17.3 % in controls) and an increased number of malignant tumors per 100 animals (34.1% vs. 17.9% in controls) were observed in male and female offspring exposed for 104 weeks (statistical analysis not presented). An increase in leukemia in offspring, which appeared to be related to length of exposure (4.2% for controls, and 8.3% and 11.4% for exposure of 15 and 104 weeks, respectively), was also observed. Tumors at other sites (total benign and malignant tumors, total benign and malignant mammary tumors, malignant mammary tumors, and pheochromocytomas) showed no change or a decreased incidence. Data from this study are also reported in Maltoni et al. (1985). Mice Lee et al. (1977, 1978) exposed 2-month-old CD-1 mice (18 males and 18 females) to 0 or 55 ppm 1,1-DCE for 6 hrs/day, 5 days/wk, for up to 12 months. No deaths occurred in the control or exposed groups. Weight gain was comparable between groups. There was no change in hematology, clinical blood chemistry, cytogenetic analysis of bone marrow, x-ray examination of extremities, or serum alpha-fetoprotein. The livers showed no increase in mitotic figures using 14C-thymidine incorporation. The incidence of bronchioalveolar adenoma (males and females combined) for 1-3 months exposure, 4-6 months exposure, 7-9 months exposure, and 10-12 months exposure was 0/24, 1/8, 2/10, and 3/28, respectively. The incidence of hemangiosarcomas in liver (males and females combined) for 6 months exposure, 7-9 months exposure, and 10-12 months exposure was 0/16, 1/10, and 2/28, respectively. No hemangiosarcomas were found in other tissues. Hong et al. (1981) evaluated mortality and tumor incidence rates in mice exposed to 1,1-DCE. Groups of 2-month-old albino CD-1 mice of both sexes were exposed to 0 or 55 ppm for 6 hrs/day, 4 days/wk, for 1 month (8 of each sex), 3 months (8 of each sex), or 6 months (12 of each sex). Following exposure, all animals were observed for an additional 12 months. In mice exposed for 6 months, there was a slight increase in mortality following the 12-month observation period (46% in exposed, 39% in controls). There was no significant increase in tumors at any site for any exposure period. Maltoni et al. (1985) conducted a carcinogenicity and toxicity study of 1,1-DCE in Swiss mice. Animals (9 or 16 weeks old) were exposed by inhalation to 0, 10, or 25 ppm. Animals were exposed for 4 hrs/day, 4-5 days/wk, for 52 weeks. There were two control groups, one with 180 animals (90 of each sex) and the other with 200 animals (100 of each sex). The 10-ppm group had 60 animals (30 of each sex). Two groups were exposed to 25 ppm: one with 60 animals (30 of each sex) and the other with 240 animals (120 of each sex). Following the 52-week exposure, animals were observed until spontaneous death (total duration 126 weeks). Body weight was measured every 2 weeks during the 52-week exposure and every 8 weeks thereafter. Full necropsy and histopathological examination were performed. No biologically significant changes occurred in body weight. The exposed animals had a somewhat higher survival than controls. There was a statistically significant increase (p<0.01) as compared with controls in kidney adenocarcinomas in male mice at 25 ppm but not in male mice at 10 ppm or in female mice at either exposure. The incidence was 0/126 (0%), 0/25 (0%), and 28/119 (23.5%) in male mice in the combined controls, 10 ppm, and combined 25 ppm groups, respectively. There was a statistically significant increase (p<0.01) as compared with controls in mammary carcinomas in female mice at both exposures, but there was no clear exposure-response relationship. The incidence was 3/185 (1.6%), 6/30 (20%), and 16/148 (11%) in females in the combined controls, 10 ppm, and combined 25 ppm groups, respectively. There was also a statistically significant increase (p < 0.01) compared with control in pulmonary adenomas in both exposed groups, but there was no clear exposure-response relationship. The incidence was 12/331 (3.6%), 14/58 (24.1%), and 41/288 (14.2%) in male and female mice combined in the combined controls, 10 ppm, and combined 25 ppm groups, respectively. There were no pulmonary carcinomas in any mice. The incidence data are reported as the number of tumor-bearing animals as compared with the number of animals alive when the first tumor was observed in that organ (kidney adenocarcinoma, 55 weeks; mammary tumor, 27 weeks; pulmonary adenoma, 36 weeks). Hamsters Maltoni et al. (1985) conducted a carcinogenicity and toxicity study of 1,1-DCE in Chinese hamsters. Animals (28 weeks old) were exposed by inhalation to 0 or 25 ppm. Animals were exposed for 4 hrs/day, 4-5 days/wk, for 52 weeks. The control group had 35 animals (18 male and 17 female); the 25 ppm group had 60 animals (30 of each sex). Following the 52-week exposure, animals were observed until spontaneous death (total duration 157 weeks). Body weight was measured every 2 weeks during the 52-week exposure and every 8 weeks thereafter. Full necropsy and histopathological examination were performed. There were no biologically significant changes in mortality or body weight. No biologically significant noncancer or tumor effects were seen in any organ. Dermal Van Duuren et al. (1979) evaluated the carcinogenicity of 1,1-DCE in male and female noninbred Ha:ICR Swiss mice. Carcinogenicity was assessed in three types of tests: a dermal initiation-promotion assay, a repeated dermal application assay, and a subcutaneous injection assay. Vehicle, no-treatment, and positive control groups were included in the tests. In the initiation-promotion assay, 1,1-DCE was tested as a tumor-initiating agent with phorbol myristate acetate as the promoter. Thirty female mice were treated with 121 mg 1,1-DCE. A significant increase (p<0.005) was observed in skin papillomas (nine in eight mice). In the repeated dermal application assay, exposures of 40 and 121 mg/mouse were used. 1,1-DCE was applied to the back of the shaved animals (30 females/dose). No sarcomas were observed at the treatment site. Although 19 mice in the high-dose group and 12 in the low-dose group had lung tumors and 2 mice in the high-dose group had stomach tumors, the tumor incidence at both sites was not significantly different from that of controls (30 lung tumors and 5 stomach tumors). In the subcutaneous injection assay, the test animals were given weekly injections of 2 mg of 1,1-DCE. After 548 days on test, none of the injected animals developed sarcomas at the injection site. 1,1-DCE showed initiating activity in the two-stage carcinogenesis experiments but was inactive as a whole-mouse dermal carcinogen and after subcutaneous injection. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Reitz et al. (1980) investigated the ability of 1,1-DCE to cause DNA alkylation, DNA repair, and DNA replication in liver and kidney of rats and mice. Male Sprague-Dawley rats (body weight 200-250 g) and male CD-1 mice (body weight 18-20 g) were exposed by inhalation for 6 hours. There was only a minimal increase in DNA alkylation in both rats and mice at 50 ppm. Similarly, DNA repair in kidneys of mice was only minimally increased at 50 ppm. However, tissue damage (kidney nephrosis at 50 ppm, minimal effect at 10 ppm), an increase in DNA replication (sevenfold increase in 3H-thymidine incorporation at 10 ppm, 25-fold increase at 50 ppm), and an increase in mitotic figures occurred. There was no observed histopathological damage or increased DNA replication in the liver of mice at 10 or 50 ppm. In rats there was a small increase in DNA replication (twofold increase in 3H-thymidine incorporation) in the kidney but no increase in liver at 10 ppm. 1,1-DCE induced mutations in Salmonella typhimurium and Escherichia coli in the presence of an exogenous metabolic system. In Saccharomyces cerevisiae, 1,1-DCE induced reverse mutation and mitotic gene conversion in vitro and in a host-mediated assay in mice. In a single study in Saccharomyces cerevisiae, it induced aneuploidy in the presence and absence of metabolic activation. In vitro, gene mutations were increased in mouse lymphoma cells but not in Chinese hamster lung cells with or without an exogenous metabolic system. In a single study, 1,1-DCE induced sister chromatid exchanges in Chinese hamster lung cells in the presence of an exogenous metabolic system but not in its absence. In single studies in vivo, 1,1-DCE did not induce micronuclei or chromosomal aberrations in bone marrow or in fetal erythrocytes of mice, nor dominant lethal mutations in mice or rats. 1,1-DCE causes gene mutations in microorganisms in the presence of an exogenous activation system. Although most tests with mammalian cells show no evidence of genetic toxicity, the test battery is incomplete because it lacks an in vivo assessment of chromosomal damage in the mouse lymphoma assay, a test that EPA considers to be an important component of a genotoxicity battery. Speerschneider and Dekant (1995) investigated the metabolic basis for the species- and sex-specific nephrotoxicity and tumorigenicity of 1,1-DCE. In kidney microsomes from male mice, the rate of oxidation of 1,1-DCE depended on the hormonal status of the animals. Oxidation of 1,1-DCE was decreased by castration and restored when the castrate was supplemented with exogenous testosterone. In kidney microsomes from naive female mice, the rate of oxidation of 1,1-DCE was significantly lower than in males, but it could be increased by administration of exogenous testosterone. Using an antibody to rat liver CYP2E1, the researchers showed expression of a cross-reacting protein in male mouse kidney microsomes that was regulated by testosterone and correlated with the ability to oxidize 1,1-DCE and other substrates for CYP2E1 (e.g., p-nitrophenol and chlorozoxazone). The researchers also showed that different strains of mice express different levels of CYP2E1, and the strains most sensitive to the effects of 1,1-DCE express greater levels of CYP2E1. Nephrotoxicity in Swiss-Webster mice after inhalation of 1,1-DCE was observed in males and in females treated with exogenous testosterone, but not in naive females. In kidney microsomes obtained from both sexes of rats and in six samples of human kidney from male donors, no p-nitrophenol oxidase activity was detected. Other research groups have also reported the absence of detectable CYP2E1 in human kidney tissue (Amet et al., 1997; Cummings et al., 2000). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not applicable. 1,1-DCE shows equivocal evidence of carcinogenicity by the oral route of exposure. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not applicable. 1,1-DCE shows suggestive evidence of human carcinogenicity by the inhalation route of exposure. The weight of evidence, however, is not sufficient to justify deriving an inhalation unit risk. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- Toxicological Review of 1,1-Dichloroethylene (2002) This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to Toxicological Review of 1,1-Dichloroethylene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0039-tr.pdf#page=61. Other EPA Documentation -- This assessment replaces previous assessments (U.S. EPA, 1985a,b). RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 06/07/2002 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ============================================================================ UDSO: 200208 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,1-Dichloroethylene (DCE) CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride Last Revised -- 08/13/2002 SORD: __VI.A. ORAL RfD REFERENCES Cresteil, T. (1998) Onset of xenobiotic metabolism in children: toxicological implications. Food Additives and Contam 15 (supplement):45-51. Dawson, BV; Johnson, PD; Goldberg, SJ; et al. (1993) Cardiac teratogenesis of halogenated hydrocarbon-contaminated drinking water. J Am Coll Cardiol 21:1466-1472. Humiston, CG; Quast, JF; Wade, CE; et al. (1978) Results of a two-year toxicity and oncogenicity study with vinylidene chloride incorporated in the drinking water of rats. Toxicology Research Laboratory, Health and Environmental Research, Dow Chemical USA, Midland MI 48640. Kluwe, WM; Abdo, KM; Huff, J. (1984) Chronic kidney disease and organic chemical exposures: evaluations of causal relationships in humans and experimental animals. Fundam Appl Toxicol 4:899-901. Kluwe, WM. (1990) Chronic chemical injury to the kidney. In: Goldstein, RS; Hewitt, WR; Hook, JB, eds. Toxic Interactions. San Diego, CA: Academic Press, pp. 367-406. Murray, FJ; Nitschke, KD; Rampy, LW; et al. (1979). Embryotoxicity and fetotoxicity of inhaled or ingested vinylidene chloride in rats and rabbits. Toxicol Appl Pharmacol 49:189-202. Nitschke, KD; Smith, FA; Quast, JF; et al. (1983) A three-generation rat reproductive toxicity study of vinylidene chloride in the drinking water. Fundam Appl Toxicol 3:75-79. NTP (National Toxicology Program). (1982) Carcinogenesis bioassay of vinylidene chloride in F344 rats and B6C3F1 mice (gavage study). National Toxicology Program Technical Report Series No. 228. Quast, JF; Humiston, CG; Wade, CE; et al. (1983) A chronic toxicity and oncogenicity study in rats and subchronic toxicity study in dogs on ingested vinylidene chloride. Fundam Appl Toxicol 3:55-62. Rampy, LW; Quast, JF; Humiston, CG; et al. (1977) Interim results of two-year toxicological studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ. Health Perspect. 21:33-43. U.S. EPA (U.S. Environmental Protection Agency). (1985a) Health assessment document for vinylidene chloride. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA /600/8-83-031F. U.S. EPA. (1985b) Drinking water criteria document for 1,1-dichloroethene (vinylidene chloride). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. (2002) Toxicological Review of 1,1-Dichloroethylene. Available online at http://www.epa.gov/iris. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES D'Souza, RW; Andersen, ME. (1988) Physiologically based pharmacokinetic model for vinylidene chloride. Toxicol Appl Pharmacol 95:230-240. Murray, FJ; Nitschke, KD; Rampy, LW; et al. (1979) Embryotoxicity and fetotoxicity of inhaled or ingested vinylidene chloride in rats and rabbits. Toxicol Appl Pharmacol 49:189-202. Prendergast, JA; Jones, RA; Jenkins, JR Jr, et al. (1967) Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethene. Toxicol Appl Pharmacol 10:270-289. Quast, JF; Mckenna, MJ; Rampy, LW; et al. (1986) Chronic toxicity and oncogenicity study on inhaled vinylidene chloride in rats. Fundam Appl Toxicol 6:105-144. Rampy, LW; Quast, JF; Humiston, CG; et al. (1977) Interim results of two-year toxicological studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ Health Perspect 21:33-43. Short, RD; Minor, JL; Winston, JM; et al. (1977) Toxicity studies of selected chemicals task II: the developmental toxicity of vinylidene chloride inhaled by rats and mice during gestation. EPA-560/6-77-022. U.S. EPA. (1991) Guidelines for developmental toxicity risk assessment. Federal Register 56(234):63798-63826. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. U.S. EPA. (2002) Toxicological Review of 1,1-Dichloroethylene. Available online at http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Amet, Y; Berthou, F; Fournier, G; et al. (1997) Cytochrome P450 4A and 2E1 expression in human kidney microsomes. Biochem Pharmacol 53:765-771. Cotti, G; Maltoni, C; Lefemine, G. (1988) Long-term carcinogenicity bioassay on vinylidene chloride administered by inhalation to Sprague-Dawley rats. New results. Ann N Y Acad Sci 534:160-168. Cummings, BS; Lasker, JM; and Lash, LH. (2000) Expression of glutathione-dependent enzymes and cytochrome P450s in freshly isolated and primary cultures of proximal tubular cells from human kidney. J Pharmacol Exp Ther 293:677-685. Hendricks, JD; Shelton, DW; Loveland, PM; et al. (1995) Carcinogenicity of dietary dimethylnitrosomorpholine, N-methyl-N'-nitro-N-nitrosoguanidine, and dibromoethane in rainbow trout. Toxicol Pathol 23:447-457. Hong, CB; Winston, JM; Thornburg, LP; et al. (1981) Follow-up study on the carcinogenicity of vinyl chloride and vinylidene chloride in rats and mice; tumor incidence and mortality subsequent to exposure. J Toxicol Environ Health 7:909-924. IARC (International Agency for Research on Cancer). (1999) IARC monographs on the evaluation of carcinogenic risks to humans. Volume 71: re-evaluation of some organic chemicals, hydrazine, and hydrogen peroxide (part 3). Lyon, France, pp. 1163-1180. Lee, CC; Bhandari, JC; Winston, JM; et al. (1977) Inhalation toxicity of vinyl chloride and vinylidene chloride. Environ Health Perspect 21:25-32. Lee, CC; Bhandari, JC; Winston, JM; et al. (1978) Carcinogenicity of vinyl chloride and vinylidene chloride. J Toxicol Environ Health 24:15-30. Maltoni, C; Lefemine, G; Cotti, G; et al. (1985) Experimental research on vinylidene chloride carcinogenesis. Archives of Research on Industrial Carcinogenesis, Volume III. Maltoni, C, Mehlman, MA, eds. Princeton, NJ: Princeton Scientific Publishers, Inc. NTP (National Toxicology Program). (1982). Carcinogenesis bioassay of vinylidene chloride in F344 rats and B6C3F1 mice (gavage study). National Toxicology Program Technical Report Series, No. 228. Ott, MG; Fishbeck, WA; Townsend, JC; et al. (1976) A health study of employees exposed to vinylidene chloride. J Occup Med 18:735-738. Ponomarkov, V; Tomatis, L. (1980) Long-term testing of vinylidene chloride and chloroprene for carcinogenicity in rats. Oncology 37:136-141. Quast, JF; Humiston, CG; Wade, CE; et al. (1983) A chronic toxicity and oncogenicity study in rats and subchronic toxicity study in dogs on ingested vinylidene chloride. Fundam Appl Toxicol 3:55-62. Quast, JF; McKenna, MJ; Rampy, LW; et al. (1986) Chronic toxicity and oncogenicity study on inhaled vinylidene chloride in rats. Fundam Appl Toxicol 6:105-144. Rampy, LW, Quast, JF, Humiston, CG, Balmer, MF, Schwetz, BA. (1977) Interim results of two-year toxicological studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation. Environ Health Perspect 21:33-43. Reitz, RH; Watanabe, PG; McKenna, MJ; et al. (1980) Effects of vinylidene chloride and DNA synthesis and DNA repair in the rat and mouse: a comparative study with dimethylnitrosamine. Toxicol Appl Pharmacol 52:357-370. Speerschneider, P; Dekant, W. (1995) Renal tumorigenicity of 1,1-dichloroethene in mice: the role of male-specific expression of cytochrome P450 2E1 in the renal bioactivation of 1,1-dichloroethene. Toxicol Appl Pharmacol 130:48-56. U.S. EPA (U.S. Environmental Protection Agency). (1985a) Health assessment document for vinylidene chloride. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-83-031F. U.S. EPA. (1985b) Drinking water criteria document for 1,1-dichloroethene (vinylidene chloride). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34003. U.S. EPA. (1999) Guidelines for carcinogen risk assessment. Review Draft, NCEA-F-0644, July 1999. Risk Assessment Forum. U.S. EPA. (2002) Toxicological Review of 1,1-Dichloroethylene. Available online at http://www.epa.gov/iris. Van Duuren, B; Goldschmidt, BM; Loewengert, G; et al. (1979). Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice. J Natl Cancer Inst 63:1433-1439. Viola, PL; Caputo, A. (1977) Carcinogenicity studies on vinylidene chloride. Environ Health Perspect 21:45-47. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,1-Dichoroethene (DCE) CASRN -- 75-35-4 Primary Synonym -- Vinylidene Chloride ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/31/1987 II. Carcinogenicity Section added 03/01/1988 I.A.1. Dose conversion clarified 03/01/1988 I.A.7. Contact changed 03/01/1988 II.A.2. Text added 03/01/1988 II.B.3. Text revised 03/01/1988 II.B.4. Confidence statement revised 03/01/1988 II.C.3. Text added 03/01/1988 II.C.4. Confidence statement revised 06/30/1988 I.A.7. Changed primary contact's telephone number 12/01/1988 II.A.3. van Durren et al. citation year corrected 04/01/1989 I.A. Oral RfD summary noted as pending change 12/01/1989 I.B. Inhalation RfD now under review 03/01/1990 II. Clarified NTP, 1982 citation 03/01/1990 VI. Bibliography on-line 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 02/01/1991 II.C.3. Information on extrapolation process included 08/01/1991 VI.A. References clarified 08/01/1991 VI.C. References clarified 01/01/1992 IV. Regulatory actions updated 08/01/1995 I.A., I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 02/01/1998 II.C.3 Slope factor corrected from 1.2 to 0.2E+0. 01/12/2000 I., II. This chemical is being reassessed under the IRIS Program. 08/13/2002 I-VIII New RfD, RfC, and cancer assessment ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 366 of 1119 in IRIS (through 2003/06) AN: 51 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199108 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Ethylbenzene- SY: 100-41-4; AETHYLBENZOL-; BENZENE,-ETHYL-; EB-; ETHYLBENZEEN-; ETHYLBENZOL-; ETILBENZENE-; ETYLOBENZEN-; NCI-C56393-; PHENYLETHANE-; UN-1175- RN: 100-41-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199106 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Ethylbenzene CASRN -- 100-41-4 Last Revised -- 06/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Liver and kidney NOEL: 136 mg/kg/day 1000 1 1E-1 toxicity (converted to 97.1 mg/kg/day mg/kg/day) Rat Subchronic to Chronic Oral Bioassay LOAEL: 408 mg/kg/day (converted to 291 Wolf et al., 1956 mg/kg/day) ---------------------------------------------------------------------------- *Conversion Factors: 5 days/7 days; thus, 136 mg/kg/day x 5 days/7 days = 97.1 mg/kg/day PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. The chosen study is a rat 182-day oral bioassay in which ethylbenzene was given 5 days/week at doses of 13.6, 136, 408, or 680 mg/kg/day in olive oil gavage. There were 10 albino female rats/dose group and 20 controls. The criteria considered in judging the toxic effects on the test animals were growth, mortality, appearance and behavior, hematologic findings, terminal concentration of urea nitrogen in the blood, final average organ and body weights, histopathologic findings, and bone marrow counts. The LOAEL of 408 mg/kg/day is associated with histopathologic changes in liver and kidney. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 1000 reflects 10 for both intraspecies and interspecies variability to the toxicity of this chemical in lieu of specific data, and 10 for extrapolation of a subchronic effect level to its chronic equivalent. MF --None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) None. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low Confidence in the chosen study is low because rats of only one sex were tested and the experiment was not of chronic duration. Confidence in the supporting data base is low because other oral toxicity data were not found. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1980. Ambient Water Quality Criteria for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA 440/5-80-048. NTIS PB 81-117590. U.S. EPA. 1985. Drinking Water Criteria Document for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. (Public review draft) U.S. EPA. 1985. Health Effects Assessment for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. ECAO-CIN-H008. The 1980 Ambient Water Quality Criteria Document for Ethylbenzene received extensive Agency and public review. The 1985 Drinking Water Criteria Document for Ethylbenzene and the 1985 Health Effects Assessment for Ethylbenzene received extensive Agency review with the help of selected outside scientists. Agency Work Group Review -- 05/20/1985 Verification Date -- 05/20/1985 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199103 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Ethylbenzene CASRN -- 100-41-4 Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Developmental toxicity NOAEL: 434 mg/cu.m (100 ppm) 300 1 1E+0 NOAEL(ADJ): 434 mg/cu.m mg/cu.m Rat and Rabbit NOAEL(HEC): 434 mg/cu.m Developmental Inhalation Studies LOAEL: 4340 mg/cu.m (1000 ppm) LOAEL(ADJ): 4340 mg/cu.m Andrew et al., 1981; LOAEL(HEC): 4340 mg/cu.m Hardin et al., 1981 ---------------------------------------------------------------------------- *Conversion Factors: MW = 106.18. Assuming 25C and 760 mmHg, NOAEL(mg/cu.m) = 100 ppm x MW/24.45 = 434 mg/cu.m. For developmental effects, this concentration is not adjusted; therefore, NOAEL(ADJ) = NOAEL. The NOAEL(HEC) was calculated for a gas:extrarespiratory effect, assuming periodicity was attained. Since b:a lambda values are unknown for the experimental animal species (a) and humans (h), a default value of 1.0 was used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x (b:a lambda(a)/lambda(h)) = 434 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Andrew, F.D., R.L. Buschbom, W.C. Cannon, R.A. Miller, L.F. Montgomery, D.W. Phelps, et al. 1981. Teratologic assessment of ethylbenzene and 2-ethoxyethanol. Battelle Pacific Northwest Laboratory, Richland, WA. PB 83-208074., 108. Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier. 1981. Testing of selected workplace chemicals for teratogenic potential. Scand. J. Work Environ. Health. 7(suppl 4): 66-75. Inhalation experiments were conducted with Wistar rats (n=78-107/concentration) and New Zealand white rabbits (n=29-30/concentration) exposed 6 to 7 hours/day, 7 days/week during days 1-19 and 1-24 of gestation, respectively, to nominal concentrations of 0, 100, or 1000 ppm (434 or 4342 mg/cu.m) (Andrew et al., 1981). A separate group of rats was exposed pregestationally for 3 weeks prior to mating and exposure was continued into the gestational period. Actual concentrations were within 10% of target concentrations. All pregnant animals were sacrificed 1 day prior to term (21 days for rats; 30 days for rabbits). Maternal organs (liver, lungs, kidney, heart, spleen, adrenals, ovaries, and brain) were examined histopathologically. Uteri were examined and fetuses were weighed, sexed, and measured for crown-to-rump length, and examined for external, internal and skeletal abnormalities. For statistical analyses, the litter was chosen as the experimental unit. Ethylbenzene did not elicit embryotoxicity, fetotoxicity, or teratogenicity in rabbits at either exposure level. There were no significant incidences of major malformations, minor anomalies, or common variants in fetal rabbits from exposed groups. Maternal toxicity in the rabbits was not evident. There was no evidence of histologic damage in any of the dams' organs. The principal observation noted by the investigators was a reduced number of live rabbit kits per litter (p<0.05) at both exposure levels when evaluated by ANOVA and Duncan's Multiple Range Test. The number of live kits per litter in the air-exposed controls was reported as 8 (3+/-s.d.), compared with 7 (3+/-s.d.) for each exposure group. However, if one recalculates the data presented in Table 9 of Andrew et al. (1981), the number of live kits per litter for the low concentration (100 ppm) was 8 rather than 7 as presented in the paper. Since the number of live kits per litter at the high concentration was 7, this may suggest an effect at 1000 ppm, but not at 100 ppm. However, the number of implantations per litter and the number of dead or resorbed per litter were not different from controls. Prenatal mortality ranged from 5 to 8% and preimplantation loss ranged from 18 to 27%. Neither indicated a concentration-related intrauterine mortality. The results of the rabbit study are indicative of a NOAEL of 100 ppm based on a lack of developmental effects in rabbits. The NOAEL(HEC) is 434 mg/cu.m. In rats exposed only during gestation, there were no histopathological effects in any of the maternal organs examined. There was no effect on fertility or on any of the other measures of reproductive status. The principal observation in fetuses was an increased incidence (p<0.05) of supernumerary and rudimentary ribs in the high exposure group and an elevated incidence of extra ribs in both the high and 100 ppm groups. Both absolute and relative liver, kidney, and spleen weights were significantly increased in pregnant rats from the 1000 ppm group. Groups of female rats were also exposed for 3 weeks prior to mating and exposure was continued during gestation. Like the 1000-ppm group exposed only during gestation, there was also an increased incidence of extra ribs (p<0.05) in the pre-gestationally exposed high exposure group. However, an increased incidence was not seen at 100 ppm in those exposed pre-gestationally, in contrast to the comparable group exposed only during gestation. There was no increase in rudimentary ribs in either of exposed groups. When extra and rudimentary ribs were grouped together, there was no significant increase in supernumerary ribs in either of the exposed groups. The apparent discrepancy in the incidence of supernumerary ribs between the pregestationally-exposed group and those exposed only during gestation may be based, in part, on the fewer numbers of litters examined in the pregestationally-exposed group. There were no effects on fertility or on any of the of the other measures of reproductive status. No fetal toxicity was noted at either exposure level. Body weights, placental weights, and sex ratios were within normal limits. Absolute and relative liver and spleen weights were significantly increased in pregant rats from the 1000 ppm group; only relative kidney weight was increased significantly. There were no histopathological effects in any of the organs examined. Skeletal variants were seen at both 434 and 4342 mg/cu.m in the rats with the effects at 432 mg/cu.m being reduced compared with those occurring at 4342 mg/cu.m. By themselves, the effects are marginally adverse, even at 4342 mg/cu.m. However, a weight-of-evidence approach, noting a cluster of other mild effects at 4342 mg/cu.m, is used to determine that 1000 ppm is a LOAEL. The skeletal variations are considered along with evidence of slightly reduced litter size in rabbits at 4342 mg/cu.m and an increase in "% skeletal retarded fetuses" at 600 mg/cu.m (Ungvary and Tatrai, 1985). Additional support for this position is derived from the observations of somewhat elevated maternal liver, kidney, and spleen weights (Andrew et al., 1981). UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- The uncertainty factor of 300 reflects a factor of 10 to protect unusually sensitive individuals, 3 to adjust for interspecies conversion and 10 to adjust for the absence of multigenerational reproductive and chronic studies. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Ungvary and Tatrai (1985) exposed CFY rats (n=17-20) to levels of 600, 1200, or 2400 mg/cu.m for 24 hours/day during days 7 to 15 of gestation. CFLP mice (n=20) were exposed to 500 mg/cu.m for 24 hours/day from gestational days 6 to 15 or for 3 days intermittently for 4 hours/day for days 6-15. It is not clear from the description if the results pertain to the continuous exposure or the intermittent exposure. New Zealand rabbits (n=3-9) were exposed for 24 hours/day to concentrations of 500 or 1000 mg/cu.m from gestational days 7 to 20. Untreated animals and those exposed to air only served as controls. It was stated that maternal toxicity (unspecified species) was moderate and concentration-dependent; however, no data were presented to support this statement. Maternal weight gain was reported to have decreased for rabbits exposed to 1000 mg/cu.m. It was reported that rabbits exposed to 1000 mg/cu.m exhibited mild maternal toxicity manifested by reduced weight gain. However, the percent weight gain was not reported. There were no data for developmental endpoints in the 1000-ppm group because there were no live fetuses. One dam had died and three others aborted in this exposure group. Four dams had total resorptions. However, four other compounds in addition to ethyl benzene were tested at 1000 mg/cu.m and all caused spontaneous abortions at this level. Thus, the results are not clearly indicative of a treatment-related effect. This observation, coupled with the lack of any indication of abortions in rabbits in the Hardin et al. (1981) study, suggests that this effect in rabbits is not treatment-related. Ungvary and Tatrai (1985) did observe a significant reduction in the mean female fetal weight in rabbit dams exposed 24 hours/day to 500 mg/cu.m. Andrew et al. (1981) did not observe such an effect in rabbits exposed up to 4348 mg/cu.m. These conflicting results in rabbits might be attributable to differences in study design. Postimplantation loss (% dead or resorbed fetuses), and exposure-related skeletal retardation were significantly elevated (p<0.05) in rats at all exposure levels with one exception. Exposure to 600 mg/cu.m for 6 hours/day (it was not stated if this was a single exposure or the exposure duration on each day of gestation) did not result in any statistically significant fetal effects although there was increased incidence of dead/resorbed fetuses, lower weight of fetuses, and skeletal retarded fetuses. In the 24-hour/day exposure groups, malformations characterized as "anomalies of the uropoietic apparatus" and an increased incidence of extra ribs were significantly increased only at the highest exposure level. No data were presented on the anomalies of the uropoeitic apparatus. There was a significant (p<0.05) increase in skeletal retardation and fetal resorption in all continuous exposure groups although the concentration-response was shallow. The percent skeletal retarded fetuses, for example, at exposure concentrations of 600, 1200, and 2400 mg/cu.m was 26, 30, and 35%, respectively; the incidence in controls was 13%. These results in rats suggest a LOAEL(HEC) of 2400 mg/cu.m for extra ribs in the absence of demonstrable maternal toxicity. In mice, an increased incidence of "anomalies of the uropoietic apparatus" was the only observation, but no data were presented. There was no discussion concerning maternal toxicity. A 90-day subchronic inhalation study was conducted in F344/N rats (n=10/sex/group) and B6C3F1 mice (n=10/sex/group) that were exposed to 0, 100, 250, 500, 750, and 1000 ppm (0, 434, 1086, 2171, 3257, and 4343 mg/cu.m) 6 hours/day, 5 days/week (NTP, 1988; 1989; 1990). The duration-adjusted values were 0, 77.5, 194, 388, 582, and 776 mg/cu.m, respectively. The test atmosphere concentrations monitored by gas chromatography were within a 10% range of the target concentrations. At study termination, necropsies were conducted on the lung, liver, kideny, heart, testes, and thymus with organ weight measurements. Clinical chemistry data were obtained for rats. Histopathological examinations were conducted on all animals in the high concentration groups and in controls; animals in the lower concentration groups were evaluated when lesions were observed until no observed effects were seen. Sperm morphology and vaginal cytology tests were performed. There were no mortalities, exposure-related clinical signs of toxicity, or significant adverse effects on body weight in any of the exposed rats or mice. In rats, hematology parameters were unaffected. Of the liver enzymes evaluated, only serum alkaline phosphatase (SAP) activity was significantly reduced in a concentration-related manner (at 500 ppm and above) for both sexes with a greater sensitivity in females. The significance of this decrease is not clear since in liver damage, SAP levels usually increase. The investigators suggested the decrease may be due to reduced water and food intake. No liver histopathology was noted for any exposure group. Significant concentration-related increases in absolute liver weights occurred in males at 250 ppm and higher (12.5, 17.3, 22.0, and 23.6% at 250, 500, 750, and 1000 ppm, respectively); in females the lowest concentration at which an increase in absolute liver weight was seen was in the 500-ppm group (11.8%). The increase in the 750- and 1000-ppm groups was 11.5 and 15.8%, respectively. Relative liver weights were significantly increased in all male exposure groups except the 100-ppm group while all female exposure groups except the two lowest groups showed significant increases. Absolute kidney weight in males significantly increased only in the 500- and 750-ppm groups; relative weight was increased in the three highest exposure groups. In females, both absolute and relative kidney weights increased significantly in the three highest exposure groups. Regeneration of renal tubules in the kidneys of male rats only was seen in all groups including controls. The severity of the lesions was greatest in the rats at in the high-exposure group. The most significant gross observation in rats was the presence of enlarged bronchial and/or mediastinal lymph nodes, but these observations were not dose-related. The incidence for minimal lung inflammation in male rats was 0/10, 3/10, 9/10, 9/10, 8/10, and 10/10 for the 0-, 100-, 250-, 500-, 750-, and 1000-ppm exposure groups, respectively. Microscopically, this enlargement was attributable to an increase in normal constituents of the lymph nodes characterized by accumulations of macrophages, lymphocytes, neutrophils, and plasma cells. It was the opinion of the NTP Pathology Working Group (PWG) that hyperplasia of the lymph nodes and lower respiratory tract was typical of an infectious agent with an associated active immune response rather than ethylbenzene exposure (NTP, 1989). This diagnosis was supported by the following observations: an uneven distribution of lesions among and within groups; foci of airway inflammation were randomly distributed throughout the lungs; considerable variability in severity within groups; and there was no consistent concentration-response relationship. No lesions were seen in the nasal cavity. The PWG described these lesions as not typical of the type of lesions which occurs with known pulmonary irritants. These lesions were not found in control animals, which were housed in separate rooms. No infectious agent was identified upon serologic examination. In the draft NTP technical report (NTP, 1990), the inflammatory lung lesions were described as probably unrelated to exposure. Antibodies to common rodent respiratory tract viruses were not detected. However, only sera from control rats were sampled. Lesions morphologically indistinguishable from those in this study have been seen in control and treatment groups of rats from other inhalation and dosed feed studies (NTP, 1990). The PWG recommended that this effect be reevaluated in another study. In mice, no significant exposure-related gross or histopathological observations were noted at terminal necropsy of any organs, including the lung. The only exposure-related effects were significantly elevated absolute and relative liver weight in both sexes of mice at of 750 and 1000 ppm and significantly elevated relative kidney weight of the females exposed to 1000 ppm. There were no significant histopathological changes or function test alterations in either liver or kidney of either sex. The NTP peer review of the subchronic study took place on November 20, 1990 at Research Triangle Park. The NTP Board of Scientific Counselors' panel of experts agreed with the conclusions of the NTP report that there were no indications of toxicity due to ethyl benzene. A 2-year lifetime study in both rats and mice has been initiated and exposures have been conducted through 7 months. No serial sacrifices are planned and results are not expected prior to 1992. Clark (1983) exposed Wistar rats (n=18/sex/group) (12-13 weeks old) to 0 and 100 ppm (0 and 434 mg/cu.m) reagent grade ethylbenzene 6 hours/day, 5 days/week for 12 weeks. The duration-adjusted values were 0 and 77.5 mg/cu.m. Clinical observations, body weight, food intake, hematology, urinalysis, organ weights, and histopathology of all major organs (including the lung and nasal cavity) were used as parameters to assess toxicity. No statistically significant effects were observed at 100 ppm. There were no differences from controls in the liver enzymes, including SAP. While slight bile duct hyperplasia was seen in 15/18 exposed males and 14/18 exposed females, hyperplasia was also common in controls (10/18 females and 8/18 males), and these observations were not statistically significant. The results of this study suggest a NOAEL of 100 ppm. The NOAEL(HEC) is 77.5 mg/cu.m. The results are in general agreement with the findings of the NTP study in F344 rats. Wolf et al. (1956) exposed rats (n=10-25/sex/group) to 400, 600 or 1250 ppm (1737, 2606, or 5428 mg/cu.m) ethylbenzene 7 hours/day, 5 days/week for about 6 months. The duration-adjusted values were 0, 362, 542, and 1131 mg/cu.m, respectively, using the 7-hour duration. Exposure ranged from 186 to 214 days. Male rats only were also exposed to 2200 ppm (9554 mg/cu.m) for 7 hours/day, 5 days/week for about 5 months. The duration-adjusted value was 1990 mg/cu.m. Histopathology was performed on a variety of organs including the lung. Data on liver and kidney weights and histopathology were not presented; these parameters were discussed only in descriptive terms. Repeated exposure of rats, guinea pigs, and rhesus monkeys was examined. Growth was depressed moderately in male rats at 2200 ppm. Liver and kidney weights in rats were increased slightly in all exposed groups compared with matched controls, and rats exposed to 1250 and 2200 ppm developed histopathological changes manifested as cloudy swelling of the liver and renal tubules and testicular degeneration. The date indicate a NOAEL for liver histopatholgy at 600 ppm (542 mg/cu.m). However, no incidence data was reported. Since it is not clear that these effects are adverse when taken in context with the results of the NTP study, a NOAEL or LOAEL is not identified. Guinea pigs (5-10/sex/group) and rabbits (1-2/sex/group) were exposed to 0, 400, or 600 ppm (duration-adjusted concentrations of 0, 362, or 542 mg/cu.m, respectively) ethylbenzene 7 hours/day, 5 days/week for about 6 months. Only females were exposed to 1250 ppm (duration-adjusted value of 1131 mg/cu.m). Growth was depressed in female guinea pigs exposed to 1250 ppm. Liver weight was described as slightly increased only in the 600-ppm exposure group. The study does not clearly indicate 600 ppm as a LOAEL so the NOAEL for guinea pigs is designated at 600 ppm. The NOAEL(HEC) is 542 mg/cu.m. Other than an observation of slight degeneration of the testicular germinal epithelium in the male rabbit at 600 ppm, there were no adverse effects reported for rabbits of either sex. One male Rhesus monkey was exposed to 600 ppm (duration-adjusted value of 542 mg/cu.m) and two females were exposed to 400 ppm (duration-adjusted value of 362 mg/cu.m). A slight degeneration of the testicular germinal epithelium and increased liver weight was observed in the male monkey. No effects were reported for the female rhesus monkeys. The small number of rabbits and monkeys preclude identification of NOAEL and LOAEL values for these species. Cragg et al. (1989) exposed B6C3F1 mice (n=5/sex/group) and F344 rats (n=5/sex/group) to actual concentrations of 0, 99, 382, and 782 ppm (0, 430, 1659, and 3396 mg/cu.m) 6 hours/day, 5 days/week for 4 weeks. The duration-adjusted values were 0, 77, 296, 606 mg/cu.m, respectively. In the same study, New Zealand White rabbits (n=5/sex/group) were exposed to actual concentrations of 0, 382, 782, or 1610 ppm (0, 1659, 3396, or 6992 mg/cu.m). The duration-adjusted values were 0, 296, 606 and 1249 mg/cu.m, respectively. No changes were evident in mortality, clinical chemistry parameters, urinalysis, nor were there treatment-related gross or histopathological findings. Urinalysis was not performed on rabbits and clinical chemistry parameters were not performed on mice. Liver enzymes measured included AP. Hematology was performed on all species. Histopathology was only conducted on the high concentration animals except all rabbits' testes were examined. There was no liver histopathology in any of the species. In the 382-ppm exposure group, rats exhibited sporadic incidences of salivation and lacrimation. (These observations were not noted in the NTP subchronic study). Absolute liver weights were significantly increased in male rats; relative weight was increased at 782 ppm. In females, absolute liver weight was significantly increased at 782 ppm and relative weight at both concentrations. Male rats of the 782 ppm group had a significant (p<0.05) increase in platelets while females only had a significant (p<0.05) increase in total leukocytes. In mice, females showed a statistically significant increase in absolute, but not relative liver weight, at 782 ppm. There were no significant liver weight changes in male mice. Both males and females exhibited an increased liver weight relative to brain weight at 782 ppm only. Rabbits showed no changes in liver weight ratios at any exposure level. Since there were no adverse histopathological findings for the liver, a NOAEL of 782 ppm is identified for rats and mice. The NOAEL(HEC) is 606 mg/cu.m. The NOAEL for rabbits is 1610 ppm; the NOAEL(HEC) is 1249 mg/cu.m. Elovaara et al. (1985) found concentration-related increases in drug-metabolizing enzymes of liver and kidney, with corresponding ultrastructural alterations in a subchronic inhalation study with rats. Male Wistar rats (n=5/group) were exposed to 0, 50, 300, or 600 ppm (0, 217, 1302, or 2604 mg/cu.m) ethylbenzene 6 hours/day, 5 days/week for 2, 5, 9, or 16 weeks. The duration-adjusted values were 0, 38.7, 233, and 465 mg/cu.m, respectively. The liver was the only organ examined histologically (light and electron microscopy). There were no changes in liver weight at any concentration. After 16 weeks exposure, NADPH-cytochrome reductase and UDPG-transferase were significantly elevated at 300 and 600 ppm. Aminopyrine N-demethylase and 7-ethoxycoumarin-0-deethylase (7-ECDE) were elevated at all exposure levels. The elevation in UDPG-transferase was exposure-related and may signify glucuronidation of ethylbenzene metabolites during detoxication. Electron microscopy also showed changes in hepatocyte ultrastructure [e.g., smooth endoplasmic reticulum (SER) proliferation, slight degranulation of rough endoplasmic reticulum] at all exposure levels beginning 2 to 9 weeks after exposure. Necrosis was not observed nor were there any increases in serum alanine aminotransferase. SAP was not measured. The proliferation of SER is consistent with enzyme induction. At 16 weeks, changes in ultrastructure were mainly confined to the high-exposure group. There was no effect of exposure on hepatic glutathione (GSH) content. Significant increases in relative kidney weight only were reported following 2 and 9, but not at 16 weeks of exposure to 600 ppm. Kidney 7-ECDE, and UDPG transferase activities showed statistically significant and exposure-related increases at all exposure levels. In the absence of histologic evidence of damage, changes in absolute or relative liver weight, and no effect on serum ALT, the microsmal enzyme induction and ultrastructural changes are considered to be adaptation phenomena. The results of this study suggest a NOAEL of 600 ppm. The NOAEL(HEC) is 465 mg/cu.m for liver and kidney. The absence of liver weight changes is not consistent with the findings of the NTP (1988) subchronic study. Angerer and Wulf (1985) evaluated 35 workers who chronically (2-24 years, average 8.2 years) sprayed varnishes containing alkyd-phenol and polyester resins dissolved in solvent mixtures consisting principally of xylene isomers and ethylbenzene. Some of the varnishes contained lead-based pigments. The air samples from personal monitors indicated average levels of 4.0 ppm for ethylbenzene. Although workers had significantly elevated lymphocytes in addition to significantly decreased erythrocyte counts and hemoglobin levels compared with controls, these effects cannot be attributed to ethylbenzene since other compounds (e.g., xylene, methylchloroform, n-butanol, toluene, C9 hydrocarbons) were detected in some of the six workplaces evaluated. Bardodej and Cirek (1988) carried out biomonitoring of 200 ethylbenzene production workers occupationally exposed for a mean duration of 12.2 years to unspecified concentrations of ethylbenzene and benzene over a 20-year period. The workers were evaluated twice a year and ethylbenzene metabolites measured. No statistically significant differences in hematological effects (e.g., RBC, WBC, leukocyte and platelet counts) or liver function tests (e.g., aminotransferase and/or SAP and LDH activities and bilirubin tests) were observed between exposed and nonexposed workers. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Low Data Base -- Low RfC -- Low The developmental study by Hardin et al. (1981) was well-conducted and indicated no clearly adverse effects in any species. The study is given a low confidence rating because higher exposure levels may have provided more information on the potential for maternal toxicity and developmental effects. The data base is given a low rating since although other studies have examined a variety of other endpoints (e.g., liver and lung), by histopathology in rats and mice, there are no chronic studies and no multi-generation developmental studies. These latter studies would be useful to determine more conclusively the potential of ethylbenzene to affect development. NTP does not consider observations of lung lesions in rats exposed in the NTP subchronic study to be treatment-related. However, no infectious agent has been detected. Therefore, there remains a possibility that ethylbenzene may play a role in producing lung lesions. It is anticipated that this issue will be clarified upon completion of the chronic study in progress. In view of the previous considerations, the RfC is given a low confidence rating. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1984; 1985; 1987 Agency Work Group Review -- 09/19/1990, 12/20/1990 Verification Date -- 12/20/1990 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199108 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Ethylbenzene CASRN -- 100-41-4 Last Revised -- 08/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity. Basis -- nonclassifiable due to lack of animal bioassays and human studies. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA None. NTP has plans to initiate bioassay. Metabolism and excretion studies at 3.5, 35 and 350 mg/kg are to be conducted as well. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The metabolic pathways for humans and rodents are different (Engstrom et al., 1984). Major metabolites in humans, mandelic acid and phenylglyoxylic acid, are minor metabolites in rats and rabbits (Kiese and Lenk, 1974). The major animal metabolites were not detected in the urine of exposed workers (Engstrom et al., 1984). Ethylbenzene at 0.4 mg/plate was not mutagenic for Salmonella strains TA98, TA1535, TA1537 and TA1538 with or without Aroclor 1254 induced rat liver homogenates (S9) (Nestmann et al., 1980). Ethylbenzene was shown to increase the mean number of sister chromatid exchanges in human whole blood lymphocyte culture at the highest dose examined without any metabolic activation system (Norppa and Vainio, 1983). Dean et al. (1985) used a battery of short-term tests including bacterial mutation assays, mitotic gene conversion in Saccharomyces cerevisiae JD1 in the presence and absence of S9 and chromosomal damage in a cultured rat liver cell line. Ethylbenzene was not mutagenic in the range of concentrations tested (0.2, 2, 20, 50 and 200 ug/plate) for S. typhimurium TA98, TA100, TA1535, TA1537 and TA1538 or for Escherichia coli WP2 and WP2uvrA. Ethylbenzene also showed no response in the S. cerevisiae JD1 gene conversion assay. In contrast, ethylbenzene hydroperoxide showed positive responses with E. coli WP2 at 200 ug/plate in the presence of S9 and an equally significant response with the gene conversion system of yeast. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1980, 1984, 1987 The Ambient Water Quality Criteria Document and the Health Assessment Document have received Agency and external review. The Drinking Water Criteria Document has been extensively reviewed. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 10/07/1987 Verification Date -- 10/07/1987 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199103 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Ethylbenzene CASRN -- 100-41-4 Last Revised -- 03/01/1991 SORD: __VI.A. ORAL RfD REFERENCES U.S. EPA. 1980. Ambient Water Quality Criteria Document for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA 440/5-80-048. NTIS PB 81-117590. U.S. EPA. 1985. Drinking Water Criteria Document for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. (Final draft) U.S. EPA. 1984. Health Effects Assessment for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Andrew, F.D., R.L. Buschbom, W.C. Cannon, R.A. Miller, L.F. Montgomery, D.W. Phelps, et al. 1981. Teratologic assessment of ethylbenzene and 2-ethoxyethanol. Battelle Pacific Northwest Laboratory, Richland, WA. PB 83-208074., 108. Angerer, J. and H. Wulf. 1985. Occupational chronic exposure to organic solvents. XI. Alkylbenzene exposure of varnish workers: Effects on hematopoietic system. Int. Arch. Occup. Environ. Health. 56(4): 307-21. Bardodej, Z. and A. Cirek. 1988. Long-term study on workers occupationally exposed to ethylbenzene. J. Hyg. Epidemiol. Microbiol. Immunol. 32(1): 1-5. Cragg, S.T., E.A. Clarke, I.W. Daly, R.R. Miller, J.B. Terrill and R.E. Quellette. 1989. Subchronic inhalation toxicity of ethylbenzene in mice, rats, and rabbits. Fund. Appl. Toxicol. 13(3): 399-408. Clark, D.G. 1983. Ethylbenzene hydroperoxide (EBHP) and ethylbenzene (EB): 12 week inhalation study in rats. (Group research report with attachments and cover sheet.) EPA OTS Public Files. Shell Oil Co. Document No. 86870001629. Fiche Number 0516206 (2). Elovaara, E., K. Engstrom, J. Nickels, A. Aito and H. Vainio. 1985. Biochemical and morphological effects of long-term inhalation exposure of rats to ethylbenzene. Xenobiotica. 15(4): 299-308. Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier. 1981. Testing of selected workplace chemicals for teratogenic potential. Scand. J. Work Environ. Health. 7(suppl 4): 66-75. NTP (National Toxicology Program). 1988. Subchronic and chronic toxicity study of ethylbenzene. 90-Day subchronic study report on inhalation exposure of F344/N rats and B6C3F1 mice. Principal investigator: Catherine Aranyi. IIT Research Institute, Chicago, IL. NTP (National Toxicology Program). 1989. Chairperson's report. Pathology Working Group (PWG) review of subchronic toxicity testing on ethylbenzene administered by inhalation in F344 rats and B6C3F1 mice. NTP (National Toxicology Program). 1990. Draft NTP Technical Report on the Toxicity Studies of ethylbenzene in F344 rats and B6C3F1 mice (Inhalation Studies). NTP TOX 10, U.S. DHHS. Ungvary, G. and E. Tatrai. 1985. On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats, and rabbits. Arch. Toxicol. Suppl 8: 425-430. U.S. EPA. 1984. Health Effects Assessment for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/540/1-86-008. U.S. EPA. 1985. Drinking Water Criteria Document for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. NTIS PB 86-117835. (Final Draft). U.S. EPA. 1987. Health Advisory for Ethylbenzene. Office of Drinking Water, Washington, DC. Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Dean, B.J., T.M. Brooks, G. Hodson-Walker and D.H. Hutson. 1985. Genetic toxicology testing of 41 industrial chemicals. Mutat. Res. 153: 57-77. Engstrom, K., V. Riihimaki and A. Laine. 1984. Urinary disposition of ethylbenzene and m-xylene in man following separate and combined exposure. Int. Arch. Occup. Environ. Health. 54: 355-363. Kiese, M. and W. Lenk. 1974. Hydroxyacetophenones: Urinary metabolites of ethylbenzene and acetophenone in the rabbit. Xenobiotica. 4(6): 337-343. Nestmann, E.R., E.G-H. Lee, T.I. Matula, G.R. Douglas and J.C. Mueller. 1980. Mutagenicity of constituents identified in pulp and paper mill effluent using the Salmonella/mammalian-microsome assay. Mutat. Res. 79: 203-212. Norppa, H. and H. Vainio. 1983. Induction of sister-chromatid exchanges by styrene analogues in cultured human lymphocytes. Mutat. Res. 116: 379-387. U.S. EPA. 1980. Ambient Water Quality Criteria Document for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA 440/5-80-048. NTIS PB 81-117590. U.S. EPA. 1984. Health Effects Assessment for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1987. Drinking Water Criteria Document for Ethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. (Final report) ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Ethylbenzene CASRN -- 100-41-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. Dose conversion clarified 03/01/1988 I.A.6. Documentation revised 03/01/1988 III.A. Health Advisory added 09/07/1988 II. Carcinogen summary on-line 08/01/1989 VI. Bibliography on-line 08/01/1990 IV.F.1. EPA contact changed 10/01/1990 I.B. Inhalation RfC now under review 03/01/1991 I.B. Inhalation RfC summary on-line 03/01/1991 VI.B. Inhalation RfC references added 06/01/1991 I.A.7. Primary contact changed 08/01/1991 II.D.3. Secondary contact changed 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/10/1998 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 367 of 1119 in IRIS (through 2003/06) AN: 56 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 198912 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Furan- SY: 110-00-9; DIVINYLENE-OXIDE-; FURFURAN-; OXACYCLOPENTADIENE-; OXOLE-; TETROLE- RN: 110-00-9 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198912 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Furan CASRN -- 110-00-9 Last Revised -- 12/01/1989 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Hepatic lesions NOAEL: 2 mg/kg converted 1000 1 1E-3 to 1.4 mg/kg/day on mg/kg/day Mouse Subchronic Oral 5 days/7 days basis Study LOAEL: 4 mg/kg/day (rat) NTP, 1982 ---------------------------------------------------------------------------- *Conversion Factors: 5 days/week feeding schedule PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1982. Subchronic toxicity report on furan in B6C3F1 mice. Prepared by Southern Research Institute under Contract No. 1-CP-95641-01 for NTP, Bethesda, MD. NTP (1982) performed a 13-week gavage study using mice and rats (10 animals/sex/group) treated 5 days/week with furan in corn oil at 0-60 mg/kg. In this study, data on mortality, body weight, organ weight, and clinical and histopathologic signs of toxicity were evaluated. Clinical signs of toxicity were, for the most part, confined to male and female rats and female mice in the high-dose (60 mg/kg) group. High-dose male and female rats and high-dose (30 mg/kg) male mice had treatment-related reduced rates of body weight gain. In rats, histopathologic examination revealed a dose-related increased severity in liver lesions; lesions observed at the 4 mg/kg dose level were considered "minimal to mild." Measurement of relative organ weights revealed a dose-related increase in liver size in all treated groups of males and in all but the lowest dose (4 mg/kg) groups of female rats. In mice, relative organ weight measurements suggest that treatment-related increases in liver weight occurred in male mice at doses greater than or equal to 15 mg/kg and in females at doses greater than or equal to 30 mg/kg. Upon histopathologic examination, toxic hepatitis of dose-related severity was noted in male mice at doses greater than or equal to 8 mg/kg and in female mice at doses greater than or equal to 15 mg/kg. Doses of 2 and 4 mg/kg/day were without toxic effect. Examination of the NTP (1982) data indicated that the rat study failed to define a threshold for toxic hepatitis, the major lesion in the target organ for the toxicity of furan. The mouse study (NTP, 1982) indicated a threshold for toxic hepatitis, in that 2 and 4 mg/kg were doses in males at which lesions did not occur; mild lesions of toxic hepatitis occurred at 8 mg/kg. In females, lesions of toxic hepatitis were absent at 8 mg/kg and present at 15 mg/kg. Considering these data together, a dose of 2 mg/kg/day is a reasonable choice for the NOAEL. Since treatment was performed 5 days/week, the 2 mg/kg dose can be transformed to an equivalent dose of 1.4 mg/kg/day. By applying an uncertainty factor of 1000 to the mouse NOAEL of 1.4 mg/kg/day, an oral RfD (ADI) of 1 ug/kg/day or 0.1 mg/day for a 70-kg human can be recommended. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was applied: 10 for extrapolation from subchronic to chronic studies, 10 for interspecies extrapolation and another factor of 10 to provide added protection for sensitive individuals. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Availability of rat and mouse subchronic oral toxicity data provided a medium level of confidence for the RfD. The National Toxicology Program (NTP, 1985) is currently evaluating histopathologic data of a chronic gavage bioassay of furan in rats and mice. The data from this study may change the RfD and the level of confidence. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The principal study provided toxicologic parameters in well-designed subchronic studies in both rats and mice and, thus, rated medium. The data base lacks supporting studies and is rated low. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 02/26/1986 Verification Date -- 02/26/1986 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Furan CASRN -- 110-00-9 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Furan CASRN -- 110-00-9 NOCA: Not available at this time. ============================================================================ UDSO: 199306 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Furan CASRN -- 110-00-9 Last Revised -- 06/01/1993 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1982. Subchronic toxicity report on furan in B6C3F1 mice. Prepared by Southern Research Institute under Contract No. 1-ES-95651-01 for NTP, Bethesda, MD. NTP (National Toxicology Program). 1985. Management Status Report dated 08/07/1985. Bethesda, MD. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Furan CASRN -- 110-00-9 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/31/1987 I.A.6. Documentation corrected 03/01/1988 I.A.2. Text revised 03/01/1988 I.A.5. Confidence levels revised 12/01/1989 I.A. Principal study clarified 12/01/1989 VI. Bibliography on-line 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 06/01/1993 VI.A. Contract number in reference corrected 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 368 of 1119 in IRIS (through 2003/06) AN: 59 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 200107 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Hexachlorocyclopentadiene- (HCCPD) SY: 77-47-4; C-56-; GRAPHLOX-; HCCP-; HCCPD-; HEX-; HEXACHLORO-1,3-CYCLOPENTADIENE-; HEXACHLOROPENTADIENE-; PCL-; PERCHLOROCYCLOPENTADIENE- RN: 77-47-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200107 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Hexachlorocyclopentadiene (HCCPD) CASRN -- 77-47-4 Last Revised -- 07/05/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: The current RfD for hexachlorocyclopentadiene (HCCPD) is a reevaluation of an assessment placed on-line on 01/31/1987. Although the current assessment used benchmark dose modeling for the dose-response analysis, the resulting RfD is similar to that reported in the 1987 assessment. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Benchmark Doses UF MF RfD ------------------------------------------ -- -- ---- Chronic irritation BMDL10: 6 mg/kg/day 1,000 1 6E-3 mg/kg-day Rat subchronic BMD10: 11 mg/kg/day gavage bioassay Abdo et al., 1984 ------------------------------------------------------------------------ BMDL10 - 95% lower confidence limit on the maximum likelihood estimate of the dose corresponding to 10% risk. BMD10 - Maximum likelihood estimate of the dose corresponding to 10% risk. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) There are no chronic oral human studies or animal studies available for dose-response assessment. There were two subchronic oral studies in rodents. One is a gavage study in rats and mice by Abdo et al. (1984) and the other is a dietary study by Industrial Bio-test Laboratories (1975b). Athough gavage administration is not ideal for extrapolation to human exposure, there are two main reasons for choosing Abdo et al. (1984) as the principal study: (1) no effects were observed in the Industrial Bio-test Studies, and (2) effects were noted at lower doses than those given in the Industrial Bio-test Laboratories (1975b) study. Although dietary administration is more relevant to human exposure, there are two main reasons not to choose Industrial Bio-test Laboratories (1975b) as the principal study: (1) the quality of the data is suspect because the study was performed during a time when critical errors were committed at Industrial Bio-test Laboratories, and (2) it was not published in the peer-reviewed literature. See Section 4.2.2.2 of U.S. EPA (2001) for a summary of the subchronic study conducted by Industrial Bio-test Laboratories (1975b). Abdo, KM; Montgomery, CA; Kluwe, WM; et al. (1984) Toxicity of hexachlorocyclopenta-diene: subchronic (13-week) administration by gavage to F344 rats and B6C3F1 mice. J Appl Toxicol 4:75-81. Young adult F344 rats (10/sex/dose) were administered 0, 10, 19, 38, 75, or 150 mg HCCPD/kg via corn oil gavage 5 days/week for 13 weeks. Young adult B6C3F1 mice were treated on the same regimen, but at doses of 0, 19, 38, 75, 150, or 300 mg/kg. Stability of the gavage mixture, or the frequency of preparation, was not reported. Standard bioassay data including body weights, organ weights, pathology, and histopathology were collected. Mortality attributed to HCCPD occurred in six male rats in the 150 mg/kg group and in one male rat in the 75 mg/kg group. Other deaths were associated with gavage error, but the authors suggested that HCCPD may have been a contributor. A dose-related increase in the incidence of forestomach lesions started occurring in female rats at 19 mg/kg and in males at 38 mg/kg. Lesions were characterized by hyperplasia, acanthosis, and hyperkeratosis of the epithelial surface of the forestomach and increased mitotic activity in the basal layer of the epithelium. The forestomach lesions ranged from minimal to marked in severity and were focal to diffuse in distribution. Toxic nephrosis was noted in both sexes at 38 mg/kg and higher. Kidney lesions were predominantly limited to the terminal portion of the proximal convoluted tubules in the inner cortex and were characterized by dilated tubules and epithelial changes consisting of cytomegaly, karyomegaly, and anisokaryosis with nuclear and cytoplasmic vacuolization. Decreased body weights were noted in males at 38 mg/kg and in females at 75 mg/kg. Mortality was observed in mice at 300 mg/kg and was greater for males (10/10) than for females (3/10). Forestomach lesions were found in both sexes at 38 mg/kg. Lesions progressed to black foci, red cysts, and ulceration at 150 mg/kg. Toxic nephrosis, which was observed beginning at 75 mg/kg, occurred only in the female mice. Chronic irritation, manifested by forestomach lesions, was chosen as the critical effect because it occurred at lower doses than the toxic nephrosis. The irritant effects on the forestomach are consistent with the observation of dermal irritation (Treon et al., 1955; Industrial Bio-test Laboratories, 1975a; HEW, 1978) and other portal-of-entry effects from HCCPD exposure (NTP, 1994; Clark et al., 1982). Female rats were more susceptible to the forestomach irritation than male rats or either sex of mice. The incidence of forestomach histopathology in female rats was 0/10, 0/10, 2/10, 5/10, 9/10, and 9/10 for the 0, 10, 19, 38, 75, or 150 mg/kg doses, respectively. Benchmark dose modeling was applied to these data because there was a clear increase in response with dose and there were at least two doses that produced more than minimal but less than maximal effects. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 1,000 Chronic studies are preferred for RfD development. To account for the uncertainty in using a subchronic study for RfD derivation, a UF of 101/2 is applied. Rather than using the default of 10, this UF was derived by comparing the data from the subchronic and chronic inhalation studies (NTP, 1994). This approach is justified by the fact that HCCPD produces local effects by both oral and inhalation routes of exposure. The subchronic NOAEL to chronic NOAEL ratio from NTP (1994) was 0.8 for respiratory effects in rats while the ratio for mice was 3 (see Section I.B.2 for a more thorough discussion of NTP, 1994). Because it is more typical for the subchronic NOAEL to be larger than the chronic NOAEL, 3, or 101/2, was chosen as the subchronic-to-chronic UF for the RfD. In the absence of data on which to base a pharmacokinetic or pharmacodynamic comparison of rodents to humans, the default UF of 10 is used for interspecies extrapolation. There are no data documenting the nature and extent of variability in human susceptibilities to HCCPD, so the default UF of 10 is used to protect sensitive human subpopulations. The database for HCCPD includes studies of genotoxicity, developmental toxicity, systemic toxicity, and cancer, but no reproductive studies are available. An additional UF of 101/2 is added for this database deficiency. Thus, the total UF is 1,000. MF = 1 ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) The irritant effect on the forestomach observed in the critical study is consistent with portal-of-entry effects from HCCPD exposure. Respiratory tract damage (NTP, 1994; Clark et al., 1982) and skin lesions (Treon et al., 1955; Industrial Bio-test Laboratories, 1975a; HEW, 1978) are observed during inhalation and dermal exposures, respectively. The kidney also has been a target organ in oral studies (Abdo et al., 1984) as well as in an inhalation study (Clark et al., 1982) that noted mild degenerative kidney and liver lesions in rats at doses that also produce respiratory tract necrosis. One report of accidental human exposure suggests that the liver may also be a target organ (Kominsky et al., 1980). HCCPD was not a developmental toxin by oral gavage in rats, mice, or rabbits (Chernoff and Kavlock, 1983; Murray et al., 1980; Goldenthal et al., 1978). For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=39. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Database -- Low RfD -- Low The confidence in the principal study is medium. Although the study was well conducted, an adequate number of doses were examined, and corroborative results in two species were obtained, the design was lacking because no data on hematology, clinical chemistry, or urine analyses were collected. Confidence in the database is low. There are no good-quality supporting subchronic oral studies with which to compare the effects noted. Oral developmental studies in three species (Chernoff and Kavlock, 1983; Goldenthal et al., 1978; Murray et al., 1980), however, indicate that HCCPD is not a developmental toxin at doses (i.e., 75 mg/kg, Murray et al., 1980) higher than those that cause portal-of-entry irritation (i.e., 19 mg/kg in Abdo et al., 1984); however, the database lacks functional information on reproductive toxicity. In the absence of data on the relative sensitivity of adults and juveniles, HCCPD's effects in children cannot be predicted (see Section 4.7.1 of U.S. EPA, 2001). Thus, confidence in the RfD can also be considered low. Additional data of increasing scientific and regulatory interest include immunotoxicity, acute and subchronic neurotoxicity, and developmental neurotoxicity. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=47. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2001. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for Hexachlorocyclopentadiene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=54. Agency Consensus Date -- 06/19/2001 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 200107 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Sustance Name -- Hexachlorocyclopentadiene (HCCPD) CASRN -- 77-47-4 Last Revised -- 07/05/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: Note: The RfC is new to the IRIS file for HCCPD. The assessment placed on IRIS 01/31/1987 did not include an RfC. SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC ------------------- ------------------- ---- --- ---- Suppurative NOAEL: 0.56 mg/m3 100 1 2E-4 inflammation NOAELADJ:0.1 mg/m3 mg/m3 of the nose NOAELHEC: 0.024 mg/m3 Chronic inhalation study in B6C3F1 mice LOAEL: 2.23 mg/m3 NTP, 1994 LOAELADJ: 0.4 mg/m3 LOAELHEC: 0.095 mg/m3 ------------------------------------------------------------------------ *Conversion Factors and Assumptions: Conversion from intermittent exposure to continuous exposure: 0.56 mg/m3 x 6/24 hrs x 5/7 days = 0.1 mg/m3. Conversion to human equivalent concentration (HEC) for interspecies dosimetric adjustment: NOAELHEC was calculated for an effect in the extrathoracic (ET) region. MVA = 0.049 L/min, MVH = 13.8 L/min, [SAET]A = 3 cm2, SA(ET)H = 200 cm2. RGDRET = (MVA/[SAET]A) / (MVH/SA[ET]H ) = 0.237. NOAELHEC = NOAELADJ x RGDRET = 0.1 mg/m3 x 0.237 = 0.024 mg/m3. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) There are no chronic human inhalation studies suitable for dose-response assessment. The only available chronic human studies found no exposure-related diseases. Thus, the one available chronic animal study was chosen as the principal study. NTP (1994) reports well-designed inhalation bioassays with two species that are suitable to evaluate dose-response. NTP. (1994) Toxicology and carcinogenesis studies of hexachlorocyclopentadiene in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series 437:318. Sixty rats or mice per sex were exposed to atmospheres containing 0, 0.11, 0.56, or 2.23 mg/m3 HCCPD for 5 days/week for 2 years. Ten male and 10 female rats and mice from each exposure group were evaluated at 15 months. The stability of the compound was monitored throughout the study, and it was found that no degradation took place for up to 2 years. Standard bioassay data including body weights, organ weights, urinalysis, and histopathology were collected. Exposure to HCCPD did not significantly affect survival of rats or mice, but the decrease in survival of female mice approached statistical significance in the 2.23 mg/m3 group owing to suppurative inflammation of the ovary. Body weights of rats were unchanged by HCCPD exposure, but body weights of male and female mice were reduced in the 2.23 mg/m3 group. Exposure was associated with a yellow-brown granular pigmentation within the cytoplasm of epithelial cells lining the respiratory tract in both rats and mice. The pigmentation, possibly produced by lipid peroxidation (NTP, 1994), was not associated with any discernible pathology and, therefore, not considered to be an adverse effect. Although the designation of this pigmentation as nonadverse conflicts with ATSDR's treatment (ATSDR, 1999), it is consistent with the guidance in the RfC methodology (U.S. EPA, 1994), which indicates that "enzyme induction and subcellular proliferation or other changes in organelles, consistent with possible mechanism of action, but no other apparent effects" should be ranked low in severity. Furthermore, the guidance states that "effects that may be considered marginal are designated as adverse only to the extent that they are consistent with other structural and functional data suggesting the same toxicity," indicating pigmentation does not qualify as an adverse effect in this situation. In female rats, significant increases in the incidence of squamous metaplasia of the larynx were seen in the 0.11 and 2.23 mg/m3 groups. The lesion, described as stratified squamous epithelium several cell layers thick in areas usually lined by columnar epithelium, was considered to be of minimal severity in all groups. Because there is individual variation in the location of the transition between squamous and columnar epithelia and in obtaining consistent tissue sections in the treated rats, NTP indicated that the significance of this metaplasia is unknown. In addition, a dose-response relationship was not evident. Thus, the NOAEL for rats was 2.23 mg/m3 HCCPD and there was no LOAEL. Increases in suppurative inflammation of the nose were noted at 2.23 mg/m3 HCCPD in both male and female mice during the interim evaluation at 15 months and at study termination. Suppurative inflammation of the nose in mice was chosen as the critical effect since it was the only respiratory tract effect that occurred in both rats and mice. Neither sex of mice was clearly more sensitive to the effect than the other, so both sexes were used for the dose-response analysis. The incidence of this effect was 4/99, 0/100, 4/100, and 76/98 in the 0, 0.11, 0.56, and 2.23 mg/m3 groups, respectively. Thus, the NOAEL in mice for suppurative inflammation of the nose was 0.56 mg/m3 HCCPD and the LOAEL was 2.23 mg/m3. The available data did not meet the suggested criteria for applying a benchmark concentration analysis (U.S. EPA, 1995) of at least three dose levels with two doses eliciting a greater than minimum and less than maximum response. Thus, the duration-adjusted NOAEL of 0.10 mg/m3 is used to derive the RfC. Female mice also exhibited a dose-related increase in the incidence of suppurative ovarian inflammation that was significantly different from controls at 0.56 and 2.23 mg/m3 HCCPD. However, these lesions were common in NTP studies at the time of the HCCPD study (1984), and have since been reduced through better laboratory practice (Rao et al. 1987). The NTP Pathology Working Group on the HCCPD study did not consider these lesions to be a direct effect of the chemical, but felt they were most likely secondary to stress resulting from exposure. Ovarian abscesses in B6C3F1 mice resulted from bacterial infection, with the bacterium Klebsiella oxytoca being isolated most commonly. Dose related increases in ovarian abscesses have been seen in other NTP chronic studies and the reason for this apparent treatment-related effect has been unclear. It has been suggested that stress related to exposure may depress the immune system allowing infection by opportunistic bacteria. The ovarian inflammation is unlikely to have been mouse grouping related, as the mice were housed separately in this inhalation study. In addition, selection of ovarian inflammation as the critical endpoint would have led to a higher RfC, even though the point of departure would have been lower, because of the changed regional deposition dose-ratio (RGDR) calculation resulting from use of a nasal effect (portal of entry) to a systemic effect (ovarian suppuration). Based on these considerations, the Agency has chosen not to base its RfC on this end point. A 13-week study (NTP, 1994) provides supporting evidence that the respiratory tract is the major target of inhalation exposure to HCCPD. In a range-finding experiment to determine doses for the 2-year bioassays, the same strains of animals (10 per sex per species) were exposed to atmospheres containing 0, 0.45, 1.7, 4.5, 11, or 22 mg/m3 HCCPD for 5 days per week, 6 hours per day. No chemical-related differences in hematology, clinical chemistry, or urinalysis parameters were reported in exposed rats. All rats in the 11 and 22 mg/m3 groups died. Necropsy of rats in the 11 and 22 mg/m3 groups revealed extensive coagulation necrosis in the respiratory epithelium of the nose, larynx, trachea, bronchi, and bronchioles. Necrosis was accompanied by inflammatory signs such as vascular congestion, edema, fibrin accumulation, and neutrophil and mononuclear cell infiltration. Male rats in the 4.5 mg/m3 group exhibited significantly increased absolute and relative lung weights, as well as necrotizing and suppurative inflammation of the nose, bronchus, and bronchioles and squamous metaplasia of the nose. The squamous metaplasia was focal in nature, generally observed on the tips of the turbinates, and characterized by stratification of the epithelium to form three to four poorly defined layers of flattened, nonkeratinized polygonal cells. Female rats seemed to be less sensitive. At the 4.5 mg/m3 exposure, the only nasal effect was suppurative inflammation, and fewer females than males exhibited necrotizing and suppurative inflammation of the bronchus and bronchioles. Because no respiratory lesions were seen at exposures lower than 4.5 mg/m3 HCCPD, the NOAEL was 1.7 mg/m3. This is similar to the NOAEL of 2.3 mg/m3 observed for rats in the chronic study. All mice in the 11 and 22 mg/m3 groups died within five weeks. Before the end of the study, seven deaths occurred in the 4.5 mg/m3 group, one death occurred in the 1.7 mg/m3 group, and three deaths occurred in the 0.45 mg/m3 group. Six deaths in the female control group were attributed to a defective feeder. No chemical-related differences in hematology, clinical chemistry, or urinalysis parameters were reported in exposed mice. Males in the 0.45 mg/m3 group exhibited a statistically significant decrease in weight that was not toxicologically significant (i.e., <10%). Body weights of exposed animals were similar to controls in all other groups. In both rats and mice some statistically significant hematological changes in red blood cell parameters occurred. Although these changes were not dose-related, they are consistent with an adaptive response to impairment of pulmonary gas exchange and add to the weight of evidence that the respiratory system is the major target. Clark et al. (1982) also noted hematological effects in subchronic studies. As evidenced by a somewhat lower frequency of effects, mice were not as sensitive to the respiratory toxicity of HCCPD as were rats. Male mice exhibited significant increases in suppurative inflammation of the nose and squamous metaplasia of the trachea at 4.5 and 11 mg/m3; and acute necrosis and suppurative inflammation of the nose; acute necrosis of the larynx, trachea, and lung; and congestion of the lung at 22 mg/m3; Female mice had serous inflammation of the nose; at 4.5 mg/m3; and suppurative inflammation of the nose, squamous metaplasia of the larynx and trachea, and necrotizing inflammation of the lung; at 11 mg/m3. At the highest dose, female mice presented the same spectrum of effects as male mice. No respiratory effects were observed in mice at 1.7 mg/m3. The chronic study observed a NOAEL of 0.56 mg/m3 HCCPD in mice. The 1.7 mg/m3 NOAEL in the 13-week study (NTP, 1994) supports the use of the chronic study (NTP, 1994) as the principal study because a lower NOAEL was observed. Clark, DG; Pilcher, A; Blair, D; et al. (1982) Thirty week chronic inhalation study of hexachlorocyclopentadiene (HEX) in rats. Group Research Report SBGR.82.051. NTIS/OTIS43022. This study also showed that the respiratory tract is the major target organ of inhaled HCCPD. Wistar rats inhaled, via whole-body exposure, 0, 0.05, 0.1, or 0.5 ppm (conversion of 1 ppm = 11.3 mg/m3 yields 0, 0.56, 1.1, or 5.6 mg/m3, respectively) HCCPD for 6 hours/day, 5 days/week, for 30 weeks and recovered from exposure for 14 weeks. Chemical purity of the compound decreased from 96% to 90% during the course of the study because of oxidation. Bronchopneumonia was noted in four males and two females, which died during exposure to 5.6 mg/m3. Two of the deceased rats had enlarged adrenals and the thorax contained watery or bloodstained fluid. Males in the 1.1 mg/m3 and 5.6 mg/m3 groups had significantly higher mean erythrocyte counts, hemoglobin concentrations, hematocrit, and absolute numbers of neutrophils, and significantly lower lymphocyte counts than the controls. Mean absolute numbers of lymphocytes were lower in females at the 5.6 mg/m3 dose. Body weights of males from the 5.6 mg/m3 dose group were significantly lower than those of controls. Several increases in body weights in females exposed to HCCPD compared with controls were noted, but by the end of the recovery period, body weights of females exposed to 1.1 and 5.6 mg/m3 HCCPD were significantly lower than controls. Kidney weights were significantly increased in females in the 5.6 mg/m3 group after exposure for 30 weeks. Male heart weights were decreased at 30 weeks in the 5.6 mg/m3 group. The organ weight effects were not considered to be biologically significant by the study authors. Clark et al. (1982) also observed mild degenerative changes in the livers and kidneys of rats in the 5.6 mg/m3 group. Rats at the 5.6 mg/m3 dose showed pulmonary degenerative changes including epithelial hyperplasia, edema, and sloughing of the bronchiolar epithelium in both sexes and epithelial ulceration and necrosis in the males. No degenerative changes in the lungs were observed in the 0.56 or 1.1 mg/m3 dose groups. The authors suggested that the toxic action of HCCPD involved an extreme local irritation of the respiratory tract and that the mild degenerative changes in the livers and kidneys of a few animals were unlikely to contribute significantly to toxicity in the rat. The 1.1 mg/m3 NOAEL for respiratory effects in rats in this study supports the use of NTP (1994) as the principal study because a lower NOAEL was observed in mice. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 100 The default uncertainty factor for interspecies extrapolation is 10. Half of that factor, 101/2, reflects the pharmacokinetic component of interspecies uncertainty and half represents the pharmacodynamic component of interspecies uncertainty. The pharmacokinetic component of interspecies uncertainty is accounted for by the dosimetric adjustment, which converts animal exposure concentrations of HCCPD to HEC. Thus, an uncertainty factor of 101/2 is employed for interspecies extrapolation to reflect the pharmacodynamic component of interspecies uncertainty. There are no data documenting the nature and extent of variability in human susceptibilities to HCCPD, so the default UF of 10 is used to protect sensitive human subpopulations. A factor of 101/2 is applied for an incomplete database because the inhalation database lacks developmental and reproductive toxicity. The total UF is 100. MF = 1 IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) Portal-of-entry irritation effects due to HCCPD have also been observed for oral (Abdo et al, 1984) and dermal (Treon et al., 1955; Industrial Bio-test Laboratories, 1975; HEW, 1978) routes of exposure. Necrosis of bronchial epithelium and pulmonary hyperemia and edema were observed in rats, mice, rabbits, and guinea pigs exposed to high concentrations of HCCPD in acute and subacute experiments (Treon et al., 1955). Tracheobronchial irritation was reported in humans after accidental exposure to high levels of HCCPD vapor (Kominsky et al., 1980). For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=39. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Database -- Medium RfC -- Medium The overall confidence in the RfC assessment is medium. The confidence in the principal study is high because it was well designed and followed standard guidelines for toxicity studies of chronic duration. The overall confidence in the database is medium. There are two chronic inhalation studies in two species accompanied by three (two with rats, one with mice) subchronic studies that verify that the respiratory tract is the major target organ. However, the inhalation database lacks reproductive and developmental studies. Oral developmental studies in three species (Chernoff and Kavlock, 1983; Goldenthal et al., 1978; Murray et al., 1980), however, indicate that HCCPD is not a developmental toxin at doses (i.e., 75 mg/kg in Murray et al., 1980) higher than those that cause portal-of-entry irritation (i.e., 19 mg/kg in Abdo et al., 1984). This suggests that the possible developmental effects of inhaled HCCPD may be less sensitive than the portal-of-entry respiratory tract effects. As there are no studies on the effects of HCCPD in juvenile animals, its effects in children cannot be predicted (see Section 4.7.1 of U.S. EPA, 2001). Additional data that would increase confidence in the assessment include immunotoxicity, acute and subchronic neurotoxicity, and developmental neurotoxicity. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=47. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 2001. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for Hexachlorocyclopentadiene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=54. Agency Consensus Date -- 06/19/2001 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 200107 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Hexachlorocyclopentadiene (HCCPD) CASRN -- 77-47-4 Last Revised -- 07/05/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY The current carcinogenicity assessment for HCCPD is a revision of the assessment placed in IRIS in 1990. WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION The apparent inability of HCCPD to cause genotoxic effects, and the lack of evidence for both human and animal carcinogenicity by the inhalation route, justify the conclusion that HCCPD is not likely to present a human cancer risk via inhalation exposure. According to the existing Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a), evaluation of the weight of evidence for carcinogenicity to humans indicates that HCCPD is most appropriately categorized as Group E, Evidence of Noncarcinogenicity to Humans, via inhalation exposure. In accordance with U.S. EPA's Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), HCCPD is not likely to be a human carcinogen by the inhalation route based on current data indicating no evidence of cancer in well-conducted bioassays in two species of rodents; the absence of increased deaths from cancer in the limited human occupational studies available; and lack of mutagenicity in a variety of test systems. In a well conducted 2-year inhalation bioassay, no increased incidence of tumors was reported in male or female rats and mice up to 2.2 mg/m3 (NTP, 1994). Several occupational epidemiological studies reported no increase in cancer mortality associated with HCCPD exposure, in the presence of other chlorinated production compounds. Mutagenicity studies were negative in five strains of S. typhimurium; negative in mouse micronucleus assays; showed no evidence of transformation of BALB/3T3 cells or forward mutations in mouse lymphoma cells; did not induce DNA repair when incubated with rat hepatocytes; and failed to induce lethal mutations in the offspring of male Drosophila. The only positive result for mutagenicity was an isolated statistically significant increase in sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells, but chromosome damage did not occur in metaphase stage rat liver cells. Because the existing chronic health effect data in both humans and animals do not include the oral route of exposure, the potential for carcinogenicity by the oral route is unknown. Additionally, there are no data on the carcinogenic potential of HCCPD in developing organisms. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=47. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=39. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Several retrospective mortality studies have been conducted on employees in plants that either produced HCCPD or used it in the manufacture of chlorinated pesticides. These studies, however, are inadequate to assess carcinogenicity of hexachlorocyclopentadiene alone because they do not estimate exposure levels to the chemical or correlate excess deaths with exposure. The studies are also limited by exposure of cohorts to other chemicals, relatively short follow-up periods, small number of person-years, and lack of data on cigarette smoking. Shindell and Associates (1980) conducted a mortality study of 783 workers employed at least 3 months between January 1, 1946, and December 31, 1979, at the Velsicol Chemical Corporation plant in Marshall, IL. This plant manufactured synthetic chlorinated hydrocarbon insecticides using HCCPD as an intermediate. The vital status of 97.4% of the cohort was known. The causes of death examined included malignant neoplasms, diseases of the heart and circulatory system, cerebrovascular disease, trauma, and others. The number of observed deaths in each category was compared to the number of expected deaths calculated from race- and sex-specific U.S. mortality rates for appropriate 5-year periods. No excess deaths related to any specific job class or product were seen. Except for "other deaths" in females, the number of deaths observed appear lower than the number expected. The 22 deaths from cancer included brain, kidney, liver, lung, and digestive system cancers; 8 of the 22 cancer deaths were from lung cancer. The number of expected deaths for each specific cancer was not calculated. Shindell and Associates (1981) conducted a mortality study with 1,115 workers employed for at least 3 months between January 1, 1952, and December 31, 1979, at the Velsicol Chemical Corporation plant in Memphis, TN. This plant manufactured synthetic chlorinated hydrocarbon insecticides using HCCPD as an intermediate. The vital status of 92.8% of the cohort was known. The study design was the same as that of the Shindell and Associates (1980) study described above. Deaths from strokes and from trauma showed an increase over the number of expected deaths, but the increases were not statistically significant. The distribution of the standard mortality ratio of cancer deaths by cancer site and job showed a nonsignificant excess of lung cancer in maintenance workers. The study authors concluded that there was no pattern of neoplasia suggestive of job-related risk. Wang and MacMahon (1979) also conducted a retrospective mortality study of the workers at the Velsicol Chemical Corporation plants in Marshall, IL, and Memphis, TN. The study group included 1,403 males who worked at either plant longer than 3 months before the spring of 1976. Person-years were calculated for January 1, 1946, to June 30, 1976, for Marshall employees and for January 1, 1952, to December 31, 1976, for Memphis employees. Approximately 34% of the subjects had fewer than 10 years follow-up and 36% had 20 or more years of follow-up study. Expected deaths for these person-years were calculated from white male national mortality rates through 1975. Observed deaths due to all causes were significantly fewer than expected. Deaths due to cerebrovascular disease, however, were statistically elevated over those expected. Deaths due to all cancers were fewer than expected, but deaths due to lung cancer were greater than expected, although not significantly. There was no relationship between lung cancer deaths and duration of exposure to HCCPD or duration of follow-up. No data on cigarette smoking are available for this study group. There was one death each from cancer of the liver, bladder, prostate, and central nervous system. A mortality study was performed involving cohorts that overlapped the one used in the Wang and MacMahon study (1979) but extended the follow-up period (Brown et al. 1980). Different cohorts from four chemical plants that manufactured organochlorine pesticides were used in this study. These cohorts comprised all workers at each plant who had worked at least 6 months prior to December 31, 1964. Causes of deaths among the cohorts occurring prior to December 31, 1976, were recorded. Observed deaths in the cohorts were far fewer than expected, reflecting the healthy-worker effect. The expected value was calculated using U.S. white-male cause-specific mortality rates, but the report did not specify the ethnicity or sex of the employees studied. The increase in cerebrovascular disease observed in the Wang and MacMahon study (1979) was not reported in this study. A deficit in deaths from all malignant neoplasms in each plant was observed, but the numbers of workers dying from cancer were too few to provide statistically significant values. There were slight, but not statistically significant, increases in stomach cancer deaths in one plant, and slight excesses of cancer of the esophagus, cancer of the rectum, liver cancer, and cancer of the lymphatic and hematopoietic system in another plant. However, exposure to multiple organochlorine compounds in each of the plants precludes linking these cancer cases with exposure to HCCPD or any other individual compound. Buncher et al. (1980) conducted an occupational mortality study with 341 workers at the Hooker Chemical Corporation plant in Montague, MI. The plant produced HCCPD and other chlorinated hydrocarbons. Employees who had worked at least 90 days between October 1, 1953, and December 31, 1974, were included in the cohort. Follow-up was through December 31, 1978. Expected deaths were calculated using sex-, age- and year-specific U.S. mortality rates. Deaths due to all causes, all cancers, diseases of the circulatory system, diseases of the digestive system, and external causes were all fewer than expected. The six observed cancer deaths included one of the kidney and two of the respiratory system. The ratio of observed-to-expected deaths for the respiratory cancers (0.87) and colon cancer (1.75) are near 1.0 and are not statistically significant. The remaining cancers have ratios greater than or equal to 5; however, the small number of deaths prevents drawing a firm conclusion. The short follow-up period is also a limitation. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA No evidence of carcinogenicity. NTP (1994) conducted a 2-year inhalation study with rats and mice and concluded that HCCPD exhibited no evidence of carcinogenic activity (NTP, 1994). Groups of 60 animals per sex per species were exposed, via whole-body inhalation, for 5 days per week, 6 hours per day, to 0, 0.11, 0.56, or 2.23 mg/m3 HCCPD. The study was well designed and involved two rodent species and an appropriate number of subjects at each dose. No exposure-related increases in neoplasms were seen in male or female rats or mice. In male rats, a significant increase in the incidence of pars distalis adenoma of the pituitary (33/50, or 66%) was seen in the 2.3 mg/m3 group. As the historical control incidence of pars distalis adenoma in male F344/N rats from other NTP inhalation studies is 60%, with a range of 45%-68%, this effect was not considered to be related to HCCPD exposure. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The weight of evidence for mutagenicity indicates that HCCPD is not mutagenic. A battery of genotoxicity studies performed by the NTP yielded generally negative results for HCCPD (NTP, 1994). NTP (1994) confirmed previous negative results for HCCPD in the Ames test (Brooks et al., 1984; Industrial Bio-test Laboratories, 1977). Negative results were also seen for changes in micronucleated erythrocyte frequency in B6C3F1 mice exposed to HCCPD for 13 weeks by inhalation, and for induction of sex-linked recessive lethal mutations in male Drosophila melanogaster. The negative results in Drosophila melanogaster confirmed those of other investigators (Mason et al., 1992; Zimmering et al., 1985). HCCPD did not induce a significant increase in morphological transformation in BALB/3T3 cells and did not induce forward mutations in mouse lymphoma cells at noncytotoxic concentrations (Litton Bionetics, Inc., 1978). Cytogenetic effects manifested as sister chromatid exchanges and chromosomal aberrations were observed in Chinese hamster ovary cells exposed to HCCPD with and without S9 (NTP, 1994), but chromosome damage did not occur in metaphase-stage rat liver (RL4) cells (Brooks et al., 1984). HCCPD at subtoxic concentrations also did not induce DNA repair when incubated with rat hepatocytes in vitro (Brat, 1983). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2001. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for Hexachlorocyclopentadiene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0059-tr.pdf#page=54. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Consensus date - 06/19/2001 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 200107 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Hexachlorocyclopentadiene (HCCPD) CASRN -- 77-47-4 Last Revised -- 07/05/2001 SORD: __VI.A. ORAL RfD REFERENCES Abdo, KM; Montgomery, CA; Kluwe, WM; et al. (1984) Toxicity of hexachlorocyclopentadiene: Subchronic (13-week) administration by gavage to F344 rats and B6C3F1 mice. J Appl Toxicol 4:75-81. Chernoff, N; Kavlock, RJ. (1983) A teratology test system which utilizes postnatal growth and viability in the mouse. Environ Sci Res 27:417-427. Clark, DG; Pilcher, A; Blair, D; et al. (1982) Thirty week chronic inhalation study of hexachloro-cyclopentadiene (HEX) in rats. Group Research Report SBGR.82.051. NTIS/OTIS43022. Goldenthal, EI; Jessup, DC; Rodwell, DE. (1978) Teratology study in rats. Unpublished report by International Research and Development Corporation for Velsicol Chemical Corporation. Report No. 163-573. Doc #40-8249076, NTIS/OTS0512884. HEW. (1978) Pathology reports of studies on rats & guinea pigs treated w/HCCPD & an ecotoxicological evaluation of environmental chemicals. Unpublished internal document from the U.S. Department of Health, Education and Welfare. February 1978. Doc. # 40-7849029. Industrial Bio-test Laboratories. (1975a) 28-day subacute dermal toxicity study with C-56 in albino rabbits. Unpublished report to Hooker Chemical Corporation. Doc. # 878212101. NTIS/OTS84003A. Industrial Bio-test Laboratories. (1975b) 90-day subacute oral toxicity study with C-56 in albino rats. Unpublished report to Hooker Chemical Corporation. Doc # 878212102. NTIS/OTS84003A. Kominsky, JR; Wisseman, CL, III; Morse, DL. (1980) Hexachlorocyclopentadiene contamination of a municipal wastewater treatment plant. Am Ind Hyg Assoc J 41:552-556. Murray, FJ; Schwetz, BA; Balmer, MF; et al. (1980) Teratogenic potential of hexachlorocyclopentadiene in mice and rabbits. Toxicol Appl Pharmacol 53:497-500. NTP. (1994) Toxicology and carcinogenesis studies of hexachlorocyclopentadiene in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series 437:318. Treon, JF; Cleveland, FP; Cappel, J. (1955) The toxicity of hexachlorocyclopentadiene. AMA Arch Ind Health Ind Health 11:459-472. U.S. EPA. (1998) Health effects test guidelines. OPPTS 870.3100 90-day oral toxicity in rodents. EPA 712-C-199. U.S. EPA. (2001) Toxicological review of hexachlorocyclopentadiene in support of summary information on Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Abdo, KM; Montgomery, CA; Kluwe, WM; et al. (1984) Toxicity of hexachlorocyclopentadiene: Subchronic (13-week) administration by gavage to F344 rats and B6C3F1 mice. J Appl Toxicol 4:75-81. Clark, DG; Pilcher, A; Blair, D; et al. (1982) Thirty week chronic inhalation study of hexa-chlorocyclopentadiene (HEX) in rats. Group Research Report SBGR.82.051. NTIS/OTIS43022. Industrial Bio-test Laboratories. (1975) 28-day subacute dermal toxicity study with C-56 in albino rabbits. Unpublished report to Hooker Chemical Corporation. Doc. # 878212101. NTIS/OTS84003A. Kominsky, JR; Wisseman, CL, III; Morse, DL. (1980) Hexachlorocyclopentadiene contamination of a municipal wastewater treatment plant. Am Ind Hyg Assoc J 41:552-556. NTP. (1994) Toxicology and carcinogenesis studies of hexachlorocyclopentadiene in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series 437:318. Treon, JF; Cleveland, FP; Cappel, J. (1955) The toxicity of hexachlorocyclopentadiene. AMA Arch Ind Health Ind Health 11:459-472. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. U.S. EPA. (2001) Toxicological review of hexachlorocyclopentadiene in support of summary information on integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Brat, SV. (1983) The hepatocyte primary culture/DNA repair assay on compound hexachlorocyclopentadiene using rat hepatocytes in culture. Naylor Dana Institute for Disease Prevention. Am. Health Foundation, Valhalla, NY. Doc. No. 878213752; Microfiche No. 0TS0206296. Brooks, TM; Hodson-Walker, G; Wiggins, DE. (1984) Genotoxicity studies with hexachloro-cyclopentadiene. Shell Oil Company Report No. 184. Doc # 878214192. NTIS/OTS0206492. Brown, DP; Ditraglia, D; Namekata, T; et al. (1980) Mortality study of workers employed at organochlorine pesticide manufacturing plants. U.S. Dept of Health, Education and Welfare and University of Illinois. Unpublished report. May 1980. Doc. # 40-8149074. Buncher, CR; Moomaw, C; Sirkeski, B. (1980) Mortality study of Montague Plant-Hooker Chemical. Univ. Cincinnati Med. Center, Div. Epi. Biostat. Unpublished report prepared for Hooker Chemical Corp. Doc. No. 878212111. Microfiche No. 0TS0205956. Industrial Bio-test Laboratories. (1977) Mutagenicity of PCL-HEX incorporated in the test medium tested against five strains of Salmonella typhimurium and as a volatilate against tester strain TA-100. Unpublished report to Velsicol Chemical Corporation, August 1977. NTIS/OTS0512876. Litton Bionetics, Inc. (1978) Evaluation of hexachlorocyclopentadiene in vitro malignant transformation in Balb/3T3 cells. Unpublished report submitted to Velsicol Chemical Company. Doc #40-8049068. NTIS/OTS0512876. Mason, JM; Valenci, R; Zimmering, S. (1992) Chemical mutagenesis testing in Drosophila: VIII. Reexamination of equivocal results. Environ Mol Mutagen 19:227-234. NTP. (1994) Toxicology and carcinogenesis studies of hexachlorocyclopentadiene in F344/N rats and B6C3F1 mice (inhalation studies). National Toxicology Program Technical Report Series 437: 318. Shindell and Associates. (1980) Report of the Epidemiologic Study of the Employees of Velsicol Chemical Corporation Plant, Marshall, Illinois, January 1946-December 1979. Velsicol Chemical Corp., Chicago, IL. Shindell and Associates. (1981) Report of the Epidemiologic Study of the Employees of Velsicol Chemical Corporation Plant, Memphis, Tennessee, January 1952-December 1979. Velsicol Chemical Corp., Chicago, IL. U.S. EPA. (1986) Guidelines for carcinogen risk assessment. Fed Reg 51(185):33992-34003. U.S. EPA. (1996) Proposed guidelines for carcinogen risk assessment. Washington, DC: National Center for Environmental Assessment. EPA/600/P-92/003C. U.S. EPA. (2001) Toxicological review of hexachlorocyclopentadiene in support of summary information on integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. Wang, HH; MacMahon, B. (1979) Mortality of workers employed in the manufacture of chlordane and heptachlor. J Occup Med 21(11):745-748. Zimmering, S; Mason, JM; Valencia, R; et al. (1985) Chemical mutagenesis testing in Drosophila. II. Results of 20 coded compounds tested for the National Toxicology Program. Environ Mutagen 7:87-100. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Hexachlorocyclopentadiene (HCCPD) CASRN -- 77-47-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1989 I.A.6. Verification date changed 09/01/1989 VI. Bibliography on-line 11/01/1989 II. Carcinogen assessment now under review 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 09/01/1990 I.A. Text edited 09/01/1990 II. Carcinogen assessment on-line 09/01/1990 VI.C. Carcinogen references added 08/01/1991 VI.A. Citations clarified 08/01/1991 VI.C. Citations clarified 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 07/05/2001 I.A Revised RfD 07/05/2001 I.B. Added RfC 07/05/2001 II. Revised carcinogen summary 07/05/2001 VI. Revised bibliography ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 369 of 1119 in IRIS (through 2003/06) AN: 61 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199507 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Hydrogen-sulfide- SY: 7783-06-4; DIHYDROGEN-MONOSULFIDE-; DIHYDROGEN-SULFIDE-; HYDROGEN-SULPHIDE-; HYDROSULFURIC-ACID-; SULFURATED-HYDROGEN-; SULFUR-HYDRIDE- RN: 7783-06-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198803 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Hydrogen sulfide CASRN -- 7783-06-4 Last Revised -- 03/01/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- GI disturbance NOAEL: 3.1 mg/kg/day 1000 1 3E-3 mg/kg/day Pig Oral Toxicity LOAEL: 15 mg/kg/day Study (subchronic) Watterau et al., 1964 ---------------------------------------------------------------------------- *Conversion Factors: 0.200 kg of diet/day x 1210 mg H2S/kg of diet / 78 kg bw = 3.1 mg/kg bw/day PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Watterau, H., W. Ockert and U.G. Knape. 1964. In: Toxicity of Hydrogen Sulfide in Animal Feeding. Survey of the literature. (Westermann et al., 1975. Landwirtsch. Forsch. 28: 70-80) Data regarding chronic/subchronic toxicity of hydrogen sulfide (H2S) was limited and H2S is not scheduled for carcinogenicity testing by the NTP (1985). The oral toxicity data (Watterau et al., 1964) may be used to calculate an RfD. Although lacking in some detail, Watterau et al. (1964) suggested that adult pigs showed digestive disorders when their diet was replaced by a high percentage of dried greens containing H2S at an approximate intake of 15 mg/kg/day. This effect was not reproduced in a second experiment. This dose may be considered a LOAEL. Watterau et al. (1964) also tested pigs for 105 days at three lower doses. An intermediate dose of approximately 3.1 mg/kg/day (determined from information given in the principal study) was associated with no changes in body weight gain when compared with controls. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 1000 represents 10 for interspecies extrapolation, 10 for sensitive population and 10 for subchronic exposure. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Based on epidemiologic data (Poda, 1966) the ACGIH (1980) has recommended a TLV-TWA of 10 ppm (13.9 mg/cu.m) for hydrogen sulfide. However, citing evidence of eye injury, headaches, nausea, and insomnia after exposure to H2S at low concentrations for several hours, NIOSH (1977) adopted a ceiling occupational exposure limit of 10 ppm with a 10-minute maximum exposure to this concentration. More rigorous epidemiologic evidence, however, is limited. Until further chronic/reproductive data are available, a low confidence in the RfD is recommended. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low The confidence in the study is rated low because the number of animals/ dose group was unspecified and the study was designed to test for only minimal toxic responses. Since insufficient studies exist, low confidence is assigned to the data base. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 08/19/1985, 11/06/1985 Verification Date -- 11/06/1985 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199507 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Hydrogen sulfide CASRN -- 7783-06-4 Last Revised -- 07/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- ----------------------- ----- --- --------- Inflammation of the NOAEL: 42.5 mg/cu.m 1000 1 1E-3 nasal mucosa (30.5 ppm) mg/cu.m NOAEL(ADJ): 7.59 mg/cu.m Mouse Subchronic NOAEL(HEC): 1.01 mg/cu.m Inhalation Study LOAEL: 110 mg/cu.m (80 ppm) CIIT, 1983a LOAEL(ADJ): 20 mg/cu.m LOAEL(HEC): 2.6 mg/cu.m ---------------------------------------------------------------------------- *Conversion Factors and Assumptions: MW = 34.08. Assuming 25 C and 760 mmHg, NOAEL (mg/cu.m = 30.5 ppm x 34.08/24.45 = 42.5. NOAEL(ADJ) = 42.5 x 6 hours/24 hours x 5 days/7 days = 7.59. The NOAEL(HEC) was calculated for a gas:respiratory effect in the extrathoracic region. MVa = 0.04 cu.m, MVh = 20 cu.m, Sa(ET) = 3.0 sq.cm, Sh(ET) = 200 sq.cm. RGDR(ET) = (MVa/Sa)/(MVh/Sh) = 0.133. NOAEL(HEC) = NOAEL(ADJ) x RGDR = 1.01 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) CIIT (Chemical Industry Institute of Toxicology). 1983a. 90-Day vapor inhalation toxicity study of hydrogen sulfide in B6C3F1 mice. U.S. EPA OTS Public Files. Fiche No. 0000255-0. Document No. FYI-OTS-0883-0255. Subchronic (90-day) inhalation studies were conducted using B6C3F1 mice (CIIT, 1983a). Three groups of 10 males and 12 female mice each were exposed to 0, 10.1, 30.5, and 80.0 ppm (0, 14.1, 42.5, and 110 mg/cu.m, respectively) hydrogen sulfide for 6 hours/day, 5 days/week (duration adjusted to 0, 2.51, 7.59, and 20 mg/cu.m, respectively) for 90 days. A control group consisting of 10 male and 12 female mice were exposed to clean air only. Animals were examined using neurological function tests of posture, gait, facial muscle tone, and reflexes; ophthalmological examination using a slit-lamp scope; hematological parameters; and detailed necropsy, including brain (5 locations), spinal cord (3 locations), peripheral nerves, eyes, heart, lungs (4 levels), nasal turbinates (4 levels), and other organs. The only exposure-related histopathological lesion was inflammation of the nasal mucosa in the anterior segments of the nose, which was observed in 8/9 male mice and in 7/9 female mice in the group exposed to 80 ppm. This lesion also was present in two high-dose mice that died during the course of the study. The lesion was generally minimal to mild in severity and was located in the anterior portion of the nasal structures, primarily in the squamous portion of the nasal mucosa, but extended to areas covered by the respiratory epithelium. This lesion was not observed in any animals in the other exposure groups. Thus, for mice, 80 ppm (HEC = 2.6 mg/cu.m) is considered a LOAEL for nasal inflammation, whereas 30.5 ppm (HEC = 1.01 mg/cu.m) is a NOAEL. A minimal submucosal lymphocytic cellular infiltrate was observed in the posterior section of the nasal structures. This lesion occurred with approximately equal frequency in control and exposed animals and is not considered to be exposure related. Significant reductions in body weight gain were noted in all exposure groups at various times during the study. Decreased weight gain in animals exposed to 80 ppm occurred consistently in both male (approximately 90% of control during the last 7 weeks of the study) and female (<90% of control during the last 3 weeks of the study) mice. This level is considered a LOAEL [HEC = 20 mg/cu.m, calculated for an extrarespiratory effect and assumes periodicity and uses the default value of 1 for lambda(a)/lambda(h)]. Statistically significant changes in absolute kidney, liver, and spleen weights also were observed in the male rats exposed to 80 ppm, but no differences were apparent when organ weights were normalized to body weight. Neurologic function examinations yielded negative results. Blood volume, appearance, occult blood, specific gravity, protein, pH, ketone, and glucose values were all normal. Ophthalmoscopic examination, hematology, serum chemistry parameters, and urinalysis also were normal. Histopathological examination revealed no abnormalities in comparison to controls, other than those discussed above. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- The uncertainty factor of 1000 reflects a factor of 10 to protect sensitive individuals, a factor of 10 to adjust from subchronic studies to a chronic study, and a factor of 10 for both interspecies conversion and data base deficiencies. It has been suggested that the uncertainty factors applied result in an excessively conservative RfC, and that effects are not likely in humans at concentrations less than 1 ppm, based on kinetic and mechanistic considerations (Kerger and Barfield, 1992). It also is argued by these same authors that the lesion is unlikely to progress with longer duration of exposure, that the lesion is mild, and that interspecies variability is minimal. Although the kinetic data do suggest rapid elimination of hydrogen sulfide, acute studies have shown that the lesion in the respiratory system can persist, which would imply that accumulation of damage is possible. A comparison of the nasal effects in acute and subchronic studies in rats suggests minimal progression with duration, but data are not available for mice or for chronic duration exposures; therefore, uncertainty remains regarding progression with longer durations of exposure. Jappinen et al., 1990, identified a potentially sensitive population in a study that exposed asthmatics to 2 ppm hydrogen sulfide and measured pulmonary function. These results, along with preliminary laboratory animal results (Hulbert et al., 1989), support the need for the intraspecies uncertainty factor. A further uncertainty that is relevant to the selection of the uncertainty factors is the lack of information on sensitive neurological endpoints. The available mechanistic information as well as human experience suggests the nervous system and inhibition of cytochrome oxidase as a potentially critical targets of hydrogen sulfide. These effects have not been studied adequately at low concentrations, with the result being that uncertainty remains in the dose-response relationship, as well as in extrapolation across species and to longer durations. The lack of a second species developmental study and a two-generation reproductive study remain as data gaps that require the application of the data base uncertainty factor. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Hydrogen sulfide is acutely toxic to humans, as evidenced by the numerous reports of fatal poisonings from individuals killed by accidental exposure (Adelson and Sunshine, 1966; Milby, 1962; Ohya et al., 1985; Osbern and Crapo, 1981; Spolyar, 1951; McDonald and McIntosh, 1951; Anon., 1986; Deng and Chang, 1987; Campanaya et al., 1989). According to the National Institute for Occupational Safety and Health, hydrogen sulfide is a leading cause of sudden death in the workplace (NIOSH, 1977). The odor threshold is reported to be at 25 ppb (0.035 mg/cu.m); levels in the 3-5-ppm range cause an offensive odor. The inhalation RfC is below the reported odor threshold in humans. At levels around 100 ppm, no odor is detected, due to loss of the olfactory sensation, resulting in loss of warning properties at lethal levels. In reports of acute poisoning, systemic intoxication can result from a single (one to two breaths) massive exposure to concentrations usually greater than 1000 ppm (Deng and Chang, 1987; Spolyar, 1951). Inhalation of high levels of hydrogen sulfide act directly on the respiratory center, causing respiratory paralysis with consequent asphyxia and subsequent death (Anon., 1986; Milby, 1962; Haggard, 1925; Adelson and Sunshine, 1966). At levels between 500 and 1000 ppm, acute intoxication is associated with symptoms of sudden fatigue, headache, dizziness, intense anxiety, loss of olfactory function, nausea, abrupt loss of consciousness, disturbances of the optic nerves, hypertension, insomnia, mental disturbances, pulmonary edema, coma, convulsions, and respiratory arrest, followed by cardiac failure and often death (Burnett et al., 1977; Frank, 1986; Anon., 1986; Thoman, 1969). Levels estimated at 250 ppm resulted in unconsciousness in three workers after several minutes of exposure (McDonald and McIntosh, 1951). Cardiac effects in acute hydrogen sulfide intoxication have been reported in humans (Arnold et al., 1985) and laboratory animals (Kosmider et al., 1967). If exposure is terminated promptly, recovery occurs quickly. However, neurological effects have been reported to persist in survivors of high-level exposure (Ahlborg, 1951). Two case studies noted neuropsychological dysfunction characterized by cognitive impairment; deficits of verbal fluency and disorders of written language; and impairment of various memory, psychomotor, and perceptual abilities in individuals acutely exposed to hydrogen sulfide (Hua and Huang, 1988; Wasch et al., 1989). The damage that has been observed to persist after hydrogen sulfide exposure is not distinguishable from the effects of systemic anoxia or ischemia of the brain or heart, and no specific hydrogen sulfide chronic systemic toxicity has been defined (U.S. EPA, 1990). The human occupational and case study literature is not adequate for a basis for the RfC because exposure levels generally are poorly defined, and results are confounded by concurrent exposures to other chemicals. Community epidemiological studies also have failed to define exposures. Hydrogen sulfide is also a potent eye and mucous membrane irritant, even at low concentrations (50-200 ppm). Pulmonary edema is often a clinical finding in persons who have been rendered unconscious by hydrogen sulfide exposure (Burnett et al., 1977; Thoman, 1969; Arnold et al., 1985; Campanaya et al. 1989). In several of the reported fatalities, the individuals apparently died of acute respiratory distress syndrome due to pulmonary edema (Anon., 1986). Irritation of the eye results in initial lacrimation, loss of coronary reflex, and changes in visual acuity and perception, usually at concentrations in excess of 50 ppm, which may progress to inflammation and ulceration, with the possibility of permanent scarring of the cornea in severe cases. Inflammation of the cornea of the eye has been reported in workers exposed to as low as 10 ppm hydrogen sulfide for 6-7 hours (Frank, 1986; Milby, 1962). Subchronic (90-day) vapor inhalation studies were conducted using Sprague-Dawley and Fischer 344 rats (CIIT, 1983b,c). These animals were exposed to 0, 10.1, 30.5, and 80.0 ppm (0, 14.1, 42.5, and 111 mg/cu.m, respectively) hydrogen sulfide for 6 hours/day, 5 days/week (duration adjusted to 0, 2.51, 7.59, and 20.00 mg/cu.m, respectively) for at least 90 days, simultaneously in the same chambers as the mice in the principal study. Three groups of 15/sex/dose of each strain of rats were employed. In addition, a control group of 15/sex were exposed to clean air only. At the termination of exposure, animals were examined as described for the critical study (CIIT, 1983a). A significant reduction in body weight gain was noted in all animals exposed to 80 ppm. In Fischer 344 and male Sprague-Dawley rats, the effect on body weight was statistically significant at some times in all exposed groups, but mean weights were never less than 93% of control. In female Sprague-Dawley rats, mean body weight in the 80-ppm group was less than 90% of the controls during most of the study. Brain weight was reduced significantly in the male Sprague-Dawley rats in the high-dose group and slightly, but not significantly reduced in females (CIIT, 1983c), indicating a LOAEL of 80 ppm [LOAEL(HEC) = 20 mg/cu.m, calculated for a gas:extrarespiratory effect using the default value for lambda(a)/lambda(h) = 1]. Thus, a NOAEL for these parameters is 30.5 ppm [NOAEL(HEC) = 7.59 mg/cu.m]. No clinical signs in rats were observed to be exposure related. Neurologic function examinations yielded negative results. Blood volume, appearance, occult blood, specific gravity, protein, pH, ketone, and glucose values were all normal. Ophthalmoscopic examination, hematology, serum chemistry parameters, and urinalysis also were normal. Histopathological examination, which included four sections of the nasal turbinates, revealed no abnormalities in comparison to controls. There is limited information available that suggests that the nasal lesion observed after hydrogen sulfide exposure would not be expected to progress substantially with continued exposure. There is no information available specifically on mice because there are no studies reporting on histology of the nasal cavity for any duration other than the principal study, and there are no range-finding studies reported in the principal study. There are, however, studies of acute and subchronic duration in rats that can be compared. In the subchronic rat studies described above, 80 ppm was a NOAEL for nasal histopathology in both rat strains (CIIT, 1983b,c). In an acute study, male Fischer 344 rats were exposed to 0, 10, 100, 200, or 400 ppm (0, 14, 140, 280, or 560 mg/cu.m) hydrogen sulfide for 4 hours, and four levels of the nasal cavity were examined histologically at 1, 18, and 44 hours after exposure (Lopez et al., 1988b). Lesions of the respiratory epithelium involved necrosis, degeneration, and exfoliation at 1 and 18 hours postexposure and regenerative cell growth at 44 hours postexposure. In the olfactory epithelium, degeneration and necrosis continued throughout the 44-hour postexposure period. No nasal lesions were seen in the controls nor in the two lower exposure groups. The acute study shows a LOAEL of 400 ppm and a NOAEL of 200 ppm for a 4-hour exposure, compared with the subchronic study with a free-standing NOAEL in rats at 80 ppm for a 6-hour exposure. This comparison suggests that there would be a maximum of a factor of 2.5 between NOAELs for a single exposure and a subchronic study. The fact that the acute exposure was only 4 hours, compared with 6 hours/day in the subchronic study, makes the possible differences in the NOAEL even less and supports the suggestion that the lesion progresses minimally in this time frame. The rapid elimination of hydrogen sulfide and its metabolites also argues against accumulation of dose during a longer exposure (Beauchamp et al., 1984). It is concluded that progression of lesions on inhalation of hydrogen sulfide progresses minimally between acute and subchronic durations in rats. It is reasonable to extend this conclusion to mice and to the subchronic-to-chronic time frame because the effect is likely to be a nonspecific reactivity, rather than some other mechanism that might have some aspect of species specificity. On this basis, the standard uncertainty factor of 10 for subchronic-to-chronic extrapolation is reduced by half to a threefold factor. Male Fischer 344 rats were exposed to 0, 10, 200, or 400 ppm nominal concentration (0, 14, 279, and 557 mg/cu.m, respectively) of hydrogen sulfide for 4 hours (Lopez et al., 1987), and samples were collected by bronchoalveolar and nasal lavage at 1, 20, and 44 hours after exposure (4 rats/exposure level/time). Increased number of cells in nasal lavage and increased protein and lactate dehydrogenase in both bronchoalveolar and nasal lavage fluids from rats exposed to 400 ppm were observed. Male Fischer 344 rats (4 rats/exposure level/time) were exposed to 0, 116, or 615 mg/cu.m hydrogen sulfide for 4 hours (Lopez et al., 1988a). Rats exposed to 615 mg/cu.m had marked perivascular and alveolar edema, and bronchioles contained PMN, proteinaceous fluid, fibrin, and exfoliated cells. Necrosis of bronchiolar ciliated cells and hyperplasia of alveolar type II cells was observed in rats exposed to 615 mg/cu.m. In rats exposed to 116 mg/cu.m, only mild perivascular edema was observed. Nasal structures were not examined. No data on human developmental effects of inhaled hydrogen sulfide were found, but, based on the limited information available in laboratory animals, hydrogen sulfide does not appear to induce developmental effects. In a preliminary study, Saillenfait et al. (1989) administered 0, 50, 100, or 150 ppm hydrogen sulfide (0, 69.7, 139, or 209 mg/cu.m, respectively) 6 hours/day to pregnant rats (n = 7-9) during gestational days 6-20. Maternal body weight gain was reduced significantly at 150 ppm, and fetal body weight was reduced slightly (4-7%) in all exposed groups. In dams exposed to 100 or 150 ppm, reduced absolute weight gain and increased implantations and live fetuses were observed. In a follow-up experiment, 20 pregnant females were exposed to 100 ppm for 6 hours/day on days 6-20 of gestation. Fetal weights, number of live and dead fetuses, number of implantation sites and resorptions, and external malformations were recorded. Viable fetuses were then prepared for soft tissue and skeletal examination. No maternal toxicity or adverse effects on the developing embryo or fetus were observed. The preliminary study identifies a LOAEL of 50 ppm for maternal weight gain. Because of the larger number of animals in the main study, a NOAEL of 100 ppm for maternal effects and developmental effects is identified [NOAEL(HEC) calculated for extrarespiratory effect = 139 mg/cu.m]. In a dominant lethal study in which 10 male Wistar rats were exposed to 220 ppm (307 mg/cu.m.) hydrogen sulfide for 3 hours/day for 1 week and then mated over a 10-week period (Andrew et al., 1980), there were no exposure-related effects on fertility, corpora lutea, implants, or resorptions. In a developmental study from the same source (Andrew et al., 1980), female Wistar rats were exposed to 220 ppm (307 mg/cu.m.) hydrogen sulfide for 3 hours/day, 5 days/week on gestation days 1-18, 7-11, or 12-16. No effect on maternal toxicity, fertility, prenatal mortality, or litter weight was observed; however, an increase in minor skeletal anomalies was observed. Several other reports have examined gestational and perinatal hydrogen sulfide exposure. Hayden et al. (1990a) exposed female Sprague-Dawley rats and pups to 20, 50, and 75 ppm (27.9, 69.7, or 105 mg/cu.m., respectively) for 7 hours/day, from day 1 of gestation to day 21 postpartum. Blood samples were analyzed for glucose, triglyceride, cholesterol, alkaline phosphatase, lactate dehydrogenase, SGOT, and protein on postpartum days 7, 14, and 21 in pups and on day 21 in the parents. Maternal blood glucose was significantly elevated in all exposed groups at day 21 postpartum. Hannah et al. (1989) measured several amino acids on postnatal days 7, 14, and 21 in rat pup cerebrum and cerebellum after exposure to 75 ppm (105 mg/cu.m) hydrogen sulfide for 7 hours/day from gestation day 5 to postnatal day 21. Changes in aspartate, glutamate, and taurine were reported; the adversity of these changes in brain levels of neurotransmitters is unclear. In a follow-up study, Hannah et al. (1990) reported that maternal blood taurine levels were significantly increased on the day of parturition and on postnatal day 21 after exposure to 50 ppm hydrogen sulfide in a similar experimental design. Hayden et al. (1990b) exposed female Sprague-Dawley rats to 20, 50, or 75 ppm (27.9, 69.7, or 105 mg/cu.m., respectively) from day 6 of gestation to day 21 postpartum and reported reproductive and physical developmental endpoints. No effect was seen in gestation length; litter size; viability; pup body and organ weights; maternal weights; or liver or brain content of protein, DNA, or cholesterol. Delivery time was increased in a concentration-related manner. Differences in time of ear detachment and hair development were reported but were not concentration related. Hannah and Roth (1991) exposed Sprague-Dawley rats (n = 10) to 0, 20, or 50 ppm (0, 27.9, or 69.7, respectively), for 7 hours/day from day 6 of gestation to day 21 postpartum and performed morphometric analyses of dendritic fields of cerebellar Purkinje cells. Significant effects were observed at both concentrations on measurements reflecting the number, symmetry, and length of branches. These results suggest significant alterations in neuronal development at concentrations that are lower than the LOAEL identified in the principal study. The lowest concentration used in this study (20 ppm) is equal to 27.9 mg/cu.m, and the human equivalent concentration would be the same because duration adjustment is not applied for developmental effects. The LOAEL(HEC) is therefore considerably higher than the LOAEL for respiratory system effects in the principal study. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Although the critical study is a well-conducted study that is very thorough in examining a large number of possible endpoints, and it places special emphasis on endpoints that are of likely concern based on acute studies (brain, eye, nervous system, nasal passages, and lung), it is given a medium confidence rating because it used a small number of animals. The confidence in the data base was rated medium due to the lack of chronic and reproductive studies. Medium confidence in the RfC results. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. This assessment was peer reviewed by external scientists. This review was completed on 05/22/1995. Their comments have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of these comments is included in the IRIS documentation files. Other EPA Documentation -- U.S. EPA, 1990 Agency Work Group Review -- 06/21/1990, 05/11/1995 Verification Date -- 05/11/1995 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Hydrogen sulfide CASRN -- 7783-06-4 NOCA: Not available at this time. ============================================================================ UDSO: 199507 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Hydrogen sulfide CASRN -- 7783-06-4 Last Revised -- 07/01/1995 SORD: __VI.A. ORAL RfD REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1980. Documentation of the Threshold Limit Values, 4th ed. ACGIH, Cincinnati, OH. p. 225-226. NIOSH (National Institute for Occupational Safety and Health). 1977. Criteria for a Recommended Standard, Occupational Exposure to Hydrogen Sulfide. PB-274 196. NTP (National Toxicology Program). 1985. Management Status Report. 4/5/85 Poda, G.A. 1966. Hydrogen sulfide can be handled safely. Arch. Environ. Health. 12: 795-800. Wetterau, H., W. Oekert and U.G. Knape. 1964. Tests for the application of dried green fodder with higher H2S cotent (experiments with poultry and fattened pigs. Lettin Feeds Testing Center and Feeding Hall. Feeds Science. Fetterung. 5: 383-393. Westermann, Von H.D., A. Thalmann and H. Kummer. 1975. Uber Die Toxizatat Von Schwefelwasserstoff In Der Tierfutterung Eine Literaturstudie. (English: The toxicity of hydrogen sulphide in animal feeding. A survey of the literature). Lanwirtsch. Forsch. 28(1): 70-80. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Adelson, L. and I. Sunshine. 1966. Fatal hydrogen sulfide intoxication. Report of three cases occurring in a sewer. Arch. Pathol. 81: 375-380. Ahlborg, G. 1951. Hydrogen sulfide poisoning in shale oil industry. Arch. Ind. Hyg. Occup. Med. 3: 247-266. Andrew, F.D., R.A. Renne and W.C. Cannon. 1980. Reproductive toxicity testing for effects of H2S in rats. In: Pacific Northwest Laboratory Annual Report for 1979. Prepared for the U.S. Department of Energy, Richland, WA. Report No. PNL-3300 PTI. p. 276-278. Anonymous. 1986. Occupational fatality following exposure to hydrogen sulfide-Nebraska. MMWR, Aug. 22. 35(33): 533-5. Arnold, I.M., R. Dufresne, B. Alleyne and P. Stuart. 1985. Health implication of occupational exposures to hydrogen sulfide. J. Occup. Med. 27(5): 373-376. Beauchamp, R.O., J.S. Bus, J.A. Popp, C.J. Boreiko and D.A. Andjelkovich. 1984. A critical review of the literature on hydrogen sulfide toxicity. CRC Crit. Rev. Toxicol. 13: 25-97. Burnett, W., E. King, M. Grace and W. Hall. 1977. Hydrogen sulfide poisoning: Review of 5 years' experience. CMA Journal. 117: 1277-1280. Campanaya, M., P. Sanz, R. Reig, et al. 1989. Fatal hydrogen sulfide poisoning. Med. Lav., May-June. 80(3): 251-3. CIIT (Chemical Industry Institute of Toxicology). 1983a. 90-Day vapor inhalation toxicity study of hydrogen sulfide in B6C3F1 mice. U.S. EPA OTS Public Files. Fiche No. 0000255-0. Document No. FYI-OTS-0883-0255. CIIT (Chemical Industry Institute of Toxicology). 1983b. 90-Day vapor inhalation toxicity study of hydrogen sulfide in Fischer-344 rats. U.S. EPA OTS Public Files. Fiche No. 0000255-0. Document No. FYI-OTS-0883-0255. CIIT (Chemical Industry Institute of Toxicology). 1983c. 90-Day vapor inhalation toxicity study of hydrogen sulfide in Sprague-Dawley rats. U.S. EPA OTS Public Files. Fiche No. 0000255-0. Document No. FYI-OTS-0883-0255. Deng, J.F. and S.C. Chang. 1987. Hydrogen sulfide poisonings in hot-spring reservoir cleaning: Two case reports. Am. J. Ind. Med. 11(4): 447-51. Frank, R. 1986. Acute and chronic respiratory effects of exposure to inhaled toxic agents. Occupational Respiratory Diseases, J.A. Merchant, ed. Division of Respiratory Disease Studies, Appalachian Laboratory for Occupational Safety and Health, National Institute for Occupational Safety and Health, U.S. Department of Health and Human Services. DHHS (NIOSH) Publ. No. 86-102. p. 571-605. Haggard, H.W. 1925. Toxicology of hydrogen sulfide. J. Ind. Hyg. Toxicol. 7(3): 113-121. Hannah, R.S. and S.H. Roth. 1991. Chronic exposure to low concentrations of hydrogen sulfide produces abnormal growth in developing cerebral Purkinje cells. Neuroscience Ltrs. 122(2): 225-228. Hannah, R.S., L.J. Hayden and S.H. Roth. 1989. Hydrogen sulfide exposure alters the amino acid content in developing rat CNS. Neuroscience Lttr. 99(3): 323-327. Hannah, R.S., R. Bennington and S.H. Roth. 1990. A relationship between hydrogen sulfide exposure and taurine levels in maternal rats. Proc. West. Pharmacol. Soc. 33: 177-179. Hayden, L.J., H. Goeden, and S.H. Roth. 1990a. Exposure to low levels of hydrogen sulfide elevates circulating glucose in maternal rats. J. Toxicol. Environ. Hlth. 31: 45-52. Hayden, L.J., H. Goeden, and S.H. Roth. 1990b. Growth and development in the rat during subchronic exposure to low levels of hydrogen sulfide. Toxicol. Ind. Hlth. 6(3-4): 389-401. Hua, M.S. and C.C. Huang. 1988. A neuro-behavioral study of a patient with acute hydrogen-sulfide intoxication. J. Clin. Exper. Neuropsychology. 10(3): 328. Hulbert, W.C., M.G. Prior, P. Pieroni and Z. Florence. 1989. Hyperresponsiveness in rats after 5 weeks exposure to hydrogen sulfide. Clin. Invest. Med. 12(4): B89. Jappinen, P., V. Vilkka, O. Marttila and T. Haahtela. 1990. Exposure to hydrogen sulfide and respiratory function. Br. J. Ind. Med. 47: 824-828. Kerger, B.D. and L. Barfield. 1992. Current understanding of hydrogen sulfide toxicity with specific reference to regulatory policies and pulp and paper mill emissions. McClaren/Hart Environmental Engineering, Irvine, CA. Kosmider, S., E. Rogala and A. Pacholek. 1967. Electrocardiographic and histochemical studies of the heart muscle in acute experimental hydrogen sulfide poisoning. Arch. Immunol. et Ther. Exper. 15: 731-740. Lopez, A., M. Prior, S. Yong, M. Albassam and L. Lillie. 1987. Biochemical and cytological alterations in the respiratory tract of rats exposed for 4 hours to hydrogen sulfide. Fund. Appl. Toxicol. 9: 753-762. Lopez, A., M. Prior, L. Lillie, C. Gulayets and O. Atwal. 1988a. Histologic and ultrastructural alterations in lungs of rats exposed to sub-lethal concentrations of hydrogen sulfide. Vet. Pathol. 25: 376-384. Lopez, A., M. Prior, S. Yong, M. Albassam, L. Lillie and M. Lefebure. 1988b. Nasal lesions in rats exposed to hydrogen sulfide for four hours. Am. J. Vet. Res. 49(7): 1107-1111. McDonald, J.M. and A.P. McIntosh. 1951. Fatalities from hydrogen sulfide in wells. Arch. Ind. Hyg. and Occup. Med. 3(5): 445-447. Milby, T.H. 1962. Hydrogen sulfide intoxication. J. Occup. Med. 4(8): 431-437. NIOSH (National Institute for Occupational Safety and Health). 1977. Criteria for a recommended standard-hydrogen sulfide. U.S. Department of Health and Human Services, Public Health Service. NIOSH Publ. No. 77-158. Ohya, I., H. Komoriya and Y. Bunai. 1985. Discoloration of surface of the brain and liver in a case of fatal hydrogen sulfide intoxication. Res. Pract. Forensic Med. 28(0): 119-123. Osbern, L.N. and R.O. Crapo. 1981. Dung lung: A report of toxic exposure to liquid manure. Ann. Intern. Med. 95(3): 312-314. Saillenfait, A., P. Bonnet and J. deCeaurriz. 1989. Effects of inhalation exposure to carbon disulfide and its combination with hydrogen sulfide on embryonal and fetal development in rats. Toxicol. Lett. 48: 57-66. Spolyar, L.W. 1951. Three men overcome by hydrogen sulfide in starch plant. Ind. Health Monthly. 11(8): 116-117. Thoman, M. 1969. Sewer gas: Hydrogen sulfide intoxication. Clin. Toxicol. 2(4): 383-386. U.S. EPA. 1990. Health Assessment Document for Hydrogen Sulfide. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-86/026A. (External Review Draft) Wasch, H.H., W.J. Estrin, P. Yip, R. Bowler and J.E. Cone. 1989. Prolongation of the P-300 latency associated with hydrogen sulfide exposure. Arch. Neurol. 46(8): 902-4. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Hydrogen sulfide CASRN -- 7783-06-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/31/1987 I.A.6. Documentation corrected 03/01/1988 I.A.3. Uncertainty factor - second sentence deleted 03/01/1988 I.A.6. Verification date changed 12/01/1989 VI. Bibliography on-line 07/01/1990 I.B. Inhalation RfC now under review 10/01/1990 I.B. Inhalation RfC summary on-line 10/01/1990 VI.B. Inhalation RfC references added 08/01/1991 VI.A. Wetterau et al. & Westermann et al. refs corrected 08/01/1991 VI.B. Citations clarified 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 06/01/1995 I.B. Inhalation RfC noted as pending change 06/01/1995 I.B.6. Work group review date added 07/01/1995 I.B. Inhalation RfC replaced; new RfC 07/01/1995 VI.B. Inhalation RfC references replaced 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/12/2000 I.,II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 370 of 1119 in IRIS (through 2003/06) AN: 63 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199211 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Isophorone- SY: 78-59-1; ISOACETOPHORONE-; ISOFORON-; ISOPHORON-; ALPHA-ISOPHORON-; ALPHA-ISOPHORONE-; 3,5,5-TRIMETHYL-2-CYCLOHEXENONE- RN: 78-59-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199101 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Isophorone CASRN -- 78-59-1 Last Revised -- 01/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- No observed effects NOEL: 150 mg/kg/day 1000 1 2E-1 mg/kg/day 90-Day Dog Feeding LEL: None Study Nor-Am Agricultural Products, Inc., 1972a Kidney pathology NOEL: None 2-Year Rat Gavage LEL: 250 mg/kg/day Study (179 mg/kg/day) NTP, 1984 ---------------------------------------------------------------------------- *Conversion Factors: The LEL of 179 mg/kg/day is based on a 5 day/week treatment schedule PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Nor-Am Agricultural Products, Inc. 1972a. MRID No. 00123976. Available from EPA. Write to FOI, EPA, Washington, DC 20460. NTP (National Toxicology Program). 1984. NTP Technical Report on the Toxicology and Carcinogenisis Studies of Isophorone in F344/N Rats and B63F1 Mice (Gavage). NIH Publication No. 84-2547, NTP-83-168. Beagle dogs (4/sex/dose) were administered gelatin capsules containing 0, 35, 75, or 150 mg isophorone/kg/day 7 days/week for 90 days (Nor-Am Agricultural Products, 1972a). All dogs survived the study in good condition. Food consumption was within normal limits and body weight was not affected by treatment. All organs appeared normal at gross examination and no significant changes in organ weight were produced with the ingestion of isophorone. There were no definitive signs of cellular change in any of the tissues examined. A NOEL for systemic toxicity was established at 150 mg/kg/day (HDT) due to the lack of effects produced at any dose tested. NTP (1984) administered 0, 250, or 500 mg isophorone/kg/day, 5 days/week for 103 weeks by corn oil gavage to groups of 50 F344/N rats/sex and 50 B63F1 mice/sex (averaged daily doses: 0, 179, and 357 mg/kg/day). Doses selected for the 2-year studies were based on 16-day repeated-administration studies in which rats and mice of each sex received 0-2000 mg/kg/day and on 13-week studies in which rats and mice of each sex received doses ranging from 0-1000 mg/kg/day by corn oil gavage. Dosed male rats showed a variety of proliferative lesions of the kidney (tubular cell hyperplasia, 0/50, 1/50, 4/50; tubular cell carcinoma, 0/50, 0/50, 2/50; tubular cell adenocarcinoma, 0/50, 3/50, 0/50; and epithelial hyperplasia of the renal pelvis, 0/50, 5/50, 5/50 in the 0, 250, and 1000 mg/kg/day, respectively). Dosed male rats also exhibited increased mineralization of the medullary collecting ducts (1/50, 31/50, 20/50 in the 0, 250, and 1000 mg/kg/day, respectively), and male rats receiving 250 mg/kg/day showed a more severe nephropathy than is commonly seen in aging F344/N rats. With the exception of a moderate increase in nephropathy, female rats did not show chemically related increased incidences of neoplastic or nonneoplastic lesions. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 100 was used to account for the inter- and intraspecies differences. An additional UF of 10 was used to account for the use of a subchronic study. (The use of the chronic study to estimate the RfD would not evoke this latter 10-fold factor, but would necessitate a 10-fold factor for the use of a LOAEL. In either case the RfD is the same.) MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Data Considered for Establishing the RfD 1) 90-Day Feeding - dog: Principal study - see previous description; core grade minimum 2) NTP 2-Year Bioassay - rats and mice: Co-principal study - see previous description; no core grade (NTP, 1984) 3) 90-Day Feeding - rat: Isophorone was fed in the diet to CFE weanling rats (20/sex/dose) at levels of 0, 750, 1500, and 3000 ppm (Male: 0, 57, 102.5, and 233.8 mg/kg/day; Female: 0, 78.9, 163.8, and 311.8 mg/kg/day) for 90 days. The only effect noted was decreased body weights for males in the high-dose group for several weeks. Body weights were not different from controls by the end of the study. (Note: Dosing in the 90-day rat study was in the diet [prepared weekly], but in the two principal studies animals were dosed by gavage. Since the stability of isophorone in feed has not been determined, the actual dosage levels in the 90-day rat study are unknown); (Nor-Am Agricultural Prod., Inc., 1972b) Data Gap(s): Chronic Rat Feeding Study, Chronic Dog Feeding Study, Rat Reproduction Study, Rat Teratology Study, Rabbit Teratology Study, Mouse Oncogenicity Study CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The critical study is of adequate quality and is given a medium confidence rating. Since numerous data gaps exist for isophorone, the data base is given a low confidence rating. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1980 The ADI in the Ambient Water Quality Criteria Document was extensively reviewed by the Agency and was reviewed by the public. Other EPA Documentation -- Pesticide Registration Files Agency Work Group Review -- 12/02/1985, 02/05/1986, 05/15/1986, 03/22/1989, 05/18/1989 Verification Date -- 05/18/1989 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199103 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Isophorone CASRN -- 78-59-1 NORC: The health effects data for isophorone were reviewed by the U.S. EPA RfD/RfC Work Group and determined to be inadequate for derivation of an inhalation RfC. The verification status of this chemical is currently not verifiable. For additional information on health effects of this chemical, interested parties are referred to the EPA documentation listed below. U.S. EPA. 1980. Ambient Water Quality Criteria Document for Isophorone. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. NTIS PB 81-117673. U.S. EPA. 1986. Health and Environmental Effects Profile for Isophorone. Prepared by the Office of Health and Environmental Assessment, Environmental Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. NTIS PB 88-242359/AS. Agency Work Group Review -- 11/15/1990 EPA Contacts: Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199211 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Isophorone CASRN -- 78-59-1 Last Revised -- 11/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Based on no data in humans; limited evidence of carcinogenicity of one tumor type in one sex of one animal species as shown by an increase of preputial gland carcinomas in male rats. The apparent renal tubular cell tumor in the male rat is associated with alpha-2u-globulin, considered to be of questionable relevance to humans. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. Evidence of carcinogenicity is limited to one sex of one animal species as shown by an increased incidence of preputial gland tumors in male rats; an apparent increase in hepatocellular and integumentary tumors in male mice was complicated by high mortality. No increases were seen in females of either species. NTP (1986) administered isophorone via corn oil gavage to F344/N rats (50/sex/group) at 0, 250 and 500 mg/kg/day, 5 days/week for 103 weeks. Preputial gland carcinomas were reported in 5 males in the high-dose group; no tumors were reported in the control or low-dose groups. Survival of high-dose male rats (28%) was significantly reduced after 96 weeks compared with controls (66%) and low-dose males (66%). The first preputial gland tumor appeared at week 56. The tumor incidences, after adjustment for survival, were 0/49, 0/46 and 5/44 for control, low- and high-dose groups, respectively. The positive trend in tumor incidence was statistically significant by the Life Table Test. The tumor incidence in the high-dose group was statistically significantly elevated when compared with the NTP historical controls (i.e., 12/1094 as of 1986) by the Fisher Exact Test. After survival adjustment, this group differed from the concurrent control as well. The treated male rats showed renal cell hyperplasia and a small number of renal tubular cell adenomas and adenocarcinomas after week 99 when the survival rate was down to 32%. Female rats showed a moderate increase in nephropathy, with no neoplastic lesions. Detailed review and analysis show that the isophorone induced male rat kidney tumor has met the criteria established by the U.S. EPA for associating renal tumors with alpha-2u-globulin (U.S. EPA, 1991a). The criteria were met as follows: (1) there was an increased number and size of hyaline droplets in renal proximal tubule cells of treated male rats; (2) the accumulating protein in the hyaline droplets was alpha-2u-globulin (Strasser et al., 1988); (3) additional aspects of the pathological sequence of lesions associated with alpha-2u-globulin nephropathy were present; (4) sex and species-specificity were demonstrated: the formation of renal tumors was specific to male rats; (5) there was noncovalent binding between isophorone and alpha-2u-globulin (Thier et al., 1990); and (6) the presence of isophorone decreased alpha-2u-globulin degradation (Lehman-McKeeman et al., 1990). The renal tubular cell tumor induced by isophorone in the male rat is associated with alpha-2u-globulin, a protein specific to male rats, and is, therefore, considered to have questionable relevance to humans (U.S. EPA, 1991a). In the same study by NTP (1986), B6C3Fl mice (50/sex/group) were administered isophorone by gavage at 0, 250 and 500 mg/kg/day, 5 days/week for 2 years. Survival of male mice was very low for control and treated animals (32, 32 and 38% for control, low- and high-dose mice, respectively). Dosed male mice showed an increased frequency of coagulative necrosis and hepatocytomegaly as compared to controls. In the high-dose male mice, isophorone exposure appeared to be associated with increased incidence of hepatocellular adenomas or carcinomas (combined incidence: control, 18/48; low-dose, 18/50; and high-dose, 29/50) and of mesenchymal tumors of the integumentary system such as fibromas, fibrosarcomas, neurofibrosarcomas or sarcomas (incidence of combined tumors: control, 6/48; low-dose, 8/50; and high-dose, 14/50). An increased incidence of lymphomas or leukemias was reported in the low-dose male mice (18/50) when compared to vehicle controls or high-dose males (8/48 and 5/50, respectively). The survival of male mice, however, was low (final rates: control, 16/50; low-dose, 16/50; and high-dose, 19/50). No significant elevation or trends for these sites was found when the data were analyzed with the Life Table Test. The survival was so low in both the treatment and control groups that the NTP and U.S. EPA consider the results in male mice to be "equivocal." No treatment-related neoplasms were observed in female mice. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Isophorone was not mutagenic in Salmonella/microsome assays, but a positive response was reported at moderately high concentrations (greater than or equal to 400 ug/mL) without S9 activation in the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay (McGregor et al., 1988). In the absence of S9 mix, isophorone induced sister chromatid exchanges in the Chinese hamster ovary cell but chromosomal aberrations in these cells were not induced either with or without S9 mix (NTP, 1986). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1.SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 9.5E-4 per (mg/kg)/day Drinking Water Unit Risk -- 2.7E-8 per ug/L Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration ------------------------------------ E-4 (1 in 10,000) 4E+3 ug/L E-5 (1 in 100,000) 4E+2 ug/L E-6 (1 in 1,000,000) 4E+1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- preputial gland carcinoma Test Animals -- rat/F344/N, male Route -- oral, gavage Reference -- NTP, 1986 ---- Dose ----- Tumor Admin- Human Incidence istered Equivalent (mg/kg)/day (mg/kg)/day ----------- ----------- --------- 0 0 0/49 179 32 0/46 357 64 5/44 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The tumor incidences were adjusted for survival by subtracting the animals that died before the first tumor appearance at week 56 from the initial number of 50 animals in each denominator. The human equivalent dose was determined using a surface area correction factor. The daily adjusted animal dose (i.e., the administered animal dose multiplied by 5/7 to adjust from 5 to 7 days), is divided by a ratio of the human weight (70 kg) to rat weight (0.4 kg) raised to the 1/3 power. The unit risk should not be used if the water concentration exceeds 4E+5 ug/L, since above this concentration the slope factor may differ from that stated. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) An adequate number of rats were observed and treated for an adequate duration of exposure at two dose levels and controls. The compound was given to the animals by gavage rather than in feed or drinking water. Exposure to a chemical by gavage can give different results than through drinking water. The crude adjustment for survival may not result in the same unit risk that would be obtained using a model also incorporating time-to-tumor, because the dose groups differed significantly in their survival experiences. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1991b The 1991 Drinking Water Health Advisory for Isophorone has received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 05/03/1989, 10/05/1989, 06/02/1992, 06/03/1992, 08/05/1992 Verification Date -- 08/05/1992 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199211 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Isophorone CASRN -- 78-59-1 Last Revised -- 11/01/1992 SORD: __VI.A. ORAL RfD REFERENCES Nor-Am Agricultural Products, Inc. 1972a. MRID No. 00123976. Available from EPA. Write to FOI, EPA, Washington DC. 20460. Nor-Am Agricultural Products, Inc. 1972b. MRID No. 00123977. Available from EPA. Write to FOI, EPA, Washington DC. 20460. NTP (National Toxicology Program). 1984. NTP Technical Report on the Toxicology and Carcinogenisis Studies of Isophorone in F344/N Rats and B63F1 Mice (Gavage). NIH Publication No. 84-2547, NTP-83-168. U.S. EPA. 1980. Ambient Water Quality Criteria Document for Isophorone. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. EPA 440/5-80-056. NTIS PB 81-117673. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES U.S. EPA. 1980. Ambient Water Quality Criteria Document for Isophorone. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. NTIS PB 81-117673. U.S. EPA. 1986. Health and Environmental Effects Profile for Isophorone. Prepared by the Office of Health and Environmental Assessment, Environmental Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. NTIS PB 88-242359/AS. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Lehman-McKeeman, L.D., M.I. Rivera-Torres and D. Caudill. 1990. Lysosomal degradation of a2u-globulin and a-2u-globulin-xenobiotic conjugates. Toxicol. Appl. Pharmacol. 103(3): 539-548. McGregor, D.B., A. Brown, P. Cattanach et al. 1988. Response of the L5178Y tk+/tk- mouse lymphoma cell forward mutation assay. III. 72 coded chemicals. Environ. Molec. Mut. 12: 85-154. NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of isophorone (CAS No. 78-59-1) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR-29l. NIH Pub. No. 86-2547. Strasser, J., Jr., M. Charbonneau, S.J. Borghoff, M.J. Turner and J.A. Swenberg. 1988. Renal protein droplet formation in male Fischer 344 rats after isophorone (IPH) treatment. Toxicologist. 8(1): 136. Thier, R., H. Peter, H.J. Wiegand and H.M. Bolt. 1990. DNA binding study of isophorone in rats and mice. Arch. Toxicol. 64: 684-685. U.S. EPA. 1991a. Alpha(2u)Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat. EPA/625/3-91/019F. U.S. EPA. l991b. Drinking Water Health Advisory on Isophorone. Office of Water, Washington, DC. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Isophorone CASRN -- 78-59-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.2. Principal study corrected 06/30/1988 I.A.2. Principal study year corrected 04/01/1989 I.A. Oral RfD summary noted as pending change 06/01/1989 I.A. Withdrawn; new Oral RfD verified (in preparation) 06/01/1989 II. Carcinogen assessment now under review 09/01/1989 I.A. Oral RfD summary replaced; RfD changed 09/01/1989 VI. Bibliography on-line 07/01/1990 II. Carcinogen summary on-line 07/01/1990 IV.F.1. EPA contact changed 07/01/1990 VI.C. Carcinogen references added 08/01/1990 II.D.2. Verification date corrected and review date added 12/01/1990 I.B. Inhalation RfC now under review 01/01/1991 I.A. Text edited 01/01/1991 II. Text edited 03/01/1991 II.D.3. Secondary contact changed 03/01/1991 I.B. Inhalation RfC message on-line 03/01/1991 VI.B. Inhalation RfC references added 04/01/1991 VI.C. Carcinogen references added 01/01/1992 IV. Regulatory actions updated 05/01/1992 II. Carcinogenicity assessment noted as pending change 09/01/1992 II.D.2. Work group review dates added 10/01/1992 II. Carcinogenicity assessment replaced; new oral quant. 10/01/1992 VI.C. Carcinogenicity references replaced 11/01/1992 II.D.2. Dates corrected 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 371 of 1119 in IRIS (through 2003/06) AN: 70 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199502 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Dichloromethane- SY: *METHYLENE-CHLORIDE-; 75-09-2; AEROTHENE-MM-; CHLORURE-DE-METHYLENE-; DCM-; DICHLORMETHAN,-UVASOL-; 1,1-DICHLOROMETHANE-; FREON-30-; METHANE-DICHLORIDE-; METHANE,-DICHLORO-; METHYLENE-BICHLORIDE-; METHYLENE-DICHLORIDE-; METYLENU-CHLOREK-; NARKOTIL-; NCI-C50102-; R-30-; SOLAESTHIN-; SOLMETHINE-; WLN: G1G RN: 75-09-2 WL: G1G HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198803 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Last Revised -- 03/01/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Liver toxicity NOAEL: 5.85 and 6.47 100 1 6E-2 mg/kg/day for males mg/kg/day 2-Year Rat Drinking and females, Water Bioassay respectively National Coffee LOAEL: 52.58 and Association, 1982 58.32 mg/kg/day for males and females, respectively ---------------------------------------------------------------------------- *Conversion Factors: Doses reflect actual values and not nominal ones. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) National Coffee Association. 1982. 24-Month chronic toxicity and oncogenicity study of methylene chloride in rats. Final Report. Prepared by Hazleton Laboratories America, Inc., Vienna, VA. (Unpublished) The chosen study appears to have been very well conducted, with 85 rats/ sex at each of four nominal dose groups (i.e., 5, 50, 125 and 250 mg/kg/day) for 2 years. A high-dose recovery group of 25 rats/sex, as well as two control groups of 85 and 50 rats/sex, was also tested. Many effects were monitored. Treatment related histological alterations of the liver were evident at nominal doses of 50 mg/kg/day or higher. The low nominal dose of 5 mg/kg/day was a NOAEL. The supporting data base is limited. A NOAEL of 87 mg/cu.m was reported in one inhalation study (Haun et al., 1972). [The equivalent oral dose is about 28 mg/kg bw/day (i.e., 87 mg/cu.m x 0.5 x 0.223 cu.m/day/0.35 kg; these exposure values are for rats).] UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- (10a x 10h) The 100-fold factor accounts for both the expected intraand interspecies variability to the toxicity of this chemical in lieu of specific data. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) None. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- Medium RfD -- Medium The study is given a high confidence rating because a large number of animals of both sexes were tested in four dose groups, with a large number of controls. Many effects were monitored and a dose-related increase in severity was observed. The data base is rated medium to low because only a few studies support the NOAEL. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1985 Other EPA Documentation -- None Agency Work Group Review -- 06/24/1985, 07/08/1985, 11/06/1985 Verification Date -- 11/06/1985 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Dichloromethane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199109 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride NORC: Not available at this time. ============================================================================ UDCA: 199502 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Last Revised -- 02/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification --B2; probable human carcinogen Basis -- Based on inadequate human data and sufficient evidence of carcinogenicity in animals; increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in male and female mice, and increased incidence of benign mammary tumors in both sexes of rats, salivary gland sarcomas in male rats and leukemia in female rats. This classification is supported by some positive genotoxicity data, although results in mammalian systems are generally negative. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Neither of two studies of chemical factory workers exposed to dichloromethane showed an excess of cancers (Ott et al., 1983; Friedlander et al., 1978; Hearne and Friedlander, 1981). The Ott et al. (1983) study was designed to examine cardiovascular effects, and consequently the study period was too short to allow for latency of site-specific cancers. In the Friedlander et al. (1978) study, exposures were low, but the data provided some suggestion of an increased incidence of pancreatic tumors. This study was recently updated to include a larger cohort, followed through 1984, and an investigation of possible confounding factors (Hearne et al., 1986, 1987). A nonsignificant excess in pancreatic cancer deaths was observed, which was interpreted by EPA (1987a) as neither clear evidence of carcinogenicity in humans, nor evidence of noncarcinogenicity. An update of the Ott et al. (1983) study, based on longer follow-up, indicated possible elevation of liver and biliary tract cancers (TSCA section 8(e) submission no. 8eHQ-0198-0772 FLWP et seq., 1989). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Dichloromethane administered in the drinking water induced a significant increase in combined hepatocellular carcinoma and neoplastic nodules in female F344 rats and a nonsignificant increase in combined hepatocellular carcinoma and neoplastic nodules in male B6C3F1 mice (NCA, 1982, 1983). Two inhalation studies with dichloromethane have shown an increased incidence of benign mammary tumors in both sexes of Sprague-Dawley (Burek et al., 1984) and F344 (NTP, 1986) rats. Male Sprague-Dawley rats had increased salivary gland sarcoma (Burek et al., 1984) and female F344 rats had increased leukemia incidence (NTP, 1986). Both sexes of B6C3F1 mice developed liver and lung tumors after dichloromethane treatment (NTP, 1986). In a 2-year study by the National Coffee Association (1982, 1983), groups of 85 F344 rats/sex/dose received 5, 50, 125, or 250 (mg/kg)/day of dichloromethane in the drinking water. Control groups consisted of 135 rats/sex. In female rats the incidence of combined hepatocellular carcinoma and neoplastic nodules was statistically significantly increased in the 50 and 250 mg/kg dose groups when compared with matched controls (0/134, 1/85, 4/83, 1/85, and 6/85 in the five dose groups 0, 5, 50, 125, and 250 (mg/kg)/day, respectively). The incidence of hepatocellular carcinoma alone was not significantly increased (0/134, 0/85, 2/83, 0/85, 2/85). The combined incidence of hepatocellular carinoma and neoplastic nodules in controls and the 4 dose groups (472 rats: 4 with carcinoma and 8 with neoplastic nodules) was similar to that for historical controls (419 rats; 5 with carcinoma, 19 with neoplastic nodules). Male rats showed no increase in liver tumors. In the same National Coffee Association study (1982, 1983), B6C3F1 mice received 0, 60, 125, 185, or 250 (mg/kg)/day of dichloromethane in drinking water. Treatment groups consisted of 50 female mice and 200, 100, 100, and 125 male mice (low to high dose). One hundred females and 125 males served as controls. Male mice had an increased incidence of combined neoplastic nodules and hepatocellular carcinoma (24/125, 51/200, 30/100, 31/99, 35/125). The increase was not dose-related, but the pairwise comparisons for the two mid-dose groups were reported to be statistically significant (U.S. EPA, 1985a). The hepatocellular carcinoma incidence alone for male mice (which was about 55 to 65% of the total) was not significantly elevated. Female mice did not have increased liver tumor incidence. The EPA (1985b) regarded this study as suggestive but not conclusive evidence for carcinogenicity of dichloromethane. A gavage bioassay of dichloromethane conducted by NTP (1982) has not been published because of high mortality, much of which was attributed to gavage accidents. Inhalation exposure of 107 to 109 Syrian hamsters/sex/dose to 0, 500, 1500, or 3500 ppm of dichloromethane for 6 hours/day, 5 days/week for 2 years did not induce neoplasia (Burek et al., 1984). Sprague-Dawley rats (129/sex/ dose) were exposed under the same conditions. Female rats administered the highest dose experienced significantly reduced survival from 18-24 months. Female rats showed a dose-related increase in the average number of benign mammary tumors per rat (1.7, 2.3, 2.6, 3.0), although the numbers of rats with tumors were not significantly increased. A similar response was observed in male rats, but to a lesser degree. In the male rats there was a statistically significant positive trend in the incidence of sarcomas of the salivary gland (1/93, 0/94, 5/91, 11/88); the incidence was significantly elevated at the high dose. There is a question as to whether these doses reached the MTD, particularly in the hamsters and the male rats. In another study (Dow Chemical Co., 1982), 90 Sprague-Dawley rats/sex were exposed by inhalation to 0, 50, 200, or 500 ppm dichloromethane for 20 months (male) or 24 months (female). No salivary tumors were observed, but there was an exposure-related increase in the total number of benign mammary tumors in female rats, although the increase was not statistically significant in any individual exposure group. Groups of 50 each male and female F344/N rats and B6C3F1 mice were exposed to dichloromethane by inhalation, 6 hours/day, 5 days/week for 2 years (NTP, 1986). Exposure concentrations were 0, 1000, 2000, or 4000 ppm for rats and 0, 2000, or 4000 ppm for mice. Survival of male rats was low; however, this apparently was not treatment-related. Survival was decreased in a treatment-related fashion for male and female mice and female rats. Mammary adenomas and fibroadenomas were significantly increased in male and female rats after survival adjustment, as were mononuclear cell leukemias in female rats. Among treated mice of both sexes there were significantly increased incidences of hepatocellular adenomas and carcinomas, and of alveolarbronchiolar adenomas and carcinomas, by life table tests. Adenomas and carcinomas were significantly increased alone as well as in combination. In addition, there were significant dose-related increases in the number of lung tumors per animal multiplicity in both sexes of mice. Two inhalation assays using dogs, rabbits, guinea pigs, and rats showed no tumors, but were not conducted for the lifetime of the animals (Heppel et al., 1944; MacEwen et al., 1972). Theiss et al., (1977) injected Strain A male mice intraperitoneally with 0, 160, 400, or 800 mg/kg of dichloromethane 16 to 17 times, over 5 to 6 weeks. Survival of the animals was poor. The animals remaining 24 weeks after the first treatment were killed and examined for lung tumors; pulmonary adenomas were found. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Dichloromethane was mutagenic for Salmonella typhimurium with or without the addition of hepatic enzymes (Green, 1983) and produced mitotic recombination in yeast (Callen et al., 1980). Results in cultured mammalian cells have generally been negative, but dichloromethane has been shown to transform rat embryo cells and to enhance viral transformation of Syrian hamster embryo cells (Price et al., 1978; Hatch et al., 1983). Although chlorinated solvents have often been suspected of acting through a nongenotoxic mechanism of cell proliferation, Lefevre and Ashby (1989) found methylene chloride to be unable to induce hepatocellular division in mice. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 7.5E-3 per (mg/kg)/day Drinking Water Unit Risk -- 2.1E-7 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 5E+2 ug/L E-5 (1 in 100,000) 5E+1 ug/L E-6 (1 in 1,000,000) 5E+0 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- hepatocellular adenomas or carcinomas (NTP) and hepatocellular cancer and neoplastic nodules (NCA) Test Animals -- mouse/B6C3F1 (female, NTP; male, NCA) Route -- inhalation (NTP); drinking water (NCA) Reference -- NTP, 1986; National Coffee Association (NCA), 1983 Dose --------------------------------- Human Administered Equivalent Tumor (ppm) mg/kg/day (mg/kg)/day Incidence Reference ----- ----------- ----------- --------- --------- 0 0 0 3/50 NTP, 1986 2000 1582 122 16/48 4000 3162 244 40/48 0 0 24/125 NCA, 1983 60 4.5 51/200 125 9.4 30/100 185 14.0 31/99 250 18.9 35/125 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The slope factor is an arithmetic mean of slope factors derived from NTP(1986) and the National Coffee Association (1983) data, 2.6E-3 per (mg/kg)/day and 1.2E-2 per (mg/kg)/day, respectively. The use of liver tumor data from the NTP inhalation bioassay was considered valid since dichloromethane is rapidly absorbed following either inhalation or ingestion. Dose conversions used the mean body weight for female mice at the midpoint of the bioassay, and an estimated inhalation rate of 0.0407 cu.m/day. To obtain estimates of unit risk for humans, an inhalation rate of 20 cu.m/day was assumed. Dichloromethane was considered to be well-absorbed as a vapor at low doses. No pharmacokinetic or metabolism data have been used to modify the oral unit risk estimate, because such analyses have not yet been carried out. The unit risk should not be used if the water concentration exceeds 5E+4 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of animals were used in both assays. Risk estimates were based on the more sensitive sex in each study. The two risk estimates were within a factor of 5. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 4.7E-7 per (ug/cu.m) Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 2E+2 ug/cu.m E-5 (1 in 100,000) 2E+1 ug/cu.m E-6 (1 in 1,000,000) 2E+0 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- combined adenomas and carcinomas Test Animals -- mouse/B6C3F1, female Route -- inhalation Reference -- NTP, 1986 Dose -------------------------------------------- Transformed Human Administered Animal Equivalent Tumor Tumor Type (ppm) (mg/kg)/day (mg/kg)/day Incidence ---------- ------------ ----------- ----------- --------- Liver 0 0 0 3/45 2000 1582 356 16/46 4000 3162 712 40/46 Lung 0 0 0 3/45 2000 1582 356 30/46 4000 3162 712 41/46 ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The unit risk of 4.7E-7 per (ug/cu.m), which incorporates information on pharmacokinetics and metabolism of dichloromethane, is approximately nine-fold lower than the previous applied dose estimate (U.S. EPA, 1987a,b). Internal dose estimates were based on the metabolism of dichloromethane by the glutathione-s-transferase pathway, as estimated by the model developed by Andersen et al. (1987). The internal dose was corrected for interspecies differences in sensitivity by using the surface area correction factor. Calculation of a slope factor from the unit risk is inappropriate when pharmacokinetic models are used. (When dose-response relationships are figured on the basis of internal or metabolized dose, a slope factor in terms of per (mg/kg)/day represents a back calculation using different absorption assumptions than the pharmacokinetic models. This introduces possible contradictions.) The unit risk should not be used if the air concentration exceeds 2E+4 ug/cu.m, since above this concentration the unit risk may differ from that stated. Since the unit risk is based on a pharmacokinetic model, the risk may change with alterations in exposure patterns. Thus, the unit risk presented here may not be applicable to acute, high exposures. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Adequate numbers of animals were observed and tumor incidences were significantly increased in a dose-dependent fashion. Analysis excluding animals that died before observation of the first tumors produced similar risk estimates, as did time-to-tumor analysis. The use of animal and human metabolism and pharmacokinetic data reduces some of the uncertainty typically associated with dose-risk extrapolation. A great deal of uncertainty still exists, however, in the estimates of internal dose generated by the model of Andersen et al. (1987). Important uncertainties remain regarding the pharmacokinetics, pharmacodynamics, and mechanisms of carcinogenicity for dichloromethane. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985a,b, 1987a,b The Addendum to the Health Assessment Document, the Update to the Health Assessment Document and Addendum, and the Technical Analysis of New Methods and Data for dichloromethane have received Agency and external review, including a review by the Science Advisory Board (SAB). Although the last two documents are not yet finalized and the SAB comments are not yet incorporated, these do not alter this document's analyses or conclusions. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 11/12/1986, 12/04/1986, 04/06/1989 Verification Date -- 04/06/1989 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Dichloromethane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199108 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride Last Revised -- 08/01/1991 SORD: __VI.A. ORAL RfD REFERENCES Haun, C.C., E.H. Vernot, K.I. Darmer Jr. and S.S. Diamond. 1972. Continous animal exposure to low levels of dichloromethane. AMRL-TR-72-13. In: Proceedings of the 3rd Annual Conference on Environmental Toxicology, Wright-Patterson Air Force Base, Ohio, Aerospace Medical Research Laboratory. p. 199-208. National Coffee Association. 1982. 24-Month chronic toxicity and oncogenicity study of methylene chloride in rats. Final Report. Prepared by Hazleton Laboratories America, Inc., Vienna, VA. (Unpublished) U.S. EPA. 1985. Drinking Water Criteria Document for Methylene Chloride. Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Andersen, M.E., H.J. Clewell, III, M.L. Gargas, F.A. Smith and R.H. Reitz. 1987. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol. Appl. Pharmacol. 87: 185-205. Burek, J.D., K.D. Nitschke, T.J. Bell, et al. 1984. Methylene chloride: A two year inhalation toxicity and oncogenicity study in rats and hamsters. Fund. Appl. Toxicol. 4: 30-47. Callen, D.F., C.R. Wolf and R.M. Philpot. 1980. Cytochrome P-450 mediated genetic activity and cytotoxicity of seven halogenated aliphatic hydrocarbons in Saccharomyces cerevisiae. Mutat. Res. 77: 55-63. Dow Chemical Company. 1982. Methylene chloride: A two-year inhalation and oncogenicity study in rats. Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical Company, Midland, MI. Friedlander, B.R., F.T. Hearne and S. Hall. 1978. Epidemiologic investigation of employees chronically exposed to methylene chloride. J. Occup. Med. 20(10): 657-666. Green, T. 1983. The metabolic activation of dichloromethane and chlorofluoromethane in a bacterial mutation assay using Salmonella typhimurium. Mutat. Res. 118(4): 277-288. Hatch, G.G., P.D. Mamay, M.L. Ayer, B.C. Casto and S. Nesnow. 1983. Chemical enhancement of viral transformation in Syrian hamster embryo cells by gaseous and volatile chlorinated methanes and ethanes. Cancer Res. 43: 1945-1950. Hearne, F.T. and B.R. Friedlander. 1981. Follow-up of methylene chloride study. J. Occup. Med. 23: 660. Hearne, F.T., F. Grose, J.W. Pifer and B.R. Friedlander. 1986. Methylene chloride mortality study update. Eastman Kodak Company, Rochester, NY. June 16. Hearne, F.T., F Grose, J.W. Pifer, B.R. Friedlander and R.L. Raleigh. 1987. Methylene Chloride mortality study: dose-response characterization and animal model comparison. J. Occup. Med. 29 (3): 217-228. Heppel, L.A., P.A. Neal, T.L. Perrin, M.L. Orr and V.T. Porterfield. 1944. Toxicology of dichloromethane (methylene chloride). I. Studies on effects of daily inhalation. J. Ind. Hyg. Toxicol. 26(1): 8-21. Lefevre, P.A. and J. Ashby. 1989. Evaluation of dichloromethane as an inducer of DNA synthesis in B6C3F1 mouse liver. Carcinogenesis. 10(6): 1067-1072. MacEwen, J.D., E.H. Vernot and C.C. Haun. 1972. Continuous animal exposure to dichloromethane. AMRL-TR-72-28, Systems Corporation Report No. W-71005. Wright Patterson Air Force Base, Ohio, Aerospace Medical Research. AD746295. NCA (National Coffee Association). 1982. Twenty-four-month chronic toxicity and oncogenicity study of methylene chloride in rats. Final Report. Prepared by Hazleton Laboratories, America, Inc., Vienna, VA. Unpublished. NCA (National Coffee Association). 1983. Twenty-four month oncogenicity study of methylene chloride in mice. Final Report. Prepared by Hazleton Laboratories, America, Inc., Vienna, VA. NTP (National Toxicology Program). 1982. Draft technical report on the carcinogenesis bioassay of dichloromethane (methylene chloride) (CAS No. 75-09-2) in F344/N rats and B6C3F1 mice (gavage study). Research Triangle Park, NC and Bethesda, MD. Unpublished. NTP-82-061. NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of dichloromethane (methylene chloride) (CAS No. 75-09-2) in F344/N rats and B6C3F1 mice (inhalaltion studies). NTP-TRS-306. Ott, M.G., L.K. Skory, B.B. Holder, J.M. Bronson and P.R. Williams. 1983. Health evaluation of employees occupationally exposed to methylene chloride: Mortality. Scand. J. Work Environ. Health. 9(Suppl. 1): 8-16. Price, P.J., C.M. Hassett and J.I. Mansfield. 1978. Transforming activities of trichloroethylene and proposed industrial alternatives. In Vitro. 14(3): 290-293. Thiess, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice. Cancer Res. 37: 2717-2720. Toxic Substances Control Act. 1989. Section 8(e) submission no. 8eHQ-0198-0772 FLWP et seq. U.S. EPA. 1985a. Health Assessment Document for Dichloromethane (Methylene Chloride). Final Report. Office of Health and Environmental Assessment, Washington, D.C. EPA/600/8-82/004F. U.S. EPA. 1985b. Addendum to the Health Assessment Document for Dichloromethane (methylene chloride). Updated carcinogenicity assessment. Prepared by the Carcinogen Assessment Group, OHEA, Washington, DC. EPA/600/8-82/004FF. U.S. EPA. 1987a. Update to the Health Assessment Document and Addendum for Dichloromethane (Methylene Chloride): Pharmacokinetics, Mechanism of Action and Epidemiology. Review Draft. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-87/030A. U.S. EPA. 1987b. Technical Analysis of New Methods and Data Regarding Dichloromethane Hazard Assessments. Review Draft. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8- 87/029A. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Dichloromethane CASRN -- 75-09-2 Primary Synonym -- Methylene Chloride ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 04/20/1987 II.C.1. Unit Risk corrected from 4.1E-4 to 4.1E-6 05/21/1987 II.A.2. Missing text replaced in 3rd paragraph 03/01/1988 I.A.1. Dose conversion clarified 03/01/1988 I.A.2. Text revised 03/01/1988 II.B.3. Text revised 03/01/1988 II.B.4. Confidence statement revised 03/01/1988 II.C.3. Text revised 03/01/1988 II.C.4. Confidence statement revised 03/01/1988 II.D.3. Primary contact changed 03/01/1988 III.A. Health Advisory added 01/01/1989 II. Carcinogen summary noted as pending change 10/01/1989 II.B.3. Inhalation rate corrected in paragraph 1 10/01/1989 II.C.2. Dose corrections in mg/kg/day 10/01/1989 II.C.3. Inhalation rate corrected in paragraph 1 10/01/1989 II.D.3. Contacts phone number changed 08/01/1990 IV.F.1. EPA contact changed 09/01/1990 II. Carcinogen assessment revised following re-evaluation 09/01/1990 II.C.1. Inhalation unit risk changed 09/01/1990 VI. Bibliography on-line 01/01/1991 II.C.1. Paragraph moved to II.C.3. 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 08/01/1991 VI.C. Citations clarified 09/01/1991 I.B. Inhalation RfC now under review 01/01/1992 IV. Regulatory actions updated 02/01/1995 II.D.3. Primary contact changed 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 372 of 1119 in IRIS (through 2003/06) AN: 85 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199502 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Pentachlorobenzene- SY: 608-93-5; BENZENE,-PENTACHLORO-; QCB-; RCRA-WASTE-NUMBER-U183- RN: 608-93-5 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198803 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Pentachlorobenzene CASRN -- 608-93-5 Last Revised -- 03/01/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Liver and kidney NOAEL: none 10,000 1 8E-4 toxicity mg/kg/day LOAEL: 8.3 mg/kg/day Subchronic Rat Oral Bioassay (including weanlings) Linder et al., 1980 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Linder, R., T. Scotti, J. Goldstein, K. McElroy and D. Walsh. 1980. Acute and subchronic toxicity of pentachlorobenzene. J. Environ. Pathol. Toxicol. 4: 183-196. This study utilized 8 experimental groups (3 male, 5 female) of 10 rats each. A statistically significant increase in kidney weights, a decreased heart weight, and an increase in hyaline droplets in proximal kidney tubules was noted in rats receiving 8.3 mg/kg/day. Female rats receiving the next highest dose, 18 mg/kg/day, and their offspring showed increased liver/body weight ratios. At higher doses (up to 72 mg/kg/day) animals of both sexes showed hepatocellular enlargement, increase in adrenal and kidney weights, increased WBC counts, and lowered RBC indices. Suckling pups of dams receiving 18 mg/kg/day and higher doses of pentachlorobenzene developed tremors. The lowest dose of 8.3 mg/kg/day is considered a LOAEL. Linder et al. (1980) published a chart on estimated dietary dosage of pentachlorobenzene from which a figure of 8.3 mg/kg/day was estimated for male rats receiving 125 ppm in the diet. The 1985 Health Assessment Document for Chlorinated Benzenes reports an estimated dosage of approximately 11 mg/kg/day calculated from the same data. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The composite uncertainty factor of 10,000 represents 10 each for the expected interspecies and interhuman variability to the toxicity of this compound in lieu of specific data, 10 to extrapolate a subchronic effect level to its chronic counterpart, and 10 to drop the LOAEL into the expected range of a NOAEL. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) An ADI of 0.0167 mg/kg was reported in the 1980 Ambient Water Quality Criteria for Chlorinated Benzenes. This was based on a paper by Khera and Villaneuve (1975) dealing with reproductive effects of short-term (10 days) feeding in rats. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The study rates a medium confidence because several effects were monitored, and both adult animals and neonates were tested. The study does not rate higher than medium because a NOAEL was not established and only a moderate number of animals was used. The data base rates a low confidence because few data exist to support this analysis. Confidence in the RfD can be considered low to medium. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1983 The ADI in the 1983 Health and Environmental Effects Profile document has received an Agency review with the help of two external scientists. Other EPA Documentation -- U.S. EPA, 1985 Agency Work Group Review -- 10/09/1985 Verification Date -- 10/09/1985 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Pentachlorobenzene CASRN -- 608-93-5 NORC: Not available at this time. ============================================================================ UDCA: 199502 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Pentachlorobenzene CASRN -- 608-93-5 Last Revised -- 02/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- No human data and no animal data available. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA None. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Haworth et al. (1983) reported that pentachlorobenzene at concentrations of 0, 33.3, 333.3, 1000 and 3333.3 ppm did not produce reverse mutations in four strains of Salmonella typhimurium (TA98, TA100, TA1535 and TA1537) in the presence or absence of rat liver microsomes (S9). Similar results wee reported at unpecified concentrations (presumably the same) by the same group in an abstract (Lawlor et al., 1979). Pentachlorobenzene was also negative in Chinese hamster ovary cell assays for induction of sister chromatid exchanges and chromosomal aberrations (NTP, 1991). In 13-week rat and mouse micronucleus assays, pentachlorobenzene tested negative in all exposed groups (NTP, 1991). The metabolites of pentachlorobenzene (chlorobenzene, tetrachlorophenols, tetrachlorobenzenes, trichlorophenols, trichlorobenzenes, pentachlorophenol, tetrachlorohydroquinone) were all negative for gene mutation assays in Salmonella (Haworth et al., 1983; Zeiger et al., 1988; NTP, 1991). Some of the metabolites (e.g., pentachlorophenol), have shown evidence of clastogenic activity in vitro (Galloway et al., 1987; NTP, 1991). In rat and monkey metabolism studies, Engst et al. (1976) and Rozman et al. (1979) identified pentachlorophenol (classified as B2, probable human carcinogen) and 2,3,4,5-tetrachlorophenol as major metabolites of pentachlorobenzene. Other chlorinated phenols were also identified as metabolites. Pentachlorophenol has also been identified in the urine of rabbits administered pentachlorobenzene (Kohli et al., 1976). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1989 The Health and Environmental Effects Document for Pentachlorobenzene has received Agency and external review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/05/1991, 04/01/1992 Verification Date -- 04/01/1992 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199211 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Pentachlorobenzene CASRN -- 608-93-5 Last Revised -- 11/01/1992 SORD: __VI.A. ORAL RfD REFERENCES Khera, K.S. and D.C. Villeneuve. 1975. Teratogenicity studies on halogenated benzenes (pentachloro-, pentachloronitro-, and hexabromo-) in rats. Toxicology. 5(1): 117-122. Linder, R., T. Scotti, J. Goldstein, K. McElroy and D. Walsh. 1980. Acute and subchronic toxicity of pentachlorobenzene. J. Environ. Pathol. Toxicol. 4: 183-196. U.S. EPA. 1983. Health and Environmental Effects Profile for Pentachlorobenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1985. Health Assessment Document for Chlorinated Benzenes. Office of Health and Environmental Assessment, Washington, DC. EPA 600/8-84-O15F. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Engst, R., R.M. Macholz, M. Kujawa, H.J. Lewerenz and R. Plass. 1976. The metabolism of lindane and its metabolites gamma-2,3,4,5,6pentachlorocyclohexene, pentachlorobenzene and pentachlorophenol in rats and the pathways of lindane metabolism. J. Environ. Sci. Health, Part B. 11(2): 95-117. Galloway, S.M., M.J. Armstrong, C. Reuben et al. 1987. Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ. Molec. Mutagen. 10(Suppl. 10): 1-175. Haworth, S., T. Lawlor, K. Mortelmans, W. Speck and E. Zeiger. 1983. Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen. Suppl. 1: 3-142. Kohli, J., D. Jones and S. Safe. 1976. The metabolism of higher chlorinated benzene isomers. Can. J. Biochem. 54(3): 203-208. Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic activity of nine chlorinated phenols, seven chlorinated benzenes and three chlorinated hexanes. Environ. Mutagen. 1(2): 143. (Abstract) NTP (National Toxicology Program). 1991. Toxicity Studies of Pentachlorobenzene in F344/N Rats and B6C3F1 Mice (Feed Studies). National Toxicology Program, Research Triangle Park, NC. NIH Publ. No. 91-3125. Rozman, K., J. Williams, W.F. Mueller, F. Coulston and F. Korte. 1979. Metabolism and pharmacokinetics of pentachlorobenzene in the rhesus monkey. Bull. Environ. Contam. Toxicol. 22: 190-195. U.S. EPA. 1980. Ambient Water Quality Criteria for Chlorinated Benzenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA/440/5-80/028. NTIS PB81-117392. U.S. EPA. 1984. Health Assessment Document for Chlorinated Benzenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8-84-015F. NTIS PB85-150332. U.S. EPA. 1989. Health and Environmental Effects Document for Pentachlorobenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. Zeiger, E., B. Anderson, S. Haworth, T. Lawlor and K. Mortelmans. 1988. Salmonella mutagenicity tests: IV. Results from the testing of 300 chemicals. Environ. Molec. Mutagen. 11(Suppl. 12): 1-158. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Pentachlorobenzene CASRN -- 608-93-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 01/01/1990 VI. Bibliography on-line 06/01/1990 IV.A.1. Area code for EPA contact corrected 10/01/1991 II. Carcinogenicity assessment now under review 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 11/01/1992 II. Carcinogenicity assessment on-line 11/01/1992 VI.C. Carcinogenicity references on-line 02/01/1995 II.D.3. Primary contact's name changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 373 of 1119 in IRIS (through 2003/06) AN: 86 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Pentachlorophenol- SY: 87-86-5; CHEM-TOL-; CHLOROPHEN-; CRYPTOGIL-OL-; DOWCIDE-7-; DOWICIDE-EC-7-; DP-2,-TECHNICAL-; DUROTOX-; EP-30-; FUNGIFEN-; GLAZD-PENTA-; GRUNDIER-ARBEZOL-; 1-HYDROXY--2,3,4,5,6-PENTACHLOROBENZENE-; LAUXTOL-; LAUXTOL-A-; LIROPREM-; NCI-C54933-; NCI-C55378-; NCI-C55389-; NCI-C56655-; PCP-; PENCHLOROL-; PENTA-; PENTACHLOORFENOL-; PENTACHLOROFENOL-; PENTACHLOROFENOLO-; PENTACHLOROPHENATE-; 2,3,4,5,6-PENTACHLOROPHENOL-; PENTACHLORPHENOL-; PENTACLOROFENOLO-; PENTACON-; PENTA-KIL-; PENTASOL-; PENWAR-; PERATOX-; PERMACIDE-; PERMAGARD-; PERMASAN-; PERMATOX-; PERMATOX-DP-2-; PERMATOX-PENTA-; PERMITE-; PHENOL,-PENTACHLORO-; PREVENTOL-P-; PRILTOX-; SANTOBRITE-; SANTOPHEN-; SANTOPHEN-20-; SINITUHO-; TERM-I-TROL-; WLN: QR BG CG DG EG FG RN: 87-86-5 WL: QR BG CG DG EG FG HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199302 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Pentachlorophenol CASRN -- 87-86-5 Last Revised -- 02/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Liver and kidney NOAEL: 3 mg/kg/day 100 1 3E-2 pathology mg/kg/day LOAEL: 10 mg/kg/day Rat Oral Chronic Study Schwetz et al., 1978 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Schwetz, B.A., J.F. Quast, P.A. Keelev, C.G. Humiston and R.J. Kociba. 1978. Results of 2-year toxicity and reproduction studies on pentachlorophenol in rats. In: Pentachlorophenol: Chemistry, Pharmacology and Environmental Toxicology, K.R. Rao, Ed. Plenum Press, NY. p. 301. Only one chronic study regarding oral exposure (Schwetz et al., 1978) was located in the available literature. Twenty-five rats/sex were administered 1 of 3 doses in the diet. At the 30 mg/kg/day level of treatment, a reduced rate of body weight gain and increased specific gravity of the urine were observed in females. Pigmentation of the liver and kidneys was observed in females exposed at 10 mg/kg/day or higher levels and in males exposed to 30 mg/kg/day. The 3 mg/kg/day level of exposure was reported as a chronic NOAEL. A number of studies that have investigated the teratogenicity of orally administered pentachlorophenol in rodents are available in the literature. Although these studies (Larsen et al., 1975; Schwetz and Gehring, 1973; Schwetz et al., 1978; Hinkle, 1973) did not reveal teratogenic effects, feto-maternal toxicity was seen at 30 mg/kg/day (Schwetz and Gehring, 1973). Since pentachlorophenol apparently does not cross the placental barrier, the observed fetotoxicity may be a reflection of maternal toxicity (Larsen et al., 1975). The NOAEL in these studies was concluded to be 3.0 mg/kg/day (U.S. EPA, 1984), which is the same as for the chronic study reported earlier. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The 100-fold factor accounts for the expected intra- and inter- species variability to the toxicity of this chemical in lieu of specific data. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) None. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- Medium RfD -- Medium The confidence in the chosen study is rated high because a moderate number of animals/sex were used in each of three doses, a comprehensive analysis of parameters was conducted, and a reproductive study was also run. Confidence in the supporting data base is rated medium because only one chronic study is available. Other subchronic studies provide adequate but weaker supporting data. The confidence in the RfD is medium. More chronic/reproductive studies are needed to provide a higher confidence in the RfD. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1984. Health Effects Assessment for Pentachlorophenol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. Limited Peer Review and Agency-wide Internal Review, 1984. U.S. EPA. 1985. Drinking Water Criteria Document for Pentachlorophenol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. Two external peer reviews and an Agency internal review. Agency Work Group Review -- 05/20/1985 Verification Date -- 05/20/1985 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Pentachlorophenol CASRN -- 87-86-5 NORC: Not available at this time. ============================================================================ UDCA: 199307 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Pentachlorophenol CASRN -- 87-86-5 Last Revised -- 07/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- The classification is based on inadequate human data and sufficient evidence of carcinogenicity in animals: statistically significant increases in the incidences of multiple biologically significant tumor types (hepatocellular adenomas and carcinomas, adrenal medulla pheochromocytomas and malignant pheochromocytomas, and/or hemangiosarcomas and hemangiomas) in one or both sexes of B6C3F1 mice using two different preparations of pentachlorophenol (PeCP). In addition, a high incidence of two uncommon tumors (adrenal medulla pheochromocytomas and hemangiomas/hemangiosarcomas) was observed with both preparations. This classification is supported by mutagenicity data, which provides some indication that PeCP has clastogenic potential. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Gilbert et al. (1990) attempted to study the effects of exposure to PeCP and other chemical preservatives among a cohort of 182 men employed in the wood treating industry in Hawaii. The study included both current and former workers who had experienced a minimum of 3 months of continuous employment treating wood between 1960 and November 1981. The first part of the study consisted of a cross-sectional clinical assessment of 88 workers (66 current, 22 former) and 58 nonexposed men employed in other occupations. Significantly elevated levels of urinary PeCP were found among the wood treaters but this was not related to any morbidity or mortality endpoint. In part two of the study, the authors attempted to compare the mortality experience of the cohort with that expected in Hawaiian males of the same age. Only deaths that occurred in Hawaii were ascertained. Six deaths were observed compared with eight expected. Overall, the authors concluded that their results do not suggest any clinically significant adverse health effects nor any increased cancer morbidity or mortality from exposure to PeCP and other wood preserving chemicals. These conclusions must be seriously questioned based on the following: inadequate detail of selection for participation, particularly among the 58 unexposed "controls"; only 50% of eligible workers participated in the clinical portion which creates the potential for selection bias; employment eligibility criteria were different for current versus former workers; the clinical examiner was not blinded as to the exposure status of participants which raises questions about the presence of observation bias; the clinical data were presented and analyzed in a nonstandard way; no details are given about methods used to compute mortality "rates"; and, failure to ascertain deaths occurring outside of Hawaii. With over 30% of the original cohort apparently lost to follow-up, the study is of questionable validity. It cannot be used as evidence of no effect of the exposures but instead must be viewed as uninformative. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Two different 90% pure preparations of PeCP were tested in 2-year bioassays in B6C3Fl mice (NTP, 1989). Typical impurities present in both preparations included tri- and tetrachlorophenol, hexachlorobenzene, polychlorinated dibenzo-p-dioxins, and polychlorinated dibenzofurans. Technical grade PeCP (TG-PeCP) is a composite that consisted of equal proportions of product from Monsanto, Reichold and Vulcan. These specific products are no longer being produced. The second 90% pure preparation of PeCP, EC-7 PeCP, differed from TG-PeCP in the level and nature of impurities present (e.g., EC-7 PeCP contained lower levels of dioxins and dibenzofurans). TG-PeCP was administered daily in the feed at dose levels of 0, 100, and 200 ppm to groups of 50 male and 50 female B6C3F1 mice for 2 years. The average doses of TG-PeCP were approximately 17-18 or 35 mg/kg for males and females, respectively. Two groups of control mice (35/sex) were fed basal diets. Survival of the mice did not appear to be affected by exposure to TG-PeCP at any dose level tested. However, it should be noted that survival of the male control mice (12/35) was low compared with historical control values. The early deaths were found to be due to urinary tract infections resulting from injuries sustained during fighting among the group-housed control male mice. After month 16 of the study, the male mice were singly housed to reduce the incidence of fighting and consequent high mortality. The incidences of hepatocellular adenomas and/or carcinomas were significantly increased in male mice exposed to TG-PeCP when compared with controls; the incidences were 7/32, 26/47 and 37/48 in control, low-dose and high-dose male mice, respectively. The incidences of benign and malignant pheochromocytomas of the adrenal medulla were also significantly greater in dosed male mice than in controls; the incidences were 0/31 in controls, 10/45 in low-dose animals and 23/45 in the high-dose animals. There was no significant increase in the numbers of liver tumors or pheochromocytomas in female mice exposed to TG-PeCP. However, the nonsignificant increase in liver tumors in TG-PeCP exposed females was considered biologically significant. TG-PeCP- and EC-7 PeCP-exposed females showed comparable responses in the 100- and 200-ppm dose groups with a marked increase observed only at 600 ppm in the EC-7 PeCP females. The liver tumor incidences for TG-PeCP exposed females was 3/33, 9/49 and 9/50, respectively. Vascular tumors (hemangiomas and/or hemangiosarcomas) were observed in female mice but not in male mice. Incidences of the hemangiosarcoma tumors were statistically significantly increased when compared to controls and all were malignant (0/30, 3/48, 6/46 in the control, low-dose and high-dose females, respectively). EC-7 PeCP was administered daily in the feed at dose levels of 0, 100, 200, and 600 ppm (NTP, 1989). The average daily doses of EC-7 PeCP were approximately 17-18, 34-37, and 114-118 mg/kg, for the low-, mid-, and high-dose groups, respectively. Two groups of control mice (35/sex) were fed basal diets. Survival did not appear to be affected by exposure to EC-7 PeCP at any of the dose levels tested. The incidences of hepatocellular adenomas and/or carcinomas were significantly increased in dosed male mice exposed to EC-7 PeCP when compared with controls (6/35, 19/48, 21/48, 34/49 in the control, low-, mid-, and high-dose males, respectively). The incidences of benign and malignant pheochromocytomas of the adrenal medulla in males were also significantly greater in treated males than in the controls (1/34, 4/48, 21/48, 45/49 in the control, low-, mid-, and high-dose males, respectively). There was a significant increase in liver tumors (adenomas and/or carcinomas) (1/34, 4/50, 6/49 and 31/48 in the control, low-, mid-, and high-dose females, respectively) and benign and malignant pheochromocytomas in female mice exposed to EC-7 PeCP at the high-dose only (0/35, 2/49, 2/46, 38/49 in the control, low-, mid-, and high-dose females, respectively). Vascular tumors (hemangiomas and/or hemangiosarcomas) were observed in female mice but not in male mice. The incidence of these latter tumors was statistically significantly elevated in the high-dose group when compared with controls and all but one of the tumors was malignant (0/34, 1/50, 3/48, 9/47 in the control, low-, mid-, and high-dose females, respectively). In a study reported by BRL (1968) and Innes et al. (1969), 18 male and 18 female crossbred mice were administered 46.4 mg/kg EC-7 PeCP in gelatin by gavage on days 7 through 28 after birth, followed by administration of 130 ppm (17 mg/kg/day) EC-7 PeCP in the diet for 18 months. It is not possible to ascertain whether the EC-7 PeCP used in this study is the same as the EC-7 used in the NTP (1989) study, since the level and nature of the impurities present in the preparation were not reported by Innes or BRL. Groups of mice from each strain served as negative or vehicle controls. Results indicated that there was no difference between the incidence of tumors in the PeCP-treated group and the control groups. Only tumor incidences were reported, so it is not known what other toxic effects (if any) may have occurred. This study is limited for drawing conclusions concerning the carcinogenicity of PeCP, however, because only one dose level was used. Furthermore, an insufficient number of animals (according to current guidelines) was studied. In a chronic oral study on a different species conducted by Schwetz et al. (1978), groups of 25 Sprague-Dawley rats/sex were fed diets of 0, 8, 23, 77, or 231 ppm PeCP for 22 (for male) or 24 (for female) months (equivalent to l, 3, 10, or 30 mg PeCP/kg/day). The PeCP preparation used in this study was reported to be 90% pure, and representative of the commercially available Dowicide EC-7 PeCP used in the NTP (1989) study. Results from the experiment indicated that in the high-dose group a reduced rate of body weight gain (i.e., a 12% lower mean monthly body weight during the last 12 months of the study) and an increased specific gravity of the urine were observed in females. Pigmentation of the liver and kidneys was observed in females exposed at 10 mg/kg/day or higher levels and in males exposed to 30 mg/kg/day. There was no significant increase in tumor incidence as compared with controls. A slight increase in pheochromocytomas of the adrenal medulla was noted at the lower dose levels. Survival was reported to be unaffected by treatment. Since the high dose (30 mg/kg/day) elicited signs of only mild toxicity, NTP suggested that the MTD had been reached but not exceeded in this study. Catilina et al. (1981) also found no evidence of carcinogenicity in Wistar rats following subcutaneous administration of purified and technical grades of PeCP (6 mg/kg/dose). Test compounds were administered 3 times/week for 40 weeks followed by a 3-month post-treatment observation period. The use of only one dose, the use of an inappropriate route of administration, the relatively short exposure time, and excessive mortality limit the usefulness of this study for drawing conclusions concerning the carcinogenicity of PeCP. In another study, Boutwell and Bosch (1959) applied a 20% solution of commercial grade PeCP in benzene to the shaved skin of Sutter mice twice weekly for 13 weeks following an initial exposure with 0.3% DMBA in benzene. Because of the dose level, frequency and duration of exposure in this study, only limited conclusions concerning the effectiveness of PeCP as a complete carcinogen can be made; these results, however, are sufficient to conclude that PeCP was not a tumor promoter in this assay. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Results from cytogenetic studies provide evidence for the clastogenic potential of PeCP. In cytogenicity studies with cultured CHO cells, TG-PeCP produced an increase in chromosomal aberrations in the presence but not the absence of S9 hepatic homogenate activation. Conversely, SCEs were induced only in the absence of S9 hepatic homogenate (NTP, 1989). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 1.2E-1 per (mg/kg)/day Drinking Water Unit Risk -- 3E-6 per (ug/L) Extrapolation Method -- Linearized multistage procedure Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 3E+l ug/L E-5 (1 in 100,000) 3E+O ug/L E-6 (1 in 1,000,000) 3E-l ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- hepatocellular adenoma/carcinoma, pheochromocytoma/malignant pheochromocytoma, hemangiosarcoma/hemangioma (pooled incidence) Test Animals -- mouse/B6C3F1, female Route -- diet Reference -- NTP, 1989 Human Equiv- Pooled Hepatocellular Administered Dose alent Dose and Hemangiosarcoma ppm (mg/kg)/day (mg/kg)/day Tumor Incidence ----- ----------- ----------- ------------------- Technical grade pentachlorophenol 0 0 0 5/31 100 17 1.4 12/48 200 35 2.7 15/46 Dowicide EC-7 pentachlorophenol 0 0 0 1/34 100 17 1.3 6/49 200 34 2.7 9/46 600 114 8.7 42/49 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Two different pentachlorophenol preparations induced liver tumors, pheochromocytomas and hemangiosarcomas in female mice and liver tumors and pheochromocytomas in male mice. All three tumor types are considered related to the administration of pentachlorophenol. The hemangiosarcomas, however, are considered to be the tumor of greatest concern; the EPA Science Advisory Board found that "these tumors were related to the administration of the pentachlorophenol formulations tested, occurred in a dose-response manner in the treated animals, and are morphologically related to known fatal human cancers that are induced by xenobiotics." Hemangiosarcomas were found only in female mice. To give preference to the data on hemangiosarcomas and because some male groups experienced significant early loss, only the female mice are used in the quantitative risk assessment. In developing these estimates, benign and malignant tumors are combined; the liver tumors and pheochromocytomas were mostly benign. The pooled incidence counts animals with any of the three tumor types. Animals dying before the first tumor was observed are not considered to be at risk and are not included in the totals. Equivalent human doses are calculated using a surface-area adjustment. There are no pharmacokinetic data on pentachlorophenol. The slope factor is calculated as the geometric mean of the slope factors for each pentachlorophenol preparation. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) For purposes of comparison, a slope factor of 0.05 can be derived from the incidence of hemangiosarcomas alone. Also for comparison, a slope factor of 0.5 can be derived from the pooled incidence of liver tumors and pheochromocytomas in male B6C3F1 mice. The carcinogenicity assessment is based on results in a single animal species. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- This assessment is not presented in any existing U.S. EPA document. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 11/10/1987, 09/22/1988, 10/19/1988, 12/06/1989, 02/08/1990, 08/02/1990 Verification Date -- 08/02/1990 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199103 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Pentachlorophenol CASRN -- 87-86-5 Last Revised -- 03/01/1991 SORD: __VI.A. ORAL RfD REFERENCES Hinkle, D.K. 1973. Fetotoxic effects of pentachlorophenol in the Golden Syrian Hamster. Toxicol. Appl. Pharmacol. 25: 445. Larsen, R.V., G.S. Born, W.V. Kessler, S.M. Shaw and D.C. Van Sickle. 1975. Placental transfer and teratology of pentachlorophenol in rats. Environ. Lett. 10: 121-128. Schwetz, B.A. and P.J. Gehring. 1973. The effect of tetrachlorophenol and pentachlorophenol on rat embryonal and fetal development. Toxicol. Appl. Pharmacol. 25: 455. Schwetz, B.A., J.F. Quast, P.A. Keelev, C.G. Humiston and R.J. Kociba. 1978. Results of 2-year toxicity and reproduction studies on pentachlorophenol in rats. In: Pentachlorophenol: Chemistry, Pharmacology and Environmental Toxicology, K.R. Rao, Ed. Plenum Press, NY. p. 301. U.S. EPA. 1984. Health Effects Assessment for Pentachlorophenol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washiington, DC. U.S. EPA. 1985. Drinking Water Criteria Document for Pentachlorophenol. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Boutwell, R.K. and D.K. Bosch. 1959. The tumor-promoting action of phenol and related compounds for mouse skin. Cancer Res. 19: 413-424. BRL (Bionetics Research Laboratories). 1968. Evaluation of the carcinogenic, teratogenic and mutagenic activities of selected pesticides and industrial chemicals, Vol. 1. Carcinogenic Study. Prepared for the National Cancer Institute, Bethesda, MD. NTIS PB-223-159. p. 393. Catilina, P., A. Chamoux, M.J. Catilina and J. Champeix. 1981. Study of the pathogenic properties of substances used as wood protectives: Pentachlorophenol. Arch. Mal. Prof. Med. Trav. Secur. Soc. 42(6): 334-337. (Fre.) Gilbert, F., C. Minn, R. Duncan and J. Wilkinson. 1990. Effects of pentachlorophenol and other chemical preservatives on the health of wood-treating workers in Hawaii. Arch. Environ. Contam. Toxicol. 19(4): 603-609. Innes, J.R.M., B.M. Ulland, M.G. Valerio, et al. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice. A preliminary note. J. Natl. Cancer Inst. 42: 1101-1114. NTP (National Toxicology Program). 1989. Technical Report on the Toxicology and Carcinogenesis Studies of Pentachlorophenol (CAS No. 87-86-5) in B6C3F1 mice (Feed Studies). NTP Tech. Report No. 349. NIH Publ. No. 89-2804. Schwetz, B.A., J.F. Quast, P.A. Keeler, C.G. Humiston and R.J Kociba. 1978. Results of two-year toxicity and reproduction studies on pentachlorophenol in rats. In: Pentachlorophenol: Chemistry, Pharmacology and Environmental Toxicology, K.R. Rao, Ed. Plenum Press, NY. p. 301-309. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Pentachlorophenol CASRN -- 87-86-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 III.A. Health Advisory added 06/30/1988 I.A.6. Documentation year corrected 01/01/1990 II. Carcinogen assessment now under review 01/01/1990 VI. Bibliography on-line 04/01/1990 I.A.2. NOEL corrected to NOAEL in last sentence, 1st paragraph 07/01/1990 I.B. Inhalation RfC now under review 07/01/1990 IV.F.1. EPA contact changed 08/01/1990 III.A.10 Primary contact changed 03/01/1991 II. Carcinogenicity assessment on-line 03/01/1991 VI.C. Carcinogenicity references added 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 02/01/1993 I.A.7. Minor text change 07/01/1993 II.D.3. Primary contact's phone number changed 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/02/1998 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 374 of 1119 in IRIS (through 2003/06) AN: 88 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0088-tr.pdf UD: 200209 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Phenol- SY: 108-95-2; BENZENOL-; CARBOLIC-ACID-; HYDROXYBENZENE-; IZAL-; MONOHYDROXYBENZENE-; MONOPHENOL-; NCI-C50124-; OXYBENZENE-; PHENIC-ACID-; PHENYL-ALCOHOL-; PHENYL-HYDRATE-; PHENYL-HYDROXIDE-; PHENYLIC-ACID-; PHENYLIC-ALCOHOL- RN: 108-95-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200209 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RFD) Substance Name -- Phenol CASRN -- 108-95-2 Last Revised -- 09/30/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: This RfD replaces the previous RfD of 0.6 mg/kg-day entered on IRIS 6/1/89, which was based on a developmental toxicity study in rats (NTP, 1983a), with a NOAEL of 60 mg/kg-day. New studies published since the previous RfD include a new two-generation study (Ryan et al., 2001; available in unpublished form as IIT Research Institute, 1999), a new developmental toxicity study using divided gavage dosing (Argus Research Laboratories, 1997), and a 13-week drinking water neurotoxicity study (ClinTrials BioResearch, 1998). Although these new studies result in a stronger database, another new study (Hsieh et al., 1992) raises questions as to whether the critical effect has been appropriately identified, or whether immunotoxicity is the critical effect. A database uncertainty factor of 3 was added to account for this uncertainty. The new developmental toxicity study (Argus Research Laboratories, 1997) is the new principal study, with a NOAEL of 60 mg/kg-day and a BMDL of 93 mg/kg-day. The RfD is based on the BMDL because, unlike the NOAEL, the BMDL is not limited to one of the experimental doses. The NTP (1983a) study was not considered appropriate as a co-principal study due to the equivocal nature of the identified LOAEL and because the effect observed was not supported in the more recent study in rats using a more environmentally relevant dosing protocol (divided gavage dosing rather than a single bolus dose). SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ------------------------- ------------------------ ---------------- Decreased maternal BMDL 93 mg/kg-day 300 1 3E-1 weight gain mg/kg-day Rat developmental BMDL 157 mg/kg-day study Argus Research Laboratories, 1997 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- This RfD is applied to ingested phenol only and is in addition to phenol formed endogenously in the gut by bacterial metabolism of protein. BMDL = 95% lower confidence limit on the maximum likelihood estimate of the dose corresponding to a one standard deviation change in the mean BMD = Maximum likelihood estimate of the dose corresponding to a one standard deviation change in the mean PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Argus Research Laboratories. (1997) Oral (gavage) developmental toxicity study of phenol in rats. Horsham, PA. Protocol number: 916-011. In an unpublished developmental toxicity study conducted according to GLP guidelines (Argus Research Laboratories, 1997), pregnant Crl:CDRBR VAF/Plus Sprague-Dawley rats (25/group) received phenol by oral gavage on gestation days (GDs) 6 through 15. Dosing was three times daily with 0, 20, 40, or 120 mg phenol/kg/dosage, using a dosing volume of 10 mL/kg. The corresponding daily doses were 0, 60, 120, and 360 mg/kg-day. The exposed dams were observed twice a day for viability and daily for clinical signs, abortions, and premature deliveries. In addition, the maternal body weights were recorded every day, and food consumption was also recorded periodically. The rats were sacrificed on GD 20 and gross necropsy was performed and the number of corpora lutea in each ovary was recorded. The uterus of each rat was excised and examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Each fetus was weighed, sexed, and examined for gross external alterations. One half of the fetuses were examined for soft tissue alterations and the rest were examined for skeletal alterations. One high-dose dam died on GD 11. The study authors attributed this death to phenol treatment, because it occurred only at the high dose, although there were no adverse clinical observations and no abnormal necropsy findings in this animal. Other high-dose animals exhibited excess salivation and tachypnea (rapid breathing). There were no other treatment-related clinical observations and no treatment-related necropsy findings. Dose-dependent decreases in body weight of the exposed animals as compared with the controls were observed. Statistically significant decreases in both maternal body weight (8%) and body weight gain (38% for GDs 6-16) were observed at the high dose; although a statistically significant decrease in body weight gain (11%) was observed at the mid dose, the decrease at the mid dose (relative to controls) in absolute maternal weight at the end of dosing (3%) was not statistically significant. Dose-dependent decreases in food consumption were also observed during the dosing period. Fetal body weights in the high-dose group were significantly lower than those of controls - by 5-7%. The high-dose group had a statistically significant decrease in ossification sites on the hindlimb metatarsals, but it is unlikely that this small change is biologically significant. The incidence of litters with incompletely ossified or unossified sternal centra was 0/23, 0/25, 3/23, and 3/24; this increase was not statistically significant. There were small, dose-related increases in the number of litters with fetuses with "any alteration" and with "any variation" at 120 mg/kg/day and higher. However, neither of these changes was statistically significant, and the response was not clearly dose-related. In addition, an increase in total variations is of questionable significance in the absence of any increase in individual variations. No other treatment-related effects were observed in uterine contents, malformations, or variations. The maternal NOAEL was 60 mg/kg-day, based on small decreases in maternal body weight gain at 120 mg/kg-day, and the developmental NOAEL was 120 mg/kg-day, based on decreased fetal body weight and delayed ossification at 360 mg/kg-day. Benchmark dose (BMD) modeling was also conducted for the decreased maternal weight. Defining the benchmark response as a one-standard-deviation decrease in maternal body weight gain, the 95% lower confidence limit on the BMD (i.e., the BMDL) was 93 mg/kg-day. This BMDL was calculated using the polynomial model, which gave slightly better fit than the power and Hill models, using BMDS Version 1.3. No human studies that addressed the developmental toxicity of phenol were identified. In a well-designed developmental toxicity study (NTP, 1983a), timed-mated CD rats were administered phenol by gavage at 0, 30, 60, or 120 mg/kg-day in 5 mL/kg distilled water on GD 6 to 15 and sacrificed on GD 20. Females were weighed on GDs 0, 6 through 15 (prior to daily dosing), and 20 (immediately following sacrifice), and they were also observed during treatment for clinical signs of toxicity. A total of 20-22 females per group were confirmed to be pregnant at sacrifice on GD 20. The dams were evaluated at sacrifice for body weight, liver weight, gravid uterine weight, and status of uterine implantation sites. Live fetuses were weighed, sexed, and examined for gross morphological abnormalities and malformations in the viscera and skeleton. Results of this study did not show any dose-related signs of maternal toxicity or any clinical symptoms of toxicity related to phenol treatment. The number of implantation sites was slightly higher in the dosed groups, but this change could not be treatment-related, because implantations in this strain take place prior to GD 6 (prior to dosing). Significant increases in the litters with nonlive (dead plus resorbed) were observed in the low- and mid-dose groups but not in the high-dose group, but this effect was not considered treatment related, because this response was not dose dependent, and the response in the high-dose group was comparable with that of the control. In addition, there was no effect on the more appropriate measure of nonlive per litter. There was also no effect on live fetuses, sex ratio, malformations, or variations. However, a clear dose-related downward trend in fetal body weight was observed, although the changes at the two lower doses were small and the effect was statistically significant only at the high dose. Fetal body weights in the high-dose group were 93% of the average in the control group; fetal body weights were not reported separately for males and females. Historical control data from the supplier report the average fetal body weight in this strain as being well below the weight in the high-dose group (Charles River Laboratories, 1988). (Concurrent control weight was 4.14 g, high-dose weight was 3.84 g, and historical control weight was 3.39 g.). The litter size in the high-dose group was also somewhat higher (but not statistically significant) than in the controls, possibly contributing to the smaller fetal weight at the high dose. The total pup burden (total fetal weight) and the gravid uterine weight were highest in the low-dose group, and then in the high-dose group; both of these values were higher than those in the control group. In addition, the treatment-period maternal weight gain was very similar in the control and high-dose groups (but higher in the low-dose group), but the absolute maternal weight gain (i.e., adjusted for the gravid uterine weight) was much lower in the high-dose group than in the controls. The results from the low-dose group suggest that the dams could have borne a somewhat higher burden of the total in utero package. However, the results also suggest that the dams were near the limit of what they could carry, based on the lower absolute weight gain but unaffected treatment-period weight gain in the high-dose group. No dose-related signs of maternal toxicity and no clinical symptoms of toxicity related to phenol treatment were observed in this study. On the basis of these considerations and the potential for the decreased fetal weight to reflect primarily the larger litter size, the decreased fetal weight in this study could be considered an equivocal LOAEL. Thus, on the basis of decreased fetal body weight, the mid dose in this study of 60 mg/kg-day was a NOAEL for developmental toxicity and the high dose of 120 mg/kg-day was an equivocal LOAEL. The high dose (120 mg/kg-day) was a maternal NOAEL. BMD modeling could not be done for the decreased fetal weight, because NTP did not have information on the fetal weight by sex, either in the report or in its archives. Data on fetal weight by sex is needed for meaningful modeling, because the average weight of males and females is different and the number of males per group varied. Although the same NOAEL of 60 mg/kg-day was identified for this study as in the principal study (Argus Research Laboratories, 1997), this study was not considered adequate to be a co-principal study in light of the equivocal nature of the LOAEL and the absence of an effect on fetal weight in another gavage developmental study in rats (Argus Research Laboratories, 1997) at a maternally toxic dose in that study of 120 mg/kg-day. In a standard mouse developmental toxicity study (NTP, 1983b), phenol was administered by gavage in water at 0, 70, 140, or 280 mg/kg-day on GDs 6 to 15 to groups of 31-36 plug-positive female CD-1 mice. The pregnancy rate in the controls was only 83%; the pregnancy rate in dosed animals ranged from approximately 83% in the low- and mid-dose groups to 71% at the high dose. In addition, 4/36 high-dose mice died; no deaths occurred in any other groups. The average maternal body weight gain during treatment was statistically significantly reduced at the high dose, as was the maternal body weight at terminal sacrifice on GD 17 (by 10%, compared with the control group). In addition, tremors were observed at the high dose throughout the dosing period. As in the rat study, a highly statistically significant decrease in fetal body weight per litter (18%) was observed at the high dose. An increased incidence of cleft palate was also reported at the highest dose level, although the incidence was not significantly different from that of the other groups, and there was no statistically significant increase in the incidence of litters with malformations. There was no other evidence of altered prenatal viability or structural development. Thus, the high dose of 280 mg/kg-day was a maternal frank effect level based on the observed deaths; tremors and decreased body weight also occurred at this dose. The high dose was also a developmental LOAEL based on decreased fetal body weight (accompanied by a possible increase in the incidence of cleft palate) in the fetuses, an effect that was likely secondary to the severe toxicity in the dams. The study NOAEL for maternal and developmental toxicity was 140 mg/kg-day. Hsieh et al. (1992) investigated the effects of phenol exposure on hematological, immune, and neurochemical endpoints in a study of 6-week-old male CD-1 mice (5 per dose) administered actual concentrations of 0, 4.7, 19.5, or 95.2 ppm in drinking water for 28 days. On the basis of measured concentrations and water intake, the authors reported that the corresponding daily doses were 0, 1.8, 6.3, and 33.6 mg/kg-day. After 28 days, the mice were sacrificed by decapitation, gross pathological examinations were performed, and the liver, spleen, thymus, and kidney were weighed. Blood was taken at sacrifice for analysis. Splenocytes were prepared for analysis of antibody production response, mitogen-stimulated lymphocyte proliferation, mixed lymphocyte response, and cell-mediated cytolysis response. During the 28-day exposure, no mortality and no overt clinical signs occurred in exposed mice. Phenol treatment had no effects on food or water consumption or on body weight gain. Exposed mice had no gross lesions in the liver, kidney, spleen, thymus, lung, heart, and brain, and no effect on organ weights for the liver, kidney, spleen, and thymus was seen. A dose-related decrease in erythrocyte counts was statistically significant at all doses. The hematocrit was decreased only at the high dose. A decreased erythrocyte count in the absence of an effect on hematocrit may have been due to macrocytosis (enlarged erythrocytes), but insufficient data were provided to evaluate this possibility. The erythrocyte counts in all dosed groups were markedly lower than the historical control values provided by the animal distributor (Charles River Laboratories, 1986), although the hematocrit concentration in all groups was above the historical control mean. There was no effect on total or differential leukocyte counts. A decreased antibody response to sheep red blood cells was observed, as indicated by both the plaque-forming cell (PFC) assay (expressed as PFC/million spleen cells and PFC/spleen) and the antibody titer using an enzyme-linked immunosorbent assay (ELISA). Two of these measures were statistically significantly decreased at the mid dose, and PFC/spleen was significantly decreased only at the high dose. These decreases reached 40% (a value often used by immunotoxicologists as a rule of thumb for clinically relevant decreases) at the high dose. Decreases in the absolute splenocyte lymphoproliferative responses to mitogens and the mixed lymphocyte response (the proliferative ability of splenic lymphocytes in response to alloantigens) were also observed at the high dose; there was no effect on the cytolytic response to tumor cells at any dose. Although these assays were conducted according to the methods of the day, the latter two do not conform to modern protocols, and there is little biological significance to the results of the mitogen response assay. Identification of a NOAEL in this study is somewhat problematic, because immunotoxicity risk assessment guidelines have not been developed. The determination of what degree of decrease is adverse is also problematic, because the clinical relevance of a decrement in immune function will depend on the magnitude and type of immune challenge, with a sufficiently large challenge resulting in illness even for unimpaired individuals. In a report on the use of immunotoxicity data for risk assessment, Selgrade (1999) recommended that any statistically significant and consistent change be considered a risk for the purposes of hazard identification, but the degree of change considered adverse for the purposes of dose-response assessment was not addressed. On the basis of the magnitude of the decreases in antibody response observed in three related assays, supported by decreased hematocrit and red blood cells, the high dose (33.6 mg/kg-day) can be considered the study LOAEL, and the mid dose (6.2 mg/kg-day) can be considered the study NOAEL. There is, however, considerable uncertainty regarding the reliability of these values due to issues of study interpretation and because the study used only 5 animals per group as compared with the recommended 8 per group (U.S. EPA, 1998). UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 300 A factor of 10 is used to protect sensitive human subpopulations (intraspecies variability). The data on the within-human variability in the toxicokinetics and toxicodynamics of ingested phenol are insufficient to adjust the default uncertainty factor for intraspecies variability. In a sample of liver fractions from 10 people, Seaton et al. (1995) found that the kinetics of phenol sulfation and hydroquinone conjugation varied by up to approximately threefold. Much larger variability is observed in CYP2E1 (the cytochrome P450 enzyme that oxidizes phenol to potentially toxic metabolites), particularly between neonates and adults (Vieira et al., 1996). These data on inter-individual variability in enzymatic metabolism are not adequate to move from the default UFH of 10 because they do not reflect potential variability in portal-of-entry metabolism of phenol or uncertainty regarding the identity of the toxic moiety. A factor of 10 is used to extrapolate from animals to humans (UFA). The absorption, distribution, and metabolism of ingested phenol in rats and humans appear to be generally qualitatively similar, although the data are insufficient for a quantitative comparison. Comparison of laboratory animal and human phenol toxicokinetics is also limited by the lack of knowledge regarding the identity of the toxic moiety. It is not possible to quantitatively use the toxicokinetic data to adjust the default 10-fold factor for interspecies variability, and the default UFA of 10 is judged to be appropriate. It may be possible to reduce this default value of 10 following review and evaluation of data comparing the toxicokinetics of phenol and its metabolites in rats and humans (perhaps supplemented by a physiologically based pharmacokinetic model), if such data become available. The BMDL was based on an effect of minimal severity (decreased maternal weight gain), and a higher BMDL and NOAEL were obtained for the related endpoint of effects on maternal weight. The BMDL is also within 50% of the NOAEL identified for the decreased maternal weight endpoint. Therefore, no uncertainty factor is required for extrapolation from a NOAEL to a LOAEL. No uncertainty factor for extrapolation across duration is needed, because this developmental study is supported by chronic bioassays in two species in which toxicity was observed only at higher doses. An additional uncertainty factor for sensitive populations such as infants and children is not needed for phenol because sufficient studies of reproductive and developmental toxicity have been performed, with the observation of decreased fetal body weight (in the absence of other indications of fetal toxicity or teratogenicity) only at doses equal to or higher than the LOAEL for the endpoint used for developing the oral RfD. The toxicity database for phenol by the oral route can be considered complete. It includes 2-year drinking water studies conducted in rats and mice (NCI, 1980), a two-generation drinking water study conducted in rats (Ryan et al., 2001; available in unpublished form as IIT Research Institute, 1999), and gavage developmental toxicity studies in rats (Argus Research Laboratories, 1997; NTP, 1983a; Narotsky and Kavlock, 1995) and mice (NTP, 1983b). However, the range of endpoints evaluated in the chronic toxicity studies was limited and did not include hematological or serum biochemistry evaluations. Immunological and hematological effects in mice were observed at low doses by Hsieh et al. (1992) in a 28-day drinking water study. These endpoints were evaluated, and no significant hematological or serum biochemistry effects were observed at doses of up to >300 mg/kg-day in the two-generation rat study (IIT Research Institute, 1999; Ryan et al., 2001). The difference in these results suggest species differences between mice and rats, but confirmation of the immunological and hematological effects in an assay done according to modern test methods would be useful. The results of a study of the effects of phenol on bone marrow cellularity in mice dosed intraperitoneally at up to 300 mg/kg-day (Eastmond et al., 1987) and an in vitro study with mouse bone marrow cells (Corti and Snyder, 1998) also do not indicate that mouse blood cells are highly susceptible to effects of phenol. However, these studies did not evaluate the same parameter measured by Hsieh et al. (1992), and significant interspecies differences in immunotoxicity are not unusual. It is of interest that the endpoints affected in the Hsieh et al. (1992) study (two measures of effects on antibody production, the PFC and ELISA) are the immune endpoints most highly predictive of effects on host resistance (Luster et al., 1992, 1993). Therefore, to account for the uncertainties regarding the immunological and hematological effects in mice, a database uncertainty factor of 3 is used. The database factor could be reconsidered with results of an immunotoxicity study in mice that is compliant with EPA immunotoxicity test guidelines (U.S. EPA, 1998). An additional degree of public health protection may also be provided by the use of a gavage study rather than the more environmentally relevant route of drinking water. This is because gavage administration results in a higher peak blood level - presumably even using a divided dosing protocol - than does ingestion of the same daily dose in drinking water, and at least some effects of phenol are related to peak blood levels. Thus, a composite uncertainty factor of 300 was used, based on default factors of 10 each for interspecies extrapolation and intraspecies variability and a database factor of 3 to account for uncertainties regarding the immunotoxic potential of phenol. MF = 1 No MF is applied because the existing uncertainties have been addressed with the standard uncertainty factors. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) Phenol is produced endogenously by bacteria in the gut at a rate estimated at 1 to 10 mg/day, corresponding to approximately 0.014-0.14 mg/kg-day (Bone et al., 1976; Lawrie and Renwick, 1987; Renwick et al., 1988), based on total phenol (free plus conjugated) levels in urine. Because endogenous phenol is formed in the gut, the toxicokinetics would be similar to that of ingested phenol. Both humans and laboratory animals efficiently conjugate and excrete phenol at low doses, resulting in only a small degree of systemic exposure to free phenol (or any of its oxidative metabolites) at these low levels. The phenol conjugation capacity of the liver is an important determinant of the ingested dose that would result in toxicity, but there is no information on the degree of phenol conjugation by humans at doses in the range of the RfD. Human variability exists in both the levels of endogenous phenol production and in the conjugative capacity of the liver. In the absence of more detailed information, it is reasonable to assume that humans have adapted by having adequate conjugation capacity for the range of endogenous phenol production. Therefore, the default total uncertainty factor of 10 for human variability in toxicokinetics and toxicodynamics described above is considered adequate. Determining whether oxidative metabolites are formed in people with high endogenous levels of phenol formation would enhance the confidence in the determination of the intraspecies uncertainty factor. The RfD is at least twice the endogenous rate of phenol formation in humans, meaning that endogenous production is approximately 5-50% of the RfD. An extensive database for the effects of orally administered phenol in laboratory animals is available. Two-year drinking water studies have been conducted in groups of F344 rats and B6C3F1 mice (50 animals/sex/dose/species). The rats were exposed to 0, 2500, or 5000 ppm, corresponding to 0, 260, and 585 mg/kg-day for male rats and 0, 280, and 630 mg/kg-day for female rats. The mice were exposed to 0, 2500, or 5000 ppm in drinking water, corresponding to estimated doses of 0, 450, and 660 mg/kg-day for both sexes. These studies identified NOAELs of 260 mg/kg-day and 480 mg/kg-day for rats and mice, respectively, based on decreased body weight gain and decreased water consumption (NCI, 1980). A complete histopathology evaluation was included, but no increases in noncancer lesions were found. Hematology and serum biochemical evaluations were not included in those chronic studies, but they were included in a recent two-generation drinking water study conducted in Sprague-Dawley rats (Ryan et al., 2001; available in unpublished form as IIT Research Institute, 1999), as described below. Toxicity in gavage studies with phenol is typically much higher than that in drinking water studies. NOAELs for systemic effects were 5- to10-fold lower in gavage studies (Berman et al., 1995; Moser et al., 1995; Dow Chemical Co., 1945) than those seen in drinking water studies. Many (but not all) of the effects in drinking water studies appeared to be due to decreased water consumption resulting from poor palatability. Effects observed in gavage studies included tremor and liver and kidney histopathology; effects in drinking water studies were less severe. As described in greater detail in the Toxicological Review, this difference between gavage and drinking water exposure is consistent with toxicokinetic data that suggest that toxicity is correlated with peak blood concentrations rather than being a measure of total dose, such as the area under the phenol blood concentration curve (AUC). Due to this marked difference in toxicity between gavage and drinking water, the RfD was not based on gavage studies of systemic effects, even though those effects occurred at lower doses. Although the principal study for the development of the RfD (Argus Research Laboratories, 1997) used gavage dosing, it is not clear whether this difference in toxicity also applies to the endpoint of decreased maternal weight gain. In addition, Argus Research Laboratories (1997) used a divided dosing protocol, a significant enhancement that made the gavage dosing more closely resemble an environmentally relevant route of exposure. In an unpublished 13-week neurotoxicity study conducted according to good laboratory practice (GLP) guidelines (ClinTrials BioResearch Ltd., 1998), groups of 15 male and 15 female Sprague-Dawley rats received phenol via drinking water at concentrations of 0, 200, 1000, or 5000 ppm for 13 weeks followed by a 4-week recovery period. The study authors calculated that the average doses were 0, 18.1, 83.1, and 308.2 mg/kg-day for males and 0, 24.6, 107.0, and 359.8 mg/kg-day for females. During the exposure period, clinical signs and water intake were recorded daily and body weight and food consumption were recorded weekly. In addition, a functional observational battery and a motor activity test were conducted pre-study and once each during weeks 4, 8, 13, and 17. At the end of the exposure and at the end of the recovery period, five rats/sex in the control and 5000 ppm groups underwent neuropathological evaluations (including a thorough evaluation of the brain and several nerves). The rest of the rats were sacrificed at the end of the 4-week recovery and were subjected to gross necropsy. The primary clinical sign was dehydration, which was associated with marked decreases in water consumption at the high dose and smaller decreases at the mid-dose. Decreases in water consumption were more pronounced in females than in males and were most evident during the first week of dosing. Water consumption was decreased to approximately 90% of the control level in mid-dose males and females, to approximately 60% of control levels in high-dose males, and to approximately 55% (40% during the first week) of control levels in high-dose females. Water consumption rebounded to levels higher than those of controls during the recovery period. The decreased water consumption was likely due to the poor palatability of phenol at high concentrations rather than being a manifestation of an overt toxicological effect. In addition, the high-dose group had decreased body weights as compared with the controls (8% for males and 12% for females) and decreased food intake (approximately 10% for males and 10-20% for females). The only toxicologically significant neurological effect was decreased motor activity in females. A statistically significant reduction in total group mean motor activity counts was observed at week 4 in the 5000 ppm group. The authors reported that the rate of linear change of motor activity with time was also significantly decreased at weeks 8 and 13 in the 1000 ppm and 5000 ppm groups. The authors attributed the decreased activity to dehydration, noting that the control group mean total activity increased by >20% at week 4 as compared with prestudy levels, whereas activity of the dehydrated females in the 5000 ppm group at week 4 was decreased by 17% and activity of the females in this group that were not dehydrated increased by 2%. However, a detailed analysis of the individual animal data, as discussed in the Toxicological Review, did not support the hypothesis that all of the decreased motor activity could be attributed to dehydration; phenol at least contributed to the decreased motor activity. On the basis of decreased motor activity, the study NOAEL in females was 1000 ppm phenol (107 mg/kg-day) and the LOAEL was 5000 ppm (360 mg/kg-day ). No LOAEL was identified in males; the high dose of 308 mg/kg-day was a NOAEL. A BMDL of 219 mg/kg-day was calculated for decreased motor activity in females in week 4 in this study. In a two-generation reproductive toxicity study following modern GLP guidelines (Ryan et al., 2001; full unpublished study available as IIT Research Institute, 1999), 30 Sprague-Dawley rats/sex/group were exposed to 0, 200, 1000, or 5000 ppm phenol in drinking water. The authors calculated that the average daily phenol intake during week 10 was 0, 14.7, 70.9, and 301.0 mg/kg-day for P1 males and 0, 20.0, 93.0, and 320.5 mg/kg-day for P1 females. For the F1 generation, the average phenol intake during week 10 was 0, 13.5, 69.8, and 319.1 mg/kg-day for males and 0, 20.9, 93.8, and 379.5 mg/kg-day for females. Most of the treatment-related changes in P1 rats were observed in the high-dose groups. The only significant observed clinical sign was redness around the nose fur, which occurred in the high-dose males and females of the F1 generation before mating and in P1 dams during lactation. This redness likely reflected a nonspecific stress response. A significant decrease in water consumption was observed throughout the study in both P1 and F1 animals of both sexes, which was attributed to poor palatability. The low water consumption at the high dose was accompanied by decreased body weights as compared with the controls. Decreased absolute organ weights and increased relative organ weights were observed for a number of organs at the high dose in both the P1 and F1 generations. Most of these changes likely reflected the lower body weight and overall dehydration in these groups. F1 females had a statistically significant, dose-related decrease in absolute uterine weights at all doses, but P1 females were not affected. The decreased uterine weight was not considered adverse because there was no evidence of a dose-response relationship for relative uterine weight, no effect on reproductive function, and no histopathological changes in the uterus and the individual animal data showed that the uterine weight was below the control range for only a few rats in each dose group. No other organ weight changes in either the P1 or the F1 generation were considered adverse. The histopathological examinations showed no treatment-related lesions in the kidneys, spleen, liver, thymus, or reproductive organs. An immunotoxicity screen in this study found no significant effects on spleen weight, cellularity, or antibody-forming cells for any test group as compared with the control group. Complete hematological evaluations and serum biochemical evaluations were conducted on P1 males prior to sacrifice, and no biologically significant changes were observed. No effect on fecundity or fertility in either generation was observed. In addition, there was no effect on other indicators of reproductive toxicity, including the frequency of estrus, testicular sperm count, sperm motility and sperm morphology. The survival of the high-dose F1 pups was significantly decreased on prenatal day 4 (pre-culling), although there was no effect on overall F1 pup survival. In the F2 generation, high-dose pup survival was significantly decreased throughout the lactation period. This decreased survival of both generations of pups was likely secondary to the decreased maternal water intake and associated decreases in milk production. In the F1 generation, delayed vaginal patency and delayed preputial separation were observed at the high dose. The delay was considered secondary to decreased fetal growth at the high dose and as resulting from decreased water consumption due to poor palatability and associated decreased food consumption. Thus, all of the adverse systemic and reproductive effects of phenol in the Ryan et al. (2001) study occurred at the high dose, and they appear to be secondary to decreased water consumption due to poor palatability rather than a toxic effect of phenol. On the basis of decreased parental and pup body weight (compared with the controls) and decreased pup survival, the high dose is a LOAEL. The study NOAEL is 70.9 mg/kg-day (based on the NOAEL corresponding to the lowest LOAEL in this study, in P1 males). BMD modeling was not conducted for this study because the observed effects appeared to be secondary to decreased water consumption and not reflective of phenol toxicity. Phenol is readily absorbed by the inhalation, oral, and dermal routes (Piotrowski, 1971; Capel et al., 1972; Dow Chemical Co., 1994). Portal-of-entry metabolism for the inhalation and oral routes appears to be extensive and involves sulfate and glucuronide conjugation and, to a lesser extent, oxidation, primarily by CYP2E1. The primary oxidative metabolites include hydroquinone and catechol, which are also substrates for conjugation. Secondary products of hydroquinone or catechol metabolism, including benzoquinone and trihydroxybenzene, can also be formed (Capel et al., 1972; Dow Chemical Co., 1994; Kenyon et al., 1995). Once absorbed, phenol is widely distributed in the body, although the levels in the lung, liver, and kidney are often reported as being higher than those in other tissues (on a per-gram-tissue basis) (Tanaka et al., 1998; Liao and Oehme, 1981; Dow Chemical Co., 1994). Elimination from the body is rapid, primarily as sulfate and glucuronide conjugates in the urine, regardless of route of administration; phenol does not appear to accumulate significantly in the body (Ohtsuji and Ikeda, 1972; Deichmann and Witherup, 1944; Dow Chemical Co., 1994). For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0088-tr.pdf#page=103. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Database -- Medium to high RfD -- Medium to high The principal study (Argus Research Laboratories, 1997) used an adequate number of animals and evaluated an appropriate array of endpoints for a developmental toxicity study. Although gavage dosing was used, the divided-dosing protocol provided a significant enhancement that made the gavage dosing more closely resemble an environmentally relevant route of exposure. Although the use of gavage dosing lowers the confidence in the study, the dosing frequency in the divided-dose gavage study may be fairly similar to that in drinking water studies, in which rodents typically consume water in a few larger doses, often in association with food consumption. Confidence in the supporting database is medium to high. Although the oral toxicity database meets the minimal criteria for a high-confidence database (chronic studies in two species, developmental toxicity studies in two species, and a multigeneration reproduction study), the chronic studies did not evaluate a sufficient array of endpoints. In particular, the chronic mouse study (NCI, 1980) did not evaluate hematological and immunological effects, making interpretation of the results of the Hsieh et al. (1992) study difficult. Considering the above issues results in medium to high confidence in the RfD. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0088-tr.pdf#page=112. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2002 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments (PDF). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0088-tr.pdf#page=132. Other EPA Documentation -- Summary Review of the Health Effects Associated with Phenol: Health Issue Assessment. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1986. Agency Consensus Date -- 08/28/2002 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS in general at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ---------------------------------------------------------------------------- UDRC: 200209 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Phenol CASRN -- 108-95-2 Last Revised -- 09/30/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Not applicable. No adequate inhalation exposure studies exist from which an inhalation RfC may be derived. A route-to-route extrapolation is not appropriate, because phenol can be a direct contact irritant, and so portal-of-entry effects are a potential concern. The minimal database needed for the development of an RfC is a well-conducted subchronic inhalation study that adequately evaluates a comprehensive array of endpoints, including the respiratory tract, and establishes a NOAEL and a LOAEL (U.S. EPA, 1994). This criterion was not met for phenol. Neither of the two available subchronic studies (Deichmann et al., 1944; Sandage, 1961) are adequate for exposure-response assessment because neither included adequate documentation of the histopathology results and neither used modern methods for generating or monitoring exposure levels. These studies can, however, be used for hazard identification, and they identify the respiratory tract, liver, and kidney as targets of inhalation exposure to phenol. The phenol database also includes a well-conducted, 2-week inhalation study with rats that used modern exposure methods, evaluated a wide array of endpoints, and included a thorough histopathology evaluation of the respiratory tract (Hoffman et al., 2001; the full unpublished study report is available as Huntingdon, 1998). The only treatment-related effect observed was a red nasal discharge in male rats, which was observed with a statistically significant duration-related, and concentration-related incidence in the mid- and high-concentration groups. However, because the red nasal discharge was likely due to a nonspecific response to stress, this response is not considered adverse. The 2-week study is of insufficient duration for the derivation of an RfC. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Not applicable. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) Not applicable. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) Not applicable. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Not applicable. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 2002 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS in general at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ============================================================================ UDCA: 200209 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Phenol CASRN -- 108-95-2 Last Revised -- 09/30/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION This carcinogenicity assessment replaces the previous assessment of 11/01/90. Under the current guidelines (U.S. EPA, 1987), phenol would be characterized as Group D, not classifiable as to human carcinogenicity. Under Draft Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), the data regarding the carcinogenicity of phenol via the oral, inhalation, and dermal exposure routes are inadequate for an assessment of human carcinogenic potential. Phenol was negative in oral carcinogenicity studies in rats and mice, but questions remain regarding increased leukemia in male rats in the bioassay as well as the positive gene mutation data and the positive results in dermal initiation/promotion studies at doses at or above the maximum tolerated dose (MTD). No inhalation studies of an appropriate duration exist. Therefore, no quantitative assessment of carcinogenic potential via any route is possible. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0088-tr.pdf#page=112. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0088-tr.pdf#page=103. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. The epidemiology data on phenol are limited. Kauppinen et al. (1986) reported a significant increase in respiratory cancer in phenol-exposed workers, but this observation appears to be due to confounding exposures, as there was no dose-response and the effect decreased after accounting for latency. No effect on cancer mortality was observed in workers exposed to phenol in the rubber industry (Wilcosky et al., 1984) or in workers exposed to formaldehyde and phenol (Dosemeci et al., 1991). However, the usefulness of each of these studies for risk assessment is limited by (depending on the study) an absence of an effect when latency was considered, a lack of a dose-response, and the potential for confounding. Because all of the subjects were also exposed to other chemicals and there was no correction for smoking, these studies are not adequate for reaching conclusions on the carcinogenic potential of phenol. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. NCI (1980) conducted a carcinogenicity bioassay in which F344 rats (50/sex/group) received phenol in drinking water at concentrations of 0, 2500, or 5000 ppm for 103 weeks and were sacrificed 1-2 weeks later. Using the reference water intake of 0.13 and 0.14 L/kg-day for chronic exposure of male and female F344 rats, respectively (U.S. EPA, 1988), the doses can be estimated as 0, 260, and 585 mg/kg-day for male rats and 0, 280, and 630 mg/kg-day for female rats. The doses shown here were adjusted to account for the reported water consumption of 80% and 90% of control at the low and high doses, respectively. The animals were observed daily for clinical signs and examined weekly for palpable masses. Body weights and food consumption were recorded every 2 weeks for the first 12 weeks and monthly thereafter; water consumption was recorded weekly. At the end of study, the animals were sacrificed and complete gross and histopathological examinations were performed. Organs and tissues examined included the bone marrow, spleen, cervical and mesenteric lymph nodes, heart, liver, kidney, thyroid, reproductive organs, brain, and other major tissues. The survival rate at study termination was comparable among all three groups of males (approximately 50%) and females (approximately 75%). Dose-related decreases in body weight as compared with the controls were observed in male and female rats, with a decrease of approximately 15% in high-dose males and approximately 10% in high-dose females. Water consumption was reduced by approximately 10% at the high dose. The authors stated that the non-neoplastic lesions were similar to those naturally occurring in aged F344 rats. However, an analysis conducted for this assessment found statistically significant increases in chronic kidney inflammation in high-dose males and females; there were no significant changes at the low dose. No other differences in the incidence of non-neoplastic lesions between the controls and the exposed rats were observed. The increased kidney inflammation and the decreased body weight as compared with controls at the high dose of 5000 ppm (585 mg/kg-day for males and 630 mg/kg-day for females) indicate that the MTD was reached. There were no dose-related trends in cancer incidence in male or female rats, but the study authors reported several tumors for which statistically significant increases were seen in low-dose males only, as indicated by pairwise comparisons. These increases were seen in the incidences of pheochromocytomas of the adrenal medulla (13/50, 22/50, and 9/50 in the control, low-, and high-dose groups, respectively) and "leukemias or lymphomas" (18/50, 31/50, and 25/50). The incidence of interstitial cell tumors of the testes was also elevated in the low-dose group (42/48, 49/50, and 47/50). The historical control incidence of pheochromocytomas in the bioassay program was 9% (data for the test laboratory were not reported), and the historical control incidence of leukemias or lymphomas in the test laboratory was 26%. The authors stated that the leukemias were "of the type usually seen in untreated F344 rats." There were no significant increases in tumor incidence in any tissue in female rats. In light of the absence of a clear dose-response in males, the high spontaneous testicular tumor rate in the matched controls and the absence of tumors in female rats, an association between the tumors and phenol exposure cannot be established. NCI concluded that phenol was "not carcinogenic in male or female F344 rats." However, the report noted uncertainties regarding the possible increase in leukemia in male rats, and the NCI reviewers recommended that phenol be considered for a retest. The increases in leukemia are of particular interest in light of the leukemogenic effects of benzene (for which phenol is a metabolite) in humans. (Benzene has not been shown to induce leukemia in experimental animals, although increases in lymphoma have been observed [e.g., NTP, 1986]). In a parallel study, NCI (1980) administered phenol at 0, 2500, or 5000 ppm in drinking water to B6C3F1 mice (50/sex/group) for 103 weeks and sacrificed the mice 1-2 weeks later. For B6C3F1 mice, the reference water intake is 0.24 L/kg-day for both sexes. The study reported that water consumption was decreased to 75% and 50-60% of the control levels at the low and high doses, respectively. The resulting doses (adjusting for decreased water intake) were 0, 450, and 660 mg/kg-day for both sexes. Dose-related decreases in body weight as compared with the controls were attributed to the decrease in water consumption. Besides the decreased water consumption, no clinical signs of toxicity were observed, and mortality rates (approximately 10% in males and 20% in females) were comparable between experimental and control groups. Histopathological examination and statistical analyses revealed no phenol-related signs of toxicity or carcinogenicity; lesions in all systems observed in the dosed groups were comparable with those in the controls. NCI concluded that, under the conditions of the assay, phenol was not carcinogenic in male or female B6C3F1 mice (NCI, 1980). Although the only sign of toxicity in the mouse study was decreased body weight (compared to the controls) secondary to decreased water consumption, higher doses probably could not have been tested in light of the decreased water consumption. If the authors had attempted to overcome the palatability issue by administering the high dose in the NCI (1980) mouse study by gavage instead of in drinking water, high toxicity would have been expected, considering the higher toxicity of phenol administered by gavage than that of phenol in drinking water. These considerations suggest that an MTD was also reached in mice, although a definitive conclusion is difficult. No other long-term oral carcinogenicity studies of phenol are available. No inhalation studies of phenol were of a sufficient duration to assess phenol carcinogenicity. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY In contrast with the negative carcinogenicity results for oral administration of phenol, dermally administered phenol has been consistently observed to be a promoter. Several authors (Salaman and Glendenning, 1957; Boutwell and Bosch, 1959; Wynder and Hoffmann, 1961) observed that dermally applied phenol promoted DMBA-initiated skin tumors. These studies have generally reported significant skin ulceration at all doses tested. The exception is Wynder and Hoffman (1961), who reported that 5% phenol promoted DMBA-initiated tumors in mice in the absence of any toxic reactions. When the same phenol dose was administered in different volumes, higher promotion activity was exhibited by the more concentrated solution, which also produced severe skin ulceration, suggesting that some of the promotion activity may have been related to the rapid cell division in the repairing of skin damage (Salaman and Glendenning, 1957). The observed response was dose-related (Boutwell and Bosch, 1959), but marked systemic toxicity was also observed at these doses. Co-carcinogenesis with dermally administered benzo[a]pyrene has also been observed (Wynder and Hoffmann, 1961). Because the benzo[a]pyrene was co-administered with the phenol, this assay cannot be classified as a true initiation/promotion assay. Production of papillomas by dermally administered phenol (in the absence of an initiator) was observed only at a concentration that caused ulceration and hence was above the MTD. Genotoxicity studies have found that phenol tends not to be mutagenic in bacteria (Pool and Lin, 1982; Rapson et al., 1980; Haworth et al., 1983), but positive or equivocal results have been obtained in gene mutation assays in mammalian cells (McGregor et al., 1988a, b; Paschin and Bahitova, 1982; Tsutsui et al., 1997). Increases were larger in the presence of S9 activation. Phenol tended to induce micronuclei in mice when administered intraperitoneally (Marrazzini et al., 1994; Chen and Eastmond, 1995; Ciranni et al., 1988), but negative (or positive only at very high doses) when administered orally (Ciranni et al., 1988; Gocke et al., 1981). This difference is likely due to the first-pass conjugation and inactivation of orally administered phenol. Phenol was also positive in vitro micro nucleus tests with human lymphocytes (Yarer et al., 1990) and Chinese hamster ovary (WHO) cells (Miller et al., 1995) and caused chromosome aberrations in the presence of S9 activation in WHO cells (Aviate et al., 1989). Phenol has been observed to act synergistically with hydroquinone in the production of genotoxic effects (Marrazzini et al., 1994; Barale et al., 1990; Chen and Eastmond, 1995). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not applicable. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not applicable. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2002 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Phenol. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0088-tr.pdf#page=132. Other EPA Documentation - Updated Health Effects Assessment for Phenol. Prepared by the Office of Health and Environment Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1988. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 08/28/2002 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 200209 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Phenol CASRN -- 108-95-2 Last Revised -- 09/30/2002 SORD: __VI.A. ORAL RfD REFERENCES Argus Research Laboratories, Inc. (1997). Oral (gavage) developmental toxicity study of phenol in rats. Horsham, PA. Protocol number: 916-011. Berman, E; Schlicht, M; Moser, VC; et al. (1995). A multi-disciplinary approach to toxicological screening: I. Systemic toxicity. J Toxicol Environ Health 45:127-143. Capel, ID; French, MR; Millburn, P; et al. (1972). Fate of C-14-phenol in various species. Xenobiotica 2:25-34. Charles River Laboratories. (1986). Technical bulletin: baseline hematology and clinical chemistry values as a function of sex and age for Charles River Outbred Mice: Crl: CD-1(ICR)BR, Crl: CF-1 BR. Charles River Laboratories. (1988). Embryo and fetal development toxicity (teratology) control data in the Charles River Crl:CD BR rat. Clin Trials BioResearch. (1998). A 13-week neurotoxicity study of phenol administered in the drinking water to the rat, vol 1 and 2. Senneville, Quebec, Canada. Project ID: 97439. Corti, M; Snyder, CA.(1998). Gender- and age- specific cytotoxic susceptibility to benzene metabolites in vitro. Toxicol Sci 41:42-48. Deichmann, WB; Witherup, B. (1944). The acute and comparative toxicity of phenol and o-, m-, and p-creosols for experimental animals. J Pharmacol Exp Ther 80:233-240. Dow Chemical Co. (1994). Pharmacokinetics, metabolism, and distribution of C14 phenol in Fischer 344 rats after gavage, drinking water, and inhalation exposure, with cover letter dated 07/13/1994. U.S. EPA/OPTS Public Files Fiche # OTS0557473; Doc#: 86940001296. Eastmond, DA; Smith, MT; Irons, RD. (1987). An interaction of benzene metabolites reproduces the myelotoxicity observed with benzene exposure. Toxicol Appl Pharmacol 91(1):85-95. Hsieh, GC; Sharma, RP; Parker, RD; et al. (1992). Immunological and neurobiochemical alterations induced by repeated oral exposure of phenol in mice. European J Pharmacol 228:107-114. IIT Research Institute. (1999). Two-generation oral (drinking water) reproductive toxicity study of phenol in rats. Chicago, IL. IITRI Project No. L08657, Study No. 2. Kenyon, EM; Seeley, ME; Janszen, D; et al. (1995). Dose-, route-, and sex-dependent urinary excretion of phenol metabolites in B6C3F1 mice. J Toxicol Environ Health 44(2):219-33. Liao, TF; Oehme, FW. (1981). Tissue distribution and plasma protein binding of carbon-14-labeled phenol in rats. Toxicol Appl Pharmacol 57(2):220-225. Luster, MI; Portier, C; Pait, DG; et al. (1992). Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fund Appl Toxicol 18:200-210. Luster, MI; Portier, C; Pait, DG; et al. (1993). Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fund Appl Toxicol 21:71-82. Moser, VC; Cheek, BM; MacPhail, RC. (1995). A multidisciplinary approach to toxicological screening: III. Neurobehavioral toxicity. J Toxicol Environ Health 45(2):173-210. Narotsky, MG; Kavlock, RJ. (1995). A multidisciplinary approach to toxicological screening: II. Developmental toxicity. J Toxicol Environ Health 45(2):145-71. NCI (National Cancer Institute). (1980). Bioassay of phenol for possible carcinogenicity in F344 rats and B6C3F1 mice. Prepared by the National Cancer Institute, Bethesda, MD for the National Toxicology Program, Research Triangle Park, NC. NCI-CG-TR-203, DHHS/PUB/NIH80-1759. NTP (National Toxicology Program). (1983a). Teratologic evaluation of phenol in CD rats. Prepared by Research Triangle Institute, Research Triangle Park, NC. NTIS PB83-247726. NTP. (1983b). Teratologic evaluation of phenol in CD-1 mice. Prepared by Research Triangle Institute, Research Triangle Park, NC. NTIS PB85104461. Ohtsuji, H; Ikeda, M. (1972). Quantitative relation between atmospheric phenol vapor and vapor in the urine of workers in Bakelite factories. Br J Ind Med 29:70-73. Piotrowski, JK. (1971). Evaluation of exposure to phenol: Absorption of phenol vapor in the lungs through the skin and excretion of phenol in urine. Br J Ind Med 28:172-178. Ryan, BM; Selby, R; Gingell, R; et al. (2001). Two-generation reproduction study and immunotoxicity screen in rats dosed with phenol via the drinking water. Inter J Toxicol 20:121-142. Seaton, MJ; Schlosser, P; Medinsky, MA. (1995). In vitro conjugation of benzene metabolites by human liver: potential influence of interindividual variability on benzene toxicity. Carcinogenesis 16(7):1519-27. Selgrade, MK. (1999). Use of immunotoxicity data in health risk assessments: uncertainties and research to improve the process. Toxicology 133:59-72. Tanaka, T; Kasai, K; Kita, T; et al. (1998). Distribution of phenol in a fatal poisoning case determined by gas chromatography/mass spectrometry. J Forensic Sci 43(5):1086-8. U.S. Environmental Protection Agency (EPA). (1988). Recommendations for and documentation of biological values for use in risk assessment. EPA 600/6-87/008. Available from: NTIS, PB88-179874/AS. U.S. Environmental Protection Agency. (1998). Health effects test guidelines. Office of Prevention, Pesticides and Toxic Substances. OPPTS 870.7800 Immunotoxicity. Washington, DC. U.S. Environmental Protection Agency. (2002). Toxicological review of phenol in support of summary information on Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris. Vieira, I; Sonnier, M; Cresteil, T. (1996). Developmental expression of CYP2E1 in the human liver: hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238:476-483. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Deichmann, WB; Kitzmiller, KV; Witherup, BS. (1944). Phenol studies. VII. Chronic phenol poisoning, with special reference to the effects upon experimental animals of the inhalation of phenol vapor. Am J Clin Pathol 14:273-277. Hoffman, GM; Dunn, BJ; Morris, CR; et al. (2001). Two-week (ten-day) inhalation toxicity and two-week recovery study of phenol vapor in the rat. Int J Toxicol 20:45-52. Huntingdon. (1998). Two-week (ten day) inhalation toxicity and two-week recovery study of phenol vapor in the rat. Chemical Manufacturers Association. CMA Reference No. PHL-4.0-INHAL-HLS. U.S. EPA/OPTS Public Files Fiche #: OTS0559328; Doc#: 40-980000008. Sandage, C. (1961). Tolerance criteria for continuous inhalation exposure to toxic material. I. effects on animals of 90-day exposure to phenol, CCl4, and a mixture of indole, skatole, hydrogen sulfide, and methyl mercaptan. Wright Patterson Air Force Base, OH. U.S Air Force systems command, Aeronautical Systems Division, ASD technical report 61-519(I). U.S. Environmental Protection Agency (EPA). (1994b). Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. U.S. EPA. (2002). Toxicological review of phenol in support of summary information on Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Barale, R; Marrazzini, A; Betti, C; et al. (1990). Genotoxicity of two metabolites of benzene: Phenol and hydroquinone show strong synergistic effects in vivo. Mutat Res 244(1):15-20. Boutwell, RK; Bosch, DK. (1959). The tumor-promoting action of phenol and related compounds for mouse skin. Cancer Res 19:413-424. Chen, H; Eastmond, DA. (1995). Synergistic increase in chromosomal breakage within the euchromatin induced by an interaction of the benzene metabolites phenol and hydroquinone in mice. Carcinogenesis 16(8):1963-9. Ciranni, R; Barale, R; Ghelardini, G; et al. (1988). Benzene and the genotoxicity of its metabolites. II. The effect of the route of administration on the micronuclei and bone marrow depression in mouse bone marrow cells. Mutat Res 209(1-2):23-8. Dosemeci, M; Blair, A; Stewart, PA; et al. (1991). Mortality among industrial workers exposed to phenol. Epidemiology 2(3):188-93. Gocke, E; King, M.-T; Eckhardt, K; et al. (1981). Mutagenicity of cosmetics ingredients licensed by the European communities. Mutat Res 90: 91-109. Haworth, S; Lawlor, T: Mortelmans, K; et al. (1983). Salmonella mutagenicity test results for 250 chemicals. Environ Mutagen 5(Suppl 1):3-142. Ivett, JL; Brown, BM; Rodgers, C; et al. (1989). Chromosomal aberration and sister chromatid exchange tests in Chinese hamster ovary cells in vitro. IV: Results for l5 chemicals. Environ Molec Mutagen 14:165-187. Kauppinen, TP; Partanen, TJ; Nurminen, NM. (1986). Respiratory cancers and chemical exposures in the wood industry: A nested case-control study. Br J Ind Med 43:84-90. Marrazzini, A; Chelotti, L; Barrai, I; et al. (1994). In vivo genotoxic interactions among three phenolic benzene metabolites. Mutation Research 341(1):29-46. McGregor, DB; Brown, A; Cattanach, P; et al. (1988a). Responses of the L5178Y TK+/TK- Mouse Lymphoma Cell Forward Mutation Assay. 3. 72 Coded Chemicals. Environ Molec Mutagen 12:85-154. McGregor, DB; Rlach, CG; Brown, A; et al. (1988b). Reactivity of catecholamines and related substances in the mouse lymphoma L5178Y cell assay. Environ Molec Mutagen 11:523-544. Miller, BM; Pujadas, E; Gocke, E. (1995). Evaluation of the micronucleus test in vitro using Chinese hamster cells: results of four chemicals weakly positive in the in vivo micronucleus test. Environ Molec Mutagen 26(3):240-7. NCI (National Cancer Institute). (1980). Bioassay of phenol for possible carcinogenicity in F344 rats and B6C3F1 mice. Prepared by the National Cancer Institute, Bethesda, MD for the National Toxicology Program, Research Triangle Park, NC. NCI-CG-TR-203, DHHS/PUB/NIH80-1759. NTP (National Toxicology Program). (1986). Toxicology and carcinogenesis studies of benzene (CAS No. 71-43-2) in F344/N rats and B6C3F1 mice (gavage studies). NTIS PB86-216967/AS. Paschin, YV; Bahitova, LM. (1982). Mutagenicity of benzo[a]pyrene and the antioxidant phenol at the HGPRT locus of V79 chinese hamster cells. Mutat Res 104(6):389-93. Pool, BL; Lin, PZ. (1982). Mutagenicity testing in the Salmonella typhimurium assay of phenolic compounds and phenolic fractions obtained from smokehouse smoke condensates. Food Chem Toxicol 20:383-391. Rapson, WH, Nazar, MA; Butsky, V. (1980). Mutagenicity produced by aqueous chlorination of organic compounds. Bull Environ Contam Toxicol 24:590-596. Salaman, MH; Glendenning, OM. (1957). Tumor promotion in mouse skin by sclerosing agents. Br J Cancer 11:434-444. Tsutsui, T; Hayashi, N; Maizumi, H; et al. (1997). Benzene-, catechol-, hydroquinone- and phenol-induced cell transformation, gene mutations, chromosome aberrations, aneuploidy, sister chromatid exchanges and unscheduled DNA synthesis in Syrian hamster embryo cells. Mutat Res 373(1):113-23. U.S. Environmental Protection Agency (EPA). (1987). Risk assessment guidelines of 1986. EPA/600/8-87/045. U.S. Environmental Protection Agency. (1988). Recommendations for and documentation of biological values for use in risk assessment. EPA 600/6-87/008. NTIS PB88-179874/AS. U.S. Environmental Protection Agency. (1999). Guidelines for carcinogen risk assessment. Review Draft, NCEA-F-0644, July 1999. Risk Assessment Forum, Washington, DC. U.S. Environmental Protection Agency. (2002). Toxicological review of phenol in support of summary information on Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available at http://www.epa.gov/iris. Wilcosky, TC; Checkoway, H; Marshall, EG; et al. (1984). Cancer mortality and solvent exposures in the rubber industry. Am Ind Hyg Assoc J 45(12):809-811. Wynder, EL; Hoffmann, D. (1961). A study of tobacco carcinogenesis. VIII. The role of the acidic fractions as promoters. Cancer 14(6):1306-1315. Yager, JW; Eastmond, DA; Robertson, ML; et al. (1990). Characterization of micronuclei induced in human lymphocytes by benzene metabolites. Cancer Res 50(2):393-399. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Phenol CASRN -- 108-95-2 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.6. Review date added 12/01/1988 I.A. Withdrawn; RfD verified (in preparation) 06/01/1989 I.A. Oral RfD summary replaced; RfD changed 06/01/1989 VI. Bibliography on-line 09/01/1989 II. Carcinogen assessment now under review 10/01/1989 I.B. Inhalation RfD now under review 02/01/1990 I.A.2. Text edited 02/01/1990 I.A.4. Text edited 06/01/1990 I.B. Data judged inadequate for derivation of inhalation RfD 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 07/01/1990 I.B. Not verified; data inadequate 11/01/1990 II. Carcinogen assessment on-line 11/01/1990 VI.C. Carcinogen references added 03/01/1991 I.B. Inhalation RfC message on-line 03/01/1991 VI.B. Inhalation RfC references added 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/10/1998 I., II. This chemical is being reassessed under the IRIS Program 09/30/2002 I., II., VII. RfD, RfC, cancer assessment sections updated. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 375 of 1119 in IRIS (through 2003/06) AN: 104 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Styrene- SY: 100-42-5; BENZENE,-VINYL-; CINNAMENE-; CINNAMENOL-; CINNAMOL-; DIAREX-HF-77-; ETHENYLBENZENE-; ETHYLENE,-PHENYL-; NCI-C02200-; PHENETHYLENE-; PHENYLETHENE-; PHENYLETHYLENE-; STIROLO-; STYREEN-; STYREN-; STYRENE,-MONOMER-; STYROL-; STYROLE-; STYROLENE-; STYRON-; STYROPOL-; STYROPOR-; UN-2055- RN: 100-42-5 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199009 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Styrene CASRN -- 100-42-5 Last Revised -- 09/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: The Oral RfD for styrene may change in the near future pending the outcome of a further review now being conducted by the Oral RfD Work Group. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Red blood cell and NOAEL: 200 mg/kg-day 1000 1 2E-1 liver effects mg/kg-day LOAEL: 400 mg/kg-day Dog Subchronic Oral Study Quast et al., 1979 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Quast, J.F., C.G. Humiston, R.Y. Kalnins, et al. 1979. Results of a toxicity study of monomeric styrene administered to beagle dogs by oral intubation for 19 months. Toxicology Research Laboratory, Health and Environmental Sciences, DOW Chemical Co., Midland, MI. Final Report. Four beagle dogs/sex were gavaged with doses of 0, 200, 400, or 600 mg styrene/kg bw/day in peanut oil for 560 days. No adverse effects were observed for dogs administered styrene at 200 mg/kg-day. In the higher dose groups, increased numbers of Heinz bodies in the RBCs, decreased packed cell volume, and sporadic decreases in hemoglobin and RBC counts were observed. In addition, increased iron deposits and elevated numbers of Heinz bodies were found in the livers. Marked individual variations in blood cell parameters were noted for animals at the same dose level. Other parameters examined were body weight, organ weights, urinalyses, and clinical chemistry. The NOAEL in this study is 200 mg/kg-day and the LOAEL is 400 mg/kg-day. Long-term studies (120 weeks) in rats and mice (Ponomarkov and Tomatis, 1978) showed liver, kidney, and stomach lesions for rats (dosed weekly with styrene at 500 mg/kg) and no significant effects for mice (dosed weekly with 300 mg/kg). Rats receiving an average daily oral dose of 95 mg styrene/kg bw for 185 days showed no adverse effects, while those receiving 285 or 475 mg/kg-day showed reduced growth and increased liver and kidney weights (Wolf et al., 1956). Other subchronic rat feeding studies found LOAELs in the 350-500 mg/kg-day range and NOAELs in the range of 100-400 mg/kg-day. The lifetime studies in rats and mice (Ponomarkov and Tomatis, 1978) are not appropriate for risk assessment of chronic toxicity because of the dosing schedule employed. The Wolf et al. (1956) study is of insufficient duration (185 days) to be considered chronic. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 1000 reflects 10 for both intraspecies and interspecies variability to the toxicity of this chemical in lieu of specific data, and 10 for extrapolation of subchronic effects to chronic effects. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) None. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The principal study is well done and the effect levels seem reasonable, but the small number of animals/sex/dose prevents a higher confidence than medium at this time. The data base offers strong support, but lacks a bona fide full-term chronic study; thus, it is also considered to have medium confidence. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1984. Health and Environmental Effects Profile for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1985. Drinking Water Criteria Document for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. The ADI in the 1984 Health and Environmental Effects Profile document has received an Agency review with the help of two external scientists. Agency Work Group Review -- 10/09/1985, 11/06/1985, 10/09/1985 Verification Date -- 10/09/1985 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199307 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Styrene CASRN -- 100-42-5 Last Revised -- 07/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- CNS effects NOAEL: 94 mg/cu.m (25 ppm = 30 1 1E+0 150 mmole urinary styrene mg/cu.m Occupational Study metabolites/mole creatinine adjusted to lower 95% Mutti et al. (1984) confidence limit = 22 ppm) NOAEL(HEC): 34 mg/cu.m LOAEL: >94 mg/cu.m (>22 ppm derived as in NOAEL listing) ---------------------------------------------------------------------------- *Conversion Factors: MW = 104.15. Assuming 25 C and 760 mmHg, NOAEL (mg/cu.m) = NOAEL (ppm) x MW/24.45 = 94 mg/cu.m. The NOAEL exposure level is based on a back extrapolation from worker urinary concentration of styrene metabolites reported in the principal study and adjusted to the lower 95% confidence limit listed in Guillemin et al. (1982), which was 88%, 25 ppm x 0.88 = 22 ppm. The NOAEL(HEC) is calculated using an 8-hour TWA occupational exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. NOAEL(HEC) = 94 mg/cu.m x MVho/MVh x 5 days/7 days = 34 mg/cu.m. The feasibility of applying the exposure model of Perbellini et al. (1988) for extrapolation of the values in the principal study is currently being investigated. Application of this model may result in changes in the NOAEL(HEC) value and, therefore, the RfC. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Mutti, A., A. Mazzucchi, P. Rusticelli, G. Frigeri, G. Arfini, and I. Franchini. 1984. Exposure-effect and exposure-response relationships between occupational exposure to styrene and neuropsychological functions. Am. J. Ind. Med. 5: 275-286. In a cross-sectional study, Mutti et al. (1984) examined the neuro-psychological function in 50 workers whose mean duration of styrene exposure was 8.6 (SD of 4.5) years. Styrene exposure was assessed by the authors to correspond to air concentrations ranging from 10-300 ppm as a mean daily exposure. These concentrations were estimated from the summation of the principal urinary metabolites of styrene, mandelic acid (MA) and phenylglyoxylic acid (PGA). Urinary metabolite levels are considered as reliable biological indicators of styrene exposure (ACGIH, 1986; WHO, 1983), and several laboratories have determined collectively that the specific method used in this study, the summation of the principal metabolites collected in next-morning urine, is the most reliable and representative of actual air exposure concentrations (Guillemin et al., 1978, 1982; Ikeda et al., 1982; Franchini et al., 1983). Workers with absence of metabolic and neurologic disorders, smoking habits of <20 cigarettes/day, and an alcohol intake of <80 mL of ethanol/day were chosen. These same eligibility criteria were used to select a control group of 50 workers that was matched for age, sex, and educational level. The exposed workers were further segregated into four subgroups (n = 9-14) according to increasing levels of urinary styrene metabolites. A battery of neuropsychological tests was conducted on the same day as the urine collection and included exams evaluating visuo-motor speed, memory, and intellectual function. No other endpoints were considered. Correlation analysis of the test results and urinary metabolite levels showed a clear concentration response in at least three of eight tests, including block design (intellectual function), digit-symbol (memory), and reaction times (visuo-motor speed). Evidence of a concentration-response relationship was also present for short- and long-term logical memory and embedded figures (impaired visual perception). When the results were analyzed using duration of exposure as a covariate, increases in reaction times and a decrease in digit symbol (memory, concentration) were apparent. The only test showing results in the lowest exposure group, short-term verbal memory loss, exhibited no concentration-response relationship. The neuropsychological results from this study are from established tests for CNS dysfunction, are present when compared against a stringently matched control population, and show concentration-response relationships. Also, the deficiencies noted in the reaction-times corroborate the results presented by Moller et al. (1990) and others discussed below. The concentration-response relationship between urinary metabolite concentration (mandelic acid and phenylglyoxylic acid levels normalized to creatinine in "morning-after" urine) and test results indicated a significant effect level in the subgroup whose urine contained 150-299 mmole urinary metabolites/mole creatinine. Workers with metabolite concentrations of up to 150 mmoles/mole appeared to have no significant effects, and this level is therefore designated as the NOAEL in this study. The authors state that this level of urinary metabolites corresponds to a mean daily 8-hour exposure to air styrene of 25 ppm (106 mg/cu.m). Derivation of this air level is from the creatinine-normalized, combined concentration of the styrene metabolites, MA and PGA, in urine collected from the workers on Saturday mornings. Guillemin et al. (1982) demonstrated a logarithmic relationship (r = 0.871) between the summation of urinary metabolites (MA + PGA, next morning) and air concentrations of styrene (ppm x hours). Guillemin calculated the mean combined urinary metabolite concentration (next morning) for an 8-hour exposure to 100 ppm. This relationship was used by both Mutti et al. (1984) and Guillemin and Berode (1988) in a proportional manner to obtain styrene air levels at lower urinary metabolite concentrations. The 95% confidence interval was also calculated for an 8-hour exposure at 100 ppm, the lower limit of the confidence calculation being 88% of the mean styrene exposure. This factor was applied directly to the NOAEL of 25 ppm [25 ppm x 0.88 = 22 ppm (94 mg/cu.m)]. Due to the construction of the subgroups, designation of a LOAEL was the lower limit of the subgroup in which adverse effects were observed [i.e., greater than the NOAEL of 22 ppm (94 mg/cu.m)]. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- A partial UF of 3 was used for data base inadequacy, including the lack of concentration-response information on respiratory tract effects. A partial UF of 3 instead of 10 was used for intraspecies variability since the lower 95% confidence limit of the exposure extrapolation was used and because Perbellini et al. (1988) demonstrated that this biological exposure index (i.e., urinary metabolites) accounts for differences in pharmacokinetic/ physiologic parameters such as alveolar ventilation rate. A partial UF of 3 instead of 10 was also evoked for lack of information on chronic studies as the average exposure duration of the principal study of Mutti et al. (1984) was not long enough (8.6 years) to be considered chronic. The total uncertainty is therefore 30 (three times the one-half logarithm of 10). MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Central nervous system effects caused by exposure to styrene have been reported by several investigators in studies since the early 1970s. Gotell et al. (1972) noted significantly increased reaction times in a group of six polyester plant workers exposed to >150 ppm styrene as compared with unexposed controls and another group exposed to <150 ppm. Gamberle et al. (1975) noted longer and more irregular reaction times in 106 exposed workers (estimated at 13-101 ppm styrene for an average of 2.7 years) as compared with a control population. Cherry et al. (1980) found no alteration in reaction times among 27 workers exposed to a mean of 92 ppm styrene (duration unspecified) and no difference in performance on four behavioral tests of memory and vigilance. However, a follow-up study conducted 21 months later by these authors on 8 of the same 27 individuals (Cherry et al., 1981) found that the three men with the highest urinary mandelic acid concentrations all improved reaction times significantly (p < 0.05) as compared with their earlier values. These alterations were correlated with those individuals having slow clearance of mandelic acid. Among 98 male laminating workers (mean styrene exposure of 5.1 years), Lindstrom et al. (1976) reported weak correlations of CNS-behavioral testing (poor psychomotor performance and visuomotor inaccuracy) with levels of styrene exposure estimated to be between 25 and 75 ppm based on urinary mandelic acid levels. The study of Mutti et al. (1984) is one of few in which extensive CNS-behavioral testing was carried out. The recent studies of Moller et al. (1990) and Flodin et al. (1989) couple functional decrements with adverse behavioral effects in a chronically exposed worker population. The effect of styrene on peripheral nerves has also been reported, although not to the extent of central effects. These studies are briefly described in the recent study of Murata et al. (1991) in which data on a small number of workers suggest that styrene may differentially affect sensory nerves. The studies of Moller et al. (1990) and Flodin et al. (1989) both examined central effects of styrene in the same worker population. The Flodin et al. (1989) study on neuropsychiatric effects of styrene exposure provides documentation of the styrene levels to which these workers were exposed. In a cross-sectional occupational study, Moller et al. (1990) studied 18 male Swedish boatbuilders exposed to styrene for an average of 10.8 years (range of 6-15 years). Personal sampling (8-hour TWA concentrations) available for 7/10 years showed that the workers had been exposed to 50-140 mg/cu.m styrene. The exposure data is discussed at length in the text of the Flodin et al. (1989) study below. These workers were not further subgrouped into high-and low-exposure groups as in the Flodin et al. (1989) study. Two reference groups were used for evaluation of the tests; both were unexposed to industrial solvents and matched to the exposure group with respect to smoking and alcohol consumption. These workers were subsequently given a thorough otoneurological examination, evaluating auditory, visual, and vestibular systems, as well as coordination of vestibular sensations with compensatory eye movements manifest in the vestibuloocular reflex (VOR). The test showing the greatest and most consistent deviation in performance between the exposed workers and the reference population was the visual suppression of the VOR. Execution of this test required the subjects to fixate on a target that moved with movement of the subjects' chair. The normal VOR functions to maintain steady gaze of the eyes despite movements of the head. However, when the target moves with the subject, this reflex must be suppressed in order to follow the target. Quantitation of a subject's capacity to suppress VOR is measured as the ratio between eye and target velocity (gain) and in the temporal relationship between eye and target velocity (phase). Abnormal functioning would be manifest by an increase in gain and a decrease in phase, if the values exceeded the mean +/- 2 SD units of the corresponding measurement in a reference population. Abnormal phase shifts were recorded for 4/18 workers; in each of the four cases, the gain was also abnormal. These differences were reflected in the group values that showed a higher mean gain (p < 0.001) and a decrease in angle of phase lead (p < 0.001) in examinations carried out with predictable (sinusoidal frequency sweep) and unpredictable (pseudorandomized) conditions. The deficits shown in these tests suggest lesions in the brainstem or cerebellar regions, because these findings are in accordance with findings in patients with known brainstem or cerebellar disorders (Odkvist et al., 1982, 1987). Other tests reported in this study also gave indications of neurological deficits. The posturography test demonstrated increases in sway area of subjects with their eyes closed, which are consistent with vestibular deficits. The overall results of this test are, however, internally inconsistent as more of these workers showed abnormal scores with their eyes open than with their eyes closed. Although examination of saccadic eye movements (brief, fast movements occurring with change in fixation point) did reveal abnormal scores in latency for 7/18 subjects, none of the 18 were found to have abnormal velocity. This also is an internal inconsistency within the exam, making these results equivocal. A similar internal inconsistency was noted in the results of the smooth-pursuit eye movement during which the subject is asked to visually track a slowly moving stimulus. Seven of the 18 subjects had abnormal results in lag time (phase), whereas none of the 18 tested abnormal for gain. Disturbances were found in the central auditory pathways of seven workers but the significance of these effects were not evaluated (see discussion of Pryor et al., 1987). This study provides credible toxicological information on the possible long-term consequences of human exposure to styrene. No effect levels are assigned based on these data as the number of subjects is small and no indication is given of a dose-response relationship among these chronically exposed workers. Twenty-one male Swedish workers were exposed to styrene for an average of 11.6 years (range of 6-21 years) as a consequence of their occupation, boatbuilding (Flodin et al., 1989). Personal sampling (8-hour average concentrations) had been carried out in 9 of the last 12 years, with the number of sampling days for each year ranging from 3 to 27; the data presented indicate an exposure range of around 40-140 mg/cu.m during this time. In one year, 30-minute sampling times were performed on most tasks and showed that peak exposures were exceptional, with only about 1% of all measurements of styrene >300 mg/cu.m; about 44% of the samples were <25 mg/cu.m, and about 65% were <50 mg/cu.m. Based on these sampling data, the workers were classified into two groups: those exposed to about 50 mg/cu.m styrene for the past 7 years and those exposed to about 25 mg/cu.m. The higher exposed workers were primarily involved in lamination processes. Workers were examined by a clinical interview that included a detailed inquiry about neuropsychiatric symptoms; psychometrical tests and some clinical chemistry were also included. The workers were examined twice, the first time (21 workers examined) occurring when they had not been exposed for 1 week. The second examination (17 workers examined; nine in the higher exposure group and eight in the lower exposure group) occurred after the workers had not been exposed for a minimum of 3 months because the factory had gone bankrupt. Two of the remaining four workers refused participation in the second interview, and results from two others were disallowed as one was diagnosed as having pulmonary thrombosis and the other psycho-organic syndrome (POS) (see discussion of Moller et al., 1989). No concurrent control group was used. According to the questionnaire, the symptoms at the first examination were distributed in a exposure-related manner, with the higher exposure group having an average of 10.4 symptoms/worker and the lower exposure group having an average of 5.3 symptoms/worker. On the second examination, the average symptoms/worker decreased to 1.9 in both exposure groups. The claim that the higher exposure group performed significantly worse in one psychometrical test (manual dexterity) is not interpretable due to lack of specifics in the text. Internal inconsistencies of the results and the lack of a concurrent matched control group cause the results from this study to be equivocal. No effect levels were designated in this study. The levels of styrene reported in the study of Mutti et al. (1984) were estimated from levels of urinary styrene metabolites. As already discussed, this method is considered as a biological indicator of exposure and has been shown to reliably reflect the total concentration of styrene to which individuals have been exposed. The relationships between styrene exposure and urinary metabolite concentrations have been established by a number of studies including those of Guillemin et al. (1982) and Ikeda et al. (1982) and reviewed by the WHO (1983). The work of Perbellini et al. (1988) has shown that the variability of urinary metabolite levels observed in styrene-exposed worker populations may reflect physiologic and metabolic variability inherent in humans. These characteristics are not shared by the extensive studies on styrene levels reported by Lemasters et al. (1985a) and of Jensen et al. (1990), both of which are historical and are based on area and personal sampling procedures. A diagnosis of psycho-organic syndrome has been used to describe the symptomatology observed in workers heavily exposed to a variety of organic solvents. Examples of specific effects include neurasthenia, personality alterations, unsteadiness, dizziness, and vertigo. Moller et al. (1989) examined nine men who had been diagnosed as having POS, subjecting them to a battery of audiological and vestibular-oculomotor tests, the latter of which measure the capacity to transform signals from the inner ear to compensatory eye movements for purposes such as maintenance of equilibrium. The men were described as having been exposed to various mixtures of alcoholic, aromatic, and aliphatic industrial solvents during their working careers of 8-30 years (mean = 21 years). Seven of them had been granted disability pensions at the time of the examinations. Abnormal static posture was noted in 4/9 members of the POS group (p < 0.001). Voluntary saccades (rapid intermittent movements of the eye) were abnormal (both prolonged latency and decreased maximum speed) in 5/9 of the POS group, but in only 2/9 matched controls. As these functions are considered to be controlled centrally in the area of the cerebellum, these findings indicate that cerebellar lesions may occur from chronic exposures to a variety of organic solvents. The results presented by Moller et al. (1990) for these tests in workers exposed to styrene indicate this chemical to be capable of eliciting this toxicity. A duration-response between length of exposure to solvents and incidence of altered cerebellar functioning (as evidenced by effects on hearing and the vestibular-oculomotor system) is indicated in the study of Odkvist et al. (1987). This study examined 23 workers, all of whom had been extensively exposed to aliphatic and aromatic solvents. Sixteen of the 23 workers were diagnosed with POS. The average length of exposure of these 16 workers was 27 years (range 9-40 years), considerably more than the average of 21 years (range 5-30 years) for the remaining seven individuals. In the battery of 11 vestibular-oculomotor tests, five (including saccade, visual-suppression, Romberg's test, and electronystagmography) showed a dose-response relationship with the percentage incidences being higher in the group diagnosed with POS; the other six tests either were not conducted in one or the other group or exhibited no change. Thus, both the number of workers diagnosed with POS and incidence of cerebellar dysfunctioning were correlated with duration of exposure to organic solvents. The specific capacity of styrene to cause alterations in cerebellar function in humans under short-term acute exposure conditions was experimentally shown by Odkvist et al. (1982). Ten people (5/sex) were exposed to 370-591 mg/cu.m styrene for 80 minutes. A battery of six vestibular-oculomotor tests was administered before, during, and after the exposure. Visual suppression and saccade tests both showed statistically significant alterations in 8/10 subjects. Results between exposed subjects and controls did not differ for the optovestibular, optokinetic, and slow pursuit movement test or the sinusoidal swing test. These results indicate that acute exposures to high concentrations of styrene may affect processes within the cerebellum. It should be noted, however, that the results obtained by Moller et al. (1990) and Flodin et al. (1989) were obtained in workers that had not been exposed to styrene for a minimum of 3 months. Larsby et al. (1978) investigated the relationship between vestibulo-oculomotor function and styrene levels in arterial blood and cerebrospinal fluid. Rabbits (n = 16) were cannulated and infused with a 10% solution of styrene introduced at 3.1-12.6 mg/minute. Vestibular function was evaluated using electronystagmography in response to rotary acceleration. Styrene concentration was monitored in both arterial (ear) and cerebrospinal fluid. During the exposure, positional nystagmus (i.e., involuntary eye movement response to rotary movement evident only when the animal is lying on one side or the other, not prone) was observed in 10/11 rabbits tested. In addition, a paradoxical rotary response was observed in 6/16 rabbits. This phenomenon is described as involuntary eye movement opposite to the direction of rotation (left-beating eye movements when rotated clockwise and vice versa). Both observations indicate that vestibular function was affected. Results also showed that, at an infusion rate of 4.9 mg/minute, arterial blood levels reached a constant level only after about 2 hours. Styrene concentrations in cerebrospinal fluid had the same shape as the arterial curve and was constantly 5-10% of the corresponding arterial concentration. A number of other occupational studies investigating the effects of styrene on workers are available in the literature. Most of these reports examine either central or peripheral nervous function, although blood effects (Stengel et al., 1990), nephrotoxicity (Viau et al., 1987), and liver effects (Hotz et al., 1980) have also been examined. Nearly all of these reports suffer from one or more deficiencies, the most common being lack of exposure information. Almost all, however, indicate that styrene affects central processes in humans. An overview of several of these studies follows. In addition to the auditory data listed in the Moller et al. (1990) study, two other studies have reported hearing loss, one in humans and the other in laboratory animals. Muijser et al. (1988) evaluated hearing thresholds up to 16 kHz in 59 workers exposed to airborne styrene. Air samples (4-hour mean averages, 6-16 samples/group work area) were taken in the breathing zone during 3 consecutive days in work areas where 31 workers were directly exposed to styrene (mean = 138 mg/cu.m) and 28 workers were indirectly exposed to styrene (mean = 61 mg/cu.m). The duration of employment for the combined group was 8.6 +/- 6.5 years. The control population consisted of 88 individuals not exposed to styrene or other chemicals but who were comparable in age and socio-economic status to the exposed workers. Audiometric analyses were corrected for age. Comparison of hearing thresholds between the controls and both exposed groups revealed no differences in hearing thresholds at frequencies up to and including 16 kHz. Comparison between the experimental groups, however, did reveal that the directly exposed workers had higher thresholds for frequencies at 8-16 kHz than did the indirectly exposed workers (p value from multivariate analysis of covariance = 0.012). Quantitative and qualitative differences in the background noise between the control and study plants may have compromised the control population in this study. Although difficulties with the control population prevent definite assignment of effect levels, human exposure to 138 mg/cu.m styrene appears to have resulted in high-frequency hearing loss [LOAEL(HEC) = 69 mg/cu.m]. Pryor et al. (1987) exposed male Fisher 344/N rats (12/group) to 0 (clean air), 800, 1000, or 1200 ppm (0, 3408, 4260, or 5112 mg/cu.m, respectively) styrene for 14 hours/day, 7 days/week for 3 weeks. The duration-adjusted values are 0, 1988, 2485, or 2982 mg/cu.m, respectively. Auditory response thresholds were determined by both behavioral and electrophysiologic methods, apparently some weeks after the last exposure. Increases in auditory thresholds were recorded at 8-20 kHz with both methods at the lowest concentration used [LOAEL(HEC) = 1988 mg/cu.m]. Several occupational studies have reported adverse health effects on workers whose exposure was at or near 25 ppm (110 mg/cu.m) styrene. Lindstrom et al. (1976) reported that the visuomotor accuracy of styrene-exposed workers (n = 98, average exposure 4.9 years, range 0.5-14 years) was significantly poorer (p < 0.05) than that of the nonexposed workers. Moreover, this deficit was shown to be related to concentration in two subgroups whose exposures (estimated from urinary mandelic acid) were 25 and 75 ppm. Seppalainen and Harkonen (1976) conducted a cross-sectional study on 96 styrene workers, all of whom received EEG examinations 24 hours after termination of exposure. Mean exposure to styrene was estimated from urinary mandelic acid to be 808 mg/L, approximately 36 ppm in air. Twenty-three of 96 (24%) EEG's were abnormal in the exposed group as compared with a normal population (indicated as about 10% in the text), a difference that is statistically significant (p < 0.05). Human irritation from styrene exposure has been characterized in a limited study by Stewart et al. (1968). Nine male volunteers were exposed to air concentrations of styrene of 50-375 ppm (213-1597 mg/cu.m) for periods of 1-7 hours. Urinalysis, hematology, and blood chemistry studies were conducted prior to exposure and at 16 and 72 hours postexposure; subjective symptoms were also recorded. Within 15 minutes following a 60-minute exposure to 375 ppm styrene, 4/5 volunteers complained of mild eye and nasal irritation. (Throughout the remainder of the exposure, all subjects noted a progressive loss of their ability to perceive the odor of styrene.) It is not clear from the text whether or not the irritation remained throughout the exposure. After 45 minutes of exposure, one of the subjects reported being nauseated and two others complained of feeling slightly inebriated. At 216 ppm styrene, 1/3 subjects noted nasal irritation 20 minutes into a 60-minute exposure. No adverse symptoms were reported by the three subjects exposed to 52 ppm styrene for 1 hour. Six subjects were then exposed to 99 ppm styrene for a total of 7 hours. Three of the six subjects complained of mild eye and throat irritation 20 minutes after the start of the exposure; in two of these subjects, the eye irritation persisted for 30 minutes before subsiding. At the end of the exposure, none of the subjects reported nausea, headache, or eye, nose, or throat irritation. The clinical studies were all normal. None of the six individuals exposed to 99 ppm (422 mg/cu.m) styrene for 7 hours or 216 ppm for 1 hour experienced any subjective symptoms of significant consequence. Although these results suggest no symptoms of consequence in humans exposed to styrene concentrations as high as 216 ppm (920 mg/cu.m), the population tested was small (only three subjects), and the duration was minimal. Considerable success has been attained in modeling levels of inhaled styrene in biological systems. The physiologically based pharmacokinetic model for styrene of Ramsey and Andersen (1984) allows simulation over a wide range of concentrations on the time course of styrene distributed to four main tissue groups: (1) highly perfused organs, (2) moderately perfused organs (predominately muscle), (3) slowly perfused tissue (predominately fat), and (4) liver. When applied to actual rat data, this model accurately predicted blood styrene levels of 80-1200 ppm (340-5112 mg/cu.m). Then the behavior of inhaled styrene in humans was simulated successfully by substitution of human physiological parameters. These authors were able to demonstrate that blood concentrations of inhaled styrene in rats, mice, and humans were nearly identical at air concentrations of less than or equal to 200 ppm (852 mg/cu.m) but differed widely at higher concentrations. Perbellini et al. (1988) developed a physiologically based mathematical model for human exposure to airborne styrene that accounts for metabolism, subsequent synthesis, transfer, and urinary excretion of the principal metabolites MA and PGA. The model comprises eight compartments: (1) lung; (2) the richly perfused tissues of heart, brain, and kidney; (3) muscle; (4) fat; (5) liver tissue for catabolism of styrene; (6) liver tissue for transfer of metabolites; (7) body water in which the metabolites are distributed; and (8) urine in which the metabolites are excreted. Simulation results using this model were in agreement with reported urinary metabolite concentrations measured in various studies of worker populations, including that of Guillemin et al. (1982). Further simulations demonstrated that the use of urinary metabolites as a biological exposure index can accurately account for variability in pharmacokinetic/ physiologic parameters such as the alveolar ventilation rate. Simulations using an alveolar ventilation rate of 6-12 L/minute resulted in less than a three-fold range in model output (urinary metabolite concentration). Jersey et al. (1978) exposed Sprague-Dawley rats (96/sex/group) to 0, 600, or 1200 ppm (0, 2556, or 5112 mg/cu.m, respectively) of 99.5% styrene for 6 hours/day, 5 days/week for up to 20 months. The exposure concentration of the 1200 ppm exposure group was reduced to 1000 ppm (4260 mg/cu.m) after 2 months because the males showed signs of toxicity (narcosis leading to anesthesia and excessive weight loss) with death coming to three animals. Exposures were terminated when mortality reached 50% for one exposure group of each sex; this was at 18.3 months for males and 20.7 months for females. All surviving rats were euthanized at the end of 2 years with interim group samplings at 6 and 12 months. Hematology, clinical chemistry, body weights, gross anatomical and histopathological analysis, and cage-side observations were performed for evaluation of toxicity. The respiratory tract (including the lungs, trachea, and nasal turbinates) was not examined in all animals; the nasal turbinates, for example, were examined only in a portion of the controls and high-exposure animals (14/28 animals, sexes combined). The number of sections examined in the nasal turbinates, trachea, or lungs is not indicated in the text. No exposure-related increase in mortality was noted in either sex. An inverse relationship between mortality and exposure was noted in male rats. A high incidence of murine pneumonia was associated with an increased mortality, but only in the control and high-exposure animals; no dose-response relationship was apparent from the data. Average body weights of both females and males were decreased at both dose levels at various times throughout the experiment. However, only the body weights of the males exposed to the highest concentration were decreased more than 10% (14% maximum), consistently only during treatment days 82-263. The only concentration-dependent alteration in organ weights observed was in absolute and relative liver weights in females sacrificed at 6 months. At the terminal sacrifice, an increase in absolute liver weights was observed only in the females exposed to the highest concentration; no histopathology accompanied this alteration. The only histological result considered to be concentration-dependent was an increase in incidence of alveolar histiocytosis (areas containing lipid-laden alveolar macrophages) that corresponded to grossly visible subpleural pale foci in the lungs of the females exposed to the highest concentration. No concentration-related effects were reported in any groups for hematology, clinical chemistry, or urinalysis. Deficiencies in this study preclude assigning effect levels. Conti et al. (1988) exposed Sprague-Dawley rats (30/sex/dose) to 0, 25, 50, 100, 200, or 300 ppm (0, 106, 213, 426, 852, or 1278 mg/cu.m, respectively) styrene for 4 hours/day, 5 days/week for 52 weeks. The animals were kept under observation until spontaneous death. Histopathologic examinations were performed on each animal; tissues examined included brain, liver, kidneys, gonads, spleen, and pancreas. The lungs were apparently the only portion of the respiratory tract examined in this study. No noncancer results were reported or discussed in this study. No effect levels could be assigned in this study. Effects of styrene on the respiratory tract have been addressed in mouse subchronic studies by the NTP (NTP, 1991a). B6C3F1 mice (10/sex/group) were exposed to 0, 62.5, 125, 250, or 500 ppm (0, 266, 532, 1065, or 2130 mg/cu.m, respectively) styrene for 6 hours/day, 5 days/week for 13 weeks. The duration-adjusted values for this exposure regime are 0, 47.5, 95, 190, or 380 mg/cu.m. Body weight changes, hematology, serum chemistry, sperm morphology, vaginal cytology, gross pathology, and histopathology (including the entire respiratory tract) were monitored for toxicity. Death occurred in the first week of exposure but only in the males exposed to 250 ppm; no deaths at the highest concentration were noted. Histopathology of these animals showed evidence of thymic and renal cortical necrosis. In exposed female mice, the average liver to body weight ratio was increased in the animals at the two highest concentrations. Histopathology revealed concentration-related increases in centrilobular liver cytomegaly, karyomegaly, and necrosis at these same concentrations with no effects being recorded at 125 ppm styrene or below. The lung to body weight ratios were increased at all levels relative to the control values. Histopathology of the respiratory tract revealed that the incidence of metaplasia and degeneration of the olfactory epithelium of the nasal cavity were already total (10/10 mice) in females at the lowest concentration, with necrosis being observed at higher concentrations. Likewise, bronchiolar regeneration was present in all female animals at all concentrations. The incidence of epithelial hyperplasia of the forestomach was also maximal at the lowest concentration. Similar results were noted for the males. No NOAEL for either respiratory or extrarespiratory effects was achieved in this study. The LOAEL(ADJ) for this study would be 47.5 mg/cu.m. The effects described occurred in both the nasal cavity [extrathoracic (ET)] and bronchiolar region [tracheobronchiolar (TB)]. The LOAEL(HEC) would therefore be based on effects in these regions with an RGDR of 1.55 = 74 mg.cu.m. In a rat subchronic study (NTP, 1991b), F344/N rats (10/sex/group) were exposed to 0, 125, 250, 500, 1000, or 1500 ppm (0, 532, 1065, 2130, 4260, or 6390 mg/cu.m, respectively) styrene for 6 hours/day, 5 days/week for 13 weeks. The duration-adjusted values for this exposure regime are 0, 95, 190, 380, 761, or 1141 mg/cu.m. The same toxicological endpoints as in the mouse study were monitored. No deaths were recorded. Liver to body weight ratios were elevated at the three highest exposure levels in males and the two highest exposure levels in females, although no histopathology accompanied this alteration. Concentration-related goblet-cell hypertrophy was noted in the nasopharyngeal duct starting at 125 ppm styrene in males and at 250 ppm in females. Concentration-related degeneration of the olfactory epithelium (described as minimal to mild) was noted starting at 1000 ppm styrene in females and at 1500 ppm in males. Degeneration of the olfactory epithelium was noted also at the two highest exposure levels in both sexes. A NOAEL of 500 ppm is designated for extrathoracic effects [NOAEL(ADJ) = 380 mg/cu.m x RGDR of 0.107 = NOAEL(HEC) = 41 mg/cu.m]. The effect of styrene on the trachea of rats was addressed in two studies conducted by Ohashi et al. (1985, 1986). Both ciliary activity and histopathology were evaluated. Male Sprague-Dawley rats (10/exposure group and 10 controls) were exposed to styrene at 30 or 800 ppm for 8 consecutive weeks or at 150 or 1000 ppm for 3 consecutive weeks. Nasal and tracheal mucosa were examined by electron microscopy, immediately and several weeks after cessation of exposure. The 8-week study (Ohashi et al., 1985) found that there was a strong increase in mucus secretion, with an increase in number of dense bodies in the nasal, but not tracheal, mucosal cells after exposure to 30 ppm styrene. There was an increase in secretory granules in goblet cells at 3-weeks postexposure. At the higher concentration in the 8-week exposure, there was a marked increase in mucus secretion, vacuolation, and sloughing of epithelial cells in both the nasal and tracheal epithelium. Compound cilia were observed, together with nuclear pyknosis, vacuolization of epithelial cells, and changes in electron density in goblet cells, which also exhibited cores with high electron density. Sloughing of epithelial cells from the basement membrane also persisted at 3-weeks postexposure. Severe ciliary denudation was observed in the high-exposure group (1000 ppm styrene) in the 3-week exposure, with ciliary activity in the nose disabled and decreased to 18% of control values in the trachea. No effect levels were designated from these studies as the quantitative relationship between ciliary activity and mucus transport is not clear. In his review of mucociliary transport, Wanner (1977) suggests considerable functional reserve of this system; in chicken trachea 30-50% of particle transport activity was present at a time when only 10% of the epithelium was ciliated. In two studies, Lemasters et al. (1985b, 1989) examined the reproductive outcomes of female workers involved in plastics manufacturing. In the 1985 study, data from a total of 174 styrene-exposed and 449 unexposed women were collected and analyzed. No increased prevalence in menstrual disorders was observed in subgroups of the workers exposed to either 13 or 52 ppm styrene. In the 1989 study, the authors examined the relationship between styrene exposure and lowered birth weights. During the study, the authors collected and analyzed data from 819 no-, 154 low- (2-29 ppm), and 75 high- (30-82 ppm) exposed pregnancies. There was not a statistically significant concentration-response relationship in decreasing average birth weights. In women who worked at the most highly exposed jobs (estimated at 82 ppm), however, a 4% reduction in average birth weight that approached statistical significance (p = 0.08), despite the small sample size (n = 50), was detected. Murray et al. (1978) exposed pregnant Sprague-Dawley rats and New Zealand rabbits to inhaled styrene at concentrations of 0, 300, or 600 ppm (0, 1278, or 2556 mg/cu.m., respectively) for 7 hours/day from gestation days 6-15 (rats) and 6-18 (rabbits). No concentration-related developmental toxicity was evident in either species by either route. Adverse maternal effects (decreased food consumption and a p < 0.05 decrease in weight gain only during the first 3 days of exposure) were noted. This study identifies a freestanding NOAEL for developmental effects of 2556 mg/cu.m. Beliles et al. (1985) conducted a three-generation reproductive study concomitantly with a 2-year chronic study of exposure of rats to styrene in their drinking water. Sprague-Dawley rats were treated with monomeric styrene in their drinking water at 0, 125, or 250 ppm. These doses corresponded to 8-14 mg/kg/day for males and 12-21 mg/kg/day for females. After animals were dosed for 90 days, 20 females and 10 males from the styrene groups and 30 females and 15 males from the controls were used for the F0 generation and then returned to the chronic study. Representatives of these pups, the F1 generation, were then exposed until they were 110 days of age, at which time they were mated to produce the F2 generation. The F3 generation was produced in the same manner. Each generation was evaluated for fertility (male and female), litter size, pup viability, pup survival, sex ratio, pup body weight, weanling liver and kidney weight, physical and behavioral abnormalities on each day of lactation, and marrow cytogenetics. Reduction in the gestation and 1-, 7-, and 14-day survival indices of the high dose F2 pups was observed. A reduction in survival was also noted among the high dose F1 pups, but only at 21 days. No other evidences of fetotoxicity were noted. Although the authors claim these effects to be due to extensive losses in only 1 or 2 litters, only data on individual fetuses is presented. The high-dose level is designated as a NOAEL for reproductive effects. Kankaanpaa et al. (1980) exposed pregnant BMR/T6T6 mice (15 controls and 13 exposed) to 250 ppm (1065 mg/cu.m) >99% pure styrene on gestation days 6-16 for 6 hours/day. Parameters monitored included number of litters and fetuses (total, live, dead, and malformed). No description of maternal toxicity is given, although narrative is provided on two preliminary experiments, one conducted at 500 ppm (2130 mg/cu.m) in which 2/6 pregnant mice and the surviving females had a fetal death rate of 47%. The other experiment was conducted at 700 ppm (2982 mg/cu.m) in which 3/5 pregnant animals died, with the surviving dams having a 95% fetal death rate. No dams died during the 250 ppm experiment, and the difference in the fetal death rate between controls and exposed dams was not statistically significant (27% vs. 18% in the controls; p < 0.10). The number of malformed fetuses was also increased in the exposed vs. the control mice (2.9% vs. 0.9%), but no statistical analysis was performed. A steep concentration response is indicated by this study: 500 ppm bringing death to both dams and fetuses, whereas 250 ppm appears to be without effect [NOAEL(HEC) = 1065 mg/cu.m]. These authors also exposed pregnant Chinese hamsters (2-7/treatment group and 15 controls) to 0, 300, 500, 750, or 1000 ppm (1278, 2130, 3195, or 4260 mg/cu.m, respectively) styrene for 6 hours/day on gestation days 6-18. Although the small number of animals limits the interpretation of this study, the highest concentration appears to be an effect level [LOAEL(HEC) = 4260 mg/cu.m], as the number of dead or resorbed fetuses was 66% as compared with 26% in the controls. There were no incidences of malformed fetuses in any treatment group or in the controls. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium The study of Mutti et al. (1984) documents concentration-response relationships of CNS effects in a relatively small worker population. However, the results of this study are consistent with a number of other studies showing central effects in chronically exposed worker populations, most notably that of Moller et al. (1990). The urinary metabolites, MA and PGA, are direct biological indicators of exposure to styrene. Numerous studies have demonstrated the relationship between urinary metabolites and air levels of styrene to be reliable and quantitative. Physiologically based pharmacological modeling of this exposure methodology demonstrates that it reflects and incorporates at least a portion of intrahuman variability related to pharmacokinetics. The study is therefore assigned a medium confidence level. The data base can be considered medium to high as chronic laboratory animal studies addressing noncancer endpoints are not yet available, but a number of human exposure studies support the choice of critical effect. Preliminary information in mice indicate that styrene is a respiratory tract irritant in mice at concentrations lower than 47.5 mg/cu.m. The RfC is assigned an overall confidence rating of medium. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- The assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA 1984a,b, 1985, 1989, 1991 Agency Work Group Review -- 09/20/1989, 03/26/1992 Verification Date -- 03/26/1992 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Styrene CASRN -- 100-42-5 NOCA: Not available at this time. ============================================================================ UDSO: 199211 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Styrene CASRN -- 100-42-5 Last Revised -- 11/01/1992 SORD: __VI.A. ORAL RfD REFERENCES Ponomarkov, V. and L. Tomatis. 1978. Effects of long-term oral administration of styrene to mice and rats. J. Work Environ. Health. 4(suppl. 2): 127-135. Quast, J.F., C.G. Humiston, R.Y. Kalnins, et al. 1979. Results of a toxicity study of monomeric styrene administered to beagle dogs by oral intubation for 19 months. Toxicology Research Laboratory, Health and Environmental Sciences, DOW Chemical Co., Midland, MI. Final Report. U.S. EPA. 1984. Health and Environmental Effects Profile for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1985. Drinking Water Criteria Document for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, styrene monomer BEI. Cincinnati, OH. Beliles, R.P., J.H. Butala, C.R. Stack, and S. Makris. 1985. Chronic toxicity and 3-generation reproduction study of styrene monomer in the drinking water of rats. Fund. Appl. Toxicol. 5: 855-868. Cherry, N., H.A. Waldron, G.G. Wells, R.T. Wilkinson, H.K. Wilson, and S. Jones. 1980. An investigation of the acute behavioral effects of styrene on factory workers. Br. J. Ind. Med. 37: 234-240. Cherry, N., B. Rodgers, H. Venables, H.A. Waldron, and G.G. Wells. 1981. Acute behavioral effects of styrene exposure: A further analysis. Br. J. Ind. Med. 38: 346-350. Conti, B., C. Maltoni, G. Perion, and A. Ciliberti. 1988. Long-term carcinogenicity bioassays on styrene administered by inhalation, ingestion and injection and styrene oxide administered by ingestion in Sprague-Dawley rats, and para-methylstyrene administered by ingestion in Sprague-Dawley rats and Swiss mice. Ann. N.Y. Acad. Sci. 534: 203-234. Flodin, U., K. Ekberg, and L. Andersson. 1989. Neuropsychiatric effects of low exposure to styrene. Br. J. Ind. Med. 46 (11): 805-808. Franchini, I., A. Angiolini, C. Arcari et al. 1983. Mandelic acid and phenylglyoxylic acid excretion in workers exposed to styrene under model conditions. In: Developments in the Science and Practice of Toxicology: Proceedings of the Third International Congress of Toxicology, A.W. Hayes, R.C. Schnell, and T.S. Miya, ed. Elsevier Science Publishers, New York, NY. Gamberale, F., H.O. Lisper, and B. Anshelm-Olson. 1975. Effect of styrene gases on reaction time among workers in plastic boat industry. Arbete och Halsa. 8: 23. (Swedish; cited in World Health Organization, 1983) Gotell, P., O. Axelson, and B. Lindelof. 1972. Field studies on human styrene exposure. Work Environ. Health. 9(2): 76-83. (Swedish; cited in World Health Organization, 1983) Guillemin, M.P., and D. Bauer. 1978. Biological monitoring of exposure to styrene by analysis of combined urinary mandelic and phenylglyoxylic acids. Am. Ind. Hyg. Assoc. J. 39(11): 873-879. Guillemin, M.P., D. Bauer, B. Martin, and A. Marazzi. 1982. Human exposure to styrene. IV. Industrial hygiene investigations and biological monitoring in the polyester industry. Int. Arch. Occup. Environ. Health. 51(2): 139-150. Guillemin, M.P., and M. Berode. 1988. Biological monitoring of styrene: A review. Am. Ind. Hyg. Assoc. J. 49(10): 497-505. Hotz, P., M.P. Guillemin, and M. Lob. 1980. Study of some hepatic effects (induction and toxicity) caused by occupational exposure to styrene in the polyester industry. Scand. J. Work Environ. Health. 6(3): 206-215. Ikeda, M., A. Koizumi, M. Miyasaka, and T. Watanabe. 1982. Styrene exposure and biologic monitoring in FRP boat production plants. Int. Arch. Occup. Environ. Health. 49(3-4): 325-339. Jensen, A.A., N.O. Breum, J. Bacher, and E. Lynge. 1990. Occupational exposures to styrene in Denmark, 1955-1988. Am. J. Ind. Med. 17: 593-606. Jersey, G.C., M.F. Balmer, J.F. Quast et al. 1978. Two-year chronic inhalation toxicity and carcinogenicity study on monomeric styrene in rats. Dow Chemical Study for the Chemical Manufacturing Association, December 6, 1978. Kankaanpaa, J.T.J., E. Elovaara, K. Hemminki, and H. Vainio. 1980. The effect of maternally inhaled styrene on embryonal and fetal development in mice and Chinese hamsters. Acta Pharmacol. Toxicol. 47(2): 127-129. Larsby, B., R. Tham, L.M. Odkvist, D. Hyden, I. Bunnfors, and G. Aschan. 1978. Exposure of rabbits to styrene. Scand. J. Work Environ. Health. 4(1): 60-65. Lemasters, G.K., A. Carson, and S.J. Samuels. 1985a. Occupational styrene exposure for 12 product categories in the reinforced-plastics industry. Am. Ind. Hyg. Assoc. J. 46(8): 434-441. Lemasters, G.K., A. Hagen, and S.J. Samuels. 1985b. Reproductive outcomes in women exposed to solvents in 36 reinforced plastics companies. I. Menstrual dysfunction. J. Occup. Med. 27(7): 490-494. Lemasters, G.K., S.J. Samuels, J.A. Morrison, and S.M. Brooks. 1989. Reproductive outcomes of pregnant workers employed at 36 reinforced plastics companies. II. Lowered birth weight. J. Occup. Med. 31(2): 115-120. Lindstrom, K., H. Harkonen, and S. Hernberg. 1976. Disturbances in psychological functions of workers occupationally exposed to styrene. Scand. J. Work Environ. Health. 3: 129-139. Moller, C., L.M. Odkvist, J. Thell et al. 1989. Otoneurological findings in Psycho-organic Syndrome caused by industrial solvent exposure. Acta Otolaryngol. 107(1-2): 5-12. Moller, C., L. Odkvist, B. Larsby et al. 1990. Otoneurological findings in workers exposed to styrene. Scand. J. Work Environ. Health. 16(3): 189-194. Muijser, H., E.M.G. Hoogendijk, and J. Hooisma. 1988. The effects of occupational exposure to styrene on high-frequency hearing thresholds. Toxicology. 49(2-3): 331-340. Murata, K., S. Araki, and K. Yokoyama. 1991. Assessment of the peripheral, central, and autonomic nervous system function in styrene workers. Am. J. Ind. Med. 20: 775-784. Murray, F.J., J.A. John, M.F. Balmer, and B.A. Schwetz. 1978. Teratologic evaluation of styrene given to rats and rabbits by inhalation or by gavage. Toxicology. 11(4): 335-343. Mutti, A., A. Mazzucchi, P. Rustichelli, G. Frigeri, G. Arfini, and I. Franchini. 1984. Exposure-effect and exposure-response relationships between occupational exposure to styrene and neuropsychological functions. Am. J. Ind. Med. 5(4): 275-286. NTP (National Toxicology Program). 1991a. Thirteen-week subchronic inhalation toxicity study in mice. Prepared by Battelle, Pacific Northwest Laboratories for the National Toxicology Program under Contract No. N01-ES-95281. This report underwent review by NTP, but the final report is not yet available. NTP (National Toxicology Program). 1991b. Thirteen-week subchronic inhalation toxicity study in rats. Prepared by Battelle, Pacific Northwest Laboratories for the National Toxicology Program under Contract No. N01-ES-95281. This report underwent review by NTP, but the final report is not yet available. Odkvist, L.M., B. Larsby, R. Tham et al. 1982. Vestibulo-oculomotor disturbances in humans exposed to styrene. Acta Otolaryngol. 94(5-6): 487-493. Odkvist, L.M., S.D. Arlinger, C. Edling, B. Larsby, and L.M. Bergholtz. 1987. Audiological and vestibulo-oculomotor findings in workers exposed to solvents and jet fuel. Scand. Audiol. 16(2): 75-81. Ohashi, Y., Y. Nakai, H. Ikeoka et al. 1985. Electron microscopic study of the respiratory toxicity of styrene. Osaka City Med. J. 31(1): 11-21. Ohashi, Y., Y. Nakai, H. Ikeoka et al. 1986. Degeneration and regeneration of respiratory mucosa of rats after exposure to styrene. J. Appl. Toxicol. 6(6): 405-412. Perbellini, L., P. Mozzo, P.V. Turri, A. Zedde, and F. Brugnone. 1988. Biological exposure index of styrene suggested by a physiologico-mathematical model. Int. Arch. Occup. Environ. Health. 60(3): 187-193. Pryor, G.T., C.S. Rebert, and R.A. Howd. 1987. Hearing loss in rats caused by inhalation of mixed xylenes and styrene. J. Appl. Toxicol. 7(1): 55-61. Ramsey, J.C. and M.E. Andersen. 1984. A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicol. Appl. Pharmacol. 73(1): 159-175. Seppalainen, A.M. and H. Harkonen. 1976. Neurophysiological findings among workers occupationally exposed to styrene. Scand. J. Environ. Health. 3: 140-146. Stengel, B., A. Touranchet, H.L. Boiteau, H. Harousseau, L. Mandereau, and D. Hemon. 1990. Hematological findings among styrene-exposed workers in the reinforced plastics industry. Int. Arch. Occup. Environ. Health. 62(1): 11-18. Stewart, R.D., H.C. Dodd, E.D. Baretta, and A.W. Schaffer. 1968. Human exposure to styrene vapor. Arch. Environ. Health. 16(5): 656-662. U.S. EPA. 1984a. Health and Environmental Effects Profile for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. EPA-600/X-84/325. NTIS Pub. No. PB88-182175/AS. U.S. EPA. 1984b. Drinking Water Criteria Document for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. EPA-600/X-84/195. NTIS Pub. No. PB86-118056/AS. U.S. EPA. 1985. Reportable Quantity Document for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. EPA-600/X-85/221. U.S. EPA. 1989. Health Effects Assessment Document for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. EPA-600/8-88/054. NTIS Pub. No. PB90-142357/AS. U.S. EPA. 1991. Drinking Water Criteria Document for Styrene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. Viau, C., A. Bernard, R. De Russis, A. Ouled, P. Maldague, and R. Lauwerys. 1987. Evaluation of the nephrotoxic potential of styrene in man and rat. J. Appl. Toxicol. 7(5): 313-316. Wanner, A. 1977. Clinical aspects of mucociliary transport. Am. Rev. Resp. Dis. 116: 73-125. WHO (World Health Organization). 1983. Environmental Health Criteria 26 Document on Styrene. International Program on Chemical Safety, Institute of Occupational Health, Helsinki, Finland. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Styrene CASRN -- 100-42-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 06/30/1988 I.A.7. Contacts changed 10/01/1989 I.B. Inhalation RfD now under review 02/01/1990 VI. Bibliography on-line 05/01/1990 I.A. Oral RfD summary noted as pending change 05/01/1990 II. Carcinogen assessment now under review 09/01/1990 I.A. Text edited 09/01/1990 III.A. Health Advisory on-line 09/01/1990 VI.D. Health Advisory references added 01/01/1992 IV. Regulatory actions updated 11/01/1992 I.B. Inhalation RfC summary on-line 11/01/1992 VI.B. Inhalation RfC references on-line 07/01/1993 I.B.1. 'E' notation added 08/01/1995 I.A., II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/02/1998 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 376 of 1119 in IRIS (through 2003/06) AN: 106 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 198803 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Tetrachloroethylene- SY: 127-18-4; ANKILOSTIN-; ANTISAL-1-; ANTISOL-1-; CARBON-BICHLORIDE-; CARBON-DICHLORIDE-; CZTEROCHLOROETYLEN-; DEE-SOLV-; DIDAKENE-; DIDOKENE-; DOWCLENE-EC-; DOW-PER-; ENT-1,860-; ETHENE,-TETRACHLORO-; ETHYLENE-TETRACHLORIDE-; ETHYLENE,-TETRACHLORO-; FEDAL-UN-; NCI-C04580-; NEMA-; PCE-; PER-; PERAWIN-; PERC-; PERCHLOORETHYLEEN,-PER-; PERCHLOR-; PERCHLORAETHYLEN,-PER-; PERCHLORETHYLENE-; PERCHLORETHYLENE,-PER-; PERCHLOROETHYLENE-; PERCLENE-; PERCLOROETILENE-; PERCOSOLV-; PERCOSOLVE-; PERK-; PERKLONE-; PERSEC-; TETLEN-; TETRACAP-; TETRACHLOORETHEEN-; TETRACHLORAETHEN-; TETRACHLORETHYLENE-; TETRACHLOROETHENE-; 1,1,2,2-TETRACHLOROETHYLENE-; TETRACLOROETENE-; TETRAGUER-; TETRALENO-; TETRALEX-; TETRAVEC-; TETROGUER-; TETROPIL-; WLN: GYGUYGG RN: 127-18-4 WL: GYGUYGG HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198803 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Tetrachloroethylene CASRN -- 127-18-4 Last Revised -- 03/01/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Hepatotoxicity in NOAEL: 20 mg/kg/day 1000 1 1E-2 mice, weight gain (converted to mg/kg/day in rats 14 mg/kg/day) 6-Week Mouse Gavage LOAEL: 100 mg/kg/day Study (converted to 71 mg/kg/day) Buben and O'Flaherty, 1985 ---------------------------------------------------------------------------- *Conversion Factors: Doses have been adjusted for treatment schedule (5 days/week) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Buben, J.A. and E.J. O'Flaherty. 1985. Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: a dose-effect study. Toxicol. Appl. Pharmacol. 78: 105-122. Buben and O'Flaherty (1985) exposed Swiss-Cox mice to tetrachloroethylene in corn oil by gavage at doses of 0, 20, 100, 200, 500, 1500, and 2000 mg/kg, 5 days/ week for 6 weeks. Liver toxicity was evaluated by several parameters including liver weight/body weight ratio, hepatic triglyceride concentration, DNA content, histopathological evaluation, and serum enzyme levels. Increased liver triglycerides were first observed in mice treated with 100 mg/kg. Liver weight/body weight ratios were significantly higher than controls for animals treated with 100 mg/kg. At higher doses, hepatotoxic effects included decreased DNA content, increased SGPT, decreased levels of G6P and hepatocellular necrosis, degeneration and polyploidy. A NOEL of 14 mg/kg/day was established in a second study, as well (Hayes et al., 1986). Groups of 20 Sprague-Dawley rats of both sexes were administered doses of 14, 400, or 1400 mg/kg/day in drinking water. Males in the high-dose group and females in the two highest groups exhibited depressed body weights. Equivocal evidence of hepatotoxicity (increased liver and kidney weight/body weight ratios) were also observed at the higher doses. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 1000 results from multiplying factors of 10 to account for intraspecies variability, interspecies variability and extrapolation of a subchronic effect level to its chronic equivalent. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Other data support the findings of the principal studies. Exposure of mice and rats to tetrachloroethylene by gavage for 11 days caused hepatotoxicity (centrilobular swelling) at doses as low as 100 mg/kg/day in mice (Schumann et al., 1980). Mice were more sensitive to the effects of tetrachloroethylene exposure than rats. Increased liver weight was observed in mice at 250 mg/kg, while rats did not exhibit these effects until doses of 1000 mg/kg/day were reached. Relative sensitivity to man cannot be readily established but the RfD of 1E-2 mg/kg/day is protective of the most mild effects observed in humans [diminished odor perception/modified Romberg test scores in volunteers exposed to 100 ppm for 7 hours; roughly equivalent to 20 mg/kg/day (Stewart et al., 1961)]. The principal studies are of short duration. Inhalation studies have been performed which indicate that the uncertainty factor of 10 is sufficient for extrapolation of the subchronic effect to its chronic equivalent. Liver enlargement and vacuolation of hepatocytes were found to be reversible lesions for mice exposed to low concentrations of tetrachloroethylene (Kjellstrand et al., 1984). In addition, elevated liver weight/body weight ratios observed in animals exposed to tetrachloroethylene for 30 days were similar to those in animals exposed for 120 days. Several chronic inhalation studies have also been performed (Carpenter, 1937; NTP, 1985; Rowe et al., 1952). None are inconsistent with a NOAEL of 14 mg/kg/day for tetrachloroethylene observed by Buben and O'Flaherty (1985) and Hayes et al. (1986). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Medium RfD -- Medium No one study combines the features desired for deriving an RfD: oral exposure, large number of animals, multiple dose groups, testing in both sexes and chronic exposure. Confidence in the principal studies is low mainly because of the lack of complete histopathological examination at the NOAEL in the mouse study. The data base is relatively complete but lacks studies of reproductive and teratology endpoints subsequent to oral exposure; thus, it receives a medium confidence rating. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD U.S. EPA. 1985. Health Assessment Document for Tetrachloroethylene (Perchloroethylene). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA 600/8-82/005F. U.S. EPA. 1987. Quantification of Toxicological Effects for Tetrachloroethylene. Prepared from the Health Assessment Document for Tetrachloroethylene (Perchloroethylene). Office of Drinking Water, Washington, DC. Agency Work Group Review -- 05/20/1985, 08/05/1986, 09/17/1987 Verification Date -- 09/17/1987 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Tetrachloroethylene CASRN -- 127-18-4 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Tetrachloroethylene CASRN -- 127-18-4 NOCA: Not available at this time. ============================================================================ UDSO: 198907 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Tetrachloroethylene CASRN -- 127-18-4 Last Revised -- 07/01/1989 SORD: __VI.A. ORAL RfD REFERENCES Buben, J.A. and E.J. O'Flaherty. 1985. Delineation of the role of metabolism in the hepatotoxicity of trichloroethylene and perchloroethylene: A dose-effect study. Toxicol. Appl. Pharmacol. 78: 105-122. Carpenter, C.P. 1937. The chronic toxicity of tetrachloroethylene. J. Ind. Hyg. Toxicol. 19(7): 323-336. Hayes, J.R., L.W. Condie, Jr. and J.F. Borzelleca. 1986. The subchronic toxicity of tetrachloroethylene (perchloroethylene) administered in the drinking water of rats. Fund. Appl. Toxicol. 7: 119-125. Kjellstrand, P., B. Holmquist, M. Kanje, et al. 1984. Perchloroethylene: Effects on body and organ weights and plasma butyrylcholinesterase activity in mice. Acta Pharmacol. Toxicol. 54(5): 414-424. NTP (National Toxicology Program). 1985. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Tetrachloroethylene (perchloroethylene). U.S. Dept. Health and Human Services, NIH Publ. No. 85-2567. Rowe, V.K., D.D. McCollister, H.C. Spencer, E.M. Adams and D.D. Irish. 1952. Vapor toxicity of tetrachloroethylene for laboratory animals and human subjects. Arch. Ind. Hyg. Occup. Med. 5: 566-579. Schumann, A.M., J.F. Quast and P.G. Watanabe. 1980. The pharmacokinetics and macromolecular interaction of perchloroethylene in mice and rats as related to oncogenicity. Toxicol. Appl. Pharmacol. 55: 207-219. Stewart, R.D., H.H. Gay, D.S. Erley, C.L. Hake and A.W. Schaffer. 1961. Human exposure to tetrachloroethylene vapor. Arch. Environ. Health. 2: 40-46. U.S. EPA. 1985. Health Assessment Document for Tetrachloroethylene (perchloroethylene). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA 600/8-82-005F. Office of Drinking Water, Washington, DC. U.S. EPA. 1987. Quantification of Toxicological Effects for Tetrachloroethylene. Prepared from the Health Assessment Document for Tetrachloroethylene (perchloroethylene). Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Tetrachloroethylene CASRN -- 127-18-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 12/23/1987 I.A. RfD withdrawn pending further review 03/01/1988 I.A. Revised Oral RfD sumary added - RfD changed 03/01/1988 III.A. Health Advisory added 07/01/1989 VI. Bibliography on-line 05/01/1990 II. Carcinogen assessment now under review 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV. Regulatory action section withdrawn 08/01/1995 II EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/02/1998 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 377 of 1119 in IRIS (through 2003/06) AN: 107 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199103 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2,4,5-Tetrachlorobenzene- SY: 95-94-3; BENZENE,-1,2,4,5-TETRACHLORO-; RCRA-WASTE-NUMBER-U207-; TETRACHLOROBENZENE,-1,2,4,5- RN: 95-94-3 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199103 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2,4,5-Tetrachlorobenzene CASRN -- 95-94-3 Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Kidney lesions NOAEL: 5.0 ppm of diet 1000 1 3E-4 or 0.34 mg/kg/day mg/kg/day Rat Oral Subchronic Study LOAEL: 50 ppm of diet Chu et al., 1984 or 3.4 mg/kg/day ---------------------------------------------------------------------------- *Conversion Factors: Dose conversions were reported by the authors. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Chu, I., D.C. Villeneuve, V.E. Valli and V.E. Secours. 1984. Toxicity of 1,2,3,4-, 1,2,3,5- and 1,2,4,5-tetrachlorobenzene in the rat: Results of a 90-day feeding study. Drug Chem. Toxicol. 7: 113-127. Groups of 15/sex weanling Sprague-Dawley rats were fed diets containing 0, 0.5, 5.0, 50, and 500 ppm of 1,2,4,5-tetrachlorobenzene (TCB) for 13 weeks. The corresponding dose range in mg/kg bw/day was given as 0.034-34. Dose-related increases in the frequency and severity of kidney lesions for male rats were observed at 1,2,4,5-TCB dose levels of 5.0 ppm and greater. The severity of effects was considered significant only at the 50 and 500 ppm levels because of a high incidence of mild kidney lesions in the controls. Liver lesions were observed for female rats at 500 ppm. A 28-day feeding study of 1,2,4,5-TCB in rats (10/sex/group) showed dose-related effects for liver and kidney pathology at 3.4 and 32 mg/kg bw/day (Chu et al., 1983). Liver lesions were reported as mild to moderately severe, while kidney lesions were judged to be mild. Relative liver weight was significantly increased (20-30%) at 32 mg/kg/day. Hepatic microsomal enzymes were induced 2- to 12-fold at 32 mg/kg/day. Males were more susceptible than females for all criteria. Adverse effects were not observed at two lower doses (0.04 and 0.4 mg/kg/day). Higher doses (50, 100, and 200 mg/kg/day) were associated with mortality (200 mg/kg/day only), elevated serum cholesterol, increased organ weights, and liver enzyme induction when administered to pregnant rats for 10 days (Ruddick et al., 1981). UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 1000 reflects 10 for both intraspecies and interspecies variability to the toxicity of this chemical in lieu of specific data, and 10 for extrapolation of a subchronic effect level to its chronic equivalent. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Braun et al. (1978) reported a NOAEL for dogs of 5 mg/kg bw/day for 1,2,4,5-TCB administered in the diet for 2 years. Increased serum alkaline phosphatase activity and increased liver weights were reported at 10 mg/kg bw/day in a separate 144-day dog study referred to in Braun et al. (1978). Both studies were unpublished and were judged inadequate for risk assessment. The 2-year study was designed for other purposes and did not employ adequate controls or timely histopathologic analysis. A Russian study (Fomenko, 1965) reported impaired liver function and learning response for rats and rabbits dosed orally for 8 months with 1,2,4,5-TCB at 0.005 or 0.05 mg/kg bw/day. A NOAEL of 0.001 mg/kg/day was established. The study was judged unsuitable because of the lack of itemized data and detailed study protocol. NTP testing is in progress. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The principal study, although of short duration, is excellent in most respects (dose range, toxicologic criteria, data presentation, range of effects) except for the high incidence of kidney lesions in the control animals and a subsequent uncertainty in interpretation of effects. Thus, the confidence in the study is rated medium. The principal supporting study is of similar high quality, although shorter in duration. Effect levels are mutually supportive. However, the data base lacks a bona fide chronic study and adequate reproductive and teratology bioassays. Thus, the data base rates a low confidence. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 10/09/1985, 11/06/1985 Verification Date -- 11/06/1985 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for 1,2,4,5-Tetrachlorobenzene conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2,4,5-Tetrachlorobenzene CASRN -- 95-94-3 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2,4,5-Tetrachlorobenzene CASRN -- 95-94-3 NOCA: Not available at this time. ============================================================================ UDSO: 199103 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2,4,5-Tetrachlorobenzene CASRN -- 95-94-3 Last Revised -- 03/01/1991 SORD: __VI.A. ORAL RfD REFERENCES Braun, W.H., L.Y. Sung, D.G. Keyes and R.J. Kociba. 1978. Pharmacokinetic and toxicological evaluation of dogs fed 1,2,4,5-tetrachlorobenzene in the diet for two years. J. Toxicol. Environ. Health. 4: 727-734. Chu, I., D.C. Villeneuve, V.E. Valli and V.E. Secours. 1984. Toxicity of 1,2,3,4-, 1,2,3,5- and 1,2,4,5-tetrachlorobenzene in the rat: Results of a 90-day feeding study. Drug Chem. Toxicol. 7: 113-127. Chu, I., D.C. Villeneuve and V.E. Secours. 1984. Comparative toxicity of 1,2,3,4-, 1,2,4,5- and 1,2,3,5-tetrachlorobenzene in the rat: Results of acute and subacute studies. J. Toxicol. Environ. Health. 11: 663-677. Fomenko, V.N. 1965. Determination of the maximum permissible concentratin of tetrachlorobenzene in water basins. Gig. Sanit. 30: 8-15. Ruddick, J.A., D.C. Villeneuve, I. Chu, S. Kacew and V.E. Valli. 1981. Transplacental and teratological evaluation of tetrachlorobenzene isomers in the rat. Teratology. 23: 59A. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2,4,5-Tetrachlorobenzene CASRN -- 95-94-3 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. Dose conversion clarified 03/01/1988 I.A.5. Confidence levels revised 03/01/1988 I.A.6. Documentation corrected 02/01/1989 I.A.7. Secondary contact's phone number corrected 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 03/01/1991 I.A.4. Fomenko, 1964 citation year corrected to 1965 03/01/1991 VI. Bibliography on-line 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 378 of 1119 in IRIS (through 2003/06) AN: 118 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199404 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Toluene- SY: 108-88-3; ANTISAL-1A-; BENZENE,-METHYL-; METHACIDE-; METHYL-BENZENE-; METHYLBENZOL-; NCI-C07272-; PHENYL-METHANE-; RCRA-WASTE-NUMBER-U220-; TOLUEEN-; TOLUEN-; TOLUOL-; TOLUOLO-; TOLU-SOL-; UN-1294- RN: 108-88-3 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199404 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Toluene CASRN -- 108-88-3 Last Revised -- 04/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- ---------- Changes in liver and NOAEL: 312 mg/kg 1000 1 2E-1 kidney weights converted to 223 mg/kg/day mg/kg/day 13-Week Rat Gavage Study LOAEL: 625 mg/kg converted to 446 NTP, 1989 mg/kg/day ---------------------------------------------------------------------------- *Conversion Factors: Dose adjusted for gavage schedule of 5 days/week. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1989. Toxicology and Carcinogenesis Studies of toluene in F344/N rats and B6C3F1 mice. Technical Report Series No. 371. Research Triangle Park, NC. The oral toxicity of toluene was investigated in this subchronic gavage study in F344 rats. Groups of 10 rats/sex/group were administered toluene in corn oil at dosage levels of 0, 312, 625, 1250, 2500, or 5000 mg/kg for 5 days/week for 13 weeks. All animals receiving 5000 mg/kg died within the first week. One female and 8 males in the 2500 mg/kg group died, but 2 of these were due to gavage errors. No deaths occurred at lower doses. Several toxic effects were noted at doses greater than or equal to 2500 mg/kg, including prostration, hypoactivity, ataxia, piloerection, lacrimation, excessive salivation, and body tremors. No signs of biologic significance were seen in groups receiving less than or equal to 1250 mg/kg. The only significant change in body weight was a decrease (p<0.05) for males in the 2500 mg/kg group. There were no toxicologically significant changes in hematology or urinalysis for any group of animals. Biochemical changes, including a significant increase (p<0.05) in SGOT in 2500 males and a dose-related increase in cholinesterase in females receiving 2500 and 5000 mg/kg, were not considered to be biologically significant. There were several pathologic findings and organ weight changes in the liver, kidney, brain, and urinary bladder. In males, absolute and relative weights of both the liver and kidney were significantly increased (p<0.05) at doses greater than or equal to 625 mg/kg. In females, absolute and relative weights of the liver, kidney, and heart were all significantly increased at doses greater than or equal to 1250 mg/kg (p<0.01 for all comparisons except p<0.05 for absolute kidney and heart weights at 1250 mg/kg). Histopathologic lesions in the liver consisted of hepatocellular hypertrophy, occurring at greater than or equal to 2500 mg/kg. Nephrosis was observed in rats that died, and damage to the tubular epithelia of the kidney occurred in terminally sacrificed rats. Histopathologic changes were also noted in the brain and urinary bladder. In the brain, mineralized foci and necrosis of neuronal cells were observed in males and females at 2500 mg/kg and males at 1250 mg/kg. In the bladder, hemorrhage of the muscularis was seen in males and females at 5000 mg/kg and males at 2500 mg/kg. The NOAEL for this study is 312 mg/kg/day based on liver and kidney weight changes in male rats at 625 mg/kg. The toxicologic significance of these organ weight changes is strengthened by the occurrence of histopathologic changes in both the liver and kidney at higher doses. Because the exposure was for 5 days/week, this dose is converted to 312 x 5/7 = 223 mg/kg/day. The LOAEL is 625 mg/kg, which is 446 mg/kg/day when converted. NTP (1989) also conducted a 13-week gavage study in B6C3F1 mice, following the same regimen described above. All mice receiving 5000 mg/kg died and 8/20 receiving 2500 mg/kg also died. Signs of toxicity seen in animals receiving greater than or equal to 2500 mg/kg included subconvulsive jerking, prostration, impaired grasping reflex, bradypnea, hypothermia, ataxia, and hypoactivity. By week 13, the mean body weight of 2500 mg/kg males was significantly (p<0.05) lower than controls. No other significant changes were reported for any group, including macroscopic observation, organ weight means, or clinical pathology parameters. The NOAEL for mice in this study was 1250 mg/kg. The subchronic study by Wolf et al. (1956) is supportive of the NTP studies. Groups of 10 female Wistar rats were administered gavage doses of 0, 118, 354, or 590 mg/kg toluene dissolved in olive oil. A total of 138 doses were administered over 193 days, resulting in average doses of approximately 0, 84, 253, or 422 mg/kg/day. Hematologic, behavioral, gross and histopathologic examinations were conducted with no toxic effects being reported at any dose. Therefore, the highest dose of 422 mg/kg/day is considered to be the NOAEL for this study. However, this study is not used as the basis for the RfD because the LOAEL of 446 mg/kg/day identified by NTP (1989) is too close to the NOAEL identified by Wolf et al. (1956). Also, the NTP study indicated that male rats are more sensitive to toluene and the Wolf study utilized only female rats. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was applied to account for inter- and intraspecies extrapolations, for subchronic-to-chronic extrapolation and for limited reproductive and developmental toxicity data. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Kostas and Hotchin (1981) exposed NYLAR mice pre- and post-natally to toluene provided in the drinking water at concentrations of 0, 16, 80, or 400 ppm. Effects were noted in all dosed groups on rotorod performance, measured at 45 to 55 days of age, but there was an inverse dose-response relationship. No effects of toluene exposure were seen on maternal fluid consumption, offspring mortality rate, development of eye or ear openings, or surface-righting response. This study is not suitable for use in risk assessment because only 6 to 9 pregnancies/dose group were obtained, and because the dose-response relationship was inverse. In an abstract providing limited information, Nawrot and Staples (1979) reported an increase in embryonic lethality in mice exposed to toluene from days 6 to 15 of gestation. Pregnant CD-1 dams were administered 0.3, 0.5, or 1.0 mL/kg bw, 3 times/day (equivalent to approximately 780, 1300, or 2600 mg/kg/day). Maternal toxicity was not observed at any dose level, but toluene was shown to be teratogenic at the high dose and embryolethal at the low dose. These levels are higher than the NOAEL demonstrated by the NTP (1989) study. Several subchronic and chronic inhalation studies have been performed on toluene but are not considered to be suitable for deriving an oral RfD. These studies are summarized nicely in the introduction to the 2-year inhalation bioassay by NTP, 1989. The studies identify the following potential target organs: kidney (male rat); hematologic effects (mice); central nervous system (rats, mice, primates); developmental toxicity (rats, rabbits). It is beyond the scope of this oral RfD summary sheet to describe each of these studies, but the two chronic (2 year) inhalation studies are summarized briefly below. In a 2-year inhalation study by NTP (1989), F344 rats (60/sex/group) were exposed to 0, 600, or 1200 ppm toluene and B6C3F1 mice (60/sex/group) to 0, 120, 600, or 1200 ppm toluene for 6.5 hours/day, 5 days/week. Ten animals/group (except male mice) were removed at 15 months for toxicologic evaluation. At 15 months, there was an increased incidence and severity of nonneoplastic lesions of the nasal cavity of exposed rats. Minimal hyperplasia of the bronchial epithelium was seen in 4/10 female mice at 1200 ppm. There were no significant differences in survival among any group of animals during the 2-year study. Mean body weights were generally similar for all groups throughout the study. Nephropathy was seen in almost all rats with the severity somewhat increased in exposed rats. There were also effects on the olfactory and respiratory epithelia of exposed rats. No biologically important lesions were seen in any groups of mice. There was no evidence of carcinogenicity for any group of animals in this study. A chronic inhalation study in rats performed by CIIT (1980) failed to produce an adverse effect. Groups of 40 F344 rats/sex were exposed to 30, 100, or 300 ppm toluene for 6 hours/day, 5 days/week for 24 months. An unexposed group of 120 rats/sex served as a control. Clinical chemistry, hematology, and urinalysis testing were conducted at 18 and 24 months. All parameters measured at the termination of the study were normal except for a dose-related reduction in hematocrit values in females exposed to 100 and 300 ppm toluene. The highest dose of 300 ppm was considered to be a NOAEL. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study: High Data Base: Medium RfD: Medium Confidence in the principal study is high because a sufficient number of animals/sex were tested in each of six dose groups (including vehicle controls) and many parameters were studied. The same protocol was tested in both mice and rats, with rats being identified as the more sensitive species. The data base is rated medium because it is supported by a 6-month oral study. It is not higher than medium because there is no reproductive study. Also, the oral studies are all subchronic, with the critical study being only 13 weeks in duration. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 05/20/1985, 08/05/1985, 08/05/1986, 05/17/1990, 06/20/1990 Verification Date -- 06/20/1990 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199208 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Toluene CASRN -- 108-88-3 Last Revised -- 08/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Neurological effects NOAEL: None 300 1 4E-1 mg/cu.m Occupational Study LOAEL: 332 mg/cu.m (88 ppm) LOAEL(ADJ): 119 mg/cu.m Foo et al., 1990 LOAEL(HEC): 119 mg/cu.m Degeneration of nasal NOAEL: None epithelium LOAEL: 2261 mg/cu.m (600 ppm) 2-Year Rat Chronic LOAEL(ADJ): 437 mg/cu.m Inhalation Study LOAEL(HEC): 79 mg/cu.m NTP, 1990 ---------------------------------------------------------------------------- *Conversion Factors: MW = 92.15. Foo et al., 1990: Assuming 25 C and 760 mmHg, LOAEL (mg/cu.m) = 88 ppm x 92.15/24.45 = 332 mg/cu.m. This is an extrarespiratory effect of a soluble vapor. The LOAEL is based on an 8-hour TWA occupational exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. LOAEL(HEC) = LOAEL(ADJ) = 332 x MVho/MVh x 5 days/7 days = 119 mg/cu.m. NTP, 1990: Assuming 25 C and 760 mmHg, LOAEL (mg/cu.m) = 600 ppm x 92.15/24.45 = 2261 mg/cu.m. LOAEL(ADJ) = LOAEL (mg/cu.m) x 6.5 hours/24 hours x 5 days/7 days = 437 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in the extrathoracic region. MVa = 0.24 cu.m/day, MVh = 20 cu.m/day, Sa (ET) = 11.6 sq.cm, Sh (ET) = 177 sq.cm. RGDR = (MVa/Sa) / (MVh/Sh) = 0.18. LOAEL(HEC) = 437 x RGDR = 79 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Foo, S., J. Jeyaratnam and D. Koh. 1990. Chronic neurobehavioral effects of toluene. Br. J. Ind. Med. 47(7): 480-484. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of toluene in F344/N rats and B6C3F1 mice (inhalation studies). NTP-TR-371. 253 p. In humans, toluene is a known respiratory irritant with central nervous system (CNS) effects. Because available studies could not provide subthreshold (NOAEL) concentrations for either of these effects, the LOAELs for both effects need to be considered in developing the RfC. Consequently, the study of Foo et al. (1990) was used for the CNS effects, and that of the National Toxicology Program (NTP, 1990) for the irritant effects. Because the CNS effect was judged to be a more severe and relevant endpoint, the LOAEL for this effect was used for deriving the RfC. Further, this effect is supported by a number of other occupational studies that show effects around 100 ppm. Foo et al. (1990) conducted a cross-sectional study involving 30 exposed female workers employed at an electronic assembly plant where toluene was emitted from glue. Toluene levels reported in the study were from personal sample monitoring and reported as an 8-hour TWA, although the number of samples taken and the actual sampling period were not given. No historical exposure values were given. Co-exposure to other solvents was not addressed in the study. The exposed and control cohorts were matched for age, ethnicity, and use of medications. Members of these cohorts did not use alcohol and were nonsmokers. Medical histories were taken to eliminate any histories of central or peripheral nervous system disorders. The average number of years (+/- SD) worked by the exposed population was 5.7 +/- 3.2 and by the controls was 2.5 +/- 2.7. Exposed workers breathed toluene air levels of 88 ppm (332 mg/cu.m) as a TWA and control workers 13 ppm (49 mg/cu.m) (TWA); both of which are averages of the individual personal samples. A battery of eight neurobehavioral tests were administered to all exposed and control workers. The tests were performed midweek, before the workers reported to their stations for the day. Group means revealed statistically significant differences in 6/8 tests; all tests showed that the exposed workers performed poorly compared with the control cohort. When individual test results were linearly regressed against personal exposure concentrations, poor concentration-response relationships resulted for the six tests, with correlation coefficients ranging from 0.44 to 0.30. Irritation effects were not evaluated in this study, and no clinical signs or symptoms were reported. The paucity of exposure information, coupled with the small size of the cohort, limits the interpretation of this study, although the results were essentially confirmed in a clinical study in which the toluene concentrations were carefully controlled (Echeverria et al., 1989) at levels bracketing 88 ppm. Although the data in Echeverria et al. (1989) were generated from short-term exposures (3-7 hours over a period of 142 days), the results may be considered relevant to longer-term exposures as several studies indicate the absence of a duration-response relationship in toluene-induced symptomatology. Fornazzari et al. (1983) noted the absence of a duration-effect relationship among toluene abusers when they were segregated into neurologically impaired vs. unimpaired (p = 0.65). The human studies of Iregren (1982), Cherry et al. (1985), Baelum et al. (1985), and the principal study of Foo et al. (1990) all report this lack of a duration-response relationship and confirm the occurrence of CNS effects. Foo et al. (1990) indicate a LOAEL of 88 ppm toluene (332 mg/cu.m) for neurobehavioral changes from chronic exposure to toluene. In a 2-year bioassay, Fischer 344 rats (60/sex/group) were exposed to 0, 600, or 1200 ppm (0, 2261, or 4523 mg/cu.m, respectively) toluene vapors, 6.5 hours/day, 5 days/week (duration-adjusted to 0, 437, and 875 mg/cu.m, respectively) for 103 weeks (NTP, 1990). To generate toluene vapor, the liquid material was heated, and the vapor diluted with nitrogen and mixed with the chamber ventilation air. An interim sacrifice was carried out at 15 months on control and 1200-ppm groups (10/sex/group) to conduct hematology and histopathology of the brain, liver, and kidney. Body weights were measured throughout the study. Gross necropsy and micropathology examinations were performed at the end of the study on all major organs including the nasal passage tissues (three sections), lungs, and mainstem bronchi. Mean body weights in both exposed groups were not different from controls for either sex. No exposure-related clinical signs were reported, and survival rate was similar for all groups. At the interim sacrifice, there was a mild-to-moderate degeneration in the olfactory and respiratory epithelium of the nasal cavity in 39/40 rats of the 600- and 1200-ppm groups compared with 7/20 controls. At the end of 2 years, there was a significant (p<0.05) increase in the incidence of erosion of the olfactory epithelium (males: 0/50, 3/50, and 8/49; females: 2/49, 11/50, and 10/50; at 0, 600, and 1200 ppm, respectively) and of degeneration of the respiratory epithelium (males: 15/50, 37/50, and 31/49; females: 29/49, 45/50, and 39/50; at 0, 600, and 1200 ppm, respectively) in the exposed animals. The females exposed to 600 and 1200 ppm also exhibited a significant increase in inflammation of the nasal mucosa (27/49, 42/50, and 41/50 at 0, 600, and 1200 ppm, respectively) and respiratory metaplasia of the olfactory epithelium (0/49, 2/50, and 6/50 at 0, 600, and 1200 ppm, respectively). A LOAEL of 600 ppm toluene was determined for the concentration-dependent increase in erosion of the olfactory epithelium in male rats and the degeneration of the respiratory epithelium in both sexes. No NOAEL could be derived from this study. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- An uncertainty factor of 10 is used to account for intraspecies variability and another factor of 10 for the use of a LOAEL. An additional factor of 3 is applied for data base deficiencies, including the lack of data and well-characterized laboratory animal exposures evaluating neurotoxicity and respiratory irritation. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Toluene-induced neurotoxicity has been documented in humans over a broad spectrum of severity that correlates well with concentration. Numerous case studies on chronic toluene abusers [repeatedly exposed to greater than 30,000 ppm (113,000 mg/cu.m)] have demonstrated functional deficits of the CNS accompanied by abnormal morphology of cerebellar and cortical areas of the brain. Under acute exposure conditions [short exposures to greater than 10,000 ppm (37,690 mg/cu.m)], toluene produces CNS narcosis [American Conference of Governmental Industrial Hygienists (ACGIH), 1991]. Lower concentrations, i.e., 800-400 ppm (3015-1508 mg/cu.m), have been associated with worker complaints of CNS-related effects (ACGIH, 1991). Clinical studies using controlled exposure to toluene have demonstrated concentration-related occurrence of complaints such as drowsiness, ataxia, visual impairment, and headache. A number of occupational studies indicate that these same effects are present in exposed worker populations at concentrations lower than 400 ppm (1508 mg/cu.m) although deficiencies in most of these studies preclude confirming this finding unequivocally. Descriptions of a number of these studies follow. The preponderence of the literature showing CNS effects and the well-known proclivity for solvents to affect CNS processes in humans leave little doubt that the brain is a principal target organ for toluene toxicity in humans. In cases of inhalation abuse of toluene, Rosenberg et al. (1988) demonstrated diffuse cerebral, cerebellar, and brainstem atrophy in 3 of 11 toluene abusers who also had neurological abnormalities. Filley et al. (1990) were able to correlate neuropsychological impairment with the degree of white matter abnormality (p<0.01). Cerebellar and cortical functions were classified as impaired in 15/24 individuals who had abused toluene daily (425 +/- 366 mg/day) for extended periods (6.3 +/- 3.9 years) (Fornazzari et al., 1983). In a limited case study, Metrick and Brenner (1982) demonstrated brainstem atrophy through computerized tomographic scans and abnormal brainstem auditory-evoked potentials in 2/2 chronic toluene abusers (12-16 years of admitted, continuous abuse). These studies confirm the occurrence of severe CNS damage in response to highly abusive concentrations of toluene. Several studies that have investigated the occurrence of neurotoxicity at lesser concentrations, such as occupational situations, have not demonstrated significant neurological or other effects. Hanninen et al. (1987) performed a battery of 11 psychological tests on 43 printing workers who had been occupationally exposed to approximately 117 ppm (441 mg/cu.m) toluene for an average of 22 years and found only mildly adverse effects in 2/11 tests. The control and exposed cohorts in this study were, however, mismatched in several areas, most notably alcohol use. Iregren (1982) examined the psychological performance of 38 printers who had been occupationally exposed to 50-150 ppm (188-565 mg/cu.m) toluene for an average of 16.3 years (range 3-32 years). No effects were seen, although the cohorts in this study were apparently matched only by age. In a cohort study, Cherry et al. (1985) attempted to better match the control and exposed cohorts and considered alcohol use. Although no differences between the cohorts were statistically significant, the exposed workers performed worse than the nonexposed workers on 10/13 psychological tests. The 52 workers in this study were not, however, rigorously matched, and the concentrations listed in the study ranged up to greater than 500 ppm (1884 mg/cu.m). The cohorts in the study of Foo et al. (1990) were well matched for a number of confounders, including alcohol use, and statistically significant psychological effects were seen. In the occupational study conducted by Yin et al. (1987), 94 solvent workers (38 men and 56 women; average employment duration, 6.8 years) and 138 controls (48 men and 90 women) were examined for exposure using diffusion dosimeters, subjective symptoms by questionnaire, hematology, and urinalysis. Exposure concentration (7-hour mean TWA) in the workers was estimated at 42.8 ppm (161 mg/cu.m) toluene with a maximum measurement of 123 ppm (464 mg/cu.m). Workers were co-exposed to 1.3 ppm benzene. No exposure-related effects were noted in any of the biochemical tests examined. In considering the prevalence of subjective symptoms (sore throat, headaches, and dizziness) workers were subgrouped into low (6-39 ppm, n = 28) and high (40-123 ppm, n = 29) categories. Although the prevalence of subjective symptoms was significantly higher in the exposed workers compared with the control cohort (p<0.01), a concentration-response relationship was not discernable among the groups. No other treatment-related effects were reported. The study was limited because the exposed and unexposed groups were not matched to control for confounding effects (e.g., age, smoking, alcohol consumption, exposure duration). Based on these results, exposure to an average of approximately 42.8 ppm toluene produced no biochemical abnormalities, although neither respiratory irritation nor psychological performance was directly evaluated in these workers. In the occupational study by Lee et al. (1988), prevalence of subjective symptoms was categorized with respect to exposure levels. The study population (193 women and 65 controls) completed a questionnaire. The exposures were reported as 8-hour TWAs, and workers were grouped in exposure categories of nonexposed, 1-50 ppm, 51-100 ppm, 101-150 ppm, and more than 151 ppm (duration of exposures was not reported). A concentration-dependent increase in prevalence was reported for 25/67 symptoms with increases in complaints over controls occurring at around 100 ppm (348 mg/cu.m). Similar to the Yin et al. study (1987) reported above, symptomatology included headaches, sore throats, and dizziness. Although an effect level in humans of around 100 ppm is indicated by this study, no objective measures of toxicity were examined. A number of acute human studies have focused on toluene effects. In general, these studies corroborate subjective CNS effects such as headaches and dizziness reported in other longer-term occupational studies (Yin et al., 1987; Lee et al., 1988) and also document irritation effects. The study of Echeverria et al. (1989) correlates the occurrence of these subjective effects with substantial neurological symptoms. Forty-two college students (21 female and 21 male) were exposed to 0, 74 ppm (279 mg/cu.m), or 151 ppm (569 mg/cu.m) toluene for 7 hours over 3 days (Echeverria et al., 1989). This exposure sequence was repeated for a total of 42 exposures over a 3-month period. The odor of toluene was masked. A battery of performance tests was administered to each participant prior to starting the exposures and again at 4 and 7 hours during the exposure; the initial test served as a control for those tests performed during the exposure. A 5-10% decrement in performance was considered significant if consistent with a linear trend. Test results for visual perception differed from control values for both exposure levels. Results of a manual dexterity test differed from control values at the higher but not the lower exposure level. Psychomotor test results were unaffected by toluene exposure. Subjective symptomatology increased with exposure with increasing numbers of complaints of eye irritation, headache, and somnolence. A NOAEL of 74 ppm (279 mg/cu.m) is indicated for these results. The duration-adjusted value is 122 mg/cu.m for these acute effects. Andersen et al. (1983) exposed 16 subjects (average age of 24 years) to 0, 10, 40, or 100 ppm (0, 38, 151, or 377 mg/cu.m) toluene for 6 hours on each of 4 consecutive days. Individuals were tested for nasal mucous flow, lung function, subjective response, and psychometric performance. At 100 ppm, irritation was experienced in the eyes and nose, but no effect on nasal mucous flow or lung function was observed. The subjects frequently reported headaches, dizziness, and a feeling of intoxication. These effects were not reported by the 10- or 40-ppm exposure groups. No effects were seen in performance tests. This study indicates an effect level of 100 ppm, and a NOAEL of 40 ppm (151 mg/cu.m). The acute study by Baelum et al. (1990) evaluated 32 males and 39 females exposed to 0 or 100 ppm (0 or 377 mg/cu.m), or to varying exposures of 50-300 ppm (188-1131 mg/cu.m) (TWA = 102 ppm), for 7 hours. Volunteers exercised on an ergometer cycle for 3 periods of 15 minutes each during the exposure. No significant differences were found in the performances between the exposed and control groups in a battery of tests for performance, visual attention, and reaction times. Exposed subjects reported an increase over nonexposed subjects (p<0.1) in nose and lower respiratory irritation, feelings of intoxication, dizziness, increased coughing, and headaches. Differences were not noted between the group exposed to a constant level (100 ppm) and the group exposed to the same TWA, but with peaks of up to 300 ppm. Baelum et al. (1985) investigated the effects of a 6.5-hour toluene exposure to 43 printers with a long-term occupational exposure to a mixture of solvents including toluene and 43 controls with no history of exposure to solvents or other chemicals. The duration of employment for the workers ranged from 9-25 years. Each individual was exposed only once to either 0 or 100 ppm (0 or 377 mg/cu.m) toluene during a 6.5-hour exposure period, preceded by a 1-hour acclimatization period. These subjects were then subgrouped into printers exposed to toluene (n = 20), printers exposed to air (n = 23), controls exposed to toluene (n = 21), and controls exposed to air (n = 22). All subjects carried out a battery of tests for psychometric performance, visual perception, and vigilance evaluation. Both printers and controls complained of nasal and eye irritation, unacceptable air quality, and unacceptable odor level during the toluene exposure. Signs of neurotoxicity, including moderate fatigue, sleepiness, headaches, and a feeling of intoxication, were likewise similarly reported for both groups. A significant decrease in performance was found for the pegboard visual motor function test in the exposed printers, but not in the controls exposed to 100 ppm toluene. A decrease in psychometric performance, primarily in visual perception and accuracy, was observed in toluene-exposed individuals. Acute exposure to toluene resulted in a lower performance in 4/10 tests conducted, 3 of these 4 evaluated visual perception. The most profound difference between subjects exposed to 100 ppm toluene and those exposed to clean air was observed in the color discrimination test; this difference was seen in both exposed vs. nonexposed printers and exposed vs. nonexposed controls. This study indicates that little tolerance develops to the irritative and central effects in humans exposed to toluene and that 100 ppm (377 mg/cu.m) is the effect level for these symptoms. Von Oettingen et al. (1942) exposed 3 humans to 100 or 200 ppm (377 or 754 mg/cu.m) toluene vapors for 8 hours. At 200 ppm, the subjects experienced muscular weakness, confusion, impaired coordination, and dilated pupils, with after-effects including fatigue, general confusion, and moderate insomnia. In 1 subject exposed to 100 ppm toluene, moderate fatigue, sleepiness, and headaches were reported. Hepatotoxicity has also been examined as a toxicologic endpoint of toluene exposure in humans. Fornazzari et al. (1983) described moderate elevation of serum AP levels in 13/24 (and SGOT in 7/24) toluene abusers upon admission to a clinic. These elevated levels were normal after 2 weeks of solvent abstinence, although the accompanying CNS effects were only minimally improved. In a cross-sectional study of 181 printing workers in which toluene exposures were less than 200 mg/cu.m, no adverse effects were apparent as judged from serum liver enzymes (Boewer et al., 1988). In another cross-sectional occupational study conducted by Guzelian et al. (1988) that involved 289 printing factory employees, 8 workers were found who had an increase described as "marked" in the ratio of ALT/AST enzyme serum activity. Biopsies revealed mild pericentral fatty livers in each of the eight cases. Based on environmental data (probably area monitors) the levels of toluene to which these workers were exposed was less than 200 mg/cu.m., 2-8 hours/day. Fischer 344 rats (120/sex/group) inhaled 0, 30, 100, or 300 ppm (0, 113, 377, or 1130 mg/cu.m, respectively) toluene (99.9% purity), 6 hours/day, 5 days/week (duration-adjusted to 0, 20, 67, or 202 mg/cu.m, respectively) for 106 weeks (CIIT, 1980; Gibson and Hardisty, 1983). Vapor, generated by bubbling clean air through toluene, was passed through the air supply duct and mixed with air by turbulent flow to produce the desired concentration. Hematology, blood chemistry, and urinalysis were conducted in all groups at 6 (5/sex), 17 (5/sex), 18 (10-20/sex), and 24 months (10/sex). Histopathology was evaluated only in the control and 300-ppm groups at 6 (5/sex), 12 (5/sex), and 18 months (20/sex). At 24 months, histopathological examinations were conducted in organs of all surviving animals, including the respiratory system and sections through the nasal turbinates (number not indicated). No treatment-related non-neoplastic effects were observed in the exposed animals. Although the male rats exposed to 300 ppm had a significant increase in body weight compared to controls, no concentration-response was evident. At the end of the exposure period, the female rats exposed to 100 or 300 ppm exhibited a slight but significant reduction in hematocrit; an increase in the mean corpuscular hemoglobin concentration was also noted but only in the females exposed to 300 ppm. The highest concentration examined in this study, 300 ppm, is designated as a NOAEL for toxicity remote from the respiratory tract in rats. CIIT (1980) reported that the technical and raw data were not audited by their quality assurance group during the study period, although CIIT did conduct a quality assessment procedure to review the data. The available pathology reports containing these data indicate that at least the lower respiratory tract was examined. Communication with the testing sponsor has provided information indicating that only one section was examined from the nasal cavity of these test animals. It is not clear whether this single section would have been sufficient to elucidate the areas of lesions noted in the NTP (1990) study. Consequently, the designation of the 300-ppm exposure level as a NOAEL for respiratory lesions (see NTP,1990) is problematic. Fischer 344/N rats (10/sex/group) were exposed to toluene vapors at 0, 100, 625, 1250, 2500, and 3000 ppm (0, 377, 2355, 4711, 9422, and 11,307 mg/cu.m, respectively) 6.5 hours/day, 5 days/week (duration-adjusted to 0, 73, 455, 911, 1823, and 2187 mg/cu.m, respectively) for 15 weeks (NTP, 1990). Organ weights were measured and histological examinations were performed only on controls, 2500- and 3000-ppm groups, and animals that died before the end of the study. Eight of 10 males exposed to 3000 ppm died, all during the 2nd exposure week. No females died at any exposure level. Compared to the controls, final body weights were 15 and 25% lower in the males and 15 and 14% lower in the females of the 2500- and 3000-ppm groups, respectively. There was a concentration-related increase in the relative liver weight, significant at 1250, 2500, and 3000 ppm in males and at 2500 and 3000 ppm in females. The relative weights of the heart, lung, kidney, and right testis were also significantly elevated in the 2500- and 3000-ppm animals compared to those of the controls, although no histopathology was observed in any exposure group. Toxic effects noted in a concurrently conducted gavage study (urinary bladder hemorrhages in the two highest exposure groups) were not noted in this subchronic inhalation study. A LOAEL of 2500 ppm [LOAEL(HEC) = 1823 mg/cu.m] was determined for the decrease in body weight gain in both males and females, and the NOAEL for this effect was 1250 ppm [NOAEL(HEC) = 911 mg/cu.m]. Toluene has been suspected to cause congenital defects in infants born to mothers who were exposed to or who abused toluene during pregnancy. In a case report study, Hersh et al. (1985) describes clinical and morphometric characteristics common to 3 children whose mothers had abused toluene (but apparently not alcohol or any other substance) for a period of 4-5 years including during their pregnancies with the affected children. Clinical findings common to these three children included microcephaly, CNS dysfunction, attention deficits, and developmental delay/mental deficiency. Phenotypic similarities included a small midface, deep-set eyes, micrognathia (smallness of the jaws), and blunting of the fingertips. A retrospective cohort study was conducted by McDonald et al. (1987) who examined the history of exposure to chemicals of 301 women who had recently given birth to an infant with an important congenital defect. An identical number of women (referents) who had given birth to normal children were matched with respect to age, employment (hours/week), date of delivery, and educational level. In initial matched-pair analysis, chemical exposure was higher in the cases than in the referents (63 cases:47 referents) due to excess cardiac and miscellaneous defects. In further analysis by chemical categories, only exposure to aromatic solvents showed a clear excess of defects, mostly in the urinary tract. Details of these cases (n = 19) showed that toluene was identified as the solvent in 11 of these cases. Hudak and Ungvary (1978) exposed three groups of pregnant CFY rats to toluene during different periods of gestation and for different durations of exposure. Two of the groups had their own control group exposed to air only and matched for period and daily duration. The first of these (n = 19) was exposed to 1500 mg/cu.m for 24 hours/day during gestational days 9 to 14. Two dams died during these exposures. No details on the deaths are given but no other maternal toxicity was observed. Fetotoxicity was also in evidence as sternebral alterations (6% vs. 1% in controls), extra ribs (22% vs. 0% in controls), and the presence of fetuses with missing tails (2/213, none observed in 315 controls) were recorded. Under these exposure conditions, 1500 mg/cu.m is a LOAEL for fetotoxicity and a frank effect level (FEL) for maternal toxicity. The second group (n = 14) received this same concentration continuously but on days 1-8 of gestation. Five dams died under these exposure conditions although toxicity parameters of the surviving dams were identical with the controls from the first group (gestational days 9-14). Slight hydrocephaly was noted in 4 fetuses (all from the same litter), and 17% growth retardation was noted vs. 7% in the controls. Thus these exposure conditions are a FEL for maternal toxicity and a LOAEL for fetotoxicity. A third group was exposed to 1000 mg/cu.m for 8 hours/day from the 1st to the 21st day of gestation. No maternal deaths or toxicity occurred. Minor skeletal retardation was present in the exposed fetuses at a higher incidence rate (25%) than in concurrent controls (0%). These results indicate that 1000 mg/cu.m is a LOAEL for developmental effects under these exposure conditions. This concentration is also a NOAEL for maternal effects. These workers also exposed groups of pregnant CFLP mice (n = 11-15) to either air or 1500 or 500 mg/cu.m toluene continuously during days 6-13 of pregnancy. All mice exposed to the high concentration died within 24 hours of the beginning of exposure. No dams died in the lower exposure group. In this group, the average fetal weight decreased to 0.96 g from the average control weight of 1.07 g, and the percentage of weight-retarded fetuses (less than 0.9 g) increased to 27.6% from 6.5% in the controls. No difference in incidence of skeletal malformations or anomalies was noted between these and control fetuses. For mice, 1500 mg/cu.m is an FEL and 500 mg/cu.m is a mild LOAEL. Since duration adjustment is not performed for developmental effects, this concentration is also the LOAEL(HEC). B6C3F1 mice (60/sex/group) were exposed to 0, 120, 600, or 1200 ppm (0, 452, 2261, or 4523 mg/cu.m, respectively) toluene 6.5 hours/day, 5 days/week (duration-adjusted to 0, 87, 47, and 875 mg/cu.m, respectively) for 2 years (NTP, 1990). Mean body weights were not significantly different among groups and no treatment-related clinical signs were observed. Deaths (moribund and natural) occurred in all exposure groups but were not related to exposure and were not greater than the control rates. An excess incidence of non-neoplastic inflammatory lesions of the urinary and genital system was observed in all the groups of male mice. At the 15-month interim sacrifice, minimal hyperplasia in the bronchial epithelium was observed in 4/10 females exposed to 1200 ppm. At the end of the study, there was a concentration-dependent increase in the incidence of splenic pigmentation in the exposed males (9/60, 11/60, and 18/59 at 120, 600, and 1200 ppm, respectively) compared to controls (4/60). In the females, the incidence was 37/50, 33/50, 34/49, and 28/47 at 0, 120, 600, and 1200 ppm, respectively. The occurrence of endometrial hyperplasia was present in 14% of the animals exposed to the highest concentration but only in 4% in the low-exposure groups and controls. No differences were noted between the exposed and control mice of either sex in the incidence of degeneration of either the olfactory or respiratory epithelium. No other non-neoplastic lesions were observed in exposed mice. As no adverse effects were noted in this study, the highest concentration, 1200 ppm was designated as a NOAEL in mice for this chronic study [NOAEL(HEC) = 875 mg/cu.m]. Sprague-Dawley rats (15/sex/group) were exposed to cumulative mean exposures of 0, 100, or 1481 ppm (0, 377, or 5653 mg/cu.m) toluene vapors, 6 hours/day, 5 days/week (duration-adjusted to 0, 67, and 1009 mg/cu.m, respectively) for 26 weeks (API, 1981). On weeks 9, 18, and 27, neurohistopathological examinations were conducted in 3-5 rats/sex/group. Hematology, clinical chemistry, and urinalysis parameters were evaluated after 13 and 26 weeks of exposure. Body weights were measured weekly. No significant treatment-related effects were reported. Therefore, a NOAEL of 1481 ppm [NOAEL(HEC) = 1009 mg/cu.m] toluene was determined for systemic effects in rats. The study was limited because there were no other neurohistopathological examinations or organ weight measurements conducted on the animals. Inhalation exposure to toluene has been shown to result in irreversible high-frequency hearing loss in rats. Pryor et al. (1984) exposed young male Fischer 344 rats to a variety of exposure concentrations and durations. Hearing loss was evaluated by a behavioral technique (avoidance response elicited to an auditory signal) or brainstem auditory-evoked responses (elicited by tone pips of differing loudness and frequency and detected by subdural scalp electrodes). Hearing loss, as measured by both techniques, was observed after as few as 2 weeks exposure to 1000 ppm toluene for 14 hours/day. Lower concentrations of 700 ppm for 14 hours/day were without effect after 16 weeks of exposure. Intermittent exposure to 3000 ppm for 30 minutes/hour for 8 hours/day caused hearing loss within 2 weeks, whereas a similar exposure schedule for only 4 hours/day was without effect after 9 weeks. These data define a NOAEL for hearing loss in rats of 700 ppm [NOAEL(HEC) = 2638 mg/cu.m]. The duration-adjusted HEC (assumed 5 days/week) would be 14/24 hours x 5/7 days = 1100 mg/cu.m. Although these results clearly document hearing loss in young adult rats, their direct significance to humans remains unclear. Among chronic toluene abusers there is only a single report of adverse effects on hearing; Metrick and Brenner (1982) claimed that the abnormal auditory-evoked potentials recorded in two chronic toluene abusers was evidence of brainstem abnormalities. Pregnant Wistar rats and hamsters (group size not indicated) inhaled 0 or 800 mg/cu.m toluene vapors 6 hours/day on gestational days 14-20 (rats) or gestational days 6 to 11 (hamsters) (DaSilva et al., 1990). In the exposed rats, there was a significant (p<0.05) increase in the number of litters with one or more low birth weight pups (less than 4.9 g), from 10% in the controls to 54% in the exposed dams. A decrease (p<0.05) in the number of live pups at birth was also noted in the litters of exposed dams. No evaluation of malformations or anomalies was performed. The neurobehavioral development of the offspring of the exposed rats was assessed using tests of spontaneous alternation, rim escape, and avoidance responses. The only effect noted in the rats, a shortened first trial latency in choosing one side of a maze, was minimal and its significance unclear. No comparable reproductive deficits occurred in the exposed hamsters. The only effect noted in the neurobehavioral tests of the hamster offspring was an equivocal effect in rota-rod performance. No neurobehavioral effect levels were designated from this study, although it appears that the rat developmental processes are more sensitive than those of the hamster, exhibiting adverse effects at 800 mg/cu.m. Ungvary and Tatrai (1985) exposed New Zealand rabbits (8-10/group) to 0, 500, or 1000 mg/cu.m toluene, 24 hours/day, on gestational days 7-20, and CFLP mice (15 females/group) to 0, 500, 1000, or 1500 mg/cu.m toluene, also continuously, on gestational days 6-15. The control groups consisted of 115 mice and 60 rabbits. All the female mice exposed to 1500 mg/cu.m died. In the mice exposed to 1000 mg/cu.m, there was an increase in fetuses with retarded weight (29%, level of retardation not indicated) and in fetuses with skeletal retardation (12%) compared to 7% and 5%, respectively, in the controls, which did not differ from the animals exposed to 500 mg/cu.m. Of the 8 pregnant rabbits exposed to 1000 mg/cu.m, 2 died, 4 had spontaneous abortions, and the remaining 2 had total litter resorption. No deaths occurred in the 10 rabbits exposed to 500 mg/cu.m but 1/10 rabbits had a spontaneous abortion (as compared to 0/60 reported for the controls). A NOAEL(HEC) of 500 mg/cu.m toluene was determined for reproductive effects in mice. For rabbits, the 500 mg/cu.m concentration is designated as a LOAEL. These results indicate that pregnant mice may be a sensitive population to the effects of toluene. Pregnant Charles River CD-1 mice (15-16 females/group) inhaled filtered air or 200 or 400 ppm (754 and 1508 mg/cu.m) toluene 7 hours/day on gestational days 7-16 (Courtney et al., 1986). The relative liver weight in the exposed dams was reported to be significantly lower in the two exposed groups compared to the controls, although no data were presented. A statistically significant increase in lactate dehydrogenase activity in the brain of the dams exposed to 400 ppm was also reported. The exposed pregnant mice did not exhibit any significant differences in the number of implantation sites, number of live fetuses, fetal deaths, or fetal body weight compared to the control values. A statistically significant increase over controls in the incidence (both per litter and per fetus) of enlarged renal pelves was noted in dams exposed to 200 ppm but not 400 ppm. A statistically significant alteration from controls in the rib profile (percentage of fetuses with 1 or 2 additional/fewer ribs) was reported for fetuses from dams exposed to 400 ppm but not 200 ppm. The toxicological significance of this finding is not clear. As no clearly significant toxicological effects were observed, the highest concentration used, 400 ppm [NOAEL(HEC) = 1508 mg/cu.m] is designated as a NOAEL for reproductive and developmental effects in mice. A 2-generation inhalation reproductive study was conducted in CD rats (10-40 males, 20-80 females/group) (API, 1985). Animals were exposed by whole-body inhalation to toluene at 0, 100, 500, or 2000 ppm (0, 377, 1885, or 7538 mg/cu.m, respectively) 6 hours/day, 7 days/week for 80 days and a 15-day mating period. The mated females were then exposed to the same concentrations during days 1-20 of gestation and days 5-20 of lactation. After weaning, the pups in this generation (F1) were exposed 80 times and then randomly mated with members of the same exposure group (2 females/1 male) to produce the second generation (F2). Mean male body weights were slightly reduced (maximum of 10%) in the first 2 weeks of the exposure in the animals exposed to 500 and 2000 ppm, although the size of the reduction was not related to exposure. No differences were observed in male or female fertility indices, length of gestation, mean numbers of viable and nonviable pups at birth, or pup survival indices during lactation. No abnormal histopathology was noted in organs examined. A significant decrease (p<0.05) in weight relative to controls was observed in the first generation offspring. The decrease was maintained throughout the lactation period in the pups from dams exposed to the highest exposure and in those from the ancillary group in which females exposed to the 2000 ppm concentration were mated with males having no exposure. No data were available in the report about the F2 generation. Based on the effects on the pups of the first generation (F1), a LOAEL of 2000 ppm [LOAEL(HEC) = 7538 mg/cu.m] is designated, the NOAEL being 500 ppm [NOAEL(HEC) = 1885 mg/cu.m]. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium The study of Foo et al. (1990) indicates adverse neurological effects of toluene in a small worker population. These effects are consistent with more severe CNS effects occurring at abusive concentrations of toluene and could not have been confounded by alcohol as the control and exposed populations did not use alcohol. However, the paucity of exposure information and identification of only a LOAEL is not sufficient to warrant a higher confidence than medium for this study. Other studies indicate that irritation may occur at around the same concentration, 100 ppm (Baelum et al., 1985; Echeverria et al., 1989). In regard to this effect, the NTP (1990) rat chronic inhalation study was well conducted, established the rat as the most sensitive species, examined an adequate number of animals, and performed histopathology on all major organs, including the brain and the respiratory tract. The sensitive endpoint was the concentration-dependent degeneration of the nasal epithelium characterized by the erosion of the olfactory epithelium and degeneration of the respiratory epithelium in male rats. The NTP study is also given medium confidence, however, as it did not establish a NOAEL. Although this data base has a complement of chronic laboratory animal studies, long-term data in humans are not available for either the neurotoxicity or irritation endpoints. The reproductive/developmental studies in three species were not comprehensive in endpoint evaluation but do identify the rabbit as the most sensitive species. The data base is thus given a medium confidence rating. A medium confidence rating for the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1984, 1985 Agency Work Group Review -- 04/21/1988, 05/26/1988, 02/16/1989, 03/21/1989, 05/18/1989, 08/15/1991, 12/11/1991 Verification Date -- 05/18/1989, 12/11/1991 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199402 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Toluene CASRN -- 108-88-3 Last Revised -- 02/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classified Basis -- No human data and inadequate animal data. Toluene did not produce positive results in the majority of genotoxic assays. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA A chronic (106-week) bioassay of toluene in F344 rats of both sexes reported no carcinogenic responses (CIIT, 1980). A total of 960 rats were exposed by inhalation for 6 hours/day, 5 days/week to toluene at 0, 30, 100, or 300 ppm. Groups of 20/sex/dose were sacrificed at 18 months. Gross and microscopic examination of tissues and organs identified no increase in neoplastic tissue or tumor masses among treated rats when compared with controls. The study is considered inadequate because the highest dose administered was well below the MTD for toluene and because of the high incidence of lesions and pathological changes in the control animals. Several studies have examined the carcinogenicity of toluene following repeated dermal applications. Toluene (dose not reported) applied to shaved interscapular skin of 54 male mice (strains A/He, C3HeB, SWR) throughout their lifetime (3 times weekly) produced no carcinogen1c response (Poel, 1963). One drop of toluene (about 6 mL) applied to the dorsal skin of 20 random-bred albino mice twice weekly for 50 weeks caused no skin papillomas or carcinomas after a 1-year latency period was allowed (Coombs et al., 1973). No increase in the incidence of skin or systemic tumors was demonstrated in male or female mice of three strains (CF, C3H, or CBaH) when toluene was applied to the back of 25 mice of each sex of each strain at 0.05-0.1 mL/mouse, twice weekly for 56 weeks (Doak et al., 1976). One skin papilloma and a single skin carcinoma were reported among a group of 30 mice treated dermally with one drop of 0.2% (w/v) solution toluene twice weekly, administered from droppers delivering 16-20 uL per drop for 72 weeks (Lijinsky and Garcia, 1972). It is not reported whether evaporation of toluene from the skin was prevented during these studies. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Toluene was found to be nonmutagenic in reverse mutation assays with S. typhimurium (Mortelmans and Riccio, 1980; Nestmann et al., 1980; Bos et al., 1981; Litton Bionetics, Inc., 1981; Snow et al., 1981) and E. coli (Mortelmans and Riccio, 1980), with and without metabolic activation. Toluene did not induce mitotic gene conversion (Litton Bionetics, Inc., 1981; Mortelmans and Riccio, 1980) or mitotic crossing over (Mortelmans and Riccio, 1980) in S. cerevisiae. Although Litton Bionetics, Inc. (1981) reported that toluene did not cause increased chromosomal aberrations in bone marrow cells, several Russian studies (Dobrokhotov, 1972; Lyapkalo, 1973) report toluene as effective in causing chromosal damage in bone marrow cells of rats. There was no evidence of chromosomal aberrations in blood lymphocytes of workers exposed to toluene only (Maki-Paakkanen et al., 1980; Forni et al., 1971), although a slight increase was noted in workers exposed to toluene and benzene (Forni et al., 1971; Funes-Craviota et al., 1977). This finding is supported by studies of cultured human lymphocytes exposed to toluene in vitro; no elevation of chromosomal aberrations or sister chromatid exchanges was observed (Gerner-Smidt and Friedrich, 1978). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987 The values in the 1987 Drinking Water Criteria Document for Toluene have received peer and administrative review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/15/1987 Verification Date -- 09/15/1987 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199208 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Toluene CASRN -- 108-88-3 Last Revised -- 08/01/1992 SORD: __VI.A. ORAL RfD REFERENCES CIIT (Chemical Industry Institute of Technology). 1980. A 24-month inhalation toxicology study in Fischer-344 rats exposed to atmospheric toluene. CIIT, Research Triangle Park, NC. Kostas, J. and J. Hotchin. 1981. Behavioral effects of low-level perinatal exposure to toluene in mice. Neurobehav. Toxicol. Teratol. 3: 467-469. Nawrot, P.S. and R.E. Staples. 1979. Embryo-fetal toxicity and teratogenicity of benzene and toluene in the mouse. Teratology. 19: 41A (abstr.) NTP (National Toxicology Program). 1989. Toxicology and carcinogenesis studies of toluene (CAS No. 108-88-3) in F344/N rats and B5C3F1 mice (inhalation studies). Technical Report Series No. 371. Research Triangle Park, NC. Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Notice of intended changes - toluene, trimethylamine, and vinyl acetate. Appl. Occup. Environ. Hyg. 6(11): 966-977. Andersen, I., G.R. Lundqvist, L. Molhave et al. 1983. Human response to controlled levels of toluene in six-hour exposures. Scand. J. Work Environ. Health. 9: 405-418. API (American Petroleum Institute). 1981. 26-Week inhalation toxicity study of toluene in the rat. Conducted by Bio/dynamics Inc. and Institute of Neurotoxicity, Albert Einstein College of Medicine for API, Washington, DC. API (American Petroleum Institute). 1985. Two-generation inhalation reproduction/fertility study on a petroleum-derived hydrocarbon. Doc. ID FYI-AX-0284-0294 IN. Microfiche No. 0294. Baelum, J., I. Andersen, G.R. Lundqvist et al. 1985. Response of solvent-exposed printers and unexposed controls to six-hour toluene exposure. Scand. J. Work Environ. Health. 11: 271-280. Baelum, J., G. Lundqvist, L. Molhave and N.T. Andersen. 1990. Human response to varying concentrations of toluene. Int. Arch. Occup. Environ. Health. 62(1): 65-71. Boewer, C., G. Enderlein, U. Wollgast, S. Nawka, H. Palowski, and R. Bleiber. 1988. Epidemiological study on the hepatotoxicity of occupational toluene exposure. Int. Arch. Occup. Environ. Health. 60: 181-186. Cherry, N., H. Hutchins, T. Pace and H.A. Waldron. 1985. Neurobehavioral effects of repeated occupational exposure to toluene and paint solvents. Br. J. Ind. Med. 42(5): 291-300. CIIT (Chemical Industry Institute of Toxicology). 1980. A twenty-four month inhalation toxicology study in Fischer-344 rats exposed to atmospheric toluene. Conducted by Industrial Bio-Test Laboratories, Inc., Decatur, IL, and Experimental Pathology Laboratories, Inc., Raleigh, NC, for CIIT, Research Triangle Park, NC. October 15, 1980. Courtney, K.D., J.E. Andrews, J. Springer et al. 1986. A perinatal study of toluene in CD-1 mice. Fund. Appl. Toxicol. 6: 145-154. DaSilva, V.A., L.R. Malheiros and F.M.R. Bueno. 1990. Effects of toluene exposure during gestation on neurobehavioral development of rats and hamsters. Brazil J. Med. Biol. Res. 23: 533-537. Echeverria, D., L. Fine, G. Langolf, A. Schork and C. Sampio. 1989. Acute neurobehavioral effects of toluene. Br. J. Ind. Med. 46(7): 483-495. Filley, C.M., R.K. Heaton and N.L. Rosenberg. 1990. White matter dementia in chronic toluene abuse. Neurology. 40: 532-534. Foo, S.C., J. Jeyaratnam and D. Koh. 1990. Chronic neurobehavioral effects of toluene. Br. J. Ind. Med. 47(7): 480-484. Fornazzari, L., D.A. Wilkinson, B.M. Kapur and P.L. Carlen. 1983. Cerebellar, cortical and functional impairment in toluene abusers. Acta Neurol. Scand. 67: 319-329. Gibson, J.E. and J.F. Hardisty. 1983. Chronic toxicity and oncogenicity bioassay of inhaled toluene in Fischer-344 rats. Fund. Appl. Toxicol. 3: 315-319. Guzelian, P., S. Mills and H.J. Fallon. 1988. Liver structure and function in print workers exposed to toluene. J. Occup. Med. 30(10): 791-796. Hanninen, H., M. Antti-Poika and P. Savolainen. 1987. Psychological performance, toluene exposure and alcohol consumption in rotogravure printers. Int. Arch. Occup. Environ. Health. 59(5): 475-483. Hersh, J.H., P.E. Podruch, G. Rogers and B. Weisskopf. 1985. Toluene embryopathy. J. Pediatr. 106: 922-927. Hudak, A. and G. Ungvary. 1978. Embryotoxic effects of benzene and its methyl derivatives: Toluene, xylene. Toxicology. 11: 55-63. Iregren, A. 1982. Effects on psychological test performance of workers exposed to a single solvent (toluene) - a comparison with effects of exposure to a mixture of organic solvents. Neurobehav. Toxicol. Teratol. 4(6): 695-701. Lee, B., S. Lee, K. Lee et al. 1988. Dose-dependent increase in subjective symptom prevalence among toluene-exposed workers. Ind. Health. 26(1): 11-23. McDonald, J.C., J. Lavoie, R. Cote and A.D. McDonald. 1987. Chemical exposures at work in early pregnancy and congenital defect: A case-referent study. Br. J. Ind. Medicine. 44: 527-533. Metrick, S.A. and R.P. Brenner. 1982. Abnormal brainstem auditory evoked potentials in chronic paint sniffers. Ann. Neurol. 12: 553-556. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of toluene (CAS No. 108-88-3) in F344/N rats and B6C3F1 mice (inhalation studies). NTP-TR-371. Pryor, G.T., C.S. Rebert, J. Dickinson and E.M. Feeney. 1984. Factors affecting toluene-induced ototoxicity in rats. Neurobehav. Toxicol. Teratol. 6: 223-238. Rosenberg, N.L., M.C. Spitz, C.M. Filley, K.A. Davis, and H.H. Schaumburg. 1988. Central nervous system effects of chronic toluene abuse - clinical, brainstem evoked response and magnetic resonance imaging studies. Neurotoxicol. Teratol. 10: 489-495. Ungvary, G. and E. Tatrai. 1985. On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats, and rabbits. Arch. Toxicol. Suppl. 8: 425-430. U.S. EPA. 1984. Health Effects Assessment for Toluene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, DC. EPA-600/X-84-188. U.S. EPA. 1985. Drinking Water Criteria Document for Toluene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. EPA/540/1-86-033. Von Oettingen, W.F., P.A. Neal, D.D. Donahue et al. 1942. The toxicity and potential dangers of toluene, with special reference to its maximal permissible concentration. U.S. Public Health Service, Public Health Bulletin No. 279: 50. Yin, S., G. Li, Y. Hu et al. 1987. Symptoms and signs of workers exposed to benzene, toluene or the combination. Ind. Health. 25(3): 113-130. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bos, R.P., R.M.E. Brouns, R. van Doorn, J.L.G. Theuws and P.Th. Henderson. 1981. Non-mutagenicity of toluene, o-, m- and p-xylene, o-methylbenzylalcohol and o-methylbenzylsulfate in the Ames assay. Mutat. Res. 88(3): 273-279. CIIT (Chemical Industry Institute of Toxicology). 1980. A twenty-four-month inhalation toxicology study in Fischer-344 rats exposed to atmospheric toluene. Executive Summary and Data Tables, October 15. CIIT, Research Triangle Park, NC. Coombs, M.M., T.S. Bhatt and C.J. Croft. 1973. Correlation between carcinogenicity and chemical structure in cyclopenta(a)phenanthrenes. Cancer Res. 33(4): 832-837. Doak, S.M.A., B.J.E. Simpson, P.F. Hunt and D.E. Stevenson. 1976. The carcinogenic response in mice to the topical application of propane sultone to the skin. Toxicology. 6: 139-154. Dobrokhotov, V.B. 1972. The mutagenic influence of benzene and toluene under experimental conditions. Gig. Sanit. 37: 36-39. (Rus.) (Evaluation based on an English translation provided by the U.S. EPA.) Forni, A., E. Pacifico and A. Limonta. 1971. Chromosome studies in workers exposed to benzene or toluene or both. Arch. Environ. Health. 22(3): 373-378. Funes-Craviota, F., B. Kolmodin-hedman, J. Lindsten, et al. 1977. Chromosome aberrations and sister-chromatid exchange in workers in chemical laboratories and a rotoprinting factory and in children of women laboratory workers. Lancet. 2: 322-325. Gerner-Smidt, P. and U. Friedrich. 1978. The mutagenic effect of benzene, toluene and xylene studied by the SCE technique. Mutat. Res. 58(2-3): 313-316. Lijinsky, W. and H. Garcia. 1972. Skin carcinogenesis tests of hydrogenated derivatives of anthanthrene and other polynuclear hydrocarbons. Z. Krebsforsch. Klin. Onkol. 77: 226-230. Litton Bionetics, Inc. 1981. Mutagenicity Evaluation of Toluene Mouse Dominant Lethal Assay. Final Report. Submitted to the American Petroleum Institute, Washington, DC in January, 1981. LBI Project No. 21141-05. Litton Bionetics, Inc., Kansington, MD. p. 58. Lyapkalo, A.A. 1973. Genetic activity of benzene and toluene. Gig. Tr. Prof. Zabol. 17(3): 24-28. (Rus.) (Evaluation based on an English translation provided by the U.S. EPA.) Maki-Paakkanen, J., K. Husgafvel-Pursiainen, P.L. Kalliomaki, J. Tuominen and M. Sorsa. 1980. Toluene-exposed workers and chromosome aberrations. J. Toxicol. Environ. Health. 6: 775-781. Mortelmans, K.E. and E.S. Riccio. 1980. In vitro microbiological genotoxicity assays of toluene. Prepared by SRI International, Menlo Park, CA, under Contract No. 68-02-2947 for the U.S. EPA, Research Triangle Park, NC. p. 25. Nestmann, E.R., E.G.H. Lee, T.I. Matula, G.R. Douglas and J.C. Mueller. 1980. Mutagenicity of constituents identified in pulp and paper mill effluents using the Salmonella/mammalian-microsome assay. Mutat. Res. 79: 203-212. Poel, W.E. 1963. Skin as a test site for the bioassay of carcinogens and carcinogen precursors. Natl. Cancer Inst. Monogr. 10: 611-625. Snow, L., P. MacNair and B.C. Casto. 1981. Mutagenesis testing of toluene in Salmonella strains TA100 and TA98. Report prepared for the U.S. EPA by Northrup Services, Inc., Research Triangle park, NC. U.S. EPA. 1987. Drinking Water Criteria Document for Toluene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Toluene CASRN -- 108-88-3 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.4. Text revised 09/07/1988 II. Carcinogen summary on-line 02/01/1989 II.D.3. Secondary contact's phone number corrected 07/01/1989 I.B. Inhalation RfD now under review 03/01/1990 VI. Bibliography on-line 04/01/1990 VI.C. Combs et al., 1973 citation corrected 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 07/01/1990 I.A. Withdrawn; new RfD verified (in preparation) 07/01/1990 VI.A. Oral RfD references withdrawn 08/01/1990 I.A. Oral RfD summary replaced; RfD changed 08/01/1990 II. Text edited 08/01/1990 VI.A. Oral RfD references revised 09/01/1990 III.A. Health Advisory on-line 09/01/1990 VI.D. Health Advisory references added 08/01/1991 VI.C. Litton Bionetics, Inc., 1981 reference title clarified 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 08/01/1992 I.B. Inhalation RfC on-line 08/01/1992 VI.B. Inhalation references on-line 02/01/1994 II.D.3. Secondary contact's phone number changed 04/01/1994 I.A.7. Primary contact changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 02/22/2001 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 379 of 1119 in IRIS (through 2003/06) AN: 125 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199612 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Vanadium-pentoxide- SY: 1314-62-1; CI-77938-; DIVANADIUM-PENTAOXIDE-; DIVANADIUM-PENTOXIDE-; VANADIC-ANHYDRIDE-; VANADIUM-OXIDE-; VANADIUM-PENTAOXIDE- RN: 1314-62-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199612 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Vanadium pentoxide CASRN -- 1314-62-1 Last Revised -- 12/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Decreased hair NOAEL: 17.85 ppm 100 1 9E-3 cystine converted to 0.89 mg/kg/day mg/kg/day Rat Chronic Oral Study LOAEL: none Stokinger et al., 1953 ---------------------------------------------------------------------------- *Conversion Factor: Adult rat food consumption assumed to be 5% bw/day. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Stokinger, H.E., W.D. Wagner, J.T. Mountain, F.R. Stacksill, O.J. Dobrogorski and R.G. Keenan. 1953. Unpublished results. Division of Occupational Health, Cincinnati, OH. (Cited in Patty's Industrial Hygiene and Toxicology, 3rd ed., 1981) In this chronic study, an unspecified number of rats were exposed to dietary levels of 10 or 100 ppm vanadium (about 17.9 or 179 ppm vanadium pentoxide) for 2.5 years. The results of this unpublished study were summarized by Stokinger et al. (1981). The criteria used to evaluate vanadium toxicity were growth rate, survival, and hair cystine content. The only significant change reported was a decrease in the amount of cystine in the hair of animals ingesting vanadium. Of the subchronic and chronic animal studies available, the lower dose level (17.9 ppm vanadium pentoxide) reported in the Stokinger et al. (1953) study is the highest oral NOAEL upon which an RfD can be derived. An oral RfD of 0.009 mg/kg/day (0.62 mg/day for a 70-kg person) can be calculated by assuming that rats eat food equivalent to 5% of their body weight and by applying an uncertainty factor of 100. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 100 was applied, 10 for interspecies extrapolation and a factor of 10 to provide added protection for unusually sensitive individuals. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) In a subchronic feeding study (Mountain et al., 1953), groups of five male Wistar rats were fed vanadium pentoxide at levels of 0, 25, or 50 ppm for 35 days, after which dietary levels of vanadium were increased to 100 and 150 ppm and continued for 68 days. There was a decrease in the amount of cystine in the hair of the high-dosed (50-150 ppm or 2.5-7.5 mg/kg/day, based on food consumption of 5% bw) rats. A significant decrease was also reported in erythrocyte and hemoglobin levels of the high-dosed rats. In an abstract of a subchronic inhalation study (Suguira, 1978), mice and rats exposed to 1 to 3 mg/cu.m vanadium pentoxide for 3 months, 6 hours/day developed histopathologic changes in their lungs and had a decrease in growth rate. Adverse effects were not detected in either species similarly exposed at 0.1 to 0.4 mg/cu.m. Although several epidemiologic studies have been conducted on factory workers exposed to vanadium pentoxide for several years, the air concentration levels of vanadium pentoxide were measured only at scattered intervals, making it impossible to determine a minimum effective dose. Also, in cases of humans exposed to relatively high atmospheric concentrations of vanadium pentoxide for short periods of time, all individuals developed respiratory symptoms that usually subsided within 7-14 days. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low Because of the lack of details in the reference study and the scarcity of data available on vanadium pentoxide, low confidence is assigned to both the study and the data base. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 02/26/1986 Verification Date -- 02/26/1986 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Vanadium pentoxide conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Vanadium pentoxide CASRN -- 1314-62-1 NORC: Not available at this time. ============================================================================ UDCA: 198806 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Vanadium pentoxide CASRN -- 1314-62-1 NOCA: The NTP (1985) has approved vanadium pentoxide for carcinogenicity testing; however, the route of administration has not been determined (i.e., oral, inhalation). ============================================================================ UDSO: 199106 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Vanadium pentoxide CASRN -- 1314-62-1 Last Revised -- 06/01/1991 SORD: __VI.A. ORAL RfD REFERENCES Mountain, J.T., L.L. Delker and H.E. Stokinger. 1953. Studies in vanadium toxicology. Arch. Ind. Hyg. Occup. Med. 8: 406-411. Stokinger, H.E. 1981. The metals: Vanadium. In: Patty's Industrial Hygiene and Toxicology, 3rd revised ed., Vol. 2A, G.D. Clayton and F.E. Clayton, Eds. John Wiley and Sons, Inc., New York. p. 2013-2033. Stokinger, H.E., W.D. Wagner, J.T. Mountain, F.R. Stocksill, O.J. Dobrogorski and R.G. Keenan. 1953. No title given. Unpublished results. Division of Occupational Health, Cincinnati, OH. (Cited in: Patty's Industrial Hygiene and Toxicology, 3rd ed., 1981). Sugiura, S. 1978. Inhalation toxicity of vanadium pentoxide dust in rats and mice. Shikoku Igaku Zasschi. 34(5): 209-219. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Vanadium pentoxide CASRN -- 1314-62-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/31/1987 I.A.6. Documentation corrected 06/30/1988 I.A.1. NOAEL and RfD corrected 06/30/1988 I.A.2. Dose levels corrected 06/30/1988 I.A.4. Last paragraph moved to Section II 06/30/1988 II. NTP status specified 06/01/1991 VI. Bibliography on-line 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 12/01/1996 I.A.7. Secondary contact removed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 380 of 1119 in IRIS (through 2003/06) AN: 139 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for IRIS support document for this chemical http://www.epa.gov/iris/supdocs/buta-sup.pdf UD: 200211 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,3-Butadiene- SY: 106-99-0; BIETHYLENE-; BIVINYL-; BUTADIEEN-; BUTA-1,3-DIEEN-; BUTADIEN-; BUTA-1,3-DIEN-; BUTADIENE-; BUTADIENE,-1,3-; ALPHA,GAMMA-BUTADIENE-; DIVINYL-; ERYTHRENE-; NCI-C50602-; PYRROLYLENE-; VINYLETHYLENE- RN: 106-99-0 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,3-Butadiene CASRN -- 106-99-0 Last Revised -- 11/05/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: An oral RfD is not calculated because 1,3-butadiene is a gas and causes hazard by inhalation only. The hazard by ingestion is unlikely since 1,3-butadiene is poorly soluble in water. When released in water, 1,3-butadiene rapidly evaporates. ---------------------------------------------------------------------------- UDRC: 200211 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,3-Butadiene CASRN -- 106-99-0 Last Revised -- 11/05/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: ------------------------------------------------------------------------------ SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC ------------------- ------------------- ---- -- ---- Ovarian atrophy BMCL10 = 0.88 ppm (HEC) 1000 1 0.9 ppb (BMC10 = 1.0 ppm) (2 x 10-3; mg/m3) 2-year mouse inhalation study (NTP, 1993) ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- ppm equivalence across species was assumed (this is the same as using EPA's inhalation dosimetry methodology with RGDRr=1 [U.S. EPA, 1994]); exposure concentrations were adjusted to 24-hour continuous daily exposure for the exposure period (i.e., exposure concentration x [6/24] x [5/7]). 1 ppm = 2.25 mg/m3. A variety of reproductive and developmental effects have been observed in mice exposed to 1,3-butadiene by inhalation (U.S. EPA, 2002, Chapter 5). There are no human data on reproductive or developmental effects. Few adverse noncancer effects, other than reproductive and developmental effects, have been observed, except for hematological effects in mice exposed to higher concentrations (U.S. EPA, 2002, Section 6.1). The most sensitive short-term developmental endpoint was decreased fetal weight in the mouse. Decreases were observed at the lowest exposure concentration (40 ppm, 6 hours/day, gestation days 6-15); thus there was not a no-observed-adverse-effect level (NOAEL) for this effect (Hacket et al., 1987). No developmental toxicity was observed in rats. The most sensitive reproductive endpoint observed in subchronic exposure studies was fetal deaths in dominant lethal studies of mice (i.e., male mice were exposed to 1,3-butadiene and effects on litters were measured after mating to unexposed females) (Anderson et al., 1998; Brinkworth et al., 1998; Anderson et al., 1993; Adler and Anderson, 1994). Significant dominant lethal effects were observed at exposures of 65 ppm, 6 hours/day, 5 days/week, for 4 weeks. (The 12.5 ppm exposure level was a NOAEL.) Dominant lethal effects in humans would likely be manifested as infertility (due to reduced fertility or very early deaths) or spontaneous abortions. The dominant lethal responses are believed to represent a genotoxic effect. From chronic exposure studies (2-year bioassays; NTP, 1993), the most sensitive reproductive effects were ovarian atrophy in female mice and testicular atrophy in male mice. Testicular atrophy was primarily a high-exposure effect. Ovarian atrophy, on the other hand, was observed at the lowest exposure level (6.25 ppm, 6 hours/day, 5 days/week, for 2 years). Uterine atrophy was also observed in the highest exposure groups; however, this is likely to be a secondary effect of the ovarian atrophy. The mechanisms of ovarian atrophy are unknown, although there is strong evidence that the effect is mediated by the diepoxide metabolite (U.S. EPA, 2002, Chapter 5). PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) The chronic RfC of 0.9 ppb is based on ovarian atrophy. A BMCL10 (0.88 ppm) was calculated from data from the 1993 NTP 2-year inhalation bioassay, including interim kill data, using benchmark concentration methodology (Weibull time-to-response model). In this bioassay, groups of 70 female B6C3F1 mice were exposed by inhalation 6 hours/day, 5 days/week to 0, 6.25, 20, 62.5, or 200 ppm 1,3-butadiene for up to 103 weeks; groups of 90 female mice were exposed to 625 ppm. Interim evaluations were conducted at 9 and 15 months on up to 10 mice per group. Significant concentration-related decreases in survival were seen in female mice exposed to concentrations >= 20 ppm, primarily due to the development of malignant neoplasms. Statistically significant increases in the incidence of ovarian atrophy were observed in all exposure groups, including the lowest exposure group (6.25 ppm), following lifetime exposures. In calculating the BMC10 and BMCL10, lesion severity was not taken into account, and the 625 ppm group was excluded because of high early mortality. In addition, ovarian atrophy was modeled to reflect extra risks only until age 50, because 1,3-butadiene-induced ovarian atrophy is believed to result from follicular failure, and after menopause, follicles would no longer be available. Exposure concentrations were converted to 24-hour exposures by multiplying by (6/24) and (5/7). Benchmark dose modeling and sample RfC calculations were also conducted for the endpoints of fetal weight (7 ppb), dominant lethal effects (20 ppb), and testicular atrophy (20 ppb) (U.S. EPA, 2002, Sections 10.3 and 10.4). Ovarian atrophy was selected as the critical effect because it yielded the lowest RfC. Ovarian atrophy also had the lowest BMC10 and was reported in a high-quality 2-year study. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 1000. For ovarian atrophy, the uncertainty/modifying factors were: 3 for interspecies extrapolation, 10 for intraspecies variability, 3 for incomplete database, and 10 for extrapolation to a level below the 10% effect level (analogous to the LOAEL-to-NOAEL extrapolation factor). The BMCL10 was estimated from a chronic bioassay; therefore, an acute/subchronic-to-chronic factor was not required. The factor of 10 used for effect level extrapolation was derived from a formula * that takes into account the benchmark response level as well as the slope of the exposure-response model at the benchmark concentration. However, because the model was supralinear at the BMC10, a maximum factor of 10 for the 10% response level was used (U.S. EPA, 2002, Chapter 10). EPA is planning to develop guidance for applying an effect level extrapolation factor to a benchmark dose; the formula mentioned above was used in the interim. An extrapolation factor for effect level is applied because the 10% response level used as the point of departure is an adverse effect level. Therefore, a factor analogous to the LOAEL-to-NOAEL factor is needed to attempt to extrapolate to a level closer to a no effect level. The default factors of 3 for interspecies extrapolation for inhalation exposures and of 10 for intraspecies variability were used. There is strong evidence that the diepoxide metabolite (1,2:3,4-diepoxybutane, DEB) is required to elicit ovarian atrophy (U.S. EPA, 2002, Chapter 5), and it is expected, based on pharmacokinetic data, that humans produce less DEB than mice (U.S. EPA, 2002, Chapter 3). However, DEB levels cannot be quantified without an adequate physiologically based pharmacokinetic (PBPK) model. Thus, default dosimetry (i.e., 1,3-butadiene exposure concentration) was used for dose-response modeling, and the default value of 1 for the pharmacokinetic portion of the interspecies uncertainty factor for inhalation exposures was retained. Finally, a factor of 3 was used to reflect an incomplete database, in particular the absence of a multigeneration study and a developmental neurotoxicity study. Dividing the BMCL10 of 0.88 ppm by the composite UF of 1000 yields 0.9 ppb. MF = 1. * The formula is as follows: uncertainty factor = y x [(slope of the line from the BMCy to 0)/(slope of the dose-response curve at the BMCy)], where y% is the response level. Results of the formula are confined within a minimum value of 3 and a maximum value of y. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) A subchronic inhalation study showed that just 13 weeks of exposure to 1,000 ppm 1,3-butadiene was also sufficient to induce ovarian atrophy in female B6C3F1 mice (Bevan et al., 1996). In addition to deriving the chronic RfC, the Health Assessment Document also provides reference concentration values for acute and subchronic exposure scenarios, based on the mouse fetal weight data of Hackett et al. (1987) (see U.S. EPA, 2002, Chapter 10, Sections 10.3.2 and 10.4). These reference concentration values are not currently part of the IRIS file. The EPA closely examined the physiologically-based pharmacokinetic (PBPK) models for 1,3-butadiene to determine if additional modeling could reduce uncertainties in the interspecies scaling between mice and humans for ovarian atrophy and other endpoints (U.S. EPA, 2002, Chapter 9). Despite advances in the models over the past decade, the current models are inadequate for this purpose. For example, the PBPK models do not yet accurately describe the distribution of the major metabolites in various compartments, they do not yet include the reportedly important epoxydiol metabolite, and they have not been adequately validated. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Database -- High RfC -- Medium The overall confidence in this RfC assessment is medium. The RfC calculation was based on data from a high-quality NTP 2-year bioassay in which many exposure levels were used, although a NOAEL was not achieved. On the other hand, rat studies showed no such evidence of reproductive and developmental effects, and there are no human data on these effects; thus, it is uncertain how humans would respond. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 2002 This assessment was peer reviewed by external scientists (the Science Advisory Board). Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 2002. Other documentation -- U.S. EPA, 1985 Agency Consensus Date -- 9/13/2001 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS in general at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ============================================================================ UDCA: 200211 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,3-Butadiene CASRN -- 106-99-0 Last Revised -- 11/05/2002 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION This weight-of-evidence carcinogenicity classification and quantitative estimate of carcinogenicity from inhalation exposure replace the previous classification of "B2; probable human carcinogen," and inhalation unit risk of 2.8 x 10-4 per ug/m3, entered on IRIS on March, 31, 1987. The new classification and unit risk estimate are based on more recent data. Under EPA's 1999 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), 1,3-butadiene is characterized as carcinogenic to humans by inhalation. This characterization is supported by the total weight of evidence provided by the following: (1) sufficient evidence from epidemiologic studies of the majority of U.S. workers occupationally exposed to 1,3-butadiene, either to the monomer or to the polymer by inhalation, showing increased lymphohematopoietic cancers and a dose-response relationship for leukemias in polymer workers (see Section II.A.2), (2) sufficient evidence in laboratory animal studies showing that 1,3-butadiene causes tumors at multiple sites in mice and rats by inhalation (see Section II.A.3), and (3) numerous studies consistently demonstrating that 1,3-butadiene is metabolized into genotoxic metabolites by experimental animals and humans (see Section II.A.4). The specific mechanisms of 1,3-butadiene-induced carcinogenesis are unknown; however, the scientific evidence strongly suggests that the carcinogenic effects are mediated by genotoxic metabolites of 1,3-butadiene, i.e., the monoepoxide, the diepoxide, and the epoxydiol. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA There is "sufficient evidence" from epidemiologic studies of exposed workers to consider 1,3-butadiene carcinogenic to humans. The exposure to 1,3-butadiene occurs in monomer production workers who produce 1,3-butadiene as a raw material or in polymer production workers who use 1,3-butadiene in styrene-butadiene rubber (SBR) production. Excesses of lymphohematopoietic cancers have been observed in 1,3-butadiene polymer production workers and monomer production workers in North America. A significant excess of leukemias was observed in polymer production workers, and significant excesses of non-Hodgkin's lymphomas (previously diagnosed as lymphosarcoma and reticular sarcoma, but now included in non-Hodgkin's lymphomas [NHL] per the new classification in the International Classification of Diseases of Oncology [ICD-O]) have been observed in monomer workers. Under the previous, as well as the current, classification system adopted by the Revised European-American Lymphoma (REAL) and the Leukemia Society of America (*), both leukemia and lymphoma are lymphohematopoietic cancers, and thus the lymphohematopoietic system is considered to be the target organ for 1,3-butadiene. The strongest evidence is provided by a retrospective cohort study of over 15,000 SBR workers in 8 plants studied by the University of Alabama at Birmingham (UAB cohort), with 49 years of follow-up (Delzell et al., 1996). Quantitative exposures (cumulative and peak) to 1,3-butadiene, styrene, and benzene were estimated for each worker (Macaluso et al., 1996). Limited validations of exposure estimates were attempted by various means. Significant excesses ranging from 43% to 336% were found for leukemia in ever hourly workers as compared with the general population, after adjusting for styrene and benzene. An internal comparison, using estimated ppm-years of 1,3-butadiene exposure, resulted in increasing risk ratios for leukemia with increasing exposures. This trend was statistically significant. A fairly consistent association between exposure to 1,3-butadiene and occurrence of leukemia across the six plants for which subanalyses were done was also found. The major strengths of this study are the detailed and comprehensive quantitative exposure estimations for 1,3-butadiene, styrene, and benzene for each individual. The cohort was also large, and there was a long follow-up period of 49 years. In addition, both external and internal comparison showed similar results, adjustments for potential confounding factors were carried out, and analyses by duration of employment and for latency were conducted. The study had some limitations. Some misclassifications of exposure may have occurred with respect to certain jobs, but these are unlikely to have occurred only in leukemia cases because the exposures were calculated a priori. Furthermore, the excess mortality observed for leukemia was based on death certificates and was not verified by medical records, thus, there may be misclassification of diagnosis. The histologic typing of leukemia was also not available, so currently it is not known whether a single cell type or more than one cell type is associated with the exposure to 1,3-butadiene. Two plants were eliminated from the final analysis due to the lack of work histories, which may have resulted in the loss of valuable data. Finally, an issue has been raised of potential confounding exposure to dithiocarbamates (DTC) (Irons and Pyatt, 1998). DTCs have been in use since the early 1940s as fungicides and treatments for parasitic skin diseases. The DTC disulfiram has also been in use since the early 1940s for the treatment of alcoholism. So far, there is not even a case report of leukemia in the literature in reference to any of the DTCs. In addition, available animal studies have not provided any evidence that DTCs cause carcinogenesis. Hence, at this time, it is conjecture that DTCs are causally associated with leukemia and, therefore, confound the results of Delzell et al. Additional evidence is provided by the earlier cohort study of some of these polymer workers (13,500 individuals; Johns Hopkins University [JHU] cohort)3 conducted by Matanoski and Schwartz (1987), as well as a nested case-control study by Santos-Burgoa et al. (1992). A significant excess of lymphohematopoietic cancer, but not of leukemia, was observed in the cohort study, while a significantly increased odds ratio of 7 for leukemia was observed in a nested case-control study, as was a significant trend of increasing risk of leukemia with increasing exposure level of 1,3-butadiene. For 1,3-butadiene monomer production workers, two of three different cohort studies found significant increased risk of NHL (previously classified as lymphosarcoma and reticulosarcoma) (Divine and Hartman, 1996; Ward et al., 1995). The third study (Cowles et al., 1994) was small and had shorter follow-up times. The strongest evidence of human carcinogenicity from monomer production worker studies is provided by the largest cohort of approximately 2,800 workers in a Texaco plant studied by several investigators (Downs et al., 1987; Divine and Hartman, 1996). The only significant excess mortality observed was for lymphosarcoma (now included in NHL) in the wartime subcohort of workers (154% to 169% higher than the general population). The investigators estimated exposures for each individual in their last follow-up (Divine and Hartman, 1996) and found that, except for an excess observed for NHL (76% higher than the general population) in the wartime subcohort, there were no excesses in any cause-specific cancer mortality. The major strengths of this study are a relatively large cohort of monomer workers, a long follow-up period of 52 years, analyses by duration of employment and latency, and adjustment for potential confounding factors. The exposures in each individual were estimated in the last follow-up. Except for "hire-age"4 in survival analysis using the Cox model, after 52 years of follow-up, this study did not find any statistically significant excess in leukemia (as was observed in polymer workers), although an increase of 13% was reported. This study may not have enough statistical power to detect a significant leukemia increase. Some of the limitations of the study are a lack of data or means available to the investigators to estimate the peak exposures that were hypothesized to be associated with the observed increase in lymphosarcomas in wartime workers. The authors' claim of the existence of extremely high peak exposures during the 1950s and 1960s cannot be validated in the absence of any information about the frequency or the variations in intensity of peak exposures for these different time periods (as compared to prior to the 1950s). Although the cohort is relatively large, it had low power to detect excess leukemias. Nonetheless, the finding of excess mortality from lymphosarcoma is consistent with the findings of Ward et al. (1995). Ward et al. (1995) studied a small cohort of 364 individuals who had potential exposure to 1,3-butadiene at three Union Carbide plants. A statistically significant excess for lymphosarcoma (477% higher than the general population) was found based on 4 cases. The main limitations of this study are that the cohort was small and that exposures were assumed based on department codes. In addition, there was no analysis for latency or adjustment for potential confounding by exposure to other chemicals. These monomer and polymer production worker cohorts demonstrate an excess number of lymphohematopoietic cancers in occupationally exposed workers. Increased NHL (lymphosarcomas) are reported for monomer production workers, whereas excess leukemias occur predominantly in polymer production workers. There are several possible explanations for this apparent difference between the monomer and polymer workers. It has been hypothesized that the observed excess of NHL (lymphosarcomas) in the monomer production workers may be related to exposure intensity, i.e., the excess risk may result from the high (peak) exposures during wartime, rather than the much lower exposures currently encountered by monomer production workers or the likewise comparatively lower exposures encountered by the polymer production workers. The absence of a significant leukemia excess in these same monomer workers may be attributable to low statistical power in the monomer studies. There is some suggestion of excess leukemias in the monomer production workers, although these were not statistically significant. The Union Carbide cohort had a leukemia excess of 23% based on 2 cases, and the Texaco cohort had an elevated risk of leukemias of 13% based on 13 cases (it should be noted though, that with every follow-up of the Texaco cohort, investigators have observed additional leukemia deaths). Even the Texaco cohort, a relatively large monomer production cohort, has low power to detect a statistically significant excess for leukemias, and with every follow-up, the investigators of the Texaco cohort increased the calendar period for the worker inclusion criteria. This added many younger workers with little cumulative exposure, shorter follow-up periods, and inadequate latency periods, thereby diluting the risk. In addition, 1,3-butadiene is produced at the end of the monomer production process, and current 1,3-butadiene exposures are very low in these workers. In fact, the apparent difference between monomer and polymer workers may be largely an artifact. Under the latest classification system for lymphohematopoietic cancers, all lymphomas not classified as Hodgkin's disease are now included under NHL (see footnote 1). Using this classification, an excess of NHL of 37% (based on 15 cases; not statistically significant) was reported for workers who had worked >= 10 years and with >= 20 years since hire in the UAB (polymer) cohort (Sathiakumar et al., 1998). (Previously lymphosarcomas and NHL were reported separately for this cohort.) Furthermore, as these investigators report, their evaluation of NHL relations was limited by their reliance on death certificates. NHL has high survival rates and may, in later clinical stages, transform into leukemia. Therefore, leukemia may be reported on the death certificates. In addition, as discussed above, nonsignificant excesses of leukemia were observed in two monomer studies. Thus, excesses of both leukemia and NHL have been observed for both monomer and polymer workers, and it may be that the increased risk of NHL is primarily observed among workers exposed to high concentrations of 1,3-butadiene (mostly wartime monomer workers), whereas the polymer production studies have greater power to detect a significant leukemia excess among SBR workers who have modest to low exposures. In any event, leukemias and NHL are related tumor types and can both be classified as lymphohematopoietic cancers (see footnote 1). Finally, an alternate explanation is that the monomer workers may lack exposure to a necessary co- or modifying factor that may be present in polymer production, resulting in the development of leukemias, although the findings of Delzell et al. (1996) and Macaluso et al. (1996) show no evidence of confounding by exposure to other chemicals. In summary, the findings of excess lymphohematopoietic cancers in polymer and monomer production workers are consistent with a causal association with exposure to 1,3-butadiene. As demonstrated above, the causality criteria of temporality, strength of association, specificity, biological gradient, and consistency are satisfied. In addition, as discussed in the next sections, 1,3-butadiene is metabolized by humans and other species to genotoxic metabolites and is carcinogenic in mice and rats, thus fulfilling the criterion of biological plausibility as well. Therefore, the human evidence is considered sufficient. (*) Under the previous classification (8th ICD, Adapted), lymphohematopoietic cancers comprised the following subcategories: lymphosarcoma and reticular sarcoma, Hodgkin's disease, leukemia, and other lymphatic tissue cancers. In 1994, the International Lymphoma Group's Revised European-American Lymphoma (REAL) classification was proposed for the lymphohematopoietic cancers, and is being adopted into the ICD-O (Berard and Hutchison, 1997). This classification is based on new ideas evolving in the fields of molecular biology, genetics, and immunology, which have rendered the old classification for lymphohematopoietic cancers obsolete. The REAL classification comprises the following subcategories: B-cell neoplasms, T-cell and putative natural killer (NK)-cell neoplasms, Hodgkin's disease, and unclassified lymphomas. It should be noted that both leukemias and lymphomas that are produced by B-cells are included under B-cell neoplasms, and leukemias and lymphomas produced by T-cells and NK-cells are included under T-cell and NK-cell neoplasms. Any lymphoma (such as B-cell, T-cell, and NK-cell) that is not classified as Hodgkin's disease is included under non-Hodgkin's lymphoma. Furthermore, the Leukemia Society of America defines lymphohematopoietic cancers as follows: "Leukemia, Lymphoma, Hodgkin's disease, and Myeloma are cancers of the body's blood forming and immune systems: the bone marrow and lymph nodes. They are considered to be related cancers because they involve the uncontrolled growth of cells with similar functions." 3 One Canadian plant and six U.S. plants were common in the JHU and the UAB cohorts. 4 Survival analyses were conducted by the investigators using three different methods in their last follow-up. Two different risk factors were used for these analyses ([1] Exposure, i.e., cumulative exposure, and [2] Hire-age, i.e., age at which the employee was hired) to calculate risks for all lymphohematopoietic cancer, leukemia, lymphosarcoma, NHL, and multiple myeloma. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Several chronic inhalation bioassay studies have been conducted with 1,3-butadiene: a 2-year rat study (Hazleton Laboratories Ltd., 1981; Owen et al., 1987); two lifetime mouse studies (NTP, 1984, 1993), the first terminated early because of excessive mortality and the second using lower exposure concentrations; a 2-year stop-exposure study with male mice (NTP, 1993); and a 1-year study comparing the induction of thymic lymphomas in two different strains of male mice (Irons et al., 1989). These studies provide unequivocal evidence that 1,3-butadiene is a multisite carcinogen in both rats and mice, with the mouse being significantly more sensitive than the rat. In the most recent mouse study (NTP, 1993), groups of 70 male and 70 female B6C3F1 mice were exposed by inhalation 6 hours/day, 5 days/week to 0, 6.25, 20, 62.5, or 200 ppm 1,3-butadiene for up to 103 weeks, while groups of 90 male and 90 female mice were exposed to 625 ppm. Interim evaluations were conducted at 9 and 15 months on up to 10 mice per group. Significant concentration-related decreases in survival were seen in male and female mice exposed to concentrations >= 20 ppm, primarily due to the development of malignant neoplasms. Significant concentration-related increases in survival-adjusted incidences were observed for the following primary neoplasms in both males and females: malignant lymphomas; histiocytic sarcomas; heart hemangiosarcomas; alveolar/bronchiolar adenoma, carcinoma, or adenocarcinomas; and forestomach squamous cell papilloma or carcinomas. Female mice also exhibited significant concentration-related increases in survival-adjusted incidences of benign or malignant granulosa cell tumors (ovary) and of adenocanthoma, carcinoma, or malignant mixed tumors of the mammary gland. Other tumor types that showed significant increases in some exposure groups versus controls for male and/or female mice were hepatocellular adenoma or carcinomas, Harderian gland adenoma or carcinomas, and preputial gland carcinomas. The most sensitive site was the female mouse lung, which exhibited significantly increased tumor incidence at the lowest exposure concentration tested (6.25 ppm). In the sole rat study (Hazleton Laboratories Ltd., 1981), Charles River CD rats (110/sex/group) were exposed by inhalation to 0, 1,000, or 8,000 ppm 1,3-butadiene 6 hours/day, 5 days/week for up to 111 weeks. There was a treatment-related increase in mortality, some of which was attributed to nephropathies in males. In exposed females, significant increases occurred in incidences of mammary gland carcinoma or fibroadenomas and thyroid follicular cell adenoma or carcinomas. In exposed males, there were also significant increases in thyroid follicular cell tumors, as well as in Leydig cell tumors and pancreatic exocrine adenomas. Although not significant by pairwise comparisons, significant exposure-response trends were observed for Zymbal gland carcinomas and uterine stromal sarcomas in females and for brain gliomas in males. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY 1,3-Butadiene is metabolized to at least three genotoxic metabolites: a monoepoxide (1,2-epoxy-3-butene, EB), a diepoxide (1,2:3,4-diepoxybutane, DEB), and an epoxydiol (3,4-epoxy-1,2-butanediol, EBD) (Himmelstein et al., 1997; Melnick and Kohn, 1995). Although there are quantitative differences in the metabolic rates for various pathways between different species, the metabolism of 1,3-butadiene is qualitatively similar among species. The enzymes responsible for the metabolic activation of 1,3-butadiene to these epoxide metabolites, as well as the enzymes responsible for the detoxification of these reactive metabolites, exist in humans as well as mice and rats. The genetic toxicology literature on 1,3-butadiene, EB, and DEB consists of more than 450 publications with positive genotoxic findings in viruses, bacteria, plants, and animals. EBD has been less extensively studied, but recent evidence suggests that most of the trihydroxybutyl-guanine adducts in mice and rats exposed to 1,3-butadiene are derived from EBD (Koc et al., 1999). In addition, 1,3-butadiene is structurally related to other (rodent) carcinogens, such as isoprene and chloroprene (NTP, 1997; Melnick et al., 1996; NTP, 1998). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. 1,3-Butadiene is a gas at room temperature and pressure, making oral exposure unlikely. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 3E-5 per (ug/cu.m) Extrapolation Method -- linear extrapolation from LEC01 (0.254 ppm); LEC01 derived from linear relative rate model (RR = 1 + bX) using lifetable analysis with leukemia incidence data; an adjustment factor of 2 was applied (see below). Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- --------------- E-4 (1 in 10,000) 3 ug/cu.m E-5 (1 in 100,000) 0.3 ug/cu.m E-6 (1 in 1,000,000) 0.03 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE The Delzell et al. (1995) retrospective cohort study of more than 15,000 male styrene-butadiene rubber production workers provides high-quality epidemiologic data on leukemia risk from 1,3-butadiene exposure. In the Delzell et al. study, 1,3-butadiene exposure was estimated for each job and work area for each study year, and these estimates were linked to workers' work histories to derive cumulative exposure estimates for each individual worker. Subsequent to the Poisson regression analyses by Delzell et al., which used four different mathematical models (linear, log-linear, power, and square root) to fit the exposure-response data, Health Canada obtained the data on this cohort and performed their own analyses. The Health Canada (1998) analyses were similar to those of Delzell et al., but involved some minor refinements (e.g., finer stratification of age and other modifying variables, and use of the actual mean exposure in the highest exposure group rather than an arbitrary value). It is the Health Canada analyses that are used for this risk assessment. The linear relative rate model reported by Health Canada was RR = 1 + 0.0099X, where X represents cumulative 1,3-butadiene exposure in ppm-years. The results were adjusted for age, calendar period, years since hire, and cumulative styrene exposure. Benzene exposure was also estimated for each worker but was not found to be a confounder, and hence, was not included in the models. Risk estimates were made using the relative rate models and an actuarial program that accounts for the effects of competing causes of death. U.S. age-specific mortality rates for all race and gender groups combined (NCHS, 1993) were used to specify the leukemia and all-cause background rates. Risks were computed up to age 85 for continuous 1,3-butadiene exposures. The occupational exposures in the epidemiology study were converted to continuous exposures by adjusting for the differences in the number of days exposed per year (240/365 days) and differences in the amount of contaminated air inhaled per day (10/20 m3). (10 m3 is the default occupational ventilation volume for an 8-hour work shift; 20 m3 is the default 24-hour ambient ventilation volume [U.S. EPA, 1994]). Interpreting the proposed new carcinogen risk assessment guidelines (U.S. EPA, 1999), linear extrapolation from the LEC01 (i.e., the 95% lower confidence limit of the exposure concentration associated with a 1% increased risk) is warranted given the clear genotoxicity of 1,3-butadiene and the fact that a 1% increase in risk is within the range of the epidemiologic data. Using the linear relative rate model for modeling the epidemiologic data in the range of observation yields an LEC01 of 0.375 ppm. Using the LEC01 as the point of departure and extrapolating linearly to 0 increased risk at 0 exposure, a unit risk estimate of 0.03/ppm is obtained for the risk of leukemia mortality from the occupational data. However, we actually wish to estimate cancer incidence, not mortality; therefore, another calculation was done using the linear relative rate model and age-specific leukemia incidence rates for 1994-1998 from SEER (Surveillance, Epidemiology and End Results program of the National Cancer Institute; NCI, 2001) in place of the leukemia mortality rates in the actuarial program. This calculation assumes that leukemia incidence and mortality have the same exposure-response relationship for 1,3-butadiene exposure and that the incidence data are for first occurrences of leukemia or that relapses provide a negligible contribution. The calculation also relies upon the fact that the leukemia incidence rates are small compared to the all-cause mortality rates. The result is an LEC01 of 0.254 ppm and a unit risk estimate of 0.04/ppm for leukemia incidence. An adjustment factor of 2 was then applied to this unit risk estimate to reflect evidence from rodent bioassays suggesting that extrapolating the excess risk of leukemia in a male-only occupational cohort may underestimate the total cancer risk from 1,3-butadiene exposure in the general population. First, studies in both rats and mice indicate that 1,3-butadiene is a multisite carcinogen. It is possible that humans exposed to 1,3-butadiene may also be at risk of cancers other than leukemia and that the epidemiologic study had insufficient power to detect excess risks at other sites (see below). Second, both the rat and mouse studies suggest that females are more sensitive to 1,3-butadiene-induced carcinogenicity than males, and the female mammary gland was the only 1,3-butadiene-related tumor site common to both species. The mammary tumor unit risk estimated from the female mouse (most sensitive species) data is just slightly lower (maximum likelihood estimate [MLE] = 0.02/ppm, 95% upper confidence limit [UCL] = 0.03/ppm) than the human (male) leukemia risk (0.04/ppm based on linear extrapolation from the LEC01). Thus, EPA decided to apply an adjustment factor of 2 to the leukemia risk estimate, resulting in a unit risk estimate of 0.08/ppm intended to cover the combined risks for leukemia and mammary cancer and to provide additional protection to account for the fact that small increases in risk at other sites, particularly the lung, cannot be ruled out. The Delzell et al. study was a large cohort study (over 15,000 subjects) with a long follow-up time (49 years; 25% of the subjects had died by the end of the follow-up), so for most tumor sites there should be sufficient power to detect an increased risk. The main tumor site that might be at issue is the lung, which was the most sensitive site in both male and female mice. Lung cancer is fairly common in humans; therefore, the epidemiology study may have lacked the power to detect an increase in lung cancer. A crude "power" calculation based on the average employment and exposure characteristics of the cohort, exposure estimates and number of subjects available for 6 of the 8 plants, and the MLE of lung cancer unit risk for the female mouse (i.e., 0.1/ppm), and assuming no confounding by smoking, suggests that if humans were as sensitive as mice to the lung cancer effects of 1,3-butadiene, one would have expected to see 26 excess lung cancer cases in the epidemiology study. In fact, only 2 excess lung cancer cases were observed in the workers from the 6 plants over a background of 312 expected cases. On the other hand, the study has low statistical power to detect such a small proportional excess (power to detect a statistically significant increase in risk if the true SMR = 338/312 = 108 is estimated to be 42% according to the method of Beaumont and Breslow [1981]), and an SMR of 107 (319 observed/297 expected) was observed for the ever hourly workers for the 8 plants (although there was no increased risk in the overall cohort [SMR=101] or in the subgroup of ever hourly workers with >= 10 years worked and >= 20 years since hire [SMR=100]). The only process group associated with an increased lung cancer SMR was maintenance (SMR = 141 observed/114 expected = 124). However, 7 mesotheliomas were also observed in maintenance workers (9 among ever hourly workers in the total cohort), suggesting that these workers may have been exposed to asbestos, a known lung carcinogen. Furthermore, the evidence for the association between the increased lung cancers in the maintenance workers and 1,3-butadiene exposure is weakened by the fact that lung cancers are not increased in other process groups which exhibited increases in leukemia cases (e.g., 1,3-butadiene production), the absence of a positive relationship with number of years worked, the absence of a trend with increasing years since hire, and the fact that the increase was attenuated when state, rather than national, lung cancer rates were used for comparison (Sathiakumar et al., 1998). Thus, the overall evidence of an association between lung cancer and 1,3-butadiene exposure is tenuous. On the other hand, because the background rate of lung cancer is high, the power of the study to detect small increases in lung cancer risk is low, and, without adjusting for amount of smoking, it is difficult to make firm conclusions. Workers are not allowed to smoke in the plants because of the explosive potential of 1,3-butadiene; therefore, the workers may have had lower cigarette consumption, and this could easily mask a small increase in lung cancer risk. Thus, while the study does not provide good evidence of an association between lung cancer and 1,3-butadiene exposure, one cannot rule out a small increase in risk. Some increases were also observed for laryngeal cancer in the Delzell et al. study; however, these are based on small numbers (for the overall cohort: 17 observed, 15 expected). On the other hand, the increases are associated with process groups in which excess leukemias are observed. No data are provided for duration of exposure or other exposure characteristics. Thus, while the evidence for an association between laryngeal cancer and 1,3-butadiene exposure is meager, a small increase in laryngeal cancer cannot be ruled out. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) For comparison purposes, human unit cancer risk estimates based on extrapolation from the results of lifetime animal inhalation studies are also presented. These unit risk estimates are 95% upper confidence limits on unit cancer risk, calculated from incidence data on all significantly elevated tumor sites using a linearized low-dose extrapolation model, consistent with the 1986 guidelines (U.S. EPA, 1986). Exposure values were adjusted to 24-hour continuous equivalent exposures by multiplying by (6/24) and (5/7). The rat-based estimates are 4.2 x 10-3/ppm from male rat data and 5.6 x 10-2/ppm from female rat data. These estimates are from EPA's 1985 assessment and were derived using the linearized multistage model and estimates of absorbed dose (U.S. EPA, 1985). The mouse-based estimates were derived from the 1993 NTP study, including interim kill data, using a Weibull multistage time-to-tumor model and an assumption of ppm equivalence across species. Unit risk estimates for each tumor type were calculated separately and a Monte Carlo analysis was used to estimate the 95% upper bound on the sum of the MLEs (U.S. EPA, 2002, Section 10.2.2.2). A cancer unit risk estimate of 0.22/ppm was calculated from the male mouse data and 0.29/ppm from the female mouse data. The estimate of 0.3/ppm based on the female mouse data is the preferred animal-based upper bound on human risk. Human health risk estimates based on extrapolation from high-quality epidemiologic results are preferable to those based on rodent data, because they avoid the uncertainties inherent in extrapolating across species and, typically, the human exposures in epidemiologic studies are closer to anticipated environmental exposures than the high exposures used in animal studies, thus reducing the extent of low-dose extrapolation. In the case of 1,3-butadiene, while the rat exposures were at least 100-fold higher than human exposures, the lowest exposure in the 1993 NTP mouse study (4.7 ppm, 8-h TWA) is within the range of occupational exposures (0.7-1.7 ppm median and 39-64 ppm max 8-hour TWAs for work-area groups). However, interspecies differences in tumor sites and susceptibilities between rats and mice are especially pronounced, and the biological bases for these differences are unresolved. A review of available pharmacokinetic data and models revealed that the state of the science is currently inadequate for explaining interspecies differences or improving on default dosimetry assumptions (see Section I.B.4 and U.S. EPA, 2002, Chapter 9). Therefore, the quantitative extrapolation of rodent risks to humans is highly uncertain for 1,3-butadiene. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Even though high-quality human data were used for the quantitative cancer risk estimation for 1,3-butadiene, there are inevitable uncertainties in the calculated risk estimate. First, there are uncertainties inherent in the epidemiologic study itself. In particular, there are uncertainties in the retrospective estimation of 1,3-butadiene exposures, which could have resulted in exposure misclassification. Nondifferential exposure misclassification would tend to bias estimates of effect toward the null, resulting in an underestimate of risk. Differential misclassification could bias results in either direction. In fact, after completing their initial study, Delzell et al. raised some concerns about the accuracy of the exposure estimates (see U.S. EPA, 2002, Section 10.1.3). In 2000, Delzell et al. completed a re-assessment of the exposure estimates and concluded that the earlier a priori estimates were too low. The revised exposure estimates need to be critically evaluated before EPA can determine whether or not they are more credible than the a priori estimates. If the revised exposure estimates are valid, the leukemia portion of the cancer risk estimate would decrease somewhat (see U.S. EPA, 2002, Section 11.1). Second, there are uncertainties regarding the appropriate dose metric for dose-response analysis. Although the dose surrogate of cumulative exposure (i.e., ppm x years) yielded highly statistically significant exposure-response relationships, cumulative exposure is strongly correlated with other possible exposure measures, and there may be a dose-rate effect (e.g., risk at high exposures may be more than proportionately greater than at lower exposures) obscured in the analysis, or operative at exposures below the observable range but relevant to low-dose extrapolation. Third, there are uncertainties pertaining to which model to use for the epidemiologic data. Several mathematical models adequately fit the exposure-response data from the epidemiology study, and because the specific mechanisms of 1,3-butadiene carcinogenesis are unknown, there is no biological basis for choosing one model over another. The linear model was chosen in this risk assessment to derive the "point of departure" for low-dose extrapolation because there was no compelling reason to deviate from historical approaches. Fourth, it is uncertain which potential modifying or confounding factors should be included in the model. The linear model of Health Canada, which is used in this risk assessment, was adjusted for age, calendar year, years since hire, race, and exposure to styrene. Plant and benzene exposure were ruled out as potential confounders. However, there may be other relevant factors that were not included in the models. Fifth, there are uncertainties in the parameter estimates used in the models. The study of Delzell et al. is large, providing some degree of reliability in the parameter estimates. However, especially given the large human variability that has been observed in metabolic activities that could affect cancer risk from 1,3-butadiene exposure, the generalizability of the occupational results is unclear. Sixth, there are uncertainties in extending the relative rate models from the epidemiology study to derive lifetime excess leukemia incidence unit risk estimates for the U.S. population. Notwithstanding, the actuarial-type analysis that was used is a well-established methodology, and the background leukemia incidence rates and mortality rates used in the analysis are from large national databases. Seventh, the precise model for low-dose extrapolation is unknown. The linear default extrapolation procedure in the 1999 proposed guidelines was used in this assessment because of the well-established genotoxicity of 1,3-butadiene via its metabolites. In addition, there are important concerns raised by comparison with the rodent data. First, the rodent studies suggest that 1,3-butadiene is a multisite carcinogen. It is possible that humans may also be at risk of 1,3-butadiene-induced carcinogenicity at other sites and that the epidemiologic study had insufficient power to detect the other excess risks. In the mouse, for example, the lung is the most sensitive tumor site. Significant excesses of lung cancer may not have been detectable in the epidemiologic study because of the high background rates of lung cancer in humans (see also II.C.2 above). Delzell et al. did observe a slight increase in lung cancer among maintenance workers. The epidemiology-based excess cancer risk estimate of 0.04/ppm, which is based only on leukemias, may be an underestimate if other sites are also at risk. Second, both the rat and mouse studies suggest that females are more sensitive to 1,3-butadiene-induced carcinogenicity than are males, and the mammary gland in females was the only tumor site common to both species. If female humans are also more sensitive than males, then the male-based risk estimates calculated from the epidemiology study would underestimate risks to females. Because of these concerns, an adjustment factor of 2 is used, as discussed above, yielding a cancer unit risk estimate of 0.08/ppm. Despite these uncertainties, confidence in the excess cancer risk estimate of 0.08/ppm is moderate. First, the estimate is based primarily on human data. Furthermore, these data are from a large, high-quality epidemiologic study in which 1,3-butadiene exposures were estimated for each individual a priori to conducting the exposure-response analysis. Although there are uncertainties in the exposure estimation, a serious attempt was made to reconstruct historical exposures for specific tasks and work areas at different time periods. It is virtually unprecedented to have such a comprehensive exposure assessment for individual workers in such a large occupational epidemiologic study. In addition, the assumption of linearity for low-dose extrapolation is reasonable given the clear evidence of genotoxicity by 1,3-butadiene metabolites. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2002 RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 09/13/2001 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS in general at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ============================================================================ UDSO: 200211 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,3-Butadiene CASRN -- 106-99-0 Last Revised -- 11/05/2002 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Adler, ID; Anderson, D. (1994) Dominant lethal effects after inhalation exposure to 1,3-butadiene. Mutat Res 309:295-297. Anderson, D; Edwards, AJ; Brinkworth, MH. (1993) Male-mediated F1 effects in mice exposed to 1,3-butadiene. In: Butadiene and styrene: assessment of health hazards. IARC Scientific Publications. Vol. 127. Sorsa, M; Peltonen, K; Vainio, H; et al., eds. Lyon, France: International Agency for Research on Cancer, pp. 171-181. Anderson, D; Hughes, JA; Edwards, AJ; et al. (1998) A comparison of male-mediated effects in rats and mice exposed to 1,3-butadiene. Mutat Res 397:77-84. Bevan, C; Stadler, JC; Elliot, GS; et al. (1996) Subchronic toxicity of 4-vinylcyclohexene in rats and mice by inhalation. Fundam Appl Toxicol 32:1-10. Brinkworth, MH; Anderson, D; Hughes, JA; et al. (1998) Genetic effects of 1,3-butadiene on the mouse testis. Mutat Res 397:67-75. Hackett, PL; Sikov, MR; Mast, TJ; et al. (1987) Inhalation developmental toxicology studies: teratology study of 1,3-butadiene in mice (final report). Richland, WA: Pacific Northwest Laboratory; PNL Report No. PNL-6412 UC-48; NIH Report No. NIH-401-ES-40131; 92. Prepared for NIEHS, NTP, under a Related Services Agreement with the U.S. Department of Energy under contract DE-AC06-76RLO-1830. National Center for Health Statistics (NCHS). (1996) Vital statistics of the United States, 1992, vol. II, mortality, part A. Washington, DC: U.S. Public Health Service. National Toxicology Program (NTP), U.S. Department of Health and Human Services. (1993) Toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). NTP TR 434, NIH Pub. No. 93-3165. Research Triangle Park, NC. U.S. Environmental Protection Agency (U.S. EPA). (1985) Mutagenicity and carcinogenicity assessment of 1,3-butadiene. Office of Health and Environmental Assessment, Office of Research and Development, Washington, DC. EPA/600/8-85/004F. U.S. Environmental Protection Agency (U.S. EPA). (1994) Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Office of Research and Development, Washington, DC. EPA/600/8-90/066F. U.S. Environmental Protection Agency (U.S. EPA). (2002) Health assessment document for 1,3-butadiene. Office of Research and Development, Washington, DC. EPA/600/P-98/001. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Beaumont, JJ; Breslow, NE. (1981) Power considerations in epidemiologic studies of vinyl chloride workers. Am J Epidemiol 114:752-34. Berard, CW; Hutchison, RE. (1997) The problem of classifying lymphomas: an orderly prescription for progress. Ann Oncol (Suppl 2):53-59. Cowles, SR; Tsai, SP; Snyder, PJ; et al. (1994) Mortality, morbidity, and haematologic results from a cohort of long-term workers involved in 1,3-butadiene monomer production. Occup Environ Med 51:323-329. Delzell, E; Sathiakumar, N; Macaluso, M.; et al. (1995) A follow-up study of synthetic rubber workers. Submitted to the International Institute of Synthetic Rubber Producers. University of Alabama at Birmingham. October 2, 1995. Delzell, E; Sathiakumar, N; Hovinga, M. (1996) A follow-up study of synthetic rubber workers. Toxicology 113:182-189. Divine, BJ; Hartman, CM. (1996) Mortality update of butadiene production workers. Toxicology 113:169-181. Downs, TD; Crane, MM; Kim, KW. (1987) Mortality among workers at a butadiene facility. Am J Ind Med 12:311-329. Hazleton Laboratories Europe Ltd. (1981) The toxicity and carcinogenicity of butadiene gas administered to rats by inhalation for approximately 24 months. Prepared for the International Institute of Synthetic Rubber Producers, New York, NY. Unpublished. Health Canada. (1998) Canadian Environmental Protection Act Priority Substances List Health Assessment: 1,3-Butadiene. Draft for second stage peer review. Ottawa. March 1998. Additional information was provided by Health Canada for calculation of the confidence intervals (personal communication from Michael Walker to Leslie Stayner, 18 June 1999). Himmelstein, MW; Acquavella, JF; Recio, L; et al. (1997) Toxicology and epidemiology of 1,3-butadiene. Crit Rev Toxicol 27(1):1-108. Irons, RD; Cathro, HP; Stillman WS; et al. (1989) Susceptibility to 1,3-butadiene-induced leukemogenesis correlates with endogenous ecotropic retroviral background in the mouse. Toxicol Appl Pharmacol 101:170-176. Irons, RD; Pyatt, DW. (1998) Commentary: dithiocarbamates as potential confounders in butadiene epidemiology. Carcinogenesis 19(4):539-542. Koc, H; Tretyakova, NY; Walker, VE; et al. (1999) Molecular dosimetry of N-7 guanine adduct formation in mice and rats exposed to 1,3-butadiene. Chem Res Toxicol 12:566-574. Macaluso, M; Larson, R; Delzell, E. (1996) Leukemia and cumulative exposure to butadiene, styrene and benzene among workers in the synthetic rubber industry. Toxicology 113:190-202. Matanoski, GM; Schwartz, L. (1987) Mortality of workers in styrene-butadiene polymer production. J Occup Med 29:675-680. Melnick, RL; Kohn, MC. (1995) Mechanistic data indicate that 1,3-butadiene is a human carcinogen. Carcinogenesis 16(2):157-163. Melnick, RL; Elwell, MR; Roycroft, JH; et al. (1996) Toxicity of inhaled chloroprene (2-chloro-1,3-butadiene) in F344 rats and B6C3F1 mice. Toxicology 113:247-252. National Cancer Institute (NCI). (2001) SEER Cancer Statistics Review, 1973-1998, National Cancer Institute. Bethseda, MD, http://seer.cancer.gov/Publications/CSR1973_1998/, 2001. National Center for Health Statistics (NCHS). (1996) Vital statistics of the United States, 1992, vol. II, mortality, part A. Washington, DC: U.S. Public Health Service. National Toxicology Program (NTP), U.S. Department of Health and Human Services. (1984) Toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). NTP TR 288, NIH Pub. No. 84-2544. Research Triangle Park, NC. NTP. (1993) Toxicology and carcinogenesis studies of 1,3-butadiene (CAS No. 106-99-0) in B6C3F1 mice (inhalation studies). NTP TR 434, NIH Pub. No. 93-3165. Research Triangle Park, NC. NTP. (1997) NTP Technical Report on the toxicology and carcinogenesis studies of isoprene in F344/N rats. Technical Report No. 486 (Draft), U.S. DHHS. NTP. (1998) Toxicology and carcinogenesis studies of chloroprene in F344/N rats and B6C3F1 mice. Technical Report No. 467, U.S. DHHS. Owen PE; Glaister, JR; Gaunt, IF; et al. (1987) Inhalation toxicity studies with 1,3-butadiene. 3. Two-year toxicity/carcinogenicity study in rats. Am Ind Hyg Assoc J 48(5):407-413. Santos-Burgoa, C; Matanoski, GM; Zeger, S; et al. (1992) Lymphohematopoietic cancer in styrene-butadiene polymerization workers. Am J Epidemiol 136:843-854. Sathiakumar, N; Delzell, E; Hovinga, M; et al. (1998) Mortality from cancer and other causes of death among synthetic rubber workers. Occup Environ Med 55:230-235. U.S. Environmental Protection Agency (U.S. EPA). (1985) Mutagenicity and carcinogenicity assessment of 1,3-butadiene. Office of Health and Environmental Assessment, Office of Research and Development, Washington, DC. EPA/600/8-85/004F. U.S. EPA. (1999) Guidelines for carcinogen risk assessment. Review Draft, NCEA-F-0644, July 1999. Risk Assessment Forum. http://www.epa.gov/ncea/raf/cancer.htm. U.S. EPA. (2002) Health assessment document for 1,3-butadiene. Office of Research and Development, Washington, DC. EPA/600/P-98/001. Ward, EM; Fajen, JM; Ruder, A. (1995) Mortality study of workers in 1,3-butadiene production units identified from a chemical workers cohort. Environ Health Perspect 103:598-603. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,3-Butadiene CASRN -- 106-99-0 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 II.A.2. Text revised 03/01/1988 II.C.4. Confidence statement revised 06/01/1989 II.D.3. Primary contact changed 07/01/1989 II.A.2. Correct Meinhardt citation 07/01/1989 II.A.4. Correct citations 07/01/1989 VI. Bibliography on-line 06/01/1990 IV.A.1. Area code for EPA contact corrected 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 01/01/1991 VI.C. Bond et al., 1986 and Cote and Bayard, 1990 refs added 02/01/1991 II.C.3. Information on extrapolation process included 01/01/1992 IV. Regulatory actions updated 04/01/1992 VI. Regulatory action section withdrawn 04/01/1997 III.,IV.,V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/10/1998 I.,II This chemical is being reassessed under the IRIS program. 11/05/2002 All Complete revision based on new health assessment document. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 381 of 1119 in IRIS (through 2003/06) AN: 144 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0144-tr.pdf UD: 199809 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Chromium(VI) SY: 18540-29-9; 7440-47-3; CHROMIC-ION-; CHROMIUM-; CHROMIUM,-ION-; CHROMIUM- (VI); CHROMIUM (VI) ION RN: 18540-29-9 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199809 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chromium(VI) CASRN -- 18540-29-9 Last Revised -- 09/03/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD --------------- ----------------------------- ------------------ None reported NOAEL: 25 mg/L of chromium 300 3 3E-3 mg/kg-day as K2CrO4 2.5 mg/kg-day (adj.) LOAEL: None Rat, 1-year drinking study MacKenzie et al., 1958 ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- Drinking water consumption = 0.1 L/kg-day (reported). PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) MacKenzie, RD; Byerrum, RU; Decker, CF, et al. (1958) Chronic toxicity studies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind Health 18:232-234. Groups of eight male and eight female Sprague-Dawley rats were supplied with drinking water containing 0.45-11.2 ppm (0.45-11.2 mg/L) hexavalent chromium (as K2CrO4) for 1 year. The control group (10/sex) received distilled water. A second experiment involved three groups of 12 male and 9 female rats. One group was given 25 ppm (25 mg/L) chromium (as K2CrO4), a second received 25 ppm chromium in the form of chromic chloride, and the controls again received distilled water. No significant adverse effects were seen in appearance, weight gain, or food consumption, and there were no pathologic changes in the blood or other tissues in any treatment group. The rats receiving 25 ppm of chromium (as K2CrO4) showed an approximate 20% reduction in water consumption. Based on the body weight of the rat (0.35 kg) and the average daily drinking water consumption for the rat (0.035 l/day), this dose can be converted to give an adjusted NOAEL of 2.5 mg/kg-day chromium(VI). For rats treated with 0-11 ppm (in drinking water), blood was examined monthly, and tissues (livers, kidneys, and femurs) were examined at 6 mo and 1 year. Spleens were also examined at 1 year. The 25 ppm groups (and corresponding controls) were examined similarly, except that no animals were killed at 6 mo. An abrupt rise in tissue chromium concentrations was noted in rats treated with more than 5 ppm. The authors stated that "apparently, tissues can accumulate considerable quantities of chromium before pathological changes result." In the 25 ppm treatment groups, tissue concentrations of chromium were approximately 9 times higher for those treated with hexavalent chromium than for the trivalent group. Similar no-effect levels have been observed in dogs. Anwar et al. (1961) observed no significant effects in female dogs (2/dose group) given up to 11.2 ppm chromium(VI) (as K2CrO4) in drinking water for 4 years. The calculated doses were 0.012-0.30 mg/kg of chromium(VI). UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 300. The uncertainty factor of 300 represents two 10-fold decreases in dose to account for both the expected interhuman and interspecies variability in the toxicity of the chemical in lieu of specific data, and an additional factor of 3 to compensate for the less-than-lifetime exposure duration of the principal study. MF = 3. The modifying factor of 3 is to account for concerns raised by the study of Zhang and Li (1987). ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) This RfD is limited to soluble salts of hexavalent chromium. Examples of soluble salts include potassium dichromate (K2Cr2O7), sodium dichromate (Na2Cr2O7), potassium chromate (K2Cr2O4), and sodium chromate (Na2CrO4). Trivalent chromium is an essential nutrient. There is evidence to indicate that hexavalent chromium is reduced in part to trivalent chromium in vivo (Petrilli and DeFlora, 1977, 1978; Gruber and Jennette, 1978). In 1965, a study of 155 subjects exposed to drinking water at concentrations of approximately 20 mg/L was conducted outside Jinzhou, China. Subjects were observed to have sores in the mouth, diarrhea, stomachache, indigestion, vomiting, elevated white blood cell counts with respect to controls, and a higher per capita rate of cancers, including lung cancer and stomach cancer. Precise exposure concentrations, exposure durations, and confounding factors were not discussed, and this study does not provide a NOAEL for the observed effects. However, the study suggests that gastrointestinal effects may occur in humans following exposures to hexavalent chromium at levels of 20 ppm in drinking water (Zhang and Li, 1987). Zahid et al. (1990) fed BALB/C albino Swiss mice trivalent (chromium disulfate) and hexavalent (potassium dichromate) chromium at concentrations of 100, 200, and 400 ppm for 35 days in the diet. The author concluded that a small but significant increase of hexavalent chromium in the testes of fed animals induced significant degeneration. The National Toxicology Program (1996a,b, 1997) recently conducted a three-part study to investigate the potential reproductive toxicity of hexavalent chromium in rats and mice. The study included oral administration of potassium dichromate in Sprague-Dawley rats, a repeat of the study of Zahid et al. (1990) using BALB/C mice, and a reproductive assessment by continuous breeding study in BALB/C mice. The reproductive assessment indicated that potassium dichromate administered at 15-400 ppm in the diet is not a reproductive toxicant in either sex of BALB/C mice or Sprague-Dawley rats. Several reports of possible fetal damage caused by chromium compounds were located in the literature. High doses (250-1,000 ppm) of orally administered chromium (VI) compounds have been reported to cause developmental toxicity in mice (Trivedi et al., 1989). The authors observed significant increases in preimplantation and postimplantation losses and dose-dependent reductions in total weight and crown-rump length in the lower dose groups. Additional effects included treatment-related increases in abnormalities in the tail and wrist forelimbs, and subdermal hemorrhagic patches in the offspring. Junaid et al. (1996) and Kanojia et al. (1996) exposed female Swiss albino mice and female Swiss albino rats, respectively, to 250, 500, or 750 ppm potassium dichromate in drinking water to determine the potential embryotoxicity of hexavalent chromium during days 6-14 of gestation. The authors reported retarded fetal development and embryo- and fetotoxic effects including reduced fetal weight, reduced number of fetuses (live and dead) per dam, and higher incidences of stillbirths and post-implantation loss in the 500 and 750 ppm dosed mothers. Significantly reduced ossification in bones was also observed in the medium- and high-dose groups. Based on the body weight and the drinking water ingested by the animals in the 250 ppm dose group, the exposure levels in the 250 ppm groups can be identified as 67 mg/kg-day and 37 mg/kg-day in mice and rats, respectively. The Junaid et al. (1996) and Kanojia et al. (1996) studies utilized doses approximately 10-fold higher than those used in Mackenzie et al (1958), but neither of the reproductive studies identified a clear NOAEL for the embryotoxic effects of hexavalent chromium. On the basis of the body weight and the drinking water ingested by the animals in the low-dose groups (250 ppm), the LOAELs of 67 mg/kg-day and 37 mg/kg-day can be identified from Junaid et al. (1996) and Kanojia et al. (1996) in mice and rats, respectively. Application of 10-fold uncertainty factor to extrapolate from LOAELs to NOAELs in these studies would generate NOAELs of 6.7 mg/kg-day and 3.7 mg/kg-day, respectively. These extrapolated NOAEL values are similar to, and support the use of, the NOAEL of 2.5 mg/kg-day identified from the study of MacKenzie et al. (1958) for development of the reference dose. Elbetieha and Al-Hamood (1997) reported impacts on fertility following potassium dichromate exposures in mice; however, many of the observed effects did not occur in a clear dose-dependent fashion. The authors did not indicate the amount of water ingested by the animals, and stated only that water ingestion was reduced in the treatment groups relative to the controls. Chromium is one of the most common contact sensitizers in males in industrialized countries and is associated with occupational exposures to numerous materials and processes, including chrome plating baths, chrome colors and dyes, cement, tanning agents, wood preservatives, anticorrosive agents, welding fumes, lubricating oils and greases, cleaning materials, and textiles and furs (Burrows and Adams, 1990; Polak et al., 1973). Solubility and pH appear to be the primary determinants of the capacity of individual chromium compounds to elicit an allergic response (Fregert, 1981; Polak et al., 1973). The low solubility chromium (III) compounds are much less efficient contact allergens than chromium (VI) (Spruit and van Neer, 1966). Dermal exposure to chromium has been demonstrated to produce irritant and allergic contact dermatitis (Bruynzeel et al., 1988; Polak, 1983; Cronin, 1980; Hunter, 1974). Primary irritant dermatitis is related to the direct cytotoxic properties of chromium, while allergic contact dermatitis is an inflammatory response mediated by the immune system. Allergic contact dermatitis is a cell-mediated immune response that occurs in a two-step process. In the first step (induction), chromium is absorbed into the skin and triggers an immune response (sensitization). Sensitized individuals will exhibit an allergic dermatitis response when exposed to chromium above a threshold level (Polak, 1983). Induction is generally considered to be irreversible. Concentrations of hexavalent chromium in environmental media that are protective of carcinogenic and noncarcinogenic effects are likely to be lower than the concentrations required to cause induction of allergic contact dermatitis. However, these concentrations may not be lower than concentrations required to elicit an allergic response in individuals who have been induced. The RfD was updated in 1998. The RfD is similar to the previous value on IRIS but now incorporates a threefold uncertainty factor to account for the less-than-lifetime exposure in the principal study and a threefold modifying factor to account for uncertainties related to reports of gastrointestinal effects following drinking water exposures in a residential population in China. For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=39. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Database -- Low RfD -- Low The overall confidence in this RfD assessment is low. Confidence in the chosen study is low because of the small number of animals tested, the small number of parameters measured, and the lack of toxic effect at the highest dose tested. Confidence in the database is low because the supporting studies are of equally low quality and the developmental toxicity endpoints are not well studied. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=53. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Hexavalent Chromium in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=72. Other EPA Documentation -- U.S. EPA. (1984) Health effects assessment for hexavalent chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. (1985) Drinking water health advisory for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC (Draft). Agency consensus date -- 04/28/1998 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 199809 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Chromium(VI) CASRN -- 18540-29-9 Last Revised -- 09/03/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC ----------------- ----------------------------------------------------- (1) Chromic acid mists and dissolved Cr (VI) aerosols: Nasal septum atrophy NOAEL: none 90 1 8E-6 mg/m3 LOAEL: 2E-3 mg/m3 7.14 E-4 mg/m3 (adj.) Human subchronic occupational study Lindberg and Hedenstierna, 1983 (2) Cr(VI) particulates: Lactate dehydrogenase in BMD: 0.016 mg/m3 300 1 1E-4 mg/m3 bronchioalveolar lavage fluid 0.034 mg/m3 (adj.) Rat subchronic study Glaser et al., 1990 Malsch et al., 1994 ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- Breathing rate for 8-hour occupational exposure = 10 m3; breathing rate for 24-hour continuous exposure = 20 m3; occupational exposure = 5 days/week; continuous exposure = 7 days/week. RDDR (regional deposited dose ratio for particulates to account for differences between rats and humans) = 2.16 Nasal mucosal irritation, atrophy, and perforation have been widely reported following occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols. However, there is uncertainty regarding the relevance of occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols to exposures to Cr(VI) dusts in the environment. Lower respiratory effects have been reported in laboratory animals following exposures to Cr(VI) dusts. However, these studies have not reported on nasal mucosal effects following the exposures. The uncertainties in the database have been addressed through the development of two RfCs; one based on nasal mucosal atrophy following occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols, and a second based on lower respiratory effects following inhalation of Cr(VI) particulates in rats. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) (1) Chromic acid mists and dissolved Cr (VI) aerosols Three studies have focused on nasal mucosal irritation, atrophy, and perforation following occupational exposures to chromic acid mists (Cohen et al., 1974; Lucas and Kramkowski, 1975; Lindberg and Hedenstierna, 1983). Of these, the study of Lindberg and Hedenstierna provides the most information on exposure levels and symptoms reported by exposed workers. Respiratory symptoms, lung function, and changes in nasal septum were studied in 104 workers (85 males, 19 females) exposed in chrome plating plants. Workers were interviewed using a standard questionnaire for the assessment of nose, throat, and chest symptoms. Nasal inspections and pulmonary function testing were performed as part of the study. The median exposure time for the entire group of exposed subjects (104) in the study was 4.5 years (0.1-36 years). A total of 43 subjects exposed almost exclusively to chromic acid experienced a mean exposure time of 2.5 years (0.2-23.6 years). The subjects exposed almost exclusively to chromic acid were divided into a low-exposure group (8-hr TWA below 0.002 mg/m3, N=19) and a high-exposure group (8-hr TWA above 0.002 mg/m3, N=24). Exposure measurements using personal air samplers were performed for 84 subjects in the study on 13 different days. Exposure for the remaining 20 workers was assumed to be similar to that measured for workers in the same area. Nineteen office employees were used as controls for nose and throat symptoms. A group of 119 auto mechanics whose lung function had been evaluated by similar techniques was selected as controls for lung function measurements. Smoking habits of workers were evaluated as part of the study. At mean exposures below 0.002 mg/m3, 4/19 workers from the low-exposure group of subjective nasal symptoms. Atrophied nasal mucosa were reported in 4/19 subjects from this group and 11/19 had smeary and crusty septal mucosa, which was statistically higher than controls. No one exposed to levels below 0.001 mg/m3 complained of subjective symptoms. At mean concentrations of 0.002 mg/m3 or above, approximately one-third of the subjects had reddened, smeary, or crusty nasal mucosa. Atrophy was seen in 8/24 workers, which was significantly different from controls. Eight subjects had ulcerations in the nasal mucosa and five had perforations of the nasal septum. Atrophied nasal mucosa was not observed in any of the 19 controls, but smeary and crusty septal mucosa occurred in 5/19 controls. Short-term effects on pulmonary function were evaluated by comparing results of tests taken on Monday and Thursday among exposed groups and controls. No significant changes were seen in the low-exposure group or the control group. Nonsmokers in the high-exposure group experienced significant differences in pulmonary function measurements from the controls, but the results were within normal limits. The authors concluded that 8-hour mean exposures to chromic acid above 0.002 mg/m3 may cause a transient decrease in lung function, and that short-term exposures to greater than 0.02 mg/m3 may cause septal ulceration and perforation. Based on the results of this study, a LOAEL of 0.002 mg/m3 can be identified for incidence of nasal septum atrophy following exposure to chromic acid mists in chromeplating facilities. At TWA exposures greater than 0.002 mg/m3, nasal septum ulceration and perforations occurred in addition to the atrophy reported at lower concentrations. The LOAEL is based on an 8-hour TWA occupational exposure. The LOAEL is adjusted to account for continuous exposure according to the following equation: LOAELc = 0.002 mg/m3 x (MVho/MVh) x 5 days/7 days where: LOAELc is the LOAEL for continuous exposure MVho is the breathing volume for an 8 hour occupational exposure (10 m3) MVh is the breathing volume for a 24 hour continuous exposure (20 m3) The LOAEL of 0.002 mg/m3 based on a TWA exposure to chromic acid is converted to a LOAEL for continuous exposure of 7.14 E-4 mg/m3. An uncertainty factor of 3 is applied to the LOAEL to extrapolate from a subchronic to a chronic exposure, an uncertainty factor of 3 is applied to account for extrapolation from a LOAEL to a NOAEL, and an uncertainty factor of 10 is applied to the LOAEL to account for interhuman variation. The total uncertainty factor applied to the LOAEL is 90. Application of the uncertainty factor of 90 to the LOAEL of 7.14E-4 mg/m3 generates an RfC of 8 E-6 mg/m3 for upper respiratory effects caused by chromic acid mists and dissolved hexavalent chromium aerosols. (2) Cr (VI) Particulates: Two studies provide high-quality data on lower respiratory effects following exposures to chromium particulates (Glaser et al., 1985, 1990). Glaser et al. (1990) exposed 8-week-old male Wistar rats to sodium dichromate at 0.05 - 0.4 mg Cr(VI)/m3 22 hr/day, 7 days/wk for 30-90 days. Chromium-induced effects occurred in a strong dose-dependent manner. The authors observed obstructive respiratory dyspnea and reduced body weight following subacute exposure at the higher dose levels. The mean white blood cell count was increased at all doses (p < 0.05) and was related to significant dose-dependent leukocytosis following subacute exposures. Mean lung weights were significantly increased at exposure levels of 0.1 mg/m3 following both the subacute and subchronic exposures. Accumulation of macrophages was seen in all of the exposure groups and was postulated to be a chromium-specific irritation effect that accounted for the observed increases in lung weights. Focal inflammation was observed in the upper airways following the subchronic exposure, and albumin and lactate dehydrogenase (LDH) in bronchioalveolar lavage fluid (BALF) were increased following the exposure. The authors concluded that chromium inhalation induced pneumocyte toxicity and suggested that inflammation is essential for the induction of most chromium inhalation effects and may influence the carcinogenicity of Cr(VI) compounds. Glaser et al. (1985) exposed 5-week-old male Wistar rats to aerosols of sodium dichromate at concentrations ranging from 0.025 to 0.2 mg Cr(VI)/m3, 22 hr/day in subacute (28 day) or subchronic (90 day) protocols. Chromium-induced effects occurred in a dose-dependent manner. Lung and spleen weights were significantly increased (p < 0.005) after both subacute and subchronic exposures at concentrations greater than 0.025 mg/m3. Differences in the mean total serum immunoglobulin were also significant at exposures above 0.025 mg/m3, while exposures to aerosol concentrations greater than 0.1 mg/m3 resulted in depression of the immune system stimulation. The immune stimulating effect of subchronic exposure was not reversed after 2 mo of fresh air regeneration. Bronchoalveolar lavage (BAL) cell counts were significantly decreased following subchronic exposure to levels above 0.025 mg/m3 chromium. The number of lymphocytes and granulocytes showed a slight but significant increase in the lavage fluids of the subacute and subchronically exposed groups. At subacute exposure concentrations up to 0.05 mg/m3 the phagocytic activity of the alveolar macrophages increased; however, subchronic exposure at 0.2 mg/m3 decreased this function significantly. The spleen T-lymphocyte subpopulation was stimulated by subchronic exposure to 0.2 mg/m3 chromium, and serum contents of triglycerides and phospholipids differed significantly from controls (p < 0.05) at this concentration. Together, these studies provide useful information on chromium exposure-related impacts including lung and spleen weight, LDH in BALF, protein in BALF, and albumin in BALF. The cellular content of BALF is considered representative of initial pulmonary injury and chronic lung inflammation, which may lead to the onset of pulmonary fibrosis (Henderson, 1988). While these studies present dose-dependent results on sensitive indicators of lower respiratory toxicity, potential upper respiratory impacts resulting from the exposures were not addressed. Glaser et al. (1990) state that the upper respiratory tract was examined, but these data were not reported. One approach for development of an RfC using the data of Glaser et al. (1985, 1990) was offered by Malsch et al. (1994), who generated an inhalation RfC for chromium dusts using a benchmark concentration (BMC) approach. The Agency developed its RfC for particulates based on this approach. After excluding exposures for periods of less than 90 days from the BMC analysis, Malsch et al. (1994) developed BMCs for lung weight, LDH in BALF, protein in BALF, albumin in BALF, and spleen weight. The Malsch et al. (1994) analysis defined the benchmark concentration as the 95% lower confidence limit on the dose corresponding to a 10% relative change in the endpoint compared to the control. Dose-effect data were adjusted to account for discontinuous exposure (22 hr/day) and the maximum likelihood model was used to fit continuous data to a polynomial mean response regression, yielding maximum likelihood estimates of 0.036 - 0.078 mg/m3 and BMCs of 0.016 - 0.067 mg/m3. Malsch et al. (1994) applied dosimetric adjustments and uncertainty factors to determine a RfC based on the following equation: RfC = BMC x RDDR UFA x UFF x UFH where: RfC is the inhalation reference concentration BMC is the benchmark concentration (lower 95% confidence limit on the dose corresponding to a 10% relative change in the endpoint compared to the control) RDDR is the regional deposited dose ratio to account for pharmacokinetic differences between species UFA is a threefold uncertainty factor to account for pharmacodynamic differences not addressed by the RDDR UFF is a threefold uncertainty factor to account for extrapolating from subchronic to chronic exposures; and UFH is a 10-fold uncertainty factor to account for the variation in sensitivity among members of the human population The RDDR factor is incorporated to account for differences in the deposition pattern of inhaled hexavalent chromium dusts in the respiratory tract of humans and the Wistar rat test animals (Jarabek et al., 1990). The RDDR of 2.1576 was determined based on the mass median aerodynamic diameter (0.28 um for dose levels of 0.05-0.1 mg/m3 and 0.39 for dose levels of 0.1-0.4 mg/m3) and the geometric standard deviation (1.63 for dose levels of 0.05-0.1 mg/m3 and 1.72 for dose levels of 0.1-0.4 mg/m3) of the particulates reported in Glaser et al. (1990). A 3.16-fold uncertainty factor (midpoint between 1 and 10 on a log scale) was incorporated to account for the pharmacodynamic differences not accounted for by the RDDR. An additional 3.16-fold uncertainty factor was incorporated to account for the less-than-lifetime exposure in Glaser et al. (1990), and a 10-fold uncertainty factor was applied to account for variation in the human population. A total uncertainty factor of 100 was applied to the BMC in addition to the RDDR. Glaser et al. (1990) reported that LDH in BALF increased in a dose-dependent fashion from 0.05 to 0.4 mg/m3 sodium dichromate, and this endpoint generated the lowest BMC (0.016 mg/m3) and RfC (3.4 E-4 mg/m3). LDH in BALF is considered the among the most sensitive indicators of potential lung toxicity (Henderson, 1984, 1985, 1988; Beck et al., 1982; Venet et al., 1985), as LDH is found extracellularly after cell damage and BALF is the closest site to the original lung injury. LDH in BALF may also reflect chronic lung inflammation, which may lead to pulmonary fibrosis through prevention of the normal repair of lung tissue (Henderson, 1988). Several uncertainties must be addressed with regard to the BMC and RfC developed by Malsch et al. (1994). Potentially important endpoints, including upper airway effects and potential renal or immunological toxicity, were not addressed in the Glaser et al. (1985, 1990) studies and could not be included in the BMC analysis. While LDH in BALF resulted in the lowest BMC and RfC, all of the effects noted in Glaser et al. (1985, 1990) can be considered indicative of an inflammatory response, and might be equally suited to development of the RfC. LDH in BALF did not generate the best fit on the regression curve of the endpoints considered in the BMC analysis. In addition, the threefold uncertainty factor accounting for the use of a subchronic study may not be sufficiently protective for long-term effects. While the analysis acknowledged the importance of particle size and airway deposition in the development of the RDDR, the potential impact of different particle sizes in respiratory toxicity by hexavalent chromium particulates was not addressed. Several of these uncertainties were conservatively addressed in the analysis of Malsch et al. (1994). LDH in BALF generated the lowest estimate of the BMC from the effects noted by Glaser et al. (1985, 1990). This effect can be considered to be indicative of cell damage that occurs prior to fibrosis, as LDH appears in BALF following cell lysis. While the Malsch et al. (1994) analysis demonstrated a relatively poor curve fit for this endpoint, the model generated a conservative fit in the data that is unlikely to overestimate the BMC. LDH in BALF as reported in Glaser et al. (1990) is considered to be an acceptable endpoint for development of an RfC for inhalation of hexavalent chromium particulates, and Malsch et al. (1994) used a reasonable approach for development of a BMC based on this endpoint. The threefold uncertainty factor used by Malsch et al. (1994) to account for the subchronic study is insufficient for development of the RfC for inhalation of chromium particulates. Glaser et al. (1985) demonstrated that at the end of the 90-day exposure period, chromium was still accumulating in the lung tissue of the test animals, suggesting that lower long-term exposures might lead to accumulation of a critical concentration in the lung. Subchronic studies also may not adequately predict the presence of inflammatory effects from lower long-term exposures. The Agency has therefore determined that a 10-fold uncertainty factor accounting for the use of a subchronic study is more appropriate in this case for the development of an RfC for inhalation of chromium particulates. Selection of a threefold uncertainty factor to account for the pharmacodynamic differences not accounted for by the RDDR, an additional 10-fold uncertainty factor to account for the less-than-lifetime exposure in Glaser et al. (1990), and a 10-fold uncertainty factor to account for variation in the human population generates a total uncertainty factor of 300. Application of the total uncertainty factor of 300 and the RDDR of 2.1576 to the BMC generated by Malsch et al. (1994) based on LDH in BALF (Glaser et al., 1990) results in an RfC of 1 E-4 mg/m3 for inhalation of hexavalent chromium particulates. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) See discussion above. (1) Chromic acid mists and dissolved Cr (VI) aerosols: UF = 90. MF = 1. (2) Chromium (VI) particulates: UF = 300. MF = 1 IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) There is considerable uncertainty with regard to the relevance of the nasal septum atrophy endpoint observed in the chromeplating industry to exposure to hexavalent chromium in the environment. The effects were observed in chromeplaters who were exposed to chromic acid mists near the plating baths. Environmental exposures would most likely occur through contact with hexavalent chromium dusts, and exposures to chromic acid mists in the environment is considered to be unlikely. An additional uncertainty is related to the determination of dose in the Lindberg and Hedenstierna study. Nasal septum atrophy in this study was related to TWA exposures to chromic acid. The most significant effects (nasal septum perforation) were observed in workers who experienced peak excursions to levels considerably greater than the TWA. It is uncertain whether the peak excursion data or the TWAs are more appropriate for the determination of dose in this study. The RfC based on the data of Lindberg and Hedenstierna (1983) should only be used to address exposures to chromic acid and dissolved hexavalent chromium aerosols. Nasal mucosal irritation, atrophy, and perforation have been widely reported following occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols. Glaser et al. (1990) did not report on upper respiratory effects following exposure of rats to sodium dichromate. The RfC based on the data of Glaser et al. should only be used to address inhalation of Cr(VI) particulates. The RfCs in this IRIS Summary were added in 1998. The previous RfC section for hexavalent chromium in IRIS was empty. For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=39. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC (1) Chromic acid mists and dissolved Cr (VI) aerosols: Study -- Low Database -- Low RfC -- Low The overall confidence in this RfC assessment is low. Confidence in the chosen study is low because of uncertainties regarding the exposure characterization and the role of direct contact for the critical effect. Confidence in the database is low because the supporting studies are equally uncertain regarding the exposure characterization. (2) Chromium (VI) particulates: Study -- Medium RfC -- Medium The overall confidence in this RfC assessment is medium. Confidence in the chosen study is medium because of uncertainties regarding upper respiratory, reproductive, and renal effects resulting from the exposures. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=53. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Hexavalent Chromium in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, External Peer Review - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0173-tr.pdf#page=62. Agency Consensus Date -- 04/28/1998 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 199809 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name: Chromium(VI) CASRN: 18540-29-9 Last Revised -- 09/03/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under the current guidelines (EPA, 1986), Cr(VI) is classified as Group A -known human carcinogen by the inhalation route of exposure. Carcinogenicity by the oral route of exposure cannot be determined and is classified as Group D. Under the proposed guidelines (EPA, 1996), Cr(VI) would be characterized as a known human carcinogen by the inhalation route of exposure on the following basis. Hexavalent chromium is known to be carcinogenic in humans by the inhalation route of exposure. Results of occupational epidemiologic studies of chromium-exposed workers are consistent across investigators and study populations. Dose-response relationships have been established for chromium exposure and lung cancer. Chromium-exposed workers are exposed to both Cr(III) and Cr(VI) compounds. Because only Cr(VI) has been found to be carcinogenic in animal studies, however, it was concluded that only Cr(VI) should be classified as a human carcinogen. Animal data are consistent with the human carcinogenicity data on hexavalent chromium. Hexavalent chromium compounds are carcinogenic in animal bioassays, producing the following tumor types: intramuscular injection site tumors in rats and mice, intrapleural implant site tumors for various Cr(VI) compounds in rats, intrabronchial implantation site tumors for various Cr(VI) compounds in rats, and subcutaneous injection site sarcomas in rats. In vitro data are suggestive of a potential mode of action for hexavalent chromium carcinogenesis. Hexavalent chromium carcinogenesis may result from the formation of mutagenic oxidatitive DNA lesions following intracellular reduction to the trivalent form. Cr(VI) readily passes through cell membranes and is rapidly reduced intracellularly to generate reactive Cr(V) and Cr(IV) intermediates and reactive oxygen species. A number of potentially mutagenic DNA lesions are formed during the reduction of Cr(VI). Hexavalent chromium is mutagenic in bacterial assays, yeasts, and V79 cells, and Cr(VI) compounds decrease the fidelity of DNA synthesis in vitro and produce unscheduled DNA synthesis as a consequence of DNA damage. Chromate has been shown to transform both primary cells and cell lines. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=53. , For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=39. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Occupational exposure to chromium compounds has been studied in the chromate production, chromeplating and chrome pigment, ferrochromium production, gold mining, leather tanning, and chrome alloy production industries. Workers in the chromate industry are exposed to both trivalent and hexavalent compounds of chromium. Epidemiological studies of chromate production plants in Japan, Great Britain, West Germany, and the United States have revealed a correlation between occupational exposure to chromium and lung cancer, but the specific form of chromium responsible for the induction of cancer was not identified (Machle and Gregorius, 1948; Baejter, 1950a,b; Bidstrup, 1951; Mancuso and Hueper, 1951; Brinton et al., 1952; Bidstrup and Case, 1956; Todd, 1962; Taylor, 1966; Enterline, 1974; Mancuso, 1975; Ohsaki et al., 1978; Sano and Mitohara, 1978; Hayes et al., 1979; Hill and Ferguson, 1979; Alderson et al., 1981; Haguenor et al., 1981; Satoh et al., 1981; Korallus et al., 1982; Frentzel-Beyme, 1983; Langard and Vigander, 1983; Watanabe and Fukuchi, 1984; Davies, 1984; Mancuso, 1997). Mancuso and Hueper (1951) conducted a proportional mortality study of a cohort of chromate workers (employed for > l year from 1931-1949 in a Painesville, OH chromate plant) in order to investigate lung cancer associated with chromate production. Of the 2,931 deaths of males in the county where the plant is located, 34 (1.2%) were due to respiratory cancer. Of the 33 deaths among the chromate workers, however, 6 (18.2%) were due to respiratory cancer. Within the limitations of the study design, this report strongly suggested an increased incidence of respiratory cancer in the chromate-production plant. In an update of the Mancuso and Hueper (1951) study, Mancuso (1975) followed 332 of the workers employed from 1931-1951 until 1974. By 1974, > 50% of this cohort had died. Of these men, 63.6%, 62.5%, and 58.3% of the cancer deaths for men employed from 1931-1932, 1933-1934, and 1935-1937, respectively, were due to lung cancer. Lung cancer death rates increased by gradient of exposure to total chromium, and significant deposition of chromium was found in the lungs of workers long after the exposure ceased. Mancuso (1975) reported that these lung cancer deaths were related to insoluble (trivalent), soluble (hexavalent), and total chromium exposure, but the small numbers involved make identification of the specific form of chromium responsible for the lung cancer uncertain. Mancuso (1997) recently updated this study, following the combined cohort of 332 workers until 1993. Of 283 deaths (85% of the cohort identified), 66 lung cancers were found (23.3% of all deaths and 64.7% of all cancers). Lung cancer rates clearly increased by gradient level of exposure to total chromium. The relationship between gradient level of exposure and lung cancer rates is less clear for trivalent and hexavalent chromium. The rates of lung cancer within the cohort are consistent with those reported in Mancuso (1975), and provide further support for the cancer risk assessment based on those data. Studies of chrome pigment workers in the United States (Hayes et al., 1989), England (Davies, 1984, 1979, 1978), Norway (Langard and Vigander, 1983; Langard and Norseth, 1975), and in the Netherlands and Germany (Frentzel-Beyme, 1983) have consistently demonstrated an association between occupational chromium exposure (predominantly to Cr [VI]) and lung cancer. Several studies of the chromeplating industry have demonstrated a positive relationship between cancer and exposure to chromium compounds (Royle, 1975; Franchini et al., 1983; Sorahan et al., 1987). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Animal data are consistent with the findings of human epidemiological studies of hexavalent chromium. Hexavalent chromium compounds were carcinogenic in animal assays producing the following tumor types: lung tumors following inhalation of aerosols of sodium chromate and pyrolized Cr(VI)/Cr(III) oxide mixtures in rats (Glaser et al., 1986), lung tumors following intratracheal administration of sodium dichromate in rats (Steinhoff et al., 1983), intramuscular injection site tumors in Fischer 344 and Bethesda Black rats and in C57BL mice (Furst et al., 1976; Maltoni, 1974, 1976; Payne, 1960a; Hueper and Payne, 1959); intrapleural implant site tumors for various Cr(VI) compounds in Sprague-Dawley and Bethesda Black rats (Payne, 1960b; Hueper 1961; Hueper and Payne, 1962), intrabronchial implantation site tumors for various Cr(VI) compounds in Wistar rats (Levy and Martin, 1983; Laskin et al., 1970; Levy, as quoted in NIOSH, 1975), and subcutaneous injection site sarcomas in Sprague-Dawley rats (Maltoni, 1974, 1976). Inflammation is considered to be essential for the induction of most chromium respiratory effects and may influence the carcinogenicity of Cr(VI) compounds (Glaser et al., 1985). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Metabolism and genotoxicity. Hexavalent chromium is rapidly taken up by cells through the sulfate transport system (Sugiyama, 1992). Once inside the cell, Cr(VI) is quickly reduced to the trivalent form by cellular reductants, including ascorbic acid, glutathione and flavoenzymes (cytochrome P-450 and glutathione reductase), and riboflavin (De Flora et al., 1989; De Flora et al., 1990; Sugiyama, 1992). The intracellular reduction of Cr(VI) generates reactive Cr(V) and Cr(IV) intermediates as well as hydroxyl free radicals (OH) and singlet oxygen (1O2) (Kawanishi et al., 1986). A variety of DNA lesions are formed during the reduction of Cr(VI) to Cr(III), including DNA strand breaks, alkali-labile sites, DNA-protein and DNA-DNA crosslinks, and oxidative DNA damage, such as 8-oxo-deoxyguanosine (Klein et al., 1992; Klein et al., 1991; De Flora et al., 1990). The relative importance of the different chromium complexes and oxidative DNA damage in the toxicity of Cr(VI) is unknown. A large number of chromium compounds have been assayed with in vitro genetic toxicology assays. In general, hexavalent chromium is mutagenic in bacterial assays whereas trivalent chromium is not (Lofroth, 1978; Petrilli and DeFlora, 1977, 1978). Likewise Cr(VI), but not Cr(III), was mutagenic in yeasts (Bonatti et al., 1976) and in V79 cells (Newbold et al., 1979). Cr(III) and (VI) compounds decrease the fidelity of DNA synthesis in vitro (Loeb et al., 1977), while Cr(VI) compounds inhibit replicative DNA synthesis in mammalian cells (Levis et al., 1978) and produce unscheduled DNA synthesis, presumably repair synthesis, as a consequence of DNA damage (Raffetto, 1977). Chromate has been shown to transform both primary cells and cell lines (Fradkin et al., 1975; Tsuda and Kato, 1977; Casto et al., 1979). Chromosomal effects produced by treatment with chromium compounds have been reported by a number of authors; for example, both Cr(VI) and Cr(III) salts were clastogenic for cultured human leukocytes (Nakamuro et al., 1978). In dogs (2/group) exposed to potassium dichromate in drinking water at concentrations up to 11.2 ppm for 4 years, gross and microscopic examination of all major organs revealed no treatment-related lesions (Anwar et al., 1961). The small number of animals and the relatively short exposure duration relative to the lifespan of the dog precludes a conclusion regarding a possible carcinogenic response. There are no other long-term studies of ingested Cr(VI). Cr(VI) is readily converted to Cr(III) in vivo, but there is no evidence that Cr(III) is oxidized to Cr(VI) in vivo. Cr(III) is an essential trace element. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE The oral carcinogenicity of Cr(VI) cannot be determined. No data were located in the available literature that suggested that Cr(VI) is carcinogenic by the oral route of exposure. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES ____II.C.1.1. Air Unit Risk -- 1.2E-2 (ug/m3) Source: Mancuso, 1975 ____II.C.1.2. Extrapolation Method -- Multistage, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) 8E-3 (ug/m3) E-5 (1 in 100,000) 8E-4 (ug/m3) E-6 (1 in 1,000,000) 8E-5 (ug/m3) DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor type -- lung cancer Test animals -- human Route -- inhalation, occupational exposure Source -- Mancuso, 1975 Exposure level Deaths from Subject age (years) midrange (ug/m3) lung cancer Person-years ------------------------------------------------------------------------ 50 5.66 3 1,345 25.27 6 931 46.83 6 299 ------------------------------------------------------------------------ 60 4.68 4 1,063 20.79 5 712 39.08 5 211 ------------------------------------------------------------------------ 70 4.41 2 401 21.29 4 345 ------------------------------------------------------------------------ ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) Mancuso (1997) recently updated the study of Mancuso (1975), following the combined cohort of 332 workers until 1993. Of 283 deaths (85% of the cohort identified), 66 lung cancers were found (23.3% of all deaths and 64.7% of all cancers). Lung cancer rates clearly increased by gradient level of exposure to total chromium. The relationship between gradient level of exposure and lung cancer rates is less clear for trivalent and hexavalent chromium. The rates of lung cancer within the cohort are consistent with those reported in Mancuso (1975), and provide further support for the cancer risk assessment based on those data. The cancer mortality in Mancuso (1975) was assumed to be due to Cr(VI), which was further assumed to be no less than one-seventh of total chromium. It was also assumed that the smoking habits of chromate workers were similar to those of the U.S. white male population. Trivalent chromium compounds have not been reported as carcinogenic by any route of administration. The unit risk should not be used if the air concentration exceeds 8E-1 ug/m3, since above this concentration the unit risk may not be appropriate. The carcinogenicity section of this IRIS Summary was updated in 1998; however, the quantitative results have not been modified. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Results of studies of chromium exposure are consistent across investigators and countries. A dose relationship for lung tumors has been established. The assumption that the ratio of Cr(III) to Cr(VI) is 6:1 may lead to a sevenfold underestimation of risk. The use of 1949 hygiene data (Bourne and Yee, 1950), which may underestimate worker exposure, may result in an overestimation of risk. Further overestimation of risk may be due to the implicit assumption that the smoking habits of chromate workers were similar to those of the general white male population, since it is generally accepted that the proportion of smokers is higher for industrial workers than for the general population. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 1998. To review this appendix, exit to the toxicological review, Appendix A, External Peer Review - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0144-tr.pdf#page=72. Other EPA Documentation -- U.S. EPA. (1984) Health assessment document for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8-83-014F. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency consensus date -- 04/28/1998 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199809 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Chromium(VI) CASRN -- 18540-29-9 Last Revised -- 09/03/1998 SORD: __VI.A. ORAL RfD REFERENCES Anwar, RA; Langham, FF; Hoppert, CA; et al. (1961) Chronic toxicity studies. III. Chronic toxicity of cadmium and chromium in dogs. Arch Environ 3:456-460. Bruynzeel, DP; Hennipman, G; van Ketel, WG. (1988) Irritant contact dermatitis and chromium-passivated metal. Contact Derm 19:175-179. Burrows, D; Adams, RM. (1990) In: Occupational skin disease, 2nd ed., Adams, RM, ed. Philadelphia: W.B. Saunders, pp. 349-386. Cronin, E. (1980) Contact dermatitis. New York: Churchill Livingstone, pp. 287-390. Elbetieha, A; Al-Hamood, MH. (1997) Long-term exposure of male and female mice to trivalent and hexavalent chromium compounds: effect on fertility. Toxicology 116:19-47. Fregert, S. (1981) Chromium valencies and cement dermatitis. Br J Dermatol 105 (suppl. 21):7-9. Gruber, JE; Jennette, KW. (1978) Metabolism of the carcinogen chromate by rat liver microsomes. Biochem Biophys Res Commun 82(2):700-706. Hunter, D. (1974) The diseases of occupations, 5th ed. Boston: Little, Brown. Junaid, M; Murthy, RC; Saxena, DK. (1996) Embryotoxicity of orally administered chromium in mice: exposure during the period of organogenesis. Toxicol Lett 84:143-148. Kanojia, RK; Junaid, M; Murthy, RC. (1996) Chromium induced teratogenicity in female rat. Toxicol Lett 89:207-213. MacKenzie, RD; Byerrum, RU; Decker, CF; et al. (1958) Chronic toxicity studies. II. Hexavalent and trivalent chromium administered in drinking water to rats. Am Med Assoc Arch Ind Health 18:232-234. National Toxicology Program (NTP). (1996a) Final Report. Potassium dichromate (hexavalent): The effects of potassium dichromate on Sprague-Dawley rats when administered in the diet. December 13, 1996. National Toxicology Program (NTP). (1996b) Final Report. Potassium dichromate (hexavalent): The effects of potassium dichromate in BALB/c mice when administered in the diet. November 27, 1996. National Toxicology Program (NTP). (1997) Final Report. Potassium dichromate (hexavalent): Reproductive assessment by continuous breeding when administered to BALB/c mice in the diet. February 18, 1997. Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagencity of hexavalent chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805-809. Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trivalent chromium to the mutagenic hexavalent form. Mutat Res 58(2-3):167-178. Polak, L. (1983) Immunology of chromium. In: Chromium: metabolism and toxicity. Burrows, D, ed. Boca Raton, FL: CRC Press, pp. 51-135. Polak, L; Turk, JL; Frey, FR. (1973) Studies on contact hypersensitivity to chromium compounds. Progr Allergy 17:145-219. Spruit, D; van Neer, FCJ. (1966) Penetration rate of Cr(III) and Cr(VI). Dermatological 132:179-182. U.S. Environmental Protection Agency (U.S. EPA). (1984) Health effects assessment for hexavalent chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. (1985) Drinking water health advisory for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available online at http://www.epa.gov/iris. Zhang, J; Li, X. (1987) Chromium pollution of soil and water in Jinzhou. J of Chinese Preventive Med 21:262-264. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Beck, BD; Brain, JD; Bohannon, DE. (1982) An in vivo hamster bioassay to assess the toxicity of particles for the lungs. Toxicol Appl Pharmacol 66:9-29. Cohen, SR; Davis, DM; Kramkowski, RS. (1974) Clinical manifestations of chronic acid toxicity--Nasal lesions in electroplate workers. Cutis 13:558-568. Glaser, U; Hochrainer, D; Kloppe, H; et al. (1985) Low level chromium (VI) inhalation effects on alveolar macrophages and immune function in Wistar rats. Arch Toxicol 57(4):250-256. Glaser, U; Hochrainer, D; Steinhoff, D. (1990) Investigation of irritating properties of inhaled Cr(VI) with possible influence on its carcinogenic action. In: Environmental Hygiene II. Seemayer, NO; Hadnagy, W, eds. Berlin/New York: Springer-Verlag. Henderson, RF. (1984) Use of bronchoalveolar lavage to detect lung damage. Environ Health Perspect 56:115-129. Henderson, RF. (1988) Use of bronchoalveolar lavage to detect lung damage. In: Toxicology of the lung. Gardner, DE; Crapo, JD; Masaro, EJ, eds., New York: Raven Press. Henderson, RF; Benson, JM; Hahn, FF. (1985) New approaches for the evaluation of pulmonary toxicity: bronchoalveolar lavage fluid analysis. Fundam Appl Toxicol 5:451-458. Lees, PSJ; Gibb, HJ; Rooney, BC. (1995) Derivation of exposure-response relationship for chromium from historic exposure data. 11th International Symposium of Epidemiology in Occupational Health, the Netherlands, September 1995. Lindberg, E; Hedensteirna, G. (1983) Chrome plating: Symptoms, finding in the upper airways and effects on lung function. Arch Environ Health 38:367-374. Lucas, JB; Kramkowski, RS. (1975) Health Hazard Evaluation Report No. 74-87-221. Cincinnati, OH. Health Hazard Evaluation Branch, U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control. National Institute for Occupational Safety and Health. Malsch, PA; Proctor, DM; Finley, BL. (1994) Estimation of a chromium inhalation reference concentration using the benchmark dose method: a case study. Regul Toxicol Pharmacol 20:58-82. U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available online at http://www.epa.gov/iris. Venet, A; Clavel, F; Israel-Biet, D; et al. (1985) Lung in acquired immune deficiency syndrome: Infectious and immunological status assessed by bronchioalveolar lavage. Bull Eur Physiopathol Respir 21:535-543. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Alderson, MR; Rattan, NS; Bidstrup, L. (1981) Health of workmen in the chromate-producing industry in Britain. Br J Ind Med 38:117-124. Baetjer, AM. (1950a) Pulmonary carcinoma in chromate workers. In: A review of the literature and report of cases. Arch Ind Hyg Occup Med 2(5):487-504. Baetjer, AM. (1950b) Pulmonary carcinoma in chromate workers. II. Incidence on basis of hospital records. Arch Ind Hyg Occup Med 2(5):505-516. Bidstrup, PL. (1951) Carcinoma of the lung in chromate workers. Br J Med 8:302-305. Bidstrup, PL; Case, RAM. (1956) Carcinoma of the lung in workmen in the bichromates-producing industry in Great Britain. Br J Ind Med 13:260-264. Bonatti, S; Meini, M; Abbondandolo, A. (1976) Genetic effects of potassium dichromate in Schizosaccharomyces pombe. Mutat Res 38:147-150. Bourne, HG, Jr; Yee, HT. (1950) Occupational cancer in a chromate plant - an environmental appraisal. Ind Med Surg 19(12):563-567. Brinton, HP; Frasier, ES; Koven AL. (1952) Morbidity and mortality experience among chromate workers. Public Health Rep 67(9):835-847. Casto, BC; Meyers, J; DiPaolo, JA. (1979) Enhancement of viral transformation for evaluation of the carcinogenic or mutagenic potential of inorganic metal salts. Cancer Res 39:193-198. Davies, JM. (1978) Lung-cancer mortality in workers making chrome pigments. Lancet 1:384. Davies, JM. (1979) Lung cancer mortality of workers in chromate pigment manufacture: An epidemiological survey. J Oil Chem Assoc 62:157-163. Davies, JM. (1984) Lung cancer mortality among workers making lead chromate and zinc chromate pigments at three English factories. Br J Ind Med 41:158-169. De Flora, S; Wetterhahn, KE. (1989) Mechanisms of chromium metabolism and genotoxicity. Life Chem Rep 7:169-244. De Flora, S; Bagnasco, M; Serra, D; et al. (1990) Genotoxicity of chromium compounds: a review. Mutat Res 238:99-172. Enterline, PE. (1974) Respiratory cancer among chromate workers. J Occup Med 16:523-526. Fradkin, A; Janoff, A; Lane, BP; et al. (1975) In vitro transformation of BHK21 cells grown in the presence of calcium chromate. Cancer Res 35:1058-1063. Frentzel-Beyme, R. (1983) Lung cancer mortality of workers employed in chromate pigment factories. A multicentric European epidemiological study. J Cancer Res Clin Oncol 105:183-188. Furst, A; Schlauder, M; Sasmore, DP. (1976) Tumorigenic activity of lead chromate. Cancer Res 36:1779-1783. Glaser, U; Hochrainer, D; Kloppel, H; et al. (1986) Carcinogenicity of sodium dichromate and chromium(VI/III) oxide aerosols inhaled by male Wistar rats. Toxicology 42:219-232. Haguenor, JM; Dubois, G; Frimat, P; et al. (1981) Mortality due to bronch-pulmonary cancer in a factory producing pigments based on lead and zinc chromates. In: Prevention of occupational cancer - International symposium, occupational safety and health series 46. Geneva, Switzerland: International Labour Office, pp. 168-176. (French). Hayes, RB; Lilienfeld, AM; Snell, LM. (1979) Mortality in chromium chemical production workers: a prospective study. Int J Epidemiol 8(4):365-374. Hayes, RB; Sheffet, A; Spirtas, R. (1989) Cancer mortality among a cohort of chromium pigment workers. Am J Ind Med 16:127-133. Hill, WJ; Ferguson, WS. (1979) Statistical analysis of epidemiological data from chromium chemical manufacturing plant. J Occup Med 21:103-106. Hueper, WC. (1961) Environmental carcinogenesis and cancers. Cancer Res 21:842-857. Hueper, WC; Payne, WW. (1962) Experimental studies in metal carcinogenesis: Chromium, nickel, iron, and arsenic. Arch Environ Health 5:445-462. Hill, WJ; Ferguson, WS. (1979) Statistical analysis of epidemiological data from a chromium chemical manufacturing plant. J Occup Med 21(2):103-106. Kawanishi, S; Inoue, S; Sano, S. (1986) Mechanism of DNA cleavage induced by sodium chromate (VI) in the presence of hydrogen peroxide. J Biol Chem 261:5952-5958. Klein, CB; Frenkel, K; Costa, M. (1992) Chromium mutagenesis in transgenic gpt+ Chinese hamster cell lines. Environ Mol Mutagen 19:29a. Klein, CB; Frenkel, K; Costa, M. (1991) The role of oxidative processes in metal carcinogenesis. Chem Res Toxicol 4:592-604. Korallus, U; Lange H; Ness, A; et al. (1982) Relationships between precautionary measures and bronchial carcinoma mortality in the chromate-producing industry. Arbeitsmedizin, Socialmedizin, Preventivmedizin. 17(7):159-167. (German - Eng. summary) Langard, S; Norseth, T. (1975) A cohort study of bronchial carcinomas in workers producing chromate pigments. Br J Ind Med 32:62-65. Langard, S; Vigander, T. (1983) Occurrence of lung cancer in workers in producing chromium pigments. Br J Ind Med 40:71-74. Laskin, S; Kuschner, M; Drew, RT. (1970) Studies in pulmonary carcinogenesis. In: Hanna, Jr., MG;, Nettesheim, P; and Gilbert, JR, eds. Levis, AG; Buttignol, M; Bianchi, V; et al. (1978) Effects of potassium dichromate on nucleic acid and protein syntheses and on precursor uptake in BHK fibroblasts. Cancer Res 38:110-116. Levy, LS; Martin, PA. (1983) The effects of a range of chromium-containing materials on rat lung. Sponsored by Dry Color Manufacturers' Association and others. (Unpublished) Loeb, LA; Sirover, MA; Agarwal, SS. (1977) Infidelity of DNA synthesis as related to mutagenesis and carcinogenesis. Adv Exp Biol Med 91:103-115. Lofroth, G. (1978) The mutagenicity of hexavalent chromium is decreased by microsomal metabolism. Naturvissenschaften 65:207-208. Machle, W; Gregorius, F. (1948) Cancer of the respiratory system in the United States chromate-producing industry. Public Health Rep 63(35):1114-1127. Maltoni, C. (1974) Occupational carcinogenesis. Excerpta Med Int Congr Ser 322:19-26. Maltoni, C. (1976) Predictive value of carcinogenesis bioassays. Ann NY Acad Sci 271:431-443. Mancuso, TF. (1975) Consideration of chromium as an industrial carcinogen. International Conference on Heavy Metals in the Environment, Toronto, Ontario, Canada, October 27-31. pp. 343-356. Mancuso, TF. (1997) Chromium as an industrial carcinogen: Part 1. Am J Ind Med 31:129-139. Mancuso, TF; Hueper, WC. (1951) Occupational cancer and other health hazards in a chromate plant: A medical appraisal. In: Lung cancers in chromate workers. Ind Med Surg 20(8):358-363. Nakamuro, K; Yoshikawa, K; Sayato, Y; et al. (1978) Comparative studies of chromosomal aberration and mutagenicity of trivalent and hexavalent chromium. Mutat Res 58:175-181. Newbold, RF; Amos, J; Connell, JR. (1979) The cytotoxic, mutagenic and clastogenic effects of chromium-containing compounds on mammalian cells in culture. Mutat Res 67:55-63. National Institute for Occupational Safety and Health (NIOSH). (1975) Criteria for a recommended standard occupational exposure to chromium (VI). U.S. Department of Health, Education, and Welfare, Washington, DC. Ohsaki, Y; Abe, S; Kimura, K; et al. (1978) Lung cancer in Japanese chromate workers. Thorax 33:372-374. Payne, WW. (1960a) The role of roasted chromite ore in the production of cancer. Arch Environ Health 1:20-26. Payne, WW. (1960b) Production of cancers in mice and rats by chromium compounds. Arch Ind Health 21:530-535. Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagenicity of hexavalent chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805-809. Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trivalent chromium to the mutagenic hexavalent form. Mutat Res 58:167-178. Raffetto, G; Parodi, S; Parodi, C; et al. (1977) Direct interaction with cellular targets as the mechanism for chromium carcinogenesis. Tumori 63:503-512. Royle, H. (1975) Toxicity of chromic acid in the chromium plating industry. Environ Res 10:141-163. Sano, T; Mitohara, I. (1978) Occupational cancer among chromium workers. Jpn J Chest Dis 37(2):90-101. Satoh, K; Fukuda, Y; Torii, K; et al. (1981) Epidemiologic study of workers engaged in the manufacture of chromium compounds. J Occup Med 23(12):835-838. Sorahan, T; Burgess, DC; Waterhouse, JA. (1987) A mortality study of nickel/chromium platers. Br J Ind Med 44:250-258. Steinhoff, S; Gad, SC; Hatfield, GK; et al. (1983) Listing sodium dichromate and soluble calcium chromate for carcinogenicity in rats. Bayer AG Institute of Toxicology. (Unpublished) Sugiyama, M. (1992) Role of physiological antioxidants in chromium (VI)-induced cellular injury. Free Rad Biol Med 12:397-407. Taylor, FH. (1966) The relationship of mortality and duration of employment as reflected by a cohort of chromate workers. Am J Public Health 56(2):218-229. Todd, GE. (1962) Tobacco manufacturer's standing committee research papers. No. 1. Statistics of Smoking in the United Kingdom, 3rd ed. Tobacco Research Council, London. Tsuda, H; Kato, K. (1977) Chromosomal aberrations and morphological transformation in hamster embryonic cells treated with potassium dichromate in vitro. Mutat Res 46:87-94. U.S. EPA. (1984) Health assessment document for chromium. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8-83-014F. U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available online at http://www.epa.gov/iris. Watanabe, S; Fukuchi, Y. (1975) An epidemiological survey on lung cancer in workers of a chromate-producing industry in Hokkaido, Japan. Presented at International Congress on Occupational Health. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Chromium(VI) CASRN --18540-29-9 Date Section Description ---------------------------------------------------------------------------- 09/30/1987 II.A.1. Citation corrected 03/01/1988 II.C.4. Confidence statement revised 03/01/1988 II.D.3. Contacts switched 03/01/1988 III.A. Health Advisory added 12/01/1989 I.B. Inhalation RfD now under review 06/01/1990 II.A.1. Basis - Text revised 06/01/1990 II.B. Text revised 06/01/1990 IV.A.1. Area code for EPA contact corrected 06/01/1990 IV.F.1. EPA contact changed 06/01/1990 VI. Bibliography on-line 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 03/01/1991 II.A.1. Text revised 03/01/1991 II.A.4. Text revised 03/01/1991 II.B. Text revised 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1992 IV.A.1. CAA regulatory action withdrawn 06/01/1992 All CASRN corrected from 7440-47-3 to 18540-29-9 09/01/1994 I.A.6. Work group review date added 02/01/1995 I.A. RfD noted as pending change: Work Grp Mtg on 08/03/1994 08/01/1995 I.A., I.A.6., I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/01/1996 I.A.7. Secondary contact removed 09/03/1998 I,II,VI Revised RfD, RfC, carcinogenicity assessment, refs. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 382 of 1119 in IRIS (through 2003/06) AN: 151 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199412 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Dichlorvos- SY: 62-73-7; ASTROBOT-; ATGARD-; ATGARD-V-; BAY-19149-; BIBESOL-; BREVINYL-; BREVINYL-E50-; BREVINYL-WEEDAT-0002-; CANOGARD-; CEKUSAN-; CELCUSAN-; CHLORVINPHOS-; CYANOPHOS-; DDVF-; DDVP-; DEDEVAP-; DERIBAN-; DERRIBANTE-; DICHLORMAN-; 2,2-DICHLOROETHENYL-PHOSPHATE-; 2,2-DICHLOROETHENYL-PHOSPHORIC-ACID-DIMETHYL-ESTER-; DICHLOROPHOS-; DICHLOROVAS-; 2,2-DICHLOROVINYL-DIMETHYL-PHOSPHATE-; DICHLOROVOS-; DICHLORPHOS-; DIMETHYL-2,2-DICHLOROETHENYL-PHOSPHATE-; DIMETHYL-DICHLOROVINYL-PHOSPHATE-; DIMETHYL-2,2-DICHLOROVINYL-PHOSPHATE-; DIVIPAN-; ENT-20738-; EQUIGARD-; EQUIGEL-; ESTROSEL-; ESTROSOL-; ETHENOL,-2,2-DICHLORO-,-DIMETHYL-PHOSPHATE-; FECAMA-; FLY-DIE-; FLY-FIGHTER-; HERKAL-; HERKOL-; KRECALVIN-; MAFU-; MARVEX-; MOPARI-UN-NA-2783-; NCI-C00113-; NERKOL-; NOGOS-; NOGOS-50-; NOGOS-G-; NO-PEST-STRIP-; NSC-6738-; NUVA-; NUVAN-; NUVAN-100-EC-; OKO-; OMS-14-; O,O-DIMETHYL-DICHLOROVINYL-PHOSPHATE-; O,O-DIMETHYL-O-2,2-DICHLOROVINYL-PHOSPHATE-; PHOSPHORIC-ACID,-2,2-DICHLOROETHENYL-DIMETHYL-ESTER-; PHOSPHORIC-ACID,-2,2-DICHLOROVINYL-DIMETHYL-ESTER-; PHOSVIT-; SD1750-; SZKLARNIAK-; TAP-9VP-; TASK-; TASK-TABS-; TENAC-; UDVF-; UNIFOS-; UNIFOS-50-EC-; VAPONA-; VAPONA-II-; VAPONA-INSECTICIDE-; VAPONITE-; VERDICAN-; VERDIPOR-; VINYL-ALCOHOL,-2,2-DICHLORO-,-DIMETHYL-PHOSPHATE-; VINYLOPHOS- RN: 62-73-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199311 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Dichlorvos CASRN -- 62-73-7 Last Revised -- 11/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Plasma and RBC ChE NOAEL: 0.05 mg/kg-day 100 1 5E-4 inhibition in males mg/kg-day and females; brain LOAEL: 0.1 mg/kg-day ChE inhibition in males 1-Year Dog Feeding Study AMVAC Chemical Corp., 1990 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- None PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) AMVAC Chemical Corporation. 1990. MRID No. 41593101; HED Doc. No. 008178. Available from EPA. Write to FOI, EPA, Washington, DC 20460. In a chronic feeding study (AMVAC Chemical Corp., 1990), groups of beagle dogs (4/sex/dose) were administered dichlorvos by capsule for 52 weeks at dose levels of 0, 0.1, 1.0 and 3.0 mg/kg-day. The 0.1 mg/kg-day dose level was lowered to 0.05 mg/kg-day on day 22 due to the inhibition of plasma ChE noted after 12 days on test material. Capsules were prepared weekly based on the most recently recorded body weight, and stored refrigerated and protected from light. Animals received food and water ad libitum. No deaths occurred. Ataxia, salivation and dyspnea were observed in one male in the high-dose group on 1 day in Week 33. The study investigator believed these signs were due to a slight overdose with dichlorvos. Formulation and dosing records could not confirm that an overdose occurred. Mean cumulative body weight gain was decreased in males in the high-dose group during Week 1 to Week 7. At termination, mean cumulative body weight gain was comparable among groups. Plasma ChE was decreased in males (21.1%) and females (25.7%) at Week 2 in the 0.1 mg/kg-day. In order to achieve a NOEL, the dose was dropped to 0.05 mg/kg-day at Day 1 of Week 4. After Week 2, plasma ChE was only significantly decreased in males (39.1 to 59.2%) and females (41.0 to 56.7%) in the mid-dose group and in males (65.1 to 74.3%) and females (61.1 to 74.2%) in the high-dose group at all other later time intervals. RBC ChE was decreased in males (23.6%) and females (50.1%) at Week 6 in the low-dose group. This is believed to be the residual effect on RBC ChE of the initial higher dose of 0.1 mg/kg-day. Much lower levels were observed in this group after Week 6. After Week 6, RBC ChE was only significantly decreased in males (43.0 to 53.9%) and females (38.0 to 51.9%) in the mid-dose group and in males (81.2 to 86.9%) and females (79.2 to 82.5%) in the high-dose group at all other later time intervals. The percent inhibition did not appear to increase with time. Brain ChE was significantly decreased in males (approximately 22%) in the mid-dose group and in males (approximately 47%) and females (approximately 29%) in the high-dose group. In the range-finding study (AMVAC Chemical Corp., 1990) for the chronic toxicity study, groups of beagle dogs were administered dichlorvos by capsule for 2 weeks at dose levels of 0, 0.1, 0.1 (10.0), 1.0 (5.0), 30 (15.0) and 60 mg/kg-day. Test Group 1 (1 male; 1 female) served as controls. Test Group 2 contained two groups of animals, each consisting of 1 male and 1 female. The first group received 0.1 mg/kg-day throughout the study. The second group received 0.1 mg/kg-day from Day 1 to 7 and 10 mg/kg-day from Day 8 to 24. Test Group 3 received 1.0 mg/kg-day from Day 1 to 14 and 5 mg/kg-day from Day 15 to 24. The male from Test Group 4 received 30 mg/kg-day throughout the study while the female received 30 mg/kg-day from Day 1 to 6, was not dosed on Days 7 and 8, and received 15 mg/kg-day from Day 9 to 15. Test Group 5 received 60 mg/kg-day throughout the study. Death occurred in the 30 and 60 mg/kg-day groups. Toxic signs observed at these dose levels included: salivation, ataxia, emesis, miosis, cyanotic appearance, lacrimation, urine stains, soft feces (mucoid, red) and/or rough coat. Soft mucoid feces were noted at 1.0 mg/kg-day. At 5.0 mg/kg-day, emesis, tremors, alopecia, salivation, soft mucoid red feces and/or few feces were observed. The male in the 0.1 mg/kg-day group exhibited emesis. Body weight loss and decreased food consumption were noted in the 5.0 and 10.0 mg/kg-day groups. The blood urea nitrogen (BUN) was elevated in dogs in the 5.0 and 10.0 mg/kg-day groups. Plasma and RBC ChE were decreased in dogs in the 1.0 mg/kg-day group and at higher dose levels. Brain ChE was decreased in the female in the 0.1 mg/kg-day by approximately 16% and in all dogs at the higher dose levels. Brain ChE levels were not determined in the 1.0 mg/kg-day group until after the dose ChE level had been changed for at least 1 week. Therefore, brain ChE levels could not be accurately determined at the 1.0 mg/kg-day level. In a subchronic feeding study (Shell Chemical Co., 1967a), groups of beagle dogs (3/sex/dose) were administered dichlorvos by capsule for 90 days at dose levels of 0, 5, 15 and 25 ppm (0, 0.125, 0.375 and 0.625 mg/kg-day). Twenty-one days after the start of the study, the 5 ppm group was increased to 50 ppm (1.25 mg/kg-day) and an additional 5 ppm group was added. Control animals received olive oil only. Excitement and hyperactivity were reported among all the high-dose dogs and two of the mid-dose dogs. Dogs in the mid- and high-dose groups showed increased urinary output. No consistent decreases in RBC or plasma cholinesterase were reported, although the greatest decrease in the high-dose dogs was seen on day 54, when RBC ChE was 41.3%, the plasma ChE was 54.2% and the total ChE value was 47.8% of the control. The greatest decrease in the 25 ppm dogs was seen on day 74 when RBC ChE was 41.3% and total cholinesterase was 51% of the control. At terminal sacrifice, brain ChE activity was decreased to 32.8% of control at 50 ppm and to 88.6% of the control at 25 ppm. No changes were observed in the two lower doses. Based on decreases in brain and blood ChE activity, the LEL for systemic toxicity is 25 ppm (0.625 mg/kg-day). The NOEL for systemic toxicity is 15 ppm (0.375 mg/kg-day). Based on the effects observed in these three dog studies, a weight of the evidence LEL for systemic toxicity can be set at 0.1 mg/kg-day based on plasma ChE inhibition in males and females and brain ChE inhibition in males. The NOEL for systemic toxicity is 0.05 mg/kg-day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 100 reflects 10 for interspecies extrapolation and 10 for intraspecies-variability. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) 1) 1-Year Feeding - dog: Principal study -- see previous description; core grade guideline (AMVAC Chemical Corp., 1990) 2) 2-Year Feeding/Oncogenicity - rat: Core grade supplementary for chronic feeding, minimum for oncogenicity (NTP, 1987) Groups of Fischer 344 rats (60/sex/dose) were administered dichlorvos by gavage once daily 5 days/week for 103 consecutive weeks at dose levels of 0, 4 and 8 mg/kg-day followed by a 1 week observation period. The control group received corn oil. Five animals/sex/dose were used to monitor the systemic toxicity of dichlorvos by determining plasma and RBC ChE levels at 6 weeks and at 3, 6, 9, 12, 18 and 24 months. An additional five animals/sex/dose were used for brain and sciatic nerve histology. Only minimal clinical signs were observed in the study. A significant decrease in both plasma and RBC ChE was observed in both test groups. Wide disparities were reported between cholinesterase values in male and female vehicle-treated rats (female plasma ChE values were 2 to 6 times higher than male values); however, the cholinesterase depressions were consistently lower in the treated animals than in the controls, indicating that cholinesterase depression was related to the administration of the test compound. Based on the plasma and RBC ChE inhibition, the LEL for systemic toxicity is 4 mg/kg-day. A NOEL for systemic toxicity was not established. 3) 13-Week Feeding - rat: No core grade (NTP, 1987) This study was conducted as the range-finding study for the 2-year rat feeding/oncogenicity study (NTP, 1983). Groups of Fischer 344 rats (10/sex/dose) were administered dichlorvos for 13 weeks at dietary levels of 0, 2, 4, 8, 16, 32 and 64 mg/kg-day. All animals treated with 32 and 64 mg/kg-day died before study termination. At 16 mg/kg-day, 1 out of 10 males and 4r out of 10 females died. The one male death was accidental. When compared to the controls, body weight gains were -6%, +2%, +1% and +4% for the males and -7%, -2%, 0% and +2% for the females receiving 16, 8, 4 and 2 mg/kg-day, respectively. Clinical signs observed in the animals that died on study were trembling, diarrhea, wet fur around the mouth and convulsions immediately preceding death. No clinical signs or significant pathology were observed in animals which survived the study. Based on mortality and clinical signs observed in this study, the MTD for the chronic rat study was selected at 16 mg/kg-day for males and 8 mg/kg-day for females. Since published information indicated that males were more sensitive than females, NTP approved doses of 0, 4 and 8 mg/kg-day for both sexes. 4) 3-Generation Reproduction - rat: Core grade supplementary (Shell Chemical Co., 1965) Groups of Sprague-Dawley rats (15/sex/dose) were administered dichlorvos over three generations at dietary levels of 0, 0.1, 1, 10, 100 and 500 ppm (0, 0.005, 0.05, 0.5, 5 and 25 mg/kg-day). No maternal or reproductive toxicity were observed at any dose tested. Therefore, the NOEL for maternal and reproductive toxicity is greater than or equal to 500 ppm (25 mg/kg-day). 5) Developmental toxicity - rat: Core grade minimum (AMVAC Chemical Corp., 1991) Groups of pregnant Sprague-Dawley rats (25/dose) were administered dichlorvos via gavage at dose levels of 0, 0.1, 3.0 and 21 mg/kg-day during gestational days 6-15. Maternal toxicity was observed at the highest dose tested. The signs of toxicity included tremors, prone positioning, hindleg splay, vocalization, labored respiration, ear shaking, ingesting of urine-marked bedding and decreased water consumption. Based on these effects, the NOEL and LEL for maternal toxicity are 3 and 21 mg/kg-day, respectively. No developmental toxicity was observed at any dose tested. Therefore, the NOEL for developmental toxicity is equal to or greater than 21 mg/kg-day. Other Data Reviewed: 1) 2-Year Feeding/Oncogenicity - mouse: Core grade minimum (NTP, 1987) Groups of B6C3F1 mice (60/sex/dose) were administered dichlorvos by gavage (corn oil) 5 days/week for 103 weeks at dose levels of 0, 10 and 20 mg/kg-day for males and 0, 20, and 40 mg/kg-day for females followed by a 1 week observation period. Five animals/sex/dose were used for determination of plasma and RBC ChE levels at 6, 13, 24, 36, 52, 78 and 104 weeks. An additional 5 animals/sex/dose were used for brain and sciatic nerve histology at study termination. Significantly decreased plasma and RBC ChE was observed in males and females at all dose levels, although the cholinesterase values returned to normal in female mice on withdrawal of the test compound. The RBC ChE values of both control and treated animals varied too widely for a valid interpretation to be made of this effect. Based on plasma ChE depression, the LEL for systemic toxicity is 10 mg/kg-day. The NOEL for systemic toxicity was not established. 2) 13-Week Feeding - mice: no core grade (NTP, 1987) This study was conducted as the range-finding study for the 2-year mouse feeding/oncogenicity study (NTP, 1987). Groups of B6C3F1 mice (10/sex/dose) were administered dichlorvos by gavage (corn oil) at dose levels of 0, 5, 10, 20, 40, 80 and 160 mg/kg-day. All males and nine females receiving 160 mg/kg-day died prior to study termination. The only decrease in weight gain observed in males during the study was in the low-dose group (-23%). For females, the percentages of weight gain of the treated groups versus the control group were -11%, 0%, 0%, -11% and +11% for the 160, 80, 40, 10 and 5 mg/kg-day groups, respectively. No toxic signs or significant pathology were observed in the animals that survived to study termination. Based on mortality and clinical signs observed at the highest dose level, the maximum tolerated dose (MTD) for the chronic feeding/oncogenicity study was set at 40 mg/kg-day for males and 80 mg/kg-day for females. Doses of 0, 10 and 20 mg/kg-day for males and 0, 20 and 40 mg/kg-day for females were approved because it was expected that the effects of cholinesterase inhibition would be cumulative. 3) 2-Year Drinking/Oncogenicity - mice: Core grade supplementary (AMVAC Chemical Corp., 1989a). Groups of B6C3F1 mice (50/sex/dose) were administered dichlorvos in the drinking water for 2 years at dose levels of 0, 58, and 94.8 mg/kg-day for males and 0, 56.2, and 102.3 mg/kg-day for females. Body weight gain and water consumption were decreased in both treated groups. There was a dose-related decrease in absolute and relative weight of the gonads of males. The absolute and/or relative weight of the pancreas was decreased in treated females. Other weight changes were apparent. Testicular atrophy was increased in males in the high-dose group. 4) 2-Year Drinking/Oncogenicity - rat: Core grade supplementary (AMVAC Chemical Corp., 1989b) Groups of F344 rats (51/sex/dose) were administered dichlorvos in drinking water for 104 weeks at dose levels of 0, 140, and 280 ppm (Male: 0, 8.3 and 10.4 mg/kg-day; Female: 0, 17.5 and 21.8 mg/kg-day) followed by a 4 week recovery period. Animals in both treated groups exhibited chromodacryorrhea during the first 2 weeks of study. High-dose females had tremors and were hypersensitive to touch. During the last 3 months of the study, treated animals exhibited an increase in the incidence and severity of lacrimation. Mean body weight of high-dose males and low- and high-dose females was lower than controls during the last few months of the study. There was a decrease in the absolute and relative liver weight in high-dose males. 5) 80-Week Feeding/Oncogenicity - rat: Core grade supplementary (NCI, 1977) Groups of Osborne Mendel rats (50/sex/dose) were administered dichlorvos for 80 weeks at dietary levels of 0, 150 and 326 ppm (0, 7.5 and 16.3 mg/kg-day). Test diets were discontinued after 80 weeks and treated animals and their matched controls were fed control diets until the termination of the study at 110 weeks. An additional 5 rats/sex/dose were used as matched controls. Another 60 male and 60 female rats being used as matched controls for other simultaneous bioassays were used as pooled controls for this study. The initial dose levels selected for this study were 150 and 1000 ppm. Because of serious toxicity observed in the 1000 ppm rats during the first 3 weeks of the study, the dose was reduced to 300 ppm for the remaining 77 weeks. The time weighted average doses were 150 and 326 ppm. Severe signs of toxicity including tremors, rough hair coats, diarrhea, and poor appearance were reported in the rats receiving 1000 ppm. When the dose was reduced to 300 ppm, the appearance and behavior were similar among all animals. During the second year of the study, rough hair coats, epistaxis, hematuria, alopecia, dark urine, bloating and abdominal distension were observed. Effects were more pronounced in high-dose females. At study termination, the surviving animals were reported to be in poor physical condition. Body weight was consistently lower in high-dose animals than in the low-dose and the matched controls (approximately 15% in males and 25% in females). Based on decreased body weight gain, the LEL for systemic toxicity is 326 ppm (16.3 mg/kg-day). The NOEL for systemic toxicity is 150 ppm (7.5 mg/kg-day). 6) 94-Week Feeding/Oncogenicity - mouse: No core grade (NCI, 1977) Groups of B6C3F1 mice (50/sex/dose) were administered dichlorvos for 80 weeks at dietary levels of 0, 318 and 635 ppm (0, 47.7 and 95.25 mg/kg-day). Five mice/sex/dose were used as matched controls. Test diets were discontinued after 80 weeks and treated animals and their matched controls were fed control diets until the termination of the study at 92-94 weeks. Another 100 male and 80 female mice being used as matched controls for other simultaneous bioassays were used as pooled controls for this study. The initial doses for this study were 1000 and 2000 ppm, but because of observed toxic signs, the doses were reduced to 300 and 600 ppm. Time-weighted averages were 318 and 635 ppm. Severe signs of toxicity were reported during the first 2 weeks of the study. When the dosages were reduced to 300 and 600, the appearance and behavior of the treated animals were comparable to that of the controls for the first year of the study. Toxic signs reported included alopecia and rough hair in all groups, and bloating and abdominal distension in all groups except high-dose females. Body weight was decreased in the high-dose. The low-dose female group had the lowest survival rate (74%) in the study. 7) 2-Year Feeding/Oncogenicity - rat: Core grade supplementary (high mortality in the control and treated animals due to infection and actual concentration of dichlorvos in the diet ranged from 22% to 80%) (Shell Chemical Co., 1967b) Groups of CD rats (Control: 40/sex; Test groups 25/sex/dose) were administered dichlorvos for 2 years at dietary levels of 0, 0.047, 0.46, 4.67, 46.7 and 234 ppm (0, 0.0024, 0.023, 0.23, 2.3 and 11.7 mg/kg-day). No toxicity was on food consumption, body weight, hematology, blood protein, urinalysis or terminal organ weights. Toxicity was demonstrated by a significant inhibition of cholinesterase activity at doses of 100 ppm and higher. Liver cell vacuolation occurred in rats receiving 100 ppm. These changes were accompanied by fatty livers in 500 ppm treated animals. Based on cholinesterase inhibition and hepatocellular vacuolation, the LEL for systemic toxicity is 46.7 ppm (2.3 mg/kg-day). The NOEL for systemic toxicity is 4.67 ppm (0.23 mg/kg-day). Data Gap(s): Rat Reproduction Study, Rabbit Developmental Toxicity Study CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- Medium RfD -- Medium The principal study is of good quality. However, due to the change in the dosing regime, the study is given a medium to high confidence rating. Additional studies are supportive of the principal study but the data base lacks a rabbit developmental toxicity study and adequate studies to fully address chronic and reproductive toxicity in the rat. Therefore, the data base is given a medium confidence rating. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 09/16/1986, 07/16/1987, 05/27/1992 Verification Date -- 05/27/1992 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Dichlorvos conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199406 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Dichlorvos CASRN -- 62-73-7 Last Revised -- 06/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- ----------------------- ----- --- --------- Decreased brain NOAEL: 0.05 mg/cu.m 100 1 5E-4 colinesterase activity NOAEL(ADJ): 0.05 mg/cu.m mg/cu.m NOAEL(HEC): 0.05 mg/cu.m Carworth Farm E Strain Rat Chronic Inhalation LOAEL: 0.48 mg/cu.m Study LOAEL(ADJ): 0.48 mg/cu.m LOAEL(HEC): 0.48 mg/cu.m Blair et al., 1976 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions: None required; exposures were essentially continuous for 2 years. The NOAEL(HEC) was calculated for a gas:extrarespiratory effect, assuming periodicity was attained. Because the b:a lambda values are unknown for the experimental animal species (a) and humans (h), a default value of 1.0 is used for this ratio. NOAEL(HEC) = 0.05 x [b:a lambda(a)/b:a lambda(h)] = 0.05 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Blair, D., K.M. Dix, P.F. Hunt, E. Thorpe, D.E. Stevenson, and A.I. Walker. 1976. Dichlorvos: A 2-year inhalation carcinogenesis study. Arch. Toxicol. 35(4): 281-294. Carworth Farm E strain (CFE) rats, 50/sex/group, were exposed whole body to atmospheres containing dichlorvos vapor for at least 23 hours/day, 7 days/week for up to 2 years. Test atmospheres were generated by bathing wicks saturated with technical grade dichlorvos (>97% pure) in a metered flow of dried, compressed air. The dichlorvos-laden air was diluted to the exposure levels required in this study as it entered 10-cu.m chambers that were operated at flow rates ranging from 2.49-2.80 cu.m/minute. Chamber concentrations, were sampled once daily and averaged 0, 0.05, 0.48, and 4.70 mg/cu.m (+/-20%). Food and water were available ad libitum. Dichlorvos tends to adsorb onto surfaces, can corrode some materials, and will hydrolyze rapidly to dichloroacetaldehyde in the presence of moisture (Blair and Rees, 1975). It is not clear whether chamber homogeneity and test atmosphere purity in normally humid inhalation chambers were confirmed during the study. Whole body exposures and around-the-clock studies such as this permit skin, hair, food, and possibly water to absorb test material and to become additional sources of exposure, doubling the dose of dichlorvos received by the animals (Stevenson and Blair, 1977; Blair et al., 1976). The animals were observed for clinical signs of toxicity, hematology, clinical chemistry (but no urinalysis), and blood and plasma cholinesterase activity. Brain cholinesterase activity was measured in rats surviving the study. Brain acetylcholine and choline were evaluated in three female rats from each exposure group. All animals on test were necropsied, and major organs, including the upper respiratory tract (number of sections unspecified), were examined histopathologically. Lower respiratory tract tissues from an unspecified number of male and female rats from the control and high-exposure group were prepared and examined by electron microscopy. Observations in both sexes for toxic signs, organ weight, organ-to-body-weight ratios, and hematologic parameters revealed no changes attributable to exposure. Survival was inversely related to treatment. Clinical chemistry determinations for both sexes were unremarkable, except for unspecified increases in SGPT and SGOT levels in animals exposed to the high concentration only. Body weights were significantly decreased over corresponding control values for a large portion of the study in both males (up to 20%) and females (up to 14%) only at the highest concentration. Evaluations of brain acetylcholine and choline were unremarkable. Brain, plasma, and erythrocyte cholinesterase activities were decreased in a concentration-related manner in both sexes of animals exposed to the high and middle concentrations. Brain cholinesterase activity, the most toxicologically relevant of those monitored, was significantly depressed in both sexes (90% of control activity) in animals exposed to 0.48 mg/cu.m dichlorvos. This activity was not different between controls and either females (97% of control activity) or males (96% of control activity) exposed to 0.05 mg/cu.m dichlorvos. The reductions in cholinesterase activity appear to have been asymptomatic. In all groups, histopathology revealed a range of lesions commonly found in aging CFE rats, none of which appeared to be compound related. The respiratory tract also exhibited minor changes in all groups, including controls, that were not correlated with exposure. Electron and light microscopic examinations of the lungs also failed to reveal any pattern of changes that could be correlated with exposure. Based on alterations in brain cholinesterase activity, the LOAEL is 0.48 mg/cu.m, and the NOAEL is 0.05 mg/cu.m. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- A UF of 10 is used for the protection of sensitive human subjects. A UF of 3 is used for interspecies extrapolation. A single factor of 3 is used for consideration of both the lack of a multigenerational reproductive study and chronic data in a second species. Concern for the latter was ameliorated as the in vivo half life of dichlorvos is brief and chronic oral studies of dichlorvos show that cholinesterase inhibition does not increase with a regime of repeated exposures. Too, this same effect is noted in oral studies with dichlorvos in several species, including humans. The total UF is 100. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) The effects on applicators and residents following fumigation of houses with dichlorvos were investigated by Gold et al. (1984). Applicators were exposed to average levels of 0.21 mg/cu.m for an average duration of approximately 25.5 minutes. Residents were exposed to an average of about 0.21 mg/cu.m for an average duration of about 15.8 hours. Data on two applicators showed decreases in plasma cholinesterase activity of 21 and 59%, respectively. The changes in erythrocyte cholinesterase activity were inconsistent but suggestive of a decrease in one applicator. Some of the 20 exposed residents complained of headache. The mean plasma cholinesterase activity for the residents 24 hours after application of dichlorvos was only slightly reduced (-7.9%) compared with preexposure levels. The mean erythrocyte cholinesterase activity was not significantly reduced, although individual decreases ranged from 5.3-37.5%. In a limited occupational study, six formulators and reactor workers in a pesticide manufacturing plant were exposed for 20 days to an average air concentration of 0.1 ppm dichlorvos (Ember et al., 1972). The text of this study claims that plasma cholinesterase activity and vitamin A levels decreased in five workers and that there was only a small recovery in these values after a 13-day period of nonexposure. Case studies of accidentally exposed humans demonstrate the acute toxicity of dichlorvos. Children exposed to vapors of insecticides containing dichlorvos (in combination with other pesticides and chemicals) experience symptoms typical of organophosphate poisoning related to the cholinesterase inhibition caused by these chemicals (Low et al., 1980). Signs of poisoning include giddiness, headache, drowsiness, sweating, cold and clammy skin, abdominal pain, nausea, vomiting, and constricted pupils. Measurements of plasma cholinesterase show a substantial decrease in activity. It has been suggested that exposure to vapors of household insecticides (containing dichlorvos in addition to other pesticides and chemicals) may produce delayed severe blood effects (Reeves et al., 1981). Six children between the ages of 2 and 12 years developed aplastic anemia or acute lymphoblastic anemia within 0.5-28.0 weeks following known exposure to an insecticide containing dichlorvos and propoxur. The 7-month-old sibling of one of the patients had transient neutropenia 2 weeks after house fumigation. Because of the mixed exposure and the possibility of other confounding factors, it is difficult to assess the potential role of dichlorvos in the observed hematological effects. Oral dosing of human volunteers also results in rapid depression of plasma cholinesterase activity, and in some cases, in decreased erythrocyte cholinesterase activity. Groups of five men were fed 1.0, 1.5, 2.0, or 2.5 mg doses of dichlorvos daily for 28 days (Rider et al., 1967). Cholinesterase activity was 71% of controls at the end of the 28 days in the group receiving 2.0 mg/day and was 70% of controls at the end of 20 days in the group administered 2.5 mg/day. No significant effect on erythrocyte cholinesterase activity was observed, and there were no clinical symptoms of exposure in the men. One hundred and seven male volunteers were administered oral doses of dichlorvos ranging from 0.1-16.0 mg/kg. A group of 44 males received only a placebo pellet (Slomka and Hine, 1981). Similar numbers of treated and control subjects reported clinical symptoms consisting of stomach rumbling, nausea, and diarrhea. There were no effects on any laboratory parameters except cholinesterase activity. The extent of depression of cholinesterase activity measured at 24 hours postadministration increased with dose and reached a maximum of approximately 80% at a dose of about 6 mg/kg. Erythrocyte cholinesterase activity also decreased with increasing dichlorvos administration, but the decrease was less than that observed in the plasma. Daily administration of the same doses to the volunteers resulted in such a dramatic rate of decrease in plasma and erythrocyte cholinesterase activity that the experiment was terminated in most subjects in less than 7 days. An attempt to gradually increase the dose in the subjects produced similar results, and, at the highest dose administered (16 mg/kg), the experiment was terminated after only 5.5 days. Walker et al. (1972) exposed beagles, cats, and New Zealand white rabbits continuously for 8 weeks to levels of dichlorvos vapor simulating normal use. The animals, bearing cortical electrodes for EEG recordings, were housed in a kennel and exposed to dichlorvos vapor as it evolved under ambient conditions from dichlorvos-impregnated resin strips that were hung in the kennel. Exposure concentrations, monitored occasionally during the study, ranged from 0.05-0.30 mg/cu.m. No effects on general health, behavior, plasma and erythrocyte cholinesterase activities, or EEG patterns were found. Thorpe et al. (1972) exposed primiparous female Dutch rabbits (20/group) and pregnant CFE rats (15/group) throughout pregnancy to dichlorvos vapors from gestation days 1-28 for rabbits and days 1-20 for rats. The exposure, test atmosphere generation, and analytical procedures were the same as those employed in the 2-year chronic study. The animals were exposed at least 23 hours/day at actual chamber concentrations targeted at 0, 0.25, 1.25, and 6.25 mg/cu.m. Concentrations in the high-level chamber spiked on 3 separate days to levels between 7 and 8 mg/cu.m. Some rats exposed to the highest concentration appeared less active, and 80% of the rabbits exposed to the highest concentration exhibited signs of toxicity (anorexia, lethargy, tremors, nasal discharge, and diarrhea) and subsequently died. The remaining groups were not subjected to these spikes, and the dams of both species appeared to be free of clinical signs during exposure to 0.25 or 1.25 mg/cu.m. A second rabbit study, conducted at concentrations of 0, 2, and 4 mg/cu.m, also suffered from a 1-day concentration spike to 6.6 mg/cu.m in the highest exposure group, resulting in mortality (6/20). Five of the six rabbits in the highest exposure group that died during the second study were lost after the spike. Brain, plasma, and erythrocyte cholinesterase activities were depressed significantly in maternal rats exposed to 1.25 and 6.25 but not 0.25 mg/cu.m. These activities were also reported depressed in dams exposed to 1.25 mg/cu.m dichlorvos. No other signs of maternal toxicity were clearly related to exposure in animals exposed at or below 1.25-2.00 mg/cu.m. Fetuses of both species showed no compound-related skeletal or soft-tissue abnormalities. No differences were observed in litter size, resorptions, or mean fetal weight between control and exposed groups for either species. A NOAEL of 1.25 mg/cu.m, based on the lack of brain cholinesterase inhibition, is identified for maternal toxicity. A NOAEL of 6.25 mg/cu.m is identified for fetoxicity. Dean and Thorpe (1972), using the same exposure methods as Blair and Rees (1975), evaluated the mutagenic potential (dominant lethal assay) of dichlorvos vapor in male CF1 mice. The animals were exposed to 30 or 55 mg/cu.m for a single 16-hour period or to 2.1 or 5.8 mg/cu.m continuously for 4 weeks prior to mating. The animals exhibited no impairment of fertility and no mutagenic effects, based on the lack of preimplantation losses or early fetal deaths. Dean and Blair (1976) were subsequently unable to induce dominant lethal mutations in mice of either sex, regardless of whether the mice were dosed orally (25 or 50 mg/kg) or by inhalation (2 or 8 mg/cu.m). On the premise that inhibition of acetylcholinesterase activity may induce cholinergic responses in portal-of-entry tissues, Schmidt et al. (1979) exposed male Sprague-Dawley rats to dichlorvos at 0.20-56.64 mg/cu.m for 3-14 days and observed a concentration-related decrease in acetylcholinesterase activity in bronchial homogenates. Histochemical preparations of tracheal and bronchial tissue corroborated acetylcholinesterase activity, which was reduced in the tissues even at the lowest level of exposure. However, the toxicological significance of those results is not clear because Pauluhn et al. (1987) could not provoke increases in lung resistance in Wistar rats after exposure to dichlorvos (1-4 hours at 183 mg/cu.m) without provocation by acetylcholine. Pregnant CF1 mice and New Zealand rabbits exposed to 4.06 mg/cu.m for 7 hours/day on days 6-15 (mice) or days 6-18 (rabbits) showed no significant compound-related differences in reproductive or developmental parameters compared with controls (Schwetz et al., 1979). Parameters monitored included clinical signs; gestational and litter weights; number of corpora lutea; number and position of live, dead, and resorbed fetuses; and malformation of fetuses. A statistically significant (p < 0.05) decrease in gestational weight was observed in the exposed mice on day 16 only. There were no signs of toxicity in the dams. This study indicates 4.06 mg/cu.m to be a NOAEL for fetotoxicity. Exposure of groups of CD-1 mice to 1.9, 3.0, or 4.6 mg/cu.m dichlorvos during a 4-day breeding period resulted in significant (p < 0.05) depression of plasma cholinesterase activity (Casebolt et al., 1990). An additional experiment exposed groups of mice to the same concentrations starting from 4 days prior to formation of breeding units and continuing through pregnancy. Despite the substantial decrease in plasma cholinesterase activity, no signs of toxicity were observed in the dams, and there was no effect on litter frequency, litter size, or length of gestation, indicating 4.6 mg/cu.m to be a NOAEL for fetoxicity. D'Souza and Batra (1976) appear to produce partial sterility in male (partial loss of seminiferous tubules) and female (hyalinized ovaries and missing follicles and oocytes) offspring during a two-generation study on the effects of dichlorvos. Closer examination, however, reveals major procedural difficulties with this study. Female mice, their offspring, and their caging were all sprayed directly each week with dichlorvos. No estimates of dose were made. The test material was available to each mouse orally and dermally, as well as by inhalation. No effect levels can be assigned from this study. Timmons et al. (1975) determined that the onset of estrous was significantly (p < 0.05) delayed in female rats exposed from birth to vapor from pesticide strips containing dichlorvos; onset of estrous was 42 days in the control group and 52 days in the exposed group. Exposure concentrations were not measured. Dichlorvos is absorbed following inhalation, oral, and dermal exposure; however, the rapid metabolism of the chemical makes it difficult to quantify the extent of absorption (WHO, 1991). Excretion data indicate that at least 85% of an orally administered dose is absorbed. Tissue deposition appears to vary between different species. It has been reported to be found primarily in the kidneys of CFE rats (Blair et al., 1975) and in the ovarian tissue and blood of female Sprague-Dawley rats (Timmons et al., 1975) exposed by inhalation. When radiolabeled dichlorvos is used, the label that is found in tissues is believed to be a metabolic breakdown product of the dichlorvos molecule and its incorporation into normal tissue constituents (Page et al., 1972; Potter et al., 1973). Metabolism of dichlorvos is very rapid in all species studied (Page et al., 1972; Hutson and Hoadley, 1972a,b). Blair et al. (1975) reported that dichlorvos was rapidly degraded in blood and tissues of rats and mice that had been exposed to various concentrations of dichlorvos vapors. Dichlorvos could not be detected in any tissue examined from rats that were exposed continuously to either 0.05 or 0.50 mg/cu.m for 14 days. Parent dichlorvos was detected in the kidneys of rats exposed to 10 mg/cu.m for 4 hours and in most tissues of rats (although remaining highest in the kidneys) exposed to 90 mg/cu.m for 4 hours. Mild signs of toxicity (lethargy and pupillary constriction) were noted in rats exposed to this highest concentration. The distribution of dichlorvos in tissues of mice exposed to the highest concentration differed from rats as fat, lung, and testes had higher concentrations than did the kidneys. Dichlorvos disappeared from the kidneys of male rats with a half-life of approximately 13.5 minutes. In vitro assays with whole blood showed dichlorvos to have a half-life ranging from 1.5-31.0 minutes. The principal metabolic products of dichlorvos are dimethyl phosphate and dichloroacetaldehyde. The blood of two human volunteers exposed to dichlorvos vapor (0.25-0.70 mg/cu.m) for up to 20 hours contained no detectable test material, and the volunteers apparently exhibited no symptoms. Two metabolic pathways have been proposed for dichlorvos, one glutathione-dependent and one glutathione-independent (Dicowsky and Morello, 1971). Gaines et al. (1966) demonstrated that significant detoxification of dichlorvos took place in the liver. Excretion studies with mice, rats, and hamsters (Hutson and Hoadley, 1972a,b), as well as swine (Potter et al., 1973), have shown that most of the label absorbed from an oral dose of dichlorvos is excreted in the urine and breath. In humans, as well as rats, mice, and swine, dimethyl phosphoric acid and dichloroacetaldehyde have been identified as the primary metabolites (Bradway et al., 1977; Das et al., 1983; Page et al., 1972; Hutson and Hoadley, 1972b; Riemer et al., 1981; Stevenson and Blair, 1977). Desmethyl dichlorvos, dichloroethanol, hippuric acid, and glutathione conjugates have also been detected (Page et al., 1972; Hutson and Hoadley, 1972a,b). Julka et al. (1992) observed various alterations (decreased levels of glutathione and decreased activity of glutathione peroxidase, along with increases in enzymes that enhance the disposal of potentially toxic radicals) in brain tissues from rats exposed intraperitoneally to 5 mg/kg dichlorvos. These results may indicate that dichlorvos significantly disturbs the antioxidant defense system in the target tissue. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Although current test guidelines recommend more frequent measurement of the chamber atmosphere, the principal study was well-conducted for its time, used a sufficient number of animals (although only one species), and monitored appropriate endpoints. The whole-body, around-the-clock exposure protocol permitted auxiliary oral and dermal dosages of dichlorvos. In spite of the augmented dose received by the animals through ingestion, no demonstrable pathologic or cholinergic symptomatology was reported. Decreases in brain cholinesterase activity were observed and are an acknowledged target organ effect for organic phosphates. The data base for this compound is relatively complete because the chronic oral studies used several species. Inhalation and oral reproductive and developmental studies are available. However, an inhalation-based assessment of its multigeneration reproductive toxicity was not found. Thus, the data base is assigned a medium level of confidence. Consequently, the confidence in the RfC is medium. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 11/05/1992 Verification Date -- 11/05/1992 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Dichlorvos conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199412 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Dichlorvos CASRN -- 62-73-7 Last Revised -- 12/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NOCA: Note: The carcinogen assessment for dichlorvos may change in the near future pending the outcome of a further review now being conducted by the CRAVE Work Group. ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Significant increases in forestomach tumors in female and male B6C3F1 mice and leukemias and pancreatic acinar adenomas in Fischer 344 rats. Supporting evidence included observation of tumors at other sites in the rat and observation of mutagenicity for both dichlorvos and a major metabolite dichloroacetaldehyde. A structurally related material, dichloropropene, also induces forestomach tumors in rodents. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. In a 2-year gavage study (NTP, 1986a), mice (60/sex/group) of the B6C3F1 strain were treated with dichlorvos at 10 and 20 (mg/kg)/day (males) or 20 and 40 (mg/kg)/day (females), 5 days/week for 104 weeks followed by a 1-week observation period. Corn oil was used as the solvent. At 40 mg/kg the incidence of squamous papillomas of the forestomach of female mice (18/50) was statistically significantly increased compared with the vehicle control (5/49). There was a significant positive trend in both males and females. The incidence of carcinomas and squamous cell papillomas of the forestomach combined showed a significant trend for the high-dose females (19/50); it was also significantly elevated in a pairwise comparison. It is noteworthy that tumor incidence was elevated at a relatively low treatment dose. Survival was unaffected by treatment. Based on a significant depression of plasma and RBC cholinesterase in treated mice of both sexes at all doses, dose selection appears to be adequate. In a 2-year gavage study (NTP, 1986b), rats (60/sex/group) of the F344 strain were treated with 4 or 8 (mg/kg)/day once daily 5 days/week. Survival was unaffected by treatment. Dose selection was adequate based on plasma and RBC cholinesterase suppression. In the males the incidence of pancreatic acinar adenoma was 16/50, 25/49, and 30/50 at 0, 4, and 8 mg/kg, respectively, which was statistically significantly elevated by pairwise comparison and showed a significant positive dose-related trend. The incidence of alveolar/bronchial adenoma of 3/49 in the high-dose males versus 0/50 in the controls was not significant on a pairwise basis but showed a positive dose-related trend. The incidence of leukemia (lymphocytic, monocytic, mononuclear or undifferentiated) was 11/50, 20/50, 21/50 for the males at 0, 4, or 8 (mg/kg)/day, respectively. These values were statistically significantly elevated at 4 and 8 mg/kg/day and also showed a significant dose-related trend. There was a statistically significant increase in lung tumors in the low-dose male rats. In the females, the incidence (19/50) of mammary fibroadenoma was significant by pairwise comparison and the trend was also significant. When analyzed for all type mammary tumors (fibroma, fibroadenoma, carcinoma, adenocarcinoma or adenoma) the incidence was 11/50, 20/50, 17/50 for 0, 4, or 8 mg/kg, respectively. The mid-dose was significant while the dose-related trend was not. There was a statistically significant increase in mammary tumors in the low-dose female rats. Four other chronic studies have been conducted on DDVP. A 2-year inhalation study was conducted by Shell Chemical Company (1967) wherein CFE rats (50/sex/dose group) were exposed to DDVP vapors at nominal concentrations of 0.1, 1.0, 10, 100, and 500 ppm (measured concentrations of 0.047, 0.46, 4.67, and 234 ppm). This study was flawed by poor survival, tissue autolysis and inadequate number of tissues examined histopathologically. A 2-year rat study (Osborne-Mendel strain bred at Charles River Breeding Lab.) was conducted by NCI (1977) in which DDVP was fed to groups of 50/sex/dose at 0, 150, and 326 ppm. This study suffered from poor animal survival resulting from intercurrent infection in the animals. A 2-year mouse study (B6C3F1 strain obtained from Charles River Breeding Lab.) was conducted by NCI (1977) wherein DDVP was fed at 0, 318, or 635 ppm. The results were considered equivocal on the basis of insufficient numbers of control animals (dichlorvos controls were pooled with those from other studies). Lastly, in a 2-year inhalation study conducted by Shell Tunstall Laboratories, England (no date), rats were exposed to DDVP at 0, 0.05, 0.5, and 5.0 mg/cu.m. The results were considered equivocal. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY DDVP was positive in mutation assays using S. typhimurium strain TA1530 and E. coli strains B/r, WP2-hcr, WP2, and Cm 881 (Moriya et al., 1978; Bridges, 1978) without metabolic activation. Results indicative of DNA interactions were obtained in the polA2 assay in E. coli (Rosenkranz, 1973) and for histidine and leucine mutants of Serratia marcescens (Dean, 1972). DDVP was mutagenic in the recessive lethal test using Drosophila (Hanna and Dyer, 1975), and in mouse lymphoma cells in culture without addition of hepatic homogenates (Litton Bionetics, 1985). It was negative in the mouse micronucleus test, in the sister chromatid exchange assay, and in the mouse dominant lethal test (Microbiological Associates, 1985). In addition, dichlorvos alkalates DNA (Segerbaeck and Ehrenberg, 1981). Dichlorvos is structurally related to dichloropropene (a probable human carcinogen), which causes forestomach squamous cell tumors in rats and mice, lung tumors in mice and neoplastic nodules in the livers of rats. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 2.9E-1 per (mg/kg)/day Drinking Water Unit Risk -- 8.3E-6 per ug/L Extrapolation Method -- linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 1E+1 ug/L E-5 (1 in 100,000) 1E+0 ug/L E-6 (1 in 1,000,000) 1E-1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- forestomach, pancreatic, leukemia (see table) Test Animals -- mouse and rat (see table) Route -- gavage Reference -- NTP, 1986a,b ---- Dose ----- Admin- Human istered Equivalent Tumor (ppm) (mg/kg/day) Incidence Reference -------- ----------- --------- --------- mouse/B6C3F1, female. forestomach tumors (papilloma, squamous and squamous cell carcinoma) 0 0.0 5/49 NTP, 1986a 140 15.75 6/49 280 31.50 19/50 ------- Dose -------- Admin- Human --- Tumor Incidence --- istered Equivalent Pancreatic (ppm) (ppm) acinar adenoma Leukemia Reference -------- ----------- -------------- -------- --------- rats/F344, male. pancreatic acinar adenoma; leukemia, all types 0 0 16/50 11/50 NTP, 1986b 80 80 25/49 20/50 160 160 30/50 21/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The oral slope factors (expressed as per (mg/kg)/day) are based on the tumors of the forestomach in B6C3F1 mice (1.1E-1), tumors of the pancreas in F344 rats (5.8E-1) and leukemia in the F344 rat (3.8E-1) individually. A geometric mean of these slope factors was taken as the final estimate [2.9E-1 per (mg/kg)/day] as all three were roughly equivalent and so that relevant data not be discarded. The unit risk should not be used if the water concentration exceeds 1E+3 ug/L, since above this concentration the slope factor may differ from that stated. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of animals, lifetime exposure, no effect on survival and adequate dose selection establishing greater confidence in the quantitative estimate. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA. 1987a,b,c,d,e, 1988a,b,c,d,c The risk assessment for dichlorvos was reviewed by the OPP Peer Review Group and by the FIFRA Science Advisory Panel. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/22/1988 Verification Date -- 09/22/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Dichlorvos conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199506 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Dichlorvos CASRN -- 62-73-7 Last Revised -- 06/01/1995 SORD: __VI.A. ORAL RfD REFERENCES AMVAC Chemical Corporation. 1989a. MRID No. 41041801; HED Doc. No. 007543. Available from EPA. Write to FOI, EPA, Washington, DC 20460. AMVAC Chemical Corporation. 1989b. MRID No. 41041802; HED Doc. No. 007543. Available from EPA. Write to FOI, EPA, Washington, DC 20460. AMVAC Chemical Corporation. 1990. MRID No. 41593101; HED Doc. No. 008178. Available from EPA. Write to FOI, EPA, Washington, DC 20460. AMVAC Chemical Corporation. 1991. MRID No. 41951501; HED Doc. No. 009305. Available from EPA. Write to FOI, EPA, Washington, DC 20460. NCI (National Cancer Institute). 1977. Bioassay of Dichlorvos for Possible Carcinogenicity. NTIS PB-270937. 103 p. NTP (National Toxicology Program). 1987. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Dichlorvos in F344/N Rats and B6C3F1 Mice: (Gavage Studies): NTP TR 342. U.S. Dept. of Health and Human Services, Public Health Service. Pub. No. NIH 88-2598. Shell Chemical Company. 1965. MRID No. 00050012; HED Doc. No. 007765 Available from EPA. Write to FOI, EPA, Washington, DC 20460. Shell Chemical Company. 1967a. MRID No. 00013550, 00050010; HED Doc. No. 007765. Available from EPA. Write to FOI, EPA, Washington, DC 20460. Shell Chemical Company. 1967b. MRID No. 00059397, 000611333; HED Doc. No. 007765. Available from EPA. Write to FOI, EPA, Washington, DC 20460. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Blair, D. and H.J. Rees. 1975. The generation and administration of atmospheres containing dichlorvos for inhalation studies. Am. Ind. Health. Assoc. J. 36(5): 385-397. Blair, D., E.C. Hoadley and D.H. Hutson. 1975. The distribution of dichlorvos in the tissues of mammals after its inhalation or intravenous administration. Toxicol. Appl. Pharmacol. 31(2): 243-253. Blair, D., K.M. Dix, P.F. Hunt, E. Thorpe, D.E. Stevenson and A.I. Walker. 1976. Dichlorvos: A 2-year inhalation carcinogenesis study in rats. Arch. Toxicol. 35(4): 281-294. Bradway, D.E., T.M. Shafik and E.M. Lores. 1977. Comparison of cholinesterase activity, residue levels, and urinary metabolite excretion of rats exposed to organophosphorus pesticides. J. Agric. Food Chem. 25(6): 1353-1358. Casebolt, D.B., S.L. Leary and L. Undeutsch. 1990. Effects of dichlorvos treatment on mouse reproduction. Lab. Anim. Sci. 40(1): 65-67. Das, Y.T., P.K. Taskar, H.D. Brown and S.K. Chattopadhyay. 1983. Exposure of professional pest control operator to dichlorvos (DDVP) and residue on house structures. Toxicol. Lett. 17(1-2): 95-99. Dean, B.J. and D. Blair. 1976. Dominant lethal assay in female mice after oral dosing with dichlorvos or exposure to atmospheres containing dichlorvos. Mutat. Res. 40(1): 67-72. Dean, B.J. and E. Thorpe. 1972. Studies with dichlorvos vapor in dominant lethal mutation tests on mice. Arch. Toxikol. 30(1): 51-59. Dicowsky, L. and A. Morello. 1971. Glutathione-dependent degradation of 2,2-dichlorovinyl dimethyl phosphate (DDVP) by the rat. Life Sci. 10(18): 1031-1037. D'Souza, A.V. and B.K. Batra. 1976. A study of the effects of DDVP (propoxure) on laboratory mouse. Curr. Sci. 45(10): 377-379. Ember, M., L. Mindszenty, B. Rengei, L. Csaszar and M. Czina. 1972. Secondary vitamin A deficiency in organophosphate formulators and spray workers. Res. Commun. Chem. Pathol. Pharmacol. 3(1): 145-154. Gaines, T.B., W.J. Hayes, Jr., and R.E. Linder. 1966. Liver metabolism of anticholinesterase compounds in live rats: Relation to toxicity. Nature. 209(5018): 88-89. Gold, R.E., T. Holcslaw, D. Tupy and J.B. Ballard. 1984. Dermal and respiratory exposure to applicators and occupants of residences treated with dichlorvos (DDVP). J. Econ. Entomol. 77(2): 430-436. Hutson, D.H. and E.C. Hoadley. 1972a. The comparative metabolism of (14-C-vinyl)dichlorvos in animals and man. Arch. Toxikol. 30(1): 9-18. Hutson, D.H. and E.C. Hoadley. 1972b. The metabolism of (C14-methyl)dichlorvos in the rat and the mouse. Xenobiotica. 2(2): 107-116. Julka, D., R. Pal and K.D. Gill. 1992. Neurotoxicity of dichlorvos: Effect on antioxidant defense system in the rat central nervous system. Exp. Mol. Pathol. 56: 144-152. Low, P.S., T.E. Ngiam and S.H. Quak. 1980. Insecticide Baygon aerosol poisoning: A report of 5 cases. J. Singapore Paediatr. Soc. 22(1-4): 44-49. Page, A.C., J.E. Loeffler, H.R. Hendrickson, C.K. Huston and D.M. DeVries. 1972. Metabolic fate of dichlorvos in swine. Arch. Toxikol. 30(1): 19-27. Pauluhn, J., L. Machemer and G. Kimmerle. 1987. Effects of inhaled cholinesterase inhibitors on bronchial tonus and on plasma and erythrocytes acetylcholine esterase activity in rats. Toxicology. 46(2): 177-190. Potter, J.C., A.C. Boyer, R.L. Marxmiller, R. Young and J.E. Loeffler. 1973. Radioisotope residues and residues of dichlorvos and its metabolites in pregnant sows and their progeny dosed with dichlorvos-14-carbon or dichlorvos-36-chlorine formulated as PVC pellets. J. Agric. Food Chem. 21(4): 734-738. Reeves, J.D., D.A. Driggers and V.A. Kiley. 1981. Household insecticide associated aplastic anaemia and acute leukemia in children. Lancet. 2(8241): 300-301. Rider, J.A., H.C. Moeller and E.J. Puletti. 1967. Continuing studies on the anticholinesterase effect of methyl parathion, initial studies with gluthion, and determination of incipient toxicity level of dichlorvos in humans. Fed. Proc. 26(2): 427. Riemer, F., C. Maruschke, E. Gensel, et al. 1981. Excretion of dimethyl phosphate and its thioderivatives after occupation exposure to selected organophosphorus pesticides. In: Industrial and Environmental Xenobiotics, Metabolism and Pharmacokinetics of Organic Chemicals and Metals, I. Gut, M. Cikrt and G.L. Plaa, Ed. Springer-Verlag, Berlin. p. 377-382. Schmidt, G., M. Schmidt, M. Nenner and F. Vetterlein. 1979. Effects of dichlorvos (DDVP) inhalation on the activity of acetylcholinesterase in the bronchial tissue of rats. Arch. Toxicol. 42(3): 191-198. Schwetz, B.A., H.D. Ioset, B.K.J. Leong and R.E. Staples. 1979. Teratogenic potential of dichlorvos given by inhalation and gavage to mice and rabbits. Teratology. 20: 383-388. Slomka, M.B. and C.H. Hine. 1981. Clinical pharmacology of dichlorvos. Acta. Pharmacol. Toxicol. 49(Suppl. 5): 105-108. Stevenson, D.E. and D. Blair. 1977. The uptake of dichlorvos during long-term inhalation studies. In: Clinical Toxicology, W.A. Duncan and B.J. Leonard, eds. Excerpta Medica, Amsterdam. p. 215-217. Thorpe, E., A.B. Wilson, K.M. Dix and D. Blair. 1972. Teratological studies with dichlorvos vapour in rabbits and rats. Arch. Toxikol. 30(1): 29-38. Timmons, E.H., R.J. Chaklos, T.M. Bannister and H.M. Kaplan. 1975. Dichlorvos effects on estrous cycle onset in the rat. Lab. Anim. Sci. 25(1): 45-47. Walker, A.I., D. Blair, D.E. Stevenson and P.L. Chambers. 1972. An inhalational toxicity study with dichlorvos. Arch. Toxikol. 30(1): 1-7. WHO (World Health Organization). 1991. IARC Monograph on Evaluation of Carcinogenic Risks to Humans, Volume 53, Dichlorvos. p. 267-299. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bridges, B.A. 1978. On the detection of volatile liquid mutagens with bacteria: Experiments with dichlorvos and epichlorohydrin. Mutat. Res. 54(3): 367-371. Dean, B.J. 1972. The mutagenic effects of organophorphorus pesticides on micro-organisms. Arch. Toxikol. 30(1): 67-74. Hanna, P. and K. Dyer. 1975. Mutagenicity of organophosphorus compounds in bacteria and Drosophila. Mutat. Res. 28: 405-420. Litton Bionetics. 1985. Accession No. 259602. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. Microbiological Associates. 1985. Accession No. 259602. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. Moriya, M., K. Kato and Y. Shirasu. 1978. Effects of cysteine and a liver metabolic activation system on the activities of mutagenic pesticides. Mutat. Res. 57(2): 259-263. NCI (National Cancer Institute). 1977. Bioassay of Dichlorvos for Possible Carcinogenicity. NCI Technical Report Series No. 10. NTP (National Toxicology Program). 1986a. Two-year mouse gavage study. Unpublished report prepared by Southern Research Institute, May 23. Study No. 05049. NTP, Research Triangle Park, NC. NTP (National Toxicology Program). 1986b. Two-year gavage study of dichlorvos in rats. Unpublished report prepared by Southern Research Institute, May 23. Study No. 05049. NTP, Research Triangle Park, NC. Rosenkranz, H.S. 1973. Preferential effect of dichlorvos (vapona) on bacteria deficient in DNA polymerase. Cancer Res. 33: 458-459. Segerbaeck, D. and L. Ehrenberg. 1981. Alkylating properties of dichlorvos (DDVP). Acta Pharmacol. Toxicol. 49(5): 56-66. Shell Chemical Company. 1967. MRID No. 00059397. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. Shell Tunstall Laboratories, England. N.D. MRID No. 00063569. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. EPA. 1987a. Memorandum dated June 16. Weight of Evidence Evaluation for the Oncogenic Potential of Dichlorvos (DDVP). U.S. EPA. 1987b. Memorandum dated July 10. Toxicology Branch Peer Review Committee Draft Document on DVVP. U.S. EPA. 1987c. Memorandum dated July 21. Dichlorvos (DDVP) - Quantitative Risk Assessment. U.S. EPA. 1987d. Memorandum dated September 25. Peer Review of Dichlorvos. U.S. EPA. 1987e. Memorandum dated October 1. Report of the FIFRA Scientific Advisory Panel. U.S. EPA. 1988a. Federal Register. 53(36): 5542-5549. Februrary 24. U.S. EPA. 1988b. Memorandum dated March 16. Second Peer Review of Dichlorvos - Reevaluation follows the September 23, 1987 Science Advisory Panel Review. U.S. EPA. 1988c. Memorandum dated May 11. Peer Review of DDVP (Dichlorvos). U.S. EPA. 1988d. Memorandum dated June 27. Third Peer Review of Dichlorvos - Reevaluation following the April 18, 1988 meeting of the NTP Panel of Experts. U.S. EPA. 1988e. One-liner: 03/17/1986. Toxchem No. 328-Dichlorvos. p. 1-7. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Dichlorvos CASRN -- 62-73-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A. NOAEL reevaluated-RfD changed 03/01/1988 I.A.5. Confidence levels revised 12/01/1988 I.A.1. Converted dose for NOEL added 12/01/1988 I.A.4. Study 2) NOEL clarified 10/01/1989 II. Carcinogen summary on-line 12/01/1989 II.A.3. Correct Kettering Lab (1974) to Shell Chemical (1967) 12/01/1989 II.A.4. Correct spelling: Setervaick to 'Segerbaeck' 12/01/1989 II.B.2. Correct reference citations 12/01/1989 VI. Bibliography on-line 01/01/1992 II. Carcinogen assessment noted as pending change 01/01/1992 IV. Regulatory Action section on-line 07/01/1992 I.A. Withdrawn; new RfD verified (in preparation) 07/01/1992 VI.A. Oral RfD references withdrawn 12/01/1992 I.B. Inhalation RfC now under review 10/01/1993 II.D.3. Primary contact changed; secondary's phone no. changed 11/01/1993 I.A. Oral RfD summary replaced; RfD changed 11/01/1993 VI.A. Oral RfD references replaced 06/01/1994 I.B. Inhalation RfC on-line 06/01/1994 VI.B. Inhalation RfC references on-line 12/01/1994 II.A.3. Animal strain clarified in NCI, 1977 study 06/01/1995 VI.C. NTP, 1986a,b reference year corrected 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 383 of 1119 in IRIS (through 2003/06) AN: 166 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199103 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Hexachlorodibenzo-p-dioxin,-mixture- (HxCDD) SY: *57653-85-7; 19408-74-3; DIBENZO-P-DIOXIN,-1,2,3,6,7,8-HEXACHLORO-; DIBENZO-P-DIOXIN,-1,2,3,7,8,9-HEXACHLORO-; 1,2,3,6,7,8-HEXACHLORODIBENZO-P-DIOXIN-; 1,2,3,7,8,9-HEXACHLORODIBENZO-P-DIOXIN-; HEXACHLORODIBENZO-P-DIOXIN,-MIXTURE-; HEXACHLORODIBENZO-P-DIOXIN-; HXCDD- RN: 19408-74-3 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Hexachlorodibenzo-p-dioxin, mixture (HxCDD) CASRN -- 19408-74-3 Primary Synonym -- 57653-85-7 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Hexachlorodibenzo-p-dioxin, mixture (HxCDD) CASRN -- 19408-74-3 Primary Synonym -- 57653-85-7 NORC: Not available at this time. ============================================================================ UDCA: 199103 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Hexachlorodibenzo-p-dioxin, mixture (HxCDD) CASRN -- 19408-74-3 Primary Synonym -- 57653-85-7 Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Hepatic tumors in mice and rats by gavage HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. There are no published epidemiologic evaluations of hexachlorodibenzo-p-dioxin, a contaminant in chlorinated phenols. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Osborne-Mendel rats (50/sex/dose) and B6C3F1 mice (50/sex/dose) were gavaged with the hexa- chlorodibenzo-p-dioxin mixture suspended in a 9:1 corn oil:acetone vehicle (NTP, 1980a). Treatment was twice weekly for 104 weeks at doses of 0, 1.25, 2.5 or 5.0 ug/kg/week for rats and male mice and 0, 2.5, 5 or 10 ug/kg/week for female mice. There were 75 each rats and mice of each sex as vehicle controls and 25 each female and male rats and mice in the untreated control group. A dose-related depression in mean body weight gain was noted in male and female rats. In rats and mice there was a dose-related toxic hepatitis consisting of degenerative liver changes and necrosis. A significant dose-related increase in incidence of hepatocellular carcinomas or neoplastic nodules was noted in male rats. NTP concluded that evidence for carcinogenicity in male rats was inconclusive. Incidence of hepatocellular carcinomas, nodules, and adenomas was significantly increased in female rats relative to vehicle controls both medium- and high-dose). Incidence of hepatocellular carcinomas and adenomas was increased in a dose-related manner in male and female mice, reaching statistical significance when the high-dose males were compared with vehicle controls. Thirty Swiss-Webster mice/sex were skin-painted with a 2:1 mixture of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin in acetone 3 times a week for 104 weeks (NTP, 1980b). Doses of 0.005 ug/application for the initial 16 weeks were followed by a 0.01 ug/application for the remainder of the study. No carcinogenic response related to treatment was observed. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY There are no published reports of genetic toxicology testing of hexachlorodibenzo-p-dioxins. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 6.2E+3 per (mg/kg)/day Drinking Water Unit Risk -- 1.8E-1 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 6E-4 ug/L E-5 (1 in 100,000) 6E-5 ug/L E-6 (1 in 1,000,000) 6E-6 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- liver tumors (see table) Test Animals -- mouse, rat (see table) Route -- gavage Reference -- NTP, 1980a Administered Human Equivalent Tumor Dose (ug/kg/week) Dose (ug/kg/week) Incidence ----------------- ----------------- --------- mouse/B6C3F1/male (adenomas and carcinomas) 0 0 27/75 vehicle 0 15/73 1.25 0.014 14/50 2.5 0.027 14/49 5.0 0.054 24/48 rat/Osborne-Mendel/female (neoplastic nodules and hepatocellular carcinomas) 0 0 1/73 vehicle 0 2/75 1.25 0.03 5/50 2.5 0.06 7/50 5.0 0.12 18/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) A geometric mean of the slope factors for male mice and female rats was used. Slope factors for each species and sex were as follows: male rat = 5.9E+2 per (mg/kg)/day, female rat = 3.5E+3 per (mg/kg)/day, male mouse = 1.1E+4 per (mg/kg)/day, female mouse = 2.9E+3 per (mg/kg)/day. Generally, the estimate derived from data for most sensitive species/sex was used. In this case female rat data were also used for the following reasons: 1) the spontaneous tumor incidence was lower in the rats; 2) statistically significant increases in incidence were observed at the mid- and high-dose in rats vs. high-dose only in mice; 3) there was a more distinct dose-response trend in the rats. The unit risk should not be used if the water concentration exceeds 6E-2 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of animals were treated and observed for their expected lifetime. Risk estimates from data sets from two species (see Section II.B.2.) range within a factor of 20. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 1.3E+0 (ug/cu.m) Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- --------------- E-4 (1 in 10,000) 8E-5 ug/cu.m E-5 (1 in 100,000) 8E-6 ug/cu.m E-6 (1 in 1,000,000) 8E-7 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Calculated from oral data in II.B.2. as follows: Unit risk = 6.2E+3 per (mg/kg)/day x E-3 mg/ug x 0.75 x 20 cu.m/day x 1/70 kg = 1.3/ug/cu.m where: 6.2E+3 per (mg/kg)/day = oral slope factor 0.75 = assumed percentage of inhaled material absorbed 20 cu.m/day = assumed breathing rate for adult human 70 kg = assumed weight for adult human ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The unit risk should not be used if the air concentration exceeds 8E-3 ug/cu.m, since above this concentration the unit risk may not be appropriate. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) See II.B.4. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985 The 1985 Health Assessment Document received both Agency and external review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 01/07/1987 Verification Date -- 01/07/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Hexachlorodibenzo-p-dioxin, mixture (HxCDD) conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 198908 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Hexachlorodibenzo-p-dioxin, mixture (HxCDD) CASRN -- 19408-74-3 Primary Synonym -- 57653-85-7 Last Revised -- 08/01/1989 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES NTP (National Toxicology Program). 1980a. Bioassay of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (gavage) for possible carcinogenicity. DHHS Publ. No. (NIH) 80-1754. NTP (National Toxicology Program). 1980b. Bioassay of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (dermal study) for possible carcinogenicity. DHHS Publ. No. (NIH) 80-1758. U.S. EPA. 1985. Health Assessment Document for Polychlorinated Dibenzo-pdioxin. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Washington, DC. EPA 600/8/84-014F. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Hexachlorodibenzo-p-dioxin, mixture (HxCDD) CASRN -- 19408-74-3 Primary Synonym -- 57653-85-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 II.B.4. Confidence statement revised 03/01/1988 II.C.4. Confidence statement revised 02/01/1989 II.D.3. Primary contact's phone number corrected 08/01/1989 All Primary synonym (CASRN) corrected 08/01/1989 VI. Bibliography on-line 06/01/1990 All Primary synonym (CASRN) corrected again 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 03/01/1991 II.A.3. Text edited 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 384 of 1119 in IRIS (through 2003/06) AN: 167 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199402 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Hexachloroethane- SY: 67-72-1; AVLOTHANE-; CARBON-HEXACHLORIDE-; DISTOKAL-; DISTOPAN-; DISTOPIN-; EGITOL-; ETHANE-HEXACHLORIDE-; ETHANE,-HEXACHLORO-; ETHYLENE-HEXACHLORIDE-; FALKITOL-; FASCIOLIN-; HEXACHLOR-AETHAN-; 1,1,1,2,2,2-HEXACHLOROETHANE-; HEXACHLOROETHYLENE-; MOTTENHEXE-; NA-9037-; NCI-C04604-; PERCHLOROETHANE-; PHENOHEP-; RCRA-WASTE-NUMBER-U131- RN: 67-72-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199104 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Hexachloroethane CASRN -- 67-72-1 Last Revised -- 04/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Atrophy and NOAEL: 1 mg/kg/day 1000 1 1E-3 degeneration of the mg/kg/day renal tubules LOAEL: 15 mg/kg/day Rat Subchronic Dietary Study Gorzinski et al., 1985 ---------------------------------------------------------------------------- *Conversion Factors: The doses were estimated by the investigators from body weights, food consumption and diet analysis data. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Gorzinski, S.J., R.J. Nolan, S.B. McCollister, R.J. Kociba and J.L. Mattsson. 1985. Subchronic oral toxicity, tissue distribution and clearance of hexachloroethane in the rat. Drug Chem. Toxicol. 8(3): 155-169. Groups of 10 male and 10 female Fischer 344 rats were treated with diets containing hexachloroethane for 16 weeks. Dosages were 0, 1, 15, or 62 mg/kg/day, as determined by the investigators. The rats were evaluated for overt signs of toxicity; body weight gain; food consumption; urinalysis, hematological, and clinical chemistry parameters; organ weights; and gross pathology. Comprehensive histologic examination was performed on the control and 62-mg/kg/day groups, while histologic examination of the 1- and 15-mg/kg/day groups was limited to the liver and kidney. At 15 and 62 mg/kg/day, male rats had dose-related increased incidences of renal lesions, including renal atrophy, degeneration, hypertrophy, and dilation. At 62 mg/kg/day, males had increased absolute and relative kidney weights and peritubular fibrosis; females had slight renal tubular atrophy and increased liver weights. No other effects were observed. Thus, 15 mg/kg/day is the LOAEL and 1 mg/kg/day is the NOAEL. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was used: 10 to account for interspecies extrapolation, 10 for the range of sensitivity within the human population to xenobiotics and 10 for the use of a subchronic study. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) The quality assessment of another chronic gavage bioassay in rats is in progress (NTP, 1986), but a draft report of results of the preliminary subchronic gavage study is available (NTP, 1983). In this study, rats were treated by gavage with 0, 47, 94, 188, 375, or 750 mg/kg/day, 5 days/week for 13 weeks. Body weight gain was reduced at 750 mg/kg/day, behavioral signs of toxicity were seen at 94 mg/kg/day, and increased relative liver and kidney weights occurred at 375 mg/kg/day. Dose-related increased incidences of renal tubular regeneration occurred at 47 mg/kg/day. In a 6-week inhalation study, rats, dogs, and guinea pigs were exposed to hexachloroethane 6 hours/day, 5 days/week for 6 weeks at 0, 145, 465, or 2520 mg/cu.m (Weeks et al., 1979). Neurobehavioral effects occurred in rats and dogs, and reduced body weights, increased relative liver weights, and deaths occurred in guinea pigs at 2520 mg/cu.m. No effects were observed at 465 mg/cu.m. Based on this inhalation NOAEL in rats, an RfD of 0.03 mg/kg/day could be calculated using an uncertainty factor of 1000. However, the more recent 16-week oral study by Gorzinski et al. (1985) is a better basis for the RfD. Hexachloroethane has been tested for teratogenicity by oral and inhalation administration to rats. At gavage doses of 500 mg/kg/day during gestation there was maternal toxicity, a reduced gestation index, and reduction in the numbers of fetuses/dam, and increased fetal resorption rates (Weeks et al., 1979). No effects occurred at 50 or 100 mg/kg/day. Weeks et al. (1979) administered hexachloroethane to rats by inhalation at 145, 465, or 2520 mg/cu.m, 6 hours/day during gestation. At the two highest doses, maternal toxicity was observed but there was no evidence of fetoxicity or teratogenicity. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium Medium to high confidence is placed in the Gorzinski et al. (1985) study because, although it defined a NOAEL and a LOAEL, the study used small groups of animals. Confidence in the data base is medium because, although hexachloroethane has been tested for carcinogenicity and teratogenicity, a NOAEL for chronic toxicity has not been defined. Confidence in the RfD is therefore medium. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 12/18/1985, 04/16/1987 Verification Date -- 04/16/1987 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199212 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Hexachloroethane CASRN -- 67-72-1 NORC: Not available at this time. ============================================================================ UDCA: 199402 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Hexachloroethane CASRN -- 67-72-1 Last Revised -- 02/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Observation of carcinomas in one mouse strain after oral exposure HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. Technical grade hexachloroethane (98% pure) was administered by gavage to Osborne-Mendel rats and B6C3F1 mice (50 each male and female) (NCI, 1978). Rats were treated with either 250 or 500 mg hexachloroethane/kg/day, 5 days/week for 23 weeks. After this time animals were rested 1 week and gavaged for 4 succeeding weeks up to week 78; an observation period of 33-34 weeks followed. Final TWA treatment doses were 212 and 432 mg/kg/day. There was no evidence of hexachloroethane-induced neoplastic growth in rats. Mice were administered 500 or 1000 mg/kg/day, 5 days/week, continuously. At week 9 the doses were increased to 600 and 1200 mg/kg/day, and this dosage was maintained until week 78. Mice were observed for 12-13 weeks after cessation of treatment. The TWA doses were 590 and 1179 mg/kg/day. Mice of both sexes showed a significant increase in the incidence of hepatocellular carcinoma. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY None. Hexachloroethane was not mutagenic for any of 5 Salmonella typhimurium strains (TA1535, TA1537, TA1538 TA98 or TA100) or for Saccharomyces cerevisiae D4 in the absence or presence of rat liver homogenates (Weeks et al., 1979). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 1.4E-2 per (mg/kg)/day Drinking Water Unit Risk -- 4.0E-7 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 3E+2 ug/L E-5 (1 in 100,000) 3E+1 ug/L E-6 (1 in 1,000,000) 3E+0 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- hepatocelluar carcinomas Test Animals -- mouse/B6C3F1, male Route -- gavage Reference -- NCI, 1978 Administered Human Equivalent Tumor Dose (mg/kg)/day Dose (mg/kg)/day Incidence ---------------- ---------------- --------- 0 0 3/20 421 27.8 15/50 841 55.5 31/49 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The administered doses are TWA-adjusted for frequency of exposure (5/7 days). Human equivalent doses were adjusted for length of exposure (546 days of a potential lifespan of 637) and weight of the animals (assumed to be 0.032 kg). The vehicle control group incidence data was used in modeling. Toxic tubular nephropathy was noted in treated animals of both species. Rats, but not mice, exhibited dose-related increases in mortality. The unit risk should not be used if the water concentration exceeds 3E+4 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of animals were treated and the tumor response was dose-related. Background incidence of these tumors is high. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 4.0E-6 per (ug/cu.m) Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- --------------- E-4 (1 in 10,000) 3E+1 ug/cu.m E-5 (1 in 100,000) 3E+0 ug/cu.m E-6 (1 in 1,000,000) 3E-1 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE The inhalation risk estimates were calculated from the oral data presented in II.B.2. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The unit risk should not be used if the air concentration exceeds 3000 ug/cu.m, since above this concentration the unit risk may not be appropriate. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) See II.B.4. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1980 The values in the Ambient Water Quality Criteria Document for Chlorinated Ethanes received extensive peer and public review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 07/23/1986 Verification Date -- 07/23/1986 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199104 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Hexachloroethane CASRN -- 67-72-1 Last Revised -- 04/01/1991 SORD: __VI.A. ORAL RfD REFERENCES Gorzinski, S.J., R.J. Nolan, S.B. McCollester, R.J. Kociba and J.L. Mattsson. 1985. Subchronic oral toxicity, tissue distribution and clearance of hexachloroethane in the rat. Drug Chem. Toxicol. 8(3): 155-169. NTP (National Toxicology Program). 1983. Subchronic study with hexachloroethane in rats. Unpublished report submitted by contract laboratory. Internal working document. NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of hexachloroethane (CAS No. 67-72-1) in F344/N rats (gavage studies). NTP Tech. Report Ser. No. 361. PB 90-170895/AS. Weeks, M.H., R.A. Angerhofer, R. Bishop, J. Thomasino and C.R. Pope. 1979. The toxicity of hexachloroethane in laboratory animals. Am. Ind. Hyg. Assoc. J. 40: 187-198. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES NCI (National Cancer Institute). 1978. Bioassay of Hexachloroethane for Possible Carcinogenicity. CAS No. 67-72-1. NCI-CG-TR-68. Tech. Report Ser. No. 68. U.S. DHEW. Publ. No. (NIH) 78-1318. U.S. EPA. 1980. Ambient Water Quality Criteria for Chlorinated Ethanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulations and Standards, Washington, DC. EPA 440/5-80-029. NTIS PB 81-117400. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Hexachloroethane CASRN -- 67-72-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/30/1987 I.A. Oral RfD assessment on-line 03/01/1988 I.A.5. Confidence levels revised 03/01/1988 II.B.3. Text clarified 03/01/1988 II.B.4. Confidence statement revised 03/01/1988 II.C.4. Confidence statement revised 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 04/01/1991 I.A. Text edited 04/01/1991 I.A.7. Secondary contact changed 04/01/1991 II. Text edited 04/01/1991 VI. Bibliography on-line 12/01/1991 I.B. Inhalation RfC now under review 12/01/1991 IV.F.1. EPA contact changed 01/01/1992 IV. Regulatory actions updated 12/01/1992 I.B. Work group review date added 02/01/1994 II.D.3. Secondary contact's phone number changed 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 385 of 1119 in IRIS (through 2003/06) AN: 169 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199104 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Isobutyl-alcohol- SY: 78-83-1; ALCOOL-ISOBUTYLIQUE-; FERMENTATION-BUTYL-ALCOHOL-; 1-HYDROXYMETHYLPROPANE-; ISOBUTANOL-; ISOBUTYLALKOHOL-; ISOPROPYLCARBINOL-; 2-METHYL-PROPANOL-; 2-METHYL-1-PROPANOL-; 2-METHYLPROPYL-ALCOHOL-; 1-PROPANOL,-2-METHYL-; RCRA-WASTE-NUMBER-U140-; UN-1212- RN: 78-83-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199104 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Isobutyl alcohol CASRN -- 78-83-1 Last Revised -- 04/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Hypoactivity and NOEL: 316 mg/kg/day 1000 1 3E-1 ataxia mg/kg/day LOAEL: 1000 mg/kg/day Rat Oral Subchronic Study U.S. EPA, 1986 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) U.S. EPA. 1986. Rat oral subchronic toxicity study with isobutyl alcohol. Office of Solid Waste, Washington, DC. Animal toxicity studies indicate that butyl alcohol may produce liver/ kidney effects and decreased red blood cell numbers. Using pathways similar to buty alcohol, isobutyl alcohol is metabolized to its aldehydes and further catabolized to carbon dioxide and water (Cornish, 1980). To evaluate the toxicity of isobutyl alcohol, U.S. EPA (1986) conducted a subchronic study in rats (30/sex/group). Animals were given oral doses of 0, 100, 316, and 1000 mg/kg/day of isobutyl alcohol for 13 weeks. This study contained data on body weight changes, food consumption, ophthalmologic examinations, clinical and biochemical parameters, and gross and microscopic examinations. An evaluation of the data revealed no effect on body weight or clinical and histopathologic parameters at doses less than or equal to 316 mg/kg/day. Treatment at the high dose (1000 mg/kg/day) resulted in a minor decrease in body weight gain during week 2 and decreased serum potassium levels and hypoactivity. Hypoactivity was the most frequently observed clinical sign. It occurred in every rat in the 1000-mg/kg/day dose group during week 1; hypoactivity was markedly decreased by week 4 and occurred only sporadically thereafter. Ataxia was also seen at low incidence in the 1000-mg/kg/day dose group throughout the study. The NOEL for this study is 316 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was applied: 10 for interspecies extrapolation, 10 for intraspecies variability and 10 for extrapolating subchronic exposure to chronic exposure. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) No adequate chronic toxicity studies have been conducted on isobutyl alcohol. Of the two other published subchronic (2- or 4-month) oral studies (Hillbom et al., 1974a,b), one was available only as an abstract (1974a) and contained insufficient information upon which to evaluate the adequacy of experimental design, etc. The second Hillbom et al. (1974b) study examined the effects of isobutanol only at a single concentration (1M), which could be considered a LOAEL for gastrointestinal damage for isobutanol. However, this study is not of appropriate design for risk assessment purposes, and histopathological examination of stomach, small and large intestine in the much more detailed and experimentally sound 1986 EPA study failed to reproduce the gastrointestinal effects reported by Hillbom et al. (1974b) at dosages five to six orders of magnitude greater than those used by Hillbom et al. (1974b). Isobutyl alcohol has not been scheduled for NTP testing for chronic toxicity, carcinogenicity, or other reproductive effects. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The oral subchronic study is a well-designed study which employed several dose levels and measured adequate toxicologic endpoints; thus, a medium to high confidence is recommended. The data base lacks adequate supporting or chronic toxicity and reproduction studies; thus, low confidence is recommended. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1986 Agency Work Group Review -- 05/14/1986 Verification Date -- 05/14/1986 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Isobutyl alcohol conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Isobutyl alcohol CASRN -- 78-83-1 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Isobutyl alcohol CASRN -- 78-83-1 NOCA: Not available at this time. ============================================================================ UDSO: 199104 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Isobutyl alcohol CASRN -- 78-83-1 Last Revised -- 04/01/1991 SORD: __VI.A. ORAL RfD REFERENCES Cornish, H.H. 1980. Solvents and vapors. In: Casarett and Doull's Toxicology, The Basic Science of Poisons, 2nd. ed., J. Doull, C.D. Klaassen and M.O. Amdur, Ed. MacMillan Publishing Co., Inc., New York. p. 480-481. Hillibom, M.E., K. Franssila and O.A. Forsander. 1974a. Effects of chronic ingestion of some lower aliphatic alcohols in rats. Arukow Kenkyu. 9(2): 101-108. (Abstract) Hillbom, M.E., K. Franssila and O.A. Forsander. 1974b. Effects of chronic ingestion of some lower aliphatic alcohols in rats. Res. Commun. Chem. Pathol. Pharmacol. 9(1): 177-180. U.S. EPA. 1986. Rat oral subchronic toxicity study with isobutyl alcohol. Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Isobutyl alcohol CASRN -- 78-83-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/30/1987 I.A.2. Citation corrected 09/30/1987 IV. Regulatory Action section on-line 03/01/1988 I.A.5. Confidence levels revised 02/01/1989 I.A.7. Secondary contact's phone number corrected 07/01/1989 I.A.2. 1st paragraph revised 07/01/1989 I.A.4. Text revised 07/01/1989 VI. Bibliography on-line 04/01/1991 I.A. Text edited 04/01/1991 I.A.2. Paragraph 1 - citation clarified 04/01/1991 I.A.7. Primary and secondary contact changed 04/01/1991 VI.A. Cassarett and Doul, 1980 corrected to Cornish, 1980 01/01/1992 IV. Regulatory actions updated 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 386 of 1119 in IRIS (through 2003/06) AN: 170 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199310 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Linuron- SY: 330-55-2; AFALON-; AFALON-INURON-; APHALON-; CEPHALON-; 3-(3,4-DICHLOOR-FENYL)-1-METHOXY-1-METHYLUREUM; 3-(3,4-DICHLORO-FENIL)-1-METOSSI-1-METIL-UREA; 3-(3,4-DICHLOROPHENYL)-1-METHOXYMETHYLUREA; 3-(3,4-DICHLOROPHENYL)-1-METHOXY-1-METHYLUREA; 1-(3,4-DICHLOROPHENYL)3-METHOXY-3-METHYLUREE; 3-(3,4-DICHLOR-PHENYL)-1-METHOXY-1-METHYL-HARNSTOFF; 3-(4,5-DICHLORPHENYL)-1-METHOXY-1-METHYLHARNSTOFF; DU-PONT-326-; GARNITAN-; HOE-2810-; LINEX-4L-; LINOROX-; LINUREX-; LOREX-; LOROX-; METHOXYDIURON-; 1-METHOXY-1-METHYL-3-(3,4-DICHLOROPHENYL)UREA; N'-(3,4-DICHLOROPHENYL)-N-METHOXY-N-METHYLUREA; N-(3,4-DICHLOROPHENYL)-N'-METHYL-N'-METHOXYUREA; PREMALIN-; SARCLEX-; SCARCLEX-; SINURON-; UREA, 3-(3,4-DICHLOROPHENYL)-1-METHOXY-1-METHYL- RN: 330-55-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199008 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Linuron CASRN -- 330-55-2 Last Revised -- 08/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Abnormal blood NOEL: none 300 1 2E-3 pigment mg/kg/day LEL: 25 ppm diet 2-Year Dog Feeding (0.625 mg/kg/day) Study du Pont, 1962 ---------------------------------------------------------------------------- *Conversion Factors: 1 ppm = 0.025 mg/kg/day (assumed dog food consumption) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) E.I. du Pont de Nemours and Co., Inc. 1962. MRID No. 00018374. Available from EPA. Write to FOI, EPA, Washington, DC 20460. Twenty-four beagle dogs were divided into four groups of six animals each (3 male, 3 female) and administered diets containing 0, 25, 125, and 625 ppm (0, 0.625, 3.125, and 15.63 mg/kg/day) linuron for 2 years. Body weight data provided no clear indication of a possible effect of linuron on body weight; all dogs gained weight except three (two females fed 625 ppm and one female fed 25 ppm). Dogs fed 25 ppm showed no significant alterations in RBC counts, hemoglobin values, or hematocrit percentages. At 125 ppm female dogs had a statistically significant decrease in their mean RBC count. In all dogs fed 625 ppm and 2/3 females fed 25 ppm, blood analysis revealed an abnormal blood pigment (the abnormal pigment was characterized by a band in the 618- to 620-millimicron region, following addition of KCN to the blood). The oxyhemoglobin band was normal for all dogs. Based on the abnormal blood pigment in females, the LEL for systemic toxicity is 25 ppm (0.625 mg/kg/day). A NOEL for systemic toxicity was not established. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 300 includes uncertainties in the extrapolation from laboratory animals to humans (100-fold) and an additional factor of 3 to account for the fact that the NOEL was not established in this study. Since the effects at the lowest level are minimal, a 3-fold UF is considered sufficient. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) None. Data Considered for Establishing the RfD: 1) 2-Year Feeding - dog: Principal study - see previous description; no core grade (E.I. du Pont de Nemours and Co., Inc., 1962a) 2) 2-Year Feeding (oncogenic) - rat: Systemic NOEL=125 ppm (6.25 mg/kg/day); Systemic LEL=625 ppm (31.25 mg/kg/day) (spleen and bone marrow changes indicative of hemolysis; increased mortality, growth retardation; no core grade (E.I. du Pont de Nemours and Co., Inc., 1962b) 3) 2-Year Feeding (oncongenic) - rat: Systemic NOEL=none; LEL=50 ppm (2.5 mg/kg/day) (increased MLV, decreased RBC count possible reticulocytosis); core grade minimum (E.I. du Pont de Nemours and Co., Inc., 1980a) 4) 3-Generation Reproduction - rat: NOEL (adults)=25 ppm (1.25 mg/kg/day); LEL (adults)=125 ppm (6.25 mg/kg/day) (reduced weights and weight gains of dams prior to mating, reduced dam weights at weaning, reduced body weight gains of both sexes, and alopecia at 625 ppm); Reproductive NOEL=25 ppm (1.25 mg/kg/day); Reproductive LEL=125 ppm (6.25 mg/kg/day) [lower weanling weights; pup weights more consistently reduced at 625 ppm (days 1 to 21); liver and kidney weights reduced at 625 ppm; liver atrophy at 625 ppm; lower fertility, reduced pup survival on days 0 to 4 in 625-ppm group]; core grade supplementary (E.I. du Pont de Nemours and Co., Inc., 1984) 5) Teratology - rat: Maternal NOEL=50 ppm (2.50 mg/kg/day) (LDT); Maternal LEL=125 ppm (6.25 mg/kg/day) (decreased food consumption, decreased body weight gain); Fetal NOEL=125 ppm (6.25 mg/kg/day); Fetal LEL=625 ppm (31.25 mg/kg/day) (increased number of resorption sites); Teratogenic NOEL=625 ppm (31.25 mg/kg/day) (HDT); no core grade (E.I. du Pont de Nemours and Co., Inc., 1979) 6) Teratology - rabbit: Maternal NOEL=5 mg/kg/day; Maternal LEL=25 ppm (depression in maternal body weight; at 100 mg/kg, increase in abortion rate and depression in liver and liver body weight ratio); Developmental NOEL=none; Developmental LEL=5 mg/kg/day (LDT); (decrease in fetal body weights and litter size; statistically significant trend in elevation of total skull alterations; core grade minimum (E.I. du Pont de Nemours and Co., Inc., 1986) 7) Teratology - rabbit: Teratogenic NOEL=125 ppm (HDT); no core grade (E.I. du Pont de Nemours and Co., Inc., 1965) Other Data Reviewed: 1) 90-Day Feeding - rat: NOEL=80 ppm (4.0 mg/kg/day); LEL=400 ppm (20 mg/kg/day) (decreased RBC, increased WBC, retarded growth at 3000 ppm); no core grade 2) 30-Day Feeding - rat: NOEL males=60 ppm (3 mg/kg/day); LEL=300 ppm (15 mg/kg/day)(decreased body weight gain - males only); no core grade; females were not affected at dose levels less than 1200 ppm. At 3000 ppm both sexes showed abnormal blood pigments (not methemoglobin), severe growth retardation and increased mortality. Data Gap(s): Reevaluation of effects on hematology. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- High RfD -- High The principal study appears to be of good quality and is given a medium rating. The data base is fairly complete and additional studies are supportive; therefore, confidence in the data base is high. High confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Pesticide Registration Standard, June l984 Special Review Position Document 1 Agency Work Group Review -- 07/22/1985, 05/l4/86 Verification Date -- 05/l4/86 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Linuron CASRN -- 330-55-2 NORC: Not available at this time. ============================================================================ UDCA: 199310 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Linuron CASRN -- 330-55-2 Last Revised -- 10/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Limited evidence indicated linuron produced increases in both testicular hyperplasia and adenomas in male rats in three separate studies. Hepatocellular adenomas were observed in female mice in a single study at the highest dose group tested; the tumors were benign and showed no progression toward malignancy. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. Charles River Crl:CD rats, 80/sex/dose group, were fed linuron (97% purity) in the diet at 0, 50, 125, or 625 ppm for 2 years (du Pont, 1980). The incidence of interstitial-cell adenoma in the testes was significantly increased in the mid-dose rats (19/64 or 29.7%) and the high-dose rats (37/66 or 56.1%) as compared with the control rats (4/68 or 5.9%). Survival was not affected by the test material as compared to the control group. The MTD was achieved at the high dose in both sexes based on decreased mean body weight and body weight gain, lower hemopoietic activity in both male and female mid- and high-dose groups, and reduced absolute and relative testicular weights in the high-dose males. In a mouse study conducted by du Pont (1982), Charles River CD-1 mice were fed linuron (97% purity) in the diet at 0, 50, 150, or 1500 ppm for 2 years. The incidence of hepatocellular adenomas was statistically significantly increased in the high dose female mice (20/8O or 25%) compared with the control mice (5/79 or 6.3%). In the low-dose males, the incidence of hepatocellular adenomas was also statistically significantly increased (18/80 or 22.5%) as compared with the controls (7/79 or 11.4%). The incidence of hepatocellular carcinomas was not significantly increased at any dose in either sex. The test substance had no effect on survival. The MTD was achieved at the high dose in both sexes of the mice based on reduced body weight and body weight gain, and increased methemoglobin formation. In a multi-generation study (not designed to investigate carcinogenicity) conducted by du Pont (1984), linuron (94.5% purity) was fed to Charles River Crl:CD rats at 0, 25, 125, or 625 ppm. There was an increase in testicular interstitial-cell adenomas and hyperplasia in treated males of both generations compared with controls. The effect was most apparent in the mid-dose group. In another study conducted by du Pont (1986a) using 12-month-old Cr1:CD (SD)BR male rats, linuron (94.5% purity) was fed in the diet at 625 ppm to three different groups. One group received dietary linuron from 12 to 24 months, a second group was fed a normal diet from 12 to 18 months followed by 6 months of dietary linuron, and the third group (control) was fed a normal diet from 12 to 24 months of age. The incidence of testicular adenoma and hyperplasia was statistically significantly increased in the group fed linuron at 625 ppm for a total of 12 months (hyperplasia: 15/25 vs. 8/25 in controls; adenoma: 6/25 vs. 0/25 in controls). No malignant tumors were observed in any group. This finding suggests the effect may be mediated through an age-related alteration of the testes that may make this organ more susceptible to oncogenic response. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Gene mutation in CHO cells and Salmonella typhimurium, unscheduled DNA synthesis, and in vivo bone marrow chromosomal aberration assays (du Pont, 1983a,b,c,d, respectively) were negative for linuron. Based on preliminary data, monuron, a structural analogue, produced kidney and liver tumors in F344/N male rats; other analogues (diuron, propanil, and dimilan) did not produce tumors in rat and mouse oncogenicity studies (propanil was tested in rats only). Linuron contains two impurities, 3,3',4,4'-tetrachloroazobenzene (TCAB) and 3,3',4,4'-tetrachloroazoxybenzene (TCAOB), which are analogues of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), classified by the EPA as a B2 carcinogen. TCAB and TCAOB are contained in linuron at levels of approximately 8.8 and <0.05 ppm, respectively (Sundstrom et al., 1978). It has been recommended by the EPA that NTP test TCAB and TCAOB in the 2-year rodent bioassays. Biochemical and histopathologic data (du Pont, 1986b) were presented which suggest that linuron may affect testosterone metabolism in horse testicular microsomes at doses of 11 to 1100 mg. Leydig cells from chronically-dosed male rats (625 ppm) exhibited a hyperactive response to leutenizing hormone (LH) manifested by increased testosterone secretion. In vitro secretion patterns of testosterone suggest that the effects of linuron on Leydig cells of rat testes are age- and dose-related. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE A quanitative estimate of carcinogenic risk was considered inappropriate. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987a,b, 1988 The 1987 Carcinogenicity Assessment for linuron has been reviewed by the Peer Review Committee and the FIFRA Scientific Advisory Panal (SAP) with agreement reached on classification. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 06/15/1988, 02/01/1989 Verification Date -- 02/01/1989 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199008 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Linuron CASRN -- 330-55-2 Last Revised -- 08/01/1990 SORD: __VI.A. ORAL RfD REFERENCES E.I. du Pont de Nemours and Company, Inc. 1962a. MRID No. 00018374, 00018376. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1962b. MRID No. 00018379, 00018381. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1980a. MRID No. 00029680. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1984. MRID No. 00146071. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1979. MRID No. 00018167. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1986. MRID No. 00153867. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1965. MRID No. 00018170. Available from EPA. Write to FOI, EPA, Washington DC 20460. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES E.I. du Pont de Nemours and Company, Inc. 1980. EPA Accession No. 241897. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1982. MRID No. 00124195. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1983a. MRID No. 00131738. Available from EPA. Write to FOI, EPA, Washington DC 20460. E.I. du Pont de Nemours and Company, Inc. 1983b. MRID No. 00137152. Available from EPA. Write to FOI, EPA, Washington DC. 20460. E.I. du Pont de Nemours and Company, Inc. 1983c. MRID No. 00132583. Available from EPA. Write to FOI, EPA, Washington DC. 20460. E.I. du Pont de Nemours and Company, Inc. 1983d. MRID No. 00137153. Available from EPA. Write to FOI, EPA, Washington DC. 20460. E.I. du Pont de Nemours and Company, Inc. 1984. EPA Accession No. 255829. Available from EPA. Write to FOI, EPA, Washington DC. 20460. E.I. du Pont de Nemours and Company, Inc. 1986a. EPA Accession No. 265423. Available from EPA. Write to FOI, EPA, Washington DC. 20460. E.I. du Pont de Nemours and Company, Inc. 1986b. EPA Accession No. 265422. Available from EPA. Write to FOI, EPA, Washington DC. 20460. Rinde, E. 1987. U.S. EPA, Scientific Mission Support Staff. Memorandum to Addressees: U.S. EPA, Toxicology Branch, Peer Review Committee. Draft Document on Linuron. Sundstrom, G., B. Tonsson and L. Renberg. 1978. Determination of the toxic impurities 2,2',4,4'-tetrachloroazoxybenzene in commercial Divron, Linuron and 3,4-dichloroaniline samples. Chemosphere. 12: 973-979. U.S. EPA. 1987a. Carcinogenicity Assessment of Linuron. Prepared by the Office of Pesticide and Toxic Substances, Office of Pesticide Programs, Hazard Evaluation Division, Toxicology Branch, Washington, DC. U.S. EPA. 1987b. Scientific Advisory Panel (SAP) Open Meeting, Arlington, VA, September 23rd. U.S. EPA. 1988. Linuron: Preliminary determination to conclude the special review. Federal Register. 53(159): 31262. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Linuron CASRN -- 330-55-2 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 05/01/1989 II. Carcinogen assessment now under review 08/01/1989 II. Carcinogen summary on-line 08/01/1989 VI. Bibliography on-line 08/01/1990 I.A. Text edited 08/01/1990 II. Text edited 08/01/1990 VI.A. RfD references added 01/01/1992 IV. Regulatory actions updated 10/01/1993 II.D.3. Secondary contact changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 387 of 1119 in IRIS (through 2003/06) AN: 191 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 198803 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Sodium-azide- SY: 26628-22-8; AZIDE-; AZIUM-; AZOTURE-DE-SODIUM-; KAZOE-; NATRIUMAZID-; NATRIUMMAZIDE-; NCI-C06462-; NSC-3072-; RCRA-WASTE-NUMBER-P105-; SMITE-; SODIUM,-AZOTURE-DE-; SODIUM,-AZOTURO-DI-; U-3886-; UN-1687- RN: 26628-22-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198803 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Sodium azide CASRN -- 26628-22-8 Last Revised -- 03/01/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Clinical signs (e.g., NOAEL: 5 mg/kg/day 1000 1 4E-3 hunched postures) and converted to 3.57 mg/kg/day reduced body weight mg/kg/day Rat Oral Subchronic LOAEL: 10 mg/kg/day Study converted to 7.14 mg/kg/day NCI, 1981 ---------------------------------------------------------------------------- *Conversion Factors: x 5 days/7 days PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NCI (National Cancer Institute). 1981. Ninety-day subchronic toxicity test with sodium azide in Fischer 344 rats. Study No. 5650.08, report submitted by Microbiological Associates, Bethesda, MD. NCI (1981) reported a 90-day gavage (distilled water) study with rats (10/sex/group) exposed to 0, 1.25, 2.5, 5, 10 or 20 mg/kg sodium azide, 5 days/week. Nearly total mortality occurred at the 20 mg/kg dose over the experimental period, but no deaths occurred at other doses. A trend in reduced weight gain was seen in the 10 mg/kg group. Females exhibited slightly elevated mean liver-to-body weights in all dosage groups, but the statistical significance of this increase was not reported. Histopathologic evaluations revealed lesions in the brain and lung of the high-dose rats that died; however, no compound-related lesions were discerned in any surviving rats. The only significant clinical signs of toxicity were hunched postures among males in the two highest dosage groups and females in the 20 mg/kg group. Thus, 5 mg/kg was considered a NOAEL. By applying an uncertainty factor of 1000 to this NOAEL and by multiplying by 5 days/7 days to account for continuous exposure, an RfD of 0.004 mg/kg/day or 0.2 mg/day for a 70-kg person is derived. Data regarding the effects of oral exposure of humans to sodium azide are available, but limited. During investigations of the effects of metabolic inhibition on cancer patients, it was observed that sodium azide lowered the blood pressure of hypertensive but not normotensive individuals (Black et al., 1954). This report further indicated that nine normotensive individuals, including both individuals and cancer patients, experienced no "sustained effect" on blood pressure from the ingestion of as much as 1.3 mg of sodium azide, 3 times/day for 10 days (3.9 mg/day or 0.056 mg/kg/day for a 70-kg man). In a separate study, Black et al. (1954) measured blood pressure 4-12 hours after the last dosage in 30 hypertensive patients treated orally with 0.5-1.3 mg sodium azide, 3 times/day for periods ranging from 7 days to 2.5 years; 25/30 patients sustained lowering of blood pressure towards normotensive levels. Some patients developed an increased sensitivity to the drug with repeated treatment, necessitating a reduction in dosage to 0.25 mg, 3 times/day (0-75 mg/day or 0.011 mg/kg/day). No evidence of damage to the kidney, heart or liver was detected in routine clinical studies of the three hypertensive patients who ingested sodium azide for 1-2.5 years. Despite short duration of exposure (10 days), sodium azide at dosages up to 0.056 mg/kg/day did not produce altered blood pressure in normotensive subjects. The limited information tends to support the rat NOEL of 3.57 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty of 1000 was applied; 10 for interspecies, 10 for intraspecies, and 10 for extrapolating from subchronic to chronic exposure. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Sodium azide is a metabolic inhibitor that interferes with oxidative enzymes and inhibits phosphorylation. A characteristic effect of acute administration of sodium azide to experimental animals is hypotension (Reinhardt and Britelli, 1982). Sodium azide is currently undergoing testing for chronic oral toxicity in rats (NTP, 1985). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The critical study is a well-designed subchronic study that defined both the NOEL and LOAEL and was supported by range-finding studies; thus, a medium confidence was assigned. The data base contained supportive animal and human subchronic studies, buy lacks chronic and reproductive toxicity studies; thus, the data base is rated medium. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 06/11/1986, 07/22/1986 Verification Date -- 07/22/1986 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Sodium azide CASRN -- 26628-22-8 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Sodium azide CASRN -- 26628-22-8 NOCA: Not available at this time. ============================================================================ UDSO: 199001 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Sodium azide CASRN -- 26628-22-8 Last Revised -- 01/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Black, M.M., B.W. Zweifach and F.D. Speer. 1954. Comparison of hypotensive action of sodium azide in normotensive and hypertensive patients. Proc. Soc. Exp. Biol. Med. 85: 11-16. NCI (National Cancer Institute). 1981. Ninety-day subchronic toxicity test with sodium azide in Fischer 344 rats. Study No. 5650.08, report submitted by Microbiological Associates, Bethesda, MD. NTP (National Toxicology Program). 1985. Management Status Report. 8/7/85 Reinhardt, C.F. and M.R. Britelli. 1982. Heterocyclic and miscellaneous nitrogen compounds: Azides. In: Patty's Industrial Hygiene and Toxicology. Vol. 2., 3rd ed., G.D. Clayton and F.E. Clayton, Ed. John Wiley and Sons, Inc., New York. p. 2778-2822. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Sodium azide CASRN -- 26628-22-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 01/01/1990 VI. Bibliography on-line 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 388 of 1119 in IRIS (through 2003/06) AN: 200 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199311 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2,3-Trichloropropane- SY: 96-18-4; ALLYL-TRICHLORIDE-; GLYCEROL-TRICHLOROHYDRIN-; GLYCERYL-TRICHLOROHYDRIN-; NCI-C60220-; PROPANE,-1,2,3-TRICHLORO-; TRICHLOROHYDRIN-; TRICHLOROPROPANE,-1,2,3- RN: 96-18-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199008 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2,3-Trichloropropane CASRN -- 96-18-4 Last Revised -- 08/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Alterations in NOAEL: 8 mg/kg/day, 5 1000 1 6E-3 clinical chemistry days/week converted mg/kg/day and reduction in red to 5.71 mg/kg/day cell mass LOAEL: 16 mg/kg/day, Rat Oral Subchronic 5 days/week converted Study to 11.4 mg/kg/day NTP, 1983 ---------------------------------------------------------------------------- *Conversion Factors: Doses adjusted for dosing schedule (5 days/week) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1983. 120-Day gavage study in mice and rats with 1,2,3-trichloropropane. Unpublished report prepared by Hazleton Laboratories. In this study, the toxic effects of 1,2,3-trichloropropane in B6C3F1 mice and Fischer 344 rats were examined following administration of the test material by gavage 5 days/week for 60 to 120 days. Groups of 20 animals/sex (mice or rats) were administered doses of 8, 16, 32, 63, 125, or 250 mg/kg/day trichloropropane in corn oil. The control animals (30/sex) received corn oil by gavage. After 60 days, 50% of the animals for each test group and 10 mice/sex and 10 rats/sex from the control group were sacrificed. Clinical pathology and histopathology were performed after 60 and 120 days. Several other parameters, such as body weight changes, food consumption, mortality and organ weight changes, were also recorded. Treatment-related deaths occurred at the 250 mg/kg/day dose level in both mice and rats during the early phase of the study. Rats were more sensitive than mice; the mortality rate was 100% in rats. Other chemical-related findings common to both mice and rats were increased liver and kidney weights accompanied by histopathological changes in the organs. Additionally, rats showed decreased body weight gains, alterations in serum enzymes associated with hepatic and renal toxicity, and decreased red cell mass. Female rats and mice as contrasted with males showed increased sensitivity to trichloropropane. Specifically, treatment-related clinical chemistry alterations were observed in male rats receiving doses of 125 and 63 mg/kg/day, whereas females showed alterations in the same parameters at doses of 125, 63 and 32 mg/kg/day and, to a lesser extent, at the 16 mg/kg/day level. Based on data reported in this study, LOAELs were 63 mg/kg/day for mice and 16 mg/kg/day for rats. The highest NOEL was 8 mg/kg/day, 5 days/week or 5.7 mg/kg/day (on 5 days/7 days basis) in rats. Applying an uncertainty factor of 1000, an RfD of 0.006 mg/kg/day or 0.4 mg/day for a 70-kg person can be derived. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was used; 10 for intraspecies, 10 for interspecies extrapolation, and 10 for extrapolating subchronic to chronic exposures. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Other than LD50 data for trichloropropane derived from oral studies and several short-term inhalation studies published as abstracts, no chronic or reproductive studies are available for quantitative risk analysis. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- Low RfD -- Low The principal study was well-designed, established a NOEL and LOAEL, and measured several toxicological endpoints in both mice and rats; therefore, a high confidence was recommended. The data base lacks pertinent supporting inhalation or oral studies; therefore, a low confidence was recommended. Confidence in the RfD can be considered low to medium. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 05/14/1986, 09/02/1986 Verification Date -- 09/02/1986 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for 1,2,3-Trichloropropane conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2,3-Trichloropropane CASRN -- 96-18-4 NORC: Not available at this time. ============================================================================ UDCA: 199311 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2,3-Trichloropropane CASRN -- 96-18-4 NOCA: Not available at this time. ============================================================================ UDSO: 199008 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2,3-Trichloropropane CASRN -- 96-18-4 Last Revised -- 08/01/1990 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1983. 120-Day gavage study in mice and rats with 1,2,3-trichloropropane. Unpublished report prepared by Hazleton Laboratories. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2,3-Trichloropropane CASRN -- 96-18-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. Principal study corrected 03/01/1988 I.A.5. Confidence levels revised 06/01/1990 IV.F.1. EPA contact changed 06/01/1990 VI. Bibliography on-line 08/01/1990 I.A. Text edited 08/01/1990 III.A. Health Advisory on-line 08/01/1990 VI.D. Health Advisory references added 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 07/01/1992 II. Carcinogen assessment summary now under review 03/01/1993 II. Work group review date added 11/01/1993 II. Work group review date added 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 389 of 1119 in IRIS (through 2003/06) AN: 205 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0205-tr.pdf UD: 199903 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Acetonitrile- (ACN) SY: 75-05-8; ACETONITRIL-; ACETONITRILE-; CYANOMETHANE-; CYANURE-DE-METHYL-; ETHANENITRILE-; ETHYL-NITRILE-; METHANECARBONITRILE-; METHANE,-CYANO-; METHYL-CYANIDE-; NA-1648-; NCI-C60822-; RCRA-WASTE-NUMBER-U003-; UN-1648-; USAF-EK-488- RN: 75-05-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199903 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Acetonitrile (ACN) CASRN -- 75-05-8 Last Revised -- 03/03/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: An oral RfD for acetonitrile is not available at this time. There are no oral studies involving ACN that have looked at all relevant endpoints. The oral RfD and supporting information previously on IRIS have been withdrawn. The oral RfD, derived via a route-to-route extrapolation, had been based on the judgment that the decreased red blood cells and hepatic lesions (i.e., vacuolization) observed in the unpublished Hazleton Laboratories (1983; referred to in previous IRIS summary as NTP, 1983) 90-day inhalation study were adverse. The decreases in red blood cells are not considered adverse in the present U.S. EPA assessment. Although blood chemistry was not evaluated in mice in the current NTP studies (1996), which represents a shortcoming in the protocol, the Hazleton investigators had described these effects as being of "low magnitude and questionable biological significance." The vacuolization noted by these investigators was described as "slightly more pronounced ... as compared to the control mice." Similar findings were noted in the NTP (1996) study. The vacuolization is not judged adverse. Route-to-route extrapolation for forestomach lesions observed in the 1996 mouse study was not considered appropriate because of the uncertain contribution of either inhalation or oral exposure to this endpoint. Similarly, route-to-route extrapolation for other endpoints was not considered because of uncertainties in the mechanisms of action. A developmental RfD was considered, but developmental toxicity occurred at or above levels at which frank toxicity in dams was observed. SURD: ___I.A.1. ORAL RfD SUMMARY Not applicable. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Not applicable. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) Not applicable. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) Not applicable. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=23 CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Not applicable. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=26 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA. (1999) Toxicological review of acetonitrile in support of summary information on the Integrated Risk Information System (IRIS). To review this appendix, exit to the toxicological review, Appendix A, External Peer Review - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=33. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1999). Agency Consensus Date -- 1/26/1999 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Acetonitrile conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 199903 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Acetonitrile (ACN) CASRN -- 75-05-8 Last Revised -- 03/03/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC ------------------------------------------------------ --------------- Mortality NOAEL: 336 mg/m3 (200 ppm) 100 10 6E-2 mg/m3 Mouse subchronic/ NOAEL(ADJ): 60 mg/m3 chronic inhalation studies NOAEL(HEC): 60 mg/m3 NTP, 1996 FEL: 672 mg/m3 (400 ppm) FEL(ADJ): 120 mg/m3 FEL(HEC): 120 mg/m3 Note: FEL = frank effect level; ADJ = duration-adjusted concentration; HEC = human equivalent concentration ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- MW = 41.05. Assuming 25 C and 760 mmHg, NOAEL (mg/m3) = 200 ppm x 41.05/24.45 = 336 mg/m3. NOAEL(ADJ) = NOAEL (mg/m3) x 6 hours/24 hours x 5/7 days = 60 mg/m3. The NOAEL(HEC) was calculated for a category 2 gas and extrarespiratory (systemic) effects assuming periodicity was attained. ACN is considered to be a category 2 gas because it has high water solubility, is metabolized to reactive cyanide in the liver but may be detoxified rapidly to thiocyanate, and does not react directly with respiratory tract tissues. The RGDR1 for a category 2 gas is assumed to be 1 (U.S. EPA, 1994). NOAEL(HEC) = NOAEL(ADJ) x 1 = 60 mg/m3. Therefore, the NOAEL(ADJ) of 60 mg/m3 will be considered equivalent to the HEC at this time. 1RGDRER equation (Equation 4-48, p. 4-59 of U.S. EPA, 1994) is currently undergoing EPA reevaluation, so no conversion will be made using the RGDRER equation until the analysis has been completed. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) National Toxicology Program (NTP). (1996) Toxicology and carcinogenesis studies of acetonitrile (CAS No. 75-05-8) in F344/N rats and B6C3F1 mice (inhalation studies). NTP TR 447. In a 13-week study, B6C3F1 mice (10/sex/group) inhaled ACN at concentrations of 0,0 100, 200, 400, 800, or 1,600 ppm (0, 168, 336, 672, 1,343, or 2,686 mg/m3, respectively [author's conversion]), 6 hours/day, 5 days/week (duration adjusted to 0, 30, 60, 120, 240, and 480 mg/m3). Clinical observation and body weights were recorded weekly. At necropsy, brain, heart, kidney, liver, lungs, testis, and thymus weights were measured. Hematology parameters were not measured. This represents a shortcoming of the study protocol. Complete histopathological examinations were performed on all organs in both sexes at 0, 800 ppm, and 1,600 ppm. Organs examined in lower dose groups included adrenals (200 and 400 ppm females), liver and stomach (200 and 400 ppm males and females), lung (400 ppm females), and thymus (400 ppm females). Mortality was observed at concentrations of 400 ppm and greater (0/10, 0/10, 0/10, 0/10,1/10, and 10/10 in males; 0/10, 0/10, 0/10, 1/10, 4/10, and 10/10 in females). All animals in the 1,600-ppm groups died by week 4 of the study. There were no effects reported for the lungs. Final body weight (92% of control) and body weight gain were significantly reduced at 400 ppm in males, but are not considered toxicologically significant. Males exhibited a significant concentration-related increase in absolute ( 200 ppm; p 0.05) and relative ( 100 ppm; p 0.01) liver weight. Significantly increased relative lung and kidney weights in some male groups also were observed, but changes were not concentration-related. Females had a significant increase in absolute liver weight at 800 ppm and in relative weight at 400 ppm. Histopathology revealed an increased incidence of hepatocellular vacuolation, with significance at 400 and 800 ppm (p 0.01) (0/10, N/A, 0/10, 8/10, 7/9, and 0/10 in males; 0/10, N/A, 0/10, 7/10, 6/10, 0/10 in females; livers in the 100 ppm groups were not examined microscopically). The extent of vacuolization, characterized by NTP as a "slight distension of preexisting cytoplasmic clear spaces," was greater in the 800-ppm groups compared to the vacuolization observed in the 400-ppm groups. No hepatocellular vacuolization was observed in the 1,600-ppm animals that died during the study. The absence of this change in the 1,600-ppm animals may be indicative of an increased utilization of glycogen stores by the animals that died. The authors considered the vacuolization to represent increased glycogen storage. Vacuolization is not considered adverse. Incidences of forestomach squamous epithelial hyperplasia were significantly increased in 800-ppm males and in females exposed to 200 ppm. The incidences were 0/10, 0/10, 3/10, 6/9, and 1/9 in males (100-ppm males were not examined) and 0/10, 0/10, 7/10, 8/10, 7/10, and 5/10 in females; severity was not concentration-related. Hyperkeratosis and inflammatory cell infiltrate (effects associated with hyperplasia) also occurred in the forestomach. A significant increase in focal ulcers of the forestomach also was observed in 1,600-ppm female mice. Forestomach hyperplasia is considered adverse because it was associated with infiltration of inflammatory cells and, at the highest concentration in females, focal ulcers. Grooming of contaminated fur or mucociliary clearance followed by ingestion likely played a central role in the increased incidence in hyperplasia of the forestomach. However, a role for inhalation cannot be ruled out and represents an area of uncertainty. In a study by Wolff et al. (1982), whole-body exposure versus nose-only exposure of rats to radiolabeled fine particles indicated that 60% of the pelt burden was ingested following whole-body exposure. A NOAEL of 200 ppm (NOAEL[ADJ] = 60 mg/m3) can be identified in this study, based on mortality as an endpoint. The data for increased absolute liver weight in males in the absence of other liver effects at this level are not considered adverse findings. The level of 400 ppm is considered a FEL, given the early death (week 2) of one female (considered treatment-related) followed by increased mortality at higher concentrations. B6C3F1 mice were exposed to concentrations of 0, 50, 100, or 200 ppm (0, 84, 168, or 336 mg/m3, respectively) for 111 weeks (duration-adjusted to 15, 30, or 60 mg/m3) for 6 hours/day, 5 days/week. The exposures selected were based on the results of the 13-week study. Ten male and 10 female mice also were evaluated at 15 months, at which time liver, kidney (right), and lung weights were measured. Hematological parameters were not measured; this represents a shortcoming in the study protocol. Clinical signs and body weight were assessed throughout the study. After 2 years, animals were necropsied and examined for gross and microscopic alterations. No differences in the survival of the treated animals were observed that differed with those of the control animals. Body weights were similar for all groups, and treatment-related clinical signs were not evident. In contrast to the 13-week study, there were no concentration-related effects on liver weight, suggesting that the changes observed in the 13-week study were adaptive. Forestomach squamous hyperplasia, the only nonneoplastic effect, was significantly increased in 200-ppm males (3/49, 3/50, 6/48, and 12/50) and in 100- and 200-ppm females (2/49, 7/50, 9/50, and 19/48), although the incidence at 50 ppm in females also was elevated; however, the severity of the effect was not concentration-related. At the 15-month interim sacrifice, there was a significant increase in the incidence of squamous hyperplasia in the forestomach of females administered 200 ppm ACN (incidences were 0/10, 1/10, 0/10, and 6/10). Because of the uncertainty of the role of inhalation in causing the forestomach lesions, neither a NOAEL nor a LOAEL can be identified for this endpoint. Thus, in the absence of unambiguous adverse effects of inhalation, only a NOAEL (200 ppm) can be identified in this study. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 100. A factor of 3 (10 ½) was used for interspecies extrapolation, a full factor of 10 was used to protect sensitive human subpopulations, and 3 was applied for database deficiencies (e.g., reproductive endpoints, hematology in mice). Because two factors of 3 coalesce to a 10, a total uncertainty factor of 100 results. No uncertainty factor was applied to the use of a subchronic study because there was no mortality in the longer term mouse study. Therefore, although this endpoint is of concern based on the subchronic study, increased exposure would not be expected to increase the sensitivity to this endpoint. A partial UF of 3, instead of a full factor of 10, was used for database insufficiencies in the areas of limited data on reproductive endpoints involving exposure of laboratory animals before and during mating through parturition and the absence of hematological measurements in either mouse study. A full factor of 10 was not considered necessary for the following reasons: (1) there is no evidence to suggest that ACN accumulates in the body, (2) the developmental effects observed seem to be marginal, and (3) these effects occur at concentrations that are lethal to dams. MF = 10. A modifying factor of 10 was applied because of the uncertain role that inhalation may have played in the development of the concentration-related increase in the incidence of forestomach lesions in both male and female mice. A potential role of inhalation can be envisioned. Ahmed et al. (1992) administered 14C-ACN to mice via intravenous injection. As early as 5 minutes postinjection, label was detected in nasal secretions, esophagus, and stomach contents. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) NTP (1996) also conducted 13-week and 2-year inhalation studies in 344/N rats. In the 13-week study, rats (10/sex/group) were exposed whole-body to concentrations of 0, 100, 200, 400, 800, or 1,600 ppm (0, 168, 336, 672, 1,343, or 2,686 mg/m3, respectively), 6 hours/day, 5 days/week (duration adjusted to 0, 30, 60, 120, 240, or 480 mg/m3, respectively). Complete histopathological examinations were performed on the 0-, 800- (excluding females), and 1,600-ppm rats. Bone marrow, testes, and thymus were examined in 400-ppm males only. Deaths occurred at 800 ppm (1 male) and 1,600 ppm (6 males and 3 females). There was a significant decrease in body weight gain and final body weight at 1,600 ppm (81% of control for males; 91% for females); no change occurred in the other groups. Clinical signs in the two high-concentration groups included hypoactivity and ruffled fur, with ataxia, abnormal posture, and clonic convulsions in the 1,600-ppm males that died. The other groups did not exhibit any treatment-related signs. Thymus weights were significantly lower in the 800- and 1,600-ppm animals (both sexes) compared to those of the control. Significant decreases in red blood cell count, hemoglobin concentration, and hematocrit occurred in the 800- and 1,600-ppm females and the 1,600-ppm males. The investigators reported that alterations were suggestive of anemia (characterized as nonresponsive, normocytic, and normochromic because of unaffected reticulocyte counts, mean cell volume, and mean cell hemoglobin concentration). The 1,600-ppm females also exhibited a decrease in triiodothyronine concentration, without changes in thyroxine and thyroid-stimulating hormone concentrations. Histopathologic effects were limited to animals who died at 800 and 1,600 ppm; effects included congestion, edema, and hemorrhage in alveoli observed in lungs (no incidence data were provided). Because of the one death at 800 ppm (in week 1), coupled with mortality in the mouse (see below) at a lower concentration, it is prudent to regard 800 ppm as a FEL [FEL(ADJ) = 240 mg/m3]. Because of limited histopathological examinations in the lower concentration groups, the reported results are insufficient to identify a NOAEL. In the 2-year study, F344/N rats (56/sex/group) were exposed to ACN concentrations of 0, 100, 200, or 400 ppm (0, 168, 336, or 672 mg/m3, respectively), 6 hours/day, 5 days/week, for 103 weeks (duration adjusted to 0, 30, 60, or 120 mg/m3, respectively). The exposures selected were based on the results of the 13-week study. Eight male and eight female rats also were evaluated at 15 months, with hematological parameters and liver, kidney, and lung weights measured. Hematology was not performed at study end and is considered a shortcoming of the study protocol. Clinical signs and body weight were assessed throughout the study. After 2 years, animals were necropsied and examined for gross and microscopic alterations. No significant changes in survival, body weights, or clinical appearance were observed in rats following the 103-week exposure to ACN. At the 15-month interim sacrifice, hematological alterations were observed, but were significant (p <= 0.05) only at the high concentration. Changes included decreased mean cell volume and mean cell hemoglobin (in both sexes), increased red cell count (males), and decreased hematocrit and hemoglobin (females); none of these effects was concentration-related, and the changes appear minimal. There were no adverse effects seen on histopathology of the lungs or other organs. Histopathological examination revealed no nonneoplastic lesions in any organs of exposed females. Although a statistically significant increase in the incidence of basophilic foci was observed in the 200- and 400-ppm groups (15/48, 22/47, 25/48, and 31/48) of male rats, basophilic foci generally are considered possible preneoplastic effects. Thus, a NOAEL of 400 ppm [NOAEL(ADJ) = 120 mg/m3] was identified for the rat. An unpublished 90-day inhalation study in the B6C3F1 mouse was conducted by Hazelton Laboratories for NTP (Hazelton, 1983). In this study, male and female mice (10/sex/group) were exposed by inhalation to ACN concentrations (purity > 99%) of 0, 25, 50, 100, 200, and 400 ppm (0, 42, 84, 168, 336, and 672 mg/m3, respectively) for 6.5 hours/day, 5 days/week, for a total of 65 exposures during a 92-day period. The duration-adjusted concentrations were 0, 8.1, 16.2, 32.5, 65, and 130 mg/m3, respectively. Histopathological examination at necropsy included all major tissues and organs, including thymus, testes, ovaries, and lungs from controls and the 400-ppm group mice. Three sections of the nasal turbinates were examined from all animals in all groups. Livers were examined from mice in the 100- and 200-ppm groups as well. Clinical chemistry and hematological parameters also were examined. All animals from the control and 100-, 200-, and 400-ppm groups at terminal necropsy were subjected to examination of sperm motility, count, and sperm head staining. Separate groups of females were exposed in the same study to 0, 100, 200, and 400 ppm ACN for 6.5 hours/day, 5 days/week, for a total of 10 exposures and used for immunotoxicology studies. Three mice died during the course of the study. Mortality was not considered to be exposure-related (one male in each of the exposure groups). There were no reported histopathological effects on the thymus. Thymus/body weight ratios were somewhat lower in the 200- and 400-ppm groups compared to controls, but were not significantly decreased. There were no adverse effects on sperm or in the nasal turbinates. In the group of females examined for hematologic and immunotoxic responses, all exposure groups exhibited significant decreases in hematocrit, hemoglobin, and red blood cell counts. They were described as of low magnitude and of questionable biological significance. Lymphocyte counts were decreased only in the 200- and 400-ppm groups. Immunoglobulin G (IgG) was significantly decreased in all exposure groups in a concentration-related manner. These decreases in IgG are consistent with the findings in the ImmuQuest Laboratories study (1984; see below) at these concentrations. Other tests of immune function (e.g., lymphocyte proliferation, delayed hypersensitivity, host resistance) were unaffected by exposure, thus the depressed IgG are of uncertain significance. In an unpublished subacute study (ImmuQuest Laboratories, 1984), B6C3F1 female mice were exposed to 0, 100, 200, or 400 ppm ACN, 6 hours/day, 5 days/week, for 10 days during a 14-day period. Gas chromatographic analysis indicated the test compound had a purity exceeding 99%. Chamber concentrations were monitored by infrared spectroscopy every 30 minutes during each 6-hour exposure. No treatment-related clinical signs were evident. Statistically significant decreases (p < 0.05) in red and white blood cell counts, hematocrit, and hemoglobin at the two highest concentrations were reported; however, mean values at these two concentrations seemed to be marginally lower than control. It was stated that thymic atrophy in the 200- and 400-ppm groups (incidence/severity not stated) was observed; the effect corresponded to reduction (not significant) in thymus/brain weight ratio (absolute organ weight and thymus-to-body-weight ratio were not reported). The number of mice examined histopathologically was not stated and appears to be no greater than six per exposure group, based on information presented for other endpoints. Inasmuch as histologic evidence of thymic atrophy was not observed in either the NTP (1996) subchronic/chronic study or the Hazleton (1983) subchronic study, the statement presented in the ImmuQuest Laboratories (1984) report remains uncorroborated and is not sufficient evidence for use in RfC derivation. Serum IgG levels were significantly decreased in a concentration-related manner (26%, 33%, and 48% decrease, respectively, of controls), but linear regression analysis indicated no concentration-related trends with immunoglobulin M and A. Tests of B-cell function were unchanged from controls. Subchronic studies were performed on rats, monkeys, and dogs by Pozzani et al. (1959). Carworth Farms-Wistar rats (15/sex/group) were exposed to 0, 166, 330, or 655 ppm ACN vapors (0, 279, 554, or 1,100 mg/m3, respectively), 7 hours/day, 5 days/week, for 90 days (duration adjusted to 0, 58, 115, or 229 mg/m3, respectively) (Pozzani et al., 1959). Body weight and liver and kidney weights were determined, and histopathology was performed on liver and lungs (any effects in these organs resulted in examination of brain, pancreas, spleen, trachea, and testis). Exposure to ACN did not affect body and organ weights in exposed animals. Pathological effects were limited primarily to the 655-ppm group; alveolar capillary congestion, focal edema, bronchial inflammation, desquamation, and hypersecretion of mucus occurred in lungs (10/27; p = 0.001), tubular swelling in kidneys (8/27; p = 0.05), and central cloudy swelling in liver (7/27; p = 0.04). No lesions were reported for other organs at 655 ppm. In the other groups, histiocyte clumps in alveoli or atelectasis (2/28 at 166 ppm), as well as bronchitis and pneumonia (3/26 at 330 ppm) were reported. No treatment-related tumors developed in any groups. Because the study was limited by a lack of details on protocol and quantitative results, an unambiguous NOAEL and LOAEL could not be identified. Pozzani et al. (1959) also examined effects of 350 ppm ACN (588 mg/m3) on three male rhesus monkeys and three male dogs (two Basenji-Cocker hybrids and one Basenji-Chow x Springer Spaniel hybrid), 7 hours/day, 5 days/week, for 91 days (duration adjusted to 123 mg/m3). Controls consisted of two male Basenji-Cocker hybrids; there was no control group for monkeys. In dogs and monkeys, focal emphysema and diffuse proliferation of alveolar septa were exhibited. Monkeys also showed hemosiderin accumulation in lungs and swelling of convoluted tubules in kidneys. This experiment was limited because of inadequate study protocol and results and the absence of a control group for monkeys. Nonpregnant female Sprague-Dawley rats (10/group) were exposed for 14 consecutive days to 0, 100, 400, or 1,200 ppm ACN (0, 168, 672, and 2,015 mg/m3, respectively) (Mast et al., 1994). One dam at the high concentration died; no treatment-related clinical signs or body weight changes were evident in exposed animals. Gross examination did not reveal any significant effects in the exposed dams. Dams were not examined for histopathological effects. Thus, a NOAEL cannot be determined. In the developmental toxicity portion of this study, sperm-positive female Sprague-Dawley rats (33/group) were exposed to 0, 100, 400, or 1,200 ppm (0, 168, 672, or 2,015 mg/m3, respectively) ACN, 6 hours/day, 7 days/week, during gestational days 6 to 19, and then sacrificed on gestational day 20. The 1,200-ppm dams exhibited hypoactivity (14/33) and appeared emaciated (6/33). Deaths occurred in two 1,200-ppm dams and one 400-ppm dam. There was no effect on body or organ weights. Fertility did not appear to be affected by ACN exposure. A slight increase in percentage of resorptions per litter (particularly late resorptions) was seen at the high concentration; however, the effect was not significant or concentration-related. The percent of live fetuses per litter was not affected for any group. There were no treatment-related fetal malformations. The only effect on variations was a significant increase in percent of supernumerary ribs per litter at 100 ppm, but the effect did not occur for the other groups. Because exposure to ACN may have played a role in the one death at 400 ppm, it is prudent to consider 400 ppm (672 mg/m3) as an FEL. Inasmuch as developmental effects were not observed, a NOAEL of 1,200 ppm (2,015 mg/m3) can be identified. Pregnant Sprague-Dawley rats (20 to 23/group) were exposed to 0, 1,000, 1,287, 1,592, or 1,827 ppm ACN (0, 1,679, 2,161, 2,673, or 3,068 mg/m3, respectively), 6 hours/day, on gestational days 6 to 20 (not duration-adjusted) (Saillenfait et al., 1993). Dams were sacrificed on gestational day 21. At 1,827 ppm, mortality occurred in 8/20 dams, and maternal body weight gain was significantly reduced from gestational days 6 to 21. ACN did not affect fertility (i.e., no differences in number of pregnancies). A markedly increased percentage of nonlive implants per litter (resorptions and dead fetuses) and early resorptions per litter were observed at 1,827 ppm, along with a decrease (not significant) in the mean number of live fetuses per litter. One litter was completely resorbed. No differences were observed between the other exposed groups and the controls. ACN exposure had no significant effect on the mean number of implantation sites per litter, fetal sex ratio, or fetal weights per litter. Incidences of any visceral or skeletal anomalies were not significantly different between exposed and control groups. A NOAEL of 1,592 ppm was determined for maternal and developmental toxicity. A FEL of 1,827 ppm was determined for maternal deaths. Based on increased percentage of nonlive implants per litter, a LOAEL of 1,827 ppm (3,068 mg/m3) and a NOAEL of 1,592 ppm (2,673 mg/m3) were identified for the developmental endpoint. Pregnant Syrian golden hamsters (6 to 12/group) were exposed to 0, 1,800, 3,800, 5,000, or 8,000 ppm ACN (0, 3,022, 6,380, 8,395, or 13,432 mg/m3, respectively) for 1 hour on gestational day 8 and then sacrificed on gestational day 14 (Willhite, 1983). Parameters of maternal and developmental toxicity were evaluated. There were no effects of exposure on dams or offspring at 1,800 ppm. One dam at 3,800 ppm died after exhibiting dyspnea, tremors, hypersalivation, ataxia, and hypothermia. All offspring from the other five surviving animals in this group were normal. At 5,000 ppm, all animals exhibited irritation and excessive salivation; one dam in this group died after displaying dyspnea, hypothermia, and tremors. Six abnormal fetuses exhibiting exencephaly and rib fusions were recovered from two litters of this exposure group. In the 8,000-ppm group, clinical effects included respiratory difficulty, lethargy, ataxia, hypothermia, irritation, and gasping (4/12 dams), followed by tremors, deep coma, and death (3/12 dams). Histopathological examination of the liver, kidneys, and lungs from the dams that died in all groups did not reveal any significant treatment-related effects. Fetotoxicity occurred in offspring of dams exposed to 8,000 ppm, as evidenced by decreased fetal body weight compared to controls (not concentration-related). Five of the nine surviving litters at 8,000 ppm developed severe axial skeletal dysraphic disorders; one 8,000-ppm fetus exhibited extrathoracic ectopia cordis with accompanying defects in the sternum of the heart. This study identifies a NOAEL and FEL of 1,800 ppm (3,022 mg/m3) and 3,800 ppm (6,380 mg/m3) for maternal toxicity, respectively, and a NOAEL and LOAEL of 3,800 ppm (6,380 mg/m3) and 5,000 ppm (8,395 mg/m3) for developmental effects. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=23 CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Database -- Medium RfC -- Medium The NTP (1996) studies were of medium confidence. Although the sample sizes were appropriate, histopathology was extensive, and data were reported in detail, hematology was not measured in mice and only at the 15-month interim evaluation in rats. The confidence in the database for the ACN RfC is rated as medium because of (1) the uncertain role of inhalation in the development of forestomach lesions in the mouse study; (2) the lack of evaluation of possible effects of ACN on heart rate, ventilatory parameters, and blood pressure; and (3) the absence of two-generation studies. Although acceptable developmental studies involving the F1 generation were carried out (via inhalation route) in two species (rats and hamsters) with evidence of developmental effects occurring at maternally toxic concentrations, there is a lack of information on reproductive endpoints in animals exposed prior to and during mating through parturition. A medium confidence in the RfC follows. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=26 EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA. (1999) Toxicological review of acetonitrile in support of summary information on the Integrated Risk Information System (IRIS). This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1999). To review this appendix, exit to the toxicological review, Appendix A, External Peer Review - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=33. Other EPA Documentation -- U.S. EPA, 1985 Agency Consensus Review Date -- 1/26/1999 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Acetonitrile conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (FAX), or rih.iris@epa.gov (Internet address). ============================================================================ UDCA: 199903 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Acetonitrile (ACN) CASRN -- 75-05-8 Last Revised -- 03/03/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under the current Risk Assessment Guidelines (U.S. EPA, 1987), ACN is assigned carcinogen class D, not classifiable as to human carcinogenicity. There is an absence of human evidence and the animal evidence is equivocal. Under the Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), the carcinogenic potential of ACN following inhalation, oral, or dermal exposure is best characterized as "cannot be determined because the existing evidence is composed of conflicting data (e.g., some evidence is suggestive of carcinogenic effects, but other equally pertinent evidence does not confirm any concern)." The National Toxicology Program (NTP, 1996) concluded that the evidence for carcinogenicity via inhalation of ACN in the F344/N rat was equivocal based on a positive trend of hepatocellular tumors in male rats. Although there was a statistically significant positive trend in the incidence of hepatocellular adenomas, hepatocellular carcinomas, and hepatocellular adenomas or carcinomas (combined) in male rats only, the incidences were not statistically significant by pairwise comparison or by life table analysis. In addition, the incidence of adenomas and carcinomas combined in the 400-ppm group was only slightly higher than the historical range for inhalation study controls. Male rats exhibited an increased incidence of basophilic foci in liver that was statistically significant in the 200- and 400-ppm groups. Although these foci were notatypical in appearance, as those more closely related to the carcinogenic process (Harada et al., 1989), altered hepatocellular foci are generally considered to be preneoplastic (Williams and Enzmann, 1998; Pitot, 1990). NTP (1996) concluded that "a causal relationship between ACN exposure and liver neoplasia in male rats is uncertain." There was no evidence of carcinogenicity in female rats or in either male or female B6C3F1 mice. The evidence from mutagenicity assays indicates that ACN does not cause point mutations. Acetonitrile was negative in assays with five strains of S. typhimurium in the absence of S9 as well as in the presence of rat or hamster S9 induced with Aroclor 1254. However, ACN does have potential to interfere with chromosome segregation, possibly leading to aneuploidy, as evidenced in experiments with D. melanogaster. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=26. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=23. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate; none are available. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA NTP (1996) conducted a 2-year study with F344/N rats (56/sex/group) exposed to ACN, actual concentrations of 0, 100, 200, or 400 ppm (0, 168, 336, or 672 mg/m3, respectively), 6 hours/day, 5 days/week, for 103 weeks (duration-adjusted to 30, 60, and 120 mg/m3, respectively) and with B6C3F1 mice exposed to concentrations of 0, 50, 100, or 200 ppm (0, 84, 168, or 336 mg/m3, respectively) for 111 weeks (duration-adjusted to 15, 30, and 60 mg/m3, respectively). An interim necropsy at 15 months involved 8 rats (each sex) and 10 mice (each sex). Complete histopathological examinations were conducted on all animals at this time, and hematological parameters and liver, kidney, and lung weights were measured. Clinical signs and body weight were assessed throughout the study. After 2 years, animals were necropsied and examined for gross and microscopic alterations. At the 15-month examination, there were no neoplastic lesions observed that were attributable to exposure. Histopathological exam at the 2-year necropsy revealed no neoplastic or nonneoplastic lesions in any organs of exposed females. In male rats, a statistically significant increase in the incidence of basophilic foci was observed in the 200- and 400-ppm groups (15/48, 22/47, 25/48, and 31/48), but the foci were not atypical in appearance. This suggests that the foci may not be preneoplastic. The incidences of eosinophilic and mixed cell foci were marginally elevated (but not to statistical significance) in 400-ppm males. Although there was a marginally significant positive trend in the incidence of adenoma, carcinoma, or adenoma and carcinoma (combined) in liver of male rats, no significant dose-related trend was present after incidences were adjusted for survival using the life table test. The incidences of hepatocellular adenomas and carcinomas in male rats were not significantly increased in the treated animals based on pairwise comparison with incidences in control animals. Also, the tumor incidences at 400 ppm were only slightly higher than the historical control range. Other effects observed in male rats included marginal (not concentration-related) increases in tumors in the adrenal medulla and pancreatic islets; incidences observed were within historical control range. Keratoacanthoma was observed in the skin of 400-ppm males (0/48, 1/47, 0/48, and 4/48) but was not considered treatment-related; the incidence was within the historical control range. At terminal sacrifice of the mice, the incidence of alveolar/bronchiolar adenomas was significantly increased in males following administration of the high concentration (p = 0.011) (6/50, 9/50, 8/48, and 18/50). Combined incidences of alveolar/bronchiolar adenomas or carcinomas also were significantly increased in 200-ppm males (p = 0.042) (10/50, 14/50, 14/48, and 21/50). The 100-ppm males also exhibited an increased incidence of hepatocellular carcinoma (7/50, 11/50, 13/49, and 7/50) (p = 0.038) and combined adenoma or carcinoma (19/50, 21/50, 30/49, and 15/50) (p = 0.013), with incidences greater than those observed in historical controls. However, the incidence of this lesion did not increase with increasing concentration. No increases in the incidence of lung tumors were observed in female mice. Forestomach squamous hyperplasia was significantly increased in 200-ppm males (3/49, 3/50, 6/48, and 12/50) and in 100- and 200-ppm females (2/49, 7/50, 9/50, and 19/48); however, severity of the effect was not concentration-related. The incidence at 200 ppm equaled the highest values observed in historical controls. The incidence of squamous cell papillomas in the forestomach was slightly increased after 2 years (incidences were 0/49, 0/50, 1/48, and 2/50 in males; 1/49, 0/50, 1/50, and 3/48 in females); however, these increases were not statistically significant and equaled the highest values in historical controls. It is likely that grooming of contaminated fur or mucociliary clearance resulting in oral ingestion of ACN plays a central role. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The overall data indicate that ACN is not a point mutagen (Mortelmans et al., 1986; NTP, 1996), but does interfere with chromosome segregation (Galloway et al., 1987; NTP, 1996; Schlegelmilch et al., 1988). ACN also induced aneuploidy (chromosome gain and chromosome loss) in the oocytes of D. melanogaster females exposed either as larvae or as adults (Osgood et al., 1991a,b), and in S. cerevisiae at 5% in the absence of S9 (Zimmerman et al., 1985). Zimmerman et al. (1985) suggested that the induction of aneuploidy by ACN and other aprotic polar solvents in the absence of point mutations or recombination resulted from interference with tubulin assembly and the formation of microtubules in the spindle apparatus. In this view, aneuploidy would be consistent with a nongenotoxic, nonlinear mechanism of carcinogenicity. Sehgal et al. (1990) obtained in vitro evidence that ACN inhibits microtubule assembly in taxol-purified drosophila or mouse microtubules, further indicating that ACN has potential to induce aneuploidy. Micronucleated normochromatic erythrocytes were increased in the peripheral blood of female mice, but not in males, in a micronucleus assay conducted in conjunction with a 13-week inhalation toxicity experiment (NTP, 1996). Positive micronucleus assays can indicate either clastogenic activity or interference with chromosome segregation. In light of the negative gene mutation assays and the marginal effects in chromosome aberration assays, these data indicate that ACN interferes with chromosome segregation both in vivo and in vitro. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not applicable. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not applicable. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA. (1999) Toxicological review of acetonitrile in support of summary information on the Integrated Risk Information System (IRIS). This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Acetonitrile in Support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1999). To review this appendix, exit to the toxicological review, Appendix A, External Peer Review - Summary of Comments and Disposition http://www.epa.gov/iris/toxreviews/0205-tr.pdf#page=33. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 1/26/1999 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Acetonitrile conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199903 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Acetonitrile (ACN) CASRN - 75-05-8 Last Revised - 03/03/1999 SORD: __VI.A. ORAL RfD REFERENCES Hazelton Laboratories. (1983) 90-day subchronic toxicity study of acetonitrile in B6C3F1 mice. Final Report (Revised). Prepared for the National Toxicology Program (NTP). National Toxicology Program. (1996) Toxicology and carcinogenesis studies of acetonitrile (CAS NO. 75-05-8) in F344/N rats and B6C3F1 mice (Inhalation Studies). NTP TR 447. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Ahmed, AE; Loh, JP; Ghanayem, B; et al. (1992) Studies on the mechanism of acetonitrile toxicity: I. Whole body autoradiographic distribution and macromolecular interaction of 214C-acetonitrile in mice. Pharmacol Toxicol 70:322-330. Hazelton Laboratories. (1983) 90-day subchronic toxicity study of acetonitrile in B6C3F1 mice. Final Report (Revised). Prepared for the National Toxicology Program (NTP). ImmuQuest Laboratories, Inc. (1984) Limited toxicity of inhaled acetonitrile on the immune system of mice. OTS FYI submission. Microfiche No. FYI-AX-0284-0292. Mast, TJ; Weigel, RJ; Westerberg, RB; et al. (1994) Inhalation Development toxicology studies: acetonitrile in rats. Battelle Laboratory for NIEHS, NTP. PNL-9401. National Toxicology Program. (1996) Toxicology and carcinogenesis studies of acetonitrile (CAS NO. 75-05-8) in F344/N rats and B6C3F1 mice (inhalation studies). NTP TR 447. Pozzani, UC; Carpenter, CP; Palm, PE; et al. (1959) An investigation of the mammalian toxicity of acetonitrile. J Occup Med 1:634-642. Saillenfait, AM; Bonnet, P; Guenier, JP; et al. (1993) Relative developmental toxicities of inhaled aliphatic mononitriles in rats. Fundam Appl Toxicol 20:365-75. U.S. EPA. (1985) Health and environmental effects profile for acetonitrile. Environmental Criteria and Assessment Office. ECAO-CIN-P137. U.S. EPA. (1989) Interim methods for development of inhalation reference doses. EPA/600/8-88/066F. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. U.S. EPA. (1999) Toxicological review of acetonitrile. Available online at: www.epa.gov/iris. Willhite, CC. (1983) Developmental toxicology of acetonitrile in the Syrian golden hamster. Teratology 27:313-325. Wolff, RK; Griffis, LC; Hobbs, CH; et al. (1982) Deposition and retention of 0.1 um 67Ga2O3 aggregate aerosols in rats following whole body exposures. Fundam Appl Toxicol 2:195-200. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Galloway, SM; Armstrong, MJ; Reuben, C; et al. (1987) Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ Mol Mutagen 10(Suppl):1-175. Harada, T; Maronpot, RR; Morris, RW; et al. (1989) Observations on altered hepatocellular foci in National Toxicology Program two-year carcinogenicity studies in rats. Toxicol Pathol 17:690-708. Mortelmans, K; Haworth, S; Lawlor, T; et al. (1986) Salmonella mutagenicity tests: II. Results from the testing of 270 chemicals. Environ Mutagen 8(Suppl 7):1-119. National Toxicology Program. (1996) Toxicology and Carcinogenesis studies of acetonitrile (CAS No. 75-05-8) in F344/N rats and B6C3F1 mice (inhalation studies). NTP TR 447. Osgood, C; Bloomfield, M; Zimmering, S. (1991a) Aneuploidy in Drosophila, IV. Inhalation studies on the induction of aneuploidy by nitriles. Mutat Res 259:165-76. Osgood, C;. Zimmering, S; Mason, JM. (1991b) Aneuploidy in Drosophila, II. Further validation of the FIX and ZESTE genetic test systems employing female Drosophila melanogaster. Mutat Res 259:147-63. Pitot, H. (1990) Altered hepatic foci: their role in murine hepatocarcinogenesis. Ann Rev Pharmacol Toxicol 30:465-500. Schlegelmich, R; Krug, A; Wolf, HU. (1988) Mutagenic activity of acetonitrile and fumaronitrile in three short term assays with special reference to autoinduction. J Appl Toxicol 8:201-209. Sehgal, A; Osgood, C; Zimmering, S. (1990) Aneuploidy in Drosophila. III: Aneuploidogens inhibit in vitro assembly of taxol-purified Drosophila microtubules. Environ Mol Mutagen 16:217-224. U.S. EPA. (1987) Risk assessment guidelines of 1986. Office of Research and Development. EPA/600/8-87/045. U.S. EPA. (1996) Proposed Guidelines for carcinogen risk assessment. Washington, DC, National Center for Environmental Assessment. EPA/600/P-92/003C. U.S. EPA. (1999) Toxicological Review of acetonitrile. Available online at: www.epa.gov/iris. Williams, GM; Enzmann, H. (1998) Rat liver hepatocellular-altered, focus-limited bioassay for chemicals with carcinogenic activity. In: Carcinogenicity: testing, predicting, and interpreting chemical effects. Kitchin, KT, ed. New York: Marcel Dekker, Inc. Zimmermann, FK; Mayer, VW; Scheel, I; et al. (1985) Acetone, methyl ethyl ketone, ethyl acetate, acetonitrile and other polar aprotic solvents are strong inducers of aneuploidy in Saccharomyces cerevisiae. Mutat Res 149:339-351. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Acetonitrile (ACN) CASRN -- 75-05-8 Date Section Description ---------------------------------------------------------------------------- 06/30/1988 I.A.2. Principal study clarified 07/01/1989 I.B. Inhalation RfD now under review 08/01/1989 I.A. Oral RfD summary noted as pending change 02/01/1990 I.A. Hazelton Labs, 1983 corrected to NTP, 1983 02/01/1990 I.A.2. Text clarified (paragraph 4) 02/01/1990 VI. Bibliography on-line 03/01/1990 VI.A. NTP, 1983 - strain of rats and mice clarified 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 02/01/1996 I.A.7. Secondary contact deleted 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 03/03/1999 I., II., VI. RfD withdrawn, discussion added; new RfC and cancer assessment 12/03/2002 I.A.6.,I.B.6.,II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 390 of 1119 in IRIS (through 2003/06) AN: 213 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199303 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Bromodichloromethane- SY: 75-27-4; DICHLOROBROMOMETHANE-; DICHLOROMONOBROMOMETHANE-; METHANE,-BROMODICHLORO-; MONOBROMODICHLOROMETHANE- RN: 75-27-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199103 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Bromodichloromethane CASRN -- 75-27-4 Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Renal cytomegaly NOAEL: None 1000 1 2E-2 mg/kg/day Chronic Mouse Gavage LOAEL: 17.9 mg/kg/day Bioassay NTP, 1986 ---------------------------------------------------------------------------- *Conversion Factors: Dose adjusted for treatment schedule (5\days/week). PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies of Bromodichloromethane in F344/N Rats and B6C3F1 Mice (gavage studies). NTP Technical Report, Ser. No. 321, NIH Publ. No. 87-2537. Bromodichloromethane (BDCM) was administered in corn oil by gavage, 5 days/week for 102 weeks, to groups of 50 male and 50 female F344/N rats at doses of 0, 50, or 100 mg/kg/day; to groups of 50 male B6C3F1 mice at doses of 0, 25, or 50 mg/kg/day; and to groups of 50 B6C3F1 female mice at doses of 0, 75, or 150 mg/kg/day. Final survival of dosed female mice was reduced compared with controls. Final mean body weights of dosed female mice and high-dose male and female rats were 75 to 91% that of vehicle controls. Compound-related nonneoplastic lesions included cytomegaly and tubular cell hyperplasia of the kidney and fatty metamorphosis of the liver in male rats; eosinophilic cytoplasmic change, clear cell change, focal cellular change, and fatty metamorphosis of the liver and tubular cell hyperplasia of the kidney in female rats; fatty metamorphosis of the liver, renal cytomegaly, and follicular cell hyperplasia of the thyroid gland in male mice; and follicular cell hyperplasia of the thyroid gland in female mice. A LOAEL of 17.9 mg/kg/day (25 mg/kg/day x 5 days/7 days) based on renal cytomegaly in male mice, an effect considered minimal in the absence of data demonstrating renal functional impairment, is indicated by these results. In a subchronic bioassay conducted by NTP (1986), male and female rats received doses of 19 to 300 mg/kg/day, male mice received doses of 6.25 to 100 mg/kg/day, and female mice received doses of 25 to 400 mg/kg/day for 5 days/week. Five of 10 male rats and 2/10 female rats at 300 mg/kg/day died. Final body weights of male and female rats in the 150 or 300 mg/kg/day treatment groups, male mice receiving 100 mg/kg/day and female mice receiving 200 or 400 mg/kg/day, were lower than those of controls. Centrilobular degeneration of the liver and degeneration and necrosis of the kidney were seen in high-dose male rats; liver lesions were observed in high-dose female rats and in female mice at 200 or 400 mg/kg/day, and kidney lesions were seen in male mice at 100 mg/kg/day. These data define a NOAEL of 35.7 mg/kg/day (50 mg/kg/day x 5 days/7 days), a dose above which produced kidney lesions and depressed body weight in male mice. Because the chronic study used more animals/dose, was of longer duration, and presented more complete data, more confidence is placed in the chronic LOAEL than in the subchronic NOAEL. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- A factor of 100 was employed for extrapolation from animal data and for protection of sensitive human subpopulations. An additional factor of 10 was used because the RfD was based on a LOAEL (although minimally adverse), and to account for data base deficiencies (no reproductive studies). MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) A study by Chu et al. (1982) who administered bromodichloromethane in the drinking water to rats for 90 days reported a no-effect level of 0.45 mg/kg/day. This study, however, is not considered suitable for derivation of the RfD because of difficulties in interpretation of study design and statistical methodology. There are no published data on teratogenicity or reproductive effects of trihalomethanes. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium Confidence in the study is rated medium because although NTP (1986) incorporated both chronic and subchronic exposures in two species using sufficient numbers of animals and measured multiple endpoints, including histopathology of most organ systems, a NOEL was not determined. Although there are some discrepancies in the dose levels producing adverse effects, there are several published subchronic studies of bromodichloromethane permitting confidence in the data base to be rated medium to low. Thus, overall confidence in the RfD is rated medium to low. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 12/02/1985, 02/05/1986, 05/14/1986, 07/16/1987 Verification Date -- 07/16/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Bromodichloromethane conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Bromodichloromethane CASRN -- 75-27-4 NORC: Not available at this time. ============================================================================ UDCA: 199303 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Bromodichloromethane CASRN -- 75-27-4 Last Revised -- 03/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Based on inadequate human data and sufficient evidence of carcinogenicity in two animal species (mice and rats) as shown by increased incidence of kidney tumors and tumors of the large intestine in male and female rats, kidney tumors in male mice, and liver tumors in female mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. There are no epidemiologic studies of bromodichloromethane alone. Bromodichloromethane is one of several trihalomethanes (including chloroform, bromoform and dibromochloromethane) that are formed from the interaction of chlorine with organic materials found in water. A large number of other byproducts are present in chlorinated water as well. Several ecologic studies (Cantor et al., 1978; Aldrich and Peoples, 1982; Isacson et al., 1983) and case-control studies (Young and Kanarek, 1983; Cantor et al., 1987) suggest a positive correlation between drinking chlorinated water and the incidence of several human cancers, particularly bladder, rectal and colon cancer. These studies have design limitations such as lack of individual exposure information, misclassification of exposure, and lack of data to control for diet, smoking or alcohol consumption. The agreement of findings in several independent studies strengthens the association between drinking chlorinated water and cancer (Cantor, 1983; Crump, 1983). However, in all studies exposure to chlorinated water resulted in intake of a mixture of compounds, including chloroform, which is considered to be a probable human carcinogen. Thus, these data are inadequate for assessing the carcinogenic potential of bromodichloromethane in humans. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. In a 2-year carcinogenicity study (NTP, 1987), bromodichloromethane was administered in corn oil by gavage, 5 days/week for 102 weeks, to F344/N rats (50/sex/dose) at 0, 50 or 100 mg/kg/day. Similarly, groups of 50 male B6C3F1 mice were given oral doses of 0, 25 or 50 mg/kg/day and groups of 50 female B6C3F1 mice were administered doses of 0, 75 or 150 mg/kg/day. The study using the male rats was restarted 10.5 months into the original study because a temperature elevation killed 45/50 of the vehicle control male rats. Survival was reduced 52%, 26% and 30% in the control, low-dose and high-dose females, respectively, after week 84; the mortality was associated with ovarian abscesses. Bromodichloromethane caused compound-related statistically significant increases in tumors of the kidney in male mice, the liver in female mice, and the kidney and large intestine in male and female rats. In male mice, the incidence of tubular cell adenomas (vehicle control, 1/46; low dose, 2/49; high dose, 6/50) and the combined incidence of tubular cell adenomas and adenocarcinomas of the kidneys were significantly increased in the high-dose (50 mg/kg/day) group (1/46, 2/49 and 9/50 in the control, low-dose and high-dose groups, respectively). In female mice, significant increases of hepatocellular adenomas occurred at 75 mg/kg/day and 150 mg/kg/day while hepatocellular carcinomas were significantly increased at 150 mg/kg/day. The combined incidence of hepatocellular adenomas or carcinomas in vehicle control, low-dose and high-dose groups were 3/50, 18/48 and 29/50, respectively. In male and female rats, the incidences of tubular cellular adenomas, adenocarcinomas, and the combined incidence of adenomas and adenocarcinomas of the kidneys were statistically significantly increased only in the high-dose (100 mg/kg/day) groups. The combined incidence of tubular cell adenomas or adenocarcinomas in vehicle control, low-dose and high-dose groups were 0/50, 1/49 and 13/50 for males, and 0/50, 1/50 and 15/50 for females, respectively. Tumors of large intestines, namely adenocarcinomas (vehicle control, 0/50; low dose, 11/49; high dose, 38/50) and adenomatous polyps (0/50, 3/49 and 33/50 in the vechicle control, low-dose and high-dose groups, respectively) were significantly increased in male rats in a dose-dependent manner. These large intestinal tumors, however, were only observed in high-dose (100 mg/kg/day) female rats (adenocarcinomas 0/46, 0/50, 6/47; adenomatous polyps 0/46, 0/50, 7/47 in the vehicle control, low-dose and high-dose groups, respectively). The combined incidence of large intestine adenocarcinomas and/or adenomatous polyps in vehicle control, low-dose and high-dose groups were 0/50, 13/49 and 45/50 for males and 0/46, 0/50 and 12/47 for females. The combined tumor incidence of large intestine and kidney in male and female rats at control, low dose and high dose were 0/50, 13/49, 46/50 and 0/46, 1/50, 24/48, respectively. Under the conditions of this bioassay, NTP concluded there was clear evidence of carcinogenicity of bromodichloromethane in male and female F344/N rats and B6C3F1 mice. Hepatic tumor data reported in female mice should be interpreted with caution, however, because of the possible role of the corn oil vehicle in induction of these tumors. Chloroform, a closely related structural analogue, induced hepatocellular carcinoma in mice (NCI, 1979) when administered in corn oil (NCI, 1976; Roe et al., 1976), but not in drinking water (Jorgenson et al., 1985). Based primarily on the fact that the drinking water study did not replicate hepatic tumors in female mice and on the potential role of corn oil in enhancing toxicity, the NAS Subcommittee on the Health Effects of Disinfectants and Disinfection By-Products recommended that kidney tumor data obtained from Jorgenson's study be used for estimating carcinogenic risk of chloroform (NAS, 1987; U.S. EPA, 1992a,b,c, 1993). On October 25-26, 1990, the Science Advisory Board's Drinking Water Committee held a meeting in Washington, DC to review the Office of Water's draft Drinking Water Criteria Document for Trihalomethanes (including bromodichloromethane) (1990 version). Based on the concern of the corn oil vehicle effect cited for chloroform, the Committee concluded that hepatic tumor induction by a trihalomethane administered in an oil vehicle should be utilized only in making the weight-of-evidence judgement for carcinogenicity, and these hepatic tumor data should be disregarded in making a quantitative estimation of the carcinogenic risk of a trihalomethane. Commenting on bromodichloromethane specifically, the Committee considered the use of renal or intestinal tumor incidence for carcinogenic risk calculation to be appropriate. The Committee regarded the resulting kidney tumors to be independent from the vehicle effects (U.S. EPA, 1992d). The Committee also commented that large intestinal tumors are not commonly seen in the rat, the tumor incidence was high in males, and was observed in both sexes (U.S. EPA, 1992d). Theiss et al. (1977) tested bromodichloromethane in a short-term lung adenoma test in strain A/St male mice. Twenty mice/group were injected intraperitoneally with 0, 20, 40 or 100 mg/kg of bromodichloromethane in tricaprylin, 3 times/week for a total of 18-24 injections (total doses were 0, 360, 960 or 2400 mg/kg, respectively). There was no effect of treatment on survival. Twenty-four weeks after the first injection, the mice were sacrificed and the lungs examined for surface adenomas. The number of pulmonary tumors per mouse appeared elevated in the high-dose animals, although the increase was not statistically significant (p=0.062). In a unpublished but documented 2-year study, SPF Wistar rats (40/sex/group) were fed a diet supplemented with 0.014, 0.055 or 0.22% microencapsulated bromodichloromethane (Tobe et al., 1982). Based on reported body weights (150-475 g) and food consumption (15-20 g/day), these levels correspond to doses of about 6, 24 or 130 mg/kg/day for males and 11, 41 or 220 mg/kg/day for females. Controls (70/sex) received empty microcapsules. At 6, 12 and 18 months, 9-12/sex of the controls and 5-7/sex/group of the treated rats were sacrificed. The remainder of the animals were sacrificed at 24 months. Body weight was decreased in the high-dose animals by 25% relative to controls. Mortality was not correlated with dose in either males or females. Survival at 24 months was 77, 81, 75 and 77% in females and 58, 60, 62 and 79% in males for the control, low-, mid- and high-dose groups, respectively. No gross tumors were observed at 18 or 24 months; histopathology was not reported. Tumasonis et al. (1985) administered 1.2 mL bromodichloromethane per liter of drinking (tap) water to male and female Wistar rats for 72 weeks, after which concentrations were halved for the remainder of the lifetime of the animals (140-180 weeks). Controls were untreated. Body weight decreased in treated animals relative to controls by approximately 35-40%. The authors estimated the treated animals consumed 150 mg/kg/day (females) or 200 mg/kg/day (males). Hepatic neoplastic nodules were significantly elevated in female rats (17/53) when compared with controls (0/18). Neoplastic nodules in males and lymphosarcomas and pituitary tumors in both sexes were reported, but did not have an significantly increased incidence relative to the controls. Of the treated animals, two males and one female were noted to have renal adenoma or adenocarcinoma, while none were reported in the control group. Voronin et al. (1987) examined the carcinogenicity of bromodichloromethane in CBA x C57Bl/6 mice. Groups of 50-55 mice/sex were treated with bromodichloromethane in drinking water at concentrations of 0.04, 4.0 or 400 mg/L (0.0076, 0.76 or 76 mg/kg/day) for 104 weeks. An untreated control group with 75 male and 50 female mice was also maintained. Total tumor incidences, based on the number of mice surviving until detection of the first tumor, were 4/63 (6%), 3/35 (8%), 1/16 (6%) and 1/18 (9%) for males, and 3/34 (9%), 1/45 (2%), 1/18 (6%) and 1/13 (8%) for females in the control, low-, mid- and high-dose groups, respectively. The authors concluded that the results were not statistically significant by chi square analysis, and that under the conditions of this bioassay, bromodichloromethane was not carcinogenic. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Bromodichloromethane was mutagenic in Salmonella typhimurium strain TA100 in the absence of liver homogenate in a vapor phase test performed in a desiccator. When tested in a standard Salmonella/microsomal assay, however, the compound was not mutagenic (Simmon et al., 1977). Varma et al. (1988) reported that bromodichloromethane was mutagenic in Salmonella typhimurium strain TA1537 without rat liver homogenate activation. Similar results were also reported by Ishidate et al. (1982) using Salmonella typhimurium strain TA100. Mortelmans et al. (1986) reported bromodichloromethane was not mutagenic in S. typhimurium strains TA98, TA100, TA1535 or TA1538 both with and without rat or hamster liver homogenate. Bromodichloromethane did not induce mitotic recombination in the presence or absence of liver homogenate in studies with Saccharomyces cerevisiae strain D3 (Simmon and Kauhanen, 1978). However, Nestmann and Lee (1985) observed weak mutagenic effects in S. cerevisiae strains D7 and XV185-14C following exposure to bromodichloromethane in the absence of liver homogenate. Bromodichloromethane was not mutagenic in the mouse lymphoma L5178/TK+/assay in the absence of rat liver homogenate, but did induce forward mutations in this system in the presence of rat liver homogenate (NTP, 1987). Morimoto and Koizumi (1983) reported that bromodichloromethane produced a significant increase in the frequency of SCEs in both cultured human peripheral blood lymphocytes treated in vitro and mouse bone marrow cells treated in vivo. Similarly, Sobti (1984) reported statistically significant increases in the frequency of SCEs in human lymphocytes and rat liver cells exposed in vitro. A statistically significant increase in the frequency of chromosomal aberrations in Chinese hamster fibroblast was observed by Ishidate et al. (1982), but only in the presence of rat liver homogenate. NTP (1987) reported no induction of chromosomal aberrations or SCEs in CHO cells following treatment with bromodichloromethane in either the presence or absence of liver homogenate. Bromodichloromethane is structurally similar to other known animal carcinogens such as dibromochloromethane and chloroform. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 6.2E-2 per (mg/kg)/day Drinking Water Unit Risk -- 1.8E-6 (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 6E+1 ug/L E-5 (1 in 100,000) 6E+0 ug/L E-6 (1 in 1,000,000) 6E-1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- Kidney (tubular cell adenoma and tubular cell adenocarcinoma) Test Animals -- B6C3F1 mice, male Route -- gavage, corn oil Reference -- NTP, 1987 ----- Dose ----- Combined Admin- Human Tumor istered Equivalent Incidence (mg/kg/day) (mg/kg/day) ----------- ----------- --------- 0 0 1/46 25 1.5 2/49 50 3.0 9/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Using the linearized multistage procedure, a range of oral slope factors were calculated for bromodichloromethane, based on the observed incidence of various types of tumors (large intestine, kidney, or combined) in mice or rats reported in the NTP bioassay. The resulting cancer slope factors fall between 4.9E-3 and 6.2E-2 per (mg/kg)/day (U.S. EPA, 1992a,b,c). An oral slope factor of 1.3E-1 per (mg/kg)/day was derived from the incidence of hepatic tumors in female mice (U.S. EPA, 1993). However, because of the possible role of corn oil used as gavage vehicle (in the NTP study) in induction of hepatic tumors, carcinogenic risk estimates based on the tumor incidence in the liver is considered inappropriate. In accordance with EPA's 1986 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986), the slope factor of the greatest sensitivity (6.2E-2 per (mg/kg)/day) is selected as the oral quantitative cancer risk estimate for bromodichloromethane (U.S. EPA, 1992b). Survival adjustments were made for the animal counts in the control and low-dose groups by subtracting 3 and 1 early death, respectively. Additional animal count adjustment was also made in the control group due to the escape of one mouse. The unit risk should not be used if the water concentration exceeds 6E+3 ug/L, since above this concentration the slope factor may differ from that stated. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of animals were used for a lifetime bioassay with two animal species. Bromodichloromethane was administered at two dose levels. Tumors of multiple tissue types were observed in a dose-related manner. Slope factors derived from tumor incidences of kidney and large intestine are similar and within one order of magnitude in differences. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1992c The Drinking Water Criteria Document for Trihalomethanes received Science Advisory Board (SAB) review in 1992. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/07/1989, 01/11/1990, 04/01/1992, 04/02/1992 Verification Date -- 04/02/1992 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Bromodichloromethane conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199303 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Bromodichloromethane CASRN -- 75-27-4 Last Revised -- 03/01/1993 SORD: __VI.A. ORAL RfD REFERENCES Chu, I., D.C. Villeneuve, V.E. Secours and G.C. Becking. 1982. Toxicity of trihalomethanes: I. The acute and subacute toxicity of chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health. B17: 205-224. NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of bromodichloromethane in F344/N rats and B6C3F mice (gavage studies). NTP Technical Report, Ser. No. 321, NIH Publ. No. 87-2537. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Aldrich, T.E. and A.J. Peoples. 1982. Malignant melanoma and drinking water contamination. Bull. Environ. Contam. Toxicol. 28: 519-523. Cantor, K.P. 1983. Epidemiologic studies of chlorination by-products in drinking water: An overview. In: Water Chlorination. Environmental Impact and Health Effects, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed., Vol. 4, Part 2. Environment, Health, and Risk; Proc. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. ISBN 0-250-40581-4. p. 1381-1398. Cantor, K.P., R. Hoover, T.J. Mason and L.J. McCabe. 1978. Associations of cancer mortality with halomethanes in drinking water. J. Natl. Cancer Inst. 61(4): 979-985. Cantor, K.P., R. Hoover, P. Hartge et al. 1987. Bladder cancer, drinking water source, and tap water consumption: A case-control study. J. Natl. Cancer Inst. 79(6): 1269-1279. Crump, K.S. 1983. Chlorinated drinking water and cancer: The strength of the epidemiologic evidence. In: Water Chlorination. Environmental Impact and Health Effects, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed., Vol. 4, Part 2. Environment, Health, and Risk; Proc. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. ISBN 0-250-40581-4. p. 1481-1491. Isacson, P., J.A. Bean and C. Lynch. 1983. Relationship of cancer incidence rates in Iowa municipalities to chlorination status of drinking water. In: Water Chlorination. Environmental Impact and Health Effects, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed., Vol. 4, Part 2. Environment, Health, and Risk; Proc. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. ISBN 0-250-40581-4. p. 1353-1364. Jorgenson, T.A., E.F. Meierhenry, C.J. Rushbrook et al. 1985. Carcinogenicity of chloroform in drinking water to male Osborne-Mendel rats and female B6C3F1 mice. Fund. Appl. Toxicol. 5: 760-769. Ishidate M., T. Sofuni, K. Yoshikawa and M. Hayashi. 1982. Studies on the mutagenicity of low boiling organohalogen compounds. Unpublished interagency report to the National Institute of Hygienic Sciences. Tokyo Medical and Dental University, Tokyo, Japan. Morimoto, K. and A. Koizumi. 1983. Trihalomethanes induce sister chromatid exchanges in human lymphocytes in vitro and mouse bone marrow cells in vivo. Environ. Res. 32: 72-79. Mortelmans, K., S. Haworth, T. Lawlor, W. Speck, B. Tainer and E. Zeiger. 1986. Salmonella mutagenicity tests. II. Results from the testing of 270 chemicals. Environ. Mutagen. 8(Suppl.7): 1-119. NAS (National Academy of Sciences). 1987. Drinking Water and Health, Vol. 7. National Academy Press, Washington, DC. p. 111-133. NCI (National Cancer Institute). 1976. Report on carcinogenesis bioassay of chloroform. Available from NTIS, Springfield, VA. NTIS PB-264018. Nestmann, E.R. and E.G-H. Lee. 1985. Genetic activity in Saccharomyces-cerevisiae of compounds found in effluents of pulp and paper mills. Mutat. Res. 155(1-2): 53-60. NTP (National Toxicology Program). 1987. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Bromodichloromethane (CAS No. 75-27-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies). NTP Tech. Report Series No. 321. U.S. Dept. Health and Human Services, Public Health Service, National Institute of Health. Roe, F.J.C., A.K. Palmer, A.N. Worden and N.J. Van Abbe. 1979. Safety evaluation of toothpaste containing chloroform. I. Long-term studies in mice. J. Environ. Pathol. Toxicol. 2: 799-819. Simmon, V.F. and K. Kauhanen. 1978. In vitro microbiological mutagenicity assays of bromodichloromethane. EPA Contract No. 68-03-11-74. SRI International, Menlo Park, CA. Final Report. Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. Dev. Toxicol. Environ. Sci. 2 (Prog. Genet. Toxicol.): 249-258. Sobti, R.C. 1984. Sister chromatid exchange induction potential of the halogenated hydrocarbons produced during water chlorination. Chromosome Information Service No. 37. p. 17-19. Theiss, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice. Cancer Res. 37: 2717-2720. Tobe, M., Y. Suzuki, K. Aida et al. 1982. Studies on the chronic oral toxicity of tribromomethane, dibromochloromethane and bromodichloromethane. Unpublished Intraagency report to the National Institute of Hygienic Sciences. Tokyo Medical and Dental Univ., Tokyo, Japan. p. 8-43. Tumasonis, C.F., D.N. McMartin and B. Bush. 1985. Lifetime toxicity of chloroform and bromodichloromethane when administered over a lifetime in rats. Ecotoxicol. Environ. Safety. 9: 233-240. U.S. EPA. 1986. Risk Assessment Guidelines of 1986. Prepared by the Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-87/045. U.S. EPA. 1987. Health Effects Assessment for Trihalogenated Methanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1992a. Revisit of Quantitative Estimate of Carcinogenic Risk for Bromodichloromethane from Oral Exposure. Office of Science and Technology, Washington, DC. U.S. EPA. 1992b. Memo from D. Lai, U.S. EPA to N. Chiu, U.S. EPA, "Comments on Revision of Quantitative Estimate of Carcinogenic Risk for Bromodichloromethane from Oral Exposure." Office of Toxic Substances, Washington, DC. U.S. EPA. 1992c. Drinking Water Criteria Document for Trihalomethanes. Office of Science and Technology, Washington, DC. (Revised External Review Draft) U.S. EPA. 1992. An SAB Report: Review of Drinking Water Health Criteria Document. Review of the Office of Water's Health Criteria Document on Trihalomethanes by the Drinking Water Committee. Science Advisory Board, Washington, DC. U.S. EPA. 1993. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. Varma, M.M., F.R. Ampy and K. Verma et al. 1988. In vitro mutagenicity of water contaminants in complex mixtures. J. Appl. Toxicol. 8(4): 243-248. Voronin, V.M., A.I. Donchenko and A.A. Korolev. 1987. Experimental study of the carcinogenicity of dichlorobromomethane and dibromochloromethane which are formed during the chlorination of water. Gig. Sanit. p. 19-21. (Eng. trans.) Young, T.B. and M.S. Kanarek. 1983. Matched pair case control study of drinking water chlorination and cancer mortality. In: Water Chlorination: Environmental Impact and Health Effects, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed. Vol. 4, Part 2. Environment, Health and Risk; Proc. 4th Conference, Pacific Grove, CA, October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. Illus. ISBN 0-250-40581-4. p. 1365-1380. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Bromodichloromethane CASRN -- 75-27-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. RfD exponent corrected 03/01/1988 I.A.1. RfD exponent corrected 03/01/1988 I.A.2. Text clarified 03/01/1988 I.A.6. Dates corrected 06/30/1988 I.A.7. Primary contact changed 12/01/1988 I.A. NTP citation corrected 01/01/1989 IV.C.1. Units corrected 08/01/1989 VI. Bibliography on-line 10/01/1989 II. Carcinogen assessment now under review 10/01/1990 II. Carcinogen assessment on-line 10/01/1990 IV.F.1. EPA contact changed 10/01/1990 VI.C. Carcinogen references added 03/01/1991 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 07/01/1992 II. Carcinogenicity assessment noted as pending change 02/01/1993 II. Carcinogen assess. replaced; oral slope factor changed 02/01/1993 VI.C. Carcinogenicity assessment references replaced 03/01/1993 II.A.3. Text corrected 03/01/1993 II.D.1. Other EPA Documentation corrected 03/01/1993 VI.C. References corrected 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 391 of 1119 in IRIS (through 2003/06) AN: 214 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199312 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Bromoform- SY: *TRIBROMOMETHANE-; 75-25-2; METHANE,-TRIBROMO-; METHENYL-TRIBROMIDE- RN: 75-25-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199103 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Bromoform CASRN -- 75-25-2 Primary Synonym -- Tribromomethane Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Hepatic lesions NOEL: 25 mg/kg/day 1000 1 2E-2 (converted to mg/kg/day Rat, Subchronic Oral 17.9 mg/kg/day) Gavage Bioassay LOAEL: 50 mg/kg/day NTP, 1989 (converted to 35.7 mg/kg/day) ---------------------------------------------------------------------------- *Conversion Factors: Doses have been adjusted for treatment schedule (5 days/week) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1989. Toxicology and Carcinogenicity Studies of Tribromomethane and Bromoform in F344/N rats and B6C3F1 mice (gavage study). NTP-350. Research Triangle Park, NC. Ten F344/N rats/sex were gavaged with 0, 12, 25, 50, 100, or 200 mg/kg bromoform and 10 B6C3F1 mice/sex were gavaged with 0, 25, 50, 100, 200, or 400 mg/kg bromoform 5 days/week for 13 weeks. Complete histology was conducted on high-dose and vehicle control groups of both species. Liver histology was conducted on all rats and on male mice receiving doses greater than 100 mg/kg. Females of both species did not show any chemically-related effects. A decrease in body weight of both sexes of mice was reported, but was not dose-related. The male mice showed fatty metamorphosis of the liver at doses of 200 and 400 mg/kg. The only effect reported for male rats was a dose-related increase in clear cell foci of the liver. A Fisher Exact Test showed that the incidence of the clear cell foci at doses of 50 mg/kg (the LOAEL) or above was statistically elevated relative to the vehicle control (p=0.035), therefore, 25 mg/kg is the NOEL for F344/N rats (NTP, 1989). Subchronic rat studies by Chu et al. (1982a,b) are not considered suitable for derivation of the RfD because of difficulties in interpretation of study design and statistical methodology. Tobe et al. (1982) described changes in histology in rats that were not supported by changes in function. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- Factors of 10 each were employed for use of a subchronic assay, for extrapolation from animal data, and for protection of sensitive human subpopulation. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) There are no adequate published data on teratogenicity or reproductive effects of trihalomethanes. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The NTP (1989) study utilized both sexes of two species of animals. Both species showed liver lesions, but the study did not investigate clinical chemistries or perform urinalysis; thus, confidence in the study is rated medium. Several studies support the choice of hepatic lesions as the critical effect for the basis of the RfD, but the chosen study is of subchronic duration and reproductive effects have not been monitored; thus, the data base is rated medium to low. Medium to low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1985 The 1985 Drinking Water Criteria Document for Trihalomethanes is currently undergoing Agency review. Other EPA Documentation -- None Agency Work Group Review -- 12/02/1985, 02/05/1986, 05/14/1986, 08/13/1987 Verification Date -- 08/13/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Bromoform conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199312 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Bromoform CASRN -- 75-25-2 Primary Synonym -- Tribromomethane NORC: The health effects data for bromoform (tribromomethane) were reviewed by the U.S. EPA RfD/RfC Work Group and determined to be inadequate for the derivation of an inhalation RfC. The verification status for this chemical is currently NOT VERIFIABLE. For additional information on the health effects of this chemical, interested parties are referred to the U.S. EPA documentation listed below. NOT VERIFIABLE status indicates that the U.S. EPA RfD/RfC Work Group deemed the database at the time of review to be insufficient to derive an inhalation RfC according to the Interim Methods for Development of Inhalation Reference Concentrations (U.S. EPA, 1990). This status does not preclude the use of information in cited references for assessment by others. Tribromomethane is a colorless, heavy liquid with a sweetish odor. Currently, tribromomethane is generated in small amounts for use in laboratories and in electronics testing (ATSDR, 1990). The health effects of exposure to tribromomethane have been reviewed (U.S. EPA, 1991). Low-level inhalation exposure of humans to tribromomethane results in irritation, lacrimation, and reddening of the face (Sax and Lewis, 1989), suggesting the potential for portal-of-entry effects. The information available on inhalation exposure in laboratory animals comes primarily from older studies that employed high concentrations for acute durations. In these studies, the CNS, liver, and kidney appear to be the major target organs following acute inhalation exposures. Exposure to tribromomethane vapors may also cause irritation to the respiratory tract and lacrimation (von Oettingen, 1955). The only studies of subchronic-duration inhalation exposure are reported in abstracts that do not provide sufficient detail for critical evaluation. Tribromomethane had a narcotic effect on rabbits administered single inhalation exposures of 1064-1741 ppm tribromomethane (Dykan, 1964). Rats administered 240 ppm tribromomethane vapor for 10 days developed CNS effects and dystrophic and vascular alterations of the liver and kidney (Dykan, 1964). Vapor concentrations of 24 ppm for 2 months also induced hepatic disorders, characterized by decreased blood clotting and impaired glycogenesis, and altered renal filtration capacity (Dykan, 1962). A concentration of 4.8 ppm tribromomethane in rats did not elicit any adverse effects in rats after 2 months of exposure (Dykan, 1964). These reports provide no details regarding exposure generation or characterization, specific effect measures, or results and are inadequate for derivation of an RfC. Severe CNS depression was observed in dogs and guinea pigs following acute exposure to extremely high levels (concentrations not specified) (Graham, 1915). Clinical signs included deep sedation, narcosis, and sleep. The CNS depression was rapid in onset and transient, disappearing within a day following cessation of exposure. This study is of limited value because of poor descriptive details on the protocol and unquantified exposure concentrations. In the early 1900s, tribromomethane was administered as a sedative to children suffering from whooping cough, and several deaths resulted from accidental overdoses (von Oettingen, 1955). The most obvious clinical sign in these fatal cases was profound depression of the CNS that was manifested as unconsciousness, stupor, and loss of reflexes. Death was usually the result of respiratory failure (von Oettingen, 1955). These case reports are of limited value because doses were not quantified; however, the doses were likely in the range of 20-40 drops (150-300 mg/kg/day). The principal cause of death in laboratory animals following acute oral exposure to tribromomethane is CNS depression (Bowman et al., 1978). Moody and Smuckler (1986) exposed Sprague-Dawley rats (n = 3) to single gavage doses of 1000 mg/kg tribromomethane and observed significant reductions in the liver microsomal cytochrome P-450 content and aminolevulinic acid-dehydratase activity and increases in porphyrin and glutathione content. These effects suggest disturbances in hepatic heme metabolism, because porphyrins are major intermediates in heme synthesis. Chu et al. (1980) reported that female rats were more sensitive than male rats to lethal doses of tribromomethane based on LD50 values of 1388 and 1147 for males and females, respectively. Studies of 14-90 days duration in rats and mice exposed by gavage have reported liver, kidney, and thyroid effects, as well as transient lethargy at high concentrations (Chu et al., 1982; Condie et al., 1983; NTP, 1989a; Munson et al., 1982). In the NTP (1989a) study, the incidences of hepatocyte vacuolization in male rats were 3/10, 6/10, 5/10, 8/10, 8/10, and 10/10 for the control, 12-, 25-, 50-, 100-, and 200-mg/kg groups, respectively. In mice, 5/10 male mice that received 200 mg/kg and 8/10 male mice that received 400 mg/kg tribromomethane developed cytoplasmic vacuolization. This dose-related, minimal-to-moderate change involved only a few cells or was diffuse. Behavioral effects (decreased response rate in an operant-conditioning test) were also reported in mice treated by gavage with 100 or 400 mg/kg/day for 60 days (Balster and Borzelleca, 1982). A 2-year chronic gavage bioassay was conducted in F344/N rats and B6C3F1 mice (50/sex/group), in which doses of 0, 100, or 200 mg/kg (rats and female mice) or 0, 50, or 100 mg/kg (male mice) tribromomethane were administered 5 days/week for 103 weeks (NTP, 1989a). In the high-dose rats (both sexes), mean body weights were significantly (10-28%) lower than controls throughout the second year of the study. Survival of the male rats administered 200 mg/kg was significantly reduced (p < 0.001) after week 91. Dose-related lethargy was observed in male and female rats. Nonneoplastic changes, including fatty change and scattered minimal necrosis (males) and mixed cell foci (females), occurred in the liver of treated rats. The incidence of focal or diffuse fatty change in both sexes was increased (males: 23/50, 49/50, and 50/50; females: 19/50, 39/50, and 46/50). The lowest dose tested in this bioassay (100 mg/kg/day) induced effects on the liver, salivary gland, prostate gland, lungs, and forestomach, and thus is considered a LOAEL for rats. High-dose female mice developed an increased incidence of follicular cell hyperplasia of the thyroid gland (5/49, 4/49, and 19/47). Female mice in both groups exhibited increased incidences of minimal-to-mild fatty change of the liver consisting of scattered hepatocyte foci with vacuolated cytoplasm (1/49, 9/50, and 24/50). Thus, 100 mg/kg also is considered a LOAEL for liver changes in female mice. No studies were available regarding the respiratory tract absorption of tribromomethane in humans or laboratory animals. After oral administration, tribromomethane is rapidly absorbed. Gastrointestinal absorption following oral exposure has been estimated to be 60-90% complete following a single gavage dose; this percentage of the administered dose was recovered in the expired air, urine, or in the tissues (Mink et al., 1986). The metabolism of tribromomethane is similar to the metabolism of other trihalomethanes (Anders et al., 1978; Stevens and Anders, 1979, 1981). Developmental effects were monitored following gavage administration of 50, 100, or 200 mg/kg/day tribromomethane to pregnant Sprague-Dawley rats (15/group) from days 6-15 of gestation (Ruddick et al., 1983). Slight increases in several skeletal anomalies were observed in treated animals and, to a lesser extent, in controls. No other significant maternal toxicity, fetotoxicity, or teratogenicity was observed. In a reproductive study, effects of tribromomethane were assessed in Swiss CD-1 mice (n = 17-20/group) exposed by gavage to 0, 50, 100, or 200 mg/kg/day (NTP, 1989b). Postnatal survival was significantly decreased in the 200-mg/kg/day group. No other reproductive effects were seen in the F1 or F2 generations. The data base for tribromomethane is inadequate for the derivation of an RfC. No chronic or subchronic inhalation studies on tribromomethane, and no reproductive or developmental studies that employed an inhalation exposure regimen were found. The toxicokinetic data for the inhalation route are insufficient for route-to-route extrapolation from oral data, and the potential for portal-of-entry (respiratory tract) toxicity has not been adequately characterized. Anders, M.W., J.L. Stevens, R.W. Sprague, Z. Shaath, and A.E. Ahmed. 1978. Metabolism of haloforms to carbon monoxide. II. In vivo studies. Drug. Metab. Dispos. 6(5): 556-560. ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Bromoform and Chlorodibromomethane. Prepared by Life Systems for ATSDR, U.S. Public Health Service. Balster, R.L. and J.R. Borzelleca. 1982. Behavioral toxicity of trihalomethane contaminants of drinking water in mice. Environ. Health. Perspect. 46: 127-136. Bowman, F., J.F. Borzelleca, and A.E. Munson. 1978. The toxicity of some halomethanes in mice. Toxicol. Appl. Pharmacol. 44(1): 213-215. Chu, I., V. Secours, I. Marino, and D.C. Villeneuve. 1980. The acute toxicity of four trihalomethanes in male and female rats. Toxicol. Appl. Pharmacol. 52(2): 351-353. Chu, I., D.C. Villeneuve, V.E. Secours, G.C. Becking, and V.E. Valli. 1982. Trihalomethanes: II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health. B17(3): 225-240. Condie, L.W., C.L. Smallwood, and R.D. Laurie. 1983. Comparative renal and hepatoxicity of halomethanes: Bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene chloride. Drug. Chem. Toxicol. 6(6): 563-578. Dykan, V.A. 1962. Changes in liver and kidney functions due to methylene bromide and bromoform. Nauchn. Tr. Ukr. Nauchn-Issled Inst. Gigieny. Truda i Profzabolevanii. 29: 82-90. (Chem. Abstracts. 60: 8541d). Dykan, V.A. 1964. Problems on toxicology, clinical practice, and work hygiene in the production of bromine-organic compounds. Gigiena. 5b: 100-103. (Chem. Abstracts. 63: 154299). Graham, E.A. 1915. Late poisoning with chloroform and other alkyl halides in relationship to the halogen acids formed by their chemical dissociation. J. Exp. Med. 221: 48-75. Mink, F.L., T.J. Brown, and J. Rickabaugh. 1986. Absorption, distribution, and excretion of 14C-trihalomethanes in mice and rats. Bull. Environ. Contam. Toxicol. 37(5): 752-758. Moody, D.E. and E.A. Smuckler. 1986. Disturbances in hepatic heme metabolism in rats administered alkyl halides. Toxicol. Lett. 32(3): 209-214. Munson, A.E., L.E. Sain, V.M. Sanders, et al. 1982. Toxicology of organic drinking-water contaminants--trichloromethane, bromodichloromethane, dibromochloromethane, and tribromomethane. Environ. Health Perspectives. 46: 117-126. NTP (National Toxicology Program). 1989a. Toxicology and carcinogenesis studies of tribromomethane (bromoform) (CAS No. 75-25-2) in F344/N rats and B6C3F1 mice (gavage studies). Technical Report Series No. 350. U.S. DHHS, Public Health Service, National Institute of Health, Research Triangle Park, NC. NIH Pub. No. 88-2805. NTIS/PB90-110149. NTP (National Toxicology Program). 1989b. Bromoform reproduction and fertility assessment in Swiss CD-1 mice when administered by gavage. NTP-89-068. NTIS/PB89-169254. Ruddick, J.A., D.C. Villeneuve, I. Chu, and V.E. Valli. 1983. A teratological assessment of four trihalomethanes in the rat. J. Environ. Sci. Health. B18(3): 333-349. Sax, N.I. and R.J. Lewis. 1989. Dangerous Properties of Industrial Materials, Seventh Ed. Van Nostrand Reinhold, New York, NY. Stevens, J.L. and M.W. Anders. 1979. Metabolism of haloforms to carbon monoxide: 3. Studies on the mechanism of the reaction. Biochem. Pharmacol. 28(21): 3189-3194. Stevens, J.L. and M.W. Anders. 1981. Metabolism of haloforms to carbon monoxide: 4. Studies on the reaction mechanism in vivo. Chem. Biol. Interact. 37(3): 365-374. U.S. EPA. 1990. Interim Methods for Development of Inhalation Reference Concentrations (External Review Draft). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066A. U.S. EPA. 1991. Health and Environmental Effects Document for Bromoform. Prepared by the Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response. NTIS/PB91-216424. von Oettingen, W.F. 1955. The halogenated aliphatics, olefinic, cyclic aromatic, and aliphatic-aromatic hydrocarbons including the halogenated insecticides, their toxicity and potential dangers. U.S. DHEW, Public Health Service, Washington, DC. Publ. No. 414. p. 65-67. (Cited In: ATSDR, 1990). Agency Work Group Review -- 02/11/1993 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Bromoform conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. EPA Contacts: Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199101 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Bromoform CASRN -- 75-25-2 Primary Synonym -- Tribromomethane Last Revised -- 01/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Based on inadequate human data and sufficient evidence of carcinogenicity in animals, namely an increased incidence of tumors after oral administration of bromoform in rats and intraperitoneal administration in mice. Bromoform is genotoxic in several assay systems. Also, bromoform is structurally related to other trihalomethanes (e.g., chloroform, bromodichloromethane, dibromochloromethane) which have been verified as either probable or possible carcinogens. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Cantor et al. (1978) suggests a positive correlation between levels of trihalomethane in drinking water and the incidence of several human cancers. Additional geographic studies of bromoform indicate that there may be an association between the levels of trihalomethanes in drinking water and the incidence of bladder, colon, rectal, or pancreatic cancer in humans (Kraybill, 1980; Cotruvo, 1981; Carlo and Mettlin, 1980; Isacson et al., 1983; Crump, 1983). However, the information from these studies is considered incomplete and preliminary because their designs do not permit consideration of several possible variables which may be involved (e.g., personal habits, information on residential histories, and past exposures) (NTP, 1988). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Bromoform has been tested for carcinogenicity in two species, rat and mouse, by oral or intraperitoneal administration. In a gavage study (NTP, 1988), F344/N rats (50/sex/group) and B6C3F1 mice (50/sex/group) were administered bromoform in corn oil by gavage 5 days/week for 2 years at 0, 100, or 200 mg/kg (rats and female mice) or 0, 50, or 100 mg/kg (male mice). Decreased body weight and survival in rats and female mice suggest that the MTD was reached. In male rats, mean body weight was decreased in the high- and low-dose groups by 12-28% and 5-14%, respectively. Survival was significantly lower in the high-dose males after week 91. In female rats, body weight was decreased in the high-dose group by 10-25%. In male mice, body weight and survival were comparable to controls. In female mice, however, body weight was decreased in the high- and low-dose groups by 5-16% and 6-11%, respectively; survival was significantly lower in both dose groups after week 77. Neoplastic lesions (adenomatous polyps or adenocarcinomas) were observed in the large intestine (colon or rectum) of male rats (0/50, 0/50, 3/50) and female rats (0/50, 1/50, 8/50) rats. Adenocarcinomas alone were not significantly increased compared with controls. The reduced survival of male rats in the high-dose group may account for the lower incidence of lesions in this group. No treatment-related tumors were observed in mice at either dose level. Under the conditions of this study, the NTP judged there was clear evidence of carcinogenicity for female rats, some evidence of carcinogenicity for male rats, and no evidence of carcinogenicity for male and female mice. Theiss et al. (1977) administered bromoform by i.p. injection to male A/St mice (20/group). Doses of 100, 48, and 4 mg/kg were given 3 times/week for a total of 24, 23 or 18 injections, respectively. Mice in the control group received 24 i.p. injections of the vehicle, tricaprylin. Animals were sacrificed 24 weeks after the first injection and the lungs were examined for surface adenomas. Some surface nodules were examined histologically to confirm the morphological appearance of adenomas. The number of lung tumors/mouse for the control, low-, mid-, and high-dose groups were 0.27, 0.53, 1.13, and 0.67 respectively. Only the ratio of the mid-dose group was statistically significantly elevated over that of controls. In a feeding study with microencapsulated bromoform, Kurokawa (1987) observed no evidence of carcinogenicity in male or female Wistar rats exposed for 24 months at concentrations of 400, 1600, or 6500 ppm. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Pereira et al. (1982a,b) determined that bromoform did not induce GGTasepositive foci in the rat liver at 1 mM (253 mg/kg) or 0.8 mM (202 mg/kg) following a 2/3 hepatectomy and promotion with phenobarbital. However, Pereira (1983) found that bromoform is a potent inducer of ornithine decarboxylase, which is an indication of tumor promotion activity in the skin and liver. Bromoform has been shown to produce mutations in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535 with and without rat hepatic homogenates (NTP, 1988; Simmon and Tardiff, 1978; Simmon, 1977, 1981; Simmon et al., 1977; Tardiff et al., 1978). Bromoform also produces mutations at the TK locus in mouse cells (NTP, 1988); SCE induction in Chinese hamster ovary cells, human lymphocytes (in vitro) and mouse bone marrow cells (in vivo) (Galloway et al., 1985; Morimoto and Koizumi, 1983; NTP, 1988); chromosomal aberrations in Chinese hamster ovary cells (Galloway et al., 1985); cell cycle delay in human lymphocytes (Morimoto and Koizumi, 1983); and an increased incidence of micronuclei in bone marrow erythrocytes from mice given bromoform i.p. (NTP, 1988). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 7.9E-3 per (mg/kg)/day Drinking Water Unit Risk -- 2.3E-7 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 4E+2 ug/L E-5 (1 in 100,000) 4E+1 ug/L E-6 (1 in 1,000,000) 4E+0 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- Neoplastic lesions in the large intestine Test Animals -- F344/N rat, female Route -- gavage in corn oil Reference -- NTP, 1988 Administered Human Equivalent Tumor Dose (ppm) Dose (mg/kg)/day Incidence ------------ ---------------- --------- 0 0 0/50 100 10.6 1/50 200 20.5 8/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The unit risk should not be used if the water concentration exceeds 4E+4 ug/L, since above this concentration the unit risk may not be appropriate. Pharmacokinetic data indicate that gastrointestinal absorption of bromoform in rats is greater than or equal to 80%. However, in the absence of more definitive data, gastrointestinal absorption of 100% was assumed. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) An adequate number of animals was treated for an adequate duration of exposure by a relevant route at two non-zero dose levels. Comprehensive histopathological and statistical analyses were performed. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 1.1E-6 per ug/cu.m Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 9E+1 ug/cu.m E-5 (1 in 100,000) 9 ug/cu.m E-6 (1 in 1,000,000) 9E-1 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE This unit risk was calculated from the oral data presented in II.B.2. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The inhalation quantitative risk estimate is based on tumor incidence in rats treated by gavage. Several factors suggest that the tumorigenic response is a systemic rather than portal-of-entry effect. Pharmacokinetic data suggest that gastrointestinal absorption is rapid and biotransformation is an activating mechanism. A default value of 50% absorption was used because no data are available to quantify the extent of respiratory absorption. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Kinetic data for the metabolism of bromoform are insufficient to establish route-specific metabolized doses. Because these data are insufficient, the inhalation cancer unit risk is based on internal dosage estimated from an oral study. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1988 The 1988 Health and Environmental Effects Document is an external draft for review purposes only and has not received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 08/02/1989 Verification Date -- 08/02/1989 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Bromoform conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199312 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Bromoform CASRN -- 75-25-2 Primary Synonym -- Tribromomethane Last Revised -- 12/01/1993 SORD: __VI.A. ORAL RfD REFERENCES Chu, I., D.C. Villeneuve, V.E. Secours and G.C. Becking. 1982a. Toxicity of trihalomethanes: I. The acute and subacute toxicity of chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health. B17(3): 205-224. Chu, I., D.C. Villeneuve, V.E. Secours and G.C. Becking. 1982b. Trihalomethanes: II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health. B17(3): 225-240. NTP (National Toxicology Program). 1989. Toxicology and Carcinogenicity Studies of Tribromomethane and Bromoform in F344/N rats and B6C3F1 mice (gavage study). NTP-350. Research Triangle Park, NC. Tobe, M., Y. Suzuki, K. Aida, H. Yoshimoto, et al. 1982. Studies on the chronic oral toxicity of tribromomethane, dibromochloromethane, and bromodichloromethane. Unpublished interagency report to the National Institute of Hygienic Sciences. Tokyo Medical and Dental University, Tokyo, Japan. U.S. EPA. 1985. Drinking Water Criteria Document for Trihalomethanes. Office of Drinking Water, Washington, DC. (External Review Draft) ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Anders, M.W., J.L. Stevens, R.W. Sprague, Z. Shaath, and A.E. Ahmed. 1978. Metabolism of haloforms to carbon monoxide. II. In vivo studies. Drug. Metab. Dispos. 6(5): 556-560. ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Bromoform and Chlorodibromomethane. Prepared by Life Systems for ATSDR, U.S. Public Health Service. Balster, R.L. and J.R. Borzelleca. 1982. Behavioral toxicity of trihalomethane contaminants of drinking water in mice. Environ. Health. Perspect. 46: 127-136. Bowman, F., J.F. Borzelleca, and A.E. Munson. 1978. The toxicity of some halomethanes in mice. Toxicol. Appl. Pharmacol. 44(1): 213-215. Chu, I., V. Secours, I. Marino, and D.C. Villeneuve. 1980. The acute toxicity of four trihalomethanes in male and female rats. Toxicol. Appl. Pharmacol. 52(2): 351-353. Chu, I., D.C. Villeneuve, V.E. Secours, G.C. Becking, and V.E. Valli. 1982. Trihalomethanes: II. Reversibility of toxicological changes produced by chloroform, bromodichloromethane, chlorodibromomethane and bromoform in rats. J. Environ. Sci. Health. B17(3): 225-240. Condie, L.W., C.L. Smallwood, and R.D. Laurie. 1983. Comparative renal and hepatoxicity of halomethanes: Bromodichloromethane, bromoform, chloroform, dibromochloromethane and methylene chloride. Drug. Chem. Toxicol. 6(6): 563-578. Dykan, V.A. 1962. Changes in liver and kidney functions due to methylene bromide and bromoform. Nauchn. Tr. Ukr. Nauchn-Issled Inst. Gigieny. Truda i Profzabolevanii. 29: 82-90. (Chem. Abstracts. 60: 8541d). Dykan, V.A. 1964. Problems on toxicology, clinical practice, and work hygiene in the production of bromine-organic compounds. Gigiena. 5b: 100-103. (Chem. Abstracts. 63: 154299). Graham, E.A. 1915. Late poisoning with chloroform and other alkyl halides in relationship to the halogen acids formed by their chemical dissociation. J. Exp. Med. 221: 48-75. Mink, F.L., T.J. Brown, and J. Rickabaugh. 1986. Absorption, distribution, and excretion of 14C-trihalomethanes in mice and rats. Bull. Environ. Contam. Toxicol. 37(5): 752-758. Moody, D.E. and E.A. Smuckler. 1986. Disturbances in hepatic heme metabolism in rats administered alkyl halides. Toxicol. Lett. 32(3): 209-214. Munson, A.E., L.E. Sain, V.M. Sanders, et al. 1982. Toxicology of organic drinking-water contaminants--trichloromethane, bromodichloromethane, dibromochloromethane, and tribromomethane. Environ. Health Perspectives. 46: 117-126. NTP (National Toxicology Program). 1989a. Toxicology and carcinogenesis studies of tribromomethane (bromoform) (CAS No. 75-25-2) in F344/N rats and B6C3F1 mice (gavage studies). Technical Report Series No. 350. U.S. DHHS, Public Health Service, National Institute of Health, Research Triangle Park, NC. NIH Pub. No. 88-2805. NTIS/PB90-110149. NTP (National Toxicology Program). 1989b. Bromoform reproduction and fertility assessment in Swiss CD-1 mice when administered by gavage. NTP-89-068. NTIS/PB89-169254. Ruddick, J.A., D.C. Villeneuve, I. Chu, and V.E. Valli. 1983. A teratological assessment of four trihalomethanes in the rat. J. Environ. Sci. Health. B18(3): 333-349. Sax, N.I. and R.J. Lewis. 1989. Dangerous Properties of Industrial Materials, Seventh Ed. Van Nostrand Reinhold, New York, NY. Stevens, J.L. and M.W. Anders. 1979. Metabolism of haloforms to carbon monoxide: 3. Studies on the mechanism of the reaction. Biochem. Pharmacol. 28(21): 3189-3194. Stevens, J.L. and M.W. Anders. 1981. Metabolism of haloforms to carbon monoxide: 4. Studies on the reaction mechanism in vivo. Chem. Biol. Interact. 37(3): 365-374. U.S. EPA. 1990. Interim Methods for Development of Inhalation Reference Concentrations (External Review Draft). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066A. U.S. EPA. 1991. Health and Environmental Effects Document for Bromoform. Prepared by the Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response. NTIS/PB91-216424. von Oettingen, W.F. 1955. The halogenated aliphatics, olefinic, cyclic aromatic, and aliphatic-aromatic hydrocarbons including the halogenated insecticides, their toxicity and potential dangers. U.S. DHEW, Public Health Service, Washington, DC. Publ. No. 414. p. 65-67. (Cited In: ATSDR, 1990). ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Cantor, K.P., R. Hoover, T.J. Mason and L.J. McCabe. 1978. Associations of cancer mortality with halomethanes in drinking water. J. Natl. Cancer Inst. 61(4): 979-985. Carlo, G.L. and C.J. Mettlin. 1980. Cancer incidence and trihalomethane concentrations in a public drinking water system. Am. J. Public Health. 70(5): 523-525. Cotruvo, J.A. 1981. THMs in drinking water. Environ. Sci. Technol. 15(3): 268-274. Crump, K.S. 1983. Chlorinated drinking water and cancer: The strength of the epidemiologic evidence. In: Water Chlorination: Environmental Impact and Health Effects, Vol. 4. Environment, Health, and Risk, Book 2, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice, V.A. Jacobs, Ed. Ann Arbor Science Publishers, Inc., Ann Arbor, MI. p. 1481-1491. Galloway, S.M., A.D. Bloom, M. Resnick, et al. 1985. Development of a standard protocol for in vitro cytogenetic testing with Chinese hamster ovary cells: Comparison of results for 22 compounds in two laboratories. Environ. Mutagen. 7: 1-51. Isacson, P., J.A. Bean and C. Lynch. 1983. Relationship of cancer incidence rates in Iowa municipalities to chlorination status of drinking water. In: Water Chlorination: Environmental Impact and Health Effects, Vol. 4. Environment, Health, and Risk, Book 2, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice, V.A. Jacobs, Ed. Ann Arbor Science Publishers, Inc., Ann Arbor, MI. p. 1353-1364. Kraybill, H.F. 1980. Evaluation of public health aspects of carcinogenic/mutagenic biorefractories in drinking water. Prev. Med. 9: 212-218. Kurokawa, Y. 1987. Personal communication from Y. Kurokawa, National Institute of Hygienic Sciences, Tokyo, Japan, to R. Melnick, National Toxicology Program, North Carolina. (Cited in NTP, 1987) Morimoto, K. and A. Koizumi. 1983. Trihalomethanes induce sister-chromatid exchanges in human lymphocytes in vitro and mouse bone marrow cells in vivo. Environ. Res. 32: 72-79. NTP (National Toxicology Program). 1987. Toxicology and Carcinogenesis Studies of Bromodichloromethane in F344/N Rats and B6C3F1 Mice. NTP Technical Report No. 321. U.S. Dept. Health and Human Services, PHS, NIS, Besthesda, MD. NTP (National Toxicology Program). 1988. Technical Report on the Toxicology and Carcinogenesis Studies of Tribromomethane (Bromoform) (CAS No. 75-25-2) in F344 rats and B6C3F1 mice (gavage studies). NTP TR 350. Pereira, M.A. 1983. Carcinogenicity of chlorination by-products: Trihalomethanes. In: Water Chlorination: Environmental Impact and Health Effects, Vol. 4. Environment, Health, and Risk, Book 2, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice, V.A. Jacobs, Ed. Ann Arbor Science Publishers, Inc., Ann Arbor, MI. p. 1165-1176. Pereira, M.A., S.L. Herren, A.L. Britt and M.M. Khoury. 1982a. Initiation/promotion bioassay in rat liver: Use of gamma glutamyltranspeptidase-positive foci to indicate carcinogenic activity. Toxicol. Pathol. 10(2): 11-18. Pereira, M.A., L-H.C. Lin, J.M. Lippitt and S.L. Herren. 1982b. Trihalomethanes as initiators and promoters of carcinogenesis. Environ. Health Perspect. 46: 151-156. Simmon, V.F. 1977. Structural correlations of carcinogenic and mutagenic alkyl halides. In: Structural Correlates of Carcinogenesis and Mutagenesis. Proc. Second FDA Office of Sci. Summer Symp., I.M. Asher and C. Zerbos, Ed. FDA Office of Science, USA. p. 163-171. Simmon, V.F. 1981. Applications of the Salmonella/microsome assay. In: Short-term Tests for Chemical Carcinogens, H.F. Stich and H.C. San, Ed. Springer-Verlag, New York. p. 120-126. Simmon, V.F. and R.G. Tardiff. 1978. The mutagenic activity of halogenated compounds found in chlorinated drinking water. In: Water Chlorination: Environ. Impact Health Eff. Proc. Conf. 2: 417-431. Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. In: Progress in Genetic Toxicology Proceedings of 2nd International Conference on Environmental Mutagens, Edinburg, July 11-15, 1977. p. 249-258. Tardiff, R.G., G.P. Carlson and V. Simmon. 1978. Halogenated organics in tap water: A toxicological evaluation. In: Water Chlorination. Environmental Impact and Health Effects, Vol. 1, R.L. Jolley, Ed. Proceedings of the Conference on the Environmental Impact of Water Chlorination. Oak Ridge, TN, USA, Oct. 22-24. p. 195-209. Theiss, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice. Cancer Res. 37(8): 2717-2720. U.S. EPA. 1988. Health and Environmental Effects Document for Bromoform. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Bromoform CASRN -- 75-25-2 Primary Synonym -- Tribromomethane ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 06/30/1988 I.A.7. Primary contact changed 09/01/1989 II. Carcinogen assessment now under review 12/01/1989 I.A. Principal study citation corrected 12/01/1989 I.A.3. Chu et al. (1982) citation clarified 12/01/1989 VI. Bibliography on-line 09/01/1990 I.A. Text edited 09/01/1990 II. Carcinogen assessment on-line 09/01/1990 IV.F.1. EPA contact changed 09/01/1990 VI.C. Carcinogen references added 11/01/1990 I.A. Principal study corrected to final NTP, 1989 report 11/01/1990 VI.A. NTP, 1989 study added to references 01/01/1991 II. Text edited 03/01/1991 I.A.7. Primary contact changed 08/01/1991 VI.A. Citations clarified 08/01/1991 VI.C. Citations clarified 01/01/1992 IV. Regulatory actions updated 03/01/1993 I.B. Inhalation RfC now under review 12/01/1993 I.B. Inhalation RfC message on-line 12/01/1993 VI.B. Inhalation RfC references on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., I.B., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 392 of 1119 in IRIS (through 2003/06) AN: 217 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199508 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Carbon-disulfide- SY: 75-15-0; CARBON-BISULFIDE-; CARBON-BISULPHIDE-; CARBON-DISULPHIDE-; CARBONE- (SUFURE DE); CARBONIO- (SOLFURO DI); CARBON-SULFIDE-; CARBON-SULPHIDE-; DITHIOCARBONIC-ANHYDRIDE-; KOHLENDISULFID- (SCHWEFELKOHLENSTOFF); KOOLSTOFDISULFIDE- (ZWAVELKOOLSTOF); NCI-C04591-; RCRA-WASTE-NUMBER-P022-; SCHWEFELKOHLENSTOFF-; SOLFURO-DI-CARBONIO-; SULPHOCARBONIC-ANHYDRIDE-; UN-1131-; WEEVILTOX-; WEGLA-DWUSIARCZEK- RN: 75-15-0 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199009 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Carbon disulfide CASRN -- 75-15-0 Last Revised -- 09/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: The Oral RfD for carbon disulfide may change in the near future pending the outcome of a further review now being conducted by the Oral RfD Work Group. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Fetal toxicity/ NOEL: 20 ppm (62.3 100 1 1E-1 malformations mg/cu.m) converted to mg/kg/day 11.0 mg/kg/day Rabbit Inhalation Teratogenic Study LOAEL: None Hardin et al., 1981 ---------------------------------------------------------------------------- *Conversion Factors: x 6 hour/24 hour x 1.6 cu.m/day breathing rate x 0.5 absorption rate / 1.13 kg bw PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Hardin, B.D., G.P. Bond, M.R. Sikor, F.D. Andrew, R.P. Beliles and R.W. Niemeir. 1981. Testing of selected work place chemicals for teratogenic potential. Scand. J. Work Environ. Health. 7(Suppl. 4): 66-75. The data reported in this study were generated at Litton Bionetics, Maryland (under contract to NIOSH). Rats and rabbits were exposed to 20 ppm or 62.3 mg/cu.m (recommended occupational exposure limit) and 40 ppm or 124.6 mg/cu.m of carbon disulfide (CS2) during the entire length of the pregnancy period and also 34 weeks before breeding to simulate occupational exposure. Hardin et al. (1981) observed no effects on fetal development in rats or rabbits following inhalation exposure to 62.3 or 124.6 mg/cu.m, which corresponds to estimated equivalent oral dosages of 5 and 10 mg/kg for rats, and 11 and 22 mg/kg for rabbits. The highest NOEL from this study, 22 mg/kg for the rabbit, should not be used for an RfD estimate because adverse effects were seen in rabbit fetuses following oral exposure of pregnant does to 25 mg/kg (Jones-Price et al., 1984a,b). Therefore, the highest NOAEL that is below an effect level is the estimated low dose from the Hardin et al. (1981) inhalation study using rabbits. This dose level, 11 mg/kg, is the most appropriate basis for RfD derivation. A NCTR-NTP oral study (Jones-Price et al., 1984a,b) observed 25 mg/kg/day in rabbits as an FEL (fetal resorption). Fetotoxicity band fetal malformations in this study were not observed in rats at the lowest level (100 mg/kg/day) of CS2 exposure. The data from this study also suggest that the rabbit fetus is more sensitive than the rat fetus to CS2-induced toxicity. Johnson et al. (1983) reported an epidemiologic study that employed a wide range of exposure with CS2, such as 0.04-5 ppm (mean: 1.2 ppm, low, exposure), 0.04-33.9 ppm (mean: 5.1 ppm, medium exposure) and 0.04-216 ppm (mean: 12.6 ppm, high exposure). In this study the entire population was exposed to a combined exposure of 7.3 ppm over a period of 12 or more years. Of the several clinical findings, the exposed population showed significant alterations in sensory conduction velocity and peroneal motor conduction velocity. However, the data indicated, in the opinion of the authors, that minimal neurotoxicity was evident, since the reduction in nerve conduction velocity was still within a range of clinically normal values and thus not associated with specific health consequences. Additionally, the exposed population had blood lead levels <40 mg/dL and the exposed air alone contained H2S, H2SO4 and tin oxide. Therefore the 7.3 ppm CS2 can be considered as a NOAEL for neurotoxicity. This dose, when extrapolated to an oral dose of 10 mg/kg/day, lends support to the animal NOAEL of 11 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 100 includes 10 for interspecies and 10 for intraspecies variability to the toxicity of this chemical in lieu of specific data. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) A Bulgarian study (Tabatcova et al., 1983) reported significant fetal malformations in rats exposed to a low CS2 dose of 0.03 mg/cu.m over three generations. Based on these data, an RfD can be drastically lower than the RfDs that could be derived from existing guidelines, epidemiologic data or other experimental data. However, the Bulgarian study did not present information on mode control exposure, animal diet, procedure for selection of F1 and F2 breeding pairs and purity of CS2 (hydrogen sulfide, a teratogenic compound, is often found as a contaminant). In a multigeneration study, toxic effects of a compound can be confounded by the above factors. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The principal study was a well-designed multispecies study that provided adequate toxicologic endpoints; a medium confidence is assigned. The data base contains supportive reproductive and epidemiologic studies; therefore, a medium confidence is assigned. The RfD was supported by adequate oral reproductive and epidemiologic studies; however, additional oral chronic toxicity and reproductive studies are needed to support a higher than medium confidence level. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1986 ECAO-Cincinnati-Internal Review, 1986. Extensive Agency wide review, 1986. Other EPA Documentation -- None Agency Work Group Review -- 06/24/1985, 07/08/1985, 07/22/1985, 08/05/1985 Verification Date -- 08/05/1985 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Carbon disulfide conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199508 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Carbon disulfide CASRN -- 75-15-0 Last Revised -- 08/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: Note: ****SEE BENCHMARK CONCENTRATION IN DISCUSSION. Discussion of the benchmark dose can be found in the Discussion of Principal and Supporting Studies Section. SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- ----------------------- ----- --- --------- Peripheral nervous Benchmark Concentration: 30 1 7E-1 system dysfunction See Conversion Factors mg/cu.m and Assumptions and Occupational Study Principal and Supporting Studies Johnson et al., 1983 ------------------------------------------------------------------------------ *Conversion Factors and Assumptions: MW = 76.14. Assuming 25 C and 760 mmHg, BMC (mg/cu.m) = 17.7 x 76.15/24.45 = 55.1 mg/cu.m. This is an extrarespiratory effect of a gas exposure. The BMC is based on an 8-hour TWA occupational exposure. MVho = 10 cu.m/day, MVh = 20 cu.m/day. BMC(HEC) = 55.1 mg/cu.m x (MVho/MVh x 5 days/7 days = 19.7 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Johnson, B.L., J. Boyd, J.R. Burg, S.T. Lee, C. Xintaras and B.E. Albright. 1983. Effects on the peripheral nervous system of workers' exposure to carbon disulfide. Neurotoxicology. 4(1): 53-66. A cohort of male viscose rayon workers exposed to carbon disulfide (n = 145) was compared with a group of nonexposed artificial fiber plant workers (n = 233) located on the same premises (also reported in NIOSH, 1984). The mean exposure period was 12.1 +/- 6.9 years [mean +/- standard deviation (SD)]. Historical exposure estimates were based on area samples taken since 1957 (5478 samples) and personal samples taken since 1974 (Fajen et al, 1981; NIOSH, 1984). Current exposures were estimated on 250 8-hour personal samples taken for 25 job titles (1-44 samples per job title) during 12 days in early 1979 (Fajen et al., 1981). Based on historical area monitoring and industrial hygiene experience, job titles were divided into low-, medium-, and high-exposure categories prior to the field component of the study. Based on current personal monitoring, the mean carbon disulfide concentrations were estimated to be 7.3 ppm for the combined exposure group and 1.2, 5.1, and 12.6 ppm for the low-, medium-, and high-exposure categories, respectively. These estimates are based on 35, 121, and 94 samples for the low, medium, and high groups, respectively. The median carbon disulfide level for the comparison group was 0.2 ppm. The overall average for the historical area samples was 18 ppm, suggesting that the current personal samples may not be representative of exposure levels in earlier years. This difference also could result from placement of area samplers in areas of expected high exposures. Individuals were assigned to exposure categories based on current job title (n = 40, 61, and 44 in the low, medium, and high groups, respectively). Cumulative exposure index also was calculated as ppm-months, based on historical records of time spent by individual subjects in various job titles and concurrent area monitoring. Cumulative exposures by exposure category were 802, 1002, and 2077 ppm-months for the low, medium, and high groups, respectively (overall cumulative exposure was 1248 ppm-months). The similarity between the low and high categories results because the current measurements for two job titles identified in the low exposure category were higher than any of the measured levels for the medium exposure category (NIOSH, 1984). Workers were excluded on the basis of excess alcohol consumption, diabetes, or elevated blood lead levels. Surface electrodes were used to measure maximum motor conduction velocity (MCV) in the ulnar and peroneal nerves and sensory nerve conduction velocity (SCV) in the sural nerve. Latency and amplitude ratios were calculated. Data were presented after they were normalized for temperature and terminal distance. The numbers of measurements actually recorded varied due to time constraints on the field investigations and were 85, 130, and 137 in the combined exposed cohort and 105, 198, and 199 in the comparison cohort for the ulnar, sural, and peroneal nerves, respectively. In addition, participants' responses to a medical questionnaire with questions relevant to both central and peripheral nervous system symptoms were tabulated. Neurophysiological test results from the comparison group were compared with the overall exposure group, as well as to the low-, medium-, and high-exposure groups. Peroneal MCV and amplitude ratio were significantly decreased in the overall exposed group, and the decrease was statistically significant in the high-concentration exposure group vs. the comparison group. A concentration-response trend is evident across exposure categories. When MCV was stratified according to the cumulative exposure index (ppm-months), a significant association was made between this index and decreased MCV. Sural nerve SCV was decreased in the combined exposed groups vs. the comparison groups, however there was no concentration-response relationship in the three exposure groups. No differences in the number of self-reported symptoms related to the peripheral nervous system were found. The decrease in MCV constitutes a LOAEL. When evaluated using the three exposure categories, the only significant effect is shown in the high exposure category. Splitting the exposed group into three exposure levels raises the concern that the resulting smaller numbers of subjects would reduce the power to observe an effect. A power analysis was conducted, and the results indicate that the power was 84% in the mid-exposure group, which is considered to be adequate power to observe an effect. Using the arithmetic mean exposures, this study identifies a LOAEL of 12.6 ppm (39.2 mg/cu.m) and a NOAEL of 5.1 ppm (15.9 mg/cu.m). The duration-adjusted LOAEL and NOAEL are 14.0 and 5.7 mg/cu.m, respectively. DERIVATION OF A BENCHMARK CONCENTRATION (BMC): A benchmark conentration analysis was performed on the neurophysiological endpoints from Johnson et al. (1983), which are reported as the means and SDs from the three exposure categories described previously. The models used for neurophysiological endpoints were the polynomial model and the Weibull model (ICF Kaiser, Inc., 1990a,b). The models were run both with and without a threshold (i.e., a background intercept) parameter, and an extra risk approach was used. In the current state of development of the BMC approach, there is considerable discussion as to the appropriate level of the benchmark response (BMR) that is used to obtain the BMC, which is the lower bound on concentration at the BMR. A 10% relative change was selected as an appropriate BMR for the nerve conduction velocity measurements because this level is about equal to a difference of one SD from the control, and because a change of about 10% would likely raise concern in a clinical setting. Also, peer reviewer comments suggested that the level of response reported in the Johnson et al. study was of minimal severity and not necessarily adverse (Graham, 1995). Identical values for the BMC were obtained for the polynomial model and the Weibull model (BMC = 11.8 ppm, 37 mg/cu.m), indicating that the BMC for this endpoint is relatively model-independent. The most appropriate BMC based on the group data from Johnson et al. (1983) is from the peroneal MCV [BMC(HEC) = 13.1 mg/cu.m], it is the best data set for BMC analysis because it has three non-zero responses, and because the model fit is excellent. The individual data from the Johnson et al. study was obtained by the Chemical Manufacturers Association's Carbon Disulfide Panel, and a BMC analysis was performed and provided to EPA (Price and Berner, 1995). An advantage of using the individual subject data is that the effect of age on nerve conduction velocity can be evaluated. Age was reported by Johnson et al. to be a significant covariate for nerve conduction velocity. For the analysis with individual data, the BMR was defined as a 10% decrease in nerve conduction velocity (for the same reasons cited previously). The resulting BMC was 20 ppm [62.3 mg/cu.m; BMC(HEC) = 22 mg/cu.m], and it is considered superior to the group level analysis because it accounts for the age effect, and because it generally is preferable to use individual data when available. Further analysis was performed using the individual data from NIOSH that confirms and extends the results of Price and Berner (1995) and evaluates the interaction of age and exposure in explaining the decline in nerve conduction (Setzer, 1995). The data sets used by Setzer were slightly different than those used by Price and Berner because there were some missing and implausible values in the former, which either were replaced by values from the original NIOSH data or were excluded if the discrepancy could not be corrected. Setzer found that the decline in conduction velocity with age was greater in the exposed group than in the control group, suggesting a possible interaction between age and exposure. When this was accounted for, the effect of exposure on conduction velocity was no longer significant. This finding suggests that the individual exposure estimates, based on the current job and on personal monitoring at the time of the study, may not be adequate measures of exposure. When the cumulative exposure estimates were regressed against nerve conduction velocity, a significant effect of exposure was observed. There are two ways to approach the BMC analysis using cumulative exposure as the independent variable. In the first approach, the individual cumulative exposure is based on the job history of each subject, and the exposure estimates for each job weighted by the time spent at each job. The cumulative exposure in ppm-months for each subject was regressed against nerve conduction velocity, and a BMC in terms of ppm-months was calculated. The BMC was divided by the average exposure duration for the entire exposed population to get a BMC in ppm. Using this approach, the BMC of 2622 ppm-months is obtained, which converts to an average of 17.9 ppm, based on the study average exposure of 12.2 years. The adjusted BMC is 19.9 mg/cu.m. The second approach is to use the average exposure in ppm for each subject, obtained by dividing the individual cumulative exposures in ppm-months by the exposure duration for each individual, as the regression variable, and calculating the BMC in ppm. The BMC was determined to be 17.7 ppm, which leads to an adjusted BMC of 19.7 mg/cu.m. Although the numbers arrived at are essentially the same, it is preferable to use the individual average exposure because all of the individual exposure information is combined prior to modeling, rather than adjusting based on a group or study average. A similar analysis showed no exposure effect for the ulnar nerve. For the sural nerve, there was a large difference in the effect of age between exposed and control groups that could not be explained by exposure or by any other variable in the data set, so a regression coefficient could not be calculated with confidence. Over the small range of the extrapolation, the dose-response relationship is anticipated to remain linear. An interesting aspect of the peroneal MCV data is that all three exposed groups show responses that are less than the BMR of 10% change. The BMC is still obtained by extrapolating slightly outside of the range of the data, but, in this case, the extrapolation is to a higher concentration and effect level. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- An uncertainty factor of 3 reflects extrapolation of human data to sensitive humans. A full uncertainty factor of 10 was not considered necessary based on concurrence with peer-reviewer comments, which indicated that the lack of metabolic activation as a precursor to toxicity and the mechanism of action (protein cross-linking in the axon) does not suggest any reason to expect differences in sensitivity. A factor of 10 is applied to account for both data base deficiencies, including concern for possible developmental effects at low levels, and to extrapolate to a lifetime exposure. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) The cross-sectional studies by NIOSH (1984) and Putz-Anderson et al. (1983) used the same exposed (n = 146) and nonexposed workers (n = 233) as did the Johnson et al. (1983) study. Exposure and companion groups and exposure levels are the same as those described for the Johnson et al. (1983) study. Historical exposures sampled from 1957 to 1978 averaged below 20 ppm (62 mg/cu.m), however brief periods of high excursions in carbon disulfide levels occurred occasionally. The exposure levels and groups were as described for the principal study. The authors examined a number of parameters in addition to those reported by Johnson et al. (1983), including cardiovascular status (clinical chemistries, ECG, and blood pressure), retinal abnormalities, CNS symptoms, psychological tests, endocrine and metabolic status (blood hormone levels and serum trace metals), and reproductive status (semen analysis and reproductive history). Results of these studies included significant increases in retinal microaneurysms and hemorrhages in exposed individuals compared with controls, but a concentration-related increase in response is not evident when analyzed by exposure category. In addition, an increased prevalence of blurred vision, memory difficulty, dizziness, insomnia, and fatigue was reported among carbon disulfide-exposed individuals. However, results of objective psychological and psychomotor tests do not corroborate the symptomatology. No effects were found in reaction time, visual acuity, visual search ability, or psychological or memory tests. No exposure-related effects on other parameters were reported. These studies support the identification of the LOAEL from the Johnson et al. study and show possible CNS and ocular effects at the same level. The LOAEL is identified as discussed for the principal study. Peripheral neuropathy was shown to result from long-term occupational exposure to carbon disulfide in a cross-sectional study of rayon workers exposed for 10.3 +/- 6.9 years (mean +/- SD, range 1-22 years; Hirata et al., 1984). Historical exposure estimates were based on area sampling between the years 1975 and 1981 (7430 samples; Sugimoto et al., 1981), but exposure monitoring prior to 1975 was not reported. Current exposure estimates were based on area sampling at the time of the study (275 samples at 24 locations) and personal samples (64 samples for eight job titles; Sugimoto et al., 1981). Personal samples were taken with a passive dosimeter; samples were collected on activated charcoal and analyzed by gas chromatography. The sampling time is not stated explicitly but is presumed to be 8 hours. The area sampling used approximately 1 L grab samples and spectrophotometric analysis. Current exposure estimates are based on the personal sampling results. The average exposure was 4.15 mg/cu.m (1.45 ppm) for the subjects examined by Hirata et al. (1984). The overall averages of all historical area samples is 19.5 mg/cu.m and, from current area samples, was 9.21 mg/cu.m. These results, coupled with the authors' statements that exposures were higher between 1961 and 1974, and that process and control improvements were made (unspecified), suggest that the current exposures measured by area and personal samples are not representative of exposures prior to the sampling program. Sugimoto et al. (1981) identified a cohort of 311 male and 65 female workers exposed to carbon disulfide; 205 male and 117 female workers from a textile machine manufacturing factory were used as the control group. Hirata et al. (1984) studied 70 exposed male workers and 70 age-matched controls selected randomly from the original cohort. Excluded from the study population were subjects with right arm trauma, diabetes, alcoholism, renal failure, neurological disease, and exposure to other toxic solvents. Besides age distribution and these exclusion criteria, no other information is given on the demographics of the control group. MCV and SCV were measured in the right ulnar nerve and normalized for skin temperature, although the room temperature in which the measurements were made was uncontrolled (range 22-31 C). Corrected MCV and conduction velocity of the slower motor fibers (CVSF) were found to be significantly lower in each age group of exposed vs. unexposed individuals (p = 0.001 for both parameters). Although compromised by the lack of information on earlier exposures and on the control group, the results are consistent with other occupationally exposed populations and show an effect at a lower concentration. A LOAEL of 1.45 ppm (4.52 mg/cu.m) is established in this study. The LOAEL(HEC), based on adjustment from an occupational study, is 1.61 mg/cu.m. Ruijten et al. (1990) studied peripheral nerves, autonomic nerves, and color discrimination in male workers at a rayon plant. Control groups of 45 and 37 workers from the same plant were evaluated. The exposed and control groups were matched on a group basis for age, socioeconomic status, and nationality. Exposure levels were determined for various areas, based on personal samples (number of samples not reported) taken over a period of 3 years prior to the study. The results of a large number of area samples (number not reported) taken since 1946 indicated that exposure levels had not changed substantially (data not provided). Individual exposures were calculated based on time spent in various areas and were reported as a cumulative exposure. Average cumulative exposures for the exposed group was 165 ppm-months, and exposed workers were exposed for 20 +/- 9 years (mean +/-SD). The mean exposure was therefore 8.25 ppm (25.7 mg/cu.m). No other information is provided to characterize the exposure. Conduction velocity and refractory period of the peroneal and sural nerves were determined. Autonomic nerve function (heart rate variation during rest, deep breathing, and isometric muscle contraction) and color discrimination also were evaluated. A decrease in conduction velocity of the peroneal nerves and an increase in the refractory period were observed and were related to cumulative exposure. This study demonstrates a LOAEL for peripheral nervous system effects of 8.25 ppm [LOAEL(HEC) = 9.18 mg/cu.m, based on adjustment for an occupational exposure scenario]. This study is supportive of the LOAEL identified in the principal study but is not used as the basis of the RfC because of inadequate information on exposure characterization. Sugimoto et al. (1984) studied cardiovascular effects and retinal effects in the cohort first described by Sugimoto et al. (1981) and used, in part, in the principal study (Hirata et al., 1984). No effects were found on blood pressure or blood cholesterol. The previously described carbon disulfide retinopathy, characterized by microaneurysms and small-dot hemorrhages, was not observed. These results suggest a NOAEL for retinal effects at the LOAEL for peripheral nerve effects that was identified in the principal study. Cohorts of male workers from a Finnish viscose rayon plant exposed to carbon disulfide for 1-27 years were examined (n = 118) and compared with male paper mill workers not exposed to carbon disulfide (n = 100) (Seppalainen and Tolonen, 1974). Carbon disulfide levels in this cohort were fairly high and were estimated from historical records of air-sampling programs (Hernberg et al., 1970, 1976; Nurminen and Hernberg, 1985). Exposure levels in the viscose film factory and the carbon disulfide factory had not exceeded 20 ppm (62 mg/cu.m) since 1958, and, since 1962, the means were "mostly lower" than 10 ppm (31 mg/cu.m). In the rayon staple and rayon filament factories, the overall levels had been lower than 60 ppm (187 mg/cu.m) and, since 1960, lower than 30 ppm (93 mg/cu.m). Some of the exposed individuals had been removed from the carbon disulfide environment. Those still in contact with carbon disulfide (n = 65/118) had been exposed for 10-27 years (mean 19 years), whereas those who were removed (n = 53/118) had been exposed for 1-22 years (mean 12 years). Conduction velocities in the slower motor fibers in the ulnar nerve (39.8 vs. 44.1 m/second, p < 0.0005) and the deep peroneal nerve (35.5 vs. 38.2 m/second, p < 0.0005) were the most significantly decreased by carbon disulfide exposure. There also were decreases in MCV of the tibial and peroneal nerves. In addition, the exposed group had a higher incidence of abnormal EEGs (21/54, compared with 6/50 in controls). No evidence of regression of the disorder after cessation of exposure was established. Increased cardiovascular-related mortality also was reported at 10-30 ppm carbon disulfide (31-93 mg/cu.m). Peripheral nerve conduction velocity was measured in carbon disulfide workers suspected to have polyneuritis (n = 60) (Vasilescu, 1972). The concentration of carbon disulfide was approximately 5 ppm (15 mg/cu.m), but high excursion levels of 225 ppm (700 mg/cu.m) sometimes were reached. The limited information on exposure characterization in this study does not allow the estimation of a mean exposure. Conduction velocity was measured in the median, ulnar, and peroneal nerves and was found decreased in exposed individuals, even in those with no clinical signs. When exposed individuals were divided into two groups on the basis of the severity of their symptoms, it was found that the more severe polyneuropathy (decreased nerve conduction velocity, muscle pain, paresthesia, fatigue, and dizziness) was not reversed 1 year after termination of carbon disulfide exposure, whereas members of the second group (lower-limb paresthesia and decreased muscular power of limbs) recovered from their symptoms. The authors concluded that decreased nerve conduction velocity may be one of the early warning signs for carbon disulfide poisoning and could be used as an index of early carbon disulfide neuropathy. This study is not useful for quantitative assessment because individuals were selected for participation in this study on the basis of reduced nerve conduction velocity, and exposure levels were not characterized. In addition, there is no information on the control subjects used. Clinical neurological examination of 16 men formerly exposed to a range of approximately 10 ppm (30 mg/cu.m) and 20 ppm (60 mg/cu.m) carbon disulfide for at least 10 years revealed abnormalities in 15 of the men (Aaserud et al., 1988, 1990). Cerebral computerized tomography scan revealed signs of atrophy in 13 men, and neuropsychological examination indicated brain organic changes in 14 men. There was no measurement of individual exposures, however, and no adjustment was made to account for other possible occupational exposure or for lifestyle factors. Cirla et al. (1978) identified a cohort of rayon workers exposed to carbon disulfide. A total of 254 exposed workers were divided into six exposure categories based on historical area and personal monitoring data. Fifty-four workers who were employed in the same plant but in areas considered free of exposure were used as a comparison group. The comparison group is stated to be similar to the exposed group in personal and social characteristics, but no comparative demographic data are presented, and no data are presented on the exposure of the comparison group. It is stated that area samples were taken intermittently prior to 1960 and every 2 months between 1960 and 1970, and personal sampling was adopted after 1970. Exposure categories are characterized in terms of the number of years worked, and the exposure concentrations are qualitatively described relative to the Italian maximum allowable concentration of 60 mg/cu.m. Sampling method, number of samples, and mean exposure levels for the groups are not provided. Gilioli et al. (1978) reported on the evaluation of neurological impairment in these workers. They performed neurological examinations, electroencephalography, ophthalmoscopy, and electromyographic measurements of nerve conduction velocity and latency of the peroneal nerve. Central and peripheral nervous system dysfunction (determined by neurological examination), retinal vascular changes, and reduced nerve conduction velocity were observed to increase with exposure. Limited statistical analyses are presented. The decrease in motor nerve conduction velocity showed significant effects using an analysis of variance, and individual t-tests showed significant differences between the comparison group and the moderately and heavily exposed groups, but not the light and very light groups. Retinal changes showed a significant trend from the light to heavy exposure groups, but individual comparisons were not made. This study shows a carbon disulfide-exposure-related effect on the retina and the peripheral nerves, but the lack of statistical analysis of the results, quantitative exposure information, and information on the comparison group make this study inadequate to form the basis of the RfC. Cirla and Graziano (1981) examined a subset of the cohort identified by Cirla et al. (1978). The exposed group (n = 50) came from a single department and is a subset of the light-exposure group (n = 73) from Cirla et al. (1978), and the entire comparison group is used. Control individuals were evaluated for carbon disulfide exposure on the basis of working history and task evaluation; however, no measurements of background carbon disulfide concentration were performed for this group. Exposure period ranged from 3-12 years. Exposure levels are characterized in the text of the paper as approximately 20 mg/cu.m and always below 30 mg/cu.m, based on area sampling (number of samples and method not reported). The information available in one table suggests an overall mean exposure of approximately 10 mg/cu.m. Mean exposure levels are reported for eight job titles and range from 5-21 mg/cu.m, but it is not possible to calculate an overall mean exposure. In addition, individuals were paired according to sex, physical features, work shift, and smoking and alcohol-use history and were assumed to have similar socioeconomic status, diet, and education level. Measurement of peripheral nervous system function, among other tests, revealed that there was no difference in MCV, slow fiber conduction velocity, or residual latency of the peroneal nerve when exposed and control individuals were compared by Student's t-test. The clinical diagnosis of peripheral impairment was made for five exposed and two control individuals. No effect was found on psychological tests, including tests of intelligence, performance, and memory. This report suggests a NOAEL for peripheral nerve function of 10 mg/cu.m [NOAEL(HEC) = 3.57, based on adjustment from an occupational exposure scenario], but this value is not used in the RfC derivation because of inadequate quantitative exposure characterization in the study. A study of two groups of viscose rayon production workers showed that decrements in nerve conduction velocity persisted 10 years after exposure ended in the most exposed group (Corsi et al., 1983). In summary, several epidemiological studies of occupational exposures are available for carbon disulfide, which consistently point to peripheral neurotoxicity as a sensitive effect of long-term exposure in humans. Laboratory animal studies on the neurotoxicity of carbon disulfide usually have been done in rats and provide histopathologic and neurochemical data that support neurotoxicity with carbon disulfide exposure. In general, however, concentrations used in these studies are considerably higher than the occupational exposures seen in epidemiological studies. Male (10/group) and female (12/group) B6C3F1 mice, Fischer 344 rats (15/sex/group), and Sprague-Dawley rats (15/sex/group) were exposed to 0, 49, 297, or 798 ppm (0, 153, 925, or 2485 mg/cu.m, respectively) carbon disulfide for 6 hours/day, 5 days/week for 90 days (CIIT, 1983). Examination of high-dose mice revealed decreased erythrocyte counts, hemoglobin, hematocrit, serum protein, and brain weight; peripheral nerve degeneration; axonal swelling; nephropathy; mineralization and tubular epithelial syncytia of the kidney; and brown pigmentation of the spleen. In Fischer 344 rats exposed to 798 ppm (2485 mg/cu.m) carbon disulfide, there was an increase in iron-positive pigmentation of the spleen. Both sexes in the high-dose group and females in the 300-ppm group had axonal swelling of nerve fibers of the spinal cord and of muscular and sural nerves (teased fiber preparation). In addition, clumping and loss of myelin sheaths were observed. These changes were not observed in animals exposed to 297 ppm (925 mg/cu.m) carbon disulfide. High-dose Sprague-Dawley rats had ataxia (slight foot dragging), slight axonal swelling of ventral and lateral funiculi of the spinal cord, excess pigmentation of the spleen, and axonal swelling of muscular and sural nerves (teased fiber preparation). Details of the nerve morphology findings are reported by Gottfried et al. (1985). There was a decrease in absolute brain weight in both sexes at the high-dose level and in females at the mid-dose level. The LOAEL for neurotoxicity is 925 mg/cu.m [LOAEL(HEC) = 165 mg/cu.m] for rats and mice. No respiratory or ocular effects of carbon disulfide exposure were noted. Rebert and Becker (1986) attempted to establish a dose response for peripheral nerve conduction time changes. Rats (10 females/group) were exposed to 0, 400, or 800 ppm carbon disulfide, 7 hours/day, 7 days/week for 11 weeks. In animals exposed to 800 ppm (2491 mg/cu.m), visual-evoked potentials and conduction time in peripheral nerves and brainstem auditory pathways were longer than in rats exposed to 400 ppm (1246 mg/cu.m). The potentials in the groups exposed to 400 ppm were longer than the controls, although the differences were not statistically significant. The LOAEL for peripheral nervous system effects is 2491 mg/cu.m [LOAEL(HEC) = 726 mg/cu.m, based on dosimetric adjustment for an extrarespiratory effect of a gas]. Neurological effects such as hindlimb motor difficulties, reduced sciatic nerve conduction velocity, and degenerating nerve fibers were seen in rats exposed to 700 ppm (2180 mg/cu.m) carbon disulfide for 5 hours/day, 5 days/week for 12 weeks and observed for 18 weeks postexposure (Colombi et al., 1981). The decreased nerve conduction velocity (measured in 40 rats) was evident 3 weeks after the beginning of exposure (significance level and statistical test unspecified), and, by the ninth week of exposure, some animals showed slight clinical signs of neurological impairment, such as difficulty in standing and running. Morphological evaluation of the sciatic nerves at week 10 revealed slight alteration of the myelin sheaths and axonal swelling. These pathologies continued to progress until three weeks postexposure; however, they were slightly improved at the 6-week postexposure point and at all points in time thereafter, indicating that the neuropathy may have been reversible. Sensory and motor function were measured in Long-Evans hooded rats (4 males/group) exposed to 5 or 12 weeks of 500 ppm (1557 mg/cu.m) carbon disulfide for 6 hours/day, 5 days/week, and compared with concurrent control animals (4 males/group) (Clerici and Fechter, 1991). Behavioral testing that utilized the acoustic startle reflex response was used in order to test acoustic and neuromuscular functioning before, during, and after exposure or control periods. Hearing function (sensory) was relatively unaffected by carbon disulfide exposure for either 5 or 12 weeks. However, mean amplitude of baseline startle responses decreased significantly after 5 weeks (48% decrease from control) and 12 weeks (66% decrease) of exposure, indicating neuromuscular damage. Partial recovery was seen on the fourth-week postexposure examination. Saillenfait et al. (1989) exposed pregnant Sprague-Dawley rats (20-23/group) to 0, 100, 200, 400, or 800 ppm (0, 311, 622, 1244, or 2488 mg/cu.m, respectively) carbon disulfide, 6 hours/day during gestational days 6-20. On day 21, maternal and fetal parameters were evaluated, including examination for external, visceral, and skeletal abnormalities. Chamber concentrations were stated to be within 5% of nominal, based on spectrophotometric analysis, but the number of samples was not given. Exposure to 400 or 800 ppm resulted in reduced maternal weight gain (19 and 48% reductions in the 400- and 800-ppm groups, respectively) and fetal body weight (6.6 and 22% in the 400- and 800-ppm groups, respectively). The number of litters examined was 40, 17, 17, 22, and 22 in the control and 100-, 200-, 400-, and 800-ppm groups, respectively. There were no effects on implantations, resorptions, live fetuses, or fetal sex ratio. Fetuses from animals in the 800-ppm exposure group had an increase in unossified sternebrae (16/289 vs. 3/558 in controls), an index of delayed fetal development. A slight increase in club foot at 400 and 800 ppm was noted (1/298 and 7/289 fetuses compared with 0/558 in controls) but was not statistically significant. No other effects were noted. A NOAEL of 400 ppm (1244 mg/cu.m) is established from this study for maternal and developmental effects. The NOAEL(HEC) for developmental effects is 1244 mg/cu.m. A developmental study was conducted using New Zealand White rabbits (PAI, 1991). In this study, rabbits (24/group) were exposed by inhalation to 0, 60, 100, 300, 600, or 1200 ppm (0, 187, 311, 934, 1868, or 3737 mg/cu.m, respectively) carbon disulfide, 6 hours/day on gestation days 6-18. Animals were evaluated on day 29. Maternal toxicity was observed as reduced body weight gain and adverse clinical signs (ataxia, lowered food consumption, or wheezing) in the 1200-ppm group, with some sporadic hematologic alterations at 600 ppm (e.g., decreased hematocrit on gestation day 19). These effects were not seen in an initial dosage range-finding study, where rabbits were exposed to 1000 ppm carbon disulfide. Embryotoxic effects (reduced mean fetal body weight, number of live fetuses, and postimplantation loss) were seen in the 600- and 1200-ppm exposure groups. In the group exposed to 1200 ppm, there were only seven litters with live fetuses, and there was a high incidence of developmental effects (increased cumulative skeletal and visceral malformations). In the other groups and controls, 20-23 litters were examined, and there were no significant increases in any gross, visceral, or skeletal abnormalities. Using dosimetric adjustment for an extrarespiratory effect, the NOAEL for developmental effects was 300 ppm [NOAEL(HEC) = 934 mg/cu.m], and the NOAEL for maternal toxicity was 600 ppm [NOAEL(HEC) = 1868 mg/cu.m]. In a developmental study performed for NIOSH [Beliles et al., 1980 (data also summarized in Hardin et al., 1981)], rabbits and rats were exposed to 0, 20, or 40 ppm (0, 62, or 125 mg/cu.m, respectively) carbon disulfide for 7 hours/day, 5 days/week for 3 weeks prior to mating. Following mating, groups of rats not exposed pregestationally were exposed to 20 or 40 ppm carbon disulfide on days 0-18 or days 6-18 of gestation, and rabbits were exposed to 20 or 40 ppm on days 0-21 or days 7-21 of gestation. Similarly, animals exposed pregestationally were divided into two groups that were exposed to the same concentration as used in the pregestational exposure and exposed during gestation days 0-18 or 6-18 (rats) or 0-21 or 7-21 (rabbits). Control animals were included that were unexposed during pregestational and gestation periods. Chamber concentrations were determined hourly, and the coefficient of variation of the chamber concentration ranged from 8-14%. In rats, there was no effect on maternal weight gain and no dose-related effect on maternal organ weights or histology of the liver or kidney. In 12-23 litters/group, there were no significant effects on uterine contents (early or late resorptions, number of fetuses, fetal weight, or fetal length), and no significant external, visceral, or skeletal malformations were observed. There was a slight but nonsignificant increase in resorptions and reduction in live fetuses in two groups (20 ppm, exposed during gestation, and 40 ppm, exposed pregestationally and during gestation). In the rabbit study there was a high level of mortality, which was not exposure related, and which makes interpretation of the rabbit study difficult. There was no effect on maternal body weight, organ weight, or histology of the liver or kidney. In 15-18 litters examined per group from the groups that were not exposed pregestationally, there was no effect on uterine contents and no increase in external, visceral, or skeletal abnormalities. This study shows a NOAEL of 40 ppm for maternal and developmental toxicity for rats and rabbits and for exposures lasting throughout gestation or during the postimplantation period. The NOAEL (HEC) for developmental effects is 125 mg/cu.m. In a developmental study of albino rats, 30-32 animals/group were exposed to carbon disulfide at concentrations of 0, 0.01, 3.20, 32.00, or 64.00 ppm (0, 0.03, 10.00, 100, or 200 mg/cu.m, respectively) for 8 hours/day throughout gestation (21 days) (Tabacova, 1989; Tabacova and Balabaeva, 1980; Tabacova et al., 1978, 1983). Some of the parental generation were examined prior to term, and some F1 animals were reared until maturity and mated within experimental groups to produce the F2 generation. The pregnant F1 females were exposed throughout gestation to the concentration of carbon disulfide to which they were exposed prenatally, including air-exposed controls. Status of the F1 and F2 generations was determined prenatally by gross examination of the uterine contents (no indication is given that visceral or skeletal malformations were examined) and several biochemical measurements. The F1 and F2 generations also were examined postnatally by examining growth, development, hexobarbital sleeping time, neurophysiologic parameters (motor coordination, open-field activity), weight gain, and survival. Some of these measurements were made on all exposure levels, and some are provided only for the two lowest concentration groups. In Tabacova et al. (1978), there also is a group exposed to 16 ppm (50 mg/cu.m), and some information is available, but this group is not included in the 1983 report, which is somewhat more detailed. The generation and measurement of the exposure atmosphere are described in Tabacova, 1989. The carbon disulfide levels were measured twice per day using a spectrophotometric method that has been used extensively (NIOSH, 1977), but has been replaced by gas chromatographic methods in the western literature since about 1970. No information is provided in any of the published reports on the purity of the test chemical or on the results of the chamber monitoring. The methods as described seem reasonable. The selection of the lowest exposure at a level that is 333 times lower than the next level was done to correspond to contemporary Bulgarian ambient (0.03 mg/cu.m) and occupational (10 mg/cu.m) standards. There is no information on whether the control groups were handled in the same way as the exposed groups, and no mention is made of the method of selection of mating pairs or whether sibling pairs were excluded in producing the F2 generation. It also is not clear whether the control group was run concurrently with the exposed groups. In the 1978 report, a control and three exposed groups (50, 100, and 200 mg/cu.m) are presented. In the 1983 report, the same data for the control and 100- and 200-mg/cu.m groups are presented with data from the two lower exposure levels. In another table, there are separate control groups reported for the 0.03- and 10.00-mg/cu.m groups and the 100- and 200-mg/cu.m groups. Despite these limitations, a variety of maternal and developmental effects were reported. Maternal toxicity (reduced weight gain during gestation) was observed in the parental and F1 generations exposed to 100 mg/cu.m (F1 generation; 59% decrease was not reported as statistically significant) or 200 mg/cu.m carbon disulfide (27% in the parental generation and 74% in the F1 generation). For this endpoint, there are two control groups reported, and large differences between the control groups are unexplained. In contrast, Saillenfait et al. (1989) report no effect on maternal weight in rats exposed to 622 mg/cu.m and a 19% decrease at 1244 mg/cu.m. Average fetal weight is significantly decreased in this study at 100 and 200 mg/cu.m (5 and 7%, respectively). A 6.6% decrease in fetal weight was reported by Saillenfait at 1244 mg/cu.m, and no effect was observed at 622 mg/cu.m. However, the Saillenfait et al. (1989) study exposed for only 6 hours/day, starting at day 6, compared with 8 hours/day throughout gestation in Tabacova's studies; this difference could account for the difference in results. Significantly increased preimplantation lethality at 200 mg/cu.m and a slight increase at 100 mg/cu.m indicate adverse developmental effects at these levels (Tabacova et al., 1978). In the only other study to include exposure throughout gestation, Beliles et al. (1980) report no preimplantation loss at concentrations up to 125 mg/cu.m. Malformations reported by Tabacova et al. (1983) include a significant increase in clubbed foot and hydrocephaly in the 100 and 200 mg/cu.m animals and increased hypognathia and tail malformations at 200 mg/cu.m. In the Saillenfait study, a nonsignificant increase in clubbed foot was observed at 2488 mg/cu.m, but no other malformations were observed. The fact that the effects seen by Tabacova were not seen at 25-fold higher concentrations in the later study could be explained by the exposure during the first 6 days of gestation in the Tabacova studies. The Beliles study did not see these effects at 125 mg/cu.m, a result that may not be inconsistent with the Tabacova data, because different rat strains were used. It is a concern that the gross effects reported by Tabacova were not seen in the F1 generation animals that were delivered and studied postnatally (hydrocephalus, clubbed foot, and tail malformation should have been visible in the surviving animals). No malformations were observed in the F1 animals or maternal weight changes in the parental generation exposed to 0.03 or 10.00 mg/cu.m. No information on fetal weight preterm or postnatal weight changes are reported for the two lower dose levels. There is, therefore, no reported evidence of prenatal developmental effects in the F1 generation exposed to 0.03 or 10.00 mg/cu.m. When pregnant F1 females were exposed during gestation, evidence of more severe maternal and developmental effects were observed. These effects included greater maternal weight loss during gestation in the 200 mg/cu.m-group (a larger reduction in weight than parental generation at the same exposure level) and increased incidence and severity of malformations compared with the previous generation. Increased malformations also occurred at lower concentrations (0.03 and 10.00 mg/cu.m), which did not affect the F1 generation. This effect was explained by the authors as intrauterine sensitization, a mechanism by which exposure of the parental generation resulted in an F1 generation that was more sensitive to the developmental effects of carbon disulfide during pregnancy. A variety of observations and measurements were made to evaluate postnatal development in F1 and F2 pups. Decreased postnatal survival at 200 mg/cu.m and decreased postnatal weight gain on days 4 and 7 was observed in animals exposed to 100 or 200 mg/cu.m carbon disulfide (Tabacova et al., 1978). Tabacova and Balabaeva (1980) report postnatal examination of animals exposed to 0.03 or 10.00 mg/cu.m. A decrease in viability at postnatal day 21 was significant, but this effect is not seen in animals exposed to 50 or 100 mg/cu.m (Tabacova et al., 1978). Postnatal observations show significant effects on eye opening (day 18), auditory startle reflex (day 14), visual placing response (day 18), and righting behavior at 10 mg/cu.m (Tabacova and Balabaeva, 1980; also reported in Tabacova and Hinkova, 1979). These responses were reported for single times postnatally and were normal at an unspecified later time. No other studies of postnatal development after exposure to carbon disulfide are available. Other parameters measured postnatally in this study (Tabacova et al., 1983) include hexobarbital sleeping time and neurophysiological tests (narrow-path crossing and open-field activity). Hexobarbital sleeping time is increased significantly in F1 and F2 animals exposed to 10 mg/cu.m (not reported for higher concentrations) at 7 and 14 days but not at 21 days of age. Because this measurement was made on only 6-8 pups/group, and the controls are variable, it is not considered a clear indication of a developmental effect. Narrow-path crossing is a measure of motor coordination. No effect is seen in F1 animals exposed to 0.03 or 10.00 mg/cu.m. In exposed F2 animals, a significant decrement in this behavior was observed as a decrease in mean distance covered in groups exposed to 0.03 or 10.00 mg/cu.m. This response shows no concentration-response relationship because the exposures differ by 300-fold, and the responses are identical, and the parameter is not reported for other exposure concentrations. Narrow-path crossing also is reported as number of slips and falls, both of which increase at 10 mg/cu.m, but are not reported at higher concentrations. Open-field motor activity is reported as the number of squares crossed, the number of rearings, and gait defects. The number of squares crossed was increased at day 14 and decreased at day 21 in F1 groups at 0.03 and 10.00 mg/cu.m; it was unchanged at day 14 and decreased at day 21 in F2 animals at 0.03 and 10.00 mg/cu.m. The number of rearings is unchanged in F1 animals and decreased in F2 animals at 0.03 and 10.00 mg/cu.m (response at 0.03 mg/cu.m was slightly greater than at 10). The percent with gait defects is increased in F1 animals at 10.00 mg/cu.m and in F2 animals at 0.03 and 10.00 mg/cu.m and shows a reasonable concentration response. The criteria for identifying a gait defect is not discussed, so the adversity of this response is unknown. Fifty and 75% increases in open-field motor activity were reported for the 0.03- and 10.00-mg/cu.m groups, respectively (Tabacova and Balabaeva, 1980). This result is not quantitatively consistent with the slight increases in the open-field parameters reported in Tabacova et al., 1983, but it is not clear whether the same parameter is reported in the two studies. In summary, this study shows a variety of developmental effects of low-level carbon disulfide exposure that are difficult to interpret due to poor reporting of experimental design details and results. The effects measured postnatally, including morphological, sensory, and behavioral endpoints, are limited because they are reported for only two exposure levels. The endpoints which are affected at both lower concentrations do not show reasonable concentration-response behavior, and the ones affected only at 10 mg/cu.m are not supported by other data at higher exposure concentrations. Nevertheless, a variety of endpoints are shown to be significantly changed at 10 mg/cu.m. The effects on preimplantation losses at 100 and 200 mg/cu.m are the strongest data in these studies; the slight inconsistency with the Beliles study could be due to strain differences. The increase in malformations in the F1 and F2 generations seems compelling due to the increase in incidence and severity with concentration and between the F1 and F2 generations. The slight inconsistency with the Beliles study (no effect at 125 mg/cu.m, compared with an effect at 100 mg/cu.m) could be explained by strain differences. The lack of effect in the Saillenfait study at a 25-fold higher concentration could be explained by strain differences or differences in protocol (exposure throughout gestation vs. exposure on days 6-18). The dramatic increase in response in the F2 generation indicates clearly adverse effects at concentrations as low as 0.03 mg/cu.m. This experimental design has not been duplicated, so no data are available for direct comparison. The more recent developmental studies use a more typical protocol and cannot address directly the effects in the F2 generation, although there is little agreement among these studies where they look at the same or similar parameters. Although the effects at 0.03 and 10.00 mg/cu.m in the Tabacova studies cannot be refuted, there are substantial issues affecting interpretation that cannot be resolved. These studies clearly define a LOAEL of 100 mg/cu.m for maternal and developmental effects. A LOAEL for developmental effects at 10 mg/cu.m, including malformations in the F2 generation and postnatal morphological development and postnatal behavior in F1 and F2 generations is identified by these studies but is not strongly supported by other data. The effects reported at 0.03 mg/cu.m are not considered to be useful because the effects are of questionable significance and do not show reasonable dose-response behavior, and because of questions regarding the ability to measure such low levels. The BMC analysis was performed for the developmental effects using the models of ICF Kaiser (1990a,b), which were run with and without a threshold parameter and with no background parameter, because the incidence of effects in the control groups was zero. The specific developmental models were not used because software was not available, and because individual litter data were not available for these studies. The BMC was calculated from the data from Tabacova et al. (1978) on total malformations and hydrocephalus in the F2 generation and for the data on external malformations from Tabacova et al. (1978). Based on the results from these analyses, the BMC from the data on total malformations from Tabacova et al. (1983) result in the lowest BMC for the developmental data sets. The fit to the points is poor, based on the chi-square test. Because of the limitations of this data, the BMC is presented for comparison but is not recommended for derivation of the RfC. The most appropriate BMC from the developmental data is from the total malformation from Tabacova et al. (1983) (18.7 mg/cu.m). The benchmark concentration was based on a response of 10% in total malformations using an extra risk model. IRCC: In humans, vascular atherosclerotic changes are a primary effect following long-term exposure to carbon disulfide. This is supported by epidemiological studies that have established a relationship between occupational exposure to carbon disulfide and increased mortality due to coronary heart disease. However, since reliable retrospective data on exposure levels are not available, it is impossible to establish a dose-response relationship or a NOAEL. In addition, coronary heart disease has a multicausal origin that is influenced by a large number of other risk factors, such as smoking, dietary habits, diabetes, and physical inactivity. A retrospective mortality study of 223 viscose rayon workers employed for more than 10 years and who were exposed to carbon disulfide levels above 20 ppm (62 mg/cu.m) revealed a statistically significant increase (2.5-fold) in cardiovascular mortality, as compared with 174 controls from the same factory (Tiller et al., 1968). Over the 30-year study period, 42% of all deaths in rayon process workers were attributed to coronary heart disease; the proportion was 24% for other rayon workers and 17% for other local males used as controls. The excess mortality was more pronounced in the 1940s and declined towards 1960, indicating a strong dependence on the intensity of exposure, which had decreased during this interval. The same study demonstrated that the death rate from coronary heart disease was proportionally higher among workers engaged in the viscose spinning process than in other workers. Nonexposed workers also had a significantly higher death rate than expected for coronary heart disease, as did controls not employed in the viscose industry; these factors limit the value of this study. Other limitations include an inappropriately selected control group, failure to control for other coronary heart disease risk factors, such as smoking, dietary habits, physical inactivity, and obesity and failure to monitor blood pressure and blood lipid levels. In addition, there may have been concomitant exposures to other chemicals in these industrial environments. A prospective mortality study at a Finnish plant from 1967-1977 revealed a similar excess of deaths (2.5-fold) due to coronary heart disease (Tolonen et al., 1979). Two cohorts were followed over a 10-year period; 343 viscose rayon workers exposed to carbon disulfide were individually matched with workers from a local paper mill. There was no significant difference between the exposed and control groups with regard to smoking habits, physical activity, obesity, or drug treatment. Atmospheric carbon disulfide concentrations were 10-30 ppm during the 1960s, 20-60 ppm during the 1950s, and higher in earlier time periods. The increase in deaths due to coronary heart disease was 29 in the exposed group versus 11 in the control group. Periodic health surveys during the study revealed increased incidence of angina and increased blood pressure, as compared with a well-matched control group. The incidence of deaths from coronary heart disease appeared to be much greater during the first 5 years, as reported in interim results of the same cohorts, but the numbers were too small to support any conclusions (Hernberg et al., 1970). Among men who had been exposed to carbon disulfide for 5 or more years between 1942 and 1967, the incidence of angina in the exposed workers was 25%, as compared with 13% in controls, and a significant increase in blood pressure was seen (Hernberg et al., 1973, 1976; Tolonen et al., 1975). Nonfatal first cardiac infarctions were more frequent in the exposed group (11) than in the control group (4). The relative risk of a fatal myocardial infarction was 4.8 times greater among those exposed to carbon disulfide; 16/343 men died of coronary heart disease within the 5-year period, in comparison to 3/343 men in the control group (p < 0.007) (Hernberg et al., 1973; Tolonen et al., 1975). In a subsequent study, the original relative-risk estimates were adjusted for potential confounding effects of hypertension and aging. After these adjustments, carbon disulfide exposure yielded a relative risk of 2.3 for coronary disease mortality (Nurminen et al., 1982). Thus, although the prognosis of exposed workers improved with improved occupational hygienic standards and with a reduction in the length of exposure over a lifetime, there is apparently some increased risk attributable to carbon disulfide exposure in this cohort. However, there were no adjustments for possible concomitant exposures to other chemicals. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Confidence in the principal study (Johnson et al., 1983) is medium. The study is well designed and conducted, uses adequate numbers of subjects, and is well supported by other occupational studies examining the same effect; however, considerable uncertainty exists regarding the exposure histories of the cohorts examined. A considerable number of well-conducted occupational studies have defined the effects of carbon disulfide in humans; however, a significant question remains regarding the possibility of developmental effects in humans. Confidence in the data base, therefore, is medium. Accordingly, confidence in the RfC is medium. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. This assessment was peer reviewed by external scientists. This review was completed on 05/22/1995. Their comments have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of these comments is included in the IRIS documentation files. Other EPA Documentation -- U.S. EPA, 1986 Agency Work Group Review -- 01/19/1989, 02/16/1989, 03/21/1989, 08/15/1991, 12/11/1991, 05/10/1995 Verification Date -- 05/10/1995 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Carbon disulfide conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Carbon disulfide CASRN -- 75-15-0 NOCA: Not available at this time. ============================================================================ UDSO: 199508 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Carbon disulfide CASRN -- 75-15-0 Last Revised -- 08/01/1995 SORD: __VI.A. ORAL RfD REFERENCES Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeir. 1981. Testing of selected workplace chemicals for teratogenic potential. Scand. J. Work Environ. Health. 7(Suppl. 4): 66-75. Johnson, B.L., J. Boyd, J.R. Burg, S.T. Lee, C. Xintaras and B.E. Albright. 1983. Effects on the peripheral nervous system of workers' exposure to carbon disulfide. Neurotoxicology. 4(1): 53-66. Jones-Price, C., R.W. Tyl, M.C. Marr and C.A. Kimmel. 1984a. Teratologic Evaluation of Carbon Disulfide (CAS No. 75-15-0) Administered to CD Rats on Gestational Days 6 through 15. National Center for Toxicological Research, Jefferson AR. Govt. Reports Announcements and Index, Issue 15. NTIS PB 84-192343. Jones-Price, C., R.W. Tyl, M.C. Marr and C.A. Kimmel. 1984b. Teratologic Evaluation of Carbon Disulfide (CAS No. 75-15-0) Administered to New Zealand White Rabbits on Gestational Days 6 through 15. National Center for Toxicological Research, Jefferson AR. Govt. Reports Announcements and Index, Issue 15. NTIS PB 84-192350. Tabacova, S., B. Nikiforov and L. Balabaeva. 1983. Carbon disulphide intrauterine sensitization. J. Appl. Toxicol. 3(5): 223-229. U.S. EPA. 1986. Health and Environmental Effects Profile on Carbon Disulfide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Aaserud, O., L. Gjerstad, P. Nakstad, et al. 1988. Neurological examination, computerized tomography, cerebral blood flow, and neuropsychological examination in workers with long-term exposure to carbon disulfide. Toxicology. 49: 277-82. Aaserud, O., O.J. Hommeren, B. Tvedt, et al. 1990. Carbon disulfide exposure and neurotoxic sequelae among viscose rayon workers. Am. J. Indust. Med. 18: 25-37. Beliles, R.P., D.J. Brusick and F.J. Mecler. 1980. Teratogenic-mutagenic risk of workplace contaminants: Trichloroethylene, perchloroethylene, and carbon disulfide. Litton Bionetics report to NIOSH. PB82-185075. CIIT (Chemical Industry Institute of Toxicology). 1983. 90-Day Vapor Inhalation Toxicity Study of Hydrogen Sulfide in B6C3F1 Mice with cover letter dated 07/26/1983. Office of Toxic Substances, U.S. EPA, Washington, DC. FYI-OTS-0883-0255. Microfiche No. 0255. Cirla, A.M. and C. Graziano. 1981. Health impairment in viscose-rayon workers with carbon disulfide risk below 30 mg/cu.m. An exposed-controls study. G. Ital. Med. Lav. 3: 69-73. Cirla, A.M., P.A. Bertazzi, M. Tomasini, et al. 1978. Study of endocrinological functions and sexual behavior in carbon disulfide workers. Med. Lavoro. 69(2): 118-129. Clerici, W.J. and L.D. Fechter. 1991. Effects of chronic carbon disulfide inhalation on sensory and motor function in the rat. Neurotoxicol. Teratol. 13: 249-255. Colombi, A., M. Maroni, O. Picchi, E. Rota, P. Castano and V. Foa. 1981. Carbon disulfide neuropathy in rats. A morphological and ultrastructural study of degeneration and regeneration. Clin. Toxicol. 18(12): 1463-74. Corsi, G., P. Maestrelli, G. Picotti, S. Manzoni and P. Negrin. 1983. Chronic peripheral neuropathy in workers with previous exposure to carbon disulfide. Br. J. Ind. Med. 40: 209-211. Fajen, J., B. Albright and S. Leffingwell. 1981. A cross-sectional medical and industrial hygiene survey of workers exposed to carbon disulfide. Scand. J. Work Environ. Health. 7(Suppl. 4): 20-27. Gilioli, R., C. Bulgheroni, P.A. Bertazzi, et al. 1978. Study of neurological and neurophysiological impairment in carbon disulfide workers. Med. Lavoro. 69(2): 130-143. Gottfried, M.R., D.G. Graham, M. Morgan, et al. 1985. The morphology of carbon disulfide neurotoxicity. Neurotoxicology. 6(4): 89-96. Graham, D. 1995. Duke University Medical Center, Durham, NC. Peer-review comments on inhalation reference concentration for carbon disulfide. Letter to D. Guth, National Center for Environmental Assessment, Research Triangle Park, NC. May 1, 1995. Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier. 1981. Testing of selected workplace chemicals for teratogenic potential. Scand. J. Work. Environ. Health. Suppl. 4: 66-75. Hernberg, S., T. Partanen, C-H. Nordman, et al. 1970. Coronary heart disease among workers exposed to carbon disulphide. Br. J. Ind. Med. 17: 313-325. Hernberg, S., M. Nurminen and M. Tolonen. 1973. Excess mortality from coronary heart disease in viscose rayon workers exposed to carbon disulfide. Work Environ. Health. 10(2): 93-99. Hernberg, S., M. Tolonen and M. Nurminen. 1976. Eight-year follow-up of viscose rayon workers exposed to carbon disulfide. Scand. J. Work Environ. Health. 2: 27-30. Hirata, M., K. Sugimoto, J. Misum, et al. 1984. A neurophysiological study among Chinese CS2 exposed workers. G. Ital. Med. Lav. 6: 107-111. ICF Kaiser, Inc. 1990a. THC: A computer program to compute a reference dose from continuous animal toxicity data using the benchmark dose method. K.S. Crump Division, Reston, LA. ICF Kaiser, Inc. 1990b. THWC: A computer program to compute a reference dose from continuous animal toxicity data using the benchmark dose method. K.S. Crump Division, Reston, LA. Johnson, B.L., J. Boyd, J.R. Burg, S.T. Lee, C. Xintaras and B.E. Albright. 1983. Effects on the peripheral nervous system of workers' exposure to carbon disulfide. Neurotoxicology. 4(1): 53-66. NIOSH (National Institute for Occupational Safety and Health). 1977. Criteria for a recommended standard: Occupational exposure to carbon disulfide. NIOSH, U.S. Department of Health and Human Services, Cincinnati, OH. NIOSH (National Institute for Occupational Safety and Health). 1984. Health Effects of Occupational Exposure to Carbon Disulfide. NIOSH, U.S. Department of Health and Human Services, Cincinnati, OH. NTIS PB85-110229. Nurminen, M. and S. Hernberg. 1985. Effects of intervention on the cardiovascular mortality of workers exposed to carbon disulphide: A 15-year follow-up. Br. J. Ind. Med. 42: 32-35. Nurminen, M., P. Mutanen, M. Tolonen and S. Hernberg. 1982. Quantitated effects of carbon disulfide exposure, elevated blood pressure, and aging on coronary mortality. Am. J. Epidemiol. 115(1): 107-18. PAI (Pathology Associates, Inc.). 1991. Developmental inhalation toxicity study of carbon disulfide in the New Zealand white rabbit. PAI, 15 Worman's Mill Court, Suite 1, Frederick, MD 21701. Price, B. and T. Berner. 1995. A benchmark dose for carbon disulfide: Analysis of nerve conduction velocity measurements from the NIOSH exposure database. Report to the Chemical Manufacturers Association, Carbon Disulfide Panel. Putz-Anderson, V., B.E. Albright, S.T. Lee, et al. 1983. A behavioral examination of workers exposed to carbon disulfide. Neurotoxicology. 4(1): 67-78. Rebert, C.S. and E. Becker. 1986. Effects of inhaled carbon disulfide on sensory-evoked potentials of Long-Evans rats. Neuro. Toxicol. Teratol. 8: 533-541. Ruijten, M.W.M.M., H.J.A. Salle, M.M. Verlseck and H. Muijser. 1990. Special nerve functions and color discrimination in workers with long-term exposure to carbon disulfide. Br. J. Ind. Med. 47: 589-595. Saillenfait, A.M., P. Bonnet and J. deCeaurriz. 1989. Effects of inhalation exposure to carbon disulfide and its combination with hydrogen sulfide on embryonal and fetal development in rats. Toxicol. Lett. 48: 57-66. Seppalainen, A.M. and M. Tolonen. 1974. Neurotoxicity of long-term exposure to carbon disulfide in the viscose rayon industry. A neurophysiological study. Work Environ. Health. 11: 145-153. Setzer, W.R. 1995. Carbon disulfide Benchmark Dose analysis. Memorandum from R. Woodrow Setzer, National Health and Environmental Research Laboratory, to Dan Guth, National Center for Environmental Assessment-RTP, June 1, 1995. Sugimoto, K., Y. Seki, S. Goto, et al. 1981. An occupational hygiene survey in a Chinese viscose rayon factory. Proceedings of the 10th Asian Conference on Occupational Health. Sugimoto, K., Y. Seki, S. Goto, et al. 1984. An epidemiological study on carbon disulfide angiopathy in a Chinese viscose rayon factory. Int. Arch. Occup. Environ. Health. 54: 127-34. Tabacova, S. 1989. Institute for Hygiene and Occupational Health, Sofia 1431, Bulgaria. Personal correspondence to H. Zenick, U.S. EPA, Washington, DC. September 12, 1989. Tabacova, S. and L. Balabaeva. 1980. Subtle consequences of prenatal exposure to low carbon disulphide levels. Arch. Toxicol., Suppl. 4: 252-254. Tabacova, S. and L. Hinkova. 1979. Neurotoxicological screening of early effects of prenatal carbon disulfide exposure. Activ. Nerv. Sup. (Praha) 21: 268-269. Tabacova, S., L. Hinkova and L. Balabaeva. 1978. Carbon disulphide teratogenicity and postnatal effects in rat. Toxicol. Letters. 2: 129-133. Tabacova, S., B. Nikoforov and L. Balabaeva. 1983. Carbon disulphide intrauterine sensitization. J. Appl. Toxicol. 3(5): 223-239. Tiller, J.R., R.S.F. Schilling and J.N. Morris. 1968. Occupational toxic factor in mortality from coronary heart disease. Br. Med. J. 4: 407-11. Tolonen, M., S. Hernberg, M. Nurminen and K. Tiitola. 1975. A follow-up study of coronary heart disease in viscose rayon workers exposed to carbon disulphide. Br. J. Indust. Med. 32: 1-10. Tolonen, M., M. Nurminen, and S. Hernberg. 1979. Ten-year coronary mortality of workers exposed to carbon disulfide. Scand. J. Work Environ. Health. 5: 109-14. U.S. EPA. 1986. Health and Environmental Effects Profile for Carbon Disulfide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. (Final draft) Vasilescu, C. 1972. Motor nerve conduction velocity and electromyogram in carbon disulphide poisoning. Rev. Boum. Neurol. 9(2): 63-71. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Carbon disulfide CASRN -- 75-15-0 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 02/01/1989 I.A. Oral RfD summary noted as pending change 09/01/1990 I.A.2. Price et al., 1984 corrected to Jones-Price et al., 1984 09/01/1990 IV.F.1. EPA contact changed 09/01/1990 VI. Bibliography on-line 09/01/1991 I.B. Inhalation RfC now under review 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 06/01/1995 I.B. Work group review date added 08/01/1995 I.B. Inhalation RfC summary on-line 08/01/1995 VI.B. Inhalation RfC references on-line 08/01/1995 I.A. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., I.B.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 393 of 1119 in IRIS (through 2003/06) AN: 222 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199201 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Dibromochloromethane- SY: 124-48-1; CHLORODIBROMOMETHANE-; DIBROMOMONOCHLOROMETHANE-; METHANE,-DIBROMOCHLORO-; MONOCHLORODIBROMOMETHANE- RN: 124-48-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199103 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Dibromochloromethane CASRN -- 124-48-1 Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Hepatic lesions NOEL: 30 mg/kg/day 1000 1 2E-2 (converted to 21.4 mg/kg/day Rat, Subchronic mg/kg/day) Gavage Bioassay LOAEL: 60 mg/kg/day NTP, 1985 (converted to 42.9 mg/kg/day) ---------------------------------------------------------------------------- *Conversion Factors: Dose adjusted for gavage schedule (5\days/week). PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis Studies of Chlorodibromomethane in F344/N Rats and B6C3F1 mice (gavage studies). NTP TR282. Groups of 10 F344/N rats of each sex and 10 B6C3F1 mice of each sex were administered 0, 15, 30, 60, 125, or 250 mg DBCM/kg/day by gavage for 5\days/week for 13 weeks. At 250 mg/kg/day, male mice showed increased incidence of vacuolar change (fatty metamorphosis) in the liver and toxic nephrosis. Both sexes of rats showed increased incidences of liver vacuolar change, centrilobular necrosis, toxic nephropathy, and salivary gland inflammation and squamous metaplasia at 250 mg/kg/day. Vacuolar changes in the livers of lower-dose male rats were also increased. A Fisher Exact test showed that incidences of these liver lesions at doses of 60 mg/kg/day or above were elevated relative to the vehicle controls, thus 30 mg/kg/day is the NOEL. In the chronic bioassay portion of the NTP (1985) study, 50 F344/N rats of each sex were administered 0, 40, or 80 mg DBCM/kg/day by gavage for 104 weeks and 50 B6C3F1 mice of each sex were similarly treated with 0, 50, or 100 mg DBCM/kg/day for 105 weeks. Treatment was 5 days/week. A dose-related increase in liver fatty changes and ground glass cytoplasmic changes in treated rats of both sexes was reported. Treated female rats also had higher incidences of kidney nephrosis. Treated mice of both sexes exhibited higher incidences of hepatomegaly, fatty metamorphosis, calcification, and liver necrosis. The incidence of nephrosis was increased in dosed males and thyroid follicular cell hyperplasia was increased in dosed female mice. The LOAELS for this portion of the study are 40 mg/kg/day for rats and 50 mg/kg/day for mice. The results in these chronic bioassays support the subchronic studies used as a basis of the RfD. In this case, the choice of the subchronic NOAEL as the basis of the RfD rather than the chronic LOAEL (either choice normally requires a 1000 UF, and the resulting RfDs are similar), reflects the slightly greater confidence in the subchronic NOAEL versus the chronic LOAEL that was associated with several adverse effects. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- Factors of 10 each were employed for use of a subchronic assay, for extrapolation from animal data, and for protection of sensitive human subpopulations. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) No adequate data on the teratogenic or reproductive effects of trihalomethanes are available. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The NTP (1985) subchronic bioassays utilized adequate numbers of animals of both sexes of two species; multiple endpoints were measured, including complete histopathology; thus confidence in the chosen study is medium. NTP also published supporting chronic studies of dibromochloromethane, but without adequate reproductive or teratology bioassays, the data base is given medium confidence. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1985 The 1985 Drinking Water Criteria Document for Trihalomethanes is currently undergoing Agency review. Other EPA Documentation -- None Agency Work Group Review -- 12/02/1985, 02/05/1986, 05/14/1986, 08/13/1987 Verification Date -- 08/13/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Dibromochloromethane conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Dibromochloromethane CASRN -- 124-48-1 NORC: Not available at this time. ============================================================================ UDCA: 199201 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Dibromochloromethane CASRN -- 124-48-1 Last Revised -- 01/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Based on inadequate human data and limited evidence of carcinogenicity in animals; namely, positive carcinogenic evidence in B6C3Fl mice (males and females), together with positive mutagenicity data, and structural similarity to other trihalomethanes, which are known animal carcinogens. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. There are no epidemiologic studies of dibromochloromethane alone. Dibromochloromethane is one of several trihalomethanes (including chloroform, bromodichloromethane, and bromoform) which are formed from the interaction of chlorine with the organic materials found in water. Several ecologic studies (Cantor et al., 1978; Aldrich and Peoples, 1982; Isacson et al., 1983) and case-control studies (Young and Kanarek, 1983; Cantor et al., 1987) suggest a positive correlation between drinking chlorinated water and the incidence of several human cancers, particularly bladder, rectal and colon cancer. Although both types of studies have design limitations, which might include lack of individual information; misclassification of exposure; or no controls for diet, smoking, or alcohol consumption, the agreement of findings in several independent studies strengthens the association between drinking chlorinated water and cancer (Cantor, 1983; Crump, 1983; Crump and Guess, 1982). In all studies, the cases were exposed to a mixture of compounds, including chloroform, which is considered to be a probable human carcinogen. The data collected are inadequate for assessing the carcinogenic potential of dibromochloromethane. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. In a 2-year carcinogenicity study, 50 F344/N rats/sex/dose were treated by gavage with dibromochloromethane (>98% pure) in corn oil at 0, 40, or 80 mg/kg, 5 days/week for 104 weeks (NTP, 1985). Groups of B6C3F1 mice (50/sex/dose) were similarly gavaged at doses of 0, 50, or 100 mg/kg, 5 days/week for 105 weeks. In rats, the final survival rates of all groups were comparable (approximately 76%); mean body weights were also comparable between dose groups in each sex, except for a decrease in the high-dose males after week 20. No compound-related clinical signs were seen, and no evidence for carcinogenicity was seen in rats under these study conditions. In mice, the mean body weights of both male and female high-dose groups were lower than those of their respective controls throughout the study. Mean body weight of the low-dose male mice was lower than the control group after both low-dose groups received an overdose of chemical in week 58. Survival of low- and high-dose males was significantly lower than the control group; the percent survival was 88, 14, and 58% in the control, low-, and high-dose groups, respectively (70% of the low-dose males were accidentally killed). The survival rate in females was comparable for all groups (approximately 63%). In female mice, the incidence of hepatocellular adenomas and the combined incidence of hepatocellular adenomas and carcinomas were statistically significantly increased in the high-dose group. The incidence of adenomas was 2/50, 4/49, and 11/50; the incidence of carcinomas was 4/45, 6/49, and 8/50; and the combined incidence was 6/50, 10/49, and 19/50 for female mice in the 0, 50, and 100 mg/kg dose groups, respectively. In high-dose male mice, there was a significantly increased incidence of hepatocellular carcinomas; however, the combined incidence of hepatocellular adenomas and carcinomas was only marginally increased. The incidence of adenomas was 14/50, 5/50, and 10/50; the incidence of carcinomas was 10/50, 9/50, and 19/50; and the combined incidence of adenomas and carcinomas was 23/50, 14/50, and 27/50 for the 0, 50, and 100 mg/kg dose groups, respectively. Under the conditions of this study, NTP (1985) determined that there was equivocal evidence of carcinogenicity of dibromochloromethane in male mice, and some evidence of carcinogenicity in female mice. Voronin et al. (1987) observed no significant tumor increases in groups of 50 CBAxC57B1/6 mice/sex treated with dibromochloromethane in the drinking water at concentrations of 0, 0.04, 4.0, or 400 mg/L (0, 0.008, 0.76, or 76 mg/kg/day) for 104 weeks. Preliminary results of an unpublished 2-year dietary study using groups of 40 SPF Wistar rats reported no increase in gross tumors in male rats treated with dibromochloromethane at doses of 10, 39, or 210 mg/kg/day, or in female rats treated at doses of 17, 66, or 350 mg/kg/day. Control groups consisted of 70 rats/sex. Only 5 or 7 rats/sex/dose group were examined following 18 or 24 months of exposure (Tobe et al., 1982). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Dibromochloromethane has been shown to produce reverse mutations in Salmonella typhimurium strain TA100 in a vapor-phase test performed in a desiccator (Simmon et al., 1977). Results were not positive when plate incorporation (Simmon et al., 1977) or preincubation (NTP, 1985; Zeiger et al., 1987) methods were used. Nestmann and Lee (1985) reported positive results for gene conversion in Saccharomyces cerevisiae strain D4 without, but not with, hepatic homogenates, and negative results for mutation in strain XV185-14C both with and without hepatic homogenates. Dibromochloromethane produces sister chromatid exchange in cultured human lymphocytes and in bone marrow cells of mice treated orally (Morimoto and Koizumi, 1983). Dibromochloromethane is structurally similar to known animal carcinogens such as bromodichloromethane, bromoform, and chloroform (B2, probable human carcinogens). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 8.4E-2 per (mg/kg)/day Drinking Water Unit Risk -- 2.4E-6 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 4E+1 ug/L E-5 (1 in 100,000) 4E+0 ug/L E-6 (1 in 1,000,000) 4E-1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- hepatocellular adenoma or carcinoma Test Animals -- mouse/B6C3F1, female Route -- gavage Reference -- NTP, 1985 Administered Human Equivalent Tumor Dose (mg/kg)/day Dose (mg/kg)/day Incidence ---------------- ---------------- --------- 0 0 6/50 50 35.71 10/49 100 71.43 19/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The unit risk should not be used if the water concentration exceeds 4E-3 mg/L, since above this concentration the slope factor may differ from that stated. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) An adequate number of animals of both sexes were treated for an adequate duration of exposure at two dose levels. Comprehensive histopathological and statistical analyses were performed. The compound was given by gavage rather than in feed or drinking water; exposure to a chemical through oral gavage is different from exposure through drinking water. Exposure could be overestimated leading to an underestimate of potency. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1988 The 1988 Health and Environmental Effects Document for Dibromochloromethane is an external draft for review purposes. It has received OHEA review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/07/1989 Verification Date -- 09/07/1989 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Dibromochloromethane conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199011 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Dibromochloromethane CASRN -- 124-48-1 Last Revised -- 11/01/1990 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1985. Toxicology and Carcinogenesis Studies of Chlorodibromomethane in F344/N Rats and B6C3F1 mice (gavage studies). NTP TR282. U.S. EPA. 1985. Drinking Water Criteria Document for Trihalomethanes. Office of Drinking Water, Washington, DC. External Review Draft. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Aldrich, T.E. and A.J. Peoples. 1982. Malignant melanoma and drinking water contamination. Bull. Environ. Contam. Toxicol. 28(5): 519-523. Cantor, K.P. 1983. Epidemiologic studies of chlorination by-products in drinking water: An overview. In: Water Chlorination, Environmental Impact and Health Effects, Vol. 4, Part 2. Environment, Health and Risk, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed. Proceed. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. p. 1381-1398. Cantor, K.P., R. Hoover, T.J. Masso and L.J. McCabe. 1978. Associations of cancer mortality with halomethanes in drinking water. J. Natl. Cancer Inst. 61: 979-985. Cantor K.P., R. Hoover, P. Hartge et al. 1987. Bladder cancer, drinking water source, and tap water consumption: A case-control study. J. Natl. Cancer Inst. 79(6): 1269-1279. Crump, K.S. 1983. Chlorinated drinking water and cancer: The strength of the epidemiologic evidence. In: Water Chlorination, Environmental Impact and Health Effects, Vol. 4, Part 2. Environment, Health and Risk, R.L. Jolley, W.A. Brungs, J.A. Cotruvo, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed. Proceed. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. p. 1481-1491. Crump, K.S. and H.A. Guess. 1982. Cancer: Review of recent epidemiological findings and assessment of risks. Ann. Rev. Public Health. 3: 339-357. Isacson, P., J.A. Bean and C. Lynch. 1983. Relationship of cancer incidence rates in Iowa USA municipalities to chlorination status of drinking water. In: Water Chlorination, Environmental Impact and Health Effects, Vol. 4, Part 2. Environment, Health and Risk, R.L. Jolley, W.A. Brungs, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed. Proceed. 4th Conference, Pacific Grove, CA. October 18-23. Ann Arbor Science Publ., Inc., Ann Arbor, MI. p. 1353-1364. Morimoto, K. and A. Koizumi. 1983. Trihalomethanes induce sister chromatid exchanges in human lymphocytes in vitro and mouse bone marrow cells in vivo. Environ. Res. 32(1): 72-79. Nestmann, E.R. and E.G.H. Lee. 1985. Genetic activity in Saccharomyces cerevisiae of compounds found in effluents of pulp and paper mills. Mutat. Res. 155(1-2): 53-60. NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of chlorodibromomethane (CAS No. 124-48-1) in F344/N rats and B6C3F1 mice (gavage studies). NTP Tech. Report Series No. 282. NTIS PB 86-166675. Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. Dev. Toxicol. Environ. Sci. 2: 249-258. Tobe, M., Y. Suzuki, K. Aida et al. 1982. Studies on the chronic oral toxicity of tribromomethane, dibromochloromethane and bromodichloromethane. Unpublished intraagency report to the National Institute of Hygienic Sciences. Tokyo Medical and Dental University, Tokyo, Japan. p. 8-43. U.S. EPA. 1988. Health and Environmental Effects Document for Dibromochloromethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. ECAO-CIN-GO40. Voronin, V.M., A.I. Donchenko and A.A. Korolev. 1987. An experimental study of the carcinogenicity of dichlorobromomethane and dibromochloromethane released during the water chlorination process. Gig. Sanit. 0(1): 19-21. Young, T.B. and M.S. Kanarek. 1983. Matched pair case control study of drinking water chlorination and cancer mortality. In: Water Chlorination, Environmental Impact and Heath Effects, Vol. 4, Part 2. Environment Health and Risk, R.L. Jolley, W.A. Brungs, R.B. Cumming, J.S. Mattice and V.A. Jacobs, Ed. Proceed. 4th Conference, Pacific Grove, CA, October 18-23. Ann Arbor Science Publ., Ann Arbor, MI. p. 1365-1380. Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Mortelmans and W. Speck. 1987. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ. Mutagen. 9(Suppl. 9): 1-4, 12-18, 20, 43. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Dibromochloromethane CASRN -- 124-48-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 06/30/1988 I.A.7. Primary contact changed 08/01/1989 VI. Bibliography on-line 10/01/1989 II. Carcinogen assessment now under review 11/01/1990 I.A. Text edited 11/01/1990 II. Carcinogen assessment on-line 11/01/1990 IV.F.1. EPA contact changed 11/01/1990 VI.C. Carcinogen references added 03/01/1991 I.A.7. Primary contact changed 08/01/1991 II.B.1. Concentration levels corrected 01/01/1992 II.B.2. Doses: Add transformed animal; human equivalent change 01/01/1992 II.B.4. Last sentence of paragraph added 01/01/1992 IV. Regulatory actions updated 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added. 02/05/2003 I.A., I.B., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 394 of 1119 in IRIS (through 2003/06) AN: 224 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0224-tr.pdf UD: 200005 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,3-Dichloropropene- (DCP) SY: 542-75-6; 3-CHLOROALLYL-CHLORIDE-; ALPHA-CHLOROALLYL-CHLORIDE-; GAMMA-CHLOROALLYL-CHLORIDE-; 3-CHLOROPROPENYL-CHLORIDE-; DCP-; DICHLOROPROPENE-; 1,3-DICHLOROPROPENE-1-; 1,3-DICHLOROPROPENE-; 1,3-DICHLORO-2-PROPENE-; DICHLOROPROPENE,-1,3-; 1,3-DICHLOROPROPYLENE-; ALPHA,GAMMA-DICHLOROPROPYLENE-; NCI-C03985-; PROPENE,-1,3-DICHLORO-; RCRA-WASTE-NUMBER-U084-; TELONE-II- RN: 542-75-6 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200005 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,3-Dichloropropene (DCP) CASRN -- 542-75-6 Last Revised -- 05/25/2000 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Benchmark Doses UF MF RfD --------------------------------------- ------ ---- ------- Chronic irritation BMDL10: 3.4 mg/kg/day 100 1 3E-2 mg/kg/day Rat chronic BMD10: 5.1 mg/kg/day feeding study (Stott et al., 1995) ---------------------------------------------------------------------------- NOTES: BMDL10 - 95% lower confidence limit on the maximum likelihood estimate of the dose corresponding to 10% risk. BMD10 - Maximum likelihood estimate of the dose corresponding to 10% risk. NOTE: The current RfD for 1,3-dichloropropene is a revision of the value placed on-line on 10/01/1990. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) There are no chronic human studies suitable for dose-response assessment. Chronic feeding studies in rats (Stott et al., 1995) and mice (Redmond et al., 1995) and chronic gavage studies (NTP, 1985)using both species are available. The feeding studies are favored over the gavage studies because the route of administration is more relevant to human exposure. The gavage studies (NTP, 1985) were previously rejected by EPA for RfD development (IRIS, online 10/01/90) because the dosing regimen (high doses by gavage three times/week) was not well designed to study chronic toxicity. Another problem with the gavage study (NTP, 1985) is that the dichloropropene formulation contained epichlorohydrin, which NTP acknowledged as a possible contributor to tumorigenic effects in the forestomach. Of the two feeding studies available, the rat study of Stott et al. (1995) is the most appropriate choice of a principal study for derivation of toxicity values for nonneoplastic effects. The dosing in the mouse dietary study by Redmond et al. (1995) is uncertain owing to the lack of cancer (urinary bladder tumors) and noncancer effects (urinary bladder hyperplasia, forestomach hyperplasia, and hydronephrosis) observed in the mouse gavage study (NTP, 1985). Stott, WT; Johnson, KA; Jeffries, TK; et al. (1995) Telone II soil fumigant: two-year chronic toxicity/oncogenicity study in Fischer 344 rats. The Dow Chemical Company. Midland, Michigan. Study # M-003993-0311. Stott et al. (1995) fed male and female Fischer 344 rats (50/sex/dose) a microencapsulated formulation of Telone II (96% 1,3-dichloropropene) in the diet at doses of 0, 2.5, 12.5, or 25 mg/kg/day for 24 months. Satellite groups of rats (10/sex/dose) were administered Telone II for 12 months. Standard bioassay data including body weights, food consumption, clinical chemistry, hematology, urine analysis, organ weights, pathology, and histopathology were collected. Body weights were decreased in a dose-dependent manner in treated animals. Decreases were statistically and toxicologically significant in both sexes at 25 mg/kg/day. Average organ weight changes in males and females were associated with decreased body weight. The only histopathology observed was in the forestomach, which exhibited a mild basal cell hyperplasia of the mucosal lining. The incidence of forestomach lesions was statistically increased in both sexes at 12.5 mg/kg/day and higher. There were no indications of basal cell hyperplasia at 2.5 mg/kg. Incidences were 3/100, 4/100, 40/100, and 67/100 for control, 2.5, 12.5, and 25 mg/kg groups, respectively. The forestomach hyperplasia is believed to be a manifestation of chronic irritation, which is consistent with the observation of primary dermal irritation (Nater and Gooskens, 1976) and other portal-of-entry effects from 1,3-dichloropropene exposure (Haut et al., 1996; Breslin et al., 1989; Lomax et al., 1989; Linnett et al., 1988; Stott et al., 1988). Of the two critical effects, body weight decrease and chronic irritation (as evidenced by the forestomach hyperplasia), data from the most sensitive effect, chronic irritation, were used to develop the RfD. Redmond, JM; Stebbins, KE; Stott, WT. (1995) Telone II soil fumigant: two-year dietary chronic toxicity/oncogenicity study in B6C3F1 mice - final report. Dow Chemical Company, Midland, MI. Study # M-003993-032. Male and female B6C3F1 mice (50/sex/dose) were administered a microencapsulated formulation of Telone II (96% 1,3-dichloropropene) in the diet at doses of 0, 2.5, 25, or 50 mg/kg/day for 24 months. Satellite groups of mice (10/sex/dose) were administered Telone II for 12 months. Standard bioassay data including body weights, food consumption, clinical chemistry, hematology, urine analysis, organ weights, pathology, and histopathology were collected. Mean body weights were significantly and toxicologically decreased in a dose-dependent manner in male mice at 25 and 50 mg/kg/day. Changes in mean organ weights were considered to be secondary to decreased body weights. No consistent treatment-related changes in hematologic, clinical chemistry, and urine analysis parameters were observed in any of the treated groups. Treatment-related pathology and histopathology were not observed in any treated groups. Although the dosing in this study is suspected to be insufficient, the decrease in body weight in mice supports the same finding in Stott et al. (1995) because it was observed in rats at the same dose. The lack of other significant effects in Redmond et al. (1995) supports the use of Stott et al. (1995) as the principal study because chronic irritation was observed at a lower dose than decreased body weight. Haut, KT; Stebbins, KE; Johnson, KA; et al. (1996) Subchronic toxicity of ingested 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 32:224-232. Male and female F344 rats and B6C3F1 mice (10/sex/group) were given 0, 5, 15, 50, or 100 mg/kg/day (rats) or 0, 15, 50, 100, or 175 mg/kg/day (mice) microencapsulated Telone II (96% 1,3-dichloropropene) in their diets for 13 weeks. Satellite groups of rats (10/sex/group) from 0 and 100 mg/kg/day groups were retained for observation for 4 weeks following treatment in order to examine recovery. Food consumption in rats was consistently decreased for 100 mg/kg/day male and female rats and occasionally depressed at lower doses relative to control values. Food consumption in mice was generally unchanged and only occasionally depressed at the higher doses relative to controls. A dose-related, statistically significant decrease in body weight was observed in male rats at 15 mg/kg/day and higher, in female rats at 50 mg/kg/day and higher, and in male and female mice at all doses. Changes in mean organ weights were consistent with decreases in body weight and were not considered toxicologically significant. At necropsy, no gross pathology was observed in treated animals. Mild basal cell hyperplasia and a slight prominence of mononuclear cells in the basement membrane of the forestomach, reflections of the irritant effect of 1,3-dichloropropene, were noted in all treated male and female rats at 50 mg/kg/day and higher. After 4 weeks of recovery, animals in the 100 mg/kg/day group (the only treated group continued through recovery) exhibited basal cell hyperplasia; however, the severity and incidence were diminished compared with that observed immediately following cessation of treatment. In mice, the only noted histopathological change was a decrease in vacuolation of tubular epithelial cells of the kidney in males at 175 mg/kg/day, the highest dose. Haut et al. (1996) supports the findings of Stott et al. (1995) by providing additional evidence of decreased body weight and chronic irritation (i.e., forestomach lesions) in response to dietary 1,3-dichloropropene. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100. The default uncertainty factor of 10 for interspecies extrapolation is applied because there are no data on the relative sensitivity of rats and humans to stomach irritation. Because there are no data documenting the nature and extent of variability in human susceptibilities to 1,3-dichloropropene, the default uncertainty factor of 10 is used for within-species variation. The database for 1,3-dichloropropene is substantial and includes studies of genotoxicity, mode of action, pharmacokinetics, reproductive and developmental toxicity, systemic toxicity, and cancer. Therefore, no additional uncertainty factors are needed. MF = None ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) The only repeated-exposure human toxicity data for 1,3-dichloropropene are case studies showing that dermatitis occurred as a result of direct contact (Bousema et al., 1991; Nater and Gooskens, 1976). Accidental high-dose poisoning following chemical spills or accidental release has caused a dose- related range of acute neurotoxic symptoms, and accidental ingestion of 1,3-dichloropropene has been fatal (Hernandez et al., 1994). The toxicokinetics in humans are similar to those observed in rats. Inhalation studies with both humans and rats have shown that 1,3-dichloropropene is readily absorbed. Biotransformation of 1,3-dichloropropene leads largely to its detoxification and excretion. In rats and humans, the major metabolic pathway is glutathione conjugation to form mercapturic acid metabolites, which are rapidly excreted in the urine (Hutson et al., 1971; Climie et al., 1979; Dietz et al., 1984a,b; Osterloh et al., 1989; van Welie et al., 1991, Waechter et al., 1992). Half-lives for disappearance from the blood and for excretion of mercapturic acid metabolites are similar for rats and humans. Distribution studies in rats indicate that the forestomach, glandular stomach, kidney, and liver are primary organs of distribution for oral 1,3-dichloropropene (Dietz et al., 1984b). Climie et al. (1979) determined that a glutathione-dependent biotransformation is the major metabolic pathway of cis-1,3-dichloro[14C]propene. A hepatic glutathione S-transferase catalyzes the conjugation of 1,3-dichloropropene with glutathione. The conjugate is further metabolized to a mercapturic acid and is excreted in the urine as N-acetyl-(S-3-chloroprop-2-enyl)cysteine (3CNAC). No evidence of saturation of dichloropropene metabolism in rats at oral gavage doses of 50 mg/kg or less was observed by Dietz et al. (1984b). 1,3-Dichloropropene underwent substantial first-pass metabolism, following linear pharmacokinetics over an oral gavage dose range of 1-100 mg/kg for mice and 1-50 mg/kg for rats (Dietz et al., 1984b). Mutagenic epoxide metabolites, from a minor metabolic pathway, have been detected at lethal doses (Schneider et al., 1998) in mice. Animal studies show that 1,3-dichloropropene is unlikely to accumulate in the body (Hutson et al., 1971; Dietz et al., 1984a). Waechter et al. (1992) showed that the absorption of 1,3-dichloropropene from inhalation exposure of humans (72%-82%) was similar to absorption in rats 82%; Stott and Kastl, 1986). The same major urinary metabolite, 3CNAC, is produced in humans, rats, and mice, and urinary elimination half-lives, 4-6 hours, are similar (Waechter et al., 1992; Dietz et al., 1985; van Welie et al., 1991; Osterloh et al., 1989). Two biological monitoring studies in humans have demonstrated that there is a dose-dependent relationship between respiratory occupational exposure to 1,3-dichloropropene and excretion of 3CNAC (Van Welie et al., 1991; Osterloh et al., 1989). Van Welie et al. (1991), studying workers in the flower bulb industry, found that urinary excretion of 3CNAC followed first-order elimination kinetics following exposure. No toxicologically significant adverse effects were observed in a two- generation rat reproductive inhalation study (Breslin et al., 1989) or in developmental toxicity inhalation studies with rats and rabbits (Hanley et al., 1988). On the basis of similar toxicokinetics, the reproductive/developmental and systemic toxicity of ingested 1,3-dichloropropene is likely to be similar to that of inhaled 1,3-dichloropropene. Owing to the absence of animal studies examining the effect of 1,3-dichloropropene exposure on juvenile animals, the effects of 1,3-dichloropropene on children cannot be predicted. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=50. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Database -- High RfD -- High The overall confidence in this RfD assessment is high. The confidence in the principal study is high. The study was well designed and well conducted and followed standard guidelines for chronic bioassays. Results from a chronic ingestion study with mice (Redmond et al., 1995) and a subchronic ingestion study with rats and mice (Haut et al., 1996) are consistent with the findings in the 2-year rat bioassay. Chronic irritation, as evidenced by forestomach histopathology, and body weight decrease were the critical effects. The relevance of the chronic irritant effects in the forestomach to humans is supported by a case report of gastric mucosal erosion produced by a fatal accidental ingestion of an unknown quantity of 1,3-dichloropropene (Hernandez et al., 1994). In addition, the forestomach lesions are consistent with observations of other irritant effects produced by 1,3-dichloropropene at the portal of entry (Nater and Gooskens, 1976; Haut et al., 1996; Breslin et al., 1989; Lomax et al., 1989; Linnett et al., 1988; Stott et al., 1988). Studies on reproductive and developmental toxicity, toxicokinetics, inhalation toxicity, and genotoxicity support high confidence in the database. Although studies on reproductive and developmental toxicity used inhalation as the route of administration, sufficient toxicokinetic data are available to demonstrate that 1,3-dichloropropene is well absorbed and metabolized via the same pathway for both routes. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=62. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2000 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for 1,3-Dichloropropene. To review this appendix, exit to the toxicological review, Appendix B, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=80. Agency Consensus Date -- 04/20/00 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (fax) or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 200005 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,3-Dichloropropene (DCP) CASRN -- 542-75-6 Last Revised -- 05/25/2000 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Benchmark Concentrations UF MF RfC -------------------- ------------------------ ---- --- ---- Hypertrophy/hyper- BMCL10(ADJ)1: 3.7 mg/m3 30 1 2E-2 plasia of the nasal mg/m3 respiratory epithelium BMCL10(HEC)2: 0.72 mg/m3 Chronic inhalation BMC10(ADJ)1: 5.9 mg/m3 study in B6C3F1 mice (Lomax et al., 1989) BMC10(HEC)2: 1.2 mg/m3 ------------------------------------------------------------------------ NOTES: The current RfC for 1,3-dichloropropene is a reevaluation of an assessment placed on-line on 01/01/1991. Although the current assessment uses benchmark dose modeling for the dose-response analysis, the dosimetric adjustment for animal-to-human exposure concentration was similar to that reported earlier. The resulting RfC is the same as that reported in the 1991 assessment. *Conversion Factors and Assumptions --(BMCL10 - 95% lower confidence limit on the maximum likelihood estimate of the dose corresponding to 10% risk. BMC10 - Maximum likelihood estimate of the dose corresponding to 10% risk.) 1 Prior to BMC analysis, exposure concentrations were converted from intermittent exposure to continuous exposure and adjusted for purity of formulation (92%): 22.7 mg/m3 x 6/24 hrs x 5/7 days x 0.92 = 3.7 mg/m3. 2 Adjusted BMC and BMCL were converted to human equivalent concentration (HEC) for interspecies dosimetric adjustment. BMC(HEC) was calculated for an effect in the extrathoracic (ET) region. Minute volumemouse = 0.041 L/min, Minute volumehuman = 13.8 L/min, Surface area(ET)mouse = 3 cm3, Surface area(ET)human = 200 cm2. Regional gas dose ratio(ET) = (Minute volumemouse/surface area(ET)mouse)/(minute volumehuman/surface area(ET)human) = 0.198. BMC(HEC) = BMC(ADJ) x Regional gas dose ratio(ET) = 3.66 mg/m3 x 0.198 = 0.72 mg/m3. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Lomax, LG; Stott, WT; Johnson, KA; et al. (1989) The chronic toxicity and oncogenicity of inhaled technical-grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 12:418-431. There are no chronic human inhalation studies suitable for dose-response assessment. The only chronic animal study available was chosen as the principal study. Lomax et al. (1989) exposed male and female F344 rats and B6C3F1 mice (50/sex/dose) via whole-body chamber inhalation to 0, 5, 20, or 60 ppm (0, 22.7, 90.8, or 272 mg/m3) technical-grade 1,3-dichloro-propene for 6 hours/day, 5 days/week for 2 years. Two satellite groups of rats and mice (10/sex/dose group) were exposed to 1,3-dichloropropene for 6 and 12 months, respectively. Standard protocols for chronic toxicity and carcinogenicity bioassays were followed. In rats, the only treatment-related effects were histopathological changes in the nasal tissues of both sexes, primarily in the olfactory epithelium, after exposure to 272 mg/m3 for 24 months, but not after exposure for 6 or 12 months. These microscopic changes were located in the olfactory mucosa covering the upper portions of the nasal cavity, nasal septum, and turbinates, and were characterized by degeneration, erosion, and fibrosis. In mice, gross pathological examination showed an increase in lung masses in males exposed to 272 mg/m3. Histopathology revealed an increased incidence of hypertrophy and hyperplasia of the respiratory epithelium and/or degeneration of the olfactory epithelium in mice of both genders at 90.8 and 272 mg/m3. In all cases, changes were graded as "slight", involved approximately 10% or less of the total respective epithelium, and did not progress in severity or extent of distribution from one time period to the next. Statistically significant hyperplastic changes in the urinary bladder were noted in female mice exposed to 90.8 mg/m3 or higher and in males exposed to 272 mg/m3. Generally, the hyperplasia increased in severity with increasing exposure concentration, and in the 272 mg/m3 females, with increasing periods of exposure. Additional microscopic changes noted in mice in the 272 mg/m3 group were (1) focal hyperplasia and hyperkeratosis in the forestomach of 8/50 males exposed for 24 months; (2) decreased vacuolation of renal proximal tubular epithelial cells in males exposed for 24 months; and (3) decreased hepatocyte vacuolation in males exposed for 6 and 12, but not 24, months and in females exposed for 24 months. Stott, WT; Young, JT; Calhoun, LL; et al. (1988) Subchronic toxicity of inhaled technical grade 1-3 dichloropropene in rats and mice. Fundam Appl Toxicol 11:207-220. Male and female F344 and B6C3F1 mice (10/sex/group) were exposed to vapors of technical-grade 1,3-dichloropropene for 6 hours/day, 5 days/week for 13 weeks at nominal concentrations of 0, 10, 30, 90, or 150 ppm (0, 45.4, 136, 409, or 681 mg/m3). The only treatment-related clinical effects observed during the study were transient brown discoloration of the fur about the muzzles of rats exposed to 150 ppm immediately following exposure and a strong mercaptan odor associated with the coats and urine of all rats and mice exposed to 409 or 681 mg/m3. There were no treatment-related differences in survival. The body weights of male and female rats exposed to 409 or 681 mg/m3 were significantly depressed in an exposure-related manner relative to control rats. Changes in mean organ weights were considered to be secondary to decreased body weights. In 2/10 male rats at 136 mg/m3, minimally detectable hyperplasia of the respiratory epithelium was present, whereas all male and female rats in the 409 and 681 mg/m3 groups exhibited mild histopathologic changes in the nasal respiratory epithelium. Rats exposed to 681 mg/m3 also exhibited slight degeneration of the olfactory epithelium. In mice, exposure-related histopathology of the nasal mucosa was similar to that observed in rats and consisted of slight to very slight degeneration of the olfactory neuroepithelium and hyperplasia of the respiratory epithelium in most of the males and females in the 409 and 681 mg/m3 groups. The urinary bladders of 7/10 and 6/10 female mice in the 409 and 681 mg/m3 groups, respectively, exhibited large confluent areas of moderate hyperplasia of the transitional epithelium. Mild aggregates of lymphoid cells in the subepithelial tissues were found to be associated with these areas of hyperplasia in about half of the affected mice. Stott et al. (1988) supports the Lomax et al. (1988) study by providing additional evidence of the ability of 1,3-dichloropropene to produce nasal respiratory and olfactory epithelial histopathology in rats and mice. Additionally, Stott et al. (1988) confirm that the urinary bladder is also a target organ in mice exposed via inhalation. Breslin, WJ; Kirk, HO; Streeter, CM; et al. (1989) 1,3-Dichloropropene: two-generation inhalation reproduction study in Fischer 344 rats. Fundam Appl Toxicol 12:129-143. In a two-generation reproductive/developmental study, F344 rats (30/sex/group) were exposed via whole-body inhalation to 0, 10, 30, or 90 ppm (0, 45.4, 136, or 409 mg/m3, respectively; converted by ppm x MW/24.45 with MW = 110.98) 1,3-dichloropropene for 6 hours/day, 5 days/week for 10 weeks before mating and for 6 hours/day, 7 days/week during mating, gestation, and lactation. No effects in any animals were noted at 10 or 30 ppm. At 90 ppm, males in the F0 and F1 generations exhibited a statistically significant decrease in body weight compared to controls. In adults and litters, no toxicologically significant changes in mating or fertility indices, including cohabitation time required for mating, gestation length, litter size, pup survival, and pup body weights, were observed. There were no increases in either physical or behavioral abnormalities of the pups. Parental toxicity was observed only at 90 ppm and consisted of histopathological changes of the nasal mucosa of the adult male and female rats. The alterations consisted of slight focal hyperplasia of the respiratory epithelium and/or focal degenerative changes of the olfactory epithelium. The findings of Breslin et al. (1989) support the use of Lomax et al. (1989) as the critical study by affirming that epithelial effects in the nasal cavity are more sensitive to 1,3-dichloropropene exposure than other effects. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 30. In general, the default uncertainty factor for interspecies extrapolation is 10. Half of that factor, 101/2, or 3, reflects the pharmacokinetic component of interspecies uncertainty and half represents the pharmacodynamic component of interspecies uncertainty. For 1,3-dichloropropene, the pharmacokinetic component of interspecies uncertainty is accounted for by the similarity in toxicokinetics between rodents and humans (U.S. EPA, 2000, Sections 3.1, 3.2, and 3.4) and by the dosimetric adjustment to convert animal exposure concentrations to human equivalent concentrations (HEC). Thus, an uncertainty factor of 3 is used for interspecies extrapolation to reflect the pharmacodynamic component of interspecies uncertainty. There are few data documenting the nature and extent of variability in human susceptibility to 1,3-dichloropropene; therefore, the default uncertainty factor of 10 is used for within-species variation. The database is substantial and includes studies of genotoxicity, mode of action, pharmacokinetics, reproductive and developmental toxicity, systemic toxicity, and cancer. Therefore, no additional uncertainty factors are needed. MF = None IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) 1,3-Dichloropropene is rapidly absorbed, conjugated with glutathione to mercapturic acids, and subsequently excreted, mainly in the urine (Stott and Kastl, 1986; Fisher and Kilgore 1988a,b, 1989). Toxicokinetics are similar in humans and in rodents (Osterloh, 1989; van Welie et al., 1991; Brouwer et al., 1991; Waechter et al., 1992). 1,3-Dichloropropene does not bioaccumulate in the body. The weight and strength of evidence of one two-generation inhalation reproductive study with rats (Breslin et al., 1989) and two developmental toxicity studies with rats and rabbits by Hanley et al. (1988) demonstrate that 1,3-dichloropropene is not a reproductive or developmental toxicant. Owing to the absence of studies examining the effect of 1,3-dichloropropene exposure on juvenile animals, the effects of 1,3-dichloropropene on children cannot be predicted. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=50. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Database -- High RfD -- High The overall confidence in this RfC assessment is high. The confidence in the principal study is high. The study used two species, was well designed and well conducted, and followed standard guidelines for chronic bioassays. The nasal histopathology findings of the principal study were supported by similar findings in a subchronic inhalation study and a two-generation reproductive/developmental study. Rats and mice of both genders were tested in both the subchronic and chronic studies. Confidence in the database is high because there are supporting toxicokinetic, reproductive, developmental, and ingestion studies in animals. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=62. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 2000 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for 1,3-Dichloropropene. To review this appendix, exit to the toxicological review, Appendix B, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=80. Agency Consensus Date -- 04/20/00 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (fax) or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 200005 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,3-Dichloropropene (DCP) CASRN -- 542-75-6 Last Revised -- 05/25/2000 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY The current carcinogenicity assessment for 1,3-dichloropropene is a revision of the assessment placed on-line on 10/01/1993. WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Human data are inadequate for assessment of the potential human carcinogenicity of 1,3-dichloropropene because the only human data available are case studies. In chronic animal bioassays, 1,3-dichloropropene produced tumors in F344 rats (forestomach, liver) and B6C3F1 mice (forestomach, urinary bladder, and lung) at high gavage doses, liver tumors in F344 rats at lower dietary doses, and benign lung tumors in male mice exposed via inhalation. Although 1,3-dichloropropene elicited a positive response for mutagenicity in bacterial assays with the addition of S9, the most compelling evidence for mutagenicity is the isolation of mutagenic epoxide metabolites from mouse liver at high (~LD50) doses. Thus, under the current Risk Assessment Guidelines (U.S. EPA, 1987), 1,3-dichloropropene is a B2, probable human carcinogen, because of the lack of data in humans and sufficient evidence of carcinogenicity in animals. Although the available human data are inadequate, 1,3-dichloropropene is characterized as "likely" to be a human carcinogen in accordance with the Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996). This characterization is based on tumors observed in chronic animal bioassays for both inhalation and oral routes of exposure. Although the chronic dietary and inhalation bioassays suggest that tumors may not occur at low doses, a nonlinear mechanism of tumor formation is not supported by the available mechanistic data. In fact, the mutagenic properties of 1,3-dichloropropene suggest a genotoxic mechanism of action. The mutagenic properties and the absence of data to support a nonlinear mechanism of tumor formation require that the quantitative assessment default to a linear model. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=62. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=50. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Human data are inadequate for assessment of the potential human carcinogenicity of 1,3-dichloropropene. The human data on 1,3-dichloropropene consist of anecdotal reports of three cases of cancer (two non-Hodgkin's lymphomas and one acute myelomonocytic leukemia). Case studies do not provide a basis for inferring a causal association between exposure to 1,3-dichloropropene and blood cancers because the possibility of confounding factors has not been considered or ruled out (U.S. EPA, 1987). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Four lifetime animal studies have been conducted to examine the carcinogenicity of 1,3-dichloropropene. There are three oral studies in rats and/or mice and one inhalation study in rats and mice. In the NTP (1985) study, F344 rats of each sex were gavaged with Telone II (92% 1,3-dichloropropene, 1% epichlorohydrin) in corn oil at doses of 0, 25, and 50 mg/kg 3 times/week while B6C3F1 mice of each sex were gavaged with 0, 50, and 100 mg/kg 3 times/ week for 104 weeks. A total of 52 rats/sex and 50 mice/sex were used for each dose group in the main oncogenicity study; an additional 5 rats/sex/group were sacrificed after 9, 16, 21, 24, and 27 months of dosing, respectively. Doses were based on earlier short-term studies that observed body weight reduction. Standard bioassay data including clinical signs, body weights, clinical chemistry, hematology, pathology, and histopathology were collected. No increased mortality occurred in treated animals. In rats, elevated incidences of the following tumors were observed at 50 mg/kg: (1) forestomach squamous cell papillomas in males and females; (2) forestomach squamous cell papillomas and carcinomas combined in males; and (3) liver adenomas/carcinomas in males. The highest dose level tested in rats, 50 mg/kg, approximated a maximum tolerated dose level. The portion of the bioassay using male mice was inadequate because of premature deaths from myocardial inflammation in the control group. Elevated incidences of the following tumors were observed in mice either at the highest dose or at both doses tested: (1) forestomach squamous cell papillomas and carcinomas in males and females, and squamous cell carcinomas in females; (2) urinary bladder transitional cell carcinomas in males and females; and (3) lung adenomas/ carcinomas in males and females. The highest dose level tested in mice, 100 mg/kg, exceeded a maximum tolerated dose level. NTP concluded that there was ôclear evidence of carcinogenicityö for female B6C3F1 mice, as the administration of Telone II had caused an increased incidence of transitional cell carcinomas of the urinary bladder, as well as an increased incidence of bronchioalveolar adenomas of the lung and of squamous cell papillomas and carcinomas of the forestomach in female mice. Although the NTP study was rejected by the Agency for RfD development (IRIS, online 10/1/90) because the thrice-weekly gavage dosing regime was not well designed to study chronic toxicity, the study provides evidence that 1,3-dichloropropene is a carcinogen at high bolus doses. Current test guidelines recommend gavaging seven times weekly, but indicate that five times/week is acceptable (U.S. EPA, 1998). Another problem with the NTP study (1985) is that the dichloropropene formulation contained epichlorohydrin, which NTP acknowledged as a possible contributor to tumorigenic effects in the forestomach. In addition, gavage administration is less relevant to human exposure than is dietary administration. In the feeding studies, Fischer 344 rats (50/sex/dose) were administered Telone II (96% 1,3-dichloropropene without epichlorohydrin) in the diet at 0, 2.5, 12.5, or 25 mg/kg/day for 24 months (Stott et al., 1995) while B6C3F1 mice (50/sex/dose) received doses of 0, 2.5, 25, or 50 mg/kg/day for 24 months (Redmond et al., 1995). In both studies, satellite groups of rats and mice (10/sex/species/dose) were administered Telone II for 12 months. Standard bioassay data including body weights, food consumption, clinical chemistry, hematology, urine analysis, organ weights, pathology, and histopathology were collected. Ophthalmologic examinations were conducted at the start of the study and prior to necropsy. In the rat study, a late-onset, statistically significant increase in the incidence of benign liver cell tumors, i.e., hepatocellular adenomas, was observed in males in the 25 mg/kg/day group (9/50 vs. 2/50 in control males). One nonfatal hepatocellular carcinoma was observed in a male rat in the 25 mg/kg/day group. Although the incidence of hepatocellular adenomas in 25 mg/kg/day female rats increased (4/50 vs. 0/50 in concurrent controls), pairwise comparison showed that the increase was statistically nonsignificant. A slight, statistically nonsignificant increase in the incidence of tumors in the 12.5 mg/kg/day male rat group was also noted (6/50 vs. 2/50 in concurrent controls). Female rats in the 25 mg/kg/day group showed a statistically significant decrease in the incidence of benign mammary gland fibroadenomas. In the mouse study, no increases in tumor incidence were observed in treated animals of either gender. Though more relevant to human exposure, the dietary studies are limited by the lack of in-cage stability studies of the food mixture. The absence of such information leaves doubt as to the actual dose received by the animals. The gavage study, however, also had limitations: the thrice-weekly high-dose gavage and possible confounding of forestomach tumors by epichlorohydrin. In the absence of a single best study, both the NTP (1985) and Stott et al. (1995) studies will be evaluated separately and used for the quantitative oral cancer assessment. The most conservative value is recommended. The inhalation bioassay involved exposing male and female F344 rats and B6C3F1 mice (50/sex/dose) via whole-body, chamber inhalation to 0, 5, 20, or 60 ppm technical-grade 1,3-dichloropropene (92% 1,3-dichloropropene without epichlorohydrin) for 6 hours/day, 5 days/week for 2 years (Lomax et al., 1989). Two satellite groups of rats and mice (10/sex/dose group) were also exposed to 1,3-dichloropropene for 6 or 12 months, respectively. Standard protocol for chronic toxicity and carcinogenicity bioassays was followed. No clinical signs indicative of toxicity were observed in treated animals throughout the study. There were no significant differences in survival between control and treated animals. In rats, there were no statistically significant increases in primary, benign, or malignant tumors in either males or females exposed to 1,3-dichloropropene for 6, 12, or 24 months. In male mice, a statistically significant increase in the incidence of late-onset bronchioalveolar adenomas was observed in the 60 ppm group at 24 months of exposure (22/50 vs. 9/50 in controls). The increase in the incidence of benign adenomas was higher than historical control values for this tumor type (7%-32%) in B6C3F1 male mice in the same laboratory. No other treatment-related tumor effects were observed in mice of either gender. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY In early in vitro mutagenicity testing, 1,3-dichloropropene was repeatedly screened in the Ames Salmonella test and usually tested positive for mutagenicity (e.g., Vithayathil et al., 1983; Stolzenberg and Hine, 1980; Haworth et al., 1983). However, in 1984, Talcott and King demonstrated that preparations of 1,3-dichloropropene assayed in vitro for mutagenic activity contained direct- acting mutagenic polar impurities. Samples of 1,3-dichloropropene tested before silicic acid chromatography were positive for mutagenic activity, whereas those tested after such purification were negative. Polar impurities isolated from 1,3-dichloropropene samples were mutagenic in the Ames Salmonella test. These data suggest that the mutagenic activity of 1,3-dichloropropene preparations in earlier prokaryotic tests was due to mutagenic polar impurities and not to 1,3-dichloropropene. NTP (1985) tested purified and unpurified samples of 1,3-dichloropropene for mutagenic activity and confirmed the finding of Talcott and King (1984) that uncontaminated 1,3-dichloropropene was not mutagenic in the Ames Salmonella test. Watson et al. (1987) also confirmed these results and reported that purification by gas chromatography can produce trace impurities that are mutagenic in bacterial assays. Although purified 1,3-dichloropropene was not directly mutagenic, Watson et al. (1987) observed mutagenic activity after the addition of washed microsomes from rat liver and showed that mutagenicity was abolished when glutathione, at normal physiological concentration, was added to the bacterial cultures. Watson et al. (1987) have suggested that 1,3-dichloropropene undergoes monooxygenase-dependent bioactivation to mutagenic metabolites only in the absence of glutathione. Schneider et al. (1998a) subsequently found that epoxidation of 1,3-dichloropropene is a minor metabolic pathway in mouse liver after administration of LD50 doses of 1,3-dichloropropene. In mouse liver microsomes in vitro, formation of the epoxides, which were mutagenic in the Salmonella TA100 assay, was decreased by the conjugation of 1,3-dichloropropene with glutathione. Thus, glutathione appears to provide protection against the formation of mutagenic epoxide metabolites of 1,3-dichloropropene. Even in the absence (verified or assumed) of mutagenic impurities, 1,3-dichloropropene has produced mixed results in mammalian in vitro and in vivo genotoxicity studies. In vitro tests for DNA fragmentation in mammalian cells were positive for both V79 cells and rat hepatocytes at concentrations of 1,3-dichloropropene much larger than measured blood concentrations in pharmacokinetic studies (Martelli et al., 1993). Increased DNA fragmentation was associated with decreased glutathione. In vivo DNA fragmentation studies using doses of 62.5 mg/kg and higher in rats found DNA fragmentation in the liver, stomach mucosa, and kidney, but not in the lung, bone marrow, or brain (Ghia et al., 1993). The same study observed no increases in micronuclei in bone marrow, spleen, or hepatocytes. Ghia et al. (1993) also found no evidence of DNA repair induction in assays for unscheduled DNA synthesis. 1,3-Dichloropropene does not produce dominant lethal mutations in Wistar or F344 rats or New Zealand White rabbits, as evidenced by the absence of reproductive effects in inhalation studies by Hanley et al. (1988) and Linnett et al. (1988). Stott et al. (1997) studied the in vitro binding potential of 1,3-dichloropropene to calf thymus DNA in the presence or absence of S9, and in the presence of S9 and glutathione. Although no evidence of DNA binding was observed under any of these treatment conditions, Schneider et al. (1998b) showed that 1,3-dichloropropene epoxides bind to deoxyguanosine in vitro. Several genotoxicity studies indicate that 1,3-dichloropropene is mutagenic. Although some in vitro studies indicate that glutathione may protect against the mutagenic effects, there is no clear evidence that it prevents tumor formation in vivo. Thus, the presumed mechanism of action for 1,3-dichloropropene is via DNA toxicity. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE The quantitative cancer risk assessment is new to the IRIS file for 1,3-dichloropropene. The carcinogenicity assessment placed on-line on 10/01/1993 did not include quantitative risk estimates. SUOE: __II.B.1. SUMMARY OF RISK ESTIMATES In the absence of a single best study, both the NTP (1985) and Stott et al. (1995) studies have been evaluated separately and used for the quantitative oral cancer assessment. Given that both studies have limitations for quantitative risk assessment, the most conservative slope factor, 1E-1 (mg/kg/day)-1 for urinary bladder tumors in mice (NTP, 1985), is recommended because there is less uncertainty in the delivered dose in that study. __II.B.1.1. Oral Slope Factor * 1E-1 per (mg/kg)/day (NTP, 1985; urinary bladder tumors) * 5E-2 per (mg/kg)/day (NTP, 1985; liver tumors) * 5E-2 per (mg/kg)/day (Stott et al., 1995; liver tumors) __II.B.1.2. Drinking Water Unit Risk * 3E-6 per (ug/L) (NTP, 1985; urinary bladder tumors) * 2E-6 per (ug/L) (NTP, 1985; liver tumors) * 1E-6 per (ug/L) (Stott et al., 1995; liver tumors) __II.B.1.3. Extrapolation Method - linearized multistage model, extra risk Drinking Water Concentrations at Specified Risk Levels (NTP, 1985; urinary bladder tumors): Risk Level Concentration E-4 (1 in 10,000) 4E+1 ug/L E-5 (1 in 100,000) 4E+0 ug/L E-6 (1 in 1,000,000) 4E-1 ug/L Drinking Water Concentrations at Specified Risk Levels (NTP, 1985; liver tumors): Risk Level Concentration E-4 (1 in 10,000) 7E+1 ug/L E-5 (1 in 100,000) 7E+0 ug/L E-6 (1 in 1,000,000) 7E-1 ug/L Drinking Water Concentrations at Specified Risk Levels (Stott et al., 1995; liver tumors): Risk Level Concentration E-4 (1 in 10,000) 8E+1 ug/L E-5 (1 in 100,000) 8E+0 ug/L E-6 (1 in 1,000,000) 8E-1 ug/L DCOE: __II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor type -- urinary bladder carcinoma Test animals -- female mouse Route -- oral, gavage Source -- NTP, 1985 Administered Human Equivalent Dose Tumor Incidence Dose (mg/kg/day) (mg/kg/event) 0 0 0/50 50 2.88 8/50 100 5.81 21/47 Tumor type -- hepatocellular adenoma/carcinoma Test animals -- male rat Route -- oral, gavage Source -- NTP, 1985 Administered Human Equivalent Dose Tumor Incidence Dose (mg/kg/day) (mg/kg/event) 0 0 1/49 25 2.75 6/48 50 5.4 8/50 Tumor type -- hepatocellular adenoma/carcinoma Test animals -- male rat Route -- oral, dietary Source -- Stott et al., 1995 Administered Human Equivalent Dose Tumor Incidence Dose (mg/kg/day) (mg/kg/event) 0 0 2/49 2.5 0.65 1/50 12.5 3.22 6/50 25 6.31 10/49 ACOE: __II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Because there was concordance in rat liver tumors in both the gavage (NTP, 1985) and feeding studies (Stott et al., 1995), these tumors were chosen for quantitative assessment. The forestomach tumor data in rats and mice in the NTP (1985) study were not chosen because of the confounding effects of epichlorohydrin in the formulation and because the tumors did not appear in the feeding studies (Stott et al., 1995; Redmond et al., 1995). The male mouse tumor data in the NTP study (bronchioalveolar adenoma/carcinoma) are unacceptable for quantitative assessment; the control group survival was inadequate because of early deaths attributed to myocarditis. Although the urinary bladder tumors in female mice in the gavage study (NTP, 1985) were not observed in the feeding study (Redmond et al., 1995), these data were chosen for quantitative assessment because transitional cell carcinoma of the bladder is a rare tumor and because the dosing for mice in the feeding study may have been inadequate. Administered doses for the gavage study (NTP, 1985) were averaged over 7 days/week. All doses were adjusted to human equivalent doses by multiplying by (animal body weight/human body weight)1/4 with human body weight = 70 kg and animal body weight = final weight at the end of the study. Both the multistage model with extra risk (per proposed cancer risk assessment guidelines; U.S. EPA, 1996) and the linearized multistage model (per existing cancer risk assessment guidelines; U.S. EPA, 1987) were used to calculate the cancer slope factors. Although the cancer slope factors for both methods were similar (U.S. EPA, 2000, Appendix A, Section II.A-C), those from the linearized multistage model are reported here because the proposed guidelines have not been finalized. The cancer slope factors are 1E-1 for urinary bladder tumors in mice, 5E-2 for rat liver adenoma/carcinoma (NTP, 1985), and 5E-2 for rat liver adenoma/carcinoma (Stott et al., 1995). The most conservative factor, 1E-1 per (mg/kg)/day, is recommended. CCOE: __II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Confidence in the database is medium to high. Two chronic bioassays were available for both rats and mice. Limitations of the gavage studies included the bolus dosing and the thrice- weekly rate of administration, which are not relevant to human exposure. In addition, the 1,3-dichloropropene formulation contained epichlorohydrin, a known carcinogen. Inadequate dosing is suspected for the Redmond et al. (1995) study because of the lack of in-cage stability data for the microencapsulated 1,3-dichloropropene in feed and the lack of cancer (urinary bladder tumors) and noncancer effects (urinary bladder hyperplasia, forestomach hyperplasia, and hydronephrosis) seen in mice in the gavage study (NTP, 1985). In the absence of a single best study, both the NTP (1985) and Stott et al. (1995) studies were used for the quantitative cancer assessment. Major database uncertainties are the importance of 1,3 dichloropropene's mutagenic potential in a whole-animal system and the mechanism of tumorigenic action. The results from short-term mutagenicity assays for the parent compound are mixed, and although 1,3-dichloropropene is metabolized to mutagenic epoxides at ~LD50 doses, the extent of epoxide formation in vivo at the low doses characteristic of chronic exposure is unknown. In vitro assays indicated that the presence of glutathione decreases epoxide formation and abolishes or greatly reduces the mutagenic response, but evidence of protection against tumor formation is lacking. Thus, the linear quantitative assessment provides a conservative estimate of cancer potency. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: __II.C.1. SUMMARY OF RISK ESTIMATES ____II.C.1.1. Inhalation Unit Risk -- 4E-6 risk per ug/m3 ____II.C.1.2. Extrapolation Method -- linearized multistage model, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) 2E+1 ug/m3 E-5 (1 in 100,000) 2E-0 ug/m3 E-6 (1 in 1,000,000) 2E-1 ug/m3 DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor type -- bronchioalveolar adenoma Test animals -- male mouse Route -- inhalation Source -- Lomax et al., 1989 Administered Human Equivalent Tumor Incidence Dose Concentration (mg/m3) (mg/m3) {1}, {2} 0 0 9/50 22.7 3.7 6/40 90.8 15 13/50 272 45 22/50 {1} Correction for purity of formulation concentration (92%) and correction for intermittent exposure to continuous exposure: 22.7 mg/m3 x 0.92 x 6/24 hrs x 5/7 days = 3.7 mg/m3. {2} Correction for thoracic effects using RGDR(TH) of 3.21 as described in II.C.3. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The critical study for assessment of cancer inhalation potency is the study by Lomax et al. (1989) in which rats and mice were exposed to up to 272 mg/m3 1,3-dichloropropene vapors for 6 hours/day, 5 days/week for 2 years. This is a well-designed and well-conducted bioassay that followed standard guidelines. Epoxidized soybean oil was the stabilizing agent in the formulation of 1,3-dichloropropene, which eliminated possible confounding effects of epichlorohydrin. Lomax et al. (1989) is the only available 2-year inhalation bioassay. Confidence in this study is supported by the results of a 90-day subchronic study (Stott et al., 1988), which are consistent with the Lomax et al. (1989) bioassay findings. The only neoplastic response observed in any species or sex was an increased incidence of bronchioalveolar adenomas with late onset, in male mice in the highest dose group. The incidence in the high-dose group exceeded the range of historical control rates among mice in the same laboratory. The administered dose was adjusted for purity and for continuous exposure as shown in the notes for Section II.C.2. Algorithms for the thoracic effects of Category 1 gases were used to adjust animal exposure concentrations of 1,3-dichloropropene to HECs (U.S. EPA, 1994). The HEC for a Category 1 gas is derived by multiplying the duration- and purity-adjusted exposure concentrations by an interspecies dosimetric adjustment for gas: respiratory effects in the tracheobronchial and pulmonary (i.e., thoracic) regions of the lung, according to the following calculation (U.S. EPA, 1994): RGDR(TH) = (MVa/Sa)/(MVh/Sh) RGDR(TH) = regional gas dose ratio for the thoracic (tracheobronchial and pulmonary) area of the lung MVa = animal minute volume (mouse = 0.041 L/min) MVh = human minute volume (13.8 L/min) Sa = surface area of the thoracic region of the animal lung (mouse = 503.5 cm2), and Sh = surface area of the thoracic region of the human lung (543,200 cm2). Using default values, the RGDR(TH) = (0.041/503.5)/(13.8/543,200) = 3.21. Using the duration-adjusted HECs and tumor incidences, both the multistage model with extra risk (per proposed cancer risk assessment guidelines; U.S. EPA, 1996) and the linearized multistage model (per existing cancer risk assessment guidelines; U.S. EPA, 1987) were used to calculate unit risk. Although the unit risk from both methods was similar (U.S. EPA, 2000, Appendix A, Section II.D), those from the linearized multistage model are reported here because the proposed guidelines have not been finalized. The unit risk (i.e., risk at 1 ug/m3) is 4E-6 risk per ug/m3. CCIE: __II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Confidence in the database is medium. One well-conducted study was available for rodent exposure via inhalation. Confidence in the study is increased by site concordance with mouse tumors in the NTP (1985) gavage study. Major database uncertainties are the importance of the mutagenic potential of 1,3-dichloropropene in a whole-animal system and the precise mechanism of tumorigenic action. The results from short-term mutagenicity assays for the parent compound are mixed, and although 1,3-dichloropropene is metabolized to mutagenic epoxides at ~LD50 doses, the extent of epoxide formation in vivo at the low doses characteristic of chronic exposure is unknown. In vitro assays indicated that the presence of glutathione decreases epoxide formation and abolishes or greatly reduces the mutagenic response, but evidence of protection against tumor formation is lacking. Thus, the linear quantitative assessment provides a very conservative estimate of cancer potency. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2000 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for 1,3-Dichloropropene. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0224-tr.pdf#page=80. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 04/20/00 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 200005 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,3-Dichloropropene (DCP) CASRN -- 542-75-6 Last Revised -- 05/25/2000 SORD: __VI.A. ORAL RfD REFERENCES Bousema, MT; Wiemer, GR; Van Joost, TH. (1991) A classic case of sensitization to DD-95. Contact Dermatitis 24(2):132-133. Breslin, WJ; Kirk, HO; Streeter, CM; et al. (1989) 1,3-Dichloropropene: two-generation inhalation reproduction study in Fischer 344 rats. Fundam Appl Toxicol 12:129-143. Climie, IJG; Hutson, DH; Morrison, BJ; et al. (1979) Glutathione conjugation in the detoxification of (Z)-1,3-dichloropropene (a component of the nematocide D-D) in the rat. Xenobiotica 9:149-156. Dietz, FK; Hermann, EA; Ramsey, JC. (1984a) The pharmacokinetics of 14C-1,3-dichloropropene in rats and mice following oral administration. Toxicologist 4:147 (Abstr. No. 585). Dietz, FK; Dittenber, DA; Kirk, HD; et al. (1984b) Non-protein sulfhydryl content and macromolecular binding in rats and mice following oral administration of 1,3-dichloropropene. Toxicologist 4:147 (Abstr. 586). Dietz, F; Hermann, E; Kastl, P; et al. (1985) 1,3-Dichloropropene: pharmacokinetics, effect on tissue non-protein sulfhydryls, and macromolecular binding in Fischer-344 rats and B6C3F1 mice following oral administration. The Dow Chemical Company, Midland, MI. No. 86-870023122. Hanley, TR, Jr.; John-Greene, JA; Young, JT; et al. (1988) Evaluation of the effects of inhalation exposure to 1,3-dichloropropene on fetal development in rats and rabbits. Fundam Appl Toxicol 8:562-570. Haut, KT; Stebbins, KE; Johnson, KA; et al. (1996) Subchronic toxicity of ingested 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 32:224-232. Hernandez, AF; Martin-Rubi, JC; Ballesteros, JL; et al. (1994) Clinical and pathological findings in fatal 1,3-dichloropropene intoxication. Hum Exper Toxicol 13:303-306. Hutson, DH; Moss, JA; Pickerine, BA. (1971) The excretion and retention of components of the soil fumigant D-D and their metabolites in the rat. Food Cosmet Toxicol 8:677-680. Linnett, SL; Clark, DG; Blair, D; et al. (1988) Effects of subchronic inhalation of D-D (1,3-dichloropropene/1,2-dichloropropene) on reproduction in male and female rats. Fundam Appl Toxicol 10:214-223. Lomax, LG; Stott, WT; Johnson, KA; et al. (1989) The chronic toxicity and oncogenicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 12:418-431. Nater, JP; Gooskens, VHJ. (1976) Occupational dermatosis due to a soil fumigant. Contact Dermatitis 2(4):227-229. NTP (National Toxicology Program). (1985) Toxicology and carcinogenesis studies of Telone II (technical grade 1,3-dichloropropene containing 1% epichlorohydrin as a stabilizer) in F344/N rats and B6C3F1 mice (gavage studies). U.S. Dept. of Health and Human Services, Technical Report Series No. 269. Osterloh, JD; Wang, R; Schneider, S; et al. (1989) Biological monitoring of dichloropropene: air concentrations, urinary metabolite, and renal enzyme excretion. Arch Environ Health 44(4):207-213. Redmond, JM; Stebbins, KE; Stott, WT; et al. (1995) Telone II soil fumigant: two-year dietary chronic toxicity/oncogenicity study in B6C3F1 mice - final report. Dow Chemical Company, Midland, MI. Study # M-003993-032. Schneider, M; Quistad, GB; Casida, JE. (1998) 1,3-Dichloropropene epoxides: intermediates in bioactivation of the promutagen 1,3-dichloropropene. Chem Res Toxicol 11:1137-1144. Stott, WT; Kastl, PE. (1986) Inhalation pharmacokinetics of technical grade 1,3-dichloropropene in rats. Toxicol Appl Pharmacol 85(3):332-341. Stott, WT; Young, JT; Calhoun LL; et al. (1988) Subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 11:207-220. Stott, WT; Johnson, KA; Jeffries, TK; et al. (1995) Telone II soil fumigant: two-year chronic toxicity/oncogenicity study in Fischer 344 rats. Dow Chemical Company, Midland, MI. Study # M-003993-031l. U.S. EPA. (2000) Toxicological review of 1,3-dichloropropene in support of summary information on the Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. van Welie, RTH; van Duyn, P; Brouwer, DH; et al. (1991) Inhalation exposure to 1,3-dichloropropene in the Dutch flower-bulb culture. Part II. Biological monitoring by measurement of urinary excretion of two mercapturic acid metabolites. Arch Environ Contam Toxicol 20(1):6-12. Waechter, JM; Brzak, KA; McCarty, LP; et al. (1992) 1,3-Dichloropropene (Telone II soil fumigant): Inhalation pharmacokinetics and metabolism in human volunteers (internal report). Dow Chemical Company, Midland, MI. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Breslin, WJ; Kirk, HO; Streeter, CM; et al. (1989) 1,3 Dichloropropene: two-generation inhalation reproduction study in Fischer 344 rats. Fundam Appl Toxicol 12:129-143. Brouwer, EJ; Evelo, CTA; Verplanke, AJW; et al. (1991) Biological effect monitoring of occupational exposure to 1,3-dichloropropene: effects on liver and renal function and on glutathione conjugation. Br J Ind Med 48(3):167-172. Fisher, GD; Kilgore, WW. (1988a) Mercapturic acid excretion by rats following inhalation exposure to 1,3-dichloropropene. Fundam Appl Toxicol 112:300-307. Fisher, GD; Kilgore, WW. (1988b) Tissue levels of glutathione following acute inhalation of 1,3-dichloropropene. J Toxicol Environ Health 23(2):171-182. Fisher, GD; Kilgore, WW. (1989) Pharmacokinetics of S-[3-chloropropene-2-enyl]glutathione in rats following acute inhalation exposure to 1,3-dichloropropene. Xenobiotica 19(3):269-278. Lomax, LG; Stott, WT; Johnson, KA; et al. (1989) The chronic toxicity and oncogenicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 12:418-431. Osterloh, JD; Wang, R; Schneider, S; et al. (1989) Biological monitoring of dichloropropene: air concentrations, urinary metabolite, and renal enzyme excretion. Arch Environ Health 44(4):207-213. Stott, WT; Kastl, PE. (1986) Inhalation pharmacokinetics of technical grade 1,3-dichloropropene in rats. Toxicol Appl Pharmacol 85(3):332-341. Stott, WT; Young, JT; Calhoun, LL; et al. (1988) Subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 11:207-220. U.S. EPA. (2000) Toxicological review of 1,3-dichloropropene in support of summary information on the Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. van Welie, RTH; van Duyn, P; Brouwer, DH; et al. (1991) Inhalation exposure to 1,3-dichloropropene in the Dutch flower-bulb culture. Part II. Biological monitoring by measurement of urinary excretion of two mercapturic acid metabolites. Arch Environ Contam Toxicol 20(1):6-12. Waechter, JM; Brzak, KA; McCarty, LP; et al. (1992) 1,3-Dichloropropene (Telone II soil fumigant): inhalation pharmacokinetics and metabolism in human volunteers (internal report). Dow Chemical Company, Midland, MI. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Ghia, M; Robbiano, L; Allavena, A; et al. (1993) Genotoxic activity of 1,3-dichloropropene in a battery of in vivo short-term tests. Toxicol Appl Pharmacol 120:120-125. Hanley, TR, Jr; John-Greene, JA; Young, JT; et al. (1988) Evaluation of the effects of inhalation exposure to 1,3-dichloropropene on fetal development in rats and rabbits. Fundam Appl Toxicol 8:562-570. Haworth, S; Lawlor, TK; Mortelmans, K; et al. (1983) Salmonella mutagenicity testing for 250 chemicals. Environ Mutagen Suppl 1:3-142. Linnett, SL; Clark, DG; Blair, D; et al. (1988) Effects of subchronic inhalation of D-D (1,3-dichloropropene/1,2-dichloropropene) on reproduction in male and female rats. Fundam Appl Toxicol 10:214-223. Lomax, LG; Stott, WT; Johnson, KA; et al. (1989) The chronic toxicity and oncogenicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 12:418-431. Martelli, A; Allavena, A; Ghia, M; et al. (1993) Cytotoxic and genotoxic activity of 1,3-dichloropropene in cultured mammalian cells. Toxicol Appl Pharmacol 120:114-119. NTP (National Toxicology Program). (1985) Toxicology and carcinogenesis studies of Telone II (technical grade 1,3-dichloropropene containing 1% epichlorohydrin as a stabilizer) in F344/N rats and B6C3F1 mice (gavage studies). U.S. Dept. of Health and Human Services, Technical Report Series No. 269. Redmond, JM; Stebbins, KE; Stott, WT. (1995) Telone II soil fumigant: two-year dietary chronic toxicity/oncogenicity study in B6C3F1 mice - final report. Dow Chemical Company, Midland, MI. Study # M-003993-032. Schneider, M; Quistad, GB; Casida, JE. (1998a) 1,3-Dichloropropene epoxides: intermediates in bioactivation of the promutagen 1,3-dichloropropene. Chem Res Toxicol 11:1137-1144. Schneider, M; Quistad, GB; Casida, JE. (1998b) N2,7-Bis(1-hydroxy-2-oxopropyl)-2'-deoxyguanosine: identical noncyclic adducts with 1,3-dichloropropene epoxides and methylglyoxal. Chem Res Toxicol 11:1536-1542. Stolzenberg, SJ; Hine, CH. (1980) Mutagenicity of 2- and 3-carbon halogenated compounds in the Salmonella/mammalian-microsome test. Environ Mutagen 2(1):59-66. Stott, WT; Young, JT; Calhoun, LL; et al. (1988) Subchronic toxicity of inhaled technical grade 1,3-dichloropropene in rats and mice. Fundam Appl Toxicol 11:207-220. Stott, WT; Johnson, KA; Jeffries, TK; et al. (1995) Telone II soil fumigant: two-year chronic toxicity/oncogenicity study in Fischer 344 rats. Dow Chemical Company, Midland, MI. Study # M-003993-031l. Stott, WT; Miller, TJ; Wardynski, AK; (1997) 1,3-Dichloropropene: in vitro DNA binding. Dow Chemical Company. Talcott, RE; King, J. (1984) Mutagenic impurities in 1,3-dichloropropene preparations. J Natl Cancer Inst 72(5):1113-1116. U.S. EPA. (1987) Risk assessment guidelines of 1986. EPA/600/8-87/045, August 1987. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F, October 1994. U.S. EPA. (1996) Proposed guidelines for carcinogen risk assessment, 1996. U.S. EPA. (1998) Health effects test guidelines, OPPTS 870.4200, carcinogenicity, prevention, pesticides and toxic substances. EPA/712C/98/211. U.S. EPA. (2000) Toxicological review of 1,3-dichloropropene in support of summary information on the Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. Vithayathil, AJ; McClure, C; Myers, JW. (1983) Salmonella/microsome multiple indicator mutagenicity test. Mutat Res 121(1):33-37. Watson, PW; Brooks, TM; Huckle, KR; et al. (1987) Microbial mutagenicity studies with (Z)-1,3-dichloropropene. Chem-Biol Interact 61:17-30. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,3-Dichloropropene (DCP) CASRN -- 542-75-6 Date Section Description ---------------------------------------------------------------------------- 09/26/1988 II. Carcinogen summary on-line 12/01/1988 II.B.3. Text added 03/01/1989 II.A.1. Text added 03/01/1989 II.A.3. Text added 10/01/1989 II.B. Oral quantitative risk estimate has been withdrawn 10/01/1989 VI. Bibliography on-line 09/01/1990 I.B. Inhalation RfC assessment now under review 10/01/1990 I.A. Text edited 10/01/1990 II. Text edited 01/01/1991 I.B. Inhalation RfC summary on-line 01/01/1991 VI.B. Inhalation RfC references added 01/01/1992 IV. Regulatory Action section on-line 02/01/1993 III.A. Health Advisory on-line 02/01/1993 VI.D. Health Advisory references on-line 09/01/1993 II. Carcinogenicity assessment noted as pending change 09/01/1993 II.D.2. Work group review date added 10/01/1993 II.D.3. Primary contact changed; secondary's phone no. changed 08/01/1995 II., II.D.2. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 05/25/2000 I.A Revised RfD 05/25/2000 I.B. Revised RfC 05/25/2000 II. Revised carcinogen summary 05/25/2000 II.A. Added oral cancer potency 05/25/2000 II.B. Added inhalation cancer potency ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 395 of 1119 in IRIS (through 2003/06) AN: 226 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199302 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Diethyl-phthalate- SY: 84-66-2; ANOZOL-; 1,2-BENZENEDICARBOXYLIC-ACID,-DIETHYL-ESTER-; DPX-F5384-; ESTOL-1550-; ETHYL-PHTHALATE-; NCI-C60048-; NEANTINE-; PALATINOL-A-; PHTHALOL-; PHTHALSAEUREDIAETHYLESTER-; PLACIDOL-E-; RCRA-WASTE-NUMBER-U088- RN: 84-66-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199302 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Diethyl phthalate CASRN -- 84-66-2 Last Revised -- 02/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Decreased growth NOAEL: 1% of diet 1000 1 8E-1 rate, food consump- (750 mg/kg bw/day) mg/kg/day tion and altered organ weights LOAEL: 5% of diet (3160 mg/kg bw/day) Rat, Subchronic Oral Feeding Study Brown et al., 1978 ---------------------------------------------------------------------------- *Conversion Factors: Converted doses estimated by principal study authors, based on food consumption and body weight data. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Brown, D., K.R. Butterworth, I.F. Gaunt, P. Grasso and S.D. Gangolli. 1978. Short-term oral toxicity study of diethyl phthalate in the rat. Food Cosmet. Toxicol. 16: 415-422. Groups of CD rats (15/sex) were fed diets containing 0, 0.2, 1.0, or 5.0% DEP for 16 weeks. The authors estimated the mean intakes to be 0, 150, 770, and 3160 mg/kg/day for the males and 0, 150, 750, and 3710 mg/kg/day for the females. Additional groups of five rats/sex were fed similar diets for 2 or 6 weeks. Hematological examinations (red blood cell count, hematocrit, hemoglobin) were performed on animals fed diets for 2, 6, and 16 weeks. Differential white blood cell counts were also conducted on 0 and 5% dose groups at 16 weeks. Food and water intake and body weight were measured for all groups weekly. Urinalyses were conducted during weeks 2, 6, and 15 on 5 to 15 rats/sex/dose group. After 16 weeks of treatment, autopsy, hematologic and histologic examinations were conducted on all animals. No changes in behavior or other clinical signs of toxicity were observed. The authors reported significantly less weight gain throughout the duration of the experiment in both sexes given 5% DEP (15 to 25% decrease) and in females (5 to 8% decrease) fed 1% DEP. Mean food consumption of the previous groups was also decreased (by 11 to 23%) relative to controls. No significant dose- or time-related trends in urinalysis or hematology results were found. Absolute weights of brain, heart, spleen, and kidneys were decreased in both sexes fed 5% DEP. Relative weights of the brain, liver, kidneys, stomach, small intestines, and full caecum were significantly greater in both sexes after 16 weeks at the 5% dietary level when compared with controls. No histologic changes because of treatment were reported. In another experiment summarized by Brown et al. (1978), groups of six rats/sex were pair-fed diets containing either 0 or 5% DEP for 16 weeks. Body weights were measured weekly. The authors reported that rats fed 5% DEP consumed more food and gained less weight than controls. The differences in food consumption (1 to 5%) were not statistically significant, and mean weight differences were 7 to 10%, which the authors reported as statistically significant. The RfD receives support from the results of a 2-year feeding study using rats (Food Research Laboratories, Inc., 1955). Albino weanling rats (strain not specified) (15/sex) were fed 0, 0.5, 2.5, and 5.0% diethyl phthalate in the diet. Animals were maintained for a 2-year period during which two males and two females/group were examined at 12-week intervals for the following: red and white blood cell counts, differential white count, hemoglobin, blood sugar and nitrogen, and urinalysis. Growth of animals in the 5% treatment group was retarded throughout the study, with no depression of food intake. There was a significant decrease in efficiency of food utilization in this group compared with controls. There were no other treatment-related effects either on the parameters listed above or on gross organ appearance or histopathology. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- A factor of 10 for extrapolation from subchronic to chronic exposure, 10 for interspecies variation, and an additional 10-fold factor to protect sensitive human subpopulations were used in determining the RfD. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Data regarding developmental and reproductive effects is extremely limited. Singh et al. (1972) observed skeletal malformations in Sprague-Dawley rats after i.p. administration (0.506, 1.012, and 1.686 mL/kg) on days 5, 10, and 15 of gestation. In addition, fetuses were significantly smaller than untreated controls. Exposure to DEP does not appear to affect the reproductive performance of mice after oral administration of 0.25, 1.25, and 2.5% DEP for 18 weeks (NTP, 1984). Second-generation breeding pairs exposed to 2.5% DEP exhibited increased right epididymis and prostate weights in males and decreased pituitary weight in females (NTP, 1984). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low Sufficient numbers of rats of both sexes were employed and multiple endpoints, including histopathology, were studied; confidence in the study is rated medium. Since only limited supporting data are available and the chosen study was of less than lifetime duration, confidence in the data base is rated low. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD The RfD Work Group meeting notes of 01/22/1986 directed a review of the Brown et al. (1978) study. The review has resulted in a different evaluation than presented on 01/22/1986. Agency Work Group Review -- 01/22/1986, 07/16/1987 Verification Date -- 07/16/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Diethyl phthalate conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Diethyl phthalate CASRN -- 84-66-2 NORC: Not available at this time. ============================================================================ UDCA: 199302 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Diethyl phthalate CASRN -- 84-66-2 Last Revised -- 02/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as a human carcinogen Basis -- Pertinent data regarding carcinogenicity were not located in the available literature. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. Dietary studies in rats with exposure durations of 2 years (Food Research Laboratories, Inc., 1955) and 16 weeks (Brown et al., 1978) were not designed to measure carcinogenic effects. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY DEP was found to be a weak direct-acting mutagen in forward and reverse mutation assays in Salmonella typhimurium (Seed, 1982; Rubin et al., 1979; Kozumbo et al., 1982). DEP was negative in mammalian cell chromosomal aberration assays (Ishidate and Odashima, 1977; Tsuchiya and Hattori, 1977). Research indicates that DEP is hydrolyzed to monoesters (Rowland et al., 1977). There is limited evidence that DEP is a weak inducer of peroxisome proliferation (U.S. EPA, 1987). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987 The 1987 Drinking Water Criteria Document for Phthalic Acid Esters has received OHEA review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 08/26/1987 Verification Date -- 08/26/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Diethyl phthalate conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 198908 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Diethyl phthalate CASRN -- 84-66-2 Last Revised -- 08/01/1989 SORD: __VI.A. ORAL RfD REFERENCES Brown, D., K.R. Butterworth, I.F. Gaunt, P. Grasso and S.D. Gangolli. 1978. Short-term oral toxicity study of diethyl phthalate in the rat. Food Cosmet. Toxicol. 16: 415-422. Food Research Laboratoes, Inc. 1955. Toxicological studies of diethyl phthalate. Laboratory No. 67567. Celanese Corp. of America. Summit Research Laboraties, Summit, NJ. NTP (National Toxicology Program). 1984. Diethyl Phthalate: Reproduction and fertility assessment in CD-1 mice when administered in the feed. Final report. NTP, Research Triangle Park, NC. Singh, A.R., W.H. Lawrence and J. Autian. 1972. Teratogenicity of phthalate esters in rats. J. Pharmacol. Sci. 61(1): 51-55. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Brown, D., K.R. Butterworth, I.F. Gaunt, P. Grasso and S.D. Gangolli. 1978. Short-term oral toxicity study of diethyl phthalate in the rat. Food Cosmet. Toxicol. 16: 415-422. Food Research Laboratoes, Inc. 1955. Toxicological studies of diethyl phthalate. Laboratory No. 67567. Celanese Corp. of America. Summit Research Laboraties, Summit, NJ. Ishidate, M., Jr. and S. Odashima. 1977. Chromosome tests with 134 compounds on Chinese hamster cells in vitro -- A screening test for chemical carcinogens. Mutat. Res. 48: 337-354. Kozumbo, W.J., R. Kroll and R.J. Rubin. 1982. Assessment of the mutagenicity of phthalate esters. Environ. Health Perspect. 45: 103-109. Rowland, I.R., R.C. Cottrell and J.C. Phillips. 1977. Hydrolysis of phthalate esters by the gastro-intestinal contents of the rat. Food Cosmet. Toxicol. 15: 17-21. Rubin, R.J., W. Kozumbo and R. Kroll. 1979. Ames mutagenic assay of a series of phthalic acid esters: Positive response of the dimethyl and diethyl esters in TA100. Soc. Toxicol. Ann. Meet., New Orleans, March 11-15. p. 11. (Abstract) Seed, J.L. 1982. Mutagenic activity of phthalate esters in bacterial liquid suspension assays. Environ. Health Perspect. 45: 111-114. Tsuchiya, K. and K. Hattori. 1977. Chromosomal study on human leukocyte cultures treated with phthalic acid ester. Hokkaidoritus Eisei Kenkyusho Ho. 26: 114. (Abstract) U.S. EPA. 1987. Drinking Water Criteria Document for Phthalic Acid Esters. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. External Review Draft. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Diethyl phthalate CASRN -- 84-66-2 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 II. Carcinogen summary on-line 08/01/1989 VI. Bibliography on-line 08/01/1991 I.A.7. Primary and secondary contacts changed 08/01/1991 II.D.3. Primary and secondary contacts changed 08/01/1991 IV.F.1. EPA contact changed 01/01/1992 IV. Regulatory actions updated 02/01/1993 I.A.7. Primary contact changed 02/01/1993 II.D.3. Primary contact changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 396 of 1119 in IRIS (through 2003/06) AN: 239 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199611 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Ethylene-thiourea- (ETU) SY: 96-45-7; 2-IMIDAZOLIDINETHIONE-; ETHYLENE-THIOUREA-; ETHYLENETHIOUREA-; ETU-; HSDB-1643-; IMIDAZOLE-2(3H)-THIONE, 4,5-DIHYDRO-; IMIDAZOLIDINETHIONE-; IMIDAZOLINE-2(3H)-THIONE; IMIDAZOLINE-2-THIOL-; L'ETHYLENE THIOUREE [FRENCH]; MERCAPTOIMIDAZOLINE-; MERCAZIN-I-; N,N'-ETHYLENETHIOUREA-; NA-22-; NA-22-D-; NCI-C03372-; NOCCELER-22-; PENNAC-CRA-; RCRA-WASTE-NUMBER-U116-; RHENOGRAN-ETU-; RHODANIN-S-62-; RODANIN S-62 [CZECH]; SODIUM-22-NEOPRENE-ACCELERATOR-; SOXINOL-22-; TETRAHYDRO-2H-IMIDAZOLE-2-THIONE-; THIOUREA, N,N'-(1,2-ETHANEDIYL)-; UREA,-1,3-ETHYLENE-2-THIO-; USAF-EL-62-; VULKACIT NPV/C; WARECURE-C-; 1,3-ETHYLENE-2-THIOUREA-; 1,3-ETHYLENETHIOUREA-; 2-IMIDAZOLINE-2-THIOL-; 2-MERCAPTO-2-IMIDAZOLINE-; 2-MERCAPTOIMIDAZOLINE-; 2-MERKAPTOIMIDAZOLIN [CZECH]; 2-THIOL-DIHYDROGLYOXALINE-; 4,5-DIHYDRO-2-MERCAPTOIMIDAZOLE-; 4,5-DIHYDROIMIDAZOLE-2(3H)-THIONE RN: 96-45-7 HSN: 1643 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199611 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Ethylene thiourea (ETU) CASRN -- 96-45-7 Last Revised -- 11/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Increased incidence NOAEL: None 3000 1 8E-5 of thyroid hyperplasia mg/kg/day LOAEL: 0.25 mg/kg/day Rat 24-Month (5 ppm in feed) Feeding Study Graham et al., 1975 ---------------------------------------------------------------------------- *Conversion Factors: 5 ppm (mg/kg of feed ) x 0.05 (assumed rat food consumption per body weight) = 0.25 mg/kg/day PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Graham, S.L., K.J. Davis, W.H. Hansen and C.H. Graham. 1975. Effects of prolonged ethylene thiourea ingestion on the thyroid of the rat. Food Cosmet. Toxicol. 13: 493-499. The oral toxicity of ethylene thiourea (ETU) was investigated in a chronic feeding study in which Charles River CD-1 rats were fed 0, 5, 25, 125, 250 and 500 ppm of the test substance for 24 months. These doses provided 0, 0.25, 1.25, 6.25, 12.5 and 25 mg/kg/day based on the assumption that rats consume 5% of their body weight of food each day. Groups of rats (68/sex) were assigned to each of the dose groups. The major endpoints of this study were histological examination of endocrine organs and other major tissues, organ weights and thyroidal uptake of Iodine-131. A significant incidence of thyroid carcinomas and adenocarcinomas was observed among rats receiving 250 and 500 ppm. Thyroid hyperplasia was observed among rats receiving 5, 25, 125 and 250 ppm with increased incidence at the higher doses. A significant decrease in body weight was found among rats receiving 500 ppm at both 18 and 24 months. A statistically significant decrease in liver-to-body weight ratio was seen in females receiving 5 or 25 ppm. Significant increases in thyroid-to-body weight ratios were seen in males and females receiving 500 ppm, and in females receiving 250 ppm. Studies of Iodine-131 uptake performed at the end of the study did not show a significant dose-response relationship. The LOAEL derived from this study based upon detection of thyroid hyperplasia was 5 ppm (0.25 mg/kg/day). Thyroid hyperplasia does not inevitably lead to development of adenomas and carcinomas. Thyroid hyperplasia can develop in response to many forms of physiologic stress and often regresses spontaneously. In the Graham et al. (1975) study many rats in the 5-ppm dose group exhibited thyroid hyperplasia following 2 years of dosing, but none of these rats showed thyroid adenomas or carcinomas. In addition, Iodine-131 uptake tests were not significantly different for the 5-ppm dose group when compared with control rats, suggesting that the thyroids of the 5-ppm rats were functionally normal. The occurrence of thyroid hyperplasia at this dose is not considered to be preneoplastic since carcinomas were not seen at higher doses (25 or 125 ppm). An interim report of the findings from the first year of the previous study was published separately by Graham et al. (1973); that study also involved feeding 0, 5, 25, 125, 250 and 500 ppm of ETU. Body weight, thyroid and other organ weights, thyroidal Iodine-131 uptake, hematology and histology were the endpoints that were determined. There were significant decreases in total body weight and increases in thyroid weight for rats receiving 125, 250 and 500 ppm of ETU. At the time intervals for which interim determinations were made (2 and 6 months), hyperplasia of the thyroid was observed only at 500 ppm. The NOAEL for 6 months ETU treatment was 25 ppm (1.25 mg/kg/day). At 1 year of treatment the lowest level of ETU tested, 5 ppm or 0.25 mg/kg/day was the LOAEL for thyroid hyperplasia. The NTP (1989) performed a chronic feeding study to determine the toxicity and carcinogenicity of ETU in F344 and B6C3F1 mice. This study combined a perinatal exposure with the traditional NTP chronic bioassay. A complicated 4x4 study design involving adult-only exposure, perinatal-only exposure, and combined perinatal-adult exposure was used. In the rats receiving adult-only exposure at 83 and 250 ppm of ETU in the diet for 36 and 105 weeks there was a dose-related increase in the incidence and severity of thyroid follicular cell hyperplasia, an increase in TSH levels, and a decrease in serum thyroxin levels. Perinatal-only exposure resulted in an increased incidence of thyroid follicular cell hyperplasia only at the highest tested level of 90 ppm. The lowest dietary level of ETU tested in adult-only exposure for rats, 83 ppm (4.1 mg/kg/day), was considered the LOAEL. In mice, exposure to 330 or 1000 ppm for 105 weeks resulted in dose-related increases of thyroid follicular cell hyperplasia with associated increases in TSH levels. Hepatic hypertrophy was also observed. For mice 1000 ppm (0.15x1000=150 mg/kg/day) was considered the LOAEL. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 100 was used to account for inter- and intra-species differences. An additional uncertainty factor of 3 is used since limited developmental toxicological and multi-generation data are available. An additional UF of 10 was used since the RfD was establised from a LOAEL rather than a NOAEL. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) The teratogenicity of ETU has been investigated in mice, rats, and rabbits in the gavage studies of Khera (1973) which show LOAELs for developmental toxicity of around 5 mg/kg/day. In perinatal studies carried out by NTP (1989), ETU was administered in the diet of F344/N rats and C57Bl/6N mice from 2 weeks prior to breeding through gestation, lactation, and up to 9 week post-weaning. Rats were fed 0, 8, 25, 83 or 250 ppm and mice 0, 33, 100, 330 or 1000 ppm. No external gross fetal anomalies or other developmental effects were noted in any dosage group of rats. Based on decreased survival of rat pups between postnatal days 0 and 4 and reduction in body weight gains in male weanling rats at 250 ppm, this dose (approximately 0.075 [weanling rats consume 0.075% of their body weight in feed each day] x 250=18.8 mg/kg/day) was considered a LOAEL and the next lowest dose 83 ppm (approximately 0.075x83=6.2 mg/kg/day) was the NOAEL. No external gross fetal anomalies or other developmental effects were noted in any dosage group of mice. Based on reduced survival of mouse pups at postnatal day 28 and lower mean body weights at 1000 ppm (approximately 0.15x1000=150 mg/kg/day), this dose was considered the LOAEL and the next lowest dose, 330 ppm (approximately 0.15x330=49.5 mg/kg/day), was the NOAEL. In an unpublished study reviewed by Rohm and Haas (1985), CD-1 mice (15/sex/group) were given ETU in the diet at 0, 1, 10, 100 or 1000 ppm for 90 days. The NOAEL was considered 10 ppm (1.72 mg/kg/day for males and 2.38 mg/kg/day for females). At 100 ppm, both sexes had increased incidences of thyroid hyperplasia and females had increased liver weights. In a study reported by Graham and Hansen (1972) male Osborne-Mendel rats (20/dose/duration) received 0, 50, 100, 500 or 750 ppm ETU in the diet for 30, 60, 90 or 120 days. Histology results were reported only for rats in the 90-day dosing period. No thyroid changes were seen in the 50-ppm group and slight hyperplasia was seen in the 100-ppm group. A NOAEL of 50 ppm was established from this study and a LOAEL of 100 ppm. Fredenthal et al. (1977) performed a study in which Sprague-Dawley rats (20/dose/duration) received 0, 1, 5, 25, 125 or 625 ppm of ETU in the diet for 30, 60 or 90 days. At 25 ppm, an increase in serum thyroxin and some degree of thyroid hyperplasia were seen at 60 days but not at 30 or 90 days. Because only slight transient histological changes were seen at 25 ppm the authors considered this dose the NOAEL for the 90-day study. Two unreported studies in rhesus monkeys, both of approximately 6-months duration, showed mild thyroid follicular cell hyperplasia at 50 ppm and moderate to severe hyperplasia was seen at 250 ppm. Doses of 0, 2, 10, 50 and 250 ppm were tested. Serum T4 levels were decreased in the 250 ppm group. No serum chemistry or histological changes were reported for the lower dosage groups. The results of these studies indicated that a NOAEL had not been demonstrated. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium A medium degree of confidence for the RfD is determined since the chronic rat study of Graham et al. (1975) provides sufficient data with multiple appropriate end points. There were adequate group sizes with many test dose groups. Additional data for chronic studies performed in mice were reported in the NTP study and the unpublished study by Rohm and Haas (1985). Seven studies in rats, three studies in mice, one study in cats, and one study in rabbits have explored the developmental effects of ETU. Adequate group sizes were used in the critical rat and mouse studies and dose levels ranging from 10-80 mg/kg/day were used in the Khera (1973) study. Thus, medium confidence in the data base is appropriate. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA. 1984. Health and Environmental Effects Profile for Ethylene Thiourea (2-imidazolidinethione). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/X-84/131. NTIS PB 88-120621/AS. The Health and Environmental Effects Profile for Ethylene Thiourea received limited peer review and extensive Agency-wide review in 1984. Other EPA Documentation -- U.S. EPA, 1985, 1990 Agency Work Group Review -- 12/09/1986, 10/15/1987, 01/21/1988, 02/25/1988, 02/20/1991 Verification Date -- 02/20/1991 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199209 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Ethylene thiourea (ETU) CASRN -- 96-45-7 NORC: Not available at this time. ============================================================================ UDCA: 199309 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Ethylene thiourea (ETU) CASRN -- 96-45-7 NOCA: Not available at this time. ============================================================================ UDSO: 199207 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Ethylene thiourea (ETU) CASRN -- 96-45-7 Last Revised -- 07/01/1992 SORD: __VI.A. ORAL RfD REFERENCES Freudenthal, R.I., G. Kerchner, R. Persing and R.L. Baron. 1977. Dietary subacute toxicity of ethylene thiourea in the laboratory rat. J. Environ. Pathol. Toxicol. 1: 147-161. Graham, S.L. and W.H. Hansen. 1972. Effects of short-term administration of ethylenethiourea upon thyroid function of the rat. Bull. Environ. Contam. Toxicol. 7: 19-25. Graham, S.L., W.H. Hansen, K.J. Davis and C.H Perry. 1973. Effects of one-year administration of ethylenethiourea upon the thyroid of the rat. J. Agric. Food Chem. 21(3): 324-329. Graham, S.L., K.J. Davis, W.H. Hansen, and C.H. Graham. 1975. Effects of prolonged ethylene thiourea ingestion on the thyroid of the rat. Food Cosmet. Toxicol. 13: 493-499. Khera, K.S. 1973. Ethylenethiourea: Teratogenicity study in rats and rabbits. Teratology. 7: 243-252. NTP (National Toxicology Program). 1989. NTP Technical Report on the perinatal toxicity and carcinogenicity studies of ethylene thiourea (CAS No. 96-45-7) in F/344 rats and B6C3F1 mice (feed studies). NTP-TR-388. NIH Publ. No. 90-28-43. Rohm and Haas Company. 1985. MRID No. 00154192. HED Doc. No. 005038, 005370. Available from EPA. Write to FOI, EPA, Washington, DC. 20460. U.S. EPA. 1984. Health and Environmental Effects Profile for Ethylene Thiourea (2-imidazolidinethione). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/X-84/131. NTIS PB 88-120621/AS. U.S. EPA. 1985. Reportable Quantity Document for Ethylene Thiourea. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1990. Drinking Water Quantification of Toxicologic Effects of Ethylene Thiourea (ETU). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Ethylene thiourea (ETU) CASRN -- 96-45-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 05/01/1991 I.A. Oral RfD summary now on-line 05/01/1991 VI. Bibliography on-line 01/01/1992 IV. Regulatory Action section on-line 07/01/1992 I.A.6. Oral RfD source references corrected 07/01/1992 VI.A. Oral RfD references corrected 09/01/1992 I.B. Inhalation RfC now under review 09/01/1993 II. Carcinogenicity assessment now under review 02/01/1994 I.A.1. NOAEL and LOAEL were reversed; corrected 11/01/1996 I.A.7. Primary contact's office changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 397 of 1119 in IRIS (through 2003/06) AN: 241 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199009 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Fluometuron- SY: 2164-17-2; C-2059-; CIBA-2059-; COTORAN-MULTI-50WP-; COTTONEX-; 1,1-DIMETHYL-3-(3-TRIFLUOROMETHYLPHENYL)UREA; 1,1-DIMETHYL-3-(ALPHA,ALPHA,ALPHA-TRIFLUORO-M-TOLYL) UREA; HERBICIDE-C-2059-; LANEX-; NCI-C08695-; N-(3-TRIFLUOROMETHYLPHENYL)-N'-N'-DIMETHYLUREA; N-(M-TRIFLUOROMETHYLPHENYL)-N',N'-DIMETHYLUREA; PAKHTARAN-; 3-(5-TRIFLUORMETHYLPHENYL)-1,1-DIMETHYLHARNSTOFF; 3-(M-TRIFLUOROMETHYLPHENYL)-1,1-DIMETHYLUREA; UREA, 1,1-DIMETHYL-3-(ALPHA,ALPHA,ALPHA-TRIFLUORO-M-TOLYL)-; UREA, N,N-DIMETHYL-N'-(3-(TRIFLUOROMETHYL)PHENYL)- RN: 2164-17-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199009 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Fluometuron CASRN -- 2164-17-2 Last Revised -- 09/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- No adverse effects NOAEL: 250 ppm diet 1000 1 1.3E-2 (12.5 mg/kg/day) mg/kg/day 103-Week Rat Feeding Study LEL: None NCI, 1980 ---------------------------------------------------------------------------- *Conversion Factors: 1 ppm = 0.05 mg/kg/day (assumed rat food consumption) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NCI (National Cancer Institute). 1980. Bioassay of Fluometuron for Possible Carcinogenicity, CAS No. 2164-17-2, NCI-CG-TR-195, NTP-80-11, NIH Publ. No. 80-1751. National Institute of Health, Bethesda, MD. Groups of rats (50/sex/dose) were fed diets containing 0, 125, or 250 ppm of fluometuron for 103 weeks. All surviving animals were killed at 103 to 105 weeks. Mean body weights and survival of the dosed groups of male and female rats were essentially the same as those of the corresponding control group. No observed effects were seen at the highest dose tested, 250 ppm (12.5 mg/kg/day), which was the NOAEL for this study. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was used to account for the inter- and intraspecies differences and for the fact that the data base on toxicity is incomplete (e.g., lacking a mammalian reproductive study). Furthermore, the available supporting studies are of low quality. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Data Considered for Establishing the RfD: 1) 103-Week Feeding - rat: Principal study - see previous description; no core grade 2) 90-Day Feeding - rat: NOEL=7.5 mg/kg/day; LEL=75 mg/kg/day (decrease in body weight and enlarged spleens); no core grade (Ciba Agrochemical, 1965a) 3) 90-Day Feeding - dog: NOEL=10 mg/kg/day; LEL=100 mg/kg/day (inflammatory reaction in kidney and liver); no core grade (Ciba Agrochemical, 1965b) 4) Teratology - rabbit: Maternal and Fetotoxic NOEL not established; LEL=50 mg/kg/day; minimum for teratogenicity otherwise supplementary (Ciba-Geigy, 1984) 5) 103-Week Feeding - mouse: NOEL=500 ppm (75 mg/kg/day); LEL=1000 ppm (150 mg/kg/day) (marginal increase in liver tumors); no core grade (NCI, 1980) Data Gap(s): Chronic Rat Feeding Study; Chronic Dog Feeding Study; Rat Reproduction Study; Rat Teratology Study; Rabbit Teratology Study CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low The principal study appears to be of low quality and is given a low confidence rating. Since the data base on toxicity is incomplete and of apparently low quality, the data base is given a low confidence rating. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- Pesticide Registration Standard, 1985; Pesticide Registration Files Agency Work Group Review -- 07/08/1986, 03/18/1987 Verification Date -- 03/18/1987 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Fluometuron CASRN -- 2164-17-2 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Fluometuron CASRN -- 2164-17-2 NOCA: Not available at this time. ============================================================================ UDSO: 199009 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Fluometuron CASRN -- 2164-17-2 Last Revised -- 09/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Ciba Agrochemical Company. 1965a. MRID No. 00019034. Available from EPA. Write to FOI, EPA, Washington, DC 20460. Ciba Agrochemical Company. 1965b. MRID No. 00019035. Available from EPA. Write to FOI, EPA, Washington, DC 20460. Ciba-Geigy Corporation. 1984. MRID No. 00147554. Available from EPA. Write to FOI, EPA, Washington, DC 20460. NCI (National Cancer Institute). 1980. Bioassay of Fluometuron for Possible Carcinogenicity, CAS No. 2164-17-2, NCI-CG-TR-195, NTP-80-11, NIH Publ. No. 80-1751. National Institute of Health, Bethesda, MD. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Fluometuron CASRN -- 2164-17-2 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.1. Dose conversion clarified 09/01/1990 I.A.2. Text edited 09/01/1990 I.A.4. Citations added 09/01/1990 III.A. Health Advisory on-line 09/01/1990 VI. Bibliography on-line 01/01/1992 IV. Regulatory action updated 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 398 of 1119 in IRIS (through 2003/06) AN: 251 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Mirex- SY: 2385-85-5; BICHLORENDO-; CG-1283-; CYCLOPENTADIENE,-HEXACHLORO-,-DIMER-; DECANE,PERCHLOROPENTACYCLO-; DECHLORANE-; DECHLORANE-4070-; 1,1A,2,2,3,3A,4,5,5,5A,5B,6-DODECACHLOROOCTAHYDRO-1,3,4-METHENO-1H-CYCLOBUTACD)PENTALENE; DODECACHLOROOCTAHYDRO-1,3,4-METHENO-2H-CYCLOBUTA (C,D)PENTALENE; DODECACHLOROPENTACYCLO(3.2.2.0(SUP 2,6),0(SUP 3,9),0(SUP 5,10))DECANE; DODECACHLOROPENTACYCLODECANE-; ENT-25,719-; FERRIAMICIDE-; GC-1283-; HEXACHLOROCYCLOPENTADIENE-DIMER-; 1,2,3,4,5,5-HEXACHLORO-1,3-CYCLOPENTADIENE-DIMER-; HRS-L276-; 1,3,4-METHENO-1H-CYCLOBUTA(CD)PENTALENE, DODECACHLOROOCTAHYDRO-; 1,3,4-METHENO-1H-CYCLOBUTA(CD)PENTALENE, 1,1A,2,2,3,3A,4,5,5,5A,5B,6-DODECACHLOROOCTAHYDRO-; NCI-C06428-; PERCHLORODIHOMOCUBANE-; PERCHLOROPENTACYCLO(5.2.1.0(SUP 2,6).0(SUP 3,9).0(SUP 5,8))DECANE; PERCHLOROPENTACYCLODECANE- RN: 2385-85-5 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199210 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Mirex CASRN -- 2385-85-5 Last Revised -- 10/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Liver cytomegaly, NOAEL: 1 ppm 300 1 2E-4 fatty metamorphosis, (0.07 mg/kg/day) mg/kg/day angiectasis; thyroid cystic follicles LOAEL: 10 ppm (0.7 mg/kg/day) Rat Chronic Dietary Feeding Study NTP, 1990 ---------------------------------------------------------------------------- *Conversion Factors: None PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1990. Toxicology and Carcinogenesis Studies of MIREX (CAS No. 2385-85-5) in F344/N Rats (Feed Studies). NTP TR 313. Groups of 52 male and 52 female F344/N rats (initial body weight 120 and 100 g, respectively) were fed mirex (reported purity >96%) for 104 weeks. Reported mirex doses were in ppm and when converted to mg/kg-day were 0, 0.007, 0.07, 0.7, 1.8 and 3.8 mg/kg-day for males and 0, 0.007, 0.08, 0.7, 2.0 and 3.9 mg/kg-day for females. In a second study, 52 female F344/N rats were fed diets containing mirex at doses of 3.9 and 7.7 mg/kg-day. The following parameters were used to assess toxicity: clinical signs, body weight, survival and histologic examination of adrenal gland, bone marrow, brain, esophagus, heart, kidney, liver, lymph node (submandibular and/or mesenteric), lung and bronchi, mammary gland, pancreas, parathyroid gland, pituitary gland, prostrate/testis or ovary/uterus, salivary gland, skin, small and large intestine, spleen, stomach, thymus, thyroid gland, trachea and urinary bladder. Survival of male rats in the 1.8 and 3.8 mg/kg-day groups was significantly less than controls (64% and 71% non-accidental deaths before termination vs. 15% in controls, p<0.001). Male rats in the 1.8 and 3.8 mg/kg-day dose groups gained less weight than controls during the first 70 weeks of exposure and lost weight between 70 and 104 weeks of exposure; body weights after 104 weeks of exposure were 11% (1.8 mg/kg-day) and 18% (3.8 mg/kg-day) less than controls. In the first study, female rats in the 3.9 mg/kg-day group gained less weight than controls; body weights after 104 weeks of exposure were 8% less than controls. In the second study, females in the 3.9 and 7.7 mg/kg-day groups gained less weight than controls; body weights after 104 weeks of exposure were 8% (3.9 mg/kg-day) and 18% (7.7 mg/kg-day) less than controls. No clinical signs of toxicity in male or female rats were reported. Histologic examinations revealed dose-related changes in the parathyroid gland, kidney, liver, spleen and thyroid. In the parathyroid gland, dose-related increased incidence of hyperplasia was observed in male rats at and above 0.007 mg/kg-day. The incidences of hyperplasia were as follows: control, 6/32 (19%); 0.007 mg/kg-day, 12/39 (31%); 0.07 mg/kg-day, 13/39 (33%); 0.7 mg/kg-day, 18/40 (45%); 1.8 mg/kg-day, 22/50 (44%); and 3.8 mg/kg-day, 24/45 (53%). A dose-related increase in severity of nephropathy was observed in male rats at and above 0.7 mg/kg-day and in female rats at and above 2 mg/kg-day. Medullary hyperplasia was also seen in male rats at and above 0.7 mg/kg-day. Parathyroid hyperplasia and renal medullary hyperplasia are consistent with and may have been secondary to nephropathy, which was more severe in the rats exposed to mirex. In the liver, fatty metamorphosis, cytomegaly and angiectasis were detected in male rats at and above 0.7 mg/kg-day with necrosis at and above 1.8 mg/kg-day. Fatty metamorphosis, cytomegaly and necrosis were also observed in female rats at and above 0.7 mg/kg-day. Splenic fibrosis and cystic follicles of the thyroid were seen in male rats at and above 0.7 mg/kg-day. Based on liver and thyroid effects, this study defines a NOAEL of 0.07 mg/kg-day and a LOAEL of 0.7 mg/kg-day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 300 reflects 10 for intraspecies variability, 10 for interspecies extrapolation and 3 for lack of a complete data base, specifically lack of multi-generational data on reproductive effects and cardiovascular toxicity data. MF -- 1. ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) The previously verified RfD was based on the Shannon (1976) study. Shannon (1976) performed studies in which prairie voles (Microtus ochrogaster) were exposed in the diet to mirex at 0, 0.1 and 0.5 ppm. The studies consisted of: single generation, 90-day exposure; single-generation, continuous exposure; and multi-generation, continuous exposure. Shannon chose M. ochrogaster to examine the effects of mirex on a wildlife species. Offspring (10/sex/dose group) from the first litter of the 0, 0.1 and 0.5 ppm groups of a single-generation, continuous exposure study were used as the first generation of the multi-generation, continuous exposure study. These animals were separated into 10 pairs (male and female) at approximately 60 days of age according to concentration of mirex exposure. The 0, 0.1 and 0.5 ppm mirex exposures continued through premating, mating, gestation and lactation for one litter. Shannon noted significant dose-related effects including decreased lactation index and increased percent mortality of pups in the first generation. In the second generation, significant differences were found in the percent survival of offspring to days 4 and 21 and in percent mortality of pups. Several difficulties were noted in this study; discrepancies in statistical analyses and lack of raw data to validate some of the results. The previous RfD was 2E-6 mg/kg-day. Effects of mirex on the parathyroid and kidney reported in NTP (1990) have not been corroborated in chronic (Ulland et al., 1977) or subchronic (Larson et al., 1979) studies. However, NTP (1990) detected a dose-related increase in severity of nephropathy against a high but not unusual incidence of age-related nephropathy in rats (98% in controls). Thus, mirex may enhance the severity of age-related nephropathy, in which case, effects on the kidney would be detected only in a chronic study in which a rigorous severity assessment of the nephropathy was performed. The Ulland et al. (1977) study does not qualify as such a study; furthermore, histologic examinations were performed in the Ulland et al. (1977) study 6 months after exposure to mirex ended. Effects on the liver and thyroid reported in NTP (1990) have been corroborated (Gaines and Kimbrough, 1970; Fulfs et al., 1977; Ulland et al., 1977; Larson et al., 1979; Chu et al., 1981a; Yarbrough et al., 1981). Effects on the testis (hypocellularity and depressed spermatogenesis) reported in Yarbrough et al. (1981) were not detected in NTP (1990), however, these effects may have been masked in the NTP (1990) study by age-related degenerative changes in the testis. Reproductive and developmental effects (decreased fertility, fetal cataracts and edema) have been reported in several studies (Yarbrough et al., 1981; Gaines and Kimbrough, 1970; Chu et al., 1981b; Chernoff et al., 1979a,b; Chernoff and Kavlock, 1982; Grabowski and Payne, 1980; Kavlock et al., 1982; Scotti et al., 1981; Ware and Good, 1967). Effects on the fetal electrocardiogram have also been reported (Grabowski, 1983; Grabowski and Payne, 1980, 1983a,b). Ulland et al. (1977) fed diets containing 0, 50 or 100 ppm mirex (reported purity 99%) to groups of 26 male and 26 female CD rats for 18 months. Reported mirex doses were 0, 1.5 and 3 mg/kg-day. Histologic evaluations made 6 months after exposure to mirex ended included adrenal glands, cerebrum, cerebellum, esophagus, heart, kidneys, liver, lungs, ovaries, pancreas, parathyroid gland, pituitary glands, spinal cord, small and large intestine, spleen, stomach, testis, thymus, thyroid, urinary bladder and uterus. Mortality of male rats in the dose groups at and above 50 ppm and females in the 100 ppm group was greater than rats in the control group. Histologic evaluation of the liver revealed cytomegaly, vacuolization, fatty metamorphosis and necrosis in rats exposed to mirex. No other treatment-related non-neoplastic lesions were reported in other tissues. This study identifies a FEL of 50 ppm (1.5 mg/kg-day). Fulfs et al. (1977) conducted chronic bioassays in mice and monkeys. Groups of 100 male and 100 female CD-1 mice were fed diets containing 0, 1, 5, 15 or 30 ppm mirex (purity not specified) for 18 months. Estimated mirex doses based on U.S. EPA (1987) and assumed average body weights of 0.036 kg were: 0, 0.17, 0.86, 2.6 and 5.2 mg/kg-day. Although survival was not specifically addressed, Fulfs et al. (1977) report that the 30 ppm group was removed from the study due to poor survival. This suggests that the 30 ppm dose is an FEL. Toxicity was assessed from biochemical, histochemical and histological (light and electron microscopy) evaluations of the liver. Female mice in the 1 ppm group had a significant increase in relative liver weight. Histologic evaluations of the liver revealed cellular hypertrophy, cellular or multicellular necrosis, and proliferation of the smooth endoplasmic reticulum (SER) at and above 5 ppm and nuclear inclusions at 30 ppm. Histochemical evaluations of the liver revealed centrilobular depletion of glucose-6-phosphatase activity at and above 5 ppm. Liver hypertrophy and SER proliferation are consistent with observed induction of mixed function oxidase over the same dose range in these animals (Byard et al., 1975). This study (Fulfs et al., 1977) identifies a NOAEL of 1 ppm (0.17 mg/kg-day) and a LOAEL of 5 ppm (0.86 mg/kg-day). In the monkey study, Fulfs et al. (1977) administered oral gavage doses of 0 or 0.25 mg/kg-day mirex (purity not specified) in corn oil, 6 days/week for 36 months (0.21 mg/kg-day when multiplied by 6/7 to adjust to 7 days/week); or 1 mg/kg-day, 6 days/week for 16, 19 or 26 months (0.85 mg/kg-day when multiplied by 6/7 to adjust to 7 days/week) to groups of 2 male and 2 female rhesus monkeys (Macaca mulatta). Histochemical and histologic evaluations of the liver revealed "occasional" focal lymphocytic infiltration in treated monkeys (dose unspecified). This study identifies a 0.21-0.85 mg/kg-day LOAEL. Yarbrough et al. (1981) conducted a 28-day study in which groups of 10 male Sprague-Dawley rats (60-85 g initial body weight) were fed diets containing 0, 0.5, 5.0, 50 or 75 ppm mirex (repurified from technical grade, reported purity 99.5%). Estimated mirex doses based on reported average food intake for controls of 14 g/day (which was not significantly different from mirex-treated groups) and reported average initial body weight (72 g) and weight gain (183 g) were 0, 0.05, 0.5, 5 and 7 mg/kg-day. Toxicity was assessed from measurements of serum enzymes, hematologic parameters, sperm counts, organ weights, and histologic evaluation of liver, thyroid and testis. There appeared to be a significantly decreased sperm count (53% decrease at 0.5 ppm, p<0.01), but this may have been due to the coincidence of the termination of the experiment and the inception of sexual maturity in all test groups. Thus, sexual maturity may have been delayed in dosed test groups due to mirex effects. Histologic evaluation of the liver revealed cytoplasmic alterations (increased density) that were "subtle and inconsistent" at 0.5 ppm, consistently observed at 5 ppm, and progressed to cytoplasmic inclusions with cell swelling at and above 50 ppm. Histologic evaluation of the testis revealed hypocellularity, decreased spermatogenesis, and luminal nucleated and giant cells, characteristic of testicular degeneration (dose not specified). Histologic evaluation of the thyroid revealed epithelial cell hypertrophy, colloid depletion, follicular atrophy and focal papillary formations present inconsistently at 5 ppm and more prominent at and above 50 ppm. This study identifies a NOAEL of 0.5 ppm (0.05 mg/kg-day) and a LOAEL of 5 ppm (0.5 mg/kg-day). Groups of 40 male Sprague-Dawley rats (initial body weight 60-90 g) were fed diets containing 0, 5 or 50 ppm mirex (reported purity 98%) for 28 days and were evaluated for toxic effects at 28 days, or at 12, 24 or 48 weeks after exposure to mirex ended (Chu et al., 1981a). Estimated doses based on reported average food intakes and assumed average initial body weight of 75 g and reported final body weights were 0, 0.7 and 6.5 mg/kg-day. Toxicity was evaluated from complete hematologic analysis, serum chemistry, measurements of testicular sorbitol dehydrogenase and hepatic mixed function oxidase activity, serum T3 and T4 levels, and histologic examination of adrenal gland, bone marrow, brain, esophagus, heart, kidney, liver, lung, trachea and bronchi, lymph node (mesenteric and mediastinal), pancreas, parathyroid, pituitary, skeletal muscle, small and large intestine, spleen, stomach, testis and epididymis, thoracic aorta, thymus and thyroid. Histologic evaluations revealed lesions of the liver and thyroid in the 5 and 50 ppm dose groups. Liver lesions included fatty infiltration, cytoplasmic vacuolization, anisokaryosis and cellular necrosis. Thyroid lesions consisted of thickening of the follicular epithelium, loss of colloid and collapse of the follicles. Thyroid lesions regressed over the 48 week post-exposure observation period. Liver lesions persisted in the 50 ppm dose group. This study identifies a LOAEL of 5 ppm (0.7 mg/kg-day). Groups of 10 male and 10 female Sherman rats (body weights not reported) were fed diets containing 0, 1, 5 or 25 ppm mirex (technical grade, reported purity 98%) for 166 days (Gaines and Kimbrough, 1970). Reported mirex doses were 0, 0.04-0.09, 0.21-0.48 and 1.3-3.1 mg/kg-day for males and 0, 0.06-0.10, 0.31-0.49 and 1.8-2.8 mg/kg-day for females. Toxicity was assessed from histologic examination (using light and electron microscopy) of the liver, which revealed dose-related hepatic cytomegaly in male and female rats. Incidences in male rats were: control, 0/10; 0.04-0.09 mg/kg-day, 2/10 (20%); 0.21-0.48 mg/kg-day, 5/10 (50%); and 1.3-3.1 mg/kg-day, 10/10 (100%). Incidences in females were: control, 0/10; 0.06-0.10 mg/kg-day, 0/10; 0.31-0.49 mg/kg-day, 3/10 (30%); and 1.8-2.8 mg/kg-day, 5/10 (50%). This study identifies a LOAEL of 0.04-0.09 mg/kg-day. In a series of subchronic studies, Larson et al. (1979) examined the effects of mirex in the diet of rats and beagle dogs. Groups of Charles River rats (10/sex/dose) were fed diets containing 0, 5, 20, 80, 320 or 1280 ppm mirex (reported purity 98%) for 13 weeks. Estimated mirex doses based on measured food consumption (the mean of food consumed at 4 and 13 weeks) were 0, 0.4, 1.3, 6.2, 24 and 96 mg/kg-day for males and 0, 0.3, 1.3, 5.8, 23 and 95 mg/kg-day for females. Toxicity was assessed from a hematologic analysis (unspecified), urinalysis (unspecified), and histologic examination of adrenal gland, bone marrow, brain, cecum, gonad, heart, kidney, liver, lung, pancreas, pituitary, small and large intestine, spleen, stomach, urinary bladder and thyroid. Male rats in the 80 ppm dose group and female rats in the 320 ppm dose group had significantly enlarged livers (increased liver/body weight ratio, p<0.05). Histologic examination revealed vacuolization and cytomegaly in livers of males in the 80 ppm dose group. Survival of male rats in the 1280 ppm dose group was decreased relative to controls (0 vs. 100% in controls) as was survival of female rats in the 1280 ppm group (50% vs. 100% in controls). This study identifies a NOAEL of 20 ppm (1.3 mg/kg-day), a LOAEL of 80 ppm (6.2 mg/kg-day), and a FEL of 1280 ppm (95 mg/kg-day). Larson et al. (1979) fed a diet containing 0, 4, 20 or 100 ppm mirex (reported purity 98%) to purebred beagle dogs (2/sex/dose) (7-12 kg initial body weight) for 13 weeks. Estimated mirex doses based on U.S. EPA (1987) and reported average body weights of 11 kg for males and 9 kg for females were 0, 1, 5 and 27 mg/kg-day for males and 0, 1, 5 and 24 mg/kg-day for females. Toxicity was assessed from hematologic analyses (unspecified), blood chemistry (glucose, urea nitrogen, glutamic oxaloacetic transaminase, alkaline phosphatase, cholinesterase), sulfobromophthalein retention, urinalyses (unspecified), and histologic examination of adrenal gland, bone marrow, brain, cecum, gonad, heart, kidney, liver, lung, pancreas, pituitary, small and large intestine, spleen, stomach, urinary bladder and thyroid. Male and female dogs in the 100 ppm dose groups gained less weight than controls and had elevated serum alkaline phosphate levels. One male and one female dog in these groups died (13 and 10 weeks, respectively); the male had increased sulfobromophthalein retention. Results of histologic examinations were reported as unremarkable. This study identifies a FEL of 100 ppm (24 mg/kg-day). Fulfs et al. (1977) fed Sprague-Dawley rats (number, sex and initial body weights not specified) diets containing 0, 5 or 30 ppm mirex (purity not specified) for 12 or 8 months, respectively. Mirex doses based on U.S. EPA (1987) and assumed average body weights of 0.43 kg were 0, 0.4 and 2.2 mg/kg-day. Histochemical and histologic evaluations of the liver revealed "minimal" proliferation of smooth endoplasmic reticulum. This study identifies a NOAEL of 5 ppm (0.4 mg/kg-day). Gaines and Kimbrough (1970) conducted a reproduction study of mirex (technical grade, reported purity 98%) in the diets of Sherman rats. Groups of 10 male rats (body weights not reported) were fed 0 or 25 ppm mirex for either 45 or 102 days. Groups of 10 female rats were fed 0 or 25 ppm mirex for 45 days or 0, 5 or 25 ppm mirex for 102 days. After the specified exposure period, rats fed mirex were mated with untreated rats. Females continued on their respective diets through gestation and lactation. Offspring from the rats exposed for 102 days were held after weaning and fed a nontreated diet until they were 90-100 days old. They were pair-mated within respective groups and their offspring held until weaning and checked for abnormalities. Reported mirex doses for males were 0 and 1.3-3.1 mg/kg-day. Reported doses for females were 0, 0.31-0.49 and 1.8-2.8 mg/kg-day. Females exposed to 25 ppm for 45 days prior to mating and through gestation and lactation had significantly smaller litters (8.5 vs. 12.0 pups per litter, p<0.05) and survival of pups to weaning was significantly decreased (53% vs. 89%, p<0.05). Pups born to these females had a 33% incidence of cataracts compared to 0% in controls. Survival to weaning of pups born to females treated with 25 ppm for 102 days prior to mating and through gestation and lactation was significantly decreased (61% vs. 94% survival, p<0.05) and pups born to these females had a 46.2% incidence of cataracts compared to 0% in controls. These parameters were not significantly affected in pups born to females treated with 5 ppm. Litters of pups born to females that had not been treated with mirex were transferred at birth to foster mothers that had been fed diets containing 0 or 5 ppm mirex for 73 days. Survival to weaning of pups transferred to treated females was significantly lower than pups transferred to untreated females (53.9% vs. 95.8%, p<0.05) and pups transferred to treated females had a significantly greater incidence of cataracts (37.5% vs. 0%, p<0.05). This study identifies a FEL of 5 ppm (0.31-0.49 mg/kg-day). Groups of 10 male and 20 female Sprague-Dawley rats (92 g initial body weight) were fed diets containing mirex (reported purity >98%) at 0, 5, 10, 20 or 40 ppm for 13 weeks prior to mating, during a 2-week mating period and through gestation and lactation (Chu et al., 1981b). Mated pairs were exposed to the same dietary levels; males were discarded from the study after mating. Estimated mirex doses for females based on U.S. EPA (1987) and reported average initial body weight of 92 g and average weight gain of controls of 195 g were: 0.5, 1, 2 and 4 mg/kg-day. Toxicity in females was assessed from a complete hematologic analysis (hemoglobin, total and differential counts, bone marrow smear), serum chemistry (electrolytes, protein, enzymes, cholesterol, uric acid, bilirubin), measurements of liver aniline hydroxylase and aminopyrine demethylase activities; and histologic examination of adrenal gland, bone marrow, brain, bronchi, trachea and lungs, esophagus, eye, heart, kidney, liver, lymph nodes (mesenteric and mediastinal), ovaries, pancreas, parathyroid, peripheral nerves, pituitary, salivary glands, skeletal muscle, small and large intestine, skin, spleen, stomach, thoracic aorta, thymus, thyroid and uterus. The same histologic examinations (including prostrate, seminal vesicles and testes of males) and measurements of hepatic microsomal enzymes) were performed on pups that survived to 21 days. Histologic examinations revealed lesions of the liver and thyroid in adult females at all dose levels (at and above 5 ppm). Lesion incidences in the 5 ppm dose group were as follows: liver, 10/10 (100%) vs. 2/13 (15%) in controls; and thyroid, 6/10 (60%) vs. 2/13 (15%) in controls. Hepatic lesions included fatty infiltration and cytoplasmic vacuolization and anisokaryosis. Thyroid lesions included follicular epithelial thickening and collapse. Similar types of lesions of the liver and thyroid were observed in pups from treated females. Pups from treated females (at and above 5 ppm) had eye cataracts; incidences were 0/14 in controls and 4/10 (40%) in the 5 ppm group. Survival of pups to 21 days was significantly decreased (70% vs. 97% controls, p<0.001) in the 40 ppm dose group. This study identifies a LOAEL of 5 ppm (0.5 mg/kg-day) and a FEL of 40 ppm. Chernoff et al. (1979a) fed diets containing 0 or 25 ppm mirex (reported purity >98%) to pregnant CD (Charles River) rats (numbers and initial weights not specified) from day 4 of gestation through day 34 post-parturition. Groups of 17-24 litters of pups were cross-fostered to yield four exposure groups: no exposure, prenatal exposure, postnatal exposure and perinatal exposure (prenatal and postnatal exposure). Estimated mirex doses based on U.S. EPA (1987) and assumed average body weight of 250 g were 0 and 2.2 mg/kg-day. Exposure to mirex during gestation resulted in a significant increase in the incidence of fetal mortality (14% vs. 3% in controls, p<0.01). Perinatal and postnatal exposure resulted in significantly decreased pup survival to 8 days (77% and 74%, respectively, vs. 94% in controls, p<0.05) and significantly increased incidence of cataracts and other lens changes (31% and 43%, respectively, vs. 0% in controls, p<0.001). Other studies by the same investigators have demonstrated cataractogenicity of postnatal exposure to mirex in Sherman and Long-Evans rats and CD-1 mice (Chernoff et al., 1979b; Scotti et al., 1981). This study (Chernoff et al., 1979a) identifies a FEL of 25 ppm (2.2 mg/kg-day). Groups of 10-37 pregnant female CD rats were administered mirex (technical grade, reported purity >98%) in corn oil by oral gavage; doses were 0, 5, 7, 9.5, 19 or 38 mg/kg-day on days 7-16 of gestation (Chernoff et al., 1979b). Animals were killed on day 21 of gestation, resorption sites and live fetuses were recorded, and live fetuses were examined for external and skeletal abnormalities. The incidence of edematous live fetuses was significantly elevated at doses at and above 7 mg/kg-day (p<0.05); incidences were as follows: control, 0%; 5 mg/kg-day, 5.8%; 7 mg/kg-day, 27.3%; 9.5 mg/kg-day, 22.9%; 19 mg/kg-day, 74.7%; and the number of sternal ossification centers was significantly decreased at doses at and above 7 mg/kg-day (p<0.05). Fetal mortality was significantly increased at doses at and above 19 mg/kg-day (p<0.001); control, 4%; 19 mg/kg-day, 65.1%; and 38 mg/kg-day, 100%. Maternal weight gain was significantly decreased at doses at and above 9.5 mg/kg-day, and maternal liver/body weight ratios were significantly increased at doses at and above 7 mg/kg-day. This study identifies a NOAEL of 5 mg/kg-day, a LOAEL of 7 mg/kg-day, and an FEL of 19 mg/kg-day. Groups of 5 or 6 pregnant CD rats were administered 0, 6 or 12 mg/kg-day mirex (purity not specified) by oral gavage on days 7-16 of gestation (Kavlock et al., 1982). Dams were killed on day 21 of gestation and fetuses examined for external abnormalities. The following evaluations were made on fetuses that had no external abnormalities: body, brain, kidney, liver and lung weights; total DNA and protein in brain; total dipalmitoyl phosphatidylcholine and sphingomyelin in lung; total glycogen in liver; and total protein and alkaline phosphatase in kidney. External abnormalities observed at and above 6 mg/kg-day included edema, ectopic gonads and hydrocephaly. Brain and liver weights adjusted for fetal body weight were significantly decreased in the 6 and 12 mg/kg-day dose groups. Total liver glycogen, total kidney protein and total kidney alkaline phosphatase, all adjusted for fetal body weight, were significantly decreased in the 6 and 12 mg/kg-day groups (p<0.05). This study identifies a LOAEL of 6 mg/kg-day. Groups of 20 mated female Wistar rats were administered mirex (reported purity 98%) in corn oil by oral gavage on days 6-15 of gestation; doses were 0, 1.5, 3, 6 or 12.5 mg/kg-day (Khera et al., 1976). Rats were killed on day 22 of gestation and fetuses were examined for external and skeletal abnormalities. Doses at and above 3 mg/kg-day increased the incidence of resorptions (7.4 vs. 3.7% in controls). Doses at and above 6 mg/kg-day significantly increased fetal mortality and the incidence of visceral anomalies (p<0.05). These included edema, scoliosis, runts and short tail at 6 mg/kg-day; and these anomalies in addition to cleft palate and heart defects at 12.5 mg/kg-day. Doses at and above 3 mg/kg-day decreased the incidence of pregnancy of survivors 22 days after mating. Doses at and above 6 mg/kg-day increased maternal mortality. This study identifies a NOAEL of 1.5 mg/kg-day, a LOAEL 3 mg/kg-day and an FEL of 6 mg/kg-day. Groups of 20 male Wistar rats were administered mirex (reported purity 98%) in corn oil by oral gavage for 10 consecutive days; doses were 0, 1.5, 3 or 6 mg/kg-day (Khera et al., 1976). Following dosing, 14 mating trials were conducted in which each treated male was paired with two untreated virgin females for 5 days. Females were killed 13-15 days after pairing and viable embryos, deciduomas and corpora lutea were recorded. At a dose of 6 mg/kg-day, weight gain in the male rats was decreased and one male rat died, and the incidence of pregnancies (% of matings) resulting from the first trial (but not subsequent trials) was significantly decreased (p<0.05). This study identifies a 6 mg/kg-day LOAEL. Groups of pregnant Long-Evans rats (group size not specified) were administered mirex (commercial grade, purity not specified) in peanut oil by oral gavage at doses of 0 or 0.25 mg/kg-day on days 15.5-21.5 of gestation (Grabowski, 1983). Pups from dams exposed to mirex had abnormal electrocardiograms, including significantly prolonged PR and QT intervals (p<0.03). In other studies with doeses at and above 5 mg/kg-day, prolongation of the PR interval correlated with edema and progressed to first and second degree heart block (missed ventricular beat) (Grabowski and Payne, 1980; 1983a,b). This study (Grabowski, 1983) identifies a LOAEL of 0.25 mg/kg-day. Groups of 100-108 male and female Swiss Balb/c and CFW mice were fed diets containing 0 or 5 ppm technical grade mirex (reported purity 99%) for 30 days prior to pairing and for 90 days after pairing (Ware and Good, 1967). The study of Balb/c mice was repeated. Estimated mirex doses based on U.S. EPA (1987) and assumed average body weight of 0.038 kg were 0 and 0.84 mg/kg-day. Numbers of litters, litter size, sex ratio and mortality were assessed. Mirex significantly increased parent mortality of Balb/c mice (p<0.05) but not CFW mice. Fecundity (young per producing pair) was significantly less in CFW mice exposed to mirex compared to controls (p<0.05). Fecundity and litter size were significantly less in Balb/c mice compared with controls (p<0.05) in one study; however, these effects were not corroborated in a duplication of the study. This study identifies an FEL of 0.84 mg/kg-day. Groups of 24 or 25 pregnant CD-1 mice were administered 0 or 7.5 mg/kg-day mirex (in corn oil, purity not specified) by oral gavage on days 8-12 of gestation (Chernoff and Kavlock, 1982). Dams were allowed to give birth and litters were counted and weighed on postnatal days 1 and 3. Body weights and survival of pups in the mirex group were significantly decreased on postnatal days 1 and 3 compared to the control group (p<0.05). This study identifies an FEL of 7.5 mg/kg-day. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- High RfD -- High Confidence in the study can be considered high to medium. NTP (1990) used an adequate number of animals and examined all tissues identified as potential targets in other studies. Confidence in the data base can be considered is high to medium. Several good quality chronic, subchronic and developmental/reproductive studies have been conducted, although the data base is lacking a rodent multi-generation study. Reflecting high to medium confidence in the study and the data base, confidence in the RfD can be considered high to medium. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA documentation. Other EPA Documentation -- U.S. EPA, 1987 Agency Work Group Review -- 06/24/1986, 04/15/1987, 06/24/1992 Verification Date -- 06/24/1992 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Mirex CASRN -- 2385-85-5 NORC: Not available at this time. ============================================================================ UDCA: 199307 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Mirex CASRN -- 2385-85-5 NOCA: Not available at this time. ============================================================================ UDSO: 199210 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Mirex CASRN -- 2385-85-5 Last Revised -- 10/01/1992 SORD: __VI.A. ORAL RfD REFERENCES Byard, J.L., U.CH. Koepke, R. Abraham, L. Goldberg and F. Coulston. 1975. Biochemical changes in the liver of mice fed mirex. Toxicol. Appl. Pharmacol. 33: 70-77. Chernoff, N., J.T. Stevens and E.H. Rogers. 1979a. Perinatal toxicology of mirex administered in the diet: I. Viability, growth, cataractogenicity and tissue levels. Toxicol. Lett. 4: 263-268. Chernoff, N., R.E. Linder, T.M. Scotti, E.H. Rogers, B.D. Carver and R.J. Kavlock. 1979b. Fetotoxicity and cataractogenicity of mirex in rats and mice with notes on kepone. Environ. Res. 18: 257-269. Chernoff, N. and R.J. Kavlock. 1982. An in vivo teratology screen utilizing pregnant mice. J. Toxicol. Environ. Health. 10: 541-550. Chu, I., D.C. Villeneuve, B.L. MacDonald, V.E. Secours and V.E. Valli. 1981a. Reversibility of the toxicological changes induced by photomirex and mirex. Toxicology. 21: 235-250. Chu, I., D.C. Villeneuve, V.E. Secours, V.E. Valli and G.C. Becking. 1981b. Effects of photomirex and mirex on reproduction in the rat. Toxicol. Appl. Pharmacol. 60: 549-556. Fulfs, J., R. Abraham, B. Drobeck, K. Pittman and F. Coulston. 1977. Species differences in the hepatic response to mirex: Ultrastructural and histochemical studies. Ecotoxicol. Environ. Saf. 1: 327-342. Gaines, T.B. and R.D. Kimbrough. 1970. Oral toxicity of mirex in adult and suckling rats. Arch. Environ. Health. 21: 7-14. Grabowski, C.T. 1983. The electrocardiogram of fetal and newborn rats and dysrhythmias induced by toxic exposure. In: Abnormal Functional Development of the Heart, Lungs and Kidneys: Approaches to Functional Teratology. Alan R. Liss, Inc., NY. p. 185-206. Grabowski, C.T. and D.B. Payne. 1980. An electrocardiographic study of cardiovascular problems in mirex-fed rat fetuses. Teratology. 22: 167-177. Grabowski, C.T. and D.B. Payne. 1983a. The causes of perinatal death induced by prenatal exposure of rats to the pesticide, mirex. Part I: Pre-parturition observations of the cardiovascular system. Teratology. 27: 7-11. Grabowski, C.T. and D.B. Payne. 1983b. The causes of perinatal death induced by prenatal exposure of rats to the pesticide, mirex. Part II. Postnatal observations. J. Toxicol. Environ. Health. 11: 301-315. Kavlock, R.J., N. Chernoff, E. Rogers et al. 1982. An analysis of fetotoxicity using biochemical endpoints of organ differentiation. Teratology. 26: 183-194. Khera, K.S., D.C. Villeneuve, G. Terry, L. Panopio, L. Nash and G. Trivett. 1976. Mirex: A teratogenicity, dominant lethal and tissue distribution study in rats. Food Cosmet. Toxicol. 14: 25-29. Larson, P.S., J.L. Egle, Jr., G.R. Hennigar and J.F. Borzelleca. 1979. Acute and subchronic toxicity of mirex in the rat, dog and rabbit. Toxicol. Appl. Pharmacol. 49: 271-277. NTP (National Toxicology Program). 1990. Toxicology and Carcinogenesis Studies of MIREX (CAS No. 2385-85-5) in F344/N Rats (Feed Studies). NTP TR 313. Scotti, T.M., N. Chernoff, R. Linder and W.K. McElroy. 1981. Histopathologic lens changes in mirex-exposed rats. Toxicol. Lett. 9: 289-294. Shannon, V.C. 1976. The effects of mirex on the reproductive performance and behavioral development of the prairie vole Microtus ochrogaster. Ph.D. Thesis. University Microfilms International Dissertation Services, Ann Arbor, MI. Ulland, B.M., N.P. Page, R.A. Squire, E.K. Weisburger and R.L. Cypher. 1977. A carcinogenicity assay of mirex in Charles River CD rats. J. Natl. Cancer Inst. 58: 133-140. U.S. EPA. 1987. Health Effects Assessment for Mirex. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency and Response, Washington, DC. EPA/600/8-88/046. Yarbrough, J.D., J.E. Chambers, J.M. Grimley et al. 1981. Comparative study of 8-monohydromirex and mirex toxicity in male rats. Toxicol. Appl. Pharmacol. 58: 105-117. Ware, G.W. and E.E. Good. 1967. Effects of insecticides on reproduction in the laboratory mouse. Toxicol. Appl. Pharmacol. 10: 54-61. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Mirex CASRN -- 2385-85-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.5. Confidence levels revised 04/01/1991 I.A.4. Citations added 04/01/1991 VI. Bibliography on-line 01/01/1992 IV. Regulatory actions updated 08/01/1992 I.A. Withdrawn; new oral RfD verified (in preparation) 08/01/1992 IV. Regualtory actions withdrawn 08/01/1992 VI.A. Bibliography withdrawn 10/01/1992 I.A. Oral RfD summary replaced; RfD changed 10/01/1992 IV. Regulatory actions returned in conjunction with RfD 10/01/1992 VI.A. Bibliography replaced 07/01/1993 II. Carcinogenicity assessment now under review 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/12/2000 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 399 of 1119 in IRIS (through 2003/06) AN: 254 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199201 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Pentachloronitrobenzene- (PCNB) SY: 82-68-8; AVICOL-; BATRILEX-; BOTRILEX-; BRASSICOL-; EARTHCIDE-; FARTOX-; FOLOSAN-; FOMAC-2-; FUNGICLOR-; GC-3944-3-4-; KOBU-; KOBUTOL-; KP-2-; NCI-C00419-; OLPISAN-; PCNB-; PENTACHLORNITROBENZOL-; PENTACHLORONITROBENZENE-; PENTAGEN-; PKHNB-; QUINTOCENE-; QUINTOZEN-; QUINTOZENE-; RCRA-WASTE-NUMBER-U185-; SANICLOR-30-; TERRACHLOR-; TERRACLOR-; TERRAFUN-; TILCAREX-; TRI-PCNB-; UN-1282- RN: 82-68-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199201 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Pentachloronitrobenzene (PCNB) CASRN -- 82-68-8 Last Revised -- 01/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Liver toxicity NOEL: 30 ppm 300 1 3E-3 (0.75 mg/kg/day) mg/kg/day 2-Year Dog Feeding Study LEL: 180 ppm (4.5 mg/kg/day) Olin Mathieson Corp., 1968a ---------------------------------------------------------------------------- *Conversion Factors: 1 ppm = 0.025 mg/kg/day (assumed dog food consumption) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Olin Mathieson Chemical Corporation. 1968a. MRID No. 00001667, 00083328, 00114201; HED Doc. No. 005188. Available from EPA. Write to FOI, EPA, Washington, DC 20460. A 2-year feeding study with dogs (four males and four females/group) given diets containing 0, 30, 180, or 1080 ppm indicated that PCNB (1.4% hexachlorobenzene) caused liver weight increases, increased liver-to-body weight ratios, elevated serum alkaline phosphatase levels, and microscopically observed cholestatic hepatosis with secondary bile nephrosis at 1080 ppm (the highest dose tested). An interim sacrifice at 1 year occurred with one dog/sex/group; the remaining animals were sacrificed at 2 years. The cholestatic changes were observed in all animals given diets containing 180 and 1080 ppm PCNB, and one of three male dogs in the 30 ppm dose group exhibited the microscopic changes (no female dogs were affected). The authors noted that these histopathologic changes were moderate in the 1080 ppm group and minimal in the 180 ppm group. Based on these results, 30 ppm was the NOEL and 180 ppm was the LEL in dogs. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 100 was used to account for the inter- and intraspecies differences. An additional UF of 3 was used since the data base for chronic toxicity is incomplete. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Data Considered for Establishing the RfD: 1) 2-Year Feeding - dog: Principal study - see previous description; core grade minimum 2) 3-Generation Reproduction - rat: NOEL=500 ppm (25 mg/kg/day) (highest level tested); LEL=none; core grade minimum (Olin Mathieson Corp., 1968b) 3) 3-Month feeding - mouse: NOEL=1250 ppm (187.5 mg/kg/day) for males and 2500 ppm (375 mg/kg/day) for females; core grade minimum (NTP, 1986) Data Gap(s): Chronic Rat Feeding Study; Rat Teratology; Rabbit Teratology CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The principal study appears to be of fair quality and is given a medium confidence rating. Because of the lack of a complete data base on chronic toxicity, the data base is given a medium confidence rating. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Pesticide Registration Standard, July 1986 Pesticide Registraion Files Agency Work Group Review -- 05/20/1985, 08/19/1986, 04/15/1987 Verification Date -- 04/15/1987 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Pentachloronitrobenzene (PCNB) CASRN -- 82-68-8 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Pentachloronitrobenzene (PCNB) CASRN -- 82-68-8 NOCA: Not available at this time. ============================================================================ UDSO: 199204 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Pentachloronitrobenzene (PCNB) CASRN -- 82-68-8 Last Revised -- 04/01/1992 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1986. Technical Report on the Toxicology and Carcinogenesis Studies of Pentachloronitrobenzene in B6C3F1 Mice (feed studies). Report No. NIH 86-2581. Olin Mathieson Chemical Corporation. 1968a. MRID No. 00001667, 00083328, 00114201; HED Doc. No. 005188. Available from EPA. Write to FOI, EPA, Washington, DC 20460. Olin Mathieson Chemical Corporation. 1968b. MRID No. 00001666; HED Doc. No. 000654. Available from EPA. Write to FOI, EPA, Washington, DC 20460. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Pentachloronitrobenzene (PCNB) CASRN -- 82-68-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 01/01/1992 I.A.4. Citations added 01/01/1992 IV. Regulatory actions updated 01/01/1992 VI. Bibliography on-line 04/01/1992 VI.A. NTP reference year corrected 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 400 of 1119 in IRIS (through 2003/06) AN: 261 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 198906 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Pyridine- SY: 110-86-1; AZABENZENE-; AZINE-; NCI-C55301-; PIRIDINA-; PIRYDYNA-; PYRIDIN-; RCRA-WASTE-NUMBER-U196-; TRITISAN- RN: 110-86-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198906 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Pyridine CASRN -- 110-86-1 Last Revised -- 06/01/1989 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Increased liver NOAEL: 1.0 mg/kg/day 1000 1 1E-3 weight mg/kg/day LOAEL: 10 mg/kg/day 90-Day Rat Oral Gavage Study U.S. EPA, 1986 ---------------------------------------------------------------------------- *Conversion Factors: none PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) U.S. EPA. 1986. Pyridine. 90-Day subchronic oral toxicity in rats. Sponsored by Office of Solid Waste, Washington, DC. In the U.S. EPA (1986) study Sprague-Dawley rats (10/dose/sex) were gavaged daily with 0, 0.25, 1.0, 10, 25, and 50 mg/kg/day pyridine for 90 days. Data generated included body and organ weights, food consumption, hematologic and clinical chemistry parameters, ophthalmologic evaluations and histopathologic examinations of target organs. Results of this study indicated a significant dose-related increase in the female liver-to-body weight ratios in the 10, 25 and 50 mg/kg/day dose groups. The males of the low-dose group showed a significant decrease in the relative liver weights; however, the males in other dose groups did not show any significant differences; thus, the effect seen in males exposed to 1 mg/kg/day pyridine is probably an artifact. In order to examine the neurotoxicity of pyridine, 10 rats/group were perfused at the time of sacrifice; histopathologic examinations of brain, liver, and other target organs were conducted. The histopathologic examinations did not reveal any morphologic alterations in the brains of exposed and unexposed animals. However, histopathologic evaluations of target organs showed a 70% incidence of nonneoplastic hepatic lesions in males of the high-dose group (50 mg/kg/day) compared with 10% incidence in the vehicle control group. The 0.25 and 1.0 mg/kg/day dosed male rats also showed a 10% incidence of these lesions; however, no such lesions were observed in the 10 or 25 mg/kg/day dose groups. In the females, the frequency of incidence of these lesions was 30% in the 50 mg/kg/day group and 10% in the vehicle control group. Based on the data presented above, 1 mg/kg/day was identified as a NOAEL and 10 mg/kg/day as a LOAEL for hepatic hypertrophy in female rats. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 1000 includes 10 for interspecies and 10 for intra- species variability in the toxicity of this chemical in lieu of specific data. An additional factor of 10 was applied to extrapolate from a subchronic to chronic effect level. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) The previous RfD of 0.002 mg/kg/day (7/8/85) for pyridine was based on a subchronic inhalation study in rats that was reported in the Encyclopedia of Occupational Safety and Health (1983). Because of lack of details of the study and a free-standing LOAEL, the confidence in the study was low. NTP (1979) also examined toxicity in mice and rats administered different doses of pyridine by gavage over a 90-day period. This study provided a NOAEL of 25 mg/kg/day in both mice and rats; however, mice exposed to 50 mg/kg/day showed clinical signs of CNS-related toxicity which were reported at much lower doses in the Encyclopedia of Occupational Safety and Health (1983). Because of these uncertainties concerning possible CNS-related toxicity, the Office of Solid Waste sponsored the subchronic rat oral gavage study (U.S. EPA, 1986). The study reported in the Encyclopedia of Occupational Safety and Health (1983) contains data taken from a rat inhalation study in which the exposure chamber contained 10 to 50 ppm pyridine vapor over 7 hours/day, 5 days/week for a 6-month period. The lower dose, 10 ppm pyridine (2.15 mg/kg/day) had no effect on growth rate and mortality, but an increase in the relative liver weights was observed. Further details of the study were unavailable from the data base. The 10 ppm exposure level was considered a LOAEL. An NTP (1979) study examined toxicity in rats and mice administered different doses of pyridine by gavage over a 90-day period. Endpoints monitored included body weight changes, food consumption, mortality, clinical observations, and histopathology of target organs. The data indicated a NOAEL for rats at 25 mg/kg/day and a LOAEL (liver histopathology) at 50 mg/kg/day. In the case of mice, clinical signs were observed at 50 mg/kg/day, which may be considered a LOAEL. Consequently, the highest NOAEL above which adverse effects were not reported for either species would be 25 mg/kg/day in rats. Mortality was observed at doses of 100 and 200 mg/kg/day in rats and at 400 mg/kg/day in mice. By applying an uncertainty factor of 1000, the NOAEL of 25 mg/kg/day in rats yields an RfD of 0.03 mg/kg/day, which is higher than the currently derived value (0.001 mg/kg/day). Continuing concerns are the reported neurotoxic symptoms associated with short-term low-level occupational exposure (Encyclopedia of Occupational Safety and Health, 1983) and the clinical signs reported in the NTP study. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The subchronic oral study provided adequate toxicologic endpoints; therefore, a medium confidence is assigned. The data base contains adequate subchronic studies to support the NOAEL of the critical study, but other chronic toxicity and reproductive studies are lacking; thus, confidence in the data base can be considered medium to low. Confidence in the RfD can also be considered medium to low. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 06/24/1985, 07/08/1985, 05/14/1986, 08/13/1987 Verification Date -- 08/13/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Pyridine conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Pyridine CASRN -- 110-86-1 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Pyridine CASRN -- 110-86-1 NOCA: Not available at this time. ============================================================================ UDSO: 199001 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Pyridine CASRN -- 110-86-1 Last Revised -- 01/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Encyclopedia of Occupational Safety and Health. Vol.II, 3rd ed. 1983. International Labor Office, Geneva, Switzerland. p. 1810-1811. NTP (National Toxicology Program). 1979. Quality assessment report subchronic study of pyridine in Fischer 344 rats and B6C3R1 mice. Report prepared by Gulf South Research Institute. U.S. EPA. 1986. Pyridine. 90-day subchronic oral toxicity in rats. Sponsored by the Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Pyridine CASRN -- 110-86-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1988 I.A.4. Text clarified 06/30/1988 I.A.2. Clarified principal study 09/26/1988 I.A.2. Corrected citation 09/26/1988 I.A.4. Corrected citation 06/01/1989 I.A.6. Work group review date corrected 01/01/1990 VI. Bibliography on-line 01/01/1992 I.A.7. Primary contact changed 01/01/1992 IV. Regulatory actions updated 08/01/1995 I.A.6. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 401 of 1119 in IRIS (through 2003/06) AN: 265 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199612 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,1,1,2-Tetrachloroethane- SY: 630-20-6; ETHANE,-1,1,1,2-TETRACHLORO-; ETHANE,-1,1,1,2-TETRACHLORO- (8CI)(9CI); HSDB-4148-; NCI-C52459-; RCRA-WASTE-NUMBER-U208-; TETRACHLOROETHANE,-1,1,1,2- RN: 630-20-6 HSN: 4148 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199612 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,1,1,2-Tetrachloroethane CASRN -- 630-20-6 Last Revised -- 12/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Mineralization of the NOAEL: none 3000 1 3E-2 kidneys in males, mg/kg/day hepatic clear cell LOAEL: 125 mg/kg/day change in females (converted to 89.3 mg/kg/day) Rat, Chronic Oral Gavage Study NTP, 1983 ---------------------------------------------------------------------------- *Conversion Factors: Dose adjusted for gavage schedule (5\days/week). PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1983. Carcinogenesis studies of 1,1,1,2-tetrachloroethane in F344/N rats and B6C3F1 mice. NTP, Washington, DC. The NTP (1983) treated groups of 50 male and 50 female F344/N rats by gavage with doses of 0, 125, or 250 mg/kg/day of technical grade 1,1,1,2-tetrachloroethane (>99% pure) in corn oil 5 days/week for 103 weeks. Mortality, body weights, and clinical signs were noted, and comprehensive histopathologic examinations were performed on rats from all groups. Mean body weights of treated and control rats were similar throughout the study. During weeks 44-103, signs of CNS effects, inactivity, and incoordination were observed in high-dose rats of both sexes. A statistically significant reduction in survival in high-dose males occurred. Eleven control and 7 low-dose males apparently died from heat stress. In addition, 20 male rats (14 control, 3 low-dose, and 3 high-dose) and 15 female rats (2 control, 5 low-dose, and 8 high-dose) died from gavage error. Male rats showed treatment-related increased incidences of mineralization of the kidneys (control 12/48, low dose 19/50, high dose 26/48). Hepatic clear cell changes in female rats were also increased in a dose-related manner (0/48 control, 3/49 low dose, 9/44 high dose). The low dose, 125 mg/kg/day, was considered the LOAEL. In the NTP (1983) study, groups of 50 male and 50 female B6C3F1 mice were treated by gavage with 0, 250, or 500 mg/kg/day of technical 1,1,1,2-tetrachloroethane (greater than 99% pure) in corn oil 5 days/week for 103 weeks (control and low-dose mice) or 65 weeks (high-dose mice). A statistically significant decrease in mean body weights was observed in high-dose mice. Beginning at week 34, CNS involvement was noted in high-dose mice. The mice appeared sluggish after treatment and by week 51 appeared uncoordinated and weak, and breathed rapidly after treatment. A statistically significant reduction in survival occurred in high-dose mice of both sexes and low-dose female mice, as compared with controls. At week 65, surviving high-dose mice were sacrificed because they were moribund. Incidences of nonneoplastic alterations of the liver (inflammation, necrosis, fatty metamorphosis, and hepatacytomegaly) were greatly increased in high-dose mice, but not in low-dose groups. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 3000 was used: 10 to extrapolate from a LOAEL, 10 for interspecies extrapolation and 10 to provide additional protection for unusually sensitive individuals, and an additional factor of 3 for lack of adequate supporting reproductive and chronic toxicity studies. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) The only oral reproductive study of 1,1,1,2-tetrachloroethane was part of a long-term oral study conducted by Truhaut et al. (1974). In this study, male and female rats were treated by gavage at 0 or 300 mg/kg/day, 5 days/week for up to 10 months. Treated females had reduced growth, and treated males and females had increased mortality. Reproductive function was not impaired, but all of the pups from treated rats died within 48 hours of birth. Hepatic fatty vacuolization was observed in adults and pups, and centrilobular necrosis was observed in adults. 1,1,1,2-Tetrachloroethane has not been tested for teratogenicity. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low Because a NOAEL in rats was not identified, confidence in the NTP (1983) study is low. Confidence in the data base is low because, although two chronic and one reproductive bioassays are available, no NOAELs were established, the effects seen at the LOAELs were significant, and only a few doses were given. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1983 Other EPA Documentation -- None Agency Work Group Review -- 04/16/1987 Verification Date -- 04/16/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for 1,1,1,2-Tetrachloroethane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,1,1,2-Tetrachloroethane CASRN -- 630-20-6 NORC: Not available at this time. ============================================================================ UDCA: 199101 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,1,1,2-Tetrachloroethane CASRN -- 630-20-6 Last Revised -- 01/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen. Basis -- increased incidence of combined hepatocellular adenomas and carcinomas in female mice; inadequate evidence from human studies. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Norman et al. (1981) reported a study of the effects on military personnel of exposure to tetrachloroethane used as a solvent on clothing during World War II. It was not specified which isomer or mixture of isomers was used. One isomer, 1,1,2,2-tetrachloroethane, has been classified as C, possible human carcinogen. Of 3859 exposed men, 833 deaths were reported during the period 1946-1976 compared with 1821 deaths among 9396 nonexposed men. Results were reported by race; further analyses were restricted to white males. Risks for leukemia, lymphoma, and cancers of the prostate and testis were shown to be slightly elevated among the exposed group, but these increases were not significant. It should be noted that there were possible concomittant exposures to dry cleaning solvents. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. One chronic study has been reported (NTP, 1983). 1,1,1,2tetrachloroethane was administered in corn oil by gavage to 50 each male and female F344/N rats and B6C3F1 mice per dose group. Rats received 0, 125, or 250 mg/kg/day 5 days/week for 103 weeks, and mice were similarly treated with 0, 250, or 500 mg/kg/day. Primarily as a consequence of heat stress during week 62, 27 male rats died (14/50 controls, 10/50 low-dose group and 3/50 high-dose group) and were excluded from statistical analysis of survival. In addition, 15 female rats were accidentally killed during the study (2 control, 5 low-dose, and 8 high-dose). Cumulative toxic effects with signs of CNS involvement were noted from week 44. There were no significant increases in tumor incidence as a consequence of treatment in female rats. Mortality was significantly increased in high-dose male rats. Male rats were also observed to have a significant dose-related trend for only the combined incidence of neoplastic nodules and carcinomas of the liver in the life table test (0/49 controls; 1/49 low dose; 3/48 high dose). While NTP concluded that carcinogenicity was not demonstrated in F344 rats, an increased proportion of male rats with liver tumors that may have been associated with treatment was observed. Accidental killing of 27 male and 15 female rats decreased the sensitivity of this assay. High-dose mice were sacrificed at 65 weeks as signs of CNS toxicity were observed. The low-dose and control mice were killed at 104-105 weeks. Increased incidences of hepatocellular adenomas and carcinomas were noted in female mice, and a dose-related trend was observed. A statistically significant dose-related increase in the incidence of hepatocellular adenomas occurred in male mice; a significant increase in hepatocellular carcinomas was not observed. Incidence of hepatocellular adenomas were 4/49, 8/46, and 24/48 in the control, low- and high-dose females and 6/48, 14/46, and 21/50 in the control, low- and high-dose males, respectively. Incidences of hepatocellular carcinomas were 1/49, 5/46, and 6/48 in the control, low-, and high-dose females and 12/48, 13/46, and 6/50 in the control, low-, and high-dose males, respectively. The NTP study authors concluded that carcinogenicity was not demonstrated for rats, but that the sensitivity of the assay was compromised by the accidental killing of animals. They concluded that although the MTD for mice was exceeded at the high dose and survival was decreased, carcinogenicity was demonstrated for mice. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY 1,1,1,2-Tetrachloroethane was not mutagenic for Salmonella typhimurium (Simmon et al., 1977) and was negative in a rat liver focus initiation/promotion assay (Story et al., 1986). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 2.6E-2 per (mg/kg)/day Drinking Water Unit Risk -- 7.4E-7 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 1E+2 ug/L E-5 (1 in 100,000) 1E+1 ug/L E-6 (1 in 1,000,000) 1E+0 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- hepatocellular adenoma or carcinoma Test Animals -- mouse/B6C3F1, female Route -- gavage Reference -- NTP, 1983 Administered Human Equivalent Tumor Dose (mg/kg)/day Dose (mg/kg)/day Incidence ---------------- ---------------- --------- 0 0 5/49 250 14.8 13/46 500 27.6 30/48 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Human equivalent doses were calculated using animal body weights of 40 g for the control and low-dose groups and 32 g for the high-dose group. Although the high-dose animals were killed at 65 weeks, no adjustment was made for early termination of the high-dose group; animals were moribund; and currently accepted adjustments were inconsistent with the dose-response data. The unit risk should not be used if the water concentration exceeds 1E+4 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Adequate numbers of mice were treated, and low-dose animals only were observed for a period approximating their natural life span. Since the high-dose animals were terminated at 65 weeks, the incidence of carcinomas that may have been developed in a lifetime study is not known, but the adenoma incidence was statistically increased and was dose related in both males and females. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 7.4E-6 per (ug/cu.m) Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 1E+1 ug/cu.m E-5 (1 in 100,000) 1 ug/cu.m E-6 (1 in 1,000,000) 1E-1 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE This inhalation risk estimate was derived from oral data presented in II.B.2. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The unit risk should not be used if the air concentration exceeds 1E+3 ug/cu.m, since above this concentration the unit risk may not be appropriate. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) See II.B.4. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987 RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 02/24/1988, 03/23/1988, 05/04/1988, 10/19/1988 Verification Date -- 05/04/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for 1,1,1,2-Tetrachloroethane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199108 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,1,1,2-Tetrachloroethane CASRN -- 630-20-6 Last Revised -- 08/01/1991 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1983. Carcinogenesis studies of 1,1,1,2-tetrachloroethane (CAS No. 630-20-6) in F344/N rats and B6C3F1 mice (gavage studies). NTP-81-53; NIH Publ. No. 83-1793; NTP Technical Report Series No. 237. NTIS, Springfield, VA. Truhaut, R., N.P. Lich, H. Dutertre-Catella, G. Molas and V.N. Huyen. 1974. Contribution to the toxicological study of 1,1,1,2-tetrachloroethane. Arch. Mal. Prof. Med. Trav. Secur. Soc. 35(6): 593-608. U.S. EPA. 1983. Health Hazard Profile on 1,1,1,2-Tetrachloroethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Norman, J.E., Jr., C.D. Robinette and J.F. Fraumeni, Jr. 1981. The mortality experience of army World War II chemical processing companies. J. Occup. Med. 23(12): 818-822. NTP (National Toxicology Program). 1983. Carcinogenesis studies of 1,1,1,2-tetrachloroethane (CAS No. 630-20-6) in F344/N rats and B6C3F1 mice (gavage studies). NTP-81-53; NIH Publ. No. 83-1793; NTP Technical Report Series No. 237. NTIS, Springfield, VA. Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. Second International Conference on Environmental Mutagens. Edinburgh, Scotland, July, 1977. Develop. Toxicol. Environ. Sci. 2: 249-258. Story, D.L., E.F. Meierhenry, C.A. Tyson and H.A. Milman. 1986. Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital. Toxicol. Ind. Health. 2(4): 351-362. U.S. EPA. 1987. Evaluation of the Potential Carcinogenicity of 1,1,1,2-tetrachloroethane (630-20-6) in support of Reportable Quantity Adjustments Persuant to CERCLA Section 102. Prepared by the Office of Emergency and Remedial Response and the Office of Solid Waste and Emergency Response by the Office of Health and Environmental Assessment, Carcinogenic Assessment Group, Washington, DC. OHEA-C-073-174. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,1,1,2-Tetrachloroethane CASRN -- 630-20-6 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1989 II.A. Carcinogen summary on-line 01/01/1990 VI. Bibliography on-line 08/01/1990 I.A. Text edited 08/01/1990 II. Text edited 08/01/1990 III.A. Health Advisory on-line 08/01/1990 IV.F.1. EPA contact changed 08/01/1990 VI.D. Health Advisory references added 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 08/01/1991 VI.A. Truhaut et al. 1974 reference clarified 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 12/01/1996 I.A.7. Secondary contact removed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 402 of 1119 in IRIS (through 2003/06) AN: 270 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0270-tr.pdf UD: 200302 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Xylenes- SY: 108-38-3; 1330-20-7; 106-42-3; 95-47-6; DIMETHYLBENZENE-; 1,2-DIMETHYLBENZENE-; 1,3-DIMETHYLBENZENE-; 1,4-DIMETHYLBENZENE-; MIXED-XYLENES-; M-XYLENE-; META-XYLENE-; O-XYLENE-; ORTHO-XYLENE-; P-XYLENE-; PARA-XYLENE- RN: 1330-20-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200302 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Xylenes CASRN -- 1330-20-7 Last Revised -- 02/21/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: The RfD in this updated assessment replaces a previous RfD value of 2 mg/kg-day. The previous and new RfD values are based on the same principal study (NTP, 1986). A data base uncertainty factor (UF) was not considered in the derivation of the previous RfD. The term xylenes refers to mixtures of the three xylene isomers (o-, m-, p-) and ethylbenzene. m-Xylene is commonly the predominant component (40-77%) in commercial preparations of xylenes (also referred to as mixed xylenes), with the other components each comprising roughly up to 20% of the mass. The use of xylenes as a solvent, in paints and coatings, and in gasoline is widespread. For the most part, studies cited in this assessment are conducted on mixed xylenes. Results from studies comparing the toxicity of individual xylene isomers indicate that differences, when they occur, are specific to the endpoint under consideration (see Section 4.4.3 of the Toxicological Review for more information). SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- NOAEL: 250 mg/kg/day 1000 1 0.2 Decreased body weight (converted to 179 mg/kg/day increased mortality mg/kg/day)* Chronic F344/N rat LOAEL: 500 mg/kg/day study Oral gavage exposure NTP, 1986 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- 250 mg/kg-day x 5 days/7 days = 179 mg/kg-day. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) The National Toxicology Program's 2-year study in rats was selected as the principal study and the subchronic toxicity studies in rats by Wolfe (1988a, b) as supporting studies. In the NTP (1986) study, groups of 50 male and 50 female Fischer 344 rats and 50 male and 50 female B6C3F1 mice were administered mixed xylenes (60% m-xylene, 13.6% p-xylene, 9.1% o-xylene, 17.0% ethylbenzene) in corn oil by gavage at doses of 0, 250, or 500 mg/kg-day (rats) and 0, 500, or 1000 mg/kg-day (mice) for 5 days per week for 103 weeks. Necropsy and histologic examinations were performed on all animals. Tissues were examined for gross lesions and masses. The tissues examined included mandibular lymph nodes, salivary gland, femur (including marrow), thyroid gland, parathyroids, small intestine, colon, liver, prostate/testis or ovaries/uterus, heart, esophagus, stomach, brain, thymus, trachea, pancreas, spleen, skin, lungs and mainstem bronchi, kidneys, adrenal glands, urinary bladder, pituitary gland, eyes (if grossly abnormal), and mammary gland. Hematology and clinical chemistry analyses were not conducted. Effects of exposure in rats were limited to decreased body weight and decreased survival in high-dose (500 mg/kg-day) males. Mean body weights were 5-8% lower in high-dose male rats than in controls from week 59 to week 97, with body weights at 103 weeks being 4% less in high-dose males than in controls (statistical significance not reported). Male rat survival rates after 103 weeks showed a dose-related decrease (36/50, 25/50, and 20/50 for the control, low-, and high-dose males, respectively). A life-table trend test for decreased survival incidence with increasing dose was statistically significant (p=0.033). Pair-wise comparisons with control survival incidence indicated that only the high-dose male rat incidence was significantly decreased (p=0.04). A number of the deaths were attributed to gavage error (3/50, 8/50, and 11/50, respectively, for the control, low-, and high-dose groups). The authors did not record observations of rat behavior during dosing. Based on the available observations, the incidence of treatment-related deaths demonstrated a dose-related increase (11/50, 17/50, and 19/50, respectively [22%, 34%, and 38%]). The LOAEL is 500 mg/kg-day and the NOAEL is 250 mg/kg-day for decreased body weight and decreased survival. There was no evidence of carcinogenicity in male or female rats exposed to doses up to 500 mg/kg-day. In mice, the only treatment-related effect observed was hyperactivity, which occurred in all high-dose mice of each sex, 5-30 minutes after dosing. This effect was observed consistently beginning at week 4, and it continued until study termination at 103 weeks. The LOAEL is 1000 mg/kg-day and the NOAEL is 500 mg/kg-day for hyperactivity. In a study by Wolfe (1988a), groups of 20 male and 20 female Sprague-Dawley rats were administered m-xylene (99% purity) by gavage in corn oil at doses of 0, 100, 200, or 800 mg/kg-day for 90 consecutive days. Survival incidences were 20/20, 17/20, 15/20, and 18/20, respectively, for males, and 20/20, 20/20, 16/20, and 16/20 for females. Mortality in the mid-dose males and mid- and high-dose females attained statistical significance (p< 0.05), but a significant trend was observed only in females. Mottled lungs and a failure of the lungs to collapse were observed in all mid- and high-dose animals that died early and in 2/3 of the low-dose males that died early but was not evident in any of the animals that survived to study termination. Histopathologic examination of the lungs from animals that died before study termination revealed foreign material in the alveoli in all but one animal. Therefore, these deaths were attributed to vehicle and/or compound aspiration. Clinical signs present throughout the study were limited to high levels of salivation prior to dosing in high-dose males and females. Body weight gains over the entire study period were decreased (p <= 0.05) in mid- and high-dose males (89% and 75% of controls', respectively) and high-dose females (85% of controls'). Food consumption was likewise decreased (p <= 0.05) in high-dose males during weeks 1-5 (90% of control levels) and in mid- and high-dose males during weeks 6-9 (92% of control levels for both groups). A thorough histologic examination revealed no other abnormal findings. Other effects noted were not definitively related to treatment and/or were not biologically significant. The NOAEL and LOAEL are identified as 200 and 800 mg/kg-day, respectively, based on decreased body weight. In a second study by Wolfe (1988b), groups of 20 male and 20 female Sprague-Dawley rats were administered p-xylene (99% purity) by gavage in corn oil at doses of 0, 100, 200, or 800 mg/kg-day for 90 consecutive days. Survival incidences were 20/20, 19/20, 17/20, and 16/20, respectively, for males, and 20/20, 18/20, 18/20, and 17/20 for females. Mortality in high-dose males attained statistical significance, and a statistically significant trend was present in the male groups. As in the Wolfe (1988a) study, mottled lungs and/or a failure of the lungs to collapse was observed in nearly all treated animals that died early but was not evident in any of the animals that survived to study termination. It was determined that most of the unscheduled deaths were the result of test material aspiration, as indicated by the presence of intra-alveolar foreign material in the lungs that was generally associated with pulmonary congestion. Treatment-related clinical signs were limited to increased salivation occurring just prior to dosing that was resolved by 1-hour post-dosing in both high-dose males and females. Body weight gains at 13 weeks were slightly reduced (89% of control levels, not statistically significant) in high-dose males and females, and high-dose females had significantly increased food consumption for weeks 10-13 (110%). No treatment-related effects were observed in hematology or clinical chemistry parameters, ophthalmologic examination, or organ weights. Histopathology revealed no abnormal findings in any tissue or organ. The NOAEL and LOAEL are identified as 200 and 800 mg/kg-day, respectively, based on early mortality in male rats that showed signs of test material aspiration into the lungs. The NTP (1986) 2-year study in rats was selected as the principal study for the derivation of the RfD for xylenes because it is the only oral animal study of chronic duration, and some effects (decreased body weight and possible increased mortality) were evident at doses lower than those for effects seen in other studies. The body weight decrease (5-8% of controls') is considered to be of marginal biological significance, but there was a statistically significant trend for decreased survival in male rats with increasing exposure levels, and survival in the high-dose males was statistically significantly decreased when compared with controls. Given the possibility of treatment-related frank toxicity, it is not considered prudent to discount the only other observed effect, i.e., decreased body weight. Thus, the highest dose in the study, 500 mg/kg-day, is considered a LOAEL for changes in body weight and mortality. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 1000. A UF of 10 was applied to account for laboratory animal-to-human interspecies differences. No information is available to support a change from default. A UF of 10 was applied for intraspecies uncertainty to account for human variability and sensitive populations. This factor accounts for humans who may be more sensitive than the general population to exposure to xylenes. A UF of 10 was used to account for data base uncertainty. The available oral data base for xylenes includes chronic and subchronic gavage toxicity studies in mice and rats and a developmental toxicity study. None of these studies indicate that additional data would result in a lower RfD. However, the data base lacks adequate studies of the oral neurotoxicity of xylenes as well as multigenerational reproductive toxicity and developmental neurotoxicity studies. Given the identification of neurological impairment as a critical health hazard from inhalation exposure to xylenes, the lack of comprehensive neurotoxicity testing following chronic oral exposure is of particular concern. It should be noted that transient neurotoxic effects (e.g., lethargy, tremors and unsteadiness) were reported in mice following oral exposure to xylenes for 13 weeks (NTP, 1986). There are no toxicokinetic data identifying oral dose levels at which first-pass hepatic metabolism of xylenes becomes saturated in animals or humans; such data could decrease uncertainty regarding whether neurological impairment may occur at dose levels below those causing body weight decreases and mortality in rats. It is uncertain whether the availability of comprehensive oral neurotoxicity data would result in a lower RfD. An additional uncertainty associated with the oral data base is that the majority of studies examined mixed xylenes, which are known to contain ethylbenzene. The IRIS assessment for ethylbenzene (U.S. EPA, 2002a), which was entered on the data base in 1987, cites effects on liver and kidney as the most sensitive endpoints following oral exposure. As discussed below, effects on the liver and kidney have been reported following oral exposure to mixed xylenes, but the most sensitive effect reported in animal bioassays is decreased body weight and increased mortality, as identified by the principal study (NTP, 1986). However, because the mechanism behind the critical effect has not been clearly elucidated, a possible contribution of ethylbenzene to the toxicity of mixed xylenes cannot be entirely eliminated. Additional studies comparing the toxicity of mixed xylenes with that of the individual isomers would better inform the data base. The RfD is based on a NOAEL from a chronic study, which obviates the need for a UF due to LOAEL to NOAEL extrapolation or subchronic extrapolation. MF = 1. ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) In a NTP (1986) study, groups of 10 male and 10 female Fischer 344 rats were administered mixed xylenes (60% m-xylene, 13.6% p-xylene, 17.0% ethylbenzene, 9.1% o-xylene) in corn oil by gavage at doses of 0, 62.5, 125, 250, 500, or 1000 mg/kg-day for 5 days per week for 13 weeks. At termination of the study, necropsy was performed on all animals and comprehensive histologic examinations were performed on vehicle and high-dose group animals. High-dose males and females gained 15% and 8% less body weight, respectively, than did controls, with final body weights being 89% and 97%, respectively, of those of controls (statistical significance not reported). No signs of toxicity or treatment-related gross or microscopic pathologic lesions were observed. The LOAEL is 1000 mg/kg-day and the NOAEL is 500 mg/kg-day based on decreased body weight in male rats without tissue lesions. In the same study, male and female B6C3F1 mice were treated with mixed xylenes. Groups of 10 mice of each sex were administered 0, 125, 250, 500, 1000, and 2000 mg/kg-day in corn oil by gavage for 5 days per week for 13 weeks. Two female mice in the high-dose group died prematurely, although gavage error could not be ruled out as the cause. At 2000 mg/kg-day, starting 5-10 minutes after dosing and lasting for 15-60 minutes, the animals exhibited lethargy, short and shallow breathing, unsteadiness, tremors, and paresis. In the high-dose group, mean body weight was 7% lower for males and 17% lower for females than in the vehicle control. Although not stated explicitly, the text implies that this was a common finding among the animals dosed at this level. No treatment-related gross or microscopic pathologic lesions were seen in this study. The NOAEL is 1000 mg/kg-day and the LOAEL is 2000 mg/kg-day for transient signs of nervous system depression in mice without tissue lesions. In a study by Condie et al. (1988) groups of 10 male and 10 female Sprague-Dawley rats were administered mixed xylenes (17.6% o-xylene, 62.3% m-xylene and p-xylene [which coeluted], 20% ethyl benzene) by gavage in corn oil for 90 consecutive days at doses of 0, 150, 750, or 1500 mg/kg-day. Effects of exposure included decreased body weights in high-dose males (94% of controls'), dose-related increased liver weights and liver-to-body weight ratios in all exposed groups of males (8, 18, and 29% increase in absolute weight above controls' in the low-, mid-, and high-dose animals, respectively) and in mid- and high-dose females (14 and 30%, respectively), and increased kidney weights and kidney-to-body weight ratios in mid- and high-dose males (16 and 19% increase in absolute weight relative to controls', respectively) and high-dose females (18% increase in absolute weight relative to controls). The authors postulated that the modest increases in aspartate aminotransferase seen in high-dose females and increases in alanine aminotransferase in high-dose males and in mid- and high-dose females, combined with the lack of significant histopathologic findings in the liver, suggest that the enlargement of the liver was an adaptation response to xylenes treatment rather than an adverse toxicological effect. Hematology analysis revealed a mild polycythemia and leukocytosis in the high-dose males and females in the absence of any observable changes in the health of the rats. Microscopic evaluation of the kidneys revealed a dose-related increase in hyaline droplet formation in male rats (0/9, 3/9, 5/10, 8/10, respectively) and a dose-related increase in the early appearance of minimal chronic nephropathy in female rats (1/10, 3/10, 6/10, 7/10, respectively). Compared with controls, the incidence of minimal nephropathy was statistically significantly elevated (p<0.05) in the 750 and 1500 mg/kg-day female groups but not in the 150 mg/kg-day group (Fishers exact test performed by Syracuse Research Corporation). The hyaline droplet formation in male rats was assumed by the authors to be related to male rat-specific a-2u-globulin accumulation and not to be relevant to humans. The LOAEL is 750 mg/kg-day, based on increased kidney weights and early appearance of mild nephropathy in female rats, and the NOAEL is 150 mg/kg-day. Kidney effects were not found in the NTP (1986) bioassay with Fisher 344/N rats or B6C3F1 mice exposed to xylenes for 13 weeks or 2 years. Likewise, no nephropathy was reported in a nephrotoxicity screening assay in male Fischer 344/N rats exposed to 2000 mg/kg m-xylene for 5 days per week for 4 weeks (Borriston Laboratories, Inc., 1983). In addition, no kidney effects were found in Sprague-Dawley rats exposed for 90 days to m-xylene or p-xylene at doses as high as 800 mg/kg-day (Wolfe et al., 1988a, b). Thus, the available data do not consistently identify the kidney as a sensitive target of xylenes in animals. Likewise, the available data do not consistently identify the liver as a sensitive target of xylenes in animals (NTP, 1986; Wolfe et al., 1988a, b; Condie et al., 1988). A developmental toxicity study in CD-1 mice (Nawrot and Staples, 1980) indicates that developmental effects may occur following exposure to xylenes. However, the study was reported as an abstract with incomplete documentation of exposure protocols and results; it does not identify reliable NOAELs and LOAELs for maternal and developmental toxicity. Nevertheless, information in the abstract indicates that exposure on gestation days 6-15 to daily doses of o-, m-, or p-xylene at 1935 or 2580 mg/kg-day - but not at 774 mg/kg-day - resulted in overt maternal toxicity and increased incidences of cleft palate in the fetuses. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=67. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Database -- Medium RfD -- Medium Confidence in the principal study is medium. The study was a 2-year toxicology and carcinogenesis assay that evaluated the critical endpoint for RfD derivation (body weight and mortality) and included comprehensive histologic examination of tissues for nonneoplastic and neoplastic lesions. Some gavage errors occurred during the study, limiting the confidence assessment to medium. Confidence in the oral exposure data base is medium because the data base contains chronic animal studies in two species (rats and mice), numerous subchronic studies, and an evaluation of the developmental effects of oral xylenes, but it is lacking oral neurotoxicity studies as well as multigenerational reproductive toxicity and developmental neurotoxicity studies. Medium confidence in the RfD follows. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=77. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document - U.S. EPA, 2002a This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA (2002a). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=92. Agency Consensus Date - 01/30/2003 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or hotline.iris@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 200302 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Xylenes CASRN -- 1330-20-7 Last Revised -- 02/21/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: Note: As noted in Section I.A. of this file, xylenes refers to mixtures of all three xylene isomers and ethylbenzene. The inhalation RfC for xylenes presented herein is based on a principal study (Korsak et al., 1994) in which rats were exposed by inhalation to m-xylene. There is some uncertainty associated with selecting a principal study for xylenes that involved exposure to m-xylene alone, but this isomer is generally predominant in commercial mixtures. In addition, although there are no studies comparing xylene isomers in affecting critical neurological endpoints following subchronic or chronic inhalation exposure, the potencies of individual xylene isomers were similar in affecting neurobehavior, as shown in a study of rats following acute exposures (Moser et al., 1985) (see Section 4.4.3 of the Toxicological Review for more information). No inhalation RfC for xylenes has previously been on IRIS. SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC -------------------- ---------------------- -- --- ----- Impaired motor NOAEL: 50 ppm 300 1 0.1 coordination (decreased NOAEL(HEC): 39 mg/m3 mg/m3 rotarod performance) Subchronic inhalation LOAEL: 100 ppm study in male rats LOAEL(HEC): 78 mg/m3 (Korsak et al., 1994) ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- MW = 106.17. Assuming 25 C and 760 mm Hg, NOAEL(mg/m3) = 50 ppm x 106.17/24.45 = 217 mg/m3. NOAEL[ADJ] = 217 mg/m3 x 6 hrs/day x 5 days/7 days = 39 mg/m3. The NOAEL*[HEC] was calculated for extrarespiratory effects of a Category 3 gas (U.S. EPA, 1994). Blood/gas partition coefficients: H(b/g)rat = 46.0; H(b/g)human=26.4 (Tardif et al., 1995). (Hb/g)rat/(Hb/g)human =1.7; value of 1 is used when the ratio is >1 (U.S. EPA, 1994). NOAEL*[HEC] = NOAEL[ADJ] x (Hb/g)rat/(Hb/g)human = 39 mg/m3. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Korsak et al. (1992) exposed groups of 12 male Wistar rats to toluene, m-xylene, or a 1:1 mixture for 6 hours per day, 5 days per week at a concentration of 0 or 100 ppm for 6 months or 1000 ppm for 3 months. Rotarod performance and spontaneous motor activity were assayed 24 hours after termination of the exposure periods. The rotarod test was used as a measure of motor coordination disturbances from exposure to m-xylene. The rotarod test involves placing the subject animals on a rotating rod and evaluating their ability to remain on the rod for a period of 2 minutes. The animals were trained to perform the task, exposed to chemical or control gas, and evaluated at defined intervals. By the time interval after exposure, considerable proportions of absorbed xylenes are expected to have been eliminated from the body (see Section 3.4 and Appendix B of the Toxicological Review). Body weights and weights of seven organs were measured; only data for animals sacrificed after 3 months of exposure was reported (controls and 1000 ppm rats). At 3 and 6 months, blood samples were collected 24 hours after termination of exposure for measurement of serum chemistry variables (e.g., alanine aminotransferase, aspartate aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, and total protein) and hematologic variables (erythrocyte counts, hemoglobin concentration, hematocrit, leukocyte count, and differential leukocyte counts). Serum chemistry and hematologic results were reported only for rats exposed to 1000 ppm for 3 months. Statistical evaluations (using a p=0.05 level of significance) of collected data included analysis of variance, Dunnet's test, and Fishers exact test. Rats exposed to m-xylene alone exhibited statistically significantly decreased rotarod performance and decreased spontaneous activity, as measured 24 hours after termination of the exposures, when compared with controls. The percentages of failures in the rotarod test were roughly 60% in rats exposed to 1000 ppm for 3 months, 35% in rats exposed to 100 ppm for 6 months, and 0% for controls at either time period. The mean spontaneous motor activity in rats exposed to 100 ppm for 6 months was about 400 movements per hour, compared with about 800 movements per hour for controls. Spontaneous motor activity data for rats exposed to 1000 ppm m-xylene for 3 months were not presented in the report. No statistically significant exposure-related changes in body weight, absolute or relative organ weights, or clinical chemistry or hematology variables were noted in rats exposed to 1000 ppm m-xylene for 3 months, with the exception of decreased differential counts (percentage of white blood cells counted) of lymphocytes (45.5 +/- 9.5 vs. 60.8 +/- 6 .4 for controls; 25% decrease) and increased counts of monocytes (16.3 +/- 8.9 vs. 8.3 +/- 4.2 for controls; 96% increase). Total counts of white blood cells (in units of cells per mm3 of blood), however, were not statistically significantly changed by exposure. The LOAEL is 100 ppm, based on decreased rotarod performance and decreased spontaneous motor activity. No NOAEL was identified. In a second study, Korsak et al. (1994) exposed groups of 12 male Wistar rats by inhalation to 0, 50, or 100 ppm m-xylene or n-butyl alcohol or a 1:1 mixture (purity of chemicals not provided) for 6 hours per day, 5 days per week, for 3 months and evaluated similar endpoints as in the earlier study (Korsak et al., 1992). Blood for clinical biochemistry and hematologic analysis was collected 24 hours after termination of exposure. The report does not specify the timing of the neurologic examinations; however, given that the 1994 study was conducted by the same group of investigators as the 1992 study and that one of the tests (rotarod performance) was the same in both studies, it appears reasonable to assume that the tests were administered 24 hours after termination of exposure. Statistical evaluations (using a p=0.05 level of significance) of the collected data included analysis of variance, Dunnet's test, and Fishers exact test. No statistically significant exposure-related changes were noted in body weight gain, absolute or relative organ weights, hepatic activities of microsomal monooxygenases, lipid peroxidation, or levels of triglycerides in the liver. Statistically significant decreases in erythrocyte number were seen in animals exposed to 50 ppm (93% of controls') or 100 ppm (80.5% of controls') of m-xylene alone. Similarly, decreased levels of hemoglobin were reported in both groups (92% of controls' for both groups). At 100 ppm, a statistically significant increase in leukocyte number (35% increase over controls') was reported. Exposure to 50 or 100 ppm m-xylene alone also resulted in decreased rotarod performance starting at 1 month of exposure, which remained at the same level until the end of the 3-month exposure. Decreases were statistically significant in the 100 ppm group when compared with the controls. The results were presented in graphical form; the actual numerical data are not provided. The decreases in performance were roughly 8% and 33% for the 50 and 100 ppm groups, respectively, versus 0% for the controls. Sensitivity to pain was assessed using the hot plate behavior test, in which the animals are placed on a hot (54 deg C) surface and the time interval between being placed on the plate and licking of the paws is measured. Rats exposed to 50 or 100 ppm m-xylene alone had statistically significantly increased sensitivity to pain at the end of the 3-month exposure (latency of the paw-lick response was 8.7 and 8.6 seconds, respectively, vs. 12.2 seconds for the controls). The LOAEL is 100 ppm, based on decreased rotarod performance and decreased latency in the paw-lick response in the hot-plate test, and the NOAEL is 50 ppm. To evaluate whether xylenes influence aging of the central nervous system or induces persistent changes in radial maze performance, Gralewicz et al. (1995) exposed 8-month-old, male LOD-Wistar rats (20 per dose level) to air containing 0, 100, or 1000 ppm "pure" m-xylene (exact purity not provided) for 6 hours per day, 5 days per week, for 3 months. One-hour electroencephalograph (EEG) recordings were performed on days 28 and 56 of exposure and on days 14, 28, 56, and 84 after exposure. The number and duration of spontaneous neocortical spike and wave discharges (SWD) from the EEG were taken as electrophysiological indices of the biological age of the brain. As rats age, SWDs increase in number and become longer. Because of large interindividual variation in number and duration of SWDs within each group, these variables were normalized to a percentage of the initial values. Exposed rats were not subjected to the daily exposure protocol when EEG recordings were made on days 28 and 56 during the exposure period. Tests of spatial learning in an 8-arm radial maze were also conducted for a 2-week period starting from day 70 after exposure to day 83. During the first adaptation stage of the test (five consecutive daily training periods), rats were familiarized with the maze. The second stage (five consecutive daily trials) measured effectiveness of finding water in the maze (e.g., duration of trial, number of entries into the arms, number of omission and preservation errors). One-way or two-way parametric analysis of variance was applied to the collected data, and effects were regarded as statistically significant at p<0.05. Body weights were also measured during and after the exposure period at various intervals, but statistically significant differences were not found among the groups. The analysis of variance indicated no group effect on the normalized number and cumulative-duration SWD variables. However, a statistically significant group x successive recording period effect was indicated. In control rats, these variables were increased to a statistically significant degree, compared with those of the exposed groups, only on day 84 after exposure. The mean cumulative SWD duration (expressed in percentage) on day 84 was about 300 for the control compared with means of about 150 in each of the exposed groups. The authors hypothesized that these exposure-related changes in the spontaneous, age-related changes in cortical SWD activity may be related to cortical excitability or to an increase in catecholaminergic transmissions. Unlike the controls, rats exposed to 100 or 1000 ppm m-xylene did not exhibit a statistically significant shortening of the time needed to complete a trial in the radial maze with successive daily trials. These results indicate a learning deficit in the exposed rats. For example, on the fifth consecutive trial, the mean trial durations in each of the exposed groups were about 240-250 seconds, compared with a mean of about 150 seconds for the control group. In addition, the exposed groups did not exhibit the statistically significant decrease in omission errors with successive days in the radial arm maze test that was exhibited by the control group (number of arms in the maze omitted during a 5-minute period when the rats explored the maze). The mean number of omission errors in control rats showed a progressive decrease from about 2.75 on the first trial to 0 on the fourth and fifth successive trials. In contrast, the means on the fifth consecutive trial were about 1.5 and 2.5 for the 100 ppm and 1000 ppm groups, respectively. The lowest exposure level in this study, 100 ppm, is designated as a LOAEL for deficits in radial maze performance. Gralewicz and Wiaderna (2001) exposed groups of male Wistar rats (10-11 animals/group) to 0 or 100 ppm of m-xylene for 6 hours per day, 5 days per week for 4 weeks. Behavioral testing was performed at various intervals before (radial maze and open-field evaluations) and after exposure (radial maze [days 14-18], open-field activity [day 25], passive avoidance [days 39-48], hot plate test [days 50-51], and active avoidance [days 54-60]). The radial maze and hot plate test protocols are described in previous studies from this group (Gralewicz and Wiaderna, 1995; Korsak et al., 1992). In the open-field activity test, animals were placed in a 100 cm x 100 cm arena that was surrounded by 20 cm high walls and divided into 49 equal squares. The number of square borders crossed (locomotor activity), number of rearings (exploratory activity), and number of grooming episodes were recorded. In the passive avoidance test, animals were placed on a platform above the floor of the cage, and the time until the animal stepped off the platform was recorded in a series of six trials. In the first two trials, the animals were allowed to explore the cage for 60 seconds after stepping down; in the third trial, the animals received a series of footshocks after stepping off the platform. In trials 4, 5, and 6 the animals received no shocks and were allowed to stay on the floor for 1 minute after stepping off the platform. In the active avoidance test, animals were trained to avoid an electric footshock by moving from one compartment of the cage to another when a sound is played. After successfully displaying avoidance behavior in four of five trials, the animals were considered to be trained. Post-exposure evaluations determined the frequency of avoidance behavior in response to the same stimulus. No differences between control and exposed rats were seen in radial maze parameters (number of arm entries, arms omitted, or arms entered multiple times) either before exposure (7 days prior to exposure) or at 14-18 days after the termination of exposure. Similarly, no differences in open-field activity were seen between groups examined on day 8 prior to exposure or day 25 postexposure or in active avoidance (number of trials to avoidance criterion), examined on days 54 and 60 post-exposure. Xylene-exposed rats showed a significantly shorter step-down time (trial 6 only; no difference in trials 1-5) in the passive avoidance test (examined on days 39-48 postexposure) and a significantly greater paw-lick latency in the hot plate behavior test (examined on days 50-51 postexposure), identifying 100 ppm as a LOAEL for neurobehavioral effects. Because available human data are insufficient for deriving an RfC and chronic animal inhalation data are lacking, the subchronic study of Korsak et al. (1994) was selected as the principal study and Korsak et al. (1992), Gralewicz et al. (1995), and Gralewicz and Wiaderna (2001) as the supporting studies. Neurological effects (impaired motor coordination) are selected as the critical effect for deriving the RfC. Two neurological endpoints were evaluated in this study. Rotarod performance was statistically significantly decreased (33% from controls') at 100 ppm, and a statistically significant decreased sensitivity to pain was observed at 50 and 100 ppm (8.6 and 8.7 seconds, respectively, vs. 12.2 seconds for controls; measurements made 24 hours postexposure). Gralewicz and Wiaderna (2001) also measured the effect of m-xylene exposure (6 hrs/day, 5 days/wk for 4 weeks; neurological endpoints measured postexposure day 50) on pain sensitivity. In this study, a statistically significant increase in pain sensitivity (35 seconds vs. 10 seconds in control) was found at the 100 ppm dose, the lowest dose tested. The variation in the response to m-xylene in these two studies decreases the confidence in using the pain sensitivity endpoint as the critical effect. A number of statistically significant neurological effects have been noted in male rats at a dose of 100 ppm m-xylene in other supporting studies: decreased rotarod performance and spontaneous movement activity following exposure for 6 hours per day, 5 days per week for 6 months (Korsak et al., 1992), decreased radial maze performance following exposure for 6 hours per day, 5 days per week for 3 months (Gralewicz et al., 1995); and shortened step-down time in the passive avoidance test following exposure for 6 hours per day, 5 days per week for 4 weeks. All studies measured neurological endpoints 24 hours postexposure with the exception of Gralewicz and Wiaderna (2001), which measured effects at postexposure day 50. For these reasons, a NOAEL of 50 ppm and a LOAEL of 100 ppm is identified for neurological effects (impaired motor coordination). The principal study (Korsak et al., 1994) reported no statistically significant exposure-related changes in body weight gain, absolute or relative organ weights, hepatic activities of monoxygenases or lipid peroxidation, or levels of triglycerides in the liver. Compared with controls, exposed rats showed statistically significant changes in red blood cell counts (7-20% decreased), hemoglobin levels (-8% decreased), and white blood cell counts (35% increased). Effects in red blood cell counts and hemoglobin levels were observed at 50 ppm. However, these changes were not observed in another study from the same laboratory (Korsak et al.,1992) in rats exposed to 1000 ppm m-xylene. Furthermore, effects on erythrocytes were not found at concentrations of 78-810 ppm in other studies (Carpenter et al., 1975; Jenkins et al., 1970). UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 300. A UF of 3 was applied to account for laboratory animal-to-human interspecies differences. A factor of 3 was applied because default NOAEL[HEC] dosimetric adjustments were used to calculate a human equivalent concentration (HEC), reducing the uncertainty involved with the extrapolation from the results of an animal study to a human exposure scenario (i.e., the toxicokinetic portion of the UF is 1; the toxicodynamic portion of the UF is 3). A uncertainty factor of 10 was applied for intraspecies uncertainty to account for human variability and sensitive populations. The degree of human variance in abilities to absorb or dispose of xylenes is unknown, as is the degree of human variance in responding to xylenes neurotoxicity. Results from developmental toxicity studies of rats exposed by inhalation during gestation indicate that adverse developmental effects occur only at higher doses than chronic doses producing the critical effects observed in adult male rats in the principal and supporting studies, suggesting that the developing fetus is not at special risk from low-level exposure to xylenes. However, as with oral exposure, the effects of inhaled xylenes in other potentially sensitive populations such as newborns or young children or animals have not been assessed. A UF of 3 was applied for extrapolation from subchronic to chronic duration. A factor of 10 was not used because the changes in rotarod performance did not increase with time from 1 to 3 months and were similar to those described in a separate study of 6-months duration (Korsak et al., 1992). A UF of 3 was applied for uncertainties in the data base. The inhalation data base includes some human studies, subchronic studies in rats and dogs, neurotoxicity studies, a one-generation reproductive toxicity study, developmental toxicity studies, and developmental neurotoxicity studies. Although the available developmental toxicity studies are confounded by a lack of litter incidence reporting, the data reported for fetal incidences do not indicate effects at levels lower than that found to induce neurologic impairment in several endpoints in male rats. The data base is lacking a two-generation reproductive toxicity study. MF = 1. IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) The weight of evidence from limited human data and more extensive animal data identify mild neurological impairment and possible developmental effects as potential health hazards from repeated inhalation exposure to xylenes. The animal inhalation exposure data base contains no chronic toxicity studies, but there are a number of subchronic toxicity studies (of which several focused on neurological endpoints), a one-generation reproduction study in rats, and several developmental toxicity studies, some of which evaluated offspring for performance in neurobehavioral tests. Subchronic toxicity assays in animals have not found consistent evidence for other noncancer effects, such as changes in body weight or in hepatic, hematologic, or renal toxicity endpoints, following exposure to concentrations of xylenes as high as 800-1000 ppm for 6 hours per day, 5 days per week (e.g., Carpenter et al., 1975; Jenkins et al., 1970; Korsak et al., 1992, 1994). Reversible symptoms of neurological impairment and irritation of the eyes and throat are well-known health hazards from acute inhalation exposure to xylenes and other aromatic solvents. In general, these acute effects are expected to involve reversible molecular interactions of the solvent itself (not metabolites) with membranes of the affected tissues, including neuronal membranes, and are most pronounced at high exposure levels in excess of 1000 ppm. At lower concentrations, more subtle effects may occur. Human volunteers exposed under controlled conditions to xylenes concentrations in the range of 200-400 ppm for short time periods (15 minutes to 4 hours) have reported symptoms of irritation (e.g., watering eyes and sore throat) or neurological impairment (e.g., mild nausea, headache) (Carpenter et al., 1975; Gamberale et al., 1978). In other studies involving single or multiple 4-hour exposures of human volunteers to 200 ppm xylenes, reversible effects on balance and reaction times have been reported (Laine et al., 1993; Savolainen and Linnavuo, 1979; Savolainen et al., 1984); however, other studies of 4-hour exposures to 200 ppm have not found impaired performance in tests of simple reaction time, short-term memory, and choice reaction time (Olson et al., 1985) or changes in visually evoked brain potentials (Seppalainen et al., 1983) or electroencephalographic patterns (Seppalainen et al., 1991). Impaired performance on tests of memory and reaction times was also reported for subjects exposed to 100 ppm xylenes for 4 hours (Dudek et al., 1990). The available controlled-exposure human studies indicate that concentrations around 100-200 ppm are close to the threshold level for short-term reversible neurological and irritation effects from xylenes. The available human data alone do not provide adequate evidence for neurological impairment from repeated exposure to xylenes concentrations less than or equal to 200 ppm. Aside from the controlled-exposure studies reviewed above, most of the human data associating xylenes exposure to neurological impairment are case reports involving acute high-level exposures (800-10,000 ppm) (e.g., Goldie, 1960; Hipolito, 1980; Klaucke et al., 1982). Epidemiologic studies are restricted to a cross-sectional health evaluation study (Uchida et al., 1993) that reported increased prevalence of self-reported neurological symptoms and irritation, but no apparent changes in serum enzymes indicative of liver or kidney damage in a group of Chinese workers. The workers were from a boot manufacturing plant that used a xylene-containing glue and two other plants that used mixed xylenes as a solvent in wire production or printing. The measured time-weighted-average mean concentration of airborne xylenes in these workplaces was 21 (+/- 21) ppm. The study has several limitations, including a lack of reporting on the duration of exposure, co-exposure to other chemicals, no clear demonstration of relationships between response and dose or duration, and the inherent bias presented by self-reporting of symptoms. Although the human evidence for persistent effects on the nervous system or other persistent effects from repeated inhalation exposure to xylenes is inadequate, results from animal studies more clearly identify potential persistent neurological impairment and possible developmental effects as potential health hazards from repeated inhalation exposure. Overall results from rat studies described in Section I.B.2 provide evidence that repeated exposure to m-xylene at concentrations >= 100 ppm (6 hrs/day, 5 days/wk) may produce persistent changes in several neurologic endpoints in adult rats. Supporting evidence for potential persistent neurologic effects from xylenes includes reports of changes in indices of hearing loss in rats exposed to >= 800 ppm mixed xylenes for 14 hours per day for 6 weeks (Pryor et al., 1987) and in rats exposed to 1000 ppm mixed xylenes for 18 hours per day, 7 days per week, for 61 days (Nylen and Hagman, 1994). There are no studies of the possible developmental toxicity of inhaled xylenes in humans, but there are a number of studies examining standard developmental toxicity endpoints and neurobehavioral endpoints in offspring of animals exposed to mixed xylenes or individual xylene isomers. Evidence for impaired neurological development in rat offspring following gestational exposure to inhaled xylenes is not strong or consistent. Changes in neurobehavioral variables reported for offspring of animals exposed during gestation are restricted to impaired cognitive but not motor performance in the Morris water maze test in female but not male offspring of rats exposed to 500 ppm mixed xylenes for 6 hours per day on gestation days 7-20 (Hass et al., 1995, 1997) and decreased rotarod performance in offspring of rats exposed to 200 ppm "technical" xylenes for 6 hours per day on gestation days 6-20 (Hass and Jakobsen, 1993). Deficits in the water maze test were only observed in female rat offspring raised in standard housing and not in female rats raised in "enriched" housing with various toys (Hass et al., 1995). Although decreased rotarod performance by offspring was observed in the study by Hass and Jakobsen (1993), it was not observed in the later study by the same group of investigators (Hass et al., 1995). The reported effect on rotarod performance in the earlier study was questioned by Hass et al. (1995) because the test was not conducted by experimenters who were blind to the exposure status of the rats. In addition, offspring of rats exposed to 800 or 1600 ppm p-xylene for 6 hours per day on gestation days 7-16 performed similarly to offspring of nonexposed rats in tests of central nervous system development: an acoustic startle response test on postnatal days 13, 17, 21, and 63 and a figure-8 maze activity test on postnatal days 22 and 65 (Rosen et al., 1986). Several other inhalation developmental toxicity studies have examined standard developmental toxicity endpoints in rats (Litton Bionetics, 1978; Bio/dynamics Inc., 1983; Rosen et al., 1986; Ungvary et al., 1980; Ungvary and Tatrai, 1985), mice (Ungvary and Tatrai, 1985) and rabbits (Ungvary and Tatrai, 1985) following gestational exposure to xylenes. These studies have most clearly identified maternally toxic levels for decreased body weight gain in pregnant rats at concentrations greater than or equal to 700 ppm o-, p-, or m-xylene for 24 hours per day (Ungvary et al., 1980) or 1600 ppm p-xylene for 6 hours per day (Rosen et al., 1986) and for maternal death and abortions in pregnant rabbits exposed to 230 ppm (but not 115 ppm) mixed xylenes or p-xylene for 24 hours per day (Ungvary and Tatrai, 1985). In rats, effects on fetal skeletal and visceral malformations (such as cleft palate) and variations (such as retarded skeletal ossification or extra ribs) were reported at concentrations of up to 700 ppm o-, m-, or p-xylene for 24 hours per day (Ungvary et al., 1980) or 780 ppm mixed xylenes for 24 hours per day (Bio/dynamics Inc., 1983; Litton Bionetics, 1978; Ungvary and Tatrai, 1985). Likewise, effects on skeletal and visceral malformations and variations were reported in mice at concentrations of up to 230 ppm mixed xylenes (12 hrs/day in three 4-hr periods) or 115 ppm o-, p-, or m-xylene by the same protocol (Ungvary and Tatrai, 1985) or in rabbits exposed to 115 ppm mixed xylenes or o-, p-, or m-xylene for 24 hours per day (Ungvary and Tatrai, 1985). Statistically significant increased incidences of fetuses with retarded skeletal ossification or extra ribs were reported in these studies, but the incidences were reported on an exposure-group basis in all but one of the studies. No litter-specific information was provided except in the Litton Bionetics (1978) study, which reported that, after adjustment for covariance with litter size, incidences of fetuses with delayed ossification in rats exposed to 400 ppm were no longer statistically significantly different from control values. The most significant effects on developmental endpoints were decreased fetal body weight or fetal survival in rats at xylene isomer concentrations of 350 or 700 ppm for 24 hours per day (Ungvary et al., 1980) or a mixed xylenes concentration of 780 ppm for 24 hours per day (Ungvary and Tatrai, 1985) and increased abortions in rabbits exposed to 230 ppm for 24 hours per day (Ungvary and Tatrai, 1985). These effects, although of concern, occurred at concentrations above those at which neurobehavioral effects were found in adult male rats following subchronic exposure (see Section I.B.2.). Information regarding the potential reproductive toxicity of xylenes in humans is restricted to case-control studies reporting possible associations between occupational exposure to xylenes and other solvents and spontaneous abortions (e.g., Taskinen et al., 1986, 1994). However, these studies are of limited usefulness in assessing the potential reproductive toxicity of xylenes, because the numbers of cases of spontaneous abortions were small, and the women had been exposed to a number of chemicals. Two reproductive toxicity studies in rats exposed to xylenes by inhalation are available (Bio/dynamics Inc., 1983; Nylen and Hagman, 1994). In a one-generation reproductive/developmental toxicity study (Bio/dynamics Inc., 1983), male and female CD rats were exposed to 0, 60, 250, or 500 ppm xylenes (technical grade xylene: 2.4% toluene, 12.8% ethylbenzene, 20.3% p-xylene, 44.2% m-xylene, 20.4% o-xylene) by inhalation for 6 hours per day, 5 days per week, for 131 days prior to mating, with exposure continued in the females during gestation days 1-20 and lactation days 5-20. Two additional 500-ppm groups used the same exposure protocol, except that only the F0 males were exposed in one, and only the F0 females were exposed in the other. The highest exposure level in this study, 500 ppm, was a NOAEL for reproductive performance in the parental generation. Likewise, a study of male Sprague-Dawley rats exposed to 0 or 1000 ppm xylene solvent for 18 hours per day, 7 days per week, for 61 days reported no differences between control and exposed rats in several testicular endpoints and fertility (Nylen and Hagman, 1994). In summary, human data are suggestive of neurological effects and irritation of the eyes and respiratory tract following inhalation exposure to xylenes. Animal studies have demonstrated that neurological effects are the most sensitive effect of xylenes inhalation, with measurable effects in several neurobehavioral endpoints beginning at concentrations as low as 100 ppm following subchronic exposure (Gralewicz et al., 1995; Korsak et al., 1992, 1994; Nylen and Hagman, 1994; Pryor et al., 1987). At higher exposure levels, changes in body weight have been reported by some studies (Tatrai and Ungvary, 1980; Tatrai et al., 1981) but not by others (Carpenter et al., 1975; Jenkins et al., 1970; Ungvary, 1990). Similarly, high-level exposure to xylenes has resulted in changes in liver morphology, weight, and enzymatic functions (Tatrai and Ungvary, 1980; Tatrai et al., 1981; Ungvary, 1990). Gestational exposure of animals to xylenes has resulted in neurodevelopmental effects (Hass et al., 1995, 1997; Hass and Jakobsen, 1993) and other possible developmental effects (Ungvary et al., 1980; Ungvary and Tatrai, 1985), but only at levels above those at which neurobehavioral effects in adult male rats were reported. Finally, no reproductive effects were found in a one-generation reproductive/developmental study of male and female rats exposed to 500 ppm xylenes (Bio/dynamics, Inc., 1983) or in male rats exposed to 1000 ppm xylenes for 61 days (Nylen and Hagman, 1994). For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=67. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Database -- Medium RfC -- Medium Confidence in the principal study is medium, because the study was an examination of a critical effect of xylenes toxicity that also examined organ weights, body weights, and hematological parameters but was of subchronic duration, examined only one sex of a single species, and did not conduct histologic examination of the animals. Confidence in the data base is medium; the data base contains several subchronic studies as well as several developmental studies, developmental neurotoxocity studies, and a one-generation reproductive toxicity study. However, a two-generation reproduction study and chronic animal data are lacking. Medium confidence in the RfC results. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=77. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document - U.S. EPA, 2002 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 2002. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=92. Agency Consensus Date - 01/30/2003 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (fax), or hotline.iris@epa.gov (Internet address). ============================================================================ UDCA: 200302 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Xylenes CASRN -- 1330-20-7 Last Revised -- 02/21/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Under the Draft Revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), data are inadequate for an assessment of the carcinogenic potential of xylenes. Adequate human data on the carcinogenicity of xylenes are not available, and the available animal data are inconclusive as to the ability of xylenes to cause a carcinogenic response. Evaluations of the genotoxic effects of xylenes have consistently given negative results. Data on the carcinogenicity of xylenes following inhalation exposure are limited. A number of human occupational studies have suggested possible carcinogenic effects of chronic inhalation exposure to xylenes. However, in each case co-exposure to other chemicals was a major confounder, leading to an inability to adequately assess the potential effects of chronic exposure to xylenes. Animal data on the carcinogenicity of xylenes following inhalation exposure are not available. Examinations of the carcinogenicity of xylenes following oral exposure in humans are not available. NTP (1986) conducted a 2-year oral cancer bioassay in male and female Fischer 344 rats and male and female B6C3F1 mice. Rats were exposed to 0, 250, or 500 mg/kg-day of mixed xylenes by gavage for 5 days per week for 103 weeks. No evidence of carcinogenesis was seen in male or female rats. Similarly, mice exposed to 0, 500, or 1000 mg/kg-day for 2 years did not show evidence of carcinogenic effects (NTP, 1986). However, a study by Maltoni et al. (1983, 1985) reported an increase in the overall number of malignant tumors in male and female rats treated by gavage with 0 or 500 mg/kg mixed xylenes for 4 days per week for 104 weeks. However, only total tumor incidence was reported; descriptions of target organs and tumor types were not included in the report. In the absence of additional information and because only one dose was used, the Maltoni et al. study does not provide sufficient evidence of the carcinogenicity of xylenes in animals. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=77. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=67. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Associations between occupational exposure to xylenes and increased risk of leukemia (Arp et al., 1983; Wilcosky et al., 1984), non-Hodgkin's lymphoma (Wilcosky et al., 1984), and cancer of the rectum (Gerin et al., 1998), colon (Gerin et al., 1998), or nervous system (Spirtas et al., 1991) have been reported. However, a number of limitations preclude the usefulness of these data, including small sample sizes, no quantified exposure concentrations, and/or concurrent exposures to other solvents. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. In National Toxicology Program toxicology and carcinogenesis studies (NTP, 1986), groups of 50 male and 50 female Fischer 344/N rats and 50 male and 50 female B6C3F1 mice were administered mixed xylenes (60% m-xylene, 13.6% p-xylene, 17.0% ethylbenzene, 9.1% o-xylene) in corn oil by gavage at doses of 0, 250, or 500 mg/kg-day (rats) and 0, 500, or 1000 mg/kg-day (mice) for 5 days per week for 103 weeks. Necropsy and histologic examinations were performed on all animals. In rats, no statistically significantly increased incidences of nonneoplastic or neoplastic lesions were found in exposed groups when compared with controls. A survival-adjusted increased incidence of interstitial cell tumors was found in the high-dose male rat group relative to controls, but this was not considered to be a treatment-related increase. The authors attributed the increase to high-dose male rats dying between weeks 62 and 92, noting that incidences for these tumors were comparable with controls during other time intervals and that the overall incidences were not statistically significantly different between control and exposed groups. In mice, no statistically significantly increased incidences of nonneoplastic or neoplastic lesions were found in male or female exposed groups when compared with controls. NTP (1986) concluded that the study provided no evidence of carcinogenicity of xylenes in male or female F344/N rats or B6C3F1 mice. Maltoni et al. (1983, 1985) exposed groups of 40 male and 40 female Sprague-Dawley rats to 500 mg/kg mixed xylenes (unspecified proportions) in olive oil orally by gavage 4-5 days per week for 104 weeks. The control groups of 50 males and 50 females were treated with olive oil only. Rats were kept under observation until spontaneous death; all rats died by 141 weeks. Percentages of mice that survived treatment were similar in controls and treated groups through 92 weeks (Maltoni et al., 1983), but survival data for later periods were not reported (Maltoni et al., 1985). For example, 50% and 65% of exposed males and females, respectively, survived at 92 weeks, compared with 58% and 66% of control males and females. Only limited information regarding tumor incidences at specific tissue sites was provided with no information provided on nonneoplastic lesions or tumor pathology. Final (i.e., 141-week) tumor incidence data were reported only for rats with hemolymphoreticular neoplasias (thymomas, others, and total) and for rats with malignant tumors at any site (Maltoni et al., 1985). Incidences for thymomas were 1/34 and 0/36 in exposed males and females, compared with 0/45 and 0/49 in controls. Incidences of rats with other hemolymphoreticular neoplasias (not otherwise specified) were 4/34 and 3/36 in exposed males and females, compared with 3/45 and 1/45 in controls [1]. Fishers exact tests (performed by Syracuse Research Corporation) indicated no significant differences between groups in the incidences for hemolymphoreticular neoplasias (including the combined incidence for thymomas and "others"). The study authors also reported an increase in the total number of exposed rats with malignant tumors (of unspecified type): 14/38 and 22/40 for exposed males and females, compared with 11/45 and 10/49 for controls [2]. The exposed female total malignant tumor incidence is statistically significantly increased when compared with controls by the Fishers exact test. Because of the incomplete reporting of site-specific tumor incidence data and pathology, the study by Maltoni et al. (1983, 1985) is of limited use in evaluating the carcinogenicity of xylenes. [1] Denominators are the number of rats reported to have been alive at 58 weeks when the first hemolymphoreticular neoplasia was observed. [2] The denominators are the reported numbers of rats alive at 33 weeks when the first malignant tumor was observed. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The genotoxicity of commercial xylenes and all three individual isomers has been studied and the results are, for the most part, negative (IARC, 1989). All studies cited in the GENE-TOX data base are negative with the exception of one study for which no conclusion was drawn. Xylenes are not mutagenic in bacterial test systems with Salmonella typhimurium (Bos et al., 1981; Florin et al., 1980; NTP, 1986) and Escherichia coli (McCarroll et al., 1981) or in cultured mouse lymphoma cells (Litton Bionetics, 1978). Xylenes do not induce chromosomal aberrations or sister chromatid exchanges in Chinese hamster ovary cells (Anderson et al., 1990) or cultured human lymphocytes (Gerner-Smidt and Friedrich, 1978), chromosomal aberrations in rat bone marrow (Litton Bionetics, 1978), micronuclei in mouse bone marrow (Mohtashamipur et al., 1985), or sperm head abnormalities in rats (Washington et al., 1983). Technical grade xylenes, but not o- and m-xylene, are weakly mutagenic in Drosophila recessive lethal tests (Donner et al., 1980). No increase in the frequency of sister chromatid exchanges was observed in peripheral lymphocytes in individuals exposed to xylenes in an occupational setting (Haglund et al., 1980; Pap and Varga, 1987) or an experimental setting (Richer et al., 1993). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not applicable. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not applicable. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document - U.S. EPA, 2002 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 2002. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0270-tr.pdf#page=92. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date - 01/30/2003 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or hotline.iris@epa.gov (internet address). ============================================================================ UDSO: 200302 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Xylenes CASRN -- 1330-20-7 Last Revised -- 02/21/2003 SORD: __VI.A. ORAL RfD REFERENCES Borriston Laboratories, Inc. (1983) Four-week oral nephrotoxicity screening study in male F-344 rats phases I and II pathology report. FYI submission AX-1283-0280. Submitted by the American Petroleum Institute to U.S. Environmental Protection Agency, Washington, DC. Condie, LW; Hill, JR; Borzelleca, JF. (1988) Oral toxicology studies with xylene isomers and mixed xylene. Drug Chem Toxicol 11:329-354. Nawrot, PS; Staples, RE. (1980) Embryotoxicity and teratogenicity of isomers of xylene in the mouse. Soc Toxicol Abst. PAP 19th: A22, 65. NTP (National Toxicology Program). (1986) NTP technical report on the toxicology and carcinogenesis of xylenes (mixed) (60% m-xylene, 13.6% p-xylene, 17.0% ethylbenzene, and 9.1% o-xylene) in F344/N rats and B6C3F1 mice (gavage studies). Research Triangle Park, NC. NTP TR 327, NIH Publ. No. 86-2583. U.S. EPA (Environmental Protection Agency). (2002a) Integrated Risk Information System (IRIS). Online. Office of Research and Development. National Center for Environmental Assessment, Washington, DC. Examined September, 2001. Online. http://www.epa.gov/iris U.S. EPA. (2002b) Toxicological review of xylenes (CAS No. 1330-20-7). National Center for Environmental Assessment, Washington, DC. Available online at: http://www.epa.gov/iris. Wolfe, GW. (1988a) Subchronic toxicity study in rats with m-xylene. Report by Hazleton Laboratories America, Inc. Sponsored by Dynamac Corporation, Rockville, MD. Project No. 2399-108. Wolfe, GW. (1988b) Subchronic toxicity study in rats with p-xylene. Report by Hazleton Laboratories America, Inc. Sponsored by Dynamac Corporation, Rockville, MD. Project No. 2399-110. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Bio/dynamics Inc. (1983) Parental and fetal reproduction toxicity study in rats with mixed xylene. EPA/OTS public files. Bio/dynamics Inc., East Millstone, NJ; Document # FYI-AX-0983-0209. Carpenter, CP; Kinkead, ER; Geary, DL Jr; et al. (1975) Petroleum hydrocarbon toxicity studies. V. Animal and human response to vapors of mixed xylene. Toxicol Appl Pharmacol 33:543-58. Dudek, B; Gralewicz, K; Jakubowski, M; et al. (1990) Neurobehavioral effects of experimental exposure to toluene, xylene and their mixture. Polish J Occup Med 3:109-116. Gamberale, F; Annwall, G; Hultengren, M. (1978) Exposure to xylene and ethylbenzene. III. Effects on central nervous functions. Scand J Work Environ Health 4:204-211. Goldie, I. (1960) Can xylene (xylol) provoke convulsive seizures? Ind Med Surg 29:33-35. Gralewicz, S; Wiaderna, D. (2001) Behavioral effects following subacute inhalation exposure to m-xylene or trimethylbenzene in the rat. A comparative study. NeuroToxicology 22: 79-89. Gralewicz, S; Wiaderna, D; Tomas, T. (1995) Development of spontaneous, age-related nonconvulsive seizure electrocortical activity and radial-maze learning after exposure to m-xylene in rats. Int J Occup Med Environ Health 8:347-360. Hass, U; Jakobsen, BM. (1993) Prenatal toxicity of xylene inhalation in the rat: a teratogenicity and postnatal study. Pharmacol Toxicol 73:20-23. Hass, U; Lund, SP; Simonsen, L; et al. (1995) Effects of prenatal exposure to xylene on postnatal development and behavior in rats. Neurotoxicol Teratol 17:341-349. Hass, U; Lund, SP; Simonsen, L. (1997) Long-lasting neurobehavioral effects of prenatal exposure to xylene in rats. Neurotoxicology 18:547-551. Hipolito, RN. (1980) Xylene poisoning in laboratory workers: case reports and discussion. Lab Med 11:593-595. Jenkins, L J Jr.; Jones, R A; Siegel, J. (1970) Long-term inhalation screening studies of benzene, toluene, o-xylene, and cumene on experimental animals. Toxicol Appl Pharmacol 16:818-823. Klaucke, DN; Johansen, M; Vogt, R. (1982) An outbreak of xylene intoxication in a hospital. Am J Ind Med 3:173-178. Korsak, Z; Sokal, JA; Gorny, R. (1992) Toxic effects of combined exposure to toluene and m-xylene in animals. III. Subchronic inhalation study. Polish J Occup Med Environ Health 5:27-33. Korsak, Z; Wisniewska-Knypl, J; Swiercz, R. (1994) Toxic effects of subchronic combined exposure to n-butyl alcohol and m-xylene in rats. Int J Occup Med Environ Health 7:155-166. Laine, A; Savolainen, K; Riihimaki, V; et al. (1993) Acute effects of m-xylene inhalation on body sway, reaction times, and sleep in man. Int Arch Occup Environ Health 65:179-188. Litton Bionetics. (1978) Teratology study in rats - xylene. Final report EPA/OTS Public Files. Litton Bionetics, Kensington, MD; Document 878210350. Moser, V C; Coggeshall, EM; Balster, RL. (1985) Effects of xylene isomers on operant responding and motor performance in mice. Toxicol Appl Pharmacol 80:293-298. Nylen, P; Hagman, M. (1994) Function of the auditory and visual systems, and of peripheral nerve, in rats after long-term combined exposure to n-hexane and methylated benzene derivatives. II. Xylene. Pharmacol Toxicol 74:124-129. Olson, BA; Gamberale, F; Inegren, A. (1985) Coexposure to toluene and p-xylene in man: central nervous functions. Br J Ind Med 42:117-122. Pryor, GT; Rebert, CS; Howd, RA. (1987) Hearing loss in rats caused by inhalation of mixed xylene and styrene. J Appl Toxicol 7:55-61. Rosen, MB; Crofton, KM; Chernoff, N. (1986) Postnatal evaluation of prenatal exposure to p-xylene in the rat. Toxicol Let 34:223-229. Savolainen, K; Linnavuo, M. (1979) Effects of m-xylene on human equilibrium measured with a quantitative method. Acta Pharmacol Toxicol 44:315-318. Savolainen, K; Kekoni, J; Riihimaki, V; et al. (1984) Immediate effects of m-xylene on the human central nervous system. Arch Toxicol Suppl 7:412-417. Seppalainen, AM; Salmi, T; Savolainen, K; et al. (1983) Visual evoked potentials in short-term exposure of human subjects to m-xylene and1,1,1-trichloroethane. Appl Behav Pharmacol Toxicol 1983:349-352. Seppalainen, AM; Laine, A; Salmi, T; et al. (1991) Electroencephalographic findings during experimental human exposure to m-xylene. Arch Environ Health 46:16-24. Tardif, R; Lapare, S; Charest-Tardif, G; et al. (1995) Physiologically-based pharmacokinetic modeling of a mixture of toluene and xylene in humans. Risk Anal 15:335-342. Trarai, E; Ungvary, G. (1980) Changes induced by o-xylene inhalation in the rat liver. Acta Med Acad Sci Hung 37:211-216. Tatrai, E; Ungvary, G; Cseh, I R; et al. (1981) The effect of long-term inhalation of o-xylene on the liver. Ind Environ Xenobiotics, Proc Int Conf.; pp. 293-300. Uchida, Y; Nakatsuka, H; Ukai, H; et al. (1993) Symptoms and signs in workers exposed predominantly to xylene. Int Arch Occup Environ Health 64:597-605. Ungvary, G. (1990) The effect of xylene exposure on the liver. Acta Morphol Hung 38:245-258. Ungvary, G; Tatrai, E. (1985) On the embryotoxic effects of benzene and its alkyl derivatives in mice, rats and rabbits. Arch Toxicol, Suppl. 8: 425-430. Ungvary, G; Tatrai, E; Hudak, A; et al. (1980) Studies on the embryotoxic effects of ortho-, meta- and para-xylene. Toxicology 18:61-74. U.S. EPA (Environmental Protection Agency). (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. October 1994. U.S. EPA. (2002) Toxicological review of xylenes (CAS No. 1330-20-7). National Center for Environmental Assessment, Washington, DC. Available online at: http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Anderson, BE; Zeiger, E; Shelby, MD; et al. (1990) Chromosome aberration and sister chromatid exchange test results with 42 chemicals. Environ Mol Mutagen 16(Suppl 18):55-137. Arp, EW, Jr; Wolf, PH; Checkoway, H. (1983) Lypmphocytic leukemia and exposures to benzene and other solvents in the rubber industry. J Occup Med 25:598-602. Bos, RP; Brouns, RME; van Doorn, R; et al. (1981) Non-mutagenicity of toluene, o-, m-, and p-xylene, o-methylbenzylalcohol and o-methylbenzylsufate in the Ames assay. Mutat Res 88:273-279. Donner, M; Maki-Paakkanen, J; Norppa, H; et al. (1980) Genetic toxicology of xylenes. Mutat Res 74:171-172. Florin, I; Rutberg, L; Curvall, M; et al. (1980) Screening of tobacco smoke constituents for mutagenicity using the Ames' test. Toxicology 15:219-232. Gerin, M; Siemiatycki, J; Desy, M; et al. (1998) Associations between several cites of cancer and occupational exposure to benzene, toluene, xylene, and styrene: results of a case-control study in Montreal. Am J Ind Med 34:144-156. Gerner-Smidt, P; Friedrich, U. (1978) The mutagenic effect of benzene, toluene, and xylene studied by the SCE technique. Mutat Res 58:313-316. Haglund, U; Lundberg, I; Zech, L. (1980) Chromosome aberrations and sister chromatid exchanges in Swedish paint industry workers. Scand J Work Environ Health 6:291-298. Litton Bionetics. (1978) Mutagenicity evaluation of xylene. EPA/OTS Public Files. Litton Bionetics, Kensington, MD: Document 878210347. Maltoni, C; Conti, B; Cotti, G. (1983) Benzene: a multipotential carcinogen. Results of long-term bioassays performed at the Bologna Institute of Oncology. Am J Ind Med 4:589-630. Maltoni, C; Conti, B; Cotti, G; et al. (1985) Experimental studies on benzene carcinogenicity at the Bologna Institute of Oncology: current results and ongoing research. Am J Ind Med 7: 415-446. McCarroll, NE; Piper, CE; Keech, BH. (1981) An E. coli microsuspension assay for the detection of DNA damage induced by direct-acting and promutagens. Environ Mutagen 3:429-444. Mohtashamipur, E; Norpoth, K; Woelke, U; et al. (1985) Effects of ethylbenzene, toluene, and xylene on the induction of micronuclei in bone marrow polychromatic erythrocytes of mice. Arch Toxicol 58:106-109. NTP (National Toxicology Program) (1986) NTP technical report on the toxicology and carcinogenesis of xylenes (mixed) (60% m-xylene, 13.6% p-xylene, 17.0% ethylbenzene, and 9.1% o-xylene) in F344/N rats and B6C3F1 mice (gavage studies). Research Triangle Park, NC. NTP TR 327, NIH Publ. No. 86-2583. Pap, M; Varga, C. (1987) Sister-chromatid exchanges in peripheral lymphocytes of workers occupationally exposed to xylene. Mutat Res 187:223-225. Richer, C L; Chakrabarti, S; Senecal-Quevillon, M; et al. (1993) Cytogenic effects of low-level exposure to toluene, xylene, and their mixture on human blood lymphocytes. Arch Occup Environ Health 64:581-585. Spirtas, R; Stewart, PA; Lee, JS; et al. (1991) Retrospective cohort mortality study of workers at an aircraft maintenance facility. I. Epidemiological results. Br J Ind Med 48:515-530. U.S. EPA (Environmental Protection Agency). (1999) Guidelines for Carcinogen Risk Assessment. Review Draft, NCEA-F-0644, July 1999. Risk Assessment Forum. U.S. EPA. (2002) Toxicological review of xylenes (CAS No. 1330-20-7). National Center for Environmental Assessment, Washington, DC. Available online at: http://www.epa.gov/iris Washington, WJ; Murthy, RC; Doye, A; et al. (1983) Induction of morphologically abnormal sperm in rats exposed to o-xylene. Arch Andrology 11:233-237. Wilcosky, TC; Checkoway, H; Marshall, EG; et al. (1984) Cancer mortality and solvent exposures in the rubber industry. Am Ind Hyg Assoc J 45:809-811. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Xylenes CASRN -- 1330-20-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/26/1988 II. Carcinogen summary on-line 07/01/1989 I.B. Inhalation RfD now under review 07/01/1989 VI. Bibliography on-line 03/01/1991 II.D.3. Primary contact changed 03/01/1991 IV.F.1. EPA contact changed 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory actions updated 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/10/1998 I., II. This chemical is being reassessed under the IRIS Program. 02/21/2003 All Revised RfD, RfC, Cancer assessment. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 403 of 1119 in IRIS (through 2003/06) AN: 276 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for support document for the inhalation carcinogenicity assessment http://www.epa.gov/ncea/pdfs/benzenef.pdf , Click here for the response to the peer review for the above http://www.epa.gov/iris/supdocs/benz-pr.htm , Click here for support document for the oral carcinogenicity assessment http://www.epa.gov/iris/supdocs/benz-sup.pdf , Click here for the response to the peer review for the above http://www.epa.gov/iris/supdocs/benz-pr2.htm , Click here for toxicological review - non-cancer effects http://www.epa.gov/iris/toxreviews/0276-tr.pdf , Click here for the response to the peer review for the above http://www.epa.gov/iris/supdocs/benzene_nc-pr.pdf UD: 200304 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Benzene- SY: 71-43-2; BENZOL-; COAL-NAPHTHA-; CYCLOHEXATRIENE-; PHENE-; PHENYL-HYDRIDE-; POLYSTREAM-; PYROBENZOL- RN: 71-43-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200304 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Benzene CASRN -- 71-43-2 Last Revised -- 04/17/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- ---------- Decreased lymphocyte BMDL = 1.2 mg/kg-day 300 1 4.0E-3 count (Human occu- (500 ppm in water) mg/kg-day pational inhalation study; Rothman et al., 1996 ---------------------------------------------------------------------------- *Conversion factors: MW = 78.11. Assuming 25°C and 760 mm Hg, BMCL (mg/m3) = 7.2 ppm x MW/24.45 = 23 mg/m3. BMCLADJ = 23 mg/m3 x 10 m3/20 m3 x 5 days/7days = 8.2 mg/m3. The BMDL was derived by route-to-route extrapolation with the assumptions that inhalation absorption was 50% and oral absorption was 100% in the dose range near the BMC. BMDLADJ = (8.2 mg/m3 x 20 m3/day x 0.5)/ 70 kg = 1.2 mg/kg/day. (The original BMC was based on a benchmark response of one standard deviation change from the control mean.) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) The RfD is based on route-to-route extrapolation of the results of benchmark dose (BMD) modeling of the absolute lymphocyte count (ALC) data from the occupational epidemiologic study by Rothman et al. (1996), in which workers were exposed to benzene by inhalation. A comparison analysis based on BMD modeling of data from the National Toxicology Program's (NTP's) experimental animal gavage study (NTP, 1986) was also conducted. In addition, comparison analyses using the lowest-observed-adverse-effect levels (LOAELs) from the Rothman et al. (1996) and NTP (1986) studies were performed. Rothman et al. (1996) conducted a cross-sectional study of 44 workers exposed to benzene and 44 age- and gender-matched unexposed controls. Twenty-one of the 44 subjects in the exposed and control groups were female. Mean (standard deviation) years of occupational exposure to benzene were 6.3 (4.4), with a range of 0.7 - 16 years. Benzene exposure was monitored by organic vapor passive dosimetry badges worn by each worker for a full workshift on 5 days within a 1-2 week period prior to collection of blood samples. The median 8-hour time-weighted average (TWA) benzene exposure concentration for all exposed workers was 31 ppm (99 mg/m3). The exposed group was subdivided into two equal groups of 22 subjects: those exposed to greater than the median concentration and those exposed to less than the median concentration. The median 8-hour TWA exposure concentration was 13.6 ppm (43.4 mg/m3) for the low-exposure group and 91.9 ppm (294 mg/m3) for the high-exposure group. Six hematological measurements were evaluated: total white blood cell (WBC) count, ALC, hematocrit, red blood cell (RBC) count, platelet count, and mean corpuscular volume (MCV). All six parameters were significantly different in the high-benzene exposure group (>31 ppm) when compared to controls. ALC, WBC count, RBC count, hematocrit, and platelets were all significantly decreased, and MCV was significantly increased. ALC was the most sensitive endpoint; it was reduced from 1.9 x 103/uL blood in controls to 1.6 x 103/uL (p<0.01) in the <31 ppm group and to 1.3 x 103/uL (p<0.001) in the group exposed to >31 ppm benzene. The ALC was also significantly reduced (1.6 x 103/uL; p=0.03) in a subgroup of 11 workers exposed to a median 8-hour TWA of 7.6 ppm (24 mg/m3) benzene. For additional details about this study see Section I.B.2. BMD modeling of the ALC data of Rothman et al. (1996) yielded a benchmark concentration (BMC) of 13.7 ppm (8-hr TWA) and a BMCL (the 95% lower bound on the BMC) of 7.2 ppm (8-hr TWA) for the default benchmark response of one standard deviation change from the control mean (see Section I.B.2 for details of the analysis). Converting the units and adjusting for continuous exposure results in a BMCLADJ of 8.2 mg/m3. [According to the Ideal Gas Law, concentration in mg/m3 = concentration in ppm x MW/24.45 at 25°C and 760 mm Hg. Thus, BMCL (mg/m3) = 7.2 x 78.11/24.45 = 23.0 mg/m3. BMCLADJ = 23.0 mg/m3 x 10 m3/20 m3 x 5 days/7 days = 8.2 mg/m3, where 10 m3 is the default human occupational volume of air inhaled in an 8-hour workshift, and 20 m3 is the default human ambient volume of air inhaled in a 24-hour day (U.S. EPA, 1994).] In the support document for the benzene cancer assessment on IRIS (U.S. EPA, 1999), EPA provided a simple method for extrapolation of benzene-induced cancer risk from the inhalation to the oral route. The same method is applied here for noncancer (hematopoietic) effects. The method is based on the relative efficiency of benzene absorption across routes of exposure, especially pulmonary and gastrointestinal barriers. An inhalation absorption rate of 50% and an oral absorption rate of 100% were used to calculate the absorbed benzene dose. These values are based on human inhalation absorption studies and the study by Sabourin et al. (1987) that compared inhalation and oral absorption in rats and mice. The authors found that during a 6-hour inhalation exposure, the retention of [14C]benzene decreased from 33 +/- 6% to 15 +/- 9% for rats and from 50 +/- 1% to 10 +/- 2% for mice as exposure concentration increased from 26 to 2,600 mg/m3 (10 to 1,000 ppm). In the same study, gastrointestinal absorption of benzene administered by gavage was >97% for doses between 0.5 and 150 mg/kg body weight. At oral doses below 15 mg/kg, >90% of the 14C excreted was in the urine as non-ethyl acetate-extractable material. At higher doses, an increasing percentage of the orally administered benzene was exhaled unmetabolized. Thus, in the dose range represented by the BMCL from the study by Rothman et al. (1996), absorption of a comparable oral dose was assumed to be 100%. See also U.S. EPA (1999) for more details about the route-to-route extrapolation of benzene inhalation results to oral exposures. To calculate an equivalent oral dose rate, the BMCLADJ is multiplied by the default inhalation rate, multiplied by 0.5 to correct for the higher oral absorption, and divided by the standard default human body weight of 70 kg: 8.2 mg/m3 x 20 m3/day x 0.5 ÷ 70 kg = 1.2 mg/kg/day. The RfD is then derived by dividing the equivalent oral dose by the overall uncertainty factor (UF) of 300: RfD = equivalent oral dose/UF = 1.2 mg/kg/day ÷ 300 = 4 x 10-3 mg/kg/day. The overall UF of 300 comprises a UF of 3 for effect-level extrapolation, 10 for intraspecies differences (human variability), 3 for subchronic-to-chronic extrapolation, and 3 for database deficiencies (see Section I.A.3). For comparison, an RfD was also calculated based on the LOAEL of 7.6 ppm (8 hr TWA) from the Rothman et al. (1996) study (see Section I.B.2). Converting the units and adjusting for continuous exposure results in a LOAELADJ of 8.7 mg/m3. Then the equivalent oral exposure is calculated as above: 8.7 mg/m3 x 20 m3/day x 0.5 ÷ 70 kg = 1.2 mg/kg/day. The equivalent oral exposure is then divided by an overall UF of 1000 to obtain the RfD: 1.2 mg/kg/day ÷ 1000 = 1 x 10-3 mg/kg/day. The combined UF of 1000 represents UFs of 10 to account for the use of a LOAEL because of the lack of an appropriate no-observed-adverse-effect level (NOAEL), 10 for intraspecies differences in response (human variability), 3 for subchronic-to-chronic extrapolation, and 3 for database deficiencies. The value of 1 x 10-3 mg/kg/day is in good agreement with the value of 4 x 10-3 mg/kg/day calculated from the BMDL (the 95% lower bound on the BMD). A comparison RfD derivation was also performed using the results of the NTP (1986) experimental animal gavage study. In that study, F344 rats and B6C3F1 mice of both sexes were administered benzene by gavage, 5 days/week for 103 weeks. Male rats (50/group) were administered doses of 0, 50, 100, or 200 mg/kg, and females (50/group) were administered doses of 0, 25, 50, or 100 mg/kg. B6C3F1 mice (50/sex/group) were administered doses of 0, 25, 50, or 100 mg/kg. Blood was drawn from 10 randomly preselected animals per species/sex/dose group at 12, 15, 18, and 21 months, as well as from all animals at the terminal kill at 24 months. Additional groups of 10 animals of each sex and species were administered benzene for 51 weeks at the same doses of the 103-week (2-year) study, and blood was drawn at 0, 3, 6, 9, and 12 months. This study identified a LOAEL of 25 mg/kg for leukopenia and lymphocytopenia in female F344 rats and male and female B6C3F1 mice and 50 mg/kg in male F344 rats. These were the lowest doses tested, and thus no NOAEL was identified. Reductions in lymphocyte count was the critical effect, and attempts were made to model the dose-response relationships using a BMD modeling approach. Modeling was performed for each dataset in two data groupings within which the datasets are comparable (6- and 9-month; and 12-,15-,18-, and 21-month), and ranges of results are presented. Each of these datasets had at most 10 animals/dose, so the dose-response results are not very robust. The males of each species exhibited more dramatic and consistent reductions in lymphocyte count, but it was not clear a priori which species was more sensitive; therefore, dose-response analyses were performed for both the male mouse and the male rat. The continuous linear, polynomial, and power models in EPA's Benchmark Dose Modeling Software (version 1.20) were used for the modeling. The software estimates the parameters using the method of maximum likelihood. Most of the data were supralinear (i.e., the magnitude of the reductions in lymphocyte count decreased with increasing unit dose), and it was necessary to transform the dose data according to the formula d' = ln(d+1) in order to fit the available models. The results are summarized in Table 1. For each dataset, the selected model was chosen based on the lowest Akaike's Information Criterion (AIC) value, with consideration of the graphical display, as suggested in EPA's draft Benchmark Dose Technical Guidance Document (U.S. EPA, 2000). For selecting between models within a family of models, for example, between a linear and a two-degree polynomial model, consideration was given to the log-likelihood values to evaluate the statistical significance of adding an extra parameter. There was substantial variability in these data, but it appeared to be random and not amenable to modeling. Therefore, constant variance was assumed for all the models, although in some cases the variances failed the test for homogeneity. In the absence of a clear definition for an adverse effect for this endpoint, a default benchmark response of one standard deviation change from the control mean response was selected, as suggested in the draft technical guidance document. This definition of the benchmark response is highly sensitive to the substantial variability in data such as these, and thus the benchmark response itself is not very robust. The usefulness of this default definition would be strengthened by the use of a larger dataset of historical control data, but such data were not located. The software uses the estimated "constant" standard deviation as the standard deviation for all the group means. The 95% lower confidence limits (BMDLs) on the BMDs are calculated using the likelihood profile method. The results shown in Table 1 suggest that the male rat is more sensitive than the male mouse to lymphocyte count reductions from exposure to benzene in this NTP gavage bioassay because the ranges of BMDs/BMDLs are substantially lower for the male rat, especially for year 2. The ranges for the male rat are fairly tight, and the models selected provide good fits to all the male rat datasets. However, all but one of the calculated BMDs for the male rat are over an order of magnitude below the lowest exposure dose of 50 mg/kg. Ideally, BMDs should be closer to the low end of the range of observation, that is, the range of the actual exposure doses, to reduce the impacts of model selection and the uncertainties inherent in extrapolating to lower doses. Nevertheless, data from two drinking water studies provide support for selecting a BMD in this range. These two studies were of shorter duration and used fewer experimental animals than the NTP (1986) study; however, they do provide dose-response data for BMD modeling, and they also have the advantage of being drinking water studies; thus the benzene exposure scenario is more relevant to human oral benzene exposures. In one study, Hsieh et al. (1988) exposed male CD-1 mice (five/group) to 0, 8, 40, or 180 mg/kg/day benzene in drinking water for 28 days. Hematological effects were observed at all exposure levels. BMD modeling of the ALC yielded a BMD of 2.2 mg/kg/day and a BMDL of 1.4 mg/kg/day, based on a linear model with transformed doses and a benchmark response of one standard deviation change from the control mean, as above. In the second study, White et al. (1984) exposed female B6C3F1 mice to 0, 12, 195, or 350 mg/kg/day benzene in drinking water for 30 days. BMD modeling of the ALC (five to six mice/group) resulted in a BMD of 11.6 mg/kg/day and a BMDL of 5.3 mg/kg/day (also based on a linear model with transformed doses and a benchmark response of one standard deviation change from the control mean, as above). The results in Table 1 from BMD modeling of the male rat ALC data from the NTP (1986) study show the lowest BMDL of about 1 mg/kg at three time points in the second year; Table 1. BMD modeling results for NTP (1986) male mouse and male rat lymphocyte counts, with transformed dose data +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ |Dataset | Model | Variance | Fit | BMD* | BMDL* | | | Homogeneity | | (mg/kg) | (mg/kg) +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ | MALE MOUSE +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ |6-month | two-degree | ok | borderline | 19.68 | 6.57 | | polynomial | | p=0.047 | | |9-month | linear | no | yes, p=0.35 | 9.07 | 4.05 |year 1 range | 9.07-19.68 | 4.05-6.57 |12-month | linear | ok | yes, p=0.30 | 3.74 | 2.32 |15-month | power | no | yes, p=0.31 | 47.46 | 18.55 |18-month | power | no | borderline | 28.93 | 13.99 | | | | p=0.09 | | |21-month | power | no | yes, p=0.15 | 23.34 | 5.80 |year 2 range | 3.74-47.46 | 2.32-18.55 +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ | MALE RAT +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ |Dataset | Model | Variance | Fit | BMD* | BMDL* | | | Homogeneity | | (mg/kg) | (mg/kg) +++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ | 6-month | power | ok | yes, p=0.30 | 9.92 | 4.52 | 9-month | linear | no | yes, p=0.11 | 3.71 | 2.30 |year 1 range | 3.71-9.92 | 2.30-4.52 |12-month | linear | no | yes, p=0.22 | 1.34 | 0.95 |15-month | linear | ok | yes, p=0.93 | 1.34 | 0.95 |18-month | linear | no | yes, p=0.22 | 2.73 | 1.74 |21-month | linear | ok | yes, p=0.54 | 1.69 | 1.10 |year 2 range | 1.34-2.73 | 0.95-1.74 *Unadjusted animal dose in mg/kg, after transforming the results back according to the formula dose = exp(transformed dose) - 1. (The BMD was based on a benchmark response of one standard deviation change from the control mean.) thus this was selected as the point of departure for an RfD calculation. Adjusting for exposure 7 days/week yields a BMDLADJ of 0.7 mg/kg/day. This value is divided by an overall UF of 1000 to obtain the RfD: RfD = 0.7 mg/kg/day ÷ 1000 = 7 x 10-4 mg/kg/day. The overall UF of 1000 comprises UFs of 3 for effect-level extrapolation, 10 for interspecies extrapolation for oral studies, 10 for intraspecies variability, and 3 for database deficiencies. This RfD value is in reasonably good agreement (within an order of magnitude) with the RfD of 4 x 10-3 mg/kg/day derived from the Rothman et al. (1996) human inhalation study. For comparison purposes, an RfD can also be derived from the LOAEL of 25 mg/kg identified for hematological effects in the NTP (1986) study (there was no NOAEL). Adjusting from 5-day to 7-day exposure yields a LOAELADJ of 18 mg/kg/day, which can be used to calculate an RfD for benzene as follows: RfD = LOAELADJ ÷ UF = 18 mg/kg/day ÷ 3000 = 6 x 10-3 mg/kg/day, where the combined UF of 3000 is made up of component factors of 10 for LOAEL-to-NOAEL extrapolation, 10 for interspecies extrapolation, 10 for intraspecies variability, and 3 for database deficiencies. This value is in good agreement with the RfD of 4 x 10-3 mg/kg/day calculated from the BMD analysis of the Rothman et al. (1996) human data. UMRD: __I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 300 for the BMCL-oral-equivalent from the Rothman et al. (1996) study. First, because the BMC is considered to be an adverse effect level, an effect level extrapolation factor analogous to the LOAEL-to-NOAEL UF is used. EPA is planning to develop guidance for applying an effect level extrapolation factor to a BMD. A factor of 3 will be used in this analysis, based on the professional judgement that, although the BMD corresponds to an adverse effect level at the low end of the observable range, the endpoint is not very serious in and of itself. Decreased ALC is a very sensitive sentinel effect that can be measured in the blood, but it is not a frank effect, and there is no evidence that it is related to any functional impairment at levels of decrement near the benchmark response. For a more serious effect, a larger factor, such as 10, might be selected. Second, a factor of 10 was used for intraspecies differences in response (human variability) as a means of protecting potentially sensitive human subpopulations. Third, a subchronic-to-chronic extrapolation factor was applied because the mean exposure duration for the subjects in the principal study was 6.3 years, which is less than the exposure duration of 7 years (one-tenth of the assumed human life span of 70 years) that has been used by the Superfund program as a cut-off for deriving a subchronic human reference dose (U.S. EPA, 1989). Furthermore, the exposure duration varied from 0.7 years to 16 years. However, because the mean exposure duration was near the borderline of what would be considered chronic (i.e., 6.3 years vs. 7 years), a value of 3 (vs. 10) was felt to be appropriate for the UF. Finally, a UF of 3 was chosen to account for database deficiencies because no two-generation reproductive and developmental toxicity studies for benzene are available. Therefore, an overall UF of 3 x 10 x 3 x 3 = 300 is used to calculate the chronic oral RfD. For the comparison analysis based on the Rothman et al. (1996) LOAELADJ-equivalent oral dose rate value of 1.2 mg/kg/day, the following UFs were selected: a factor of 10 for use of a LOAEL due to lack of an appropriate NOAEL, a factor of 10 for intraspecies variability, a factor of 3 for subchronic-to-chronic extrapolation, and a factor of 3 for database deficiencies, as above. Hence, an overall UF of 10 x 10 x 3 x 3 = 1000 was used in the comparison analysis. For the comparison analysis based on the BMDLADJ calculated from BMD modeling of the male rat data from the NTP (1986) gavage study, the following UFs were used: a UF of 3 for effect-level extrapolation, which is analogous to the LOAEL-to-NOAEL extrapolation factor, because the BMC is considered an adverse effect level; a UF of 10 for interspecies extrapolation for oral studies; a UF of 10 for intraspecies variability; and a UF of 3 for database deficiencies. Thus, an overall UF of 3 x 10 x 10 x 3 = 1000 was used in this comparison analysis. Finally, for the comparison analysis based on the LOAEL from the NTP (1986) gavage study, the following UFs were used: 10 for LOAEL-to-NOAEL extrapolation, 10 for interspecies extrapolation, 10 for intraspecies variability, and 3 for database deficiencies. Therefore, an overall UF of 3000 was used in this comparison analysis. ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) Benzene is toxic by all routes of administration. Hematotoxicity and immunotoxicity have been consistently reported to be the most sensitive indicators of noncancer toxicity in both humans and experimental animals, and these effects have been the subject of several reviews (Aksoy, 1989; Goldstein, 1988, Snyder et al., 1993; Ross, 1996; U.S. EPA, 2002). The bone marrow is the target organ for the expression of benzene hematotoxicity and immunotoxicity. Leukocytopenia has been consistently shown to be a more sensitive indicator of benzene toxicity in experimental animal systems than anemia, and lymphocytopenia has been shown to be an even more sensitive indicator of benzene toxicity than overall leukocytopenia. Neither gastrointestinal effects from oral exposure nor pulmonary effects due to inhalation exposure have been reported. (see Section I.B.4 for a more detailed summary of benzene toxicity). For more detail on Susceptible Populations, exit to the toxicological review, section 4.4 http://www.epa.gov/iris/toxreviews/0276-tr.pdf#page=124 CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Database -- Medium RfD -- Medium The overall confidence in this RfD assessment is medium. The principal study of Rothman et al. (1996) was well conducted, and the availability of good-quality human data for a sensitive endpoint eliminates the uncertainty associated with basing the RfD on experimental animal data. A dose-response relationship was established between ALC and benzene air concentration and benzene urine metabolites. Six blood parameters measured (ALC, WBC count, RBC count, hematocrit, platelets, and MCV) were significantly different in the high- benzene-exposure group when compared with controls. However, only the ALC was reduced in a subgroup of 11 subjects exposed to a median 8-hour TWA of 7.6 ppm benzene, suggesting that this exposure level may be at the low end of the range of benzene exposures eliciting hematotoxic effects in humans. In addition, the RfD of 4 x 10-3 mg/kg/day obtained from route-to-route extrapolation of the BMD modeling results from the Rothman et al. (1996) study is in good agreement with the value of 1 x 10-3 mg/kg/day based on the oral equivalent LOAEL. The RfD is also in good agreement with the value of 7 x 10-4 mg/kg/day, based on BMD modeling of the male rat ALC data from the NTP (1986) chronic rodent gavage study and the value of 6 x 10-3 mg/kg/day based on the LOAEL from the NTP (1986) study. With continuous endpoints such as hematological parameters, there is uncertainty about when a change in a parameter that has inherent variability becomes an adverse effect. Other uncertainties explicitly recognized in the quantitative derivation of the chronic oral RfD include intraspecies variability (to accommodate sensitive human subgroups), the applicability of the subchronic inhalation data to chronic oral exposures, and database deficiencies due to the lack of a two-generation reproductive/developmental toxicity study for benzene. Route-to-route extrapolation was used to estimate oral equivalent doses from inhalation exposures resulting from analysis of the Rothman et al. (1996) occupational data. In experiments conducted to compare the metabolite doses to the target organ following oral or inhalation exposure, Sabourin et al. (1987, 1989) found that there was no simple relationship between the two routes of exposure. All published experimental animal models of the in vivo metabolism and disposition of benzene have used the physiologically based approach to pharmacokinetics, and they conclude that formation of metabolites follow Michaelis-Menten kinetics. Although these models predict the urinary metabolites formed from benzene exposures, they offer no information regarding the dosimetry of oxidative metabolites in the bone marrow, a site of action. However, the target specificity of benzene toxicity for the bone marrow progenitor cells irrespective of route of administration is well documented in both humans and experimental animal models. Thus, route-to-route extrapolation is justified and introduces a lower degree of uncertainty than extrapolating from test animals to humans (U.S. EPA, 1999). Use of a modifying factor of 3 was considered to recognize uncertainties in the route-to-route extrapolation; however, it was deemed unnecessary. The RfD is based on human data for a sensitive endpoint; thus, it was felt that the composite UF of 300 provides sufficient protection. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0276-tr.pdf#page=156 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2002 This assessment was peer reviewed by external scientists as well as in response to public comments. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. Click here for the peer review document http://www.epa.gov/iris/supdocs/benzene_nc-pr.pdf. Other EPA Documentation -- U.S. EPA, 1985, 1999 Date of Agency Consensus -- January 23, 2002 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or hotline.iris@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 200304 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Benzene CASRN -- 71-43-2 Last Revised -- 04/17/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- ------------------------- ----- --- --------- Decreased lymphocyte BMCL = 8.2 mg/m3 300 1 3E-2 count (Human occu- pational inhalation study of Rothman et al., 1996) ---------------------------------------------------------------------------- *Conversion Factors: MW = 78.11. BMCL = 7.2 ppm, 8-hour TWA. Assuming 25°C and 760 mm Hg, BMCL (mg/m3) = 7.2 ppm x MW/24.45 = 23.0 mg/m3. BMCLADJ = 23.0 mg/m3 x 10 m3/20 m3 x 5 days/7days = 8.2 mg/m3. (The BMC was based on a benchmark response of one standard deviation change from the control mean.) PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) The RfC is based on BMD modeling of the ALC data from the occupational epidemiologic study of Rothman et al. (1996), in which workers were exposed to benzene by inhalation. A comparison analysis based on BMD modeling of hematological data from the Ward et al. (1985) subchronic experimental animal inhalation study was also conducted. In addition, comparison analyses using the LOAEL from the Rothman et al. (1996) study and the NOAEL from the Ward et al. (1985) study were performed. Rothman et al. (1996) conducted a cross-sectional study of 44 workers exposed to a range of benzene concentrations and 44 age- and gender-matched unexposed controls, all from Shanghai, China. Twenty-one of the 44 subjects in the exposed and control groups were female. The exposed workers were from three workplaces where benzene was used - a factory that manufactured rubber padding for printing presses, a factory that manufactured adhesive tape, and a factory that used benzene-based paint. The unexposed workers were from two workplaces: a factory that manufactured sewing machines and an administrative facility. Workers who had a prior history of cancer, therapeutic radiation, chemotherapy, or current pregnancy were excluded. Requirements for inclusion in the study were current employment for at least 6 months in a factory that used benzene, minimal exposure to other aromatic solvents, and no exposure to other chemicals known to be toxic to bone marrow or to ionizing radiation. Controls who had no history of occupational exposure to benzene or other bone marrow-toxic agents were frequency-matched to the exposed subjects on age (5-year intervals) and gender. Benzene exposure was monitored by organic vapor passive dosimetry badges worn by each worker for a full workshift on 5 days within a 1-2 week period prior to collection of blood samples. Benzene exposure of controls in the sewing machine factory was monitored for 1 day, but no exposure monitoring was performed in the administrative facility. Benzene exposure was also evaluated by analyzing for benzene metabolites in urine samples collected at the end of the benzene exposure period for the exposed subjects. Historical benzene exposure of the subjects was evaluated by examining employment history. Data on age, gender, current and lifelong tobacco use, alcohol consumption, medical history, and occupational history were collected by interview. Six hematological measurements were evaluated: total WBC count, ALC, hematocrit, RBC count, platelet count, and MCV. Total WBC counts and ALC were performed using a Coulter T540 blood counter. Abnormal counts were confirmed. Benzene metabolites in urine were measured by an isotope dilution gas chromatography/mass spectometry assay. Correlation analyses were performed with Spearman rank order correlation. The Wilcoxon rank sum test was used to test for hematological differences. Mean (standard deviation) years of occupational exposure to benzene were 6.3 (4.4) with a range of 0.7-16 years. The median 8-hour TWA benzene exposure concentration for all exposed workers was 31 ppm (99 mg/m3). Exposure to toluene and xylene was <= 0.2 ppm (0.6 mg/m3) in all groups. The exposed group was subdivided into two equal groups of 22 - one group comprising workers who were exposed to greater than the median concentration and the other containing those exposed to less than the median concentration. The median (range) 8-hour TWA exposure concentration was 13.6 (1.6-30.6) ppm (43.4 [5.1-97.8] mg/m3] for the low-exposure group and 91.9 (31.5-328.5) ppm (294 [101-1049] mg/m3) for the high-exposure group. A subgroup of the low-exposure group composed of 11 individuals who were not exposed to >31 ppm (100 mg/m3) at any time during the monitoring period was also examined in some comparisons. The median (range) 8-hour TWA exposure of these individuals was 7.6 (1-20) ppm (24 [3.2-64] mg/m3). The urinary concentrations of the metabolites phenol, muconic acid, hydroquinone, and catechol were all significantly correlated with measured benzene exposure. All six blood parameters measured were significantly different in the high-benzene exposure group as compared to controls. ALC, WBC count, RBC count, hematocrit, and platelets were all significantly decreased, and MCV was significantly increased. The ALC was reduced from 1.9 x 103/uL blood in controls to 1.6 x 103/uL (p<0.01) in the <31 ppm (99 mg/m3) group and to 1.3 x 103/uL (p<0.001) in the group exposed to >31 ppm benzene. In the subgroup of 11 workers exposed to a median 8-hour TWA of 7.6 ppm (24 mg/m3) benzene, the ALC (1.6 x 103/uL) was also significantly reduced (p=0.03). The RBC and platelet counts were also significantly reduced in the <31 ppm exposure group, but only ALC was significantly different in the low-exposure subgroup. The fact that no other measured blood cell parameters were significantly different in this subgroup suggests that ALC was the most sensitive measure of benzene hematotoxicity and that this exposure level (median 8-hour TWA of 7.6 ppm) may be at the low end of the range of benzene exposures eliciting hematotoxic effects in humans. ALC is also thought to have a potential role as a "sentinel" effect for a cascade of early hematological and related biological changes that might be expected to result in the more profound examples of benzene poisoning observed in other cohorts of the National Cancer Institute/Chinese Academy of Preventive Medicine study, as described by Dosemeci et al. (1996). That ALC depletion is accompanied by gene-duplicating mutations in somatic cells under the same range of exposure conditions suggests that benzene can cause repeated damage to longer-lived stem cells in human bone marrow, further implicating the compound as etiologically important in the onset of benzene-associated leukemia. This finding underlines the importance of basing public health concern for benzene on a toxicological effect that is representative of the earliest biological changes induced by the compound. BMD modeling of the ALC exposure-response data from Rothman et al. (1996) was done using U.S. EPA's Benchmark Dose Modeling Software (version 1.20). The data are rather supralinear, that is, the change in ALC per unit change in exposure decreases with increasing exposure; therefore, in order to fit the data with one of the available continuous models, the exposure levels were first transformed according to the equation d' = ln(d+1). Then the exposure-response data were fitted using the continuous linear model, which provided a good fit (p=0.54). A two-degree polynomial and a power model also fit the data, but the linear model was selected because it is the most parsimonious. The parameters were estimated using the method of maximum likelihood. A constant variance model was used. In the absence of a clear definition for an adverse effect for this continuous endpoint, a default benchmark response of one standard deviation change from the control mean was selected, as suggested in EPA's draft Benchmark Dose Technical Guidance Document (U.S. EPA, 2000). This default definition of a benchmark response for continuous endpoints corresponds to an excess risk of approximately 10% for the proportion of individuals below the 2nd percentile (or above the 98th percentile) of the control distribution for normally distributed effects (see U.S. EPA, 2000). A 95% lower confidence limit (BMCL) on the resulting BMC was calculated using the likelihood profile method. Transforming the results back to the original exposure scale yields a BMC of 13.7 ppm (8-hr TWA) and a BMCL of 7.2 ppm (8-hr TWA). As suggested in the draft technical guidance document (U.S. EPA, 2000), the BMCL is chosen as the point of departure for the RfC derivation. An adjusted BMCL is calculated by converting ppm to mg/m3 and adjusting the 8-hour TWA occupational exposure to an equivalent continuous environmental exposure. The BMCL is first converted to mg/m3 using the molecular weight of 78.11 for benzene and assuming 25°C and 760 mm Hg: 7.2 ppm x 78.11/24.45 = 23.0 mg/m3. The converted value is then adjusted from the 8-hour occupational TWA to a continuous exposure concentration using the default respiration rates (U.S. EPA, 1994): BMCLADJ = 23.0 mg/m3 x (10 m3/20 m3) x 5 days/7 days = 8.2 mg/m3. The RfC is then derived by dividing the adjusted BMCL by the overall UF of 300: RfC = BMCLADJ/UF = 8.2 mg/m3 ÷ 300 = 3 x 10-2 mg/m3. The overall UF of 300 comprises a UF of 3 for effect-level extrapolation, 10 for intraspecies differences (human variability), 3 for subchronic-to-chronic extrapolation, and 3 for database deficiencies (see Section I.B.3). For comparison, an RfC was also calculated based on the LOAEL of 7.6 ppm (8-hr TWA) from the Rothman et al. (1996) study. Converting the units and adjusting for continuous exposure as above results in a LOAELADJ of 8.7 mg/m3. The LOAELADJ is then divided by an overall UF of 1000 to obtain the RfC: 8.7 mg/m3 ÷ 1000 = 9 x 10-3 mg/m3. The combined UF of 1000 represents UFs of 10 to account for the use of a LOAEL because of the lack of an appropriate NOAEL, 10 for intraspecies differences in response (human variability), 3 for subchronic-to-chronic extrapolation, and 3 for database deficiencies. The value of 9 x 10-3 mg/m3 is in good agreement with the RfC of 3 x 10-2 mg/m3 calculated from the BMC. A comparison RfC derivation based on BMD modeling of hematological data from the Ward et al. (1985) subchronic experimental animal inhalation study was also conducted. The Ward study was selected because it used a relatively long inhalation exposure duration and an adequate number of animals, and it provided dose-response data. Ward et al. exposed male and female CD-1 mice and Sprague-Dawley rats to 0, 1, 10, 30 or 300 ppm (0, 3.2, 32, 96 or 960 mg/m3) benzene, 6 hours/day, 5 days/week for 91 days and measured various hematological endpoints. The study identified both a LOAEL of 300 ppm and a NOAEL of 30 ppm. The male mouse appeared to be the most sensitive sex/species in this study. The exposure-response relationships for the different hematological endpoints for the male mouse were modeled using a BMD modeling approach and decreased hematocrit (i.e., volume percentage of erythrocytes in whole blood) was chosen as the critical effect. U.S. EPA's Benchmark Dose Modeling Software (version 1.20) was used for the modeling. An assumption of constant variance was used, although the test for homogeneity of the variances failed. The continuous linear, polynomial, and power models all resulted in the same BMC and BMCL estimates; however, the linear model had better results for the fit statistics. The linear model had a p-value of 0.09, which is of borderline adequacy (the draft technical guidance document [U.S. EPA, 2000] recommends a p-value of > 0.1), and the other models had p-values of 0.04. Thus the continuous linear model was selected. The parameters were estimated using the method of maximum likelihood. In the absence of a clear definition for an adverse effect for this continuous endpoint, a default benchmark response of one standard deviation from the control mean was selected, as suggested in the draft technical guidance document (U.S. EPA, 2000). The software uses the estimated standard deviation. A 95% lower confidence limit (BMCL) on the resulting BMC was calculated using the likelihood profile method. A BMC of 100.7 ppm and a BMCL of 85.0 ppm were obtained. It should be noted that the dose spacing in this study was less than ideal. Responses in the three lower exposure groups for all the hematological endpoints tended to clump near control group levels, and significant deviations in response were generally seen only in the 300 ppm group, with a large exposure range in between, including where the BMC is located, for which there are no response data. Therefore, there is some uncertainty about the actual shape of the exposure-response curve in the region of the benchmark response and, thus, some corresponding uncertainty about the values of the BMC and BMCL estimates. ALCs were not reported in Ward et al. (1985), so this endpoint could not be compared to the human ALC results. Total WBC counts were reported and exhibited the largest percent change in response between the control and the 300 ppm group; however, the data for this endpoint also had substantial variance, and because the benchmark response used for this analysis is a function of the standard deviation, WBC count did not yield the lowest BMC estimate. The actual lowest BMC estimates were obtained for increased mean cell hemoglobin (MCH) (78 ppm; BMCL = 67 ppm) and increased mean cell volume (79 ppm; BMCL = 68 ppm); however, these endpoints are probably not adverse per se. On the other hand, they are likely to be compensatory effects and, thus, markers of toxicity, and one could probably justify using them as the critical effects. In any event, the BMC estimates are not much different from the BMC of 100 ppm obtained for decreased hematocrit. The results are also similar for total blood hemoglobin (BMC = 104 ppm, BMCL = 88 ppm). RBC count results were in between those for MCV and MCH and those for hematocrit and total hemoglobin; however, the model fits were not adequate for the RBC data and, thus, the RBC results have more uncertainty. To derive the RfC, the BMCL is used as the point of departure, as suggested in the draft Benchmark Dose Technical Guidance Document (U.S. EPA, 2000). For conversion of the inhalation exposures across species, ppm equivalence was assumed; this is identical to using EPA's inhalation dosimetry methodology with Regional Gas Dose Ratio for the respiratory tract region (RGDRr) = 1 (U.S. EPA, 1994). The BMCL is first converted to mg/m3 using the molecular weight of 78.11 for benzene and assuming 25°C and 760 mm Hg: BMCL (mg/m3) = 85.0 ppm x 78.11/24.45 = 272 mg/m3. The converted value is then adjusted to an equivalent continuous exposure: BMCLADJ = 272 mg/m3 x (6 hrs/24 hrs) x 5 days/7 days = 48.5 mg/m3. The RfC is then obtained by dividing the adjusted BMCL by the overall UF of 1000: RfC = 48.5 mg/m3 ÷ 1000 = 5 x 10-2 mg/m3. The overall UF of 1000 comprises a UF of 3 for effect-level extrapolation, 3 for interspecies extrapolation (inhalation), 10 for intraspecies differences, 3 for subchronic-to-chronic extrapolation, and 3 for database deficiencies (see Section I.B.3). This value is in good agreement with the RfC of 3 x10-2 mg/m3 calculated from the BMC from the Rothman et al. (1996) human study. For further comparison, an RfC was also calculated, based on the NOAEL of 30 ppm from the Ward et al. (1985) study. Converting the units and adjusting for continuous exposure as above results in a NOAELADJ of 17.1 mg/m3. The NOAELADJ is then divided by an overall UF of 300 to obtain the RfC: 17.1 mg/m3 ÷ 300 = 6 x 10-2 mg/m3. The combined UF of 300 represents a UF of 3 for interspecies extrapolation (inhalation), 10 for intraspecies differences, 3 for subchronic-to-chronic extrapolation, and 3 for database deficiencies. The value of 6 x 10-2 mg/m3 is also in good agreement with the RfC of 3 x 10-2 mg/m3 calculated from the BMC from the Rothman et al. (1996) human study. It should be noted, however, that other experimental animal studies have reported significant hematological effects at benzene exposures of 10-25 ppm, which are lower than the NOAEL of 30 ppm from the Ward et al. (1985) study. These studies have insufficient data for dose-response modeling, and they used shorter exposure durations and/or fewer experimental animals than did the Ward et al. (1985) study; nonetheless, they observed statistically significant hematological effects at 10-25 ppm. Baarson et al. (1984), for example, exposed male C57BL/6J mice (five/group) to 10 ppm benzene, 6 hours/day, 5 days/week, for 178 days and observed statistically significant reductions in blood lymphocytes at each of the three monitoring time points (32, 66, and 178 days) when compared to controls. The magnitude of the reduction in lymphocytes ranged from about 53% at 32 days to about 68% at 178 days. Cronkite et al. (1985) exposed male and female C57BL/6 BNL mice to various concentrations of benzene 6 hours/day, 5 days/week for 2 weeks and observed no decrease in blood lymphocytes at 10 ppm, but they did observe a statistically significant reduction of about 21% at 25 ppm as compared to controls (5-10 mice/group). Thus, lower RfCs than those calculated above for the Ward et al. (1985) study are possible, based on other experimental animal results. In the most extreme case, using a LOAEL of 10 ppm and an overall UF of 3000 yields a LOAELADJ of 5.7 mg/m3 and an RfC of 2 x 10-3 mg/m3. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 300 for the BMCL from the Rothman et al. (1996) study. First, because the BMC is considered to be an adverse effect level, an effect level extrapolation factor analogous to the LOAEL-to-NOAEL UF is used. U.S. EPA is planning to develop guidance for applying an effect level extrapolation factor to a BMD. In the interim, a factor of 3 will be used in this analysis (see Section I.A.3). For a more serious effect, a larger factor, such as 10, might be selected. Second, a factor of 10 was used for intraspecies differences in response (human variability) as a means of protecting potentially sensitive human subpopulations. Third, a UF of 3 for subchronic-to-chronic extrapolation was applied (see Section I.A.3). Finally, a UF of 3 was chosen to account for database deficiencies, because no two-generation reproductive and developmental toxicity studies for benzene are available. Therefore, an overall UF of 3 x 10 x 3 x 3 = 300 is used to calculate the RfC. For the comparison analysis based on the Rothman et al. (1996) LOAEL, the following UFs were selected: a factor of 10 for use of a LOAEL due to lack of an appropriate NOAEL, a factor of 10 for intraspecies variability, a factor of 3 for subchronic-to-chronic extrapolation, and a factor of 3 for database deficiencies. Hence, an overall UF of 10 x 10 x 3 x 3 = 1000 was used in the comparison analysis. For the comparison analysis based on the BMCL calculated from BMD modeling of the male mouse data from the Ward et al. (1985) subchronic inhalation study, the following UFs were used: a UF of 3 for effect-level extrapolation, which is analogous to the LOAEL-to-NOAEL extrapolation factor, because the BMC is considered an adverse effect level; a UF of 3 for interspecies extrapolation for inhalation studies; a UF of 10 for intraspecies variability; and a UF of 3 for database deficiencies. In addition, a partial UF of 3 was used to extrapolate from subchronic to chronic exposure. This partial value was selected based on the observation that hematological fluctuations such as reductions in RBCs and WBCs in the high-dose mice were noted at interim sacrifice (14 days) as well as at termination (91 days), suggesting that the responses occurred early in the exposure cycle and then remained comparatively unchanged. Thus, an overall UF of 3 x 3 x 10 x 3 x 3 = 1000 was used in this comparison analysis. Finally, for the comparison analysis based on the NOAEL from the Ward et al. (1985) subchronic inhalation study, the following UFs were used: 3 for interspecies extrapolation for inhalation studies, 10 for intraspecies variability, 3 for database deficiencies, and 3 for subchronic-to-chronic extrapolation, as above. Therefore, an overall UF of 300 was used in this comparison analysis. MF = None. No modifying factor was considered necessary. IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Benzene is toxic by all routes of administration. Hematotoxicity and immunotoxicity have been consistently reported to be the most sensitive indicators of noncancer toxicity in both humans and experimental animals, and these effects have been the subject of several reviews (Aksoy, 1989; Goldstein, 1988, Snyder et al., 1993; Ross, 1996; U.S. EPA, 2002). The bone marrow is the target organ for the expression of benzene hematotoxicity and immunotoxicity. Neither gastrointestinal effects from oral exposure nor pulmonary effects due to inhalation exposure have been reported. Chronic exposure to benzene results in progressive deterioration in hematopoietic function. Anemia, leukopenia, lymphocytopenia, thrombocytopenia, pancytopenia, and aplastic anemia have been reported after chronic benzene exposure (Aksoy, 1989; Goldstein, 1988). In an earlier follow-up study of benzene-exposed workers, Aksoy et al. (1972) reported that 8 of 32 workers who had been diagnosed with pancytopenia died, mainly from infection and bleeding. In contrast to these blood cellularity depression effects, benzene is also known to induce bone marrow hyperplasia. Acute myelogenous leukemia has been frequently observed in studies of human cohorts exposed to benzene, and there is evidence linking benzene exposure to several other forms of leukemia. Whether the hematotoxic/immunotoxic effects of benzene exposure and its carcinogenic effects are due to a common mechanism is not yet known. This is in part due to the fact that although the bone marrow depressive effects of exposure to benzene in humans can be readily duplicated in several experimental animal model systems, a suitable experimental animal system for the induction of leukemia has not been found. The hematotoxicity/immunotoxicity effects of benzene exposure lead to significant health effects apart from potential induction of leukemia, as several deaths due to aplastic anemia have been reported (ATSDR, 1997). Leukocytopenia has been consistently shown to be a more sensitive indicator of benzene toxicity in experimental animal systems than anemia, and lymphocytopenia has been shown to be an even more sensitive indicator of benzene toxicity than overall leukocytopenia (Snyder et al., 1980, Ward et al., 1985; Baarson et al., 1984). Rothman et al. (1996) also found that a decrease in ALC was the most sensitive indicator of benzene exposure in a group of workers. Ward et al. (1996) observed a strong relationship between benzene exposure and decreased WBC counts in a rubber worker cohort, but no significant relationship with RBC counts was found. Bogardi-Sare et al. (2000) found that exposure to benzene concentrations of less than 15 ppm can induce depression of circulating B-lymphocytes. Dosemeci et al. (1996) were able to demonstrate the presence of benzene poisoning (WBC <4000 cells/mm3 and platelet count <80,000/mm3) at levels of exposure in the 5-19 ppm range. As is the case with many other organic solvents, benzene has been shown to produce neurotoxic effects in test animals and humans after short-term exposures to relatively high concentrations (U.S. EPA, 2002). The neurotoxicity of benzene, however, has not been extensively studied, and no systematic studies of the neurotoxic effects of long-term exposure have been conducted. Additionally, there is some evidence from human epidemiologic studies of reproductive and developmental toxicity of benzene, but the data did not provide conclusive evidence of a link between exposure and effects (U.S. EPA, 2002). Some test animal studies provide limited evidence that exposure to benzene affects reproductive organs; however, these effects were limited to high exposure concentrations that exceeded the maximum tolerated dose (U.S. EPA, 2002). Results of inhalation studies conducted in test animals are fairly consistent across species and have demonstrated that at concentrations of greater than 150 mg/m3 (47 ppm) benzene is fetotoxic and causes decreased fetal weight and/or minor skeletal variants (U.S. EPA, 2002). Exposure of mice to benzene in utero has also been shown to cause changes in the hematogenic progenitor cells in fetuses, 2-day neonates, and 6 week-old adults (Keller and Snyder, 1986, 1988). For more detail on Susceptible Populations, exit to the toxicological review, section 4.4 http://www.epa.gov/iris/toxreviews/0276-tr.pdf#page=124 CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study --Medium Database --Medium RfC -- Medium The overall confidence in this RfC assessment is medium. The principal study of Rothman et al. (1996) was well conducted, and the availability of good-quality human data for a sensitive endpoint eliminates the uncertainty associated with basing the RfC on experimental animal data. In addition, the RfC of 3 x 10-2 mg/m3 obtained from the BMD modeling results from the Rothman et al. (1996) study is in good agreement with the value of 9 x 10-3 mg/m3 based on the LOAEL. The RfC is also in good agreement with the values of 5 x 10-2 mg/m3 and 6 x 10-2 mg/m3 based on the BMC and the NOAEL, respectively, from the Ward et al. (1985) subchronic rodent inhalation study. This consistency in results provides increased confidence in the RfC. With continuous endpoints such as hematological parameters, there is uncertainty about when a change in a parameter that has inherent variability becomes an adverse effect. Other uncertainties explicitly recognized in the quantitative derivation include intraspecies variability (to accommodate sensitive human subgroups), subchronic-to-chronic extrapolation, and database deficiencies due to the lack of two-generation reproductive and well-conducted developmental toxicity studies for benzene. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0276-tr.pdf#page=156 EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 2002. This assessment was peer reviewed by external scientists as well as in response to public comments. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. Click here for the peer review document http://www.epa.gov/iris/supdocs/benzene_nc-pr.pdf. Other EPA Documentation -- None Date of Agency Consensus -- January 23, 2002 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or hotline.iris@epa.gov (internet address). ============================================================================ UDCA: 200001 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Benzene CASRN -- 71-43-2 Last Revised -- 01/19/2000 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Benzene is classified as a "known" human carcinogen (Category A) under the Risk Assessment Guidelines of 1986. Under the proposed revised Carcinogen Risk Assessment Guidelines (U.S. EPA, 1996), benzene is characterized as a known human carcinogen for all routes of exposure based upon convincing human evidence as well as supporting evidence from animal studies. (U.S. EPA, 1979, 1985, 1998; ATSDR, 1997). Epidemiologic studies and case studies provide clear evidence of a causal association between exposure to benzene and acute nonlymphocytic leukemia (ANLL) and also suggest evidence for chronic nonlymphocytic leukemia (CNLL) and chronic lymphocytic leukemia (CLL). Other neoplastic conditions that are associated with an increased risk in humans are hematologic neoplasms, blood disorders such as preleukemia and aplastic anemia, Hodgkin's lymphoma, and myelodysplastic syndrome (MDS). These human data are supported by animal studies. The experimental animal data add to the argument that exposure to benzene increases the risk of cancer in multiple species at multiple organ sites (hematopoietic, oral and nasal, liver, forestomach, preputial gland, lung, ovary, and mammary gland). It is likely that these responses are due to interactions of the metabolites of benzene with DNA (Ross, 1996; Latriano et al., 1986). Recent evidence supports the viewpoint that there are likely multiple mechanistic pathways leading to cancer and, in particular, to leukemogenesis from exposure to benzene (Smith, 1996). HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Benzene is a known human carcinogen based upon evidence presented in numerous occupational epidemiological studies. Significantly increased risks of leukemia, chiefly acute myelogenous leukemia (AML), have been reported in benzene-exposed workers in the chemical industry, shoemaking, and oil refineries. The following epidemiologic studies briefly described are the key studies that support the weight-of-evidence classification that exposure to benzene is causally related to an increase in the risk of cancer, specifically leukemia. Aksoy et al. (1974) reported effects of benzene exposure among 28,500 Turkish workers employed in the shoe industry. The mean duration of employment was 9.7 years (range 1 to 15 years) and the mean age was 34.2 years. Peak exposure to benzene was reported to be 210 to 650 ppm. Twenty-six cases of leukemia and a total of 34 leukemias or preleukemias were observed, corresponding to an incidence of 13/100,000 (by comparison to 6/100,000 for the general population). A follow-up analysis of the study (Aksoy, 1980) reported eight additional cases of leukemia as well as evidence suggestive of increases in other malignancies. This case study lacks detailed information on personal exposure to benzene and potential exposure to other chemicals, a well-defined comparison population, and control of confounding variables. Infante et al. (1977b), in a retrospective cohort mortality study, examined the leukemogenic effects of benzene exposure in 748 white male workers exposed at least 1 day while employed in the manufacture of rubber products. Exposure occurred from 1940 to 1949 and vital status was obtained through 1975. A statistically significant increased risk of leukemia (7 observed, 1.48 expected; p < .002) was found by comparison of observed leukemia deaths in this cohort with those expected based upon general U.S. population death rates. The risk of leukemia was said by the authors to be potentially understated since follow-up was only 75% complete. According to the authors, there was no evidence of solvent exposure other than benzene. No effort was made to evaluate individual exposures to benzene for the purpose of doing a dose-response analysis. The main criticism of this study, as well as its later updates, is the small size of the cohort. In an extension and elaboration of the analysis done by Infante et al. (1977b), Rinsky et al. (1981) reported seven deaths from leukemia in this same cohort after achieving a 98% vital status ascertainment through June 1975. Forty additional deaths from all causes were reported, but no new leukemia deaths. Again, the risk of death from leukemia was statistically significant (standardized mortality ratio [SMR] was 560 based upon 7 leukemia deaths, p < .001). Some 437 members of the cohort were exposed for less than 1 year. Those who received 5 or more years of exposure exhibited an SMR of 2100, based upon 5 leukemia deaths versus 0.25 expected (p < .01). All seven leukemia cases were of the myelogenous or monocytic cell type. Four additional deaths from leukemia were also noted but could not be added to the total because they did not fit the criteria for inclusion. The authors tried to reconstruct past exposure to benzene at the two locations of this company and found that in some areas of the plants airborne benzene concentrations occasionally rose to several hundred parts per million, but most often employee 8-hour time-weighted averages (TWA) fell within the limits considered permissible at the time of exposure. No dose-response analysis was attempted. In an updated version of the Rinsky et al. (1981) study, the same authors examined a somewhat expanded cohort of 1165 nonsalaried white men employed in the rubber hydrochloride department for at least 1 day through December 1965 and followed to December 31, 1981 (Rinsky et al., 1987). Followup was 98.6% complete. Again, a statistically significant excess risk of leukemia was found for the total cohort (9 observed, 2.7 expected; p < 0.05). For the first time, individual measurements of cumulative exposure in terms of ppm-years were generated for all members of the cohort utilizing the historical air-sampling data discussed above or interpolating estimates based on the existing data. SMRs for leukemia ranged from a nonsignificant 109 (2 observed, 1.83 expected) at cumulative exposures under 40 ppm-years to a statistically significant SMR of 2339 (5 observed, 0.21 expected; p < .05) at 200 ppm-years or more of exposure. The authors found significantly elevated risks of leukemia at cumulative exposures less than the then equivalent current standard for occupational exposure, which was 10 ppm over a 40-year working lifetime. The Rinsky et al. (1981, 1987) study analyses, based upon the original cohort of Pliofilm rubber workers studied by Infante et al. (1977b), were selected by the Agency as the critical study for dose-response analysis and for the quantitative estimation of cancer risk to humans. The Rinsky et al. (1981, 1987) analyses show ample power, latency, reasonably good estimates of exposure to benzene except prior to 1946, few confounders, and a wide range of exposure to benzene from low levels to high levels. Limitations include the small cohort size, reporting only nine leukemia deaths with no estimates of risk according to cell type. There remain questions about the estimation of personal exposure to benzene, especially prior to 1946 when no measurements of airborne benzene were made. And finally, at levels less than 200 ppm-years it is not possible to determine leukemia risk in this cohort because of lack of sensitivity of the data at low levels. Ott et al. (1978) observed a nonsignificantly increased risk of leukemia (3 deaths) among 594 chemical workers exposed to benzene followed for at least 23 years in a retrospective cohort mortality study. Benzene exposures ranged from under 2 ppm to over 25 ppm 8-hour TWA. Bond et al. (1986) updated this report by following this cohort an additional 9 years to the end of 1982 and adding an additional 362 exposed workers not studied previously. The authors reported finding a nonsignificant excess risk (SMR = 194) of deaths from leukemia based upon 4 cases. All were diagnosed as myelogenous leukemias. The authors reported that this represented a significant excess (4 observed versus 0.9 expected, p < .011) for myelogenous leukemia based upon the International Classification of Diseases and Causes of Death. It is not stated whether these four deaths were acute or chronic. One additional death was classified as a "pneumonia" death, but on the death certificate "acute myelogenous leukemia" was noted as a significant contributing condition. Cumulative exposure estimates ranged from 18 ppm-months to a high of 4211 ppm-months. The Bond et al. (1986) study has little power to detect significant risk of leukemia at low doses. The authors also state that their data should not be used for determining unit risk estimates because of the small number of events, competing exposures to other potentially hazardous materials, and the contribution of unquantified brief exposures to benzene. Wong (1983, 1987) reported on the mortality of male chemical workers who had been exposed to benzene for at least 6 months during the years 1946 to 1975. The study population of 4602 persons was drawn from seven chemical plants and cumulative exposures to benzene were determined for all subjects. The control subjects (3074 persons) held jobs at the same plants for at least 6 months but were never subjected to benzene exposure. Dose-dependent increases were seen in the risk of leukemia and the risk of lymphatic and hematopoietic cancer. Chemical workers with a cumulative exposure to benzene of 720 ppm-months were subject to a borderline significant relative risk of 3.93 (p = .05) for lymphatic and hematopoietic cancer. None of the leukemia deaths were of the acute myeloid cell type, the type that was known to be associated with exposure to benzene in other studies. The author further observed that cumulative exposure, not peak exposure, was the major variable in quantifying mortality risk from lymphopoietic cancer. The Mantel-Haenszel chi-square for upward trend in risk of leukemia with increasing cumulative exposure was significantly elevated at the 99% level of confidence. Some of the limitations of this study include imprecise historical industrial hygiene data, unusual distribution of leukemia cell types, i.e., there were no acute cases of myelogenous leukemia out of seven leukemia cases, and possible exposure of comparison subjects to potentially carcinogenic solvents other than benzene. The National Cancer Institute of the U.S. National Institutes of Health and the Chinese Academy of Preventative Medicine have been conducting a comprehensive epidemiological study of 74,828 benzene-exposed workers employed from 1972 to 1987 in 672 factories in 12 cities of China (Dosemeci et al., 1994; Hayes et al., 1996, 1997; Yin et al., 1987, 1989, 1994, 1996). A comparison group of workers consisting of 35,805 employees was assembled from non-benzene-exposed units of 69 of the same factories and 40 factories elsewhere. Workers in a variety of jobs in painting, printing, footwear, rubber, chemical, and other industries were followed for vital status for an average period of time of less than 12 years. Less than 0.3% were lost to follow-up. Employee work histories were linked to benzene exposure data in order to derive individual time-specific estimates for each worker (Dosemeci et al., 1994). This large cohort mortality study produced a significantly elevated risk of hematologic neoplasms (RR = 2.2, 95% C.I. = 1.1-4.2) in workers exposed to benzene at an average level of less than 10 ppm. A combination of ANLL and MDS produced a risk of 3.2 (95% C.I .= 1.0-10.1). For exposure to a sustained concentration of 25 ppm benzene, the risk of ANLL and MDS increased to 7.1 (95% C.I. = 2.1-23.7). The risk of other leukemias (other than ANLL), including chronic myeloid and monocytic leukemia, was not significantly elevated (RR = 2.0). Additionally, the risk of non-Hodgkin's lymphoma was significantly elevated (RR = 4.2 with 95% C.I. = 1.1-15.9) for those with a sustained exposure to benzene that occurred at least 10 years prior to diagnosis. The authors concluded that benzene exposure "is associated with a spectrum of hematologic neoplasms and related disorders in humans and that risks for these conditions are elevated at average benzene-exposure levels of less than 10 ppm." Limitations of this study include possible concurrent exposures to many different chemicals found in the factories where the benzene exposure occurred. There is a lack of reliable exposure information in the early days of the observation period, when only 3% of the exposure estimates were based on actual measurements. All of the epidemiological studies referred to above have some methodological problems, i.e., confounding exposures, lack of sufficient power, and other limitations, but the consistent excess risk of leukemia across all of these studies argues that such problems could not be entirely responsible for the elevated risks of cancer. Most of these epidemiologic and case studies have been reviewed in peer-reviewed publications (IARC, 1982; ATSDR, 1997; U.S. EPA, 1998). They provide clear evidence of a causal association between exposure to benzene and ANLL. The evidence is suggestive with respect to CNLL and CLL. The limitations of these studies, except for Rinsky et al. (1981, 1987), preclude their use in quantitative risk estimation. This is further discussed in the quantitative risk estimation sections (II.C.3 and II.C.4). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Although human epidemiological studies provide the bulk of the evidence reaffirming the classification of benzene as a category A, "known" human carcinogen (U.S. EPA, 1979, 1985, 1998), many experimental animal studies, both inhalation and oral, also support the evidence that exposure to benzene increases the risk of cancer in multiple organ systems including the hematopoietic system, oral and nasal cavities, liver, forestomach, preputial gland, lung, ovary, and mammary gland. The key animal studies that support the finding of an excess risk of leukemia in humans from exposure to benzene by the inhalation route are Maltoni et al. (1982, 1983, 1985, 1989), Cronkite et al. (1984, 1985, 1989), Snyder et al. (1988), and Farris et al. (1993); and by the oral route, Huff et al. (1989), NTP (1986), and Maltoni et al. (1983, 1985, 1989). The details of these studies have been reviewed (ATSDR, 1997). Studies on the carcinogenicity of benzene in rodents include inhalation exposures to Sprague-Dawley rats, C57BL/6 mice, AKR mice, CD-1 mice, and CBA mice; and gavage treatment of Sprague-Dawley rats, Wistar rats, F344 rats, RF/J mice, Swiss mice, and B6C3F1 mice (Cronkite et al., 1989; Goldstein et al., 1982; Huff et al., 1989; Maltoni et al., 1983, 1988; NTP, 1986; Snyder et al., 1980, 1982, 1984; Farris et al., 1993). Inhalation concentrations ranged from 0 to 1000 ppm and gavage doses ranged from 0 to 200 mg/kg. It is noted that in humans the cancer induced by benzene exposure is predominantly acute nonlymphocytic leukemia, while in rodents lymphocytic leukemia was observed in two series of experiments in C57BL/6 mice (Snyder et al., 1980) and CBA/Ca mice (Cronkite et al., 1989). The difference in induction of hematopoietic cancers in mice and humans is not fully understood, but it may be related to species-specific differences in hematopoiesis. Lymphocytes make up a larger portion of the nucleated cells in mouse bone marrow than in human bone marrow (Parmley, 1988) and could simply represent a larger target cell population for benzene metabolites. The bone marrow, Zymbal gland, and Harderian gland all contain peroxidases, which can activate phenols to toxic quinones and free radicals. Sulfatases, which remove conjugated sulfate and thus reform free phenols, are also present at high levels in these target organs. The selective distribution of these two types of enzymes in the body may explain the accumulation of free phenol, hydroquinone, and catechol in the bone marrow and the resulting differences in target organ toxicity of benzene metabolites in humans and animals. The animal bioassay results may have some relevance to human leukemia, but it should be emphasized that there is no well-demonstrated and reproducible animal model for leukemia resulting from benzene exposure. The mechanism of leukemia development following exposure to benzene is not well understood (Low et al., 1989, 1995). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The supporting evidence for the carcinogenic effects of exposure to benzene comes from our current understanding of the metabolism and mode of action (Stephens et al., 1994; Medinsky et al., 1996; Lee et al., 1996; Valentine et al., 1996; Rothman, 1997). This is briefly summarized below and reviewed in U.S. EPA (1998). It is generally agreed that the toxicity of inhaled benzene results from its biotransformation to reactive species. Benzene is metabolized in the liver by cytochrome P4502E1 (CYP2E1) to its major metabolites: phenol, hydroquinone, and catechol. The intermediate benzene oxide can also undergo ring opening to trans-trans muconic acid. Although there is a scientific consensus that metabolism of benzene is required for resultant toxicity and carcinogenic response, the role of a metabolite or metabolites of benzene in producing these adverse effects is controversial and more research data are needed to better define sequelae of pathogenesis following exposure to benzene and its metabolites. Current evidence indicates that benzene-induced myelotoxicity and genotoxicity result from a synergistic combination of phenol with hydroquinone, muconaldehyde, or catechol. Molecular targets for the action of these metabolites, whether acting alone or in concert, include tubulin, histone proteins, topoisomerase II, and other DNA-associated proteins. Damage to these proteins would potentially cause DNA strand breakage, mitotic recombination, chromosomal translocations, and malsegregation of chromosomes to produce aneuploidy. If these effects took place in stem or early progenitor cells, a leukemic clone with selective advantage to grow could arise as a result of protooncogene activation, gene fusion, and suppressor-gene inactivation. Epigenetic effects of benzene metabolites on the bone marrow stroma, and perhaps the stem cells themselves, could then foster development and survival of a leukemic clone. Since these plausible events have not been conclusively demonstrated, this remains a hypothesis (Smith, 1996). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 1.5 x 10E-2 to 5.5 x 10E-2 per (mg/kg)/day Drinking Water Unit Risk -- 4.4 x 10E-4 to 1.6 x 10-E3 per (mg/L) Extrapolation Method -- Linear extrapolation of human occupational data Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ---------------------- E-4 (1 in 10,000) 10E2 ug/L to 10E3 ug/L E-5 (1 in 100,000) 10E1 ug/L to 10E2 ug/L E-6 (1 in 1,000,000) 10E0 ug/L to 10E1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- leukemia Test Species -- human Route -- inhalation, occupational exposure Reference -- Rinsky et al., 1981, 1987; Paustenbach et al., 1993; Crump 1994; U.S. EPA, 1998; U.S. EPA, 1999. The quantitative oral unit risk estimate is an extrapolation from the known inhalation dose-response to the potential oral route of exposure documented in Section II.C. The inhalation risk estimate is reported as a range, from 2.2 x 10E-6 to 7.8 x 10E-6 per ug/m3. No relevant data exist in the published literature for oral absorption of benzene in humans. Inhalation absorption is assumed to be about 50% while that of oral is selected as 100% based upon a review of the relevant human and animal literature (U.S. EPA, 1999). Absorption of benzene via the dermal route of exposure is usually less than 1% of the applied dose and therefore it is not considered to contribute significantly the oral risk estimation. In the previous oral unit risk estimate it was assumed that absorption was equal for both the inhalation and oral routes of exposure (U.S. EPA, 1992). The inhalation unit risk range (per ug/m3) is first converted to the oral slope factor, which is in units of risk per ug/kg/day, by assuming a standard air intake of 20 m3/day, a standard body weight of 70 kg for an adult human, and 50% absorption via inhalation. The drinking water unit risk was then calculated from the oral slope factor assuming a drinking water intake of 2 L/day. In calculating the drinking water concentrations for specific risk levels, the upper and lower end of the range round off to a single value. This assessment of the oral unit risk range replaces the previous oral carcinogenicity assessment on IRIS dated April 1, 1992. ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) EPA's quantitative estimate for the cancer risk associated with inhalation exposure to benzene was recently updated (U.S. EPA, 1998). The new inhalation unit risk estimate is reported as a range, from 2.2 x 10-6 to 7.8 x 10-6 per ug/m3 (U.S. EPA, 1999b). To extrapolate to oral risk, the inhalation unit risk range is first converted to units of dose (ug/kg/day). Using the standard air intake factor of 20 m3/day, the standard weight estimate of 70 kg, and the 50% absorption factor for inhalation exposure given above, the dose from 1 ug/m3 continuous daily exposure is: 1 ug/m3*20 m3/day*0.5*(1/70) kg = 0.143 ug/kg/day The risk estimate range is then divided by this dose, to generate an oral slope factor in units of inverse dose: risk/(ug/kg/day) = 2.2 x 10E-6/0.143 ug/kg/day to 7.8 x 10E-6/0.143 ug/kg/day = 1.54 x 10E-5 to 5.45 x 10-5 per ug/kg/day Assuming 100% oral absorption and a standard intake of 2 L/day, the concentration in drinking water that would produce a dose of 1 ug/kg/day is: 1 ug/kg/day*70 kg*(2 L/day)-1 = 35 ug/L Thus, the oral unit risk, in units of risk/(ug/L) would be: (1.54 x 10E-5 to 5.45 X 10E-5)/35 ug/L = 4.4 x 10E-7 to 1.6 x 10E-6/ug/L Note: This estimate is a risk factor for ingested benzene, and is not sufficient to account for total exposure to drinking water. For development of a drinking water safe concentration, the risk due to inhalation of volatilized benzene from drinking water and to dermal uptake must be added to the ingestion risk (Beavers et al., 1996; Lindstrom et al., 1994). If one assumes a 20% respiratory absorption rate, the lowest value in a group of subjects (range 20% to 50%) that was found in one study (Srbova et al., 1950), then the oral unit risk range becomes 1.10 x 10E-6 to 3.89 x 10E-6. This may represent an upper bound on the risk range. The standard values (20 m3/day, 70 kg, 2 L/day) used for the risk estimation do not necessarily account for the population variability. The range of risk estimates of 4.4 x 10E-7 to 1.6 x 10E-6 /ug/L is recommended, within which any value will have equal scientific plausibility. The assumption is made that the leukemia effect is dependent on the absorbed dose. For inhalation, the metabolized dose is assumed to be 50% of the inhaled dose. This conclusion is supported by studies in humans (Pekari et al., 1992; Hunter, 1966; Hunter, 1968; Hunter and Blair, 1972; Nomiyama and Nomiyama, 1974; Srbova et al., 1950; Teisinger et al., 1952, as cited in Fiserova-Bergerova et al., 1974; Yu and Weisel, 1998) and by a pharmacokinetic model developed by Bois et al. (1996). In the absence of data in humans regarding the fraction of orally-ingested benzene that is metabolized, data from mice and rats (Sabourin et al., 1987) suggests that there is a complete absorption of the dose received by corn oil gavage and intraperitoneally. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) The most useful available human epidemiological data for evaluation of the risk of cancer from exposure to benzene comes from occupational inhalation exposure studies (Rinsky et al., 1981, 1987). There are few human data regarding oral exposure to benzene. Route-to-route extrapolation is justified because similar toxic effects are observed in animals through either the oral or inhalation route of exposure to benzene (ATSDR, 1997) and toxicokinetic data available from animal studies (Gerrity et al., 1990). Experimental animal data also demonstrate that benzene is metabolized to the same products whether it is inhaled or ingested. Therefore, it is reasonable to extrapolate from inhalation dose-response to estimate an equivalent oral dose-response. A rigorous method for route-to-route extrapolation that involves the development of a pharmacokinetic model to predict the concentration of the ultimate carcinogen in bone marrow has been proposed but has not been validated (Smith and Fanning, 1997). Furthermore, the nature of the distribution of benzene metabolites to the bone marrow is not well understood. The chemical species responsible for the induction of leukemia in animals and humans may involve more than one metabolite (Smith, 1996). The absorption efficiencies across pulmonary and gastrointestinal barriers provide an informed basis to adopt reasonable values for benzene absorption. The oral slope factor is derived from the inhalation slope factor currently documented in the IRIS database (Section II.C). No relevant oral benzene exposure data on humans are available, but it is known that complete gastrointestinal absorption occurs in the rat and mouse study as reported by Sabourin et al (1987); it is reasonable to assume complete absorption in humans. However, it is clear from numerous studies of pulmonary absorption in humans that absorption of benzene via the inhalation route is incomplete. There is a general consensus in the literature supporting the use of a 50% absorption via inhalation and not using default assumptions that assume both exposure routes have equivalent absorption efficiencies. Based upon several inhalation studies, EPA has judged an absorption factor of 50% to be the most scientifically sound. In the absence of evidence to the contrary, key studies support the reasonableness of extrapolating from inhalation to oral cancer risk. The calculations use standard EPA conversion factors for air and water intake and informed assumptions about the amount of absorption of benzene from oral and inhalation exposure. A substantial literature provides information on pulmonary absorption in humans. The animal study selected for this assessment provides excellent information in two species for both inhalation and oral absorption. However, data on oral absorption from drinking water exposure would be a useful addition. While the human data demonstrate good agreement indicating that approximately one- half of inhaled benzene is absorbed into the bloodstream at exposure concentrations between 1 and 100 ppm, considerable interindividual variability was observed in all studies that reported on multiple subjects. Many factors, including activity level, pulmonary health, and metabolic clearance, are likely to influence the amount of benzene actually taken up in a diverse population exposed by the inhalation route. To date, characterization of the extent of variability is limited. The simple absorption ratio approach taken to route-to-route extrapolation here cannot account for differences in disposition of benzene after it crosses the pulmonary or gastrointestinal barrier. First-pass metabolism of ingested benzene may have significant effects on the dose of benzene metabolites that reaches the target bone marrow cells (Sabourin et al., 1989). Leukemogenic metabolites may be produced more efficiently after ingestion, but on the other hand, rapid clearance of benzene and metabolites after ingestion may be a mitigating factor. The data are inadequate to address these questions for humans at this time, but a variety of biomarkers of benzene exposure can help to address questions of internal dose of benzene metabolites. Biomarker data, together with further development of PBPK models, using human data to define parameters wherever possible, may provide improved dose metrics for benzene risk assessment in the near future. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES ____II.C.1.1. Air Unit Risk: A range of 2.2 x 10-6 to 7.8 x 10-6 is the increase in the lifetime risk of an individual who is exposed for a lifetime to 1 ug/m3 benzene in air. ____II.C.1.2. Extrapolation Method: Low-dose linearity utilizing maximum likelihood estimates (Crump, 1992, 1994). Air Concentrations at Specified Risk Levels: Risk Level Concentration ---------- ------------- E-4 (1 in 10,000) 13.0 to 45.0 ug/m3 E-5 (1 in 100,000) 1.3 to 4.5 ug/m3 E-6 (1 in 1,000,000) 0.13 to 0.45 ug/m3 DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- Leukemia Test Species -- Humans Route -- Inhalation References -- Rinsky et al., 1981, 1987; Paustenbach et al., 1993; Crump and Allen, 1984; Crump, 1992, 1994; U.S. EPA, 1998. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The Pliofilm workers of Rinsky et al. (1981, 1987) provide the best published set of data to date for evaluating human cancer risks from exposure to benzene. Compared to the published studies of Ott et al. (1978), Bond et al. (1986), and Wong (1987), this cohort has fewer reported co-exposures to other potentially carcinogenic substances in the workplace that might confound risk analysis for benzene. This cohort also provides a greater range of exposures than those of Ott et al. (1978), Bond et al. (1986), and Wong (1987). The Rinsky et al. data were used for developing the unit cancer risk by Crump (1992, 1994). Differences in the unit risk estimates, in addition to the choice of model used, stem largely from differences in the exposure estimates and the dose-response model used. Although the ongoing Chinese cohort studies (Dosemeci et al., 1994; Hayes et al., 1996, 1997; Yin et al., 1987, 1989, 1994, 1996) provide a large data set and perhaps may provide information in the future to better characterize risk of cancer at low dose exposure, their use in the derivation of risk estimates remains problematic at present for the reasons cited in Section II.A.2. The two most important determinants of the magnitude of the unit risk number are the choice of extrapolation model to be used to estimate risk at environmental levels of exposure and the choice of the exposure estimates to which the Pliofilm workers (Rinsky et al., 1981, 1987) were subjected. Crump (1992, 1994) presented 96 unit risk calculation analyses by considering different combinations of the following factors: (1) different disease endpoints, (2) additive or multiplicative models, (3) linear/nonlinear exposure-response relationships, (4) two different sets of exposure measurements (Crump and Allen [1984] vs. exposure estimates by Paustenbach et al. [1993]) and (5) cumulative or weighted exposure measurements. The unit risk estimates range from 8.6 x 10-5 to 2.5 x 10-2 at 1 ppm (3200 ug/m3) of benzene air concentration (Crump, 1992, 1994). The risk estimates would fall into the lower range if a sublinear exposure response model were found to be more plausible. However, the shape of the exposure dose-response curve cannot be considered without a better understanding of the biological mechanism(s) of benzene-induced leukemia. Understanding of the mechanisms by which exposure to benzene and its metabolites exert their toxic and carcinogenic effects remains uncertain (U.S. EPA, 1998). It is likely that more than one mechanistic pathway may be responsible for the toxicity of benzene contributing to the leukemogenic process. Not enough is known to determine the shape of the dose-response curve at environmental levels of exposure and to provide a sound scientific basis to choose any particular extrapolation model to estimate human cancer risk at low doses. In fact, recent data (Hayes et al., 1997) suggest that because genetic abnormalities appear at low exposures in humans, and the formation of toxic metabolites plateaus above 25 ppm, the dose-response curve could be supralinear below 25 ppm. Given this, EPA believes that use of a linear extrapolation model as a default approach is appropriate. When a linear model was employed, the choice of cancer unit risk estimates narrows to a range between 7.1 x 10-3 and 2.5 x 10-2 at 1 ppm (2.2 x 10-6 to 7.8 x 10-6 at 1 ug/m3 of benzene in air), depending on which exposure measurements were used, i.e., Crump and Allen (1984) or Paustenbach et al. (1993). The choice of these limits was dictated by the following considerations: (1) use of the (1981, 1987) Rinsky cohort, (2) use of Crump's (1992, 1994) analysis of the Crump and Allen (1984) and the Paustenbach (1992, 1993) exposure measurements. The range of risks nearly includes the 1985 EPA risk estimate of 2.6 x 10-2 at 1 ppm (8.1 x 10-6 at 1 ug/m3). The set of risk estimates falling within this interval reflects both the inherent uncertainties in the risk assessment of benzene and the limitations of the epidemiologic studies in determining dose-response and exposure data. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) The major conclusion of this update (U.S. EPA, 1998) is a reaffirmation within an order of magnitude of the benzene interim unit risk estimates derived in EPA's 1985 interim risk assessment (U.S. EPA, 1985), which established the probability of humans developing cancer from exposure to 1 ppm of benzene. Review of the 1985 interim risk assessment required addressing two main concerns. The first concern was the use of the updated epidemiologic data from Rinsky et al.'s (1987) cohort of Pliofilm workers and selection of appropriate estimates of their exposure to benzene for the derivation of the unit risk estimate. Although numerous epidemiological studies demonstrate an association of exposure to benzene and increased risk of human cancer, these studies are not without methodological limitations. The Rinsky et al. (1981, 1987) study continues to provide the best available data for derivation of unit cancer risk estimates. This study had the least number of confounders and a wide range of exposure to benzene. The second major concern was continued application of the low-dose linearity concept to the model used to generate estimates of unit risk. It was concluded that at present there is insufficient evidence to reject this concept, and a linear extrapolation was used (U.S. EPA, 1998). If one assumes that the linear extrapolation model is the appropriate model to be used, given the uncertainties outlined, then the range of suitable estimates is defined by the choice of exposure estimates selected. The lowest unit risk among linear choices is determined by the exposure estimates of Paustenbach et al. (1993) according to the calculations of Crump (1992, 1994), simply because Paustenbach's exposure estimates for the Rinsky cohort are highest. That estimate is 7.1 x 10-3 at 1 ppm (2.2 x 10-6 at 1 ug/m3). The highest risk number is determined by Crump (1992, 1994) using the lower exposure estimates from Crump and Allen (1984), and that is 2.5 x 10-2 at 1 ppm (7.8 x 10-6 at 1 ug/m3). At present, the true cancer risk from exposure to benzene cannot be ascertained, even though dose-response data are used in the quantitative cancer risk analysis, because of uncertainties in the low-dose exposure scenarios and lack of clear understanding of the mode of action. A range of estimates of risk is recommended, each having equal scientific plausibility. The range estimates are maximum likelihood values (i.e., best statistical estimates) and were derived from observable dose responses using a linear extrapolation model to estimate low environmental exposure risks. The extrapolation range is on the order of 20-60 depending on what environmental level is of interest. This range is fairly low and thus does not suggest any unusual lack of plausibility about the estimates. The use of a linear model is a default public health protective approach and an argument both for and against recognizing supra- and sublinear relationships at low doses and nonthreshold or threshold modes of action on exposure to benzene. Therefore, the true risk could be either higher or lower. The numerical difference between the 1985 risk estimate (2.6 x 10-2 at 1 ppm or 8.1 x 10-6 at 1 ug/m3) compared to the new high-end risk (2.5 x 10-2 at 1 ppm or 7.8 x 10-6 at 1 ug/m3) is insignificant and no scientific inferences about the merit of one value versus the other should be made. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Documents -- U.S. EPA, 1999; U.S. EPA, 1998; U.S. EPA, 1985; U.S. EPA, 1979. The U.S. EPA. (1998) inhalation assessment and the U.S. EPA (1999) extrapolation of the inhalation unit risk estimate to the oral route of exposure were externally peer reviewed. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A summary record of the comments and EPA responses is included as an appendix to the benzene support document file. The EPA 1979 and 1985 documents provide the basis for the classification of benzene as a Group A carcinogen. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date: inhalation carcinogenicity: 9/30/1998 oral carcinogenicity: 1/3/2000 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 200304 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Benzene CASRN -- 71-43-2 Last Revised -- 04/17/2003 SORD: __VI.A. ORAL RfD REFERENCES Aksoy, M. 1989. Hematotoxicity and carcinogenicity of benzene. Environ. Health Perspect. 82: 193-197. Goldstein, B.D. 1988. Benzene toxicity. Occupational medicine. State of the Art Reviews. 3: 541-554. Hsieh, G.C., R.P. Sharma, and R.D.R. Parker. 1988. Subclinical effects of groundwater contaminants. I. Alteration of humoral and cellular immunity by benzene in CD-1 mice. Arch. Environ. Contam. Toxicol. 17: 151-158. NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). NTP, Research Triangle Park, NC. Ross, D. 1996. Metabolic basis of benzene toxicity. Eur. J. Haematol. 57: 111-118. Rothman, N., G.L. Li, M. Dosemeci, W.E. Bechtold, G.E. Marti, Y.Z. Wang, M. Linet, L.Q. Xi, W. Lu, M.T. Smith, N. Titenko-Holland, L.P. Zhang, W. Blot, S.N. Yin, and R.B. Hayes. 1996. Hematotoxicity among Chinese workers heavily exposed to benzene. Am. J. Ind. Med. 29: 236-246. Sabourin, P.J., B.T. Chen, G. Lucier, L.S. Birnbaum, E. Fisher, and R.F. Henderson. 1987. Effect of dose on the absorption and excretion of [C14]benzene administered orally or by inhalation in rats and mice. Toxicol. Appl. Pharmacol. 87: 325-336. Sabourin, P.J., W.E. Bechtold, W. Griffith, L.S. Birnbaum, G. Lucier and R.F. Henderson. 1989. Effect of exposure concentration, exposure rate, and route of administration on metabolism of benzene by F344 rats and B6C3F1 mice. Toxicol. Appl. Pharmacol. 99: 421-444. Snyder, R., G. Witz, and B.D. Goldstein. 1993. The toxicology of benzene. Environ. Health Perspect. 100: 293-306. U.S. EPA (U.S. Environmental Protection Agency). 1985. Final Draft for Drinking Water Criteria Document on Benzene. Office of Drinking Water, Washington, DC. PB86-118122. U.S. EPA. 1989. Workgroup for Risk Assessment Guidance for Superfund. Volume 1. Human Health Evaluation Manual. Part A. Office of Solid Waste and Emergency Response, Washington, DC. EPA/540/1-89/002. U.S. EPA. 1994. Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry, EPA/600/8-90/066F, dated October, 1994. U.S. EPA. 1999. Extrapolation of the Benzene Inhalation Unit Risk Estimate to the Oral Route of Exposure. National Center for Environmental Assessment, Office of Research and Development, Washington, DC. NCEA-W-0517. U.S. EPA. 2000. Benchmark Dose Technical Guidance Document (External Review Draft). EPA/630/R-00/001. U.S. EPA. 2002. Toxicological Review of Benzene (Noncancer Effects). Available online at: www.epa.gov/iris. White, K.L. Jr., H.H. Lysy, J.A. Munson, et al. 1984. Immunosuppression of B6C3F1 female mice following subchronic exposure to benzene from drinking water. TSCA 8E Submission. OTS Fiche # OTS0536214. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Aksoy, M. 1989. Hematotoxicity and carcinogenicity of benzene. Environ. Health Perspect. 82: 193-197. Aksoy, M., K. Dincol, K. Erdem, T. Akgun, and G. Dincol. 1972. Details of blood changes in 32 patients with pancytopenia associated with long-term exposure to benzene. Br. J. Ind. Med. 29: 56-64. ATSDR (Agency for Toxic Substances and Disease Registry) 1997. Toxicological profile for benzene (Update). Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA. Baarson, K.A., C.A. Snyder, and R.E. Albert. 1984. Repeated exposure of C57B1 mice to inhaled benzene at 10 ppm markedly depressed erythropoietic colony formation. Toxicol. Lett. 20: 337-342. Bogardi-Sare, A., M. Zavalic, I. Trosic et al. 2000. Study of some immunological parameters in workers occupationally exposed to benzene. Int. Arch. Occup. Environ. Health. 73: 397-400. Cronkite, E.P., R.T. Drew, T. Inoue and J.E. Bullis. 1985. Benzene hematotoxicity and leukemogenesis. Am. J. Ind. Med. 7: 447-456. Dosemeci, M., S-N. Yin, M. Linet et al. 1996. Indirect validation of benzene exposure assessment by association with benzene poisoning. Environ. Health Perspect. 104(Suppl. 6): 1343-1347. Goldstein, B.D. 1988. Benzene toxicity. Occupational medicine. State of the Art Reviews. 3: 541-554. Keller, K.A. and C.A. Snyder. 1986. Mice exposed in utero to low concentrations of benzene exhibit enduring changes in their colony forming hematopoietic cells. Toxicology. 42: 171-181. Keller, K.A. and C.A. Snyder. 1988. Mice exposed in utero to 20 ppm benzene exhibit altered numbers of recognizable hematopoietic cells up to seven weeks after exposure. Fund. Appl. Toxicol. 10: 224-232. Ross, D. 1996. Metabolic basis of benzene toxicity. Eur. J. Haematol. 57: 111-118. Rothman, N., G.L. Li, M. Dosemeci, W.E. Bechtold, G.E. Marti, Y.Z. Wang, M. Linet, L.Q. Xi, W. Lu, M.T. Smith, N. Titenko-Holland, L.P. Zhang, W. Blot, S.N. Yin, and R.B. Hayes. 1996. Hematotoxicity among Chinese workers heavily exposed to benzene. Am. J. Ind. Med. 29: 236-246. Snyder, C.A., B.D. Goldstein, A.R. Sellakumar, I. Bromberg, S. Laskin, and R.E. Albert. 1980. The inhalation toxicity of benzene: Incidence of hematopoietic neoplasms and hematoxicity in AKR/J and C57BL/6J mice. Toxicol. Appl. Pharmacol. 54: 323-331. Snyder, R., G. Witz, and B.D. Goldstein. 1993. The toxicology of benzene. Environ. Health Perspect. 100: 293-306. U.S. EPA (U.S. Environmental Protection Agency). 1994. Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry. Prepared by the Office of Health and Environmental Assessment, Research Triangle Park, NC. EPA/600/8-90/066F. U.S. EPA. 2000. Benchmark Dose Technical Guidance Document (External Review Draft). EPA/630/R-00/001. U.S. EPA. 2002. Toxicological Review of Benzene (Noncancer Effects). Available online at: www.epa.gov/iris. Ward, E., R. Hornung, J. Morris, R. Risnsky, D. Wild, W. Halperin, and W. Guthrie. 1996. Risk of low red or white blood cell count related to estimated benzene exposure in a rubberworker cohort (1940-1975). Am. J. Ind. Med. 29: 247-257. Ward, C.O., R.A. Kuna, N.K. Snyder, R.D. Alsaker, W.B. Coate, and P.H. Craig. 1985. Subchronic inhalation toxicity of benzene in rats and mice. Am. J. Ind. Med. 7: 457-473. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). (1997) Toxicological profile for benzene. Update. Public Health Service, U.S. Department of Health and Human Services, Atlanta, Ga. Bois, FY; Jackson, ET; Pekari, K; et al. (1996) Population toxicokinetics of benzene. Environ Health Perspect 104 (Suppl 6):1405-1411. Crump, KS. (1994) Risk of benzene-induced leukemia: a sensitivity analysis of the Pliofilm cohort with additional follow-up and new exposure estimates. J Toxicol Environ Health 42:219-242. Crump, KS; Allen, BC. (1984) Quantitative estimates of risk of leukemia from occupational exposure to benzene. Prepared for the Occupational Safety and Health Administration by Science Research Systems, Inc., Ruston, LA. Unpublished Fiserova-Bergerova, V; Vlach, J; Singhal, K. (1974) Simulation and prediction of uptake, distribution, and exhalation of organic solvents. Br J Ind Med 31:45-52. Gerrity, TR Henry, CJ, eds. (1990) Principles of route-to-route extrapolation for risk assessment: Proceedings of the Workshops on Principles of Route-to-route Extrapolation for Risk Assessment, held 1990: Hilton Head, SC, and Durham, NC. New York: Elsevier. Hunter, CG. (1966) Aromatic solvents. Ann Occup Hyg 9:191-198. Hunter, CG. (1968) Solvents with reference to studies on the pharmacodynamics of benzene. Proc R Soc Med 61:913-915. Hunter, CG; Blair, D. (1972) Benzene: pharmacokinetic studies in man. Ann Occup Hyg 15:193-201. Nomiyama, K; Nomiyama, H. (1974) Respiratory retention, uptake and excretion of organic solvents in man. Int Arch Arbeitsmed 32:75-83. Paustenbach, D; Bass, R; Price, P. (1993) Benzene toxicity and risk assessment, 1972-1992: implications for future regulation. Environ Health Perspect 101 (Suppl 6):177-200. Pekari, K; Vainiotalo, S; Heikkila, P; et al. (1992) Biological monitoring of occupational exposure to low levels of benzene. Scand J Work Environ Health 18:317-322. Rinsky, RA; Young, RJ; Smith, AB. (1981) Leukemia in benzene workers. Am J Ind Med 2:217-245. Rinsky, RA; Smith, AB; Horning, R; et al. (1987) Benzene and leukemia: an epidemiologic risk assessment. N Engl J Med 316:1044-1050. Sabourin, PJ; Chen, BT; Lucier, G; et al. (1987) Effect of dose on the absorption and excretion of [14C] benzene administered orally or by inhalation in rats and mice. Toxicol Appl Pharmacol 87:325-336. Sherwood, RJ. (1988) Pharmacokinetics of benzene in a human after exposure at about the permissible limit. Ann N Y Acad Sci 534:635-647. Smith, MT. (1996) The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect 104 (Suppl 6):1219-1225. Smith, MT; Fanning, EW. (1997) Report on the workshop entitled: "Modeling chemically induced leukemia-implications for benzene risk assessment." Leuk Res 21:361-374. Srbova, J; Teisinger, J; Skramovsky, S. (1950) Absorption and elimination of inhaled benzene in man. Arch Ind Hyg Occup Med 2:1-8. U.S. EPA. (1992, April 1) Integrated Risk Information System (IRIS). Substance file - benzene. Washington, DC: National Center for Environmental Assessment. U.S. EPA. (1998, April 10) Carcinogenic effects of benzene: an update. Prepared by the National Center for Environmental Health, Office of Research and Development. Washington, DC. EPA/600/P-97/001F. U.S. EPA. (1999) Extrapolation of the benzene inhalation unit risk estimate to the oral route of exposure. National Center for Environmental Health, Office of Research and Development. Washington, DC. NCEA-W-0517. Yu, R; Weisel, CP. (1998) Measurement of benzene in human breath associated with an environmental exposure. J Expo Anal Environ Epidemiol 6,3:261-277. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Benzene CASRN -- 71-43-2 Date Section Description ---------------------------------------------------------------------------- 12/01/1988 II.A.4. Anderson and Richardson citation year corrected 12/01/1988 II.A.4. Kissling and Speck citation year corrected 07/01/1989 I.B. Inhalation RfD now under review 02/01/1990 II. Clarified citations 02/01/1990 II.A.3. Corrected Maltoni, 1979 to Maltoni and Scarnato, 1979 02/01/1990 II.A.3. Corrected Maltoni, 1983 to Maltoni et al., 1983 02/01/1990 II.A.3. Corrected Synder et al., 1980 to 1981 02/01/1990 VI. Bibliography on-line 03/01/1990 VI.C. Clarify Maltoni et al., 1983 and NTP, 1986 references 08/01/1990 III.A.10 Primary contact changed 08/01/1990 IV.F.1. EPA contact changed 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 01/01/1992 IV. Regulatory actions updated 04/01/1992 II.B.2. Text revised 02/01/1994 II.D.3. Secondary contact's phone number changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 10/16/1998 II., VI. Revised inhalation carcinogenicity section and references 01/19/2000 II., VI. Revised oral carcinogenicity section and references 02/22/2001 I., II. This chemical is being reassessed under the IRIS Program. 04/17/2003 IA., IB., VI. New RfD and RfC sections; references. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 404 of 1119 in IRIS (through 2003/06) AN: 293 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199302 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Butyl-benzyl-phthalate- SY: 85-68-7; BBP-; 1,2-BENZENEDICARBOXYLIC-ACID,-BUTYL-PHENYLMETHYL-ESTER-; BENZYL-BUTYLESTER-KYSELINY-FTALOVE-; BENZYL-BUTYL-PHTHALATE-; BENZYL-N-BUTYL-PHTHALATE-; N-BUTYL-BENZYL-PHTHALATE-; BUTYL-PHENYLMETHYL-1,2-BENZENEDICARBOXYLATE-; NCI-C54375-; PALATINOL-BB-; PHTHALIC-ACID,-BENZYL-BUTYL-ESTER-; SANTICIZER-160-; SICOL-160-; UNIMOLL-BB- RN: 85-68-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199302 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Butyl benzyl phthalate CASRN -- 85-68-7 Last Revised -- 02/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses UF MF RfD -------------------- ----------------------- ----- --- ---------- Significantly NOAEL: 2800 ppm 1000 1 2E-1 increased liver- (159 mg/kg/day) mg/kg/day to-body weight and liver-to-brain LOAEL: 8300 ppm weight ratios (470 mg/kg/day) 6-Month Rat Study Oral Exposure (diet) NTP, 1985 ---------------------------------------------------------------------------- *Conversion Factors: approximately 300 g bw and 17 g of food consumption/day from data presented in the report PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1985. Twenty-six week subchronic study and modified mating trial in F344 rats. Butyl benzyl phthalate. Final Report. Project No. 12307-02, -03. Hazelton Laboratories America, Inc. Unpublished study. NTP (1985) conducted a toxicity study in F344 rats in which 15 males/group were administered concentrations of either 0, 0.03, 0.09, 0.28, 0.83, or 2.5% BBP in the diet for 26 weeks. Using body weight and food consumption data presented in the report these dietary levels correspond to 0, 17, 51, 159, 470, and 1417 mg/kg/day, respectively. In this study powdered rodent meal was provided in such a way that measured food consumption at the highest dose level could include significant waste and spillage rather than true food intake. For this reason a standard food consumption rate of 5% rat body weight was used in the 2.5% dose conversion. Throughout the study body weight gain was significantly depressed at the 2.5% BBP level when compared with the controls. There were no deaths attributed to BBP toxicity. All the rats given 2.5% BBP had small testes upon gross necropsy; 5/11 had soft testes and 1/11 had a small prostate and seminal vesicle. In the 0.03, 0.09, 0.28, and 0.83% dose groups there were no grossly observable effects on male reproductive organs. Terminal mean organ weight values were significantly decreased (p<0.05) for the heart, kidney, lungs, seminal vesicles and testes in the 2.5% group. Hematological effects at 2.5% BBP included decreased red cell mass (which the authors state is indicative of deficient hemoglobin synthesis), reduced values for hemoglobin, total RBC and hematocrit. The kidneys of six animals in the 2.5% group contained focal cortical areas of infarct-like atrophy. In addition, testicular lesions were also observed at the 2.5% dose level. Lesions were characterized by atrophy of seminiferous tubules and aspermia. At 0.83% the effects noted were significantly (p<0.05) increased absolute liver weight, increased liver-to-body weight and liver-to-brain weight ratios and increases in mean corpuscular hemoglobin. The 0.03, 0.09, 0.28, and 0.83% treatment groups showed no evidence of abnormal morphology in any organ. No adverse effects were observed at the 0.28% treatment level or below. The only other information on subchronic effects is reported by Krauskopf (1973) from an unpublished study by Monsanto (1972). Rats fed diets containing 0.25% (125 mg/kg/day) and 0.5% (250 mg/kg/day) for 90 days showed no toxic effects. Liver weights were increased in animals fed diets containing 1.0, 1.5, or 2.0% (500, 750, or 1000 mg/kg/day, respectively) for 90 days, and a mild decrease in growth rate was reported for the 1.5 and 2.0% groups. No other hematologic, histopathologic or urinalysis effects were observed. When dogs were administered gelatin capsules containing doses equivalent to 1.0, 2.0, or 5.0% of the daily diet (10,000 20,000 and 50,000 ppm) for 90 days, no effect on hematological parameters, urinalysis or liver and kidney functions were observed. No further details of this study were available for review. Similar LOAELs of 470 and 500 mg/kg/day for increased liver weight were identified in both the NTP (1985) and Monsanto (1972) studies, respectively. NOAELs differ slightly: 159 (NTP, 1985) versus 250 mg/kg/day (Monsanto, 1972). It is recommended that the NOAEL of 159 mg/kg/day from the NTP (1985) study be used to derive the RfD for two reasons: 1) the NTP (1985) study is of longer duration, and 2) The Monsanto (1972) study provides an incomplete description of methods comparing study design and clinical analysis. Treatment-related effects across similar dose ranges including liver effects in both studies support the use of 159 mg/kg/day as a NOAEL. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- 10 for intraspecies sensitivity, 10 for interspecies variability and 10 for extrapolating from subchronic to chronic NOAELs. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Two 14-day studies support the selection of the NTP (1985) bioassay for deriving the oral RfD. Agarwal et al. (1985) administered BBP to male F344 rats in the diet for 14 consecutive days at dose levels of 0.625, 1.25, 2.5, and 5.0%. Significant increases in liver and kidney weights and kidney pathology (proximal tubular regeneration) was observed at 0.625% (375 mg/kg/day), which represents a LOAEL. In male Sprague-Dawley rats administered 160, 480, or 1600 mg/kg/day BBP for 14 days by gastric intubation, biochemical or morphological changes in the liver as well as effects on testes weights were not observed in the 160 mg/kg/day dose group (Lake et al., 1978). However, at 480 mg/kg/day activities of ethyl morphine N-demethylase and cytochrome oxidase were significantly increased and testicular atrophy was observed in one-third Sprague-Dawley rats in the first portion of this experiment. In the second position, the 480 mg/kg/day dose induced testicular atrophy in one-sixth Sprague-Dawley rats, whereas the Wistar albino strain revealed no such effects. A NOAEL for this study would be 160 mg/kg/day based on the absence of liver and testicular effects. In an addendum to the NTP (1985) final report, evaluation of the data revealed a significantly reduced total marrow cell count in the 2.5% dose group (NTP, 1986). The change in total cell count was comprised primarily of significant decreases in neutrophil, metamyelocytes, bands, segmeters, lymphocytes and leasophilic rubricytes. The total marrow cell counts, metamyelocyte, and leasophilic rubricyte counts were also significantly decreased in the lowest dose group, 0.03%. No statistically significant differences were noted in the middle dose groups (0.09, 0.28, or 0.83%) when compared with controls. The addendum states that decreased total marrow cell count in the 0.03 and 2.5% dose group represent change of uncertain meaning in light of the systemic effects noted in the middle dose groups. Trend analysis by the Terpstra-Jonckheere test revealed significantly (p<0.05%) decreasing trends in all of the previously mentioned parameters as well as an increasing trend for monocytes at 0.03 and 2.5%. NTP (1985) also conducted a male mating trial study concomitantly with the toxicity study. Testicular atrophy was observed in male F344 rats after 10 weeks of exposure to 2.5% (2875 mg/kg/day) BBP. Throughout the study, body weight gain was significantly depressed at the 2.5% BBP level when compared with the controls. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The critical study is of adequate quality and is given a medium confidence rating. Since the critical study used only male rats and there are no adequate supporting studies of chronic duration, the data base is given a low confidence rating. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1987a,b; 1988 U.S. EPA (1987a, 1988) have been both OHEA reviewed and Agency reviewed. U.S. EPA (1987b) has been OHEA reviewed. Other EPA Documentation -- None Agency Work Group Review -- 06/15/1989 Verification Date -- 06/15/1989 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Butyl benzyl phthalate CASRN -- 85-68-7 NORC: Not available at this time. ============================================================================ UDCA: 199302 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Butyl benzyl phthalate CASRN -- 85-68-7 Last Revised -- 02/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen. Basis -- Based on statistically significant increase in mononuclear cell leukemia in female rats; the response in male rats was inconclusive and there was no such response in mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. A bioassay was performed by the NTP (1982) to evaluate the carcinogenic potential of orally administered butyl benzyl phthalate (BBP) to both rats and mice. Dietary levels of 0, 6000, and 12,000 ppm BBP were fed to groups of 50 male and 50 female F344 rats and 50 male and 50 female B6C3F1 mice for 103 weeks. The male rats at both dose levels experienced high mortality within the first 30 weeks of the study due to apparent internal hemorrhaging; all male rats were, thus, terminated at 30 weeks. No chronic toxicity or carcinogenic effects were observed in male or female mice. Among female rats a statistically significant increase in mononuclear cell leukemia (MCL) or lymphoma (p=0.007) was observed at the high dose level compared with controls with an increasing trend at p=0.006. The time to first tumor was 83 weeks in control as well as in the high-dose group. NTP indicated that BBP was "probably" carcinogenic in female rats. The tumor incidence was 7/49 (14%) for controls, 7/49 (14%) in low dose and 19/50 (38%) in the high dose as compared with historical control incidence in the laboratory of 19% (12-24% range). Given the similarity of the MCL pathology in the control and the dosed female rats as well as the absence of a reduction in time to first tumor, the response is judged to be an acceleration of an old age tumor in the F344 rats. This weakens somewhat the interpretive value of the MCL response. The NTP has initiated a retest in the rats. BBP did not induce lung adenomas in strain A mice administered 24 intraperitoneal injections of 160, 400 or 800 mg/kg (Theiss et al., 1977). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Studies indicate that BBP is not a direct acting mutagen in the reverse mutation assay in Salmonella typhimurium (Rubin et al., 1979; Kozumbo et al., 1982; Zeiger et al., 1982) or in E. coli (NTP, 1982). Mammalian cytogenicity studies using chinese hamster ovary cells were also negative (NTP, 1982). NTP (1982) noted that additional studies on metabolites, benzyl alcohol and n-butanol was important. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. The qualitative weaknesses of the MCL response does not provide a compelling basis to model the dose-response data. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987 The 1987 Draft Drinking Water Quality Criteria Document received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 08/26/1987 Verification Date -- 08/26/1987 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 198909 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Butyl benzyl phthalate CASRN -- 85-68-7 Last Revised -- 09/01/1989 SORD: __VI.A. ORAL RfD REFERENCES Agarwal, D.K., R.R. Maronpot, J.C. Lamb, IV and W.M. Kluwe. 1985. Adverse effects of butylbenzyl phthalate on the reproductive and hematopoietic systems of male rats. Toxicology. 35: 189-206. Krauskopf, L.G. 1973. Studies on the toxicity of phthalates via ingestion. Environ. Health Perspect. 3: 61-72. Lake, B.G., R.A. Harris, P. Grasso and S.D. Gangollia. 1978. Studies on the metabolism and biological effects of n-butyl benzyl phthalate in the rat. Prepared by British Industrial Biological Research Association for Monsanto, Report No. 232/78, June. Monsanto Chemical Company. 1972. Unpublished work. (Cited in Krauskopf, 1973) NTP (National Toxicology Program). 1985. Twenty-six week subchronic study and modified mating trial in F344 rats. Butyl benzyl phthalate. Final Report. Project No. 12307-02, -03. Hazelton Laboratories America, Inc. Unpublished study. NTP (National Toxicology Program). 1986. Addendum to Final Report. Bone marrow differential results - 26 Week study. LBI/HLA Project No. 12307-02. Hazelton Laboratories America, Inc. Unpublished report. U.S. EPA. 1987a. Health and Environmental Profile for Phthalic Acid Alkyl, Aryl and Alkyl/Aryl Esters. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1987b. Health Effects Assessment for Selected Phthalic Acid Esters. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1988. Drinking Water Criteria Document for Phthalic Acid Esters (PAEs). Prepared by the Office of Health and Environmental Assessment Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. Final Draft. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Kozumbo, W.J., R. Kroll and R.J. Rubin. 1982. Assessment of the mutagenicity of phthalate esters. Environ. Health Perspect. 45: 103-109. NTP (National Toxicology Program). 1982. Carcinogenesis Bioassay of Butyl Benzyl Phthalate (CAS No. 85-68-7) in F344 Rats and B6C3F1 Mice (Feed Study). NTP Tech. Rep. Ser. TR No. 213, NTP, Research Triangle Park, NC. p. 98 Rubin, R.J., W. Kozumbo and R. Kroll. 1979. Ames mutagenic assay of a series of phthalic acid esters: Positive response of the dimethyl and diethyl esters in TA100. Soc. Toxicol. Ann. Meet., New Orleans, March 11-15. p. 11. (Abstract) Theiss, J.C., G.D. Stoner, M.B. Shimkin and E.K. Weisburger. 1977. Test for carcinogenicity of organic contaminants of United States drinking waters by pulmonary tumor response in strain A mice. Cancer Res. 37: 2717-2720. U.S. EPA. 1987. Drinking Water Criteria Document for Phthalic Acid Esters. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. External Review Draft. Zeiger, E., S. Haworth, W. Speck and V. Mortlemans. 1982. Phthalate ester testing in the National Toxicology Program's environmental mutagenesis test development program. Environ. Health Perspect. 45: 99-101. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Butyl benzyl phthalate CASRN -- 85-68-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/22/1988 II.A. Carcinogen summary on-line 02/01/1989 II.D.3. Primary contact's phone number corrected 07/01/1989 I.A. Oral RfD now under review 09/01/1989 I.A. Oral RfD summary on-line 09/01/1989 VI. Bibliography on-line 08/01/1991 I.A.7. Primary and secondary contacts changed 08/01/1991 II.D.3. Primary and secondary contacts changed 01/01/1992 IV. Regulatory Action section on-line 02/01/1993 I.A.7. Primary contact changed 02/01/1993 II.D.3. Primary contact changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 405 of 1119 in IRIS (through 2003/06) AN: 294 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199706 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Polychlorinated-biphenyls- (PCBs) SY: 1336-36-3; AROCLOR-; AROCLOR-1221-; AROCLOR-1232-; AROCLOR-1242-; AROCLOR-1248-; AROCLOR-1254-; AROCLOR-1260-; AROCLOR-1262-; AROCLOR-1268-; AROCLOR-2565-; AROCLOR-4465-; AROCLOR-5442-; BIPHENYL,-POLYCHLORO-; CHLOPHEN-; CHLOREXTOL-; CHLORINATED-BIPHENYL-; CHLORINATED-DIPHENYL-; CHLORINATED-DIPHENYLENE-; CHLORO-BIPHENYL-; CHLORO-1,1-BIPHENYL-; CLOPHEN-; DYKANOL-; FENCLOR-; INERTEEN-; KANECHLOR-; KANECHLOR-300-; KANECHLOR-400-; MONTAR-; NOFLAMOL-; PCB-; PCBS-; PHENOCHLOR-; PHENOCLOR-; POLYCHLORINATED-BIPHENYL-; POLYCHLORINATED-BIPHENYLS-; POLYCHLOROBIPHENYL-; PYRALENE-; PYRANOL-; SANTOTHERM-; SANTOTHERM-FR-; SOVOL-; THERMINOL-FR-1-; UN-2315- RN: 1336-36-3 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199406 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Polychlorinated biphenyls (PCBs) CASRN -- 1336-36-3 SURD: ___I.A.1. ORAL RfD SUMMARY Please check the following individual aroclor files for RfD assessments: Aroclor 1016, Aroclor 1248, Aroclor 1254, Aroclor 1260. RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Polychlorinated biphenyls (PCBs) CASRN -- 1336-36-3 NORC: Not available at this time. ============================================================================ UDCA: 199706 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Polychlorinated biphenyls (PCBs) CASRN -- 1336-36-3 Last Revised -- 06/01/1997 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- A 1996 study found liver tumors in female rats exposed to Aroclors 1260, 1254, 1242, and 1016, and in male rats exposed to 1260. These mixtures contain overlapping groups of congeners that, together, span the range of congeners most often found in environmental mixtures. Earlier studies found high, statistically significant incidences of liver tumors in rats ingesting Aroclor 1260 or Clophen A 60 (Kimbrough et al., 1975; Norback and Weltman, 1985; Schaeffer et al., 1984). Mechanistic studies are beginning to identify several congeners that have dioxin-like activity and may promote tumors by different modes of action. PCBs are absorbed through ingestion, inhalation, and dermal exposure, after which they are transported similarly through the circulation. This provides a reasonable basis for expecting similar internal effects from different routes of environmental exposure. Information on relative absorption rates suggests that differences in toxicity across exposure routes are small. The human studies are being updated; currently available evidence is inadequate, but suggestive. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. A cohort study by Bertazzi et al. (1987) analyzed cancer mortality among workers at a capacitor manufacturing plant in Italy. PCB mixtures with 54%, then 42% chlorine were used through 1980. The cohort included 2100 workers (544 males and 1556 females) employed at least 1 week. At the end of followup in 1982, there were 64 deaths reported, 26 from cancer. In males, a statistically significant increase in death from gastrointestinal tract cancer was reported, compared with national and local rates (6 observed, 1.7 expected using national rates, SMR=346, CI=141-721; 2.2 expected using local rates, SMR=274, CI=112-572). In females, a statistically significant excess risk of death from hematologic cancer was reported, compared with local, but not national, rates (4 observed, 1.1 expected, SMR=377, CI=115-877). Analyses by exposure duration, latency, and year of first exposure revealed no trend; however, the numbers are small. A cohort study by Brown (1987) analyzed cancer mortality among workers at two capacitor manufacturing plants in New York and Massachusetts. At both plants the Aroclor mixture being used changed twice, from 1254 to 1242 to 1016. The cohort included 2588 workers (1270 males and 1318 females) employed at least 3 months in areas of the plants considered to have potential for heavy exposure to PCBs. At the end of followup in 1982, there were 295 deaths reported, 62 from cancer. Compared with national rates, a statistically significant increase in death from cancer of the liver, gall bladder, and biliary tract was reported (5 observed, 1.9 expected, SMR=263, p<0.05). Four of these five occurred among females employed at the Massachusetts plant. Analyses by time since first employment or length of employment revealed no trend; however, the numbers are small. A cohort study by Sinks et al. (1992) analyzed cancer mortality among workers at a capacitor manufacturing plant in Indiana. Aroclor 1242, then 1016, had been used. The cohort included 3588 workers (2742 white males and 846 white females) employed at least 1 day. At the end of followup in 1986, there were 192 deaths reported, 54 from cancer. Workers were classified into five exposure zones based on distance from the impregnation ovens. Compared with national rates, a statistically significant excess risk of death from skin cancer was reported (8 observed, 2.0 expected, SMR=410, CI=180-800); all were malignant melanomas. A proportional hazards analysis revealed no pattern of association with exposure zone; however, the numbers are small. Other occupational studies by NIOSH (1977), Gustavsson et al. (1986) and Shalat et al. (1989) looked for an association between occupational PCB exposure and cancer mortality. Because of small sample sizes, brief followup periods, and confounding exposures to other potential carcinogens, these studies are inconclusive. Accidental ingestion: Serious adverse health effects, including liver cancer and skin disorders, have been observed in humans who consumed rice oil contaminated with PCBs in the "Yusho" incident in Japan or the "Yu-Cheng" incident in Taiwan. These effects have been attributed, at least in part, to heating of the PCBs and rice oil, causing formation of chlorinated dibenzofurans, which have the same mode of action as some PCB congeners (ATSDR, 1993; Safe, 1994). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Brunner et al. (1996) compared carcinogenicity across different Aroclors, dose levels, and sexes. Groups of 50 male or female Sprague-Dawley rats were fed diets with 25, 50, or 100 ppm Aroclor 1260 or 1254; 50 or 100 ppm Aroclor 1242; or 50, 100, or 200 ppm Aroclor 1016. There were 100 controls of each sex. The animals were killed at 104 weeks, after which a complete histopathologic evaluation was performed for control and high-dose groups; histopathologic evaluations of liver, brain, mammary gland, and male thyroid gland were also performed for low- and mid-dose groups. Statistically significant increased incidences of liver adenomas or carcinomas were found in female rats for all Aroclors and in male rats for Aroclor 1260. Some of these tumors were hepatocholangiomas, a rare bile duct tumor seldom seen in control rats. To investigate tumor progression after exposure has stopped, groups of 24 female rats were exposed for 52 weeks, then exposure was discontinued for an additional 52 weeks before the rats were killed. For Aroclors 1254 and 1242, tumor incidences from the stop study were approximately half those of the lifetime study; that is, nearly proportional to exposure duration. In contrast, stop-study tumor incidences were zero for Aroclor 1016, while for Aroclor 1260 they were generally greater than half those of the lifetime study. For 100 ppm Aroclor 1260, the stop study incidence was greater than that of the lifetime study, 71 vs. 48 percent. Thyroid gland follicular cell adenomas or carcinomas were increased in males for all Aroclors; significant dose trends were noted for Aroclors 1254 and 1242. The increases did not continue proportionately above the lowest dose. No trends were apparent in females. In female rats, the incidence of mammary tumors was decreased with lifetime exposure to Aroclor 1254 and, to a lesser extent, to 1260 or 1242; this result was not observed for Aroclor 1016. Decreases did not occur for any Aroclor in the stop study. The first mammary tumor was observed at a later age in the dosed groups. Kimbrough et al. (1975) fed groups of 200 female Sherman rats diets with 0 or 100 ppm Aroclor 1260 for about 21 months. Six weeks later the rats were killed and their tissues were examined. Hepatocellular carcinomas and neoplastic nodules were significantly increased in rats fed Aroclor 1260. The National Cancer Institute (NCI, 1978) fed groups of 24 male or female Fischer 344 rats diets with 0, 25, 50, or 100 ppm Aroclor 1254 for 104-105 weeks (24 months). Then the rats were killed and their tissues were examined. The combined incidence of leukemia and lymphoma in males was significantly increased by the Cochran-Armitage trend test; however, since Fisher exact tests were not also significant, NCI did not consider this result clearly related to Aroclor 1254. Hepatocellular adenomas and carcinomas were increased. Morgan et al. (1981) and Ward (1985) reevaluated gastric lesions from this study and found 6 adenocarcinomas in 144 exposed rats. This result is statistically significant, as gastric adenocarcinomas had occurred in only 1 of 3548 control male and female Fischer 344 rats in the NCI testing program. Intestinal metaplasia in exposed rats differed morphologically from controls, suggesting Aroclor 1254 can act as a tumor initiator. Schaeffer et al. (1984) fed male weanling Wistar rats a standard diet for 8 weeks, then divided them into three groups. One group was fed the basic diet; for the other groups 100 ppm Clophen A 30 or A 60 was added. Rats were killed at 801 832 days (26.3 27.3 months) and were examined for lesions in the liver and some other tissues. For both mixtures, preneoplastic liver lesions were observed after 500 days (16.4 months) and hepatocellular carcinomas after 700 days (23 months) in rats dying before the end of the study. The investigators concluded, "Clophen A 60 had a definite, and Clophen A 30 a weak, carcinogenic effect on rat liver." Norback and Weltman (1985) fed groups of male and female Sprague-Dawley rats diets of 0 or 100 ppm Aroclor 1260 for 16 months; the latter dose was reduced to 50 ppm for 8 more months. After 5 additional months on the control diet, the rats were killed and their livers were examined. Partial hepatectomy was performed on some rats at 1, 3, 6, 9, 12, 15, 18, and 24 months to evaluate sequential morphologic changes. In males and females fed Aroclor 1260, liver foci appeared at 3 months, area lesions at 6 months, neoplastic nodules at 12 months, trabecular carcinomas at 15 months, and adenocarcinomas at 24 months, demonstrating progression of liver lesions to carcinomas. By 29 months, 91% of females had liver carcinomas and 95% had carcinomas or neoplastic nodules; incidences in males were smaller, 4% and 15%, respectively. Vater et al. (1995) obtained individual animal results to determine whether the partial hepatectomies, which exert a strong proliferative effect on the remaining tissue, affected the incidence of liver tumors. They reported that the hepatectomies did not increase the tumor incidence. Among females fed Aroclor 1260, liver tumors developed in 4 of 7 animals with hepatectomies and 37 of 39 without hepatectomies; no liver tumors developed in controls or males with hepatectomies. Moore et al. (1994) reevaluated the preceding rat liver findings (Kimbrough et al., 1975; NCI, 1978; Schaeffer et al., 1984; Norback and Weltman, 1985) using criteria and nomenclature that had changed to reflect new understanding of mechanisms of toxicity and carcinogenesis. The reevaluation found somewhat fewer tumors than did the original investigators. The apparent increase for Clophen A 30 (Schaeffer et al., 1984) is no longer statistically significant. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Several studies of less-than-lifetime exposure are supportive of a carcinogenic response (Kimbrough et al., 1972; Kimbrough and Linder, 1974; Kimura and Baba, 1973; Ito et al., 1973, 1974; Rao and Banerji, 1988). PCBs give generally negative results in tests of genetic activity (ATSDR, 1993), implying that PCBs induce tumors primarily through modes of action that do not involve gene mutation. Initiation-promotion studies for several commercial PCB mixtures and congeners show tumor promoting activity in liver and lung; these studies are beginning to identify a subset of mixture components that may be significant contributors to cancer induction (Silberhorn et al., 1990). Toxicity of some PCB congeners is correlated with induction of mixed-function oxidases; some congeners are phenobarbital-type inducers, others are 3-methylcholanthrene-type inducers, and some have mixed inducing properties (McFarland and Clarke, 1989). The latter two groups most resemble 2,3,7,8-tetrachlorodibenzo-p-dioxin in structure and toxicity. Studies of structurally related agents: Studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin and a polybrominated biphenyl (PBB) mixture are summarized here because the pattern of tumors found by Brunner et al. (1996) mimics the tumors induced in rats by these structurally related agents. The National Toxicology Program (NTP, 1982) exposed groups of 50 male or female Osborne-Mendel rats by gavage to 0, 1.4, 7.1, or 71 ng/kg-day 2,3,7,8-tetrachlorodibenzo-p-dioxin for 2 years. Similar to the Brunner et al. (1996) study, liver tumors were increased in female rats and thyroid gland follicular cell tumors were increased in male rats. Mammary tumors were not, however, decreased in dosed female rats. In another study, NTP (1983) exposed groups of 51 male or female Fischer 344/N rats by gavage to 0, 0.1, 0.3, 1, 3, or 10 mg/kg-day of a PBB mixture ("Firemaster FF 1") for 6 months, then exposure was discontinued for 23 months before the animals were killed. Statistically significant increased incidences of liver tumors were found in male and female rats. Dose-related increased incidences of cholangiocarcinomas were found in male and female rats. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- See text Drinking Water Unit Risk -- See text Extrapolation Method -- Linear extrapolation below LED10s (U.S. EPA, 1996b) Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) See text E-5 (1 in 100,000) See text E-6 (1 in 1,000,000) See text DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- Liver hepatocellular adenomas, carcinomas, cholangiomas, or cholangiocarcinomas Test Animals -- Female Sprague-Dawley rats Route -- Diet Reference -- Brunner et al., 1996; Norback and Weltman, 1985 Administered Human Equivalent Tumor Dose (ppm) Dose (mg/kg)/day Incidence ------------ ---------------- --------- Aroclor 1260 0 0 1/85 25 0.35 10/49 50 0.72 11/45 100 1.52 24/50 Aroclor 1254 0 0 1/85 25 0.36 19/45 50 0.76 28/49 100 1.59 28/49 Aroclor 1242 0 0 1/85 50 0.75 11/49 100 1.53 15/45 Aroclor 1016 0 0 1/85 50 0.72 1/48 100 1.43 7/45 200 2.99 6/50 Aroclor 1260 (Norback and Weltman, 1985) 0 0.75 1/45 100/50/0 1.3 41/46 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The cancer potency of PCB mixtures is determined using a tiered approach that depends on the information available. The following tier descriptions discuss all environmental exposure routes: TIERS OF HUMAN SLOPE FACTORS FOR ENVIRONMENTAL PCBs HIGH RISK AND PERSISTENCE Upper-bound slope factor: 2.0 per (mg/kg)/day Central-estimate slope factor: 1.0 per (mg/kg)/day Criteria for use: - Food chain exposure - Sediment or soil ingestion - Dust or aerosol inhalation - Dermal exposure, if an absorption factor has been applied - Presence of dioxin-like, tumor-promoting, or persistent congeners - Early-life exposure (all pathways and mixtures) LOW RISK AND PERSISTENCE Upper-bound slope factor: 0.4 per (mg/kg)/day Central-estimate slope factor: 0.3 per (mg/kg)/day Criteria for use: - Ingestion of water-soluble congeners - Inhalation of evaporated congeners - Dermal exposure, if no absorption factor has been applied LOWEST RISK AND PERSISTENCE Upper-bound slope factor: 0.07 per (mg/kg)/day Central-estimate slope factor: 0.04 per (mg/kg)/day Criteria for use: Congener or isomer analyses verify that congeners with more than 4 chlorines comprise less than 1/2% of total PCBs. Slope factors are multiplied by lifetime average daily doses to estimate the cancer risk. SAMPLE CALCULATIONS ARE GIVEN IN U.S. EPA (1996a). Although PCB exposures are often characterized in terms of Aroclors, this can be both imprecise and inappropriate. Total PCBs or congener or isomer analyses are recommended. When congener concentrations are available, the slope-factor approach can be supplemented by analysis of dioxin TEQs to evaluate dioxin-like toxicity. Risks from dioxin-like congeners (evaluated using dioxin TEQs) would be added to risks from the rest of the mixture (evaluated using slope factors applied to total PCBs reduced by the amount of dioxin-like congeners). SAMPLE CALCULATIONS ARE GIVEN IN U.S. EPA (1996a). Depending on the specific application, either central estimates or upper bounds can be appropriate. Central estimates describe a typical individual's risk, while upper bounds provide assurance that this risk is not likely to be underestimated if the underlying model is correct. The upper bounds calculated in this assessment reflect study design and provide no information about sensitive individuals or groups. Central estimates are useful for estimating aggregate risk across a population. Central estimates are used for comparing or ranking environmental hazards, while upper bounds provide information about the precision of the comparison or ranking. Some PCBs persist in the body and retain biological activity after exposure stops (Anderson et al., 1991a). Compared with the current default practice of assuming that less-than-lifetime effects are proportional to exposure duration, rats exposed to a persistent mixture (Aroclor 1260) had more tumors, while rats exposed to a less persistent mixture (Aroclor 1016) had fewer tumors (Brunner et al., 1996). Thus there may be greater-than-proportional effects from less-than-lifetime exposure, especially for persistent mixtures and for early-life exposures. Highly exposed populations include some nursing infants and consumers of game fish, game animals, or products of animals contaminated through the food chain. Highly sensitive populations include people with decreased liver function and infants (Calabrese and Sorenson, 1977). Because of the potential magnitude of early-life exposures (ATSDR, 1993; Dewailly et al., 1991, 1994), the possibility of greater perinatal sensitivity (Calabrese and Sorenson, 1977; Rao and Banerji, 1988), and the likelihood of interactions among thyroid and hormonal development, it is reasonable to conclude that early-life exposures may be associated with increased risks. Due to this potential for higher sensitivity early in life, the "high risk" tier is used for all early-life exposure. It is crucial to recognize that commercial PCBs tested in laboratory animals were not subject to prior selective retention of persistent congeners through the food chain (that is, the rats were fed Aroclor mixtures, not environmental mixtures that had been bioaccumulated). Bioaccumulated PCBs appear to be more toxic than commercial PCBs (Aulerich et al., 1986; Hornshaw et al., 1983) and appear to be more persistent in the body (Hovinga et al., 1992). For exposure through the food chain, risks can be higher than those estimated in this assessment. In calculating these estimates, administered doses were expressed as a lifetime daily average calculated from weekly body weight measurements and food consumption estimates (Keenan and Stickney, 1996). Doses were scaled from rats to humans using a factor based on the 3/4 power of relative body weight. UNIT RISK ESTIMATE AND DRINKING WATER CONCENTRATIONS For ingestion of water-soluble congeners, the middle-tier slope factor can be converted to a unit risk estimate and drinking water concentrations associated with specified risk levels. Upper-bound slope factor: 0.4 per (mg/kg)/day Upper-bound unit risk: 1 x 10-5 per ug/L Drinking water concentration associated with a risk of: 1 in 10,000 10 ug/L 1 in 100,000 1 ug/L 1 in 1,000,000 0.1 ug/L These estimates should not be used if drinking water concentrations exceed 1000 ug/L, since above this concentration the dose-response curve in the experimental range may provide better estimates. For food chain exposure or ingestion that includes contaminated sediment or soil, the slope factor for "high risk and persistence" should be used instead. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) Joint consideration of cancer studies and environmental processes leads to a conclusion that environmental PCB mixtures are highly likely to pose a risk of cancer to humans. Although environmental mixtures have not been tested in cancer assays, this conclusion is supported by several complementary sources of information. Statistically significant, dose-related, increased incidences of liver tumors were induced in female rats by Aroclors 1260, 1254, 1242, and 1016 (Brunner et al., 1996). These mixtures contain overlapping groups of congeners that, together, span the range of congeners most frequently found in environmental mixtures. Several congeners have dioxin-like activity (Safe, 1994) and may promote tumors by different modes of action (Silberhorn et al., 1990); these congeners are found in environmental samples and in a variety of organisms, including humans (McFarland and Clarke, 1989). The range of potency observed for commercial mixtures is used to represent the potency of environmental mixtures. The range reflects experimental uncertainty and variability of commercial mixtures, but not human heterogeneity or differences between commercial and environmental mixtures. Environmental processes alter mixtures through partitioning, transformation, and bioaccumulation, thereby decreasing or increasing toxicity. The overall effect can be considerable, and the range observed for commercial mixtures may underestimate the true range for environmental mixtures (Hutzinger et al., 1974; Callahan et al., 1979). Limiting the potency of environmental mixtures to the range observed for commercial mixtures reflects a decision to base potency estimates on experimental results, however uncertain, rather than apply safety factors to compensate for lack of information. A tiered approach allows use of different kinds of information in estimating the potency of environmental mixtures. When congener information is limited, exposure pathway is used to indicate whether environmental processes have decreased or increased a mixture's potency. Partitioning, transformation, and bioaccumulation have been extensively studied (Hutzinger et al., 1974; Callahan et al., 1979) and can be associated with exposure pathway, thus the use of exposure pathway to represent environmental processes increases confidence in the risks inferred for environmental mixtures. For example, evaporated or dissolved congeners tend to be lower in chlorine content than the original mixture; they tend also to be more inclined to metabolism and elimination and lower in persistence and toxicity. On the other hand, congeners adsorbed to sediment or soil tend to be higher in chlorine content and persistence, and bioaccumulated congeners ingested through the food chain tend to be highest of all. Rates of these processes vary over several orders of magnitude (Hutzinger et al., 1974; Callahan et al., 1979). When available, congener information is an important tool for refining a potency estimate that was based on exposure pathway. Extrapolation to environmental levels is based on models that are linear at low doses. Low-dose-linear models are appropriate when a carcinogen acts in concert with other exposures and processes that cause a background incidence of cancer (Crump et al, 1976; Lutz, 1990). Even when the mode of action indicates a nonlinear dose-response curve in homogeneous animal populations, the presence of genetic and lifestyle factors in a heterogeneous human population tends to make the dose-response curve more linear (Lutz, 1990). This is because genetic and lifestyle factors contribute to a wider spread of human sensitivity, which extends and straightens the dose-response curve over a wider range. Uncertainty around these estimates extends in both directions. The slope factor ranges primarily reflect mixture variability, and so are not necessarily appropriate for probabilistic analyses that attempt to describe model uncertainty and parameter uncertainty. Estimates based on animal studies benefit from controlled exposures and absence of confounding factors; however, there is uncertainty in extrapolating dose and response rates across species. Information is lacking to evaluate high-to-low-dose differences. PCBs are absorbed through ingestion, inhalation, and dermal exposure, after which they are transported similarly through the circulation (ATSDR, 1993). This provides a reasonable basis for expecting similar internal effects from different routes of environmental exposure. Information on relative absorption rates suggests that differences in toxicity across exposure routes are small. The principal uncertainty, though, is using commercial mixtures to make inferences about environmental mixtures. When exposure involves the food chain, uncertainty extends principally in one direction: through the food chain, living organisms selectively bioaccumulate persistent congeners, but commercial mixtures tested in laboratory animals were not subject to prior selective retention of persistent congeners. Bioaccumulated PCBs appear to be more toxic than commercial PCBs (Aulerich et al., 1986; Hornshaw et al., 1983) and appear to be more persistent in the body (Hovinga et al., 1992). For exposure through the food chain, risks can be higher than those estimated in this assessment. Two highly exposed populations, nursing infants and consumers of contaminated game animals, are exposed through the food chain. The dioxin-like nature of some PCBs raises a concern for cumulative exposure, as dioxin-like congeners add to background exposure of other dioxin-like compounds and augment processes associated with dioxin toxicity. This weighs against considering PCB exposure in isolation or as an increment to a background exposure of zero. Confidence in this assessment's use of low-dose-linear models is enhanced when there is additivity to background exposures and processes (Crump et al, 1976; Lutz, 1990). ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- See text Extrapolation Method -- Linear extrapolation below LED10s (U.S. EPA, 1996b) Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) See text E-5 (1 in 100,000) See text E-6 (1 in 1,000,000) See text DCIE: ___II.C.2. DOSE-RESPONSE DATA (CARCINOGENICITY, INHALATION EXPOSURE) See Dose-Response Data for oral exposure. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) See Additional Comments for oral exposure. For inhalation of evaporated congeners, the middle-tier slope factor can be converted to a unit risk estimate and ambient air concentrations associated with specified risk levels. Upper-bound slope factor: 0.4 per (mg/kg)/day Upper-bound unit risk: 1 x 10-4 per ug/cu.m Ambient air concentration associated with a risk of: 1 in 10,000 1 ug/cu.m 1 in 100,000 0.1 ug/cu.m 1 in 1,000,000 0.01 ug/cu.m These estimates should not be used if ambient air concentrations exceed 100 ug/cu.m, since above this concentration the dose-response curve in the experimental range may provide better estimates. For inhalation of an aerosol or dust contaminated with PCBs, the slope factor for "high risk and persistence" should be used instead. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) See Discussion of Confidence for oral exposure. Information on relative absorption rates suggests that differences in toxicity across exposure routes are small. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1996a [Available from the Risk Information Hotline, Cincinnati OH. Telephone: (301)345-2870; FAX (301)345-2876)]. The source document and IRIS summary were considered at a public, external peer review workshop in May 1996. A workshop report was written by the review panel (U.S. EPA, 1996c). All comments have been carefully evaluated and considered in this IRIS summary. A record of these comments is summarized in the IRIS documentation files. Other EPA Documentation -- U.S. EPA, 1988 RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 08/22/1996 Verification Date -- 08/22/1996 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199611 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Polychlorinated biphenyls (PCBs) CASRN -- 1336-36-3 Last Revised -- 11/01/1996 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Amano, M., K. Yagi, H. Nakajima, R. Takehara, H. Sakai and G. Umeda. 1984. Statistical observations about the causes of the death of patients with oil poisoning. Japan Hygiene. 39(1): 1-5. Anderson, L.M., S.D. Fox, D. Dixon, L.E. Beebe and H.J. Issaq. 1991. Long-term persistence of polychlorinated biphenyl congeners in blood and liver and elevation of liver aminopyrine demethylase activity after a single high dose of Aroclor 1254 to mice. Environ. Toxicol. Chem. 10: 681 690. ATSDR (Agency for Toxic Substances and Disease Registry). 1993. Toxicological profile for polychlorinated biphenyls. ATSDR, Atlanta, GA. TP 92/16, update. Aulerich, R.J., R.K. Ringer and J. Safronoff. 1986. Assessment of primary vs. secondary toxicity of Aroclor 1254 to mink. Arch. Environ. Contam. Toxicol. 15: 393 399. Bahn, A.K., I. Rosenwaike, N. Herrmann, P. Grover, J. Stellman and K. O'Leary. 1976. Melanoma after exposure to PCB's. New Engl. J. Med. 295: 450. Bahn, A.K., P. Grover, I. Rosenwaike, K. O'Leary and J. Stellman. 1977. Reply to letter from C. Lawrence entitled, "PCB? and melanoma". New Eng. J. Med. 296: 108. Bertazzi, P.A., L. Riboldi, A. Pesatori, L. Radice and C. Zocchetti. 1987. Cancer mortality of capacitor manufacturing workers. Am. J. Ind. Med. 11(2): 165-176. Brown, D.P. 1987. Mortality of workers exposed to polychlorinated biphenyls -An update. Arch. Environ. Health. 42(6): 333-339. Brown, D.P. and M. Jones. 1981. Mortality and industrial hygiene study of workers exposed to polychlorinated biphenyls. Arch. Environ. Health. 36(3): 120-129. Brunner, M.J., T.M. Sullivan, A.W. Singer, et. al. 1996. An assessment of the chronic toxicity and oncogenicity of Aroclor-1016, Aroclor-1242, Aroclor-1254, and Aroclor-1260 administered in diet to rats. Study No. SC920192. Chronic toxicity and oncogenicity report. Battelle, Columbus OH. Calabrese, E.J. and A.J. Sorenson. 1977. The health effects of PCBs with particular emphasis on human high risk groups. Rev. Environ. Health. 2: 285-304. Callahan, M.A., M.W. Slimak, N.W. Gabel, et al. 1979. Water-related environmental fate of 129 priority pollutants, Vol. I, Ch. 36. U.S. EPA, Washington, DC. EPA 440/4 79 029a. Crump, K.S., D.G. Hoel, C.H. Langley and R. Peto. 1976. Fundamental carcinogenic processes and their implications for low dose risk assessment. Cancer Res. 36: 2973-2979. Dewailly, E., J.-P. Weber, S. Gingras and C. Laliberte. 1991. Coplanar PCBs in human milk in the province of Quebec, Canada: Are they more toxic than dioxin for breast fed infants? Bull. Environ. Contam. Toxicol. 47: 491-498. Dewailly, E., J.J. Ryan, C. Laliberte, et al. 1994. Exposure of remote maritime populations to coplanar PCBs. Environ. Health Perspect. 102(Suppl. 1): 205-209. Gustavsson, P., C. Hogstedt and C. Rappe. 1986. Short-term mortality and cancer incidence in capacitor manufacturing workers exposed to polychlorinated biphenyls (PCBs). Am. J. Ind. Med. 10: 341-344. Hornshaw, T.C., R.J. Aulerich and H.E. Johnson. 1983. Feeding Great Lakes fish to mink: Effects on mink and accumulation and elimination of PCBs by mink. J. Toxicol. Environ. Health. 11: 933-946. Hovinga, M.E., M. Sowers and H.E.B. Humphrey. 1992. Historical changes in serum PCB and DDT levels in an environmentally-exposed cohort. Arch. Environ. Contam. Toxicol. 22: 362-366. Hutzinger, O., S. Safe and V. Zitko. 1974. The chemistry of PCB's. CRC Press, Boca Raton, FL. Ito, N., H. Nagasaki, M. Arai, S. Makiura, S. Sugihara and K. Hirao. 1973. Histopathologic studies on liver tumorigenesis induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors induced by benzene hexachloride. J. Natl. Cancer Inst. 51(5): 1637-1646. Ito, N., H. Nagasaki, S. Makiura and M. Arai. 1974. Histopathological studies on liver tumorigenesis in rats treated with polychlorinated biphenyls. Gann. 65: 545-549. Keenan, R.E. and J.A. Stickney. 1996. ChemRisk, Portland, ME. Letter to J. Cogliano, U.S. EPA, Washington, DC. June 24. Kimbrough, R.D. and R.E. Linder. 1974. Induction of adenofibrosis and hepatomas in the liver of BALB/cJ mice by polychlorinated biphenyls (Aroclor 1254). J. Natl. Cancer Inst. 53(2): 547-552. Kimbrough, R.D., R.E. Linder and T.B. Gaines. 1972. Morphological changes in livers of rats fed polychlorinated biphenyls: Light microscopy and ultrastructure. Arch. Environ. Health. 25: 354-364. Kimbrough, R.D., R.A. Squire, R.E. Linder, J.D. Strandberg, R.J. Montali and V.W. Burse. 1975. Induction of liver tumors in Sherman strain female rats by polychlorinated biphenyl Aroclor 1260. J. Natl. Cancer Inst. 55(6): 1453-1459. Kimura, N.T. and T. Baba. 1973. Neoplastic changes in the rat liver induced by polychlorinated biphenyl. Gann. 64: 105-108. Lutz, W.K. 1990. Dose-response relationship and low dose extrapolation in chemical carcinogenesis. Carcinogenesis. 11(8): 1243-1247. McFarland, V.A. and J.U. Clarke. 1989. Environmental occurrence, abundance, and potential toxicity of polychlorinated biphenyl congeners: Considerations for a congener-specific analysis. Environ. Health Perspect. 81: 225-239. Moore, J.A., J.F. Hardisty, D.A. Banas and M.A. Smith. 1994. A comparison of liver tumor diagnoses from seven PCB studies in rats. Reg. Toxicol. Pharmacol. 20: 362-370. Morgan, R.W., J.M. Ward and P.E. Hartman. 1981. Aroclor 1254-induced intestinal metaplasia and adenocarcinoma in the glandular stomach of F344 rats. Cancer Res. 41: 5052-5059. NTP (National Toxicology Program). 1982. Carcinogenesis bioassay of 2,3,7,8-tetrachlorodibenzo-p-dioxin (CAS no. 1746 01 6) in Osborne-Mendel rats and B6C3F1 mice (gavage study). NTP Tech. Rep. Ser. No. 209. Research Triangle Park, NC. NTP (National Toxicology Program). 1983. Carcinogenesis studies of polybrominated biphenyl mixture (Firemaster FF 1) (CAS no. 67774 32 7) in F344/N rats and B6C3F1 mice (gavage studies). NTP Tech. Rep. Ser. No. 244. Research Triangle Park, NC. NCI (National Cancer Institute). 1978. Bioassay of Aroclor 1254 for possible carcinogenicity. Carcinogenesis Tech. Rep. Ser. No. 38. NIOSH (National Institute for Occupational Safety and Health). 1977. Criteria for a Recommended Standard . . . Occupational Exposure to Polychlorinated Biphenyls (PCBs). U.S. DHEW, PHS, CDC, Rockville, Md. Publ. No. 77-225. Norback, D.H. and R.H. Weltman. 1985. Polychlorinated biphenyl induction of hepatocellular carcinoma in the Sprague-Dawley rat. Environ. Health Perspect. 60: 97-105. Rao, C.V. and A.S. Banerji. 1988. Induction of liver tumors in male Wistar rats by feeding polychlorinated biphenyls (Aroclor 1260). Cancer Lett. 39: 59-67. Safe, S. 1994. Polychlorinated biphenyls (PCBs): Environmental impact, biochemical and toxic responses, and implications for risk assessment. Crit. Rev. Toxicol. 24(2): 87-149. Schaeffer, E., H. Greim and W. Goessner. 1984. Pathology of chronic polychlorinated biphenyl (PCB) feeding in rats. Toxicol. Appl. Pharmacol. 75: 278-288. Shalat, S.L., L.D. True, L.E. Fleming and P.E. Pace. 1989. Kidney cancer in utility workers exposed to polychlorinated biphenyls (PCBs). Br. J. Ind. Med. 46(11): 823-824. Silberhorn, E.M., H.P. Glauert and L.W. Robertson. 1990. Carcinogenicity of polyhalogenated biphenyls: PCBs and PBBs. Crit. Rev. Toxicol. 20(6): 439-496. Sinks, T., G. Steele, A.B. Smith, K. Watkins and R.A. Shults. 1992. Mortality among workers exposed to polychlorinated biphenyls. Am. J. Epidemiol. 136(4): 389-398. U.S. EPA. 1988. Drinking Water Criteria Document for Polychlorinated Biphenyls (PCBs). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. U.S. EPA, 1996a. PCBs: Cancer Dose-Response Assessment and Application to Environmental Mixtures. Prepared by the National Center for Environmental Assessment, Washington DC. U.S. EPA. 1996b. Proposed Guidelines for Carcinogen Risk Assessment; notice. Fed. Reg. 61(79): 17960-18011. U.S. EPA. 1996c. Report on peer review workshop on "PCBs: Cancer-dose response assessment and application to environmental mixtures." National Center for Environmental Assessment, Washington, DC. Vater, S.T., S.F. Velazquez and V.J. Cogliano. 1995. A case study of cancer data set combinations for PCBs. Reg. Toxicol. Pharmacol. 22: 2-10. Ward, J.M. 1985. Proliferative lesions of the glandular stomach and liver in F344 rats fed diets containing Aroclor 1254. Environ. Health Perspect. 60: 89-95. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Polychlorinated biphenyls (PCBs) CASRN -- 1336-36-3 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 05/01/1989 II. Carcinogen summary on-line 01/01/1990 II. Text edited 01/01/1990 VI. Bibliography on-line 01/01/1992 IV. Regulatory Action section on-line 06/01/1994 I.A. Message only 01/01/1996 II. Note added to assessment 10/01/1996 II. File replaced; cancer potency of mixtures addressed 11/01/1996 VI.C. References revised 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 06/01/1997 II.C.3. Units corrected in Upper-bound Unit Risk 01/02/1998 I. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 406 of 1119 in IRIS (through 2003/06) AN: 304 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0304-tr.pdf UD: 200009 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Chloral-hydrate- SY: CHLORAL-MONOHYDRATE-; TRICHLOROACETALDEHYDE-HYDRATE-; TRICHLOROACETALDEHYDE-MONOHYDRATE-; 1,1,1-TRICHLORO-2,2-DIHYDROXYETHANE- RN: 302-17-0 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200009 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chloral hydrate CASRN -- 302-17-0 Last Revised -- 09/15/2000 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: This summary replaces the former summary on chloral (CAS # 75-87-6) dated 02/22/88. A new RfD has been derived based on different data. The name was changed from chloral because the chemical exists as the hydrated form in water. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ----------------------------------------- -- -- ------- CNS depression and NOAEL: None 100 1 0.1 mg/kg-day GI irritation in humans LOAEL: 10.7 mg/kg-day Goodman and Gilman, 1985 ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- The LOAEL is based on an exposure of 250 mg, three times a day, causing CNS depression (sedation) and GI irritation (nausea, vomiting), and on an average body weight of 70 kg. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Although the reference value of 0.1 mg/kg-day derived from the pharmacologically active dose in humans is an acute RfD, keeping the exposure below this level will also be protective for any noncancer health effect from chronic exposure. For example, chronic exposure to chloral hydrate does not cause adverse effects in the liver of rats or mice until the exposure approaches 135 or 160 mg/kg-day, respectively. Similarly, there are no reproductive, developmental, neurobehavioral, or immunological effects following long-term treatment of laboratory animals until the exposure approaches 160 mg/kg-day. Therefore, it is appropriate to use the acute RfD also as the chronic RfD. Chloral hydrate has been widely used as a sedative/hypnotic drug in humans. The recommended dose for an adult as a sedative is 250 mg, three times a day (equivalent to 10.7 mg/kg-day); the recommended dose as an hypnotic is 500-1,000 mg (equivalent to 7-14 mg/kg) (Goodman and Gilman, 1985). The recommended dose for a child as a sedative is 9 mg/kg, three times a day, to 25 mg/kg in single dose (Hindmarsh et al., 1991). The recommended dose for a child undergoing a medical or dental procedure is 50 to 100 mg/kg (Badalaty et al., 1990; Fox et al., 1990). A child is typically given a higher dose than an adult because a deeper level of sedation is desired to obtain better cooperation from the child during the medical or dental procedure. There is no evidence that a child is less sensitive than an adult to the sedative effects of chloral hydrate. Because of the rapid metabolism of chloral hydrate, trichloroethanol is responsible for the majority of the pharmacological activity (Marshall and Owens, 1954; Breimer, 1977; Goodman and Gilman, 1985). The concentration of trichloroethanol in the plasma in the pharmacologically active range is approximately 5 mg/L and above and in the toxic range is 100 mg/L and above. Chloral hydrate is irritating to the skin and mucous membranes and often causes gastric distress (nausea and vomiting) at recommended doses. There are no reports of sensitization in humans. Overdoses produce (in order of progression) ataxia, lethargy, deep coma, respiratory depression, hypotension, and cardiac arrhythmias. The life-threatening effects are from severe respiratory depression, hypotension, and cardiac arrhythmias. For some representative case reports, see Anyebuno and Rosenfeld (1991), Ludwigs et al. (1996), Marshall (1977), and Sing et al. (1996). A potentially life-threatening oral dose for humans is approximately 10 g (143 mg/kg), although death has been reported from as little as 4 g, and some individuals have survived ingesting 30 g or more. Extended abuse of chloral hydrate may result in development of paranoid behavior, in tolerance to the pharmacological effect, and in physical dependence or addiction. Sudden withdrawal after habituation can precipitate seizure, delirium, and death in untreated individuals. Shapiro et al. (1969) reviewed the medical records of 1,618 patients who had received chloral hydrate at 1 g (213 patients, 13%), 0.5 g (1345 patients, 83%), or various other doses (60 patients, 4%). Adverse reactions were reported in 38 patients (2.3%). Of these patients, four received 1 g, one received 0.75 g, and 33 received 0.5 g. Reported adverse reactions included gastrointestinal symptoms in 10 patients, depression of the central nervous system (CNS) in 20 patients, skin rash in 5 patients, prolonged prothrombin time in 1 patient, and bradycardia in 1 patient. In all patients the side effects disappeared when chloral hydrate therapy was stopped. There was no evidence of association between adverse side effects and age, weight, or sex. Miller and Greenblatt (1979) reviewed medical records of 5,435 hospital patients who received chloral hydrate at a dose of either 0.5 g (about 7 to 8 mg/kg) or 1 g (about 14 to 16 mg/kg). Adverse reactions were noted in 119 cases (2.2%). CNS depression was most common (58 patients, or 1.1%), with minor sensitivity reactions, including rash, pruritus, fever, and eosinophilia, second most common (19 patients, or 0.35%). Other adverse reactions included gastrointestinal disturbances (0.28%) and CNS excitement (0.22%). Three individuals (0.05%) were judged to have life-threatening reactions involving CNS depression, asterixis (flapping tremor characterized by an intermittent lapse of assumed posture due to involuntary sustained contractions of groups of muscles), or hypotension. The data show that adverse reactions involving the CNS became more frequent with increasing dosage in patients older than 50 years, in patients who died during hospitalization, in patients who received concurrently benzodiazepine antianxiety drugs, and in patients with elevated levels of blood urea nitrogen. Greenberg et al. (1991) reported various side effects experienced by children receiving chloral hydrate sedation in preparation for computer tomography (CT) procedures. In a "high-dose" group, composed of 295 children (average age 2.18 years) that received a single dose of 80 to 100 mg/kg and a maximum total dose of 2 g, adverse reactions occurred in 23 of the patients (7%) and included vomiting (14 patients), hyperactivity (5 patients), and respiratory symptoms such as wheezing and secretion aspiration (4 patients). Cardiac monitoring did not reveal any abnormalities or arrhythmias in any of the children. A second "lower-dose" cohort of 111 children (average age 1.9 years) received 40 to 75 mg/kg chloral hydrate. These patients received the lower dose because of existing liver or renal impairment, respiratory insufficiency, or CNS depression. There were no adverse side effects or complications reported in this group. Children with severe liver or renal disease or affected by severe CNS depression were not treated with chloral hydrate. Lambert et al. (1990) conducted a retrospective analysis of hospital medical records to investigate a possible link between chloral hydrate administration and direct hyperbilirubinemia (DHB), an increase in the concentration of unconjugated bilirubin in the serum, in neonates following prolonged administration of chloral hydrate (25 to 50 mg/kg administered for up to 20 days). In the first study, the DHB was of unknown etiology in 10 of the 14 newborns with DHB; all 10 of these DHB patients had received chloral hydrate. In the second study, among 44 newborns who had received chloral hydrate, 10 patients that developed DHB had received a mean cumulative dose of 1,035 mg/kg. In contrast, 34 patients whose direct bilirubin levels were within normal ranges received a mean cumulative dose of 183 mg/kg. As the total bilirubin levels (free plus conjugated bilirubin) were the same in both groups and within the normal range, the increased direct bilirubin could result from competition between trichloroethanol and bilirubin in the glucuronidation pathway, known to function suboptimally in neonates. Kaplan et al. (1967) investigated whether ethanol ingestion altered the metabolism of chloral hydrate or increased subjective symptoms. Five male volunteers weighing 70 to 107 kg consumed ethanol (880 mg/kg), chloral hydrate (1 g, 9 to 14 mg/kg), or both. Blood pressure and cardiac rate did not vary significantly among treatments. In the presence of ethanol, the concentration of trichloroethanol in the blood rose more rapidly and reached a higher concentration, but the rate of depletion was not significantly changed. The increase in the concentration of trichloroethanol was not sufficient to produce a marked enhancement of the hypnotic effect. The volunteers reported symptoms (drowsiness, dizziness, blurred vision) and their severity during the 6-hour observation period. At all time points, the rank order of effects was: ethanol plus chloral hydrate > ethanol > chloral hydrate. No long-term studies of chloral hydrate in humans were located in the published literature. Chloral hydrate is addictive and is a controlled substance (Schedule IV) in the United States. The effect that occurs at the lowest exposure is CNS depression and gastrointestinal irritation in humans. As these effects would not be intended or desirable in the general population, EPA considers these responses as adverse effects and are used to derive the reference dose. Acute gavage exposure in mice shows neurological effects (ataxia) at about the same exposure for the comparable effect in humans. A subchronic study in mice using sensitive tests for neurobehavioral changes found none. Chronic studies in rats and mice show no evidence of neurobehavioral changes and no evidence of histopathological changes in nervous tissue. As with other chlorinated chemicals, there is some evidence of hepatotoxicity in rodent liver following chronic oral exposure. These effects are of minimal severity, may be related to precancerous lesions, and occur at an exposure greater than that required for CNS depression and gastrointestinal irritation following an acute bolus dose. No data are available to determine a NOAEL in humans. The recommended clinical dose for sedation in adults is 250 mg, taken 3 times a day (Goodman and Gilman, 1985). The LOAEL is 10.7 mg/kg-day (assuming a 70 kg body weight). The pharmacokinetic information shows that chloral hydrate and the pharmacologically active metabolite, trichloroethanol, will not bioaccumulate. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100. An uncertainty factor of 10 was used to extrapolate from a LOAEL to NOAEL. An uncertainty factor of 10 was used for intraspecies variability. An uncertainty factor for chronic duration is not used. Chloral hydrate and the active metabolite, trichloroethanol, do not bioaccumulate. Therefore, continuous daily exposure to chloral hydrate at the reference dose will not result in a concentration of trichloroethanol in the blood required for the pharmacological effect. Developmental toxicity, including developmental neurotoxicity, and immunotoxicity are not critical effects. Although there is no two-generation reproduction study, an uncertainty factor for database limitations is not needed, as there is evidence from several studies that reproductive toxicity is not likely to be a critical effect. Although the reference value derived from the pharmacologically active dose in humans is an acute RfD, keeping the exposure below this level will also be protective for any noncancer health effect from chronic exposure. For example, chronic exposure to chloral hydrate does not cause adverse effects in the liver of rats or mice until the exposure approaches 135 or 160 mg/kg-day, respectively. Similarly, there are no reproductive, developmental, neurobehavioral, or immunological effects following long-term treatment of laboratory animals until exposure approaches 160 mg/kg-day. Therefore, it is appropriate to use the acute RfD also as the chronic RfD. Simultaneous ingestion of ethanol and chloral hydrate increases the sedative and side-effects of chloral hydrate. The mechanism is the increase in the concentration of the pharmacologically active metabolite, trichloroethanol, in the presence of ethanol. Chronic abusers of ethanol are, therefore, somewhat more sensitive to the adverse effects of chloral hydrate. Because of the immaturity of hepatic metabolism, particularly the glucuronidation pathway, and decreased glomerular filtration, the half-life of trichloroethanol is longer in infants (pre-term and full term) than in adults. The half-life of trichloroethanol in toddlers and adults is similar. Because of the longer half-life of trichloroethanol, pre-term and full term infants will experience prolonged effects when chloral hydrate is administered. However, at the reference dose for chloral hydrate, the steady-state concentration of trichloroethanol in these groups is far below the concentration required for the pharmacological effect. Although male laboratory rodents seem to be more sensitive than female laboratory rodents to hepatic effects, there is no evidence of a gender effect in humans to the sedative or side-effects of chloral hydrate at the recommended clinical dose. MF = 1 ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) Metabolism and Toxicokinetics Chloral hydrate is completely absorbed following oral administration. Qualitatively similar metabolism occurs in mice, rats, dogs, Japanese Medaka, and humans (Abbas et al., 1996; Abbas and Fisher, 1997; Beland et al., 1998; Breimer, 1977; Elfarra et al., 1998; Fisher et al., 1998; Goodman and Gilman, 1985; Gorecki et al., 1990; Gosselin et al., 1981; Greenberg et al., 1999; Henderson et al., 1997; Hindmarsh et al., 1991; Hobara et al., 1986, 1987a,b, 1988a,b; Lipscomb et al., 1996, 1998; Marshall and Owens, 1954; Mayers et al., 1991; Merdink et al., 1998, 1999; Owens and Marshall, 1955; Reimche et al., 1989; Stenner et al., 1997, 1998). Chloral hydrate is rapidly metabolized in both hepatic and extrahepatic tissues to trichloroethanol and trichloroacetic acid. The alcohol dehydrogenase responsible for reducing it to trichloroethanol is located in both liver and erythrocytes. A portion of the trichloroethanol produced is conjugated with glucuronic acid to form trichloroethanol-ß-glucuronide, which is excreted in the urine. A portion of the trichloroethanol-glucuronide is secreted into the bile and is subject to enterohepatic circulation. Oxidation of chloral hydrate to trichloracetic acid occurs primarily in the liver and kidney via an aldehyde dehydrogenase using nicotinamide adenine dinucleotide (NAD) as a cofactor. The major route of excretion of the metabolites of chloral hydrate is the urine. Chloral hydrate and its metabolites have been found in milk (Bernstine et al., 1956). As soon as lactation started, mothers (n=50) were treated with a 1.33 g rectal suppository of chloral hydrate. Samples of maternal blood and breast milk were taken for analysis from 15 minutes and at varying intervals up to 24 hours following administration of the drug. The maximum concentration of the sum of chloral hydrate, trichloroethanol, and trichloroethanol-glucuronide (the potential pharmacologically active species) in milk occurred within 1 hour after administration of the drug and averaged 53 mg/L (n=11). The amount of chloral hydrate required for sedation in infants is 10 mg in a single feeding of 100 mL of milk. In mice and rats, 8% of the administered dose of chloral hydrate is directly eliminated in urine, 15% is converted to trichloroacetic acid (including the contribution from enterohepatic circulation), and 77% is converted to trichloroethanol (Beland et al., 1998). In humans 92% of the administered dose of chloral hydrate is converted to trichloroethanol and 8% is converted directly to trichloroacetic acid; additional trichloroacetic acid is formed during enterohepatic circulation of trichloroethanol such that 35% of the initial dose of chloral hydrate is converted to trichloroacetic acid (Allen and Fisher, 1993). Although earlier reports claimed the detection of substantial quantities of dichloroacetic acid in blood from studies in rodents (Abbas et al., 1996), data show that the dichloroacetic acid is most likely formed by an acid-catalyzed dechlorination of trichloroacetic acid in the presence of reduced hemoglobin (Ketcha et al., 1996). Recent experimental data and pharmacokinetic model simulations in rodents suggest that dichloroacetic acid occurs only as a short-lived metabolite in the liver and is rapidly converted to two-carbon, nonchlorinated metabolites and carbon dioxide (Merdink et al., 1998). Using a different extraction procedure less likely to induce the artifactual formation of dichloroacetic acid, Henderson et al. (1997) showed the presence of dichloroacetic acid in children treated with chloral hydrate in a clinic. Breimer (1977) administered an aqueous solution of chloral hydrate to five human volunteers. Each volunteer received a single oral dose of 15 mg/kg. Chloral hydrate could not be detected in the plasma even at the first sampling time of 10 minutes. A method with a limit of detection of 0.5 mg/L was used. Trichloroethanol and trichloroethanol-glucuronide reached peak concentrations 20 to 60 minutes after administration of chloral hydrate. The maximum concentration of trichloroethanol in the plasma was about 5 mg/L. The average half-lives of trichloroethanol and trichloroethanol-glucuronide were 8 hours (range 7-9.5 hours) and 6.7 hours (range 6-8 hours), respectively. The half-life of trichloroacetic acid was about 4 days. Zimmermann et al. (1998) administered a single dose of 250 mg chloral hydrate in 150 mL of drinking water to 18 healthy male volunteers (20 to 28 years of age). Chloral hydrate, trichloroethanol, and trichloroacetic acid were measured in plasma. Chloral hydrate could only be detected 8 to 60 minutes after dosing in 15 of 18 plasma samples. The measured concentration of chloral hydrate in plasma ranged from 0.1 mg/L (the limit of detection) to 1 mg/L. The mean maximum plasma concentration of trichloroethanol of 3 mg/L was achieved 0.67 hours after dosing. The mean maximum plasma concentration of trichloroacetic acid of 8 mg/L was achieved 32 hours after dosing. The terminal half-life for trichloroethanol was 9.3 to 10.2 hours and for trichloroacetic acid was 89 to 94 hours. Two toxicokinetic models for chloral hydrate in rats and mice are available (Abbas et al., 1996; Beland et al., 1998). Beland et al. (1998) treated rats and mice with chloral hydrate by gavage with one or 12 doses using 50 or 200 mg/kg per dose. The maximum concentrations of chloral hydrate, trichloroethanol, and trichloroethanol-glucuronide in the plasma were observed at the initial sampling time of 0.25 hour. The half-life of chloral hydrate in the plasma was approximately 3 minutes. The half-lives of trichloroethanol and trichloroethanol-glucuronide in the mouse plasma were approximately 5 and 7 minutes, respectively. Trichloroacetic acid was the major metabolite found in the mouse plasma, with the maximum concentration being reached 1-6 hours after dosing. The half-life of trichloroacetic acid in the mouse plasma was approximately 8-11 hours. Comparable values were obtained for rats. Several studies have investigated the age-dependence of the metabolism of chloral hydrate (Gorecki et al., 1990; Hindmarsh et al., 1991; Mayers et al., 1991; Reimche et al., 1989). These studies were conducted in critically ill patients in neonatal and pediatric intensive care units and may not be representative of a population of healthy infants. The half-lives for trichloroethanol and its glucuronide were increased fourfold in preterm and threefold in full-term infants. The half-life for trichloroethanol in toddlers was similar to that reported for adults. The reported half-lives for elimination of trichloroethanol were 39.8 hours, 27.8 hours, and 9.67 hours for pre-term infants, full-term infants, and toddlers, respectively (Mayers et al., 1991), compared with 7-9.5 hours reported by Breimer (1977) and 9.3-10.2 hours reported by Zimmermann et al. (1998). These age-related differences likely are the result of the immaturity of hepatic metabolism, particularly glucuronidation, and decreased glomerular filtration. Kaplan et al. (1967) investigated the effect of ethanol consumption on the metabolism of chloral hydrate in adults. Subjects ingested doses of ethanol (880 mg/kg), chloral hydrate (9 to 14 mg/kg), or both. In subjects consuming both ethanol and chloral hydrate, the concentration of trichloroethanol in blood rose more rapidly and reached a higher concentration than in subjects consuming chloral hydrate only. Ethanol promotes the formation of trichloroethanol because the oxidation of ethanol provides NADH used for the reduction of chloral hydrate (Watanabe et al., 1998). Chronic Bioassays Daniel et al. (1992a) exposed 40 male B6C3F1 mice for 104 weeks to drinking water containing chloral hydrate at 1 g/L (equivalent to 166 mg/kg-day). Untreated control animals (23 in one group and 10 in a second group) received distilled water. Interim sacrifices were conducted at 30 and 60 weeks of exposure (5 animals per group at each sacrifice interval). Complete necropsy and microscopic examination were performed. There were no significant treatment-related effects on survival or body weight. With the exception of changes in the liver, there were no changes in organ weight (spleen, kidneys, or testes) or histopathological changes in any tissues. The toxicity in the liver was characterized by increased absolute liver weight and liver-to-body weight ratio at all three sacrifice intervals. At week 104, liver weight was 37% higher than controls, and liver-to-body weight ratio was 42% higher than controls. Hepatocellular necrosis was noted in 10/24 (42%) treated animals; other pathological changes of mild severity reported in the livers of treated animals included cytoplasmic vacuolization, cytomegaly, and cytoplasmic alteration. This study shows a LOAEL at 166 mg/kg-day (the only exposure tested). George et al. (2000) conducted a chronic bioassay for carcinogenicity in male B6C3F1 mice. Mice were administered chloral hydrate in drinking water for 104 weeks. Mice (72 in each group) had a mean exposure of 0, 13.5, 65, or 146.6 mg/kg-day. At the termination of the study, a complete necropsy and histopathological examination of liver, kidney, spleen, and testes from all animals was conducted. In addition a complete histopathological examination was conducted on five animals from the high-dose group. There was no change in water consumption, survival, behavior, body weight, or organ weights (liver, kidney, spleen, and testes) at any exposure. There was no evidence of hepatocellular necrosis at any exposure and only minimal changes in the levels of serum enzymes. This study identifies a NOAEL for noncancer effects in male mice of 146.6 mg/kg-day (the highest exposure tested). NTP (2000a) conducted a chronic bioassay for carcinogenicity in female B6C3F1 mice. Mice were administered chloral hydrate by gavage in distilled water at 0, 25, 50, or 100 mg/kg 5 days a week for up to 2 years. The calculated exposures are 0, 17.9, 35.7, or 71.4 mg/kg-day. Additional groups were administered chloral hydrate by gavage for 3, 6, or 12 months and held without further dosing for the duration of the study (stop-exposure studies). There was no significant effect on survival, body weight, or organ weights at any exposure. The NOAEL in this study is 71.4 mg/kg-day (the highest exposure tested). NTP (2000b) conducted a chronic bioassay for carcinogenicity in male B6C3F1 mice. Groups of 120 male mice received chloral hydrate by gavage in distilled water at 0, 25, 50, or 100 mg/kg for up to 2 years. The calculated exposures are 0, 17.9, 35.7, or 71.4 mg/kg-day. At each exposure 60 mice received feed ad libitum; the other 60 mice received feed in measured daily amount calculated to maintain body weight on a previously computed idealized body weight curve. Twelve mice from each diet and dose group were evaluated after 15 months of exposure. The remaining 48 animals from each diet and dose group were evaluated at 2 years. Survival, body weight, organ weights, and serum enzymes in the dosed groups were comparable to the respective vehicle control. Following complete necropsy and histopathological examination, no non-neoplastic changes were found in any organ when compared to the respective vehicle control. The NOAEL for non-neoplastic effects in this study is 71.4 mg/kg-day (the highest exposure tested). Leuschner and Beuscher (1998) conducted a chronic bioassay in Sprague-Dawley rats. Chloral hydrate was administered in drinking water for 124 weeks (males) and 128 weeks (females). The rats (50 males and 50 females in each group) had an exposure of 15, 45, or 135 mg/kg-day. There was no effect on survival, appearance, behavior, body weight, food and water consumption, and organ weights. There was no evidence of increased incidence of tumors in any organ. Histopathological examination revealed an increased incidence of hepatocellular hypertrophy at the highest exposure in males only (11% in controls versus 28% at the highest exposure, p< 0.01 ). This finding, graded as minimal to slight in severity, was characterized by a diffuse liver cell enlargement with slightly eosinophilic cytoplasm and was considered by the authors as a first sign of toxicity. The type, incidence, and severity or other non-neoplastic lesions were not increased in treated animals compared to controls. Based on the evidence of minimal toxicity in the liver, which is of doubtful biological significance, this study establishes a NOAEL of 45 mg/kg-day and a LOAEL of 135 mg/kg-day. George et al. (2000) conducted a chronic bioassay for carcinogenicity in male F344 rats. Rats were administered chloral hydrate in drinking water for 104 weeks. Rats (78 in each group) had a mean daily exposure of 0, 7.4, 37.4, or 162.6 mg/kg-day. At the termination of the study, a complete necropsy and histopathological examination of liver, kidney, spleen, and testes from all animals was conducted. In addition a complete histopathological examination was conducted on five animals from the high-dose group. There was no change in water consumption, survival, behavior, body weight, or organ weights (liver, kidney, spleen, and testes) at any exposure. There was no indication of liver toxicity at any exposure as shown by the lack of liver necrosis, hyperplasia, increased mitotic index, and only minimal changes in the levels of serum enzymes. The NOAEL in this study is 162.6 mg/kg-day (the highest exposure tested). Subchronic Bioassays Sanders et al. (1982) administered chloral hydrate in drinking water to CD-1 mice at 70 or 700 mg/L (equivalent to 16 mg/kg-day or 160 mg/kg-day) for 90 days. In males, hepatomegaly (an increase in weight of 20% and 34% at the low and high exposure, respectively) and microsome proliferation (increase in cytochrome b5 of 26% and 40%, increase in aminopyrine N-demethylase of 28% and 20%, and increase in aniline hydroxylase of 24% and 30% at the low and high exposure, respectively). There were no biologically significant changes in serum enzymes. Hepatomegaly was not seen in females, but there were changes in hepatic microsomal parameters (increase in total microsomal protein of 10%, increase in aniline hydroxylase of 23%, and decrease in cytochrome b5 of 12%) but only at the high exposure. No other significant toxicological changes were observed. Based on hepatomegaly and changes in microsomal parameters in males at the high exposure, this study identifies a LOAEL of 160 mg/kg-day and a NOAEL of 16 mg/kg-day. Daniel et al. (1992b) exposed male and female Sprague-Dawley rats (10/sex/dose) for 90 days to chloral hydrate in drinking water at a concentration of 300, 600, 1,200, or 2,400 mg/L (equivalent to 24, 48, 96, or 168 mg/kg-day in males and 33, 72, 132, or 288 mg/kg-day in females). The tissues of animals from the high-exposure group and liver sections from all treated males were examined histopathologically. No mortality occurred in any groups prior to sacrifice. Organ weights, including liver weight, and clinical chemistry values in treated animals were only sporadically or inconsistently different from control animal values. Focal hepatocellular necrosis was observed in 2 of 10 males in each of the groups exposed to 96 and 168 mg/kg-day. The necrotic lesion was minimal at 96 mg/kg-day and was significantly more severe at 168 mg/kg-day. Necrotic lesions were not reported in any treated females or in any control animals. While serum enzymes were generally increased in treated animals, dramatic increases were reported in males in the 168 mg/kg-day group; mean aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels in this group were elevated 89%, 54% and 127% above the corresponding control values, respectively. Based on the focal hepatocellular necrosis and accompanying serum enzyme changes, the study identifies a LOAEL of 168 mg/kg-day and a NOAEL of 96 mg/kg-day. The 96 mg/kg-day exposure is not considered a LOAEL because the authors reported only minimal microscopic necrosis, there was not a corresponding increase in serum enzymes, and because chronic exposure in Sprague-Dawley rats showed no necrosis at higher exposure (Leuschner and Beuscher, 1998; George et al., 2000). Reproductive/Developmental Studies Klinefelter et al. (1995) evaluated sperm morphology and motility in F344 rats administered chloral hydrate in drinking water for 52 weeks at 0, 55, or 188 mg/kg-day. The researchers examined cauda epididymal sperm motion parameters and testicular and epididymal histopathology. Chloral hydrate did not cause any visible systemic toxicity, and had no effects on epididymal or testicular histopathology. However, the percentage of motile sperm was significantly decreased (p<0.01) from 68% in controls to 58% in rats exposed to 188 mg/kg-day. The percentage of progressively motile sperm was also significantly decreased (p<0.01) from 63% in controls to 53% in this group. In addition, the frequency distribution of the average straight-line velocities of sperm at this exposure was significantly shifted (p<0.01) to the lower ranges when compared to controls. In this study the NOAEL is 55 mg/kg-day; the LOAEL is 188 mg/kg-day. Kallman et al. (1984) exposed male and female CD-1 mice to chloral hydrate in drinking water at 21.3 or 204.8 mg/kg-day. Animals were exposed for 3 weeks prior to breeding. Exposure of females (5 per group) continued during gestation and until pups were weaned at 21 days of age. There was no change in drinking water consumption or weight gain in the dams. No gross malformations were noted in pups, and no significant effects were observed in duration of gestation, number of pups delivered, pup weight, or number of stillborn pups. All pups (15 per group) showed the same rate of development and level of performance on several neurobehavioral tests, except that pups exposed to 204.8 mg/kg-day when tested at 23 days of age showed impaired retention of passive avoidance learning on both the 1-hour and 24-hour retention tests (p<0.05). This study identified a NOAEL for neurodevelopmental toxicity of 21.3 mg/kg-day and a LOAEL of 204.8 mg/kg-day based on the impairment in passive avoidance learning. This study also identifies a NOAEL for reproductive and other developmental effects of 204.8 mg/kg-day (the highest exposure tested). Johnson et al. (1998) tested the potential for chloral hydrate to cause developmental toxicity in Sprague-Dawley rats. Chloral hydrate was administered in drinking water to 20 rats from gestational day 1 to 22 at an average exposure of 151 mg/kg-day. Control animals were given distilled water. There was no evidence of maternal toxicity, no change in the number of implantation or resorption sites, no change in the number of live or dead fetuses, no change in placental or fetal weight, no change in crown-rump length, and no increase in the incidence of morphological changes. At necropsy there was no evidence of cardiac anomalies. Based on this study, the NOAEL for developmental toxicity is 151 mg/kg-day (the highest exposure tested). Johnson et al. (1998) also tested the potential for trichloroethanol and trichloroacetic acid to cause developmental toxicity in Sprague-Dawley rats. The protocol was identical to the study with chloral hydrate. Trichloroethanol was administered to 10 rats at an average exposure of 153 mg/kg-day. No evidence of developmental toxicity was found. In contrast, when trichloroacetic acid was administered to 11 rats at an average exposure of 291 mg/kg-day, developmental toxicity was observed. The effects included a statistically significant (p<0.05) increase in total cardiac defects per litter and an increased number of implantation and resorption sites. The results with trichloroacetic acid are generally consistent with those reported by Smith et al. (1989), who reported adverse developmental effects (levocardia) from trichloroacetic acid at an exposure of 330 mg/kg-day and above. Saillenfait et al. (1995) tested the potential of chloral hydrate to cause developmental toxicity in vitro using a rat whole-embryo culture system. Embryos from Sprague-Dawley rats were explanted on gestational day 10 and exposed to chloral hydrate at a concentration of 0, 0.5, 1, 1.5, 2, or 2.5 mM (20 embryos/dose) for 46 hours. At 2.5 mM all embryos died. No lethality was seen at lower exposures. Chloral hydrate caused concentration-dependent decreases in growth and differentiation and increases in the incidence of morphologically abnormal embryos. No effects were observed in any parameter at 0.5 mM. Decreases in crown-rump length, somite (embryonic segment) number, and the protein or DNA content of embryos were seen at 1 mM and above. At 1, 1.5, and 2 mM chloral hydrate, respectively, 18%, 68%, and 100% of embryos were malformed. Brain, eye, and ear malformations were the most prominent effects at these concentrations. Abnormalities in the trunk and pericardial dilation also occurred at 2 mM. In this in vitro test system, chloral hydrate was a slightly more potent teratogen than trichloroacetic acid or dichloroacetic acid. Although chloral hydrate did not cause meiotic delay in the oocytes of adult mice when administered at the time of resumption of maturation induced by hormones (Mailhes et al., 1994), it did cause adverse effects in vitro when a synchronized population of oocytes was exposed prior to resumption of maturation (Eichenlaub-Ritter and Betzendahl, 1995; Eichenlaub-Ritter et al., 1996). In this test system, chloral hydrate induced lagging of chromosomes during telophase I, inhibited spindle elongation in anaphase B, and caused chromosome displacement from the spindle equator in metaphase I and II. Oocytes became irreversibly arrested in maturation when exposed to chloral hydrate prior to resumption of maturation, or when chloral hydrate was present during the first or second 8 hours of maturation. Spindle aberrations (lagging chromosomes and a short interpolar space) were observed when oocytes were treated with trichloroethanol (Eichenlaub-Ritter et al., 1996). Neurological Study Kallman et al. (1984) exposed groups of 12 male 5-week-old CD-1 mice to drinking water containing chloral hydrate at 70 or 700 mg/L (equivalent to 15.7 or 160 mg/kg-day) for 90 days. When measured 24 hours after the 90-day exposure was terminated, no treatment-related effects were observed on mortality, body weight, physical appearance, behavior, locomotor activity, learning in repetitive tests of coordination, response to painful stimuli, strength, endurance, or passive avoidance learning. Both exposures resulted in a decrease of about 1 °C in mean body temperature (p<0.05). Because of the lack of increased effect with a tenfold increase in exposure and because hypothermia has not been reported as a side effect of chloral hydrate in humans, the decrease in body temperature is not considered an adverse effect. This study identifies a NOAEL for neurobehavioral toxicity of 160 mg/kg-day (the highest exposure tested). Immunological Study Kauffmann et al. (1982) administered chloral hydrate to male and female 4-week-old CD-1 mice in drinking water at 70 or 700 mg/L (equivalent to 16 or 160 mg/kg-day) for 90 days. Humoral immunity was assessed by the number of splenic antibody-forming cells produced against sheep red blood cells (12 mice in the control group and 8 mice in the exposed groups) and hemagglutination titers (20-21 mice in the control group and 13-16 mice in the exposed groups). Cell-mediated immunity was assessed by delayed type hypersensitivity to sheep red blood cells (17-20 mice in the control group and 15-16 mice in the exposed groups). Lymphocyte response was assessed using a T-cell mitogen (Con A) and a B-cell mitogen (LPS) (17-22 animals in the control group and 13-16 mice in the exposed groups). In males, no effects were detected in either humoral or cell-mediated immunity at either exposure. No effects on cell-mediated immunity were noted in females at either exposure. In females, both exposures resulted in a statistically significant decrease (p<0.05) in humoral immune function (36% and 40% at the low and high exposure, respectively) when expressed as antibody-forming cells per spleen. The decrease, however, was statistically significant only at the higher exposure when expressed as antibody-forming cells per million spleen cells (a 32% decrease). There was no effect on hemagglutination titers or on spleen cell response to the B-cell mitogen at either exposure. The antibody-forming cell response is considered an excellent indicator of the status of humoral immunity because of the complex cellular cooperation required to produce antibody and because the number of cells that produce antibody can be quantified. A depression in the number of these cells is considered an adverse response because the production of antibodies is important to the defense strategy of the organism. However, the quantitative relationship between the depression in antibody-forming cells in the spleen and the concentration of circulating antibody is unknown. In this study, because there was no depression in circulating antibodies measured by the hemagglutination titer, there might be no significant depression in the ability of the host to mount a protective antibody response. EPA, however, considers the decrease in antibody-forming cells per million spleen cells at the higher exposure in female mice an adverse response. Accordingly, the NOAEL for immunotoxicity is 16 mg/kg-day; the LOAEL is 160 mg/kg-day. For more detail on Synthesis and Evaluation of Major Noncancer Effects and Mode of Action, exit to the toxicological review, section 4.5 http://www.epa.gov/iris/toxreviews/0304-tr.pdf#page=25. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- medium Database -- high RfD -- high The overall confidence in this RfD assessment is high. Chloral hydrate has been extensively used as a sedative and hypnotic drug in human and veterinary medicine. The metabolite, trichloroethanol, is responsible for the pharmacological effect. Chloral hydrate is irritating to the skin and mucous membranes and often causes gastric distress, nausea, and vomiting at recommended doses. Acute overdoses produce (in order of progression) ataxia, lethargy, deep coma, respiratory depression, hypotension, and cardiac arrhythmias. There is some evidence of hepatic injury in people surviving near-lethal acute overdoses, but no convincing evidence that hepatic injury results from the recommended clinical dose. Despite chloral hydrate's long use in human medicine, there is no published information on toxicity in controlled studies in humans following extended exposure, and no study clearly establishing a NOAEL in humans. Therefore, confidence in the principal study is medium-to-high. Acute administration of chloral hydrate to mice causes loss of coordination (ataxia) at about the same exposure as in humans for the same effect. A 90-day study in mice shows no evidence of behavioral changes or other neurotoxicity. Chronic studies in rats and mice show no evidence of behavioral changes and no evidence of histopathological changes in nervous tissue. There is some evidence of mild liver toxicity in rodents. These effects are generally observed in males at lower exposures than in females. The effects in the liver in male mice may be associated with enzyme induction and precancerous lesions. A slight decrement in humoral immunity was observed in female mice following exposure for 90 days. Chloral hydrate has been tested for developmental effects in rats and mice. No structural abnormalities were observed. A slight effect was observed in mice in passive avoidance learning when dams were exposed prior to breeding, during gestation and nursing, and pups were tested at 23 days of age. Although chloral hydrate has not been tested in a two-generation reproduction study, the data on reproductive performance and on effects on sperm and oocytes do not suggest that reproductive toxicity is likely to be a critical effect. In addition, no histopathological effects are observed in reproductive organs of rodents in subchronic or chronic studies. All of the studies in laboratory animals show noncancer health effects at an exposure far in excess of the exposure that is effective for sedation in humans. Therefore, confidence in the database is high. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0304-tr.pdf#page=30 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2000. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA (2000). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0304-tr.pdf#page=45 Other EPA Documentation - Final draft for the drinking water criteria document on chlorinated acids/aldehydes/ketone/alcohols. U.S. EPA, Office of Water, March 1994. Agency Consensus Date - 9/6/2000 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Chloral hydrate conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 200009 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Chloral hydrate CASRN-- 302-17-0 NORC: Not available at this time. Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Chloral hydrate conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ============================================================================ UDCA: 200009 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chloral hydrate CASRN --302-17-0 Last Revised -- 09/15/2000 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under the 1986 cancer guidelines (U.S. EPA, 1986), chloral hydrate is assigned to Group C, possible human carcinogen. Under the 1996 proposed guidelines for carcinogen risk assessment (U.S. EPA, 1996), chloral hydrate shows suggestive evidence of human carcinogenicity by the oral route of exposure. There are no carcinogenicity data from humans. Two bioassays in rats in which chloral hydrate was administered by drinking water show no increase in tumors at any site. Because only minimal toxicity was observed in the livers of the rats in these bioassays, the tests were not conducted at the maximum tolerated dose. A chronic bioassay in female mice showed a slight increase in the severity grade of hyperplasia and a slight increase in the incidence of adenoma in the pituitary gland pars distalis at the highest exposure tested. There is some evidence that chloral hydrate causes hepatocellular tumors in male mice. An earlier study showing an increase in hepatic adenomas or trabecular carcinomas following a single bolus exposure could not be confirmed in a study using more animals and higher exposures. Three separate 2-year bioassays in male mice show an increased incidence of hepatocellular adenoma or carcinoma. There are no data identifying a lesion that is a precursor to the hepatocellular tumors. The strain of mice used has a very high spontaneous incidence of hepatocellular tumors. Two of the metabolites of chloral hydrate, trichloroacetic acid and dichloroacetic acid, have been shown to cause hepatocellular tumors in rodents. Trichloroacetic acid causes hepatocellular tumors only in mice. Dichloroacetic acid causes hepatocellular tumors in both rats and mice. There is an extensive database on genetic toxicity. A variety of results show that chloral hydrate is a weak gene mutagen and clastogen. Chloral hydrate induces aneuploidy in a wide variety of cell types. These latter effects are thought to arise by disruption of the spindle apparatus. A high concentration of chloral hydrate is required to cause observable effects. Although these data suggest that genotoxicity may play a role in the toxicity of chloral hydrate, the data indicate that these effects require concentrations that are unlikely to occur under physiological conditions at the exposures typically encountered from the environment. Collectively, these data provide suggestive evidence of carcinogenicity, but the weight of evidence is not sufficient to conduct a risk assessment assuming a linear response at low exposure. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0304-tr.pdf#page=30 , For more detail on Susceptible Populations, exit to the toxicological review, section 4.6.1 http://www.epa.gov/iris/toxreviews/0304-tr.pdf#page=28. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. NTP (2000a) conducted a chronic bioassay for carcinogenicity in female B6C3F1 mice. Mice were administered chloral hydrate by gavage in distilled water at 0, 25, 50, or 100 mg/kg 5 days a week for up to 2 years. The calculated exposures are 0, 17.9, 35.7, or 71.4 mg/kg-day. Additional groups were administered chloral hydrate by gavage for 3, 6, or 12 months and held without further dosing for the duration of the study (stop-exposure studies). There was no significant effect on survival, body weight, or organ weights at any exposure. Following complete necropsy and histopathological examination, the only significant findings were in the pituitary gland pars distalis. There were no significant effects in the pituitary in the stop-exposure studies. Following the full exposure regime, the incidence of hyperplasia in the pituitary gland pars distalis was 4/45, 6/44, 4/50, and 9/50 in the control, 25, 50, and 100 mg/kg group, respectively. The average severity grade for hyperplasia was 1.5, 1.0, 1.0, and 2.2 in the control, 25, 50, and 100 mg/kg group, respectively. Only the average severity grade at 100 mg/kg was statistically different from the control (p<0.05). The incidence of adenoma in the pituitary gland pars distalis was 0/45, 2/44, 0/47, and 5/41 in the control, 25, 50, and 100 mg/kg group, respectively. Only at 100 mg/kg was the incidence significantly greater than the control (p=0.0237). For non-neoplastic effects, the NOAEL in this study is 71.4 mg/kg-day (the highest exposure tested). NTP concluded that this study provided equivocal evidence of carcinogenic activity for chloral hydrate in female mice. NTP (2000b) conducted a chronic bioassay for carcinogenicity in male B6C3F1 mice. Groups of 120 male mice received chloral hydrate by gavage in distilled water at 0, 25, 50, or 100 mg/kg for up to 2 years. The calculated exposures are 0, 17.9, 35.7, or 71.4 mg/kg-day. At each exposure 60 mice received feed ad libitum; the other 60 mice received feed in measured daily amounts calculated to maintain body weight on a previously computed idealized body weight curve. Twelve mice from each diet and dose group were evaluated after 15 months of exposure. The remaining 48 animals from each diet and dose group were evaluated at 2 years. Survival, body weight, organ weights, and serum enzymes in the dosed groups were comparable to the respective vehicle control. Following complete necropsy and histopathological examination, no changes were found in any organ except the liver when compared to the respective vehicle control. The incidence of hepatocellular adenoma or carcinoma in the ad libitum study was 16/48, 25/48, 23/47, and 22/48 in the control, 25, 50, or 100 mg/kg groups, respectively. Only in the 25 mg/kg group was the incidence significantly greater than control (p= 0.0437). In the dietary-controlled study, the incidence of hepatocellular adenoma or carcinoma was 11/48, 11/48, 14/48, and 18/48 and the incidence of hepatocellular carcinoma was 2/48, 5/48, 4/48, and 8/48 in the control, 25, 50, or 100 mg/kg group, respectively. The only statistically significant increase in incidence was for hepatocellular carcinoma in the 100 mg/kg group (p=0.042). The NOAEL for non-neoplastic effects in this study is 71.4 mg/kg-day (the highest exposure tested). NTP concluded that this study provided some evidence of carcinogenic activity for chloral hydrate in male mice. George et al. (2000) conducted a chronic bioassay for carcinogenicity in male B6C3F1 mice. Mice were administered chloral hydrate in drinking water for 104 weeks. Mice (72 in each group) had a mean exposure of 0, 13.5, 65, or 146.6 mg/kg-day. At the termination of the study, a complete necropsy and histopathological examination of liver, kidney, spleen, and testes from all animals was conducted. In addition, a complete histopathological examination was conducted on five animals from the high-dose group. There was no change in water consumption, survival, behavior, body weight, or organ weights (liver, kidney, spleen, and testes) at any exposure. There was no increase in the prevalence of neoplasia at sites other than the liver. The male mice showed an increase of proliferative lesions in the liver (hyperplasia, adenoma, carcinoma, and combined adenoma and carcinoma) at all exposures. The prevalence of proliferative lesions in the control, 13.5, 65, or 146.6 mg/kg-day groups was as follows: hyperplasia, 3/42, 15/46, 13/39, 12/32; adenoma, 9/42, 20/46, 20/39, 16/32; carcinoma, 23/42, 25/46, 23/39, 27/32; adenoma or carcinoma, 27/42, 36/46, 31/39, 29/32. All of the changes were statistically significant (p<0.05) except for carcinoma at the two lower exposures. Daniel et al. (1992) exposed 40 male B6C3F1 mice for 104 weeks to drinking water containing chloral hydrate at 1 g/L (equivalent to 166 mg/kg-day). Untreated control animals (23 in one group and 10 in a second group) received distilled water. Interim sacrifices were conducted at 30 and 60 weeks of exposure (5 animals per group at each sacrifice interval). Complete necropsy and microscopic examination were performed. There were no significant treatment-related effects on survival or body weight. The prevalence of liver tumors at terminal sacrifice was statistically significantly (p<0.05) increased over controls, with hepatocellular carcinomas in 11/24 and hepatocellular adenomas in 7/24; for carcinomas and adenomas combined, the prevalence was 17/24. In control animals, carcinomas, adenomas, and carcinomas and adenomas (combined) occurred in 2/20, 1/20, and 3/20, respectively. At the 60-week sacrifice, there were 2/5 treated animals with hepatocellular carcinomas, compared to 0/5 controls. No carcinomas, adenomas, or hyperplastic nodules were reported in animals sacrificed at week 30. NTP (2000a) investigated the ability of a single exposure to chloral hydrate to induce tumors in female and male B6C3F1 mice. Groups of 15-day-old or 28-day-old female mice (48 animals per dose group) received a single gavage dose of chloral hydrate in distilled water at 0, 10, 25, or 50 mg/kg. An identical study was conducted in 15-day-old male mice. All animals were sacrificed at 105 weeks of age. No neoplastic or non-neoplastic effects were found in any organ at any exposure. Rijhsinghani et al. (1986) evaluated carcinogenic potential in male mice (C57BL x C3HF1). Groups of 15-day-old mice received a single dose of chloral hydrate by gavage in distilled water at 0, 5, or 10 mg/kg (26, 15, and 14 mice per group, respectively). Animals were sacrificed when moribund or at week 78, week 88, or between weeks 89 and 92. Livers were examined histopathologically using light and electron microscopy. In mice sacrificed 48 to 92 weeks after treatment, the incidence of hepatic nodules (adenomas or trabecular carcinomas) was 3/9 and 6/8 for animals from the 5 and 10 mg/kg-day dose groups, respectively, compared to 2/19 in controls. The increase in hepatic nodules was statistically significant (p<0.05) only in the 10 mg/kg group. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Leuschner and Beuscher (1998) conducted a chronic bioassay for carcinogenicity in Sprague-Dawley rats. Chloral hydrate was administered in drinking water for 124 weeks (males) and 128 weeks (females). The rats (50 males and 50 females in each group) had an exposure of 15, 45, or 135 mg/kg-day. There was no effect on survival, appearance, behavior, body weight, food and water consumption, and organ weights. There was no evidence of increased incidence of tumors in any organ. George et al. (2000) conducted a chronic bioassay for carcinogenicity in male F344 rats. Rats were administered chloral hydrate in drinking water for 104 weeks. Rats (78 in each group) had a mean daily exposure of 0, 7.4, 37.4, or 162.6 mg/kg-day. At the termination of the study, a complete necropsy and histopathological examination of liver, kidney, spleen, and testes from all animals was conducted. In addition a complete histopathological examination was conducted on five animals from the high-dose group. There was no change in water consumption, survival, behavior, body weight, or organ weights (liver, kidney, spleen, and testes) at any exposure. There was no indication of liver toxicity at any exposure, as shown by the lack of liver necrosis, hyperplasia, increased mitotic index, and only minimal changes in the levels of serum enzymes. There was no increase at any exposure in the prevalence or multiplicity of hepatocellular neoplasia or neoplasia at any other site. Two of the metabolites of chloral hydrate, trichloroacetic acid and dichloroacetic acid, have been associated with increased hepatocellular adenomas or carcinomas in rodents. For example, trichloroacetic acid in drinking water induced hepatocellular adenomas or carcinomas in male and female mice when the exposure exceeded 200 mg/kg-day (Bull et al., 1990; Herren-Freund et al., 1987; Pereira, 1996). There was no evidence of increased carcinogenicity, however, when male rats were exposed to trichloroacetic acid at 360 mg/kg-day (DeAngelo et al., 1997). Dichloroacetic acid in drinking water induced hepatocellular adenomas or carcinomas in male and female mice when the exposure exceeded 160 mg/kg-day (Bull et al., 1990; Daniel et al., 1992a; DeAngelo et al., 1991; Ferreira-Gonzalez et al., 1995; Herren-Freund et al., 1987; Pereira, 1996). Dichloroacetic acid also induced hepatocellular adenomas or carcinomas in male rats when the exposure exceeded 40 mg/kg-day (DeAngelo et al., 1996; Richmond et al., 1995). Genetic Toxicity There is an extensive database on the genotoxicity of chloral hydrate and its metabolites. The European Union included chloral hydrate in a collaborative study on aneuploidy (Adler, 1993; Natarajan et al., 1993; Parry, 1993; Parry and Sors, 1993). These data are summarized in U. S. EPA (2000). Chloral hydrate did not induce mutation in most strains of Salmonella typhimurium, but did in some studies with Salmonella typhimurium TA 100 and in a single study with Salmonella typhimurium TA 104. The latter response was inhibited by free-radical scavengers a-tocopherol and menadione (Ni et al., 1994). Chloral hydrate did not induce mitotic crossing over in Aspergillus nidulans in the absence of metabolic activation. Chloral hydrate caused weak induction of meiotic recombination in the presence of metabolic activation and gene conversion in the absence of metabolic activation in Saccharomyces cerevisiae. It did not induce reverse mutation in Saccharomyces cerevisiae. Chloral hydrate clearly induced aneuploidy in various fungi in the absence of metabolic activation. Chloral hydrate induced somatic and germ cell mutations in Drosophila melanogaster. Choral hydrate did not produce DNA-protein crosslinks in rat liver nuclei, DNA single-strand breaks/alkaline-labile sites in primary hepatocytes in vitro, or DNA repair in Escherichia coli. One study showed induction of single-strand breaks in liver DNA of both rats and mice treated in vivo; another study in both species using higher concentrations of chloral hydrate found no such effect. Chloral hydrate was weakly mutagenic, but did not induce micronuclei in mouse lymphoma cells in vitro. Chloral hydrate increased the frequency of micronuclei in Chinese hamster cell lines. Although a single study suggested that chloral hydrate induces chromosomal aberrations in Chinese hamster CHED cells in vitro, the micronuclei produced probably contained whole chromosomes and not chromosome fragments, as the micronuclei could all be labeled with antikinetochore antibodies. In kangaroo rat kidney epithelial cells, choral hydrate inhibited spindle elongation and broke down mitotic microtubuli, although it did not inhibit pole-to-pole movement of chromosomes. It produced multipolar spindles, chromosomal dislocation from the mitotic spindle, and a total lack of mitotic spindles in Chinese hamster DON:Wg3h cells. Chloral hydrate weakly induced sister chromatid exchange in cultures of human lymphocytes. It induced micronuclei, aneuploidy, C-mitosis, and polyploidy in human lymphocytes in vitro. Micronuclei were induced in studies with human whole blood cultures but not in one study with isolated lymphocytes. The differences seen in the micronucleus test have been attributed to differences between whole blood and purified lymphocytes cultures (Vian et al., 1995), but this hypothesis has not been tested. Chloral hydrate increased the frequency of chromosomal aberrations in mouse bone marrow, spermatogonia, and primary and secondary spermatocytes, but not in oocytes, after in vivo treatment. Chloral hydrate induced chromosomal aberrations in mouse bone-marrow erythrocytes after treatment in vivo. Chloral hydrate induced micronuclei in the spermatids of mice treated in vivo in some studies. Chloral hydrate induced aneuploidy in the bone marrow of mice treated in vivo. It increased the rate of aneuploidy in mouse secondary spermatocytes. It did not produce polyploidy in bone marrow, oocytes, or gonosomal or autosomal univalents in primary spermatocytes of mice treated in vivo. Chloral hydrate, however, induced polyploidy and meiotic delay when a synchronized population of mouse oocytes were exposed in vitro prior to the resumption of maturation. Trichloroethanol, a reduction product of chloral hydrate, did not induce l prophage in Escherichia coli or mutation in Salmonella typhimurium TA 100. Trichloroethanol caused spindle aberrations when mouse oocytes were treated in vitro. Trichloroacetic acid did not induce l prophage in Escherichia coli and was not mutagenic to Salmonella typhimurium in the presence or absence of metabolic activation. Trichloroacetic acid was weakly positive in the mouse lymphoma assay with metabolic activation. Trichloroacetic acid also did not induce chromosomal damage in human lymphocytes or micronuclei in bone marrow in vitro. It is unclear whether trichloroacetic acid can induce chromosomal damage in vivo because some studies have been positive and others negative. Dichloroacetic acid did not induce differential toxicity in DNA-repair-deficient strains of Salmonella typhimurium but did induce l prophage in Escherichia coli. Dichloroacetic acid gave equivocal results for gene mutation in Salmonella typhimurium TA100 and TA98. Dichloroacetic acid was weakly mutagenic in the in vitro mouse lymphoma assay and induced chromosomal aberrations but not micronuclei or aneuploidy in that test system. Dichloroacetic acid induced micronuclei in mouse polychromatic erythrocytes in vivo and mutations at the LacI locus in the transgenic B6C3F1 mouse (Big Blue (R) mouse) in vivo at an exposure that induces liver tumors in male mice. It is unclear whether dichloroacetic acid can induce primary DNA damage, as some assays are positive and others negative. Cell Proliferation The acute effects of chloral hydrate on liver cell proliferation were evaluated by Rijhsinghani et al. (1986) in 15-day-old mice (C57BL x C3HF1). Mice were given 0, 5, or 10 mg/kg chloral hydrate by gavage in distilled water (9, 10, and 6 mice per group, respectively) and sacrificed after 24 hours. Cell proliferation was evaluated by calculating the mitotic index (number of mitoses/100 nuclei) from liver sections. The mitotic index in liver cells was significantly increased (0.9235) in mice receiving 5 mg/kg when compared to the control value (0.3382), and elevated (0.7433) (although not statistically significantly) in mice receiving 10 mg/kg. Hepatic necrosis was not observed in mice from either treatment group at autopsy. As part of the chronic bioassay for carcinogenicity, George et al. (2000) evaluated hepatocyte proliferation in F344 rats and B6C3F1 mice. Exposures are given in Sections II.A.3 and II.A.4. Five days prior to sacrifice at 13, 26, 52, or 72 weeks in rats and 26, 52, or 78 weeks in mice, animals were given bromodeoxyuridine. Labeled nuclei were identified by chromogen pigment over the nuclei and the labeling index was calculated. Outside of the areas with tumors in the livers of male mice, there was no significant evidence of increased hepatocyte proliferation in rats or mice. Oncogene Activation The induction of the H-ras proto-oncogene in rodents by chloral hydrate was investigated by Velazquez (1994). DNA from normal liver and tumor tissue was obtained from male B6C3F1 mice administered 1 g/L (166 mg/kg-day) chloral hydrate in drinking water for 2 years. H-ras mutations were present in one out of seven (14%) tumors. The spectrum of mutations was the same as that of spontaneous liver tumors. Based on these data, it is unlikely that H-ras activation is a mechanism of carcinogenicity relevant to chloral hydrate. Free Radicals and DNA Adduct Formation Ni et al. (1994, 1995, 1996) studied the metabolism of chloral hydrate in an in vitro system using microsomes from male B6C3F1 mice. The metabolism of chloral hydrate generated free radicals as detected by electron spin resonance spectroscopy and caused endogenous lipid peroxidation, resulting in the production of malondialdehyde, formaldehyde, and acetaldehyde, all of which are known to produce liver tumors in rodents. Trichloroacetic acid and trichloroethanol also produced free radicals and induced lipid peroxidation when tested in this system. The authors speculated that the free radicals were Cl3CCO2· and/or Cl3C·. Incubation of chloral hydrate, trichloroethanol, or trichloroacetic acid in the presence of microsomes and calf thymus DNA resulted in the formation of a malondialdehyde-modified DNA adduct. This research group further showed that chloral hydrate induced an increase in mutations at the hprt and tk loci in transgenic human lymphoblastoid cells containing CYP2E1. In contrast, when the parental cell line lacking CYP2E1 was treated with the same concentration of chloral hydrate, no mutations were found at either loci. These data implicate CYP2E1 as the primary cytochrome subfamily involved in the metabolism of chloral hydrate to reactive intermediates. Cell Communication The effects of 1-, 4-, 6-, 24-, 48-, and 168-hour exposures to chloral hydrate (0, 1, 5, or 10 mM) on gap junction intercellular communication in Clone 9 cell cultures (normal rat hepatocytes) were reported by Benane et al. (1996). No differences in intercellular communication were seen between the groups treated with 1 mM at 1, 4, and 6 hours of exposure and controls, as measured by a dye transfer protocol. There were significant differences between all other groups and the controls. The shortest exposure time and lowest exposure concentration that reduced dye transfer significantly was in the group treated with 1 mM for 24 hours. Peroxisome Proliferation As part of the chronic bioassay for carcinogenicity in mice, George et al. (2000) found no evidence of peroxisome proliferation using cyanide-insensitive palmitoyl CoA oxidase in the livers of mice treated with chloral hydrate for 26 weeks. As part of the chronic bioassay for carcinogenicity in male mice, NTP (2000b) found that chloral hydrate in the 100 mg/kg group significantly induced (p<0.05) both lauric acid w-hydroxylase activity and CYP4A immunoreactive protein in the dietary-controlled study, but not in the ad libitum study. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Insufficient data are available to calculate an oral slope factor. DCOE: __II.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) None ACOE: __II.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) None CCOE: __II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) There are no carcinogenicity data from humans. Two bioassays in rats show no increase in tumors at any site. Because only minimal toxicity was observed in the livers of the rats in these bioassays, the tests were not conducted at the maximum tolerated dose. A chronic bioassay in female mice showed a slight increase in the severity grade of hyperplasia and a slight increase in the incidence of adenoma in the pituitary gland pars distalis at the highest exposure tested. There is some evidence that chloral hydrate causes hepatocellular tumors in male mice. An earlier study showing an increase in hepatic adenomas or trabecular carcinomas following a single bolus exposure could not be confirmed in a study using more animals and higher exposures. Three separate 2-year bioassays in male mice show an increased incidence of hepatocellular adenoma or carcinoma. There are no data identifying a lesion that is a precursor to the hepatocellular tumors. The strain of mice used has a very high spontaneous incidence of hepatocellular tumors. Two of the metabolites of chloral hydrate, trichloroacetic acid and dichloroacetic acid, have been shown to cause hepatocellular tumors in rodents. Trichloroacetic acid causes hepatocellular tumors only in mice. Dichloroacetic acid causes hepatocellular tumors in both rats and mice. Chloral hydrate has been extensively studied as a genotoxic agent. Chloral hydrate was positive in some bacterial mutation tests, indicating that it may be capable of inducing point mutations. It was also positive in the mouse lymphoma assay for mutations at the TK locus. Chloral hydrate also induced somatic and germ cell mutations in Drosophila melanogaster. Some data also show chloral hydrate to be a very weak clastogen in mammalian cells. Chloral hydrate has been shown to induce aneuploidy in a variety of cells, including Saccharomyces cerevisiae, Aspergillus nidulans, Chinese hamster embryonic fibroblasts, Chinese hamster primary cell lines LUC2 and DON:Wg3h, human peripheral blood lymphocytes, mouse spermatocytes, and mouse spermatids. Because there is a mixture of positive and negative in vivo data, with no reason to weigh some studies more than others, it is not clear whether chloral hydrate is capable of inducing genetic damage in vivo. Additional in vivo studies using standard protocols would help clarify the relevance of genetic damage to a human health risk assessment. The aneugenic effects of chloral hydrate are exposure-dependent and thought to arise via disruption of the mitotic spindle structure and/or function by inhibition of tubulin and/or microtubule-associated proteins; both substances are components of the spindle apparatus (Brunner et al., 1991; Lee at al., 1987; Wallin and Hartley-Asp, 1993). Some data also suggest that chloral hydrate may act on the spindle apparatus through an increase in the concentration of intracellular free calcium (Lee et al; 1987). Although chloral hydrate and its metabolites, trichloroacetic acid and dichloroacetic acid, can induce a variety of mutational events, they do so with very low potency. Owing to the high concentration of chloral hydrate and its metabolites required to induce an observable effect in these assays, it is not likely that a genotoxic mode of action can be held responsible for the pituitary adenomas found in female mice or the hepatocellular tumors found in male mice. Several other mechanisms may play a role in the induction of tumors in the liver of male mice. There is no convincing evidence that chloral hydrate causes direct damage to DNA. In vitro studies with chloral hydrate, trichloroethanol, and trichloroacetic acid and mouse microsomes, however, show lipid peroxidation and the formation of covalently bound DNA adducts. These effects appear to be mediated by the formation of free radicals by CYP2E1. Another possibility concerns exposure-dependent cytotoxicity leading to compensatory hyperplasia. A single treatment of mice with chloral hydrate caused an increase in the mitotic index in liver cells. The increased cell division is hypothesized to either provide additional opportunities for errors in DNA replication or allow initiated cells to progress to a tumor. Some data suggest a role for peroxisomal proliferation in the liver of male mice. Another potentially contributing mechanism of carcinogenesis is disruption of intercellular communication, which has been shown in one experiment to be influenced by chloral hydrate. Although the mechanism of chloral hydrate-induced carcinogenicity in mice is unclear, one mechanisms that appears less likely to be responsible is H-ras proto-oncogene activation. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE No data are available to calculate an inhalation unit risk. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2000. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA (2000).To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0304-tr.pdf#page=45 RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 9/6/2000 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Chloral hydrate conducted in November 2001 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address) ============================================================================ UDSO: 200009 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Chloral hydrate CASRN --302-17-0 Last Revised -- 09/15/2000 SORD: __VI.A. ORAL RfD REFERENCES Abbas, R; Fisher, JW. (1997) A physiologically based pharmacokinetic model for trichloroethylene, and its metabolites, chloral hydrate, trichloroacetate, dichloroacetate, trichloroethanol, and trichloroethanol glucuronide in B6C3F1 mice. Toxicol Appl Pharmacol 137:15-30. Abbas, R; Seckel, CS; Kidney, JK; et al. (1996) Pharmacokinetic analysis of chloral hydrate and its metabolism in B6C3F1 mice. Drug Metab Dispos 24:1340-1346. See also Erratum. 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(1992a) Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fundam Appl Toxicol 19:159-168. Daniel, FB; Robinson, M; Stober, JA; et al. (1992b) Ninety-day toxicity study of chloral hydrate in the Sprague-Dawley rat. Drug Chem Toxicol 15:217-232. Eichenlaub-Ritter, U; Betzendahl, I. (1995) Chloral hydrate induced spindle aberrations, metaphase I arrest and aneuploidy in mouse oocytes. Mutagenesis 10:477-486. Eichenlaub-Ritter, U; Baart, E; Yin, H; et al. (1996) Mechanisms of spontaneous and chemically-induced aneuploidy in mammalian oogenesis: basis of sex specific differences in response to aneugens and the necessity for further tests. Mutat Res 372:274-294. Elfarra, AA; Krause, RJ; Last, AR; et al. (1998) Species- and sex-related differences in metabolism of trichloroethylene to yield chloral and trichloroethanol in mouse, rat, and human liver microsomes. Drug Metab Dispos 26:779-785. Fisher, JW; Mahle, D; Abbas, R. 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(1987a) The cholecystohepatic circulation of trichloroethylene and its metabolites in dogs. Toxicology 44:283-295. Hobara, T; Kobayashi, H; Kawamoto, T; et al. (1987b) Extrahepatic metabolism of chloral hydrate, trichloroethanol, and trichloroacetic acid in dogs. Pharmacol Toxicol 61:58-62. Hobara, T; Kobayashi, H; Kawamoto, T; et al. (1988a) Intestinal absorption of chloral hydrate, free trichloroethanol, and trichloroacetic acid in dogs. Pharmacol Toxicol 62:250-258. Hobara, T; Kobayashi, H; Kawamoto, T; et al. (1988b) The absorption of trichloroethylene and its metabolites from the urinary bladder of anesthetized dogs. Toxicology 48:141-153. Johnson, PD; Dawson, BV; Goldberg, SJ. (1998) Cardiac teratogenicity of trichloroethylene metabolites. J Am Coll Cardiol 32:540-545. Kallman, MJ; Kaempf, GL; Balster, RL. (1984) Behavioral toxicity of chloral in mice: an approach to evaluation. Neurobehav Toxicol Teratol 6:137-146. Kaplan, HL; Forney, RB; Hughes, FW; et al. (1967) Chloral hydrate and alcohol metabolism in human subjects. J Forensic Sci 12:295-304. Kauffmann, BM; White, KL; Sanders, VM; et al. (1982) Humoral and cell-mediated immune status in mice exposed to chloral hydrate. Environ Health Perspect 44:147-151. Ketcha, MM; Stevens, DK; Warren, DA; et al. (1996) Conversion of trichloroacetic acid to dichloroacetic acid in biological samples. J Anal Toxicol 20:236-241. Klinefelter, GR; Suarez, JD; Roberts, NL. (1995) Preliminary screening test for the potential of drinking water disinfectant by-products to alter male reproduction. Reprod Toxicol 9:571-578. Lambert, GH; Muraskas, J; Anderson, CL; et al. (1990) Direct hyperbilirubinemia associated with chloral hydrate administration in the newborn. Pediatrics 86:277-281. Leuschner, J; Beuscher, N. (1998) Studies on the mutagenic and carcinogenic potential of chloral hydrate. Arzneim-Forsch/Drug Res 48:961-968. Lipscomb, JC; Mahle, DA; Brashear, WT; et al. (1996) A species comparison of chloral hydrate metabolism in blood and liver. Biochem Biophys Res Commun 227:340-350. Lipscomb, JC; Confer, PD; Miller, MR; et al. (1998) Metabolism of trichloroethylene and chloral hydrate by the Japanese Medaka (Oryzias latipes) in vitro. Environ Toxicol Chem 17:325-332. Ludwigs, U; Divino-Fiiho, JC; Magnusson, N. (1996) Suicidal chloral hydrate poisoning. J Clin Toxicol 344:97-99. Mailhes, JB; Marchette, F. (1994) Chemically induced aneuploidy in mammalian oocytes. Mutat Res 320:87-111. Marshall, AJ. (1977) Cardiac arrhythmias caused by chloral hydrate. Br Med J 2:994. Marshall, EK; Owens, AH. (1954) Absorption, excretion and metabolic fate of chloral hydrate and trichloroethanol. Bull Johns Hopkins Hosp 95:1-18. Mayers, DJ; Hindmarsh, KW; Sankaran, K; et al. (1991) Chloral hydrate disposition following single-dose administration to critically ill neonates and children. Dev Pharmacol Ther 16:71-77. Merdink, JL; Conzalez-Leon, A; Bull, RJ; et al. (1998) The extent of dichloroacetate formation from trichloroethylene, chloral hydrate, trichloroacetate, and trichloroethanol in B6C3F1 mice. Toxicol Sci 45:33-41. Merdink, JL; Stenner, RD; Stevens, DK; et al. (1999) Effect of enterohepatic circulation on the pharmacokinetics of chloral hydrate and its metabolites in F344 rats. J Toxicol Environ Health 56:357-368. Miller, RR; Greenblatt, DJ. (1979) Clinical effects of chloral hydrate in hospitalized medical patients. J Clin Pharmacol 19:669-674. National Toxicology Program (NTP). (2000a) Toxicology and carcinogenesis studies of chloral hydrate in B6C3F1 mice (gavage studies). NTP TR 502. NTP. (2000b) Toxicology and carcinogenesis studies of chloral hydrate (ad libitum and dietary controlled) in male B6C3F1 mice (gavage study). NTP TR 503. Owens, AH; Marshall, EK. (1955) Further studies on the metabolic fate of chloral hydrate and trichloroethanol. Bull Johns Hopkins Hosp 97:320-326. Reimche, LD; Sankaran, K; Hindmarsh, KW; et al. (1989) Chloral hydrate sedation in neonates and infants - clinical and pharmacologic considerations. Dev Pharmacol Ther 12:57-64. Saillenfait, AM; Langonne, I; Abate, JP. (1995) Developmental toxicity of trichloroethylene, tetrachloroethylene and four of their metabolites in rat whole embryo culture. Arch Toxicol 70:71-82. Sanders, VM; Kauffman, BM; White, KL; et al. (1982) Toxicology of chloral hydrate in the mouse. Environ Health Perspect 44:137-146. Shapiro, S; Stone, D; Lewis, GP; et al. (1969) Clinical effects of hypnotics. II. An epidemiological study. J Am Med Assoc 209:2016-2020. Sing, K; Erickson, T; Amitai, Y; et al. (1996) Chloral hydrate toxicity from oral and intravenous administration. J Toxicol Clin Toxicol 34:101-106. Stenner, RD; Merdink, JL; Stevens, DK; et al. (1997) Enterohepatic recirculation of trichloroethanol glucuronide as a significant source of trichloroacetic acid. Drug Metab Dispos 25:529-535. Stenner, RD; Merdink, JL; Fisher, JW; et al. (1998) Physiologically-based pharmacokinetic model for trichloroethylene considering enterohepatic recirculation of major metabolites. Risk Anal 18:261-269. U.S. EPA. (2000) Toxicological review of chloral hydrate. Available at http://www.epa.gov/iris. Zimmermann, T; Wehling, M; Schultz, HU. (1998) Untersuchungen zur relativen Bioverfugbarkeit und Pharmakokinetik von Chloralhydrat und seinen Metaboliten [The relative bioavailability and pharmacokinetics of chloral hydrate and its metabolites]. Arzneimittelforschung 48:5-12. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Adler, ID. (1993) Synopsis of the in vivo results obtained with 10 known or suspected aneugens tested in the CEC collaborative study. Mutat Res 287:131-137. Benane, SG; Blackman, CF; House, DE. (1996) Effect of perchloroethylene and its metabolites on intercellular communication in clone 9 rat liver cells. J Toxicol Environ Health 48:427-437. Brunner, M; Albertini, S; Würgler, FE. (1991) Effects of 10 known or suspected spindle poisons in the in vitro porcine brain tubulin assembly assay. Mutagenesis 6:65-70. Bull, RJ; Sanchez, IM; Nelson, MA; et al. (1990) Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology 63:341-359. Daniel, FB; DeAngelo, AB; Stober, JA; et al. (1992) Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fundam Appl Toxicol 19:159-168. DeAngelo, AB; Daniel, FB; Stober, JA; et al. (1991) The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse. Fundam Appl Toxicol 16:337-347. DeAngelo, AB; Daniel, FB; Most, BM; et al. (1996) The carcinogenicity of dichloroacetic acid in the male Fischer 344 rat. Toxicology 114:207-221. DeAngelo, AB; Daniel, FB; Most, BM; et al. (1997) The failure of monochloroacetic acid and trichloroacetic acid administered in the drinking water to produce liver cancer in male F344/N rats. J Toxicol Environ Health 52:425-445. Ferreira-Gonzalez, A; DeAngelo, AB; Nasim, S; et al. (1995) Ras oncogene activation during hepatocarcinogenesis in B6C3F1 male mice by dichloroacetic and trichloroacetic acid. Carcinogenesis 16:495-500. George, MH; Kilburn, S; Moore, T; et al. (2000) The carcinogenicity of chloral hydrate administered in the drinking water to the male B6C3F1 mouse and F344/N rat. Toxicol Pathol, in press. Herren-Freund, SL; Pereira, MA; Khoury, MD; et al. (1987) The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol Appl Pharmacol 90:183-189. Lee, GM; Diguiseppi, J; Gawdi, GM; et al. (1987) Chloral hydrate disrupts mitosis by increasing intracellular free calcium. J Cell Sci 88:603-612. Leuschner, J; Beuscher, N. (1998) Studies on the mutagenic and carcinogenic potential of chloral hydrate. Arzneim-Forsch/Drug Res 48:961-968. Natarajan, AT. (1993) An overview of the results of testing of known or suspected aneugens using mammalian cells in vitro. Mutat Res 287:113-118. National Toxicology Program (NTP). (2000a) Toxicology and carcinogenesis studies of chloral hydrate in B6C3F1 mice (gavage studies). NTP TR 502. NTP. (2000b) Toxicology and carcinogenesis studies of chloral hydrate (ad libitum and dietary controlled) in male B6C3F1 mice (gavage study). NTP TR 503. Ni, Y-C; Wong, T-Y; Kadlubar, FF; et al. (1994) Hepatic metabolism of chloral hydrate to free-radical(s) and induction of lipid peroxidation. Biochem Biophys Res Commun 204:937-943. Ni, Y-C; Kadlubar, FF; Fu, FF. (1995) Formation of malondialdehyde-modified 2'-deoxyguanosinyl adduct from metabolism of chloral hydrate by mouse liver microsomes. Biochem Biophys Res Commun 205:1110-1117. Ni, Y-C; Wong, T-Y; Lloyd, RV; et al. (1996) Mouse liver microsomal metabolism of chloral hydrate, trichloroacetic acid, and trichloroethanol leading to induction of lipid peroxidation via a free radical mechanism. Drug Metab Dispos 24:81-90. Parry, JM. (1993) An evaluation of the use of in vitro tubulin polymerization, fungal and wheat assays to detect the activity of potential chemical aneugens. Mutat Res 287:23-28. Parry, JM; Sors, A. (1993) The detection and assessment of the aneuploidogenic potential of environmental chemicals: the European Community Aneuploidy Project Mutat Res 287:3-16. Pereira, MA. (1996) Carcinogenic activity of dichloroacetic acid and trichloroacetic acid in the liver of female B6C3F1 mice. Fundam Appl Toxicol 31:192-199. Richmond, RE; Carter, JH; Carter, HW; et al. (1995) Immunohistochemical analysis of dichloroacetic acid (DCA)-induced hepatocarcinogenesis in male Fischer (F344) rats. Cancer Lett 92:67-76. Rijhsinghani, KS; Abrahams, C; Swerdlow, MA; et al. (1986) Induction of neoplastic lesions in the livers of C57BL x C3HF1 mice by chloral hydrate. Cancer Detect Prev 9:279-288. U.S. Environmental Protection Agency (EPA). (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34002. U.S. EPA. (1996) Proposed guidelines for carcinogen risk assessment. Federal Register 61(79):17960-18011. U.S. EPA. (2000) Toxicological review of chloral hydrate. Available at http://www.epa.gov/iris. Velazquez, SF. (1994) Activation of the H-ras oncogene by drinking water disinfection by-products. NTIS/PB95-200515. Vian, L; Van Hummelen, P; Bichet, N; et al. (1995) Evaluation of hydroquinone and chloral hydrate on the in vitro micronucleus test on isolated lymphocytes. Mutat Res 334:1-7. Wallin, M; Hartley-Asp, B. (1993) Effects of potential aneuploidy inducing agents on microtubule assembly in vitro. Mutat Res 287:17-22. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Chloral hydrate CASRN -- 302-17-0 Date Section Description ---------------------------------------------------------------------------- 08/22/1988 I.A. Oral RfD Summary on-line 01/01/1990 VI. Bibliography on-line 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 02/01/1996 I.A.1. Minor test change 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 09/15/2000 I-VIII New RfD and cancer assessment; name changed from chloral to chloral hydrate. 12/03/2002 I.A.6., I.B., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 407 of 1119 in IRIS (through 2003/06) AN: 306 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0306-tr.pdf UD: 199708 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Cumene- SY: 98-82-8; ISOPROPYL-BENZENE-; ISOPROPYLBENZOL-; 2-PHENYLPROPANE- RN: 98-82-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199708 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Cumene CASRN -- 98-82-8 Last Revised -- 08/01/1997 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- ---------- Increased average NOAEL: 154 mg/kg-day 1000 1 1E-1 kidney weight in adjusted to 110 mg/kg-day mg/kg-day female rats Rat Oral Gavage LOAEL: 462 mg/kg-day Study adjusted to 331 mg/kg-day Wolf et al., 1956 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- Dose adjustments based on dosing schedule given in study, where 139 doses were administered in 194 days. NOAEL(ADJ) = 154 mg/kg-day x 139/194 = 110 mg/kg-day, and LOAEL(ADJ) = 462 mg/kg-day x 139/194 = 331 mg/kg-day. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth, and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzenes. Arch. Ind. Health. 14: 387-398. Groups of 10 female Wistar rats were administered 139 doses of cumene by gavage in olive oil at 154, 462, or 769 mg/kg-day over a 194-day period; 20 rats given olive oil served as controls. Body weights, food consumption and mortality were noted throughout the study, although no results are shown. Hematological evaluations were conducted after the 20th, 40th, 80th, and 130th doses, and blood urea nitrogen determinations and gross and histological examinations (lungs, heart, liver, kidneys, testes, spleen, adrenals, pancreas, and femoral bone marrow) were conducted at the end of the study. No compound-related histopathological results were noted at any dose level. An increase in average kidney weight was noted as a "slight effect" at 462 mg/kg-day. A more pronounced weight increase in average kidney weight, noted as a "moderate effect," occurred at 769 mg/kg-day, although no quantitative data is presented. Effects were not observed at 154 mg/kg-day. Similar weight alterations have been reported in other less-than-lifetime exposures to cumene (Cushman et al., 1995), in which they also have shown limited reversibility. These alterations are considered toxicologically significant and adverse, because such persistence indicates limited reversibility and uncertainty about the progression and fate of these alterations under true chronic exposures. The weight increase described at the middle dose is considered a LOAEL, and the low dose in this study (154 mg/kg-day), at which no effects were noted in any systems examined, was designated the NOAEL. Benchmark dose analysis was not attempted for this endpoint because no quantitative data are presented. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- 1000. The following uncertainty factors are applied: 10 for extrapolation for interspecies differences and 10 for consideration of interspecies variation. A partial UF of 3 is applied for subchronic-to-chronic duration extrapolation. Justification for the use of a partial UF for subchronic-to-chronic extrapolation was that the duration of the study (6 to 7 months) is intermediate between subchronic (3 months) and chronic (24 months) duration. A partial UF also is used for database deficiencies (lack of reproductive information). The total UF = 10 x 10 x 3 x 3, which is rounded to 1000. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) No human information on the toxicity of this compound was located. There is a pharmacokinetic study in which humans were exposed head-only for 8 hours to concentrations of cumene as high as 720 mg/cu.m (Senczuk and Litewka, 1976). The results from this study show that cumene is well absorbed from the respiratory tract (approximately 50%), and that excretion of cumene, estimated from urinary amounts of 2-phenyl-2-propanol, was maximal after 6 to 8 hours of exposure and approached zero at 40 hours postexposure. These results concur with those reported in rats (Research Triangle Institute, 1989), showing efficient absorption, distribution, and metabolism of cumene following single administration by both the oral and inhalation routes. Increased organ weights have been noted in other toxicity studies with cumene. The inhalation RfC also is based on increased renal and adrenal weights observed after a 13-week inhalation study with cumene (Cushman et al., 1995). Increases in kidney weights also were reported in another 4-week inhalation study (Monsanto Company, 1986) and a 2-week inhalation study (Chemical Manufacturers' Association, 1989). These independent observations reinforce and corroborate the findings of the principal study. Neurotoxicological effects from long-term exposure to cumene warrant examination. Short-term exposures of mice to high concentrations (20 minutes at 2000 to 8000 ppm) of cumene produce transient symptoms typical of CNS depression typical of many other solvents (Tegeris and Balster, 1994). Longer term exposures to smaller concentrations, such as in the Cushman et al. (1995) study, did not elicit detectable neurotoxic effects. Extensive examinations in the latter study, including repeated functional observational batteries, motor activity tests, and neurohistopathology, produced no objective reproducible indications of neurotoxicological effects in rats that had undergone repeated exposures to cumene for 13 weeks at concentrations as high as 1202 ppm. Inhalation developmental studies with cumene are reported in the inhalation RfC for cumene. The kinetics of cumene via oral and inhalation exposure have been examined in rats (Research Triangle Institute, 1989) and indicate similar quantitative and qualitative results of absorption, distribution, elimination, and metabolism of cumene between these routes, thereby providing at least a partial scientific basis for the use of the inhalation studies to judge the developmental toxicity of cumene via the oral route. No indications of developmental toxicity were observed in a pair of studies in which pregnant rats and rabbits were exposed to vapors of cumene. Pregnant Sprague-Dawley rats (25/group) were exposed to 0, 487, 2399, or 5953 mg/cu.m cumene for 6 hours/day on Days 6 through 15 of gestation (Bushy Run Research Center, 1989a). Clinical signs of toxicity were observed in some dams at the two highest concentrations. There were no statistically significant adverse effects on reproductive parameters or fetal development. New Zealand White rabbits (15/group) were exposed to 0, 2418, 5928, or 11,292 mg/cu.m cumene for 6 hours/day on Days 6 through 18 of gestation (Bushy Run Research Center, 1989b). Two does died at the highest exposure concentration. Other clinical signs of toxicity were observed at this exposure level only. Nonsignificant alterations observed in several gestational parameters (increases in nonviable implants, early resorptions, and percent of live fetuses) were consistent with adverse developmental effects occurring among animals exposed to the highest exposure concentration. The highest exposure level is considered a LOAEL for both maternal and developmental effects. The next lower level, 5928 mg/cu.m, is considered a NOAEL for both developmental and maternal effects. No multigenerational or other reproductive studies exist for this compound. However, Cushman et al. (1995) conducted morphological evaluation of epididymal and testicular sperm in rats exposed for 13 weeks to cumene vapors. No cumene-related differences in count, morphology, or stages of spermatogenesis were noted, although one high-dose rat did have diffuse testicular atrophy. (The IRIS entry for the structurally related compound toluene (methyl benzene) reports occurrence of a significant decrease in weight of offspring in a one-generation reproductive study at a NOAEL of 1885 mg/cu.m.) For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=18. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Medium RfD -- Low The overall confidence in this RfD assessment is low to medium. The confidence in the principal study is low. For purposes of quantitative assessment, the quality of the principal study (Wolf et al., 1956) is marginal because the group sizes are minimal and little quantitative information is presented. The confidence in the database, judged here as medium to low, is improved from the earlier version of this assessment on IRIS, principally because of the availability of inhalation developmental studies, some reproductive measures, and kinetic information. Kinetic information on oral and inhalation routes of exposure (Research Triangle Institute, 1989) justifies utilization of the inhalation developmental studies performed in two species, rats and rabbits, in which marginally adverse results were noted in the rabbit study. Neither 2-year chronic nor multigenerational reproductive studies are available for this compound. Results on some male reproductive parameters were, however, documented in Cushman et al. (1995), the principal study for the inhalation RfC. The critical effect, altered tissue weights, was the same across routes of exposure (this was also the critical effect for the RfC) and was observed in several studies giving confidence in the consistency of this effect. The major areas of scientific uncertainty in this assessment are the lack of both full-scale reproductive and 2-year chronic animal studies and the absence of any human toxicity information. These areas are compensated for by the UFs indicated above. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=23. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1997 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 1997. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=31. Other EPA Documentation -- U.S. EPA, 1987 Agency Consensus Review Date -- 06/06/1997 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Cumene conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199708 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Cumene CASRN -- 98-82-8 Last Revised -- 08/01/1997 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Increased kidney NOAEL: 2438 mg/cu.m (496 ppm) 1000 1 4E-1 weights in female NOAEL(ADJ): 435 mg/cu.m mg/cu.m rats and adrenal NOAEL(HEC): 435 mg/cu.m weights in male and female rats Rat 13-Week LOAEL: 5909 mg/cu.m (1202 ppm) Inhalation Study LOAEL(ADJ): 1055 mg/cu.m LOAEL(HEC): 1055 mg/cu.m Cushman et al., 1995 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- MW = 120.2. Assuming 25 C and 760 mmHg, NOAEL (mg/cu.m) = 496 ppm x 120.2/24.45 = 2438 mg/cu.m. NOAEL(ADJ) = NOAEL (mg/cu.m) x 6 hours/24 hours x 5/7 days = 435 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extrarespiratory (systemic) effect assuming periodicity was obtained. Because the b:a lambda values are unknown for the experimental animal species and humans, a default value of 1 is used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x b:a lambda(a) / b:a lambda(h) = 435 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Cushman, J.R., J.C. Norris, D.E. Dodd, K.I. Darmer, and C.R. Morris. 1995. Subchronic inhalation toxicity assessment of cumene in Fischer 344 rats. J. Am. Coll. Toxicol. 14(2): 129-147. Two successive subchronic inhalation toxicity studies with cumene vapor (>99.9% pure) were conducted on Fischer 344 rats. In the first study, groups, (21/sex) were exposed to 0, 100, 496, or 1202 ppm (0, 492, 2438, or 5909 mg/cu.m, respectively) cumene vapor for 6 hours/day, 5 days/week, for 13 weeks (duration adjusted to 0, 88, 435, and 1055 mg/cu.m). In the second study, the group size was decreased to 15/sex, an additional group (50 ppm, duration adjusted to 44 mg/cu.m) was added, and a 4-week postexposure recovery period was incorporated at the end of the experiment. Animals were sacrificed a few days after the last exposure in the first study and after the 4-week postexposure period in the second study. Parameters monitored included clinical signs of toxicity, body weight, food and water consumption, hematology and serum chemistry, organ weights, gross and histopathology (including examination of all respiratory tract tissues, including three sections of the lungs and four sections of the nasal turbinates). Extensive neurotoxicity (including motor activity tests and neurohistopathology) and auditory brain stem responses were assessed in the second study. Some quantitative and morphologic evaluations of spermatogenesis also were examined in the first study (epididymal tissue was taken from 15 rats/group in the first study, and the left testis was taken from each male) in an effort to judge the potential of cumene to cause reproductive toxicity. Both absolute and relative weights were increased significantly (>10%, p< /= 0.05) in the kidneys and adrenal glands of both sexes at the highest concentration in the first study. The results of the second study, with a 4-week postexposure period, indicated limited reversibility to these alterations. In this second study, significant mean weight increases were present 4 weeks postexposure in adrenals from females exposed to the highest concentration. These alterations are considered toxicologically significant and adverse, because such persistence indicates limited reversibility and uncertainty about the progression and fate of these alterations under chronic exposures. No reproducible or dose-related neurotoxicological effects or neurohistopathology were noted. Morphological evaluation of epididymal and testicular sperm showed no cumene-related differences in count, morphology, or stages of spermatogenesis, although one high-dose rat did have diffuse testicular atrophy. The only microscopic effect associated with these organ weight changes was increased incidence of kidney lesions at the two highest exposure concentrations in male rats only. The renal histopathology reported in this study fulfill several criteria for assignation to male specific renal nephropathy caused by chemicals that induce excessive accumulation of alpha-2u-globulin (U.S. EPA, 1991; Hard et al., 1993): lesions were limited to males; hyaline droplet formation was noted, which increased in severity in a dose-related fashion; and lesions associated with the pathologic sequence of alpha-2u-globulin nephropathy were noted, including tubular proteinosis (presumably from exfoliation of epithelial cells into the proximal tubular lumen) and tubular epithelial cell hyperplasia/hypertrophy (presumed to be regenerative from tubular necrosis). Although one criterion is not met within the study, positive identification of the accumulating protein in the hyaline droplets as alpha-2u-globulin, the pattern described strongly suggests male rat specific nephropathy. The U.S. EPA does not consider nephropathy associated with accumulation of alpha-2u-globulin as an appropriate endpoint to determine noncancer toxicity. Chronic progressive nephropathy, which also occurs predominantly in male rats, also is characterized by tubular hyperplasia and proteinosis (Montgomery and Seely, 1990), and this condition also may contribute to these renal lesions. These lesions, as well as the renal weight increases in males, which may be confounded by this species and sex-specific nephropathy, thus are not used in this assessment. The critical effects in this subchronic study are increased relative and absolute kidney weights in females and increased relative and absolute adrenal weights in both sexes at the highest concentration tested, 1202 ppm, the LOAEL. The next lower concentration, 496 ppm, is the NOAEL. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- 1000. The following full uncertainty factors are applied to the NOAEL: 10 for subchronic-to-chronic extrapolation and 10 for consideration of intraspecies variation. Partial uncertainty factors also are applied to this effect level for consideration of interspecies extrapolation (which already has been addressed partially through the calculation of an HEC) and for database deficiencies (lack of reproductive studies). The total UF = 10 x 10 x 3 x 3, which is rounded to 1000. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) No information on the toxicity of this compound in humans was located. There does exist a pharmacokinetic study where humans were exposed head-only for 8 hours to concentrations of cumene as high as 720 mg/cu.m (Senczuk and Litewka, 1976). The results of this study show that cumene is well absorbed from the respiratory tract (approximately 50%), and that excretion of cumene, estimated from urinary amounts of 2-phenyl-2-propanol, was maximal after 6 to 8 hours of exposure and approached zero at 40 hours postexposure. These results concur with those reported in rats (Research Triangle Institute, 1989), showing efficient absorption, distribution, and metabolism of cumene following administration by both the oral and inhalation routes. Neurotoxicological effects from long-term exposure to cumene warrant examination. Short-term exposures of mice to high concentrations (20 minutes at 2000 to 8000 ppm) cumene produced transient symptoms typical of CNS depression typical of many other solvents (Tegeris and Balster, 1994). Longer term exposures to smaller concentrations do not appear to result in detectable neurotoxic effects because extensive examinations, including repeated functional observational batteries, motor activity tests, and neurohistopathology, produced no objective reproducible indications of neurotoxicological effects in rats that had undergone repeated exposures to cumene for 13 weeks at concentrations as high as 1202 ppm (Cushman et al., 1995). Results from two short-term inhalation studies corroborate the results of organ weight alterations reported in Cushman et al. (1995). Male and female Sprague-Dawley rats (10/sex/group) were exposed to cumene vapor concentrations of 0, 516, 1475, or 2945 mg/cu.m for 6 hours/day, 5 days/week for approximately 4 weeks, for a minimum exposure of 20 days (Monsanto Company, 1986). Among exposed males, increases (p < 0.05) in mean absolute left and right kidney weights were observed at the highest dose and, in left kidney weights, in the mid- and low-dose groups. Among high-dose females, the mean absolute weight of left kidneys was greater (p < 0.05) than in controls. No compound-related pathological changes were detected during gross or microscopic examination of these or other organs. Fischer 344 rats (10/sex/group) were exposed to cumene at 0, 1234, 2689, 5147, or 6342 mg/cu.m, for 6 hours/day, 5 days/week for 2 weeks (Chemical Manufacturers' Association, 1989). Among females in the two highest dose groups, the average relative kidney weight and relative and absolute adrenal weights all were increased significantly over control values. Fabre et al. (1955) exposed Wistar rats to a single concentration of cumene vapor, 2500 mg/cu.m, for 8 hours/day, 6 days/week for up to 180 days (duration adjusted to 714 mg/cu.m), and rabbits were exposed to 6500 mg/cu.m, using the same exposure regimen (duration-adjusted concentration is 1857 mg/cu.m). Histological effects reported were "passive congestion" in the lungs, liver, spleen, kidney, and adrenals, the presence of hemorrhagic zones in the lung and hemosiderosis in the spleen, and lesions from epithelial nephritis "in some cases". It was not clear if these effects occurred in both species. In an inhalation exposure study, groups of Sprague-Dawley or Long-Evans rats (n = 15), Princeton-derived guinea pigs (n = 15), beagles (n = 2), and squirrel monkeys (n = 2) were exposed to cumene at concentrations of 18 or 147 mg/cu.m continuously for 90 days (Jenkins et al., 1970). A group of rats also was exposed to cumene at 1200 mg/cu.m for 8 hours/day, 5 days/week for 30 exposures (duration adjusted concentration = 286 mg/cu.m). No toxicologically significant findings were reported. No indications of developmental toxicity were observed in a pair of studies in which pregnant rats and rabbits were exposed to vapors of cumene. Pregnant Sprague-Dawley rats (25/group) were exposed to 0, 487, 2399, or 5953 mg/cu.m cumene for 6 hours/day on Days 6 through 15 of gestation (Bushy Run Research Center, 1989a). Clinical signs of toxicity were observed in some dams at the two highest concentrations. There were no statistically significant adverse effects on reproductive parameters or fetal development. New Zealand White rabbits (15/group) were exposed to 0, 2418, 5928, or 11,292 mg/cu.m cumene for 6 hours/day on Days 6 through 18 of gestation (Bushy Run Research Center, 1989b). Two does died at the highest exposure concentration. Nonsignificant alterations observed in several gestational parameters (increases in nonviable implants, early resorptions, and percent of live fetuses) were consistent with adverse developmental effects occurring among animals exposed to the highest exposure concentration. The highest exposure level is considered a LOAEL for both maternal and developmental effects. The next lower level, 5928 mg/cu.m, is considered a NOAEL for both developmental and maternal effects. No multigenerational reproductive study exists for this compound. Cushman et al. (1995), however, conducted morphological evaluation of epididymal and testicular sperm in rats exposed for 13 weeks to cumene vapors. No cumene-related differences in count, morphology, or stages of spermatogenesis were noted, although one high-dose rat did have diffuse testicular atrophy. The IRIS entry for the structurally related compound toluene (methyl benzene) reports occurrence of a significant decrease in weight of offspring in a one-generation reproductive study at a NOAEL of 1885 mg/cu.m. For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=18. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Data Base -- Medium RfC -- Medium The overall confidence in this RfC assessment is medium. The principal study was performed with adequately sized groups, had extensive and thorough histopathological analyses, and included ancillary studies for neurotoxicity and ocular pathology. The quality of this evidence is high in comparison to the study of Fabre et al. (1955), who used only a single exposure concentration, and to the study of Jenkins et al. (1970), who used small groups of animals. Neither 2-year chronic nor multigenerational reproductive studies are available for this compound. Results on some male reproductive parameters were, however, documented in the principal study of Cushman et al. (1995). The critical effect, altered tissue weights, was the same across routes of exposure (this was also the critical effect for the oral RfD) and was observed in several studies, giving confidence in the consistency of this effect.||The major areas of scientific uncertainty in this assessment are the lack of 2-year chronic and full-scale reproductive studies and the absence of any information on human toxicity. These areas are compensated for by partial UFs. Assessment of the renal lesions observed in male rats in the principal study requires special attention. As noted above, the renal histopathology reported in this study fulfills several criteria for assignation to male-specific renal nephropathy caused by chemicals that induce excessive alpha-2u-globulin, such as d-limonene and decalin (U.S. EPA, 1991; Hard et al., 1993). Although positive identification of the accumulating protein in the hyaline droplets as alpha-2u-globulin was not accomplished, the pattern described strongly suggests male-rat-specific alpha-2u-globulin nephropathy. This assessment has discounted these histopathological lesions in establishing an effect level for derivation of the RfC because the U.S. EPA has expressed the opinion that these lesions are not an appropriate endpoint to determine noncancer toxicity. So, too, have the increased renal weights observed in the male rats been discounted because this effect may be confounded by the presence of the factors involved in the progression of the nephropathy or by another mechanism altogether, such as rat chronic progressive nephropathy, which is known to be exacerbated by certain compounds (Montgomery and Seely, 1990). What has been accepted as toxicologically relevant from the profile of kidney toxicity in the principal study is the increase in female renal weights. Other repeated-dose studies with cumene also have reported increased renal weights among female rats (Wolf et al., 1956; Monsanto Company, 1986; Chemical Manufacturers' Association, 1989). These independent observations, coupled with their persistence postexposure and uncertainty about the progression/outcomes of these alterations (because of the absence of any chronic studies), justify considering the weight alterations in kidneys and adrenals as toxicologically significant. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=23. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 1997 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary in June 1997. A record of these comments is included as an appendix to U.S. EPA, 1997. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=31. Other EPA Documentation -- U.S. EPA, 1987 Agency Consensus Review Date -- 06/06/1997 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Cumene conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199708 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Cumene CASRN -- 98-82-8 Last Revised -- 08/01/1997 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- Under the current Risk Assessment Guidelines (U.S. EPA, 1987a), cumene is assigned carcinogen category D, not classifiable, indicating no or inadequate human or animal data. Under the proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), it is concluded that the carcinogenic potential of cumene cannot be determined because no adequate data, such as well-conducted long-term animal studies or reliable human epidemiological studies, are available for any assessment. Concern for the carcinogenic potential of cumene is judged to be limited from several standpoints. The metabolic pathways of this compound are, for the most part, known for both rats and humans and do not involve any suspect reactive species. Cumene has been examined in a relatively complete battery of in vivo and in vitro mutagenicity tests, including gene mutation, chromosomal aberration, and primary DNA damage. Only a single test, a micronucleus assay, was mildly positive, and then at a dose that resulted in mortality in some animals. Trends in structure-activity relationships are unclear for cumene. It is, however, clear with respect to metabolism that cumene is more analogous to methyl benzene (toluene) than to ethyl benzene, and that toluene showed no evidence of carcinogenic activity in rats or mice in a 2-year inhalation study (NTP, 1990). In summary, there is not much suspicion that cumene would pose a significant carcinogenic hazard. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=23. , For more details on other Hazard Identification issues, exit the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=18. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate; none are available. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate; none are available. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Cumene was tested at concentrations up to 2000 ug/plate in a S. Typhimurium reverse mutation assay (modified Ames test); negative results were observed with and without metabolic activation (Lawlor and Wagner, 1987). Cumene was negative in an Ames assay at concentrations up to 3606 ug/plate (Florin et al., 1980). Cumene also tested negative, with and without metabolic activation, in a set of hypoxanthine-guanosine phosphoribosyltransferase assays (using CHO cells) at concentrations up to 225 ug/mL (Yang, 1987; Gulf Life Sciences Center, 1985a). A micronucleus assay performed in mice gavaged up to 1 g/kg cumene was negative (Gulf Life Sciences Center, 1985b). A recent micronucleus assay performed in rats (NTP, 1996) gave a weakly positive result at an extraordinarily high dose (2.5 g/kg ip). Cumene failed to induce significant rates of transformation in BALB/3T3 cells (without activation) at concentrations up to 500 ug/mL (Putnam, 1987) but tested positive in an earlier cell transformation test that also used BALB/3T3 cells, in which an increase in transformations was observed at 60 ug/mL (Gulf Oil Corporation, 1984a). One test for unscheduled DNA synthesis (UDS) in rat primary hepatocytes, using exposures of up to 24 ug/mL cumene (without activation), was negative (Curren, 1992), whereas results from an earlier test indicated UDS at cumene doses of 16 and 32 ug/mL (Gulf Oil Corporation, 1984b). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1987b, 1997 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to U.S. EPA, 1997. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0306-tr.pdf#page=31. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Review Date -- 06/06/1997 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Cumene conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199708 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Cumene CASRN -- 98-82-8 Last Revised -- 08/01/1997 SORD: __VI.A. ORAL RfD REFERENCES Bushy Run Research Center. 1989a. Developmental toxicity study of inhaled cumene vapor in CD (Sprague-Dawley) rats. Final project report 52-621. TSCATS/0522881; EPA/OTS Doc. No. 40-8992172. Bushy Run Research Center. 1989b. Developmental toxicity study of inhaled cumene vapor in New Zealand White rabbits. Final project report 52-622. TSCATS/0522881; EPA/OTS Doc. No. 40-8992172. Chemical Manufacturers' Association. 1989. A two-week pilot inhalation toxicity study of cumene vapors in rats, with attachments and cover letter dated September 7, 1989. TSCATS/0522867; EPA/OTS Doc. No. 40-8992168. Cushman, J.R., J.C. Norris, D.E. Dodd, K.I. Darmer, and C.R. Morris. 1995. Subchronic inhalation toxicity and neurotoxicity assessment of cumene in Fischer 344 rats. J. Am. Coll. Toxicol. 14(2): 129-147. Monsanto Company. 1986. One-month study of cumene vapor administered to male and female Sprague-Dawley rats by inhalation. U.S. EPA/OTS Public Files, 8D submission. Microfiche No. OTS0513229. Research Triangle Institute. 1989. Metabolism, disposition and pharmacokinetics of cumene in F-344 rats following oral, IV administration or nose-only inhalation exposure. Report RTI/4353-01F. CMA Reference No. CU-5.0-PK-RTI. Senczuk, W. and B. Litewka. 1976. Absorption of cumene through the respiratory tract and excretion of dimethylphenylcarbinol in urine. Br. J. Ind. Med. 33: 100-105. Tegeris, J.S. and R.L. Balster. 1994. A comparison of the acute behavioral effects of alkylbenzenes using a functional observational battery in mice. Fund. Appl. Toxicol. 22: 240-250. U.S. EPA. 1987. Health and Environmental Effects Document on Cumene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC. August. U.S. EPA. 1997. Toxicological Review of Cumene. U.S. Environmental Protection Agency, Washington, DC. Contact the IRIS Hotline at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth, and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Bushy Run Research Center. 1989a. Developmental toxicity study of inhaled cumene vapor in CD (Sprague-Dawley) rats. Final project report 52-621. TSCATS/0522881; EPA/OTS Doc. No. 40-8992172. Bushy Run Research Center. 1989b. Developmental toxicity study of inhaled cumene vapor in New Zealand White rabbits. Final project report 52-622. TSCATS/0522881; EPA/OTS Doc. No. 40-8992172. Chemical Manufacturers' Association. 1989. A two-week pilot inhalation toxicity study of cumene vapors in rats, with attachments and cover letter dated September 7, 1989. TCCATS/0522867: EPA/OTS Doc. No. 40-8992168. Cushman, J.R., J.C. Norris, D.E. Dodd, K.I. Darmer, and C.R. Morris. 1995. Subchronic inhalation toxicity and neurotoxicity assessment of cumene in Fischer 344 rats. J. Am. Coll. Toxicol. 14(2): 129-147. Fabre, R.R. Truhaut, J. Bernuchon, and F. Loisillier. 1955. Toxicologic studies of solvents to replace benzene. III. Study of isopropylbenzene or cumene. Arch. Mal. Prof. 16(4): 285-299. Hard, G.C., I.S. Rodgers, K.P. Baetcke, W.L. Richards, R.E. McGaughy, and L.R. Valcovic. 1993. Hazard evaluation of chemicals that cause accumulation of alpha2-microglobulin, hyaline droplet nephropathy, and tubular neoplasia in the kidneys of male rats. Environ. Health Perspect. 99: 313-349. Jenkins, L.J., Jr., R.A. Jones, J. Siegel. 1970. Long-term inhalation screening studies of benzene, toluene, ortho-xylene, and cumene on experimental animals. Toxicol. Appl. Pharmacol. 16: 818-823. Monsanto Company. 1986. One-month study of cumene vapor administered to male and female Sprague-Dawley rats by inhalation. U.S. EPA/OTS Public Files, 8D submission. Microfiche No. OTS0513229. Montgomery, C.A., Jr. and J.C. Seely. 1990. Chapter 10, Kidney, in Pathology of the Fischer Rat, Reference and Atlas, G.A. Boorman, et al., Eds. Academic Press. p. 127-153. Research Triangle Institute. 1989. Metabolism, disposition and pharmacokinetics of cumene in F-344 rats following oral, IV administration or nose-only inhalation exposure. Report RTI/4353-01F. CMA Reference No. CU-5.0-PK-RTI. Senczuk, W. and B. Litewka. 1976. Absorption of cumene through the respiratory tract and excretion of dimethylphenylcarbinol in urine. Br. J. Ind. Med. 33: 100-105. Tegeris, J.S. and R.L. Balster. 1994. A comparison of the acute behavioral effects of alkylbenzenes using a functional observational battery in mice. Fund. Appl. Toxicol. 22: 240-250. U.S. EPA. 1987. Health and Environmental Effects Document on Cumene. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response. August. U.S. EPA. 1991. Alpha-2 microglobulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Rat. EPA/625/3-91/019F. September. U.S. EPA. 1997. Toxicological Review of Cumene. U.S. Environmental Protection Agency, Washington, DC. Contact the IRIS Hotline at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). Wolf, M.A., V.K. Rowe, D.D. McCollister, R.L. Hollingsworth, and F. Oyen. 1956. Toxicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Curren, R.D. 1992. Unscheduled DNA synthesis in rat primary hepatocytes -test article: Cumene. Microbiological Associates, Inc. Study No. T4786.380005, May 28, 1987. EPA/OTS 40-8792124. Microfiche No. OTS 0522853. Florin, I., L. Rutberg, M. Curvall, and C.R Enzell. 1980. Screening of tobacco smoke constituents for mutagenicity using the Ames test. Toxicology. 18: 219-232. Gulf Life Sciences Center. 1985a. CHO/HGPRT test of cumene. Gulf Project No. 84-2128. EPA/OTS Doc. No. 878216011. Microfiche No. OTS 0206775. Gulf Life Sciences Center. 1985b. Micronucleus test of cumene. Gulf Project No. 84-2129. EPA/OTS Doc. No. 878216015. Microfiche No. OTS 0206782. Gulf Oil Corporation. 1984a. TSCA 8(e) submission 8EHQ-11840536 88-8500694. Project No. 84-2131: Cell transformation test of cumene. Office of Toxic Substances, U.S. EPA, Washington, DC. Microfiche No. OTS 0509712. Gulf Oil Corporation. 1984b. TSCA 8(e) submission 8EHQ-11840536 88-8500694. Project No. 84-2130: Hepatocyte primary culture/DNA repair test of cumene. Office of Toxic Substances, U.S. EPA, Washington, DC. EPA/OTS Doc. No. 40-8492086 or Microfiche No. OTS 0512292. Lawlor, T.E. and V.O. Wagner. 1987. Salmonella/Mammalian-microsome preincubation mutagenicity assay (Ames test); test article: Cumene. Microbiological Associates, Inc., Study Number T4786.502009, March 23. EPA/OTS Doc. No. 40-8792121. Microfiche No. OTS 0522851. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of toluene in F344/N rats and B6C3F1 mice. (Available from National Toxicology Program, NIEHS, Research Triangle Park, NC.) NTP (National Toxicology Program). 1996. In-vivo cytogenetics testing results for cumene, micronucleus induction results. (Available from National Toxicology Program, NIEHS, Research Triangle Park, NC.) Putnam, D.L. 1987. Chromosome aberrations in Chinese hamster ovary (CHO) cells - test article: Cumene. Microbiological Associates, Inc., Study No. T4786.337012, May 12. EPA/OTS Doc. No. 40-8792123. Microfiche No. OTS 0922892. U.S. EPA. 1987a. Risk Assessment Guidelines of 1986. EPA/600/8-87/045, August. Prepared by the Office of Health and Environmental Assessment, Washington, DC. U.S. EPA. 1987b. Health and Environmental Effects Document on Cumene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response, Washington, DC, August. U.S. EPA. 1996. (New proposed) Guidelines for Carcinogen Risk Assessment, 1996. (Currently, these guidelines are available only as a draft). U.S. EPA. 1997. Toxicological Review of Cumene. U.S. Environmental Protection Agency, Washington, DC. Contact the IRIS Hotline at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). Yang, L.L. 1987. CHO/HGPRT mutation assay; test article: Cumene. Microbiological Associates, Inc., Study Number T4786.332010, June 1. EPA/OTS Doc. No. 40-8792124. Microfiche No. OTS 0522853. ------------------------------------------------------------------------------ ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Cumene CASRN -- 98-82-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 I.A. Oral RfD summary on-line 07/01/1989 I.B. Inhalation RfD now under review 09/01/1990 VI. Bibliography on-line 01/01/1991 I.A. Text edited 04/01/1991 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 08/01/1997 I.A. Oral RfD replaced; RfD changed 08/01/1997 I.B. Inhalation RfC on-line 08/01/1997 II. Carcinogenicity assessment on-line 10/01/1997 VI.A. Oral RfD references revised 10/01/1997 VI.B. Inhalation RfC references revised 10/01/1997 VI.C. Carcinogenicity assessment references revised 12/03/2002 I.A.6., I.B.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 408 of 1119 in IRIS (through 2003/06) AN: 317 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199602 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Furfural- SY: 98-01-1; FURALE-; FURANCARBONAL-; FURFURALDEHYDE-; FURFUROLE-; FURFURYLALDEHYDE-; FUROLE-; PYROMUCIC-ALDEHYDE- RN: 98-01-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199602 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Furfural CASRN -- 98-01-1 Last Revised -- 02/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Mild hepatocellular NOAEL: none 3000 1 3E-3 vacuolization mg/kg/day LOAEL: 11 mg/kg/day Rat Oral Subchronic converted to 7.9 mg/kg/day Study NTP, 1981a ---------------------------------------------------------------------------- *Conversion Factors: Doses adjusted for gavage schedule of 5 days/week. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1981a. 90-day Rat Report. Unpublished study performed by Southern Research Institute. Useful studies of oral exposure are restricted to 13-week gavage experiments with F-344 rats (NTP, 1981a) and B6C3F1 mice (NTP, 1981b), which indicate that the liver is the target organ of furfural in these species. In groups of 10 male and 10 female rats treated with 11, 22, 45, 90 or 180 mg/kg, 5 days/week, mortality was associated with greater than or equal to 90 mg/kg and cytoplasmic vacuolization was seen in all treated groups. The lesions were described as mild to moderate, and the low dose level of 11 mg/kg may be considered a LOAEL in rats. Lacking a suitable NOAEL, the LOAEL of 11 mg/kg, 5 days/week in rats reported by NTP (1981a) is chosen for the derivation of an RfD. An RfD of 0.003 mg/kg/day or 0.2 mg/day for a 70 kg human is derived by application of an uncertainty factor of 3000. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- Because toxicity data is available on several animal species, a factor of 3 was used to estimate a NOAEL from a LOAEL, 10 to extrapolate from rats to humans, 10 to protect unusually sensitive individuals and 10 for the use of subchronic data in deriving the RfD. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) No oral exposure studies other than those reported by NTP (1981a,b) were available to consider for the derivation of the RfD, and a NOAEL could not be identified. Mice appear to be more resistant than rats to the effects of orally administered furfural. In mice treated by the same schedule as rats with doses of 75, 150, 300, 600 or 1200 mg/kg, heavy mortality occurred at greater than or equal to 600 mg/kg (NTP, 1981b). Degenerative, necrotic and inflammatory liver lesions were noted at greater than or equal to 150 but not at 75 mg/kg. A 13-week study reported by Feron et al. (1979) identifies a NOAEL and LOAEL in hamsters for subchronic inhalation exposure. Data indicate that toxicity may be greater by the oral exposure route and use of oral data eliminates the added uncertainties involved in route-to-route extrapolations. In addition, chronic toxicity and developmental and reproductive toxicity of furfural have not been adequately investigated. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low A low confidence in the RfD reflects a low level of confidence in the study and the data base. Confidence in the RfD is low because the key study, a 13-week gavage rat study (NTP, 1981a) did not identify a NOAEL for liver effects in rats, the more sensitive of the species tested. In addition no studies supporting the RfD were available in the literature. Furthermore, the developmental and reproductive toxicity of furfural have not been adequately investigated. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1987 Limited peer review and Agency-wide review, 1987. Other EPA Documentation -- None Agency Work Group Review -- 12/15/1987 Verification Date -- 12/15/1987 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Furfural conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199108 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Furfural CASRN -- 98-01-1 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Furfural CASRN -- 98-01-1 NOCA: Not available at this time. ============================================================================ UDSO: 199001 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Furfural CASRN -- 98-01-1 Last Revised -- 01/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Feron, V.J., A. Druysse and H.C. Dreef-Van Der Meulen. 1979. Repeated exposure to furfural vapour: 13-week study in Syrian Golden Hamsters. Zbl. Bakt. Hyg. I. Abt. Orig. B 168: 442-451. NTP (National Toxicology Program). 1981a. 90-day Rat Report. Unpublished study performed by Southern Research Institute. NTP (National Toxicology Program). 1981b. 90-day Mouse Report. Unpublished study performed by Southern Research Institute. U.S. EPA. 1987. Health and Environmental Effects Document on Furfural. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Furfural CASRN -- 98-01-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 I.A. Oral RfD summary on-line 01/01/1990 I.A. Correct citations 01/01/1990 VI. Bibliography on-line 08/01/1991 I.B. Inhalation RfC now under review 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 02/01/1996 I.A.7. Secondary contact deleted 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 409 of 1119 in IRIS (through 2003/06) AN: 320 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199502 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: p-Chloroaniline- SY: 106-47-8; 1-AMINO-4-CHLOROBENZENE-; ANILINE,-4-CHLORO-; ANILINE,-P-CHLORO-; BENZENEAMINE,-4-CHLORO-; 4-CHLORANILIN-; P-CHLORANILINE-; 4-CHLOROANILINE-; P-CHLOROANILINE,-LIQUID-; CHLOROANILINE,-P-; P-CHLOROANILINE,-SOLID-; 4-CHLOROBENZENAMINE-; 4-CHLOROPHENYLAMINE-; NCI-C02039-; RCRA-WASTE-NUMBER-P024-; UN-2018-; UN-2019- RN: 106-47-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199502 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- p-Chloroaniline CASRN -- 106-47-8 Last Revised -- 02/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Nonneoplastic lesions NOAEL: None 3000 1 4E-3 of splenic capsule mg/kg/day LOAEL: 250 ppm in diet Rat, Chronic Oral converted to 12.5 Bioassay mg/kg/day NCI, 1979 ---------------------------------------------------------------------------- *Conversion Factors: Food consumption = 5% bw/day; thus 250 mg/kg food x 0.05 kg/kg bw/day = 12.5 mg/kg/day PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NCI (National Cancer Institute). 1979. Bioassay of p-chloroaniline for possible carcinogenicity. NCI Carcinogenesis Tech. Rep. Ser. No. 189. NTIS PB 295896. Groups of 20 and 50 F344 rats of each sex were exposed to p-chloroaniline in the diet at concentration of 0, 250 or 500 ppm for 78 weeks followed by an observation period of 24 weeks. Gross and comprehensive histological examinations were performed on all animals after sacrifice. Significantly increased mortality occurred in the high-dose males and decreased average body weight gain occurred in the high-dose females. Nonneoplastic proliferative lesions of the capsule of the spleen (focal fibrosis with subcapsular mesenchymal proliferation) occurred in most of the treated rats. Fibrosis or fatty infiltration of the splenic parenchyma occurred in some of the high-dose males and one of the high-dose females. Splenic lesions did not occur in any of the control rats. This study did not define a NOEL. The 250 ppm level (12.5 mg/kg/day) is considered to be the LOAEL, which when divided by an uncertainty factor of 3000 results in a RfD of 0.004 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- 10 to extrapolate from a LOAEL to a NOEL, 10 to extrapolate from rats to humans and 10 to protect sensitive humans. An additional UF of 3 was added for lack of supporting reproductive and other toxicity data. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) A 2-year gavage rat bioassay is currently being conducted by the NTP. The RfD must be considered provisional until final results of the gavage bioassay are available. Information regarding teratogenicity or other reproductive effects of p-chloroaniline is not available. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low Data Base -- Low RfD -- Low Although the NCI (1979) bioassay is a well designed chronic oral study, confidence in the study is low because a NOEL or NOAEL was not defined. Confidence in the data base is low because corroborating data are not available. Confidence in the RfD is also low, reflecting the low confidence in the study and data base. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 12/15/1987 Verification Date -- 12/15/1987 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- p-Chloroaniline CASRN -- 106-47-8 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- p-Chloroaniline CASRN -- 106-47-8 NOCA: Not available at this time. ============================================================================ UDSO: 198908 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- p-Chloroaniline CASRN -- 106-47-8 Last Revised -- 08/01/1989 SORD: __VI.A. ORAL RfD REFERENCES NCI (National Cancer Institute). 1979. Bioassay of p-chloroaniline for possible carcinogenicity. NCI Carcinogenesis Tech. Rep. Ser. No. 189. NTIS PB 295896. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- p-Chloroaniline CASRN -- 106-47-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/22/1988 I.A. Oral RfD summary on-line 08/01/1989 VI. Bibliography on-line 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 02/01/1995 I.A.7. Secondary contact's name changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 410 of 1119 in IRIS (through 2003/06) AN: 332 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 198809 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Benzaldehyde- SY: 100-52-7; ARTIFICIAL-ALMOND-OIL-; BENZENE-CARBONAL-; BENZOIC-ALDEHYDE- RN: 100-52-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198809 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Benzaldehyde CASRN -- 100-52-7 Last Revised -- 09/07/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Forestomach lesions, NOEL: 200 mg/kg/day 1000 1 1E-1 kidney toxicity converted to mg/kg/day 143 mg/kg/day Rat Oral Toxicity Study (subchronic) LOAEL: 400 mg/kg/day Kluwe et al., 1983 ---------------------------------------------------------------------------- *Conversion Factors: Doses adjusted for gavage schedule of 5 days/week. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Kluwe, W.M., C.A. Montgomery, H.D. Giles and J.D. Prejeau. 1983. Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde. Food Chem. Toxicol. 21(3):245-250. Kluwe et al. (1983) orally treated groups of 10 mice of each sex with 0, 75, 150, 300, 600 or 1200 mg/kg/day benzaldehyde, and groups of 10 rats of each sex with 0, 50, 100, 200, 400 or 800 mg/kg/day benzaldehyde, 5 days/week for 13 weeks by corn oil gavage. Administration of 600 mg/kg/day in mice was associated with renal tubular necrosis, and administration of 400 mg/kg/day to rats resulted in forestomach hyperplasia and hyperkeratosis. Using the rat NOEL of 200 mg/kg/day, multiplying by 5 days/7 days, and dividing by an uncertainty factor of 1000, results in an RfD of 0.1 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 1000 includes factors of 10 for extrapolation from subchronic to chronic exposure, 10 for intraspecies extrapolation, and 10 for consideration of sensitive human subgroups. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Additional pertinent data regarding the chronic, subchronic or reproductive effects of oral or inhalation exposure to benzaldehyde, were not located in the available literature. The NTP (1986) assayed benzaldehyde in rat and mouse 2-year oral studies, and is currently doing chronic histopathology. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low Confidence in the study was medium because, although two species were studied at five dose levels each and a NOEL and a LOAEL were defined, dosing was subchronic. The absence of appropriate supporting studies makes confidence in the data base low. Confidence in the RfD is low because of these limitations. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1985 Limited peer review and extensive agency-wide review, 1985. Other EPA Documentation -- None Agency Work Group Review -- 10/15/1987 Verification Date -- 10/15/1987 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Benzaldehyde CASRN -- 100-52-7 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Benzaldehyde CASRN -- 100-52-7 NOCA: Not available at this time. ============================================================================ UDSO: 198912 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Benzaldehyde CASRN -- 100-52-7 Last Revised -- 12/01/1989 SORD: __VI.A. ORAL RfD REFERENCES Kluwe, W.M., C.A. Montgomery, H.D. Giles and J.D. Prejeau. 1983. Encephalopathy in rats and nephropathy in rats and mice after subchronic oral exposure to benzaldehyde. Food Chem. Toxicol. 21(3):245-250. NTP (National Toxicology Program). 1986. Benzaldehyde. Management Status Report. Research Triangle Park, NC. U.S. EPA. 1985. Health and Environmental Effects Profile for Benzaldehyde. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Benzaldehyde CASRN -- 100-52-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 I.A. Oral RfD summary on-line 12/01/1989 VI. Bibliography on-line 01/01/1992 I.A.7. Secondary contact changed 01/01/1992 IV. Regulatory Action section on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 411 of 1119 in IRIS (through 2003/06) AN: 344 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 198809 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Rotenone- SY: 83-79-4; CUBE-; DERRIN-; DERRIS-; DERRISROOT-; NICOULINE-; ROTESSENOL-; TUBATOXIN- RN: 83-79-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198809 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Rotenone CASRN -- 83-79-4 Last Revised -- 09/07/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Reduced pup weight NOEL: 7.5 ppm 100 1 4E-3 (0.38 mg/kg/day) mg/kg/day 2-Generation Rat Reproduction Study LEL: 37.5 ppm (1.88 mg/kg/day) U.S. Fish and Wildlife Service, 1983 ---------------------------------------------------------------------------- *Conversion Factors: 1 ppm = 0.05 mg/kg/day (assumed rat food consumption) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) U. S. Fish and Wildlife Service. 1983. MRID No. 00141408 Available from EPA. Write to FOI, EPA, Washington, DC 20460. Diets containing 0, 7.5, 37.5, or 75 ppm (0, 0.38, 1.88, or 3.8 mg/kg/day) rotenone were given to groups of 15 male and 25 male Charles River CD (SD) BR strain rats through two generations. The first parental generation (F0) animals were 6 weeks old at the beginning of the test, and they were given test diets for 105 days prior to mating. Parental rats were selected from pups 21 days after birth for the second (F1) generation mating, and they were given test diets for a period of 120 days before they were mated. Test diets were also administered during gestation and lactation for both generations. Litter sizes were reduced in the 75 ppm (3.8 mg/kg/day) dose group (highest dose tested) in the F0 and F1a generations indicating a reproductive effect at 75 ppm. Pup weights were reduced in both generations during lactation for the 37.5 and 75 ppm dose groups. Body weights and body weight gains in adult rats were reduced during the two generations also. Based on these results, the lowest effect level for reproductive toxicity (LEL) is 37.5 ppm (1.88 mg/kg/day) and the no-observed effects level (NOEL) is 7.5 ppm (0.38 mg/kg/day). UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 100 was used to account for the inter- and intraspecies differences. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Data Considered for Establishing the RfD: 1) 2-Generation Reproduction - rat: Principal study - see previous description; core grade minimum 2) 6-Month Feeding - dog: NOEL=0.4 mg/kg/day; LEL=2 mg/kg/day (decreased mean body weights; decreased hematocrit and hemoglobin; decreased cholesterol, total lipids, and glucose levels in the blood; increased incidence of emesis and diarrhea); core grade guideline (U.S. Fish and Wildlife Service, 1980) 3) 2-Year Feeding (oncogenic) - rat: NOEL could not be established because microscopic examination of mid (37.5) and low (7.5 ppm) group animals was not performed; Effects observed at 75 ppm (3.8 mg/kg/day) (HDT) included reduced body weight in males and females, reduced food consumption in females, lower total protein and albumin levels in the blood, increased blood urea nitrogen levels, and increased incidences of adrenal gland angiectasis and hemorrhage; core grade supplementary (U.S. Fish and Wildlife Service, 1985) 4) Teratology - mouse: Maternal, Teratogenic, and Fetotoxic NOEL=15 mg/kg/day; LEL=none; core grade minimum when considered with range finding study (U.S. Fish and Wildlife Service, 1981a) 5) Teratology (range finding) - mouse: Maternal NOEL=12 mg/kg/day; Maternal LOEL=24 mg/kg/day (HDT; decreased gravid uterine weight and mortality); Fetotoxic NOEL=12 mg/kg/day; Fetotoxic LEL=24 mg/kg/day (HDT; decreased litter size and increased resorptions); core grade supplementary but used to support the main mouse teratology study (U.S. Fish and Wildlife Service, 1981b) 6) Teratology - rat: Maternal NOEL=3 mg/kg/day; Maternal LOEL=6 mg/kg/day (decreased body weight); Fetotoxic NOEL=3 mg/kg/day; Fetotoxic LOEL=6 mg/kg/day (increased incidence of unossified sternebrae, renal pelvic cavitation, and distended ureters); core grade minimum (U.S. Fish and Wildlife Service, 1982) Other Data Reviewed: 1) 2-Year Oncogenic - mouse: No toxicologically significant effects were noted at 1200 ppm (180 mg/kg/day) (HDT); core grade supplementary (NTP, 1986) Data Gap(s): Chronic Rat Feeding Study CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The critical study is of adequate quality and is given a medium confidence rating. Since an adequate chronic rodent study is lacking, the data base is given a medium confidence rating. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- Pesticide Registration Standard, December 1987; Pesticide Registration Files Agency Work Group Review -- 01/21/1988 Verification Date -- 01/21/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Rotenone conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Rotenone CASRN -- 83-79-4 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Rotenone CASRN -- 83-79-4 NOCA: Not available at this time. ============================================================================ UDSO: 198910 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Rotenone CASRN -- 83-79-4 Last Revised -- 10/01/1989 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1986. MRID No. 40179801. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. Fish and Wildlife Service. 1980. MRID No. 00141406. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. Fish and Wildlife Service. 1981a. MRID No. 00141407. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. Fish and Wildlife Service. 1981b. MRID No. 00103047. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. Fish and Wildlife Service. 1982. MRID No. 00144294. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. Fish and Wildlife Service. 1983. MRID No. 00141408. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. U.S. Fish and Wildlife Service. 1985. MRID No. 00156739. Available from EPA. Write to FOI, EPA, Washington D.C. 20460. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Rotenone CASRN -- 83-79-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 I.A. Oral RfD summary on-line 10/01/1989 VI. Bibliography on-line 06/01/1991 II. Carcinogen assessment now under review 01/01/1992 IV. Regulatory Action section on-line 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 412 of 1119 in IRIS (through 2003/06) AN: 356 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Bisphenol-A- SY: 80-05-7; BISFEROL-A-; BISHPENOL-A-; 2,2-BIS-4'-HYDROXYFENYLPROPAN-; BIS(4-HYDROXYPHENYL) DIMETHYLMETHANE; 2,2-BIS(4-HYDROXYPHENYL)PROPANE; 2,2-BIS(P-HYDROXYPHENYL)PROPANE; BIS(4-HYDROXYPHENYL)PROPANE; BISPHENOL-; 4,4'-BISPHENOL-A-; DIAN-; 4,4'-DIHYDROXYDIPHENYLDIMETHYLMETHANE-; P,P'-DIHYDROXYDIPHENYLDIMETHYLMETHANE-; 2,2-(4,4'-DIHYDROXYDIPHENYL)PROPANE; 4,4'-DIHYDROXYDIPHENYLPROPANE-; 4,4'-DIHYDROXYDIPHENYL-2,2-PROPANE-; P,P'-DIHYDROXYDIPHENYLPROPANE-; 2,2-DI(4-HYDROXYPHENYL)PROPANE; BETA-DI-P-HYDROXYPHENYLPROPANE-; DIMETHYL BIS(P-HYDROXYPHENYL)METHANE; DIMETHYLMETHYLENE-P,P'-DIPHENOL-; DIPHENYLOLPROPANE-; 2,2-DI(4-PHENYLOL)PROPANE; 4,4'-ISOPROPYLIDENEBISPHENOL-; P,P'-ISOPROPYLIDENEBISPHENOL-; P,P'-ISOPROPYLIDENEDIPHENOL-; NCI-C50635-; PHENOL,-4,4'-DIMETHYLMETHYLENEDI-; PHENOL,-4,4'-ISOPROPYLIDENEDI-; PROPANE, 2,2-BIS(P-HYDROXYPHENYL)- RN: 80-05-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199307 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Bisphenol A. CASRN -- 80-05-7 Last Revised -- 07/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Reduced mean body NOEL: None 1000 1 5E-2 weight mg/kg/day LOAEL: 1000 ppm diet Rat Chronic Oral (50 mg/kg/day) Bioassay NTP, 1982 ---------------------------------------------------------------------------- *Conversion Factors: Assumed food consumption equivalent to 5% of body weight/day PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1982. NTP Technical report on the carcinogenesis bioassay of bisphenol A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice (feed study). NTP-80-35. NIH Publ. No. 82-1771. In this 103-week dietary study, groups of 50 rats/sex were fed diets containing 0, 1000, or 2000 ppm bisphenol A. All treated groups of rats had reduced body weights, compared with controls, evident from the 5th week of exposure. Food consumption was also reduced, compared with controls, but this effect was not observed until the 12th week of treatment. Reduced body weights in rats, therefore, was considered a direct adverse effect of exposure to bisphenol A. In the same study (NTP, 1982), male mice (50/group) were fed diets containing 0, 1000, or 5000 ppm bisphenol A and female mice (50/group) were fed 0, 5000, or 10,000 ppm bisphenol A. Male mice at 5000 ppm and female mice at 5000 and 10,000 had reduced body weights. At 1000 and 5000 ppm, there was an increase in the number of multinucleated giant hepatocytes in male mice. This effect was not considered to be adverse, and this level is a NOAEL in mice. Assuming a food factor for mice of 0.13, this dietary concentration corresponds to a dosage of 130 mg/kg/day. Because the LOAEL of 50 mg/kg/day in rats is less than the NOAEL of 130 mg/kg/day in mice, the NOAEL in mice cannot be chosen as a basis for the RfD. The LOAEL of 50 mg/kg/day in rats, the lowest dosage used in either species in the chronic studies, is chosen as the basis for a chronic oral RfD. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 1000 includes 10 for uncertainty in the extrapolation of dose levels for animals to humans, 10 for uncertainty in the threshold for sensitive humans, and 10 for uncertainty in the effects of duration on toxicity when extrapolating for subchronic to chronic exposure. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Three subchronic oral toxicity studies of bisphenol A have been considered using dogs, rats and mice (U.S. EPA, 1984a,b,c; NTP, 1982). The only toxic effect seen in beagle dogs fed 1000-9000 ppm bisphenol A in the diet for 90 days was an increase in group mean liver weight in the high-dose group (U.S. EPA, 1984a). The only effect seen in 2-generation bisphenol A feeding studies (100-9000 ppm) conducted with Charles River rats (U.S. EPA, 1984b,c) were decreases in body weight in the F0 generation at 9000 ppm and F1 generation at greater than or equal to 1000 ppm. Rats and mice of both sexes were fed bisphenol A (250 to 4000 ppm rats; 5000to 25,000 ppm mice) in the diet for 90 days (NTP, 1982). Doses >1000 ppm produced decreased body weight in both sexes of rats with no alteration in food consumption. Male mice receiving >15,000 ppm and all treated females had decreased body weight gain compared with controls. A dose-related increase in severity of multinucleated giant hepatocytes was found in the treated male mice. In mice, a dosage of 1250 mg/kg/day was associated with fetotoxicity and maternal toxicity, but did not cause a significant increase in the incidence of malformations at any dose level (NTP, 1985a). In rats, dosages of less than or equal to 1280 mg/kg/day were not toxic and did not cause malformations to the fetus (NTP, 1985b). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- High RfD -- High Confidence in the key study is medium because this study, although well controlled and performed, failed to identify a chronic NOAEL for reduced body weight, the critical effect, in rats, the most sensitive species. Confidence in the data base is high, however, because the subchronic studies in rats indicate that the NOAEL for reduced body weight in rats is probably not far below the LOAEL of 1000 ppm of the diet and the uncertainty factor of 10 to estimate a NOAEL from the LOAEL is probably conservative. The developmental toxicity of bisphenol A has been adequately investigated. Confidence in the RfD, therefore, is high. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1987 Other EPA Documentation -- U.S. EPA, 1984a,b,c Agency Work Group Review -- 09/16/1987, 03/24/1988, 04/20/1988 Verification Date -- 04/20/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Bisphenol A. conducted in September 2002 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Bisphenol A. CASRN -- 80-05-7 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Bisphenol A. CASRN -- 80-05-7 NOCA: Not available at this time. ============================================================================ UDSO: 199207 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Bisphenol A. CASRN -- 80-05-7 Last Revised -- 07/01/1992 SORD: __VI.A. ORAL RfD REFERENCES NTP (National Toxicology Program). 1982. NTP Technical Report on the carcinogenesis bioassay of bisphenol A (CAS No. 80-05-7) in F344 rats and B6C3F1 mice (feed study). NTP-80-35. NIH Publ. No. 82-1771. NTP (National Toxicology Program). 1985a. Teratologic evaluation of bisphenol A (CAS No. 80-05-7) administered to CD-1 mice on gestational days 6-15. NTP, NIEHS, Research Triangle Park, NC. NTP (National Toxicology Program). 1986a. Teratologic evaluation of bisphenol A (CAS No. 80-05-7) administered to CD(R) rats on gestational days 6-15. NTP, NIEHS, Research Triangle Park, NC. U.S. EPA. 1984a. Ninety-day oral toxicity study in dogs. Office of Pesticides and Toxic Substances. Fiche No. OTS0509954. U.S. EPA. 1984b. Reproduction and ninety-day oral toxicity study in rats. Office of Pesticides and Toxic Substances. Fiche No. OTS0509954. U.S. EPA. 1984c. Fourteen-day range finding study in rats. Office of Pesticides and Toxic Substances. Fiche No. OTS0509954. U.S. EPA. 1987. Health and Environmental Effects Document on Bisphenol A. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Bisphenol A. CASRN -- 80-05-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/26/1988 I.A. Oral RfD summary on-line 07/01/1992 I.A.2. Principal study clarified 07/01/1992 I.A.4. Citations clarified 07/01/1992 VI.A. Oral RfD references on-line 07/01/1993 I.A.6. Other EPA Documentation clarified 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 413 of 1119 in IRIS (through 2003/06) AN: 357 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199409 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Caprolactam- SY: 105-60-2; A1030-; A1030N0-; AKULON-; AKULON-M-2W-; ALKAMID-; AMILAN-CM-1001-; AMILAN-CM-1001C-; AMILAN-CM-1001G-; AMILAN-CM-1011-; 6-AMINOCAPROIC-ACID-LACTAM-; AMINOCAPROIC-LACTAM-; 6-AMINOHEXANOIC-ACID-CYCLIC-LACTAM-; ATM 2(NYLON); 1-AZA-2-CYCLOHEPTANONE-; 2-AZACYCLOHEPTANONE-; 2H-AZEPIN-2-ONE,-HEXAHYDRO-; 2H-AZEPIN-7-ONE,-HEXAHYDRO-; BONAMID-; CAPRAN-77C-; CAPRAN-80-; 6-CAPROLACTAM-; EPSILON-CAPROLACTAM-; CAPROLACTAM-MONOMER-; CAPROLATTAME-; CAPROLON-B-; CAPROLON-V-; CAPRON-; CAPRON-8250-; CAPRON-8252-; CAPRON-8253-; CAPRON-8256-; CAPRON-8257-; CAPRON-B-; CAPRON-GR-8256-; CAPRON-GR-8258-; CAPRON-PK4-; CHEMLON-; CYCLOHEXANONE-ISO-OXIME-; DANAMID-; DULL-704-; DURETHAN-BK-; EPSYLON-KAPROLAKTAM-; ERTALON-6SA-; EXTROM-6N-; GRILON-; HEXAHYDRO-2-AZEPINONE-; HEXAHYDRO-2H-AZEPIN-2-ONE-; HEXAMETHYLENIMINE,-2-OXO-; 6-HEXANELACTAM-; HEXANOIC-ACID,-6-AMINO-,-CYCLIC-LACTAM-; HEXANOIC-ACID,-6-AMINO-,-LACTAM-; HEXANOLACTAM-; HEXANONE-ISOXIME-; HEXANONISOXIM-; 1,6-HEXOLACTAM-; ITAMID-; E-KAPROLAKTAM-; KAPROLIT-; KAPROLON-; KAPROMINE-; KAPRON-; 2-KETOHEXAMETHYLENEIMINE-; 2-KETOHEXAMETHYLENIMINE-; KS-30P-; METAMID-; NCI-C50646-; NYLON-A1035SF-; NYLON-CM-1031-; NYLON-X-1051-; OMEGA-CAPROLACTAM-; ORGAMIDE-; ORGAMID-RMNOCD-; 2-OXOHEXAMETHYLENEIMINE-; P-6-; PA-6-; 2-PERHYDROAZEPINONE-; PK-4-; PKA-; POLYAMIDE-PK-4-; RELON-P-; RENYL-MV-; SIPAS-60-; STEELON-; STILON-; STYLON-; TARNAMID-T-; TNK-2G5-; TORAYCA-N-6-; UBE-1022B-; VIDLON-; WIDLON-; ZYTEL-211- RN: 105-60-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 198809 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Caprolactam CASRN -- 105-60-2 Last Revised -- 09/07/1988 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Reduced offspring NOAEL: 1000 ppm of diet 100 1 5E-1 body weight (50 mg/kg day) mg/kg/day Rat Oral Three LOAEL: 5000 ppm of diet Generation (250 mg/kg/day) Reproduction Study Serotta et al., 1984 ---------------------------------------------------------------------------- *Conversion Factor: Assumed food consumption equivalent to 5% of body weight/day. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Serota, C.G., A.M. Hoberman and S.C. Gad. 1984. A three-generation reproduction study with caprolactam in rats. In: Proc. Symp. Ind. Approach Chem. Risk Assess.: Caprolactam Relat. Compd. Case Study. Ind. Health Found., Pittsburgh, PA. p. 191-204. In this study, groups of 10 male and 20 female F344 rats were fed diets containing caprolactam at 0, 1000, 5000 or 10,000 ppm for three-generations. Mean body weights and food consumption were reduced in both parental generations at 5000 and 10,000 ppm. Body weights of offspring were also reduced at these dietary concentrations. A slight increase in the severity of spontaneous nephropathy was observed on histopathologic examination of males in the high-dose group of the first parental generation. No adverse effects were noted at 1000 ppm (50 mg/kg/day), which was chosen as the NOAEL to serve as the basis for the RfD. Application of an uncertainty factor of 100 resulted in an RfD of 0.5 mg/kg/day or 35 mg/day for a 70 kg human. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 100 includes 10 for uncertainty in the extrapolation of dose levels for animals to humans, and 10 for uncertainty in the threshold for sensitive humans. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Rat and mouse chronic feeding bioassay: rat doses 0, 3750 and 7500 ppm; mouse doses 0, 7500 and 15000 ppm; LOAEL for rat is 125 mg/kg/day and LOAEL for mouse is 650 mg/kg/day for body weight depression (NTP, 1982). Rat developmental study: oral gavage doses 0, 100, 500, 100 mg/kg/day on gestation days 6-20; 1000 mg/kg/day is LOAEL for fetal resorption and 500 mg/kg/day NOAEL (Gad et al., 1984). Rabbit developmental study: oral gavage doses 0, 50, 150, 250 mg/kg/day on gestation days 6-28; 150 mg/kg/day is LOAEL for maternal and fetal body weight depression (Gad et al., 1984). 90-day rat feeding study, three strains of male rats: doses 0, 0.01, 0.05, 0.1 and 0.5%; 0.5% (250 mg/kg/day) is LOAEL for slightly increased BUN and NOAEL at 0.1% (50 mg/kg/day) (Powers et al., 1984). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- High RfD -- High Confidence in the study is high because the threshold for the most sensitive reproductive effect, reduced body weight of offspring, was clearly identified. Confidence in the data base is high because subchronic and chronic dietary studies identified no effect levels for kidney effects in rats, another critical effect in the most sensitive species. The carcinogenicity, developmental and reproductive toxicity have been adequately studied. Therefore, confidence in the RfD is high. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1987 Limited peer review and extensive Agency-wide review, 1987. Other EPA Documentation -- None Agency Work Group Review -- 09/17/1987, 03/24/1988 Verification Date -- 03/24/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Caprolactam conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199409 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Caprolactam CASRN -- 105-60-2 NORC: The health effects data for caprolactam were reviewed by the U.S. EPA RfD/RfC Work Group and determined to be inadequate for the derivation of an inhalation RfC. The verification status for this chemical is currently NOT VERIFIABLE. For additional information on the health effects of this chemical, interested parties are referred to the U.S. EPA documentation listed below. NOT VERIFIABLE status indicates that the U.S. EPA RfD/RfC Work Group deemed the data base at the time of review to be insufficient to derive an inhalation RfC according to the Interim Methods for Development of Inhalation Reference Concentrations (U.S. EPA, 1990). This status does not preclude the use of information in cited references for assessment by others. Derivation of an inhalation RfC for caprolactam is not recommended at this time. Because no adequate long-term studies examining the effects of inhalation exposure to caprolactam exist, the requirements for a minimal data base have not been met (U.S. EPA, 1990). Caprolactam is a respiratory tract irritant (ACGIH, 1991; U.S. EPA, 1988), and no data exist to definitively rule out portal-of-entry effects associated with long-term chronic inhalation exposure. No inhalation pharmacokinetic data exist for this compound. Caprolactam is a highly water soluble, hygroscopic powder with a vapor pressure sufficient to allow it to exist in the air as a vapor at up to 13 mg/cu.m at 25 C and 29 mg/cu.m at 35 C. Unless otherwise indicated, the discussions in this document regarding caprolactam toxicity are for caprolactam vapor, not the dust. Ferguson and Wheeler (1973) present retrospective information on occupational exposures to caprolactam. Little actual data on workers is presented in this study, although some corroborative documentation on this study (Ferguson, 1972) shows that medical records of 155 workers (several of whom apparently had worked in the plants for more than 17 years) in two plants were examined for possible indications of reported health effects due to caprolactam over a period of 17 years prior to the study. The search yielded only three cases of skin irritation, all relating to direct exposure to caprolactam. TWA exposures of workers, based on area samples, in various plant locations ranged up to 4.8 ppm (23 mg/cu.m). As an experiment, effects of caprolactam were investigated in five volunteer workers who were stationed at various distances from a caprolactam source, and their subjective complaints were noted after momentary exposure. These workers had not been exposed continuously in their work duties. Irritation associated with caprolactam exposure was characterized as transient, ceasing promptly after termination of exposure. The authors claim a concentration response for these effects because transient irritant effects of the eyes, nose, and throat were noted in workers at 100 ppm with distress decreasing as concentration decreased such that no eye irritation was noted below 25 ppm. The majority (4/5) experienced upper airway irritation at 10 ppm (46 mg/cu.m) caprolactam, the lowest concentration tested. Transient nose and throat irritation occurred in some subjects at all levels above 10 ppm, and no distress was noted at concentrations ranging up to about 7 ppm. The authors claim that discomfort from irritation generally was absent in workers located where these lower exposures (<7 ppm) were measured. Reported complaints varied greatly with respect to perceived magnitude of discomfort, however. Somewhat higher discomfort levels were reported from subjects in the polymer plant versus those in the monomer plant. The authors suggest that the higher humidity in the monomer plant may have protected those subjects from the irritant effects of caprolactam by ensuring tissue hydration and biological clearance. Both components of the study by Ferguson and Wheeler (1973) have significant deficiencies. Neither the number of workers nor the average duration or distribution of exposure are given in the occupational portion of the study. No historical air levels are given, and all exposures are determined from area rather than personal samplers. No attempt to reconstruct individual exposure histories was made. The relationship of some of the supporting data on worker medical and employment records (Ferguson, 1972) to the formal study is not linked clearly. No firm basis exists for consideration of this study as chronic in duration because no definite worker population is present and no average exposure duration is reported. Although judgment about the onset and intensity of irritation is known to have substantial subjective components (OSHA, 1989), only five individuals were used in the irritation portion of the study and no concentration was examined at which irritation was absent in all. The animal-based evaluation for sensory irritation (Alarie, 1973) provides a more objective measure, although this methodology recently has been criticized (Bos et al., 1992). These deficiencies preclude the use of this study in the derivation of an RfC. Billmaier et al. (1992) examined medical records of 39 workers from two plants for health effects related to caprolactam exposure. Each of the exposed workers was matched for age, sex, race, and smoking history with at least one control who had not been exposed to caprolactam. Worker selection was also based on a minimum of 10 years work exposure (mean 18.7 +/- 7.0, range 8.2-31.7 years) and the existence of pulmonary function test data for this period. Pulmonary function test data consisted of expiratory spirographs from which forced vital capacity, forced expiratory volume in one second, and other values related to these measures were obtained. Other health record information, available for all shifts from 1980-1991, was examined for worker complaints associated with exposure to caprolactam. Historical industrial hygiene monitoring of one plant indicated caprolactam air concentrations to be 3.7 mg/cu.m and for the areas of highest exposure in the other plant, 4.5 and 9.9 mg/cu.m. No personal air samples were taken. In comparing exposed workers and their controls, no statistically significant alterations were noted in any pulmonary function test. Possible detection of a smoking effect indicates that the study may have been sensitive enough to detect pulmonary obstruction. Of 878 worker visits to the medical clinic from 1980-1991, two could be related to direct dermal contact with solid caprolactam, and there was one episode of eye irritation and one episode of inhalation of material possibly containing caprolactam. Although the results from this study suggest that prolonged inhalation exposure to caprolactam vapors at concentrations as high as 9.9 mg/cu.m are without adverse consequence for the lower respiratory tract, the small sample size precludes further conclusions. Furthermore, it appears that the spirometry performed and evaluated in this study was not in accordance with current guidelines (ATS, 1987) and quality assurance procedures (Gardner et al., 1986). Upper respiratory tract symptomatology was not investigated in this report. Spirometry was performed on 173 caprolactam plant workers who had an average exposure of 12 years (Patel, 1990). After adjusting for age, height, and smoking habits, no differences were noted between the exposed cohort and 60 nonexposed workers. No exposure information was given in this study. Guirguis (1990) reports on a case control study of six workers who developed respiratory problems within a year after being exposed to a mixture of emissions of which one was caprolactam at 0.46 mg/cu.m. The respiratory problems (including symptoms of bronchial hyperreactivity, asthmatic responses, and deficits in pulmonary functions tests) were preceded by eye, nasal, and upper respiratory tract irritation. Information on human exposure to caprolactam dust is limited. Kelman (1986) reported that workers exposed to caprolactam dust/vapor at 68-84 mg/cu.m for an average of 4.8 years showed evidence of dermal damage but not systemic toxicity. Hohensee (1951) states that worker complaints at the end of an 8-hour work shift where caprolactam vapor/dust was claimed to be present at 61 mg/cu.m included irritability, nervousness, nosebleeds, irritation/inflammation of the upper respiratory passages, dry nose, abdominal gas, and heartburn. Ferguson and Wheeler (1973) reported that exposure to caprolactam dust produces skin irritation, although no concentrations are given. OSHA and ACGIH both promulgate a TLV-TWA for caprolactam dust of 1 mg/cu.m for avoidance of dermal irritation in workers, this value being 20-fold less than for the vapor. Male albino rats (15/group) were exposed either to air or to 0.06, 0.6, or 6.0 mg/cu.m caprolactam for 82 days (Krichevskaya, 1968). Information regarding length of daily exposure is not given. Alterations in whole blood cholinesterase, "chronaxial ratio," and several biochemical measures were claimed to occur in rats exposed to the highest concentration. Effects on cerebral electrical activity in three volunteers also were claimed at concentrations as low as 0.11 mg/cu.m. Little data is available in this report, and the significance of the results is unclear. Albino mice (sex not specified) were exposed either to air or to 10 mg/cu.m caprolactam for 4 hours/day for 4 months. Body weights were monitored, various behavioral tests and some pathology were performed. Little data is presented in this study. No effects attributable to caprolactam were reported (Lomonova, 1966). Alarie and Stock (1990) exposed guinea pigs (groups of four) for 0.5 hours on 5 consecutive days to air or to 3, 10, or 30 mg/cu.m aerosols generated from a 15% aqueous solution of caprolactam. Animals were monitored with whole-body plethysmography for indications of irritation, coughing, pulmonary hypersensitivity, and airway hyperreactivity. No significant respiratory responses were noted during the 5-day repeated exposure period, including sensory or pulmonary irritation, even at the highest concentration. No tissues were examined in this study. Three successive generations of Fischer 344 rats (20 females and 10 males/generation) were mated after a 10-week dietary exposure to 0, 1000, 5000, or 10,000 ppm (500 mg/kg/day) caprolactam (Serota et al., 1984, 1988). The number of live and dead pups was noted for each litter, with individual body weights and any abnormalities noted on days 1, 7, and 21 of lactation. In pups chosen as parents for the following generations, all reproduction indices were noted. Lower mean body weights (accompanied by concomitant decreases in food consumption) were observed in the P2 and P3 generations of both sexes treated at the highest dose level. All pregnancy and fertility indices were unaffected by caprolactam treatment. There was a consistently lower mean body weight in both female and male pups in all filial generations at both the 10,000 ppm and 5000 ppm (500 and 250 mg/kg/day, respectively), but not at the 1000-ppm dose level (50 mg/kg/day). The results in this study were used in the derivation of the current RfD for caprolactam, 0.5 mg/kg/day. Pregnant Fischer 344 rats (20/dose group) were intubated with caprolactam at 0, 100, 500, or 1000 mg/kg/day on gestation days 6-15. Dams in the highest dose group experienced mortality (>50%). The mean body weight changes (and food consumption) in the two highest dose groups were less (p = 0.05) than controls and the lowest dose group on days 6-11. The mean incidence of resorption in the highest dose group was nearly 10-fold higher in the controls and all other dose groups. No dose-related malformations or anomalies were noted among the offspring of any exposure group, although skeletal variants (including incomplete ossification of the skull or vertebral column, and the presence of extra ribs) were markedly increased among offspring from animals exposed to the highest dose (Gad et al., 1987). This study identifies a NOAEL of 100 mg/kg/day for developmental effects in rats and an FEL of 1000 mg/kg/day. Pregnant New Zealand white rabbits (25/group) were intubated with water or 50, 150, or 250 mg/kg caprolactam/day on gestation days 6-28. Mortality was observed (4/25) in the highest dose group only, and maternal body weight gain was significantly depressed (p < 0.05) on gestation days 6-9. Lower mean fetal weights (p < 0.05) were noted among fetuses in the two highest dose groups. An increased incidence of unilateral or bilateral thirteenth ribs was noted among fetuses whose mothers had been exposed to the highest concentration of caprolactam (Gad et al., 1987). A NOAEL of 50 mg/kg is identified by this study, with 250 mg/kg being an FEL. A number of limited studies exist on reproductive effects in both humans and animals from inhalation of caprolactam vapors/dust. The human studies, many of which have been reviewed by Gross (1984), are confounded due mostly to coexposures. The studies do, however, report effects that are internally consistent with one another and with the animal studies. The numerous deficiencies in these studies in reporting, data presentation, and methods preclude their use in a concentration-response assessment. They do, however, indicate an area of uncertainty on reproductive endpoints (ovarian-menstrual functions and male gonadal parameters) that were not evaluated specifically in the long-term oral studies of NTP (1982) or the three-generation reproductive study of Serota et al. (1988). These studies are described briefly below. The human occupational studies in which female workers were exposed to caprolactam vapors/dusts consistently report alterations in ovarian-menstrual functions and condition. Nadezhdina and Talakina (1971) also reported in Livke et al., 1971) report unspecified disturbances in ovarian menstrual function occurring in 37.1% of 170 pregnant workers exposed to caprolactam (no levels given) versus 12.8% in a control population of 101 pregnant women. Petrov (1975) reported that inflammatory diseases of the uterus and "uterine appendages" were more prevalent in a female worker population (n = 492) exposed to <10 mg/cu.m caprolactam and biphenyl than in a control population (8.9% versus 1.08%). Martynova et al. (1972) reported a 48.2% incidence of menstrual function disorders, the most frequent being hypomenstrual syndrome, in a group (n = 300) of female caprolactam workers; the authors give no exposure levels but do state that this rate was 2.5 times that of the controls. In a cohort of 304 female workers exposed to <10 mg/cu.m caprolactam (no duration given), irregular menstruation was significantly greater in paired controls (34.3% vs. 25%; p < 0.005) (Liu et al., 1988). In a cross-sectional study of 200 female workers exposed to <10 mg/cu.m caprolactam, Angelov (1988) noted that the incidence of uterine myoma (a tumor containing muscle tissue) in a cohort of 616 female workers exposed to a number of compounds including caprolactam, was 2-3 times higher than in a control population of 182 women. Martynova et al. (1972) also claim that the number of pregnancy/birth complications occurred at a higher rate in a group of women (n = 137) exposed to caprolactam than in a group of 150 control women, including hemorrhage at 33.8% in exposed vs. 18.1% in controls. The animal studies available on inhalation exposure to caprolactam also have numerous deficiencies. The studies are not, however, confounded by coexposure. Khadzhieva (1969a) exposed inseminated female rats either to air (n = 22) or to 139.2 (n = 40) or 473 (n = 46) mg/cu.m caprolactam vapor/dust. The daily duration of exposure was 4 hours, but the number of days is not clearly stated; some animals were exposed during the preimplantation phase, some during the period of organogenesis, and still others during fetal development. The results show concentration responses in the percent impregnated, in alteration of pregnancy duration, in mean birth weights, and in the percent of live-born young (based on corpora lutea). These parameters were clearly different from controls at both exposure levels. In a report apparently conducted on the same animals prior to their insemination, this author reports significant shortening of the rutting stage and prolongation of the dormancy phase of the estrous cycle (assumed to be estrus and diestrus, respectively), the latter effect occurring at both levels of exposure (Khadzhieva, 1969b). Gabpielyan et al. (1975) exposed three groups (number unspecified) of male rats either to air or to 10.6 or 124.6 mg/cu.m caprolactam dust/vapor for 4 hours/day for 2.5 months, and various measures of the gonads were taken at the end of this period. Statistically significant alterations relative to controls (p < 0.05) were noted in the spermatogenesis index (unspecified), the total quantity of normal spermatogonia, and the number of tubules at twelfth-stage meiosis in those animals exposed to the higher concentration. No significant alterations relative to controls were noted in those animals exposed to the lower concentration. In an effort to explain his observation of increased uterine hemorrhage during and after birth in female workers exposed to caprolactam, Martynova et al. (1972) showed a reduction in spontaneous uterine contractions in pregnant rabbits after injection with an unspecified volume of a 10% solution of caprolactam. The excretion and tissue distribution of caprolactam has been examined in male Fischer 344 rats after a single oral dose (Unger et al., 1981). By 24 hours post dosing, over 75% of the radiolabel had been excreted in the urine, predominantly as two unidentified metabolites. Small amounts of radiolabel were also present in feces and expired air. Concentration of radiolabel in tissues was substantially the same as blood except for portal-of-entry (stomach) and excretory (bladder and kidney) tissues. Waddell et al. (1984) examined the excretion and tissue distribution of radiolabled caprolactam in male and pregnant female Swiss-Webster mice by whole-body autoradiography. Caprolactam was administered by oral intubation to five pregnant and one nonpregnant female mice and intravenously to two male mice. The radioactivity was distributed throughout the animals (including fetuses) and, by 24 hours, had been nearly eliminated through renal secretion. Small amounts of radioactivity were retained in the cephalic region (including nasal epithelium, optic lens, and olfactory lobe). These data are not suitable for purposes of oral-to-inhalation extrapolation because they are not the appropriate route and provide no information on identity of circulating metabolites. The latter issue may be especially relevant because portal-of-entry tissues capable of metabolism (nasal epithelium) show retention of radiolabeled caprolactam. ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation of Threshold Limit Values and Biological Exposure Indices, 6th ed. p. 208-211. Alarie, Y. 1973. Sensory irritation by airborne chemicals. Crit. Rev. Toxicol. 2: 299-363. Alarie, Y. and M.F. Stock. 1990. Report on caprolactam with respect to pulmonary sensitization and irritation potential in guinea pigs. (Unpublished report for the Industrial Health Foundation). Angelov, A. 1988. Gynecological morbidity in female workers engaged in the production of nitrogen fertilizers and caprolactam. Akush. i Ginekol. (Sofia). 27(5): 51-54. ATS (American Thoracic Society). 1987. Standardization of spirometry--1987 update. Am. Rev. Respir. Dis. 136: 1285-1298. Billmaier, D.J., N.F. Knowlden, and D.W. Stidham. 1992. Caprolactam: A study of current workers. (An unpublished report of Allied-Signal, Inc.). Bos, P.M.J., A. Zwart, P.G.J. Reuzel, and P.C. Bragt. 1992. Evaluation of the sensory irritation test for the assessment of occupational health risk. Crit. Rev. Toxicol. 21(6): 423-450. Ferguson, W.S. 1972. Data supplied to the TLV Committee of ACGIH from Allied Chemical Corporation, Morristown, New Jersey, April, 1972. (Cited in: ACGIH, 1991; Reference 14). Ferguson, W.S. and D.D. Wheeler. 1973. Caprolactam vapor exposure. Am. Ind. Hyg. Assoc. J. 34: 384-389. Gabpielyan, N.I., G.E. Kuchukhibsa, and E.M. Chirkova. 1975. Characterization of the General and Gonadotropic Action of Caprolactam. Gig. Trud. Prof. Zabol. 10: 40-42. Gad, S.C., K. Robinson, D.G. Serota, and B.R. Colpean. 1987. Developmental toxicity studies of caprolactam in rat and rabbit. J. Appl. Toxicol. 7(5): 317-326. Gardner, R.M., J.L. Clausen, R.O. Crapo et al. 1986. Quality assurance in pulmonary function laboratories. Am. Rev. Respir. Dis. 134: 625-627. Gross, P. 1984. Biologic activity of epsilon-caprolactam. CRC Crit. Rev. Toxicol. 13(3): 205-216. Guirguis, S. 1990. Occupational asthma related to the finishing of nylon yarn. Cahiers de Notes Documentaires No. 138, p. 261-265. Health and Safety Support Services Branch, Ontario Ministry of Labour, Ontario, Canada. Hohensee, F. 1951. Uber die pharmakologische und physiologische Wirkung des caprolactams. Faser-forschung und Textiltechnik. 8: 299-303. (Eng. Trans.) Kelman, G.R. 1986. Effects of human exposure to atmospheric epsilon-caprolactam. Hum. Toxicol. 5: 57-59. Khadzhieva, E.D. 1969a. Effect of caprolactam on the reproductive functions of albino rats. Hyg. Sanit. 34(7): 28-31. Khadzhieva, E.D. 1969b. Influence of caprolactam on the sexual cycle. Gig. Trud. Prof. Zabde. 13(10): 22-25. Krichevskaya, I.M. 1968. Biological effect of caprolactam and its sanitary-hygienic assessment as an atmospheric pollutant. Hyg. Sanit. 33(1): 24-30. Liu, F., Y. Bao, and C.L. Zheng. 1988. The investigation on the effect of caprolactam on the sexual functions of a female worker. J. China Work Health Occupat. Dis. 6(4): 201-203. Livke, T.M., L.Z. Nadezhdina, and M.R. Simonova. 1971. The status of some metabolic processes in pregnant workers in the caprolactam industry. Pediatr. Akush. Ginekol. 33(6): 54-56. Lomonova, G.V. 1966. Toxicity of caprolactam. Gig. Tr. i Prof. Zabol. 10(10): 54-57. Martynova, A.P., V.M. Lotis, E.D. Khadzhieva, and E.S. Gaidova. 1972. Occupational hygiene of women engaged in the production of capron fiber. Gig. Trud. Prof. Zabde. 11: 9-13. Nadezhdina, L.D. and E.I. Talakina. 1971. Status of the menstrual and child-bearing function of pregnant female workers in the caprolactam industry. Gig. Trud. Prof. Zabde. 15(11): 43-44. NTP (National Toxicology Program). 1982. Technical Report No. 214 on the Carcinogenesis Bioassay of Caprolactam. National Institutes of Health Pub. No. 81-1770. OSHA (Occupational Safety and Health Administration). 1989. Air Contaminants, Final Rule, 29 CFR, Part 1910. Fed. Reg. 54(12): 2434-2455. Patel, M.B. 1990. Study of lung functions in caprolactam workers. Ind. J. Indust. Med. 36(2): 76-81. Petrov, N.V. 1975. Health status of women working in the chemical fiber industry based on data from medical examinations. Vrachebnoye Delo. 10: 145-148. Serota, D.G., A.M. Hoberman, and S.C. Gad. 1984. A three-generation reproduction study with caprolactam in rats. In: Proceedings of a Symposium on an Industry Approach to Chemical Risk Assessment: Caprolactam and Related Compounds as a Case Study. Ind. Health Fdn. Arlington, VA. p. 191-204. Serota, D.G., A.M. Hoberman, M.A. Friedman, and S.C. Gad. 1988. Three-generation reproduction study with caprolactam in rats. J. Appl. Toxicol. 8(4): 285-293. Unger, P.D., A.J. Salerno, and M.A. Friedman. 1981. Disposition of 14C-caprolactam in the rat. Fd. Cosmet. Toxicol. 19: 457-462. U.S. EPA. 1988. Health and Environmental Effects Document for Caprolactam (Draft). Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response. (Draft) U.S. EPA. 1990. Interim Methods for Development of Inhalation Reference Concentrations. Office of Research and Development, Washington, DC. EPA/600/8-90/066A. Waddell, W.J., C. Marlowe, and M.A. Friedman. 1984. The distribution of 14C-caprolactam in male, female, and pregnant mice. Fd. Cosmet. Toxicol. 22(4): 293-303. Agency Work Group Review -- 08/03/1994 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Caprolactam conducted in November 2001 IDENTIFIED ONE OR MORE SIGNIFICANT NEW STUDIES. IRIS users may request the references for those studies from the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. EPA Contacts: Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Caprolactam CASRN -- 105-60-2 NOCA: Not available at this time. ============================================================================ UDSO: 199409 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Caprolactam CASRN -- 105-60-2 Last Revised -- 09/01/1994 SORD: __VI.A. ORAL RfD REFERENCES Gad, S.C., W.J. Powers, K. Robinson, D.G. Serota and B.R. Colpean. 1984. Rat and rabbit teratology studies of caprolactam. In: Proc. Symp. Ind. Approach Chemical Risk Assessment: Caprolactam related compound case study. Ind. Health Foundation, Pittsburgh, PA. p. 164-189. NTP (National Toxicology Program). 1982. Carcinogenic bioassay of caprolactam (CAS No. 105-60-2) in F344 rats and B6C3F1 mice (feed study). NTP Tech. Report Series No. 214. (Also published as NIH Publ. NIH-8-11770) Powers, W.J., J.C. Peckham, K.M. Siino and S.C. Gad. 1984. Effects of subchronic dietary caprolactam on renal function. In: Proc. Symp. Ind. Approach Chemical Risk Assessment: Caprolactam related compund case study. Ind. Health Foundation, Pittsburgh, PA. p. 77-96. Serota, C.G., A.M. Hoberman and S.C. Gad. 1984. A three-generation reproduction study with caprolactam in rats. In: Proc. Symp. Ind. Approach Chem. Risk Assess.: Caprolactam Relat. Compd. Case Study. Ind. Health Found., Pittsburgh, PA. p. 191-204. U.S. EPA. 1987. Health and Environmental Effects Document on Caprolactam. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation of Threshold Limit Values and Biological Exposure Indices, 6th ed. p. 208-211. Alarie, Y. 1973. Sensory irritation by airborne chemicals. Crit. Rev. Toxicol. 2: 299-363. Alarie, Y. and M.F. Stock. 1990. Report on caprolactam with respect to pulmonary sensitization and irritation potential in guinea pigs. (Unpublished report for the Industrial Health Foundation). Angelov, A. 1988. Gynecological morbidity in female workers engaged in the production of nitrogen fertilizers and caprolactam. Akush. i Ginekol. (Sofia). 27(5): 51-54. ATS (American Thoracic Society). 1987. Standardization of spirometry--1987 update. Am. Rev. Respir. Dis. 136: 1285-1298. Billmaier, D.J., N.F. Knowlden, and D.W. Stidham. 1992. Caprolactam: A study of current workers. (An unpublished report of Allied-Signal, Inc.). Bos, P.M.J., A. Zwart, P.G.J. Reuzel, and P.C. Bragt. 1992. Evaluation of the sensory irritation test for the assessment of occupational health risk. Crit. Rev. Toxicol. 21(6): 423-450. Ferguson, W.S. 1972. Data supplied to the TLV Committee of ACGIH from Allied Chemical Corporation, Morristown, New Jersey, April, 1972. (Cited in: ACGIH, 1991; Reference 14). Ferguson, W.S. and D.D. Wheeler. 1973. Caprolactam vapor exposure. Am. Ind. Hyg. Assoc. J. 34: 384-389. Gabpielyan, N.I., G.E. Kuchukhibsa, and E.M. Chirkova. 1975. Characterization of the General and Gonadotropic Action of Caprolactam. Gig. Trud. Prof. Zabol. 10: 40-42. Gad, S.C., K. Robinson, D.G. Serota, and B.R. Colpean. 1987. Developmental toxicity studies of caprolactam in rat and rabbit. J. Appl. Toxicol. 7(5): 317-326. Gardner, R.M., J.L. Clausen, R.O. Crapo et al. 1986. Quality assurance in pulmonary function laboratories. Am. Rev. Respir. Dis. 134: 625-627. Gross, P. 1984. Biologic activity of epsilon-caprolactam. CRC Crit. Rev. Toxicol. 13(3): 205-216. Guirguis, S. 1990. Occupational asthma related to the finishing of nylon yarn. Cahiers de Notes Documentaires No. 138, p. 261-265. Health and Safety Support Services Branch, Ontario Ministry of Labour, Ontario, Canada. Hohensee, F. 1951. Uber die pharmakologische und physiologische Wirkung des caprolactams. Faser-forschung und Textiltechnik. 8: 299-303. (Eng. Trans.) Kelman, G.R. 1986. Effects of human exposure to atmospheric epsilon-caprolactam. Hum. Toxicol. 5: 57-59. Khadzhieva, E.D. 1969a. Effect of caprolactam on the reproductive functions of albino rats. Hyg. Sanit. 34(7): 28-31. Khadzhieva, E.D. 1969b. Influence of caprolactam on the sexual cycle. Gig. Trud. Prof. Zabde. 13(10): 22-25. Krichevskaya, I.M. 1968. Biological effect of caprolactam and its sanitary-hygienic assessment as an atmospheric pollutant. Hyg. Sanit. 33(1): 24-30. Liu, F., Y. Bao, and C.L. Zheng. 1988. The investigation on the effect of caprolactam on the sexual functions of a female worker. J. China Work Health Occupat. Dis. 6(4): 201-203. Livke, T.M., L.Z. Nadezhdina, and M.R. Simonova. 1971. The status of some metabolic processes in pregnant workers in the caprolactam industry. Pediatr. Akush. Ginekol. 33(6): 54-56. Lomonova, G.V. 1966. Toxicity of caprolactam. Gig. Tr. i Prof. Zabol. 10(10): 54-57. Martynova, A.P., V.M. Lotis, E.D. Khadzhieva, and E.S. Gaidova. 1972. Occupational hygiene of women engaged in the production of capron fiber. Gig. Trud. Prof. Zabde. 11: 9-13. Nadezhdina, L.D. and E.I. Talakina. 1971. Status of the menstrual and child-bearing function of pregnant female workers in the caprolactam industry. Gig. Trud. Prof. Zabde. 15(11): 43-44. NTP (National Toxicology Program). 1982. Technical Report No. 214 on the Carcinogenesis Bioassay of Caprolactam. National Institutes of Health Pub. No. 81-1770. OSHA (Occupational Safety and Health Administration). 1989. Air Contaminants, Final Rule, 29 CFR, Part 1910. Fed. Reg. 54(12): 2434-2455. Patel, M.B. 1990. Study of lung functions in caprolactam workers. Ind. J. Indust. Med. 36(2): 76-81. Petrov, N.V. 1975. Health status of women working in the chemical fiber industry based on data from medical examinations. Vrachebnoye Delo. 10: 145-148. Serota, D.G., A.M. Hoberman, and S.C. Gad. 1984. A three-generation reproduction study with caprolactam in rats. In: Proceedings of a Symposium on an Industry Approach to Chemical Risk Assessment: Caprolactam and Related Compounds as a Case Study. Ind. Health Fdn. Arlington, VA. p. 191-204. Serota, D.G., A.M. Hoberman, M.A. Friedman, and S.C. Gad. 1988. Three-generation reproduction study with caprolactam in rats. J. Appl. Toxicol. 8(4): 285-293. Unger, P.D., A.J. Salerno, and M.A. Friedman. 1981. Disposition of 14C-caprolactam in the rat. Fd. Cosmet. Toxicol. 19: 457-462. U.S. EPA. 1988. Health and Environmental Effects Document for Caprolactam (Draft). Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solid Waste and Emergency Response. (Draft) U.S. EPA. 1990. Interim Methods for Development of Inhalation Reference Concentrations. Office of Research and Development, Washington, DC. EPA/600/8-90/066A. Waddell, W.J., C. Marlowe, and M.A. Friedman. 1984. The distribution of 14C-caprolactam in male, female, and pregnant mice. Fd. Cosmet. Toxicol. 22(4): 293-303. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Caprolactam CASRN -- 105-60-2 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 I.A. Oral RfD summary on-line 11/01/1989 VI. Bibliography on-line 09/01/1994 I.B. Inhalation RfC under review and message on-line 09/01/1994 VI.B. Inhalation RfC references on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., I.B.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 414 of 1119 in IRIS (through 2003/06) AN: 361 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199707 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2-Dibromoethane- SY: *ETHYLENE-DIBROMIDE-; 106-93-4; DIBROMOETHANE-; DIBROMOETHANE,-1,2-; ALPHA,BETA-DIBROMOETHANE-; ETHYLENE-BROMIDE-; GLYCOL-DIBROMIDE-; S-DIBROMOETHANE- RN: 106-93-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2-Dibromoethane CASRN -- 106-93-4 Primary Synonym -- Ethylene dibromide NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199212 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2-Dibromoethane CASRN -- 106-93-4 Primary Synonym -- Ethylene dibromide NORC: Not available at this time. ============================================================================ UDCA: 199707 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2-Dibromoethane CASRN -- 106-93-4 Primary Synonym -- Ethylene dibromide Last Revised -- 07/01/1997 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen. Basis -- Increased incidences of a variety of tumors in rats and mice in both sexes by three routes of administration at both the site of application and at distant sites. EDB is mutagenic in various in vitro and in vivo assays. EDB is structurally similar to DBCP, a probable human carcinogen and to EDC, a probable human carcinogen. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Mortality studies of workers occupationally exposed to EDB (Ott et al., 1980) found neither total deaths nor total malignancies of individuals exposed to EDB exceeded the control rate. The studies are inconclusive due to their small cohort size; lack of, or poorly characterized, exposure concentrations; and/or concurrent exposure to other potential or known carcinogens. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. EDB has been tested for carcinogenicity by gavage, inhalation, and dermal administration. The NCI (1978) administered TWA doses of 27 and 29 mg EDB/kg bw/day to male and 26 and 28 mg EDB/kg bw/day to female rats by gavage for 49 and 61 weeks for the low- and high-dose groups, respectively. High treatment-related mortality prompted the early termination of the study (planned for 110 weeks) and alterations of the dosing regimen, resulting in similar TWA dosages for high- and low-treatment groups. Significant increased incidences of squamous cell carcinomas of the stomach (both sexes), hepatocellular carcinomas and neoplastic nodules of the liver (females), and hemangiosarcomas of the circulatory system (males) were observed upon histologic examination. The stomach tumors developed after a short latency period and were observed to metastasize to multiple sites. Male and female B6C3F1 mice received TWA doses of 44 or 77 mg EDB/kg bw/day by gavage for 53 weeks and were observed for their lifetimes (NCI, 1978). The incidence of squamous cell carcinomas and alveolar/bronchiolar adenomas of the lung was significantly increased over the controls in all the mice. As in the rat bioassay, no tumors were observed in the controls, and high treatment-related mortality prompted dosing regimen alterations. Fischer 344 rats and B6C3F1 mice of both sexes were exposed to EDB vapors at 0, 10, or 40 ppm, 6 hours/day, 5 days/week for their lifespans (NTP, 1982). The incidence of nasal cavity carcinomas and adenocarcinomas in the rats of both sexes and alveolar/bronchiolar carcinomas in female rats and mice of both sexes was significantly increased over the controls. The chronic inhalation of EDB was also associated with circulatory system hemangiosarcomas in both sexes of rats (high-dose only), mammary gland fibroadenomas of female rats, mammary gland adenocarcinomas of female mice, subcutaneous fibrosarcomas of female mice, and tunica vaginalis mesotheliomas of male rats. Stinson et al. (1981), in a chronic inhalation study of experimental design indentical to the NTP study (with B6C3F1 mice only), reported an elevated incidence of nasal cavity carcinomas in the female mice exposed to 40 ppm EDB. Both sexes had dose-related epithelial hyperplastic lesions of the nasal cavity. Histologic and pathologic exams were conducted only on the nasal cavity. Wong et al. (1982) exposed Sprague-Dawley rats of both sexes by inhalation to 0 or 20 ppm EDB, 7 hours/day, 5 days/week for 18 months. Splenic hemangiosarcomas and adrenal gland tumors of both sexes, subcutaneous mesenchymal tumors in males, and mammary gland tumors in females were significantly increased over the controls. Histologic examination excluded the nasal cavity. Lifetime dermal application of EDB to female He:ICR Swiss mice caused both skin papillomas at 50 mg and lung papillomas at 25 and 50 mg, a significant increase by comparison to the controls (van Duuren et al., 1979). A single dermal application of EDB followed by thrice weekly treatment with phorbol myristate acetate (PMA) did not result in an increased papilloma incidence. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY EDB has been studied for mutagenic potential by a variety of in vitro and in vivo test systems. Reverse and forward mutations have been consistently produced in bacterial assays and in in vitro assays using eukaryotic cells. EDB caused an increase in unscheduled DNA synthesis in cultured mammalian cells (Meneghini, 1974; Perocco and Prodi, 1981; Williams et al., 1982) and single-strand DNA breaks in in vitro cultured cells (Sina et al., 1983) and in in vivo rat liver cells (Nachtomi and Sarma, 1977). Direct evidence of interactions with DNA have been provided by the formation of nonextractable radiolabeled DNA following both in vivo and in vitro exposure to radiolabeled EDB. EDB is structurally similar to 1,2-dibromo-3-chloropropane (DBCP), a probable human carcinogen and to ethylene dichloride (EDC) a probable human carcinogen. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 8.5E+1 per (mg/kg)/day Drinking Water Unit Risk -- 2.5E-3 per (ug/L) Extrapolation Method -- Modified linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 4E-2 ug/L E-5 (1 in 100,000) 4E-3 ug/L E-6 (1 in 1,000,000) 4E-4 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- squamous cell carcinoma of the forestomach Test Animals -- rat/Osborne-Mendel, male Route -- gavage Reference -- NCI, 1978 Administered Tumor Dose (ppm) Incidence ------------ --------- 0 0/20 27.4 45/50 29.1 33/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The slope factor was calculated using a model (U.S. EPA, 1985; Thorslund, 1982) that permits consideration of variable partial lifetime exposure. It resembles a model that is multistage in dose and Weibull in time. Surface area corrections were made assuming a 500-g rat and a 70-kg human. Conversions from gavage to oral/diet were made assuming that the relative potency of ingestion exposure compared to gavage exposure is the same for EDB and dibromochloropropane (DBCP). DBCP is chemically similar to EDB, has been assayed in both an ingestion and a gavage study in male rats and caused the same types of tumors as EDB when administered by gavage. All the human ingestion exposures of EDB are multiplied by 0.59 (relative potency factor for DBCP) when estimating risk based on models derived from EDB animal gavage data in order to correct for potential microexposure differences. Since the rats were exposed only 5 days out of 7, human equivalent exposure is (mg EDB/day x 1/60-kg human) x 5/7. The unit risk should not be used if the water concentration exceeds 4.0 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) The estimate of risk is based upon a study having early mortality which prompted an alteration of dose levels during the experiment, thereby producing essentially only one treatment group. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 2.2E-4 per (ug/cu.m) Extrapolation Method -- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 5E-1 ug/cu.m E-5 (1 in 100,000) 5E-2 ug/cu.m E-6 (1 in 1,000,000) 5E-3 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- nasal cavity (includes adenoma, adenocarcinoma, papillary adenoma, squamous cell carcinoma, and or/papilloma) Test Animals -- rat/Fischer 344, male Route -- inhalation Reference -- NTP, 1982 ---- Dose ----- Tumor Admin- Human Incidence istered Equivalent (ppm) (mg/kg/day) -------- ----------- --------- 0 0/50 10 39/50 40 41/50 ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) The unit risk was calculated using a multistage model (Crump and Howe, 1984) that permits consideration of variable partial lifetime exposure. It resembles a model that is multistage for dose and Weibull for time. The model should be used to estimate risk whenever exposure or follow-up is for less than a full lifetime. Equivalent units of exposure for humans and rats in regard to carcinogenic response were assumed (ppm). Since rats were exposed for 6 hours/day, 5 days/week, continuous exposures were determined by multiplying by 5/7 x 6/24. It should be noted that a particularly sensitive subgroup of the general population exists that could be 20 or 30 times more sensitive than these results indicate; namely, alcoholics being treated with Antabuse, a compound demonstrated to increase the inhalation potency of EDB (Wong et al., 1982). The unit risk should not be used if the air concentration exceeds 5E+1 ug/cu.m, since above this concentration the unit risk may not be appropriate. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Adequate numbers of animals were observed for their lifetime. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985 The 1986 Drinking Water Criteria Document for Ethylene Dibromide (EDB) has received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 04/22/1987, 05/13/1987 Verification Date -- 05/13/1987 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199108 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2-Dibromoethane CASRN -- 106-93-4 Primary Synonym -- Ethylene dibromide Last Revised -- 08/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Crump, K.S. and R.B. Howe. 1984. The multistage model with a time-dependent dose pattern: Applications to carcinogenic risk assessment. Risk Anal. 4(3): 163-176. Meneghini, R. 1974. Repair replication of opossum lymphocyte DNA: Effect of compounds that bind to DNA. Chem.-Biol. Interact. 8: 113-126. Nachtomi, E. and D.S.R. Sarma. 1977. Repair of rat liver DNA in vivo damaged by ethylene dibromide. Biochem. Pharmacol. 26: 1941-1945. NCI (National Cancer Institute). 1978. Bioassay of 1,2-dibromoethane for possible carcinogenicity, CAS No. 106-93-4. NCI Carcinogenicity Tech. Rep. Ser. No. 86. PB-288-428, p. 64. [Also published as CHHA (NIH) 78-1336] NTP (National Toxicology Program). 1982. Carcinogenesis bioassay of 1,2-dibromomethane in F344 rats and B6C3F1 mice (Inhalation Study), NTP-80-28. NIH Pub. No. 82-1766. Ott, M.G., H.C. Scharnweber and R.R. Langner. 1980. Mortality experience of 161 employees exposed to ethylene dibromide in two production units. Br. J. Ind. Med. 37: 163-168. Perocco, P. and G. Prodi. 1981. DNA damage by haloalkanes in human lymphocytes cultured in vitro. Cancer Lett. 13: 213-218. Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 1983. Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutat. Res. 113(5): 357-391. Stinson, S.F., G. Reznik and J.M. Ward. 1981. Characteristics of proliferative lesions in the nasal cavities of mice following chronic inhalation of 1,2-dibromoethane. Cancer Lett. 12: 121-129. Thorslund, T.W. 1982. Estimation of the effects of exposure to a carcinogen that fluctuate over time on the lifetime risk of cancer death. Submitted for the Pacific Division, AAAS. U.S. EPA. 1985. Drinking Water Criteria Document for Ethylene Dibromide (EDB). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA/600/X-84-181-1. van Duuren, B.L., B.M. Goldschmidt, G. Loewengart, et al. 1979. Carcinogenicity of halogenated olefinic and aliphatic hydrocarbons in mice. J. Natl. Cancer Inst. 63(6): 1433-1439. Williams, G.M., M.F. Laspia and V.C. Dunkel. 1982. Reliability of the hepatocyte primary culture/DNA repair test in testing of coded carcinogens and noncarcinogens. Mutat. Res. 97(5): 359-370. Wong, L.C.K., J.M. Winston, C.B. Hong and H. Plotnick. 1982. Carcinogenicity and toxicity of 1,2-dibromoethane in the rat. Toxicol. Appl. Pharmacol. 63: 155-165. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2-Dibromoethane CASRN -- 106-93-4 Primary Synonym -- Ethylene dibromide ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/26/1988 II. Carcinogen summary on-line 04/01/1989 II.C.1. Units corrected 08/01/1989 VI. Bibliography on-line 05/01/1990 I.B. Inhalation RfD now under review 09/01/1990 II. Text edited 09/01/1990 III.A. Health Advisory added 09/01/1990 VI.D. Health Advisory references added 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 08/01/1991 VI.C. Citations clarified 01/01/1992 IV. Regulatory Action section on-line 12/01/1992 I.B. Work group review date added 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 07/01/1997 II.C.3. Paragraph 1, multiplication factor corrected 01/12/2000 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 415 of 1119 in IRIS (through 2003/06) AN: 364 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0364-tr.pdf UD: 200306 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Acrolein- SY: ACRALALDEHYDE-; ACRYLALDEHYDE-; ALLYL-ALDEHYDE-; ETHYLENE-ALDEHYDE-; PROPENAL-; PROP-2-EN-L-AL-; 2-PROPENAL- RN: 107-02-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200306 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Acrolein CASRN -- 107-02-8 Last Revised -- 06-03-2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Decreased survival NOAEL: 0.05 mg/kg/day 100 1 5E-4 mg/kg/day Chronic gavage rat FEL:* 0.5 mg/kg/day study Parent et al., 1992a ---------------------------------------------------------------------------- *Conversion Factors: *FEL û frank effect level (an objective, clinically evident effect) PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Parent et al. (1992a) administered acrolein in water daily via gavage to Sprague-Dawley rats, 70/sex/group, at dose levels of 0, 0.05, 0.5, and 2.5 mg/kg BW. Dosing volume was 10 ml/kg. Ten animals from each group were sacrificed after one year and the remainder after two years. An extensive array of tissues was examined microscopically, including stomach tissue. Although it was not explicitly stated that both the glandular stomach and forestomach were examined, it is unlikely that both parts of the stomach were not examined. Daily observations were made and various clinical, hematological and urinary parameters were measured after 3, 6, 12, and 18 months of treatment and immediately prior to sacrifice. There were no statistically significant increased incidences of microscopic lesions in the treated rats, whether neoplastic or non-neoplastic. Food consumption and body weights were unaffected by treatment. With the exception of a statistically significant depression of creatinine phosphokinase (creatine kinase) at all dose levels and at most time intervals (except 12 months), clinical chemistry parameters, hematology and urinalysis measurements were unaffected by treatment. The most definitive responses reported were treatment-related increases in early cumulative mortality. Data were provided in the form of survival curves. Among high-dose males, survival was significantly reduced after one year (p<0.05), and marginally reduced among mid-dose males (p value not reported). Among high-dose males, a trend test for survival during the first year indicated a highly statistically significant (p=0.003) decrease; however, the statistical differences are nullified when the survival data for two years are included in the analysis. Survival among females during the first year corresponded closely to those obtained for males. A statistically significant decrease in survival (p<0.05) was reported in the high-dose group, while a decrease in survival in the mid-dose group was marginally significant (p value not reported). Unlike responses in males, the significant associations between dosing and survival persisted in females through the end of the study. After two years, a statistically significant reduction in survival was noted based on four different statistical tests for the mid-dose group and in three of four statistical tests in the high-dose group (p values not reported). Although the differences in survival were statistically significant in females after two years, it should be noted that the differences were relatively small. No differences in survival compared to controls were seen in either the male or female low-dose groups (0.05 mg/kg/day). Thus, 0.5 mg/kg/day is considered a frank effect level (FEL) for the rat, and 0.05 mg/kg/day the no-observed-adverse-effect level (NOAEL). The FEL is defined as "a level of exposure or dose which produces irreversible, adverse effects at a statistically or biologically significant increase in frequency or severity between those exposed and those not exposed" (IRIS, 2003). Other studies support the findings of reduced survival in laboratory animals exposed to acrolein as reported by Parent et al. (1992a). In a study designed to evaluate the potential carcinogenicity of acrolein (Parent et al., 1991), Swiss albino CD-1 mice (70-75/sex/group) were dosed via gavage (acrolein in distilled water and stabilized with hydroquinone) with 0, 0.5, 2.0 or 4.5 mg/kg/day for 18 months. The primary effect was increased mortality only in high-dose males of the 4.5 mg/kg/day group; mortality in the mid- and low-dose groups was less than control. There were no dose-related adverse histopathological or clinical findings. In a 13-week daily gavage study of acrolein (in 0.5% methyl cellulose) in F344 rats and B6C3F1 mice conducted for the National Toxicology Program (NTP, 1995), 10 rats/sex/dose were administered 0, 0.75, 1.25, 2.5, 5.0, and 10 mg acrolein/kg; 10 mice/sex/dose received 0, 1.25, 2.5, 5.0, 10 and 20 mg/kg. Dose volume was 5 ml/kg for rats and 10 ml/kg for mice. Treatment resulted in similar dose-related effects in both sexes of both species: hemorrhage and necrosis and other lesions of the forestomach and glandular stomach and secondary changes associated with acrolein-induced mortality in high-dose animals (NTP, 1995; Pathology Working Group Review, 1997). Abnormal breathing and nasal/eye discharge were among the clinical findings in high-dose rats. Nearly all high-dose animals died or were removed from study because of gastrointestinal toxicity. The NOAEL was 0.75 mg/kg for female rats and 1.25 mg/kg for males, based on forestomach squamous epithelial hyperplasia in the 1.25 mg/kg group and 2.5 mg/kg group, respectively. There were no clinical signs of toxicity in mice. The forestomach lesions in mice were similar to those in the rat. Glandular stomach lesions were only seen in the 10 and 20 mg/kg males and in the 20 mg/kg females. Statistically significant increases in absolute and relative liver weights were seen in male mice at 10 mg/kg without attendant hepatic histopathology. There was no NOAEL for the male mouse (i.e., one male had squamous epithelial hyperplasia at the lowest dose of 1.25 mg/kg). The NOAEL for female mice was 1.25 mg/kg. Reasons for no reported observations of stomach lesions in Sprague-Dawley female rats at the highest dose (2.5 mg/kg) of the Parent et al. (1992a) study compared with forestomach squamous epithelial hyperplasia observed in female F344 rats in the NTP study at 1.25 mg/kg/day are not readily apparent, but may relate to differences in strain sensitivity or vehicle. The vehicle dose volume was 5 ml/kg in the NTP (1995) study and 10 ml/kg in the Parent et al. (1992a) study for rats, and there may have been a reduced local gastric mucosal irritation and pathology by virtue of dilution. There were also differences in the vehicle solution and, possibly, the stability of the dosing solutions. Parent et al. (1992a) conducted stability studies on acrolein in water, and monitored the stability of their dosing solutions (reporting losses of less than 10% for 3 hours at room temperature). They used a stabilizing agent, 0.25% hydroquinone, in the stock solution, and prepared dosing solutions daily. The NTP study used a dose vehicle of 0.5% methylcellulose in deionized water, and no information was available on stability or stabilizing agents. For the mouse results, there is a similar divergence between the absence of reported forestomach lesions in the CD-1 mice at 4.5 mg/kg in the Parent et al. (1991) study compared with effects observed in female B6C3F1 at 2.5 mg/kg in the NTP study. Species differences and dose volume again may have accounted for observed differences in response. Dose volume in the NTP study for mice was 10 ml/kg, and was unspecified in the Parent et al. (1991) study. A benchmark dose approach was unsuitable for RfD development because the data in the Parent et al. (1992a) study were presented graphically, with statistical evaluation at one and two-year time points, but no numerical values. Moreover, the NOAEL derived from the Parent et al. study and used as the basis for the RfD is from a statistically significant increase in mortality, a frank effect. A benchmark dose analysis would not be appropriate when the dose-response is for early cumulative mortality. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 100. A default UFA of 10 was applied to account for interspecies differences between laboratory animals and humans. No information was available to support a change from the default. A default UFH of 10 was applied for intraspecies uncertainty to account for human variability and sensitive subpopulations, i.e., to account for human variability in the severity or range of response from any given acrolein exposure amongst different individuals. A UFD was not applied because the data base for acrolein was considered complete. The available oral data base includes chronic toxicity studies in the rat and mouse, an oral reproductive toxicity study in Sprague-Dawley rats and an oral developmental toxicity study in New Zealand white rabbits. The findings from the oral reproductive and developmental toxicity studies are supported by an inhalation reproductive toxicity study of acrolein in Fisher 344 rats that revealed no reproductive or developmental effects. Acrolein's high reactivity at the point of contact and the evidence for minimal systemic distribution of acrolein obviates the need for additional repeat dose studies. The RfD is based on a NOAEL from a chronic study, which obviates the need for an uncertainty factor for LOAEL to NOAEL extrapolation or for subchronic to chronic extrapolation. MF = 1. ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Administration of acrolein in water by oral gavage at 0.05, 0.5, and 5.0 mg/kg to male and female Sprague-Dawley rats (30/sex/group) daily, 5 days per week for 13 weeks did not produce any significant adverse effects on mortality, on clinical, hematological, or urinalysis parameters, or on histopathology (Bioassay Systems Corp., 1981). This study was a precursor to Parent et al. (1992a), identified as the principal study. In a range-finding gavage study in artificially inseminated New Zealand white rabbits (3-4/group), acrolein (0, 0.5, 1.0, 2.0, 4.0, and 6.0 mg/kg/day) produced high incidences of maternal mortality, spontaneous abortion, resorption, clinical signs, gastric ulceration, and/or sloughing of the gastric mucosa. The dose-response curve for mortality was steep. A factor of 2 in dose (from 2 to 4 mg/kg) resulted in 25% mortality in the high-dose animals compared to 0% in lower-dose animals (Parent et al., 1993). Mortality was 100% at 6 mg/kg. In a two-generation reproductive toxicity study, four groups of 30 male and 30 female Sprague-Dawley rats were gavaged with 70 daily doses of acrolein at levels of 0, 1, 3, or 6 mg/kg in a dosing volume of 5 ml/kg (Parent, 1992b). Rats within each dosing group (F0 generation) were then assigned to a 21-day period of cohabitation. Dosing continued for females through cohabitation, gestation, and lactation. A similar regime was carried out for F1 generation offspring, resulting in F2 generation pups. Mortality was significant (at 6 mg/kg) in both males and female of the F0 and F1 generations with the pattern continuing with F1 mid-dose animals, the latter showing signs of respiratory distress and histopathological lesions in the lungs and stomach. Reproductive parameters (i.e., mating performance and fertility indices) were unaffected. No treatment-related gross or microscopic effects were observed in the reproductive tissues of the F0 or F1 animals, and no gross abnormalities were observed in F2 generation pups. The data provide evidence that acrolein is not a selective reproductive toxicant but does produce toxicological effects at doses as low as 3 mg/kg/day. Arumugam et al. (1999) exposed male Wistar rats, 5 animals/group, daily to acrolein via intubation (2.5 mg/kg BW) for 45 days. The incidence of mortality, if any, was not reported in this study. This study clearly showed damage to mitochondria (through the loss of mitochondrial lamellae of the cristae), a decrease in the availability of reduced glutathione (a substrate for glutathione peroxidase), and a 30-56% decrease in activities of citric acid cycle enzymes, resulting in decreased energy production in liver cells. These results indicate that at least some uptake occurs from the oral route; however, the stomach was not examined by light microscopy. Because of the highly reactive nature of acrolein, the concentration of a dose administered by gavage can affect the time course and degree of severity of toxicity at the point of entry and the relevance of the gavage bolus dose to human exposure. Rats have both a forestomach and a glandular stomach, while humans have only a glandular stomach. The glandular stomach is more resistant than the forestomach to pH changes and irritation. The residence time in the forestomach (of approximately 2 hours) is sufficiently long compared to the reaction time for toxicity with airway tissue observed in inhalation studies (i.e., microseconds) so that the dose to the glandular stomach may be much lower than that to the forestomach (TERA, 1998). The dog is a better model for glandular stomach toxicity than the rat, however, Parent et al. (1992c) administered acrolein (0.1% aqueous) in gelatin capsules to beagle dogs, so the dose concentration to the glandular tissue is not known. In lieu of studies that provide data on glandular stomach toxicity, the Parent et al. (1992a) study in the rat remains the most suitable choice for the principal study. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=67. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Database -- High RfD -- Medium to High The overall confidence in this RfD assessment is medium to high. Confidence in the principal study is medium. Several supporting studies involving other species also indicated that mortality increases sharply with elevated dose. The research demonstrating acrolein's high reactivity, low systemic distribution, toxicity at the point of entry, pronounced decreases in serum creatinine phosphokinase (creatine kinase), citric acid cycle enzymes and liver GSH, and increased mitochondrial damage in the Wistar rat suggest interference with normal metabolic processes or possibly the absorption of essential nutrients sufficient to lead to early mortality. Further research is needed, however, to support a definitive mode of action. In the NTP (1995) study, glandular stomach and forestomach lesions were reported at higher doses and likely played a role in the observed mortality. Confidence in the database is judged high with chronic exposure studies in 2 species. Moreover, two studies (Parent et al., 1992b; Parent et al., 1993) provide evidence that reproductive and developmental effects are not critical endpoints although only one species was tested for reproductive effects (rat) and for developmental effects (rabbit). While the possibility of some transport of acrolein or a metabolite of acrolein to systemic sites remains, the critical target sites (discussed further in the Toxicological Review of Acrolein) are at the point of contact, e.g., the respiratory system, the gastrointestinal tract, mucous membranes, and skin. The high reactivity of acrolein and the lack of significant systemic distribution obviates the need to examine reproductive/developmental effects in a second species. The overall confidence in this RfD assessment is medium-to-high; a variety of studies across different durations of exposure and in several different laboratory animal species has been consistent in demonstrating that in the absence of mortality there are no clear indications of adverse effects. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=76. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document - U.S. EPA (2003) This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of the IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Acrolein (U.S. EPA, 2003). To review this appendix, exit to the toxicological review, Appendix A, Summary of External Peer Review Comments and Dispostion http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=101. Agency Consensus Date - 05/16/2003 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or hotline.iris@epa.gov (email address). ---------------------------------------------------------------------------- UDRC: 200306 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Acrolein CASRN -- 107-02-8 Last Revised -- 06/03/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experiental Doses* UF MF RfC -------------------- --------------------------- ----- --- --------- Nasal lesions NOAEL: None 1000 1 2E-5 mg/m3 Subchronic rat LOAEL: 0.4 ppm (0.9 mg/m3) inhalation study LOAEL(ADJ): 0.16 mg/cu.m LOAEL(HEC): 0.02 mg/cu.m Feron et al., 1978 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions: MW = 56.06 (HSDB, 2003). Assuming 25°C and 760 mm Hg, the LOAEL of 0.4 ppm (0.9 mg/m3) was adjusted to a continuous exposure as follows: LOAEL (ADJ) = 0.9 mg/m3 x 6/24 x 5/7 = 0.16 mg/m3. The LOAEL(HEC) was calculated for a Category 1 gas:respiratory effect in the extra-thoracic region by multiplying the LOAEL (ADJ) by the Regional Gas Dosimetry Ratio (RGDR(ET)), to derive a comparable human exposure (U.S. EPA, 1994). The calculation for the RGDR(ET) = (MVa/SAa) / (MVh/SAh) where MVa = 0.20 m3/day, MVh = 20 m3/day, SAa(ET) = 15.0 cm2, SAh(ET) = 200 cm2 RGDR(ET) = (0.20/15)/(20/200) = 0.14. The LOAEL(HEC) = LOAEL(ADJ) x RGDR(ET) = 0.16 mg/m3 x 0.14 = 0.02 mg/m3. Derivation of the RGDR is further described in the Toxicological Review for Acrolein. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Feron et al. (1978) exposed 6 Wistar rats/sex/concentration, 10 Syrian golden hamsters/sex/concentration, and 2 Dutch rabbits/sex/concentration for 6 hr/day, 5 days/week for 13 weeks to 0, 0.4, 1.4, or 4.9 ppm (0, 0.9, 3.2, or 11 mg/m3) acrolein in a whole-body exposure chamber. Incidence data were not reported, but histopathological changes in the nasal cavity, lung, larynx, and trachea were graded as slightly, moderately, or severely affected. In rats, hematological parameters were unaffected by acrolein. Body weight gain was significantly inhibited at the high dose in rats, and less so at the intermediate concentration, but food consumption appeared to be decreased in these groups as well. At the intermediate concentration, both male and female rats showed significantly retarded weight gain (p<0.05). Three male and 3 female rats died during exposure at the highest dose. No other deaths considered to be treatment-related were reported in any of the species or exposure groups. Histopathologic changes described as "slightly affected" were found in the nasal cavity of 1 of 12 rats exposed to 0.4 ppm (0.9 mg/m3). Severity increased at the higher levels of exposure. No nasal lesions were reported in other species at 0.4 ppm (0.9 mg/m3). The severity of nasal lesions was concentration-related in all 3 species, most clearly so in the rat. In the 4.9 ppm (11 mg/m3) groups of all 3 species, slightly to markedly increased lesions were reported in the nasal cavity and trachea; moderate to marked effects were seen in the bronchi and lungs of rats and rabbits (but not hamsters). Based upon the concentration-related severity of lesions, the rat is clearly the most sensitive species, with hamsters and rabbits intermediate in sensitivity. Although the Feron et al. (1978) study was adequately designed, the incidence of nasal lesions for treated groups was not reported. However, histopathological grading allowed the determination of NOAELs, LOAELs and FELs for the 3 species, identification of the critical target site, and a comparison of sensitivities among the 3 species tested. Other limitations of this study include an exposure duration of 3 months rather than lifetime, histopathological examination of only 3 sections of the nasal cavity, lack of characterization of the type of nasal lesions by sex, and only 6 rats/sex exposed. A more recent study, Cassee et al. (1996) examined the nasal effects of inhalation exposure of formaldehyde, acetaldehyde, and acrolein on male Wistar rats (5-6/group) exposed 6 hr/day, for 3 consecutive days, in a nose-only exposure chamber to acrolein at concentrations of 0, 0.25, 0.67, or 1.4 ppm (0, 0.6, 1.5, or 3.2 mg/m3). The Cassee et al. (1996) study was designed to evaluate the severity of effects from mixtures versus single chemical exposure, and analyzed six levels of the nasal tract for histopathological and biochemical changes immediately after the last exposure. After one 6-hour exposure, no treatment-related histopathological lesions were found in any of the treatment groups. Only the histopathology of the 0.25 and 0.67 ppm (0.6 or 1.5 mg/m3) groups were reported following 3 days of exposure; effects at 1.4 ppm (3.2 mg/m3) were not reported. After 3 days, slight to moderate effects were observed from acrolein exposure in two of the four histopathology categories evaluated. In the category for disarrangement, necrosis, thickening and desquamation in the respiratory/transitional epithelium, 4/5 animals exposed to 0.25 ppm (0.6 mg/m3) were observed to have slight effects (characterized as mainly disarrangement) and 1/5 developed a moderate level of effect. In the 0.67 ppm (1.5 mg/m3) group, 3/6 were classified as slightly affected and 3/6 rats developed a moderate degree of response. For rhinitis, 1/5 of the 0.25 ppm (0.6 mg/m3) rats developed a moderate response, and only 1/6 of the 0.67 ppm (1.5 mg/m3) rats had a response and it was scored as a slight response. For the other two categories, single cell necrosis or atrophy of the olfactory epithelium, no effects were observed in either the 0.25 ppm (0.6 mg/m3) or 0.67 ppm (1.5 mg/m3) group. After one 6-hr exposure, no treatment-related proliferative response (defined as basal cell proliferation and/or an increased number of mitotic figures in respiratory/transitional epithelium) was found in any of the treatment groups. After 3 days, 3/5 rats at 0.25 ppm (0.6 mg/m3) developed a slight focal proliferative response, and all rats in the 0.67 ppm (1.5 mg/m3) group developed a slight or moderate response. Proliferative effects were not reported for the 1.4 ppm (3.2 mg/m3) exposure group. Among biotransformation enzymes measured in homogenates of nasal tissue, glutathione S-transferase activity was significantly depressed in the 1.4 ppm (3.2 mg/m3) exposure group (p<0.01) while formaldehyde dehydrogenase and aldehyde dehydrogenase activities was significantly increased (p<0.05). No changes were reported in the lower dose groups, or for glutathione peroxidase activity in any of the dose groups. Non-protein sulfhydryl (NPSH) depletion was not observed in this study. No biochemical effects were observed in olfactory tissue. The LOAEL in this study was 0.25 ppm (0.6 mg/m3). The occurrence of lesions at lower doses in the Cassee et al. (1996) study than used in the Feron et al. (1978) study may be: (1) a consequence of nose-only exposure where, unlike whole-body exposure, the animals cannot minimize exposure by burying their noses in their fur, so that animals receive a full and uninterrupted dose; or (2) due to a higher resolution evaluation from the use of extended sectioning (6 sections) of the nasal tract compared to only 3 in the Feron et al. (1978) study. Cassee et al. (1996) do not discuss the persistence or reversibility of the observed histopathological changes in the low-dose group with exposures greater than 3 days (e.g., adaptive response). An adaptive response in nonprotein sulfhydryl levels after 3 days of exposure was observed and is discussed. Because the Feron et al. (1978) study was much longer in duration, it is possible that some adaptation to the irritant effects of acrolein occurred with increasing duration, or that cessation of exposure for 2 days each week provided a period during which partial recovery from nasal effects might have occurred. The rationale for choosing the Feron et al. (1978) study over the Cassee et al. (1996) study includes: (1) the higher number of test animals [12 (6/sex) vs. 6 male only]; (2) the longer duration [5 days/week for 13 weeks vs. 3 days]; (3) the testing of multiple species and both sexes in the Feron et al. study; and 4) the better characterization of multiple endpoints and the dose-response. Feron et al. evaluated many different end points and demonstrated dose response for all 3 dose groups in all 3 species tested. The Feron et al. study also evaluated a dose response over a 12-fold increase in dose from low to high dose. The Cassee et al. study used about a 6-fold increase in dose level from low to high. A benchmark dose approach for derivation of the RfC was not possible because nasal pathology incidence data were not provided. Therefore, the approach used to derive the RfC was the determination of a LOAEL as the point of departure and application of uncertainty factors. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 1,000. A UFA of 3 (101/2) was used for interspecies extrapolation, since this factor embodies two areas of uncertainty: pharmacokinetics and pharmacodynamics. In this assessment, the pharmacokinetic component was addressed by the calculation of the human equivalent concentration (HEC) according to the procedures in the RfC methodology (U.S. EPA, 1994b). Accordingly, only the pharmacodynamic area of uncertainty remains as a partial factor for interspecies uncertainty (101/2 or approximately 3). A default UFH of 10 was applied for intraspecies uncertainty to account for human variability and sensitive subpopulations, i.e., to account for human variability in the severity or range of response from any given acrolein exposure amongst different individuals. A UFS of 10 was applied for adjustment from subchronic to chronic duration because the principal study involved a 13-week dosing period and because there are insufficient inhalation data to preclude an increase in severity (or incidence) with an increase in exposure duration from subchronic to chronic. A UFL of 3 (101/2) was applied for use of a minimal LOAEL of 0.4 ppm (0.9 mg/m3) in lieu of a NOAEL. Although the severity of the nasal effect at the 0.4 ppm level was minimal and in only 1 of 12 animals in the Feron et al. (1978) study, a 3-day study in the male Wistar rat by Cassee et al. (1996) also reported slight nasal effects in the respiratory/transitional epithelium from nose-only inhalation exposure at 0.25 ppm (0.6 mg/m3). An exposure concentration of 0.4 ppm (0.9 mg/m3) was designated a minimal LOAEL instead of a NOAEL, considering the Cassee et al. (1996) results and the observed increase in the severity of the effects with increasing dose in the Feron et al. (1978) study. A UFD was not applied because the data base for acrolein was considered complete. The available inhalation data base includes subchronic toxicity studies in multiple species, and an inhalation reproductive toxicity study of acrolein in Fisher 344 rats that revealed no reproductive or developmental effects. Acrolein's high reactivity at the point of contact and the evidence for minimal systemic distribution of acrolein obviates the need for additional studies of repeat-dose toxicity or reproductive/developmental toxicity. MF = 1. IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Studies by Kutzman (1981), Kutzman et al. (1985) and Costa et al. (1986) support the Feron et al. (1978) results with additional evidence of lung deficits from exposure to acrolein. The Kutzman studies were cited as co-principal studies in the assessment previously on IRIS. Male F344 rats exposed to 0, 0.4, 1.4, or 4.0 ppm (0, 0.9, 3.2, or 9.2 mg/m3) 6 hr/day, for a total of 62 exposure days over a duration of 12.4 weeks were examined on the sixth day post-exposure (to minimize acute effects) (Kutzman, 1981; Kutzman et al., 1985). Mortality (32/57) was observed only in males at the highest concentration, with many displaying severe acute bronchopneumonia. The changes in the nasal region consisted of only minimal evidence of submucosal lymphoid aggregates at 0.4 ppm (0.9 mg/m3); although degree of involvement increased to moderate at higher concentrations, more extensive damage to the nasal epithelium was not observed. Lungs from the 0.4 or 1.4 ppm (0.9 or 3.2 mg/m3) groups did not display treatment-related histopathological changes. At 4.0 ppm (9.2 mg/m3) the surviving animals demonstrated bronchiolar epithelial necrosis and sloughing, bronchiolar edema with macrophages, and focal pulmonary edema. Support for acrolein's respiratory effects and association with increased mortality is provided by Kutzman et al. (1984). Dahl rats (derived from the Sprague-Dawley rat) that were either susceptible (DS) or resistant (DR) to salt-induced hypertension were exposed in whole body inhalation chambers to 0.4, 1.4, and 4.0 ppm (0.9, 3.2, and 9.2 mg/m3) acrolein; increased mortality (100% and 40% in DS and DR rats, respectively) was reported at 4.0 ppm (9.2 mg/m3). Dose-response increases in the severity of epithelial lesions occurred in both species with the DS rats being more sensitive, and demonstrating a different pathological response at the high dose. A continuous 90-day inhalation study involving exposure of dogs, guinea pigs, rats and monkeys to acrolein did not include an examination of the nasal tract by light microscopy (Lyon et al., 1970). Exposure concentrations were 0.22, 1.0 and 1.8 ppm (0.5, 2.3, and 4.1 mg/m3). There was no mention of the use of control animals in the report although Lyon (2001) indicated that controls (not concurrent) were used. Two of the four dogs exposed to 0.22 ppm (0.5 mg/m3) acrolein in this study showed moderate emphysema, acute congestion and occasionally some degree of constriction of the bronchioles. Monkeys also showed some apparent inflammatory effects at this concentration. It is uncertain if the effects seen at this concentration were directly related to exposure given the absence of control results. No histopathologic effects were reported for rats or guinea pigs at 0.22 ppm (0.5 mg/m3). For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=67. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Low to Medium RfC -- Medium The overall confidence in this RfC assessment is medium. The confidence in the principal study is medium. Although the principal study (3 species) was adequately designed and examined a wide range of endpoints, it had several shortcomings: (1) only 3 sections of the nasal cavity were examined, (2) there was low sample size, and (3) a lack of incidence data. Support for the minimal LOAEL is provided by subchronic studies in 2 other species (rabbit and hamster) and a 3-day study (Cassee et al., 1996) in the rat in which nasal lesions of similar type and severity were observed. The primary limitation in the database is the lack of a chronic inhalation study and the attendant uncertainty relating to the incidence/severity of nasal lesions at subchronic/chronic exposure levels lower than 0.4 ppm (0.9 mg/m3). The high reactivity of acrolein at the point of contact, the lack of significant systemic distribution demonstrated in studies with the dog and rat, and the lack of effects in oral studies lessens the priority for an evaluation of reproductive/developmental endpoints in a two-generation inhalation study. Additional evaluation of immunological endpoints is warranted especially focusing on potential contribution to asthma or compromise in respiratory response. Thus, confidence in the database is judged low to medium. The confidence in the RfC is judged medium. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=76. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA (2003) This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Acrolein (U.S. EPA, 2003). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=101. Agency Consensus Date -- 05/16/2003 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RFC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 200306 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Acrolein CASRN -- 107-02-8 Last Revised -- 06/03/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Under the Draft Revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), the potential carcinogenicity of acrolein cannot be determined because the existing "data are inadequate for an assessment of human carcinogenic potential for either the oral or inhalation route of exposure." There are no adequate human studies of the carcinogenic potential of acrolein. Collectively, experimental studies provide inadequate evidence that acrolein causes cancer in laboratory animals. Specifically, two inhalation bioassays in laboratory animals are inadequate to make a determination because of protocol limitations. Two gavage bioassays failed to show an acrolein-induced tumor response in 2 species of laboratory animals. Suggestive evidence of an extra-thoracic tumorigenic response in a drinking water study in female rats was not supported in the reanalysis of data by an independently-convened pathology working group. Questions were also raised about the accuracy of the reported levels of acrolein in the drinking water from this study. A skin tumor initiation-promotion study was negative, and the findings from an intraperitoneal injection study were of uncertain significance. Although acrolein has been shown to be capable of inducing sister chromatid exchange, DNA cross-linking and mutations under certain conditions, its highly reactive nature and the lack of tumor induction at portals of entry make it unlikely that acrolein reaches systemic sites at biologically-significant exposure levels. The observations of positive mutagenic results in bacterial systems occurred at high concentrations near the lethal dose. This evaluation replaces the cancer assessment for acrolein added to the IRIS data base in 1988. Under the Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) applied at that time, acrolein was classified as a possible human carcinogen (Category C). The 1988 classification for acrolein was based on the increased incidence of adrenal cortical adenomas in female rats and carcinogenic potential of an acrolein metabolite, its mutagenicity in bacteria, and its structural relationship to probable or known human carcinogens. The updated cancer characterization considered new study results and reevaluated previous studies. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=76. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.8 http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=67. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA No data are available on carcinogenicity in humans exposed solely to acrolein. The only study relating to cancer was a nested case control study by Ott et al. (1989), in which individuals were classified as having been exposed to one of a large number of chemicals in the work environment. The study investigators reported non-Hodgkin's lymphoma (52 cases), multiple myeloma (20 cases), nonlymphocytic leukemia (39 cases), and lymphocytic leukemia (18 cases) within a cohort of employed men from two chemical manufacturing facilities and a research and development center. Exposure odds ratios were examined in relation to 111 work areas, 21 specific chemicals, and 52 chemical activity groups. Odds ratios of 2.6 (2 cases) for non-Hodgkin's lymphoma, 1.7 (1 case) for multiple myeloma, and 2.6 (3 cases) for nonlymphocytic leukemia were reported for workers exposed to acrolein. None of the lower 95% confidence limits exceeded 1.0. Because of a lack of a statistically significant increase in the cancer endpoints and the likelihood of confounding by concomitant exposure to other chemicals in the workplace, the results must be considered equivocal. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Feron and Kryusse (1977) reported negative findings for lung cancer induction in Syrian golden hamsters exposed 35 hours/week for 52 weeks to 4.0 ppm (9.2 mg/m3) acrolein via inhalation, followed by sacrifice at 81 weeks. Le Bouffant et al. (1980) exposed 20 female Sprague-Dawley rats to 8 ppm (18 mg/m3) acrolein, 5 hours/week for 10 or 18 months, with negative results. These findings, while negative, nevertheless fail to provide conclusive evidence that acrolein is not carcinogenic by the inhalation route. Both the rat and hamster studies were (1) less than lifetime, (2) the maximum tolerated dose may not have been achieved, and (3) only one concentration was used. Negative results for carcinogenicity were reported for Sprague-Dawley rats, 70/sex/group, exposed via gavage to acrolein at doses of 0.0, 0.05, 0.5 and 2.5 mg/kg BW for 24 months (Parent et al., 1992a). Parent et al. (1991) also reported negative results in Swiss albino mice, 70-75/sex/group, administered acrolein via gavage at doses of 0.2, 2.0 and 4.5 mg/kg/day for 18 months. The only suggestive evidence for carcinogenicity of acrolein was marginally significant increases in adrenal cortical tumors in a drinking water study reported by Lijinsky and Reuber (1987), and weak evidence for tumor initiating ability of acrolein reported by Cohen et al. (1992). Because no increase in adrenal cortical tumors was noted for either species in the Parent et al. (1991, 1992a) studies, an independent pathology working group (PWG) was convened to reevaluate the adrenocortical tumors reported by Lijinsky and Reuber (1987). According to the PWG (cited in Parent et al., 1992a), the "slightly elevated incidence of pheochromocytomas (3/20; 15%) in the treated females were well within limits for historical controls (3/34; 9%) and were of no biological significance (sic)." Parent et al. (1992a) further suggested that acrolein at a high dose may not have been as stable as assumed in the Lijinsky and Reuber study. Based on some assumptions about water intake and rat weight, Parent et al. estimated that the daily dose at the highest concentration administered by Lijinsky and Reuber would have exceeded the LD50 for rats. These questions concerning the stability of acrolein in high dose solutions and the rate of intake render the results of the Lijinsky and Reuber study less certain. Moreover, concurrent controls were not used in the Lijinsky and Reuber study. Cohen et al. (1992) administered acrolein via intraperitoneal injection, 2 mg/kg/twice weekly to male Fischer 344 rats, 30/group, for either 53 weeks or for six weeks followed by an additional 47 weeks without treatment. Because of extreme toxicity, the animals were sacrificed after 53 weeks, rather than two years as originally planned. No increases in tumor incidences were reported. In an additional group administered acrolein for six weeks followed by tumor promotion with 3% uracil in the drinking water for 20 weeks, urinary bladder papillomas were reported in 18 of 30 and carcinoma in 1 of 30 rats, compared with papillomas in 8 of 30 and carcinoma in 1 of 30 rats treated with uracil alone (p<0.05). While it appears that acrolein may have some tumor initiating capability, when the incidence of nodular hyperplasias (considered precursors to papillomas) and papillomas were combined, there were no significant differences between the two groups. Acrolein was too toxic to evaluate its tumor promoting potential, and the impact of its cytotoxicity on conclusions about its tumor initiating potential cannot be determined from this study alone. No sarcomas were reported in a group of 15 female albino mice administered 0.2 mg acrolein by subcutaneous injection, weekly for 24 weeks, then held for a lifetime (Steiner et al., 1943). No evidence for skin tumor initiating capability was reported in S strain mice administered acrolein dermally in ten weekly applications for a total dose of 12.6 mg/animal, followed by treatment with the tumor promoter croton oil (Salaman and Roe, 1956). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY In vitro, acrolein has been shown to induce DNA adducts in a variety of cell types as well as mutagenesis in Drosophila and microorganisms under certain conditions, but there is only limited information regarding the ability of acrolein to induce mutations in normal mammalian cells. In mammalian cell in vitro assays, acrolein has been shown to induce sister chromatid exchange, DNA cross-linking, and binding to DNA polymerase. Even in the in vitro assays, acrolein is so reactive that special techniques must generally be employed to reduce cytotoxicity and induce positive effects. While mutagenic activity has occasionally been shown, positive results generally occurred only in a narrow, near lethal, dose range. There have been conflicting results reported in the literature for in vitro mutagenicity. In a series of Ames assays, Parent et al. (1996b) proposed an explanation for the conflicting data by considering the presence or absence of non-DNA nucleophiles from the S9 activation mixture, in the test chemical solution, or in the plating solutions. Parent et al. suggest that in the presence of non-DNA nucleophiles, acrolein will rapidly and indiscriminately react with any available species and not reach the DNA target. According to Beauchamp et al. (1985), acrolein administered by the inhalation route is retained primarily in the upper respiratory tract because of its reactivity. Some evidence for systemic uptake following oral exposure was noted by Draminski et al. (1983); however, the large doses used (10 mg/kg) would be expected to induce cellular damage, which may allow for some absorption. Tissues at the site of contact are, therefore, expected to be most highly exposed, and no evidence of tumor induction in the respiratory tract, skin or gastrointestinal tract has been reported. Studies by Parent et al. (1996a, 1998) indicate little systemic distribution to tissues. The highly reactive nature of acrolein and studies supporting the lack of systemic distribution of acrolein suggest that acrolein is not likely to reach potential target sites at a sufficient concentration to initiate a carcinogenic process in mammalian species. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not applicable. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not aapplicable. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA (2003). This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Acrolein (U.S. EPA, 2003). To review this appendix, exit to the toxicological review, Appendix A, Summary of External Peer Review Comments and Disposition http://www.epa.gov/iris/toxreviews/0364-tr.pdf#page=101. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 05/16/2003 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 200306 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Acrolein CASRN -- 107-02-8 Last Revised -- 06/03/2003 SORD: __VI.A. ORAL RfD REFERENCES Arumugam, N; Thanislass, J; Ragunath, K; et al. (1999) Acrolein-induced toxicity - defective mitochondrial function as a possible mechanism. Arch Environ Contam Toxicol 36(4):373-376. Bioassay Systems Corp. (1981) Subchronic oral toxicity of acrolein in rats. Project #10258. (Results section and tables). IRIS. (2003). Glossary of IRIS Terms. Available online at: http://www.epa.gov/iris/gloss8.htm National Toxicology Program (NTP). (1995) 13-week gavage toxicity studies of allyl acetate, allyl alcohol, and acrolein in Fischer 344 rats and B6C3F1 mice. Abstract with tables. Parent, RA; Caravello, HE; Long, JE. (1991) Oncogenicity study of acrolein in mice. J Am Coll Toxicol 10(6):647-659. Parent, RA; Caravello, HE; Long, JE. (1992a) Two-year toxicity and carcinogenicity study of acrolein in rats. J Appl Toxicol 12(2):131-139. Parent, RA; Caravello, HE; Hoberman, AM. (1992b) Reproductive study of acrolein on two generations of rats. Fundam Appl Toxicol 19(2):228-237. Parent, RA; Caravello, HE; Balmer, MF; et al. (1992c) One-year toxicity of orally administered acrolein to the beagle dog. J Appl Toxicol 12(5):311-316. Parent, RA; Caravello, HE; Christian, MS; et al. (1993) Developmental toxicity of acrolein in New Zealand white rabbits. Fundam Appl Toxicol 20(2):248-256. Pathology Working Group. (1997) Chairperson's report, Pathology Working Group review of acrolein 13-week subchronic gavage study in F344 rats and B6C3F1 mice conducted at Battelle-Columbus. TERA (Toxicology Excellence for Risk Assessment). (1998). ITER peer review meeting summary to review risk assessment documents on acrolein, acrylamide, and acrylonitrile. November 16-17, 1998. Available online: http://www.tera.org/peer/nov98final.htm U.S. EPA (U.S. Environmental Protection Agency). (2003) Toxicological review of acrolein in support of summary information on Integrated Risk Information System (IRIS) National Center for Environmental Assessment, Washington, DC. EPA/635/R-03/003. Available online at: http://www.epa.gov/iris. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Cassee, FR; Groton, JP; Feron, VJ. (1996) Changes in the nasal epithelium of rats exposed by inhalation to mixtures of formaldehyde, acetaldehyde, and acrolein. Fundam Appl Toxicol 29:208-218. Costa, DL; Kutzman, RS; Lehmann, JR; et al. (1986) Altered lung function and structure in the rat after subchronic exposure to acrolein. Am Rev Resp Dis 133:286-291. Feron, VJ; Kryusse, A; Til, HP; et al. (1978) Repeated exposure to acrolein vapor: subacute studies in hamsters, rats and rabbits. Toxicology 9:47-57. Kutzman, RS. (1981) A subchronic inhalation study of Fischer 344 rats exposed to 0, 0.4 1.4, or 4.0 ppm acrolein. Brookhaven National Laboratory, Upton, NY. Conducted for the National Toxicology Program: Interagency Agreement No. 222-Y01-ES-9-0043. Kutzman, RS; Wehner, RW; Haber, SB. (1984) Selected responses of hypertension-sensitive and resistant rats to inhaled acrolein. Toxicology 31(1):53-65. Kutzman, RS; Popenoe, EA; Schmaeler, M; et al. (1985) Changes in rat lung structure and composition as a result of subchronic exposure to acrolein. Toxicology 34(2):139-151. Lyon, JP; Jenkins, LJ, Jr; Jones, RA; et al. (1970) Repeated and continuous exposure of laboratory animals to acrolein. Toxicol Appl Pharmacol 17(3):726-732. Lyon, JP. (2001) Personal communication with Mark Greenberg, USEPA. U.S. EPA (U.S. Environmental Protection Agency). (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F. U.S. EPA. (2003) Toxicological review of acrolein in support of summary information on Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. EPA/635/R-03/003. Available online at: http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Beauchamp, RO, Jr; Andjelkovich, DA; Kligerman, AD; et al. (1985) A critical review of the literature on acrolein toxicity. CRC Crit Rev Toxicol 14:309-378. Cohen, SM; Garland, EM; St John, M; et al. (1992) Acrolein initiates rat urinary bladder carcinogenesis. Cancer Res 52(13):3577-3581. Draminski, W; Eder, E; Henschler, D. (1983) A new pathway of acrolein metabolism in rats (Short communication). Arch Toxicol 52(3):243-247. Feron, VJ; Kryusse, A. (1977) Effects of exposure to acrolein vapor in hamsters simultaneously treated with benzo(a)pyrene or diethylnitrosamine. J Toxicol Environ Health 3:379-394. Le Bouffant, L; Martin, JC; Daniel, H; et al. (1980) Actions of intensive cigarette smoke inhalations on the rat lung. Role of particulate and gaseous cofactors. J. Natl Cancer Inst 64(2):273-281. Lijinsky, W; Reuber, MD. (1987) Chronic carcinogenesis studies of acrolein and related compounds. Toxicol Ind Health 3(3):337-345. Ott, MG; Teta, J; Greenberg, HL. (1989) Lymphatic and hematopoietic tissue cancer in a chemical manufacturing environment. Am J Ind Med 16:631-643. Parent, RA; Caravello, HE; Long, JE. (1991) Oncogenicity study of acrolein in mice. J Am Coll Toxicol 11:91-95. Parent, RA; Caravello, HE; Long, JE. (1992a) Two-year toxicity and carcinogenicity study of acrolein in rats. J Appl Toxicol 12(2):131-139. Parent, RA; Caravello, HE; Sharp, DE. (1996a) Metabolism and disposition of [2,3-14C] acrolein in Sprague-Dawley rats. J Appl Toxicol 16(5):449-457. Parent, RA; Caravello, HE; San, RH (1996b) Mutagenic activity of acrolein in S. typhimurium and E. coli. J Appl Toxicol 16(2):103-8. Parent, RA; Paust, DE; Schrimpf, MK; et al. (1998) Metabolism and distribution of [2,3-14C]acrolein in Sprague-Dawley rats. II. Identification of urinary and fecal metabolites. Toxicol Sci 43(2):110-120. Salaman, MH; Roe, FJC. (1956) Further tests for tumour initiating activity: N,N-di(2-chloroethyl)-p-aminophenylbutyric acid (CB1348) as an initiator of skin tumour formation in the mouse. Br J Cancer 10:363-378. Steiner, PE; Steele, R; Koch, FC. (1943) The possible carcinogenicity of overcooked meats, heated cholesterol, acrolein and heated sesame oil. Cancer Res 3:100-143. U.S. EPA (U.S. Environmental Protection Agency). (1999) Guidelines for carcinogen risk assessment. Review draft. NCEA-F-0644, July 1999. Risk Assessment Forum. U.S. EPA. (2003) Toxicological review of acrolein in support of summary information on Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. EPA/635/R-03/003. Available online at: http://www.epa.gov/iris. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Acrolein CASRN -- 107-02-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/07/1988 II. Carcinogen summary on-line 04/01/1989 V. Supplementary data on-line 07/01/1989 I.B. Inhalation RfD now under review 03/01/1990 II.A.4. Citations clarified (3rd paragraph) 03/01/1990 VI. Bibliography on-line 05/01/1990 VI.C. Hemminki et al., 1980 citation corrected 10/01/1991 I.B. Inhalation RfC summary on-line 10/01/1991 I.B. Inhalation RfC references added 01/01/1992 IV. Regulatory Action section on-line 07/01/1993 I.B.1. LOAEL(ADJ) corrected 02/01/1994 II.D.3. Secondary contact's phone number changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/12/2000 I., II. This chemical is being reassessed under the IRIS Program. 06/03/2003 I., II., VI. RfD, RfC and cancer sections updated. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 416 of 1119 in IRIS (through 2003/06) AN: 371 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Asbestos- SY: 1332-21-4; CALIDRIA-ASBESTOS- RN: 1332-21-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Asbestos CASRN -- 1332-21-4 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Asbestos CASRN -- 1332-21-4 NORC: Not available at this time. ============================================================================ UDCA: 199307 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Asbestos CASRN -- 1332-21-4 Last Revised -- 07/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NOCA: Note: The carcinogen assessment summary for asbestos may change in the near future pending the outcome of a further review now being conducted by the CRAVE Work Group. ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- A; human carcinogen Basis -- Observation of increased mortality and incidence of lung cancer, mesotheliomas and gastrointestinal cancer in occupationally exposed workers are consistent across investigators and study populations. Animal studies by inhalation in two strains of rats showed similar findings for lung cancer and mesotheliomas. Animal evidence for carcinogenicity via ingestion is limited (male rats fed intermediate-range chrysotile fibers; i.e., >10 um length, developed benign polyps), and epidemiologic data in this regard are inadequate. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Sufficient. Numerous epidemiologic studies have reported an increased incidence of deaths due to cancer, primarily lung cancer and mesotheliomas associated with exposure to inhaled asbestos. Among 170 asbestos insulation workers in North Ireland followed for up to 26 years, an increased incidence of death was seen due to all cancers (SMR=390), cancers of the lower respiratory tract and pleura (SMR=1760) (Elmes and Simpson, 1971) and mesothelioma (7 cases). Exposure was not quantified. Selikoff (1976) reported 59 cases of lung cancer and 31 cases of mesothelioma among 1249 asbestos insulation workers followed prospectively for 11 years. Exposure was not quantified. A retrospective cohort mortality study (Selikoff et al., 1979) of 17,800 U.S. and Canadian asbestos insulation workers for a 10-year period using best available information (autopsy, surgical, clinical) reported an increased incidence of cancer at all sites (319.7 expected vs. 995 observed, SMR=311) and cancer of the lung (105.6 expected vs. 486 observed, SMR=460). A modest increase in deaths from gastrointestinal cancer was reported along with 175 deaths from mesothelioma (none expected). Years of exposure ranged from less than 10 to greater than or equal to 45. Levels of exposure were not quantified. In other epidemiologic studies, the increase for lung and pleural cancers has ranged from a low of 1.9 times the expected rate, in asbestos factory workers in England (Peto et al., 1977), to a high of 28 times the expected rate, in female asbestos textile workers in England (Newhouse et al., 1972). Other occupational studies have demonstrated asbestos exposure-related increases in lung cancer and mesothelioma in several industries including textile manufacturing, friction products manufacture, asbestos cement products, and in the mining and milling of asbestos. The studies used for the inhalation quantitative estimate of risk are listed in the table in Section II.C.2. A case-control study (Newhouse and Thompson, 1965) of 83 patients with mesothelioma reported 52.6% had occupational exposure to asbestos or lived with asbestos workers compared with 11.8% of the controls. Of the remaining subjects, 30.6% of the mesothelioma cases lived within one-half mile of an asbestos factory compared with 7.6% of the controls. The occurrence of pleural mesothelioma has been associated with the presence of asbestos fibers in water, fields and streets in a region of Turkey with very high environmental levels of naturally-occurring asbestos (Baris et al., 1979). Kanarek et al. (1980) conducted an ecologic study of cancer deaths in 722 census tracts in the San Francisco Bay area, using cancer incidence data from the period of 1969-1971. Chrysotile asbestos concentrations in drinking water ranged from nondetectable to 3.6E+7 fibers/L. Statistically significant dose-related trends were reported for lung and peritoneal cancer in white males and for gall bladder, pancreatic and peritoneal cancer in white females. Weaker correlations were reported between asbestos levels and female esophageal, pleural and kidney cancer, and stomach cancer in both sexes. In an extension of this study, Conforti et al. (1981) included cancer incidence data from the period of 1969-1974. Statistically significant positive associations were found between asbestos concentration and cancer of the digestive organs in white females, cancers of the digestive tract in white males and esophageal, pancreatic and stomach cancer in both sexes. These associations appeared to be independent of socioeconomic status and occupational exposure to asbestos. Marsh (1983) reviewed eight independent ecologic studies of asbestos in drinking water carried out in five geographic areas. It was concluded that even though one or more studies found an association between asbestos in water and cancer mortality (or incidence) due to neoplasms of various organs, no individual study or aggregation of studies exists that would establish risk levels from ingested asbestos. Factors confounding the results of these studies include the possible underestimates of occupational exposure to asbestos and the possible misclassification of peritioneal mesothelioma as GI cancer. Polissar et al. (1984) carried out a case-control study which included better control for confounding variables at the individual level. The authors concluded that there was no convincing evidence for increased cancer risk from asbestos ingestion. At the present time, an important limitation of both the case-control and the ecologic studies is the short follow-up time relative to the long latent period for the appearance of tumors from asbestos exposure. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. There have been about 20 animal bioassays of asbestos. Gross et al. (1967) exposed 61 white male rats (strain not reported) to 86 mg chrysotile asbestos dust/cu.m for 30 hours/week for 16 months. Of the 41 animals that survived the exposure period, 10 had lung cancer. No lung cancer was observed in 25 controls. Reeves (1976) exposed 60-77 rats/group for 4 hours/day, 4 days/week for 2 years to doses of 48.7-50.2 mg/cu.m crocidolite, 48.2-48.6 mg/cu.m amosite and 47.4-47.9 mg/cu.m chrysotile. A 5-14% incidence of lung cancer was observed among concentration groups and was concentration-dependent. Wagner et al. (1974) exposed CD Wistar rats (19-52/group) to 9.7-14.7 mg/cu.m of several types of asbestos for 1 day to 24 months for 7 hours/day, 5 days/week. A duration-dependent increased incidence of lung carcinomas and mesotheliomas was seen for all types of asbestos after 3 months of exposure compared with controls. F344 rats (88-250/group) were exposed to intermediate range chrysotile asbestos (1291E+8 f/g) in drinking water by gavage to dams during lactation and then in diet throughout their lifetime (NTP, 1985). A statistically significant increase in incidence of benign epithelial neoplasms (adenomatous polyps in the large intestine) was observed in male rats compared with pooled controls of all NTP oral lifetime studies (3/524). In the same study, rats exposed to short range chrysotile asbestos (6081E+9 f/g) showed no significant increase in tumor incidence. Ward et al. (1980) administered 10 mg UICC amosite asbestos 3 times/week for 10 weeks by gavage to 50 male F344 rats. The animals were observed for an additional 78-79 weeks post-treatment. A total of 17 colon carcinomas were observed. This result was statistically significant compared with historical controls; no concurrent controls were maintained. Syrian golden hamsters (126-253/group) were exposed to short and intermediate range chrysotile asbestos at a concentration of 1% in the diet for the lifetime of the animals (NTP, 1983). An increased incidence of neoplasia of the adrenal cortex was observed in both males and females exposed to intermediate range fibers and in males exposed to short range fibers. This increase was statistically significant by comparison to pooled controls but not by comparison to concurrent controls. NTP suggested that the biologic importance of adrenal tumors in the absence of target organ (GI tract) neoplasia was questionable. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Sincock (1977) reported an increased number of chromosomes and chromosome breaks after passive inclusion of asbestos with CHO-K1 cells. Chamberlain and Tarmy (1977) reported asbestos not to be mutagenic for E. coli or S. typhimurium. A positive response was unlikely, however, since prokaryotic cells do not phagocytize particles as do eukaryotic cells. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk -- 2.3E-1 per (f/mL) Extrapolation Method -- Additive risk of lung cancer and mesothelioma, using relative risk model for lung cancer and absolute risk model for mesothelioma Air Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 4E-4 f/mL E-5 (1 in 100,000) 4E-5 f/mL E-6 (1 in 1,000,000) 4E-6 f/mL DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Reported Average Human Data Fiber Exposure % Increase Reference Occupational Type (fiber- in Cancer per Group yr/mL) fiber-yr/mL ---------------------------------------------------------------------------- Lung Cancer: Textile Products Predominantly 44 2.8 Dement et al., Chrysotile 1983b Textile Products Chrysotile 31 2.5 McDonald et al., 1983a Textile Products Chrysotile 200 1.1 Peto, 1980 Textile Products Chrysotile 51 1.4 McDonald et al., 1983b Friction Products Chrysotile 32 0.058 Berry and Newhouse, 1983 Friction Products Chrysotile 31 0.010 McDonald et al., 1984 Insulation Products Amosite 67 4.3 Seidman, 1984 Insulation Workers Mixed 300 0.75 Selikoff et (Chrysotile, al., 1979 Crocidolite and Amosite) Asbestos Products 374 0.49 Henderson and Enterline, 1979 Cement Products 89 0.53 Weill et al., 1979 112 6.7 Finkelstein, 1983 Mesothelioma: Insulation workers Mixed 375 1.5E-6 Selikoff et al., 1979; Peto et al., 1982 Insulation Products Amosite 400 1.0E-6 Seidman et al., 1979 Textile Products Chrysotile 67 3.2E-6 Peto, 1980; Manufacturer Peto et al., 1982 Cement Products Mixed 108 1.2E-5 Finkelstein, 1983 ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) Risks have been calculated for males and females according to smoking habits for a variety of exposure scenarios (U.S. EPA, 1986). The unit risk value is calculated for the additive combined risk of lung cancer and mesothelioma, and is calculated as a composite value for males and females. The epidemiological data show that cigarette smoking and asbestos exposure interact synergistically for production of lung cancer and do not interact with regard to mesothelioma. The unit risk value is based on risks calculated using U.S. general population cancer rates and mortality patterns without consideration of smoking habits. The risks associated with occupational exposure were adjusted to continuous exposure by applying a factor of 140 cu.m/50 cu.m based on the assumption of 20 cu.m/day for total ventilation and 10 cu.m/8-hour workday in the occupational setting. The unit risk is based on fiber counts made by phase contrast microscopy (PCM) and should not be applied directly to measurements made by other analytical techniques. The unit risk uses PCM fibers because the measurements made in the occupational environment use this method. Many environmental monitoring measurements are reported in terms of fiber counts or mass as determined by transmission electron microscopy (TEM). PCM detects only fibers longer than 5 um and >0.4 um in diameter, while TEM can detect much smaller fibers. TEM mass units are derived from TEM fiber counts. The correlation between PCM fiber counts and TEM mass measurements is very poor. Six data sets which include both measurements show a conversion between TEM mass and PCM fiber count that range from 5-150 (ug/cu.m)/(f/mL). The geometric mean of these results, 30 (ug/cu.m)/(f/mL), was adopted as a conversion factor (U.S. EPA, 1986), but it should be realized that this value is highly uncertain. Likewise, the correlation between PCM fiber counts and TEM fiber counts is very uncertain and no generally applicable conversion factor exists for these two measurements. In some cases TEM results are reported as numbers of fibers <5 um long and of fibers longer than 5 um. Comparison of PCM fiber counts and TEM counts of fibers >5 um show that the fraction of fibers detected by TEM that are also >0.4 um in diameter (and detectable by PCM) varies from 22-53% (U.S. EPA, 1986). It should be understood that while TEM can be specific for asbestos, PCM is a nonspecific technique and will measure any fibrous material. Measurements by PCM which are made in conditions where other types of fibers may be present may not be reliable. In addition to the studies cited above, there were three studies of asbestos workers in mining and milling which showed an increase in lung cancer (McDonald et al., 1980, Nicholson et al., 1979; Rubino et al., 1979). The slope factor calculated from these studies was lower than the other studies, possibly because of a substantially different fiber size distribution, and they were not included in the calculation. The slope factor was calculated by life table methods for lung cancer using a relative risk model, and for mesothelioma using a absolute risk model. The final slope factor for lung cancer was calculated as the weighted geometric mean of estimates from the 11 studies cited in section II.C.2. The final slope factor for mesothelioma is based on the calculated values from the studies of Selikoff et al. (1979), Peto et al. (1982), Seidman et al. (1979), Peto (1980) and Finkelstein (1983) adjusted for the mesothelioma incidence from several additional studies cited previously. There is some evidence which suggests that the different types of asbestos fibers vary in carcinogenic potency relative to one another and site specificity. It appears, for example, that the risk of mesothelioma is greater with exposure to crocidolite than with amosite or chrysotile exposure alone. This evidence is limited by the lack of information on fiber exposure by mineral type. Other data indicates that differences in fiber size distribution and other process differences may contribute at least as much to the observed variation in risk as does the fiber type itself. The unit risk should not be used if the air concentration exceeds 4E-2 fibers/ml, since above this concentration the slope factor may differ from that stated. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) A large number of studies of occupationally-exposed workers have conclusively demonstrated the relationship between asbestos exposure and lung cancer or mesothelioma. These results have been corroborated by animal studies using adequate numbers of animals. The quantitative estimate is limited by uncertainty in the exposure estimates, which results from a lack of data on early exposure in the occupational studies and the uncertainty of conversions between various analytical measurements for asbestos. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985 The 1985 Drinking Water Criteria Document for Asbestos and the 1986 Airborne Asbestos Health Assessment Update have received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/15/1987, 12/02/1987 Verification Date -- 12/02/1987 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199307 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Asbestos CASRN -- 1332-21-4 Last Revised -- 07/01/1993 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Baris, Y.I., M. Artivinli and A.A. Sahin. 1979. Environmental mesothelioma in Turkey. Ann. N.Y. Acad. Sci. 330: 423-432. Berry, G. and M.L. Newhouse. 1983. Mortality of workers manufacturing friction materials using asbestos. Br. J. Ind. Med. 40: 1-7. Chamberlain, M. and E.M. Tarmy. 1977. Asbestos and glass fibers in bacterial mutation tests. Mutat. Res. 43: 159-164. Conforti, P.M., M.S. Kanarek, L.A. Jackson, R.C. Cooper and J.C. Murchio. 1981. Asbestos in drinking water and cancer in the San Francisco Bay Area: 1969-1974 incidence. J. Chr. Dis. 34: 211-224. Dement, J.M., R.L. Harris Jr., M.J. Symons and C.M. Shy. 1983. Exposures and mortailty among chrysotile asbestos workers. Part II: Mortality. Am. J. Ind. Med. 4: 421-433. Elmes, P.C. and M.J. Simpson. 1971. Insulation workers in Belfast. III. Mortality 1940-1966. Br. J. Ind. Med. 28: 226-236. Finkelstein, M.M. 1983. Mortality among long-term employees of an Ontario asbestos-cement factory. Br. J. Ind. Med. 40: 138-144. Gross, P., R.T.P. deTreville, E.B. Tolker, M. Kaschak and M.A. Babyak. 1967. Experimental asbestosis: The development of lung cancer in rats with pulmonary deposits of chrysotile asbestos dust. Arch. Environ. Health. 15: 343-355. Henderson, V.L. and P.E. Enterline. 1979. Asbestos exposure: Factors associated with excess cancer and respiratory disease mortality. Ann. N.Y. Acad. Sci. 330: 117-126. Kanarek, M.S., P.M. Conforti, L.A. Jackson, R.C. Cooper and J.C. Murchio. 1980. Asbestos in drinking water and cancer incidence in the San Francisco bay area. Am. J. Epidemiol. 12-1: 54-72. Marsh, G.M. 1983. Critical review of epidemiologic studies related to ingested asbestos. Environ. Health. Perspect. 53: 49-56. McDonald, J.C., F.D.K. Liddell, G.W. Gibbs, G.E. Eyssen and A.D. McDonald. 1980. Dust exposure and mortality in chrysotile mining, 1910-1975. Br. J. Ind. Med. 37: 11-24. McDonald, A.D., J.S. Fry, A.J. Wooley and J.C. McDonald. 1983a. Dust exposure and mortality in an American chrysotile textile plant. Br. J. Ind. Med. 40: 361-367. McDonald, A.D., J.S. Fry, A.J. Wooley and J.C. McDonald. 1983b. Dust exposure and mortality in an American factory using chrysotile, amosite and crocidolite in mainly textile manufacturing. Br. J. Ind. Med. 40: 368-374. McDonald, A.D., J.S. Fry, A.J. Wooley and J.C. McDonald. 1984. Dust exposure and mortality in an American chrysotile asbestos friction products plant. Br. J. Ind. Med. 41: 151-157. Newhouse, M.L. and H. Thompson. 1965. Mesothelioma of the pleura and peritoneum following exposure to asbestos in the London area. Br. J. Ind. Med. 22: 261-269. Newhouse, M.L., G. Berry, J.C. Wagner and M.E. Turok. 1972. A study of the mortility of female asbestos workers. Br. J. Ind. Med. 29: 134-141. Nicholson, W.J., I.J. Selikoff, H. Seidman, R. Lilis and P. Formby. 1979. Long-term mortality experience of chrysotile miners and millers in Thetford Mines, Quebec. Ann. N.Y. Acad. Sci. 330: 11-21. NTP (National Toxicology Program). 1983. Carcinogenesis lifetime studies of chrysotile asbestos (CAS No. 12001-29-5) in Syrian golden hamsters (feed studies). Technical report series No. 246. Department of Health and Human Services, Research Triangle Park, NC. NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of chrysotile asbestos (CAS No. 12001-29-5) in F344/N rats (feed studies). Technical report series No. 295. Department of Health and Human Services, Research Triangle Park, NC. Peto, J. 1980. Lung cancer mortality in relation to measured dust levels in an asbestos textile factory. In: Biological effects of mineral fibers: Effets biologiques des fibers minerals, Vol. 2, J.C. Wagner and W. Davis, Ed. Proceedings of a symposium, September 1979, Lyon, France. World Health Organization, International Agency for Research on Cancer Lyon, France. p. 829-836. (IARC scientific publ. no. 30; INSERM symposia series: Vol. 92.) Peto, J., R. Doll, S.V. Howard, L.J. Kinlen and H.C. Lewinsohn. 1977. A mortility study among workers in an English asbestos factory. Br. J. Ind. Med. 34: 169-172. Peto, J., H. Siedman and I.J. Selikoff. 1982. Mesothelioma mortality in asbestos workers: Implications for models of carcinogenesis and risk assessment. Br. J. Cancer. 45: 124-135. Polissar, L., R.K. Severson and E.S. Boatman. 1984. A case-control study of asbestos in drinking water and cancer risk. Am. J. Epidemiol. 119(3): 456-471. Reeves, A.L. 1976. The carcinogenic effect of inhaled asbestos fibers. Ann. Clin. Lab. Sci. 6: 459-466. Rubino, G.F., G. Piolatto, M.L. Newhouse, G. Scansetti, G.A. Aresini and R. Murrary. 1979. Mortality of chrysotile asbestos workers at the Balangero mine, Northern Italy. Br. J. Ind. Med. 36: 187-194. Seidman, H. 1984. Short-term asbestos work exposure and long-term observation. In: [Docket of current rulemaking for revision of the asbestos (dust) standard]. U.S. Department of Labor, Occupational Safety and Health Administration, Washington, DC Available for inspection at U.S. Department of Labor, OSHA Technical Data Center, Francis Perkins Building; docket no. H033C, exhibit nos. 261-A and 261-B. Seidman, H., I.J. Selikoff and E.C. Hammond. 1979. Short-term asbestos work exposure and long-term observation. Ann. N.Y. Acad. Sci. 330: 61-89. Selikoff, I.J. 1976. Lung cancer and mesothelioma during prospective surveillance of 1249 asbestos insulation workers, 1963-1974. Ann. N.Y. Acad. Sci. 271: 448-456. Selikoff, I.J., E.C. Hammond and H. Siedman. 1979. Mortality experience of insulation workers in the United States and Canada, 1943-1976. Ann. N.Y. Acad. Sci. 330: 91-116. Sincock, A.M. 1977. Preliminary studies of the in vitro cellular effects of asbestos and fine glass dusts. In: Origins of Human Cancer: Book B, Mechanisms of Carcinogenesis, H.H. Hiatt, J.D. Watson and J.A. Winsten, Ed. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY. p. 941-954. (Cold Spring Harbor conference on cell proliferation: Vol. 4.) U.S. EPA. 1985. Drinking Water Criteria Document for Asbestos. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. U.S. EPA. 1986. Airborne Asbestos Health Assessment Update. Prepared by the Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-84/003F. Wagner, J.C., G. Berry, J.W. Skidmore and V. Timbrell. 1974. The effects of the inhalation of asbestos in rats. Br. J. Cancer. 29: 252-269. Ward, J.M., A.L. Frank, M. Wenk, D. Devor and R.E. Tarone. 1980. Ingested asbestos and intestinal carcinogenesis in F344 rats. J. Environ. Pathol. Toxicol. 3: 301-312. Weill, H., J. Hughes and C. Waggenspack. 1979. Influence of dose and fiber type on respiratory malignancy risk in asbestos cement manufacturing. Am. Rev. Respir. Dis. 120: 345-354. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Asbestos CASRN -- 1332-21-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/26/1988 II. Carcinogen summary on-line 05/01/1989 II. Carcinogen summary noted as pending change 12/01/1989 VI. Bibliography on-line 03/01/1991 II.A.1. Text revised 07/01/1991 II.C.3. Last paragraph units changed from ug/cu.m to fibers/ml 01/01/1992 IV. Regulatory Action section on-line 07/01/1993 II.D.1. EPA Documentation clarified 07/01/1993 VI.C. References alphabetized correctly 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 02/22/2001 I.,II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 417 of 1119 in IRIS (through 2003/06) AN: 399 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Chlorobenzene- SY: *MONOCHLOROBENZENE-; 108-90-7; BENZENE-CHLORIDE-; BENZENE,-CHLORO-; CHLOORBENZEEN- (DUTCH); CHLORBENZENE-; CHLORBENZOL-; CHLOROBENZEN- (POLISH); CHLOROBENZENU- (CZECH); CHLOROBENZOL-; CLOROBENZENE- (ITALIAN); MCB-; MONOCHLOORBENZEEN- (DUTCH); MONOCHLORBENZENE-; MONOCHLORBENZOL- (GERMAN); MONOCLOROBENZENE- (ITALIAN); NCI-C54886-; PHENYL-CHLORIDE-; UN-1134- RN: 108-90-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199307 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chlorobenzene CASRN -- 108-90-7 Primary Synonym -- Monochlorobenzene Last Revised -- 07/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Histopathologic NOAEL: 27.25 mg/kg/day 1000 1 2E-2 changes in liver (adjusted dose: mg/kg/day 19 mg/kg/day) 13-Week Dog Study, Oral Exposure (capsule) LOAEL: 54.5 mg/kg/day Monsanto Co., 1967a; Knapp et al., 1971 ---------------------------------------------------------------------------- *Conversion Factors: Doses adjusted for dosing schedule of 5 days/7 days. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Monsanto Company. 1967a. 13-week oral administration - dogs. Monchlorobenzene. Final report. Prepared by Hazelton Laboratories, Project No. 241-105, February 24. Knapp, W.K., W.M. Busey and W. Kundzins. 1971. Subacute oral toxicity of monochlorobenzene in dogs and rats. Toxicol. Appl. Pharmacol. 19: 393 (Abstract). Male and female beagle dogs given chlorobenzene orally by capsule at doses of 27.25, 54.5, or 272.5 mg/kg/day, 5 days/week, for 13 weeks. NOAEL = 27.25 mg/kg/day; LOAEL = 54.5 mg/kg/day (slight bile duct proliferation, cytologic alternations, and leukocytic infiltration of the stroma, all in liver). Death; body weight loss; changes in hematology, clinical chemistry, and urine analysis; and pathologic changes in liver (bile duct hyperplasia, cytologic changes, leukocytic infiltration, centrolobular degeneration), kidney, gastrointestinal mucosa, and hematopoietic tissue were observed at 272.5 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 1000 allows for uncertainty in the extrapolation of dose levels from laboratory animals to humans (10A), uncertainty in the threshold for sensitive humans (10H), and uncertainty in the effect of duration when extrapolating from subchronic to chronic exposure (10S). MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Other Data Reviewed: 1) 90-Day Feeding - rat: NOAEL=50 mg/kg/day; LOAEL=100 mg/kg/day; (increased liver and kidney weights) (Monsanto Co., 1967b; Knapp et al., 1971) 2) 6-Month Gavage - rat: NOAEL=14.4 mg/kg/day; LOAEL=144 mg/kg/day; (liver histopathology) (Irish, 1963) 3) 90-Day Gavage - rat: NOAEL=60 mg/kg/day; LOAEL=125 mg/kg/day; (increased liver weights) (NTP, 1985) 4) 90-Day Gavage - mouse: NOAEL=60 mg/kg/day; LOAEL=125 mg/kg/day; (increased liver weights) (NTP, 1985) 5) 2-Year Gavage - rat: NOAEL=60 mg/kg/day; LOAEL=120 mg/kg/day; (liver histopathology in rats) (NTP, 1985) 6) 2-Year Gavage - mouse: NOAEL=60 mg/kg/day; LOAEL=120 mg/kg/day; (liver histopathology in rats) (NTP, 1985) 7) Developmental - rat: Developmental NOAEL=590 ppm (6 hour/day, equivalent to 216 mg/kg/day) (exposed by inhalation during periods of major organogenesis); Maternal NOAEL=210 ppm (77 mg/kg/day) (John et al., 1984) 8) Developmental - rabbit: Developmental NOAEL=590 ppm (6 hour/day, equivalent to 125 mg/kg/day; (exposed by inhalation during periods of major organogenesis); Maternal NOAEL=75 ppm (16 mg/kg/day) (John et al., 1984) 9) 2-Generation Reproduction (inhalation) - rat: Reproductive NOAEL=450 ppm (165 mg/kg/day); Systemic NOAEL=50 ppm (18 mg/kg/day) (Nair et al., 1987) CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The referenced subchronic study was given medium confidence since it provided both a NOAEL and a LOAEL and incorporated several biochemical and biological endpoints. Several subchronic, chronic, developmental, and reproductive toxicity studies provide supportive data, but they did not give a complete assessment of toxicity. Thus, the data base was given medium confidence. A medium level of confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1986 U.S. EPA, 1986 received EPA Science Advisory Board Reveiw 7/86. Other EPA Documentation -- None Agency Work Group Review -- 06/24/1985, 07/08/1985, 07/22/1985, 04/16/1987, 01/19/1989. Verification Date -- 01/19/1989 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Chlorobenzene CASRN -- 108-90-7 Primary Synonym -- Monochlorobenzene NORC: Not available at this time. ============================================================================ UDCA: 199103 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chlorobenzene CASRN -- 108-90-7 Primary Synonym -- Monochlorobenzene Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- No human data, inadequate animal data and predominantly negative genetic toxicity data in bacterial, yeast, and mouse lymphoma cells. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. Only one study, an NTP (1985a) gavage study in rats and mice has been performed. Groups of F344/N rats and B6C3F1 mice (50/sex/dose) were administered chlorobenzene (>99% pure) by gavage in corn oil 5 days/week for 103 weeks. Fifty animals/sex/species served as untreated and vehicle controls. The rats received 60 or 120 mg/kg/day; the female mice groups received 60 or 120 mg/kg/day and the male mice groups 30 or 60 mg/kg/day. Body weights in all groups of both species were comparable. At the end of the study survival in the male rats was 68, 78, 64, and 52% for the untreated-control, vehicle-control, low-, and high-dose groups, respectively; survival in the female rat groups was 74, 58, 60, and 62% for the untreated-control, vehicle-control, low-, and high-dose groups, respectively. Using the pairwise comparison test, only the high-dose male rats had a statistically significant elevation in mortality relative to their vehicle controls. No chlorobenzene-related signs of clinical toxicity were observed in the rats during the experiment; histological examination of the liver showed hepatocellular necrosis (graded as minimal to mild in all groups) caused by chlorobenzene. A statistically significant positive trend in the incidence of hepatocellular neoplastic nodules was observed in male rats; the incidence was 4/50, 2/50, 4/49 and 8/49 for the untreated-control, vehicle-control, low-, and high-dose groups, respectively. No hepatocellular tumors were observed in dosed male rats and none of the high-dose males with neoplastic nodules showed signs of hepatocellular necrosis. There was no increase in neoplastic nodules, hepatocellular carcinomas or combined neoplastic nodules and hepatocellular carcinomas in females. In the high-dose females, there was a single incidence of hepatocellular carcinoma. The incidence of neoplastic liver nodules in female rats was 1/49, 0/50, 1/50, and 1/50 in the untreated-control, vehicle-control, low-, and high-dose groups, respectively. No other significant increase in site-specific tumors or neoplastic pathology was observed in rats; however, a transitional cell bladder papilloma was observed in one low-dose and in one high-dose male rat and a kidney tubular cell carcinoma was observed in a high-dose female. These rare tumor types were not observed in the untreated or vehicle control groups. In the female mice, survival was approximately 78% in all groups. In male mice, however, survival was reduced in both dosed groups; it was 70, 78, 56, and 58 in the untreated-control, vehicle-control, low-, and high-dose groups, respectively. The mortality in the dosed males was statistically significantly increased. No chlorobenzene-related clinical toxicity and no significant increase in site-specific tumors or neoplastic pathology were observed in any mouse group. In 1986, the Environmental Health Committee of the Science Advisory Board reviewed this study; overall, the Committee considered the study to be of good quality, but the Comittee questioned the biological significance of the increased incidence of neoplastic liver nodules (Doull and Abrahamson, 1986). The NTP report does not specify the number of liver sections pathologically examined or which sections of the liver were examined; the location of the liver sections could cause the difference in the number and the diagnosis of lesions formed. Liver nodules are currently not considered necessarily to be progressive, and consequently lethal to the host. In this study, there was no incidence of hepatocellular carcinoma in male rats after 2 years of the study. The incidence of liver nodules in the untreated control male rats, however, was significantly higher than the recent historical NTP controls (67/3618, 1.9%). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Chlorobenzene was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 or TA1538, with or without addition of rat liver or hamster liver homogenate (duPont, 1977; Lawlor et al., 1979; Merck, 1978; Monsanto, 1976a; NTP, 1982; Simmon et al., 1979). Chlorobenzene did not induce DNA damage in Escherichia coli strains WP2 uvr A+ rec A+ or WP100 uvr A- rec A- or S. typhimurium strains TA1978 uvr B+ or TA1538 uvr B- (Lawlor et al., 1979; Simmon et al., 1979). Chlorobenzene caused increases in the number of revertants in Actinomycetes antibioticus-400 (Keskinova, 1968) and Aspergillus nidulans (Prasad, 1970; Prasad and Pramer, 1968) and mitotic disturbances in Allium cepa (Ostergen and Levan, 1943). Chlorobenzene did not induce specific locus forward mutations in mouse lymphoma L5178Y cells, either with or without metabolic activation (Monsanto, 1976b). Chlorobenzene induced reciprocal recombination in Saccharomyces cerevasiae strain D3 with metabolic activation (Simmon et al., 1979), but was ineffective in S. cerevesiae strain D4 with or without metabolic activation (Monsanto, 1976a). In carcinogenesis studies with 1,2-dichlorobenzene and 1,3-dichlorobenzene in rats and mice (NTP, 1985b, 1987), 1,3-dichlorobenzene induced kidney tumors in male rats and liver tumors in both sexes of mice. Neither compound induced liver tumors in rats. The NTP (1985a) study speculated that chlorobenzene was related to the carcinogen, benzene, because of similarities in structure, metabolism and hematological effects in rodents; and therefore, a toxic human response could be predicted based upon a rodent model. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1986, 1989 The Health Effects Criteria Document on Chlorobenzene by the Office of Drinking Water has undergone public review and Science Advisory Board review (1986). The proposed drinking water standard for chlorobenzene has been reviewed by EPA and the public (1989 Federal Register notice). RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 04/04/1990 Verification Date -- 04/04/1990 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199011 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Chlorobenzene CASRN -- 108-90-7 Primary Synonym -- Monochlorobenzene Last Revised -- 11/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Irish, D.D. 1963. Halogenated hydrocarbons. II. Cyclic. In: Patty's Industrial Hygiene and Toxicology, Vol. II., D.W. Fassett and D.D. Irish, Ed. Interscience Publishers, New York, NY. p. 1333-1362. John, J.A., W.C. Hayes, T.R. Hanley, Jr., K.A. Johnson, T.S. Gushow and K.S. Rao. 1984. Inhalation teratology study on monochlorobenzene in rats and rabbits. Toxicol. Appl. Pharmacol. 76: 365-373. Knapp, W.K., W.M. Busey and W. Kundzins. 1971. Subacute oral toxicity of monochlorobenzene in dogs and rats. Toxicol. Appl. Pharmacol. 19: 393. (Abstract). Monsanto Chemical Company. 1967a. 13-week oral administration -- dogs. Monochlorobenzene. Final report. Prepared by Hazelton Laboratories, Project No. 241-105, February 24. Monsanto Chemical Company. 1967b. Three-month subacute oral study -- rats. Monchlorobenzene. Final report. Prepared by Hazelton Laboraties, Project No. 241-104, March 9. Nair, R.S., J.A. Barter, R.E. Schroeder, A. Knezevich and C.R. Stack. 1987. A two-generation reproduction study with monochlorobenzene vapor in rats. Fund. Appl. Toxicol. 9: 678-686. NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of chlorobenzene (CAS No. 108-90-7) in F344/N rats and B6C3Fl mice (gavage studies). U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health. NTP No. 261. NIH Publ. No. 83-2517. U.S. EPA. 1986. Drinking Water Criteria Document for Chlorobenzene. Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES E.I. duPont deNemours and Company. 1977. Mutagenic activity of monochlorobenzene in the Salmonella-microsome assay. Haskell Laboratory for Toxicology and Industrial Medicine. Unpublished report. Doull, J. and S. Abrahamson. 1986. Chair, Halogenated Organics Subcommittee of Science Advisory Board U.S. EPA and Vice-Chair Halogenated Organics Subcommittee of Science Advisory Board U.S. EPA. Memorandum to R.A. Griesemer, Chair Environmental Health Committee of Science Advisory Board, U.S. EPA. Technical comments of the Halogenated Organics Subcommittee on EPA's Draft Drinking Water Criteria Document for Monochlorobenzene. December 16. Keskinova, D.V. 1968. The effect of dimethylcyclodiazomethane in chlorobenzene solution on the process of mutagenesis in Actinomyces antibioticus-400. Genetika. 4(8): 121-125. Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic activity of nine chlorinated phenols, seven chlorinated benzenes, and three chlorinated hexanes. Environ. Mutagen. 1: 143. (Abstract) Merck and Company. 1978. Summary of monochlorobenzene bacterial mutagen test (Ames Test). Office of Pesticide and Toxic Substances, U.S. EPA, Washington, DC. TSCA Sec 8(d) submission 8DHQ-1078-0302. Monsanto Company. 1976a. Mutagenicity evaluation of B10-76-86-CP-5535 (WGK). Final report. LBI Project No. 2457. Litton Bionetics, Kensington, MD. Unpublished. Monsanto Company. 1976b. Mutagenicity evaluation of B10-76-86-CP-5535 (LOX). Final report. LBI Project No. 2547. Litton Bionetics, Kensington, MD. Unpublished. NTP (National Toxicology Program). 1982. Environmental Mutagen Test Development Program, Research Triangle Park, NC. (Cited in NTP, 1985a) NTP (National Toxicology Program). 1985a. Toxicology and carcinogenesis studies of chlorobenzene (CAS No. 108-90-7) in F344/N rats and B6C3F1 mice (gavage studies). U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. NTP No. 261. NIH Publ. No. 83-2517. NTP (National Toxicology Program). 1985b. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 235. NIH Publ. No. 86-2511. NTP (National Toxicology Program). 1987. Toxicology and carcinogenesis studies of 1,4-dichlorobenzene (CAS No. 106-46-7) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 319. NIH Publ. No. 86-2575. Ostergren, G. and A. Levin. 1943. The connection between c-mitotic activity and water solubility in some monocyclic compounds. Hereditas. 29: 496-498. Prasad, I. 1970. Mutagenic effects of the herbicide 3,4-dichlororopionanilide and its degradation products. Can. J. Biochem. 16: 369-372. Prasad, I. and D. Pramer. 1968. Mutagenic activity of some chloroanilines and chlorobenzenes. Genetics. 60: 212-213. Simmon, V.F., E.C. Ricco and M.V. Pierce. 1979. In vitro microbiological genotoxicity tests of chlorobenzene, m-dichlorobenzene, o-dichlorobenzene and p-dichlorobenzene. Final report. SRI International, Menlo Park, CA. Unpublished. U.S. EPA. 1986. Draft Health Effects Criteria Document for Chlorobenzene. Criteria and Standards Division, Office of Drinking Water, Washington, DC. U.S. EPA. 1989. National Primary and Secondary Drinking Water Regulations; Proposed Rule. Monochlorobenzene. Federal Register. 54(97): 22087-22088. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Chlorobenzene CASRN -- 108-90-7 Primary Synonym -- Monochlorobenzene ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1989 I.A. Oral RfD summary on-line 08/01/1989 VI. Bibliography on-line 06/01/1990 I.B. Inhalation RfD now under review 11/01/1990 I.A. Text edited 11/01/1990 II. Carcinogen assessment on-line 11/01/1990 VI.C. Carcinogen references added 03/01/1991 I.A.7. EPA contacts changed 03/01/1991 II.D.3. EPA contacts changed 01/01/1992 IV. Regulatory actions on-line 07/01/1993 I.A.6. Source document review statement clarified 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 418 of 1119 in IRIS (through 2003/06) AN: 403 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199404 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Propylene-oxide- SY: 75-56-9; AD-6- (SUSPENDING AGENT); CASWELL NO. 713A; EPA-PESTICIDE-CHEMICAL-CODE-042501-; EPOXYPROPANE-; 1,2-EPOXYPROPANE-; ETHYLENE-OXIDE,-METHYL-; HSDB-173-; METHYL-ETHYLENE-OXIDE-; METHYL-OXIRANE-; METHYLOXIRANE-; NCI-C50099-; OXIDO DE PROPILENO [SPANISH]; OXIRANE,-METHYL-; OXYDE DE PROPYLENE [FRENCH]; PROPANE,-EPOXY-; PROPANE,-1,2-EPOXY-; PROPENE-OXIDE-; PROPYLENE-EPOXIDE-; 1,2-PROPYLENE-OXIDE-; UN-1280- RN: 75-56-9 HSN: 173 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Propylene oxide CASRN -- 75-56-9 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199011 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Propylene oxide CASRN -- 75-56-9 Last Revised -- 11/01/1990 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Nest-like infolds of NOAEL: None 100 1 3E-2 the nasal respiratory mg/cu.m epithelium LOAEL: 71 mg/cu.m (30 ppm) LOAEL(ADJ): 13 mg/cu.m 2-Year Rat Chronic LOAEL(HEC): 2.9 mg/cu.m Inhalation Study Kuper et al., 1988 ---------------------------------------------------------------------------- *Conversion Factors: MW = 58.08. Assuming 25C and 760 mmHg, LOAEL (mg/cu.m) = 30 ppm x 58.08/24.45 = 71. LOAEL(ADJ) = 71 mg/cu.m x 6 hours/day, 5 days/week = 13. The LOAEL(HEC) was calculated for a gas:respiratory effect in the ExtraThoracic region. MVa = 0.30 cu.m/day, MVh = 20 cu.m/day, Sa(ET) = 11.6 sq. cm, Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa) / (MVh/Sh) = 0.23. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 2.9 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Kuper, C.F., P.G.J. Reuzel, V.J. Feron and H. Verschuuren. 1988. Chronic inhalation toxicity and carcinogenicity study of propylene oxide in Wistar rats. Food Chem. Toxicol. 26(2): 159-167. The nasal mucosa was the primary tissue affected by exposure to propylene oxide in a chronic inhalation toxicity study conducted by Kuper et al. (1988). One-hundred Wistar rats/sex/group were exposed to 0, 30, 100, or 300 ppm propylene oxide (0, 71, 238, and 713 mg/cu.m) 6 hours/day, 5 days/week for 123 weeks (females) and for 124 weeks (males, duration adjusted concentrations: 0, 13, 43, and 127 mg/cu.m). Interim sacrifices were performed on 10 rats/sex/group after 12, 18, and 24 months of exposure with remaining animals sacrificed at 28 months. Hematology, urinalysis, serum chemistry, and histopathology, including lung, trachea, bronchial lymph nodes, spinal cord, and skeletal muscle, were performed. Survival was adversely affected by exposure to propylene oxide; by week 115, there was a statistically significant increase in mortality in rats of both sexes exposed to 300 ppm propylene oxide (HEC = 127 mg/cu.m, based on an extrarespiratory effect assuming periodicity). By week 119, mortality was significantly increased (43% compared with 30% in controls) in the female rats exposed to 100 ppm (43 mg/cu.m), but not at other times during the study. A FEL is identified at 300 ppm (FEL[HEC] = 127 mg/cu.m). Body weights were statistically significantly reduced in the high-dose males throughout the study, but in females the weight reduction was only significant in the high-dose group for the first year of the study. Body weight data were not included in the report. The NOAEL for body weight changes is 100 ppm [NOAEL(HEC) = 43 mg/cu.m]. The authors state that no treatment-related changes were observed in any of the biochemical, urinalysis, or organ weight endpoints but detailed data were not presented. Statistically significantly increased incidences of several non-neoplastic degenerative and hyperplastic nasal lesions were observed in all exposure groups. These changes occurred in the respiratory and olfactory epithelium of the dorso-medial region, and on the septum and the nasomaxillary turbinates. The lesions in the group exposed to 300 ppm (127 mg/cu.m) were characterized by moderate atrophy of the olfactory epithelium accompanied by a thickened submucosa and moderate to marked basal-cell hyperplasia of the olfactory epithelium at 28 months only. Moderate to marked nest-like infolds of the respiratory epithelium was observed at 18, 24, and 28 months. At 100 ppm (43 mg/cu.m) slight basal cell hyperplasia of the olfactory epithelium was observed in female rats at 28 months and slight nest-like infolds of the respiratory epithelium in both males (18, 24, and 28 months) and females (24 and 28 months). This latter effect was the only respiratory change that was statistically significant in the animals exposed to 30 ppm (13 mg/cu.m) and was seen only in rats exposed for 28 months. No other non-neoplastic treatment-related effects were observed. This study identifies the LOAEL for extrathoracic respiratory tract effects at a concentration of 30 ppm [LOAEL(HEC) = 2.9 mg/cu.m]. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- An uncertainty factor of 10 is used for protection of sensitive human subpopulations. A factor of 10 is used for interspecies extrapolation and to account for the use of a LOAEL because the effect is mild and occurs only at the 28-month exposure and not at the 24-month exposure. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) NTP (1985) conducted a 2-year bioassay in F344 rats and B6C3F1 mice to determine the chronic toxic and carcinogenic effects of inhaled propylene oxide. Fifty animals/species/sex were exposed to 99.9% pure propylene oxide at concentrations of 0, 200, and 400 ppm (0, 475, and 950 mg/cu.m) for 6 hours/day, 5 days/week for 103 weeks (duration adjusted concentrations: 0, 85, and 170 mg/cu.m). Hematology, serum chemistry, urinalysis, and histopathology were performed. Survival in the rats was unaffected by exposure to propylene oxide, and terminal body weights were slightly depressed in the high-dose male (8%) and female (9%) rats. In mice, survival tended to be adversely affected in all treated groups, but the decrease was statistically significant only for male and female mice in the 400 ppm group. Terminal body weights were 10% below control values for the high-dose female mice and 22% below control values for the high-dose male mice. The FEL for body weight changes is 400 ppm (FEL[HEC] = 170 mg/cu.m). The respiratory epithelium of the nasal turbinates was the primary tissue affected by propylene oxide exposure in both rats and mice. Rats exhibited exposure-related increases in suppurative inflammation of the nasal cavity (7/50, 19/50, and 33/50 in the control, 200, and 400 ppm males, respectively, and 3/50, 5/50, and 20/50 in the control, 200, and 400 ppm females, respectively) in addition to exposure-related increases in epithelial hyperplasia (0/50, 1/50, and 11/50 in males; 0/50, 0/48, and 5/48 in females in respective dose groups) and squamous metaplasia (1/50, 3/50, and 21/50 in males; 1/50, 2/48, and 11/48 in females in respective dose groups). Chronic inflammation of the nasal cavity was observed in 1/50, 13/50, and 38/50 of the male mice and in 0/50, 13/50, and 17/50 of the female mice exposed to 0, 200 ppm, and 400 ppm, respectively. Hyperplasia and metaplasia were also observed sporadically in mice exposed to 400 ppm propylene oxide. These lesions were most pronounced in the anterior portion of the nasal cavity and on the greater curvatures of the nasal maxillary turbinates. No consistent effect was observed in the tracheobronchiolar or pulmonary region of the respiratory tract, or in skeletal muscle, bronchial lymph nodes, or central nervous system. The LOAEL(ADJ) for extrathoracic respiratory effects for rats and mice was identified in this study as 200 ppm [LOAEL(HEC) = 16 mg/cu.m for rats (RGDR = 0.183 for female F-344 rat) and 16 mg/cu.m for mice (RGDR = 0.183 for female B6C3F1 mice)]. The chronic toxicity of inhaled propylene oxide was studied in male F344 rats by Lynch et al. (1984). Eighty rats/group were exposed to 0, 100, or 300 ppm propylene oxide (0, 238, and 713 mg/cu.m) for an average of 6.9 hours/day, 5 days/week for 104 weeks (duration adjusted concentrations, 0, 49, and 150 mg/cu.m). Body weight and survival were significantly reduced in the 300 ppm treatment group. Hemoglobin concentrations were significantly elevated above control values in both groups of propylene oxide-treated rats. Differential leukocyte counts were also elevated in the rats exposed to propylene oxide, but this effect is probably a result of the outbreaks of Mycoplasma pneumonia infection which occurred at 8, 16, and 20 months of the study. The authors state that the presence of Mycoplasma was confirmed by serology but do not indicate that the infection was confined to the exposed groups. None of the observed changes in absolute and relative organ weights were consistently associated with histopathological changes and were not considered to be treatment-related. Effects observed in exposed groups in this study included suppurative rhinitis and complex epithelial hyperplasia in the nasal cavity; pulmonary pneumonia and edema; tracheitis; bronchial lymph node hyperplasia; and multifocal myopathy of the skeletal muscle. Nasal suppurative rhinitis was increased significantly in both exposed groups. The nasal epithelial hyperplasia was statistically significant only in the 713 mg/cu.m group and was also observed in 2 animals in the 240 mg/cu.m group; it appears to be exposure related, although the effect of the mycoplasmosis is unknown. The respiratory effects cited above occurred with significantly greater frequency in both exposed groups. This study suggests a LOAEL of 100 ppm [LOAEL(HEC) = 13 mg/cu.m] for the extrathoracic respiratory effect and for the thoracic effect [LOAEL(HEC) = 163 mg/cu.m, RGDR = 3.33]. Skeletal muscle myopathy was increased in 25/78 rats exposed to 300 ppm compared with 7/77 controls, but was not indicated as statistically significant. This study indicates a LOAEL of 300 ppm [LOAEL(HEC) = 710 mg/cu.m] for skeletal myopathy and effects on body weight based on a systemic effect of a soluble gas. NIOSH sponsored an investigation of the developmental toxicity of inhaled propylene oxide in Sprague-Dawley rats and rabbits (Hackett et al., 1982; Hardin et al., 1983). The study population consisted of 23-30 artificially inseminated rabbits per group and 32 to 45 sperm-positive rats per group. The number of litters examined ranged from 9 to 19 per group for the rabbits and 41 to 46 per group for the rats. All animals were exposed to 500 ppm propylene oxide (1188 mg/cu.m) for 7 hours/day. The protocol for the rats was: Group 1, control (filtered air); Group 2, propylene oxide on gestation days 7-16; Group 3, propylene oxide on gestation days 1-16; Group 4, propylene oxide for 3 weeks (5 days/week) prior to mating and daily on gestation days 1-16. The protocol for the rabbits was: Group 1, control (filtered air); Group 2, propylene oxide on gestation days 7-19; Group 3, propylene oxide on gestation days 1-19. The animals were necropsied and uterine contents were examined on gestation day 21 (rats) or 30 (rabbits). Maternal body weight gain and food consumption were decreased in all exposed rats. Reproductive capacity was impaired in rats exposed prior to breeding (Group 4). The number of corpora lutea, implantation sites, and live fetuses was reduced in rats exposed pregestationally to propylene oxide. Dams exposed during gestation (especially those exposed on gestation days 7-16) had more resorptions. Some degree of fetotoxicity was observed in all exposed groups of rats and included a significant reduction in fetal body weight and crown-rump length. The only evidence of fetal malformations seen in rats was an increase in wavy ribs and reduced ossification in rats exposed from gestation days 1-16. The incidence of rib dysmorphology and reduced ossification of fetal ribs and vertebrae were more frequent in exposed animals. The only signs of maternal toxicity reported in the rabbits was a significant reduction in food consumption and a slight but significant decrease in maternal body weight gain in both groups exposed at some times during gestation (Hackett et al., 1982; Hardin et al., 1983). The only evidence of fetal toxicity observed in the rabbits was an increase in resorptions per litter, comparing only litters with resorptions from does exposed during gestation days 1-19 (Group 3), with no change in total resorptions. Reproductive measures, including number of corpora lutea, implantations, and live fetuses, were similar for all groups. Fetal size, sex ratio, and placental weights were unaffected by exposure in any group. Minor musculoskeletal anomalies (sternebral and limb anomalies) were significantly increased in fetal rabbits from Group 3. These studies suggest a LOAEL of 1188 mg/cu.m [LOAEL(HEC) = 1188 mg/cu.m] for reproductive and minor developmental effects, but it is not known whether these effects occurred as a result of maternal toxicity. Harris et al. (1989) exposed groups of 25 mated female Fischer 344 rats to 0, 100, 300, or 500 ppm propylene oxide for (0, 238, 713, and 1188 mg/cu.m) 6 hours/day on gestation days 6-15. Reduced maternal body weight gain and food consumption was observed in the dams exposed to 500 ppm propylene oxide, similar to the NIOSH study findings. However, there was no exposure-related fetotoxicity (e.g., the number of viable fetuses or fetal body weight, postimplantation losses, total implantations, and corpora lutea) observed in this study, in contrast to the NIOSH study findings. The only fetal malformation observed was an increased frequency of seventh cervical rib in the 500 ppm group. The authors attribute the difference in results obtained between the two studies to a difference in strain susceptibility to the toxic effects of propylene oxide. This study identifies a NOAEL of 300 ppm [NOAEL(HEC) = 713 mg/cu.m] for minor developmental variations and maternal toxicity as measured by decreased weight gain. Hayes et al. (1988) conducted a 2-generation reproductive toxicity study in F344 rats exposed to propylene oxide by inhalation. Thirty rats of each sex (F0) were exposed to 0, 30, 100, or 300 ppm (0, 71, 238 , and 713 mg/cu.m) propylene oxide 6 hours/day, 5 days/week for 14 weeks prior to mating to produce the F1 litters. Thirty randomly selected F1 pups/sex/group were then exposed to the same concentrations of propylene oxide for 17 weeks after weaning and subsequently mated to produce the F2 generation. Data on body weight, litter size, live pups, litter weight was collected, and complete histopathology on F1 and F2 pups (10 pups/sex/exposure) in the control and 300 ppm groups. Body weight was significantly decreased in F0 (94% and 92% of control in females and males respectively) and F1 (89% of control in males and females) rats exposed to 713 mg/cu.m propylene oxide. No treatment-related effect was observed in any of the following reproductive parameters: fertility, litter size and neonatal growth, and survival. Furthermore, no effects attributable to propylene oxide exposure were observed at gross pathological examination in either the adults or weanlings or histopathological examination of the pups. This study identifies a NOAEL for reproductive effects of 300 ppm [NOAEL(HEC) = 713 mg/cu.m] and a NOAEL for changes in body weight of 100 ppm [NOAEL(HEC) = 238 mg/cu.m]. Functional and histopathological evidence of neurotoxicity in Wistar rats exposed to 1500 ppm propylene oxide (3563 mg/cu.m) for 6 hours/day, 5 days/week for 7 weeks (Ohnishi et al., 1988) (duration-adjusted concentration = 636 mg/cu.m). Awkward gait was apparent in exposed rats by the third to fourth week of exposure and all rats exhibited obvious ataxia by the seventh week. Histopathological examination revealed axonal degeneration of the hindleg nerve and fasciculus gracilis myelinated fibers, and myelinated fibers in the sacral spinal root. The LOAEL(HEC) for this study is 636 mg/cu.m. Sprinz et al. (1982) exposed male cynomolgus monkeys for 2 years (2/group) to 0, 100, or 300 ppm propylene oxide (0, 237, and 712 mg/cu.m). Nerve conduction velocity was measured throughout the exposure and at the termination of exposure, sections of peripheral nerves, spinal cord, and brain (19 regions) were examined. No exposure-related changes were observed in the peripheral nerves or the spinal cord. Axonal dystrophy was observed in the medulla oblongata and in the most distal portions of the fasciculus gracilus in one control monkey and in all four exposed monkeys. The extent of the lesion was similar in all affected monkeys and was not dose-related. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium The study by Kuper et al. (1988) used a large number of animals, examined the critical effect with sensitive techniques and at multiple durations and exposure levels, and was of chronic duration, but did not identify a NOAEL, resulting in medium confidence. There are several corroborative chronic inhalation studies and inhalation developmental studies, but the inhalation 2-generation reproductive study is inadequate, resulting in medium confidence in the data base. Medium confidence in the RfC results. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1985, 1987 Agency Work Group Review -- 06/21/1990, 09/20/1990 Verification Date -- 09/20/1990 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199404 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Propylene oxide CASRN -- 75-56-9 Last Revised -- 04/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification-- B2; probable human carcinogen Basis-- Based on inadequate human data and an increased incidence of benign and malignant tumors at the site of exposure in two species of animals, when exposed by subcutaneous injection, by inhalation, and by gavage. There was also evidence of mutagenicity in a variety of test systems. Propylene oxide is structurally similar to other chemicals that demonstrate carcinogenic activity in animals. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Theiss et al. (1982) conducted a retrospective cohort study of 602 employees in eight German production plants, where there was exposure to alkylene oxides (propylene oxide and ethylene oxide) and other chemicals, including dichloropropane and epichlorohydrin. The mortality in each cancer category was not significantly higher than expected. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. The animal data consist of oral, inhalation and subcutaneous studies in three strains of rats and two strains of mice. Propylene oxide caused tumors at or near the site of administration in rodents, causing forestomach tumors following ingestion (Dunkelberg, 1982) and nasal tumors after inhalation exposure (NTP, 1985). Dunkelberg (1982) treated groups of 50 female Sprague-Dawley rats by gavage with 0, 15 or 60 mg/kg of 1,2-propylene oxide in salad oil twice weekly for 150 weeks (a total of 219 treatments) for total average doses of 0, 2714, or 10,798 mg/kg, as reported by the author. (Treatments were temporarily suspended due to a pneumonia outbreak.) All animals were treated with antibiotics when pneumonia interrupted treatment for 3 weeks. Controls consisted of both vehicle-treated and untreated groups. Survival of treated animals was comparable to controls with approximately 30% mortality at 104 weeks. Forestomach tumors, primarily squamous cell carcinomas, first developed in treated animals during week 79 in the high-dose group. The incidence of squamous cell carcinomas of the forestomach was 0/100 (combined untreated and vehicle controls), 2/50 (low-dose) and 19/50 (high-dose). No statistical analyses were conducted. The incidence of tumors at sites distant from the site of administration appeared to be similar in treated and untreated groups. F344/N rats and B6C3F1 mice (50/sex/dose) were exposed by inhalation to 0, 200, or 400 ppm (0, 475, or 950 mg/cu.m) of propylene oxide for 6 hours/day, 5 days/week for 103 weeks (NTP, 1985; Renne et al., 1986). Survival of treated rats was comparable to that of controls. Dose-related increases in inflammation and metaplasia of the nasal cavities in both sexes of rats and a positive trend in papillary adenomas of the nasal turbinate epithelium (0/50, 0/50, 3/50) in female rats were reported. Incidence of thyroid gland C-cell adenoma or carcinomas (2/45, 2/35, 7/37) in female rats showed a positive trend that was statistically significantly elevated in the high-dose group relative to controls, when the incidences of benign and malignant tumors were combined (there were equal proportions of both tumor types). The incidence of endometrial stromal polyps and sarcomas combined (3/49, 12/50, 10/47) (the majority was polyps) was statistically significantly greater in rats at all doses compared to controls inhaling propylene oxide than in controls. In male rats, a significant positive trend for keratoacanthomas occurred (1/50, 1/50, 5/50). The NTP, however, considered only the nasal cavity tumors as being treatment-related because the other tumors were either a relatively common type (thyroid) or were of low incidence relative to that in historical controls. Nineteen weeks after the initial start date, a technical error caused excessive chamber concentration, killing all low-dose mice. New groups of low-dose mice of each sex were started, but additional control groups were not included. Survival in mice showed dose-related decreases in both sexes with a statistically significant decrease in high-dose animals relative to controls. At termination, 58% of males and 20% of females in the high-dose group survived as compared with 84 and 76% of the respective controls. Terminal body weights of high-dose animals were decreased by 10-21%, indicating a MTD had been achieved. One squamous cell carcinoma and one papilloma in the nasal cavity of two high-dose males, and nasal cavity adenocarcinomas of two high-dose females were reported. The incidences of these lesions (combined) were 0/50 and 0/1615 in males, and 0/50 and 0/1668 in females for concurrent and historical control mice of this strain in the NTP program, respectively. Hemangiomas (0/50, 0/50, 5/50) and hemangiosarcomas (0/50, 0/50, 5/50) of the nasal cavity were statistically significantly increased both individually and when combined in male mice receiving 400 ppm propylene oxide when compared with concurrent controls. In females, the incidence of combined hemangiomas or hemangiosarcomas of the nasal cavity (0/50, 0/50, 5/50) was also statistically significantly elevated at the high dose. Statistical analysis of these tumors included adjustment for intercurrent mortality. When compared by life table tests, mammary gland adenocarcinomas (all types) showed a significant dose-related trend and significant elevation in high-dose females relative to controls (0/50, 3/50, 3/50). One hundred Cpb:WU Wistar rats/sex/group were exposed by inhalation to 0, 30, 100, or 300 ppm (0, 71, 238, or 713 mg/cu.m) propylene oxide for 6 hours/day, 5 days/week for 123 to 124 weeks (Reuzel and Kuper, 1983; Kuper et al., 1988). Interim sacrifices of 10 rats/sex/group were conducted at 12, 18, and 24 months. Survival was significantly decreased in high-dose animals relative to controls with only 21 to 47% of treated males and females surviving after week 115, as compared with 54 to 71% of controls. By week 119, survival in females at the mid-dose level, 100 ppm, was also significantly decreased (survival was 39%). While there were no tumors in the nasal cavity, a statistically significant increase in nonneoplastic alterations (degenerative changes and hyperplasia) of the olfactory and respiratory epithelium was observed in each sex in each exposure group. A statistically significant increase in mammary gland fibroadenomas (32/69, 30/71, 39/69, 47/70) and adenocarcinomas (3/69, 6/71, 5/69, 8/70), which appeared earlier in life, were found in the high-dose females when compared with controls. The authors suggested malignant mammary tumor development in the high-dose females may not be related to propylene oxide exposure, since the historical control incidence of malignant mammary tumors in this laboratory is in the range of 0 to 15% (0/30 to 15/99). Although not statistically significantly elevated, squamous-cell carcinomas of the nose, larynx/pharynx and trachea, and adenocarcinomas of the larynx/pharynx and lungs were reported in five high-dose males; none of these tumor types were reported in control males. Lynch et al. (1984a) exposed male F344 rats (80/group) to 0, 100, or 300 ppm propylene oxide 7 hours/day, 5 days/week for 104 weeks. A statistically significant increase in mortality was observed in each treated group relative to controls. At 104 weeks, survival was approximately 50, 45, and 35% for the control, low-dose and high-dose groups, respectively. An outbreak of mycoplasmosis at approximately 68 weeks contributed to the decreased survival of all animals. A statistically significant increase in hyperplasia of the nasal epithelium was reported in high-dose rats. The incidence of adrenal pheochromocytomas (8/78, 25/78, 22/80), although without increasing trend, was statistically significantly elevated in each group of the propylene oxide-exposed rats (not explicit when a trend test was conducted). Dunkelberg (1981) treated groups of 100 female NMRI mice weekly by subcutaneous injection with 0.1, 0.3, 1.0, or 2.5 mg propylene oxide in tricaprylin once a week for 95 weeks for average total doses of 6.8, 21.7, 72.8, 165.4 mg/mouse. Controls consisted of groups of 100 untreated or vehicle-treated mice. A dose-related increase (approximately 2 to 16%) in injection site tumors (mostly fibrosarcomas) was reported with the first tumor appearing in the high-dose group at 39 weeks, while no tumors were noted among vehicle or untreated controls. Tumor incidence at other sites was similar in control and treated groups. Propylene oxide in either arachis oil or water was injected subcutaneously in groups of 12 rats (sex and strain not specified) over 325 days for a total dose of 1500 mg/kg (Walpole, 1958). Injection site sarcomas developed in 8/12 and 3/12 rats receiving propylene oxide in the oil and water vehicles, respectively. No controls appear to have been run and no other experimental details were available. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Like other epoxides, propylene oxide is DNA-reactive. Propylene oxide has been found to be mutagenic in a variety of test systems. Reverse mutations were produced in Salmonella typhimurium both with and without mammalian hepatic homogenates as a metabolic activating system (Wade et al., 1978; Bootman et al., 1979; McMahon et al., 1979; Hemminki and Falck, 1979; Pfeiffer and Dunkelberg, 1980; Yamaguchi, 1982; Yamaguchi and Nakagawa, 1983; Djuric et al. 1986) and Escherichia coli (Bootman et al., 1979; McMahon et al., 1979; Hemminki et al., 1980), and without mammalian hepatic homogenates as a metabolic activating system in Klebsiella pneumoniae (Voogd et al., 1981). Forward mutations were produced in Schizosaccharomyces pombe (Migliore et al., 1982) and chinese hamster ovary cells (Zamora et al., 1983). Propylene oxide induced sex-linked recessive lethal mutations in Drosophila melanogaster (Hardin et al., 1983). Chromosome aberrations (Dean and Hodson-Walker, 1979) and DNA strand breaks (Sina et al., 1983) have been reported in rat hepatocytes, but no significant increases in sister-chromatid exchange (SCE) or chromosomal aberrations in lymphocytes from Cynomolgus monkeys were reported by Lynch et al. (1984b). Bootman et al. (1979) reported increased chromosomal aberrations and Tucker et al. (1986) found increased SCE frequency in human lymphocytes. DNA synthesis and repair was reduced in lymphocytes of workers occupationally exposed to less than 12 ppm propylene oxide for 2 to 20 years (Pero et al., 1982) and lymphocyte chromosome aberrations were increased in workers exposed to alkylene oxides (ethylene oxide and propylene oxide) for >20 years compared with a presumably unexposed group of workers. No baseline values were available for the exposed workers (Theiss et al., 1981). Propylene oxide is structurally-related to epichlorohydrin and ethylene oxide, which have induced carcinogenic responses in animals. Limited human evidence for cancer risk also exists for ethylene oxide. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 2.4E-1 per (mg/kg)/day Drinking Water Unit Risk -- 6.8E-6 per (ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 1E+1 ug/L E-5 (1 in 100,000) 1E+0 ug/L E-6 (1 in 1,000,000) 1E-1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- forestomach, squamous cell carcinoma Test Animals -- rat/Sprague-Dawley, female Route -- gavage, salad oil Reference -- Dunkelberg, 1982 -------------- Dose ---------------- Admin- Transformed Human istered Animal Dose Equivalent Tumor (mg/kg) (mg/kg)/day (mg/kg)/day Incidence -------- ----------- ----------- --------- 0 0 0 0/100 15 2.58 0.44 2/50 60 10.28 1.76 19/50 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Human equivalent doses were determined using a rat body weight of 0.35 kg, a human body weight of 70 kg, 1029 days as the length of the exposure, and 1050 days as the length of the experiment and lifespan of the animal. The unit risk should not be used if the water concentration exceeds 1E+3 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) The study was conducted for a long period of time (150 weeks) with a sufficient number of animals surviving for analysis of late-developing tumors. Survival of treated animals was comparable with that of controls at 104 weeks; both had approximately 30% mortality. Exposure was by a relevant route and a comprehensive necropsy was performed. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES Inhalation Unit Risk-- 3.7E-6 per (ug/cu.m.) Extrapolation Method-- Linearized multistage procedure, extra risk Air Concentrations at Specified Risk Levels Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 3E+1 ug/cu.m E-5 (1 in 100,000) 3E+0 ug/cu.m E-6 (1 in 1,000,000) 3E-1 ug/cu.m DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE Tumor Type -- nasal cavity hemangioma or hemangiosarcoma Test Animals -- mouse/B6C3F1, male Route -- Inhalation Reference -- NTP, 1985; Renne et al., 1986 ---- Dose ----- Tumor Admin- Transformed Human Incidence istered Animal Dose Equivalent (ppm) (mg/kg)/day (mg/kg)/day -------- ----------- ----------- --------- 0 0 0 0/50 200 55 4.15 0/50 400 110 8.29 10/50 ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) Transformed animal doses were calculated assuming 50% pulmonary absorption, and an exposure duration and length of experiment of 103 weeks. The 50% absorption assumption is consistent with the absorption efficiency observed for epichlorohydrin in the respiratory tract of rats (Stott and Mckenna, 1984). The transformed animal dose level was used in the calculation of an animal slope factor of 9.8E-4 per (mg/kg)/day. The human slope factor, 1.3E-2 per (mg/kg)/day was determined using an animal body weight of 0.03 kg, a human body weight of 70 kg and animal lifespan of 103 weeks. The above unit risk should not be used if the air concentration exceeds 3E+3 ug/cu.m., as above this concentration the unit risk may not be appropriate. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Adequate numbers of animals of both sexes of mice were treated for a lifetime. Propylene oxide exposure was by a relevant route and a complete histopathological examination was performed. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985, 1987 The 1985 Health and Environmental Effects Profile and 1987 Health Issue Assessment for Propylene Oxide have received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 05/30/1989, 04/05/1990 Verification Date -- 04/05/1990 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199108 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Propylene oxide CASRN -- 75-56-9 Last Revised -- 08/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Hackett, P.L., M.G. Brown, R.L. Buschbom, M.L. Clark and R.A. Miller. 1982. Teratogenic study of ethylene and propylene oxide and n-butyl acetate. National Institute for Occupational Safety and Health, Cincinnati, OH, NTIS PB 83-258-38. Hardin, B., R. Niemeier, M. Sikov and P. Hackett. 1983. Reproductive-toxicologic assessment of the epoxides ethylene oxide, propylene oxide, butylene oxide, and styrene oxide. Scand. J. Work. Environ. Health. 9: 94-102. Harris, S.B., J.L. Schardein, C.E. Ulrich and S.A. Ridlon. 1989. Inhalation developmental toxicity study of propylene oxide in Fischer 344 rats. Fund. Appl. Toxicol. 13(2): 232-331. Hayes, W.C., H.D. Kirk, T.S. Gushow and J.T. Young. 1988. Effect of inhaled propylene oxide on reproductive parameters in Fischer 344 rats. Fund. Appl. Toxicol. 10(1): 82-88. Kuper, C.F., P.G.J. Reuzel, V.J. Feron and H. Verschuuren. 1988. Chronic inhalation toxicity and carcinogenicity study of propylene oxide in Wistar rats. Food Chem. Toxicol. 26(2): 159-167. Lynch, D.W., T.R. Lewis, W.J. Moorman et al. 1984. Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats. Toxicol. Appl. Pharmacol. 76(1): 69-84. NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of propylene oxide (CAS No. 75-56-9) in F344/N rats and B6C3F1 mice (Inhalation studies). NTP-TR-267. Ohnishi, A., T. Yamamato, Y. Murai, Y. Hayashida, H. Hori and I. Tanaka. 1988. Propylene oxide causes central-peripheral distal axonopathy in rats. Arch. Environ. Health. 43(5): 353-356. Sprinz, H., H. Matzke and J. Carter. 1982. Neuropathological evaluation of monkeys exposed to ethylene and propylene oxide. National Institute for Occupational Safety and Health, Cincinnati, OH. NTIS PB 83-134817. U.S. EPA. 1985. Health and Environmental Effects Profile for Propylene Oxide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/X-85/401. U.S. EPA. 1987. Summary Review of the Health Effects Associated with Propylene Oxide. Health Issue Assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-86/007F. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bootman, J., D.C. Lodge and H.E. Whalley. 1979. Mutagenic activity of propylene oxide in bacterial and mammalian systems. Mutat. Res. 67: 101-112. Dean, B.J. and G. Hodson-Walker. 1979. An in vitro chromosome assay using cultured rat-liver cells. Mutat. Res. 64: 329-337. Djuric, Z., B.H. Hooberman, L. Rosman and J.E. Sinsheimer. 1986. Reactivity of mutagenic propylene oxides with deoxynucleosides and DNA. Environ. Mutagen. 8: 369-383. Dunkelberg, H. 1981. Carcinogenic activity of ethylene oxide and its reaction products 2-chloroethanol, 2-bromoethanol, ethylene glycol and diethylene glycol: 1. Carcinogenicity of ethylene oxide in comparison with 1,2-propylene oxide after subcutaneous administration in mice. Zentralbl. Bakteriol., Mikrobiol. Hyg., Abt. 1 Orig. B Hyg Umwelthyg Krankenhaushyg Arbeitshyg Praev Med. 174(5): 383-404. (CA 96:157113) Dunkelberg, H. 1982. Carcinogenicity of ethylene oxide and 1,2-propylene oxide upon intragastric administration to rats. Br. J. Cancer. 46(6): 924-933. Hardin, B.D., R.L. Schuler, P.M. McGinnis, R.W. Niemeier and R.J. Smith. 1983. Evaluation of propylene oxide for mutagenic activity in 3 in vivo test systems. Mutat. Res. 117: 337-344. Hemminki, K. and K. Falck. 1979. Correlation of mutagenicity and 4-(p-nitrobenzyl)-pyridine alkylation by epoxides. Toxicol. Lett. 4: 103-106. Hemminki, K., J. Paasivirta, T. Kurkirinne and L. Virkki. 1980. Alkylation products of DNA bases by simple epoxides. Chem. Biol. Interact. 30: 259-270. Kuper, C.F., P.G.J. Reuzel and V.J. Fernon. 1988. Chronic inhalation toxicity and carcinogenicity study of propylene oxide in Wistar rats. Food Chem. Toxicol. 26(2): 159-167. Lynch, D.W., T.R. Lewis, W.J. Moorman et al. 1984a. Carcinogenic and toxicologic effects of inhaled ethylene oxide and propylene oxide in F344 rats. Toxicol. Appl. Pharmacol. 76: 69-84. Lynch, D.W., T.R. Lewis, W.J. Moorman et al. 1984b. Sister-chromatid exchanges and chromosome aberrations in lymphocytes from monkeys exposed to ethylene oxide and propylene oxide by inhalation. Toxicol. Appl. Pharmacol. 76: 85-95. McMahon, R.E., J.C. Cline and C.Z. Thompson. 1979. Assay of 855 test chemicals in ten tester strains using a new modification of the Ames test for bacterial mutagens. Cancer Res. 39: 682-693. Migliore, L., A.M. Rossi and N. Loprieno. 1982. Mutagenic action of structurally related alkene oxides on Schizosaccharomyces pombe: The influence, 'in vitro,' of mouse-liver metabolizing system. Mutat. Res. 102: 425-437. NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of propylene oxide (CAS No. 75-56-9) in F344/N rats and B6C3F1 mice (inhalation studies). NTP Tech. Rep. Ser. No. 267. NTP, Research Triangle Park, NC. NIH Publ. No. 85-2527. Pero, R.W., T. Bryngelsson, B. Widegren, B. Hogstedt and H. Welinder. 1982. A reduced capacity for unscheduled DNA synthesis in lymphocytes from individuals exposed to propylene oxide and ethylene oxide. Mutat. Res. 104: 193-200. Pfeiffer, E.H. and H. Dunkelberg. 1980. Mutagenicity of ethylene oxide and propylene oxide and of the glycols and halohydrins formed from them during the fumigation of foodstuffs. Food Cosmet. Toxicol. 18: 115-118. Renne, R.A., W.E. Giddens, G.A. Boorman, R. Kovatch, J.E. Haseman and W.J. Clarke. 1986. Nasal cavity neoplasia in F344/N rats and (C57BL/6xC3H)F1 mice inhaling propylene oxide for up to two years. J. Natl. Cancer Inst. 77(2): 573-582. Reuzel, P.G.J. and C.F. Kuper. 1983. Chronic (28-month) inhalation toxicity/carcinogenicity study of 1,2-propylene oxide in rats. Zeist, The Netherlands: Civo Institutes TNO; Report No. V 82.215/280853. Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 1983. Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutat. Res. 113(5): 357-391. Stott, W.T. and M.J. McKenna. 1984. The comparative absorption and excretion of chemical vapors by the upper, lower and intact respiratory tract of rats. Fund. Appl. Toxicol. 4: 594-602. Thiess, A.M., H. Schwegler, I. Fleig and W.G. Stocker. 1981. Mutagenicity study of workers exposed to alkylene oxides (ethylene oxide/propylene oxide) and derivatives. J. Occup. Med. 23(5): 343-347. Thiess, A.M., R. Frentzel-Beyme, R. Link and W.G. Stocker. 1982. Mortality study on employees exposed to alkylene oxides (ethylene oxide/propylene oxide) and their derivatives. In: Prevention of Occupational Cancer -- International Symposium; April 1981; Helinski, Finland. International Labour Office, Geneva, Switzerland. p. 249-259. (Occupational Safety and Health Series No. 46) Tucker, J.D., J. Xu, J. Stewart, P. Baciu and T. Ong. 1986. Detection of sister chromatid exchanges induced by volatile genotoxicants. Teratog. Carcinog. Mutagen. 6: 15-21. U.S. EPA. 1985. Health and Environmental Effects Profile for Propylene Oxide. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1987. Summary Review of the Health Effects associated with Propylene Oxide. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-86/007F. Voogd, C.E., J.J. van der Stel and J.J.J.A.A. Jacobs. 1981. The mutagenic action of aliphatic epoxides. Mutat. Res. 89: 269-282. Wade, D.R., S.C. Airy and J.E. Sinsheimer. 1978. Mutagenicity of aliphatic epoxides. Mutat. Res. 58: 217-223. Walpole, A.L. 1958. Carcinogenic action of alkylating agents. Ann. NY Acad. Sci. 68: 750-761. Yamaguchi, T. 1982. Mutagenicity of trioses and methyl glyoxal on Salmonella typhimurium. Agric. Biol. Chem. 46(3): 849-851. Yamaguchi, T. and K. Nakagawa. 1983. Mutagenicity of and formation of oxygen radicals by trioses and glyoxal derivatives. Agric. Biol. Chem. 47(11): 2461-2465. Zamora, P.O., J.M. Benson, A.P. Li and A.L. Brooks. 1983. Evaluation of an exposure system using cells grown on collagen gels for detecting highly volatile mutagens in the CHO/HGPRT mutation assay. Environ. Mutagen. 5(6): 795-801. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Propylene oxide CASRN -- 75-56-9 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 10/01/1990 II. Carcinogen assessment on-line 10/01/1990 VI. Bibliography on-line 11/01/1990 I.B. Inhalation RfC summary on-line 11/01/1990 VI.B. Inhalation RfC references added 01/01/1991 II. Text edited 01/01/1991 II.C.1. Inhalation slope factor removed (global change) 02/01/1991 II.C.3. Information on extrapolation process included 08/01/1991 VI.C. References clarified 01/01/1992 IV. Regulatory Action section on-line 03/01/1994 II.D.3. Contact's phone number changed 04/01/1994 II.D.3. Contact changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 419 of 1119 in IRIS (through 2003/06) AN: 405 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199406 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Chlorine- SY: 7782-50-5; 7681-52-9; 7790-92-3; BERTHOLITE-; CASWELL NO. 179; CHLOOR [DUTCH]; CHLORE [FRENCH]; CHLOR [GERMAN]; CLORO [ITALIAN]; CLORO [SPANISH]; EPA-PESTICIDE-CHEMICAL-CODE-020501-; HSDB-206-; HYPOCHLORITE- (SODIUM); HYPOCHLOROUS-ACID-; MOLECULAR-CHLORINE-; UN-1017- RN: 7782-50-5 HSN: 206 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199406 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Chlorine CASRN -- 7782-50-5 Last Revised -- 06/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- No observed adverse NOAEL: 14.4 mg/kg-day 100 1 1E-1 effects mg/kg-day LOAEL: None Rat Chronic Drinking Water Study NTP, 1992 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions: Doses determined based on body weight and water consumption values from the study. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1992. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Chlorinated and Chloraminated Water in F344/N Rats and B6C3F1 Mice (drinking water studies). U.S. Dept. of Health and Human Services. NTP TR 392. In a 2-year study (NTP, 1992) Fischer 344/N rats and B6C3F1 mice (70/sex/group) were administered chlorinated drinking water containing 0, 70, 140 or 275 ppm of available chlorine (based on IR measurements of available atomic chlorine) for up to 104 weeks. Based on body weights and water consumption values reported in the study, these doses correspond to doses of 4.2, 7.3 and 13.6 mg/kg-day for male rats; 4.2, 7.8 and 14.4 mg/kg-day for female rats; 7.4, 14.0 and 24 mg/kg-day for male mice; and 7.6, 14.2 and 24.2 mg/kg-day for female mice. Interim sacrifices of 10 animals/sex/dose were performed at 15 and 66 weeks. A complete necropsy and hematologic examination was performed on all animals at these times; additionally, a complete histopathologic examination was conducted for all animals in the control and high-dose groups. Results from these evaluations were unremarkable for both rats and mice. All animals were subjected to complete necropsy and a histopathologic examination at completion of the study. Survival among treated rats and mice was similar to controls. A decrease in water consumption noted in both rats and mice apparently was dose-related. Mean body weights of all dosed male rat groups, high-dose female rats, high-dose male mice and all dosed female mice groups appeared decreased compared with controls; these decreases never exceeded 10%. In rats, water consumption was decreased 21% for males and 23% for females at the highest dose from weeks 53-104. No decreases were reported in food consumption and survival rates were similar for all groups of animals (treated and controls). At interim sacrifices (14 and 66 weeks) no significant differences in body weight, organ weights or body-to-organ weight ratios were reported. No differences were reported in blood chemistry or gross or microscopic histologic parameters. In the second year of the study, body weights were slightly reduced; however, the reduction in body weights was <10%. No other nonneoplastic lesions or effects were seen at 104 weeks in any treated animals. In mice, body weights were decreased 5-8% for males and 5-7% for females, and water consumption was reduced 31% for males and 26% for females. Survival rates were similar for all groups. Significant decreases were noted in brain weights at 15 weeks and liver weights at 66 weeks for the high-dose males. These effects were not reported at 104 weeks and may be attributed to lower body weights and reduced water consumption. No alterations were reported in hematologic or histologic parameters. The NOAEL of 275 ppm (13.6 or 14.4 mg/kg-day for male and female rats, respectively) is chosen as the basis for the chronic oral RfD. Mice received a higher dose on a weight basis (24 mg/kg) but effects, although equivocal, were observed. Doses between 14.0 and 24.0 mg/kg were not tested in rats. In addition, this NOAEL is supported by NOAELs from other chronic and subchronic rat studies. Therefore the 14.4 mg chlorine/kg in females is selected as the basis of the RfD. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 100 reflects 10 for interspecies extrapolation and 10 for the protection of sensitive human subpopulations. An additional factor to account for the lack of reproductive and developmental toxicity data is not considered necessary because these data are available from existing studies conducted with the related compounds monochloramine and chlorine. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) NOTE: In pure water, chlorine forms elemental chlorine (Cl2), chloride ion (Cl-) and hypochlorous acid (HOCl). As pH increases, hypochlorous acid dissociates to hypochlorite ion (OCl-). The term "free chlorine" (free available chlorine, free residual chlorine) refers to the concentrations of elemental chlorine, hypochlorous acid and hypochlorite ion that collectively occur in water. Several factors, including chlorine concentration, pH, temperature, exposure to light and the presence of catalysts or organic material, affect the stability of free chlorine in aqueous solution. When free chlorine is added to water containing ammonia, chloramines are formed. For more information about the chemistry of chlorines, see U.S. EPA, 1992. Other chronic oral studies as well as subchronic studies evaluating additional toxicologic parameters (hematology, serum chemistry and histopathology) support the NOAEL selected for deriving the RfD. These studies reported NOAEL values ranging from 10-24 mg/kg-day. Hasegawa et al. (1986) studied the potential adverse effects in rats of long-term exposure to sodium hypochlorite in drinking water. Sodium hypochlorite (14% effective chlorine, purity not specified) was evaluated in F344 rats (50/sex/group) in a 2-year study at levels of 0.05% or 0.1% (approximately 13.5 and 27.7 mg/kg-day) in males and 0.01% or 0.2% (approximately 34.3 and 63.2 mg/kg-day) in females. Doses were estimated based on the authors' data. No difference in water consumption was observed during the experiment (104 weeks), except in the last 20 weeks when intake was higher in treated animals (10-20%). High mortality was reported in all groups; 62 rats died during the experimental period and an additional 49 rats died during the 8-week recovery period. Survival rates were similar in all groups and for both sexes. In treated males, body weights were decreased <10% compared with controls; decreased weights were 96 and 93% of controls for low- and high-dose groups, respectively. For females, body weights were decreased 11% in the low-dose group and 20% in the high-dose group relative to controls. However, weight gains of 1-9% were reported for all treated animals during an 8-week recovery period. In males, absolute liver and brain weights were decreased as well as absolute and relative heart weight at the high dose only. In females, absolute and relative salivary gland weights were decreased at the low dose but not at the high dose. Additionally, in females absolute kidney weights were decreased at the high dose. No dose-related changes in hematologic or histologic parameters were observed. It should be noted that the extremely high water consumption rates reported in this study appear to be inconsistent with those reported by other investigators who have reported marked reductions in water consumption at similar or lower chlorine concentrations. This inconsistency precludes use of this study as the principal study. F344 rats (50/sex) received sodium hypochlorite in drinking water for 104 weeks at doses of 0, 500 or 1000 ppm in males and 0, 1000 or 2000 ppm in females (Kurokawa et al., 1986). These doses correspond to 0, 70 and 140 mg/kg-day for males and 0, 95 and 190 mg/kg-day for females based on reference body weight and water consumption values (U.S. EPA, 1986). Following exposure, survival, clinical signs, water consumption and body weights were monitored. Hematologic parameters and serum biochemical analyses were evaluated, and gross necropsy and histopathologic examinations were performed. In female rats a dose-related decrease in body weight relative to controls, approximately 10% in those exposed to 95 mg/kg-day and approximately 20% in those exposed to 105 mg/kg-day, was observed. No other dose-related effects were noted. A LOAEL of 95 mg/kg-day, based on weight loss, is indicated. Abdel-Rahman et al. (1984) investigated the toxicity of hypochlorous acid in male rats (4/dose) that received dose levels of 0, 1, 10 or 100 mg/L in drinking water for up to 12 months. These doses correspond to approximately 0, 0.14, 1.4 and 14 mg/kg-day (based on assumed daily water consumption of 0.14 L/kg-day [U.S. EPA, 1986]). Although significant increases in blood glutathione levels and decreases in osmotic fragility were reported at various intervals in the study, these changes were inconsistent and did not indicate a dose-response pattern. A NOAEL of 14 mg/kg-day is identified for this study. Groups of B6C3F1 mice (50/sex) received sodium hypochlorite in drinking water for 103 weeks at dose levels of 0, 500 or 1000 ppm (approximately 84 and 140 mg/kg-day, based on data provided in the study) (Kurokawa et al., 1986). No statistically significant effects on survival, clinical signs, water consumption, hematologic parameters or serum chemistry were noted. However, body weight gain was reduced as compared with controls in animals receiving sodium hypochlorite. Male and female Sprague-Dawley rats (10/sex/dose) received chlorine in drinking water at dose levels of 0, 25, 100, 175 and 250 mg/L for 90 days (Daniel et al., 1990). Calculated dose levels were 0, 2, 7.5, 12.8 and 16.7 mg/kg-day for males and 0, 3.5, 12.6, 19.5 and 24.9 mg/kg-day for females (conversion provided by the author). Food and water consumption and body weight gain were monitored and hematologic and serum chemistry examinations were conducted. Organ weights were measured and tissues examined from the high-dose group. No consistent effects were observed on any of the parameters tested up to 250 mg/L of chlorine. Groups of B6C3F1 mice (10/sex) were administered chlorine in drinking water at 0, 12.5, 25, 50, 100 and 200 mg/L for 90 days (Daniel et al., 1991). These doses correspond to 0, 2.7, 5.1, 10.3, 19.8 and 34.4 mg/kg-day for males and 0, 2.8, 5.8, 11.7, 21.2 and 39.2 mg/kg-day for females (conversions provided by authors). Clinical signs, survival, body weight, and food and water consumption were monitored. Hematologic and clinical chemistry parameters were evaluated, and gross and histopathologic examinations were performed. A concentration-related decrease in average water consumption was observed in both males and females with statistically significant decrease in females at the two highest doses. Decreased body weight gain, compared with controls, was observed in males and females with significant reduction (>10%) in males at the two highest doses; however, no other effects were observed in any of the other parameters measured. A NOAEL of 10 mg/kg-day is identified for this study. In general, animal studies have demonstrated no evidence of reproductive or teratogenic effects of chlorine. Druckrey (1986) studied the effects of highly chlorinated drinking water (100 mg/L) given daily to seven consecutive generations of BD II rats. Solutions were prepared weekly by bubbling chlorine gas through tap water. To insure a stable total dietary chlorine concentration, dry rat chow was cooked with chlorinated water prior to distribution to the parental generation. Subsequent generations received chlorine only in the water and ate a standard diet, resulting in an average daily dose of approximately 10 mg/kg-day chlorine. Parental animals began treatment at 100 days of age. Rats were repeatedly mated and remained on treatment during pregnancy and lactation. Selected progeny were separated from their dams at 30-40 days and were designated the subsequent generation. Animals of the F3 and F4 generations consumed chlorinated water only until the birth of progeny. Subsequent generations remained on chlorinated water for their entire life span. Two groups of animals served as controls at the beginning and ending of the experimental period. Weight gain among neonates was somewhat depressed during the first few days of life. By maturity the average body weight for all generations of test animals was about 5-10% greater than that of the untreated rats. Of 236 rats observed, no treatment-related effects were noted on the life span, fertility, growth, hematologic measurements or histology of liver, spleen, kidney and other organs. The incidence of malignant tumors in the treated rats was not found to differ from that of control group rats. A NOAEL of 10 mg chlorine/kg could be identified from this study. In a reproductive study by Carlton et al. (1986), chlorine was administered by gavage in deionized water at doses of 1.0, 2.0 and 5.0 mg chlorine/kg-day to male (12/dose group) and female (24/dose group) Long Evans rats for 66-76 days. Males were treated for 56 days and females for 14 days prior to mating. Dosing continued during the 10-day mating period and afterwards females were dosed with chlorine daily during gestation and lactation. Males were necropsied at the end of the mating period. Dams and some offspring were necropsied at 21 days after birth. Other offspring were dosed with chlorine after weaning until they were 28-40 days old. No statistical differences were observed between the control and dose group in litter survival, litter size and pup weight. Developmental landmarks such as the mean day of eye opening and the average day of observed vaginal patency also were comparable across groups. Adult male rats exposed up to 5.0 mg/kg-day showed no adverse reproductive effects. A NOAEL of 5 mg/kg-day for maternal, fetal and neonatal effects can be defined from this study. C3H/HEJ and C57Bl/6J mice were administered drinking water that had been treated with sodium hypochlorite and hydrochloric acid (10-13 ppm) to maintain the water at pH 2.5 over a 6-month trial period (Les, 1968). Control animals received tap water, which varied in pH from 9.2-9.8, but was usually 9.6. In the treated animals, the number of mice born and the number weaned/dam were greater than in the control (p<0.01). The authors concluded that the treatment of C3H/HEJ and C57Bl/6J mice with chlorine and hydrochloric acid had no adverse effects on their reproductive performance. McKinney et al. (1976) noted a periodic increase in reproductive failure among CD-1 mice. Mating, number of embryos per fertile female and embryonic development were affected. The effect was seasonal and was most severe in the winter. In the absence of any other observed variations in the animal husbandry, the authors attributed the reproductive deficiencies to the heavily chlorinated Durham, NC, city water consumed by the mice. Two attempts were made to repeat the observations reported by McKinney et al. (1976). Chernoff et al. (1979) found no significant difference in the reproductive parameters of CD-1 mice consuming Durham, NC, drinking water as compared with the control group maintained on distilled water. The animals were maintained on the test or control water for a 2-week period after which mating was begun. Dams were sacrificed on day 18 of gestation. Exposure was continued throughout the course of the study (December-September). Dams were analyzed for differences in numbers inseminated, number pregnant, weight gain during gestation, organ weight and percent resorption. Fetuses were examined for skeletal and visceral anomalies as well as mortality and body weight. No statistically significant maternal or fetal effects were noted, except for a 28.1% incidence of supernumerary ribs in the group consuming tap water compared with 21.1% in the control group consuming distilled water (p<0.05). In a second study, Staples et al. (1979) reported no significant overall influence on the incidence of malformed fetuses (skeletal or visceral malformations) that could be attributed to the chlorination of drinking water. The incidence of malformations in the controls was 8.1% compared with 7.8% in treated animals. Differences pointed in the opposite direction of the finding of McKinney et al. (1976). Two significant effects occurred in the month of January, and one occurred in the month of February. In January, a lower number of mated females CD-1 became pregnant, and the average number of implants/pregnant females was lower in the group consuming purified water. In February, the average fetal weight was lower in the purified-water group than in the tap-water group. Indeed, the presence of chlorine in the water seemed to confer a beneficial effect. The authors concluded that the results of their study did not support the findings of McKinney et al. (1976), although there were complicating factors in the Staples et al. (1979) study. There appears to be no evidence that would link chlorination at levels consistent with current practice to any adverse reproductive effects in the species so far examined. Hulan and Proudfoot (1982) studied the effects of sodium hypochlorite in drinking water on Shaver broiler chickens. Sodium hypochlorite was added to the drinking water of chicks (240/sex) at doses of 0, 300, 600 and 1200 ppm. A significant (p<0.01) reduction was found in the weight of chick, testes at dose levels of 600 and 1200 ppm of available chlorine. At these higher concentrations, however, there was also a decrease in total body weight, food and water consumption and an increase in mortality. Meier et al. (1985) demonstrated that oral administration of a sodium hypochlorite solution, but not hypochlorous acid, resulted in dose-related increases in the amount of sperm-head abnormalities in male B6C3F1 mice. Ten animals/group were given 1 mL of a residual chorine solution daily for 5 days. Test solutions were prepared by bubbling Cl2 into a 1M solution of NaOH and adjusting the pH to either pH 8.5 (predominant species OCl-) or pH 6.5 (predominant species HOCl). The solutions were diluted with distilled water to 200 mg/L, 100 mg/L and 40 mg/L chlorine equivalents (8.0, 4.0 or 1.6 mg/kg-day, respectively). The mice were then sacrificed at 1, 3 or 5 weeks after the last dose was administered. In mice given OCl-, significant increases in sperm-head abnormalities were observed only at the 3-week interval at doses of 1.6 and 4.0 mg/kg-day. These results were reproduced in retrials of the experiment. HOC1 administration at any dose was not associated with increases in sperm-head abnormalities. Six virgin Sprague-Dawley rats were administered 0, 1, 10 or 100 mg HOCl/L in drinking water for 2.5 months prior to mating. Animals were maintained on the treated water after pregnancy was confirmed (day 0) and killed on day 20. Maternal weight at time of death was not reported. The incidence of fetal anomalies associated with exposure to hypochlorous acid solutions was not found to be statistically significant. Mean fetal weights from the 10 and 100 mg/L groups were less than the control, but this decrease was not statistically significant. Neither was there a significant difference in numbers of resorptions between control and treated groups. Examination of general trends in the study indicated an increase (not significant) in skeletal anomalies in animals treated with 10 mg HOCl/L. Soft tissue anomalies for the 100 mg HOCl/L treatment group were increased significantly by comparison with the control. The findings of these experiments were limited by the small number of study animals. Some of the calculations of anomaly percentages reported in the paper were incorrect. Furthermore, the rate of both skeletal and soft tissue anomalies appeared to be higher in the control group than in the low-dose treatment groups (Abdel-Rahman et al., 1982). Exon et al. (1987) reported immunotoxic effects when sodium hypochlorite (5, 15 and 30 ppm) was administered in drinking water to Sprague-Dawley rats (12/sex/dose group) from weaning to 12 weeks of age. Based on reference body weight and water consumption values for subchronic exposure (U.S. EPA, 1986) the corresponding intake of chlorine was 0.7, 2.1 and 4.2 mg/kg-day. Parameters monitored were body weight, spleen and thymus weight, antibody production, delayed-type hypersensitivity (DTH) reactions, natural killer cell (NKC) cytotoxicity, oxidative metabolism response, phagocytosis by macrophages and production of interleukin 2 (IL2). The effects attributed to sodium hypochlorite treatment (at only the high dose) were reductions of spleen weight, DTH reactions, oxidative metabolism by macrophages and elevated prostaglandin E2 production. The toxicological significance of these effects is not clear. A NOAEL and/or LOAEL were not defined in this study. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- Medium RfD -- Medium Confidence in the principal study (NTP, 1992) is high to medium. Relevant endpoints in two animal species were examined after prolonged exposure by an appropriate route. An effect level was not achieved in the study, however, and higher levels may not be practicable due to taste aversion (and therefore reduced water consumption). Confidence in the data base is medium. Information is available for mice and rats on the noncarcinogenic toxicity of oral exposure to chlorine for subchronic periods. Developmental and reproductive toxicity of chlorine have been examined in mice and rats, but with suboptimal studies. Due to the chemical relationship between chlorine and monochloramine, reproductive and developmental studies for monochloramine may be used to satisfy data gaps for chlorine. Confidence in the RfD is medium. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1992 The Drinking Water Criteria Document for Chlorine/Hypochlorous Acid/Hypochlorite Ion has undergone limited Agency review. Other EPA Documentation -- None Agency Work Group Review -- 07/20/1993, 10/14/1993, 12/15/1993 Verification Date -- 12/15/1993 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Chlorine conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Chlorine CASRN -- 7782-50-5 NORC: Not available at this time. ============================================================================ UDCA: 199301 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Chlorine CASRN -- 7782-50-5 NOCA: Not available at this time. ============================================================================ UDSO: 199406 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Chlorine CASRN -- 7782-50-5 Last Revised -- 06/01/1994 SORD: __VI.A. ORAL RfD REFERENCES Abdel-Rahman, M.S., M.R. Bernardi and R.J. Bull. 1982. Effect of chlorine and monochloramine in drinking water in the developing rat fetus. J. Appl. Toxicol. 2(3): 156-159. Abdel-Rahman, M.S., D.H. Suh and R.J. Bull. 1984. Pharmacodynamics and toxicity of chlorine in drinking water in the rat. J. Appl. Toxicol. 4(2): 82-86. Carlton, B.D., P. Bartlett, A. Basaran, K. Colling, I. Osis and M.K. Smith. 1986. Reproductive effects of alternative disinfectants. Environ. Health Perspect. 69: 237-241. Chernoff, N., E. Rogers, B. Carver, B. Kavlock and E. Gray. 1979. The fetotoxic potential of municipal drinking water in the mouse. Teratology. 19: 165-169. Daniel, F.B., L.W. Condie, M. Robinson et al. 1990. Comparative subchronic toxicity studies of three disinfectants. J. Am. Water Works Assoc. 82: 61-69. Daniel, F.B., H.P. Ringhand, M. Robinson, J.A. Stober, G.R. Olson and N.P. Page. 1991. Comparative subchronic toxicity of chlorine and monochlorine in the B6C3F1 mouse. J. Am. Water Works Assoc. 83(11): 68-75. Druckrey, H. 1968. Chlorinated drinking water toxicity tests involving seven generations of rats. Food Cosmet. Toxicol. 6: 147-154. Exon, J.H., L.D. Koller, C.A. O'Reilly and J.P. Bercz. 1987. Immunotoxicologic evaluation of chlorine-based drinking water disinfectants, sodium hypochlorite and monochloramine. Toxicology. 44: 257-269. Hasegawa, R., M. Takahashi, T. Kokubo et al. 1986. Carcinogenicity study of sodium hypochlorite in F344 rats. Food Chem. Toxicol. 24(12): 1295-1302. Hulan, H.W. and F.G. Proudfoot. 1982. Effect of sodium hypochlorite (Javex) on the performance of broiler chickens. Am. J. Vet. Res. 43(10): 1804-1806. Kurokawa, Y., S. Takayama, Y. Konishi et al. 1986. Long-term in vivo carcinogenicity test of potassium bromate, sodium hypochlorite and sodium chlorite conducted in Japan. Environ. Health Perspect. 69: 221-235. Les, E.P. 1968. Effect of acidified - chlorinated water on reproduction in C3H/HEJ and C57B1/6J mice. Lab. Anim. Care. 18(2): 210-213. McKinney, J.D., R.R. Maurer, J.R. Hass and R.O. Thomas. 1976. Possible factors in the drinking water of laboratory animals causing reproductive failure. In: Identification and Analysis of Organic Pollutants in Water, L.H. Keith, Ed. Ann Arbor Science Publishers, Inc., Ann Arbor, MI. p. 417-432. Meier, J.R., R.J. Bull, J.A. Stober and M.C. Cimono. 1985. Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and sperm-head abnormalities in mice. Environ. Mutagen. 7: 201-211. NTP (National Toxicology Program). 1992. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Chlorinated and Chloraminated Water in F344/N Rats and B6C3F1 Mice (drinking water studies). NTP TR 392, National Institutes of Health. Staples, R.E., W.C. Worthy and T.A. Marks. 1979. Influence of drinking water: Tap versus purified on embryo development in mice. Teratology. 19: 237-244. U.S. EPA. 1986. Reference Values for Risk Assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1992. Drinking Water Criteria Document for Chlorine, Hypochlorous Acid and Hypochlorite Ion. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water, Washington, DC. (External review draft) ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Chlorine CASRN -- 7782-50-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1991 I.B. Inhalation RfC now under review 01/01/1993 II. Carcinogenicity assessment now under review 08/01/1993 I.A. Oral RfD now under review 12/01/1993 I.A. Work group review date added 01/01/1994 I.A. Work group review date added 06/01/1994 I.A. Oral RfD on-line 06/01/1994 VI.A. Oral RfD references on-line 06/01/1994 SYN Synonyms revised 08/01/1995 I.B., II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 420 of 1119 in IRIS (through 2003/06) AN: 408 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199103 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2-Dichlorobenzene- SY: 95-50-1; BENZENE,-1,2-DICHLORO-; BENZENE,-O-DICHLORO-; CHLOROBEN-; CHLORODEN-; CLOROBEN-; DCB-; O-DICHLORBENZENE-; O-DICHLOR-BENZOL-; O-DICHLOROBENZENE-; DICHLOROBENZENE,-ORTHO-; DILANTIN-DB-; DILATIN-DB-; DIZENE-; DOWTHERM-E-; NCI-C54944-; ODB-; ODCB-; ORTHODICHLOROBENZENE-; ORTHODICHLOROBENZOL-; SPECIAL-TERMITE-FLUID-; TERMITKIL-; UN-1591- RN: 95-50-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199103 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2-Dichlorobenzene CASRN -- 95-50-1 Last Revised -- 03/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- No adverse effects NOAEL: 120 mg/kg/day 1000 1 9E-2 observed (adjusted to 85.7 mg/kg/day mg/kg/day) 2-Year Rat Study, Oral Exposure (gavage) LOAEL: None NTP, 1985 ---------------------------------------------------------------------------- *Conversion Factors: Doses adjusted for gavage schedule of 5 days/week. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene (o-dichlorobenzene) (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 255. NIH Publ. No. 86-2511. 1,2-Dichlorobenzene in corn oil was given by gavage to F344/N rats and B6C3F1 mice (50 males and 50 females/group) at doses of 0, 60, or 120 mg/kg/day, 5 days/week for 103 weeks (NTP, 1985). Survival of high-dose male rats was decreased compared with controls (19/50 vs. 42/50, P=>0.001), but the difference appears largely because of deaths from gavage error (4 controls vs. 20 high-dose). Although an increase (P=>0.05) in renal tubular regeneration in high-dose male mice was observed (17/49 compared with 12/50 in the low-dose group and 8/48 in the control group), there was no other evidence of treatment-related renal lesions in either species. Further, the incidence of this lesion in male control mice was below those of three similar control groups that were studied during approximately the same period at the testing facility (31/50, 15/50, 24/50). There was no other evidence of treatment-related effects in this study. Because the decrease in survival and the increase in renal tubular regeneration in the high-dose animals were of questionable significance, a NOAEL of 120 mg/kg/day is established. 1,2-Dichlorobenzene in corn oil was given orally by gavage to F344/N rats and B6C3F1 mice (10 males and 10 females/group) at doses of 0, 30, 60, 125, 250, or 500 mg/kg/day, 5 days/week for 13 weeks (NTP, 1985). Liver necrosis was found in mice and rats given 250 mg/kg/day. Deaths, degeneration and necrosis in the liver, lymphocyte depletion in the spleen and thymus, renal tubular degeneration (male rats only), and slight decreases in hemoglobin, hematocrit and red blood cell counts (rats only) were induced at 500 mg/kg/day. Hepatocellular necrosis (focal or individual hepatocyte) was observed in 1 male and 3 female rats given 125 mg/kg/day (NTP, 1985). Increases (P=>0.05) in serum cholesterol at all doses except 60 mg/kg/day in male rats and at doses of 125 to 500 mg/kg/day for female rats; liver weight/body weight ratios in male and female rats at 125 to 500 mg/kg/day; and serum protein at all doses in female rats and at 250 to 500 mg/kg/day in male rats indicate treatment-related liver effects at doses >125 mg/kg/day. However, no evidence of treatment-related liver pathology in rats and mice given 60 or 120 mg/kg/day, 5 days/week in the 2-year NTP (1985) carcinogenicity bioassay and no increase (P=>0.05) in serum enzymes (SGPT, GGPT, alkaline phosphatase) for either rats or mice in the 13-week study are grounds for considering 125 mg/kg/day as a NOAEL in the 13-week study. In rats dosed by gavage with 1,2-dichlorobenzene at 18.8, 188, or 376 mg/kg/day, 5 days/week for 192 days, liver and kidney weights were increased at 188 mg/kg/day, and liver pathology and increased spleen weight were observed at 376 mg/kg/day (Hollingsworth et al., 1958). No effects were observed at 18.8 mg/kg/day. Thus, the NOAEL was 18.8 mg/kg/day. Rats, guinea pigs, mice, rats, and monkeys were exposed by inhalation to 1,2-dichlorobenzene at levels of 49 or 93 ppm, 7 hours/day, 5 days/week for 6 to 7 months. At 93 ppm, body weight gain in rats and spleen weight in guinea pigs were reduced (P=>0.05) (Hollingsworth et al., 1958). Estimated daily doses with 49 ppm exposure are 387 mg/kg (mouse), 19.3 mg/kg (rat), 14.4 mg/kg (guinea pig), 15.9 mg/kg (rabbit), and 20.3 mg/kg (monkey). Pregnant F344/N rats and New Zealand rabbits were exposed by inhalation to 0, 100, 200, or 400 ppm 1,2-dichlorobenzene 6 hours daily on days 6 through 15 (rats) or 6 through 18 (rabbits) of gestation (Hayes, 1985). Body weight gain was lower (P=>0.05) in rats at all doses and in rabbits at 400 ppm, during the first 3 days of exposure. Liver weights (absolute and relative to body weight) were increased in rats at 400 ppm. No developmental toxicity was evident at any dose. Estimated daily doses at 100 ppm exposure are 40 mg/kg (rat) and 32 mg/kg (rabbit). UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The UF of 1000 allows for uncertainty in the extrapolation of dose levels from laboratory animals to humans (10A), uncertainty in the threshold for sensitive humans (10H), and uncertainty because of the lack of studies assessing reproductive effects and adequate chronic toxicity in a second species (10D). MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) Taking into consideration the 13-week and 2-year NTP studies together, the NOAEL is supported. The 1000-fold uncertainty factor takes into account data gaps and endpoints assessed in the 13-week NTP study which were not assessed in the 2-year NTP study. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Low RfD -- Low The chronic study, coupled with results of subchronic studies provides a NOAEL and LOAEL for several toxicologic endpoints, but the chronic study did not assess biochemical and clinical endpoints. Therefore, a medium level of confidence is assigned. Lack of reproductive and adequate additional supporting toxicity studies in nonrodent species lead to low confidence in the data base. Low confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1987 . Drinking Water Criteria Document for ortho-Dichlorobenzene, meta-Dichlorobenzene, para-Dichlorobenzene. Office of Drinking Water, Washington, DC. Science Advisory Board review of ODW health advisory document in 1986, and ODW criteria document in 1987. Public comments on proposed drinking water regulation in 1985. Agency Work Group Review -- 06/24/1985, 07/08/1985, 04/20/1988, 02/16/1989 Verification Date -- 02/16/1989 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2-Dichlorobenzene CASRN -- 95-50-1 NORC: Not available at this time. ============================================================================ UDCA: 199101 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2-Dichlorobenzene CASRN -- 95-50-1 Last Revised -- 01/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- Based on no human data and evidence of both negative and positive trends for carcinogenic responses in rats and mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. Two carcinogenicity studies were conducted by the National Toxicology Program (NTP, 1985) using 1,2-dichlorobenzene. Groups of 50 F344/N rats/sex and 50 B6C3F1 mice/sex were gavaged with 0, 60 or 120 mg/kg of the chemical in corn oil, 5 days/week for 103 weeks. In the rat study, survival in the 0, 60 and 120 mg/kg groups was 84, 72 and 38% in males and 62, 66 and 64% in females; NTP concluded that a maximum-tolerated-dose (MTD) had been achieved. Survival was statistically significantly reduced in the high-dose males due to causes incidental to treatment (3 accidental deaths, 5 deaths due to gavage error, and 12 deaths caused by aspiration). An increased incidence of pheochromocytomas of the adrenal gland was found in low-dose males (significant by life table test) but not the high-dose males (9/50, 16/50, 6/49 in the control, low- and high-dose groups, respectively). The increased incidence of pheochromocytomas in low-dose males was discounted because there was no dose-response trend or high-dose effect, no malignant pheochromocytomas had been observed, and no incidence increase was seen in females; additionally, the biological consequence of this endpoint is often questioned because pheochromocytomas are not considered to be a life-threatening condition. There was a decrease in the incidence of testicular interstitial cell tumors (47/50, 49/50 and 41/50). In the mouse study, no significant differences in survival were noted in the treatment groups when compared with controls. It is unclear if an MTD had been achieved. A dose-related increase was seen in malignant histiocytic lymphoma in male mice (0/50, 1/50, 4/50 for control, low- and high-dose groups, respectively) and female mice (0/49, 0/50, 3/49 for control, low- and high-dose groups, respectively). An increased incidence of alveolar and bronchiolar carcinomas (combined) in male mice (4/50, 2/50 and 10/50 for the control, low- and high-dose groups, respectively) was significant by a trend test; the combined incidence of alveolar and bronchiolar adenomas and carcinomas (8/50, 8/50 and 13/50, respectively) did not show a significant elevation. One high-dose male had a testicular interstitial cell tumor. In males there was a decrease in the incidence of hepatocellular adenomas (8/50, 5/49 and 2/46, respectively) and carcinomas (14/50, 10/49 and 9/46, respectively). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY 1,2-Dichlorobenzene, at concentrations up to 333 ug/plate, did not produce reverse mutations in Salmonella typhimurium strains TA98, TA100, TA1535 or TA1537 with and without liver homogenates from Sprague-Dawley rat or Syrian hamster (NTP, 1985). In an abstract, Lawlor et al. (1979) reported that 1,2-dichlorobenzene (doses not specified) did not produce reverse mutations in TA98, TA100, TA1535, TA1537 or TA1538 with and without rat liver homogenates. An increase in the frequency of mutations by 1,2-dichlorobenzene was reported in auxotrophic strain of Aspergillus nidulans (Prasad and Pramer, 1968). Chromosome studies, in workers occupationally exposed for 4 days (8 hours/day) to 1,2-dichlorobenzene vapors (the concentration was thought to have exceeded 100 ppm), showed a statistically significant increase in the incidence of chromosomal alterations (in chromosomes isolated from peripheral blood cells) when compared to chromosomes isolated from the blood cells of a control population (Zapata-Gayon et al., 1982). The number of single and double chromosome breaks was also increased. A followup study 6 months after the initial exposure indicated a significant increase in only double chromosome breaks. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985 The 1985 Health Assessment Document for Chlorinated Benzenes has received Agency review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 12/06/1989 Verification Date -- 12/06/1989 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199011 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2-Dichlorobenzene CASRN -- 95-50-1 Last Revised -- 11/01/1990 SORD: __VI.A. ORAL RfD REFERENCES Hayes, W.C., T.R. Hanley, Jr., T.S. Gushow, K.A. Johnson, and J.A. John. 1985. Teratogenic potential of inhaled dichlorobenzene in rats and rabbits. Fund. Appl. Toxicol. 5: 190-202. Hollingsworth, R.L., V.K. Rowe, F. Oyen, T.R. Torkelson, and E.M. Adams. 1958. Toxicity of o-dichlorobenzene. Studies on animals and industrial experience. A.M.A. Arch. Indust. Health 17: 180-187. NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene (o-dichlorobenzene) (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 255. NIH Publ. No. 86-2511. U.S. EPA. 1987. Drinking Water Criteria Document for ortho-Dichlorobenzene, meta-Dichlorobenzene, para-Dichlorobenzene. Office of Drinking Water, Washington, DC. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Lawlor, T., S.R. Haworth and P. Voytek. 1979. Evaluation of the genetic activity of nine chlorinated phenols, seven chlorinated benzenes, and three chlorinated hexanes. Environ. Mutagen. 1(2): 143. (Abstr.) NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene (o-dichlorobenzene) (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage study). NTP, Research Triangle Park, NC. NTP-TR-255. NIH Publ. No. 86-2511. Prasad, I. and D. Pramer. 1968. Mutagenic activity of some chloroanilines and chlorobenzenes. Genetics. 60: 212-213. (Abstract) U.S. EPA. 1985. Health Assessment Document for chlorinated benzenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Solide Waste and Emergency Response, Washington, DC. Zapata-Gayon, C., N. Zapata-Gayon and A. Gonzalez-Angulo. 1982. Clastogenic chromosomal aberrations in 26 individuals accidentally exposed to ortho dichlorobenzene vapors in the National Medical Center in Mexico City. Arch. Environ. Health. 37(4): 231-235. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2-Dichlorobenzene CASRN -- 95-50-1 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1989 I.A. Oral RfD summary on-line 08/01/1989 VI. Bibliography on-line 01/01/1990 II. Carcinogen assessment now under review 06/01/1990 I.A.2. Text edited 11/01/1990 II. Carcinogen assessment on-line 11/01/1990 VI.C. Carcinogen references added 01/01/1991 II.D.2. Agency review and verification dates corrected 03/01/1991 I.A.7. EPA contacts changed 01/01/1992 IV. Regulatory Action section on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/12/2000 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 421 of 1119 in IRIS (through 2003/06) AN: 409 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199612 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,1-Dichloroethane- SY: 75-34-3; AETHYLIDENCHLORID [GERMAN]; CHLORINATED-HYDROCHLORIC-ETHER-; CHLORURE D'ETHYLIDENE [FRENCH]; CLORURO DI ETILIDENE [ITALIAN]; 1,1-DICHLOORETHAAN [DUTCH]; 1,1-DICHLORAETHAN [GERMAN]; 1,1-DICHLORETHANE-; DICHLORO-1,1 ETHANE [FRENCH]; 1,1-DICLOROETANO [ITALIAN]; 1,1-DICLOROETANO [SPANISH]; ETHANE,-1,1-DICHLORO-; ETHYLIDENE-CHLORIDE-; ETHYLIDENE-DICHLORIDE-; HSDB-64-; NCI-C04535-; RCRA-WASTE-NUMBER-U076-; UN-2362- RN: 75-34-3 HSN: 64 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 NORC: Not available at this time. ============================================================================ UDCA: 199612 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 Last Revised -- 12/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Based on no human data and limited evidence of carcinogenicity in two animal species (rats and mice) as shown by an increased incidence of mammary gland adenocarcinomas and hemangiosarcomas in female rats and an increased incidence of hepatocellular carcinomas and benign uterine polyps in mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. An NCI bioassay (1978a) provides limited evidence of the carcinogenicity of 1,1-dichloroethane in Osborne-Mendel rats and B6C3F1 mice. This is based on significant dose-related increases in the incidence of hemangiosarcomas at various sites and mammary carcinomas in female rats and statistically significant increases in the incidence of liver carcinoma in male mice and benign uterine polyps in female mice. The study is limited by high mortality in many groups; the low survival rates precluded the appearance of possible late-developing tumors and decreased the statistical power of this bioassay. Technical grade 1,1-dichloroethane in corn oil was administered by gavage 5 days/week for 78 weeks to groups of 50 Osborne-Mendel rats/sex/dose. All surviving animals were necropsied following a 33-week observation period. Due to toxicity, dosing was not continuous (3 weeks on then 1 week off), making the TWAs for 5 days/week 382 and 764 mg/kg/day for low- and high-dose males and 475 and 950 mg/kg/day for low- and high-dose females, respectively. Both a vehicle and an untreated (not intubated) control group (20 rats/sex/group) were included in the study. A high incidence of pneumonia (approximately 80%) in all 4 groups of each sex was considered to be the cause for the low survival at termination of the study. Survival at 111 weeks was 30, 5, 4,and 8% in the untreated control, the vehicle control, the low-dose, and the high-dose male rat groups, respectively. Survival at termination for the female rat groups was 40, 20, 16, and 18% for the untreated control, vehicle control, low- and high-dose groups, respectively. In female rats there was a statistically significant positive dose-related trend in incidence of hemangiosarcomas (0/19 for matched vehicle controls, 0/50 for the low-dose group, and 4/50 for the high-dose group). The incidence of mammary gland adenocarcinomas (1/20 for the untreated group, 0/19 for the vehicle control group, 1/50 for low-dose, and 5/50 for high-dose groups) showed a statistically significant dose-related positive trend in those female rats surviving at least 52 weeks; tumor incidence was 0/16, 1/28 and 5/31 for vehicle control, low- and high-dose groups, respectively. (Tumor incidence at termination for the untreated control females surviving at least 52 weeks was not reported.) This bioassay was conducted before the life table tests were implemented, so results adjusted for mortality are not available. No mammary gland adenomas or hemangiosarcomas were observed in the dosed-male rats. In the same NCI (1978a) study, groups of 50 B6C3F1 mice/sex/group were administered technical grade 1,1-dichloroethane in corn oil by gavage 5 days/week for 70 weeks. As in the rat study, the dosage pattern was 3 weeks on and 1 week off; the surviving animals were necropsied 13 weeks after the termination of dosing. The TWAs for 5 days/week for the low- and high-dose groups were 1442 and 2885 mg/kg/day for male and 1665 and 3331 mg/kg/day for female mice. Control groups, identical to those in the rat study and consisting of 20 mice/sex/group were also used. Survival at termination was 80, 80, 80, and 50% for the untreated control group, the vehicle control group, the low-, and high-dose females, respectively. In male mice survival was 35, 55, 62, and 32% in the untreated control group, the vehicle control group, the low-, and high-dose groups, respectively. An increased incidence of hepatocellular carcinoma in male mice was not statistically significant by either pair-wise or trend test (2/17 in the untreated control group, 1/19 in the vehicle control group, 8/49 in the low-dose and 8/47 in the high-dose groups). The incidence of hepatocellular carcinoma in male mice surviving at least 52 weeks was 1/19, 6/72, 8/48, and 8/32 in the matched vehicle control group, a pooled vehicle control group consisting of mice from this and identical controls from other concurrent experiments, and the low-, and high-dose groups, respectively; this positive trend was statistically significant. In female mice, liver carcinomas were reported in only the vehicle control (1/19) and the low-dose groups (1/47): no liver tumors were seen in the untreated controls or in the high-dose group. A statistically significant increase in benign uterine endometrial stromal polyps (4/46) was observed in high-dose females; these were not observed in any other group. A preliminary report of the NCI (1978a) study was published by Weisburger (1977). SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY To determine if 1,1-dichloroethane in drinking water could act as a tumor promoter or a complete carcinogen, Klaunig et al. (1986) exposed groups of 35 male B6C3F1 mice to 1,1-dichloroethane in drinking water at 0, 835, or 2500 mg/L for up to 52 weeks following a 4-week treatment with either drinking water containing 10 mg/L diethyl nitrosamine (DENA-initiated groups) or with deionized water (noninitiated groups). The investigators estimated that the approximate weekly dose of 1,1-dichloroethane was 3.8 mg/g/week (corresponding to 543 mg/kg/day) for the groups exposed to 2500 mg/L. Upon sacrifice at the end of either 24 weeks (10 mice/group) or 52 weeks (25 mice/group) of promotion, all tissues were examined for gross pathologic lesions and histologic sections of the liver, kidneys and lungs were examined. Neither the initiated nor the noninitiated 1,1-dichloroethane-treated groups showed a significant increase in the incidence of liver or lung tumors compared with initiated or noninitiated controls, respectively. The authors concluded that 1,1-dichloroethane was not carcinogenic to mice and did not act as a tumor promotor following initiation with DENA. These conclusions may not be entirely justified, since the duration of the study may have been inadequate for the development of tumors in noninitiated 1,1-dichloroethane-treated animals. In addition, the incidence of liver tumors in DENA-initiated controls was 70% at 24 weeks and 100% at 52 weeks, and the number of tumors/mouse in DENA-initiated controls at these times was 3.00 and 29.30, respectively. Hence, an increase in tumors or decrease in latency in 1,1-dichloroethane-treated DENA-initiated animals would have to be marked in order to be detectable. Milman et al. (1988) and Story et al. (1986) investigated the chlorinated ethanes and ethylenes to detect their potential tumor initiating or promoting effects in a liver foci assay in Osborne-Mendel rats. In this assay, 1,1-dichloroethane did not give positive results for initiation (with phenobarbital as promotor), or as a complete carcinogen when administered in the absence of initiation or promotion. Positive results for were seen for promotion with DENA as initiator. The assumption that the liver foci seen in this type of assay are precancerous has not been validated. When tested by plate incorporation in a desiccator (because of volatility) in the presence and absence of metabolic activation systems, 1,1-dichloroethane was reported to be mutagenic for Salmonella typhimurium TA1535, TA98, and TA100, but not to TA1537 (Riccio et al., 1983; Mitoma et al., 1984). Negative results were reported for 1,1-dichloroethane in a cell transformation assay with BALB/c-3T3 cells, tested in the absence of an exogenous metabolic activation system in a sealed glass incubation chamber (Tu et al., 1985; Arthur D. Little, Inc., 1983). When tested in a similar manner in a DNA repair assay with hepatocyte primary cultures from rats or mice, 1,1-dichloroethane produced positive results (Williams, 1977). The results obtained in these three assays were also summarized in a joint publication (Milman et al., 1988). Positive results were obtained in a viral transformation assay in which 1,1-dichloroethane was incubated with cultured Syrian Hamster embryo cells in a sealed glass chamber prior to addition of adenovirus SA7 (Hatch et al., 1983). Lattanzi et al. (1988) determined that 1,1-dichloroethane, like 1,2-dichloroethane, binds covalently to DNA, forming DNA adducts. The Covalent Binding Index (CBI) of both 1,1-dichloroethane and 1,2-dichloroethane classifies them as weak initiators. Chronic bioassays performed by NCI (1978b) on the isomer 1,2-dichloroethane resulted in many of the same tumor types as seen in the bioassays of 1,1-dichloroethane. Significant increases in the incidences of forestomach squamous cell carcinomas and hemangiosarcomas were observed in male rats and an increased incidence of mammary adenocarcinomas was observed in both female rats and mice. In addition, alveolar and bronchiolar adenomas were reported in male and female mice; endometrial stromal polyps and sarcomas in female mice; and hepatocellular carcinomas in male mice. Based on these findings, as well as the appearance of lung papillomas in mice after topical treatment, 1,2-dichloroethane was classified as a group B2 chemical, a probable human carcinogen (U.S. EPA, 1990). Because of similarities in structure and target organs, the carcinogenic evidence for 1,2-dichloroethane is considered to be supportive of the classification of 1,1-dichloroethane in group C, a possible human carcinogen. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1985, 1986, 1990 The 1984 Health Effects Assessment for 1,1-Dichloroethane has received Office of Health and Environmental Assessment review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 12/07/1989 Verification Date -- 12/07/1989 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for 1,1-Dichloroethane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199010 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 Last Revised -- 10/01/1990 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Arthur D. Little, Inc. 1983. Cell transformation assays of 11 chlorinated hydrocarbon analogs. Microfiche No. OTS0509392, Document No. 40-8324457. Hatch, G.G., P.D. Mamay, M.L. Ayer, B.C. Casto and S. Nesnow. 1983. Chemical enhancement of viral transformation in Syrian hamster embryo cells by gaseous and volatile chlorinated methanes and ethanes. Cancer Res. 43(5): 1945-1950. Klaunig, J.E., R.J. Ruch and M.A. Pereira. 1986. Carcinogenicity of chlorinated methane and ethane compounds administered in drinking water to mice. Environ. Health Perspect. 69: 89-95. Lattanzi, G., A. Colacci, S. Grilli, et al. 1988. Binding of hexachloroethane to biological macromolecules from rat and mouse organs. J. Toxicol. Environ. Health. 24: 403-411. Milman, H.A., D.L. Story, E.S. Riccio, et al. 1988. Rat liver foci and in vitro assays to detect initiating and promoting effects of chlorinated ethanes and ethylenes. Ann. NY Acad. Sci. 534: 521-530. Mitoma, C., C.A. Tyson and E.S. Riccio. 1984. Investigations of the species sensitivities and mechanism of carcinogenicity of halogenated hydrocarbons. Microfiche No. OTS0509408, Document No. 40-8424225. NCI (National Cancer Institute). 1978a. Bioassay of 1,1-dichloroethane for possible carcinogenicity. CAS No. 78-34-3. NCI/NTP Technical Report No. 066. DHEW Publ. No. (NIH) 78-1316, Washington, DC. NCI (National Cancer Institute). 1978b. Bioassay of 1,2-Dichloroethane for Possible Carcinogenicity. NCI Carcinogenesis Technical Report Series No. 55. DHEW Publ. No. (NIH) 78-1361, Washington, DC. Riccio, E., A. Griffin, K. Mortelmans and H.A. Milman. 1983. A comparative mutagenicity study of volatile halogenated hydrocarbons using different metabolic activation systems. Environ. Mutagen. 5: 472. (Abstract) Story, D.L., E.F. Meierhenry, C.A. Tyson and H.A. Milman. 1986. Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital. Toxicol. Ind. Health. 2(4): 351-362. Tu, A.S., T.A. Murray, K.M. Hatch, A. Sivak and H.A. Milman. 1985. In vitro transformation of BALB/c-3T3 cells by chlorinated ethanes and ethylenes. Cancer Lett. 28(1): 85-92. U.S. EPA. 1985. Health and Environmental Effects Profile for Dichloroethanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. U.S. EPA. 1990. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. Weisburger, E.K. 1977. Carcinogenicity studies on halogenated hydrocarbons. Environ. Health Perspect. 21: 7-16. Williams, E.M. 1977. Detection of chemical carcinogens by unscheduled DNA synthesis in rat liver primary cell cultures. Cancer Res. 37(6): 1845-1851. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,1-Dichloroethane CASRN -- 75-34-3 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1989 I.A. Oral RfD now under review 05/01/1990 I.B. Inhalation RfC now under review 10/01/1990 II. Carcinogen assessment on-line 10/01/1990 VI. Bibliography on-line 11/01/1991 ALL FILES AD 01/01/1992 IV. Regulatory Action section on-line 12/01/1996 II.D.3. Primary contact removed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 422 of 1119 in IRIS (through 2003/06) AN: 410 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199506 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Boron- (Boron and Borates only) SY: 7440-42-8; BORON- RN: 7440-42-8 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199506 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Boron (Boron and Borates only) CASRN -- 7440-42-8 Last Revised -- 06/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: The Oral RfD for boron may change in the near future pending the outcome of a further review now being conducted by the RfD/RfC Work Group. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Testicular atrophy, NOAEL: 350 ppm 100 1 9E-2 spermatogenic arrest (8.8 mg/kg/day) mg/kg/day 2-Year Dog Study Oral Exposure (diet) LOAEL: 1170 ppm (29 mg/kg/day) Weir and Fisher, 1972 ---------------------------------------------------------------------------- *Conversion Factors: 1 ppm = 0.025 mg/kg/day (assumed dog food consumption). Author converted borax and boric acid doses to boron equivalents. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Weir, R.J., Jr. and R.S. Fisher. 1972. Toxicological studies on borax and boric acid. Toxicol. Appl. Pharmacol. 23: 351-364. Groups of 4 male and 4 female dogs were fed borax and boric acid in the diet for 2 years. The NOAEL was established at 350 ppm of boron equivalents (8.8 mg/kg/day), highest dose tested. In an additional study, dogs were fed 1170 ppm (29 mg/kg/day) for 38 weeks. At this dose, severe testicular atrophy and spermatogenic arrest occurred. Groups of 35 male and 35 female rats were fed borax and boric acid in the diet for 2 years at boron-equivalent doses of 117, 350, and 1170 ppm (5.9, 17.5 or 58.5 mg B/kg/day). No treatment-related effects were seen at 5.9 or 17.5 mg/kg/day, so the highest NOAEL is 17.5 mg/kg/day. The LOAEL is 58.5 mg/kg/day, based on the following: significantly decreased testes weights and testes-to-body weight ratios; atrophied seminiferous epithelium; and decreased tubular size in the testes. Brain and brain-to-body weight ratios were also significantly decreased. Schroeder and Mitchener (1975) reported a lifetime study in which mice were administered boron in drinking water at 5 mg/L (equivalent to 8.1 mg B/kg/day). No effects were observed with regard to body weight, longevity or survival. The NOAEL in this study was 8.1 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- Used in accordance with Agency guidelines for a NOAEL from a lifetime animal study. MF -- None ACRD: ___I.A.4. ADDITIONAL COMMENTS (ORAL RfD) The two principal studies indicate that the dog is more sensitive than the rat, with more severe testicular effects occurring at half the dose level in the dog vs. the rat (29 mg/kg/day vs. 58 mg/kg/day). Other studies reviewed: 1) 70-Day Study - rats: Groups of 15 rats were exposed to boron in drinking water. LOAEL=23.7 mg/kg/day (150 mg B/L) (LDT: decreased body weights; decreased weights of testes, seminal vesicles, spleens, and right femurs; lower fat content of bones; and lower plasma triglycerides and protein concentrations). At 300 mg B/L (44.7 mg/kg/day), spermatogenesis was impaired. There was no NOAEL in this study (Seal and Weeth, 1980). 2) 13-Week Study - mice: Male and female mice were fed boric acid. LOAEL= 34-47 mg/kg/day (1200 ppm) (LDT: extramedullary hematopoiesis of spleen of minimal to mild severity was observed in all groups). At the higher doses, 68 mg/kg/day (2500 ppm) to 544 mg/kg/day (20,000 ppm), degeneration or atrophy of seminiferous tubules was observed in males (NTP, 1987). 3) 90-Day Study - rats: Boric acid and borax were administered in the diet at 52.5, 175, 525, 1750, and 5250 ppm (2.6, 8.8, 26, 88, and 260 mg B/kg/day. The low dose caused an increase in the weight of the brain, spleen, kidneys, liver, and ovaries in females. Increased kidney weight occurred at 175 ppm in males. No organ weight changes were seen at 525 ppm in either sex. Severe effects in both sexes were seen at 1750 ppm and above (organ and body weight decreases) (Weir and Fisher, 1972). 4) 90-Day Feeding Study - dogs: Fed boron at levels of 17.5, 175, and 1750 ppm (0.44, 4.4, or 44 mg/kg/day). The lowest dose resulted in decreased spleen/body weight ratio in male dogs; 175 ppm resulted in decreased testes/body weight ratio; the highest dose produced severe testicular atrophy. No changes in female organ weights were observed at 17.5 or 175 ppm. No histologic changes were seen in dogs fed 175 ppm or below. Severe testicular atrophy seen at highest dose (Weir and Fisher, 1972). 5) Multigeneration Reproductive Study - rats: Dosed at 117, 350, and 1170 ppm (5.9, 17.5, 58.5 mg/kg/day). NOAEL=17.5 mg/kg/day; LOAEL=58.5 mg/kg/day; (HDT: males showed lack of spermatazoa in atrophied testes; females showed decreased ovulation) (Weir and Fisher, 1972). 6) 90-Day Reproductive Study - rats: Males were dosed with 0.3, 1.0, or 6.0 mg B/L (0.02, 0.072, or 0.426 mg/kg/day). NOAEL=0.426 mg/kg/day (HDT) (Dixon et al., 1976). 7) 60-Day Reproductive Study - rats: Doses were 0, 500, 1000, or 2000 mg/kg diet (equivalent to 25, 50, or 100 mg/kg/day). NOAEL=25 mg/kg/day; LOAEL=50 mg/kg/day; (decreased weights in liver, testes, and epididymis, and reduced fertility) (Dixon et al., 1979). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium RfD -- Medium The referenced lifetime dog study provides both a NOAEL and a LOAEL and examines many biological endpoints, but has a limited number of experimental animals; it rates a medium confidence. Several sub-chronic, chronic and reproductive toxicity studies provide supportive data, but developmental data do not exist; hence the data base rates a medium level of confidence. Medium confidence in the RfD follows. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 06/23/1988, 07/20/1989, 06/15/1993, 08/03/1994, 05/09/1995 Verification Date -- 07/20/1989 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Boron (Boron and Borates only) CASRN -- 7440-42-8 NORC: Not available at this time. ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Boron (Boron and Borates only) CASRN -- 7440-42-8 NOCA: Not available at this time. ============================================================================ UDSO: 198910 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Boron (Boron and Borates only) CASRN -- 7440-42-8 Last Revised -- 10/01/1989 SORD: __VI.A. ORAL RfD REFERENCES Dixon, R.L., I.P. Lee and R.J. Sherins. 1976. Methods to assess reproductive effects of environmental chemicals - Studies of cadmium and boron administered orally. Environ. Health Perspec. 13: 59-67. Dixon, R.L., R.J. Sherins, and I.P. Lee. 1979. Assessment of environmental factors affecting male fertility. Environ. Health Perspec. 30: 53-68. Seal, B.S. and H.J. Weeth. 1980. Effect of boron in drinking water on the male laboratory rat. Bull. Environ. Contam. Toxicol. 25: 782-789. Schroeder, H.A. and M. Mitchener. 1975. Life-term effects of mercury, methyl mercury and nine other trace metals in mice. J. Nutr. 105: 452-458. NTP (National Toxicology Program). 1987. Toxicology and carcinogenesis studies of boric acid in B6C3F1 mice (feed studies). NTP Technical Report Series No. 324. Research Triangle Park, NC. Weir, R.J., Jr. and R.S. Fisher. 1972. Toxicologic studies on borax and boric acid. Toxicol. Appl. Pharmacol. 23: 351-364. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Boron (Boron and Borates only) CASRN -- 7440-42-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 10/01/1989 I.A. Oral RfD summary on-line 10/01/1989 VI. Bibliography on-line 11/01/1989 I.A.6. Work group review date corrected 08/01/1990 I.A. Text edited 01/01/1992 IV. Regulatory Action section on-line 01/01/1993 II. Carcinogenicity assessment now under review 05/01/1993 II Work group review date added 07/01/1993 I.A. Oral RfD noted as pending change 07/01/1993 I.A.6. Work grp. rev. date added; mtg. & verif. date corrected 09/01/1994 I.A.6. Work group review date added 06/01/1995 I.A.6. Work group review date added 08/01/1995 I.A., I.A.6, EPA's RfD/RfC and CRAVE workgroups were 08/01/1995 II discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III.,IV.,V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/02/1998 I., II This chemical is being reassessed under the IRIS program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 423 of 1119 in IRIS (through 2003/06) AN: 414 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199110 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2-Dibromo-3-chloropropane- (DBCP) SY: 96-12-8; PROPANE,-1,2-DIBROMO-3-CHLORO-; DIBROMOCHLOROPROPANE-; 1,2-DIBROMO-3-CHLOROPROPANE-; AI3-18445-; BBC-12-; CASWELL NO. 287; CCRIS-215-; DBCP-; DIBROMCHLORPROPAN [GERMAN]; EPA-PESTICIDE-CHEMICAL-CODE-011301-; FUMAGON-; FUMAZONE-; FUMAZONE-86E-; HSDB-1629-; NCI-C00500-; NEMABROM-; NEMAFUME-; NEMAGON-; NEMAGON-SOIL-FUMIGANT-; NEMAGON-20-; NEMAGON-20G-; NEMAGON-206-; NEMAGON-90-; NEMANAX-; NEMANEX-; NEMAPAZ-; NEMASET-; NEMAZON-; OS-1897-; OXY-DBCP-; PROPANE,-1-CHLORO-2,3-DIBROMO-; RCRA-WASTE-NUMBER-U066-; SD-1897-; 1-CHLORO-2,3-DIBROMOPROPANE-; 1,2-DIBROM-3-CHLOR-PROPAN [GERMAN]; 1,2-DIBROMO-3-CLORO-PROPANO [ITALIAN]; 1,2-DIBROOM-3-CHLOORPROPAAN [DUTCH]; 3-CHLORO-1,2-DIBROMOPROPANE- RN: 96-12-8 HSN: 1629 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2-Dibromo-3-chloropropane (DBCP) CASRN -- 96-12-8 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199110 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2-Dibromo-3-chloropropane (DBCP) CASRN -- 96-12-8 Last Revised -- 10/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Testicular effects NOAEL: 0.94 mg/cu.m (0.1 ppm) 1000 1 2E-4 NOAEL(ADJ): 0.17 mg/cu.m mg/cu.m 13-Week Subchronic NOAEL(HEC): 0.17 mg/cu.m Rabbit Inhalation Study LOAEL: 9.4 mg/cu.m (1 ppm) Rao et al., 1982 LOAEL(ADJ): 1.7 mg/cu.m LOAEL(HEC): 1.7 mg/cu.m ---------------------------------------------------------------------------- *Conversion Factors: MW = 236.3. Assuming 25C and 760 mmHg, NOAEL (mg/cu.m) = 0.1 ppm x 236.3/24.45 = 0.97; adjusted for compound purity of 0.973 = 0.94 mg/cu.m. NOAEL(ADJ) = NOAEL (mg/cu.m) x 6 hours/24 hours x 5 days/7 days = 0.17 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extrarespiratory effect in rabbits assuming periodicity was attained. Since b:a lambda values are unknown for the experimental species (a) and humans (h), a default value of 1.0 is used for this ratio. NOAEL(HEC) = 0.17 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Rao, K.S., J.D. Burek, F. Murray, et al. 1982. Toxicologic and reproductive effects of inhaled 1,2-dibromo-3-chloropropane in male rabbits. Fund. Appl. Toxicol. 2(5): 241-251. Rao et al. (1982) exposed 6-month-old male New Zealand white rabbits (10/group) to 0, 0.1, 1 or 10 ppm (0, 0.94, 9.4 or 94 mg/cu.m) DBCP vapors (adjusted for 97.3% purity), 6 hours/day, 5 days/week (duration-adjusted to 0, 0.17, 1.7, and 17 mg/cu.m), for 14 weeks. The rabbits receiving the 10-ppm concentration were exposed for only 8 weeks due to high mortality (apparently from pneumonia). Body weights and hematological and clinical chemistry parameters were monitored, but no significant differences were found between the DBCP-exposed animals and the controls. Semen was collected and evaluated during the exposure and during a 32 to 38 week recovery period to assess sperm motility, viability, and count. The average sperm count of the rabbits exposed to the 10-ppm concentration was significantly less than that of the controls after 7 weeks of exposure, and remained decreased for the duration of the exposure period and through week 42 of postexposure. At 1 ppm DBCP, sperm counts were significantly reduced compared with controls from weeks 11 to 13 of exposure. At 0.1 ppm, sperm counts were sporadically lower than control values although this was statistically significant only once, during exposure week 12. The percentage of live sperm in the semen of the rabbits exposed to 10 ppm DBCP was also significantly decreased compared with control values during weeks 8 to 26. Rabbits exposed to 1 ppm DBCP, but not those exposed to 0.1 ppm, exhibited significant decreases in the percentage of live sperm during weeks 6, 12 and 13. From the 8th week of exposure onward, the rabbits exposed to 10 ppm DBCP had a marked decrease in the percentage of progressively motile sperm. No consistent statistically significant decreases in this parameter were noted in the two lower exposure groups. Abnormal spermatozoa within the seminiferous tubules of 3 to 4 rabbits from each exposure group were counted; the percentage of abnormal sperm at 14 weeks was 5% for controls, 10% for animals exposed to 0.1 ppm DBCP and 18% for animals exposed to 1 ppm DBCP. To assess the effects of DBCP on fertility, exposed male rabbits were mated to unexposed female rabbits at weeks 14 and 41 of the study. DBCP did not affect the libido of the exposed male rabbits during week 14 based on the percentage of males (78-100%) that copulated with unexposed females. However, the five males exposed to 10 ppm DBCP were infertile since none of the females became pregnant. The mean number of implantations/litter in the 1 ppm group was significantly less than that of the control group. During week 41 (27 weeks post-exposure), all rabbits exposed to 0.1 and 1 ppm DBCP produced normal litters, and 2 of the 5 males exposed to 10 ppm regained fertility (i.e., increased sperm count) and produced normal litters. The follicle stimulating hormone (FSH) serum levels were also significantly elevated at 14 weeks in the males exposed to 1 ppm DBCP and at 46 weeks in the males exposed to 10 ppm DBCP. Increased FSH serum levels were consistent with a marked decrease in sperm count, whereas serum levels of testosterone were unchanged. The only gross lesion observed under macroscopic examination was the small size of the testes for rabbits exposed to 1 and 10 ppm DBCP. No gross lesions were observed in either the lungs or upper respiratory tract, and micropathology was not performed. Other histopathologic examination revealed changes in the reproductive system. These effects included atrophy of the testes, epididymides, and accessory sex glands including the prostate. The testes weight was significantly decreased to 50% of control values (week 14) in the group exposed to 1 ppm and to 75% of control values (week 8) in the group exposed to 10 ppm. Severe testicular atrophy was characterized by nearly complete or complete loss of spermatogenic elements in nearly all seminiferous tubules. Following the recovery period, tubular regeneration was observed in testes of some rabbits exposed to 10 ppm DBCP; 3 of 5 rabbits had regeneration such that 25% of the seminiferous tubules appeared normal. At the 1 ppm exposure, recovery was nearly complete in some rabbits although no incidences were given. Testes of rabbits exposed to 0.1 ppm DBCP appeared normal. Thus, rabbits exposed to 0.1 ppm DBCP showed no major treatment-related changes, and this level is designated as a no effect level. The NOAEL(HEC) is 0.17 mg/cu.m and the LOAEL(HEC) is 1.7 mg/cu.m. The respiratory tracts were not histologically examined in this study. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- An uncertainty factor of 10 is used for the protection of sensitive human subpopulations. A factor of 3 is used for interspecies extrapolation, as the concentration was dosimetrically adjusted to humans. A full factor of 10 is applied for the use of a subchronic study to reflect the marginal NOAEL in the principal study, as the minor testicular effects seen at the NOAEL were consistent with the effects seen at the higher LOAEL in this and other investigations. A study of chronic duration could result in these minor effects progressing into more delineated adverse effects. A factor of 3 is used for data base deficiency because of the lack of a multigenerational reproductive study, and inhlation development toxicity studies. The total uncertainty factor is therefore 1000. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Whereas a number of occupational studies on exposure to DBCP demonstrate this compound to be a potent testicular toxicant in humans, none of these occupational studies to date have evaluated the possible respiratory tract effects of DBCP exposure. This is especially disturbing when the inhalation studies conducted by NTP (1982) established the efficacy of this compound to produce lesions and tumors in the nasal cavity of both rats and mice; Sax (1989) lists this compound as both an eye and skin irritant. Little reliable exposure data are available from any of these studies. Also, most are confounded as they have been conducted in pesticide manufacturing plants where workers are co-exposed to a number of other chemicals. Limited followup studies of effected worker populations indicate that paternal exposure to DBCP sufficient to produce oligospermia or azoospermia did not detectably increase the rate of congenital malformations or impair the health status of offspring conceived during or after DBCP exposure. DBCP is, however, a potential mutagen capable of inducing a dominant lethal effect in mice (Teramoto et al., 1980). A cross-sectional study of 23 male workers at a DBCP production facility showed a 79% incidence (18 of 23) of azoospermia and oligospermia (Potashnik et al., 1979). No estimates of DBCP concentrations were given although exposure hours were presented. The exposure hours reported for a subgroup of 12 of these men diagnosed as azoospermic (sperm count = 0) ranged from 100 to 6726 hours. For another subgroup of six men diagnosed as oligospermic (designated as less than 10 million sperm/mL) the reported exposure hours ranged from 34 to 95 hours. The remaining 5 men had normal sperm counts and exposure hours ranging from 10 to 60. The azoospermic men had elevated FSH, but normal LH and testosterone levels. Testicular biopsy showed atrophy of seminiferous epithelium and tubules lined by Sertoli cells. In a 4-year followup study on 17 of these effected workers (plus three others not in the original study group), sperm count recovered in 4 of the 13 initially azoospermic men and 5 of the 7 oligospermic men (Potashnik, 1983). There was no improvement in the sperm count of the remaining 11 men who had prolonged exposure to DBCP. In another followup study (8-year) on 15 of the same group of effected workers, perinatal outcome as measured by birth defects, prematurity, mortality, or spontaneous abortions was not associated with paternal exposure to DBCP (Potashnik and Yanai-Inbar, 1987). In another subgroup of 11 of these effected workers, the rate of birth or health defects in their families following exposure was not different from that of a group of children from the same families conceived during the pre-exposure period (Potashnik and Phillip, 1988). In contrast, Kharrazi et al. (1980) report a statistically significant increase in the percentage of spontaneous abortions in wives of men working in Israeli banana plantations and in direct contact with DBCP. Levels of DBCP exposure were not given although the extent of exposure ranged from 1 season to 20 consecutive seasons. Sperm levels were not measured in this study, and there may have been selection bias among the participants as only 62 of 102 possible participants were interviewed for the study. In a limited cross-sectional study, 11 of 25 men working in a DBCP-formulating plant were found to be azoospermic or oligospermic (designated as less than 1 million sperm/mL ejaculate) and had elevated serum levels of FSH and LH (Whorton et al., 1977). The average exposure of the 11 men with a very low sperm count was 8 years. DBCP levels were purported to have been measured early in 1977 with personal air-sampling devices and indicated an 8 hour average concentration of 0.4 ppm (3.9 mg/cu.m), although no further specifics were available. Testicular biopsy, performed in 10 of these 25 men by Biava et al. (1978) showed that the diminution of spermatogenesis was correlated with duration of exposure to DBCP. Men with 10-year exposures had ejaculate without sperm and seminiferous tubules devoid of germ cells. Exposure for 1 to 3 years produced marked diminution of sperm formation and spermatogenic activity limited to a few segments of the tubules. Spermatogenic activity in men exposed for less than a year was classified as normal. A followup study in a subgroup of these same workers conducted 7 years after the initial evaluation showed that 2 of 8 workers that were originally classified as azoospermic produced some sperm during the followup, although only one had normal sperm production (Eaton et al., 1986). These results suggest that damage to germinal tissue by DBCP exposure sufficient to produce sterility is permanent. Although the exposure is poorly characterized, 3.9 mg/cu.m DBCP appears to be a frank-effect-level (FEL) in humans based on cases of azoospermia. Laboratory animal studies via other routes confirm the testicular, respiratory, and adrenal effects of DBCP. Studies with other species indicate the rabbit to be the most sensitive test species for testicular effects (Pease et al., 1991). The drinking water studies of Foote et al. (1986a,b) in rabbits were carefully and thoroughly executed to elucidate several aspects of DBCP on male reproductive function. In the 1986a study, dose-related decreases in the proportion of abnormal sperm as well as a biochemical indicator of impaired spermatogenesis (elevated FSH levels) were documented. The 1986b study demonstrated dose-related quantitative testicular histology including effects on testicular weight, alterations in seminiferous tubular diameter and a marked decrease of all germ cell types. Sprague-Dawley rats (30/sex/group) were exposed to 0, 0.1, 1 or 10 ppm (0, 0.97, 9.7, or 97 mg/cu.m) DBCP vapor, 6 hours/day, 5 days/week (duration adjusted to 0, 0.17, 1.7 or 17 mg/cu.m), for 14 weeks, followed by a 32-week recovery period (Rao et al., 1983) for a total of 46 weeks. Body weight and clinical examinations were made throughout the study. At the 14-week sacrifice, absolute and relative testes and epididymides weights were significantly decreased compared with controls only in the group exposed to 10 ppm DBCP. At the 46-week sacrifice, only the relative testes weight in the males exposed to 10 ppm was significantly lower than controls. No significant differences were seen in organ weights of exposed female rats compared with their controls. There were no treatment-related gross lesions observed in animals after 4 weeks of exposure. At the 14-week sacrifice, histopathological changes occurred in testes (decreased size and dark color; decreased spermatogenesis in individual seminiferous tubules, lack of germinal cells in 5/5 males) and in the adrenal gland (foci of altered cells in cortex in 3/5 males and 3/5 females) of the animals exposed to 10 ppm DBCP. At the 46-week terminal sacrifice, testicular atrophy was observed in a concentration-related manner in all male groups (12/18 at 10 ppm, 5/20 at 1 ppm, 3/19 at 0.1 ppm) including controls (2/17). Adrenal cortical hyperplasia was noted in both sexes at the 10 ppm concentration (32/35) and in the females at the terminal kill at the 1 ppm concentration (7/19). Ovarian cysts were observed in females at the terminal sacrifice at the highest concentration (7/17). Another concentration-related effect observed only in the female animals at terminal (46 week) sacrifice was cortical hematocyst formation in 1 of 20 animals exposed to 0.1 ppm, in 4 of 19 animals exposed to 1 ppm, and in 16 of 17 animals exposed to 10 ppm. Mineralized deposits occurred in the cerebrum of the brain of both sexes (15/18 males and 6/17 females) in the high exposure animals at the terminal sacrifice. Although significance was not reported, DBCP markedly effected the animals exposed to 10 ppm and slightly effected the testes and the adrenals of the animals exposed to 1 ppm. Therefore, a mild LOAEL of 1 ppm DBCP (HEC = 1.73 mg/cu.m), based on testicular and adrenal effects, was determined from this subchronic study. The respiratory tract was not examined histopathologically in this study. To assess fertility in male rats in this study (Rao et al., 1983), 20 males per exposure group were mated with unexposed females during weeks 2, 4, 6, 10, 12, 14, 16, 20, 24, 28, and 42. The percentage of males that impregnated at least one female was at least 85% for all the groups; no difference was seen between exposed and control males. In the group exposed to 10 ppm DBCP, a statistically significant increase (p<0.05) in post-implantation loss was observed during the fourth week of exposure and remained high through the remainder of the exposure period; this finding appears to be a treatment-related dominant lethal effect. By the tenth week of recovery, the average number of resorptions in the 10-ppm group was similar to that of the controls. No anomalies were observed in fetuses sired by exposed males during week 41 of the study. To assess fertility in exposed female rats, 20 exposed females per group were mated with unexposed males for a 5-day period during weeks 14, 18 and 20. Fertility of the exposed female rats was not significantly different from that of the controls except for a higher incidence of 10-ppm dams having litters of 4 or fewer pups. There were no significant differences between control and exposure groups and no major gross alterations in the pups. The inhalation carcinogenesis bioassay conducted by NTP (1982) comprises four different studies involving rats and mice. These studies establish DBCP as a carcinogen, with high incidences of tumors appearing in the nasal cavity and on the tongues of rats and in the nasal cavity and lungs of mice. Focal hyperplasia in the nasal cavity was apparent in both species at the lower of the two exposure concentrations but may have been obscured by tumors at the higher concentration. Hyperplasia lower in the respiratory tract was also observed but at a less frequent incidence. Progression of these lesions, either into the lower respiratory tract or onto cancer, is implied but not proven by these observations. Consequently, HECs for respiratory effects in these studies are given for both extrathoracic (ET) and total pulmonary (TOT) surface areas. Though several HECs for effects in the ET area are as low as the proposed NOAEL(HEC), the RfC is based on testicular effects because of the human correlate and the confounding of nasal cavity lesions with cancerous lesions in the same anatomical area. In a chronic carcinogenesis bioassay, F344 rats (50/sex/group) were exposed to 0, 0.6 or 3 ppm (0, 5.8 or 29 mg/cu.m) DBCP vapors, 6 hours/day, 5 days/week (duration adjusted to 0, 1.04 or 5.2 mg/cu.m). Results from this study are reported both in NTP (1982) and in Reznik et al. (1980b). The low-exposed rats were exposed for 103 weeks, and the high-exposed rats were exposed for 84 weeks due to excessive mortality. Body weights and clinical signs were recorded. Gross and microscopic examinations were performed on all major tissues including the testes and the nasal cavity where step cuts were made from the nostril to the cranium (the number of sections was not specified). A concentration-related respiratory effect observed in the male rats was focal hyperplasia of the nasal cavity in low-exposed and high-exposed (31/50 and 1/49) animals, respectively, that was not accompanied by an increased incidence in hyperplasia in either the bronchioles or the alveolar epithelium. In the female rats, the incidences of nasal cavity abscesses in the low- and high-exposed animals was 5/50 and 12/50, respectively, and 1/50 in the controls. Focal hyperplasia of the nasal cavity was noted in 24/50 of the low-exposure animals and in 23/50 of the high-exposure animals. This nasal cavity hyperplasia was not accompanied by increased incidences of hyperplasia in either the bronchioles or the alveolar epithelium. It should be noted that the decrease in focal hyperplasia of the nasal cavity of both male and female rats at the highest exposure level was concomitant with an increase in neoplastic lesions at this exposure. The nasal cavity of the high-exposed females also showed chronic inflammation (6/50), hyperkeratosis (11/50), and squamous metaplasia (15/50). Other systemic effects in the high-exposed female rats include hyperkeratosis of the esophagus (22/49), stomach hyperkeratosis (15/48) and acanthosis (12/48), toxic nephropathy (46/49), and necrosis of cerebrum (8/49). Pigmentation of the spleen occurred in 10/50, 28/50, and 34/48 female rats in the 0-, 0.6- and 3-ppm DBCP groups, respectively. Degeneration of adrenal cortex occurred in 19/50 and 13/48 of low- and high-exposed females compared with 4/50 in the controls. The incidence of pathology of the testes was inversely related to the concentration, hyperplasia of interstitial cells occurring in 41/50 controls and in 18/50 of low- and 6/48 high-exposed animals. Likewise, testicular degeneration occurred in 8/50 low-exposed animals, but only in 4/48 high-exposed animals. Other systemic effects in the high-exposed males were splenic pigmentation (13/49) and atrophy (8/49), hyperkeratosis of esophagus (18/49), and toxic nephropathy (49/49). A LOAEL of 0.6 ppm was identified based on the splenic, and adrenal gland effects; LOAEL(HEC) = 1.04 mg/cu.m. The concentration of 0.6 ppm is also designated as a LOAEL for respiratory effects; for the total pulmonary area, LOAEL(HEC) = 2.3 mg/cu.m and for the extrathoracic area, LOAEL:(HEC) = 0.19 mg/cu.m. B6C3F1 mice (50/sex/group) were exposed to 0, 0.6, and 3 ppm (0, 5.8 and 29 mg/cu.m) DBCP vapors, 6 hours/day, 5 days/week (duration adjusted to 0, 1.04 and 5.2 mg/cu.m). Results from this study are reported both in NTP (1982) and in Reznik et al. (1980a). The low-exposed female mice were exposed for 103 weeks and the low-exposed male mice and high-exposed animals were exposed for only 76 weeks due to excessive mortality. Body weights and clinical signs were recorded. Gross and microscopic examinations were performed on all major tissues including the testes and the nasal cavity where step cuts were made from the nostril to the cranium (number of sections not specified). Mean body weight gain was depressed by 17-28% in the high-exposed males after week 60 and by 25% in high-exposed females after week 76. The mortality in high-exposed females was significantly higher (p<0.001) than that of the other groups; 43 of 50 died during weeks 51 through 74, while mortality in the high-exposed males was comparable with other groups. Concentration-dependent respiratory effects observed in the male mice were focal hyperplasia of the nasal cavity in low-exposed and high-exposed (2/42 and 12/48) animals, respectively, as well as focal hyperplasia in the bronchioles (7/40 and 29/45) and hyperplasia of the alveolar epithelium (2/40 and 7/45). None of these effects were noted in any control animal. The high-exposed males also had a high incidence of suppurative inflammation in the nasal cavity (21/48) and focal hyperplasia of bronchi (14/45). Splenic atrophy (16/45), toxic nephropathy (9/46), and leukocytosis of lungs (4/45) were also evident in high-exposed males. There was also a high incidence of hyperkeratosis (10/41 and 17/44) and acanthosis (6/41 and 11/44) in the stomach, kidney inflammation (9/42 and 7/46), and necrosis of prepuce (7/42 and 3/48) in the 0.6 and 3 ppm groups compared with very low or no incidences in the controls. No concentration-dependent effects were noted in the testes, seminal vesicles, or epididymides. In the female mice, the incidences in the low- and high-exposed animals of suppurative inflammation was 5/50 and 13/50; of focal hyperplasia of the nasal cavity, 17/50 and 3/50; of hyperplasia of bronchioles, 5/49 and 11/47; of hyperplasia of alveolar epithelium, 5/49 and 11/47. It should be noted that the decrease in focal hyperplasia of the nasal cavity of both male and female mice at the highest exposure level was concomitant with an increase in neoplastic lesions at this exposure. A greater incidence of splenic atrophy (19/43) and endometrium cyst (11/45) occurred in the high-exposed animals. A high incidence of hyperkeratosis (20/48 and 24/46) and acanthosis (12/48 and 18/46) of the stomach was evident in both exposure groups. A LOAEL of 0.6 ppm DBCP, due to gastrointestinal and kidney effects (HEC = 1.04 mg/cu.m) was determined for this chronic study. The concentration of 0.6 ppm is also designated a LOAEL for respiratory effects; for the total pulmonary area, LOAEL(HEC) = 6.7 mg/cu.m and for the extrathoracic area, LOAEL(HEC) = 0.19 mg/cu.m. In the rat subchronic study (NTP, 1982; also reported in Reznik et al., 1980c), Fischer 344 rats (5/sex/group) inhaled 0 (filtered room air), 1, 5 or 25 ppm (0, 9.66, 48.3 or 241.6 mg/cu.m) DBCP (96% purity), 6 hours/day, 5 days/week (duration adjusted to 1.7, 8.6 or 43 mg/cu.m), for 13 weeks. Both sexes of rats in the highest group exhibited blood stains around the nasal orifice throughout the 13-week period. Two females died during weeks 10 and 11 of exposure while two females and one male were sacrificed during weeks 10, 11, and 12 due to moribund conditions. There was a 60% decrease in body weight compared with controls, and severe hair loss in the rats exposed to 25 ppm DBCP. The high exposure animals also had inflammation and severe necrosis of the respiratory and olfactory epithelium in the dorsal part of the nasal cavity. The incidence of these lesions is reported to be concentration-related and is reported in the narrative section of the report only. Necrosis of the tracheal epithelium was found in 7 of the 10 rats exposed to 25 ppm DBCP. In the lung, squamous metaplasia of the bronchial epithelium was present along with hyperplasia and partial regeneration of the bronchial and bronchiolar epithelium (data not presented). Atrophy with hypospermatogenesis was revealed in the testes of five male rats exposed to 25 ppm DBCP. With 1 and 5 ppm exposure levels, focal hepatic necrosis, hepatocytic hydropic changes, cytomegaly, and toxic tubular nephrosis were reported. A LOAEL of 1 ppm DBCP (HEC = 1.73 mg/cu.m) for liver and kidney alterations was determined. A LOAEL of 1 ppm is assumed for respiratory effects; for the total pulmonary area, LOAEL(HEC) = 2.23 mg/cu.m and for the extrathoracic area, LOAEL(HEC) = 0.19 mg/cu.m. In the subchronic study in mice (NTP,1982; also reported in Reznik et al., 1980c) B6C3F1 mice (10/sex/group) were exposed to 0, 1, 5 or 25 ppm (9.66, 48.3 or 241.6 mg/cu.m) DBCP, 6 hours/day, 5 days/week (duration adjusted to 1.7, 8.6 or 43 mg/cu.m), for 13 weeks. Four of the males exposed to 25 ppm DBCP died before the end of the exposure period. Weight loss was 69% in males and 19% in females of the high-exposed group. Hydropic changes of the hepatocytes and nephrosis in the male mice exposed to 25 ppm and necrosis of the bronchiolar epithelium in the animals exposed to 25 ppm were reported. Regeneration and hyperplasia of the bronchiolar epithelium and megalocytic epithelial cells were found in all mice exposed to 5 ppm. Lesions in the epithelium of the nasal cavity (i.e., inflammation, necrosis, proliferative lesions) were also observed in mice exposed to 25 ppm DBCP. No data are presented for these effects; they are described in the narrative section of the report. Occurrence of lesions in other organs (e.g., testes, kidneys, or liver) are not discussed. A systemic NOAEL(HEC) for weight loss would be HEC = 1.73 mg/cu.m. A NOAEL of 1 ppm was assumed for respiratory effects; for the total pulmonary area, NOAEL(HEC) = 7.5 mg/cu.m and for the extrathoracic area, LOAEL(HEC) = 0.21 mg/cu.m. Torkelson et al. (1961) conducted a series of inhalation exposures with DBCP in several species. In single exposures to rats at concentrations of 60 ppm (580 mg/cu.m) and higher, ocular and respiratory irritation was apparent. In preliminary range-finding studies, the authors reported mortality in rats subjected to a total of 15 7-hour exposures to 386 mg/cu.m (13/15 rats died), 48 such exposures to 193 mg/cu.m (10/15 died), and 50 such exposures at 97 mg/cu.m (2/15 died). Animals in the latter exposure group were described as having dulling of the corneas; weight loss; and hair loss, as well as gross lesions in the lungs, intestinal mucosa, kidneys, and testes. In a more extensive experiment, rats (20/sex), guinea pigs (10/sex), rabbits (3/sex), and monkeys (2 females) inhaled 12 ppm DBCP (116 mg/cu.m), 7 hours/day, 5 days/week, for a period of 70 to 92 days. Mortality was 40 to 50% in rats, and was attributed to lung infections. Much of the text is concerned with alterations in the genitalia, with severe atrophy and degeneration of the testes described in all species. Effects in rats included degenerative changes in the seminiferous tubules, increased Sertoli cells, reduced sperm count, and abnormal sperm. The respiratory tract was apparently not examined. Although no inhalation developmental studies were located for this compound, Ruddick and Newsome (1979) performed a developmental study in which Wistar rats were gavaged with DBCP in corn oil. Pregnant rats (15/group) were randomized into four groups and gavaged doses of either 0 (vehicle), 12.5, 25, or 50 mg/kg of 97.5% DBCP on days 6 through 15 of gestation. Necropsies were carried out on day 22. DBCP was not teratogenic. No skeletal or visceral anomalies of significance were observed above those noted for control fetuses (data not shown). Mean fetal weights were significantly decreased in the highest dose group. Maternal weight gain was significantly decreased in the two highest dosed groups. The dose of 12.5 mg/kg was considered a NOAEL for maternal effects and 25 mg/kg was considered a NOAEL for fetal effects. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium The subchronic inhalation study in rabbits of Rao et al (1982) is given a medium confidence rating due to the lack of reporting respiratory effects. The database is given medium confidence. Although chronic studies in 2 different species exist, the available reproductive studies were limited and there is uncertainty about occurrence of respiratory tract effects relative to testicular effects. A medium confidence in the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1988 Agency Work Group Review -- 08/15/1991 Verification Date -- 08/15/1991 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2-Dibromo-3-chloropropane (DBCP) CASRN -- 96-12-8 NOCA: Not available at this time. ============================================================================ UDSO: 199110 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2-Dibromo-3-chloropropane (DBCP) CASRN -- 96-12-8 Last Revised -- 10/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Biava, C., E. Smuckler and D. Whorton. 1978. The testicular morphology of individuals exposed to dibromochloropropane. Exp. Mol. Pathol. 29(3): 448-458. Eaton, M., M. Schenker, M. Whorton, S. Samuels, C. Perkins and J. Overstreet. 1986. Seven-year follow-up of workers exposed to 1,2-dibromo-3-chloropropane. J. Occup. Med. 28(11): 1145-1150. Foote, R.H., E.C. Schermerhorn and M.E. Simkin. 1986a. Measurement of semen quality, fertility, and reproductive hormones to assess dibromochloropropane effects in live rabbits. Fund. Appl. Toxicol. 6: 628-637. Foote, R.H., W.E. Berndtson and T.R. Rounsaville. 1986b. Use of quantitative testicular histology to assess the effect of dibromochloropropane on reproduction in rabbits. Fund. Appl. Toxicol. 6: 638-647. Kharrazi, M., G. Potashnik and J.R. Goldsmith. 1980. Reproductive effects of dibromochloropropane. Isr. J. Med. Sci. 16(5): 403-406. NTP (National Toxicology Program). 1982. Carcinogenesis bioassay of 1,2-dibromo-3-chloropropane (CAS No. 96-12-8) in F344 rats and B6C3F1 mice (inhalation study). Tech. Rep. Ser. No. 206. Pub. No. 82-1762. 188 p. Pease, W., J. Vandenburg and K. Hooper. 1991. Comparing alternative approaches to establishing regulatory levels for reproductive toxicants: DBCP as a case study. Environ. Health Perspect. 91: 141-155. Potashnik, G. 1983. A four-year assessment of workers with dibromochloropropane-induced testicular dysfunction. Andrologia. 15(2): 164-170. Potashnik, G. and M. Phillip. 1988. Lack of birth defects among offspring conceived during or after paternal exposure to dibromochloropropane (DBCP). Andrologica. 20(1): 90-94. Potashnik, G. and I. Yanai-Inbar. 1987. Dibromochloropropane (DBCP): An 8-year reevaluation of testicular function and reproductive performance. Fertil. Steril. 47(2): 317-323. Potashnik, G., I. Yanai-Inbar, M. Sacks and R. Israeli. 1979. Effect of dibromochloropropane on human testicular function. Isr. J. Med. Sci. 15(5): 438-442. Rao, K.S., J.D. Burek, F. Murray, et al. 1982. Toxicologic and reproductive effects of inhaled 1,2-dibromo-3-chloropropane in male rabbits. Fund. Appl. Toxicol. 2(5): 241-251. Rao, K.S., J. Burek, F. Murray, et al. 1983. Toxicologic and reproductive effects of inhaled 1,2-dibromo-3-chloropropane in rats. Fund. Appl. Toxicol. 3(2): 104-110. Reznik, G., S. Stinson and J. Ward. 1980a. Lung tumors induced by chronic inhalation of 1,2-dibromo-3-chloropropane in B6C3F1 mice. Cancer Lett. 10(4): 339-342. Reznik, G., H. Reznik-Schuller, J.M. Ward, and S.F. Stinson. 1980b. Morphology of nasal-cavity tumours in rats after chronic inhalation of 1,2-dibromo-3-chloropropane. Br. J. Cancer. 42(5): 772-781. Reznik, G., S. Stinson and J. Ward. 1980c. Respiratory pathology in rats and mice after inhalation of 1,2-dibromo-3-chloropropane or 1,2-dibromoethane for 13 weeks. Arch. Toxicol. 46(3-4): 233-240. Ruddick, J.A. and W.H. Newsome. 1979. A teratogenicity and tissue distribution study on dibromochloropropane in the rat. Bull. Environ. Contam. Toxicol. 21: 483-487. Sax, N.I. 1987. Dangerous Properties of Industrial Materials. Van Nostrand Reinhold, Inc., New York. Teramoto, S., R. Saito, H. Aoyama and Y. Shirasu. 1890. Dominant lethal mutation induced in male rats by 1,2-dibromo-3-chloropropane (DBCP). Mutat. Res. 77: 71-78. Torkelson, T.R., S.E. Sadek, V.K. Rowe, et al. 1961. Toxicologic investigations of 1,2-dibromo-3-chloropropane. Toxicol. Appl. Pharmacol. 3: 545-559. U.S. EPA. 1988. Drinking Water Criteria Document for 1,2-dibromochloropropane (DBCP). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA 600/X-84/209-2. Whorton, D., R. Krauss, S. Marshall and T. Milby. 1977. Infertility in male pesticide workers. Lancet. 2(8051): 1259-1261. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2-Dibromo-3-chloropropane (DBCP) CASRN -- 96-12-8 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1991 II. Carcinogenicity assessment now under review 09/01/1991 I.B. Inhalation RfC now under review 10/01/1991 I.B. Inhalation RfC now on-line 10/01/1991 VI. Bibliography on-line 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 424 of 1119 in IRIS (through 2003/06) AN: 415 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199101 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1-Chlorobutane- SY: 109-69-3; BUTANE,-1-CHLORO-; AI3-15309-; BUTYL-CHLORIDE-; CHLORURE DE BUTYLE [FRENCH]; HSDB-4167-; N-BUTYL-CHLORIDE-; N-PROPYLCARBINYL-CHLORIDE-; NCI-C06155- RN: 109-69-3 HSN: 4167 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1-Chlorobutane CASRN -- 109-69-3 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1-Chlorobutane CASRN -- 109-69-3 NORC: Not available at this time. ============================================================================ UDCA: 199101 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1-Chlorobutane CASRN -- 109-69-3 Last Revised -- 01/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- Based on no human carcinogenicity data and inadequate animal data. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. The National Toxicology Program (NTP, 1986) conducted a 2-year toxicology and carcinogenesis study of 1-chlorobutane in male and female B6C3F1 mice and F-344/N rats. Groups of 50 animals/sex/species were gavaged with 1-chlorobutane (99.5% pure) in corn oil at 0, 500, or 1000 mg/kg/day (mice) or 0, 60, or 120 mg/kg/day (rats), 5 days/week for 103 weeks. Because of high mortality, all mice dosed at 1000 mg/kg/day were sacrificed in the 45th week and a second study with additional groups of 50 mice/sex was started at 0 and 250 mg/kg/day. In the mouse studies, survival (54-64%) was comparable for vehicle controls and 500-mg/kg/day groups in the first study, and also for vehicle controls and 250-mg/kg/day groups in the second study (50-72%) (NTP, 1986). Only the 1000-mg/kg/day male mice showed lower mean body weights compared with vehicle controls after week 36. An increased incidence of alveolar/ bronchiolar adenomas or carcinomas (combined) (as evaluated by the Incidental Tumor Test) was observed in females in the 500 mg/kg group (9/50) compared with its vehicle controls (3/50), and no effect was seen in the 250 mg/kg group (8/50 treated vs. 6/50 vehicle control). The incidences of these tumors were not statistically significantly elevated (Incidental Tumor Test) when treated groups were compared with pooled vehicle control groups (9/100) from the first and second part of the study. In addition, the lack of hyperplasia in females and the negative trend seen in males suggest that these marginal effects were not treatment-related. A statistically significant increased incidence of hepatocellular adenomas or carcinomas (combined) was observed in females in the 500 mg/kg group (8/50 vs. 3/50) but not in the 250 mg/kg group (9/50 vs. 7/50) when compared by Incidental Tumor Tests. When compared by Incidental Tumor Tests with pooled vehicle controls from the two studies, however, the incidence was not statistically significantly elevated. In the first study, there was an increased incidence (not statistically significant) of hemangiosarcomas in males (1/50, control; 3/50, low-dose; 4/50, high-dose), but such an increase was not observed in males in the second study (4/50 control vs. 2/50 at 250 mg/kg); nor when treated animals were compared with pooled vehicle controls. Since the incidences of hepatocellular adenomas and carcinomas in females were highly variable between the vehicle controls in the two studies (2-16%) and there were no dose-related effects in male mice, these tumors in female mice were not considered treatment-related. The hemangiosarcomas in male mice were also not considered to be compound-related, as the incidence in the vehicle controls was highly variable (2-8%) and the incidence in the first study was lower than the NTP historical incidence which is 4%. In the rat study (NTP, 1986), survival was significantly reduced in high-dose males (17/50 treated vs. 50/50 vehicle control) and females (11/50 vs. 35/50); however, the authors felt survival throughout the study was adequate for proper analysis of the carcinogenic potential of 1-chlorobutane. Mean body weight of treated and control rats were comparable throughout the study. Pheochromocytomas of the adrenal gland were significantly increased in the low-dose females (1/50, vehicle control; 6/50, low-dose; and 1/49, high-dose). The incidence of medullary hyperplasia, an expected preneoplastic observation associated with these tumors (observed in 3/50 vehicle controls; 7/50 low-dose females; and 4/49 high-dose females) did not suggest a neoplastic phenomenon in progress. The incidence of pheochromocytomas was low, not dose-related, and not seen in male rats. Furthermore, pheochromocytomas are late-developing tumors and they were not considered to be treatment related. Thus, NTP concluded that there was no evidence of carcinogenicity of 1-chlorobutane for male and female mice or male and female rats under the conditions of these studies. It was noted, however, that the chemical-induced mortality in high-dose rats suggest toxic levels were reached and reduce the sensitivity of the study for determining carcinogenicity. Poirier et al. (1975) gave groups of 10 male and 10 female strain A/Heston mice a total of 24 i.p. injections (3 injections/week) of 12.9, 32.4, or 65 mmol/kg (1194, 3000, or 6017 mg/kg) 1-chlorobutane in tricaprylin. Untreated and tricaprylin-treated mice were used as negative controls, and urethane-treated mice were used as positive controls. Mice were sacrificed 24 weeks after the first injection. Survival at termination of the study was >90%. No statistically significant increase in the average number of lung tumors per mouse occurred in mice given 1-chlorobutane. This assay scores only lung tumors and is considered to be a short-term in vivo screening test. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY When tested in the Salmonella/microsomal assay, 1-chlorobutane was nonmutagenic in strains TA98, TA100, TA1535, and TA1537 with and without the addition of hepatic homogenates (Eder et al., 1980, 1982a,b; Barber et al., 1981; Barber and Donish, 1982; Zeiger, 1987; Zeiger et al., 1987; NTP, 1986). In contrast, Simmon (1981) reported positive results in strain TA100 in the absence of hepatic homogenates; however, no control data were provided. Negative results were obtained in a chromosomal aberration test in rat bone marrow cells (Rudnev et al., 1979) and in a DNA damage assay in Escherichia coli (Fluck et al., 1976). 1-Chlorobutane was mutagenic in mouse lymphoma L5178Y assay in the absence of Aroclor-induced male rat liver S9 and was not tested in the presence of rat liver S9 (NTP, 1986). Negative results were obtained in chromosomal aberration tests and sister chromatid exchanges in Chinese hamster ovary cells with and without Aroclor-induced Sprague-Dawley rat liver S9 (NTP, 1986). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1988 The 1988 Health and Environmental Effects Document for Monochlorobutanes has received Agencey review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 09/07/1989 Verification Date -- 09/07/1989 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for 1-Chlorobutane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199004 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1-Chlorobutane CASRN -- 109-69-3 Last Revised -- 04/01/1990 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Barber, E.D. and W.H. Donish. 1982. An exposure system for quantitative measurements of the microbial mutagenicity of volatile liquids. Environ. Sci. Res. 25: 1-18. Barber, E.D., W.H. Donish and K.R. Mueller. 1981. A procedure for the quantitative measurement of the mutagenicity of volatile liquids in the Ames Salmonella typhimurium mammalian/microsome assay. Mutat. Res. 90(1): 31-34. Eder, E., T. Neudecker, D. Lutz and D. Henschler. 1980. Mutagenic potential of allyl and allylic compounds. Structure-activity relationship as determined by alkalating and direct in vitro mutagenic properties. Biochem. Pharmacol. 29: 993-998. Eder, E., D. Henschler and T. Neudecker. 1982a. Mutagenic properties of allylic and a,B-unsaturated compounds: Consideration of alkylating mechanisms. Xenobiotica. 12: 831-848. Eder, E., T. Neudecker, D. Lutz and D. Henschler. 1982b. Correlation of alkylating and mutagenic activities of allyl and allylic compounds: Standard alkylation test vs. kinetic investigation. Chem. Biol. Interact. 38: 303-315. Fluck, E.R., L.A. Poirier and H.W. Ruelius. 1976. Evaluation of a DNA polymerase-deficient mutant of E. coli for the rapid detection of carcinogens. Chem. Biol. Interact. 15: 219-231. NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of n-butyl chloride in F344/N rats and B6C3F1 mice (gavage studies). CAS No. 109-69-3. NTP-TR-312. 198 p. Poirier, L.A., G.D. Stoner and M.B. Shimkin. 1975. Bioassay of alkyl halides and nucleotide base analogs by pulmonary tumor response in strain A mice. Cancer Res. 35(6): 1411-1415. Rudnev, M.I., L.A. Tomashevskaya, G.I. Vinogradov, A.A. Kapustin, Z.I. Zholdakova and G.I. Leonskaya. 1979. Hygienic substantiation of the permissible concentration of benzyl and butyl chlorides in water. Gig. Sanit. 3: 11-15. (Rus.) Simmon, V.F. 1981. Applications of the Salmonella/microsome assay. In: Short-term Tests Chemical Carcinogens, H. Stich and R. San, Ed. Springer-Verlag, New York. p. 120-126. U.S. EPA. 1988. Health and Environmental Effects Document for Monochlorobutanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. Zeiger, E. 1987. Carcinogenicity of mutagens: Predictive capability of the Salmonella mutagenesis assay for rodent carcinogenicity. Cancer Res. 47(5): 1287-1296. Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, K. Mortelmans and W. Speck. 1987. Salmonella mutagenicity tests: III. Results from the testing of 255 chemicals. Environ. Mutagen. 9(9): 1-109. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1-Chlorobutane CASRN -- 109-69-3 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 04/01/1990 II. Carcinogen assessment on-line 04/01/1990 VI. Bibliography on-line 08/01/1990 II.A.3. Text edited 01/01/1991 II. Text edited 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 425 of 1119 in IRIS (through 2003/06) AN: 420 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199412 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Di(2-ethylhexyl)adipate SY: *HEXANEDIOIC-ACID-; 103-23-1; ADIPIC ACID, BIS(2-ETHYLHEXYL) ESTER; ADIPOL-2EH-; BEHA-; BIS(2-ETHYLHEXYL) ADIPATE; BIS-(2-ETHYLHEXYL)ESTER KYSELINY ADIPOVE (CZECH); BISOFLEX-DOA-; DEHA-; DI-2-ETHYLHEXYL-ADIPATE-; DIOCTYL-ADIPATE-; DOA-; EFFEMOLL-DOA-; EFFOMOLL-DOA-; ERGOPLAST-ADDO-; FLEXOL-A-26-; FLEXOL-PLASTICIZER-10-A-; FLEXOL-PLASTICIZER-A-26-; HEXANEDIOIC ACID, BIS(2-ETHYLHEXYL) ESTER (9CI); HEXANEDIOIC-ACID,-DIOCTYL-ESTER-; KEMESTER-5652-; KODAFLEX-DOA-; MOLLAN-S-; MONOPLEX-DOA-; NCI-C54386-; OCTYL-ADIPATE-; PLASTOMOLL-DOA-; PX-238-; REOMOL-DOA-; RUCOFLEX-PLASTICIZER-DOA-; SICOL-250-; STAFLEX-DOA-; TRUFLEX-DOA-; UNIFLEX-DOA-; VESTINOL-OA-; WICKENOL-158-; WITAMOL-320- RN: 103-23-1 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199207 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Di(2-ethylhexyl)adipate CASRN -- 103-23-1 Primary Synonym -- Hexanedioic acid Last Revised -- 07/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Changes in body weight NOAEL: 1800 ppm 300 1 6E-1 and liver weight (170 mg/kg/day) mg/kg/day increased liver weight of male and LOAEL: 12000 ppm female parents; (1080 mg/kg/day) reduced ossification and slightly dilated ureters in fetuses; reduced offspring weight gain, total litter weight, and litter size Rat Teratogenicity Feeding Study ICI, 1988a One-generation Rat Reproductive Study ICI, 1988b ---------------------------------------------------------------------------- *Conversion Factors: Doses were calculated based on actual body weight and food consumption. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) ICI (ICI Central Toxicology Laboratory). 1988a. Di-(2-ethylhexyl)adipate: Teratogenicity study in the rat. Report CTL/P/2119 (unpublished study). ICI (ICI Central Toxicology Laboratory). 1988b. Di-(2-ethylhexyl)adipate (DEHA) fertility study in rats. Report CTL/P/2229 (unpublished study). The oral RfD is based on two studies that used dietary administration of di(2-ethylhexyl)adipate (DEHA) to rats; one assessed the effects of DEHA on gestating females and their developing fetuses (ICI, 1988a) and the other study examined effects on fertility, reproductive outcome and gross and histological parameters in parents of both sexes (ICI, 1988b). In the developmental toxicity study, Wistar-derived pregnant rats (24/dose) were fed diets containing 0, 300, 1800 or 12,000 ppm DEHA (corresponding to doses of 0, 28, 170 or 1080 mg/kg/day) on gestational days 1-22 (ICI, 1988a). At the high dose, slight reductions in maternal body weight gain and food consumption were observed, and reduced ossification and kinked or dilated ureters were found in the fetuses. In a companion one-generation reproductive study (ICI, 1988b), groups of Wistar-derived rats (15 males/dose; 30 females/dose) were administered DEHA in their diets at the same levels (0, 28, 170, or 1080 mg/kg/day). After 10 weeks on the diet, the animals were mated to produce one-generation of offspring that was reared to day 36 post partum. Test diets were fed continuously throughout the study (approximately 18-19 weeks of exposure). No effects were seen on male or female fertility. However, at the highest dose, there was a reduction in the body weight gain of the dams during gestation; an increase in liver weight in both male and female parents; and reductions in offspring weight gain, total litter weight, and litter size. The NOAEL and LOAEL for this study were also 170 and 1080 mg/kg/day, respectively. Other studies that were considered include the NTP (1982) 2-year bioassays in rats and mice. In a 91-day range-finding feeding study, DEHA was administered to rats and mice of both sexes at 0, 1600, 3100, 6300, 12500, or 25000 ppm in feed, corresponding to doses of 0, 100, 200, 400, 700, or 1500 mg/kg/day for the rat and 0, 400, 700, 1300, 2800 or 7000 mg/kg/day for the mouse, based on food consumption and body weight data. Decreased body weight gain was observed in both species and sexes at the 2 highest doses (8-18% decrease in female and male rats, respectively; and 13-25% decrease in female and male mice, respectively). No gross or microscopic lesions were noted at any dose tested. The two highest doses, 12500 and 25000 ppm, corresponding to approximately 700 and 1500 mg/kg/day in the rat, and 2800 and 7000 mg/kg/day in the mouse, were then used in a 2-year feeding study. In the rat, survival was not adversely affected by treatment with DEHA. At 105-107 weeks, survival was 68%, 68%, and 80% for control, low-dose, and high-dose male rats, respectively, and 58%, 78%, and 88% for females. Both species and sexes showed a dose-related suppression of weight gain. Most non-neoplastic lesions were observations in single animals; some frequently observed lesions were not dose-related or were inversely dose-related. For example, the incidence of nephrosis was 45/49 (92%), 42/50 (84%), and 41/50 (82%) in male rats in control, low-dose, and high-dose groups, respectively, and 29/50 (58%), 31/50 (62%), and 20/50 (40%) in female rat groups. The LOAEL for mild depression of weight gain in rats was 1500 mg/kg/day and the NOAEL was 700 mg/kg/day. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 300 includes the standard uncertainty factor of 10 for interspecies and 10 intrahuman-variability and an additional uncertainty factor of 3 for data base deficiencies including the lack of a multi-generation reproductive study and the lack of data in species other than rodents. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) The 2-year NTP study was not used to calculate the RfD, because the sensitive effects on fetal development, reproductive outcome, and other parameters in the ICI (1988a,b) studies were seen at a lower concentration of DEHA. Singh et al. (1975) investigated dominant-lethal mutations by administering DEHA by single intraperitoneal injection to male Harlan/ICR albino Swiss mice (10/dose) (8-10 weeks old; 25-30 grams) at doses of 0, 0.45, 0.9, 4.6, or 9.2 g/kg body weight, followed by caging with 2 different female mice each week for 8 weeks. On day 15 of gestation, the pregnant mice were killed by an overdose of ether, and the uterine horns and ovaries were examined for corpora lutea, total implantations, preimplantation losses, early and late fetal deaths, and viable fetuses. DEHA was associated with a dose-related decrease in fertility (mean percentage of pregnancies: 82, 81, 76, 76, and 67, from control to high-dose group, respectively), and a dose-related increase in dominant-lethal mutations as measured by early fetal deaths (mean incidence of early fetal deaths per prepregnancy: 0.29, 0.39, 0.48, 0.74, and 0.96, from control to high-dose group, respectively). Both pre-meiotic and post-meiotic effects were inferred by the investigators. The lowest dose tested, 0.45 g/kg (450 mg/kg), appeared to be a LOAEL in this study. This study was not used as the basis for the RfD, because the single bolus intraperitoneal injection is less relevant to human exposure than is oral exposure. Singh et al. (1973) injected (i.p.) groups of 5 pregnant rats on days 5, 10, and 15 of gestation with DEHA at 1, 5, or 10 mL/kg (0.9, 4.6, or 9.2 g/kg). There was no increase in embryolethality, but reduced fetal weight was statistically significant at the two highest doses. One skeletal abnormality was reported at the low dose, but one skeletal abnormality was also found in the blunt-needle control group; the specific skeletal abnormalities were not described. The NOAEL in this study for "embryonic-fetal toxicity and teratogenic effects" was 0.9 g/kg (900 mg/kg). CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base --- Medium RfD -- Medium The level of confidence in the critical studies is medium. Results are obtained from a short-term (22-day exposure) developmental study (ICI, 1988a) and a companion one-generation (18-19 week exposure) reproductive study assessed an even broader spectrum of toxicological parameters (ICI, 1988b). However, a multi-generation reproductive study and a toxicity study in a second species are lacking. Thus, the data base can be considered medium to low. Confidence in the RfD can also be considered medium to low. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1992 The 1992 Drinking Water Criteria Document for Di-(2-ethylhexyl) adipate received extensive Agency and public review. Other EPA Documentation -- U.S. EPA, 1991 Agency Work Group Review -- 02/16/1989, 03/21/1989, 07/16/1991 Verification Date -- 07/16/1991 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Di(2-ethylhexyl)adipate CASRN -- 103-23-1 Primary Synonym -- Hexanedioic acid NORC: Not available at this time. ============================================================================ UDCA: 199412 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Di(2-ethylhexyl)adipate CASRN -- 103-23-1 Primary Synonym -- Hexanedioic acid Last Revised -- 12/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Based on an absence of human data and increased incidence of liver tumors in female mice. Except for a positive dominant lethal assay, there was no evidence of genotoxicity; this compound does, however, exhibit structural relationships to other nongenotoxic compounds classified as probable and possible human carcinogens. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. There was an increased incidence of a single type of tumor in female mice. In an NTP (1982) (see also Kluwe et al., 1985; Kluwe, 1986) bioassay 50 B6C3F1 mice/sex/dose were fed 0, 12,000 or 25,000 ppm di(2-ethylhexyl)adipate (DEHA) in their diet for 104 weeks and observed for 106 weeks. The two DEHA preparations used were 98.1 and 99.7% pure. The estimated doses for female mice were 0, 3222 and 8623 mg/kg/day in the control, low- and high-dose groups, respectively, and for male mice were 0, 2659 and 6447 mg/kg/day, respectively. An MTD was achieved in the high-dose group of both sexes. There was a significant dose-related decrease in the mean body weights of both dose groups in each sex. The survival rate in female mouse groups was 84, 78 and 73% in the control, low- and high-dose groups, respectively, and in the male groups 72, 64 and 82%, respectively. In females there was a statistically significant positive trend with dose for the hepatocellular carcinoma incidence; the incidences were 1/50, 14/50 and 12/49, for the control, low- and high-dose groups, respectively. The combined hepatocellular carcinoma or adenoma incidences also showed a statistically significant trend test; the incidences were 3/50, 19/50 and 18/49 in the control, low- and high-dose groups, respectively. Time-to-tumor analysis showed that the development time of carcinomas and adenomas in the dosed groups was significantly shorter (by pair-wise comparison test) than their development in the control group. In this laboratory the incidence of combined hepatocellular adenomas and carcinomas in the historical control was 31/397 (7.8%) for female mice of this strain. In male mice a statistically significant positive trend was seen in the incidences of hepatocellular adenomas and carcinomas combined. The incidences of hepatocellular adenomas were 6/50, 8/49 and 15/49 in the control, low- and high-dose groups, respectively, and the combined hepatocellular adenoma and carcinoma incidences were 13/50, 20/49 and 27/49 in the control, low- and high-dose groups, respectively. It should be noted that the combined incidence of hepatocellular adenomas and carcinomas of the high-dose group does not differ greatly from the male B6C3F1 historical control incidence (116/398) in this laboratory. Furthermore, the time-to-tumor analysis did not show significant differences between the control and dose groups in males. In a companion study, F344 rats (50/sex/dose) were fed 0, 12,000 or 25,000 ppm DEHA in a powdered diet for 103 weeks and observed for 106 or 107 weeks (NTP, 1982). (The two DEHA preparations used were 98.1 and 99.7% pure.) The estimated intake for female rats was 0, 860 and 1674 mg/kg/day in the control, low- and high-dose groups, respectively, and for male rats was 0, 697 and 1509 mg/kg/day in the control, low- and high-dose groups, respectively. Mean body weights in the high-dose groups of both sexes were lower than those of the respective control groups. The MTD appeared to be achieved in the high-dose groups. The survival rates in the female rat groups were 58, 78 and 88% in the control, low- and high-dose groups, respectively, and in male rat groups 68, 68 and 88% in the control, low- and high-dose groups, respectively. No differences attributable to DEHA administration, were observed in the incidences or types of tumors seen in this study. A statistically significant increase in interstitial cell tumors in the testes of high-dose male rats was discounted because incidences of this tumor type normally approach 100% in aging F344 males. Hodge et al. (1966) investigated the carcinogenicity of DEHA for mice, rats and dogs in a series of assays which proved to be of limited value. A single subcutaneous injection of trioctinonin (control) or 0.1 mg DEHA in trioctinonin was administered to 50 C3H/Anf mice/sex/group. No carcinogenic activity was attributed to the DEHA injections; a breast tumor (fibromyxoma) was, however, reported in one DEHA-dosed male. In a skin-painting study, 50 C3H/Anf mice/sex/group were treated once weekly with either 0.1 mg DEHA in 20 mL acetone or 10 mg DEHA in 50 mL of acetone (for maximum total doses of 8.8 and 920 mg in males and 9.8 and 1010 mg in females, respectively). No gross or microscopic evidence of application site tumors was observed in any of the groups. In an unpublished study reported by Hodge et al. (1966) unknown numbers of rats and dogs were fed DEHA. Rats were fed 0, 0.1, 0.5 or 2.5% DEHA in the diet for 2 years. A total of 33 tumors was reported; however, the incidences for each group were not reported. Tumor incidence was reportedly not related to dietary treatment. Groups of 2 to 4 dogs were fed 0, 0.7, 0.15 or 0.2% DEHA in the diet for 1 year; no tumors were observed. It was not stated if an MTD was achieved in any of these studies. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY DEHA was negative in a variety of genetic toxicity assays. DEHA with hepatic homogenates added for metabolism was not mutagenic at 5 ug/plate or the lowest dose giving a toxic response in a reverse mutation assay in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98 and TA100 (Barber et al., 1985; Simmon et al., 1977; Zieger et al., 1982). DEHA was also negative in a mouse lymphoma L5178Y genotoxicity assay, an unscheduled DNA synthesis assay in rat hepatocytes, and a mouse micronucleus assay (Barber et al., 1985). DEHA did not increase transformation frequencies in mouse BALB/3T3 cells at concentrations of up to 12.5 ug/mL (U.S. EPA, 1981, 1984a,b; Barber et al., 1985). Von Daniken et al. (1984) reported that DEHA did not covalently bind to female mouse liver DNA. Oral dosing with DEHA by gavage did not increase the mutagenicity of rat urine for Salmonella strains TA98, TA100, TA1535, TA1537 and TA1538 (DiVincenzo et al., 1985). DEHA was administered through a single i.p. injection to 10 male Harlan/ICR albino Swiss strain mice/dose at doses of 0, 0.5, 1.0, 5.0 and 10.0 mL/kg. Immediately after injection each male was mated to two virgin females; two new virgin females were exchanged once/week for each of the next 7 weeks. In the high-dose group there was a significant increase in early fetal deaths (Singh et al., 1975). In structure-activity relationship studies based upon NTP data, four compounds containing the 2-ethylhexyl moiety (di(2-ethylhexyl)phthalate, tris(2-ethylhexyl)phosphate, 2-ethylhexyl sulfate and DEHA) exhibited some evidence of liver carcinogenicity in rats and/or mice (Kluwe et al., 1985; Kluwe, 1986). Peroxisome production and induction of peroxisome-associated enzymes in the livers of rodents exposed to DEHA, di(2-ethylhexyl)phthalate, tris(2-ethylhexyl)phosphate and 2-ethylhexyl sulfate have been extensively studied (Reddy et al., 1986; Kawashima, 1983a,b; Moody and Reddy, 1978). The induction of peroxisomes is associated with a several-fold increase in the activity of the peroxisomal fatty acid beta-oxidation system and a 2-fold increase in catalase activity (Kawashima et al., 1983b). In addition, long-term exposure to these peroxisome proliferators results in the induction of hepatocellular carcinomas in rats and mice. The lack of mutagenicity of these agents, combined with consistent findings of proliferation of hydrogen peroxide-generating peroxisomes, indicates that persistent proliferation of peroxisomes serves as an endogenous initiator of neoplastic transformation by enhancing oxidative stress. In a comparative peroxisome proliferation assay (U.S. EPA, 1987; Lin, 1987), the relative potency of several phthalate compounds, as well as DEHA, was measured in rats. Criteria used in this assay differed from those in the previous assay. DEHA was found to be the least potent peroxisome proliferator tested. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES Oral Slope Factor -- 1.2E-3 per(mg/kg)/day Drinking Water Unit Risk -- 3.4E-8 per(ug/L) Extrapolation Method -- Linearized multistage procedure, extra risk Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------- ------------- E-4 (1 in 10,000) 3E+3 ug/L E-5 (1 in 100,000) 3E+2 ug/L E-6 (1 in 1,000,000) 3E+1 ug/L DCOE: ___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- combined hepatocellular adenomas and carcinomas Test Animals -- mouse/B6C3F1, female Route -- diet Reference -- NTP, 1982 ------- Dose --------- Admin- Human istered Equivalent Tumor (ppm) (mg/kg)/day Incidence -------- ----------- --------- 0 0 3/50 12,000 255 19/50 25,000 625 18/49 ACOE: ___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Animal doses were calculated as time-weighted averages using measured body weights and food consumption. Human equivalent doses were calculated using a human body weight of 70 kg and animal body weights of 0.028 and 0.037 kg for the high- and low-dose groups, respectively; the length of the exposure was 103 weeks for both treated groups, and the length of the experiment and lifespan of the animals were 105 and 105.5 weeks for the high- and low-dose groups, respectively. The unit risk should not be used if the water concentration exceeds 2.9E+5 ug/L, since above this concentration the unit risk may not be appropriate. CCOE: ___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) An adequate number of animals was observed in a lifetime study. The mice were group housed in this study and fed powdered food. There was a possibility of spillage of the powdered food, suggesting the estimated food consumption may be an overestimate. Overestimating consumption would lead to an underestimate of the risk. The female mouse data for combined hepatocellular adenomas and carcinomas was selected as the basis for the oral quantitative estimate. The results of the likelihood ratio test indicated that these combined incidences of hepatocellular carcinomas and adenomas data sets for both male and female mice should not be combined to derive the oral quantitative estimate. In addition, there are some biological concerns about using the male mice data for quantitation (e.g., adenoma incidence within historical control range). ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1992 The Drinking Water Criteria Document for Di(2-ethylhexyl)adipate has received Program Office and external review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 03/07/1991, 04/04/1991 Verification Date -- 04/04/1991 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199412 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Di(2-ethylhexyl)adipate CASRN -- 103-23-1 Primary Synonym -- Hexanedioic acid Last Revised -- 12/01/1994 SORD: __VI.A. ORAL RfD REFERENCES ICI. 1988a. ICI Central Toxicology Laboratory. Di-(2-ethylhexyl)adipate: Teratogenicity study in the rat. Report CTL/P/2119 (unpublished study). ICI. 1988b. ICI Central Toxicology Laboratory. Di-(2-ethylhexyl)adipate (DEHA): Fertility study in rats. Report CTL/P/2229 (unpublished study). NTP (National Toxicology Program). 1982. Carcinogenesis bioassay of di(2-ethylhexyl)adipate (CAS No. 103-23-1) in F344 rats and B6C3F1 mice (Feed Study). U.S. Department of Health and Human Services, National Toxicology Program, Technical Report Series, No. 212. Singh, A.R., W.H. Lawrence and J. Autian. 1973. Embryonic-fetal toxicity and teratogenic effects of adipic acid esters in rats. J. Pharmacol. Sci. 62(10): 1596-1600. Singh, A.R., W.H. Lawrence and J. Autian. 1975. Dominant lethal mutations and antifertility effects of di-(2-ethylhexyl)adipate and diethyl adipate in male mice. Toxicol. Appl. Pharmacol. 32: 566-576. U.S. EPA. 1992. Drinking Water Criteria Document for Di-(2-ethylhexyl) adipate. Office of Water, Washington, DC. (Final) U.S. EPA. 1991. Toxicology Review Panel: Basis for RfD for Adipate. Human Risk Assessment Branch, Health and Ecological Criteria Division, Office of Water, Washington, DC. May 22. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Barber, E.D., A. Mulholland, D.R. Jagannath, et al. 1985. The testing of di(2-ethylhexyl)phthalate (DEHP), mono(2-ethylhexyl)phthalate (MEHP), di(2-ethylhexyl)adipate (DEHA), and 2-ethylhexanol (2 EH) in a battery of genotoxicity assays. Toxicologist. 5: 211. DiVincenzo, G.D., M.L. Hamilton, K.R. Mueller, W.H. Donish and E.D. Barber. 1985. Bacterial mutagenicity testing of urine from rats dosed with 2-ethylhexanol-derived plasticizers. Toxicology. 34: 247-259. Hodge, H.C., E.A. Maynard, W.L. Downs, J.K. Ashton and L.L. Salerno. 1966. Tests on mice for evaluating carcinogenicity. Toxicol. Appl. Pharmacol. 9: 583-596. Kawashima, Y., N. Hanioka, M. Matsumura and H. Kozuka. 1983a. Induction of microsomal stearoyl-CoA desaturation by the administration of various peroxisome proliferators. Biochim. Biophys. Acta. 752(2): 259-264. Kawashima, Y., S. Nakagawa, Y. Tachibana and H. Kozuka. 1983b. Effects of peroxisome proliferators on fatty acid-binding protein in rat liver. Biochim. Biophys. Acta. 754(1): 21-27. Kluwe, W.M. 1986. Carcinogenic potential of phthalic acid esters and related compounds: Structure-activity relationships. Environ. Health Perspect. 65: 271-278. Kluwe, W.M., J.E. Huff, H.B. Mathews, R. Irwin and J.K. Haseman. 1985. Comparative chronic toxicities and carcinogenic potentials of 2-ethylhexyl-containing compounds in rats and mice. Carcinogenesis. 6(11): 1577-1583. Lin, L.I. 1987. The use of multivariate analysis to compare peroxisome induction data on phthalate esters in rats. Toxicol. Ind. Health. 3(2): 25-48. Moody, D.E. and J.K. Reddy. 1978. Hepatic peroxisome (microbody) proliferation in rats fed plasticizers and related compounds. Toxicol. Appl. Pharmacol. 45(2): 497-504. NTP (National Toxicology Program). 1982. Carcinogenesis bioassay of di(2-ethylhexyl)adipate (CAS No. 103-23-1) in F344 rats and B6C3F1 mice. NTP-80-29. NIH Publ. No. 81-1768. Reddy J.K., M.K. Reddy, M.I. Usman, N.D. Lalwani and M.S. Rao. 1986. Comparison of hepatic peroxisome proliferative effect and its implication for hepatocarcinogenicity of phthalate esters, di(2-ethylhexyl) phthalate, and di(2-ethylhexyl) adipate with a hypolipidemic drug. Environ. Health Perspect. 65: 317-327. Simmon, V.F., K. Kauhanen and R.G. Tardiff. 1977. Mutagenic activity of chemicals identified in drinking water. Prog. Ingen. Toxicol. 2: 249-258. Singh, A.R., W.H. Lawrence and J. Autian. 1975. Dominant lethal mutations and antifertility effects of di-2-ethylhexyl adipate and diethyl adipate in male mice. Toxicol. Appl. Pharmacol. 32: 566-576. U.S. EPA. 1981. FYI-OTS-0584-0286 Supplement, Sequence F. Available from EPA. Write to FOI, EPA, Washington, DC 20460. U.S. EPA. 1984a. Fiche No. OTS-286. FYI-AX-0384-0286 Supplement, Sequence B. Available from EPA. Write to FOI, EPA, Washington, DC 20460. U.S. EPA. 1984b. FYI-OTS-0584-0286 Supplement, Sequence F. Available from EPA. Write to FOI, EPA, Washington, DC 20460. U.S. EPA. 1987. Phthalates and peroxisomes. Unpublished study prepared for the Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. U.S. EPA. 1992. Drinking Water Criteria Document for Di(2-ethylhexyl)adipate. Prepared for the Health and Ecological Criteria Division, Office of Science and Technology, Office of Water, Washington, DC. Von Daniken, A., W.K. Lutz, R. Jackh and C. Schlatter. 1984. Investigation of the potential for binding of di(2-ethylhexyl)phthalate (DEHP) and di(2-ethylhexyl)adipate (DEHA) to liver DNA in vivo. Toxicol. Appl. Pharmacol. 73: 373-387. Zeiger, E., S. Haworth, W. Speck and K. Mortelmans. 1982. Phthalate ester testing in the National Toxicology Program's Environmental Mutagenesis Test Development Program. Environ. Health Perspect. 45: 99-101. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Di(2-ethylhexyl)adipate CASRN -- 103-23-1 Primary Synonym -- Hexanedioic acid ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 10/01/1989 I.A. Oral RfD summary on-line 10/01/1989 VI. Bibliography on-line 08/01/1990 I.A. Text edited 03/01/1991 I.A.7. Primary contact changed 04/01/1991 II. Carcinogenicity assessment now under review 08/01/1991 I.A. Withdrawn; new oral RfD verified (in preparation) 08/01/1991 VI.A Oral RfD references withdrawn 08/01/1991 II. Carcinogenicity assessment now on-line 08/01/1991 VI.C. Carcinogenicity references added 01/01/1992 IV. Regulatory Action section on-line 04/01/1992 II.A.4. Text revised, 4th paragraph 04/01/1992 II.D.1. EPA Documentation changed 04/01/1992 II.D.2. Review statement revised 07/01/1992 I.A. Oral RfD summary replaced; new RfD and new studies 07/01/1992 VI.A. Oral RfD references added 07/01/1993 VI.C. Source document added to references 12/01/1994 II.A.4. Deleted U.S. EPA, 1986 unpub. study-same as Lin, 1987 12/01/1994 VI.C. Deleted U.S. EPA, 1986 unpub. study-same as Lin, 1987 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/09/2002 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 426 of 1119 in IRIS (through 2003/06) AN: 436 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0436-tr.pdf UD: 199809 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Naphthalene- SY: 91-20-3; ALBOCARBON-; CASWELL NO. 587; DEZODORATOR-; EPA-PESTICIDE-CHEMICAL-CODE-055801-; HSDB-184-; MOTH-BALLS-; MOTH-FLAKES-; NAFTALEN [POLISH]; NAFTALENO [SPANISH]; NAPHTALENE [FRENCH]; NAPHTHALIN-; NAPHTHALINE-; NAPHTHENE-; NAPTHALENE,-MOLTEN-; NCI-C52904-; NSC-37565-; RCRA-WASTE-NUMBER-U165-; TAR-CAMPHOR-; UN-1334-; UN-2304-; WHITE-TAR- RN: 91-20-3 HSN: 184 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199809 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Naphthalene CASRN -- 91-20-3 Last Revised -- 09/17/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ------------------- --------------------- ------ --- ---- Decreased mean NOAEL: 100 mg/kg-day; 3000 1 2E-2 terminal body 71 mg/kg-day (adjusted) mg/kg-day weight in males LOAEL: 200 mg/kg-day; Subchronic oral rat study 142 mg/kg-day (adjusted) BCL, 1980a ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- MW = 128.19. Duration adjustment (5/7) of the doses (100, 200 mg/kg-day) arrived at a critical NOAEL/LOAEL pair of 71 and 143 mg/kg-day for decreased mean terminal body weight in male rats. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Battelle's Columbus Laboratories (BCL). (1980a) Unpublished subchronic toxicity study: Naphthalene (C52904), Fischer 344 rats. Prepared by Battelle Laboratories under NTP Subcontract No. 76-34-106002. Naphthalene (> 99% pure) in corn oil was administered by gavage to groups of 10 male and 10 female Fischer 344 rats at dose levels of 0, 25, 50, 100, 200, or 400 mg/kg (duration-adjusted 0, 17.9, 35.7, 71.4, 142.9, and 285.7 mg/kg-day), 5 days/week for 13 weeks (BCL, 1980a). Measured parameters included food consumption and body weight weekly, twice-daily observation for clinical signs of toxicity, hematological parameters for blood collected at termination (hemoglobin, hematocrit, total and differential white blood cell count, red blood cell count, mean cell volume, mean cell hemoglobin concentration), necropsy of all rats in the study, and complete histopathological examination of 27 organs and tissues (including the eyes, lungs, stomach, liver, kidney, reproductive organs, thymus, and kidney) from all control and 400-mg/kg rats. Male kidneys and female thymuses from the 200-mg/kg group were also examined histopathologically (according to the histopathology tables; however, the report text states that the 100-mg/kg group was examined). Organ weight data were not reported. At the highest dose level, two males died during the last week of treatment, and rats of both sexes displayed diarrhea, lethargy, hunched posture, and rough coats at intermittent intervals throughout the study (BCL, 1980a). Food consumption was not affected by exposure, but mean decreases in terminal body weight greater than 10% compared with control values were found in several groups of exposed rats (over the 13-week period); namely, 23% depression in females at 400 mg/kg and a 29% and 12% depression in males at 400 and 200 mg/kg-day, respectively. Differences between mean values of hematological parameters in exposed groups and control groups were < 10% of control values, except for a 94% increase in numbers of mature neutrophils and a 25.1% decrease in numbers of lymphocytes in male 400-mg/kg rats and a 37.2% increase in mature neutrophils in 400-mg/kg females. Histological examinations revealed low incidences of lesions in exposed male kidneys and exposed female thymuses; no lesions were observed in respective control kidneys or thymuses. Lesions such as focal cortical lymphocytic infiltration or focal tubular regeneration were observed in kidneys of 2/10 male rats exposed to 200 mg/kg naphthalene, and diffuse renal tubular degeneration occurred in 1/10 male rats exposed to 400 mg/kg naphthalene. Other lesions include lymphoid depletion of the thymus, which occurred in 2/10 females exposed to 400 mg/kg naphthalene, but not in any other females. No other tissue lesions were detected. Decreased body weight was the most sensitive effect noted in this study and was identified as the most appropriate critical effect for the purposes of RfD derivation. Mean terminal body weight decreases greater than 10% compared with control values were found in male rats following a 90-day gavage exposure to 200 mg/kg-day (LOAEL). The NOAEL for a > 10% decrease in body weight in this study was 100 mg/kg-day (71 mg/kg-day duration-adjusted). Shopp, GM; White, KL, Jr.; Holsapple, MP; et al. (1984) Naphthalene toxicity in CD-1 mice: general toxicology and immunotoxicology. Fundam Appl Toxicol 4(3 pt 1):406-419. Groups of male and female albino CD-1 mice (approximately 6 weeks old at the start) were administered gavage doses of 0, 5.3, 53, or 133 mg/kg naphthalene (99.3% pure) in corn oil for 90 consecutive days (Shopp et al., 1984). A naive control group and the 5.3- and 53-mg/kg dose groups each contained 76 male mice and 40 female mice. The vehicle control group contained 112 male mice and 76 female mice. The high-dose group contained 96 male mice and 60 female mice. Significant chemical-related decreases in terminal body weights or survival were not observed in either sex. No significant alterations in absolute or relative organ weights occurred in exposed male mice. Significant decreases in absolute weights of brain, liver, and spleen and relative weight of spleen occurred in high-dose females; however, organ-to-body weight ratios were significantly different only for the spleen. Histopathological examination of organs was not conducted, but the authors noted that cataracts were not formed in exposed mice (methods used to assess the presence of cataracts were not specified). Examination of hematological parameters (including numbers of leukocytes, erythrocytes, and platelets and determination of hematocrit and hemoglobin) at termination revealed only slight, but statistically significant, increases in hemoglobin in high-dose females only; however, the hematological data were not shown in the report. Chemical analysis of serum showed statistically significant decreased blood urea nitrogen in all exposed female groups, and increased serum globulin and protein in the two highest female dose groups. In the same study, no exposure-related responses were found in a battery of immunological assays (humoral immune response, lymphocyte responsiveness, delayed-type hypersensitivity response, popliteal lymph node response, and bone marrow function); immunotoxic responses were observed in positive controls given intraperitoneal injections of 50 mg/kg cyclophosphamide on days 87, 88, 89, and 90. The study identified a LOAEL of 133 mg/kg-day and a NOAEL of 53 mg/kg-day with significant decreases in absolute weight of brain, liver, and spleen and relative weight of spleen in high-dose females. Therefore, the LOAEL of 133 mg/kg-day is based on the observed organ effects, especially the decrease in the relative weight of the spleen along with the suggestive evidence for effects on hepatic enzyme function. The toxicological significance of the statistically significant alterations in hematological and serum chemical parameters is not clear. The use of the BCL (1980a) study in deriving the RfD was based on the following reasons: The verification of the chemical dose, animal maintenance, and study design (10 rats/sex/dose group for 5 dose groups and 1 control group) are consistent with GLP guidelines submitted for 90-day studies, unlike the Shopp et al. (1984) study, in which the numbers of animals actually evaluated compared to those exposed for most endpoints (organ weights, clinical chemistry, and immunological testing) were small. The decrease in mean terminal body weight in the BCL (1980a) study was not a result of decreased food consumption and was accompanied by clinical signs (diarrhea, lethargy, and rough coats) consistent with sick animals. Decreases in mean terminal body weight of at least 10% were observed in females and males in the case of the BCL (1980a) study, unlike the Shopp et al. (1984) study, in which no significant changes in body weight were reported at any dose level. The statistically significant alterations (p < 0.05) observed in the absolute (brain, liver, and spleen) and relative weight (spleen) of some organs in the absence of any decrease in body weight (Shopp et al., 1984) is not consistent with the absence of lesions and the lack of significant alterations in the clinical chemistry data, hematology, mixed-function oxidase activity, or the immunotoxicity assays for either sex. Although the gross and histopathological examination was limited to the control and high-dose group in the BCL (1980a) study, renal lesions of low incidence were observed in the kidneys (focal cortical lymphocytic infiltration, focal and diffuse tubular regeneration) and thymus (lymphoid depletion) in males and females, respectively, at 100 mg/kg (71 mg/kg-day), unlike the Shopp et al. (1984) study, in which gross necropsy (no histopathological examination of tissues) on a randomly selected number of animals revealed no lesions. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 3000. The duration-adjusted NOAEL for terminal body weight decrease (> 10% of control) in male rats from the BCL (1980a) 90-day gavage study, 71 mg/kg-day, was divided by an uncertainty factor of 3000 (10 to extrapolate from rats to humans, 10 to protect sensitive humans, 10 to extrapolate from subchronic to chronic exposure, and 3 for database deficiencies including the lack of chronic oral exposure studies and 2-generation reproductive toxicity studies) to arrive at a chronic RfD for naphthalene of 2E-2 mg/kg-day. MF = 1. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) In deriving the RfD additional studies were evaluated for a variety of critical effects. Nervous system depression in pregnant rats (NTP, 1991) occurring at a lower dose (50 mg/kg-day), was judged to be nonadverse, because the effect was considered to be transient in nature. Data from studies of mice exposed acutely to injections of naphthalene, or 1- or 2-methylnaphthalene (Buckpitt and Franklin, 1989), or chronically to 1- or 2-methylnaphthalene in the diet (Murata et al., 1993, 1997) provide suggestive evidence that chronic oral exposure to naphthalene at low doses may produce lung injury. However, deriving an RfD for naphthalene based on the methylnaphthalene data was judged to be too uncertain, because of metabolic differences between naphthalene and methylnaphthalenes and the absence of lung injury in subchronic oral studies in rats (BCL, 1980a) and mice with naphthalene (BCL, 1980b; Shopp et al., 1984). A benchmark dose (BMD) approach to modeling the male rat body weight data fits mathematical models for a continuous variable to the data using maximum likelihood methods (see Appendix B to the Toxicological Review of Naphthalene, "Benchmark Dose Calculations"). In this approach, maximum likelihood estimates (MLEs) of dose (with no duration adjustment) associated with a 10% decrease in mean body weight compared with nonexposure conditions were 171 and 172 mg/kg-day using a polynomial and power model, respectively; respective 95% confidence lower limits on these doses, taken as BMDs, were 130 and 135 mg/kg-day. Assuming that either of these BMDs are surrogates for NOAELs, as suggested by the analysis of developmental toxicity data by Allen et al. (1994a,b) and Kavlock et al. (1995), making duration adjustments (BMD x 5/7) and applying the same 3000 uncertainty factor used for the NOAEL/LOAEL approach arrives at a prospective RfD for naphthalene, 3E-2 mg/kg-day, that is comparable to the RfD derived with the NOAEL/LOAEL approach. Benchmark dose approaches to deriving a chronic RfD for naphthalene were also examined using data for maternal body weight decreases in the NTP (1991) rat developmental toxicity study and data for lung proteinosis in mice exposed for 81 weeks to 1-methylnaphthalene in the diet (Murata et al., 1993). Decreased maternal body weight was not selected as the basis of chronic RfD derivation because the pregnant rats were exposed for only a small percentage of their lives. As discussed earlier, deriving the naphthalene RfD based on 1-methylnaphthalene data was judged to be too uncertain because of metabolic differences between naphthalene and methylnaphthalenes and the absence of lung injury in rats and mice orally exposed to naphthalene for subchronic periods. The benchmark methodology for naphthalene is contained within an appendix of the Toxicological Review for the readers' information, however it was decided to use the LOAEL/NOAEL approach rather than the benchmark approach in the derivation of the RfD/RfC. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=42. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Database -- Low RfD -- Low The principal study was given a high confidence rating because adequate numbers of animals were included and experimental protocols were adequately designed, conducted, and reported. Confidence in the database was rated low because of the lack of adequate chronic oral data for naphthalene; the lack of any dose-response data for naphthalene-induced hemolytic anemia, probably one of the most well-known health hazards to humans exposed to naphthalene; and the lack of two-generation reproductive toxicity studies. Humans exposed via inhalation, combined inhalation and dermal exposure, and combined inhalation and oral exposure have developed hemolytic anemia. Hemolytic anemia is characterized by findings of lowered hemoglobin, hematocrit, and erythrocyte values, elevated reticulocyte counts, Heinz bodies, elevated serum bilirubin, and fragmentation of erythrocytes. In severe cases, the hemolytic anemia was accompanied by jaundice, high serum levels of bilirubin, cyanosis, and kernicterus with pronounced neurological signs. Neither oral nor inhalation exposure levels were available in human studies reporting anemia (Melzer-Lange and Walsh-Kelly, 1989; Owa, 1989; Owa et al., 1993). Infants deficient in G6PDH are thought to be especially sensitive to naphthalene-induced hemolytic anemia. Resulting confidence in the RfD is low. A quantitative comparison of the acute dog study (7 days at 262 mg/kg-day; free-standing LOAEL of 262 mg/kg-day based hemolytic anemia) with the RfD (chronic oral rat study based on decrease in mean terminal body weight) to determine whether the RfD is protective of hemolytic anemia in humans is not possible since adequate dose-response data in a subchronic or chronic dog study are lacking. Therefore, because of the absence of an appropriate animal model one cannot extrapolate either qualitatively or quantitatively to humans with respects to hemolytic anemia. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=48. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included in an appendix to the Toxicological Review of Naphthalene in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=62. Other EPA Documentation -- U.S. EPA, 1980, 1986, 1987a, 1988 Agency Consensus Date - 07/01/1998 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 199809 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Naphthalene CASRN -- 91-20-3 Last Revised -- 09/17/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC ----------------- -------------------- ----- ---- ------ Nasal effects: hyperplasia NOAEL: None 3000 1 3E-3 and metaplasia in respiratory mg/m3 and olfactory epithelium, LOAEL(HEC): 9.3 mg/m3 respectively Chronic mouse inhalation study NTP, 1992a ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- Following the Category 3 guidance (U.S. EPA, 1994), experimental exposure concentrations of 0, 10, and 30 ppm were converted to 0, 52, and 157 mg/m3, respectively; adjusted to a continuous exposure basis in mg/m3 (6/24 hr x 5/7 days) equals mg/m3 x 0.1786: 0, 9.3, and 28 mg/m3. Because the blood:gas (air) coefficients for naphthalene were not available, the default ratio of 1 was used and the values for the LOAEL(HEC) were 0, 9.3, and 28 mg/m3. Scenario -- The LOAEL human equivalent concentration (HEC) was calculated for an extrarespiratory effect for a category 3 gas. Since the b:a lambda for humans (h) is unknown, a default value of 1.0 is used for this ratio. LOAEL(HEC) x [b:a lambda(animal)/b:a lambda(human)] = 9.3 mg/m3. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) National Toxicology Program (NTP). (1992a) Toxicology and carcinogenesis studies of naphthalene in B6C3F1 mice (inhalation studies). Technical Report Series No. 410. NIH Publication No. 92-3141. B6C3F1 mice (75/sex/group) were exposed to naphthalene (scintillation grade, > 99% pure) at target concentrations of 0, 10, and 30 ppm (0, 52, 157 mg/m3) for 6 hr/day, 5 days/week, for 103 weeks (NTP, 1992a). The duration-adjusted levels were 0, 9.3, and 28 mg/m3, respectively. Additional groups of 75 male and 75 female replacement animals were exposed to 30 ppm to ensure that a sufficient number of mice lived to study termination. Naphthalene vapor was generated by direct sublimation and monitored by a software feedback arrangement. Average weekly concentrations were within 20% of target concentrations, except one week when the mean concentration in the low-concentration chamber was 5.5 ppm. Supplemental hematology studies were scheduled with 25 animals/sex/group, but only the first sacrifice (at 14 days) was conducted because of high mortality in the male control group from fighting. Serial slit-lamp biomicroscopy and indirect ophthalmoscopic examinations were conducted on 5 animals/sex/group at 6-mo intervals. Gross necropsies were conducted on all animals. Complete histopathologic examinations of major tissues were conducted on all animals, except that the only tissues examined from low-concentration animals dying or killed after 21 mo of exposure were the lungs and nasal cavities. Survival of the male controls was significantly lower than in the exposed males. Reduced survival was related to wound trauma and lesions from increased fighting in this group. Similar effects were not seen in the exposed males, because they tended to huddle in cage corners during exposure periods and so fought less. There was no significant difference in survival between the treatment and control females. There were no treatment-related ocular lesions in the selected mice that underwent ophthalmologic examinations at 6-mo intervals. There were no biologically significant changes in hematology parameters at day 14 of the study. Final mean body weights of the treated animals were within 10% of the corresponding controls. Inflammation, metaplasia of the olfactory epithelium, and hyperplasia of the respiratory epithelium were noted in the noses of virtually all exposed mice of both sexes, but in only one control female mouse. These effects were slightly more severe in the high-concentration group. See Table 1 for incidence data. The lesions were focal or multifocal, occurred mainly in the posterior nasal cavity, and were minimal to mild in severity. Inflammatory lesions included substantia propria edema, congestion, mixed inflammatory cell infiltrates, necrotic debris, and intraluminal serous to fibrinopurulent exudate. Respiratory epithelial hyperplasia resulted in a thickened, folded, irregular mucosal surface. Olfactory epithelial metaplasia often involved ciliated columnar or pseudocolumnar respiratory-like epithelial cells replacing the usual olfactory cell layer. The lesions were collectively considered features of a generalized inflammatory and regenerative process. Table 1. Incidence of nonneoplastic respiratory lesions in B6C3F1 mice exposed by inhalation to naphthalene, 6 hr/day, 5 days/week for 2 years R E S P I R A T O R Y L E S I O N Exposure Hyperplasia, nasal level/sex respiratory Metaplasia, nasal (ppm) Inflammation, lung epithelium olfactory epithelium ---------------------------------------------------------------------------- 0/male 0/70 0/70 0/70 0/female 3/69 0/69 0/69 ---------------------------------------------------------------------------- 10/male 21/69 66/69 66/69 10/female 13/65 65/65 65/65 ---------------------------------------------------------------------------- 30/male 56/135 134/135 134/135 30/female 52/135 135/135 135/135 ---------------------------------------------------------------------------- Source: NTP, 1992a. Minimal to mild lung lesions, including infiltration of histiocytes or lymphocytes, inflammation, hyperplasia of the alveolar epithelium, and bronchial submucosal gland distension, were observed in both controls and treated mice. The incidence and severity were generally higher in the treated groups of both sexes, but there was no clear concentration-response relationship. Females in the high-exposure group had elevated incidences of alveolar/bronchiolar adenomas and carcinomas (combined incidence 22%, compared with 7% in the control group and 3% in the low-exposure group). The incidence was also above that of historical controls and was considered compound-related. The incidences of alveolar/bronchiolar adenomas and carcinomas in treated males were marginally increased (10%, 25%, and 23%, in the control, low-concentration, and high-concentration groups, respectively). However, because the increase was not statistically significant and was within the range of historical controls, it was not considered exposure related. Instead, it was attributed to the longer life span of the treated animals. Nasal adenomas occurred in the anterior nasal cavities of two females in the low-concentration group. They were not considered compound related because the increase was not concentration related or statistically significant. Therefore, the nasal lesions discussed above should not be considered preneoplastic. Calculation of the Human Equivalent Concentration (HEC) Dose conversion: Because of its low water solubility and low reactivity, naphthalene-related effects on the nasal epithelium are expected to result following absorption of naphthalene and metabolism to reactive oxygenated metabolites, rather than being a result of direct contact. This hypothesis is supported by data on naphthalene metabolism indicating that toxic effects on the respiratory tract are due to a naphthalene metabolite that may be formed either in the liver or in the respiratory tract. For example, necrosis of bronchial epithelial (Clara) cells in mice (O'Brien et al., 1985, 1989; Tong et al., 1981) and necrosis of olfactory epithelium in mice, rats, and hamsters (Plopper et al., 1992) occur following intraperitoneal injection of naphthalene. The nasal effects from inhalation exposure to naphthalene were considered to be extra-respiratory effects of a category 3 gas, as defined in the U.S. EPA guidance for deriving RfCs (U.S. EPA, 1994). Following this guidance, experimental exposure concentrations were adjusted to a mg/m3 basis (0, 52, and 157 mg/m3), adjusted to a continuous exposure basis (mg/m3 x 6h/24h x 5d/7d = mg/m3 x 0.1786: 0, 9.3, and 28 mg/m3), and converted to human equivalent concentrations (HECs) by multiplying the adjusted concentrations by the ratio of mouse:human blood/gas partition coefficients. Because the blood/gas coefficients for naphthalene were not available, the default ratio of 1 was used. Dose-response modeling: Whereas the data from the NTP (1992a) study show nasal effects to be the most sensitive effects from chronic inhalation exposure to naphthalene, they provide no indication of the shape of the dose-response curve because the incidence of nasal lesions at the lowest exposure level was 100% in females and nearly 100% in males (see Table 1). In this case, application of a BMD approach, in which quantal mathematical models are fit to the incidence data for nasal effects, does not sensibly assist in extrapolating to a NOAEL, and a NOAEL/LOAEL approach was taken for deriving an RfC for naphthalene. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF = 3000. The adjusted LOAEL(HEC) of 9.3 mg/m3 for nasal effects (hyperplasia in respiratory epithelium and metaplasia in olfactory epithelium) was divided by an uncertainty factor of 3000 (10 to extrapolate from mice to humans, 10 to protect sensitive humans, 10 to extrapolate from a LOAEL to a NOAEL, and 3 for database deficiencies including the lack of a 2-generation reproductive toxicity study and chronic inhalation data for other animal species) to arrive at a chronic RfC for naphthalene of 3E-3 mg/m3. MF = 1. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) SUPPORTING STUDIES Human experience with acute accidental exposures to naphthalene identifies the development of hemolytic anemia and cataracts as health hazards of concern. However, information is not available regarding dose-response relationships for these effects in humans with acute, subchronic, or chronic exposure by any route. Animal inhalation studies are restricted to three studies of mice: a 2-year study (NTP, 1992), a 6-mo study (Adkins et al., 1986), and a 4-hr study (Buckpitt, 1982). Results from the chronic study, supported by the subchronic and acute studies, identify nasal and pulmonary injuries as critical effects from chronic inhalation exposure to naphthalene; effects in other organs or tissues were not found. Incidence data for male and female mice with hyperplasia of the nasal respiratory epithelium, metaplasia of the nasal olfactory epithelium, and chronic pulmonary inflammation clearly show that the nose is more sensitive than the lung to chronic inhalation exposure to naphthalene. At both exposure levels (10 and 30 ppm, 6 hr/day, 5 days/week), > 95% of mice of either sex showed nasal lesions, whereas pulmonary lesions were found in < 1/3 and < 1/2 of mice exposed at 10 and 30 ppm, respectively (Table 1). Nasal lesions in the respiratory and olfactory epithelium in mice found in the NTP (1992a) study were therefore selected as the critical effects for the purpose of RfC derivation. Adkins et al. (1986) exposed female A/J mice (30/group) to 0, 10, or 30 ppm (0, 52, or 157 mg/m3) naphthalene for 6 hr/day, 5 days/week for 6 mo, and counted the number of adenomas in each lung. The duration-adjusted concentrations were 0, 9.2, and 28 mg/m3, respectively. Exposure to naphthalene caused increases in the total number of adenomas and the percentage of animals with adenomas, but the differences were not significant. The number of tumors per tumor-bearing mouse lung was significantly increased at both exposure levels. Buckpitt (1982) subjected groups of five male mice (Swiss Webster) plus control group to 1-hr exposures to naphthalene concentrations of 0, 52.4, 95.8, 204, or 380 mg/m3. Adverse effects were seen only at the highest concentration, and included swelling of cells and sloughing into the airway lumen of cells from either the major and/or terminal airways. The effects were milder in the presence of cytochrome P450 inhibitor and stronger in the presence of a glutathione depletor, suggesting that cytotoxicity is due to a naphthalene metabolite produced by P450 and that glutathione plays a protective role. Naphthalene reduced glutathione levels in the lung, liver, and kidney, but the concentration-response curve was flat. Following a single 4-hr exposure of five male and five female Wistar Albino rats to 77.7 ppm (407 mg/m3), closed eyes, lacrimation, and mouth breathing were observed (Bushy Run Research Center, 1986). No signs of toxicity were observed postexposure or during the 14-day observation period, and gross necropsy revealed no exposure-related lesions. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=42. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Database -- Low to Medium RfC -- Medium The principal study was given medium confidence because adequate numbers of animals were used, and the severity of nasal effects increased at the higher exposure concentration. However, the study produced high mortality, (< 40% survival in the male control group due to wound trauma and secondary lesions resulting from increased fighting). Also, hematological evaluation was not conducted beyond 14 days. The database was given a low-to-medium confidence rating because there are no chronic or subchronic inhalation studies in other animal species, and there are no reproductive or developmental studies for inhalation exposure. In the absence of human or primate toxicity data, the assumption is made that nasal responses in mice to inhaled naphthalene are relevant to humans; however, it cannot be said with certainty that this RfC for naphthalene based on nasal effects will be protective for hemolytic anemia and cataracts, the more well-known human effects from naphthalene exposure. Medium confidence in the RfC follows. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=48. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included in an appendix to the Toxicological Review of Naphthalene in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=62. Other EPA Documentation -- U.S. EPA, 1980, 1986, 1987a, 1988 Agency Consensus Date - 07/01/1998 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 199809 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Naphthalene CASRN -- 91-20-3 Last Revised -- 09/17/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Using criteria of the 1986 Guidelines for Carcinogen Risk Assessment, naphthalene is classified in Group C, a possible human carcinogen. This is based on the inadequate data of carcinogenicity in humans exposed to naphthalene via the oral and inhalation routes, and the limited evidence of carcinogenicity in animals via the inhalation route. Using the 1996 Proposed Guidelines for Carcinogen Risk Assessment, the human carcinogenic potential of naphthalene via the oral or inhalation routes "cannot be determined" at this time based on human and animal data; however, there is suggestive evidence (observations of benign respiratory tumors and one carcinoma in female mice only exposed to naphthalene by inhalation [NTP, 1992a]). Additional support includes increase in respiratory tumors associated with exposure to 1-methylnaphthalene. At the present time the mechanism whereby naphthalene produces benign respiratory tract tumors are not fully understood, but are hypothesized to involve oxygenated reactive metabolites produced via the cytochrome P-450 monooxygenase system. However, based on the many negative results obtained in genotoxicty tests, a genotoxic mechanism appears unlikely. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=48. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=42. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Available data are inadequate to establish a causal association between exposure to naphthalene and cancer in humans. Adequately scaled epidemiological studies designed to examine a possible association between naphthalene exposure and cancer were not located. Overall, no data are available to evaluate the carcinogenic potential in exposed human populations. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inhalation: In an NTP (1992a) cancer bioassay, groups of male and female B6C3F1 mice were exposed (whole-body) to naphthalene (> 99% pure) vapors at concentrations of 0 (75 mice/sex), 10 (75 mice/sex), or 30 ppm (150 mice/sex) 6 hr/day, 5 days/week for 2 years. Mice were housed five to a cage. There were 150 mice housed in each of 4 inhalation chambers; 2 chambers were used for the high-exposure level. A comprehensive histological examination was performed on all control and high-dose mice and on low-dose mice that died or were sacrificed before 21 months of exposure. After 21 months of exposure, only the nasal cavity and lung were examined in the low-dose group. In each chamber, 50 animals per sex were designated for the 2-year studies; 5 animals per sex were designated for hematological evaluations at 14 days and 3, 6, 12, and 18 mo. However, because of high mortality in the male control group (see next paragraph), only the 14-day hematological evaluation was conducted. The other surviving interim mice were incorporated into the 2-year study. Statistically significant decreases in survival were observed in the control male mice compared with the exposed groups. Exposed male mice were observed to huddle in corners of the cages during exposure and were less inclined to fight. Survival percentages at the end of the study were 37% (26/70), 75% (52/69), and 89% (118/133) for the 0, 10, and 30 ppm male groups, respectively. Survival percentages did not include mice sacrificed at 14 days, mice that died before the study began, mice that were accidentally killed, or mice that were lost during the study. Survival at 2 years in the control female mice (86%; 59/69) was comparable to survival in the exposed groups; survival percentages were 88% (57/65) and 76% (102/135) for low- and high-dose females. Body weights were not affected by exposure in either sex. Statistically significant increases in incidences of nonneoplastic lesions were found in the lung and nose of males and females at both exposure levels. Observed nonneoplastic effects included the following (with respective incidences listed in the order of control, low-, and high-exposure groups): chronic inflammation of the lung (0/70, 21/69, and 56/135 for males; 3/69, 13/65, and 52/135 for females); chronic inflammation (0/70, 67/69, and 133/135 for males and 1/69, 65/65, and 135/135 for females); metaplasia of the olfactory epithelium (0/70, 66/69, and 134/135 for males; 0/69, 65/65, and 135/135 for females); and hyperplasia of the respiratory epithelium in the nose (0/70, 66/69, and 134/135 for males; 0/69, 65/65, and 135/135 for females). The lung inflammation in the exposed mice was described as consisting of "focal intra-alveolar mixed inflammatory cell exudates and interstitial fibrosis" that in more advanced lesions consisted "primarily of large foamy macrophages, sometimes accompanied by multinucleated giant cells." Foci of alveolar epithelial hyperplasia were noted to occur generally in regions distant to inflammation. A statistically significant increase in the incidence of alveolar/bronchiolar adenomas was observed in the 30 ppm group of females (28/135), but not in the 10 ppm group (2/65), relative to the control female group (5/69). Among females, an additional mouse in the 30-ppm group displayed an alveolar/bronchiolar carcinoma. The historical combined incidence of alveolar/bronchiolar adenomas and carcinomas in control B6C3F1 female mice from NTP inhalation studies was cited as 39/466 (8.4%, range 0-12%). The authors commented that alveolar/bronchiolar adenomas and carcinomas constitute a morphologic continuum. The incidences of male mice with alveolar/bronchiolar adenomas were 7/70, 15/69, and 27/135 for the control, 10 ppm, and 30 ppm groups, respectively; for combined adenomas and carcinomas of the alveolar/bronchiolar region, the respective incidences were 7/70, 17/69, and 31/135. A statistical analysis that adjusted for intercurrent mortality (logistics regression analysis) determined that the tumor incidences for control and exposed groups of male mice were not significantly different (NTP, 1992a). Historical incidence for combined alveolar/bronchiolar adenomas and carcinomas in control male B6C3F1 mice from NTP inhalation studies was cited as 94/478 (19.7%, range 10%-30%). The adenomas were described as "locally compressive nodular masses consisting of cords of well-differentiated epithelial cells," whereas the carcinoma was "composed of ribbons and/or coalescing sheets of smaller, more anaplastic, cells which sometimes extended into adjacent parenchyma." Hemangiosarcomas occurred at various sites within the vascular endothelium in five high-dose female mice (5/135), but not within the other groups of female mice (0/69 and 0/65 for control and 10 ppm females, respectively). The high-dose female incidence (3.7%) was not significantly different from the concurrent control incidence and was within the range of historical control incidences from NTP inhalation studies (range: 0-8%; overall incidence: 17/467 or 3.6%). No significantly elevated incidences of tumors were found at other tissue sites in exposed male or female mice (NTP, 1992a). Adkins et al. (1986) exposed groups of 30 female A/J strain mice (6 to 8 weeks old) to 0, 10, or 30 ppm naphthalene (98%-99% pure) vapors, 6 hr/day, 5 days/week for 6 mo. After the 6-mo exposure period, excised lungs were examined for tumors. Tumors were examined histologically. The authors did not describe any noncancer histopathological effects that their examinations may have revealed. Survival was not different between the exposed and control groups. Lung tumors were found in all 20 positive control mice given single intraperitoneal injections of 1 g urethane/kg; the mean number of tumors per mouse in the positive control was 28.9. Increased numbers of lung tumors were found in the naphthalene-exposed groups compared with the control group, but the differences were not statistically significant (6, 10, and 11 for the 0, 10, and 30 ppm groups). Tumors were described as alveolar adenomas consisting of "large cuboidal or columnar pithelial cells supported by a sparse fibroblastic stroma and arranged in poorly defined acinar structures with papillary formations." No carcinomas were found. Naphthalene exposure did not significantly increase the percentage of animals with tumors (21%, 29%, and 30% for 0, 10, and 30 ppm mice, respectively). Statistically significant increases in the number of adenomas per tumor-bearing lung were observed in the exposed mice, but there was no increase in response with increasing dose. Mean numbers of tumors per tumor-bearing lung (sd noted in parentheses) were: 1.00 (0.00), 1.25 (0.07), and 1.25 (0.07) for 0, 10, and 30 ppm mice, respectively. Applicability of this study to the assessment of risk for lifetime exposure is limited due to the less-than-lifetime exposure and observation periods, and the limited tissue evaluation examining only the lung. Nevertheless, the finding that only 6 months of exposure caused statistically significant increased numbers of lung tumors per tumor-bearing lung in the exposed groups, coupled with the results of the NTP (1992a) mouse bioassay, provides further suggestive evidence that naphthalene produces a tumorigenic response in the mouse lung. Oral: Schmahl (1955) reported that naphthalene administered in food did not cause cancer in a group of 28 rats (in-house strains BDI and BDII). Naphthalene (purchased from Merck Co. and described as "Naphthalene puriss. cryst. alcoh. depur. [54935]") was dissolved in oil and given 6 times/week in food. The absorption spectrum of the test material displayed no atypical peaks compared with published data for naphthalene, suggesting high purity. The daily dose was reported to vary between 10 and 20 mg, but further details regarding dose variation were not provided. After reaching a total dose of 10 g/rat (food intake and body weights were not reported), treatment was stopped on the 700th experimental day, and animals were observed until spontaneous death, between 700 and 800 days of age. Assuming an average daily dose of 15 mg/rat and a body weight of 0.36 kg (U.S. EPA, 1987b, reference body weight for male Fischer 344 rats), an estimated average daily dose of 42 mg/kg is calculated. Autopsies were performed on dead animals, and organs that appeared unusual were examined histologically (the report did not specify which organs were histologically examined). The number of rats in the control group was not reported; survival for control and exposed rats was reported to be similar. Reported results from the autopsy and histological examinations were restricted to the statement that no toxic effects were seen, including eye damage and tumors. Inadequacies in experimental design (e.g., only one dose level was administered, the histopathological examination was not complete, hematological endpoints were not evaluated, and some rats lived as long as 300 days beyond exposure before being examined) and inadequacies in reporting of experimental details and results limit the conclusions that can be drawn from this study regarding either the carcinogenicity or noncarcinogenic toxicity of naphthalene. This study is considered inadequate as a cancer bioassay because of reporting and design inadequacies and the likelihood that the maximum tolerated dose may not have been approached. Other Routes of Administration: Schmauhl (1955) reported that naphthalene repeatedly administered by subcutaneous or intraperitoneal injection did not produce tumors in rats (in-house strains BDI and BDIII). Groups of 10 rats were given either subcutaneous or intraperitoneal weekly injections of naphthalene in oil (20 mg/rat per injection) starting at 100 days of age and continuing for 40 weeks (the total doses were 820 mg/rat). Rats were maintained until spontaneous death occurred. Life spans were reported to be 700 or 900 days for rats with subcutaneous or intraperitoneal doses, respectively. Autopsies were performed on dead animals, and organs which appeared unusual were examined histologically (the report did not specify which organs were examined, if any). The author reported that no toxic effects were found with parenteral administration of naphthalene. No tumors developed in either group. Reported information on control rats was restricted to the statement that lifespan for exposed rats was similar to lifespan for control rats (700 days with subcutaneous doses and 900 days with intraperitoneal doses). Boyland et al. (1964) implanted naphthalene into the bladder of stock Chester Beatty mice and examined them after 30 weeks in an effort to determine the suitability of naphthalene as a potential vehicle for carcinogenicity testing. The original number of mice implanted with naphthalene was not reported, but 23 mice were reported to have survived 30 weeks. One mouse developed a bladder carcinoma (1/23; 4%); no adenomas or papillomas were found. Tumor incidence was as low as when paraffin wax was used (2-4%), and lower than with the implantation of cholesterol (12%). There are limitations of this study that make it an inadequate lifetime cancer bioassay including the short exposure and observation periods, and the lack of untreated controls. Coal tar-derived naphthalene that contained approximately 10% unidentified impurities was tested for carcinogenicity by Knake (1956). White rats (40, sex unspecified) were given seven subcutaneous injections of 0 or 500 mg/kg naphthalene in sesame oil at 2-week intervals over an approximate 3.5-month period. Thirty-four of 38 naphthalene rats and 32/38 control rats survived the injection period. Survival was somewhat reduced in the naphthalene-exposed rats compared with the vehicle-control rats during the following 18-month period. Survival incidences at 6, 11, and 17 months after the injection period were 21/34, 6/34, and 0/34 for the naphthalene-exposed rats and 17/32, 12/32, and 4/32 for the control rats. Lymphosarcomas were found in 5/34 (14.7%) exposed rats during the 18-month observation period; one exposed rat showed a mammary fibrosarcoma. Vehicle controls showed a 6% (2/32) incidence of tumors (one with lymphosarcoma and one with mammary fibrosarcoma). Mice (25, inbred black) were painted with 0.5% naphthalene in benzene 5 days/week for life; 21 control mice were painted with benzene alone. Four treated mice developed lymphomatic leukemia, three had lung adenomas, one had lymphosarcoma, and one had a non-specified tumor (9/25 with tumors). In the benzene controls, one had lymphosarcoma, one had lung adenoma, and one had a non-specified tumor (3/21 with tumors). These studies are limited for the assessment of carcinogenicity due to the presence of unknown impurities that may have carcinogenic properties. Moreover, the vehicle (benzene) in the mouse study has been shown to cause leukemia in humans and rodents, and the site of injection in the rat study was painted, prior to injection, with carbolfuchsin, a known carcinogen. La Voie et al. (1988) gave intraperitoneal naphthalene doses (in dimethylsulfoxide) of 0.25, 0.50, and 1.0 umole to male and female newborn CD-1 mice on days 1, 8, and 15 of life (total dose = 1.75 umole naphthalene). The report did not specify the purity of the naphthalene tested. Forty-nine pups were treated with naphthalene and 46 control pups were treated with dimethylsulfoxide alone. Mice were maintained (10 mice/cage) until moribund or until 52 weeks when survivors were killed. All gross lesions as well as liver sections from all mice were examined histologically. No statistically significant increased incidence of liver tumors (adenomas or hepatomas) was found in the exposed mice. Reported incidences for the number of mice with liver tumors were (denominators are for the number of mice that lived at least 6 months): 0/16 and 2/31 for exposed females and males, and 0/21 and 4/21 for vehicle-control females and males. This assay is inadequate to assess the carcinogenicity of lifetime exposure to naphthalene because the exposure period (2 weeks) and observation period (52 weeks) were significantly less than the lifetime for mice (approximately 2 years), and complete histological examinations were not conducted. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The genotoxic potential of naphthalene has been evaluated in many test systems. Most studies provided negative results. Naphthalene was not mutagenic in Salmonella typhimurium assays in the presence or absence of liver metabolic preparations (Bos et al., 1988; Connor et al., 1985; Florin et al., 1980; Godek et al., 1985; McCann et al., 1975; Nakamura et al., 1987; Narbonne et al., 1987; NTP, 1992a; Sakai et al., 1985). Naphthalene did not damage DNA (as assayed by the induction of the SOS-repair system) in E. coli PQ37 (Mersch-Sundermann et al., 1993). NTP (1992a) found that naphthalene induced, in cultured Chinese hamster ovary cells, sister chromatid exchanges within a concentration range of 27 to 90 ug/mL in the presence or absence of metabolic activation, and chromosomal aberrations within a range of 30 to 67.5 ug/mL only in the presence of metabolic activation. Naphthalene was mutagenic in the marine bacterium Vibrio fischeri (Arfsten et al., 1994) and in the Drosophila melanogaster wing somatic mutation and recombination test (Delgado-Rodriguez et al., 1995). Culture of mouse embryos in medium containing 0.16 mM naphthalene produced a 10-fold increase in chromosomal damage compared to untreated controls; the genotoxic response to naphthalene was amplified by the inclusion of a hepatic metabolic activation system in the medium (Gollahon et al., 1990). Incubation of human peripheral lymphocytes in medium containing naphthalene and a human liver metabolic activation system did not produce increased frequency of sister chromatid exchanges compared with controls (Tingle et al., 1993; Wilson et al., 1995). Naphthalene did not induce unscheduled DNA synthesis in cultured rat hepatocytes (Barfknecht et al., 1985) or increased numbers of micronuclei in bone marrow cells of mice following intraperitoneal injection of single 250-mg/kg doses (Sorg et al., 1985). Single oral doses of naphthalene as high as 500 mg/kg did not increase the frequency of micronucleated erythrocytes in exposed mice compared with untreated control mice (Harper et al., 1984). Naphthalene did not induce in vitro transformations of Fischer rat embryo cells (Freeman et al., 1973) or Swiss mouse embryo cells (Rhim et al., 1974). Sina et al. (1983) reported that naphthalene did not induce single-strand DNA breaks in cultured rat hepatocytes as detected by alkaline dilution. Naphthalene metabolites 1-naphthol and 2-naphthol were not mutagenic in S. typhimurium, with or without metabolic activation (Florin et al., 1980; McCann et al., 1975; Narbonne et al., 1987). Another proposed naphthalene metabolite, naphthoquinone, was not mutagenic in several strains of S. typhimurium with or without metabolic activation (Sakai et al., 1985), but Flowers-Geary et al. (1994) reported that naphthalene-1,2-dione was mutagenic in strains of S. typhimurium without metabolic activation. The naphthalene metabolite, 1-naphthol, failed to produce positive results in several other genotoxicity assays including tests for sex- linked recessive lethal mutations in Drosophila melanogaster (Gocke et al., 1981), mutations in mouse L5178Y cells (Amacher and Turner, 1982), unscheduled DNA synthesis in cultured rat hepatocytes (Probst and Hill, 1980), and induction of micronuclei in bone marrow cells of mice (Gocke et al., 1981) and rats (Hossack and Richardson, 1977) after acute in vivo exposure. Tsuda et al. (1980) found no evidence for neoplastic transformation of liver cells in a group of 10 young adult F344 rats (sex not specified) treated with single gavage doses of 100 mg/kg naphthalene in corn oil compared with a group of 10 vehicle control rats. Rats were given gavage doses of naphthalene or vehicle following partial hepatectomy, but before dietary treatment with an anti-cell proliferation agent (2-acetylaminofluorene) and a necrotizing agent (carbon tetrachloride). Gamma-glutamyl transpeptidase foci (observed following the dietary treatments of exposed and control rats) were used as an indicator of neoplastic transformation. In contrast to naphthalene, a single gavage dose of 200 mg/kg benzo[a]pyrene induced significant increases in the number, area, and size of gamma-glutamyl transpeptidase foci. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE An oral slope factor for naphthalene was not derived because of a lack of chronic oral naphthalene studies. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE An inhalation unit risk estimate for naphthalene was not derived because of the weakness of the evidence (observations of predominant benign respiratory tumors in mice at high dose only) that naphthalene may be carcinogenic in humans. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1998 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included in an appendix to the Toxicological Review of Naphthalene in support of Summary Information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1998). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0436-tr.pdf#page=62. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date - 07/01/1998 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199809 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Naphthalene CASRN -- 91-20-3 Last Revised -- 09/17/1998 SORD: __VI.A. ORAL RfD REFERENCES Allen, BC; Kavlock, RJ; Kimmel, CA; et al. (1994a) Dose response assessments for developmental toxicity: II. Comparison of generic benchmark dose estimates with NOAELs. Fundam Appl Toxicol 23:487-495. Allen, BC; Kavlock, RJ; Kimmel, CA; et al. (1994b) Dose response assessments for developmental toxicity: III. Statistical models. Fundam Appl Toxicol 23:496-509. Battelle's Columbus Laboratories (BCL). (1980a) Unpublished subchronic toxicity study: Naphthalene (C52904), Fischer 344 rats. Prepared by Battelle Laboratories under NTP Subcontract No. 76-34-106002. Available from the Center for Environmental Research Information, (513) 569-7254. Battelle's Columbus Laboratories (BCL). (1980b) Unpublished subchronic toxicity study: Naphthalene (C52904), B6C3F1 mice. Prepared by Battelle Laboratories under NTP Subcontract No. 76-34-106002. Buckpitt, AR; Franklin, RB. (1989) Relationship of naphthalene and 2-methylnaphthalene metabolism to pulmonary bronchiolar epithelial cell necrosis. Pharm Ther 41:393-410. Kavlock, RJ; Allen, BC; Faustman, EM; et al. (1995) Dose response assessments for developmental toxicity: IV. Benchmark doses for fetal weight changes. Fundam Appl Toxicol 26:211-222. Melzer-Lange, M; Walsh-Kelly, C. (1989) Naphthalene-induced hemolysis in a black female toddler deficient in glucose-6-phosphate dehydrogenase. Pediatr Emerg Care 5(1):24-26. Murata, T; Denda, A; Maruyama, H; et al. (1993) Chronic toxicity and carcinogenicity studies of 1-methylnaphthalene in B6C3F1 mice. Fundam Appl Toxicol 21:44-51. Murata, Y; Denda, A; Maruyama, H; et al. (1997) Chronic toxicity and carcinogenicity studies of 2-methylnaphthalene in B6C3F1 mice. Fundam Appl Toxicol 36:90-93. National Toxicology Program (NTP). (1991) Final report on the developmental toxicity of naphthalene (CAS no. 91-20-3) in Sprague Dawley (CD) rats. #TER91006. NTIS Technical Report (NTIS/PB92-135623). Owa, JA. (1989) Relationship between exposure to icterogenic agents, glucose-6-phosphate dehydrogenase deficiency and neonatal jaundice in Nigeria. Acta Paediatr Scand 78(6):848-852. Owa, JA; Izedonmwen, OE; Ogundaini, AO; et al. (1993) Quantitative analysis of 1-naphthol in urine of neonates exposed to mothballs: the value in infants with unexplained anaemia. Afr J Med Sci 22:71-76. Shopp, GM; White, KL, Jr.; Holsapple, MP; et al. (1984) Naphthalene toxicity in CD-1 mice: general toxicology and immunotoxicology. Fundam Appl Toxicol 4(3 pt 1):406-419. U.S. Environmental Protection Agency (U.S. EPA). (1980) Ambient water quality criteria for naphthalene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Water Regulations and Standards, Washington, DC. EPA/440/5-80-059. NTIS PB81-117707. U.S. EPA. (1986) Health and environmental effects profile for naphthalene. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH 45268. EPA/600/X-86/241. NTIS/PB88-24238. U.S. EPA. (1987a) Summary review of health effects associated with naphthalene: health issue assessment. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-87/055F. U.S. EPA. (1988) Health effects assessment for naphthalene. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH 45268. EPA/600/8-89/094. NTIS/PB90-142464. U.S. EPA. (1998) Toxicological review for naphthalene. Available online at http://www.epa.gov/iris. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES ACGIH. (1986) Documentation of the threshold limit values and biological exposure indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists. Adkins, B, Jr.; Van Stee, EW; Simmons, JE; et al. (1986) Oncogenic response of strain A/J mice to inhaled chemicals. J Toxicol Environ Health 17(2-3):311-322. Buckpitt, AR. (1982) Comparative biochemistry and metabolism. Part II: naphthalene lung toxicity. Prepared for Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. AFAMRL-TR-82-52. p. 25-30. Bushy Run Research Center. (1986) Naphthalene acute inhalation toxicity study. TSCATS/303984, EPA/OTS Doc no. 86-870000558. National Toxicology Program (NTP). (1992a) Toxicology and carcinogenesis studies of naphthalene in B6C3F1 mice (inhalation studies). Technical Report Series No. 410. NIH Publication No. 92-3141. O'Brien, KAF; Smith, LL; Cohen, GM. (1985) Differences in naphthalene-induced toxicity in the mouse and rat. Chem Biol Interact 55(1-2):109-122. O'Brien, KAF; Suverkropp, C; Kanekal, S; et al. (1989) Tolerance to multiple doses of the pulmonary toxicant, naphthalene. Toxicol Appl Pharmacol 99(3):487-500. Plopper, CG; Suverkropp, C; Morin, D; et al. (1992) Relationship of cytochrome P-450 activity to Clara cell cytotoxicity. I. Histopathologic comparison of the respiratory tract of mice, rats and hamsters after parenteral administration of naphthalene. J Pharmacol Exp Ther 261(1):353-363. Tong, SS; Hirokata, Y; Trush, MA; et al. (1981) Clara cell damage and inhibition of pulmonary mixed-function oxidase activity by naphthalene. Biochem Biophys Res Commun 100(3):944-950. U.S. Environmental Protection Agency (U.S. EPA). (1980) Ambient water quality criteria for naphthalene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Water Regulations and Standards, Washington, DC. EPA/440/5-80-059. NTIS PB81-117707. U.S. EPA. (1986) Health and environmental effects profile for naphthalene. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/X-86/241. NTIS/PB88-24238. U.S. EPA. (1987a) Summary review of health effects associated with naphthalene: health issue assessment. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-87/055F. U.S. EPA. (1988) Health effects assessment for naphthalene. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Cincinnati, OH 45268. EPA/600/8-89/094. NTIS/PB90-142464. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC. EPA/600/8-90/066F. U.S. EPA. (1998) Toxicological review for naphthalene. Available online at http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Adkins, B; Van Stee, EW; Simmons, JE; et al. (1986) Oncogenic response of strain A/J mice to inhaled chemicals. J Toxicol Environ Health 17:311-322. Amacher, DE; Turner, GN. (1982) Mutagenic evaluation of carcinogens and non-carcinogens in the L5178Y/TK assay utilizing postmitochondrial fractions (S9) from normal rat liver. Mutat Res 97:49-65. Arfsten, DP; Davenport, R; Schaeffer DJ. (1994) Reversion of bioluminescent bacteria (MutatoxTM) to their luminescent state upon exposure to organic compounds, munitions, and metal salts. Biomed Environ Sci 7:144-149. Barfknecht, TR; Naismith, RW; Matthews RJ. (1985) Rat hepatocyte primary culture/DNA repair test. PH 311-TX-008-85. 5601-56-1 (unpublished material). Pharmakon Research International, Inc., Waverly, PA. Submitted to Texaco, Inc., Beacon, NY. Submitted to U.S. EPA by Texaco, Inc. Office of Toxic Substances Microfiche No. 0TS0513638. Bos, RP; Theuws, JL; Jongeneelen, FJ; et al. (1988) Mutagenicity of bi-, tri- and tetracyclic aromatic hydrocarbons in the taped-plate assay and in the conventional Salmonella mutagenicity assay. Mutat Res 204:2033-206. Boyland, E; Busby, ER; Dukes, CE; et al. (1964) Further experiments on implantation of materials into the urinary bladder of mice. Br J Cancer 18:575-581. Buckpitt, AR. (1982) Comparative biochemistry and metabolism. Part II: naphthalene lung toxicity. Prepared for Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH. AFAMRL-TR-82-52. p. 25-30. Connor, TH; Theiss, JC; Hanna, HA; et al. (1985) Genotoxicity of organic chemicals frequently found in the air of mobile homes. Toxicol Lett 25:33-40. Delgado-Rodriguez, A; Ortiz-Marttelo, R; Graf, U; et al. (1995) Genotoxic activity of environmentally important polycyclic aromatic hydrocarbons and their nitro derivatives in the wing spot test of Drosophila melanogaster. Mutat Res 341:235-247. Florin, I., Rutberg, L; Curvall, M; et al. (1980) Screening of tobacco smoke constituents for mutagenicity using the Ames test. Toxicology 18:219-232. Flowers-Geary, L; Bleczinski, W; Harvey, RG; et al. (1994) Cytotoxicity and mutagenicity of polycyclic aromatic hydrocarbons (PAH) o-quinones produced by dihydrodiol dehydrogenase. Proc Ann Meet Am Assoc Cancer Res 35:A965. Freeman, AE; Weisburger, EK; Weisburger, JH; et al. (1973) Transformation of cell cultures as an indication of the carcinogenic potential of chemicals. J Natl Cancer Inst 51:799-808. Gocke, E; King, M-T; Eckhardt, K; et al. (1981) Mutagenicity of cosmetics ingredients licensed by the European communities. Mutat Res 90:91-109. Godek, EG; Naismith, RW; Matthews, RJ. (1985) Ames Salmonella/microsome plate test (EPA/OECD) (unpublished material). Pharmakon Research International Inc, Waverly, PA. Submitted to Texaco, Inc, Beacon, NY. Submitted to U.S. EPA by Texaco, Inc. Office of Toxic Substances Microfiche No. OTS0513637. Gollahon, LS; Iyer, P; Martin, JE; et al. (1990) Chromosomal damage to preimplantation embryos in vitro by naphthalene. Toxicologist 10:274. Harper, BL; Ramanujam, VMS; Gad-El-Karim, MM; et al. (1984) The influence of simple aromatics on benzene clastogenicity. Mutat Res 128:105-114. Hossack, DJN; Richardson, JC. (1977) Examination of the potential mutagenicity of hair dye constituents using the micronucleus test. Experientia 33:377-378. Ijiri, I; Shimosato, K; Ohmae, M; et al. (1987) A case report of death from naphthalene poisoning. Jpn J Legal Med 41(1):52-55. Knake, E. (1956) Weak tumor producing effect of naphthalene and benzene. Virchows Arch Pathol Anat Physiol 329:141-176. (Ger.) La Voie, EJ; Dolan, S; Little, P; et al. (1988) Carcinogenicity of quinoline, 4- and 8-methylquinoline and benzoquinolines in newborn mice and rats. Food Chem Toxicol 26:625-629. McCann, J; Choi, E; Yamasaki, E; et al. (1975) Detection of carcinogens as mutagens in the Salmonella/microsome test: assay of 300 chemicals. Proc Natl Acad Sci 72:5135-5139. Mersch-Sundermann, V; Mochayedi, S; Kevekordes, S; et al. (1993) The genotoxicity of unsubstituted and nitrated polycyclic aromatic hydrocarbons. Anticancer Res 13:2037-2044. Murata, T; Denda, A; Maruyama, H; et al. (1993) Chronic toxicity and carcinogenicity studies of 1-methylnaphthalene in B6C3F1 mice. Fundam Appl Toxicol 21:44-51. Murata, Y; Denda, A; Maruyama, H; et al. (1997) Chronic toxicity and carcinogenicity studies of 2-methylnaphthalene in B6C3F1 mice. 36:90-93 (1997). Nakamura, S; Oda, Y; Shimada, T; et al. (1987) SOS-inducing activity of chemical carcinogens and mutagens in Salmonella typhimurium TA1535/pSK 1002: examination with 151 chemicals. Mutat Res 192:239-246. Narbonne, JF; Cassand, P; Alzieu, P; et al. (1987) Structure-activity relationships of the N-methylcarbamate series in Salmonella typhimurium. Mutat Res 191:21-27. National Toxicology Program (NTP). (1992a) Technical Report on the Toxicology and Carcinogenesis Studies of Naphthalene (CAS No. 91-20-3) in B6C3F1 Mice. (Inhalation Studies). DHHS, PHS, NIH, Rockville, MD. Probst, GS; Hill, LE. (1980) Chemically-induced DNA repair synthesis in primary rat hepatocytes: A correlation with bacterial mutagenicity. Ann NY Acad Sci 349:405-406. Rhim, JS; Parks, DK; Weisburger, EK. (1974) Evaluation of an in vitro assay system for carcinogens based on prior infection of rodent cells with nontransforming RNA tumor virus. J Natl Cancer Inst 52:1167-1173. Sakai, M; Yoshida, D; Mizusdki, S. (1985) Mutagenicity of polycyclic aromatic hydrocarbons and quinones on Salmonella typhimurium TA97. Mutat Res 156:61-67. Schmauhl, D. (1955) Examination of the carcinogenic action of naphthalene and anthracene in rats. Z Krebsforsch 60:697-710. Sina, JF; Bean, CL; Dysart, GR; et al. (1983) Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutat Res 113:357-391. Sorg, RM; Naismith, RW; Matthews, RJ. (1985) Micronucleus test (MNT) OECD (unpublished material). Pharmakon Research International Inc., Waverly PA. Submitted to U.S. EPA by Texaco, Inc. Office of Toxic Substances Microfiche No. OTS0513639. Tingle, MD; Pirmohamed, M; Templeton, E; et al. (1993) An investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from naphthalene by human liver microsomes. Biochem Pharmacol 46:1529-1538. Tsuda, H; Lee, G; Farber, E. (1980) Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens. Cancer Res 40:1157-1164. U.S. EPA. (1987b) Recommendations for and documentation of biological values for use in risk assessment. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. EPA/600/6-87-008. U.S. EPA. (1996, April 23) Proposed guidelines for carcinogen risk assessment. Federal Register 61(79):17960-18011. U.S. EPA. (1998) Toxicological review for naphthalene. Available online at http://www.epa.gov/iris. Wilson, AS; Tingle, MD; Kelly, MD; et al. (1995) Evaluation of the generation of genotoxic and cytotoxic metabolites of benzo[a]pyrene, aflatoxin B, naphthalene and tamoxifen using human liver microsomes and human lymphocytes. Human Exp Toxicol 14:507-515. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Naphthalene CASRN -- 91-20-3 Last Revised - 09/17/1998 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 12/01/1990 II. Carcinogen assessment on-line 12/01/1990 VI. Bibliography on-line 01/01/1992 IV. Regulatory Action section on-line 09/01/1992 II. Classification noted as pending change 09/01/1992 II.D.2. Work group review date added 11/01/1993 I.A. Work group review date added 09/01/1994 I.A. Work group review date added 05/01/1995 II. Pending change note replaced 05/01/1995 II.D.2. Work group review date added 07/01/1995 II. Pending change note replaced; see new note 08/01/1995 II. Note revised 08/01/1995 II.A.3. Paragraph 1 revised 08/01/1995 I.A., II., II.D.2. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 09/17/1998 I, II, VI Revised RfD, RfC, carcinogenicity assessments 09/01/2002 II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 427 of 1119 in IRIS (through 2003/06) AN: 458 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199307 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Selenium-sulfide- SY: 7446-34-6; HSDB-679-; NCI-C50033-; SELENIUM-MONOSULFIDE-; SELENIUM-SULPHIDE-; SELENSULFID [GERMAN]; SULFUR-SELENIDE-; 7488-56-4; CASWELL NO. 732A; DISULFURE DE SELENIUM [FRENCH]; DISULFURO DE SELENIO [SPANISH]; EPA-PESTICIDE-CHEMICAL-CODE-072003-; EXSEL-; SELEEN-; SELENIUM-DISULFIDE-; SELENIUM-DISULPHIDE-; SELSUN-; SELSUN-BLUE-; UN-2657- RN: 7446-34-6 HSN: 679 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Selenium sulfide CASRN -- 7446-34-6 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Selenium sulfide CASRN -- 7446-34-6 NORC: Not available at this time. ============================================================================ UDCA: 199307 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Selenium sulfide CASRN -- 7446-34-6 Last Revised -- 07/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NOCA: Note: This assessment is also for selenium disulfide (CASRN 7488-56-4). ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Based on inadequate data from human studies and sufficient evidence in animals. When administered orally, selenium sulfide produced hepatocellular carcinomas in both sexes of F344 rats and female B6C3F1 mice and alveolar/bronchiolar carcinomas or adenomas in female B6C3F1 mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Data on the possible carcinogenicity of selenium sulfide in humans are inadequate. Some human data for selenium and various selenium compounds are, however, available. Several investigators have studied the association between serum selenium and the risk of cancer through prospective, case-control and nested case-control studies. Analysis of blood serum levels indicated that patients with cancer, particularly gastrointestinal cancer, prostatic cancer, or Hodgkin's lymphoma, had significantly lower blood selenium levels than healthy patients (Shamberger et al., 1973; Salonen et al., 1984; Kok et al., 1987; Willet et al., 1983; Willet and Stampfer, 1986). The risk of cancer for men (Kok et al., 1987) or for all subjects (Willet et al., 1983) in the lowest quintile of serum selenium was twice that of subjects with higher levels. Geographic correlational studies have compared cancer mortality in areas of high vs. low levels of naturally occurring selenium. Shamberger and Frost (1969) reported that an inverse relationship existed between cancer death rates and the selenium concentrations in foliage plants of several Canadian provinces. The human cancer death rate in provinces with selenium-containing plants was 122.2 +/- 7.8 (presumably per 100,000 population although this was not specified), while in the provinces devoid of these plants, the human death rate was 139.9 +/- 4.0. In an ecological study Shamberger and Willis (1971) reported that there was a correlation between decreased cancer death rates in humans and an increase in the selenium in the forage crops in California. In high-selenium areas (selenium 0.11 ppm of forage crops) the cancer death rate per 100,000 was 141.2. In the medium-selenium areas (0.05-0.10 ppm) the cancer death rate was 190.1. In low-selenium areas (0.02-0.05 ppm) the cancer death rate was 233.0. Shamberger and Willis (1971) also investigated the ratio of observed to expected cancer death rates by anatomic site for men in 17 paired cities including high- and low-selenium areas. The anatomic sites that would come into contact with dietary selenium, such as pharynx, esophagus, stomach, bladder and intestine, showed a substantially lower rate ratio in the high-selenium cities than in the low-selenium cities. Other ecological and prospective studies have correlated an increased incidence of colon, breast and other forms of cancer in humans in geographic areas where selenium is deficient and a lowered cancer incidence with higher selenium concentrations (Schrauzer and Ishmael, 1974; Shamberger, 1976; Schrauzer et al., 1976; Jansson et al., 1978; Yang et al., 1983). In a study of approximately 300 employees exposed to selenium (form not specified) in a rectifier (electronics) process over a 26-year period, only 17 deaths occurred, 6 of which were due to cancer (Glover, 1970). This number, however, is not statistically different from the 5.1 deaths expected based on national mortality rates. The source of the mortality rates was not specified. Several toxic effects including pulmonary irritation, epigastric pain and dermal irritation and dermatitis were associated with selenium exposure in men, but no carcinogenic effect was reported. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. NCI (1980a) conducted a bioassay of selenium sulfide on F344 rats and B6C3F1 mice. Selenium sulfide (a mixture of selenium monosulfide and selenium disulfide) in 0.5% aqueous carboxymethyl cellulose was administered by gavage at 3 or 15 mg/kg/day to F344 rats (50/sex/group) 7 days/week for 103 weeks. Survivors were sacrificed at 104-105 weeks. Controls (50/sex/group) consisted of an untreated group and a group receiving the vehicle only. Body weights were slightly decreased relative to vehicle controls (approximately 10%) in high-dose male and female rats, suggesting an MTD had been achieved. Survival was comparable (approximately 78%) between treated groups and vehicle controls. A significant dose-related trend was seen in the incidence of hepatocellular carcinoma or neoplastic nodules in males and females. A statistically significant increase in the incidence of hepatocellular carcinomas and combined hepatocellular carcinoma or neoplastic nodules was observed in high-dose males and females relative to their respective vehicle controls. In males, incidence of hepatocellular carcinoma was 0/50, 0/50 and 14/49, and the incidence of hepatocellular carcinoma or neoplastic nodules was 1/50, 0/50 and 24/49 for the vehicle control, low-, and high-dose groups, respectively. In females, the incidence of hepatocellular carcinoma was 0/50, 0/50 and 21/50, and the incidence of hepatocellular carcinoma or neoplastic nodules was 1/50, 0/50 and 37/50 for vehicle control, low-, and high-dose groups, respectively. In male rats, there was a statistically significant dose-related increase in the incidence of lymphoma or leukemia. The incidence in the treated groups was significantly higher than the vehicle-control group; however, the untreated-control group was not included in the statistical analysis, and the incidence of lymphoma or leukemia in untreated controls was 21/49 (43%) compared with 7/50 (14%), 15/50 (30%), and 17/49 (35%) for the vehicle control, low-dose and high-dose groups, respectively. Because the incidence of these tumors was lower in the low- and high-dose groups than in the untreated controls, their occurrence in male rats cannot be clearly related to administration of selenium sulfide. In male rats, incidence of testicular interstitial-cell tumors showed a statistically significant dose-related trend (41/50, 82% vehicle control; 45/50, 90% low dose; 47/49, 96% high dose) and the elevation in the high-dose group was statistically significant relative to vehicle controls. The untreated control incidence was 42/48 (88%). No historical records for this laboratory in which aqueous carboxymethyl cellulose was used as a vehicle are available for comparison. However, NCI reports that interstitial-cell tumors occur in 75-100% of aged control male F344 rats. Female rats showed a statistically significant dose-related decrease in pituitary chromophobe adenoma (23/50, 14/49, 11/48). Selenium sulfide (a mixture of selenium monosulfide and selenium disulfide) in 0.5% aqueous carboxymethyl cellulose was administered at 20 or 100 mg/kg/day by gavage to B6C3F1 mice (50/sex/group) 7 days/week for 103 weeks (NCI, 1980a). Survivors were sacrificed at 104-105 weeks. Controls (50/sex) consisted of an untreated group and a group receiving the vehicle. Body weights and survival of the treated mice were comparable with those of the vehicle control groups, suggesting an MTD may not have been reached. Survival at termination was approximately 60-70% for males and approximately 78-86% for females. The incidence of alveolar/bronchiolar carcinoma in female mice (0/49, 1/50, 4/49 for control, low-dose and high-dose females, respectively) showed a statistically significant dose-related increase. The incidence of alveolar/bronchiolar carcinomas or adenomas in females also showed a statistically significant dose-related elevation. The incidence in the high-dose group was statistically significantly increased above vehicle controls and untreated controls. Incidence of alveolar/bronchiolar carcinomas or adenomas in the untreated controls, vehicle controls, low-dose, and high-dose groups was 2/50 (4%), 0/49, 3/50 (6%) and 12/49 (24%), respectively. The incidence of these tumors in other vehicle control groups maintained in the same room ranged from 2-12% (selenium sulfide untreated control females were 4%). NCI concluded the lung tumors in female mice were related to administration of selenium sulfide, but there was a high variability of these tumors. In males, incidence of alveolar/bronchiolar carcinomas or adenomas (4/50, 10/50, 13/50 for control, low-dose and high-dose males, respectively) showed a statistically significant dose-related elevation and was significant in the high-dose group only when compared with the vehicle controls. When compared with the untreated control males (9/48, 18%), the incidence of alveolar/bronchiolar carcinomas or adenomas in treated male mice was not statistically significant. Because it uses a Bonferoni adjustment for pairwise comparisons, which has a more stringent significance criterion, NCI concluded that the incidence of lung tumors in male mice could not be clearly related to selenium sulfide administration. In male mice, the incidence of lymphoma or leukemia (4/50, 12/50, 8/50 in the control, low- and high-dose groups, respectively) was statistically significantly elevated only in the low-dose group relative to vehicle controls. The incidence of hepatocellular carcinoma alone (15/50, 11/50, 23/50) and when combined with adenomas (15/50, 14/50, 23/50) showed a significant positive trend, but pairwise comparisons were not statistically significant. Incidence of hepatocellular carcinomas alone or when combined with adenomas showed a statistically significant dose-related increase in female mice. Incidence of hepatocellular carcinoma alone (0/49, 1/50, 22/49 in the control, low- and high-dose groups, respectively) and hepatocellular carcinoma or adenoma (0/49, 2/50, 25/49) was statistically significantly elevated in the high-dose females relative to vehicle control females. Because selenium sulfide is used as an antidandruff agent in shampoos, NCI conducted two bioassays to assess possible carcinogenicity by the dermal route. In the first study, a suspension of selenium sulfide in 0.5% aqueous carboxymethyl cellulose was applied to the clipped backs of ICR Swiss mice (50/sex/group) at 0, 0.5 or 1.0 mg/animal three times weekly for 86 weeks (NCI, 1980b). The mice were housed individually. Body weights and mortality were comparable between treated and control mice, although mortality was high in all groups after 52 weeks and the study was terminated after 88 weeks. Survival at termination was approximately 10-20% for all groups. NCI attributed most of the deaths to multiple organ amyloidosis, especially that of the liver, kidney and spleen. Incidence of alveolar/bronchiolar carcinoma or adenoma in female mice (2/50, 4% control; 4/49, 8% low dose; 8/49, 16% high dose) showed a statistically significant dose-related increase and was elevated in the high-dose animals when compared with vehicle controls. However, the incidence of these tumors in untreated controls (9/49, 18%) was greater than the vehicle control group or the dosed groups. The time-to-tumor onset in the high-dose group was 25 weeks, whereas in the vehicle controls the first tumor was observed at 86 weeks. In female mice a statistically significant dose-related increase was reported in the total hemangiomas or hemangiosarcomas incidence for all sites combined. The incidence was 1/50, 0/50, 1/50 and 4/50 for the untreated, vehicle, low-dose and high-dose groups, respectively. No tumors were found in male mice. While an MTD did not appear to be reached, skin irritation (hyperkeratosis and acanthosis) at the application site suggests higher doses might not have been tolerated. Under the conditions of this bioassay, dermal application of selenium sulfide produced an equivocal carcinogenic effect in ICR Swiss mice, but the study was limited by the relatively short lifespan of this strain of mouse. In the second bioassay (NCI, 1980c), Selsun shampoo, which contains 2.5% selenium sulfide, was applied to the clipped backs of ICR Swiss mice (50/sex/group). Doses of 0.05 mL of 25% or 50% Selsun in distilled water (0.313 or 0.625 mg selenium sulfide/animal) were applied three times weekly for 86 weeks. Vehicle controls were clipped and treated with distilled water; untreated controls were clipped only. The mice were housed individually. Mean body weights and mortality were comparable between groups, although mortality was high in all groups after 52 weeks and the study was terminated after 88 weeks. Survival at termination was approximately 10-20% for all groups. NCI attributed most of the deaths to multiple organ amyloidosis, especially that of the liver, kidney and spleen. In male mice, alveolar/bronchiolar carcinomas or adenomas occurred with a significant dose-related trend. Incidences in the high-dose group (9/48, two of which were carcinomas) and in the low-dose group (7/50, all adenomas) were statistically significantly higher than the incidence in the vehicle control group (1/49). The time to observation of the first tumor was 49, 68, 87 and 53 weeks for the high-dose, low-dose, vehicle control and untreated control groups, respectively. NCI concluded that comparison of matched vehicle-control groups with the high-dose group indicates the possibility of an association of the administration of Selsun with the occurrence of lung tumors. However, since alveolar/bronchiolar adenomas have been reported as common tumors in aged Swiss mice, the incidences of these tumors observed among male mice could not be clearly related to dermally-applied Selsun. Tumor incidences in treated female mice were comparable to controls. While an MTD did not appear to be reached, skin irritation (hyperkeratosis and acanthosis) at the application site suggests higher doses might not have been tolerated. The study is limited by the short lifespan of the animals. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Although selenium sulfide has not been assayed for genotoxicity, other selenium compounds have given conflicting results in genotoxicity assays. These results have been reviewed in U.S. EPA (1989a,b) and in the Selenium and Compounds IRIS assessment. Selenium is an essential micronutrient for several species, including humans, and is part of several enzymes, such as glutathione peroxidase, an enzyme involved in cellular defense against oxidative damage, and heme oxidase. While low doses of selenium are essential, high doses of selenium or a deficiency of dietary selenium may produce toxicity, such as a carcinogenic response. Under some conditions selenium may be protective against tumor development. Bioavailability of selenium is dependent on numerous factors, including the intake levels, chemical form and nutritional status. Organic forms of selenium are more bioavailable than inorganic forms; selenates and selenites are the inorganic forms more readily absorbed. Selenium sulfide is less soluble in water than sodium selenate and selenite, but the extent to which selenium sulfide is absorbed dermally or through the gastrointestinal tract has not been fully elucidated (U.S. EPA, 1989b). Exposure to selenium sulfide is primarily through the use of antidandruff shampoos and pharmaceuticals. The greatest daily exposure to selenium is via food (U.S. EPA, 1989b). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1989a,b The 1989 Health and Environmental Effects Document on Selenium and Compounds has received OHEA review. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 11/09/1989, 03/07/1990, 05/03/1990 Verification Date -- 05/03/1990 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Selenium sulfide conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199103 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Selenium sulfide CASRN -- 7446-34-6 Last Revised -- 03/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Glover, J.R. 1970. Selenium and its industrial toxicology. Industr. Med. Surg. 39: 26-30. Jansson, B., M.M. Jacobs and A.C. Griffin. 1978. Gastrointestinal cancer: Epidemiology and experimental studies. Adv. Exp. Med. Biol. 91: 305-322. Kok, F.J., A.M. De Bruijn, A. Hofman, R. Vermeeren and H.A. Valkenburg. 1987. Is serum selenium a risk factor for cancer in men only? Am. J. Epidemiol. 125(1): 12-16. NCI (National Cancer Institute). 1980a. Bioassay of selenium sulfide (gavage) for possible carcinogenicity. NCI Tech. Report Ser. No. 194. NTP No. 80-17. NCI (National Cancer Institute). 1980b. Bioassay of selenium sulfide (dermal study) for possible carcinogenicity. NCI Tech. Report Ser. No. 197. NTP No. 80-18. NCI (National Cancer Institute). 1980c. Bioassay of Selsun for possible carcinogenicity. NCI Tech. Report Ser. No. 199. NTP No. 80-19. Salonen, J.T., G. Alfthan, J.K. Huttunen and P. Puska. 1984. Association between serum selenium and the risk of cancer. Am. J. Epidemiol. 120(3): 342-349. Schrauzer, G.N. and D. Ishmael. 1974. Effects of selenium and of arsenic on the genesis of spontaneous mammary tumors in inbred C3H mice. Ann. Clin. Lab. Sci. 4(6): 441-447. Schrauzer, G.N., D.A. White and C.J. Schneider. 1976. Inhibition of the genesis of spontaneous mammary tumors in C3H mice: Effects of selenium and of selenium-antagonistic elements and their possible role in human breast cancer. Bioinorg. Chem. 6(3): 265-270. Shamberger, R.J. 1976. Selenium in health and disease. Proceedings of the Symposium on Selenium-Tellurium in the Environment. Industrial Health Foundation, Inc., Pittsburgh, PA. p. 253-267. Shamberger, R.J. and D.V. Frost. 1060. Possible protection effect of selenium against human cancer. Canad. Med. Assoc. J. 100: 682. Shamberger, R.J. and C.E. Willis. 1971. Selenium distribution and human cancer mortality. Crit. Rev. Clin. Lab. Sci. 2: 211-221. Shamberger, R.J., E. Rukovena, A.K. Longfield et al. 1973. Antioxidants and cancer. I. Selenium in the blood of normals and cancer patients. J. Natl. Cancer Inst. 50: 863-870. U.S. EPA. 1989a. Evaluation of the Potential Carcinogenicity of Selenium Sulfide (Selenium Disulfide). Prepared by the Carcinogen Assessment Group, Office of Health and Environmental Assessment for the Office of Emergency and Remedial Response, Office of Solid Waste and Emergency Response, Washington, DC. OHEA-C-073-174. U.S. EPA. 1989b. Health and Environmental Effects Document on Selenium and Compounds. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste, Washington, DC. Willitt, W.C., B.F. Polk, J.S. Morris et al. 1983. Prediagnostic serum selenium and risk of cancer. Lancet. 2: 130-134. Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium intoxication of humans in China. Am. J. Clin. Nutr. 37: 872-881. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Selenium sulfide CASRN -- 7446-34-6 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 03/01/1991 II. Carcinogenicity assessment on-line 03/01/1991 VI. Bibliography on-line 01/01/1992 IV. Regulatory Action section on-line 07/01/1993 II.D.3. Primary contact's phone number changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 428 of 1119 in IRIS (through 2003/06) AN: 500 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/0500-tr.pdf UD: 199912 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Ethylene-glycol-monobutyl-ether- (EGBE) SY: 2-BUTOXYETHANOL- RN: 111-76-2 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199912 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Ethylene glycol monobutyl ether (EGBE) CASRN -- 111-76-2 Last Revised -- 12/30/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- ---------- Changes in mean HED: 5.1 mg/kg/day 10 1 0.5 corpuscular mg/kg/day volume (MCV) (PBPK and BMD05) Subchronic (rat and mice) drinking water study NTP, 1993 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions - A benchmark dose (BMD) assessment was performed using EPA Benchmark Dose Software (BMDS) version 1.1b. A copy of the latest BMDS program can be obtained from the Internet at www.epa.gov/ncea/bmds.htm. Cmax (peak blood concentrations) for butoxyacetic acid (BAA) in arterial blood of female rats following oral exposure was estimated using the PBPK model of Corley et al. (1994) as modified by Corley et al. (1997). The BMD05 was determined to be 64 uM, using the 95% lower confidence limit of the dose-response curve expressed in terms of the Cmax for BAA in blood. The PBPK model of Corley was used to "back-calculate" human equivalent dose of 5.1 mg/kg/day, assuming that rats and humans receive their entire dose of EGBE from drinking water over a 12-hr period each day. A detailed textual description of this assessment is provided in U.S. EPA (1999). PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP. (1993) Technical report on toxicity studies of ethylene glycol ethers 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol administered in drinking water to F344/N rats and B6C3F1 mice. U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP No. 26. NIH Publ. No. 93-3349. NTP (1993) performed a 13-week toxicity study in Fischer 344 rats and B6C3F1 mice using EGBE (2-butoxyethanol). Groups of 10/sex/species received EGBE in drinking water at doses of 0, 750, 1500, 3000, 4500, and 6000 ppm. The daily consumption of EGBE was calculated to be 0, 69, 129, 281, 367, or 452 mg/kg/day in male rats (based on water consumption of 22.3, 20.9, 19.6, 20.5, 17.7, and 16.4 g/day); 0, 82, 151, 304, 363, or 470 mg/kg/day in female rats (based on water consumption of 18.8, 17.1, 15.5, 15.2, 11.8, and 10.7 g/day); 0, 118, 223, 553, 676, or 694 mg/kg/day in male mice (based on water consumption of 5.1, 5.2, 4.9, 6.0, 4.8, and 3.7 g/day); and 0, 185, 370, 676, 861, or 1306 mg/kg/day in female mice (based on water consumption of 6.2, 6.6, 6.5, 5.6, 4.8, and 5.6 g/day). Complete histological exams were performed on all control animals and all animals in the highest dose group. Vaginal cytology and sperm indices were evaluated in rats and mice from the control and three highest dose groups. Hematologic changes in both sexes persisting until or developing by 13 weeks included dose-related indications of mild to moderate anemia. Male rats evaluated at 13 weeks showed significantly reduced red blood cell (RBC) counts at 281 mg/kg/day, reduced hemoglobin (Hgb) concentration, reduced platelets, and increased bone marrow cellularity at 367 mg/kg/day. Significant hematologic effects in female rats at week 13 included reduced RBC counts and Hgb concentration at 82 mg/kg/day, and increased reticulocytes, decreased platelets, and increased bone marrow cellularity at approximately 304 mg/kg/day. There were no histopathological changes in the testes and epididymis at any dose. Liver lesions, including cytoplasmic alterations, hepatocellular degeneration, and pigmentation, were observed in the males above 129 mg/kg/day and in the females above 151 mg/kg/day. As with the hematologic effects, these effects appeared to be more severe in females than in males. Cytoplasmic alterations of liver hepatocytes, consisting of hepatocytes staining more eosinophilic and lacking the basophilic granularity of the cytoplasm in hepatocytes of control animals, were observed in the low-dose groups (69 mg/kg/day for males [54.9 mg/kg/day using water consumption rates and body weights measured during the last week of exposure], and 82 mg/kg/day for females [58.6 mg/kg/day using water consumption rates and body weights measured during the last week of exposure]). The lack of cytoplasmic granularity or "ground-glass" appearance of the hepatocytes suggests that this response was not due to enzyme induction (Greaves, 1990). The hematological (decreased RBC count and Hgb) and hepatic changes were dose-related and were associated with more severe blood and liver effects at higher doses; 69-82 mg/kg/day was considered a lowest-observed-adverse-effect level (LOAEL). A no-observed-adverse-effect level (NOAEL) was not identified. Fewer effects were observed in male and female mice exposed to EGBE. Mean final body weight and body weight gain were essentially the same as control values at the two lower dose levels, but were slightly reduced at the three highest dose levels. Based on a comparison of NOAELs and LOAELs for hematological and liver effects, rats are more sensitive to EGBE than are mice. However, it is less clear whether male or female rats are the more sensitive to oral exposure. Hematologic and hepatocellular changes were noted in both sexes of rats. In female rats, both hematologic and hepatocellular changes were noted at the low-dose level (58.6 mg/kg/day). Only hepatocellular cytoplasmic changes were observed in low-dose male rats (54.9 mg/kg/day). However, these changes are likely to be adaptive responses to the subclinical level of hemolysis produced at this dose. Although a lower LOAEL was reported in male rats, this value gives no indication of the relative slope of the dose-response curve for males and females. Because this is an important factor for BMD analyses, a comparison of the mean corpuscular volume (MCV) and RBC count results for both male and female rats was performed, which demonstrated that female rats are more sensitive to the effects of EGBE than are males. For this reason, dose-response information on the hematological effects in female rats was selected as the basis for the oral RfD BMD analyses. As discussed in Section I.A.4 below, until more is known about the molecular interaction between 2-butoxyacetic acid (BAA) and specific cellular molecules, changes in MCV (as an indicator of erythrocyte swelling and increased numbers of reticulocytes) and RBC count (as an indicator of cell lysis) serve as the earliest measurable response for both oral and inhalation exposures to EGBE. Model analyses of the data from this study (NTP, 1993) estimated steeper dose-response curves for MCV. For this reason, dose-response information on MCV is used to derive an RfD for EGBE. Two important pieces of information were used to select Cmax for BAA in the blood as the more appropriate dose metric. First, there is convincing evidence (for details see Section I.A.4 and U.S. EPA, 1999) to indicate that an oxidative metabolite, BAA, is the causative agent for EGBE-induced hemolysis (Carpenter et al., 1956; Ghanayem et al., 1987a, 1990). With this in mind, dose metrics for BAA in blood appear to be more appropriate than those for EGBE in blood, since they are more closely linked mechanistically to the toxic response. Second, EGBE-induced hemolysis appears to be highly dependent upon the dose rate. Ghanayem et al. (1987b) found that gavage doses to F344 male rats of 125 mg/kg EGBE resulted in hemolytic effects including reduced RBC count, Hgb, and Hct, and kidney pathology (Hgb casts and intracytoplasmid Hgb). However, hemolytic effects were not reported at a similar acute drinking water dose of 140 mg/kg (Medinsky et al., 1990). Although a slight drop in RBC count and Hgb (9% and 7%, respectively) was noted in F344 male rats after 1 week of drinking water exposure to 129 mg/kg/day EGBE, dose-related kidney pathology was not observed in these rats, even after 13 weeks of drinking water exposure to up to 452 mg/kg/day EGBE (NTP, 1993). Finally, Corley et al. (1994) have also suggested that Cmax may be a better dose metric than AUC (area under the blood concentration x time curve). Cmax (peak blood concentrations) for BAA in arterial blood of female rats following oral exposure was estimated using the PBPK model of Corley et al. (1994) as modified by Corley et al. (1997). This model incorporates allometrically scalable physiological and biochemical parameters (e.g., blood flows, tissue volumes, and metabolic capacity) in place of the standard values for a 70-kg human. These parameters normalize standard values to the actual body weights of the subjects in several human kinetic studies. The physiology of humans under exercise conditions was maintained in the model. The rat was included to expand the database for model validation and to assist in interspecies comparisons of target tissue doses (BAA in blood). Using Cmax for BAA in blood as the dose metric, the BMD05 was determined to be 64 uM. The PBPK model was used to "back-calculate" a human equivalent dose of 5.1 mg/kg/day, assuming that rats and humans receive their entire dose of EGBE from drinking water over a 12-hour period each day. For a more detailed discussion of these and other issues pertaining to the derivation of EGBE RfD, reference concentration (RfC), or cancer assessment, refer to U.S. EPA (1999). UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- 10 (to account for intrahuman sensitivity). A value of 10 was selected to account for variation in sensitivity within the human population (UFH). Potentially susceptible subpopulations include individuals with enhanced metabolism or decreased excretion of BAA, and individuals whose red blood cell walls are less resistant to the lysis caused by BAA. An uncertainty factor of 10 was retained in order to account for the uncertainty associated with the variability of the human response to the effects of EGBE. Human in vitro studies suggest that the elderly and patients with fragile RBCs would not be more sensitive to the hemolytic effects of EGBE than normal adults, and laboratory animal (rats, calves, and mice) studies suggest that older animals are more sensitive than neonates and females are more sensitive than males (see further details in I.A.4). However, actual human responses to EGBE have not been observed in a broad enough range of exposure conditions (e.g., repeat/long-term exposures) and potentially sensitive subjects (e.g., individuals predisposed to hemolytic anemia, infants) to warrant reduction of the UFH below the default value of 10. Even though developmental studies do not reveal increased susceptibility in infants, none of the developmental studies examined fetal or infant blood for signs of effects from prenatal exposure to EGBE. The UF for interspecies variation (UFA) accounts for pharmacodynamic and pharmacokinetic differences between animals and humans. There is in vivo (Carpenter et al., 1956) and in vitro (Ghanayem and Sullivan, 1993; Udden and Patton, 1994; Udden, 1995) information indicating that, pharmacodynamically, humans are less sensitive than rats to the hematological effects of EGBE. For this reason, a fractional component of the UFA was considered. However, the in vivo relative insensitivity of humans cannot be quantified at this time. Thus, a value of 1 was used to account for pharmacodynamic differences between rats and humans. Because pharmacokinetic differences were adequately accounted for by a PBPK model, an overall UFA of 1 (1 for pharmacodynamics x 1 for pharmacokinetics) was used. A value of 1 was selected for extrapolating the results from a subchronic study to chronic exposures (UFS). Although no chronic oral studies are currently available for EGBE, there does not appear to be a significant increase in the severity of hemolytic effects beyond 1-3 weeks of oral (NTP, 1993) or inhalation (NTP, 1998) EGBE exposures. A value of 1 was used for the database UFD for all methods of analyses. Although no chronic oral studies or adequate human data are available for EGBE, oral and inhalation dose-response data indicate that there would be little if any increase in severity of hemolytic effects beyond subchronic exposure durations (NTP, 1993; NTP, 1998). There are chronic and subchronic studies available in two species (rats and mice) and adequate reproductive and developmental studies, as well as limited studies in humans following short-term inhalation exposure. MF -- 1. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) In laboratory animals, EGBE is absorbed following inhalation, oral (gavage), or percutaneous administration, and distributed rapidly to all tissues via the bloodstream. The uptake and metabolism of EGBE is essentially linear following a 6-hour inhalation exposure of up to 438 ppm, a concentration that caused mortality (Dill et al., 1998; Sabourin et al., 1992a). BAA is the primary metabolite in rats (Medinsky et al., 1990; Dill et al., 1998) and humans (Corley et al., 1997) following drinking water and inhalation exposures to EGBE. EGBE is eliminated primarily as BAA in urine, with lesser amounts of the glucuronide and sulfate conjugates of the parent alcohol (Bartnik et al., 1987; Ghanayem et al., 1987c). No significant differences in the urinary levels of BAA were found following administration of equivalent doses of EGBE either dermally or in the drinking water (Medinsky et al., 1990; Sabourin et al., 1992b; Shyr et al., 1993). Corley et al. (1997) report that elimination kinetics of EGBE and BAA appear to be independent of the route of exposure. Elimination of EGBE and BAA following repeated inhalation exposure appears to be dependent on species, sex, age, time of exposure, and exposure concentration (NTP, 1998; Dill et. al., 1998). Hematological effects appear to be the most sensitive of the adverse effects caused by EGBE in laboratory animals. Less clear, however, is the decision as to which of the hematological endpoints (changes in RBC count, reticulocyte count [RTC], MCV, hematocrit [Hct], and Hb) observed in EGBE-exposed animals is the most appropriate basis for an RfC/RfD. The suggested mechanism of action of EGBE is based on the fact that BAA, an oxidative metabolite of EGBE, appears to be the causative agent in hemolysis (Carpenter et al., 1956; Ghanayem et al., 1987a, 1990). The first event in this mechanism of action is the interaction between BAA and cellular molecule(s) in erythrocytes. The second event is erythrocyte swelling. The third event is cell lysis mediated by increase in osmotic fragility, and a loss of deformability of the erythrocyte (Ghanayem, 1989; Udden, 1994; Udden and Patton, 1994), which results in decreased values for RBC count, Hb, and Hct. The last event is compensatory erythropoiesis; that is, in response to the loss of erythrocytes, the bone marrow increases production of young RBCs (reticulocytes). Although changes in RTC sometimes represent the largest measurable differences between exposed animals and unexposed controls, this parameter is highly variable (CV = 30%-60%) and does not always exhibit a clear dose-dependent trend (NTP, 1993; 1998). The use of RTC as the critical endpoint is analogous to the use of cell proliferation versus quantification of cell death (histopathological). Whereas cell death has a direct relationship to chemical exposure, cell proliferation has multiple feedback control processes that can be both very sensitive and variable. Therefore, changes in RTC are not considered a suitable endpoint for deriving the RfC or RfD. Thus, until more is known about the molecular interaction between BAA and specific cellular molecules, changes in MCV (as an indicator of the second and last event of the mechanism described above) and RBC count (as an indicator of the third event) serve as the earliest measurable responses for both oral and inhalation exposures to EGBE. For this reason, dose-response information on MCV and RBC count are considered for derivation of an RfC and an RfD for EGBE. While the toxicokinetic mechanism proposed above may suggest that MCV should theoretically be the earlier indicator of hemolytic effects from EGBE exposure, recent studies suggest that the relationship between the rate of MCV increase and RBC count decrease may not be consistent across exposure protocols. In gavage studies of Ghanayem et al. (1987b) and NTP (1998) inhalation studies Hct, a measure of erythrocyte volume relative to blood volume, tended to decrease along with RBC count and Hgb at all exposure levels for which a hematologic effect was observed. However, Hct did not change as RBC count and Hgb decreased following drinking water exposures (NTP, 1993). Thus, the loss of erythrocytes (reduced RBC count) was apparently offset by a concurrent increase in the size of the individual cells (increased MCV) in the drinking water studies. This was not the case in the gavage and inhalation studies. Until the reason for this difference is known, EPA has chosen to make use of the empirically more sensitive endpoint (the endpoint that results in the steepest dose-response curve) in the following RfD/RfC derivations. A case of an intentional suicide attempt with an industrial-strength window cleaner was reported by Gualtieri et al. (1995). An 18-year-old male weighing 70 kg consumed between 360 and 480 mL of a concentrated glass cleaner containing 22% EGBE (dose 1131-1509 mg/kg). The patient was admitted to the hospital within 3 hours after ingestion with no abnormalities other than epigastric discomfort. Approximately 10 hours after admission, the patient was noticeably more lethargic, weak, and hyperventilating, consistent with the onset of metabolic acidosis. BAA and EGBE levels were measured. The patient was transferred to a tertiary care hospital, where hemodialysis was initiated (approximately 24 hours after ingestion) and ethanol therapy started 30 minutes later. Treatment also consisted of intravenous doses of 100 mg thiamine and 50 mg folic acid every 12 hours, and 50 mg pyridoxine every 6 hours. Following 4 hours of dialysis, the patient was alert and remained hemodynamically stable. Ten days following discharge, the patient was readmitted following a second ingestion of 480 mL of the same cleaner (EGBE dose 1509 mg/kg). Treatment, including ethanol therapy and hemodialysis, was initiated within a few hours of ingestion to control the metabolic acidosis. Because treatment was initiated soon after ingestion, ethanol therapy did have an impact on the disposition of EGBE (higher concentrations were detected than following the first ingestion) and BAA (lower levels were detected). As with the first episode, clinical manifestations of high-dose oral ingestion of nearly 1.1-1.5 g/kg body weight consisted of metabolic acidosis. No evidence of hemolysis or renal abnormalities was detected. As discussed in Sections I.A.2 and I.A.3 above, adult females have been identified as a sensitive subgroup for the purposes of deriving the RfD. Section I.A.2 describes laboratory animal studies that indicate that female rats are more sensitive than male rats to the hemolytic effects of EGBE. The following discussion describes why adults are believed to be more sensitive than neonates, infants, and children. The only human toxicity information available on the toxicity of EGBE to children is from the case study by Dean and Krenzelok (1991), who observed 24 children, age 7 months to 9 years, subsequent to oral ingestion of at least 5 mL of glass window cleaner containing EGBE in the 0.5% to 9.9% range (potentially 25 to 1500 mg EGBE exposures). The two children who had taken greater than 15 mL amounts of the cleaner did well after gastric emptying or lavage and observation in the hospital. The remainder were watched at home after receiving diluting oral fluids. No symptoms of EGBE poisoning or hemolysis were observed. Although the effects reported in adult poisonings have been more severe than those reported in these children, the adults tended to consume larger volumes and different concentrations of EGBE, making a comparison of toxic effects observed to age sensitivity of the human extremely difficult. There are numerous risk factors for anemia that might predispose an individual to or compound the adverse effects of EGBE-induced hemolysis (Berliner et al., 1999). It is generally recognized, however, that children have fewer risk factors for anemia than are present for adults because of (1) a higher rate of RBC turnover, (2) lower incidence of neoplastic disease in childhood as either a direct or indirect cause of anemia (<7000 of the 1,000,000 new cases of cancer each year in the United States occur in individuals < 15 years of age), (3) the fact that iron deficiency is almost always secondary to nutritional factors in children, (4) the relative rarity of alcoholism and its related liver disease, (5) a much lower incidence of anemia associated with thyroid disease, and (6) a rarity of cardiovascular disease other than congenital heart diseases so that valve replacement, malignant hypertension, and the use of certain drugs are not usually a factor (Berliner et al., 1999; Hord and Lukens, 1999). The primary cause for anemia in children is usually associated with an abnormality of the hematopoietic system (Berliner et al., 1999; Hord and Lukens, 1999). Studies of the osmotic fragility and deformability of RBCs exposed to EGBE's toxic metabolite BAA (Udden, 1994) suggest that certain patients with abnormal hematopoietic systems (sickle-cell anemia and hereditary spherocytosis patients) are not more sensitive to the hemolytic effects of EGBE than normal adults. Other studies suggest that the RBCs of children may be pharmacodynamically less sensitive to hemolysis than those of adults. RBCs of neonates and children (up to 6 months) differ from normal adult red blood cells in that they are larger and have higher levels of Hemoglobin F versus adult Hemoglobin A (Lewis, 1970). Frei et al. (1963) showed that the larger calf erythrocytes containing Hemoglobin F were osmotically more resistant than smaller adult erythrocytes containing Hemoglobin A. Frei et al. (1963) suggested that as fetal erythrocytes are replaced by postnatal erythrocytes, the total population of RBCs becomes more susceptible to lysis. The effect of age on EGBE-induced hematotoxicity was studied in male F344 rats by Ghanayem and co-workers (1987c, 1990). These studies also demonstrated the time course for the onset and resolution of hematological and histopathological changes accompanying hemolysis. Adult (9-13 week) male F344 rats were significantly more sensitive to the hemolytic effects of EGBE than were young (4-5 week) male rats following administration of a single gavage dose of EGBE at 32, 63, 125, 250, or 500 mg/kg. Concurrent metabolism studies also found increased blood retention of EGBE metabolite BAA (as measured by increased Cmax, AUC, and T1/2). It was also found that young rats eliminated a significantly greater proportion of the administered EGBE dose as exhaled carbon dioxide (CO2) or as urinary metabolites as well as excreting a greater proportion of the EGBE conjugates (glucuronide and sulfate) in the urine. These researchers suggested that the pharmacokinetic basis of the age-dependent toxicity of EGBE may be due to a reduced ability by older rats to metabolize the toxic metabolite BAA to CO2 and a diminished ability to excrete BAA in the urine. NTP (1998) also found that young mice (6-7 weeks) eliminated BAA 10 times faster than aged mice (19 months) following a 1-day exposure to 125 ppm EGBE. This difference was not as apparent after 3 weeks of exposure, suggesting that factors other than age may be involved (Dill et. al., 1998). Because of the known reproductive toxicity (i.e., toxicity to male testes and sperm) of two other glycol ethers, ethylene glycol methyl ether (EGME; 2-methoxyethanol) and ethylene glycol ethyl ether (EGEE; 2-ethoxyethanol), the reproductive toxicity of EGBE has been studied in a variety of well-conducted oral (Nagano et al., 1979, 1984; Grant et al., 1985; Foster et al., 1987; Heindel et al., 1990; Exon, 1991; NTP, 1993) and inhalation (Dodd et al., 1983; Doe, 1984; Nachreiner, 1994; NTP, 1998) studies using rats, mice, and rabbits. In addition, several developmental studies have addressed EGBE's toxicity from conception to sexual maturity, including toxicity to the embryo and fetus, following oral (Wier et al., 1987; Sleet et al., 1989), inhalation (Nelson et al., 1984; Tyl et al., 1984) and dermal (Hardin et al., 1984) exposures to rats, mice, and rabbits. In many instances, LOAELs and NOAELs were reported for both parental and developmental effects, therefore the developmental studies can also be used to assess systemic toxicity as well as developmental toxicity. EGBE did not cause adverse effects in any reproductive organ, including testes, in any study. In a two-generation reproductive toxicity study, fertility was reduced in mice only at very high, maternally toxic doses (> 1000 mg/kg). Maternal toxicity related to the hematologic effects of EGBE and relatively minor developmental effects have been reported in developmental studies. No teratogenic toxicities were noted in any of the studies. It can be concluded from these studies that EGBE is not significantly toxic to the reproductive organs (male or female) of parents, nor to the developing fetuses of laboratory animals. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=38. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Medium Data Base -- Medium-to-high RfD -- Medium-to-high The overall confidence in this RfD assessment is medium-to-high. The RfD value was calculated for EGBE using the combined PBPK/BMD method. A higher confidence is placed in the RfD values derived from internal dose measures because pharmacokinetic differences between rats and humans were accounted for using a validated PBPK model (Corley et al., 1994). Medium confidence is placed in the NTP (1993) study because it was not a chronic study; however, the study employed both male and female rats and mice, provided a wide range of exposure levels (0-6000 ppm EGBE in drinking water), and observed animals twice daily. Medium-to-high confidence is placed in the database because data are available for a variety of animal species, including humans. Although the database lacks long-term human studies, the available short-term human controlled studies and case reports, and laboratory animal and in vitro studies, provide ample evidence to suggest that long-term human exposures would be no more adverse than long-term rat exposures. Confidence in the database is not "high" because the potential for liver effects in humans from long-term exposure has not been investigated. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=57. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1999. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Ethylene Glycol Monobutyl Ether in support of summary information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1999). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=68. Agency Consensus Date -- 11/16/1999 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Ethylene glycol monobutyl ether (EGBE) conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 199912 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Ethylene glycol monobutyl ether (EGBE) CASRN -- 111-76-2 Last Revised -- 12/30/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Experimental Doses* UF MF RfC ------------------- ------------------- --- -- --- Changes in red blood HEC: 380 mg/m3 30 1 13 mg/m3 cell (RBC) count (PBPK and BMC05) Subchronic rat inhalation study NTP, 1998 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions - A benchmark dose (BMD) assessment was performed using EPA Benchmark Dose Software (BMDS) version 1.1b. A copy of the latest BMDS program can be obtained from the Internet at www.epa.gov/ncea/bmds.htm. Cmax (peak blood concentrations) for BAA in arterial blood of female rats following inhalation exposure was estimated using the PBPK model of Lee et al. (1998). The BMD05 was calculated to be 225 uM, using the 95% lower confidence limit of the dose-response curve expressed in terms of the Cmax for BAA in blood. The PBPK model of Corley et al. (1994; 1997) was used to "back-calculate" human equivalent concentration of 78 ppm (380 mg/m3) assuming continuous exposure (24 hours/day). A detailed textual description of this assessment is provided in U.S. EPA (1999). PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) National Toxicology Program (NTP). (1998) NTP technical report on the toxicology and carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP TR 484 NIH Draft Publication No. 98-3974. In the subchronic portion of this study, both F344 rats and B6C3F1 mice (10/sex) were exposed via inhalation to concentrations of 0, 31, 62.5, 125, 250, and 500 ppm of EGBE 6 hours/day, 5 days/week for 14 weeks (NTP, 1998). Both sexes of rats exhibited clinical signs consistent with hemolytic effects of EGBE at the three highest doses. Hematologic evaluation showed a mild to moderate regenerative anemia at all concentrations in females and at the highest three concentrations in males. Exposure-related trends were noted for reticulocytes (RTC), RBC count, MCV, hemoglobin, and hematocrit. Liver-to-body weight ratios were significantly increased in males at the two highest concentrations and in females at the highest concentration. Histopathological effects consisted of excessive splenic congestion in the form of extramedullary hematopoiesis, hemosiderin accumulation in Kupffer cells, liver necrosis, centrilobular hepatocellular degeneration, renal tubular degeneration, intracytoplasmic hemoglobin and hemosiderin deposition, and bone marrow hyperplasia at concentrations in excess of 62.5 ppm for male rats and 31 ppm for females. Also, five female rats were sacrificed moribund from the highest concentrations and one from the 250 ppm group. The LOAEL for hematological alterations was 31 ppm for female rats and 62.5 ppm for male rats. The 31 ppm exposure level was considered a NOAEL for male rats. The mice exposed via the inhalation route exhibited clinical signs consistent with the hemolytic effects of EGBE at the two highest concentrations for both sexes. Hematologic evaluation indicated a moderate regenerative anemia with an increase in platelets at the three higher concentrations in both sexes. Histopathological effects consisted of excessive extramedullary splenic hematopoiesis and hemosiderosis, hemosiderin accumulation in Kupffer cells, renal tubular degeneration and hemosiderin deposition, and testicular degeneration. Forestomach necrosis, ulceration, inflammation, and epithelial hyperplasia were observed at concentrations greater than 31 ppm for females and 62.5 ppm for males. Also, four females and four males either died or were sacrificed moribund at the highest concentration. The NOAEL for male and female mice was 31 ppm and the LOAEL in mice was 62.5 ppm, based on histopathological changes in the forestomach. NTP also completed a two-species, 2-year inhalation study on EGBE (NTP, 1998). In the chronic study, exposure concentrations of EGBE were 0, 31, 62.5, and 125 ppm for groups of 50 F344/N rats, and 0, 62.5, 125, and 250 ppm for groups of 50 B6C3F1 mice. The highest exposure was selected to produce a 10% to 15% depression in hematologic indices. Survival was significantly decreased in male mice at 125 and 250 ppm (54.0% and 53.1%, respectively), but no effect on survival was observed in rats. Mean body weights of all groups of male and female rats exposed to 31 and 62.5 ppm were similar to controls. From week 17 to the end of the study, the mean body weights of 125 ppm female rats were generally less than those of controls. Mean body weights of the exposed male and female mice were generally less than for controls, with females experiencing greater and earlier reductions. Nonneoplastic effects in rats included hyaline degeneration of the olfactory epithelium in males (13/48, 21/49, 23/49, 40/50) and females (13/50, 18/48, 28/50, 40/49), and Kupffer cell pigmentation in the livers of males (23/50, 30/50, 34/50, 42/50) and females (15/50, 19/50, 36/50, 47/50). The severity of the nasal lesion was not affected by exposure and was deemed to be, in general, an adaptive rather than adverse response to exposure (NTP, 1998). The Kupffer cell pigmentation results from hemosiderin accumulation and is a recognized secondary effect of the hemolytic activity of EGBE (NTP, 1998). Nonneoplastic effects in mice included forestomach ulcers and epithelium hyperplasia, hematopoietic cell proliferation and hemosderin pigmentation in the spleen, Kupffer cell pigmentation in the liver, hyaline degeneration of the olfactory epithelium (females only) and bone marrow hyperplasia (males only). As in the rats, the nasal lesion is deemed an adaptive rather than an adverse response to exposure, and the Kupffer cell pigmentation is considered a secondary effect of the hemolytic activity of EGBE. Bone marrow hyperplasia, and hematopoietic cell proliferation and hemosiderin pigmentation in the spleen, are also attributed to the primary hemolytic effect, which is followed by regenerative hyperplasia of the hematopoietic tissue. The forestomach lesions do not appear to be related to the hemolytic effect of EGBE. Incidences of ulcers were significantly increased in males exposed to 125 ppm and in all exposed female groups. Ulcers consisted of a defect in the forestomach wall that penetrated the full thickness of the forestomach epithelium, and frequently contained accumulations of inflammatory cells and debris. Incidences of epithelial hyperplasia, usually focal, were significantly increased in all exposed groups of males and females. The hyperplasia was often associated with ulceration, particularly in the females, and consisted of thickness of the stratified squamous epithelium and sometimes the keratinized layer of the forestomach. Using the same exposure groups described above, additional groups of rats (27/sex/exposure group) and mice (30/sex/exposure group) in the 2-year study were examined at 3, 6, and 12 months (8-10/duration) for hematologic effects. Rats in the 31 ppm exposure group were not examined at 12 months, and only hematology was examined at 3 months. As in the 14-week study, inhalation of EGBE by both species resulted in the development of exposure-related hemolytic effects, inducing a responsive anemia. In rats, the anemia was persistent and did not progress or ameliorate in severity from 3 months to the final blood collection at 12 months. Statistically significant (p < 0.05) decreases in automated and manual hematocrit values, hemoglobin, and erythrocyte counts occurred at 3, 6, and 12 months in the 62.5 ppm females and the 125 ppm males and females. Statistically significant decreases in these same endpoints were also observed in 31 ppm females exposed for 3 and 6 months, and in 62.5 ppm males exposed for 12 months. At 3 months, MCV was increased following 31 ppm and higher exposures in both males and females. In vitro studies by Ghanayem et al. (1989) have shown that the hemolysis caused by EGBE metabolite BAA is preceded by erythrocyte swelling. If the observed increase in MCV is in reponse to cell swelling, it could be a preliminary indicator of the hemolytic effect. Other researchers, however, have attributed the increased MCV at all exposures and the increased mean cell hemoglobin at higher exposure levels to the erythropoietic response subsequent to hemolysis and the corresponding increase in the number of larger reticulocytes in circulation (NTP, 1998). Reticulocyte count was increased significantly in female rats at 62.5 ppm (6 and 12 months) and in male rats at 125 ppm (3 and 6 months). Since a statistically significant increase in reticulocyte count was not observed at any duration in males or females exposed to 31 ppm, nor in males exposed to 62.5 ppm, it appears that reticulocyte count alone cannot account for the increase in MCV at these levels of exposure. The observed increases in MCV may be a combined result of erythrocyte swelling prior to and an increased number of reticulocytes subsequent to hemolysis, with the former being more influential at lower exposure levels and the latter having more relative impact at higher exposure levels. Similar effects indicating anemia were also observed in mice, with females being the more sensitive of the species. However, the anemia response was observed at higher doses and changed somewhat with duration of exposure. Statistically significant (p < 0.05) decreases in automated and manual hematocrit values, hemoglobin, and erythrocyte counts occurred at 3, 6, and 12 months in the 125 ppm females and the 250 ppm males and females. Statistically significant decreases in these endpoints were also observed in 62.5 ppm females exposed for 6 months and in 125 ppm males exposed for 6 and 12 months (decreases in hematocrit were observed only at 3 and 6 months). No changes were observed in the MCV of mice, except for an increase in females at the highest duration (12 months) and exposure (250 ppm) levels. Reticulocyte count was increased significantly in 125 ppm females at 3 and 6 months, and in 125 ppm males at 6 months. Based on a comparison of NOAELs and LOAELs for hematological and liver effects, rats are more sensitive than mice to EGBE. Based on a comparison of effect levels, female rats (NTP, 1998) appear to be more sensitive to the hematological effects of EGBE than the other animals. For this reason, concentration-response information on the hematological effects in female rats was selected as the basis for the inhalation RfC BMD analyses. As discussed in Section I.B.4 below, until more is known about the molecular interaction between BAA and specific cellular molecules, changes in MCV (as an indicator of erythrocyte swelling and increased number of reticulocytes) and RBC count (as an indicator of cell lysis) serve as the earliest measurable response for both oral and inhalation exposures to EGBE. Model analyses of the data from this study (NTP, 1998) predicted steeper dose-response curves for RBC count. For this reason, dose-response information on RBC count is used to derive an RfC for EGBE. Two important pieces of information were used to select Cmax for BAA in the blood as the more appropriate dose metric. First, there is convincing evidence (for details see I.B.4 and U.S. EPA, 1999) to indicate that an oxidative metabolite, BAA, is the causative agent for EGBE-induced hemolysis (Carpenter et al., 1956; Ghanayem et al., 1987a, 1990). With this in mind, dose metrics for BAA in blood appear to be more appropriate than those for EGBE in blood, since they are more closely linked mechanistically to the toxic response. Second, EGBE-induced hemolysis appears to be highly dependent upon the dose rate. Ghanayem et al. (1987b) found that gavage doses to F344 male rats of 125 mg/kg EGBE resulted in hemolytic effects including reduced RBC count, Hgb, and Hct, and kidney pathology (Hgb casts and intracytoplasmid Hgb). However, hemolytic effects were not reported at a similar acute drinking water dose of 140 mg/kg (Medinsky et al., 1990). While a slight drop in RBC count and Hgb (9% and 7%, respectively) was noted in F344 male rats after 1 week of drinking water exposure to 129 mg/kg/day EGBE, dose related kidney pathology was not observed in these rats, even after 13 weeks of drinking water exposure to up to 452 mg/kg/day EGBE (NTP, 1993). Finally, Corley et al. (1994) have also suggested that Cmax may be a better dose metric than AUC. Cmax (peak blood concentrations) for BAA in arterial blood of female rats following inhalation exposure was determined using the PBPK model of Lee et al. (1998). Using Cmax for BAA in blood as the dose metric, the BMC05 was determined to be 225 uM. The PBPK model of Corley et al. (1994; 1997) was used to "back-calculate" human equivalent concentration of 78 ppm (380 mg/m3) assuming continuous exposure (24 hours/day). For a more detailed discussion of these and other issues pertaining to the derivation of EGBE RfD, RfC, or cancer assessment, refer to U.S. EPA (1999). UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- 30 (a UF of 10 including 10 for intrahuman sensitivity and 3 for extrapolation from an adverse effect level). A value of 10 was selected to account for variation in sensitivity within the human population (UFH). Potentially susceptible subpopulations include individuals with enhanced metabolism or decreased excretion of BAA and individuals whose red blood cell walls are less resistant to the lysis caused by BAA. An uncertainty factor of 10 was retained in order to account for the uncertainty associated with the variability of the human response to the effects of EGBE. Human in vitro studies suggest that the elderly and patients with fragile RBCs would not be more sensitive to the hemolytic effects of EGBE than normal adults, and laboratory animal (rats, calves, and mice) studies suggest that older animals are more sensitive than neonates and females are more sensitive than males (see further details in I.B.4). However, actual human responses to EGBE have not been observed in a broad enough range of exposure conditions (e.g., repeat/long-term exposures) and potentially sensitive subjects (e.g., individuals predisposed to hemolytic anemia, infants) to warrant the reduction of the UFH below the default value of 10. While developmental studies do not reveal increased susceptibility in infants, none of the developmental studies examined fetal or infant blood for signs of effects from prenatal exposure to EGBE. The UF for interspecies variation (UFA) accounts for pharmacodynamic and pharmacokinetic differences between animals and humans. There is in vivo (Carpenter et al., 1956) and in vitro (Ghanayem and Sullivan, 1993; Udden and Patton, 1994; Udden, 1995) information indicating that, pharmacodynamically, humans are less sensitive than rats to the hematological effects of EGBE. For this reason, a fractional component of the UFA was considered. However, the in vivo relative insensitivity of humans cannot be quantified at this time. Thus, a value of 1 was used to account for pharmacodynamic differences between rats and humans. Because pharmacokinetic differences are adequately accounted for by a PBPK model, an overall UFA of 1 (1 for pharmacodynamics x 1 for pharmacokinetics) was used. A value of 3 was selected for extrapolating an adverse effect level to a NOAEL (UFL). A UFL value of less than 10 is justifiable because there is information that indicates that the estimated BMC05 value is near the threshold level for the hematological effects of concern. The effect (decreased RBC count) that formed the basis for this value was within 5% of the control value. In addition, the female rat BMC05 (130 mg/m3) derived from the NTP (1998) subchronic/chronic inhalation study was very close to the 121 mg/m3 (25 ppm) NOAEL identified for male and female rats in the Dodd et al. (1983) subchronic inhalation study. In the case of the RfD (Section I.A.3), a UFL value of 1 was used for the BMD analyses because the RfD BMD was based on a minimal and precursive lesion (cell swelling as measured by increased MCV). A threefold UFL is retained for the RfC because the RfC BMC is based on a more serious hematologic endpoint (red blood cell lysis as measured by a decrease in RBC count). A value of 1 was used for the database UFD for all methods of analyses. Subchronic and chronic inhalation studies suggest that there is little, if any, increase in severity of hemolytic effects beyond subchronic exposure durations (NTP, 1993; 1998). There are chronic and subchronic studies available in two species (rats and mice) and adequate reproductive and developmental studies, as well as limited studies in humans following short-term inhalation exposure. MF -- 1. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) In laboratory animals, EGBE is absorbed following inhalation, oral (gavage), or percutaneous administration and distributed rapidly to all tissues via the bloodstream. The uptake and metabolism of EGBE are essentially linear following a 6-hour inhalation exposure of up to 438 ppm, a concentration that caused mortality (Dill et al., 1998; Sabourin et al., 1992a). BAA is the primary metabolite in rats (Medinsky et al., 1990; Dill et al., 1998) and humans (Corley et al., 1997) following drinking water and inhalation exposures to EGBE. EGBE is eliminated primarily as BAA in urine, with lesser amounts of the glucuronide and sulfate conjugates of the parent alcohol (Bartnik et al., 1987; Ghanayem et al., 1987c). No significant differences in the urinary levels of BAA were found following administration of equivalent doses of EGBE either dermally or in the drinking water (Medinsky et al., 1990; Sabourin et al., 1992b; Shyr et al., 1993). Corley et al. (1997) report that elimination kinetics of EGBE and BAA appear to be independent of the route of exposure. Elimination of EGBE and BAA following repeated inhalation exposure appears to be dependent on species, sex, age, time of exposure, and exposure concentration (NTP, 1998; Dill et. al., 1998). Hematological effects appear to be the most sensitive of the adverse effects caused by EGBE in laboratory animals. Less clear, however, is the decision as to which of the hematological endpoints (changes in RBC count, reticulocyte count [RTC], MCV, Hct, and Hb) observed in EGBE-exposed animals is the most appropriate basis for an RfC/RfD. The suggested mechanism of action of EGBE is based on the fact that BAA, an oxidative metabolite of EGBE, appears to be the causative agent in hemolysis (Carpenter et al., 1956; Ghanayem et al., 1987a, 1990). The first event in this mechanism of action is the interaction between BAA and cellular molecule(s) in erythrocytes. The second event is erythrocyte swelling. The third event is cell lysis mediated by increase in osmotic fragility, and a loss of deformability of the erythrocyte (Ghanayem, 1989; Udden, 1994; Udden and Patton, 1994), which results in decreased values for RBC count, Hb, and Hct. The last event is compensatory erythropoiesis; that is, in response to the loss of erythrocytes, the bone marrow increases production of young RBCs (reticulocytes). Although changes in RTC sometimes represent the largest measurable differences between exposed animals and unexposed controls, this parameter is highly variable (CV = 30%-60%) and does not always exhibit a clear dose-dependent trend (NTP, 1993; 1998). The use of RTC as the critical endpoint is analogous to the use of cell proliferation versus quantification of cell death (histopathological). Whereas cell death has a direct relationship to chemical exposure, cell proliferation has multiple feedback control processes that can be both very sensitive and variable. Therefore, changes in RTC are not considered a suitable endpoint for deriving the RfC or RfD. Thus, until more is known about the molecular interaction between BAA and specific cellular molecules, changes in MCV (as an indicator of the second and last events of the mechanism described above) and RBC count (as an indicator of the third event) serve as the earliest measurable responses for both oral and inhalation exposures to EGBE. For this reason, dose-response information on MCV and RBC count is considered for derivation of an RfC and an RfD for EGBE. While the toxicokinetic mechanism proposed above may suggest that MCV should theoretically be the earlier indicator of hemolytic effects from EGBE exposure, recent studies suggest that the relationship between the rate of MCV increase and RBC count decrease may not be consistent across exposure protocols. In gavage studies of Ghanayem et al. (1987b) and NTP (1998) inhalation studies Hct, a measure of erythrocyte volume relative to blood volume, tended to decrease along with RBC count and Hgb at all exposure levels for which a hematologic effect was observed. However, Hct did not change as RBC count and Hgb decreased following drinking water exposures (NTP, 1993). Thus, the loss of erythrocytes (reduced RBC count) was apparently offset by a concurrent increase in the size of the individual cells (increased MCV) in the drinking water studies. This was not the case in the gavage and inhalation studies. Until the reason for this difference is known, EPA has chosen to make use of the empirically more sensitive endpoint (the endpoint that results in the steepest dose-response curve) in the following RfD/RfC derivations. Three controlled studies using inhalation exposure were conducted by Carpenter et al. (1956). In the first study, a group of two men and six rats was exposed simultaneously to an EGBE concentration of 113 ppm in a 1250 cubic ft. room for two 4-hour periods. Effects observed in humans included nasal and ocular irritation, a metallic taste in the mouth, and belching. Erythrocyte osmotic fragility did not change for the men; however, it rose appreciably for the rats. In a second study, a group of two men, one woman, and three rats was exposed to 195 ppm EGBE for two 4-hour periods, separated by a 30-minute recess, in a 6.5 cubic ft. room. There was no change in the blood pressure, erythrocyte fragility, or pulse rate of the human subjects. Irritation of the nose and throat followed by ocular irritation and disturbed taste were noted; one subject reported a headache. In the rats, an increase in erythrocyte fragility values was noted during exposure. In the third study, a group of two men and two women was exposed for an 8-hour period to an EGBE concentration of 100 ppm. No change in blood pressure, erythrocyte fragility, or pulse rate was observed. Irritation of the nose and throat followed by ocular irritation and a disturbing metallic taste were mentioned. Two subjects reported headaches. A cross-section of 31 male workers (22 to 45 years old; employed for 1 to 6 years) exposed to low levels of EGBE in a beverage packing production plant was evaluated by Haufroid et al. (1997). The effect of external EGBE and internal BAA exposure on erythrocyte lineage (RBC numeration, Hb, Hct, MCV, MCH, mean corpuscular hemoglobin concentration [MCHC], haptoglobin [Hp], reticulocyte numeration [Ret] and osmotic resistance [OR]), as well as hepatic (SGOT, SGPT) and renal creatinine and urinary retinol binding protein parameters was investigated. The average airborne concentration of EGBE was 2.91 mg/m3 (0.6 ppm) (SD +/- 1.30 mg/m3 or 0.27 ppm). Single determinations of BAA in post-shift urine samples were used to assess exposure to low levels of EGBE. No difference between exposed and control workers was observed for RBC count, Hb, MCV, MCH, Hp, Ret, and OR (a measure of osmotic fragility). The only statistically significant change observed in exposed workers when compared with a matched control group (n=21) was a 3.3% decrease in Hct (p = 0.03) and a 2.1% increase in MCHC (p = 0.02). The implications of these small erythroid effects are unclear. Both values are within their corresponding normal clinical ranges and, given that no statistically significant changes were observed in other erythroid parameters, do not appear to be related to the more severe adverse effects observed in laboratory animals. No significant differences were observed in hepatic and renal biomarkers. As discussed in Sections I.B.2 and I.B.3 above, adult females have been identified as a sensitive subgroup for the purposes of deriving the RfC. Section I.B.2 describes why females were identified as being more sensitive than males. The following discussion describes why adults are believed to be more sensitive than children. The only human toxicity information available on the toxicity of EGBE to children is from the case study by Dean and Krenzelok (1991), who observed 24 children, age 7 months to 9 years, subsequent to oral ingestion of at least 5 mL of glass window cleaner containing EGBE in the 0.5% to 9.9% range (potentially 25 to 1500 mg EGBE exposures). The two children who had taken greater than 15 mL amounts of the cleaner did well after gastric emptying or lavage and observation in the hospital. The remainder were watched at home after receiving diluting oral fluids. No symptoms of EGBE poisoning or hemolysis were observed. Although the effects reported in adult poisonings have been more severe than those reported in these children, the adults tended to consume larger volumes and different concentrations of EGBE, making a comparison of toxic effects observed to age sensitivity of the human extremely difficult. There are numerous risk factors for anemia that might predispose an individual to or compound the adverse effects of EGBE induced hemolysis (Berliner et al., 1999). It is generally recognized, however, that children have fewer risk factors for anemia than are present for adults because of (1) a higher rate of RBC turnover, (2) lower incidence of neoplastic disease in childhood as either a direct or indirect cause of anemia (<7000 of the 1,000,000 new cases of cancer each year in the United States occur in individuals < 15 years of age), (3) the fact that iron deficiency is almost always secondary to nutritional factors in children, (4) the relative rarity of alcoholism and its related liver disease, (5) a much lower incidence of anemia associated with thyroid disease, and (6) a rarity of cardiovascular disease other than congenital heart diseases, so that valve replacement, malignant hypertension, and the use of certain drugs are not usually a factor (Berliner et al., 1999; Hord and Lukens, 1999). The primary cause for anemia in children is usually associated with an abnormality of the hematopoietic system (Berliner et al., 1999; Hord and Lukens, 1999). Studies of the osmotic fragility and deformability of RBCs exposed to EGBE's toxic metabolite BAA (Udden, 1994) suggest that certain patients with abnormal hematopoietic systems (sickle-cell anemia and hereditary spherocytosis patients) are not more sensitive to the hemolytic effects of EGBE than normal adults. Other studies suggest that the RBCs of children may be pharmacodynamically less sensitive to hemolysis than those of adults. RBCs of neonates and children (up to 6 months) differ from normal adult red blood cells in that they are larger and have higher levels of Hemoglobin F versus adult Hemoglobin A (Lewis, 1970). Frei et al. (1963) showed that the larger calf erythrocytes containing Hemoglobin F were osmotically more resistant than smaller, adult erythrocytes containing Hemoglobin A. Frei et al. (1963) suggested that as fetal erythrocytes are replaced by postnatal erythrocytes, the total population of RBCs becomes more susceptible to lysis. The effect of age on EGBE-induced hematotoxicity was studied in male F344 rats by Ghanayem and co-workers (1987c, 1990). These studies also demonstrated the time course for the onset and resolution of hematological and histopathological changes accompanying hemolysis. Adult (9-13 week) male F344 rats were significantly more sensitive to the hemolytic effects of EGBE than were young (4-5 week) male rats following administration of a single gavage dose of EGBE at 32, 63, 125, 250, or 500 mg/kg. Concurrent metabolism studies also found increased blood retention of EGBE metabolite BAA (as measured by increased Cmax, AUC, and T1/2), and that young rats eliminated a significantly greater proportion of the administered EGBE dose as exhaled carbon dioxide (CO2) or as urinary metabolites, as well as excreting a greater proportion of the EGBE conjugates (glucuronide and sulfate) in the urine. These researchers suggested that the pharmacokinetic basis of the age-dependent toxicity of EGBE may be due to a reduced ability by older rats to metabolize the toxic metabolite BAA to CO2 and a diminished ability to excrete BAA in the urine. NTP (1998) also found that young mice (6-7 weeks) eliminated BAA 10 times faster than aged mice (19 months) following a 1-day exposure to 125 ppm EGBE. This difference was not as apparent after 3 weeks of exposure, suggesting that factors other than age may be involved (Dill et al., 1998). Because of the known reproductive toxicity (i.e., to male testes and sperm) of two other glycol ethers, ethylene glycol methyl ether (EGME; 2-methoxyethanol) and ethylene glycol ethyl ether (EGEE; 2-ethoxyethanol), the reproductive toxicity of EGBE has been studied in a variety of well-conducted oral (Nagano et al., 1979, 1984; Grant et al., 1985; Foster et al., 1987; Heindel et al., 1990; Exon, 1991; NTP, 1993) and inhalation (Dodd et al., 1983; Doe, 1984; Nachreiner, 1994; NTP, 1998) studies using rats, mice, and rabbits. In addition, several developmental studies have addressed EGBE's toxicity from conception to sexual maturity, including toxicity to the embryo and fetus, following oral (Wier et al., 1987; Sleet et al., 1989), inhalation (Nelson et al., 1984; Tyl et al., 1984), and dermal (Hardin et al., 1984) exposures to rats, mice, and rabbits. In many instances, LOAELs and NOAELs were reported for both parental and developmental effects; therefore the developmental studies can also be used to assess systemic toxicity as well as developmental toxicity. EGBE did not cause adverse effects in any reproductive organ, including testes, in any study. In a two-generation reproductive toxicity study, fertility was reduced in mice only at very high, maternally toxic doses (> 1000 mg/kg). Maternal toxicity related to the hematologic effects of EGBE and relatively minor developmental effects have been reported in developmental studies. No teratogenic toxicities were noted in any of the studies. It can be concluded from these studies that EGBE is not significantly toxic to the reproductive organs (male or female) of parents, nor to the developing fetuses of laboratory animals. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=38. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Data Base -- Medium-to-high RfC -- Medium-to-high The overall confidence in the RfC assessment is medium to high. A higher confidence is placed in the RfC values derived from internal dose measures because pharmacokinetic differences between rats and humans were accounted for using two PBPK models (Lee et al., 1998; Corley et al., 1994; 1997). High confidence is placed in the NTP (1998) study because it was a chronic study, it employed both male and female rats and mice, it had a wide range of exposure levels, and it observed animals twice daily. Medium-to-high confidence is placed on the database because data are available for a variety of animal species including humans. Although the database lacks long-term human studies, the available short-term human controlled studies and case reports, and laboratory animal and in vitro studies, provide ample evidence to suggest that with respect to the hemolytic effects of EGBE, long-term human exposures would be no more adverse than long-term rat exposures. Confidence in the database is not "high" because the potential for liver effects in humans from long-term exposure has not been investigated. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=57. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 1999. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Ethylene Glycol Monobutyl Ether in support of summary information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1999). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=68. Agency Consensus Date -- 11/16/1999 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Ethylene glycol monobutyl ether (EGBE) conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 199912 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Ethylene glycol monobutyl ether (EGBE) CASRN -- 111-76-2 Last Revised -- 12/30/1999 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION No reliable human epidemiological studies are available that address the potential carcinogenicity of EGBE. A draft report of the results of a 2-year inhalation bioassay performed using rats and mice has recently become available (NTP, 1998). NTP (1998) reported no evidence of carcinogenic activity in male F344/N rats, and equivocal evidence of carcinogenic activity in female F344/N rats on the basis of increased combined incidences of benign and malignant pheochromocytoma (mainly benign) of the adrenal medulla. They also reported some evidence of carcinogenic activity in male B6C3F1 mice on the basis of increased incidences of hemangiosarcoma of the liver, and some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of forestomach squamous cell papilloma or carcinoma (mainly papilloma). As is discussed in more detail below, because of the uncertain relevance of these tumor increases to humans, the fact that EGBE is generally negative in genotoxic tests, and the lack of human data to support the findings in rodents, the human carcinogenic potential of EGBE, in accordance with the recently proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), cannot be determined at this time, but suggestive evidence exists from rodent studies. Under existing EPA guidelines (U.S. EPA, 1986), EGBE is judged to be a possible human carcinogen, Group C. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=57. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=38. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA There are currently no human epidemiological or occupational studies addressing the potential carcinogenicity of EGBE. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Two-year inhalation bioassays were conducted in mice and rats exposed to EGBE (NTP, 1998). In the chronic portion of this study, exposure concentrations of EGBE were 0, 31, 62.5, and 125 ppm for groups of 50 F344/N rats, and 0, 62.5, 125, and 250 ppm for groups of 50 B6C3F1 mice. The highest exposure was selected to produce a 10% to 15% depression in hematologic indices. Survival was significantly decreased in male mice at 125 and 250 ppm (54.0% and 53.1%, respectively), but no effect on survival was observed at other exposure levels in mice or in rats at any exposure level. Significant increases in several tumor types were observed. NTP (1998) reported no evidence of carcinogenic activity in male F344/N rats, and equivocal evidence of carcinogenic activity in female F344/N rats on the basis of increased combined incidences of benign and malignant pheochromocytoma (mainly benign) of the adrenal medulla. They also reported some evidence of carcinogenic activity in male B6C3F1 mice on the basis of increased incidences of hemangiosarcoma of the liver, and some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of forestomach squamous cell papilloma or carcinoma (mainly papilloma). With respect to the pheochromocytomas reported in female rats, the NTP (1998) tables indicate a marginally significant trend (p=0.044), and high-dose findings (16%) are only slightly different from the upper range of historical controls (13%). Further, pheochromocytomas can be difficult to distinguish from nonneoplastic adrenal medullary hyperplasia and, according to the NTP report, most of these tumors were "small and not substantially larger than the more severe grades of adrenal medullary hyperplasia." Thus, these tumors must be interpreted with caution. The hemangiosarcomas in livers of male mice appear to be exposure related. However, the fact that the incidence of hemangiosarcomas was not increased in other organs (bone, bone marrow), and an increased incidence of liver hemangiosarcomas was not noted in either rats or female mice, raises the question of whether this effect is related to accumulation of hemosiderin from hemolytic effects in the liver and related oxidative stress in male mice. Mice are known to be more susceptible to oxidative stress than are rats because of their lower antioxidant capability (Bachowski et al., 1997). On page 118 of their draft report, NTP (1998) states that a review of past NTP studies found no association between hemosiderin deposition in the liver and liver neoplasms in 79 male mice and 103 female mice from 2-year NTP studies in which liver was a site of chemical-related neoplasms. NTP (1998) goes on to state that: "At least for mice, it does not appear that an accumulation of hemosiderin and possible oxidative stress alone were the cause of liver neoplasm in male mice." However, recent work suggests that iron accumulation from the hemolytic effects of EGBE occurs in the livers of mice and can lead to oxidative stress (Xue et al., 1999). Humans have been shown to be much less sensitive to the hemolytic effects of EGBE. Thus, if the slight increase in the incidence of hemangiosarcomas in male mice observed in the NTP study is related to the hemolytic effects of EGBE, they are unlikely to be relevant to human risk. Ongoing research on the effects of hemosiderin accumulation in male mice could help to resolve this issue. The increased incidence of forestomach squamous cell papillomas or carcinomas was another effect observed in mice, but not rats. Increased incidences of forestomach neoplasms in the male and female mice occurred in groups in which ulceration and hyperplasia were also noted. NTP (1998) notes (page 115) that: "A direct association of neoplasia with ulceration and hyperplasia was not shown in this study although it is hypothesized that 2-butoxyethanol exposure-induced irritation caused the inflammatory and hyperplastic effects in the forestomach, and that the neoplasia was associated with a continuation of the injury/degeneration process." The mechanism for forestomach accumulation of EGBE or a metabolite following inhalation exposure is not known. However, Ghanayem et al. (1987) found that the levels of EGBE in the forestomach of rats 48 hours after gavage exposure were three times the levels in the glandular stomach, suggesting a different reactivity and/or absorption in the two parts of the stomach. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY In addition to the 2-year bioassay data, data from short-term tests and subchronic studies were evaluated along with EGBE's chemical and physical properties to gain some insight into EGBE's potential carcinogenicity. From what is known of the metabolic pathways of EGBE in animals, metabolic production of a species capable of significant reactivity with DNA is not anticipated. Available data on EGBE derived from conventional genotoxicity tests do not support a mutagenic or clastogenic (chromosomal breaking) potential of the compound. Further details on these genotoxicity tests can be found in U.S. EPA (1999). Not all carcinogens, however, are DNA reactive (Ashby and Tennant, 1991). A paucity of information was available on other potential modes of action for EGBE. Some information was available on gap-junctional intercellular communication (GJIC), which is widely believed to play a role in tissue and organ development and in the maintenance of a normal cellular phenotype with tissues. Thus, interference of GJIC may be a contributing factor in tumor development. Elias et al. (1996) reported that EGBE inhibited intercellular communication in Chinese hamster V79 fibroblast cells. They reported negative results for cell transformation in Syrian Chinese hamster embryos. This cell transformation assay is capable of detecting genotoxic or nongenotoxic carcinogens; however, the gene mutation data presented by Elias et al. (1996) is in graphic form and cannot be critically evaluated given that only mean values are displayed with no standard deviations. Furthermore, survival data are not reported. On the basis of chemical structure, EGBE does not resemble any known chemical carcinogens and is not expected to have any electrophilic or DNA reactive activity. As discussed above, genotoxicity data on EGBE are predominantly negative. Thus, considering the weight of evidence on EGBE, it is not expected to be a mutagen or clastogen. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE As discussed above, there are currently no human epidemiological occupational studies addressing the potential carcinogenicity of EGBE. A 2-year inhalation bioassay using mice and rats has recently been completed (NTP, 1998) and reports significant increases in certain types of tumors in exposed mice compared to controls, but not in rats. Because of the uncertain relevance of these tumor increases to humans, the fact that EGBE is generally negative in genotoxic tests, and the lack of human data to support the findings in rodents, the human carcinogenic potential of EGBE, in accordance with the recently proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), cannot be determined, though suggestive evidence exists in rodent studies. Thus, inhalation or oral quantitative assessments are not being performed at this time. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE As discussed above, there are currently no human epidemiological occupational studies addressing the potential carcinogenicity of EGBE. A 2-year inhalation bioassay using mice and rats has recently been completed (NTP, 1998) and reports significant increases in certain types of tumors in exposed mice compared to controls, but not in rats. The relevancy of these tumors to humans is not clear at this time. Consequently, a quantitative assessment was not performed. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1999. This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review of Ethylene Glycol Monobutyl Ether in support of summary information on the Integrated Risk Information System (IRIS) (U.S. EPA, 1999). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/0500-tr.pdf#page=68. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 11/16/1999 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Ethylene glycol monobutyl ether (EGBE) conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199912 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Ethylene glycol monobutyl ether (EGBE) CASRN -- 111-76-2 Last Revised -- 12/30/1999 SORD: __VI.A. ORAL RfD REFERENCES Bartnik, FG; Reddy, AK; Klecak, G; et al. (1987) Percutaneous absorption, metabolism, and hemolytic activity of n-butoxyethanol. Fundam Appl Toxicol 8:59-70. Berliner, N; Duffy, TP; Abelson, HT. (1999) Approach to adult and child with anemia. In: Hoffman, R., ed. Hematology: basic principles and practice. 2nd ed. New York: Churchill Livingstone; pp. 468-483. Carpenter, CP; Pozzani, UC; Wiel, CS; et al. (1956) The toxicity of butyl cellosolve solvent. AMA Arch Ind Health 14:114-131. Corley, RA; Bormett, GA; Ghanayem, BI. (1994) Physiologically-based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans. Toxicol Appl Pharmacol 129:61-79. Corley, RA; Markham, DA; Banks, C; et al. (1997) Physiologically-based pharmacokinetics and the dermal absorption of 2-butoxyethanol vapors by humans. Toxicol Appl Pharmacol 39:120-130. Dean, BS; Krenzelok, EP. (1991) Critical evaluation of pediatric ethylene glycol monobutyl ether poisonings. Vet Hum Toxicol 33:362. Dill, JA; Lee, KM; Bates, DJ; et al. (1998) Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol 153:227-242. Dodd, DE; Snelling, WM; Maronpot, RR; et al. (1983) Ethylene glycol monobutyl ether: acute, 9-day, and 90-day vapor inhalation studies in Fischer 344 rats. Toxicol Appl Pharmacol 68:405-414. Doe, JE. (1984) Further studies on the toxicology of the glycol ethers with emphasis on rapid screening and hazard assessment. Environ Health Perspect 57:199-206. Exon, JH; Mather, GG; Bussiere, JL; et al. (1991) Effects of subchronic exposure of rats to 2-methyoxyethanol or 2-butoxyethanol: thymic atrophy and immunotoxicity. Fundam Appl Toxicol 20:508-510. Foster, PMD; Lloyd, SC, Blackburn, DM. (1987) Comparison of the in vivo and in vitro testicular effects produced by methoxy-, ethoxy-, and n-butoxy acetic acids in the rat. Toxicology 43:17-30. Frei, YF; Perk, K; Dannon, D. (1963) Correlation between osmotic resistance and fetal hemoglobin in bovine erythrocytes. Exp Cell Res 30:561. Ghanayem, BI. (1989) Metabolic and cellular basis of 2-butoxyethanol-induced hemolytic anemia in rats and assessment of human risk in vitro. Biochem Pharmacol 38:1679-1684. Ghanayem, BI; Sullivan, CA. (1993) Assessment of the hemolytic activity of 2-butoxyethanol and its major metabolite, butoxyacetic acid, in various mammals including humans. Hum Exp Toxicol 12(4):305-311. Ghanayem, BI; Burka, LT; Matthews, HB. (1987a) Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases. J Pharmacol Exp Ther 242:222-231. Ghanayem, BI; Blair, PC; Thompson, MB; et al. (1987b) Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. Toxicol Appl Pharmacol 91:222-234. Ghanayem, BI; Burka, LT; Sanders, JM; et al. (1987c) Metabolism and disposition of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. J Pharmacol Exp Ther 15:478-484. Ghanayem, BI; Sanders, JM; Clark, AM; et al. (1990) Effects of dose, age, inhibition of metabolism and elimination on the toxicokinetics of 2-butoxyethanol and its metabolites. J Pharmacol Exp Ther 253:136-143. Grant, D; Sulsh, S; Jones, HB; et al. (1985) Acute toxicity and recovery in the hemopoietic system of rats after treatment with ethylene glycol monomethyl and monobutyl ethers. Toxicol Appl Pharmacol 77:187-200. Greaves, P. (1990) Hepatocellular hypertrophy and hyperplasia. In: Histopathology of preclinical toxicity studies: interpretation and relevance in drug safety evaluation. New York: Elsevier, pp. 403-406. Gualtieri, JF; Harris, CR; Corley, RA; et al. (1995) Multiple 2-butoxyethanol intoxications in the same patient: clinical findings, pharmacokinetics, and therapy. Rochester, NY: North American Congress of Clinical Toxicology. Hardin, BD; Goad, PhT; Burg, JR. (1984) Developmental toxicity of four glycol ethers applied cutaneously to rats. Environ Health Perspect 57:69-74. Heindel, JJ; Gulati, DK; Russell, VS; et al. (1990) Assessment of ethylene glycol monobutyl and monophenyl ether reproductive toxicity using a continuous breeding protocol in Swiss CD-1 mice. Fundam Appl Toxicol 15:683-696. Hord, JD; Lukens, JN. (1999) Anemias unique to infants and young children. In: Lee, R. G., ed. Wintrobe's clinical hematology, volume 2. 10th ed. Baltimore, MD: Williams & Wilkins; pp. 1518-1537. Krasavage, WJ. (1986) Subchronic oral toxicity of ethylene glycol monobutyl ether in male rats. Fundam Appl Toxicol 6:349-355. Lewis, AE. (1970) Principles of hematology. New York: Appleton-Century-Crofts. Medinsky, MA; Singh, G; Bechtold, WE; et al. (1990) Disposition of three glycol ethers administered in drinking water to male F344/N rats. Toxicol Appl Pharmacol 102:443-455. Nachreiner, DJ. (1994) Ethylene glycol butyl ether: acute vapor inhalation toxicity study in guinea pigs. Bushy Run Research Center, Union Carbide Corporation. Sponsored by Chemical Manufacturers Association, Washington, DC, 94N1392. Nagano, K; Nakayama, E; Koyano, M; et al. (1979) Testicular atrophy of mice induced by ethylene glycol mono alkyl ethers. Jpn J Ind Health 21:29-35. Nagano, K; Nakayama, E; Oobayashi, H; et al. (1984) Mouse testicular atrophy induced by ethylene glycol alkyl ethers in Japan. Environ Health Perspect 57:75-84. National Toxicology Program (NTP). (1993) Technical report on toxicity studies of ethylene glycol ethers 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol administered in drinking water to F344/N rats and B6C3F1 mice. U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP No. 26. NIH Publ. No. 93-3349. National Toxicology Program (NTP). (1998) NTP technical report on the toxicology and carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP TR 484 NIH Draft Publication No. 98-3974. Nelson, BK; Setzer, JV; Brightwell, WS; et al. (1984) Comparative inhalation teratogenicity of four glycol ether solvents and an amino derivative in rats. Environ Health Perspect 57:261-271. Sabourin, PJ; Medinsky, MA; Birnbaum, LS; et al. (1992a) Effect of exposure concentration on the disposition of inhaled butoxyethanol by F344 rats. Toxicol Appl Pharmacol 114:232-238. Sabourin, PJ; Medinsky, MA; Thurmond, F; et al. (1992b) Effect of dose on the disposition of methoxyethanol, ethoxyethanol, and butoxyethanol administered dermally to male F344/N rats. Fundam Appl Toxicol 19:124-132; and Erratum, Fundam Appl Toxicol 20:508-510 (1993). Shyr, LJ; Sabourin, PJ; Medinsky, MA; et al. (1993) Physiologically based modeling of 2-butoxyethanol disposition in rats following different routes of exposure. Environ Res 63:202-218. Sleet, RB; Price, CJ; Marr, MC; et al. (1989) Teratologic evaluation of ethylene glycol monobutyl ether administered to Fischer 344 rats on either gestational days 9-11 or days 11-13. Final Report. Research Triangle Institute/National Toxicology Program. NTP-CTER-86-103. Tyl, RW; Millicovsky, G; Dodd, DE; et al. (1984) Teratologic evaluation of ethylene glycol monobutyl ether in Fischer 344 rats and New Zealand white rabbits following inhalation exposure. Environ Health Perspect 57:47-68. Udden, MM. (1994) Hemolysis and decreased deformability of erythrocytes exposed to butoxyacetic acid, a metabolite of 2-butoxyethanol: II. Resistance in red blood cells from humans with potential susceptibility. J Appl Toxicol 14:97-102. Udden, MM. (1995) Effects of butoxyacetic acid on rat and human erythrocytes. Abstract, 37th annual meeting, American Society of Hematology, Dec. 1-5, Seattle, WA. Udden, MM; Patton, CS. (1994) Hemolysis and decreased deformability of erythrocytes exposed to butoxyacetic acid, a metabolite of 2-butoxyethanol: I. Sensitivity in rats and resistance in normal humans. J Appl Toxicol 14:91-96. U.S. EPA. (1999) Toxicological review of ethylene glycol monobutyl ether (111-76-2) in support of summary information on the Integrated Risk Information System (IRIS). Available online at http://www.epa.gov/iris. Wier, PJ; Lewis, SC; Traul, KA. (1987) A comparison of developmental toxicity evident at term to postnatal growth and survival using ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and ethanol. Teratog Carcinog Mutag 7:55-64. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Bartnik, FG; Reddy, AK; Klecak, G; et al. (1987) Percutaneous absorption, metabolism, and hemolytic activity of n-butoxyethanol. Fundam Appl Toxicol 8:59-70. Berliner, N; Duffy, TP; Abelson, HT. (1999) Approach to adult and child with anemia. In: Hoffman, R., ed. Hematology: basic principles and practice. 2nd ed. New York: Churchill Livingstone; pp. 468-483. Carpenter, CP; Pozzani, UC; Wiel, CS; et al. (1956) The toxicity of butyl cellosolve solvent. AMA Arch Ind Health 14:114-131. Corley, RA; Bormett, GA; Ghanayem, BI. (1994) Physiologically-based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans. Toxicol Appl Pharmacol 129:61-79. Corley, RA; Markham, DA; Banks, C; et al. (1997) Physiologically-based pharmacokinetics and the dermal absorption of 2-butoxyethanol vapors by humans. Toxicol Appl Pharmacol 39:120-130. Dean, BS; Krenzelok, EP. (1991) Critical evaluation of pediatric ethylene glycol monobutyl ether poisonings. Vet Hum Toxicol 33:362. Dill, JA; Lee, KM; Bates, DJ; et al. (1998) Toxicokinetics of inhaled 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in F344 rats and B6C3F1 mice. Toxicol Appl Pharmacol 153: 227-242. Dodd, DE; Snelling, WM; Maronpot, RR; et al. (1983) Ethylene glycol monobutyl ether: acute, 9-day, and 90-day vapor inhalation studies in Fischer 344 rats. Toxicol Appl Pharmacol 68:405-414. Doe, JE. (1984) Further studies on the toxicology of the glycol ethers with emphasis on rapid screening and hazard assessment. Environ Health Perspect 57:199-206. Exon, JH; Mather, GG; Bussiere, JL; et al. (1991) Effects of subchronic exposure of rats to 2-methyoxyethanol or 2-butoxyethanol: thymic atrophy and immunotoxicity. Fundam Appl Toxicol 20:508-510. Foster, PMD; Lloyd, SC; Blackburn, DM. (1987) Comparison of the in vivo and in vitro testicular effects produced by methoxy-, ethoxy-, and n-butoxy acetic acids in the rat. Toxicology 43:17-30. Frei, YF; Perk, K; Dannon, D. (1963) Correlation between osmotic resistance and fetal hemoglobin in bovine erythrocytes. Exp Cell Res 30:561. Ghanayem, BI. (1989) Metabolic and cellular basis of 2-butoxyethanol-induced hemolytic anemia in rats and assessment of human risk in vitro. Biochem Pharmacol 38:1679-1684. Ghanayem, BI; Sullivan, CA. (1993) Assessment of the hemolytic activity of 2-butoxyethanol and its major metabolite, butoxyacetic acid, in various mammals including humans. Hum Exper Toxicol 12(4):305-311. Ghanayem, BI; Burka, LT; Matthews, HB. (1987a) Metabolic basis of ethylene glycol monobutyl ether (2-butoxyethanol) toxicity: role of alcohol and aldehyde dehydrogenases. J Pharmacol Exper Ther 242:222-231. Ghanayem, BI; Blair, PC; Thompson, MB; et al. (1987b) Effect of age on the toxicity and metabolism of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. Toxicol Appl Pharmacol 91:222-234. Ghanayem, BI; Burka, LT; Sanders, JM; et al. (1987c) Metabolism and disposition of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. J Pharmacol Exp Ther 15:478-484. Ghanayem, BI; Sanders, JM; Clark, A; et al. (1990) Effects of dose, age, inhibition of metabolism and elimination on the toxicokinetics of 2-butoxyethanol and its metabolites. J Pharmacol Exp Ther 253:136-143. Grant, D; Sulsh, S; Jones, HB; et al. (1985) Acute toxicity and recovery in the hemopoietic system of rats after treatment with ethylene glycol monomethyl and monobutyl ethers. Toxicol Appl Pharmacol 77:187-200. Hardin, BD; Goad, PhT; Burg, JR. (1984) Developmental toxicity of four glycol ethers applied cutaneously to rats. Environ Health Perspect 57:69-74. Haufroid, V; Thirion, F; Mertens, P; et al. (1997) Biological monitoring of workers exposed to low levels of 2-butoxyethanol. Int Arch Occup Environ Health 70:232-236. Heindel, JJ; Gulati, DK; Russell, VS; et al. (1990) Assessment of ethylene glycol monobutyl and monophenyl ether reproductive toxicity using a continuous breeding protocol in Swiss CD-1 mice. Fundam Appl Toxicol 15:683-696. Hord, JD; Lukens, JN. (1999) Anemias unique to infants and young children. In: Lee, RG, ed. Wintrobe's clinical hematology, volume 2. 10th ed. Baltimore, MD: Williams & Wilkins; pp. 1518-1537. Krasavage, WJ. (1986) Subchronic oral toxicity of ethylene glycol monobutyl ether in male rats. Fundam Appl Toxicol 6:349-355. Lee, KM; Dill, JA; Chou, BJ; et al. (1998) Physiologically based pharmacokinetic model for chronic inhalation of 2-butoxyethanol. Toxicol Appl Pharmacol 153:211-226. Lewis, AE. (1970) Principles of hematology. New York: Appleton-Century-Crofts. Medinsky, MA; Singh, G; Bechtold, WE; et al. (1990) Disposition of three glycol ethers administered in drinking water to male F344/N rats. Toxicol Appl Pharmacol 102:443-455. Nachreiner, DJ. (1994) Ethylene glycol butyl ether: acute vapor inhalation toxicity study in guinea pigs. Bushy Run Research Center, Union Carbide Corporation. Sponsored by Chemical Manufacturers Association, Washington, DC, 94N1392. Nagano, K; Nakayama, E; Koyano, M; et al. (1979) Testicular atrophy of mice induced by ethylene glycol mono alkyl ethers. Jpn J Ind Health 21:29-35. Nagano, K; Nakayama, E; Oobayashi, H; et al. (1984) Mouse testicular atrophy induced by ethylene glycol alkyl ethers in Japan. Environ Health Perspect 57:75-84. National Toxicology Program (NTP). (1993). Technical report on toxicity studies of ethylene glycol ethers 2-methoxyethanol, 2-ethoxyethanol, 2-butoxyethanol administered in drinking water to F344/N rats and B6C3F1 mice. U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP No. 26. NIH Publ. No. 93-3349. National Toxicology Program (NTP). (1998) NTP technical report on the toxicology and carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP TR 484 NIH Draft Publication No. 98-3974. Nelson, BK; Setzer, JV; Brightwell, WS; et al. (1984) Comparative inhalation teratogenicity of four glycol ether solvents and an amino derivative in rats. Environ Health Perspect 57:261-271. Sabourin, PJ; Medinsky, MA; Birnbaum, LS; et al. (1992a) Effect of exposure concentration on the disposition of inhaled butoxyethanol by F344 rats. Toxicol Appl Pharmacol 114:232-238. Sabourin, PJ; Medinsky, MA; Thurmond, F; et al. (1992b) Effect of dose on the disposition of methoxyethanol, ethoxyethanol, and butoxyethanol administered dermally to male F344/N rats. Fundam Appl Toxicol 19:124-132; and Erratum, Fundam Appl Toxicol 20:508-510 (1993). Shyr, LJ; Sabourin, PJ; Medinsky, MA; et al. (1993) Physiologically based modeling of 2-butoxyethanol disposition in rats following different routes of exposure. Environ Res 63:202-218. Sleet, RB; Price, CJ; Marr, MC; et al. (1989) Teratologic evaluation of ethylene glycol monobutyl ether administered to Fischer 344 rats on either gestational days 9-11 or days 11-13. Final Report. Research Triangle Institute/National Toxicology Program. NTP-CTER-86-103. Tyl, RW; Millicovsky, G; Dodd, DE; et al. (1984) Teratologic evaluation of ethylene glycol monobutyl ether in Fischer 344 rats and New Zealand white rabbits following inhalation exposure. Environ Health Perspect 57:47-68. Udden, MM. (1994) Hemolysis and decreased deformability of erythrocytes exposed to butoxyacetic acid, a metabolite of 2-butoxyethanol: II. Resistance in red blood cells from humans with potential susceptibility. J Appl Toxicol 14:97-102. Udden, MM; Patton, CS. (1994) Hemolysis and decreased deformability of erythrocytes exposed to butoxyacetic acid, a metabolite of 2-butoxyethanol: I. Sensitivity in rats and resistance in normal humans. J Appl Toxicol 14:91-96. Udden, MM. (1995) Effects of butoxyacetic acid on rat and human erythrocytes. Abstract, 37th annual meeting, American Society of Hematology, Dec. 1-5, Seattle, WA. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. Research Triangle Park, NC: Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office; EPA report no. EPA/600/8-90/066F October 1994. U.S. EPA. (1999) Toxicological review of ethylene glycol monobutyl ether (111-76-2) in support of summary information on the Integrated Risk Information System (IRIS). Available online at http://www.epa.gov/iris. Wier, PJ; Lewis, SC; Traul, KA. (1987) A comparison of developmental toxicity evident at term to postnatal growth and survival using ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, and ethanol. Teratog Carcinog Mutag 7:55-64. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Ashby, J; Tennant, RW. (1991) Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the U.S. NTP. Mutat Res 257(3):229-306. Bachowski, S; Kolaga, KL; Xu, Y; et al. (1997) Role of oxidative stress in the mechanism of dieldrin's hepatotoxicity. Ann Clin Lab Sci 27(3):196-209. Elias, Z; Daniere, MC; Marande, AM; et al. (1996) Genotoxic and/or epigenetic effects of some glycol ethers: results of different short-term tests. Occup Hyg 2:187-212. Ghanayem, BI; Burka, LT; Sanders, JM; et al. (1987a) Metabolism and disposition of ethylene glycol monobutyl ether (2-butoxyethanol) in rats. J Pharmacol Exper Ther 15:478-484. National Toxicology Program (NTP). (1998) NTP technical report on the toxicology and carcinogenesis studies of 2-butoxyethanol (CAS No. 111-76-2) in F344/N rats and B6C3F1 mice (inhalation studies). U.S. DHHS, PHS, NIH, Research Triangle Park, NC. NTP TR 484 NIH Draft Publication No. 98-3974. U.S. EPA. (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34003. U.S. EPA. (1996) (new proposed) Guidelines for carcinogen risk assessment, 1996. (Currently, these guidelines are available only as a draft.) U.S. EPA. (1999) Toxicological review of ethylene glycol monobutyl ether (111-76-2) in support of summary information on the Integrated Risk Information System (IRIS). Available online at http://www.epa.gov/iris. Xue, H; Kamendulis, LM; Klaunig, JE. (1999) A potential mechanism for 2-butoxyethanol (2-BE) induced mouse liver neoplasia. Abstract, Annual Meeting, Society of Toxicology, March 14-18, New Orleans, LA. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Ethylene glycol monobutyl ether (EGBE) CASRN -- 111-76-2 Date Section Description ---------------------------------------------------------------------------- 12/30/1999 I ... VI RfD, RfC, and carcinogenicity assessment first on line. 12/03/2002 I.A.6., I.B.6, II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 429 of 1119 in IRIS (through 2003/06) AN: 523 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199501 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Ethyl-chloride- SY: *CHLOROETHANE-; 75-00-3; ETHANE,-CHLORO-; AETHYLCHLORID [GERMAN]; AETHYLIS-; AETHYLIS-CHLORIDUM-; ANODYNON-; CHELEN-; CHLOORETHAAN [DUTCH]; CHLORENE-; CHLORETHYL-; CHLORIDUM-; CHLOROAETHAN [GERMAN]; CHLORURE D'ETHYLE [FRENCH]; CHLORYL-; CHLORYL-ANESTHETIC-; CLORETILO-; CLOROETANO [ITALIAN]; CLORURO DE ETILO [SPANISH]; CLORURO DI ETILE [ITALIAN]; DUBLOFIX-; ETHER-CHLORATUS-; ETHER-HYDROCHLORIC-; ETHER-MURIATIC-; ETYLU CHLOREK [POLISH]; HSDB-533-; HYDROCHLORIC-ETHER-; KELENE-; MONOCHLORETHANE-; MONOCHLOROETHANE-; MURIATIC-ETHER-; NARCOTILE-; NCI-CO6224-; NCI-C06224-; UN-1037- RN: 75-00-3 HSN: 533 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199104 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane Last Revised -- 04/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Delayed fetal NOAEL: 4000 mg/cu.m (1504 ppm) 300 1 1E+1 ossification NOAEL(ADJ): 4000 mg/cu.m mg/cu.m NOAEL(HEC): 4000 mg/cu.m Mouse Developmental Inhalation study LOAEL: 13,000 mg/cu.m (4946 ppm) LOAEL(ADJ): 13,000 mg/cu.m Scortichini et al., LOAEL(HEC): 13,000 mg/cu.m 1986 ---------------------------------------------------------------------------- *Conversion Factors: MW = 64.5. Assuming 25C and 760 mm Hg, NOAEL (mg/cu.m) = 1504 ppm x MW/24.45 = 4000 mg/cu.m. For developmental effects this concentration is not adjusted; therefore NOAEL(ADJ) = NOAEL. The NOAEL(HEC) was calculated for a gas:extrarespiratory effect assuming periodicity was attained. b:a lambda(a) is unknown, b:a lambda(h) = 2.69, (Gargas et al., 1989). Since b:a lambda(a) is unknown, a default value of 1.0 is used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x 1 = 4000 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Scortichini, B.H., K.A. Johnson, J.J. Momany-Pfruender, and T.R. Hanley, Jr. 1986. Ethyl chloride: Inhalation teratology study in CF-1 mice. Dow Chemical Co. EPA Document #86-870002248. In a developmental study conducted in groups of 30 CF-1 mice, Scortichini et al. (1986) exposed animals to mean time-weighted averages of 0 (air), 491 +/-37 ppm (1.3 g/cu.m), 1504 +/- 84 ppm (4000 mg/cu.m), and 4946 +/- 159 ppm (13,000 mg/cu.m.) 99.9% ethyl chloride for 6 hours/day on days 6 through 15 of gestation. The animals were sacrificed on the 18th day of gestation. In accordance with current EPA practice these values are not duration adjusted. No maternal toxicity was recorded in this study (clinical signs, body weight, liver weight, and food and water consumption were monitored), although an earlier pilot study with non-pregnant female mice at these same concentrations showed an exposure-related decrease in body weight gain (data not presented). In the present study, no exposure-related changes were noted in resorption rate, litter size, sex ratios, or fetal body weights. No exposure-related fetal visceral malformations were observed. In the fetuses of the dams exposed to 4946 ppm, there was a statistically significant increased incidence (p < 0.05) of foramina of the skull bones, a small area of delayed ossification. At this concentration, 5 fetuses were affected in a total of 5 litters vs. 1 fetus in 1 litter in the controls and in each lower exposure group (the skull bones were examined in 22 to 25 litters in the controls and at each exposure level). The authors cite that the historical incidence of foramina of the skull bones in their facility with this strain of mice is 0.2% of the fetuses with a range of 0 to 1.2% The effect in this study at 4946 ppm ethyl chloride represented 4% of the fetuses. Additional information volunteered by one author (TRH) indicated that the foramina in question were small, pin-point lesions although apparently the openings were not measured. This skull effect was accompanied by an increasing incidence of cervical ribs (a supernumerary rib considered to be a malformation). The incidence of fetuses having this malformation was 2/257 (1%) of the controls, and, in order of increasing exposure concentrations, 1/299 (0.3%), 6/311 (2%), and 4/242 (2%). The corresponding figures for the incidence in litters was 2/22 (9%) in controls and 1/25 (4%), 5/26 (19%), and 4/22 (18%) in the litters of exposed dams. This effect was not indicated as statistically significant and no historical incidence for this malformation is given in the text. This study shows that exposure to ethyl chloride results in fetotoxicity. The exposure concentration of 1504 ppm is the NOAEL of this study NOAEL(HEC) = 4000 mg/cu.m based on foramina of the skull bones. The highest concentration used in this study, 4946 ppm, is a LOAEL, (HEC) = 13,000 mg/cu.m. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- A factor of 10 is used to account for sensitive populations. An uncertainty factor of 3 (rather than 10) is used for interspecies extrapolation due to dosimetric adjustment of the inhaled concentration. As no multigeneration reproductive study and no definitive developmental toxicity studies were available, a full factor of 10 is proposed for data base deficiencies. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Although used as a surgical anesthetic, ethyl chloride has a narrow margin of safety for this purpose as anesthesia occurs at 20 to 30 mg% and respiratory failure at 40 mg% (Dobkin and Byles, 1971). Ethyl chloride is explosive at 4% (40,000 ppm, 106 g/cu.m) in air, overlapping the concentrations required to produce anesthesia (3 to 4.5%). Neurological symptoms have been observed in human case-studies in instances of ethyl chloride abuse. Hes et al. (1979) noted cerebellar-related symptoms including ataxia, tremors, dysarthria (speech difficulties), slowed reflexes, nystagmus (involuntary movement of the eyeball), and hallucinations in a 28-year old female who sniffed 200 to 300 mL of ethyl chloride off her coat sleeve daily for 4 months. Examination revealed that her liver was enlarged (3 cm) and slightly tender and was accompanied by a mild and transient disturbance (not clinically described) of liver function. All symptoms were resolved by the end of 4 weeks. Similar neurological symptoms were noted in a 52-year old male who had a 30-year history of intermittent ethyl chloride (as well as alcohol and barbiturate) abuse (Nordin et al., 1988). Questioning upon hospitalization revealed that he had been inhaling at least 100 mL of ethyl chloride daily for the previous 4 months. No liver effects were reported and the patient fully recovered from the neurological symptoms by 6 weeks after admission. Ethyl chloride has been demonstrated to be a cardiac sensitizer (Balazs, et al., 1986) in dogs at or near concentrations producing anesthesia, i.e., 30,000 to 45,000 ppm (du Pont, 1971). In this condition, cardiac tissue is hypersensitized to the effects of stimulatory endogenous catecholamines which can result in arrhythmias and cardiac arrest. Rowe et al. (1939) exposed groups of rabbits (4/group) and rats (12/group; strain unspecified) to 26.4 g/cu.m ethyl chloride 7.5-8 hours/day, 5 days/week for 6.5 months. No effects on weight gain, liver weights, histopathology (including lungs), or clinical signs were noted. Landry et al. (1989) exposed groups of 14 (7/sex) B6C3F1 mice to 0 (air), 250 ppm (0.66 g/cu.m), 1247 ppm (3.3 g/cu.m), or 4843 ppm (12.8 g/cu.m) 99.9% EC, 23 hours/day for 11 consecutive days. The duration-adjusted values for these exposures in increasing concentrations are 0, 0.63, 3.2, and 12.2 g/cu.m. The actual duration of exposure in this study (253 hours) was comparable to that obtained in a 4 hour/day, 5-day exposure week (260 hours). A blind neurobehavioral observation battery was conducted on the 12th day followed by collection of samples for clinical chemistry and hematology. Body and organ weights were taken and histopathology was performed. The only exposure-related effect observed in this study was a slight increase in the mean liver weights of both male and female mice exposed to 4843 ppm. (The increase in liver weight was approximately 6 g/100g vs. 5.3 g/100 g in controls; p=0.05.) Histopathologic examination revealed a minimal increase in the degree of hepatocellular vacuolization in 4 of 7 animals of both sexes at this exposure. These alterations were minimal and not accompanied by any increase in serum enzymes. This study defines a free-standing NOAEL of 4843 ppm, the NOAEL(HEC) for this extrarespiratory effect = 12.2 g/cu.m. Landry et al. (1982) exposed groups of 8-10 week old F344 rats (6/sex/group) to 0 (air), 1600 ppm (4.2 g/cu.m), 4000 ppm (10.6 g/cu.m), or 10000 ppm (26.4 g/cu.m) of 99.7% ethyl chloride 6 hours/day, 5 days/week for 2 weeks. The duration-adjusted values are 0, 0.8, 1.9, or 4.7 g/cu.m, respectively. Clinical observations and chemistry, hematology, urinalysis, and complete histopathology (including the entire respiratory tract) were performed. The only exposure-related effect observed was a statistically significant increase in liver to body weight ratios in male rats exposed to 4000 ppm (3.64 g/100g) and 10,000 ppm (3.73 g/100g) as compared with controls (3.47 g/100 g) ethyl chloride. As this alteration was not accompanied by any histopathology or increases in serum enzymes it is considered an adaptive response, not an adverse effect. Therefore this study identifies the highest level of exposure in this study (10,000 ppm) as a free-standing NOEL, NOEL(HEC) for extrarespiratory effects = 4.7 g/cu.m. Groups of F344 rats and B6C3F1 mice (50/group/sex) were exposed to either 0 (air) or 15,000 ppm of 99.5% ethyl chloride (39.6 g/cu.m) 5 days/week, 6 hours/day for 102 weeks (rats) or 100 weeks (mice) in an NTP (1989) study. The duration-adjusted concentration becomes 7.1 g/cu.m. The exposure level was set at this limit because of safety considerations for explosions. A single level of exposure was chosen as no exposure-related changes were seen in the 90-day study (see below) at a slightly higher concentration (19,000 ppm). Monitoring for toxicological effects was by twice daily observation, body weights, and a complete necropsy and histologic examination including tissues of the entire respiratory tract (3 levels of the nasal epithelium, personal communication with study director) and brain. Survival of female mice after week 82 was significantly lower than controls apparently due to an increase in deaths from carcinomas of the uterus; there were no other statistically significant differences in survival between control and treated animals of either species. The incidences and severity of microscopic pathologies noted in tissues (including uterine tissue) were not different between the treated and control animals of either species. Hyperactivity was observed but only in female mice (no incidences given) and only during exposure. Mean body weights were decreased in both male and female rats. In females, the maximum difference in body weights between exposed and control animals was 13% and occurred at 59 weeks of exposure when 49 of 50 test animals were still alive. Although some fluctuations towards normalcy were observed from this time forward, terminal body weights of 23 surviving treated animals were still 10% less than their corresponding controls. In male rats, mean body weights were also decreased when compared with controls, although the decrease achieved a maximum differential of only 8%. The mean body weights of mice were not affected by exposure. Based on the mild decrease in mean body weight gain, 15,000 ppm is judged as a free-standing NOAEL. The NOAEL(HEC) = 7.1 g/cu.m. Groups of F344 rats and B6C3F1 mice (10/group) were exposed to either 0 (air), 2500 ppm (6.6 g/cu.m), 5000 ppm (13.2 g/cu.m), 10,000 ppm (26.4 g/cu.m), or 19,000 ppm (50.1 g/cu.m) of 99.5% ethyl chloride 5 days/week, 6 hours/day for 13 weeks (NTP, 1989). The duration-adjusted concentrations are 0, 1.2, 2.4, 4.7, or 9.0 g/cu.m, respectively. Monitoring for toxicological effects was by daily observation, body weights, and a complete necropsy and histologic examination including tissues of the entire respiratory tract and brain. No exposure-related clinical signs or gross or histopathological effects were observed in either species. Relative liver weights were slightly increased in the male rats (14%) and female mice (18%) exposed to 19,000 ppm. Slight decreases in mean body weights were noted in the rats (8% in the males, 4% in the females) exposed to 19,000 ppm; no dose-related tendency could be discerned from the data. As no toxicity was apparent, 19,000 ppm is considered as a free-standing NOAEL in this study. The NOAEL(HEC) = 9.0 g/cu.m. The results obtained in the two studies of Troshina (1964 & 1966) discussed below do not concur with those found by NTP (1989), Landry et al. (1982, 1989), or Rowe et al. (1939). All of the latter are carefully conducted studies with appropriate controls and relatively complete presentation and description of the data obtained. As presented, the studies of Troshina may be described as ambiguously conducted with deficient use of controls and no or little presentation of data. These deficiencies preclude consideration of these studies as a reliable source of information about the toxic effects of this chemical. In the study published in 1964, Troshina exposed 12 rats (sex or strain not specified) for 2 hours/day for 60 days (assumed consecutive) 14 g/cu.m ethyl chloride, the duration-adjusted value being 1.2 g/cu.m. There is mention of but no description of controls used in this study. Body weight, hematology, some histopathology, and the "functional state of the nervous system and the liver" were assessed for adverse effects. Body weights were unaffected. Using a functional test of liver metabolic capacity (conversion of gastrically administered sodium benzoate to hippuric acid as measured by urinary excretion), a decrease in hippuric acid excretion was noted after the exposure, from 90.3% in controls to 33.6% in the exposed animals. Lung pathology was described as bronchitis, hyperemia, and (apparently) intraalveolar thickening. The author claims these effects are exposure-related indications of irritant action, although no mention is made of histology from control lungs. Description of liver pathology included nodule formation originating from the reticuloendothelial cells while "very slight" adiposity was also noted. Belying this description of substantial pathology, the author states that these changes were "weakly pronounced." After noting a increased tendency of exposed animals to form cutaneous abscesses (4 of 12), the authors examined other animals (apparently exposed under identical conditions for 2 weeks, n = at least 3) for decrements in phagocytic activity. Their data showed a decrease in phagocyte number, index (not described), and percent of active cells at the end of the 2-week period, although evaluation past this early time point was apparently not done. No scientific conclusions could be reliably drawn from this study, although effects would suggest the exposure level of 1.2 g/cu.m to be a frank-effect level (FEL). For extrarespiratory effects, FEL(HEC) = 1.2 g/cu.m. The FEL(HEC) was also calculated for a gas:respiratory effect in the thoracic region. MVa = 0.14 cu.m/day, MVh = 20 cu.m/day, Sa(TH) = 3461.6 sq.cm., Sh(TH) = 640581 sq.cm. RGDR = (MVa/Sa) / (MVh/Sh) = 1.3. FEL(HEC) = FEL(ADJ) x RGDR = 1.6 g/cu.m. In the 1966 study by the Troshina, exposures were lowered substantially from the 1964 experiments (presumably due to the frank effects) and are reported as 0, 0.06, or 0.57 g/cu.m in exposures to 12 rats which lasted for 6 months at 4 hours/day, 6 days/week. The duration-adjusted values would be 0, 0.0085, or 0.0811 g/cu.m. Using the same indicators of toxicity as in the 1964 study, the author reported decreases in phagocytic activity although these indices "fluctuated within considerable limits." Although no data are presented, the author also describes several exposure-related effects including disturbed liver function, lowered blood pressure, fatty liver, and what is interpreted as intraalveolar thickening in the lungs. No scientific conclusions could be reliably drawn from this study, although effects claimed would suggest the exposure level of 0.0085 g/cu.m = 8.5 mg/cu.m = NOAEL(HEC) based on extrarespiratory effects. The NOAEL(HEC) was also calculated for a gas:respiratory effect in the pulmonary region. MVa = 0.14 cu.m/day, MVh = 20 cu.m/day, Sa(PU) = 3424 sq.cm., Sh(TH) = 635545 sq.cm. RGDR = (MVa/Sa) / (MVh/Sh) = 1.3. NOAEL(HEC) = NOAEL(ADJ) x RGDR = 11.1 mg/cu.m. Experiments conducted by Breslin et al. (1988) suggest that exposure to ethyl chloride may disrupt the estrus cycle of mice. Two groups (10/group) of female B6C3F1 mice were acclimated in exposure chambers over a 2-week period or until the estrus cycles of most mice was a 4-6 day interval (as judged by a vaginal lavage technique). Males were included in each chamber to synchronize and promote regular estrus cyclicity. Following acclimatization one group was exposed to 15,000 ppm (39.6 g/cu.m) ethyl chloride 6 hours/day for a minimum of 14 consecutive days (through 3 estrus cycles). No effects on behavior, gross or histopathology were observed in the group undergoing exposure although the mean body weights in the exposed group was significantly increased rather than decreased. The mean length of the estrus cycle in exposed mice was 5.6 days, significantly longer in duration than the pre-exposure duration for the same group (5.0 days) and for the corresponding controls (4.5 days). The protraction of the period could not be attributed to an increase in any particular phase of the estrus cycle and is therefore suggestive of a general stress response. A direct exposure-related effect of ethyl chloride on neuroendocrine function cannot be excluded. As this effect is regarded as a systemic effect, the exposure is duration adjusted to establish a free-standing LOAEL of 6.6 g/cu.m. The LOAEL(HEC) = 6.6 g/cu.m. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Although the principal study is well-conducted, it does not establish a firm concentration-response relationship with an adverse effect and was not performed at levels eliciting maternal toxicity. There are no multigenerational reproductive studies for this compound, and without a developmental study in a second species, the overall confidence in the data base is medium. Medium confidence in the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1987, 1988 Agency Work Group Review -- 12/20/1990 Verification Date -- 12/20/1990 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199501 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane NOCA: Not available at this time. ============================================================================ UDSO: 199104 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane Last Revised -- 04/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Balazs, T., J.P. Hanib and E.H. Herman. 1986. Toxic responses of the cardiovascular system. Chapter 14. In: Casarett and Doul's Toxicology, The Basic Science of Poisons, 3rd ed., MacMillan Publishing Co., NY, NY. p. 390. Breslin, W.J., N.M. Berdasco, J.E. Phillips, and K.A. Johnson. 1988. Ethyl Chloride (E+Cl): Effects on Estrous Cycling in B6C3F1 Mice. Final report with cover letter dated 11/21/1988. Dow Chemical Company. EPA Document #86-890000040. Dobkin, A.B. and P.H. Byles. 1971. The pharmacodynamics of divinyl ether, ethyl chloride, fluorexene, nitrous oxide, and trichloroethylene. In: Textbook Vet. Anesth. p. 94-104. E.I. du Pont deNemours and Company. 1971. Cardiac sensitization testing in dogs with ethyl chloride. EPA Document #86-870000982. Gargas, M.L., R.J. Burgess, D.E. Voisard, G.H. Cason, and M.E. Andersen. 1989. Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. Toxicol. Appl. Pharmacol. 98: 87-99. Hes, J.Ph., D.F. Cohn and M. Streifler. 1979. Ethyl chloride sniffing and cerebellar dysfunction (case report). Isr. Ann. Psychiatr. Relat. Discip. 17(2): 122-125. Landry, T.D., J.A. Ayres, K.A. Johnson and J.M. Wall. 1982. Ethyl chloride: A two-week inhalation toxicity study and effects on liver non-protein sulfhydryl concentrations. Fund. Appl. Toxicol. 2(4): 230-234. Landry, T.D., K.A. Johnson, J.E. Phillips and S.K. Weiss. 1989. Ethyl chloride: 11-day continuous exposure inhalation toxicity study in B6C3F1 mice. Fund. Appl. Toxicol. 13: 516-522. NTP (National Toxicology Program). 1989. Toxicology and carcinogenesis studies of chloroethane (ethyl chloride) (CAS No. 75-00-3) in F344/N rats and B6C3F1 mice. NTP Tech. Report Ser. No. 346. Nordin, C., M. Rosenqvist and C. Hollstedt. 1988. Sniffing of ethyl chloride - an uncommon form of abuse with serious mental and neurological symptoms. Int. J. Addict. 23(6): 623-627. Rowe, V.K., E.M. Adams and H.C. Spencer. 1939. Toxicity of ethyl chloride. Dow Chemical Company. EPA Document #86-870002251. Scortichini, B.H., K.A. Johnson, J.J. Momany-Pfruender and T.R. Hanley, Jr. 1986. Ethyl chloride: Inhalation teratology study in CF-1 mice. Dow Chemical Co. EPA Document #86-870002248. Troshina, M.M. 1964. Toxicology of ethyl chloride. Toksikol. Novykh. Prom. Khim. Veshchestv. 6: 45-55. (Russian translation). Troshina, M.M. 1966. Determination of maximum permissible concentration of ethyl chloride in the atmosphere of work premises. Gig. Tr. Prof. Zabol. 10: 37-42. U.S. EPA. 1987. Health Effects Assessment for Ethyl Chloride. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/8-88/036. U.S. EPA. 1988. Summary Review of Health Effects Associated with Monochloroethane: Health Issue Assessment. Prepared for the Office of Health and Environmental Assessment, Office of Research and Development, U.S. EPA by the Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-88/080. 35 p. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Ethyl chloride CASRN -- 75-00-3 Primary Synonym -- Chloroethane ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 04/01/1991 I.B. Inhalation RfC summary on-line 04/01/1991 VI. Bibliography on-line 01/01/1992 IV. Regulatory Action section on-line 01/01/1995 II. Carcinogenicity assessment now under review 08/01/1995 II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/02/1998 I., II. This chemical is being reassessed under the IRIS program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 430 of 1119 in IRIS (through 2003/06) AN: 537 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199110 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 2-Chloroacetophenone- SY: *PHENACYL-CHLORIDE-; 532-27-4; 1-CHLOROACETOPHENONE-; 2-CHLORO-1-PHENYLETHANONE-; ACETOPHENONE,-2-CHLORO-; ALPHA-CHLOROACETOPHENONE-; CAF-; CASWELL NO. 179C; CHLORACETOPHENONE-; CHLOROACETOPHENONE-; CHLOROMETHYL-PHENYL-KETONE-; CLOROACETOFENONA [SPANISH]; CN-; EPA-PESTICIDE-CHEMICAL-CODE-018001-; ETHANONE,-2-CHLORO-1-PHENYL-; HSDB-972-; MACE- (LACRIMATOR); MACE [LACRIMATOR]; NCI-C55107-; NSC-41666-; OMEGA-CHLOROACETOPHENONE-; PHENYL-CHLOROMETHYL-KETONE-; PHENYLCHLOROMETHYLKETONE-; UN-1697- RN: 532-27-4 HSN: 972 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 2-Chloroacetophenone CASRN -- 532-27-4 Primary Synonym -- Phenacyl chloride NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199110 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 2-Chloroacetophenone CASRN -- 532-27-4 Primary Synonym -- Phenacyl chloride Last Revised -- 10/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Squamous hyperplasia NOAEL: None 1000 1 3E-5 of the nasal respira- mg/cu.m tory epithelium LOAEL: 1 mg/cu.m LOAEL(ADJ): 0.18 mg/cu.m Chronic rat LOAEL(HEC): 0.03 mg/cu.m Inhalation Study NTP, 1990 ---------------------------------------------------------------------------- *Conversion Factors: MW = 154.6. The LOAEL(ADJ) = 1 mg/cu.m x 6 hours/24 hours x 5 days/7 days = 0.18 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in the ExtraThoracic region. MVa = 0.24 cu.m/day, MVh = 20 cu.m/day, Sa(ET) = 11.6 sq.cm., Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa) / (MVh/Sh) = 0.18. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 0.03 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) NTP (National Toxicology Program). 1990. Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone (CAS No. 532-27-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). Technical Report No. 379. The NTP conducted a 2-year inhalation study (with a 15-month interim sacrifice) of 2-chloroacetophenone (CN) in F344/N and B6C3F1 mice (NTP, 1990). The formulation used to generate CN vapor was 85% pure, with impurities of insoluble material identified as primarily magnesium oxide with traces of silicon dioxide and iron in methylene chloride (11.2%), water (2.2%), and unidentified substances (approximately 1.7%) comprising the rest of the formulation. The CN was volatilized leaving behind the magnesium oxide. CN was measured by GC/EC and actual concentrations were within +/-10% of nominal values. Sixty animals/sex/group/species were exposed to CN vapor at the following average concentrations 6 hours/day, 5 days/week for 103 weeks: 0, 1, or 2 mg/cu.m (rats) or 0, 2, or 4 mg/cu.m (mice). The duration-adjusted concentrations were 0, 0.18, or 0.36 mg/cu.m for rats, and 0, 0.36, or 0.71 mg/cu.m for mice. At 15 months, blood samples were taken from up to 10 animals/sex/group and the animals were necropsied. Complete histopathological examinations, which included the entire respiratory tract, were performed on all of the control and high- and low-concentration animals. No significant treatment-related effects on survival, clinical signs, or body weight were observed in the exposed rats. After 15 months of exposure, rats did not exhibit any clearly treatment-related hematological effects, although the lymphocyte count and the nucleated erythrocyte count of the male rats exposed to 2 mg/cu.m were significantly elevated. The female rats exposed to 1 mg/cu.m exhibited a significant increase in leukocyte and lymphocyte count, but this effect was not seen in the female rats exposed to 2 mg/cu.m. Brain, liver, kidney, and body weight were not affected by exposure to CN vapor in the rats sacrificed at 15 months; brain weight was increased in the 1 mg/cu.m female group, but this effect was not seen at 2 mg/cu.m. The incidence of focal squamous metaplasia and hyperplasia of the respiratory epithelium was increased in a concentration-related manner in both sexes. The incidence of hyperplasia in male rats was 12/46, 17/50, and 44/49 at 0, 1, and 2 mg/cu.m, respectively. In female rats, the incidence was 20/48, 31/50, and 38/49 at 0, 1, and 2 mg/cu.m., respectively. The incidence of squamous metaplasia was 2/46, 11/50, and 27/49 (males) and 1/48, 7/50, and 26/49 (females), at 0, 1, and 2 mg/cu.m, respectively. The authors suggest that the irritant effects of CN on the nasal mucosa may have been exacerbated by viral infection since serologic determinations for sentinel or control animals were positive for antibodies to rat coronavirus or sialodacryoadenitis virus at months 6, 12, 18, and 24 of the studies. Inflammation, ulcers, and squamous hyperplasia of the forestomach was observed in the exposed female rats. These effects may have been due to a direct effect of CN resulting from ingestion of the compound from the fur during grooming, since the compound has a low vapor pressure. Based on nasal respiratory hyperplasia findings, the LOAEL is 1 mg/cu.m. The LOAEL(HEC) of 0.03 mg/cu.m was calculated using the ventilation rate for female rats. In mice, the only sign of clinical toxicity was rapid, shallow breathing during the first 6 months in animals of the 4 mg/cu.m-group, and in all exposed mice during months 3-6. There were no exposure-related effects on body weight. Survival in females of the 2 mg/cu.m group only was significantly less than controls when both natural and moribund deaths were tabulated. A number of hematological parameters were significantly decreased in females of both exposure groups and in males at the highest concentration. However, these alterations were not considered to be exposure-related by the investigators. There was little indication of an effect of exposure on the nasal cavity. In females of the 4 mg/cu.m-group only, the incidence of squamous metaplasia of the respiratory epithelium was 4/49 and for respiratory hyperplasia, 2/49. The incidence of squamous metaplasia in males at 4 mg/cu.m was 2/48 and no respiratory hyperplasia was reported. These effects were not seen in control animals or animals in the 2 mg/cu.m-groups. Based on the low incidence of nasal effects, the NOAEL is established in mice at 4 mg/cu.m [NOAEL(HEC) = 0.13 mg/cu.m]. It should be noted that this NOAEL is tempered by the likelihood that the clinical signs noted are indicative of reflex apnea, a characteristic response of mice to irritating agents. If this is the case, the apparent NOAEL would likely overestimate the actual concentration delivered to the nasal respiratory epithelium. Mice have previously shown an ability to decrease their minute volume by approximately 75% as compared with 45% in rats when exposed to formaldehyde (Barrow et al., 1983; Chang et al., 1983). Mice did not exhibit the tolerance demonstrated by rats. A theoretical 75% reduction in the NOAEL(HEC) would result in a value of 0.1 mg/cu.m for mice. Since minute volume was not monitored in either species, the LOAEL in rats is used despite the concern of concommitant respiratory infection. Since rats did not show clinical signs of irritation and because an effect is established, this results in the most conservative HEC estimate for operational derivation of the RfC. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- The uncertainty factor of 1000 reflects a factor of 10 to protect unusually sensitive individuals, 10 for the use of a LOAEL rather than a NOAEL, and an additional 10 for both interspecies extrapolation, and for the lack of data on neurotoxicity and reproductive/developmental effects. MF -- None IRCC: ___I.B.4. ADDITIONAL COMMENTS / STUDIES (INHALATION RfC) Since CN has been used extensively as a tear gas agent, there are numerous reports in the literature on the effects of acute inhalation exposure to this compound. Several estimations have been made with regard to safe, irritating, and lethal concentrations of CN. For example, Punte et al. (1962a) estimated that the maximum concentration of CN that is free from systemic toxicity is 350 mg-min/cu.m for up to 5 minutes. Dosage for the inhalation of irritant compounds is often expressed as the function of the atmospheric concentration of the irritant (C) and the time of exposure (T) such that the inhalation exposure dose (CxT) is a product of C (in mg/cu.m) and T (in min) and expressed as mg-min/cu.m. The median incapacitating dose of CN has been estimated to be approximately 80 mg-min/cu.m (Taylor, 1975), and the LC50 has been estimated to be 8,000-11,000 mg-min/cu.m (Taylor, 1975). One human study is available in which four volunteers were exposed to concentrations of CN that ranged from 40-350 mg/cu.m until they could no longer tolerate the effects or a maximum of 4 minutes exposure was attained (Punte et al., 1962b). The subjects complained of tingling of the nose and rhinorrhea, burning of the throat, burning of the eyes with lacrimation, and some degree of blurred vision. Other complaints included burning of the skin around the eyes and throat, which was worse when the subjects sweated; blinking; burning in the chest with dyspnea; slight gagging and nausea; and slight transient increases in airway resistance. The EC50 (airborne concentration that produces a 50% response in a group of subjects during the time indicated) was 213 mg-min/cu.m for 1 minute, 119 mg-min/cu.m for 2 minutes, and 93 mg-min/cu.m for 3 minutes. All effects subsided after removal from the CN atmosphere. Several reports are available that describe the outcome of the use of CN alone or in combination with other lacrimating agents such as chlorobenzalmalononitrile (CS), in riot control situations in prisons. Chapman and White (1978) reported the death of one 33-year-old male inmate 46 hours after an initial gassing with tear gas containing CN and CS. His death was diagnosed as being due to "acute necrotizing laryngotracheobronchitis" resulting from exposure to tear gas. Exact exposure concentrations were not available, but the authors estimated a C x T (for a combination of CN and CS) of 41,000 mg-min/cu.m based on the dimensions of the room and the reported amount of tear gas used. In another prison, CN was sprayed into 44 prison cells resulting in the hospitalization of 8 inmates and the outpatient care of another 20 inmates (Thorburn, 1982). The inmates whose cells were sprayed directly were estimated to have received a dose of 1.75 g of CN. Those who required hospitalization presented with one or more of the following: laryngotracheobronchitis, first and second degree chemical burns, apparent allergic reaction including severe systemic illness, uncontrollable emesis, or syncope. Other symptoms noted in the hospitalized patients included malaise, lethargy, dysuria, cough, pruritis, and conjunctivitis. Those requiring outpatient clinic had primarily dermal and ocular injuries. All 28 patients recovered from the effects of exposure to CN. Dermal exposure to CN is irritating (Punte et al., 1962a) and can result in severe second and third degree chemical burns (Thorburn, 1982). These effects are exacerbated when the skin is wet. CN has also been shown to be a dermal sensitizer in humans (Penneys, 1971). CN caused contact sensitization or delayed hypersensitivity in guinea pigs following either dermal or intradermal application (Chung and Giles, 1972). In addition, cross-reactivity to 1-bromoacetophenone; 1,1-dichloroacetophenone; and acetophenone was seen in animals that were sensitized to CN. Chloroacetophenone has been found to react irreversibly with free sulfhydryl groups of proteins and enzymes. This reaction was observed to be the main cause of denaturation associated with sensory nerve activity (Chung and Giles, 1972). Since CN is a sensory irritant, Ballantyne et al. (1977) determined the RD50, or the concentration required to cause a 50% depression of respiratory rate, for this compound in mice. Animals were exposed to an aerosol of CN for 1 minute, and respiratory rate was recorded 15 seconds prior to exposure, during exposure, for 30 seconds after exposure, and at 1 minute intervals for up to 10 minutes. Respiratory rate was measured with a plethysmograph. The calculated RD50 for CN aerosol was 52 mg/cu.m. Punte et al. (1962a) exposed groups of male rats, mice, and guinea pigs to various concentrations of CN aerosol for 5-90 minutes and calculated LC50 values based on the mortality data obtained. The mass median diameter of the CN aerosol particles was 2.0 micrometers. The LC50 values for the three species tested were 3700, 73,500, and 3500 mg-min/cu.m for rats, mice, and guinea pigs, respectively. Thus, it would appear that mice are far less susceptible to the toxic effects of CN than rats or guinea pigs. All animals exhibited similar signs during exposure: hyperactivity following by nasal and ocular irritation, lacrimation, and salivation. After 5-15 minutes the hyperactivity gave way to lethargy then labored breathing which persisted for 1-2 hours after exposure. Death was usually attributed to asphyxia after pulmonary congestion, hemorrhage, and edema. Animals exposed to concentrations of CN at less than or equal to 1000 mg-min/cu.m exhibited no treatment-related histopathological effects. A similar sort of investigation was conducted by Ballantyne and Swanston (1978) in which rats, rabbits, mice, and guinea pigs were exposed to 250-750 mg/cu.m of CN aerosol for 15-60 minutes. The calculated LC50 values in mg-min/cu.m for the various species were as follows: 8750 (male rat); 11,480 (female rabbit); 13,140 (female guinea pig); and 18,200 (male mouse). These values are similar to those obtained by Punte et al. (1962a) with respect to the relative sensitivities of the various species to the toxic effects of CN aerosol. The clinical signs and histopathological findings seen in this study are similar to those described by Punte et al. (1962a). In the 14-day range-finding NTP studies (NTP, 1990), groups of 5 animals/sex from both rats and mice were exposed to 0, 4.8, 10, 19, 43, or 64 mg/cu.m CN vapor 6 hours/day, 5 days/week. All rats exposed to more than or equal to 19 mg/cu.m and all mice exposed to more than or equal to 10 mg/cu.m died during the study. Clinical signs evident during the exposures include dacryorrhea in both species and dyspnea, erythema, partially closed eyelids, and epistaxis in rats. Rats that were exposed to 4.8 and 10 mg/cu.m lost weight in an exposure-related manner. Reddened lungs were observed at necropsy in several of the mice that died, but no compound-related lesions were observed in mice exposed to 4.8 mg/cu.m CN vapor. Although results were not further described, histopathological examinations were performed on 2 rats and 3 mice of each sex from the 4.8 mg/cu.m-group and 1 rat of each sex from the 10 mg/cu.m-group. Based on the results of the 14-day studies, exposure concentrations used in the 13-week studies were 0, 0.25, 0.5, 1.2, or 4 mg/cu.m CN vapor (NTP, 1990). Ten animals/sex/group from each species were exposed for 6 hours/day, 5 days/week. None of the exposed rats died, but 1/10 female mice exposed to 4 mg/cu.m and 1/10 female mice exposed to 0.5 mg/cu.m died during the course of the study. A 9% decrease (as compared with the control animals) in body weight was observed in the rats of both sexes exposed to 4 mg/cu.m, and final body weights in the exposed mice ranged from 12-15% lower than controls in the females and 7-12% lower than controls in the males. However, the decrease in body weight did not follow an exposure-related pattern. The only compound-related clinical sign observed in either species was eye irritation during exposure. Relative (but not absolute) liver weights were increased in the female rats exposed to 4 mg/cu.m, and no compound-related lesions were observed in either species at necropsy. Histological examinations were performed for all controls and animals in the 4 mg/cu.m-group and in all animals that died before the end of the study. No information is available on the toxicokinetics of inhaled CN or its reproductive or developmental toxicity. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Low RfC -- Low Although the NTP study used an adequate experimental design (number of animals, exposure concentrations, controls), and the incidence and severity of the nasal lesions were exposure-related and seen in both genders of rats, this study is given a medium confidence rating because of the presence of other materials in the exposure atmosphere, the chance that the nasal lesions were exacerbated by concurrent viral infection in the exposed rats, and reflex apnea may have occurred to a greater degree in mice, thereby skewing the concentration-response relationship. Confidence in the data base can be considered low to medium because the NTP studies are the only available chronic or subchronic studies on CN, and there are no data on the toxicokinetics, reproductive, or developmental toxicity of CN. Confidence in the RfD can also be considered low to medium. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 03/28/1991 Verification Date -- 03/28/1991 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 2-Chloroacetophenone CASRN -- 532-27-4 Primary Synonym -- Phenacyl chloride NOCA: Not available at this time. ============================================================================ UDSO: 199110 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 2-Chloroacetophenone CASRN -- 532-27-4 Primary Synonym -- Phenacyl chloride Last Revised -- 10/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Ballantyne, B., M.F. Gazzard and D.W. Swanston. 1977. Irritancy testing by respiratory exposure. Chapter 11. In: Current Approaches in Toxicology, B. Ballantyne, Ed. John Wright and Sons, Ltd., Bristol, England. p. 129-138. Ballantyne, B. and D.W. Swanston. 1978. The comparative acute mammalian toxicity of 1-chloroacetophenone (CN) and 2-chlorobenzylidene malononitrile (CS). Arch. Toxicol. 40(2): 75-95. Barrow, C.S., W. H. Steinhagen and J.C.F. Chang. 1983. Formaldehyde Sensory Irritation. Chapter 3. In: Formaldehyde Toxicity, J.E. Gibson, Ed. Hemisphere Publishing Company, Washington, DC. Chang, J.C.F., E.A. Gross, J.A. Swenberg and C.S. Barrow. 1983. Nasal cavity deposition, histopathology, and cell proliferation after single or repeated formaldehyde exposures in B6C3F1 mice and F-344 rats. Toxicol. Appl. Pharmacol. 68: 161-176. Chapman, A.J. and C. White. 1978. Death resulting from lacrimatory agents. J. Forensic Sci. 23(3): 527-530. Chung, C.W. and A.L. Giles, Jr. 1972. Sensitization of guinea pigs to alpha-chloroacetophenone (CN) and ortho-chlorobenzylidenemalononitrile (CS), tear gas chemicals. J. Immunol. 109(2): 284-293. Gaskins, J.R., R.M. Hehir, D.F. McCaulley and E.W. Ligon, Jr. 1972. Lacrimating agents (CS and CN) in rats and rabbits. Acute effects on mouth, eyes, and skin. Arch. Environ. Health. 24(6): 449-454. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of 2-chloroacetophenone (CAS No. 532-27-4) in F344/N rats and B6C3F1 mice (inhalation studies). NTP Technical Report 379. Park, S. and S.T. Giammona. 1972. Toxic effects of tear gas on an infant following prolonged exposure. Am. J. Dis. Child. 123(3): 245-246. Penneys, N.S. 1971. Contact dermatitis to chloroacetophenone. Fed. Proc. 30(1): 96-99. Punte, C.L., T.A. Ballard and J.T. Weimer. 1962a. Inhalation studies with chloroacetophenone, diphenylaminochloroarsine, and pelargonic morpholide -- I. Animal Exposures. Am. Ind. Hyg. Assoc. J. 23: 194-198. Punte, C.L., P.J. Gutentag, E.J. Owens and L.E. Gongwyer. 1962b. Inhalation studies with chloroacetophenone, diphenylaminochloroarsine, and pelargonic morpholide -- II. Human Exposures. Am. Ind. Hyg. Assoc. J. 23: 199-202. Taylor, G.D. 1975. Military dog training aids: Toxicity and treatment. NTIS AD/A Rep.; ISS No. 006438/6GA. 36 p. Thorburn, K.M. 1982. Injuries after use of the lacrimatory agent chloroacetophenone in a confined space. Arch. Environ. Health. 37(3): 182-186. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 2-Chloroacetophenone CASRN -- 532-27-4 Primary Synonym -- Phenacyl chloride ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1991 I.B. Inhalation RfC now under review 10/01/1991 I.B. Inhalation RfC summary on-line 10/01/1991 VI. Bibliography on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 431 of 1119 in IRIS (through 2003/06) AN: 545 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199309 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Methyl-tert-butyl-ether- (MTBE) SY: 1634-04-4; PROPANE,-2-METHOXY-2-METHYL-; METHYL-TERT-BUTYL-ETHER-; T-BUTYL-METHYL-ETHER-; ETHER METHYL TERT-BUTYLIQUE [FRENCH]; ETHER,-TERT-BUTYL-METHYL-; HSDB-5847-; METHYL-1,1-DIMETHYLETHYL-ETHER-; METHYL-TERT-BUTYL-ETHER-; METHYL-TERT-BUTYLETHER-; METIL-TERC-BUTILETER [SPANISH]; TERT-BUTYL-METHYL-ETHER-; 2-METHOXY-2-METHYLPROPANE-; 2-METHYL-2-METHOXYPROPANE- RN: 1634-04-4 HSN: 5847 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199303 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Methyl tert-butyl ether (MTBE) CASRN -- 1634-04-4 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199309 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Methyl tert-butyl ether (MTBE) CASRN -- 1634-04-4 Last Revised -- 09/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- ----------------------- ----- --- --------- Increased absolute and NOAEL: 1453 mg/cu.m (403 ppm) 100 1 3E+0 relative liver and NOAEL(ADJ): 259 mg/cu.m mg/cu.m kidney weights and NOAEL(HEC): 259 mg/cu.m increased severity of spontaneous renal LOAEL: 10899 mg/cu.m (3023 ppm) lesions (females), LOAEL(ADJ): 1946 mg/cu.m increased prostration LOAEL(HEC): 1946 mg/cu.m (females), and swollen periocular tissue (males and females) Chronic Rat 24-Month Inhalation Study Chun et al., 1992 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- MW = 88.15. Assuming 25 C and 760 mmHg, NOAEL(mg/cu.m) = 403 ppm x 88.15/24.45 = 1453. NOAEL(ADJ) = 1453 x 6 hours/24 hours x 5 days/7 days = 259 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extrarespiratory effect in rats assuming periodicity was attained. Because the b:a lambda values are unknown for the experimental species (a) and humans (h), a default value of 1.0 is used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x [b:a lambda(a)/b:a lambda(h)] = 259 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Chun, J.S., H.D. Burleigh-Flayer, and W.J. Kintigh. 1992. Methyl tertiary butyl ether: vapor inhalation oncogenicity study in Fischer 344 rats (unpublished material). Prepared for the MTBE Committee by Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. Docket No. OPTS-42098. In a chronic inhalation study (Chun et al., 1992), Fischer 344 rats (50 males, 50 females/group) were exposed to analytical mean concentrations of 403, 3023, or 7977 ppm methyl tertiary-butyl ether (MTBE) vapors (1453, 10,899, or 28,760 mg/cu.m) 6 hours/day, 5 days/week for 24 months (duration-adjusted values are 259, 1946, and 5136 mg/cu.m, respectively). The control animals breathed air. Hematology (all rats) was performed halfway through the experiment (control and high-concentration groups) and prior to final sacrifice (all groups). Blood and urine samples were collected and stored, but complete serum chemistry and urinalysis were not performed. Corticosterone levels were measured on 10 rats/sex/group prior to sacrifice. Clinical signs, body weights, organ weights, and food consumption were monitored. Complete necropsy and histopathology, including examination of the nasal turbinates and lower respiratory tract, were performed on all animals. Survival times for females were not significantly different between exposed and control rats. A slight decrease in mean survival time was observed in the males exposed to the low concentration (controls, 632 days; low-concentration group, 617 days; p < 0.05). Survival time clearly decreased in males exposed to both the mid and high concentrations (mid-concentration group, 587 days; high-concentration group, 516 days; p < 0.01), leading to earlier sacrifice times at 97 and 82 weeks, respectively. According to study pathologists, chronic, progressive nephropathy was the main cause of death in the higher concentration groups and also contributed to a slight increase in mortality in the males exposed to the low concentration (Garman, 1993a,b). In NTP oral and inhalation 2-year studies of other compounds that exacerbate rat chronic, progressive nephropathy (e.g., 1,4-dichlorobenzene, dimethyl methylphosphonate, hexachloroethane, isophorone, pentachloroethane, tetrachloroethylene, chlorothalonil, and trichloroethylene), survival rates in male rats have been low, particularly in the high-dose groups (U.S. EPA, 1991). As with MTBE, decreased survival of male rats exposed to dimethyl methylphoshponate was attributed, at least in part, to chemically related kidney toxicity (i.e., nephropathy) (NTP, 1987). For animals exposed to the high concentration, clinical signs that were markedly increased over controls were ataxia (2-4% of controls at end of study vs. 100% of males and females at high-exposure level starting day 2) and earlier onset and increased incidence of swollen periocular tissue (<50% of controls at end of study vs. 84% of males and 100% of females starting day 12). The observation of ataxia at this exposure level is consistent with findings from the subchronic study discussed below (Dodd and Kintigh, 1989). Increased salivation was observed in males only at the high-exposure level. At the mid-concentration level, the authors did not report increased ataxia, but an increase in incidence of prostration was observed in females (6/50 controls vs. 15/50 at the mid concentration). Early onset and increased incidence of swollen periocular tissue were also reported at the mid-concentration level (68% of males and 100% of females starting days 12 and 19, respectively). Swollen periocular tissue, salivation, and prostration were not reported at any exposure level in the subchronic study (Dodd and Kintigh, 1989). As is discussed in Section I.B.4., the corresponding subchronic study by Dodd and Kintigh (1989) assessed several neurological endpoints, including pathological examinations, brain size parameters, and functional observational batteries (FOBs). The only CNS effect found in the subchronic study at the 4000-ppm level was a slight decrease in brain length of the male rats (p < 0.05). Significant (p < 0.05) decreases in absolute brain weights of 8000-ppm males and females supported the use of this endpoint as a critical effect for derivation of the previously reported MTBE RfC, which was based on these 90-day study data. The chronic study did not measure brain length as a parameter, but did assess brain weight. The lack of brain length measurements in the chronic study is not considered a major study deficit because no significant differences in male or female brain weights were observed at any chronic exposure level. As was observed in the subchronic study (Dodd and Kintigh, 1989), body weight gain and absolute body weight were decreased in both sexes of the high-concentration group. Just prior to sacrifice at week 81, body weight gain and absolute body weight in males were decreased 29 and 19%, respectively. Body weight gain and absolute body weight in females were decreased 22 and 13%, respectively, at the end of the study. Exposure-related, 18-25% increases in kidney and liver weights (absolute and relative to body and brain weights) were reported in females in the mid- and high-exposure groups (p < 0.01). No significant increases in liver or kidney weights were observed in the male rats. No concentration-related histopathologic findings were reported in the livers of either sex. Increased incidence of hepatocellular hypertrophy (males) and degeneration (females) were observed in animals exposed to the mid concentration, but not the high concentration. No treatment-related lesions were observed in the respiratory tract in any group. Similarly, no pathologic changes were reported in the corresponding subchronic study by Dodd and Kintigh (1989). Increases in microscopic kidney changes indicative of chronic nephropathy were seen in a concentration-related manner in all groups of exposed male rats and, to a lesser extent, in females exposed to the mid and high MTBE concentrations. Increases in the severity of mineralization and interstitial fibrosis were observed at all chronic-exposure concentrations in the male rats. Increased mineralization was not observed in females, but increases in mild to moderate glomerulosclerosis and interstitial fibrosis and tubular proteinosis were observed at the mid- and high-exposure levels in the female rats. U.S. EPA (1991) clearly indicates that nephropathy in male rats associated with the induction of alpha-2u-globulin (a male-rat-specific protein) accumulation in hyaline droplets (located in the P2 segment of the proximal tubule cells of the kidneys) "is not an appropriate endpoint to determine noncancer (systemic) effects potentially occurring in humans." U.S. EPA (1991) further outlines the following criteria for identification of an alpha-2u-globulin toxicant: (1) increased number and size of hyaline droplets in renal proximal tubule cells of treated male rats, (2) the accumulating protein in the hyaline droplets is alpha 2u globulin, and (3) additional aspects of pathological sequence of lesions associated with alpha-2u-globulin nephropathy are present, as described in U.S. EPA (1991). For reasons discussed below, the nephropathy in the male rats (and the associated decreased survival time) is thought to be at least partially due to alpha-2u-globulin accumulation, confounding the results of the male rat chronic bioassay and precluding its use as a basis for a quantitative determination of human noncancer risk. The first criterium listed above was addressed in the subchronic study by Dodd and Kintigh (1989). They reported that slides of kidney sections from five male rats in each treatment group and from five female rats from the high-level (7977-ppm) treatment group were independently "blind" evaluated by three pathologists for treatment-related differences in hyaline droplet formation. The average grades for extent of hyaline droplet formation based on a scale ranging from 0 (no findings) to 5 (severe) were 0 for the female rats exposed to 7977 ppm and 2.56, 1.94, 3.06, and 3.66 for the control and 800-, 4000-, and 7977-ppm males, respectively. Thus, these results indicate no hyaline droplet formation in female rats and a moderate (one-grade) increase in hyaline droplet formation for male rats at the high-exposure level. Further, hyaline droplet increases at the high dose were observed in a subchronic gavage study (Robinson et al., 1990) and in a subchronic drinking-water study (Lindamood et al., 1992) of male Fischer 344 rats exposed to tert-butyl alcohol (TBA), the principal metabolite of MTBE. The second criterium, alpha-2u-globulin levels in the hyaline droplets, was addressed in a separate analysis of male rats from the subject subchronic study (Swenberg and Dietrich, 1991). Although they were not increased in a concentration-related manner, Swenberg and Dietrich (1991) observed an approximate doubling in the percentage of renal cortex staining for alpha 2u globulin in all male rat exposure groups of the subchronic study. Although the pattern of alpha-2u-globulin accumulation is not consistent with other known alpha-2u-globulin toxicants (e.g., limonene), these results suggest that the aforementioned increase in hyaline droplet formation could, at least partially, be due to the accumulation of this male-rat-specific protein. Finally, subchronic and chronic inhalation studies reveal that MTBE does induce most of the pathologic progression (from hyaline droplet formation to acceleration of chronic progressive nephropathy to renal tubular cell tumors) identified as characteristic of alpha-2u-globulin-type toxicity (U.S. EPA 1991). Swenberg and Dietrich (1991) reported that alpha-2u-globulin-positive proteinaceous casts at the junction of the proximal tubules and the thin limb of Henle were not observed. However, Robinson et al. (1990) found that 50% of male Sprague-Dawley rats orally dosed with 1200 mg MTBE/kg displayed "small numbers of tubules which were plugged with granular casts." Further, granular casts at this part of the nephron can lead to subsequent tubular dilation (U.S. EPA, 1991), an effect that was noted in the chronically exposed male (1/50, 13/50, 14/50, and 11/50 in control and low-, mid-, and high-exposure groups, respectively), but not female (2/50, 0/50, 3/50, and 3/50 in control, low-, mid-, and high-exposure groups, respectively) rats (Chun et al., 1992). The reason this pathology was not observed following the 90-day study is not known at this time but may be related to differences in test species strain or due to differences resulting from differing administration routes. Another indication that MTBE exacerbation of chronic progressive nephropathy (CPN) may be related to alpha 2u globulin is that MTBE accelerates CPN to a much lesser degree in animals that can not produce alpha 2u globulin (i.e., female rats, all mice). The graded kidney lesion responses observed in male and female rats (Tables 40 and 45) were analyzed by logistic regression models to determine the extent to which MTBE impacted male and female kidneys differently. Males and females differed significantly with respect to concentration-response slopes for interstitial nephritis (p < 0.025), interstitial fibrosis (p < 0.005), and mineralization (p < 0.005), but not with respect to tubular proteinosis (p > 0.1) and glomerulosclerosis (p > 0.1) (Allen, 1993). In all cases where the slopes differed significantly, the slope for males was greater than the slope for females. As with the male rats, the nephropathy present in the female MTBE-exposed rats did not differ histologically from the "spontaneous" nephropathy common in older Fischer 344 rats. The heightened degrees of nephropathy seen in relation to the MTBE exposures represent an exacerbation of this spontaneous rat nephropathy (Garman, 1993a). Of the observed kidney lesions, the study pathologist's diagnosis of tubular proteinosis was considered most representative of overall nephropathy (Garman, 1993b). An analysis of the average severity grade for these lesions in the different exposure groups (where 1 = minimal, 2 = mild, 3 = moderate, 4 = marked, and 5 = severe) revealed scores of 2.8, 2.8, 3.8, and 3.5 for females sacrificed at 24 months in the control group and 403-, 3023-, and 7977-ppm exposure groups, respectively (Eldridge, 1993). Trend analyses (using methods described by Tukey et al., 1985) of this and other kidney lesions confirm the 403-ppm NOAEL and 3023-ppm LOAEL with respect to renal effects in the female rats (Allen, 1993). In males, 403-ppm was determined to be a NOAEL for interstitial nephritis, tubular proteinosis, and glomerulosclerosis, and a LOAEL for mineralization and interstitial fibrosis. The 403-ppm NOAEL for renal effects in the female rats was also confirmed via a blinded reevaluation of the original kidney slides by a second pathologist (Busey, 1993). In summary, there is some evidence for alpha-2u-globulin nephropathy in male rats. This limited evidence, however, is sufficient to eliminate male rat kidney nephropathy as a possible critical endpoint for use in the derivation of an RfC. Also, the induction of nephropathy in females indicates that MTBE induces renal pathology by more than one mechanism. Because the female rat lacks alpha 2u globulin, the mechanism of pathologic induction is not considered to be unique, and renal pathology in females is thus considered to be suitable for use in the development of an RfC. Exposure to MTBE vapor for 24 months produced various signs of toxicity in female rats exposed to 3023 ppm MTBE, including prostration, swollen periocular tissue, increased relative and absolute liver and kidney weights, and increased severity of certain renal lesions. Thus, 3023 ppm was a LOAEL [LOAEL(HEC) = 1946 mg/cu.m], and 403 ppm [NOAEL(HEC) = 259 mg/cu.m] was a NOAEL for chronic exposure to female rats. A two-generation reproduction study (Neeper-Bradley, 1991) of Sprague-Dawley rats lends support to the NOAEL level determined in the Chun et. al. (1992) chronic study. In accordance with current U.S. EPA risk assessment policy, no adjustment is made to approximate an equivalent continuous exposure level for developmental endpoints (U.S. EPA, 1989a). As a result, the NOAEL(HEC) for this developmental endpoint is higher than the NOAEL(HEC) derived from the Chun et al. (1992) study. Neeper-Bradley (1991) conducted a two-generation reproduction study in CD (Sprague-Dawley) rats. Male and female rats were exposed to mean MTBE concentrations of 0, 402, 3019, and 8007 ppm over two generations. F0 animals, 25/sex/concentration, were exposed for 10 weeks and then bred once to produce F1 litters. Twenty-five pups/sex/group from the F1 generation were selected randomly to be parents of the F2 generation and were exposed for at least 8 weeks prior to mating. Exposures continued through mating, through day 19 of gestation, and from lactation days 5-28 for both generations of parents. The rats were exposed for 6 hours/day, 5 days/week during the prebreeding exposure period and for 7 days/week during mating, gestation, and postnatal periods. The approximate age of the F0 animals at the start of prebreeding exposures was 6 weeks. Prebreeding exposures for the selected F1 weanlings began 29-31 days from birth. Parental animals were monitored for clinical signs of toxicity, food consumption, and body weight. All F0 and F1 parents were necropsied and examined for gross lesions; liver weights of F1 parents were measured at necropsy. Upper and lower respiratory tracts and selected reproductive tissues from the high-concentration and control groups were examined histologically, as were tissues with gross lesions. Offspring were evaluated for viability, survival, body weight, and sex distribution. Prebreeding exposures of 7977 ppm resulted in reduced food consumption during the first 2-3 weeks (F0 and F1 males) and body weight and body weight gain reductions throughout the exposure period (F0 and F1 males and F1 females). Other signs of parental toxicity at 7977 ppm included perioral wetness, hypoactivity, lack of startle reflex, ataxia, blepharospasm, and increased relative liver weights (F1 generation only). At 3023 ppm, adult effects included hypoactivity, lack of startle reflex, blepharospasm, increased relative liver weights (F1 males only), and transient reductions in body weight (F1 males and females). The histopathologic evaluation revealed no exposure-related lesions in the organs examined from males and females of either parental generation. The NOAEL and LOAEL for paternal effects in this study were 403 and 3023 ppm, respectively, which support the effect levels designated for the principal study (Chun et al., 1992). Mating, fertility, and gestational indices were not adversely affected in either of the two parental generations. Body weights, weight gains, and food consumption were similar for treated and control groups throughout gestation. However, maternal exposure to 3023 and 7977 ppm resulted in statistically significant reduced body weights and reduced body weight gains in F1 pups (p < 0.05 at 3023 ppm; p < 0.01 at 7977 ppm) and F2 pups (p < 0.01 for both exposure groups), principally during the latter periods of lactation. A significant (p < 0.01) decrease in pup survival in the F1 litter on lactation days 0-4 (precull) for the 7977-ppm exposure group (91.5% survival, 259/283) compared with controls (98.6%, 289/293) was attributed to the loss of an entire litter (16 pups). The authors state that this loss was not related to MTBE toxicity, but no further explanation is provided. In the 7977-ppm F2 litters, pup survival was reduced on postnatal day 4 (93.5% survival, 275/294) compared with controls (98.1%, 305/311). A NOAEL of 403 ppm [1442 mg/cu.m; NOAEL(HEC) = 1442 mg/cu.m] and a LOAEL of 3023 ppm (10,816 mg/cu.m) for reduced body weight and body weight gain in both F1 and F2 pups during postnatal development (lactation period) were determined. Biles et al. (1987) conducted a one-generation reproductive toxicity investigation. Sprague-Dawley rats (15 males, 30 females/group) were exposed to MTBE concentrations of 0, 290, 1180, and 2860 ppm (0, 1046, 4254, and 10,311 mg/cu.m) (males) and 0, 300, 1240, and 2980 ppm (0, 1082, 4470, and 10,743 mg/cu.m) (females), 6 hours/day, 5 days/week, during the premating interval (12 weeks for males, 3 weeks for females). There were two 5-day mating intervals (two females for every male). Males (F0 generation) continued to be exposed during and between matings, whereas F0 females were exposed 7 days/week on days 0-21 of gestation and 5 days/week on days 5-20 of lactation. After unexposed litters (F1a) were weaned, the F0 males and F0 females underwent another mating period with the same exposure regimen to produce a second litter (F1b). F0 males were sacrificed after this mating period, and females were sacrificed after the end of F1b weaning. Thus, F0 males were exposed overall to MTBE for approximately 28 weeks, and F0 females were exposed for 16 weeks. These animals were examined for gross changes, especially in their reproductive organs. Histopathologic examination revealed an increased incidence of dilated renal pelves in females exposed to 300 (4/30, 13%) and 2980 ppm (5/30, 17%) compared with controls (1/30, 3%). However, this finding was not observed at the mid concentration of 1240 ppm (0/30, 0%), which preclude establishing an unequivocal concentration-response relationship. The pregnancy rate was not significantly affected in either mating interval (F1a and F1b), although the F1b matings were slightly reduced in the high-exposure group (18/25, 76%) compared with controls (22/25, 88%). On day 4 of lactation, each litter with greater than 10 pups was culled. Pups were sacrificed on day 21 of lactation. The pup viability indices at birth were slightly, but significantly, decreased (p < 0.05) in the F1b litters of the dams exposed to 1240 (95.5% viability, 278/291) and 2980 ppm (95.5% viability, 234/245) compared with litters of controls (99% viability, 292/295). The F1a litter's pup viability indices did not differ from controls. Pup survival in the F1a litter was significantly decreased (p < 0.01) on lactation days 0-4 (precull) for the 300- (91.4% survival, 317/347) and 1240-ppm (89.1% survival, 205/230) exposure groups compared with controls (98.2% survival, 324/330). However, the F1a high-exposure group displayed no reduction in pup survival when compared to controls, and no reduction in pup survival was seen in the F1b litters. Further, pup survival indices for lactation days 4-21 (post-cull) were not increased over controls. Consequently, the reduced pup survival in the F1a low- and mid-exposure groups is not believed to be a treatment-related effect. A NOAEL of 300 ppm [1082 mg/cu.m; NOAEL(HEC) = 1082 mg/cu.m] and a LOAEL of 1240 ppm (4470 mg/cu.m) (female rats) for decreased pup viability in F1b litters were determined. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- An uncertainty factor of 10 is applied to account for extrapolation to sensitive human subpopulations. An additional factor of 3 is used to account for interspecies extrapolation. A full 10-fold adjustment for interspecies extrapolation is not deemed necessary due to the use of dosimetric adjustments. An uncertainty factor of 3 is applied for data base deficiencies because of the lack of certain information from the chronic exposure bioassay (e.g., urinalysis results, serum chemistry, and limited reporting of motor activity/clinical signs during exposure). MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Information on human exposure to MTBE is limited. Humans are acutely exposed to MTBE as a part of a medical treatment to dissolve cholesterol gallstones (Thistle, 1992). Injection of the gall bladder with a high dose of MTBE can be associated with several types of health effects (e.g., nausea, vomiting, sleepiness). Minor transient mucosal damage in the gallbladder has been demonstrated with extensive exposure, but no clinically significant consequences have been reported. One patient has been reported to have developed intravascular hemolysis and renal failure following inadvertent extravasation of a large bolus of MTBE (Ponchon et al., 1988). Reliable data from epidemiology studies of human exposure to airborne MTBE are not currently available. In a chronic inhalation study (Burleigh-Flayer et al., 1992), CD-1 mice (50 males, 50 females/group) were exposed to mean concentrations of 402, 3014, or 7973 ppm MTBE vapors (1442, 10,816, or 28,843 mg/cu.m) for 6 hours/day, 5 days/week (duration-adjusted values are 258, 1288, and 2575 mg/cu.m, respectively) for 18 months. The control animals breathed air. Hematology (all mice) and urinalysis (20 mice/sex) were performed halfway through the experiment (control and high-concentration groups) and prior to final sacrifice (all groups). In addition, corticosterone was measured on 10 mice/sex/group prior to sacrifice. Clinical signs, body weights, organ weights, and food consumption were monitored. A complete necropsy and histopathology, which included examination of the nasal turbinates and the lower respiratory tract, was performed on all animals. Male mice from the high-exposure group exhibited an increased mortality rate, probably due to a slightly increased frequency of obstructive uropathy. However, the frequency of death due to this disease in the high-concentration group was still within the range noted for historical controls (Maita et al., 1988). Ataxia was observed in 50/50 animals (both sexes) exposed to the high MTBE concentration. In addition, prostration was noted between days 25 and 522 in 8/50 female mice exposed to the highest concentration (vs. 1/50 controls). Other effects reported in both sexes of the high-concentration group included decreased body weight gain and absolute body weight (not statistically significant for females), and a slight decrease in urinary pH. No concentration-related hematologic effects were reported. Concentration-related increases in liver weight (absolute and relative to body and brain weights) were reported in both male and female mice. In the females, the liver weight increases were statistically significant at all but the lowest exposure level (p < 0.01). In males, significant increases in liver weights were observed at the lowest exposure level (p < 0.05), but the only measure that indicated a concentration response was liver weight relative to brain weight (p < 0.05). Absolute and relative male kidney weights were significantly increased in the lowest (p < 0.01) and mid-exposure groups (p < 0.05), but, as with the male liver weights, the increases were less than 10%, and a concentration-response relationship was not apparent (i.e., there was no statistical difference at the high-exposure level and significance at the mid-exposure level was less than at the low-exposure level). Female kidney weights were only increased significantly (p < 0.01) relative to body weight for animals exposed to the highest concentration. Decreases in absolute brain weight were also reported in both sexes of the high-concentration group (6% for both sexes; p < 0.01). Absolute and relative spleen weights were increased for the high-exposure group females (p < 0.01), and absolute and relative adrenal weights were increased for the high-exposure group males (p < 0.01). Histopathologic evaluation revealed no lesions in any organ except the liver. An increased incidence of hepatocellular hypertrophy was seen at the highest exposure level in both sexes, but was only significant (p < 0.05) in the male mice. The increased liver, kidney, and adrenal weights, as well as the decreased brain weights, reported in this study at the highest exposure level are consistent with the subchronic rat study (Dodd and Kintigh, 1989). Although statistically significant (p < 0.05) increases in both absolute and relative liver and kidney weights were observed in the low- and mid-concentration groups, the male liver and kidney weights did not tend to increase with increasing exposure concentration, and the female liver and kidney weight increases (both absolute and relative) at the low- and mid-concentration levels were only 9% or less over controls. The high-exposure level is considered a LOAEL [LOAEL(HEC) = 2575 mg/cu.m] based on the significant increase in absolute (females only) and relative liver weights (around 30%; p < 0.01), the increased incidence of anesthetic effects, and the significant (as much as 24%) decrease in body weight. The decreased survival time in the male mice may suggest that the highest concentration exceeded the MTD, but it may also be due to increased frequency of a spontaneous obstructive uropathy common in this strain of male mice. The mid-exposure level is considered a NOAEL [NOAEL(HEC) = 1288 mg/cu.m] for this study. In a subchronic inhalation study (Dodd and Kintigh, 1989), Fischer 344 rats (25/sex/group) were exposed to mean concentrations of 797, 3920, or 8043 ppm MTBE vapors (2873, 14,133, or 28,998 mg/cu.m) for 6 hours/day, 5 days/week (duration-adjusted values are 513, 2524, and 5178 mg/cu.m, respectively) for 13 weeks. The control animals breathed air. The high-exposure concentration was set at 50% of the LEL. Hematologic tests were performed before exposure (5/sex/group) and during weeks 5 and 14 (10/sex/group) of the study. Clinical observations were made of the groups; ophthalmic observations were made prior to the first exposure and at study end; and body weights, organ weights (15/sex/group), and food consumption were monitored. Ten rats/sex/group were perfusion-fixed for microscopic evaluation of the nervous system tissues. Brain weights and measurements were taken on all perfusion-fixed rats, and light microscopic evaluations were performed on the nervous system of 6/sex/group. The remaining 15 rats/sex/group received complete necropsy evaluations. Nasal turbinates (four sections), trachea, and lung (three sections) were examined in the control and high-exposure groups and the lung only in the low- and mid-concentration groups. A battery of neurobehavioral tests was performed on 15 rats/sex/group prior to first exposure and at exposure weeks 1, 2, 4, 8, and 13, and motor activity was determined prior to first exposure and at exposure weeks 4, 8, and 13. No treatment-related findings were noted for the respiratory tract. Lymphoid hyperplasia within the submandibular lymph nodes of the males in the high-exposure group was noted, but no reason was found for its occurrence. Necropsy examination of nervous system tissue (10/sex/group) showed no evidence of treatment-related changes in exposed animals compared with the controls. However, at both the mid- and high-exposure levels, an absolute decrease in brain length was observed in male rats. Reductions in absolute brain weight in both sexes were noted at the high-exposure level, but not at the mid concentration. The authors observed no statistically significant changes in brain weight, expressed as a percentage of body weight, nor in brain width. Nevertheless, the effect on brain length was statistically significant (p < 0.05) and concentration related. Thus, this effect was felt to be consistent with the toxicity observed in other organ systems. Dodd and Kintigh (1989) also evaluated the neurotoxic effects of MTBE using an FOB for 10 rats/sex/group and a motor activity test for the remaining 30 animals from each group. The mid- and high-concentration groups deviated from controls with respect to several FOB endpoints. The authors cite elevated body temperature in the high-exposure group males (day 7) and in the mid- and high-exposure group females (day 91). However, the overall downward trend in body temperature across control and exposure groups suggests an anomaly in the test procedure and calls to question the validity of these data. The authors note a decreased mean latency to rotate on the inclined screen in low- (days 14 and 28) and mid-concentration (days 7, 14, and 28) males. However, the data reported for this procedure are highly variable across groups and over time. Decreased hind limb grip strength was observed in mid-concentration males (days 28 and 91), but increased hind-limb grip strength was observed in mid-concentration females (day 91). Cumulative test-session motor activity was decreased for males exposed to the highest MTBE concentration (28% at day 55) and increased for females exposed to the lowest (20% at day 55) and mid concentrations (36% at day 55). The lack of a clearly defined concentration-response relationship calls into question the toxicological significance of these data. Slight hematologic alterations were observed in both male and female rats exposed to mid- and high-exposure levels. All of these changes, however, were within the range of historical measurements for this species (Charles River Breeding Laboratories, 1984). The most noteworthy biochemical finding, however, was a significant (p < 0.05) increase in corticosterone levels for the high-exposure group, which is consistent with the observed increase of relative adrenal weight. The interaction of MTBE with the neuroendocrine system (e.g., at the hypothalamus, pituitary, or adrenal glands) is unknown. There were no exposure-related alterations in mean body weight for rats exposed to the low concentration. Male rats in the mid-concentration group had reduced body weight gain during the first week, but their mean body weights were similar to controls after week 5. Female rats in the mid-concentration group experienced a slight body weight gain reduction during weeks 3 and 4. Body weight gains were depressed in both male and female rats in the high-exposure group for the first 3 weeks of exposure. There was a concentration-related increase in liver, kidney, and adrenal weights relative to body weight of the treatment groups compared with controls. Absolute weights of these organs were also significantly increased, and relative weights were at least 10% greater (p < 0.01) than controls for male and female rats in the 4000- and 8000-ppm groups. In the mid- and high-exposure groups, relative weight increases in the males were 20 and 39% in the liver, 12 and 19% in kidneys, and 18 and 55% in adrenals, whereas increases in the females were 13 and 15% in the liver, 13 and 10% in kidneys, and 13 and 29% in adrenals, respectively. The relative lung weight in the high-concentration group was 3.5-6.5% greater than the controls. An increase in the degree, but not frequency, of hemosiderosis within the spleens of males exposed to the high concentration was observed, and there was also a mild increase in number and/or size of hyaline droplets within renal proximal tubules. Consistent with the chronic studies in rats (Chun et al., 1992) and mice (Burleigh-Flayer et al., 1992), the overall weight of evidence indicates that the mid-exposure level is moderately adverse to several organ systems, as indicated by decreased brain length and increased relative kidney (females), adrenal, and liver weights. Thus, a NOAEL of 797 ppm (2873 mg/cu.m) and a LOAEL of 3920 ppm (14,133 mg/cu.m) were determined. CD-1 mice and Fischer 344 rats (5/sex/species/group) were exposed to 0, 2000, 4000, and 8000 ppm (0, 7211, 14,421, and 28,843 mg/cu.m) MTBE for 6 hours/day in the 13-consecutive-day, range-finding study (Dodd and Kintigh, 1989). Duration-adjusted exposure levels are 0, 1288, 2572, and 5150 mg/cu.m, respectively. Body weights, organ weights (brain, liver, kidneys, lungs, and adrenals), and individual clinical signs were monitored. Complete necropsy was performed on each animal, and all gross lesions were submitted to microscopy. Detailed behavioral observations were performed on rats only. A statistically significant depression in body weight gain was observed in male rats at the high-exposure concentration. There were no exposure-related effects on absolute body weight or body weight gain for mice. Relative liver weights (both sexes) and relative kidney weights (males only) were increased in rats at the high- and mid-exposure concentrations. Relative adrenal weights were increased at the high concentration in both sexes. Relative brain weights in the female rats in the 8000-ppm group were also significantly reduced. For mice, relative liver weights were increased at all concentrations (females only at the low- and mid-exposure levels). There were no weight changes in the lungs, brains, adrenals, or testes of mice when compared with control mean weights. No treatment-related macroscopic lesions were observed in either species. Reversible behavioral alterations (ataxia, decreased startle and pain reflexes, and decreased muscle tone) were observed in both sexes of rats exposed to 8000 ppm. These data suggested that 2000 ppm was a minimal effect level based on the relative liver weight changes in the female rats. Greenough et al. (1980) exposed Sprague-Dawley rats (10/sex/group) to MTBE at 250, 500, or 1000 ppm (901, 1802, or 3605 mg/cu.m) 6 hours/day, 5 days/week for 13 weeks (duration-adjusted concentrations are 161, 322, or 644 mg/cu.m, respectively). Controls inhaled air only. Food and water consumption, body and organ weights, clinical signs, ophthalmoscopy, necropsy, and histopathology of animals were reported. Histopathology included examination of one transverse section through the nasal cavity, a series of transverse sections through the larynx and trachea, and one cut through the left lung (control and high-exposure groups) and cuts through both lungs (low- and mid-exposure groups). No clinical signs were observed. Mean body weights were inconsistent, and differences were less than 10% compared with controls. The 1000-ppm females had significant (p < 0.05) reductions in absolute and relative (27% decrease) lung weights compared with controls. The 500- and 1000-ppm males showed a mean decrease of 8% in relative lung weight compared with controls. However, these findings do not appear to be concentration related, are not associated with adverse histopathologic or functional observations, and are not reproduced in the Dodd and Kintigh (1989) study. Significant (p < 0.05) differences in the absolute weights of the heart (male) and thymus (female) of 1000-ppm animals, kidneys of 500-ppm males, and adrenals of 250-ppm females were reported, but were not concentration-related changes. Histopathologic effects observed in the nasal cavity, larynx, trachea, and lungs of treated and control animals included focal inflammatory changes (pulmonary lymphoid vascular cuffing, localized polymorphonuclear leukocytes, and alveolar macrophages), epithelial and goblet cell hyperplasia, and congestion (lung only). Although these changes occurred in control and exposed animals, the changes did not appear to be concentration related and may be indicative of infection due to inadequate description of animal husbandry; any attempt to isolate causative organisms precludes conclusion. The possibility thus remains that respiratory effects of MTBE may have been unfounded by concomitant respiratory infection. Hematologic and clinical chemistry tests were performed only on the control and 1000-ppm groups. Hemoglobin levels were increased (p < 0.001), as were BUN levels (p < 0.05) in 1000-ppm male rats compared with control values after 13 weeks of exposure. Female rats in the 1000-ppm group showed a significant decrease (p < 0.05) in LDH levels, as well as an increase in glucose and albumin levels. The mean corpuscular hemoglobin concentration (MCHC) increased significantly in 1000-ppm males (p < 0.01) and decreased in females (p < 0.05). It could not be determined if any changes were concentration related because the two low-concentration groups were not evaluated. These effects are not corroborated by the Dodd and Kintigh (1989) study at higher concentrations. A free-standing NOAEL of 1000 ppm [3600 mg/cu.m; NOAEL(HEC) = 3600 mg/cu.m] was determined for this study based on the lack of treatment-related effects in any organ or system. Gill (1989) evaluated neurotoxicity of MTBE in a single acute inhalation study in which Fischer 344 rats (22/sex/group) were exposed to 0, 800, 4000, or 8000 ppm MTBE (0, 2884, 14,421, and 28,843 mg/cu.m) for 6 hours. Transient increases in motor activity were observed for males in the 800- and 4000-ppm exposure groups. After 1 hour of exposure, a significant (p < 0.01) increase in the incidence of abnormal gait was observed in the 8000-ppm group. This was evidenced by a concentration-dependent increase in the incidence and severity of ataxia and duck-walk gait in males and females at the two highest concentrations. Labored respiratory pattern, increased lacrimation, decreased muscle tone, decreased mean performance on the treadmill, increased mean latency to tail withdrawal reflex, increased mean forelimb grip strength, and increased hindlimb splay were also observed in the 8000-ppm group (p < 0.01) at 1 hour of exposure. None of these motor function changes remained after 6 hours of exposure. Results also show that a 6-hour exposure to 8000 ppm MTBE significantly affected the motor activity of rats, especially during the first 50 minutes of the test session. The NOAEL based on these neurologic effects is 4000 ppm (14,421 mg/cu.m), and the LOAEL is 8000 ppm (28,843 mg/cu.m). A 9-day inhalation study was performed (Bio/Dynamics, 1984) on Sprague-Dawley rats (20/sex/group) in which fasted and nonfasted animals were exposed to concentrations of 101, 300, 1020, and 2970 ppm MTBE vapors (364, 1082, 3677, and 10,708 mg/cu.m) 6 hours/day, 5 days/week. Lacrimation, conjunctival swelling, and corneal changes were observed in both treated and control animals; however, statistical significance was not reported. Although data were not shown, the authors report that there was a greater incidence of these clinical signs in males. A significant increase in the relative liver weight was evident in the fasted animals at 2970 ppm. Relative adrenal weights were significantly elevated in nonfasted, 300-ppm females and relative kidney weights were increased (p < 0.05) in nonfasted females exposed to 300 and 2970 ppm. Because a similar trend was not seen in fasted females at these exposure levels, and because these findings apparently were not concentration related, these observations in the nonfasted females are not considered treatment related. Both the nasal mucosa and the trachea were examined microscopically in controls and rats exposed to 1020 and 2970 ppm. Microscopic examinations revealed a significant increase in incidence of chronic inflammation in the nasal mucosa and the trachea at 1020 and 2970 ppm compared with pretest controls, but lung weight was not different from controls. Savolainen et al. (1985) exposed 3-month-old male Wistar rats (20/group) to 50, 100, or 300 ppm MTBE vapor (181, 361, or 1082 mg/cu.m) 6 hours/day, 5 days/week for 2-15 weeks (duration-adjusted concentrations are 32, 64, or 193 mg/cu.m., respectively). Five animals from each chamber were weighed and sacrificed after weeks 2, 6, 10, and 15. The rats were bled, and their cerebral hemispheres, livers, kidneys, samples of right gluteal muscle (1 g), and samples of perirenal fat (1 g) were taken at autopsy. Although body weights did not differ significantly between groups early in the study, exposed rats did have higher weights than controls by week 15; mean weights were 365 g, 408 g (12% increase), 420 g (15% increase), and 407 g (12% increase) in animals exposed to 0, 50, 100, and 300 ppm, respectively. A significant (p < 0.05) concentration-dependent increase in microsomal uridine diphosphate-glucuronosyltransferase activity in liver and kidney, as well as NADPH cytochrome c-reductase activity in kidney, occurred after 2 weeks of exposure. These effects were not observed after 15 weeks of exposure. The study was limited because histopathology was not conducted and organs were not weighed. Conaway et al. (1985) exposed pregnant Sprague-Dawley rats (23-25/group) and pregnant CD-1 mice (24-29/group) to 0, 260, 1100, or 3300 ppm MTBE (0, 937, 3965, or 11,897 mg/cu.m) 6 hours/day during gestational days 6-15. Maternal body weights were recorded for both species on days 0, 6, 12, 15, and 18 and on day 20 for rats. Physical examinations for signs of toxicity were performed at the same time as weights were recorded. Food and water consumption was recorded for days 6-9, 9-12, 12-15, and 15-18 and for days 18-20 for rats. Dams were sacrificed on day 20 (rats) or day 18 (mice) by carbon dioxide inhalation. Laparotomies were performed, and dams and pups were examined for gross abnormalities. Each fetus was weighed, and crown-rump distance was recorded. Late and early resorptions were scored. When no uterine implantation sites were observed, the uterus was stained to examine the foci of implantation. One-third of the fetuses in each litter were examined for soft-tissue abnormalities, and two-thirds of the fetuses were examined for skeletal abnormalities. The pregnancy rate in rats was similar for all groups. Organ weights were not significantly different in exposed animals compared with control values. The mean number of corpora lutea, implantations, resorptions, and live fetuses was not significantly different among groups. Fetuses were weighed and examined for deformities, but no significant incidence of soft-tissue or skeletal anomalies was observed. A free-standing NOAEL of 3300 ppm [11,897 mg/cu.m; NOAEL(HEC) = 11,897 mg/cu.m] for reproductive and developmental toxicity effects was determined for rats with no reported maternal toxicity. In mice, a slight increase in the incidence of lacrimation was observed among females (groups not specified) during exposure. The number of implantations in treatment groups was not statistically different compared with controls. The numbers of resorptions were 17, 11, and 17.3% in the 260-, 1100-, and 3300-ppm groups, respectively, compared with 9% in controls. These differences are of questionable significance because they do not appear to be concentration dependent, and the high number of resorptions in the low- and high-exposure groups were due to nearly complete resorptions in two females of the low-exposure group and complete resorption in two females of the high-exposure groups. Excluding the data for these four females, resorption data for these groups did not differ from controls. Mean fetal weights in treated animals were not significantly different from the controls. Soft-tissue anomalies per litter or per fetus were not found to be different among groups. Although not statistically significant, concentration-related skeletal variations per litter were found to be 2/27 (7.4%) in the control group and 3/26 (11.5%), 4/25 (16%), and 6/27 (22.2%) in the 260-, 1100-, and 3300-ppm groups, respectively. Cleft palates were noted in control (0.7%, 2/281), 260-ppm (0%, 0/265), 1100-ppm (0.4%, 1/251), and 3300-ppm (0.7%, 2/290) groups. A free-standing NOAEL of 3300 ppm [11,977 mg/cu.m; NOAEL(HEC) = 11,977 mg/cu.m] for developmental effects was determined for mice with minimal indications of maternal toxicity. Pregnant CD-1 mice (30/group) were exposed to MTBE at concentrations of 0, 1035, 4076, and 8153 ppm (0, 3731, 14,695, and 29,394 mg/cu.m) 6 hours/day from gestational days 6 to 15 (Bushy Run Research Center, 1989a). No animals died and none aborted during the exposure period. Three dams at 0 ppm and two dams at 400 ppm delivered early and were removed from the study. The remaining dams were sacrificed on day 18 of gestation. No signs of maternal toxicity were observed in the dams exposed to 1035 ppm. At 4076 ppm, there were slight, but not statistically significant, indications of reduced maternal body weight and body weight gain. Though the only observation for this exposure group reported was lacrimation in one dam, the authors indicate in the abstract and text of the report that hypoactivity and ataxia were observed in dams at 4076 and 8153 ppm. Clinical signs of maternal toxicity, including hypoactivity, ataxia, prostration, labored respiration, lacrimation, and periocular encrustation, were significantly increased at 8153 ppm. Significant reductions in food consumption, body weight, and body weight gain were also observed in dams exposed to 8153 ppm. A NOAEL of 1035 ppm [3731 mg/cu.m; NOAEL(HEC) = 3731 mg/cu.m] and a LOAEL of 4076 ppm [14,695 mg/cu.m; LOAEL(HEC) = 14,695 mg/cu.m] were determined for maternal toxicity. MTBE did not affect the number of corpora lutea, total implants, or preimplantation loss per litter in any exposure group. There were significant (p < 0.01) increases in the number of nonviable implantations per litter, late resorptions, and dead fetuses; and significant reductions in the number of viable implantations (p < 0.01), percent of live fetuses (p < 0.01), and percent of male fetuses (p < 0.05) in the 8153-ppm group. Fetal body weight per litter (male and female) were significantly (p < 0.01) decreased at 4076 and 8153 ppm. A significant reduction in the incidence of partial fetal atelectasis and an increase in fetal atelectasis occurred at 8153 ppm. There were 24 skeletal variations (i.e., defects in cervical, thoracic, and caudal centra, forepaws, hindpaws, sternebrae, and skull plates/bones), all indicative of reduced ossification, that were significantly elevated in fetuses at 8153 ppm. There was a decreased incidence of unossified intermediate phalanges of the hindlimb at the high concentration. At 4076 ppm, there were seven skeletal variations related to reduced ossification (cervical centra, forepaw, hindpaw, and sternebrae) that showed a significantly increased incidence. At 1035 ppm, a significantly increased incidence of poorly ossified intermediate phalanges of the hindlimb was found. This finding was probably not treatment related because the alteration was not seen at the higher concentrations. In general, the effects were significant at the p < 0.01 level. A NOAEL of 1035 ppm [3725 mg/cu.m; NOAEL(HEC) = 3725 mg/cu.m] and a LOAEL of 4076 ppm (14,670 mg/cu.m) were determined for mice based on fetal body weight reductions with minimal maternal toxicity. Developmental toxicity in rabbits was also investigated by Bushy Run Research Center (1989b). Pregnant New Zealand white rabbits (15/group) were exposed to 0, 1021, 4058, and 8021 ppm MTBE (0, 3681, 14,630, and 28,918 mg/cu.m) 6 hours/day, during gestational days 6-18. None of the does died, aborted, delivered early, or had to be removed from the study. There were no differences in maternal body weights among the groups. Reduced maternal body weight gain and food consumption were observed during the major period of organogenesis at 4058 and 8021 ppm. However, there were large standard deviations across the groups for body weight gain measurements. Relative liver weight was significantly increased by 14% (p < 0.05), and absolute liver weight was slightly, but not significantly, increased in does exposed to 8021 ppm. No histopathologic examination of the liver was conducted. The number of corpora lutea, resorptions, and viable and nonviable implantations were not significantly different among groups. Fetal body weights per litter were not statistically different among groups. There was no significant difference in the incidence of fetal malformations. This study identifies a free-standing NOAEL for developmental toxicity in rabbits of 8021 ppm [28,918 mg/cu.m; NOAEL(HEC) = 28,918 mg/cu.m]. Groups of male and female rats received a single 6-hour exposure to MTBE vapor in nose-only inhalation chambers at targeted MTBE concentrations of 400 and 8000 ppm and daily repeat 6-hour exposures for 15 days at a targeted MTBE concentration of 400 ppm (Ferdinandi et al., 1990). Four rats/sex/group were then euthanized and examined. Steady-state plasma concentrations were reached at approximately 4 to 6 hours for MTBE and roughly 6.5 hours for TBA, the principal metabolite of MTBE. MTBE-metabolizing enzymes were saturated during high-concentration exposure. The elimination half-life (t1/2) of MTBE was approximately the same after single low- and high-concentration exposures (0.52 and 0.63 hours, respectively). After the repeat exposures, the MTBE t1/2 was slightly shorter (0.48 and 0.51, respectively). The TBA t1/2 ranged from 2.8 to 3.4 hours after the low- and high-concentration single exposures. After the repeat exposure regimen, the TBA t1/2 was significantly lower (1.8 and 1.5 hours in the male and female rats, respectively). There was a slight, but statistically significant, sex difference in the pharmacokinetics of MTBE (e.g., plasma clearance was faster in females), but no sex differences in the elimination kinetics of TBA were observed. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Confidence in the study is medium. It was well-designed (e.g., with respect to exposure protocol, number of animals, and exposure duration), identified a consistent LOAEL and NOAEL for a constellation of organ systems, and involved extensive histopathology on both sexes. However, the results of the rat study are confounded by the high mortality in the males, which is presumed to be the result of rat chronic nephropathy. Further, the lack of certain information from the chronic bioassay reduces confidence in the study (e.g., urinalysis results, serum chemistry, and limited reporting of motor activity/clinical signs during exposure). Confidence in the data base is medium to high because of the existence of chronic and subchronic bioassays in more than one species, developmental studies in several different species, and the existence of single- and two-generation reproductive studies in the rat. Medium to high confidence in the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1989, 1993 Agency Work Group Review -- 06/13/1991, 04/01/1993, 07/21/1993 Verification Date -- 07/21/1993 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Methyl tert-butyl ether (MTBE) CASRN -- 1634-04-4 NOCA: Not available at this time. ============================================================================ UDSO: 199309 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Methyl tert-butyl ether (MTBE) CASRN -- 1634-04-4 Last Revised -- 09/01/1993 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Allen, B. 1993. ICF Kaiser. Telefaxed communication to Jeffrey S. Gift of U.S. EPA. Description of logistic model: Summary of test for trend (unpublished material), June 23. Biles, R.W., R.E. Schroeder, and C.E. Holdsworth. 1987. Methyl tertiary butyl ether inhalation in rats: A single generation reproduction study. Toxicol. Indust. Health. 3: 519-534. Bio/Dynamics Inc. 1984. A nine-day inhalation toxicity study of MTBE in the rat (final report vol. I) (unpublished material). TSCATS/301698. EPA/OTS No. 86870000264. Burleigh-Flayer, H.D., J.S. Chun, and W.J. Kintigh. 1992. Methyl tertiary butyl ether: Vapor inhalation oncogenicity study in CD-1 mice (unpublished material). Prepared for the MTBE Committee by Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. Docket No. OPTS-42098. Busey, W.M. 1993. Histopathologic evaluation of kidneys from male and female rats utilized in a vapor inhalation oncogenicity study of methyl tertiary butyl ether. MTBE Task Force Study No. 91N00138 dated July 19, 1993 (unpublished material). Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. 1989a. Developmental toxicity study of inhaled methyl tertiary butyl ether in CD-1 mice (final report). TSCATS/403186. EPA/OTS No. FYI-OTS-0889-0689. Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. 1989b. Developmental toxicity study of inhaled methyl tertiary butyl ether in New Zealand white rabbits (final report). TSCATS/403186. EPA/OTS No. FYI-OTS-0889-0689. Chun, J.S., H.D. Burleigh-Flayer, and W.J. Kintigh. 1992. Methyl tertiary butyl ether: Vapor inhalation oncogenicity study in Fischer 344 rats (unpublished material). Prepared for the MTBE Committee by Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. Docket No. OPTS-42098. Conaway, C.C., R.E. Schroeder, and N.K. Synder. 1985. Teratology evaluation of methyl tertiary butyl ether in rats and mice. J. Toxicol. Environ. Health. 16(6): 797-809. Charles River Breeding Laboratories. 1984. Baseline hematology and clinical chemistry values for Charles River Fischer-344 rats-CDF (F-344)CrlBR as a function of sex and age. January 1984 Technical Bulletin published by the Charles River Breeding Laboratories, Vol. 8, No. 1. Dodd, D.E. and W.J. Kintigh. 1989. Methyl tertiary butyl ether (MTBE): Repeated (13-week) vapor inhalation study in rats with neurotoxicity evaluation (unpublished material). Prepared for the MTBE Committee by Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. TSCATS 403187. EPA/OTS No. FYI-OTS-0889-0689. Eldridge, S.R. 1993. Nephropathy in female F344 rats: A summary of the MTBE oncogenicity study and review of historical findings (unpublished material). Attachment to letter to Mr. John Kneiss (Chair of the Synthetic Organic Chemical Manufacturers Association, MTBE Task Force), May 20. Ferdinandi, E.S., L. Buchanan, and R.G. Alexander. 1990. Pharmacokinetics of methyl tert-butyl ether (MTBE) and tert-butyl alcohol (TBA) in male and female Fischer-344 rats after single and repeat inhalation nose-only exposures to MTBE (unpublished material). Prepared for the MTBE Committee by Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. Docket No. OPTS-42098. Garman, R.H. 1993a. Bushy Run Research Center. Correspondence to Larry S. Andrews of ARCO Chemical Company. May 3. Garman, R.H. 1993b. Bushy Run Research Center. Correspondence to Larry S. Andrews of ARCO Chemical Company. May 15. Gill, M.W. 1989. Methyl tertiary butyl ether single exposure vapor inhalation neurotoxicity study in rats (unpublished material). Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. Greenough, R.J., P. McDonald, P. Robinson et al. 1980. Methyl tertiary-butyl ether (Driveron) three-month inhalation toxicity in rats (unpublished material). Prepared for Chemische Werke Huls AG, West Germany, by Inveresk Research International. TSCATS/303353. EPA/OTS No. 86-870000172. Lindamood, C., III, D.R. Farnell, H.D. Giles et al. 1992. Subchronic toxicity studies of t-butyl alcohol in rats and mice. Fund. Appl. Toxicol. 19: 91-100. Maita, K., M. Hirano, T. Harada et al. 1988. Mortality, major cause of moribundity, and spontaneous tumors in CD-1 mice. Toxicol. Pathol. 16: 340-349. Neeper-Bradley, T.L. 1991. Two-generation reproduction study of inhaled methyl tert-butyl ether in CD Sprague-Dawley rats (unpublished material). Bushy Run Research Center, Union Carbide Chemicals and Plastics Company Inc. NTP (National Toxicology Program). 1987. Toxicology and carcinogenisis studies of dimethyl methylphosphonate (CAS No. 756-79-6) in F344/N rats and B6C3F1 mice (gavage studies). NIH Publication No. 88-2579. Ponchon, T., J. Baroud, B. Pugol et al. 1988. Renal failure during dissolution of gallstones by methyl tert-butyl ether. Lancet. 2: 276-277. Robinson, M., R.H. Bruner, and G.R. Olson. 1990. Fourteen- and ninety-day oral toxicity studies of methyl tertiary-butyl ether in Sprague-Dawley rats. J. Am. Coll. Toxicol. 9: 525-539. Savolainen, H., P. Pfaffli, and E. Elovaara. 1985. Biochemical effects of methyl tertiary-butyl ether in extended vapour exposure of rats. Arch. Toxicol. 57: 285-288. Swenberg, J.A. and D.R. Dietrich. 1991. Immunohistochemical localization of alpha-2u-globulin in kidneys of treated and control rats of a 13-week vapor inhalation study undertaken with methy tertiary butyl ether (MTBE). Report to John Kneiss (Manager, MTBE Task Force), July 26, 1991. Thistle, J.L. 1992. Direct contact dissolution therapy. Clin. Gastroenterol. 6: 715-725. Tukey, J.W., J.L. Ciminera, and J.F. Heyse. 1985. Testing the statistical certainty of a response to increasing doses of a drug. Biometrics. 41: 295-301. U.S. EPA. 1989a. Proposed amendments to the guidelines for the health assessment of suspect developmental toxicants. Federal Register. 54: 9386-9403. U.S. EPA. 1989b. Reportable Quantity Document for Methyl Tertiary Butyl Ether. Prepared by Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991. Alpha-2u-globulin: Association with chemically induced renal toxicity and neoplasia in the male rat. Risk Assessment Forum. EPA/625/3-91/019F. U.S. EPA. 1993. MTBE-oxygenated gasolines and public health issues. Office of Research and Development, Washington, DC. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Methyl tert-butyl ether (MTBE) CASRN -- 1634-04-4 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1991 I.B. Inhalation RfC now under review 12/01/1991 I.B. Inhalation RfC on-line 12/01/1991 VI. Bibliography on-line 03/01/1993 I.A. Oral RfD now under review 05/01/1993 I.B. Inhalation RfC noted as pending change 05/01/1993 I.B.6. Work group review date added 08/01/1993 I.B. Withdrawn; new RfC verified (in preparation) 08/01/1993 I.B.6. Work group review date added 08/01/1993 I.B.7. EPA contact changed 08/01/1993 VI. Bibliography withdrawn 09/01/1993 I.B. Inhalation RfC replaced; RfC changed 09/01/1993 VI.B. Inhalation RfC references on-line 08/01/1995 I.A. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/10/1998 I.,II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 432 of 1119 in IRIS (through 2003/06) AN: 552 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199611 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,4-Dichlorobenzene- SY: 106-46-7; 1,4-DICHLOORBENZEEN [DUTCH]; 1,4-DICLOROBENZENE [ITALIAN]; BENZENE,-1,4-DICHLORO-; BENZENE,-P-DICHLORO-; CASWELL NO. 632; DI-CHLORICIDE-; DICHLOROBENZENE,-PARA-; EPA-PESTICIDE-CHEMICAL-CODE-061501-; EVOLA-; HSDB-523-; NCI-C54955-; NSC-36935-; PARADI-; PARADICHLORBENZOL [GERMAN]; PARADICHLOROBENZENE-; PARADICHLOROBENZOL-; PARADOW-; PARAMOTH-; PARAZENE-; P-CHLOROPHENYL-CHLORIDE-; PDB-; P-DICHLOORBENZEEN [DUTCH]; P-DICHLORBENZOL [GERMAN]; P-DICHLOROBENZENE-; P-DICHLOROBENZOL-; P-DICLOROBENCENO [SPANISH]; P-DICLOROBENZENE [ITALIAN]; PERSIA-PERAZOL-; RCRA-WASTE-NUMBER-U070-; RCRA-WASTE-NUMBER-U072-; SANTOCHLOR-; UN-1592- RN: 106-46-7 HSN: 523 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,4-Dichlorobenzene CASRN -- 106-46-7 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199611 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,4-Dichlorobenzene CASRN -- 106-46-7 Last Revised -- 11/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Increased liver NOAEL: 301 mg/cu.m (50 ppm) 100 1 8 E-1 weights in P1 males NOAEL(ADJ): 75 mg/cu.m mg/cu.m NOAEL(HEC): 75 mg/cu.m Rat Multigeneration Reproductive Study LOAEL: 902 mg/cu.m (150 ppm) LOAEL(ADJ): 225 mg/cu.m Chlorobenzene LOAEL(HEC): 225 mg/cu.m Producers Assn., 1986 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions: MW=147.01. Assuming 25 degrees C and 760 mm Hg, NOAEL(mg/cu.m) = 50 ppm x 147.01/24.45= 301 mg/cu.m. NOAEL(ADJ) = NOAEL mg/cu. m. x 6h/day = 75 mg/cu.m. The NOAEL(HEC) was calculated for a gas:extra respiratory effect assuming periodicity was attained. Since the b:a lambda values are unknown for the experimental animal species (a) and humans (h), a default value of 1.0 is used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x (b:a lambda (a)/b:a lambda (h)) = 301 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Chlorobenzene Producers Association. 1986. Parachlorobenzene: Two-generation Reproduction Study in Sprague-Dawley Rats. Study 86-81-90605. MRID No. 411088-1. Available from EPA. Write to FOI, EPA, Washington, DC 20460. In a two-generation reproductive study Sprague-Dawley rats (P1) {28/sex/group} were exposed to 1,4-dichlorobenzene (1,4-DCB) vapor at concentrations of 0, 50, 150, or 450 ppm (0, 301, 902, 2705 mg/cu.m) for 10 weeks, 6 hours/day, 7 days/week, then the rats were mated for 3 weeks. For exposure of the next generation, selected F1 weanlings were exposed to 1,4-DCB for 11 weeks then mated. Adult males in the 150 ppm group exhibited reduced body weights and weight gain, reduced food consumption, increased incidence of tremors, unkempt appearance and nasal and ocular discharges. A statistically significant (p=0.01) increase in liver weights was noted at necropsy in the 150 and 450 ppm groups (16 and 38%, respectively). In addition, there was a statistically significant (p-0.01) increase in kidney weight for both parental males and females. At 450 ppm there was a statistically significant (p=0.01) decrease in live births, a decrease in pup weights, and decreased pup survival at day 4 of lactation for both the F1 and F2 generations. In addition, histological observations showed significant increases in incidence of hepatocellular hypertrophy in F0 and F1 males and females. No developmental abnormalities were observed in the pups examined. All dose levels caused hyaline droplet nephrosis in post-puberal males; this change was associated with the formation of alpha-2u-globulin but is recognized as an abnormality specific for male rats and does not have significance relative to human health (U.S. EPA, 1991). The lesions observed in the male rats treated with 1,4-DCB met the criteria for alpha-2u-globulin nephropathy, that is, excessive accumulation of hyaline droplets in the P2 segment of the proximal tubule, single cell necrosis, accumulation of granular casts, increased cellular proliferation in the P2 segment and linear mineralization of tubules. Charbonneau et al. (1989) has demonstrated that 1,4-DCB induces a nephrotoxicity in male rats that is associated with reversible binding to alpha-2u-globulin. The degree of binding follows a dose-response pattern; 2,5-dichlorophenol, the major metabolite of 1,4-DCB, also binds to alpha-2u-globulin, and 1,4-DCB shows much greater binding than 1,2-DCB. These authors postulated that the alpha-2u-globulin accumulation was due to decreased lysosomal catabolism. The NOAEL established from this study was 50 ppm (301 mg/cu m) and the LOAEL is 150 ppm (902 mg/cu.m); the critical effect was the significant increase in liver weights of P1, parental males. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- An uncertainty factor of 10 was used to account for sensitive subpopulations among humans. An uncertainty factor of 3 rather than 10 was used to account for interspecies differences since dosimetry adjustments were applied. An additional factor of 3 was used since the NOAEL was based on a subchronic rather than chronic study. A full factor of 10 was not used because the LOAEL estimated by a route-to-route extrapolation from the chronic NTP (1987) oral study suggested limited progression of the hepatic lesions when terminal results were compared with interim kills. In addition, comparison of histopathologic results from the interim and final kills of the Riley et al. (1980) study also indicated that there was no progression in severity of liver lesions. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) An NTP (1987) chronic bioassay study was performed for 1,4-DCB in which 50 male and female F344 rats and 50 male and female B6C3F1 mice were assigned to each dose group. Female rats and both sexes of mice received 0, 300 and 600 mg/kg and male rats received 0, 150 and 300 mg/kg-day of 1,4-DCB in corn oil gavage for 2 years. An increased incidence of nephropathy was noted in low-dose and high-dose female rats when compared with vehicle controls (43, 64 and 84% incidence in control, low and high-dose groups, respectively). There were no other significant dose-related lesions noted in female rats. From the results noted in female rats a LOAEL of 300 mg/kg-day was determined. The renal lesions noted in male rats can be attributed to excess production of alpha-2u-globulin; these lesions will not be discussed since they have been determined to be inappropriate for human health considerations (U.S. EPA, 1991). The non-neoplastic lesions noted in male mice included thymic lymphoid depletion, hepatic cellular degeneration and focal necrosis, and focal hyperplasia of adrenal cortex. The non-cancer lesions noted in female mice included lymphoid hyperplasia, and hepatocellular degeneration. Comparison of the results of interim kills and terminal sacrifices indicated that hepatic lesions did not progress with time, either for incidence or severity. This finding supports the choice of the Chlorobenzene Producers Assn. (1986) study as critical. The LOAEL established in male and female mice is 300 mg/kg-day. Since the critical adverse effect occurred in the adult animals in a reproductive study of short duration and because the Riley et al. (1980) 2-year inhalation study was of limited value for risk assessment, an objective was to identify chronic data that supported the choice of hepatic lesions and showed that the severity of liver effects did not progress. (The Riley et al., 1980 study showed similar incidence and severity of hepatic and renal lesions in the control and exposed groups and the rats did not receive 1,4-DCB exposure for extended times during the study.) The 1987 NTP study was a chronic bioassay done via oral administration (corn oil gavage). Although the only pharmacokinetic data available (Hawkins, et al., 1980; Umemura et al., 1989) were limited for a number of reasons (differences in vehicle to that of the Riley study, limited number of doses and test animals), a route-to-route extrapolation using the NTP data was attempted to gauge where the chronic hepatic toxicity would fall relative to that of the principal study (CPA, 1986). The data conversions, rationale and calculations for this extrapolation are provided elsewhere (Cicmanec, 1993). The route-to-route extrapolation involves considerable uncertainty and is not used as a quantitative basis for RfC derivation. Nevertheless, the equivalent inhalation exposure concentration calculated from the NTP study is within the same order of magnitude as both the Riley et al. (1980) data and the principal study, so that these chronic systemic toxicity data were considered supportive of the Chlorobenzene Producers Assn. (1986) as the principal study. In the Hollingsworth et al. (1956) study, rats, guinea pigs and rabbits were exposed to 0, 96, 158, 341 or 798 ppm (0, 577, 950, 2050 or 4800 mg/cu.m) of 1,4-DCB for 7 hours/day, 5 days/week for 6-7 months. Clinically, animals receiving the highest concentration showed marked tremors, weakness, loss of weight, eye irritation and unconsciousness. Microscopic examination of tissues revealed moderate, cloudy swelling of the liver and kidneys and centrilobular hepatic necrosis. The NOAEL determined from this study is 577 mg/cu.m (NOAEL (HEC) = 120 mg/cu.m). The LOAEL established in this study was 950 mg/cu.m (HEC=198 mg/cu.m) on the basis of increases in liver and kidney weights. Microscopically cloudy swelling of the liver and kidney centrilobular cellular degeneration of the liver were observed at this dose. Companion oral dosing studies were reported for ducks, rats and rabbits in this paper at doses of 10, 100 and 500 mg/kg. Clinical, gross, and microscopic changes were seen only at 500 mg/kg. The liver and kidney were also the target organs for the oral studies. Groups of 76-79/sex of Alderly Park Wistar rats were chamber-exposed to 1,4-DCB vapor at 0, 75 or 500 ppm (0, 451 or 3006 mg/cu.m. for 5 hours/day, 5 days/week for 76 weeks (Riley et al., 1980). At the termination of exposure, a recovery period of 36 weeks for surviving rats was included. Clinical observations, clinical chemistry, and urinalysis were performed at weeks 5, 14, 27, 40 and 50 of the study. Complete histopathology (45 tissues/rat including complete respiratory tract) was performed on all rats that died or were killed except those that were cannibalized or severely autolyzed. Interim kills (5 rats/sex) were performed at 26 and 52 weeks. At 500 ppm there were increases in liver and kidney weights at some time points but not all. Kidney weights for males at 500 ppm were increased 16% above controls at 26 weeks, 33% at 76 weeks and 10% at the end of the recovery week. Kidney weights for females were increased 21% at the end of the recovery period. Focal chronic hepatitis, focal hepatic vacuolation and focal necrosis were observed at 500 ppm but similar lesions were also seen in control rats at the end of the recovery period. Moderate nephropathy, suppurative nephritis, and papillary mineralization were seen at 500 ppm but similar changes were seen in the control group. Microscopic examination of the nasal cavity revealed olfactory epithelial degeneration, respiratory epithelial hyperplasia, subacute rhinitis, squamous metaplasia and adenitis of nasal glands in moderate incidence, however, similar changes were noted in the control groups. Changes in the lungs that were noted included the presence of peribronchial lymphoid accumulations, chronic interstitial inflammatory infiltrates, alveolar histiocytosis and the presence of pigmented and foamy histiocytes. The NOAEL(HEC) established was 67 mg/cu.m and the LOAEL(HEC) was 447 mg/cu.m on the basis of increased liver and kidney weights. Hayes et al. (1985) exposed rabbits to 0, 100, 300 or 800 ppm (0, 601, 1804 or 4810 mg/cu.m) for 6 hours/day on days 6-18 of gestation. Twenty-four to 28 dams and their litters were examined at the various dose levels. The maternal body weight gain during gestation as well as absolute and relative liver and kidney weights were also determined. The number of litters, corpora lutea/dam, implantation sites/dam, fetuses/litter, resorptions/litter, fetal sex ratio, fetal body weights and fetal crown-rump lengths were determined. Only the differences in percentage of implantations resorbed and percentage of litters with resorptions for the 300 ppm group were statistically significant. The occurrence of retroesophageal positioning of the right subclavian artery was increased in the 800 ppm group and was determined to be not indicative of a teratogenic response. The authors concluded that no significant teratogenic or fetotoxic effects were observed at 100, 300 or 800 ppm. Anderson and Hodge (1976) exposed mice to 0, 75, 225 or 450 ppm (0, 451, 1353 or 2706 mg/cu.m) for 6 hours/day for 5 days. No reduction in reproductive performance was observed at any dose. The summary of reports for human exposure to 1,4-DCB presented in the Health Assessment Document for Chlorinated Benzenes (U.S. EPA, 1985) indicates that malaise and nausea are frequently observed as well as hepatic manifestations such as yellow atrophy and cirrhosis of the liver. Proteinuria, bilirubinuria, hematuria and anemia are also observed. A Japanese report describes a young woman who was exposed to unusually high concentrations of 1,4-DCB continuously at home. Her exposure had lasted for 6 years before a clinical examination was performed. She presented with severe cerebellar ataxia, dysarthria, moderate weakness in all limbs and hyporeflexia. Once removed from the contaminated environment, her bedroom, her symptoms disappeared after 8 months. The authors emphasized the similarities of rapid reversibility of CNS symptoms to those reported by Hollingsworth et al., (1956) in rats, rabbits and guinea pigs and attributed it to rapid elimination of 1,4-DCB (Miyai et al., 1988). CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Confidence in the principal study is medium. The critical study employed an extensive reproductive protocol including histopathologic examination of tissues of adults and offspring. Confidence in the data base is rated medium. There are a number of supporting studies for the developmental and reproductive toxicology data base. Supporting data for chronic exposure was obtained by performing a route-to-route extrapolation from the chronic NTP (1987) study and resonably close correlation for the LOAEL was found. This comparison was done in order to justify using the adult liver data following 10 weeks of exposure from the Chlorobenzene Producers Assn. (1986) study. Essentially the results of the NTP (9187) study and the Riley et al. (1980) study, which were chronic lifetime exposures, indicate a lack of progression of the hepatic lesions. This information, in turn, supports the use of the Chlorobenzene Producers Assn. (1986) study as the critical study and obviates to some extent the concern for the lack of chronic data. Medium confidence in the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1985 Agency Work Group Review -- 06/23/1988, 10/13/1988, 08/15/1991, 12/12/1991, 06/25/1992 Verification Date -- 06/25/1992 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,4-Dichlorobenzene CASRN -- 106-46-7 NOCA: Not available at this time. ============================================================================ UDSO: 199401 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,4-Dichlorobenzene CASRN -- 106-46-7 Last Revised -- 01/01/1994 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Anderson, D. and M.C.E. Hodge. 1976. Paradichlorobenzene: Dominant lethal study in the mouse. ICI Report No. CTL/P/296. November. Charbonneau, M., J. Strasser, Jr., E.A. Lock, M.J. Turner, Jr. and J.A. Swenberg. 1989. Involvement of reversible binding to alpha-2-microglobulin in 1,4-dichlorobenzene-induced nephrotoxicity. Toxicol. Appl. Pharmacol. 99: 122-132. Chlorobenzene Producers Association. 1986. Paradichlorobenzene: Two-generation Reproduction Study in Sprague-Dawley Rats. Study 86-81-90605. MRID No. 411088-1. Available from EPA. Write to FOI, EPA, Washington, DC 20460. Cicmanec, J.L. 1993. U.S. EPA, Cincinnati, OH. Memorandum to Annie M. Jarabeck, U.S. EPA, Research Triangle Park, NC. on route-to-route extrapolation for 1,4-Dichlorobenzene. December 13. Hawkins, D.R., L.F. Chasseaud, R.N. Woodhouse and D.G. Cresswell. 1980. The distribution, excretion and biotransformation of p-dichloro[14C]benzene in rats after repeated inhalation, oral and subcutaneous doses. Xenobiotica. 10: 81-95. Hayes, W.C., T.R. Hanley, Jr., T.S. Gushow, K.A. Johnson and J.A. John. 1985. Teratogenic potential of inhaled dichlorobenzenes in rats and rabbits. Fund. Appl. Toxicol. 5(1): 190-202. Hollingsworth, R.L., V.K. Rowe, F. Oyen, H.R. Hoyle and H.C. Spencer. 1956. Toxicity of paradichlorobenzene: Determinations of experimental animals and human subjects. AMA Arch. Ind. Health. 14: 138-147. Miyai, I., N. Hirono, M. Fujita and M. Kameyama. 1988. Reversible ataxia following chronic exposure to paradichlorobenzene. J. Neurol. Neurosurg. Psychiat. 51(3): 453-454. NTP (National Toxicology Program). 1987. Toxicology and carcinogenesis studies of 1,4-dichlorobenzene in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 319. NIH Publ. No. 87-2575. Riley, R.A., I.S. Chart, A. Doss, C.W. Gore, D. Patton and T.M. Weight. 1980. Para-dichlorobenzene: Long-term inhalation study in the rat. ICI Report No. CTL/P/447. August, 1980. Umemura, J., K. Takada, Y. Nakaji, et al. 1989. Comparison of toxicity of p-dichlorobenzene administered to male F344 rats orally or by the inhalation route. Sci. Rep. Res. Inst. Tohoku Univ. 36: 1-9. U.S. EPA. 1985. Health Assessment Document for Chlorinated Benzenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. EPA/600/8-84/015F. U.S. EPA. 1991. Alpha-2u-Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat. Prepared for the Risk Assessment Forum, U.S. EPA, Washington, DC 20460. EPA/625/3-91/019F. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,4-Dichlorobenzene CASRN -- 106-46-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1991 I.B. Inhalation RfC now under review 08/01/1992 I.B.6. Work group review date added 01/01/1994 I.B. Inhalation RfC on-line 01/01/1994 VI.B. Inhalation RfC references on-line 02/01/1995 IV. Regulatory actions on-line 03/01/1995 IV.C. Clean Water Act section added 11/01/1996 I.B.7. Primary contact's office changed 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/12/2000 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 433 of 1119 in IRIS (through 2003/06) AN: 601 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199112 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2-Dichloropropane- SY: 78-87-5; PROPANE,-1,2-DICHLORO-; PROPYLENE-DICHLORIDE-; AI3-15406-; ALPHA,BETA-DICHLOROPROPANE-; ALPHA,BETA-PROPYLENE-DICHLORIDE-; BICHLORURE DE PROPYLENE [FRENCH]; CASWELL NO. 324; CCRIS-951-; DICHLORO-1,2 PROPANE [FRENCH]; DICHLORURE DE PROPYLENE [FRENCH]; DICLORURO DE PROPILENO [SPANISH]; DWUCHLOROPROPAN [POLISH]; ENT-15,406-; EPA-PESTICIDE-CHEMICAL-CODE-029002-; HSDB-1102-; NCI-C55141-; PROPYLENE-CHLORIDE- RN: 78-87-5 HSN: 1102 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2-Dichloropropane CASRN -- 78-87-5 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199112 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2-Dichloropropane CASRN -- 78-87-5 Last Revised -- 12/01/1991 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Hyperplasia of the NOAEL: None 300 1 4E-3 nasal mucosa mg/cu.m LOAEL: 69.3 mg/cu.m (15 ppm) Rat 13-week LOAEL(ADJ): 12.4 mg/cu.m Inhalation Study LOAEL(HEC): 1.3 mg/cu.m Nitschke et al., 1988 ---------------------------------------------------------------------------- *Conversion Factors: MW = 112.99. Assuming 25C and 760 mmHg, LOAEL(mg/cu.m) = LOAEL(ppm) x MW/24.45 = 69.3 mg/cu.m. LOAEL(ADJ) = LOAEL(mg/cu.m) x 6 hours/day/24 hours/day x 5 days/7 days = 12.4 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in the ExtraThoracic region. MVa = 0.14 cu.m/day, MVh = 20 cu.m/day, Sa(ET) = 11.6 sq. cm., Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa) / (MVh/Sh) = 0.107. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 1.3 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Nitschke K.D., K.A. Johnson, D.L. Wackerle, J.E. Phillips and D.A. Dittenber. 1988. Propylene dichloride: A 13-week inhalation toxicity study with rats, mice, and rabbits. Dow Chemical Company, Mammalian and Environmental Toxicology Research Laboratory, Midland, MI. OTS Doc. #86-870001397 Male and female F344 and B6C3F1 mice (10/group) were exposed to 0, 15, 50, or 150 ppm dichloropropane (0, 69.3, 231, or 693 mg/cu.m) for 6 hours/day, 5 days/week for 13 weeks (duration-adjusted concentrations = 0, 12.4, 41.3, and 124 mg/cu.m). New Zealand rabbits (7/sex/group) were exposed to 0, 150, 500, or 1000 ppm dichloropropane (0, 693, 2310, or 4621 mg/cu.m) according to the same regimen (duration-adjusted concentrations = 0, 124, 413, and 825 mg/cu.m). The animals were observed daily after exposure for overt signs of toxicity as well as changes in behavior pattern and nervous system activity. Body weights were measured weekly. Hematology, clinical chemistry, and urinalysis were done prior to exposure and 2 weeks before study termination. Histopathology was conducted on 52 tissues in the control and high-concentration groups for all three species. The nasal tissues, larynx, trachea, and lungs were evaluated in all concentration groups for all three species. Histopathological examinations were also made on the liver and kidney in mice and on the liver, bone marrow, and spleen in rabbits at all exposure concentrations. The number of sections of the nasal cavity was not stated; it was assumed that four sections were taken as was done in the preliminary 2-week study in the same lab (Nitschke and Johnson, 1983). No treatment-related deaths were observed in any species. Body weights were statistically significantly reduced in the male rats (90% of control) and female rats (92-94% of control) exposed to 150 ppm, and slightly reduced at 50 ppm dichloropropane. No significant treatment-related effects on any hematological, clinical chemistry, or urinalysis parameters studied were noted in the rats or mice. Histopathological effects were seen in the upper respiratory tract of the rats that were concentration-related in incidence and severity. Very slight to slight hyperplasia of the respiratory epithelium of the nasal cavity was observed (0/10, 2/9, 5/10 and 9/10 in males and 0/10, 3/10, 7/10 and 9/10 in females at 0, 15, 50, and 150 ppm, respectively). This hyperplasia occurred primarily in the anterior regions of the nasal cavity. Very slight to slight degeneration of the olfactory mucosa in the rostral portion of the nasal cavity was noted for all male and female rats exposed to 50 or 150 ppm dichloropropane, but not in the control and 15-ppm groups. Statistical analysis of these results was not reported. Slight inflammation of the larynx was also noted in several male rats exposed to 150 ppm dichloropropane; no other treatment related effects were observed in the respiratory tract of rats. No effects were observed in the liver, spleen, or bone marrow in rats exposed to 150 ppm. No treatment-related pathological effects were observed in the mice. Anemia was seen in the rabbits exposed to dichloropropane in a concentration related manner. Red blood cell counts (RBC), hemoglobin concentration, and percent packed cell volume were statistically significantly decreased in the animals exposed to 150 ppm (red blood cell count only), 500, or 1000 ppm dichloropropane. Animals in the 500- and 1000-ppm groups exhibited evidence of a regenerative response (bone marrow hyperplasia and hemosiderin-laden macrophages). Minimal degeneration of the olfactory epithelium was also observed in the nasal cavity of some rabbits from all exposure groups and the controls, but the incidence and severity were higher in the 1000 ppm male animals. This study demonstrates that respiratory effects are apparently the most sensitive endpoint of dichloropropane-induced toxicity, and that species vary considerably with regard to their susceptibility to these effects. A LOAEL of 15 ppm [LOAEL(HEC) = 1.3 mg/cu.m] can be estimated for this study, based on nasal epithelial hyperplasia in female rats. This LOAEL should be considered minimal because of the low incidence and severity of the lesion seen at this concentration. Despite the minimal nature of the effects, they are considered to be adverse because of the increase in incidence and severity with increasing exposure concentration. This relationship is additionally supported by the short-term data (described later). Based on the exposure concentrations used in this study, rats are more than 10 times more sensitive than mice and 100 times more sensitive than rabbits to the nasal effects. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- The uncertainty factor of 300 reflects a factor of 10 to protect sensitive individuals. A factor of 3 is used for extrapolation from a subchronic study, since study of the critical effect shows little progression with exposure time. A factor of 3 is used for the use of a minimal LOAEL due to the minimal nature of the effect. A factor of 3 is used for interspecies extrapolation due to the use of dosimetric adjustments. The factors of 3 represent operational application of a geometric half of the standard factor of 10, rounded to a single significant figure. As a result, multiplication of 3 factors of 3 results in a composite factor of 30. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) Nitschke and Johnson (1983) exposed groups of 5 male and female F344 rats and male rabbits to 0, 100, 300, or 1000 ppm (0, 462, 1386, or 4621 mg/cu.m) 6 hours/day for 2 weeks (9 exposures) in a preliminary study to the critical study. Male and female B6C3F1 mice were exposed to 0, 30, 100, or 300 ppm (0, 139, 462, or 1386 mg/cu.m) with the same protocol. Hematology, serum chemistry, and urine chemistry measurements were made either prior to or after the ninth exposure. Histopathological examination of the respiratory tract (nasal turbinates - four sections, larynx, trachea, lungs), adrenals, liver, kidney, testes, bone marrow, and thymus was performed. Body weights of male and female rats were significantly reduced compared with controls in all groups. No exposure-related changes in hematology, serum chemistry, or urinalysis were found in rats. Slight to moderate degeneration of the nasal olfactory epithelium was observed in all 5 male and 5 female rats exposed to 100 or 300 ppm. Severe degeneration was observed in 4/5 males and 5/5 females at 1000 ppm. In the critical study, degeneration of the olfactory epithelium was described as slight to very slight in all male and female rats exposed to 50 or 150 ppm, indicating a very limited progression of this lesion between 2 and 13 weeks. In contrast, the hyperplasia of the respiratory epithelium noted in the 13-week study was not reported in the 2-week study. This suggests that some progression of the lesion occurs since an area of the nasal epithelium was affected at 13 weeks, but not at 2 weeks. The severity of the lesion at 13 weeks was characterized as slight to very slight. Slightly reduced cellularity of the bone marrow was also reported in males exposed to 1000 ppm and females exposed to 300 or 1000 ppm. In mice, body weight was not affected by exposure (Nitschke and Johnson, 1983). Mild liver lesions were observed in male and female mice exposed to 300 ppm and absolute and relative liver weight increases were found in females. Mice exposed to 300 ppm also had decreased RBC, decreased hemoglobin concentration, and decreased packed cell volume, but these were within the range of historical controls. Slight degeneration of the nasal olfactory epithelium was observed in 4/5 males exposed to 300 ppm and in females exposed to 100 ppm (2/5) or 300 ppm (4/5). Moderate degeneration was observed in 1 male and 1 female exposed to 300 ppm. No nasal lesions were observed in the critical study in mice exposed to 50 or 150 ppm, suggesting that these lesions may resolve with time and do not progress substantially. The only clearly exposure-related lesion in rabbits was slight degeneration of the nasal olfactory epithelium in 2/5 males exposed to 1000 ppm. This result is similar to the critical study in which minimal degeneration was seen in a few rabbits exposed to 1000 ppm and no effect was observed in the nasal epithelium at 500 ppm. These results agree with those of Nitschke et al. (1988) in showing that the nasal epithelium is the most sensitive target tissue in rats, mice, and rabbits. The rat appears to be somewhat more sensitive than the mouse and considerably more sensitive than the rabbit. In addition, comparison of the results at 2 weeks and 13 weeks for three species shows little or no increase in incidence or severity of this lesion, suggesting that the lesion does not progress substantially between 2 weeks and 13 weeks of exposure. Although not directly addressing the issue of progression during a lifetime exposure, these data reduce the concern about progression and the uncertainty in extrapolation to chronic exposure. In a study conducted by Heppel et al. (1946), dogs, rats, mice, rabbits, and guinea pigs were exposed to 1000-2200 ppm dichloropropane 7 hours/day, "nearly always" 5 days/week. Deaths were observed in rats, rabbits, and guinea pigs after less than 8 exposures to 2200 ppm dichloropropane. Most animals could survive 35 exposures to 1500 ppm dichloropropane. Deaths were observed in dogs, guinea pigs, and rats exposed to 1000 ppm dichloropropane. Mice died after only a few hours of exposure to 1000 ppm dichloropropane. Food intake and body weight were adversely affected at all exposure levels. Hematological evaluation failed to reveal any treatment-related effects. Although clinical tests of liver function failed to reveal any adverse effects, histopathological evaluation of the animals that died after only 2-11 exposures to 1000-2200 ppm dichloropropane revealed a friable fatty liver with fatty degeneration characterized by fat accumulation in the centrilobular hepatocytes and coagulation necrosis in guinea pigs. Pulmonary congestion was seen in similarly exposed rats. Hepatic lesions were also noted in rabbits, dogs, and mice exposed to dichloropropane at varying concentrations. Fatty degeneration was also observed in the kidneys of most test species, while lipoid depletion or extensive necrosis was seen in the adrenal cortices of rats and guinea pigs, respectively. Histopathological effects in the respiratory tract were not discussed. It appears that if animals survived the first several exposures, they became resistant to most of these toxic effects because marked splenic hemosiderosis in rats and subcortical fibrosis of the adrenal in guinea pigs were the only notable treatment-related lesions seen in animals that survived 35 exposures. In a subsequent experiment, Highman and Heppel (1946) compared the pathological findings occurring in guinea pigs and rats after 1-5 7-hour exposures to 2200 ppm dichloropropane with those found in the same species exposed once for 7 hours to 2200 ppm dichloropropane and sacrificed at various intervals up to 21 days after exposure. Treatment-related lesions noted in guinea pigs following either exposure regimen included fatty degeneration of the liver and the kidneys and degeneration and necrosis of both the cortex and the medulla of the adrenal glands. Rats also exhibited hepatic lesions and depletion of lipoid material of the adrenal cortex. The effects were most severe 24-48 hours after the first exposure, and appeared to resolve with time regardless of whether exposure was continued. For example, in rats after one exposure, slight diffuse fatty degeneration was observed in the liver that progressed, after an additional exposure, to marked diffuse fatty degeneration and extensive, often confluent centrilobular coagulation and focal hemorrhagic necrosis. The hepatic lesions appeared to diminish at this point until only minimal fatty changes were observed after five exposures to dichloropropane. Because of the high mortality observed in most species at concentrations greater than or equal to 1000 ppm dichloropropane, Heppel et al. (1948) investigated the effects of exposure to 400 ppm dichloropropane in rats, mice, guinea pigs, and dogs. The animals received 7-hour exposures, 5 days/week for 25-30 weeks. The rats were killed at various intervals during the exposure period and several were observed for 6-8 months after they had received 140 exposures. High mortality was observed in the mice during the first 12 exposures. The majority of the mice (5/8) that were killed within 48 hours of the first exposure exhibited slight fatty degeneration of the liver, and slight fatty degeneration of the kidney was observed in 1/2 mice killed after the second exposure. In a group of 80 C3H mice given up to a total of 37 4to 8-hour exposures to 400 ppm dichloropropane, only 3 survived the entire treatment and observation period. Those mice that died during the exposure period were found to have moderate to marked congestion and fatty degeneration of the liver, extensive centrilobular coagulation necrosis of the liver, and slight to moderate fatty degeneration of the kidney. Multiple hepatomas were found in the three mice that survived the full 37 exposures. The most prominent treatment-related effect observed in the other species was decreased body weight gain in rats. The only other exposure-related effect in rats was slight hemosiderin deposition in the liver. Most of the control and exposed guinea pigs exhibited minimal fatty changes in the heart, liver, or kidney and slight to moderate hemosiderosis of the spleen and adrenal gland, but the severity of these changes was slightly greater in the exposed animals. No treatment-related effects were observed in the dogs. Histology of the lungs was performed and no respiratory tract effects were reported. Drew et al. (1978) exposed rats to 1000 ppm dichloropropane for 4 hours and then measured several serum enzyme indicators of hepatic function immediately after exposure and at 24 and 48 hours after exposure. They found that SGOT, SGPT, and ornithine carbamyl transferase activities were significantly elevated by at least 1-day post exposure, but that glucose-6-phosphatase activity was unaffected. Although no histopathology was conducted in this study, these results, together with the earlier studies that demonstrated liver histopathology after one exposure to comparable concentrations of dichloropropane, indicate that serum enzymes may serve as a reliable early biomarker of dichloropropane-induced liver toxicity. The respiratory tract was not examined in this study. Oral subchronic and chronic studies have demonstrated toxic effects in the liver, spleen, testes, and blood. Bruckner et al. (1989) exposed male Sprague-Dawley rats to 0, 100, 250, 500, or 750 mg/kg/day in corn oil gavage on 5 days/week for 13 weeks. Increased mortality occurred in the 500- and 750-mg/kg/day groups. Body weight reduction was significant in all groups. Manifestations of hemolytic anemia included decreased hematocrit, decreased hemoglobin concentration, increased serum bilirubin, and hemosiderosis and hyperplasia of the erythropoietic elements of the spleen. Some of these effects were evident in the 100-mg/kg/day group. Relative spleen weight was increased in the 250- and 500-mg/kg/day groups. Testicular degeneration was observed in 500- and 750-mg/kg/day animals and not in the lower dose groups. Liver toxicity was indicated by increased serum OCT levels, histopathological changes, and increased liver weight in the 250- and 500-mg/kg/day groups. The NTP (1986) exposed female rats and male and female mice to 0, 125, and 250 mg/kg/day, and male rats to 0, 62, and 125 mg/kg/day in corn oil by gavage 5 days/week for 103 weeks. Decreased body weight was observed in the high-dose males (86% of control) and females (76% of control). Liver histopathological effects showed focal clear cell changes in females (3/50, 5/50, and 11/50 in 0-, 125-, and 250-mg/kg/day groups) and necrosis in the high-dose group only. No liver effects were seen in males at either dose. Increased hemosiderosis was also observed in the high-dose female rats. In mice, liver lesions were observed in dosed males but not in females. Hepatocytomegaly occurred in 3/50, 5/49, and 15/50 and necrosis was seen in 2/50, 5/49, and 10/50 in 0-, 125-, and 250-mg/kg/day dose groups, respectively. In the NTP 13-week study, rats were dosed by gavage with 0, 60, 125, 250, 500, or 1000 mg/kg/day on 5 days/week. High-dose rats showed liver histopathology including congestion in 5/10 males and 2/10 females and necrosis and fatty change in 2/10 females. Mice were dosed with 0, 30, 60, 125, 250, and 500 mg/kg/day and no treatment-related histological effects were observed. Taken together the oral studies indicate that the LOAEL for liver effects in mice and rats is at 250 mg/kg/day for chronic exposures. The subchronic LOAEL in rats was 1000 mg/kg/day and in mice the NOAEL was 500 mg/kg/day. Body weight reduction occurred at 125 mg/kg/day in male rats in the chronic study and at 250 mg/kg/day in the females. Blood effects in rats show a clear LOAEL at 250 mg/kg/day with mild effects at 100 mg/kg/day. Kirk et al. (1989) conducted an oral teratology study with dichloropropane in Sprague-Dawley rats. Groups of 30 bred females were administered 0, 10, 30, or 125 mg dichloropropane/kg/day in corn oil by gavage on gestation days 6-15. Based on the findings of the study, dichloropropane is fetotoxic in Sprague-Dawley rats at the maternally toxic dose of 125 mg/kg/day. Maternal toxicity was evidenced in the high-dose group by the clinical findings including significantly decreased body weight gain during days 8-16, decreased movement, decreased muscle tone, decreased extensor thrust reflex, increased salivation, decreased food consumption (25%) during gestation days 6-9, and increased water consumption (25%) during days 9-15. These effects were not seen in controls and in the 10- and 30-mg/kg/day dose groups. Although no teratogenic effects were seen, a statistically significant increase in the incidence of delayed ossification of skull bones was evident among fetuses in the 125-mg/kg/day dose group. Thus, dichloropropane is fetotoxic in rats at a maternally toxic dose; the NOAEL and LOAEL for this study were 30 and 125 mg/kg/day, respectively. In an oral teratology study with dichloropropane in New Zealand White rabbits (Hanley et al., 1989), groups of 18 inseminated females were administered 0, 15, 50, or 150 mg dichloropropane/kg/day in corn oil by gavage on gestation days 7-19. The results of the study indicate that oral administration of dichloropropane at 150 mg/kg/day caused anemia, anorexia, and a statistical decrease in the body weight gain of the maternal animal. There was a significant decrease in RBC count, hemoglobin concentration, and hematocrit, and significant elevation in the WBC, platelet, and reticulocyte counts. Maternal toxicity was not observed in the 15- and 50-mg/kg/day groups. A statistically significant increase in the incidence of delayed ossification of skull bones among fetuses in the 150 mg/kg/day group was noted. An increased incidence of delayed skeletal ossification (not statistically significant) was observed at 50 mg/kg/day. No such effects were seen in the 15-mg/kg/day dose group and in controls. Under the conditions of the study, dichloropropane is fetotoxic to rabbits at the highest dose and also causes deleterious effects on the maternal physiology; the NOAEL and LOAEL for developmental and maternal effects were 50 and 150 mg/kg/day, respectively. In a 2-generation reproduction study in Sprague-Dawley rats (Kirk et al., 1990), groups of 30 rats/sex/dose were provided access to drinking water that contained 0, 0.024, 0.10, or 0.24% (w/v) dichloropropane over 2 generations. Premating exposure of male and female F0 generation rats to 0.24% dichloropropane caused a statistically significant decrease in body weight gain. There was also a significant decrease in water consumption (50% less than controls) and a decrease in body weight gain during gestation and lactation in F0 generation females and a statistically significant decrease in neonatal body weight and survival. RBC counts, hemoglobin concentration, and hematocrit were significantly decreased in F0 females. Although some of these effects were seen at 0.10 and 0.024%, they were not significant. Treatment-related histopathological changes in the liver were seen at all exposure levels but were more remarkable in the 0.24% group. No treatment-related changes in the reproductive organs or in other reproductive indices, including fertility, mating index, conception index, viable litters, gestation length, litter size, live pups, and sex ratio, were noted. In F1 generation animals, water consumption and weight gain decreased significantly during gestation and lactation, but no statistically significant decrease in survival was noted among F2 neonates. There were no treatment-related histologic changes in the reproductive organs of parental rats. Some sporadic hematological and histopathological changes in the liver and kidney were seen in parental F1 animals but these findings were not biologically meaningful, except mild liver lesions at 0.24%. Under the conditions of the study, dichloropropane did not affect fertility but decreased neonatal body weight and survival at the 0.24% concentration and produced deleterious effects on the maternal animal. The NOAEL and LOAEL for reproductive toxicity were 0.10 and 0.24%, respectively. Based on measured drinking water intake, the doses were calculated for males and females for prebreeding, post-breeding in males, and pregestation and gestation in females. The NOAEL and LOAEL levels correspond to approximate doses of 100 and 200 mg/kg/day, respectively. The oral studies indicate that fetotoxicity, minor developmental effects, and a NOAEL for reproductive effects are found at doses approximating those found to adversely affect blood and body weight, and approaching doses found to affect the liver in chronic and subchronic studies. Because of the lack of inhalation, developmental, and reproductive studies, these oral studies were used to infer that developmental and reproductive effects are not significantly more sensitive than liver and blood effects. This supports the use of the respiratory effect as the critical effect, since respiratory effects are considerably more sensitive than liver and blood effects in rats in inhalation studies. Pharmacokinetic studies conducted by Timchalk et al. (1989) indicate that dichloropropane appears to be rapidly absorbed, metabolized, and excreted after oral gavage or inhalation exposure. No meaningful sex-related differences were found in these studies. The majority of the radioactivity was excreted within 24 hours. The principle routes of elimination following oral or inhalation exposure were via the urine (37-52%) and expired air (37-40%). The major urinary metabolites after oral or inhalation exposure were identified as three mercapturates, the N-acetylcysteine conjugates of dichloropropane. The majority (61-80%) of the expired volatile material was the parent dichloropropane after oral exposure. After inhalation exposure, recovery of label was 56-65% in the urine and 16-23% in the expired air (primarily CO2). The peak blood dichloropropane concentrations in the inhalation study showed a dose-dependent nonlinearity in the blood clearance of dichloropropane; however, upon termination of exposure, dichloropropane was rapidly eliminated (T1/2 = 24-30 minutes). Elimination route and metabolites were studied after 6-hour inhalation exposure to 5, 50, or 1000 ppm dichloropropane. With increasing concentration, a greater proportion of the recovered dose was eliminated as expired organics (1.7, 2.1-3.4, and 6.3-6.7%), although relative urinary excretion and relative elimination as expired CO2 were not affected in a concentration related way. These results suggest saturation of oxidative metabolism at the highest concentrations. Repeated exposure resulted in a slight shift in the urinary metabolite profile and reduced urinary excretion. However, repeated dose studies were only performed at the 1-mg/kg/day oral dose level, and changes in metabolism with repeated higher doses or inhalation exposures were not studied. Overall, this study appears to be well conducted with a few deficiencies noted during the evaluation of data. These are that the position of radiolabel in relation to chemical structure was not stated and the rates of absorption and excretion were not determined. Although the study author stated that the test solution was stable even after 8 days (94.4% of the initial concentration), no supporting data were provided. Comparison of the area under the curve and peak plasma C-14 concentrations indicated no clear pattern of dose-dependent C-14 elimination after oral or inhalation exposure. Dichloropropane is used extensively in Italy as a commercial solvent and in the commercial stain remover formulation Trielina, which contains 60-100% dichloropropane. Pozzi et al. (1985) reported two cases of dichloropropane intoxication following inhalation exposure to Trielina. In the first case, a 20-year-old woman was admitted to the hospital with oliguria, epistaxis, hematuria, uterine bleeding, and periorbital and conjunctival hemorrhages. Two days before admission she had abdominal pain, vomiting, fever, facial edema, and erythema. She admitted to sniffing Trielina every night. Clinical tests confirmed severe renal failure, acute liver damage, hemolytic anemia, and disseminated intravascular coagulation. Following transfusions with fresh blood and four hemodialfiltration sessions, the patient was discharged with complete recovery of her renal and liver function and normal coagulation tests. In the second case, a 55-year-old woman was admitted to the hospital with severe liver failure, hemolytic anemia, and slight disseminated intravascular coagulation 3 days after she had spent 6 hours cleaning her flat using 2 liters of solvent containing dichloropropane. She had been suffering from membranoproliferative glomerulonephritis and was on home hemodialysis when exposure to dichloropropane occurred. Hemodialysis treatments continued in the hospital, and within a week the hemolytic anemia and intravascular coagulation disappeared, and her liver disease improved considerably. These two cases demonstrate that acute as well as repeated high-level inhalation exposure to dichloropropane (level not specified in either case) are associated with adverse effects on the liver, kidney, and hematopoietic systems in humans, and that these effects can be reversed following cessation of exposure. No respiratory symptoms were reported. The health effects in humans (truck drivers, highway patrol officers, fire fighters, and hospital employees) that were exposed to dichloropropane following the accidental spill of 2000 gallons from a truck were described by Rubin (1988). The exposed individuals complained of chest discomfort, dyspnea, and cough, and some had persistent chest pain or discomfort and fatigue. These symptoms indicate that dichloropropane is a respiratory irritant. The level of exposure to dichloropropane was not quantified. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Data Base -- Medium RfC -- Medium The Nitschke et al. (1988) study used an adequate number of animals, exposure concentrations, and controls, examined three species, focused on known target organs, and the incidence and severity of the nasal lesions were exposure-related. The data base is given a medium confidence rating because there are no chronic inhalation studies. A medium confidence rating for the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- U.S. EPA, 1987a,b Agency Work Group Review -- 07/17/1991 Verification Date -- 07/17/1991 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for 1,2-Dichloropropane conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2-Dichloropropane CASRN -- 78-87-5 NOCA: Not available at this time. ============================================================================ UDSO: 199112 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2-Dichloropropane CASRN -- 78-87-5 Last Revised -- 12/01/1991 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Bruckner, J.V., W.F. MacKenzie, R. Ramanathan, S. Muralidhara, H.J. Kim and C.E. Dallas. 1989. Oral toxicity of 1,2-dichloropropane: Acute, short-term, and long-term studies in rats. Fund. Appl. Toxicol. 12: 713-730. Drew, R.T., J.M. Patel and F-N. Lin. 1978. Changes in serum enzymes in rats after inhalation of organic solvents singly and in combination. Toxicol. Appl. Pharmacol. 45: 809-819. Hanley, T.R., N.M. Berdasco, J.E. Battjes and K.A. Johnson. 1989. Propylene dichloride: Oral teratology study in New Zealand White Rabbits. Mammalian and Environmental Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI. Heppel, L.A., P.A. Neal, B. Highman and V.T. Porterfield. 1946. Toxicology of 1,2-dichloropropane (propylene dichloride). I. Studies on effects of daily inhalations. J. Ind. Hyg. Toxicol. 28(1): 1-8. Heppel, L.A., B. Highman and E.G. Peake. 1948. Toxicology of 1,2-dichloropropane (propylene dichloride). IV. Effect of repeated exposures to a low concentration of the vapor. J. Ind. Hyg. Toxicol. 30: 189-191. Highman, B. and L.A. Heppel. 1946. Toxicology of 1,2-dichloropropane (propylene dichloride). III. Pathologic changes produced by a short series of daily exposures. Arch. Pathol. 42: 525-534. Kirk, H.D., T.R. Hanley, K.A. Johnson and F.K. Dietz. 1989. Propylene dichloride: Oral teratology study in Sprague-Dawley rats. Mammalian and Environmental Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI. Kirk, H.D., T.R. Hanley, Jr., D.M. Bond, et al. 1990. Propylene dichloride: Two-generation reproduction study in Sprague-Dawley rats. Mammalian and Environmental Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI. Nitschke, K.D. and K.A. Johnson. 1983. Propylene dichloride: One day and two week inhalation toxicity study in rats, mice, and rabbits. Mammalian and Environmental Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical Company, Midland, MI. Nitschke, K.D., K.A. Johnson, D.L. Wackerle, J.E. Phillips and D.A. Dittenber. 1988. Propylene dichloride: A 13-week inhalation toxicity study with rats, mice, and rabbits. Dow Chemical Company, Mammalian and Environmental Toxicology Research Laboratory, Midland, MI. OTS Doc. #86-870001397 NTP (National Toxicology Program). 1986. Toxicology and Carcinogenesis studies of 1,2-dichloropropane (Propylene dichloride) (CAS No. 78-87-5) in F344/N rats and B6C3F1 mice (gavage studies). TR-263, NIH Publication No. 86-2519. National Toxicology Program, Research Triangle Park, NC. Pozzi, C., P. Marai, R. Ponti, et al. 1985. Toxicity in man due to stain removers containing 1,2-dichloropropane. Br. J. Ind. Med. 42(11): 770-772. Rubin, D.F. 1988. Occupational health implications of a toxic spill of propylene dichloride. Western J. Med. 148(1): 78-79. Timchalk, C., M.J. Bartels, M.D. Dryzga and F.A. Smith. 1989. Propylene dichloride: Pharmacokinetics and metabolism in Fischer 344 rats following oral and inhalation exposure. Mammalian and Environmental Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI. U.S. EPA. 1987a. Drinking Water Criteria Document for 1,2-Dichloropropane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA/600/x-84/162-2. U.S. EPA. 1987b. Health Effects Assessment for 1,2-Dichloropropane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. EPA/600/8-88/029. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2-Dichloropropane CASRN -- 78-87-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1991 I.B. Inhalation RfC now under review 12/01/1991 I.B. Inhalation RfC on-line 12/01/1991 VI. Bibliography on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.B.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 434 of 1119 in IRIS (through 2003/06) AN: 630 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199205 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: 1,2-Epoxybutane- (EBU) SY: 106-88-7; 1,2-EPOXYBUTANE-; BUTANE,-1,2-EPOXY-; BUTYLENE-OXIDE-; ETHYLETHYLENE-OXIDE-; N-BUTENE-1,2-OXIDE-; 1-BUTENE-OXIDE-; 1-BUTYLENE-OXIDE-; 1,2-BUTENE-OXIDE-; 1,2-BUTYLENE-OXIDE-; 2-ETHYLOXIRANE- RN: 106-88-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- 1,2-Epoxybutane (EBU) CASRN -- 106-88-7 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199205 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- 1,2-Epoxybutane (EBU) CASRN -- 106-88-7 Last Revised -- 05/01/1992 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ----- --- --------- Degenerative lesions NOAEL: None 300 1 2E-2 of the nasal cavity mg/cu.m LOAEL: 147 mg/cu.m (50 ppm) 2-Year Mouse LOAEL(ADJ): 26 mg/cu.m Inhalation Study LOAEL(HEC): 4.8 mg/cu.m NTP, 1988 ---------------------------------------------------------------------------- *Conversion Factors: MW = 72.12. Assuming 25 C and 760 mmHg, LOAEL (mg/cu.m) = 50 ppm x 72.12/24.45 = 147 mg/cu.m. LOAEL(ADJ) = 147 x 6 hours/24 hours x 5 days/7 days = 26 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in the extrathoracic region. MVa = 0.06 cu.m/day, MVh = 20 cu.m/day, Sa (ET) = 2.9 sq. cm., Sh (ET) = 177 sq. cm. RGDR(ET) = (Mva/Sa) / (Mvh/Sh) = 0.183. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 4.8 mg/cu.m. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) NTP (National Toxicology Program). 1988. Toxicology and carcinogenesis studies of 1,2-epoxybutane (CAS No. 106-88-7) in F344/N rats and B6C3F1 mice (inhalation studies). ISS NTP-TR-329, NIH/PUB-88-2585. F344/N rats (50/sex) were exposed to 0, 200, or 400 ppm 1,2-epoxybutane (EBU) (0, 590, or 1180 mg/cu.m; duration-adjusted concentrations were 0, 105, or 210 mg/cu.m) 6 hours/day, 5 days/week for 2 years. B6C3F1 mice (50/sex) were exposed to 0, 50, or 100 ppm EBU (0, 590, or 1180 mg/cu.m; duration-adjusted concentrations were 0, 26, or 52 mg/cu.m) under the same exposure regime. The purity of the EBU was reported as more than 99% (NTP, 1988; also reported in Dunnick et al., 1988). The animals were observed twice daily, weighed weekly for 13 weeks and monthly thereafter, and subjected to a clinical examination once a month. Necropsy and histological examination of approximately 30 tissues were performed on all animals. Survival was adversely affected in both male and female rats by both concentrations of EBU. In the mice, survival was adversely affected by the 100-ppm concentration in both sexes; only 9/50 female mice exposed to 100 ppm EBU survived until study termination. In mice exposed to 100 ppm, body weight gain was reduced significantly (more than 10%). Relative to control values, a 10-14% (male) and a 13-23% (female) decrease in body weight was noted. Female mice exposed to the lower concentration suffered a 12-16% decrease. Increases in the incidence of both granulocytic hyperplasia and splenic hematopoiesis were observed in female mice in a concentration-dependent manner. The incidence for both these lesions at the lower concentration was increased over controls. This effect was limited to female mice and did not occur in male mice or in male or female rats. These effects could be secondary to the inflammatory processes in the nasal cavity. Blood effects would be an extrarespiratory effect, and the LOAEL(HEC) would be 26 mg/cu.m. Blood effects were also reported in mice and rats in the study of Miller et al. (1981) discussed following. Significant increases in the incidence of nonneoplastic degenerative and proliferative lesions of the nasal cavity were observed in male and female rats exposed to both concentrations of EBU. Concentration-related increases in the incidence rate were noted for inflammation, epithelial hyperplasia of the respiratory epithelium, atrophy of the olfactory sensory epithelium, and hyperostosis of the nasal turbinate bone. Similarly, significant increases in the incidence of non-neoplastic lesions of the nasal cavity of both sexes of mice were documented. Concentration-related increases in the incidence of chronic inflammation, epithelial hyperplasia, and erosion (occurring in 23 of 99 mice at the lower concentration) were noted in exposed mice, including suppurative inflammation, epithelial hyperplasia, and erosion. For rats, this study indicates a LOAEL for effects in the nasal tract of 200 ppm [the corresponding LOAEL(HEC) = 19 mg/cu.m]. For mice, 50 ppm is a LOAEL based on the lesions in the upper respiratory tract [LOAEL(HEC) = 4.8 mg/cu.m]. No NOAEL could be derived from this study for either species. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- The uncertainty factor of 300 reflects factors of 10 to protect unusually sensitive individuals, 10 for the use of a LOAEL rather than a NOAEL, and 3 for interspecies extrapolation. An additional factor for lack of developmental/reproductive effects is not deemed necessary as the results from the chronic NTP study, in concert with chronic studies of epoxy analogs of EBU, indicate extrarespiratory circulation of EBU to be minimal. MF -- None IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) Male and female B6C3F1 mice (10/sex/group) were exposed to greater than 99% pure EBU at the following concentrations for a total of 13 weeks: 0, 50, 100, 200, 400, or 800 ppm (0, 147, 295, 590, 1180, or 2360 mg/cu.m) (NTP, 1988). Based on exposure for 6 hours/day, 5 days/week, the corresponding duration-adjusted values are 0, 26, 53, 105, 211, or 421 mg/cu.m. The vapor was generated from the heated liquid and pumped directly into the exposure chamber. The animals were observed twice daily and weighed weekly. Histopathological examinations were performed on approximately 30 tissues from control animals and animals from the two highest concentration groups except in the case of the nasal turbinates which were examined in all animals at all exposure levels. NTP procedures were followed in the preparation and examination of all tissues. All mice exposed to 800 ppm and 2 of 10 males exposed to 50 ppm died, although no mortality was noted at any other exposure level. No significant weight depression was observed in any exposure group compared to controls. Systemic histopathology, which occurred only in the mice at the highest exposure level, included atrophy and necrosis of the spleen and thymus, and renal necrosis. The principal tissue affected at the highest concentration was the nasal passage. These tissues were necrotic in 15 of 20 animals at the highest exposure with less severe effects occurring at lower concentrations. Acute inflammation of the turbinates was observed in a concentration-related manner in 14/20 animals at 800 ppm and in 5/20 at 400 ppm; none was observed at lower concentrations. A lesser grade of inflammation, serous, was also observed in a concentration-related manner at lower concentrations in 20 of 20 mice exposed to 200 ppm, in 7/20 mice (all females) at 100 ppm, but not in any of the animals exposed to 50 ppm or the controls. The NOAEL for these effects is 50 ppm. As the serous inflammation was noted exclusively in female mice at 100 ppm, the LOAEL, the HEC is calculated based on default female ventilatory parameters [NOAEL(HEC) = 3.2 mg/cu.m, LOAEL(HEC) = 6.5 mg/cu.m]. Although this study identifies a NOAEL at 50 ppm, it should be noted that this level (50 ppm) produced severe nasal effects in mice in the chronic study discussed above (NTP, 1988), precluding use of this study in deriving an RfC. Male and female F344/N rats (10/sex/group) were exposed to greater than 99% pure EBU for 13 weeks at the following concentrations: 0, 50, 100, 200, 400, or 800 ppm (0, 147, 295, 590, 1180, or 2360 mg/cu.m) (NTP, 1988). The corresponding duration-adjusted values, based on exposure 6 hours/day, 5 days/week, were 0, 26, 53, 105, 211, or 421 mg/cu.m. Vapor was generated from the heated liquid and pumped directly into the exposure chamber. The animals were observed twice daily and weighed weekly. Histopathological examinations were performed on approximately 30 tissues from control animals and animals from the two highest concentration groups. The nasal turbinates were examined in all animals at all exposure levels. NTP procedures were followed in the preparation and examination of all tissues. A significant reduction in body weight was observed in rats exposed to 800 ppm EBU, but surviving rats exhibited no change in body weight compared with controls. Inflammation of the nasal turbinates was noted in rats exposed to 800 ppm (10/10 with acute rhinitis) but not in rats at lower concentrations. The inflammation was present in both the dorsal and lateral portions of the nasal cavity, affecting both the respiratory and olfactory epithelium. The NOAEL for these effects was 400 ppm, RGDR = 0.107, [NOAEL(HEC) = 22.6 mg/cu.m]. A lower concentration, 200 ppm, was a LOAEL in the chronic study described above (NTP, 1988). Groups of 15 F344/N rats and B6C3F1 mice/sex were exposed to 0, 75, 150, or 600 ppm EBU (more than 99% pure) 6 hours/day 5 days/week for 13 weeks (Miller et al., 1981). These values correspond to 0, 221, 442, or 1770 mg/cu.m. Adjusted for exposure duration, these values become 0, 38, 79, or 317 mg/cu.m. The experimental protocol was the same as reported for the 2-week study (see next paragraph), except that 5 animals/sex/group were sacrificed after 4 weeks of exposure. No treatment-related deaths were observed. At the termination of the experiment, both sexes of mice exposed to the highest concentration had significant decreases in weight gain (7.6 g vs. 5.3 g for males and 7.5 g vs. 5.0 g for females). The authors noted alterations in the absolute and relative weights of several organs but did not present the data. Hematological data were not reported for the rats, and the authors claimed that no consistent treatment-related effects were observed. Male and female mice exhibited several statistically significant changes although there was no concentration-response relationship and the alterations were claimed to be within the range of historical controls (not reported). Clinical chemistry and urinalysis data were not reported, but the authors state that with the exception of reduced urine specific gravity in the 600-ppm male and female rats, no treatment-related effects were seen. In both the rats and mice exposed to 600 ppm EBU, histopathological examination revealed evidence of nasal mucosal irritation that consisted of flattening of the olfactory and respiratory epithelium with some focal thickening of the respiratory epithelium and increased numbers of inflammatory cells in the nasal cavity. No incidence rates were given in the study, nor was any information presented other than in narrative format concerning these effects. No effects were seen in the trachea or lungs. Other histopathological changes noted in rats and mice exposed to 600 ppm EBU included decreased hepatocellular size, decreased cell content in the cortex of the thymus gland, and myeloid hyperplasia in vertebral bone marrow (3 of 10 male rats). There were no histopathologic observations in rats or mice in the two lower exposure groups that were considered treatment related. It is not clear why there is such a large discrepancy between this study, which supports a NOAEL at 150 ppm for both species, and the NTP subchronic studies, which clearly show effects in mice at 100 ppm as well as marked species differences in toxic response for the tissues of the upper respiratory tract. This study, however, does confirm that the nasal mucosa is the target of EBU toxicity in both rats and mice. A NOAEL of 150 ppm EBU is indicated for both rats and mice, [NOAEL(HEC) for female mice (RGDR = 0.122) = 9.6 mg/cu.m and for females rats (RGDR = 0.107) 8.4 mg/cu.m]. Miller et al. (1981) exposed F344 rats and B6C3F1 mice (5/sex/group) to 0, 400, 800, or 1600 ppm (0, 1180, 2360, or 4720 mg/cu.m) 99% EBU for a total of 9 days over a 2-week period. Exposures were for 6 hours/day, 5 days/week; the duration-adjusted concentrations were 0, 211, 422, or 845 mg/cu.m. The test atmosphere was analyzed 2-3 times/hour by infrared spectroscopy. Clinical observations were conducted daily, and body weights were monitored throughout the study. Hematology, clinical chemistry, and urinalyses were conducted. Complete necropsies were conducted at study termination and approximately 40 tissues were examined histopathologically including the nasal turbinates (number of sections not specified). All mice in the 1600-ppm group died by the third day of exposure, while the rats exposed to this concentration exhibited no clinical signs of toxicity, even though their body weight gain was significantly reduced (21% in males and 25% in females). Body weights of male rats exposed to 800 and 400 ppm EBU were not different from control values at the end of the experiment. Elevated mean white blood cell counts, a trend toward a decreased percentage of lymphocytes, and an increased percentage of neutrophils were reported for rats of both sexes exposed to 1600 ppm EBU (data not presented). Inflammatory and degenerative changes were noted in both the olfactory and respiratory portions of the nasal turbinates of both rats and mice exposed to 800 and 1600 ppm but not in animals exposed to 400 ppm. No treatment-related changes were seen in the trachea or lungs of these animals. Myeloid hyperplasia, noted in the vertebral bone marrow of most rats exposed to 1600 ppm and in some rats and mice exposed to 800 ppm EBU, may have been secondary to the nasal inflammation. No adverse effects were reported in the animals exposed to 400 ppm. The NOAEL(HEC) at this concentration based on the nasal tract (extrathoracic) effects is 21.9 mg/cu.m for both mice and rats (RGDR = 0.104 for both female rats and mice). The brevity of the exposure period (2 weeks) precludes the use of this study as the principal study. Fourteen-day studies were also reported in the NTP (1988) study. Groups of five animals/sex of F344/N rats and B6C3F1 mice were exposed to 0, 400, 800, 1600, 3200, or 6400 ppm EBU (0, 1180, 2360, 4720, 9439, or 18878 mg/cu.m) 6 hours/day, 5 days/week (NTP, 1988). The corresponding duration-adjusted values are 0, 211, 421, 843, 1686, or 3371 mg/cu.m. Clinical observations were carried out twice daily and body weights were determined at study initiation, after 1 week, and at necropsy. Only a fraction of the animals were histologically examined. All rats exposed to the two highest concentrations of EBU died before study termination, and 2/5 female rats exposed to 1600 ppm EBU died. A concentration-related reduction in body weight was observed in male and female rats exposed to 800 or 1600 ppm. Moderate multifocal pulmonary hemorrhage and acute suppurative rhinitis were observed in some of the rats exposed to 1600 ppm EBU. All mice exposed to concentrations greater than or equal to 1600 ppm EBU died, and 1/5 male mice exposed to 800 ppm EBU died before study termination. Body weight was reduced in the mice exposed to 800 ppm. The text of the study reports that moderate nephrosis was noted in 2/2 males exposed to 1600 ppm, and mild to slight nephrosis was seen in 2/2 males and 1/2 females exposed to 800 ppm EBU. This study indicates that mice are more sensitive than rats to the toxic effects of EBU, although other studies reported on below indicate that the rabbit may be more sensitive to the effects of this compound than either of these species. The occurrence of systemic toxicity or cancer caused directly by EBU would be a function of dose to the target organ thereby implying systemic circulation of parent EBU. Data from NTP inhalation studies available for structural analogs of EBU indicate that the occurrence of neoplasms in organ systems other than the nasal cavity is present with the 2-carbon analog (ethylene oxide), but absent with the 3-carbon analog (propylene oxide) and the 4-carbon analog (EBU). One implication of this limited structure-response relationship is that EBU may not have significant distribution to remote sites under the conditions employed by NTP since only portal-of-entry neoplasia was noted. Thus, concern for remote or extrarespiratory effects, including reproductive and developmental effects, caused directly by EBU in these species is ameliorated. The studies discussed below may reflect this circumstance as no reproductive/developmental effects were noted. No evidence exists for EBU to exert toxicity through a secondary mechanism (e.g., through a metabolite). The limited metabolic data for EBU indicates that it is converted to a mercapturic acid via conjugation with glutathione (NTP, 1988). Wolf (1961) exposed 4 groups of animals, each comprised of 10 rats (strain not indicated), 8 guinea pigs, and 2 rabbits per sex, to either 0 (2 groups of unexposed controls), 400 ppm, or 800 ppm of a blend of EBU isomers: 70% EBU, 15% 2,3-epoxybutane, and 10% isobutylene oxide (2-methyl-1,2-epoxypropane) for 7 hours/day. Each exposed group was subjected to 135-141 exposures over a period of 198 days (about 6.5 months). These exposure values correspond to 1180 and 2340 mg/cu.m. The duration-adjusted values (assuming 5 exposures days/week) would be 246 or 488 mg/cu.m. Growth and mortality records were kept for each group and the animals were observed frequently. At the end of the experiment, hematological exams were performed on the rats and rabbits, urinalysis on some of the same animals, and BUN on selected rats and rabbits. The lung, heart, kidneys, liver, spleen, and testes (but apparently no portion of the upper respiratory tract) were examined histologically. The lungs and other organs were weighed at the end of the experiment. Although mention is made of increased mortality among male rats, no data are given. Data presented showed that the growth of male, but not female, rats was adversely effected by the exposure, with an 11% weight deficit relative to controls at the higher concentration. A similar growth depression (12%) was noted for male guinea pigs at this same concentration. Relative lung weights were increased in both sexes of rats and guinea pigs at 800, but not at 400, ppm. Erratic results from the few rabbits prevented the authors from making any claims about effects in those exposed to the higher concentration, although those exposed at the lower concentration were not different from the controls in the parameters noted. No adverse effects were reported at the 400-ppm exposure level indicating this concentration to be a NOAEL. Based on the increased lung weights (a thoracic effect, RGDR for female rats = 2.23), [NOAEL(HEC) = 548 mg/cu.m]. Sikov et al. (1981) exposed groups of 38-45 Wistar rats to 0, 250, or 1000 ppm EBU (more than 99% pure) 7 hours/day, 5 days/week for a 3 week pregestational period; or for 7 hours/day on gestation days 1-19; or for a combination of pregestational and gestational exposure. The test atmosphere was analyzed using a gas chromatograph. Analysis of the test material showed that none of the other isomeric butylene oxides were present in concentrations greater than 0.1%. Standard procedures were used to examine the fetuses on day 21 of gestation. One death occurred and body weight deficits of 10% relative to controls were noted in the dams exposed to 1000 ppm (n = 42) exposed during pregestation and gestation. Absolute and relative weights of the liver, lung, kidneys, or placenta of the exposed dams did not differ from the controls. Histopathology of the dams' lungs showed no exposure-related effects. No parameters of reproductive function were significantly altered by exposure to EBU, nor was fetal growth, viability, and development affected by these conditions of exposure. These results indicate that 250 ppm is a NOAEL for maternal toxicity (weight loss) and that the higher concentration of 1000 ppm (2950 mg/cu.m) is a free-standing NOAEL for fetotoxicity. Sikov et al. (1981) also exposed groups of 24-49 New Zealand white rabbits to 0, 250, or 1000 ppm EBU (more than 99% pure) for 7 hours/day on gestation days 1-24. Standard techniques were used to evaluate the fetuses on gestation day 21. Death occurred in 14/24 rabbits exposed to 1000 ppm EBU and in 6/48 rabbits exposed to 250 ppm EBU. However, no effect on maternal weight gain was observed in the surviving animals. Absolute and relative weights of the liver, lung, kidneys, or placenta of the exposed animals did not differ from the controls. A decreased pregnancy rate was observed in the rabbits exposed to the highest concentration, although this finding may be confounded by the high mortality in this group. A decreased number of live fetuses per litter was observed in the two litters born to rabbits exposed to 1000 ppm EBU. Both a hypoplastic tail and unilateral renal agenesis was observed in 1 of the 8 surviving fetuses born to rabbits exposed to 1000 ppm EBU. No other embryotoxic or developmentally toxic effects were observed. Based on maternal effects, 250 ppm (737 mg/cu.m) is a frank effect level (FEL), as mortality was noted at this concentration. Evaluation of fetotoxicity in this study was not possible due to the limited data presented. Since extensive mortality was observed with rabbits but not rats (see above), rabbits could be considered as the more sensitive species of the two. The relative sensitivity to EBU of rabbits and female mice (NTP,1988), however, is not clear. Pharmacokinetic studies were conducted in male F344 rats by Reitz et al. (1983) to determine the major routes and rates of clearance following a 6-hour exposure to either 50 or 1000 ppm EBU or gavage administration of 20 mg/kg EBU in corn oil. Results of these studies indicate that EBU is rapidly absorbed, metabolized, and eliminated following either inhalation or oral exposure. EBU was eliminated primarily as nonvolatile urinary metabolites in the urine or as expired carbon dioxide. Practically all of the administered EBU was recovered within the first 36 hours after exposure, with small amounts remaining in the carcass after 32 or 66 hours. The identity of the urinary metabolites was not determined. There were significant differences in the amount of radioactivity recovered in the urine and expired air between animals given C1-labeled EBU and uniformly labeled EBU. Exposure to C1-EBU resulted in the recovery of 40-46% of the radioactivity in the urine whereas exposure to uniformly labeled EBU resulted in the recovery of only 12% of the radioactivity in the urine. The recovery of radioactivity in the expired air was less in animals exposed to C1-labeled EBU (27-34%) and more in animals exposed to uniformly labeled EBU (58%). The authors concluded that this labeling pattern indicates that the urinary metabolites contain only the label associated with the C1-atom of EBU and thus cannot be simple conjugates of EBU. There was no significant differences in the percentages of radioactivity recovered in the urine and expired air following exposure to either 50 or 2000 ppm, indicating that the pharmacokinetics of EBU are linear over this range of concentrations. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- Medium Data Base -- Medium RfC -- Medium Although the NTP (1988) chronic inhalation study was well-conducted, used an appropriate number of animals, chose well-spaced exposure levels, and provided a thorough histopathological examination of the respiratory tract, it did not establish a NOAEL and can be given no more than a medium confidence rating. The critical effect identified in this study, lesions of the nasal tract, is supported by the effects seen in rats in the subchronic NTP (1988) studies, as well as in subchronic studies in rats and mice (Miller et al., 1981; NTP, 1988). Female mice are more sensitive than males to EBU. The maternal effects seen in rabbits indicate that this species may be even more sensitive than female mice. The data base is given a medium confidence rating because there is a chronic inhalation study in two species supported by subchronic inhalation studies in several species, and because inhalation studies are available on developmental effects. There are no multigenerational reproductive studies available. A medium confidence rating in the RfC follows. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is not presented in any existing U.S. EPA document. Other EPA Documentation -- None Agency Work Group Review -- 12/11/1991 Verification Date -- 12/11/1991 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for 1,2-Epoxybutane (EBU) conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- 1,2-Epoxybutane (EBU) CASRN -- 106-88-7 NOCA: Not available at this time. ============================================================================ UDSO: 199205 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- 1,2-Epoxybutane (EBU) CASRN -- 106-88-7 Last Revised -- 05/01/1992 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Dunnick, J.K., S.L. Eustis, W.W. Piegorsch and R.A. Miller. 1988. Respiratory tract lesions in F344/N rats and B6C3F1 mice after inhalation exposure to 1,2-epoxybutane. Toxicology. 50(1): 69-82. Miller, R.R., J. F. Quast, J.A. Ayres and M.J. McKenna. 1981. Inhalation toxicity of butylene oxide. Fund. Appl. Toxicol. 1(4): 319-324. NTP (National Toxicology Program). 1988. Toxicology and carcinogenesis studies of 1,2-epoxybutane (CAS No. 106-88-7) in F344/N rats and B6C3F1 mice (inhalation studies). ISS NTP-TR-329, NIH/PUB-88-2585. Additional data on the subchronic studies were supplied by NTP and are included in the IRIS data file on this chemical. Reitz, R.H., T.R. Fox and E.A. Hermann. 1983. Fate of 1,2-butylene oxide in male rats following inhalation exposure. Toxicology Research Laboratory. Health and Environmental Sciences USA, Dow Chemical, USA, Midland, MI. EPA/OTS Document No. 878213688. Sikov, M.R., W.C. Cannon, D.B. Carr, R.A. Miller, L.F. Montgomery and D.W. Phelps. 1981. Teratologic assessment of butylene oxide, styrene oxide, and methyl bromide. Division of Biomedical and Behavioral Science, NIOSH. NIOSH/00099314. NIOSH Technical Report No. 81-124. Wolf, M.A. 1961. Results of repeated exposures of laboratory animals to the vapors of butylene oxide(s) (Mixed isomers). Dow Chemical Biochemical Research Department. EPA/OTS Document No. 878211232. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- 1,2-Epoxybutane (EBU) CASRN -- 106-88-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 01/01/1992 I.B. Inhalation RfC now under review 05/01/1992 I.B. Inhalation RfC on-line 05/01/1992 VI.B. Bibliography on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.B.6. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 435 of 1119 in IRIS (through 2003/06) AN: 642 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the health assessment document for this chemical http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=29060 , Click here for the support document for this chemical http://www.epa.gov/iris/supdocs/dies_sup_summary.pdf UD: 200302 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Diesel-engine-exhaust- SY: DIESEL-SOOT-; DIESEL-PARTICULATE-MATTER-; DPM- HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200302 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Diesel engine exhaust CASRN -- Not found Last Revised -- 02/28/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: An oral RfD for diesel engine exhaust is not provided. All available studies are focused on inhalation exposure. ---------------------------------------------------------------------------- UDRC: 200302 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Diesel engine exhaust CASRN -- Not found Last Revised -- 02/28/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORC: Note: Diesel engine exhaust (DE) is a complex mixture of airborne particles and gases. Diesel particulate matter (DPM), composed of elemental carbon particles and adsorbed organic compounds, is the most frequently determined measure of DE and the measure reported in toxicological studies of diesel engine exhaust. The previous RfC of 5 x 10-3 mg DPM/m3 was entered on IRIS 6/1/93. This updated RfC reflects the use of a revised model for lung deposition of DPM, and remains unchanged. SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC -------------------- --------------------------- ---- --- ----- Pulmonary inflammation NOAEL: 0.46 mg/m3 30 1 5 ug/m3 and histopathology Rat chronic inhalation NOAEL(HEC): 0.144 mg DPM/m3 study Ishinishi et al. (1988) ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- Human equivalent concentrations were derived using a mathematical model of diesel particulate matter (DPM) deposition and clearance (Yu et al., 1991), assuming that equal pulmonary surface loadings (in mg DPM/cm2) in rats and humans would be associated with similar effects. First, the model was used to estimate the loading in rats corresponding to the NOAEL, administered 16 hr/day, 6 days/week, for 130 weeks. Then the model was used to estimate the continuous exposure conditions for humans which would lead to the loading estimated in rats. In performing the modeling, rats were taken to weigh 300g, with a total pulmonary surface area of 4090 cm2. Human equivalent concentrations were derived using respiratory parameters for a 25 year-old human male having a total pulmonary surface area of 627,000 cm2, tidal volume of 0.926 L, respiratory frequency of 15 breaths/min, and total daily pulmonary volume of 20 m3, with exposure assumed to last 70 years. For more details of the derivation of human equivalent concentrations, see the Support Document (U.S. EPA, 2002; Appendix A). PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Chronic respiratory effects are the principal noncancer hazard to humans from long-term environmental exposure to diesel engine exhaust, or emissions (DE). Several occupational studies have evaluated the noncancer effects of chronic exposure to DE (U.S. EPA, 2002, Chapter 5.1.1.2). There is some evidence suggesting that exposure may impair pulmonary function, though the results are not robust. While the increased occurrence of mostly transient symptoms such as cough, phlegm, and chronic bronchitis is clear in noncancer occupational studies, the studies are deficient in exposure information. Other effects (e.g., neurological, growth and survival, neurobehavioral, lowered resistance to respiratory infection, liver effects) are observed in animal studies at higher exposures than those producing the respiratory effects (U.S. EPA, 2002, Chapter 5.6). The human and animal data for the immunological effects of DE exposure (i.e., exacerbation of allergenicity, and asthma symptomology) are currently inadequate for dose-response evaluation. Reproductive toxicity has been evaluated in six studies. No teratogenic, embryotoxic, fetotoxic or female reproductive effects have been observed in mice, rats, or rabbits at inhalation exposure levels lower than those where respiratory effects were observed. Respiratory effects are considered the "critical effect" for the derivation of a chronic RfC for DE. The evidence for chronic respiratory effects is based mainly on animal studies showing consistent findings of inflammatory, histopathological (including fibrosis), and functional changes in the pulmonary and tracheobronchial regions of laboratory animals, including the rat, mouse, hamster, guinea pig, monkey, and cat. Of 17 studies covering these species, the rat is the most studied test animal, though positive responses are also seen in mice, guinea pigs, monkeys, and hamsters. Most are single dose studies, except for five multi-dose studies discussed below. The multi-dose studies, by Ishinishi et al. (1986, 1988), Mauderly et al. (1987a), Heinrich et al. (1995), and Nikula et al. (1995), show exposure-response relationships based on chronic inhalation exposure to whole diesel exhaust in rats. The effects observed include inflammation, histopathology (including fibrosis), and functional changes in the pulmonary and tracheobronchial regions. An array of these key studies and their effect levels (NOAEL, LOAEL, BMCL10, AEL) prior to conversion to human equivalent concentrations (HECs) is shown in Table I.B.1. This array provides an inter-study concentration-response continuum, normalized to human equivalent continuous diesel particulate matter (DPM) exposure levels, facilitating the choice of a concentration to use as a point of departure in deriving an RfC. TABLE I.B.1 Human equivalent continuous concentrations: 70-year HECs calculated with the model of Yu et al. (1991) from key long-term studies of rats repeatedly exposed to DPMa ------------------------------------------------------------------------------------------------- Study Exposure Effect Lung burden (b) HEC (mg/m3) concentration (mg/m3) level (a) (modeled) (ug DPM/cm2) ------------------------------------------------------------------------------------------------- Ishinishi et al. (1988) 0.11 NOAEL 0.0587 0.032 LD (c) Mauderly et al. (1987a) 0.35 NOAEL 0.0685 0.038 Ishinishi et al. (1988) 0.41 NOAEL 0.245 0.128 LD (c) Ishinishi et al. (1988) 0.46 NOAEL 0.281 0.144 HD (c) Heinrich et al. (1995) 0.84 LOAEL 0.94 0.33 Nikula et al. (1995) 2.44 & 6.3 (d) BMCL10 -inflam 1.34 0.37 Ishinishi et al. (1988) 0.96 LOAEL 3.16 0.883 HD (c) Ishinishi et al. (1988) 1.18 LOAEL 4.50 1.25 LD (c) Nikula et al. (1995) 2.44 & 6.3 (d) BMCL10 - fibrosis 4.70 1.3 Mauderly et al. (1987a) 3.47 LOAEL 4.95 1.375 Nikula et al. (1995) 2.44 LOAEL 7.00 1.95 Ishinishi et al. (1988) 1.84 AEL 7.63 2.15 HD (c) Heinrich et al. (1995) 2.5 AEL 8.40 2.35 Ishinishi et al. (1988) 2.32 AEL 9.75 2.75 LD (c) Mauderly et al. (1987a) 7.08 AEL 10.9 3.05 Ishinishi et al. (1988) 3.72 AEL 15.8 4.4 HD (c) -------------------------------------------------------------------------------------------------- (a) Effect levels are based on the critical effects of pulmonary histopathology and inflammation as reported in the individual studies. NOAEL: no-observed-adverse-effect level; LOAEL: lowest-observed-adverse-effect level; AEL: adverse-effect level; BMCL10: lower 95% confidence estimate of the concentration of diesel particulate matter (DPM) associated with a 10% incidence of chronic pulmonary inflammation (inflam) or fibrosis (see Appendices A and B for more specifics). (b) Lung burdens were derived from data generated from the animal portion of the Yu model using the concentration and duration scenario of each study. The human portion of the Yu model was then used to estimate the continuous, 70-year exposures that would result in this same lung burden, i.e., the HEC. See Table A-4 in Appendix A and accompanying text for further specifics on derivation. (c) LD/HD = light-duty/heavy-duty diesel engine. (d) These values are the actual exposure levels used in the Nikula study. These values were converted into HEC and entered into bench mark concentration (BMC) equations to obtain the estimate of the BMCL10 listed. The lung burdens for the two BMCL10s listed here were derived by interpolation. Among these five studies, the study with the highest NOAEL is Ishinishi et al. (1988). In this study, Fischer 344 rats (120 males and 95 females/exposure level) were exposed for 16 hours/day, 6 days/week for 30 months to 0.11, 0.41, 1.18, or 2.32 mg/m3 DPM from a light-duty (LD) engine, or to 0.46, 0.96, 1.84, or 3.72 mg/m3 DPM from a heavy-duty (HD) engine. Equivalent duration-adjusted concentrations were 0.063, 0.23, 0.67, or 1.3 mg/m3 DPM from LD engine exhaust and 0.26, 0.55, 1.05, or 2.13 mg/m3 DPM from HD engine exhaust. Hematology, clinical chemistry, urinalysis, and light and electron microscopic examinations of histopathology were performed. Findings included minor body weight changes and equivocal alterations in liver and kidney function. The body weight of female rats exposed to 3.72 mg/m3 was 15-20% less than controls throughout the study. A dose-dependent decrease in body weight of the other groups was mentioned, but neither data nor statistical analyses are reported. In addition, although impaired liver and kidney function were indicated by changes in serum measures (increased liver enzyme activities and increased urea nitrogen, electrolyte levels, gamma globulin concentration and reduced total blood proteins), neither was confirmed histopathologically. More notably, while no histopathological changes were observed in the lungs of rats exposed to 0.46 mg/m3 DPM or less, at higher concentrations, severe morphological changes were observed, including shortened and absent cilia in the tracheal and bronchial epithelium, marked hyperplasia of the bronchiolar epithelium, and swelling of the Type II cellular epithelium. There was no difference in the degree of changes in pulmonary pathology at similar exposure concentrations between the LD and the HD series, however. This study identifies LOAELs for chronically exposed rats at 1.18 and 0.96 mg/m3 (actual exposure) for LD and HD series and NOAELs at 0.41 and 0.46 mg/m3 (actual) for LD and HD engines. Human equivalent concentrations corresponding to the animal NOAEL, LOAEL, AEL, and BMCL10 values were computed using a dosimetry model developed by Yu et al. (1991), as described in the Support Document (U.S. EPA, 2002; Chapter 6.5.2, and Appendix A). The dosimetry model accounts for species differences (rat to human) in respiratory exchange rates, particle deposition efficiency, differences in particle clearance rates at high and low doses, and transport of particles to lymph nodes. Because the particle sizes are not reported for the NOAEL for the 0.41 mg/m3 LD group or the 0.46 mg/m3 HD group, the size distributions for these are assumed to be the same as the next highest group. Thus, for both LD and HD series, the LOAEL(HEC) and NOAEL(HEC) are estimated using the particle deposition and retention model developed by Yu and Yoon (1990) using the same MMAD and sigma g. The resulting LOAEL(HEC) for the LD and HD series are 1.25 and 0.883 mg/m3, respectively. The NOAEL(HEC) for the LD and HD series based on the retention model are 0.128 and 0.144 mg/m3, respectively. The single-dose studies provide valuable supporting information for designation of the critical effect of pulmonary histopathology. These studies [Heinrich et al. (1982, 1986), in hamsters, mice, and rats; Iwai et al. (1986) in rats; Lewis et al. (1989) in monkeys; and Pepelko (1982a) in rats] are all single-dose analyses conducted to study mechanisms or the comparative responses of different species. For instance, the single-dose monkey study (Lewis et al., 1989) at 1.95 mg/m3 showed minor precursor symptoms consistent with airway and lung toxicity, but no fibrosis, inflammation or emphysema; the duration of exposure was also relatively short. The lack of any clear dose-response data, however, precludes consideration of these studies as a quantitative basis for RfC derivation. Likewise, studies of chronic, multiple-level exposure involving species other than rats, i.e., hamsters (Pepelko, 1982b), cats (Plopper et al., 1983), and guinea pigs (Barnhart et al., 1981, 1982), provide cross-species corroboration of the critical effects of pulmonary histopathology and inflammatory alteration. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) The highest human equivalent dose associated with no apparent effect (NOAELHEC) is 144 ug DPM/m3 from the Ishinishi et al. (1988) study; this becomes the point of departure for deriving an RfC. To obtain the RfC, this point of departure was divided by two types of uncertainty factors (UFs): a factor of 3 recognizes residual interspecies (i.e., rat to human) extrapolation uncertainties, and a factor of 10 reflects uncertainties about interindividual human variation in sensitivity. Kinetic differences between rats and humans were addressed through the use of a dosimetry model. Although there is uncertainty in the dosimetry model, as in the application of most kinetic models, U.S. EPA guidance (U.S. EPA, 1994) recommends no further quantitative adjustment for uncertainty in the modeling results without chemical-specific data. In this case, the maximum default interspecies extrapolation UF is reduced from 10 to 3, due to the use of the dosimetry model to account for kinetic differences. The use of 3, the full amount of this UF addressing only interspecies differences in pharmacodynamics, is supported by several studies suggesting that humans may be as sensitive or somewhat more so than rats for respiratory tract inflammation. In the absence of mechanistic or specific data, a default value of 10 is considered appropriate to account for possible human variability in sensitivity, particularly for children and people with preexisting respiratory conditions. The spectrum of the population that may have a greater susceptibility cannot be better characterized until there is additional knowledge about mode of action. The point of departure was derived from a chronic study, therefore an UF for using a study of less than chronic duration of exposure is unnecessary. In addition, evaluation of chronic effects other than respiratory effects, as well as some aspects of reproductive and developmental toxicity, showed that none of these effects were expected to occur at DPM levels lower than the identified point of departure. While data demonstrating immunological and allergenic effects were suggestive, the available database specific to diesel engine exhaust does not support further adjustment of the RfC. Consequently, an UF for database adequacy was not judged necessary. IRCC: ___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC) There is no specific information in humans showing that children are more susceptible to DE's chronic respiratory effects. Limited data from studying children exposed to "black smoke" (presumed to be a surrogate for DPM), through attending schools near freeways, indicates that childrens' reactions (respiratory symptomology and reduced lung function) are no different than adult reactions (van Vliet et al., 1997; Brunekreef et al., 1997, 2000). One study in rats (Mauderly, 1987b) showed that DE did not affect the developing rat lung more severely than the adult rat lung, and in fact that particle clearance was faster in the younger lung. While diesel exhaust is a mixture of gases and particles, health concerns have long focused on DPM, and the organics adhering to the particles. DPM is considered to be the prime etiologic agent of noncancer health effects when DE is sufficiently diluted to limit the concentrations of gaseous irritants (NO2 and SO2), irritant vapors (aldehydes), CO, or other systemic toxicants (U.S. EPA, 2002). The small size of DPM, combined with large surface area, likely enhances the potential for subcellular interactions with important cellular components of respiratory tissues, once the particles are inhaled by humans or other species (Johnston et al., 2000; Oberdorster et al., 2000). Mode-of-action information about respiratory effects from DE exposure indicates that, at least in rats, the pathogenic sequence following the inhalation of DPM begins with the phagocytosis of diesel particles by alveolar macrophages (AMs). These activated AMs release chemotactic factors that attract neutrophils and additional AMs. As the lung burden of DPM increases, there are aggregations of particle-laden AMs in alveoli adjacent to terminal bronchioles, increases in the number of Type II cells lining particle-laden alveoli, and the presence of particles within alveolar and peribronchial interstitial tissues and associated lymph nodes. The neutrophils and AMs release mediators of inflammation and oxygen radicals, and particle-laden macrophages are functionally altered, resulting in decreased viability and impaired phagocytosis and clearance of particles. This series of events may result in pulmonary inflammation, fibrosis, and eventually lesions like those described in the chronic exposure rat studies. Although definitive information describing the possible pathogenesis of respiratory effects in humans is not available, the symptomology reported in studies of humans exposed to DE are not inconsistent with the findings in controlled laboratory animal studies. (See U.S. EPA, 2002, for more information.) It also should be noted that diesel particles make up a portion of ambient particulate matter (PM). U.S. EPA has established an annual National Ambient Air Quality Standard (NAAQS) for fine particulate matter (PM2.5), to provide protection against adverse health effects associated with both long- and short-term exposures to ambient fine PM. DPM is a typical constituent of ambient fine PM, generally about 6-10% of PM2.5 with some examples up to 36% (U.S. EPA, 1996a, 1996b). Given the similarity of health concerns for respiratory inflammation and pulmonary health effects from both DPM and fine particles, it is reasonable to expect that DPM contributes to some of the health effects associated with PM2.5. Current knowledge is insufficient, however, to describe the relative potencies of DPM and the other components of PM2.5. As long as the percentage of DPM to total ambient PM2.5 remains in similar proportion, protective levels for PM2.5 would be expected to offer a measure of protection from effects associated with DPM. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC The confidence level in the RfC is considered medium in a range of low to high confidence. The critical effects, chronic inflammation and pathologic changes, which are well characterized in four animal species, are considered relevant to humans, though animal data are still being used to predict a human hazard. Although in general the rat is thought to be more sensitive to lung injury than humans to poorly soluble particles (ILSI, 2000), it is not clear that this is the case specifically for diesel exhaust particulates and the resulting inflammation effects. Since DE is a mixture of not just carbon particles but also various organics, both on the particles and in gases, there is some concern that the full impact of DE has not been assessed. In addition, differences in particle deposition, retention, and clearance mechanisms have been largely but perhaps not completely addressed by the use of the rat-to-human dosimetry model. In terms of the potential for other critical health effects, there is growing evidence suggesting that DE can exacerbate allergenic effects to known sensitizers, while also evoking production of biochemical markers typically associated with asthma. While some work in this area indicates that humans may be as sensitive as rats and mice to the immunologic effects (U.S. EPA, 2002; Chapter 6.3.4), this data base is currently lacking key exposure-response data. It also should be noted that the ambient PM health effects data show a broader array of adverse human health concerns (e.g., cardiovascular effects, as well as acute exposure effects). EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- U.S. EPA, 2002 The Health Assessment Document (HAD) on which this IRIS Summary is based was peer reviewed by EPA's Clean Air Science Advisory Committee (CASAC) in October 2000. Written comments from CASAC were received in December 2000. Their comments were evaluated carefully and incorporated in finalization of the HAD. A record of these comments is available with the HAD. Agency Consensus Date - 1/31/03 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (fax), or hotline.iris@epa.gov (E-mail address). ============================================================================ UDCA: 200302 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Diesel engine exhaust CASRN -- Not found Last Revised -- 02/28/2003 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Using U.S. EPA's revised draft 1999 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), diesel exhaust (DE) is likely to be carcinogenic to humans by inhalation from environmental exposures. The basis for this conclusion includes the following lines of evidence: - strong but less than sufficient evidence for a causal association between DE exposure and increased lung cancer risk among workers in varied occupations where exposure to DE occurs; - extensive supporting data including the demonstrated mutagenic and/or chromosomal effects of DE and its organic constituents, and knowledge of the known mutagenic and/or carcinogenic activity of a number of individual organic compounds that adhere to the particles and are present in the DE gases; - evidence of carcinogenicity of DPM and the associated organic compounds in rats and mice by other routes of exposure (dermal, intratracheal, and subcutaneous and intraperitoneal injection); and - suggestive evidence for the bioavailability of DE organic compounds from DE in humans and animals. It is noted that there are also several well conducted studies in rats that show that inhalation exposure to diesel exhaust results in lung tumors, while results in other traditional rodent test species are equivocal or not positive for inhalation induced lung tumors. There is a substantial body of evidence showing that the rat is more responsive than other species to the induction of lung tumors by poorly soluble particles, with diesel exhaust particles being one example. While directly comparable human data are lacking, some human cohorts exposed to very high levels of poorly soluble particles (e.g., coal miners) do not show the sequence of events leading to lung tumors that has been seen in rats. This mode-of-action information for the rat, involving particle overload and consequent persistent inflammation and cell proliferation, supports a nonlinear mode of action for lung cancer in the rat (ILSI, 2000). The nonlinear cancer response is further characterized as occurring at relatively high exposures of diesel exhaust (>3500 ug DPM/m3 DPM), which is far beyond the range of environmental levels. The rat tumor occurrences, thus, are not particularly influential in judging the hazards at environmental levels of exposure. Support for a human cancer hazard at environmental levels of exposure comes from two considerations: (1) the evidence for a mutagenic mode of action, and (2) exposure comparisons. Concern for a human cancer hazard is consistent with EPA's science policy position that assumes a linear response for carcinogens with a mutagenic component, in the absence of definitive data demonstrating a nonlinear mechanism. Additional support for an environmental hazard also comes from a comparison of the estimated environmental levels to the estimated occupational exposure levels where risk is observed in many studies. Given that there is only a minimal margin between environmental and occupational exposure ranges, if not an overlap, the extrapolation of observable hazard from the occupational setting to the ambient environment is relatively confident. Overall, the qualitative evidence for potential human carcinogenicity for DE is considered strong, even though inferences are involved and uncertainties are present. First, there has been a considerable scientific debate about the significance of the available human evidence for a causal association between occupational exposure and increased lung cancer risk. Some experts view the evidence as weak and/or inconsistent while others consider the evidence compelling, due to a lack of consensus about whether the effects of smoking and other potential confounders have been adequately accounted for in key studies, and the lack of agreed-upon historical DE exposure data for the key studies. These issues highlight the difficulty in delineating an exposure-based dose-response relationship. In addition, while the mode of action for lung tumors in rats at high DE exposures is sufficiently understood, the mode of action for the DE lung cancer risk in humans is not known. To date, available evidence for the role of both the adsorbed organics and the carbon core particle has only been shown under high-exposure experimental animal test conditions. There is virtually no information about the relative role of DE constituents in mediating carcinogenic effects at the low-exposure levels or in humans. Data gaps also limit conclusions regarding the full extent of DE's carcinogenic potential. These limitations include lack of knowledge concerning the susceptibility of young animals to DE's carcinogenic effects relative to more mature animals, the human carcinogenic potential of DE by oral and dermal exposures, and the inconclusive epidemiologic evidence for DE being associated with other forms of cancer. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA A persistent association of risk for lung cancer associated with DE exposure has been observed in more than 30 epidemiologic studies published in the literature over the past 40 years. The majority of the epidemiologic studies evaluate distinct populations of occupational groups, including railroad workers, truck drivers, heavy-equipment operators, farm tractor operators, and professional diesel vehicle drivers. The remaining studies include reanalyses of specific studies, and three meta-analyses. The Support Document (U.S. EPA, 2002; Section 7.2) provides a review of this literature. Increased lung cancer risk has been observed in 8 out of 10 cohort studies, 5 of which were statistically significant. Increased lung cancer risk has also been observed in 10 of 12 case-control studies, 8 of which were statistically significant. Overall, the increased lung cancer relative risks generally range from 1.2 to 1.5, although a few studies show overall relative risks as high as 2.6. Statistically significant increases in relative risk (RR), 1.33 to 1.47, are also shown in two independent meta-analyses of epidemiologic studies. The meta-analyses demonstrate the effect of pooling many studies and in this case show the positive relationship between DE exposure and lung cancer across a variety of DE-exposed occupations. The strongest studies are summarized below. The most extensive study linking lung cancer and diesel engine exhaust is the case-control study by Bruske-Hohlfeld et al. (1999). These investigators conducted a pooled analysis of two case-control studies among male workers occupationally exposed in Germany (Jockel et al., 1995, 1998; Wichmann et al., 1988). Lung cancer cases and controls matched for sex, age, and region of residence were selected randomly from compulsory municipal registries. The investigators collected data on demographic information, detailed smoking, and occupational history for 3,498 cases and 3,541 controls. Job titles and industries were classified in 33 and 21 categories, respectively. Job descriptions were written and verified to avoid misclassification of estimation of exposure to diesel engine exhaust. Individual cumulative exposures were estimated by categorizing the duration of exposure determined from complete work histories. Smoking information in pack-years was calculated from personal interview information. Asbestos exposures were estimated by certain job-specific supplementary questions. This study shows increased risk for all DE-exposed job categories. Analyses yielded statistically significant ORs ranging from 1.25 (95% CI = 1.05, 1.47) for professional drivers, to 2.31 (95% CI = 1.44, 3.7) for heavy equipment operators, adjusted for smoking and asbestos exposure. These investigators presented analyses by various job categories, by total years of exposure, calendar year of first and end exposure and, when possible, separately for West and East Germany. Significantly higher risks were found among all four job categories. For professional drivers (of trucks, buses, and taxis) ORs ranged from 1.25 to 2.53. For other traffic-related jobs (switchmen, diesel locomotive drivers, diesel forklift truck drivers), ORs ranged from 1.53 to 2.88. For heavy equipment operators (bulldozers, graders, and excavators), ORs ranged from 2.31 to 4.3, and for drivers of farming equipment the only significant excess (OR = 6.81, 95% CI = 1.17, 39.5) was for exposure for >30 years. The professional drivers and the other traffic-related jobs also have some mixed exposures to gasoline exhaust in general traffic. On the other hand, it should be noted that exposure to DE among heavy equipment and farm tractor drivers is much higher and not as mixed as in professional drivers. The heavy equipment drivers usually drive repeatedly through their own equipment's exhaust. Therefore, the observed highest risk for lung cancer in this job category establishes a strong link with the DE. Only one other study found a significantly higher relative risk (RR) for heavy equipment operators, at 2.6 (Boffetta and Stellman, 1988). Although the only significant excess in the group was observed for farming tractor operators with more than 30 years of exposure, a steady increase in risk was observed for this job category with increasing exposure. The investigators stated that the working conditions and the DE of tractors remained fairly constant over the years. This increase may be due mainly to exposure to DE and PM10. The main strengths of the study are large sample size, resulting in good statistical power; inclusion of incident cases diagnosed not more than 3 months prior to the interview; use of only personal interviews, reducing recall bias; diagnoses ascertained by cytology or histology; and availability of lifelong detailed occupational and smoking history. Exposure estimation done for each individual was based on job codes and industry codes, which were validated by written job descriptions to avoid misclassification. The main limitation of the study is lack of data on actual exposure to DE. The cumulative quantitative exposures were calculated on the basis of time spent in each job with potential exposure to DE and the type of equipment used. Thus, this study provides strong evidence for causal association between exposure to diesel exhaust and occurrence of lung cancer. In addition to the study by Bruske-Hohlfeld et al. (1999), evidence for a lung cancer hazard comes from several other case-control studies: among railroad workers by Garshick et al. (1987), and among truck drivers of the Teamsters Union by Steenland et al. (1990), among truck drivers, railroad workers. Garshick et al. (1987) found increased risk of lung cancer associated with increasing cumulative exposure to diesel engine exhaust. The investigators used US Railroad Retirement Board records to identify 1,319 lung cancer deaths and 2,385 matched controls. An analysis using number of years in a diesel-exposed job as a continuous variable, and adjustment for asbestos and smoking, yielded an odds ratio (OR) of 1.41 (95% CI = 1.06, 1.88) for >=20 years of DE exposure in the <64 years of age group. When DE exposure was categorized as 0 to 4, 5 to 19, and >=20 diesel years, the risk of lung cancer in the same group increased when compared to the 0- to 4-year group, with an OR of 1.64 (95% CI = 1.18, 2.29). This appears to be a well-conducted and well-analyzed study with reasonably good power. Potential confounders were controlled adequately, and interactions between diesel exhaust and other lung cancer risk factors were tested. Some of the limitations of this study are inadequate latency period, misclassification of exposure because Interstate Commerce Commission job classifications were used as a surrogate for exposure, and use of death certificates for identification of cases and controls. Steenland et al. (1990) also observed an increased risk of lung cancer with increasing years of exposure. The investigators studied lung cancer deaths in Teamsters Union truck drivers and support personnel, using death certificates from pension files to identify 1,058 cases and 1,160 controls. Information on work history and potential confounders were collected from next-of-kin interviews. Using duration of employment as a categorical variable and considering employment after 1959 (when presumed dieselization occurred for most trucking companies), the risk of lung cancer increased with increasing years of exposure, for both long-haul and short-haul drivers. Using 1964 as the cutoff, a similar trend was observed for long-haul drivers. Using 1964 as the cutoff (presumed dieselization for independent driver and non-trucking firms), long-haul drivers continued to show a significant positive trend, while short-haul drivers did not show a positive trend. For truck drivers who primarily drove diesel trucks and worked for 35 years, the OR was 1.89 (95% CI = 0.81, 2.22). The main strengths of the study are availability of detailed records from the Teamsters Union, a relatively large sample size, availability of smoking data, and measurements of exposure. The limitations of this study include possible misclassifications of exposure and smoking, lack of levels of diesel exposure, a smaller nonexposed group, and an insufficient latency period. Substantive evidence from cohort studies linking diesel exhaust exposure to lung cancer comes from the Garshick et al. (1988) study of 55,407 railroad workers, conducted in the United States. Relative risks (RRs) of 1.57 (95% CI = 1.19, 2.06) and 1.34 (95% CI = 1.02, 1.76) were found for ages 40 to 44 and 45 to 49, respectively, after the exclusion of workers exposed to asbestos. The investigators reported that the risk of lung cancer increased with increasing duration of employment. As this was a large cohort study with a lengthy follow-up and adequate analysis, including dose response (based on duration of employment as a surrogate) as well as adjustment for other confounding factors such as asbestos, the observed association between increased lung cancer and exposure to diesel exhaust is more meaningful. Reanalyses of the Garshick et al. (1988) study yielded varying conclusions. Crump et al. (1991) found that the relative risk could be positively or negatively related to duration of exposure depending on how age was controlled. Additional analysis by Garshick et al. (1991) found that the relationship between years exposed, when adjusted for the attained age, and calendar years was flat to negative, depending on the choice of the model. They also found that deaths were under-reported by approximately 20% to 70% between 1977 and 1980, and their analysis based on job titles, limited to 1959-1976, showed that the youngest workers still had the highest risk of dying of lung cancer. An analysis of the same data by California EPA (Cal EPA, 1998) yielded a positive dose response, using age at 1959 and an interaction term of age and calendar year in the model. Crump (1999) reported that the negative dose-response continued to be upheld in his latest analysis when age was controlled more carefully and years of exposure quantified more accurately. Crump (1999) also asserted that the negative dose response trends for lung cancer observed either with the cumulative exposure or duration of exposure may be due to the under-ascertainment of deaths in last 4 years of follow-up of the Garshick et al. (1988) study, as well as to incomplete follow-up in earlier years. A HEI special panel (HEI, 1999) conducted their own analyses of the Garshick et al. (1988) data to support quantitative risk assessment, and found similar results as Crump et al. (1991) and Garshick (1991). The HEI panel reported consistently elevated risk of lung cancer for train workers compared to clerks for each duration of employment, and an intermediate risk of lung cancer for shop workers; however, they found decreasing risk of lung cancer with increasing duration of employment. The panel discussed various possibilities for the negative dose response and advised against using the Garshick et al. (1988) data for quantitative risk assessment. These possible explanations included biases such as unmeasured confounding by smoking, exposure to other sources of pollution, previous occupations exposures, exposure misclassification, use of "duration of employment" as a surrogate measure for exposure, health worker survivor effect, and differential or incomplete ascertainment of lung cancer deaths. The panel also reported the strengths of Garshick et al. (1988) study, such as large population, control for asbestos and smoking, and concluded that the study was generally consistent with findings of weak association between exposure to diesel exhaust and occurrence of lung cancer. The divergent results of these recent analyses do not negate the positive evidence this study provides for the weight of evidence evaluation. Three aggregate analyses of studies concerned with the relationship of diesel exhaust exposure and lung cancer risk are Cohen and Higgins (1995), Bhatia et al. (1998), and Lipsett and Campleman (1999). The Cohen and Higgins (1995) report is a qualitative review of 35 epidemiologic studies (16 cohort and 19 case-control) of occupational exposure to diesel engine exhaust published between 1957 and 1993. Control for smoking was identified in 15 studies. Six of the studies (17%) reported RR estimates less than 1, whereas 29 (83%) reported at least one RR greater than one, indicating a positive association. Twelve studies indicating a RR greater than 1 had 95% confidence intervals that excluded unity. The evidence suggests that occupational exposure to diesel exhaust from diverse sources increases the rate of lung cancer by 20% to 40% in exposed workers generally, and to a greater extent among workers with prolonged exposure. They also found that the results are not explicable by confounding due to cigarette smoking or other known sources of bias. Bhatia et al. (1998) found a small but consistent increase in the risk for lung cancer among workers with exposure to DE, in a quantitative meta-analysis of 23 studies that met criteria for inclusion. The observed RR estimates were greater than 1 in 21 of these studies. The pooled RR weighted by study precision was 1.33 (95% CI= 1.24, 1.44), which indicated increased RR for lung cancer from occupational exposure to diesel exhaust. Subanalyses by study design (case-control and cohort studies) and by control for smoking produced results that did not differ from those of the overall pooled analysis. Cohort studies using internal comparisons showed slightly higher RRs than those using external comparisons. Lipsett and Campleman (1999) is a quantitative meta-analysis which identified 39 independent estimates of RR among 30 eligible studies of diesel exhaust and lung cancer published between 1975 and 1995. Pooled RRs for all studies and for study subsets were estimated using a random effects model. A pooled smoking-adjusted RR was 1.47 (95% CI = 1.29, 1.67). Substantial heterogeneity was found in the pooled-risk estimates. Adjustment for confounding by smoking, having a lower likelihood of selection bias, and increased study power were all found to contribute to lower heterogeneity and increased pooled estimates of RR. The three aggregate analyses conclude that the data support a causal association between lung cancer and diesel exhaust exposure. Further, the analyses find that smoking is unlikely to account for the observed effects. On the other hand, Stober and Abel (1996), Muscat and Wynder (1995), and Cox (1997) call into question the assertions by Cohen and Higgins (1995), Bhatia et al. (1998), and Lipsett and Campleman (1999) that the associations seen for diesel exhaust and lung cancer are unlikely to be due to bias. They argue that methodologic problems are prevalent among the studies, especially in evaluation of diesel engine exposure and control of confounding by cigarette smoking, and thus the observed associations are more likely to be due to bias. The conclusions of the two quantitative meta-analyses report on magnitude of pooled RR estimates and evaluation of potential sources of heterogeneity in the estimates. Despite the statistical sophistication of the meta-analyses, the statistical models used cannot compensate for deficiencies in the original studies and will remain biased to the extent that bias exists in the original studies. In view of the discussion of these studies, the body of epidemiologic evidence supports a causal association between exposure to DE and occurrence of lung cancer. The causality criteria of temporality, strength of association, consistency, and biological plausibility are generally satisfied. Temporality, that the exposure preceded the outcome, was established in all of the studies discussed above, including those in the meta-analyses. The strength of association was weak to modest (RRs/ORs between 1.2 and 2.6), with a dose-response relationship observed in several studies. Small increases in lung cancer relative risks (typically <2.0) potentially weaken the evidence of causality, because if confounders (e.g., smoking, asbestos exposure) were having an effect on the observed risk increases, then it could be enough to account for the increased risk. With the strongest risk factor for lung cancer being smoking, there is a lingering uncertainty as to whether smoking effects may be influencing the magnitude of the observed increased RRs, in spite of the fact that in key studies the investigating epidemiologists assert that they have effectively controlled for smoking. In studies in which the effects of smoking were controlled, increased RRs for lung cancer prevailed. While some studies did not have information on smoking, confounding by smoking is judged unlikely to be significant if the comparison populations were from the same socioeconomic class (see the Support Document for more information). The lung cancer increase observed with diesel exhaust exposure in a number of studies is unlikely to be due to chance or bias. The excess risk is observed in both cohort and case-control designs, which contradicts the concern that a methodologic bias specifically characteristic of either design (e.g., recall bias) might account for the observed effect. Selection bias is certainly present in some of the occupational cohort studies that use external population data in estimating RRs, but this form of selection bias (a healthy worker effect) would only obscure, rather than spuriously produce, an association between DE and lung cancer. In effect, the usual standard mortality ratios observed in cohort mortality studies are likely to be underestimations of true risk. Selection biases may be operating in some case-control studies, but it is not obvious how such a bias could be sufficiently uniform in effect, prevalent, and strong enough to lead to the consistent association seen in the aggregate data. Given the variety of designs used in studying the DE and lung cancer association and the number of studies in different populations, it is unlikely that routinely studying noncomparable groups is an explanation for the consistent association seen. Moreover, various methodologic limitations of individual studies have been considered, such as small sample size, short follow-up period, lack of data on confounding variables, use of death certificates to identify the lung cancer cases, and lack of latency analysis. The studies with small sample sizes (i.e., not enough power) and short follow-up periods (i.e., not enough latent period) have been difficult to interpret due to these limitations. Some other uncertainties are methodologic bias specifically characteristic of either cohort or case-control design, nondifferential misclassification of exposure and/or outcome bias (i.e. use of inaccurate surrogates for diesel exposure and lung cancer incidence can lead to substantial bias), and confounding by smoking. Finally, exposure information bias is certainly a problem for almost all of the studies concerned. For detailed discussion about these uncertainties see the Support Document (U.S. EPA, 2002; Section 7.2.4.4). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Many animal studies have evaluated various aspects of the carcinogenic potential of whole diesel exhaust, including traditional chronic inhalation studies using rats, mice, hamsters, and limited studies using cats and monkeys. Some of the studies used whole DE, while others used filtered DE (free of DPM) to differentiate gaseous phase effects from effects induced by the particle and its adsorbed organics. Other studies were designed to evaluate the relative importance of the carbon core of DPM versus that of the particle-adsorbed compounds, and a number of studies were carried out to determine the combined effects of inhaled DE and tumor initiators, promoters and cocarcinogens. The Support Document (U.S. EPA, 2002; Chapter 7.3) describes and discusses results from 27 studies. It has been repeatedly shown that, with sufficient exposure, inhalation of DE is capable of inducing lung cancer in rats, several strains, males and females (Mauderly et al.,1987; Heinrich et al., 1986, 1995; Iwai et al., 1986, 1997; Ishinishi et al., 1988a; Takaki et al., 1989; Brightwell et al., 1986; Nikula et al., 1995). Although lung tumor responses correlate best with cumulative exposure (concentration x daily exposure duration x days of exposure), examination of rat data indicates a nonlinear trend, with increasing tumor incidence at exposures exceeding 1 x 104 mg hr/m3, and more generally with experimental chronic exposure concentrations at or greater than 3500 ug/m3. While tumorigenic responses were not observed at exposures less than those demonstrating particle overload exposure, thus supporting a hypothesis of a nonlinear response, the rat studies lack the sensitivity statistically to confirm the absence of response at lower doses. If low-dose effects do occur, it can be hypothesized that the organic constituents on the particle or in the gases, are playing a role. Notably, several reports (Wong et al., 1985; Bond et al., 1990) also make comment on a possible mode of action by providing evidence for DNA damage in rats. Exposures at or greater than 3500 ug/m3 are shown to result in lung particle overload, characterized by slowed particle clearance, lung tissue inflammation, lung pathology and eventually a tumorigenic response (ILSI, 2000). The rats develop adenomas, adenocarcinomas, and adenosquamous cell carcinomas, as well as squamous keratinizing lesions. This latter lesion appears for the most part to be unique to the rat, and may not have relevance for human safety evaluation (Boorman et al., 1996). Studies in rats of particles (e.g., carbon black, titanium dioxide) such as those reported by Driscoll et al. (1996, 1997) support the existence of a nonlinear response if it is assumed that inflammation is a prerequisite for lung tumor induction. Evidence for the importance of DPM's carbon core was initially provided by studies of Kawabata et al. (1986), which showed induction of lung tumors in F344 rat following intratracheal instillation of carbon black that contained no more than traces of organics, and studies of Heinrich (1990) that indicated that exposure via inhalation to carbon black (Printex 90) particles induced rat lung tumors at concentrations similar to those effective in DPM studies. Additional studies by Heinrich et al. (1995) and Nikula et al. (1995) confirmed the capability of carbon particles to induce rat lung tumors. Rittinghausen et al. (1997) reported an increase in cystic keratinizing epitheliomas following intratracheal instillation of rats with either original DPM or DPM extracted to remove the organic fraction, with the unextracted particles inducing a slightly greater effect. The evidence for a lung tumor response in other common strains of laboratory animals exposed to DE under standard inhalation protocols is equivocal. Inhalation of DE induced significant increases in lung tumors in female NMRI mice (Heinrich et al., 1986b; Stober, 1986) and in female Sencar mice (Pepelko and Peirano, 1983). An apparent increase was also seen in female C57BL mice (Takemoto et al., 1986). However, in a repeat of their earlier study, Heinrich et al. (1995) failed to detect lung tumor induction in either NMRI or C57BL/6N mice. No increases in lung tumor rates were reported in a series of inhalation studies using strain A mice (e.g., Orthoefer et al., 1981). Mauderly et al. (1996) reported no tumorigenic responses in CD-1 mice exposed under conditions resulting in positive responses in rats. The successful induction of lung tumors in mice by Ichinose et al. (1997a,b) via intratracheal instillation may have been the result of local deposition of larger doses. Positive effects in Sencar mice may be due to use of a strain sensitive to tumor induction in epidermal tissue by organic agents, as well as exposure from conception, although proof for such a hypothesis is lacking. Attempts to induce significant increases in lung tumors in Syrian hamsters by inhalation of whole DE were unsuccessful (Heinrich et al., 1982, 1986b, 1989; Brightwell et al., 1986). Intratracheal instillation did not induce lung tumors in Syrian hamsters (Kunitake et al., 1986; Ishinishi et al., 1988b). However, hamsters are considered to be relatively insensitive to lung tumor induction (e.g., Dontenwill et al., 1973). Neither cats (Pepelko and Peirano, 1983) nor monkeys (Lewis et al., 1989) developed tumors following 2-year exposure to DE. These studies are less definitive, however, due to inadequate duration of these exposures for these longer-lived species, small group sizes, and exposure levels below the maximum tolerated dose (MTD). Studies of filtered DE in laboratory animal species have been carried out to differentiate gaseous phase effects from effects induced by the particle and its adsorbed organics. Long-term exposure to DE filtered to remove particulate matter failed to induce lung tumors in rats (Heinrich et al., 1986a; Iwai et al., 1986; Brightwell et al., 1989), or in Syrian hamsters (Heinrich et al., 1986a; Brightwell et al., 1989). A significant increase in lung carcinomas was reported by Heinrich et al. (1986a) in NMRI mice exposed to filtered exhaust. However, in a more recent study the authors were unable to confirm earlier results in either NMRI or C57BL/6N mice (Heinrich et al., 1995). Although filtered exhaust appeared to potentiate the carcinogenic effects of DEN (Heinrich et al., 1982), because of the lack of positive data in rats and equivocal or negative data in mice it can be concluded that filtered exhaust is either not carcinogenic or has a low cancer potency. Dermal exposure and subcutaneous (s.c.) and intraperitoneal (i.p.) injection in mice provided additional evidence for tumorigenic effects of DPM. Particle extracts applied dermally to mice have been shown to induce significant skin tumor increases in two studies (Kotin et al., 1955; Nesnow et al., 1982). Kunitake et al. (1986) also reported a marginally significant increase in skin papillomas in ICR mice treated with an organic extract from an HD diesel engine. Negative results were reported by Depass et al. (1982) for skin-painting studies using mice and acetone extracts of DPM suspensions. However, in this study the exhaust particles were collected at temperatures of 100 deg. C, which would minimize the condensation of vapor-phase organics and, therefore, reduce the availability of potentially carcinogenic compounds that might normally be present on DE particles. A significant increase in the incidence of sarcomas in female C57Bl mice was reported by Kunitake et al. (1986) following s.c. administration of LD DPM extract at doses of 500 mg/kg. Takemoto et al. (1988) provided additional data for this study and reported an increased tumor incidence in the mice following injection of LD engine DPM extract at doses of 100 and 500 mg/kg. Results of i.p. injection of DPM or DPM extracts in strain A mice were generally negative (Orthoefer et al., 1981; Pepelko and Peirano, 1983), suggesting that the strain A mouse may not be a good model for testing diesel engine exhaust. Results of experiments using tumor initiators such as DEN (diethylnitrosamine), B[a]P (benzo[a]pyrene, DPN (dipentylnitrosamine), or DBA (dibenz[a,h]anthracene) (Brightwell et al., 1986; Heinrich et al., 1986b; Takemoto et al., 1986) were generally inconclusive regarding the tumor-promoting potential of either filtered or whole DE. A report by Heinrich et al. (1982), however, indicated that filtered exhaust may promote the tumor-initiating effects of DEN in hamsters. In summary, a number of intratracheal instillation studies in rats and mice exposed to high doses of whole diesel exhaust, and a variety of skin painting studies using extracts (organic fraction of whole diesel exhaust), provide animal evidence for carcinogenicity or the potential for carcinogenicity of DE or fractions of the DE mixture, in addition to the many chronic inhalation rats studies showing a positive lung cancer at high exposures. The rat evidence, however, is not relevant for human hazard characterization that is focused on environmental levels of exposure, where a human lung particle overload is not expected (note that a preliminary 75th percentile nationwide estimate of DE human environmental exposure for 1996 is about 1.7 ug/m3). The contribution of the various fractions of DE to the carcinogenic response is uncertain beyond that which can been seen in rats. Inhalation exposure to filtered exhaust generally failed to induce lung tumors in animal species. The presence of known carcinogens and mutagens adsorbed to diesel particles and the demonstrated tumorigenicity of particle extracts in a variety of injection, instillation, and skin-painting studies indicates a carcinogenic potential for the organic fraction. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY For the human, it is not clear what constituent(s) of DPM or the whole diesel exhaust could be responsible for the observed lung cancer. DNA adduct formation and/or mutations in blood cells following exposure to DE, especially at levels insufficient to induce lung overload, can be presumed to be the result of organics diffusing into the blood. Hemminki et al. (1994) reported increased levels of DNA adducts in lymphocytes of bus maintenance and truck terminal workers. Osterholm et al. (1995) studied mutations at the hprt-locus of T-lymphocytes in bus maintenance workers. Although they were unable to identify clear-cut exposure-related differences in types of mutations, adduct formation was significantly increased in the exposed workers. Nielsen et al. (1996) reported significantly increased levels of lymphocyte DNA adducts, hydroxyvaline adducts in hemoglobin, and 1-hydroxypyrene in urine of garage workers exposed to DE. An extensive array of studies with DPM and gaseous fractions of diesel exhaust has demonstrated mutagenic activity in Salmonella and several vitro mammalian cell lines, and structural chromosome aberrations and increased sister chromatid exchanges (SCE) in mammalian cells. On the other hand, dilutions of whole diesel exhaust did not induce sex-linked recessive lethals in Drosophila or specific-locus mutations in male mouse germ cells. Whole exhaust induced micronuclei but not SCE or structural aberrations in bone marrow of male Chinese hamsters exposed to whole diesel engine exhaust for 6 mo. In a shorter exposure (7 weeks), neither micronuclei nor structural aberrations were increased in bone marrow of female Swiss mice. Likewise, whole diesel exhaust did not induce dominant lethals or heritable translocations in male mice exposed for 7.5 and 4.5 weeks, respectively. All of these studies are discussed in the Support Document (U.S. EPA, 2002). The application of mutagenicity data to the question of the potential carcinogenicity of diesel engine exhaust is based on the premise that genetic alterations are found in all cancers and that several of the chemicals found in diesel engine exhaust possess mutagenic activity in a variety of genetic assays. These genetic alterations can be produced by gene mutations, deletions, translocations, aneuploidy, or amplification of genes, hence no single genotoxicity assay should be expected to either qualitatively or quantitatively predict rodent carcinogenicity. With diesel engine exhaust or other mixtures, additional complications arise because of the complexity of the material being tested. In addition to the toxicological evidence associating lung tumors with DPM, many of the other constituents of DE are known to have mutagenic and carcinogenic properties. California EPA (Cal EPA, 1998) identified at least 19 hydrocarbons present in DE that are known or suspected carcinogens, according to evaluations by the International Agency for Research on Cancer (IARC, 1989). The organic compounds present in the DE gases and adsorbed onto the particles include a wide spectrum of compounds which originate from unburned diesel fuel, lube oil, low levels of partial combustion, and pyrolysis products, including: alkanes, alkenes, aldehydes, monocyclic aromatic compounds, and polycyclic aromatic hydrocarbons (PAHs). The principal aldehydes are formaldehyde, acetaldehyde and acrolein. Other gaseous components of DE include benzene, 1,3-butadiene, and nitro-PAHs (including those with <= 4 rings and nitro-PAHs with 2 and 3 rings). PAHs and their derivatives comprise <1% of the DPM mass. See the Support Document (U.S. EPA, 2002) for more details. ADDITIONAL COMMENTS Several organizations have reviewed available relevant data and evaluated the potential human carcinogenicity of DE or DPM, and have concluded that DE is probably carcinogenic to humans (IARC, 1989; IPCS, 1996), or is reasonably anticipated to be a carcinogen (NTP, 2000). The relevance of this hazard characterization to current ambient DE exposures hinges on recognizing that the health effects data are derived from engine technologies and fuels that existed in the past, and that some changes in the DE exhaust mixture have occurred and can be expected in the future (see the Support Document (U.S. EPA, 2002), Section 2). Although decreases in amount and changes in composition of DE engine exhaust have occurred over time for on-road engines, a change is slow to manifest in the environment because vehicular fleet turnover is slow. Available studies have not focused on the potential toxicological effect of the emission changes. There is no compelling evidence at present to show that past and present exhaust characteristics are so toxicologically dissimilar as to render the current use of the assessment's findings outdated. It is clear that with the implementation of U.S. EPA's regulations affecting 2007 model year on-road diesel engines, the exhaust from these engines will be notably different and thus the hazard potential for this exhaust would need to be re-evaluated. DISCUSSION OF CONFIDENCE While the weight of evidence indicates that DE has the potential to pose a lung cancer hazard to humans at anticipated levels of environmental exposure, as shown by occupational epidemiology studies, a confident dose-response relationship based on occupational exposure levels is currently lacking. Among the occupational studies, the railroad worker studies (Garshick et al., 1987, 1988) and the Teamsters Union truck driver studies (Steenland et al., 1990) are considered to have the best available combination of response and surrogate exposure information (based on worker years in a job category) for possible use in establishing exposure-response relationships and thereafter deriving a cancer unit risk. There have been different views on the suitability of the railroad workers and Teamster Union truck drivers set of studies for estimating environmental cancer risks (e.g., Cal EPA, 1998; Cohen and Higgins, 1995; HEI, 1999). Given the equivocal evidence for the presence or absence of an exposure-response relationship for the studies of railroad workers, and current exposure uncertainties for the study of truck drivers, it is judged that available data are too uncertain at this time for a confident quantitative dose-response analysis and subsequent derivation of cancer unit risk for DE. Even though occupational data are considered most relevant for use in dose-response assessment, the following data gaps and uncertainties must be critically evaluated before a confident dose-response can be recommended: - the lack of actual DE exposure data for workers in the available epidemiologic studies; - the lack of DE exposure data for controls in the available epidemiologic studies, owing to the presence of diesel engine exhaust in ambient air for non-occupational settings; - possible confounders (smoking and asbestos exposure) that could contribute to the observed lung cancer risk in occupational studies of DE if the control for these confounders is not adequate; - whether or not an exposure-response relationship for occupational lung cancer risk can be estimated for DE: - the use of DPM (expressed as ug/m3) as a surrogate dosimeter for DE exposure, given that the relative roles of various constituents in mediating carcinogenic effects and the carcinogenic mode of action are still not known, and - the representativeness of occupational populations for the general population and vulnerable subgroups, including infants and children and individuals with preexisting diseases, particularly respiratory conditions. Use of animal data to develop dose-response based unit cancer risk values was judged inappropriate, since the only animal model with direct inhalation exposure and lung tumor responses was the rat, and the rat results were discounted because of mode-of-action information showing that the high exposure rat responses would not be a suitable basis for human dose-response analysis at environmental levels of exposure. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE N.A. There are no chronic data from which to estimate carcinogenic risk from oral exposure. All available studies are focused on inhalation exposure. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE N.A. The absence of adequate data to develop a sufficiently confident dose-response relationship from the epidemiologic studies has prevented the estimation of inhalation carcinogenic risk. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2002 The Health Assessment Document (HAD) (U.S. EPA, 2002) on which this IRIS Summary is based was peer reviewed by EPA's Clean Air Science Advisory Committee (CASAC) in October 2000. Written comments from CASAC were received in December 2000. Their comments were evaluated carefully and incorporated in finalization of the HAD. A record of these comments is available with the HAD. RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 1/31/03 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or hotline.iris@epa.gov (email address). ============================================================================ UDSO: 200302 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Diesel engine exhaust CASRN -- Not found Last Revised -- 02/28/2003 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Barnhart, MI; Chen, S-T; Salley, SO; et al. (1981) Ultrastructure and morphometry of the alveolar lung of guinea pigs chronically exposed to diesel engine exhaust: six month's experience. J Appl Toxicol 1:88-103. Barnhart, MI; Salley, SO; Chen, S-T; et al. (1982) Morphometric ultrastructural analysis of alveolar lungs of guinea pigs chronically exposed by inhalation to diesel exhaust (DE). In: Toxicological effects of emissions from diesel engines: proceedings of the Environmental Protection Agency diesel emissions symposium; October, 1981; Raleigh, NC. Lewtas, J., ed. New York: Elsevier Biomedical; pp. 183-200. (Developments in toxicology and environmental science: v. 10). Brunekreef, B; Janssen, NA; de Hartog, J; et al. (1997) Air pollution from truck traffic and lung function in children living near motorways. Epidemiology 8(3):298-303. Brunekreef, B; Janssen, NA; van Vliet, P; et al. (2000) Traffic related air pollution and its effect on respiratory health of children living near motorways. Presented at: PM 2000: Particulate matter and health-the scientific basis of regulatory decision-making. Sponsored by the Air and Waste Management Association, January 24-28, 2000. Heinrich, U; Peters, L; Funcke, W; et al. (1982) Investigation of toxic and carcinogenic effects of diesel exhaust in long-term inhalation exposure of rodents. In: Toxicological effects of emissions from diesel engines: proceedings of the Environmental Protection Agency diesel emissions symposium; October 1981; Raleigh, NC. Lewtas, J., ed. New York: Elsevier Biomedical; pp. 225-242. (Developments in toxicology and environmental science: v. 10). Heinrich, U; Muhle, H; Takenaka, S; et al. (1986) Chronic effects on the respiratory tract of hamsters, mice, and rats after long-term inhalation of high concentrations of filtered and unfiltered diesel engine emissions. J Appl Toxicol 6:383-395. Heinrich, U; Fuhst, R; Rittinghausen, S; et al. (1995) Chronic inhalation exposure of Wistar rats and two different strains of mice to diesel engine exhaust, carbon black, and titanium dioxide. Inhal Toxicol 7:533-556. International Life Sciences Institute (ILSI). (2000) ILSI Risk Science Institute workshop: The relevance of the rat lung response to particle overload for human risk assessment. Gardner, DE, ed. Inhal Toxicol:12(1-2):1-17. Ishinishi, N; Kuwabara, N; Nagase, S; et al. (1986) Long-term inhalation studies on effects of exhaust from heavy and light duty diesel engines on F344 rats. In: Carcinogenic and mutagenic effects of diesel engine exhaust: proceedings of the international satellite symposium on toxicological effects of emissions from diesel engines; July; Tsukuba Science City, Japan. Ishinishi, N; Koizumi, A; McClellan, RO; et al., eds. Amsterdam, Holland: Elsevier Science Publishers B. V.; pp. 329-348. (Developments in toxicology and environmental science: v. 13). Ishinishi, N; Kuwabara, N; Takaki, Y; et al. (1988) Long-term inhalation experiments on diesel exhaust. In: Diesel exhaust and health risks: Results of the HERP studies. Ibaraki, Japan: Japan Automobile Research Institute, Inc., Research Committee for HERP Studies; pp. 11-84. Iwai, K; Udagawa, T; Yamagishi, M; et al. (1986) Long-term inhalation studies of diesel exhaust on F344 SPF rats. Incidence of lung cancer and lymphoma. In: Carcinogenic and mutagenic effects of diesel engine exhaust: proceedings of the international satellite symposium on toxicological effects of emissions from diesel engines; July; Tsukuba Science City, Japan. Ishinishi, N; Koizumi, A; McClellan, RO; et al., eds. Amsterdam, Holland: Elsevier Science Publishers B. V.; pp. 349-360. (Developments in toxicology and environmental science: v. 13). Johnston, CJ; Finkelstein, JN; Mercer, P, et al. (2000) Pulmonary effects induced by ultrafine PTFE particles. Toxicol Appl Pharmacol 168:208-215. Lewis, TR; Green, FHY; Moorman, WJ; et al. (1989) A chronic inhalation toxicity study of diesel engine emissions and coal dust, alone and combined. J Am. Coll Toxicol 8:345-375. Mauderly, JL; Jones, RK; Griffith, WC; et al. (1987a) DE is a pulmonary carcinogen in rats exposed chronically by inhalation. Fundam. Appl Toxicol 9:208-221. Mauderly, JL; Jones, RK; Griffith, WC; et al. (1987b) Effects of inhaled nitrogen dioxide and diesel exhaust on developing lung. Cambridge, MA: Health Effects Institute; research report no. 8. Nikula, KJ; Snipes, MB; Barr, EB; et al. (1995) Comparative pulmonary toxicities and carcinogenicities of chronically inhaled diesel exhaust and carbon black in F344 rats. Fundam Appl Toxicol 25:80-94. Oberdorster, G; Finkelstein, JN; Johnston, CJ; (2000) Ultrafine particles as inducers of acute lung injury; mechanisms and correlation with disease and age. Health Effects Institute 96:1-88. Pepelko, WE. (1982a) Effects of 28 days exposure to diesel engine emissions in rats. Environ Res 27:16-23. Pepelko, WE. (1982b) EPA studies on the toxicological effects of inhaled diesel engine emissions. In: Toxicological effects of emissions from diesel engines: proceedings of the Environmental Protection Agency diesel emissions symposium; October 1981; Raleigh, NC. Lewtas, J, ed. New York: Elsevier Biomedical; pp. 121-142. (Developments in toxicology and environmental science: v. 10). Plopper, CG; Hyde, DM; Weir, AJ. (1983) Centriacinar alterations in lungs of cats chronically exposed to diesel exhaust. Lab Invest 49:391-399. U.S. Environmental Protection Agency (U.S. EPA). (1994) Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry, EPA/600/8-90/066F October 1994. U.S. EPA. (1996a) Air quality criteria for particulate matter. Research Triangle Park, NC: National Center for Environmental Assessment - RTP Office; report nos. EPA/600/P-95/001aF-cF. 3v. Available from: NTIS, Springfield, VA; PB96-168224. U.S. EPA. (1996b) Review of the national ambient air quality standards for particulate matter: policy assessment of scientific and technical information. OAQPS staff paper. Research Triangle Park, NC: Office of Air Quality Planning and Standards; report no. EPA/452/R-96-013. Available from: NTIS, Springfield, VA; PB97-115406REB. U.S. EPA. (2002) Health assessment document for diesel engine exhaust. May 2002. National Center for Environmental Assessment - Office of Research and Development. Washington, DC. EPA/600/8-90/057F. Available from http://www.epa.gov/iris. van Vliet, P; Knape, M; de Hartog, J; et al. (1997) Motor vehicle exhaust and chronic respiratory symptoms in children living near freeways. Environ Res 74(2):122-132. Yu, CP; Yoon, KJ. (1990) Retention modeling of DE particles in rats and humans. Amherst, NY: State University of New York at Buffalo (Health Effects Institute research report no. 40). Yu, CP; Yoon, KJ; Chen, YK. (1991) Retention modeling of DE particles in rats and humans. J Aerosol Med 4:79-115. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bhatia, R; Lopipero, P; Smith, A. (1998) Diesel exhaust exposure and lung cancer. Epidemiology 9(1):84-91. Boffetta, P; Stellman, SD. (1988) Association between diesel exhaust exposure and multiple myeloma: an example of confounding. Prev Med 17:236-237. Bond, JA; Johnson, NF; Snipes, MB; et al. (1990) DNA adduct formation in rat alveolar type II cells: cells potentially at risk for inhaled diesel exhaust. Environ Mol Mutagen 16:64-69. Boorman, GA; Brockman, M; Carlton, WW; et al. (1996) Classification of cystic keratinizing squamous lesions of the rat lung: report of a workshop. Toxicol Pathol 24:564-572. Brightwell, J; Fouillet, X; Cassano-Zoppi, AL; et al. (1986) Neoplastic and functional changes in rodents after chronic inhalation of engine exhaust emissions. In: Carcinogenic and mutagenic effects of diesel engine exhaust: proceedings of the international satellite symposium on toxicological effects of emissions from diesel engines; July; Tsukuba Science City, Japan. Ishinishi, N; Koizumi, A; McClellan, RO; et al., eds. Amsterdam, Holland: Elsevier Science Publishers B. V.; pp. 471-485. (Developments in toxicology and environmental science: v. 13). Brightwell, J; Fouillet, X; Cassano-Zoppi, AL; et al. (1989) Tumors of the respiratory tract in rats and hamsters following chronic inhalation of engine exhaust emissions. J Appl Toxicol 9:23-31. Bruske-Hohlfeld, I; Mohner, M; Ahrens, W; et al. (1999) Lung cancer risk in male workers occupationally exposed to diesel motor emissions in Germany. Am J Ind Med 36:405-414. California Environmental Protection Agency (Cal EPA). (1998) Part B: Health risk assessment for diesel exhaust, Public and Scientific Review Draft. February 1998. Cohen, AJ; Higgins, MWP. 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(1973) Investigations on the effects of chronic cigarette smoke inhalation in Syrian golden hamsters. J Natl Cancer Inst 51:1681-1832. Driscoll, KE; Carter, JM; Howard, BW; et al. (1996) Pulmonary inflammatory, chemokine, and mutagenic responses in rats after subchronic inhalation of carbon black. Toxicol Appl Pharmacol 136:372-380. Driscoll, KE; Deyo, KC; Carter, JM; et al. (1997) Effects of particle exposure and particle-elicited inflammatory cells on mutation in rat alveolar epithelial cells. Carcinogenesis 18:423-430. Garshick, E; Schenker, MB; Munoz, A; et al. (1987) A case-control study of lung cancer and diesel exhaust exposure in railroad workers. Am Rev Respir Dis 135:1242-1248. Garshick, E; Schenker, MB; Munoz, A; et al. (1988) A retrospective cohort study of lung cancer and diesel exhaust exposure in railroad workers. Am Rev Respir Dis 137:820-825. Garshick, E. (1991) Letter from E. Garshick, Harvard Medical School, to C. Chen, U.S. EPA, August 15, 1991. 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III. Presence in the particulate phase of diesel engine exhausts and the carcinogenicity of exhaust extracts. Arch Ind Health 11:113-120. Kawabata, Y; Iwai, K; Udagawa, T; et al. (1986) Effects of diesel soot on unscheduled DNA synthesis of tracheal epithelium and lung tumor formation. In: Carcinogenic and mutagenic effects of diesel engine exhaust. Ishinishi, N; Koizumi, A; McClellan R; et al., eds. Amsterdam: Elsevier; pp. 213-232. Kunitake, E; Shimamura, K; Katayama, H; et al. (1986) Studies concerning carcinogenesis of diesel particulate extracts following intratracheal instillation, subcutaneous injection, or skin application. In: Carcinogenic and mutagenic effects of diesel engine exhaust. Ishinishi, N; Koizumi, A; McClellan, R; et al., eds. Amsterdam: Elsevier; pp. 235-252. Lewis, TR; Green, FHY; Moorman, WJ; et al. (1989) A chronic inhalation toxicity study of diesel engine emissions and coal dust, alone and combined. J Am. Coll Toxicol 8:345-375. Lipsett, M; Campleman, S. 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(1983) Health effects of exposure to diesel engine emissions: a summary of animal studies conducted by the U.S. Environmental Protection Agency's Health Effects Research Laboratories at Cincinnati, Ohio. J Am Coll Toxicol 2:253-306. Rittinghausen, S; Mohr, U; Dungworth, DL. (1997) Pulmonary cystic keratinizing squamous cell lesions after inhalation/instillation of different particles. Exper Toxicol Pathol 49:433-446. Steenland, K; Silverman, DT; Hornung, RW. (1990) Case-control study of lung cancer and truck driving in the Teamsters Union. Am J Public Health 80:670-674. Stober, W. (1986) Experimental induction of tumors in hansters, mice and rats after long-term inhalation of filtered and unfiltered diesel engine exhaust. Ishinishi, N; Koizumi, A; McClellan, R; et al., eds. Amsterdam: Elsevier; pp. 421-429. Stober, W; Abel, UR. (1996) Lung cancer due to diesel soot particles in ambient air? A critical appraisal of epidemiological studies addressing this question. 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Am Ind Hyg Assoc J 52:529-541. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Diesel engine exhaust CASRN -- Not found ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 07/01/1992 I.B. Inhalation RfC now under review 08/01/1992 I.B.6. Work group review date added 06/01/1993 I.B. Inhalation RfC on-line 06/01/1993 VI.B. Inhalation RfC references on-line 07/01/1993 VI.B. Minor corrections made 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 02/28/2003 I.B., II. RfC, Cancer sections updated based on new health assessment document. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 436 of 1119 in IRIS (through 2003/06) AN: 644 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199403 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Monochloramine- SY: 10599-90-3; CHLORAMIDE-; CHLORAMINE-; CHLORAMINE [INORGANIC COMPOUND]; CHLOROAMINE-; HSDB-4293-; MONOCHLOROAMINE-; MONOCHLOROAMMONIA- RN: 10599-90-3 HSN: 4293 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199403 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Monochloramine CASRN -- 10599-90-3 Last Revised -- 03/01/1994 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NORD: Note: Chloramines are formed when free chlorine is added to water containing ammonia. Free chlorine refers to the concentrations of elemental chlorine, hypochlorous acid and hypochlorite ion that collectively occur in water. The type of chloramine formed is dependent on the chlorine to ammonia ratio, pH, temperature, and contact time. Monochloramine is formed when the pH of ammonia containing water is >8 and the molar ratio of hypochlorite to ammonia is <1. At hypochlorite to ammonia ratios of >1 or at lower pH values dichloramine and trichloramine are formed. Chloramines eventually decompose by several mechanisms, not all of which have been elucidated. For more information about the chemistry of chloramines see U.S. EPA, 1992. SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- No observed effects NOAEL: 200 ppm 100 1 1E-1 (9.5 mg/kg-day) mg/kg-day Rat Chronic Oral Study LOAEL: None NTP, 1992 ---------------------------------------------------------------------------- *Conversion Factors: 200 ppm = 9.5 mg/kg-day computed from summary water consumption data provided by the investigators. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) NTP (National Toxicology Program). 1992. Toxicology and Carcinogenesis Studies of Chlorinated and Chloraminated Water (CAS Nos. 7782-50-5, 7681-52-9 and 10599-90-3) in F344/N Rats and B6C3F1 Mice (drinking water studies). NTP TR 392. The long-term effects of chloraminated water were examined in F344/N rats and B6C3F1 mice (NTP, 1992). Groups of rats (70/sex/dose) and mice (70/sex/dose) were administered chloraminated drinking water at 0 (controls), 50, 100 or 200 ppm for 103-104 weeks. Based on body weight and water consumption data provided in the study, the intake of chloramine was 0, 2.6, 4.8 and 8.7 mg/kg-day for male rats; 0, 3.4, 5.3 and 9.5 mg/kg-day for female rats. Consumption of chloramine in mice was 0, 5.0, 8.9 and 15.9 mg/kg-day for males; and 0, 4.9, 9.0 and 17.2 mg/kg-day for females. Interim sacrifices (10/sex/dose) were conducted at weeks 14 and 66. At these times, a complete hematologic examination and necropsy were performed in all sacrificed animals. In addition, histopathologic examination was conducted in all control and high-dose animals. At the completion of the study, a complete histopathologic evaluation was performed in all animals. A dose-related decrease in water consumption was evident in rats throughout the study; food consumption was not affected by treatment. Mean body weights of high-dose male and female rats were lower than their respective controls. However, mean body weights were within 10% of controls until week 97 for females and week 101 for males. Decreases (p<0.05) in liver and kidney weight in the high-dose males and increases (p<0.05) in the brain- and kidney-to-body weight ratios in the high-dose rats (both sexes) were related to lower body weights in these groups and were not considered toxicologically significant. Results from pathologic evaluation at weeks 14 and 66 were unremarkable. The authors found no clinical changes attributable to consumption of chloraminated water. There were no non-neoplastic lesions after the 2-year treatment with chloraminated water. A NOAEL for rats of 200 ppm chloramine, or 9.5 mg chloramine/kg/day, can be defined in this study. In treated mice, water consumption throughout the study was also decreased in a dose-related manner. Food consumption was slightly lower in high-dose females compared with controls. Body weights of treated male and female mice were lower than in controls; the effect was dose-related. On the average, body weights of high-dose males were 10-22% lower than controls after week 37; those of high-dose females were 10-35% lower than controls after week 8. Mice exhibited no adverse clinical signs attributed to treatment with chloramine. Survival rates between treated and control mice were not significantly different. Interim evaluations revealed no biologically significant differences in organ weights or in relative organ weights. There were occasional statistically significant differences, such as decreases in liver weights and increases in brain- and kidney-to-body weight ratios in high-dose male and female mice, but these were attributed to the lower body weights and were not considered toxicologically significant. Results from hematology tests, and gross or microscopic examination of tissues and organs were unremarkable. The 2-year evaluation revealed no non-neoplastic lesions attributable to chloramine treatment. The concentration of 200 ppm chloramine, or 17.2 mg chloramine/kg/day is considered a NOAEL for mice in this study. The NOAEL of 9.5 mg chloramine/kg/day in rats is chosen as the basis for the chronic oral RfD. Although a higher NOAEL in the study of 17.2 mg/kg-day is found for mice, rats may be the more sensitive species since doses between 9.5 and 17.2 mg/kg-day were not tested in rats. Significant decreased weight gain in subchronic rat studies, such as Daniel et al. (1990), at 200 ppm was considered a consequence of decreased water consumption associated with taste aversion. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- The uncertainty factor of 100 reflects 10 for interspecies extrapolation and 10 for the protection of sensitive human subpopulations. An additional factor for the lack of reproductive and developmental toxicity data is not considered necessary because data from existing studies across chemical class (monochloramine and chlorine) provide sufficient confidence that the reproductive and developmental issues have been addressed. Although the studies with chlorine are marginal in quality, they do give an indication that adverse effects from monochloramine are not likely to occur. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) Daniel et al. (1990) conducted a 90-day drinking water study with monochloramine at 0, 25, 50, 100 and 200 mg/L in Sprague-Dawley rats (10/sex/dose group). Based on body weight and water consumption data, the investigators estimated the chloramine intake to be 0, 1.8, 3.4, 5.8 and 9.0 mg/kg-day for males and 0, 2.6, 4.3, 7.7 and 12.1 mg/kg-day for females. Endpoints examined included mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, gross pathology, and histopathology. Water consumption was significantly reduced (p<0.05) in all treated groups in a concentration-related manner. Food consumption was significantly reduced in high-dose males. At the 200 mg/L dose level, the average weight gain for male and female treated rats was 51% of controls; water consumption at this dose level was 31-34% of controls. Significant changes (p<0.05) in hematologic and clinical chemistry parameters included decreased hematocrit at 100 mg/L, decreased red blood cell counts at 100 and 200 mg/L in males, and decreased serum calcium levels in all treated male groups. These findings were not dose-related, were within the normal ranges, and were not considered biologically significant. There were significant reductions (p<0.05) in organ weights (absolute, relative or both); as spleen and liver weight reductions occurred in both males and females at the highest dose but, histopathologic examinations did not reveal any treatment-related changes in these tissues. The authors suggested that to clearly identify the NOAEL, a matched watering and feeding study would be useful for distinguishing between systemic toxic effects and weight gain depression from taste aversion. Male and female B6C3F1 mice (10/sex/dose group) were treated with monochloramine in the drinking water for 90 days (Daniel et al., 1991). The concentration levels of the disinfectant in water were 0 (controls), 12.5, 25, 50, 100 and 200 mg/L, and provided doses (calculated by the investigators from water consumption and body weight data) of 0, 2.5, 5.0, 8.6, 11.1 and 15.6 mg monochloramine/kg/day for males; and 0, 2.8, 5.3, 9.2, 12.9 and 15.8 mg chloramine/kg/day for females. Endpoints examined in control and high-dose groups included mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, organ weights, gross pathology and histopathology. A significant, dose-related decrease in water consumption (p<0.05) occurred in females at all dose levels and in males at the two highest dose levels. Food consumption was decreased in females at the two highest dose levels. Final body weight and body weight gain were decreased (p<0.05) in both sexes at the two highest concentration levels. No overt clinical signs of toxicity and gross or histopathologic changes could be detected. Changes in hematologic and clinical chemistry parameters were not concentration-related and were attributed to the decrease in water and nutrient consumption and altered electrolyte balance. Changes in organ weights included a significant (p<0.05) decrease in liver, heart, and lung weight in males and in liver, heart, and spleen weight in females at concentrations of 100 and 200 mg/L. Minor weight changes occurred at 100 mg/L, including minor (less than 10%) depression of body weight relative to controls. These effects were considered a consequence of decreased water consumption associated with taste aversion and not chemically induced. Male Sprague-Dawley rats (16/dose group) were administered monochloramine in the drinking water (ad libitum) at 0 (controls), 1, 10 or 100 mg/L for up to 12 months (Abdel-Rahman et al., 1984). This intake corresponds to 0.12, 1.2 and 12 mg monochloramine/kg/day based on reference body weight and water intake data for mature male rats of this strain (U.S. EPA, 1987). Hematologic parameters, as well as blood glutathione (GSH) levels, were monitored throughout the treatment period. Incorporation of 3H-thymidine was studied in liver, kidney, testes, intestinal mucosa, and spleen after 3 months of treatment. Treatment-related (p<0.05) decreases in blood GSH were observed at 6 and 12 months; changes in GSH levels at other times were inconsistent. A significant increase in red blood cell fragility was detected after 2 and 10 months of treatment at the mid-dose level, and after 2 and 6 months at the high-dose level. Significant changes in hematologic parameters were limited to decreased red blood cell count and hematocrit at the 10 and 100 mg/L levels at 3 months and a reduced hemoglobin concentration and mean corpuscular hemoglobin at the 100 mg/L level after 10 months of treatment. Increased incorporation of 3H-thymidine was observed in the kidney and spleen at 1 and 10 mg/L, and in testes at 100 mg/L at 3 months; other time periods were not examined. Body weights were reported to be significantly reduced relative to controls after 3 months of treatment at 100 mg/L and remained lower than controls throughout the experiment. Blood levels of chloroform monitored during the study were no different than in untreated rats. Single gavage doses of 0.19, 0.38 and 0.75 mg monochloramine/kg (estimated from initial body weights given by the investigators) significantly increased blood GSH for 1 hour following dosing, but GSH levels returned to control levels after 2 hours. The increased osmotic fragility observed was not corroborated by NTP (1992) and was not affected in the acute experimental series. The significance of these changes to health is uncertain, particularly in the absence of food consumption and water intake data. GSRI (1981) conducted a subchronic study of chloramine in the drinking water of F344 rats and B6C3F1 mice (10/sex/group for the two species) at concentrations of 0, 25, 50, 100, 200 and 400 ppm for 13 weeks. Based on body weight and water consumption data provided in the study, the intake of chloramine was estimated to be 0, 2.6, 5.0, 10.2, 19.4 and 40.7 mg/kg-day for male rats and 0, 4.1, 6.9, 15.1, 28.7 and 51.7 mg/kg-day for female rats. Intake of chloramine for mice was 0, 5.1, 8.4, 15.9, 30.7 and 50 for males and 0, 8.3, 12.9, 23.3, 35.2 and 92 mg/kg-day for females. Water consumption was not significantly altered in rats. There was a dose-related decrease in body weight gain in treated male rats. Results of microscopic examination of organs and tissues did not reveal any compound-related lesions in rats. Mice exhibited a dose-related reduction in water consumption. Male and female mice gained less weight than controls at the 200 and 400 ppm levels. Absolute and relative liver weight was reduced in high dose males; absolute liver weight was reduced in females at 100 ppm or greater. Histopathologic examination revealed a pattern of necrotic changes in the liver at the low doses and inflammatory response in the livers of female mice at the 100-400 ppm levels. (Confidence in this study is low due to questions regarding the conduct of this study, the histopathological evaluations, and lack of corroboration of its findings.) Bercz et al. (1982) evaluated the toxicity of monochloramine administered in drinking water to five adult male and seven adult female African Green monkeys for 6 weeks at 100 mg/L. Each animal served as its own control. Chloramine was only one of several water disinfectants tested in the animals; between each chemical, the animals were rested for 6-9 weeks. The mean daily dose was 10 mg/kg-day. No effects were detectable on various hematologic parameters, including red cell glutathione levels. No evidence of thyroid suppression was detected in serum. A NOAEL of 10 mg/kg-day, the only dose tested, was reported. Bull (1980) administered monochloramine to rats (number, sex and strain not reported) at doses of 0, 10, 50 or 100 mg/L in drinking water for 45 days. Based on default reference body weight and water consumption values for F344 male and female rats for subchronic exposure (U.S. EPA, 1987), the corresponding intake of monochloramine was 0, 1.6, 8.1 and 16 mg/kg-day. Body weight gain (no data provided) and hematologic parameters in exposed animals did not differ significantly from control animals. A significant decrease in methemoglobin was reported at 100 mg/L, the biologic significance of which is unclear. A NOAEL of 16 mg monochloramine/kg/day was defined in this study. Immunotoxic effects were reported by Exon et al. (1987) when monochloramine was administered to male Sprague-Dawley rats (12/sex/dose group) from weaning to 12 weeks of age at doses of 0, 9, 19 and 38 ppm in drinking water. Based on reference body weight and water consumption values for subchronic exposure (U.S. EPA, 1987), the corresponding intake of monochloramine was 0, 1.3, 2.6 and 5.3 mg/kg-day. Parameters monitored were body weight, spleen and thymus weight, antibody production, delayed-type hypersensitivity (DTH) reactions, natural killer cell (NKC) cytotoxicity, oxidative metabolism response and phagocytosis by macrophages, and production of interleukin 2 (IL2) and prostaglandin E2 (PGE2). The effects attributed to monochloramine treatment were limited to a significant reduction in relative spleen weight at 38 ppm, decreased antibody synthesis (9 and 19 ppm) and augmented PGE2 production at 19 and 38 ppm. These changes were not considered to be biologically significant. There were not significant effects on the other endpoints monitored. A NOAEL and/or LOAEL are not defined in this study. In a reproductive study by Carlton et al. (1986), chloramine was administered by gavage in deionized water at doses of 0, 2.5, 5.0 and 10 mg chloramine/kg/day to male (12/dose group) and female (24/dose group) Long Evans rats for a total of 66-76 days. Males were treated for 56 days and females for 14 days prior to mating. Dosing continued during the 10-day mating period and afterwards females were dosed with chloramine daily during gestation and lactation. Males were necropsied at the end of the mating period. Dams and some offspring were necropsied at 21 days after birth. Other offspring were dosed with chloramine after weaning until they were 28-40 days old. No statistical differences were observed between control and exposed rats in fertility, viability, litter size, day of eye opening or average day of vaginal patency. There were no alterations in sperm count, direct progressive sperm movement, percent mobility or sperm morphology in adult males. Weights of male and female reproductive organs were not significantly different among control and test groups, and there were no significant morbid anatomic changes evident on tissue examination. There were no signs of toxicity, changes in blood counts, or effects on body weight in adult rats of either sex at any dose level. The mean weight of the pups was not affected by chloramine treatment. A NOAEL of 10 mg/kg-day for reproductive effects can be defined from this study. Abdel-Rahman et al. (1982) administered monochloramine in the drinking water to female Sprague-Dawley rats (6/dose group) at 0, 1, 10 and 100 mg/L for 2.5 months prior to and throughout gestation. By using body weights provided by the investigators and a reference water consumption value (U.S. EPA, 1987), the intake of monochloramine was estimated to be to 0, 0.15, 1.5 and 15 mg monochloramine/kg/day. Treatment with monochloramine did not increase the number of fetal resorptions or affect fetal weight. In addition, monochloramine did not induce soft-tissue anomalies or skeletal malformations. A developmental NOAEL of 15 mg monochloramine/kg/day is provided by this study, although confidence is low due to the small number of animals exposed. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Data Base -- Medium RfD -- Medium Confidence in the principal study (NTP, 1992) is high-to-medium. Relevant endpoints in two animal species were examined after prolonged exposure by an appropriate route. However, an effect level was no achieved in the study, and higher dose levels may not be practicable due to taste aversion (and therefore reduced water consumption). Confidence in the data base is medium. Information is available for mice, rats and monkeys on the noncarcinogenic toxicity of oral exposure to monochloramine for subchronic periods. The developmental toxicity and reproductive toxicity of monochloramine have been examined in rats, but with suboptimal studies. Due to the chemical relationship between monochloramine and chlorine (U.S. EPA, 1992), reproductive and developmental studies for chlorine (Druckrey, 1968; McKinney et al., 1976; Chernoff et al., 1979; Staples et al., 1979; Meier et al., 1985) may be used to satisfy these data gaps for monochloramine. The overall confidence of the RfD is medium. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1992 The Drinking Water Criteria Document for Chloramines has undergone a limited Agency review. Other EPA Documentation -- None Agency Work Group Review -- 06/23/1992, 10/14/1993, 12/15/1993 Verification Date -- 06/23/1992 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Monochloramine CASRN -- 10599-90-3 NORC: Not available at this time. ============================================================================ UDCA: 199312 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Monochloramine CASRN -- 10599-90-3 Last Revised -- 12/01/1993 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- D; not classifiable as to human carcinogenicity Basis -- Based on inadequate human data and equivocal evidence of carcinogenicity from animal bioassays. A 2-year bioassay showed a marginal increase in mononuclear cell leukemia in female F344/N rats. No evidence of carcinogenic activity was reported in male rats or in male or female B6C3F1 mice. Genotoxicity studies, both in vitro and in vivo, gave negative results. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. There are no epidemiologic studies of monochloramine itself. Numerous studies have attempted to assess the relationship between drinking water quality and cancer, however, these studies differ greatly in both their objectives and design, thus precluding specific inferences being drawn from their findings. In general, these studies were intended to assess whether trihalomethanes or other organic compounds occurring in drinking water as a result of chlorination are associated with an increase in gastrointestinal and urinary cancer. A pilot study by Zierler et al. (1986) found no correlation between cancer mortality and consumption of chloraminated water in individuals who resided for over 40 years in communities with chloraminated drinking water. A small excess of bladder cancer, however, occurred in residents of communities using chlorine as a disinfectant. These data were preliminary, and the investigators indicated that considerable potential for error exist in the classification of exposure and disease status. A subsequent report by the same group of investigators (Zierler et al., 1988) presented data on 614 individuals who died of primary bladder cancer who had been exposed to water disinfected with either chlorine or chloramine for 40-46 years. Potential confounders were controlled by a multiple logistic regression model. A control group (1074 individuals) comprised five disease groups: cardiovascular disease, cerebrovascular disease, lung cancer, chronic obstructive pulmonary disease, and lymphatic cancer. The mortality odds ratio for bladder cancer among individuals who resided only in communities supplied with chlorinated drinking water was significantly elevated at 1.6 (95% confidence interval = 1.2-2.1) relative to individuals who resided only in communities supplied with chloraminated drinking water using all controls. When only lymphoma controls were utilized, the bladder cancer risk rose to 2.7 (statistically significant with 95% CI=1.7-4.3). The use of deceased controls and the difference in the two odds ratios suggest the possibility that some of the underlying causes of death in the controls may have been a result of increased exposure to either chloramines or chlorines. This would have the effect of reducing the odds ratios toward the null. Unfortunately, it is impossible to find controls who have not been exposed to chlorine or chloramine. Hence the true cancer risk from exposure to chloraminated drinking water relative to unchloraminated drinking water absent chlorination cannot be determined at this time. Furthermore, the relationship between consumption of chloraminated water and bladder cancer incidence cannot be defined based on the results of these studies. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Inadequate. NTP (1990) administered monochloramine in the drinking water of rats and mice for 103-104 weeks. The incidence of mononuclear cell leukemia was marginally increased in treated female rats. NTP (1990) considered this evidence of carcinogenicity to be equivocal. Small numbers of renal tubular cell neoplasms in male mice were considered unrelated to consumption of chloraminated water. The potential carcinogenicity of chloraminated water was examined in F344/N rats (NTP, 1990). Groups of rats (70/sex/dose) were administered chloraminated drinking water at 0 (controls), 50, 100 or 200 ppm for 103-104 weeks. Based on body weight and water consumption data provided in the study, the intake of chloramine was 0, 2.6, 4.8, and 8.7 mg/kg/day for male rats; 0, 3.4, 5.3, and 9.5 mg/kg/day for female rats. The rate-limiting factor in administering monochloramine in drinking water was its palatibility (Daniel et al., 1990). Interim sacrifices (10/sex/dose) were conducted at weeks 14 and 66 for evaluation. At these times, a complete hematological examination and necropsy were performed in all animals. In addition, histopathologic examination was conducted in all control and high dose animals. At the completion of the study, a complete histopathologic evaluation was performed in all animals. A dose-related decrease in water consumption was evident in rats throughout the study; food consumption was not affected by treatment. Mean body weights of high-dose male and female rats were lower than their respective controls. However, mean body weights were within 10% of controls until week 97 for females and week 101 for males. No treatment-related clinical findings were observed in rats. Survival of rats was not reduced by chloramine treatment, instead, low-dose males lived longer than controls. Results from pathologic evaluation at weeks 14 and 66 were unremarkable. There were no nonneoplastic lesions after the 2-year treatment with chloraminated water. Splenic histiocytic lymphoid hyperplasia was marginally increased in high-dose female rats (3/50 controls, 4/50 low-dose, 2/50 mid-dose, 6/50 high dose). Because of the lack of dose-response, the marginal increase in incidence, and small numbers, this lesion was considered unrelated to treatment with chloraminated water. The incidence of mononuclear cell leukemia was also marginally increased in treated female rats. The incidence of mononuclear cell leukemia was: 8/50 (controls), 11/50 (low-dose), 15/50 (mid-dose), and 16/50 (high-dose). A life table trend test was positive (p=0.021). The mean time to observations for leukemia among early deaths was similar among control and dosed groups. There was no decrease in tumor latency associated with treatment. Because the overall evidence is weakly supportive of an association between occurrence of mononuclear leukemia in female rats and consumption of chloraminated water, NTP (1990) considered the evidence of carcinogenicity equivocal. The potential carcinogenicity of chloraminated water was also examined in B6C3F1 mice (NTP, 1990). Groups of mice (70/sex/dose) were administered chloraminated drinking water at 0 (controls), 50, 100 or 200 ppm (highest palatable dose) for 103-104 weeks. Consumption of chloramine in mice was 0, 5.0, 8.9 and 15.9 mg/kg/day for males, and 0, 4.9, 9.0 and 17.2 for females. In treated mice, water consumption throughout the study was decreased in a dose-related manner. Food consumption was slightly lower in high-dose females compared with controls. Body weights of treated male and female mice were lower than in controls; the effect was dose-related. On the average, body weights of high dose-males were 10-22% lower than controls after week 37; those of high-dose females were 10-35% lower after week 8. Mice exhibited no adverse clinical signs attributed to treatment with chloramine. Survival rates between treated and control mice were not significantly different. Interim evaluations revealed no biologically significant differences in organ weights or in relative organ weights. Results from hematology tests, and gross or microscopic examination of tissues and organs were unremarkable. The 2-year evaluation revealed no nonneoplastic lesions attributable to chloramine treatment. Renal tubular cell adenomas occurred in two high-dose males, while one low-dose, two mid-dose, and one high-dose male showed focal tubule hyperplasia. Examination of additional kidney sections of all male mice showed hyperplasia in two controls and one mid-dose male, and an adenoma in one low-dose male. Since no additional neoplasms were found in the mid-dose and high-dose groups, and since focal hyperplasia was found at similar incidences in the control and treated groups, the small number of renal tubular cell neoplasms in male mice were considered unrelated to consumption of chloraminated water. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The initiation-promotion activity of chloramine was tested in rats in a rat liver focus bioassay (Herren-Freund and Pereira, 1986). In this assay, an increased incidence of gamma-glutamyltranspeptidase-(GGT-) positive foci serves as an indicator of early events in a carcinogenic process. Male Sprague-Dawley or Fischer 344 rats were administered 14.75 mg chloramine/kg body weight (presumably in the drinking water) 24 hours after a partial (two-thirds) hepatectomy. One week after initiation, nine rats received 500 ppm phenobarbital in the drinking water for 10 weeks. Diethylnitrosamine was used as positive control. Under the conditions of the study, chloramine did not induce GGT foci. Miller et al. (1986) tested concentrates of monochloramine treated drinking water samples from a pilot-scale water plant as initiators in the GGT focus bioassay and the concentrates did not induce an incidence of GGT foci greater than that of the vehicle control (2% Emulphor). Miller et al. (1986) also tested these water sample concentrates in the mouse lung adenoma assay. Three control groups, a negative control, a vehicle control (2% Emulphor), and a positive control (10 mg urethane/mouse by gavage) were used. Lung adenomas were observed in the positive controls with a mean of 11.5 adenomas per animal, the vehicle control had 0.1 adenoma per animal and the monochloramine-treated animals had a mean number of tumors of less than or equal to 0.09 adenomas per animal. Bull (1980) and Bull et al. (1982) conducted initiation-promotion studies in SENCAR mice (25/treatment group, sex distribution not specified) using concentrates from several alternately disinfected waters. In these studies, settled, coagulated and sand-filtered river water was treated with chloramine at 3 mg/L; the residual disinfectant was allowed to dissipate for 48 hours. The water was then concentrated (concentration factor was 142X) by reverse osmosis and a total of 1.5 mL of this concentrate was injected subcutaneously to the back of mice in six doses over a 2-week period. Two weeks after the last dose of concentrate was applied, phorbol myristate acetate in acetone was applied 3 times weekly to the backs of the animals for 20 weeks. Controls were treated with acetone. Nondisinfected water samples (untreated water concentrates) and samples treated with dimethylbenzanthracene (positive controls) were also tested. Chloraminated water concentrate induced tumors in 5/25 mice, whereas none of the animals treated with nondisinfected water exhibited tumors. Lesions included papillomas (1/25), squamous cell carcinomas (2/25), and lung adenomas (5/50, nonpromoted animals included). Results from three additional experiments (Bull et al., 1982) showed a 19% incidence of papillomas in mice treated with chloraminated water concentrates compared with 11 and 13% in mice treated with saline and nondisinfected water concentrates, respectively. This increase was not statistically significant. In the last two of these three initiation promotion experiments, 23 and 15% of animals treated with concentrated monochloramine-treated waters developed papillomas. For these assays, papillomas were also observed in 15 and 13% of mice treated with saline and in 20% of mice exposed to nondisinfected water concentrates. The increase in the response rate for the nondisinfected water concentrate in these two experiments over that of the first experiment may be due to greater concentration factors. The carcinogenic activity associated with chloramine disinfected water concentrate did not significantly exceed that in the nondisinfected water concentrates in these two experiments. Using a similar protocol, Miller et al. (1986) used concentrated monochloramine-treated drinking water samples from a pilot-scale water plant in the SENCAR mouse initiation-promotion assay (in addition to the GGT focus and lung adenoma bioassays described previously). Mice treated with this concentrated chloraminated water did not exhibit an increase in tumors. Chloramine was weakly mutagenic when assayed in Bacillus subtilis for the reversion of trpC locus (Lu Shih and Lederberg, 1976). Treatment of B. subtilis with high concentrations of chloramine resulted in single-strand breaks in the DNA and a few double-strand scissions (Lu Shih and Lederberg, 1976). Thomas et al. (1987) reported that while monochloramine slightly increased the number of revertant colonies over controls in Salmonella typhimurium strains TA97a, TA100 and TA102, cytotoxicity eclipsed mutation before a doubling of revertants was reached. Drinking water samples treated with monochloramine collected at a pilot-scale drinking water treatment plant were not mutagenic in Salmonella typhimurium strains TA98 or TA100 with or without metabolic activation (Miller et al., 1986). Gavage administration of chloramine at doses of 40, 100 or 200 mg/L to CD-1 mice did not induce chromosomal aberrations or micronuclei, nor did it induce sperm-head abnormalities in B6C3F1 mice (Meier et al., 1985). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Not available. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1992 The Draft Final Drinking Water Criteria Document for Monochloramine has been reviewed by the Office of Health and Environmental Assessment (OHEA/ORD) and by the Science Advisory Board (SAB) of the U.S. EPA. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 10/21/1992, 12/02/1992 Verification Date -- 12/02/1992 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199403 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Monochloramine CASRN -- 10599-90-3 Last Revised -- 03/01/1994 SORD: __VI.A. ORAL RfD REFERENCES Abdel-Rahman, M.S., M.R. Berardi and R.J. Bull. 1982. Effect of chlorine and monochloramine in drinking water on the developing rat fetus. J. Appl. Toxicol. 2(3): 156-159. Abdel-Rahman, M.S., D.H. Suh and R.J. Bull. 1984. Toxicity of monochloramine in rat: An alternative drinking water disinfectant. J. Toxicol. Environ. Health. 13: 825-834. Bercz, J.P., L. Jones, L. Garner, D. Murray, D.A. Ludwig and J. Boston. 1982. Subchronic toxicity of chlorine dioxide and related compounds in drinking water in the nonhuman primate. Environ. Health Perspect. 46: 47-55. Bull, R.J. 1980. Health effects of alternate disinfectants and their reaction products. J. Am. Water Works Assoc. 72: 299-303. Carlton, B.D., P. Bartlett, A. Basaran, K. Colling, I. Osis and M.K. Smith. 1986. Reproductive effects of alternative disinfectants. Environ. Health Perspect. 69: 237-241. Chernoff, N., E. Rogers, B. Carver, B. Kavlock and E. Gray. 1979. The fetotoxic potential of municipal drinking water in the mouse. Teratology. 19: 165-169. Daniel, F.B., L.W. Condie, M. Robinson et al. 1990. Comparative subchronic toxicity studies of three disinfectants. J. Am. Water Works Assoc. 82: 61-69. Daniel, F.B., H.P. Ringhand, M. Robinson, J.A. Stober, G.R. Olson and N.P. Page. 1991. Comparative subchronic toxicity of chlorine and monochloramine in the B6C3F1 mouse. J. Am. Water Works Assoc. 83: 68-75. Druckrey, H. 1968. Chlorinated drinking water toxicity tests involving seven generations of rats. Food Cosmet. Toxicol. 6: 147-154. Exon, J.H., L.D. Koller, C.A. O'Reilly and J.P. Bercz. 1987. Immunotoxicologic evaluation of chlorine-based drinking water disinfectants, sodium hypochlorite and monochloramine. Toxicology. 44: 257-269. GSRI (Gulf South Research Institute). 1981. A subchronic study of chloramine generated in-situ in the drinking water of F344 rats and B6C3F1 mice. Draft Report prepared for Tracor-Jitco, Inc., Rockville, MD. McKinney, J.D., R.R. Maurer, J.R. Hass and R.O. Thomas. 1976. Possible factors in the drinking water of laboratory animals causing reproductive failure. In: Identification and Analysis of Organic Pollutants in Water, L.H. Keith, ed. Ann Arbor Science Publishers, Inc., Ann Arbor, MI. p. 417-432. Meier, J.R., R.J. Bull, J.A. Stober and M.C. Cimino. 1985. Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and spermhead abnormalities in mice. Environ. Mutat. 7: 201-211. NTP (National Toxicology Program). 1992. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Chlorinated and Chloraminated Water in F344/N Rats and B6C3F1 Mice (drinking water studies). NTP TR 392, National Institutes of Health. Staples, R.E., W.C. Worthy and T.A. Marks. 1979. Influence of drinking water-tap versus purified on embryo development in mice. Teratology. 19: 237-244. U.S. EPA. 1987. Recommendations for and Documentation of Biological Values for Use in Risk Assessment. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA/600/6-87/008. NTIS PB88-179874/AS. U.S. EPA. 1992. Drinking Water Criteria Document for Chloramines. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Science and Technology, Office of Water, Washington, DC. (External Review Draft) ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bull, R.J. 1980. Health effects of alternate disinfectants and their reaction products. J. AWWA. 72: 299-303. Bull, R.J., M. Robinson, J.R. Meier and J. Stober. 1982. Use of biological assay systems to assess the relative carcinogenic hazards of disinfection by-products. Environ. Health Perspect. 46: 215-227. Daniel, F.B., L.W. Condie, M. Robinson et al. 1990. Comparative subchronic toxicity studies of three disinfectants. J. AWWA. 82: 61-69. Herren-Freund, S.L. and M.A. Pereira. 1986. Carcinogenicity of by-products of disinfection in mouse and rat liver. Environ. Health Perspect. 69: 59-65. Lu Shih, K.L. and J. Lederberg. 1976. Chloramine mutagenesis in Bacillus subtilis. Science. 192: 1141-1143. Meier, J.R., R.J. Bull, J.A. Stober and M.C. Cimino. 1985. Evaluation of chemicals used for drinking water disinfection for production of chromosomal damage and sperm-head abnormalities in mice. Environ. Mutagen. 7: 201-211. Miller, R.G., F.C. Kopfler, L.W. Condie et al. 1986. Results of toxicological testing of Jefferson Parish Pilot Plant samples. Environ. Health Perspect. 69: 129-139. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of chlorinated and chloraminated water (CAS Nos. 7782-50-5, 7681-52-9 and 10599-90-3) in F344/N rats and B6C3F1 mice (drinking water studies). NTP Technical Report. No. 392. Thomas, E.L., M.M. Jefferson, J.J. Bennett and D.B. Learn. 1987. Mutagenic activity of chloramines. Mutat. Res. 188: 35-43. U.S. EPA. 1992. Drinking Water Criteria Document for Chloramines. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Science and Technology, Office of Water, Washington, DC. (External Review Draft). Zierler, S., R.A. Danley and L. Feingold. 1986. Type of disinfectant in drinking water and patterns of mortality in Massachusetts. Environ. Health Perspect. 69: 275-279. Zierler, S., L. Feingold, R.A. Danley and G. Craun. 1988. Bladder cancer in Massachusetts related to chlorinated and chloraminated drinking water: A case-control study. Arch. Environ. Health. 43(2): 195-200. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Monochloramine CASRN -- 10599-90-3 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 08/01/1992 I.A. Oral RfD now under review 11/01/1992 I.A. Oral RfD summary on-line 11/01/1992 VI.A. Oral RfD references on-line 11/01/1992 II. Carcinogenicity assessment now under review 01/01/1993 II.D.2. Work group review date added 12/01/1993 I.A.6. Work group review date added 12/01/1993 II. Carcinogenicity assessment on-line 12/01/1993 VI.C. Carcinogenicity references on-line 01/01/1994 I.A. Oral RfD noted as pending change 01/01/1994 I.A.6. Work group review date added 03/01/1994 I.A. Oral RfD revised; study and number unchanged 03/01/1994 VI.A. Oral RfD references revised 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 437 of 1119 in IRIS (through 2003/06) AN: 654 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199603 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Dichloroacetic-acid- SY: 79-43-6; ACETIC-ACID,-DICHLORO-; ACIDE DICHLORACETIQUE [FRENCH]; ACIDO DICLOROACETICO [SPANISH]; AI3-18370-; DICHLORACETIC-ACID-; DICHLORETHANOIC-ACID-; KYSELINA DICHLOROCTOVA [CZECH] RN: 79-43-6 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Dichloroacetic acid CASRN -- 79-43-6 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Dichloroacetic acid CASRN -- 79-43-6 NORC: Not available at this time. ============================================================================ UDCA: 199603 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Dichloroacetic acid CASRN -- 79-43-6 Last Revised -- 03/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- B2; probable human carcinogen Basis -- Based on a lack of human carcinogenicity data and increased incidence of hepatocellular adenomas and carcinomas in male and female mice. Hyperplastic liver nodules, which are expected to progress into hepatocellular adenomas and carcinomas, were increased in both rats and mice. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Human data on the carcinogenic potential of dichloroacetic acid (DCA) were not available. The primary source of exposure to dichloroacetic acid in humans is as a byproduct of chlorination of drinking water. Since the early 1970s, numerous epidemiological studies have attempted to assess the relationship between the chlorination byproducts in drinking water and several different human cancers. None of these studies has shown an association of exposure to DCA with an increased incidence of site specific cancer. Moore et al. (1979) administered daily oral doses of DCA at 50 mg/kg to two male patients (ages 8 and 21) with severe familial hypercholesterolemia for 16 weeks. Serum cholesterol levels dropped but did not reach normal levels. No adverse clinical or laboratory signs related to DCA treatment were detected in the 8-year-old individual. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Increases were observed in hepatocellular adenomas and carcinomas in male mice receiving DCA (DeAngelo et al., 1991). Groups of 50 male B6C3F1 mice received drinking water containing neutralized DCA at levels of 0.05, 0.5 and 5 g/L (corresponding to time-weighted mean intake of 7.6, 77 and 486 (mg/kg)/day. Interim sacrifices of 5/group were scheduled at 4, 15, 30 and 45 weeks. Controls received 2 g/L sodium chloride (NaCl) or 1.5 g/L acetic acid; an additional group of 12 mice received 3.5 g/L DCA 410 (mg/kg)/day). At 60 weeks, all mice receiving 3.5 and 5 g/L were sacrificed, as well as 9-10 mice in each of the other groups. The remaining mice in the NaCl control, 0.05 and 0.5-g/L groups (18 19/group) were sacrificed at 75 weeks. Final mean body weights were significantly lower in the 3.5- and 5-g/L groups (87 and 83% of control, respectively). Statistically significant increases in the relative liver weights were seen in the 0.5-, 3.5-, and 5-g/L groups (36, 132, and 250% greater than control) at 60 weeks. Histopathological examination was performed on the liver, kidney, testes and spleen. Hepatocellular adenomas in the 0.5- and 3.5-g/L groups were first seen (in sacrificed animals) at 45 and 30 weeks, respectively, while hepatocellular carcinomas in the 0.05-g/L group were first seen at 60 weeks. In the high-dose group, hepatocellular adenomas and carcinomas were first seen at 45 weeks. At the 60-week sacrifice, hepatocellular adenomas were present in 12/12 (100%) and 24/30 (80%) mice receiving 3.5 and 5 g/L, respectively, and carcinomas were found in 8/12 (67%) and 25/30 (83%) mice, respectively. The incidences of combined hepatocellular tumors showed a significant statistical increase, 100% and 90% for the 3.5- and 5-g/L groups, respectively, and the multiplicity of liver tumors was 4 and 4.5/mouse, respectively. Hyperplastic liver nodules were noted in 7/12 (58%) and 25/30 (83%) of the 3.5- and 5-g/L groups, respectively (incidence not significantly elevated). Male B6C3F1 mice (33/group) were treated with 0 or 0.5 g/L DCA 88 (mg/kg)/day in drinking water for 104 weeks (Daniel et al., 1992). In the interim sacrifices, five animals/group were sacrificed at 30 weeks and five control animals were sacrificed at 60 weeks. All organs and tissues were examined histopathologically. Survival was not affected in the study, with 85 and 83% survival for the control and treated groups, respectively. Absolute and relative liver weights were significantly increased in the treated group (52 and 57%, respectively, of control). Nonneoplastic changes in the liver of the 0.5-g/L animals included hepatocellular necrosis (33% incidence), hyperplasia (33%), and cytomegaly (92%), compared with controls (less than or equal to 5%). Hepatocellular carcinomas developed in 15/24 (63%) treated mice compared with 2/20 (10%) controls, and hepatocellular adenomas occurred in 10/24 (42%) treated mice compared with 1/20 (5%) controls. The incidence of combined hepatocellular tumors was 18/24 (75%) in 0.5-g/L mice compared with 3/20 (15%) in controls. Individual type and combined tumor incidences showed a significant statistical elevation in the treated group compared with controls. Hyperplastic liver nodules were observed in 2/24 (8%) of the treated males but none in the controls (elevation not statistically significant). Herren-Freund et al. (1987) investigated the initiation/promotion potential of DCA in male B6C3F1 mice (26 32/group). Mice were either given 5 g/L DCA or pretreated with a single intraperitoneal dose of 2.5 mg/kg ethylnitrosourea (ENU) at 15 days of age and then given 2 or 5 g/L DCA in the drinking water (400 or 1000 mg/kg/day as calculated by the authors) during the period from 4 to 65 weeks of age. The negative control group (66 animals) received 2 g/L NaCl in drinking water. Animals were sacrificed after 61 weeks of exposure. Survival data were not provided. A significant decrease in the final mean body weight was observed in the 5-g/L groups (uninitiated and initiated) (both 92% of control), while a significant increase in the relative liver weight was found in all treatment groups (140 190% of control). In the uninitiated group receiving 5 g/L DCA, the incidences were 25/26 (96%) for hepatocellular adenomas and 21/26 (81%) for hepatocellular carcinomas compared with 2/22 and 0/22, respectively, for the controls. For the initiated groups, the incidence was 22/29 (76%) and 31/32 (97%) for hepatocellular adenoma in the 2- and 5-g DCA/L groups, respectively, compared with 2/22 (9%) in the controls. The incidence was 19/29 (66%) and 25/32 (72%) for hepatocellular carcinomas in the initiated 2- and 5-g DCA/L groups, respectively, compared with 1/22 (4.5%) in the controls. All tumor incidences in the treated groups showed a significant statisticall elevation. Hyperplastic nodules were not reported in the treated animals, and no other tumor sites were found. Bull et al. (1990) also demonstrated that DCA was carcinogenic in male B6C3F1 mice. In the study, males received 1 g/L DCA [170 (mg/kg)/day] in drinking water for 52 weeks (11 animals) or 2 g/L (340 mg/kg/day) (11-24 animals) for 37 or 52 weeks. Ten females received 2 g/L DCA for 52 weeks. The control group consisted of 61 males (sacrificed at 15, 24, 37, or 52 weeks) and 10 females (sacrificed at 52 weeks). No effects of treatment on survival or body weight were observed. Food and water consumption data were not reported. A significant increase in the relative liver weight was seen in 1 g/L males (41% increase from control), 2 g/L males (128% increase), and 2 g/L females (88% increase) compared with controls at 52 weeks. Nonneoplastic lesions included degenerative changes (multifocal areas of necrosis with frequent lymphocyte infiltration), cytomegaly and glycogen accumulation in the liver of all treated animals (incidence data were not provided). The high-dose mice also exhibited basophilic foci of cellular alteration in the livers at the 24- and 37-week sacrifice. Hepatocellular adenomas and carcinomas both developed only in the 2-g/L males; in 2/11 and 2/24 males treated for 37 and 52 weeks, respectively. Hepatocellular carcinomas alone developed in 5/24 males treated for 52 weeks. Tumor incidences in all treated groups were statistically significantly elevated. Hyperplastic nodules were observed in 6/11 and 9/24 males treated with 2 g/L DCA for 37 and 52 weeks, respectively, and in 3/10 females treated with 2 g/L for 52 weeks. The appearance of hyperplastic nodules in the treated females suggests that tumors might develop in female mice if DCA exposure were continued beyond 52 weeks. Tumors were not found in any other organs. Since the total exposure duration in this study did not exceed 52 weeks, this study may not have evaluated animals for an adequate length of time to observe the full carcinogenic potential of DCA in mice. In addition, the numbers of animals tested are inadequate. U.S. EPA (1991) reported on the carcinogenicity of DCA in female B6C3F1 mice. Following exposure to 0, 0.5 or 3.5 g/L DCA in drinking water for 104 weeks, the high-dose group had a 100% hepatocellular tumor incidence and a tumor multiplicity of 8.36 tumors/animal. Females receiving 0.5 g/L DCA had a tumor incidence of 20% and a tumor multiplicity of 0.2 tumors/animal. These values were compared with an incidence of 7.7% and a multiplicity of 0.1 tumors/animal in the control group. It was concluded that, although statistical analysis was not performed for the study, it appeared that female mice may be less sensitive than male mice. Groups of 50-60 male Fischer 344 rats were exposed to 0.05, 0.5 and 5 g/L DCA administered in the drinking water for 60-100 weeks (DeAngelo et al., 1993). Mean daily doses were 4.26, 40.2 and 295 (mg/kg)/day, respectively. The control group received 1.5 g/L acetic acid in drinking water. Due to excessive toxicity in the high-dose group, the 5-g/L dose was decreased to 2.5 g/L after 9 weeks, to 2 g/L after 23 weeks and to 1 g/L after 51 weeks (TWA). The group was terminated at 60 weeks. The investigators reported that 0.5 g/L did not exceed the maximum tolerated dose as there was very little weight loss (<5%). Survival was 63% and 70% for the 0.05- and 0.5-g/L groups, respectively, at 100 weeks and 51% for the 5-g/L group at 60 weeks. Body-weight gain was significantly decreased in the 0.5-g/L group (14% decrease from controls) at the end of the exposure period. In the 0.5-g/L group, increases of 20, 100 and 37% were observed in the relative liver, spleen and testes weights, respectively, compared with controls. Histopathology revealed hepatocellular necrosis, chronic inflammation, cytoplasmic vacuolization and foci of cellular alteration in the high-dose group; effects were evident as early as 15 weeks. A smaller incidence of hepatic effects were reported for the 0.5-g/L group than the high-dose group, while no treatment-related changes were found in the low-dose group. The only other nonneoplastic change was severe testicular degeneration in the high-dose group. A slight, but not statistically significant, increase in the incidence of hepatocellular adenomas and carcinomas combined was reported in the 0.5- and 5-g/L groups (incidences were not available). Hyperplastic liver nodules occurred in 41% of the 5-g/L group (sacrificed at 60 weeks) and 13% in the 0.5-g/L group (at l00 weeks), but none were found in the control and 0.05-g/L groups. The hyperplastic nodules indicate the potential for carcinogenicity of DCA; however, the animals were evaluated for less than a lifetime. Therefore, there was insufficient time for typical development of hepatic tumors. Richmond et al. (1991) examined the potential role of hyperplastic liver nodules in the progression of DCA-induced hepatocarcinogenesis. By detecting the expression of five different tumor markers, all known from previous studies to be expressed more in the neoplastic liver lesion than in the normal liver, the investigators determined that hyperplastic nodules expressed the markers significantly less often than did hepatoadenomas and carcinomas. Those hyperplastic nodules that expressed multiple markers, however expressed them at the same frequency as hepatoadenomas and carcinomas, and the expression was confined to the same nests of cells. The authors contended that the data suggest that these nests of marker-positive cells within the hyperplastic nodules are preneoplastic and could develop into later-appearing hepatoadenomas and hepatocarcinomas. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The majority of data on mutagenicity and genotoxicity in a number of in vitro and in vivo test systems indicates that DCA is not mutagenic. No data were found on the genotoxic effects of DCA in eukaryotic organisms. In an unpublished NTP study, DCA was tested in a preincubation modification of the Salmonella assay in the presence and absence of activation (from Arochlor 1254-induced Sprague Dawley rats and Syrian hamsters) in strains TA98, TA100 and TA1535 (NTP, 1991a,b). DCA was found to be positive in strains TA100 and TA1535 in the absence of metabolic activation and negative in TA98 in the presence and absence of activation. Results are in conflict regarding the ability of DCA to cause DNA damage. In the alkaline unwinding assay, administration of oral doses of 1-10 mmol/kg DCA to B6C3F1 mice and Fischer 344 rats did not induce DNA strand breaks in a dose-related manner (Chang et al., 1992). Nelson and Bull (1988) demonstrated that DCA induced a steep log-dose-response curve for single-strand DNA breaks in vivo in Sprague-Dawley rats beginning at 0.1 mmol/kg DCA. DCA also induced single-strand breaks in B6C3F1 mice at similar dose levels, with a less steep dose-response curve (Nelson and Bull, 1988). A dose of 58.5 ug/mL DCA increased DNA repair in Salmonella typhimurium TA1535 when rat liver homogenates were induced with phenobarbital/5,6-benzoflavone, but the response was negative in the absence of exogenous metabolic activation (Ono et al., 1991). DeAngelo et al. (1989) studied the effects of DCA on peroxisome proliferation in Sprague-Dawley rats and B6C3F1 mice receiving drinking water at 1-5 g/L DCA for 14 days. Activities of hepatic palmitoyl-CoA oxidase (PCO) and carnitine acetyl Co-A transferase (markers of peroxisome proliferators), peroxisome proliferation protein (PP-A) content and the volume of peroxisomes in hepatic cytoplasm were measured. Peroxisome proliferation was increased in both species at the lowest dose tested 166 (mg/kg)/day for rats and 90 (mg/kg)/day for mice. Long-term peroxisomal proliferation induced by several nonmutagenic chemicals correlates with induction of hepatocellular carcinomas in rats and mice. Two metabolic pathways were proposed for DCA by Larson and Bull (1992). The first is enzymatic hydroxylation of the C-H bond, with spontaneous dehydrodechlorination to an acid chloride intermediate that is expected to rapidly hydrolyze to oxalic acid. The second pathway, originally proposed by Stacpoole et al. (1990), involves reductive dechlorination of the chlorinated acetates to form monochloroacetate (MCA) and eventually thiodiacetic acid through glutathione conjugation. The formation of free radicals in this latter pathway suggests that lipid peroxidation may be involved in DCA toxicity. These free-radical species might be expected to initialize DNA damages such as strand breaks and cross-links, which might trigger ameliorative cellular repair processes leading, in turn, to gene mutation and chromosomal aberrations (Chang et al., 1992). Larson and Bull (1992) also suggested that lipid peroxidation also play a role in the induction of focal necrosis as observed in mice by Bull et al. (1990) and Daniel et al. (1992). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATION OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not Available. The Agency is exploring development of a biologically based model to accommodate the existing database and other data under development at ORD/HERL. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1994, 1991 The Drinking Water Criteria Document was externally peer reviewed by the Drinking Water Subcommittee of the Science Advisory Board on April 4-5, 1991. In addition, a review of this was completed by the American Water Works Association in August 1992. The comments from these reviews have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of the comments are included in the IRIS documentation files. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 02/03/1993, 03/31/1993 Verification Date -- 03/31/1993 COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199603 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Dichloroacetic acid CASRN -- 79-43-6 Last Revised -- 03/01/1996 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bull, R.J., I.M. Sanchez, M.A. Nelson, J.L. Larson and A.J. Lansing. 1990. Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology. 63: 341-359 Chang, L.W., F.B. Daniel and A.B. DeAngelo. 1992. Analysis of DNA strand breaks induced in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes. Environ. Mol. Mutagen. 20(4): 277-288. Daniel, F.B., A.B. DeAngelo, J.A. Stober, G.R. Olson and N.P. Page. 1992. Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fund. Appl. Toxicol. 19: 159-168. DeAngelo, A.B., F.B. Daniel, L. McMillan, P. Wernsing and R.E. Savage, Jr. 1989. Species and strain sensitivity to the induction of peroxisome proliferation by chloroacetic acids. Toxicol. Appl. Pharmacol. 101: 285-298. DeAngelo, A.B., F.B. Daniel, J.A. Stober and G.R. Olson. 1991. The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse. Fund. Appl. Toxicol. 16: 337-347. DeAngelo, A.B., F.B. Daniel, J.A. Stober, G.R. Olson and N.P. Page. 1993. Carcinogen Bioassays of Chloroacetic Acids in Fischer 344 Rats. Submitted to Toxicologic Pathology. (In press) Herren-Freund, S.L., M.A. Pereira, M.D. Khoury and G. Olson. 1987. The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid in mouse liver. Toxicol. Appl. Pharmacol. 90: 183-189. Larson, J.L. and R.J. Bull. 1992. Metabolism and lipoperoxidative activity of trichloroacetate and dichloroacetate in rats and mice. Toxicol. Appl. Pharmacol. 115: 268-277. Moore, G.W., L.L. Swift, D. Rabinowitz, O.B. Crofford, J.A. Oates and P.W. Stacpoole. 1979. Reducction in serum cholestrol in two patients with homozygous familial hypercholestremia by dichloroacetate. Atherosclerosis. 33: 285-293. NTP (National Toxicology Program). 1991a. NTP results report - Results and status information on all NTP chemicals produced for NTP Chemtrack System. NTP (National Toxicology Program). 1991b. Salmonella testing results. Unpublished study. Dept. Health and Human Services, Research Triangle Park, NC. Nelson, M.A. and R.J. Bull. 1988. Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo. Toxicol. Appl. Pharmacol. 94: 45-54. Ono, Y., I. Somiya and M. Kawamura. 1991. The evaluation of genotoxicity using DNA repairing test for chemicals produced in chlorination and ozonation processes. Water Sci. Technol. 23: 329-338. Richmond, R.E., A.B. DeAngelo, C.L. Potter and F.B. Daniel. 1991. The role of hyperplastic nodules in dichloroacetic acid-induced hepatocarcinogenesis in B6C3F1 male mice. Carcinogenesis. 12(8): 1383-1387. Stacpoole, P.W., H.J. Harwood Jr., D.F. Cameron, et al. 1990. Chronic toxicity of dichloroacetate: Possible relation to thiamine deficiency in rats. Fund. Appl. Toxicol. 14(2): 327-337. U.S. EPA. 1991. Toxicology of the Chloroacetic Acids, By-Products of the Drinking Water Disinfection Process. II. The Comparative Carcinogenicity of Dichloroacetic and Trichloroacetic Acid: Implication for Risk Assessment. Health Effects Research Laboratory, Research Triangle Park, NC. Document No. HERL-0820. U.S. EPA. 1994. Drinking Water Criteria Document on Chlorinated Acids/Aldehydes/Ketones/Alcohols. Prepared by Office of Science and Technology, Office of Water, Washington, DC. PB94-179918. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Dichloroacetic acid CASRN -- 79-43-6 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 10/01/1992 I.A. Oral RfD now under review 03/01/1993 II. Carcinogenicity assessment now under review 05/01/1993 I.A. Work group review date added 05/01/1993 II. Work group review date added 07/01/1993 I.A. Work group review date added 02/01/1996 II. Carcinogenicity assessment on-line 02/01/1996 VI.C. Carcinogenicity assessment references on-line 03/01/1996 II.A.4. NTP study citation revised 03/01/1996 II.D.3. Primary contact changed 03/01/1996 VI.C. NTP references revised 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 01/02/1998 I., II. This chemical is being reassessed under the IRIS Program. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 438 of 1119 in IRIS (through 2003/06) AN: 655 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199603 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Trichloroacetic-acid- SY: 76-03-9; ACETIC-ACID,-TRICHLORO-; TCA-; ACETO-CAUSTIN-; ACIDE TRICHLORACETIQUE [FRENCH]; ACIDO TRICLOROACETICO [ITALIAN]; ACIDO TRICLOROACETICO [SPANISH]; AI3-24157-; AMCHEM-GRASS-KILLER-; CASWELL NO. 870; EPA-PESTICIDE-CHEMICAL-CODE-081002-; HSDB-1779-; KYSELINA TRICHLOROCTOVA [CZECH]; TRICHLOORAZIJNZUUR [DUTCH]; TRICHLORESSIGSAEURE [GERMAN]; TRICHLOROETHANOIC-ACID- RN: 76-03-9 HSN: 1779 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Trichloroacetic acid CASRN -- 76-03-9 NORD: Not available at this time. ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Trichloroacetic acid CASRN -- 76-03-9 NORC: Not available at this time. ============================================================================ UDCA: 199603 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Trichloroacetic acid CASRN -- 76-03-9 Last Revised -- 03/01/1996 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- The classification is based on a lack of human data and limited evidence of an increased incidence of liver neoplasms in both sexes of one strain of mice. No evidence of carcinogenicity was found in rats. Results from genotoxicity studies are mixed; trichloroacetic acid does not appear to be a point mutagen. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. The primary source of exposure to trichloroacetic acid (TCA) in humans is as a byproduct of chlorination of drinking water. Since the early 1970s, numerous epidemiologic studies have attempted to assess the relationship between the chlorination byproducts in drinking water and several different human cancers. None of these studies has shown an association of exposure to TCA with an increased incidence of site-specific cancer. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. U.S. EPA (1994) described two separate experiments that examined the carcinogenicity of TCA in male B6C3F1 mice (50/group). Dose selection was based on the study by Herren-Freund et al. (1987). In the first study, mice were exposed to 0.05, 0.5 or 5 g/L TCA in drinking water for 60 weeks. The time-weighted mean daily doses were 8, 71 or 595 (mg/kg)/day, respectively. The control group received 2 g/L sodium chloride (NaCl) in drinking water. Animals were sacrificed at the end of the exposure period. Treatment with TCA had no effect on survival. In the high-dose group, significant depression of weight-gain (73% of control) and body-weight reduction (85% of control) were reported (DeAngelo, 1993). A dose-related increase in relative liver weight was observed, with a 69% increase in the high-dose group compared with the control group (DeAngelo, 1993). The incidences of combined hepatocellular tumors (adenoma and carcinoma) were 37.9 and 55.2% in mice receiving 0.5 and 5 g/L, respectively, compared with 13.3% in controls. The increase was statistically significant in the high-dose group compared with controls. Hyperplastic nodules (24.1%) were observed only at the 5-g/L dose level. The highest dose level tested in this study (5 g/L) was not considered excessive for assessment of the carcinogenic potential of TCA (DeAngelo, 1993). In a second experiment reported by U.S. EPA (1991), male B6C3F1 mice were administered 4.5 g/L TCA (583 mg/kg)/day in the drinking water over a lifetime exposure (94 weeks). Body weights in the treated animals were not significantly different from controls until the end of the study (data not provided) (DeAngelo, 1993). In the treated mice, the incidences of adenomas, carcinoma, and combined hepatocellular tumors were 42, 74 (both estimated from graph) and 86.7%, respectively, compared with 0, 11 (both estimated from graph), and 10%, respectively, in control mice. All incidences reported for the treated animals were significantly different from controls. U.S. EPA (1991) also reported on TCA-induced liver cancer in the female B6C3F1 mouse (55/group) exposed to 0, 0.5 or 4.5 g/L TCA in drinking water. The female mouse appeared to be less sensitive than the male mouse; a significantly increased incidence (60%) for combined hepatocellular adenomas/carcinomas occurred in females treated with 4.5 g/L TCA compared with controls (8%) after a 104-week exposure. A lower dose of 0.5 g/L TCA for 104 weeks resulted in a combined hepatocellular tumor incidence of 16.7% compared with control (not significant). Body weight gain was reduced by 8% and relative liver weight was increased by 47% in the high-dose group compared to the control, while survival was not affected in any group. It should be noted that the mouse studies reported in U.S. EPA (1991) did not provide adequate experimental details. For example, no information on time-to-first tumor was provided for any of the experiments and no historical control data were available. Comparison with historical control data from NTP carcinogenicity studies indicates that combined hepatocellular adenomas/carcinomas occur in approximately 30% (range 14-58%) of control male B6C3F1 mice and 8% of females (range 0-20%) (Haseman et al., 1984; Maronpot et al., 1987). The incidence of the combined hepatocellular tumors in the mice studies reported by U.S. EPA (1991) exceeded the upper end of this historical control range. An increase in liver neoplasms has been reported in male mice receiving TCA in drinking water for 52 weeks. Bull et al. (1990) exposed groups of B6C3F1 mice (11 35 males/group, 10 females/group) to neutralized TCA (males: 0, 1 or 2 g/L; females: 0 or 2 g/L). Animals were sacrificed after the 52-week exposure period. The calculated dosage rates averaged 164 (for males) or 329 ( mg/kg )/day (for both sexes) for 52 weeks. An additional group of 11 males received 2 g/L TCA for 37 weeks, followed by a 15-week recovery period. This corresponded to a dosage rate of 309 mg/kg/day for 37 weeks. No effects of treatment on survival or body weight were obseved. Food and water consumption data were not reported. A significant increase in the relative liver weight was seen in the 1-g/L males (30% increase from control), 2-g/L males (63% increase), and 2 g/L females (25% increase) compared with controls at 52 weeks. Nonneoplastic histopathological lesions included mild intracellular swelling and glycogen accumulation in the livers of treated mice (both sexes) at 52 weeks. Male mice in the 2-g/L group had accumulation of lipofuscin near hepatoproliferative lesions (no incidence reported), and hyperplastic liver nodules (9/24). The incidences of hepatocellular adenomas in male mice were 0/35 (0%), 2/11 (18%) and 1/24 (4%), and the incidences of hepatocellular carcinomas were 0/35 (0%), 2/11 (18%), and 4/24 (17%) after exposure to 0, 1 and 2 g/L, respectively. These findings were not statistically significant at any dose level. Female mice did not develop any tumors in response to TCA treatment. Fifteen weeks after exposure to 2 g/L for 37 weeks, hepatocellular carcinomas developed in 3/11 (30%) male mice, but hepatic adenomas had not occurred by that date. Tumors were not found in any other organs. Since the total exposure duration in this study did not exceed 52 weeks, this study may not have evaluated mice for an adequate length of time to observe the full carcinogenic potential of TCA. In addition, the numbers of animals tested were inadequate. The maximum tolerated dose appears to have been reached because nonneoplastic lesions were observed. Herren-Freund et al. (1987) investigated the initiation/promotion potential of TCA in male B6C3F1 mice (22-33/group). Mice were pretreated with a single intraperitoneal dose of 2.5 or 10 mg/kg ethylnitrosourea (ENU) at 15 days of age and then given 2 or 5 g/L TCA in drinking water [400 or 1000 (mg/kg)/day as calculated by the authors] from 4 to 65 weeks of age. The two negative control groups (66 animals) received 2 g/L NaCl in drinking water or 2.5 mg ENU/kg. Animals were sacrificed after 61 weeks of exposure. Survival data were not provided. A significant decrease of 8 10% in the final mean body weight was observed in the 5-g/L group, while a significant increase of 25-47% in the relative liver weight was found in all treatment groups compared with controls. In an uninitiated group receiving 5 g/L, the incidence was statistically significantly increased: 8/22 (36%) for hepatocellular adenomas and 7/22 (32%) for hepatocellular carcinomas compared with 2/22 and 0/22, respectively, for the NaCl controls. For the initiated groups (2.5 mg ENU/kg), the incidences of hepatocellular adenomas were also statistically significantly increased: 11/33 (33%) and 6/22 (26%) in the 2-and 5-g TCA/L groups, respectively, compared with 2/22 (9%) in the controls given 2.5 mg-ENU/kg. The incidences of hepatocellular carcinomas were 16/33 (48%) and 11/22 (50%) in the 2- and 5-g TCA/L groups, respectively, compared with 1/22 (4.5%) in the controls. Mice initiated with 10 mg ENU/kg and then administered 5 g/L TCA showed no significant increase in the incidence of hepatocellular adenomas or carcinomas and, therefore, TCA did not appear to inhibit or promote ENU-initiated hepatocarcinogenicity. Hyperplastic nodules were not observed in the treated animals and no other tumor sites were found. The authors concluded that TCA acted as a complete hepatocarcinogen in mice since ENU did not affect the ability of TCA to induce carcinogenicity. The mutation-promotion experiment could not be adequately evaluated, however since the TCA dose also produced tumors in a large number of animals. DeAngelo et al. (1993) exposed groups of 50 male Fischer 344 rats to 0, 0.05, 0.5 and 5 g/L TCA administered in drinking water for 104 weeks. Mean daily doses were approximately 2.83, 26 and 283.9 (mg/kg)/day, respectively. The control group received 2 g/L NaCl in drinking water. No significant differences in survival were found among groups; survival rates were 88, 84, 74 and 86% for the 0, 0.05-, 0.5- or 5 g/L-groups. Body weight and body-weight gain were significantly reduced in the high-dose group (89 and 85% of control, respectively) at the end of the exposure period. A decrease of 10% in absolute liver weight was reported in the high-dose group compared with controls. Histopathology revealed an increase in cytoplasmic vacuolization (beginning at 15 weeks) and hepatocellular necrosis at the high dose but no evidence of hyperplastic nodules. At 0.5 g/L, the incidence of cytoplasmic vacuolization was lower and was not consistently observed in all interim sacrifices. No evidence of increased carcinogenicity was observed in any treatment groups compared with controls. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The overall genetic toxicology database indicates that TCA is unlikely to induce point mutations in microbial systems. It did not induce gene mutations in either Escherichia coli (Andersen et al. 1972) or Salmonella typhimurium (Rapson et al., 1980). Similarly, neither point mutations nor somatic segregation resulted from exposure of Aspergillus nidulans to TCA (Bignami et al., 1977). A significant increase in the percentage of cells with abnormal chromosome morphology was seen in Swiss-Webster mice receiving 500 mg/kg TCA by oral gavage; however, the aberration yield was approximately 4 times lower than the response when the same dose was administered intraperitoneally (Bhunya and Behera, 1987). The intraperitoneal administration of two consecutive daily doses of 125, 250 or 500 mg/kg TCA resulted in dose-related and stastisticaly significant increase in micronuclei in bone marrow polychromatic erythrocytes while administration of 5 consecutive daily doses of 25, 50 or 100 mg/kg TCA caused a dose related and statistically significant increase in the frequency of sperm-head abnormalities. Although the data from this study strongly suggest that TCA is a clastogen for both somatic and germinal mouse cells, the findings have not been confirmed. Results are in conflict regarding the ability of TCA to cause DNA damage. In an alkaline unwinding assay, administration of oral doses of 1 10 mmol/kg TCA to B6C3F1 mice and Fischer 344 rats did not induce DNA strand breaks in a dose-related manner (Chang et al., 1992). Nelson and Bull (1988) evaluated the ability of TCA to induce single-strand DNA breaks in vivo in Sprague-Dawley rats and B6C3F1 mice. Oral gavage doses as low as 0.006 mmol/kg caused a significant increase in single-strand breaks in the hepatic DNA of mice while single-strand breaks occurred at 0.6 mmol/kg in rats. A dose of 58.5 ug/mL TCA increased DNA repair in Salmonella typhimurium TA1535 (Ono et al., 1991). The response was equivocal in the absence of exogenous metabolic activation and only weakly positive when the test material was activated by rat liver homogenates induced with phenobarbital/5,6-benzoflavone. A whole-body half-life of 50 hours was determined for TCA in three healthy male volunteers who ingested 3 mg/kg (Mueller et al., 1974) and a half-life of 6 hours for rats and mice administered an oral dose of 100 mg/kg (Larson and Bull 1992). In a study by Fisher et al. (1991), half-lives of 9 10 hours and 2 5 hours were reported for rats and mice, respectively, after administration of 5 or 10 mg/kg TCA by intravenous infusion and intraperitoneal injection. The variations in rates of systemic clearance of TCA between species and sex may reflect differences in binding preferences of ionized TCA with proteins such as albumin or with conjugates such as glucuronides (Fisher et al., 1991). In addition, the volume of distribution (Vd) was calculated and found to be different between species (Fisher et al., 1991; Allen and Fisher, 1993). Data show that rodents have smaller Vd values than humans. Furthermore, the Vd values for humans and rats were more similar than those for humans and mice. Dichloroacetic acid (DCA), carbon dioxide and an unidentifiable group of nonchlorinated acids are formed in Fischer 344 rats and B6C3F1 mice after administration of a single gavage dose of 20 or 100 mg/kg TCA (Bull et al., 1993; Larson and Bull, 1992). Kinetic parameters of TCA in plasma were similar in rats and mice at 20 and 100 mg/kg doses, except for a longer plasma half-life in rats than in mice at the lower dose. Systemic clearance for TCA was relatively similar between the two species, but plasma concentrations of DCA were dissimilar. Although the amount of DCA in the blood was equivalent after a 20 mg/kg TCA dose for the two species, peak concentrations of DCA after the 100 mg/kg TCA dose were about 30-fold greater than the low dose for rats, but only 5-fold greater than the low dose for mice (Bull et al., 1993; Larson and Bull, 1992). The area under the curve (AUC) values for DCA were also disproportionately increased between the two species. Unresolved nonchlorinated acids detected in the plasma had comparable concentrations and AUCs in the two species. Larson and Bull (1992) found no species differences in urinary metabolites. A small amount of DCA (1 3%) was detected in the urine of TCA-treated animals while unresolved nonchlorinated acids represented 5-11%. About 4-8% of TCA was exhaled as carbon dioxide. Most of the administered dose (>50%) was excreted as unchanged parent compound in the urine of both rats and mice. No human data on TCA metabolism were available for comparison of metabolites in humans and rodents. Investigators have suggested that enhanced peroxisomal proliferation by TCA in rats and mice may be involved in the induction of hepatocarcinogenicity (Bull et al., 1990; DeAngelo et al., 1989; Larson and Bull, 1992; Mather et al., 1990); however, no clear evidence to indicates an association. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATION OF CARCINOGENIC RISK FROM ORAL EXPOSURE Not available. The Agency is exploring development of a biologically based model to accommodate the existing database and other data under development at ORD/HERL. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source document -- U.S. EPA, 1994, 1991 The Drinking Water Criteria Document was externally peer reviewed by the Drinking Water Subcommittee of the Science Advisory Board on April 4-5, 1991. In addition, a review of this was completed by the American Water Works Association in August 1992. The comments from these reviews have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of the comments are included in the IRIS documentation files. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 02/03/1993, 03/31/1993, 08/04/1993 Verification Date -- 08/04/1993 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Trichloroacetic acid conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199603 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Trichloroacetic acid CASRN -- 76-03-9 Last Revised -- 03/01/1996 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Allen, B.C. and J.W. Fisher. 1993. Pharmacokinetic modeling of trichloroethylene and trichloroacetic acid in humans. Risk Anal. 13(1): 71-86. Andersen, K.J., E.G. Leighty and M.T. Takahashi. 1972. Evaluation of herbicides for possible mutagenic properties. J. Agric. Food Chem. 20(3): 649-656. Bhunya, S.P. and B.C. Behera. 1987. Relative genotoxicity of trichloroacetic acid (TCA) as revealed by different cytogenetic assays: Bone marrow chromosome aberration, micronucleus and sperm-head abnormality in the mouse. Mutat. Res. 188: 215-221. Bignami, M., G. Cardamone, P. Comba, V. Ortali, G. Morpugo and A. Carere. 1977. Relationship between chemical structure and mutagenic activity in some pesticides: The use of Salmonella typhimurium and Aspergillus nidulans. Mutat. Res. 46: 243-244. Bull, R.J., I.M. Sanchez, M.A. Nelson, J.L. Larson and A.J. Lansing. 1990. Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology. 63: 341-359. Bull, R.J., M. Templin, J.L. Larson and D.K. Stevens. 1993. The role of dichloroacetate in the hepatocarcinogenicity of trichloroethylene. Toxicol. Lett. 68: 203-211. Chang, L.W., F.B. Daniel and A.B. DeAngelo. 1992. Analysis of DNA strand breaks induced in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes. Environ. Molec. Mutagen. 20(4): 277-288. DeAngelo, A. 1993. HERL, U.S. EPA. Personal communication to R. Cantilli, OST, U.S. EPA, regarding data from the carcinogenicity studies on trichloroacetic acid in B6C3F1 mice. July 26. DeAngelo, A.B., F.B. Daniel, L. McMillan, P. Wernsing and R.E. Savage, Jr. 1989. Species and strain sensitivity to the induction of peroxisome proliferation by chloroacetic acids. Toxicol. Appl. Pharmacol. 101: 285-289. DeAngelo, A.B., F.B. Daniel, J.A. Stober, G.R. Olson and N.P. Page. 1993. Carcinogen bioassays of chloroacetic acids in Fischer 344 rats. Submitted to Toxicologic Pathology. (In press) Fisher, J.W., M.L. Gargas, B.C. Allen and M.E. Andersen. 1991. Physiologically-based pharmacokinetic modeling with trichloroethylene and its metabolite, trichloroacetic acid, in the rat and mouse. Toxicol. Appl. Pharmacol. 109: 183-195. Haseman, J., J. Huff and G. Boorman. 1984. Use of historical control data in carcinogenicity studies in rodents. Toxicol. Pathol. 12(2): 126-135. Herren-Freund, S.L., M.A. Pereira, M.D. Khoury and G. Olson. 1987. The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol. Appl. Pharmacol. 90: 183-189. Larson, J.L. and R.J. Bull. 1992. Metabolism and lipoperoxidative activity of trichloroacetate and dichloroacetate in rats and mice. Toxicol. Appl. Pharmacol. 115: 268-277. Maronpot, R.R., J. Haseman, G. Boorman, S. Eustis, G. Rao and J. Huff. 1987. Liver lesions in B6C3F1 mice: The National Toxicology Program, experience and position. Arch. Toxicol. Suppl. 10: 10-26. Mather, G.G., J.H. Exon and L.D. Koller. 1990. Subchronic 90-day toxicity of dichloroacetic and trichloroacetic acid in rats. Toxicology. 64: 71-80. Mueller, G., M. Spassovski and D. Henschler. 1974. Metabolism of trichloroethylene in man. II: Pharmacokinetics of metabolite. Arch. Toxicol. 32(4): 283-295. Nelson, M.A. and R.J. Bull. 1988. Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo. Toxicol. Appl. Pharmacol. 94: 45-54. Ono, Y., I. Somiya and M. Kawamura. 1991. The evaluation of Genotoxicity Using DNA Repairing Test for Chemicals Produced in Chlorination and Ozonation Processes. Water Sci. Technol. 23: 329-338. Rapson, W.H., M.A. Nazar and V.V. Butsky. 1980. Mutagenicity produced by aqueous chlorination of organic compounds. Bull. Environ. Contam. Toxicol. 24: 590-596. U.S. EPA. 1991. Toxicology of the Chloroacetic Acids, By-Products of the Drinking Water Disinfection Process. II. The Comparative Carcinogenicity of Dichloroacetic and Trichloroacetic Acid: Implication for Risk Assessment. Health Effects Research Laboratory, Research Triangle Park, NC. Document No. HERL-0820. U.S. EPA. 1994. Drinking Water Criteria Document on Chlorinated Acids/Aldehydes/Ketones/Alcohols. Prepared by Office of Science and Technology, Office of Water, Washington, DC. PB94-179918. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Trichloroacetic acid CASRN -- 76-03-9 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 10/01/1992 I.A. Oral RfD now under review 03/01/1993 II. Carcinogenicity assessment now under review 05/01/1993 I.A. Work group review date added 05/01/1993 II. Work group review date added 07/01/1993 I.A. Work group review date added 09/01/1993 II. Work group review date added 01/01/1994 I.A. Work group review date added 08/01/1995 I.A., II. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 02/01/1996 II. Carcinogenicity assessment on-line 02/01/1996 VI.C. Carcinogenicity assessment references on-line 03/01/1996 II.A.3. Citation revised 03/01/1996 II.D.3. Primary contact changed 03/01/1996 VI.C. U.S. EPA, 1993 revised to DeAngelo, 1993 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 II.D.2 Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 439 of 1119 in IRIS (through 2003/06) AN: 682 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199312 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: d-Limonene- SY: 5989-27-5; CYCLOHEXENE, 1-METHYL-4-(1-METHYLETHENYL)-, (R)- (9CI); (+)-LIMONENE; (+)-P-MENTHA-1,8-DIENE; (R)-(+)-LIMONENE; (R)-1-METHYL-4-(1-METHYLETHENYL)CYCLOHEXENE; AI3-15191-; CARVENE-; CCRIS-671-; D-(+)-LIMONENE; D-LIMONENO [SPANISH]; HSDB-4186-; NCI-C55572-; P-MENTHA-1,8-DIENE, (R)-(+)-; REFCHOLE- RN: 5989-27-5 HSN: 4186 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- d-Limonene CASRN -- 5989-27-5 NORD: Not available at this time. ---------------------------------------------------------------------------- UDRC: 199312 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- d-Limonene CASRN -- 5989-27-5 NORC: The health effects data for d-limonene were reviewed by the U.S. EPA RfD/RfC Work Group and determined to be inadequate for the derivation of an inhalation RfC. The verification status for this chemical is currently NOT VERIFIABLE. For additional information on the health effects of this chemical, interested parties are referred to the documentation listed below. NOT VERIFIABLE status indicates that the U.S. EPA RfD/RfC Work Group deemed the database at the time of review to be insufficient to derive an inhalation RfC according to the Interim Methods for Development of Inhalation Reference Concentrations (U.S. EPA, 1990). This status does not preclude the use of information in cited references for assessment by others. d-Limonene (1-methyl-4-isopropenyl-1-cyclohexene) is a liquid with a lemonlike odor. It is a major constituent in several citrus oils (orange, lemon, mandarin, lime, and grapefruit) and is present in a number of other essential oils, as well. d-Limonene is included on the Food and Drug Administration's (FDA's) Generally Recognized as Safe List and is approved for use by the FDA as a food additive (Opdyke, 1975). d-Limonene has a boiling point of 176 C and a vapor pressure of <3 mmHg at 14 C. d-Limonene is used primarily as a flavor and fragrance ingredient. No information is available on the health effects of inhalation exposure to d-limonene in humans, and no long-term inhalation studies have been conducted in laboratory animals. NTP (1990) conducted a series of studies that investigated the toxicity of d-limonene (>99% pure) in both Fischer 344/N rats and B6C3F1 mice. In the first of the preliminary range-finding studies, doses ranging from 413-6600 mg/kg/day were administered by gavage in corn oil to five animals/species/sex/dose for 5 days/week for 16 days. All but 2/20 rats and 1/20 mice that were administered 3300 and 6600 mg/kg/day died. Body weight gain was reduced at 1650 mg/kg/day. No compound-related signs of toxicity were observed in those animals administered <1650 mg/kg/day. In the 13-week study, 10 animals/species/sex/dose were administered 0, 150, 300, 600, 1200, or 2400 mg/kg/day (rats) or 0, 125, 250, 500, 1000, or 2000 mg/kg/day (mice) d-limonene by gavage in corn oil for 5 days/week. Survival was reduced in the high-dose rats, and body weight gain decreased in a dose-related fashion in the male rats starting at 600 mg/kg/day. Male rats that were administered 1200 or 2400 mg/kg/day exhibited rough hair coats, lethargy, and excessive lacrimation. The only compound-related effect noted in rats was nephropathy in males. Survival also was reduced slightly in the mice that received 2000 mg/kg/day, and decreased body weight gain was observed in those male mice that were administered the two highest doses of d-limonene. Aside from the observation of rough hair coats and decreased activity in the mice receiving 1000 and 2000 mg/kg/day, no other compound-related signs of toxicity or lesions were noted. In the 2-year study, 50 animals/species/sex/dose were administered 0, 75, or 150 mg/kg/day (male rats); 0, 300, or 600 mg/kg/day (female rats); 0, 250, or 500 mg/kg/day (male mice); or 0, 500, or 1000 mg/kg/day (female mice) d-limonene by gavage in corn oil once a day for 5 days/week. The survival of the female rats administered 600 mg/kg/day was significantly lower than that of the vehicle controls. The only microscopic evidence of compound-related toxicity noted in the rats was nephropathy in the males. d-Limonene is one of a diverse group of hydrocarbons that has been shown to induce a unique syndrome of nephropathy in male rats following subchronic or chronic exposure. Based on a review of the literature concerning this effect (U.S. EPA, 1991), EPA's Risk Assessment Forum concluded that nephropathy in male rats that is associated with alpha-2u-globulin accumulation in hyaline droplets is not an appropriate endpoint to determine noncancer effects potentially occurring in humans. Female mice exposed to 1000 mg/kg/day d-limonene exhibited 5-15% lower mean body weights than their respective vehicle controls after week 28 of the study. No compound-related clinical signs of toxicity were noted in either sex. An increased incidence of multinucleated hepatocytes and cytomegaly was observed in the high-dose male mice but not in female mice. Based on the occurrence of these liver lesions, a NOAEL of 250 mg/kg/day and a LOAEL of 500 mg/kg/day can be estimated from this study in mice. Nephrotoxicity, consisting of granular casts characteristic of alpha-2u-globulin-mediated nephropathy, was observed in male Sprague-Dawley rats administered 277, 554, or 1385 mg/kg/day d-limonene daily by gavage in 1% Tween 80 for 6 months (Tsuji et al., 1975). These lesions were not observed in the female rats similarly exposed. The developmental toxicity of d-limonene has been investigated in mice and rabbits. In the mouse study, 15 pregnant ICR mice/group were administered 0, 591, or 2363 mg/kg/day d-limonene by gavage on gestation days 7-12 (Kodama et al., 1977a). Maternal toxicity (significant reduction in body weight) and developmental toxicity (significant increase in the number of fetuses with skeletal abnormalities, including lumbar ribs, fused ribs, and delayed ossification of several bones in the paws) were observed in the animals administered 2363 mg/kg/day. No maternal or fetal effects were observed at the low dose. This study is limited in that an inadequate number of animals was used, only two doses were tested, and dosing did not continue throughout the entire period of organogenesis. In the rabbit study, 10-18 pregnant Japanese white rabbits were administered 0, 250, 500, or 1000 mg/kg/day d-limonene by gavage on gestation days 6-18 (Kodama et al., 1977b). Exposure of does to 500 or 1000 mg/kg/day resulted in maternal toxicity. There were significant reductions in food consumption and body weight at both doses, and death also occurred in the 1000-mg/kg/day group. Developmental toxicity was not observed at any dose. This study is limited by the small sample size. No reproductive toxicity studies have been conducted on d-limonene. Igimi et al. (1974) studied the metabolism of d-limonene after oral administration and found that about 65% of the dose was recovered in urine, feces, and expired carbon dioxide, suggesting that the majority of an oral dose is absorbed. Although it is possible that an inhaled dose would also be largely absorbed, there is no information on inhalation exposures. An RfC cannot be derived because of the lack of information on possible respiratory tract effects and the limited pharmacokinetic data on which to base a route extrapolation. Igimi, H., M. Nishimura, R. Kodama, and H. Ide. 1974. Studies on the metabolism of d-limonene (p-mentha-1,8-diene). I. The absorption, distribution, and excretion of d-limonene in rats. Xenobiotica. 4(2): 77-84. Kodama, R., A. Okubo, E. Araki, K. Noda, H. Ide, and T. Ikeda. 1977a. Studies on d-limonene as a gallstone solubilizer. (VII). Effects on development of mouse fetuses and offsprings. Oyo Yakuri. 13(6): 863-873. Kodama, R., A. Okubo, K. Sato et al. 1977b. Studies on d-limonene as a gallstone solubilizer. (IX). Effects on development of mouse fetuses and offsprings. Oyo Yakuri. 13(6): 885-898. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of d-limonene (CAS No. 5989-27-5) in F344/N rats and B6C3F1 mice (gavage studies). NTP Technical Report Series No. 347, NIH PB No. 90-2802, U.S. DHHS, National Institutes of Health. Opdyke, D.J.L. 1975. Special Issue II: Monographs on fragrance raw materials. Food Cosmet. Toxicol. 13: 825-826. Tsuji, M., Y. Fujisaki, Y. Arikawa et al. 1975. Studies on d-limonene as a gallstone solubilizer. (III). Chronic toxicity in rats. Oyo Yakuri. 9(3): 403-412. U.S. EPA. 1990. Interim Methods for Development of Inhalation Reference Concentrations (External Review Draft). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066A. U.S. EPA. 1991. Alpha2u-globulin: Association with chemically-induced renal toxicity and neoplasia in the male rat. Washington, DC. EPA/625/3-91/019F. Agency Work Group Review -- 09/23/1993 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for d-Limonene conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. EPA Contacts: Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- d-Limonene CASRN -- 5989-27-5 NOCA: Not available at this time. ============================================================================ UDSO: 199312 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- d-Limonene CASRN -- 5989-27-5 Last Revised -- 12/01/1993 SORD: __VI.A. ORAL RfD REFERENCES None ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfD REFERENCES Igimi, H., M. Nishimura, R. Kodama, and H. Ide. 1974. Studies on the metabolism of d-limonene (p-mentha-1,8-diene). I. The absorption, distribution, and excretion of d-limonene in rats. Xenobiotica. 4(2): 77-84. Kodama, R., A. Okubo, E. Araki, K. Noda, H. Ide, and T. Ikeda. 1977a. Studies on d-limonene as a gallstone solubilizer. (VII). Effects on development of mouse fetuses and offsprings. Oyo Yakuri. 13(6): 863-873. Kodama, R., A. Okubo, K. Sato et al. 1977b. Studies on d-limonene as a gallstone solubilizer. (IX). Effects on development of mouse fetuses and offsprings. Oyo Yakuri. 13(6): 885-898. NTP (National Toxicology Program). 1990. Toxicology and carcinogenesis studies of d-limonene (CAS No. 5989-27-5) in F344/N rats and B6C3F1 mice (gavage studies). NTP Technical Report Series No. 347, NIH PB No. 90-2802, U.S. DHHS, National Institutes of Health. Opdyke, D.J.L. 1975. Special Issue II: Monographs on fragrance raw materials. Food Cosmet. Toxicol. 13: 825-826. Tsuji, M., Y. Fujisaki, Y. Arikawa et al. 1975. Studies on d-limonene as a gallstone solubilizer. (III). Chronic toxicity in rats. Oyo Yakuri. 9(3): 403-412. U.S. EPA. 1990. Interim Methods for Development of Inhalation Reference Concentrations (External Review Draft). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-90/066A. U.S. EPA. 1991. Alpha2u-globulin: Association with chemically-induced renal toxicity and neoplasia in the male rat. Washington, DC. EPA/625/3-91/019F. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES None ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- d-Limonene CASRN -- 5989-27-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 11/01/1993 I.B. Inhalation RfC now under review 12/01/1993 I.B. Inhalation RfC message on-line 12/01/1993 VI.B. Inhalation RfC references on-line 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.B. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 440 of 1119 in IRIS (through 2003/06) AN: 692 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm UD: 199506 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Mercuric-chloride- (HgCl2) SY: 7487-94-7; HGCL2-; MERCURIC-CHLORIDE-; MERCURY-CHLORIDE- (HGCL2); MERCURY-DICHLORIDE-; MERCURY(II) CHLORIDE; BICHLORIDE-OF-MERCURY-; BICHLORURE DE MERCURE [FRENCH]; CASWELL NO. 544; CHLORID RTUTNATY [CZECH]; CHLORURE DE MERCURE II [FRENCH]; CHLORURE MERCURIQUE [FRENCH]; CLORURO DI MERCURIO [ITALIAN]; CLORURO MERCURICO [SPANISH]; CORROSIVE-MERCURY-CHLORIDE-; CORROSIVE-SUBLIMATE-; DICHLOROMERCURY-; EPA-PESTICIDE-CHEMICAL-CODE-052001-; MERCURIC-BICHLORIDE-; MERCURY-BICHLORIDE-; MERCURY-PERCHLORIDE-; NCI-C60173-; NSC-353255-; QUECKSILBER CHLORID [GERMAN]; SUBLIMAT [CZECH]; SULEMA [RUSSIAN] RN: 7487-94-7 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199505 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Mercuric chloride (HgCl2) CASRN -- 7487-94-7 Last Revised -- 05/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD -------------------- ----------------------- ----- --- --------- Autoimmune effects NOAEL: None 1000 1 3E-4 mg/kg-day Rat Subchronic LOAEL: 0.226 mg/kg-day Feeding and Subcutaneous LOAEL: 0.317 mg/kg-day Studies LOAEL: 0.633 mg/kg-day U.S. EPA, 1987 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- Dose conversions in the three studies employed a 0.739 factor for HgCl2 to Hg2+, a 100% factor for subcutaneous (s.c.) to oral route of exposure, and a time-weighted average for days/week of dosing. This RfD is based on the back calculations from a Drinking Water Equivalent Level (DWEL), recommended to and subsequently adopted by the Agency, of 0.010 mg/L: (RfD = 0.010 mg/L x 2 L/day/70 kg bw = 0.0003 mg/kg bw/day). The LOAEL exposure levels, utilized in the three studies selected as the basis of the recommended DWEL, are from Druet et al. (1978), Bernaudin et al. (1981) and Andres (1984), respectively. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) U.S. EPA. 1987. Peer Review Workshop on Mercury Issues. Summary Report. Environmental Criteria and Assessment Office, Cincinnati, OH. October 26-27. On October 26-27, 1987, a panel of mercury experts met at a Peer Review Workshop on Mercury Issues in Cincinnati, Ohio, and reviewed outstanding issues concerning the health effects and risk assessment of inorganic mercury (U.S. EPA, 1987). The following five consensus conclusions and recommendations were agreed to as a result of this workshop: 1) The most sensitive adverse effect for mercury risk assessment is formation of mercuric-mercury-induced autoimmune glomerulonephritis. The production and deposition of IgG antibodies to the glomerular basement membrane can be considered the first step in the formation of this mercuric-mercury-induced autoimmune glomerulonephritis. 2) The Brown Norway rat should be used for mercury risk assessment. The Brown Norway rat is a good test species for the study of Hg2+-induced autoimmune glomerulonephritis. The Brown Norway rat is not unique in this regard (this effect has also been observed in rabbits). 3) The Brown Norway rat is a good surrogate for the study of mercury-induced kidney damage in sensitive humans. For this reason, the uncertainty factor used to calculate criteria and health advisories (based on risk assessments using the Brown Norway rat) should be reduced by 10-fold. 4) Hg2+ absorption values of 7% from the oral route and 100% from the s.c. route should be used to calculate criteria and health advisories. 5) A DWEL of 0.010 mg/L was recommended based on the weight of evidence from the studies using Brown Norway rats and limited human tissue data. Three studies using the Brown Norway rat as the test strain were chosen from a larger selection of studies as the basis for the panel's recommendation of 0.010 mg/L as the DWEL for inorganic mercury. The three studies are presented below for the sake of completeness. It must be kept in mind, however, that the recommended DWEL of 0.010 mg/L and back calculated oral RfD of 0.0003 mg/kg-day were arrived at from an intensive review and workshop discussions of the entire inorganic mercury data base, not just from one study. In the Druet et al. (1978) study, the duration of exposure was 8-12 weeks; s.c. injection was used instead of oral exposure. In this study the development of kidney disease was evaluated. In the first phase the rats developed anti-GBM antibodies. During the second phase, which is observed after 2-3 months, the patterns of fixation of antisera changed from linear to granular as the disease progressed. The immune response was accompanied by proteinuria and in some cases by a nephrotic syndrome. Both male and female Brown Norway rats 7-9 weeks of age were divided into groups of 6-20 animals each. The numbers of each sex were not stated. The animals received s.c. injections of mercuric chloride (HgCl2) 3 times weekly for 8 weeks, with doses of 0, 100, 250, 500, 1000 and 2000 ug/kg. An additional group was injected with a 50 ug/kg dose for 12 weeks. Antibody formation was measured by the use of kidney cryostat sections stained with a fluoresceinated sheep anti-rat IgG antiserum. Urinary protein was assessed by the biuret method (Druet et al., 1978). Tubular lesions were observed at the higher dose levels. Proteinuria was reported at doses of 100 ug/kg and above, but not at 50 ug/kg. Proteinuria was considered a highly deleterious effect, given that affected animals developed hypoalbuminemia and many died. Fixation of IgG antiserum was detected in all groups except controls (Druet et al., 1978). Bernaudin et al. (1981) reported that mercurials administered by inhalation or ingestion to Brown Norway rats developed a systemic autoimmune disease. The HgCl2 ingestion portion of the study involved the forcible feeding of either 0 or 3000 ug/kg-week of HgCl2 to male and female Brown Norway rats for up to 60 days. No abnormalities were reported using standard histological techniques in either experimental or control rats. Immunofluorescence histology revealed that 80% (4/5) of the mercuric-exposed rats were observed with a linear IgG deposition in the glomeruli after 15 days of exposure. After 60 days of HgCl2 exposure, 100% (5/5) of the rats were seen with a mixed linear and granular pattern of IgG deposition in the glomeruli and granular IgG deposition in the arteries. Weak proteinuria was observed in 60% (3/5) of the rats fed HgCl2 for 60 days. The control rats were observed to have no deposition of IgG in the glomeruli or arteries as well as normal urine protein concentrations. Andres (1984) administered HgCl2 (3 mg/kg in 1 mL of water) by gavage to five Brown Norway rats and two Lewis rats twice a week for 60 days. A sixth Brown Norway rat was given only 1 mL of water by gavage twice a week for 60 days. All rats had free access to tap water and pellet food. After 2-3 weeks of exposure, the Brown Norway HgCl2-treated rats started to lose weight and hair. Two of the HgCl2-treated Brown Norway rats died 30-40 days after beginning the study. No rats were observed to develop detectable proteinuria during the 60-day study. The kidneys appeared normal in all animals when evaluated using standard histological techniques, but examination by immunofluorescence showed deposits of IgG present in the renal glomeruli of only the mercuric-treated Brown Norway rats. The Brown Norway treated rats were also observed with mercury-induced morphological lesions of the ileum and colon with abnormal deposits of IgA in the basement membranes of the intestinal glands and of IgG in the basement membranes of the lomina propria. All observations in the Lewis rats and the control Brown Norway rat appeared normal. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- An uncertainty factor of 1000 was applied to the animal studies using Brown Norway rats as recommended in U.S. EPA (1987). An uncertainty factor was applied for LOAEL to NOAEL conversion: 10 for use of subchronic studies and a combined 10 for both animal to human and sensitive human populations. MF -- None ACRD: ___I.A.4. ADDITIONAL STUDIES / COMMENTS (ORAL RfD) Kazantzis et al. (1962) performed renal biopsies in 2 (out of 4) workers with nephrotic syndrome who had been occupationally exposed to mercuric oxide, mercuric acetate and probably mercury vapors. Investigators reported that the nephrotic syndrome observed in 3 of the 4 workers may have been an idiosyncratic reaction since many other workers in a factory survey had similarly high levels of urine mercury without developing proteinuria. This conclusion was strengthened by work in Brown Norway rats indicating a genetic (strain) susceptibility and that similar mercury-induced immune system responses have been seen in affected humans and the susceptible Brown Norway rats (U.S. EPA, 1987). The only chronic ingestion study designed to evaluate the toxicity of mercury salts was reported by Fitzhugh et al. (1950). In this study, rats of both sexes (20-24/group) were given 0.5, 2.5, 10, 40 or 160 ppm mercury as mercuric acetate in their food for up to 2 years. Assuming food consumption was equal to 5% bw/day, the daily intake would have been 0.025, 0.125, 0.50, 2.0 and 8.0 mg/kg for the five groups, respectively. At the highest dose level, a slight depression of body weight was detected in male rats only. The statistical significance of this body-weight depression was not stated. Kidney weights were significantly (p<0.05) increased at the 2.0 and 8.0 mg/kg dose levels. Pathological changes originating in the proximal convoluted tubules of the kidneys were also noted, with more severe effects in females than males. The primary weaknesses of this study were (1) the lack of reporting on which adverse effects were observed with which dosing groups and (2) that the most sensitive strain, the Brown Norway rat, was not used for evaluating the mercury-induced adverse health effects. NTP (1993) conducted subchronic and chronic gavage toxicity studies on Fischer 344 rats and B6C3F1 mice to evaluate the effects of HgCl2, and the kidney appeared to be the major organ affected. In the 6-month study, Fischer 344 rats (10/sex /group) were administered 0, 0.312, 0.625, 1.25, 2.5 or 5 mg/kg-day of HgCl2 (0.23, 0.46, 0.92, 1.9 and 3.7 mg/kg-day) 5 days/week by gavage. Survival was not affected, although body-weight gains were decreased in males at high dose and in females at or above the 0.46 mg/kg-day dose. Absolute and relative kidney weights were significantly increased in both sexes with exposure to at least 0.46 mg/kg-day. In males, the incidence of nephropathy was 80% in the controls and 100% for all treated groups; however, severity was minimal in the controls and two low-dose groups and minimal to mild in the 0.92 mg/kg-day group and higher. In females, there was a significant increased incidence of nephropathy only in the high-dose group (4/10 with minimal severity). Nephropathy was characterized by foci of tubular regeneration, thickened tubular basement membrane and scattered dilated tubules containing hyaline casts. No treatment-related effects were observed in the other organs; however, histopathology on the other organs was performed only on control and high-dose rats. B6C3F1 mice (10/sex/group) were administered 0, 1.25, 2.5, 5, 10 or 20 mg/kg-day HgCl2 (0, 0.92, 1.9,3.7, 7.4 or 14.8 mg/kg-day) 15 days/week by gavage for 6 months (NTP 1993). A decrease in body-weight gain was reported in only the males at the highest dose tested. Significant increases occurred in absolute kidney weights of male mice at 3.7 mg/kg-day or greater and relative kidney weights of male mice at 7.4 and 14.8 mg/kg-day doses. The kidney weight changes corresponded to an increased incidence of cytoplasmic vacuolation of renal tubule epithelium in males exposed to at least 3.7 mg/kg-day. The exposed female mice did not exhibit any histopathologic changes in the kidneys. In the 2-year NTP study, Fischer 344 rats (60/sex/group) were administered 0, 2.5 and 5 mg/kg-day HgCl2 (1.9 and 3.7 mg/kg-day) 5 days week by gavage (NTP, 1993). After 2 years, survival was reduced in only the treated male rat groups compared with the control. Mean body weights were decreased in both male and female treated groups. After 2 years, an increased incidence of nephropathy of moderate-to-marked severity and increased incidence of tubule hyperplasia was observed in the kidneys of exposed males compared with the controls. The control males exhibited nephropathy, primarily of mild-to-moderate severity. Hyperparathyroidism, mineralization of various tissues and fibrous osteodystrophy were observed and considered secondary to the renal impairment. No significant differences were found in renal effects between exposed and control females. Other nonneoplastic effects included an increased incidence of forestomach hyperplasia in the exposed males and high-dose females. NTP (1993) also administered to B6C3F1 mice (60/sex/group) daily oral gavage doses of 0, 5 or 10 mg/kg-day HgCl2 (0, 3.7 and 7.4 mg/kg-day) 5 days/week by gavage for 2 years. Survival and body weights of mice were slightly lower in HgCl2-treated mice compared with controls. Absolute kidney weights were significantly increased in the treated males, while relative kidney weights were significantly increased in high-dose males and both lowand high-dose females. Histopathology revealed an increase in the incidence and severity of nephropathy in exposed males and an increase in the incidence of nephropathy in exposed females. Nephropathy was defined as foci of proximal convoluted tubules with thickened basement membrane and basophilic cells with scant cytoplasm. Some affected convoluted tubules contained syaline casts. Also, an increase in nasal cavity inflammation (primarily infiltration of granulocytes in nasal mucosa) was observed in the exposed animals. Gale and Ferm (1971) studied the teratogenic effects of mercuric acetate on Syrian golden hamsters. Single doses of 2, 3 or 4 mg/kg were injected by the i.v. route on day 8 of gestation. Growth retardation, increased resorption rates and edema of the fetuses were found at all three dose levels, while an increase in the number of abnormalities was detected at the two higher doses. In a more recent study, Gale (1981) compared the embryotoxic effects of a single s.c. dose of 15 mg/kg mercuric acetate on the eighth day of gestation in five inbred strains and one noninbred strain of Syrian hamsters. While strain differences were apparent, a variety of abnormalities were reported in all the strains. Gale (1974) also compared the relative effectiveness of different exposure routes in Syrian hamsters. The following sequence of decreasing efficacy was noted for mercuric acetate; i.p. > i.v. > s.c. > oral. The lowest doses used, 2 mg/kg for i.p. and 4 mg/kg for the other three routes, were all effective in causing increased resorption and percent abnormalities. In male mice administered a single i.p. dose of 1 mg/kg HgCl2, fertility decreased between days 28 and 49 post treatment with no obvious histological effects noted in the sperm (Lee and Dixon, 1975). The period of decreased fertility indicated that spermatogonia and premeiotic spermatocytes were affected. The effects were less severe than following a similar dose of methyl mercury. A single i.p. dose of 2 mg/kg HgCl2 in female mice resulted in a significant decrease in the total number of implants and number of living embryos and a significant increase in the percentage of dead implants (Suter, 1975). These effects suggest that mercury may be a weak inducer of dominant lethal mutations. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- N/A Data Base -- High RfD -- High No one study was found adequate for deriving an oral RfD; however, based on the weight of evidence from the studies using Brown Norway rats and the entirety of the mercuric mercury data base, an oral RfD of high confidence results. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 1988 This IRIS summary is included in The Mercury Study Report to Congress, which was reviewed by OHEA and EPA's Mercury Work Group in November 1994. An interagency review by scientists from other federal agencies took place in January 1995. The report was also reviewed by a panel of non-federal external scientists in January 1995 who met in a public meeting on January 25-26. All reviewers comments have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of these comments is summarized in the IRIS documentation files. Other Docmentation -- U.S. EPA, 1987 Agency Work Group Review -- 08/05/1985, 02/05/1986, 08/19/1986, 11/16/1988 Verification Date -- 11/16/1988 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Mercuric chloride (HgCl2) conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Mercuric chloride (HgCl2) CASRN -- 7487-94-7 NORC: Not available at this time. ============================================================================ UDCA: 199506 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Mercuric chloride (HgCl2) CASRN -- 7487-94-7 Last Revised -- 06/01/1995 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** NOCA: __II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Mercuric Chloride CASRN -- 7487-94-7 Preparation Date -- 05/24/1994 ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION Classification -- C; possible human carcinogen Basis -- Based on the absence of data in humans and limited evidence of carcinogenicity in rats and mice. Focal papillary hyperplasia and squamous cell papillomas in the forestomach as well as thyroid follicular cell adenomas and carcinomas were observed in male rats gavaged with mercuric chloride for 2 years. The relevance of the forestomach papillomas to assessment of cancer in humans is questionable because no evidence indicated that the papillomas progressed to malignancy. The relevance of the increase in thyroid tumors has also been questioned because these tumors are generally considered to be secondary to hyperplasia; this effect was not observed in the high-dose males. It should also be noted that the authors considered the doses used in the study to exceed the MTD for male rats. In the same study, evidence for increases in squamous cell papillomas in the forestomach of female rats was equivocal. In a second study, equivocal evidence for renal adenomas and adenocarcinomas was observed in male mice; there was a significant positive trend. This tumor type is rare in mice, and the increase in incidence was statistically significant when compared with historic controls. Two other nonpositive lifetime rodent studies were considered inadequate. Mercuric chloride showed mixed results in a number of genotoxicity assays. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. No data are available on the carcinogenic effects of mercuric chloride in humans. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Limited. The results from a dietary study in rats and mice show equivocal evidence for carcinogenic activity in male mice and female rats and some evidence for carcinogenic activity in male rats. Two other dietary studies did not show any evidence for carcinogenicity, but these studies are limited by inadequacies in the data and experimental design, including the small number of animals/dose and/or a lack of complete histopathological examinations. Mercuric chloride (purity >99%) was administered by gavage in water at doses of 0, 2.5 or 5 (mg/kg)/day (0, 1.9 and 3.7 (mg/kg)/day) to 60 F344 rats/sex/group, 5 days/week for 104 weeks (NTP, 1993). An interim sacrifice (10/sex/dose) was conducted after 15 months of exposure. Complete histopathological examinations were performed on all animals found dead, killed in extremis, or killed by design. Survival after 24 months was lower in low- and high-dose males at a statistically significant rate; survival was 43, 17 and 8% in control, low-, and high-dose males, respectively, and 58, 47 and 50% in control, low-, and high-dose females, respectively. During the second year of the study, body weight gains of low- and high-dose males were 91 and 85% of controls, respectively, and body weight gains of low- and high-dose females were 90 and 86% of controls, respectively. At study termination, nephropathy was evident in almost all male and female rats including controls, but the severity was much greater in treated males. The incidence of "marked" nephropathy was 6/50, 29/50 and 29/50 in control, low- and high-dose males, respectively. Squamous cell papillomas of the forestomach showed a statistically significant positive trend with dose by life table adjusted analysis; the incidences were 0/50, 3/50 and 12/50 in control, low- and high-dose males, respectively. For females, the incidence was 0/50, 0/49 and 2/50 in control, low- and high-dose groups, respectively. These neoplasms are rare in male rats and occurred in only 1/264 historical controls. The incidence of papillary hyperplasia of the stratified squamous epithelium lining of the forestomach was elevated at a statistically significant rate in all dosed males (3/49, 16/50 and 35/50 in control, low- and high-dose males, respectively) and in high-dose females (5/50, 5/49 and 20/50 in control, low-and high-dose females, respectively). The incidence of thyroid follicular cell carcinomas, adjusted for survival, showed a significant positive trend in males; the incidence was 1/50, 2/50 and 6/50 in control, low- and high-dose groups, respectively. The combined incidence of thyroid follicular cell neoplasms (adenoma and/or carcinoma) was not significantly increased (2/50, 6/50 and 6/50 in control, low- and high-dose males, respectively). In female rats a significant decrease in the incidence of mammary gland fibroadenomas was observed (15/50, 5/48 and 2/50 in control, low- and high-dose females, respectively). The high mortality in both groups of treated males indicates that the MTD was exceeded in these groups and limits the value of the study for assessment of carcinogenic risk. NTP (1993) considered the forestomach tumors to be of limited relevance to humans because the tumors did not appear to progress to malignancy. NTP (1993) also questioned the relevance of the thyroid carcinomas because these neoplasms are usually seen in conjunction with increased incidences of hyperplasia and adenomas. In this study, however, no increases in hyperplasia or adenomas were observed. Hyperplasia incidence was 2/50, 4/50 and 2/50 in control, low- and high-dose males, respectively; adenoma incidence was 1/50, 4/50 and 0/50 in control, low- and high-dose males, respectively. In the same study, mercuric chloride was administered by gavage in water at doses of 0, 5 or 10 (mg/kg)/day (0, 3.7 and 7.4 (mg/kg)/day) to 60 B6C3F1 mice/sex/group 5 days/week for 104 weeks (NTP, 1993). An interim sacrifice (10/sex/dose) was conducted after 15 months of exposure. Terminal survival and body weight gain were not affected in either sex by the administration of mercuric chloride. It should be noted that survival of high-dose females was lower than controls; female survival rates were 82, 70 and 62% in control, low- and high-dose females, respectively. Female mice exhibited a significant increase in the incidence of nephropathy (21/49, 43/50 and 42/50 in control, low- and high-dose females, respectively). Nephropathy was observed in 80-90% of the males in all groups. The severity of nephropathy increased with increasing dose. The incidence of renal tubular hyperplasia was 1/50, 0/50 and 2/49 in control, low- and high-dose males. The combined incidence of renal tubular adenomas and adenocarcinomas was 0/50, 0/50 and 3/49 in control, low- and high-dose males, respectively. Although no tumors were seen in the low-dose males, a statistically significant positive trend for increased incidence with increased dose was observed. These observations were considered important because renal tubular hyperplasia and tumors in mice are rare. The 2-year historical incidence of renal tubular adenomas or adenocarcinomas in males dosed by gavage with water was 0/205, and only 4 of the nearly 400 completed NTP studies have shown increased renal tubular neoplasms in mice. Data from this study were not statistically compared with historical control data by NTP. EPA's analysis of the reported data with Fisher's Exact test showed that the incidence of renal tubular adenomas or adenocarcinomas in the high-dose males was significantly elevated when compared with historical controls (Rice and Knauf, 1994). A 2-year feeding study in rats (20 or 24/sex/group; strain not specified) was conducted in which mercuric acetate was administered in the diet at doses of 0, 0.5, 2.5, 10, 40 and 160 ppm (0, 0.02, 0.1, 0.4, 1.7 and 6.9 (mg Hg/kg)/day (Fitzhugh et al., 1950). Survival was not adversely affected in the study. Increases in kidney weight and renal tubular lesions were observed at the two highest doses. No statement was made in the study regarding carcinogenicity. This study was not intended to be a carcinogenicity assay, and the number of animals/dose was rather small. Histopathological analyses were conducted on only 50% of the animals (complete histopathology conducted on only 31% of the animals examined), and no quantitation of results or statistical analyses were performed. No increase in tumor incidence was observed in a carcinogenicity study using white Swiss mice (Schroeder and Mitchener, 1975). Groups of mice (54/sex/group) were exposed until death to mercuric chloride in drinking water at 5 ppm Hg (0.95 (mg/kg)/day). No effects on survival or body weights were observed. After dying, mice were weighed and dissected. The animals were examined for gross tumors, and some sections were made of the heart, lung, liver, kidney and spleen for microscopic examination. No toxic effects of mercuric chloride were reported in the study. No statistically significant differences were observed in tumor incidences for treated animals and controls. This study is of limited use for evaluation of carcinogenicity because complete histological examinations were not performed, only a single dose was tested, and the MTD was not achieved. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY The increasing trend for renal tubular cell tumors in mice observed in the NTP (1993) study receives some support from similar findings in mice after chronic dietary exposure to methylmercury (Hirano et al., 1986; Mitsumori et al., 1981, 1990). In these studies, dietary exposure to methylmercuric chloride resulted in increases in renal tubular tumors at doses wherein substantial nephrotoxicity was observed (see methylmercury file on IRIS). As summarized in NTP (1993) and U.S. EPA (1985), mercuric chloride has produced some positive results for clastogenicity in a variety of in vitro and in vivo genotoxicity assays; mixed results regarding its mutagenic activity have been reported. Mercuric chloride was negative in gene mutation tests with Salmonella typhimurium (NTP, 1993; Wong, 1988) but produced DNA damage as measured in the Bacillus subtilis rec assay (Kanematsu et al., 1980). A weakly positive response for gene mutations was observed in mouse lymphoma (L5178Y) cells in the presence of microsomal activation (Oberly et al., 1982). DNA damage has also been observed in assays using rat and mouse embryo fibroblasts (Zasukhina et al., 1983), CHO cells and human KB cells (Cantoni and Costa, 1983; Cantoni et al., 1982, 1984a,b; Christie et al., 1984, 1986; NTP, 1993; Williams et al., 1987). Mercuric chloride also produced chromosome aberrations and SCEs in CHO cells (Howard et al., 1991) and chromosome aberrations in human lymphocytes (Morimoto et al., 1982). Sex-linked recessive lethal mutations were not observed in male Drosophila melanogaster (NTP, 1993). Although mice given intraperitoneal doses of mercuric chloride have shown no increase in chromosomal aberrations in bone marrow cells (Poma et al., 1981) and no increase in aneuploidy in spermatogonia (Jagiello and Lin, 1973), mercuric chloride administered to mice by gavage induced a dose-related increase in chromosome aberrations and aberrant cells in the bone marrow (Ghosh et al., 1991). Similarly, an increased incidence of chromosomal aberrations (primarily deletion and numeric aberrations) was observed in livers of fetal mice exposed to mercury in utero as the result of maternal inhalation of aerosols of mercuric chloride (Selypes et al., 1984). Positive dominant lethal results (increased resorptions and post-implantation deaths in untreated females) have been obtained in studies in which male rats were administered mercuric chloride orally (Zasukhina et al., 1983). A slight increase in post-implantation deaths and a decrease in living embryos were also reported in treated female mice mated to untreated males (Suter, 1975); however, it was not clear whether these effects were the result of germ cell mutations or were secondary to maternal toxicity. The effects of mercuric chloride on genetic material has been suggested to be due to the ability of mercury to inhibit the formation of the mitotic spindle, an event known as c-mitosis (U.S. EPA, 1985). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE None. The incidences of squamous cell papillomas of the forestomach and thyroid follicular cell carcinomas were evaluated. No slope factor was derived using the forestomach tumors because these tumors are probably the result of doses of mercuric chloride above-MTD resulting in irritation of the forestomach and subsequent cell death and epithelial proliferation. The carcinogenic mechanism for mercuric chloride at the high doses observed may be specific to effects of irritation of the forestomach. Regarding the thyroid carcinomas, a variety of drugs, chemicals and physiological perturbations result in the development of thyroid follicular tumors in rodents. For a number of chemicals, the mechanism of tumor development appears to be a secondary effect of long-standing hypersecretion of thyroid-stimulating hormone by the pituitary (Capen and Martin, 1989; McClain, 1989). In the absence of such long-term stimulatory effects, induction of thyroid follicular cell cancer by such chemicals usually does not occur (Hill, 1989). The mechanism whereby thyroid tumors developed in the NTP (1993) assay is very unclear given that hyperplasia was not observed. The study reviewers concluded that it was difficult to associate the increase in thyroid tumors with mercuric chloride administration. Thus, it would be of questionable value to use the thyroid tumors in rats as the basis for a quantitative cancer risk estimate for humans. All tumors in rats were observed at doses equalling or exceeding the MTD. Kidney tumors in mice were observed in only the high-dose males. The increased incidence was not statistically significant in comparison to the concurrent controls, but was significant when compared with historical controls. A linear low-dose extrapolation based on the male mouse kidney tumor data (three tumors in the high-dose group only) is not appropriate. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE None. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 1995 This IRIS summary is included in The Mercury Study Report to Congress which was reviewed by OHEA and EPA's Mercury Work Group in November 1994. An interagency review by scientists from other federal agencies took place in January 1995. The report was also reviewed by a panel of non-federal external scientists in January 1995 who met in a public meeting on January 25-26. All reviewers comments have been carefully evaluated and considered in the revision and finalization of this IRIS summary. A record of these comments is summarized in the IRIS documentation files. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Work Group Review -- 03/03/1994 Verification Date -- 03/03/1994 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Mercuric chloride (HgCl2) conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX) or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDSO: 199505 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Mercuric chloride (HgCl2) CASRN -- 7487-94-7 Last Revised -- 05/01/1995 SORD: __VI.A. ORAL RfD REFERENCES Andres, P. 1984. IgA-IgG disease in the intestine of Brown Norway rats ingesting mercuric chloride. Clin. Immunol. Immunopathol. 30: 488-494. Bernaudin, J.F., E. Druet, P. Druet and R. Masse. 1981. Inhalation or ingestion of organic or inorganic mercurials produces auto-immune disease in rats. Clin. Immunol. Immunopathol. 20: 129-135. Druet, P., E. Druet, F. Potdevin and C. Sapin. 1978. Immune type glomerulonephritis induced by HgCl2 in the Brown Norway rat. Ann. Immunol. 129C: 777-792. Fitzhugh, O.G., A.A. Nelson, E.P. Laug and F.M. Kunze. 1950. Chronic oral toxicants of mercuric-phenyl and mercuric salts. Arch. Ind. Hyg. Occup. Med. 2: 433-442. Gale, T.F. 1974. Embryopathic effects of different routes of administration of mercuric acetate in the hamster. Environ. Res. 8: 207-213. Gale, T.F. 1981. The embryotoxic response produced by inorganic mercury in different strains of hamsters. Environ. Res. 24: 152-161. Gale, T. and V. Ferm. 1971. Embryopathic effects of mercuric salts. Life Sci. 10(2): 1341-1347. Kazantzis, G., K.F.R. Schiller, A.W. Asscher and R.G. Drew. 1962. Albuminuria and the nephrotic syndrome following exposure to mercury and its compounds. Q. J. Med. 31(124): 403-419. Lee, I.D. and R.L. Dixon. 1975. Effects of mercury on spermatogenesis studied by velocity sedimentation, cell separation and serial mating. J. Pharmacol. Exp. Ther. 194(1): 171-181. NTP (National Toxicology Program). 1993. Toxicology and carcinogenesis studies of mercuric chloride (CAS No. 7487-94-7) in F344 rats and B3C3F1 mice (gavage studies). NTP Technical Report Series No. 408. National Toxicology Program, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC. Suter, K.E. 1975. Studies on the dominant lethal and fertility effects of the heavy metal compounds methyl mercuric hydroxide, mercuric chloride, and cadmium chloride in male and female mice. Mutat. Res. 30: 365-374. U.S. EPA. 1987. Peer Review Workshop on Mercury Issues. Environmental Criteria and Assessment Office, Cincinnati, OH. Summary report. October 26-27. U.S. EPA. 1988. Drinking Water Criteria Document for Inorganic Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA/600/X-84/178. NTIS PB89-192207. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Cantoni, O. and M. Costa. 1983. Correlations of DNA strand breaks and their repair with cell survival following acute exposure to mercury (II) and X-rays. Mol. Pharmacol. 24(1): 84-89. Cantoni, O., R.M. Evans and M. Costa. 1982. Similarity in the acute cytotoxic response of mammalian cells to mercury (II) and X-rays: DNA damage and glutathione depletion. Biochem. Biophys. Res. Commun. 108(2): 614-619. Cantoni, O., N.T. Christie, A. Swann, D.B. Drath and M. Costa. 1984a. Mechanism of HgCl2 cytotoxicity in cultured mammalian cells. Mol. Pharmacol. 26: 360-368. Cantoni, O., N.T. Christie, S.H. Robinson and M. Costa. 1984b. Characterization of DNA lesions produced by HgCl2 in cell culture systems. Chem. Biol. Interact. 49: 209-224. Capen, C.C. and S.L. Martin. 1989. The effects of xenobiotics on the structure and function of thyroid follicular and C-cells. Toxicol. Pathol. 17(2): 266-293. Christie, N.T., O. Cantoni, R.M. Evans, R.E. Meyn and M. Costa. 1984. Use of mammalian DNA repair-deficient mutants to assess the effects of toxic metal compounds on DNA. Biochem. Pharmacol. 33(10): 1661-1670. Christie, N.T., O. Cantoni, M. Sugiyama, F. Cattabeni and M. Costa. 1986. Differences in the effects of Hg(II) on DNA repair induced in Chinese hamster ovary cells by ultraviolet or X-rays. Mol. Pharmacol. 29: 173-178. Fitzhugh, O.G., A.A. Nelson, E.P. Lauge and F.M. Kunze. 1950. Chronic oral toxicities of mercuric-phenyl and mercuric salts. Arch. Ind. Hyg. Occup. Med. 2: 433-442. Ghosh, A.K., S. Sen, A. Sharma and G. Talukder. 1991. Effect of chlorophyllin on mercuric chloride-induced clastogenicity in mice. Food. Chem. Toxicol. 29(11): 777-779. Hill, R.N., L.S. Erdreich, O.V. Paynter, P.A. Roberts, S.L. Rosenthal and C.F. Wilkinson. 1989. Review. Thyroid follicular cell carcinogenesis. Fund. Appl. Toxicol. 12: 629-697. Hirano, M., K. Mitsumori, K. Maita and Y. Shiraso. 1986. Further carcinogenicity study on methylmercury chloride in ICR mice. Jap. J. Vet. Sci. 48(1): 127-135. Howard, W., B. Leonard, W. Moody and T.S. Kochhar. 1991. Induction of chromosome changes by metal compounds in cultured CHO cells. Toxicol. Lett. 56(1-2): 179-186. Jagiello, G. and J.S. Lin. 1973. An assessment of the effects of mercury on the meiosis of mouse ova. Mutat. Res. 17: 93-99. Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagencity studies on metal compounds. Mutat. Res. 77: 109-116. McClain, R.M. 1989. The significance of hepatic microsomal enzyme induction and altered thyroid function in rats: Implications for thyroid gland neoplasia. Toxicol. Pathol. 17(2): 294-306. Mitsumori, K., K. Maita, T. Saito, S. Tsuda and Y. Shirasu. 1981. Carcinogenicity of methylmercury chloride in ICR mice: Preliminary note on renal carcinogenesis. Cancer Lett. 12: 305-310. Mitsumori, K., M. Hirano, H. Ueda, K. Maita and Y. Shirasu. 1990. Chronic toxicity and carcinogenicity of methylmercury chloride in B6C3F1 mice. Fund. Appl. Toxicol. 14: 179-190. Morimoto, K., S. Iijima and A. Koizumi. 1982. Selenite prevents the induction of sister-chromatid exchanges by methyl mercury and mercuric chloride in human whole-blood cultures. Mutat. Res. 102: 183-192. NTP (National Toxicology Program). 1993. NTP technical report on the toxicology and carcinogenesis studies of mercuric chloride (CAS No. 7487-94-7) in F344 rats and B6C3F1 mice (gavage studies). NTP TR 408. National Toxicology Program, U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC. Oberly, T.J., C.E. Piper and D.S. McDonald. 1982. Mutagenicity of metal salts in the L5178Y mouse lymphoma assay. J. Toxicol. Environ. Health. 9: 367-376. Poma, K., M. Kirsch-Volders and C. Susanne. 1981. Mutagenicity study of mice given mercuric chloride. J. Appl. Toxicol. 1(6): 314-316. Rice, G. and L. Knauf. 1994. Further Statistical Evaluation of the NTP Mercuric Chloride Mouse Bioassay. Memorandum to the U.S. EPA CRAVE File for Mercuric Chloride, March 1. Schroeder, H. and M. Mitchener. 1975. Life-time effects of mercury, methyl mercury, and nine other trace metals in mice. J. Nutr. 105: 452-458. Selypes, A., L. Nagymajtenyi and G. Berencsi. 1984. Study of the mutagenic and teratogenic effect of aerogenic mercury exposition in mouse. Collect. Med. Leg. Toxicol. Med. 125: 65-69. Suter, K.E. 1975. Studies on the dominant-lethal and fertility effects of the heavy metal compounds methylmercuric hydroxide, mercuric chloride and cadmium chloride in male and female mice. Mutat. Res. 30: 365-374. U.S. EPA. 1980. Ambient Water Quality Criteria Document for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Water Regulation and Standards, Washington, DC. EPA/440/5-80/058. NTIS PB 81-117699. U.S. EPA. 1984a. Mercury Health Effects Update: Health Issue Assessment. Final Report. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA/600/8-84/019F. NTIS PB81-85-123925. U.S. EPA. 1984b. Health Effects Assessment for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. EPA/540/1086/042. NTIS PB86-134533/AS. U.S. EPA. 1985. Drinking Water Criteria Document for Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA/600/X-84/178. NTIS PB86-117827. U.S. EPA. 1988. Drinking Water Criteria Document for Inorganic Mercury. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA/600/X-84/178. NTIS PB89-192207. U.S. EPA. 1993. Summary Review of Health Effects Associated with Mercuric Chloride: Health Issue Assessment (Draft). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Air Quality Planning and Standards, Research Triangle Park, NC. EPA/600/R-92/199. U.S. EPA. 1995. Mercury Study Report to Congress. Office of Research and Development, Washington, DC. External Review Draft. EPA/600/P-94/002Ab. Williams, M.V., T. Winters and K.S. Waddel. 1987. In vivo effects of mercury (II) on deoxyuridine triphosphate nucleotidohydrolase, DNA polymerase (alpha, beta) and uracil-DNA glycosylase activities in cultured human cells: Relationship to DNA damage, DNA repair, and cytotoxicity. Mol. Pharmacol. 31: 200-207. Wong, P.K. 1988. Mutagenicity of heavy metals. Bull. Environ. Contam. Toxicol. 40(4): 597-603. Zasukhina, G.D., I.M. Vasilyeva, N.I. Sdirkova, G.N. Krasovsky, L.Y. Vasyukovich, U.I. Kenesariev and P.G. Butenko. 1983. Mutagenic effect of thallium and mercury salts on rodent cells with different repair activities. Mutat. Res. 124: 163-173. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Mercuric chloride (HgCl2) CASRN -- 7487-94-7 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 04/01/1994 I.B. Inhalation RfC noted as under review on 03/22/1990 04/01/1994 II. Carcinogenicity assessment now under review 05/01/1995 I.A. Oral RfD summary on-line 05/01/1995 II. Carcinogenicity assessment summary on-line 05/01/1995 VI. Bibliography on-line 06/01/1995 II.B. Text revised; first paragraph 08/01/1995 I.B. EPA's RfD/RfC and CRAVE workgroups were discontinued in May, 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 12/03/2002 I.A.6., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 441 of 1119 in IRIS (through 2003/06) AN: 1000 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/1000-tr.pdf UD: 199803 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Methyl-Methacrylate- SY: METHACRYLIC-ACID,-METHYL-ESTER-; METHACRYLATE-MONOMER-; METHYL-A-METHYLACRYLATE-; METHYL-2-METHYL-2-PROPENOATE- RN: 80-62-6 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 199803 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Methyl Methacrylate CASRN -- 80-62-6 Last Revised -- 03/02/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Dose UF MF RfD ------------------- ---------- ----- ---- -------- None NOAEL:136 100 1 1.4 mg/kg/day mg/kg/day Rat drinking water study Borzelleca et al. (1964) ------------------------------------------------------------------------ PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) Borzelleca, JF; Larson, PS; Hennigar, GR, Jr; Huf, EG; Crawford, EM; Smith, RB, Jr., (1964) Studies on the chronic oral toxicity of monomeric ethyl acrylate and methyl methacrylate. Toxicol. Appl. Pharmacol. 6:29-36. Borzelleca et al. (1964) exposed groups of 25 male and 25 female Wistar rats to MMA in drinking water continuously for 104 weeks. The initial exposure concentrations were 6, 60, and 2,000 ppm MMA. The low and medium exposures were increased to 7 and 70 ppm, respectively, at the start of the fifth month, resulting in TWA exposure concentrations of 6.85 and 68.46 ppm MMA. Survival of exposed rats was not significantly different from controls. An initial reduction in body weight gain was observed in both males and females exposed to 2,000 ppm MMA; this reverted to control levels by week 3 (females) and week 6 (males). This is likely the result of reported reduced food intake during the first month, which was not observed in the second month and beyond. No other effects on body weight gain were reported, but drinking water consumption was significantly lower than controls in males and particularly females of the high-exposure groups. Hematological parameters were normal throughout the study in all groups, and no compound-related effects were observed on urinary protein or reducing substances. No abnormalities or lesions related to MMA were identified from histopathological examination of the tissues of exposed rats. The only effect observed was an increased kidney/body-weight ratio in female rats exposed to 2,000 ppm MMA, but the increase was only marginally significant and was not associated with any histopathological findings. Thus, the highest exposure level, 136 mg/kg/day (2,000 mg/L x 0.0313 L/rat/day divided by the default body weight for Wistar rats of 0.462 kg), is considered a NOAEL for this study. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF -- 100. The following uncertainty factors are applied to this effect level: 10 for consideration of intraspecies variation (UFH; human variability), a partial uncertainty factor of 3 for extrapolation for interspecies differences (UFA; animal to human), and an uncertainty factor of 3 to account for a deficient database (UFD). The total UF = 10 x 3 x 3 = 100. A full uncertainty factor for intraspecies differences (UFH) was used to account for potentially sensitive human subpopulations. This UF was not reduced because of the lack of human oral exposure information. A partial threefold uncertainty factor to account for laboratory animal-to-human interspecies differences (UFA) was used. The slower blood metabolism of MMA in humans (Bereznowski, 1995), combined with the fact that humans do not have a forestomach (target organ in the Borzelleca et al., 1964 study) lowers the potential for a more pronounced portal-of-entry effect in humans. However, complete elimination of this UF is not justified, given the lack of human oral exposure information and remaining uncertainty regarding MMA's potential to cause other effects in humans following chronic oral exposure. The major areas of uncertainty in this assessment are the lack of an identified critical effect to humans, the lack of a chronic study in a second species, the lack of a neurologic study, and the lack of a developmental or reproductive toxicity study via the oral route (given that developmental effects have been seen in laboratory animals following other routes of exposure). A partial three-fold database uncertainty factor (UFD) was employed, however, because a number of repeat exposure inhalation studies, including developmental, reproductive, and chronic studies, lend support to the oral database. MF -- 1. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) There are three repeat exposure studies that were of long enough duration to be considered for use in the derivation of an oral RfD: the Motoc et al. (1971) rat study, the Borzelleca et al. (1964) rat study, and the Borzelleca et al. (1964) dog study. Of the three, only the Borzolleca et al. (1964) drinking water study in rats was of chronic duration (2 years). Motoc et al. (1971) was a subchronic gavage study, and the assessment of dogs by Borzelleca et al. (1964) involved the administration of MMA in gelatin capsules. The Motoc et al. (1971) gavage study showed that large bolus doses can overwhelm detoxification mechanisms and cause stomach ulcerations in rats. Thus, the less-than-chronic gavage studies of Motoc et al. (1971) and Borzelleca et al. (1964) were considered less desirable for use in the derivation of an RfD than the chronic drinking water study in rats of Borzelleca et al. (1964). Borzelleca et al. (1964) reported an increase in kidney-to-body ratios for female rats, but it was only marginally significant and was not associated with any histopathological findings. The fact that MMA was not reported to cause gastric toxicity in this study is not in and of itself a reason to doubt the results of the study. Substitution on the number 2 carbon of acrylic acid has been shown in gavage studies to abolish gastric toxicity (Ghanayem et al., 1985) and cell proliferation (Ghanayem et al., 1986). Borzelleca et al. (1964) found no significant toxic effects in male and female dogs (2 males and 2 females per treatment group) receiving MMA via gelatin capsule in the diet at 10, 100, or 1,473 ppm daily for 1 year. The high exposure concentration represented a time-weighted average based on the 1,000 ppm value, increasing to 1,200 ppm at 5 weeks, to 1,400 ppm at 7 weeks, and to 1,500 ppm at 9 weeks. Motoc et al. (1971) orally administered methyl methacrylate to albino rats for 3 (20 exposures), 5 (41 exposures), or 8 (63 exposures) months. Total doses were reported as 2,750, 5,500, and 8,125 mg/kg, respectively, for these exposure periods. The authors reported duration-related increases in histopathological alterations of the liver, ulcerations of the stomach, and biochemical alterations (elevated serum enzyme activity), but no further details were described. The LD50 for MMA was estimated to be 8.41-10 mL/kg (7.87-9.36 g/kg) in rats, 6.3 mL/kg (5.9 g/kg) in guinea pigs, and 5 (4.68 g/kg) in dogs (Deichmann, 1941; Spealman et al., 1945). The lowest lethal concentration in rabbits administered MMA by gavage was 6.55 g/kg body weight. Toxic symptoms in both species included increased respiratory rate and motor weakness. These were followed by decreased respiration at 15 to 40 minutes post-administration, shallow and irregular respiration, increased urination and defecation, hemoglobinuria, loss of reflex activity, coma, and death. Adverse intestinal changes were observed in orally exposed animals. Central nervous system effects were observed in Wistar rats given 500 mg/kg body weight/day MMA in olive oil by gavage for 21 days (Husain et al., 1985; Husain et al., 1989). Treated rats were observed to be lethargic and had gait defects and hind limb weakness for about 10 min after each treatment. Locomotor activity and learning ability were significantly decreased and aggressive behavior was significantly increased in exposed rats compared to controls. No oral studies have investigated the developmental or reproductive toxicity of MMA. Evidence for developmental effects from inhalation exposure is mixed and generally occurred at maternally toxic exposure levels. Solomon et al. (1993) found no developmental effects in rats exposed 6 h/day during days 6-15 of gestation to atmospheric concentrations of up to 2,028 ppm (8,304 mg/m3). Tansy (1979) and McLaughlin et al. (1978) found no developmental effects in mice exposed 6 h/day to up to 400 ppm and 2 h/day to 1,330 ppm, respectively, during days 6-15 of gestation. However, Nicholas et al. (1979) found evidence of developmental effects (early fetal deaths, delayed ossification, decreased fetal body weight and crown-rump length, hematomas) in Sprague-Dawley rats exposed for approximately 1 h/day during days 6-15 of gestation to levels more than an order of magnitude higher (110,000 mg/m3). Nearly 20% of the exposed pregnant rats died at this exposure level. In addition, ICI (1977) and Luo et al. (1986) describe both delayed ossification and increased resorptions in rats exposed during days 6-15 of gestation to 1,000 ppm MMA (5 h/day and 2 h/3 days, respectively). No adequate one- or two-generation reproductive studies were available by any route of exposure. MMA did not reveal an effect on male fertility in mice inhaling up to 9,000 ppm MMA for 6 h/day over a period of 5 days. MMA is readily absorbed through the lungs, gastrointestinal tract, and skin. The experiments of Bratt and Hathway (1977) show that MMA is rapidly absorbed from the gastrointestinal tract of rats. Adult male Wistar rats were treated with 5.7 mg/kg 14C-MMA by gavage. Up to 65% of the dose was expired from the lungs in 2 h, which shows the rapidity of the absorption. Recovery of radiolabel in the urine and feces accounted for only 7.4% of the administered dose, thereby indicating nearly complete absorption from the gastrointestinal tract. In addition, significant levels of methacrylic acid (> 0.5mM), a product of MMA degradation, were found in rat serum 5 min after a single dose of 8 mmol MMA/kg body weight (Bereznowski, 1995). The only studies that provide definitive information regarding the distribution of MMA in a mammalian system following inhalation, oral, or intravenous exposures are those of Raje et al. (1985), Bratt and Hathway (1977), and Wenzel et al. (1973). Once absorbed, MMA is largely metabolized to methacrylic acid and eventually to CO2 via the TCA cycle. In the experiments of Bratt and Hathway (1977), it was found that 10 days after oral or i.v. dosing of rats with 14C-MMA, only 4.1%-6.6% 14C-MMA remained in the carcass. That which is not metabolized to CO2 and exhaled or excreted in the urine or feces is primarily retained in the liver and adipose tissue, though Raje et al. (1985) report finding small amounts of MMA in the brain and lungs following acute exposures. Metabolism of MMA has been studied in vitro (Corkill et al., 1976; Bereznowski, 1995) and oral in vivo (Bratt and Hathway, 1977; Crout et al., 1982) in both rodents and humans. Several studies have confirmed the initial hydrolysis of MMA to methacrylic acid and methanol, and one in vitro study (Bereznowski, 1995) indicates that the rate of hydrolysis is slower in human than in rat blood. Available evidence suggests that MMA is enzymatically converted to methacrylic acid and is esterified to CoA, which is hydroxylated to -hydroxyisobutyric acid, oxidized and esterified by CoA to methylmalonyl CoA, and enters the citric acid cycle as succinyl CoA. Methacrylic acid, methyl malonic acid, ethyl malonic acid, b-hydroxyisobutyric acid, and mercapturic acid have been identified as urinary metabolites of the rat (Bratt and Hathway, 1977; Crout et al., 1982), and methyl malonic acid has been shown to be a urinary metabolite of humans (Crout et al., 1982). Most of an orally or parenterally administered dose of 14C-labeled MMA is excreted as CO2 (Bratt and Hathway, 1977; Crout et al., 1982). Wistar rats given MMA orally, intraperitoneally, or intravenously exhaled 65%-86% of the administered radiolabel as CO2 within 10 h of dosing. After 10 days, 88% and 84% of 5.7 mg/kg doses given orally and intravenously, respectively, were excreted as 14CO2. An estimated 0.19%-1.4% of the administered dose was excreted by the lungs as unmetabolized MMA. The percent excreted as CO2 decreased and the percent exhaled as unchanged MMA increased with increasing dose regardless of route (Bratt and Hathway, 1977). Urinary excretion accounted for about 4.7%-14.5% of the administered radioactivity (Bratt and Hathway, 1977; Crout et al., 1982), with about 0.22% of the radioactivity in the methylmalonic acid fraction (Crout et al., 1982). Other metabolites detected in the urine following oral or intravenous dosing with radiolabeled MMA include methacrylic acid, succinic acid, methylmalonic semialdehyde, -hydroxyisobutyric acid, and an unidentified 14C-labeled acid. An estimated 1.7%-3% was excreted in feces following intragastric or intravenous administration (Bratt and Hathway, 1977). Methylmalonic acid was also detected in the urine of a human volunteer administered an 2H-labeled dose of the sodium salt of MMA. 2H-labeled methylmalonic acid was detected in the urine in an amount equal to about 1% of the administered dose (Crout et al., 1982). For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=48. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- Low to medium Data Base -- Low to medium RfD -- Low to medium The overall confidence in the RfD assessment is low to medium. The confidence in the principal study is low to medium. The Borzelleca (1964) study is well documented, but does not appear to be conducted in accordance with what would now be considered Good Laboratory Practice and did not identify a LOAEL. Confidence in the database is judged to be low to medium. Relevant, quantitative human subchronic or chronic studies are not available. Although repeat exposure inhalation studies, including developmental, reproductive, and chronic studies, bolster the weak and dated oral database somewhat, no developmental or reproductive studies are available by the oral route, and no multigenerational studies are available by any route of exposure. Gastrointestinal irritation has been identified in a rat subchronic gavage study (Motoc et al., 1971), but acute exposures to humans via the oral route are rare. Irritation is still considered the most likely effect of concern from oral exposure to humans, however, primarily because of extensive evidence from occupational studies and case reports that MMA is a respiratory irritant in humans. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=53. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- This assessment is presented in the Toxicological Review of Methyl Methacrylate. (CAS No. 80-62-6). (EPA, 1998) U. S. Environmental Protection Agency. (1985) Health and environmental effects profile for methyl methacrylate. Cincinnati, OH: Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office; report no. EPA/600/X-85/364. Available from: NTIS, Springfield, VA; PB88-17885/XAB. U.S. Environmental Protection Agency. (1988) Health and environmental effects profile for methyl methacrylate. NTIS/PB88-178785. U.S. Environmental Protection Agency. (1991) Summary review of health effects associated with methyl methacrylate: health issue assessment. Environmental Criteria and Assessment Office, Research Triangle Park, NC; ECAO-R-092A. Other EPA Documentation -- U.S. EPA, 1987 Date of Agency Consensus -- 11/25/1997 To review the Summary of and Response to External Peer Review comments, exit to the toxicological review, Appendix B http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=71. Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Methyl methacrylate conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (513-569-7159 (FAX), or Hotline.IRIS@epa.gov (internet address). ---------------------------------------------------------------------------- UDRC: 199803 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Methyl Methacrylate CASRN -- 80-62-6 Last Revised -- 03/02/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Critical Effect Exposures* UF MF RfC ------------------------------ --------------- ----- ----- ---- Degeneration/atrophy BMC10: 35 ppm 10 1 7 E-1 of olfactory epithelium BMC10(ADJ): mg/m3 (male rats) 25.6 mg/m3 BMC10(HEC): 7.2 Rat chronic inhalation study mg/m3 Hazelton Laboratories 1979a; Lomax, 1992; Lomax et al., 1997 ---------------------------------------------------------------------------- *Conversion Factors and Assumptions -- The concentration associated with a 10% increased incidence (or extra risk) in the critical effect was determined using two dose-response functions. The 95% confidence limit on the concentration causing this benchmark response (BMC10) was estimated to be 35 ppm (polynomial regression model). Assuming 25 oC and 760 mmHg and a molecular weight of 100.11, BMC10 (mg/m3) = 35 ppm x 100.11/24.45 = 143 mg/m3. BMC10(ADJ) = 143 mg/m3 x 6 h/24 h/day x 5 days/7 days = 25.6 mg/m3. The BMC10(HEC) was calculated for a gas:respiratory effect in the extrathoracic region. MVa = 0.25 L/min, MVh = 13.8 L/min, Sa(ET) = 11.6 cm2, Sh(ET) = 177 cm2. RGDR = (MVa/Sa)/(MVh/Sh) = 0.28. BMC(HEC) = 25.6 x RGDR = 7.2 mg/m3. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) Hazelton Laboratories America, Inc. (1979a). A two-year vapor inhalation safety evaluation study in rats: methyl methacrylate, final report. Vienna, VA: Hazleton Laboratories America, Inc.; project no. 417-354. Lomax, LG. (1992) Histopathologic evaluation of the nasal cavities from Fisher 344 rats exposed to methyl methacrylate vapor for two years. Spring House, PA: Rohm and Haas Company. Lomax, LG; Krivanek, N; Frame, SR. (1997) Chronic inhalation toxicity and oncogenicity of methyl methacrylate in rats and hamsters. Food Chem Toxicol 35:393-407. F344 rats (70 of each sex per group) were exposed to mean concentrations of 0, 25, 99.79, or 396.07 ppm (0, 102.4, 408.6, 1,621.7 mg/m3) for 6 h/day, 5 days/week (duration adjusted to 0, 18.3, 73, 289.6 mg/m3) for 2 years (Hazelton Laboratories 1979a). No consistent trend with exposure was revealed, but microscopic examination of nasal tissues revealed minimal to slight focal rhinitis in 4/10 females exposed to 396.07 ppm (compared with 1 male and 1 female in the control group), and an inflammatory exudate was observed in 3 of the 4 exposed females. At 52 weeks, livers of 9/10 males and 6/10 females exposed to 396.07 ppm showed minimal nonsuppurative pericholangitis (compared with 5/10 control males and 2/10 control females). An increased incidence in lesions of mild rhinitis was observed in the nasal turbinates of exposed animals at week 104. These consisted of serous and purulent exudates, pleocellular infiltrates, distended submucosal glands, focal squamous metaplasia, and inflammatory polyps. Because the increased incidence was found in all exposure groups and did not appear to be concentration-dependent, these lesions may not have been treatment-related. At the request of EPA, the U.S. Methacrylate Producers Association (MPA) commissioned a reexamination of the nasal tissue block and a rereview of the histopathology of the rat nasal tissues from the Hazelton (1979a) study (Lomax, 1992; Lomax et al., 1995). This reevaluation was requested because the initial study did not involve examination of the nasal tissues of the low- and mid-exposure groups. In addition, because of MMA's propensity to cause effects in the olfactory epithelium as demonstrated in other studies (NTP, 1986), this reanalysis included examination of nasal tissue blocks in accordance with contemporary techniques with prescribed levels of sectioning. This reanalysis confirmed that chronic exposure to MMA does not appear to effect squamous epithelium at any exposure level. Effects in the respiratory epithelium were observed primarily at the 400 ppm exposure level, and were described as hyperplasia of submucosal glands and/or goblet cells in the anterior regions of the nasal cavity, especially around the dorsal meati and along the nasal septa. Inflammation of the mucosa and /or submucosa was also observed. Changes to respiratory epithelium were bilateral and slight to moderate in severity. Rats exposed to 100 or 400 ppm MMA had concentration-dependent histopathological changes to the olfactory portion of the dorsal meatus in the anterior portions of the nasal cavity. Microscopic changes were primarily observed in the olfactory region lining the dorsal meatus in the anterior region of the nasal cavity. These changes were characterized by degeneration and atrophy of the neurogenic epithelium and submucosal glands lining the dorsal meatus, basal cell hypoplasia, replacement of olfactory epithelium with ciliate (respiratory-like) epithelium, and inflammation of mucosa and submucosa. These changes were generally bilateral in distribution and the severity of the lesions varied from minimal to slight at 100 ppm to slight to moderate at 400 ppm. One male rat from the 400 ppm exposure group showed severe olfactory degenerative effects (Lomax, 1992). One male rat from each of the 100 and 400 ppm exposure groups had a small solitary polypoid mass attached to the lateral wall of one side of the anterior nasal cavity. These masses were morphologically similar, consisting of differentiated pseudoglandular structures arising from the respiratory epithelium, and were diagnosed as polypoid adenomas. The male rat from the 100 ppm group with the adenoma had concurrent moderate chronic inflammation of the nearby respiratory epithelium. Two male rats exposed to 400 ppm MMA had squamous metaplasia of the respiratory epithelium in the anterior region of the nasal cavity. The hydrolysis of MMA by carboxylesterase enzymes and subsequent release of methacrylic acid in the olfactory tissue (Morris and Frederick, 1995) is likely the cause of the cytotoxicity in the olfactory region. Though it has been suggested that MMA metabolism is a detoxifying mechanism following oral exposure (Bereznowski, 1995), the metabolite, methacrylic acid, appears to be the toxic moiety in the olfactory tissues (Morris and Frederick, 1995; Lomax et al., 1995). In support of this assumption, the localization and activity of the metabolic enzyme, carboxylesterase, correlates quite well with the localization and severity of nasal lesions in rodents following MMA exposure (i.e., both occur predominantly in the olfactory epithelium and not respiratory epithelium) (Dahl et al., 1987; Bogdanffy et al., 1987; Bogdanffy, 1990; Frederick et al., 1994). Further, similar toxicity from compounds that metabolize to acids via the same metabolic route has been seen with ethyl acrylate (Miller et al., 1985), methyl and butyl acrylate (Klimisch, 1984), dibasic esters (Keenan et al., 1990), and glycol ether acetates (Miller et al., 1984), and exposures to acrylic and acetic acids directly have also caused similar olfactory- specific lesions (Miller et al., 1981; Stott and McKenna, 1985). A polynomial mean response regression model (THRESH, I.C.F. Kaiser, 1990a) and a Weibull power mean response regression model (THRESHW, I.C.F. Kaiser, 1990b) were used to fit data from Lomax (1992) and Lomax et al. (1995) by the maximum likelihood method. These models were developed for use with dichotomous (incidence) data, and can either calculate a response threshold (for circumstances in which it is appropriate to presume the existence of an exposure level below which there is no response) or assign a threshold of zero (for circumstances in which it is appropriate to presume that all exposure levels emit a response). Because the mechanism for MMA olfactory toxicity is not well understood, the conservative model assumption of no threshold was employed. These models also provide the option of assuming a zero or nonzero background response. The only effect noted in control animals was minimal basal cell hyperplasia (5/39 control animals). For the purpose of calculating a BMC, it appears reasonable to assume a zero background for slight, moderate, and severe olfactory lesions. Minimal lesions were excluded from the BMC analysis and a zero background was assumed. Using these criteria, the two models were applied to incidence data reported by Lomax (1992) and Lomax et al. (1995) for observed olfactory lesions in male and female rats. Data for degeneration/atrophy of olfactory epithelium in males (0/39, 0/47, 35/48, and 38/38) were chosen for the derivation of the RfC because the concentration-response curves generated by both THRESH and THRESHW models were similar and of reasonable goodness of fit (p values = 0.616 and 0.768, respectively), and the resultant BMC values were lower than the BMCs for replacement by ciliated epithelium, the only other endpoint for which good model fit could be reached. An EPA review of benchmark analysis performed for several upper respiratory toxicants indicates that both the BMC values for the 5% and the 10% benchmark response (BMR) levels for a given endpoint generally fall between the NOAEL and the LOAEL for that endpoint (Gift, 1996). The benchmark response (BMR) chosen for use in the RfC derivation was a 10% increase in the incidence of a slight, moderate, or severe lesion. The 10% response level was chosen because of its closer proximity to the actual experimental data and because of the overall mild severity of the effect. The RfC is based on the BMC10, which is the lower 95% confidence bound on the maximum likelihood estimate (MLE) of the concentration that causes a 10% increased incidence of this lesion. The two model predictions for the BMC10 from degeneration/atrophy of male rat olfactory epithelium were virtually identical, 39 (Weibull) and 35 (polynomial) ppm. The 35 ppm (143 mg/m3) value was chosen for use in the RfC calculation because it results in a slightly more environmentally protective RfC. This value is slightly above the 25 ppm NOAEL and well below the 100 ppm LOAEL for degeneration/atrophy and inflammation. Details of the BMC10 derivation for this data set (model used, input assumptions, etc.) are provided in the IRIS support document for this compound. When the BMC10(mg/ m3) is derived from a study in which laboratory animals are exposed intermittently (e.g., 6 h/day, 5 days/week), an adjustment is usually applied to account for the fact that the RfC is to protect against the worst-case scenario, continuous exposures. However, the EPA guidelines (EPA, 1994) recognize that, depending on the mechanism of action, such duration adjustment may not always be appropriate. In the case of acrylic acid, a compound that causes similar olfactory damage, there is information to suggest that a limited C x T relationship of exposure to toxic effects is operative over the course of at least the first 2 weeks of exposure at concentrations that cause minimal to moderate, reversible (if exposure is discontinued) olfactory effects (Lomax et al., 1994). The lack of lesions in rats after 28 days of exposure to 100 ppm MMA (Green, 1996), combined with the presence of lesions in rats following chronic (2-year) exposure to 100 ppm MMA (Lomax et al., 1997), suggests that these effects can progress with increased exposure duration. Thus, it is reasonable to suggest that continuous exposure to MMA could result in effects at concentrations below the NOAEL of an intermittent exposure study, and that the application of an adjustment factor to account for this is appropriate. Thus, the BMC10 of 143 mg/m3 is adjusted to a BMC10(ADJ) of 25.6 mg/m3 (143 mg/m3 x 6 h/24 h/day x 5 days/7 days = 25.6 mg/m3). A human equivalent BMC10, BMC10(HEC), of 7.2 mg/m3. is then calculated using default procedures for a gas:respiratory effect in the extrathoracic region [MVa = 0.25 L/min, MVh = 13.8 L/min, Sa(ET) = 11.6 cm2, Sh(ET) = 177 cm2. RGDR = (MVa/Sa)/(MVh/Sh) = 0.28. BMC(HEC) = 25.6 x RGDR = 7.2 mg/m3], appropriate when peer-reviewed PBPK models are not available (US EPA, 1994). UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) UF -- 10. A partial threefold uncertainty factor (UF) is applied to this effect level in consideration of possible intraspecies variation (UFH; to protect sensitive human subpopulations). This UF is reduced from 10 because of extensive human occupational studies and case reports that consistently identify the irritant properties of MMA as the principal effect of concern from MMA inhalation exposures. Little intraspecies variance is observed with respect to the identified critical effect, olfactory degeneration in laboratory animals (ECETOC, 1995; Lomax et al., 1997), and there is no reason to expect a high degree of intrahuman variability from this type of effect. Although Pickering et al. (1986) reported delayed asthmatic response following challenge with MMA, which would suggest that MMA is a possible respiratory sensitizer, no occupational studies identified MMA as a respiratory sensitizer. A partial intraspecies uncertainty factor of 3 is deemed sufficiently protective. Two studies have noted increased resorptions in rats at 1,000 ppm exposures (Luo et al., 1986; ICI, 1977) and one did not (Solomon et al., 1993). However, the latter study was peer reviewed whereas Luo et al. (1986) was an abstract and ICI (1977) was an unpublished industry report. Multigenerational reproductive studies are not available for MMA; however, MMA is so reactive at the portal of entry that the potential for systemic effects is deemed remote. The observation of a portal-of-entry effect is consistent across both the oral and inhalation routes of exposure. Given these considerations, no uncertainty factor is applied to the RfC for database deficiencies. A partial threefold uncertainty factor is used for interspecies extrapolation to account for potential toxicodynamic differences between rats and humans. This concern for potential toxicodynamic differences is warranted given the fact that humans may be less capable of recovering from olfactory damage than rats. "Rapid potentially anatomically correct recovery after massive destruction" is observed in rats when underlying basal cells are not damaged (Youngentob, 1997) and small islands of intact olfactory epithelium are "sufficient to allow for olfactory function" (Wong et al., 1997). In humans, it has been reported that patients with relatively mild to moderate olfactory damage fail to recover olfaction and "...even when basal cells remain intact, differentiating cells developing from them do not mature into receptor cells but can develop into squamous cells..." (Yamagishi and Nakano, 1992). An attempt was made to account for toxicokinetic differences between the rat and human in the derivation of BMC10(HEC). The HEC calculation attempts to account for the morphologic interspecies differences in the species as reflected by the different ratio of normal minute volume to surface area in rats versus humans. While, there remain several differences between rats and human that are not accounted for, most of these differences suggest that rat nasal passages are likely to be affected at lower MMA concentrations than those of humans. Most evidence suggests that the main metabolite of MMA, methacrylic acid, is the toxic moiety of concern (Lomax et al., 1997; Bereznowski, 1995; Morris and Frederick, 1995; ECETOC, 1995). Studies of carboxylesterase metabolic rates suggest that humans metabolize MMA in blood (Bereznowski, 1995) and in olfactory tissue (Mattes and Mattes, 1992; Greene, 1996) at a slower rate than rats, though at a slightly faster rate in the liver (Greene, 1996). In addition, rats are obligate nose breathers, whereas humans can breathe through the mouth during exertion and to avoid overpowering odors. EPA is aware of PBPK models for MMA (developed for the Methacrylate Producers Association by Andersen et al., 1996) and other acrylates (Morris and Frederick, 1995; Bogdanffy and Taylor, 1993) that should eventually help to reduce uncertainty in the quantification of these differences. The use of a PBPK model to update this assessment will be considered when EPA has completed its analysis of these various model approaches. In the meantime, a majority of the dosimetric/toxicokinetic evidence currently available suggests that humans would not be more sensitive than rats on this basis and that further reduction of the BMC10(HEC) to account for interspecies dosimetric/toxicokinetic uncertainty is not necessary. MF -- 1. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) A. SUPPORTING STUDIES The absorption and hydrolysis of MMA to methacrylic acid and subsequent metabolism via physiological pathways results in a low systemic toxicity by any route of exposure. However, 10% to 20% of inhaled MMA is deposited in the upper respiratory tract of rats and the hydrolysis of MMA by local nasal tissue esterases to methacrylic acid in this region has been cited as the primary reason for MMA's selective olfactory toxicity (Lomax, 1992; Lomax et al., 1997). The EPA Toxicological Review for MMA summarizes key subchronic and chronic laboratory animals and human studies of MMA. Subchronic and chronic exposure of rats and mice to MMA by oral and inhalation routes (as well as dermal) results in effects consistent with its irritant properties. In inhalation studies, dose-related lesions have been observed in the upper respiratory tract, including rhinitis, inflammation associated with necrosis, degeneration/loss of olfactory epithelium in the nasal turbinates, and lung congestion. Exposures to very high levels of MMA (>1,000 ppm) can result in neurochemical and behavioral changes, reduced body weight gain, and degenerative and necrotic changes in the liver, kidney, brain, spleen, and bone marrow. Relatively low concentrations can cause changes in liver enzyme activities. The data concerning MMA's ability to cause cardiovascular effects are inconsistent. Several publications in the literature suggest that MMA may have cardiovascular and/or neurotoxic effects in occupationally exposed human beings. These effects may not represent neurotoxicity, as they are generally nonspecific and workers were exposed to several other toxic compounds. In general, MMA has not resulted in serious adverse effects to humans. In certain individuals it has been shown to induce allergic dermatitis from skin contact. Mild eye irritation and respiratory tract irritation have been reported, but the evidence available does not allow for a determination regarding respiratory sensitization. Evidence for developmental effects from inhalation exposure is mixed and generally occurred at maternally toxic exposure levels. Solomon et al. (1993) found no developmental effects in rats exposed 6 h/day during days 6-15 of gestation to atmospheric concentrations of up to 2,028 ppm (8,304 mg/m3). Tansy (1979) and McLaughlin et al. (1978) found no developmental effects in mice exposed 6 h/day to up to 400 ppm and 2 h/day to 1,330 ppm, respectively, during days 6-15 of gestation. However, Nicholas et al. (1979) found evidence of developmental effects (early fetal deaths, delayed ossification, decreased fetal body weight and crown-rump length, hematomas) in Sprague-Dawley rats exposed for approximately 1 h/day during days 6-15 of gestation to levels more than an order of magnitude higher (110,000 mg/m3). However, nearly 20% of the exposed pregnant rats died at this exposure level. In addition, ICI (1977) and Luo et al. (1986) describe both delayed ossification and increased resorptions in rats exposed during days 6-15 of gestation to 1,000 ppm MMA (5 h/day and 2 h/3 days, respectively). No adequate one- or two-generation reproductive studies were available by any route of exposure. MMA did not reveal an effect on male fertility in mice inhaling up to 9,000 ppm MMA for 6 h/day over a period of 5 days (ICI, 1976). These data suggest that at high, maternally toxic doses, MMA can cause developmental effects. However, there is no reason to believe that developmental toxicity should represent a critical or co-critical effect in the RfC or RfD derivation. The lack of adequate reproductive studies is not a major concern given the limited evidence for systemic or genotoxic effects from MMA exposure, but has been considered in the determination of uncertainty factors. For more detail on other Hazard Identification issues, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=48. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC Study -- High Data Base -- Medium to high RfC -- Medium to high The overall confidence in this RfC assessment is medium to high. The RfC is based on a long-term rat inhalation study (Hazelton Laboratories, Inc., 1979a) performed with relatively large group sizes in which, with additional investigations (Lomax, 1992; Lomax et al., 1995), thorough histopathologic analyses were performed on all relevant tissues. What is considered to be the primary target organ, the nasal passage, was particularly well described, and the study was able to identify both a NOAEL and a LOAEL. The scientific quality of the combined Hazelton Laboratories (1979a) and subsequent reanalyses (Lomax, 1992; Lomax et al., 1995) is high. The confidence in the inhalation database available for MMA is rated as medium to high. Acceptable developmental studies were carried out in two species, rats and mice, with effects only observed in offspring at levels more than 10-fold higher than the LOAEL for the chosen critical (olfactory) effect. Multigenerational reproductive studies are not available for MMA. However, protection against the portal-of-entry effects observed at low exposure levels across both the oral and inhalation routes of exposure is deemed likely to also protect against any possible multigenerational reproductive effects. Given these considerations the inhalation database and the RfC are given medium to high confidence. EPA recognizes that PBPK models are under development for MMA (Andersen et al., 1996) and other acrylates (Morris and Frederick, 1995; Bogdanffy and Taylor, 1993). The results of these ongoing investigations are under review by the Agency and are expected to help increase confidence in the estimation of a human equivalent concentration and clarify the different species sensitivities. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=53. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document -- This assessment is presented in the Toxicological Review of Methyl Methacrylate (CAS No. 80-62-6). (EPA, 1998). U. S. Environmental Protection Agency. (1985) Health and environmental effects profile for methyl methacrylate. Cincinnati, OH: Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office; report no. EPA/600/X-85/364. Available from: NTIS, Springfield, VA; PB88-178785/XAB. U.S. Environmental Protection Agency. (1988) Health and environmental effects profile for methyl methacrylate. NTIS/PB88-178785. U.S. Environmental Protection Agency. (1991) Summary review of health effects associated with methyl methacrylate: health issue assessment. Environmental Criteria and Assessment Office, Research Triangle Park, NC;-092A. Agency Consensus Review Date -- 11/25/1997 To review the Summary of and Response to External Peer Review comments, exit to the toxicological review, Appendix B http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=71. Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Methyl methacrylate conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (internet address). ============================================================================ UDCA: 199803 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Methyl Methacrylate CASRN -- 80-62-6 Last Revised -- 03/02/1998 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under EPA's 1986 Guidelines for Carcinogen Risk Assessment, MMA would be classified as evidence of non-carcinogenicity for humans or a Group E chemical. Under the Proposed Guidelines for Carcinogenic Risk Assessment (U.S. EPA, 1996), MMA is considered not likely to be carcinogenic to humans by any route of exposure because it has been evaluated in four well-conducted chronic inhalation studies in three appropriate animal species without demonstrating carcinogenic effects. Basis -- The results of the 2-year inhalation studies conducted for NTP showed no evidence of carcinogenicity of MMA for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for female B6C3F1 mice exposed at 500 or 1,000 ppm. In addition, no increase was seen in the number or type of tumors in either rats or hamsters from the chronic inhalation study performed by Hazelton Laboratories (1979a,b). No carcinogenic activity was reported in a chronic oral study (Borzelleca et al., 1964). Fewer animals were used and the experimental protocal and results of this oral study were not as well documented as for the inhalation study. However, acute oral exposure studies and structure-activity relationship comparisons with other acrylates suggest that the introduction of a methyl group to the acrylate moiety (e.g., EA to MMA) negates carcinogenic activity. Epidemiology studies show no clear excess of cancer. Though a report suggesting increased colon cancer among ethyl acrylate/MMA- exposed workers exists, a high background for this effect has been documented for the location and time of this study, the effects were not reproduced in other similar and more recent studies, a clear relationship between exposure and effect was not demonstrated, and the extent that ethyl acrylate concurrent exposure confounded results could not be determined. Given these structure-activity relationship considerations, the low potential for cancer from MMA exposure indicated in genotoxicity, laboratory animal and epidemiology studies suggests that MMA does not represent a carcinogenic hazard to humans. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=53. , For more detail on other Hazard Identification issues,exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=48. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Limited epidemiological data are available to determine whether the incidence of various malignancies is higher in groups occupationally exposed to MMA versus those not exposed, and no studies have been reported on whether or not smoking is a related factor in the occurrence of malignancies in MMA-exposed workers. One retrospective epidemiological study that relates to malignancies was conducted at the Bristol Plant, PA, which manufactures plastics, leather chemicals, etc. (Monroe, 1984; Walker et al., 1991). In this study of Bristol Plant employees hired prior to 1946 (Early Bristol cohort), an excess of cancer of the large intestine and rectum was noted. However, an increase in these types of cancers was not observed in similar populations at separate sites, and in subsequent evaluations of the same site (Walker et al., 1991; ECETOC, 1995; Collin et al, 1989). Collins et al. (1989) have noted that during the 1970's, the county in which the plant was located had a high colorectal cancer rate, at the 75th percentile for the United States. Some evidence of an increased death rate from cancer and noncancer respiratory disease is provided by the American Cyanamid (Collins et al., 1989) and Knoxville (Walker et al., 1991) cohorts. However, in both of these cohorts, exposure to MMA was considerably lower than in the Early Bristol cohort, which showed no such excess. Others have suggested that these increases were lifestyle related (ECETOC, 1995). Some instances of possible association of human neoplasms with MMA have been reported, but most have been clearly associated with polymethyl methacrylate. Wines (1973) reported on a patient who developed bladder carcinoma adjacent to intrapelvic cement (polymethyl methacrylate) following a Charnley total hip replacement; Thompson and Entin (1969) reported on the occurrence of a chondrosarcoma intimately associated with the fibrous capsule surrounding lucite (polymethacrylate) spheres used as plombage for compressing a tuberculous cavity; Routledge (1973) described a case of granuloma of the upper lobe of the left lung in a worker in a hospital department making polymethacrylate contact lenses. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA No Evidence. Carcinogenic tests have been performed which suggest that tumors can form when laboratory animals are subjected to subcutaneous implants of poly-MMA (Laskin et al., 1954; Ferguson, 1977). While some researchers (Homsy et al., 1972, Bright et al., 1972) have shown some leaching of monomeric MMA from poly-MMA surgical implants, Ferguson (1977) suggests that sarcomas that arise following subcutaneous implants of poly-MMA can be attributed to mechanical processes involving topographic interaction of the solid surface with normal cells, especially macrophages. In the experiments of Oppenheimer et al. (1955), no tumors were induced when monomeric MMA was applied dermally to the back of the neck of rats. While suggestive with respect to whether mode of application has bearing on the results of such experiments, the Oppenheimer study should not be considered sufficient for evaluating the carcinogenic potential of MMA, as the exposure period was just 4 mo and only 10 animals were tested. In the studies by Hazelton Laboratories (1979a,b) Fischer 344 rats and Charles River Lakeview Golden Hamsters were exposed to MMA vapors at 0, 25, 100, and 400 ppm for 6 h/day for 5 days/week for 2 years and 18 mo, respectively. No increase was seen in the number or type of tumors in either rats or hamsters, indicating that MMA was not carcinogenic in these two species under those conditions. Appearance of a polypoid adenoma in the nasal cavity of two MMA-exposed male rats (Lomax, 1992) is not likely to be associated with MMA exposure, and these benign neoplasms have been reported in control rats as well. Similarly, a 2-year NTP inhalation bioassay in rats and mice gave negative results for carcinogenicity, although the animals may not have been tested at the maximum tolerated dose (National Toxicology Program, 1986; Chan et al., 1988). Borzelleca et al. (1964) found no significant toxic effects in male and female dogs (2 males and 2 females per treatment group) receiving MMA via gelatin capsule in the diet at 10, 100, or 1,473 ppm daily for 1 year. The high exposure concentration represented a time-weighted average based on the 1,000 ppm value increasing to 1,200 ppm at five weeks, to 1,400 ppm at seven weeks, and to 1,500 ppm at nine weeks. Borzelleca et al. (1964) also exposed groups of 25 male and 25 female Wistar rats to MMA in drinking water for 104 weeks. The initial exposure concentrations were 6, 60, and 2,000 ppm MMA. The low and medium exposures were increased to 7 and 70 ppm, respectively, at the start of the fifth month, resulting in TWA exposure concentrations of 6.85 and 68.46 ppm MMA. Survival of exposed rats was not significantly different from controls. An initial reduction in body weight gain was observed in both males and females exposed to 2,000 ppm MMA, which reverted to control levels by week 3 (females) and week 6 (males). This is likely the result of reported reduced food intake during the first month, which was not observed in the second month and beyond. Tissues examined included heart, lung, liver, kidney, urinary bladder, spleen, gastroenteric, skeletal, muscle, skin, brain, thyroid, adrenal, pancreas, pituitary, and gonads. The only effect observed was an increased kidney/body-weight ratio in female rats exposed to 2,000 ppm MMA. No abnormalities or lesions related to MMA were identified from histopathological examination of the tissues of exposed rats. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY When tested at cytotoxic concentrations, MMA does not appear to be mutagenic to bacteria (National Toxicology Program, 1986; ECETOC, 1995; Waegemaekers and Bensink, 1984). MMA has been shown to be an in vitro clastogen in mammalian cell gene mutation and chromosomal aberration assays (National Toxicology Program, 1986; ECETOC, 1995). However, MMA has not been shown to result in clastogenic effects or dominant lethal mutations following laboratory animal in vivo inhalation (ICI, 1976a) or oral exposures (Hachiya et al., 1981), and reports of chromosomal damage from in vivo human data (Marez et al., 1991; Seji et al., 1994) are equivocal. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE No data available. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE No data available. SUIE: ___II.C.1. SUMMARY OF RISK ESTIMATES _II.C.1.1. Unit Risk No data available. _II.C.1.2. Extrapolation Method No data available. DCIE: ___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE No data available. ACIE: ___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE) Acrylic acid, four monofunctional acrylates, eight polyfunctional (di- or tri-) acrylates, a dimethacrylate, and a trimethacrylate have been tested in skin-painting cancer bioassays. Acrylic acid, 2-ethylhexyl acrylate, and three diacrylates caused skin tumors. Methyl acrylate (MA), ethyl acrylate (EA), n-butyl acrylate (BA), and methyl methacrylate have been tested in chronic inhalation bioassays and found to be negative with respect to carcinogenicity (Woo et al., 1988). While the Borzelleca et al. (1964) drinking water studies did not report carcinogenicity for either EA or MMA exposure, EA was found to cause forestomach tumors following gavage exposure (NTP, 1983). However, the fact the EA has been found to cause forestomach tumors at high gavage doses (NTP, 1983) does not necessarily implicate MMA. This is suggested by structure-activity relationship studies that demonstrate that the addition of a methyl group to the acrylate moiety tends to abolish carcinogenic activity (Woo et al., 1988) and gavage dosing of analogues of EA demonstrating that the forestomach toxicity required the intact molecule (an ester moiety, the double bond, and no substitution at carbon number 2) (Ghanayem et al., 1985). In another paper, Ghanayem et al. (1986) reported that cell proliferation of the rat forestomach (believed to be a precursor effect to tumors caused by this compound) was apparent in all rats (12/12) following 2-week gavage administration of EA at both 100 and 200 mg/kg, but was not apparent in any rats exposed to 100 mg/kg MMA (0/8) and in just 1/8 rats exposed to 200 mg/kg MMA. This latter increase was not statistically significant and the effect was much less severe than the effects caused by EA at either dose. Thus, structure-activity relationship analysis does not suggest that MMA would be carcinogenic by any route. CCIE: ___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE) Although some cases of sarcomas have been reported following implants of poly-MMA, it is likely that these are the result of mechanical processes involving topographic interaction of the solid surface with normal cells and are not due to leaching of monomeric MMA from poly-MMA surgical implants. The results of the 2-yr inhalation studies conducted for NTP showed no evidence of carcinogenicity of MMA for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for female B6C3F1 mice exposed at 500 or 1,000 ppm. In addition, no increase was seen in the number or type of tumors in either rats or hamsters from the chronic inhalation study performed by Hazelton Laboratories (1979a,b). Appearance of a polypoid adenoma in the nasal cavity of two MMA exposed male rats (Lomax, 1992) is not likely to be associated with MMA exposure, and these benign neoplasms have been reported in control rats as well. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- This assessment is presented in the Toxicological Review of Methyl Methacrylate (CAS No. 80-62-6). (EPA, 1998). This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to Toxicological Review of Methyl Methacrylate (MMA) in support of summary information on Integrated Risk Information System (IRIS). To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/1000-tr.pdf#page=71. RECA: ___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 11/25/1997 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Methyl methacrylate conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: ___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS in general at (301)345-2870 (phone), (301)345-2876 (FAX), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 199803 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Methyl Methacrylate CASRN -- 80-62-6 Last Revised -- 03/02/1998 SORD: __VI.A. ORAL RfD REFERENCES Bereznowski, Z. (1995) In vivo assessment of methyl methacrylate metabolism and toxicity. Int. J Biochem 27:1311-1316. Borzelleca, JF; Larson, PS; Hennigar, GR, Jr.; Huf, EG; Crawford, EM; Smith, RB, Jr. (1964) Studies on the chronic oral toxicity of monomeric ethyl acrylate and methyl methacrylate. Toxicol Appl Pharmacol 6:29-36. Bratt, H; Hathway, DE. (1977) Fate of methyl methacrylate in rats. Br J Cancer 36:114-119. Corkill, JA; Lloyd, EJ; Hoyle, P; Crout, DHG; Ling, RSM; James, ML; Piper, RJ. (1976) Toxicology of methyl methacrylate: the rate of disappearance of methyl methacrylate in human blood in vitro. Clin Chim Acta 68:141-146. Crout, DHG; Lloyd, EJ; Singh, J. (1982) Metabolism of methyl methacrylate: evidence for metabolism by the valine pathway of catabolism in rat and in man. Xenobiotica 12:821-829. Deichmann, W. (1941) Toxicity of methyl, ethyl and n-butyl methacrylate. J Ind Hyg Toxicol 23:343-351. Ghanayem, BI; Bour, PJ; Ahmed, AE. (1985) Acrylonitrile-induced gastric mucosal necrosis: role of gastric glutathione. J Pharmacol Exp Ther 232:570-577. Ghanayem, BI; Maronpot, RR; Matthews, HB. (1986) Association of chemically induced forestomach cell proliferation and carcinogenesis. Cancer Lett 32:271-278. Husain R; Khan, S; Husain, I; Seth, PK; Pandya, KP. (1989) Effect of methyl methacrylate on selected lipids in rat brain and sciatic nerve. Ind Health 27(3):121-124. Husain, R; Srivastava, SP; Seth, PK. (1985) Methyl methacrylate induced behavioural and neurochemical changes in rats. Arch Toxicol 58:33-36. ICI (1977) Methylmethacrylate monomer: teratogenicity studies in the rat. Hodge, MCE and Palmer, S., eds. Report CTL/P/316. ICI, Macclesfield, Cheshire. Luo, SQ, et al. (1986) Study on embryotoxicity and fetotoxicity in rats by maternal inhalation of low level methyl methacrylate. Toxicol Lett 31:80. McLaughlin, RE; Reger, SI; Barkalow, JA; Allen, MS; Difazio, CA. (1978) Methylmethacrylate: a study of teratogenicity and fetal toxicity of the vapor in the mouse. J Bone Jt Surg Am 60-A:355-358. Motoc, F; Constantinescu, S; Filipescu, G; Dobre, M; Bichir, E; Pambuccian, G. (1971) Noxious effects of certain substances used in the plastics industry (acetone cyanohydrin, methyl methacrylate, azobis-isobutylronitrile and anthracene oil). Relation between the agressor agent and its effects. Arch Mal Prof Med Trav Secur Soc 32:653-658. Nicholas, CA; Lawrence, WH; Autian, J. (1979) Embryotoxicity and fetotoxicity from maternal inhalation of methyl methacrylate monomer in rats. Toxicol Appl Pharmacol 50:451-458. Raje, RR; Ahmad, S; Weisbroth, SH. (1985) Methylmethacrylate: tissue distribution and pulmonary damage in rats following acute inhalation. Res Commun Chem Pathol Pharmacol 50:151-154. Solomon, HM; McLaughlin, JE; Swenson, RE; Hagan, JV; Wanner, FJ; O'Hara, GP; Krivanek, ND. (1993) Methyl methacrylate: inhalation developmental toxicity study in rats. Teratology 48:115-125. Spealman, CR; Main, RJ; Haag, HB; Larson, PS. (1945) Monomeric methyl methacrylate: studies on toxicity. Ind Med 14:292-298. Tansy MF. (1979) Final report of teratology studies of mice exposed to methyl methacrylate vapor. Rohm and Haas Company, Spring House, PA; Report No. 78RC-1021. U.S. Environmental Protection Agency (U.S. EPA). (1985) Health and environmental effects profile for methyl methacrylate. Cincinnati, OH: Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office; report no. EPA/600/X-85/364. Available from: NTIS, Springfield, VA; PB88-178785/XAB. U.S. Environmental Protection Agency (U.S. EPA). (1986) The Risk Assessment Guidelines of 1986. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-87/045. U.S. Environmental Protection Agency (U.S. EPA). (1988) Health and environmental effects profile for methyl methacrylate. NTIS/PB88-178785. U.S. Environmental Protection Agency (U.S. EPA). (1991) Summary review of health effects associated with methyl methacrylate: health issue assessment. Environmental Criteria and Assessment Office, Research Triangle Park, NC; ECAO-R-092A. U.S. Environmental Protection Agency (U.S. EPA). (1998). Toxicological review of Methyl Methacrylate (CAS No. 80-62-6). in Support of Summary Information on Integrated Risk Information System (IRIS). Available online at http://www.epa.gov/iris. Wenzel, H; Garbe, A; Nowak, H. (1973) Untersuchungen zur pharmakokinetik von monomethylmethacrylat. 1st Int. Kongr. Prothesentecknok funkt. Rehabil. Wien. (Cited in Borchard, 1982) ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES Andersen, ME; Barton, HA; Covington, TR. (1996) Applying a physiologically based deposition model for methyl methacrylate in the olfactory regions of the rat and human nose to estimate dosimetric adjustment factors. Report prepared by ICF Kaiser Engineers, Inc. for the Methacrylate Producers Association, Inc. Bereznowski, Z. (1995) In vivo assessment of methyl methacrylate metabolism and toxicity. Int J Biochem 27:1311-1316. Chan, PC; Eustis, SL; Huff, JE; Haseman, JK; Ragan, H. (1988) Two-year inhalation carcinogenesis studies of methyl methacrylate in rats and mice: inflammation and degeneration of nasal epithelium. Toxicology 52:237-252. Dahl, AR; Miller, SC; Petridou-Fischer, J. (1987) Carboxylesterases in the respiratory tracts of rabbits, rats and Syrian hamsters. Toxicol Lett 36:129-136. Frederick, CB; Udinsky, JR; Finch, L. (1994) The regional hydrolysis of ethyl acrylate to acrylic acid in the rat nasal cavity. Toxicol Lett 70:49-56. Gift, JS. (1996) Deriving reference concentrations when adverse effects are reported in all exposure groups. 1996 Society for Risk Analysis Meeting. New Orleans, LA, December, 1996. Greene, T. (1996) The metabolism of methyl methacrylate in the nasal tissues of rat and human. Zeneca/Central Toxicology Laboratory Report No. CTL/R/1290, issued December 4, 1996. Sponsor: CEFIC. Hazleton Laboratories America, Inc. (1979a) 18-month vapor inhalation safety evaluation study in hamsters: methyl methacrylate vapor, final report. Vienna, VA: Hazleton Laboratories America, Inc.; project no. 417-354. ICF Kaiser, Inc., (1990a) THC: A computer program to compute a reference dose from continuous animal toxicity data using the benchmark dose method. K.S. Crump Division, Ruston, LA. ICF Kaiser, Inc., (1990b) THWC: A computer program to compute a reference dose from continuous animal toxicity data using the benchmark dose method. K.S. Crump Division, Ruston, LA. ICI. (1976) Methylmethacrylate monomer: dominant lethal study in the mouse. Anderson, D. and Hodge, MCE, eds. Report CTL/P/295. ICI, Macclesfield, Cheshire. ICI. (1977) Methylmethacrylate monomer: teratogenicity studies in the rat. Hodge, MCE and Palmer, S, eds. Report CTL/P/316. ICI, Macclesfield, Cheshire. Keenan, CM; Kelly, DP; Bogdanffy, MS. (1990) Degeneration and recovery of rat olfactory epithelium following inhalation of dibasic esters. Fundam Appl Toxicol 15:381-393. Klimisch, HJ. (1984) Carcinogenicity of acrylates: long-term inhalation studies on methyl acrylate (MA) and n-butyl acrylate (BA) in rats. Toxicologist 4:53. Lomax, LG. (1992) Histopathologic evaluation of the nasal cavities from Fisher 344 rats exposed to methyl methacrylate vapor for two years. Spring House, PA: Rohm and Haas Company. Lomax, LG, Krivanek, ND; Frame, SR. (1997) Chronic inhalation toxicity and oncogenicity of methyl methacrylate in rats and hamsters. Food Chemi Toxicol 35:393-407. Lomax, LG; Brown, DW; Frederick, CB. (1994) Regional histopathology of the mouse nasal cavity following two weeks of exposure to acrylic acid for either 6 or 22 hours per day. Spring House, PA: Rohm and Haas Company. Luo, SQ, et al. (1986) Study on embryotoxicity and fetotoxicity in rats by maternal inhalation of low level methyl methacrylate. Toxicol Lett 31:80. Mattes, PM; Mattes, WB. (1992) Alpha-naphthyl butyrate carboxylesterase in human and rat nasal tissue. Toxicol Appl Pharmacol 114:71-76. McLaughlin, RE; Reger, SI; Barkalow, JA; Allen, MS; Difazio, CA. (1978) Methylmethacrylate: a study of teratogenicity and fetal toxicity of the vapor in the mouse. J Bone Jt Surg Am Vol. 60-A:355-358. Miller, RR; Ayres, JA; Jersey, GC; McKenna, MJ. (1981) Inhalation toxicity of acrylic acid. Fundam Appl Toxicol 1:271-277. Miller, RR; Hermann, EA; Young, JT; Calhoun, LL; Kastl, PE. (1984) Propylene glycol monomethyl ether actetate (PGMEA) metabolism, disposition, and short-term vapor inhalation toxicity studies. Toxicol Appl Pharmacol 75:521-530. Miller, RR; Young, JT; Kociba, RJ; Keyes, DG; Bodner, KM; Calhoun, LL; Ayres, JA. (1985) Chronic toxicity and oncogenicity bioassay of inhaled ethyl acrylate in Fischer 344 rats and B6C3F1 mice. Drug Chem Toxicol 8:1-42. Morris, JB.; Frederick, CB. (1995) Upper respiratory tract uptake of acrylate ester and acid vapors. Inhal Toxicol 7:557-574. National Toxicology Program (NTP). (1986) Toxicology and carcinogenesis studies of methyl methacrylate (CAS no. 80-62-6) in F344/N rats and B6C3F1 mice (inhalation studies). Research Triangle Park, NC: U. S. Department of Health and Human Services, National Institutes of Health; report nos. NTP-TR-314 and NIH/PUB-87-2570. Available from: NTIS, Springfield, VA; PB87-146742/XAB. Nicholas, CA; Lawrence, WH; Autian, J. (1979) Embryotoxicity and fetotoxicity from maternal inhalation of methyl methacrylate monomer in rats. Toxicol Appl Pharmacol 50:451-458. Pickering, CAC; Bainbridge, D; Birtwistle, IH; Griffiths, DL. (1986) Occupational asthma due to methyl methacrylate in an orthopedic theater sister. Br Med J 192:1362-1363. Solomon, HM; McLaughlin, JE; Swenson, RE; Hagan, JV; Wanner, FJ; O'Hara, GP; Krivanek, ND. (1993) Methyl methacrylate: inhalation developmental toxicity study in rats. Teratology 48:115-125. Stott, WT; McKenna, MJ. (1985) Hydrolysis of several glycol ether acetates and acrylate esters by nasal mucosal carboxylesterase in vitro. Fundam Appl Toxicol 5:399-404. Tansy MF. (1979) Final report of teratology studies of mice exposed to methyl methacrylate vapor. Rohm and Haas Company, Spring House, PA; Report No. 78RC-1021. U.S. Environmental Protection Agency (U.S. EPA). (1985) Health and environmental effects profile for methyl methacrylate. Cincinnati, OH: Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office; report no. EPA/600/X-85/364. Available from: NTIS, Springfield, VA; PB88-178785/XAB. U.S. Environmental Protection Agency (U.S. EPA). (1986) The Risk Assessment Guidelines of 1986. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-87/045. U.S. Environmental Protection Agency (U.S. EPA). (1988) Health and environmental effects profile for methyl methacrylate. NTIS/PB88-178785. U.S. Environmental Protection Agency (U.S. EPA). (1991) Summary review of health effects associated with methyl methacrylate: health issue assessment. Environmental Criteria and Assessment Office, Research Triangle Park, NC; ECAO-R-092A. U.S. Environmental Protection Agency (U.S. EPA). (1998) Toxicological Review of Methyl Methacrylate (CAS No. 80-62-6) in Support of Summary Information on Integrated Risk Information System (IRIS). Available online at http://www.epa.gov/iris. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Bright, DS; Clark, HG; McCollum, DE. (1972) Serum analysis and toxic effects of methylmethacrylate. Surg Forum 23:455-457. Chan, PC; Eustis, SL; Huff, JE; Haseman, JK; Ragan, H. (1988) Two-year inhalation carcinogenesis studies of methyl methacrylate in rats and mice: inflammation and degeneration of nasal epithelium. Toxicology 52:237-252. Collins, JJ; Page, LC; Caporossi, JC; Utidjian, HM; Saipher, JN. (1989) Mortality patterns among men exposed to methyl methacrylate. JOM J Occup Med 31:41-46. Ferguson, DJ. (1977) Cellular attachment to implanted foreign bodies in relation to tumorigenesis. Cancer Res 37:4367-4371. Hazleton Laboratories America, Inc. (1979b) A two-year inhalation safety evaluation study in rats: methyl methacrylate, final report. Vienna, VA: Hazleton Laboratories America, Inc.; project no. 417-354. Homsy, CA; Tullos, HS; Anderson, MS; Diferrante, NM; King, JW. (1972) Some physiological aspects of prosthesis stabilization with acrylic polymer. Clin Orthop Relat Res 83:317-328. Laskin, DM; Robinson, IB; Weinmann, JP. (1954) Experimental production of sarcomas by methyl methacrylate implants. Proc Soc Exp Biol Med 87:329-332. Lomax, LG. (1992) Histopathologic evaluation of the nasal cavities from Fisher 344 rats exposed to methyl methacrylate vapor for two years. Spring House, PA: Rohm and Haas Company. Marez, T; Shirali, P; Hildebrand, HF; Haguenoer, JM. (1991) Increased frequency of sister chromatid exchange in workers exposed to high doses of methylmethacrylate. Mutagenesis 6:127-129. Monroe, CB. (1984) Interim communication on the results of a mortality study of Bristol plant employees hired prior to 1946. Philadelphia, PA: Rohm and Haas Co.; FYI-OTS-0384-0300. National Toxicology Program. (1986) Toxicology and carcinogenesis studies of methyl methacrylate (CAS no. 80-62-6) in F344/N rats and B6C3F1 mice (inhalation studies). Research Triangle Park, NC: U. S. Department of Health and Human Services, National Institutes of Health; report nos. NTP-TR-314 and NIH/PUB-87-2570. Available from: NTIS, Springfield, VA; PB87-146742/XAB. Oppenheimer, BS; Oppenheimer, ET; Danishefsky, I; Stout, AP; Eirich, FR. (1955) Further studies of polymers as carcinogenic agents in animals. Cancer Res 15:333-340. Routledge, R. (1973) Possible hazard of contact lens manufacture. Br Med J 1:487-488. Thompson, JR; Entin, SD. (1969) Primary extraskeletal chondrosarcoma: report of a case arising in conjunction with extrapleural lucite ball plombage. Cancer 23:936-939. U.S. Environmental Protection Agency (U.S. EPA). (1986) The risk assessment guidelines of 1986. Office of Health and Environmental Assessment, Washington, DC. EPA/600/8-87/045. U. S. E nvironmental Protection Agency. (U.S. EPA). (1996, April 23) Proposed guidelines for carcinogen risk assessment Federal Register 61 (79):17960-18011. U.S. Environmental Protection Agency (US EPA). (1998) Toxicological review of Methyl Methacrylate (CAS No. 80-62-6) in Support of Summary Information on Integrated Risk Information System (IRIS). Available online at http://www.epa.gov/iris. Wines, RD. (1973) Possible hazard of polymethyl methacrylate. Br Med J 3:409. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Methyl Methacrylate CASRN -- 80-62-6 Last Revised -- 03/02/1998 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 03/02/1998 I.A., I.B., II., VI. New RfD, RfC, cancer assessments 12/03/2002 I.A.6., I.B.6, II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 442 of 1119 in IRIS (through 2003/06) AN: 1002 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/1002-tr.pdf UD: 200106 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Bromate- SY: 15541-45-4; BROMATE(1-), BROMOCHLORO-, RUBIDIUM; BROMIC-ACID,-POTASSIUM-SALT-; BROMIC-ACID,-SODIUM-SALT-; BROMIC-ACID,-ZINC-SALT- RN: 15541-45-4 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200106 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Bromate CASRN -- 15541-45-4 Last Revised -- 06/06/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY Critical Effect Experimental Doses* UF MF RfD ----------------------------------------- -- -- ------- Renal effects: NOAEL: 300 1 4E-3 mg Urothelial 1.5 mg KBrO3-/kg-day BrO3-/kg-day hyperplasia (1.1 mg BrO3-/kg-day) LOAEL: 7.9 mg KBrO3/kg-day Rat (6.1 mg BrO3-/kg-day) feeding study DeAngelo et al., 1998 ------------------------------------------------------------------------ *Conversion Factors and Assumptions -- Doses of potassium bromate were calculated by DeAngelo et al. (1998) on the basis of measured water consumption, body weight, and water concentrations. Potassium bromate doses were converted to bromate ion doses by multiplying by 0.766, the ratio of molecular weights for bromate ion (127.9) and potassium bromate (167). PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) DeAngelo, AB; George, MH; Kilburn, SR; et al. (1998) Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats. Toxicol Pathol 26(5):587-594. DeAngelo et al. (1998) administered potassium bromate in drinking water at concentrations of 0, 0.02, 0.1, 0.2, and 0.4 g/L and of 0, 0.08, 0.4, and 0.8 g/L to male F344 rats and male B6C3F1 mice (78/group), respectively, for 100 weeks. Time-weighted mean daily doses were calculated by the authors from the mean daily water consumption and the measured concentrations of potassium bromate. Bromate doses for the rats were 0, 1.1, 6.1, 12.9, and 28.7 mg BrO3-/kg-day. For rats, 6 animals/group were included for interim sacrifices, which occurred at 12, 26, 52, and 77 weeks. Parameters evaluated included survival, body weight, organ weight, serum chemistry, and histopathology. In male rats, survival in the 28.7 mg BrO3-/kg-day dose group was decreased compared with controls beginning by approximately week 79 (Wolf, 1998a); this decrease was statistically significant by study termination. In the 12.9 mg BrO3-/kg-day dose group, survival was decreased compared with controls beginning by approximately week 88 (Wolf, 1998a); this decrease was also significant by study termination. Male rats in the 28.7 mg BrO3-/kg-day dose group also had a statistically significant decrease (18%) in the final mean body weight compared with controls. The decrease in survival and body weight was attributed to an excessive mesothelioma burden (Wolf, 1998a). The effects of potassium bromate on survival and body weight in rats indicate that the maximum tolerated dose (MTD) was reached in this study. In rats, water consumption was statistically significantly increased in the 12.9 and 28.7 mg/kg-day dose groups; the dose-related trend was also statistically significant. Rats in the 12.9 mg/kg-day dose group had increases, not statistically significant, in absolute and relative kidney weight and relative spleen weight. Rats in the 28.7 mg/kg-day dose group had statistically significant increases in relative liver weight, absolute and relative kidney weight, absolute and relative thyroid weight, and relative spleen weight. Nonneoplastic kidney lesions were observed in rats. Although the severity of chronic nephropathy was comparable between control and treated rats, there was a significant dose-dependent increase in the incidence of urothelial hyperplasia in rats in dose groups of 6.1 mg/kg-day and higher. The authors also observed foci of mineralization of the renal papilla and eosinophilic droplets in the proximal tubule epithelium, although no information on the dose levels for these findings was presented. No other treatment-related nonneoplastic effects were observed in any other tissue examined. On the basis of kidney effects in male rats, this study identifies a NOAEL of 1.1 mg BrO3-/kg-day and a LOAEL of 6.1 mg BrO3-/kg-day. Results of DeAngelo et al. (1998) in male B6C3F1 mice indicate that mice may be less sensitive than rats to the effects of bromate exposure. Time-weighted mean daily doses were calculated by the authors from the mean daily water consumption and the measured concentrations of potassium bromate. Bromate doses for mice were 0, 6.9, 32.5, and 59.6 mg BrO3-/kg-day. For mice, 7 animals/group were included for interim sacrifice, which occurred at 14, 31, 53, and 78 weeks. Bromate in drinking water had no effect on the survival, body weight, or organ weight of male mice. Water consumption was decreased by 17% in the 59.6 mg BrO3-/kg-day dose group; this decrease was statistically significantly different from controls. Serum chemistry results were comparable between controls and treated mice, and no increased incidence of nonneoplastic lesion occurred in any tissue examined. Therefore, the highest dose tested, 59.6 mg BrO3-/kg-day, is a freestanding NOAEL in mice. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) UF = 300. An uncertainty factor (UF) of 10 is applied to account for extrapolating from animals to humans and another factor of 10 is used to protect sensitive subpopulations and to account for potential differences between adults and children. A factor of 3 is used to account for some deficiencies in the database. The bromate database consists of chronic and subchronic studies in rats and mice and a screening-level reproductive/developmental study in rats. The database is missing developmental studies in two species and a multigeneration study. This results in a total uncertainty factor of 300. MF = 1. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) Several cases of acute bromate intoxication have been reported in humans following accidental or suicidal ingestion of permanent hair wave neutralizing solutions (Benson, 1951; Parker and Barr, 1951; Quick et al., 1975; Gradus et al., 1984; Warshaw et al., 1985; Lue et al., 1988; Mack, 1988; Matsumoto et al., 1980; Lichtenberg et al., 1989; Watanabe et al., 1992). These products usually contain either 2% potassium bromate or 10% sodium bromate. The most common acute signs are severe gastrointestinal irritation (vomiting, pain, diarrhea) and the Central Nervous System depression (lethargy, hypotension, hypotonicity, loss of reflexes). Anemia from intravascular hemolysis may also occur. These effects are usually reversible. Later sequelae (usually within several days) include marked renal injury and hearing loss. Death from renal failure may ensue if medical intervention is not successful. If support is successful, renal function generally returns after 5-10 days. Hearing loss is usually irreversible. Estimated doses in these cases ranged from about 20 to 1,000 mg BrO3-/kg. Nakano et al. (1989) exposed male Wistar rats to 0.04% potassium bromate in drinking water for up to 15 months. If an intake of 0.1 L/kg-day is assumed, this corresponds to a dose of about 30 mg BrO3-/kg-day. Body weight gain was markedly inhibited in the exposed animals. Histological examination of kidneys at 7-11 weeks revealed karyopyknotic foci in tubules of the inner medulla. Increased blood urea nitrogen (BUN), along with marked structural abnormalities of the cortical tubules, was noted after 15 months. Based on the decreased body weight gain and renal effects, this study identified a LOAEL of 30 mg BrO3-/kg-day, but did not identify a NOAEL. Kurokawa et al. (1983) investigated the carcinogenicity of potassium bromate in the drinking water of F344 rats. Potassium bromate was administered to F344 rats (53/sex/group) at concentrations of 0, 250, and 500 ppm for 110 weeks. (Equivalent doses of bromate ion were approximately 12 and 33 mg bromate/kg-day, estimated from average reported body weights and water consumption.) However, the growth of males in the high-dose group was severely inhibited, so the concentration was reduced to 400 ppm at week 60. Body weights were recorded weekly. At autopsy, blood was collected for hematological analysis. Organs were collected, weighed, and evaluated histopathologically. Body weight gain was significantly reduced in high-dose males, but not in the other treated groups. Survival was reduced in high-dose males by about week 60 and in low-dose males by about week 100. No effect on survival was observed in treated female rats. A variety of noncancer effects was reported, including degenerative, necrotic, and regenerative changes in renal tubules; formation of hyaline droplets; thickening of transitional epithelium of renal pelvis, papillary hyperplasia, and papillary growth. The authors noted that the lesions were more extensive in degree and distribution in treated rats compared with controls, especially males. However, no information is provided on the incidence of these lesions or on the statistical significance of these findings; therefore, a NOAEL for noncancer effects cannot be determined. In a chronic study of bromate carcinogenicity, Kurokawa et al. (1986a) treated groups of 20-24 male F344 rats with water containing potassium bromate at 0, 15, 30, 60, 125, 250, or 500 mg/L for 104 weeks. The average doses in Kurokawa et al. (1986a) for male rats were 0, 0.7, 1.3, 2.5, 5.6, 12.3, and 33 mg BrO3-/kg-day. The weights of selected organs and all tumors were recorded. Histological examination of tissues only involved counting of neoplastic lesions. Compared with controls, the males in the high-dose group had decreased body weight gain and decreased survival, beginning at approximately week 70. Survival and body weight gain were comparable with controls for all remaining dose groups. The only nonneoplastic effect noted by the authors was a dose-related enhancement of the severity of nephropathic changes; however, no information was given regarding the doses at which these changes were observed. Kurokawa et al. (1986b) studied the carcinogenic potential of potassium bromate in both male and female F344 rats and female B6C3F1 mice. Potassium bromate in drinking water was administered to the animals. Time-weighted mean doses of potassium bromate were estimated by the authors based on measured water consumption and body weight. The average bromate doses for rats were 0, 9.6, and 21.3 mg BrO3-/kg-day in males and 0, 9.6, and 19.6 mg BrO3-/kg-day in females. The average bromate doses for mice were 0, 43.5, and 91.6 mg BrO3-/kg-day. Parameters evaluated include body and organ weight, hematology, serum chemistry, and histopathology. Compared with controls, male rats in the high-dose group had a marked decrease in body weight gain and a decrease in survival, beginning at approximately week 70. The authors did not describe the cause of the decreased survival and body weight. For the low-dose groups in male rats and all dose groups in female rats and mice, survival and body weight gain were comparable to controls. Several non-neoplastic effects were described by the authors. Significant decreases in serum chemistry, including glutamate pyruvate transaminase (GPT), albumin-to-globulin ratio, potassium, and cholinesterase were observed in female rats in the high-dose group. Also, slightly increased BUN was observed in both male and female rats; dose groups were not specified. Degenerative and necrotic kidney lesions were observed in treated rats. Specific findings included hyaline casts in the tubular lumen, hyaline droplets, eosinophilic bodies, and brown pigments in the tubular epithelium. Again, however, the doses at which these changes were observed were not specified. No nonneoplastic changes in bromate-treated mice were discussed by the authors. The subchronic effects of bromate were evaluated in Kurokawa et al. (1990). Potassium bromate in water at concentrations of 0, 150, 300, 600, 1,250, 2,500, 5,000 or 10,000 ppm was administered to groups of F344 rats (10/sex/group) for 13 weeks. Daily doses corresponding to these concentrations are about 0, 16, 32, 63, 140, 270, 650, or 1,080 mg BrO3-/kg. All animals exposed to >1,250 ppm died within 7 weeks. Observed signs of toxicity included significant inhibition of body weight gain in males at 600 ppm and above and significant increases of serum parameters (glutamate oxaloacetate transaminase, glutamate pyruvate transaminase, lactate dehydrogenase, ALP, BUN, Na+, cholinesterase) in both sexes at 600 ppm. Serum potassium levels were significantly decreased. Droplets of various sizes and regenerative changes in the renal tubules were observed. This study identifies 63 mg/kg as an adverse effect level, but insufficient data were provided to determine whether effects occurred at lower doses. In a study conducted for the National Toxicology Program, Wolf and Kaiser (1996) evaluated the potential reproductive and developmental toxicity of sodium bromate in Sprague-Dawley rats following oral administration in drinking water at concentrations of 0.25 ppm (2.6 mg/kg-day), 80 ppm (9.0 mg/kg-day), or 250 ppm (25.6 mg/kg-day) over a 35-day period. (Equivalent bromate ion doses are 2.2, 7.7, and 22.0 mg BrO3-/kg-day.) Two groups of female rats were treated. The first group (10/dose group) was dosed from study days 1-34 to test for effects during conception and early gestation. The second group (13/dose group) was dosed from gestation day 6 to postnatal day 1 to test for effects during late gestation and birth. Male rats (10/group) were cohabitated with the second group for 5 days before dosing (study days 1-5) and were dosed from study day 6 to day 34/35. Endpoints evaluated in males included clinical pathology, organ weight, sperm analysis, and histopathology. Endpoints evaluated in females included maternal body weight, number and weight of pups, and number of uterine implantations. Treated males in the 250-ppm dose group demonstrated a statistically significant decrease (18%) in epididymal sperm density. All other endpoints evaluated were comparable between controls and treated groups. Female reproductive function was not adversely affected. No treatment-related gross or microscopic changes occurred in the kidney, liver, spleen, testis, or epididymis. These results indicate that sodium bromate treatment does not produce any adverse signs of general toxicity at any of the dose levels tested, and on the basis of these findings, a MTD was not reached. This study identifies a NOAEL of 80 ppm (7.7 mg BrO3-/kg-day) and a LOAEL of 250 ppm (22.0 mg BrO3-/kg-day) on the basis of changes in sperm density. For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/1002-tr.pdf#page=37 CORD: ___I.A.5. CONFIDENCE IN THE ORAL RfD Study -- High Database -- Medium RfD -- Medium The overall confidence in this RfD assessment is medium. Confidence in the principal study is high because the study was well conducted, used adequate numbers of animals, and evaluated appropriate endpoints. Confidence in the database is medium. Although the database contains several subchronic and chronic studies of bromate, only one study provides adequate dose-response information regarding renal effects of bromate. A screening-level reproductive/developmental study suggests bromate may be a male reproductive toxicant; this effect needs to be more completely characterized. In addition, the database is missing a reproductive/developmental study for a second species and a multigeneration study. Reflecting medium confidence in the database, the confidence in the RfD is medium. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/1002-tr.pdf#page=45 EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document: -- U.S. EPA, 2001 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included in Appendix A of the source document. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/1002-tr.pdf#page=54 Other EPA Documentation -- None Agency Consensus Date -- 5/22/01 ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (FAX), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Bromate CASRN -- 15541-45-4 Last Revised -- 06/06/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY Currently, no data are available to derive an RfC for bromate. No data are available to predict the effect of inhaled bromate on the respiratory tract; therefore, it would not be appropriate to derive an RfC for bromate on the basis of oral data. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) None. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) None. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) None. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC None. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Source Document U.S. EPA, 2001 Other EPA Documentation -- None Agency Consensus Date -- 5/22/01 ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (FAX), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDCA: 200106 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Bromate CASRN -- 15541-45-4 Last Revised --06/06/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION Under the current Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986), bromate would be classified as B2, probable human carcinogen. Under the Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996), bromate should be evaluated as a likely human carcinogen by the oral route of exposure. Insufficient data are available to evaluate the human carcinogenic potential of bromate by the inhalation route. Although no epidemiological studies or studies of long-term human exposure to bromate are available, bromate is carcinogenic to male and female rats following exposure in drinking water. Three key studies (Kurokawa et al., 1986a, 1986b; DeAngelo et al., 1998) demonstrate the carcinogenicity of bromate in rats. All studies were well conducted, with an appropriate route of exposure and adequate numbers of animals. Several aspects of these bioassay studies support the conclusion that bromate has the potential to be a human carcinogen. First, tumors were observed at multiple sites, including the kidney (adenomas and carcinomas), the thyroid (follicular cell adenomas and carcinomas), and the peritoneum (mesotheliomas). In DeAngelo et al. (1998) the mesotheliomas arose from the tunica vaginalis testis and spread throughout the peritoneal cavity on the serosal surfaces of many organs. Kurokawa et al. (1986a, 1986b) do not specify the origin of the peritoneal mesotheliomas observed. Whereas male rats had tumors at all three sites, only kidney tumors were observed in female rats. However, the kidney tumors in female rats developed in the absence of the significant toxicity observed in the male rats. Second, a clear dose-response relationship existed in tumor incidence and in severity/progression of tumors. Kurokawa (1986a) observed a progression in severity from renal dysplastic foci, a preneoplastic lesion, through renal adenomas to renal carcinoma as the dose increased. Kurokawa et al. (1986b) observed dose-response relationships for kidney tumors in both male and female rats. Kurokawa (1986a) observed dose-response relationships for two other tumor types, mesotheliomas and thyroid follicular cell, in male rats. DeAngelo et al. (1998) observed dose-response relationships for all three tumor types in rats. There is some concern that the high dose in each of these studies exceeded the MTD for male rats. However, in all three studies, the decrease in survival began to appear relatively late in the study: at approximately week 70 in the Kurokawa et al. (1986a, 1986b) studies and at approximately week 79 in the DeAngelo et al. (1998) study. Two studies reported the time of first tumor observation: In Kurokawa et al. (1986b), the first tumor of any type was observed at 14 weeks, and in DeAngelo et al. (1998), the first tumor of any type was observed at 26 weeks. Therefore, the male rats in these studies were surviving long enough to have developed tumors. In addition, in the DeAngelo et al. (1998) study, the decreased survival and body weight gain appeared to be caused by the heavy mesothelioma burden of the animals (Wolf, 1998a); the cause of decreased survival and body weight gain in the Kurokawa et al. (1986b) study is not apparent. The decreased survival for high-dose groups these studies does not compromise these studies for use in risk assessment. The evidence is too limited to give high confidence in a conclusion about any mode of carcinogenic action. Oxidative stress may play a role in the formation of kidney tumors, but the evidence is insufficient to establish lipid peroxidation and free-radical production as the key events responsible for the induction of kidney tumors. In addition, no data are currently available to suggest any mechanism for the production of thyroid tumors and mesotheliomas by bromate. Bromate is mutagenic in both rats and mice in vivo and in vitro assays; albeit, the testing has been limited to the Ames assay and in vitro cytogenetics and bone marrow assays. Given the limited data on the possible mechanism of carcinogenic action for bromate, it is a reasonable assumption that the production of tumors in rats occurs by a mode of action that is relevant to humans. With the lack of human data, the uncertainty surrounding the mode of action, and the inconsistency between the rat and mouse results, the human relevance of the rat data relies on the assumption that rat data, in general, are relevant to humans. In the absence of a biologically based model, the assumption of low-dose linearity is considered to be a reasonable public health protective approach for estimating the potential risk for bromate because of the limited data on its mode of action and because of some evidence of mutagenicity. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/1002-tr.pdf#page=45 , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/1002-tr.pdf#page=37 HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA None. ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Oral exposure to bromate results in an increased incidence of renal tubular tumors in male and female rats and an increased incidence of mesotheliomas and thyroid follicular cell tumors in male rats. In a chronic study of bromate carcinogenicity, Kurokawa et al. (1986a) treated groups of 20-24 male F344 rats with water containing potassium bromate at 0, 15, 30, 60, 125, 250, or 500 mg/L for 104 weeks. The average doses in Kurokawa et al. (1986a) for male rats were 0, 0.7, 1.3, 2.5, 5.6, 12.3, or 33 mg BrO3-/kg-day. The weights of selected organs and all tumors were recorded. Histological examination of tissues only involved counting of neoplastic lesions. Compared with controls, the males in the high-dose group had decreased body weight gain and decreased survival, beginning at approximately week 70. Survival and body weight gain were comparable with controls for all remaining dose groups. A statistically significantly increased incidence was observed for dysplastic foci at doses of 1.3 mg BrO3-/kg-day and above (incidence is 0/19, 1/19, 5/20, 6/24, 12/24, 19/20, and 19/20 for the 0, 0.7, 1.3, 2.5, 5.6, 12.3, and 33 mg BrO3-/kg-day dose groups, respectively), for kidney tumors at doses of 5.6 mg BrO3-/kg-day dose group and above (incidence is 0/19, 0/19, 0/20, 1/24, 5/24, 5/20, and 9/20 for the 0, 0.7, 1.3, 2.5, 5.6, 12.3, and 33 mg BrO3-/kg-day dose groups, respectively) and for the thyroid tumors (incidence is 0/19, 0/19, 0/20, 1/24, 0/24, 3/20, and 7/20 for the 0, 0.7, 1.3, 2.5, 5.6, 12.3, and 33 mg BrO3-/kg-day dose groups, respectively) and mesotheliomas (incidence is 0/19, 0/19, 3/20, 4/24, 2/24, 3/20, and 15/20 for the 0, 0.7, 1.3, 2.5, 5.6, 12.3, and 33 mg BrO3-/kg-day dose groups, respectively) in the high-dose group only. Kurokawa et al. (1986b) studied the carcinogenic potential of potassium bromate in both male and female F344 rats and female B6C3F1 mice. Potassium bromate in drinking water was administered to the animals. Time-weighted mean doses of potassium bromate were estimated by the authors based on measured water consumption and body weight. The average bromate doses for rats were 0, 9.6, and 21.3 mg BrO3-/kg-day in males and 0, 9.6, and 19.6 mg BrO3-/kg-day in females. The average bromate doses for mice were 0, 43.5, and 91.6 mg BrO3-/kg-day. Parameters evaluated include body and organ weight, hematology, serum chemistry, and histopathology. Compared with controls, male rats in the high-dose group had a marked decrease in body weight gain and a decrease in survival beginning at approximately week 70. The authors did not describe the cause of the decreased survival and body weight. For the low-dose groups in male rats and all dose groups in female rats and mice, survival and body weight gain were comparable to controls. Treatment-related, statistically significant tumors observed in rats included renal cell adenomas and carcinomas and peritoneal mesotheliomas (in males only). The incidence of kidney tumors was 3/53, 32/53, and 46/53 in male rats and 0/47, 28/50, and 39/49 in female rats for the control, low-dose, and high-dose groups, respectively. The incidence of mesotheliomas in male rats was 6/53, 17/52, and 28/46 for the control, low-dose, and high-dose groups, respectively. The authors note that a "high incidence" of tumors was observed in the thyroid; however, this incidence was not statistically significant. In male rats, the earliest renal tumor was observed at 14 weeks and the earliest mesothelioma was observed at 72 weeks. In female rats, the earliest renal tumor was observed at 85 weeks. In female mice, no significant differences in tumor incidence between exposed and control animals were apparent after 78 weeks of dosing, based on histological examination of tissues at week 104. The authors concluded that potassium bromate was carcinogenic in rats of both sexes, but not in mice. DeAngelo et al. (1998) administered potassium bromate in drinking water at concentrations of 0, 0.02, 0.1, 0.2, and 0.4 g/L and of 0, 0.08, 0.4, and 0.8 g/L to male F344 rats and male B6C3F1 mice (78/group), respectively, for 100 weeks. Time-weighted mean daily doses were calculated by the authors from the mean daily water consumption and the measured concentrations of potassium bromate. Bromate doses for the rats were 0, 1.1, 6.1, 12.9, and 28.7 mg BrO3-/kg-day. For rats, 6 animals/group were included for interim sacrifices, which occurred at 12, 26, 52, and 77 weeks. Parameters evaluated included survival, body weight, organ weight, serum chemistry, and histopathology. In male rats, survival in the 28.7 mg BrO3-/kg-day dose group was decreased compared with controls beginning by approximately week 79 (Wolf, 1998a); this decrease was statistically significant by study termination. In the 12.9 mg BrO3-/kg-day dose group, survival was decreased compared with controls beginning by approximately week 88 (Wolf, 1998a); this decrease was also significant by study termination. Male rats in the 28.7 mg BrO3-/kg-day dose group also had a statistically significant decrease (18%) in the final mean body weight compared with controls. The decrease in survival and body weight was attributed to an excessive mesothelioma burden (Wolf, 1998a). The effects of potassium bromate on survival and body weight in rats indicate that the MTD was reached in this study. Tumor incidence for the terminal sacrifice in DeAngelo et al. (1998) is presented in Table 4. Statistically significant, dose-dependent increased tumor incidence was observed in the kidney (incidence of adenomas and carcinomas combined is 1/45, 1/43, 6/47, 3/39, and 12/32 for the 0, 1.1, 6.1, 12.9, and 28.7 mg BrO3-/kg-day dose groups, respectively), thyroid (incidence of adenomas and carcinomas combined is 0/36, 4/39, 1/43, 4/35, and 14/30 for the 0, 1.1, 6.1, 12.9, and 28.7 mg BrO3-/kg-day dose groups, respectively), and tunica vaginalis testis (incidence of mesotheliomas is 0/47, 4/49, 5/49, 10/47, and 27/43 for the 0, 1.1, 6.1, 12.9, and 28.7 mg BrO3-/kg-day dose groups, respectively). Based on data from the National Toxicology Program historical controls database (NTP, 1998), the historical control rates for these tumor types in male F344 rats are 0.6% for kidney renal tubule adenomas and carcinomas, 2.1% for thyroid follicular cell adenomas and carcinomas, and 1.5% for mesotheliomas. The earliest renal tumors and mesotheliomas in DeAngelo et al. (1998) were observed at 52 weeks; the thyroid tumors were first seen at 26 weeks. Results of DeAngelo et al. (1998) in male B6C3F1 mice indicate that mice may be less sensitive than rats to the effects of bromate exposure. Time-weighted mean daily doses were calculated by the authors from the mean daily water consumption and the measured concentrations of potassium bromate. Bromate doses for mice were 0, 6.9, 32.5, and 59.6 mg BrO3-/kg-day. For mice, 7 animals/group were included for interim sacrifice, which occurred at 14, 31, 53, and 78 weeks. Bromate in drinking water had no effect on the survival, body weight, or organ weight of male mice. Water consumption was decreased by 17% in the 59.6 mg BrO3-/kg-day dose group; this decrease was statistically significantly different from controls. The only type of tumor reported for male mice was kidney tumors; however, the incidence of adenoma and carcinoma combined was not dose dependent Tumor incidence at terminal sacrifice for combined kidney tumors in male mice was 0/40, 5/38 (p < 0.05; 3 carcinomas), 3/41 (1 carcinoma), and 1/44 for the 0, 6.9, 32.5, and 59.6 mg BrO3-/kg-day groups, respectively. Kurokawa et al. (1983) investigated the carcinogenicity of potassium bromate in the drinking water of F344 rats. Potassium bromate was administered to F344 rats (53/sex/group) at concentrations of 0, 250, and 500 ppm for 110 weeks. (Equivalent doses of bromate ion were approximately 12 and 33 mg bromate/kg-day, estimated from average reported body weights and water consumption.) However, the growth of males in the high-dose group was severely inhibited, so the concentration was reduced to 400 ppm at week 60. Body weights were recorded weekly. At autopsy, blood was collected for hematological analysis. Organs were collected, weighed, and evaluated histopathologically. Body weight gain was significantly reduced in high-dose males, but not in the other treated groups. Survival was reduced in high-dose males by about week 60 and in low-dose males by about week 100. No effect on survival was observed in treated female rats. The first tumor was observed at 14 weeks in males and at 58 weeks in females. Therefore, animals surviving beyond these times were included in the analysis. Incidences of several tumor types were elevated in a dose-dependent manner (although not statistically significant) in treated rats, including thyroid (male and female), adrenal gland (male), large intestine (male and female), liver (male), and spleen (male). In male rats, the incidence of renal cell tumors (both adenocarcinomas and adenomas) and peritoneal mesotheliomas were statistically significantly increased in both dose groups compared with controls. In female rats, the incidence of renal cell tumors (both adenomas and adenocarcinomas) was statistically significantly increased in both treated groups compared with controls. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Matsushima et al. (1986) investigated the carcinogenicity of KBrO3 administered subcutaneously to newborn rats and mice. One group of male and female newborn F344 rats and ICR mice (24 hours old) were given single subcutaneous injections of 9.6, 19, 38, 77, or 154 mg BrO3-/kg. Another group of newborn rats and mice received four weekly injections of 9.6, 19, 38, 77, or 154 mg BrO3-/kg until weaning. Control animals received injections of olive oil. Rats were sacrificed at 82 weeks, mice were sacrificed at 78 weeks, and organs were examined histologically. No significant differences in the incidence of tumors in male or female rats or mice were observed. Under the conditions of the study, potassium bromate had no potential for carcinogenicity in newborn male or female rats or mice. Kurata et al. (1992) tested the tumor initiation potential of bromate in a 104-week study in which male F344/NCr rats (29 or 39/group) were given an intragastric dose of 300 mg/kg KBrO3 (231 mg/kg BrO3-), the maximum tolerated single dose. The rats were administered bromate alone, bromate followed by 4,000 ppm sodium barbital in the animal diet as a promoter, or sodium barbital alone in the diet. Sodium barbital was added to the diet starting 2 weeks after the animals were dosed with potassium bromate. Rats were examined at 30, 52, and 104 weeks for nephropathy. At 30 weeks, renal damage (dysplastic tubular foci) was evident in the rats exposed to potassium bromate followed by sodium barbital and in rats exposed to sodium barbital, but not in those exposed to potassium bromate alone. The results indicated that a single oral dose of 300 mg/kg KBrO3 (231 mg/kg BrO3-) administered to rats does not initiate renal tumors within a 104-week observation period. Kurokawa et al. (1987) supplied groups of 8, 14, 20, and 26 male F344 rats with water containing 500 mg BrO3-/L for up to 104 weeks to assess the time course of renal cell tumor induction. The average daily consumption of potassium bromate was 41.9 mg/kg (32.3 mg BrO3-/kg). At 104 weeks, the surviving animals were sacrificed and examined histopathologically for dysplastic foci, renal adenomas and adenocarcinomas, thyroid follicular cell tumors and peritoneal mesotheliomas. The occurrence of all tumors was significantly increased as treatment continued. Dysplastic foci and renal adenomas were first observed following 26 weeks of continuous treatment. Renal dysplastic foci and adenomas were each significantly increased over controls by 52 weeks of treatment (mean number of renal cell tumors per rat was 0.81, vs. 0 in the controls). Continuous potassium bromate administration over 104 weeks resulted in renal adenocarcinomas in 3/20 (15%) and renal adenomas in 6/20 (30%) rats. At 104 weeks the mean number of renal cell tumors/rat was 1.25 compared with 0 in the controls. The combined incidence of follicular adenomas and adenocarcinomas of the thyroid was increased significantly (7/20 [35%]; p < 0.01) in rats receiving treatment for 104 weeks. The authors concluded that the minimum induction time for renal adenoma development was 26 weeks. Kurokawa et al. (1987) exposed F344 rats (14-20/group) to water containing 500 ppm KBrO3 (29.6-35.5 mg BrO3-/kg) for 13, 26, 39, or 52 weeks and studied the incidence of renal cell tumors at 104 weeks. The incidence of renal dysplastic foci, adenomas, and adenocarcinomas in rats exposed for 13-52 weeks was equal to or greater than that in rats receiving potassium bromate treatment continuously for 104 weeks (as reported elsewhere in Kurokawa et al., 1987). The combined incidence of renal adenomas and adenocarcinomas was significantly higher in exposed animals than in controls (p < 0.001). The authors concluded that the minimum dose necessary for the induction of renal adenomas and adenocarcinomas was a cumulative dose of 4 g KBrO3/kg (3.08 g BrO3-/kg) and that the minimum treatment period for the induction of these tumors was 13 weeks. However, the authors also noted that the "true" minimum treatment time will be shorter than 13 weeks in experiments involving shorter exposure periods. The genotoxicity of bromate has been evaluated in a variety of in vitro and in vivo systems. It has tested positive in the Salmonella typhimurium assay in the presence of metabolic activation and in an in vitro test for chromosomal aberrations that uses Chinese hamster fibroblasts (Ishidate et al., 1984). Dose-dependent increases in the number of aberrant metaphase cells were observed following single oral doses of potassium bromate to Long-Evans rats (Fuji et al., 1988). Bromate caused significant increases in the number of micronuclei following either i.p. injection (Hayashi et al., 1988; Awogi et al., 1992) or gavage dose (Hayashi et al., 1989; Nakajima et al., 1989) in mice. Also, i.p. injection of bromate in F344 rats resulted in significantly increased micronuclei in reticulocytes (Sai et al., 1992a). Bromate was cytotoxic, increased the frequency of cells with micronuclei, increased the number of chromosome aberrations, and increased DNA migration in a series of assays that used V79 Chinese hamster cells (Speit et al., 1999). Furthermore, potassium bromate clearly induced gene mutations at the HPRT locus of V79 Chinese hamster cells (Speit et al., 1999). ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: ___II.B.1. SUMMARY OF RISK ESTIMATES ____II.B.1.1. Oral Slope Factor -- 7E-1 per (mg/kg-day) ____II.B.1.2. Drinking Water Unit Risk* -- 2E-5 per ug/L. *The unit risk should not be used if the water concentration exceeds 5E+2 ug/L, because above this concentration the unit risk may not be appropriate. _____II.B.1.3. Extrapolation Method Time-to-tumor, Weibull Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration E-4 (1 in 10,000) 5E+0 ug/L E-5 (1 in 100,000) 5E-1 ug/L E-6 (1 in 1,000,000) 5E-2 ug/L DCOE: __II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor type: testicular mesothelioma, renal tubular adenoma and carcinoma, and thyroid follicular cell adenoma and carcinoma Test animals: F344 rats, male Route: Ingestion, drinking water Reference: DeAngelo et al., 1998 Incidence (a) Administered Human Equivalent Testicular Thyroid Kidney Adenoma dose Dose (b) Mesothelioma Follicular and Carcinoma (mg BrO3- (mg BrO3-/kg-day) Adenoma and /kg-day) Carcinoma 0 0 0/71 0/60 1/69 1.1 0.3 4/73 4/63 1/67 6.1 1.7 5/73 2/67 6/71 12.9 3.5 11/71 5/58 3/62 28.7 7.9 31/67 17/54 18/56 (a) Includes tumor incidences from interim sacrifice groups. (b) Human equivalent dose was estimated using body weight to the 0.75 power. Tumor ED10 (a) LED10 (b) 0.1/LED10 (c) (mg/kg-day) (mg/kg-day) [(mg/kg-day)-1] Mesothelioma 0.38 0.20 0.50 Kidney 1.3 0.59 0.17 Thyroid 2.1 1.1 0.09 Tumor MLE of cancer q1* (e) potency (d) [(mg/kg-day)-1] [(mg/kg-day)-1] Mesothelioma 0.27 0.54 Kidney 0.08 0.18 Thyroid 0.05 0.10 (a) Estimated human equivalent dose, obtained by body weight to the 3/4 power scaling factor, resulting in a 10% increase in cancer risk. (b) 95% lower confidence limit on estimated human equivalent dose resulting in a 10% increase in cancer risk. (c) Unit cancer risk estimate based on drawing a straight line from the LED10 as described for the linear extrapolation default in U.S. EPA's 1996, "Proposed Guidelines for Carcinogen Risk Assessment." (d) Maximum likelihood estimate of cancer potency from Weibull time-to-tumor model, calculated at a dose of 1 ng/kg-day. (e) 95% upper confidence limit on cancer potency. ACOE: __II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) Oral cancer risk was calculated based on the incidence of renal tubular tumors, thyroid follicular tumors, and testicular mesotheliomas from the DeAngelo et al. (1998) study. The analyses were conducted using the individual male rat data, including the 12-, 26-, 52-, and 77-week interim kill data, for each site demonstrating an increased cancer incidence. Benign and malignant tumors were combined for the sites, that is, testicular mesotheliomas, kidney tubular adenomas and carcinomas, and thyroid follicular adenomas and carcinomas. Tumors were modeled for each site separately, and then the tumor site risks were combined to represent the total cancer risk. The multistage Weibull model was used in time-to-tumor analysis to help account for the early mortality in the highest dose groups. In the time-to-tumor analysis, tumor types are categorized as either fatal or incidental. Fatal tumors are those tumors thought to act rapidly to cause the animal to die, whereas incidental tumors are thought not to cause the death of the animal, or at least not rapidly. Each of the three tumor types observed in the U.S. EPA study was considered incidental (Wolf, 1998b). Thus, t0 was set equal to 0. In addition, a one-stage model was the preferred model for each tumor type. The highest cancer potency estimate for any individual tumor site was 0.54/mg/kg-day based on mesotheliomas. However, although time-to-tumor modeling does help account for decreased survival times in the rats, considering the tumor sites individually does not convey the total amount of risk potentially arising from multiple sites. To get some indication of the total unit risk from multiple tumor sites, assuming the tumors at these different sites arise independently, the MLEs of low-dose cancer potency from the Weibull time-to-tumor models were summed across tumor sites and an estimate of the 95% upper bound on the sum was calculated using a Monte Carlo analysis. The 95% upper bound for the total unit risk was 0.70/mg BrO3-/kg-day. A sensitivity analysis based on the contribution to variance reported that the variability associated with the risk estimate for the mesotheliomas was contributing 85% of the variance of the sum. CCOE: __II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) A low-dose linear extrapolation based on the U.S. EPA bromate study (DeAngelo et al., 1998) was conducted using a one-stage Weibull time-to-tumor model. This time-to-tumor model was selected because it can help account for the early mortality observed in treated animals as compared with control animals. Modeling was conducted on the individual tumor types, and cancer potency estimates were generated for the individual sites and for total risk from all three sites combined. Incidence of testicular mesotheliomas was the most sensitive response; however, the total cancer potency estimate was selected because it accounts for the total cancer risk posed by statistically significant tumors arising at multiple sites. It is assumed that these different tumors at different sites arise independently and that the different tumors are not necessarily induced by similar mechanisms. A source of uncertainty is the interspecies differences between rats and humans. Studies indicate that mice are less sensitive than rats to the effects of bromate. The reasons for this difference are unknown, and it is also unknown what the relative sensitivity between rats and humans is. Another uncertainty concerns how well the linear extrapolation predicts the low-dose human risks for bromate. The major limitation of the bromate hazard characterization is the lack of data on the effects of long-term exposure to bromate in humans. The available human data are limited to case reports of toxicity following acute, accidental ingestion. Therefore, to extrapolate rat tumor data for bromate to the human situation, it must be assumed that humans will respond like the rat. Nevertheless, the choice of using the rat tumor data from DeAngelo et al. (1998) in the absence of human data is a reasonable assumption. Overall, there is not enough evidence to give high confidence in a conclusion about any mode of carcinogenic action. Some studies show that bromate is weakly mutagenic and causes chromosomal aberrations (Ishidate et al., 1984; Fujie et al., 1988; Hayashi et al., 1988; Hayashi et al., 1989; Sai et al., 1992a; Speit et al., 1999). The mode of action by which bromate induces mutations and, thus, tumors, in the target organs is uncertain. Some studies show that bromate may generate oxygen radicals, which increase lipid peroxidation and damage DNA (Kasai et al., 1987; Sai et al., 1991; Sai et al., 1992a, 1992b, 1992c; Sai et al., 1994; Umemura et al., 1995). However, no data link this proposed mechanism to tumor induction. Thus, the available evidence is insufficient to establish this mechanism as a key event in the induction of tumors at the target organs observed. Given the uncertainty about the mode of action, a science policy decision is made to use a low-dose linear extrapolation approach as more protective of public health. The cancer risk estimation presented for bromate is considered to be protective of susceptible groups, including children, given that the low-dose linear default approach is used as a conservative approach. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE Lack of data by the inhalation route of exposure for bromate precludes the development of a quantitative estimate of carcinogenic risk from inhalation exposure. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2001 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in the finalization of in this IRIS summary. A record of these comments is included in Appendix A of the source document. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/1002-tr.pdf#page=54 RECA: ___II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 5/22/01 COCA: ___II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (513) 569-7254 (phone), (513) 569-7159 (FAX), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 200106 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Bromate CASRN -- 15541-45-4 Last Revised -- 06/06/2001 SORD: __VI.A. ORAL RfD REFERENCES Benson, CI. (1951) Potassium bromate poisoning. Br Med J 1:1516. DeAngelo, AB; George, MH; Kilburn, SR; et al. (1998) Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats. Toxicol Pathol 26(5):587-594. Gradus (Ben-Ezer), D; Rhoads, M; Bergstrom, LB; et al. (1984) Acute bromate poisoning associated with renal failure and deafness presenting as hemolytic uremic syndrome. Am J Nephrol 4:188-191. Kurokawa, Y; Hayashi, Y; Maekawa, A; et al. (1983) Carcinogenicity of potassium bromate administered orally to F344 rats. J Natl Cancer Inst 71:965-972. Kurokawa, Y; Aoki, S; Matsushima, Y; et al. (1986a) Dose-response studies on the carcinogenicity of potassium bromate in F344 rats after long-term oral administration. J Natl Cancer Inst 77:977-982. Kurokawa, Y; Takayama, S; Konishi, Y; et al. (1986b) Long-term in vivo carcinogenicity tests of potassium bromate, sodium hypochlorite and sodium chlorite conducted in Japan. Environ Health Perspect 69:221-236. Kurokawa, Y; Maekawa, A; Takahashi, M; et al. (1990) Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen. Environ Health Perspect 87:309-335. Lichtenberg, R; Zeller, WP; Gatson, R; et al. (1989) Bromate poisoning. J Pediatr 114:891-894. Lue, JN; Johnson, CE; Edwards, DL. (1988) Bromate poisoning from ingestion of professional hair-care neutralizer. Clin Pharm 7:66-70. Mack, RB. (1988) Round up the usual suspects. Potassium bromate poisoning. NC Med J 49:243-245. Matsumoto, I; Morizono, T; Paparella, MM. (1980) Hearing loss following potassium bromate: two case reports. Otolaryngol Head Neck Surg 88:625-629. Nakano, K; Okada, S; Toyokuni, S; et al. (1989) Renal changes induced by chronic oral administration of potassium bromate or ferric nitrilotriacetate in Wistar rats. Jpn Arch Intern Med 36:41-47. Quick, CA; Chole, RA; Mauer, SM. (1975) Deafness and renal failure due to potassium bromate poisoning. Arch Otolaryngol 101:494-495. U.S. EPA. (2001) Toxicological review of bromate. Integrated Risk Information System. http://www.epa.gov/iris. Warshaw, BL; Carter, MC; Hymes, LC; et al. (1985) Bromate poisoning from hair permanent preparations. Pediatrics 76(6):975-978. Watanabe, T; Abe, T; Satoh, M; et al. (1992) Two children with bromate intoxication due to ingestion of the second preparation for permanent hair waving. Acta Paediatr Jpn 34(6):601-605. Wolf, DC. (1998a) Personal communication from Douglas Wolf, National Health and Environmental Effects Research Laboratory, U.S. EPA, to Vicki Dellarco, Office of Water, U.S. EPA. February 20, 1998. ---------------------------------------------------------------------------- SORC: __VI.B. INHALATION RfC REFERENCES None. ---------------------------------------------------------------------------- SOCA: __VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Awogi, T; Murata, K; Uejima, M; et al. (1992) Induction of micronucleated reticulocytes by potassium bromate and potassium chromate in CD-1 male mice. Mutat Res 278(2-3):181-185. DeAngelo, AB; George, MH; Kilburn, SR; et al. (1998) Carcinogenicity of potassium bromate administered in the drinking water to male B6C3F1 mice and F344/N rats. Toxicol Pathol 26(5):587-594. Fujie, K; Shimazu, H; Matsuda, M; et al. (1988) Acute cytogenetic effects of potassium bromate on rat bone marrow cells in vivo. Mutat Res 206:455-458. Hayashi, M; Kishi, M; Sofuni, T; et al. (1988) Micronucleus tests in mice on 39 food additives and eight miscellaneous chemicals. Food Chem Toxicol 26:487-500. Hayashi, M; Sutou, S; Shimada, H; et al. (1989) Difference between intraperitoneal and oral gavage application in the micronucleus test: The 3rd collaborative study by CSGMT/JEMS-HMS. Mutat Res 223:329-344. Ishidate, M; Sofuni, T; Yoshikawa, K; et al. (1984) Primary mutagenicity screening of food additives currently used in Japan. Food Chem Toxicol 22:623-636. Kasai, H; Nishimura, S; Kurokawa, Y; et al. (1987) Oral administration of the renal carcinogen, potassium bromate, specifically produces 8-hydroxydeoxyguanosine in rat target organ DNA. Carcinogenesis 8:1959-1961. Kurata, Y; Diwan, BA; Ward, JM. (1992) Lack of renal tumour-initiating activity of a single dose of potassium bromate, a genotoxic renal carcinogen in male F344/NCr rats. Food Chem Toxicol 30(3):251-259. Kurokawa, Y; Hayashi, T; Maekawa, A; et al. (1983) Carcinogenicity of potassium bromate administered orally to F344 rats. J Natl Cancer Inst 71: 965-972. Kurokawa, Y; Aoki, S; Matsushima, Y; et al. (1986a) Dose-response studies on the carcinogenicity of potassium bromate in F344 rats after long-term oral administration. J Natl Cancer Inst 77:977-982. Kurokawa, Y; Takayama, S; Konishi, Y; et al. (1986b) Long-term in vivo carcinogenicity tests of potassium bromate, sodium hypochlorite and sodium chlorite conducted in Japan. Environ Health Perspect 69:221-236. Kurokawa, Y; Matsushima, Y; Takamura, N; et al. (1987). Relationship between the duration of treatment and the incidence of renal cell tumors in male F344 rats administered potassium bromate. Jpn J Cancer Res 78:358-364. Matsushima, Y; Takamura, N; Imazawa, T; et al. (1986) Lack of carcinogenicity of potassium bromate after subcutaneous injection to newborn mice and newborn rats. Sci Rep Res Inst Tohoku Univ 33:22-26. Nakajima, M; Kitazawa, M; Oba, K; et al. (1989) Effect of route of administration in the micronucleus test with potassium bromate. Mutat Res 223:399-402. NTP. (1998) National Toxicology Program Historical Controls Database. http://ehis.niehs.nih.gov. Sai, K; Takagi, A; Umemura, T; et al. (1991) Relation of 8-hydroxydeoxyguanosine formation in rat kidney to lipid peroxidation, glutathione level and relative organ weight after a single administration of potassium bromate. Jpn J Cancer Res 82(2):165-169. Sai, K; Hayashi, M; Takagi, A; et al. (1992a) Effects of antioxidants on induction of micronuclei in rat peripheral blood reticulocytes by potassium bromate. Mutat Res 269(1):113-118. Sai, K; Uchiyama, S; Ohno, Y; et al. (1992b) Generation of active oxygen species in vitro by the interaction of potassium bromate with rat kidney cell. Carcinogenesis 13(3):333-339. Sai, K; Umemura, T; Takagi, A; et al. (1992c) The protective role of glutathione, cysteine and vitamin C against oxidative DNA damage induced in rat kidney by potassium bromate. Jpn J Cancer Res 83(1):45-51. Sai, K; Tyson, CA; Thomas, DW; et al. (1994) Oxidative DNA damage induced by potassium bromate in isolated rat renal proximal tubules and renal nuclei. Cancer Lett 87:1-7. Speit, G; Haupter, S; Schutz, P; et al. (1999) Comparative evaluation of the genotoxic properties of potassium bromate and potassium superoxide in V79 Chinese hamster cells. Mutat Res 439:213-221. Umemura, T; Sai, K; Takagi, A; et al. (1995) A possible role for oxidative stress in potassium bromate (KBrO3) carcinogenesis. Carcinogenesis 16:593-597. Wolf, GW; Kaiser, L. (1996) Final report. Sodium bromate: short term reproductive and developmental toxicity study when administered to Sprague-Dawley rats in the drinking water. Submitted to National Toxicology Program, National Institute of Environmental Health Sciences. NTP/NIEHS No.: NOI-ES-15323. U.S. EPA. (1986) Guidelines for carcinogen risk assessment. Federal Register 51(185):33992-34003. U.S. EPA. (1996) Proposed guidelines for carcinogen risk assessment; notice. April 23, 1996. Fed. Reg. 61, No. 79: 17960-18011. U.S. EPA. (2001) Toxicological review of bromate. Integrated Risk Information System. http://www.epa.gov/iris. Wolf, DC. (1998a) Personal communication from Douglas Wolf, National Health and Environmental Effects Research Laboratory, U.S. EPA, to Vicki Dellarco, Office of Water, U.S. EPA. February 20, 1998. Wolf, DC. (1998b) Personal communication from Douglas Wolf, National Health and Environmental Effects Research Laboratory, U.S. EPA, to Jennifer Jinot, National Center for Environmental Assessment, U.S. EPA. January 12, 1998. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Bromate CASRN -- 15541-45-4 Date Section Description ---------------------------------------------------------------------------- 04/01/1997 III., IV., V. Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. 06/06/2001 I.A., II., VI RfD and carcinogenicity assessments first on line. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 443 of 1119 in IRIS (through 2003/06) AN: 1004 LNKS: Click here for IRIS background documents http://www.epa.gov/iris/backgr-d.htm , Click here for the toxicological review for this chemical http://www.epa.gov/iris/toxreviews/1004-tr.pdf UD: 200109 NTIR: ***{The general Introductory Paragraph to an IRIS record is now in the on-screen IRIS guide.}*** ID: -------------------SUBSTANCE IDENTIFICATION (USE CODE ZID)------------------ PN: Quinoline- SY: 91-22-5; 1-AZANAPHTHALENE-; 1-BENZAZINE-; BENZOPYRIDINE-; LEUCOLINE-; BENZO[B]PYRIDINE; 1-BENZINE-; CHINOLEINE-; CHINOLINE-; LEUCOL-; LEUKOL-; B-500- RN: 91-22-5 HANE: ============================================================================ _I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS UDRD: 200109 RFDO: -------------------------------USE CODE ZRFD-------------------------------- __I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD) Substance Name -- Quinoline CASRN -- 91-22-5 Last Revised -- 09/27/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURD: ___I.A.1. ORAL RfD SUMMARY An oral RfD for quinoline is not available at this time. PSRD: ___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD) No human studies pertaining to subchronic or chronic toxicity or carcinogenicity of quinoline were identified. Limited information from the studies summarized below regarding the oral toxicity of quinoline in animals following subchronic exposures was available from carcinogenicity bioassays. All of these oral studies had limitations, some major. The oral carcinogenicity study by Hirao et al. (1976) reported minimal hepatic changes in rats fed diets containing 0.05% (low-dose), 0.10% (mid-dose), or 0.25% (high-dose) quinoline for 16-40 weeks. These changes included increased absolute and relative liver weights, fatty change, slight-to-moderate bile duct proliferation, and slight-to-moderate oval cell infiltration. None of these data were reported in a manner that would allow for an appropriate and meaningful quantitative dose-response assessment (e.g., variance information was not provided for body weight change, liver weight change was not reported, and lesions were reported categorically). Nodular hyperplasia, a preneoplastic lesion, was observed in the mid- and high-dose animals. The dose-response for fatty change and nodular hyperplasia paralleled that for hepatocellular carcinoma. SGOT and alkaline phosphatase activities were slightly increased in the low-dose animals; liver enzyme activity was not measured in mid- or high-dose animals. There was a dose-dependent decrease in terminal body weights. Early mortality was high in the mid- and high-dose animals because of rupture of vascular tumors of the liver. The average survival periods for the control, low-, mid,- and high-dose animals were 40, 36.5, 27.3, and 20 weeks. This study's limitations include small sample size, only males being examined, a lack of statistical analyses, early death and the examination of a limited number of toxicity parameters. Minimal hepatic lesions were also reported in the carcinogenicity bioassay by Shinohara et al. (1977). In one experiment of the study, rats, mice, hamsters, and guinea pigs were administered 0.2% quinoline in the diet for 30 weeks. Mice and rats exhibited oval cell formation, bile duct proliferation, megalocytosis, and nodular hyperplasia. Fatty change was also seen in the rat. Hamsters, but not guinea pigs, displayed megalocytosis and oval cell formation. No controls were used in the first experiment; therefore, it is difficult to fully interpret the significance of the findings. In the second series of experiments, increased absolute and relative liver weights, trace oval cell formation, trace bile duct proliferation, moderate fatty change, moderate megalocytosis, and nodular hyperplasia were observed in rats fed 0.075% quinoline in the diet for 30 weeks. The increase in liver weight was attributed to the development of tumors. Limitations of this study include that only one dose level was examined, there were no controls for the first series of experiments, only one sex was examined in the second series of experiments, no statistical analysis was conducted, and only limited parameters were examined. Similar hepatic effects to those described above were noted in the carcinogenicity bioassay by Hasegawa et al. (1989). The Hasegawa et al. (1989) study was designed to assess the effect of duration on tumor induction. Changes consisted of increased liver weight, increased SGOT and alkaline phosphatase activities, megalocytosis, gross findings (black nodules or cysts), endothelial dysplasia, and hyperplastic nodules. The study authors considered the increase in alkaline phosphatase at weeks 16 and 20 an endothelial marker enzyme reflecting the increased size of tumors. Body weights were decreased in the treated animals at all exposure durations. Deaths due to rupture of tumors were also reported. This study also had limitations, including examination of only one dose level and only one sex, and lack of measurement of all relevant endpoints including food consumption, urinalysis, and hematology. Although the above-mentioned studies were limited, hepatic changes, decreased body weight, and mortality due to rupture of tumors were consistent findings. Hepatic changes included tumor formation (as discussed in detail in Section 4.2.2). The hepatic changes (increased liver weight, fatty change, increased liver enzyme activity, oval cell infiltration, preneoplastic lesions), early mortalities, and body weight loss were considered by the various study authors to be related to the process of hepatocarcinogenesis. In support of this hypothesis, Hasegawa et al. point out that increase in ALP levels coincided with increased tumor size in the groups they exposed for longer duration (16 and 20 weeks), and effects such as megalocytosis, endothelial dysplasia, and nodular hyperplasia appeared to be strongly correlated with increased tumor size and incidence. It is also likely that the weight changes, and possibly the histopathological changes, were at least confounded by the formation of tumors. Thus, noncancer effects from oral exposure were confounded by and could not be disassociated from the carcinogenic effects of quinoline, and were not reported in a manner that would allow for a meaningful quantitative dose-response assessment. For these reasons, and in accordance with minimum database requirements outlined in EPA methods (U.S. EPA, 1994), an RfD was not derived. UMRD: ___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD) Not applicable. ACRD: ___I.A.4. ADDITIONAL STUDIES/COMMENTS (ORAL RfD) Not applicable. CORD: ___I.A.5. CONFIDENCE IN THE ORAL RFD Not applicable. EDRD: ___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD Source Document -- U.S. EPA, 2001 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in the finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for Quinoline. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/1004-tr.pdf#page=35. Agency Consensus Date -- 09/21/01 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Quinoline conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRD: ___I.A.7. EPA CONTACTS (ORAL RfD) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (fax), or Hotline.IRIS@epa.gov (Internet address). ---------------------------------------------------------------------------- UDRC: 200109 RFCO: -------------------------------USE CODE ZRFC-------------------------------- __I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC) Substance Name -- Quinoline CASRN -- 91-22-5 Last Revised -- 09/27/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** SURC: ___I.B.1. INHALATION RfC SUMMARY No human or animal inhalation toxicity data were available for consideration of an RfC. In accordance with minimum database requirements outlined in EPA methods (U.S. EPA, 1994) an RfC was not derived. See Sections I.A. and II for a discussion of the available toxicity data from other routes of exposure, including information on EPA support documents, reviews, and contacts associated with this assessment. PSRC: ___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC) None. UMRC: ___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC) None. IRCC: ___I.B.4. ADDITIONAL STUDIES/COMMENTS (INHALATION RfC) None. CORC: ___I.B.5. CONFIDENCE IN THE INHALATION RfC None. EDRC: ___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Quinoline conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. ECRC: ___I.B.7. EPA CONTACTS (INHALATION RfC) Not applicable. ============================================================================ UDCA: 200109 CALE: _II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE Substance Name -- Quinoline CASRN -- 91-22-5 Last Revised -- 09/27/2001 **{The Introductory Paragraph for this (sub)section is now in the on-screen IRIS guide.}** ECHC: -------------------------------USE CODE ZEHC-------------------------------- __II.A. EVIDENCE FOR HUMAN CARCINOGENICITY WEHC: ___II.A.1. WEIGHT-OF-EVIDENCE CHARACTERIZATION No reliable human epidemiological studies are available that address the potential carcinogenicity of quinoline. However, laboratory studies have shown that quinoline is mitogenic and mutagenic in vitro and in vivo (U.S. EPA, 1985; Hamoud et al., 1989; LaVoie et al., 1991; Lefevre and Ashby, 1992; Asakura et al., 1997; Suzuki et al., 1998), and that humans and rats share a common quinoline-metabolizing P450 enzyme (Reigh et al., 1996). As is discussed below, quinoline has been shown to be a hepatocarcinogen in male Sprague-Dawley and SHR rats and both sexes of ddY mice and Wistar rats following oral exposure. Quinoline has also been found to be a hepatocarcinogen in newborn male mice following intraperitoneal exposure (LaVoie et al., 1987, 1988; Weyland et al., 1993). Two important aspects of the carcinogenicity of quinoline are the relatively short latency period (as low as 12 weeks) for tumor formation, and the fact that one of the tumor types observed, hemangioendotheliomas, is uncommon in rats and mice. Quinoline is considered likely to be carcinogenic in humans in accordance with proposed EPA carcinogen risk assessment guidelines (U.S. EPA, 1996) on the basis of observations of exposure-related increased incidence of an unusual malignant tumor in multiple strains of rats and mice, multiple experiments using oral, i.p. and s.c. dosing at an early age. This determination is supported by studies that demonstrate that quinoline is genotoxic. EPA (1985) previously classified quinoline as a Group C possible human carcinogen under the existing EPA cancer guidelines (U.S. EPA, 1986). However, recent evidence from mitogenicity and mutagenicity studies and two dietary studies in rats (Futakuchi et al., 1996; Hasegawa et al., 1989) indicate that "sufficient" animal evidence exists, and that quinoline would now be classified as a Group B2 probable human carcinogen under the 1986 guidelines. For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, section 6 http://www.epa.gov/iris/toxreviews/1004-tr.pdf#page=29. , For more detail on Susceptible Populations, exit to the toxicological review, section 4.7 http://www.epa.gov/iris/toxreviews/1004-tr.pdf#page=23. HCDA: ___II.A.2. HUMAN CARCINOGENICITY DATA Inadequate. Human data are inadequate for assessment of the potential human carcinogenicity of quinoline. No reliable human epidemiological studies are available that address the potential carcinogenicity of quinoline, although Reigh et al. (1996) identified cytochrome P450 enzymes common to both rats and humans that mediate quinoline metabolic activity. In particular, CYP2E1 was shown to be involved in the formation of 3-hydroxyquinoline (3-OHQ) in both rat and human liver microsomes. This is important because 3-OHQ is a possible intermediate in the pathway to the formation of the 2,3-epoxide of quinoline, which has been suggested to be the active mutagenic metabolite of quinoline (Takahashi et al., 1988). Although no human studies are available to assess the potential for sensitive subpopulations, animal studies have shown that exposure to quinoline at an early age (1, 8, and 15 days after birth) can result in a tumorigenic response later in life of newborn mice and rats, particularly males, suggesting a need for further study into the childhood susceptibility of quinoline (LaVoie et al., 1987, 1988; Weyland et al., 1993; Shinohara et al., 1977). ACDA: ___II.A.3. ANIMAL CARCINOGENICITY DATA Sufficient. Several animal studies report hepatocarcinogenicity (hepatocellular carcinomas and hemangioendotheliomas or hemangiosarcomas, a vascular tumor) in rats and mice following oral dosing with quinoline (Futakuchi et al., 1996; Hasegawa et al., 1989; Hirao et al., 1976; Shinohara et al., 1977). Limitations of these studies include small sample size, examination of only one sex in some cases, early mortality, the lack of statistical analyses, the lack of clear distinction between hemangioendotheliomas and hemangiosarcomas, and/or short duration of exposure. Hirao et al. (1976) fed groups of 20 male Sprague-Dawley rats a diet containing 0.05% (low-dose), 0.10% (mid-dose), or 0.25% (high-dose) quinoline for approximately 16-40 weeks. A control group consisting of six rats was also included. Early mortality due to rupture of vascular tumors of the liver was observed in treated animals at all dose levels. Absolute and relative liver weights were significantly increased in all treatment groups, and the difference between initial and final mean body weights decreased with increasing dose. Histological examination of the liver revealed fatty change, bile duct proliferation, and oval cells in treated animals. Also, nodular hyperplasia was seen in the mid- and high-dose animals. The activities of serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase were slightly increased in the low-dose animals; these parameters were not measured in the mid- and high-dose animals. Tumors were evaluated for all rats after 40 weeks of treatment. Rats that died within the first 16 weeks were excluded. Mortality was observed in all dose groups; the mean survival period was 36.5 +/- 5.0 weeks, 27.3 +/- 6.0 weeks, and 20.0 +/- 3.8 weeks in the low-, mid-, and high-dose groups, respectively. An increased incidence of hepatic tumors and nodular hyperplasia was noted in treated rats. Hirao et al. (1976) stated that the liver tumors induced by quinoline were classified histologically as hemangioendotheliomas or hemangiosarcomas and trabecular hepatocellular carcinomas. Hirao et al. (1976) did not make a clear distinction between hemangioendotheliomas (benign tumors) and hemangiosarcomas (malignant tumors). The incidences of hemangioendotheliomas or hemangiosarcomas in the control, low-dose, mid-dose, and high-dose groups were 0/6, 6/11, 12/16, and 18/19, respectively. Metastatic changes arising from these tumors were detected in the lungs of some of the rats. The authors' report that these foci "showed the same histological pattern as hemangiosarcomas with large irregular nuclei and many mitotic figures" is sufficient evidence to suggest that they were related to the liver tumors and did not originate in the lungs. The incidences of hepatocellular carcinomas in the control, low-dose, mid-dose, and high-dose groups were 0/6, 3/11, 3/16, and 0/19, respectively. The incidences of nodular hyperplasia in these dose groups were 0/6, 6/11, 4/16, and 0/19, respectively. The decreased incidence of hepatocellular carcinomas and nodular hyperplasia in the high-dose group might be reflective of early mortality (i.e., rats died of ruptured hemangiosarcomas before they had time to contract other liver carcinomas). Limitations of this study include its small sample size, the fact that only males were examined, the limited toxicity parameters examined, early deaths, and the lack of statistical analyses. Shinohara et al. (1977) studied sex and species differences in susceptibility to quinoline-induced histological lesions and tumors. Male and female ddY mice, Wistar rats, Syrian golden hamsters, and Hartley guinea pigs were examined in the first series of experiments, whereas only male Sprague-Dawley rats were examined in the second series of experiments. In the first series of experiments, animals were given a basal diet containing 0.2% quinoline for 30 weeks. A control group was not included. Animals that died prior to 26 weeks were excluded from the study. Examinations were limited to the liver, kidneys, and spleen. For the first series of experiments, body weight changes for all species tested were reported but are difficult to evaluate without corresponding controls. Further complicating the evaluation of this first experiment was the fact that half of the male and half of the female mice died of pneumonia within the first 6 weeks of the experiment. Liver weight, as a percentage of body weight, increased in all species tested. Liver hepatic changes (graded as trace in severity) in the mouse included oval cells, bile duct proliferation, and megalocytosis. These same hepatic changes were observed in the rat; however, the severity was graded as slight. Rats also exhibited fatty changes (trace severity). Nodular hyperplasia was observed in both rats (58% in males, 64% in females) and mice (10% in males, 20% in females). Only trace oval cell and megalotcytosis lesions were observed in the livers of hamsters (males only) and no lesions were observed in guinea pigs. The incidences of hemangioendotheliomas, hepatocellular carcinomas, and nodular hyperplasia in rats were 11/15, 2/15, and 7/15, respectively, in males and 7/22, 2/22, and 14/22 in females. The incidences of hemangioendotheliomas, hepatocellular carcinomas, and nodular hyperplasia in mice were 8/10, 1/10, and 1/10, respectively, in males, and 8/10, 0/10, and 2/10 in females. The authors stated that "some of the rats [four males and one female] had hemorrhagic metastatic foci in the lungs," without indicating the basis for the determination that these tumors did not originate in the lungs. However, given that these lung tumors occurred only in the mid- and high-dose groups and that Hirao et al. (1976) reported metastatic foci in the lungs that had the same histological pattern as hemangiosarcomas of the liver, it is reasonable to assume, for the purposes of this assessment, that these authors are correct in this regard. There were no tumors in hamsters or guinea pigs; however, the duration of the experiment was only 30 weeks. In the second series of experiments, male Sprague-Dawley rats were treated with 0.075% quinoline in the diet for 30 weeks. A control group was included. The same liver lesions reported for rats in the first series of experiments (trace severity) were also noted in the second phase of the experiment. The incidences of hemangioendotheliomas, hepatocellular carcinomas, and nodular hyperplasia in the treated male rats were 6/20, 0/20, and 9/20, respectively. These tumors were not observed in the control rats. The results of the Shinohara et al. (1977) study indicate species differences in regard to liver tumorigenesis by quinoline, with mice and rats being most susceptible and hamsters and guinea pigs being resistant. Limitations of this study include that only one dose level was examined, there were no controls for the first series of experiments, only one sex was examined in the second series of experiments, there was no statistical analysis, and only limited parameters were examined. Hasegawa et al. (1989) reported hepatic effects in an oral carcinogenicity bioassay designed to assess the effect of exposure duration on liver tumor induction. In this study, groups of male Wistar rats were administered 0.25% quinoline in the diet for 0 (control), 4, 8, 12, 16, or 20 weeks. Quinoline intake was reported to be 0.56, 1.21, 1.88, 2.59, or 3.33 grams/rat at weeks 4, 8, 12, 16, and 20, respectively. Rats were either sacrificed immediately after these time intervals or were sacrificed at 4, 8, 12, 16, or 20 weeks after cessation of treatment. The study authors stated that main organs and any gross pathological lesions were subjected to histologic examination. Hepatic alterations observed in the treated rats consisted of gross findings (black nodules or cysts at >12 weeks), increased SGOT activity (>= 4 weeks), increased alkaline phosphatase activity (16 weeks), increased relative liver weights (>= 4 weeks), megalocytosis (>= 4 weeks), endothelial dysplasia (>= 16 weeks), and hyperplastic nodules (at 20 weeks). Body weights were decreased in the treated animals at all exposure durations. The authors reported that several rats died during the period between the scheduled sacrifice times from to rupture of the vascular tumors of the liver. An increased incidence of hepatic hemangioendotheliomas was observed in rats treated with quinoline for >= 12 weeks. The incidences of hepatic hemangioendotheliomas in rats treated with quinoline for 12 weeks, and then sacrificed at the intervals described above, were 1/11 (12 weeks), 2/12 (16 weeks), and 5/12 (20 weeks; p < 0.05). After 16 weeks of treatment prior to sacrifice, the incidences were 4/14 (16 weeks; p < 0.05) and 4/18 (20 weeks). Following 20 weeks of treatment and immediate sacrifice, the incidence was 5/16 (p < 0.05). Incidence in control animals sacrificed at 20 weeks following no treatment was 0/12. In addition, no tumors were observed in animals exposed to quinoline for 4 and 8 weeks and sacrificed after a latency period of from 0 to 16 weeks (not exceeding 20 weeks treatment + latency period). An increase in the incidence of endothelial dysplasia (stated by the study authors as a preneoplastic precursor) was also observed in rats treated with quinoline. Hasegawa et al. (1989) concluded that the critical period for induction of tumors with 0.25% quinoline is 12 weeks, and that it is likely that quinoline possesses strong initiating potential rather than promoting activity for hepatic hemangiocellular carcinogenesis, assuming an analogy to the two-stage carcinogenesis hypothesis in skin and hepatocytes. This study is limited in that only one dose level and only one sex were examined, and not all relevant endpoints (such as food consumption, urinalysis, and hematology) were studied. Quinoline can apparently act as a promoter of liver carcinogenicity as well (Saeki et al., 1997). Quinoline, 3-fluoroquinone, or 5-fluoroquinone was fed to F344 male rats in their diet (0.1% and 0.05%) for a period of 6 weeks following a single i.p. injection of the liver carcinogen diethylnitrosamine (DEN, 200 mg/kg). Control groups were administered DEN alone. All rats were subjected to a partial (two-thirds) hepatectomy at the end of week 3 and sacrificed at the end of week 8. The number and areas of GST-P (placental glutathione S-transferase)-positive foci induced in the liver increased significantly as a result of treatment with 0.1%, but not 0.05%, quinoline. Futakuchi et al. (1996) conducted a study to determine the susceptibility of the spontaneously hypertensive rat (SHR) to quinoline-induced hepatic hemangioendothelial sarcomas, considered a vascular neoplasm originating from hepatic endothelial cells. Male SHR and Wistar Kyoto rats (WKY), the parent strain of SHR, were administered 0.2% quinoline in the diet for 32 weeks. The number of rats with hepatic hemangioendothelial sarcomas was 7% for SHR and 93% for WKY. The results of this study show that the SHR is less susceptible to hepatic carcinogenicity than is the WKY. On the basis of the lack of findings of vascular lesions, the authors concluded that the observed vascular tumorigenesis was not directly related to vascular physiological injury. The strain differences in carcinogenic response reported in this study are most likely the result of differences in metabolic activation between the two strains of rats. Quinoline has also been reported to be a hepatocarcinogen in newborn male mice following intraperitoneal exposure (LaVoie et al., 1987, 1988; Weyland et al., 1993). Hepatic tumors (carcinomas, adenomas, and basophilic altered foci) were observed in male newborn mice, but not male or female newborn rats. Only basophilic altered foci were observed in female newborn mice. Quinoline initiated skin tumors in female SENCAR mice following dermal application (LaVoie et al., 1984). Male mice were not examined. SDCA: ___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY Numerous reports are available regarding the in vitro mutagenicity of quinoline activated with S-9, a supernatant fraction from Arochlor, 3-methylcholanthrene and beta-naphthoflavone-treated rats, in both reverse and forward mutation assays with several strains of Salmonella typhimurium (U.S. EPA, 1985; LaVoie et al., 1991). Quinoline was found to have significant activity in the Salmonella typhimurium strain TA100 but generally not in strains TA1537 and TA1538 (U.S. EPA, 1985), nor TA98 (Debnath et al., 1992), suggesting that it may be acting via base-pair substitution (U.S. EPA, 1985). The fact that quinoline mutagenicity requires S-9 activation indicates that it must be metabolized to its active moeity by liver enzymes, presumably cytochrome P450 (or P448) enzymes (Hollstein et al., 1978; U.S. EPA, 1985). In rat microsomal preparations, quinoline has been shown to bind to various nucleic acids, including RNA and DNA, to form adducts (Tada et al., 1980). The results suggest that the cytochrome P450-linked monooxygenase system is involved in the binding process. Chemical hydrolysis of the quinoline-nucleic acid adducts resulted in the liberation of 3-hydroxyquinoline, a metabolite of quinoline. These results suggest that a 2,3- or 3,4-epoxy derivative of quinoline is the reactive intermediate for nucleic acid modification. Support for this hypothesis comes from more recent studies involving fluorine and chlorine substitution at various locations on the quinoline rings. 3-Fluoro- and 2- and 3-chloro-quinolines were less mutagenic than all other fluoro- and chloro-substituted derivatives of quinoline (Takahashi et al., 1988; Saeki et al., 1993). The 3-fluoro derivative of quinoline completely blocks the mutagenic activity of quinoline. Substitutions at other locations do not reduce quinoline's mutagenicity, and in some cases enhance it (presumably by inhibiting detoxification pathways). Takahashi et al. (1988) suggest that it is the 2,3-epoxide that is the active metabolite, based on the fact that the 4-chloro isomer is weakly mutagenic (presumably no mutagenicity would be observed if a 3,4-epoxide were necessary), the 4-methyl isomer is strongly mutagenic (suggested to be because of suppression of detoxification of the 2,3-epoxide), and the 2-methyl isomer is weakly mutagenic (the authors report that methyl substitution at the site of epoxide formation is known to partially reduce mutagenicity). LaVoie et al. (1983) proposed that the 5,6-epoxide of quinoline is the carcinogenic moeity. However, quinoline is still mutagenic when halogenated at the 5 or 6 position, and the 5,6-epoxide of quinoline is much less mutagenic than quinoline itself (Saeki et al., 1993). Using this and information on the metabolism of 3-fluoroquinone, Saeki et al. (1993) proposed human and rat metabolic pathways for detoxification and activation, with a 2,3-epoxide of quinoline forming the ultimate DNA adduct. Reigh et al. (1996) claim to have identified the cytochrome P450 enzymes responsible for quinoline metabolite formation in human and rat liver microsomes. In particular, CYP2E1 was shown to be involved in the formation of 3-hydroxyquinoline (3-OHQ) in both rat and human liver microsomes, which may be an important intermediate in the pathway to the formation of the mutagenic epoxide discussed above. Reigh et al. (1996) also pointed out some possible species differences between rats and humans in the metabolism of quinoline that suggest the need for further investigations in this area. In vitro studies show that microsomally activated quinoline can induce unscheduled DNA synthesis (UDS) in rat hepatocytes (LaVoie et al., 1991). These in vitro UDS results together with the in vitro results discussed above suggest that the genotoxicity of quinoline may play an important role in its hepatocarcinogenicity. However, equivocal results were reported in a study designed to evaluate the ability of quinoline to initiate UDS in rat liver in vivo (Ashby et al., 1989). Ashby et al. (1989) reported marginal positive responses for some individual animals but there were no clear group-positive responses and no dose relationship. The authors concluded that quinoline is unclassifiable in the in vivo UDS test. They also determined that a structurally related chemical, 8-hydroxyquinoline, which was mutagenic to Salmonella (Nagao et al., 1977) but noncarcinogenic in an NTP (1985) chronic bioassay, was inactive in the UDS assay. However, during the course of studies performed to determine whether quinoline was active in the UDS assay, Ashby et al. (1989) observed an increased incidence of semiconservative DNA synthesis (S-phase) in the rat liver cells, which led them to perform S-phase and micronucleus assays for quinoline and 8-hydroxyquinoline. Quinoline was found to be a powerful S-phase inducer, with an optimum response between 16 and 36 hours after oral dosing of 225-500 mg/kg, whereas the same doses of 8-hydroxyquinoline did not induce S-phase. The mitogenicity of quinoline was also indicated by a subsequently elevated incidence of mitotic figures and by its ability to act as a chemical mitogen in the liver micronucleus assay. In a similar S-phase assay, quinoline was also shown to be a mitogen to the mouse liver, but not the guinea pig liver (Lefevre and Ashby, 1992), corresponding to the relative sensitivity of these two species to quinoline induced tumor formation. Recent studies by Asakura et al. (1997) and Suzuki et al. (1998), however, lend further support to the proposed genotoxicity mechanism. Asakura et al. (1997) examined the potential of quinoline to induce chromosome aberrations and sister chromatid exchanges in the rat liver utilizing an in vivo cytogenetic assay. Hepatocytes were isolated 4-48 hours following a single dose of 200 mg/kg bodyweight or 24 hours after 28 repeated doses (once daily) of 25-200 mg/kg/day by gastric intubation. Both treatment regimens resulted in the induction of chromosome aberrations and sister chromatid exchanges in the liver. Cytogenetic effects induced in the liver by repeated doses of quinoline were shown to be greater than those induced by a single dose. In addition, quinoline induced replicative DNA synthesis in the rat liver but, contrary to findings in CD1 mice (Hamoud et al., 1989), it did not induce micronucleus formation in the bone marrow of rats. The results of the Asakura et al. (1997) study suggest that quinoline is a genotoxic carcinogen to the rat liver, having both tumor-initiating and tumor-promoting activity. Suzuki et al. (1998) conducted a study to evaluate the mutagenicity of quinoline in an in vivo mutation assay system using the lac Z transgenic mouse (Muta Mouse). Mutation was induced in the liver, the target organ of carcinogenesis by quinoline, but not in the other organs examined, i.e., lung, kidney, and spleen. Mutant frequency in the liver was fourfold higher than in the untreated control animals. Dimethylnitrosamine, used as a positive control, induced mutation at a frequency fivefold higher in the liver and threefold higher in the spleen than in their respective control organs. Given the studies that show quinoline to be genotoxic, and those discussed above concerning the in vivo mitogenicity of quinoline, it is possible that there are both genotoxic and mitogenic components to the pathogenesis of the hepatocarcinogenicity of quinoline. It is also apparent that conjugation of quinoline can play an important detoxification role, depending upon the site at which quinoline is conjugated (Takahashi et al., 1988; Saeki et al., 1993). However, specific detoxification pathways have not been identified. ---------------------------------------------------------------------------- CROE: -------------------------------USE CODE ZCOE-------------------------------- __II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE SUOE: __II.B.1. SUMMARY OF RISK ESTIMATES Limitations in the available studies that impact the dose-response assessment for quinoline include small sample sizes, examination of only one sex in some cases, early mortality, the lack of statistical analyses, the lack of clear distinction between hemangioendotheliomas and hemangiosarcomas, and/or short durations of exposure. Nevertheless, they provide ample evidence of hepatocarcinogenesis (including vascular tumors of the liver) in the rat and the mouse by the oral route of exposure, particularly because of the relatively short latency. One of the tumor types, hemangioendotheliomas, is uncommon in the rat and the mouse. In addition, quinoline has been shown to be a tumor initiator in the skin of female SENCAR mice. Also, the mutagenicity and mitogenicity of quinoline has been demonstrated in the rat and mouse liver. EPA previously performed a cancer dose-response assessment based on the oral carcinogenicity bioassay of Hirao et al. (1976) (U.S. EPA, 1985). The current reassessment of the Hirao et al. (1976) study by EPA is summarized below. Both the previous and current assessments are discussed in more detail in the toxicological review (U.S. EPA, 2001) associated with this summary profile. ___II.B.1.1. Oral Slope Factor -- 3 per (mg/kg)/day (see text discussion below) (Hirao et al., 1976; hepatic hemangioendotheliomas or hemangiosarcomas) ___II.B.1.2. Drinking Water Unit Risk -- 9E-5 per (ug/L) (represents the upper-bound excess lifetime cancer risk estimated to result from continuous exposure to 1 ug quinoline/L in water) ___II.B.1.3. Extrapolation Method -- EPA (1985) made an adjustment to reflect the fact that the different treatment groups were terminated before the end of the normal lifespan of the rats, which is typically 104 weeks in experimental studies. The doses were adjusted by a factor [Le/L]3, where Le is the length of the experiment and L is the normal lifespan. This factor is used because tumor rate generally increases by at least the third power of age, and adjusting the doses by a factor of [Le/L]3 is consistent with adjusting the slope factor (unit risk) by [L/Le]3. The mean length of experiment for the control, low-, mid-, and high-dose animals was 40, 36.5, 27.3, and 20 weeks, respectively. Thus the adjusted doses for these dose groups were 0, 1.08, 0.90, and 0.89 mg/kg/day, respectively. In the present reassessment, the mean survival time for each dose group was employed directly in a time-to-tumor dose-response model, using administered dose levels of 25, 50, and 125 mg/kg/day, rather than dose levels adjusted for fractions of a lifespan. This procedure should more accurately compensate for the shorter experiment duration than that used earlier by EPA (1985). Animal doses were adjusted to human doses using 3/4 power scaling. Humans were assumed to have daily exposure, beginning at age 0 and ending at age 70. The present risk estimate was calculated with the computer software TOX_RISK version 3.5 (Crump et al., ICF Kaiser International, Ruston, LA), which uses multistage Weibull models taken from Krewski et al. (1983). The one-stage Weibull model was selected based on the values of the log likelihoods. Although individual time-to-tumor data are preferred, they were unavailable in the Hirao et al. (1976) study. Mean data for each dose group were therefore employed for quantitating cancer risk. It was assumed that all the animals in each dose group died at the end of the mean experimental period for that dose group (i.e., 36.5, 27.3, and 20 weeks for the 25, 50, and 125 mg/kg/day dose groups, respectively). For the controls, historical control data from Anver et al. (1982) were used. This approach resulted in the calculation of an LED10 (i.e., lower bound 95% confidence limit on the dose that causes a 10% increase in the extra risk of an effect) of 32.6 ug/kg/day and an oral slope factor (0.1/LED10) of 3 (mg/kg/day)-1 for humans (in accordance with EPA policy, only one significant figure is retained). The linear extrapolation method described in EPA's proposed cancer guidelines (U.S. EPA, 1996) was used to obtain this estimate. Linear extrapolation is warranted by the positive evidence of mutagenicity for quinoline. Further details of this calculation are presented in the toxicological review associated with this assessment (U.S. EPA, 2001). The estimated oral cancer slope factor of 3 (mg/kg/day)-1 was used to obtain the following risk levels, which can be thought of as 95% lower bound risk estimates. Drinking Water Concentrations at Specified Risk Levels: Risk Level Concentration -------------------------------------------------------- E 4 (1 in 10,000) 1 ug/L E 5 (1 in 100,000) 0.1 ug/L E 6 (1 in 1,000,000) 0.01 ug/L DCOE: __II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE) Tumor Type -- hepatic hemangioendotheliomas or hemangiosarcomas Test animals -- male Sprague-Dawley rats Route -- oral, dietary Reference -- Hirao et al., 1976 Dose Incidence level* No. responding/No. tested or examined ----------------------------------------------------------------------- 0 0/6 [2/83]** 0.05% (500 ppm; 25 mg/kg/day) 6/11 0.10% (1,000 ppm; 50 mg/kg/day) 12/16 0.25% (2,500 ppm; 125 mg/kg/day) 18/19 *Because food consumption data were not provided, EPA (1985) converted the dose levels (% in feed) to mg/kg/day values by assuming that a rat consumes a daily amount of food equal to 5% of its body weight. ** Historical controls as reported by Anver et al. (1982). ACOE: __II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE) The cancer oral slope factor for quinoline is based on a limited study (Hirao et al., 1976) that was of less than lifetime duration, involved just 20 animals per dose group, and did not report individual animal data. However, the study does provide dose-response data that clearly indicate the induction of hemangioendotheliomas (or hemangiosarcomas) in rats. The tumors could not be classified as to their exact degree of malignancy. However, it is assumed that a significant percentage of the hemangioendotheliomas were malignant (U.S. EPA, 1985). There was a dose-dependent increase in the incidence of hemangioendotheliomas that was associated with increased mortalities and body weight loss. CCOE: __II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE) No reliable human epidemiological studies are available that address the potential carcinogenicity of quinoline. However, laboratory studies have shown that quinoline is mitogenic and mutagenic in vitro and in vivo, and that humans and rats share a common quinoline-metabolizing P450 enzyme (Reigh et al., 1996). The evidence that quinoline is carcinogenic in rats and mice is strengthened by observations of a short latency period for the formation of tumors and the formation of tumors (hemangioendotheliomas) that are rarely observed in these rodent species. Taken together, these facts strengthen the potential relevance to humans of studies that show quinoline to be hepatocarcinogenic in rats and mice following oral and i.p. exposures. The oral cancer slope factor of 3 (mg/kg/day)-1 is based on the linear extrapolation method described in EPA proposed cancer guidelines (U.S. EPA, 1996). Uncertainty is reduced from the 1985 assessment by using time-to-tumor modeling, eliminating the need to adjust dose by the cube of experiment duration/lifespan. The inclusion of 83 historical controls from a study reported by Anver et al. (1982) using the same strain of rats decreases uncertainty further. However, only one study was identified that provided dose-response data for the induction of hemangioendotheliomas (or hemangiosarcomas), and the limitations in the Hirao et al. (1976) study (e.g., few animals, study terminated after only 40 weeks, no individual animal data) are too significant to warrant any more than low confidence in the slope factor estimate. ---------------------------------------------------------------------------- CRIE: -------------------------------USE CODE ZCIE-------------------------------- __II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE No human or animal inhalation toxicity data were available for derivation of an inhalation cancer slope factor. There are no pharmacokinetic data available that would allow for the use of oral data to postulate the effects of inhalation exposures. Further, there is evidence to suggest that first-pass liver metabolism that can occur subsequent to oral and i.p., but not inhalation and s.c. exposures, may play an important role in the formation of liver tumors. Liver tumors have been observed in rats and mice exposed to quinoline via oral and i.p. routes of exposure, but not in rats exposed subcutaneously, despite the fact that the s.c. injections resulted in maximally tolerated doses more than 40 times higher than i.p. doses given to mice (LaVoie et al., 1988). The observation of skin tumors on mice dermally exposed to quinoline and a tumor promoter, tetradecanoyl phorbol acetate (LaVoie et al., 1984), suggest that quinoline can initiate skin tumors (no other tumor types were reported) without first-pass metabolism in the liver. See Sections I.A, II.A, and II.B for a discussion of the available toxicity data from other routes of exposure, including information on EPA support documents, reviews, and contacts associated with this assessment. ---------------------------------------------------------------------------- EDCA: -------------------------------USE CODE ZECA-------------------------------- __II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT) DOCA: ___II.D.1. EPA DOCUMENTATION Source Document -- U.S. EPA, 2001 Other EPA Documentation -- U.S. EPA, 1985 This assessment was peer reviewed by external scientists. Their comments have been evaluated carefully and incorporated in finalization of this IRIS summary. A record of these comments is included as an appendix to the Toxicological Review for Quinoline. To review this appendix, exit to the toxicological review, Appendix A, Summary of and Response to External Peer Review Comments http://www.epa.gov/iris/toxreviews/1004-tr.pdf#page=35. RECA: __II.D.2. EPA REVIEW (CARCINOGENICITY ASSESSMENT) Agency Consensus Date -- 09/21/01 Screening-Level Literature Review Findings -- A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Quinoline conducted in September 2002 DID NOT IDENTIFY ANY CRITICAL NEW STUDIES. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 301-345-2870. COCA: __II.D.3. EPA CONTACTS (CARCINOGENICITY ASSESSMENT) Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (301) 345-2870 (phone), (301) 345-2876 (fax), or Hotline.IRIS@epa.gov (Internet address). ============================================================================ UDSO: 200109 SO: -------------------------------USE CODE ZBIB-------------------------------- _VI. BIBLIOGRAPHY Substance Name -- Quinoline CASRN -- 91-22-5 Last Revised -- 09/27/2001 NOSO: _VI.A. ORAL RfD REFERENCES Hasegawa, R; Furukawa, F; Toyoda K; et al. (1989) Sequential analysis of quinoline-induced hepatic hemangioendothelioma development in rats. Carcinogenesis 10(4):711-716. Hirao, K; Shinohara,Y; Tsuda, H; et al. (1976) Carcinogenic activity of quinoline on rat liver. Cancer Res 36(1):329. Shinohara, Y; Ogiso, T; Hananouchi, M; et al. (1977) Effect of various factors on the induction of liver tumors in chemicals by quinoline. GANN 68:785-796. U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F, October 1994. U.S. EPA. (2001) Toxicological Review of Quinoline in Support of Summary Information on the Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. -------------------------------------------------------------------------------- _VI.B. INHALATION RfC REFERENCES U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F, October 1994. -------------------------------------------------------------------------------- _VI.C. CARCINOGENICITY ASSESSMENT REFERENCES Anver, MR; Cohen BJ; Lattuada CP; et al. (1982) Age-associated lesions in barrier-reared male Sprague-Dawley rats: a comparison between Hap: (SD) and Crl:COBS[R](SD)[R] stocks. Exp Aging Res 8(1):3-24. Asakura, S; Sawada, S; Sugihara, T; et al. (1997) Quinoline-induced chromosome aberrations and sister chromatid exchanges in rat liver. Environ Mol Mutagen 30(4):459-467. Ashby, J; Mohammed, R; LeFevre, PA; et al. (1989) Quinoline: unscheduled DNA synthesis and mitogenesis data from the rat liver in vivo. Environ Mol Mutagen 14:221-228. Debnath, AK; Lopez de Compadre, RL; Hansch, C. (1992) Mutagenicity of quinolines in Salmonella typhimurium TA100. A QSAR study based on hydrophobicity and molecular orbital determinants. Mutat Res 280(1):55-65. Futakuchi, M; Hasegawa, R; Yamamoto, A; et al. (1996) Low susceptibility of the spontaneously hypertensive rat (SHR) to quinoline-induction of hepatic hemangioendothelial sarcomas. Cancer Lett 104:37-41. Hamoud, MA; Ong, T; Petersen M; et al. (1989) Effects of quinoline and 8-hydroxyquinoline on mouse bone marrow erythrocytes as measured by the micronucleus assay. Carcinogen Mutagen 9(2):111-118. Hasegawa, R; Furukawa, F; Toyoda, K; et al. (1989) Sequential analysis of quinoline-induced hepatic hemangioendothelioma development in rats. Carcinogenesis 10(4):711-716. Hirao, K; Shinohara,Y; Tsuda, H; et al. (1976) Carcinogenic activity of quinoline on rat liver. Cancer Res 36(1):329. Hollstein, MR; Talcott, R; Wei, E. (1978) Quinoline: conversion to a mutagen by human and rodent liver. J Natl Cancer Inst 60(2):405-410. Krewski D; Crump KS; Farmer J; et al. (1983) A comparison of statistical methods for low dose extrapolation utilizing time-to-tumor data. Fundam Appl Toxicol 3:140-160. La Voie EJ; Adams EA; Shigematsu A; et al. (1983) On the metabolism of quinoline and isoquinoline: possible molecular basis for differences in biological activities. Carcinogenesis (4):1169-1173. LaVoie, EJ; Shigematsu, A; Adams EA; et al. (1984) Tumor-initiating activity of quinoline and methylated quinolines on the skin of SENCAR mice. Cancer Lett 22:269-273. LaVoie, EJ; Shigematsu, A; Rivenson, A. (1987) The carcinogenicity of quinoline and benzoquinolines in newborn CD-1 mice. Jpn J Cancer Res (78):139-143. LaVoie, EJ; Dolan, S; Little, P; et al. (1988) Carcinogenicity of quinoline, 4-and 8-methylquinoline and benzoquinolines in newborn mice and rats. Food Chem Toxicol 26(7):625-629. LaVoie, EJ; Defauw, J; Fealy, M; et al. (1991) Genotoxicity of fluoroquinolines and methylquinolines. Carcinogenesis 12: 217-220. LeFevre, P; Ashby, J. (1992) Mitogenic activity of quinoline to the rat, mouse and guinea pig liver. Environ Mol Mutagen 20:39-43. Nagao, M; Yahagi, T; Seino, Y; et al. (1977) Mutagenicities of quinoline and its derivatives. Mutat Res (42):335-342. National Toxicology Program (NTP). (1985) National Toxicology Program (NTP) toxicological and carcinogenesis studies of 8-hydroxyquinoline in F344-N rats and B6C3F1 mice (feed studies). NTP Technical Report 276. Reigh, G; McMahon, H; Ishizaki, M; et al. (1996) Cytochrome P450 species involved in the metabolism of quinoline. Carcinogenesis 17(9):1989-1996. Saeki, K; Takahashi, K.; Kawazoe, Y. (1993) Metabolism of mutagenicity deprived 3-fluoroquinoline: comparison with mutagenic quinoline. Biol Pharm Bull 16(3):232-234. Saeki, K; Kadoi, M; Kawazoe, Y; et al. (1997) Modification of the carcinogenic potency of quinoline, a hepatocarcinogen, by fluorine atom substitution: evaluation of carcinogenicity by a medium-term assay. Biol Pharm Bull (20):40-43. Shinohara, Y; Ogiso, T; Hananouchi, M; et al. (1977) Effect of various factors on the induction of liver tumors in chemicals by quinoline. GANN 68:785-796. Suzuki, T; Miyata, Y; Saeki, K; et al. (1998) In vivo mutagenesis by the hepatocarcinogen quinoline in the lacZ transgenic mouse: evidence for its in vivo genotoxicity. Mutat Res (412):161-166. Tada, M; Takahashi, K; Kawazoe, Y; et al. (1980) Binding of quinoline to nucleic acid in a subcellular microsomal system. Chem Biol Interact 29:257-266. Takahashi et al. (1988) Deprivation of the mutagenicity property of quinoline: inhibition of mutagenic metabolism by fluorene substitution. Chem Pharm Bull 36(11):4630-4633. U.S. EPA. (1985) Health and Environmental Effects Profile for Quinoline. Environmental Criteria and Assessment Office; EPA, Cincinnati, OH. U.S. EPA. (1986) Guidelines for carcinogen risk assessment (51 FR 33992). U.S. EPA. (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry. EPA/600/8-90/066F, October 1994. U.S. EPA. (1996) Proposed guidelines for carcinogen risk assessment, Notice, 1996. Federal Register 61(79):17960-18011. U.S. EPA. (2001) Toxicological Review of Quinoline in Support of Summary Information on the Integrated Risk Information System (IRIS). National Center for Environmental Assessment, Washington, DC. Available online from http://www.epa.gov/iris. Weyland, EH; Defauw, J; McQueen, CA; et al. (1993) Bioassay of quinoline, 5-fluoroquinoline, carbazole, 9-methylcarbazole and 9-ethylcarbazole in newborn mice. Food Chem Toxicol 31(10):707-715. ============================================================================ HIST: _VII. REVISION HISTORY Substance Name -- Quinoline CASRN -- 91-22-5 ---------------------------------------------------------------------------- Date Section Description ---------------------------------------------------------------------------- 09/27/2001 I., II., VI. Assessment first on-line 12/03/2002 I.A.6., I.B., II.D.2. Screening-Level Literature Review Findings message has been added. ++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++ Record 444 of 1119 in OHMTADS (Final version) AN: 7216674 ID: -------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)--------------- PN: 1,3-DICHLOROPROPENE- SY: 1-PROPENE,-1,3-DICHLORO- (9CI); PROPENE,-1,3-DICHLORO- (8CI); ALPHA-CHLOROALLYL-CHLORIDE-; ALPHA,GAMMA-DICHLOROPROPYLENE-; GAMMA-CHLOROALLYL-CHLORIDE-; DICHLOROPROPENE-; NCI-CO3985-; PROPYLENE,-1,3-DICHLORO-; 1,3-D-; 1,3-DICHLORO-1-PROPENE-; 1,3-DICHLORO-2-PROPENE-; 1,3-DICHLOROPROPENE-1-; 1,3-DICHLOROPROPENE,-E,Z-; 1,3-DICHLOROPROPYLENE-; 3-CHLOROALLYL-CHLORIDE-; 3-CHLOROPROPENYL-CHLORIDE-; (SEE OHMTADS ACCESSION NUMBERS 8500391 AND 8500392 FOR SPECIFIC INFORMATION ON THE CIS AND TRANS-ISOMERS, RESPECTIVELY.); TELONE- (Tradename); TELONE II (DOW CHEMICAL) (SEE FIELD IMP FOR TRADENAMES OF MIXTURES.) (Tradename) RN: 542-75-6 RTEC: UC8310000 ST: C3H4CL2; CLCH2CH:CHCL IMP: 1,3-DICHLOROPROPENE IS A MAJOR CONSTITUENT IN A NUMBER OF COMMERCIAL FUMIGANT MIXTURES WITH OTHER DICHLOROPROPENES, DICHLOROPROPANES, AND SUCH COMPONENTS AS EPICHLOROHYDRIN, ISOTHIOCYANATOMETHANE, CHLOROPICRIN, TRICHLORONITROMETHANE, AND ETHYLENE DIBROMIDE. TRADE NAMES FOR THE MIXTURES INCLUDE D-D SOIL FUMIGANT (SHELL); DOWFUME NC; VIDDEN D (DOW); NEMEX; EP-201; VORLEX (NOR-AM); DI-TRAPEX; D-D-PICFUME; TERR-O-CIDE 30-D, TERR-O-GAS (GREAT LAKES CHEMICAL); PIC-CLOR 60; DOWLONE (DOW); NEW FIELDFUME (FMC). TELONE SOIL FUMIGANT IS 99% 1,3-DICHLOROPROPENE; TELONE II SOIL FUMIGANT CONTAINS 92% 1,3-DICHLOROPROPENE. (CL2C3* 81/FRA) UPDATED 12/1984. CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)----------- MP: -84 DEGREES CELSIUS IS FREEZING POINT FOR 92% MATERIAL. (14CYAT 2B,81/CLA) BP: BOILING POINT OF MIXED CIS- AND TRANS-ISOMERS IS 108 DEGREES CELSIUS. (MERCK* 83/WIN) SOL: 2700 TO 2800; 2700 PPM IS REPORTED FOR THE CIS-ISOMER; 2800 PPM, FOR THE TRANS-ISOMER. (AQFAT* 81/MAB) THE SOLUBILITY OF THE TECHNICAL GRADE PRODUCT IS 0.1 G/100 G WATER (~1000 PPM). (RREVAH 36,1,71/MEL) UPDATED 12/1984. DEN: 1.220 (AT 25 DEGREES CELSIUS. MIXTURE OF CIS- AND TRANS-ISOMERS. (MERCK* 83/WIN) UPDATED 12/1984) VAP: 28 MM HG AT 20 DEGREES CELSIUS. (FMCHA2 83/BER) SATURATED AIR CONTAINS 3.7% AT 25 DEGREES CELSIUS. (14CYAT 2B,81/CLA) UPDATED 12/1984. VAPD: 3.8 (FPGHM* 78/NFPA) IRCI: ---------------REACTIVITY INFORMATION CATEGORY (USE CODE ZRCI)-------------- ADD: EPICHLOROHYDRIN AT 1 TO 2% IS OFTEN ADDED AS A STABILIZER AND CORROSION INHIBITOR. (CL2C3* 81/FRA) BIN: 1,3-DICHLOROPROPENE REACTS VIGOROUSLY WITH OXIDIZERS. DANGEROUS FIRE HAZARD WHEN EXPOSED TO OXIDIZERS AS WELL AS HEAT OR FLAME. (DPMADX 79/SAX) COR: DO NOT PLACE OR STORE 1,3-DICHLOROPROPENE IN CONTAINERS MADE OF ALUMINUM, MAGNESIUM, OR THEIR ALLOYS. (FMCHA2 83/BER) SGM: COMPOUNDS USED IN MIXTURES WITH 1,3-DICHLOROPROPENE OFTEN POSE A GREATER HAZARD THAN THE DICHLOROPROPENE ITSELF. SEE FIELD IMP. (CL2C3* 81/FRA) IENE: --------ENVIRONMENTAL CHEMISTRY INFORMATION CATEGORY (USE CODE ZENE)-------- LOC: 1,3-DICHLOROPROPENE IS A LIQUID WITH THE ODOR OF CHLOROFORM. IT IS OFTEN MIXED WITH OTHER COMPOUNDS. (MERCK* 83/WIN) WILL SINK AND DISSOLVE. CLEAR STRAW-COLORED LIQUID WITH A SHARP, SWEET, PENETRATING, AND IRRITATING ODOR. (85FHA9 2,83/VER) DRT: SOME SOIL BACTERIA CAN UTILIZE 1,3-DICHLOROPROPENE AS A CARBON SOURCE. ADSORPTION BY SOIL MAY BE PROPORTIONAL TO ORGANIC CONTENT OF THE SOIL. 1,3-DICHLOROPROPENE UNDERGOES CHEMICAL HYDROLYSIS IN SOIL TO 3-CHLOROALLYL ALCOHOL. (USPEDU 2,79/CAL) 1,3-DICHLOROPROPENE MAY PERSIST IN SOILS 2 TO 4 MONTHS. (AWQCD* PB81-117541,80/ECAO) WHEN 1,3-DICHLOROPROPENE IN A COMMERCIAL NEMATOCIDE WITH METHYL ISOTHIOCYANATE WAS APPLIED TO A PODZOLIZED SANDY SOIL, IT WAS HIGHLY MOBILE. AFTER IRRIGATION OF THE TREATED AREA (40 L/M2), IT WAS FOUND 4 DAYS AFTER THE NEMATOCIDE APPLICATION AT A DEPTH OF 4 M AND BY 140 DAYS AFTER APPLICATION, IT WAS FOUND IN NEIGHBORING IRRIGATION WELLS. (NDPBA6 34(11)161,82/REX) HOH: HYDROLYSIS-HYDROLYSIS PRODUCTS OF 1,3-DICHLOROPROPENE INCLUDE 3-CHLOROALLYL ALCOHOL WITH POSSIBLE DEGRADATION TO 3-CHLOROACROLEIN OR MALONDIALDEHYDE. HALF-LIFE FOR HYDROLYSIS EXPECTED TO BE SEVERAL MONTHS. (USPEDU 2,79/CAL) DRUMS. (CHMCY* 3,84/KUN) CONTAINERS REQUIRED BY LAW-DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS TABLE (49CFR* 172.101,6-12-84/DOT): SHIPPING NAME DICHLOROPROPENE. PACKAGING EXCEPTIONS CITED IN 49CFR 173.118. SPECIFIC PACKAGING REQUIREMENTS CITED IN 49CFR 173.119 (FLAMMABLE LIQUIDS NOT SPECIFICALLY PROVIDED FOR) MAXIMUM NET QUANTITY IN ONE PACKAGE: 1 QUART ON PASSENGER AIRCRAFT OR RAILCARS; 10 GALLONS ON CARGO-ONLY AIRCRAFT. DEPARTMENT OF TRANSPORTATION OPTIONAL HAZARDOUS MATERIALS TABLE (49CFR* 172.102,10-31-83/DOT): UN PACKING GROUP II. ICAO INSTRUCTIONS (ICAO** 83/ICAO)-PACKING GROUP II; PACKING INSTRUCTIONS FOR PASSENGER AIRCRAFT 305 AND FOR CARGO AIRCRAFT 307. MAXIMUM NET QUANTITY IN ONE PACKAGE: 5 L ON PASSENGER AIRCRAFT; 60 ON CARGO-ONLY AIRCRAFT. UPDATED 12/1984. PER: BASED UPON DATA FOR CHLORINATED ETHENES, DIRECT PHOTOLYSIS OF 1,3-DICHLOROPROPENE IS EXPECTED TO BE SLOW ALTHOUGH RAPID PHOTOOXIDATION IS EXPECTED IN THE TROPOSPHERE. 1,3-DICHLOROPROPENE HAS A HALF-LIFE IN SOIL OF 20 TO 70 DAYS. THE EVAPORATIVE HALF-LIFE IS EXPECTED TO BE IN THE RANGE OF 0.5 HOUR TO SEVERAL HOURS, DEPENDING ON CONDITIONS. (USPEDU 2,79/CAL) AT 1 PPM IN WATER AT 25 DEGREES CELSIUS, 50% EVAPORATED AFTER 31 MINUTES AND 90%, AFTER 98 MINUTES. (85FHA9 2,83/VER) UPDATED 12/1984. PFA: BASED ON AN ESTIMATED LOG OCTANOL/WATER PARTITION COEFFICIENT (LOG P) OF 1.98 FOR 1,3-DICHLOROPROPENE, BIOACCUMULATION MAY BE POSSIBLE UNDER CHRONIC EXPOSURE CONDITIONS. NO EXPERIMENTAL DATA ON BIOACCUMULATION WERE REPORTED. HOWEVER, BIODEGRADATION HAS BEEN REPORTED. (USPEDU 2,79/CAL) UPDATED 12/1984. FOO: POTENTIAL ITRN: -------TRANSPORTATION AND STORAGE INFORMATION CATEGORY (USE CODE ZTRN)------ USE: 1,3-DICHLOROPROPENE IS USED AS A MAJOR INGREDIENT IN SOIL FUMIGANTS TO CONTROL NEMATODES AND OTHER CROP PESTS AND AS FEEDSTOCK FOR CHLORINATED SOLVENT MANUFACTURE. USE AS FEEDSTOCK IS EXPECTED TO DECREASE IN FUTURE YEARS. (CL2C3* 81/FRA) UPDATED 12/1984. TRNS: 40.3 (RAL), 47.8 (BRG), 11.9 (TRK) STRG: Containers USUAL SHIPPING CONTAINERS FOR 1,3-DICHLOROPROPENE--DOW CHEMICAL'S TELONE IS SHIPPED IN TANKCARS, TANK TRUCKS, AND 30- AND 55-GALLON DRUMS. (CHMCY* 3,84/KUN) CONTAINERS REQUIRED BY LAW--DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS TABLE (49CFR* 172.101,6-12-84/DOT): SHIPPING NAME DICHLOROPROPENE. PACKAGING EXCEPTIONS CITED IN 49CFR 173.118. SPECIFIC PACKAGING REQUIREMENTS CITED IN 49CFR 173.119 (FLAMMABLE LIQUIDS NOT SPECIFICALLY PROVIDED FOR) MAXIMUM NET QUANTITY IN ONE PACKAGE: 1 QUART ON PASSENGER AIRCRAFT OR RAILCARS; 10 GALLONS ON CARGO-ONLY AIRCRAFT. DEPARTMENT OF TRANSPORTATION OPTIONAL HAZARDOUS MATERIALS TABLE (49CFR* 172.102,10-31-83/DOT): UN PACKING GROUP II. ICAO INSTRUCTIONS (ICAO** 83/ICAO)--PACKING GROUP II; PACKING INSTRUCTIONS FOR PASSENGER AIRCRAFT 305 AND FOR CARGO AIRCRAFT 307. MAXIMUM NET QUANTITY IN ONE PACKAGE: 5 L ON PASSENGER AIRCRAFT; 60 ON CARGO-ONLY AIRCRAFT. UPDATED 12/1984. General Storage Procedures DO NOT PLACE OR STORE 1,3-DICHLOROPROPENE IN CONTAINERS MADE OF ALUMINUM, MAGNESIUM, OR ALLOYS OF THESE METALS. HANDLE AS A FLAMMABLE LIQUID. STORE IN TIGHTLY CLOSED CONTAINERS IN A COOL PLACE. (FMCHA2 83/BER) UPDATED 12/1984. HND: WEAR RUBBER GLOVES (THIDD6 80/ITII) AND PROTECTIVE CLOTHING. WEAR NIOSH- OR MSHA- APPROVED RESPIRATORY PROTECTION FOR OPERATIONS IN WHICH 1,3-DICHLOROPROPENE CAN VENT TO THE ATMOSPHERE. AN APPROVED HALF-FACE RESPIRATOR WITH CHEMICAL WORKER'S GOGGLES OR A FULL-FACE RESPIRATOR IS NECESSARY FOR WORK INVOLVING SMALL SPILLS, REPAIRS, CALIBRATIONS, TRANSFERS, SAMPLING, AND POOR VENTILATION. REPLACE CANISTERS OR CARTRIDGES DAILY OR AT FIRST SIGN OF ODOR BREAKTHROUGH. (FMCHA2 83/BER) SEE ADDITIONAL INFORMATION IN FIELD SAF. UPDATED 12/1984. MFS: DOW CHEMICAL COMPANY U.S.A., TEXAS DIVISION, FREEPORT, BRAZORIA COUNTY, TX, 77541, EPA REGION 06, MID NO. 1022; COLUMBIA ORGANIC CHEMICALS COMPANY, P. O. BOX 9096, 912 DRAKE STREET, COLUMBIA, RICHLAND COUNTY, SC, 29290, EPA REGION 04, MID NO. 2596; SHELL CHEMICAL COMPANY, NORCO MANUFACTURING COMPLEX, P. O. BOX 10, NORCO, ST. CHARLES PARRISH, LA, 70079, EPA REGION 06, MID NO. 4632; (PRDTN* 81/TSCA) ISAF: ----------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)---------------- STD: 1,3-DICHLOROPROPENE IS ON THE SUPERFUND DESIGNATED (HAZARDOUS SUBSTANCES) LIST. (FEREAC 50FR13456, 4-4-85) RCRA HAZARDOUS WASTE NUMBER U084. REPORTABLE QUANTITY (RQ): 5000 LB (STATUTORY SOURCES UNDER CERCLA ARE CWA SECTION 307(A) AND RCRA SECTION 3001.) FINAL RQ: 5000 LB (2270 KG). CATEGORY B. NFPA SUGGESTED HAZARD IDENTIFICATION CODE: 2,3,0. (FPGHM* 78/NFPA) ASSOCIATION OF AMERICAN RAILROADS STCC NUMBER FOR 1,3-DICHLOROPROPENE: 4909255. (BUXEH* 81/STU) DEPARTMENT OF TRANSPORTATION HAZARDOUS MATERIALS TABLE (49CFR* 172.101,6-12-84/DOT)-SHIPPING NAME DICHLOROPROPENE. HAZARD CLASS: FLAMMABLE LIQUID; UN 2047; LABEL(S) REQUIRED: FLAMMABLE LIQUID. SEE FIELD STRG FOR PACKAGING EXCEPTIONS AND SPECIFIC REQUIREMENTS FOR WATER SHIPMENTS. ON CARGO VESSELS, STOW ON DECK OR UNDER DECK; ON PASSENGER VESSELS, STOW ON DECK. DEPARTMENT OF TRANSPORTATION OPTIONAL HAZARDOUS MATERIALS TABLE (49CFR* 172.102,10-31-83/DOT)-IMCO CLASS 3.3; UN 2047; LABEL(S) REQUIRED: FLAMMABLE LIQUID; PACKING GROUP 88. VESSEL STOWAGE REQUIREMENTS: ON CARGO VESSELS, STOW ON DECK OR UNDER DECK; ON PASSENGER VESSELS, STOW ON DECK OR UNDER DECK. ICAO RECOMMENDATIONS (ICAO** 83/ICAO)-UN CLASS OR DIVISION 3; LABEL(S) LIQUID FLAMMABLE. UPDATED 12/1984. FPOT: 1,3-DICHLOROPROPENE IS QUITE FLAMMABLE. (FPGHM* 78/NFPA) IGNITABLE UNDER ALMOST ALL NORMAL CONDITIONS. (FPGHM* 78/NFPA) FLASHBACK MAY OCCUR ALONG VAPOR TRAIL. VAPOR IN AN ENCLOSED AREA MAY IGNITE. (CGHCD* 78/USCG) DANGEROUS FIRE HAZARD WHEN EXPOSED TO HEAT, FLAME, OR OXIDIZING MATERIALS. (DPMADX 79/SAX) UPDATED 12/1984. FLMT: LFL: 5.3 (FPGHM* 78/NFPA) UFL: 14.5 (FPGHM* 78/NFPA) TOXC: DICHLOROPROPENES WILL EMIT TOXIC FUMES OF HCL AND OTHER CHLORIDES WHEN HEATED TO DECOMPOSITION. (AWQCD* PB81-117541,80/ECAO) 216674 031 USE POWDERS, HALONS, CARBON DIOXIDE. KEEP TANKS AND DRUMS COOL BY SPRAYING WATER. (HCSDA* 80/DAS) NFPA RECOMMENDATIONS FOR 1,3-DICHLOROPROPENE-USE WATER SPRAY, DRY CHEMICAL, FOAM, OR CARBON DIOXIDE. WATER SPRAY MAY NOT EXTINGUISH THE FIRE BUT CAN DISPERSE VAPORS, PROTECT WORKERS, OR FLUSH SPILLS. (FPGHM* 78/NFPA) DOT RECOMMENDATIONS FOR DICHLOROPROPENE-FOR SMALL FIRES, DRY CHEMICALS, CO2, OR FOAM. FOR LARGE FIRES, USE WATER SPRAY, FOG, OR FOAM. MOVE CONTAINER FROM FIRE AREA IF IT CAN BE DONE WITHOUT RISK. KEEP WATER OUT OF CONTAINERS. COOL CONTAINERS EXPOSED TO A FIRE WITH WATER FROM THE SIDE UNTIL WELL AFTER FIRE IS OUT, AND WITHDRAW IMMEDIATELY IF A RISING SOUND IS HEARD FROM THE VENTING SAFETY DEVICE OR IF THE TANK DISCOLORS. (85EWAF 80/DOT) BUREAU OF EXPLOSIVES RECOMMENDATIONS FOR 1,3 DICHLOROPROPENE-GENERALLY SIMILAR TO THOSE OF DOT. DO NOT ATTEMPT TO EXTINGUISH FIRE UNLESS FLOW CAN BE STOPPED. USE WATER IN FLOODING QUANTITIES AS A FOG SINCE SOLID STREAMS OF WATER MAY SPREAD FIRE. APPLY WATER FROM AS FAR AWAY AS POSSIBLE. USE WATER SPRAY TO KNOCK DOWN VAPORS. (BUXEH* 81/STU) FLPT: 35 (DEGREES CELSIUS/95 DEGREES FAHRENHEIT (FPGHM* 78/NFPA)) AUTO: 21 (APPROXIMATELY FOR TECHNICAL GRADE 1,3-DICHLOROPROPENE . (RREVAH 36,1,71/MEL)) EXPL: CONTAINER MAY EXPLODE IN HEAT OF FIRE AND RUNOFF TO SEWER MAY BE A FIRE OR EXPLOSION HAZARD. DICHLOROPROPENES ARE A VAPOR EXPLOSION HAZARD INDOORS, OUTDOORS, OR IN SEWERS. (85EWAF 80/DOT) 1,3-DICHLOROPROPENE CAN REACT VIGOROUSLY WITH OXIDIZING MATERIALS. (DPMADX 79/SAX) LEL: 4.3 (APPROXIMATE VALUE GIVEN FOR A 92% TECHNICAL PRODUCT OF 1,3-DICHLOROPROPENE (14CYAT 2B,81/CLA)) UEL: 10.6 (APPROXIMATE VALUE GIVEN FOR A 92% TECHNICAL PRODUCT OF 1,3-DICHLOROPROPENE (14CYAT 2B,81/CLA)) SAF: DO NOT TOUCH SPILLED DICHLOROPROPENE. STAY UPWIND AND OUT OF LOW AREAS. (85EWAF 80/DOT) RESPIRATORY PROTECTION IS REQUIRED FOR 1,3-DICHLOROPROPENE; SELECTION IS BASED ON EXPOSURE. VERY HIGH CONCENTRATIONS OF VAPOR REQUIRES A SELF-CONTAINED RESPIRATOR; SHORT-TERM EXPOSURE MAY REQUIRE ONLY A HALF-FACE RESPIRATOR WITH APPROVED CARTRIDGES AND CHEMICAL WORKER'S GOGGLES FOR EYE PROTECTION. WEAR CLEAN BODY COVERING INCLUDING GLOVES AND HEAVY FOOTWEAR. REMOVE CONTAMINATED CLOTHING IMMEDIATELY; AERATE AND WASH THOROUGHLY AFTER USE. IN CASE OF CONTACT, WASH SKIN THOROUGHLY WITH SOAP AND WATER AND EYES WITH WATER THOROUGHLY FOR AT LEAST 15 MINUTES. NO PROTECTIVE CLOTHING MATERIAL IS COMPLETELY IMPERVIOUS. LEATHER GIVES NO PROTECTION. PROTECTIVE GEAR OF RUBBER, VINYL, OR 1 TO 3-MIL-THICK POLYETHYLENE WILL PROTECT FOR A SHORT TERM AND MUST BE REMOVED AND DISCARDED IMMEDIATELY UPON CONTAMINATION. HEAVY POLYETHYLENE (3 MIL), RUBBER, AND NEOPRENE WILL GIVE LONGER TERM PROTECTION. NEVER WEAR GEAR SMELLING OF 1,3-DICHLOROPROPENE. (FMCHA2 83/BER) U.S. COAST GUARD RECOMMENDATIONS FOR 1,3-DICHLOROPROPENE-WEAR APPROVED FULL-FACE MASK WITH A FRESH BLACK CANISTER MEETING ORGANIC VAPOR SPECIFICATIONS OF THE U.S. BUREAU OF MINES, A FULL-FACE SELF-CONTAINED BREATHING APPARATUS, OR A FULL-FACE AIR-SUPPLIED RESPIRATOR. (CGHCD* 78/USCG) UPDATED 12/1984. HTOX: Acute Hazard Level STRONG INGESTIVE AND INHALATIVE TOXICANT. MODERATELY TOXIC BY DERMAL ROUTE. STRONG IRRITANT. HAS PRODUCED LIVER AND KIDNEY DAMAGE IN EXPERIMENTAL ANIMALS. (DPMADX 79/SAX) TOXIC TO AQUATIC MICROLIFE. EMITS HIGHLY TOXIC VAPORS WHEN HEATED TO DECOMPOSITION. SERIOUS CENTRAL NERVOUS SYSTEM EFFECTS PRODUCED IN WORKERS CLEANING UP A HIGHWAY SPILL OF 1,3-DICHLOROPROPENE. THE WORKERS WORE CLOTHING CONTAMINATED BY THE COMPOUND. (CL2C3* 81/FRA) MAY POLLUTE SOIL AND GROUNDWATERS. (NDPBA6 34(11)161,82/REX) UPDATED 12/1984. Chronic Hazard Level UNKNOWN CHRONIC HAZARD. MAY WELL CONCENTRATE IN FOOD CHAIN TO TOXIC LEVELS. Degree of Hazard to Public Health LIMITED DATA ON 1,3-DICHLOROPROPENE INDICATE HUMAN CARCINOGENICITY AND BACTERIAL MUTAGENICITY. PROTECTION OF THE PUBLIC FROM DICHLOROPROPENE IS OF VITAL IMPORTANCE. HIGHLY TOXIC VIA INGESTION OR INHALATION. STRONG IRRITANT. EMITS HIGHLY TOXIC VAPORS WHEN HEATED TO DECOMPOSITION. UPDATED 12/1984. Air Pollution TOXIC, ACUTE LOCAL IRRITANT. HIGH. Inhalation Limit Data (NO IDLH HAS BEEN RECOMMENDED BY NIOSH.) Inhalation Limit Text THERE ARE NO OSHA REGULATIONS. RECOMMENDATIONS FOR 1,3-DICHLOROPROPENE--ACGIH TLV (TWA) (SKIN) 5 MG/M3 (1 PPM) (TLVADM 84/ACGIH) ACGIH STEL (SKIN) 50 MG/M3/15 MIN (10 PPM/15 MIN) (TLVADM 84/ACGIH) (SKIN) UPDATED 12/1984. ACT: ANY SPILLS SHOULD BE REPORTED TO THE FIRE DEPARTMENT, LOCAL HEALTH DEPARTMENT, WATER TREATMENT AGENCIES AND WILDLIFE AUTHORITIES. KEEP UNNECESSARY PEOPLE AWAY BY ISOLATING HAZARD AREA AND DENYING ENTRY. ISOLATE FOR 0.5 MILE IN ALL DIRECTIONS IF A TANK OR A TANKCAR IS INVOLVED IN A FIRE. DO NOT ALLOW FLARES, SMOKING, OR FLAMES IN THE HAZARD AREA. TRY TO STOP THE LEAK IF IT CAN BE DONE WITHOUT RISK. (85EWAF 80/DOT) UPDATED 12/1984. AML: DOT RECOMMENDATIONS FOR A SPILL OR LEAK OF DICHLOROPROPENE-USE WATER SPRAY TO REDUCE VAPORS, BUT AVOID GETTING WATER IN THE CONTAINERS. FOR SMALL SPILLS, TAKE UP WITH SAND OR OTHER NONCOMBUSTIBLE ABSORBENT MATERIAL AN FLUSH AREA WITH WATER. FOR LARGE SPILLS, DIKE FAR AHEAD OF SPILL FOR LATER DISPOSAL. (85EWAF 80/DOT) U.S. COAST GUARD RECOMMENDATIONS-PUMP AND DREDGE MATERIAL FROM AFFECTED WATER BODIES. (CGRSP* 78/USCG) BUREAU OF EXPLOSIVES RECOMMENDATIONS FOR 1,3-DICHLOROPROPENE-CONTAIN FLOW BY BUILDING DIKES. FOR LAND SPILLS, DIG A PIT, POND, LAGOON, OR HOLDING AREA TO CONTAIN THE SPILLED MATERIAL. USE SOIL, SAND BAGS, FOAMED POLYURETHANE, OR FOAMED CONCRETE TO DIKE SURFACE FLOW. USE FLY ASH, CEMENT POWDER, SAWDUST, OR COMMERCIAL SORBENTS TO ABSORB BULK LIQUID. DIMINISH VAPOR AND FIRE HAZARD BY APPLYING A FLUOROCARBON-WATER FOAM. FOR WATER SPILLS, TRAP MATERIAL AT BOTTOM WITH NATURAL DEEP WATER POCKETS, EXCAVATED LAGOONS, OR SAND BAG BARRIERS. USE SUCTION HOSES TO REMOVE TRAPPED MATERIAL AND MECHANICAL DREDGES OR LIFTS TO REMOVE IMMOBILIZED MASSES OF [SORBENTS]. (BUXEH* 81/STU) MRI RECOMMENDATIONS 12/1984-SEEK PROFESSIONAL ASSISTANCE FROM EPA'S ENVIRONMENTAL RESPONSE TEAM (ERT), EDISON, NJ, 24-HOUR NUMBER (201) 321-6660. CONTAIN AND ISOLATE SPILL TO LIMIT SPREAD. CONSTRUCT CLAY OR BENTONITE SWALE TO DIVERT UNCONTAMINATED PORTION OF WATERSHED AROUND CONTAMINATED PORTION. ISOLATION PROCEDURES INCLUDE CONSTRUCTION OF BENTONITE COMPATIBLE MATERIAL, NEOPRENE RUBBER, HARD RUBBER (EBONITE), OR NATURAL RUBBER DAMS, INTERCEPTOR TRENCHES, OR IMPOUNDMENTS. SEEK PROFESSIONAL HELP TO EVALUATE PROBLEM AND IMPLEMENT CONTAINMENT PROCEDURES. CONDUCT BENCH-SCALE AND PILOT-SCALE TESTS PRIOR TO IMPLEMENTATION OF FULL-SCALE DECONTAMINATION PROGRAM. FOR DENSITY STRATIFICATION AND IMPOUNDMENT, REMOVE PRODUCT FROM BOTTOM LAYER BY PUMPING THROUGH MANIFOLD OR BY POLYETHYLENE ROPE COLLECTION OR REMOVE CLARIFIED UPPER PORTION BY SKIMMERS OR SIPHONING. SOLIDS MAY BE REMOVED BY SETTLING BASINS. TREATMENT IS REQUIRED FOR BOTH CLARIFIED AND CONCENTRATED PRODUCT FRACTIONS. TREATMENT ALTERNATIVES FOR CONTAMINATED WATER INCLUDE ULTRAVIOLET IRRADIATION AND SOLAR OXIDATION; AERATION; EVAPORATION; AND BIODEGRADATION. CONTAMINATED WATER MAY BE KEPT FOR EXTENDED HOLDING PERIODS FOR HYDROLYSIS IMPOUNDED IN A LINED PIT WITH LEACHATE COLLECTION SYSTEM AND DOMED COVER. TREATMENT ALTERNATIVES FOR CONTAMINATED SOILS INCLUDE WELL POINT COLLECTION WITH TREATMENT OF LEACHATES AS FOR CONTAMINATED WATERS AND BENTONITE/CEMENT GROUND INJECTION TO IMMOBILIZE SPILL. PHYSICALLY REMOVE IMMOBILIZED RESIDUES. PLACE IMMOBILIZED RESIDUES IN A LINED PIT WITH LEACHATE COLLECTION SYSTEM AND DOMED COVER. CONTAMINATED SOIL OR IMMOBILIZED RESIDUES MAY BE PACKAGED FOR DISPOSAL. CONFIRM ALL TREATMENT PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. DISP: Disposal Method MRI RECOMMENDATIONS 12/1984--PRODUCT RESIDUES AND SORBENT MEDIA MAY BE PACKAGED IN EPOXY-LINED DRUMS AND DISPOSED OF AT A RCRA-APPROVED SECURE LANDFILL. DESTROY BY HIGH-TEMPERATURE INCINERATION WITH HYDROCHLORIC ACID SCRUBBER IF AVAILABLE. CONFIRM DISPOSAL PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. Disposal Notification CONTACT LOCAL AIR AUTHORITY. IFP: MAY REDUCE HEAT TRANSFER OR CAUSE HOT SPOTS AND SCALING. WAT: ALL USES. ITOX: ------------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOX)------------ CARC: NTP CARCINOGENESIS BIOASSAY FOR 1,3-DICHLOROPROPENE WAS IN PROGRESS AS OF JUNE 1983. (RTECS ONLINE 11/1984) IN THIS STUDY, ORAL DOSING OF A COMMERCIAL SOIL FUMIGANT FOR 2 YEARS PRODUCED MALIGNANT TUMORS IN THE LIVER AND FORESTOMACH IN MALE RATS AND IN THE FORESTOMACH, LUNGS, AND BLADDER IN FEMALE MICE. (OSAHR* 14(35)705,85/ANO) ONE STUDY FOUND STATISTICALLY SIGNIFICANT FORMATION OF TUMORS FROM INJECTIONS OF CIS-1,3-DICHLOROPROPENE IN HA: ICR SWISS RATS. (CL2C3* 81/FRA) THREE CASE HISTORIES INDICATE A RELATIONSHIP BETWEEN EXPOSURE TO 1,3-DICHLOROPROPENE AND HEMATOLOGIC MALIGNANCIES. TWO FIREMEN EXPOSED DURING A SPILL CLEANUP DIED OF LYMPHOMA WITHIN 7 YEARS; A FARMER HEAVILY EXPOSED DURING SOIL FUMIGATION DIED WITHIN 2 YEARS. (AIMDAP 144(7)1409,84/MAR) UPDATED 4/1985. ME: 1,3-DICHLOROPROPENE AND BOTH THE CIS- AND TRANS-ISOMERS SEPARATELY HAVE BEEN SHOWN TO BE MUTAGENIC IN AMES BIOASSAYS OF SALMONELLA TYPHIMURIUM BY SEVERAL RESEARCHERS. (CL2C3* 81/FRA) (GENETOX AND CCRIS ONLINE 3/1985). UPDATED 12/1984. RE: NO INFORMATION ON TERATOGENICITY. NO DETRIMENTAL EFFECTS ON FERTILITY IN 64 EMPLOYEES WITH SIGNIFICANT OCCUPATIONAL EXPOSURE TO 1,3-DICHLOROPROPENE. (CL2C3* 81/FRA) UPDATED 12/1984. ETXV: Fresh Water Toxicity Data Con Exp Species Effe Test E Ref c ct nv --- ----- -------------------------------------------- ---- ------ -------------------- 6.2 48 WATER FLEA (DAPHNIA MAGNA) LC50 STATIC BECTA6 24(5)684,80/L EB 6.1 96 YOUNG BLUEGILL (LEPOMIS MACROCHIRUS LC50 STATIC BECTA6 24(5)684,80/L EB 0.2 CHRON EMBRYO-LARVAL STAGE FATHEAD MINNOW (PIMEPHAL AWQCD* PB81-117541,8 44 IC ES PROMELAS) 0/ECAO UPDATED 12/1984. Chronic Aquatic Toxicity Limits <0.244; CHRONIC TOXIC EFFECTS TO FRESHWATER AQUATIC LIFE OCCURS AT CONCENTRATIONS AS LOW AS 0.244 MG 1,3-DICHLOROPROPENE/L AND TO SALT WATER AQUATIC LIFE, AS LOW AS 0.790 MG/L. PRESUMABLY, TOXICITY WOULD OCCUR AT LOWER CONCENTRATIONS TO SPECIES MORE SENSITIVE THAN THOSE TESTED. (AWQCD* PB81-117541,80/ECAO) UPDATED 12/1984. NTXV: Animal Toxicity Data Val Time Speci Tes Ad Ref es t m ---------- ----- ----- --- -- --------------------------------------------------------- 4650 (MG/M 2 HOU MUS LC5 IN 85GMAT -,48,82 [AS CITED IN RTECS ONLINE 3/1985] 3) RS 0 H 250 RAT LD5 OR GUCHAZ 6,192,73 [AS CITED IN RTECS ONLINE 11/1984] 0 L 504 RBT LD5 SK GUCHAZ 6,192,73 [AS CITED IN RTECS ONLINE 11/1984]. UPDA 0 N TED 12/1984. AQN: SALT WATER ALGAE 96-HOUR EC50 VALUE WAS 1.0 MG/L. FRESH WATER 96-HOUR EC50 VALUES WERE ABOUT 4.95 MG/L. SCENEDESMUS DETERIORATES FROM 40 PPM OR MORE. MST: ALL SPECIES. MAY SMOTHER BENTHIC LIFE. (85FHA9 2,83/VER) UPDATED 12/1984. IRL: SKIN IRRITATION GRADE 5 - NECROSIS FROM UNDILUTED; EYE IRRITATION GRADE 5 - SEVERE BURNS FROM .005 MG (R119** 0001). DRC: 1,3-DICHLOROPROPENE IS IRRITATING TO THE SKIN. CAUSES BLISTERS AND BURNS IN A VERY SHORT TIME. CAN CAUSE HUMAN EYE INJURIES. (CL2C3* 81/FRA) IRRITATING TO RESPIRATORY TRACT. (CL2C3* 81/FRA) CONTACT WITH LIQUID 1,3-DICHLOROPROPENE MAY CAUSE FIRST-DEGREE BURNS ON SHORT EXPOSURE AND SECOND-DEGREE BURNS ON LONGER EXPOSURE. SYMPTOMS OF EXPOSURE: SMARTING OF SKIN AND EYES. VAPORS CAUSE MODERATE IRRITATION SUCH THAT HIGH CONCENTRATIONS (>1 PPM IN AIR) ARE UNPLEASANT. (CGHCD* 80/USCG) UPDATED 12/1984. JNS: WARNING PROPERTIES OF 1,3-DICHLOROPROPENE-ODOR OF CHLOROFORM, BUT OLFACTORY FATIGUE IS OFTEN NOTED. ACUTE SYMPTOMS OR SIGNS FOR 1,3-DICHLOROPROPENE EXPOSURE-RESPIRATORY EFFECTS, ABDOMINAL CRAMPS, CHEMICAL CONJUNCTIVITIS, CHEMICAL BURN, RASH, HEADACHE, BLISTERS, WEAKNESS, EYE IRRITATION. (CL2C3* 81/FRA) RESPIRATORY EFFECTS MAY PROGRESS TO A FATAL PNEUMONIA OR TO LUNG CANCER (HISTIOCYTIC LYMPHOMA) BASED ON THREE REPORTED CASE STUDIES. (AIMDAP 144(7)1409,84/MAR) 1,3-DICHLOROPROPENE HAS PRODUCED LIVER AND KIDNEY DAMAGE IN EXPERIMENTAL ANIMALS. (DPMADX 79/SAX) SUBACUTE INHALATION EXPOSURE OF ANIMALS TO UP TO 50 PPM CAUSED MARKED LIVER AND KIDNEY CHANGES. (85FHA9 2,83/VER) CHRONIC SYMPTOMS OR SIGNS-VARIOUS LABORATORY SPECIES EXPOSED TO 3 PPM 1,3-DICHLOROPROPENE IN AIR FOR 125 TO 130 TIMES WITHIN 185 DAYS SHOWED NO EFFECT. RATS EXPOSED TO 3 PPM FOR 4 HOURS/DAY FOR 6 MONTHS SHOWED VERY SLIGHT CLOUDY SWELLING OF THE RENAL EPITHELIUM. (85FHA9 2,83/VER) ODOR: LOT: SEVEN OF 10 VOLUNTEERS DETECTED THE ODOR AT 1 PPM, WHICH WAS MUCH FAINTER TO THEM THAN AT 3 PPM. (85FHA9 2,83/VER) DRK: THE DRINKING WATER CRITERION RECOMMENDED BY EPA IN 1980 WAS 0.087 MG/L FOR DICHLOROPROPENES INGESTED THROUGH WATER AND CONTAMINATED ORGANISMS. (AWQCD* PB117541,80/ECAO) IDTI: ---------------DETECTION INFORMATION CATEGORY (USE CODE ZDTI)--------------- LDL: IN WASTEWATER, PURGE AND TRAP 1,3-DICHLOROPROPENE AND DETERMINE BY GAS CHROMATOGRAPHY WITH AN ELECTROLYTIC CONDUCTIVITY OR MICROCOULOMETRIC DETECTOR (EPA PRIORITY POLLUTANT METHOD 601). DETECTION LIMIT 8E-6 PPM. (FEREAC 44FR69468, 12-3-79) 1,3-DICHLOROPROPENE MAY ALSO BE DETERMINED IN WASTEWATER BY GAS CHROMATOGRAPHY/MASS SPECTROMETRY (GC/MS) AFTER PURGE AND TRAP PROCEDURES (EPA PRIORITY POLLUTANT METHOD 624). DETECTION LIMIT 0.01 PPM. (FEREAC 44FR69532, 12-3-79) IN DRINKING WATER, PURGE AND TRAP (HIGH IONIC STRENGTH), THEN DETERMINE BY CAPILLARY GC/MS. DETECTION LIMIT: 0.0001 PPM. (ME009* 80/RTI) IN SURFACE WATER, PURGE AND TRAP (HIGH IONIC STRENGTH), THEN DETERMINE BY CAPILLARY GC/MS. DETECTION LIMIT: 0.001 PPM. (ME009* 80/RTI) IN WASTE WATER, PURGE AND TRAP (HIGH IONIC STRENGTH), THEN DETERMINE BY CAPILLARY GC/MS. DETECTION LIMIT IS 0.01 PPM. (ME009* 80/RTI) UPDATED 12/1984. Record 445 of 1119 in OHMTADS (Final version) AN: 8300176 ID: -------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)--------------- PN: TETRAHYDROFURAN- SY: FURAN,-TETRAHYDRO-; 1,4-EPOXYBUTANE-; BUTANE-ALPHA,DELTA-OXIDE-; CYCLOTETRAMETHYLENE-OXIDE-; FURANIDINE-; OXACYCLOPENTANE-; OXOLANE-; TETRAMETHYLENE-OXIDE-; THF- RN: 109-99-9 SIC: 286 ST: C4H8O CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)----------- MP: -108 DEGREES CELSIUS (CHCPDT 61,80/WEA) UPDATED 3/1984 BP: 67 DEGREES CELSIUS (CHCPDT 61,80/WEA) UPDATED 3/1984 SOL: MISCIBLE IN ALL PROPORTIONS (QOTHF* 0001) DEN: 0.888 (AT 20 DEGREES CELSIUS (HCDB** 0001)) VAP: 142 MM HG AT 20 DEGREES CELSIUS. VAPOR PRESSURE IN ATMOSPHERES (DEGREES CELSIUS)- 0.06 (0); 0.11 (10); 0.173 (20); 0.26 (30) (85FHA9 0001) VAPD: 2.5 (QOTHF* 0001) IRCI: ---------------REACTIVITY INFORMATION CATEGORY (USE CODE ZRCI)-------------- ADD: BUTYLATED HYDROXY TOLUENE (BHT) PRESENT AT 0.025% TO PREVENT PEROXIDE FORMATION. (HCDB** 0001) BIN: INHIBITED THF GIVES NO REACTION WITH COMMON MATERIALS BUT A POWERFUL SOLVENT (SEE FIELD COR). (HCDB** 0001) HOWEVER, IT READILY FORMS EXPLOSIVE PEROXIDES ON EXPOSURE TO AIR. (AIHG** 0001) USING THF AS A SOLVENT FOR LITHIUM ALUMINUM HYDRIDE CAN CAUSE VIGOROUS REACTION (PROBABLY DUE TO PEROXIDES OR THEIR REACTION PRODUCTS) AND SUBSEQUENT FIRE. PREPARATION OF SODIUM ALUMINUM HYDRIDE FROM SODIUM AND ALUMINUM IN THF CAUSED A VIOLENT EXPLOSION, PROBABLY DUE TO LOCALIZED HEATING IN THE REACTION VESSEL. USING POTASSIUM HYDROXIDE OR SODIUM, HYDROXIDE TO DRY IMPURE THF CONTAINING PEROXIDES MAY CAUSE SERIOUS EXPLOSIONS. (NFICAM 0001) COR: NONCORROSIVE AT NORMAL ATMOSPHERIC TEMPERATURES, BUT RESINS SOLUBLE IN THF INCLUDE ACRYLICS, ALKYDS, CELLULOSICS, AMINO RESINS, VARIOUS ELASTOMERS, VINYL RESINS, AND VARIOUS NATURAL RESINS. (QOTHF* 0001) IENE: --------ENVIRONMENTAL CHEMISTRY INFORMATION CATEGORY (USE CODE ZENE)-------- LOC: FLOATS AND MIXES WITH WATER. MATERIAL IS COLORLESS LIQUID WITH AN ETHER-LIKE ODOR AND PUNGENT TASTE. (AIHG** 0001) HOH: CHEMICAL AND BIOCHEMICAL OXIDATION OF THF IN WATER REQUIRES CONSIDERABLE CONSUMPTION OF DISSOLVED OXYGEN. IN DISTILLED WATER, THF AT 0.5,5, AND 10 PPM REQUIRED 1 TO 2, 6 TO 8, AND 10 DAYS, RESPECTIVELY, TO DEGRADE. MICROBIAL CONTAMINATION REDUCED THE DEGRADATION PERIODS BY 2 TO 3 DAYS. AT CONCENTRATIONS >0.5 PPM, HYDROPEROXIDES ARE FORMED THAT MAY BE BACTERICIDAL. (CHIPS* 0001) COL: COLORLESS LIQUID WITH FAINT FRUITY OR ETHER-LIKE ODOR. (HCDB** 0001) AT CONCENTRATIONS OF 100 TO 250 PPM IN WATER, THF AUTOOXIDIZES IN THE PRESENCE OF LIGHT AND EXCESS ATMOSPHERIC OXYGEN TO FORM RESINOUS PRODUCTS THAT COLOR WATER VARIOUSLY FROM PINK TO BROWN. (CHIPS* 0001) BIOD: DATA NOT AVAILABLE (HCDB** 0001) PER: THF IS OFTEN DETECTED IN EFFLUENT DISCHARGES FROM CHEMICAL MANUFACTURING PLANTS AND RAW SEWAGE. IT IS FAIRLY STABLE IN WATER BUT WILL BE CHEMICALLY AND BIOCHEMICALLY OXIDIZED. IT HAS A GENERALLY LOW DEGREE OF REACTIVITY COMPARTED TO OTHER ORGANICS IN PHOTOCHEMICAL ATMOSPHERIC REACTIONS INDUCED BY ULTRAVIOLET IRRADIATION. (CHIPS* 0001) THE HALF-LIFE FOR REACTION WITH HYDROXYL RADICALS IN AIR AT 300 DEGREES KELVIN IS 0.55 DAY. (ARPOC* 0001) FOO: NONE (HCDB** 0001) ITRN: -------TRANSPORTATION AND STORAGE INFORMATION CATEGORY (USE CODE ZTRN)------ USE: SOLVENT FOR NATURAL AND SYNTHETIC RESINS, ESPECIALLY VINYLS, IN TOPCOATING SOLUTIONS, POLYMER COATING CELLOPHANE, PROTECTIVE COATINGS, ADHESIVES, PRINTING INKS, ETC. REACTION SOLVENT, E.G., GRIGNARD REACTIONS, LITHIUM ALUMINUM HYDRIDE REDUCTIONS, AND POLYMERIZATIONS. CHEMICAL INTERMEDIATE AND MONOMER. (QOTHF* 0001) MOST THF PRODUCED FROM FURFURAL IS USED CAPTIVELY IN THE MANUFACTURE OF POLYTETRAMETHYLENE GLYCOL, A PRECURSOR OF SPANDEX FIBERS, POLYURETHANE ELASTOMERS, AND ELASTIC POLYESTERS. (CHIPS* 0001) MAY BE USED UNDER FEDERAL FOOD, DRUG AND COSMETIC ACT FOR FABRICATION OF ARTICLES FOR PACKAGING, TRANSPORTATION, OR STORING OF FOODS IF RESIDUAL AMOUNT DOES NOT EXCEED 1.5% OF THE FILM ACCORDING TO 27FR3919, 4-25-62, CITED IN (MEIEDD 0001) STRG: Containers USUAL SHIPPING CONTAINERS: ONE-GALLON CANS, 5- AND 55-GALLON DRUMS; TANK CARS, TANK TRUCKS. (NFICAM 0001) DOT AND CFR--10 GALLON MAXIMUM ON CARGO-ONLY AIRCRAFT. (49CFR* 0001) (FEREAC 0017) ICAO--CLASS 3, GROUP II, LIQUID CARGO AIRCRAFT, NO SPECIAL EXCEPTIONS: MAXIMUM NET QUANTITY PER PACKAGE ON CARGO AIRCRAFT: 60 L. PACKING INSTRUCTION 3218: INNER PACKAGING IN 2.5 L GLASS OR EARTHENWARE, 5-L PLASTIC, 10-L METAL, OR 0.5- L GLASS AMPUL IN OUTER WOODEN, PLYWOOD, FIBERBOARD, OR RECONSTITUTED WOOD BOXES OR STEEL OR ALUMINUM DRUMS. SINGLE PACKAGING OF STEEL, PLASTIC, OR ALUMINUM DRUMS; STEEL DRUMS WITH INSIDE PLASTIC RECEPTACLES; OR STEEL OR PLASTIC JERRICANS. (ICAO** 0001) IATA--MAXIMUM 40-L NET QUANTITY PER PACKAGE ON CARGO-ONLY AIRCRAFT. (RARAD5 0002) IMCO--CLASS 3.1 INFLAMMABLE LIQUIDS (RED LABEL). PACKAGING GROUP II: HERMETICALLY SEALED CONTAINERS: UP TO 5-L GLASS BOTTLES WITH INERT CUSHIONING AND ABSORBENT MATERIAL IN A WOODEN BOX (PACKAGE GROSS 75 L); UP TO 30-L METAL CANS IN A WOODEN BOX (PACKAGE GROSS 75 L); CYLINDERS; AND METAL DRUMS (PACKAGE GROSS 250 L). (85EZAO 0001) General Storage Procedures PROTECT FROM PHYSICAL DAMAGE AND SEPARATE FROM OXIDIZING MATERIALS. STORE AWAY FROM HEAT SOURCES IN A COOL, DARK, VENTILATED AREA, PREFERABLY OUTSIDE OR IN A DETACHED BUILDING. STORE INSIDE IN A STANDARD FLAMMABLE LIQUIDS STORAGE ROOM OR CABINET. CHECK PERIODICALLY FOR PEROXIDE CONTENT AND ADD INHIBITOR TO KEEP BELOW 1%. (NFICAM 0001) THF CAN BE STORED AND HANDLED IN ORDINARY STEEL TANKS AND PIPING. ADEQUATE VENTILATION WILL KEEP THE FIRE HAZARD FROM BECOMING ACUTE. ORGANIC PEROXIDES FORM WHEN UNSTABILIZED THF IS EXPOSED TO AIR. PEROXIDE CONCENTRATIONS >0.1% MAY LEAD TO VIOLENT EXPLOSION IF IT IS DISTILLED TO DRYNESS. ALTERNATIVELY, IF A STABILIZER IS NOT USED, THF MAY BE STORED UNDER AN INERT GAS BLANKET. PEROXIDES CAN BE REMOVED BY TREATMENT WITH STRONG FERROUS SULFATE SOLUTION MADE SLIGHTLY ACIDIC WITH SODIUM BISULFATE. (AIHG** 0001) (QOTHF* 0001) HND: NON-SPARKING TOOLS SHOULD BE USED WHEN OPENING OR CLOSING METAL CONTAINERS AND CONTAINERS MUST BE BONDED AND GROUNDED WHEN POURING OR TRANSFERRING THE LIQUID. (AIHG** 0001) MFS: E.I. DUPONT DE NEMOURS and COMPANY, INCORPORATED, P.O. BOX 34, LA PORTE, HARRIS COUNTY, TX, 77571, MID NO. 7383, EPA REGION 06; BASF WYANDOTTE CORPORATION, PARSIPPANY, 100 CHERRY HILL RD., PARSIPPANY, NJ, 07054, MID NO. 3340, EPA REGION 02; BASF WYANDOTTE CORPORATION, GEISMAR, P.O. BOX 457, GEISMAR, ASCENSION PARISH COUNTY, LA, 70734, MID NO. 3341, EPA REGION 06; ACETO CHEMICAL CO., INC., 126-02 NORTHERN BLVD., FLUSHING, QUEENS COUNTY, NY, 11368, MID NO. 3465, EPA REGION 02; ABBOTT LABORATORIES, ATTN: J. TURNER V.P. CAPDMFG., NORTH CHICAGO, LAKE COUNTY, IL, 60064, MID NO. 3835, EPA REGION 05; MITSUBISHI INTERNATIONAL CORPORATION, 277 PARK AVE., NEW YORK, NY, 10017, MID NO. 5040, EPA REGION 02; GAF CORPORATION, F. GROSSER (WAYNE), P.O. BOX 12, LINDEN, UNION COUNTY, NJ, 07036, MID NO. 6185, EPA REGION 02; QUAKER OATS CHEMICALS DIVISION, ATTN: R. FINCHER PLANT MGR., 3324 CHELSEA AVENUE, MEMPHIS, TN, 38108, MID NO. 7812, EPA REGION 04; QUAKER OATS CO. CHEMICAL DIVISION, P.O. BOS 3514, 617 WEST MAIN ST., CHICAGO, COOK COUNTY, IL, 60654, MID NO. 7820, EPA REGION 05. (PRDTN* 0002) 38101 OR CHEMICALS DIVISION, MERCHANDISE MART PLAZA, CHICAGO, IL, (312) 222-6880; GAF CORPORATION, CHEMICAL PRODUCTS DIVISION, 140 WEST 51ST STREET, NEW YORK, NY 10020. (CHIPS* 0001) ISAF: ----------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)---------------- STD: SUPERFUND DESIGNATED (HAZARDOUS SUBSTANCES) LIST. HAZARDOUS WASTE NO. U213. UN NO. 2056. STCC NO. 4908290. (BUXEH* 0001) DOT-HAZARD CLASS AND LABEL: FLAMMABLE LIQUID; PACKAGING SPECIFIC REQUIREMENTS 173.119; PERMITTED CARGO-ONLY AIRCRAFT (MAXIMUM 10-GALLON PACKAGE); ON CARGO VESSEL, STOW ON DECK OR UNDER DECK AWAY FROM HEAT IN A VENTILATED COMPARTMENT OR HOLD; KEEP COOL. (FEREAC 0017) IMCO-CLASS 3.1; PACKAGING GROUP II. STOW ON OR UNDER DECK ON CARGO SHIPS OR PASSENGER SHIPS CARRYING NOT MORE THAN 25 PASSENGERS OR ONE PER 3 METERS OF LENGTH. PROHIBITED ON OTHER PASSENGER SHIPS. (85EZAO 0001) CFR-FLAMMABLE LIQUID. (49CFR* 0001) NFPA- 2,3,1,- (NFICAM 0001) IATA-NOT ACCEPTABLE ON PASSENGER AIRCRAFT; MAXIMUM NET QUANTITY PER PACKAGE 40 L ON CARGO-ONLY AIRCRAFT (RARAD5 0002) FPOT: QUITE FLAMMABLE. VAPOR IS HEAVIER THAN AIR AND MAY TRAVEL CONSIDERABLE DISTANCE TO A SOURCE OF IGNITION AND FLASH BACK. BURNING RATE IS 4.7 MM/MIN. (HCDB** 0001) FLMT: LFL: 1.8 (HCDB** 0001) UFL: 11.8 (HCDB** 0001) FIRP: SMALL FIRES: DRY CHEMICAL, CARBON DIOXIDE, OR ALCOHOL FOAM; LARGE FIRES: WATER SPRAY, FOG, OR ALCOHOL FOAM. DO NOT EXTINGUISH FIRE UNLESS FLOW CAN BE STOPPED. NFPA RECOMMENDS DRY CHEMICAL OR CARBON DIOXIDE. SOLID STREAMS OF WATER MAY BE INEFFECTIVE ON FIRE. USE WATER IN FLOODING QUANTITIES AS A FOG. COOL EXPOSED CONTAINERS FROM THE SIDE WITH WATER UNTIL WELL AFTER FIRE IS OUT TO AVOID EXPLOSION. APPLY WATER FROM AS FAR A DISTANCE AS POSSIBLE. FOR MASSIVE FIRE IN CARGO AREA, USE UNMANNED HOSE HOLDER OR MONITOR NOZZLES. WITHDRAW IMMEDIATELY IN CASE OF RISING SOUND FROM VENTING SAFEY DEVICE OR DISCOLORATION OF TANK. (HCDB** 0001) (BUXEH* 0001) (85EWAF 0001) (NFICAM 0001) FLPT: -20 (-4 DEGREES FAHRENHEIT) (CGHCD* 0001); -14.5 (DEGREES CELSIUS TAG CLOSED CUP) (AIHG** 0001) AUTO: 321 (610 DEGREES FAHRENHEIT) (CGHCD* 0001) EXPL: VAPOR MAY EXPLODE IF IGNITED IN AN ENCLOSED AREA. IF 0.1% PEROXIDES HAS ACCUMULATED BECAUSE OF PROLONGED STORAGE IN PRESENCE OF AIR, THE PEROXIDES MAY EXPLODE WHEN CONCENTRATED BY EVAPORATION OF SOLUTION. (HCDB** 0001) CONTAINER MAY EXPLODE IN HEAT OF FIRE. VAPOR EXPLOSION HAZARD INDOORS, OUTDOORS, OR IN SEWERS. RUNOFF TO SEWER MAY CREAT FIRE OR EXPLOSION HAZARD. (85EWAF 0001) LEL: 2.3 (AIHG** 0001) UEL: 11.8 (AIHG** 0001) SAF: STAY UPWIND AND KEEP OUT OF LOW AREAS. WEAR SELF-CONTAINED BREATHING APPARATUS AND FULL PROTECTIVE CLOTHING. (85EWAF 0001) DO NOT HANDLE BROKEN PACKAGES WITHOUT PROTECTIVE EQUIPMENT. USE COPIOUS AMOUNTS OF WATER OR SOAP AND WATER TO WASH AWAY ANY MATERIAL THAT MAY HAVE CONTACTED THE BODY. (BUXEH* 0001) HTOX: Acute Hazard Level (CONCENTRATIONS OF THF RESULTING IN DEEP NARCOSIS ARE ABOUT THE SAME AS FOR DIETHYL ETHER. (QOTHF* 0001) CONCENTRATIONS IN AIR OF 20,000 PPM ARE CONSIDERED IMMEDIATELY DANGEROUS TO LIFE OR HEALTH. (PKTGD* 0001) CONCENTRATIONS OF 11,000 PPM CAUSED ANESTHESIA IN MICE AFTER 43 MINUTES; 22,000 PPM, IN 28 MINUTES; AND 50% DIED IN AVERAGE TIME OF 109 MINUTES. (AIHG** 0001) Chronic Hazard Level NO TOXIC EFFECTS DUE TO INDUSTRIAL EXPOSURE REPORTED IN THE LITERATURE. DOGS EXPOSED TO 200 PPM IN THE AIR FOR 6 HOURS PER DAY FOR THREE TO FOUR WEEKS SHOWED LOWERED BLOOD PRESSURE BUT NO HISTOPATHOLOGICAL CHANGES. (CHIPS* 0001) RATS EXPOSED TO 3000 PPM IN AIR, 8 HOURS/DAY FOR 20 MONTHS SHOWED NO CLINICAL SYMPTOMS. (85FHA9 0001) Air Pollution RATE OF EVAPORATION 800 RELATIVE TO BUTYL ACETATE (=100). (RATE BETWEEN THOSE OF ACETONE AND METHYL ETHYL KETONE.)(QOTHF* 0001) IRRITATING VAPOR GENERATED WHEN HEATED. (HCDB** 0001) Inhalation Limit Data 20000 (PPM: IDLH) Inhalation Limit Text REGULATIONS--PEL (TWA) 590 MG/M3 200 PPM (29CFR* 1910)MENDATIONS--IDLH 20000 PPM (PKTGD* 80/MAC)TLV (TWA) 590 MG/M3 200 PPM (TLVADM 83/ACGIH)STEL 735 MG/M3/15 MIN 250 PPM/15 MIN (TLVADM 83/ACGIH)ED 3/1984. ACT: EFFECT OF LOW CONCENTRATION ON AQUATIC LIFE IS UNKNOWN. MAY BE DANGEROUS IF IT ENTERS WATER INTAKES. NOTIFY LOCAL HEALTH AND WILDLIFE OFFICIALS AND OPERATORS OF NEARBY WATER INTAKES. (HCDB** 0001) KEEP UNNECESSARY PEOPLE AWAY. ISOLATE HAZARD AREA AND DENY ENTRY. (85EWAF 0001) IF FIRE BECOMES UNCONTROLLABLE OR CONTAINER IS EXPOSED TO DIRECT FLAME, EVACUATE FOR A RADIUS OF 1500 FEET. IF MATERIAL IS LEAKING BUT NOT ON FIRE, DOWNWIND EVACUATION MUST BE CONSIDERED. (BUXEH* 0001) ISOLATE FOR 0.5 MILE IN ALL DIRECTIONS IF TANK OR TANKCAR IS INVOLVED IN FIRE. (85EWAF 0001) AML: SEEK PROFESSIONAL ADVICE FROM EPA'S ENVIRONMENTAL RESPONSE TEAM (ERT), EDISON, NJ, 24-HOUR NUMBER (201) 321-6660. KEEP SPARKS, FLAME, AND OTHER SOURCES OF IGNITION AWAY. KEEP MATERIAL OUT OF WATER SOURCES AND SEWERS. BUILD DIKES TO CONTAIN FLOW AS NECESSARY. ATTEMPT TO STOP LEAK IF WITHOUT HAZARD. USE WATER SPRAY TO DISPERSE VAPORS AND DILUTE STANDING POOLS OF LIQUID. (BUXEH* 0001) FOR SMALL SPILLS, TAKE UP WITH SAND OR OTHER NONCOMBUSTIBLE ABSORBENT MATERIAL; THEN FLUSH AREA WITH WATER. (85EWAF 0001) DILUTE AND DISPERSE IF OTHER CORRECTIVE MEASURES CANNOT BE USED. (CGRSP* 0001) CONSTRUCT CLAY/BENTONITE SWALE TO DIVERT UNCONTAMINATED PORTION OF WATERSHED AROUND CONTAMINATED PORTION. ISOLATION PROCEDURES INCLUDE CONSTRUCTION OF BENTONITE LINED DAMS, INTERCEPTOR TRENCHES OR IMPOUNDMENTS. SEEK PROFESSIONAL HELP TO EVALUATE PROBLEM AND IMPLEMENT CONTAINMENT PROCEDURES. CONDUCT BENCH-SCALE AND PILOT-SCALE TESTS PRIOR TO IMPLEMENTATION OF FULL-SCALE DECONTAMINATION PROGRAM. TREATMENT ALTERNATIVES FOR CONTAMINATED WATER INCLUDE AERATION AND EVAPORATION. ACTIVATED CHARCOAL MAY NOT BE EFFECTIVE. PHYSICALLY REMOVE IMMOBILIZED RESIDUES. CONTAMINATED SOIL OR IMMOBILIZED RESIDUES MAY BE PACKAGED FOR DISPOSAL. CONFIRM ALL TREATMENT PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. (85FEAY 0001) (THIDD6 0001) (RMRNR* 0005) DISP: Disposal Method PRODUCT RESIDUES AND SORBENT MEDIA MAY BE PACKAGED IN 17H EPOXY LINED DRUMS AND DISPOSED OF AT AN EPA APPROVED SITE. DESTROY BY HIGH TEMPERATURE INCINERATION. CONFIRM DISPOSAL PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. IFP: POTENTIAL RUPTURE HAZARD WHEN INCLUDED IN BOILER FEED OR COOLING WATER (FLASHPOINT LESS THAN 50 DEGREES CELSIUS). WTP: INHIBITION OF CELL MULTIPLICATION OF PSEUDOMONAS PUTIDAS STARTS AT 580 PPM. (85FHA9 0001) ITOX: ------------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOX)------------ CARC: NO EPIDEMIOLOGICAL STUDIES OR CASE REPORTS WERE FOUND IN THE LITERATURE AS OF 1979 THAT EXAMINED THE RELATION OF THF EXPOSURE AND HUMAN CANCER INCIDENCES. TOPICAL APPLICATIONS OF 0.1 ML THF TWICE WEEKLY FOR 25 WEEKS TO 25 MICE PRODUCED 4 UNSPECIFIED BENIGN ORGAN TUMORS AFTER 17.5 MONTHS. THIS STUDY BY MULLER AND REICHER (1969) MAY BE INADEQUATE TO ASSESS CARCINOGENICITY BECAUSE OF THE LACK OF DATA ON CONTROLS AND INADEQUATE REPORTING OF RESULTS. (CHIPS* 0001) ME: NO RELEVANT MUTAGENICITY TESTS FOUND IN THE LITERATURE AS OF 1979. (CHIPS* 0001) NEGATIVE RESULTS IN 1981 SALMONELLA ASSAYS; NTP NO. 10170-V (NTP82* 0001) NTXV: Animal Toxicity Data SEE RTECS Acute Waterfowl Toxicity Data DATA NOT AVAILABLE (HCDB** 0001) AQN: INHIBITION OF CELL MULTIPLICATION OF THE ALGA MICROCYSTIS AERUGINOSA STARTS AT 225 PPM. (85FHA9 0001) DRC: MINIMUM HAZARD FOR LIQUID AS IRRITANT. IF SPILLED ON CLOTHING AND ALLOWED TO REMAIN, MAY CAUSE SMARTING AND REDDENING OF THE SKIN. THF DOES NOT IRRITATE THE SKIN BEYOND THE DEFATTING ACTION COMMON WITH ORGANIC SOLVENTS. IT IS NONSENSITIZING. VAPOR IS IRRITATING TO EYES, NOSE, AND THROAT. LIQUID ALSO IRRITATES EYES. SLIGHT SMARTING OF EYES OR RESPIRATORY TRACT DUE TO HIGH CONCENTRATIONS OF THF ARE ONLY TEMPORARY EFFECTS. (QOTHF* 0001) (HCDB** 0001) JNS: VAPORS CAUSE NAUSEA, DIZZINESS, HEADACHE, AND ANESTHESIA (LOSS OF CONSCIOUSNESS). HARMFUL IF SWALLOWED. (HCDB** 0001) PEROXIDES MAY BE RESPONSIBLE FOR THE KIDNEY, LIVER, AND/OR LUNG DAMAGE AFTER ORAL INGESTION BY LABORATORY MAMMALS REPORTED BY SOME WORKERS BUT NOT SUBSTANTIATED BY OTHERS. (CHIPS* 0001) TARGET ORGANS: EYES, SKIN, RESPIRATORY TRACT, CENTRAL NERVOUS SYSTEM. (PKTGD* 0001) ODOR: LOT: 20 TO 30, (HCDB** 0001); 2.5 TO 30, (AIHG** 0001) MOT: 30 PPM (90 MG/CU M) (ODPAR* 0001) TAST: LTT: 3; (CHIPS* 0001) IDTI: ---------------DETECTION INFORMATION CATEGORY (USE CODE ZDTI)--------------- LDL: IN DRINKING WATER, PURGE AND TRAP (HIGH IONIC STRENGTH), THEN CAPILLARY GC/MS; DETECTION LIMIT 0.0001 PPM; MASTER SCHEME, LOW RECOVERIES. SAME METHOD FOR SURFACE WATER BUT DETECTION LIMIT 0.001 PPM. SAME METHOD FOR WASTEWATER BUT DETECTION LIMIT 0.01 PPM. (ME009* 0001) Record 446 of 1119 in OHMTADS (Final version) AN: 8300177 ID: -------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)--------------- PN: FURAN- SY: DIVINYLENE-OXIDE-; OXOLE-; TETROLE-; TETROL-; FURFURAN-; OXACYCLOPENTADIENE- RN: 110-00-9 ST: C4H4O CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)----------- MP: -85.61; (QOFRN* 0001) BP: 32 DEGREES CELSIUS AT 758 MM HG. IGNITES, FLASH POINT -35 DEGREES CELSIUS (MERCK* 83/WIN) UPDATED 3/1984 SOL: 10,000 PPM (1%) (QOFRN* 0001) DEN: 0.937 (QOFRN* 0001) VAPD: 2.5 (MMIII* 79/KIN) ALSO GIVEN AS 0.170 LB/CU FT (QOFRN* 0001) IRCI: ---------------REACTIVITY INFORMATION CATEGORY (USE CODE ZRCI)-------------- ADD: BUTYLATED HYDROXYTOLUENE (BHT) IS ADDED TO INHIBIT FORMATION OF PEROXIDES. (QOFRN* 0001) BIN: UNSTABILIZED FURAN FORMS PEROXIDES VERY SLOWLY ON EXPOSURE TO AIR. LIKE THE VINYL ETHERS, FURAN IS CLEAVED BY AQUEOUS ACIDS. THE REACTION IS ACCOMPANIED BY RESINIFICATION. (QOFRN* 0001) IENE: --------ENVIRONMENTAL CHEMISTRY INFORMATION CATEGORY (USE CODE ZENE)-------- LOC: COLORLESS LIQUID WILL FLOAT. COL: COLORLESS LIQUID WITH CHARACTERISTIC ETHEREAL ODOR. (QOFRN* 0001) ITRN: -------TRANSPORTATION AND STORAGE INFORMATION CATEGORY (USE CODE ZTRN)------ USE: ORGANIC SYNTHESIS, ESPECIALLY FOR PYRROLE, TETRAHYDROFURAN, AND THIOPHENE. (CCDCDS 0002) CHEMICAL INTERMEDIATE FOR PHARMACEUTICALS, INSECTICIDES, AND FINE CHEMICALS. (QOFRN* 0001) STRG: Containers TANK CARS, DRUMS (400 LB NET), AND CANS (35 LB NET AND 7 LB NET) (QOFRN* 0001) IMCO--PACKAGING GROUP I: ALL CONTAINERS SHOULD BE HERMETICALLY SEALED. FOR GLASS BOTTLES PACKED WITH INERT CUSHIONING AND ADSORBENT MATERIAL TOGETHER IN A WOODEN BOX, THE MAXIMUM RECEPTACLE SIZE IS 5 L NET AND THE PACKAGE GROSS IS 75 L. FOR METAL CANS PACKED TOGETHER IN A WOODEN BOX, THE MAXIMUM RECEPTACLE SIZE IS 30 L NET AND THE PACKAGE GROSS IS 75 L. NO SIZE LIMIT FOR CYLINDERS. PACKAGE GROSS LIMIT FOR METAL DRUMS IS 250 L. (85EZAO 0001) DOT--MAXIMUM NET QUANTITY IN ONE PACKAGE--1 QUART FOR PASSENGER-CARRYING AIRCRAFT OR RAILCAR, 10 GALLONS FOR CARGO-ONLY AIRCRAFT. (FEREAC 0017) ICAO--MAXIMUM NET QUANTITY PER PACKAGE IN PASSENGER AIRCRAFT AND CARGO AIRCRAFT: 1 L AND 30 L, RESPECTIVELY. (ICAO** 0001) HND: KEEP AWAY FROM HEAT AND OPEN FLAME. VENTILATE TO AVOID BUILDUP OF A DANGEROUS CONCENTRATION OF VAPOR. DRUMS-BEFORE EMPTYING, DRUMS SHOULD BE SUPPORTED AND BLOCKED TO PREVENT MOVEMENT DURING EMPTYING. ELECTRICALLY GROUND DRUMS BEFORE THEY ARE EMPTIED TO PREVENT POSSIBLE STATIC DISCHARGE DURING EMPTYING. ONLY NON-SPARKING TOOLS SHOULD BE USED AND CARE SHOULD BE TAKEN TO AVOID STRIKING SPARKS WITH TOOLS OR OTHER HARD OBJECTS. WEAR GOGGLES WHEN REMOVING PLUGS. PLACE DRUM BUNG END UP AND ALLOW INTERNAL PRESSURE TO VENT BEFORE COMPLETELY LOOSENING PLUG. NEVER USE GRAVITY OR PRESSURE PUMPS TO EMPTY DRUMS. HAND PUMPS OR ELECTRICAL PUMPS THAT HAVE EXPLOSION-PROOF MOTORS ARE SAFE. TANK CARS-UNLOAD THROUGH DOME CONNECTIONS RATHER THAN THROUGH BOTTOM OUTLETS. PUMPING IS THE RECOMMENDED METHOD OF UNLOADING. RELIEVE ALL INTERNAL PRESSURE BEFORE REMOVING THE MANHOLE COVER. IF THERE IS NO VENT VALVE, COOL THE CAR BY SPRAYING WITH WATER OR ALLOWING IT TO STAND OVERNIGHT. (QOFRN* 0001) MFS: PETRO-TEX CHEMICAL CORPORATION, ATTN: H.R. BOWERS, P.O. BOX 2584, HOUSTON, HARRIS COUNTY, TX, 77001, MID NO. 5667, EPA REGION 06; QUAKER OATS CHEMICALS DIVISION, ATTN: R. FINCHER PLANT MGR., 3324 CHELSEA AVE., MEMPHIS, TN, 38108, MID NO. 7812, EPA REGION 04. (PRDTN* 0002) ISAF: ----------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)---------------- STD: SUPERFUND DESIGNATED (HAZARDOUS SUBSTANCES) LIST. HAZARDOUS WASTE NO. U124. UN NO. 2389. STCC NO. 4909175 (BUXEH* 0001) IMCO-CLASS 3.1, PACKAGING GROUP I, RED LABEL "INFLAMMABLE LIQUID". KEEP COOL AS REASONABLY PRACTICAL. STOW ON OR UNDER DECK ON CARGO SHIPS OR ON PASSENGER SHIPS CARRYING NOT MORE THAN 25 PASSENGERS OR 1 PER 3 METERS (10 FEET) OF LENGTH. PROHIBITED ON OTHER PASSENGER SHIPS. (85EZAO 0001) IATA-NOT LISTED. DOT-HAZARD CLASS AND LABEL-FLAMMABLE LIQUID. PACKAGING-EXCEPTIONS 173.118, SPECIFIC REQUIREMENTS 173.119. ON A CARGO VESSEL, STOW ON DECK OR UNDER DECK IN A COMPARTMENT OR HOLD SUBJECT TO REQUIREMENTS OF 176.63. ON A PASSENGER VESSEL, STOW ON DECK OR, PREFERABLY, UNDER DECK. (FEREAC 0017) FLMT: LFL: 2.3 (QOFRN* 0001) UFL: 14.3 (QOFRN* 0001) FIRP: DO NOT EXTINGUISH UNLESS FLOW CAN BE STOPPED. USE WATER IN FLOODING QUANTITIES AS A FOG. SOLID STREAMS OF WATER MAY SPREAD FIRE. COOL ALL AFFECTED CONTAINERS FROM THE SIDE WITH FLOODING QUANTITIES OF WATER. APPLY WATER FROM AS FAR A DISTANCE AS POSSIBLE. (BUXEH* 0001) STAY AWAY FROM ENDS OF TANKS. FOR SMALL FIRES, USE DRY CHEMICAL, CARBON DIOXIDE, WATER SPRAY, OR ALCOHOL FOAM. FOR LARGE FIRES, WATER SPRAY, FOG, OR ALCOHOL FOAM. FOR MASSIVE FIRE IN CARGO AREA, USE UNMANNED HOSE HOLDER OR MONITOR NOZZLES. WITHDRAW IMMEDIATELY IN CASE OF RISING SOUND FROM VENTING SAFETY DEVICE OR DISCOLORATION OF TANK. (85EWAF 0001) FLPT: -50 (DEGREES CELSIUS CLOSED CUP (85EZAO 0001)); -32 (DEGREES FAHRENHEIT, TAG. CLOSED CUP (QOFRN* 0001)) EXPL: CONTAINER MAY EXPLODE IN HEAT OF FIRE. VAPOR EXPLOSION HAZARD INDOORS, OUTDOORS, OR IN SEWERS. RUNOFF TO SEWER MAY CREATE FIRE OR EXPLOSION HAZARD. (85EWAF 0001) LEL: 1.3 (85EZAO 0001) UEL: 14.3 (85EZAO 0001) SAF: ADEQUATE VENTILATION, PROTECTIVE CLOTHING, PERSONAL RESPIRATORY EQUIPMENT. (QOFRN* 0001)IN IN SPILL SITUATIONS, AVOID BREATHING VAPORS. KEEP UPWIND. WEAR BOOTS, PROTECTIVE GLOVES, AND GOGGLES. DO NOT HANDLE BROKEN PACKAGES WITHOUT PROTECTIVE EQUIPMENT. WASH AWAY ANY MATERIAL THAT MAY HAVE CONTACTED THE BODY WITH COPIOUS AMOUNTS OF WATER OR SOAP AND WATER. (BUXEH* 0001) HTOX: Chronic Hazard Level CHRONIC EXPOSURE OF DOGS TO CONCENTRATIONS OF 10 PPM PRODUCED NOTICEABLE CIRCULATORY DISTURBANCES. (QOFRN* 0001) Etiological Potential WORKERS WHO HAVE CIRCULATORY DISORDERS, ABNORMAL LIVER CONDITIONS, OR CHRONIC GASTROINTESTINAL COMPLAINTS SHOULD NOT BE ALLOWED TO WORK IN AREAS WITH FURAN. (QOFRN* 0001) Air Pollution FIRE MAY PRODUCE IRRITATING OR POISONOUS GASES. (85EWAF 0001) Inhalation Limit Text TLV NOT ESTABLISHED FOR MAN. (QOFRN* 0001) ACT: KEEP UNNECESSARY PEOPLE AWAY. ISOLATE HAZARD AREA AND DENY ENTRY. ISOLATE FOR 0.5 MILE IN ALL DIRECTIONS IF TANK OR TANKCAR IS INVOLVED IN FIRE. IN CASE OF WATER POLLUTION, CALL LOCAL AUTHORITIES. (85EWAF 0001) AML: SEEK PROFESSIONAL ASSISTANCE FROM EPA'S ENVIRONMENTAL RESPONSE TEAM (ERT), EDISON, NJ, 24-HOUR NUMBER (201) 321-6660. KEEP SPARKS, FLAMES, AND OTHER SOURCES OF IGNITION AWAY. KEEP MATERIAL OUT OF WATER SOURCES AND SEWERS. BUILD DIKES TO CONTAIN FLOW AS NECESSARY. ATTEMPT TO STOP LEAK IF WITHOUT HAZARD. USE WATER SPRAY TO KNOCK DOWN VAPORS. (BUXEH* 0001) FOR SMALL SPILLS, TAKE UP WITH SAND OR OTHER NONCOMPBUSTIBLE ABSORBENT MATERIAL; THEN FLUSH AREA WITH WATER. FOR LARGE SPILLS, DIKE FAR AHEAD OF SPILL FOR LATER DISPOSAL. (85EWAF 0001) CONSTRUCT CLAY/BENTONITE SWALE TO DIVERT UNCONTAMINATED PORTION OF WATERSHED AROUND CONTAMINATED PORTION. ISOLATION PROCEDURES INCLUDE CONSTRUCTION OF BENTONITE LINED DAMS, INTERCEPTOR TRENCHES OR IMPOUNDMENTS. SEEK PROFESSIONAL HELP TO EVALUATE PROBLEM AND IMPLEMENT CONTAINMENT PROCEDURES. CONDUCT BENCH-SCALE AND PILOT-SCALE TESTS PRIOR TO IMPLEMENTATION OF FULL-SCALE DECONTAMINATION PROGRAM. TREATMENT ALTERNATIVES FOR CONTAMINATED WATER INCLUDE ACID TREATMENT, AERATION, AND EVAPORATION. CONTAMINATED WATER MAY BE KEPT FOR EXTENDED HOLDING PERIODS FOR HYDROLYSIS. PHYSICALLY REMOVE IMMOBILIZED RESIDUES. DECOMPOSE BY ACID HYDROYLSIS. CONTAMINATED SOIL OR IMMOBILIZED RESIDUES MAY BE PACKAGED FOR DISPOSAL. CONFIRM ALL TREATMENT PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. (85FEAY 0001) (RMRNR* 0005) DISP: Disposal Method PRODUCT RESIDUES AND SORBENT MEDIA MAY BE PACKAGED IN 17H EPOXY LINED DRUMS AND DISPOSED OF AT AN EPA APPROVED SITE. DESTROY BY HIGH TEMPERATURE INCINERATION OR ACID HYDROLYSIS. CONFIRM DISPOSAL PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. (85FEAY 0001) (RMRNR* 0001 11,71/OTT) IFP: POTENTIAL RUPTURE HAZARD WHEN INCLUDED IN BOILER WATER FEED OR COOLING WATER (FLASH POINT <50 DEGREES CELSIUS). ITOX: ------------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOX)------------ ME: NEGATIVE IN SALMONELLA MUTAGENICITY ASSAYS; NTP NO. 10119-H (NTP82* 0001) DRC: ABSORBED THROUGH SKIN CONTACT. (QOFRN* 0001) CONTACT MAY IRRITATE OR BURN SKIN AND EYES. (85EWAF 0001) JNS: FATIGUE, HEADACHE, GASTROINTESTINAL DISTURBANCES. (QOFRN* 0001) VAPORS MAY CAUSE DIZZINESS OR SUFFOCATION. (85EWAF 0001) IDTI: ---------------DETECTION INFORMATION CATEGORY (USE CODE ZDTI)--------------- LDL: IN DRINKING WATER, SURFACE WATER, AND WASTEWATER, THE DETECTION LIMITS ARE 0.0001, 0.001, AND 0.01 PPM, RESPECTIVELY, FOR THE FOLLOWING MASTER SCHEME (PROBABLY LOW RECOVERIES): PURGE AND TRAP (HIGH IONIC STRENGTH), THEN CAPILLARY GC/MS. (ME009* 0001) Record 447 of 1119 in OHMTADS (Final version) AN: 8400260 ID: -------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)--------------- PN: PENTACHLOROETHANE- SY: ETHANE-PENTACHLORIDE-; PENTALIN-; ETHANE,-PENTACHLORO- (9CI) RN: 76-01-7 RTEC: KI6300000 ST: C2HCL5 CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)----------- MP: SOLIDIFIES OR FREEZES AT -29 DEGREES CELSIUS. (MEIEDD 76/WIN) BP: 161 TO 162 DEGREES CELSIUS (MEIEDD 76/WIN) SOL: INSOLUBLE IN WATER; MISCIBLE WITH ALCOHOL AND ETHER. (MEIEDD 76/WIN) DEN: 1.685 (THIDD6 80/ITII); 1.67 (AT 25/4 (85FHA9 77/VER)) VAP: 3.4 MM AT 20 DEGREES CELSIUS; 6 MM AT 30 DEGREES CELSIUS. (85FHA9 77/VER) VAPD: 7.2 (85FHA9 77/VER) IRCI: ---------------REACTIVITY INFORMATION CATEGORY (USE CODE ZRCI)-------------- BIN: MIXTURES OF PENTACHLOROETHANE AND SODIUM-POTASSIUM ALLOY CAN EXPLODE ON STANDING AT ROOM TEMPERATURE AND ARE ESPECIALLY SENSITIVE TO IMPACT. (NFICAM 13,80/NFPA) IENE: --------ENVIRONMENTAL CHEMISTRY INFORMATION CATEGORY (USE CODE ZENE)-------- LOC: COLORLESS, HEAVY LIQUID WITH A SWEETISH ODOR. (HTAHC* 81/SIT) CHLOROFORM-LIKE, ETHEREAL ODOR. (OCAC** 75/COX) BECAUSE OF LOW WATER SOLUBILITY, HIGH SPECIFIC GRAVITY, IF SPILLED DROPLETS MAY SINK RAPIDLY IN WATER. WILL PROBABLY BE ADSORBED ONTO SEDIMENTS BASED ON HIGH OCTANOL/WATER PARTITION COEFFICIENT. HOWEVER, THE 1980 BACKGROUND FOR LISTING DOCUMENT (RCRAC* 80/EPA) ESTIMATED THAT LESS THAN 0.01% OF EMITTED PENTACHLOROETHANE WOULD BE SORBED TO SEDIMENT PARTICLES. (CHIP** 76017,83/EPA) HOH: RESIDENCE TIME IN WATER MAY BE VERY LONG. IN WATER THAT IS BASIC OR WITH NEUTRAL PH, MOST PENTACHLOROETHANE IS EXPECTED TO BE CONVERTED TO TETRACHLOROETHANE IN AQUIFERS. (CHIP** 76017,83/EPA) PER: CAN BE PHOTOXIDIZED IN AIR TO HCL, PHOSGENE, AND TRICHLOROACETYL CHLORIDE. (JPCAAC 28(3)250,78/SPE) PERSISTENCY IN WATER LOW. IT IS ESTIMATED THAT IN 5 DAYS >94 PERCENT OF PENTACHLOROETHANE EMITTED TO A RIVER HAS BEEN RELEASED TO THE ATMOSPHERE. FOR PONDS, RESERVOIRS, OR LAKES, >97 PERCENT RELEASE IN 365 DAYS. (RCRAC* 80/EPA) PENTACHLOROTHANE HAS A RELATIVELY HIGH OCTANOL/WATER PARTITION COEFFICIENT WHICH WOULD FAVOR ITS BEING SORBED ONTO SEDIMENTS. IF TRANSPORTED INTO THE HYPOLIMNION OF LAKES OR THE LOWER LAYER OF A STRATIFIED LAKE IN SUMMER, ITS RESIDENCE TIME IN WATER MAY BE VERY LONG. (CHIP** 76019,83/EPA) PFA: LOG OCTANOL/WATER PARTITION COEFFICIENT (LOG P): 3.6. POTENTIAL FOR BIOACCUMULATION IN RIVERS, PONDS, RESERVOIRS, AND LAKES RECEIVING PENTACHLOROETHANE IS LOW. ESTIMATED BIOCONCENTRATION IN FISH OF 1.6 TIMES DISSOLVED CONCENTRATION IN WATER. (RCRAC* 80/EPA) STEADY-STATE BIOCONCENTRATION FACTOR FOR BLUEGILL IS 67; ESTIMATED HALF-LIFE IN BLUEGILL IS < 2 DAYS. (AWQCD* PB81-117400,80/ECAO) ITRN: -------TRANSPORTATION AND STORAGE INFORMATION CATEGORY (USE CODE ZTRN)------ USE: USED AS SOLVENT FOR FATS AND OILS IN METAL CLEANING. (THIDD6 80/ITII) USED IN THE MANUFACTURE OF TETRACHLOROETHYLENE AND AS A SOLVENT FOR CELLULOSE ACETATE, CERTAIN CELLULOSE ETHERS, RESINS, AND GUMS. USED AS A DRYING AGENT FOR TIMBER BY IMMERSION AT TEMPERATURES GREATER THAN 100 DEGREES CELSIUS. (HTAHC* 81/SIT) STRG: Containers IATA-APPROVED CONTAINERS FOR PASSENGER AIRCRAFT: EARTHENWARE, GLASS, OR INCOMPATIBLE PLASTICS OF UP TO 0.5 L OR METAL CONTAINER OF UP TO 1 L PACKED IN STRONG WOODEN OR FIBERBOARD OR SIMILAR OUTER PACKING. FOR CARGO AIRCRAFT (FOR FULL INFORMATION, SEE PACKING NOTE 620): VARIOUS METAL DRUMS; EARTHENWARE OR GLASS OF UP TO 5 L, PLASTIC OF UP TO 25 L OR METAL CANS OF UP TO 10 L PACKED IN WOODEN BOXES OR DRUMS, OR FIBERBOARD DRUMS; EARTHEN- WARE OR GLASS OF UP TO 1 L, PLASTIC OF UP TO 5 L OR METAL CANS OF UP TO 5 L PACKED IN FIBERBOARD BOXES. (RARAD5 80/IATA) ICAO-APPROVED CONTAINERS FOR PASSENGER AIRCRAFT: GLASS, PLASTIC, OR EARTHENWARE OF 1 L, METAL OF 2.5 L OR 0.5 L GLASS AMPULS; ALL MUST BE PACKED IN BOXES OF WOOD, PLYWOOD, RECONSTITUTED WOOD, OR FIBERBOARD OR DRUMS OF PLYWOOD, FIBERBOARD, STEEL, OR ALUMINUM. FOR CARGO AIRCRAFT: GLASS, EARTHENWARE, OR PLASTIC 2.5 L, METAL OF 5 L, OR 0.5 L GLASS AMPULS; ALL MUST BE PACKED IN OUTER CONTAINERS AS DESCRIBED FOR PASSENGER AIRCRAFT. SINGLE PACKAGINGS ARE ALLOWED-- STEEL (WITH OR WITHOUT PLASTIC INSIDE RECEPTACLES), ALUMINUM, OR PLASTIC DRUMS OR JERRICANS. (ICAO** 81/ICAO) IMCO-APPROVED CONTAINERS: GLASS OR PLASTIC OF 5 L PACKED IN FIBERBOARD (PACKAGE GROSS 40 KG), 15 L IF PACKED IN WOODEN BOX (GROSS WEIGHT 75 KG); 20 L METAL CANS PACKED IN FIBERBOARD BOX (GROSS 40 KG); NO LIMIT ON SIZE OF CANS IN WOODEN BOX EXCEPT PACKAGE GROSS LIMIT IS 75 KG; 450 L METAL DRUM. (85EZA0 78/IMCO) HND: WHEN HANDLING, WEAR RUBBER GLOVES, BREATHING APPARATUS, AND OVERALLS. (THIDD6 80/ITII) MFS: DOW CHEMICAL COMPANY U.S.A., TEXAS DIVISION, FREEPORT, BRAZORIA COUNTY, TX, 77541, MID NO. 1022, EPA REGION 06; EM LABORATORIES, INC., 500 EXECUTIVE BOULEVARD, ELMSFORD, WESTCHESTER COUNTY, NY, 10523, MID NO. 1235, EPA REGION 02; PPG INDUSTRIES, INC., ATTN: J.R. FARST, P.O. BOX 1000, LAKE CHARLES, CALCASIEU COUNTY, LA, 70601, MID NO. 1273, EPA REGION 06; COLUMBIA ORGANIC CHEMICALS CO., P.O. BOX 9096, 912 DRAKE ST., COLUMBIA, RICHLAND COUNTY, SC, 29290, MID NO. 2596, EPA REGION 04, DUNSNO 003343571. (PRDTN* 81/TSCA) ISAF: ----------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)---------------- STD: SUPERFUND DESIGNATED (HAZARDOUS SUBSTANCES) LIST. HAZARDOUS WASTE NO. U184. REPORTABLE QUANTITY 1 LB (STATUTORY SOURCE FOR DESIGNATION UNDER CERCLA IS RCRA SECTION 3001. (FEREAC 48FR23551, 5-25-83) UN1669. DOT-OPTIONAL HAZARDOUS MATERIALS TABLE: IMCO CLASS 6.1 (POISON B). LABEL: POISON. PACKAGING GROUP II. STOW EITHER ON DECK OR UNDER ON PASSENGER AND CARGO VESSELS. (FEREAC 45FR34560, 5-22-80) IATA-UN CLASS NO. 6. CLASS POISON B. LABEL: POISON. MAXIMUM NET QUANTITY PER PACKAGE ON PASSENGER AIRCRAFT 1 L, PACKING NOTE 600; MAXIMUM FOR CARGO AIRCRAFT 220 L, PACKING NOTE 620. (RARAD5 80/IATA) ICAO-UN CLASS 6.1. LABEL: POISON. UN PACKING GROUP II. MAXIMUM NET QUANTITY PER PACKAGE ON PASSENGER AIRCRAFT 5 L, PACKING INSTRUCTION 6210; MAXIMUM ON CARGO AIRCRAFT 60 L, PACKING INSTRUCTION 6218. (ICAO** 81/ICAO) IMCO-CLASS 6.1. PACKAGING GROUP II. (85EZAO 78/IMCO) FPOT: NONFLAMMABLE (HTAHC* 81/SIT) TOXC: MAY FORM PHOSGENE AND HALO ACIDS. (HTAHC* 81/SIT) EXPL: MIXTURES OF PENTACHLOROETHANE AND SODIUM-POTASSIUM ALLOY CAN EXPLODE STANDING AT ROOM TEMPERATURE AND ARE ESPECIALLY SENSITIVE TO IMPACT. (NFICAM 13,80/NFPA) SAF: WHEN HANDLING, WEAR RUBBER GLOVES, BREATHING APPARATUS, AND OVERALLS. INDOORS, USE ADEQUATE VENTILATION AND PROTECTORS. PRECLUDE FROM WORK THOSE PEOPLE WITH DISEASES OF THE LIVER. (THIDD6 80/ITII) USE PROTECTIVE MEASURES IF VAPOR CONCENTRATION > 2 PPM. (85FHA9 77/VER) HTOX: Acute Hazard Level VAPOR CONCENTRATIONS > 4 PPM ARE TOXIC TO MAMMALS. (85FHA9 77/VER) Etiological Potential CATS AND DOGS HAVE SHOWN SIGNIFICANT HISTOPATHOLOGIC CHANGES IN THE LIVER, LUNGS, AND KIDNEYS AFTER INHALATION OF VAPORS. PENTACHLOROETHANE HAS A STRONG NARCOTIC EFFECT IN HUMANS AND CAN CAUSE LIVER, LUNG, AND KIDNEY DAMAGE. (HTAHC* 81/SIT) Inhalation Limit Data 40(5); 30 Inhalation Limit Text NO U.S. TLV. GERMANY AND YUGOSLAVIA HAVE SET LIMITS OF 40 MG/M3 (5 PPM) AND RUMANIA HAS MAXIMUM ALLOWABLE CONCENTRATION OF 30 MG/M3. (HTAHC* 81/SIT) AML: SEEK PROFESSIONAL ASSISTANCE FROM EPA'S ENVIRONMENTAL RESPONSE TEAM (ERT), EDISON, NJ, 24-HOUR NO. (201)321-6660. SPILLS ON LAND: IF SPILL OCCURS ON LAND, BUILD A DIKE FAR AHEAD TO CONTAIN THE CHEMICAL, STOP FROM ENTERING THE SEWER. THROW ANY KIND OF ABSORBENT (DOES NOT HAVE TO BE NONCOMBUSTIBLE). COLLECT THE ABSORBENT AND CONTAMINATED SOIL, LABEL AND STORE FOR LATER TREATMENT AND DISPOSAL. SPILLS ON WATER BODY: IF THE SPILL OCCURS ON A NONFLOWING SMALL WATER BODY, CONTAIN THE WATER FOR LATER TREATMENT. IF THE SPILL OCCURS ON A LARGE FLOWING WATER BODY, DREDGE THE CHEMICAL FROM THE BOTTOM OF THE WATER BODY, STORE IN LABELED CONTAINERS FOR LATER DISPOSAL. NOTIFY THE LOCAL RCRA AGENCIES. ALSO NOTIFY THE DOWNSTREAM USERS OF THE WATER ABOUT THE CONTAMINATION. DISP: Disposal Method DISSOLVE IN A COMBUSTIBLE SOLVENT, SCATTER THE SPRAY OF THE SOLUTION INTO A FURNACE WITH AFTERBURNER AND ALKALI [SIC] SCRUBBER. (THIDD6 80/ITII) INCINERATE IN A RCRA-APPROVED INCINERATOR AFTER MIXING WITH ANOTHER COMBUSTIBLE FUEL. CARE MUST BE EXERCISED TO ASSURE COMPLETE COMBUSTION TO PREVENT THE FORMATION OF PHOSGENE. AN ACID SCRUBBER IS NECESSARY TO REMOVE THE HALO ACIDS PRODUCED. (HTAHC* 81/SIT) IF THE WASTE CANNOT BE INCINERATED FOR SOME REASON, DISPOSE IN A RCRA- APPROVED SECURE LANDFILL, MEETING ITS LIMITS ON LIQUID CONTENT. WTP: EVAPORATION RATE FROM WATER AT 25 DEGREES CELSIUS OF 1 PPM SOLUTION: 50 PERCENT AFTER 48 MIN, 90 PERCENT AFTER > 140 MIN. (85FHA9 77/VER) ITOX: ------------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOX)------------ CARC: CARCINOGEN IN MICE. TECHNICAL PENTACHLOROETHANE CONTAMINATED WITH 4.2 PERCENT HEXACHLOROETHANE, A KNOWN HEPATO-CARCINOGEN IN MICE, ADMINISTERED ORALLY TO RATS AND MICE CAUSED SIGNIFICANT INCREASE OF HEPATOCELLULAR CARCINOMAS IN THE MICE. INCREASED CHRONIC RENAL INFLAMMATION IN MALE RATS BUT NO PRIMARY TUMORS. (FAATDF 2(2)82,82/MEN) ACCORDING TO THE NATIONAL CANCER INSTITUTE, THE COMBINATION OF POSITIVE CARCINOGENICITY RESULTS WITH NEGATIVE MUTAGENICITY RESULTS IS OFTEN OBSERVED FOR CHLOROHYDROCARBONS AND SUGGESTS THAT THIS MAY INDICATE THEY PLAY THE ROLE OF PROMOTERS RATHER THAN INITIATORS OF CANCER. (CHIP** 76017,83/EPA) NATIONAL CANCER INSTITUTE/NTP BIOASSAY PROGRAM HAS REPORTED PENTACHLOROETHANE TO BE POSITIVE IN CARCINOGENICITY STUDIES. (PESTC* 11(38)42,83/ANON) ME: NOT MUTAGENIC IN AMES BIOASSAY. (CHIP** 76017,83/EPA) RE: NO DATA ON TERATOGENICITY OR REPRODUCTIVE EFFECTS AVAILABLE. (CHIP** 76017,83/EPA) ETXV: Fresh Water Toxicity Data Con Exp Species Effec Test Env Ref c t --- ---- --------------------------- ----- -------------------- ----------------------- 62. 48 H WATER FLEA (DAPHNIA MAGNA) LC50 STATIC, UNMEASURED AWQCD* PB81-117400,80/E 9 R CAO 7.3 96 H BLUEGILL (LEPOMIS MACROCHIR LC50 FLOW-THROUGH, MEASUR AWQCD* PB81-117400,80/E R US) ED CAO 7.2 96 H BLUEGILL (LEPOMIS MACROCHIR LC50 STATIC, UNMEASURED AWQCD* PB81-117400,80/E 4 R US) CAO 8.2 24 H BLUEGILL (LEPOMIS MACROCHIR LC50 STATIC BECTA6 26,446, 81/BUC R US) 7.2 96 H BLUEGILL (LEPOMIS MACROCHIR LC50 STATIC BECTA6 26,446,81/BUC R US) 63 24 H WATER FLEA (DAPHNIA MAGNA) LC50 STATIC BECTA6 24,684,80/LEB R 63 48 H WATER FLEA (DAPHNIA MAGNA) LC50 STATIC BECTA6 24,684,80/LEB R Chronic Aquatic Toxicity Limits CRITERIA DERIVED PERMISSIBLE CONCENTRATION IN WATER TO PROTECT FRESHWATER AQUATIC LIFE, 1.1 PPM (7.24 PPM FOR ACUTE TOXICITY BASIS). CRITERIA DERIVED PERMISSIBLE CONCENTRATION IN WATER TO PROTECT SALTWATER AQUATIC LIFE, 0.39 PPM ON AN ACUTE TOXICITY BASIS (0.231 PPM ON A CHRONIC BASIS). (HTAHC* 81/SIT) (AWQCD* PB81-117400,80/ECAO) Salt Water Toxicity Data Conc Exp Species Effect Test Env Ref ----- --- ----------------- ------ ---------------------- -------------------------- 5.06 MYSID SHRIMP LC50 STATIC, UNMEASURED AWQCD* PB81-117400,80/ECAO 0.39 MYSID SHRIMP LC50 FLOW-THROUGH, MEASURED AWQCD* PB81-117400,80/ECAO 116.0 SHEEPSHEAD MINNOW LC50 STATIC, UNMEASURED AWQCD* PB81-117400,80/ECAO NTXV: Animal Toxicity Data Val Time Species Test Adm Ref ----------------- ---- ------- ---- --- ---------------- 4238 (PPM IN AIR) RAT LCLO INH AEPPAE 141,19,29 500 DOG LDLO ORL AJHYA2 16,325,32 [BOTH AS CITED BY RTECS ONLINE 12/1983] AQN: GREEN ALGA SELENASTRUM CAPRICORNUTUM 96-HR EC50 WAS 121 PPM; SALTWATER ALGA SKELETONEMA COSTATUM 96-HR EC50 WAS 58 PPM. (AWQCD* PB81-117400,80/ECAO) DRC: LOCAL IRRITANT TO THE EYES AND UPPER RESPIRATORY TRACT. (HTAHC* 81/SIT) JNS: CENTRAL NERVOUS SYSTEM DEPRESSANT, NARCOSIS. (85EVA9 80/BLO) IRRITATION OF EYES AND RESPIRATORY TRACT, MILD NARCOSIS. (THIDD6 80/ITII) EXPOSURE AT HIGH CONCENTRATIONS LEADS TO LOSS OF CONSCIOUSNESS AND DEATH. (HTAHC* 81/SIT) IDTI: ---------------DETECTION INFORMATION CATEGORY (USE CODE ZDTI)--------------- LDL: TO DETERMINE IN DRINKING WATER, PURGE AND TRAP (HIGH IONIC STRENGTH), THEN CAPILLARY GC/MS. DETECTION LIMIT 0.0001 PPM IN SURFACE WATER, THE SAME METHOD GIVES A DETECTION LIMIT OF 0.001 PPM. IN WASTEWATER, THE SAME METHOD GIVES A DETECTION LIMIT OF 0.01 PPM. (ME009* 80/RTI) PRIORITY POLLUTANT METHOD 601 IS NOT VALIDATED FOR THIS COMPOUND. TO DETERMINE IN WASTEWATER BY THIS METHOD, PURGE AND TRAP, THEN GC/HECD. (FEREAC 44FR69468, 12-3-79) SIMILARLY, PRIORITY POLLUTANT METHOD 624 IS NOT VALIDATED FOR THIS COMPOUND. TO DETERMINE IN WASTEWATER BY METHOD 624, PURGE AND TRAP, THEN GC/MS. (FEREAC 44FR69532, 12-3-79) Record 448 of 1119 in OHMTADS (Final version) AN: 8400275 ID: -------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)--------------- PN: P-CHLOROANILINE- SY: BENZENAMINE,-4-CHLORO- (9CI); 4-CHLOROANILINE-; ANILINE,-P-CHLORO-; P-CA-; P-CHLOROPHENYLAMINE-; P-AMINOCHLOROBENZENE-; 1-AMINO-4-CHLOROBENZENE-; 4-CHLOROBENZENAMINE-; 4-CHLORO-11-AMINOBENZENE-; 4-CHLOROPHENYLAMINE-; NCI-C02039- RN: 106-47-8 RTEC: BX0700000 ST: C6H4CLNH2; CLC6H4NH2 IMP: 99% CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)----------- MP: 72.5 DEGREES CELSIUS (MEIEDD 76/WIN) BP: 232 DEGREES CELSIUS (MEIEDD 76/WIN) SOL: 2,400; SLIGHTLY SOLUBLE. THE SATURATION POINT OF AN AQUEOUS SOLUTION AT 20 DEGREES CELSIUS IS 0.24%. (PCAMS* 80/DUP) DEN: 1.43 (PCAMS* 80/DUP) VAP: 0.3 MM HG AT 37.7 DEGREES CELSIUS; 0.15 MM HG AT 25 DEGREES CELSIUS (PCAMS* 80/DUP); 0.05 MM HG AT 30 DEGREES CELSIUS; 0.015 MM HG AT 20 DEGREES CELSIUS (85FHA9 77/VER) VAPD: 4.4 (PCAMS* 80/DUP) IRCI: ---------------REACTIVITY INFORMATION CATEGORY (USE CODE ZRCI)-------------- BIN: OXIDIZING AGENTS. AVOID ACIDIC CONDITIONS AND CONTAMINATION, WHICH WILL LOWER THE TEMPERATURE AT WHICH SPONTANEOUS THERMIC DECOMPOSITION MAY OCCUR. (PCAMS* 80/DUP) COR: THE USE OF PLASTIC PACKAGING OR EQUIPMENT SHOULD BE AVOIDED BECAUSE THESE MATERIALS MAY BE SOFTENED OR DISSOLVED BY P-CHLOROANILINE. (PCADS* 80/DUP) IENE: --------ENVIRONMENTAL CHEMISTRY INFORMATION CATEGORY (USE CODE ZENE)-------- LOC: THIS MATERIAL IS A WHITE TO LIGHT AMBER CRYSTALLINE SOLID THAT DARKENS SOMEWHAT WITH STORAGE. IF SPILLED AS A MOLTEN LIQUID, IT WOULD TEND TO SOLIDIFY AS IT COOLED. THE SOLID OR LIQUID MATERIAL WOULD BE HEAVIER THAN WATER. (PCAMS* 80/DUP) DRT: INFILTRATION OF RHINE RIVER WATER THROUGH SOIL BANKS FOR 1 TO 12 MONTHS AS A MEANS OF PURIFYING IT REDUCED ITS CONCENTRATION OF 4-CHLOROANILINE FROM 0.1 PPB TO 0.03 TO 0.1 PPB. (CMSHAF 9(4),231, 80/ZOE) 4-CHLOROANILINE IS RESISTANT TO BIODEGRADATION BY SOIL MICROORGANISMS. SUESS ET AL. (1980) FOUND THAT AFTER CARBON-14 LABELED 4-CHLOROANILINE HAD BEEN INCUBATED IN BAUMANNSHOF AND HUMUS SOILS FOR 16 WEEKS, THE MINERALIZATION TO CARBON DIOXIDE WAS LESS THAN 15%. (ARBIS* 201,80/SUE) LABORATORY EXPERIMENTS ON THE BEHAVIOR OF P-CHLOROANILINE IN A WET SOIL MEDIA RESULTED IN SUBSTANTIAL DEGRADATION OF THE MATERIAL. THE SOIL USED WAS A MEADOW-CHERNOZEMLIKE SOIL. AFTER AN INITIAL LAG PERIOD, MICROBIAL ACTIVITY CAUSED THE RELEASE OF APPROXIMATELY 60% OF THE CHLORINE FROM CHLOROANILINES TESTED. IN THE SOIL SUSPENSIONS, P-CHLOROANILINE (50 MG/L) AT PH7 WITHOUT GLUCOSE ADDITION DISAPPEARED IN 3 DAYS, SOMEWHAT MORE SLOWLY THAN DID ANILINE (1 DAY) BUT CONSIDERABLY FASTER THAN 3-CHLOROANILINE (30 DAYS) OR DICHLOROANILINE (45 DAYS). (IANBAM (1)80,83/VAS) THE RESEARCHERS ASSUMED THAT VARIOUS INTERMEDIATE BREAKDOWN PRODUCTS ALSO SERVED AS CARBON SOURCES FOR THE MICROBES PRESENT BECAUSE BACTERIAL COUNTS INCREASED FOLLOWING THE DECOMPOSITION OF THE MAJORITY OF THE AVAILABLE ORIGINAL CHEMICAL. THE ORGANISMS WHICH WERE RESPONSIBLE FOR THE OBSERVED DEGRADATION WERE FACULTATIVE AEROBIC BACTERIA. HOH: THE ESTIMATED HALF-LIFE OF 4-CHLOROANILINE IN RIVER WATER IS 0.3 TO 3 DAYS AND IN GROUNDWATER 30 TO 300 DAYS. (CMSHAF 9(4),231,80/ZOE) PER: DEGRADES READILY IN WASTEWATER TREATMENT SYSTEMS. ORGANISMS OF THE AEROBACTER GENUS HAVE ACHIEVED 100% RING DISRUPTION ON A 500 MG/L SOLUTION AT 30 DEGREES CELSIUS IN 59 HOURS. MUTANT ORGANISMS OF THE SAME GENUS EFFECTED THE SAME BREAKDOWN IN 12 HOURS. (85FHA9 77/VER) THE PRESENCE OF INDIGENOUS GREEN AND BLUE GREEN ALGAE MAY ACCELERATE THE RATE OF PHOTOLYTIC DEGRADATION PATHWAYS APPLICABLE TO P-CHLOROANILINE IN SURFACE WATERS. (ESTHAG 17(8)462,83/ZEP) THE OXIDATION DEGRADATION RATE OF THIS MATERIAL IS 4E-3 PER HOUR. (RCRAC* 80/EPA) PFA: DISTRIBUTION OF RADIOACTIVITY IN OAT PLANTS HARVESTED AFTER GROWING FOR 3 WEEKS IN VERMICULITE-NUTRIENT SOLUTION CONTAINING 1 PPM LABELED 4-CHLOROANILINE WAS 56.2% IN THE ROOTS AND 1.3% IN THE SHOOTS (SUESS ET AL., 1980). (ARBIS* 201,80/SUE) LOG OCTANOL/WATER PARTITION COEFFICIENT (LOG P) 1.83. (PCAMS* 80/DUP) ITRN: -------TRANSPORTATION AND STORAGE INFORMATION CATEGORY (USE CODE ZTRN)------ USE: INTERMEDIATE USED IN THE MANUFACTURE OF DYES, PIGMENTS, PHARMACEUTICALS, AND AGRICULTURAL CHEMICALS. STRG: Containers SHIPPED IN TANK CARS, TANK TRUCKS, 55 GALLON DRUMS, OR 51 GALLON DRUMS. (CHMCY* 82/PLA) THE 55 GALLON DRUMS ARE TYPICALLY STEEL DRUMS (500 LB NET) CONTAINING CAST SOLID MATERIAL. TANK CARS AND TANK TRUCKS ALSO CARRY CAST SOLID MATERIAL. THE 51 GALLON DRUMS ARE TYPICALLY FIBER DRUMS (250 LB NET) CONTAINING MATERIAL IN FLAKE FORM. (PCADS* 80/DUP) DOT--OPTIONAL HAZARDOUS MATERIALS TABLE. IMCO CLASS 6.1, PACKAGING GROUP II. ICAO--IN LIQUID FORM: PASSENGER AIRCRAFT, PACKING INSTRUCTIONS 6210, MAXIMUM NET QUANTITY PER PACKAGE--5 L; CARGO AIRCRAFT, PACKING INSTRUCTIONS 6218, MAXIMUM NET QUANTITY PER PACKAGE--60 KG. IN SOLID FORM: PASSENGER AIRCRAFT, PACKING INSTRUCTIONS 6220, MAXIMUM NET QUANTITY PER PACKAGE--25 KG; CARGO AIRCRAFT, PACKING INSTRUCTIONS 6228, MAXIMUM NET QUANTITY PER PACKAGE--100 KG. (ICAO** 81/ICAO) IATA--RESTRICTED ARTICLE NO. 432. LIQUIDS NOT LISTED. SOLIDS: MAXIMUM NET QUANTITY PER PACKAGE--25 KG ON PASSENGER AIRCRAFT AND 100 KG ON CARGO AIRCRAFT; PACKING NOTES (EXCEPTIONS FOR CLASS B POISONOUS SOLIDS) 651 AND 670 APPLY, RESPECTIVELY. (RARAD5 80/IATA) General Storage Procedures STEEL STORAGE TANKS ARE SUITABLE FOR BULK STORAGE. TANKS SHOULD BE EQUIPPED WITH STEAM JACKETS OR EQUIVALENT HEATING PANELS AND INSULATED TO PERMIT TEMPERATURE CONTROL IN A RANGE BETWEEN 80 AND 90 DEGREES CELSIUS (176 TO 194 DEGREES FAHRENHEIT). STEEL IS ALSO AN APPROPRIATE MATERIAL FOR PIPING AND PUMPS. ALL TRANSFER SYSTEMS SHOULD BE HEATED AND INSULATED. PLASTICS ARE NOT RECOMMENDED FOR CONTAINER AND/OR TRANSFER SYSTEMS FOR THIS MATERIAL, BECAUSE MANY PLASTICS ARE DISSOLVED OR SOFTENED BY P-CHLOROANILINE. PREFERRED MATERIALS FOR GASKETS AND PACKINGS INCLUDE TEFLON, TFE, OR FEP FLUOROCARBON RESINS. DRUMS OF THIS MATERIAL SHOULD BE STORED IN COOL, DRY, WELL VENTILATED AREAS AWAY FROM FLAMMABLE AND/OR OXIDIZING MATERIALS. STORAGE TANKS AND EQUIPMENT SHOULD BE ELECTRICALLY GROUNDED AND EQUIPPED WITH CONSERVATION VENTS AND FLAME ARRESTERS. (PCAD5* 80/DUP) HND: P-CHLOROANILINE IS HANDLED HOT BECAUSE OF ITS HIGH FREEZING RANGE OF 69 TO 71 DEGREES CELSIUS (156 TO 160 DEGREES FAHRENHEIT). MATERIAL CAST SOLID IN DRUMS MAY BE HEATED IN THAW BOXES PRIOR TO HANDLING. DRUM BUNGS SHOULD BE LOOSENED PRIOR TO HEATING TO PREVENT PRESSURE BUILDUP. VENTILATION TO AVOID THE BUILDUP OF TOXIC AND FLAMMABLE VAPORS IS ESSENTIAL. MELTING PROCESSES SHOULD USE ONLY A CAREFULLY MANAGED, EASILY CONTROLLED HEAT SOURCE SUCH AS 10 P.S.I. STEAM AND AUTOMATIC CONTROLS SHOULD BE IN PLACE THAT PREVENT HEATING THE MATERIAL ABOVE 100 DEGREE CELSIUS (212 DEGREES FAHRENHEIT). HEATING BEYOND THIS POINT MAY PRODUCE A FLAMMABLE VAPOR IN THE THAW BOX. THE FLASH POINT OF P-CHLOROANILINE IS 113 DEGREES CELSIUS (235 DEGREES FAHRENHEIT). PROTECTION FROM FLAMES OR SPARKS IS VERY IMPORTANT. ALSO, THE MATERIAL MAY DECOMPOSE EXOTHERMICALLY AT TEMPERATURES ABOVE 300 DEGREES CELSIUS (570 DEGREES FAHRENHEIT). ACIDIC CONDITIONS AND CONTAMINATION WILL LOWER THE TEMPERATURE AT WHICH SPONTANEOUS EXOTHERMIC DECOMPOSITION MAY OCCUR. THE PREFERRED METHOD OF REMOVING HOT LIQUID P-CHLOROANILINE FROM DRUMS INVOLVES THE USE OF A CIP HOSE ATTACHED TO A VACUUM RECEIVER. GRAVITY DRAINAGE THROUGH A HOSE REPRESENTS ANOTHER ALTERNATIVE. THE USE OF PRESSURE ON DRUMS DURING UNLOADING IS NOT RECOMMENDED. THE EMPTYING OF DRUMS SHOULD TAKE PLACE IN AREAS PROVIDED WITH POSITIVE, FORCED VENTILATION SO THAT CONTACT WITH VAPORS OR DUST BY PERSONNEL IS AVOIDED. ONLY TRAINED PERSONNEL SHOULD BE PERMITTED IN SUCH AREAS. PROTECTIVE EQUIPMENT AND CLOTHING SHOULD INCLUDE LONG-SLEEVED SHIRTS, LONG PANTS, HARD HAT WITH BRIM, CHEMICAL SPLASH GOGGLES, BUTYL RUBBER OVERSHOES (OR BUTYL RUBBER SAFETY SHOES), AND WHATEVER DEGREE OF RESPIRATORY PROTECTION IS NECESSARY TO PREVENT INHALATION OF VAPORS AND/OR DUST. ADDITIONAL SAFETY EQUIPMENT THAT SHOULD BE AVAILABLE IN HANDLING AREAS FOR USE AS NEEDED INCLUDES FULL-LENGTH FACE SHIELDS, BUTYL RUBBER APRONS, SAFETY SHOWERS, AND EYE-WASH FOUNTAINS. (PCADS* 80/DUP) MFS: MONSANTO COMPANY, P. O. BOX 174, LULING, ST CHARLES COUNTY, LA 70070, MID NO 2052, EPA REGION 06, DUNSNO 001700756; BASF WYANDOTTE CORP., 100 CHERRY HILL ROAD, PARSIPPANY, COUNTY A, NJ 07054, MID NO. 3340, EPA REGION 02; ACETO CHEMICAL CO. INC., 126-02 NORTHERN BLVD, FLUSHING, QUEENS COUNTY, NY 11368, MID NO. 3465, EPA REGION 02; AMERICAN HOECHST CORPORATION, RTE 202-206 NORTH, BRIDGEWATER, SOMERSET COUNTY, NJ 08876, MID NO. 3611, EPA REGION 02; SANDOZ COLORS and CHEMICALS-NJ, ROUTE 10, EAST HANOVER, MORRIS COUNTY, NJ 07936, MID NO 4331, EPA REGION 02, DUNSNO 002147023; MONTEDISON USA, 1114 AVENUE OF THE AMERICAS, NEW YORK, MANHATTAN COUNTY, NY 10036, MID NO. 5011, EPA REGION 02, DUNSNO. 062528153; GAF CORPORATION, 140 W 51ST ST, NEW YORK, NEW YORK COUNTY, NY 10020, MID NO. 6355, EPA REGION 02, DUNSNO. 001294172; E. I. DUPONT DE NEMOURS and CO., ROUTE 130, DEEPWATER, SALEM COUNTY, NJ 08023, MID NO. 7372, EPA REGION 02. (PRDTN* 81/TSCA) ISAF: ----------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)---------------- STD: SUPERFUND DESIGNATED (HAZARDOUS SUBSTANCES) LIST. HAZARDOUS WASTE NO. 0924. REPORTABLE QUANTITY-1 LB (STATUTORY SOURCE UNDER CERCLA IS RCRA SECTION 3001). PROPOSED REPORTABLE QUANTITY IN MAY 1983 IS 1000 LB (454 KG) (CATEGORY C). (FEREAC 48FR23551, 5-25-83) DOT (OPTIONAL HAZARDOUS MATERIALS TABLE)-CHLOROANILINES, LIQUID: UN2019, IMCO CLASS 6.1, POISON LABEL REQUIRED, PACKAGING GROUP II, STOW ON OR UNDER DECK ON PASSENGER OR CARGO VESSEL. CHLOROANILINES, SOLID: UN2018. REQUIREMENTS SAME AS FOR THE LIQUID. (49CFR* 172.101,10-31-83/DOT) FPOT: VERY FLAMMABLE. (PCAMS* 80/DUP) FLAMMABLE VAPORS MAY BE PRODUCED ABOVE 100 DEGREES CELSIUS. (PCADS* 80/DUP) FLMT: LFL: 2.2 (PCAMS* 80/DUP) TOXC: DECOMPOSES ABOVE 300 DEGREES CELSIUS. TOXIC AND/OR IRRITATING COMBUSTION PRODUCTS INCLUDE HYDROGEN CHLORIDE AND OXIDES OF NITROGEN. (CGHCD* 78/USCG) FIRP: U.S. COAST GUARD RECOMMENDATIONS: FIRE FIGHTERS SHOULD WEAR GOGGLES AND SELF-CONTAINED BREATHING APPARATUS. EXTINGUISH FLAMES WITH WATER, DRY CHEMICALS, FOAM, OR CARBON DIOXIDE. COOL EXPOSED CONTAINERS WITH WATER. (CGHCD* 78/USCG) MANUFACTURER RECOMMENDATIONS: FIRE-FIGHTING ACTIVITIES SHOULD BE CONDUCTED FROM UPWIND POSITIONS. CAUTION SHOULD BE EXERCISED NEAR HOT CONTAINERS BECAUSE EXOTHERMIC DECOMPOSITION MAY RUPTURE SUCH CONTAINERS. SMOKE AND FUMES MAY CONTAIN HCL AND NOX, AS WELL AS P-CHLOROANILINE. (PCADS* 80/DUP) DOT RECOMMENDATIONS: SMALL FIRES-DRY CHEMICAL, CO2, WATER SPRAY OR FOAM. LARGE FIRES-WATER SPRAY, FOG, OR FOAM. MOVE CONTAINER FROM FIRE AREA IF YOU CAN DO SO WITHOUT RISK. IF THE MATERIAL IS LIQUID, FIGHT FIRE FROM MAXIMUM DISTANCE. (85EWAF 80/DOT) FLPT: 113 (235 DEGREES FAHRENHEIT, CLOSED CUP. (PCADS* 80/DUP)) EXPL: IN THE ADVANCED STAGES OF A FIRE OR IN A MASSIVE FIRE, THIS MATERIAL MAY DECOMPOSE EXOTHERMICALLY AND RUPTURE ITS CONTAINERS. (PCADS* 80/DUP) SAF: STAY OUT OF LOW AREAS WHERE TOXIC AND/OR FLAMMABLE VAPORS MAY ACCUMULATE. (85EWAF 80/DOT) CLEANUP PERSONNEL SHOULD WEAR COMPLETE BUTYL RUBBER SUITS WITH HOODS AND SELF-CONTAINED BREATHING APPARATUS. IN CASE OF FIRE, FIRE FIGHTERS SHOULD BE EQUIPPED WITH RESPIRATORY PROTECTION INCLUDING BREATHING AIR SUPPLIES. FIRE FIGHTING ACTIVITIES SHOULD BE CONDUCTED FROM UPWIND POSITIONS IF POSSIBLE. CAUTION SHOULD BE EXERCISED WHEN APPROACHING HOT CONTAINERS OF P-CHLOROANILINE. EXOTHERMIC DECOMPOSITION MAY RUPTURE SUCH CONTAINERS. SMOKE AND FUMES MAY CONTAIN HCL AND NOX, AS WELL AS P-CHLOROANILINE. USE WATER SPRAY TO REDUCE VAPORS AND/OR DUST. (85EWAF 80/DOT) HTOX: Acute Hazard Level TOXIC IF INHALED, SWALLOWED, OR ABSORBED THROUGH THE SKIN. EXPOSURE CAUSES CYANOSIS. (PCAMS* 80/DUP) SYMPTOMS OF ILLNESS OCCUR AT 4 PPM IN THE AIR, EQUIVALENT TO 22 MG/M3. ANY LEVEL GREATER THAN 2 PPM IS UNSATISFACTORY FOR HUMAN EXPOSURE, AND EXPOSURES AT LEVELS OF 8 PPM (44 MG/CU M) FOR EVEN 1 MINUTE CARRY A RISK OF SEVERE TOXIC EFFECTS. (85FHA9 77/VER) Inhalation Limit Data 0.06; 0.008; 0.002 Inhalation Limit Text NO OSHA REGULATIONS AND NO NIOSH RECOMMENDATIONS HAVE BEEN PUBLISHED. HOWEVER, ACGIH RECOMMENDS A TLV (TWA) OF 2 PPM (10 MG/M3) WITH "SKIN" NOTATION AND A STEL OF 5 PPM (20 MG/M3) FOR ANILINE AND ITS HOMOLOGS. (TLVADM 83/ACGIH) ACT: LEAKS AND SPILLS SHOULD RECEIVE PROMPT ATTENTION DUE TO THE TOXIC NATURE OF THIS MATERIAL. ALL PERSONS IN THE IMMEDIATE VICINITY OF A SPILL SHOULD BE EVACUATED OR MOVED TO AN UPWIND LOCATION. PCADS* 80/DUP) AML: SEEK PROFESSIONAL ASSISTANCE FROM EPA'S ENVIRONMENTAL RESPONSE TEAM (ERT), EDISON, NJ, 24-HOUR NUMBER (201)321-6660. CONTAIN AND ISOLATE SPILL TO LIMIT SPREAD. ABSORB MINOR SPILLS WITH DRY SAND, EARTH, OR VERMICULITE. IF SUITABLE WASTEWATER COLLECTION IS AVAILABLE, SPILLS CAN BE WASHED DOWN WITH WATER TO FREEZE THE CHLOROANILINE PRIOR TO SHOVELING THE MATERIAL INTO DRUMS. (PCADS* 80/DUP) CONSTRUCT SWALE TO DIVERT UNCONTAMINATED PORTION OF WATERSHED AROUND CONTAMINATED PORTION. ISOLATION PROCEDURES INCLUDE CONSTRUCTION OF EARTHEN OR SAND DAMS, INTERCEPTOR TRENCHES, OR IMPOUNDMENTS. (PCADS* 80/DUP) SEEK PROFESSIONAL HELP TO EVALUATE PROBLEM AND IMPLEMENT CONTAINMENT PROCEDURES. CONDUCT BENCH-SCALE AND PILOT-SCALE TESTS PRIOR TO IMPLEMENTATION OF FULL-SCALE DECONTAMINATION PROGRAM. FOR DENSITY STRATIFICATION AND IMPOUNDMENT, REMOVE PRODUCT FROM BOTTOM LAYER BY PUMPING THROUGH MANIFOLD OR BY POLYETHYLENE ROPE COLLECTION OR REMOVE CLARIFIED UPPER PORTION BY SKIMMERS OR SIPHONING. SOLIDS MAY BE REMOVED IN SETTLING BASINS. TREATMENT ALTERNATIVES FOR CONTAMINATED WATER INCLUDE AERATION OR EVAPORATION AND BIODEGRADATION. (85FHA9 77/VER) A METHOD FOR REMOVING P-CHLOROANILINE AND SIMILAR PHENOLS AND ANILINES FROM WASTEWATERS MAY BE USEFUL IN SPILL CLEANUP ACTIVITIES: THIS METHOD INVOLVES THE ADDITION OF HORSERADISH PEROXIDASE AND HYDROGEN PEROXIDE TO THE CONTAMINATED WATER. PRECIPITATION OF THE CONTAMINANT FOLLOWS. REMOVAL OF THE CONTAMINANT CAN THEN BE ACHIEVED BY SEDIMENTATION OR FILTRATION. (JABIDV 2,414,80/KLI) DISP: Disposal Method PRODUCT RESIDUES AND SORBENT MEDIA MAY BE PACKAGED IN 17H EPOXY LINED DRUMS AND DISPOSED OF AN A RCRA-APPROVED SECURE LANDFILL. (PCAMS* 80/DUP) DESTROY BY HIGH-TEMPERATURE INCINERATION USING A HYDROCHLORIC ACID SCRUBBER, IF AVAILABLE. (PCAMS* 80/DUP) CONFIRM DISPOSAL PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. WTP: MICROBIAL DEGRADATION OF THIS MATERIAL HAS BEEN REPORTED. (IANBAM (1)80/83/VAS) DEGRADES READILY IN WASTEWATER TREATMENT SYSTEMS. ORGANISMS OF THE AEROBACTER GENUS HAVE ACHIEVED 100% RING DISRUPTION ON A 500 MG/L (PPM) SOLUTION AT 30 DEGREES CELSIUS IN 59 HOURS. MUTANT ORGANISMS OF THE SAME GENUS EFFECTED THE SAME BREAKDOWN IN 12 HOURS. (85FHA9 77/VER) SEE FIELD PER. ITOX: ------------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOX)------------ ME: SHORT-TERM IN VITRO MAMMALIAN CELL ASSAY RESULTS INDICATE THAT P-CHLOROANILINE IS MUTAGENIC. (NPTB* (9)7,83/NTP) ETXV: Fresh Water Toxicity Data Conc Exp Species Effect Test Env Ref ---- --- --------------- ------ -------- --------------- 14 96 RAINBOW TROUT LC50 STATIC 85FHA9 2,83/VER 12 96 FATHEAD MINNOW LC50 STATIC 85FHA9 2,83/VER 23 96 CHANNEL CATFISH LC50 STATIC 85FHA9 2,83/VER 2 96 BLUEGILL LC50 STATIC 85FHA9 2,83/VER NTXV: Animal Toxicity Data Val Time Species Test Adm Ref ---- ---- ------------- ---- --- ------------------------------------------------ 310 RAT LD50 ORL AIHAAP 23,95,62 [CITED IN RTECS ONLINE DEC 83] 3200 RAT LD50 SKN AGGHAR 15,447,57 [CITED IN RTECS ONLINE DEC 83] 100 DOG LDLO IVN AEPPAE 244,387,63 [CITED IN RTECS ONLINE DEC 83] 100 HOUSE SPARROW LD50 ORL AECTCV 12(3)355,83/SCH 1000 STARLING LD50 ORL AECTCV 12(3)355,83/SCH IRL: APPLIED TO THE SKIN OF RABBITS FOR 24 HOURS, 500 MG P-CHLOROANILINE WAS A MILD IRRITANT, BUT 250 .MU.G FOR 24 HOURS SEVERELY IRRITATED RABBIT EYES. (RTECS ONLINE 12/1983 CITES 28ZPAK -,96,72.) DRC: THIS MATERIAL IS TOXIC IF ABSORBED THROUGH THE SKIN OR INHALED. EYE CONTACT MAY ALSO CAUSE CORNEAL DAMAGE. (PCADS* 80/DUP) JNS: ABSORPTION INTO THE BODY MAY RESULT IN CYANOSIS (BLUISH SKIN COLOR DUE TO POORLY OXYGENATED BLOOD). WHEN SKIN ABSORPTION OCCURS SYMPTOMS MAY BE DELAYED 2 TO 4 HOURS. ODOR IS SIMILAR TO THAT OF OTHER CHLOROAMINES. (PCAMS* 80/DUP) MATERIAL HAS A PLEASANT SWEET ODOR. (85FHA9 77/VER) SYMPTOMS OF EXPOSURE MAY ALSO INCLUDE SHORTNESS OF BREATH, HEADACHE, DIZZINESS, OR FAINTNESS. (HCSDA* 80/DAS) ODOR: LOT: 287; 0.01; ODOR THRESHOLD IN PPM, EQUIVALENT TO 1.5 MG/CU M (PCAMS* 80/DUP); ZOETEMAN (1980) ESTIMATED THE ODOR THRESHOLD CONCENTRATION IN WATER TO BE 10 .MU.G/L. (PSSID2 2,80/ZOE) DRK: M.A.C. IN WATERS CLASS I FOR THE PRODUCTION OF DRINKING WATER IN THE NETHERLANDS IS 0.2 MG/L. (85FHA9 77/VER) IDTI: ---------------DETECTION INFORMATION CATEGORY (USE CODE ZDTI)--------------- FDL: SPOT TESTS ON METAL, PAINTED, AND CONCRETE SURFACES. THE METHOD USES FILTER PAPER SWABS CONTAINING METHANOL TO WIPE THE SURFACE OF INTEREST, THEREBY SAMPLING FOR AROMATIC AMINES. THE SAMPLES ARE SUBSEQUENTLY TESTED WITH CHROMOGENIC AND FLUOROGENIC REAGENTS. THE CHROMOGENIC VISUALIZATION REAGENT OF CHOICE IS EHRLICH'S REAGENT. THE LOWER LIMIT OF DETECTION IS 15 TO 30 NG/CM2 DEPENDING ON THE NATURE OF THE SURFACE BEING TESTED. THE FLUOROGENIC REAGENT OF CHOICE IS FLUORESCAMINE. THE LOWER LIMIT OF DETECTION IS 6 TO 150 NANOGRAMS PER SQUARE CENTIMETER. (ANCHAM 48(14),2227,76/WEE) LDL: CONFIRMATORY IR SPECTRUM NO. 638B. (ALIRS* 2,75/POU) P-CHLOROANILINE HAS BEEN ANALYZED BY HPLC USING A THIN LAYER FLOW-THROUGH ELECTROCHEMICAL CELL. DETECTION LIMIT 0.5 NANOGRAM INJECTED OR BY HPLC USING A UV DETECTOR @ 254 NM. DETECTION LIMIT 2 NG INJECTED. (ACSMC8 149,413,81/VAN) P-CHLOROANILINE HAS BEEN SEPARATED ON STANDARD TLC SILICA GEL LAYERS USING A VARIETY OF SOLVENT SYSTEMS. DETECTION MEANS INCLUDE UV LIGHT AND SEVERAL VISUALIZATION REAGENTS. (JOCRAM 155,227,78/DAM) Record 449 of 1119 in OHMTADS (Final version) AN: 8400301 ID: -------------SUBSTANCE IDENTIFICATION CATEGORY (USE CODE ZID)--------------- PN: METHAPYRILENE- SY: PYRIDINE, 2-[DIMETHYLAMINOETHYL)-2-THENYLAMINO]- (REGULATORY SYNONYM); N,N-DIMETHYL-N'-2-PYRIDINYL-N'-(2-THIENYLMETHYL)-1,2-ETHANEDIAMINE; 2-[2-DIMETHYLAMINOETHYL)-2-THENYLAMINO]PYRIDINE; N,N-DIMETHYL-N'-(2-PYRIDYL)-N'-(2-THIENYL)ETHYLENEDIAMINE; N,N-DIMETHYL-N'-(ALPHA-PYRIDYL)-N'-(2-METHYLTHIENYL)ETHYLENEDIAMINE; THENYLPYRAMINE-; THENYLENE (ABBOTT) (Tradename); SEMIKON (MASSENGILL) (Tradename); HISTADYL (LILLY) (Tradename); PYRATHYN- (Tradename); THIONYLIN- (Tradename); TENALIN- (Tradename); DORMIN- (Tradename); RESTRYL- (Tradename); REST-ON- (Tradename); SLEEPWELL- (Tradename); PARADORMALENE- (Tradename); PYRINISTAB- (Tradename); PYRINISTOL- (Tradename); LULLAMIN. (MEIEDD 76/WIN) (DSPUS* 22,55/OSO) (Tradename) RN: 91-80-5 RTEC: UT1400000 ST: C14H19N3S IMP: METHAPYRILENE IS LISTED IN TWO FORMULATIONS IN CTCP ONLINE 11/1983: PRIMATENE TABLETS M (WHITEHALL LABS.), AN OTHER-THE-COUNTER ASTHMATIC BRONCHODILATOR, WITH THEOPHYLLINE AND EPHEDRINE AND QUIET WORLD TABLETS (WHITEHALL LABS.), A SEDATIVE, WITH ASPIRIN, ACETAMINOPHEN, AND SCOPOLAMINE. THE HYDROCHLORIDE MAY BE MARKETED AS A PARENTERAL OR NASAL SOLUTION, AN OPHTHALMIC OINTMENT, A SKIN CREAM, OR AS TABLETS. (DSPUS* 25,55/OSO) CPP: --------CHEMICAL AND PHYSICAL PROPERTIES CATEGORY (USE CODE ZCPP)----------- SOL: 670,000 (HYDROCHLORIDE); ONE GRAM OF THE HYDROCHLORIDE DISSOLVES IN APPROXIMATELY 0.5 ML WATER. (MEIEDD 76/WIN) IENE: --------ENVIRONMENTAL CHEMISTRY INFORMATION CATEGORY (USE CODE ZENE)-------- LOC: LIQUID (FREE BASE) OR BITTER CRYSTALS (HYDROCHLORIDE). THE HYDROCHLORIDE IS FREELY SOLUBLE IN WATER.)(MEIEDD 76/WIN) THE HYDROCHLORIDE IS A WHITE, CRYSTALLINE POWDER THAT USUALLY HAS A FAINT ODOR. (DSPUS* 25,55/OSO) ITRN: -------TRANSPORTATION AND STORAGE INFORMATION CATEGORY (USE CODE ZTRN)------ USE: ANTIHISTAMINIC. (MEIEDD 76/WIN) USED IN SEDATIVE FORMULATIONS. MARKETED AS THE CHLORIDE AND THE FUMARATE . (DSPUS* 25,55/OSO) STRG: General Storage Procedures STORE THE HYDROCHLORIDE IN TIGHT, LIGHT-RESISTANT CONTAINERS. (DSPUS* 25,55/OSO) ISAF: ----------------SAFETY AND HANDLING CATEGORY (USE CODE ZSAF)---------------- STD: SUPERFUND DESIGNATED (HAZARDOUS SUBSTANCES) LIST. HAZARDOUS (RCRA) WASTE NO. U155. REPORTABLE QUANTITY 1 LB (STATUTORY SOURCE UNDER CERCLA IS RCRA SECTION 3001). PROPOSED REPORTABLE QUANTITY 5000 LB (2270 KG) (CATEGORY D). (FEREAC 48FR23551, 5-25-83) HTOX: Acute Hazard Level MODERATELY TOXIC ORALLY. THE USUAL DOSE IS 25 MG FOR A CHILD AND 50 MG FOR AN ADULT. THE TOTAL ADULT INTAKE SHOULD NOT EXCEED 400 MG IN 24 HOURS. AN ORAL DOSE OF 100 MG METHAPYRILENE HYDROCHLORIDE WAS FATAL IN A 16-MONTH-OLD CHILD; WHEREAS A 20-MONTH-OLD CHILD SURVIVED 800 MG (ALTHOUGH SUPPORTIVE MEASURES AND A SHORT-ACTING BARBITURATE WERE NEEDED TO COMBAT THE CONVULSIONS AND OTHER SYMPTOMS). (DSPUS* 25,55/OSO) AML: SEEK PROFESSIONAL ASSISTANCE FROM EPA'S ENVIRONMENTAL RESPONSE TEAM (ERT), EDISON, NJ, 24-HOUR NUMBER (201) 321-6660. CONTAIN AND ISOLATE SPILL TO LIMIT SPREAD. CONSTRUCT SWALE TO DIVERT UNCONTAMINATED PORTION OF WATERSHED AROUND CONTAMINATED PORTION. ISOLATION PROCEDURES INCLUDE CONSTRUCTION OF DAMS, INTERCEPTOR TRENCHES, OR IMPOUNDMENTS. SEEK PROFESSIONAL HELP TO EVALUATE PROBLEM AND IMPLEMENT CONTAINMENT PROCEDURES. CONDUCT BENCH-SCALE AND PILOT-SCALE TESTS PRIOR TO IMPLEMENTATION OF FULL-SCALE DECONTAMINATION PROGRAM. CONTAMINATED SOIL OR IMMOBILIZED RESIDUES MAY BE PACKAGED FOR DISPOSAL. CONFIRM ALL TREATMENT PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. DISP: Disposal Method PRODUCT RESIDUES AND SORBENT MEDIA MAY BE PACKAGED IN 17H EPOXY LINED DRUMS AND DISPOSED OF AT A RCRA-APPROVED SECURE LANDFILL. DESTROY BY HIGH TEMPERATURE INCINERATION WITH SCRUBBING EQUIPMENT. ALTERNATIVELY, ENCAPSULATE BY ORGANIC POLYESTER RESIN OR USE SILICATE FIXATION. CONFIRM DISPOSAL PROCEDURES WITH RESPONSIBLE ENVIRONMENTAL ENGINEER AND REGULATORY OFFICIALS. ITOX: ------------TOXICITY/BIOMEDICAL EFFECTS CATEGORY (USE CODE ZTOX)------------ CARC: CURRENTLY TESTED FOR CARCINOGENESIS BIOASSAY BY NTP AS OF JUNE 1983 ACCORDING TO RTECS ONLINE 12/1983. LIJINSKY AND TAYLOR (1977) GAVE 30 RATS 0.1% METHAPYRILINE PLUS 0.2% SODIUM NITRITE IN THEIR DRINKING WATER FOR 90 WEEKS. EACH RAT RECEIVED A TOTAL DOSE OF 9 G METHAPYRILENE AND 18 G NITRITE. THE TREATMENT INDUCED LIVER TUMORS IN 30% OF THE RATS-4 OF 14 FEMALES AUTOPSIED AND 1 OF 15 MALES AUTOPSIED HAD LIVER CHOLANGIOCARCINOMAS; 1 FEMALE AND 1 MALE HAD HEPATOCELLULAR CARCINOMAS; AND 1 FEMALE HAD LIVER HEMANGIOENDOTHELIAL SARCOMA COMPARED TO 1 MALE OF THE 26 MALE CONTROLS AUTOPSIED (WHO WERE GIVEN ONLY NITRITE) THAT EXHIBITED LIVER TUMOR (HEPATOCELLULAR CARCINOMA); NONE OF THE 30 FEMALE CONTROLS AUTOPSIED HAD LIVER TUMORS. (FCTXAV 15,269,77/LIJ) ME: MUTAGEN DATA: DND-ESC 30 .MU.MOL/L (MUREAV 89,95,81) [AS LISTED IN RTECS ONLINE 12/1983] NTXV: Animal Toxicity Data Va Tim Specie Tes Ad Ref l e s t m -- --- ------ --- -- ---------------------------------------------------------------- 18 MUS LD5 OR PSEBAA 80,458,521 2 0 L 20 MUS LD5 IV PSEBAA 80,458,52. [TESTS AND REFERENCE FROM RTECS ONLINE 12/198 0 N 3] DRC: LOCAL SKIN SENSITIVITY TO METHAPYRILENE HAS BEEN REPORTED, BUT IT HAS BEEN FREQUENTLY USED TO TREAT ALLERGIC DERMATOSES. (DSPUS* 25,55/OSO) JNS: A 20-MONTH-OLD CHILD WHO INGESTED 800 MG OF THE HYDROCHLORIDE SUFFERED CYANOSIS, UNCONSCIOUSNESS, CONVULSIONS, AND CARDIORESPIRATORY DEPRESSION. A 16-MONTH-OLD CHILD WHO DIED FROM INGESTING 100 MG OF THE HYDROCHLORIDE EXHIBITED NAUSEA, VOMITING, DROWSINESS FOLLOWED RAPIDLY BY EXCITATION, TREMORS, AND CONVULSIONS. CEREBRAL EDEMA AND UPPER NEPHRON NEPHROSIS (WITH IMMEDIATE ANURIA AND A GREAT RISE IN NONPROTEIN NITROGEN) WERE REVEALED AT AUTOPSY. (DSPUS* 25,55/OSO) IDTI: ---------------DETECTION INFORMATION CATEGORY (USE CODE ZDTI)--------------- FDL: WHEN 25 MG OF THE HYDROCHLORIDE IS DISSOLVED IN 5 ML SULFURIC ACID, A PRONOUNCED ORANGE-BROWN COLOR FORMS, WHICH CHANGES TO GREENISH-YELLOW UPON DILUTION WITH 20 ML WATER. THE SOLUTION ALSO BECOMES SLIGHTLY TURBID ON DILUTION. (DSPUS* 25,55/OSO) LDL: A SOLUTION OF 10 PPM OF THE HYDROCHLORIDE IN WATER SHOWS ABSORPTION MAXIMA AT 238 PLUS OR MINUS 1 .MU.M AND 304 PLUS OR MINUS 1 .MU.M AND A MINIMUM OF 272 .MU.M PLUS OR MINUS 1 .MU.M. THE ABSORPTIVITY (1% SOLUTION, 1 CM PATH LENGTH) AT 238 .MU.M IS BETWEEN 601 TO 621. (DSPUS* 25,55/OSO) THE U.S. PHARMACOPOEIA PROVIDES AN ASSAY FOR THE HYDROCHLORIDE (A POTENTIOMETRIC TITRATION IN GLACIAL ACETIC ACID WITH ADDITION OF MERCURIC ACETATE TO FORM NONIONIZED MERCURIC CHLORIDE AND THUS AVOID INTERFERENCE), WHICH REACTS AS A DIACIDIC BASE. IN THE ASSAY, EACH ML OF 0.1 NORMAL PERCHLORIC ACID REPRESENTS 14.89 MG OF THE HYDROCHLORIDE. (DSPUS* 25,55/OSO)(RMPPH* 61/MAR) DUGAL ET AL. (1980) DESCRIBE ANALYSIS OF BIOLOGICAL FLUIDS USING GAS CHROMATOGRAPHY WITH NITROGEN SELECTIVE DETECTION FOLLOWED BY GC/MS FOR IDENTIFICATION. (JATOD3 4,1,80/DUG) METHAPYRILENE CAN BE DETERMINED BY GC/FLAME IONIZATION BY USING A GLASS COLUMN PACKED WITH 3% OV-17 COLUMN ON ANACHROM ABS SUPPORT. COLUMN TEMPERATURE PROGRAMMED FROM 100 TO 250 DEGREES CELSIUS AT 4 DEGREES PER MINUTE. (ANCHAM 49,906,77/BAK) METHAPYRILENE CAN BE DETERMINED BY HIGH PRESSURE LIQUID CHROMATOGRAPHY WITH 254 NM UV DETECTOR. INVESTIGATORS USED A WATERS ASSOCIATES MICROPORASIL COLUMN AND A FLOW RATE OF 2.0 ML/MINUTE. MOBILE PHASE WAS METHANOL-2N AMMONIA-1N AMMONIUM NITRATE IN RATIO OF 27:2:1. (JOCRAM 168,417,79/BAK) ALTERNATIVELY, METHAPYRILENE CAN BE DETERMINED BY HPLC WITH A 254 NM UV DETECTOR AND A COLUMN CONSISTING OF NITRILE-BONDED PHASE ON MICROSILICAGEL 10 .MU.M. THE MOBILE PHASE WAS ACETONITRILE-WATER-PROPYLAMINE IN RATIO OF 90:10:0.01. (JCHSBZ 18,139,80/MAS) Record 450 of 1119 in RTECS (through 2003/06) AN: AB1925000 PN: Acetaldehyde- SY: Acetaldehyd- (German); Acetaldehyde- (ACGIH:OSHA); NCI-C56326-; RCRA-waste-number-U001-; Acetic-aldehyde-; Acetylaldehyde-; Aldehyde-acetique- (French); Aldeide-acetica- (Italian); Ethanal-; Octowy-aldehyd- (Polish) RN: Current: 75-07-0 UD: 200302 MF: C2-H4-O MW: 44.06 WL: VH1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: eye-hmn 50 ppm/15M Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 28, p. 262, 1946 (JIHTAB); skn-rbt 500 mg open MLD Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 12/13/1963 (UCDS**); eye-rbt 40 mg SEV Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 12/13/1963 (UCDS**) ME: mmo-sat 7880 ug/plate (+S9) EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 21, p. 79, 1977 (EVHPAZ); dnr-esc 7880 ug/plate EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 21, p. 79, 1977 (EVHPAZ); slt-dmg-orl 180 umol/L/48H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 222, p. 359, 1989 (MUREAV); sln-dmg-par 22500 ppm Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 677, 1985 (ENMUDM); mmo-smc 44060 ug/L (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 180, 1993 (EMMUEG); cyt-smc 850 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 326, p. 165, 1995 (MUREAV); sln-smc 13 mmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 180, 1993 (EMMUEG); sln-asn 250 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 215, p. 187, 1989 (MUREAV); dnd-hmn-lym 1560 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 337, p. 9, 1995 (MUREAV); dnd-hmn-oth 3 mmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 985, 1994 (CRNGDP); dni-hmn-oth 30 mmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 2522, 1985 (CNREA8); oms-hmn-oth 30 mmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 2522, 1985 (CNREA8); dni-hmn-hla 10 mmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 13, p. 2389, 1992 (CRNGDP); cyt-hmn-leu 1000 ppm/72H-C Tsitologiya. Cytology. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1959- v. 20, p. 421, 1978 (TSITAQ); sce-hmn-lym 1200 umol/L Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 543, p. 369, 1988 (ANYAA9); sce-hmn-fbr 40 umol/L Experientia. (Birkhaeuser Verlag, POB 133, CH-4010 Basel, Switzerland) V.1- 1945- v. 34, p. 195, 1978 (EXPEAM); msc-hmn-fbr 5 mmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 985, 1994 (CRNGDP); mnt-rat-fbr 500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 101, p. 237, 1982 (MUREAV); mtr-rat-kdy 3 mmol/L/3H European Journal of Cancer and Clinical Oncology. (Pergamon Press, c/o Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.17(7)- 25, 1981-89. For publisher information, see EJCAEL v. 22, p. 671, 1986 (EJCODS); mtr-rat-fbr 100 umol/L Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 6, p. 811, 1980 (JTEHD6); dnd-rat-lvr 200 mmol/L Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 42, p. 183, 1988 (TOLED5); dnd-rat-ihl 1000 ppm/6H/5D-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 6, p. 541, 1986 (FAATDF); dnd-rat-oth 500 mmol/L Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 6, p. 541, 1986 (FAATDF); oms-rat-oth 12500 umol/L Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 83, p. 86, 1986 (TXAPA9); dni-rat-fbr 1 mmol/L Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 6, p. 811, 1980 (JTEHD6); oms-rat-fbr 1 mmol/L Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 6, p. 811, 1980 (JTEHD6); cyt-rat-fbr 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 101, p. 237, 1982 (MUREAV); mnt-mus-ipr 95 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 389, p. 3, 1997 (MUREAV); mtr-mus-emb 10 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 331, 1982 (ENMUDM); sce-mus-ipr 15 ng/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 68, p. 291, 1979 (MUREAV); msc-mus-lym 4 mmol/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 3, p. 193, 1988 (MUTAEX); cyt-ham-emb 40 ppm Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 3, p. 207, 1988 (MUTAEX); sce-ham-ipr 500 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 88, p. 389, 1981 (MUREAV); sce-ham-ovr 30 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 171, p. 169, 1986 (MUREAV); sln-ham-emb 20 ppm Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 3, p. 207, 1988 (MUTAEX); dnd-mam-lym 1 mol/L/30M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 115, 1978 (MUREAV) RE: T34-T49-T51 orl-rat TDLo: 4800 mg/kg (1-20D preg) Arukoru Kenkyu to Yakubutsu Izon. Alcohol Studies and Drug Dependence. (Japan Kyoto-furitsu Ika Daigaku Hoigaku Kyoshitsu, 465 Kajii-cho, Hirokoji-agaru, Kawara-machi, Kamigyo-ku, Kyoto, 602, Japan) V.16- 1981- v. 27, p. 334, 1992 (AKYIDF); T41-T52-T53 orl-rat TDLo: 5040 mg/kg (1-21D preg) Arukoru Kenkyu to Yakubutsu Izon. Alcohol Studies and Drug Dependence. (Japan Kyoto-furitsu Ika Daigaku Hoigaku Kyoshitsu, 465 Kajii-cho, Hirokoji-agaru, Kawara-machi, Kamigyo-ku, Kyoto, 602, Japan) V.16- 1981- v. 27, p. 334, 1992 (AKYIDF); T81 orl-rat TDLo: 5040 mg/kg (1-21D preg) Arukoru Kenkyu to Yakubutsu Izon. Alcohol Studies and Drug Dependence. (Japan Kyoto-furitsu Ika Daigaku Hoigaku Kyoshitsu, 465 Kajii-cho, Hirokoji-agaru, Kawara-machi, Kamigyo-ku, Kyoto, 602, Japan) V.16- 1981- v. 27, p. 334, 1992 (AKYIDF); T85 ipr-rat TDLo: 300 mg/kg (8-13D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 36, p. 31A, 1987 (TJADAB); T25-T31-T34 ipr-rat TDLo: 50 mg/kg (12D preg) Drug and Alcohol Dependence. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 9, p. 339, 1982 (DADEDV); T55 ipr-rat TDLo: 100 mg/kg (12D preg) Drug and Alcohol Dependence. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 9, p. 339, 1982 (DADEDV); T42-T46 ipr-rat TDLo: 400 mg/kg (8-15D preg) Senten Ijo. Congenital Anomalies. (Nippon Senten Ijo Gakkai, c/o Kinki Daigaku Igakubu Kaibagaku Kyoshitsu, 380 Nishiyama, Sayama-cho, Mirami-Kawachi-gun, Osaka-fu, Japan) V.1-26, 1960-86. For publisher information, see CGANE7. v. 23, p. 13, 1983 (SEIJBO); T43 ipr-rat TDLo: 600 mg/kg (8-15D preg) Senten Ijo. Congenital Anomalies. (Nippon Senten Ijo Gakkai, c/o Kinki Daigaku Igakubu Kaibagaku Kyoshitsu, 380 Nishiyama, Sayama-cho, Mirami-Kawachi-gun, Osaka-fu, Japan) V.1-26, 1960-86. For publisher information, see CGANE7. v. 23, p. 13, 1983 (SEIJBO); T46 ipr-mus TDLo: 640 ug/kg (10D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 27, p. 231, 1983 (TJADAB); T25-T34 ivn-mus TDLo: 120 mg/kg (7-9D preg) Journal of Anatomy. (Cambridge Univ. Press, 32 E. 57th St., New York, NY 10022) V.51- 1916- v. 128, p. 65, 1979 (JOANAY); T25-T41 ivn-mus TDLo: 4 gm/kg (6D preg) Journal of Anatomy. (Cambridge Univ. Press, 32 E. 57th St., New York, NY 10022) V.51- 1916- v. 132, p. 107, 1981 (JOANAY); T25-T34-T59 unr-mus TDLo: 1000 mg/kg (10D preg) "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1994 (VCVGK*); T31-T34 ihl-rat TCLo: 5 mg/m3 (60D pre/1-10D preg) "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 361, 1994 (VCVGK*); T31-T34 ihl-rat TCLo: 5 mg/m3 (60D pre/11-21D preg) "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 361, 1994 (VCVGK*) TE: V01-D09 ihl-rat TCLo: 735 ppm/6H/2Y-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 41, p. 213, 1986 (TXCYAC); V03-D09-J60 ihl-ham TCLo: 2040 ppm/7H/52W-I European Journal of Cancer and Clinical Oncology. (Pergamon Press, c/o Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.17(7)- 25, 1981-89. For publisher information, see EJCAEL v. 18, p. 13, 1982 (EJCODS); V03-D09 ihl-rat TC :1410 ppm/6H/65W-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 31, p. 123, 1984 (TXCYAC) ORNG: 661000000 ng/kg. [661.000000 mg/kg] C06-F05-J22 SRNG: 3540000000 ng/kg. [3540.000000 mg/kg] T/E unlistd IHPB: 13300000 ppb/4H. [13300.000000 ppm/4H] F13-J22 AT: J30 ihl-hmn TCLo: 134 ppm/30M JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- v. 165, p. 1908, 1957 (JAMAAP); C06-F05-J22 orl-rat LD50: 661 mg/kg Agents and Actions, A Swiss Journal of Pharmacology. (Birkhaeuser Verlag, POB 133, CH-4010 Basel, Switzerland) V.1- 1969/70- v. 4, p. 125, 1974 (AGACBH); F13-J22 ihl-rat LC50: 13300 ppm/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0534485 (NTIS**); J22-J30 ipr-rat LDLo: 500 mg/kg Journal of Biological Chemistry. (428 E. Preston St., Baltimore, MD 21202) V.1- 1905- v. 152, p. 41, 1944 (JBCHA3); F01 scu-rat LD50: 640 mg/kg Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 6, p. 299, 1950 (APTOA6); T/E unlistd orl-mus LD50: 900 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 25(11), p. 57, 1981 (GTPZAB); T/E unlistd ihl-mus LC50: 23 gm/m3/4H Current Toxicology. (Nova Science Publishers, Inc., 6080 Jericho Turnpike, Suite 207, Commack, NY 11725) V.1 1993- v. 1, p. 47, 1993 (CUTOEX); T/E unlistd ipr-mus LD50: 500 mg/kg IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 36, p. 101, 1985 (IMEMDT); F01 scu-mus LD50: 560 mg/kg Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 6, p. 299, 1950 (APTOA6); T/E unlistd skn-rbt LD50: 3540 mg/kg Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 12/13/1963 (UCDS**); F12-J30 scu-rbt LDLo: 1200 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 30, p. 429, 1927 (JPETAB); F12-J30 ivn-rbt LDLo: 300 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 30, p. 429, 1927 (JPETAB); T/E unlistd ihl-ham LC50: 17000 ppm/4H Progress in Experimental Tumor Research. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1960- v. 24, p. 162, 1979 (PEXTAR); T/E unlistd itr-ham LD50: 96 mg/kg Progress in Experimental Tumor Research. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1960- v. 24, p. 162, 1979 (PEXTAR); F01-G30-J30 ivn-frg LDLo: 800 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 30, p. 429, 1927 (JPETAB); D35-F13-J22 ihl-mam LC50: 20100 mg/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 19(7), p. 54, 1975 (GTPZAB); T/E unlistd ihl-mus LC50: 20300 mg/m3/2H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); T/E unlistd scu-mus LD50: 560 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); T/E unlistd orl-rat LD50: 1930 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); T/E unlistd ihl-mam LCLo: 10000 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); J25 ihl-rat TCLo: 600 mg/m3/10M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); G30 ihl-mam TCLo: 13000 mg/m3/60M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); F01 ivn-mam TDLo: 350 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); L30-N04-Y37 orl-rat TDLo: 300 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); A30 unr-rat TDLo: 0.3 ml/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); L30-P28 orl-rat TDLo: 5 ml/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); J21-J22 ihl-cat TCLo: 2000 mg/m3/7H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); J15-J30 ihl-cat LCLo: 20000 mg/m3/1H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 359, 1984 (VCVGK*); G07-G30 ihl-man TCLo: 100000 mg/m3/30M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1984 (VCVGK*); G07-J30 ivn-hmn TDLo: 10.6 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1984 (VCVGK*) MD: F17 orl-rat TDLo: 1540 mg/kg/22W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB234-882 (NTIS**); F16-P28-P30 orl-rat TDLo: 18900 mg/kg/4W-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 26, p. 447, 1988 (FCTOD7); L30 orl-rat TDLo: 1659 mL/kg/15W-C Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 121, p. 681, 1966 (PSEBAA); D09-M11-U01 ihl-rat TCLo: 2217 ppm/6H/4W-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 23, p. 293, 1982 (TXCYAC); N30-N72 ipr-rat TDLo: 12600 mg/kg/9W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB234-882 (NTIS**); P16 orl-gpg TDLo: 1540 mg/kg/22W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB234-882 (NTIS**); J02-M30-U01 ihl-ham TCLo: 4560 ppm/6H/90D-I Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 30, p. 449, 1975 (AEHLAU); L14-Y20 ihl-mus TCLo: 2500 mg/m3/2H/2W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1994 (VCVGK*); F15-F16 orl-rat TDLo: 700 mg/kg/4W-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1994 (VCVGK*); L30-Y39 unr-rat TDLo: 8.4 mg/kg/4W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1994 (VCVGK*); D01-D07 ihl-rat TCLo: 750 mg/m3/6H/52W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 360, 1994 (VCVGK*) TR: ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-CL 25 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 36, p. 101, 1985 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 319, 1999 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 36, p. 101, 1985 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 319, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 319, 1999 (IMEMDT); TOXICOLOGY REVIEW EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 11, p. 163, 1975 (EVHPAZ) SR: MSHA STANDARD-air: TWA 100 ppm (180 mg/m3) "Documentation of the Threshold Limit Values for Substances in Workroom Air," Supplements. For publisher information, see 85INA8. v. 3, p. 10, 1973 (DTLWS*); OSHA PEL (Gen Indu): 8H TWA 200 ppm (360 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 200 ppm (360 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 200 ppm (360 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 200 ppm (360 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 100 ppm (180 mg/m3), JAN 1993; OEL-AUSTRALIA: TWA 100 ppm (180 mg/m3), STEL 150 ppm, JAN 1993; OEL-AUSTRIA: MAK 50 ppm (90 mg/m3), Suspected Carcinogen, JAN 1999; OEL-BELGIUM: TWA 100 ppm (180 mg/m3), STEL 150 ppm (270 mg/m3), JAN 1993; OEL-DENMARK: TWA 25 ppm (45 mg/m3), JAN 1999; OEL-FINLAND: TWA 50 ppm (90 mg/m3), STEL 75 ppm (135 mg/m3), JAN 1993; OEL-FRANCE: VME 100 ppm (180 mg/m3), C3 Carcinogen, JAN 1999; OEL-GERMANY: MAK 50 ppm (90 mg/m3), Carcinogen, JAN 1999; OEL-HUNGARY: STEL 25 mg/m3, Carcinogen, JAN 1993; OEL-INDIA: TWA 100 ppm (180 mg/m3), STEL 150 ppm (270 mg/m3), JAN 1993; OEL-JAPAN: OEL 50 ppm (90 mg/m3), 2B Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 100 ppm (180 mg/m3), JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 1 mg(Cu)/m3 (dust), JAN 1993; OEL-THE PHILIPPINES: TWA 200 ppm (360 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 5 mg/m3, MAC(STEL) 10 mg/m3, JAN 1999; OEL-RUSSIA: STEL 5 mg/m3, Skin, JAN 1993; OEL-SWEDEN: NGV 25 ppm (45 mg/m3), KTV 50 ppm (90 mg/m3), Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 50 ppm (90 mg/m3), KTV 100 ppm (180 mg/m3), JAN 1999; OEL-TURKEY: TWA 200 ppm (360 mg/m3), JAN 1993; OEL-UNITED KINGDOM: TWA 20 ppm (37 mg/m3), STEL 50 ppm (92 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ACETALDEHYDE-air: CA (18 ppm LOQ) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 01038; NIS 4; TNF 85; NOS 10; TNE 1745; NOES 1983: HZD 01038; NIS 85; TNF 7801; NOS 95; TNE 216533; TFE 97770 SL: EPA GENETOX PROGRAM 1988, Positive: E coli polA without S9, In vitro SCE-nonhuman; EPA GENETOX PROGRAM 1988, Positive/dose response: In vitro SCE-human lymphocytes; EPA GENETOX PROGRAM 1988, Positive/dose response: In vitro SCE-human; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH CURRENT INTELLIGENCE BULLETIN #55, September 1991; NIOSH Analytical Method, 1994: Acetaldehyde by GC, 2538, by HPLC, 3507; NIOSH Analytical Method, 1994: Aldehydes, screening, 2539; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #ID-68 Record 451 of 1119 in RTECS (through 2003/06) AN: AB9450000 PN: Acetamide,-N-fluoren-2-yl- SY: 2-(Acetylamino)fluorene; 2-AAF-; 2-Acetamidofluorene-; 2-Acetaminofluorene-; 2-Acetylamino-fluoren- (German); 2-Acetylaminofluorene-; 2-Acetylaminofluorene- (OSHA); 2-FAA-; 2-Fluorenylacetamide-; 2AAF-; AAF-; Acetamide,-N-9H-fluoren-2-yl- (9CI); Acetoaminofluorene-; Acetylaminofluorene-; Azetylaminofluoren- (German); FAA-; N-2-Fluorenylacetamide-; N-9H-Fluoren-2-ylacetamide-; N-Acetyl-2-aminofluorene-; N-Fluoren-2-ylacetamide-; RCRA-waste-number-U005- RN: Current: 53-96-3 BRN: 2807677 BHR: 4-12-00-03373 UD: 200305 MF: C15-H13-N-O MW: 223.29 WL: L B656 HHJ EMV1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 300 ng/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6(Suppl 2), p. 1, 1984 (ENMUDM); oms-sat 50 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 192, p. 239, 1987 (MUREAV); dns-sat 1 ug Experimental Cell Biology. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.44- 1976- v. 50, p. 271, 1982 (ECEBDI); oms-esc 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 203, p. 81, 1988 (MUREAV); mmo-esc 100 ug/plate (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 387, 1981 (PMRSDJ); dnr-esc 10 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 873, 1979 (JJIND8); dna-esc 5 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); pic-esc 200 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 224, 1981 (PMRSDJ); dnd-bcs 1 mg/disc Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 175, 1981 (PMRSDJ); mmo-omi 200 ug/plate (+S9) Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 22, p. 297, 1978 (CBINA8); slt-dmg-par 20 mmol/L International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 9, p. 284, 1972 (IJCNAW); dnr-dmg-orl 500 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 290, p. 175, 1993 (MUREAV); mmo-smc 100 mg/L (+S9) Chemical and Pharmaceutical Bulletin. (Japan Pub. Trading Co., USA, 1255 Howard St., San Francisco, CA 94103) V.6- 1958- v. 33, p. 1576, 1985 (CPBTAL); mrc-smc 1 gm/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 434, 1981 (PMRSDJ); sln-smc 50 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); mmo-ssp 100 ug/L (+/-S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 424, 1981 (PMRSDJ); dnr-ssp 2800 nmol/L Canadian Journal of Genetics and Cytology. (National Research Council of Canada, Publication Sales and Distribution, Ottawa ON K1A OR6, Canada) V.1- 1959- v. 24, p. 771, 1982 (CNJGA8); sln-slw-par 500 ug Kokuritsu Idengaku Kenkyusho Nenpo. Annual Report of the National Institute of Genetics. (Kokuritsu Idengaku Kenkyusho, 1111 Yata, Mishima, Shizuoka-ken 411, Japan) No. 1- 1949- v. (28), p. 71, 1977 (KIKNAJ); slt-oin-orl 1000 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 268, p. 155, 1992 (MUREAV); dnd-hmn-oth 50 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 468, p. 277, 2000 (MUREAV); dna-hmn-hla 5 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); dna-hmn-oth 1200 nmol/L Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 24, p. 63, 1983 (PAACA3); dnd-hmn-fbr 1 mmol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 267, 1985 (ENMUDM); dns-hmn-fbr 100 umol/L/5H International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 16, p. 284, 1975 (IJCNAW); dns-hmn-hla 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); dns-hmn-lvr 1 umol/L Banbury Report. (Cold Spring Harbor Laboratory, POB 100, Cold Spring Harbor, NY 11724) V.1- 1979- v. 13, p. 101, 1982 (BANRDU); sce-hmn-lym 4400 ug/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 4775, 1980 (CNREA8); msc-hmn-lym 25 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 304, 1982 (ENMUDM); mnt-rat-orl 50 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 251, p. 59, 1991 (MUREAV); dnr-rat-lvr 1 umol/L Japanese Journal of Cancer Research. (Elsevier Science Pub. BV, POB 211, 1000 AE Amsterdam, Netherlands) V.76- 1985- v. 79, p. 204, 1988 (JJCREP); mtr-rat-ipr 200 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 10, p. 435, 1989 (CRNGDP); mtr-rat-orl 480 mg/kg/8W-I Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 171, 1984 (CRNGDP); mtr-rat-emb 100 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); mtr-rat-lvr 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 5087, 1983 (CNREA8); dnd-rat-lvr 3 umol/L Personal Communication from J.F. Sina, Merck Institute for Therapeutic Research, West Point, PA 19486, Oct. 26, 1982 26 OCT 1982 (SinJF#); dna-rat-ipr 18 umol/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 48, p. 15, 1984 (CBINA8); dna-rat-orl 70 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 857, 1994 (CRNGDP); dnd-rat-lvr 2000 ppm Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 667, 1982 (ENMUDM); dns-rat-lvr 2 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 190, p. 159, 1987 (MUREAV); dns-rat-orl 5 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 150, p. 383, 1985 (MUREAV); dnd-rat-lvr 50 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6, p. 427, 1984 (ENMUDM); dns-rat-oth 3200 umol/L Shika Kiso Igakkai Zasshi. Journal of the Japanese Association for Basic Dentistry. (Shika Kiso Igakkai, Hanayama Bldg., 1-44-2 Komagome, Toshima-ku, Tokyo 170, Japan) V.1- 1959- v. 22, p. 300, 1980 (SHKKAN); dns-rat-spr 100 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6, p. 273, 1984 (ENMUDM); dns-rat-ipr 10 mg/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 22, p. 211, 1984 (CALEDQ); dni-rat-lvr 100 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 337, 1985 (CNREA8); dni-rat-orl 420 mg/kg/6W Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 397, 1973 (CNREA8); oms-rat-orl 72 mg/kg/3D-C Experimental and Molecular Pathology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1962- v. 31, p. 333, 1979 (EXMPA6); oms-rat-orl 420 mg/kg/6W Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 397, 1973 (CNREA8); bfa-rat-sat 1600 ug/kg Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 71, p. 737, 1974 (PNASA6); bfa-rat-ovr 53 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 143, p. 263, 1985 (MUREAV); cyt-rat-orl 50 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 251, p. 59, 1991 (MUREAV); cyt-rat-lvr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 64, p. 329, 1979 (MUREAV); sce-rat-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 91, p. 363, 1981 (MUREAV); sce-rat-skn 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 91, p. 363, 1981 (MUREAV); sce-rat-lvr 4500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 409, 1982 (MUREAV); sce-rat-oth 400 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 409, 1982 (MUREAV); sce-rat-orl 25 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 251, p. 59, 1991 (MUREAV); sln-rat-orl 50 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 17, p. 1051, 1996 (CRNGDP); msc-rat-lvr 1 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 130, p. 53, 1984 (MUREAV); hma-rat-sat 90 mg/kg/5D American Journal of Clinical Nutrition. (American Soc. for Clinical Nutrition, Inc., 9650 Rockville Pike, Bethesda, MD 20814) V.2- 1954- v. 30, p. 1921, 1977 (AJCNAC); mnt-mus-ipr 2 mg/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 686, 1981 (PMRSDJ); mnt-mus-orl 75 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 223, p. 361, 1989 (MUREAV); mmo-mus-lym 40 mg/L (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 3), p. 10, 1985 (ENMUDM); slt-mus-ipr 223 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 117, p. 201, 1983 (MUREAV); mtr-mus-mmr 1 ug/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 1784, 1979 (CNREA8); dna-mus-lvr 60 umol/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 947, 1979 (JJIND8); dna-mus-ast 5 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); dns-mus-lvr 10 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5, p. 1, 1983 (ENMUDM); dni-mus-orl 160 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 5, p. 153, 1972 (CBINA8); dni-mus-ipr 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 305, 1977 (MUREAV); oms-mus-orl 160 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 5, p. 153, 1972 (CBINA8); bfa-mus-sat 20 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 117, p. 79, 1983 (MUREAV); sce-mus-ipr 20 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 157, p. 181, 1985 (MUREAV); msc-mus-lym 15 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 125, p. 291, 1984 (MUREAV); hma-mus-sat 495 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 911, 1979 (JJIND8); spm-mus-ipr 625 mg/kg/5D-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 124, p. 235, 1983 (MUREAV); mnt-ham-ipr 2 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 43, p. 255, 1977 (MUREAV); mnt-ham-emb 1 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 203, p. 397, 1988 (MUREAV); mnt-ham-lng 100 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 468, p. 137, 2000 (MUREAV); mmo-ham-ovr 20 mg/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 112, p. 329, 1983 (MUREAV); mtr-ham-ipr 750 mg/kg Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 95, p. 380, 1973 (ARPAAQ); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); mtr-ham-emb 12500 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dnd-ham-lng 300 umol/L/2H Biochemical and Biophysical Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 72, p. 732, 1976 (BBRCA9); dns-ham-lvr 10 nmol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6, p. 1, 1984 (ENMUDM); cyt-ham-lng 10 mg/L Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 4, p. 41, 1980 (ATSUDG); sce-ham-ipr 50 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 113, p. 33, 1983 (MUREAV); sce-ham-ovr 100 umol/L/150M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 103, 1978 (MUREAV); sce-ham-orl 50 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 113, p. 33, 1983 (MUREAV); sce-ham-lvr 6 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 207, p. 69, 1988 (MUREAV); sln-ham-lvr 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 397, 1985 (PMRSDJ); mmo-mus-lym 12300 ug/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); dna-bwd-lym 700 pmol/plate Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 37, p. 3756, 1977 (CNREA8); dns-rbt-oth 10 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 8, p. 401, 1987 (CRNGDP); sce-rbt-ipr 3 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 321, 1978 (MUREAV); sce-ckn-par 3125 ng/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 2, p. 435, 1980 (ENMUDM); dnd-oin-orl 0.25 umol/tube Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 480-481, p. 139, 2001 (MUREAV); dna-hmn-fbr 50 umol/L/2H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 484, p. 3, 2001 (MUREAV); dns-hmn-lvr 0.00002 umol/L/24H Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 999, 2001 (FCTOD7); dns-rat-lvr 0.1 mg/L/18H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 472, p. 75, 2000 (MUREAV); dnd-mus-ipr 300 mg/kg Mutation Research. (Elsevier Science Pub. 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B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 519, p. 163, 2002 (MUREAV); dnd-hmn-lvr 150 umol/L/12H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 519, p. 163, 2002 (MUREAV); dna-rat-ipr 50 mg/kg Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 17, p. 45, 2002 (MUTAEX); mmo-sat 15 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 498, p. 107, 2001 (MUREAV); slt-dmg-orl 1 mmol/L/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 514, p. 87, 2002 (MUREAV); slt-ham-ovr 5 mg/L/9D Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 16, p. 260, 1990 (EMMUEG) RE: T41 orl-rat TDLo: 300 mg/kg (9D preg) IARC Scientific Publications. (Geneva, Switzerland) No.1-26, 1971-78. For publisher information, see IAPUDO. v. 4, p. 112, 1973 (IARCCD); T34-T46 ipr-mus TDLo: 100 mg/kg (10D preg) Kaibogaku Zasshi. Journal of Anatomy. (Nippon Kaibo Gakkai, c/o Tokyo Daigaku Igakubu, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan) V.1- 1928- v. 37, p. 239, 1962 (KAIZAN); T25 ipr-mus TDLo: 100 mg/kg (8D preg) Kaibogaku Zasshi. Journal of Anatomy. (Nippon Kaibo Gakkai, c/o Tokyo Daigaku Igakubu, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan) V.1- 1928- v. 37, p. 239, 1962 (KAIZAN); T01 ipr-mus TDLo: 625 mg/kg (5D male) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 124, p. 235, 1983 (MUREAV); T02 ipr-mus TDLo: 2500 mg/kg (5D male) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 124, p. 235, 1983 (MUREAV) TE: V01-L60-M60 orl-rat TDLo: 4368 mg/kg/2Y-C Japanese Journal of Cancer Research. (Elsevier Science Pub. BV, POB 211, 1000 AE Amsterdam, Netherlands) V.76- 1985- v. 84, p. 237, 1993 (JJCREP); V01-L60 orl-rat TDLo: 672 mg/kg/8W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 74, p. 63, 1984 (TXAPA9); V01-N61-R60 skn-rat TDLo: 260 mg/kg/71W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 10, p. 1201, 1950 (JNCIAM); V01-J60-R60 ipr-rat TDLo: 192 mg/kg/4W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 32, p. 1554, 1972 (CNREA8); V01-L60 scu-rat TDLo: 2600 mg/kg/43W-I Japanese Journal of Cancer Research. (Elsevier Science Pub. BV, POB 211, 1000 AE Amsterdam, Netherlands) V.76- 1985- v. 85, p. 794, 1994 (JJCREP); V03-K60-R60 par-rat TDLo: 1700 mg/kg/17W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 6, p. 617, 1946 (CNREA8); V03-R60-V10 imp-rat TDLo: 22 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 2489, 1973 (CNREA8); V01-L60-M60 orl-mus TDLo: 2738 mg/kg/2.5Y-C Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 33, p. 327, 1991 (JTEHD6); V01-L60-M60 orl-mus TDLo: 7840 mg/kg/49W-C European Journal of Cancer (Elsevier Science, P.O.Box 7247-7682,Philadelphia,PA 19170 -7682,USA OR Elsevier Science B.V.,P.O.Box 1270,1000 BG Amsterdam,The Netherlands) V. 1- 1965- v. 5, p. 41, 1969 (EJCAAH); V02-J60 ipr-mus TDLo: 60 mg/kg/2W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 82, p. 19, 1986 (TXAPA9); V03-T65-L60 scu-mus TDLo: 400 mg/kg (15D preg) International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 20, p. 293, 1977 (IJCNAW); V03-M60 imp-mus TDLo: 96 mg/kg Gann Monograph on Cancer Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) No. 11- 1971- v. 17, p. 383, 1975 (GMCRDC); V02-L60 orl-dog TDLo: 2625 mg/kg/25W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 10, p. 266, 1950 (CNREA8); V03-J60 orl-cat TDLo: 11 gm/kg/69W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 11, p. 280, 1951 (CNREA8); V01-M60-M61 orl-rbt TDLo: 6500 mg/kg/65W-I Pathologica et Microbiologia. (Basel, Switzerland) V.23-43, 1960-75. For publisher information, see ECEBDI. v. 32, p. 177, 1968 (PAMIAD); V03-M60 ipr-rbt TDLo: 3600 mg/kg/40W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 27, p. 838, 1967 (CNREA8); V01-L60 orl-ham TDLo: 9240 mg/kg/44W-C Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 59, p. 239, 1968 (GANNA2); V01-M60 itr-ham TDLo: 8800 mg/kg/73W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 50, p. 503, 1973 (JNCIAM); V03-M60 mul-ham TDLo: 3370 mg/kg/37W-I Investigative Urology. (Baltimore, MD) V.1-19, 1963-81. For publisher information, see JOURAA. v. 14, p. 206, 1976 (INURAQ); V03-K60-L60 orl-ckn TDLo: 2800 mg/kg/13W-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 9, p. 163, 1955 (BJCAAI); V03-J60-M61 par-ckn TDLo: 3430 mg/kg/3Y British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 8, p. 147, 1954 (BJCAAI); V01-D45-L60 skn-rat TD :2590 mg/kg/23W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 28, p. 234, 1968 (CNREA8); V01-L60 orl-rat TD :2100 mg/kg/25W-C Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 19, p. 55, 1983 (CALEDQ); V01-L60-R60 orl-rat TD :1220 mg/kg/19W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 22, p. 1002, 1962 (CNREA8); V01-R60 orl-rat TD :2100 mg/kg/30W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 526, 1963 (TXAPA9); V01-L60-R60 orl-rat TD :2610 mg/kg/23W-C Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 10, p. 1201, 1950 (JNCIAM); V01-L60-M60 orl-mus TD :13 gm/kg/53W-C Journal of Clinical Pharmacology. (Hall Assoc., PO Box 482, Stamford, CT 06904) V.13- 1973- v. 19, p. 591, 1979 (JCPCBR); V01-L60-L04 orl-rat TD :1344 mg/kg/16W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 19, p. 687, 1971 (TXAPA9); V01-L60-U01 orl-rat TD :2940 mg/kg/35W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 19, p. 687, 1971 (TXAPA9); V01-M60-T63 orl-rbt TD :14 gm/kg/56W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 27, p. 838, 1967 (CNREA8); V01-L60-R60 orl-mus TD :13140 mg/kg/1Y-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 41, p. 535, 1977 (TXAPA9); V03-K61-V08 orl-mus TDLo: 792.8 mg/kg/12W-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 477, p. 125, 2001 (MUREAV); V02-P60-V16 orl-rat TDLo: 1.008 mg/kg/6W-C Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 154, p. 121, 2000 (CALEDQ) AT: T/E unlistd ipr-rat LDLo: >200 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 56, p. 151, 1985 (ARTODN); C06-F05-M16 orl-mus LD50: 810 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 143, p. 1117, 1973 (PSEBAA); T/E unlistd ipr-mus LD50: 470 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 223, p. 361, 1989 (MUREAV); L70-N74-U01 orl-rat TDLo: 150 mg/kg Cell and Tissue Research. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.148- 1974- v. 288, p. 371, 1997 (CTSRCS); R25-V15 orl-rat TDLo: 345 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 189, p. 204, 1961 (NATUAS); F01 orl-rat TDLo: 517.5 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 189, p. 204, 1961 (NATUAS) MD: L03-L04-L30 orl-rat TDLo: 564 mg/kg/3W-C Acta Pathologica Japonica. (Japan Publications Trading Co., Ltd., POB 5030, Tokyo International, Tokyo 101-31, Japan) V.1- 1951- v. 36, p. 1039, 1986 (APJAAG) TR: TOXICOLOGY REVIEW "Teratology," Berry, C.L., and D.E. Poswillo, eds., New York, Springer, 1975 -,49,1975 (32XPAD); TOXICOLOGY REVIEW "Oncology 1970, Proceedings of the Tenth International Cancer Congress," Chicago, Year Book Medical Pub., 1971 5,63,1970 (85CVA2); TOXICOLOGY REVIEW Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 71, p. 32, 1968 (ZEKBAI); TOXICOLOGY REVIEW Advances in Chemistry Series. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) No.1- 1950- v. 13, p. 271, 1970 (ADCSAJ); TOXICOLOGY REVIEW Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 24, p. 129, 1983 (BLFSBY) SR: MSHA STANDARD: air-SUSPECTED CARCINOGEN "Documentation of the Threshold Limit Values for Substances in Workroom Air," Supplements. For publisher information, see 85INA8. v. 3, p. 8, 1973 (DTLWS*); OSHA PEL (Gen Indu): see CFR 29,1910.1014 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): see CFR 29,1926.1114 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): see CFR 29,1915.1014 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA-cancer suspect agent Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1014, 1987 (CFRGBR); OEL-BELGIUM: Carcinogen, JAN 1993; OEL-FINLAND: Carcinogen, JAN 1993; OEL-SWEDEN: Carcinogen, JAN 1999 ND: NIOSH REL TO 2-ACETYLAMINOFLUORENE-air: CA use 29 CFR 1910.1014 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD X6612; NIS 1; TNF 75; NOS 1; TNE 373 SL: EPA GENETOX PROGRAM 1988, Positive: Body fluid assay, Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Host-mediated assay, L5178Y cells in vitro-TK test; EPA GENETOX PROGRAM 1988, Positive: Mammalian micronucleus, E coli polA with S9; EPA GENETOX PROGRAM 1988, Positive: Histidine reversion-Ames test, In vitro SCE-nonhuman; EPA GENETOX PROGRAM 1988, Positive: In vitro UDS in rat liver; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-BALB/c-3T3, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Negative: Cell transform.-SA7/SHE, E coli polA without S9; EPA GENETOX PROGRAM 1988, Negative: In vitro SCE-human lymphocytes, In vitro SCE-human; EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse, V79 cell culture-gene mutation; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae gene conversion, S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Inconclusive: In vivo SCE-nonhuman, D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Inconclusive: In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Positive: CHO gene mutation; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 452 of 1119 in RTECS (through 2003/06) AN: AC3662000 PN: Acetamide, N-(4-((2-hydroxy-5-methylphenyl)azo)phenyl)- SY: Calcosyn-Yellow-GC-; Calcosyn-Yellow-GCN-; Celliton-Discharge-Yellow-GL-; Celliton-Fast-Yellow-G-; Celliton-Fast-Yellow-GA-; Celliton-Fast-Yellow-GA-CF-; Celliton-Yellow-G-; Celutate-Yellow-GH-; Hispacet-Fast-Yellow-G-; Hisperse-Yellow-G-; Interchem-Acetate-Yellow-G-; Interchem-Disperse-Yellow-GH-; Intraperse-Yellow-GBA-; Intrasperse-Yellow-GBA-Extra-; Kayalon-Fast-Yellow-G-; Kayaset-Yellow-G-; Kca-Acetate-Fast-Yellow-G-; NCI-C53781-; 4-Acetamido-2'-hydroxy-5'-methylazobenzene-; Acetamine-Yellow-CG-; Acetate-Fast-Yellow-G-; Acetoquinone-Light-Yellow-; Acetoquinone-Light-Yellow-4JLZ-; Altco-Sperse-Fast-Yellow-GFN-New-; Amacel-Yellow-G-; Artisil-Direct-Yellow-G-; Artisil-Yellow-G-; Artisil-Yellow-2GN-; C.I. 3/11855; C.I. 11855; Cibacete-Yellow-GBA-; Cibacet-Yellow-GBA-; Cibacet-Yellow-2GC-; C.I. Disperse Yellow 3; Cilla-Fast-Yellow-G-; C.I. Solvent Yellow 77; CI-Solvent-Yellow-92-; CI-Solvent-Yellow-99-; Diacelliton-Fast-Yellow-G-; Disperse-Yellow-3-; Disperse-Yellow-G-; Disperse-Yellow-Z-; Dispersive-Yellow-3T-; Dispersol-Fast-Yellow-G-; Dispersol-Printing-Yellow-G-; Dispersol-Yellow-A-G-; Disperse-Fast-Yellow-G-; Durgacet-Yellow-G-; Durosperse-Yellow-G-; Eastone-Yellow-GN-; Esteroquinone-Light-Yellow-4JL-; Estone-Yellow-GN-; Fenacet-Fast-Yellow-G-; Fenacet-Yellow-G-; Genacron-Yellow-G-; N-(4-((2-Hydroxy-5-methylphenyl)azo)phenyl)acetamide; 4'-((6-Hydroxy-m-tolyl)azo)acetanilide; Microsetile-Yellow-GR-; Miketon-Fast-Yellow-G-; Nacelan-Fast-Yellow-CG-; Nyloquinone-Light-Yellow-4JL-; Nyloquinone-Yellow-4J-; Novalon-Yellow-2GN-; Ostacet-Yellow-P2G-; Palacet-Yellow-GN-; Palanil-Yellow-G-; Pamacel-Yellow-G-3-; Perliton-Yellow-G-; Reliton-Yellow-C-; Resiren-Yellow-TG-; Safaritone-Yellow-G-; Samaron-Yellow-PA3-; Serinyl-Hosiery-Yellow-GD-; Seriplas-Yellow-GD-; Serisol-Fast-Yellow-GD-; Setacyl-Yellow-G-; Setacyl-Yellow-2GN-; Setacyl-Yellow-P-2GL-; Silotras-Yellow-TSG-; Supracet-Fast-Yellow-G-; Synten-Yellow-2G-; Synton-Yellow-2G-; Terasil-Yellow-GBA-Extra-; Terasil-Yellow-2GC-; Tertranese-Yellow-N-2GL-; Tuladisperse-Fast-Yellow-2G-; Vonteryl-Yellow-G-; Vonteryl-Yellow-R-; Yellow-reliton-G-; Yellow-Z-; Zlut-disperzni-3- (Czech); Zlut-rozpoustedlova-77- (Czech) RN: Current: 2832-40-8 BRN: 753492 UD: 200302 MF: C15-H15-N3-O2 MW: 269.33 WL: QR D BNUNR DMV1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 10 ug/plate (+/-S9) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); mmo-mus-lym 10 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); dnd-mus-orl 2 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 465, p. 11, 2000 (MUREAV); sce-ham-ovr 5 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-frg-par 28 gm/L Cytobios. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1969- v. 25, p. 175, 1979 (CYTBAI) TE: V01-L60-P61 orl-rat TDLo: 180 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-222, 1982 (NTPTR*); V01-J60-L60 orl-mus TDLo: 433 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-222, 1982 (NTPTR*); V03-J60-J61 orl-mus TD :216 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-222, 1982 (NTPTR*); V01-L60-P61 orl-rat TD :216 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-222, 1982 (NTPTR*); V01-L60 orl-rat TDLo: 432600 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-230061 (NTIS**); V02-J60 orl-mus TDLo: 432600 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-230061 (NTIS**); V02-L60-P62 orl-mus TDLo: 432600 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-230061 (NTIS**) AT: T/E unlistd orl-rat LD :>14 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 53(10), p. 93, 1988 (GISAAA); F07-G30-J22 ipr-rat LD50: 8190 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 53(10), p. 92, 1988 (GISAAA); T/E unlistd orl-mus LD :>14 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 53(10), p. 93, 1988 (GISAAA); F07-G30-J22 ipr-mus LD50: 8080 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 53(10), p. 92, 1988 (GISAAA) MD: Z01 orl-rat TDLo: 35 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-222, 1982 (NTPTR*); N30-P27-U01 orl-rat TDLo: 91 gm/kg/13W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. NTP-TR-222, 1982 (NTIS**); Z01 orl-mus TDLo: 168 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-222, 1982 (NTPTR*); M03-P27 orl-mus TDLo: 109 gm/kg/13W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. NTP-TR-222, 1982 (NTIS**) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 48, p. 149, 1990 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 8, p. 97, 1975 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 8, p. 97, 1975 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 48, p. 149, 1990 (IMEMDT); TOXICOLOGY REVIEW Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 15, p. 311, 1996 (JACTDZ) ND: NOHS 1974: HZD M2104; NIS 8; TNF 164; NOS 17; TNE 3929; NOES 1983: HZD M2104; NIS 9; TNF 516; NOS 16; TNE 20479; TFE 1215 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), clear evidence: mouse, rat Record 453 of 1119 in RTECS (through 2003/06) AN: AC5955000 PN: Acetamide, N-(2-(5-methoxyindol-3-yl)ethyl)- SY: Acetamide, N-(2-(5-methoxy-1H-indol-3-yl)ethyl)- (9CI); N-Acetyl-5-methoxytryptamine-; Melatonin-; Melatonine-; 5-Methoxy-N-acetyltryptamine-; N-(2-(5-Methoxy-1H-indol-3-yl)ethyl)acetamide RN: Current: 73-31-4 BRN: 205542 BHR: 5-22-12-00042 UD: 200305 MF: C13-H16-N2-O2 MW: 232.31 WL: T56 BMJ D2MV1 GO1 CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Hormone (H) ME: oms-hmn-lym 200 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 351, p. 187, 1996 (MUREAV); oms-rat-scu 7 mg/kg/8W-I Cytobios. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1969- v. 65, p. 115, 1991 (CYTBAI); dnd-ham-ovr 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 417, p. 75, 1998 (MUREAV); dni-mus-orl 1500 mg/kg/30D Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 151, p. 119, 2000 (CALEDQ) RE: T29 orl-rat TDLo: 27 mg/kg (1D pre) Journal of Medicinal Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC 20037) V.6- 1963- v. 22, p. 63, 1979 (JMCMAR); T14 ipr-rat TDLo: 2800 ug/kg (28D pre) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 75, p. 238, 1964 (ENDOAO); T12 ipr-rat TDLo: 140 ug/kg (28D pre) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 141, p. 277, 1963 (SCIEAS); T29 ipr-rat TDLo: 7500 ug/kg (1D pre) Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 4, p. 385, 1971 (CCPTAY); T21-T25 scu-rat TDLo: 900 mg/kg (30D male) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 31(Suppl), p. 68, 1986 (TOLED5); T14 scu-rat TDLo: 1400 ug/kg (28D pre) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 75, p. 238, 1964 (ENDOAO); T12 scu-rat TDLo: 140 ug/kg (28D pre) Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 117, p. 228, 1964 (ANYAA9); T03 scu-rat TDLo: 80 ug/kg (20D male) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 33, p. 618, 1985 (BIREBV); T29 scu-rat TDLo: 500 ug/kg (1D pre) Neuroendocrinology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965/66- v. 12, p. 354, 1973 (NUNDAJ); T29 ivn-rat TDLo: 500 ug/kg (1D pre) Neuroendocrinology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965/66- v. 12, p. 354, 1973 (NUNDAJ); T83 scu-rat TDLo: 33 mg/kg (1-22D preg) Journal of Steroid Biochemistry and Molecular Biology. (Pergamon Press, c/o Elsevier Science, POB 945, New York, NY 10159) V.37- 1990- v. 72, p. 61, 2000 (JSBBEZ); T29 ocu-rat TDLo: 375 ug/kg (1D pre) Neuroendocrinology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965/66- v. 12, p. 354, 1973 (NUNDAJ); T12 ocu-rat TDLo: 50 ug/kg (1D pre) Neuroendocrinology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965/66- v. 12, p. 354, 1973 (NUNDAJ); T02-T03 par-rat TDLo: 36 mg/kg (30D male) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 21, p. 363, 1970 (JRPFA4); T14 ipr-mus TDLo: 4 mg/kg (19D pre) International Journal of Fertility. (Allen Press, 1041 New Hampshire, St., Lawrence, KS 66044) V.1- 1955- v. 21, p. 65, 1976 (INJFA3); T19-T52 scu-mus TDLo: 560 mg/kg (70D preg) Journal of Pineal Research. (Munksgaard International Publishers, POB 2148, DK-1016, Copenhagen K, Denmark) V.1- 1984- v. 13, p. 13, 1992 (JPRSE9); T02 par-mus TDLo: 14 mg/kg (70D male) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 23, p. 1069, 1980 (BIREBV); T03 par-mus TDLo: 70 mg/kg (70D male) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 23, p. 1069, 1980 (BIREBV); T14 unr-mus TDLo: 5600 ug/kg (14D pre) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 75, p. 238, 1964 (ENDOAO); T29 scu-rbt TDLo: 7500 ug/kg (1D pre) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 83, p. 599, 1968 (ENDOAO); T02-T03-T09 scu-ham TDLo: 12 mg/kg (60D male) Hormone Research. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.4- 1978- v. 15, p. 99, 1981 (HRMRA3); T12-T13 scu-ham TDLo: 1260 ug/kg (9W pre) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 78, p. 381, 1986 (JRPFA4); T14 scu-ham TDLo: 9800 ug/kg (49D pre) Neuroendocrinology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965/66- v. 33, p. 112, 1981 (NUNDAJ); T02 scu-ham TDLo: 7 mg/kg (35D male) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 22, p. 277, 1980 (BIREBV); T02-T03 par-ham TDLo: 21 mg/kg (15W male) Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 175, p. 254, 1984 (PSEBAA); T13-T19 par-ham TDLo: 14 mg/kg (10W pre) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 36, p. 719, 1987 (BIREBV); T01-T02-T03 imp-ham TDLo: 12480 ug/kg (60D male) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 190, p. 280, 1975 (SCIEAS); T01 imp-ham TDLo: 4032 ug/kg (42D male) Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 151, p. 502, 1976 (PSEBAA); T02-T03 unr-grb TDLo: 14 mg/kg (56D male) Journal of Reproductive Biology and Comparative Endocrinology. (P.G. Institute of Basic Medical Sciences, Dept. of Endocrinology, Taramani, 600 113, India) V.1- 1981- v. 6, p. 1, 1994 (JRBED2); T14 orl-dom TDLo: 1700 ug/kg (51D pre) Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 66, p. 459, 1988 (JANSAG); T14-T19 orl-dom TDLo: 1429 ug/kg (30D pre) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 95, p. 709, 1992 (JRPFA4); T14 scu-dom TDLo: 1200 ug/kg (40D pre) Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 66, p. 1855, 1988 (JANSAG); T52 imp-dom TDLo: 16 mg/kg (17W preg) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 125, p. 400, 1989 (ENDOAO); T19 ivg-dom TDLo: 4600 ug/kg (1D pre) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 74, p. 287, 1985 (JRPFA4) TE: V01-P61-P62 scu-mus TDLo: 4200 mg/kg/20W-I Gematologiya i Transfuziologiya. Hematology and Transfusion Science. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.28- 1983- v. 28(2), p. 47, 1983 (GETRE8); V01-J60-R60 orl-mus TDLo: 144 mg/kg/103W-I Voprosi oncologii (Questions of oncology. Journal of Petrov's Institute of Oncology, B. Zelenina str, 43a, Spb 197110, Russia) V.1- 1955- v. 46, p. 311, 2000 (VOONC*) AT: T/E unlistd orl-rat LD50: >3200 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 227, p. 587, 1983 (JPETAB); T/E unlistd ipr-rat LD50: 1131 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 227, p. 587, 1983 (JPETAB); T/E unlistd scu-rat LD50: >1600 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 227, p. 587, 1983 (JPETAB); T/E unlistd ivn-rat LD50: 356 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 227, p. 587, 1983 (JPETAB); T/E unlistd orl-mus LD50: 1250 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 227, p. 587, 1983 (JPETAB); T/E unlistd ipr-mus LD50: 1375 mg/kg Pharmaceutical Chemistry Journal (English Translation). Translation of KHFZAN. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) No.1- 1967- v. 17, p. 559, 1983 (PCJOAU); T/E unlistd scu-mus LD50: >1600 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 227, p. 587, 1983 (JPETAB); T/E unlistd ivn-mus LD50: 180 mg/kg U.S. Army Armament Research and Development Command, Chemical Systems Laboratory, NIOSH Exchange Chemicals. (Aberdeen Proving Ground, MD 21010) NX#02739 (CSLNX*); H02 ivn-rat TDLo: 18.58 mg/kg Pharmacology and Toxicology (Copenhagen). (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.60- 1987- v. 86, p. 125, 2000 (PHTOEH); F04-F21 orl-rat TDLo: 200 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB98-137300 (NTIS**); U01 orl-rat TDLo: 200 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB98-137300 (NTIS**); F15 orl-rat TDLo: 200 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB98-137300 (NTIS**) MD: M16-P28-Z73 scu-rat TDLo: 134 mg/kg/28D-I International Journal of Toxicology. (Taylor and Francis, 47 Runway Rd., Suite g, Levittown, PA 19057) V.16- 1997- v. 19, p. 107, 2000 (IJTOFN); P08-P71-P72 scu-mus TDLo: 15 mg/kg/2W-I Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 34, p. 19758, 1996 (IJEBA6); T64-V25-V30 orl-mus TDLo: 320 mg/kg/16W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 156, p. 199, 2000 (CALEDQ); V30 orl-mus TDLo: 1500 mg/kg/30D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 151, p. 119, 2000 (CALEDQ); T01-T02-Z73 scu-rat TDLo: 134.4 mg/kg/28D-I International Journal of Toxicology (Continous: Journal of the American College of Toxicology,Taylor and Francis Health Sciences) V.16- 1997- v. 19, p. 107, 2000 (IJOTO*); V25-V30 orl-rat TDLo: 6 mg/kg/3D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 138, p. 37, 1999 (CALEDQ); N30 ipr-rat TDLo: 5 mg/kg/5D-I Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 48, p. 84, 1985 (FATOAO) SL: NTP Carcinogenesis studies, laboratory assigned, October 2000; NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 454 of 1119 in RTECS (through 2003/06) AN: AC8925000 PN: Acetamide,-thio- SY: RCRA-waste-number-U218-; Acetothioamide-; Ethanethioamide-; Thiacetamide-; Thioacetamide-; Thioacetimidic-acid-; USAF-CB-21-; USAF-EK-1719- RN: Current: 62-55-5 UD: 200302 MF: C2-H5-N-S MW: 75.14 WL: ZY1&US CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: dnr-esc 400 ug/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 53, 1977 (MUREAV); dna-esc 50 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); oms-omi 10 mg/L Cytobiologie. (Stuttgart, Fed. Rep. Ger.) V.1-18, 1969-79. For publisher information, see EJCBDN. v. 11, p. 392, 1975 (CYTZAM); sln-dmg-orl 100 ppm/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 259, 1978 (MUREAV); sln-dmg-par 2500 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 259, 1978 (MUREAV); mmo-smc 19900 umol/L (-S9) Molecular and General Genetics. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.99- 1967- v. 174, p. 39, 1979 (MGGEAE); mrc-smc 2 pph JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 901, 1979 (JJIND8); dni-hmn-hla 150 mmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 13, p. 2389, 1992 (CRNGDP); oms-hmn-fbr 100 mg/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 42, p. 112, 1980 (BJCAAI); mtr-rat-orl 1512 mg/kg/6W Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 9, p. 387, 1988 (CRNGDP); mtr-rat-emb 30 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dna-rat-ipr 60 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 36, p. 4647, 1976 (CNREA8); dnd-rat-lvr 300 mmol/L Personal Communication from J.F. Sina, Merck Institute for Therapeutic Research, West Point, PA 19486, Oct. 26, 1982 26 OCT 1982 (SinJF#); dns-rat-orl 2940 mg/kg/12W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 29, p. 2039, 1969 (CNREA8); dns-rat-scu 100 mg/kg Planta Medica. (Georg Thieme Verlag, Postfach 732, D-7000 Stuttgart 1, Fed. Rep. 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Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG) RE: T25 ipr-rat TDLo: 1 gm/kg (7D preg) "Malformations Congenitales des Mammiferes," Tuchmann-Duplessis, H., Paris, Masson et Cie, 1971 -,95,1971 (85DJA5); T33-T51 ipr-rat TDLo: 150 mg/kg (9-11D preg) Folia Histochemica et Cytochemica. (Cracow, Poland) V.1-21, 1963-83. v. 8, p. 11, 1970 (FHCYAI); T34 scu-mus TDLo: 1935 mg/kg (6-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-160 (NTIS**) TE: V01-L60 orl-rat TDLo: 7350 mg/kg/40W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 79, p. 1047, 1987 (JJIND8); V02-L60 orl-mus TDLo: 10 gm/kg/39W-C British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. 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First St., Duluth, MN 55802) V.1- 1959- v. 27, p. 380, 1974 (TXAPA9); L02-L30-Y16 ipr-rat LDLo: 600 mg/kg Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 45, p. 233, 1998 (TOSCF2); L02-L30-Y16 scu-rat LD :>200 mg/kg Journal of Gastroenterology. (Japanese Society of Gastroenterology, Ginza Orient BLDG, 9-13 Ginza 8, Chuo-ku, Tokyo 104 Japan) V.29- 1994- v. 29, p. 293, 1994 (JOGAET); T/E unlistd ipr-mus LD50: 300 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD277-689 (NTIS**); T/E unlistd scu-mus LDLo: 2 gm/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 12, p. 447, 1904 (AIPTAK); Y15 ipr-rat TDLo: 300 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. 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(CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- v. 1(1), p. 93, 1971 (CRTXB2) SR: OEL-UNITED KINGDOM: Carcinogen, SEP 2000 ND: NOHS 1974: HZD 83086; NIS 2; TNF 47; NOS 2; TNE 1130; NOES 1983: HZD 83086; NIS 3; TNF 53; NOS 6; TNE 786; TFE 592 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-mouse embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo, Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Weakly Positive: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Negative: E coli polA with S9, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 455 of 1119 in RTECS (through 2003/06) AN: AE4200000 PN: Acetanilide,-4'-hydroxy- SY: 4'-Hydroxyacetanilide-; 4-Acetamidophenol-; 4-Hydroxyacetanilide-; 4-Hydroxyanilid-kyseliny-octove- (Czech); APAP-; Abensanil-; Acamol-; Acetagesic-; Acetalgin-; Acetamide, N-(4-hydroxyphenyl)-; Acetamide, N-(p-hydroxyphenyl)-; Acetaminofen-; Acetaminophen-; Algotropyl-; Alvedon-; Amadil-; Anaflon-; Anelix-; Apamid-; Apamide-; Ben-u-ron-; Bickie-mol-; Calpol-; Cetadol-; Clixodyne-; Datril-; Dial-a-gesic-; Dirox-; Dymadon-; Eneril-; Febrilix-; Febro-gesic-; Febrolin-; Fendon-; Finimal-; Hedex-; Homoolan-; Lestemp-; Liquagesic-; Lonarid-; Lyteca-; Lyteca-syrup-; Multin-; N-(4-Hydroxyphenyl)acetamide; N-Acetyl-p-aminophenol-; N-Acetyl-para-aminophenol-; NAPA- (analgesic); NCI-C55801-; Napafen-; Napap-; Naprinol-; Nobedon-; Pacemo-; Panadol-; Panets-; Paracetamol-; Paracetamole-; Paracetamolo- (Italian); Parmol-; Pedric-; Phendon-; Phenol,-p-acetamido-; Pyrinazine-; SK-Apap-; Tabalgin-; Tapar-; Temlo-; Tempanal-; Tempra-; Tralgon-; Tussapap-; Tylenol-; Valadol-; Valgesic-; p-Acetamidophenol-; p-Acetaminophenol-; p-Acetylaminophenol-; p-Hydroxyacetanilide- RN: Current: 103-90-2 Previous: 8055-08-1 BRN: 2208089 BHR: 4-13-00-01091 UD: 200305 MF: C8-H9-N-O2 MW: 151.18 WL: QR DMV1 CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: mmo-sat 100 ug/disc (+S9) Journal of Nihon University School of Dentistry. (Nihon University School of Dentistry, 1-8-13 Surugadai, Kanda, Chiyoda-ku, Tokyo, 101, Japan) V.1- 1958- v. 34, p. 183, 1992 (JNUDAT); mnt-hmn-orl 42857 ug/kg/8H-I Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 227, p. 147, 1989 (MUREAV); dni-hmn-lym 300 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 261, p. 1, 1991 (MUREAV); oms-hmn-lym 200 mg/L Nippon Eiseigaku Zasshi. Japanese Journal of Hygiene. (Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 37, p. 673, 1982 (NEZAAQ); cyt-hmn-lym 200 mg/L Nippon Eiseigaku Zasshi. Japanese Journal of Hygiene. (Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 37, p. 673, 1982 (NEZAAQ); cyt-hmn-orl 42860 ug/kg Mutation Research. (Elsevier Science Pub. 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(American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 80, p. 761, 1991 (JPMSAE); dns-mus-lvr 7500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 164, p. 167, 1986 (MUREAV); mtr-mus-emb 1 gm/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 49, p. 1038, 1989 (CNREA8); dnd-mus-ipr 600 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 106, p. 346, 1990 (TXAPA9); dnd-mus-lvr 1 mmol/L Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 111, p. 242, 1991 (TXAPA9); dns-mus-orl 84 gm/kg/40W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 96, p. 494, 1988 (TXAPA9); cyt-mus-orl 50 mg/kg Cytobios. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1969- v. 27, p. 27, 1980 (CYTBAI); cyt-mus-ipr 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 278, p. 253, 1992 (MUREAV); sce-mus-ipr 50 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 278, p. 253, 1992 (MUREAV); sln-mus-orl 25 mg/kg Caryologia. (Via G. LaPira 4, 50121 Florence, Italy) V.1- 1948- v. 38, p. 347, 1985 (CARYAB); mnt-ham-lng 50 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 272, p. 223, 1992 (MUREAV); dnd-ham-lng 3 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 333, 1988 (MUREAV); dni-ham-lng 160 umol/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 3, p. 51, 1988 (MUTAEX); oms-ham-lng 3 mmol/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 3, p. 13, 1989 (TIVIEQ); cyt-ham-ovr 70 mg/L/24H Progress in Clinical and Biological Research. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1975- v. 209A, p. 365, 1986 (PCBRD2); cyt-ham-fbr 60 mg/L Eisei Shikenjo Hokoku. Bulletin of the Institute of Hygienic Sciences. (Kokuritsu Eisei Shikenjo Kagaku, 18-1 Bushitsu Johobu, Setagaya-ku, Tokyo 158, Japan) V.1- 1886- v. (96), p. 55, 1978 (ESKHA5); cyt-ham-lng 10 mg/L Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 4, p. 41, 1980 (ATSUDG); sce-ham-ovr 200 mg/L Progress in Clinical and Biological Research. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1975- v. 209A, p. 365, 1986 (PCBRD2); sce-ham-lng 1 mmol/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 3, p. 51, 1988 (MUTAEX) RE: T74-T77-T87 orl-wmn TDLo: 650 mg/kg (29W preg) Archives of Disease in Childhood. (British Medical Journal, POB 560B, Kennebunkport, ME 04046) V.1- 1926- v. 58, p. 631, 1983 (ADCHAK); T43-T51 orl-wmn TDLo: 417 mg/kg (20W preg) British Journal of Obstetrics and Gynaecology. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.82- 1975- v. 91, p. 286, 1984 (BJOGAS); T19-T39-T77 orl-wmn TDLo: 1300 mg/kg (31-32W preg) British Journal of Obstetrics and Gynaecology. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.82- 1975- v. 96, p. 491, 1989 (BJOGAS); T39 orl-rat TDLo: 500 mg/kg (3D preg) Zhejiang Yike Daxue Xuebao. Journal of Zhejiang Medical University. (Zhejiang Yike Daxue, Yan'an Lu, Hanzhou, Zhejiang, Peop. Rep. China) V.1- 1972(?)- v. 27, p. 49, 1998 (ZYDXDM); T25-T34 orl-rat TDLo: 1500 mg/kg (8-19D preg) Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 66, p. 111, 1977 (JPMSAE); T33 orl-rat TDLo: 12500 mg/kg (14D pre/1-11D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 26(1), p. 42A, 1982 (TJADAB); T81-T85-T87 orl-rat TDLo: 1 gm/kg (3D preg) Zhejiang Yike Daxue Xuebao. Journal of Zhejiang Medical University. (Zhejiang Yike Daxue, Yan'an Lu, Hanzhou, Zhejiang, Peop. Rep. China) V.1- 1972(?)- v. 22, p. 196, 1993 (ZYDXDM); T02-T09 orl-rat TDLo: 35 gm/kg (70D male) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 7, p. 164, 1984 (ATSUDG); T01 orl-mus TDLo: 25 mg/kg (1D male) Cytobios. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1969- v. 27, p. 27, 1980 (CYTBAI); T01-T02 orl-mus TDLo: 600 mg/kg (1D male) Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 4, p. 170, 1984 (TOXID9); T34-T43-T46 orl-mus TDLo: 2500 mg/kg (6-15D preg) Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 4, p. 166, 1984 (TOXID9); T53 orl-mus TDLo: 2500 mg/kg (6-15D preg) Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 4, p. 166, 1984 (TOXID9); T19 orl-mus TDLo: 1430 mg/kg (2D preg) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 150, 2000 (TOSCF2); T29-T39 orl-mus TDLo: 15730 mg/kg (8D pre/1-3D preg) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 150, 2000 (TOSCF2); T29 orl-rbt TDLo: 2 gm/kg (1D pre) Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 38, p. 238, 1982 (FESTAS); T26 orl-mus TDLo: 49 gm/kg (7D male/7D pre/21 preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB85204667/AS (NTIS**); T81 orl-mus TDLo: 370 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB85204667/AS (NTIS**); T53 orl-mus TDLo: 1400 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB85204667/AS (NTIS**); T51 orl-mus TDLo: 1400 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB85204667/AS (NTIS**) TE: V01-M60 orl-rat TDLo: 164 gm/kg/78W-C Acta Pathologica, Microbiologica et Immunologica Scandinavica, Section A: Pathology. (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.90-95, 1982-87. v. 93, p. 367, 1985 (ACPADQ); V01-L02-L60 orl-mus TDLo: 135 gm/kg/77W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 4, p. 363, 1983 (CRNGDP); V03-L60-N30 orl-mus TD :270 gm/kg/77W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 4, p. 363, 1983 (CRNGDP); V01-L60 orl-rat TD :329 gm/kg/78W-C Acta Pathologica, Microbiologica et Immunologica Scandinavica, Section A: Pathology. (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.90-95, 1982-87. v. 93, p. 367, 1985 (ACPADQ); V01-P61 orl-rat TDLo: 218400 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB93-227478 (NTIS**) ORNG: 1944000000 ng/kg. [1944.000000 mg/kg] T/E unlistd AT: F08-M03 orl-wmn TDLo: 325 mg/kg Postgraduate Medical Journal. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.1- 1925- v. 68, p. 116, 1992 (PGMJAO); L14-M03-P25 orl-chd TDLo: 591 mg/kg/2D-I Clinical Pediatrics (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1962- v. 33, p. 42, 1994 (CPEDAM); K02-L14-P30 orl-wmn TDLo: 4962 ug/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 29, p. 223, 1991 (JTCTDW); L30 orl-man LDLo: 714 mg/kg Human Toxicology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants., RG 21 2XS, UK) V.1- 1981- v. 1, p. 25, 1981 (HUTODJ); F33-K12-U25 orl-inf TDLo: 1440 mg/kg/6D American Journal of Diseases of Children. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1-80(3), 1911-50: V.100- 1960- v. 137, p. 386, 1983 (AJDCAI); F01 orl-hmn LDLo: 143 mg/kg British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 282, p. 199, 1981 (BMJOAE); K13-L30-R03 orl-chd LDLo: 360 mg/kg/2D Journal of Pediatrics. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63141) V.1- 1932- v. 92, p. 832, 1978 (JOPDAB); F01-K13-L30 orl-chd TDLo: 801 mg/kg Pediatrics. (American Academy of Pediatrics, P.O. Box 1034, Evanston, IL 60204) V.1- 1948- v. 61, p. 68, 1978 (PEDIAU); G06 orl-man TDLo: 714 mg/kg Postgraduate Medical Journal. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.1- 1925- v. 69, p. 52, 1993 (PGMJAO); F14-F24-K13 orl-hmn LDLo: 357 mg/kg Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 1, p. 66, 1973 (LANCAO); F24-K13-M03 orl-wmn LDLo: 260 mg/kg JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- v. 236, p. 1874, 1976 (JAMAAP); F07-K30-M30 orl-wmn TDLo: 490 mg/kg Southern Medical Journal. (Southern Medical Assoc., POB 2446, Birmingham, AL 35205) V.1- 1908- v. 71, p. 906, 1978 (SMJOAV); F14-L02-L12 orl-man LDLo: 143 mg/kg/24H-I American Journal of Medicine. (Technical Pub., 875 Third Ave., New York, NY 10022) V.1- 1946- v. 74, p. 349, 1983 (AJMEAZ); H02-H30-U20 orl-wmn LDLo: 650 mg/kg American Journal of Emergency Medicine. (WB Saunders, Philadelphia, PA) V.1- 1983- v. 6, p. 511, 1988 (AJEMEN); G30-J15-M03 orl-chd LDLo: 50 mg/kg American Journal of Emergency Medicine. (WB Saunders, Philadelphia, PA) V.1- 1983- v. 6, p. 510, 1988 (AJEMEN); F24-L14-U21 orl-wmn LDLo: 400 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 35, p. 325, 1997 (JTCTDW); F24-L02-P28 orl-chd LDLo: 140 mg/kg/7D-I Medical Journal of Australia. (Australasian Medical Pub. Co. Ltd., 71-79 Arundel St., Glebe, N.S.W., Australia) V.1- 1914- v. 171, p. 472, 1999 (MJAUAJ); F13 orl-wmn TDLo: 13 mg/kg Allergy. (Munksgaard International Publishers Ltd., POB 2148, 35 Norre Sogade, DK-1016 Copenhagen K, Denmark) V.33- 1978- v. 50(Suppl 26), p. 206, 1995 (LLRGDY); D35-D45-R03 orl-man TDLo: 9286 ug/kg Allergy. (Munksgaard International Publishers Ltd., POB 2148, 35 Norre Sogade, DK-1016 Copenhagen K, Denmark) V.33- 1978- v. 50(Suppl 26), p. 206, 1995 (LLRGDY); T/E unlistd orl-rat LD50: 1944 mg/kg United States Patent Document. (U.S. Patent Office, Box 9, Washington, DC 20231) #4636513 (USXXAM); F07-F11 ipr-rat LD50: 1205 mg/kg Studi Sassaresi, Sezione 2. (Societa Sassarese di Scienze Mediche e Naturali, Via Muroni 23-A, I-07100 Sassari, Italy) V.42- 1964- v. 57, p. 561, 1979 (SSSEAK); T/E unlistd orl-mus LD50: 338 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 19, p. 20, 1971 (TXAPA9); F29-U28 ipr-mus LD50: 367 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 15, p. 520, 1965 (ARZNAD); T/E unlistd scu-mus LD50: 310 mg/kg Human Toxicology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants., RG 21 2XS, UK) V.1- 1981- v. 3, p. 13S, 1984 (HUTODJ); F05-P27-U28 orl-dog LDLo: 2 gm/kg Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- v. 24, p. 602, 1993 (IYKEDH); F29 ivn-dog LDLo: 826 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 149, p. 571, 1964 (AIPTAK); L30-M30-Y03 ivn-pig LDLo: 1 gm/kg Veterinary and Human Toxicology. (American College of Veterinary and Comparative Toxicology, Publication Office, Comparative Toxicology, Manhattan, KS 66506) V.19- 1977- v. 30, p. 324, 1988 (VHTODE); F05-F07-F11 orl-gpg LD50: 2620 mg/kg Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. v. 47, p. 479, 1958 (JAPMA8); F05-F19-J30 scu-frg LDLo: 50 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 33, p. 216, 1894 (AEXPBL); T/E unlistd orl-mam LDLo: 512 mg/kg United States Patent Document. (U.S. Patent Office, Box 9, Washington, DC 20231) #4035499 (USXXAM); T/E unlistd unr-mam LD50: 891 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 48(6), p. 22, 1983 (GISAAA); L02-L14-Y20 ipr-mus TDLo: 400 mg/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 174, p. 73, 2001 (CALEDQ); M30-Y53 ipr-mus TDLo: 600 mg/kg Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 61, p. 925, 2001 (BCPCA6); L30-Y10 ipr-mus TDLo: 500 mg/kg Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 271, 2001 (FCTOD7); L60-N60-P60 ipr-rat TDLo: 400 mg/kg JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 20, p. 427, 2000 (JJATDK); L02-L14 ipr-mus TDLo: 150 mg/kg Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 65, p. 135, 2002 (TOSCF2); E08 ipr-mus TDLo: 500 mg/kg Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 65, p. 135, 2002 (TOSCF2); Y07 orl-rat TDLo: 250 mg/kg Acta Biochimica Polonica (Published by Polish Biochemical Society and the Committee of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa Panstwowe Wydawnictwo Naukowe, L.Pasteura 3 02-093 Warszawa, Poland) V.1- 1954- v. 47, p. 1129, 2000 (ABCPO*); F29 ipr-mus TDLo: 100 mg/kg Biological and pharmaceutical bulletin. (Pharmaceutical Society of Japan, 2-12-15, Shibuya, Shibuya-ku, Tokyo 150-0002, Japan) V.1- 1993- v. 24, p. 1149, 2001 (BIPBU*); U28 scu-rbt TDLo: 100 mg/kg Biological and pharmaceutical bulletin. (Pharmaceutical Society of Japan, 2-12-15, Shibuya, Shibuya-ku, Tokyo 150-0002, Japan) V.1- 1993- v. 24, p. 1149, 2001 (BIPBU*); L30-L14 ipr-mus TDLo: 500 mg/kg Veterinary and Human Toxicology. (American College of Veterinary and Comparative Toxicology, Publication Office, Comparative Toxicology, Manhattan, KS 66506) V.19- 1977- v. 42, p. 146, 2000 (VHTODE); L01 orl-hmn TDLo: 166.7 mg/kg British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 288, p. 50, 1984 (BMJOAE); F29 orl-rat TDLo: 200 mg/kg British Journal of Pharmacology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.34- 1968- v. 129, p. 77, 2000 (BJPCBM); F29 scu-rat TDLo: 499 mg/kg British Journal of Pharmacology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.34- 1968- v. 129, p. 77, 2000 (BJPCBM); L02-P28-Y17 orl-rat TDLo: 151 mg/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 135, p. S130, 2002 (TOLED5); M05-M12 orl-hmn TDLo: 283.5 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 39, p. 441, 2001 (JTCTDW); F27 orl-hmn TDLo: 10 mg/kg Contact Dermatitis. Environmental and Occupational Dermatitis. (Munksgaard International Pub., c/o Publications Expediting Inc., 200 Meacham Ave., Elmont, NY 11003) V.1- 1975- v. 43, p. 60, 2000 (CODEDG) MD: L30-U01-Z01 orl-rat TDLo: 105 gm/kg/35D-C Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- v. 4, p. 2536, 1970 (KSRNAM); L30-M70-U01 orl-rat TDLo: 68 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-394, 1992 (NTPTR*); K30-L70-P72 orl-rat TDLo: 6080 mg/kg/19D-I Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- v. 24, p. 615, 1993 (IYKEDH); L30-Y07-Y09 ipr-rat TDLo: 1600 mg/kg/2D-I Ukrainskii Biokhimicheskii Zhurnal. Ukranian Biochemical Journal. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.50- 1978- v. 68(6), p. 92, 1996 (UBZHD4); L30-M70-U01 orl-mus TDLo: 136 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-394, 1992 (NTPTR*); L01-L30-L70 orl-mus TDLo: 336 gm/kg/40W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 96, p. 494, 1988 (TXAPA9); F15 orl-mus TDLo: 19600 mg/kg/14D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB85204667/AS (NTIS**); L50 orl-rat TDLo: 5000 mg/kg/2D-I Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 47, p. 105, 1984 (FATOAO); R01-S18 orl-hmn TDLo: 20 mg/kg/3W-I Contact Dermatitis. Environmental and Occupational Dermatitis. (Munksgaard International Pub., c/o Publications Expediting Inc., 200 Meacham Ave., Elmont, NY 11003) V.1- 1975- v. 43, p. 60, 2000 (CODEDG) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 307, 1990 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 307, 1990 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 401, 1999 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 401, 1999 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 401, 1999 (IMEMDT); TOXICOLOGY REVIEW Journal of Reproductive Medicine. (2 Jacklynn Ct., St. Louis, MO 63132) V.3- 1969- v. 12, p. 27, 1974 (JRPMAP); TOXICOLOGY REVIEW Australian Journal of Hospital Pharmacy. (B.R. Miller, POB 125, Heidelberg, Vic., Australia) V.1- 1971- v. 3(3), p. 100, 1973 (AUHPAI); TOXICOLOGY REVIEW Clinical Toxicology. (New York, NY) V.1-18, 1968-81. For publisher information, see JTCTDW. v. 12, p. 601, 1978 (CTOXAO); TOXICOLOGY REVIEW National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB282-666 (NTIS**); TOXICOLOGY REVIEW Obstetrics and Gynecology. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1953- v. 58, p. 57S, 1981 (OBGNAS) SR: OEL-UNITED KINGDOM: TWA 10 mg/m3, total inhalable dust, SEP 2000 ND: NOHS 1974: HZD 80396; NIS 7; TNF 1829; NOS 14; TNE 9269; NOES 1983: HZD 80396; NIS 7; TNF 1261; NOS 26; TNE 65107; TFE 56260 SL: EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: mouse Record 456 of 1119 in RTECS (through 2003/06) AN: AF1750000 PN: Acetic-acid,-allyl-ester- SY: Acetic-acid,-2-propenyl-ester- (9CI); 3-Acetoxypropene- RN: Current: 591-87-7 BRN: 1742050 BHR: 4-02-00-00180 UD: 200012 MF: C5-H8-O2 MW: 100.13 WL: 1VO2U1 CC: Tumorigen (C); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,355,1986 (85JCAE); eye-rbt 100 mg MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,355,1986 (85JCAE) ORNG: 130000000 ng/kg. [130.000000 mg/kg] T/E unlistd SRNG: 1021000000 ng/kg. [1021.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 130 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 60, 1949 (JIHTAB); T/E unlistd ihl-rat LC50: 1000 ppm/1H AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 21, p. 28, 1960 (AMIHAB); F07 orl-mus LD50: 170 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); T/E unlistd skn-rbt LD50: 1021 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 60, 1949 (JIHTAB) SR: OEL-RUSSIA: STEL 2 mg/m3, Skin, JAN 1993; OEL-UNITED KINGDOM: TWA 50 ppm (270 mg/m3, STEL 100 ppm (541 mg/m3), SEP 2000 ND: NOES 1983: HZD X4803; NIS 1; TNF 18; NOS 4; TNE 4280; TFE 1701 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 457 of 1119 in RTECS (through 2003/06) AN: AF5075000 PN: Acetic-acid,-benzyl-ester- SY: NCI-C06508-; Acetic-acid,-phenylmethyl-ester-; alpha-Acetoxytoluene-; Benzyl-acetate-; Benzyl-acetate- (ACGIH); Benzylester-kyseliny-octove- (Czech); Benzyl-ethanoate-; Phenylmethyl-acetate- RN: Current: 140-11-4 UD: 200305 MF: C9-H10-O2 MW: 150.19 WL: 1VO1R CC: Tumorigen (C); Mutagen (M); Natural-Product (N); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 100 mg/24H MOD Cosmetics and Toiletries. (Allured Pub. Corp., POB 318, Wheaton, IL 60189) V.91- 1976- v. 94(8), p. 41, 1979 (CTOIDG) ME: pic-esc 6250 ng/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 349, 1991 (MUREAV); dnr-bcs 21 mg/disc Osaka-shi Igakkai Zasshi. Journal of Osaka City Medical Association. (Osaka-shi Igakkai, c/o Osaka-shiritsu Daigaku Igakubu, 1-4-54 Asahi-cho, Abeno-ku, Osaka, 545, Japan) V.24- 1975- v. 34, p. 267, 1985 (OIGZDE); mmo-hmn-lym 1500 mg/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 196, p. 61, 1988 (MUREAV); mmo-mus-lym 500 mg/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 196, p. 61, 1988 (MUREAV); oms-mus-orl 1600 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV); msc-mus-lym 700 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-ham-lng 600 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 369, p. 243, 1996 (MUREAV) TE: V02-K60 orl-rat TDLo: 258 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-250, 1986 (NTPTR*); V02-L60 orl-mus TDLo: 258 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-250, 1986 (NTPTR*); V02-K60-T69 orl-rat TDLo: 257500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-115044 (NTIS**); V01-L60-K60 orl-mus TDLo: 515000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-115044 (NTIS**) ORNG: 2490000000 ng/kg. [2490.000000 mg/kg] F07 AT: F25-J30-M30 ihl-hmn TCLo: 50 ppm "Handbook of Organic Industrial Solvents," 2nd ed., Chicago, National Assoc. of Mutual Casualty Companies, 1961 v. 2, p. 31, 1961 (TGNCDL); F07 orl-rat LD50: 2490 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); T/E unlistd orl-mus LD50: 830 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 17, 1985 (GISAAA); F01 ihl-mus LCLo: 1300 mg/m3/22H Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 5, p. 1, 1933 (AGGHAR); T/E unlistd ihl-cat LC50: 245 ppm/8H AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 21, p. 28, 1960 (AMIHAB); F11-F18-K01 skn-cat LDLo: 10 gm/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 84, p. 358, 1945 (JPETAB); T/E unlistd orl-rbt LD50: 2200 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 17, 1985 (GISAAA); T/E unlistd skn-rbt LD50: >5 gm/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 11, p. 875, 1973 (FCTXAV); F12 scu-rbt LDLo: 4 gm/kg Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 5, p. 1, 1933 (AGGHAR); T/E unlistd orl-gpg LD50: 2200 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 17, 1985 (GISAAA); T/E unlistd scu-gpg LDLo: 3 gm/kg Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 5, p. 1, 1933 (AGGHAR); D07-J21 ihl-hmn TCLo: 0.015 mg/m3 Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. -, p. 7, 1993 (GISAAA) MD: A30-M03-Z01 orl-rat TDLo: 355 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-431, 1993 (NTPTR*); Z01 orl-rat TDLo: 65 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-250, 1986 (NTPTR*); F11-U01 orl-mus TDLo: 271 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-431, 1993 (NTPTR*); K30-Z01 orl-mus TDLo: 28 gm/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-250, 1986 (NTPTR*); A11-P08-P71 orl-mam TDLo: 4200 mg/kg/21D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 17, 1985 (GISAAA); U01 orl-rat TDLo: 42.5 gm/kg/17W-I EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 68, p. 197, 1986 (EVHPAZ); U01 orl-rat TDLo: 321.3 gm/kg/17W-C EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 68, p. 197, 1986 (EVHPAZ) TR: ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 40, p. 109, 1986 (IMEMDT); IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1255, 1999 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 40, p. 109, 1986 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1255, 1999 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1255, 1999 (IMEMDT) SR: OEL-RUSSIA: STEL 5 mg/m3, JAN 1993 ND: NOHS 1974: HZD 01600; NIS 11; TNF 512; NOS 42; TNE 93580; NOES 1983: HZD 01600; NIS 107; TNF 17141; NOS 108; TNE 275806; TFE 133629 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis Studies (gavage), some evidence: mouse, rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-250, 1986 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse; NCI Carcinogenesis Studies (feed), no evidence: mouse, rat Record 458 of 1119 in RTECS (through 2003/06) AN: AF5957282 PN: Acetic-acid,-bromochloro- SY: Bromochloroacetate-; Bromochloroacetic-acid-; Chlorobromoacetic-acid- RN: Current: 5589-96-8 UD: 200302 MF: C2-H2-Br-Cl-O2 MW: 173.40 CC: Tumorigen (C); Reproductive-Effector (T) RE: T25 orl-rat TDLo: 98 mg/kg (1-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB98-172414 (NTIS**) MD: L70-U01-Y35 orl-mus TDLo: 8400 mg/kg/3W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 110, p. 103, 1996 (TXCYAC); K30-U01-Y21 orl-rat TDLo: 3585 mg/kg/5W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 282, 2000 (TOSCF2); L30-V05 orl-mus TDLo: 0.84 gm/kg/2W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); L70-N30 orl-mus TDLo: 16.8 gm/kg/12W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); N22 orl-mus TDLo: 33.6 gm/kg/8W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); U01 orl-mus TDLo: 50.4 gm/kg/12W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); L30-P28 orl-rat TDLo: 98 mg/kg/14D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB98-172414 (NTIS**); Y15 orl-rat TDLo: 280 mg/kg/14D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB98-172414 (NTIS**); F16-P28 orl-rat TDLo: 700 mg/kg/14D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB98-172414 (NTIS**); F16 orl-rat TDLo: 700 mg/kg/14D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB98-172414 (NTIS**) SL: NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 459 of 1119 in RTECS (through 2003/06) AN: AF5958500 PN: Acetic-acid,-bromodichloro- SY: Bromodichloroacetate-; Dichlorobromoacetic-acid- RN: Current: 71133-14-7 UD: 200207 MF: C2-H-Br-Cl2-O2 MW: 207.84 CC: Tumorigen (C) MD: L70 orl-mus TDLo: 5.04 gm/kg/12W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); N24 orl-mus TDLo: 50.4 gm/kg/12W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*) SL: NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 460 of 1119 in RTECS (through 2003/06) AN: AF8575000 PN: Acetic-acid,-chloro- SY: Kyselina-chloroctova- (Czech); NCI-C60231-; Acide-chloracetique- (French); Acide-monochloracetique- (French); Acidomonocloroacetico- (Italian); Chloracetic-acid-; Chloroacetic-acid-; alpha-Chloroacetic-acid-; Chloroethanoic-acid-; MCA-; Monochloorazijnzuur- (Dutch); Monochloracetic-acid-; Monochloressigsaeure- (German); Monochloroacetic-acid-; Monochloroethanoic-acid- RN: Current: 79-11-8 BRN: 605438 BHR: 4-02-00-00474 UD: 200302 MF: C2-H3-Cl-O2 MW: 94.50 WL: QV1G CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M) ME: mmo-mus-lym 548 mg/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 97, p. 49, 1982 (MUREAV); msc-mus-lym 400 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9, p. 143, 1987 (ENMUDM); sce-ham-ovr 160 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); slt-mus-oth 5 mg/L/4H (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 38, p. 69, 2001 (EMMUEG) TE: V03-J60-L60 scu-mus TDLo: 100 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-159 (NTIS**); V03-V10 scu-mus TD :1300 mg/kg/65W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 53, p. 695, 1974 (JNCIAM) ORNG: 55000000 ng/kg. [55.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 55 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(9), p. 32, 1974 (GTPZAB); T/E unlistd ihl-rat LC50: 180 mg/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(9), p. 32, 1974 (GTPZAB); T/E unlistd ipr-rat LD50: 16600 ug/kg Russian Pharmacology and Toxicology (English Translation). Translation of FATOAO. (Euromed Pub., 33, Woodlands Rd., Surbiton, Surrey, UK) V.30- 1967- v. 41, p. 113, 1978 (RPTOAN); T/E unlistd scu-rat LD50: 5 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 22, p. 303, 1972 (TXAPA9); T/E unlistd scu-mus LD50: 250 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 116, p. 154, 1958 (AIPTAK) MD: G30-P71-Z01 orl-rat TDLo: 9750 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-396, 1992 (NTPTR*); M30-P08 ihl-rat TCLo: 20800 ug/m3/17W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(9), p. 32, 1974 (GTPZAB); L30-L70-Z01 orl-mus TDLo: 13 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-396, 1992 (NTPTR*); D17-F19-Z01 orl-mus TDLo: 3840 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-396, 1992 (NTPTR*); M30-P08 ihl-gpg TCLo: 20800 ug/m3/17W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(9), p. 32, 1974 (GTPZAB); P62-V30 orl-mus TDLo: 25750 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-189372 (NTIS**) TR: TOXICOLOGY REVIEW Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 11, p. 13, 1955 (APTOA6) SR: OEL-POLAND: MAC(TWA) 2 mg/m3, MAC(STEL) 4 mg/m3, JAN 1999; OEL-RUSSIA: STEL 1 mg/m3, JAN 1993; OEL-SWEDEN: TWA 1 ppm (4 mg/m3), STEL 2 ppm (8 mg/m3), Skin, JAN 1999; OEL-UNITED KINGDOM: TWA 0.3 ppm (1.2 mg/m3), Skin, SEP 2000 ND: NOHS 1974: HZD 18070; NIS 9; TNF 1196; NOS 14; TNE 4726; NOES 1983: HZD 18070; NIS 12; TNF 265; NOS 20; TNE 10912; TFE 1723 SL: EPA GENETOX PROGRAM 1988, Negative: Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Chloroacetic acid, 2008; NCI Carcinogenesis Studies (gavage), no evidence: mouse, rat Record 461 of 1119 in RTECS (through 2003/06) AN: AG2915000 PN: Acetic acid, ((4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thio)- SY: Acetic acid, ((4-chloro-6-((2,3-dimethylphenyl)amino)-2-pyrimidinyl)thio)-; Pirinixic-acid-; Pirnixic-acid-; (4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthio)acetic acid; WY-14,643-; Wyeth-14,643- RN: Current: 50892-23-4 BRN: 759945 BHR: 5-25-12-00458 UD: 200302 MF: C14-H14-Cl-N3-O2-S MW: 323.82 WL: T6N CNJ BS1VQ DG FMR B1 C1 CC: Tumorigen (C); Drug (D); Mutagen (M) ME: mnt-hmn-lvr 30 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 286, p. 123, 1993 (MUREAV); mnt-rat-lvr 20 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 286, p. 123, 1993 (MUREAV); mtr-rat-orl 15540 mg/kg/37W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 111, 1994 (CRNGDP); dnd-rat-lvr 50 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 59, 1996 (MUREAV); dns-rat-lvr 1 mmol/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 24, p. 147, 1984 (CALEDQ); dns-rat-orl 375 mg/kg/5D-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 152, 1979 (CNREA8); cyt-rat-lvr 20 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 286, p. 123, 1993 (MUREAV); sce-rat-lvr 5 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 286, p. 123, 1993 (MUREAV); dni-mus-oth 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 36, 1980 (CNREA8); mtr-ham-emb 85 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 356, p. 85, 1996 (MUREAV); slt-mus-orl 10800 mg/kg/180D-C Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 62, p. 685, 2001 (BCPCA6); dni-rat-orl 840 mg/kg/2W-C Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 135, p. 145, 1999 (CALEDQ); dnd-hmn-oth 0.5 mmol/L/3H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 439, 2001 (MUTAEX) TE: V01-L60 orl-rat TDLo: 22 gm/kg/1Y-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 48, p. 6739, 1988 (CNREA8); V01-L60 orl-mus TDLo: 37 gm/kg/62W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 152, 1979 (CNREA8); V01-L60 orl-rat TD :46 gm/kg/65W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 2, p. 645, 1981 (CRNGDP); V03-L60 orl-rat TD :27 gm/kg/64W-C Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 32, p. 33, 1986 (CALEDQ); V01-L60 orl-rat TD :29 gm/kg/69W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 152, 1979 (CNREA8) ORNG: 1050000000 ng/kg. [1050.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1050 mg/kg Journal of Medicinal Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC 20037) V.6- 1963- v. 27, p. 1621, 1984 (JMCMAR); T/E unlistd orl-mus LD50: 1600 mg/kg Atherosclerosis (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.11- 1970- v. 30, p. 45, 1978 (ATHSBL) MD: L70-Y03-Y15 orl-rat TDLo: 1500 mg/kg/25D-C Toxicologic Pathology. (c/o Dr. F.A. de la Iglesia, Warner-Lambert Co., Pharmaceutical Research Div., POB 1047, Ann Arbor, MI 48106) V.6(3/4)- 1978- v. 25, p. 165, 1997 (TOPADD); D15-L30-L70 orl-rat TDLo: 2800 mg/kg/4W-I Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- v. 24, p. 371, 1999 (JTSCDR); L70-Z72-Z73 orl-rat TDLo: 126 mg/kg/21D-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 19, p. 590, 1992 (FAATDF); K02-L70-Y07 orl-rat TDLo: 1092 mg/kg/26W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 145, p. 425, 1997 (TXAPA9); P08-P73-Z01 orl-rat TDLo: 1545 mg/kg/2Y-C Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 20, p. 1, 1997 (DCTODJ); U01 orl-ham TDLo: 100.8 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03 orl-rat TDLo: 50.4 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03-U01 orl-rat TDLo: 252 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03 orl-mus TDLo: 100.8 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03-U01 orl-mus TDLo: 1008 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7) SL: NTP Carcinogenesis studies, on test (prechronic studies), October 2000; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 462 of 1119 in RTECS (through 2003/06) AN: AG5980000 PN: Acetic-acid,-dibromo- SY: Dibromoacetate-; Dibromoacetic-acid- RN: Current: 631-64-1 UD: 200207 MF: C2-H2-Br2-O2 MW: 217.86 CC: Tumorigen (C); Reproductive-Effector (T) RE: T23-T24-T26 orl-rat TDLo: 3500 mg/kg (2W male) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 28, p. 9, 1995 (FAATDF); T01-T02-T09 orl-rat TDLo: 10500 mg/kg (6W pre) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 28, p. 9, 1995 (FAATDF); T01-T02 orl-rat TDLo: 4000 mg/kg (16D male) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 28, p. 9, 1995 (FAATDF); T02 orl-rat TDLo: 3500 mg/kg (14D male) Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- v. 24, p. 350, 1999 (JTSCDR) MD: N19 orl-rat TDLo: 3780 mg/kg/30D-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 54, p. 367, 2000 (TOXID9); L30-L70-Y35 orl-mus TDLo: 8400 mg/kg/3W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 110, p. 103, 1996 (TXCYAC); L70-N74 orl-mus TDLo: 2800 mg/kg/28D-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 54, p. 157, 2000 (TOXID9); K30-U01-Y21 orl-rat TDLo: 5208 mg/kg/5W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 282, 2000 (TOSCF2); L30-V05-Y12 orl-mus TDLo: 2.8 gm/kg/2W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); L70-N30 orl-mus TDLo: 16.8 gm/kg/12W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); N22 orl-mus TDLo: 11.2 gm/kg/4W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*); U01 orl-mus TDLo: 22.4 gm/kg/8W-C Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 21, p. 81, 2001 (JAPTO*) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 463 of 1119 in RTECS (through 2003/06) AN: AG6125000 PN: Acetic-acid,-dichloro- SY: 2,2-Dichloroacetic-acid-; Analytical-grade-dichloroacetic-acid-; Bichloracetic-acid-; DCA-; DCA- (acid); Dichloracetic-acid-; Dichlorethanoic-acid-; Dichloroacetic-acid-; Dichloroacetic-acid- (IUPAC); Dichloroethanoic-acid-; Kyselina-dichloroctova- (Czech); Urner's-liquid- RN: Current: 79-43-6 Previous: 42428-47-7 BRN: 1098596 BHR: 4-02-00-00498 UD: 200207 MF: C2-H2-Cl2-O2 MW: 128.94 WL: QVYGG CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Primary-Irritant (S) ID: skn-rbt 2 mg/24H SEV "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,570,1986 (85JCAE) ME: mnt-mus-orl 1800 mg/kg/9D-C Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 27, p. 1, 1996 (EMMUEG); dnd-mus-orl 645 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 20, p. 277, 1992 (EMMUEG); cyt-mus-lym 600 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 413, p. 265, 1998 (MUREAV); msc-mus-lym 400 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 413, p. 265, 1998 (MUREAV) RE: T25-T34 orl-rat TDLo: 9 gm/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 46, p. 217, 1992 (TJADAB); T73 orl-rat TDLo: 24 gm/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 46, p. 217, 1992 (TJADAB); T47 orl-rat TDLo: 4 gm/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 46, p. 217, 1992 (TJADAB); T53 orl-rat TDLo: 14 gm/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 46, p. 217, 1992 (TJADAB) TE: V01-L60 orl-rat TDLo: 100 gm/kg/2Y-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 114, p. 207, 1996 (TXCYAC); V01-L60 orl-mus TDLo: 427 gm/kg/61W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 90, p. 183, 1987 (TXAPA9); V02-L60 orl-rat TDLo: 101 gm/kg/60W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 92, p. 67, 1995 (CALEDQ); V01-L60 orl-mus TD :58800 mg/kg/2Y-C Journal of Toxicology and Environmental Health, Part A. (Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 58, p. 485, 1999 (JTEHF8); V01-L60-V16 orl-mus TDLo: 166 gm/kg/46W-C Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 158, p. 185, 2000 (CALEDQ); V03-L60 orl-mus TDLo: 60.9 gm/kg/87W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 59, p. 178, 2001 (TOSCF2) ORNG: 2820000000 ng/kg. [2820.000000 mg/kg] T/E unlistd SRNL: 510000 nL/kg. [0.510000 mL/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 2820 mg/kg AMA Archives of Industrial Hygiene and Occupational Medicine. (Chicago, IL) V.2-10, 1950-54. For publisher information, see AEHLAU. v. 4, p. 119, 1951 (AMIHBC); T/E unlistd skn-rbt LD50: 510 uL/kg AMA Archives of Industrial Hygiene and Occupational Medicine. (Chicago, IL) V.2-10, 1950-54. For publisher information, see AEHLAU. v. 4, p. 119, 1951 (AMIHBC) MD: M70-U01-Y03 orl-rat TDLo: 3195 mg/kg/90D-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 64, p. 71, 1990 (TXCYAC); L30-L70-Y26 orl-mus TDLo: 7100 mg/kg/10W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 110, p. 103, 1996 (TXCYAC); K30-U01-Y21 orl-rat TDLo: 3588 mg/kg/5W-I Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 282, 2000 (TOSCF2); N21 orl-mus TDLo: 5.6 gm/kg/2W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 59, p. 178, 2001 (TOSCF2); L30 orl-mus TDLo: 1.4 gm/kg/2W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 59, p. 178, 2001 (TOSCF2); L30-Y13 orl-mus TDLo: 7 gm/kg/10W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 59, p. 178, 2001 (TOSCF2) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 63, p. 271, 1995 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 63, p. 271, 1995 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 63, p. 271, 1995 (IMEMDT) SR: OEL-RUSSIA: STEL 4 mg/m3, JAN 1993 ND: NOHS 1974: HZD 84531; NIS 3; TNF 44; NOS 5; TNE 164; NOES 1983: HZD 84531; NIS 1; TNF 39; NOS 2; TNE 1592; TFE 579 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 464 of 1119 in RTECS (through 2003/06) AN: AG6825000 PN: Acetic acid, (2,4-dichlorophenoxy)- SY: (2,4-Dichloor-fenoxy)-azijnzuur (Dutch); (2,4-Dichlor-phenoxy)-essigsaeure (German); 2,4-D-; 2,4-D- (ACGIH:OSHA); 2,4-D-acid-; 2,4-Dichlorophenoxy-acetic-acid-; 2,4-Dichlorophenoxyacetic-acid-; 2,4-Dichlorphenoxyacetic-acid-; 2,4-Dwuchlorofenoksyoctowy-kwas- (Polish); Acide-2,4-dichloro-phenoxyacetique- (French); Acido(2,4-dicloro-fenossi)-acetico (Italian); Acme-LV-4-; Agrotect-; Amidox-; Amoxone-; Aqua-Kleen-; B-Selektonon-; BH-2,4-D-; Barrage-; Brush-rhap-; Chipco-turf-herbicide-D-; Chloroxone-; Citrus-fix-; Crop-rider-; DMA-4-; Debroussaillant-600-; Deherban-; Dichlorophenoxyacetic-acid-; Dichlorophenoxyacetic-acid- (OSHA); Dicopur-; Dormone-; ENT-8,538-; Emulsamine-BK-; Emulsamine-E-3-; Envert-171-; Envert-DT-; Estone-; Farmco-; Fernimine-; Fernoxone-; Ferxone-; Foredex-75-; Hedonal- (the herbicide); Herbidal-; Hivol-44-; Ipaner-; Kwas-2,4-dwuchlorofenoksyoctowy- (Polish); Kwasu-2,4-dwuchlorofenoksyoctowego- (Polish); Kyselina-2,4-dichlorfenoxyoctova- (Czech); Lawn-keep-; Macrondray-; Miracle-; Moxone-; NSC-423-; Netagrone-; Netagrone-600-; Pennamine-; Pennamine-D-; Phenox-; Pielik-; Plantgard-; RCRA-waste-number-U240-; Rhodia-; Superormone-concentre-; U-46DP-; U-5043-; Vergemaster-; Verton-2D-; Vidon-638-; Weed-TOX-; Weed-Ag-Bar-; Weed-rhap-; Weedar-64-; Weedatul-; Weedez-Wonder-BAR-; Weedone-LV4-; Weedtrol- RN: Current: 94-75-7 BRN: 1214242 BHR: 4-06-00-00908 UD: 200305 MF: C8-H6-Cl2-O3 MW: 221.04 WL: QV1OR BG DG CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MLD "Sbornik Vysledku Toxixologickeho Vysetreni Latek A Pripravku," Marhold, J.V., Institut Pro Vychovu Vedoucicn Pracovniku Chemickeho Prumyclu Praha, Czechoslovakia, 1972 -,279,1972 (28ZPAK); eye-rbt 750 ug/24H SEV "Sbornik Vysledku Toxixologickeho Vysetreni Latek A Pripravku," Marhold, J.V., Institut Pro Vychovu Vedoucicn Pracovniku Chemickeho Prumyclu Praha, Czechoslovakia, 1972 -,279,1972 (28ZPAK) ME: mmo-sat 250 ug/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 615, 1988 (MUREAV); dnr-esc 5 mg/disc National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB80-133226 (NTIS**); dna-esc 20 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); dnr-bcs 5 mg/disc National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB80-133226 (NTIS**); mmo-omi 1 gm/L (-S9) Microbios Letters. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1976- v. 5, p. 103, 1977 (MILEDM); slt-dmg-orl 5 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 237, 1993 (MUREAV); slt-dmg-mul 10 ppb Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 25, p. 148, 1995 (EMMUEG); sln-dmg-orl 25 ppm Ecological Bulletins. (Editorial Service of FRN, Box 6710, S-11385, Stockholm, Sweden) No.19- 1975- v. 27, p. 190, 1978 (ECBUDQ); sln-dmg-unr 1000 ppm/15D Ecological Bulletins. (Editorial Service of FRN, Box 6710, S-11385, Stockholm, Sweden) No.19- 1975- v. 27, p. 182, 1978 (ECBUDQ); mmo-smc 150 mg/L (-S9) Ecological Bulletins. (Editorial Service of FRN, Box 6710, S-11385, Stockholm, Sweden) No.19- 1975- v. 27, p. 193, 1978 (ECBUDQ); mrc-asn 4 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 615, 1988 (MUREAV); dnd-sal-spr 1 mmol/L Phytochemistry. An International Journal of Plant Biochemistry. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1961- v. 11, p. 3135, 1972 (PYTCAS); dns-hmn-fbr 1 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 42, p. 161, 1977 (MUREAV); cyt-hmn-lym 20 ug/L Cytology and Genetics (English Translation). Translation of TGANAK. (Allerton Press Inc., 150 Fifth Ave., New York, NY 10011) V.8- 1974- v. 8(3), p. 6, 1974 (CYGEDX); sce-hmn-lym 10 mg/L Journal of Heredity. (American Genetic Assoc., 818 18th St., NW, Washington, DC 20006) V.5- 1914- v. 73, p. 224, 1982 (JOHEA8); cyt-rat-ipr 100 ug/kg Cytologia. (Japan Pub. Trading Co. (USA), 1255 Howard St., San Francisco, CA 94103) V.1- 1929- v. 52, p. 275, 1987 (CYTOAN); dni-mus-orl 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 55, p. 197, 1978 (MUREAV); cyt-mus-orl 100 mg/kg Cytology and Genetics (English Translation). Translation of TGANAK. (Allerton Press Inc., 150 Fifth Ave., New York, NY 10011) V.8- 1974- v. 8(3), p. 6, 1974 (CYGEDX); dni-ham-ovr 1 mmol/L Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 29, p. 137, 1985 (TOLED5); cyt-ham-ovr 2400 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ham-ovr 167 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); msc-ham-lng 10 umol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 19, p. 369, 1977 (CBINA8); cyt-ctl-kdy 1 ppm In Vitro. (Rockville, MD) V.1-20, 1965-85. For publisher information, see ICDBEO. v. 8, p. 416, 1973 (ITCSAF); dnd-mam-lym 1 mmol/L Phytochemistry. An International Journal of Plant Biochemistry. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1961- v. 11, p. 3135, 1972 (PYTCAS); sce-mus-orl 100 mg/kg Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 941, 2001 (FCTOD7); cyt-mus-orl 9.9 mg/kg/3D Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 494, p. 1, 2001 (MUREAV); spm-mus-orl 33 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 494, p. 1, 2001 (MUREAV); mmo-smc 4 mmol/L/4H Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 74, p. 560, 2000 (ARTODN); cyt-mus-ipr 3.5 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 74, p. 560, 2000 (ARTODN) RE: T48 orl-rat TDLo: 220 ug/kg (1-22D preg) Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(10), p. 76, 1985 (GISAAA); T46-T34-T35 orl-rat TDLo: 1 gm/kg (6-15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 22, p. 14, 1972 (TXAPA9); T46 orl-rat TDLo: 125 mg/kg (6-15D preg) Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 9, p. 801, 1971 (FCTXAV); T34-T41-T53 orl-rat TDLo: 500 mg/kg (6-15D preg) Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 9, p. 801, 1971 (FCTXAV); T46 orl-rat TDLo: 80 mg/kg (6-15D preg) Zhonghua Minguo Shouyi Xuehui Zashi. (Chinese Society of Veterinary Science, c/o Kuo Li Tai-wan Ta Hsueh, 142 Chou Shan Lu, Taipei, 106, Taiwan) V.1- 1975- v. 24, p. 29, 1998 (CKSCDN); T81-T83 ipr-rat TDLo: 1600 mg/kg (9-25D preg) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 18, p. 691, 1996 (NETEEC); T81-T83 ipr-rat TDLo: 600 mg/kg (9-15D preg) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 18, p. 691, 1996 (NETEEC); T83 ipr-rat TDLo: 1 gm/kg (15-24D preg) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 18, p. 691, 1996 (NETEEC); T34-T35-T43 orl-mus TDLo: 707 mg/kg (11-14D preg) Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 6, p. 33, 1977 (AECTCV); T26-T31-T42 orl-mus TDLo: 900 mg/kg (6-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-160 (NTIS**); T81 orl-mus TDLo: 438 mg/kg (8-12D preg) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 7, 1987 (TCMUD8); T35-T41-T31 scu-mus TDLo: 882 mg/kg (6-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-160 (NTIS**); T34-T42-T43 scu-mus TDLo: 900 mg/kg (6-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-160 (NTIS**); T24-T26 scu-mus TDLo: 900 mg/kg (6-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-160 (NTIS**); T26 orl-ham TDLo: 200 mg/kg (7-11D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 6, p. 559, 1971 (BECTA6); T81-T87 orl-mus TDLo: 715 mg/kg (6-16D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 165, p. 39, 2001 (TXCYAC); T54-T81-T87 orl-mus TDLo: 7150 mg/kg (6-16D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 165, p. 39, 2001 (TXCYAC); T81 orl-mam TDLo: 20 mg/kg (multigenerations) Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 67, p. 10624, 2002 (FEREAC); T46 orl-mam TDLo: 750 mg/kg (6-15D preg) Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 67, p. 10624, 2002 (FEREAC); T81 orl-mus TDLo: 407 mg/kg (6-16D preg) Veterinary and Human Toxicology. (American College of Veterinary and Comparative Toxicology, Publication Office, Comparative Toxicology, Manhattan, KS 66506) V.19- 1977- v. 42, p. 129, 2000 (VHTODE); T41-T83 orl-rat TDLo: 3150 mg/kg (16-22D preg/23D post) Neurotoxicology. (Intox Press, Inc., POB 34075, Little Rock, AR 72203) V.1- 1979- v. 24, p. 149, 2003 (NRTXDN); T34-T39 orl-rat TDLo: 400 mg/kg (7-14D preg) Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 40, p. 102, 1975 (GISAAA); T41-T83 orl-rat TDLo: 70 mg/kg (multigenerations) Neurotoxicology. (Intox Press, Inc., POB 34075, Little Rock, AR 72203) V.1- 1979- v. 24, p. 149, 2003 (NRTXDN) TE: V03-A60 orl-rat TDLo: 32850 mg/kg/2Y-C Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 67, p. 10624, 2002 (FEREAC) ORNG: 375000000 ng/kg. [375.000000 mg/kg] T/E unlistd SRNG: 1400000000 ng/kg. [1400.000000 mg/kg] F19-R10 SKNG: 1500000000 ng/kg. [1500.000000 mg/kg] T/E unlistd AT: F24-J25 orl-man TDLo: 2 gm/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 66, p. 518, 1992 (ARTODN); F24-G10-J25 orl-man TDLo: 5714 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 66, p. 518, 1992 (ARTODN); K13-F24-F07 orl-hmn LDLo: 80 mg/kg Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 94, p. 270, 1972 (ARPAAQ); F12 orl-man LDLo: 93 mg/kg Pharmacological Reviews. (Williams and Wilkins, 428 E. Preston St., Baltimore, MD 21202) V.1- 1949- v. 14, p. 225, 1962 (PAREAQ); T/E unlistd orl-rat LD50: 375 mg/kg Farm Chemicals Handbook. (Meister Pub., 37841 Euclid Ave., Willoughy, OH 44094) v. -, p. C174, 1991 (FMCHA2); T/E unlistd skn-rat LD50: 1500 mg/kg World Review of Pest Control. (London, UK) V.1-10, 1962-71. Discontinued. v. 9, p. 119, 1970 (WRPCA2); C06-F18-F24 ipr-rat LD50: 666 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 29, p. 85, 1947 (JIHTAB); T/E unlistd orl-mus LD50: 347 mg/kg Roczniki Panstwowego Zakladu Higieny. (Ars Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1950- v. 31, p. 373, 1980 (RPZHAW); T/E unlistd ipr-mus LDLo: 125 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 23, p. 288, 1972 (TXAPA9); F20-F24 orl-dog LD50: 100 mg/kg Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 7, p. 202, 1963 (AEHLAU); T/E unlistd orl-rbt LDLo: 800 mg/kg Archives des Maladies Professionnelles de Medecine du Travail et de Securite Sociale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.7- 1946- v. 12, p. 26, 1951 (AMPMAR); F19-R10 skn-rbt LD50: 1400 mg/kg Quarterly Bulletin--Association of Food and Drug Officials of the United States. (Denver, CO) V.3-38, 1939-74. v. 16, p. 3, 1952 (AFDOAQ); C06-F18-F24 ipr-rbt LD50: 400 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 29, p. 85, 1947 (JIHTAB); C06-F18-F24 ivn-rbt LD50: 400 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 29, p. 85, 1947 (JIHTAB); T/E unlistd orl-gpg LD50: 469 mg/kg American Journal of Veterinary Research. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.1- 1940- v. 15, p. 622, 1954 (AJVRAH); C06-F18-F24 ipr-gpg LD50: 666 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 29, p. 85, 1947 (JIHTAB); T/E unlistd orl-ham LD50: 500 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 48, p. A192, 1979 (TXAPA9); K05-F07-L03 orl-ckn LD50: 541 mg/kg American Journal of Veterinary Research. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.1- 1940- v. 15, p. 622, 1954 (AJVRAH); T/E unlistd orl-mam LD50: 375 mg/kg Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 165, p. 465, 1969 (SCIEAS); F07-U28 orl-mus TDLo: 200 mg/kg Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 941, 2001 (FCTOD7); T/E unlistd orl-hmn TDLo: 66 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 60, 2001 (HBPTO*); T/E unlistd orl-rat LD50: 3670 mg/kg/18H Toho Igakkai Zasshi. Journal of Medical Society of Toho University. (Toho Daigaku Igakkai, 21-16, Omori-nishi, 5-chome, Ota-ku, Tokyo 143, Japan) V.1- 1954- v. 19, p. 356, 1972 (TOIZAG); T/E unlistd orl-bwd LD50: 200 mg/kg TA:Pesticide residues in food - 1997. Toxicological evaluations v. -, p. 253, 1998 (PESFO*); T/E unlistd orl-rbt LD50: 699 mg/kg TA:Pesticide residues in food - 1997. Toxicological evaluations v. -, p. 253, 1998 (PESFO*); T/E unlistd skn-rbt LD50: >2000 mg/kg TA:Pesticide residues in food - 1997. Toxicological evaluations v. -, p. 253, 1998 (PESFO*); T/E unlistd ihl-rbt LC50: 1800 mg/m3 TA:Pesticide residues in food - 1997. Toxicological evaluations v. -, p. 253, 1998 (PESFO*) MD: L70-N75-Y15 orl-rat TDLo: 54600 mg/kg/2Y-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 33, p. 166, 1996 (FAATDF); U01 orl-rat TDLo: 13650 mg/kg/13W-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 9, p. 423, 1987 (FAATDF); F18 orl-rat TDLo: 200 mg/kg/5W-I Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 5, p. 331, 1983 (NTOTDY); D20-F17 orl-rat TDLo: 54750 mg/kg/1Y-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 15, p. 23, 1995 (TOXID9); M03-M70 orl-mus TDLo: 91 gm/kg/2Y-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 33, p. 166, 1996 (FAATDF); P70-U01-Z01 orl-dog TDLo: 700 mg/kg/90D-I AMA Archives of Industrial Hygiene and Occupational Medicine. (Chicago, IL) V.2-10, 1950-54. For publisher information, see AEHLAU. v. 7, p. 61, 1953 (AMIHBC); M03-L30-P28 orl-dog TDLo: 1820 mg/kg/52W-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 29, p. 78, 1996 (FAATDF); Q01-R03-Z01 ivn-dog TDLo: 300 mg/kg/6D-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 29, p. 85, 1947 (JIHTAB); M03-M71-U01 orl-mus TDLo: 18144 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03-M71 orl-rat TDLo: 3780 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03 orl-rat TDLo: 418.3 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7); M03 orl-ham TDLo: 50400 mg/kg/12W-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 440, 2001 (JTPAE7) TR: ACGIH TLV-TWA 10 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 10 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Human Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 41, p. 357, 1986 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 15, p. 111, 1977 (IMEMDT); TOXICOLOGY REVIEW Residue Reviews. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1962- v. 59, p. 1, 1975 (RREVAH); TOXICOLOGY REVIEW Deutsche Tieraerztliche Wochenschrift. (Hanover, Fed. Rep. Ger.) V.1-77, 1893-1970. v. 80, p. 485, 1973 (DTTIAF); TOXICOLOGY REVIEW Residue Reviews. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1962- v. 56, p. 107, 1975 (RREVAH); TOXICOLOGY REVIEW Economie et Medecine Animales. (Paris, France) V.1-17, 1960-76. Discontinued. v. 14, p. 141, 1973 (ECMAAI); TOXICOLOGY REVIEW Biologico. (Instituto Biologica, Av. Cons. Rodriques Alves, 1252, CEP 04014, Sao Paulo, Brazil) V.1- 1935- v. 40(2), p. 44, 1974 (BIOGAL); TOXICOLOGY REVIEW Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 31(7-9), p. 383, 1966 (HYSAAV); TOXICOLOGY REVIEW Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 11, p. 5, 1992 (JACTDZ) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 10 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 67, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 10 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 10 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 10 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 10 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 10 mg/m3, JAN 1993; OEL-AUSTRIA: MAK 10 mg/m3, JAN 1999; OEL-BELGIUM: TWA 10 mg/m3, JAN 1993; OEL-DENMARK: TWA 5 mg/m3, JAN 1999; OEL-FINLAND: TWA 10 mg/m3, STEL 20 mg/m3, Skin, JAN 1993; OEL-FRANCE: VME 10 mg/m3, JAN 1999; OEL-GERMANY: MAK 1 mg/m3, JAN 1999; OEL-HUNGARY: TWA 1 mg/m3, STEL 2 mg/m3, Skin, JAN 1993; OEL-THE NETHERLANDS: MAC-TGG 10 mg/m3, JAN 1999; OEL-NORWAY: TWA 5 mg/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 10 mg/m3, JAN 1993; OEL-POLAND: MAC(TWA) 7 mg/m3, MAC(STEL) 20 mg/m3, JAN 1999; OEL-SWITZERLAND: MAK-W 10 mg/m3, KZG-W 50 mg/m3, JAN 1999; OEL-THAILAND: TWA 10 mg/m3, JAN 1993; OEL-TURKEY: TWA 10 mg/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 10 mg/m3, STEL 20 mg/m3, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO 2,4-D-air: 10H TWA 10 mg/m3 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 24270; NIS 6; TNF 1132; NOS 8; TNE 6266; NOES 1983: HZD 24270; NIS 1; TNF 94; NOS 1; TNE 471 SL: EPA GENETOX PROGRAM 1988, Positive: In vivo cytogenetics-nonhuman bone marrow; EPA GENETOX PROGRAM 1988, Positive: In vitro cytogenetics-human lymphocyte; EPA GENETOX PROGRAM 1988, Positive: B subtilis rec assay, E coli polA without S9; EPA GENETOX PROGRAM 1988, Positive: V79 cell culture-gene mutation; EPA GENETOX PROGRAM 1988, Positive: S cerevisiae gene conversion; EPA GENETOX PROGRAM 1988, Negative: D melanogaster-whole sex chrom. loss; EPA GENETOX PROGRAM 1988, Negative: D melanogaster-nondisjunction; EPA GENETOX PROGRAM 1988, Negative: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Negative: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Negative: In vitro UDS-human fibroblast, TRP reversion; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: Carcinogenicity-mouse/rat, Mammalian micronucleus; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: 2, 4-D, 5001; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 465 of 1119 in RTECS (through 2003/06) AN: AH1350000 PN: Acetic-acid,-ester-with-2,6-dimethyl-m-dioxan-4-ol- SY: Acetomethoxane-; Dimethoxane-; 2,6-Dimethyl-m-dioxan-4-ol-acetate-; 2,6-Dimethyl-m-dioxan-4-yl-acetate-; m-Dioxan-4-ol,-2,6-dimethyl-,-acetate-; 1,3-Dioxan-4-ol,-2,6-dimethyl-,-acetate-; Dioxin (bactericide) (Obs.); G1V-Gard-DXN-; NCI-C56213-; Acetic-acid,-2,6-dimethyl-m-dioxan-4-yl-ester-; Acetomethoxan-; 6-Acetoxy-2,4-dimethyl-m-dioxane- RN: Current: 828-00-2 BRN: 128710 BHR: 4-19-00-00641 UD: 200210 MF: C8-H14-O4 MW: 174.22 WL: T6O COTJ B1 DOV1 F1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 5500 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 7), p. 1, 1986 (ENMUDM); sln-dmg-par 6000 ppm National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*); cyt-ham-ovr 20200 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*); sce-ham-ovr 3660 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*) TE: V01-L60-P61 orl-rat TDLo: 948 gm/kg/88W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 53, p. 791, 1974 (JNCIAM); V03-K60 orl-mus TD :25750 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*); V03-K60 orl-mus TDLo: 257500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-220096 (NTIS**) ORNG: 1930000000 ng/kg. [1930.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1930 mg/kg Givaudan Corporation, Corporate Communications. (100 Delawanna Ave., Clifton, NJ 07014) 25MAR1977 (GCTB**); T/E unlistd orl-mus LDLo: 2800 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*) MD: K30-L70 orl-rat TDLo: 12 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*); A70-K30-M70 orl-rat TDLo: 32500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*); K30-L70-Z01 orl-mus TDLo: 24 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-354, 1989 (NTPTR*) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 15, p. 177, 1977 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 15, p. 177, 1977 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC) ND: NOHS 1974: HZD 83665; NIS 2; TNF 76; NOS 8; TNE 491; NOES 1983: HZD 83665; NIS 114; TNF 11278; NOS 90; TNE 183978; TFE 80381 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse; NCI Carcinogenesis Studies (gavage), no evidence: rat Record 466 of 1119 in RTECS (through 2003/06) AN: AI5250000 PN: Acetic acid, lead(2+) salt SY: Acetate-de-plomb- (French); Bleiacetat- (German); Dibasic-lead-acetate-; Lead-acetate-; Lead-diacetate-; Lead-dibasic-acetate-; Lead(2+) acetate; Lead(II) acetate; Normal-lead-acetate-; Plumbous-acetate-; RCRA-waste-number-U144-; Salt-of-saturn-; Sugar-of-lead- RN: Current: 301-04-2 UD: 200302 MF: C4-H6-O4.Pb MW: 325.29 WL: QV1 &-PB- CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Organometallic (O); Human-Data (P); Reproductive-Effector (T) ME: dna-esc 50 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); sln-smc 250 umol/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 1, p. 21, 1986 (MUTAEX); cyt-hmn-lym 1 mmol/L/24H Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 10, p. 67, 1978 (TXCYAC); mnt-rat-ipr 51800 ug/kg Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 40, p. 144, 1985 (AEHLAU); mtr-rat-emb 200 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dns-rat-ipr 50 ug/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 143, p. 446, 1973 (PSEBAA); dns-rat-par 5 mg/kg Laboratory Investigation. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1952- v. 30, p. 647, 1974 (LAINAW); oms-rat-ipr 10400 ug/kg Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 40, p. 144, 1985 (AEHLAU); cyt-rat-orl 5000 ppm Tokyo Igaku Zasshi. Tokyo Journal of Medical Sciences. (Tokyo, Japan) V.59-76, 1951-68. v. 82, p. 232, 1974 (TKIZAM); cyt-rat-unr 9 mg/kg/26W-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 49(3), p. 15, 1984 (GISAAA); cyt-rat-ipr 51800 ug/kg Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 40, p. 144, 1985 (AEHLAU); dlt-rat-unr 1825 ug/kg/1Y-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 49(3), p. 15, 1984 (GISAAA); mnt-mus-ipr 7500 ug/kg Gongye Weisheng Yu Zhiyebing. Industrial Health and Occupational Diseases. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) V.1- 1973- v. 12, p. 77, 1986 (GWZHEW); mtr-mus-fbr 800 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); cyt-mus-orl 16800 mg/kg/4W Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 2, p. 619, 1977 (JTEHD6); sce-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 158, p. 217, 1985 (MUREAV); sce-mus-orl 19200 mg/kg/48D Nanjing Yixueyuan Xuebao. Journal of Nanjing Medical College. (Nanjing Yixueyuan, 140 Hanzhonglu, Nanjing, Peop. Rep. China) V.1- 1981(?)- v. 5, p. 114, 1985 (NAYXEW); sln-mus-ipr 179 ug/kg Genetika (Zemun, Yugoslavia). (Unija Bioloskih Naucnih Drustava Jugoslavije, Postanski fah 12 7, Zemun, Yugoslavia) V.1- 1969- v. 18, p. 147, 1986 (GNTKDF); spm-mus-par 1 gm/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 46, p. 159, 1980 (ARTODN); spm-mus-ipr 400 mg/kg/5D-I Chemical Mutagens. Principles and Methods for Their Detection. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.1- 1971- v. 5, p. 257, 1978 (CMMUAO); mtr-ham-emb 1 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dnd-ham-lng 1700 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 298, p. 97, 1992 (MUREAV); dns-ham-emb 200 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 131, p. 173, 1984 (MUREAV); msc-ham-lng 1700 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 298, p. 97, 1992 (MUREAV); cyt-mky-orl 206 mg/kg/64W-I Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 45, p. 77, 1977 (MUREAV); cyt-dom-orl 364 mg/kg/52W-C Nippon Chikusan Gakkaiho. Journal of the Japanese Society of Zootechnical Science. (Nippon Chikusan Gakkai, 201 Nagatani Koporasu, 2-9-4 Ikenohata, Taito-ku, Tokyo 110, Japan) V.1- 1924- v. 52, p. 619, 1981 (NICKA3); spm-dom-itt 10 mg/kg Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 11, p. 143, 1973 (IJEBA6); dnd-mus-lng 0.01 umol/L/10M Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 265, 2001 (MUTAEX); dnd-mus-lvr 0.01 umol/L/10M Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 265, 2001 (MUTAEX); dnd-mus-kdy 0.01 umol/L/10M Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 265, 2001 (MUTAEX); dnd-mus-ihl 0.408 mg/L/60M Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 265, 2001 (MUTAEX); dnd-mus-ihl 3.264 mg/L/4W Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 17, p. 55, 2002 (MUTAEX) RE: T19-T48-T59 orl-rat TDLo: 1257 uL/kg (10D pre/1-22D preg) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 42, p. 129, 1998 (TOSCF2); T01-T03-T04 orl-rat TDLo: 600 ug/kg (30D male) American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 115, p. 1058, 1973 (AJOGAH); T85 orl-rat TDLo: 97 mg/kg (5W male/5W pre-3W post) EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 12, p. 119, 1975 (EVHPAZ); T72-T76-T81 orl-rat TDLo: 14700 mg/kg (1-21D preg/21D post) Arhiv za Higijenu Rada i Toksikologiju. Archives of Industrial Hygiene and Toxicology. (Jugoslovenska Knjiga, POB 36, YU-11001 Belgrade, Yugoslavia) V.7- 1956- v. 47, p. 245, 1996 (AHRTAN); T83 orl-rat TDLo: 1800 mg/kg (1-22D preg/14D post) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 7, p. 373, 1981 (TOLED5); T81 orl-rat TDLo: 460 mg/kg (49D pre-21D post) EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 17, p. 290, 1976 (EVHPAZ); T48-T87 orl-rat TDLo: 230 mg/kg (49D pre-21D post) Clinical and Experimental Immunology. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.1- 1966- v. 35, p. 413, 1979 (CEXIAL); T25 orl-rat TDLo: 1950 mg/kg (6-18D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 26, p. 229, 1982 (TJADAB); T32-T34 orl-rat TDLo: 1413 mg/kg (1-18D preg) Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 30, p. 152, 1983 (ENVRAL); T25-T35-T42 ipr-rat TDLo: 25 mg/kg (9D preg) Folia Morphologica (Warsaw). (Panstwowy Zaklad Wydawnictw Lekarskich, ul. Dluga 38-40, 00 238 Warsaw, Poland) V.1- 1929- v. 33, p. 23, 1974 (FOMOAJ); T02-T03 ipr-rat TDLo: 120 mg/kg (30D male) Current Science. (Current Science Assoc., Sadashivanagar P.O., Bangalore 560 080, India) V.1- 1932- v. 56, p. 281, 1987 (CUSCAM); T39 ipr-rat TDLo: 60 mg/kg (13-19D preg) Zhongguo Yike Daxue Xuebao. Journal of China Medical University. (China International Book Trading Corp. POB 399, Beijing 100044, Peop. Rep. China) V.1- 19??- v. 21, p. 349, 1992 (ZYDXEN); T01-T02 ipr-rat TDLo: 1256 mg/kg (14W male) Experimental Pathology (1981). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.19- 1981- v. 31, p. 249, 1987 (EXPADD); T01-T91 orl-rat TDLo: 2380 mg/kg (17W male) Khigiena i Zdraveopazvane. Hygiene and Sanitation. (Hemus, Blvd. Russki 6, Sofia, Bulgaria) V.9- 1966- v. 23(4), p. 304, 1980 (KHZDAN); T34 orl-mus TDLo: 236 mg/kg (7-16D preg) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 41, p. 125, 1978 (ARTODN); T24 orl-mus TDLo: 4800 mg/kg (1-8D preg) Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 172, p. 1037, 1978 (CRSBAW); T27 orl-mus TDLo: 9 gm/kg (7-21D preg) Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 170, p. 1319, 1976 (CRSBAW); T48 orl-mus TDLo: 259 mg/kg (7-17D preg) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 41, p. 125, 1978 (ARTODN); T34-T35-T46 ipr-mus TDLo: 35 mg/kg (8D preg) Biomedicine. (Paris, France) V.18-34, 1973-81. v. 30, p. 223, 1979 (BIMDB3); T42-T81-T85 ipr-mus TDLo: 180 mg/kg (10-16D preg) Zhongguo Yike Daxue Xuebao. Journal of China Medical University. (China International Book Trading Corp. POB 399, Beijing 100044, Peop. Rep. China) V.1- 19??- v. 21, p. 349, 1992 (ZYDXEN); T34-T35-T43 ivn-mus TDLo: 100 mg/kg (11D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 26(1), p. 13A, 1982 (TJADAB); T25 ivn-mus TDLo: 200 mg/kg (7-8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 24(1), p. 18A, 1981 (TJADAB); T85 orl-mky TDLo: 765 mg/kg (90D pre/1-23W preg) Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 5, p. 391, 1983 (NTOTDY); T14 orl-mky TDLo: 1557 mg/kg (62W pre) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 9, p. 722, 1987 (FAATDF); T19-N02 orl-mky TDLo: 600 mg/kg (57W pre) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 6, p. 123, 1992 (REPTED); T85-T87 scu-rat TDLo: 110 mg/kg (15W male) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 19, p. 191, 1997 (NETEEC); T19-T41-T48 orl-gpg TDLo: 300 mg/kg (22-52D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 59, p. 81, 1989 (TXCYAC); T19-T52 orl-gpg TDLo: 1108 mg/kg (22-52D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 72, p. 89, 1992 (TXCYAC); T41 ipr-gpg TDLo: 12500 ug/kg (20D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 30, p. 413, 1984 (TJADAB); T46-T41-T42 ivn-ham TDLo: 50 mg/kg (8D preg) Experimental and Molecular Pathology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1962- v. 7, p. 208, 1967 (EXMPA6); T25-T46 ivn-ham TDLo: 25 mg/kg (8D preg) Anatomical Record. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1906/08- v. 157, p. 358, 1967 (ANREAK); T01-T02 itt-dom TDLo: 10 mg/kg (1D male) Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 11, p. 143, 1973 (IJEBA6); T25 ivn-mam TDLo: 256 mg/kg (7-10D preg) Veterinary Toxicology. (Manhattan, KS) V.15-18, 1973-76. For publisher information, see VHTODE v. 18(2), p. 58, 1976 (VETODR); T81 orl-rat TDLo: 322.5 mg/kg (1-22D preg/21D post) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 337, 2000 (NETEEC); T81 orl-rat TDLo: 660 mg/kg (1-22D preg) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 337, 2000 (NETEEC); T81-T85 orl-rat TDLo: 30 mg/kg (multigeneration)) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 337, 2000 (NETEEC); T41-T83-T85 orl-rat TDLo: 4200 mg/kg (21D post) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 41, 2000 (NETEEC); T81-T85 orl-rat TDLo: 900 mg/kg (30D post) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 151, 2000 (NETEEC); T81-T85 orl-rat TDLo: 3120 mg/kg (1-22D preg/30D post) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 151, 2000 (NETEEC); T26-T75-T81 orl-rat TDLo: 500 mg/kg (multigenerations) Fertility and Sterility. (American Fertility Soc., 608 13th Ave. S, Birmingham, AL 35282) V.1- 1950- v. 22, p. 755, 1971 (FESTAS); T52-T86 orl-rat TDLo: 600 mg/kg (multigenerations) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 136, p. 361, 1996 (TXAPA9); T81-T83 orl-rat TDLo: 17550 mg/kg (5-22D preg/1-21D post) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 54, p. 101, 1998 (JTEHD6); T76-T81 orl-mus TDLo: 11 gm/kg (1-22D preg) Human and Experimental Toxicology. (Macmillan Press Ltd., Brunel Road, Houndmills, Basingstoke, Hampshire, RG21 2XS, UK) V.9- 1990- v. 14, p. 872, 1995 (HETOEA); T25-T53 orl-mus TDLo: 500 mg/kg (multigenerations) Human and Experimental Toxicology. (Macmillan Press Ltd., Brunel Road, Houndmills, Basingstoke, Hampshire, RG21 2XS, UK) V.9- 1990- v. 14, p. 872, 1995 (HETOEA); T83 scu-rat TDLo: 800 mg/kg (9-22D preg/14D post) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 10, p. 653, 1982 (JTEHD6); T83 orl-rat TDLo: 68 mg/kg (multigenerations) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 32, p. 255, 1986 (TOLED5); T86 orl-rat TDLo: 1275 mg/kg (5-22D preg) Journal of Toxicology and Environmental Health, Part A. (Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 54, p. 77, 1998 (JTEHF8); T71 orl-rat TDLo: 3825 mg/kg (5-22D preg) Journal of Toxicology and Environmental Health, Part A. (Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 54, p. 77, 1998 (JTEHF8); T86 orl-rat TDLo: 25 mg/kg (multigenerations) Journal of Toxicology and Environmental Health, Part A. (Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 54, p. 77, 1998 (JTEHF8); T53-T52-T91 orl-rat TDLo: 75 mg/kg (multigenerations) Journal of Toxicology and Environmental Health, Part A. (Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 54, p. 77, 1998 (JTEHF8) TE: V02-J60-N61 orl-rat TDLo: 900 mg/kg/60D-C Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 24, p. 391, 1981 (ENVRAL); V03-M61 orl-rat TD :250 gm/kg/47W-C British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 16, p. 283, 1962 (BJCAAI); V03-A60-N60 orl-rat TD :2430 mg/kg/23W-C Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 24, p. 391, 1981 (ENVRAL); V03-J60-N61 orl-rat TD :4605 mg/kg/44W-C Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 24, p. 391, 1981 (ENVRAL); V02-N60-N62 orl-rat TD :7560 mg/kg/72W-C Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 24, p. 391, 1981 (ENVRAL); V02-M61 orl-rat TD :9150 mg/kg/44W-C American Journal of Pathology. (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1925- v. 50, p. 571, 1967 (AJPAA4); V03-M61 orl-rat TD :218 gm/kg/1Y-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 23, p. 464, 1979 (BECTA6); V03-M61 orl-rat TD :138 gm/kg/76W-C Toxicologic Pathology. (c/o Dr. F.A. de la Iglesia, Warner-Lambert Co., Pharmaceutical Research Div., POB 1047, Ann Arbor, MI 48106) V.6(3/4)- 1978- v. 13, p. 50, 1985 (TOPADD) AT: A30-F12-K13 orl-hmn LDLo: 714 mg/kg International Polymer Science and Technology. (Rapra Technology Ltd., Shawbury, Shrewsbury, Shropshire SY4 4NR, UK) v. 3, p. 93, 1976 (IPSTB3); L01-P05-Y53 ivn-man TDLo: 71 mg/kg Human Toxicology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants., RG 21 2XS, UK) V.1- 1981- v. 4, p. 301, 1985 (HUTODJ); T/E unlistd ipr-rat LD50: 150 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd ipr-mus LD50: 140 mg/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 64, p. 19, 1990 (TXCYAC); U01 ivn-mus LD50: 104 mg/kg Igaku to Seibutsugaku. Medicine and Biology. (c/o Ogato Igaku Kagaku Kenkyusho, 2-3-5 Bakuro-cho, Nihonbashi, Chuo-ku, Tokyo 103, Japan) V.1- 1942- v. 93, p. 461, 1977 (IGSBAL); T/E unlistd orl-dog LDLo: 300 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1289, 1935 (HBAMAK); T/E unlistd scu-dog LDLo: 80 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1289, 1935 (HBAMAK); T/E unlistd ivn-dog LDLo: 300 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd scu-cat LDLo: 100 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1289, 1935 (HBAMAK); T/E unlistd scu-rbt LDLo: 300 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1289, 1935 (HBAMAK); F12-F15-K12 ivn-rbt LD50: 25 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 301, 1949 (JIHTAB); T/E unlistd ipr-pgn LDLo: 150 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 46, p. 265, 1980 (ARTODN); T/E unlistd scu-frg LDLo: 1600 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1289, 1935 (HBAMAK) MD: L30-M30-Y10 orl-rat TDLo: 240 mg/kg/17W-I Khigiena i Zdraveopazvane. Hygiene and Sanitation. (Hemus, Blvd. Russki 6, Sofia, Bulgaria) V.9- 1966- v. 17, p. 21, 1974 (KHZDAN); G06-H01-U07 orl-rat TDLo: 122 gm/kg/90D-C Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 14, p. 305, 1991 (DCTODJ); A30-H01-U11 orl-rat TDLo: 2006 mg/kg/61W-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 63, p. 135, 1992 (TOLED5); M30-P28 orl-rat TDLo: 43 mg/kg/1.5Y-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 44(2), p. 9, 1979 (GISAAA); C04-C16-U01 orl-rat TDLo: 923 gm/kg/28W-C Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 62, p. 148, 1993 (ENVRAL); P71-U01-Y15 orl-rat TDLo: 192 gm/kg/5W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. 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(Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 63, p. 23, 1989 (ARTODN); M30-P30-U11 ipr-mus TDLo: 37680 ug/kg/5D-I Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 16, p. 190, 1976 (BECTA6); M16-P30-Y21 orl-dog TDLo: 286 mg/kg/13W-I Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 3(5-6), p. 465, 1980 (JEPTDQ); P05-P30 scu-rbt TDLo: 117 mg/kg/33W-I Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 64, p. 522, 1990 (ARTODN); M03-P05-P30 orl-pgn TDLo: 4396 mg/kg/64W-I Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 28, p. 344, 1982 (ENVRAL); A11-D35-Y41 orl-dom TDLo: 105 mg/kg/7D-I American Journal of Veterinary Research. 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(Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 55, p. 45, 1998 (JTEHF8); N16-P30 ipr-rat TDLo: 300 mg/kg/6W-I Journal of Toxicology and Environmental Health, Part A. (Taylor and Francis, 47 Runway Rd., Suite G, Levittown, PA 19057) V.53- 1998- v. 55, p. 45, 1998 (JTEHF8); Z01 orl-mus TDLo: 28 gm/kg/16W-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 19, p. 266, 1978 (BECTA6); Z01 orl-mus TDLo: 58.8 gm/kg/14W-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 19, p. 266, 1978 (BECTA6); T01 orl-mus TDLo: 33.6 gm/kg/8W-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 19, p. 266, 1978 (BECTA6); U01 orl-mus TDLo: 16.8 gm/kg/4W-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 19, p. 266, 1978 (BECTA6); M16-T02-U01 orl-rat TDLo: 1500 mg/kg/60D-C Biomedica Biochimica Acta. (Akademie-Verlag GmbH, Postfach 1233, Berlin DDR-1086, Ger. Dem. Rep.) V.42- 1983- v. 43, p. 95, 1984 (BBIADT); T01 orl-rat TDLo: 3000 mg/kg/60D-C Biomedica Biochimica Acta. (Akademie-Verlag GmbH, Postfach 1233, Berlin DDR-1086, Ger. Dem. Rep.) V.42- 1983- v. 43, p. 95, 1984 (BBIADT); Z73 orl-rat TDLo: 6000 mg/kg/60D-C Biomedica Biochimica Acta. (Akademie-Verlag GmbH, Postfach 1233, Berlin DDR-1086, Ger. Dem. Rep.) V.42- 1983- v. 43, p. 95, 1984 (BBIADT); N72 ipr-rat TDLo: 58.33 mg/kg/70D-I Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 14, p. 689, 1976 (RCOCB8) TR: IARC Cancer Review: Animal Inadequate Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 230, 1987 (IMSUDL); IARC Cancer Review: Human Inadequate Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 230, 1987 (IMSUDL); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 230, 1987 (IMSUDL); TOXICOLOGY REVIEW Advances in Teratology. (New York, NY) V.1-5, 1966-72. Discontinued. v. 5, p. 51, 1972 (ADTEAS); TOXICOLOGY REVIEW Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 13, p. 36, 1977 (ENVRAL); TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 Pb,256,1972 (85DHAX); TOXICOLOGY REVIEW Nutrition Reviews. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1942- v. 38, p. 129, 1980 (NUREA8) ND: NIOSH REL TO LEAD, INORGANIC-air: 10H TWA <0.1 mg(Pb)/m3 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD X8211; NIS 4; TNF 156; NOS 5; TNE 2145; TFE 50 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/SHE, Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-BALB/c-3T3; EPA GENETOX PROGRAM 1988, Negative: In vitro cytogenetics-human lymphocyte; EPA GENETOX PROGRAM 1988, Negative: In vivo cytogenetics-human lymphocyte; EPA GENETOX PROGRAM 1988, Negative: B subtilis rec assay, In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: SHE-clonal assay, Mammalian micronucleus; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 467 of 1119 in RTECS (through 2003/06) AN: AI7700000 PN: Acetic-acid,-mercapto-,-monosodium-salt- SY: Mercaptoacetic-acid-sodium-salt-; Sodium-mercaptoacetate-; Sodium-thioglycolate-; Sodium-thioglycollate-; Thioglycolate-sodium-; Thioglycollic-acid,-sodium-salt-; USAF-EK-5199- RN: Current: 367-51-1 UD: 200012 MF: C2-H3-O2-S.Na MW: 114.10 WL: SH1VQ &-NA- CC: Tumorigen (C); Drug (D); Primary-Irritant (S) ID: skn-hmn 7%/24H Industrial Medicine. (Chicago, IL) V.1-18, 1932-49. For publisher information, see IOHSA5. v. 15, p. 669, 1946 (INMEAF) AT: F07-F12-J22 ipr-rat LD50: 126 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 118, p. 296, 1956 (JPETAB); F07-F12 orl-mus LD50: 504 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 118, p. 296, 1956 (JPETAB); T/E unlistd ipr-mus LD50: 200 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD277-689 (NTIS**); T/E unlistd scu-mus LD50: 293 mg/kg Japanese Journal of Antibiotics. (Japan Antibiotics Research Assoc., 2-20-8 Kamiosaki, Shinagawa-ku, Tokyo 141, Japan) V.21- 1968- v. 41, p. 105, 1988 (JJANAX); T/E unlistd ivn-mus LD50: 422 mg/kg Japanese Journal of Antibiotics. (Japan Antibiotics Research Assoc., 2-20-8 Kamiosaki, Shinagawa-ku, Tokyo 141, Japan) V.21- 1968- v. 38, p. 137, 1985 (JJANAX); T/E unlistd unr-mus LD50: 8200 ug/kg Canadian Journal of Technology. (Ottawa, Ont., Canada) V.29(1)-34(8), 1951-57, Continues Canadian Journal of Research. Section F., Changed to Canadian Journal of Chemical Engineering. v. 34, p. 21, 1956 (CJTEAO); F11-K12-K13 ivn-dog LDLo: 500 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 118, p. 296, 1956 (JPETAB); F24-K12 ivn-mky LDLo: 300 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 118, p. 296, 1956 (JPETAB); F12-F18-J26 ivn-rbt LDLo: 100 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 35, p. 343, 1929 (JPETAB) ND: NOHS 1974: HZD 84380; NIS 4; TNF 265; NOS 6; TNE 3978; NOES 1983: HZD 84380; NIS 3; TNF 605; NOS 10; TNE 7551; TFE 6204 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis studies, laboratory assigned, October 2000 Record 468 of 1119 in RTECS (through 2003/06) AN: AJ0175000 PN: Acetic-acid,-nitrilotri- SY: N,N-Bis(carboxymethyl)glycine; CHEL-300-; Complexon-I-; Glycine, N,N-bis(carboxymethyl)- (9CI); Hampshire-NTA-acid-; Komplexon-I-; Kyselina-nitrilotrioctova- (Czech); NCI-C02766-; Nitrilotriacetic-acid-; Nitrilotris(methylenecarboxylic acid); Titriplex-I-; Versene-NTA-acid-; Aminotriacetic-acid-; NTA-; Triglycine-; Triglycollamic-acid-; Trilon-A-; alpha,alpha',alpha''-Trimethylaminetricarboxylic-acid- RN: Current: 139-13-9 Previous: 26627-44-1; 26627-45-2; 80751-51-5 BRN: 1710776 BHR: 4-04-00-02441 UD: 200006 MF: C6-H9-N-O6 MW: 191.16 WL: QV1N1VQ1VQ CC: Tumorigen (C); Mutagen (M) ME: mtr-ham-emb 2 gm/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 356, p. 85, 1996 (MUREAV) TE: V01-M60 orl-rat TDLo: 430 gm/kg/75W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-6, 1977 (NCITR*); V02-M60 orl-mus TDLo: 832 gm/kg/66W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-6, 1977 (NCITR*) ORNG: 1100000000 ng/kg. [1100.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1100 mg/kg Angewandte Chemie, International Edition in English. (VCH Pub., Inc., 303 NW 12th Ave., Deerfield Beach, FL 33441) V.1- 1962- v. 14, p. 94, 1975 (ACIEAY); T/E unlistd orl-mus LD50: 3160 mg/kg Progress Report for Contract No. NIH-NCI-E-C-72-3252, Submitted to the National Cancer Institute by Litton Bionetics, Inc. (Bethesda, MD) NCI-E-C-72-3252, 1973 (NCILB*); T/E unlistd ipr-mus LD50: 325 mg/kg CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- v. 20, p. 83, 1989 (CRTXB2) MD: M03 orl-rat TDLo: 41292 mg/kg/7W-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 20, p. 925, 1982 (FCTOD7); M16-M70-U07 orl-rat TDLo: 29439 ug/kg/4W-C Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 17, p. 137, 1979 (FCTXAV) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 48, p. 181, 1990 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 385, 1999 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 48, p. 181, 1990 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 385, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 385, 1999 (IMEMDT) ND: NOHS 1974: HZD 80058; NIS 31; TNF 1115; NOS 32; TNE 13454; NOES 1983: HZD 80058; NIS 24; TNF 1082; NOS 23; TNE 25216; TFE 7169 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: D melanogaster Sex-linked lethal; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-6, 1977 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 469 of 1119 in RTECS (through 2003/06) AN: AK3600000 PN: Acetin,-1-mono- SY: Acetic-acid,-monoglyceride-; 2,3-Dihydroxypropyl-acetate-; Glycerol,-1-acetate-; Glycerol-alpha-monoacetate-; Glycerol-1-monoacetate-; Monacetin-; Monoacetin-; alpha-Monoacetin-; 1-Monoacetin-; Monoacetyl-glycerine-; Glycerol-monoacetate-; Glyceryl-acetate-; Glyceryl-monoacetate-; 1,2,3-Propanetriol,-1-acetate- (9CI); 1,2,3,-Propanetriol-monoacetate- RN: Current: 106-61-6 UD: 199912 MF: C5-H10-O4 MW: 134.15 WL: Q1YQ1OV1 CC: Mutagen (M) ME: mmo-sat 3333 ug/plate (+S9) NTP Technical Bulletin. (National Toxicology Program, Landow Bldg. 3A-06, 7910 Woodmont Ave., Bethesda, MD 20205) JAN1982 (NTPTB*) AT: F07-J22 scu-rat LD50: 5500 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 46, p. 26, 1941 (PSEBAA); F07-J22 scu-mus LD50: 3500 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 46, p. 26, 1941 (PSEBAA); T/E unlistd ivn-dog LD50: 5 gm/kg "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,665,1986 (85JCAE) Record 470 of 1119 in RTECS (through 2003/06) AN: AL3150000 PN: Acetone- SY: Aceton- (German, Dutch, Polish); Chevron-acetone-; Dimethylformaldehyde-; Dimethylketal-; Dimethyl-ketone-; Ketone,-dimethyl-; Ketone-propane-; beta-Ketopropane-; Methyl-ketone-; Pyroacetic-acid-; Pyroacetic-ether-; RCRA-waste-number-U002-; Acetone- (ACGIH:OSHA); Propanone-; 2-Propanone- RN: Current: 67-64-1 UD: 200305 MF: C3-H6-O MW: 58.09 WL: 1V1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: eye-hmn 500 ppm Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 25, p. 282, 1943 (JIHTAB); skn-rbt 395 mg open MLD Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 5/7/1970 (UCDS**); skn-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,280,1986 (85JCAE); eye-rbt 20 mg SEV American Journal of Ophthalmology. (Ophthalmic Pub. Co., 435 N. Michigan Ave., Suite 1415, Chicago, IL 60611) Series 3: V.1- 1918- v. 29, p. 1363, 1946 (AJOPAA); eye-rbt 20 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,280,1986 (85JCAE); eye-rbt 10 uL MLD Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 187, 2001 (JTPAE7) ME: sln-smc 47600 ppm Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 407, p. 186, 1983 (ANYAA9); cyt-ham-fbr 40 gm/L Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 22, p. 623, 1984 (FCTOD7); sln-mus-ihl 12 gm/L "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1994 (VCVGK*) RE: T01 orl-rat TDLo: 273 gm/kg (13W male) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB91-185975 (NTIS**); T25 ihl-mam TCLo: 31500 ug/m3/24H (1-13D preg) Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 26(6), p. 24, 1982 (GTPZAB); T24-T25-T35 ihl-rat TCLo: 30 mg/m3 (1-13D preg) "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1994 (VCVGK*) ORNG: 5800000000 ng/kg. [5800.000000 mg/kg] F05-F11 AT: F24-M30 orl-man TDLo: 2857 mg/kg "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,64,1969 (34ZIAG); F24-Y53 orl-man TDLo: 2857 mg/kg Diabetes. (American Diabetes Assoc., 2 Park Ave., New York, NY 10016) V.1- 1952- v. 15, p. 810, 1966 (DIAEAZ); A11 ihl-man TCLo: 440 ug/m3/6M Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 42(8), p. 42, 1977 (GISAAA); Y44 ihl-man TCLo: 10 mg/m3/6H Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 42(8), p. 42, 1977 (GISAAA); D07-D25-J30 ihl-hmn TCLo: 500 ppm Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 25, p. 282, 1943 (JIHTAB); K13-F18 ihl-man TCLo: 12000 ppm/4H Annals of Occupational Hygiene. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 16, p. 73, 1973 (AOHYA3); T/E unlistd unr-man LDLo: 1159 mg/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); F05-F11 orl-rat LD50: 5800 mg/kg Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 15, p. 609, 1985 (JTEHD6); T/E unlistd ihl-rat LC50: 50100 mg/m3/8H American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 20, p. 364, 1959 (AIHAAP); F01-F18-M12 ipr-rat LDLo: 500 mg/kg Journal of Pharmacy and Pharmacology. (Pharmaceutical Soc. of Great Britain, 1 Lambeth High St., London SEI 7JN, UK) V.1- 1949- v. 11, p. 150, 1959 (JPPMAB); T/E unlistd ivn-rat LD50: 5500 mg/kg Raw Material Data Handbook, Vol.1: Organic Solvents, 1974. (National Assoc. of Printing Ink Research Institute, Francis McDonald Sinclair Memorial Laboratory, Lehigh Univ., Bethlehem, PA 18015) v. 1, p. 1, 1974 (NPIRI*); T/E unlistd orl-mus LD50: 3 gm/kg Pharmaceutical Chemistry Journal (English Translation). Translation of KHFZAN. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) No.1- 1967- v. 14, p. 162, 1980 (PCJOAU); T/E unlistd ihl-mus LC50: 44 gm/m3/4H Current Toxicology. (Nova Science Publishers, Inc., 6080 Jericho Turnpike, Suite 207, Commack, NY 11725) V.1 1993- v. 1, p. 47, 1993 (CUTOEX); T/E unlistd ipr-mus LD50: 1297 mg/kg Shell Chemical Company. Unpublished Report. (2401 Crow Canyon Rd., San Romon, CA 94583) v. -, p. 1, 1961 (SCCUR*); T/E unlistd ivn-mus LDLo: 4 gm/kg FAO Nutrition Meetings Report Series. (Rome, Italy) No.?-57, 1948-77. Discontinued. v. 48A, p. 86, 1970 (FAONAU); F19-F24-Q15 orl-dog LDLo: 8 gm/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 18, p. 218, 1884 (AEXPBL); F24-K04 ipr-dog LDLo: 8 gm/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 18, p. 218, 1884 (AEXPBL); T/E unlistd scu-dog LDLo: 5 gm/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 18, p. 218, 1884 (AEXPBL); T/E unlistd orl-rbt LD50: 5340 mg/kg FAO Nutrition Meetings Report Series. (Rome, Italy) No.?-57, 1948-77. Discontinued. v. 48A, p. 86, 1970 (FAONAU); T/E unlistd skn-rbt LDLo: 20 mL/kg Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 5/7/1970 (UCDS**); F23-J25 ivn-rbt LDLo: 1576 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 33, p. 175, 1928 (JPETAB); T/E unlistd skn-gpg LD50: >9400 uL/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 559, 1965 (TXAPA9); T/E unlistd scu-gpg LDLo: 5 gm/kg Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 5, p. 1, 1933 (AGGHAR); T/E unlistd orl-dog LDLo: 8000 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); Y21-Y27 orl-mam TDLo: 3.49 gm/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); F40 ihl-mus TCLo: 30000 mg/m3/2H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); F40 ihl-rat TCLo: 30000 mg/m3/2H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); F40 ihl-gpg TCLo: 72000 mg/m3/2H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); T/E unlistd ihl-mus LCLo: 150000 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); F40 ihl-rbt TCLo: 1250 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); D25-F04 ihl-cat TCLo: 8000 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); D25-J21 ihl-hmn TCLo: 12000 mg/m3/3M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); Y01 ihl-hmn TCLo: 10 mg/m3/6H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 408, 1984 (VCVGK*); T/E unlistd orl-hmn LDLo: 714 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1984 (VCVGK*) MD: L70-M70-P05 orl-rat TDLo: 273 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-91-3122 (NTPTR*); A70 ihl-rat TCLo: 19000 ppm/3H/8W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 61, p. 302, 1981 (TXAPA9); F23 ihl-rat TCLo: 199 mg/m3/8H/45D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 25(5), p. 3, 1960 (GISAAA); L70-N73 orl-mus TDLo: 546 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-91-3122 (NTPTR*); L30-Y07 orl-rat TDLo: 5 mg/kg/5D-C Life Sciences. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1-8, 1962-69: V.14- 1974- v. 69, p. 923, 2001 (LIFSAK); L30-Y07 orl-mus TDLo: 2 mg/kg/5D-C Life Sciences. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1-8, 1962-69: V.14- 1974- v. 69, p. 923, 2001 (LIFSAK); Y37 ihl-rat TCLo: 30 mg/m3/13D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1994 (VCVGK*); G06-G07-Y01 ihl-hmn TCLo: 100 mg/m3/6H/5D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1994 (VCVGK*); N04-N07-Y52 ihl-rat TCLo: 2000 mg/m3/4H/45D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1994 (VCVGK*); F40 ihl-rat TCLo: 199 mg/m3/8H/45D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 409, 1994 (VCVGK*); P71-P13 ihl-hmn TCLo: 440 mg/m3/3Y-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 410, 1994 (VCVGK*); Y03-T19 ihl-rat TCLo: 206 mg/m3/21D-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 4, p. 12, 1994 (GISAAA) TR: ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 750 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 500 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 1000 ppm (2400 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 3, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 1000 ppm (2400 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 1000 ppm (2400 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 1000 ppm (2400 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 1000 ppm (2400 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 500 ppm (1185 mg/m3), STEL 1000 ppm, JAN 1993; OEL-AUSTRIA: MAK 750 ppm (1780 mg/m3), JAN 1999; OEL-BELGIUM: TWA 750 ppm (1780 mg/m3), STEL 1000 ppm, JAN 1993; OEL-DENMARK: TWA 250 ppm (600 mg/m3, JAN 1999; OEL-FINLAND: TWA 500 ppm (1200 mg/m3), STEL 625 ppm (1500 mg/m3), JAN 1993; OEL-FRANCE: VME 750 ppm (1800 mg/m3), JAN 1999; OEL-GERMANY: MAK 500 ppm (1200 mg/m3), JAN 1999; OEL-HUNGARY: TWA 600 mg/m3, STEL 1200 mg/m3, JAN 1993; OEL-INDIA: TWA 750 ppm (1780 mg/m3), STEL 1000 ppm (2375 mg/m3), JAN 1993; OEL-JAPAN: OEL 200 ppm (470 mg/m3), JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 750 ppm (1780 mg/m3), JAN 1999; OEL-NORWAY: TWA 125 ppm (295 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 1000 ppm (2400 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 600 mg/m3, MAC(STEL) 1800 mg/m3, JAN 1999; OEL-RUSSIA: TWA 200 ppm, STEL 200 mg/m3, JAN 1993; OEL-SWEDEN: NGV 250 ppm (600 mg/m3), KTV 500 ppm (1200 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 500 ppm (1200 mg/m3), STEL 1000 ppm (2400 mg/m3), JAN 1999; OEL-TURKEY: TWA 1000 ppm (2400 mg/m3), JAN 1993; OEL-UNITED KINGDOM: TWA 750 ppm (1810 mg/m3), STEL 1500 ppm (3620 mg/m3),; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ACETONE-air: 10H TWA 250 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 02820; NIS 350; TNF 99713; NOS 188; TNE 1287794; NOES 1983: HZD 02820; NIS 358; TNF 97342; NOS 215; TNE 1740164; TFE 540313 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/95/100095/AS); EPA GENETOX PROGRAM 1988, Negative: SHE-clonal assay, Cell transform.-mouse embryo; EPA GENETOX PROGRAM 1988, Negative: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Negative: In vitro cytogenetics-nonhuman; EPA GENETOX PROGRAM 1988, Negative: Histidine reversion-Ames test, In vitro SCE-nonhuman; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Ketones I, 1300; NIOSH Analytical Method, 1996: Volatile organic compound, 2549; NTP Toxicity studies, RPT# TOX-03, October 2000; OSHA ANALYTICAL METHOD #ID-69 Record 471 of 1119 in RTECS (through 2003/06) AN: AL7700000 PN: Acetonitrile- SY: Acetonitril- (German, Dutch); Cyanomethane-; Cyanure-de-methyl- (French); Ethanenitrile-; Ethyl-nitrile-; Methanecarbonitrile-; Methane,-cyano-; Methylkyanid- (Czech); NCI-C60822-; RCRA-waste-number-U003-; USAF-EK-488-; Acetonitrile- (ACGIH:OSHA) RN: Current: 75-05-8 UD: 200210 MF: C2-H3-N MW: 41.06 WL: NC1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 500 mg open MLD Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 3/18/1965 (UCDS**); eye-rbt 100 uL/24H MOD International Journal of Toxicology. (Taylor and Francis, 47 Runway Rd., Suite g, Levittown, PA 19057) V.16- 1997- v. 19, p. 363, 2000 (IJTOFN) ME: sln-dmg-ihl 131 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 259, p. 165, 1991 (MUREAV); sln-smc 47600 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 149, p. 339, 1985 (MUREAV); sce-ham-ovr 5 gm/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) RE: T25 ihl-rat TCLo: 1800 ppm/6H (6-20D preg) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 20, p. 365, 1993 (FAATDF); T19-T35-T46 orl-rbt TDLo: 390 mg/kg (6-18D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555575 (NTIS**); T46 orl-ham TDLo: 300 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 27, p. 313, 1983 (TJADAB); T25 orl-ham TDLo: 400 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 27, p. 313, 1983 (TJADAB); T25-T41 ihl-ham TCLo: 5000 ppm/1H (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 27, p. 313, 1983 (TJADAB); T34-T46 ihl-ham TCLo: 8000 ppm/1H (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 27, p. 313, 1983 (TJADAB); T39 orl-rat TDLo: 2 mg/kg (10D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 163, p. 149, 2000 (TXAPA9) TE: V03-L60 ihl-rat TCLo: 400 ppm/6H/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-447, 1996 (NTPTR*) ORNG: 2460000000 ng/kg. [2460.000000 mg/kg] T/E unlistd AT: F24-G07-J25 orl-wmn TDLo: 500 mg/kg Postgraduate Medical Journal. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.1- 1925- v. 73, p. 299, 1997 (PGMJAO); F08-F12-K13 orl-chd TDLo: 800 mg/kg American Journal of Emergency Medicine. (WB Saunders, Philadelphia, PA) V.1- 1983- v. 9, p. 268, 1991 (AJEMEN); F12-K13-U20 orl-man TDLo: 571 mg/kg Acta Pharmacologica et Toxicologica, Supplementun. (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) No.1- 1947- v. 41, p. 340, 1977 (APTSAI); F13 orl-man TDLo: 64 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 29, p. 447, 1991 (JTCTDW); J30 ihl-hmn TCLo: 160 ppm/4H "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,65,1969 (34ZIAG); T/E unlistd orl-rat LD50: 2460 mg/kg Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 3/18/1965 (UCDS**); F05-F12-P01 ihl-rat LC50: 7551 ppm/8H Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); T/E unlistd ipr-rat LD50: 850 mg/kg Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); T/E unlistd scu-rat LD50: 3500 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,16,1982 (85GMAT); T/E unlistd ivn-rat LD50: 1680 mg/kg Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); T/E unlistd par-rat LD50: 1100 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,16,1982 (85GMAT); T/E unlistd orl-mus LD50: 269 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 55, p. 47, 1984 (ARTODN); L30 ihl-mus LC50: 2693 ppm/1H Clinical Toxicology. (New York, NY) V.1-18, 1968-81. For publisher information, see JTCTDW. v. 18, p. 991, 1981 (CTOXAO); D26-F19-J22 ipr-mus LD50: 175 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 59, p. 589, 1981 (TXAPA9); T/E unlistd scu-mus LD50: 4480 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,16,1982 (85GMAT); T/E unlistd ivn-mus LD50: 612 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,16,1982 (85GMAT); T/E unlistd ihl-dog LCLo: 16000 ppm/4H Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); T/E unlistd orl-cat LD50: 200 mg/kg Zentralblatt fuer Arbeitsmedizin und Arbeitsschutz. (Darmstadt, Fed. Rep. Ger.) V.1-25, 1951-75. v. 19, p. 225, 1969 (ZAARAM); T/E unlistd ihl-cat LC50: 18 gm/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,16,1982 (85GMAT); T/E unlistd orl-rbt LD50: 50 mg/kg Zentralblatt fuer Arbeitsmedizin und Arbeitsschutz. (Darmstadt, Fed. Rep. Ger.) V.1-25, 1951-75. v. 19, p. 225, 1969 (ZAARAM); F05-F12-P01 ihl-rbt LC50: 2828 ppm/4H Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); T/E unlistd skn-rbt LD50: >2 gm/kg International Journal of Toxicology. (Taylor and Francis, 47 Runway Rd., Suite g, Levittown, PA 19057) V.16- 1997- v. 19, p. 363, 2000 (IJTOFN); T/E unlistd scu-rbt LDLo: 105 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 36, p. 455, 1929 (AIPTAK); T/E unlistd orl-gpg LD50: 177 mg/kg Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); F05-F12-P01 ihl-gpg LC50: 5655 ppm/4H Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); C06-J22 scu-frg LDLo: 9100 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 5, p. 161, 1899 (AIPTAK); T/E unlistd orl-mam LD50: 1670 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 39(4), p. 86, 1974 (GISAAA) MD: J16-L30-M03 ihl-rat TCLo: 655 ppm/7H/90D-I Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); F07-F19-Z01 ihl-rat TCLo: 800 ppm/6H/13W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0535664 (NTIS**); F07-J16-Z01 ihl-mus TCLo: 800 ppm/6H/13W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0535664 (NTIS**); U01 ihl-dog TCLo: 350 ppm/7H/91D-I Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7); A04-J06-P71 ihl-mky TCLo: 350 ppm/7H/91D-I Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 1, p. 634, 1959 (JOCMA7) TR: ACGIH TLV-TWA 20 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 60 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-TWA 40 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); TOXICOLOGY REVIEW Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 33, p. 463, 1991 (SAIGBL) SR: MSHA STANDARD-air: TWA 40 ppm (70 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 3, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 40 ppm (70 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 40 ppm (70 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 40 ppm (70 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 40 ppm (70 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 40 ppm (70 mg/m3), Skin, JAN 1993; OEL-AUSTRALIA: TWA 40 ppm (70 mg/m3), STEL 60 ppm , Skin, JAN 1993; OEL-AUSTRIA: MAK 40 ppm (70 mg/m3), JAN 1999; OEL-BELGIUM: TWA 40 ppm (67 mg/m3), STEL 60 ppm (101 mg/m3), Skin, JAN 1993; OEL-DENMARK: TWA 40 ppm (70 mg/m3), JAN 1999; OEL-FINLAND: TWA 40 ppm (70 mg/m3), STEL 60 ppm (105 mg/m3), JAN 1993; OEL-FRANCE: VME 40 ppm (70 mg/m3), Skin, JAN 1999; OEL-GERMANY: MAK 40 ppm (70 mg/m3), JAN 1999; OEL-HUNGARY: TWA 50 mg/m3, STEL 100 mg/m3, Skin, JAN 1993; OEL-THE NETHERLANDS: MAC-TGG 40 ppm (70 mg/m3), JAN 1999; OEL-NORWAY: TWA 30 ppm (50 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 40 ppm (70 mg/m3), JAN 1993; OEL-POLAND: TWA 70 mg/m3, STEL 140 mg/m3, JAN 1999; OEL-RUSSIA: STEL 10 mg/m3, JAN 1993; OEL-SWEDEN: TWA 30 ppm (50 mg/m3), STEL 50 ppm (100 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 500 ppm (1200 mg/m3), STEL 1000 ppm (2400 mg/m3), JAN 1999; OEL-TURKEY: TWA 40 ppm (70 mg/m3), JAN 1993; OEL-UNITED KINGDOM: TWA 40 ppm (68 mg/m3), STEL 60 ppm (102 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ACETONITRILE-air: 10H TWA 20 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 02900; NIS 9; TNF 302; NOS 25; TNE 28201; NOES 1983: HZD 02900; NIS 19; TNF 1172; NOS 27; TNE 31341; TFE 7975 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Acetonitrile, 1606; NTP Carcinogenesis studies (inhalation), equivocal evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-447, 1996 (NTPTR*); NTP Carcinogenesis studies (inhalation), no evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-447, 1996 (NTPTR*) Record 472 of 1119 in RTECS (through 2003/06) AN: AL8450000 PN: Acetonitrile,-dibromo- SY: Dibromoacetonitrile- RN: Current: 3252-43-5 BRN: 1739037 BHR: 4-02-00-00533 UD: 200302 MF: C2-H-Br2-N MW: 198.86 WL: NCYEE CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 16 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 7), p. 1, 1986 (ENMUDM); oms-esc 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 341, p. 289, 1995 (MUREAV); mnt-nml-mul 120 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 341, p. 289, 1995 (MUREAV); dnd-hmn-lym 5 umol/L National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. 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[245.000000 mg/kg] F07-F24-J25 AT: F07-F24-J25 orl-rat LD50: 245 mg/kg EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 69, p. 183, 1986 (EVHPAZ); F07-F24-J25 orl-mus LD50: 289 mg/kg EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 69, p. 183, 1986 (EVHPAZ); T/E unlistd ivn-mus LD50: 56 mg/kg U.S. Army Armament Research and Development Command, Chemical Systems Laboratory, NIOSH Exchange Chemicals. (Aberdeen Proving Ground, MD 21010) NX#05210 (CSLNX*) MD: L70-M70-U01 orl-rat TDLo: 630 mg/kg/14D-I EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 69, p. 183, 1986 (EVHPAZ); M70-P28-U01 orl-rat TDLo: 4050 mg/kg/90D-I EHP, Environmental Health Perspectives. 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(WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1369, 1999 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1369, 1999 (IMEMDT) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 473 of 1119 in RTECS (through 2003/06) AN: AM4375000 PN: p-Acetophenetidide- SY: Acetamide, N-(4-ethoxyphenyl)- (9CI); 1-Acetamido-4-ethoxybenzene-; Acetanilide,-4'-ethoxy-; Aceto-para-phenalide-; p-Acetophenetide-; Aceto-para-phenetidide-; para-Acetophenetidide-; Acetophenetidine-; Aceto-4-phenetidine-; Acetophenetin-; Acetphenetidin-; p-Acetphenetidin-; Acet-p-phenetidin-; Achrocidin-; Bromo-seltzer-; Buff-A-Comp-; Citra-fort-; Clistanol-; Codempiral-; Commotional-; Contradol-; Contradouleur-; Coricidin-; Coriforte-; Coryban-D-; Daprisal-; Darvon-compound-; Dasikon-; Dasin-; Dasin-CH-; Dolostop-; Edrisal-; Empiral-; Emprazil-; Emprazil-C-; Epragen-; p-Ethoxyacetanilide-; 4-Ethoxyacetanilide-; 4'-Ethoxyacetanilide-; p-Ethoxyanilid-kyseliny-octove- (Czech); N-para-Ethoxyphenylacetamide-; N-(4-Ethoxyphenyl)acetamide; Fenacetin- (Czech); Fenacetina-; Fenidina-; Fenia-; Fenina-; Fiorinal-; Fortacyl-; Gelonida-; Gewodin-; Helvagit-; Hjorton's-powder-; Hocophen-; KAFA-; Kalmin-; Malex-; Melabon-; Melaforte-; Pamprin-; Paracetophenetidin-; Paramette-; Paratodol-; Pertonal-; Phenacetin-; para-Phenacetin-; Phenacetine-; Phenacetinum-; Phenacitin-; Phenaphen-; Phenaphen-plus-; Phenazetin-; Phenazetina-; Phenedina-; p-Phenetidine,-N-acetyl-; Pyraphen-; Pyrroxate-; Quadronal-; RCRA-waste-number-U187-; Robaxisal-PH-; Salgydal-; Sanalgine-; Saridon-; Seranex-; Sinedal-; Sinubid-; Sinutab-; Stellacyl-; Super-anahist-; Synalgos-DC-; Synalogos-; Tacol-; Tetracydin-; Thephorin-A-C-; Treupel-; Veganine-; Viden-; Wigraine-; Xaril-; Acetophenetidin-; p-Acetophenetidine-; Acet-p-phenalide-; Acetylphenetidin-; N-Acetyl-p-phenetidine-; Anapac-; Norgesic-; Phenidin-; Phenin-; Phenodyne- RN: Current: 62-44-2 BRN: 1869238 BHR: 4-13-00-01092 UD: 200210 MF: C10-H13-N-O2 MW: 179.24 WL: 2OR DMV1 CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: mmo-sat 333 ug/plate (-S9) IARC Publications. 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(Raven Press, 1185 Ave. of the Americas, New York, NY 10036) V.1- 1979- v. 6, p. 139, 1984 (ADIRDF); V03-D45-R60 orl-rat TD :206 gm/kg/2Y-C Acta Pathologica et Microbiologica Scandinavica, Section A: Pathology. (Copenhagen, Denmark) V.78-89, 1970-81. For publisher information, see ACPADQ. v. 84, p. 375, 1976 (AMBPBZ); V01-M60 orl-hmn TD :28 gm/kg/28Y-I Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 20, p. 192, 1979 (ENVRAL); V01-M60 orl-man TD :126 gm/kg/25Y-I Annals of Internal Medicine. (American College of Physicians, 4200 Pine St., Philadelphia, PA 19104) V.1- 1927- v. 93, p. 249, 1980 (AIMEAS); V01-M61 orl-wmn TD :140 gm/kg/13Y-I British Journal of Urology. (Longman Group Ltd., POB 11318, Birmingham, AL 35202) V.1- 1929- v. 51, p. 188, 1979 (BJURAN) ORNG: 1650000000 ng/kg. [1650.000000 mg/kg] F07-G08-U28 AT: T/E unlistd unr-man LDLo: 74 mg/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); F07-G08-U28 orl-rat LD50: 1650 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 1, p. 240, 1959 (TXAPA9); T/E unlistd ipr-rat LD50: 634 mg/kg Nippon Yakurigaku Zasshi. Japanese Journal of Pharmacology. (Nippon Yakuri Gakkai, c/o Kyoto Daigaku Igakubu Yakurigaku Kyoshitsu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.40- 1944- v. 62, p. 11, 1966 (NYKZAU); T/E unlistd orl-mus LD50: 866 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 28, p. 1644, 1978 (ARZNAD); T/E unlistd ihl-mus LC50: 33900 mg/m3 Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 34(10), p. 36, 1969 (GISAAA); T/E unlistd ipr-mus LD50: 540 mg/kg Yakugaku Zasshi. Journal of Pharmacy. (Nippon Yakugakkai, 2-12-15 Shibuya, Shibuya-ku, Tokyo 150, Japan) No.1- 1881- v. 81, p. 659, 1961 (YKKZAJ); T/E unlistd scu-mus LD50: 1625 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 8, p. 25, 1958 (ARZNAD); T/E unlistd ivn-dog LDLo: 260 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB282-666 (NTIS**); T/E unlistd orl-rbt LD50: 2500 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 21(9), p. 53, 1977 (GTPZAB); F12 scu-rbt LD50: 1 gm/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 21, p. 719, 1971 (ARZNAD); J25 orl-gpg LD50: 1870 mg/kg Toxicology and Applied Pharmacology. 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(Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 26, p. 105, 1968 (APTOA6); L70-M03-N74 orl-mus TDLo: 704 gm/kg/67W-C Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 50, p. 82, 1999 (TOSCF2); P08-P71-Z01 orl-cat TDLo: 5625 mg/kg/9W-I Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 15, p. 727, 1965 (ARZNAD) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 310, 1987 (IMSUDL); IARC Cancer Review: Human Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 24, p. 135, 1980 (IMEMDT); IARC Cancer Review: Group 2A IARC Monographs, Supplement. 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Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 24, p. 253, 1983 (BLFSBY) SR: OEL-RUSSIA: STEL 0.5 mg/m3, JAN 1993 ND: NOHS 1974: HZD 80478; NIS 2; TNF 126; NOS 10; TNE 4186; NOES 1983: HZD X4389; NIS 1; TNF 9; NOS 2; TNE 869; TFE 617; NOES 1983: HZD 80478; NIS 4; TNF 1271; NOS 12; TNE 18808; TFE 15338 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 474 of 1119 in RTECS (through 2003/06) AN: AM6300000 PN: Acetophenone,-2-chloro- SY: 1-Chloroacetophenone-; 2-Chloro-1-phenylethanone-; 2-Chloroacetophenone-; CN-; Chemical-mace-; Chloromethyl-phenyl-ketone-; Ethanone,-2-chloro-1-phenyl-; Mace- (lacrimator); NCI-C55107-; Phenacyl-chloride-; Phenylchloromethylketone-; alpha-Chloroacetophenone-; alpha-Chloroacetophenone- (ACGIH:OSHA); omega-Chloroacetophenone- RN: Current: 532-27-4 BRN: 507950 BHR: 4-07-00-00641 UD: 200210 MF: C8-H7-Cl-O MW: 154.60 WL: G1VR CC: Tumorigen (C); Mutagen (M); Human-Data (P); Primary-Irritant (S) ID: skn-rat 12%/6H open MOD Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); skn-rbt 5 mg/24H MLD Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 17, p. 295, 1970 (TXAPA9); skn-rbt 12%/6H open MOD Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); eye-rbt 1 mg MLD Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 17, p. 295, 1970 (TXAPA9); eye-rbt 3 mg SEV Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 17, p. 295, 1970 (TXAPA9); skn-gpg 12%/6H open MOD Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); skn-hmn 0.5 mg/1H MOD Contact Dermatitis. Environmental and Occupational Dermatitis. (Munksgaard International Pub., c/o Publications Expediting Inc., 200 Meacham Ave., Elmont, NY 11003) V.1- 1975- v. 86, p. 150, 1972 (CODEDG); eye-rbt 2% rinse MLD Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 34, p. 183, 1975 (ARTODN); eye-rbt 1% "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 463, 1994 (VCVGK*) ME: dnd-rat-lvr 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 59, 1996 (MUREAV); cyt-ham-ovr 3 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-379, 1990 (NTPTR*) TE: V03-N60-R60 ihl-rat TCLo: 2 mg/m3/6H/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-379, 1990 (NTPTR*); V02-R60-V10 skn-mus TDLo: 2400 mg/kg/27W-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 7, p. 482, 1953 (BJCAAI) ORNG: 50000000 ng/kg. [50.000000 mg/kg] T/E unlistd AT: T/E unlistd ihl-hmn LCLo: 159 mg/m3/20M "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,163,1969 (34ZIAG); D17-D25-J22 ihl-hmn TCLo: 93 mg/m3/3M American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 23, p. 199, 1962 (AIHAAP); D35-J21-J22 ihl-hmn TCLo: 20 mg/m3 British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 29, p. 298, 1972 (BJIMAG); T/E unlistd orl-rat LD50: 50 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 17, p. 295, 1970 (TXAPA9); D07-J15-P01 ihl-rat LCLo: 417 mg/m3/15M Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); F24-J30-R21 ipr-rat LD50: 36 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); F12-J26-M30 ivn-rat LD50: 41 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); T/E unlistd orl-mus LD50: 139 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD837-111 (NTIS**); T/E unlistd ihl-mus LC50: 59 mg/m3 Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 58(10), p. 4, 1993 (GISAAA); T/E unlistd ipr-mus LD50: 60 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD837-111 (NTIS**); F12-J26-M30 ivn-mus LD50: 81 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); F24-J30-R21 orl-rbt LD50: 118 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); D07-J15-P01 ihl-rbt LCLo: 465 mg/m3/20M Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); F12-J26-M30 ivn-rbt LD50: 30 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); F24-J30-R21 orl-gpg LD50: 158 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); D07-J15-P01 ihl-gpg LCLo: 490 mg/m3/30M Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN); T/E unlistd skn-gpg LD50: >1 gm/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0556684 (NTIS**); F24-J30-R21 ipr-gpg LD50: 17 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 40, p. 75, 1978 (ARTODN) MD: Z01 ihl-rat TCLo: 19 mg/m3/6H/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-379, 1990 (NTPTR*); Z01 ihl-mus TCLo: 10 mg/m3/6H/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-379, 1990 (NTPTR*); U01-J30-N24 ihl-mus TCLo: 87.6 mg/m3/15M/5D-I Journal of Applied Toxicology (John Wiley and Sons, Ltd., Oldlands Way Bognor Regis West Sussex, PO22 9SA England) V.1- 1981- v. 14, p. 411, 1994 (JAPTO*) TR: ACGIH TLV-TWA 0.05 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.05 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: MSHA STANDARD-air: TWA 0.05 ppm (0.3 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 48, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 0.05 ppm (0.3 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.05 ppm (0.3 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.05 ppm (0.3 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.05 ppm (0.3 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 0.05 ppm (0.3 mg/m3), JAN 1993; OEL-AUSTRIA: MAK 0.05 ppm (0.3 mg/m3), JAN 1999; OEL-BELGIUM: TWA 0.05 ppm (0.32 mg/m3), JAN 1993; OEL-DENMARK: TWA 0.05 ppm (0.3 mg/m3), JAN 1999; OEL-FINLAND: STEL 0.05 ppm (0.3 mg/m3), Skin, JAN 1993; OEL-FRANCE: VME 0.05 ppm (0.4 mg/m3), JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.05 ppm (0.3 mg/m3), JAN 1999; OEL-NORWAY: TWA 0.05 ppm (0.3 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 0.05 ppm (0.3 mg/m3), JAN 1993; OEL-SWITZERLAND: MAK-W 0.05 ppm (0.3 mg/m3), JAN 1999; OEL-UNITED KINGDOM, TWA 0.05 ppm (0.32 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO alpha-CHLOROACETOPHENONE-air: 10H TWA 0.05 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD X4754; NIS 1; TNF 35; NOS 4; TNE 2294; TFE 1412 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (inhal), equivocal evidence: rat; NCI Carcinogenesis Studies (inhal), no evidence: mouse Record 475 of 1119 in RTECS (through 2003/06) AN: AN2900000 PN: o-Acetotoluidide- SY: Acetamide, N-(2-methylphenyl)- (9CI); o-Methylacetanilide-; 2-Methylacetanilide-; 2'-Methylacetanilide-; N-(2-Methylphenyl)acetamide; Acetyl-o-toluidine- RN: Current: 120-66-1 UD: 199701 MF: C9-H11-N-O MW: 149.21 WL: 1VMR B1 CC: Mutagen (M) ME: mmo-sat 1 mg/plate (+S9) NTP Technical Bulletin. (National Toxicology Program, Landow Bldg. 3A-06, 7910 Woodmont Ave., Bethesda, MD 20205) JAN1982 (NTPTB*); mmo-sat 47 nmol/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 137, p. 39, 1984 (MUREAV) AT: T/E unlistd ipr-rat LD :>500 mg/kg National Academy of Sciences, National Research Council, Chemical-Biological Coordination Center, Review. (Washington, DC) v. 5, p. 9, 1953 (NCNSA6); T/E unlistd orl-mus LD50: 1450 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 19, p. 20, 1971 (TXAPA9) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY Record 476 of 1119 in RTECS (through 2003/06) AN: AS1050000 PN: Acrolein- SY: Acraldehyde-; Acraldehydeacroleina- (Italian); Acroleina- (Italian); Acrolein- (ACGIH:OSHA); Acroleine- (Dutch, French); Acrylaldehyde-; Acrylic-aldehyde-; Aqualin-; Aqualine-; Crolean-; Ethylene-aldehyde-; Magnacide-B-; Magnacide-H-; RCRA-waste-number-P003-; Slimicide-; trans-Acrolein-; Acrylaldehyd- (German); Akrolein- (Czech); Akroleina- (Polish); Aldehyde-acrylique- (French); Aldeide-acrilica- (Italian); Allyl-aldehyde-; Biocide-; Magnacide-; NSC-8819-; Prop-2-en-1-al-; 2-Propenal- RN: Current: 107-02-8 Previous: 25314-61-8 UD: 200302 MF: C3-H4-O MW: 56.07 WL: VH1U1 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: eye-hmn 500 ppb/12M International Journal of Air and Water Pollution. (London, UK) V.4(1-4), 1961. For publisher information, see ATENBP. v. 4, p. 79, 1961 (IAPWAR); skn-rbt 5 mg open SEV Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 6/18/1971 (UCDS**); skn-rbt 2 mg/24H SEV "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,268,1986 (85JCAE); eye-rbt 1 mg SEV Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 6/18/1971 (UCDS**); eye-rbt 50 ug/24H SEV "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,268,1986 (85JCAE); skn-hmn 1% "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 386, 1994 (VCVGK*) ME: mmo-sat 50 ug/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mmo-sat 50 ug/plate (-S9) NTP Technical Bulletin. (National Toxicology Program, Landow Bldg. 3A-06, 7910 Woodmont Ave., Bethesda, MD 20205) JAN1982 (NTPTB*); dna-esc 286 nmol/L Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 46, p. 277, 1980 (ARTODN); slt-dmg-orl 5 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 247, 1991 (MUREAV); sln-dmg-par 3 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 247, 1991 (MUREAV); dnd-hmn-oth 30 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 48, p. 1717, 1988 (CNREA8); dna-hmn-fbr 100 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 12, p. 1483, 1991 (CRNGDP); sce-hmn-lym 5 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 46, p. 203, 1986 (CNREA8); msc-hmn-fbr 200 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 209, p. 17, 1988 (MUREAV); dnd-rat-oth 30 mmol/L Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 58, p. 67, 1985 (ARTODN); dni-rat-ipr 500 ug/kg Biochimie. (SPPIF, B.P.22, F-41353 Vineuil, France) V.53- 1971- v. 53, p. 243, 1971 (BICMBE); oms-rat-ipr 500 ug/kg Biochimie. (SPPIF, B.P.22, F-41353 Vineuil, France) V.53- 1971- v. 53, p. 243, 1971 (BICMBE); sce-ham-ovr 10 umol/L Cytogenetics and Cell Genetics. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.12- 1973- v. 26, p. 108, 1980 (CGCGBR); msc-ham-lng 500 nmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 11, p. 497, 1990 (CRNGDP); dna-mam-lym 58 gm/L/3H Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 990, 1984 (CNREA8); dni-mam-lym 80 umol/L FEBS Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1968- v. 30, p. 286, 1973 (FEBLAL); mmo-esc 320 nmol/plate Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 516, p. 81, 2002 (MUREAV); sce-ham-unr 1.5 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*) RE: T81 orl-rat TDLo: 840 mg/kg (multigeneration) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 19, p. 228, 1992 (FAATDF); T25 ivn-rbt TDLo: 6 mg/kg (9D preg) Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 30, p. 2080, 1980 (ARZNAD) ORNG: 26000000 ng/kg. [26.000000 mg/kg] T/E unlistd SRNG: 200000000 ng/kg. [200.000000 mg/kg] T/E unlistd IHNG: 18000000 ng/m3/4H. [18.000000 mg/m3/4H] T/E unlistd IHPB: 8000 ppb/4H. [8.000000 ppm/4H] A30-C08-J25 AT: D17 ihl-man TCLo: 1 ppm British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 2, p. 913, 1956 (BMJOAE); T/E unlistd ihl-hmn LCLo: 5500 ppb "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,73,1969 (34ZIAG); T/E unlistd ihl-hmn LCLo: 153 ppm/10M National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB214-270 (NTIS**); J02-J20-J30 ihl-chd TCLo: 300 ppb/2H Nouvelle Presse Medicale. (Paris, France) V.1-11, 1972-82. v. 8, p. 2469, 1979 (NPMDAD); T/E unlistd orl-rat LD50: 26 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 58(10), p. 4, 1993 (GISAAA); T/E unlistd ihl-rat LC50: 18 mg/m3/4H Current Toxicology. (Nova Science Publishers, Inc., 6080 Jericho Turnpike, Suite 207, Commack, NY 11725) V.1 1993- v. 1, p. 47, 1993 (CUTOEX); T/E unlistd ipr-rat LD50: 4 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 71, p. 84, 1983 (TXAPA9); F01-L03 scu-rat LD50: 50 mg/kg Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 6, p. 299, 1950 (APTOA6); F07-R21-U01 orl-mus LD50: 13900 ug/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0533812 (NTIS**); T/E unlistd ihl-mus LC50: 66 ppm/6H Internationales Archiv fuer Arbeitsmedizin. (Berlin, Ger.) V.26-34, 1970-75. For publisher information, see IAEHDW. v. 26, p. 281, 1970 (IAANBS); T/E unlistd ipr-mus LD50: 9008 ug/kg National Cancer Institute Screening Program Data Summary, Developmental Therapeutics Program. (Bethesda, MD 20205) JAN1986 (NCISP*); F01-L03 scu-mus LD50: 30 mg/kg Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 6, p. 299, 1950 (APTOA6); T/E unlistd ihl-cat LCLo: 1570 mg/m3/2H Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 6, p. 299, 1950 (APTOA6); P30 ivn-cat LDLo: 15 mg/kg Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 8, p. 275, 1952 (APTOA6); T/E unlistd orl-rbt LD50: 7 mg/kg Pesticide Chemicals Official Compendium, Association of the American Pesticide Control Officials, Inc., 1966. (Topeka, KS) v. -, p. 1, 1966 (PCOC**); J02-J06-J15 ihl-rbt LCLo: 24 mg/m3/6H British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 2, p. 913, 1956 (BMJOAE); T/E unlistd skn-rbt LD50: 200 mg/kg Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 6/18/1971 (UCDS**); J22 scu-rbt LDLo: 250 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 43, p. 351, 1900 (AEXPBL); J02-J06-J15 ihl-gpg LCLo: 24 mg/m3/6H British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 2, p. 913, 1956 (BMJOAE); F12-G30-J22 scu-gpg LDLo: 178 ug/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 43, p. 351, 1900 (AEXPBL); D17-J15-K01 ihl-ham LCLo: 1000 ppm/10M Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 19, p. 367, 1977 (SAIGBL); T/E unlistd orl-mam LDLo: 10 mg/kg American Journal of Hygiene. (Baltimore, MD) V.1-80, 1921-64. For publisher information, see AJEPAS. v. 29, p. 32, 1939 (AJHYA2); T/E unlistd unr-mam LD50: 45 mg/kg "Chemistry of Pesticides," Melnikov, N.N., New York, Springer-Verlag New York, Inc., 1971 -,111,1971 (30ZDA9); A30-C08-J25 ihl-mus LC50: 875 ppm/1M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); A30-C08-J25 ihl-mus LC50: 175 ppm/10M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); A30-C08-J25 ihl-mus LC50: 152 mg/m3/6H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); A30-C08-J25 ihl-rat LC50: 131 ppm/30M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); A30-C08-J25 ihl-rat LC50: 8 ppm/4H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); T/E unlistd ihl-ham LC50: 25.4 ppm/4H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); A30-C08-J25 ihl-gpg LC50: 10.5 ppm/6H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); T/E unlistd ihl-rbt LC50: 10.5 ppm/6H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); T/E unlistd ihl-mus LCLo: 200 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); J30 ihl-mus LCLo: 650 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); J25 ihl-mus TCLo: 1.7 ppm/10M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); J25 ihl-rat TCLo: 23 ppm "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); T/E unlistd orl-mus LD50: 28 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); T/E unlistd scu-rbt LD50: 164 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); H30 ihl-rat TCLo: 2.5 ppm/4H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); D17-F01-K01 ihl-cat TCLo: 250 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); J30 ihl-cat TCLo: 200 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); J15-L50-M30 ihl-cat LCLo: 1500 mg/m3/2H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); F13-H08 scu-mus LDLo: 400 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 383, 1984 (VCVGK*); K30-P70 ivn-rat TDLo: 3 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); H02 ivn-rat TDLo: 0.5 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); H01 ivn-rat TDLo: 0.05 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); T/E unlistd ihl-hmn LCLo: 350 mg/m3/10M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); T/E unlistd orl-hmn LDLo: 140 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); D17-J25 ihl-hmn TCLo: 7 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); D25-J21 ihl-hmn TCLo: 2 mg/m3/2M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); D25-J21 ihl-hmn TCLo: 0.6 mg/m3/5M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); J22 ihl-hmn TCLo: 0.8 ppm "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); J21 ihl-hmn TCLo: 0.3 ppm "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*); D25 ihl-hmn TCLo: 0.14 ppm/2M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1984 (VCVGK*) MD: L30-Y11-Y21 orl-rat TDLo: 113 mg/kg/45D-I Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 35, p. 1373, 1997 (IJEBA6); J30-U01-Z01 ihl-rat TCLo: 4 ppm/6H/62D-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 34, p. 139, 1985 (TXCYAC); D07-N72-Z01 ihl-rat TCLo: 4900 ppb/6H/13W-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 9, p. 47, 1978 (TXCYAC); M16-P72-U01 ihl-rat TCLo: 510 ug/m3/24H/9W-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 31(1), p. 9, 1966 (GISAAA); D07-N73 ihl-rat TCLo: 3 ppm/6H/3W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 39, p. 189, 1987 (TOLED5); J02 ihl-dog TCLo: 3700 ppb/8H/6W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 17, p. 726, 1970 (TXAPA9); J02-Z01 ihl-mky TCLo: 3700 ppb/8H/6W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 17, p. 726, 1970 (TXAPA9); D07-J30-J70 ihl-rbt TCLo: 4900 ppb/6H/13W-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 9, p. 47, 1978 (TXCYAC); D07-J30-J70 ihl-ham TCLo: 4900 ppb/6H/13W-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 9, p. 47, 1978 (TXCYAC); A70-J70-L70 ihl-ham TCLo: 4 ppm/7H/52W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 3, p. 379, 1977 (JTEHD6); J16-U01 ihl-mus TCLo: 6 ppm/6H/2W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1994 (VCVGK*); Z01 ihl-mus TCLo: 25 ppm/6H/2W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1994 (VCVGK*); J30 ihl-rat TCLo: 1.52 ppm/61D-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1994 (VCVGK*); J02 ihl-rat TCLo: 0.51 ppm/61D-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1994 (VCVGK*); J21-S05 ihl-rat TCLo: 0.55 ppm/10D-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 384, 1994 (VCVGK*); Z01 ihl-rat TCLo: 4 ppm/6H/62D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); J02-J30 ihl-rat TCLo: 1.4 ppm/6H/62D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); U01-Z01 ihl-rat TCLo: 1.52 mg/m3/60D-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); F40-Y01-Y36 ihl-rat TCLo: 0.51 mg/m3/60D-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); P72 ihl-rat TCLo: 0.15 mg/m3/60D-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); P70-P71 ihl-ham TCLo: 4.9 ppm/13W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); J02 itr-ckn TDLo: 200 ppm/5M/3D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*); L14-M30 orl-rat TDLo: 91 mg/kg/26W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 385, 1994 (VCVGK*) TR: ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-CL 0.1 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 19, p. 479, 1979 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. 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(U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 0.1 ppm (0.25 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 5, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 0.1 ppm (0.25 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.1 ppm (0.25 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.1 ppm (0.25 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.1 ppm (0.25 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 0.1 ppm (0.25 mg/m3), JAN 1993; OEL-AUSTRALIA: TWA 0.1 ppm (0.25 mg/m3), STEL 0.3 ppm, JAN 1993; OEL-AUSTRIA: MAK 0.1 ppm (0.25 mg/m3), JAN 1999; OEL-BELGIUM: TWA 0.1 ppm (0.23 mg/m3), STEL 0.3 ppm, JAN 1993; OEL-FINLAND: STEL 0.1 ppm (0.25 mg/m3), Skin, JAN 1993; OEL-FRANCE: VLE 0.1 ppm (0.25 mg/m3), JAN 1999; OEL-GERMANY: MAK 0.1 ppm (0.25 mg/m3), JAN 1999; OEL-HUNGARY: TWA 0.25 mg/m3, STEL 0.5 mg/m3, JAN 1993; OEL-INDIA: TWA 0.1 ppm (0.25 mg/m3), STEL 0.3 ppm (0.8 mg/m3), JAN 1993; OEL-JAPAN: OEL 0.1 ppm (0.23 mg/m3), JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.1 ppm (0.25 mg/m3), JAN 1999; OEL-NORWAY: TWA 0.1 ppm (0.25 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 0.1 ppm (0.25 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 0.2 mg/m3, MAC(STEL) 0.5 mg/m3, JAN 1999; OEL-RUSSIA: TWA 0.1 ppm, STEL 0.2 mg/m3, JAN 1993; OEL-SWEDEN: NGV 0.1 ppm (0.2 mg/m3), KTV 0.3 ppm (0.7 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 0.1 ppm (0.25 mg/m3), KZG-W 0.2 ppm (0.5 mg/m3), JAN 1999; OEL-TURKEY: TWA 0.1 ppm (0.25 mg/m3), JAN 1993; OEL-UNITED KINGDOM: TWA 0.23 mg/m3, STEL 0.70 mg.m3, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ACROLEIN-air: 10H TWA 0.1 ppm, STEL 0.3 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 03530; NIS 16; TNF 845; NOS 25; TNE 7299; NOES 1983: HZD 03530; NIS 4; TNF 37; NOS 18; TNE 1298; TFE 5 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/91/180307/AS); EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH CURRENT INTELLIGENCE BULLETIN #55, September 1991; NIOSH Analytical Method, 1994: Acrolein, 2501; NIOSH Analytical Method, 1994: Aldehydes, screening, 2539; NTP Carcinogenesis studies, test completed (peer review), October 2000; OSHA ANALYTICAL METHOD #52 Record 477 of 1119 in RTECS (through 2003/06) AN: AS3325000 PN: Acrylamide- SY: 2-Propenamide-; 2-Propenamide- (9CI); Acrylamide- (ACGIH:OSHA); Acrylamide-monomer-; Acrylic-acid-; Acrylic-amide-; Akrylamid- (Czech); Amid-kyseliny-akrylove- (Czech); Ethylenecarboxamide-; Propenamide-; Propenoic-acid-amide-; RCRA-waste-number-U007-; Vinyl-amide- RN: Current: 79-06-1 BRN: 605349 BHR: 4-02-00-01471 UD: 200305 MF: C3-H5-N-O MW: 71.09 WL: ZV1U1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Primary-Irritant (S) ID: skn-rbt 50 mg/3D MLD Toxicology and Applied Pharmacology. 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(Intox Press, Inc., POB 34075, Little Rock, AR 72203) V.1- 1979- v. 13, p. 219, 1992 (NRTXDN); T34-T85 ipr-rat TDLo: 400 mg/kg (8D male) Neurotoxicology. (Intox Press, Inc., POB 34075, Little Rock, AR 72203) V.1- 1979- v. 13, p. 219, 1992 (NRTXDN); T02 orl-mus TDLo: 571 mg/kg (16D male) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 47, p. 179, 1981 (ARTODN); T01-T23-T25 orl-mus TDLo: 95 gm/kg (4W male) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 59, p. 201, 1986 (ARTODN); T25 orl-mus TDLo: 95 gm/kg (4W pre) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 59, p. 201, 1986 (ARTODN); T26 orl-mus TDLo: 71 gm/kg (4W male) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 59, p. 201, 1986 (ARTODN); T34-T46 ipr-mus TDLo: 225 mg/kg (10-12D preg) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 226, p. 157, 1989 (MUREAV); T34 ipr-mus TDLo: 125 mg/kg (1D preg) Congenital Anomalies. (Nippon Senten Ijo Gakkai, 377-2 Ono-higashi, Osakasayama, Osaka-Fu 589 Japan) V.27- 1987- v. 34, p. 35, 1994 (CGANE7); T23-T24-T25 ipr-mus TDLo: 250 mg/kg (5D male) Congenital Anomalies. (Nippon Senten Ijo Gakkai, 377-2 Ono-higashi, Osakasayama, Osaka-Fu 589 Japan) V.27- 1987- v. 34, p. 35, 1994 (CGANE7); T34 ipr-mus TDLo: 300 mg/kg (8-10D preg) Congenital Anomalies. (Nippon Senten Ijo Gakkai, 377-2 Ono-higashi, Osakasayama, Osaka-Fu 589 Japan) V.27- 1987- v. 34, p. 35, 1994 (CGANE7); T46 ipr-mam TDLo: 75 mg/kg (12D preg) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 226, p. 157, 1989 (MUREAV); T25-T34-T35 ipr-mam TDLo: 225 mg/kg (10-12D preg) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 226, p. 157, 1989 (MUREAV); T25 orl-mus TDLo: 840 mg/kg (20W male) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 11, 1991 (EMMUEG); T34 ihl-rat TCLo: 300 ppm/6H (6-20D preg) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 48, p. 240, 1999 (TOSCF2); T24-T25-T35 orl-rat TDLo: 225 mg/kg (5D male) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 147, 2000 (REPTED); T24-T25-T72 orl-rat TDLo: 945 mg/kg (70D male/70D pre-4W post) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); T75-T81-T85 orl-rat TDLo: 945 mg/kg (70D male/70D pre-4W post) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); T81-T91 orl-rat TDLo: 378 mg/kg (70D male/70D pre-4W post) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); T24-T25-T72 orl-rat TDLo: 945 mg/kg (multigeneration)) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); T85-T91 orl-rat TDLo: 945 mg/kg (multigeneration)) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); T24 orl-rat TDLo: 35 mg/kg (70D male/70D pre) Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); T26 orl-mus TDLo: 3462.48 mg/kg (189D male/189D pre) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB93-158285 (NTIS**); T25-T26 orl-mus TDLo: 1282.4 mg/kg (140D male) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB93-158285 (NTIS**); T46 orl-mus TDLo: 2.39 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB93-158285 (NTIS**) TE: V01-T61 orl-rat TDLo: 1456 mg/kg/2Y-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 85, p. 154, 1986 (TXAPA9); V02-J60 ipr-mus TDLo: 24 mg/kg/8W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 107, 1984 (CNREA8); V01-J60-R60 orl-mus TDLo: 300 mg/kg/2W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 24, p. 209, 1984 (CALEDQ); V02-J60 ipr-mus TD :72 mg/kg/8W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 107, 1984 (CNREA8); V01-T64 orl-rat TD :1456 mg/kg/2Y-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 85, p. 154, 1986 (TXAPA9); V01-A60-R60 orl-rat TD :1460 mg/kg/2Y-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555720 (NTIS**) ORNG: 124000000 ng/kg. [124.000000 mg/kg] T/E unlistd SRNL: 1680000 nL/kg. [1.680000 mL/kg] F08 SKNG: 400000000 ng/kg. [400.000000 mg/kg] P30-Y15-Y17 AT: T/E unlistd orl-rat LD50: 124 mg/kg Archives des Maladies Professionnelles de Medecine du Travail et de Securite Sociale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.7- 1946- v. 36, p. 58, 1975 (AMPMAR); P30-Y15-Y17 skn-rat LD50: 400 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 44(10), p. 73, 1979 (GISAAA); T/E unlistd ipr-rat LD50: 90 mg/kg Archives des Maladies Professionnelles de Medecine du Travail et de Securite Sociale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.7- 1946- v. 36, p. 58, 1975 (AMPMAR); F11-F12-F17 unr-rat LD50: 208 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 43(9), p. 38, 1978 (GISAAA); T/E unlistd orl-mus LD50: 107 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 47, p. 179, 1981 (ARTODN); T/E unlistd ipr-mus LD50: 170 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 33, p. 142, 1975 (TXAPA9); F11-F12-F17 unr-mus LD50: 156 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 43(9), p. 38, 1978 (GISAAA); T/E unlistd orl-rbt LD50: 150 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 172, 1964 (TXAPA9); F08 skn-rbt LD50: 1680 uL/kg Acute Toxicity Data. Journal of the American College of Toxicology, Part B. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1- 1990- v. 1, p. 115, 1990 (ATDAEI); F11-F12-F17 unr-rbt LD50: 280 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 43(9), p. 38, 1978 (GISAAA); T/E unlistd orl-gpg LD50: 150 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 172, 1964 (TXAPA9); F11-F23-K13 scu-gpg LD50: 170 mg/kg Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 47, p. 192, 1956 (MELAAD); F11-F12-F17 unr-gpg LD50: 173 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 43(9), p. 38, 1978 (GISAAA); C08-F05-F17 orl-qal LD50: 186 mg/kg Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 7, p. 935, 1981 (JTEHD6); T/E unlistd orl-mam LD50: 100 mg/kg Kagaku to Seibutsu. Chemistry and Biology. (Gakkai Shuppan Senta, 6-2-10 Hongo, Bunkyo-ku, Tokyo 113, Japan) V.1- 1962- v. 17, p. 495, 1979 (KASEAA); T/E unlistd ivn-mam LDLo: 190 mg/kg Comptes Rendus Hebdomadaires des Seances, Academie des Sciences. (Paris, France) V.1-261, 1835-1965. For publisher information, see CRASEV. v. 153, p. 895, 1911 (COREAF) MD: F18-F19-U01 orl-rat TDLo: 1035 mg/kg/15W-I Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 5, p. 91, 1983 (NTOTDY); B30-U01 orl-rat TDLo: 608 mg/kg/16D-C Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 3, p. 487, 1981 (NTOTDY); C18-F16-U01 orl-rat TDLo: 1800 mg/kg/90D-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 4(5/6), p. 157, 1980 (JEPTDQ); F17-F19 orl-rat TDLo: 600 mg/kg/6W-C Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 4, p. 355, 1982 (NTOTDY); A70-G70-P08 orl-rat TDLo: 286 mg/kg/28D-C Water Research. (Pergamon Press Ltd., Headington Hill Hall, Oxford OX3 0BW, UK) V.1- 1967- v. 24, p. 661, 1990 (WATRAG); A30-B30-Y20 ipr-rat TDLo: 108 mg/kg/3W-I Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 14, p. 273, 1992 (NETEEC); F18 ipr-rat TDLo: 168 mg/kg/2W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 40, p. 589, 1977 (TXAPA9); B04-C18-F19 ipr-rat TDLo: 780 mg/kg/13W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 18, p. 343, 1992 (FAATDF); A30-B30-Y16 ipr-rat TDLo: 400 mg/kg/8D-I Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 61, p. 37, 1993 (ENVRAL); C04-C16-U01 scu-rat TDLo: 1155 mg/kg/13W-I Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 63, p. 229, 1993 (ENVRAL); C06-C18 scu-rat TDLo: 1 gm/kg/8W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 139, p. 15, 1996 (TXAPA9); F18-F19-U01 scu-rat TDLo: 400 mg/kg/10D-I Journal of Occupational Health. (Japan Society for Occupational Health, 1-29-8 Shinjuku, Shinjuku-ku, Tokyo, 160, Japan) V.38- 1996- v. 41, p. 181, 1999 (JOCHFV); A30-Y03-Y21 ipr-rat TDLo: 120 mg/kg/12D-I Weisheng Dulixue Zazhi. Journal of Health Toxicology. (Weisheng Dulixue Zazhi Bianjibu, Dongdaqiao, Chaoyang Menwai, Beijing, Peop. Rep. China) V.1- 1987 v. 6, p. 71, 1992 (WDZAEK); Z73 orl-mus TDLo: 568 mg/kg/8W-I Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 47, p. 179, 1981 (ARTODN); F18-Z01 ipr-mus TDLo: 1200 mg/kg/4W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 63, p. 470, 1982 (TXAPA9); A30-F17-Y21 ipr-mus TDLo: 400 mg/kg/8D-I Nippon Eiseigaku Zasshi. Japanese Journal of Hygiene. (Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 50, p. 292, 1995 (NEZAAQ); C16-F18-F19 orl-dog TDLo: 330 mg/kg/22D-I Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 23, p. 1566, 1973 (ARZNAD); F18-F19-K13 orl-dog TDLo: 392 mg/kg/8W-I Journal of Neurology, Neurosurgery and Psychiatry. (British Medical Journal, POB 560B, Kennebunkport, ME 04046) V.7- 1944- v. 44, p. 906, 1981 (JNNPAU); E08-F17-Z01 orl-mky TDLo: 671 mg/kg/75W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 172, 1964 (TXAPA9); C04 orl-mky TDLo: 450 mg/kg/61D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 71, p. 266, 1983 (TXAPA9); J16-L03-Z01 ipr-mky TDLo: 200 mg/kg/2D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 172, 1964 (TXAPA9); Z01 ivn-mky TDLo: 200 mg/kg/4D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 172, 1964 (TXAPA9); F18 orl-cat TDLo: 771 mg/kg/1Y-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 172, 1964 (TXAPA9); A30-Y10-Y21 scu-cat TDLo: 150 mg/kg/10D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 60, p. 324, 1981 (TXAPA9); B30-F18 ims-cat TDLo: 300 mg/kg/10D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 88, p. 175, 1987 (TXAPA9); F18-F19 orl-ckn TDLo: 450 mg/kg/3W-I British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 32, p. 31, 1975 (BJIMAG); F19-L30-Y04 orl-rat TDLo: 680 mg/kg/34D-C Neurotoxicology. (Intox Press, Inc., POB 34075, Little Rock, AR 72203) V.1- 1979- v. 22, p. 341, 2001 (NRTXDN); F19-L30-Y04 ipr-rat TDLo: 550 mg/kg/11D-I Neurotoxicology. (Intox Press, Inc., POB 34075, Little Rock, AR 72203) V.1- 1979- v. 22, p. 341, 2001 (NRTXDN); U01 orl-rat TDLo: 75 mg/kg/5D-I Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 147, 2000 (REPTED); F40 orl-rat TDLo: 225 mg/kg/5D-I Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 147, 2000 (REPTED); F04-T01 orl-rat TDLo: 300 mg/kg/5D-I Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 147, 2000 (REPTED); C16-F18-Y53 ipr-rat TDLo: 300 mg/kg/2W-I Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 22, p. 247, 2000 (NETEEC); U01 orl-rat TDLo: 56 mg/kg/28D-C Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); U01 orl-rat TDLo: 28 mg/kg/14D-C Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); F15 orl-rat TDLo: 84 mg/kg/42D-C Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); U01-F17 orl-rat TDLo: 3.5 mg/kg/70D-C Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 14, p. 385, 2000 (REPTED); F16 orl-mus TDLo: 5.04 mg/kg/1W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB93-158285 (NTIS**); T01 orl-mus TDLo: 451.71 mg/kg/27W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB93-158285 (NTIS**); U01-F17 orl-mus TDLo: 105 mg/kg/3W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 135, p. S52, 2002 (TOLED5); F18-U01-Z01 orl-mus TDLo: 210 mg/kg/3W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 135, p. S52, 2002 (TOLED5) TR: ACGIH TLV-TWA 0.03 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.03 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 41, 1986 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 389, 1994 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 41, 1986 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 389, 1994 (IMEMDT); IARC Cancer Review: Group 2A IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 389, 1994 (IMEMDT); TOXICOLOGY REVIEW EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 11, p. 129, 1975 (EVHPAZ); TOXICOLOGY REVIEW CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- v. 2, p. 365, 1973 (CRTXB2); TOXICOLOGY REVIEW Cahiers de Medecine du Travail. (Association Professionnelle Belge des Medecine du Travail, rue du Bultia, 6280 Gerpinnes, Belgium) V.1- 1963- v. 10(3), p. 49, 1973 (CMTVAS); TOXICOLOGY REVIEW Canadian Journal of Neurological Sciences. (Faculty of Medicine, 2500 University Dr., Calgary, Alberta, Canada) V.1- 1974- v. 1, p. 143, 1974 (CJNSA2); TOXICOLOGY REVIEW Canadian Journal of Neurological Sciences. (Faculty of Medicine, 2500 University Dr., Calgary, Alberta, Canada) V.1- 1974- v. 1, p. 152, 1974 (CJNSA2); TOXICOLOGY REVIEW Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 3, p. 445, 1981 (NTOTDY); TOXICOLOGY REVIEW Toxicologic Pathology. (c/o Dr. F.A. de la Iglesia, Warner-Lambert Co., Pharmaceutical Research Div., POB 1047, Ann Arbor, MI 48106) V.6(3/4)- 1978- v. 14, p. 279, 2001 (TOPADD) SR: MSHA STANDARD-air: TWA 0.3 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 5, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 0.3 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.3 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.3 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.3 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 0.3 mg/m3, Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Skin, Carcinogen, JAN 1999; OEL-BELGIUM: TWA 0.3 mg/m3, Skin, Carcinogen JAN 1993; OEL-DENMARK: TWA 0.03 mg/m3, Skin, JAN 1999; OEL-FINLAND: TWA 0.3 mg/m3, STEL 0.9 mg/m3, JAN 1993; OEL-FRANCE: VME 0.1 ppm (0.3 mg/m3), Skin, C2 Carcinogen, JAN 1999; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-HUNGARY: STEL 0.3 mg/m3, Skin, Carcinogen, JAN 1993; OEL-JAPAN: OEL 0.3 mg/m3, Skin, 2A Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.3 mg/m3, Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.3 mg/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 0.3 mg/m3, Skin, JAN 1993; OEL-POLAND: TWA 0.1 mg/m3, JAN 1999; OEL-RUSSIA: STEL 0.2 mg/m3, Skin, JAN 1993; OEL-SWEDEN: NGV 0.03 mg/m3, KTV 0.1 mg/m3, Skin, JAN 1999; OEL-SWITZERLAND: MAK-W 0.03 mg/m3, Skin, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: TWA 0.3 mg/m3, Skin, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ACRYLAMIDE-air: 10H CA TWA 0.03 mg/m3 (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 03540; NIS 10; TNF 442; NOS 24; TNE 7047; NOES 1983: HZD 03540; NIS 19; TNF 453; NOS 22; TNE 10651; TFE 721 SL: EPA GENETOX PROGRAM 1988, Positive: Cytogenetics-male germ cell; EPA GENETOX PROGRAM 1988, Negative: In vivo cytogenetics-nonhuman bone marrow; EPA GENETOX PROGRAM 1988, Inconclusive: In vivo SCE-nonhuman; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #21 Record 478 of 1119 in RTECS (through 2003/06) AN: AS3600000 PN: Acrylamide, N-(hydroxymethyl)- SY: 2-Propenamide, N-(hydroxymethyl)-; Methylolacrylamide-; Monomethylolacrylamide-; N-(Hydroxymethyl)-2-propenamide; N-(Hydroxymethyl)acrylamide; N-Ethanolacrylamide-; N-Methanolacrylamide-; N-Methylolacrylamide-; NCI-C60333-; Uramine-T-80- RN: Current: 924-42-5 Previous: 90456-67-0 BRN: 506646 BHR: 4-02-00-01472 UD: 200305 MF: C4-H7-N-O2 MW: 101.12 WL: Q1MV1U1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: spm-mus-orl 730 mg/kg/6W-C Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 59, p. 201, 1986 (ARTODN); cyt-ham-ovr 375 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); sce-ham-ovr 250 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); mtr-mus-fbr 0.1 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) RE: T02 orl-mus TDLo: 4608 mg/kg (16D male) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 47, p. 179, 1981 (ARTODN); T01-T02-T25 orl-mus TDLo: 730 gm/kg (6W male) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 59, p. 201, 1986 (ARTODN); T26 orl-mus TDLo: 730 gm/kg (6W male) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 59, p. 201, 1986 (ARTODN); T72-T81-T85 orl-mus TDLo: 15.6 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); T81 orl-mus TDLo: 15.6 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); T46 orl-mus TDLo: 188.8 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); T53-T81 orl-mus TDLo: 188.8 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**) TE: V01-J60-L60 orl-mus TDLo: 25750 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); V01-L60 orl-mus TDLo: 25750 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-226374/AS (NTIS**); V01-N60 orl-mus TDLo: 12875 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-226374/AS (NTIS**) ORNG: 474000000 ng/kg. [474.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 474 mg/kg Nippon Eiseigaku Zasshi. Japanese Journal of Hygiene. (Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 34, p. 183, 1979 (NEZAAQ); T/E unlistd ipr-rat LD50: 563 mg/kg Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 19, p. 2591, 1970 (BCPCA6); T/E unlistd orl-mus LD50: 420 mg/kg "Kirk-Othmer Encyclopedia of Chemical Technology," 3rd ed., Grayson, M., and D. Eckroth, eds., New York, John Wiley and Sons, Inc., 1978 1,306,1978 (37ASAA); F11 skn-rbt LDLo: 16 gm/kg Acute Toxicity Data. Journal of the American College of Toxicology, Part B. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1- 1990- v. 1, p. 111, 1990 (ATDAEI) MD: F18 orl-rat TDLo: 8736 mg/kg/27W-C British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 27, p. 147, 1970 (BJIMAG); Z01 orl-rat TDLo: 2400 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); F19-M70-Z73 orl-rat TDLo: 3250 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); Z73 orl-mus TDLo: 4688 mg/kg/8W-I Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 47, p. 179, 1981 (ARTODN); F19-L70-Z73 orl-mus TDLo: 1625 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); Z01 orl-mus TDLo: 4800 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-352, 1989 (NTPTR*); F18 orl-mus TDLo: 9525.6 mg/kg/12W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); F18 orl-mus TDLo: 10973.3 mg/kg/27W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); T02 orl-mus TDLo: 19040 mg/kg/34W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); T26 orl-mus TDLo: 19 gm/kg/34W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**); T25 orl-mus TDLo: 8330 mg/kg/34W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB93-151561 (NTIS**) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 435, 1994 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 435, 1994 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 435, 1994 (IMEMDT) ND: NOHS 1974: HZD 81901; NIS 7; TNF 154; NOS 17; TNE 2938; NOES 1983: HZD 81901; NIS 5; TNF 117; NOS 7; TNE 20665; TFE 13852 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), clear evidence: mouse; NCI Carcinogenesis Studies (gavage), no evidence: rat; NTP Carcinogenesis studies, on test (prechronic studies), October 2000; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 479 of 1119 in RTECS (through 2003/06) AN: AS4750000 PN: Acrylic acid, 3-p-anisoyl-3-bromo-, sodium salt, (E)- SY: (E)-3-p-Anisoyl-3-bromoacrylic acid sodium salt; 2-Butenoic acid, 3-bromo-4-(4-methoxyphenyl)-4-oxo-, sodium salt, (E)- (9CI); Cytembena-; NCI-C50737-; Sodna-sul-kyseliny-cis-beta-4-methoxybenzoyl-beta-bromakrylove- (Czech); NSC-104801- RN: Current: 21739-91-3 UD: 200302 MF: C11-H8-Br-O4.Na MW: 307.09 CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 100 ug/plate (+/-S9) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); msc-mus-lym 25 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-ham-ovr 25300 ug/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); sce-ham-ovr 1 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS) TE: V01-R60-T69 ipr-rat TDLo: 7 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-207, 1981 (NTPTR*); V01-R60-T69 ipr-rat TD :14 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-207, 1981 (NTPTR*); V01-R60 ipr-rat TDLo: 2184 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-163312 (NTIS**) AT: T/E unlistd ipr-rat LD50: 155 mg/kg Cesko-Slovenska Farmacie. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1-42, 1952-93. For publisher information, see CSLFEK v. 29, p. 106, 1980 (CKFRAY); T/E unlistd scu-rat LD50: 155 mg/kg Cesko-Slovenska Farmacie. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1-42, 1952-93. For publisher information, see CSLFEK v. 29, p. 106, 1980 (CKFRAY); T/E unlistd ivn-rat LD50: 245 mg/kg Cesko-Slovenska Farmacie. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1-42, 1952-93. For publisher information, see CSLFEK v. 29, p. 106, 1980 (CKFRAY); T/E unlistd ipr-mus LD50: 50 mg/kg Cesko-Slovenska Farmacie. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1-42, 1952-93. For publisher information, see CSLFEK v. 29, p. 106, 1980 (CKFRAY); T/E unlistd scu-mus LD50: 52 mg/kg Cesko-Slovenska Farmacie. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1-42, 1952-93. For publisher information, see CSLFEK v. 29, p. 106, 1980 (CKFRAY); T/E unlistd ivn-mus LD50: 98 mg/kg Cesko-Slovenska Farmacie. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1-42, 1952-93. For publisher information, see CSLFEK v. 29, p. 106, 1980 (CKFRAY) MD: U01 ipr-rat TDLo: 1131 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-207, 1981 (NTPTR*); K17-P27 ipr-mus TDLo: 1872 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-207, 1981 (NTPTR*) SL: EPA GENETOX PROGRAM 1988, Positive: Mammalian micronucleus; EPA GENETOX PROGRAM 1988, Positive/limited: Carcinogenicity-mouse/rat; NCI Carcinogenesis Studies (ipr), clear evidence: rat; NCI Carcinogenesis Studies (ipr), no evidence: mouse Record 480 of 1119 in RTECS (through 2003/06) AN: AT0700000 PN: Acrylic-acid,-ethyl-ester- SY: 2-Propanoic-acid,-ethyl-ester-; 2-Propenoic-acid,-ethyl-ester-; Acrylate-d'ethyle- (French); Acrylsaeureaethylester- (German); Aethylacrylat- (German); Akrylanem-etylu- (Polish); Carboset-511-; Ethoxycarbonylethylene-; Ethyl-2-propenoate-; Ethyl-acrylate-; Ethyl-acrylate- (ACGIH:OSHA); Ethyl-propenoate-; Ethylacrylaat- (Dutch); Ethylakrylat- (Czech); Ethylester-kyseliny-akrylove- (Czech); Etil-acrilato- (Italian); Etilacrilatului- (Romanian); NCI-C50384-; RCRA-waste-number-U113- RN: Current: 140-88-5 BRN: 773866 BHR: 4-02-00-01460 UD: 200302 MF: C5-H8-O2 MW: 100.13 WL: 2OV1U1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: eye-rat 1204 ppm/14H-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 317, 1949 (JIHTAB); eye-mky 1204 ppm/15H-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 317, 1949 (JIHTAB); skn-rbt 500 mg open MLD Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 12/14/1971 (UCDS**); skn-rbt 10 mg/24H MLD Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 311, 1949 (JIHTAB); eye-rbt 45 mg MLD Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 12/14/1971 (UCDS**); eye-rbt 1204 ppm/7H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 317, 1949 (JIHTAB); eye-gpg 1204 ppm/7H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 317, 1949 (JIHTAB) ME: mmo-sat 100 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mnt-mus-ipr 225 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 135, p. 189, 1984 (MUREAV); mmo-mus-lym 20 mg/L (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 6), p. 4, 1986 (ENMUDM); cyt-mus-lym 20 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 6), p. 4, 1986 (ENMUDM); msc-mus-lym 20 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 6), p. 4, 1986 (ENMUDM); cyt-ham-ovr 299 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-ham-lng 9800 ug/L Gann Monograph on Cancer Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) No. 11- 1971- v. 27, p. 95, 1981 (GMCRDC); sce-ham-ovr 150 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS) RE: T19 orl-rat TDLo: 8 gm/kg (0-19D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0557583 (NTIS**); T34 ihl-rat TCLo: 200 ppm/6H (6-20D preg) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 48, p. 240, 1999 (TOSCF2); T34-T19 ihl-rat TCLo: 200 ppm (6-20D preg) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 48, p. 240, 1999 (TOSCF2) TE: V01-K60 orl-rat TDLo: 51500 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-259, 1986 (NTPTR*); V01-K60 orl-mus TDLo: 103 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-259, 1986 (NTPTR*); V01-K60 orl-rat TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-204061/AS (NTIS**); V01-K60 orl-rat TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-204061/AS (NTIS**); V01-K60 orl-mus TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-204061/AS (NTIS**) ORNG: 800000000 ng/kg. [800.000000 mg/kg] T/E unlistd SRNL: 500000 nL/kg. [0.500000 mL/kg] J15-L30-R03 IHPB: 1414000 ppb/4H. [1414.000000 ppm/4H] D07-J22-K01 AT: D07-D35-J30 ihl-hmn TCLo: 50 ppm "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,75,1969 (34ZIAG); T/E unlistd orl-rat LD50: 800 mg/kg Bromatologia i Chemia Toksykologiczna. (Ars Polona, POB 1001, 00-068 Warsaw 1, Poland) V.4- 1971- v. 12, p. 405, 1979 (BCTKAG); D07-J22-K01 ihl-rat LC50: 1414 ppm/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0520180 (NTIS**); T/E unlistd skn-rat LDLo: 1800 mg/kg Polish Journal of Pharmacology and Pharmacy. (ARS Polona, POB 1001, 00-068 Warsaw 1, Poland) V.25-44, 1973-92. For publisher information, see PJPAE3 v. 32, p. 223, 1980 (PJPPAA); T/E unlistd ipr-rat LD50: 450 mg/kg Archives des Maladies Professionnelles de Medecine du Travail et de Securite Sociale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.7- 1946- v. 36, p. 58, 1975 (AMPMAR); T/E unlistd orl-mus LD50: 1799 mg/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 11, p. 125, 1982 (TOLED5); T/E unlistd ihl-mus LC50: 16200 mg/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 23(9), p. 55, 1979 (GTPZAB); T/E unlistd skn-mus LD50: 2997 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0520999 (NTIS**); T/E unlistd ipr-mus LD50: 599 mg/kg Journal of Dental Research. (International Assoc. for Dental Research, 734 15th St., NW, Suite 809, Washington, DC 20005) V.1- 1919- v. 51, p. 526, 1972 (JDREAF); D01-D02 ihl-mky LC :>75 ppm/6H Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 36(1, p. pt2), 113,1997 (TOXID9); K01-K13 orl-cat LD :>800 uL/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521003 (NTIS**); K04 orl-rbt LD50: 370 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521003 (NTIS**); F07-F19-K12 ihl-rbt LCLo: 1204 ppm/7H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 317, 1949 (JIHTAB); J15-L30-R03 skn-rbt LD50: 500 uL/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0520180 (NTIS**); F07-F12-J21 ihl-gpg LCLo: 1204 ppm/7H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 317, 1949 (JIHTAB); L30-N24-Y53 ihl-rat TCLo: 4.2 gm/m3/6H Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 65, p. 209, 1990 (TXCYAC) MD: K30 orl-rat TDLo: 6500 mg/kg/13W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0540988 (NTIS**); F15-F16-U01 orl-rat TDLo: 183 gm/kg/2Y-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 6, p. 29, 1964 (TXAPA9); K06 orl-rat TDLo: 11200 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-259, 1986 (NTPTR*); K06-K30 orl-rat TDLo: 800 mg/kg/4D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 80, p. 323, 1985 (TXAPA9); D07-U01 ihl-rat TCLo: 75 ppm/6H/2Y-I Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 8, p. 1, 1985 (DCTODJ); M70-U01-Z01 ihl-rat TCLo: 300 ppm/7H/30D-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31(6), p. 311, 1949 (JIHTAB); D07 ihl-rat TCLo: 75 ppm/6H/26W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0520180 (NTIS**); K30-U01 orl-rat TDLo: 5600 mg/kg/28D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0533909 (NTIS**); K30 orl-mus TDLo: 2800 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-259, 1986 (NTPTR*); D07-U01 ihl-mus TCLo: 75 ppm/6H/26W-I Abstracts of Papers, Society of Toxicology. Annual Meetings. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) v. 19, p. A53, 1980 (APTOD9); D07-U01 ihl-mus TCLo: 75 ppm/6H/2Y-I Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 8, p. 1, 1985 (DCTODJ); D07-U01 ihl-mus TCLo: 75 ppm/6H/1Y-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0544830 (NTIS**); D01-D02-D07 ihl-mus TCLo: 300 ppm/6H/30D-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0540690 (NTIS**) TR: ACGIH TLV-TWA 5 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 15 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 5 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 81, 1986 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1447, 1999 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 81, 1986 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1447, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1447, 1999 (IMEMDT); TOXICOLOGY REVIEW EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 11, p. 141, 1975 (EVHPAZ) SR: MSHA STANDARD-air: TWA 25 ppm (100 mg/m3) (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 102, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 25 ppm (100 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 25 ppm (100 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 25 ppm (100 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 25 ppm (100 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 5 ppm (20 mg/m3), JAN 1993; OEL-AUSTRIA: MAK 5 ppm (20 mg/m3), JAN 1999; OEL-BELGIUM: TWA 5 ppm (20 mg/m3), STEL 25 ppm (100 mg/m3), JAN 1993; OEL-DENMARK: TWA 5 ppm (20 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 5 ppm (20 mg/m3), STEL 10 ppm (40 mg/m3), Skin, JAN 1993; OEL-FRANCE: VME 5 ppm (20 mg/m3), Skin, JAN 1999; OEL-GERMANY: MAK 5 ppm (20 mg/m3), JAN 1999; OEL-HUNGARY: STEL 10 mg/m3, Skin, Carcinogen, JAN 1993; OEL-THE NETHERLANDS: MAC-TGG 5 ppm (20 mg/m3), Skin, JAN 1999; OEL-NORWAY: TWA 5 ppm (20 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 25 ppm (100 mg/m3), Skin, JAN 1993; OEL-POLAND: TWA 20 mg/m3, STEL 80 mg/m3, JAN 1999; OEL-RUSSIA: STEL 5 mg/m3, JAN 1993; OEL-SWEDEN: NGV 5 ppm (20 mg/m3), KTV 10 ppm (40 mg/m3), Skin, JAN 1999; OEL-SWITZERLAND: MAK-W 5 ppm (20 mg/m3), KZG-W 10 ppm (40 mg/m3), JAN 1999; OEL-TURKEY: TWA 25 ppm (100 mg/m3), Skin, JAN 1993; OEL-UNITED KINGDOM: TWA 5 ppm (21 mg/m3), STEL 15 ppm (62 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ETHYL ACRYLATE-air: CA (4.0 ppm LOQ) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 31490; NIS 42; TNF 3312; NOS 51; TNE 40491; NOES 1983: HZD 31490; NIS 26; TNF 2898; NOS 42; TNE 44604; TFE 7205 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Esters I, 1450; NCI Carcinogenesis Studies (gavage), clear evidence: mouse, rat; OSHA ANALYTICAL METHOD #92 Record 481 of 1119 in RTECS (through 2003/06) AN: AT4810000 PN: Acrylic acid, triester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol SY: 2-Ethyl-2-(hydroxymethyl)-1,3-propanediol triacrylate; M-309-; MFM-; Saret-351-; Sartomer-SR-351-; Setalux-UV-2241-; SR-351-; TMPTA-; Viscoat-295-; Acrylic acid, 1,1,1-(trihydroxymethyl)propane triester; NK-Ester-A-TMPT-; Ogumont-T-200-; 1,3-Propanediol, 2-ethyl-2-(hydroxymethyl)-, triacrylate; 2-Propenoic acid, 2-ethyl-2-(((1-oxo-2-propenyl)oxy)methyl)-1,3-propanediyl ester (9CI); Trimethylolpropane-triacrylate- RN: Current: 15625-89-5 UD: 200302 MF: C15-H20-O6 MW: 296.35 WL: 1U1VO1K2&1OV1U1&1OV1U1 CC: Tumorigen (C); Mutagen (M); Human-Data (P); Primary-Irritant (S); Reproductive-Effector (T) ID: skn-hmn 1% American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 42(11), p. B53, 1981 (AIHAAP); skn-rbt 500 mg/24H MOD Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 19, p. 149, 1986 (JTEHD6); eye-rbt 100 mg MOD Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 19, p. 149, 1986 (JTEHD6); skn-hmn 0.5%/48H Journal of Occupational Medicine. (Chicago, IL) V.1-9, 1957-67. For publisher information, see:JJOMDZ v. 121, p. 373, 1985 (JOCMA7) ME: mnt-mus-lym 650 ug/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 4, p. 381, 1989 (MUTAEX); cyt-mus-lym 600 ug/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 4, p. 381, 1989 (MUTAEX); msc-mus-lym 3300 nmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 264, 1991 (EMMUEG) RE: T13-T25 orl-rat TDLo: 5 gm/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571218 (NTIS**) ORNL: 5190000 nL/kg. [5.190000 mL/kg] T/E unlistd SRNG: 5170000000 ng/kg. [5170.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 5190 uL/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 28, p. 313, 1974 (TXAPA9); F05-F12-F19 ipr-rat LD50: 55 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555702 (NTIS**); T/E unlistd skn-rbt LD50: 5170 mg/kg American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 42(11), p. B53, 1981 (AIHAAP) MD: R03 skn-rbt TDLo: 5 gm/kg/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555406 (NTIS**); R13 skn-gpg TDLo: 5 pph/12W-I Contact Dermatitis. Environmental and Occupational Dermatitis. (Munksgaard International Pub., c/o Publications Expediting Inc., 200 Meacham Ave., Elmont, NY 11003) V.1- 1975- v. 9, p. 55, 1983 (CODEDG) ND: NOES 1983: HZD X3216; NIS 10; TNF 388; NOS 12; TNE 5274; TFE 809 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, on test (prechronic studies), October 2000; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 482 of 1119 in RTECS (through 2003/06) AN: AT5250000 PN: Acrylonitrile- SY: Acrylnitril- (German, Dutch); Acrylon-; Acritet-; Acrylonitrile- (ACGIH:OSHA); Akrylonitril- (Czech); Akrylonitryl- (Polish); Carbacryl-; Cianuro-di-vinile- (Italian); Cyanoethylene-; Cyanure-de-vinyle- (French); ENT-54-; Fumigrain-; Miller's-fumigrain-; Nitrile-acrilico- (Italian); Nitrile-acrylique- (French); RCRA-waste-number-U009-; TL-314-; VCN-; Ventox-; Vinyl-cyanide-; Vinylcyanide- (OSHA); Vinylkyanid- (Czech); Acrylonitrile-monomer-; Propenenitrile-; 2-Propenenitrile- RN: Current: 107-13-1 Previous: 29754-21-0; 63908-52-1 BRN: 605310 BHR: 4-02-00-01473 UD: 200302 MF: C3-H3-N MW: 53.07 WL: NC1U1 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-hmn 500 mg rinse Industrial Medicine. (Chicago, IL) V.1-18, 1932-49. For publisher information, see IOHSA5. v. 17, p. 199, 1948 (INMEAF); skn-rbt 500 mg SEV Acute Toxicity Data. Journal of the American College of Toxicology, Part B. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1- 1990- v. 1, p. 114, 1990 (ATDAEI); eye-rbt 100 mg MOD Acute Toxicity Data. Journal of the American College of Toxicology, Part B. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1- 1990- v. 1, p. 114, 1990 (ATDAEI) ME: mmo-sat 25 uL/plate (+S9) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. 5AUG1977 (NIOSH*); mmo-sat 57 ppm (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 48, p. 271, 1977 (MUREAV); mmo-esc 300 umol/L (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 45, p. 283, 1977 (MUREAV); slt-dmg-orl 1520 umol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 325, 1985 (PMRSDJ); sln-dmg-ihl 3 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 259, p. 165, 1991 (MUREAV); mmo-smc 800 ug/L (+/-S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 271, 1985 (PMRSDJ); mrc-smc 14 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 225, 1985 (PMRSDJ); oms-smc 500 ppm Ecotoxicology and Environmental Safety. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1977- v. 8, p. 162, 1984 (EESADV); mrc-asn 806 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 307, 1985 (PMRSDJ); sln-asn 4800 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 147, p. 288, 1985 (MUREAV); mmo-hmn-lym 40 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 497, 1985 (PMRSDJ); dnd-hmn-oth 200 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 241, p. 355, 1990 (MUREAV); sce-hmn-oth 150 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 241, p. 355, 1990 (MUREAV); msc-hmn-lym 25 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 497, 1985 (PMRSDJ); dna-rat-orl 46500 ug/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 47, p. 363, 1983 (CBINA8); oms-rat-orl 46500 ug/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 47, p. 363, 1983 (CBINA8); dna-rat-lvr 16500 umol/L Xenobiotica. (Taylor and Francis Ltd., 4 John St., London WC1N 2ET, UK) V.1- 1971- v. 13, p. 19, 1983 (XENOBH); oms-rat-lvr 16500 umol/L Xenobiotica. (Taylor and Francis Ltd., 4 John St., London WC1N 2ET, UK) V.1- 1971- v. 13, p. 19, 1983 (XENOBH); dns-rat-lvr 1 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 371, 1985 (PMRSDJ); dns-rat-orl 50 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 46, p. 3932, 1986 (CNREA8); bfa-rat-sat 30 mg/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 16, p. 67, 1980 (TXCYAC); mmo-mus-lym 161 mg/L (+S9) Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 23, p. 115, 1985 (FCTOD7); mmo-mus-emb 50 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 639, 1985 (PMRSDJ); mtr-mus-emb 8800 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 639, 1985 (PMRSDJ); mtr-mus-fbr 6300 ug/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 32, p. 293, 1986 (CALEDQ); bfa-mus-sat 30 mg/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 16, p. 67, 1980 (TXCYAC); msc-mus-lym 12500 nL/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 555, 1985 (PMRSDJ); mnt-ham-ovr 100 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 359, 1985 (PMRSDJ); mtr-ham-emb 2 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 665, 1985 (PMRSDJ); dnd-ham-ovr 3710 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 359, 1985 (PMRSDJ); dnd-ham-emb 200 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 1025, 1979 (JJIND8); cyt-ham-ovr 4 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 433, 1985 (PMRSDJ); cyt-ham-lng 6250 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 427, 1985 (PMRSDJ); cyt-ham-lvr 2500 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 397, 1985 (PMRSDJ); sce-ham-ovr 2 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 433, 1985 (PMRSDJ); dna-mam-lym 68 mmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 51, p. 167, 1984 (CBINA8); mtr-ham-emb 50 mg/L/7D Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 21, p. 727, 2000 (CRNGDP) RE: T22-T34-T46 orl-rat TDLo: 650 mg/kg (6-15D preg) Dow Chemical Company Reports. (Dow Chemical USA, Health and Environment Research, Toxicology Research Lab., Midland, MI 48640) 03NOV1976 (DOWCC*); T46-T47 orl-rat TDLo: 650 mg/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 17, p. 50A, 1978 (TJADAB); T01-T02 orl-rat TDLo: 644 mg/kg (2W male) Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 87, 1994 (TOXID9); T19-T46-T47 orl-rat TDLo: 650 mg/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555785 (NTIS**); T19-U01 ihl-rat TCLo: 40 ppm/6H (6-15D preg) Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 16, p. 547, 1978 (FCTXAV); T46 ihl-rat TCLo: 80 ppm/6H (6-15D preg) Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 16, p. 547, 1978 (FCTXAV); T34 ihl-rat TCLo: 25 ppm/6H (6-20D preg) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 20, p. 365, 1993 (FAATDF); T01-T02-T09 orl-mus TDLo: 600 mg/kg (60D male) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 42, p. 55, 1988 (TOLED5); T25 ipr-mus TDLo: 32 mg/kg (5D preg) Zeitschrift fuer die Gesamte Hygiene und Ihre Grenzgebiete. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1955- v. 26, p. 564, 1980 (ZHYGAM); T25-T41 ipr-ham TDLo: 641 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 23, p. 317, 1981 (TJADAB); T31-T33-T34 ipr-ham TDLo: 641 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 23, p. 325, 1981 (TJADAB); T41-T46 ipr-ham TDLo: 641 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 23, p. 325, 1981 (TJADAB); T39 orl-rat TDLo: 100 mg/kg (10D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 163, p. 149, 2000 (TXAPA9) TE: V01-A60 orl-rat TDLo: 18200 mg/kg/52W-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 24, p. 129, 1986 (FCTOD7); V03-R60 ihl-rat TCLo: 5 ppm/52W-I Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 68, p. 401, 1977 (MELAAD); V03-A60 ihl-rat TC :20 ppm/4H/52W-I Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 381, p. 216, 1982 (ANYAA9); V03-A60 ihl-rat TC :40 ppm/4H/52W-I Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 381, p. 216, 1982 (ANYAA9); V02-D45-K60 orl-rat TD :3640 mg/kg/52W-C Dow Chemical Company Reports. (Dow Chemical USA, Health and Environment Research, Toxicology Research Lab., Midland, MI 48640) MAR1977 (DOWCC*); V01-A30-K60 orl-rat TDLo: 2490 mg/kg/2Y-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0540235 (NTIS**); V01-K60 orl-mus TDLo: 10400 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2002-102198 (NTIS**) ORNG: 78000000 ng/kg. [78.000000 mg/kg] F12-J22-K01 SRNG: 63000000 ng/kg. [63.000000 mg/kg] F07-R03 SKNG: 148000000 ng/kg. [148.000000 mg/kg] T/E unlistd IHPB: 333000 ppb/4H. [333.000000 ppm/4H] D17-F11-J22 AT: D07-D25-J30 ihl-hmn TCLo: 16 ppm/20M Industrial Medicine. (Chicago, IL) V.1-18, 1932-49. For publisher information, see IOHSA5. v. 17, p. 199, 1948 (INMEAF); F07-K12-K13 ihl-man LCLo: 1 gm/m3/1H Zentralblatt fuer Arbeitsmedizin und Arbeitsschutz. (Darmstadt, Fed. Rep. Ger.) V.1-25, 1951-75. v. 16, p. 1, 1966 (ZAARAM); F01-J24-K13 skn-chd LDLo: 2015 mg/kg Deutsche Medizinische Wochenschrift. (Stuttgart, Fed. Rep. Ger.) V.1-104, 1875-1979. v. 75, p. 1087, 1950 (DMWOAX); F12-J22-K01 orl-rat LD50: 78 mg/kg Journal of Hygiene, Epidemiology, Microbiology, and Immunology. (Avicenum, Malostranske namesti 28, 11802 Prague 1, Czechoslovakia) V.1- 1957- v. 3, p. 106, 1959 (JHEMA2); D17-F11-J22 ihl-rat LC50: 333 ppm/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571605 (NTIS**); T/E unlistd skn-rat LD50: 148 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 41(10), p. 103, 1976 (GISAAA); T/E unlistd ipr-rat LD50: 65 mg/kg Archives des Maladies Professionnelles de Medecine du Travail et de Securite Sociale. (SPPIF, B.P.22, F-41353 Vineuil, France) V.7- 1946- v. 36, p. 58, 1975 (AMPMAR); C06-F12-J24 scu-rat LD50: 75 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 102, p. 142, 1990 (TXAPA9); N30 unr-rat LDLo: 200 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 133, 1976 (TXAPA9); F12-J22-K01 orl-mus LD50: 27 mg/kg Journal of Hygiene, Epidemiology, Microbiology, and Immunology. (Avicenum, Malostranske namesti 28, 11802 Prague 1, Czechoslovakia) V.1- 1957- v. 3, p. 106, 1959 (JHEMA2); D26-F19-J22 ipr-mus LD50: 46 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 59, p. 589, 1981 (TXAPA9); D35-F17-K12 scu-mus LD50: 25 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 367, 1965 (TXAPA9); C08-F12-F24 ihl-dog LCLo: 110 ppm/4H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 27, 1942 (JIHTAB); F12-K13-J25 ivn-dog LDLo: 200 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 367, 1965 (TXAPA9); T/E unlistd ihl-mky LC :>90 ppm/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB280-478 (NTIS**); F12-J22-K13 ihl-cat LCLo: 600 ppm/4H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 27, 1942 (JIHTAB); F12-F24-J22 ihl-rbt LCLo: 260 ppm/4H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 27, 1942 (JIHTAB); F07-R03 skn-rbt LD50: 63 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0534646 (NTIS**); C07-F11-F12 ivn-rbt LD50: 69 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB280-478 (NTIS**); T/E unlistd orl-gpg LD50: 50 mg/kg Zeitschrift fuer die Gesamte Hygiene und Ihre Grenzgebiete. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1955- v. 16, p. 316, 1970 (ZHYGAM); D17-J15-J21 ihl-gpg LCLo: 575 ppm/4H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 27, 1942 (JIHTAB); T/E unlistd skn-gpg LD50: 202 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 63, 1948 (JIHTAB); C07-F11-F12 scu-gpg LD50: 130 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB280-478 (NTIS**); L30-N24-Y53 ihl-rat TCLo: 350 mg/m3/6H Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 65, p. 209, 1990 (TXCYAC) MD: F13-L30-Z01 orl-rat TDLo: 1440 mg/kg/12W-I Weisheng Dulixue Zazhi. Journal of Health Toxicology. (Weisheng Dulixue Zazhi Bianjibu, Dongdaqiao, Chaoyang Menwai, Beijing, Peop. Rep. China) V.1- 1987 v. 5, p. 24, 1991 (WDZAEK); F15-M16-Y03 orl-rat TDLo: 10920 mg/kg/1Y-C Dow Chemical Company Reports. (Dow Chemical USA, Health and Environment Research, Toxicology Research Lab., Midland, MI 48640) MAR1977 (DOWCC*); N30-U05 orl-rat TDLo: 2100 mg/kg/21D-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 133, 1976 (TXAPA9); N12-N72-P30 orl-rat TDLo: 120 mg/kg/60D-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 4, p. 131, 1984 (JJATDK); L30-M03-Y10 ihl-rat TCLo: 1500 ug/m3/5H/26W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 27(4), p. 50, 1983 (GTPZAB); D07-U01-Z01 ihl-rat TCLo: 330 mg/kg/4H/8W-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 255, 1942 (JIHTAB); M16-Y01-Y09 skn-rat TDLo: 3751 mg/kg/19W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 41(10), p. 103, 1976 (GISAAA); L70-U01 orl-rat TDLo: 945 mg/kg/90D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555089 (NTIS**); P28-U30-Y07 ipr-rat TDLo: 99 mg/kg/3D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 6, p. 399, 1980 (TOLED5); N73-N74-Y02 ihl-mus TCLo: 60 mg/m3/4H/21D-I Weisheng Dulixue Zazhi. Journal of Health Toxicology. (Weisheng Dulixue Zazhi Bianjibu, Dongdaqiao, Chaoyang Menwai, Beijing, Peop. Rep. China) V.1- 1987 v. 4, p. 245, 1990 (WDZAEK); F07-J30-Q30 orl-dog TDLo: 900 mg/kg/26W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555089 (NTIS**); F18-Z01 ihl-mky TCLo: 330 mg/kg/4H/8W-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 255, 1942 (JIHTAB); D07-D25-Z01 ihl-cat TCLo: 330 mg/m3/4H/8W-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 255, 1942 (JIHTAB); Z01 ihl-rbt TCLo: 330 mg/m3/4H/8W-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 255, 1942 (JIHTAB); Z01 ihl-gpg TCLo: 330 mg/m3/4H/8W-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 24, p. 255, 1942 (JIHTAB); C16-F13-K01 orl-rat TDLo: 750 mg/kg/12W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 18, p. 25, 1998 (JJATDK) TR: ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 2 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Human Limited Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 79, 1987 (IMSUDL); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 19, p. 73, 1979 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 43, 1999 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 43, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 43, 1999 (IMEMDT); TOXICOLOGY REVIEW Cahiers de Medecine du Travail. (Association Professionnelle Belge des Medecine du Travail, rue du Bultia, 6280 Gerpinnes, Belgium) V.1- 1963- v. 10(3), p. 49, 1973 (CMTVAS); TOXICOLOGY REVIEW Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 22, p. 327, 1980 (SAIGBL) SR: MSHA STANDARD-air: TWA 20 ppm (45 mg/m3) (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 6, 1971 (DTLVS*); OSHA PEL (Construc): 8H TWA 20 ppm (45 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 39, 1926.55, 1994 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 20 ppm (45 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OSHA-cancer hazard Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1045, 1987 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 2 ppm, Skin, JAN 1993; OEL-AUSTRALIA: TWA 2 ppm (4.5 mg/m3), Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Skin, Carcinogen, JAN 1999; OEL-BELGIUM: TWA 2 ppm (4.3 mg/m3), Skin, Carcinogen JAN 1993; OEL-DENMARK: TWA 2 ppm (4 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 2 ppm (4.5 mg/m3), STEL 4 ppm, Skin, Carcinogen, JAN 1993; OEL-FRANCE: VME 2 ppm (4.5 mg/m3), VLE 15 ppm (32.4 mg/m3), C2 Carcinogen, JAN 1999; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-HUNGARY: STEL 0.5 mg/m3, Skin, Carcinogen, JAN 1993; OEL-INDIA: TWA 2 ppm (4.5 mg/m3), Skin, Carcinogen, JAN 1993; OEL-JAPAN: OEL 2 ppm (4.3 mg/m3), Skin, 2A Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 4 ppm (9 mg/m3), STEL 10 ppm, Skin, Carcinogen, JAN 1999; OEL-NORWAY: TWA 2 ppm (4 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 20 ppm (45 mg/m3), Skin, JAN 1993; OEL-POLAND: MAC(TWA) 2 mg/m3, MAC(STEL) 10 mg/m3, JAN 1999; OEL-RUSSIA: TWA 2 ppm, STEL 0.5 mg/m3, Skin, JAN 1993; OEL-SWEDEN: NGV 2 ppm (4.5 mg/m3), KTV 6 ppm, Skin, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 2 ppm (4.5 mg/m3), Skin, Carcinogen, JAN 1999; OEL-TURKEY: TWA 20 ppm (45 mg/m3, Skin, JAN 1993; OEL-UNITED KINGDOM: TWA 2 ppm (4.4 mg/m3), Skin, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ACRYLONITRILE-air: 8H CA TWA 1 ppm, CL 10 ppm/15M (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 03800; NIS 45; TNF 3610; NOS 55; TNE 55698; NOES 1983: HZD 03800; NIS 24; TNF 2522; NOS 39; TNE 81691; TFE 27358 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-focus assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/SHE, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: TRP reversion; EPA GENETOX PROGRAM 1988, Positive/dose response: TRP reversion; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster Sex-linked lethal; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH CURRENT INTELLIGENCE BULLETIN 18, 1977; NIOSH Analytical Method, 1994: Acrylonitrile, 1604; NCI Carcinogenesis Studies (gavage), clear evidence: mouse; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; NTP Carcinogenesis studies, on test (two year studies), October 2000; OSHA ANALYTICAL METHOD #37 Record 483 of 1119 in RTECS (through 2003/06) AN: AU9700000 PN: Adipic acid, bis(2-ethylhexyl) ester SY: ADO- (lubricating oil); Adipol-2EH-; BEHA-; Bis(2-ethylhexyl) adipate; Bis-(2-ethylhexyl)ester kyseliny adipove (Czech); Bisoflex-DOA-; Crodamol-DOA-; DOA-; Di(2-ethylhexyl) adipate; Di(2-ethylhexyl)adipate; Di-2-ethylhexyl-adipate-; Dioctyl-adipate-; Effomoll-DOA-; Ergoplast-ADDO-; Flexol-A-26-; Hatcol-2908-; Hexanedioic acid, bis(2-ethylhexyl) ester (9CI); Hexanedioic-acid,-dioctyl-ester-; Kemester-5652-; Kodaflex-DOA-; Lankroflex-DOA-; Mollan-S-; Monoplex-DOA-; Morflex-310-; NCI-C54386-; Octyl-adipate-; PX-238-; Plastomoll-DOA-; Reomol-DOA-; Rucoflex-Plasticizer-DOA-; Sansocizer-DOA-; Sicol-250-; Staflex-DOA-; Truflex-DOA-; Uniflex-DOA-; Vestinol-OA-; Wickenol-158-; Witamol-320- RN: Current: 103-23-1 Previous: 39393-67-4; 63637-48-9; 70147-21-6 BRN: 1803774 BHR: 4-02-00-01964 UD: 200302 MF: C22-H42-O4 MW: 370.64 WL: 4Y2&1OV4VO1Y4&2 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: pic-esc 25 ug/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 349, 1991 (MUREAV); dns-rat-orl 378 umol/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 8, p. 1433, 1987 (CRNGDP); oms-mus-orl 2 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV); dlt-mus-ipr 1000 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 32, p. 566, 1975 (TXAPA9); cyt-ham-ovr 400 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) RE: T34 ipr-rat TDLo: 15 gm/kg (5-15D preg) Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 62, p. 1596, 1973 (JPMSAE); T59 ipr-rat TDLo: 30 gm/kg (5-15D preg) Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 62, p. 1596, 1973 (JPMSAE) TE: V01-L60 orl-mus TDLo: 1038 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-212, 1981 (NTPTR*); V01-L60 orl-mus TD :2163 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-212, 1981 (NTPTR*); V01-L60 orl-mus TD :1048 gm/kg/2Y-C EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 65, p. 271, 1986 (EVHPAZ); V01-L60 orl-mus TDLo: 2163000 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-185927 (NTIS**); V01-L60 orl-mus TDLo: 1038240 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-185927 (NTIS**) ORNG: 7392000000 ng/kg. [7392.000000 mg/kg] T/E unlistd SRNL: 16000000 nL/kg. [16.000000 mL/kg] T/E unlistd AT: T/E unlistd ipr-rat LD50: >50 mL/kg Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 62, p. 1596, 1973 (JPMSAE); T/E unlistd skn-rbt LD50: 16 mL/kg AMA Archives of Industrial Hygiene and Occupational Medicine. (Chicago, IL) V.2-10, 1950-54. For publisher information, see AEHLAU. v. 4, p. 119, 1951 (AMIHBC); T/E unlistd orl-mam LD50: 15 gm/kg International Polymer Science and Technology. (Rapra Technology Ltd., Shawbury, Shrewsbury, Shropshire SY4 4NR, UK) v. 3, p. 93, 1976 (IPSTB3); T/E unlistd orl-gpg LD50: 12900 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd orl-mus LD50: 15000 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd ipr-mus LD50: 5000 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd orl-rat LD50: 7392 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd ivn-rat LD50: 900 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd ipr-rat LD50: 46000 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd skn-rbt LD50: 8410 mg/kg/24H Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); T/E unlistd ivn-rbt LD50: 540 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); D17-D25 ipr-rbt LD50: 38000 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*) MD: P28 orl-rat TDLo: 25200 mg/kg/3W-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 10, p. 379, 1982 (TOLED5); L70-U01-Y07 orl-rat TDLo: 191 gm/kg/13W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 123, p. 217, 1997 (TXCYAC); Z01 orl-mus TDLo: 168 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-212, 1981 (NTPTR*); L30-L70-Y07 orl-mus TDLo: 280 gm/kg/13W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 123, p. 217, 1997 (TXCYAC); L70-L14-Y37 orl-mus TDLo: 500 mg/kg/5D-C Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); L70-L14-Y37 orl-rat TDLo: 500 mg/kg/5D-C Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. -, p. 153, 1997 (BFUUA*); L30-Y37 orl-rat TDLo: 8.45 gm/kg/14D-I Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. Suppl.12, p. 274, 1988 (ARTODN) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT) ND: NOHS 1974: HZD 80276; NIS 19; TNF 534; NOS 31; TNE 11847; NOES 1983: HZD 80276; NIS 15; TNF 524; NOS 21; TNE 15636; TFE 3628 SL: EPA GENETOX PROGRAM 1988, Positive/dose response: Rodent dominant lethal; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA Section 8(e) Risk Notification, 8EHQ-0892-8917; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), clear evidence: mouse; NCI Carcinogenesis Studies (feed), no evidence: rat Record 484 of 1119 in RTECS (through 2003/06) AN: AV1645000 PN: Adipic-acid,-dimethyl-ester- SY: Dimethyl-adipate-; Dimethyl-hexanedioate-; Hexanedioic-acid,-dimethyl-ester- (9CI); Methyl-adipate- RN: Current: 627-93-0 BRN: 1707443 BHR: 4-02-00-01959 UD: 200012 MF: C8-H14-O4 MW: 174.22 WL: 1OV4VO1 CC: Tumorigen (C); Reproductive-Effector (T) RE: T46-T59 ipr-rat TDLo: 362 mg/kg (5-15D preg) Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 62, p. 1596, 1973 (JPMSAE); T25 ipr-rat TDLo: 181 mg/kg (5-15D preg) Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 62, p. 1596, 1973 (JPMSAE) AT: T/E unlistd ipr-rat LD50: 1809 uL/kg Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 62, p. 1596, 1973 (JPMSAE) ND: NOES 1983: HZD T1493; NIS 18; TNF 2425; NOS 25; TNE 24766; TFE 3381 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, selected, October 2000 Record 485 of 1119 in RTECS (through 2003/06) AN: AW5950000 PN: Aflatoxin- RN: Current: 1402-68-2 UD: 200305 CC: Tumorigen (C); Mutagen (M); Natural-Product (N); Human-Data (P); Reproductive-Effector (T) ME: cyt-hmn-leu 50 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 16, p. 373, 1972 (MUREAV); mnt-rat-orl 8500 ug/kg Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 10, p. 291, 1987 (DCTODJ); cyt-mus-orl 84 ug/kg Nucleus (Calcutta). (Dr. A.K. Sharma, Centre of Advanced Studies in Cell and Chromosome Research, Calcutta, 35 Baliygunge Circular Rd., Calcutta 700 019, India) V.1- 1958- v. 32, p. 142, 1989 (NULSAK); dlt-mus-ipr 68 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 219, p. 385, 1968 (NATUAS) RE: T26-T34-T46 par-ham TDLo: 4 mg/kg (8D preg) Dissertation Abstracts International, B: The Sciences and Engineering. (University Microfilms International, 300 N. Zeeb Rd., Ann Arbor, MI 48106) V.30- 1969- v. 34, p. 5251, 1973 (DABBBA); T53 par-ham TDLo: 6 mg/kg (8D preg) Dissertation Abstracts International, B: The Sciences and Engineering. (University Microfilms International, 300 N. Zeeb Rd., Ann Arbor, MI 48106) V.30- 1969- v. 34, p. 5251, 1973 (DABBBA) TE: V03-L60 orl-rat TDLo: 7788 ug/kg/13W-C Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 202, p. 1016, 1964 (NATUAS); V03-T65-L60 orl-rat TDLo: 2250 ug/kg (10-21D preg) Cancer Research. 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(London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 227, 1976 (FCTXAV); L02-Y55 ims-mky LD50: 2020 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 227, 1976 (FCTXAV); T/E unlistd orl-qal LDLo: 4 mg/kg British Poultry Science. (Longman Group UK Ltd., Longman House, Burnt Mill, Harlow, Essex CM20 2JE, UK) V.1- 1960- v. 21, p. 29, 1980 (BPOSA4) MD: P02-P28-Y03 orl-dog TDLo: 1 gm/kg/10W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 579, 1971 (TXAPA9); P08-P70-P71 orl-rbt TDLo: 900 mg/kg/60D-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 49, p. 861, 1992 (BECTA6); P02-P28-U09 orl-pig TDLo: 56 mg/kg/28D-C Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 40, p. 576, 1988 (BECTA6); M16-M70-U07 orl-ckn TDLo: 20 mg/kg/10D-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 34, p. 309, 1991 (JTEHD6); P30 orl-ckn TDLo: 80 mg/kg/32D-C Research in Veterinary Science. (British Veterinary Assoc., 7 Mansfield St., London W1M OAT, UK) V.1- 1960- v. 58, p. 119, 1995 (RVTSA9); U01 orl-qal TDLo: 105 mg/kg/3W-C British Poultry Science. (Longman Group UK Ltd., Longman House, Burnt Mill, Harlow, Essex CM20 2JE, UK) V.1- 1960- v. 21, p. 29, 1980 (BPOSA4); L12-P01-Z01 orl-dom TDLo: 2925 ug/kg/39D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 65, p. 354, 1982 (TXAPA9); P71-U01-Y15 orl-dom TDLo: 1680 ug/kg/21D-C JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 16, p. 85, 1996 (JJATDK); P30-Y03-Y10 orl-ctl TDLo: 2100 ug/kg/3W-C Journal of Dairy Science. (American Dairy Science Assoc., 309 W. Clark St., Champaign, IL 61820) V.1- 1917- v. 68, p. 437, 1985 (JDSCAE); L01-K20 orl-mus TDLo: 4.62 ug/kg/60D-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 579, 2001 (FCTOD7); P28-U07 orl-mus TDLo: 7.28 ug/kg/90D-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 579, 2001 (FCTOD7); N16-T02-Y10 ims-mus TDLo: 45 gm/kg/45D-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 40, p. 669, 2001 (FCTOD7) TR: IARC Cancer Review: Human Sufficient Evidence IARC Monographs, Supplement. 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(Sri Avinashilingam Home Science College for Women, Coimbatore 641 043, India) V.7- 1970- v. 8, p. 85, 1971 (IJNDAN); TOXICOLOGY REVIEW Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 6, p. 80, 1968 (FCTXAV); TOXICOLOGY REVIEW Zeitschrift fuer Krebsforschung und Klinische Onkologie. (Berlin, Fed. Rep. Ger.) V.76-92, 1971-78. For publisher information, see JCROD7. v. 78, p. 99, 1972 (ZKKOBW) SR: OEL-UNITED KINGDOM: Carcinogen, SEP 2000 SL: EPA GENETOX PROGRAM 1988, Positive: Aspergillus-forward mutation; EPA GENETOX PROGRAM 1988, Inconclusive: In vitro cytogenetics-human lymphocyte; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster-reciprocal translocation; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster Sex-linked lethal; NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen Record 486 of 1119 in RTECS (through 2003/06) AN: AY3675000 PN: Alanine, 3-(p-(bis(2-chloroethyl)amino)phenyl)-, L- SY: Alkeran-; L-3-(p-(Bis(2-chloroethyl)amino)phenyl)alanine; p-Bis(beta-chloroethyl)aminophenylalanine; p-N-Bis(2-chloroethyl)amino-L-phenylalanine; 3-(p-(Bis(2-chloroethyl)amino)phenyl)-L-alanine; 4-(Bis(2-chloroethyl)amino)-L-phenylalanine; CB-3025-; 3025 C.B.; p-Di-(2-chloroethyl)amino-L-phenylalanine; p-N-Di(chloroethyl)aminophenylalanine; 3-p-(Di(2-chloroethyl)amino)-phenyl-L-alanine; Levofalan-; Melfalan-; Melphalan-; NCI-C04853-; L-PAM-; RCRA-waste-number-U150-; L-Sarcolysin-; p-L-Sarcolysin-; L-Sarcolysine-; L-Sarkolysin-; SK-15673-; Alanine-nitrogen-mustard-; L-Phenylalanine, 4-(bis(2-chloroethyl)amino)-; Phenylalanine-mustard-; L-Phenylalanine-mustard-; Phenylalanine-nitrogen-mustard- RN: Current: 148-82-3 BRN: 2816456 BHR: 4-14-00-01689 UD: 200210 MF: C13-H18-Cl2-N2-O2 MW: 305.23 WL: QVYZ1R DN2G2G -L CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 5 mg/24H rinse Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 14, p. 117, 1979 (TXCYAC); skn-rbt 1 pph/24H MLD National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB270-483 (NTIS**) ME: mmo-sat 100 ug/plate (+S9) Revista de Chirurgui, Oncologie, Radiologie, ORL, Oftalmologie, Stomatologie, Seria: Oncologia. (Rompresfilatelia, POB 12-201, Bucharest, Romania) V.13(4)- 1974- v. 18, p. 95, 1979 (ONCODU); mmo-sat 200 ug/plate (-S9) Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 72, p. 5135, 1975 (PNASA6); dnr-esc 100 ug/disc Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 34, p. 1658, 1974 (CNREA8); dnd-omi 50 umol/L Mutation Research. (Elsevier Science Pub. 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(5 Argyropoulou St., Kato Patissia, Athens 907, Greece) V.1- 1981- v. 10, p. 297, 1990 (ANTRD4); dnd-hmn-lng 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 413, p. 83, 1998 (MUREAV); dnd-hmn-lym 5 umol/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 38, p. 3122, 1989 (BCPCA6); dns-hmn-fbr 800 ug/L Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 21, p. 151, 1981 (TXCYAC); dns-hmn-oth 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 84, 1982 (CNREA8); dns-hmn-leu 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 84, 1982 (CNREA8); dns-hmn-bmr 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 84, 1982 (CNREA8); dni-hmn-lym 25 umol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 51, p. 191, 1984 (CBINA8); dni-hmn-oth 4 mg/L International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 21, p. 438, 1978 (IJCNAW); oms-hmn-leu 10 umol/L European Journal of Cancer and Clinical Oncology. (Pergamon Press, c/o Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.17(7)- 25, 1981-89. For publisher information, see EJCAEL v. 17, p. 991, 1981 (EJCODS); oms-hmn-oth 1 mmol/L Anticancer Research. (5 Argyropoulou St., Kato Patissia, Athens 907, Greece) V.1- 1981- v. 10, p. 297, 1990 (ANTRD4); oms-hmn-lym 150 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 206, p. 361, 1988 (MUREAV); cyt-hmn-oth 1 mg/L International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 21, p. 438, 1978 (IJCNAW); cyt-hmn-lym 500 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 19, p. 225, 1973 (MUREAV); sce-hmn-oth 400 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 49, p. 605, 1989 (CNREA8); sce-hmn-lym 1 umol/L Cancer Treatment Reports. (Washington, DC) V.60-71, 1976-87. For publisher information, see JNCIEQ. v. 69, p. 505, 1985 (CTRRDO); sce-hmn-fbr 1 umol/L European Journal of Cancer and Clinical Oncology. (Pergamon Press, c/o Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.17(7)- 25, 1981-89. For publisher information, see EJCAEL v. 17, p. 991, 1981 (EJCODS); sce-hmn-lym 100 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 14, p. 6, 1989 (EMMUEG); dni-rat-oth 160 nmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 39, p. 191, 1982 (CBINA8); mnt-mus-ipr 1250 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 389, p. 3, 1997 (MUREAV); mmo-mus-lym 100 ug/L (+S9) Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 1, p. 277, 1978 (DCTODJ); slt-mus-ipr 5 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 282, p. 151, 1992 (MUREAV); mtr-mus-emb 100 ug/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 37, p. 2202, 1977 (CNREA8); dnd-mus-oth 40 umol/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 37, p. 3189, 1988 (BCPCA6); dnd-mus-unr 2 mg/kg Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 24, p. 246, 1983 (PAACA3); dnd-mus-ipr 40 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 467, p. 83, 2000 (MUREAV); dns-mus-unr 37600 nmol/kg Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 24, p. 248, 1983 (PAACA3); dni-mus-ipr 37700 nmol/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 46, p. 2340, 1986 (CNREA8); dni-mus-lym 2 mg/L Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 25, p. 378, 1975 (ARZNAD); sce-mus-oth 2 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 2025, 1985 (CNREA8); sce-mus-ipr 1500 ug/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 6), p. 32, 1986 (ENMUDM); dlt-mus-ipr 7500 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 345, p. 167, 1995 (MUREAV); msc-mus-lym 100 ug/L Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 1, p. 277, 1978 (DCTODJ); trn-mus-ipr 7500 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 345, p. 167, 1995 (MUREAV); dnd-ham-lng 1 mg/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 35, p. 1163, 1986 (BCPCA6); dnd-ham-ovr 3 mg/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 3175, 1983 (CNREA8); cyt-ham-emb 1 mg/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 37, p. 2202, 1977 (CNREA8); sce-ham-fbr 5 ug/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 797, 1979 (CNREA8); dnd-mam-lym 2500 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 235, 1996 (MUREAV); mnt-hmn-oth 4 umol/L/10H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 472, p. 93, 2000 (MUREAV); mtr-mus-fbr 0.01 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) RE: T14 orl-wmn TDLo: 3750 ug/kg (25D pre) Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 1, p. 1174, 1977 (LANCAO); T12-T19 unr-chd TDLo: 8800 ug/kg (1D pre) Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 1, p. 1425, 1987 (LANCAO); T14 unr-wmn TDLo: 5946 ug/kg (1D pre) Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 1, p. 1425, 1987 (LANCAO) TE: V01-P30-P62 orl-wmn TDLo: 80 ug/kg Blood. (Grune and Stratton, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1946- v. 41, p. 17, 1973 (BLOOAW); V01-P30-P62 orl-man TDLo: 57 ug/kg Blood. (Grune and Stratton, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1946- v. 41, p. 17, 1973 (BLOOAW); V01-P60 unr-wmn TDLo: 26 mg/kg/2Y-C Journal of Clinical Pathology. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1947- v. 26, p. 649, 1973 (JCPAAK); V02-V10 ipr-rat TDLo: 70 mg/kg/26W-I Recent Results in Cancer Research. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1965- v. 52, p. 1, 1975 (RRCRBU); V03-J60-R60 skn-mus TDLo: 58 mg/kg/9W-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 10, p. 363, 1956 (BJCAAI); V01-J60-P62 ipr-mus TDLo: 60 mg/kg/26W-I Recent Results in Cancer Research. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1965- v. 52, p. 1, 1975 (RRCRBU); V02-R60 ipr-mus TD :15 mg/kg/6W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 37, p. 317, 1977 (CNREA8); V01-P61 orl-man TD :66 mg/kg/4Y-I Blood. (Grune and Stratton, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1946- v. 44, p. 333, 1974 (BLOOAW); V01-P61 orl-man TD :34 mg/kg/2Y-I Scandinavian Journal of Haematology. (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.1- 1964- v. 8, p. 375, 1971 (SJHAAQ); V01-P61 orl-wmn TD :12 mg/kg/3Y-I Oncology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.21- 1967- v. 40, p. 268, 1983 (ONCOBS); V01-P61 orl-wmn TD :23 mg/kg/2Y-I Acta Medica Scandinavica. (Almqvist and Wiksell, POB 45150, S-10430 Stockholm, Sweden) V.52-224, 1919-88. v. 211, p. 203, 1982 (AMSVAZ); V01-P61 orl-man TD :17 mg/kg/4Y-I Acta Medica Scandinavica. (Almqvist and Wiksell, POB 45150, S-10430 Stockholm, Sweden) V.52-224, 1919-88. v. 211, p. 203, 1982 (AMSVAZ) ORNG: 11200000 ng/kg. [11.200000 mg/kg] T/E unlistd AT: K13 orl-hmn TDLo: 700 mg/kg/7D "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,367,1969 (34ZIAG); K13 orl-hmn TDLo: 1200 ug/kg/5D-I Cancer Chemotherapy Reports, Part 1. (Washington, DC) V.52(6)-59, 1968-75. For publisher information, see CTRRDO. v. 57, p. 369, 1973 (CCROBU); F14-K12-P15 ivn-chd LDLo: 4500 mg/kg New Zealand Medical Journal. (New Zealand Medical Assoc., P.O. Box 156, Wellington, New Zealand) V.1- 1900- v. 97, p. 816, 1984 (NZMJAX); F14-K12-P15 ivn-man LDLo: 8140 mg/kg New Zealand Medical Journal. (New Zealand Medical Assoc., P.O. Box 156, Wellington, New Zealand) V.1- 1900- v. 97, p. 816, 1984 (NZMJAX); K12-P15-P17 ivn-inf TDLo: 28 mg/kg Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 2, p. 1048, 1984 (LANCAO); T/E unlistd orl-rat LD50: 11200 ug/kg Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- v. 10, p. 710, 1979 (IYKEDH); T/E unlistd ipr-rat LD50: 4484 ug/kg Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 13, p. 969, 1964 (BCPCA6); T/E unlistd ivn-rat LD50: 4100 ug/kg Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- v. 10, p. 710, 1979 (IYKEDH); T/E unlistd ice-rat LD50: 200 ug/kg Journal of Pharmacy and Pharmacology. (Pharmaceutical Soc. of Great Britain, 1 Lambeth High St., London SEI 7JN, UK) V.1- 1949- v. 18, p. 760, 1966 (JPPMAB); T/E unlistd scu-mus LD10: 32 mg/kg European Journal of Cancer (Elsevier Science, P.O.Box 7247-7682,Philadelphia,PA 19170 -7682,USA OR Elsevier Science B.V.,P.O.Box 1270,1000 BG Amsterdam,The Netherlands) V. 1- 1965- v. 10, p. 667, 1974 (EJCAAH); F07-P30-U01 ivn-mus LD50: 20800 ug/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-133921 (NTIS**); T/E unlistd par-mus LD50: 6 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 47, p. 62, 1987 (CNREA8); T/E unlistd unr-mus LD50: 29600 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 46, p. 2703, 1986 (CNREA8); F07-K12-P05 ivn-dog LDLo: 3 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-133921 (NTIS**) MD: N73-S04-U01 orl-rat TDLo: 14 mg/kg/7D-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 107, p. 47, 1996 (TXCYAC) TR: IARC Cancer Review: Human Sufficient Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 239, 1987 (IMSUDL); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 9, p. 167, 1975 (IMEMDT); IARC Cancer Review: Group 1 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 239, 1987 (IMSUDL) ND: NOES 1983: HZD X4742; NIS 1; TNF 140; NOS 4; TNE 2418; TFE 974 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, Cell transform.-C3H/10T1/2; EPA GENETOX PROGRAM 1988, Positive: In vitro cytogenetics-nonhuman; EPA GENETOX PROGRAM 1988, Positive: In vitro cytogenetics-human, E coli polA with S9; EPA GENETOX PROGRAM 1988, Positive: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: In vitro SCE-human lymphocytes; EPA GENETOX PROGRAM 1988, Positive: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Positive/dose response: In vitro SCE-nonhuman; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster-reciprocal translocation; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; NCI Carcinogenesis Studies (ipr), clear evidence: mouse, rat Recent Results in Cancer Research. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1965- v. 52, p. 1, 1975 (RRCRBU); NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen; NTP Carcinogenesis studies, on test (prechronic studies), October 2000; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 487 of 1119 in RTECS (through 2003/06) AN: AY4375000 PN: Alanine, N-((5-chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl)carbonyl)-3-phenyl-, (-)- SY: N-(((3R)-5-Chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl)carbonyl)-3-phenyl-L-alanine; (-)-N-((5-Chloro-8-hydroxy-3-methyl-1-oxo-7-isochromanyl)carbonyl)-3-phenylalanine; NCI-C56586-; Ochratoxin-A-; Phenylalanine---ochratoxin-A- RN: Current: 303-47-9 BRN: 1301486 BHR: 5-18-09-00056 UD: 200305 MF: C20-H18-Cl-N-O6 MW: 403.84 WL: T66 BVOT&J D1 GG IVMYVQ1R& JQ CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Natural-Product (N) ME: oms-esc 2 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 307, p. 141, 1994 (MUREAV); dnd-rat-orl 10080 ug/kg/12W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 31(Suppl), p. 195, 1986 (TOLED5); dnd-rat-fbr 200 mg/L Folia Biologica (Prague). (Academic Press Inc. Ltd., 24-28 Oval Rd., London NW1 7DX, UK) V.1- 1955- v. 32, p. 128, 1986 (FOBLAN); dnd-mus-oth 1 mg/L Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 179, p. 688, 1985 (CRSBAW); dnd-mus-ipr 2500 ug/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 28, p. 29, 1985 (TOLED5); dna-mus-orl 2500 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 289, p. 265, 1993 (MUREAV); dns-mus-lvr 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 2918, 1984 (CNREA8); mnt-ham-emb 10 umol/L Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 37, p. 713, 1999 (FCTOD7); dnd-ham-ovr 200 mg/L Folia Biologica (Prague). (Academic Press Inc. Ltd., 24-28 Oval Rd., London NW1 7DX, UK) V.1- 1955- v. 32, p. 128, 1986 (FOBLAN); sce-ham-ovr 160 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-358, 1989 (NTPTR*); cyt-mky-kdy 20 mg/L Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 32, p. 198, 1975 (TXAPA9); dns-mam-kdy 24 umol/L Toxicon. (Pergamon Press Ltd., Headington Hill Hall, Oxford OX3 OBW, UK) V.1- 1962- v. (Suppl 3), p. 353, 1983 (TOXIA6); dni-mam-kdy 50 umol/L Toxicon. (Pergamon Press Ltd., Headington Hill Hall, Oxford OX3 OBW, UK) V.1- 1962- v. (Suppl 3), p. 353, 1983 (TOXIA6); dna-hmn-lng 10 umol/L/4H Environmental Toxicology and Pharmacology (Elsevier Science, P.O.Box 7247-7682,Philadelphia,PA 19170 -7682,USA OR Elsevier Science B.V.,P.O.Box 1270,1000 BG Amsterdam,The Netherlands) V.1- Feb.1996- v. 7, p. 95, 1999 (ETOPFR); dnd-dog-kdy 100 umol/L/3H Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 75, p. 734, 2002 (ATSUDG); mnt-hmn-lvr 5 mg/L/24H Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 40, p. 1085, 2001 (FCTOD7); dnd-hmn-lvr 5 mg/L/24H Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 40, p. 1085, 2001 (FCTOD7) RE: T25-T35-T46 orl-rat TDLo: 8 mg/kg (7-10D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 28, p. 37A, 1983 (TJADAB); T72-T75 orl-rat TDLo: 5 mg/kg (8-9D preg) Annales Recherches Veterinaires. (Institut National de la Recherche Agronomique, Service des Publ., Route de Saint-Cyr, 78000 Versailles, France) V.1- 1970- v. 6, p. 379, 1975 (ARCVBP); T25-T34-T53 orl-rat TDLo: 7500 ug/kg (6-15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 331, 1976 (TXAPA9); T85 orl-rat TDLo: 1 mg/kg (11-14D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 28, p. 16A, 1983 (TJADAB); T42-T47 orl-rat TDLo: 10 mg/kg (6-15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 331, 1976 (TXAPA9); T55-T46 orl-rat TDLo: 5 mg/kg (6-15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 331, 1976 (TXAPA9); T31-T34 orl-rat TDLo: 8 mg/kg (11-14D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 28, p. 37A, 1983 (TJADAB); T12-T25 ipr-rat TDLo: 35 mg/kg (6-12D preg) Endokrinologie. (Leipzig, Ger. Dem. Rep.) V.1-80, 1928-82. For publisher information, see EXCEDS. v. 77, p. 152, 1981 (ENDKAC); T02-T03 ipr-rat TDLo: 40 mg/kg (8D male) Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 17, p. 121, 1979 (IJEBA6); T41-T45-T50 scu-rat TDLo: 1750 ug/kg (7D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 25, p. 175, 1982 (TXCYAC); T25-T34 scu-rat TDLo: 1750 ug/kg (7D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 25, p. 175, 1982 (TXCYAC); T46-T53 scu-rat TDLo: 1750 ug/kg (6D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 25, p. 175, 1982 (TXCYAC); T42 scu-rat TDLo: 1750 ug/kg (5D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 25, p. 175, 1982 (TXCYAC); T25-T26-T34 scu-rat TDLo: 1750 ug/kg (7D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 32, p. 277, 1984 (TXCYAC); T81-T85 orl-mus TDLo: 3750 ug/kg (15-17D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 27, p. 293, 1983 (TJADAB); T33-T41 orl-mus TDLo: 3 mg/kg (15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 57, p. 127, 1981 (TXAPA9); T34-T46 orl-mus TDLo: 3 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 32, p. 381, 1985 (TJADAB); T34-T35-T46 orl-mus TDLo: 7 mg/kg (7-13D preg) Kankyo Igaku Kenkyusho Nenpo (Nagoya Daigaku). Annual Report of the Research Institute of Environmental Medicine, Nagoya University. (Nagoya Daigaku Kankyo Igaku Kenkyusho, Furo-cho, Chikosa-ku, Nagoya 464, Japan) V.1- 1949- v. 34, p. 261, 1983 (NDKIA2); T41-T42 orl-mus TDLo: 1 mg/kg (9D preg) Acta Veterinaria Scandinavica. (Danske Dyrlargeforening, Alhambravej 15, DK-1826 Copenhagen V, Denmark) V.1- 1959- v. 22, p. 535, 1981 (AVSCA7); T43-T72 orl-mus TDLo: 3 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 29(2), p. 58A, 1984 (TJADAB); T41-T75-T81 ipr-mus TDLo: 2 mg/kg (10D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 28, p. 15A, 1983 (TJADAB); T33-T39 ipr-mus TDLo: 3 mg/kg (11D preg) Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- v. 9, p. 297, 1984 (JTSCDR); T42-T41 ipr-mus TDLo: 5 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 9, p. 93, 1974 (TJADAB); T34-T41-T43 ipr-mus TDLo: 2 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 17, p. 25, 1978 (TJADAB); T25 ipr-mus TDLo: 4 mg/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 17, p. 25, 1978 (TJADAB); T43-T46-T35 ipr-ham TDLo: 5 mg/kg (7D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 13, p. 11, 1976 (TJADAB); T41 ipr-ham TDLo: 7500 ug/kg (8D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 13, p. 11, 1976 (TJADAB); T34 ipr-ham TDLo: 20 mg/kg (9D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 13, p. 11, 1976 (TJADAB) TE: V01-M61 orl-rat TDLo: 36050 ug/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-358, 1989 (NTPTR*); V01-L60-M61 orl-mus TDLo: 2216 mg/kg/44W-C Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 69, p. 599, 1978 (GANNA2); V02-L60 orl-mus TD :1478 mg/kg/44W-C Maikotokishin (Tokyo). Mycotoxin. (Maikotokishin Kenkyukai, c/o Tokyo Rika Daigaku Yakugakubu, 12 Funagawara-machi, Ichigaya, Shinjuku-ku, Tokyo 162, Japan) No.1- 1975- v. (18), p. 15, 1983 (MAIKD3); V03-L60 orl-mus TD :1478 mg/kg/44W-C Gan no Rinsho. Cancer Clinics. (Shinohara Shuppan K.K., 2-11-7 Hongo, Bunkyo-ku, Tokyo, Japan) V.1- 1954- v. 30, p. 1445, 1984 (GANRAE); V01-M61 orl-mus TD :3504 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 75, p. 733, 1985 (JJIND8); V03-L60-M61 orl-mus TD :2 gm/kg/30W-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 31(Suppl), p. 206, 1986 (TOLED5); V01-M61-M03 orl-rat TDLo: 10.815 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-219478/AS (NTIS**); V02-R60 orl-rat TDLo: 108.15 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-219478/AS (NTIS**) ORNG: 20000000 ng/kg. [20.000000 mg/kg] J16-U01 AT: J16-U01 orl-rat LD50: 20 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 6, p. 479, 1968 (FCTXAV); F05-K06-R21 ipr-rat LD50: 12600 ug/kg Annales Recherches Veterinaires. (Institut National de la Recherche Agronomique, Service des Publ., Route de Saint-Cyr, 78000 Versailles, France) V.1- 1970- v. 5, p. 233, 1974 (ARCVBP); F05-K06-R21 ivn-rat LD50: 12750 ug/kg Annales Recherches Veterinaires. (Institut National de la Recherche Agronomique, Service des Publ., Route de Saint-Cyr, 78000 Versailles, France) V.1- 1970- v. 5, p. 233, 1974 (ARCVBP); T/E unlistd unr-rat LD50: 22 mg/kg Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 29, p. 813, 1991 (IJEBA6); T/E unlistd orl-mus LD50: 46 mg/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 25, p. 1, 1985 (TOLED5); T/E unlistd ipr-mus LD50: 22 mg/kg Acta Pharmacologica et Toxicologica. (Copenhagen, Denmark) V.1-59, 1945-86. For publisher information, see PHTOEH v. 2, p. 109, 1946 (APTOA6); F05-K06-R21 ivn-mus LD50: 25710 ug/kg Annales Recherches Veterinaires. (Institut National de la Recherche Agronomique, Service des Publ., Route de Saint-Cyr, 78000 Versailles, France) V.1- 1970- v. 5, p. 233, 1974 (ARCVBP); G03-L30-M30 orl-ckn LD50: 3300 ug/kg Applied Microbiology. (Washington, DC) V.1-30, 1953-75. For publisher information, see AEMIDF. v. 21, p. 492, 1971 (APMBAY); L02 scu-ckn LDLo: 11 mg/kg Applied Microbiology. (Washington, DC) V.1-30, 1953-75. For publisher information, see AEMIDF. v. 21, p. 492, 1971 (APMBAY); F07-F19-U01 orl-qal LD50: 16500 ug/kg Poultry Science. (Poultry Science Assoc., Inc., 309 W. Clark St., Champaign, IL 61820) V.1- 1921- v. 55, p. 786, 1976 (POSCAL); L03 orl-dck LD50: 500 ug/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 205, p. 1112, 1965 (NATUAS); F07-F19-U01 orl-trk LD50: 5900 ug/kg Poultry Science. (Poultry Science Assoc., Inc., 309 W. Clark St., Champaign, IL 61820) V.1- 1921- v. 55, p. 786, 1976 (POSCAL); J15-L30 ivn-dom LD50: 1 mg/kg CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- v. 2, p. 499, 1974 (CRTXB2) MD: M03-M30 orl-rat TDLo: 36050 ug/kg/2Y-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 6, p. 181, 1986 (TOXID9); L30-P28-Y20 orl-rat TDLo: 46667 ug/kg/8W-I Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 43, p. 180, 1989 (BECTA6); M70 orl-rat TDLo: 8125 ug/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-358, 1989 (NTPTR*); L70-M11-P28 orl-rat TDLo: 8 mg/kg/2W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 28, p. 180, 1974 (TXAPA9); P70-P71-P72 orl-rat TDLo: 40 mg/kg/10D-I Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 17, p. 49, 1979 (FCTXAV); M03 orl-rat TDLo: 7 mg/kg/7D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 104, p. 83, 1999 (TOLED5); M16-M30-U01 ipr-rat TDLo: 3750 ug/kg/5D-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 12, p. 5, 1979 (TXCYAC); M30-Y03-Y10 ipr-rat TDLo: 6 mg/kg/4W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 109(Suppl 1), p. 72, 1999 (TOLED5); N74-P26-P70 ipr-mus TDLo: 40 mg/kg/8D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 72, p. 304, 1984 (TXAPA9); P28-Y03-Y10 ipr-mus TDLo: 30 mg/kg/6W-I Indian Journal of Pharmacology. (Dept. of Pharmacology, Baranas Hindu Univ., Varanasi 221 005, India) V.1- 1968(?)- v. 16, p. 238, 1984 (INJPD2); D25-M16-P30 orl-dog TDLo: 2800 ug/kg/14D-I Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- v. 10, p. 135, 1973 (VTPHAK); M03-P27-Z01 orl-pig TDLo: 6 mg/kg/6D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 25, p. 456, 1973 (TXAPA9); M04-M16-U01 orl-pig TDLo: 4880 ug/kg/17W-C Acta Pathologica et Microbiologica Scandinavica, Section A, Supplement. (Copenhagen, Denmark) No.210-274, 1970-81. For publisher information, see ACPADQ. v. 246, p. 1, 1974 (APMSBI); F07-M03-Z01 orl-pig TDLo: 13200 ug/kg/22D-C Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- v. 10, p. 347, 1973 (VTPHAK); M03-Y39-Z01 orl-gpg TDLo: 140 mg/kg/14D-I Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 15, p. 563, 1977 (FCTXAV); K70-M70-P28 orl-ckn TDLo: 9198 ug/kg/21D-C Poultry Science. (Poultry Science Assoc., Inc., 309 W. Clark St., Champaign, IL 61820) V.1- 1921- v. 78, p. 1380, 1999 (POSCAL); F15 orl-dom TDLo: 3150 ug/kg/2W-C Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 77, p. 1217, 1999 (JANSAG); M12-M13-U01 orl-rat TDLo: 6.069 mg/kg/48H/6W-I Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 75, p. 176, 2001 (ARTODN) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 31, p. 191, 1983 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 56, p. 489, 1993 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 31, p. 191, 1983 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 56, p. 489, 1993 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 56, p. 489, 1993 (IMEMDT); TOXICOLOGY REVIEW Journal of the American Veterinary Medical Association. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.48- 1915- v. 163, p. 1269, 1973 (JAVMA4); TOXICOLOGY REVIEW Progress in Medical Chemistry. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1961- v. 10, p. 85, 1974 (PMDCAY); TOXICOLOGY REVIEW Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 127, p. 19, 2002 (TOLED5) SL: EPA GENETOX PROGRAM 1988, Positive: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Negative: B subtilis rec assay; EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; NCI Carcinogenesis Studies (gavage), clear evidence: rat; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 488 of 1119 in RTECS (through 2003/06) AN: AY5940000 PN: Alanine, 3-(3,4-dihydroxyphenyl)-2-methyl-, DL- SY: 3-Hydroxy-alpha-methyl-DL-tyrosine-; Metholes-; (+-)-alpha-Methyldopa; DL-Methyldopa-; DL-alpha-Methyl-DOPA-; racemic-alpha-Methyldopa-; (RS)-alpha-Methyldopa; Mulfasin-; DL-Tyrosine,-3-hydroxy-alpha-methyl- (9CI) RN: Current: 555-29-3 UD: 199403 MF: C10-H13-N-O4 MW: 211.24 WL: QVXZ1&1R CQ DQ CC: Drug (D) ORNG: 5710000000 ng/kg. [5710.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 5710 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-348, 1989 (NTPTR*); T/E unlistd ipr-rat LD50: 430 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-348, 1989 (NTPTR*); T/E unlistd orl-mus LD50: 5370 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-348, 1989 (NTPTR*); L01-M03 ipr-mus LD50: 1317 mg/kg Journal of Medicinal Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC 20037) V.6- 1963- v. 23, p. 1318, 1980 (JMCMAR); T/E unlistd ivn-mus LD50: 1760 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-348, 1989 (NTPTR*) Record 489 of 1119 in RTECS (through 2003/06) AN: BA5075000 PN: Allyl-alcohol- SY: Allilowy-alkohol- (Polish); Alcool-allilco- (Italian); Alcool-allylique- (French); AA-; Allyl-alcohol- (ACGIH:OSHA); Allylalkohol- (German); Allylic-alcohol-; 3-Hydroxypropene-; Orvinylcarbinol-; RCRA-waste-number-P005-; Shell-unkrautted-A-; Vinylcarbinol-; Weed-drench-; 2-Propene-1-ol-; Propenol-; Propen-1-ol-3-; 1-Propenol-3-; 1-Propen-3-ol-; 2-Propen-1-ol-; Propenyl-alcohol-; 2-Propenyl-alcohol- RN: Current: 107-18-6 UD: 200305 MF: C3-H6-O MW: 58.09 WL: Q2U1 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Human-Data (P); Primary-Irritant (S) ID: eye-hmn 25 ppm SEV AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 18, p. 303, 1958 (AMIHAB); skn-rbt 10 mg/24H open Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 63, 1948 (JIHTAB); eye-rbt 20 mg SEV American Journal of Ophthalmology. (Ophthalmic Pub. Co., 435 N. Michigan Ave., Suite 1415, Chicago, IL 60611) Series 3: V.1- 1918- v. 29, p. 1363, 1946 (AJOPAA) ME: mmo-sat 100 umol/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 305, 1982 (MUREAV); mmo-sat 50 ug/plate (-S9) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 1, p. 259, 1980 (TCMUD8); msc-ham-lng 1 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 11, p. 497, 1990 (CRNGDP) ORNG: 64000000 ng/kg. [64.000000 mg/kg] T/E unlistd SRNG: 45000000 ng/kg. [45.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 64 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 63, 1948 (JIHTAB); J15 ihl-rat LC50: 76 ppm/8H AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 18, p. 303, 1958 (AMIHAB); T/E unlistd ipr-rat LD50: 37 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 83, p. 108, 1986 (TXAPA9); J15-F19 orl-mus LD50: 96 mg/kg AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 18, p. 303, 1958 (AMIHAB); T/E unlistd ihl-mus LC50: 500 mg/m3/2H "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,17,1982 (85GMAT); F07-F13-F19 ipr-mus LD50: 60 mg/kg AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 18, p. 303, 1958 (AMIHAB); T/E unlistd ivn-mus LD50: 78 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 135, p. 330, 1962 (AIPTAK); F24-K13-P30 unr-dog LDLo: 4270 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 25, p. 144, 1925 (JPETAB); K12-P01-Y55 ihl-mky LCLo: 1000 ppm/4H JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- v. 98, p. 2269, 1932 (JAMAAP); T/E unlistd orl-rbt LD50: 52 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571508 (NTIS**); D27-J22-P01 ihl-rbt LCLo: 1000 ppm/3.5H JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- v. 98, p. 2269, 1932 (JAMAAP); T/E unlistd skn-rbt LD50: 45 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 63, 1948 (JIHTAB); T/E unlistd scu-rbt LDLo: 100 mg/kg "Zur Pharmakologie Ungesattigter Alkohole, Dissertation," Bock, H., Pharmakologischen Institut der Universitat Breslau, Poland, 1930 v. -, p. -, 1930 (BDBU**); F13-K13 par-frg LDLo: 51 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 50, p. 296, 1935 (AIPTAK); T/E unlistd orl-mam LD50: 70 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 32(10), p. 25, 1988 (GTPZAB); T/E unlistd ihl-mam LC50: 1 gm/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 32(10), p. 25, 1988 (GTPZAB); T/E unlistd unr-mam LD50: 66 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 51(5), p. 61, 1986 (GISAAA); T/E unlistd ipr-mus TDLo: 64 mg/kg Environmental Toxicology and Pharmacology (Elsevier Science, P.O.Box 7247-7682,Philadelphia,PA 19170 -7682,USA OR Elsevier Science B.V.,P.O.Box 1270,1000 BG Amsterdam,The Netherlands) V.1- Feb.1996- v. 3, p. 129, 1997 (ETOPFR); L30-P28-Y03 ihl-rat TCLo: 140 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1984 (VCVGK*); P28 ihl-rat TCLo: 200 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1984 (VCVGK*); T/E unlistd orl-mus LD50: 75 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1984 (VCVGK*); G30-L01 ihl-mus LC50: 500 mg/m3/2H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1984 (VCVGK*); L01-Y03 orl-rat TDLo: 0.05 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1984 (VCVGK*); J06-K30-M30 orl-hmn LDLo: 0.43 ml/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1984 (VCVGK*); L50 orl-rat TDLo: 50 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 50, p. 100, 1987 (FATOAO); L02-L14 orl-rat TDLo: 50 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 50, p. 100, 1987 (FATOAO) MD: F15-M70-U01 orl-rat TDLo: 4200 mg/kg/15W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 9, p. 29, 1978 (TXCYAC); J70-M70-U01 ihl-rat TCLo: 60 ppm/7H/13W-I AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 18, p. 303, 1958 (AMIHAB); L14-P28-Y39 orl-rat TDLo: 610 mg/kg/244D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 121, 1994 (VCVGK*) TR: ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.5 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*) SR: MSHA STANDARD-air: TWA 2 ppm (5 mg/m3) (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 7, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 2 ppm (5 mg/m3), Skin, JAN 1993; OEL-AUSTRALIA: TWA 2 ppm (5 mg/m3), STEL 4 ppm, Skin, JAN 1993; OEL-AUSTRIA: MAK 2 ppm (5 mg/m3), Skin, JAN 1999; OEL-BELGIUM: TWA 2 ppm (4.8 mg/m3), STEL 4 ppm (9.5 mg/m3), Skin, JAN 1993; OEL-DENMARK: TWA 2 ppm (5 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 2 ppm (5 mg/m3), STEL 4 ppm (10 mg/m3), Skin, JAN 1993; OEL-FRANCE: VME 2 ppm (5 mg/m3), VLE 4 ppm (10 mg/m3), Skin, JAN 1999; OEL-GERMANY: MAK 2 ppm (5 mg/m3), Skin, JAN 1999; OEL-HUNGARY: TWA 3 mg/m3, STEL 6 mg/m3, Skin, JAN 1993; OEL-JAPAN: OEL 1 ppm (2.4 mg/m3), Skin, JAN 1999; OEL-NORWAY: TWA 2 ppm (5 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 2 ppm (5 mg/m3), Skin, JAN 1993; OEL-POLAND: MAC(TWA) 2 mg/m3, MAC(STEL) 10 mg/m3, Skin, JAN 1999; OEL-RUSSIA: TWA 1 ppm, JAN 1993; OEL-SWEDEN: NGV 2 ppm (5 mg/m3), KTV 6 ppm (14 mg/m3), Skin, JAN 1999; OEL-SWITZERLAND: MAK-W 2 ppm (5 mg/m3), KZG-W 4 ppm (10 mg/m3), Skin, JAN 1999; OEL-TURKEY: TWA 2 ppm (5 mg/m3), Skin, JAN 1993; OEL-UNITED KINGDOM: TWA 2 ppm (4.8 mg/m3), STEL 4 ppm (9.7 mg/m3), Skin, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ALLYL ALCOHOL-air: 10H TWA 2 ppm (Sk), STEL 4 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 04370; NIS 3; TNF 69; NOS 7; TNE 780; NOES 1983: HZD 04370; NIS 3; TNF 60; NOS 4; TNE 3246; TFE 157 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Alcohols III, 1402; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 490 of 1119 in RTECS (through 2003/06) AN: BO7175000 PN: Ammonium, benzyldimethyl(2-(2-(p-(1,1,3,3-tetramethylbutyl)phenoxy)ethoxy)ethyl)-,chloride SY: Anti-germ-77-; Antiseptol-; Antiseptol- (quarternary compound); Benzethonium-chloride-; Benzethonium-chloride-1622-; Benzyldimethyl-p-(1,1,3,3-tetramethylbutyl)phenoxyethoxy-ethylammonium chloride; Benzyldimethyl(2-(2-(p-(1,1,3,3-tetramethylbutyl)phenoxy)ethoxy)ethyl)ammonium chloride; BZT-; Diapp-; Diisobutylphenoxyethoxyethyl-dimethyl-benzyl-ammonium-chloride-; Disilyn-; Hyamine-; Hyamine-1622-; NCI-C61494-; Phemeride-; Phemerol-; Phemerol-chloride-; Phemithyn-; Polymine-D-; Quatrachlor-; Solamin-; Solamine-; p-tert-Octylphenoxyethoxyethyldimethylbenzylammonium-chloride- RN: Current: 121-54-0 UD: 200207 MF: C27-H42-N-O2.Cl MW: 448.15 WL: 1X1&1&1X1&1&R DO2O2K1&1&1R &Q &G CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M); Primary-Irritant (S) ID: eye-rbt 30 ug SEV Proceedings of the Scientific Section of the Toilet Goods Association. (Washington, DC) No.1-48, 1944-67. Discontinued. v. 20, p. 16, 1953 (PSTGAW) ME: dnr-esc 1500 ng/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 133, p. 161, 1984 (MUREAV); sce-ham-emb 1 mg/L Shigaku. Ondotology. (Nippon Shika Daigaku Shigakkai, 1-9-20 Fujimi, Chiyodaku, Tokyo 102, Japan) V.38- 1949- v. 74, p. 1365, 1987 (SHIGAZ) TE: V02-R60-V10 scu-rat TDLo: 104 mg/kg/1Y-I Clinical Toxicology. (New York, NY) V.1-18, 1968-81. For publisher information, see JTCTDW. v. 4, p. 185, 1971 (CTOXAO) ORNG: 368000000 ng/kg. [368.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 368 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 120, p. 511, 1965 (PSEBAA); F05-F12-J25 ipr-rat LD50: 16500 ug/kg Fukuoka Shika Daigaku Gakkai Zasshi. Journal of Fukuoka Dental College. (700 Ta, O-aza, Sawara-ku, Fukuoka 814-01, Japan) V.1- 1974- v. 9, p. 729, 1983 (FSDZD4); T/E unlistd scu-rat LD50: 119 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB195-158 (NTIS**); F07-M14-P20 ivn-rat LD50: 19 mg/kg Soap and Chemical Specialties. (New York, NY) V.30-47, 1954-71. For publisher information, see SCCSC8. v. 30, p. 147, 1954 (SCHSAV); T/E unlistd unr-rat LD50: 420 mg/kg "Merck Index: an Encyclopedia of Chemicals, Drugs, and Biologicals", 11th ed., Rahway, NJ 07065, Merck and Co., Inc. 1989 11,167,1989 (85KYAH); T/E unlistd orl-mus LD50: 338 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 120, p. 511, 1965 (PSEBAA); T/E unlistd ipr-mus LD50: 7813 ug/kg Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 4(5), p. 65, 1985 (JACTDZ); T/E unlistd ivn-mus LD50: 30 mg/kg Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. v. 40, p. 267, 1951 (JAPMA8) MD: K30-U01-Z01 orl-rat TDLo: 182 gm/kg/2Y-C Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 109, p. 422, 1953 (JPETAB); N74-R03-U01 skn-rat TDLo: 60 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-438, 1995 (NTPTR*); R03 skn-rat TDLo: 203 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-438, 1995 (NTPTR*); U01 scu-rat TDLo: 312 mg/kg/1Y-I Clinical Toxicology. (New York, NY) V.1-18, 1968-81. For publisher information, see JTCTDW. v. 4(2), p. 185, 1971 (CTOXAO); G70-N74-R03 skn-mus TDLo: 1200 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-438, 1995 (NTPTR*); R03 skn-mus TDLo: 101 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-438, 1995 (NTPTR*); B30 isp-pig TDLo: 13 mg/kg/7D-I Regional Anesthesia and Pain Medicine. (Churchill Livingstone, The Curtis Center, Independence Square West, Philadelphia, PA 19106) V.23- 1998- v. 24, p. 146, 1999 (RAPMFX) TR: TOXICOLOGY REVIEW Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 4(5), p. 65, 1985 (JACTDZ) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC) ND: NOHS 1974: HZD 25830; NIS 15; TNF 2975; NOS 26; TNE 26546; NOES 1983: HZD 25830; NIS 11; TNF 1657; NOS 20; TNE 26949; TFE 18054 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (derm), no evidence: mouse, rat Record 491 of 1119 in RTECS (through 2003/06) AN: BO8400000 PN: Ammonium,-benzyltrimethyl-,-chloride- SY: Benzenemethanaminium,-N,N,N-trimethyl-,-chloride- (9CI); Benzyltrimethylammonium-chloride-; BTM-; Tmbac-; N,N,N-Trimethylbenzenemethanaminium-chloride-; Trimethylbenzylammonium-chloride- RN: Current: 56-93-9 UD: 200012 MF: C10-H16-N.Cl MW: 185.72 WL: 1K1&1&1R &G CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C) AT: T/E unlistd orl-rat LDLo: 250 mg/kg National Academy of Sciences, National Research Council, Chemical-Biological Coordination Center, Review. (Washington, DC) v. 5, p. 39, 1953 (NCNSA6); T/E unlistd orl-mus LDLo: 1600 mg/kg Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 69, p. 327, 1980 (JPMSAE) ND: NOHS 1974: HZD 83392; NIS 39; TNF 3855; NOS 51; TNE 32889; NOES 1983: HZD 83392; NIS 4; TNF 122; NOS 3; TNE 5002; TFE 2721 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(e) Risk Notification, 8EHQ-1292-8625; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Toxicity studies, RPT# TOX-57, October 2000 Record 492 of 1119 in RTECS (through 2003/06) AN: BQ1180000 PN: Ammonium, (4-(p-(dimethylamino)-alpha-phenylbenzylidene)-2,5-cyclohexadien-1-ylidene)- dimethyl-, chloride SY: ADC-Malachite-Green-Crystals-; Acryl-Brilliant-Green-B-; Aizen-Malachite-Green-; Aizen-Malachite-Green-Crystals-; Aniline-Green-; Astra-Malachite-Green-; Astra-Malachite-Green-B-; Astra-Malachite-Green-BXX-; Basic-Green-4-; Benzal-Green-; Benzaldehyde-Green-; Bronze-Green-Toner-A-8002-; Burma-Green-B-; C.I. 42000; C.I. Basic Green 4; Calcozine-Green-V-; China-Green-; China-Green- (biological stain); Diabasic-Malachite-Green-; Diamond-Green-B-; Diamond-Green-B-Extra-; Diamond-Green-BX-; Diamond-Green-P-Extra-; Fast-Green-; Fast-Green-O-; Green-MX-; Grenoble-Green-; Hidaco-Malachite-Green-Base-; Hidaco-Malachite-Green-LC-; Hidaco-Malachite-Green-SC-; Light-Green-N-; Light-Green-N- (biological stain); Lincoln-Green-Toner-B-15-2900-; Malachit-grun- (German); Malachite-Green-; Malachite-Green- (indicator); Malachite-Green-A-; Malachite-Green-AN-; Malachite-Green-B-; Malachite-Green-CP-; Malachite-Green-Crystals-; Malachite-Green-Crystals-BPC-; Malachite-Green-J3E-; Malachite-Green-WS-; Malachite-Green-chloride-; Malachite-Green-hydrochloride-; Malachite-Green-powder-; Malachite-Lake-Green-A-; Malachite-green-; Mitsui-Malachite-Green-; New-Victoria-Green-Extra-I-; New-Victoria-Green-Extra-II-; New-Victoria-Green-Extra-O-; Oji-Malachite-Green-; Solid-Green-Crystals-O-; Solid-Green-O-; Tertrophene-Green-M-; Tokyo-Aniline-Malachite-Green-; Victoria-Green-; Victoria-Green-B-; Victoria-Green-S-; Victoria-Green-WB-; Victoria-Green-WPB-; Zelen-malachitova- (Czech); Zelen-zasadita-4- (Czech) RN: Current: 569-64-2 UD: 200210 MF: C23-H25-N2.Cl MW: 364.95 WL: L6Y DYJ AUYR&R DN1&1& DUK1&1 &Q &G CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M) ME: dnd-ham-emb 1 mg/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 2445, 1994 (CRNGDP); dna-mam-lym 10 pph Biopolymers. (John Wiley and Sons, Inc., 605 Third Ave., New York, NY 10158) V.1- 1963- v. 11, p. 2537, 1972 (BIPMAA); mtr-mus-fbr 10 ug/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) AT: T/E unlistd orl-mus LD50: 80 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 1, p. 5, 1951 (ARZNAD); T/E unlistd ipr-mus LD50: 4200 ug/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 1, p. 5, 1951 (ARZNAD) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC) ND: NOHS 1974: HZD 84620; NIS 25; TNF 2852; NOS 47; TNE 28485; NOES 1983: HZD 84620; NIS 84; TNF 5859; NOS 65; TNE 181763; TFE 18135 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, on test (two year studies), October 2000 Record 493 of 1119 in RTECS (through 2003/06) AN: BV8060000 PN: 5-alpha,17-beta-Androstan-3-one, 17-hydroxy-2-(hydroxymethylene)-17-methyl- SY: Adroidin-; Adroyd-; Anadroyd-; Anapolon-; Anasteron-; Anasteronal-; Anasterone-; Androstan-3-one, 17-hydroxy-2-(hydroxymethylene)-17-methyl-, (5-alpha,17-beta)- (9CI); 5-alpha-Androstan-3-one, 17-beta-hydroxy-2-(hydroxymethylene)-17-methyl- (8CI); Anadrol-; Becorel-; CI-406-; 4,5-Dihydro-2-hydroxymethylene-17-alpha-methyltestosterone-; Dynasten-; HMD-; 17-Hydroxy-2-(hydroxymethylene)-17-methyl-5-alpha-17-beta-androst-3-one; 17-beta-Hydroxy-2-hydroxymethylene-17-alpha-methyl-3-androstanone-; 17-beta-Hydroxy-2-(hydroxymethylene)-17-alpha-methyl-5-alpha-androstan-3-one; 17-beta-Hydroxy-2-(hydroxymethylene)-17-methyl-5-alpha-androstan-3-one; 2-Hydroxymethylene-17-alpha-methyl-5-alpha-androstan-17-beta-ol-3-one-; 2-Hydroxymethylene-17-alpha-methyl-dihydrotestosterone-; 2-(Hydroxymethylene)-17-alpha-methyldihydrotestosterone; 2-Hydroxymethylene-17-alpha-methyl-17-beta-hydroxy-3-androstanone-; Methabol-; 17-alpha-Methyl-2-hydroxymethylene-17-hydroxy-5-alpha-androstan-3-one-; Nastenon-; Oximetholonum-; Oximetolona-; Oxitosona-50-; Oxymethalone-; Oxymethenolone-; Oxymetholone-; Pavisoid-; Plenastril-; Protanabol-; Roboral-; Synasteron-; Zenalosyn-; Androstano(2,3-c)(1,2,5)oxadiazol-17-ol, 17-methyl-, (5-alpha,17-beta)- (9CI); NSC-26,198- RN: Current: 434-07-1 UD: 200302 MF: C21-H32-O3 MW: 332.53 WL: L E5 B666 OVTJ A1 E1 FQ F1 P1Q CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Hormone (H) ME: mnt-ham-emb 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 392, p. 61, 1997 (MUREAV) RE: T53 orl-rat TDLo: 20 mg/kg (17-20D preg) Endocrinologia Japonica. (Japan Pub. Trading Co., Ltd., POB 5030, Tokyo International, Tokyo, Japan) V.1- 1954- v. 24, p. 77, 1977 (ECJPAE); T03 orl-rat TDLo: 128 mg/kg (10D male) Japanese Journal of Pharmacology. (Japanese Pharmacological Soc., c/o Dept. of Pharmacology, Faculty of Medicine, Kyoto Univ., Sakyo-ku, Kyoto 606, Japan) V.1- 1951- v. 24, p. 551, 1974 (JJPAAZ); T25 scu-rat TDLo: 150 mg/kg (7-12D preg) Steroids. (Holden-Day Inc., 4432 Telegraph Ave., Oakland, CA 94609) V.1- 1963- v. 18, p. 731, 1971 (STEDAM); T12-T29 scu-rat TDLo: 28 mg/kg (14D pre) Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 5, p. 489, 1972 (CCPTAY); T13 scu-rat TDLo: 14 mg/kg (14D pre) Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 5, p. 489, 1972 (CCPTAY); T24 scu-rbt TDLo: 30 mg/kg (1-3D preg) American Journal of Obstetrics and Gynecology. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63146) V.1- 1920- v. 117, p. 167, 1973 (AJOGAH) TE: V01-L60 orl-chd TDLo: 270 mg/kg/9W-C New England Journal of Medicine. (Massachusetts Medical Soc., 10 Shattuck St., Boston, MA 02115) V.198- 1928- v. 296, p. 1411, 1977 (NEJMAG); V01-L30-L60 orl-man TDLo: 2336 mg/kg/2Y-C Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 43, p. 440, 1979 (CANCAR); V01-L60 unr-chd TDLo: 3050 mg/kg/3Y-I Journal of Pediatrics. (C.V. Mosby Co., 11830 Westline Industrial Dr., St. Louis, MO 63141) V.1- 1932- v. 87, p. 122, 1975 (JOPDAB); V01-L60 orl-rat TDLo: 52 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-485, 1999 (NTPTR*); V03-R60 skn-mus TDLo: 6720 mg/kg/20W-I Toxicologic Pathology. (c/o Dr. F.A. de la Iglesia, Warner-Lambert Co., Pharmaceutical Research Div., POB 1047, Ann Arbor, MI 48106) V.6(3/4)- 1978- v. 27, p. 507, 1999 (TOPADD); V01-L60 orl-chd TD :3735 mg/kg/3Y-C Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 2, p. 1273, 1972 (LANCAO); V03-N61-R60 orl-rat TDLo: 1560 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-101419 (NTIS**); V01-J60-L60 orl-rat TDLo: 52000 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-101419 (NTIS**) AT: L14 orl-hmn TDLo: 46 mg/kg/14W-I JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- v. 240, p. 243, 1978 (JAMAAP); T/E unlistd ipr-rat LD50: >1 gm/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 156, 1982 (NIIRDN) MD: P28-P70-P71 orl-rat TDLo: 5200 mg/kg/13W-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 13, p. 381, 1993 (TOXID9); U01 orl-rat TDLo: 1920 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-485, 1999 (NTPTR*); M03-Z74 orl-rat TDLo: 11200 mg/kg/14W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-485, 1999 (NTPTR*); L70-M30-Z74 orl-mus TDLo: 11200 mg/kg/14W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-485, 1999 (NTPTR*); T61-P61-V30 orl-rat TDLo: 15600 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-101419 (NTIS**); T64-P61-V30 orl-rat TDLo: 52000 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-101419 (NTIS**) TR: IARC Cancer Review: Animal No Adequate Data IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 96, 1987 (IMSUDL); TOXICOLOGY REVIEW Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 8, p. 259, 1973 (BIREBV) ND: NOES 1983: HZD X6172; NIS 1; TNF 28; NOS 1; TNE 742; TFE 359 SL: EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), clear evidence: rat; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 494 of 1119 in RTECS (through 2003/06) AN: BV8150000 PN: Androst-4-ene-3,17-dione- SY: Androstenedione-; delta(sup 4)-Androstene-3,17-dione; delta-4-Androstenedione-; 4-Androstene-3,17-dione-; SKF-2170-; Androtex- RN: Current: 63-05-8 Previous: 104534-78-3; 117598-81-9 UD: 200305 MF: C19-H26-O2 MW: 286.45 WL: L E5 B666 FV OV MUTJ A1 E1 CC: Tumorigen (C); Drug (D); Hormone (H); Reproductive-Effector (T) RE: T12-T13-T29 scu-rat TDLo: 7 mg/kg (14D pre) Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 5, p. 489, 1972 (CCPTAY); T13-T24-T29 scu-rat TDLo: 80 mg/kg (2-5D preg) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 81, p. 1091, 1967 (ENDOAO); T24 scu-rat TDLo: 20 mg/kg (5D preg) Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 18, p. 271, 1959 (JOENAK); T25 scu-rat TDLo: 20 mg/kg (8D preg) Journal of Endocrinology. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1939- v. 18, p. 271, 1959 (JOENAK); T01-T02 scu-rat TDLo: 10500 ug/kg (25D male) Acta Medica Turcica. (Dr. Ayhan Okcuoglu, Cocuk Hastalikari Klinigi, c/o Ankara Univ., Tip Facultesi, Cebeci, Ankara, Turkey) V.1-10/11, 1948-58: New series: V.1- 1964- v. 8, p. 68, 1971 (AMTUA3); T44-T72-T91 ims-rat TDLo: 80 mg/kg (14-21D preg) Journal of Comparative and Physiological Psychology. (Washington, DC) V.40-96, 1947-82. v. 92, p. 13, 1978 (JCPPAV); T53-T81 ims-rat TDLo: 40 mg/kg (14-21D preg) Journal of Comparative and Physiological Psychology. (Washington, DC) V.40-96, 1947-82. v. 92, p. 13, 1978 (JCPPAV); T14-T29 imp-rat TDLo: 5056 ug/kg (16D pre) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 56, p. 675, 1979 (JRPFA4); T24 scu-ham TDLo: 35 mg/kg (1-4D preg) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 80, p. 1152, 1967 (ENDOAO); T12 scu-ham TDLo: 17500 ug/kg (1-4D preg) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 80, p. 1152, 1967 (ENDOAO); T13 scu-ham TDLo: 70 mg/kg (1-4D preg) Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 80, p. 1152, 1967 (ENDOAO) TE: V01-V10 scu-mus TDLo: 750 mg/kg/9W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 19, p. 977, 1957 (JNCIAM) AT: F01-F40 ipr-rat TDLo: 340 mg/kg Clinical Pharmacology and Therapeutics. (American Society for Clinical Pharmacology and Therapeutics, St. Louis Mo Mosby-Year Book) V.1- 1960- v. 14, p. 727, 1976 (CLPTAT) MD: T13 ims-mus TDLo: 200 mg/kg/4D-I Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 297, p. 1099, 2001 (JPETAB) SL: NTP Carcinogenesis studies, on test (prechronic studies), October 2000 Record 495 of 1119 in RTECS (through 2003/06) AN: BV8387230 PN: Androst-5-en-17-one, 16-fluoro-, (16-alpha)- SY: 16-alpha-Fluoro-5-androsten-17-one- UD: 200207 MF: C19-H27-F-O MW: 290.46 CC: Tumorigen (C); Organometallic (O) MD: L60-V25-V30 orl-rat TDLo: 10500 mg/kg/10W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 21, p. 301, 2000 (CRNGDP) SL: NTP Carcinogenesis studies, selected, October 2000 Record 496 of 1119 in RTECS (through 2003/06) AN: BX0350000 PN: Aniline,-m-chloro- SY: m-Aminochlorobenzene-; 1-Amino-3-chlorobenzene-; Benzenamine,-3-chloro- (9CI); 3-Chlooranilinen- (Dutch); m-Chloraniline-; m-Chloroaniline-; 3-Chloroaniline-; 3-Chlorobenzenamine-; m-Chlorophenylamine-; 3-Chlorophenylamine-; 3-Cloroaniline- (Italian); Fast-Orange-GC-Base-; Orange-GC-Base- RN: Current: 108-42-9 UD: 200012 MF: C6-H6-Cl-N MW: 127.58 WL: ZR CG CC: Tumorigen (C); Mutagen (M) ME: mmo-asn 200 mg/L (-S9) Canadian Journal of Microbiology. (National Research Council of Canada, Publication Sales and Distribution, Ottawa ON K1A OR6, Canada) V.1- 1954- v. 16, p. 369, 1970 (CJMIAZ); msc-ham-lng 300 ug/L Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 39, p. 359, 1986 (BLFSBY) ORNG: 256000000 ng/kg. [256.000000 mg/kg] T/E unlistd SKNG: 250000000 ng/kg. [250.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 256 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 31(12), p. 6, 1966 (GISAAA); D26-F12-J24 ihl-rat LD50: 150 ppm/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555316 (NTIS**); T/E unlistd skn-rat LD50: 250 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,34,1982 (85GMAT); T/E unlistd ipr-rat LD50: 200 mg/kg Office of Toxic Substances Report. (U.S. Environmental Protection Agency, Office of Toxic Substances, 401 M St., SW, Washington, DC 20460) OTS 206512 (TSCAT*); T/E unlistd orl-mus LD50: 334 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 13(5), p. 29, 1969 (GTPZAB); T/E unlistd ihl-mus LC50: 550 mg/m3/4H "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,34,1982 (85GMAT); T/E unlistd ipr-mus LD50: 200 mg/kg Office of Toxic Substances Report. (U.S. Environmental Protection Agency, Office of Toxic Substances, 401 M St., SW, Washington, DC 20460) OTS 206512 (TSCAT*); J30 ivn-dog LDLo: 50 mg/kg Naunyn-Schmiedeberg's Archiv fuer Experimentelle Pathologie und Pharmakologie. (Berlin, Ger.) V.110-253, 1925-66. For publisher information, see NSAPCC. v. 244, p. 387, 1963 (AEPPAE); T/E unlistd skn-cat LD50: 223 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 13(5), p. 29, 1969 (GTPZAB); D16-F12-J24 scu-cat LDLo: 125 mg/kg Archiv fuer Hygiene und Bakteriologie. (Munich, Fed. Rep. Ger.) V.101-154, 1929-71. For publisher information, see ZHPMAT. v. 110, p. 12, 1933 (AHBAAM); T/E unlistd orl-gpg LD50: 250 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 31(12), p. 6, 1966 (GISAAA); T/E unlistd skn-gpg LD50: 100 mg/kg Office of Toxic Substances Report. (U.S. Environmental Protection Agency, Office of Toxic Substances, 401 M St., SW, Washington, DC 20460) OTS 206512 (TSCAT*) MD: P24-P71-M16 orl-rat TDLo: 10 gm/kg/13W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 32(7), p. 13, 1967 (GISAAA); A11 orl-rat TDLo: 6125 mg/kg/35W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 31(12), p. 6, 1966 (GISAAA); N73-P08-P24 orl-mus TDLo: 14560 mg/kg/13W-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 394, 1994 (TOXID9) SR: OEL-POLAND: TWA 3 mg/m3, STEL 10 mg/m3, JAN 1999 ND: NOES 1983: HZD X4029; NIS 1; TNF 17; NOS 1; TNE 851; TFE 187 SL: EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA Section 8(e) Risk Notification, 8EHQ-0193-8687; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Toxicity studies, RPT# TOX-43, October 2000 Record 497 of 1119 in RTECS (through 2003/06) AN: BX0525000 PN: Aniline,-o-chloro- SY: 1-Amino-2-chlorobenzene-; Benzenamine,-2-chloro- (9CI); o-Chloraniline-; o-Chloroaniline-; 2-Chloroaniline-; 2-Chlorobenzenamine-; Fast-Yellow-GC-Base- RN: Current: 95-51-2 UD: 200012 MF: C6-H6-Cl-N MW: 127.58 WL: ZR BG CC: Tumorigen (C); Mutagen (M) ME: dnr-esc 500 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 873, 1979 (JJIND8); mmo-asn 200 mg/L (-S9) Canadian Journal of Microbiology. (National Research Council of Canada, Publication Sales and Distribution, Ottawa ON K1A OR6, Canada) V.1- 1954- v. 16, p. 369, 1970 (CJMIAZ); slt-mus-lym 300 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 196, 1991 (EMMUEG); msc-ham-lng 600 ug/L Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 39, p. 359, 1986 (BLFSBY) IHPB: 797000 ppb/4H. [797.000000 ppm/4H] D26-F11-J24 AT: D26-F11-J24 ihl-rat LC50: 797 ppm/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571625 (NTIS**); T/E unlistd orl-mus LD50: 256 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 13(5), p. 29, 1969 (GTPZAB); T/E unlistd skn-cat LD50: 222 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 13(5), p. 29, 1969 (GTPZAB); F12-J25-U28 scu-cat LDLo: 310 mg/kg Archiv fuer Hygiene und Bakteriologie. (Munich, Fed. Rep. Ger.) V.101-154, 1929-71. For publisher information, see ZHPMAT. v. 110, p. 12, 1933 (AHBAAM) MD: N73-P08-P24 orl-rat TDLo: 14560 mg/kg/13W-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 394, 1994 (TOXID9); D35-F11-J22 ihl-rat TCLo: 1230 mg/m3/4H/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571672 (NTIS**); N73-P08-P24 orl-mus TDLo: 14560 mg/kg/13W-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 394, 1994 (TOXID9) SR: OEL-POLAND: TWA 3 mg/m3, STEL 10 mg/m3, JAN 1999 ND: NOHS 1974: HZD 83962; NIS 2; TNF 38; NOS 3; TNE 18138 SL: EPA GENETOX PROGRAM 1988, Positive: E coli polA without S9; EPA GENETOX PROGRAM 1988, Negative: SHE-clonal assay, Sperm morphology-mouse; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae-homozygosis; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Toxicity studies, RPT# TOX-43, October 2000 Record 498 of 1119 in RTECS (through 2003/06) AN: BX1394000 PN: Aniline,-p-chloro-,-hydrochloride- SY: 1-Amino-4-chlorobenzene-hydrochloride-; 4-Chloroaniline-hydrochloride-; 4-Chlorobenzenamine-hydrochloride-; 4-Chlorobenzeneamine-hydrochloride-; 4-Chlorophenylamine-hydrochloride-; Benzenamine,-4-chloro-,-hydrochloride-; p-Chloroaniline-hydrochloride-; p-Chloroanilinium-chloride-; p-Chlorophenylamine-hydrochloride-; para-Chloroaniline-hydrochloride- RN: Current: 20265-96-7 UD: 200210 MF: C6-H6-Cl-N.Cl-H MW: 164.04 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 1 mg/plate (-S9) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); msc-mus-lym 375 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); cyt-ham-ovr 900 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); sce-ham-ovr 200 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*) TE: V01-N60-N61 orl-rat TDLo: 9270 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); V01-L60-N60 orl-mus TDLo: 15450 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); V01-P60 orl-rat TDLo: 9270 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-222563/AS (NTIS**); V03-N61 orl-rat TDLo: 9270 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-222563/AS (NTIS**); V01-L60-P60 orl-mus TDLo: 15450 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-222563/AS (NTIS**) MD: M03-P27 orl-rat TDLo: 1200 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); G70-M70-P24 orl-rat TDLo: 5200 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); L30-P27-Z01 orl-mus TDLo: 1200 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); P24-P71-Z01 orl-mus TDLo: 1950 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (gavage), clear evidence: rat; NTP Carcinogenesis Studies (gavage), some evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-351, 1989 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse Record 499 of 1119 in RTECS (through 2003/06) AN: BX4725000 PN: Aniline,-N,N-dimethyl- SY: (Dimethylamino)benzene; Benzenamine,-N,N-dimethyl-; Dimethylaniline-; Dimethylaniline- (ACGIH:OSHA); Dwumetyloanilina- (Polish); N,N-Dimethylaniline-; N,N-Dimethylaniline- (OSHA); N,N-Dimethylbenzenamine-; N,N-Dimethylphenylamine-; NCI-C56428-; NL-63-10P-; Versneller NL 63/10 RN: Current: 121-69-7 Previous: 162744-63-0; 168153-21-7; 171745-67-8 UD: 200210 MF: C8-H11-N MW: 121.20 WL: 1N1&R CC: Tumorigen (C); Mutagen (M); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 10 mg/24H open MLD American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 23, p. 95, 1962 (AIHAAP); skn-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,461,1986 (85JCAE); eye-rbt 20 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,461,1986 (85JCAE) ME: dnd-rat-ipr 485 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 349, 1993 (EMMUEG); dnd-mus-ipr 485 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 349, 1993 (EMMUEG); msc-mus-lym 20 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*); mnt-ham-lng 900 umol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 349, 1993 (EMMUEG); cyt-ham-ovr 83 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 13, p. 60, 1989 (EMMUEG); sce-ham-ovr 30 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 13, p. 60, 1989 (EMMUEG) TE: V03-N60 orl-rat TDLo: 15450 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*); V03-N60 orl-mus TDLo: 15450 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*); V01-P60 orl-rat TDLo: 15450 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-227240/AS (NTIS**); V03-K60 orl-mus TDLo: 15450 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-227240/AS (NTIS**) ORNG: 951000000 ng/kg. [951.000000 mg/kg] F07-F11-J24 SRNL: 1770000 nL/kg. [1.770000 mL/kg] T/E unlistd AT: K13-K30 orl-hmn LDLo: 50 mg/kg National Clearinghouse for Poison Control Centers, Bulletin. (U.S. Department of Health, Education, and Welfare, Washington, DC) Jan/Feb, 1969 (NCPBBY); F07-F11-J24 orl-rat LD50: 951 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571982 (NTIS**); F07-F13 ihl-rat LCLo: 250 mg/m3/4H Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 37(4), p. 35, 1972 (GISAAA); T/E unlistd scu-rat LDLo: 100 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,55,1982 (85GMAT); T/E unlistd orl-mus LDLo: 350 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*); T/E unlistd skn-rbt LD50: 1770 uL/kg American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 23, p. 95, 1962 (AIHAAP); R03 skn-gpg LD50: >20 mL/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571982 (NTIS**) MD: M30-P27-U01 orl-rat TDLo: 32500 mg/kg/13W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 29, p. 77, 1990 (JTEHD6); L30-P26-P27 orl-rat TDLo: 16250 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*); P08-P24-Y11 ihl-rat TCLo: 10700 ug/m3/5H/17W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 37(4), p. 35, 1972 (GISAAA); F23-P24-P71 ihl-rat TCLo: 300 ug/m3/24H/14W-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 34(3), p. 7, 1969 (GISAAA); F15-F19-Z01 orl-rat TDLo: 2 gm/kg/2D-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571982 (NTIS**); N73 orl-rat TDLo: 1100 mg/kg/15D-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571982 (NTIS**); P27 orl-mus TDLo: 32500 mg/kg/13W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 29, p. 77, 1990 (JTEHD6); L30-M30-P27 orl-mus TDLo: 32500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*) TR: ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 10 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 5 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 337, 1993 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 337, 1993 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 337, 1993 (IMEMDT) SR: OSHA PEL (Gen Indu): 8H TWA 5 ppm (25 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 5 ppm (25 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 5 ppm (25 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 5 ppm (25 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 5 ppm (25 mg/m3), STEL 10 ppm, Skin, JAN 1993; OEL-AUSTRIA: MAK 5 ppm (25 mg/m3), Skin, Suspected Carcinogen, JAN 1999; OEL-BELGIUM: TWA 5 ppm (25 mg/m3), STEL 10 ppm (50 mg/m3), Skin, JAN 1993; OEL-DENMARK: TWA 5 ppm (25 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 5 ppm (25 mg/m3), STEL 10 ppm (50 mg/m3), Skin, JAN 1993; OEL-FRANCE: VME 5 ppm (25 mg/m3), Skin, JAN 1999; OEL-GERMANY: MAK 5 ppm (25 mg/m3)Skin, Carcinogen, JAN 1999; OEL-HUNGARY: TWA 5 mg/m3, STEL 10 mg/m3, Skin, JAN 1993; OEL-JAPAN: OEL 5 ppm (25 mg/m3), Skin, 2B Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 5 ppm (25 mg/m3), Skin, JAN 1999; OEL-NORWAY: TWA 5 ppm (25 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 5 ppm (25 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 5 mg/m3, MAC(STEL) 40 mg/m3, JAN 1999; OEL-RUSSIA: STEL 0.2 mg/m3, Skin, JAN 1993; OEL-SWEDEN: TWA 1 ppm (5 mg/m3), STEL 2 ppm (10 mg/m3), Skin, JAN 1999; OEL-SWITZERLAND: MAK-W 5 ppm (25 mg/m3), KZG-W 10 ppm (50 mg/m3), Skin, JAN 1999; OEL-UNITED KINGDOM: TWA 5 ppm (25 mg/m3), STEL 10 ppm (50 mg/m3), Skin, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO DIMETHYLANILINE-air: 10H TWA 5 ppm (Sk), STEL 10 ppm (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 26335; NIS 4; TNF 100; NOS 10; TNE 2456; NOES 1983: HZD 26335; NIS 15; TNF 1428; NOS 27; TNE 30480; TFE 7448 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Amines, aromatic, 2002; NTP Carcinogenesis Studies (gavage), some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-360, 1989 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse, rat Record 500 of 1119 in RTECS (through 2003/06) AN: BX7350000 PN: Aniline,-N,N-dimethyl-p-phenylazo- SY: 4-(N,N-Dimethylamino)azobenzene; 4-(Phenylazo)-N,N-dimethylaniline; 4-Dimethylaminoazobenzene- (OSHA); 4-Dimethylaminoazobenzol-; 4-Dimethylaminophenylazobenzene-; Atul-Fast-Yellow-R-; Azobenzene,-p-dimethylamino-; Benzenamine, N,N-dimethyl-4-(phenylazo)- (9CI); Benzeneazodimethylaniline-; Brilliant-Fast-Oil-Yellow-; Brilliant-Fast-Spirit-Yellow-; Brilliant-Fast-Yellow-; Brilliant-Oil-Yellow-; Butter-Yellow-; C.I. 11020; C.I. Solvent Yellow 2; Cerasine-Yellow-GG-; DAB-; DAB- (carcinogen); DMAB-; Dimethyl-Yellow-; Dimethyl-Yellow-Analar-; Dimethyl-Yellow-N,N-dimethylaniline-; Enial-Yellow-2G-; Fast-Oil-Yellow-B-; Fast-Yellow-; Fat-Yellow-; Fat-Yellow-A-; Fat-Yellow-AD-OO-; Fat-Yellow-ES-; Fat-Yellow-ES-Extra-; Fat Yellow Extra Conc.; Fat-Yellow-R-; Fat-Yellow-R- (8186); Grasal-Brilliant-Yellow-; Iketon-Yellow-Extra-; Jaune-de-beurre- (French); Methyl-Yellow-; N,N-Dimethyl-4-(phenylazo)benzamine; N,N-Dimethyl-4-(phenylazo)benzenamine; N,N-Dimethyl-4-aminoazobenzene-; N,N-Dimethyl-p-aminoazobenzene-; N,N-Dimethyl-p-azoaniline-; N,N-Dimethyl-p-phenylazoaniline-; Oil-Yellow-20-; Oil-Yellow-2625-; Oil-Yellow-2G-; Oil-Yellow-7463-; Oil-Yellow-BB-; Oil-Yellow-D-; Oil-Yellow-DN-; Oil-Yellow-FF-; Oil-Yellow-FN-; Oil-Yellow-G-; Oil-Yellow-G-2-; Oil-Yellow-GG-; Oil-Yellow-GR-; Oil-Yellow-II-; Oil-Yellow-N-; Oil-Yellow-PEL-; Oil-Yellow-S-; Oleal-Yellow-2G-; Organol-Yellow-ADM-; Orient-Oil-Yellow-GG-; P.D.A.B.; Petrol-Yellow-WT-; RCRA-waste-number-U093-; Resinol-Yellow-GR-; Resoform-Yellow-GGA-; Silotras-Yellow-T2G-; Somalia-Yellow-A-; Stear-Yellow-JB-; Sudan-GG-; Sudan-Yellow-; Sudan-Yellow-GG-; Sudan-Yellow-GGA-; Toyo-Oil-Yellow-G-; USAF-EK-338-; Waxoline-Yellow-AD-; Waxoline-Yellow-ADS-; Yellow-G-soluble-in-grease-; Zlut-maselna- (Czech); Zlut-rozpoustedlova-2- (Czech); p-Dimethylamino-azobenzol- (German); p-Dimethylaminoazobenzen- (Czech); p-Dimethylaminoazobenzene- RN: Current: 60-11-7 UD: 200302 MF: C14-H15-N3 MW: 225.32 WL: 1N1&R DNUNR CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 5 mg/plate (+S9) Applied and Environmental Microbiology. (American Soc. for Microbiology, 1913 I St., NW, Washington, DC 20006) V.31- 1976- v. 42, p. 641, 1981 (AEMIDF); mmo-sat 33 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9(Suppl 9), p. 1, 1987 (ENMUDM); mmo-esc 200 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 396, 1981 (PMRSDJ); dnr-esc 80 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 119, p. 135, 1983 (MUREAV); dnr-smc 600 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 502, 1981 (PMRSDJ); mrc-smc 5 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 491, 1981 (PMRSDJ); sln-smc 50 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); dns-hmn-hla 10 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); dns-hmn-fbr 4 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 528, 1981 (PMRSDJ); dni-hmn-hla 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 92, p. 427, 1982 (MUREAV); dns-rat-lvr 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 46, p. 1654, 1986 (CNREA8); mtr-rat-emb 12 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dna-rat-orl 300 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 36, p. 4647, 1976 (CNREA8); dna-rat-ipr 150 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 213, p. 1206, 1967 (NATUAS); dns-rat-lvr 1 umol/L Japanese Journal of Cancer Research. (Elsevier Science Pub. BV, POB 211, 1000 AE Amsterdam, Netherlands) V.76- 1985- v. 78, p. 505, 1987 (JJCREP); bfa-rat-sat 600 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 249, p. 850, 1974 (NATUAS); cyt-rat-orl 756 mg/kg/3W Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 54, p. 1245, 1975 (JNCIAM); mnt-mus-ipr 6400 ug/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 686, 1981 (PMRSDJ); mmo-mus-lym 6250 ug/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); mtr-mus-emb 89 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 152, p. 113, 1985 (MUREAV); dna-mus-ipr 120 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 2493, 1980 (CNREA8); dna-mus-skn 192 umol/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 231, 1984 (CRNGDP); dns-mus-lvr 1 umol/L Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 72, p. 930, 1981 (GANNA2); dni-mus-ipr 20 gm/kg Archiv fuer Geschwulstforschung. (VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 51, p. 605, 1981 (ARGEAR); dni-mus-orl 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 305, 1977 (MUREAV); sce-mus-ipr 29 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 108, p. 225, 1983 (MUREAV); msc-mus-lym 89 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 110, p. 147, 1983 (MUREAV); hma-mus-sat 255 mg/kg/3H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 45, p. 291, 1977 (MUREAV); spm-mus-ipr 3 gm/kg/5D-I Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 712, 1981 (PMRSDJ); mtr-ham-ipr 500 mg/kg Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 95, p. 380, 1973 (ARPAAQ); mtr-ham-emb 50 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); mtr-ham-kdy 25 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 638, 1981 (PMRSDJ); dns-ham-lvr 1 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5, p. 1, 1983 (ENMUDM); mtr-nml-oth 250 ug/L Annals of Occupational Hygiene. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 20, p. 297, 1977 (AOHYA3); dnd-mus-ipr 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 493, p. 39, 2001 (MUREAV); dnd-mus-orl 500 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 493, p. 39, 2001 (MUREAV); mrc-dmg-orl 2.0 mmol/L/48H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 385, 2001 (MUTAEX); mtr-mus-fbr 1 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG) RE: T01 ipr-mus TDLo: 3 gm/kg (5D male) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 712, 1981 (PMRSDJ); T46 scu-mus TDLo: 200 mg/kg (10D preg) Okajimas Folia Anatomica Japonica. (Keio Univ., School of Medicine, Dept. of Anatomy, 35 Shinano-machi, Shinjuku-ku, Tokyo 160, Japan) V.14- 1936- v. 36, p. 195, 1960 (OFAJAE) TE: V01-L60 orl-rat TDLo: 5426 mg/kg/17W-C Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 53, p. 107, 1985 (CBINA8); V02-R60 skn-rat TDLo: 1440 mg/kg/90W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 26, p. 2406, 1966 (CNREA8); V02-L60 ipr-mus TDLo: 3830 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 2540, 1984 (CNREA8); V01-T65-J60 scu-mus TDLo: 4000 mg/kg (15-21D preg) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 78, p. 1402, 1974 (BEXBAN); V03-L60-V10 mul-mus TDLo: 400 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 1, p. 397, 1941 (CNREA8); V03-M60 orl-dog TDLo: 9600 mg/kg/69W-C Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 13, p. 1497, 1953 (JNCIAM); V03-L15-P23 orl-ham TDLo: 9600 mg/kg/42W-I Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 71, p. 566, 1961 (ARPAAQ); V02-L60 orl-rat TD :2600 mg/kg/13W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 17, p. 387, 1957 (CNREA8); V02-L60 orl-rat TD :13 gm/kg/53W-C Medicina Experimentalis. (Basel, Switzerland) V.1-11, 1959-64: V.18-19, 1968-69. For publisher information, see JNMDBO. v. 4, p. 1, 1961 (MEXPAG); V03-L60 orl-rat TD :1920 mg/kg/14W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 5, p. 235, 1945 (CNREA8); V03-L60 orl-rat TD :1800 mg/kg/14W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 8, p. 141, 1948 (CNREA8); V03-L60 orl-rat TD :2331 mg/kg/7W-I K'at'ollik Taehak Uihakpu Nonmunjip. Journal of Catholic Medical College. (Catholic Medical College, Graduate School, Seoul 135, S. Korea) V.1- 1957- v. 32, p. 229, 1979 (KTUNAA); V02-L60 orl-rat TD :17200 mg/kg/17W-C Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 81, p. 162, 1966 (ARPAAQ); V02-L60 orl-rat TD :8316 mg/kg/33W-C Journal of Pathology and Bacteriology. (London, UK) V.1-96, 1892-1968. For publisher information, see JPTLAS. v. 59, p. 1, 1947 (JPBAA7); V02-J08-L60 orl-rat TD :3990 mg/kg/19W-C Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 63, p. 131, 1972 (GANNA2); V02-L60 ipr-mus TD :11 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 2540, 1984 (CNREA8); V03-L60 orl-rat TD :800 mg/kg/64D-C Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 61, p. 327, 1956 (ZEKBAI) ORNG: 200000000 ng/kg. [200.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 200 mg/kg Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 69, p. 103, 1967 (ZEKBAI); J22-J24 ipr-rat LD50: 230 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 34, p. 2274, 1974 (CNREA8); T/E unlistd orl-mus LD50: 300 mg/kg Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 54, p. 455, 1963 (GANNA2); J22-J24 ipr-mus LD50: 230 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 34, p. 2274, 1974 (CNREA8) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 8, p. 125, 1975 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 8, p. 125, 1975 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW Alimentation et la Vie. (Societe Scientifique d'Hygiene Alimentaire, 16, rue de l'Estrapade, 75005 Paris, France) V.39- 1951- v. 50, p. 77, 1962 (ALLVAR); TOXICOLOGY REVIEW British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 6, p. 270, 1952 (BJCAAI); TOXICOLOGY REVIEW Advances in Chemistry Series. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) No.1- 1950- v. 13, p. 271, 1970 (ADCSAJ); TOXICOLOGY REVIEW Journal of Nutrition. (Subscription Dept., 9650 Rockville Pike, Bethesda, MD 20014) V.1- 1928- v. 44, p. 345, 1951 (JONUAI); TOXICOLOGY REVIEW Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 24, p. 129, 1983 (BLFSBY) SR: OSHA PEL (Construc): see CFR 29,1926.1115 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA-cancer suspect agent Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1015, 1987 (CFRGBR); OEL-FINLAND: Carcinogen, JAN 1993; OEL-FRANCE: Carcinogen, JAN 1993; OEL-SWEDEN: Carcinogen, JAN 1993 ND: NIOSH REL TO 4-DIMETHYLAMINOAZOBENZENE-air: CA use 29 CFR 1910.1015 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 26175; NIS 2; TNF 29; NOS 2; TNE 42; NOES 1983: HZD 26175; NIS 2; TNF 56; NOS 2; TNE 1453; TFE 996 SL: EPA GENETOX PROGRAM 1988, Positive: Body fluid assay, Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Mammalian micronucleus, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Negative: Cell transform.-BALB/c-3T3, E coli polA with S9; EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse, S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: SHE-clonal assay, B subtilis rec assay; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Inconclusive: In vitro UDS-human fibroblast; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 501 of 1119 in RTECS (through 2003/06) AN: BY5250000 PN: Aniline, 4,4'-methylenebis(N,N-dimethyl- SY: BAZE-michlerova- (Czech); Benzenamine, 4,4'-methylenebis(N,N-dimethyl- (9CI); p,p'-Bis(dimethylamino)diphenylmethane; 4,4'-Bis(dimethylamino)diphenylmethane; Bis(p-dimethylaminophenyl)methane; Bis(4-(dimethylamino)phenyl)methane; Bis(p-(N,N-dimethylamino)phenyl)methane; Bis(4-(N,N-dimethylamino)phenyl)methane; p,p'-Bis(N,N-dimethylaminophenyl)methane; p,p-Dimethylaminodiphenylmethane-; Diphenylmethane,-tetramethyldiamino-; Methane-base-; Methane, bis(p-(dimethylamino)phenyl)-; Methylene-base-; 4,4'-Methylenebis(N,N-dimethylaniline); 4,4'-Methylenebis(N,N-dimethylbenzenamine); Michler's-base-; Michler's-hydride-; Michler's-methane-; NCI-C01990-; Reduced-michler's-ketone-; Tetra-base-; Tetramethyldiaminodiphenylmethane-; p,p-Tetramethyldiaminodiphenylmethane-; N,N,N'N'-Tetramethyl-p,p'-diaminodiphenylmethane-; N,N,N'N'-Tetramethyl-4,4'-diaminodiphenylmethane- RN: Current: 101-61-1 UD: 200007 MF: C17-H22-N2 MW: 254.41 WL: 1N1&R D1R DN1&1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 10 ug/plate (-S9) IARC Publications. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.27- 1979- v. 27, p. 283, 1980 (IAPUDO); dnr-esc 20 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 873, 1979 (JJIND8); dns-rat-lvr 5 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 97, p. 359, 1982 (MUREAV); mmo-mus-lym 2500 ug/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); mtr-mus-emb 800 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 21, 1988 (EMMUEG); oms-mus-orl 750 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV); msc-mus-lym 32800 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); hma-mus-sat 125 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 911, 1979 (JJIND8); mtr-ham-emb 100 ug/L International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 19, p. 642, 1977 (IJCNAW); sce-rbt-lym 50 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 197, 1981 (MUREAV) TE: V01-P62 orl-rat TDLo: 8500 mg/kg/59W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-186, 1979 (NCITR*); V02-L60 orl-mus TDLo: 82 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-186, 1979 (NCITR*); V02-L60 orl-mus TD :164 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-186, 1979 (NCITR*); V01-N62 orl-rat TD :27 gm/kg/2Y-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 6, p. 391, 1980 (TOLED5); V03-N62 orl-rat TD :14 gm/kg/2Y-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 6, p. 391, 1980 (TOLED5); V01-N62 orl-rat TD :310 gm/kg/59W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 119, 1982 (IMEMDT); V03-N62 orl-rat TD :155 gm/kg/59W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. 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(WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SR: OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999; OEL-SWITZERLAND: Carcinogen, JAN 1999; OEL-UNITED KINGDOM: LTEL 0.1 ppm (0.8 mg/m3), STEL 0.5 ppm, JAN 1993 ND: NOHS 1974: HZD M3405; NIS 4; TNF 53; NOS 11; TNE 1563; NOES 1983: HZD M3405; NIS 15; TNF 631; NOS 9; TNE 4140 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo, Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive: E coli polA without S9; EPA GENETOX PROGRAM 1988, Negative: In vitro UDS-human fibroblast, S cerevisiae-homozygosis; EPA TSCA Section 8(b) CHEMICAL INVENTORY; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-186, 1979 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 502 of 1119 in RTECS (through 2003/06) AN: BY5425000 PN: Aniline,-4,4'-methylenedi- SY: 4,4'-Diaminodiphenylmethan- (German); 4,4'-Diaminodiphenylmethane-; 4,4'-Diphenylmethanediamine-; 4,4'-Methylene-dianiline-; 4,4'-Methylenebis(benzeneamine); 4,4'-Methylenebisaniline-; 4,4'-Methylenedianiline-; 4,4-Methylenedianiline- (ACGIH); 4-(4-Aminobenzyl)aniline; Ancamine-TL-; Araldite-hardener-972-; Avaldite-HT-972-; Benzenamine,-4,4'-methylenebis-; Bis(4-aminophenyl)methane; Bis(p-aminophenyl)methane; Bis-p-aminofenylmethan- (Czech); Curithane-; DAPM-; Dadpm-; Di-(4-aminophenyl)methane; Diaminodiphenylmethane-; Dianilinomethane-; Epicure-DDM-; Epikure-DDM-; HT-972-; Jeffamine-AP-20-; MDA-; Methylenebis(aniline); Methylenedianiline-; Sumicure-M-; Tonox-; p,p'-Diaminodifenylmethan- (Czech); p,p'-Diaminodiphenylmethane-; p,p'-Methylenedianiline- RN: Current: 101-77-9 BRN: 474706 BHR: 4-13-00-00390 UD: 200302 MF: C13-H14-N2 MW: 198.29 WL: ZR D1R DZ CC: Tumorigen (C); Mutagen (M); Human-Data (P); Primary-Irritant (S) ID: eye-rbt 100 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,481,1986 (85JCAE) ME: mmo-sat 250 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 67, p. 123, 1979 (MUREAV); dnd-rat-ipr 370 umol/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 2, p. 1317, 1981 (CRNGDP); dnd-rat-lvr 2 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 59, 1996 (MUREAV); dns-rat-lvr 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 683, 1988 (MUREAV); dnd-mus-orl 250 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); sce-mus-ipr 9 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 108, p. 225, 1983 (MUREAV); mnt-ham-fbr 50 mg/L Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 58, p. 102, 2000 (TOSCF2); cyt-ham-fbr 125 mg/L/3H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 497, p. 29, 2001 (MUREAV); mmo-sat 1 nmol/plate/20M Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 38, p. 268, 2001 (EMMUEG) TE: V03-L60-M61 orl-rat TDLo: 320 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 219, p. 1162, 1968 (NATUAS); V03-L60 scu-rat TDLo: 1410 mg/kg Naturwissenschaften. (Springer-Verlag, Heidelberger Platz 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1913- v. 57, p. 247, 1970 (NATWAY) ORNG: 517000000 ng/kg. [517.000000 mg/kg] T/E unlistd SRNG: 200000000 ng/kg. [200.000000 mg/kg] T/E unlistd AT: F21-L12-L30 orl-man TDLo: 8420 ug/kg British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 1, p. 514, 1966 (BMJOAE); T/E unlistd orl-rat LD50: 517 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0539752 (NTIS**); T/E unlistd ipr-rat LD50: 193 mg/kg Zeitschrift fuer die Gesamte Hygiene und Ihre Grenzgebiete. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1955- v. 20, p. 393, 1974 (ZHYGAM); T/E unlistd scu-rat LD50: 200 mg/kg Naturwissenschaften. (Springer-Verlag, Heidelberger Platz 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1913- v. 57, p. 247, 1970 (NATWAY); T/E unlistd orl-mus LD50: 264 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555063 (NTIS**); T/E unlistd ipr-mus LD50: 74 mg/kg Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 14, p. 677, 1976 (RCOCB8); K12-K13 orl-dog LDLo: 300 mg/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 11, p. 185, 1978 (TXCYAC); T/E unlistd scu-dog LDLo: 400 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 58, p. 167, 1907 (AEXPBL); T/E unlistd orl-rbt LD50: 620 mg/kg Zeitschrift fuer die Gesamte Hygiene und Ihre Grenzgebiete. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1955- v. 20, p. 393, 1974 (ZHYGAM); T/E unlistd skn-rbt LD50: 200 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555064 (NTIS**); T/E unlistd orl-gpg LD50: 260 mg/kg Zeitschrift fuer die Gesamte Hygiene und Ihre Grenzgebiete. (VEB Verlag Volk und Gesundheit, Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1955- v. 20, p. 393, 1974 (ZHYGAM) MD: L30-Y10 orl-rat TDLo: 16800 mg/kg/40W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 48, p. 145, 1979 (TXAPA9); L30-P27-Y40 orl-rat TDLo: 6972 mg/kg/12W-I Acta Poloniae Pharmaceutica (English Translation). Translation of APPHAX. (Warsaw, Poland) V.20-29, 1963-72. Discontinued. v. 26, p. 352, 1969 (APPFAR); F19-L70-Z01 orl-rat TDLo: 1386 mg/kg/1W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555074 (NTIS**); L03-M05-P05 orl-dog TDLo: 456 mg/kg/15W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. 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DE85-017376 (NTIS**) SR: OEL-AUSTRALIA: TWA 0.1 ppm (0.8 mg/m3), Skin, JAN 1993; OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-BELGIUM: TWA 0.1 ppm (0.81 mg/m3), Skin, Carcinogen, JAN 1993; OEL-DENMARK: TWA 0.1 ppm (0.8 mg/m3), JAN 1999; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-JAPAN: OEL 0.4 mg/m3, Skin, 2B Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.1 ppm (0.8 mg/m3), Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.1 ppm (0.8 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 0.1 ppm, Skin, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: LTEL 0.1 ppm (0.8 mg/m3), STEL 0.5 ppm, JAN 1993; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO 4,4'-METHYLENEDIANILINE-air: CA lowest feasible conc. National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 83609; NIS 16; TNF 363; NOS 27; TNE 9163; NOES 1983: HZD 83609; NIS 25; TNF 741; NOS 30; TNE 15170; TFE 3407 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/99/102568/AS); EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH CURRENT INTELLIGENCE BULLETIN 8, 1976 AND BULLETIN 47, 1986; NIOSH Analytical Method, 1994: 4, 4'-Methylenedianiline, 5029; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #ID-57 Record 503 of 1119 in RTECS (through 2003/06) AN: BY5426000 PN: Aniline,-4,4'-methylenedi-,-dihydrochloride- SY: Benzenamine,-4,4'-methylenebis-,-dihydrochloride-; p,p'-Methylenedianiline-dihydrochloride-; 4,4'-Methylenedianiline-dihydrochloride-; NCI-C54604- RN: Current: 13552-44-8 UD: 200210 MF: C13-H14-N2.2 Cl-H MW: 271.21 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 1 ug/plate (-S9) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); sln-dmg-orl 10 ppb Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 23, p. 208, 1994 (EMMUEG); mnt-mus-ipr 111 mg/kg/3D-C Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 160, 1993 (EMMUEG); msc-mus-lym 250 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); cyt-ham-ovr 500 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 13, p. 133, 1989 (EMMUEG); sce-ham-ovr 500 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 13, p. 133, 1989 (EMMUEG) TE: V01-L60 orl-rat TDLo: 10950 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-248, 1983 (NTPTR*); V01-L60-N61 orl-mus TDLo: 21900 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-248, 1983 (NTPTR*); V01-L60-N62 orl-rat TD :21900 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-248, 1983 (NTPTR*); V01-L60-N62 orl-mus TD :43800 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-248, 1983 (NTPTR*); V01-L60-N62 orl-rat TD :21630 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 1457, 1984 (JJIND8); V02-L60 orl-rat TD :10815 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 1457, 1984 (JJIND8); V01-L60 orl-mus TD :21630 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 1457, 1984 (JJIND8); V01-L60-N62 orl-rat TDLo: 12978 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-238824 (NTIS**); V02-N62 orl-rat TDLo: 10815 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-238824 (NTIS**); V01-L60-N61 orl-mus TDLo: 12978 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-238824 (NTIS**); V01-L60-P62 orl-mus TDLo: 25956 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-238824 (NTIS**); V02-T63 orl-mus TDLo: 12978 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-238824 (NTIS**) MD: L30-N05-N30 orl-rat TDLo: 7280 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTR-TR-248, 1983 (NTPTR*); Z01 orl-mus TDLo: 2240 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTR-TR-248, 1983 (NTPTR*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 347, 1986 (IMEMDT) SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (water), clear evidence: mouse, rat; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 504 of 1119 in RTECS (through 2003/06) AN: BY7000000 PN: Aniline,-p-nitro- SY: 1-Amino-4-nitrobenzene-; 4-Nitraniline-; 4-Nitroaniline-; 4-Nitrobenzenamine-; Aniline,-4-nitro-; Azoamine-Red-ZH-; Azoic-Diazo-Component-37-; Benzenamine,-4-nitro- (9CI); C.I. 37035; C.I. Azoic Diazo Component 37; C.I. Developer 17; Developer-P-; Devol-Red-GG-; Diazo-Fast-Red-GG-; Fast-Red-2G-Base-; Fast-Red-Base-2J-; Fast-Red-Base-GG-; Fast-Red-GG-Base-; Fast-Red-MP-Base-; Fast-Red-P-Base-; NCI-C60786-; Naphtoelan-Red-GG-Base-; Nitrazol-CF-Extra-; PNA-; RCRA-waste-number-P077-; Red-2G-Base-; Shinnippon-Fast-Red-GG-Base-; p-Aminonitrobenzene-; p-Nitraniline-; p-Nitroanilina- (Polish); p-Nitroaniline-; p-Nitroaniline- (ACGIH:OSHA); p-Nitrophenylamine- RN: Current: 100-01-6 UD: 200302 MF: C6-H6-N2-O2 MW: 138.14 WL: ZR DNW CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 333 ug/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mmo-sat 50 ug/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 44, p. 9, 1977 (MUREAV); pic-esc 100 mmol/L Medycyna Doswiadczalna i Mikrobiologia. For English translation, see EXMMAV. (Ars Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1949- v. 31, p. 11, 1979 (MDMIAZ); dnr-bcs 5 mg/disc Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 170, p. 11, 1986 (MUREAV); mmo-omi 1500 ug/L (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 173, p. 233, 1986 (MUREAV); cyt-ham-ovr 173 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 27, p. 67, 1996 (EMMUEG); sce-ham-ovr 1600 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) RE: T22 orl-rat TDLo: 1764 mg/kg (14W male/14W pre) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 15, p. 607, 1990 (FAATDF); T26-T72-T81 orl-mus TDLo: 9600 mg/kg (6-13D preg) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 29, 1987 (TCMUD8) TE: V03-H60 orl-mus TDLo: 51500 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-418, 1993 (NTPTR*); V03-L61-P05 orl-mus TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-104528 (NTIS**) ORNG: 750000000 ng/kg. [750.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 750 mg/kg Ceskoslovenska Hygiena. Czechoslovak Hygiene. (PNS-Ustredni Expedice a Dovoz Tisku, Kafkova 19, 160 00 Prague 6, Czechoslovakia) V.1- 1956- v. 23, p. 168, 1978 (CEHYAN); T/E unlistd ipr-rat LDLo: 600 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,92,1982 (85GMAT); T/E unlistd orl-mus LD50: 810 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 42, p. 417, 1977 (TXAPA9); T/E unlistd ipr-mus LD50: 250 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD691-490 (NTIS**); T/E unlistd ims-mus LD50: 800 mg/kg Igiena. (Bucharest, Romania) V.5-23, 1956-74(?). For publisher information, see RABIDH. v. 15, p. 151, 1966 (IGIBA5); F07-F12 orl-gpg LD50: 450 mg/kg Voprosy Kommunal'noi Gigieny. Problems of Communal Hygiene. (Kiev, USSR) V.6, 1966. For publisher information, see GNAMAP. v. 6, p. 89, 1966 (VKMGA7); T/E unlistd skn-gpg LD50: >500 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0572389 (NTIS**); T/E unlistd orl-qal LD50: 1 gm/kg Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 12, p. 355, 1983 (AECTCV); P24 ivn-mam LDLo: 40 mg/kg U.S. Public Health Service, Public Health Bulletin. (Washington, DC) v. 271, p. 34, 1941 (XPHBAO); T/E unlistd orl-bwd LD50: 75 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 21, p. 315, 1972 (TXAPA9) MD: U01-Z01 orl-rat TDLo: 6750 mg/kg/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0533716 (NTIS**); P24-P27-P70 orl-rat TDLo: 2700 mg/kg/90D-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 3, p. 128, 1983 (TOXID9); P24-P71-U01 orl-rat TDLo: 120 mg/kg/30D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(4), p. 82, 1985 (GISAAA); F40-P24-P71 orl-rat TDLo: 180 mg/kg/26W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(4), p. 82, 1985 (GISAAA); N73-P24-P72 ihl-rat TCLo: 80 mg/m3/6H/4W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 6, p. 618, 1986 (FAATDF); P24-P71-N73 orl-rat TDLo: 6552 mg/kg/2Y-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 15, p. 607, 1990 (FAATDF); P23-P24-P71 ihl-rat TCLo: 510 mg/m3/6H/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0546534 (NTIS**); P24-P71-P73 orl-mus TDLo: 300 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-418, 1993 (NTPTR*); L30-P24-P27 orl-mus TDLo: 650 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-418, 1993 (NTPTR*) TR: ACGIH TLV-TWA 3 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 3 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: MSHA STANDARD-air: TWA 1 ppm (6 mg/m3) (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 182, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 1 ppm (6 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 1 ppm (6 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 1 ppm (6 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 1 ppm (6 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 1 ppm (6 mg/m3), Skin, JAN 1993; OEL-AUSTRALIA: TWA 3 mg/m3, Skin, JAN 1993; OEL-AUSTRIA: MAK 1 ppm (6 mg/m3), Skin, JAN 1999; OEL-BELGIUM: TWA 3 mg/m3, Skin, JAN 1993; OEL-DENMARK: TWA 0.5 ppm (3 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 1 ppm (6 mg/m3), STEL 3 ppm (18 mg/m3), Skin, JAN 1993; OEL-FRANCE: VME 3 mg/m3, Skin, JAN 1999; OEL-GERMANY: MAK 1 ppm (6 mg/m3), Skin, JAN 1999; OEL-HUNGARY: TWA 3 mg/m3, STEL 6 mg/m3, Skin, JAN 1993; OEL-JAPAN: OEL 3 mg/m3, Skin, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 1 ppm (6 mg/m3), Skin, JAN 1999; OEL-NORWAY: TWA 1 mg/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 1 ppm (6 mg/m3), Skin, JAN 1993; OEL-POLAND: MAC(TWA) 3 mg/m3, MAC(STEL) 10 mg/m3, JAN 1999; OEL-RUSSIA: STEL 0.1 mg/m3, Skin, JAN 1993; OEL-SWITZERLAND: MAK-W 0.5 ppm (3 mg/m3), Skin, JAN 1999; OEL-TURKEY: TWA 1 ppm (6 mg/m3), Skin, JAN 1993; OEL-UNITED KINGDOM: TWA 6 mg/m3, Skin, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO p-NITROANILINE-air: 10H TWA 3 mg/m3 (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD M3131; NIS 4; TNF 281; NOS 10; TNE 2814; NOES 1983: HZD M3131; NIS 2; TNF 48; NOS 7; TNE 1448; TFE 262 SL: EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: p-Nitroaniline, 5033; NCI Carcinogenesis Studies (gavage), equivocal evidence: rat Record 505 of 1119 in RTECS (through 2003/06) AN: BY7900000 PN: Aniline,-4,4'-oxydi- SY: p-Aminophenyl-ether-; 4-Aminophenyl-ether-; Benzenamine,-4,4'-oxybis-; Bis(p-aminophenyl)ether; Bis(4-aminophenyl)ether; Dadpe-; 4,4-Dadpe-; 4,4'-Diaminobiphenyloxide-; Diaminodiphenyl-ether-; 4,4-Diaminodiphenyl-ether-; p,p'-Diaminodiphenyl-ether-; 4,4'-Diaminodiphenyl-oxide-; 4,4'-Diaminophenyl-ether-; 4,4'-Diaminophenyl-oxide-; Ether,-4,4'-diaminodiphenyl-; NCI-C50146-; Oxybis(4-aminobenzene); 4,4'-Oxybisaniline-; p,p'-Oxybis(aniline); 4,4'-Oxybisbenzenamine-; Oxydianiline-; 4,4-Oxydianiline-; p,p'-Oxydianiline-; 4,4'-Oxydiphenylamine-; Oxydi-p-phenylenediamine- RN: Current: 101-80-4 BRN: 475735 BHR: 4-13-00-01038 UD: 200007 MF: C12-H12-N2-O MW: 200.26 WL: ZR DOR DZ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 333 ug/plate (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11(Suppl 12), p. 1, 1988 (EMMUEG); mmo-sat 10 ug/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 143, p. 11, 1985 (MUREAV); pic-esc 6250 ng/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 349, 1991 (MUREAV); slt-dmg-orl 250 umol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 24, p. 75, 1994 (EMMUEG); dnd-rat-ipr 3640 umol/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 2, p. 1317, 1981 (CRNGDP); dns-rat-lvr 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 683, 1988 (MUREAV); mnt-mus-ipr 225 mg/kg/3D-C Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 160, 1993 (EMMUEG); dnd-mus-orl 500 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); msc-mus-lym 50 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); mtr-ham-emb 2 mmol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8, p. 515, 1986 (ENMUDM); cyt-ham-ovr 160 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); sce-ham-ovr 50 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS) TE: V01-L60-N62 orl-rat TDLo: 8652 mg/kg/2Y-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-205, 1980 (NCITR*); V03-P61-R60 scu-rat TDLo: 8550 mg/kg/76W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 21(3), p. 69, 1975 (VOONAW); V01-D29-L60 orl-mus TDLo: 13 gm/kg/2Y-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-205, 1980 (NCITR*); V03-J60-P61 scu-mus TDLo: 7000 mg/kg/39W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 21(3), p. 69, 1975 (VOONAW); V03-M61-P60 orl-rat TD :19 gm/kg/77W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 21(3), p. 69, 1975 (VOONAW); V03-J60-P61 orl-mus TD :11 gm/kg/30W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 21(3), p. 69, 1975 (VOONAW); V01-L60-N62 orl-rat TD :8652 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 1457, 1984 (JJIND8); V01-L60-N62 orl-mus TD :69216 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 1457, 1984 (JJIND8); V02-D29 orl-mus TD :12978 mg/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 1457, 1984 (JJIND8) ORNG: 725000000 ng/kg. [725.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 725 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(10-12), p. 137, 1968 (HYSAAV); F18-J22-U28 ipr-rat LD50: 365 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(10-12), p. 137, 1968 (HYSAAV); T/E unlistd orl-mus LD50: 685 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(10-12), p. 137, 1968 (HYSAAV); F18-J22-U28 ipr-mus LD50: 300 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(10-12), p. 137, 1968 (HYSAAV); T/E unlistd orl-rbt LD50: 700 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(10-12), p. 137, 1968 (HYSAAV); F18-J22-U28 ipr-rbt LD50: 650 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(10-12), p. 137, 1968 (HYSAAV); T/E unlistd orl-gpg LD50: 650 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,43,1982 (85GMAT) MD: N05-N30-U01 orl-rat TDLo: 4277 mg/kg/13W-C Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- v. 15, p. 649, 1978 (VTPHAK); G06-H01 orl-rat TDLo: 619 mg/kg/26W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 51(6), p. 31, 1986 (GISAAA); N72-N73-P08 orl-rat TDLo: 1087 mg/kg/15D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 33(10), p. 110, 1968 (GISAAA); N05-N30-U01 orl-mus TDLo: 2366 mg/kg/13W-C Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- v. 15, p. 649, 1978 (VTPHAK) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 203, 1982 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 203, 1982 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SR: OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999; OEL-RUSSIA: STEL 5 mg/m3, JAN 1993; OEL-SWITZERLAND: Carcinogen, JAN 1999 ND: NOHS 1974: HZD T0239; NIS 1; TNF 8; NOS 1; TNE 45 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-205, 1980 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 506 of 1119 in RTECS (through 2003/06) AN: BZ6500000 PN: o-Anisidine,-hydrochloride- SY: o-Aminoanisole-hydrochloride-; 2-Aminoanisole-hydrochloride-; 2-Anisidine-hydrochloride-; o-Anisylamine-hydrochloride-; Benzenamine,-2-methoxy-,-hydrochloride- (9CI); C.I. 37115; Fast-Red-BB-Base-; 2-Methoxy-1-aminobenzene-hydrochloride-; o-Methoxyaniline-hydrochloride-; 2-Methoxyaniline-hydrochloride-; 2-Methoxybenzenamine-hydrochloride-; 2-Methoxybenzeneamine-hydrochloride-; o-Methoxyphenylamine-hydrochloride-; NCI-C03747- RN: Current: 134-29-2 UD: 200012 MF: C7-H9-N-O.Cl-H MW: 159.63 WL: ZR BO1 &GH CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 10 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); mmo-esc 1 mg/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); slt-dmg-orl 500 umol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 24, p. 75, 1994 (EMMUEG); mtr-rat-emb 195 ug/plate JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 1, p. 190, 1981 (JJATDK); msc-mus-orl 2250 mg/kg/3D-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 2291, 1994 (CRNGDP) TE: V01-M60-M61 orl-rat TDLo: 180 gm/kg/2Y-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*); V01-M60 orl-mus TDLo: 721 gm/kg/2Y-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*); V01-M60-M61 orl-rat TD :360 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*); V03-M60 orl-mus TD :216 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*); V02-M60-U01 orl-mus TD :1803 gm/kg/1Y-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); V01-M60-U01 orl-mus TD :3605 gm/kg/1Y-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); V01-M60-U01 orl-rat TD :2905 gm/kg/83W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); V01-M60-U01 orl-rat TD :5810 gm/kg/83W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT) MD: P27-U01 orl-rat TDLo: 73500 mg/kg/7W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*); P27-U01 orl-mus TDLo: 58800 mg/kg/7W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) ND: NOES 1983: HZD X8301; NIS 1; TNF 50; NOS 3; TNE 1108 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-89, 1978 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 507 of 1119 in RTECS (through 2003/06) AN: BZ6600000 PN: p-Anisidine,-hydrochloride- SY: p-Aminoanisole-hydrochloride-; 4-Aminoanisole-hydrochloride-; 1-Amino-4-methoxybenzene-hydrochloride-; p-Anisidine-monohydrochloride-; p-Anisylamine-hydrochloride-; Benzenamine,-4-methoxy-,-hydrochloride- (9CI); 4-Methoxy-1-aminobenzene-hydrochloride-; p-Methoxyaniline-hydrochloride-; 4-Methoxyaniline-hydrochloride-; 4-Methoxybenzenamine-hydrochloride-; 4-Methoxybenzeneamine-hydrochloride-; p-Methoxyphenylamine-hydrochloride-; NCI-C03758-; 4-Anisidine-hydrochloride- RN: Current: 20265-97-8 UD: 200012 MF: C7-H9-N-O.Cl-H MW: 159.63 WL: ZR DO1 &GH CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 33 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); mmo-esc 1 mg/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM) TE: V01-M60-N60 orl-rat TDLo: 2163 gm/kg/1Y-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); V03-N60 orl-rat TD :116 gm/kg/92W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-116, 1978 (NCITR*) TR: IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 63, 1982 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Bioassay (feed), no evidence: mouse National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-116, 1978 (NCITR*); NCI Carcinogenesis Bioassay (feed), inadequate studies: rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-116, 1978 (NCITR*); NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 508 of 1119 in RTECS (through 2003/06) AN: BZ6720000 PN: o-Anisidine,-5-methyl- SY: m-Amino-p-cresol,-methyl-ester-; 3-Amino-p-cresol-methyl-ether-; 1-Amino-2-methoxy-5-methylbenzene-; 3-Amino-4-methoxytoluene-; 2-Amino-4-methylanisole-; Azoic-Red-36-; Benzenamine,-2-methoxy-5-methyl- (9CI); C.I. Azoic Red 83; Cresidine-; p-Cresidine-; p-Kresidin- (Czech); Krezidine-; 2-Methoxy-5-methylaniline-; 2-Methoxy-5-methylbenzenamine-; 4-Methoxy-m-toluidine-; 4-Methyl-2-aminoanisole-; 5-Methyl-o-anisidine-; NCI-C02982- RN: Current: 120-71-8 BRN: 637071 BHR: 3-13-00-01577 UD: 200210 MF: C8-H11-N-O MW: 137.20 WL: ZR C1 FO1 CC: Tumorigen (C); Mutagen (M); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,721,1986 (85JCAE); eye-rbt 100 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,721,1986 (85JCAE) ME: mmo-sat 62500 ng (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); mmo-esc 2 mg/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); mtr-rat-emb 31 ug/plate JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 1, p. 190, 1981 (JJATDK); dnd-mus-orl 595 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 412, p. 155, 1998 (MUREAV); mtr-mus-fbr 5 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) TE: V01-A60-M60 orl-rat TDLo: 364 gm/kg/2Y-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-142, 1979 (NCITR*); V01-L60-M60 orl-mus TDLo: 355 gm/kg/92W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-142, 1979 (NCITR*); V02-A60-M60 orl-rat TD :182 gm/kg/2Y-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-142, 1979 (NCITR*); V01-L60-M60 orl-rat TD :3640 gm/kg/2Y-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 91, 1982 (IMEMDT); V01-L60-M60 orl-mus TD :1607 gm/kg/2Y-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 91, 1982 (IMEMDT); V01-L60-M60 orl-rat TD :7280 gm/kg/2Y-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 91, 1982 (IMEMDT); V01-L60-M60 orl-mus TD :2961 gm/kg/92W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 91, 1982 (IMEMDT); V01-D09 orl-rat TD :364 gm/kg/2Y-C Anticancer Research. (5 Argyropoulou St., Kato Patissia, Athens 907, Greece) V.1- 1981- v. 1, p. 279, 1981 (ANTRD4); V01-D09 orl-rat TD :437 gm/kg/2Y-C Anticancer Research. (5 Argyropoulou St., Kato Patissia, Athens 907, Greece) V.1- 1981- v. 1, p. 279, 1981 (ANTRD4) ORNG: 1450000000 ng/kg. [1450.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1450 mg/kg Huntingdon Research Center Reports. (Box 527, Brooklandville, MD 21022) v. -, p. -, 1972 (HURC**) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 91, 1982 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 91, 1982 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SR: OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1993; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-SWITZERLAND: Carcinogen, JAN 1999 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-142, 1979 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 509 of 1119 in RTECS (through 2003/06) AN: BZ8225000 PN: Anisole,-p-allyl- SY: p-Allylanisole-; p-Allylmethoxybenzene-; 4-Allyl-1-methoxybenzene-; Chavicol-methyl-ether-; Esdragol-; Esdragon-; Estragole-; Isoanethole-; p-Methoxyallylbenzene-; 1-Methoxy-4-(2-propenyl)benzene; Methyl-chavicol-; NCI-C60946-; Tarragon- RN: Current: 140-67-0 BRN: 1099454 BHR: 4-06-00-03817 UD: 200012 MF: C10-H12-O MW: 148.22 WL: 1U2R DO1 CC: Tumorigen (C); Mutagen (M); Natural-Product (N); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MOD Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 603, 1976 (FCTXAV) ME: mmo-sat 20 umol/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 60, p. 143, 1979 (MUREAV); dns-rat-lvr 1 mmol/L Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 28, p. 537, 1990 (FCTOD7); dns-rat-orl 2 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 325, p. 129, 1994 (MUREAV); bfa-rat-sat 2500 mg/kg Nutrition and Cancer. (Franklin Institute Press, POB 2266, Phildelphia, PA 19103) V.1- 1978- v. 1, p. 10, 1979 (NUCADQ); dna-mus-ipr 80 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 1613, 1984 (CRNGDP) TE: V02-L60 orl-mus TDLo: 97 gm/kg/1Y-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 1124, 1983 (CNREA8); V01-L60 ipr-mus TDLo: 111 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 47, p. 2275, 1987 (CNREA8); V01-J60-L60 scu-mus TDLo: 140 mg/kg/22D-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 57, p. 1323, 1976 (JNCIAM); V02-L60-L61 orl-mus TD :195 gm/kg/1Y-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 1124, 1983 (CNREA8) ORNG: 1230000000 ng/kg. [1230.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1230 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 603, 1976 (FCTXAV); F25 ipr-rat LD50: 1030 mg/kg Comptes Rendus Hebdomadaires des Seances, Academie des Sciences. (Paris, France) V.1-261, 1835-1965. For publisher information, see CRASEV. v. 246, p. 1465, 1958 (COREAF); F07-F24 orl-mus LD50: 1250 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); F25 ipr-mus LD50: 1260 mg/kg Comptes Rendus Hebdomadaires des Seances, Academie des Sciences. (Paris, France) V.1-261, 1835-1965. For publisher information, see CRASEV. v. 246, p. 1465, 1958 (COREAF); T/E unlistd skn-rbt LD50: >5 gm/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 603, 1976 (FCTXAV) ND: NOES 1983: HZD X5058; NIS 2; TNF 668; NOS 6; TNE 9128; TFE 6777 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis studies, selected, October 2000 Record 510 of 1119 in RTECS (through 2003/06) AN: BZ8790000 PN: Anisole,-o-nitro- SY: Benzene,-1-methoxy-2-nitro- (9CI); 2-Methoxynitrobenzene-; 1-Methoxy-2-nitrobenzene-; NCI-C60388-; o-Nitroanisole-; 2-Nitroanisole-; ortho-Nitrobenzene-methyl-ether-; o-Nitrophenyl-methyl-ether- RN: Current: 91-23-6 Previous: 35973-13-8 UD: 200302 MF: C7-H7-N-O3 MW: 153.15 WL: WNR BO1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 666 ug/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mmo-sat 1 mg/plate (-S9) Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 29, p. 34, 1987 (SAIGBL); dnr-bcs 500 nL/disc Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 170, p. 11, 1986 (MUREAV); cyt-ham-ovr 1060 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ham-ovr 123 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) TE: V01-P61 orl-rat TDLo: 9604 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-416, 1993 (NTPTR*); V01-L60 orl-mus TDLo: 173 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-416, 1993 (NTPTR*); V01-P61 orl-rat TDLo: 28811.16 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-109758 (NTIS**); V01-P61 orl-rat TDLo: 72100 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-109758 (NTIS**); V03-L60 orl-mus TDLo: 173040 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-109758 (NTIS**) ORNG: 740000000 ng/kg. [740.000000 mg/kg] J22-U30 AT: J22-U30 orl-rat LD50: 740 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 51(1), p. 85, 1986 (GISAAA); J22-U30 orl-mus LD50: 1300 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 51(1), p. 85, 1986 (GISAAA) MD: P24-P71-U01 orl-rat TDLo: 8960 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-416, 1993 (NTPTR*); M30-P27-P71 orl-rat TDLo: 27300 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-416, 1993 (NTPTR*); A70-L70-U01 orl-mus TDLo: 2772 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-416, 1993 (NTPTR*); L70-P08-U01 orl-mus TDLo: 16380 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-416, 1993 (NTPTR*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 369, 1996 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 369, 1996 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 369, 1996 (IMEMDT) SR: OEL-GERMANY: Carcinogen, JAN 1999; OEL-RUSSIA: STEL 1 mg/m3, Skin, JAN 1993 SL: EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), clear evidence: mouse, rat; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 511 of 1119 in RTECS (through 2003/06) AN: BZ8820000 PN: Anisole,-2,3,4,5,6-pentachloro- SY: Benzene,-pentachloromethoxy- (9CI); Methyl-pentachlorophenate-; Methyl-pentachlorophenyl-ester-; NCI-C56520-; Pentachloroanisole-; 2,3,4,5,6-Pentachloroanisole-; Pentachloromethoxybenzene-; Pentachlorophenyl-methyl-ether- RN: Current: 1825-21-4 BRN: 2052667 BHR: 4-06-00-01027 UD: 200302 MF: C7-H3-Cl5-O MW: 280.35 WL: GR BG CG DG EG FO1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 3333 ug/plate (+/-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 7), p. 1, 1986 (ENMUDM); mmo-mus-lym 75 mg/L (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9, p. 143, 1987 (ENMUDM) RE: T25-T26 orl-rat TDLo: 7420 mg/kg (23W pre/1-22D preg) Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 25, p. 163, 1987 (FCTOD7); T34 orl-rat TDLo: 724 mg/kg (23W pre/1-22D preg) Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 25, p. 163, 1987 (FCTOD7) TE: V02-N60 orl-rat TDLo: 10300 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*); V02-L61-N60 orl-mus TDLo: 20800 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*); V02-N61 orl-rat TDLo: 5150 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-104536 (NTIS**); V03-N61 orl-rat TDLo: 10300 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-104536 (NTIS**); V01-L50-L61 orl-mus TDLo: 10300 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-104536 (NTIS**) AT: T/E unlistd orl-rat LDLo: 500 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 90, p. 260, 1947 (JPETAB); F07-F11-F18 orl-mus LD50: 318 mg/kg Toxicological and Environmental Chemistry. (Gordon and Breach Science Pub. Inc., 1 Park Ave., New York, NY 10016) V.3(3/4)- 1981- v. 11, p. 37, 1986 (TECSDY); F07-F11-F18 ipr-mus LD50: 281 mg/kg Toxicological and Environmental Chemistry. (Gordon and Breach Science Pub. Inc., 1 Park Ave., New York, NY 10016) V.3(3/4)- 1981- v. 11, p. 37, 1986 (TECSDY) MD: U01-Z01 orl-rat TDLo: 2 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*); L02-M70-U01 orl-rat TDLo: 5200 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*); Z01 orl-mus TDLo: 1600 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*); L30-M70 orl-mus TDLo: 2600 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*) SL: EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Studies (gavage), some evidence: :mouse, rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-414, 1993 (NTPTR*); NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: mouse Record 512 of 1119 in RTECS (through 2003/06) AN: CA1119000 PN: Annatto- SY: Annatto-coloring-dye-; Arnatta-; Annotta-; Arnatto-; Arnotta- RN: Current: 1393-63-1 UD: 200012 CC: Tumorigen (C); Mutagen (M); Natural-Product (N) ME: mmo-sat 100 ug/plate (+S9) Kanagawa-ken Eisei Kenkyusho Kenkyu Hokoku. Bulletin of Kanagawa Prefectural Public Health Laboratories. (Kanagawa-ken Eisei Kenkyusho, 52-2, Nakao-cho, Asahi-ku, Yokohama 241, Japan) No.1- 1971- v. (9), p. 11, 1979 (KEKHB8); mmo-esc 100 ug/plate (-S9) Kanagawa-ken Eisei Kenkyusho Kenkyu Hokoku. Bulletin of Kanagawa Prefectural Public Health Laboratories. (Kanagawa-ken Eisei Kenkyusho, 52-2, Nakao-cho, Asahi-ku, Yokohama 241, Japan) No.1- 1971- v. (9), p. 11, 1979 (KEKHB8) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis studies, selected, October 2000 Record 513 of 1119 in RTECS (through 2003/06) AN: CB0540000 PN: 9,10-Anthracenedione,-1,4,5,8-tetraamino- SY: Amacel-Blue-GG-; Amacel-Pure-Blue-B-; Miketon-Fast-Blue-; Miketon-Fast-Blue-B-; Nacelan-Blue-G-; NCI-C54900-; Neosetile-Blue-EB-; Oracet-Sapphire-Blue-G-; Perliton-Blue-B-; Serinyl-Blue-2G-; Serinyl-Blue-3G-; Serinyl-Blue-3GN-; Setacyl-Blue-2GS-; Setacyl-Blue-2GS-II-; Supracet-Brilliant-Blue-2GN-; Supracet-Deep-Blue-R-; 1,4,5,8-Tetraaminoanthraquinone-; 1,4,5,8-Tetraminoanthraquinone-; Acetate-Blue-G-; Acetoquinone-Blue-L-; Acetoquinone-Blue-R-; Acetylon-Fast-Blue-G-; Anthraquinone,-1,4,5,8-tetramino-; Artisil-Blue-SAP-; Artisil-Blue-SAP-Conc-; Brasilazet-Blue-GR-; Celanthrene-Pure-Blue-BRS-; Celliton-Blue-BB-CF-; Celliton-Blue-Extra-; Celliton-Blue-G-; Celliton-Blue-GA-CF-; Cibacet-Sapphire-Blue-G-; C.I. 64500; C.I. Disperse Blue 1; C.I. Solvent Blue 18; Cilla-Blue-Extra-; Diacelliton-Fast-Blue-R-; Disperse-Blue-1-; Disperse-Blue-NO-1-; Duranol-Brilliant-Blue-CB-; Fenacet-Blue-G-; Grasol-Blue-2GS-; Kayalon-Fast-Blue-BR-; Microsetile-Blue-EB-; Nyloquinone-Blue-2J- RN: Current: 2475-45-8 BRN: 925672 BHR: 4-14-00-00487 UD: 200210 MF: C14-H12-N4-O2 MW: 268.30 WL: L C666 BV IVJ DZ GZ KZ NZ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 33 ug/plate (+S9) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); mmo-sat 100 ug/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 203, 1976 (MUREAV) TE: V01-M60-P61 orl-rat TDLo: 90125 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); V01-N60-T61 orl-rat TD :180 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); V01-M60 orl-rat TDLo: 32760 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-248051/AS (NTIS**); V01-M60 orl-rat TDLo: 40768 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-248051/AS (NTIS**); V03-L60 orl-mus TDLo: 81536 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-248051/AS (NTIS**); V03-L60 orl-mus TDLo: 78624 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-248051/AS (NTIS**) AT: M16 orl-rat LD :>3 gm/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); M16 orl-mus LD :>2 gm/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*) MD: U01 orl-rat TDLo: 5208 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); M03-M20-N30 orl-rat TDLo: 54600 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); U01 orl-mus TDLo: 10416 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*); M03-Z01 orl-mus TDLo: 109200 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-299, 1986 (NTPTR*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 48, p. 139, 1990 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 48, p. 123, 1990 (IMEMDT); TOXICOLOGY REVIEW Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 14, p. 433, 1995 (JACTDZ) SR: OEL-UNITED KINGDOM: Carcinogen, SEP 2000 ND: NOHS 1974: HZD T0840; NIS 1; TNF 17; NOS 5; TNE 482; NOES 1983: HZD T0840; NIS 2; TNF 4292; NOS 3; TNE 43522; TFE 32059 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), clear evidence: rat; NCI Carcinogenesis Studies (feed), equivocal evidence: mouse; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 514 of 1119 in RTECS (through 2003/06) AN: CB2625000 PN: Anthranilic-acid,-4-chloro-N-furfuryl-5-sulfamoyl- SY: Aisemide-; Aluzine-; 5-(Aminosulfonyl)-4-chloro-2-((2-furanylmethyl)amino)benzoic acid; Aquasin-; Arasemide-; Benzoic acid, 5-(aminosulfonyl)-4-chloro-2-((2-furanylmethyl)amino)- (9CI); Beronald-; Chlor-N-(2-furylmethyl)-5-sulfamylanthranilsaeure (German); 4-Chloro-N-furfuryl-5-sulfamoylanthranilic-acid-; 4-Chloro-N-(2-furylmethyl)-5-sulfamoylanthranilic acid; Desdemin-; Discoid-; Diural-; Diurolasa-; Dryptal-; Durafurid-; Errolon-; Eutensin-; Franyl-; Frusemide-; Frusemin-; Frusetic-; Frusid-; Fulsix-; Fuluvamide-; Furanthril-; Furanthryl-; Furantril-; Furesis-; Furose-; Furosedon-; Furosemid-; Furosemide-; Furosemide-mita-; Furosemidu- (Polish); Furoside-; Fursemid-; Fursemide-; Fusid-; Hydrex-; Hydro-rapid-; Impugan-; Katlex-; Lasex-; Lasiletten-; Lasilix-; Lasix-; LB-502-; Lowpstron-; Macasirool-; Moilarorin-; NCI-C55936-; Neo-renal-; Prefemin-; Promedes-; Puresis-; Radonna-; Rosemide-; Salix-; Seguril-; Sigasalur-; Transit-; Urex-; Uritol-; Urosemide-; Laxur-; Novosemide-; Odemase-; Trofurit-; Urex-M- RN: Current: 54-31-9 BRN: 840915 BHR: 5-18-09-00555 UD: 200305 MF: C12-H11-Cl-N2-O5-S MW: 330.76 WL: T5OJ B1MR CG FVQ DSZW CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: cyt-hmn-leu 200 mg/L/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 66, p. 69, 1979 (MUREAV); mmo-mus-lym 1 mg/L (+S9) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); cyt-mus-ipr 312 ug/kg Indian Journal of Medical Research. (Indian Council of Medical Research, Ansari Nagar, New Delhi 110 029, India) V.1- 1913- v. 66, p. 104, 1977 (IJMRAQ); cyt-ham-lng 1 gm/L Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 4, p. 41, 1980 (ATSUDG); cyt-ham-fbr 2 gm/L Eisei Shikenjo Hokoku. Bulletin of the Institute of Hygienic Sciences. (Kokuritsu Eisei Shikenjo Kagaku, 18-1 Bushitsu Johobu, Setagaya-ku, Tokyo 158, Japan) V.1- 1886- v. (96), p. 55, 1978 (ESKHA5); cyt-ham-ovr 200 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); sce-ham-ovr 500 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*) RE: T46 orl-rat TDLo: 150 mg/kg (12-14D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 31, p. 401, 1985 (TJADAB); T31-T46 orl-rat TDLo: 300 mg/kg (16D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 34, p. 452, 1986 (TJADAB); T01-T02 orl-rat TDLo: 122 mg/kg (6W male) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 81, p. 259, 1987 (JRPFA4); T46 orl-rat TDLo: 150 mg/kg (16D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 40, p. 668, 1989 (TJADAB); T46 unr-rat TDLo: 1800 mg/kg (6-17D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 60, p. 142, 1981 (TXAPA9); T25-T34 orl-mus TDLo: 12500 mg/kg (6-15D preg) Senten Ijo. Congenital Anomalies. (Nippon Senten Ijo Gakkai, c/o Kinki Daigaku Igakubu Kaibagaku Kyoshitsu, 380 Nishiyama, Sayama-cho, Mirami-Kawachi-gun, Osaka-fu, Japan) V.1-26, 1960-86. For publisher information, see CGANE7. v. 24, p. 111, 1984 (SEIJBO); T46 orl-mus TDLo: 5 gm/kg (6-15D preg) Senten Ijo. Congenital Anomalies. (Nippon Senten Ijo Gakkai, c/o Kinki Daigaku Igakubu Kaibagaku Kyoshitsu, 380 Nishiyama, Sayama-cho, Mirami-Kawachi-gun, Osaka-fu, Japan) V.1-26, 1960-86. For publisher information, see CGANE7. v. 24, p. 111, 1984 (SEIJBO); T01 ipr-mus TDLo: 1560 ug/kg (1D male) Indian Journal of Medical Research. (Indian Council of Medical Research, Ansari Nagar, New Delhi 110 029, India) V.1- 1913- v. 66, p. 104, 1977 (IJMRAQ) TE: V03-A60-M61 orl-rat TDLo: 21112 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); V01-R60-P62 orl-mus TDLo: 15652 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); V01-R60 orl-mus TD :122 gm/kg/2Y-C JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 10, p. 369, 1990 (JJATDK); V03-A60-M60 orl-rat TDLo: 15288 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-106162/AS (NTIS**); V01-R60 orl-mus TDLo: 122304 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-106162/AS (NTIS**) ORNG: 2600000000 ng/kg. [2600.000000 mg/kg] T/E unlistd AT: M05 orl-wmn TDLo: 120 mg/kg/21W-I Journal of the Royal Society of Medicine. (Oxford Univ. Press, Walton St., Oxford OX2 6DP, UK) V.71- 1978- v. 79, p. 239, 1986 (JRSMD9); D40-D41-M11 ivn-man TDLo: 29 mg/kg New England Journal of Medicine. (Massachusetts Medical Soc., 10 Shattuck St., Boston, MA 02115) V.198- 1928- v. 282, p. 1413, 1970 (NEJMAG); F18-U07-U11 orl-wmn TDLo: 6250 ug/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 31, p. 341, 1993 (JTCTDW); G30-H04 ivn-hmn TDLo: 1300 ug/kg Annals of Internal Medicine. (American College of Physicians, 4200 Pine St., Philadelphia, PA 19104) V.1- 1927- v. 103, p. 1, 1985 (AIMEAS); U21 ivn-inf TDLo: 1 mg/kg/4H-I Archives of Disease in Childhood. (British Medical Journal, POB 560B, Kennebunkport, ME 04046) V.1- 1926- v. 59, p. 907, 1984 (ADCHAK); G08 ivn-wmn TDLo: 2500 ug/kg/2M-C Intensive Care Medicine. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.3- 1977- v. 12, p. 54, 1986 (ICMED9); T/E unlistd orl-rat LD50: 2600 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 185, 1971 (TXAPA9); T/E unlistd ipr-rat LD50: 800 mg/kg Acta Poloniae Pharmaceutica. For English translation, see APPFAR. (Ars Polona, POB 1001, 00-680 Warsaw 1, Poland) V.1- 1937- v. 42, p. 199, 1985 (APPHAX); T/E unlistd scu-rat LD50: 4600 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly. (Yakugyo Jihosha, Inaoka Bldg., 2-36 Jinbo-cho, Kanda, Chiyoda-ku, Tokyo 101, Japan) V.1- 1959- v. 9, p. 759, 1967 (YAKUD5); T/E unlistd ivn-rat LD50: 800 mg/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 725, 1982 (NIIRDN); T/E unlistd orl-mus LD50: 2 gm/kg European Patent Application. (U.S. Patent and Trademark Office, Foreign Patents, Washington, DC 20231) #0008367 (EPXXDW); T/E unlistd ivn-mus LD50: 308 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 14, p. 44, 1964 (ARZNAD); T/E unlistd unr-mus LD50: 900 mg/kg European Journal of Medicinal Chemistry--Chimie Therapeutique. (Editions Scientifiques Elsevier, 29 rue Buffon, F-75005, Paris, France) V.9- 1974- v. 15, p. 386, 1980 (EJMCA5); T/E unlistd orl-dog LD50: 2 gm/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 725, 1982 (NIIRDN); T/E unlistd ivn-dog LD50: >400 mg/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 725, 1982 (NIIRDN); T/E unlistd orl-rbt LD50: 800 mg/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 725, 1982 (NIIRDN); T/E unlistd ivn-rbt LD50: 400 mg/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 725, 1982 (NIIRDN); M01-M10-M16 scu-rat TDLo: 2 mg/kg Farmakologiya i Toksikologiya (Kiev). Pharmacology and Toxicology. (Kievskii Nauchno- Issledovatel'skii Institut Farmakologii i Toksikologii, Kiev, USSR) No.1- 1964- v. 159, p. 21, 1986 (FATOBP); M10-M16 orl-rat TDLo: 24 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 49, p. 58, 1986 (FATOAO); M10 orl-mus TDLo: 1 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 49, p. 58, 1986 (FATOAO); M16 orl-mus TDLo: 24 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 49, p. 58, 1986 (FATOAO); M16 ivn-dog TDLo: 0.1 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 49, p. 58, 1986 (FATOAO); T/E unlistd ipr-mus LD50: 430 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 49, p. 58, 1986 (FATOAO); M10 orl-rat TDLo: 10 mg/kg Biological and Pharmaceutical Bulletin. (Pharmaceutical Society of Japan, 2-12-15-201 Shibuya Shibuya-ku, Tokyo 150, Japan) V.16- 1993- v. 23, p. 182, 2000 (BPBLEO); M10-M16-M30 ivn-rat TDLo: 30 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 299, p. 978, 2001 (JPETAB) MD: M03-M10-L70 orl-rat TDLo: 1400 mg/kg/5W-I Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- v. 18, p. 5029, 1984 (KSRNAM); M03-Z01 orl-rat TDLo: 32200 mg/kg/14D-C JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 10, p. 369, 1990 (JJATDK); L70-M03 orl-rat TDLo: 27300 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); M10-M70-U05 orl-rat TDLo: 15288 mg/kg/26W-I Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- v. 18, p. 5113, 1984 (KSRNAM); G70-U01-U05 orl-rat TDLo: 4200 mg/kg/4W-C Pharmacology and Toxicology (Copenhagen). (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.60- 1987- v. 60, p. 77, 1987 (PHTOEH); M03-Z01 orl-mus TDLo: 77280 mg/kg/14D-C JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 10, p. 369, 1990 (JJATDK); L70 orl-mus TDLo: 54600 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); M16-U05 orl-rat TDLo: 72 mg/kg/6D-I Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 49, p. 58, 1986 (FATOAO) TR: IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 277, 1990 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 277, 1990 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 277, 1990 (IMEMDT) ND: NOHS 1974: HZD 84036; NIS 1; TNF 25; NOS 1; TNE 275; NOES 1983: HZD 84036; NIS 1; TNF 202; NOS 7; TNE 14103; TFE 11997 SL: EPA GENETOX PROGRAM 1988, Negative: S cerevisiae gene conversion; EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; NTP Carcinogenesis Studies (feed), some evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-356, 1989 (NTPTR*); NCI Carcinogenesis Studies (feed), equivocal evidence: mouse, rat Record 515 of 1119 in RTECS (through 2003/06) AN: CB4725000 PN: Anthraquinone- SY: Anthradione-; Anthracene,-9,10-dihydro-9,10-dioxo-; 9,10-Anthracenedione-; 9,10-Anthrachinon- (Czech); Corbit-; 9,10-Dioxoanthracene-; Hoelite-; Morkit-; 9,10-Anthraquinone- RN: Current: 84-65-1 UD: 200302 MF: C14-H8-O2 MW: 208.22 WL: L C666 BV IVJ CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M) ME: mmo-sat 2 ug/plate (+S9) Applied and Environmental Microbiology. (American Soc. for Microbiology, 1913 I St., NW, Washington, DC 20006) V.31- 1976- v. 43, p. 1354, 1982 (AEMIDF); mmo-sat 333 ug/plate (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11(Suppl 12), p. 1, 1988 (EMMUEG); dnd-mus-ipr 250 mg/kg Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 5, p. 355, 1982 (ATSUDG); mnt-ham-emb 12500 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 392, p. 61, 1997 (MUREAV) TE: V02-M61 orl-rat TDLo: 32760 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. NIH No. 99-3953 (NTIS**); V03-L60-M61 orl-rat TDLo: 36400 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. NIH No. 99-3953 (NTIS**); V01-L60 orl-mus TDLo: 194775 mg/kg/105W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. NIH No. 99-3953 (NTIS**); V01-L60 orl-mus TDLo: 172725 mg/kg/105W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. NIH No. 99-3953 (NTIS**) AT: T/E unlistd orl-rat LDLo: 15 gm/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,22,1982 (85GMAT); T/E unlistd ihl-rat LC50: >1300 mg/m3/4H Pesticide Manual. (The British Crop Protection Council, 20 Bridport Rd., Thornton Heath CR4 7QG, UK) V.1- 1968- v. 9, p. 37, 1991 (PEMNDP); T/E unlistd skn-rat LD50: >1 gm/kg "Agrochemicals Handbook," with updates, Hartley, D., and H. Kidd, eds., Nottingham, Royal Soc. of Chemistry, 1983-86 A019,1983 (85JFAN); T/E unlistd ipr-rat LD50: 3500 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 21(12), p. 27, 1977 (GTPZAB); T/E unlistd orl-mus LD50: >5 gm/kg Pesticide Manual. (The British Crop Protection Council, 20 Bridport Rd., Thornton Heath CR4 7QG, UK) V.1- 1968- v. 9, p. 37, 1991 (PEMNDP); T/E unlistd unr-qal LD50: >2 gm/kg Farm Chemicals Handbook. (Meister Pub., 37841 Euclid Ave., Willoughy, OH 44094) v. -, p. C23, 1991 (FMCHA2) MD: L70-M70-U01 orl-rat TDLo: 164 mg/kg/13W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 15, p. 318, 1995 (TOXID9); J06-P08-U01 orl-rat TDLo: 12200 mg/m3/5H/17W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 15(2), p. 58, 1971 (GTPZAB); L30-L70-M30 orl-mus TDLo: 328 mg/kg/13W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 15, p. 318, 1995 (TOXID9) SR: OEL-RUSSIA: STEL 5 mg/m3, JAN 1993 ND: NOHS 1974: HZD 81710; NIS 4; TNF 81; NOS 8; TNE 2202; NOES 1983: HZD 81710; NIS 5; TNF 435; NOS 7; TNE 6187; TFE 1602 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), clear evidence: mouse, rat; NTP Carcinogenesis studies, test completed (post peer review), October 2000 Record 516 of 1119 in RTECS (through 2003/06) AN: CB5120000 PN: Anthraquinone,-2-amino- SY: 2-Amino-9,10-anthracenedione-; Aminoanthraquinone-; beta-Aminoanthraquinone-; 2-Aminoanthraquinone-; 2-Amino-9,10-anthraquinone-; 9,10-Anthracenedione,-2-amino- (9CI); AAQ-; NCI-C01876-; beta-Anthraquinonylamine- RN: Current: 117-79-3 UD: 200006 MF: C14-H9-N-O2 MW: 223.24 WL: L C666 BV IVJ EZ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 1 mg/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); mmo-esc 1 mg/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); mnt-mus-oth 6 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 24, p. 96, 1994 (EMMUEG) TE: V01-L60 orl-rat TDLo: 115 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-144, 1978 (NCITR*); V01-L60-P62 orl-mus TDLo: 655 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-144, 1978 (NCITR*); V02-L60 orl-rat TD :225 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-144, 1978 (NCITR*); V03-L60-P62 orl-mus TD :330 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-144, 1978 (NCITR*); V02-L60 orl-rat TD :32 gm/kg/77W-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 4, p. 71, 1979 (TOLED5); V01-L60 orl-rat TD :1890 gm/kg/78W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 191, 1982 (IMEMDT); V01-L60 orl-rat TD :3780 gm/kg/78W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 191, 1982 (IMEMDT); V03-L60 orl-mus TD :2730 gm/kg/78W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 191, 1982 (IMEMDT); V01-L60 orl-mus TD :5600 gm/kg/80W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 191, 1982 (IMEMDT) AT: T/E unlistd ipr-rat LD50: 1500 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 21(12), p. 27, 1977 (GTPZAB) MD: M10-M13 orl-rat TDLo: 336 gm/kg/8W-C Medical Biology. (Finnish Medical Soc. Duodecim, Runeberginkatu 47 A, SF-00260 Helsinki 26, Finland) V.52- 1974- v. 58, p. 337, 1980 (MDBYAS); M03-N24-P08 orl-rat TDLo: 77 gm/kg/48W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 25, p. 453, 1973 (TXAPA9) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 191, 1982 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 191, 1982 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-144, 1978 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 517 of 1119 in RTECS (through 2003/06) AN: CB5500000 PN: Anthraquinone,-1-amino-2,4-dibromo- SY: 1-Amino-2,4-dibromanthrachinon- (Czech); 1-Amino-2,4-dibromoanthraquinone-; 9,10-Anthracenedione,-1-amino-2,4-dibromo-; 2,4-Dibromo-1-anthraquinonylamine-; NCI-C55458- RN: Current: 81-49-2 BRN: 1993373 BHR: 4-14-00-00444 UD: 200302 MF: C14-H7-Br2-N-O2 MW: 381.04 WL: L C666 BV IVJ DZ EE GE CC: Tumorigen (C); Mutagen (M); Primary-Irritant (S); Reproductive-Effector (T) ID: eye-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,565,1986 (85JCAE) ME: mmo-sat 333 ug/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mmo-sat 333 ug/plate (-S9) NTP Technical Bulletin. (National Toxicology Program, Landow Bldg. 3A-06, 7910 Woodmont Ave., Bethesda, MD 20205) JAN1982 (NTPTB*); mtr-rat-orl 329 gm/kg/39W-C Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 26, p. 78, 1985 (PAACA3); dnd-mus-orl 876000 mg/kg/2Y-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 422, 2001 (JTPAE7) TE: V01-K60-L60 orl-rat TDLo: 65520 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB97-116636 (NTIS**); V01-K60-L60 orl-rat TDLo: 80080 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB97-116636 (NTIS**); V01-K60-L60 orl-mus TDLo: 1230320 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB97-116636 (NTIS**); V01-K60-L60 orl-mus TDLo: 1419600 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB97-116636 (NTIS**); V01-J60-K60 orl-mus TDLo: 876000 mg/kg/2Y-I Journal of Toxicologic Pathology. (Nihon Dokusei Byori Gakkai, editor, 3-25-8 Nishi- shinbashi, Minato-ku, Tokyo 105, Japan) V.1- 1988 v. 29, p. 422, 2001 (JTPAE7) MD: L70-P28-P71 orl-rat TDLo: 130500 mg/kg/90D-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 82, p. 389, 1986 (TXAPA9); L70-P28-U06 orl-mus TDLo: 42075 mg/kg/90D-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 82, p. 389, 1986 (TXAPA9); P61-V30 orl-rat TDLo: 65520 mg/kg/104W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB97-116636 (NTIS**) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), no evidence: mouse, rat Record 518 of 1119 in RTECS (through 2003/06) AN: CB5740000 PN: Anthraquinone,-1-amino-2-methyl- SY: 1-Amino-2-methyl-9,10-anthracenedione-; 1-Amino-2-methylanthraquinone-; 9,10-Anthracenedione,-1-amino-2-methyl- (9CI); Acetate-Fast-Orange-R-; Acetoquinone-Light-Orange-JL-; Celliton-Orange-R-; C.I. 60700; C.I. Disperse Orange 11; Cilla-Orange-R-; Disperse-Orange-; Duranol-Orange-G-; 2-Methyl-1-anthraquinonylamine-; Microsetile-Orange-RA-; NCI-C01901-; Oranz-disperzni-11- (Czech); Perliton-Orange-3R-; Serisol-Orange-YL-; Supracet-Orange-R-; Artisil-Orange-3RP-; Nyloquinone-Orange-JR- RN: Current: 82-28-0 BRN: 650595 BHR: 4-14-00-00496 UD: 200006 MF: C15-H11-N-O2 MW: 237.27 WL: L C666 BV IVJ DZ E1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 33 ug/plate (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11(Suppl 12), p. 1, 1988 (EMMUEG) TE: V01-L60-M61 orl-rat TDLo: 30 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-111, 1978 (NCITR*); V01-L60 orl-mus TDLo: 37 gm/kg/73W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-111, 1978 (NCITR*); V01-L60-M61 orl-rat TD :60 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-111, 1978 (NCITR*); V02-L60-M61 orl-rat TD :39 gm/kg/77W-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 4, p. 71, 1979 (TOLED5); V03-L60 orl-mus TD :307 gm/kg/73W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 199, 1982 (IMEMDT); V03-L60-M61 orl-rat TD :557 gm/kg/79W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 199, 1982 (IMEMDT); V01-L60-M61 orl-rat TD :1113 gm/kg/79W-C IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 199, 1982 (IMEMDT) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 199, 1982 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 27, p. 199, 1982 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-111, 1978 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 519 of 1119 in RTECS (through 2003/06) AN: CB6650000 PN: Anthraquinone,-1,8-dihydroxy- SY: Altan-; 9,10-Anthracenedione,-1,8-dihydroxy-; Antrapurol-; Chrysazin-; Criasazin-; Danthron-; Dantron-; Diaquone-; 1,8-Dihydroxy-9,10-anthracenedione-; 1,8-Dihydroxyanthrachinon- (Czech); 1,8-Dihydroxyanthraquinone-; Dionone-; Dorbane-; Duolax-; Istin-; Istizin-; Laxanorm-; Laxanthreen-; Laxipur-; Laxipurin-; Neokutin-S-; Pastomin-; Prugol-; Roydan-; Scatron-D-; 1,4,5,8-Tetroxyantraquinone-; USAF-ND-59-; Zwitsalax- RN: Current: 117-10-2 Previous: 32072-07-4 UD: 200207 MF: C14-H8-O4 MW: 240.22 WL: L C666 BV IVJ DQ NQ CC: Tumorigen (C); Drug (D); Mutagen (M); Primary-Irritant (S) ID: eye-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,654,1986 (85JCAE) ME: mmo-sat 100 ug/plate (+/-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 203, 1976 (MUREAV); mmo-smc 5000 ppm/2D (-S9) Acta Dermato-Venereologica. (Almqvist and Wiksell, POB 45150, S-10430 Stockholm, Sweden) V.1- 1920- v. 51, p. 45, 1971 (ADVEA4); dns-rat-lvr 50 umol/L Cell Biology and Toxicology. (Princeton Scientific Pub., Inc., 301 N. Harrison St., CN 5279, Princeton, NJ 08540) V.1- 1984- v. 2, p. 457, 1986 (CBTOE2); mnt-mus-lym 20 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 165, 1996 (MUREAV); dns-mus-lvr 20 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 2918, 1984 (CNREA8); msc-mus-lym 42 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 165, 1996 (MUREAV); mmo-sat 30 ug/plate/44H Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 40, p. 105, 2002 (FCTOD7); mmo-sat 30 ug/plate/72H (+S9) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 116, p. 189, 2000 (TOLED5) TE: V01-K60-K61 orl-rat TDLo: 292 gm/kg/70W-C British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 52, p. 781, 1985 (BJCAAI); V01-K61-L60 orl-mus TDLo: 129 gm/kg/77W-C Japanese Journal of Cancer Research. (Elsevier Science Pub. BV, POB 211, 1000 AE Amsterdam, Netherlands) V.76- 1985- v. 77, p. 871, 1986 (JJCREP); V02-K61 orl-mus TD :130 gm/kg/77W-C Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 31(Suppl), p. 206, 1986 (TOLED5) AT: D07-F18-J30 ipr-rat LD50: 1110 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 52(12), p. 93, 1987 (GISAAA); T/E unlistd orl-mus LD50: >7 gm/kg Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 1, p. 89, 1977/1978 (DCTODJ); T/E unlistd ipr-mus LD50: 500 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD277-689 (NTIS**); T/E unlistd ivn-mus LD50: >10 gm/kg Pharmacology and Toxicology (Copenhagen). (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.60- 1987- v. 61, p. 153, 1987 (PHTOEH) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 265, 1990 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 265, 1990 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 265, 1990 (IMEMDT) ND: NOHS 1974: HZD 80355; NIS 2; TNF 110; NOS 7; TNE 3120; NOES 1983: HZD 80355; NIS 1; TNF 36; NOS 1; TNE 357; TFE 187 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 520 of 1119 in RTECS (through 2003/06) AN: CB7920600 PN: Anthraquinone,-6-methyl-1,3,8-trihydroxy- SY: 9,10-Anthracenedione,-1,3,8-trihydroxy-6-methyl- (9CI); C.I. 75440; C.I. Natural Yellow 14; Emodin-; Emodol-; Frangula-emodin-; 6-Methyl-1,3,8-trihydroxyanthraquinone-; Persian-Berry-Lake-; Rheum-emodin-; Schuttgelb-; Anthraquinone,-1,3,8-trihydroxy-6-methyl-; 1,3,8-Trihydroxy-6-methyl-9,10-anthracenedione- RN: Current: 518-82-1 BRN: 1888141 BHR: 4-08-00-03575 UD: 200305 MF: C15-H10-O5 MW: 270.25 WL: L C666 BV IVJ DQ FQ L1 NQ CC: Tumorigen (C); Mutagen (M); Natural-Product (N); Reproductive-Effector (T) ME: mmo-sat 50 ug/plate (+S9) Biochemical Society Transactions. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1973- v. 5, p. 1489, 1977 (BCSTB5); mmo-sat 2 ug/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 188, p. 161, 1987 (MUREAV); dns-rat-lvr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 240, p. 1, 1990 (MUREAV); mnt-mus-lym 60 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 165, 1996 (MUREAV); mtr-mus-fbr 3 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 240, p. 1, 1990 (MUREAV); msc-mus-mmr 5 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 329, 1988 (MUREAV); msc-mus-lym 55500 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 165, 1996 (MUREAV); mnt-ham-emb 13750 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 392, p. 61, 1997 (MUREAV); sce-ham-ovr 5 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 269, p. 27, 1992 (MUREAV); msc-ham-lng 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 240, p. 1, 1990 (MUREAV) RE: T34 orl-mus TDLo: 12.06 gm/kg (6-17D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108977 (NTIS**) TE: V03-N60 orl-rat TDLo: 808500 mg/kg/105W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2001-108194 (NTIS**); V03-M61 orl-mus TDLo: 55125 mg/kg/105W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2001-108194 (NTIS**) AT: K30 ipr-mus LD50: 35 mg/kg Journal of Agricultural and Food Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) V.1- 1953- v. 27, p. 1342, 1979 (JAFCAU) MD: P61-V30 orl-rat TDLo: 808500 mg/kg/105W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2001-108194 (NTIS**); K30 orl-mus TDLo: 12060 mg/kg/12D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108977 (NTIS**); U01 orl-mus TDLo: 4020 mg/kg/4D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108977 (NTIS**); F15 orl-mus TDLo: 376 mg/kg/4D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108977 (NTIS**); F16 orl-mus TDLo: 1564 mg/kg/4D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108977 (NTIS**); M71-R21 orl-rat TDLo: 372 mg/kg/12D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108975 (NTIS**); F15-F16-U01 orl-rat TDLo: 228 mg/kg/4D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108975 (NTIS**); L70 orl-rat TDLo: 1344 mg/kg/12D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB2002-108975 (NTIS**) SL: EPA GENETOX PROGRAM 1988, Negative: B subtilis rec assay; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NTP Carcinogenesis studies, test completed (post peer review), October 2000 Record 521 of 1119 in RTECS (through 2003/06) AN: CC6825000 PN: Antimony-potassium-tartrate-trihydrate- SY: Antimonate(2)-, bis(mu-tartrato(4-))di-, dipotassium, trihydrate; Antimonyl-potassium-tartrate-; Emetique- (French); ENT-50,434-; Potassium-antimonyl-tartrate-trihydrate-; Tartar-emetic-; Tartaric-acid,-antimony-potassium-salt,-trihydrate-; Tartarized-antimony-; Tartox-; Tartrate-antimonio-potassique- (French); Tartrated-antimony-; Potassium-antimonyl-tartrate-; Potassium-antimonyl-d-tartrate-; Potassium-antimony-tartrate-; Tartaric-acid,-antimony-potassium-salt- RN: Current: 28300-74-5 Previous: 304-61-0 UD: 200302 MF: C8-H4-O12-Sb2.3 H2-O.2 K MW: 635.88 WL: QVYQYQVO-SB-O &-KA- CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M); Human-Data (P) ME: dni-esc 19 umol/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 23, p. 1451, 1974 (BCPCA6); oms-esc 19 umol/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 23, p. 1451, 1974 (BCPCA6); cyt-hmn-fbr 100 umol/L Journal of Drug Research. (National Organization for Drug Research and Control, POB 29, Cairo, Egypt) V.2- 1969- v. 7(3), p. 27, 1975 (JDGRAX); cyt-rat-ipr 2 mg/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 83, 1982 (ENMUDM) ORNG: 115000000 ng/kg. [115.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-hmn LDLo: 2 mg/kg Pesticide Chemicals Official Compendium, Association of the American Pesticide Control Officials, Inc., 1966. (Topeka, KS) v. -, p. 1097, 1966 (PCOC**); D16-F07-J22 ivn-hmn TDLo: 1392 ug/kg Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 210, p. 227, 1926 (LANCAO); L30-M30 ivn-man LDLo: 12 mg/kg/1W-I Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 210, p. 227, 1926 (LANCAO); F08-K13-U25 ivn-man LD50: 249 mg/kg/9D-I Journal of Tropical Medicine and Hygiene. (Blackwell Scientific Pub. Ltd., POB 88, Oxford, UK) V.10- 1907- v. 21, p. 38, 1918 (JTMHA9); T/E unlistd orl-rat LD50: 115 mg/kg Agricultural Research Service, USDA Information Memorandum. (Beltsville, MD 20705) v. 20, p. 24, 1966 (ARSIM*); T/E unlistd ipr-rat LD50: 11 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd ims-rat LDLo: 33 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd orl-mus LDLo: 600 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd ipr-mus LD50: 33 mg/kg Bulletin of the World Health Organization. (WHO, Pub. Center USA, 49 Sheridan Ave., Albany, NY 12210) v. 53, p. 379, 1976 (BWHOA6); F18-J22 scu-mus LD50: 55 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 129, p. 284, 1968 (PSEBAA); T/E unlistd ivn-mus LD50: 45 mg/kg Fortschritte der Arzneimittelforschung. Progress in Drug Research. (Birkhauser Boston, Inc., c/o Springer-Verlag New York, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1959- v. 17, p. 108, 1973 (FAZMAE); T/E unlistd orl-rbt LD50: 115 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd ivn-rbt LD50: 12 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 89, p. 196, 1947 (JPETAB); T/E unlistd ipr-gpg LD50: 15 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd ims-gpg LDLo: 55 mg/kg Environmental Quality and Safety, Supplement. (Stuttgart, Fed. Rep. Ger.) V.1-5, 1975-76. Discontinued. v. 1, p. 1, 1975 (EQSSDX); T/E unlistd scu-mus LD50: 55 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1391, 2001 (HBPTO*); T/E unlistd orl-mus LD50: 600 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1391, 2001 (HBPTO*); K13 orl-hmn TDLo: 428.6 ug/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1392, 2001 (HBPTO*); Z01 orl-hmn LDLo: 1857 ug/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1392, 2001 (HBPTO*) MD: L30-M70-U01 orl-rat TDLo: 4500 mg/kg/13W-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 36, p. 21, 1998 (FCTOD7); L02-M03-Z01 ipr-rat TDLo: 264 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3130 (NTPTR*); L70-Y10-Y15 ipr-rat TDLo: 936 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3130 (NTPTR*); L30-U01-Z01 orl-mus TDLo: 5698 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3130 (NTPTR*); L03-Z01 ipr-mus TDLo: 600 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3130 (NTPTR*); L70-N73-P71 ipr-mus TDLo: 1152 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3130 (NTPTR*); C06-R21 unr-rbt TDLo: 657 mg/kg/31W-I Voeding. (Stichting TOT Wetenchappelijke Voorlichting OP Voedings Gebied, LAAN Copes Van Catenburch 44,2585 GB's Gravenhage, Netherlands) V.26- 1965- v. 19, p. 297, 1958 (VOEDAK); Z01 orl-mus TDLo: 219 mg/kg/2Y-C Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1391, 2001 (HBPTO*); Z01 orl-rat TDLo: 219 mg/kg/2Y-C Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1391, 2001 (HBPTO*) TR: ACGIH TLV-TWA 0.5 mg(Sb)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 0.5 mg(Sb)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 15, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 0.5 mg(Sb)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.5 mg(Sb)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.5 mg(Sb)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.5 mg(Sb)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 0.5 mg(Sb)/m3, JAN 1993; OEL-AUSTRALIA: TWA 0.5 mg(Sb)/m3, JAN 1993; OEL-AUSTRIA: MAK 0.5 mg(Sb)/m3, JAN 1993; OEL-BELGIUM: TWA 0.5 mg(Sb)/m3, JAN 1993; OEL-DENMARK: TWA 0.5 mg(Sb)/m3, JAN 1999; OEL-FINLAND: TWA 0.5 mg(Sb)/m3, JAN 1993; OEL-FRANCE: VME 0.5 mg(Sb)/m3, JAN 1993; OEL-GERMANY: MAK 0.5 mg(Sb)/m3 (total dust), JAN 1999; OEL-HUNGARY: STEL 0.5 mg(Sb)/m3, JAN 1993; OEL-JAPAN: OEL 0.1 mg(Sb)/m3, 2B Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.5 mg(Sb)/m3, JAN 1999; OEL-NORWAY: TWA 0.5 mg(Sb)/m3, JAN 1999; OEL-POLAND: MAC(TWA) 0.5 mg(Sb)/m3, JAN 1993; OEL-RUSSIA: TWA 0.2 mg(Sb)/m3, STEL 0.5 mg(Sb)/m3, JAN 1993; OEL-SWEDEN: NGV 0.5 mg(Sb)/m3, JAN 1999; OEL-SWITZERLAND: MAK-W 0.5 mg(Sb)/m3, JAN 1999; OEL-TURKEY: TWA 0.5 mg(Sb)/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 0.5 mg(Sb)/m3, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ANTIMONY-air: 10H TWA 0.5 mg(Sb)/m3 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 07370; NIS 6; TNF 116; NOS 10; TNE 3112; NOES 1983: HZD 07370; NIS 2; TNF 9; NOS 3; TNE 88; TFE 16 SL: NTP Toxicity studies, RPT# TOX-11, October 2000 Record 522 of 1119 in RTECS (through 2003/06) AN: CG0430000 PN: Arsenenous-acid,-calcium-salt- (2:1) SY: Calcium-arsenite- (2:1); Protars- RN: Current: 15194-98-6 UD: 200007 MF: As2-O4.Ca MW: 253.92 CC: Tumorigen (C) ORNG: 114000000 ng/kg. [114.000000 mg/kg] F11-F18-K20 AT: F11-F18-K20 orl-rat LD50: 114 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 28(7), p. 53, 1984 (GTPZAB); F11-F18-K20 orl-mus LD50: 48600 ug/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 28(7), p. 53, 1984 (GTPZAB); F11-F18-K20 ipr-mus LD50: 73400 ug/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 28(7), p. 53, 1984 (GTPZAB); T/E unlistd skn-mam LD50: 800 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 28(7), p. 53, 1984 (GTPZAB) MD: A11-K30-M05 orl-rat TDLo: 390 mg/kg/30D-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 28(7), p. 53, 1984 (GTPZAB) SL: NTP 9TH Report on Carcinogens, 2000: known to be human carcinogen Record 523 of 1119 in RTECS (through 2003/06) AN: CG0460000 PN: Arsenic acid (HAsO2), potassium salt SY: Arsenious acid, (HAsO2), potassium salt (8CI); Potassium-arsenite-; Arsenenous-acid,-potassium-salt- (9CI) RN: Current: 13464-35-2 UD: 200302 MF: As-O2.K MW: 146.02 CC: Tumorigen (C); Drug (D) SKNG: 150000000 ng/kg. [150.000000 mg/kg] T/E unlistd AT: P26-P60 ipr-mus TDLo: 10 mg/kg EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- 95,,1991 (EVHPAZ); T/E unlistd skn-rat LD50: 150 mg/kg "Vrednie chemichescie veshestva. Neorganicheskie soedinenia elementov V-VII groopp" (Hazardous substances. Inornanic substances containing V-VII group elements), Bandman A.L. et al., Chimia, 1989. v. -, p. 87, 1993 (VCVN5*); T/E unlistd orl-dog LD50: 3 mg/kg "Vrednie chemichescie veshestva. Neorganicheskie soedinenia elementov V-VII groopp" (Hazardous substances. Inornanic substances containing V-VII group elements), Bandman A.L. et al., Chimia, 1989. v. -, p. 87, 1993 (VCVN5*) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP 9TH Report on Carcinogens, 2000: known to be human carcinogen Record 524 of 1119 in RTECS (through 2003/06) AN: CG0830500 PN: Arsenic-acid,-calcium-salt- SY: Calcium-arsenate- RN: Current: 10103-62-5 UD: 200302 MF: As-H3-O4.x Ca MW: 422.51 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C) ORNG: 298000000 ng/kg. [298.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 298 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1393, 2001 (HBPTO*) MD: Z01 orl-rat TDLo: 29.2 gm/kg/2Y-C Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1384, 2001 (HBPTO*) SL: NTP 9TH Report on Carcinogens, 2000: known to be human carcinogen Record 525 of 1119 in RTECS (through 2003/06) AN: CG0900000 PN: Arsenic-acid,-disodium-salt,-heptahydrate- SY: Dibasic-sodium-arsenate-heptahydrate-; Disodium-arsenate,-heptahydrate-; Sodium-acid-arsenate,-heptahydrate-; Sodium-arsenate,-dibasic,-heptahydrate-; Sodium-arsenate-heptahydrate-; Sodium-arseniate-heptahydrate- RN: Current: 10048-95-0 UD: 200204 MF: As-H-O4.2 Na.7 H2-O MW: 427.00 WL: .NA2.AS-O2-Q2.Q7 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: cyt-dmg-orl 454 ppm Soviet Genetics. English translation of GNKAA5. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.2- 1966- v. 10, p. 608, 1974 (SOGEBZ); mtr-hmn-fbr 2500 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 47, p. 3815, 1987 (CNREA8); cyt-hmn-leu 7200 nmol/L Mutation Research. 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(440), p. 312, 1978 (EXMDA4); F07-F12-F19 scu-gpg LDLo: 50 mg/kg British Medical Journal. (British Medical Assoc., BMA House, Tavistock Sq., London WC1H 9JR, UK) V.1- 1857- v. 2, p. 217, 1913 (BMJOAE) MD: L30-N22-P28 orl-mus TDLo: 43 mg/kg/4W-C Journal of Toxicology and Environmental Health. 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(U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1018, 1987 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 0.2 mg(As)/m3, JAN 1993; OEL-AUSTRALIA: TWA 0.05 mg(As)/m3, Carcinogen, JAN 1993; OEL-BELGIUM: TWA 0.2 mg(As)/m3, JAN 1993; OEL-DENMARK: TWA 0.05 mg(As)/m3, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1993; OEL-FRANCE: VME 0.2 mg(As)/m3, JAN 1993; OEL-HUNGARY: STEL 0.5 mg(As)/m3, Carcinogen, JAN 1993; OEL-INDIA: TWA 0.2 mg(As)/m3, JAN 1993; OEL-NORWAY: TWA 0.01 mg(As)/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 0.5 mg(As)/m3, JAN 1993; OEL-POLAND: MAC(TWA) 0.3 mg(As)/m3, JAN 1999; OEL-SWEDEN: NGV 0.03 mg(As)/m3, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.1 mg(As)/m3, Carcinogen, JAN 1999; OEL-THAILAND: TWA 0.5 mg(As)/m3, JAN 1993; OEL-TURKEY: TWA 0.5 mg(As)/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 0.1 mg(As)/m3, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ARSENIC, INORGANIC-air: CA CL 0.002 mg(As)/m3/15M National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*) SL: NIOSH CURRENT INTELLIGENCE BULLETIN 14, 1976; NTP 9TH Report on Carcinogens, 2000: known to be human carcinogen Record 526 of 1119 in RTECS (through 2003/06) AN: CG3325000 PN: Arsenic-trioxide- SY: Anhydride-arsenieux- (French); Arsenic-blanc- (French); Arsenic-sesquioxide-; Acide-arsenieux- (French); Arsenic-oxide-; Arsenic(III) oxide; Arsenic-trioxide- (ACGIH); Arsenous-acid-; Arsenous-anhydride-; Arsenous-oxide-; Arsenous-oxide-anhydride-; Arsentrioxide-; Claudelite-; Claudetite-; Crude-arsenic-; Diarsenic-trioxide-; RCRA-waste-number-P012-; White-arsenic-; Arsenicum-album-; Arsenigen-saure- (German); Arsenious-acid-; Arsenious-oxide-; Arsenious-trioxide-; Arsenite-; Arsenolite-; Arsenous-acid-anhydride-; Arsodent- RN: Current: 1327-53-3 UD: 200305 MF: As2-O3 MW: 197.84 WL: AS2 O3 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: dnr-bcs 50 mmol/L Mutation Research. 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(VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 51, p. 605, 1981 (ARGEAR); cyt-mus-orl 3696 mg/kg Cytologia. (Japan Pub. Trading Co. (USA), 1255 Howard St., San Francisco, CA 94103) V.1- 1929- v. 52, p. 445, 1987 (CYTOAN); cyt-mus-oth 28500 ug/m3 JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 5, p. 61, 1985 (JJATDK); mnt-ham-lng 250 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 412, p. 213, 1998 (MUREAV); dnd-mus-orl 0.13 mg/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 162, p. 171, 2001 (TXCYAC); slt-mus-ipr 38 mg/kg/5D Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 513, p. 205, 2002 (MUREAV) RE: T74-T77 orl-wmn TDLo: 600 mg/kg (30W preg) American Journal of Diseases of Children. 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(Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 50, p. 135, 1995 (NEZAAQ); T26 orl-mus TDLo: 224 mg/kg (multigenerations) Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 23, p. 102, 1971 (AEHLAU); T27 orl-mus TDLo: 3636 mg/kg (1-18D preg) "Anorganische Stoffe in der Toxikologie and Kriminalistik, Symposium, Mosbach, Fed. Rep. Ger., 1983," Heppenheim, Fed. Rep. Ger., Verlag Dr. Dieter Helm, 1983 -,91,1983 (52GUAX); T54-T85 orl-mus TDLo: 8250 ug/kg (7-17D preg) Zhonghua Yufangyixue Zazhi. Chinese Journal of Preventive Medicine. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) Beginning history not known. v. 28, p. 20, 1994 (CHYCDW); T41 orl-mus TDLo: 1650 ug/kg (7-17D preg) Zhonghua Yufangyixue Zazhi. Chinese Journal of Preventive Medicine. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) Beginning history not known. v. 28, p. 20, 1994 (CHYCDW); T33-T46 ihl-mus TCLo: 28500 ug/m3/4H (9-12D preg) JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 5, p. 61, 1985 (JJATDK); T34 ihl-mus TCLo: 260 ug/m3/4H (9-12D preg) JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 5, p. 61, 1985 (JJATDK) TE: V03-J60 itr-rat TDLo: 16 mg/kg/15W-I EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 19, p. 191, 1977 (EVHPAZ); V02-J60 itr-ham TDLo: 45 mg/kg/15W-I Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 7, p. 403, 1984 (ATSUDG); V03-J60 itr-rat TD :75 mg/kg/15W-I Fukuoka Igaku Zasshi. (c/o Kyushu Daigaku Igakubu, Tatekasu, Fukuoka-shi, Fukuoka, Japan) V.33- 1940- v. 71, p. 19, 1980 (FKIZA4); V03-J60 itr-ham TD :40 mg/kg/15W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 21, p. 141, 1983 (CALEDQ); V02-J60 itr-ham TD :55450 ug/kg/15W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 21, p. 141, 1983 (CALEDQ); V03-J60 itr-rat TD :167 mg/kg/15W-I Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 20, p. 230, 1978 (SAIGBL); V03-J60 itr-ham TD :39608 ug/kg/24W-I Journal of UOEH (University of Occupational and Environmental Health). (Univ. of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807, Japan) V.1- 1979- v. 5(Suppl), p. 109, 1983 (JOUOD4); V03-J60 itr-ham TD :55456 ug/kg/24W-I Journal of UOEH (University of Occupational and Environmental Health). (Univ. of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807, Japan) V.1- 1979- v. 5(Suppl), p. 109, 1983 (JOUOD4); V02-J60 itr-ham TD :30 mg/kg/15W-I Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 24, p. 523, 1982 (SAIGBL); V01-J60 ihl-hmn TCLo: 50 ug/m3/24Y-C Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1398, 2001 (HBPTO*) ORNG: 10000000 ng/kg. [10.000000 mg/kg] T/E unlistd AT: G06-H02-K13 orl-wmn TDLo: 100 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 38, p. 471, 2000 (JTCTDW); F18-J15-M11 orl-man LDLo: 114 mg/kg Human and Experimental Toxicology. (Macmillan Press Ltd., Brunel Road, Houndmills, Basingstoke, Hampshire, RG21 2XS, UK) V.9- 1990- v. 18, p. 640, 1999 (HETOEA); J30-K13-P26 orl-wmn TDLo: 549 mg/kg Japanese Journal of Acute Medicine. (Nihon Kyukyu Igakkai Jun Kikanshi, Herusu Shuppan, 2-3 Nakano 2-chome, Nakanoku Tokyo 164, Japan) V.1- 196(?)- v. 20, p. 1557, 1996 (JJAMA*); F04-F18-K12 orl-man LDLo: 29 mg/kg Annals of Emergency Medicine. (American College of Emergency Physicians, 1125 Executive Circle, Irving, TX 75038) v. 16, p. 702, 1987 (AEMED3); G04-L14-Q30 orl-man LDLo: 286 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 29, p. 45, 1991 (JTCTDW); D14-K12-P28 orl-man TDLo: 14857 ug/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 36, p. 27, 1998 (JTCTDW); T/E unlistd orl-hmn LDLo: 1429 ug/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 31, p. 1247, 1980 (YKYUA6); F24-L03-M12 orl-man LDLo: 2857 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 29, p. 131, 1991 (JTCTDW); A30-K13-L30 orl-man LDLo: 123 mg/kg Journal of Forensic Sciences. (American Soc. for Testing and Materials, 1916 Race St., Philadelphia, PA 19103) V.1- 1956- v. 36, p. 1163, 1992 (JFSCAS); K13-K30-L30 orl-wmn TDLo: 20 mg/kg International Archives of Occupational and Environmental Health. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.35- 1975- v. 68, p. 342, 1996 (IAEHDW); T/E unlistd unr-man LDLo: 2941 ug/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); T/E unlistd ipr-rat LD50: 871 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 19(3), p. 30, 1975 (GTPZAB); R11 scu-rat LDLo: 8 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 19, p. 337, 1922 (JPETAB); T/E unlistd unr-rat LDLo: 8 mg/kg Biochemische Zeitschrift. (Berlin, Ger.) V.1-346, 1906-67. For publisher information, see EJBCAI. v. 184, p. 360, 1927 (BIZEA2); T/E unlistd scu-mus LD50: 9800 ug/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 78, p. 392, 1951 (PSEBAA); T/E unlistd ivn-mus LD50: 10700 ug/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 78, p. 392, 1951 (PSEBAA); T/E unlistd orl-dog LDLo: 10 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1306, 1935 (HBAMAK); T/E unlistd idr-dog LDLo: 2 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1306, 1935 (HBAMAK); T/E unlistd orl-rbt LD50: 20190 ug/kg Zhonghua Yufangyixue Zazhi. Chinese Journal of Preventive Medicine. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) Beginning history not known. v. 22, p. 284, 1988 (CHYCDW); J30-K12-P30 ivn-rbt LDLo: 10560 ug/kg Biochemische Zeitschrift. (Berlin, Ger.) V.1-346, 1906-67. For publisher information, see EJBCAI. v. 70, p. 144, 1915 (BIZEA2); T/E unlistd idr-pgn LDLo: 100 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1306, 1935 (HBAMAK); T/E unlistd idr-ckn LDLo: 13 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1306, 1935 (HBAMAK); T/E unlistd orl-ctl LDLo: 30 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1306, 1935 (HBAMAK); T/E unlistd orl-rat LD50: 10 mg/kg "Vrednie chemichescie veshestva. Neorganicheskie soedinenia elementov V-VII groopp" (Hazardous substances. Inornanic substances containing V-VII group elements), Bandman A.L. et al., Chimia, 1989. v. -, p. 88, 1993 (VCVN5*); T/E unlistd orl-mus LD50: 20 mg/kg "Vrednie chemichescie veshestva. Neorganicheskie soedinenia elementov V-VII groopp" (Hazardous substances. Inornanic substances containing V-VII group elements), Bandman A.L. et al., Chimia, 1989. v. -, p. 88, 1993 (VCVN5*); T/E unlistd ipr-mus LD50: 10 mg/kg "Vrednie chemichescie veshestva. Neorganicheskie soedinenia elementov V-VII groopp" (Hazardous substances. Inornanic substances containing V-VII group elements), Bandman A.L. et al., Chimia, 1989. v. -, p. 88, 1993 (VCVN5*); T/E unlistd unr-hmn LDLo: 0.29 mg/kg "Vrednie chemichescie veshestva. Neorganicheskie soedinenia elementov V-VII groopp" (Hazardous substances. Inornanic substances containing V-VII group elements), Bandman A.L. et al., Chimia, 1989. v. -, p. 92, 1993 (VCVN5*); F27-G08-K13 orl-man TDLo: 2 mg/kg Journal of Toxicology, Clinical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.19- 1982- v. 39, p. 13, 2001 (JTCTDW) MD: F07-R21-U01 orl-rat TDLo: 1820 mg/kg/26W-C Weisheng Dulixue Zazhi. Journal of Health Toxicology. (Weisheng Dulixue Zazhi Bianjibu, Dongdaqiao, Chaoyang Menwai, Beijing, Peop. Rep. China) V.1- 1987 v. 8, p. 95, 1994 (WDZAEK); L01-L03-P28 orl-rat TDLo: 180 mg/kg/4D-I Weisheng Dulixue Zazhi. Journal of Health Toxicology. (Weisheng Dulixue Zazhi Bianjibu, Dongdaqiao, Chaoyang Menwai, Beijing, Peop. Rep. China) V.1- 1987 v. 4, p. 4, 1990 (WDZAEK); F17-U01-Z01 orl-rat TDLo: 900 mg/kg/15W-I Neurobehavioral Toxicology and Teratology. (Fayetteville, NY) V.3-8, 1981-86. For publisher information, see NETEEC. v. 5, p. 91, 1983 (NTOTDY); M16-U05-U10 orl-rat TDLo: 350 ug/kg/30D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 52(1), p. 21, 1987 (GISAAA); A11-P30 ihl-rat TCLo: 31 ug/m3/24H/22W-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 47(1), p. 6, 1982 (GISAAA); A11-P28-Y01 ihl-rat TCLo: 500 ug/m3/24H/33D-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 47(11), p. 74, 1982 (GISAAA); L70 itr-rat TDLo: 20800 ug/kg/8W-I Nippon Eiseigaku Zasshi. Japanese Journal of Hygiene. (Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 50, p. 133, 1995 (NEZAAQ); J12-J70-L70 itr-ham TDLo: 20800 ug/kg/8W-I Fukuoka Igaku Zasshi. (c/o Kyushu Daigaku Igakubu, Tatekasu, Fukuoka-shi, Fukuoka, Japan) V.33- 1940- v. 91, p. 21, 2000 (FKIZA4) TR: IARC Cancer Review: Human Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 48, 1973 (IMEMDT); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 23, p. 39, 1980 (IMEMDT); IARC Cancer Review: Animal Limited Evidence IARC Monographs, Supplement. 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(U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1018, 1987 (CFRGBR); OEL-AUSTRALIA: Carcinogen, JAN 1993; OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-BELGIUM: Carcinogen, JAN 1993; OEL-DENMARK: TWA 0.05 mg(As)/m3, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1993; OEL-FRANCE: VME 0.2 mg/m3, C1 Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999; OEL-JAPAN: Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.01 mg(As)/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 0.1 mg/m3, Carcinogen, JAN 1993; OEL-POLAND: TWA 0.01 mg(As)/m3, JAN 1999; OEL-SWEDEN: TWA 0.03 mg(As)/m3, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.1 mg(As)/m3, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: TWA 0.1 mg(As)/m3, Carcinogen, SEP 2000; OEL-UNITED KINGDOM: TWA 0.1 mg(Se)/m3, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ARSENIC, INORGANIC-air: CA CL 0.002 mg(As)/m3/15M National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 07570; NIS 6; TNF 1284; NOS 6; TNE 3980; NOES 1983: HZD 07570; NIS 8; TNF 107; NOS 16; TNE 4657; TFE 2001 SL: EPA GENETOX PROGRAM 1988, Positive: B subtilis rec assay; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH CURRENT INTELLIGENCE BULLETIN 14, 1976; NIOSH Analytical Method, 1994: Arsenic trioxide as As, 7901; NTP Carcinogenesis studies, selected, October 2000 Record 527 of 1119 in RTECS (through 2003/06) AN: CG3380000 PN: Arsenious-acid,-calcium-salt- SY: Calcium-arsenite- (Ca3As2O6); Calcium-arsenite- (3:2); Monocalcium-arsenite- RN: Current: 27152-57-4 UD: 200012 MF: As2-O6.3 Ca MW: 366.08 WL: .CA..AS-O2-Q CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Human-Data (P) AT: T/E unlistd orl-hmn LDLo: 1666 ug/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 28, p. 329, 1977 (YKYUA6); T/E unlistd orl-mus LD50: 1 mg/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 28, p. 329, 1977 (YKYUA6); T/E unlistd orl-dog LDLo: 85 mg/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 28, p. 329, 1977 (YKYUA6); T/E unlistd orl-pig LDLo: 5 mg/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 28, p. 329, 1977 (YKYUA6) TR: ACGIH TLV-TWA 0.01 mg(As)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-Confirmed human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: MSHA STANDARD-air: TWA 0.5 mg(As)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 16, 1971 (DTLVS*); OSHA-cancer hazard Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1018, 1987 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 0.2 mg(As)/m3, JAN 1993; OEL-AUSTRALIA: TWA 0.05 mg(As)/m3, Carcinogen, JAN 1993; OEL-BELGIUM: TWA 0.2 mg(As)/m3, JAN 1993; OEL-DENMARK: TWA 0.5 mg(As)/m3, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1993; OEL-FRANCE: VME 0.2 mg(As)/m3, JAN 1993; OEL-HUNGARY: STEL 0.5 mg(As)/m3, Carcinogen, JAN 1993; OEL-INDIA: TWA 0.2 mg(As)/m3, JAN 1993; OEL-NORWAY: TWA 0.01 mg(As)/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 0.5 mg(As)/m3, JAN 1993; OEL-POLAND: MAC(TWA) 0.3 mg(As)/m3, JAN 1993; OEL-SWEDEN: NGV 0.03 mg(As)/m3, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.1 mg(As)/m3, Carcinogen, JAN 1999; OEL-THAILAND: TWA 0.5 mg(As)/m3, JAN 1993; OEL-TURKEY: TWA 0.5 mg(As)/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 0.1 mg(As)/m3, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ARSENIC, INORGANIC-air: CA CL 0.002 mg(As)/m3/15M National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*) SL: NIOSH CURRENT INTELLIGENCE BULLETIN 14, 1976; NTP 9TH Report on Carcinogens, 2000: known to be human carcinogen Record 528 of 1119 in RTECS (through 2003/06) AN: CH9492050 PN: Arsonic-acid,-calcium-salt- (1:1) SY: Calcium-arsonate- (1:1) RN: Current: 52740-16-6 UD: 200007 MF: As-H2-O3.Ca MW: 165.02 CC: Tumorigen (C) SL: NTP 9TH Report on Carcinogens, 2000: known to be human carcinogen Record 529 of 1119 in RTECS (through 2003/06) AN: CI6475000 PN: Asbestos- SY: Amianthus-; Amosite- (Obs.); Amphibole-; Asbest- (German); Asbestos- (ACGIH:OSHA); Asbestos-fiber-; Asbestos-fibre-; Asbestos,-all-forms-; Fibrous-grunerite-; NCI-C08991- RN: Current: 1332-21-4 UD: 200210 CC: Tumorigen (C); Mutagen (M); Human-Data (P); Natural-Product (N) ME: mmo-esc 10 mg/plate (+/-S9) Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 177, p. 343, 1984 (PSEBAA) TE: V03-V10 imp-rat TDLo: 750 mg/kg Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 62, p. 561, 1958 (ZEKBAI); V03-V10 ipr-mus TDLo: 80 mg/kg Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 24, p. 61, 1983 (PAACA3) AT: J17-J22-J23 ihl-hmn TCLo: 1.2 fb/cc/19Y-C American Review of Respiratory Disease. (American Lung Assoc., 1740 Broadway, New York, NY 10019) V.80- 1959- v. 104, p. 576, 1971 (ARDSBL); J02-J30-Y10 itr-rat LD :>4 mL/kg Zhonghua Yufangyixue Zazhi. Chinese Journal of Preventive Medicine. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) Beginning history not known. v. 32, p. 139, 1998 (CHYCDW) TR: ACGIH TLV-TWA 0.1 f/cc (F) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Confirmed Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.1 f/cc (f) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 17, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 17, 1973 (IMEMDT); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 14, p. 11, 1977 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 14, p. 11, 1977 (IMEMDT); IARC Cancer Review: Group 1 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 106, 1987 (IMSUDL); TOXICOLOGY REVIEW Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 64, p. 1435, 1975 (JPMSAE); TOXICOLOGY REVIEW Pediatrics. (American Academy of Pediatrics, P.O. Box 1034, Evanston, IL 60204) V.1- 1948- v. 57, p. 462, 1976 (PEDIAU); TOXICOLOGY REVIEW JOM, Journal of Occupational Medicine. (American Occupational Medicine Assoc., 150 N. Wacker Dr., Chicago, IL 60606) V.10- 1968- v. 15, p. 808, 1973 (JJOMDZ); TOXICOLOGY REVIEW Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 39, p. 1792, 1977 (CANCAR); TOXICOLOGY REVIEW "Oncology 1970, Proceedings of the Tenth International Cancer Congress," Chicago, Year Book Medical Pub., 1971 5,55,1970 (85CVA2); TOXICOLOGY REVIEW "Experimental Lung Cancer: Carcinogenesis and Bioassays, International Symposium, 1974," Karbe, E., and J.F. Park, eds., Springer-Verlag New York, Inc., 1974 -,92,1974 (31BYAP); TOXICOLOGY REVIEW Zentralblatt fuer Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene, Abteilung 1: Originale, Reihe B: Hygiene, Krankenhaushygiene, Betriebshygiene, Praeventive Medizin. (Stuttgart, Fed. Rep. Ger.) V.155-169, 1971-1979. For publisher information, see ZAOMDC. v. 166, p. 113, 1978 (ZHPMAT); TOXICOLOGY REVIEW Nobel Symposium. (Nobel Foundation, Sturegatan 14, S-11436 Stockholm, Sweden) No.1- 1966- v. 40, p. 311, 1977 (NOSYBW); TOXICOLOGY REVIEW Progress in Experimental Tumor Research. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1960- v. 12, p. 102, 1969 (PEXTAR); TOXICOLOGY REVIEW National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. CONF-691001 (NTIS**); TOXICOLOGY REVIEW Cahiers de Notes Documentaires. (Institut National de Recherche et de Securite, 30 rue Olivier Noyer, 75680 Paris Cedex, 14, France) No.1- 1955- v. 85, p. 559, 1976 (CNDIBJ) SR: MSHA STANDARD-air: TWA 5 fb/cc (fb > 5 um) "Documentation of the Threshold Limit Values for Substances in Workroom Air," Supplements. For publisher information, see 85INA8. v. 3, p. 33, 1973 (DTLWS*); OSHA PEL (Construc): see CFR 29,1926.58 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.2 f/cc Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA-CANCER AND LUNG DISEASE HAZARD Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1001, 1991 (CFRGBR); OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FRANCE: VME 0.3 fiber/ml, C1 Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999; OEL-THE NETHERLANDS: Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.1 fiber/cm3, JAN 1999; OEL-SWITZERLAND: MAK-W 0.25 fiber/ml, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ASBESTOS-air: 100M TWA 0.1 fb/cc in a 400L air sample National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 90310; NIS 154; TNF 30863; NOS 117; TNE 449904; NOES 1983: HZD 90310; NIS 81; TNF 15617; NOS 86; TNE 215265; TFE 9727 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/2001/109101); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: TRP reversion; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH CURRENT INTELLIGENCE BULLETIN 5, 1975; NIOSH Analytical Method, 1994: Asbestos (bulk) by PLM, 9002, by PCM, 7400, by TEM, 7402; NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen Record 530 of 1119 in RTECS (through 2003/06) AN: CI6477000 PN: Asbestos,-amosite- SY: Amosite-; Amosite- (Obs.); Amosite-asbestos-; Asbestos- (ACGIH); Grunerite-asbestos-; Mysorite-; NCI-C60253A- RN: Current: 12172-73-5 Previous: 53799-45-4 UD: 200305 CC: Tumorigen (C); Mutagen (M); Natural-Product (N) ME: sln-dmg-orl 25 gm/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 261, p. 9, 1991 (MUREAV); mtr-ham-emb 3 mg/m3 Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 9, p. 891, 1988 (CRNGDP); dni-ham-lng 125 mg/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 1, p. 71, 1987 (TIVIEQ); cyt-ham-ovr 10 mg/L Cold Spring Harbor Conferences on Cell Proliferation. (Cold Spring Harbor, NY) V.1-10, 1974-83. v. 4, p. 941, 1977 (CSHCAL); sce-ham-ovr 10 mg/L Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 4(2-3), p. 373, 1980 (JEPTDQ); msc-ham-lng 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 68, p. 265, 1979 (MUREAV) TE: V01-J60 ihl-rat TCLo: 11 mg/m3/2Y-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 29, p. 252, 1974 (BJCAAI); V01-J60 ipl-rat TDLo: 80 mg/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 13, p. 143, 1982 (TOLED5); V03-J60 itr-rat TDLo: 12 mg/kg/12W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 13, p. 143, 1982 (TOLED5); V02-V10 imp-rat TDLo: 200 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 965, 1981 (JJIND8); V01-V10 ipr-mus TDLo: 80 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 35, p. 277, 1984 (ENVRAL); V01-J60-V10 scu-mus TDLo: 2400 mg/kg/13W-I Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 6, p. 566, 1968 (FCTXAV); V03-V16 mul-ham TDLo: 290 gm/kg/35W-C Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 132, p. 456, 1965 (ANYAA9); V02-J60 ipl-rat TD :200 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 28, p. 173, 1973 (BJCAAI); V02-J60 ihl-rat TC :12 mg/m3/13W-I Recent Results in Cancer Research. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1965- v. 39, p. 37, 1972 (RRCRBU); V02-J61 ipl-rat TD :200 mg/kg Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 48, p. 797, 1972 (JNCIAM); V01-J60 ipl-rat TD :100 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. 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(Published by Taylor and Francis Health, 11 New Fetter Lane, London EC4P 4EE) V.1- 1989- v. 7, p. 503, 1995 (INHTE5); J30-J70 itr-rat TDLo: 195 mg/kg/90D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. -, p. 35, 1993 (GISAAA) TR: ACGIH TLV-Confirmed human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-TWA 0.2 mg/m3 f/cc (f) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 17, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 17, 1973 (IMEMDT); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 14, p. 11, 1977 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 14, p. 11, 1977 (IMEMDT); IARC Cancer Review: Group 1 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 106, 1987 (IMSUDL); TOXICOLOGY REVIEW "Experimental Lung Cancer: Carcinogenesis and Bioassays, International Symposium, 1974," Karbe, E., and J.F. Park, eds., Springer-Verlag New York, Inc., 1974 -,93,1974 (31BYAP) SR: MSHA STANDARD-air: TWA 5 fb/cc (fb > 5 um) "Documentation of the Threshold Limit Values for Substances in Workroom Air," Supplements. For publisher information, see 85INA8. v. 3, p. 33, 1973 (DTLWS*); OSHA-cancer hazard Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1001, 1987 (CFRGBR); OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FRANCE: VME 0.6 fiber/ml, C1 Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.1 fiber/cm3, JAN 1999; OEL-SWEDEN: TWA 0.2 fiber/ml, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.25 fiber/ml, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ASBESTOS-air: 100M TWA 0.1 fb/cc in a 400L air sample National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD T1575; NIS 45; TNF 5924; NOS 48; TNE 92033; TFE 13262 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: TRP reversion; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Asbestos (bulk) by PLM, 9002, by PCM, 7400, by TEM, 7402; NIOSH Analytical Method, 1994: Asbestos, chrysotile by XRD, 9000; NTP Carcinogenesis Studies (feed): some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-295, 1985 (NTPTR*); NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: hamster; NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen Record 533 of 1119 in RTECS (through 2003/06) AN: CI6479000 PN: Asbestos,-crocidolite- SY: Amorphous-crocidolite-asbestos-; Asbestos- (ACGIH); Crocidolite-; Crocidolite- (9CI); Crocidolite-asbestos-; Crocidolite-asbestos- (ACGIH); Fibrous-crocidolite-asbestos-; Krokydolith- (German); NCI-C09007- RN: Current: 12001-28-4 Previous: 132207-33-1 UD: 200305 MF: O-Na2Fe2-O33Fe-O8Si-O2H2-O MW: 765.98 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 ug/plate (-S9) Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 1749, 1994 (CRNGDP); dnd-hmn-leu 50 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 311, p. 209, 1994 (MUREAV); oms-hmn-fbr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 116, p. 369, 1983 (MUREAV); msc-hmn-oth 50 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 26, p. 67, 1995 (EMMUEG); dnd-rat-emb 847 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 49, p. 5713, 1989 (CNREA8); dns-rat-oth 4 ug/cm2 Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 241, p. 361, 1990 (MUREAV); cyt-rat-ipr 100 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 48, p. 6455, 1988 (CNREA8); sce-rat-oth 10 mg/L British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 44, p. 281, 1987 (BJIMAG); sln-rat-ipr 100 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 48, p. 6455, 1988 (CNREA8); mtr-mus-oth 10 mg/L Cold Spring Harbor Conferences on Cell Proliferation. (Cold Spring Harbor, NY) V.1-10, 1974-83. v. 4, p. 941, 1977 (CSHCAL); mnt-ham-emb 2 ug/cm2 Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 5017, 1984 (CNREA8); mtr-ham-emb 2600 ug/m3 Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 9, p. 891, 1988 (CRNGDP); dni-ham-lng 62 mg/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 1, p. 71, 1987 (TIVIEQ); oms-ham-ovr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 116, p. 369, 1983 (MUREAV); cyt-ham-emb 2 mg/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 473, 1985 (CRNGDP); cyt-ham-lng 5 mg/L/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 57, p. 225, 1978 (MUREAV); cyt-ham-ovr 10 mg/L Cold Spring Harbor Conferences on Cell Proliferation. (Cold Spring Harbor, NY) V.1-10, 1974-83. v. 4, p. 941, 1977 (CSHCAL); sce-ham-ovr 10 mg/L Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 4(2-3), p. 373, 1980 (JEPTDQ); sln-ham-emb 2 ug/cm2 Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 5017, 1984 (CNREA8); sln-ham-lng 40 mg/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 8, p. 553, 1987 (CRNGDP); msc-ham-lng 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 68, p. 265, 1979 (MUREAV); oms-mus-ihl 5.75 mg/m3/6H/5D EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 108, p. 341, 2000 (EVHPAZ); dna-mus-ihl 5.75 mg/m3/6H/5D EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 108, p. 341, 2000 (EVHPAZ); slt-mus-ihl 5.75 mg/m3/6H/5D EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 108, p. 341, 2000 (EVHPAZ) TE: V01-J60 ihl-rat TCLo: 11 mg/m3/1Y-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 29, p. 252, 1974 (BJCAAI); V03-V10 ipr-rat TDLo: 100 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 29, p. 238, 1982 (ENVRAL); V01-V10 ipr-rat TDLo: 100 mg/kg Progress in Biochemical Pharmacology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965- v. 14, p. 47, 1978 (PBPHAW); V01-K60 scu-rat TDLo: 112 mg/kg Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 271, p. 431, 1976 (ANYAA9); V01-J60-V10 ipl-rat TDLo: 100 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 23, p. 567, 1969 (BJCAAI); V03-V10 ipl-rat TDLo: 100 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 41, p. 918, 1980 (BJCAAI); V02-V10 imp-rat TDLo: 200 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 965, 1981 (JJIND8); V03-K60-Q60 ipr-mus TDLo: 480 mg/kg/60W-I American Review of Respiratory Disease. (American Lung Assoc., 1740 Broadway, New York, NY 10019) V.80- 1959- v. 141(Suppl), p. A3-A937, 1990 (ARDSBL); V01-J60-V10 scu-mus TDLo: 2400 mg/kg/12W-I Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 6, p. 566, 1968 (FCTXAV); V03-V10 ipl-mus TDLo: 200 mg/kg "Experimental Lung Cancer: Carcinogenesis and Bioassays, International Symposium, 1974," Karbe, E., and J.F. Park, eds., Springer-Verlag New York, Inc., 1974 -,92,1974 (31BYAP); V03-G60-J60 itr-dog TDLo: 52 mg/kg/2Y-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 47, p. 1994, 1981 (CANCAR); V03-V10 ipl-rbt TDLo: 8 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 4, p. 496, 1971 (ENVRAL); V02-V10 ipl-ham TDLo: 83 mg/kg "Experimental Lung Cancer: Carcinogenesis and Bioassays, International Symposium, 1974," Karbe, E., and J.F. Park, eds., Springer-Verlag New York, Inc., 1974 -,92,1974 (31BYAP); V03-V10 ipr-rat TD :90 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 4, p. 496, 1971 (ENVRAL); V03-V10 scu-rat TD :112 mg/kg Progress in Biochemical Pharmacology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1965- v. 14, p. 47, 1978 (PBPHAW); V02-J60 ihl-rat TC :12 mg/m3/13W-I Recent Results in Cancer Research. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1965- v. 39, p. 37, 1972 (RRCRBU); V03-V10-Y55 scu-mus TD :1200 mg/kg/10W-I International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 2, p. 628, 1967 (IJCNAW); V02-J61 ipl-rat TD :10 mg/kg Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 48, p. 797, 1972 (JNCIAM); V03-V10 imp-rat TD :200 mg/kg IARC Scientific Publications. (Geneva, Switzerland) No.1-26, 1971-78. For publisher information, see IAPUDO. v. 8, p. 289, 1973 (IARCCD); V03-J60 ipl-rat TD :100 mg/kg IARC Publications. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.27- 1979- v. 30, p. 311, 1980 (IAPUDO); V03-V10 ipr-rat TD :250 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 29, p. 123, 1982 (ENVRAL); V03-V10 ipr-rat TD :100 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 29, p. 238, 1982 (ENVRAL); V03-V10 ipr-rat TD :125 mg/kg Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 29, p. 238, 1982 (ENVRAL) AT: F17-K12-K17 ipr-rat LDLo: 300 mg/kg American Journal of Pathology. (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1925- v. 70, p. 291, 1973 (AJPAA4); J30 itr-rat LD :>400 ug/kg American Review of Respiratory Disease. (American Lung Assoc., 1740 Broadway, New York, NY 10019) V.80- 1959- v. 141(Suppl), p. A3-A937, 1990 (ARDSBL); J30-U09 ipl-rat TDLo: 150 mg/kg Archives of Biochemistry and Biophysics. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.31- 1951- v. 311, p. 13, 1994 (ABBIA4); S01-Y20 ipr-mus TDLo: 100 mg/kg EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 51, p. 147, 1983 (EVHPAZ) MD: J13-J14 ihl-rat TCLo: 10 mg/m3/6H/1Y-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 21, p. 193, 1987 (JTEHD6); J13 ihl-rat TCLo: 7200 ug/m3/6H/20D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 137, p. 67, 1996 (TXAPA9); J14 ihl-mus TCLo: 13600 ug/m3/6H/5D-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 109, p. 147, 1996 (TXCYAC) TR: ACGIH TLV-Confirmed human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-TWA 0.1 mg/m3 f/cc (f) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 17, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 2, p. 17, 1973 (IMEMDT); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 14, p. 11, 1977 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 14, p. 11, 1977 (IMEMDT); IARC Cancer Review: Group 1 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 106, 1987 (IMSUDL); TOXICOLOGY REVIEW "Experimental Lung Cancer: Carcinogenesis and Bioassays, International Symposium, 1974," Karbe, E., and J.F. Park, eds., Springer-Verlag New York, Inc., 1974 -,93,1974 (31BYAP) SR: MSHA STANDARD-air: TWA 5 fb/cc (fb > 5 um) "Documentation of the Threshold Limit Values for Substances in Workroom Air," Supplements. For publisher information, see 85INA8. v. 3, p. 33, 1973 (DTLWS*); OSHA-cancer hazard Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1001, 1987 (CFRGBR); OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FRANCE: VME 0.3 fiber/ml, C1 Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.1 fiber/cm3, JAN 1999; OEL-SWEDEN: TWA 0.2 fiber/ml, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.25 fiber/ml, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ASBESTOS-air: 100M TWA 0.1 fb/cc in a 400L air sample National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD X6692; NIS 2; TNF 85; NOS 4; TNE 2415; TFE 247 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: TRP reversion; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Asbestos (bulk) by PLM, 9002, by PCM, 7400, by TEM, 7402; NCI Carcinogenesis Studies (feed), no evidence: rat; NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen Record 534 of 1119 in RTECS (through 2003/06) AN: CI7650000 PN: L-Ascorbic-acid- SY: 3-Keto-L-gulofuranolactone-; 3-Oxo-L-gulofuranolactone-; 3-Oxo-L-gulofuranolactone- (enol form); Adenex-; Allercorb-; Antiscorbic-vitamin-; Antiscorbutic-vitamin-; Arco-cee-; Ascoltin-; Ascor-B.I.D.; Ascorbajen-; Ascorbate-; Ascorbic-acid-; Ascorbutina-; Ascorin-; Ascorteal-; Ascorvit-; C-Level-; C-Long-; C-Quin-; C-Span-; C-Vimin-; CE-VI-Sol-; Cantan-; Cantaxin-; Catavin-C-; Ce-Mi-Lin-; Cebicure-; Cebid-; Cebion-; Cebione-; Cecon-; Cee-caps-TD-; Cee-vite-; Cegiolan-; Ceglion-; Celaskon-; Celin-; Cemagyl-; Cemill-; Cenetone-; Cereon-; Cergona-; Cescorbat-; Cetamid-; Cetane-caps-TD-; Cetemican-; Cevalin-; Cevatine-; Cevex-; Cevi-bid-; Cevimin-; Cevital-; Cevitamic-acid-; Cevitamin-; Cevitan-; Cevitex-; Cewin-; Ciamin-; Cipca-; Citriscorb-; Colascor-; Concemin-; Davitamon-C-; Dora-C-500-; Duoscorb-; Hicee-; Hybrin-; IDO-C-; Kyselina-askorbova- (Czech); L(+)-Ascorbic acid; L-3-Ketothreohexuronic-acid-lactone-; L-Ascorbate-; L-Lyxoascorbic-acid-; L-Xyloascorbic-acid-; L-threo-Hex-2-enonic-acid,-gamma-lactone-; Laroscorbine-; Lemascorb-; Liqui-Cee-; NCI-C54808-; NSC-33832-; Planavit-C-; Proscorbin-; Redoxon-; Ribena-; Roscorbic-; Scorbacid-; Scorbu-C-; Secorbate-; Testascorbic-; Vicelat-; Vicomin-C-; Viforcit-; Viscorin-; Vitace-; Vitacee-; Vitacimin-; Vitacin-; Vitamin-C-; Vitamisin-; Vitascorbol-; Xitix-; ce-lent- RN: Current: 50-81-7 Previous: 14536-17-5; 30208-61-8; 50976-75-5; 56533-05-2; 57304-74-2; 57606-40-3; 89924-69-6; 129940-97-2 UD: 200305 MF: C6-H8-O6 MW: 176.14 WL: T5OV EHJ CQ DQ EYQ1Q CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: mmo-sat 500 ug/plate (+/-S9) Agricultural and Biological Chemistry. (Maruzen Co. Ltd., POB 5050, Tokyo International, Tokyo 100-31, Japan) V.25- 1961- v. 45, p. 327, 1981 (ABCHA6); dnd-bcs 2 mg/disc Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 175, 1981 (PMRSDJ); mmo-omi 1000 ppm (-S9) Proceedings of the Oklahoma Academy of Science. (Oklahoma Academy of Science, c/o Executive Secretary-Treasurer, Southwestern Oklahoma State Univ., Weatherford, OK 73096) V.1- 1910/1920- v. 34, p. 114, 1953 (POASAD); mmo-nsc 2 mmol/L (-S9) Mechanisms of Ageing and Development. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1972- v. 10, p. 249, 1979 (MAGDA3); dnr-smc 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 502, 1981 (PMRSDJ); mrc-smc 300 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 491, 1981 (PMRSDJ); sln-smc 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); spm-slw-par 25 ug Eiyo to Shokuryo. Food and Nutrition. (Tokyo, Japan) V.10-35, 1957-82. v. 34, p. 367, 1981 (EISOAU); dnd-hmn-fbr 200 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3783, 1982 (CNREA8); dnd-hmn-oth 200 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3783, 1982 (CNREA8); dni-hmn-hla 2500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 92, p. 427, 1982 (MUREAV); dni-hmn-oth 200 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3783, 1982 (CNREA8); oms-hmn-fbr 200 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3783, 1982 (CNREA8); oms-hmn-oth 200 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3783, 1982 (CNREA8); dni-hmn-oth 200 mg/L Oncology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.21- 1967- v. 35, p. 160, 1978 (ONCOBS); mnt-mus-ipr 4500 mg/kg/3D-C Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 21, p. 160, 1993 (EMMUEG); oms-mus-lvr 500 umol/L Journal of Nutritional Science and Vitaminology. (Business Center for Academic Soc. Japan, 2-4-16 Yayoi, Bunkyo-ku, Tokyo 113, Japan) V.19- 1973- v. 24, p. 263, 1978 (JNSVA5); cyt-mus-ipr 1600 mg/kg Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 9, p. 51, 1989 (TCMUD8); sce-mus-ipr 1600 mg/kg Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 9, p. 51, 1989 (TCMUD8); mnt-ham-ovr 400 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 26, p. 240, 1995 (EMMUEG); cyt-ham-ovr 300 mg/L Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 18, p. 497, 1980 (FCTXAV); sce-ham-ovr 500 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); dnd-mam-lym 500 umol/L Journal of Nutritional Science and Vitaminology. (Business Center for Academic Soc. Japan, 2-4-16 Yayoi, Bunkyo-ku, Tokyo 113, Japan) V.19- 1973- v. 24, p. 263, 1978 (JNSVA5) RE: T25 orl-rat TDLo: 2500 mg/kg (1-22D preg) American Journal of Anatomy. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1-192, 1901-91. v. 110, p. 29, 1962 (AJANA2); T35 ipr-mus TDLo: 6680 mg/kg (11D preg) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 64, p. 423, 1990 (ARTODN); T41-T46 ivn-mus TDLo: 800 mg/kg (8D preg) Toho Igakkai Zasshi. Journal of Medical Society of Toho University. (Toho Daigaku Igakkai, 21-16, Omori-nishi, 5-chome, Ota-ku, Tokyo 143, Japan) V.1- 1954- v. 8, p. 175, 1961 (TOIZAG); T83 orl-gpg TDLo: 19500 mg/kg (30-58D preg/10D post) Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 258, p. 401, 1975 (ANYAA9); T71-T75 orl-gpg TDLo: 5800 mg/kg (1-58D preg) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 57, p. 483, 1964 (BEXBAN); T81 orl-gpg TDLo: 2471 mg/kg (multigenerations) Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 258, p. 465, 1975 (ANYAA9) TE: V01-P61 orl-rat TDLo: 1802500 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-201194 (NTIS**) ORNG: 11900000000 ng/kg. [11900.000000 mg/kg] D17-F07-K12 AT: P22 ivn-man TDLo: 2300 mg/kg/2D Annals of Internal Medicine. (American College of Physicians, 4200 Pine St., Philadelphia, PA 19104) V.1- 1927- v. 82, p. 810, 1975 (AIMEAS); M03 ivn-wmn LDLo: 900 mg/kg Archives of Internal Medicine. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1908- v. 145, p. 950, 1985 (AIMDAP); D17-F07-K12 orl-rat LD50: 11900 mg/kg Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- v. 12, p. 131, 1976 (OYYAA2); T/E unlistd scu-rat LD50: >10 gm/kg Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- v. 12, p. 131, 1976 (OYYAA2); F05-F07 ivn-rat LD50: >4 gm/kg Oyo Yakuri. Pharmacometrics. (Oyo Yakuri Kenkyukai, CPO Box 180, Sendai 980-91, Japan) V.1- 1967- v. 12, p. 131, 1976 (OYYAA2); T/E unlistd orl-mus LD50: 3367 mg/kg National Cancer Institute Screening Program Data Summary, Developmental Therapeutics Program. (Bethesda, MD 20205) JAN1986 (NCISP*); T/E unlistd ipr-mus LD50: 643 mg/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 682, 1981 (PMRSDJ); T/E unlistd ivn-mus LD50: 518 mg/kg Research Progress in Organic-Biological and Medicinal Chemistry. (New York, NY) V.1-3, 1964-72. Discontinued. v. 2, p. 269, 1970 (RPOBAR); S01 skn-mus TDLo: 50 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 47, p. 84, 1984 (FATOAO) MD: P26-U01 orl-rat TDLo: 455 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-247, 1983 (NTPTR*); Z01 orl-mus TDLo: 546 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-247, 1983 (NTPTR*); N24-P30 orl-rat TDLo: 2500 mg/kg/10D-I Farmakologiya i Toksikologiya (Kiev). Pharmacology and Toxicology. (Kievskii Nauchno- Issledovatel'skii Institut Farmakologii i Toksikologii, Kiev, USSR) No.1- 1964- v. 159, p. 75, 1986 (FATOBP); Y55 skn-mus TDLo: 500 mg/kg/10D-I Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 47, p. 84, 1984 (FATOAO) ND: NOHS 1974: HZD M0462; NIS 24; TNF 5030; NOS 33; TNE 69440; NOES 1983: HZD M0462; NIS 41; TNF 7888; NOS 56; TNE 137698; TFE 84231 SL: EPA GENETOX PROGRAM 1988, Positive: In vitro SCE-human lymphocytes, In vitro SCE-human; EPA GENETOX PROGRAM 1988, Positive: In vitro SCE-nonhuman; EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse; EPA GENETOX PROGRAM 1988, Inconclusive: Mammalian micronucleus, Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), no evidence: mouse, rat Record 535 of 1119 in RTECS (through 2003/06) AN: CI9900000 PN: Asphalt- SY: Asphalt-fumes- (ACGIH); Asphalt,-petroleum-; Asphaltum-; Bitumen-; Bitumen-fumes-; Judean-pitch-; Mineral-pitch-; Petroleum-asphalt-; Petroleum-bitumen-; Petroleum-pitch-; Petroleum-roofing-tar-; Road-asphalt- RN: Current: 8052-42-4 UD: 200305 CC: Tumorigen (C); Mutagen (M) ME: dna-mus-skn 600 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 9, p. 1253, 1988 (CRNGDP) TE: V02-V16 ims-rat TDLo: 5400 mg/kg/24W-I Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 70, p. 372, 1960 (ARPAAQ); V01-J60-R60 skn-mus TDLo: 130 gm/kg/81W-I Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(4-6), p. 180, 1968 (HYSAAV); V02-V10 ims-mus TDLo: 12 gm/kg/12W-I Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 70, p. 372, 1960 (ARPAAQ); V03-J60-R60 skn-mus TD :69 gm/kg/43W-I Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(4-6), p. 180, 1968 (HYSAAV); V02-J60-R60 skn-mus TDLo: 905 gm/kg/2Y-I Industrial Medicine and Surgery. (Northbrook, IL) V.18-42, 1949-73. For publisher information, see IOHSA5. v. 34, p. 255, 1965 (IMSUAI) MD: D09-F15-U01 ihl-rat TCLo: 100 mg/m3/6H/14W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 135, p. S140, 2002 (TOLED5) TR: ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-TWA 0.5 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 35, p. 39, 1985 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 133, 1987 (IMSUDL) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 5 mg/m3 (fume) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 19, 1971 (DTLVS*); OEL-ARAB Republic of Egypt: TWA 5 mg/m3, JAN 1993; OEL-AUSTRALIA: TWA 5 mg/m3, JAN 1993; OEL-BELGIUM: TWA 5 mg/m3, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-NORWAY: TWA 5 mg/m3, JAN 1999; OEL-POLAND: TWA 5 mg/m3 (fume), STEL 15 mg/m3 (fume), JAN 1999; OEL-UNITED KINGDOM: LTEL 5 mg/m3, STEL 10 mg/m3, JAN 1993; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ASPHALT FUMES-air: CA CL 5 mg/m3/15M National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 90320; NIS 175; TNF 38326; NOS 111; TNE 573807; NOES 1983: HZD 90320; NIS 177; TNF 26349; NOS 109; TNE 471039; TFE 18959 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, selected, October 2000 Record 536 of 1119 in RTECS (through 2003/06) AN: CM3675000 PN: 2H-Azepin-2-one,-hexahydro- SY: 1,6-Hexolactam-; 1-Aza-2-cycloheptanone-; 2-Azacycloheptanone-; 2-Ketohexamethyleneimine-; 2-Ketohexamethylenimine-; 2-Oxohexamethyleneimine-; 2-Oxohexamethylenimine-; 2-Perhydroazepinone-; 2H-Azepin-7-one,-hexahydro-; 6-Aminocaproic-acid-lactam-; 6-Aminohexanoic-acid-cyclic-lactam-; 6-Caprolactam-; 6-Hexanelactam-; A1030-; Aminocaproic-lactam-; Caprolactam-; Caprolactam-monomer-; Caprolactam,-fume-; Caprolattame- (French); Capron-PK4-; Cyclohexanone-iso-oxime-; Epsylon-kaprolaktam- (Polish); Extrom-6N-; Hexahydro-2-azepinone-; Hexahydro-2H-azepin-2-one- (9CI); Hexamethylenimine,-2-oxo-; Hexanoic-acid,-6-amino-,-cyclic-lactam-; Hexanoic-acid,-6-amino-,-lactam-; Hexanolactam-; Hexanone-isoxime-; Hexanonisoxim- (German); Kapromine-; NCI-C50646-; Stilon-; e-Kaprolaktam- (Czech); epsilon-Caprolactam-; epsilon-Caprolactam- (ACGIH); omega-Caprolactam- RN: Current: 105-60-2 BRN: 106934 BHR: 5-21-06-00444 UD: 200302 MF: C6-H11-N-O MW: 113.18 WL: T7MVTJ CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MLD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,883,1986 (85JCAE); eye-rbt 20 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,883,1986 (85JCAE) ME: pic-esc 1950 ug/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 349, 1991 (MUREAV); slt-dmg-orl 5 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 313, 1985 (PMRSDJ); sln-dmg-orl 5 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 339, 1989 (MUREAV); mmo-smc 100 mg/L (+/-S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 271, 1985 (PMRSDJ); mrc-smc 400 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 271, 1985 (PMRSDJ); mnt-nml-mul 100 ppm Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 4, p. 17, 1989 (MUTAEX); dni-hmn-fbr 1 mmol/L Neoplasma. (Karger-Libri, P.O. Box, CH-4009 Basel, Switzerland) V.4- 1957- v. 33, p. 699, 1986 (NEOLA4); cyt-hmn-lym 270 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 457, 1985 (PMRSDJ); sln-hmn-lym 25 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 333, 1989 (MUREAV); dnd-rat-ipr 580 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 379, 1989 (MUREAV); bfa-rat-ovr 76 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 143, p. 263, 1985 (MUREAV); spm-rat-ihl 125 mg/m3/10W Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 19(10), p. 40, 1975 (GTPZAB); slt-mus-ipr 500 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 369, 1989 (MUREAV); mtr-mus-emb 2500 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 639, 1985 (PMRSDJ); dnd-mus-ipr 580 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 379, 1989 (MUREAV); mtr-ham-emb 100 mg/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 2, p. 103, 1988 (TIVIEQ); cyt-ham-lng 8 gm/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 427, 1985 (PMRSDJ); sce-ham-ovr 125 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 333, 1989 (MUREAV) RE: T25 orl-rat TDLo: 10 gm/kg (6-15D preg) JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 7, p. 317, 1987 (JJATDK); T81 orl-rat TDLo: 10 gm/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0537802 (NTIS**); T19-T25 orl-rat TDLo: 10 gm/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0557708 (NTIS**); T01 ihl-rat TCLo: 125 mg/m3/24H (76D male) Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 19(10), p. 40, 1975 (GTPZAB); T24-T35 ihl-rat TDLo: 473 mg/m3/4H (1-5D preg) Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 34(7), p. 25, 1969 (GISAAA); T24 ihl-rat TDLo: 139 mg/m3/4H (6-12D preg) Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 34(7), p. 25, 1969 (GISAAA); T14 ihl-rat TCLo: 473 mg/m3/4H (60D pre) Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 13(10), p. 22, 1969 (GTPZAB); T34 orl-rbt TDLo: 3450 mg/kg (6-28D preg) JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 7, p. 317, 1987 (JJATDK); T81 orl-rbt TDLo: 2500 mg/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0537802 (NTIS**) ORNG: 1210000000 ng/kg. [1210.000000 mg/kg] D18-F12-U28 SRNL: 1410000 nL/kg. [1.410000 mL/kg] T/E unlistd AT: J21 ihl-hmn TCLo: 100 ppm American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 34, p. 384, 1973 (AIHAAP); D18-F12-U28 orl-rat LD50: 1210 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-214, 1982 (NTPTR*); T/E unlistd ihl-rat LC50: 300 mg/m3/2H "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,32,1982 (85GMAT); T/E unlistd skn-rat LD50: >2 gm/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0557720 (NTIS**); F12-K01-U28 ipr-rat LDLo: 800 mg/kg British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 11, p. 1, 1954 (BJIMAG); F12-M10 unr-rat LD50: 580 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 55(10), p. 33, 1990 (GISAAA); F23-J22 orl-mus LD50: 930 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 10(10), p. 54, 1966 (GTPZAB); F23 ihl-mus LC50: 450 mg/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 10(10), p. 54, 1966 (GTPZAB); F12-F25-F29 ipr-mus LD50: 650 mg/kg Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 60, p. 1058, 1971 (JPMSAE); T/E unlistd scu-mus LD50: 750 mg/kg IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 247, 1986 (IMEMDT); T/E unlistd ivn-mus LD50: 480 mg/kg IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 247, 1986 (IMEMDT); F12-M10 unr-mus LD50: 930 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 55(10), p. 33, 1990 (GISAAA); T/E unlistd skn-rbt LD50: 1410 uL/kg American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 30, p. 470, 1969 (AIHAAP); F12-K01-U28 ivn-rbt LD :>300 mg/kg British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 11, p. 1, 1954 (BJIMAG); F12-M10 unr-rbt LD50: 1 gm/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 55(10), p. 33, 1990 (GISAAA); T/E unlistd scu-gpg LDLo: 950 mg/kg Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 43, p. 124, 1952 (MELAAD); E08-F07-F12 scu-frg LDLo: 2800 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 50, p. 199, 1903 (AEXPBL) MD: U01 orl-rat TDLo: 42 gm/kg/8W-C Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 9, p. 9, 1959 (ARZNAD); D07-J22-J30 ihl-rat TCLo: 243 mg/m3/6H/13W-I Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 44, p. 197, 1998 (TOSCF2); M16-Y01 ihl-rat TCLo: 5960 mg/kg/82D-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 33(1), p. 22, 1968 (GISAAA); U01 orl-rat TDLo: 6750 mg/kg/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555505 (NTIS**); P28-P70-Z01 ipr-rat TDLo: 9100 mg/kg/26W-I Medycyna Pracy. Industrial Medicine. (Ars-Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1950- v. 18, p. 357, 1967 (MEPAAX) TR: ACGIH TLV-TWA 1 mg/m3 (particulate) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 5 ppm (vapor) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 5 ppm (vapor) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-STEL 3 mg/m3 (particulate) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 10 ppm (vapor) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal NO EVIDENCE IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 247, 1986 (IMEMDT); IARC Cancer Review: Animal No Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 383, 1999 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 247, 1986 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 383, 1999 (IMEMDT); IARC Cancer Review: Group 4 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 383, 1999 (IMEMDT) SR: OEL-AUSTRALIA: TWA 1 mg/m3, STEL 3 mg/m3 (dust), JAN 1993; OEL-AUSTRALIA: TWA 5 ppm (20 mg/m3), STEL 10 ppm (vapor), JAN 1993; OEL-AUSTRIA: MAK 5 mg/m3 (dust), JAN 1999; OEL-BELGIUM: TWA 1 mg/m3, STEL 3 mg/m3 (dust), JAN 1993; OEL-BELGIUM: TWA 4.3 ppm (20 mg/m3), STEL 8.6 ppm (40 mg/m3), JAN 1993; OEL-DENMARK: TWA 5 ppm (25 mg/m3), JAN 1999; OEL-DENMARK: TWA 1 mg/m3 (dudt), JAN 1999; OEL-FINLAND: TWA 1 mg/m3, STEL 3 mg/m3 (dust), JAN 1999; OEL-FINLAND: TWA 5 ppm (20 mg/m3), STEL 10 ppm (46 mg/m3) (vapor), JAN 1999; OEL-FRANCE: VME 1 mg/m3 (dust), JAN 1999; OEL-FRANCE: VME 5 ppm (20 mg/m3) (vapor), JAN 1993; OEL-GERMANY: MAK 25 mg/m3 (dust and vapor), JAN 1999; OEL-HUNGARY: TWA 1 mg/m3, STEL 2 mg/m3 (dust), JAN 1993; OEL-THE NETHERLANDS: MAC-TGG 1 mg/m3 (vapor), JAN 1993; OEL-THE NETHERLANDS: MAC-TGG 5 ppm (20 mg/m3) (dust), JAN 1999; OEL-NORWAY: TWA 5 ppm (25 mg/m3), moist, JAN 1999; OEL-POLAND: MAC(TWA) 10 mg/m3 (dust), JAN 1999; OEL-RUSSIA: STEL 10 mg/m3 (dust), JAN 1993; OEL-SWEDEN: TWA 5 mg/m3, STEL 10 mg/m3, JAN 1999; OEL-SWITZERLAND: MAK-W 5 mg/m3 (dust), JAN 1999; OEL-UNITED KINGDOM: TWA 1 mg/m3, STEL 3 mg/m3, dust, SEP 2000; OEL-UNITED KINGDOM: TWA 5 ppm (23 mg/m3), STEL 10 ppm, vapor, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO CAPROLACTAM, dust-air: 10H TWA 1 mg/m3, STEL 3 mg/m3 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #95-121, 1995 (NIOSH*); NIOSH REL TO CAPROLACTAM, vapor-air: 10H TWA 0.22 ppm, STEL 0.66 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #95-121, 1995 (NIOSH*); NOHS 1974: HZD 83732; NIS 14; TNF 955; NOS 14; TNE 6208; NOES 1983: HZD 83732; NIS 12; TNF 812; NOS 19; TNE 25091; TFE 8291 SL: EPA GENETOX PROGRAM 1988, Negative: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: CHO gene mutation; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), no evidence: mouse, rat Record 537 of 1119 in RTECS (through 2003/06) AN: CM8050000 PN: Aziridine,-2-methyl- SY: 2-Methylazacyclopropane-; 2-Methylaziridine-; Methylethylenimine-; 2-Methylethylenimine-; Propylene-imine-; 1,2-Propyleneimine-; Propylene-imine- (ACGIH:OSHA); Propylenimine-; 1,2-Propylenimine-; RCRA-waste-number-P067- RN: Current: 75-55-8 BRN: 102386 BHR: 5-20-01-00150 UD: 200210 MF: C3-H7-N MW: 57.11 WL: T3MTJ B1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 3300 ng/plate (+/-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6(Suppl 2), p. 1, 1984 (ENMUDM); mmo-esc 10 ug/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6(Suppl 2), p. 1, 1984 (ENMUDM); oms-esc 80 nmol/tube Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 147, p. 79, 1985 (MUREAV); dnr-esc 2 ug/plate JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 873, 1979 (JJIND8); slt-dmg-orl 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 252, p. 305, 1991 (MUREAV); mrc-smc 100 ppm JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 901, 1979 (JJIND8); mmo-ssp 5470 umol/L (-S9) Abhandlungen der Deutschen Akademie der Wissenschaften zu Berlin, Klasse fuer Medizin. (Berlin, Ger. Dem. Rep.) 1950-68. Discontinued. v. -, p. 193, 1962 (ADWMAX); mtr-rat-emb 15 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dns-rat-lvr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 97, p. 359, 1982 (MUREAV); mnt-mus-ipr 10 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 389, p. 3, 1997 (MUREAV); mtr-mus-fbr 80 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dnd-mus-ipr 40 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 467, p. 83, 2000 (MUREAV); hma-mus-sat 355 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 911, 1979 (JJIND8); mtr-ham-emb 1 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dnd-ham-lng 300 umol/L/1H Biochemical and Biophysical Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 72, p. 732, 1976 (BBRCA9) TE: V01-A60-R60 orl-rat TDLo: 1120 mg/kg/28W-I Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 230, p. 460, 1971 (NATUAS); V01-P61-R60 orl-rat TD :3920 mg/kg/27W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 75, 1981 (JJIND8); V01-R60 orl-rat TD :4129 mg/kg/58W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 75, 1981 (JJIND8) ORNG: 19000000 ng/kg. [19.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 19 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 63, 1948 (JIHTAB); T/E unlistd ihl-rat LCLo: 500 ppm/4H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 31, p. 343, 1949 (JIHTAB); T/E unlistd ihl-mus LC :>2 gm/m3/10M National Defense Research Committee, Office of Scientific Research and Development, Progress Report. v. NDCrc-132, p. Feb, 1942 (NDRC**); T/E unlistd ipr-mus LD50: 355 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 911, 1979 (JJIND8); J16-J22-M03 ihl-gpg LCLo: 500 ppm/1H Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 2, 1948 (JIHTAB); T/E unlistd skn-gpg LD50: 43 mL/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 30, p. 63, 1948 (JIHTAB) TR: ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 2 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 9, p. 61, 1975 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1497, 1999 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 9, p. 61, 1975 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1497, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 1497, 1999 (IMEMDT) SR: MSHA STANDARD-air: TWA 2 ppm (5 mg/m3) (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 218, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 2 ppm (5 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 2 ppm (5 mg/m3), Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Skin, Carcinogen, JAN 1999; OEL-DENMARK: TWA 2 ppm (5 mg/m3), Skin, JAN 1999; OEL-FINLAND: STEL 2 ppm (5 mg/m3), Skin, Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-JAPAN: OEL 2 ppm (4.7 mg/m3), Skin, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 2 ppm (5 mg/m3), Skin, JAN 1999; OEL-NORWAY: TWA 2 ppm (5 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 2 ppm (5 mg/m3), Skin, JAN 1993; OEL-RUSSIA: TWA 2 ppm, JAN 1993; OEL-SWITZERLAND: MAK-W 2 ppm (5 mg/m3), Skin, Carcinogen, JAN 1999; OEL-TURKEY: TWA 2 ppm (5 mg/m3), Skin, JAN 1993; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO PROPYLENE IMINE-air: 10H CA TWA 2 ppm (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 08390; NIS 1; TNF 5; NOS 2; TNE 20 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo, Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive: E coli polA without S9, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: In vitro UDS-human fibroblast, S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Positive: S pombe-reversion; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-BALB/c-3T3; EPA TSCA Section 8(b) CHEMICAL INVENTORY; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 538 of 1119 in RTECS (through 2003/06) AN: CN2980000 PN: Azobenzene,-3,3',4,4'-tetrachloro- SY: Bis(3,4-dichlorophenyl)diazene; Diazene, bis(3,4-dichlorophenyl)- (9CI); TCAB-; 3,3',4,4'-Tetrachloroazobenzene-; 3,4,3',4'-Tetrachloroazobenzene- RN: Current: 14047-09-7 BRN: 4871675 UD: 200204 MF: C12-H6-Cl4-N2 MW: 320.00 WL: GR BG DNUNR CG DG CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 ug/plate (-S9) Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 17, p. 225, 1977 (RCOCB8); mmo-asn 5 mg/L (-S9) Canadian Journal of Microbiology. (National Research Council of Canada, Publication Sales and Distribution, Ottawa ON K1A OR6, Canada) V.1- 1954- v. 16, p. 369, 1970 (CJMIAZ); dns-rat-lvr 1 umol/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 6, p. 207, 1979 (CALEDQ); mtr-mus-fbr 1 mg/L Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 17, p. 225, 1977 (RCOCB8); dns-ham-ovr 6400 ug/L Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 11, p. 429, 1988 (FAATDF); mnt-mus-orl 650 mg/kg/13W Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 472, p. 147, 2000 (MUREAV) ORNG: 5000000000 ng/kg. [5000.000000 mg/kg] L30 AT: L30 orl-rat LD50: 5 gm/kg United States Environmental Protection Agency, Office of Pesticides and Toxic Substances. (U.S. Environmental Protection Agency, 401 M St., SW, Washington, DC 20460) History unknown. 8EHQ-0981-0409 (EPASR*); L30 ihl-rat LCLo: 920 mg/m3/4H United States Environmental Protection Agency, Office of Pesticides and Toxic Substances. (U.S. Environmental Protection Agency, 401 M St., SW, Washington, DC 20460) History unknown. 8EHQ-0981-0409 (EPASR*) MD: L70-P28-Y07 orl-rat TDLo: 84 mg/kg/17W-C Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 3, p. 47, 1980 (DCTODJ); F15-U01-Z01 ipr-rat TDLo: 650 mg/kg/13W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 25, p. 247, 1985 (TOLED5) SL: EPA GENETOX PROGRAM 1988, Positive: Aspergillus-forward mutation; EPA GENETOX PROGRAM 1988, Positive/dose response: In vitro UDS in rat liver; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Toxicity studies, RPT# TOX-43, October 2000; NTP Carcinogenesis studies, laboratory assigned, October 2000 Record 539 of 1119 in RTECS (through 2003/06) AN: CO4150000 PN: Azoxybenzene,-3,3',4,4'-tetrachloro- SY: Bis(3,4-dichlorophenyl)diazene 1-oxide; Diazene, bis(3,4-dichlorophenyl)-, 1-oxide (9CI); TCAOB-; 3,3',4,4'-Tetrachloroazoxybenzene-; 3,4,3',4'-Tetrachloroazoxybenzene- RN: Current: 21232-47-3 UD: 200204 MF: C12-H6-Cl4-N2-O MW: 336.00 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: cyt-mus-orl 134 mg/kg/4W-C Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 14, p. 677, 1985 (AECTCV); mnt-mus-orl 65 mg/kg/13W Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 472, p. 147, 2000 (MUREAV) RE: T48-T72 orl-mus TDLo: 75600 ug/kg (14D pre-28D post) Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 14, p. 677, 1985 (AECTCV); T81 orl-mus TDLo: 7560 ug/kg (14D pre-28D post) Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 14, p. 677, 1985 (AECTCV); T25-T35 ipr-mus TDLo: 16 mg/kg (12D preg) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 55, p. 20, 1984 (ARTODN); T43-T53 ipr-mus TDLo: 6 mg/kg (11D preg) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 55, p. 20, 1984 (ARTODN) MD: L70-P71-Z73 orl-rat TDLo: 80 mg/kg/17W-C Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 3, p. 47, 1980 (DCTODJ); J70-L70-N74 orl-rat TDLo: 150 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-99-3946 (NTPTR*); L70-P28-Y03 orl-rat TDLo: 65 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-99-3946 (NTPTR*); F15-U01-Z01 ipr-rat TDLo: 650 mg/kg/13W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 25, p. 247, 1985 (TOLED5); L30-N74-Z73 ipr-rat TDLo: 350 mg/kg/48D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 25, p. 247, 1985 (TOLED5); L30-Y03-Y15 ipr-rat TDLo: 200 mg/kg/28D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 25, p. 247, 1985 (TOLED5); L70-N74 orl-mus TDLo: 38400 ug/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-99-3946 (NTPTR*); L70-N74 orl-mus TDLo: 195 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-99-3946 (NTPTR*) SL: EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Toxicity studies, RPT# TOX-43, October 2000 Record 540 of 1119 in RTECS (through 2003/06) AN: CQ8751000 PN: Barium-chloride,-dihydrate- SY: Barium-chloride-dihydrate-; Barium-dichloride-dihydrate-; NCI-C61074- RN: Current: 10326-27-9 UD: 200207 MF: Ba-Cl2.2 H2-O MW: 244.28 CC: Tumorigen (C) AT: T/E unlistd ipr-mus LD50: 51 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 63, p. 461, 1982 (TXAPA9) MD: M70-U01-U08 orl-rat TDLo: 16 gm/kg/13W-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 19, p. 527, 1992 (FAATDF); L70-M30-U01 orl-mus TDLo: 47 gm/kg/13W-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 19, p. 527, 1992 (FAATDF); L70 orl-mus TDLo: 1868 mg/kg/15D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-432, 1994 (NTPTR*) TR: ACGIH TLV-TWA 0.5 mg(Ba)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: MSHA STANDARD-air: TWA 0.5 mg(Ba)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 21, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 0.5 mg(Ba)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.5 mg(Ba)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.5 mg(Ba)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.5 mg(Ba)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 0.5 mg(Ba)/m3, JAN 1993; OEL-AUSTRIA: MAK 0.5 mg(Ba)/m3, JAN 1999; OEL-BELGIUM: TWA 0.5 mg(Ba)/m3, JAN 1993; OEL-DENMARK: TWA 0.5 mg(Ba)/m3, JAN 1999; OEL-FINLAND: TWA 0.5 mg(Ba)/m3, JAN 1999; OEL-FRANCE: VME 0.5 mg(Ba)/m3, JAN 1999; OEL-GERMANY: MAK 0.5 mg(Ba)/m3, JAN 1999; OEL-HUNGARY: STEL 0.5 mg(Ba)/m3, JAN 1993; OEL-THE NETHERLANDS: MAC-TGG 0.5 mg(Ba)/m3, JAN 1999; OEL-NORWAY: TWA 0.5 mg(Ba)/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 0.5 mg(Ba)/m3, JAN 1993; OEL-POLAND: MAC(TWA) 0.5 mg(Ba)/m3, MAC(STEL) 1.5 mg(Ba)/m3, JAN 1999; OEL-SWEDEN: TWA 0.5 mg(Ba)/m3, JAN 1999; OEL-SWITZERLAND: MAK-W 0.5 mg(Ba)/m3, JAN 1999; OEL-TURKEY: TWA 0.5 mg(Ba)/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 0.4 mg(Ba)/m3, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NOES 1983: HZD X7401; NIS 3; TNF 42; NOS 3; TNE 320 SL: EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (water), no evidence: mouse, rat Record 541 of 1119 in RTECS (through 2003/06) AN: CT9450000 PN: Bentonite- SY: Albagel-Premium-USP-4444-; Bentonite-2073-; HI-Jel-; Imvite I.G.B.A; Magbond-; Montmorillonite-; Panther-creek-bentonite-; Southern-bentonite-; Tixoton-; Volcaly-bentonite-BC-; Volclay-; Wilkinite-; Bentonite-magma- RN: Current: 1302-78-9 Previous: 11004-12-9 UD: 200302 WL: .AL2.SI4.C10.Q2.QH# CC: Tumorigen (C) TE: V03-L60 orl-mus TDLo: 12000 gm/kg/28W-C Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 57, p. 678, 1954 (ANYAA9) AT: J15 ivn-rat LD50: 35 mg/kg Bolletino della Societe Italiana di Biologia Sperimentale. (Casa Editrice Idelson, Via A. de Gasperi, 55, 80133 Naples, Italy) V.2- 1927- v. 44, p. 1685, 1968 (BSIBAC); H17 ivn-dog LDLo: 10 mg/kg Journal of Clinical Investigation. (Rockefeller Univ. Press, 1230 York Ave., New York, NY 10021) V.1- 1924- v. 42, p. 860, 1963 (JCINAO); J30-J70-Y03 itr-rat TDLo: 240 mg/kg/1H In Vitro Effects of Mineral Dusts (Third International Workshop, E. G. Beck, J. Bignon, Editors: Berlin, Springer-Verlag) 1985. v. -, p. 453, 1985 (IVIEM*) ND: NOHS 1974: HZD 90340; NIS 169; TNF 22741; NOS 130; TNE 286502; NOES 1983: HZD X1608; NIS 3; TNF 70; NOS 3; TNE 1732; NOES 1983: HZD X9436; NIS 2; TNF 171; NOS 4; TNE 6525; NOES 1983: HZD X9494; NIS 4; TNF 115; NOS 3; TNE 11850; TFE 11045; NOES 1983: HZD 90340; NIS 212; TNF 31430; NOS 147; TNE 545795; TFE 36750 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, selected, October 2000 Record 542 of 1119 in RTECS (through 2003/06) AN: CU1400000 PN: Benz(e)acephenanthrylene SY: 3,4-Benz(e)acephenanthrylene; 2,3-Benzfluoranthene-; 3,4-Benzfluoranthene-; Benzo(b)fluoranthene; Benzo(b)fluoranthene (ACGIH); Benzo(e)fluoranthene; 2,3-Benzofluoranthene-; 3,4-Benzofluoranthene-; 2,3-Benzofluoranthrene-; B(b)F RN: Current: 205-99-2 BRN: 1872553 BHR: 4-05-00-02686 UD: 200305 MF: C20-H12 MW: 252.32 WL: L C65 K666 1A TJ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 31 nmol/plate (-S9) Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 1023, 1985 (CRNGDP); dna-ham-lng 3 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 419, p. 91, 1998 (MUREAV); msc-hmn-lym 55 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 123, 1996 (MUREAV); mnt-rat-ipr 100 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17(Suppl 19), p. 13, 1991 (EMMUEG); dna-rat-ipr 100 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 13, p. 1731, 1992 (CRNGDP); dna-rat-lvr 3 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 419, p. 91, 1998 (MUREAV); sce-rat-ipr 100 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17(Suppl 19), p. 13, 1991 (EMMUEG); mtr-ham-lng 100 ug/L Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 17, p. 149, 1980 (TXCYAC); sce-ham-ipr 900 mg/kg/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 66, p. 65, 1979 (MUREAV); dnd-esc 414.5 ug/L/3H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 515, p. 85, 2002 (MUREAV); dna-mus-orl 6.3 mg/kg/9W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 15, p. 59, 1995 (JJATDK); mnt-mus-orl 6.3 mg/kg/9W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 15, p. 59, 1995 (JJATDK); dns-mus-orl 6.3 mg/kg/9W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 15, p. 59, 1995 (JJATDK) TE: V03-J60-V10 imp-rat TDLo: 5 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 71, p. 539, 1983 (JJIND8); V01-R60-V10 skn-mus TDLo: 88 ng/kg/120W-I Archiv fuer Geschwulstforschung. (VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 50, p. 266, 1980 (ARGEAR); V02-M61 ipr-mus TDLo: 5046 ug/kg/15D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 34, p. 15, 1987 (CALEDQ); V03-V10 scu-mus TDLo: 72 mg/kg/9W-I Acta Unio Internationalis Contra Cancrum. (Louvain, Belgium) V.1-20, 1936-64. For publisher information, see IJCNAW. v. 19, p. 490, 1963 (AICCA6); V03-R60-V10 skn-mus TD :72 mg/kg/60W-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 12, p. 1194, 1959 (CANCAR); V03-J60-V10 imp-rat TD :5 mg/kg "Polynuclear Aromatic Hydrocarbons, International Symposium, 7th, 1982," Cooke, M., and A.J. Dennis, eds., Columbus, OH, Battelle Press, 1983 7,571,1983 (50NNAZ); V03-R60 skn-mus TD :4037 ug/kg/20D-I Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 1023, 1985 (CRNGDP) TR: ACGIH TLV-Suspected Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 3, p. 69, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 147, 1983 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 147, 1983 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW Advances in Cancer Research. (Academic Press, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1953- v. 7, p. 475, 1963 (ACRSAJ); TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 Pc,4,1972 (85DHAX) SR: OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-THE NETHERLANDS: Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.04 mg/m3, JAN 1999 ND: NOES 1983: HZD E0466; NIS 3; TNF 142; NOS 3; TNE 2283 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/95/264370); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Inconclusive: In vivo SCE-nonhuman; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Polynuclear aromatic hydrocarbons by HPLC, 5506, by GC, 5515; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 543 of 1119 in RTECS (through 2003/06) AN: CU4375000 PN: Benzaldehyde- SY: Almond-artificial-essential-oil-; Artificial-almond-oil-; Artificial-essential-oil-of-almond-; Benzene-carbaldehyde-; Benzenecarbonal-; NCI-C56133-; Benzaldehyde-FFC-; Benzoic-aldehyde-; Phenylmethanal- RN: Current: 100-52-7 UD: 200302 MF: C7-H6-O MW: 106.13 WL: VHR CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MOD Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 693, 1976 (FCTXAV) ME: sce-hmn-lym 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 206, p. 17, 1988 (MUREAV); slt-mus-lym 400 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 196, 1991 (EMMUEG); msc-mus-lym 400 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); cyt-ham-lng 1 gm/L Eisei Shikenjo Hokoku. Bulletin of the Institute of Hygienic Sciences. (Kokuritsu Eisei Shikenjo Kagaku, 18-1 Bushitsu Johobu, Setagaya-ku, Tokyo 158, Japan) V.1- 1886- v. (103), p. 64, 1985 (ESKHA5); sce-ham-ovr 50 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) TE: V02-K60 orl-mus TDLo: 154 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); V02-K60 orl-mus TDLo: 206000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-253782/AS (NTIS**); V02-K60 orl-mus TDLo: 154500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-253782/AS (NTIS**) ORNG: 1300000000 ng/kg. [1300.000000 mg/kg] F07-F24 AT: F07-F24 orl-rat LD50: 1300 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); D25-F07-J30 ihl-rat LC :>500 mg/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(11), p. 40, 1974 (GTPZAB); J25-J30 scu-rat LDLo: 5 gm/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 27, p. 163, 1922 (AIPTAK); F07-F11-J30 orl-mus LD50: 28 mg/kg European Journal of Toxicology and Environmental Hygiene. (Paris, France) V.7-9, 1974-76. For publisher information, see TOERD9. v. 9, p. 99, 1976 (EJTXAZ); D25-F07-J30 ihl-mus LC :>500 mg/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(11), p. 40, 1974 (GTPZAB); F07-F11-J30 ipr-mus LD50: 9 mg/kg European Journal of Toxicology and Environmental Hygiene. (Paris, France) V.7-9, 1974-76. For publisher information, see TOERD9. v. 9, p. 99, 1976 (EJTXAZ); T/E unlistd scu-rbt LD50: 5 gm/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 14, p. 693, 1976 (FCTXAV); F11-K08-M10 orl-gpg LD50: 1 gm/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); T/E unlistd orl-mam LD50: 2020 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 39(4), p. 86, 1974 (GISAAA); T/E unlistd orl-mus LD50: 2020 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 396, 1984 (VCVGK*); T/E unlistd orl-rat LD50: 2400 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 396, 1984 (VCVGK*); D25-J21 ihl-hmn TCLo: 0.15 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 396, 1984 (VCVGK*); T/E unlistd orl-hmn LDLo: 714.3 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 396, 1984 (VCVGK*) MD: Z01 orl-rat TDLo: 9600 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); A30-L03-M03 orl-rat TDLo: 52 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); L70-P70-U01 ihl-rat TCLo: 500 ppm/6H/14D-C American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 52, p. 503, 1991 (AIHAAP); P71-P72-U01 ihl-rat TCLo: 26 mg/m3/5H/17W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 18(11), p. 40, 1974 (GTPZAB); Z01 orl-mus TDLo: 9600 mg/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); M03-Z01 orl-rat TDLo: 78 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); J30-L50 orl-rat TDLo: 600 mg/kg/5W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 396, 1994 (VCVGK*) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); OEL-HUNGARY: TWA 5 mg/m3, STEL 10 mg/m3, JAN 1993; OEL-POLAND: TWA 10 mg/m3, STEL 40 mg/m3, JAN 1999; OEL-RUSSIA: STEL 5 mg/m3, JAN 1993; OEL-UNITED KINGDOM: Carcinogen, SEP 2000 ND: NOHS 1974: HZD 84494; NIS 18; TNF 1409; NOS 43; TNE 15976; NOES 1983: HZD 84494; NIS 31; TNF 3776; NOS 58; TNE 67721; TFE 27021 SL: EPA GENETOX PROGRAM 1988, Positive: N crassa-reversion; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1996: Volatile organic compound, 2549; NTP Carcinogenesis Studies (gavage), some evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-378, 1990 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse; NCI Carcinogenesis Studies (gavage), no evidence: rat Record 544 of 1119 in RTECS (through 2003/06) AN: CV9275000 PN: Benz(a)anthracene SY: Benzanthracene-; 1,2-Benz(a)anthracene; 1,2-Benzanthrazen- (German); Benzanthrene-; Naphthanthracene-; RCRA-waste-number-U018-; 1,2-Benzanthracene-; 1,2-Benzanthrene-; Benzo(a)anthracene; 1,2-Benzoanthracene-; Benzo(b)phenanthrene; 2,3-Benzophenanthrene-; 2,3-Benzphenanthrene-; Tetraphene- RN: Current: 56-55-3 UD: 200210 MF: C18-H12 MW: 228.30 WL: L D6 B666J CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 4 ug/plate (-S9) Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 747, 1984 (CRNGDP); oms-sat 2400 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 192, p. 239, 1987 (MUREAV); dna-esc 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); pic-esc 50 mg/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 41, p. 532, 1981 (CNREA8); dni-omi 200 ug/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 74, p. 1378, 1977 (PNASA6); slt-dmg-par 5 mmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 2354, 1973 (CNREA8); slt-dmg-orl 5 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 234, p. 71, 1990 (MUREAV); dnr-dmg-orl 36 gm/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 290, p. 175, 1993 (MUREAV); sln-dmg-par 5 mmol/L Egyptian Journal of Genetics and Cytology. (Egyptian Soc. of Genetics, c/o Alexandria Univ., Faculty of Agriculture, Dept. of Genetics, Alexandria, Egypt) V.1- 1972- v. 4, p. 400, 1975 (EJGCA9); mnt-nml-mul 188 ppb Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 292, p. 83, 1993 (MUREAV); dna-sal-tes 5 ug/1H-C Biochemical Journal. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1906- v. 110, p. 159, 1968 (BIJOAK); dns-ofs-lvr 200 nmol/L Huanjing Kexue Xuebao. Environmental Sciences Journal. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) V.1- 1981- v. 4, p. 368, 1984 (HKXUDL); dns-ofs-oth 100 umol/L Comparative Biochemistry and Physiology, C: Pharmacology, Toxicology and Endocrinology. (Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.74- 1983- v. 86, p. 399, 1987 (CBPCEE); dna-hmn-lym 30 umol/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 85, p. 3513, 1988 (PNASA6); dna-ham-lng 3 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 419, p. 91, 1998 (MUREAV); dns-hmn-fbr 100 umol/L Comparative Biochemistry and Physiology, C: Pharmacology, Toxicology and Endocrinology. (Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.74- 1983- v. 86, p. 399, 1987 (CBPCEE); dns-hmn-hla 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); dni-hmn-oth 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3676, 1982 (CNREA8); msc-hmn-lym 9 umol/L Developments in Toxicology and Environtal Science. (Elsevier Science, New York, NY) V.1-15, 1977-87. Discontinued v. 10, p. 277, 1982 (DTESD7); mnt-rat-itr 75 mg/kg/16H-I Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 326, p. 147, 1995 (MUREAV); mtr-rat-orl 180 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 1157, 1980 (CNREA8); mtr-rat-emb 3 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dna-rat-itr 75 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 312, p. 165, 1994 (MUREAV); dna-rat-lvr 3 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 419, p. 91, 1998 (MUREAV); dns-rat-lvr 100 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 3, p. 11, 1981 (ENMUDM); sce-rat-itr 150 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 312, p. 165, 1994 (MUREAV); sce-rat-lvr 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 91, p. 467, 1981 (MUREAV); mnt-mus-ipr 500 mg/kg Tokyo Jikeikai Ika Daigaku Zasshi. Tokyo Jikeikai Medical Journal. (3-25-8, Nishi Shinbashi, Minato-ku, Tokyo 105, Japan) V.66- 1951- v. 101, p. 259, 1986 (TJIDAH); mmo-mus-lym 2 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); mtr-mus-fbr 4 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); mtr-mus-emb 12500 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 105, 1982 (ENMUDM); dna-mus-lvr 60 umol/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 947, 1979 (JJIND8); dna-mus-oth 1 mg/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 4, p. 389, 1971/1972 (CBINA8); dna-mus-skn 192 umol/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 231, 1984 (CRNGDP); dni-mus-oth 10 umol/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 65, p. 1321, 1980 (JJIND8); hma-mus-sat 1600 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 911, 1979 (JJIND8); mnt-ham-ipr 1800 mg/kg/24H Acta Morphologica Academiae Scientiarum Hungaricae. (Budapest, Hungary) V.1-30, 1951-82. v. 27, p. 199, 1979 (AMSHAR); mmo-ham-lng 109 umol/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 27, 1977 (MUREAV); mtr-ham-emb 6 mg/L/7D-C International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 9, p. 435, 1972 (IJCNAW); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); mtr-ham-lng 100 ug/L Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 17, p. 149, 1980 (TXCYAC); dnd-ham-fbr 5 mg/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 20, p. 1297, 1971 (BCPCA6); dnd-ham-kdy 5 mg/L Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 20, p. 1297, 1971 (BCPCA6); dna-ham-lng 1 mg/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 4, p. 389, 1971/1972 (CBINA8); oms-ham-lng 1 mg/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 4, p. 389, 1971/1972 (CBINA8); dni-ham-oth 450 umol/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 53, p. 163, 1990 (CALEDQ); cyt-ham-ipr 1800 mg/kg/24H Acta Morphologica Academiae Scientiarum Hungaricae. (Budapest, Hungary) V.1-30, 1951-82. v. 27, p. 199, 1979 (AMSHAR); sce-ham-ipr 900 mg/Kg/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 66, p. 65, 1979 (MUREAV); sce-ham-ovr 100 umol/L Chemical Mutagens. Principles and Methods for Their Detection. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.1- 1971- v. 6, p. 1, 1980 (CMMUAO); sce-ham-lng 5 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 137, 1985 (ENMUDM); msc-ham-lng 1 mg/L/3H British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 39, p. 540, 1979 (BJCAAI); spm-ham-orl 900 mg/kg/24H Acta Morphologica Academiae Scientiarum Hungaricae. (Budapest, Hungary) V.1-30, 1951-82. v. 27, p. 199, 1979 (AMSHAR); dnd-esc 78.6 ug/L/3H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 515, p. 85, 2002 (MUREAV) TE: V02-R60 skn-mus TDLo: 18 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 1699, 1978 (CNREA8); V03-V10 scu-mus TDLo: 2 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 15, p. 632, 1955 (CNREA8); V01-M60 imp-mus TDLo: 80 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 22, p. 825, 1968 (BJCAAI); V03-R60 skn-mus TD :18 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 1705, 1978 (CNREA8); V03-R60 skn-mus TD :360 mg/kg/56W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 11, p. 892, 1951 (CNREA8); V02-R60 skn-mus TD :240 mg/kg/1W-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 9, p. 177, 1955 (BJCAAI) AT: T/E unlistd ivn-rat LD50: >200 mg/kg Molecular Pharmacology. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1965- v. 4, p. 427, 1968 (MOPMA3); T/E unlistd ivn-mus LDLo: 10 mg/kg Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 1, p. 225, 1940 (JNCIAM) TR: ACGIH TLV-Suspected Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 3, p. 45, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 135, 1983 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 135, 1983 (IMEMDT); IARC Cancer Review: Group 2A IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 23, p. 6, 1971 (AEHLAU); TOXICOLOGY REVIEW Advances in Cancer Research. (Academic Press, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1953- v. 7, p. 475, 1963 (ACRSAJ); TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 Pc,4,1972 (85DHAX) SR: OEL-FRANCE: Carcinogen, JAN 1993; OEL-NORWAY: TWA 0.04 mg/m3, JAN 1999 ND: NOES 1983: HZD B0045; NIS 4; TNF 149; NOS 4; TNE 2311 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/95/264370); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-mouse prostate; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo, Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: V79 cell culture-gene mutation; EPA GENETOX PROGRAM 1988, Negative: Cell transform.-BALB/c-3T3, In vitro UDS in rat liver; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9, In vivo SCE-nonhuman; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Inconclusive: In vitro UDS-human fibroblast; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Polynuclear aromatic hydrocarbons by HPLC, 5506, by GC, 5515; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 545 of 1119 in RTECS (through 2003/06) AN: CX9850100 PN: Benzenamine, 4-((4-aminophenyl)(4-imino-2,5-cyclohexadien-1-ylidene)methyl),monohydrochloride SY: 4,4'-((4-Imino-2,5-cyclohexadien-1-ylidene)methylene)dianiline monohydrochloride; 4,4'4''-Triaminotriphenylmethan-hydrochlorid- (German); Basic-Red-9-; Basic-Rubine-; Basic-parafuchsine-; C.I. 42500; C.I. Basic Red 9 monohydrochloride; C.I. Basic Red 9, monohydrochloride; Calcozine-magenta-N-; Cerven-zasadita-9- (Czech); Fuchsin-SP-; Fuchsine-DR-001-; Fuchsine-SP-; Fuchsine-SPC-; NCI-C54739-; Orient-Paramagenta-Base-; Parafuchsin- (German); Parafuchsine-; Pararosaniline-; Pararosaniline-chloride-; Pararosaniline-hydrochloride-; Schultz-tab. No. 779 (German); p-Fuchsin-; p-Rosaniline-HCl-; para-Magenta- RN: Current: 569-61-9 Previous: 70426-60-7; 131883-55-1 UD: 200302 MF: C19-H17-N3.Cl-H MW: 323.85 WL: L6Y DHJ AUM DYR DZ&R DZ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6(Suppl 2), p. 1, 1984 (ENMUDM); dnr-esc 20 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 873, 1979 (JJIND8); dni-hmn-hla 300 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 13, p. 2389, 1992 (CRNGDP); mtr-rat-emb 1400 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dns-rat-lvr 2200 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5, p. 482, 1983 (ENMUDM); bfa-rat-sat 1680 mg/kg/2W-C Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9, p. 69, 1987 (ENMUDM); mmo-mus-lym 41 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); mtr-mus-fbr 8 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dnd-mus-orl 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); bfa-mus-sat 840 mg/kg/1W-C Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9, p. 69, 1987 (ENMUDM); msc-mus-lym 1020 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); dns-ham-lvr 10 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6, p. 1, 1984 (ENMUDM); dna-mam-lym 10 pph Biopolymers. (John Wiley and Sons, Inc., 605 Third Ave., New York, NY 10158) V.1- 1963- v. 11, p. 2537, 1972 (BIPMAA); mtr-mus-fbr 0.01 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG) TE: V01-L60-N62 orl-rat TDLo: 728 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-285, 1986 (NTPTR*); V03-V10 scu-rat TDLo: 1714 mg/kg/43W-I Naturwissenschaften. (Springer-Verlag, Heidelberger Platz 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1913- v. 43, p. 543, 1956 (NATWAY); V01-L60-N61 orl-mus TDLo: 364 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-285, 1986 (NTPTR*); V01-N62-R60 orl-rat TDLo: 74263 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-186509/AS (NTIS**); V02-N62 orl-rat TDLo: 42539 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-186509/AS (NTIS**); V02-R60 orl-rat TDLo: 20188 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-186509/AS (NTIS**); V01-L60 orl-mus TDLo: 141316 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-186509/AS (NTIS**); V01-N61-P62 orl-mus TDLo: 107429 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-186509/AS (NTIS**) AT: T/E unlistd orl-mus LD50: 5 gm/kg Fortschritte der Arzneimittelforschung. Progress in Drug Research. (Birkhauser Boston, Inc., c/o Springer-Verlag New York, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1959- v. 17, p. 108, 1973 (FAZMAE) MD: N05-Z01 orl-rat TDLo: 18200 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-285, 1986 (NTPTR*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 215, 1993 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 4, p. 57, 1974 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 4, p. 57, 1974 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 215, 1993 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 215, 1993 (IMEMDT) ND: NOHS 1974: HZD M1440; NIS 4; TNF 148; NOS 6; TNE 494; NOES 1983: HZD M1440; NIS 4; TNF 165; NOS 6; TNE 907; TFE 733 SL: EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: E coli polA without S9; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-BALB/c-3T3; EPA GENETOX PROGRAM 1988, Positive/limited: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: Host-mediated assay, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: SHE-clonal assay; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), clear evidence: mouse, rat; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 546 of 1119 in RTECS (through 2003/06) AN: CY1050000 PN: Benzenamine, 4,4'-methylenebis(2-chloro- SY: 3,3'-Dichlor-4,4'-diaminodiphenylmethan- (German); 3,3'-Dichloro-4,4'-diaminodifenilmetano- (Italian); 3,3'-Dichloro-4,4'-diaminodiphenylmethane-; 4,4'-Diamino-3,3'-dichlorodiphenylmethane-; 4,4'-Methylene bis(2-chloroaniline); 4,4'-Methylene bis(2-chloroaniline) (ACGIH); 4,4'-Methylene(bis)-chloroaniline; 4,4'-Methylenebis(2-chloroaniline); 4,4'-Methylenebis(o-chloroaniline); 4,4'-Methylenebis-2-chlorobenzenamine-; 4,4-Metilene-bis-O-cloroanilina- (Italian); Aniline, 4,4'-methylenebis(2-chloro-; Bis-amine-; Bis(3-chloro-4-aminophenyl)methane; Bis(4-amino-3-chlorophenyl)methane; Bis-amine-A-; Bisamine-S-; CL-Mda-; Cuamine-M-; Cuamine-MT-; Curalin-M-; Curene-442-; Cyanaset-; Dacpm-; Di(-4-amino-3-chlorophenyl)methane; Di-(4-amino-3-clorofenil)metano (Italian); Diamet-Kh-; LD-813-; MBOCA-; MOCA-; Mboca-; Methylene 4,4'-bis(o-chloroaniline); Methylene-bis-orthochloroaniline-; Millionate-M-; Quodorole-; RCRA-waste-number-U158-; p,p'-Methylenebis(alpha-chloroaniline); p,p'-Methylenebis(o-chloroaniline) RN: Current: 101-14-4 Previous: 29371-14-0; 51065-07-7; 78642-65-6 BRN: 1882318 BHR: 1-13-00-00074 UD: 200210 MF: C13-H12-Cl2-N2 MW: 267.17 WL: ZR CG D1R DZ CG CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 ug/plate (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 261, 1981 (PMRSDJ); mmo-sat 33 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mmo-esc 100 ug/plate (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 387, 1981 (PMRSDJ); dnr-esc 500 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 195, 1981 (PMRSDJ); pic-esc 1 gm/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 224, 1981 (PMRSDJ); dnd-bcs 1 mg/disc Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 175, 1981 (PMRSDJ); slt-dmg-orl 5 mmol/L/48H-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 211, p. 279, 1988 (MUREAV); mrc-smc 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 491, 1981 (PMRSDJ); sln-smc 50 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); mtr-rat-emb 1 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dns-rat-lvr 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 204, p. 683, 1988 (MUREAV); mnt-mus-ipr 6400 ug/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 686, 1981 (PMRSDJ); mmo-mus-lym 5 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); mtr-mus-fbr 10 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dnd-mus-orl 600 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); dns-mus-lvr 10 umol/L Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 58, p. 231, 1981 (TXAPA9); mtr-ham-emb 2500 ug/L Advances in Modern Environmental Toxicology. (Senate Press, Inc., P.O. Box 252, Princeton Junction, NJ 08550) V.1- 1980- v. 1, p. 241, 1980 (AETODY); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); dns-ham-lvr 10 umol/L Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 58, p. 231, 1981 (TXAPA9); sce-ham-ovr 500 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 1, 1985 (ENMUDM); dns-rbt-lvr 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 3120, 1983 (CNREA8) TE: V01-J60-R60 orl-rat TDLo: 4050 mg/kg/77W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(1), p. 149, 1978 (JEPTDQ); V01-J60-L60 scu-rat TDLo: 25 gm/kg/89W-C Naturwissenschaften. (Springer-Verlag, Heidelberger Platz 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1913- v. 58, p. 578, 1971 (NATWAY); V03-J60-L60 orl-rat TD :27 gm/kg/79W-C Naturwissenschaften. (Springer-Verlag, Heidelberger Platz 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1913- v. 58, p. 578, 1971 (NATWAY); V01-J60-L60 orl-rat TD :27 gm/kg/78W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 159, 1975 (TXAPA9); V01-J60-R60 orl-rat TD :11 gm/kg/2Y-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(1), p. 149, 1978 (JEPTDQ); V01-J60-N60 orl-rat TD :8100 mg/kg/77W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(1), p. 149, 1978 (JEPTDQ); V01-J60-R60 orl-rat TD :16 gm/kg/77W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(1), p. 149, 1978 (JEPTDQ); V01-J60-R60 orl-rat TD :27 gm/kg/65W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(1), p. 149, 1978 (JEPTDQ); V01-J60-L60 orl-rat TD :34 gm/kg/80W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 159, 1975 (TXAPA9); V01-J60-R60 orl-rat TD :21 gm/kg/60W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 159, 1975 (TXAPA9); V01-J60-L60 orl-rat TD :24 gm/kg/57W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 159, 1975 (TXAPA9) ORNG: 1140000000 ng/kg. [1140.000000 mg/kg] D07-F19-J24 AT: D07-F19-J24 orl-rat LD50: 1140 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 55(6), p. 86, 1990 (GISAAA); T/E unlistd scu-rat LD50: >5 gm/kg Naturwissenschaften. (Springer-Verlag, Heidelberger Platz 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1913- v. 58, p. 578, 1971 (NATWAY); F18-J24-M10 unr-rat LDLo: 1 gm/kg American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 32, p. 802, 1971 (AIHAAP); D07-F19-J24 orl-mus LD50: 640 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 55(6), p. 86, 1990 (GISAAA); T/E unlistd ipr-mus LD50: 64 mg/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 682, 1981 (PMRSDJ); T/E unlistd skn-rbt LD50: >5 gm/kg "Documentation of the Threshold Limit Values and Biological Exposure Indices," 5th ed., Cincinnati, OH, American Conference of Governmental Industrial Hygienists, Inc., 1986 6,988,1991 (85INA8); D07-F19-J24 orl-gpg LD50: 400 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 55(6), p. 86, 1990 (GISAAA) MD: F15-N30-Z01 ipr-rat TDLo: 300 mg/kg/3D-I Weisheng Dulixue Zazhi. Journal of Health Toxicology. (Weisheng Dulixue Zazhi Bianjibu, Dongdaqiao, Chaoyang Menwai, Beijing, Peop. Rep. China) V.1- 1987 v. 7, p. 30, 1993 (WDZAEK) TR: ACGIH TLV-Suspected Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.01 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 4, p. 65, 1974 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 271, 1993 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 246, 1987 (IMSUDL); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 271, 1993 (IMEMDT); IARC Cancer Review: Group 2A IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 271, 1993 (IMEMDT); TOXICOLOGY REVIEW American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 39, p. 496, 1978 (AIHAAP) SR: OEL-AUSTRALIA: TWA 0.02 ppm (0.22 mg/m3), Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-BELGIUM: TWA 0.02 ppm (0.22 mg/m3), Skin, Carcinogen, JAN 1993; OEL-FINLAND: TWA 0.02 ppm (0.2 mg/m3), STEL 0.06 ppm, Skin, JAN 1993; OEL-FINLAND: TWA 0.02 ppm (0.2 mg/m3), STEL 0.06 ppm, Carcinogen, JAN 1999; OEL-FRANCE: VME 0.02 ppm (0.22 mg/m3), C2 Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999; OEL-JAPAN: OEL 0.005 mg/m3, Skin, 2A Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.01 ppm (0.11 mg/m3), Skin, Carcinogen, JAN 1999; OEL-SWEDEN: Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.02 mg/m3, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: TWA 0.005 mg/m3, Skin, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO MOCA-air: 10H CA TWA 0.003 mg/m3 (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 83341; NIS 15; TNF 376; NOS 13; TNE 2094; NOES 1983: HZD 83341; NIS 1; TNF 4; NOS 1; TNE 114 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/95/100186/AS); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/SHE, Mammalian micronucleus; EPA GENETOX PROGRAM 1988, Positive: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-BALB/c-3T3; EPA TSCA Section 8(b) CHEMICAL INVENTORY; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: MBOCA in urine, 8302; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #24; OSHA ANALYTICAL METHOD #ID-71 Record 547 of 1119 in RTECS (through 2003/06) AN: CY1203055 PN: Benzenamine, 4,4'-(phenylmethylene)bis(N,N-dimethyl- SY: Aniline, 4,4'-benzylidenebis(N,N-dimethyl-; Leucomalachite-green-; Malachite-green-leuco-; Malachite-green-leuco-base-; 4,4'-(Phenylmethylene)bis(N,N-dimethylbenzenamine) RN: Current: 129-73-7 BRN: 2140506 BHR: 4-13-00-00481 UD: 200302 MF: C23-H26-N2 MW: 330.51 CC: Tumorigen (C); Mutagen (M) ME: slt-rat-orl 543 ppm/16W Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 506-507, p. 55, 2002 (MUREAV); dna-rat-orl 91 ppm/4W Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 506-507, p. 55, 2002 (MUREAV) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis studies, on test (two year studies), October 2000 Record 548 of 1119 in RTECS (through 2003/06) AN: CY1400000 PN: Benzene- SY: (6)Annulene; Benzeen- (Dutch); Benzen- (Polish); Benzene- (ACGIH:OSHA); Carbon-oil-; Cyclohexatriene-; NCI-C55276-; RCRA-waste-number-U019-; Benzin- (Obs.); Benzine- (Obs.); Benzol- (OSHA); Benzole-; Benzolene-; Benzolo- (Italian); Bicarburet-of-hydrogen-; Coal-naphtha-; Fenzen- (Czech); Mineral-naphtha-; Phene-; Phenyl-hydride-; Pyrobenzol-; Pyrobenzole- RN: Current: 71-43-2 UD: 200305 MF: C6-H6 MW: 78.12 WL: RH CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 15 mg/24H open MLD American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 23, p. 95, 1962 (AIHAAP); skn-rbt 20 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,25,1986 (85JCAE); eye-rbt 88 mg MOD AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 387, 1956 (AMIHAB); eye-rbt 2 mg/24H SEV "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,25,1986 (85JCAE) ME: mmo-sat 10 ppm (-S9) EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 82, p. 81, 1989 (EVHPAZ); slt-dmg-orl 11250 umol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 325, 1985 (PMRSDJ); sln-dmg-orl 7500 ppm Contaminacion Ambiental. (Centro de Ciencias de la Atmosfera, Universidad Nacional Autonoma de Mexico, 04510 Mexico City, Mexico) V.1- 1985- v. 1, p. 35, 1985 (CONAEL); sln-dmg-mul 27000 ppm Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 25, p. 211, 1995 (EMMUEG); mmo-smc 549 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 271, 1985 (PMRSDJ); mrc-smc 275 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 271, 1985 (PMRSDJ); sln-asn 35000 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 147, p. 288, 1985 (MUREAV); oms-grh-ihl 14 pph/16H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 113, p. 467, 1983 (MUREAV); oms-nml-ipr 75 gm/kg Acta Haematologica. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.1- 1948- v. 26, p. 281, 1961 (ACHAAH); dni-hmn-leu 2200 umol/L Industrial Health. (National Institute of Industrial Health, 6-21-1 Nagao, Tama-ku, Kawasaki, 213 Japan) V.1- 1963- v. 12, p. 23, 1974 (INHEAO); dni-hmn-hla 2200 umol/L Industrial Health. (National Institute of Industrial Health, 6-21-1 Nagao, Tama-ku, Kawasaki, 213 Japan) V.1- 1963- v. 12, p. 23, 1974 (INHEAO); oms-hmn-lym 5 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 2471, 1985 (CNREA8); cyt-hmn-ihl 125 ppm/1Y Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 22, p. 373, 1971 (AEHLAU); cyt-hmn-leu 1 mmol/L/72H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 47, p. 75, 1978 (MUREAV); cyt-hmn-lym 1 mg/L Biologicheskii Zhurnal Armenii. Biological Journal of Armenia. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.19- 1966- v. 26(12), p. 38, 1973 (BZARAZ); cyt-hmn-unr 10 ppm/4W Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 19, p. 33, 1979 (ENVRAL); sce-hmn-lym 200 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 1330, 1983 (CNREA8); msc-hmn-lym 1 gm/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 497, 1985 (PMRSDJ); mnt-rat-ihl 1 ppm/6H Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8, p. 29, 1986 (ENMUDM); dns-rat-lvr 1 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 371, 1985 (PMRSDJ); dni-rat-ihl 400 ppm Blut. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1955- v. 21, p. 250, 1970 (BLUTA9); oms-rat-lvr 1 mmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 42, p. 353, 1982 (CBINA8); oms-rat-bmr 1 mmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 42, p. 353, 1982 (CBINA8); oms-rat-scu 1 gm/L Nagoya Journal of Medical Science. (Nagoya Univ. School of Medicine, 65 Tsuruma-cho, Showa- ku, Nagoya 466, Japan) V.2- 1927- v. 28, p. 204, 1966 (NJMSAG); oms-rat-scu 2200 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 42, p. 353, 1982 (CBINA8); cyt-rat-ihl 300 mg/m3/16W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 42(1), p. 32, 1977 (GISAAA); cyt-rat-scu 2400 mg/kg/12D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 37(10), p. 36, 1972 (GISAAA); cyt-rat-ipr 234 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 242, p. 111, 1990 (MUREAV); cyt-rat-orl 39060 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 298, p. 81, 1992 (MUREAV); sce-rat-ihl 3 ppm/6H Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8, p. 29, 1986 (ENMUDM); sce-rat-leu 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 300, p. 241, 1993 (MUREAV); mnt-mus-emb 12500 nmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 19(Suppl 20), p. 21, 1992 (EMMUEG); mnt-mus-scu 440 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 39, p. 129, 1982 (CBINA8); mnt-mus-orl 40 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 147, p. 294, 1985 (MUREAV); mnt-mus-ipr 264 mg/kg/24H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 111, 1987 (MUTAEX); mnt-mus-ihl 10 ppm/6H Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8, p. 29, 1986 (ENMUDM); mmo-mus-lym 62500 ug/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 587, 1985 (PMRSDJ); mmo-mus-emb 2500 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 639, 1985 (PMRSDJ); mtr-mus-emb 1 gm/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 659, 1985 (PMRSDJ); mtr-mus-fbr 150 gm/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 3, p. 1235, 1982 (CRNGDP); dnd-mus-lym 3840 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 203, p. 155, 1988 (MUREAV); dna-mus-ipr 2640 mg/kg/3D-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 17, p. 151, 1996 (CRNGDP); oms-mus-orl 2 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV); oms-mus-oth 5 mmol/L Cell Biology and Toxicology. (Princeton Scientific Pub., Inc., 301 N. Harrison St., CN 5279, Princeton, NJ 08540) V.1- 1984- v. 2, p. 231, 1986 (CBTOE2); dni-mus-orl 20 gm/kg Archiv fuer Geschwulstforschung. (VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 51, p. 605, 1981 (ARGEAR); oms-mus-lym 10 mmol/L Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 29, p. 161, 1985 (TOLED5); dni-mus-ipr 880 mg/kg Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 60, p. 27, 1988 (RCOCB8); dni-mus-ihl 3000 ppm/4H-C Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 60, p. 27, 1988 (RCOCB8); dni-mus-bmr 3 mmol/L Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 60, p. 27, 1988 (RCOCB8); sce-mus-ihl 10 ppm/6H Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8, p. 29, 1986 (ENMUDM); sce-mus-ipr 5 gm/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5, p. 450, 1983 (ENMUDM); cyt-mus-orl 20 mg/kg Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 96, p. 1741, 1984 (BEXBAN); cyt-mus-ipr 264 mg/kg/3D-C Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 2, p. 43, 1980 (ENMUDM); cyt-mus-ihl 3000 ppm Environmental Science Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.1- 1972- v. 25, p. 257, 1982 (EVSRBT); dlt-mus-orl 1 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 39, p. 173, 1978 (ARTODN); dlt-mus-ipr 5 mg/kg Toksikologiya Novykh Promyshlennykh Khimicheskikh Veshchestv. Toxicology of New Industrial Chemical Substances. For English translation, see TNICS*. (Izdatel'stvo Meditsina, Moscow, USSR) No.1- 1961- v. 15, p. 30, 1979 (TPKVAL); msc-mus-lym 12500 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 525, 1985 (PMRSDJ); msc-mus-ihl 40 ppb/6W-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 268, p. 49, 1992 (MUREAV); msc-mus-orl 2 gm/kg/5D-C Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 28, p. 342, 1996 (EMMUEG); mtr-ham-emb 100 ug/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 4, p. 291, 1983 (CRNGDP); dnd-ham-ovr 17 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 367, 1985 (PMRSDJ); cyt-ham-lng 550 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 427, 1985 (PMRSDJ); cyt-ham-ovr 600 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 443, 1985 (PMRSDJ); sce-ham-ovr 750 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); sln-ham-lvr 62500 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 397, 1985 (PMRSDJ); sln-ham-emb 30 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 373, p. 113, 1997 (MUREAV); msc-ham-emb 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 373, p. 113, 1997 (MUREAV); dnd-rbt-scu 2344 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 63, p. 209, 1989 (ARTODN); dni-rbt-scu 2 gm/kg Acta Haematologica. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.1- 1948- v. 38, p. 104, 1967 (ACHAAH); oms-rbt-bmr 1 mmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 42, p. 353, 1982 (CBINA8); oms-cat-bmr 1 mmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 42, p. 353, 1982 (CBINA8); cyt-rbt-scu 8400 mg/kg Proceedings of the European Society for the Study of Drug Toxicity. (Princeton, NJ 08540) V.1-15, 1963-74. For publisher information, see PESTD5. v. 15, p. 275, 1974 (PSDTAP); dnd-mus-ipr 2000 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 493, p. 39, 2001 (MUREAV); dnd-mus-orl 2000 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 493, p. 39, 2001 (MUREAV); mnt-mus-ihl 15000 ppm/5W Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 163, 2001 (MUTAEX); cyt-mus-skn 8.5 gm/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 185, 2001 (EMMUEG); mtr-mus-fbr 0.01 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG) RE: T22 ihl-rat TCLo: 670 mg/m3/24H (15D pre/1-22D preg) Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(1-3), p. 327, 1968 (HYSAAV); T83 ihl-rat TCLo: 56600 ug/m3/24H (1-22D preg) Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 33(7-9), p. 112, 1968 (HYSAAV); T31-T34 ihl-rat TCLo: 50 ppm/24H (7-14D preg) Journal of Hygiene, Epidemiology, Microbiology, and Immunology. (Avicenum, Malostranske namesti 28, 11802 Prague 1, Czechoslovakia) V.1- 1957- v. 24, p. 363, 1980 (JHEMA2); T25-T46 ihl-rat TCLo: 150 ppm/24H (7-14D preg) Journal of Hygiene, Epidemiology, Microbiology, and Immunology. (Avicenum, Malostranske namesti 28, 11802 Prague 1, Czechoslovakia) V.1- 1957- v. 24, p. 363, 1980 (JHEMA2); T34 orl-mus TDLo: 9 gm/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 19, p. 41A, 1979 (TJADAB); T25 orl-mus TDLo: 12 gm/kg (6-15D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 19, p. 41A, 1979 (TJADAB); T81 orl-mus TDLo: 6500 mg/kg (8-12D preg) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 6, p. 361, 1986 (TCMUD8); T34-T35 orl-mus TDLo: 16880 mg/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0554056 (NTIS**); T34-T46 ihl-mus TCLo: 500 ppm/7H (6-15D preg) American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 40, p. 993, 1979 (AIHAAP); T34-T46 ihl-mus TCLo: 500 mg/m3/12H (6-15D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG); T33-T48 ihl-mus TCLo: 5 ppm (6-15D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 42, p. 171, 1986 (TXCYAC); T48 ihl-mus TCLo: 20 ppm/6H (6-15D preg) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 10, p. 224, 1988 (FAATDF); T24-T35 ipr-mus TDLo: 5 mg/kg (1D male) Toksikologiya Novykh Promyshlennykh Khimicheskikh Veshchestv. Toxicology of New Industrial Chemical Substances. For English translation, see TNICS*. (Izdatel'stvo Meditsina, Moscow, USSR) No.1- 1961- v. 15, p. 30, 1979 (TPKVAL); T48-T51 ipr-mus TDLo: 219 mg/kg (14D preg) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 18, p. 1, 1991 (EMMUEG); T39 scu-mus TDLo: 1100 mg/kg (12D preg) Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 1, p. 125, 1981 (TOXID9); T31-T34-T46 scu-mus TDLo: 7030 mg/kg (12-13D preg) Senten Ijo. Congenital Anomalies. (Nippon Senten Ijo Gakkai, c/o Kinki Daigaku Igakubu Kaibagaku Kyoshitsu, 380 Nishiyama, Sayama-cho, Mirami-Kawachi-gun, Osaka-fu, Japan) V.1-26, 1960-86. For publisher information, see CGANE7. v. 15, p. 47, 1975 (SEIJBO); T33 ivn-mus TDLo: 13200 ug/kg (13-16D preg) Yichuan. Heredity. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) V.1- 1979- v. 4(6), p. 24, 1982 (ICHUDW); T76 par-mus TDLo: 4 gm/kg (12D preg) Nippon Eiseigaku Zasshi. Japanese Journal of Hygiene. (Nippon Eisei Gakkai, c/o Kyoto Daigaku Igakubu, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606, Japan) V.1- 1946- v. 25, p. 438, 1970 (NEZAAQ); T25-T27-T35 ihl-rbt TCLo: 1 gm/m3/24H (7-20D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG); T34-T59 ihl-rbt TCLo: 1 gm/m3/24H (7-20D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG); T19 ihl-rbt TCLo: 500 ppm/7H (6-18D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0545179 (NTIS**) TE: V01-P61-P17 ihl-man TCLo: 200 mg/m3/78W-I European Journal of Cancer (Elsevier Science, P.O.Box 7247-7682,Philadelphia,PA 19170 -7682,USA OR Elsevier Science B.V.,P.O.Box 1270,1000 BG Amsterdam,The Netherlands) V. 1- 1965- v. 7, p. 83, 1971 (EJCAAH); V01-P61 ihl-hmn TCLo: 10 ppm/8H/10Y-I Texas Reports on Biology and Medicine. (Galveston, TX) V.1-41(2), 1943-81/82. Discontinued. v. 37, p. 153, 1978 (TRBMAV); V01-N60-P61 orl-rat TDLo: 52 gm/kg/52W-I Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 70, p. 352, 1979 (MELAAD); V03-D45 ihl-rat TCLo: 1200 ppm/6H/10W-I Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 25, p. 75, 1984 (PAACA3); V01-N60-P62 orl-mus TDLo: 18250 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-289, 1986 (NTPTR*); V03-P62 ihl-mus TCLo: 300 ppm/6H/16W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 75, p. 358, 1984 (TXAPA9); V02-R60 skn-mus TDLo: 1200 gm/kg/49W-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 16, p. 275, 1962 (BJCAAI); V02-J60 ipr-mus TDLo: 1200 mg/kg/8W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 82, p. 19, 1986 (TXAPA9); V03-P61-P62 scu-mus TDLo: 600 mg/kg/17W-I Krankheitsforschung. (Leipzig, Ger. Dem. Rep.) V.1-9, 1925-32. Discontinued. v. 9, p. 403, 1932 (KRANAW); V03-P61-P62 par-mus TDLo: 670 mg/kg/19W-I Klinische Wochenscrift. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.1- 1922- v. 12, p. 109, 1933 (KLWOAZ); V01-P61 ihl-hmn TC :150 ppm/15M/8Y-I Blood. (Grune and Stratton, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1946- v. 52, p. 285, 1978 (BLOOAW); V01-D45-P61 orl-rat TD :52 gm/kg/1Y-I American Journal of Industrial Medicine. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 4, p. 589, 1983 (AJIMD8); V01-N60-P61 orl-rat TD :10 gm/kg/52W-I Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 70, p. 352, 1979 (MELAAD); V01-P61 ihl-man TC :600 mg/m3/4Y-I New England Journal of Medicine. (Massachusetts Medical Soc., 10 Shattuck St., Boston, MA 02115) V.198- 1928- v. 271, p. 872, 1964 (NEJMAG); V01-P62 ihl-man TC :150 ppm/11Y-I Blut. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1955- v. 28, p. 293, 1974 (BLUTA9); V03-D45-J60 ihl-mus TC :1200 ppm/6H/10W-I Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 25, p. 75, 1984 (PAACA3); V02-J60 orl-mus TD :2400 mg/kg/8W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 82, p. 19, 1986 (TXAPA9); V01-P61 ihl-hmn TC :8 ppb/4W-I New England Journal of Medicine. (Massachusetts Medical Soc., 10 Shattuck St., Boston, MA 02115) V.198- 1928- v. 316, p. 1044, 1987 (NEJMAG); V01-P61 ihl-hmn TC :10 mg/m3/11Y-I British Journal of Industrial Medicine. (British Medical Journal, Box 560B, Kennebunkport, ME 04046) V.1- 1944- v. 44, p. 124, 1987 (BJIMAG); V01-P61 ihl-mus TC :300 ppm/6H/16W-I Immunology and Hematology Research, Monograph. (Immunology Research Foundation, Inc., 5022 W. Timberwood, Newburg, IN 47630) No.1- 1983- v. (3), p. 156, 1984 (IHRMEQ); V01-N60 orl-rat TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-216967/AS (NTIS**); V01-R60 orl-rat TDLo: 103000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-216967/AS (NTIS**); V01-K60-N60 orl-rat TDLo: 12875 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-216967/AS (NTIS**); V01-L60-P62 orl-mus TDLo: 12875 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-216967/AS (NTIS**); V01-N60 orl-mus TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-216967/AS (NTIS**) ORNG: 930000000 ng/kg. [930.000000 mg/kg] F11-F12 AT: T/E unlistd ihl-hmn LCLo: 2 pph/5M Tabulae Biologicae. (The Hague, Netherlands) V.1-22, 1925-63. Discontinued. v. 3, p. 231, 1933 (TABIA2); T/E unlistd orl-man LDLo: 50 mg/kg Gekkan Yakuji. Pharmaceuticals Monthly. (Yakugyo Jihosha, Inaoka Bldg., 2-36 Jinbo-cho, Kanda, Chiyoda-ku, Tokyo 101, Japan) V.1- 1959- v. 22, p. 883, 1980 (YAKUD5); P30-U25 ihl-man TCLo: 150 ppm/1Y-I Blut. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1955- v. 28, p. 293, 1974 (BLUTA9); F07-K13-R03 ihl-hmn TCLo: 100 ppm Industrial Medicine. (Chicago, IL) V.1-18, 1932-49. For publisher information, see IOHSA5. v. 17, p. 199, 1948 (INMEAF); P30 ihl-hmn LCLo: 65 mg/m3/5Y Archiv fuer Geschwulstforschung. (VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 44, p. 145, 1974 (ARGEAR); T/E unlistd unr-man LDLo: 194 mg/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); F11-F12 orl-rat LD50: 930 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 767, 1965 (TXAPA9); T/E unlistd ihl-rat LC50: 10000 ppm/7H "Toxicology and Biochemistry of Aromatic Hydrocarbons," Gerarde, H., New York, Elsevier, 1960 -,113,1960 (28ZRAQ); T/E unlistd ipr-rat LD50: 1100 ug/kg Acta Physiologica Polonica. (Karger-Libri, POB CH-4009, Warszawa, Switzerland) V.1-41, 1950-90. v. 12, p. 173, 1961 (APYPAY); T/E unlistd orl-mus LD50: 4700 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 32(3), p. 349, 1967 (HYSAAV); F01-F18-J22 ihl-mus LC50: 9980 ppm Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 25, p. 366, 1943 (JIHTAB); T/E unlistd skn-mus LD50: 48 mg/kg Raw Material Data Handbook, Vol.1: Organic Solvents, 1974. (National Assoc. of Printing Ink Research Institute, Francis McDonald Sinclair Memorial Laboratory, Lehigh Univ., Bethlehem, PA 18015) v. 1, p. 5, 1974 (NPIRI*); T/E unlistd ipr-mus LD50: 340 mg/kg Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 243, p. 104, 1975 (ANYAA9); T/E unlistd orl-dog LDLo: 2 gm/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1313, 1935 (HBAMAK); T/E unlistd ihl-dog LCLo: 146000 mg/m3 "Handbook of Toxicology," 4 vols., Philadelphia, W.B. Saunders Co., 1956-59 v. 1, p. 324, 1955 (HBTXAC); T/E unlistd ihl-cat LCLo: 170000 mg/m3 "Handbook of Toxicology," 4 vols., Philadelphia, W.B. Saunders Co., 1956-59 v. 1, p. 324, 1955 (HBTXAC); T/E unlistd ihl-rbt LCLo: 45000 ppm/30M Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 26, p. 69, 1944 (JIHTAB); T/E unlistd skn-rbt LD50: >9400 uL/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 559, 1965 (TXAPA9); C06-D21-K05 ivn-rbt LDLo: 88 mg/kg Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. (Suppl 2), p. 45, 1977 (JTEHD6); T/E unlistd skn-gpg LD50: >9400 uL/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 559, 1965 (TXAPA9); T/E unlistd ipr-gpg LDLo: 527 mg/kg "Handbook of Toxicology," 4 vols., Philadelphia, W.B. Saunders Co., 1956-59 v. 1, p. 42, 1955 (HBTXAC); T/E unlistd scu-frg LDLo: 1400 mg/kg "Abdernalden's Handbuch der Biologischen Arbeitsmethoden." (Leipzig, Ger. Dem. Rep.) v. 4, p. 1313, 1935 (HBAMAK); T/E unlistd orl-mam LD50: 5700 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 39(4), p. 86, 1974 (GISAAA); T/E unlistd ihl-mam LCLo: 20000 ppm/5M Naunyn-Schmiedeberg's Archiv fuer Experimentelle Pathologie und Pharmakologie. (Berlin, Ger.) V.110-253, 1925-66. For publisher information, see NSAPCC. v. 138, p. 65, 1928 (AEPPAE); C08-F12-F33 ipr-mam LDLo: 1500 mg/kg American Journal of Hygiene. (Baltimore, MD) V.1-80, 1921-64. For publisher information, see AJEPAS. v. 7, p. 276, 1927 (AJHYA2); F11 scu-rat LDLo: 5 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0544815 (NTIS**); P26 orl-mus TDLo: 880 mg/kg/12H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 208, p. 61, 1988 (MUREAV) MD: P14-P71 orl-rat TDLo: 6600 mg/kg/27W-I AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 387, 1956 (AMIHAB); L70-N71 ihl-rat TCLo: 23 mg/m3/4H/8D-I Toksikologiya Novykh Promyshlennykh Khimicheskikh Veshchestv. Toxicology of New Industrial Chemical Substances. For English translation, see TNICS*. (Izdatel'stvo Meditsina, Moscow, USSR) No.1- 1961- v. 12, p. 5, 1971 (TPKVAL); P14 ihl-rat TCLo: 300 ppm/6H/13W-I American Journal of Industrial Medicine. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 457, 1985 (AJIMD8); P14-P26-Z01 ihl-rat TCLo: 300 ppm/6H/99W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 4, p. 605, 1978 (JTEHD6); P27-P72 orl-rat TDLo: 17 gm/kg/17W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-289, 1986 (NTPTR*); P70 ihl-rat TCLo: 1000 ppm/7H/28W-I Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 26, p. 37, 1944 (JIHTAB); P08-P26-P72 ihl-rat TCLo: 500 ppm/6H/3W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 5, p. 1025, 1979 (JTEHD6); P26-P70-P72 scu-rat TDLo: 12 gm/kg/6W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 109(Suppl 1), p. 32, 1999 (TOLED5); P71-P72-U01 scu-rat TDLo: 18 mg/kg/21D-I American Journal of Hygiene. (Baltimore, MD) V.1-80, 1921-64. For publisher information, see AJEPAS. v. 7, p. 276, 1927 (AJHYA2); P08-P72-U01 scu-rat TDLo: 2197 mg/kg/5D-I Industrial Health. (National Institute of Industrial Health, 6-21-1 Nagao, Tama-ku, Kawasaki, 213 Japan) V.1- 1963- v. 3, p. 91, 1965 (INHEAO); L30-M16-Y04 scu-rat TDLo: 13536 mg/kg/12W-I Bromatologia i Chemia Toksykologiczna. (Ars Polona, POB 1001, 00-068 Warsaw 1, Poland) V.4- 1971- v. 17, p. 101, 1984 (BCTKAG); L30-U09 ipr-rat TDLo: 5 mL/kg/10D-I Indian Journal of Experimental Biology. (Publications and Information Directorate, CSIR, Hillside Rd., New Delhi 110 012, India) V.1- 1963- v. 36, p. 283, 1998 (IJEBA6); P30-P72 orl-mus TDLo: 4250 mg/kg/17W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-289, 1986 (NTPTR*); P05-P17-Z73 ihl-mus TCLo: 300 ppm/6H/13W-I American Journal of Industrial Medicine. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 457, 1985 (AJIMD8); N73-P72 ihl-mus TCLo: 25 ppm/6H/5D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 56, p. 159, 1991 (TOLED5); N73-P27 ihl-mus TCLo: 10 ppm/6H/10W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 58, p. 492, 1981 (TXAPA9); P27-P70-P71 ihl-mus TCLo: 10 ppm/6H/26W-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 20, p. 337, 1984 (TOLED5); P14-N73-P72 orl-mus TCLo: 211 ppm/6H/7D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 85, p. 92, 1986 (TXAPA9); P26-P70-Z01 ihl-mus TCLo: 300 ppm/6H/16W-I American Journal of Industrial Medicine. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 447, 1985 (AJIMD8); P14-N73-S04 ihl-mus TCLo: 48 ppm/6H/14D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 85, p. 92, 1986 (TXAPA9); N73-N74-P72 scu-mus TDLo: 2197 mg/kg/5D-I Industrial Health. (National Institute of Industrial Health, 6-21-1 Nagao, Tama-ku, Kawasaki, 213 Japan) V.1- 1963- v. 3, p. 91, 1965 (INHEAO); P05-P14-Z01 ihl-mus TCLo: 100 ppm/6H/72W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 54, p. 323, 1980 (TXAPA9); P01-P30-J30 ihl-rbt TCLo: 500 mg/m3/3H/13W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 24(1), p. 80, 1959 (GISAAA); M16-P08-P26 ihl-pig TCLo: 100 ppm/6H/3W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 5, p. 1025, 1979 (JTEHD6); A30-P27-S02 orl-mus TDLo: 929.6 mg/kg/4W-C Immunopharmacology. (New York, Elsevier/North-Holland) V. 1-49, 1978-2000 v. 21, p. 23, 1991 (IMMPH*); N12 orl-mus TDLo: 232.4 mg/kg/7D-C Immunopharmacology. (New York, Elsevier/North-Holland) V. 1-49, 1978-2000 v. 21, p. 23, 1991 (IMMPH*); P30-S02 scu-mus TDLo: 4000 mg/kg/5D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 103, p. 198, 1990 (TXAPA9) TR: ACGIH TLV-Confirmed Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 2.5 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.5 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Human Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 7, p. 203, 1974 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 120, 1987 (IMSUDL); IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 93, 1982 (IMEMDT); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 93, 1982 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 7, p. 203, 1974 (IMEMDT); IARC Cancer Review: Group 1 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 120, 1987 (IMSUDL); TOXICOLOGY REVIEW Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 11, p. 434, 1931 (ARPAAQ); TOXICOLOGY REVIEW EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 11, p. 163, 1975 (EVHPAZ); TOXICOLOGY REVIEW Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 22, p. 373, 1971 (AEHLAU); TOXICOLOGY REVIEW Pharmacological Reviews. (Williams and Wilkins, 428 E. Preston St., Baltimore, MD 21202) V.1- 1949- v. 4, p. 1, 1952 (PAREAQ); TOXICOLOGY REVIEW Forensic Science. (Lausanne, Switzerland) V.1-11, 1972-78. For pub lisher information, see FSINDR. v. 2, p. 67, 1973 (FNSCA6); TOXICOLOGY REVIEW Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 47, p. 75, 1978 (MUREAV); TOXICOLOGY REVIEW Acta Medica Scandinavica. (Almqvist and Wiksell, POB 45150, S-10430 Stockholm, Sweden) V.52-224, 1919-88. v. 118, p. 354, 1944 (AMSVAZ); TOXICOLOGY REVIEW Zentralblatt fuer Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene, Abteilung 1: Originale, Reihe B: Hygiene, Krankenhaushygiene, Betriebshygiene, Praeventive Medizin. (Stuttgart, Fed. Rep. Ger.) V.155-169, 1971-1979. For publisher information, see ZAOMDC. v. 166, p. 113, 1978 (ZHPMAT); TOXICOLOGY REVIEW Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. (Suppl 2), p. 69, 1977 (JTEHD6); TOXICOLOGY REVIEW Public Health Reports. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1878- v. 41, p. 1357, 1926 (PHRPA6); TOXICOLOGY REVIEW American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 41, p. 616, 1980 (AIHAAP); TOXICOLOGY REVIEW Clinical Toxicology. (New York, NY) V.1-18, 1968-81. For publisher information, see JTCTDW. v. 11, p. 531, 1977 (CTOXAO); TOXICOLOGY REVIEW Bulletin of the New York Academy of Medicine. (New York Academy of Medicine, 2 E. 103rd St., New York, NY 10029) Ser 2: V.1- 1925- v. 54, p. 413, 1978 (BNYMAM); TOXICOLOGY REVIEW Krankheitsforschung. (Leipzig, Ger. Dem. Rep.) V.1-9, 1925-32. Discontinued. v. 9, p. 403, 1932 (KRANAW); TOXICOLOGY REVIEW Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 61, p. 339, 2000 (JTEHD6); TOXICOLOGY REVIEW Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 61, p. 353, 2000 (JTEHD6) SR: MSHA STANDARD: air-CL 25 ppm (80 mg/m3) (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 22, 1971 (DTLVS*); OSHA PEL (Construc): see CFR 29,1926.1128 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Fed Cont): CL 25 ppm (80 mg/m3) (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OSHA-cancer hazard Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 52, p. 34460, 1987 (FEREAC); OEL-AUSTRALIA: TWA 5 ppm (16 mg/m3), Carcinogen, JAN 1993; OEL-AUSTRIA: Skin, Carcinogen, JAN 1999; OEL-BELGIUM: TWA 10 ppm (32 mg/m3), Carcinogen, JAN 1993; OEL-DENMARK: TWA 5 ppm (16 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 5 ppm (15 mg/m3), STEL 10 ppm (30 mg/m3), Skin, Carcinogen, JAN 1993; OEL-UNITED KINGDOM: TWA 3 ppm (9.6 mg/m3), Carcinogen, SEP 2000; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-HUNGARY: STEL 5 mg/m3, Skin, Carcinogen, JAN 1993; OEL-INDIA: TWA 10 ppm (30 mg/m3), Carcinogen, JAN 1993; OEL-JAPAN: OEL 10 ppm (32 mg/m3), Group 1 Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 10 ppm (30 mg/m3), Skin, Carcinogen, JAN 1999; OEL-NORWAY: TWA 1 ppm (3 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 25 ppm (80 mg/m3), Skin, JAN 1993; OEL-POLAND: MAC(TWA) 10 mg/m3, MAC(STEL) 40 mg/m3, JAN 1999; OEL-RUSSIA: TWA 10 ppm (5 mg/m3), STEL 25 ppm (15 mg/m3), Skin, Carcinogen, JAN 1993; OEL-SWEDEN: NGV 0.5 ppm (1.5 mg/m3), KTV 3 ppm (9 mg/m3), Skin, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 1 ppm (3.2 mg/m3), Skin, Carcinogen, JAN 1999; OEL-THAILAND: TWA 10 ppm (30 mg/m3), STEL 25 ppm (75 mg/m3), JAN 1993; OEL-TURKEY: TWA 20 ppm (64 mg/m3), Skin, JAN 1993; OEL-UNITED KINGDOM: LTEL 10 ppm (30 mg/m3), JAN 1993; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO BENZENE-air: 8H CA TWA 0.1 ppm, CL 1 ppm/15M National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 09070; NIS 126; TNF 11184; NOS 106; TNE 147583; NOES 1983: HZD 09070; NIS 92; TNF 10054; NOS 117; TNE 272275; TFE 143066 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/98/101157/AS); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: In vitro cytogenetics-human lymphocyte; EPA GENETOX PROGRAM 1988, Positive: In vivo cytogenetics-human lymphocyte; EPA GENETOX PROGRAM 1988, Positive: Mammalian micronucleus, Sperm morphology-mouse; EPA GENETOX PROGRAM 1988, Negative: Cell transform.-SA7/SHE, In vitro SCE-human lymphocytes; EPA GENETOX PROGRAM 1988, Negative: In vitro SCE-human; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Hydrocarbons, BP 36-126 degree C, 1500; NIOSH Analytical Method, 1994: Benzene, by portable GC, 3700; NIOSH Analytical Method, 1994: Hydrocarbons, aromatic, 1501; NCI Carcinogenesis Studies (gavage), clear evidence: mouse, rat; NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen; NTP Carcinogenesis studies, on test (prechronic studies), October 2000; OSHA ANALYTICAL METHOD #12 Record 549 of 1119 in RTECS (through 2003/06) AN: CY2450000 PN: Benzene,-4-allyl-1,2-dimethoxy- SY: 1,2-Dimethoxy-4-allylbenzene-; 1,3,4-Eugenol-methyl-ether-; 1-(3,4-Dimethoxyphenyl)-2-propene; 1-Allyl-3,4-dimethoxybenzene-; 4-Allyl-1,2-dimethoxybenzene-; 4-Allylveratrole-; ENT-21040-; Eugenyl-methyl-ether-; Methyl-eugenol-; Methyleugenol-; Veratrole-methyl-ether- RN: Current: 93-15-2 BRN: 1910871 BHR: 4-06-00-06337 UD: 200302 MF: C11-H14-O2 MW: 178.25 WL: 1U2R CO1 DO1 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Primary-Irritant (S) ID: skn-rbt 500 mg/24H Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 13, p. 857, 1975 (FCTXAV) ME: mrc-smc 1360 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 427, 1989 (MUREAV); dns-rat-lvr 100 umol/L Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 28, p. 537, 1990 (FCTOD7); dns-rat-orl 500 mg/kg Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 34, p. 337, 1996 (FCTOD7); dna-mus-ipr 80 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 1613, 1984 (CRNGDP) TE: V01-L60-N60 orl-rat TDLo: 39375 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-491, 2000 (NTPTR*); V01-L60 orl-mus TDLo: 19495 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-491, 2000 (NTPTR*); V01-L60-R60 orl-rat TDLo: 39375 mg/kg/105W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-107865 (NTIS**); V01-K60-L60 orl-rat TDLo: 78750 mg/kg/105W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-107865 (NTIS**); V01-L61 orl-rat TDLo: 78000 mg/kg/52W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-107865 (NTIS**); V01-L60 orl-mus TDLo: 19425 mg/kg/105W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB2000-107865 (NTIS**) ORNG: 810000000 ng/kg. [810.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 810 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 13, p. 857, 1975 (FCTXAV); T/E unlistd ihl-rat LC50: >4800 mg/m3 Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 421, 1975 (TXAPA9); F17-F07-F05 ipr-mus LD50: 540 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 199, p. 226, 1972 (AIPTAK); F17-F07-F05 ivn-mus LD50: 112 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 199, p. 226, 1972 (AIPTAK); T/E unlistd skn-rbt LD50: >2025 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 421, 1975 (TXAPA9) MD: L70-M70-P71 orl-rat TDLo: 27300 mg/kg/13W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555639 (NTIS**); U01 ipr-rat TDLo: 4200 mg/kg/6W-I Pharmacology: International Journal of Experimental and Clinical Pharmacology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1968- v. 14, p. 367, 1976 (PHMGBN); L70-M70-Z01 orl-mus TDLo: 27300 mg/kg/13W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555639 (NTIS**); L70-Z73 orl-mus TDLo: 700 mg/kg/14W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-491, 2000 (NTPTR*); L70-M71-N74 orl-rat TDLo: 2100 mg/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K01 orl-rat TDLo: 2100 mg/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); U01-Y15-Y39 orl-rat TDLo: 21 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); J70-P72-Y03 orl-rat TDLo: 21 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); N74 orl-rat TDLo: 700 mg/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); U01-M71-N73 orl-rat TDLo: 700 mg/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); N73-P73-Y15 orl-rat TDLo: 7 mg/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); L70-P73-Y39 orl-rat TDLo: 7 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); G70-Z73-P06 orl-rat TDLo: 70 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); G70-N74-Y15 orl-rat TDLo: 70 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K30-L70 orl-mus TDLo: 2100 mg/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); U01-Z01 orl-mus TDLo: 21 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); L01-L50-Z01 orl-mus TDLo: 70 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); Z01 orl-mus TDLo: 0.7 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K30 orl-mus TDLo: 21 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); N74 orl-mus TDLo: 7 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); L70-L50-U01 orl-mus TDLo: 21 gm/kg/14W-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K04 orl-rat TDLo: 792 mg/kg/30D-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K30-V05 orl-mus TDLo: 4500 mg/kg/30D-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K04 orl-mus TDLo: 1.6 gm/kg/30D-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K04-L30-V05 orl-rat TDLo: 9.6 gm/kg/90D-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7); K30-V05 orl-mus TDLo: 1665 mg/kg/90D-I Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 303, 2001 (FCTOD7) ND: NOHS 1974: HZD 04500; NIS 2; TNF 41; NOS 21; TNE 2840; NOES 1983: HZD 04500; NIS 5; TNF 1074; NOS 10; TNE 12682; TFE 9413 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), clear evidence: mouse, rat; NTP Carcinogenesis studies, selected, October 2000 Record 550 of 1119 in RTECS (through 2003/06) AN: CY2625000 PN: Benzene, 5-allyl-1-methoxy-2,3-(methylenedioxy)- SY: 5-Allyl-1-methoxy-2,3-(methylenedioxy)benzene; 1,3-Benzodioxole, 4-methoxy-6-(2-propenyl)- (9CI); Myristicin- (6CI) RN: Current: 607-91-0 BRN: 166218 BHR: 5-19-02-00631 UD: 200012 MF: C11-H12-O3 MW: 192.23 WL: T56 BO DO CHJ FO1 H2U1 CC: Tumorigen (C); Mutagen (M); Human-Data (P) ME: dna-mus-ipr 400 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 1613, 1984 (CRNGDP) ORNG: 4260000000 ng/kg. [4260.000000 mg/kg] T/E unlistd AT: F03-F06-F08 orl-hmn TDLo: 5700 ug/kg Journal of Neuropsychiatry. (Chicago, IL) V.1-5, 1959-64. For publisher information, see BENPBG. v. 2, p. 205, 1961 (JNEUAY); T/E unlistd orl-rat LD50: 4260 mg/kg Journal of Agricultural and Food Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) V.1- 1953- v. 30, p. 563, 1982 (JAFCAU); F01-L03 orl-cat LDLo: 400 mg/kg American Journal of Pharmacy (1835-1936). (Philadelphia, PA) V.1-108, 1835-1936. v. 80, p. 563, 1909 (AMJPA6); A11-L30-U28 scu-rbt LDLo: 900 mg/kg American Journal of Pharmacy (1835-1936). (Philadelphia, PA) V.1-108, 1835-1936. v. 80, p. 563, 1909 (AMJPA6); A11-L30-U28 scu-gpg LDLo: 2 gm/kg American Journal of Pharmacy (1835-1936). (Philadelphia, PA) V.1-108, 1835-1936. v. 80, p. 563, 1909 (AMJPA6) SL: NTP Carcinogenesis studies, selected, October 2000 Record 551 of 1119 in RTECS (through 2003/06) AN: CY2800000 PN: Benzene, 4-allyl-1,2-(methylenedioxy)- SY: 1,2-Methylenedioxy-4-allylbenzene-; 1,3-Benzodioxole,-5-allyl-; 1-Allyl-3,4-methylenedioxybenzene-; 4-Allyl-1,2-methylenedioxybenzene-; 4-Allylpyrocatechol-formaldehyde-acetal-; 5-(2-Propenyl)-1,3-benzodioxole; 5-Allyl-1,3-benzodioxole-; Allylcatechol-methylene-ether-; Allyldioxybenzene-methylene-ether-; Allylpyrocatechol-methylene-ether-; Benzene,-1,2-methylenedioxy-4-allyl-; RCRA-waste-number-U203-; Rhyuno-oil-; Safrol-; Safrol-glass-; Safrole-; Safrole-MF-; Shikimole-; Shikomol-; m-Allylpyrocatechin-methylene-ether- RN: Current: 94-59-7 BRN: 136380 BHR: 5-19-01-00553 UD: 200210 MF: C10-H10-O2 MW: 162.20 WL: T56 BO DO CHJ G2U1 CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Natural-Product (N); Primary-Irritant (S) ID: skn-rbt 500 mg/24H MOD Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 12, p. 983, 1974 (FCTXAV) ME: mmo-sat 50 ug/plate (+S9) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD-A116-715 (NTIS**); mmo-sat 100 ug/plate (-S9) British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); mmo-esc 5 gm/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 219, 1981 (PMRSDJ); dnr-esc 25 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 873, 1979 (JJIND8); dnd-bcs 20 uL/disc Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 175, 1981 (PMRSDJ); slt-dmg-orl 500 umol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 313, 1985 (PMRSDJ); mmo-smc 21920 ug/L (-S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 271, 1985 (PMRSDJ); mmo-smc 7400 ug/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 257, 1985 (PMRSDJ); dnr-smc 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 502, 1981 (PMRSDJ); mrc-smc 175 ppm JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 901, 1979 (JJIND8); sln-smc 25 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); sln-asn 5500 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 147, p. 288, 1985 (MUREAV); mmo-hmn-lym 625 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 497, 1985 (PMRSDJ); dnd-hmn-oth 4 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 468, p. 213, 2000 (MUREAV); dns-hmn-hla 10 uL/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 347, 1985 (PMRSDJ); dni-hmn-fbr 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 183, p. 89, 1987 (MUREAV); mtr-rat-orl 450 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 1157, 1980 (CNREA8); dnd-rat-lvr 500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 189, p. 69, 1987 (MUREAV); dna-rat-orl 10 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 19, p. 141, 1998 (CRNGDP); dns-rat-orl 1 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 320, p. 189, 1994 (MUREAV); dns-rat-lvr 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 3010, 1982 (CNREA8); oms-rat-orl 625 mg/kg/5D-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 19, p. 141, 1998 (CRNGDP); bfa-rat-ovr 400 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 143, p. 263, 1985 (MUREAV); cyt-rat-orl 625 mg/kg/5D-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 19, p. 141, 1998 (CRNGDP); sce-rat-orl 100 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 19, p. 141, 1998 (CRNGDP); mmo-mus-lym 54800 ug/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 587, 1985 (PMRSDJ); mmo-mus-emb 250 mg/L (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 639, 1985 (PMRSDJ); mtr-mus-emb 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 659, 1985 (PMRSDJ); dna-mus-ipr 80 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 1613, 1984 (CRNGDP); dnd-mus-lym 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 203, p. 155, 1988 (MUREAV); dni-mus-ipr 640 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 37, p. 67, 1976 (MUREAV); msc-mus-lym 15400 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 580, 1981 (PMRSDJ); hma-mus-sat 5500 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 911, 1979 (JJIND8); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); mtr-ham-emb 10 ppm International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 19, p. 642, 1977 (IJCNAW); dnd-ham-ovr 1 mmol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 367, 1985 (PMRSDJ); oms-ham-ovr 162 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 359, 1985 (PMRSDJ); cyt-ham-lng 75 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 427, 1985 (PMRSDJ); cyt-ham-ovr 83330 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 443, 1985 (PMRSDJ); sce-ham-ovr 50 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 413, 1985 (PMRSDJ); sce-ham-lng 500 umol/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 469, 1985 (PMRSDJ); mtr-mus-fbr 0.001 pph/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) RE: T01 ipr-mus TDLo: 1 gm/kg (5D male) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 712, 1981 (PMRSDJ) TE: V01-K60-L60 orl-rat TDLo: 200 gm/kg/94W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 37, p. 1883, 1977 (CNREA8); V01-L60 orl-mus TDLo: 22 gm/kg/90W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 4378, 1979 (CNREA8); V02-T65-M61 orl-mus TDLo: 480 mg/kg (12-18D preg) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 4378, 1979 (CNREA8); V02-L60 orl-mus TD :210 gm/kg/52W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 37, p. 1883, 1977 (CNREA8); V01-L60-L61 orl-mus TD :212 gm/kg/1Y-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 1124, 1983 (CNREA8); V01-L60 orl-mus TD :187 gm/kg/56W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 590, 1973 (CNREA8); V01-L60 orl-mus TD :132 gm/kg/81W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 42, p. 1101, 1969 (JNCIAM); V01-L60 orl-mus TD :121 gm/kg/36W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 365, 1981 (JJIND8); V01-L60 orl-mus TD :175 gm/kg/52W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 365, 1981 (JJIND8); V01-L60 orl-mus TD :252 gm/kg/75W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 365, 1981 (JJIND8); V01-L60 orl-mus TD :82602 mg/kg/81W-C Digestion. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.1- 1968- v. 19, p. 42, 1979 (DIGEBW); V02-L60 orl-mus TD :56 gm/kg/52W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 5163, 1983 (CNREA8); V01-L60 orl-rat TD :183 gm/kg/2Y-C Federation Proceedings, Federation of American Societies for Experimental Biology. (Bethesda, MD) V.1-46, 1942-87. v. 20, p. 287, 1961 (FEPRA7) ORNG: 1950000000 ng/kg. [1950.000000 mg/kg] F07 AT: F07 orl-rat LD50: 1950 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 18, 1965 (TXAPA9); F07-F19 orl-mus LD50: 2350 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); F13 scu-mus LD50: 1020 mg/kg Sapporo Igaku Zasshi. Sapporo Medical Journal. (Sapporo Igaku Daigaku, Nishi-17-chome, Minami-1-jo, Chuo-ku, Sapporo 060, Japan) V.3- 1952- v. 3, p. 73, 1952 (SIZSAR); C06-F19-M16 orl-rbt LDLo: 1 gm/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 35, p. 342, 1895 (AEXPBL); T/E unlistd skn-rbt LD50: >5 gm/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 12, p. 983, 1974 (FCTXAV); C06-F07-U28 scu-rbt LDLo: 1 gm/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 35, p. 342, 1895 (AEXPBL); H01-H02 ivn-rbt LDLo: 200 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 35, p. 342, 1895 (AEXPBL) MD: L30-L70 orl-rat TDLo: 74375 ug/kg/85W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 7, p. 307, 1977 (TXCYAC); Z01 orl-mus TDLo: 15 gm/kg/60D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 7, p. 18, 1965 (TXAPA9); V01-L30 scu-mus TDLo: 26.4 mg/kg/4W-I Toxicology and Clinical Pharmacology of Herbal Products Melanie Johns Cupp ed., Humana press, 2000. v. -, p. 247, 2000 (TCPHP*); J60 scu-mus TDLo: 264 mg/kg/4W-I Toxicology and Clinical Pharmacology of Herbal Products Melanie Johns Cupp ed., Humana press, 2000. v. -, p. 247, 2000 (TCPHP*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 10, p. 231, 1976 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 10, p. 231, 1976 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW Israel Journal of Medical Sciences. (POB 1435, Jerusalem 91013, Israel) V.1- 1965- v. 10, p. 416, 1974 (IJMDAI); TOXICOLOGY REVIEW Cancer Treatment Reports. (Washington, DC) V.60-71, 1976-87. For publisher information, see JNCIEQ. v. 60, p. 1171, 1976 (CTRRDO) SR: OEL-FRANCE: Carcinogen, JAN 1993; OEL-UNITED KINGDOM: Carcinogen, SEP 2000 ND: NOHS 1974: HZD 83472; NIS 1; TNF 68; NOS 1; TNE 68; NOES 1983: HZD 83472; NIS 4; TNF 74; NOS 5; TNE 6475; TFE 5761 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive: Host-mediated assay, E coli polA without S9; EPA GENETOX PROGRAM 1988, Positive: E coli polA with S9, S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Negative: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Negative: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Negative: In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Inconclusive: Mammalian micronucleus, Sperm morphology-mouse; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 552 of 1119 in RTECS (through 2003/06) AN: CY5250000 PN: Benzenearsonic-acid,-4-hydroxy-3-nitro- SY: Aklomix-3-; Arsonic acid, (4-hydroxy-3-nitrophenyl)-; Kyselina-4-hydroxy-3-nitrofenylarsonova- (Czech); NCI-C56508-; 3-Nitro-10-; 3-Nitro-20-; 3-Nitro-50-; 3-Nitro-80-; 2-Nitro-1-hydroxybenzene-4-arsonic-acid-; 3-Nitro-4-hydroxybenzenearsonic-acid-; 3-Nitro-4-hydroxyphenylarsonic-acid-; Nitrophenolarsonic-acid-; 4-Hydroxy-3-nitrobenzenearsonic-acid-; 4-Hydroxy-3-nitrophenylarsonic-acid-; NSC-2101-; Ren-O-sal-; Ristat-; Roxarsone- RN: Current: 121-19-7 BRN: 1976533 BHR: 4-16-00-01188 UD: 200210 MF: C6-H6-As-N-O6 MW: 263.05 WL: WNR BQ E-AS-QQO CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M) ME: dnd-rat-lvr 4 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 59, 1996 (MUREAV); msc-mus-lym 400 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*) TE: V03-K60 orl-rat TDLo: 2920 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*); V03-K60 orl-rat TDLo: 4326 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB89216543/AS (NTIS**) ORNG: 81000000 ng/kg. [81.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 81 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*); F18-K30-M05 ipr-rat LD50: 66 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9); T/E unlistd orl-mus LD50: 244 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*); K13-L01-M14 orl-dog LD50: 50 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9); K30-P01 orl-ckn LD50: 110 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9); F07-K30-L01 ipr-ckn LD50: 34 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9); K30-P01 orl-trk LD50: 61 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9) MD: F15-Z01 orl-rat TDLo: 2647 mg/kg/13W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9); Z01 orl-rat TDLo: 11200 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*); Z01 orl-mus TDLo: 1680 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*); J03-L70-Z01 orl-mus TDLo: 8736 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-345, 1989 (NTPTR*); B30-C06-F12 orl-pig TDLo: 5625 mg/kg/30D-C Veterinary Pathology. (Waverly Press, Inc., POB 64025, Baltimore, MD 21264) V.8- 1971- v. 23, p. 454, 1986 (VTPHAK); M70-P01-Z01 orl-ckn TDLo: 3625 mg/kg/13W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 5, p. 507, 1963 (TXAPA9); C18-U01-Z01 orl-trk TDLo: 2019 mg/kg/36D-C Research in Veterinary Science. (British Veterinary Assoc., 7 Mansfield St., London W1M OAT, UK) V.1- 1960- v. 16, p. 336, 1974 (RVTSA9) TR: TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 As,-,1977 (85DHAX) SR: MSHA STANDARD-air: TWA 0.5 mg(As)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 16, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 0.5 mg(As)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.5 mg(As)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.5 mg(As)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.5 mg(As)/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 0.2 mg(As)/m3, JAN 1993; OEL-AUSTRALIA: TWA 0.05 mg(As)/m3, Carcinogen, JAN 1993; OEL-BELGIUM: TWA 0.2 mg(As)/m3, JAN 1993; OEL-FINLAND: Carcinogen, JAN 1999; OEL-FRANCE: VME 0.2 mg(As)/m3, JAN 1993; OEL-HUNGARY: STEL 0.5 mg(As)/m3, Carcinogen, JAN 1993; OEL-INDIA: TWA 0.2 mg(As)/m3, JAN 1993; OEL-THE PHILIPPINES: TWA 0.5 mg(As)/m3, JAN 1993; OEL-POLAND: MAC(TWA) 0.3 mg(As)/m3, JAN 1993; OEL-SWEDEN: NGV 0.03 mg(As)/m3, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.1 mg(As)/m3, Carcinogen, JAN 1999; OEL-THAILAND: TWA 0.5 mg(As)/m3, JAN 1993; OEL-TURKEY: TWA 0.5 mg(As)/m3, JAN 1993; OEL-UNITED KINGDOM: LTEL 0.2 mg(As)/m3, JAN 1993; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NOHS 1974: HZD M0637; NIS 1; TNF 21; NOS 2; TNE 124; NOES 1983: HZD M0637; NIS 1; TNF 210; NOS 6; TNE 3230 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: mouse Record 553 of 1119 in RTECS (through 2003/06) AN: CZ0175000 PN: Benzene,-chloro- SY: Benzene-chloride-; Chloorbenzeen- (Dutch); Chlorbenzene-; Chlorbenzol-; Chlorobenzen- (Polish); Chlorobenzene-; Chlorobenzene- (ACGIH:OSHA); Chlorobenzenu- (Czech); Clorobenzene- (Italian); MCB-; Monochloorbenzeen- (Dutch); Monochlorbenzene-; Monochlorbenzol- (German); Monochlorobenzene-; Monochlorobenzene- (OSHA); Monoclorobenzene- (Italian); NCI-C54886-; Phenyl-chloride-; Tetrosin-SP- RN: Current: 108-90-7 UD: 200302 MF: C6-H5-Cl MW: 112.56 WL: GR CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mrc-smc 1000 ppm National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB84-138973 (NTIS**); mnt-mus-ipr 225 mg/kg/24H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 111, 1987 (MUTAEX); mmo-mus-lym 70 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); cyt-mus-ipr 1 gm/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 25, p. 302, 1995 (EMMUEG); msc-mus-lym 100 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); sce-ham-ovr 300 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-rat-ihl 500 ug/L/275D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 20, 1994 (VCVGK*) RE: T46 ihl-rat TCLo: 75 ppm/6H (6-15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 76, p. 365, 1984 (TXAPA9); T51 ihl-rat TCLo: 210 ppm/6H (6-15D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 76, p. 365, 1984 (TXAPA9); T25 ihl-rbt TCLo: 590 ppm/6H (6-18D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 76, p. 365, 1984 (TXAPA9); T46 ihl-rbt TCLo: 10 ppm/6H (6-18D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 76, p. 365, 1984 (TXAPA9) TE: V02-L60-P60 orl-rat TDLo: 61800 mg/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-261, 1985 (NTPTR*); V02-L60 orl-rat TDLo: 61800 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-144714/AS (NTIS**) ORNG: 1110000000 ng/kg. [1110.000000 mg/kg] F07-F11-F19 AT: F07-F11-F19 orl-rat LD50: 1110 mg/kg Science Reports of the Research Institutes, Tohoku University, Series C: Medicine. (Tohoku University, Research Institute for Tuberculosis and Cancer, 4-1 Seiryo-machi, Sendai, Japan) V.1- 1949- v. 36(1-4), p. 10, 1989 (SRTCAC); T/E unlistd ihl-rat LC50: 2965 ppm National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521601 (NTIS**); T/E unlistd ipr-rat LD50: 1655 mg/kg Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 5, p. 105, 1985 (FAATDF); T/E unlistd orl-mus LD50: 2300 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,34,1982 (85GMAT); T/E unlistd ihl-mus LCLo: 15 gm/m3 Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 20(8), p. 19, 1955 (GISAAA); T/E unlistd ipr-mus LD50: 515 mg/kg Pharmacologist. (American Soc. for Pharmacology and Experimental Therapeutics, 9650 Rockville Pike, Bethesda, MD 20014) V.1- 1959- v. 10, p. 172, 1968 (PHMCAA); T/E unlistd orl-rbt LD50: 2250 mg/kg "Patty's Industrial Hygiene and Toxicology," 3rd rev. ed., Clayton, G.D., and F.E. Clayton, eds., New York, John Wiley and Sons, Inc., 1978-82. Vol. 3 originally pub. in 1979: pub. as 2nd rev. ed. in 1985. 2B,3603,1981 (38MKAJ); T/E unlistd skn-rbt LD :>2200 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD-A180-198 (NTIS**); T/E unlistd orl-gpg LD50: 2250 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,34,1982 (85GMAT); T/E unlistd skn-gpg LD :>11 gm/kg "Documentation of the Threshold Limit Values and Biological Exposure Indices," 5th ed., Cincinnati, OH, American Conference of Governmental Industrial Hygienists, Inc., 1986 6,271,1991 (85INA8); F18-L03-M30 ipr-gpg LDLo: 4100 mg/kg Revue Medicale de la Suisse Romande. (Societe Medicale de La Suisse Romande, 2 rue Bellefontaine, 1003 Lausanne, Switzerland) V.1- 1881- v. 16, p. 449, 1896 (RMSRA6); T/E unlistd orl-mam LD50: 2300 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 32(10), p. 25, 1988 (GTPZAB); T/E unlistd ihl-mam LC50: 10 gm/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 32(10), p. 25, 1988 (GTPZAB); T/E unlistd unr-mam LD50: 2300 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 51(5), p. 61, 1986 (GISAAA); L30-M03-Y15 ipr-rat TDLo: 2 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 111, p. 69, 1991 (TXAPA9); L30 unr-rat LDLo: 4000 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1984 (VCVGK*); L30 unr-rat LD50: 2950 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1984 (VCVGK*); L30 unr-rbt LD50: 2830 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1984 (VCVGK*); F15-P28-Y21 unr-rat TDLo: 0.026 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1984 (VCVGK*); L30-Y36 orl-ckn TDLo: 800 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1984 (VCVGK*) MD: F07-Z01 orl-rat TDLo: 14 gm/kg/14D-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 15, p. 745, 1985 (JTEHD6); L70-Y17-Z01 orl-rat TDLo: 32500 mg/kg/13W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 15, p. 745, 1985 (JTEHD6); P08-P16-P71 orl-rat TDLo: 27300 ug/kg/39W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 33(10), p. 15, 1968 (GISAAA); A11-Y01-Y39 ihl-rat TCLo: 1 mg/m3/60D-C Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 30(3), p. 8, 1965 (GISAAA); L70-P30-Y15 ihl-rat TCLo: 250 ppm/7H/24W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555046 (NTIS**); L01-M16-Z01 orl-mus TDLo: 16250 mg/kg/13W-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 15, p. 745, 1985 (JTEHD6); P72-Y15-Z01 orl-dog TDLo: 17712 mg/kg/93D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 19, p. 393, 1971 (TXAPA9); K05-L02-M03 orl-rbt TDLo: 441 mg/kg/63W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 20(7), p. 7, 1955 (GISAAA); L70-P28-Y15 ihl-rbt TCLo: 250 ppm/7H/24W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0555046 (NTIS**); K05-L02-M03 orl-gpg TDLo: 441 mg/kg/63W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 20(7), p. 7, 1955 (GISAAA); L03-P20-U01 ihl-rbt TCLo: 2.5 mg/m3/3W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1994 (VCVGK*); L01-Z01 unr-mus TDLo: 7000 mg/kg/2W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 19, 1994 (VCVGK*); L01-M03-Z01 orl-rat TDLo: 22750 mg/kg/13W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 20, 1994 (VCVGK*); L01-M03-Z01 orl-mus TDLo: 22750 mg/kg/13W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 20, 1994 (VCVGK*); N12 ihl-rbt TCLo: 5 mg/m3/213D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 20, 1994 (VCVGK*); K30-K60 orl-rat TDLo: 1170 mg/kg/31W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 20, 1994 (VCVGK*) TR: ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: MSHA STANDARD-air: TWA 75 ppm (350 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 49, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 75 ppm (350 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 75 ppm (350 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 75 ppm (350 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 75 ppm (350 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 1 ppm, JAN 1993; OEL-AUSTRALIA: TWA 75 ppm (350 mg/m3), JAN 1993; OEL-AUSTRIA: MAK 50 ppm (230 mg/m3), JAN 1999; OEL-BELGIUM: TWA 75 ppm (345 mg/m3), JAN 1993; OEL-DENMARK: TWA 10 ppm (46 mg/m3), JAN 1999; OEL-FINLAND: TWA 50 ppm (230 mg/m3), STEL 75 ppm (345 mg/m3), JAN 1999; OEL-FRANCE: VME 10 ppm, JAN 1999; OEL-GERMANY: MAK 50 ppm (230 mg/m3), JAN 1999; OEL-INDIA: TWA 75 ppm (350 mg/m3), JAN 1993; OEL-JAPAN: OEL 10 ppm (46 mg/m3), JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 10 ppm (46 mg/m3), JAN 1999; OEL-NORWAY: TWA 25 ppm (115 mg/m3), JAN 1999; OEL-POLAND: MAC(TWA) 50 mg/m3, STEL 150 mg/m3, JAN 1999; OEL-SWITZERLAND: MAK-W 50 ppm (230 mg/m3), KZG-W 100 ppm (460 mg/m3), JAN 1999; OEL-TURKEY: TWA 75 ppm (350 mg/m3), JAN 1993; OEL-UNITED KINGDOM: LTEL 50 ppm (230 mg/m3), JAN 1993; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NOHS 1974: HZD 18190; NIS 36; TNF 1965; NOS 46; TNE 46734; NOES 1983: HZD 18190; NIS 24; TNF 912; NOS 35; TNE 18050; TFE 3881 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/91/180505/AS); EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Hydrocarbons, halogenated, 1003; NTP Carcinogenesis Studies (gavage), some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-261, 1985 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: rat; NCI Carcinogenesis Studies (gavage), no evidence: mouse Record 554 of 1119 in RTECS (through 2003/06) AN: CZ0875000 PN: Benzene,-1-chloro-2-nitro- SY: o-Nitrochlorobenzene-; 1-Nitro-2-chlorobenzene-; Chloro-o-nitrobenzene-; o-Chloronitrobenzene-; 1-Chloro-2-nitrobenzene-; 2-Chloro-1-nitrobenzene-; 2-Chloronitrobenzene-; ONCB- RN: Current: 88-73-3 UD: 200302 MF: C6-H4-Cl-N-O2 MW: 157.56 WL: WNR BG CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 205 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 116, p. 217, 1983 (MUREAV); mmo-sat 100 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM) RE: T01 ihl-rat TCLo: 18 ppm/6H (13W male) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); T01 ihl-mus TCLo: 4500 ppb/6H (13W male) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); T81 orl-mus TDLo: 16800 mg/kg (105D male/105D pre) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-187608/AS (NTIS**) TE: V02-K60-N60 orl-rat TDLo: 22 gm/kg/78W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(2), p. 325, 1978 (JEPTDQ); V01-L60 orl-mus TDLo: 140 gm/kg/78W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(2), p. 325, 1978 (JEPTDQ); V01-L60 orl-mus TD :280 gm/kg/78W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(2), p. 325, 1978 (JEPTDQ) ORNG: 268000000 ng/kg. [268.000000 mg/kg] T/E unlistd SRNG: 400000000 ng/kg. [400.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 268 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB214-270 (NTIS**); T/E unlistd orl-mus LD50: 135 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB214-270 (NTIS**); T/E unlistd orl-rbt LD50: 280 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,92,1982 (85GMAT); T/E unlistd skn-rbt LD50: 400 mg/kg Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 7, p. 609, 1986 (FAATDF) MD: L70-N73-P24 ihl-rat TCLo: 30 mg/m3/6H/4W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 7, p. 609, 1986 (FAATDF); L70-P24-P71 ihl-rat TCLo: 4500 ppb/6H/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); P23-P24-P71 ihl-rat TCLo: 530 mg/m3/6H/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0546562 (NTIS**); L02-M70-N73 ihl-mus TCLo: 18 ppm/6H/2W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); L70-M70 ihl-mus TCLo: 2300 ppb/6H/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); U01-N73-P24 orl-mus TDLo: 16800 mg/kg/105D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-187608/AS (NTIS**); P28-U01 orl-mus TDLo: 16800 mg/kg/27W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-187608/AS (NTIS**) TR: IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 263, 1996 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 263, 1996 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 263, 1996 (IMEMDT) SR: OEL-AUSTRIA: Suspected Carcinogen, JAN 1999; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-POLAND: MAC(TWA) 1 mg/m3, MAC(STEL) 3 mg/m3, JAN 1999; OEL-RUSSIA: STEL 1 mg/m3, Skin, JAN 1993 ND: NOES 1983: HZD X4011; NIS 3; TNF 42; NOS 5; TNE 2897; TFE 662 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA Section 8(e) Risk Notification, 8EHQ-0892-9198; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Toxicity studies, RPT# TOX-33, October 2000 Record 555 of 1119 in RTECS (through 2003/06) AN: CZ1050000 PN: Benzene,-1-chloro-4-nitro- SY: 1-Chloor-4-nitrobenzeen- (Dutch); 1-Chlor-4-nitrobenzol- (German); 1-Chloro-4-nitrobenzene-; 1-Cloro-4-nitrobenzene- (Italian); 4-Chloro-1-nitrobenzene-; 4-Chloronitrobenzene-; 4-Nitro-1-chlorobenzene-; PNCB-; p-Chloronitrobenzene-; p-Nitrochloorbenzeen- (Dutch); p-Nitrochlorobenzene-; p-Nitrochlorobenzene- (ACGIH:OSHA); p-Nitrochlorobenzol- (German); p-Nitroclorobenzene- (Italian) RN: Current: 100-00-5 UD: 200305 MF: C6-H4-Cl-N-O2 MW: 157.56 WL: WNR DG CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 819 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 116, p. 217, 1983 (MUREAV); mmo-sat 100 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); dnd-rat-lvr 5 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 131, p. 215, 1984 (MUREAV); dnd-mus-ipr 60 mg/kg Bolletino della Societe Italiana di Biologia Sperimentale. (Casa Editrice Idelson, Via A. de Gasperi, 55, 80133 Naples, Italy) V.2- 1927- v. 56, p. 1680, 1980 (BSIBAC); cyt-ham-ovr 600 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ham-ovr 250 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) RE: T01 ihl-rat TCLo: 24 ppm/6H (13W male) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); T81 orl-mus TDLo: 4.4 gm/kg (7D male/7D pre/21D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**); T72-T75-T81 orl-mus TDLo: 58 gm/kg (15W male/15W pre/21D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**); T72-T81 orl-mus TDLo: 250 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**); T53 orl-mus TDLo: 250 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**); T48-T51 orl-mus TDLo: 250 mg/kg (multigenerations) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**) TE: V01-H60-L60 orl-mus TDLo: 194 gm/kg/78W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(2), p. 325, 1978 (JEPTDQ); V01-H60-L60 orl-mus TD :390 gm/kg/78W-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(2), p. 325, 1978 (JEPTDQ) ORNG: 420000000 ng/kg. [420.000000 mg/kg] F07-L03-P24 SRNG: 3040000000 ng/kg. [3040.000000 mg/kg] T/E unlistd SKNG: 16000000000 ng/kg. [16000.000000 mg/kg] F15-M03-P24 AT: F07-L03-P24 orl-rat LD50: 420 mg/kg Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 17, p. 217, 1959 (AGGHAR); D07-D26-J24 ihl-rat LCLo: 16100 mg/m3/4H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0571644 (NTIS**); F15-M03-P24 skn-rat LD50: 16 gm/kg Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 17, p. 217, 1959 (AGGHAR); F12-F19-P24 ipr-rat LD50: 420 mg/kg Archiv fuer Gewerbepathologie und Gewerbehygiene. (Berlin, Ger.) V.1-18, 1930-61. For publisher information, see IAEHDW. v. 17, p. 217, 1959 (AGGHAR); T/E unlistd orl-mus LD50: 440 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,92,1982 (85GMAT); T/E unlistd ihl-cat LCLo: 25 ppm/7H Industrial Medicine and Surgery. (Northbrook, IL) V.18-42, 1949-73. For publisher information, see IOHSA5. v. 19, p. 317, 1950 (IMSUAI); T/E unlistd skn-rbt LD50: 3040 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*) MD: L02-U01-Z01 orl-rat TDLo: 1350 mg/kg/2W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0533716 (NTIS**); P24-P27-N73 orl-rat TDLo: 3640 mg/kg/2Y-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0526382 (NTIS**); N73-P24-P71 ihl-rat TCLo: 46 mg/m3/6H/4W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 6, p. 618, 1986 (FAATDF); L30-P24-P73 ihl-rat TCLo: 3 ppm/6H/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); N73-P24-U01 orl-rat TDLo: 1400 mg/kg/4W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0546099 (NTIS**); P30 scu-rat TDLo: 1 gm/kg/10D-I Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 35, p. 108, 1972 (FATOAO); L70-M70-P27 ihl-mus TCLo: 12 ppm/6H/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-93-3382 (NTPTR*); Z01 orl-mus TDLo: 8960 mg/kg/14D-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**); J24 orl-mus TDLo: 4480 mg/kg/14D-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**); J24 orl-mus TDLo: 21000 mg/kg/12W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #RACB19077 (NTIS**) TR: ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.1 ppm (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 263, 1996 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 263, 1996 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 65, p. 263, 1996 (IMEMDT) SR: MSHA STANDARD-air: TWA 1 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 184, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 1 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 1 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 1 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 1 mg/m3 (skin) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 0.1 ppm (0.6 mg/m3), Skin, JAN 1993; OEL-AUSTRIA: Suspected Carcinogen, JAN 1999; OEL-BELGIUM: TWA 0.1 ppm (0.64 mg/m3), Skin, JAN 1993; OEL-DENMARK: TWA 0.1 ppm (0.64 mg/m3), Skin, JAN 1999; OEL-FINLAND: TWA 1 mg/m3, STEL 3 mg/m3, Skin, JAN 1999; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-HUNGARY: TWA 1 mg/m3, STEL 2 mg/m3, Skin, JAN 1993; OEL-JAPAN: OEL 0.1 ppm (0.64 mg/m3), Skin, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 1 mg/m3, Skin, JAN 1999; OEL-NORWAY: TWA 1 mg/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 1 mg/m3, Skin, JAN 1993; OEL-POLAND: MAC(TWA) 1 mg/m3, MAC(STEL) 3 mg/m3, JAN 1999; OEL-RUSSIA: TWA 0.1 ppm, STEL 1 mg/m3, Skin, JAN 1993; OEL-SWITZERLAND: MAK-W 1 mg/m3, KZG-W 2 mg/m3, Skin, JAN 1999; OEL-UNITED KINGDOM: TWA 1 mg/m3, STEL 2 mg/m3, Skin, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO p-NITROCHLOROBENZENE-air: CA lowest feasible conc. (Sk) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD 50775; NIS 4; TNF 30; NOS 20; TNE 2948; TFE 401 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA Section 8(e) Risk Notification, 8EHQ-0892-9003, 8EHQ-0892-9298; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Nitrobenzenes, 2005; NTP Toxicity studies, RPT# TOX-33, October 2000 Record 556 of 1119 in RTECS (through 2003/06) AN: CZ4200000 PN: 1,2-Benzenedicarboxylic-acid,-di-2-propenyl-ester- SY: Dapon-35-; Dapon-R-; Diallyl-phthalate-; Diallylester-kyseliny-ftalove- (Czech); Diallylphthalate-; NCI-C50657-; Phthalic-acid,-diallyl-ester-; o-Phthalic-acid,-diallyl-ester- RN: Current: 131-17-9 BRN: 1880877 BHR: 4-09-00-03188 UD: 200210 MF: C14-H14-O4 MW: 246.28 WL: 1U2OVR BVO2U1 CC: Tumorigen (C); Mutagen (M); Primary-Irritant (S) ID: skn-rbt 500 mg MOD National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521089 (NTIS**); eye-rbt 500 mg MLD American Journal of Ophthalmology. (Ophthalmic Pub. Co., 435 N. Michigan Ave., Suite 1415, Chicago, IL 60611) Series 3: V.1- 1918- v. 29, p. 1363, 1946 (AJOPAA) ME: mmo-mus-lym 67200 ug/L (+S9) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-mus-ipr 300 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 25, p. 302, 1995 (EMMUEG); msc-mus-lym 67200 ug/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); cyt-ham-ovr 200 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); sce-ham-ovr 160 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS) TE: V01-P61 orl-rat TDLo: 52 gm/kg/2Y-I EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 65, p. 271, 1986 (EVHPAZ); V01-P61 orl-mus TDLo: 156 gm/kg/2Y-I EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 65, p. 271, 1986 (EVHPAZ); V01-P61 orl-rat TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-203742/AS (NTIS**); V01-K60-P62 orl-mus TDLo: 154500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-200824 (NTIS**); V02-K60 orl-mus TDLo: 154500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-200824 (NTIS**) ORNG: 656000000 ng/kg. [656.000000 mg/kg] F07 SRNG: 3300000000 ng/kg. [3300.000000 mg/kg] T/E unlistd AT: F07 orl-rat LD50: 656 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-284, 1985 (NTPTR*); D35-J22-K01 ihl-rat LC50: 5200 mg/m3/1H National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521092 (NTIS**); T/E unlistd orl-mus LDLo: 681 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-242, 1983 (NTPTR*); T/E unlistd orl-dog LDLo: 800 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521092 (NTIS**); T/E unlistd orl-rbt LD50: 1700 mg/kg "Industrial Hygiene and Toxicology," 2nd ed., Patty, F.A., ed., New York, John Wiley and Sons, Inc., 1958-63 2,1904,1963 (14CYAT); T/E unlistd skn-rbt LD50: 3300 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521092 (NTIS**); J30-L01 scu-rbt LDLo: 1 gm/kg Federation Proceedings, Federation of American Societies for Experimental Biology. (Bethesda, MD) V.1-46, 1942-87. v. 5, p. 191, 1946 (FEPRA7) MD: J30-K30-Z01 orl-rat TDLo: 5600 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-284, 1985 (NTPTR*); L04-Z01 orl-rat TDLo: 26 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-284, 1985 (NTPTR*); Z01 orl-mus TDLo: 5600 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-242, 1983 (NTPTR*) TR: TOXICOLOGY REVIEW Residue Reviews. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1962- v. 54, p. 1, 1975 (RREVAH); TOXICOLOGY REVIEW EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 4, p. 3, 1973 (EVHPAZ) SR: OEL-GERMANY: No MAK Established, JAN 1999; OEL-RUSSIA: STEL 1 mg/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 5 mg/m3, SEP 2000 ND: NOHS 1974: HZD 23180; NIS 15; TNF 390; NOS 27; TNE 8596; NOES 1983: HZD 23180; NIS 11; TNF 484; NOS 18; TNE 8784; TFE 2027 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse, rat; NTP Carcinogenesis Studies (gavage), inadequate studies: mouse, rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-242, 1983 (NTPTR*) Record 557 of 1119 in RTECS (through 2003/06) AN: CZ4500000 PN: Benzene,-o-dichloro- SY: NCI-C54944-; Special-termite-fluid-; Benzene,-1,2-dichloro-; Chloroben-; o-Dichlor-benzol-; o-Dichlorbenzene-; o-Dichlorobenzene-; o-Dichlorobenzene- (ACGIH:OSHA); 1,2-Dichlorobenzene-; Dilatin-DB-; Dizene-; Dowtherm-E-; Orthodichlorobenzene-; Orthodichlorobenzol-; Termitkil- RN: Current: 95-50-1 UD: 200302 MF: C6-H4-Cl2 MW: 147.00 WL: GR BG CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Primary-Irritant (S) ID: eye-rbt 100 mg/30S rinse MLD AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 17, p. 180, 1958 (AMIHAB) ME: mrc-smc 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 413, p. 205, 1998 (MUREAV); spm-rat-ipr 250 mg/kg Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 4(2), p. 224, 1985 (JACTDZ); mnt-mus-ipr 187 mg/kg/24H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 111, 1987 (MUTAEX); mmo-mus-lym 6500 ug/L (+S9) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS); sce-ham-ovr 59 mg/L Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS) RE: T46 ihl-rat TCLo: 200 ppm/6H (6-15D preg) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 5, p. 190, 1985 (FAATDF); T19-T35 ihl-rat TCLo: 500 ppm/6H (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0535228 (NTIS**); T01 ipr-rat TDLo: 50 mg/kg (1D male) Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 4(1), p. 224, 1985 (JACTDZ) TE: V02-N61 orl-rat TDLo: 30900 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB86-144888/AS (NTIS**) ORNG: 500000000 ng/kg. [500.000000 mg/kg] T/E unlistd IHNG: 8150000000 ng/m3/4H. [8150.000000 mg/m3/4H] C08-F01-F23 AT: T/E unlistd orl-rat LD50: 500 mg/kg World Review of Pest Control. (London, UK) V.1-10, 1962-71. Discontinued. v. 9, p. 119, 1970 (WRPCA2); F01-L02-D17 ihl-rat LCLo: 821 ppm/7H AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 17, p. 180, 1958 (AMIHAB); T/E unlistd ipr-rat LD50: 840 mg/kg Medycyna Pracy. Industrial Medicine. (Ars-Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1950- v. 20, p. 519, 1969 (MEPAAX); T/E unlistd scu-rat LD50: 5 gm/kg Office of Toxic Substances Report. (U.S. Environmental Protection Agency, Office of Toxic Substances, 401 M St., SW, Washington, DC 20460) OTS 205976 (TSCAT*); T/E unlistd orl-mus LD50: 4386 mg/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 32, p. 471, 1981 (YKYUA6); T/E unlistd ipr-mus LD50: 1228 mg/kg Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 111, 1987 (MUTAEX); T/E unlistd ivn-mus LDLo: 400 mg/kg Journal of Pathology and Bacteriology. (London, UK) V.1-96, 1892-1968. For publisher information, see JPTLAS. v. 44, p. 281, 1937 (JPBAA7); T/E unlistd orl-rbt LD50: 500 mg/kg "Agricultural Chemicals," Thomson, W.T., 4 vols., Fresno, CA, Thomson Publications, 1976/77 revision 3,32,1976/1977 (85ARAE); T/E unlistd skn-rbt LD50: >10 gm/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0521597 (NTIS**); T/E unlistd ivn-rbt LDLo: 250 mg/kg Journal of Pathology and Bacteriology. (London, UK) V.1-96, 1892-1968. For publisher information, see JPTLAS. v. 44, p. 281, 1937 (JPBAA7); T/E unlistd orl-gpg LDLo: 2 gm/kg "Industrial Hygiene and Toxicology," 2nd ed., Patty, F.A., ed., New York, John Wiley and Sons, Inc., 1958-63 2,1336,1963 (14CYAT); L01 ihl-gpg LCLo: 800 ppm/24H Journal of Pathology and Bacteriology. (London, UK) V.1-96, 1892-1968. For publisher information, see JPTLAS. v. 44, p. 281, 1937 (JPBAA7); C08-F01-F23 ihl-rat LC50: 8150 mg/m3/4H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 24, 1984 (VCVGK*); T/E unlistd ipr-rat TDLo: 735 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 24, 1984 (VCVGK*) MD: M16-P15-P71 orl-rat TDLo: 27300 ug/kg/39W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 33(10), p. 15, 1968 (GISAAA); L70-N73-P72 orl-rat TDLo: 3 gm/kg/10D-I Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 14, p. 83, 1991 (DCTODJ); L70-N73-P71 orl-rat TDLo: 32500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-255, 1985 (NTPTR*); L03-Z01 orl-mus TDLo: 7 gm/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-255, 1985 (NTPTR*); L70-N73 orl-mus TDLo: 32500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-255, 1985 (NTPTR*); L30 ihl-rat TCLo: 290 mg/m3/7H/26W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 24, 1994 (VCVGK*); A30-P20 ihl-rat TCLo: 200 mg/m3/4H/17W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 24, 1994 (VCVGK*) TR: ACGIH TLV-TWA 25 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 50 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 25 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 7, p. 231, 1974 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 7, p. 231, 1974 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 213, 1982 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 213, 1982 (IMEMDT); IARC Cancer Review: Animal No Cancer Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 223, 1999 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 223, 1999 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 223, 1999 (IMEMDT) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD: air-CL 50 ppm (300 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 76, 1971 (DTLVS*); OSHA PEL (Gen Indu): CL 50 ppm (300 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): CL 50 ppm (300 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): CL 50 ppm (300 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): CL 50 ppm (300 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 50 ppm (300 mg/m3), JAN 1993; OEL-AUSTRIA: MAK 50 ppm (300 mg/m3), Skin, JAN 1999; OEL-BELGIUM: STEL 50 ppm (301 mg/m3), Skin, JAN 1993; OEL-FINLAND: TWA 50 ppm (300 mg/m3), STEL 75 ppm (450 mg/m3), Skin, JAN 1999; OEL-FRANCE: VLE 50 ppm (300 mg/m3), JAN 1999; OEL-GERMANY: MAK 50 ppm (300 mg/m3), Skin, JAN 1999; OEL-HUNGARY: TWA 50 mg/m3, STEL 100 mg/m3, Skin, JAN 1993; OEL-JAPAN: STEL 25 ppm (150 mg/m3), JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 25 ppm (150 mg/m3), MAC-K 50 ppm (301 mg/m3), JAN 1999; OEL-NORWAY: TWA 25 ppm (150 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 50 ppm (300 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 20 mg/m3, MAC(CEILING) 300 mg/m3, JAN 1999; OEL-RUSSIA: STEL 50 mg/m3, JAN 1993; OEL-SWEDEN: CEILING 50 ppm (300 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 50 ppm (300 mg/m3), KZG-W 100 ppm (600 mg/m3), JAN 1999; OEL-THAILAND: TWA 50 ppm (300 mg/m3), JAN 1993; OEL-TURKEY: TWA 50 ppm (300 mg/m3), JAN 1993; OEL-UNITED KINGDOM: STEL 50 ppm (306 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO o-DICHLOROBENZENE-air: CL 50 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 24003; NIS 83; TNF 8838; NOS 69; TNE 72149; NOES 1983: HZD 24003; NIS 59; TNF 10577; NOS 59; TNE 92246; TFE 12686 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Hydrocarbons, halogenated, 1003; NIOSH Analytical Method, 1996: Volatile organic compound, 2549; NCI Carcinogenesis Studies (gavage), no evidence: mouse, rat Record 558 of 1119 in RTECS (through 2003/06) AN: CZ4550000 PN: Benzene,-p-dichloro- SY: 1,4-Dichloorbenzeen- (Dutch); 1,4-Dichlor-benzol- (German); 1,4-Dichlorobenzene-; 1,4-Diclorobenzene- (Italian); Di-chloricide-; Evola-; Globol-; NCI-C54955-; PDB-; PDCB-; Para-crystals-; Paracide-; Paradi-; Paradichlorbenzol- (German); Paradichlorobenzene-; Paradichlorobenzol-; Paradow-; Paramoth-; Paranuggets-; Parazene-; Persia-perazol-; RCRA-waste-number-U070-; RCRA-waste-number-U071-; RCRA-waste-number-U072-; Santochlor-; p-Chlorophenyl-chloride-; p-Dichloorbenzeen- (Dutch); p-Dichlorbenzol- (German); p-Dichlorobenzene-; p-Dichlorobenzene- (ACGIH:OSHA); p-Dichlorobenzol-; p-Diclorobenzene- (Italian); para-Chlorophenyl-chloride-; para-Dichlorobenzene- RN: Current: 106-46-7 UD: 200305 MF: C6-H4-Cl2 MW: 147.00 WL: GR DG CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: eye-hmn 80 ppm AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 138, 1956 (AMIHAB) ME: mrc-smc 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 413, p. 205, 1998 (MUREAV); mmo-asn 200 mg/L (-S9) Canadian Journal of Microbiology. (National Research Council of Canada, Publication Sales and Distribution, Ottawa ON K1A OR6, Canada) V.1- 1954- v. 16, p. 369, 1970 (CJMIAZ); sce-hmn-lym 100 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 263, p. 57, 1991 (MUREAV); spm-rat-ipr 800 mg/kg Advances in Contraceptive Delivery Systems. (Reproductive Health Center, 78 Surfsong Rd., Kiawah Island, SC 29455) V.1- 1985- v. 2, p. 248, 1985 (ACDSEL); mnt-mus-ipr 355 mg/kg/24H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 111, 1987 (MUTAEX); dnd-mus-ipr 2 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 391, p. 201, 1997 (MUREAV); oms-mus-orl 750 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV) RE: T46 orl-rat TDLo: 7500 mg/kg (6-15D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 37, p. 164, 1986 (BECTA6); T34 orl-rat TDLo: 10 gm/kg (6-15D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 37, p. 164, 1986 (BECTA6); T47 ihl-rbt TCLo: 800 ppm/6H (6-18D preg) Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 5, p. 190, 1985 (FAATDF) TE: V01-M61 orl-rat TDLo: 155 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-319, 1987 (NTPTR*); V01-L60 orl-mus TDLo: 155 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-319, 1987 (NTPTR*); V01-M61 orl-rat TDLo: 77250 mg/kg/13W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-208617/AS (NTIS**); V01-L60 orl-mus TDLo: 309000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-208617/AS (NTIS**); V03-N61 orl-mus TDLo: 309000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB87-208617/AS (NTIS**) ORNG: 500000000 ng/kg. [500.000000 mg/kg] T/E unlistd SKNG: 2000000000 ng/kg. [2000.000000 mg/kg] T/E unlistd IHNG: 5000000000 ng/m3/4H. [5000.000000 mg/m3/4H] T/E unlistd AT: D35-J30-K12 orl-hmn TDLo: 300 mg/kg Pesticide Chemicals Official Compendium, Association of the American Pesticide Control Officials, Inc., 1966. (Topeka, KS) v. -, p. 851, 1966 (PCOC**); T/E unlistd orl-hmn LDLo: 857 mg/kg "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,210,1969 (34ZIAG); T/E unlistd unr-hmn LDLo: 357 mg/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 31, p. 1499, 1980 (YKYUA6); T/E unlistd unr-man LDLo: 221 mg/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); T/E unlistd orl-rat LD50: 500 mg/kg World Review of Pest Control. (London, UK) V.1-10, 1962-71. Discontinued. v. 9, p. 119, 1970 (WRPCA2); T/E unlistd ipr-rat LD50: 2562 mg/kg Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. v. 38, p. 124, 1949 (JAPMA8); T/E unlistd orl-mus LD50: 2950 mg/kg Guide to the Chemicals Used in Crop Protection. (Information Canada, 171 Slater St., Ottawa, Ont., Canada) v. 6, p. 183, 1973 (GUCHAZ); T/E unlistd ipr-mus LD50: 2 gm/kg Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 111, 1987 (MUTAEX); F11 scu-mus LD50: 5145 mg/kg Toho Igakkai Zasshi. Journal of Medical Society of Toho University. (Toho Daigaku Igakkai, 21-16, Omori-nishi, 5-chome, Ota-ku, Tokyo 143, Japan) V.1- 1954- v. 20, p. 772, 1973 (TOIZAG); F01 ihl-cat LCLo: 37 gm/m3/30M Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 38, p. 1045, 1987 (YKYUA6); T/E unlistd orl-rbt LD50: 2830 mg/kg Yakkyoku. Pharmacy. (Nanzando, 4-1-11, Yushima, Bunkyo-ku, Tokyo, Japan) V.1- 1950- v. 29, p. 453, 1978 (YKYUA6); T/E unlistd skn-rbt LD50: >2 gm/kg Special Publication of the Entomological Society of America. (4603 Calvert Rd., College Park, MD 20740) v. 78-1, p. 18, 1978 (SPEADM); T/E unlistd orl-gpg LDLo: 2800 mg/kg AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 138, 1956 (AMIHAB); T/E unlistd orl-mam LD50: 2600 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 32(10), p. 25, 1988 (GTPZAB); T/E unlistd ihl-mam LC50: 12 gm/m3 Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 32(10), p. 25, 1988 (GTPZAB); L70 ipr-rat TDLo: 4 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 111, p. 69, 1991 (TXAPA9); D25-D07 ihl-hmn TCLo: 480 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 24, 1984 (VCVGK*); T/E unlistd skn-rat LD50: 2000 mg/kg Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. 185, p. 1, 1996 (BFUUA*); T/E unlistd ihl-rat LC50: 5000 mg/m3/4H Beratergremium fuer umweltrelevante Altstoffe (BUA. Gesellschaft Deutscher Chemiker. Weinheim : New York : VCH) 1992- v. 185, p. 1, 1996 (BFUUA*) MD: Z01 orl-rat TDLo: 14 gm/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-319, 1987 (NTPTR*); L70-M03-P71 orl-rat TDLo: 58500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-319, 1987 (NTPTR*); L02-M03 orl-rat TDLo: 10 gm/kg/4W-I AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 138, 1956 (AMIHAB); L70-M70 ihl-rat TCLo: 158 ppm/7H/31W-I AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 138, 1956 (AMIHAB); F01-F11-P13 ihl-rat TCLo: 100 gm/m3/20M/25D-I Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. v. 38, p. 124, 1949 (JAPMA8); D07-M30 ihl-rat TCLo: 140 ppm/6H/2Y-I Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- v. 22, p. 357, 1997 (JTSCDR); L02-M70-P72 orl-mus TDLo: 58500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-319, 1987 (NTPTR*); L30-L70-Y07 orl-mus TDLo: 3 gm/kg/1W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 39, p. 67, 1997 (FAATDF); F11-Z01 orl-rbt TDLo: 92 gm/kg/31W-I AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 138, 1956 (AMIHAB); D07-D35-P13 ihl-rbt TCLo: 100 gm/m3/30M/31D-I Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. v. 38, p. 124, 1949 (JAPMA8); L70 ihl-gpg TCLo: 158 ppm/7H/31W-I AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 138, 1956 (AMIHAB); P13-Z01 ihl-gpg TCLo: 100 gm/m3/20M/20D-I Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. v. 38, p. 124, 1949 (JAPMA8); L30 ihl-rat TCLo: 950 mg/m3/7H/22W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 24, 1994 (VCVGK*) TR: ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 192, 1987 (IMSUDL); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 223, 1999 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 7, p. 231, 1974 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 7, p. 231, 1974 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 213, 1982 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 213, 1982 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 223, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 73, p. 223, 1999 (IMEMDT); TOXICOLOGY REVIEW CRC Critical Reviews in Toxicology. (CRC Press, Inc., 2000 Corporate Blvd., NW, Boca Raton, FL 33431) V.1- 1971- v. 1(1), p. 93, 1971 (CRTXB2) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 75 ppm (450 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 77, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 75 ppm (450 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 75 ppm (450 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 75 ppm (450 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 75 ppm (450 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 75 ppm (450 mg/m3), STEL 110 ppm, JAN 1993; OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-BELGIUM: TWA 75 ppm (451 mg/m3), STEL 110 ppm (661 mg/m3), JAN 1993; OEL-FINLAND: TWA 75 ppm (450 mg/m3), STEL 115 ppm (690 mg/m3), Skin, JAN 1999; OEL-FRANCE: VME 75 ppm (450 mg/m3), VLE 110 ppm (675 mg/m3), JAN 1999; OEL-GERMANY: MAK 50 ppm (300 mg/m3), JAN 1999; OEL-JAPAN: OEL 50 ppm (300 mg/m3), 2B Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 25 ppm (150 mg/m3), MAC-K 50 ppm (300 mg/m3), JAN 1999; OEL-NORWAY: TWA 40 ppm (240 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 75 ppm (450 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 20 mg/m3, JAN 1999; OEL-RUSSIA: TWA 50 ppm, JAN 1993; OEL-SWEDEN: NGV 75 ppm (450 mg/m3), KTV 110 ppm (700 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 50 ppm (300 mg/m3), KZG-W 100 ppm (600 mg/m3), JAN 1999; OEL-TURKEY: TWA 75 ppm (450 mg/m3), JAN 1993; OEL-UNITED KINGDOM: TWA 25 ppm (153 mg/m3), STEL 50 ppm (306 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO p-DICHLOROBENZENE-air: CA (1.7 ppm LOQ) National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 24006; NIS 21; TNF 1963; NOS 18; TNE 23116; NOES 1983: HZD 24006; NIS 22; TNF 2629; NOS 21; TNE 33978; TFE 9412 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/99/121972); EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA Section 8(e) Risk Notification, 8EHQ-0892-9004; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Hydrocarbons, halogenated, 1003; NIOSH Analytical Method, 1996: Volatile organic compound, 2549; NCI Carcinogenesis Studies (gavage), clear evidence: mouse, rat; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 559 of 1119 in RTECS (through 2003/06) AN: CZ6310000 PN: Benzene,-2,6-diisocyanato-1-methyl- SY: Isocyanic-acid,-2-methyl-meta-phenylene-ester-; 2-Methyl-meta-phenylene-diisocyanate-; 2-Methyl-meta-phenylene-isocyanate-; Toluene-2,6-diisocyanate-; 2,6-Toluene-diisocyanate-; Tolylene-2,6-diisocyanate-; meta-Tolylene-diisocyanate-; 2,6-Diisocyanato-1-methylbenzene-; 2,6-Diisocyanatotoluene-; 2,6-TDI- RN: Current: 91-08-7 BRN: 2211546 BHR: 4-13-00-00259 UD: 200210 MF: C9-H6-N2-O2 MW: 174.17 WL: OCNR B1 CNCO CC: Tumorigen (C); Mutagen (M); Human-Data (P) ME: mmo-sat 10 ug/plate (-S9) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-251, 1986 (NTPTR*); mmo-sat 300 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 438, p. 109, 1999 (MUREAV); slt-mus-lym 25 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 196, 1991 (EMMUEG); cyt-ham-ovr 600 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 13, p. 133, 1989 (EMMUEG); sce-ham-ovr 300 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 13, p. 133, 1989 (EMMUEG); mtr-mus-fbr 20 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) AT: D07-D35-J30 ihl-hmn TCLo: 50 ppb Archiv fuer Toxikologie. (Berlin, Fed. Rep. Ger.) V.15-31, 1954-74. For publisher information, see ARTODN. v. 19, p. 364, 1962 (ATXKA8); T/E unlistd orl-bwd LD50: 100 mg/kg Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 12, p. 355, 1983 (AECTCV) TR: ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-TWA 0.005 ppm; STEL 0.02 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 287, 1986 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 865, 1999 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 39, p. 287, 1986 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 865, 1999 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 71, p. 865, 1999 (IMEMDT) SR: OEL-AUSTRIA: MAK 0.01 ppm (0.07 mg/m3), JAN 1999; OEL-DENMARK: TWA 0.005 ppm (0.035 mg/m3), JAN 1999; OEL-GERMANY: MAK 0.01 ppm (0.07 mg/m3), JAN 1999; OEL-NORWAY: TWA 0.005 ppm (0.035 mg/m3), JAN 1999; OEL-POLAND: MAC(TWA) 0.035 mg/m3, MAC(STEL) 0.070 mg/m3, JAN 1999; OEL-SWITZERLAND: MAK-W 0.005 ppm (0.04 mg/m3), KZG-W 0.01 ppm (0.8 mg/m3), JAN 1999; OEL-UNITED KINGDOM: TWA 0.02 mg(NCO)/m3, STEL 0.07 mg(NCO)/m3, SEP 2000 ND: NOHS 1974: HZD M0788; NIS 14; TNF 609; NOS 18; TNE 15830; NOES 1983: HZD M0788; NIS 12; TNF 415; NOS 22; TNE 2872; TFE 284 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Isocyanates, monomeric, 5521; OSHA ANALYTICAL METHOD #42 Record 560 of 1119 in RTECS (through 2003/06) AN: CZ9370000 PN: Benzene,-divinyl- SY: Benzene,-diethenyl- (9CI); Diethenylbenzene-; Divinyl-benzene-; Divinyl-benzene- (ACGIH); Divinylbenzene-; Vinylstyrene- RN: Current: 1321-74-0 UD: 200210 MF: C10-H10 MW: 130.20 CC: Tumorigen (C); Mutagen (M) ME: mnt-mus-ihl 53 ppm/6H/3D-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 370, p. 107, 1996 (MUREAV); cyt-mus-ihl 53 ppm/6H/3D-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 370, p. 107, 1996 (MUREAV); sce-mus-ihl 53 ppm/6H/3D-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 370, p. 107, 1996 (MUREAV) AT: J12-J15-P01 orl-rat LDLo: 10 mL/kg AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 19, p. 403, 1959 (AMIHAB) TR: ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 10 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*) SR: OEL-DENMARK: TWA 10 ppm (50 mg/m3), JAN 1999; OEL-UNITED KINGDOM: TWA 10 ppm (54 mg/m3), SEP 2000 ND: NIOSH REL TO DIVINYL BENZENE-air: 10H TWA 10 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 83286; NIS 5; TNF 164; NOS 14; TNE 12271; NOES 1983: HZD 83286; NIS 1; TNF 3; NOS 1; TNE 11 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, on test (two year studies), October 2000 Record 561 of 1119 in RTECS (through 2003/06) AN: CZ9625000 PN: Benzene, (epoxyethyl)- SY: 1,2-Epoxy-1-phenylethane-; 1,2-Epoxyethylbenzene-; 1-Phenyl-1,2-epoxyethane-; 1-Phenyloxirane-; 2-Phenyloxirane-; EP-182-; Epoxyethylbenzene- (8CI); Epoxystyrene-; Fenyloxiran- (Czech); NCI-C54977-; Oxirane,-phenyl-; Phenethylene-oxide-; Phenyl-oxirane-; Phenylethylene-oxide-; SO-; Styrene-epoxide-; Styrene-oxide-; Styrene-7,8-oxide-; Styryl-oxide-; alpha,beta-Epoxystyrene- RN: Current: 96-09-3 Previous: 62497-63-6 BRN: 108582 BHR: 5-17-01-00577 UD: 200302 MF: C8-H8-O MW: 120.16 WL: T3OTJ BR CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 100 ug/plate (+S9) Journal of Pharmacobio-Dynamics. (Japan Pub. Trading Co. (USA), 1255 Howard St., San Francisco, CA 94103) V.1- 1978- v. 1, p. 301, 1978 (JOPHDQ); mmo-sat 500 ug/plate (-S9) Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 72, p. 5135, 1975 (PNASA6); oms-sat 70 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 192, p. 239, 1987 (MUREAV); mmo-esc 2 mmol/L (-S9) Chemosphere. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1972- v. 7, p. 737, 1978 (CMSHAF); oms-esc 300 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 231, p. 205, 1990 (MUREAV); dnr-esc 5 ug/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 133, p. 161, 1984 (MUREAV); mmo-bcs 5 mmol/L (-S9) Microbiology Series. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1973- v. 5, p. 131, 1981 (MSERDS); mmo-klp 500 umol/L (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 269, 1981 (MUREAV); dnd-omi 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 235, 1996 (MUREAV); mrc-smc 20 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 317, 1976 (MUREAV); mmo-ssp 10 mmol/L (-S9) Colloques Internationaux du Centre National de la Recherche Scientifique. (Kluwer Academic Pub., POB 358, Accord Stn., Hingham, MA 02018) V.1- 1946- v. 256, p. 315, 1977 (COINAV); mmo-ssp 5 mmol/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 317, 1976 (MUREAV); mrc-ssp 20 mmol/L Colloques Internationaux du Centre National de la Recherche Scientifique. (Kluwer Academic Pub., POB 358, Accord Stn., Hingham, MA 02018) V.1- 1946- v. 256, p. 315, 1977 (COINAV); dns-hmn-lym 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 395, p. 37, 1997 (MUREAV); dns-hmn-oth 4400 umol/L Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 18, p. 434, 1980 (FCTXAV); dni-hmn-hla 4400 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 447, 1982 (MUREAV); cyt-hmn-lym 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 190, p. 221, 1987 (MUREAV); sce-hmn-lym 100 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 1, p. 357, 1980 (CRNGDP); dnd-rat-oth 30 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 13, p. 417, 1992 (CRNGDP); dnd-rat-lvr 300 umol/L Personal Communication from J.F. Sina, Merck Institute for Therapeutic Research, West Point, PA 19486, Oct. 26, 1982 26 OCT 1982 (SinJF#); dnd-mus-ipr 3500 umol/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 21, p. 9, 1983 (CALEDQ); oms-mus-fbr 1 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 1367, 1985 (CRNGDP); sce-mus-ihl 50 ppm/5H-C Environmental Science Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.1- 1972- v. 25, p. 433, 1982 (EVSRBT); msc-mus-lym 13800 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 97, p. 49, 1982 (MUREAV); hma-mus-smc 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 317, 1976 (MUREAV); hma-mus-ssp 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 317, 1976 (MUREAV); cyt-ham-ipr 500 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 26, p. 305, 1979 (CBINA8); cyt-ham-lng 57 mg/L Gann Monograph on Cancer Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) No. 11- 1971- v. 27, p. 95, 1981 (GMCRDC); sce-ham-ipr 500 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 26, p. 305, 1979 (CBINA8); sce-ham-ovr 25 mg/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 20, p. 163, 1978 (CBINA8); sce-ham-lng 100 mg/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 3270, 1984 (CNREA8); msc-ham-fbr 17 mmol/L/60M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 317, 1976 (MUREAV); msc-ham-lng 2080 umol/L/2H Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 39, p. 57, 1982 (CBINA8); dna-hmn-fbr 3 mmol/L/2H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 484, p. 3, 2001 (MUREAV); dnd-hmn-leu 50 umol/well/30M Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 126, p. 61, 2002 (TOLED5); sce-rat-lym 60 mg/L/72H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 472, p. 85, 2000 (MUREAV); mnt-hmn-leu 100 umol/L/30M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 491, p. 163, 2001 (MUREAV); sce-hmn-leu 50 umol/L/30M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 491, p. 163, 2001 (MUREAV); dnd-hmn-leu 200 umol/L/30M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 491, p. 163, 2001 (MUREAV); dnr-hmn-lym 200 umol/L/24H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 127, 2001 (MUTAEX); slt-hmn-oth 1.25 mmol/L/1H Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 285, 2001 (EMMUEG) RE: T25-T34 ihl-rat TCLo: 100 ppm/7H (1-19D preg) Scandinavian Journal of Work, Environment and Health. (Haartmaninkatu 1, SF-00290 Helsinki, 29, Finland) V.1- 1975- v. 7(Suppl 4), p. 66, 1981 (SWEHDO); T24-T46 ihl-rat TCLo: 100 ppm/7H (1-19D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB81-168510 (NTIS**); T29-T34-T46 ihl-rat TCLo: 100 ppm/7H (1-19D preg) Scandinavian Journal of Work, Environment and Health. (Haartmaninkatu 1, SF-00290 Helsinki, 29, Finland) V.1- 1975- v. 9, p. 94, 1983 (SWEHDO); T25 ihl-rbt TCLo: 15 ppm/7H (1-24D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB81-168510 (NTIS**) TE: V01-J60 orl-rat TDLo: 65 gm/kg/52W-I Annals of the New York Academy of Sciences. (New York Academy of Sciences, 2 E. 63rd St., New York, NY 10021) V.1- 1877- v. 534, p. 203, 1988 (ANYAA9); V01-K60-L60 orl-rat TDLo: 10 gm/kg/52W-I Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 70, p. 358, 1979 (MELAAD); V01-K60 orl-mus TDLo: 273 gm/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 77, p. 471, 1986 (JJIND8); V03-R60-V10 skn-mus TDLo: 74 gm/kg/62W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 31, p. 41, 1963 (JNCIAM); V03-P62 unr-mus TDLo: 96 mg/kg Radiation Research, Supplement. (New York, NY) No.1-7, 1959-67. Discontinued. v. 3, p. 193, 1963 (RARSAM); V01-K60-L60 orl-rat TD :52 gm/kg/52W-I Medicina del Lavoro. Industrial Medicine. (Via S. Barnaba, 8, 20122 Milan, Italy) V.16- 1925- v. 70, p. 358, 1979 (MELAAD); V01-K60 orl-rat TD :200 gm/kg/2Y-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 77, p. 471, 1986 (JJIND8) ORNG: 2000000000 ng/kg. [2000.000000 mg/kg] T/E unlistd SRNL: 890000 nL/kg. [0.890000 mL/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 2 gm/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB81-168510 (NTIS**); T/E unlistd ihl-rat LCLo: 500 ppm/4H AMA Archives of Industrial Hygiene and Occupational Medicine. (Chicago, IL) V.2-10, 1950-54. For publisher information, see AEHLAU. v. 10, p. 61, 1954 (AMIHBC); T/E unlistd ipr-rat LD50: 460 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 321, 1971 (TXAPA9); T/E unlistd orl-mus LD50: 1500 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 77, p. 471, 1986 (JJIND8); T/E unlistd skn-rbt LD50: 890 uL/kg Union Carbide Data Sheet. (Union Carbide Corp., 39 Old Ridgebury Rd., Danbury, CT 06817) 7/21/1977 (UCDS**); T/E unlistd orl-gpg LD50: 2 gm/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB81-168510 (NTIS**) MD: L30-Y37 ipr-rat TDLo: 8400 mg/kg/7W-I Journal of Toxicological Sciences. (Japanese Soc. of Toxicological Sciences, 4th Floor, Gakkai Center Bldg., 4-16, Yayoi 2-chome, Bunkyo-ku, Tokyo 113, Japan) V.1- 1976- v. 14, p. 1, 1989 (JTSCDR); A30-Y08-Y61 ipr-rat TDLo: 350 mg/kg/14D-I Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 34, p. 722, 1985 (BECTA6) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 36, p. 245, 1985 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 321, 1994 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 36, p. 245, 1985 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 321, 1994 (IMEMDT); IARC Cancer Review: Group 2A IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 60, p. 321, 1994 (IMEMDT) SR: OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993 ND: NOHS 1974: HZD 84819; NIS 2; TNF 59; NOS 5; TNE 1740; NOES 1983: HZD 84819; NIS 2; TNF 109; NOS 4; TNE 458 SL: EPA GENETOX PROGRAM 1988, Positive: Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive: In vitro human lymphocyte micronucleus; EPA GENETOX PROGRAM 1988, Positive: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Positive: In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Positive: V79 cell culture-gene mutation; EPA GENETOX PROGRAM 1988, Positive: S cerevisiae gene conversion; EPA GENETOX PROGRAM 1988, Weakly Positive: S pombe-forward mutation; EPA GENETOX PROGRAM 1988, Positive/dose response: TRP reversion; EPA GENETOX PROGRAM 1988, Positive/limited: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Negative: Rodent dominant lethal; EPA GENETOX PROGRAM 1988, Inconclusive: Mammalian micronucleus; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Studies (gavage), clear evidence: mouse, rat JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 77, p. 471, 1986 (JJIND8) Record 562 of 1119 in RTECS (through 2003/06) AN: DA0700000 PN: Benzene,-ethyl- SY: Aethylbenzol- (German); Ethyl-benzene-; Ethyl-benzene- (ACGIH:OSHA); Ethylbenzeen- (Dutch); Ethylbenzene-; Ethylbenzol-; Etilbenzene- (Italian); Etylobenzen- (Polish); NCI-C56393-; Phenylethane- RN: Current: 100-41-4 UD: 200305 MF: C8-H10 MW: 106.18 WL: 2R CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Primary-Irritant (S) ID: skn-rbt 15 mg/24H open MLD American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 23, p. 95, 1962 (AIHAAP); eye-rbt 500 mg SEV American Journal of Ophthalmology. (Ophthalmic Pub. Co., 435 N. Michigan Ave., Suite 1415, Chicago, IL 60611) Series 3: V.1- 1918- v. 29, p. 1363, 1946 (AJOPAA) ME: sce-hmn-lym 10 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 116, p. 379, 1983 (MUREAV); msc-mus-lym 80 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); mnt-ham-emb 25 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 392, p. 61, 1997 (MUREAV) RE: T22 ihl-rat TCLo: 97 ppm/7H (15D pre) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-208074 (NTIS**); T34 ihl-rat TCLo: 985 ppm/7H (1-19D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-208074 (NTIS**); T46 ihl-rat TCLo: 96 ppm/7H (1-19D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-208074 (NTIS**); T25-T35-T46 ihl-rat TCLo: 600 mg/m3/24H (7-15D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG); T34 ihl-rat TCLo: 2400 mg/m3/24H (7-15D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG); T26 ihl-rbt TCLo: 99 ppm/7H (1-18D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-208074 (NTIS**); T34 ihl-rbt TCLo: 500 mg/m3/24H (7-20D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG); T27 ihl-rbt TCLo: 1 gm/m3/24H (7-20D preg) Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 8, p. 425, 1985 (ATSUDG) TE: V01-M60 ihl-rat TCLo: 750 ppm/6H/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-466, 1999 (NTPTR*); V01-J61-L60 ihl-mus TCLo: 750 ppm/6H/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-466, 1999 (NTPTR*); V03-M61-T61 ihl-rat TCLo: 23400 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB99-134694 (NTIS**); V02-M61 ihl-rat TCLo: 19500 mg/kg/104W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB99-134694 (NTIS**); V03-J60 ihl-mus TCLo: 46350 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB99-134694 (NTIS**); V03-L60 ihl-mus TCLo: 46350 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB99-134694 (NTIS**) ORNG: 3500000000 ng/kg. [3500.000000 mg/kg] L30-M30 SRNL: 17800000 nL/kg. [17.800000 mL/kg] T/E unlistd AT: D35-F04-J30 ihl-hmn TCLo: 100 ppm/8H American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 31, p. 206, 1970 (AIHAAP); L30-M30 orl-rat LD50: 3500 mg/kg AMA Archives of Industrial Health. (Chicago, IL) V.11-21, 1955-60. For publisher information, see AEHLAU. v. 14, p. 387, 1956 (AMIHAB); T/E unlistd ihl-rat LCLo: 4000 ppm/4H American Industrial Hygiene Association Journal. (AIHA, 475 Wolf Ledges Pkwy., Akron, OH 44311) V.19- 1958- v. 23, p. 95, 1962 (AIHAAP); T/E unlistd ihl-mus LCLo: 50 gm/m3/2H Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 5(5), p. 3, 1961 (GTPZAB); T/E unlistd ipr-mus LD50: 2624 uL/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 58, p. 106, 1985 (ARTODN); T/E unlistd skn-rbt LD50: 17800 uL/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 13, p. 803, 1975 (FCTXAV); D07-D17-F11 ihl-gpg LCLo: 10000 ppm Public Health Reports. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1878- v. 45, p. 1241, 1930 (PHRPA6); F24 ihl-gpg LCLo: 2500 ppm/8H Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 24, p. 503, 2002 (NETEEC) MD: J70-L70-M70 ihl-rat TCLo: 740 ppm/6H/92D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3129 (NTPTR*); L70-P72-P73 ihl-rat TCLo: 782 ppm/6H/4W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 13, p. 399, 1989 (FAATDF); L70-M70 ihl-mus TCLo: 975 ppm/6H/97D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3129 (NTPTR*); L70 ihl-mus TCLo: 782 ppm/6H/4W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 13, p. 399, 1989 (FAATDF); P28-P30-P72 ihl-rbt TCLo: 100 mg/m3/4H/30W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 8(2), p. 9, 1964 (GTPZAB); A11-U01 orl-rbt TDLo: 1386 mg/kg/24W-C "Vrednie chemichescie veshestva, galogenproisvodnie uglevodorodov". (Hazardous substances: Galogenated hydrocarbons) Bandman A.L. et al., Chimia, 1990. v. -, p. 154, 1990 (VCVGH*); F27-F33 ihl-hmn TCLo: 30 mg/m3/7Y-I "Vrednie chemichescie veshestva, galogenproisvodnie uglevodorodov". (Hazardous substances: Galogenated hydrocarbons) Bandman A.L. et al., Chimia, 1990. v. -, p. 154, 1990 (VCVGH*); D40-D44 ihl-rat TCLo: 550 ppm/8H/5D-I Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 24, p. 503, 2002 (NETEEC) TR: ACGIH TLV-TWA 100 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-STEL 125 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 100 ppm; STEL 125 ppm The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 77, p. 564, 2000 (IMEMDT) SR: MSHA STANDARD-air: TWA 100 ppm (435 mg/m3) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 104, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 100 ppm (435 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 100 ppm (435 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 100 ppm (435 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 100 ppm (435 mg/m3) Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 100 ppm (435 mg/m3), STEL 125 ppm, JAN 1993; OEL-AUSTRIA: MAK 100 ppm (440 mg/m3), JAN 1999; OEL-BELGIUM: TWA 100 ppm (434 mg/m3), STEL 125 ppm (543 mg/m3), JAN 1993; OEL-DENMARK: TWA 50 ppm (217 mg/m3), JAN 1999; OEL-FINLAND: TWA 100 ppm (435 mg/m3), STEL 150 ppm (655 mg/m3), JAN 1999; OEL-FRANCE: VME 100 ppm (435 mg/m3), JAN 1999; OEL-GERMANY: MAK 100 ppm (440 mg/m3), Skin, JAN 1999; OEL-HUNGARY: TWA 100 mg/m3, STEL 200 mg/m3, Skin, JAN 1993; OEL-JAPAN: OEL 100 ppm (430 mg/m3), JAN 1999; OEL-NORWAY: TWA 50 ppm (220 mg/m3), JAN 1999; OEL-THE PHILIPPINES: TWA 100 ppm (435 mg/m3), JAN 1993; OEL-POLAND: MAC(TWA) 100 mg/m3, MAC(STEL) 350 mg/m3, JAN 1999; OEL-RUSSIA: TWA 100 ppm, STEL 50 mg/m3, JAN 1993; OEL-SWEDEN: NGV 50 ppm (200 mg/m3), KTV 100 ppm (450 mg/m3), JAN 1999; OEL-SWITZERLAND: MAK-W 100 ppm (435 mg/m3), KZG-W 500 ppm (2175 mg/m3), Skin, JAN 1999; OEL-TURKEY: TWA 100 ppm (435 mg/m3), JAN 1993; OEL-UNITED KINGDOM: TWA 100 ppm (441 mg/m3), STEL 125 ppm (552 mg/m3), SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ETHYL BENZENE-air: 10H TWA 100 ppm, STEL 125 ppm National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 31830; NIS 64; TNF 7190; NOS 55; TNE 57442; NOES 1983: HZD 31830; NIS 126; TNF 17633; NOS 92; TNE 201833; TFE 34405 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/99/166647); EPA GENETOX PROGRAM 1988, Negative: Cell transform.-SA7/SHE; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Hydrocarbons, aromatic, 1501; NCI Carcinogenesis Studies (inhal), clear evidence: rat; NTP Carcinogenesis Studies (inhalation): some evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-475, 1998 (NTPTR*); NCI Carcinogenesis Studies (inhal), equivocal evidence: mouse; NTP Toxicity studies, RPT# TOX-10, October 2000; OSHA ANALYTICAL METHOD #1002 Record 563 of 1119 in RTECS (through 2003/06) AN: DA2975000 PN: Benzene,-hexachloro- SY: Amatin-; Anticarie-; Bunt-cure-; Bunt-no-more-; CEKU C.B.; CO-OP-Hexa-; Esaclorobenzene- (Italian); Granox-NM-; HCB-; Hexa C.B.; Hexachlorbenzol- (German); Hexachlorobenzene-; Hexachlorobenzene- (ACGIH); Julin's-carbon-chloride-; NO-Bunt-; NO-Bunt-40-; NO-Bunt-80-; NO-Bunt-liquid-; Pentachlorophenyl-chloride-; Perchlorobenzene-; Phenyl-perchloryl-; RCRA-waste-number-U127-; Saatbeizfungizid- (German); Sanocid-; Sanocide-; Smut-Go-; Snieciotox- RN: Current: 118-74-1 BRN: 1912585 BHR: 4-05-00-00670 UD: 200302 MF: C6-Cl6 MW: 284.76 WL: GR BG CG DG EG FG CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: dna-esc 20 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); mmo-smc 100 ppm (-S9) Rivista di Scienza e Technologia degli Alimenti e di Nutrizione Umana. Review of Science and Technology of Food and Human Nutrition. (Bologna, Italy) V.5-6, 1975-76. Discontinued. v. 6, p. 161, 1976 (RSTUDV); oms-mus-orl 1 gm/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV); msc-ham-lng 6 mg/L Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 39, p. 359, 1986 (BLFSBY) RE: T76 orl-rat TDLo: 556 mg/kg (96D pre-21D post) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 23, p. 33, 1982 (TXCYAC); T46 orl-rat TDLo: 40 mg/kg (10-13D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 29, p. 109, 1974 (TXAPA9); T48-T54 orl-rat TDLo: 6450 mg/kg (1-22D preg/21D post) Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 2, p. 61, 1979 (DCTODJ); T81 orl-rat TDLo: 88 mg/kg (70D male/70D pre-22D preg) "Pesticide and the Environment: a Continuing Controversy, Selected Papers Presented and Papers Reviewed at the 8th Inter-American Conference on Toxicology and Occupational Medicine, Miami, FL, 1973," Deichmann, W.B., ed., New York, Stratton Intercontinental Medical Book Corp., 1973 -,189,1973 (32OAAP); T76 orl-rat TDLo: 812 mg/kg (multigenerations) Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 5, p. 207, 1977 (AECTCV); T83 orl-rat TDLo: 212 mg/kg (14D pre-17D post) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 38, p. 191, 1977 (ARTODN); T43-T53 orl-mus TDLo: 1 gm/kg (7-16D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 35, p. 239, 1976 (TXAPA9); T76-T83 orl-mus TDLo: 600 mg/kg (6-17D preg) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 22, p. 223, 1984 (TOLED5); T72-T75 orl-mus TDLo: 625 mg/kg (8-12D preg) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 7, 1987 (TCMUD8); T12 orl-mky TDLo: 910 ug/kg (13W pre) Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 76, 1974 (TOXID9); T76 orl-mam TDLo: 27562 ug/kg (66D pre-28D post) Environmental Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1967- v. 31, p. 116, 1983 (ENVRAL); T41 orl-rat TDLo: 100 mg/kg (14D pre) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 45, p. 524, 1992 (TJADAB) TE: V01-M61-P61 orl-rat TDLo: 2738 mg/kg/2Y-C Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 24, p. 59, 1983 (PAACA3); V02-L60-P62 orl-mus TDLo: 6972 mg/kg/83W-C International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 23, p. 47, 1979 (IJCNAW); V01-L60-N62 orl-ham TDLo: 1000 mg/kg/18W-C Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 269, p. 510, 1977 (NATUAS); V02-L60 orl-ham TD :3360 mg/kg/80W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 41, p. 155, 1977 (TXAPA9); V01-L60 orl-ham TD :3360 mg/kg/80W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 41, p. 155, 1977 (TXAPA9); V01-L60-M61 orl-rat TD :5475 mg/kg/2Y-C Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 24, p. 59, 1983 (PAACA3); V02-L60-Y36 orl-rat TD :1050 mg/kg/30W-C Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 11, p. 169, 1980 (CALEDQ); V01-L60 orl-rat TD :6300 mg/kg/90W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 631, 1985 (CRNGDP) ORNG: 10000000000 ng/kg. [10000.000000 mg/kg] T/E unlistd AT: T/E unlistd unr-man LDLo: 220 mg/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); T/E unlistd orl-rat LD50: 10 gm/kg Farm Chemicals Handbook. (Meister Pub., 37841 Euclid Ave., Willoughy, OH 44094) v. -, p. C163, 1991 (FMCHA2); T/E unlistd ihl-rat LC50: 3600 mg/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd ipr-rat LD :>500 mg/kg National Academy of Sciences, National Research Council, Chemical-Biological Coordination Center, Review. (Washington, DC) v. 5, p. 18, 1953 (NCNSA6); T/E unlistd orl-mus LD50: 4 gm/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd ihl-mus LC50: 4 gm/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd orl-cat LD50: 1700 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd ihl-cat LC50: 1600 mg/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd orl-rbt LD50: 2600 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd ihl-rbt LC50: 1800 mg/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,72,1982 (85GMAT); T/E unlistd orl-gpg LD50: >3 gm/kg Pesticide Manual. (The British Crop Protection Council, 20 Bridport Rd., Thornton Heath CR4 7QG, UK) V.1- 1968- v. 9, p. 469, 1991 (PEMNDP); T/E unlistd orl-qal LD50: >6400 mg/kg Mededelingen van de Faculteit Landbouwwetenschappen, Rijksuniversiteit Gent. Communications of the Faculty of Agricultural Sciences, State University of Ghent. (Rijksuniversiteit Gent, Faculteit Labdbouwwettenschappen, Coupure 653, B-9000, Ghent, Belgium) V.35- 1970- v. 38, p. 709, 1973 (MFLRA3); F07-F17 orl-mam LD50: >5 gm/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB288-416 (NTIS**); T/E unlistd ipr-rat TDLo: 150 mg/kg Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 12, p. 223, 1983 (JTEHD6); N08 orl-rat TDLo: 1 gm/kg Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 39, p. 817, 1990 (BCPCA6); J02-L30-M03 orl-rat LD50: 3500 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 32, 1984 (VCVGK*); F22-F33-F40 ihl-rbt LC50: 1800 mg/m3/6H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 32, 1984 (VCVGK*); F22-F33-F40 ihl-cat LC50: 1800 mg/m3/6H "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. 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First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 433, 1976 (TXAPA9); M70-N75-Y07 orl-pig TDLo: 455 mg/kg/13W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 43, p. 137, 1978 (TXAPA9); N74-N75-P28 orl-ham TDLo: 4704 mg/kg/28W-C Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 60, p. 343, 1987 (ARTODN); L30-U01-Y07 orl-qal TDLo: 5 gm/kg/10D-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 15, p. 431, 1985 (JTEHD6); L30-Y07 orl-qal TDLo: 2500 mg/kg/5D-I Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 15, p. 93, 1985 (JTEHD6); F07-F11-Z01 orl-mam TDLo: 7104 mg/kg/30D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. 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Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 33, 1994 (VCVGK*); T12 orl-mky TDLo: 480 mg/kg/60D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 33, 1994 (VCVGK*); Z01 ihl-rat TCLo: 30 mg/m3/4H/17W-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 33, 1994 (VCVGK*); L30-P27 orl-rat TDLo: 59.5 mg/kg/17W-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 33, 1994 (VCVGK*); J30-Y12-Z01 orl-pig TDLo: 5414.5 mg/kg/13W-C "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 33, 1994 (VCVGK*) TR: ACGIH TLV-TWA 0.002 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.002 mg/m3 (skin) The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. 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(Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.B11- 1976- v. 21, p. 319, 1986 (JPFCD2); mmo-esc 10 mg/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 11, p. 247, 1971 (MUREAV); dna-esc 20 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); mmo-asn 5 umol/L (-S9) Phytopathology. (American Phytopathological Soc., 3340 Pilot Knob Rd., St. Paul, MN 55121) V.1- 1911- v. 66, p. 217, 1976 (PHYTAJ); mrc-asn 40 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 147, p. 288, 1985 (MUREAV); sln-asn 17 umol/L EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 31, p. 81, 1979 (EVHPAZ); cyt-ham-ovr 7500 ug/L Environmental and Molecular Mutagenesis. (Alan R. 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(Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 42, p. 1101, 1969 (JNCIAM) ORNG: 1100000000 ng/kg. [1100.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1100 mg/kg Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 7, p. 299, 1986 (FAATDF); T/E unlistd ihl-rat LC50: 1400 mg/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,96,1982 (85GMAT); T/E unlistd ipr-rat LD50: 5 gm/kg "Documentation of the Threshold Limit Values and Biological Exposure Indices," 5th ed., Cincinnati, OH, American Conference of Governmental Industrial Hygienists, Inc., 1986 5,462.1(89),1986 (85INA8); T/E unlistd orl-mus LD50: 1400 mg/kg "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,96,1982 (85GMAT); T/E unlistd ihl-mus LC50: 2 gm/m3 "Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure," Izmerov, N.F., et al., Moscow, Centre of International Projects, GKNT, 1982 -,96,1982 (85GMAT); T/E unlistd ipr-mus LD50: 4500 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 51, p. 329, 1982 (ARTODN); K13 orl-dog LD :>2500 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 114, p. 38, 1958 (AIPTAK); T/E unlistd orl-rbt LD50: 800 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 114, p. 38, 1958 (AIPTAK); T/E unlistd skn-rbt LD :>4 gm/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 522, 1971 (TXAPA9) MD: L70-M70-U01 orl-rat TDLo: 11250 mg/kg/90D-C Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 114, p. 38, 1958 (AIPTAK); L70 orl-mus TDLo: 13650 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-325, 1987 (NTPTR*); F07-R21-Z01 orl-mam TDLo: 62660 mg/kg/30D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB288-416 (NTIS**) TR: ACGIH TLV-TWA 0.5 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 0.5 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 5, p. 211, 1974 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 5, p. 211, 1974 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW Residue Reviews. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1962- v. 56, p. 107, 1975 (RREVAH); TOXICOLOGY REVIEW "Oncology 1970, Proceedings of the Tenth International Cancer Congress," Chicago, Year Book Medical Pub., 1971 5,250,1970 (85CVA2) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); OEL-DENMARK: TWA 0.5 mg/m3, JAN 1999 ND: NOHS 1974: HZD M0806; NIS 1; TNF 18; NOS 1; TNE 18; NOES 1983: HZD M0806; NIS 1; TNF 38; NOS 2; TNE 574; TFE 77 SL: EPA GENETOX PROGRAM 1988, Negative: Host-mediated assay, In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Negative: TRP reversion, S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Negative/limited: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Inconclusive: B subtilis rec assay, E coli polA without S9; EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Inconclusive: D melanogaster Sex-linked lethal; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (feed), no evidence: mouse; NTP Carcinogenesis Studies (feed), no evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-325, 1987 (NTPTR*) Record 566 of 1119 in RTECS (through 2003/06) AN: DB5042500 PN: Benzenesulfonic acid, 2-anilino-5-(2,4-dinitroanilino)-, monosodium salt SY: 2-Anilino-5-(2,4-dinitroanilino)-benzenesulfonic acid, monosodium salt; 2-Anilino-5-(2,4-dinitroanilino)benzenesulfonic acid sodium salt; 5-((2,4-Dinitrophenol)amine)-2-(phenylamine)-benzenesulfonic acid, monosodium salt; 5-((2,4-Dinitrophenyl)amino)-2-(phenylamino)benzenesulfonic acid monosodium salt; Acid-Fast-Yellow-AG-; Acid-Fast-Yellow-E5R-; Acid-Leather-Light-Brown-G-; Acid Orange No. 3; Acid-Yellow-E-; Airedale-Yellow-E-; Amido-Yellow-E-; Amido-Yellow-EA-; Amido-Yellow-EA-CF-; Anthralan-Yellow-RRT-; Benzenesulfonic acid, 5-((2,4-dinitrophenyl)amino)-2-(phenylamino)-, monosodium salt; C.I. 10385; C.I. Acid Orange 3; Coranil-Brown-H-EPS-; Derma-FUR-Yellow-RT-; Derma-Yellow-P-; Dimacide-Yellow-N-5RL-; Duasyn-Acid-Yellow-RRT-; Elbenyl-Orange-A-3RD-; Erio-Fast-Yellow-AE-; Erio-Fast-Yellow-AEN-; Erio-Yellow-AEN-; Erionyl-Yellow-E-aen-; Fast-Light-Yellow-E-; Fenalan-Yellow-E-; Heliacid-Light-Yellow-4R-; Intranyl-Orange-T-4R-; Kiton-Fast-Yellow-A-; Lanaperl-Yellow-Brown-GT-; Light-Fast-Yellow-ES-; Lissamine-Fast-Yellow-AE-; Lissamine-Fast-Yellow-AES-; Lissamine-Yellow-AE-; Multacid-Yellow-3R-; Multicuer-Brown-MPH-; NCI-C54911-; Nailamide-Yellow-Brown-E-L-; Nylocrom-Yellow-3R-; Nylomine-Acid-Yellow-B-RD-; Nylosan-Yellow-E-3R-; Polan-Yellow-E-3R-; Sellacid-Yellow-AEN-; Sodium 4-(2,4-dinitroanilino)diphenylamine-2-sulfonate; Solanile-Yellow-E-; Sulfacid-Light-Yellow-5RL-; Superian-Yellow-R-; Tectilon-Orange-3GT-; Tertracid-Light-Yellow-2R-; Tetracid-Light-Yellow-2R-; Unitertracid-Light-Yellow-RR-; Vondacid-Fast-Yellow-AE-; Vondacid-Light-Yellow-AE-; Xylene-Fast-Yellow-ES- RN: Current: 6373-74-6 Previous: 74968-36-8 UD: 200210 MF: C18-H13-N4-O7-S.Na MW: 452.40 WL: WSQR BMR& DMR BNW DNW &-NA- CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 ug/plate (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11(Suppl 12), p. 1, 1988 (EMMUEG) TE: V01-M61 orl-rat TDLo: 386 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-335, 1988 (NTPTR*); V01-M61-N10 orl-rat TDLo: 386250 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB89-216550/AS (NTIS**) MD: M30-Z01 orl-rat TDLo: 97500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-335, 1988 (NTPTR*); M30 orl-mus TDLo: 65 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-335, 1988 (NTPTR*) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 121, 1993 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 121, 1993 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 121, 1993 (IMEMDT) ND: NOES 1983: HZD X9543; NIS 1; TNF 2258; NOS 1; TNE 22238; TFE 14728 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), clear evidence: rat; NTP Carcinogenesis Studies (gavage), clear evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-335, 1988 (NTPTR*); NCI Carcinogenesis Studies (gavage), no evidence: mouse Record 567 of 1119 in RTECS (through 2003/06) AN: DB5500000 PN: Benzenesulfonic acid, 5-chloro-2-((2-hydroxy-1-naphthalenyl)azo)-4-methyl-, barium salt SY: 1-(4-Chloro-o-sulfo-5-tolylazo)-2-naphthol, barium salt; 1-(4-Chloro-o-sulpho-5-tolylazo)-2-naphthol, barium salt; 1860-Red-; 5-Chloro-2-((2-hydroxy-1-naphthalenyl)azo)-4-methylbenzenesulfonic acid, barium salt (2:1); 5-Chloro-2-((2-hydroxy-1-naphthalenyl)azo)-4-methylbenzenesulphonic acid, barium salt; 5-Chloro-2-((2-hydroxy-1-naphthyl)azo)-p-toluenesulfonic acid, barium salt; Astro-Orange-; Atomic-Red-; Brilliant-Red-; Brilliant-Scarlet-CA-; Brilliant-Scarlet-CBA-; Brilliant-Scarlet-CTA-; Brilliant-Toner-Z-; Bronze-Red-16913-Yellowish-; Bronze-Red-RO-; Bronze-Scarlet-; Bronze-Scarlet-C-; Bronze-Scarlet-CA-; Bronze-Scarlet-CBA-; Bronze-Scarlet-CT-; Bronze-Scarlet-CTA-; Bronze-Scarlet-Toner-; C.I. 15585:1; C.I. Pigment Red 53, barium salt; C.I. Pigment Red 53:1; Carnation-Red-; Cosmetic-Coral-Red-KO-Bluish-; Cosmetic-DVR-; Cosmetic-Pigment-Yellow-Red-DVR-; D & C Red No. 9; D and C Red No. 9; Dainichi-Lake-Red-C-; Desert-Red-; Duplex-Red-Lake-C20-5925-; Eljon-Lake-Red-C-; Hamilton-Red-; Helio-Red-Toner-LCLL-; Irgalite-Red-CBN-; Irgalite-Red-CBR-; Irgalite-Red-CBT-; Irgalite-Red-MBC-; Isol-Lake-Red-LCS-12527-; Isol-Red-LCR-2517-; Lake-Red-1520-; Lake-Red-C-; Lake-Red-C-18287-; Lake-Red-C-21245-; Lake-Red-C-27200-; Lake-Red-C-27217-; Lake-Red-C-27218-; Lake-Red-C-Barium-Toner-; Lake-Red-C-Toner-8195-; Lake-Red-C-Toner-8366-; Lake-Red-CC-; Lake-Red-CCT-; Lake-Red-CR-; Lake-Red-CRLC-232- (barium); Lake-Red-GB-barium-salt-; Lake-Red-RRG-; Lake-Red-Toner-C-; Lake-Red-Toner-LCLL-; Latexol-Scarlet-R-; Latexol-Scarlet-R-Solupowder-; Ld-Rubber-Red-16913-; Lutetia-Red-CLN-; Lutetia-Red-CLN-ST-; Microtex-Lake-Red-CR-; Mohican-Red-A-8008-; NCI-C53792-; No.3 Conc. Bronze Scarlet; No.3 Conc. Scarlet; Paridine-Red-LCL-; Pigment-Lake-Red-BFC-; Pigment-Lake-Red-CD-; Pigment-Lake-Red-LC-; Pigment Red 53:1; Pigment-Red-CD-; Potomac-Red-; Recolite-Red-Lake-C-; Recolite-Red-Lake-CR-; Red-16913H-; Red-1860-; Red-For-Lake-C-; Red-For-Lake-C-Toner-RA-5190-; Red-For-Lake-Toner-RA-5190-; Red-Lake-C-; Red-Lake-C-Toner-; Red-Lake-C-Toner-20-5650-; Red-Lake-C-Toner-RA-5190-; Red-Lake-CM-20-5650-; Red-Lake-CR-1-; Red-Lake-R-91-; Red-Scarlet-; Red-Toner-Z-; Rubber-Red-16913R-; Sanyo-Lake-Red-C-; Scarlet-Toner-Y-; Segnale-Red-LC-; Segnale-Red-LCG-; Segnale-Red-LCL-; Sico-Lake-Red-2L-; Superol-Red-C-RT-265-; Symuler-Lake-Red-C-; Termosolido-Red-LCG-; Texan-Red-Toner-D-; Toner-Lake-Red-C-; Transparent-Bronze-Scarlet-; Vulcafix-Scarlet-R-; Vulcafix-Scarlet-R-D-masse-; Vulcafor-Red-2R-; Vulcan-Red-LC-; Vulcol-Fast-Red-L-; Wayne-Red-X-2486- RN: Current: 5160-02-1 Previous: 12237-52-4; 12238-39-0; 12238-41-4; 12238-43-6; 24777-23-9; 52627-68-6; 68894-03-1 UD: 200302 MF: C17-H12-Cl-N2-O4-S.1/2 Ba MW: 444.49 WL: L66J BNUNR DG C FSWQ& CQ & 2-BA- CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 1 mg/plate (+S9) Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 236, p. 933, 1987 (SCIEAS) TE: V01-L60-P60 orl-rat TDLo: 130 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-225, 1982 (NTPTR*); V02-P60 orl-rat TD :109 gm/kg/2Y-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 25, p. 619, 1987 (FCTOD7); V02-P27-P30 orl-rat TDLo: 16380 mg/kg/13W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-229592 (NTIS**); V02-P27-P30 orl-rat TDLo: 27300 mg/kg/13W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-229592 (NTIS**); V01-P60 orl-rat TDLo: 129780 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-229592 (NTIS**); V01-L60 orl-rat TDLo: 108150 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-229592 (NTIS**) MD: L30-Z01 orl-rat TDLo: 27300 mg/kg/91D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-225, 1982 (NTPTR*); N73 orl-rat TDLo: 546 gm/kg/2Y-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 4, p. 200, 1962 (TXAPA9); Z01 orl-mus TDLo: 21 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-225, 1982 (NTPTR*); P71 orl-mus TDLo: 87600 mg/kg/2Y-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0543935 (NTIS**); P61-T61-V30 orl-rat TDLo: 43260 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-229592 (NTIS**); P61-V30 orl-rat TDLo: 36050 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB82-229592 (NTIS**) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 203, 1993 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 8, p. 107, 1975 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 8, p. 107, 1975 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 203, 1993 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 57, p. 203, 1993 (IMEMDT) ND: NOHS 1974: HZD M3849; NIS 15; TNF 1160; NOS 21; TNE 14370; NOES 1983: HZD M3849; NIS 43; TNF 8245; NOS 49; TNE 122313; TFE 23095 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Bioassay (feed), clear evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-225, 1982 (NTPTR*); NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NTP Carcinogenesis Bioassay (feed), no evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-225, 1982 (NTPTR*) Record 568 of 1119 in RTECS (through 2003/06) AN: DB6831000 PN: Benzenesulfonic acid, 2,2'-(1,2-ethanediyl)bis(5-amino-, disodium salt SY: 2,2'-Disulfo-4,4'-stilbenediamine-disodium-salt-; 2,2'-Stilbenedisulfonic-acid,-4,4'-diamino-,-disodium-salt-; 2,3'-(1,2-Ethenediyl)bis(5-aminobenzenesulfonic acid) disodium salt; 4,4'-Diamino-2,2'-stilbenedisulfonic-acid-disodium-salt-; Amsonic-acid-disodium-salt-; Diaminostilbene-disulphonate-disodium-salt-; Flavonic-acid-disodium-salt-; p,p'-Diaminostilbene-o,o'-disulfonic-acid-disodium-salt- RN: Current: 7336-20-1 UD: 200207 MF: C14-H12-N2-O6-S2.2 Na MW: 414.38 CC: Tumorigen (C) MD: U01 orl-rat TDLo: 42 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-412, 1992 (NTPTR*); P28-U01-Y40 orl-rat TDLo: 546 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-412, 1992 (NTPTR*); U01 orl-mus TDLo: 168 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-412, 1992 (NTPTR*); F11-P28-U01 orl-mus TDLo: 1092 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-412, 1992 (NTPTR*) ND: NOES 1983: HZD X2053; NIS 7; TNF 3525; NOS 13; TNE 15522; TFE 8206 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), no evidence: mouse, rat Record 569 of 1119 in RTECS (through 2003/06) AN: DB9450000 PN: Benzene,-1,2,4,5-tetrachloro- SY: Benzene-tetrachloride-; RCRA-waste-number-U207-; 1,2,4,5-Tetrachlorbenzol- (Russian); s-Tetrachlorobenzene-; 1,2,4,5-Tetrachlorobenzene- RN: Current: 95-94-3 BRN: 1618315 BHR: 4-05-00-00668 UD: 200302 MF: C6-H2-Cl4 MW: 215.88 WL: GR BG DG EG CC: Tumorigen (C) ORNG: 1500000000 ng/kg. [1500.000000 mg/kg] F01-F07-F12 AT: F01-F07-F12 orl-rat LD50: 1500 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 30(1-3), p. 8, 1965 (HYSAAV); F01-F07-F12 orl-mus LD50: 1035 mg/kg Hygiene and Sanitation (USSR). English translation of GISAAA. (Springfield, VA) 1964-71. Discontinued. v. 30(1-3), p. 8, 1965 (HYSAAV); T/E unlistd ipr-mus LD :>500 mg/kg "Summary Tables of Biological Tests," National Research Council Chemical-Biological Coordination Center. (National Academy of Science Library, 2101 Constitution Ave., NW, Washington, DC 20418) v. 4, p. 107, 1952 (CBCCT*); F12-F17-F18 orl-rbt LD50: 1500 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 30(1), p. 9, 1965 (GISAAA); F18-F24-U28 orl-rat LD50: 1727 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 28, 1984 (VCVGK*) MD: L70-M16-P08 orl-rat TDLo: 5460 mg/kg/13W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB91-185330 (NTIS**); L70-P28-Y07 orl-rat TDLo: 896 mg/kg/28D-C Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 11, p. 663, 1983 (JTEHD6); L70-M70-P28 orl-rat TDLo: 2700 mg/kg/90D-C Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 7, p. 113, 1984 (DCTODJ); N72-P26-Y01 orl-rat TDLo: 4567 mg/kg/9W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 30(1), p. 9, 1965 (GISAAA); F40-L70 orl-rat TDLo: 12 mg/kg/35W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 30(1), p. 9, 1965 (GISAAA); F07-J22-Z01 orl-mus TDLo: 2100 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-91-3126 (NTPTR*); L70-P06-Y10 orl-mus TDLo: 4550 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-91-3126 (NTPTR*); P08-P70 orl-rbt TDLo: 12 mg/kg/35W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 30(1), p. 9, 1965 (GISAAA); F18-F24-Z01 orl-rat TDLo: 5600 mg/kg/28D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 29, 1994 (VCVGK*); J30-L30-U01 unr-rat TDLo: 575 mg/kg/60D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 29, 1994 (VCVGK*); L70 orl-mus TDLo: 4.536 mg/kg/105D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-128388 (NTIS**); Z01 orl-mus TDLo: 4.725 mg/kg/105D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-128388 (NTIS**) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA 8(a) PRELIMINARY ASSESSMENT INFORMATION, FINAL RULE Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 47, p. 26992, 82 (FEREAC); EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Polychlorobenzenes, 5517; NTP Toxicity studies, RPT# TOX-07, October 2000 Record 570 of 1119 in RTECS (through 2003/06) AN: DC9625000 PN: Benzidine- SY: (1,1'-Biphenyl)-4,4'-diamine (9CI); 4,4'-Bianiline-; 4,4'-Biphenyldiamine-; 4,4'-Biphenylenediamine-; 4,4'-Diamino-1,1'-biphenyl-; 4,4'-Diaminobiphenyl-; 4,4'-Diaminodiphenyl-; 4,4'-Diphenylenediamine-; Benzidin-; Benzidin- (Czech); Benzidina- (Italian); Benzidine- (ACGIH:OSHA); Benzydyna- (Polish); Biphenyl,-4,4'-diamino-; C.I. 37225; C.I. Azoic Diazo Component 112; Fast-Corinth-Base-B-; NCI-C03361-; RCRA-waste-number-U021-; p,p'-Diaminobiphenyl-; p,p'-Dianiline-; p,p-Bianiline-; p-Diaminodiphenyl- RN: Current: 92-87-5 BRN: 742770 BHR: 4-13-00-00364 UD: 200305 MF: C12-H12-N2 MW: 184.26 WL: ZR DR DZ CC: Tumorigen (C); Mutagen (M); Human-Data (P) ME: mmo-sat 400 ng/plate (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 175, p. 11, 1986 (MUREAV); oms-sat 567 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 192, p. 239, 1987 (MUREAV); mmo-esc 100 ug/plate (+S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 387, 1981 (PMRSDJ); dnr-esc 1 mg/plate Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 54, p. 101, 1978 (MUREAV); pic-esc 100 mmol/L Medycyna Doswiadczalna i Mikrobiologia. For English translation, see EXMMAV. (Ars Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1949- v. 31, p. 11, 1979 (MDMIAZ); dnd-bcs 2 mg/disc Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 175, 1981 (PMRSDJ); slt-dmg-orl 5 mmol/L/48H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 222, p. 359, 1989 (MUREAV); sln-dmg-par 5 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 56, p. 31, 1977 (MUREAV); dnr-smc 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 502, 1981 (PMRSDJ); mrc-smc 100 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 491, 1981 (PMRSDJ); sln-smc 50 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); mnt-ofs-ipr 10 mg/kg Cytobios. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1969- v. 47, p. 147, 1986 (CYTBAI); cyt-ofs-ipr 10 mg/kg Comparative Biochemistry and Physiology, C: Pharmacology, Toxicology and Endocrinology. (Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.74- 1983- v. 82, p. 489, 1985 (CBPCEE); dnd-hmn-fbr 3 mmol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 267, 1985 (ENMUDM); dna-hmn-lym 30 umol/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 85, p. 3513, 1988 (PNASA6); dns-hmn-lvr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 206, p. 91, 1988 (MUREAV); dns-hmn-hla 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); dns-hmn-fbr 160 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 528, 1981 (PMRSDJ); dni-hmn-hla 600 umol/L/30M-C Journal of Environmental Pathology and Toxicology. (Park Forest South, IL) V.1-5(3), 1977-81(?). For publisher information, see JEPOEC. v. 2(1), p. 65, 1978 (JEPTDQ); sce-man-ihl 7 ug/m3/27W Polski Tygodnik Lekarski. Polish Medical Weekly. (Ars Polona, POB 1001, 00 068 Warsaw 1, Poland) V.1- 1946- v. 35, p. 53, 1980 (POLEAQ); sce-hmn-lym 2 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 241, p. 109, 1990 (MUREAV); mnt-rat-scu 410 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 40, p. 43, 1976 (MUREAV); mnt-rat-ipr 25 mg/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 57, p. 217, 1989 (TXCYAC); dnd-rat-lvr 3 mmol/L Personal Communication from J.F. Sina, Merck Institute for Therapeutic Research, West Point, PA 19486, Oct. 26, 1982 26 OCT 1982 (SinJF#); dnd-rat-ipr 63 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 1285, 1985 (CRNGDP); dna-rat-par 11600 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 2678, 1982 (CNREA8); dnd-rat-orl 200 mg/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 667, 1982 (ENMUDM); dns-rat-orl 200 mg/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 553, 1982 (ENMUDM); dns-rat-lvr 100 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 136, p. 255, 1984 (MUREAV); dni-rat-orl 100 umol/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 8, p. 1433, 1987 (CRNGDP); bfa-rat-sat 250 umol/kg Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 21, p. 223, 1981 (TXCYAC); cyt-rat-lvr 12500 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 570, 1981 (PMRSDJ); cyt-rat-ipr 250 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 182, p. 309, 1987 (MUREAV); hma-rat-sat 1 mmol/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 317, 1982 (MUREAV); mnt-mus-ipr 6400 ug/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 686, 1981 (PMRSDJ); mnt-mus-orl 300 mg/kg Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 267, 1987 (MUTAEX); mtr-mus-emb 2500 ug/L Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 3, p. 101, 1983 (TCMUD8); dnd-mus-ipr 150 mg/kg Bolletino della Societe Italiana di Biologia Sperimentale. (Casa Editrice Idelson, Via A. de Gasperi, 55, 80133 Naples, Italy) V.2- 1927- v. 56, p. 1673, 1980 (BSIBAC); dna-mus-orl 9600 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 2678, 1982 (CNREA8); dna-mus-lvr 60 umol/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 947, 1979 (JJIND8); dnd-mus-orl 160 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); dni-mus-orl 20 gm/kg Archiv fuer Geschwulstforschung. (VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 51, p. 605, 1981 (ARGEAR); dni-mus-orl 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 305, 1977 (MUREAV); oms-mus-ipr 25 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 268, p. 255, 1992 (MUREAV); oms-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); cyt-mus-ipr 25 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 320, p. 69, 1994 (MUREAV); cyt-mus-lym 100 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 320, p. 69, 1994 (MUREAV); sce-mus-ipr 7700 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 108, p. 225, 1983 (MUREAV); msc-mus-lym 500 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 125, p. 291, 1984 (MUREAV); hma-mus-esc 220 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 272, p. 161, 1992 (MUREAV); slt-ham-ovr 600 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 594, 1981 (PMRSDJ); mtr-ham-emb 50 ug/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 3, p. 45, 1977 (CALEDQ); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); dnd-ham-lng 100 umol/L/2H Biochemical and Biophysical Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 72, p. 732, 1976 (BBRCA9); dns-ham-lvr 20 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 136, p. 255, 1984 (MUREAV); cyt-ham-ovr 160 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ham-ovr 5 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); dna-dog-orl 60 umol/kg EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 49, p. 125, 1983 (EVHPAZ); oms-dog-oth 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 1893, 1984 (CNREA8); dna-dog-oth 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 1893, 1984 (CNREA8); dns-rbt-oth 100 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 8, p. 401, 1987 (CRNGDP); dns-rbt-lvr 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 3120, 1983 (CNREA8); mmo-sat 3 ug/plate (+S9) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 351, 2000 (TOSCF2); mmo-sat 1 nmol/plate/20M Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 38, p. 268, 2001 (EMMUEG); mtr-mus-fbr 1 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG); slt-ham-ovr 25 mg/L/9D Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 16, p. 260, 1990 (EMMUEG) TE: V01-M14-M60 ihl-man TCLo: 17600 ug/m3/14Y-C Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 27, p. 1, 1973 (AEHLAU); V01-R60 orl-rat TDLo: 108 mg/kg/27D-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 28, p. 924, 1968 (CNREA8); V03-L60-P61 ihl-rat TCLo: 10 mg/m3/56W-I Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 69, p. 68, 1970 (BEXBAN); V01-V10 scu-rat TDLo: 1200 mg/kg/26W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 10(5), p. 50, 1964 (VOONAW); V03-L60-R60 itr-rat TDLo: 315 mg/kg/34W Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 69, p. 68, 1970 (BEXBAN); V03-J60-L60 scu-mus TDLo: 8400 mg/kg/35W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 17(5), p. 61, 1971 (VOONAW); V03-L60 orl-ham TDLo: 75 mg/kg/3Y-C "Bladder Cancer, A Symposium, Fifth Inter-American Conference on Toxicology and Occupational Medicine, Coral Gables, FL," Lampe, K.F., et al., eds., Coral Gables, FL, Aesculapius Pub., 1966 5,129,1966 (85DAAC); V03-L60 scu-mus TD :1620 gm/kg/45W-I Acta Unio Internationalis Contra Cancrum. (Louvain, Belgium) V.1-20, 1936-64. For publisher information, see IJCNAW. v. 7, p. 46, 1950 (AICCA6); V03-L60-R60 scu-rat TD :850 mg/kg/32W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 20(2), p. 53, 1974 (VOONAW); V03-D45-P60 scu-rat TD :800 mg/kg/60W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 20(8), p. 69, 1974 (VOONAW); V01-D45-L60 scu-rat TD :2025 mg/kg/27W-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 3, p. 789, 1950 (CANCAR); V03-L60 orl-rat TD :25560 ng/kg/2Y-C Eksperimental'naya Onkologiya. Experimental Oncology. (V/O Mezhdunarodnaya Kniga, 113095 Mosow, USSR) V.1- 1979- v. 9(4), p. 73, 1987 (EKSODD); V01-R60 scu-rat TDLo: 1425 mg/kg/57W-I Voprosi oncologii (Questions of oncology. Journal of Petrov's Institute of Oncology, B. Zelenina str, 43a, Spb 197110, Russia) V.1- 1955- v. 37, p. 60, 1991 (VOONC*) ORNG: 309000000 ng/kg. [309.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 309 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB214-270 (NTIS**); T/E unlistd orl-mus LD50: 214 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB214-270 (NTIS**); T/E unlistd ipr-mus LD50: 110 mg/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 682, 1981 (PMRSDJ); T/E unlistd orl-dog LDLo: 200 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 58, p. 167, 1907 (AEXPBL); T/E unlistd orl-rbt LDLo: 200 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 58, p. 167, 1907 (AEXPBL) TR: ACGIH TLV-Confirmed Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Human Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 1, p. 80, 1972 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 1, p. 80, 1972 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 149, 1982 (IMEMDT); IARC Cancer Review: Human Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 149, 1982 (IMEMDT); IARC Cancer Review: Group 1 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 123, 1987 (IMSUDL); TOXICOLOGY REVIEW Environmental and Health Criteria for Benzidine. Meeting of DHEW Committee to Coordinate Toxicology and Related Programs, Feb. 15, 1974 at Sterling Forest, NY v. -, p. 38, 1974 (EAHB**); TOXICOLOGY REVIEW Khimiya i Zhizn. Chemistry and Life. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1965- v. 12(2), p. 85, 1976 (KHZHAZ); TOXICOLOGY REVIEW Advances in Chemistry Series. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) No.1- 1950- v. 13, p. 271, 1970 (ADCSAJ); TOXICOLOGY REVIEW Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 24, p. 253, 1983 (BLFSBY) SR: MSHA STANDARD: skin-HUMAN CARCINOGEN, NO ASSIGNED TWA "Documentation of the Threshold Limit Values for Substances in Workroom Air," Supplements. For publisher information, see 85INA8. v. 3, p. 11, 1973 (DTLWS*); OSHA PEL (Gen Indu): see CFR 29,1910.1010 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): see CFR 29,1926.1110 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926, 55,1994 (CFRGBR); OSHA PEL (Shipyard): see CFR 29,1915.1010 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA-cancer suspect agent Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1010, 1987 (CFRGBR); OEL-AUSTRALIA: (Prohibited) Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Skin, Carcinogen, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1999; OEL-FRANCE: VME 0.001 ppm (0.008 mg/m3), C1 Carcinogen, JAN 1999; OEL-GERMANY: Skin, Carcinogen, JAN 1999; OEL-THE NETHERLANDS: Skin, JAN 1999; OEL-POLAND: MAC(TWA) 0 mg/m3, MAC(STEL) 0 mg/m3, JAN 1999; OEL-SWEDEN: Carcinogen, JAN 1999; OEL-SWITZERLAND: Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO BENZIDINE-air: CA use 29 CFR 1910.1010 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #95-121, 1995 (NIOSH*); NOHS 1974: HZD 09830; NIS 4; TNF 263; NOS 5; TNE 1166; NOES 1983: HZD 09830; NIS 3; TNF 252; NOS 8; TNE 1554; TFE 426 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/2001/109102); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-mouse embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Mammalian micronucleus, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: In vitro UDS in rat liver; EPA GENETOX PROGRAM 1988, Negative: Sperm morphology-mouse; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9, In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Positive: CHO gene mutation; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Benzidine, 5509, in urine, 8306; NTP 9th Report on Carcinogens, 2000: Known to be human carcinogen; OSHA ANALYTICAL METHOD #ID-65 Record 571 of 1119 in RTECS (through 2003/06) AN: DD0525000 PN: Benzidine,-3,3'-dichloro- SY: (1,1'-Biphenyl)-4,4'-diamine, 3,3'-dichloro-; 3,3'-Dichlorbenzidin- (Czech); 3,3'-Dichloro-4,4'-biphenyldiamine-; 3,3'-Dichloro-4,4'-diamino(1,1-biphenyl); 3,3'-Dichloro-4,4'-diaminobiphenyl-; 3,3'-Dichlorobenzidina- (Spanish); 3,3'-Dichlorobenzidine-; 3,3'-Dichlorobenzidine- (ACGIH); 3,3'-Dichlorobenzidine- (OSHA); 3,3'-Dichlorobiphenyl-4,4'-diamine-; 4,4'-Diamino-3,3'-dichlorobiphenyl-; 4,4'-Diamino-3,3'-dichlorodiphenyl-; C.I. 23060; Curithane-C126-; Dichlorobenzidine-; Dichlorobenzidine-base-; RCRA-waste-number-U073-; o,o'-Dichlorobenzidine- RN: Current: 91-94-1 BRN: 2108022 BHR: 4-13-00-00384 UD: 200302 MF: C12-H10-Cl2-N2 MW: 253.14 WL: ZR BG DR DZ CG CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 50 ug/plate (+S9) Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 4, p. 21, 1977 (CALEDQ); mmo-sat 10 nmol/plate (-S9) Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 225, 1987 (MUTAEX); dns-hmn-hla 100 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); mtr-rat-emb 5 mg/L Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 51, p. 799, 1973 (JNCIAM); bfa-rat-sat 40 mg/kg Sangyo Igaku. Japanese Journal of Industrial Health. (Nippon Sangyo Eisei Igakkai, Kosu Eisei Bldg., 1-29-8, Shinjuku, Shinjuku-ku, Tokyo 160, Japan) V.1- 1959- v. 23, p. 426, 1981 (SAIGBL); mnt-mus-orl 1 gm/kg Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 2, p. 267, 1987 (MUTAEX); dnd-mus-orl 300 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); oms-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); cyt-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); mtr-ham-emb 12500 ug/L Advances in Modern Environmental Toxicology. (Senate Press, Inc., P.O. Box 252, Princeton Junction, NJ 08550) V.1- 1980- v. 1, p. 241, 1980 (AETODY); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); dna-mam-lym 25500 nmol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 38, p. 369, 1982 (CBINA8); mtr-mus-fbr 0.1 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG) TE: V01-P60-R60 orl-rat TDLo: 17 gm/kg/50W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 159, 1975 (TXAPA9); V03-R25 scu-rat TDLo: 3600 mg/kg/61W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 21(6), p. 110, 1975 (VOONAW); V03-L60 orl-mus TDLo: 5100 mg/kg/43W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 5(5), p. 524, 1959 (VOONAW); V01-T65-J60 scu-mus TDLo: 320 mg/kg (15-21D preg) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 78, p. 1402, 1974 (BEXBAN); V03-L60-V10 scu-mus TDLo: 5200 mg/kg/47W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 5(5), p. 524, 1959 (VOONAW); V03-L60-M60 orl-dog TDLo: 17 gm/kg/7Y-I E.I. Dupont de Nemours and Company, Technical Sheet. (1007 Market St., Wilmington, DE 19898) HL623-74, 1974 (DUPON*); V03-L60-M60 orl-ham TDLo: 176 gm/kg/70W-C Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 10, p. 78, 1969 (PAACA3); V03-K60-R60 orl-rat TD :20 gm/kg/52W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 5(5), p. 524, 1959 (VOONAW); V01-P60-R60 orl-rat TD :21 gm/kg/50W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 31, p. 159, 1975 (TXAPA9); V03-V10 scu-rat TD :7 gm/kg/43W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 5(5), p. 524, 1959 (VOONAW) TR: ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 4, p. 49, 1974 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 239, 1982 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 29, p. 239, 1982 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 193, 1987 (IMSUDL); TOXICOLOGY REVIEW Advances in Chemistry Series. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) No.1- 1950- v. 13, p. 271, 1970 (ADCSAJ) SR: MSHA STANDARD: skin-HUMAN CARCINOGEN, NO ASSIGNED TWA The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 77, 1971 (DTLVS*); OSHA PEL (Gen Indu): see CFR 29,1910.1007 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): see CFR 29,1926.1107 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): see CFR 29,1915.1007 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA-cancer suspect agent Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1007, 1987 (CFRGBR); OEL-AUSTRALIA: Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Skin, Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Skin, Carcinogen, JAN 1993; OEL-SWEDEN: Carcinogen, JAN 1999; OEL-SWITZERLAND: TWA 0.1 mg/m3, Skin, Carcinogen JAN 1993; OEL-SWITZERLAND: 0.1 mg/m3, Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO 3,3'-DICHLOROBENZIDINE-air: CA use 29 CFR 1910.1007 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*) SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/99/121980); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/SHE, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Inconclusive: In vitro UDS-human fibroblast; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: 3, 3'-Dichlorobenzidine, 5509; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #ID-65 Record 572 of 1119 in RTECS (through 2003/06) AN: DD0550000 PN: Benzidine,-3,3'-dichloro-,-dihydrochloride- SY: (1,1'-Biphenyl)-4,4'-diamine, 3,3'-dichloro-, dihydrochloride; 3,3'-Dichlorobenzidine-dihydrochloride- RN: Current: 612-83-9 UD: 200207 MF: C12-H10-Cl2-N2.2 Cl-H MW: 326.06 WL: ZR BG D- 2 &GH &GH CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 3 ug/plate (-S9) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 351, 2000 (TOSCF2); mmo-sat 3 ug/plate (+S9) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 351, 2000 (TOSCF2) ORNG: 3820000000 ng/kg. [3820.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 3820 mg/kg "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,211,1969 (34ZIAG) SR: OSHA-cancer suspect agent Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1007, 1987 (CFRGBR) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 573 of 1119 in RTECS (through 2003/06) AN: DD0875000 PN: Benzidine,-3,3'-dimethoxy- SY: 3,3'-Dianisidine-; 3,3'-Dimethoxybenzidin- (Czech); 3,3'-Dimethoxybenzidine-; 3,3'-Dimetossibenzodina- (Italian); 4,4'-Diamino-3,3'-dimethoxybiphenyl-; Acetamine-Diazo-Black-RD-; Acetamine-Diazo-Navy-RD-; Amacel-Developed-Navy-SD-; Azoene-Fast-Blue-Base-; Azogene-Fast-Blue-B-; Blue-BN-Base-; Blue-Base-NB-; Blue-Base-irga-B-; Brentamine-Fast-Blue-B-Base-; C.I. 24110; C.I. Azoic Diazo Component 48; C.I. Disperse Black 6; Cellitazol-B-; Cibacete-Diazo-Navy-Blue-2B-; DMB-; Diacel-Navy-DC-; Diacelliton-Fast-Grey-G-; Dianisidine-; Diato-Blue-Base-B-; Diazo-Fast-Blue-B-; Fast-Blue-B-Base-; Fast-Blue-DSC-Base-; Hiltonil-Fast-Blue-B-Base-; Kayaku-Blue-B-Base-; Lake-Blue-B-Base-; Meisei-Teryl-Diazo-Blue-HR-; Mitsui-Blue-B-Base-; Naphthanil-Blue-B-Base-; RCRA-waste-number-U091-; Setacyl-Diazo-Navy-R-; Spectrolene-Blue-B-; o,o'-Dianisidine-; o-Dianisidin- (Czech, German); o-Dianisidina- (Italian); o-Dianisidine- RN: Current: 119-90-4 UD: 200207 MF: C14-H16-N2-O2 MW: 244.32 WL: 1OR BZ ER DZ CO1 CC: Tumorigen (C); Mutagen (M); Human-Data (P) ME: mmo-sat 1 ug/plate (-S9) Igaku No Ayumi. Progress in Medicine. (Ishiyaku Shuppan K.K., 1-7-10, Honkomagom, Bunkyo-ku, Tokyo, Japan) V.1- 1946- v. 123, p. 18, 1982 (IGAYAY); pic-esc 100 mmol/L Medycyna Doswiadczalna i Mikrobiologia. For English translation, see EXMMAV. (Ars Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1949- v. 31, p. 11, 1979 (MDMIAZ); dns-hmn-hla 100 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); dns-rat-lvr 500 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 3, p. 11, 1981 (ENMUDM); dnd-mus-orl 600 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); oms-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); cyt-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); sce-ham-ovr 500 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 1, 1985 (ENMUDM); oms-dog-oth 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 1893, 1984 (CNREA8); dna-dog-oth 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 1893, 1984 (CNREA8); dnd-rat-lvr 56 umol/L Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 53, p. 71, 2000 (TOSCF2); dnd-hmn-lvr 100 umol/L Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 53, p. 71, 2000 (TOSCF2); dnd-hmn-oth 100 umol/L Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 53, p. 71, 2000 (TOSCF2); mnt-rat-lvr 180 umol/L Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 53, p. 71, 2000 (TOSCF2); dnd-rat-orl 960 mg/kg Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 53, p. 71, 2000 (TOSCF2); mmo-sat 3 ug/plate (+S9) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 351, 2000 (TOSCF2) TE: V03-D45-R60 orl-rat TDLo: 12 gm/kg/56W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 9(7), p. 18, 1965 (GTPZAB); V03-M60 orl-ham TDLo: 588 gm/kg/70W-C Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 10, p. 78, 1969 (PAACA3) ORNG: 1920000000 ng/kg. [1920.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 1920 mg/kg "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,723,1986 (85JCAE); T/E unlistd orl-dog LDLo: 600 mg/kg Archiv fuer Experimentelle Pathologie und Pharmakologie. (Leipzig, Ger. Dem. Rep.) V.1-109, 1873-1925. For publisher information, see NSAPCC. v. 58, p. 167, 1907 (AEXPBL); L30-M30-Y40 orl-rat TDLo: 960 mg/kg Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 53, p. 71, 2000 (TOSCF2) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 4, p. 41, 1974 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 198, 1987 (IMSUDL); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 198, 1987 (IMSUDL); TOXICOLOGY REVIEW Archives of Environmental Health. (Heldref Pub., 4000 Albemarle St., NW, Washington, DC 20016) V.1- 1960- v. 23, p. 6, 1971 (AEHLAU); TOXICOLOGY REVIEW Advances in Chemistry Series. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) No.1- 1950- v. 13, p. 271, 1970 (ADCSAJ) SR: OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-SWEDEN: Carcinogen, JAN 1999; OEL-SWITZERLAND: Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000 ND: NIOSH REL TO o-DIANISIDINE-BASED DYES-air: CA lowest feasible conc. National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 80274; NIS 2; TNF 49; NOS 3; TNE 122; NOES 1983: HZD 80274; NIS 4; TNF 92; NOS 11; TNE 2481; TFE 866 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #ID-71 Record 574 of 1119 in RTECS (through 2003/06) AN: DD1050000 PN: Benzidine,-3,3'-dimethoxy-,-dihydrochloride- SY: (1,1'-Biphenyl)-4,4'-diamine, 3,3-dimethoxy-, dihydrochloride (9CI); o-Dianisidine-dihydrochloride-; C.I. Disperse Black 6 dihydrochloride; 3,3'-Dimethoxybenzidine-dihydrochloride-; 3,3'-Dimethoxy-(1,1-biphenyl)-4,4'-diamine dihydrochloride; 3,3'-Dimethoxy-4,4'-diaminobiphenyl-dihydrochloride- RN: Current: 20325-40-0 UD: 200302 MF: C14-H16-N2-O2.2 Cl-H MW: 317.24 WL: 1OR BZ ER DZ CO1 &GH 2 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 nmol/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 136, p. 33, 1984 (MUREAV); mmo-sat 10 nmol/plate (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10, p. 263, 1987 (EMMUEG); mmo-mus-lym 50 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); msc-mus-lym 33 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); cyt-ham-ovr 500 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-372, 1990 (NTPTR*); sce-ham-ovr 50 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-372, 1990 (NTPTR*) TE: V01-D45-T61 orl-rat TDLo: 1040 mg/kg/1Y-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 41, p. 985, 1968 (JNCIAM); V03-L60-R60 orl-mus TDLo: 5760 mg/kg/2Y-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 25(7), p. 43, 1979 (VOONAW); V03-L60-T64 scu-mus TDLo: 1152 mg/kg/2Y-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 25(7), p. 43, 1979 (VOONAW); V01-D45-R60 orl-rat TD :11 gm/kg/51W-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 41, p. 985, 1968 (JNCIAM); V01-K60-L60 orl-rat TD :6497 mg/kg/91W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-372, 1990 (NTPTR*); V01-A60-L60 orl-rat TDLo: 2822.4 mg/kg/84W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-241072 (NTIS**); V01-A60-L60 orl-rat TDLo: 2352 mg/kg/84W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-241072 (NTIS**) MD: L70-M70-P28 orl-rat TDLo: 9100 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-372, 1990 (NTPTR*); L70-M70-U01 orl-rat TDLo: 8271 mg/kg/13W-C Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 59, p. 297, 1989 (TXCYAC); P30-L70-M70 orl-rat TDLo: 9009 mg/kg/39W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-372, 1990 (NTPTR*) ND: NIOSH REL TO o-DIANISIDINE-BASED DYES-air: CA lowest feasible conc. National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOES 1983: HZD X7012; NIS 1; TNF 7; NOS 1; TNE 489; TFE 300 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (water), clear evidence: rat Record 575 of 1119 in RTECS (through 2003/06) AN: DD1225000 PN: Benzidine,-3,3'-dimethyl- SY: Bianisidine-; (1,1'-Biphenyl)-4,4'-diamine-3,3'-dimethyl-; 4,4'-Bi-o-toluidine-; 4,4'-Diamino-3,3'-dimethylbiphenyl-; 4,4'-Diamino-3,3'-dimethyldiphenyl-; Diaminoditolyl-; RCRA-waste-number-U095-; o-Tolidin-; 2-Tolidin- (German); 2-Tolidina- (Italian); Tolidine-; o-Tolidine-; o,o'-Tolidine-; 2-Tolidine-; 3,3'-Tolidine-; o-Tolidine- (ACGIH); C.I. 37230; C.I. Azoic Diazo Component 113; 3,3'-Dimethylbenzidin-; 3,3'-Dimethylbenzidine-; 3,3'-Dimethyl-4,4'-biphenyldiamine-; 3,3'-Dimethylbiphenyl-4,4'-diamine-; 3,3'-Dimethyl-4,4'-diphenyldiamine-; 3,3'-Dimethyldiphenyl-4,4'-diamine-; 4,4'-Di-o-toluidine-; Fast-Dark-Blue-Base-R- RN: Current: 119-93-7 BRN: 2210640 BHR: 4-13-00-00419 UD: 200210 MF: C14-H16-N2 MW: 212.32 WL: ZR B1 DR DZ C1 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 100 nmol/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 136, p. 33, 1984 (MUREAV); mmo-sat 4 ug/plate (-S9) British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); dns-hmn-hla 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); mtr-rat-emb 5 mg/L Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 51, p. 799, 1973 (JNCIAM); dns-rat-lvr 1 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 136, p. 255, 1984 (MUREAV); bfa-rat-sat 10 ug/plate Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 79, p. 173, 1980 (MUREAV); mnt-mus-orl 16 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 444, p. 175, 1999 (MUREAV); mmo-mus-lym 105 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); mtr-mus-emb 1 mg/L Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 52, p. 1167, 1974 (JNCIAM); dnd-mus-orl 200 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 440, p. 1, 1999 (MUREAV); dni-mus-orl 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 305, 1977 (MUREAV); oms-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); cyt-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 19, 1993 (MUREAV); msc-mus-lym 26 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); dns-ham-lvr 1 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 136, p. 255, 1984 (MUREAV); cyt-ham-ovr 450 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ham-ovr 5 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ckn-par 169 ug/kg "Cytogenetic Assays of Environmental Mutagens," Hsu, T.C., ed., Totowa, NJ, Allanheld, Osmun and Co., 1982 -,137,1982 (47JMAE); sce-rbt-lym 50 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 197, 1981 (MUREAV); mmo-sat 3 ug/plate (+S9) Toxicological Sciences (Oxford University Press, 6277 Sea Harbor Drive, Orlando, FL 32887 ) V. 41, Jan. 1998- v. 56, p. 351, 2000 (TOSCF2) TE: V01-R60 orl-rat TDLo: 4500 mg/kg/27D-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 28, p. 924, 1968 (CNREA8); V03-R60 scu-rat TDLo: 1650 mg/kg/33W-I Voprosy Onkologii. Problems of Oncology. For English translation, see PONCAU. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-10, 1928-37: V.1- 1955- v. 20(2), p. 53, 1974 (VOONAW); V03-L60-R60 imp-rat TDLo: 5040 mg/kg/1Y-I Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 45, p. 283, 1970 (JNCIAM); V03-D45 scu-rat TD :9 gm/kg/51W-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 3, p. 789, 1950 (CANCAR); V03-D45-N60 scu-rat TD :5040 mg/kg/56W-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. 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For publisher information, see NSAPCC. v. 58, p. 167, 1907 (AEXPBL) TR: ACGIH TLV-Confirmed Animal Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 1, p. 87, 1972 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 1, p. 87, 1972 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SR: OEL-AUSTRALIA: Skin, Carcinogen, JAN 1993; OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-FINLAND: Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-SWITZERLAND: Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO o-TOLIDINE-air: CA CL 0.02 mg/m3/60M National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 84756; NIS 1; TNF 11; NOS 5; TNE 421; NOES 1983: HZD 84756; NIS 8; TNF 854; NOS 20; TNE 9640; TFE 6005 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Mammalian micronucleus, Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Inconclusive: In vitro UDS-human fibroblast; EPA TSCA Section 8(b) CHEMICAL INVENTORY; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #ID-71 Record 576 of 1119 in RTECS (through 2003/06) AN: DD1226000 PN: Benzidine,-3,3'-dimethyl-,-dihydrochloride- SY: (1,1'-Biphenyl)-4,4'-diamine, 3,3'-dimethyl-, dihydrochloride (9CI); 4,4'-Diamino-3,3'-dimethylbiphenyl-dihydrochloride-; o-Tolidine-dihydrochloride-; 3,3'-Dimethylbenzidine-dihydrochloride-; 2,3'-Dimethylbiphenyl-4,4'-diamine-dihydrochloride- RN: Current: 612-82-8 UD: 200302 MF: C14-H16-N2.2 Cl-H MW: 285.24 WL: ZR B1 DR DZ C1 &GH 2 CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 10 ug/plate (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11(Suppl 12), p. 1, 1988 (EMMUEG); slt-dmg-unr 2750 ppm National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-390, 1991 (NTPTR*); sln-dmg-orl 14 pph Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 325, 1985 (ENMUDM); sln-dmg-par 2750 ppm Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7, p. 325, 1985 (ENMUDM); cyt-ham-ovr 10 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-390, 1991 (NTPTR*); sce-ham-ovr 20 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-390, 1991 (NTPTR*) TE: V01-L60-R60 orl-rat TDLo: 1820 mg/kg/65W-C Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 10(2), p. 255, 1991 (JACTDZ); V01-J60 orl-mus TDLo: 15288 mg/kg/78W-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 27, p. 801, 1989 (FCTOD7); V01-R60-T69 orl-rat TDLo: 705.6 mg/kg/56W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-103779 (NTIS**); V01-R60-L60 orl-rat TDLo: 1176 mg/kg/56W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-103779 (NTIS**) MD: N30-U01-Z01 orl-rat TDLo: 1120 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-390, 1991 (NTPTR*); N74-P26-P71 orl-rat TDLo: 18200 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-390, 1991 (NTPTR*) ND: NOES 1983: HZD X1372; NIS 3; TNF 132; NOS 6; TNE 1178; TFE 105 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (water), clear evidence: rat Record 577 of 1119 in RTECS (through 2003/06) AN: DF1400000 PN: 2H-1,4-Benzodiazepin-2-one,-7-chloro-1,3-dihydro-3-hydroxy-5-phenyl- SY: Adumbran-; Ansioxacepam-; Anxiolit-; Aplakil-; Astress-; Azutranquil-; Abboxapam-; Bonare-; N-Desmethyltemazepam-; Hi-Long-; Isodin-; Limbial-; Nesontil-; Sigacalm-; Sobril-; Tranquo-buscopan-wirkstoff-; 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one- (IUPAC); 1,3-Dihydro-7-chloro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one-; Durazepam-; Enidrel-; Noctazepam-; Nortemazepam-; Oxazepam-; Pacienx-; Praxiten-; Propax-; Ro-5-6789-; Rondar-; Serax-; Serenid-; Serenid-D-; Serepax-; Seresta-; Tazepam-; Uskan-; Vaben-; WY-3498-; Zaxopam-; Z10-TR- RN: Current: 604-75-1 Previous: 61036-43-9 UD: 200302 MF: C15-H11-Cl-N2-O2 MW: 286.73 WL: T67 GMV JN IHJ CG IQ KR CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: mmo-sat 5200 pmol/plate (-S9) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 4478, 1978 (CNREA8); slt-mus-orl 54000 mg/kg/180D-C Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 62, p. 685, 2001 (BCPCA6); dnd-hmn-oth 1 mmol/L/3H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 439, 2001 (MUTAEX) RE: T85 orl-mus TDLo: 150 mg/kg (12-16D preg) Neurotoxicology and Teratology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.9- 1987- v. 13, p. 75, 1991 (NETEEC); T25 orl-mus TDLo: 400 mg/kg (14D preg) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 25, p. 453, 1973 (TXAPA9); T16 orl-mus TDLo: 1560 mg/kg (26D pre) Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 11, p. 155, 1975 (RCOCB8); T76-T81 orl-mus TDLo: 4140 mg/kg (5D male/3W pre-3W post) Pharmacological Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1969- v. 9, p. 187, 1977 (PLRCAT); T21 orl-mus TDLo: 2 gm/kg (5D male/15D pre) Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 13, p. 601, 1976 (RCOCB8) TE: V01-L60-N62 orl-mus TDLo: 219 gm/kg/2Y-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 23, p. 280, 1994 (FAATDF); V01-L60 orl-mus TDLo: 219 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-443, 1993 (NTPTR*); V03-L60 orl-mus TDLo: 120 gm/kg/57W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 13, p. 373, 1993 (TOXID9); V02-L60 orl-mus TD :65 gm/kg/52W-C Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 8, p. 481, 1974 (RCOCB8); V01-L60 orl-mus TD :239 gm/kg/57W-C Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 8, p. 481, 1974 (RCOCB8); V02-N62 orl-mus TD :219 gm/kg/2Y-C Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 8, p. 481, 1974 (RCOCB8); V01-L60 orl-mus TDLo: 239400 mg/kg/57W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-184181 (NTIS**); V01-L60 orl-mus TDLo: 216300 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB94-184181 (NTIS**); V02-M61-K06 orl-rat TDLo: 78750 mg/kg/105W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB99-120875 (NTIS**) AT: F07-F09-F19 orl-chd TDLo: 8 mg/kg JAMA, Journal of the American Medical Association. (AMA, 535 N. Dearborn St., Chicago, IL 60610) V.1- 1883- v. 196, p. 662, 1966 (JAMAAP); T/E unlistd orl-rat LD50: >8 gm/kg Current Therapeutic Research, Clinical and Experimental. (Therapeutic Research Press, Inc., POB 514, Tenafly, NJ 07670) V.1- 1959- v. 7, p. 590, 1965 (CTCEA9); T/E unlistd ipr-rat LD50: 1535 mg/kg Pharmacology: International Journal of Experimental and Clinical Pharmacology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1968- v. 10, p. 345, 1973 (PHMGBN); T/E unlistd scu-rat LD50: >8 gm/kg Gekkan Yakuji. Pharmaceuticals Monthly. (Yakugyo Jihosha, Inaoka Bldg., 2-36 Jinbo-cho, Kanda, Chiyoda-ku, Tokyo 101, Japan) V.1- 1959- v. 10, p. 183, 1968 (YAKUD5); F02 orl-mus LD50: 1540 mg/kg European Journal of Pharmacology. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1967- v. 4, p. 467, 1968 (EJPHAZ); F02 ipr-mus LD50: 767 mg/kg Journal of Medicinal Chemistry. (American Chemical Soc., Distribution Office Dept. 223, POB POB 57136, West End Stn., Washington, DC 20037) V.6- 1963- v. 11, p. 777, 1968 (JMCMAR); T/E unlistd scu-mus LD50: >400 mg/kg Current Therapeutic Research, Clinical and Experimental. (Therapeutic Research Press, Inc., POB 514, Tenafly, NJ 07670) V.1- 1959- v. 7, p. 590, 1965 (CTCEA9); T/E unlistd orl-rbt LD50: >2 gm/kg Current Therapeutic Research, Clinical and Experimental. (Therapeutic Research Press, Inc., POB 514, Tenafly, NJ 07670) V.1- 1959- v. 7, p. 590, 1965 (CTCEA9) MD: F15-P72 orl-rat TDLo: 61250 mg/kg/35W-I Gekkan Yakuji. Pharmaceuticals Monthly. (Yakugyo Jihosha, Inaoka Bldg., 2-36 Jinbo-cho, Kanda, Chiyoda-ku, Tokyo 101, Japan) V.1- 1959- v. 10, p. 183, 1968 (YAKUD5); L70-M70-N72 orl-rat TDLo: 5250 mg/kg/6W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 16, p. 556, 1970 (TXAPA9); M70-Z72 orl-rat TDLo: 28224 mg/kg/56W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 16, p. 556, 1970 (TXAPA9); P71-P72 orl-rat TDLo: 9411 mg/kg/30D-I Agressologie. Revue Internationale de Physio-Biologie et de Pharmacologie Appliquees aux Effets de l'Agression. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1960- v. 22, p. 209, 1981 (AGSOA6); K06 orl-rat TDLo: 125 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-468, 1998 (NTPTR*); F07-L30-L70 orl-mus TDLo: 7350 mg/kg/14W-C Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 23, p. 280, 1994 (FAATDF); N73 orl-dog TDLo: 10920 mg/kg/52W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 16, p. 556, 1970 (TXAPA9); P28-K70-L70 orl-dog TDLo: 26880 mg/kg/4W-C Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 16, p. 556, 1970 (TXAPA9); F15-Y15 orl-dog TDLo: 36400 mg/kg/26W-I Gekkan Yakuji. Pharmaceuticals Monthly. (Yakugyo Jihosha, Inaoka Bldg., 2-36 Jinbo-cho, Kanda, Chiyoda-ku, Tokyo 101, Japan) V.1- 1959- v. 10, p. 183, 1968 (YAKUD5) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 13, p. 57, 1977 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 66, p. 115, 1996 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 13, p. 57, 1977 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 66, p. 115, 1996 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 66, p. 115, 1996 (IMEMDT); TOXICOLOGY REVIEW Internist. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1960- v. 15, p. 7, 1974 (INTEAG) ND: NOES 1983: HZD X3707; NIS 2; TNF 37; NOS 3; TNE 2657; TFE 1586 SL: NCI Carcinogenesis Studies (feed), clear evidence: mouse; NTP Carcinogenesis Studies (feed), equivocal evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-468, 1998 (NTPTR*); NCI Carcinogenesis Studies (feed), equivocal evidence: rat Record 578 of 1119 in RTECS (through 2003/06) AN: DF6300000 PN: Benzo(j)fluoranthene SY: Benz(j)fluoranthene; 10,11-Benzfluoranthene-; Benzo(l)fluoranthene; 10,11-Benzofluoranthene-; Benzo-12,13-fluoranthene-; B(j)F; 7,8-Benzofluoranthene-; Dibenzo(a,jk)fluorene RN: Current: 205-82-3 BRN: 2049099 BHR: 4-05-00-02687 UD: 200210 MF: C20-H12 MW: 252.32 WL: L D6 C6566 1A TJ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 10 ug/plate (-S9) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 4528, 1980 (CNREA8); msc-hmn-lym 53 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 123, 1996 (MUREAV); dnd-mus-skn 3760 nmol/kg Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 25, p. 121, 1984 (PAACA3); dnd-esc 148.4 ug/L/3H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 515, p. 85, 2002 (MUREAV) TE: V01-J60-V10 imp-rat TDLo: 25 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 71, p. 539, 1983 (JJIND8); V03-R60-V10 skn-mus TDLo: 312 mg/kg/26W-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 12, p. 1194, 1959 (CANCAR); V02-J60-M61 ipr-mus TDLo: 11102 ug/kg/15D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 34, p. 15, 1987 (CALEDQ); V03-J60-V10 imp-rat TD :5 mg/kg "Polynuclear Aromatic Hydrocarbons, International Symposium, 7th, 1982," Cooke, M., and A.J. Dennis, eds., Columbus, OH, Battelle Press, 1983 7,571,1983 (50NNAZ) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 3, p. 82, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 155, 1983 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 155, 1983 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 Pc,4,1972 (85DHAX) SR: OEL-FRANCE: Carcinogen, JAN 1993; OEL-NORWAY: TWA 0.04 mg/m3, JAN 1999 ND: NOES 1983: HZD E0465; NIS 3; TNF 142; NOS 3; TNE 2283 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 579 of 1119 in RTECS (through 2003/06) AN: DF6350000 PN: Benzo(k)fluoranthene SY: 8,9-Benzofluoranthene-; 11,12-Benzofluoranthene-; 11,12-Benzo(k)fluoranthene; 2,3,1',8'-Binaphthylene-; Dibenzo(b,jk)fluorene RN: Current: 207-08-9 BRN: 1873745 BHR: 4-05-00-02686 UD: 200210 MF: C20-H12 MW: 252.32 WL: L E6 C6566 1A TJ CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 10 ug/plate (-S9) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 4528, 1980 (CNREA8); dnd-ofs-orl 125 umol/kg/5D-I Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 427, p. 135, 1999 (MUREAV); msc-hmn-lym 120 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 371, p. 123, 1996 (MUREAV); dnd-esc 129.9 ug/L/3H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 515, p. 85, 2002 (MUREAV) TE: V03-J60-V10 imp-rat TDLo: 5 mg/kg "Polynuclear Aromatic Hydrocarbons, International Symposium, 7th, 1982," Cooke, M., and A.J. Dennis, eds., Columbus, OH, Battelle Press, 1983 7,571,1983 (50NNAZ); V03-R60-V10 skn-mus TDLo: 2820 mg/kg/47W-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 12, p. 1194, 1959 (CANCAR); V03-V10 scu-mus TDLo: 72 mg/kg/9W-I Acta Unio Internationalis Contra Cancrum. (Louvain, Belgium) V.1-20, 1936-64. For publisher information, see IJCNAW. v. 19, p. 490, 1963 (AICCA6) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 163, 1983 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 163, 1983 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) SR: OEL-FRANCE: Carcinogen, JAN 1993; OEL-NORWAY: TWA 0.04 mg/m3, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000 ND: NOES 1983: HZD E0464; NIS 3; TNF 142; NOS 3; TNE 2283 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/95/264370); EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Polynuclear aromatic hydrocarbons by HPLC, 5506, by GC, 5515; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 580 of 1119 in RTECS (through 2003/06) AN: DF6423800 PN: Benzofuran- SY: NCI-C56166-; Benzofuran- (IUPAC); Benzo(b)furan; 2,3-Benzofuran-; Benzofurfuran-; Coumarone-; Cumarone-; 1-Oxindene- RN: Current: 271-89-6 BRN: 107704 BHR: 5-17-02-00003 UD: 200302 MF: C8-H6-O MW: 118.14 WL: T56 BOJ CC: Tumorigen (C); Drug (D); Mutagen (M) ME: oms-mus-orl 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 343, p. 157, 1995 (MUREAV); msc-mus-lym 100 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11, p. 91, 1988 (EMMUEG); sce-ham-ovr 199 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*) TE: V01-M61 orl-rat TDLo: 61800 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*); V01-K60-L60 orl-mus TDLo: 30900 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*); V01-M61 orl-rat TDLo: 30900 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-231127/AS (NTIS**); V01-K60-L60 orl-mus TDLo: 30900 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-231127/AS (NTIS**); V01-K60-L60 orl-mus TDLo: 61800 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-231127/AS (NTIS**) AT: T/E unlistd ipr-mus LD50: 500 mg/kg European Journal of Medicinal Chemistry--Chimie Therapeutique. (Editions Scientifiques Elsevier, 29 rue Buffon, F-75005, Paris, France) V.9- 1974- v. 12, p. 383, 1977 (EJMCA5) MD: Z01 orl-rat TDLo: 7 gm/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*); M03-M04 orl-rat TDLo: 16250 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*); Z01 orl-mus TDLo: 32500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*); Z01 orl-mus TDLo: 437 mg/kg/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 63, p. 431, 1995 (IMEMDT); IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 63, p. 431, 1995 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 63, p. 431, 1995 (IMEMDT) ND: NOHS 1974: HZD M3271; NIS 2; TNF 40; NOS 2; TNE 111 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/93/110666/AS); EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Studies (gavage), clear evidence: mouse; NTP Carcinogenesis Studies (gavage), some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-370, 1989 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: rat Record 581 of 1119 in RTECS (through 2003/06) AN: DG1925000 PN: Benzoic-acid,-3-amino-2,5-dichloro- SY: ACPM-629-; ACP-M-728-; Ambiben-; Amiben-; Amiben-DS-; Amibin-; 3-Amino-2,5-dichlorobenzoic-acid-; Amoben-; Kyselina-3-amino-2,5-dichlorbenzoova- (Czech); NCI-C00055-; Chloramben-; 2,5-Dichloro-3-aminobenzoic-acid-; Ornamental-weeder-; Ornamental-weeder-4G-; Vegiben- RN: Current: 133-90-4 BRN: 2365906 UD: 199904 MF: C7-H5-Cl2-N-O2 MW: 206.03 WL: ZR BG EG CVQ CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M) ME: mmo-sat 10 mg/plate (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5(Suppl 1), p. 3, 1983 (ENMUDM); mmo-sat 1 mg/plate (-S9) NTP Technical Bulletin. (National Toxicology Program, Landow Bldg. 3A-06, 7910 Woodmont Ave., Bethesda, MD 20205) JAN1982 (NTPTB*); cyt-mus-ipr 58500 ug/kg Caryologia. (Via G. LaPira 4, 50121 Florence, Italy) V.1- 1948- v. 33, p. 527, 1980 (CARYAB); cyt-mus-orl 234 mg/kg Caryologia. (Via G. LaPira 4, 50121 Florence, Italy) V.1- 1948- v. 33, p. 527, 1980 (CARYAB) TE: V01-L60 orl-mus TDLo: 672 gm/kg/80W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-25, 1977 (NCITR*); V01-L60 orl-mus TD :1344 gm/kg/80W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-25, 1977 (NCITR*) ORNG: 3500000000 ng/kg. [3500.000000 mg/kg] T/E unlistd SRNG: 3136000000 ng/kg. [3136.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 3500 mg/kg Residue Reviews. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1962- v. 10, p. 97, 1965 (RREVAH); T/E unlistd skn-rat LD50: >2200 mg/kg Pesticide Manual. (The British Crop Protection Council, 20 Bridport Rd., Thornton Heath CR4 7QG, UK) V.1- 1968- v. 9, p. 136, 1991 (PEMNDP); T/E unlistd orl-mus LD50: 3725 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 45(4), p. 74, 1980 (GISAAA); T/E unlistd skn-rbt LD50: 3136 mg/kg World Review of Pest Control. (London, UK) V.1-10, 1962-71. Discontinued. v. 9, p. 119, 1970 (WRPCA2) MD: Y15-Y16-Z01 orl-rat TDLo: 364 mg/kg/52W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 45(4), p. 74, 1980 (GISAAA) SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; On EPA IRIS database; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-25, 1977 (NCITR*); NCI Carcinogenesis Bioassay (feed), no evidence: rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-25, 1977 (NCITR*) Record 582 of 1119 in RTECS (through 2003/06) AN: DG9400000 PN: Benzoic acid, p-(dipropylsulfamoyl)- SY: Apurina-; Benacen-; Benecid-; Benemid-; Benemide-; Benuryl-; Benzoic acid, 4-((dipropylamino)sulfonyl)- (9CI); NCI-C56097-; 4-((Dipropylamino)sulfonyl)benzoic acid; p-(Dipropylsulfamoyl)benzoic acid; 4-(Dipropylsulfamoyl)benzoic acid; p-(Dipropylsulfamyl)benzoic acid; Ethamide-; Probecid-; Proben-; Probenecid-; Probenecid-acid-; Probenemid-; Probenid-; Probalan-; Prolongine-; Robenecid-; Synergid-R-; Tubophan-; Uricosid- RN: Current: 57-66-9 BRN: 2815775 BHR: 4-11-00-00691 UD: 200302 MF: C13-H19-N-O4-S MW: 285.39 WL: QVR DSWN3&3 CC: Tumorigen (C); Drug (D); Mutagen (M); Human-Data (P) ME: sce-ham-ovr 5 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*) TE: V02-L60 orl-mus TDLo: 206 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*); V02-L60 orl-mus TDLo: 206000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-129584/AS (NTIS**) ORNG: 1600000000 ng/kg. [1600.000000 mg/kg] T/E unlistd AT: P23 orl-man TDLo: 50 mg/kg/1W-I Journal of Rheumatology. (920 Yonge St., Suite 608, Toronto, Ont., Canada) V.1- 1974- v. 13, p. 208, 1986 (JRHUA9); T/E unlistd orl-rat LD50: 1600 mg/kg "Merck Index: an Encyclopedia of Chemicals, Drugs, and Biologicals", 11th ed., Rahway, NJ 07065, Merck and Co., Inc. 1989 11,1230,1989 (85KYAH); T/E unlistd ipr-rat LDLo: 394 mg/kg Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) (CLDND*); T/E unlistd scu-rat LDLo: 611 mg/kg Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) (CLDND*); T/E unlistd orl-mus LD50: 1666 mg/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. 6, p. 735, 1982 (NIIRDN); T/E unlistd ipr-mus LDLo: 1 gm/kg Chemical and Pharmaceutical Bulletin. (Japan Pub. Trading Co., USA, 1255 Howard St., San Francisco, CA 94103) V.6- 1958- v. 16, p. 1655, 1968 (CPBTAL); T/E unlistd scu-mus LDLo: 1156 mg/kg Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) (CLDND*); T/E unlistd ivn-mus LDLo: 458 mg/kg Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) (CLDND*); T/E unlistd ivn-dog LDLo: 230 mg/kg Compilation of LD50 Values of New Drugs. (J.R. MacDougal, Dept. of National Health and Welfare, Food and Drug Divisions, 35 John St., Ottawa, Ont., Canada) (CLDND*); T/E unlistd ivn-rbt LD50: 304 mg/kg Drugs in Japan (Ethical Drugs). (Yakugyo Jiho Co., Ltd., Tokyo, Japan) v. -, p. 1045, 1990 (NIIRDN); L14-Y51 ivn-rat TDLo: 18.8 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 297, p. 1036, 2001 (JPETAB) MD: U01 orl-rat TDLo: 9600 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*); D35-L30-U01 orl-rat TDLo: 52 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*); L70-N30-U01 ivn-rat TDLo: 6720 mg/kg/2W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 48, p. 319, 1999 (TOXID9); Z01 orl-mus TDLo: 38400 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*); U01-Z01 orl-mus TDLo: 52 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*); F15-L70-N30 ivn-dog TDLo: 3360 mg/kg/2W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 48, p. 319, 1999 (TOXID9); N61-V30 orl-rat TDLo: 206000 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-129584/AS (NTIS**); R60-N62-V30 orl-rat TDLo: 51500 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB92-129584/AS (NTIS**) ND: NOES 1983: HZD X4171; NIS 2; TNF 66; NOS 9; TNE 4059; TFE 1675 SL: EPA GENETOX PROGRAM 1988, Negative: S cerevisiae gene conversion; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Studies (gavage), some evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-395, 1991 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse; NCI Carcinogenesis Studies (gavage), no evidence: rat Record 583 of 1119 in RTECS (through 2003/06) AN: DH0175000 PN: Benzoic acid, o-(6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl)-,ethyl ester, monohydrochloride SY: Aizen-Rhodamine-6GCP-; Basic-Red-1-; Basic-Rhodamine-Yellow-; Basic-Rhodaminic-Yellow-; Calcozine-Red-6G-; Calcozine-Rhodamine-6GX-; Heliostable-Brilliant-Pink-B-Extra-; NCI-C56122-; Silosuper-Pink-B-; Cerven-zasadita-1- (Czech); C.I. 45160; C.I. Basic Red 1; C.I. Basic Red 1, monohydrochloride; Elcozine-Rhodamine-6GDN-; Eljon-Pink-Toner-; Fanal-Pink-B-; Fanal-Pink-GFK-; Fanal-Red-25532-; Flexo-Red-482-; Mitsui-Rhodamine-; Mitsui-Rhodamine-6GCP-; Nyco-Liquid-Red-GF-; Rh-6G-; Rhodamine-590-chloride-; Rhodamine-69DN-Extra-; Rhodamine-F4G-; Rhodamine-F5G-; Rhodamine-F5G-chloride-; Rhodamine-F-5GL-; Rhodamine-6G-; Rhodamine-6GB-; Rhodamine-6G- (biological stain); Rhodamine-6G-chloride-; Rhodamine-6GBN-; Rhodamine-6GCP-; Rhodamine-4GD-; Rhodamine-6GD-; Rhodamine-GDN-; Rhodamine-5GDN-; Rhodamine-6-GDN-; Rhodamine-6-GDN-Extra-; Rhodamine-6GEX-ethyl-ester-; Rhodamine-6G-Extra-; Rhodamine-6G-Extra-Base-; Rhodamine-4GH-; Rhodamine-6GH-; Rhodamine-5GL-; Rhodamine-6G-Lake-; Rhodamine-6GO-; Rhodamine-6GX-; Rhodamine-J-; Rhodamine-6JH-; Rhodamine-7JH-; Rhodamine-Lake-Red-6G-; Rhodamine-Y-20-7425-; Rhodamine-6Zh-DN-; Rhodamine-ZH-; Rhodamine-6ZH-; Rhodamin-6G-; Vali-Fast-Red-1308-; Xanthylium, 9-(2-(ethoxycarbonyl)phenyl)-3,6-bis(ethylamino)-2,7-dimethyl-, chloride RN: Current: 989-38-8 UD: 200302 MF: C28-H31-N2-O3.Cl MW: 479.06 WL: T C666 BO EYJ EUN2 F1 IR BVO2& L1 MN1&1 &GH CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 20 nmol/plate (-S9) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 4412, 1979 (CNREA8); msc-mus-lym 2500 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*); dnd-ham-ovr 90 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 4412, 1979 (CNREA8); cyt-ham-ovr 20 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*); sce-ham-ovr 19900 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*) RE: T35 ipr-mus TDLo: 4 mg/kg (7-10D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 33, p. 67C, 1986 (TJADAB); T39 ipr-mus TDLo: 2 mg/kg (7-10D preg) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 9, p. 29, 1989 (TCMUD8); T25-T34-T35 ipr-mus TDLo: 2 mg/kg (7-10D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 40, p. 143, 1989 (TJADAB); T39-T46 ipr-mus TDLo: 2 mg/kg (7-10D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 40, p. 143, 1989 (TJADAB) TE: V03-R60 orl-rat TDLo: 7725 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*); V03-V10 scu-rat TDLo: 100 mg/kg/1Y-I Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 47, p. 51, 1956 (GANNA2); V02-R60 orl-rat TDLo: 10815 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-219460/AS (NTIS**); V03-N61 orl-rat TDLo: 9012.5 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-219460/AS (NTIS**) AT: T/E unlistd orl-rat LDLo: 125 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*); G30-L30-P23 orl-mus LDLo: 50 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 7(2), p. 34, 1963 (GTPZAB); T/E unlistd ipr-mus LD50: 6150 ug/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 51, p. 35, 1990 (TOLED5) MD: Z01 orl-rat TDLo: 2310 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*); P27 orl-rat TDLo: 10192 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*); J02-U01-Z01 ihl-rat TCLo: 130 mg/kg/35D-I Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 7(2), p. 34, 1963 (GTPZAB); U01 orl-mus TDLo: 51 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-364, 1989 (NTPTR*) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 16, p. 233, 1978 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 16, p. 233, 1978 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) ND: NOHS 1974: HZD M2209; NIS 20; TNF 917; NOS 21; TNE 15041; NOES 1983: HZD M2209; NIS 27; TNF 2416; NOS 32; TNE 41538; TFE 8238 SL: EPA GENETOX PROGRAM 1988, Inconclusive: B subtilis rec assay; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: mouse Record 584 of 1119 in RTECS (through 2003/06) AN: DH5075000 PN: Benzoic-acid,-p-nitro- SY: 1-Carboxy-4-nitrobenzene-; Kyselina-p-nitrobenzoova- (Czech); p-Nitrobenzenecarboxylic-acid-; p-Nitrobenzoic-acid-; 4-Nitrobenzoic-acid-; 4-Nitrodracylic-acid- RN: Current: 62-23-7 UD: 200305 MF: C7-H5-N-O4 MW: 167.13 WL: WNR DVQ CC: Tumorigen (C); Mutagen (M); Primary-Irritant (S); Reproductive-Effector (T) ID: eye-rbt 20 mg/24H MOD "Prehled Prumyslove Toxikologie: Organicke Latky," Marhold, J., Prague, Czechoslovakia, Avicenum, 1986 -,739,1986 (85JCAE) ME: mmo-sat 100 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 137, p. 71, 1984 (MUREAV); mmo-sat 1 mg/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9(Suppl 9), p. 1, 1987 (ENMUDM); dnr-bcs 50 ug/disc Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 170, p. 11, 1986 (MUREAV); bfa-rat-sat 400 mg/kg/4D Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 72, p. 4607, 1975 (PNASA6); cyt-ham-ovr 875 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9, p. 269, 1987 (ENMUDM); sce-ham-ovr 1 gm/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9, p. 269, 1987 (ENMUDM) RE: T22-T72-T81 orl-mus TDLo: 132.3 gm/kg (21W pre) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB90253766 (NTIS**) TE: V02-R60 orl-rat TDLo: 45063 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-442, 1994 (NTPTR*); V03-T69 orl-rat TDLo: 43260 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB95-226254 (NTIS**) ORNG: 1960000000 ng/kg. [1960.000000 mg/kg] D17-F12 AT: D17-F12 orl-rat LD50: 1960 mg/kg Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 160, p. 1097, 1966 (CRSBAW); D17-F12 ipr-rat LD50: 1210 mg/kg Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 160, p. 1097, 1966 (CRSBAW); D17-F12 par-rat LD50: 1960 mg/kg Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 160, p. 1097, 1966 (CRSBAW); F07-F12-F43 ipr-mus LD50: 880 mg/kg Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 160, p. 1097, 1966 (CRSBAW); F07-F12-F43 ivn-mus LD50: 770 mg/kg Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 160, p. 1097, 1966 (CRSBAW); F07-F12-F43 par-mus LD50: 1470 mg/kg Comptes Rendus des Seances de la Societe de Biologie et de Ses Filiales. (SPPIF, B.P.22, F-41353 Vineuil, France) V.1- 1849- v. 160, p. 1097, 1966 (CRSBAW) MD: P05-P24-U01 orl-rat TDLo: 11760 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-442, 1994 (NTPTR*); M03-P27 orl-rat TDLo: 10400 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-442, 1994 (NTPTR*); L70-N74 orl-mus TDLo: 56 gm/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-442, 1994 (NTPTR*); U01 orl-mus TDLo: 11050 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-442, 1994 (NTPTR*); P61-V30 orl-rat TDLo: 90125 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB95-226254 (NTIS**); U01 orl-mus TDLo: 264.6 gm/kg/21W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. #PB86167053 (NTIS**) SR: OEL-RUSSIA: STEL 2 mg/m3, JAN 1993 ND: NOHS 1974: HZD 83217; NIS 2; TNF 32; NOS 3; TNE 396; NOES 1983: HZD 83217; NIS 31; TNF 3573; NOS 46; TNE 42700; TFE 12407 SL: EPA GENETOX PROGRAM 1988, Negative: Host-mediated assay; EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Carcinogenesis Studies (feed), some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-442, 1994 (NTPTR*); NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: mouse Record 585 of 1119 in RTECS (through 2003/06) AN: DI5775000 PN: Benzo(rst)pentaphene SY: DB(a,i)P; RCRA-waste-number-U064-; Dibenzo(a,i)pyrene; Dibenzo(b,h)pyrene; 1,2,7,8-Dibenzopyrene-; 3,4:9,10-Dibenzopyrene; Dibenz(a,i)pyrene; 1,2:7,8-Dibenzpyrene; 3,4:9,10-Dibenzpyrene RN: Current: 189-55-9 BRN: 1881370 BHR: 4-05-00-02803 UD: 200007 MF: C24-H14 MW: 302.38 WL: L D6 B66 P666 2AB A&J CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 20 ug/plate (-S9) Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 72, p. 5135, 1975 (PNASA6); dnr-esc 600 ug/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 53, 1977 (MUREAV); dna-esc 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); msc-hmn-lym 3200 nmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 342, p. 9, 1995 (MUREAV); mnt-rat-itr 30 mg/kg/16H-I Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 326, p. 147, 1995 (MUREAV); mtr-rat-itr 3750 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 412, p. 283, 1998 (MUREAV); mtr-rat-oth 50 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 412, p. 283, 1998 (MUREAV); dna-rat-itr 7500 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 312, p. 165, 1994 (MUREAV); sce-rat-itr 7500 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 312, p. 165, 1994 (MUREAV); mmo-ham-lng 30 ug/L (+S9) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 1646, 1982 (CNREA8); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI) TE: V01-R60 par-rat TDLo: 96761 ug/kg Journal of Cancer Research and Clinical Oncology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.93- 1979- v. 115, p. 67, 1989 (JCROD7); V03-R60 skn-mus TDLo: 47 mg/kg/39W-I Cancer (Philadelphia). (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1948- v. 12, p. 1079, 1959 (CANCAR); V03-V10 scu-mus TDLo: 1000 ug/kg Progress in Experimental Tumor Research. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1960- v. 11, p. 384, 1969 (PEXTAR); V02-V10 scu-ham TDLo: 2 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 203, p. 308, 1964 (NATUAS); V03-J60 itr-ham TDLo: 33 gm/kg/8W-I Zeitschrift fuer Krebsforschung und Klinische Onkologie. (Berlin, Fed. Rep. Ger.) V.76-92, 1971-78. For publisher information, see JCROD7. v. 82, p. 175, 1974 (ZKKOBW); V03-J60-L60 scu-mus TD :72 mg/kg/9W-I Comptes Rendus Hebdomadaires des Seances, Academie des Sciences. (Paris, France) V.1-261, 1835-1965. For publisher information, see CRASEV. v. 246, p. 1477, 1958 (COREAF); V03-R60-V10 skn-mus TD :141 mg/kg/47W-I Indian Journal of Medical Research. (Indian Council of Medical Research, Ansari Nagar, New Delhi 110 029, India) V.1- 1913- v. 53, p. 638, 1965 (IJMRAQ); V03-V10 scu-ham TD :16 mg/kg Progress in Experimental Tumor Research. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1960- v. 11, p. 384, 1969 (PEXTAR); V03-V10 scu-mus TD :80 mg/kg Indian Journal of Medical Research. (Indian Council of Medical Research, Ansari Nagar, New Delhi 110 029, India) V.1- 1913- v. 53, p. 638, 1965 (IJMRAQ); V03-V10 scu-mus TD :4 mg/kg Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 13, p. 37, 1972 (PAACA3) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 3, p. 215, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 337, 1983 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 337, 1983 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 Pc,4,1972 (85DHAX) SR: OEL-FRANCE: Carcinogen, JAN 1993 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat, Histidine reversion-Ames test; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 586 of 1119 in RTECS (through 2003/06) AN: DI9950000 PN: Benzophenone- SY: Benzene,-benzoyl-; Benzoylbenzene-; Ketone,-diphenyl-; Diphenyl-ketone-; Diphenylmethanone-; alpha-Oxodiphenylmethane-; alpha-Oxoditane-; Phenyl-ketone- RN: Current: 119-61-9 UD: 200012 MF: C13-H10-O MW: 182.23 WL: RVR CC: Tumorigen (C); Mutagen (M) SRNG: 3535000000 ng/kg. [3535.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: >10 gm/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 11, p. 873, 1973 (FCTXAV); F07-F11-J30 orl-mus LD50: 2895 mg/kg European Journal of Toxicology and Environmental Hygiene. (Paris, France) V.7-9, 1974-76. For publisher information, see TOERD9. v. 9, p. 99, 1976 (EJTXAZ); F07-F11-J30 ipr-mus LD50: 727 mg/kg European Journal of Toxicology and Environmental Hygiene. (Paris, France) V.7-9, 1974-76. For publisher information, see TOERD9. v. 9, p. 99, 1976 (EJTXAZ); T/E unlistd skn-rbt LD50: 3535 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 11, p. 873, 1973 (FCTXAV) MD: P08-P28-P71 orl-rat TDLo: 14 gm/kg/28D-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 29, p. 741, 1971 (FCTOD7); U01 orl-rat TDLo: 91 gm/kg/13W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 221, 1994 (TOXID9); L70-M03-Y03 orl-rat TDLo: 7350 mg/kg/14W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-00-3943 (NTPTR*); L70-P28-U01 orl-mus TDLo: 109 gm/kg/13W-C Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 14, p. 221, 1994 (TOXID9); L30-L70 orl-mus TDLo: 19600 mg/kg/14W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-00-3943 (NTPTR*); L30-L04 ihl-gpg TDLo: 75 mg/kg/15D-I Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 50, p. 282, 1993 (BECTA6) ND: NOHS 1974: HZD 83170; NIS 8; TNF 1495; NOS 11; TNE 6944; NOES 1983: HZD 83170; NIS 27; TNF 1809; NOS 50; TNE 41516; TFE 18162 SL: EPA GENETOX PROGRAM 1988, Negative: E coli polA without S9; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis studies, on test (two year studies), October 2000 Record 587 of 1119 in RTECS (through 2003/06) AN: DJ0250000 PN: Benzophenone, 4,4'-bis(dimethylamino)- SY: p,p'-Bis(N,N-dimethylamino)benzophenone; 4,4'-Bis(dimethylamino)benzophenone; Bis(p-(N,N-dimethylamino)phenyl)ketone; Bis(4-(dimethylamino)phenyl)methanone; NCI-C02006-; Michler-ketone-; Michler's-ketone-; p,p'-Michler's-ketone-; Tetramethyldiaminobenzophenone- RN: Current: 90-94-8 UD: 200210 MF: C17-H20-N2-O MW: 268.39 WL: 1N1&R D- 2V CC: Tumorigen (C); Mutagen (M) ME: mmo-sat 33300 ng/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 5), p. 1, 1985 (ENMUDM); pic-esc 12500 ng/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 260, p. 349, 1991 (MUREAV); mtr-rat-emb 1240 ng/plate JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 1, p. 190, 1981 (JJATDK); dnd-rat-ipr 7500 ug/kg NATO ASI Series, Series A: Life Sciences. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.53- 1983- v. 60, p. 745, 1983 (NALSDJ); dns-rat-orl 200 mg/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 7(Suppl 3), p. 73, 1985 (ENMUDM); dns-rat-lvr 5 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 97, p. 359, 1982 (MUREAV); mmo-mus-lym 4 mg/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); mtr-mus-emb 30 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 21, 1988 (EMMUEG); sce-rat-ipr 7500 ug/kg NATO ASI Series, Series A: Life Sciences. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.53- 1983- v. 60, p. 745, 1983 (NALSDJ); msc-mus-lym 13100 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 37, 1988 (EMMUEG); cyt-ham-fbr 1500 ug/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 1, p. 17, 1986 (MUTAEX); sln-ham-fbr 1500 ug/L Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 1, p. 17, 1986 (MUTAEX); mtr-mus-fbr 1 ug/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) TE: V01-L60 orl-rat TDLo: 15 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-181, 1979 (NCITR*); V01-H60-L60 orl-mus TDLo: 82 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-181, 1979 (NCITR*); V01-L60 orl-rat TD :27 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-181, 1979 (NCITR*); V02-L60 orl-rat TD :8 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-181, 1979 (NCITR*); V01-H60-L60 orl-mus TD :164 gm/kg/78W-C National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-181, 1979 (NCITR*) AT: T/E unlistd orl-bwd LD50: 100 mg/kg Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 12, p. 355, 1983 (AECTCV) SR: OEL-AUSTRIA: Suspected Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999 ND: NOES 1983: HZD X1044; NIS 7; TNF 174; NOS 11; TNE 2026; TFE 405 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NCI Carcinogenesis Bioassay (feed), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-181, 1979 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 588 of 1119 in RTECS (through 2003/06) AN: DJ1575000 PN: Benzophenone,-2-hydroxy-4-methoxy- SY: Benzophenone-3-; Cyasorb-UV-9-; Methanone, (2-hydroxy-4-methoxyphenyl)phenyl-; 4-Methoxy-2-hydroxybenzophenone-; NCI-C60957-; Spectra-sorb-UV-9-; 2-Hydroxy-4-methoxybenzophenone-; (2-Hydroxy-4-methoxyphenyl)phenylmethanone; MOB-; NSC-7778-; Oxybenzone-; Syntase-62-; UF-3-; USAF-CY-9-; Uvinul-M-40- RN: Current: 131-57-7 BRN: 1913145 BHR: 4-08-00-02442 UD: 200012 MF: C14-H12-O3 MW: 228.26 WL: 1OR CQ DVR CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T) ME: mmo-sat 100 ug/plate (-S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 9(Suppl 9), p. 1, 1987 (ENMUDM) RE: T12 orl-rat TDLo: 45 gm/kg (90D pre) Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 10, p. 41, 1972 (FCTXAV); T02 orl-rat TDLo: 54 gm/kg (90D male) Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 10, p. 41, 1972 (FCTXAV); T01-T02 orl-rat TDLo: 333 gm/kg (13W male) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); T14 orl-rat TDLo: 297 gm/kg (13W pre) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); T01-T02 orl-mus TDLo: 1268 gm/kg (13W male) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); T14 orl-mus TDLo: 1687 gm/kg (13W pre) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); T01-T02 skn-mus TDLo: 5915 mg/kg (13W male) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*) ORNG: 7400000000 ng/kg. [7400.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 7400 mg/kg Journal of the American College of Toxicology. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1-12, 1982-1993. Discontinued. v. 2(5), p. 35, 1983 (JACTDZ); T/E unlistd ipr-mus LD50: 300 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD277-689 (NTIS**) MD: M03-P70-U01 orl-rat TDLo: 189 gm/kg/90D-C Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 10, p. 41, 1972 (FCTXAV); L70-M70 orl-rat TDLo: 8246 mg/kg/2W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); L70-M03-P73 orl-rat TDLo: 164 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); L70-M70 skn-rat TDLo: 1 gm/kg/2W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); L70-M70-P70 skn-rat TDLo: 6500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); L70-M70 orl-mus TDLo: 104 gm/kg/2W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); L70-M70-U01 orl-mus TDLo: 544 gm/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*); L70-M70-U01 skn-mus TDLo: 400 mg/kg/2W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NIH-92-3344 (NTPTR*) ND: NOHS 1974: HZD M3220; NIS 3; TNF 51; NOS 5; TNE 549; NOES 1983: HZD M3220; NIS 21; TNF 1336; NOS 18; TNE 27518; TFE 8664 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NTP Toxicity studies, RPT# TOX-21, October 2000; NTP Carcinogenesis studies, laboratory assigned, October 2000 Record 589 of 1119 in RTECS (through 2003/06) AN: DJ2800000 PN: (1)Benzopyrano(3,4-b)furo(2,3-h)(1)benzopyran-6(6ah)-one, 1,2,12,12a-tetrahydro-2-alpha- isopropenyl-8,9-dimethoxy- SY: (-)-Rotenone; (-)-cis-Rotenone; 5'-beta-Rotenone-; Barbasco-; Canex-; Cenol-garden-dust-; Chem-fish-; Chem-Mite-; Cube-; Cube-extract-; Cube-root-; Cube-Pulver-; Cubor-; Curex-flea-duster-; Dactinol-; Deril-; Derrin-; Derris-; Derris- (insecticide); Dri-Kil-; ENT-133-; Extrax-; Fish-Tox-; Gerane-; Green-cross-warble-powder-; Haiari-; Liquid-derris-; Mexide-; NCI-C55210-; Nekoe-; Nicouline-; Noxfish-; Paraderil-; Powder-and-root-; Prenfish-; Pro-Nox-fish-; Ro-KO-; Ronone-; Rotefive-; Rotefour-; Rotenon-; Rotenona- (Spanish); Rotenone-; Rotenone- (ACGIH:OSHA); Rotenone-commercial-; Rotenox-5EC-; Rotessenol-; Rotocide-; Synpren-; Tubatoxin- RN: Current: 83-79-4 Previous: 12679-58-2 UD: 200210 MF: C23-H22-O6 MW: 394.45 WL: T G5 D6 B666 CV HO MO POT&TT&J IY1&U1 SO1 TO1 CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Human-Data (P); Natural-Product (N); Primary-Irritant (S) ID: eye-rbt 1% MLD Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 34, p. 135, 1936 (PSEBAA) ME: mnt-hmn-lym 250 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 414, p. 1, 1998 (MUREAV); dnd-rat-lvr 15 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 59, 1996 (MUREAV); mnt-mus-oth 1 mg/L Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 56, p. 357, 1976 (JNCIAM); msc-mus-lym 250 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12, p. 85, 1988 (EMMUEG); sce-ham-ovr 600 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-320, 1988 (NTPTR*); sln-ham-lng 50 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 263, p. 173, 1991 (MUREAV) RE: T25-T26 orl-rat TDLo: 100 mg/kg (6-15D preg) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 10, p. 111, 1982 (JTEHD6); T46 orl-rat TDLo: 50 mg/kg (6-15D preg) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 10, p. 111, 1982 (JTEHD6); T13 orl-rat TDLo: 2960 ug/kg (6-9D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 28, p. 360, 1982 (BECTA6); T72 orl-rat TDLo: 98 mg/kg (6-15D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 28, p. 360, 1982 (BECTA6); T25-T26 orl-mus TDLo: 288 mg/kg (6-17D preg) Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 126, 2001 (HBPTO*); T46-T53 orl-rat TDLo: 132 mg/kg (1-22D preg) Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1185, 2001 (HBPTO*); T46 orl-rat TDLo: 50 mg/kg (6-15D preg) Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1185, 2001 (HBPTO*); T35 orl-rat TDLo: 132 mg/kg (1-22D preg) Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1185, 2001 (HBPTO*); T25-T26 orl-mus TDLo: 504 mg/kg (1-21D preg) Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 2, p. 1185, 2001 (HBPTO*) TE: V03-N60 orl-rat TDLo: 3245 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-320, 1988 (NTPTR*); V02-R60 ipr-rat TDLo: 71 mg/kg/42D-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 3047, 1973 (CNREA8); V03-R60 ipr-rat TD :68 mg/kg/40D-I British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 36, p. 243, 1977 (BJCAAI); V03-N62 orl-rat TD :3285 mg/kg/2Y-C Drug and Chemical Toxicology. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.1- 1977/78- v. 11, p. 225, 1988 (DCTODJ); V02-N60 orl-rat TDLo: 3244.5 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB89-139760/AS (NTIS**); V01-R60 orl-rat TDLo: 1369.9 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB89-139760/AS (NTIS**) ORNG: 25000000 ng/kg. [25.000000 mg/kg] T/E unlistd AT: K30 orl-hmn LDLo: 143 mg/kg "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,521,1969 (34ZIAG); T/E unlistd unr-man LDLo: 294 mg/kg "Poisoning: Toxicology, Symptoms, Treatments," 2nd ed., Arena, J.M., Springfield, IL, C.C. Thomas, 1970 2,73,1970 (85DCAI); T/E unlistd ihl-rat LCLo: 500 mg/m3/30M Farmaco, Edizione Scientifica. (Casella Postale 227, 27100 Pavia, Italy) V.8-43 1953-88 For publisher information, see FRMCE8 v. 20, p. 270, 1965 (FRPSAX); T/E unlistd skn-rat LD50: >940 mg/kg World Review of Pest Control. (London, UK) V.1-10, 1962-71. Discontinued. v. 9, p. 119, 1970 (WRPCA2); F12-F24-G07 ipr-rat LD50: 1600 ug/kg Farmaco, Edizione Scientifica. (Casella Postale 227, 27100 Pavia, Italy) V.8-43 1953-88 For publisher information, see FRMCE8 v. 20, p. 270, 1965 (FRPSAX); F12-F24-G07 ivn-rat LD50: 200 ug/kg Farmaco, Edizione Scientifica. (Casella Postale 227, 27100 Pavia, Italy) V.8-43 1953-88 For publisher information, see FRMCE8 v. 20, p. 270, 1965 (FRPSAX); T/E unlistd unr-rat LD50: 132 mg/kg Journal of Environmental Science and Health, Part B: Pesticides, Food Contaminants, and Agricultural Wastes. (Marcel Dekker, 270 Madison Ave., New York, NY 10016) V.B11- 1976- v. 15, p. 929, 1980 (JPFCD2); T/E unlistd orl-mus LD50: 2800 ug/kg EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 14, p. 109, 1976 (EVHPAZ); T/E unlistd ipr-mus LD50: 2650 ug/kg Radiation Research. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1954- v. 91, p. 186, 1982 (RAREAE); K06-K13 orl-dog LDLo: 300 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); F19-J26-K13 ivn-dog LDLo: 650 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); F19-J26-K13 ivn-cat LDLo: 650 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); K06-K12 orl-rbt LDLo: 1600 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); T/E unlistd skn-rbt LD50: >1 gm/kg Special Publication of the Entomological Society of America. (4603 Calvert Rd., College Park, MD 20740) v. 78-1, p. 5, 1978 (SPEADM); T/E unlistd scu-rbt LDLo: 20 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); F19-F23-J26 ivn-rbt LDLo: 350 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); T/E unlistd ims-rbt LDLo: 5 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); F19-J25-K13 orl-pig LDLo: 3700 ug/kg Journal of the American Veterinary Medical Association. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.48- 1915- v. 130, p. 410, 1957 (JAVMA4); J16-K06 orl-gpg LDLo: 100 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 34, p. 135, 1936 (PSEBAA); F12-F19-J25 ipr-gpg LDLo: 10 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 34, p. 135, 1936 (PSEBAA); F19-J26-K13 ivn-pgn LDLo: 1 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); T/E unlistd orl-dck LD50: >2 gm/kg Down to Earth. (Dow Chemical USA, Agricultural Products Dept., Midland, MI 48640) V.1- 1945- v. 35, p. 25, 1979 (DOEAAH); J22 orl-frg LDLo: 4 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 43, p. 193, 1931 (JPETAB); T/E unlistd orl-rat LD50: 25 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-rat LD70: 600 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-gpg LD50: 12 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-gpg LDLo: 75 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-gpg LD70: 60 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd scu-gpg LDLo: 16 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd ipr-gpg LDLo: 2 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-rbt LDLo: 1500 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-rbt LD70: 3000 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-ckn LD50: 996 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-brd LD50: 850 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-pgn LD50: 100 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd orl-bwd LD50: 195 mg/kg Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*); T/E unlistd unr-frg LC50: 2 ppm Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*) MD: Z01 orl-rat TDLo: 1505 mg/kg/14D-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-320, 1988 (NTPTR*); L70-P26-Z01 orl-rat TDLo: 5460 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-320, 1988 (NTPTR*); L70-Z01 orl-mus TDLo: 54600 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-320, 1988 (NTPTR*); J16-U01-Z01 orl-ham TDLo: 180 mg/kg/9D-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB81-190936 (NTIS**); T15 orl-rat TDLo: 13.5 mg/kg/60D-I Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 124, 2001 (HBPTO*); T15 ipr-rat TDLo: 7.1 mg/kg/42D-I Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 124, 2001 (HBPTO*); F15 orl-rat TDLo: 185 mg/kg/37D-I Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 124, 2001 (HBPTO*); F15 orl-rat TDLo: 746.2 mg/kg/26W-C Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 124, 2001 (HBPTO*); F15 orl-dog TDLo: 1820 mg/kg/26W-I Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 124, 2001 (HBPTO*); L03 orl-dog TDLo: 300 mg/kg/30D-C Handbook of pesticide toxicology. Robert Krieger ed, Academic press, 2001 v. 1, p. 125, 2001 (HBPTO*) TR: ACGIH TLV-TWA 5 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Not classifiable as a human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-TWA 5 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); TOXICOLOGY REVIEW Cancer Treatment Reports. (Washington, DC) V.60-71, 1976-87. For publisher information, see JNCIEQ. v. 60, p. 1171, 1976 (CTRRDO) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); MSHA STANDARD-air: TWA 5 mg/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 v. 3, p. 224, 1971 (DTLVS*); OSHA PEL (Gen Indu): 8H TWA 5 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 5 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 5 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 5 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: TWA 5 mg/m3, JAN 1993; OEL-AUSTRIA: MAK 5 mg/m3, JAN 1999; OEL-BELGIUM: TWA 5 mg/m3, JAN 1993; OEL-DENMARK: TWA 5 mg/m3, JAN 1999; OEL-FINLAND: TWA 5 mg/m3, STEL 10 mg/m3, JAN 1993; OEL-GERMANY: MAK 5 mg/m3, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 5 mg/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 5 mg/m3, JAN 1993; OEL-SWITZERLAND: MAK-W 5 mg/m3, JAN 1999; OEL-TURKEY: TWA 5 mg/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 5 mg/m3, STEL 10 mg/m3, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO ROTENONE-air: 10H TWA 5 mg/m3 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. DHHS #92-100, 1992 (NIOSH*); NOHS 1974: HZD 67530; NIS 3; TNF 70; NOS 4; TNE 2937; NOES 1983: HZD 67530; NIS 3; TNF 913; NOS 3; TNE 8100; TFE 2470 SL: On EPA IRIS database; NIOSH Analytical Method, 1994: Rotenone, 5007; NCI Carcinogenesis Studies (feed), equivocal evidence: rat; NCI Carcinogenesis Studies (feed), no evidence: mouse; NTP Carcinogenesis studies, test completed (peer review), October 2000 Record 590 of 1119 in RTECS (through 2003/06) AN: DJ3675000 PN: Benzo(a)pyrene SY: 3,4-BP-; 3,4-Benz(a)pyrene; 3,4-Benzopirene- (Italian); 3,4-Benzopyrene-; 3,4-Benzpyren- (German); 3,4-Benzpyrene-; 3,4-Benzypyrene-; 6,7-Benzopyrene-; B(a)P; BP-; BaP-; Benz(a)pyrene; Benzo(d,e,f)chrysene; Coal tar pitch volatiles: benzo(a)pyrene (OSHA); RCRA-waste-number-U022- RN: Current: 50-32-8 UD: 200305 MF: C20-H12 MW: 252.32 WL: L D6 B6666 2AB TJ CC: Tumorigen (C); Mutagen (M); Reproductive-Effector (T); Primary-Irritant (S) ID: skn-mus 14 ug MLD Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 4, p. 333, 1978 (CALEDQ) ME: mmo-sat 312 ng/plate (-S9) Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 44, p. 131, 1984 (RCOCB8); oms-sat 1 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 192, p. 239, 1987 (MUREAV); dna-sat 147 gm/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 109, p. 183, 1983 (MUREAV); pic-sat 3900 pmol/plate Proceedings of the International Symposium of the Princess Takamatsu Cancer Research Fund. (Japan Scientific Soc. Press, 6-2-10 Hongo, Bunkyo-ku, Tokyo 113, Japan) 1st- 1971- v. 9, p. 337, 1979 (PPTCBY); mmo-esc 1 umol/L (-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 60, p. 395, 1979 (MUREAV); oms-esc 700 pmol/tube Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 79, p. 5971, 1982 (PNASA6); mmo-esc 200 nmol/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 135, p. 87, 1984 (MUREAV); dnr-esc 70 ug/well Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 53, 1977 (MUREAV); dnd-esc 500 mg/L Biochimica et Biophysica Acta. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1947- v. 103, p. 275, 1965 (BBACAQ); pic-esc 400 ng/plate Cold Spring Harbor Conferences on Cell Proliferation. (Cold Spring Harbor, NY) V.1-10, 1974-83. v. 4, p. 1451, 1977 (CSHCAL); mmo-bcs 5 gm/L (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 42, p. 19, 1977 (MUREAV); dnd-bcs 200 ug/disc Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 175, 1981 (PMRSDJ); dna-omi 3 umol/L Proceedings, National Cancer Conference. (Philadelphia, PA) V.1-7, 1949-72. For publisher information, see CANCAR. v. 5, p. 39, 1965 (PNCCA2); dns-omi 1 mg/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 2, p. 417, 1981 (CRNGDP); dni-omi 200 ug/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 74, p. 1378, 1977 (PNASA6); dni-omi 100 ug/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 74, p. 1378, 1977 (PNASA6); dna-omi 11 ng/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 39, p. 205, 1982 (CBINA8); dnd-omi 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 235, 1996 (MUREAV); slt-dmg-orl 250 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 234, p. 71, 1990 (MUREAV); dnr-dmg-orl 100 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 290, p. 175, 1993 (MUREAV); dna-dmg-orl 1 mmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 23, p. 171, 1994 (EMMUEG); sln-dmg-par 5 mmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 302, 1973 (CNREA8); sln-dmg-orl 100 umol/L Biologisches Zentralblatt. (VEB Georg Thieme, Postfach 946, Leipzig DDR-7010, Ger. Dem. Rep.) V.1- 1881- v. 102, p. 271, 1983 (BIZNAT); mmo-smc 1 gm/L (-S9) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 414, 1981 (PMRSDJ); mmo-smc 50 mg/L (+S9) Chemical and Pharmaceutical Bulletin. (Japan Pub. Trading Co., USA, 1255 Howard St., San Francisco, CA 94103) V.6- 1958- v. 33, p. 1576, 1985 (CPBTAL); mrc-smc 10 ug/plate Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 456, 1981 (PMRSDJ); sln-smc 150 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 468, 1981 (PMRSDJ); mnt-nml-mul 1000 ppb Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 390, p. 33, 1997 (MUREAV); mnt-nml-mul 10 ppb/8D-C Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8, p. 41, 1986 (ENMUDM); mnt-ofs-ipr 10 mg/kg Cytobios. (Faculty Press, 88 Regent St., Cambridge, UK) V.1- 1969- v. 47, p. 147, 1986 (CYTBAI); slt-oin-orl 500 ppm Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 268, p. 155, 1992 (MUREAV); mnt-nml-mul 60 ppb Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 292, p. 83, 1993 (MUREAV); dna-ofs-orl 125 umol/kg/5D-I Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 427, p. 135, 1999 (MUREAV); dna-nml 1700 nmol/L Gann Monograph. (Tokyo, Japan) No.1-10, 1966-71. For publisher information, see GMCRDC. v. 6, p. 49, 1968 (GANMAX); dna-ofs-ipr 20 mg/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 49, p. 81, 1990 (CALEDQ); dna-sal-tes 5 ug/1H-C Biochemical Journal. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1906- v. 110, p. 159, 1968 (BIJOAK); dnd-sal-oth 80 umol/L EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 23, p. 51, 1978 (EVHPAZ); dnd-ofs-ipr 125 gm/kg Science of the Total Environment. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1972- v. 32, p. 13, 1983 (STEVA8); dns-ofs-lvr 10 umol/L National Cancer Institute, Monograph. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) No.1- 1959- v. 65, p. 163, 1984 (NCIMAV); dns-ofs-lvr 20 nmol/L Huanjing Kexue Xuebao. Environmental Sciences Journal. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) V.1- 1981- v. 4, p. 368, 1984 (HKXUDL); dns-ofs-lvr 1 umol/L Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 14, p. 555, 1985 (AECTCV); dns-ofs-oth 10 umol/L Comparative Biochemistry and Physiology, C: Pharmacology, Toxicology and Endocrinology. (Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.74- 1983- v. 86, p. 399, 1987 (CBPCEE); cyt-ofs-skn 100 ng/L Ecotoxicology and Environmental Safety. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1977- v. 5, p. 261, 1981 (EESADV); cyt-ofs-oth 100 ug/L/48H Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 181, 1982 (ENMUDM); cyt-nml-mul 10 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 319, p. 223, 1993 (MUREAV); msc-ofs-fbr 5 mg/L Archives of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 070944) V.1- 1973- v. 10, p. 663, 1981 (AECTCV); mnt-hmn-oth 10 mg/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 5, p. 515, 1991 (TIVIEQ); mnt-hmn-lym 50 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 291, p. 93, 1993 (MUREAV); mmo-hmn-lym 4 mg/L (+S9) JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 63, p. 309, 1979 (JJIND8); dna-hmn-lvr 100 nmol/L Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 25, p. 117, 1984 (PAACA3); mtr-hmn-oth 10 mg/L In Vitro. (Rockville, MD) V.1-20, 1965-85. For publisher information, see ICDBEO. v. 17, p. 719, 1981 (ITCSAF); mtr-hmn-fbr 3200 ug/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 13, p. 119, 1981 (CALEDQ); dna-hmn-lym 1 umol/L/72H Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 49, p. 6503, 1989 (CNREA8); dna-hmn-fbr 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 390, p. 179, 1997 (MUREAV); dnd-hmn-fbr 10 mg/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 1638, 1978 (CNREA8); dna-hmn-oth 1500 nmol/L Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 1, p. 3, 1980 (TCMUD8); dnd-hmn-hla 1500 nmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 20, 1991 (EMMUEG); dnd-hmn-leu 500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 346, p. 49, 1995 (MUREAV); dna-hmn-oth 400 nmol/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 78, p. 6251, 1981 (PNASA6); dns-hmn-oth 1 umol/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 5, p. 377, 1991 (TIVIEQ); dns-hmn-hla 1 mmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 2621, 1978 (CNREA8); dna-hmn-lng 1 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 3, p. 195, 1982 (CRNGDP); dns-hmn-lvr 1 umol/L Banbury Report. (Cold Spring Harbor Laboratory, POB 100, Cold Spring Harbor, NY 11724) V.1- 1979- v. 13, p. 101, 1982 (BANRDU); dni-hmn-hla 1500 nmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 20, 1991 (EMMUEG); dna-hmn-oth 4 umol/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 18, p. 11, 1983 (CALEDQ); dns-hmn-oth 10 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 122, p. 377, 1983 (MUREAV); dns-hmn-oth 3 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 140, p. 43, 1984 (MUREAV); dns-hmn-oth 5 umol/L Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 79, p. 28, 1985 (TXAPA9); dni-hmn-fbr 1 mg/L Neoplasma. (Karger-Libri, P.O. Box, CH-4009 Basel, Switzerland) V.4- 1957- v. 33, p. 699, 1986 (NEOLA4); dns-hmn-mmr 10 umol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 20, p. 148, 1992 (EMMUEG); dnd-hmn-oth 150 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 441, p. 215, 1999 (MUREAV); dnd-hmn-oth 40 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 467, p. 21, 2000 (MUREAV); cyt-hmn-fbr 40 umol/L/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 297, 1977 (MUREAV); cyt-hmn-leu 1 mg/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 30, p. 103, 1974 (BJCAAI); cyt-hmn-lym 2400 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 113, p. 239, 1983 (MUREAV); sce-hmn-leu 50 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 346, p. 49, 1995 (MUREAV); sce-hmn-lym 1 umol/L/72H Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 49, p. 6503, 1989 (CNREA8); sce-hmn-fbr 1 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 317, 1978 (MUREAV); sce-hmn-lvr 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 117, p. 47, 1983 (MUREAV); msc-hmn-oth 100 nmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 1, p. 765, 1980 (CRNGDP); msc-hmn-fbr 100 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 4070, 1980 (CNREA8); msc-hmn-lym 3 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 128, p. 221, 1984 (MUREAV); msc-hmn-lym 1200 nmol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 304, 1982 (ENMUDM); mnt-rat-ipr 800 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 182, p. 309, 1987 (MUREAV); mnt-rat-orl 125 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 278, p. 165, 1992 (MUREAV); mtr-rat-oth 1 mg/L Neoplasma. (Karger-Libri, P.O. Box, CH-4009 Basel, Switzerland) V.4- 1957- v. 30, p. 303, 1983 (NEOLA4); mtr-rat-lvr 100 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 5087, 1983 (CNREA8); dnd-rat-oth 4 ug/tube Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 24, p. 331, 1983 (BLFSBY); mtr-rat-orl 200 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 40, p. 1157, 1980 (CNREA8); dna-rat-lng 2 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 3, p. 267, 1982 (CRNGDP); mtr-rat-emb 15400 ug/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 67, p. 1303, 1981 (JJIND8); dna-rat-ivn 140 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 4640, 1978 (CNREA8); dna-rat-skn 800 nmol/kg International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 28, p. 387, 1981 (IJCNAW); dna-rat-ipr 40 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 5, p. 231, 1984 (CRNGDP); dnd-rat-lvr 80 umol/L Journal of Biological Chemistry. (428 E. Preston St., Baltimore, MD 21202) V.1- 1905- v. 252, p. 6424, 1977 (JBCHA3); dnd-rat-fbr 1500 umol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 18, p. 337, 1977 (CBINA8); dna-rat-oth 1500 nmol/L Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 1, p. 3, 1980 (TCMUD8); dnd-rat-itr 50 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 36, p. 129, 1981 (CBINA8); dna-rat-oth 1 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 4, p. 297, 1983 (CRNGDP); dns-rat-orl 240 mg/kg/8D-C Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 218, p. 13, 1989 (MUREAV); dnd-rat-oth 31 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 3, p. 203, 1982 (CRNGDP); dns-rat-lvr 5 umol/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 6, p. 207, 1979 (CALEDQ); dns-rat-oth 100 mmol/L Shika Kiso Igakkai Zasshi. Journal of the Japanese Association for Basic Dentistry. (Shika Kiso Igakkai, Hanayama Bldg., 1-44-2 Komagome, Toshima-ku, Tokyo 170, Japan) V.1- 1959- v. 22, p. 300, 1980 (SHKKAN); dnd-rat-orl 62500 ug/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 10, p. 393, 1989 (CRNGDP); dna-rat-emb 500 ug/L Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 25, p. 86, 1984 (PAACA3); dni-rat-lvr 10 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 337, 1985 (CNREA8); dns-rat-oth 1 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 241, p. 361, 1990 (MUREAV); dni-rat-ipr 40 mg/kg Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 34, p. 755, 1985 (BCPCA6); dna-rat-oth 5 mg/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 661, 1994 (CRNGDP); bfa-rat-sat 10 mg/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 1, p. 155, 1979 (ENMUDM); bfa-rat-ovr 2 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 143, p. 263, 1985 (MUREAV); dna-rat-lvr 3 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 419, p. 91, 1998 (MUREAV); cyt-rat-ivn 50 mg/kg Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 64, p. 637, 1973 (GANNA2); cyt-rat-ipr 800 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 182, p. 309, 1987 (MUREAV); cyt-rat-unr 423 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 113, p. 239, 1983 (MUREAV); cyt-rat-oth 100 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 169, p. 141, 1986 (MUREAV); sce-rat-lvr 1600 pmol/L Experimental Cell Biology. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.44- 1976- v. 52, p. 355, 1984 (ECEBDI); sce-rat-oth 500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 409, 1982 (MUREAV); sce-rat-ast 1 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 122, p. 47, 1983 (MUREAV); sce-rat-ipr 25 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 10, p. 1041, 1989 (CRNGDP); msc-rat-oth 18850 nmol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5, p. 33, 1983 (ENMUDM); msc-rat-mmr 1 mg/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 70, p. 777, 1983 (JJIND8); msc-rat-lvr 1 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 130, p. 53, 1984 (MUREAV); mnt-mus-fbr 250 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 279, p. 217, 1992 (MUREAV); mnt-mus-orl 40 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 234, p. 179, 1990 (MUREAV); mnt-mus-skn 20 ug/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 17, p. 163, 1991 (EMMUEG); mnt-mus-ipr 30 mg/kg Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 698, 1981 (PMRSDJ); mmo-mus-lym 250 ug/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 12(Suppl 13), p. 103, 1988 (EMMUEG); slt-mus-orl 80 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 38, p. 99, 1977 (ARTODN); slt-mus-par 100 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 38, p. 75, 1977 (ARTODN); mtr-mus-orl 100 mg/kg/8D-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 49, p. 1236, 1989 (CNREA8); dnd-mus-lym 500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 203, p. 155, 1988 (MUREAV); mtr-mus-oth 100 ug/L International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 4, p. 166, 1969 (IJCNAW); mtr-mus-emb 100 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 659, 1985 (PMRSDJ); mtr-mus-fbr 500 ug/L Advances in Modern Environmental Toxicology. (Senate Press, Inc., P.O. Box 252, Princeton Junction, NJ 08550) V.1- 1980- v. 1, p. 133, 1980 (AETODY); oms-mus-skn 4 mg/kg Science. (American Assoc. for the Advancement of Science, 1333 H St., NW, Washington, DC 20005) V.1- 1895- v. 199, p. 778, 1978 (SCIEAS); dna-mus-lvr 6 umol/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 62, p. 947, 1979 (JJIND8); dnd-mus-fbr 3 mg/L Colloques Internationaux du Centre National de la Recherche Scientifique. (Kluwer Academic Pub., POB 358, Accord Stn., Hingham, MA 02018) V.1- 1946- v. 256, p. 389, 1977 (COINAV); dna-mus-emb 1200 nmol/L International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 4, p. 813, 1969 (IJCNAW); dna-mus-skn 40 umol/kg International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 23, p. 201, 1979 (IJCNAW); dns-mus-skn 8 mg/kg Pharmacology: International Journal of Experimental and Clinical Pharmacology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1968- v. 18, p. 281, 1979 (PHMGBN); dna-mus-orl 240 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 1199, 1982 (CNREA8); dns-mus-orl 12 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 44, p. 1547, 1984 (CNREA8); dni-mus-fbr 7 umol/L Journal of UOEH (University of Occupational and Environmental Health). (Univ. of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu 807, Japan) V.1- 1979- v. 5, p. 147, 1983 (JOUOD4); dni-mus-oth 100 umol/L JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 65, p. 1321, 1980 (JJIND8); dni-mus-ipr 100 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 46, p. 305, 1977 (MUREAV); dns-mus-lvr 1 umol/L Toxicologic Pathology. (c/o Dr. F.A. de la Iglesia, Warner-Lambert Co., Pharmaceutical Research Div., POB 1047, Ann Arbor, MI 48106) V.6(3/4)- 1978- v. 12, p. 119, 1984 (TOPADD); oms-mus-skn 200 mg/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 4, p. 155, 1971/1972 (CBINA8); oms-mus-ipr 50 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 19, p. 259, 1992 (EMMUEG); bfa-mus-sat 100 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 4478, 1978 (CNREA8); cyt-mus-ipr 50 mg/kg Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 19, p. 259, 1992 (EMMUEG); cyt-mus-orl 25 mg/kg Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 3, p. 321, 1983 (TCMUD8); cyt-mus-leu 100 ug/L/17H-C International Journal of Cancer. (International Union Against Cancer, 3 rue du Conseil- General, 1205 Geneva, Switzerland) V.1- 1966- v. 9, p. 435, 1972 (IJCNAW); cyt-mus-fbr 5 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 1866, 1982 (CNREA8); cyt-mus-lym 2500 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 6), p. 24, 1986 (ENMUDM); sce-mus-lng 25 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 158, p. 269, 1978 (PSEBAA); sce-mus-emb 1 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 2, p. 245, 1980 (ENMUDM); sce-mus-fbr 100 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 1866, 1982 (CNREA8); sce-mus-ipr 20 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 10, p. 1041, 1989 (CRNGDP); sce-mus-ivn 100 mg/kg Japanese Journal of Medical Science and Biology. (National Institute of Health, 2-chome, Kamiosaki, Shinagawa-ku, Tokyo 141, Japan) V.5- 1952- v. 38, p. 207, 1985 (JJMCAQ); sce-mus-bmr 30 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 465, 1989 (MUREAV); sce-mus-oth 30 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 224, p. 465, 1989 (MUREAV); dlt-mus-ipr 750 mg/kg Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 219, p. 385, 1968 (NATUAS); msc-mus-lym 4500 ug/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 580, 1981 (PMRSDJ); msc-mus-emb 3 umol/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 76, p. 930, 1979 (PNASA6); msc-mus-fbr 200 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 42, p. 1866, 1982 (CNREA8); hma-mus-esc 50464 ug/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 241, p. 83, 1990 (MUREAV); spm-mus-ipr 100 mg/kg/5D Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 72, p. 4425, 1975 (PNASA6); spm-mus-par 500 mg/kg Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 38, p. 75, 1977 (ARTODN); spm-mus-unr 200 mg/kg Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 318, 1982 (ENMUDM); mnt-ham-emb 100 ug/L Zhonghua Zhongliu Zazhi. Chinese Journal of Oncology. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) V.1- 1978- v. 8, p. 90, 1986 (CCLCDY); mmo-ham-emb 4 umol/L (+S9) Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 10, p. 419, 1989 (CRNGDP); mmo-ham-ovr 1 mg/L (+S9) Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 4, p. 354, 1982 (ENMUDM); mmo-ham-lng 25 nmol/plate (+S9) Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 39, p. 2660, 1979 (CNREA8); slt-ham-ovr 5 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 594, 1981 (PMRSDJ); dnr-ham-oth 1 umol/L Toxicology In Vitro. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 5, p. 511, 1991 (TIVIEQ); mtr-ham-oth 1200 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 35, p. 2413, 1975 (CNREA8); mtr-ham-lng 10 ug/L Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 1000(Sp Iss 1), p. 18, 1980 (TOLED5); mtr-ham-ipr 500 mg/kg Archives of Pathology. (Chicago, IL) V.5(3)-50(3), 1928-50: V.70-99, 1960-75. For publisher information, see APLMAS. v. 95, p. 380, 1973 (ARPAAQ); mtr-ham-emb 400 ug/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 13, p. 105, 1976 (CBINA8); mtr-ham-kdy 80 ug/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 37, p. 873, 1978 (BJCAAI); mtr-ham-fbr 1 mg/L Nature. (Nature Subscription Dept., POB 1018, Manasguan, NJ 08736) V.1- 1869- v. 264, p. 360, 1976 (NATUAS); mtr-ham-par 1 mg/L Proceedings of the National Academy of Sciences of the United States of America. (National Academy of Sciences, Printing and Pub. Office, 2101 Constitution Ave., Washington, DC 20418) V.1- 1915- v. 56, p. 672, 1966 (PNASA6); dnd-ham-lng 30 umol/L/2H Biochemical and Biophysical Research Communications. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 72, p. 732, 1976 (BBRCA9); dnd-ham-ovr 100 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 77, p. 259, 1980 (MUREAV); dna-ham-emb 500 ug/L Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 25, p. 86, 1984 (PAACA3); dna-ham-oth 800 nmol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 33, p. 2837, 1973 (CNREA8); dns-ham-emb 300 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 129, p. 111, 1984 (MUREAV); oms-ham-emb 1 mg/L Biochemistry. (American Chemical Soc., Distribution Office Dept. 223, POB 57136, West End Stn., Washington, DC 20037) V.1- 1962- v. 17, p. 1597, 1978 (BICHAW); dnd-ham-oth 100 nmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 3, p. 1283, 1982 (CRNGDP); dna-ham-oth 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 4723, 1983 (CNREA8); dns-ham-lvr 10 umol/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 5, p. 1, 1983 (ENMUDM); dns-ham-oth 100 ug/L Environmental Science Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.1- 1972- v. 27, p. 277, 1983 (EVSRBT); dns-ham-lng 6 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 230, p. 111, 1990 (MUREAV); pic-ham-emb 60 ug/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 6, p. 474, 1984 (ENMUDM); dni-ham-oth 150 umol/L Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 53, p. 163, 1990 (CALEDQ); dnd-ham-fbr 10 umol/L Life Sciences. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1-8, 1962-69: V.14- 1974- v. 48, p. 1255, 1991 (LIFSAK); dna-ham-oth 5 mg/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 15, p. 661, 1994 (CRNGDP); cyt-ham-ovr 3970 nmol/L Molecular Toxicology. (Taylor and Francis, Inc., 242 Cherry St., Philadelphia, PA USA 19106) V.1- 1987- v. 1, p. 217, 1987 (MOTOEX); cyt-ham-ihl 100 ug/L/5D-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 1, p. 139, 1981 (TOXID9); cyt-ham-ipr 200 mg/kg Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 2, p. 277, 1978 (TOLED5); cyt-ham-lng 100 mg/L Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 4, p. 41, 1980 (ATSUDG); cyt-ham-fbr 1 mg/L British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 30, p. 103, 1974 (BJCAAI); sce-ham-ipr 900 mg/kg/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 66, p. 65, 1979 (MUREAV); sce-ham-ovr 5610 nmol/L Molecular Toxicology. (Taylor and Francis, Inc., 242 Cherry St., Philadelphia, PA USA 19106) V.1- 1987- v. 1, p. 217, 1987 (MOTOEX); sce-ham-emb 10 ng/L Zhonghua Yufangyixue Zazhi. Chinese Journal of Preventive Medicine. (China International Book Trading Corp., POB 2820, Beijing, Peop. Rep. China) Beginning history not known. v. 17, p. 221, 1983 (CHYCDW); sce-ham-lng 1 ug/L Journal of Clinical Investigation. (Rockefeller Univ. Press, 1230 York Ave., New York, NY 10021) V.1- 1924- v. 64, p. 1245, 1979 (JCINAO); sce-ham-fbr 500 umol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 93, p. 409, 1982 (MUREAV); sce-ham-ihl 100 ug/L/5D-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. DE83-007112 (NTIS**); sce-ham-unr 25 mg/kg Experientia. (Birkhaeuser Verlag, POB 133, CH-4010 Basel, Switzerland) V.1- 1945- v. 33, p. 25, 1977 (EXPEAM); sce-ham-oth 9900 nmol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 1627, 1985 (CRNGDP); sln-ham-lvr 1 mg/L Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 5, p. 397, 1985 (PMRSDJ); sce-ham-lvr 110 ug/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 207, p. 69, 1988 (MUREAV); msc-ham-ipr 200 mg/kg Toxicology Letters. (Elsevier Science Pub. 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(Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 35, p. 1035, 1975 (CNREA8); dna-mky-lng 25 umol/L "Polynuclear Aromatic Hydrocarbons, International Symposium, 7th, 1982," Cooke, M., and A.J. Dennis, eds., Columbus, OH, Battelle Press, 1983 7,845,1983 (50NNAZ); dna-mky-oth 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 4723, 1983 (CNREA8); dna-mky-oth 25 umol/L "Polynuclear Aromatic Hydrocarbons, International Symposium, 7th, 1982," Cooke, M., and A.J. Dennis, eds., Columbus, OH, Battelle Press, 1983 7,845,1983 (50NNAZ); dns-mky-lvr 10 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 206, p. 91, 1988 (MUREAV); sce-mky-kdy 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 45, p. 3626, 1985 (CNREA8); mnt-frg-mul 60 ppb Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 4, p. 12, 1989 (MUTAEX); dna-rbt-ivn 1 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 51, p. 151, 1984 (CBINA8); dnd-frg-ipr 125 gm/kg Science of the Total Environment. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1972- v. 32, p. 13, 1983 (STEVA8); dna-rbt-ipr 11 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 3, p. 1405, 1982 (CRNGDP); dna-mam-lym 30 umol/L Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 47, p. 87, 1983 (CBINA8); dnd-mam-kdy 1 mmol/L Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 6, p. 333, 1980 (JTEHD6); dns-rbt-skn 100 ug/L Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 21, p. 94, 1980 (PAACA3); dna-dog-oth 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 4723, 1983 (CNREA8); dna-dog-lng 1 umol/L Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 43, p. 4723, 1983 (CNREA8); cyt-ckn-par 31 ug/kg "Cytogenetic Assays of Environmental Mutagens," Hsu, T.C., ed., Totowa, NJ, Allanheld, Osmun and Co., 1982 -,137,1982 (47JMAE); sce-rbt-skn 30 ug/L Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 21, p. 94, 1980 (PAACA3); sce-rbt-lym 10 umol/L/30M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 58, p. 321, 1978 (MUREAV); sce-ckn-par 31 ug/kg "Cytogenetic Assays of Environmental Mutagens," Hsu, T.C., ed., Totowa, NJ, Allanheld, Osmun and Co., 1982 -,137,1982 (47JMAE); sce-frg-mul 10 mg/L Environmental Mutagenesis. (New York, NY) V.1-9, 1979-87. For publisher information, see EMMUEG. v. 8(Suppl 6), p. 30, 1986 (ENMUDM); msc-mus-orl 1750 mg/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 164, p. 1, 2001 (CALEDQ); sce-hmn-lym 0.03 mg/L/24H Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 485, 2001 (FCTOD7); trn-dmg-skn 2 mmol/L/48H Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 485, 2001 (FCTOD7); mmo-sat 10 umol/L/20M Mutation Research. (Elsevier Science Pub. 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B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 471, p. 57, 2000 (MUREAV); dna-hmn-mmr 0.08 umol/L/12H Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 155, p. 47, 2000 (CALEDQ); slt-hmn-oth 15 ug/L/10H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 472, p. 93, 2000 (MUREAV); dna-rat-orl 10 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 1, p. 87, 2000 (CRNGDP); dna-rat-itr 10 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 1, p. 87, 2000 (CRNGDP); dna-rat-skn 10 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 1, p. 87, 2000 (CRNGDP); mmo-sat 2 ug/plate/72H (+S9) Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 116, p. 189, 2000 (TOLED5); mmo-sat 5 ug/plate/20M (+/-S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 492, p. 13, 2001 (MUREAV); dna-mus-ipr 13.200 mg/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 21, p. 629, 2000 (CRNGDP); msc-rat-ipr 120 mg/kg/3D Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 21, p. 715, 2000 (CRNGDP); dna-mus-orl 7840 mg/kg/2W-C Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 21, p. 1601, 2000 (CRNGDP); dnd-mus-ipr 500 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 493, p. 39, 2001 (MUREAV); dnd-mus-orl 500 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 493, p. 39, 2001 (MUREAV); dna-ham-emb 1 mg/L/6H Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 22, p. 1505, 2001 (CRNGDP); spm-hmn-spr 200 mg/L/2H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 491, p. 57, 2001 (MUREAV); mnt-ham-oth 1 umol/L/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 491, p. 87, 2001 (MUREAV); msc-mus-ipr 32.3 mg/kg/8D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 137, p. 137, 1999 (CALEDQ); mnt-hmn-oth 0.2 mg/L/28H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 495, p. 89, 2001 (MUREAV); slt-hmn-lym 0.1 mg/L/72H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 495, p. 157, 2001 (MUREAV); dnd-esc 24.1 ug/L/3H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 515, p. 85, 2002 (MUREAV); slt-ham-oth 0.5 umol/L/24H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 517, p. 135, 2002 (MUREAV); cyt-ham-fbr 0.01 gm/L/48H (+S9) Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 183, 2001 (MUTAEX); pic-esc 0.5 umol/L (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 36, p. 206, 2000 (EMMUEG); dna-hmn-mmr 1 umol/L/24H Chemical Research in Toxicology. (American Chemical Soc., Distribution Office Dept. 223, POB 57/36, West End Station, Washington, DC 20037) V.1- 1988- v. 13, p. 10, 2000 (CRTOEC); dnd-hmn-mmr 1 umol/L/4H Chemical Research in Toxicology. (American Chemical Soc., Distribution Office Dept. 223, POB 57/36, West End Station, Washington, DC 20037) V.1- 1988- v. 13, p. 10, 2000 (CRTOEC); dnd-hmn-mmr 1 umol/L/24H Chemical Research in Toxicology. (American Chemical Soc., Distribution Office Dept. 223, POB 57/36, West End Station, Washington, DC 20037) V.1- 1988- v. 13, p. 10, 2000 (CRTOEC); sce-ham-lng 5 mg/L/6H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 515, p. 181, 2002 (MUREAV); dnd-rat-lvr 5 umol/L/12H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 519, p. 163, 2002 (MUREAV); dnd-hmn-lvr 10 umol/L/12H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 519, p. 163, 2002 (MUREAV); dnd-ham-lng 0.1 umol/L/1H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 17, p. 45, 2002 (MUTAEX); dna-ham-lng 0.5 umol/L/6H Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 17, p. 45, 2002 (MUTAEX); dna-mus-orl 273 mg/kg/7W Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 333, 2001 (MUTAEX); mmo-sat 2.5 ug/plate/48H (+S9) Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 16, p. 523, 2001 (MUTAEX); mtr-mus-fbr 0.033 umol/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 35, p. 300, 2000 (EMMUEG); cyt-hmn-spr 200 mg/L/120M (+S9) Mutagenesis. (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1986- v. 504, p. 183, 2002 (MUTAEX); mmo-sat 6.125 nmol/plate/20M Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 519, p. 133, 2002 (MUREAV); mmo-sat 10 mg/L/48H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 520, p. 161, 2002 (MUREAV); dnd-esc 1000 ng/plate/2H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 520, p. 161, 2002 (MUREAV); sce-ham-ovr 20 mg/L/4H (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 520, p. 161, 2002 (MUREAV); mmo-sat 1.25 ug/plate (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 498, p. 107, 2001 (MUREAV); dnd-ofs-emb 10 mg/L/16H Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 513, p. 83, 2002 (MUREAV); mnt-rat-skn 1 pph/3D Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 513, p. 93, 2002 (MUREAV); mnt-mus-skn 0.5 pph/3D Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 513, p. 93, 2002 (MUREAV); mmo-sat 10 ug/plate/20M (+S9) Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 514, p. 19, 2002 (MUREAV); slt-ham-ovr 1 mg/L/9D Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 16, p. 260, 1990 (EMMUEG); dna-mus-orl 6.3 mg/kg/9W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 15, p. 59, 1995 (JJATDK); mnt-mus-orl 6.3 mg/kg/9W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 15, p. 59, 1995 (JJATDK); dns-mus-orl 6.3 mg/kg/9W-I JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 15, p. 59, 1995 (JJATDK) RE: T31-T39 orl-rat TDLo: 40 mg/kg (14D preg) Naunyn-Schmiedeberg's Archives of Pharmacology. (Springer Verlag, Heidelberger, Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.272- 1972- v. 272, p. 89, 1972 (NSAPCC); T71-T81 orl-rat TDLo: 2 gm/kg (28D pre/1-22D preg) Experientia. (Birkhaeuser Verlag, POB 133, CH-4010 Basel, Switzerland) V.1- 1945- v. 20, p. 224, 1964 (EXPEAM); T72 orl-rat TDLo: 1344 mg/kg (15D pre-5D post) DOE Symposium Series. (NTIS, 5285 Port Royal Rd., Springfield, VA 22161) No.45- 1978- v. 54, p. 410, 1981 (DOESD6); T83 ipr-rat TDLo: 60 mg/kg (16-18D preg) Biology of the Neonate. (S. Karger Pub., Inc., 79 Fifth Ave., New York, NY 10003) V.15- 1970- v. 38, p. 291, 1980 (BNEOBV); T25-T34-T35 scu-rat TDLo: 150 mg/kg (6-8D preg) Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 42, p. 195, 1986 (TXCYAC); T85 ims-rat TDLo: 2100 ug/kg (15-19D preg) Journal of Developmental Physiology. (Oxford University Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1979- v. 19, p. 67, 1993 (JDPHDH); T11 orl-mus TDLo: 100 mg/kg (16D pre-5D post) DOE Symposium Series. (NTIS, 5285 Port Royal Rd., Springfield, VA 22161) No.45- 1978- v. 54, p. 410, 1981 (DOESD6); T82 orl-mus TDLo: 1280 mg/kg (16D pre-5D post) DOE Symposium Series. (NTIS, 5285 Port Royal Rd., Springfield, VA 22161) No.45- 1978- v. 54, p. 410, 1981 (DOESD6); T91 orl-mus TDLo: 100 mg/kg (7-16D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 19, p. 37A, 1979 (TJADAB); T26-T22-T23 orl-mus TDLo: 100 mg/kg (multigenerations) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 24, p. 183, 1981 (BIREBV); T83 orl-mus TDLo: 75 mg/kg (12-14D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 32, p. 29A, 1985 (TJADAB); T81 orl-mus TDLo: 100 mg/kg (7-16D preg) Biology of Reproduction. (Soc. for the Study of Reproduction, 309 W. Clark St., Champaign, IL 61820) V.1- 1969- v. 24, p. 183, 1981 (BIREBV); T11 ipr-mus TDLo: 50 mg/kg (1D pre) Pediatric Pharmacology. (New York, NY) V.1-5, 1980-86. For publisher information, see DPTHDL. v. 1, p. 143, 1980 (PPHAD4); T01 ipr-mus TDLo: 1500 mg/kg (5D male) Progress in Mutation Research. (Elsevier Science Pub. Co., Inc., 52 Vanderbilt Ave., New York, NY 10017) V.1- 1981- v. 1, p. 712, 1981 (PMRSDJ); T54 ipr-mus TDLo: 300 mg/kg (16-18D preg) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 6, p. 569, 1980 (JTEHD6); T43-T44-T46 ipr-mus TDLo: 200 mg/kg (7D preg) Teratology, The International Journal of Abnormal Development. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1968- v. 20, p. 365, 1979 (TJADAB); T71 ipr-mus TDLo: 150 mg/kg (8D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. CONF-771017 (NTIS**); T33-T48-T54 ipr-mus TDLo: 250 mg/kg (13-17D preg) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 42, p. 259, 1994 (JTEHD6); T72-T83 scu-mus TDLo: 160 mg/kg (12D preg) Pediatric Pharmacology. (New York, NY) V.1-5, 1980-86. For publisher information, see DPTHDL. v. 1, p. 85, 1980 (PPHAD4); T49 scu-mus TDLo: 12 gm/kg (multigeneration) Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 55, p. 227, 1990 (CALEDQ); T11 unr-mus TDLo: 40 ug/kg (1D pre) Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 76, p. 18, 1984 (TXAPA9); T01-T02 ipr-ham TDLo: 10 mg/kg (5D male) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 8, p. 929, 1981 (JTEHD6) TE: V01-K60-Q60 orl-rat TDLo: 15 mg/kg Experimentelle Pathologie (1967-1980). (Jena, Ger. Dem. Rep.) V.1-18, 1967-80. For publisher information, see EXPADD. v. 18, p. 288, 1980 (EXPTAX); V03-V10 ipr-rat TDLo: 16 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 12, p. 65, 1958 (BJCAAI); V02-V10 scu-rat TDLo: 455 ug/kg/60D-I Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 29, p. 159, 1980 (CBINA8); V03-R60 ivn-rat TDLo: 39 mg/kg/6D-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 29, p. 506, 1969 (CNREA8); V01-V10 ims-rat TDLo: 2400 ug/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. DOE/EV/03140-5 (NTIS**); V03-A60-V10 ice-rat TDLo: 22 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 29, p. 1927, 1969 (CNREA8); V01-J60-R60 itr-rat TDLo: 1200 ug/kg Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 10, p. 1285, 1989 (CRNGDP); V01-J60-V10 imp-rat TDLo: 150 ug/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 72, p. 733, 1984 (JJIND8); V01-J60-P61 orl-mus TDLo: 700 mg/kg/75W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 45(12), p. 14, 1980 (GISAAA); V03-J60 ihl-mus TCLo: 200 ng/m3/6H/13W-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 47(7), p. 23, 1982 (GISAAA); V01-T65 skn-mus TDLo: 120 mg/kg (multigenerations) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 71, p. 677, 1971 (BEXBAN); V01-R60 skn-mus TDLo: 28500 ug/kg/19W-I Fundamental and Applied Toxicology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1-40, 1981-97. For publisher information, see TOSCF2 v. 9, p. 297, 1987 (FAATDF); V01-R60-V10 skn-mus TDLo: 25 ng/kg/110W-I Archiv fuer Geschwulstforschung. (VEB Verlag Volk und Gesundheit Neue Gruenstr. 18, Berlin DDR-1020, Ger. Dem. Rep.) V.1- 1949- v. 50, p. 266, 1980 (ARGEAR); V02-J60 ipr-mus TDLo: 10 mg/kg Archives of Toxicology, Supplement. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) No.1- 1978- v. 4, p. 74, 1980 (ATSUDG); V01-T65-J60 ipr-mus TDLo: 300 mg/kg (16-18D preg) Journal of Toxicology and Environmental Health. (Hemisphere Pub., 1025 Vermont Ave., NW, Washington, DC 20005) V.1- 1975/76- v. 6, p. 569, 1980 (JTEHD6); V02-J60-T49 scu-mus TDLo: 300 mg/kg (18-19D preg) Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 55, p. 227, 1990 (CALEDQ); V01-V10 scu-mus TDLo: 9 mg/kg JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 71, p. 309, 1983 (JJIND8); V01-T65-J60 scu-mus TDLo: 480 mg/kg (11-15D preg) Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 135, p. 84, 1970 (PSEBAA); V03-J60 ivn-mus TDLo: 10 mg/kg Journal of the National Cancer Institute. (Washington, DC) V.1-60, 1940-78. For publisher information, see JJIND8. v. 1, p. 225, 1940 (JNCIAM); V02-J60 itr-mus TDLo: 200 mg/kg/10W-I Proceedings of the Western Pharmacology Society. (Univ. of California Dept. of Pharmacology, Los Angeles, CA 90024) V.1- 1958- v. 22, p. 269, 1979 (PWPSA8); V01-V10 imp-mus TDLo: 200 mg/kg British Journal of Cancer. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.1- 1947- v. 39, p. 761, 1979 (BJCAAI); V03-V10 unr-mus TDLo: 80 mg/kg/8D-I Byulleten' Eksperimental'noi Biologii i Meditsiny. Bulletin of Experimental Biology and Medicine. For English translation, see BEXBAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 88(11), p. 592, 1979 (BEBMAE); V01-P61-K61 rec-mus TDLo: 200 mg/kg Oncology. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.21- 1967- v. 37, p. 77, 1980 (ONCOBS); V03-V10 par-dog TDLo: 819 mg/kg/26W-I JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 65, p. 921, 1980 (JJIND8); V03-J22-V10 imp-dog TDLo: 651 mg/kg/21W-C JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 65, p. 921, 1980 (JJIND8); V03-J60-V10 scu-mky TDLo: 40 mg/kg Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 127, p. 594, 1968 (PSEBAA); V03-R60 skn-rbt TDLo: 17 mg/kg/57W-I Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie. (Walter de Gruyter, Inc., 200 Saw Mill River Rd., Hawthorne, NY 10532) V.21- 1895/96- v. 236, p. 79, 1935 (HSZPAZ); V02-T65-C18 ivn-rbt TDLo: 30 mg/kg (25D preg) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 85, p. 369, 1978 (BEXBAN); V03-J61-P61 itr-rbt TDLo: 145 mg/kg/2Y-I Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 71, p. 197, 1980 (GANNA2); V03-K60-R60 orl-ham TDLo: 420 mg/kg/21W-I Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 65, p. 56, 1962 (ZEKBAI); V03-D09-J60 ihl-ham TCLo: 9500 ug/m3/4H/96W-I JNCI, Journal of the National Cancer Institute. (Washington, DC) V.61-79, 1978-87. For publisher information, see JNCIEQ. v. 66, p. 575, 1981 (JJIND8); V03-J61 scu-ham TDLo: 4000 ug/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 32, p. 360, 1972 (CNREA8); V01-J60 itr-ham TDLo: 64 mg/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 3, p. 231, 1977 (CALEDQ); V02-J60 itr-ham TDLo: 120 mg/kg/17W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 25, p. 271, 1985 (CALEDQ); V03-J60 imp-ham TDLo: 5 mg/kg/22W-C Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 47, p. 5202, 1987 (CNREA8); V03-L60-M61 imp-frg TDLo: 45 mg/kg Experientia. (Birkhaeuser Verlag, POB 133, CH-4010 Basel, Switzerland) V.1- 1945- v. 20, p. 143, 1964 (EXPEAM); V01-J60-V10 imp-rat TD :500 ug/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 20, p. 97, 1983 (CALEDQ); V01-R60 skn-mus TD :12 mg/kg/20D-I Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 6, p. 1483, 1985 (CRNGDP); V01-J60-L60 itr-rat TD :200 mg/kg/15W-I "Experimental Lung Cancer: Carcinogenesis and Bioassays, International Symposium, 1974," Karbe, E., and J.F. Park, eds., Springer-Verlag New York, Inc., 1974 -,199,1974 (31BYAP); V01-R60 skn-mus TD :26 mg/kg/65W-I American Journal of Pathology. (Lippincott/Harper, Journal Fulfillment Dept., 2350 Virginia Ave., Hagerstown, MD 21740) V.1- 1925- v. 102, p. 381, 1981 (AJPAA4); V01-J60-R60 rec-mus TD :560 mg/kg/14W-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 20, p. 117, 1983 (CALEDQ); V01-V10 scu-mus TD :8 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 12, p. 657, 1952 (CNREA8); V01-J60 itr-ham TD :360 mg/kg/36W-I Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 32, p. 28, 1972 (CNREA8); V01-V10 ims-rat TD :3150 ug/kg Proceedings of the American Association for Cancer Research. (Waverly Press, 428 E. Preston St., Baltimore, MD 21202) V.1- 1954- v. 21, p. 72, 1980 (PAACA3); V01-R60-V10 skn-mus TD :18 mg/kg/73W-I EHP, Environmental Health Perspectives. (U.S. Government Printing Office, Supt of Documents, Washington, DC 20402) No.1- 1972- v. 38, p. 149, 1981 (EVHPAZ); V01-V10 scu-mus TD :12 mg/kg Gann. Japanese Journal of Cancer Research. (Tokyo, Japan) V.1-75, 1907-84. For publisher information, see JJCREP. v. 62, p. 309, 1971 (GANNA2); V03-J60 itr-mus TDLo: 0.5 mg/kg Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 477, p. 41, 2001 (MUREAV); V03-R60 skn-mus TDLo: 480 mg/kg/32W-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 163, p. 1, 2001 (TXCYAC); V01-J30 orl-mus TDLo: 20 mg/kg/5D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 159, p. 113, 2000 (CALEDQ); V01-J60 orl-mus TDLo: 240 mg/kg/12D-I Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 21, p. 179, 2000 (CRNGDP); V01-L60 ipr-mus TDLo: 32.3 mg/kg/8D-I Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 137, p. 137, 1999 (CALEDQ); V03-L60 ipr-mus TDLo: 38 ug/kg Cancer Letters (Shannon, Ireland). (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1975- v. 185, p. 13, 2002 (CALEDQ); V01-R60 ipr-rat TDLo: 200 mg/kg Voprosi oncologii (Questions of oncology. Journal of Petrov's Institute of Oncology, B. Zelenina str, 43a, Spb 197110, Russia) V.1- 1955- v. -, p. 950, 1992 (VOONC*) AT: T/E unlistd scu-rat LD50: 50 mg/kg Zeitschrift fuer Krebsforschung. (Berlin, Fed. Rep. Ger.) V.1-75, 1903-71. For publisher information, see JCROD7. v. 69, p. 103, 1967 (ZEKBAI); T/E unlistd ipr-mus LDLo: 500 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 23, p. 288, 1972 (TXAPA9); T/E unlistd irn-frg LDLo: 9 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 24, p. 1969, 1964 (CNREA8); Y20 orl-rat TDLo: 100 mg/kg Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 39, p. 541, 2001 (FCTOD7); L15-L30-Y53 ipr-rat TDLo: 40 mg/kg Biochemical Pharmacology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1958- v. 17, p. 1049, 1968 (BCPCA6); T12 ipr-mus TDLo: 100 mg/kg Reproductive Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.1- 1987- v. 5, p. 379, 1991 (REPTED); T11-T12 ipr-mus TDLo: 80 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 28, p. 133, 1979 (CBINA8); T11-T12 ipr-rat TDLo: 100 mg/kg Chemico-Biological Interactions. (Elsevier Scientific Pub. Ireland Ltd., POB 85, Limerick, Ireland) V.1- 1969- v. 28, p. 133, 1979 (CBINA8); T11-T12-Y12 ipr-mus TDLo: 80 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 53, p. 249, 1980 (TXAPA9) MD: M03 orl-rat TDLo: 9 gm/kg/90D-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 30, p. 323, 1996 (TOXID9); P27-S05-U01 orl-rat TDLo: 2250 mg/kg/5W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 148, p. 126, 1998 (TXAPA9); S04 scu-mus TDLo: 400 mg/kg/2W-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 3, p. 86, 1983 (TOXID9); S25 unr-mus TDLo: 180 mg/kg/12D-I Toxicologist. (Soc. of Toxicology, Inc., 475 Wolf Ledge Parkway, Akron, OH 44311) V.1- 1981- v. 48, p. 13, 1999 (TOXID9); N16-N17-Z71 orl-nml TDLo: 171 mg/kg/30D-C Marine Environmental Research. (Kidlington, Oxford : Elsevier) V. 1- 1978- v. 24, p. 179, 1988 (MAERE*) TR: ACGIH TLV-Suspected Human Carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 2002 (DTLVS*); ACGIH TLV-Suspected human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 3, p. 91, 1973 (IMEMDT); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 211, 1983 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 32, p. 211, 1983 (IMEMDT); IARC Cancer Review: Group 2A IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW "Teratology," Berry, C.L., and D.E. Poswillo, eds., New York, Springer, 1975 -,49,1975 (32XPAD); TOXICOLOGY REVIEW Advances in Cancer Research. (Academic Press, Inc., 465 S. Lincoln Dr., Troy, MO 63379) V.1- 1953- v. 7, p. 475, 1963 (ACRSAJ); TOXICOLOGY REVIEW Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 39, p. 257, 1977 (MUREAV); TOXICOLOGY REVIEW Zentralblatt fuer Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene, Abteilung 1: Originale, Reihe B: Hygiene, Krankenhaushygiene, Betriebshygiene, Praeventive Medizin. (Stuttgart, Fed. Rep. Ger.) V.155-169, 1971-1979. For publisher information, see ZAOMDC. v. 166, p. 144, 1978 (ZHPMAT); TOXICOLOGY REVIEW Bulletin of the New York Academy of Medicine. (New York Academy of Medicine, 2 E. 103rd St., New York, NY 10029) Ser 2: V.1- 1925- v. 54, p. 413, 1978 (BNYMAM); TOXICOLOGY REVIEW Progress in Experimental Tumor Research. (S. Karger AG, Postfach CH-4009 Basel, Switzerland) V.1- 1960- v. 5, p. 157, 1964 (PEXTAR); TOXICOLOGY REVIEW "Oncology 1970, Proceedings of the Tenth International Cancer Congress," Chicago, Year Book Medical Pub., 1971 5,257,1970 (85CVA2); TOXICOLOGY REVIEW "Medical and Biologic Effects of Environmental Pollutants Series," Washington, DC, National Academy of Sciences, 1972-77 Pc,4,1972 (85DHAX); TOXICOLOGY REVIEW National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. CONF-691001 (NTIS**); TOXICOLOGY REVIEW Basic Life Sciences. (Plenum Pub. Corp., 223 Spring St., New York, NY 10003) V.1- 1973- v. 24, p. 129, 1983 (BLFSBY); TOXICOLOGY REVIEW Preventive Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1972- v. 9, p. 622, 1980 (PVTMA3) SR: OSHA PEL (Gen Indu): 8H TWA 0.2 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1910.1000, 1994 (CFRGBR); OSHA PEL (Construc): 8H TWA 0.2 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1926.55, 1994 (CFRGBR); OSHA PEL (Shipyard): 8H TWA 0.2 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 29, 1915.1000, 1993 (CFRGBR); OSHA PEL (Fed Cont): 8H TWA 0.2 mg/m3 Code of Federal Regulations. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-AUSTRALIA: Carcinogen, JAN 1993; OEL-BELGIUM: Carcinogen, JAN 1993; OEL-FINLAND: TWA 0.01 mg/m3, Skin, Carcinogen, JAN 1999; OEL-FRANCE: Carcinogen, JAN 1993; OEL-GERMANY: Carcinogen, JAN 1999; OEL-THE NETHERLANDS: Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.04 mg/m3, JAN 1999; OEL-POLAND: TWA 0.003 mg/m3, JAN 1999; OEL-RUSSIA: STEL 0.00015 mg/m3, Carcinogen, JAN 1993; OEL-SWEDEN: NGV 0.002 mg/m3, KTV 0.02 mg/m3, Skin, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.0002 ppm (0.002 mg/m3), Carcinogen, JAN 1999; OEL-UNITED KINGDOM: Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NOHS 1974: HZD T0450; NIS 1; TNF 11; NOS 1; TNE 32; NOES 1983: HZD T0450; NIS 1; TNF 75; NOS 1; TNE 896; TFE 299 SL: ATSDR TOXICOLOGY PROFILE (NTIS** PB/95/264370); EPA GENETOX PROGRAM 1988, Positive: Body fluid assay, Carcinogenicity-mouse/rat; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/F344 rat, SHE-focus assay; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-mouse embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-mouse prostate; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-RLV F344 rat embryo; EPA GENETOX PROGRAM 1988, Positive: Cell transform.-SA7/SHE, Host-mediated assay; EPA GENETOX PROGRAM 1988, Positive: L5178Y cells in vitro-TK test, Mammalian micronucleus; EPA GENETOX PROGRAM 1988, Positive: Mouse spot test, E coli polA with S9; EPA GENETOX PROGRAM 1988, Positive: Histidine reversion-Ames test; EPA GENETOX PROGRAM 1988, Positive: In vitro SCE-human lymphocytes, In vitro SCE-human; EPA GENETOX PROGRAM 1988, Positive: Sperm morphology-mouse, D melanogaster Sex-linked lethal; EPA GENETOX PROGRAM 1988, Positive: In vitro UDS in rat liver, V79 cell culture-gene mutation; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-BALB/c-3T3, SHE-clonal assay; EPA GENETOX PROGRAM 1988, Positive/dose response: Cell transform.-C3H/10T1/2; EPA GENETOX PROGRAM 1988, Positive/dose response: In vitro SCE-nonhuman, In vivo SCE-nonhuman; EPA GENETOX PROGRAM 1988, Negative: D melanogaster-nondisjunction; EPA GENETOX PROGRAM 1988, Negative: Rodent heritable translocation, Mouse specific locus; EPA GENETOX PROGRAM 1988, Negative: UDS in mouse germ cells, S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9, In vitro UDS-human fibroblast; EPA GENETOX PROGRAM 1988, Positive: CHO gene mutation; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; On EPA IRIS database; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NIOSH Analytical Method, 1994: Polynuclear aromatic hydrocarbons by HPLC, 5506, by GC, 5515; NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen; OSHA ANALYTICAL METHOD #ID-58 Record 591 of 1119 in RTECS (through 2003/06) AN: DK9100000 PN: 2H-1,2,4-Benzothiadiazine-7-sulfonamide,-6-chloro-3,4-dihydro-,-1,1-dioxide- SY: 3,4-Dihydro-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide-; 3,4-Dihydrochlorothiazide-; 6-Chloro-3,4-dihydro-2H-1,2,4-benzothia-diazine-7-sulfonamide-1,1-dioxide-; 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide-1,1-dioxide-; 6-Chloro-3,4-dihydro-7-sulfamoyl-2H-1,2,4-benzothiadiazine-1,1-dioxide-; 6-Chloro-7-sulfamoyl-3,4-dihydro-2H-1,2,4-benzothiadiazine-1,1-dioxide-; Aquarills-; Aquarius-; Bremil-; Chlorosulthiadil-; Chlorsulfonamidodihydrobenzothiadiazine-dioxide-; Chlorzide-; Cidrex-; Dichlorosal-; Dichlotiazid-; Dichlotride-; Diclotride-; Dihydrochlorothiazid-; Dihydrochlorothiazide-; Dihydroxychlorothiazidum-; Direma-; Disalunil-; Drenol-; Dyazide-; Esidrex-; Esidrix-; Fluvin-; HCTZ-; HCZ-; Hidril-; Hidrochlortiazid-; Hidroronol-; Hidrotiazida-; Hydril-; Hydro-aquil-; Hydro-diuril-; Hydrochlorothiazid-; Hydrochlorothiazide-; Hydrochlorthiazide-; Hydrodiuretic-; Hydrosaluric-; Hydrothide-; Hypothiazid-; Hypothiazide-; Idrotiazide-; Ivaugan-; Jen-Diril-; Maschitt-; Megadiuril-; NCI-C55925-; Nefrix-; Neo-codema-; Neoflumen-; Oretic-; Panurin-; Ro-Hydrazide-; SU-5879-; Thiaretic-; Thiuretic-; Urodiazin-; Vetidrex- RN: Current: 58-93-5 BRN: 625101 UD: 200210 MF: C7-H8-Cl-N3-O4-S2 MW: 297.75 WL: T66 BSWM EM DHJ HG ISZW CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: dna-esc 5 mg/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 89, p. 95, 1981 (MUREAV); sln-asn 1 gm/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 26, p. 159, 1974 (MUREAV); msc-mus-lym 500 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-357, 1989 (NTPTR*); cyt-ham-lng 500 mg/L/48H Gann Monograph on Cancer Research. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) No. 11- 1971- v. 27, p. 95, 1981 (GMCRDC); sce-ham-ovr 43 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG) RE: T19 orl-rat TDLo: 10 gm/kg (6-15D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB85-103588 (NTIS**) TE: V03-L60 orl-mus TDLo: 309 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-357, 1989 (NTPTR*); V03-L60 orl-mus TDLo: 432600 mg/kg/103W-C National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-110156/AS (NTIS**) ORNG: 2750000000 ng/kg. [2750.000000 mg/kg] T/E unlistd AT: F17-P28-U10 orl-wmn TDLo: 34884 ug/kg/30D-I Tokyo Joshi Ika Daigaku Zasshi. Journal of Tokyo Women's Medical College. (Society of Tokyo Women's Medical College, c/o Tokyo Joshi Ika Daigaku Toshokan, 10, Kawada-cho, Shinjuku-ku, Tokyo 162, Japan.) V.1- 1931- v. 53, p. 1226, 1983 (TJIZAF); F17-F18-K30 orl-man TDLo: 75 mg/kg/30W-I Rinsho Shinkeigaku. Clinical Neurology. (Societas Neurologica Japonica, Ichi-Maru Bldg. 31-21 Yushima 2-Chome, Bunkyo-ku 113 Tokyo, Japan) V.1- 1960- v. 17, p. 162, 1977 (RISHDJ); J15-J30 orl-wmn TDLo: 500 ug/kg Lancet. (7 Adam St., London WC2N 6AD, UK) V.1- 1823- v. 348, p. 1035, 1996 (LANCAO); U25 orl-wmn TDLo: 500 ug/kg Israel Journal of Medical Sciences. (POB 1435, Jerusalem 91013, Israel) V.1- 1965- v. 28, p. 880, 1992 (IJMDAI); F24-U30 orl-wmn LDLo: 2500 ug/kg/5D-I American Journal of Medicine. (Technical Pub., 875 Third Ave., New York, NY 10022) V.1- 1946- v. 70, p. 1163, 1981 (AJMEAZ); F12-K13-U30 orl-man TDLo: 12857 ug/kg/9D-I American Journal of Medicine. (Technical Pub., 875 Third Ave., New York, NY 10022) V.1- 1946- v. 70, p. 1163, 1981 (AJMEAZ); H02-J15-J24 orl-wmn TDLo: 500 ug/kg Annals of Emergency Medicine. (American College of Emergency Physicians, 1125 Executive Circle, Irving, TX 75038) v. 16, p. 901, 1987 (AEMED3); U05-U06 orl-wmn TDLo: 2 mg/kg/12H-I Southern Medical Journal. (Southern Medical Assoc., POB 2446, Birmingham, AL 35205) V.1- 1908- v. 76, p. 1363, 1983 (SMJOAV); J15-K13 orl-wmn TDLo: 500 ug/kg Drug Intelligence and Clinical Pharmacy. (POB 42435, Cincinnati, OH 45242) V.3- 1969- v. 18, p. 238, 1984 (DICPBB); G07-H08-J15 orl-wmn TDLo: 250 ug/kg Annals of Pharmacotherpy. (Harvey Whitney Books Co., POB 42696, Cincinnati, OH 45242) V. 26- 1992- v. 29, p. 701, 1995 (APHRER); T/E unlistd orl-rat LD50: 2750 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 1, p. 333, 1959 (TXAPA9); T/E unlistd ipr-rat LD50: 234 mg/kg "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973 -,124,1973 (27ZIAQ); T/E unlistd scu-rat LD50: 1270 mg/kg "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973 -,124,1973 (27ZIAQ); T/E unlistd ivn-rat LD50: 990 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 140, p. 249, 1963 (JPETAB); T/E unlistd orl-mus LD50: 1175 mg/kg Farmatsevtichnii Zhurnal (Kiev). (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.3- 1930- v. (1), p. 44, 1983 (FRZKAP); T/E unlistd ipr-mus LD50: 578 mg/kg "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973 -,77,1965 (27ZIAQ); T/E unlistd scu-mus LD50: 1470 mg/kg "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973 -,124,1973 (27ZIAQ); C06-F12-J30 ivn-mus LD50: 590 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 134, p. 273, 1961 (JPETAB); T/E unlistd unr-mus LD50: 1100 mg/kg Farmatsevtichnii Zhurnal (Kiev). (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.3- 1930- v. (5), p. 26, 1983 (FRZKAP); T/E unlistd ivn-dog LD50: 250 mg/kg "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973 -,124,1973 (27ZIAQ); T/E unlistd ivn-rbt LD50: 461 mg/kg "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973 -,124,1973 (27ZIAQ) MD: A04-L30-M03 orl-rat TDLo: 18540 mg/kg/60D-I Metal-Based Drugs. (Freund Publishing House, Suite 500, Chesham House, 150 Regent St., London W1R 5FA, UK) V.1- 1994- v. 6, p. 87, 1999 (MBADEI); P30-Y15-Z71 orl-rat TDLo: 499 gm/kg/26W-I Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- v. 11, p. 294, 1980 (IYKEDH); M14-P72-Z01 orl-rat TDLo: 30 gm/kg/30D-C Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 13, p. 665, 1963 (ARZNAD); L70-M30-U01 orl-rat TDLo: 4550 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-357, 1989 (NTPTR*); M03-Z01 orl-mus TDLo: 273 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-357, 1989 (NTPTR*) TR: IARC Cancer Review: Human Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 293, 1990 (IMEMDT); IARC Cancer Review: Animal Inadequate Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 293, 1990 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 50, p. 293, 1990 (IMEMDT) SL: EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), equivocal evidence: mouse; NCI Carcinogenesis Studies (feed), no evidence: rat Record 592 of 1119 in RTECS (through 2003/06) AN: DL6475000 PN: 2-Benzothiazolethiol- SY: 2(3H)-Benzothiazolethione; 2-Benzothiazolyl-mercaptan-; 2-Mercaptobenzothiazole-; 2-Merkaptobenzotiazol- (Polish); 2-Merkaptobenzthiazol- (Czech); Benzothiazole-2-thione-; Captax-; Dermacid-; Kaptax- (Czech); MBT-; Mercaptobenzothiazole-; Mertax-; NCI-C56519-; Pennac-MBT-powder-; Rokon-; Rotax-; Sulfadene-; Thiotax-; USAF-GY-3-; USAF-XR-29-; Vulkacit-mercapto- RN: Current: 149-30-4 UD: 200210 MF: C7-H5-N-S2 MW: 167.25 WL: T56 BN DSJ CSH CC: Agricultural-Chemical-and-Pesticide (A); Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T) ME: sce-ham-ovr 351 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); mtr-mus-fbr 0.001 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) RE: T25-T34-T35 par-rat TDLo: 800 mg/kg (2D male/2D pre) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 93, p. 107, 1982 (BEXBAN); T34-T35 par-rat TDLo: 400 mg/kg (4-11D preg) Bulletin of Experimental Biology and Medicine (English Translation). Translation of BEBMAE. (Plenum Pub. Corp., 233 Spring St., New York, NY 10013) V.41- 1956- v. 93, p. 107, 1982 (BEXBAN); T34-T42-T50 scu-mus TDLo: 4176 mg/kg (6-14D preg) National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-160 (NTIS**) TE: V01-P61-K60 orl-rat TDLo: 195 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); V03-L60-P60 orl-mus TDLo: 35 gm/kg/78W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-159 (NTIS**); V01-P60 scu-mus TDLo: 215 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB223-159 (NTIS**); V03-L60 orl-mus TD :195 gm/kg/2Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); V01-P61 orl-rat TDLo: 193125 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-245154/AS (NTIS**); V02-K60 orl-rat TDLo: 193125 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-245154/AS (NTIS**); V02-A60-N61 orl-rat TDLo: 193125 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-245154/AS (NTIS**); V03-L60 orl-mus TDLo: 193125 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-245154/AS (NTIS**); V03-N61-T69 orl-rat TDLo: 386250 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB88-245154/AS (NTIS**) ORNG: 100000000 ng/kg. [100.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 100 mg/kg International Polymer Science and Technology. (Rapra Technology Ltd., Shawbury, Shrewsbury, Shropshire SY4 4NR, UK) v. 3, p. 93, 1976 (IPSTB3); T/E unlistd ihl-rat LC50: >1270 mg/m3 United States Environmental Protection Agency, Office of Pesticides and Toxic Substances. (U.S. Environmental Protection Agency, 401 M St., SW, Washington, DC 20460) History unknown. 8EHQ-1190-0987S (EPASR*); T/E unlistd ipr-rat LD50: 300 mg/kg Medycyna Pracy. Industrial Medicine. (Ars-Polona, POB 1001, 00-068 Warsaw 1, Poland) V.1- 1950- v. 16, p. 35, 1965 (MEPAAX); F07-F12 orl-mus LD50: 1158 mg/kg Science Reports of the Research Institutes, Tohoku University, Series C: Medicine. (Tohoku University, Research Institute for Tuberculosis and Cancer, 4-1 Seiryo-machi, Sendai, Japan) V.1- 1949- v. 36(1-4), p. 10, 1989 (SRTCAC); T/E unlistd ipr-mus LD50: 100 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. AD277-689 (NTIS**); F15-F17 skn-rbt LD50: >7940 mg/kg Acute Toxicity Data. Journal of the American College of Toxicology, Part B. (Mary Ann Liebert, Inc., 1651 Third Ave., New York, NY 10128) V.1- 1990- v. 1, p. 62, 1990 (ATDAEI); T/E unlistd orl-qal LD50: >2150 mg/kg National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. OTS0535428 (NTIS**) MD: L70 orl-rat TDLo: 12220 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); Z01 orl-mus TDLo: 18 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); L70-Z01 orl-mus TDLo: 97500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); M30-U01 orl-mus TDLo: 174 gm/kg/86W-C Eisei Shikenjo Hokoku. Bulletin of the Institute of Hygienic Sciences. (Kokuritsu Eisei Shikenjo Kagaku, 18-1 Bushitsu Johobu, Setagaya-ku, Tokyo 158, Japan) V.1- 1886- v. (107), p. 44, 1989 (ESKHA5); L02-L14 ipr-mus TDLo: 770 mg/kg/7D-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 14, p. 221, 1969 (TXAPA9) TR: TOXICOLOGY REVIEW JOM, Journal of Occupational Medicine. (American Occupational Medicine Assoc., 150 N. Wacker Dr., Chicago, IL 60606) V.10- 1968- v. 15, p. 808, 1973 (JJOMDZ) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC) ND: NOHS 1974: HZD 84030; NIS 45; TNF 2428; NOS 40; TNE 42637; NOES 1983: HZD 84030; NIS 74; TNF 4825; NOS 62; TNE 86509; TFE 16409 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Studies (gavage), some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-332, 1988 (NTPTR*); NCI Carcinogenesis Studies (gavage), equivocal evidence: mouse, rat Record 593 of 1119 in RTECS (through 2003/06) AN: DM2550000 PN: 1H-2-Benzoxacyclotetradecin-1-one, 3,4,5,6,7,8,9,10-octahydro-14,16-dihydroxy-3-methyl-7-oxo-, (E)- SY: Benzoxacyclotetradec-11-en-1-one,-14,16-dihydroxy-3-methyl-7-oxo-,-trans-; NCI-C50226-; Toxin-F2-; FES-; F-2-toxin-; Fusarium-toxin-; 6-(10-Hydroxy-6-oxo-trans-1-undecenyl)-beta-resorcylic acid-N-lactone; Mycotoxin-F2-; Resorcylic acid, 6-(10-hydroxy-6-oxo-1-undecenyl)-, mu-lactone, trans-; Zearalenone-; (-)-Zearalenone; (S)-Zearalenone; (10S)-Zearalenone; trans-Zearalenone-; Zenone- RN: Current: 17924-92-4 Previous: 18695-28-8 BRN: 1350216 UD: 200305 MF: C18-H22-O5 MW: 318.40 WL: T6-14- GVO MV QU&TJ CQ EQ I -T CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Natural-Product (N); Primary-Irritant (S) ID: skn-gpg 50 mg/24H SEV Journal of the Association of Official Analytical Chemists. (Assoc. of Official Analytical Chemists, 1111 N. 19th St., Suite 210, Arlington, VA 22209) V.49- 1966- v. 57, p. 1121, 1974 (JANCA2) ME: dnr-bcs 2500 mg/L IRCS Medical Science: Library Compendium. (Lancaster, UK) V.3-11, 1975-83. For publisher information, see IMSCE2. v. 7, p. 204, 1979 (IRLCDZ); dni-hmn-hla 70 umol/L Carcinogenesis (London). (Oxford Univ. Press, Pinkhill House, Southfield Road, Eynsham, Oxford OX8 1JJ, UK) V.1- 1980- v. 13, p. 2389, 1992 (CRNGDP); cyt-ham-ovr 15 mg/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); sce-ham-ovr 12500 ug/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 10(Suppl 10), p. 1, 1987 (EMMUEG); mtr-mus-fbr 0.01 mg/L/21D (-S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 37, p. 231, 2001 (EMMUEG) RE: T46 orl-rat TDLo: 10 mg/kg (6-15D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 15, p. 678, 1976 (BECTA6); T34-T19-U01 orl-rat TDLo: 100 mg/kg (6-15D preg) Bulletin of Environmental Contamination and Toxicology. (Springer-Verlag New York, Inc., Service Center, 44 Hartz Way, Secaucus, NJ 07094) V.1- 1966- v. 15, p. 678, 1976 (BECTA6); T24-T25-T29 orl-rat TDLo: 770 mg/kg (4W male/4W pre-3W preg) JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 2, p. 201, 1982 (JJATDK); T42-T43-T46 orl-rat TDLo: 77 mg/kg (4W male/4W pre-3W preg) JAT, Journal of Applied Toxicology. (John Wiley and Sons Ltd., Baffins Lane, Chichester, W. Sussex PO19 1UD, UK) V.1- 1981- v. 2, p. 201, 1982 (JJATDK); T12-T13-T14 scu-rat TDLo: 5 mg/kg (1D pre) Archives of Toxicology. (Springer-Verlag, Heidelberger Pl. 3, D-1000 Berlin 33, Fed. Rep. Ger.) V.32- 1974- v. 50, p. 279, 1982 (ARTODN); T35 orl-mus TDLo: 20 mg/kg (9D preg) Acta Veterinaria Scandinavica. (Danske Dyrlargeforening, Alhambravej 15, DK-1826 Copenhagen V, Denmark) V.1- 1959- v. 22, p. 524, 1981 (AVSCA7); T13-T22 ipr-mus TDLo: 7143 ug/kg (1D pre) Maikotokishin (Tokyo). Mycotoxin. (Maikotokishin Kenkyukai, c/o Tokyo Rika Daigaku Yakugakubu, 12 Funagawara-machi, Ichigaya, Shinjuku-ku, Tokyo 162, Japan) No.1- 1975- v. (18), p. 45, 1983 (MAIKD3); T91 par-mus TDLo: 480 ug/kg (15-20D preg) Oncology Reports. (Oncology Reports, POB 18179, Athens, 116 10, Greece) V.1- 1994- v. 5, p. 609, 1998 (OCRPEW); T81 orl-pig TDLo: 123 mg/kg (6D pre/1-16W preg) American Journal of Veterinary Research. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.1- 1940- v. 40, p. 1260, 1979 (AJVRAH); T22 orl-pig TDLo: 492 mg/kg (17W pre) American Journal of Veterinary Research. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.1- 1940- v. 40, p. 1260, 1979 (AJVRAH); T14-T21 orl-pig TDLo: 162 mg/kg (45D pre) Comptes Rendus des Seances de l'Academie des Sciences, Serie D: Sciences Naturelles. (Paris, France) V.262-291, 1966-80. For publisher information, see CRASEV. v. 288, p. 779, 1979 (CHDDAT); T31-T34-T48 orl-pig TDLo: 4700 ug/kg (1-80D preg) Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 55, p. 1, 1982 (JANSAG); T13-T14-T29 orl-pig TDLo: 3 mg/kg (50D pre) Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 55, p. 1, 1982 (JANSAG); T19-T22 orl-gpg TDLo: 90 mg/kg (1-3D preg) American Journal of Veterinary Research. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.1- 1940- v. 50, p. 1220, 1989 (AJVRAH); T12-T13-T14 orl-dom TDLo: 2 mg/kg (10D pre) Journal of Reproduction and Fertility. (Biochemical Soc. Book Depot, POB 32, Commerce Way, Colchester, Essex CO2 8HP, UK) V.1- 1960- v. 89, p. 99, 1990 (JRPFA4); T46 orl-rat TDLo: 22 mg/kg (1-22D preg) "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 353, 1998 (VCVPS*) TE: V02-L60-N60 orl-mus TDLo: 8652 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-235, 1982 (NTPTR*); V03-L60-N60 orl-mus TD :4326 mg/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-235, 1982 (NTPTR*); V01-A60 orl-mus TDLo: 8652 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-165753 (NTIS**); V01-A60-L60 orl-mus TDLo: 8652 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB83-165753 (NTIS**) AT: T/E unlistd orl-rat LD50: >16 gm/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 37, p. 144, 1976 (TXAPA9); T/E unlistd orl-mus LD :>2 gm/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-235, 1982 (NTPTR*); T/E unlistd ipr-mus LD50: 5 mg/kg Veterinary and Human Toxicology. (American College of Veterinary and Comparative Toxicology, Publication Office, Comparative Toxicology, Manhattan, KS 66506) V.19- 1977- v. 25, p. 335, 1983 (VHTODE); T/E unlistd orl-dom LD50: >5 mg/kg Veterinary and Human Toxicology. (American College of Veterinary and Comparative Toxicology, Publication Office, Comparative Toxicology, Manhattan, KS 66506) V.19- 1977- v. 25, p. 335, 1983 (VHTODE); T13-Z74 ipr-rat TDLo: 4 mg/kg Cancer Research. (Public Ledger Building, Suit 816, 6th and Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- v. 38, p. 3611, 1978 (CNREA8); T13 scu-rat TDLo: 100 ug/kg Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 105, p. 33, 1979 (ENDOAO); N17-Z74 scu-rat TDLo: 20 mg/kg Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 105, p. 33, 1979 (ENDOAO); T/E unlistd ipr-gpg LD50: 500 mg/kg "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 352, 1998 (VCVPS*); T/E unlistd ipr-rat LD50: 5.5 gm/kg "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 352, 1998 (VCVPS*); P30-U07-U08 orl-ckn TDLo: 15 gm/kg "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 352, 1998 (VCVPS*) MD: F15-L70-Z74 orl-rat TDLo: 175 mg/kg/14D-I Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 55, p. 110, 1982 (JANSAG); Q02 orl-rat TDLo: 455 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-235, 1982 (NTPTR*); P28-U01 orl-rat TDLo: 700 mg/kg/5W-I American Journal of Veterinary Research. (American Veterinary Medical Assoc., 930 N. Meacham Rd., Schaumburg, IL 60196) V.1- 1940- v. 56, p. 954, 1995 (AJVRAH); P71 orl-mus TDLo: 113 mg/kg/8W-C Food and Chemical Toxicology. (Pergamon Press Inc., Maxwell House, Fairview Park, Elmsford, NY 10523) V.20- 1982- v. 24, p. 213, 1986 (FCTOD7); P26-Q02 orl-mus TDLo: 10920 mg/kg/13W-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-235, 1982 (NTPTR*); N73-N74-S05 ipr-mus TDLo: 37500 ug/kg/15D-I Proceedings of the Society for Experimental Biology and Medicine. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1903/04- v. 160, p. 302, 1979 (PSEBAA); Z74 orl-pig TDLo: 11200 ug/kg/28D-I Journal of Animal Science. (American Soc. of Animal Science, 309 W. Clark St., Champaign, IL 61820) V.1- 1942- v. 55, p. 110, 1982 (JANSAG); Y03 orl-rbt TDLo: 140 ug/kg/14D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 121, p. 145, 2001 (TOLED5); Y20 orl-rbt TDLo: 14000 ug/kg/14D-I Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 121, p. 145, 2001 (TOLED5); T13 scu-rat TDLo: 60 mg/kg/3D-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC); T13-F17 scu-rat TDLo: 600 mg/kg/3D-I Toxicology. (Elsevier Scientific Pub. Ireland, Ltd., POB 85, Limerick, Ireland) V.1- 1973- v. 170, p. 21, 2002 (TXCYAC); Z74 scu-rat TDLo: 1.8 mg/kg/3D-I Endocrinology (Baltimore). (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21203) V.1- 1917- v. 105, p. 33, 1979 (ENDOAO); Z74 unr-rat TDLo: 0.42 mg/kg/7D-I "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 352, 1998 (VCVPS*); Z72 orl-rat TDLo: 9.1 mg/kg/7D-I "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 353, 1998 (VCVPS*); N17 orl-ctl TDLo: 1125 mg/kg/6W-C "Vrednie chemichescie veshestva. Prirodnie organicheskie soedinenia" (Hazardous substances. Nature products.) Volkova N.V. et al., Sankt-Peterburg, 1998. v. -, p. 353, 1998 (VCVPS*) TR: IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 31, p. 279, 1983 (IMEMDT); IARC Cancer Review: Animal Limited Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 56, p. 397, 1993 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 31, p. 279, 1983 (IMEMDT); IARC Cancer Review: Group 3 IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL); TOXICOLOGY REVIEW Toxicology Letters. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1977- v. 127, p. 19, 2002 (TOLED5) SL: EPA GENETOX PROGRAM 1988, Positive: B subtilis rec assay; EPA GENETOX PROGRAM 1988, Negative: S cerevisiae-homozygosis; EPA GENETOX PROGRAM 1988, Inconclusive: Histidine reversion-Ames test; EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), clear evidence: mouse; NCI Carcinogenesis Studies (feed), no evidence: rat Record 594 of 1119 in RTECS (through 2003/06) AN: DN3150000 PN: Benzyl-alcohol- SY: Benzenemethanol-; Benzal-alcohol-; Benzenecarbinol-; Benzoyl-alcohol-; Methanol,-phenyl-; NCI-C06111-; alpha-Toluenol-; Hydroxytoluene-; alpha-Hydroxytoluene-; Phenolcarbinol-; Phenylcarbinol-; Phenylmethanol-; Phenylmethyl-alcohol- RN: Current: 100-51-6 BRN: 878307 BHR: 4-06-00-02222 UD: 200302 MF: C7-H8-O MW: 108.15 WL: Q1R CC: Tumorigen (C); Mutagen (M); Natural-Product (N); Human-Data (P); Primary-Irritant (S); Reproductive-Effector (T) ID: skn-man 16 mg/48H MLD Cosmetics and Toiletries. (Allured Pub. Corp., POB 318, Wheaton, IL 60189) V.91- 1976- v. 94(8), p. 41, 1979 (CTOIDG); skn-rbt 100 mg/24H MOD Cosmetics and Toiletries. (Allured Pub. Corp., POB 318, Wheaton, IL 60189) V.91- 1976- v. 94(8), p. 41, 1979 (CTOIDG); skn-pig 100% MOD Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 11, p. 1011, 1973 (FCTXAV) ME: dnr-bcs 21 mg/disc Osaka-shi Igakkai Zasshi. Journal of Osaka City Medical Association. (Osaka-shi Igakkai, c/o Osaka-shiritsu Daigaku Igakubu, 1-4-54 Asahi-cho, Abeno-ku, Osaka, 545, Japan) V.24- 1975- v. 34, p. 267, 1985 (OIGZDE); dnd-rat-lvr 10 mmol/L Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 24, p. 181, 1994 (EMMUEG); mmo-mus-lym 250 mg/L (+S9) National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-343, 1989 (NTPTR*); cyt-ham-ovr 4 ug/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-343, 1989 (NTPTR*) RE: T81 orl-mus TDLo: 6 gm/kg (6-13D preg) Teratogenesis, Carcinogenesis, and Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1980- v. 7, p. 29, 1987 (TCMUD8) ORNG: 1230000000 ng/kg. [1230.000000 mg/kg] F07-F13-F24 SRNG: 2000000000 ng/kg. [2000.000000 mg/kg] T/E unlistd AT: F07-F13-F24 orl-rat LD50: 1230 mg/kg Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 2, p. 327, 1964 (FCTXAV); T/E unlistd ihl-rat LCLo: 1000 ppm/8H AMA Archives of Industrial Hygiene and Occupational Medicine. (Chicago, IL) V.2-10, 1950-54. For publisher information, see AEHLAU. v. 4, p. 119, 1951 (AMIHBC); T/E unlistd ipr-rat LD50: 400 mg/kg Raw Material Data Handbook, Vol.1: Organic Solvents, 1974. (National Assoc. of Printing Ink Research Institute, Francis McDonald Sinclair Memorial Laboratory, Lehigh Univ., Bethlehem, PA 18015) v. 1, p. 6, 1974 (NPIRI*); D15-F24-M30 scu-rat LDLo: 1700 mg/kg Revue Medicale de la Suisse Romande. (Societe Medicale de La Suisse Romande, 2 rue Bellefontaine, 1003 Lausanne, Switzerland) V.1- 1881- v. 15, p. 561, 1895 (RMSRA6); J22 ivn-rat LD50: 53 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 60, 1971 (TXAPA9); J16-J22 iat-rat LD50: 441 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 60, 1971 (TXAPA9); T/E unlistd orl-mus LD50: 1360 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 81, 1985 (GISAAA); F05-F07-J22 ipr-mus LD50: 650 mg/kg Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- v. 75, p. 702, 1986 (JPMSAE); T/E unlistd ivn-mus LD50: 324 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 135, p. 330, 1962 (AIPTAK); F19-J22-K12 ivn-dog LDLo: 50 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 18, p. 60, 1971 (TXAPA9); F11-J30 par-dog LDLo: 9 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 25, p. 153, 1973 (TXAPA9); F11-F18-K01 skn-cat LDLo: 10 gm/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 84, p. 358, 1945 (JPETAB); T/E unlistd ivn-cat LDLo: 625 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 16, p. 1, 1920 (JPETAB); F07 orl-rbt LD50: 1040 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 84, p. 358, 1945 (JPETAB); T/E unlistd orl-gpg LD50: 2500 mg/kg Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 81, 1985 (GISAAA); T/E unlistd orl-bwd LD50: 100 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 21, p. 315, 1972 (TXAPA9); F07-F19-J25 ihl-mus LC50: >500 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F07-F19-J25 ihl-rat LC50: >500 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F07-F19-J25 orl-mus LD50: 1360 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F07-F19-J25 orl-rat LD50: 1660 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F07-F19-J25 orl-gpg LD50: 2500 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F07-F19-J25 orl-rbt LD50: 1040 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F07-F19-J25 ipr-rat LDLo: 650 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); A30-F40 ihl-rat TCLo: 46 mg/m3 "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); F19 ipr-rat TDLo: 514 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); T/E unlistd skn-rat LD50: 100 pph/90M "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*); T/E unlistd skn-rbt LD50: 2000 mg/kg "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1984 (VCVGK*) MD: U01-Z01 orl-rat TDLo: 2100 mg/kg/21D-I Gigiena i Sanitariya. For English translation, see HYSAAV. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1- 1936- v. 50(7), p. 81, 1985 (GISAAA); A30-Z01 orl-rat TDLo: 13 gm/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-343, 1989 (NTPTR*); L30-Y10 orl-rat TDLo: 24 mL/kg/12D-I Comparative Biochemistry and Physiology, C: Pharmacology, Toxicology and Endocrinology. (Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.74- 1983- v. 99, p. 445, 1991 (CBPCEE); Z01 orl-mus TDLo: 12 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-343, 1989 (NTPTR*); F07-F27-K13 ihl-hmn TCLo: 10 pph/45D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1994 (VCVGK*); G30-L30-M30 ihl-mam TCLo: 42 mg/m3/122D-I "Vrednie chemichescie veshestva, galogen I kislorod sodergashie organicheskie soedinenia". (Hazardous substances. Galogen and oxygen containing substances), Bandman A.L. et al., Chimia, 1994. v. -, p. 132, 1994 (VCVGK*) SR: EPA FIFRA 1988 PESTICIDE SUBJECT TO REGISTRATION OR RE-REGISTRATION Federal Register. (U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) V.1- 1936- v. 54, p. 7740, 1989 (FEREAC); OEL-RUSSIA: STEL 5 mg/m3, Skin, JAN 1993 ND: NOHS 1974: HZD 11360; NIS 85; TNF 7284; NOS 68; TNE 138757; NOES 1983: HZD 11360; NIS 128; TNF 19005; NOS 127; TNE 404916; TFE 236470 SL: EPA GENETOX PROGRAM 1988, Negative: E coli polA without S9; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Studies (gavage), no evidence: mouse, rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-343, 1989 (NTPTR*); NCI Carcinogenesis Studies (gavage), no evidence: mouse, rat Record 595 of 1119 in RTECS (through 2003/06) AN: DO3150000 PN: Benzyl alcohol, 3,4-dihydroxy-alpha-((methylamino)methyl)-, hydrochloride, (-)- SY: Adrenalin-chloride-; Adrenaline-chloride-; l-Adrenaline-chloride-; Adrenaline-hydrochloride-; Adrenaline hydrochloride, (-)-; (-)-Adrenaline hydrochloride; l-Adrenaline-hydrochloride-; Adrenalin-hydrochloride-; 1,2-Benzenediol, 4-(1-hydroxy-2-(methylamino)ethyl)-, hydrochloride, (R)- (9CI); l-Methylaminoethanolcathechol-hydrochloride-; NCI-C55663-; (-)-3,4-Dihydroxy-alpha-((methylamino)methyl)benzyl alcohol hydrochloride; l-1-(3,4-Dihydroxyphenyl)-2-methylamino-1-ethanol hydrochloride; Epinephrine-chloride-; l-Epinephrine-chloride-; Epinephrine,-hydrochloride-; (-)-Epinephrine hydrochloride; l-Epinephrine-hydrochloride-; Gelatin-epinephrine-; Supranephrin-solution-; Suprarenin-hydrochloride- RN: Current: 55-31-2 Previous: 66240-90-2 UD: 200305 MF: C9-H13-N-O3.Cl-H MW: 219.69 WL: QR BQ DYQ1M1 &GH -L CC: Tumorigen (C); Drug (D); Reproductive-Effector (T); Hormone (H) RE: T48 ipr-rat TDLo: 125 ug/kg (17D preg) British Journal of Pharmacology. (Macmillan Press Ltd., Houndmills, Basingstoke, Hants. RG21 2XS, UK) V.34- 1968- v. 43, p. 270, 1971 (BJPCBM); T34-T71 scu-rat TDLo: 3200 ug/kg (13-20D preg) Canadian Journal of Physiology and Pharmacology. (National Research Council of Canada, Publication Sales and Distribution, Ottawa ON K1A OR6, Canada) V.42- 1964- v. 43, p. 473, 1965 (CJPPA3); T34 ivn-rbt TDLo: 7950 ng/kg (22D preg) Anatomical Record. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.1- 1906/08- v. 153, p. 373, 1965 (ANREAK) ORNG: 24000000 ng/kg. [24.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 24 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 180, p. 155, 1969 (AIPTAK); T/E unlistd scu-rat LD50: 5 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 180, p. 155, 1969 (AIPTAK); F07-J26-K01 ivn-rat LDLo: 50 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 24, p. 101, 1925 (JPETAB); T/E unlistd idu-rat LD50: 35 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 180, p. 155, 1969 (AIPTAK); T/E unlistd orl-mus LDLo: 50 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 13, p. 51, 1963 (ARZNAD); H02 ipr-mus LD50: 4664 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 90, p. 110, 1947 (JPETAB); F12-F13 scu-mus LD50: 1980 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 87, p. 214, 1946 (JPETAB); F12-J22-J30 ivn-mus LD50: 140 ug/kg European Journal of Pharmacology. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1967- v. 9, p. 289, 1970 (EJPHAZ); T/E unlistd scu-gpg LDLo: 2 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 13, p. 51, 1963 (ARZNAD); T/E unlistd ivn-gpg LDLo: 200 ug/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 13, p. 51, 1963 (ARZNAD); G30-U08-Y03 ipr-rat TDLo: 0.025 mg/kg Farmakologiya i Toksikologiya (Moscow). For English translation, see PHTXA6 and RPTOAN. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.2- 1939- v. 44, p. 571, 1981 (FATOAO) MD: Z01 ihl-rat TCLo: 12500 ug/m3/6H/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-380, 1990 (NTPTR*); G70-N72-Z01 ihl-rat TCLo: 40 mg/m3/6H/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-380, 1990 (NTPTR*); L70 ihl-rat TCLo: 5 mg/m3/6H/1.3Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-380, 1990 (NTPTR*); Z01 ihl-mus TCLo: 50 mg/m3/6H/14D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-380, 1990 (NTPTR*); K30-L70-Z01 ihl-mus TCLo: 40 mg/m3/6H/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-380, 1990 (NTPTR*); M70 ihl-mus TCLo: 3 mg/m3/6H/1.3Y-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-380, 1990 (NTPTR*) ND: NOHS 1974: HZD M4602; NIS 1; TNF 37; NOS 1; TNE 372; NOES 1983: HZD M4602; NIS 1; TNF 284; NOS 12; TNE 7694; TFE 6481 SL: NCI Carcinogenesis Studies (inhal), inadequate study: mouse, rat Record 596 of 1119 in RTECS (through 2003/06) AN: DO7525000 PN: Benzyl alcohol, m-hydroxy-alpha-((methylamino)methyl)-, hydrochloride, (-)- SY: Adrianol-; Alcon-efrin-; Almefrin-; Benzenemethanol, 3-hydroxy-alpha-((methylamino)methyl)-, hydrochloride, (-)-; Histabid-; Isophrine-hydrochloride-; Isophrin-hydrochloride-; Lexatol-; meta-Sympatol-; meta-Synephrine-hydrochloride-; m-Methylaminoethanolphenol-hydrochloride-; NCI-C55641-; Neooxedrine-chloride-; Neophryn-; Neosympatol-; Neosynephrine-hydrochloride-; Neo-Synesin-1-; Pyracort-D-; Stanephrin-; Biomydrin-; Consdrin-; Consdrin-hydrochloride-; Efricel-; Emagrin-; Fenilfar-; Fenox-; (-)-alpha-Hydroxy-beta-(methylamino)ethyl-alpha-(3-hydroxybenzene) hydrochloride; (R)-3-Hydroxy-alpha-((methylamino)methyl)benzenemethanol hydrochloride; 1-m-Hydroxy-alpha-(methylaminomethyl)benzyl alcohol hydrochloride; l-1-(m-Hydroxyphenyl)-2-methyl-aminoethanol hydrochloride; Idrianol-; Metroxedrine-; Mydfrin-; Oftalfrine-; OP-Isophrin-; Phenistan-; Phenylephrine-hydrochloride-; D-(-)-Phenylephrine hydrochloride; Prefrin-; Pyristan-; Rhinall-; Sucraphen-; Synasal-; Synethenate-; URI- RN: Current: 61-76-7 Previous: 644-22-4 UD: 200305 MF: C9-H13-N-O2.Cl-H MW: 203.69 WL: QR CYQ1M1 &GH -L CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: dnd-rat-lvr 7 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 368, p. 59, 1996 (MUREAV); msc-mus-lym 1500 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-322, 1987 (NTPTR*); cyt-ham-ovr 10 mmol/L Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- v. 400, p. 169, 1998 (MUREAV); sce-ham-ovr 1500 mg/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-322, 1987 (NTPTR*) RE: T16-T34 scu-rbt TDLo: 15 mg/kg (22-31D preg) Surgery, Gynecology and Obstetrics. (Franklin H. Martin Memorial Foundation, 55 E. Erie St., Chicago, IL 60611) V.1- 1905- v. 129, p. 341, 1969 (SGOBA9) ORNG: 350000000 ng/kg. [350.000000 mg/kg] T/E unlistd AT: A04-F18 ocu-man TDLo: 120 mg/kg Southern Medical Journal. (Southern Medical Assoc., POB 2446, Birmingham, AL 35205) V.1- 1908- v. 86, p. 1064, 1993 (SMJOAV); T/E unlistd orl-rat LD50: 350 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 180, p. 155, 1969 (AIPTAK); T/E unlistd ipr-rat LD50: 17 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 86, p. 284, 1946 (JPETAB); T/E unlistd scu-rat LD50: 27 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 86, p. 284, 1946 (JPETAB); F07-F12-J22 ivn-rat LD50: 440 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 113, p. 341, 1955 (JPETAB); T/E unlistd orl-mus LD50: 120 mg/kg International Journal of Neuropharmacology. (New York, NY) V.1-8, 1962-69. For publisher information, see NEPHBW. v. 4, p. 219, 1965 (IJNEAQ); T/E unlistd ipr-mus LD50: 89 mg/kg Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 28, p. 227, 1974 (TXAPA9); T/E unlistd scu-mus LD50: 22 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 86, p. 284, 1946 (JPETAB); F12-J22-J30 ivn-mus LD50: 1120 ug/kg European Journal of Pharmacology. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1967- v. 9, p. 289, 1970 (EJPHAZ); T/E unlistd ipr-dog LDLo: 16 mg/kg International Journal of Neuropharmacology. (New York, NY) V.1-8, 1962-69. For publisher information, see NEPHBW. v. 4, p. 219, 1965 (IJNEAQ); T/E unlistd scu-rbt LD50: 22 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 86, p. 284, 1946 (JPETAB); T/E unlistd ivn-rbt LD50: 500 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 86, p. 284, 1946 (JPETAB); T/E unlistd ims-rbt LD50: 7200 ug/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 86, p. 284, 1946 (JPETAB); G10-H01 ivn-rat TDLo: 10 ug/kg European Journal of Pharmacology. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1967- v. 455, p. 59, 2002 (EJPHAZ) MD: D15-G70-N72 orl-rat TDLo: 84 gm/kg/12W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-322, 1987 (NTPTR*); G70-N72-Z01 orl-mus TDLo: 202 gm/kg/12W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-322, 1987 (NTPTR*) ND: NOHS 1974: HZD M0845; NIS 1; TNF 169; NOS 6; TNE 4376; NOES 1983: HZD M0845; NIS 1; TNF 360; NOS 6; TNE 14244; TFE 10911 SL: EPA TSCA Section 8(b) CHEMICAL INVENTORY; NCI Carcinogenesis Studies (feed), no evidence: mouse Record 597 of 1119 in RTECS (through 2003/06) AN: DO9275000 PN: Benzyl-alcohol,-alpha-methyl- SY: Benzenemethanol,-alpha-methyl-; Methanol,-methylphenyl-; alpha-Methylbenzenemethanol-; Methylphenylcarbinol-; NCI-C55685-; Phenylmethylcarbinol-; Ethanol,-1-phenyl-; 1-Fenylethanol- (Czech); Fenyl-methylkarbinol- (Czech); alpha-Phenethyl-alcohol-; 1-Phenethyl-alcohol-; 1-Phenylethanol-; Styrallyl-alcohol-; Styralyl-alcohol- RN: Current: 98-85-1 UD: 200302 MF: C8-H10-O MW: 122.18 WL: QY1&R CC: Tumorigen (C); Mutagen (M); Primary-Irritant (S) ID: skn-rbt 10 mg/24H open Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 26, p. 269, 1944 (JIHTAB); skn-rbt 500 mg/24H MOD Food and Cosmetics Toxicology. (London, UK) V.1-19, 1963-81. For publisher information, see FCTOD7. v. 12, p. 995, 1974 (FCTXAV); eye-rbt 2 mg SEV American Journal of Ophthalmology. (Ophthalmic Pub. Co., 435 N. Michigan Ave., Suite 1415, Chicago, IL 60611) Series 3: V.1- 1918- v. 29, p. 1363, 1946 (AJOPAA) ME: msc-mus-lym 250 mg/kg National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*); cyt-ham-ovr 1 gm/L National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*) TE: V02-M61 orl-rat TDLo: 386 gm/kg/2Y-C National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*); V01-M61 orl-rat TDLo: 386250 mg/kg/103W-I National Technical Information Service. (Springfield, VA 22161) Formerly U.S. Clearinghouse for Scientific and Technical Information. PB90-241092 (NTIS**) ORNG: 400000000 ng/kg. [400.000000 mg/kg] T/E unlistd AT: T/E unlistd orl-rat LD50: 400 mg/kg Journal of Industrial Hygiene and Toxicology. (Cambridge, MA) V.18-31, 1936-49. For publisher information, see AEHLAU. v. 26, p. 269, 1944 (JIHTAB); F07-J25 orl-mus LD50: 558 mg/kg Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. (V/O Mezhdunarodnaya Kniga, 113095 Moscow, USSR) V.1-36, 1957-1992. For publisher information, see MTPEEI v. 29(11), p. 51, 1985 (GTPZAB); T/E unlistd scu-mus LD50: 250 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 116, p. 154, 1958 (AIPTAK); T/E unlistd ivn-dog LDLo: 200 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 15, p. 129, 1920 (JPETAB); T/E unlistd skn-gpg LD50: >15 mL/kg "Toxicology of Drugs and Chemicals," Deichmann, W.B., New York, Academic Press, Inc., 1969 -,695,1969 (34ZIAG) MD: L70-Z01 orl-rat TDLo: 97500 mg/kg/13W-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*); Z01 orl-rat TDLo: 24 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*); Z01 orl-mus TDLo: 12 gm/kg/16D-I National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*) ND: NOES 1983: HZD X9925; NIS 17; TNF 653; NOS 15; TNE 15991; TFE 1959 SL: EPA GENETOX PROGRAM 1988, Inconclusive: E coli polA without S9; EPA TSCA Section 8(b) CHEMICAL INVENTORY; EPA TSCA Section 8(d) unpublished health/safety studies; EPA TSCA TEST SUBMISSION (TSCATS) DATA BASE, JANUARY 2001; NTP Carcinogenesis Studies (gavage), some evidence: rat National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*); NTP Carcinogenesis Studies (gavage), no evidence: mouse National Toxicology Program Technical Report Series. (Research Triangle Park, NC 27709) No.206- NTP-TR-369, 1990 (NTPTR*) Record 598 of 1119 in RTECS (through 2003/06) AN: DP3750000 PN: Benzylamine, N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)-, hydrochloride SY: Bensylyt-NEN-; Benzenemethanamine, N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)-, hydrochloride; 688A-; Benzyl(2-chloroethyl)(1-methyl-2-phenoxyethyl)amine hydrochloride; Blocadren-; NCI-C01661-; SKF-688A-; 2-(N-Benzyl-2-chloroethylamino)-1-phenoxypropane hydrochloride; N-Benzyl-N-phenoxyisopropyl-beta-chlorethylamine-hydrochloride-; N-(2-Chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzenemethanamine hydrochloride; N-(2-Chloroethyl)-N-(1-methyl-2-phenoxyethyl)benzylamine, hydrochloride; Dibenzyline-hydrochloride-; Dibenzyran-; Fenossibenzamina- (Italian); Fenoxybenzamin-; Phenoxybenzamide-hydrochloride-; Phenoxybenzamine-hydrochloride-; N-Phenoxyisopropyl-N-benzyl-beta-chloroethylamine-hydrochloride-; N-2-Phenoxyisopropyl-N-benzyl-chloroethylamine-hydrochloride- RN: Current: 63-92-3 UD: 200006 MF: C18-H22-Cl-N-O.Cl-H MW: 340.32 WL: G2N1R&Y1&1OR &GH CC: Tumorigen (C); Drug (D); Mutagen (M); Reproductive-Effector (T); Human-Data (P) ME: mmo-sat 3 ug/plate (+S9) Environmental and Molecular Mutagenesis. (Alan R. Liss, Inc., 41 E. 11th St., New York, NY 10003) V.10- 1987- v. 11(Suppl 12), p. 1, 1988 (EMMUEG) RE: T34 orl-rat TDLo: 12 mg/kg (5-12D preg) Research Communications in Chemical Pathology and Pharmacology. (PJD Pub. Ltd., P.O. Box 966, Westbury, NY 11590) V.1- 1970- v. 7, p. 701, 1974 (RCOCB8); T01-T02-T03 par-rat TDLo: 24500 ug/kg (35D male) Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 29, p. 189, 1984 (CCPTAY); T23 par-rat TDLo: 24500 ug/kg (35D male) Contraception. (Geron-X, Inc., POB 1108, Los Altos, CA 94022) V.1- 1970- v. 29, p. 189, 1984 (CCPTAY) TE: V01-K60 ipr-rat TDLo: 780 mg/kg/1Y-I National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-72, 1978 (NCITR*); V01-K60 ipr-mus TDLo: 3900 mg/kg/52W-I National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-72, 1978 (NCITR*); V01-K60 ipr-rat TD :1560 mg/kg/1Y-I National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-72, 1978 (NCITR*) AT: M03 orl-man TDLo: 7143 ug/kg/5D-I Annals of Internal Medicine. (American College of Physicians, 4200 Pine St., Philadelphia, PA 19104) V.1- 1927- v. 107, p. 119, 1987 (AIMEAS); T/E unlistd orl-rat LDLo: 800 mg/kg Journal of Pharmacology and Experimental Therapeutics. (Williams and Wilkins Co., 428 E. Preston St., Baltimore, MD 21202) V.1- 1909/10- v. 110, p. 463, 1954 (JPETAB); T/E unlistd orl-mus LD50: 900 mg/kg Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- v. 108, p. 102, 1956 (AIPTAK); T/E unlistd ipr-mus LD50: 99 mg/kg Gazzetta Chimica Italiana. (Societa Chimica Italiana, Rome, Italy) V.1- 1871- v. 92, p. 3, 1962 (GCITA9); T/E unlistd scu-mus LD50: 105 mg/kg Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- v. 17, p. 305, 1967 (ARZNAD); F12-J22-J30 ivn-mus LD50: 63750 ug/kg European Journal of Pharmacology. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1967- v. 9, p. 289, 1970 (EJPHAZ) TR: IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 24, p. 185, 1980 (IMEMDT); IARC Cancer Review: Human No Adequate Data IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) V.1- 1972- v. 24, p. 185, 1980 (IMEMDT); IARC Cancer Review: Group 2B IARC Monographs, Supplement. (WHO Publications Centre USA, 49 Sheridan Ave., Albany, NY 12210) No.1- 1979- v. 7, p. 56, 1987 (IMSUDL) ND: NOES 1983: HZD X5625; NIS 1; TNF 44; NOS 2; TNE 796; TFE 406 SL: EPA GENETOX PROGRAM 1988, Positive: Carcinogenicity-mouse/rat; NCI Carcinogenesis Bioassay (ipr), clear evidence: mouse, rat National Cancer Institute Carcinogenesis Technical Report Series. (Bethesda, MD) No.0-205. For publisher information, see NTPTR*. NCI-TR-72, 1978 (NCITR*); NTP 9th Report on Carcinogens, 2000: Reasonably anticipated to be human carcinogen Record 599 of 1119 in RTECS (through 2003/06) AN: DS1400000 PN: Beryl- SY: Beryl-ore-; Beryllium-aluminium-silicate-; Beryllium-aluminosilicate-; Beryllium-aluminum-silicate- RN: Current: 1302-52-9 UD: 200007 MF: Al.3/2 Be.3 H2-O3-Si MW: 537.53 WL: AL2 SI-O3*6 &-BE- 3 CC: Tumorigen (C); Natural-Product (N) TE: V02-J60 ihl-rat TCLo: 15 mg/m3/74W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 15, p. 10, 1969 (TXAPA9); V03-J60 ihl-rat TC :15 mg/m3/6H/73W-I Toxicology and Applied Pharmacology. (Academic Press, Inc., 1 E. First St., Duluth, MN 55802) V.1- 1959- v. 8, p. 361, 1966 (TXAPA9) TR: ACGIH TLV-Suspected human carcinogen "Documentation of the Threshold Limit Values and Biological Exposure Indices," 5th ed., Cincinnati, OH, American Conference of Governmental Industrial Hygienists, Inc., 1986 6,1/BEI,1997 (85INA8); ACGIH TLV-TWA 0.002 mg(Be)/m3 The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); ACGIH TLV-Suspected human carcinogen The Threshold Limit Values (TLVs) and Biological Exposure Indices (BEIs) booklet issues by American Conference of Governmental Industrial Hygienists (ACGIH), Cincinnati, OH, 1996 TLV/BEI, 1999 (DTLVS*); IARC Cancer Review: Animal Sufficient Evidence IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. 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(U.S. Government Printing Office, Supt. of Documents, Washington, DC 20402) 41, 50-204.50, 1994 (CFRGBR); OEL-ARAB Republic of Egypt: TWA 0.002 mg/m3, JAN 1993; OEL-AUSTRALIA: TWA 0.002 mg/m3, Carcinogen, JAN 1993; OEL-AUSTRIA: Carcinogen, JAN 1999; OEL-BELGIUM: TWA 0.002 mg/m3, Carcinogen JAN 1993; OEL-DENMARK: TWA 0.001 mg/m3, JAN 1999; OEL-FINLAND: TWA 0.002 mg/m3, STEL 0.006 mg/m3, Carcinogen, JAN 1999; OEL-FRANCE: VME 0.002 mg/m3, C2 Carcinogen, JAN 1999; OEL-GERMANY: Carcinogen, JAN 1999; OEL-HUNGARY: STEL 0.001 mg/m3, Carcinogen, JAN 1993; OEL-INDIA: TWA 0.002 mg/m3, Carcinogen, JAN 1993; OEL-JAPAN: OEL 0.002 mg/m3, 2A Carcinogen, JAN 1999; OEL-THE NETHERLANDS: MAC-TGG 0.002 mg/m3, Carcinogen, JAN 1999; OEL-NORWAY: TWA 0.001 mg/m3, JAN 1999; OEL-THE PHILIPPINES: TWA 0.002 mg/m3, JAN 1993; OEL-POLAND: MAC(TWA) 0.001 mg/m3, MAC(STEL) 0.003 mg/m3, JAN 1999; OEL-RUSSIA: STEL 0.001 mg/m3, Carcinogen, JAN 1993; OEL-SWEDEN: NGV 0.002 mg/m3, Carcinogen, JAN 1999; OEL-SWITZERLAND: MAK-W 0.002 mg/m3, Carcinogen, JAN 1999; OEL-THAILAND: TWA 0.002 mg/m3, STEL 0.005 mg/m3, JAN 1993; OEL-TURKEY: TWA 0.002 mg/m3, JAN 1993; OEL-UNITED KINGDOM: TWA 0.002 mg/m3, Carcinogen, SEP 2000; OEL IN ARGENTINA, BULGARIA, COLOMBIA, JORDAN, KOREA check ACGIH TLV,; OEL IN NEW ZEALAND, SINGAPORE, VIETNAM check ACGIH TLV ND: NIOSH REL TO BERYLLIUM-air: CA not to exceed 0.0005 mg(Be)/m3 National Institute for Occupational Safety and Health, U.S. Dept. of Health, Education, and Welfare, Reports and Memoranda. 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